PMID- 26506783 TI - [Determination of N-isopropylaniline in workplace air by high-performance liquid chromatography]. AB - OBJECTIVE: To establish the method of high-performance liquid chromatography (HPLC) for the determination of N-isopropylaniline in workplace air. METHODS: N isopropylaniline in the air was collected by silicone tube, and was then dissolved by acetonitrile and determined by HPLC-UV detector. RESULTS: There was a linear relationship within the range of 0.0-100.0 ug/ml with the method, and the regression equation was y=22 863x+10 665(r=0.999 9); the detection limit was 0.005 ug/ml, and the minimum detectable concentration was 1.7x10(-3) mg/m3 (3.0 L sampling volume); the average recoveries of standard addition were 96.2%-101.3%. The within-run precision was 2.31%-2.99%, and the between-run precision was 3.21% 4.55%. The average desorption efficiency was 97.6%, the breakthrough volume was more than 8.12 mg, the sampling efficiency waE 100%, and the samples could be stored for at least 7 days at room temperature. CONCLUSION: The indicators ol the method all meet the requirements of GBZ/T 210.4-2008 (Determination methods of air chemicals in workplace), and can be used for the determination of N isopropylaniline in workplace air. PMID- 26506784 TI - [Readspace solid-phase microextraction-gas chromatography for determination of 2,5-hexanedione in urine]. AB - OBJECTIVE: To establish a method for determination of 2,5-hexanedione in urine by headspace solid-phase microextraction-gas chromatography. METHODS: After extraction by solid-phase microextraction head, 2,5-hexanedione in urine was determined by gas chromatography and was quantified by external standard method. RESULTS: The concentration of 2,5-hexanedione in urine showed a linear relationship within the range of 0.1-20.0 ug/ml. The regression equation was y=261.36x-1.903 3, r=0.999 2. The minimum detectable concentration was 0.01 ug/ml. The recovery rate was 92.6%-97.1%, with a relative standard deviation (RSD) of 3.3%-5.8%. The intra-day and inter-day RSDs were 3.8%-6.2% and 4.7%-6.3% respectively. CONCLUSION: This determination method has no requirement for organic solvents, features simple and rapid operation, possesses higher detection sensitivity, and applies well to the determination of 2,5-hexanedione in urine. PMID- 26506785 TI - [Determination of lead in workplace air by portable X-ray fluorescence spectrometry]. AB - OBJECTIVE: To investigate the permance index ofof portable X-ray fluorescence spectrometer in the determination of lead on filter membrane and to provide data for the determination of lead in workplace air. METHODS: Irradiated with X-ray, the lead would emit specific X-ray fluorescence during the process from the excited state back to the ground state. Rapid determination of lead was completed using fluorescence energy and wave length for qualitative analysis and fluorescence intensity for quantitative measurement. Under set conditions, a series of customized calibration samples were measured to create a standard curve for quantitative analysis of lead on filter membrane. RESULTS: The regression equation obtained using a portable X-ray fluorescence spectrometer to determine the lead on filter membrane was y=0.004x-0.182 (r2= 0.9999). The linear range was 0.00 -10.40 mg/m3, the minimum detectable concentration was 0.53 ug/m3, and the minimum quantifiable concentration was 1.76ug/m3. The relative standard deviation (RSD) of within-run precision of samples with different concentrations was 0.48% 6.22%, the RSD of between-run precision was 2.51%-5.09%, and the degree of accuracy was in the calibration range of standard samples. CONCLUSION: Portable X ray fluorescence spectrometry is a simple, rapid, repeatable, and accurate method for the determination of lead on filter membrane. PMID- 26506786 TI - [Determination of mandelic acid and phenylglyoxylic acid in urine by reagent-free ion chromatography]. AB - OBJECTIVE: To develop a method for determination of mandelic acid (MA) and phenylglyoxylic acid (PGA) in urine by reagent-free ion chromatography. METHODS: Ion chromatography was performed on an AS19 column with a gradient elution solution containing 10-35 mmoL/L KOH at a flow rate of 1.00 ml/min, and MA and PGA were detected at ultraviolet wavelengths of 225 nm and 254 nm, respectively. The samples were diluted 10 times with purified water, then purified on a silver column to remove high concentrations of chloride ion, and injected after being filtered through a 0.2-um m filter membrane. RESULTS: The recoveries of standard addition of MA and PGA were 96.5% and 99.3%, respectively, with both relative standard deviations less than 5.0%. Good linear relationships were noted in the range of 1.0-100.0 mg/L for both MA and PGA (r >0.9995). The detection limits of MA and PGA were 0.02 mg/L and 0.05 mg/L, respectively; the minimum detectable concentrations of MA and PGA were 0.2 mg/L and 0.5 mg/L (when the sampling amount was 5.0 ml and diluted to 50.0 ml with water, and the injection volume was 300 uL). CONCLUSIONS: This method is fast, convenient, and highly sensitive and selective. It can be used for the analysis of MA and PGA in the urine of styrene exposed workers. PMID- 26506787 TI - [Determination of n-pentanol in workplace air by solvent desorption gas chromatography]. AB - OBJECTIVE: To develop a solvent desorption gas chromatographic method for determination of n-pentanol in the workplace air. METHODS: n-Pentanol in the workplace air was collected with activated carbon tubes, desorbed with 2% 2 propanol in carbon disulfide, separated with a nitroterephthalic acid-modified FFAP capillary column, and detected with flame ionization detector. RESULTS: The limit of detection was 0.2 mg/L; the lower limit of quantification was 0.6 mg/L; the linear range was 0.6-4072.0 mg/L. The minimum detectable mass concentration was 0.2 mg/m3 for 1.5 L of air sample. This method was highly repeatable. The relative standard deviations were 2.3%-5.4%. The average desorption efficiencies were 86.9%-94.2%. The absorption efficiencies were 100%. The breakthrough volume was above 8.0 mg in 100-mg activated carbon. The samples in activated carbon tubes could be stored for at least 14 days at room temperature. CONCLUSION: The method is feasible for determination of n-pentanol in the workplace air. PMID- 26506788 TI - [Determination of epichlorohydrin in workplace air by gas chromatograph-electron capture detector]. AB - OBJECTIVE: To develop a method for determining epichlorohydrin in the workplace air by gas chromatograph-electron capture detector (GC-ECD). METHODS: Epichlorohydrin in the workplace air was collected by activated charcoal tubes, desorbed using acetone, and analyzed by GC-ECD. RESULTS: A good linearity was obtained in the range of 1.0-50 ug/mL (r=0.999 7). The detection limit was 0.012 ug/ml, while the recovery rate was 88.1% and relative standard deviation ranged from 1.11% to 3.57%. The samples could be stored for seven days at room temperature. CONCLUSION: This method effectively eliminates the interferences of alkanes on determination of epichlorohydrin and improves the sensitivity by 1 to 2 orders of magnitude, which can solve the problem of detection limit above standard in GBZ/T 160.58-2004. PMID- 26506790 TI - [Thought about basic occupational health service]. PMID- 26506789 TI - [Relationship between dust mass concentration and fiber number concentration of refractory ceramic fibers]. AB - OBJECTIVE: To explore the quantitative relationship between the dust mass concentration and fiber number concentration of refractory ceramic fibres. METHODS: A typical refractory ceramic fiber plant was selected as the study site. Fifty-three paired samples of total dust mass concentration and fiber number concentration were collected using the long-time fixed site mode. The total dust mass concentration was measured according to the GBZ/T 192.1-2007 (Measurement of dust in the air of workplace, part 1: Total dust concentration). Membrane filter method/phase-contrast optical microscopy was used to determine the fiber number concentration. Univariate analysis was used to describe the distribution of the two concentrations and their ratio. Spearman rank correlation, as well as linear regression, logarithmic curve, polynomial, power function, and exponential curve model, were used to explore the relationship between the two concentrations. Results The range of the total dust mass concentration (x) was 0.45-13.82 mg/m3. The range of the fiber number concentration (y) was 0.01-1.04 f/ml. The range of the ratio (x/y) was 4-158. All of the three parameters did not follow normal distribution (P<0.000 1). The two concentrations showed a positive correlation (r,=0.705 22, P< 0.000 1). All the coefficients of determination (R2) of linear regression, logarithmic curve, polynomial, power function, and exponential curve model were relatively low. The trinomial curve model had the highest R2 (0.6848) and the fitted equation was y=-0.001, 1x+0.010 4x2+0.101 4x-0.055 1. CONCLUSION: There is a positive correlation between the total dust mass concentration and fiber number concentration of refractory ceramic fibers. However, there is no fixed regression relationship between the two concentrations, and neither is a definite coefficient which can be used to convert each other. The two concentrations cannot be replaced by each other. PMID- 26506791 TI - [Application of hemoperfusion in treatment of acute paraquat poisoning]. PMID- 26506792 TI - Abuse and oral health. PMID- 26506793 TI - Response to sugar letter. PMID- 26506794 TI - Reply to SASA. PMID- 26506795 TI - SADA Communique. PMID- 26506796 TI - Knowledge, attitudes and practices of oral health care workers in Lesotho regarding the management of patients with oral manifestations of HIV/AIDS. AB - Lesotho has the third highest prevalence of HIV in the world with an estimated 23% of the adult population infected. At least 70% of people living with HIV/AIDS (PLWHA) have presented with oral manifestation of HIV as the first sign of the disease. Oral health workers regularly encounter patients presenting with oral lesions associated with HIV disease and therefore need to have adequate knowledge of these conditions for diagnosis and management. The aim of the present study was to determine the knowledge, attitudes and practices of oral health care workers (OHCW) of Lesotho regarding the management of oral manifestations of HIV/AIDS. A descriptive cross-sectional survey was conducted on all 46 OHCW in 26 public and private care facilities in all ten districts of Lesotho. A self administered questionnaire was used to gather information. The response rate was 100%. Nearly all (94.7%) agreed that oral lesions are common in people living with HIV and/or AIDS. The majority (91.3%) named oral candidiasis (OC) as the most common lesion found in PLWHA while Kaposi's Sarcoma (KS) (34.7%) and Oral Hairy Leukoplakia (OHL) (32.6%) were mentioned as the least common oral lesions of HIV. Most correctly identified the images of oral candidiasis (97.8%), angular cheilitis (86.9%) and herpes zoster (80.4%). Only 16.7% felt they had comprehensive knowledge of oral HIV lesions, although 84.8% reported having previously received training. Almost three quarters (71%) reported that there was no need to treat HIV positive patients differently from HIV negative patients. OHCW in Lesotho demonstrated high confidence levels in their competence in managing dental patients with oral lesions associated with HIV, however, they lacked an in-depth knowledge in this regard. Amongst this group there is a need for comprehensive training with regards to diagnosis and management of oral lesions of HIV including the training of other cadres of health care workers together with nurses and community health workers. PMID- 26506797 TI - Substance abuse and maxillofacial injuries. PMID- 26506798 TI - A novel use of the Reciproc R25 Endodontic file for root canal obturation. PMID- 26506799 TI - Do precursor tests influence the performance of Oral Hygiene students in subsequent semester tests? AB - INTRODUCTION: Precursor tests may be useful educational tools in dentistry to enhance learning among Oral Hygiene students, but their application and possible effect on the subsequent performance of these students have not been studied. AIM: To determine whether precursor tests, used as dental educational and formative assessment tools, influence the performance of undergraduate Oral Hygiene students in ensuing formal semester tests in the discipline of Basic Restorative Dentistry. METHODS: This descriptive cross sectional study involved seventeen consenting Oral Hygiene students. An electronic Odontology Theory Test (OTT) and an electronic Objective Structured Practical Test (OSPT), were prepared and introduced as precursor tests prior to scheduled semester tests in the Division of Restorative Dentistry (Department of Odontology). Eleven (65%) of the seventeen students completed the precursor OTT, as well as the precursor OSPT, fourteen days prior to their scheduled semester OTT and semester OSPT and sixty two days prior to their final examinations. The results of the precursor and the semester tests were entered into a Microsoft Excel database for comparative analysis, using a Student's t-test. RESULTS: For both OTT and OSPT tests there were significant differences between the means of the scores of the students for precursor and semester tests (OTT: p = 0.0009; OSPT: p = 0.0180). DISCUSSION: The students performed significantly better in their precursor OTT, whilst their performance in the OSPT was significantly better in the semester test. CONCLUSION: In the context of this investigation, the precursor OTT did not enhance the performance of the students in their semester OTT, whilst the precursor OSPT was associated with an enhanced performance of the students in their semester OSPT. PMID- 26506800 TI - Oral medicine case book 65: Necrotising stomatitis. AB - Necrotising stomatitis is a fulminating anaerobic polybacterial infection affecting predominantly the oral mucosa of debilitated malnourished children or immunosuppressed HIV-seropositive subjects. It starts as necrotising gingivitis which progresses to necrotising periodontitis and subsequently to necrotising stomatitis. In order to prevent the progression of necrotising stomatitis to noma (cancrum oris), affected patients should be vigorously treated and may require admission to hospital. Healthcare personnel should therefore be familiar with the signs and symptoms of necrotising gingivitis/necrotising periodontitis, of their potential sequelae and of the need for immediate therapeutic intervention. PMID- 26506801 TI - Maxillo-facial radiology case 126. Gigantiform cementoma. PMID- 26506802 TI - Privacy and disclosure in the consulting room. PMID- 26506803 TI - Publicity? PMID- 26506804 TI - Setting the highest possible standards of healthcare. PMID- 26506805 TI - The Truth about Sugar. AB - Sugars are used by the industry to enhance the attractiveness of foods and drinks. These added sugars, or 'free sugars', are not easily identified in food or drink labels. Certain manufactured foods and drinks with 'safe' names, such as dried fruit and fruit juice, still contain free sugars and can be confusing. Guidance states that daily consumption of free sugars should be less than 10% of total energy intake (no more than 5% in the UK). However, it is found that both tooth decay and obesity are associated with consumption of free sugars in large quantities and at inappropriate times. PMID- 26506806 TI - Maintenance and Monitoring of Dental Implants in General Dental Practice. AB - A lot of effort has been directed towards developing dental implant surfaces which in turn have seen the increased success rate of osseointegration. Peri implantitis and peri-implant mucositis are inflammatory conditions of implants that can lead to implant failure. Monitoring and maintaining implant restorations is aimed at preventing these complications. PMID- 26506807 TI - Facial Skin Lesions Dentists Should Know. AB - Facial skin lesions are common; patients may present with a.nodule, crack, ulcer or abnormal discoloration of the skin that is not normally present. Ideally, dentists should include face examination in their routine clinical examination. Any suspicious lesion should be referred to a dermatologist as an early diagnosis and treatment could be life-saving. This article will discuss the diagnosis and treatment of common lesions of the face. PMID- 26506808 TI - Worn Down by Toothwear? Aetiology, Diagnosis and Management Revisited. AB - The incidence of toothwear in the population is increasing, as is the number of referrals regarding this problem to secondary care dental hospital consultants and specialists. This paper outlines current theories in aetiology, diagnosis and management of localized and generalized toothwear, as well as describing clinical tips for assessing such patients. PMID- 26506809 TI - Pain-Related Temporomandibular Disorder - Current Perspectives and Evidence-Based Management. AB - Pain-related temporomandibular disorder (TMD) is one of the top three most common chronic pain conditions, along with headaches and back pain. TMD has complex pathophysiology and significant associations with a variety of other chronic pain conditions, eg fibromyalgia, irritable bowel syndrome and migraine. Chronic TMD is associated with a negative impact upon quality of life and high levels of healthcare utility. It is important that clinicians are able to diagnose TMD correctly, provide appropriate management in keeping with current evidence-based practice, and identify when to refer patients to specialist care. The presence of risk factors, eg anxiety, depression, pain-related disability and chronic pain conditions elsewhere in the body, may help to identify which TMD patients require referral for multidisciplinary management. TMD should be managed using a holistic approach, incorporating patient education and encouragement towards self management. TMD care pathways should consider using the three'pillars'of pain management: physical therapies, pharmacotherapy and clinical psychology. PMID- 26506810 TI - Odontogenic Cysts - An Overview. AB - This article aims to discuss the clinical features, radiological assessment, histopathology and management of a variety of odontogenic cysts. It also highlights the reclassification of odontogenic keratocysts to keratocystic odontogenic tumours. PMID- 26506811 TI - Current Applications and Future Prospects of Stem Cells in Dentistry. AB - Stem cells are defined as clonogenic, unspecialized cells capable of both selt renewal and multi-lineage differentiation, contributing to regenerating specific tissues. For years, restorative treatments have exploited the lifelong regenerative potential of dental pulp stem cells to give rise to tertiary dentine, which is therapeutically employed for direct and indirect pulp capping. Current applications of stem cells in endodontic research have revealed their potential to continue root development in necrotic immature teeth and transplanted/replanted teeth. Successful application of pulp revascularization is highlighted here with support of a clinical case report. This article also discusses the role of dental stem cells as a promising tool for regeneration of individual tissue types like dentine, pulp and even an entire functional tooth. PMID- 26506812 TI - Management of Recurrent Aphthous Stomatitis in Children. AB - Recurrent oral ulceration is common and may present in childhood. Causes of recurrent oral ulceration are numerous and there may be an association with underlying systemic disease. Recurrent aphthous stomatitis (RAS) is the most common underlying diagnosis in children. The discomfort of oral ulcers can impact negatively on quality of life of a child, interfering with eating, speaking and may result in missed school days. The role of the general dental practitioner is to identify patients who can be treated with simple measures in primary dental care and those who require assessment and treatment in secondary care. Management may include topical agents for symptomatic relief, topical corticosteroids and, in severe recalcitrant cases, systemic agents may be necessary. PMID- 26506813 TI - The Implications of the New GDC Standards for Dental Professionals. AB - This article is about the publication by the General Dental Council in 2013 of the Standards expected of those members of the dental team who are registered with the Council, on each of their Registers, and discusses the implications of the new Standards for dental professionals. PMID- 26506814 TI - An Unusual Allergic Response to Orthodontic Treatment. AB - This paper describes a case of a 13-year-old patient with a systemic hypersensitivity reaction to orthodontic treatment. Her allergy was investigated resulting in a provisional diagnosis of pressure urticaria. The aetiology, diagnosis and clinical management of allergic reactions to dental procedures are discussed. PMID- 26506815 TI - Oral Ulceration in Newly Diagnosed Leukaemic Patient with Undiagnosed Sweet's Syndrome. AB - Sweet's syndrome is a relatively rare but important skin condition which can affect the oral cavity. Awareness of this reactive condition is important for dentists who work in hospitals, where it is most likely to present. This report summarizes one such case and aims to introduce the reader to Sweet's syndrome. PMID- 26506816 TI - Safeguarding. PMID- 26506817 TI - Home remedies for toothache - believe it or not. PMID- 26506818 TI - Clinical Challenges Q&A. 12. Blisters on Lips. PMID- 26506819 TI - Technique Tips - The Cost of One Defective Class II Contact (with a Posterior Composite). PMID- 26506820 TI - Propensity-matched analysis of three different chemotherapy sequences in patients with locoregionally advanced nasopharyngeal carcinoma treated using intensity modulated radiotherapy. AB - BACKGROUND: To compare the survival outcomes and acute toxicities of concurrent chemoradiotherapy (CCRT), induction chemotherapy (IC) plus radiotherapy (RT), and IC plus CCRT in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated using intensity-modulated radiotherapy (IMRT). METHODS: Patients with stage III-IVB NPC who were treated with IMRT between 2009 and 2012 at a single institution were retrospectively reviewed. The induction regimens included PF (cisplatin and fluorouracil) and TP (docetaxel and cisplatin) every 3 weeks for 2-3 cycles; the concurrent regimen was cisplatin every three weeks for 2-3 cycles. A propensity score matching method was used to match patients from each group in a 1:1:1 ratio. RESULTS: In total, 147 eligible patients were propensity matched, with 49 patients in each treatment group. The median follow-up duration was 38.5 months (range, 4.5 - 56 months). The 3-year disease-free survival, overall survival, distant metastasis-free survival, and locoregional relapse-free survival rates were 82.1%, 92.8%, 87%, and 90.4% in the CCRT group; 86.3%, 91.0%, 91.6%, and 94.4% in the IC plus RT group; and 87.8%, 95.8%, 93.8%, and 93.9% in the IC plus CCRT group, respectively. No statistically significant survival differences were observed between the three treatment groups in either univariate or multivariate analyses. The incidence of grade 3-4 acute toxicities was similar among groups. CONCLUSIONS: This study suggests that CCRT, IC plus RT, and IC plus CCRT are similarly efficacious treatment strategies for patients with locoregionally advanced NPC treated using IMRT; however, long-term, large-scale randomized trials are required to confirm these findings. PMID- 26506821 TI - Lactobacillus plantarum LB95 impairs the virulence potential of Gram-positive and Gram-negative food-borne pathogens in HT-29 and Vero cell cultures. AB - Listeria monocytogenes, Salmonella enterica and verocytotoxigenic Escherichia coli (VTEC) are amongst the most important agents responsible for food outbreaks occurring worldwide. In this work, two Lactobacillus spp. strains (LABs), Lactobacillus plantarum (LB95) and Lactobacillus paraplantarum (LB13), previously isolated from spontaneously fermenting olive brines, and two reference probiotic strains, Lactobacillus casei Shirota and Lactobacillus rhamnosus GG, were investigated for their ability to attenuate the virulence of the aforementioned pathogens using animal cell culture assays. In competitive exclusion assays, the relative percentages of adhesion and invasion of S. enterica subsp. enterica serovar Enteritidis were significantly reduced when the human HT-29 cell line was previously exposed to LB95. The relative percentage of invasion by Listeria monocytogenes was significantly reduced when HT-29 cells were previously exposed to LB95. In the cytotoxicity assays, the cell-free supernatant of the co-culture (CFSC)of VTEC with LB95 accounted for the lowest value obtained amongst the co cultures of VTEC with LABs, and was significantly lower than the value obtained with the co-culture of VTEC with the two probiotic reference strains. The cytotoxicity of CFSC of VTEC with both LB95 and LB13 exhibited values not significantly different from the cell-free supernatant of the nonpathogenic E. coli B strain. Our results suggested that LB95 may be able to attenuate the virulence of Gram-positive and Gram-negative food-borne pathogens; together with other reported features of these strains, our data reveal their possible use in probiotic foods due to their interesting potential in preventing enteric infections in humans. PMID- 26506822 TI - Genetic variation in the ABCG2 gene is associated with gout risk in the Chinese Han population. AB - Gout is a common type of arthritis that is characterized by hyperuricemia, tophi, and joint inflammation. Current evidence suggests that heredity contributes to the progression of gout. Previous studies have shown that regulation of the ATP binding cassette subfamily G member 2 (ABCG2) pathways plays a role in gout occurrence. To investigate and validate potential genetic associations with the risk of gout, we conducted a case-control study. We conducted 143 cases and 310 controls and genotyped seven single-nucleotide polymorphisms (SNPs) in ABCG2 gene. ABCG2 SNP association analyses were performed using SPSS 17.0 Statistical Package, PLINK Software, HaploView software package, and SHEsis software platform. We identified that four susceptibility SNPs were potentially associated with occurrence of gout. Rs2622621 and rs3114018 in ABCG2 can actually increase the risk of gout in log-additive model (rs2622621, odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.39-2.61, p < 0.001; rs3114018, OR = 1.55, 95% CI 1.13 2.13, p = 0.006). We found that rs17731799G/T-G/G and rs3114020 T/C-T/T in ABCG2 can actually increase the risk of gout in dominant model (rs17731799, OR = 1.67, 95% CI 1.05-2.66, p = 0.028; rs3114020, OR = 1.58, 95% CI 1.00-2.51, p = 0.048). The ABCG2 haplotype "GGCTCTC" (OR = 0.46, 95% CI 0.28-0.75, p = 0.0019) decreased the gout risk. Our results, combined with those from previous studies, suggest that genetic variation in ABCG2 may influence gout susceptibility in the Han population. PMID- 26506823 TI - Dissecting the complex molecular evolution and expression of polygalacturonase gene family in Brassica rapa ssp. chinensis. AB - Polygalacturonases (PGs) participate in pectin disassembly of cell wall and belong to one of the largest hydrolase families in plants. In this study, we identified 99 PG genes in Brassica rapa. Comprehensive analysis of phylogeny, gene structures, physico-chemical properties and coding sequence evolution demonstrated that plant PGs should be classified into seven divergent clades and each clade's members had specific sequence and structure characteristics, and/or were under specific selection pressures. Genomic distribution and retention rate analysis implied duplication events and biased retention contributed to PG family's expansion. Promoter divergence analysis using "shared motif method" revealed a significant correlation between regulatory and coding sequence evolution of PGs, and proved Clades A and E were of ancient origin. Quantitative real-time PCR analysis showed that expression patterns of PGs displayed group specificities in B. rapa. Particularly, nearly half of PG family members, especially those of Clades C, D and F, closely relates to reproductive development. Most duplicates showed similar expression profiles, suggesting dosage constraints accounted for preservation after duplication. Promoter-GUS assay further indicated PGs' extensive roles and possible redundancy during reproductive development. This work can provide a scientific classification of plant PGs, dissect the internal relationships between their evolution and expressions, and promote functional researches. PMID- 26506824 TI - Resurgence of duckweed research and applications: report from the 3rd International Duckweed Conference. AB - Duckweed, flowering plants in the Lemnaceae family, comprises the smallest angiosperms in the plant kingdom. They have some of the fastest biomass accumulation rates reported to date for plants and have the demonstrated ability to thrive on wastewater rich in dissolved organic compounds and thus could help to remediated polluted water resources and prevents eutrophication. With a high quality genome sequence now available and increased commercial interest worldwide to develop duckweed biomass for renewables such as protein and fuel, the 3rd International Duckweed Conference convened at Kyoto, Japan, in July of 2015, to update the community of duckweed researchers and developers on the progress in the field. In addition to sharing results and ideas, the conference also provided ample opportunities for new-comers as well as established workers in the field to network and create new aliances. We hope this meeting summary will also help to disseminate the key advances and observations that have been presented in this conference to the broader plant biology community in order to encourage increased cross-fertilization of ideas and technologies. PMID- 26506825 TI - Generalized Multifactor Dimensionality Reduction (GMDR) Analysis of Drug Metabolizing Enzyme-Encoding Gene Polymorphisms may Predict Treatment Outcomes in Indian Breast Cancer Patients. AB - BACKGROUND: Prediction of response and toxicity of chemotherapy can help personalize the treatment and choose effective yet non-toxic treatment regimen for a breast cancer patient. Interplay of variations in various drug-metabolizing enzyme (DME)-encoding genes results in variable response and toxicity of chemotherapeutic drugs. Generalized multi-analytical (GMDR) approach was used to determine the influence of the combination of variants of genes encoding phase 0 (SLC22A16); phase I (CYP450, NQO1); phase II (GSTs, MTHFR, UGT2B15); and phase III (ABCB1) DMEs along with confounding factors on the response and toxicity of chemotherapeutic drugs in breast cancer patients. METHODS: In an Indian breast cancer patient cohort (n = 234), response to neo-adjuvant chemotherapy (n = 111) and grade 2-4 toxicity to chemotherapy were recorded. Patients were genotyped for 19 polymorphisms selected in four phases of DMEs by PCR or PCR-RFLP or Taqman allelic discrimination assay. Binary logistic regression and GMDR analysis was performed. Bonferroni test for multiple comparisons was applied, and p value was considered to be significant at <0.025. RESULTS: For ABCB1 1236C>T polymorphism, CT genotype was found to be significantly associated with response to NACT in uni variate and multi-variate analysis (p = 0.018; p = 0.013). The TT genotype of NQO1 609C>T had a significant association with (absence of) grade 2-4 toxicity in uni-variate analysis (p = 0.021), but a non-significant correlation in multi variate analysis. In GMDR analysis, interaction of CYP3A5*3, NQO1 609C>T, and ABCB1 1236C>T polymorphisms yielded the highest testing accuracy for response to NACT (CVT = 0.62). However, for grade 2-4 toxicity, CYP2C19*2 and ABCB1 3435C>T polymorphisms yielded the best interaction model (CVT = 0.57). CONCLUSION: This pharmacogenetic study suggests a role of higher order gene-gene interaction of DME-encoding genes, along with confounding factors, in determination of treatment outcomes and toxicity in breast cancer patients. This can be used as a potential objective tool for individualizing breast cancer chemotherapy with high efficacy and low toxicity. PMID- 26506826 TI - Costal exostoses as an unusual cause of spontaneous hemothorax. AB - A 20-year-old male presented with chest pain lasting several days. A radiologic examination revealed pleural effusion in the right hemithorax. Video-assisted thoracoscopic surgery demonstrated a bleeding focus at the diaphragm caused by injury due to a costal exostosis. PMID- 26506827 TI - A double-barrelled fibula graft restoring pelvic stability after late posterior ring instability related to a surgical treated osteitis pubis: a case report. AB - BACKGROUND: Osteitis pubis or symphysitis pubis is a rare occurring non infectious inflammation of the symphysis, the adjacent pubic bones and surrounding tissue. The therapy might be conservative or surgical by a resection of the symphysis and involved parts of the pubic bone. Nevertheless, this resection might lead to an anterior instability impairing the posterior arch and the sacroiliac joints in the aftermath. CASE PRESENTATION: Here, we report about a 50-year-old women suffering from osteitis pubis treated by wedge resection of the symphysis and parts of the pubic bone. To maintain stability and for local antibiotic treatment a cement spacer was implemented. By clinical inconspicuous findings and the patient's desire, no further surgery was performed. However, 2 years after surgery the spacer dislocated and the patient complained about pain in the posterior arch due to an impaired mobility. Reconstruction surgery was planned including the bridging of the accrued space with a vascularized double barrelled fibula graft, plate osteosynthesis and rectus abdominis flap coverage. The performed surgery led to pain relief and increased mobility. CONCLUSION: The present case highlights the possible complication of surgical treated osteitis pubis leading to anterior arch instability affecting the posterior arch and thus impairing pelvic ring stability and patient mobility. Furthermore, we describe an opportunity to treat this complication or other etiologies contributing to anterior pelvic ring stability with large bone defects using a vascularized double-barrelled fibula graft to restore pelvic stability. PMID- 26506828 TI - Mosaicplasty for the treatment of a large traumatic osteochondral femoral head lesion: a case report with 2 year follow-up and review of the literature. AB - Different joint-preserving techniques have been described for the treatment of traumatic osteochondral lesions of the femoral head especially in young active patients. Mosaicplasty with autologous transplantation of osteochondral cylinders is an established surgical technique in the knee. Little evidence, however, exists for the treatment of osteochondral lesions in the hip using this technique. Here, we report on the result of treatment of a traumatic 5 cm(2) osteochondral lesion of the femoral head in a young patient treated with mosaicplasty. Grafts were taken from the ipsilateral knee. After 2 years, the outcome was satisfactory with partial return to previous activity level. PMID- 26506829 TI - Dislocation is a risk factor for poor outcome after supination external rotation type ankle fractures. AB - INTRODUCTION: Ankle fractures are one of the most common fractures requiring surgical treatment. Ankle fracture-dislocations are significant injuries to the osseous and soft tissue envelope, but studies focused on the effect of dislocation on radiographic and functional outcomes are lacking. The objective of this study was to evaluate the effect of dislocations on postoperative outcomes in SER IV ankle fracture patients. MATERIALS AND METHODS: From 2004 through 2010, all operative SER IV ankle fractures treated by a single surgeon were enrolled in a prospective database. SER IV ankle fractures were separated into two groups based on clinical or radiographic evidence of dislocation. The primary and secondary functional outcomes measures were the Foot and Ankle Outcome Score (FAOS) and ankle and subtalar range of motion (ROM) with a minimum of 1-year follow-up, respectively. RESULTS: 108 patients with SER IV ankle fractures were identified, with 73 in the non-dislocation group (68%) and 35 patients in the dislocation group (32%). Patient demographics and co-morbidities were similar between the two groups. The incidence of open fractures and the application of an external fixator were significantly higher in the dislocation group (p = 0.037 and p = 0.003, respectively). The dislocation group showed a significant decrease in the accuracy of articular reduction (p = 0.003). At a mean follow-up of 21 months, ankle fracture-dislocation patients had increased pain (p = 0.005) and decreased activities of daily living (p = 0.014) on FAOS outcome measures and significantly worse ankle and subtalar ROM. CONCLUSIONS: The results of this study suggest that concurrent dislocation at time of ankle fracture is associated with worse radiographic and functional outcomes, but not an increase in superficial or deep infection. The results from this study may be helpful in counseling patients regarding expected clinical outcomes after ankle fracture dislocation and in the surgical management of this complex injury. PMID- 26506830 TI - Can C-reactive protein and white blood cell count alone rule out an urgent condition in acute abdominal pain? AB - Up to 10% of all patients at the Emergency Department present for acute abdominal pain. The C-reactive protein (CRP) and white blood cell (WBC) are routinely determined as part of the workup of patients with abdominal pain. Three large prospective cohort studies comprising a total of 2961 adult patients with acute abdominal pain were selected. CRP levels and WBC counts were compared between patients with urgent and nonurgent final diagnoses. These studies conclude that the laboratory values individually are weak discriminators and cannot be used as a triage instrument in the selection of patients with acute abdominal pain requiring additional diagnostic tests. PMID- 26506831 TI - Acute heart failure in the emergency department: a follow-up study. AB - Acute heart failure (AHF) is a major public health issue due to high incidence and poor prognosis. Only a few studies are available on the long-term prognosis and on outcome predictors in the unselected population attending the emergency department (ED) for AHF. We carried out a 1-year follow-up analysis of 1234 consecutive patients from selected Italian EDs from January 2011 to June 2012 for an episode of AHF. Their prognosis and outcome-associated factors were tested by Cox proportional hazard model. Patients' mean age was 84, with 66.0% over 80 years and 56.2% females. Comorbidities were present in over 50% of cases, principally a history of acute coronary syndrome, chronic obstructive pulmonary disease, diabetes, chronic kidney disease, valvular heart disease. Death occurred within 6 h in 24 cases (1.9%). At 30-day follow-up, death was registered in 123 cases (10.0%): 110 cases (89.4%) died of cardiovascular events and 13 (10.6%) of non-cardiovascular causes (cancer, gastrointestinal hemorrhages, sepsis, trauma). At 1-year follow-up, all-cause death was recorded in 50.1% (over 3 out of 4 cases for cardiovascular origin). Six variables (older age, diabetes, systolic arterial pressure <110 mm/Hg, high NT pro-BNP, high troponin levels and impaired cognitive status) were selected as outcome predictors, but with limited discriminant capacity (AUC = 0.649; SE 0.015). Recurrence of AHF was registered in 31.0%. The study identifies a cluster of variables associated with 1-year mortality in AHF, but their predictive capacity is low. Old age and the presence of comorbidities, in particular diabetes are likely to play a major role in dictating the prognosis. PMID- 26506832 TI - Reliability and validity of intraoral and extraoral scanners. AB - BACKGROUND: This study evaluated the reliability and validity of one extraoral [Ortho Insight 3DTM (Motionview Software, Hixson, TN/USA)] and two intraoral [ITeroTM (Align Technologies, San Jose, CA/USA) and LythosTM (Ormco Corp., Orange, CA/USA)] scanners. METHODS: Fifteen dry human mandibles were scanned twice with each of the scanners, and digital models were generated. Five measurements were made on the dry mandibles and on each of the generated models, including intermolar width, intercanine width, posterior arch length, premolar crown diameter, and canine height. Systematic and random errors were evaluated based on replicate analyses. Differences were assessed using paired Student's t tests. RESULTS: Replicate analyses showed statistically significant systematic errors for only one measure (intermolar width measured from Ortho Insight 3D scans). Measurements taken from all three scanners were highly reliable, with intraclass correlations ranging from .926 to .999. Method errors were all less than 0.25 mm (averaged ~ 0.12 mm). Posterior arch length and canine height were significantly smaller when measured on the Ortho Insight 3D scans than when measured on the dry mandibles and significantly smaller than when measured from the ITero and Lythos models. CONCLUSIONS: While all three scanners produced reliable measures, Ortho Insight 3D systematically underestimated arch length and canine height. PMID- 26506833 TI - A case of unilateral hemolacria. PMID- 26506834 TI - Punjab Medical Council investigates doctors for alleged payments from drug companies. PMID- 26506835 TI - Spontaneous chylous ascites, chylomediastinum and bilateral chylothoraces encountered during laparoscopic incarcerated paraesophageal hernia repair. AB - Chylous ascites is an accumulation of milky lipid-rich lymph in the peritoneal cavity. Spontaneous chyle leak is a rare occurrence, often associated with malignancy or cirrhosis. This is a report of spontaneous chylous ascites, chylomediastinum and chylothoraces encountered in the setting of an incarcerated paraesophageal hernia. A 60-year-old female presented to the emergency department with epigastric pain, dysphagia and vomiting. Clinical presentation and imaging were concerning for an incarcerated paraesophageal hernia, and the patient was taken to the operating room. During laparoscopic reduction of the hernia and repair, chyle was encountered in the peritoneal cavity, mediastinum and pleural spaces. Postoperatively, the chyle leak resolved with a nonfat diet. The unusual occurrence of a chyle leak in this case may have been due to compression of the thoracic duct within the chest by the incarcerated paraesophageal hernia. PMID- 26506836 TI - Impact of previous cardiac surgery on long-term outcome of cavotricuspid isthmus dependent atrial flutter ablation. AB - AIMS: The aim of this study was to determine the acute and long-term outcome of radiofrequency catheter ablation (RFCA) for cavotricuspid isthmus-dependent atrial flutter (CTI-AFL) in adults with and without previous cardiac surgery (PCS), and predictors of these outcomes. Structural alterations of the anatomical substrate of the CTI-AFL are observed in post-operative patients, and these may have an impact on the acute success of the ablation and in the long-term. METHODS AND RESULTS: Clinical records of consecutive adults undergoing RFCA of CTI-AFL were analysed. Two main groups were considered: No PCS and PCS patients, who were further subdivided into acquired heart disease (AHD: ischaemic heart disease and valvular/mixed heart disease) and congenital heart disease [CHD: ostium secundum atrial septal defect (OS-ASD) and complex CHD]. Multivariate analysis identified clinical and procedural factors that predicted acute and long-term outcomes. A total of 666 patients (73% men, age 65 +/- 12 years) were included: 307 of them with PCS. Ablation was successful in 647 patients (97%), 96% in the PCS group and 98% in the No PCS group (P = 0.13). Regression analysis showed that surgically corrected complex CHD was related to failure of the procedure [odds ratio 5.6; 95% confidence interval (CI) 1.6-18, P = 0.008]. After a follow-up of 45 +/- 15 months, recurrences were observed in 90 patients (14%), more frequently in the PCS group: absolute risk of recurrence 18 vs. 10.5%, relative risk 1.71, 95% CI: 1.2-2.5, P = 0.006. Multivariate analysis indicated that the types of PCS [OS-ASD vs. No PCS: hazard ratio (HR) 2.57; 95% CI: 1.1-6.2, P = 0.03 and complex CHD vs. No PCS: HR 2.75; 95% CI: 1.41-5.48, P = 0.004], female gender (HR 1.55; 95% CI: 1.04-2.4, P = 0.048), and severe LV dysfunction (HR 1.36; 95% CI: 1.06-1.67, P = 0.04) were independent predictors of long-term recurrence. CONCLUSION: Radiofrequency catheter ablation of CTI-AFL after surgical correction of AHD and CHD is associated with high acute success rates. The severity of the structural alterations of the underlying heart disease and consequently the type of surgical correction correlates with higher risk for recurrence. PMID- 26506837 TI - An experimental study on providing a scientific evidence for seven-time alcohol steaming of Rhei Rhizoma when clinically used. AB - BACKGROUND: Rhei Rhizoma (RR) has been widely used as laxative and processed to alter its therapeutic actions or reduce its side effects. In this study, we evaluated experimentally the clinical application guideline that RR should be alcohol-steamed seven times before being used in elderly patients, as described in Dongeuibogam, the most famous book on Korean traditional medicine. METHODS: Unprocessed RR (RR-U) was soaked in rice wine, steamed and then fully dried (RR P1). The process was repeated four (RR-P4) or seven times (RR-P7). Reversed-phase high-performance liquid chromatography was used to determine the RR-U, RR-P1, RR P4 and RR-P7 (RRs) constituents. To evaluate the effect of RRs on liver toxicity, human hepatoma cells (HepG2) were treated with RRs at 100 MUg/mL for 4 h and then cell viabilities were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide method. To confirm the effects in vivo, 5-week-old male Sprague-Dawley rats were treated with RRs at 3 g/kg/day for 21 days. Body weight and serum biochemical parameters were measured and liver histology was assessed. RESULTS: The levels of sennosides decreased in processed RRs in an iteration-dependent manner, while the emodin level was unaffected. In HepG2 cells, cell viability was reduced with RR-U, while the toxicity decreased according to the number of processing cycles. The changes in body weight, relative liver weight and liver enzymes of RR-U-treated rats were reduced in processed RRs-treated rats. Histopathological analysis indicated swelling and cholestasis improved following seven times alcohol-steaming cycles. CONCLUSIONS: These results provide experimental evidence that RR-P7 almost completely reduces RR hepatotoxicity. PMID- 26506838 TI - Hysteroscopic sterilization in immunocompromised patients who have intrauterine devices in place: two case reports. AB - INTRODUCTION: The micro-inserts used in the hysteroscopic sterilization procedure elicit a benign occlusive tissue response leading to permanent tubal occlusion. Little is known about whether immunosuppressed patients mount the immunological response necessary to ensure tubal occlusion. Theoretical concern for non occlusion has limited the use of hysteroscopic sterilization in patients on immunosuppressive therapies. In all patient populations, if an intrauterine device is in place, it is usually removed at the time of hysteroscopic sterilization. Little is known about maintaining intrauterine devices during the 3-month period to tubal occlusion. CASE PRESENTATION: Our patient in case 1 was a 35-year-old Hispanic woman, gravida 2, para 2002, with a history of a living donor kidney transplant. Our patient in case 2 was a 32-year-old Hispanic woman, gravida 3, para 2103, diagnosed with undifferentiated autoimmune disease. Both patients underwent hysteroscopic sterilization. In both cases, a levonorgestrel intrauterine device was in place for contraception. At the time of micro-insert placement, our patients were both on daily immunosuppressive medications, including long-term glucocorticoids. Three months after the hysteroscopic procedure, both patients had successful tubal occlusion, demonstrated by a hysterosalpingogram. CONCLUSION: Hysteroscopic sterilization in an outpatient setting is a reasonable option for sterilization in immunocompromised patients on immunosuppressive therapies. Intrauterine devices can be maintained during the procedure and during the 3-month period to tubal occlusion. PMID- 26506839 TI - Metformin and soybean-derived bioactive molecules attenuate the expansion of stem cell-like epithelial subpopulation and confer apoptotic sensitivity in human colon cancer cells. AB - Colorectal cancer (CRC) is a disease whose genesis may include metabolic dysregulation. Cancer stem cells are attractive targets for therapeutic interventions since their aberrant expansion may underlie tumor initiation, progression, and recurrence. To investigate the actions of metabolic regulators on cancer stem cell-like cells (CSC) in CRC, we determined the effects of soybean derived bioactive molecules and the anti-diabetes drug metformin (MET), alone and together, on the growth, survival, and frequency of CSC in human HCT116 cells. Effects of MET (60 MUM) and soybean components genistein (Gen, 2 MUM), lunasin (Lun, 2 MUM), beta-conglycinin (beta-con, 3 MUM), and glycinin (Gly, 3 MUM) on HCT116 cell proliferation, apoptosis, and mRNA/protein expression and on the frequency of the CSC CD133(+)CD44(+) subpopulation by colonosphere assay and fluorescence-activated cell sorting/flow cytometry were evaluated. MET, Gen, and Lun, individually and together, inhibited HCT116 viability and colonosphere formation and, conversely, enhanced HCT116 apoptosis. Reductions in frequency of the CSC CD133(+)CD44(+) subpopulation with MET, Gen, and Lun were found to be associated with increased PTEN and reduced FASN expression. In cells under a hyperinsulinemic state mimicking metabolic dysregulation and without and with added PTEN-specific inhibitor SF1670, colonosphere formation and frequency of the CD133(+)CD44(+) subpopulation were decreased by MET, Lun and Gen, alone and when combined. Moreover, MET + Lun + Gen co-treatment increased the pro-apoptotic and CD133(+)CD44(+)-inhibitory efficacy of 5-fluorouracil under hyperinsulinemic conditions. Results identify molecular networks shared by MET and bioavailable soy food components, which potentially may be harnessed to increase drug efficacy in diabetic and non-diabetic patients with CRC. PMID- 26506840 TI - 2015 Colorado Alphaherpesvirus Latency Society Symposium. PMID- 26506841 TI - Detection of virus in CSF from the cases with meningoencephalitis by next generation sequencing. AB - We screened for viral DNA in cerebrospinal fluid samples using next-generation sequencing (NGS) technology to diagnose CNS viral infections. We collected CSF samples from four cases with clinically suspected viral meningoencephalitis. DNA extracted from the samples was analyzed with NGS, and the results were further validated using PCR. Herpes simplex virus 1 (HSV-1) was detected in the CSF of two patients, HSV-2 and human herpes virus type 3 (HHV-3, VZV) in the CSF of two other patients separately. The number of unique reads of the identified viral genes ranged from 144 to 44205 (93.51 to 99.57%). The coverage of identified viral genes ranged from 12 to 98% with a depth value of 1.1 to 35, respectively. The results were further confirmed using PCR in three cases. The clinical presentation and outcomes of these four cases were consistent with the diagnostic results of NGS. NGS of CSF samples can be used as a diagnostic assay for CNS viral infection. Its further application for "pan-viral" or even "pan-microbial" screening of CSF might influence the diagnosis of CNS infectious diseases. PMID- 26506842 TI - Readers in Adult Basic Education. AB - The present study explored the reading skills of a sample of 48 adults enrolled in a basic education program in northern Florida, United States. Previous research has reported on reading component skills for students in adult education settings, but little is known about eye movement patterns or their relation to reading skills for this population. In this study, reading component skills including decoding, language comprehension, and reading fluency are reported, as are eye movement variables for connected-text oral reading. Eye movement comparisons between individuals with higher and lower oral reading fluency revealed within- and between-subject effects for word frequency and word length as well as group and word frequency interactions. Bivariate correlations indicated strong relations between component skills of reading, eye movement measures, and both the Test of Adult Basic Education ( Reading subtest) and the Woodcock-Johnson III Diagnostic Reading Battery Passage Comprehension assessments. Regression analyses revealed the utility of decoding, language comprehension, and lexical activation time for predicting achievement on both the Woodcock Johnson III Passage Comprehension and the Test of Adult Basic Education Reading Comprehension. PMID- 26506843 TI - A literature review on observational learning for medical motor skills and anesthesia teaching. AB - Motor skill practice is very important to improve performance of medical procedures and could be enhanced by observational practice. Observational learning could be particularly important in the medical field considering that patients' safety prevails over students' training. The mechanism of observational learning is based on the mirror neuron system, originally discovered in the monkey pre-motor cortex. Today we know that humans have a similar system, and its role is to understand and reproduce the observed actions of others. Many studies conclude that humans are able to plan and to make movements based on visual information by mapping a representation of observed actions, especially when the motor system is committed to do it. Moreover most researchers considered observational learning effective for complex skills, such as medical procedures. Additionally, observational learning could play a relevant role during anesthesia training since the learner works in pairs most of the time (dyad practice). Some teaching approaches should be taken into consideration: an implicit engagement of the observer motor system is required, immediate feedback seems to have an important effect, and a combination of observational and physical practice could be better than physical practice alone. In an environment where effectiveness and efficacy are essential, observational learning seems to fit well. PMID- 26506844 TI - Cartilage morphology at 2-3 years following anterior cruciate ligament reconstruction with or without concomitant meniscal pathology. AB - PURPOSE: To examine differences in cartilage morphology between young adults 2-3 years post-anterior cruciate ligament reconstruction (ACLR), with or without meniscal pathology, and control participants. METHODS: Knee MRI was performed on 130 participants aged 18-40 years (62 with isolated ACLR, 38 with combined ACLR and meniscal pathology, and 30 healthy controls). Cartilage defects, cartilage volume and bone marrow lesions (BMLs) were assessed from MRI using validated methods. RESULTS: Cartilage defects were more prevalent in the isolated ACLR (69 %) and combined group (84 %) than in controls (10 %, P < 0.001). Furthermore, the combined group showed higher prevalence of cartilage defects on medial femoral condyle (OR 4.7, 95 % CI 1.3-16.6) and patella (OR 7.8, 95 % CI 1.5-40.7) than the isolated ACLR group. Cartilage volume was lower in both ACLR groups compared with controls (medial tibia, lateral tibia and patella, P < 0.05), whilst prevalence of BMLs was higher on lateral tibia (P < 0.001), with no significant differences between the two ACLR groups for either measure. CONCLUSIONS: Cartilage morphology was worse in ACLR patients compared with healthy controls. ACLR patients with associated meniscal pathology have a higher prevalence of cartilage defects than ACLR patients without meniscal pathology. The findings suggest that concomitant meniscal pathology may lead to a greater risk of future OA than isolated ACLR. LEVEL OF EVIDENCE: III. PMID- 26506845 TI - Epidemiology of meniscal injuries in US high school athletes between 2007 and 2013. AB - PURPOSE: Knowledge of epidemiologic trends of meniscal injuries in young active populations is limited. Better awareness of injury patterns is a first step to lowering injury rates. Our hypothesis was that meniscal injuries in high school athletes would vary by gender, sport, and type of exposure. METHODS: During the 2007/2008 and 2012/2013 academic years, a large nationally disperse sample of US high schools reported athlete exposure and injury data for 22 sports by having certified athletic trainers complete an internet-based data collection tool. RESULTS: One thousand and eighty-two meniscal injuries were reported during 21,088,365 athlete exposures for an overall injury rate of 5.1 per 100,000 athlete exposures. The overall rate of injury was higher in competition (11.9) than practice (2.7) (RR = 4.4; 95% CI 3.9-5.0), and 12/19 sports showed significantly higher injury rates in competition compared to practice. Of all injuries, 68.0% occurred in boys, yet among the gender-comparable sports of soccer, basketball, track and field, lacrosse, and baseball/softball injury rates were higher for girls than boys (5.5 and 2.5, respectively, RR = 2.2; 95% CI 1.8 2.7). Contact injury represented the most common mechanism (55.9%). Surgery was performed for the majority of injuries (63.8%), and 54.0% of athletes had associated intra-articular knee pathology. CONCLUSIONS: Meniscal injury patterns among high school athletes vary by gender, sport, and type of exposure. Our study is clinically relevant because recognition of distinct differences in these injury patterns will help drive evidence-based, targeted injury prevention strategies and efforts. LEVEL OF EVIDENCE: III. PMID- 26506846 TI - Thinking the unthinkable about the NHS. PMID- 26506847 TI - Migraine and subclinical atherosclerosis in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - INTRODUCTION: The relationship between migraine and coronary heart disease (CHD) remains controversial. We aimed to investigate the association of subclinical atherosclerosis and migraine with or without aura compared to a non-migraine subgroup (reference) in a large Brazilian multicentric cohort study, the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS: Migraine diagnostic was based on International Headache Society criteria, and aura symptoms were validated by a medical doctor in a sub-sample of the ELSA-Brasil, who also underwent coronary artery calcium score (CAC) and carotid intima-media thickness (C-IMT) evaluations. Subclinical atherosclerosis indexes (CAC and C IMT) were analyzed as dependent variables and migraine (all, with aura, without aura) as an independent variable in the linear and multinomial logistic regression models adjusted for possible confounders. RESULTS: Of 3217 ELSA participants free from CVD at baseline, we found a migraine frequency of 11.9% (5.1% with aura and 6.8% without aura). Overall, migraineurs were mostly women, younger and had lower frequency of CV risk factors, such as hypertension, diabetes and low HDL-cholesterol, compared to non-migraineurs. The strongest inverse correlation between migraine and subclinical atherosclerosis was verified with CAC score. However, all associations lost their significance after multivariate adjustment. CONCLUSIONS: In this cross-sectional evaluation of the ELSA study, migraine was not associated with subclinical atherosclerosis, regardless of aura symptoms. PMID- 26506848 TI - Stem cell protein Piwil1 endowed endometrial cancer cells with stem-like properties via inducing epithelial-mesenchymal transition. AB - BACKGROUND: Stem cell protein Piwil1 functions as an oncogene in various tumor types. However, the exact function and mechanism of Piwil1 in endometrial cancer remains unclear. METHODS: The expression of Piwil1 and its relationships with clinicopathological factors were investigated using immunohistochemistry. Up- or down-regulation of Piwil1 were achieved by stable or transient transfection with plasmids or short hairpin RNA (shRNA). Effects of Piwil1 on cancer cells viability, invasion and migration were evaluated by MTT, plate colony formation, transwell assay and nude mouse tumor xenograft assay. The stem-like properties of endometrial cancer cells was detected by spheroid formation assay. Effects of Piwil1 on expression levels of target genes were detected by qRT-PCR, western blotting and Immunofluorescence. RESULTS: Compared with atypical hyperplasia and normal tissues, Piwil1 was much higher in endometrial carcinoma tissues. We found that Piwil1 expression was significantly correlated with FIGO stage, lymphovascular space involvement, lymph node metastasis and level of myometrial invasion. Overexpression of Piwil1 functioned to maintain stem-like characteristics, including enhancing tumor cell viability, migration, invasion and sphere-forming activity. Conversely, Piwil1 knockdown inhibited cell viability, migration, invasion, sphere-forming activity in vitro and tumor formation in xenograft model in vivo. Furthermore, study of the expression of epithelial and mesenchymal markers showed that Piwil1 was responsible for an EMT like phenotype associated with an increase in mesenchymal markers and suppression of E-cadherin. Moreover, Piwil1 augmented expression levels of CD44 and ALDH1 expression, two known endometrial CSC markers, as well as other stemness associated genes. CONCLUSIONS: Our results suggested that stem cell protein Piwil1 play important roles in regulating EMT and the acquisition of stem-like properties of endometrial cancer cells. Therefore, it indicated that Piwil1 may represent a promising target for developing a novel treatment strategy for endometrial cancer. PMID- 26506849 TI - Expanding the light absorption of poly(3-hexylthiophene) by end-functionalization with pi-extended porphyrins. AB - Poly(3-hexylthiophene)s end-functionalized with pi-extended porphyrins have been synthesized in a one-pot procedure. The polymers show a broad absorption profile extending to 700 nm and a fibrillar microstructure, which can be tuned through judicious selection of the porphyrin molar ratio. PMID- 26506850 TI - Xenopericardial roll graft replacement for infectious pseudoaneurysms and graft infections of the aorta. AB - BACKGROUND: Which graft material is the optimal graft material for the treatment of infected aortic aneurysms and aortic graft infections is still a matter of controversy. Orthotopic aortic reconstruction with intraoperatively prepared xenopericardial roll grafts without omentopexy was performed as the "initial" operation to treat aortic infection or as a "rescue" operation to treat graft infection. Mid-term outcomes were evaluated. METHODS: Between 2009 and 2013, orthotopic xenopericardial roll graft replacement was performed to treat eight patients (male/female: 6/2; mean age: 69.5 [55-80] yr). Graft material: equine/bovine pericardium: 2/6; type of operation: initial 4/rescue 4; omentopexy 0. Additional operation: esophagectomy 2. Mean follow-up period: 2.6 +/- 1.6 (1.1 5.1) years. RESULTS: Replacement: ascending 3, arch 1 (reconstruction of neck vessels with small xenopericardial roll grafts), descending 3, and thoracoabdominal 1. Pathogens: MRSA 2, MSSA 1, Candida 1, E. coli 1, oral bacillus 1, and culture negative 2. Postoperative local recurrence of infection: 0. Graft-related complications: stenosis 0, calcification 0, non-infectious pseudoaneurysm of anastomosis 2 (surgical repair: 1/TEVAR 1). In-hospital mortality: 2 (MOF: initial 1/rescue 1); Survival rate exclusive of in-hospital deaths (~3 y): 100 %, but one patient died of lung cancer (3.6 yr). CONCLUSIONS: Because xenopericardial roll grafts are not composed of synthetic material, the replacement procedure is simpler and less invasive than the standard procedure. Based on the favorable results obtained, this procedure may have the possibility to serve as an option for the treatment of aortic infections and aortic graft infections not only as a "rescue" treatment but as an "initial" treatment as well. PMID- 26506851 TI - Leptin acts in the brain to influence hypoglycemic counterregulation: disparate effects of acute and recurrent hypoglycemia on glucagon release. AB - Leptin has been shown to diminish hyperglycemia via reduced glucagon secretion, although it can also enhance sympathoadrenal responses. However, whether leptin can also inhibit glucagon secretion during insulin-induced hypoglycemia or increase epinephrine during acute or recurrent hypoglycemia has not been examined. To test whether leptin acts in the brain to influence counterregulation, hyperinsulinemic hypoglycemic (~45 mg/dl) clamps were performed on rats exposed to or not exposed to recurrent hypoglycemia (3 days, ~40 mg/dl). Intracerebroventricular artificial cerebral spinal fluid or leptin was infused during the clamp. During acute hypoglycemia, leptin decreased glucagon responses by 51% but increased epinephrine and norepinephrine by 24 and 48%, respectively. After recurrent hypoglycemia, basal plasma leptin levels were undetectable. Subsequent brain leptin infusion during hypoglycemia paradoxically increased glucagon by 45% as well as epinephrine by 19%. In conclusion, leptin acts within the brain to diminish glucagon secretion during acute hypoglycemia but increases epinephrine, potentially limiting its detrimental effects during hypoglycemia. Exposure to recurrent hypoglycemia markedly suppresses plasma leptin, whereas exogenous brain leptin delivery enhances both glucagon and epinephrine release to subsequent hypoglycemia. These data suggest that recurrent hypoglycemia may diminish counterregulatory responses in part by reducing brain leptin action. PMID- 26506852 TI - A systems-based investigation into vitamin D and skeletal muscle repair, regeneration, and hypertrophy. AB - Skeletal muscle is a direct target for vitamin D. Observational studies suggest that low 25[OH]D correlates with functional recovery of skeletal muscle following eccentric contractions in humans and crush injury in rats. However, a definitive association is yet to be established. To address this gap in knowledge in relation to damage repair, a randomised, placebo-controlled trial was performed in 20 males with insufficient concentrations of serum 25(OH)D (45 +/- 25 nmol/l). Prior to and following 6 wk of supplemental vitamin D3 (4,000 IU/day) or placebo (50 mg of cellulose), participants performed 20 * 10 damaging eccentric contractions of the knee extensors, with peak torque measured over the following 7 days of recovery. Parallel experimentation using isolated human skeletal muscle derived myoblast cells from biopsies of 14 males with low serum 25(OH)D (37 +/- 11 nmol/l) were subjected to mechanical wound injury, which enabled corresponding in vitro studies of muscle repair, regeneration, and hypertrophy in the presence and absence of 10 or 100 nmol 1alpha,25(OH)2D3. Supplemental vitamin D3 increased serum 25(OH)D and improved recovery of peak torque at 48 h and 7 days postexercise. In vitro, 10 nmol 1alpha,25(OH)2D3 improved muscle cell migration dynamics and resulted in improved myotube fusion/differentiation at the biochemical, morphological, and molecular level together with increased myotube hypertrophy at 7 and 10 days postdamage. Together, these preliminary data are the first to characterize a role for vitamin D in human skeletal muscle regeneration and suggest that maintaining serum 25(OH)D may be beneficial for enhancing reparative processes and potentially for facilitating subsequent hypertrophy. PMID- 26506853 TI - Agricultural Media Coverage of Farm Safety: Review of the Literature. AB - Agricultural media merit increased attention in addressing dynamic changes in safety aspects of one of the nation's most hazardous industries. Changes in farming, such as larger-scale, new "niche" enterprises and new technologies, bring new forms of risk to the safety of those who live and work on farms and ranches. At the same time, traditional agricultural media--commercial firms that publish farm periodicals and commercial radio/television stations and networks that provide farm programming--are changing dramatically. In the face of media convergence, these enterprises provide an increasing menu of agricultural information services delivered by print, radio, and television, plus a host of new electronic media. This review of literature addressed the role and importance of commercial agricultural media in the United States, the scope and pattern of their safety coverage, and the opportunities they represent. The review involved searches of 14 bibliographic databases, as well as reference lists of relevant studies and contacts with farm safety experts. Analysis of 122 documents suggested that limited focus has been directed to the role of commercial agricultural media in safety decisions on US farms. Findings revealed that they continue to serve an efficient, early-stage role in creating awareness and interest, providing information, forming attitudes, and stirring consideration of farm safety. Potentials are seen as expanding through the interactive features of social media and other new services offered by these media firms. Findings also identified research needs, 100 farm safety topics for reporting, and opportunities for strengthening safety coverage by commercial agricultural media. PMID- 26506854 TI - Achieving high treatment success for multidrug-resistant TB in Africa: initiation and scale-up of MDR TB care in Ethiopia--an observational cohort study. AB - BACKGROUND: In Africa, fewer than half of patients receiving therapy for multidrug-resistant TB (MDR TB) are successfully treated, with poor outcomes reported for HIV-coinfected patients. METHODS: A standardised second-line drug (SLD) regimen was used in a non-governmental organisation-Ministry of Health (NGO MOH) collaborative community and hospital-based programme in Ethiopia that included intensive side effect monitoring, adherence strategies and nutritional supplementation. Clinical outcomes for patients with at least 24 months of follow up were reviewed and predictors of treatment failure or death were evaluated by Cox proportional hazards models. RESULTS: From February 2009 to December 2014, 1044 patients were initiated on SLD. 612 patients with confirmed or presumed MDR TB had >= 24 months of follow-up, 551 (90.0%) were confirmed and 61 (10.0%) were suspected MDR TB cases. 603 (98.5%) had prior TB treatment, 133 (21.7%) were HIV coinfected and median body mass index (BMI) was 16.6. Composite treatment success was 78.6% with 396 (64.7%) cured, 85 (13.9%) who completed treatment, 10 (1.6%) who failed, 85 (13.9%) who died and 36 (5.9%) who were lost to follow-up. HIV coinfection (adjusted HR (AHR): 2.60, p<0.001), BMI (AHR 0.88/kg/m(2), p=0.006) and cor pulmonale (AHR 3.61, p=0.003) and confirmed MDR TB (AHR 0.50, p=0.026) were predictive of treatment failure or death. CONCLUSIONS: We report from Ethiopia the highest MDR TB treatment success outcomes so far achieved in Africa, in a setting with severe resource constraints and patients with advanced disease. Intensive treatment of adverse effects, nutritional supplementation, adherence interventions and NGO-MOH collaboration were key strategies contributing to success. We argue these approaches should be routinely incorporated into programmes. PMID- 26506855 TI - Response to: 'Lumacaftor/ivacaftor for patients homozygous for Phe508del-CFTR: should we curb our enthusiasm?' by Jones and Barry. PMID- 26506856 TI - A Pharmacovigilance Study in First Episode of Psychosis: Psychopharmacological Interventions and Safety Profiles in the PEPs Project. AB - BACKGROUND: The characterization of the first episode of psychosis and how it should be treated are principal issues in actual research. Realistic, naturalistic studies are necessary to represent the entire population of first episode of psychosis attended in daily practice. METHODS: Sixteen participating centers from the PEPs project recruited 335 first episode of psychosis patients, aged 7 to 35 years. This article describes and discusses the psychopharmacological interventions and safety profiles at baseline and during a 60-day pharmacovigilance period. RESULTS: The majority of first episode of psychosis patients received a second-generation antipsychotic (96.3%), orally (95%), and in adjusted doses according to the product specifications (87.2%). A total of 24% were receiving an antipsychotic polytherapy pattern at baseline, frequently associated with lower or higher doses of antipsychotics than the recommended ones. Eight patients were taking clozapine, all in monotherapy. Males received higher doses of antipsychotic (P=.043). A total of 5.2% of the patients were being treated with long-acting injectable antipsychotics; 12.2% of the patients received anticholinergic drugs, 12.2% antidepressants, and 13.7% mood stabilizers, while almost 40% received benzodiazepines; and 35.52% reported at least one adverse drug reaction during the pharmacovigilance period, more frequently associated with higher antipsychotic doses and antipsychotic polytherapy (85.2% vs 45.5%, P<.001). CONCLUSIONS: These data indicate that the overall pharmacologic prescription for treating a first episode of psychosis in Spain follows the clinical practice guideline recommendations, and, together with security issues, support future research of determinate pharmacological strategies for the treatment of early phases of psychosis, such as the role of clozapine, long-acting injectable antipsychotics, antipsychotic combination, and the use of benzodiazepines. PMID- 26506857 TI - Incoordination among Subcellular Compartments Is Associated with Depression-Like Behavior Induced by Chronic Mild Stress. AB - BACKGROUND: Major depressive disorder is characterized as persistent low mood. A chronically stressful life in genetically susceptible individuals is presumably the major etiology that leads to dysfunctions of monoamine and hypothalamus pituitary-adrenal axis. These pathogenic factors cause neuron atrophy in the limbic system for major depressive disorder. Cell-specific pathophysiology is unclear, so we investigated prelimbic cortical GABAergic neurons and their interaction with glutamatergic neurons in depression-like mice. METHODS: Mice were treated with chronic unpredictable mild stress for 3 weeks until they expressed depression-like behaviors confirmed by sucrose preference, Y-maze, and forced swimming tests. The structures and functions of GABAergic and glutamatergic units in prelimbic cortices were studied by cell imaging and electrophysiology in chronic unpredictable mild stress-induced depression mice vs controls. RESULTS: In depression-like mice, prelimbic cortical GABAergic neurons show incoordination among the subcellular compartments, such as decreased excitability and synaptic outputs as well as increased reception from excitatory inputs. GABAergic synapses on glutamatergic cells demonstrate decreased presynaptic innervation and increased postsynaptic responsiveness. CONCLUSIONS: Chronic unpredictable mild stress-induced incoordination in prelimbic cortical GABAergic and glutamatergic neurons dysregulates their target neurons, which may be the pathological basis for depressive mood. The rebalance of compatibility among subcellular compartments would be an ideal strategy to treat neural disorders. PMID- 26506858 TI - Micromonospora lycii sp. nov., a novel endophytic actinomycete isolated from wolfberry root (Lycium chinense Mill). AB - A novel actinomycete, designated strain NEAU-gq11(T), was isolated from wolfberry root (Lycium chinense Mill) and characterized using a polyphasic approach. Strain NEAU-gq11(T) was observed to form rough-surfaced spores that borne singly on the substrate hyphae but aerial mycelia were not developed. The organism showed closest 16S rRNA gene sequence similarity to Micromonospora saelicesensis Lupac 09(T) (99.4%), and phylogenetically clustered with M. chokoriensis 2-19/6(T) (99.3%), 'M. zeae' NEAU-gq9(T) (99.3%), M. violae NEAU-zh8(T) (99.1%), 'M. jinlongensis' NEAU-GRX11(T) (99.1%), M. zamorensis CR38(T) (99.0%), M. taraxaci NEAU-P5(T) (98.9%) and M. lupini Lupac 14N(T) (98.6%). Phylogenetic analysis based on the gyrB gene sequences also indicated that the isolate clustered with the above type strains except M. violae NEAU-zh8(T). The cell-wall peptidoglycan consisted of meso-diaminopimelic acid and glycine. The major menaquinones were MK 9(H8), MK-10(H6) and MK-10(H2). The phospholipid profile contained diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol. The major fatty acid was iso-C16:0. Furthermore, some physiological and biochemical properties and low DNA-DNA relatedness values enabled the strain to be differentiated from members of closely related species. Therefore, it is proposed that strain NEAU-gq11(T) represents a novel species of the genus Micromonospora, for which the name Micromonospora lycii sp. nov. is proposed. The type strain is NEAU-gq11(T) (=CGMCC 4.7149(T)=DSM 46703(T)). PMID- 26506859 TI - Synthesis of Thienamycin methyl ester from 2-deoxy-D-ribose via Kinugasa reaction. AB - A novel synthesis of thienamycin is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from D-lactic acid and suitable, partially protected, five-membered cyclic nitrone obtained from 2-deoxy-D-ribose. The reaction was performed in the presence of tetramethylguanidine as a base to provide 5,6-trans substituted carbapenam as the main product. Thus obtained carbapenam 11 with (5R,6S) configuration at the azetidinone ring was subsequently subjected to oxidation/deprotection/oxidation reaction sequence to afford the beta-keto ester 20, which was directly transformed into N,O-protected methyl ester of thienamycin. PMID- 26506860 TI - Pyrrocidine A, a metabolite of endophytic fungi, has a potent apoptosis-inducing activity against HL60 cells through caspase activation via the Michael addition. AB - Pyrrocidine A is a known antimicrobial compound produced by endophytic fungi and has a unique 13-membered macrocyclic alkaloid structure with an alpha,beta unsaturated carbonyl group. We have previously reported that pyrrocidine A shows potent cytotoxicity against human acute promyelocytic leukemia HL60 cells, and the activity is 70-fold higher than that of pyrrocidine B which is the analog lacking the alpha,beta-unsaturated carbonyl group. Pyrrocidine A induced nuclear condensation, DNA fragmentation and caspase activation in HL60 cells. Since the DNA fragmentation was suppressed by pretreatment with the pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (z-VAD-fmk), caspase mediated apoptosis contributes to pyrrocidine A-induced cytotoxicity. JFCR39 human cancer cells panel indicated that the mechanism of action of pyrrocidine A is different from other clinical anticancer drugs, and this compound broadly inhibited the growth of various cancer cell lines. The apoptosis induction by pyrrocidine A was suppressed by both N-acetyl-l-cysteine (NAC) and glutathione, both of which are thiol-containing antioxidants. Furthermore, pyrrocidine A directly bound to N-acetyl-l-cysteine methyl ester (NACM) through the Michael type addition at the alpha,beta-unsaturated carbonyl group and was detected by HPLC and liquid chromatography-ESI-tandem MS (LC-ESI-MS/MS) analyses. This indicates that this moiety is crucial for the potent apoptosis-inducing activity of pyrrocidine A. PMID- 26506861 TI - A classical case of the Gasul phenomenon. AB - This case demonstrates the development of secondary infundibular stenosis in a 10 year-old male child with documented large non-restrictive perimembranous ventricular septal defect in infancy - the classical Gasul phenomenon. PMID- 26506862 TI - Exercise intervention in people with cancer undergoing neoadjuvant cancer treatment and surgery: A systematic review. AB - BACKGROUND: Neoadjuvant cancer treatment decreases physical fitness. Low levels of physical fitness are associated with poor surgical outcome. Exercise training can stimulate skeletal muscle adaptations, such as increased mitochondrial content and improved oxygen uptake capacity that may contribute to improving physical fitness. This systematic review evaluates the evidence in support of exercise training in people with cancer undergoing the "dual hit" of neoadjuvant cancer treatment and surgery. METHODS: We conducted a systematic database search of Embase Ovid, Ovid Medline without Revisions, SPORTDiscus, Web of Science, Cochrane Central Register of Controlled Trials Library and ClinicalTrials.gov to identify trials addressing the effect of exercise training in people scheduled for neoadjuvant cancer treatment and surgery. Data extraction and analysis were based on a pre-defined plan. RESULTS: The database search yielded 6489 candidate abstracts. Ninety-four references included the required terms. Four studies were eligible for inclusion (breast cancer, locally advanced rectal cancer). All studies reported that exercise training was safe and feasible and that adherence rates were acceptable (66-96%). In-hospital exercise training improves physical fitness however the impact on HRQoL and other clinical important outcomes was uncertain. CONCLUSION: This is the first systematic review of the effects of exercise training in people scheduled for "dual-hit" treatment. This evidence synthesis indicates that this approach is safe and feasible but that there are insufficient controlled trials in this area to draw reliable conclusions about the efficacy of such an intervention, the optimal characteristics of the intervention, or the impact on clinical or patient reported outcomes. PMID- 26506863 TI - Watch and wait policy after preoperative radiotherapy for rectal cancer; management of residual lesions that appear clinically benign. AB - BACKGROUND: During an ongoing phase II observational study on watch and wait policy in rectal cancer, a substantial number of patients presented residual lesion after radiotherapy with a clinical benign appearance. This article aims to discuss the clinical significance of such findings. MATERIALS AND METHODS: Main entry criteria were age >=70 years and small tumour (<=5 cm and <=60% of circumferential involvement) located in the low rectum. Patients received chemoradiation (50 Gy, 2 Gy per fraction concomitantly with a 5-Fu bolus and leucovorin) or 5 * 5 Gy if considered unfit for chemotherapy. Patients with clinical complete response (cCR) were observed. Those with persistent tumours underwent transanal endoscopic microsurgery [TEM] if the baseline tumour was <=3 cm and cN0 or total mesorectal excision. RESULTS: The watch and wait procedure was used in 11 out of the total 35 patients (31%) with a cCR; 17 patients (49%) with residual tumours that appeared clinically malignant were referred for TEM or abdominal surgery. In the remaining seven (20%), the residual tumour clinically appeared benign. Of these, there were two invasive cancers, four high-grade dysplasias and one low-grade dysplasia. The five patients with dysplasia, underwent local lesion resection without recurrence within a median of 11 months follow-up. CONCLUSIONS: The majority of lesions that appeared clinically benign after radio(chemo)therapy were also benign on pathological examination. Thus, local excision of such lesions should be considered. PMID- 26506864 TI - How We Engage Graduating Professional Students in Interprofessional Patient Safety. AB - PROBLEM: Interprofessional curricula on patient safety do not acknowledge the culture and vulnerabilities of the student experience and often do not engage students. METHODS: We describe a patient safety collaboration between graduating nursing and medical students during their Capstone courses that fostered conversations about the similarities and differences in professional school experiences around patient safety. Students wrote reflections about an unanticipated patient outcome. Qualitative content analysis was used to characterize themes within student reflections, and to create audience response system questions to highlight differences in each profession's reflections and to facilitate discussion about those differences during the collaboration. FINDINGS: Medical students identified events in which perceived patient outcomes were worse than events identified by nursing students. Nursing students identified more near miss events. Nursing students positively impacted the event and attributed action to the presence of a clinical instructor and personal responsibility for patient care. Medical students described themselves as "only a witness" and attributed inaction to hierarchy and concern about grades. CONCLUSIONS: Students felt the session would change their future attitudes and behaviors. Stevenson Chudgar Molloy Phillips Engle Clay. PMID- 26506865 TI - Density dependent composition of InAs quantum dots extracted from grazing incidence x-ray diffraction measurements. AB - Epitaxial InAs quantum dots grown on GaAs substrate are being used in several applications ranging from quantum communications to solar cells. The growth mechanism of these dots also helps us to explore fundamental aspects of self organized processes. Here we show that composition and strain profile of the quantum dots can be tuned by controlling in-plane density of the dots over the substrate with the help of substrate-temperature profile. The compositional profile extracted from grazing incidence x-ray measurements show substantial amount of inter-diffusion of Ga and In within the QD as a function of height in the low-density region giving rise to higher variation of lattice parameters. The QDs grown with high in-plane density show much less spread in lattice parameter giving almost flat density of In over the entire height of an average QD and much narrower photoluminescence (PL) line. The results have been verified with three different amounts of In deposition giving systematic variation of the In composition as a function of average quantum dot height and average energy of PL emission. PMID- 26506866 TI - Laryngeal cancer incidence and mortality in China, 2010. AB - PURPOSE: To analyze the incidence and mortality of laryngeal cancer in cancer registration areas of China in 2010. MATERIALS AND METHODS: Until June 1, 2013, 219 population-based cancer registries submitted data of 2010 to the National Central Cancer Registry of China covering about 207,229,403 population, and 120 cancer registries were selected after quality evaluation for this analysis. Laryngeal cancer cases were selected from the database according to International Classification of Diseases 10th Revision coded as "C32." We calculated the crude incidence and mortality rates of laryngeal cancer by sex, age, and location (urban/rural). The China population in 2000 and Segi's population were used as standardized populations for the calculation of age-standardized rates. RESULTS: In 2010, it was estimated that there were 20,272 new cases diagnosed as laryngeal cancer in China, including 17,703 males and 2569 females. The crude incidence rate of laryngeal cancer was 1.54/100,000 in 2010, accounting for 0.66% of overall new cancer cases. The age-standardized by China population (ASRcn) and by world population (ASRwld) were 1.18/100,000 and 1.20/100,000, respectively. Cumulative rate (0-74 years old) and truncated age-standardized rate (35-64 years old) were 0.15% and 1.98/100,000, respectively. Moreover, it was estimated that there were 11 914 cases died in laryngeal cancer in China, including 10,038 males and 1876 females. The crude mortality rate was 0.91/100,000, accounting for 0.61% of overall cancer deaths. The ASRcn and ASRwld were 0.68/100,000 and 0.69/100,000, respectively. Cumulative rate and truncated age-standardized rates were 0.08% and 0.88/100,000, respectively. CONCLUSIONS: Both incidence and mortality of laryngeal cancer in China were still low in 2010. PMID- 26506867 TI - Oral cavity cancer incidence and mortality in China, 2010. AB - PURPOSE: To analyze the incidence and mortality of oral cavity cancer in the cancer registration areas of China in 2010. MATERIALS AND METHODS: Until June 1, 2013, 219 population-based cancer registries submitted the data of 2010 to the National Central Cancer Registry of China covering about 207,229,403 population, and 120 cancer registries were selected after the quality evaluation for this analysis. Oral cavity cancer cases were selected from the database according to the International Classification of Diseases-10 coded as "C00-C10, C11-C12." We calculated the crude incidence and mortality rates of oral cavity cancer by sex, age, and location (urban/rural). The China population in 2000 and Segi's population were used as standardized populations for the calculation of age standardized rates. RESULTS: In 2010, it was estimated that there were 34,319 new cases diagnosed as oral cavity cancer in China, including 23,096 males and 11,223 females. The crude incidence rate of oral cavity cancer was 2.61/100,000 in 2010, accounting for 1.11% of overall new cancer cases, ranked the 20th in all cancer sites. The age standardized by China population (ASRcn) and by world population (ASRwld) were 2.06/100,000 and 2.02/100,000, respectively. Cumulative rate (0-74 years old) and truncated age standardized rate (35-64 years old) were 0.23% and 3.82/100 000, respectively. In 2010, it was estimated that there were 14,652 cases died in oral cavity cancer in China, including 10,363 males and 4289 females. The crude mortality rate of oral cavity cancer was 1.11/100,000 in 2010, accounting for 0.75% of overall cancer deaths, ranked the 20th in all cancer sites. The ASRcn and ASRwld were 0.86/100,000 and 0.85/100,000, respectively. Cumulative rate and truncated age standardized rates were 0.10% and 1.30/100,000, respectively. CONCLUSIONS: Both the incidence and mortality of oral cavity cancer in China were still low in 2010. Primary prevention such as smoking control, reducing alcohol consumption, changing the habit of chewing betel nut, and chemical prevention should be enhanced in the general population. PMID- 26506868 TI - Incidence and mortality of laryngeal cancer in Zhejiang cancer registry, 2000 2011. AB - BACKGROUND: Laryngeal cancer is the one of the most prevalent cancer of the upper respiratory tract. Aiming to get a better understanding of the epidemiological characteristics and trends of laryngeal cancer in Zhejiang cancer registry in China during 2000-2011, we used the standardized quality control and statistical methods to analyze the incidence and mortality that were vital for making decision about laryngeal cancer prevention and control. MATERIALS AND METHODS: Comparably high-quality data from eight population-based cancer registries in Zhejiang from 2000 to 2011 were qualified for analysis. The pooled data were stratified by area, sex, and age group. All incidence and mortality rates were age-standardized to the 2000 Chinese standard population and Segi's population, which were expressed per 100,000 populations. Average annual percent changes (AAPCs) and 95% confidence intervals of laryngeal cancer incidence and mortality were calculated for the temporal trends. The logarithmic trend line was also drawn to reflect the time trends of incidence and mortality. RESULTS: During the 12 years, the 8 cancer registries covered a total of 81,758,277 person-year population (65,500,842 in urban and 16,257,435 in rural areas) including 41,315,911 person-year males and 40,442,366 person-year females. The age standardized incidence rates were 1.10/10(5) by Chinese population and 1.12/10(5) by world population, respectively. The incidence of laryngeal cancer was relatively low in subjects under 44 years old. Then, it increased sharply after 45 years old and finally reached the peak in subjects of 75-79 years old. The age standardized mortality rates of the Chinese population and world population were 0.28/10(5) and 0.35/10(5), respectively. The mortality of laryngeal cancer was at a low level in subjects under 49 years old. The rate dramatically increased in subjects over 50 years old, and then peaked in the age group of 80-84 years. The crude incidence of laryngeal cancer in Zhejiang cancer registration areas in 2000 was approximately 1.39/10(5), and it reached 1.78/10(5) in 2011, with the AAPC of 2.47%; the temporal trend line indicates that the incidence remained steady during the 12 years. The crude mortality of laryngeal cancer in Zhejiang registration areas in 2000 was about 0.30/10(5) and increased to 0.66/10(5), with the AAPC of 4.24% which showed no statistical significance; the temporal trend line indicates that mortality was going up to a certain extent, but not evident. CONCLUSIONS: Laryngeal cancer significantly influenced the quality of life for the patients. The comprehensive measures should be carried out to prevent the upward trend of laryngeal cancer. PMID- 26506869 TI - Squamous cell carcinoma of cervical lymph nodes from an unknown primary site: The impact of neck dissection. AB - OBJECTIVE: To investigate the treatment strategies of squamous cell carcinoma of cervical lymph nodes from an unknown primary site (SCCUP) and the value of neck dissection (ND). MATERIALS AND METHODS: The study included 133 patients referred to the Zhejiang Cancer Hospital from 2001 to 2012, with 109 males and 24 females. Distribution of patients by N status was as follows: N1 - 14 cases; N2a - 21 cases; N2b - 78 cases; N2c - 7 cases; and N3 - 13 cases. 104 patients underwent surgeries of ND while 29 patients underwent nonsurgical treatment. Among 104 patients, 24 underwent classic radical ND, 16 modified ND, 53 selective ND, and 11 extended ND. The selection of surgical strategy was determined by the extent and location of disease. According to the range of ND, 50 patients underwent ND for Levels I-V, 46 for Levels II-V, 4 for Levels I-III, 3 for Levels II-VI, and 1 for Levels I-VI. The data were analyzed with SPSS version 16.0. The differences between groups were calculated by chi2 tests. The actual overall survival (OS) rates were calculated by the Kaplan-Meier method. Different factors affecting the OS were determined by the log-rank test on univariate analysis. Cox regression was used to evaluate the multivariate analysis. RESULTS: The 5-year OS rate of the whole cohort was 67.1%; and the median survival time was 70.0 months. The 5 year OS of ND group and of the non-ND group were 71.3% and 53.2%, respectively (P = 0.061). Cox analysis indicated that N stage (P = 0.000), bilateral neck metastasis (P = 0.001), extracapsular spread (ES) (P = 0.016), and ND (P = 0.028) were independent prognostic factors for the OS of SCCUP. 25 patients (18.8%) had neck recurrence or residue. The locoregional failure rate of ND group and of the non-ND group were 13.5% and 37.9%, respectively (P = 0.003). Logistic regression analysis indicated that higher N stage was the main risk factor for locoregional failure (P = 0.015). CONCLUSION: N stage, bilateral neck metastasis, ES, and ND were the main factors for the survival rate of SCCUP. N3 stage was the independent risk factor for locoregional failure. ND could significantly increase the locoregional control and may benefit the survival rate. PMID- 26506870 TI - Lower serum levels of bilirubin in the newly diagnosed lung cancer patients: A case-control study in China. AB - PURPOSE: A few prospective studies demonstrated that bilirubin levels were inversely associated with the risk of lung cancer. However, the retrospective study about the relationship between bilirubin levels and lung cancer in China was not available. So, we want to know whether there has a difference in serum bilirubin concentrations between normal people and lung cancer patients. MATERIALS AND METHODS: Using a case-control study, we investigated the bilirubin levels in 317 patients with lung cancer and 317 age-, sex-matched controls from Zhejiang Cancer Hospital. Furthermore, we analyzed the associations between serum bilirubin expressions and baseline clinical features of lung cancer patients using a Wilcoxon rank sum test. RESULTS: Bilirubin levels, including total bilirubin, direct bilirubin, and indirect bilirubin, were significantly lower in human lung cancer serum relative to normal control (P < 0.001), and the older (> 50 years) had higher bilirubin levels compared with the younger (27-50 years) in lung cancer group. Besides, the duration of smoking was negatively related to bilirubin levels, but they did not reach statistical significance except for indirect bilirubin (P = 0.041). However, there was no difference in bilirubin levels between small cell lung cancer (SCLC) and non-SCLC (NSCLC), and we did not find that the bilirubin levels were correlated with sex, drinking status in patients of lung cancer. CONCLUSION: Serum total bilirubin, indirect bilirubin, and direct bilirubin levels of the patients with lung cancer were all significantly lower than those of control group (P < 0.001). Lower levels of bilirubin may be a risk factor for lung cancer, and it could serve as a potential screening biomarker for lung cancer. Large-scale investigations and additional improvements are urgently needed to demonstrate the mechanism and molecular pathway in order to achieve the clinical utility in the future. PMID- 26506871 TI - Transoral laser microsurgery for recurrent laryngeal carcinoma after primary treatment: A systematic review and meta-analysis. AB - PURPOSE: To evaluate the efficacy and oncologic outcomes of transoral laser microsurgery (TLM) for recurrent laryngeal carcinoma after previous treatment. MATERIALS AND METHODS: A systematic search in PubMed was performed using mesh word for "laryngeal cancer," crossed with "recurrent," and "TLM." The primary endpoints, including overall survival (OS) rate, local control rate, and disease specific survival (DSS) were summarized using RevMan software. Adverse events and complications were recorded if reported. RESULTS: The pooled odds ratios (ORs) for main outcomes, including local control, 5-year OS, and DSS were 3.08 (95% confidential indexed [95% CI], 1.88-5.05), 2.29 (95% CI, 1.42-3.67), and 5.05 (95% CI, 2.75-9.27), respectively. The pooled OR for functional outcome, larynx preservation, was 3.82 (95% CI, 2.46-5.94), whereas the pooled risk difference of local recurrence was 45% (95% CI, 26-64%). CONCLUSIONS: It seems that TLM is an effective option for recurrent laryngeal cancer with regard to the high incidence of OS, local control, and especially organ preservation. However, more prospective studies are needed to confirm its efficiency. PMID- 26506872 TI - Long-term outcomes and failure patterns of patients with nasopharyngeal carcinoma staged by magnetic resonance imaging in intensity-modulated radiotherapy era: The Zhejiang Cancer Hospital's experience. AB - PURPOSE: To study and report the clinical outcomes and patterns of failure in the patients with nasopharyngeal carcinoma (NPC) staged by magnetic resonance imaging (MRI) and treated with intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: From January 2007 to December 2011, 720 NPC patients without metastasis staged by MRI were treated with definitive IMRT at Zhejiang Cancer Hospital. The IMRT prescribed dose was 69 Gy to planning target volume (PTV) of gross disease in nasopharynx and 67.5 Gy to PTV of positive lymph nodes in 30 fractions, high risk, and low risk region PTV was 60 and 54 Gy in 30 fractions, respectively. The treatment outcomes and patterns of failure were observed. RESULTS: Using the 7th edition of the American Joint Committee on Cancer staging system for NPC, the proportions of the 720 patients with Stages I, II, III, and IVa-b disease were 2.1% (15/720), 17.8% (128/720), 51.7% (372/720), and 28.5% (205/720), respectively. After the median follow-up period of 48 months (range: 3-89 months), a total of 146/720 (20.3%) patients had experienced failure: 37 (5.1%) at primary sites, 17 (2.4%) at regional sites, 79 (11.0%) at distant sites, and 13 (1.8%) at multiple sites. The 5-year overall survival, cancer-specific survival, disease-free survival, local relapse-free survival (LRFS), regional relapse-free survival, and distant metastasis (DM) free survival were 86.1%, 88.1%, 76.6%, 90.8%, 93.6%, and 87.2%, respectively. LRFS of T1 to T3 was all >90% and has no significant difference. In addition to N stage, T category, and neoadjuvant chemotherapy were independent predictors for DM in multivariate analysis. CONCLUSION: Our long-term outcome of large NPC series supports the effectiveness of IMRT for excellent local-regional control though up to 20% patients would develop DM, which becomes the main pattern of failure. T4 disease remained difficult to be cured not only for local recurrence but distant failure. A taxane-based combination chemotherapy might be useful to reduce DM in the induction setting and worth further studying. PMID- 26506873 TI - Relationship between toxicities and clinical benefits of newly approved tyrosine kinase inhibitors in thyroid cancer: A meta-analysis of literature. AB - BACKGROUND: The aim of this meta-analysis was to analyze the relationship of toxicities and clinical benefits of newly approved lenvatinib and sorafenib to thyroid cancer (TC) in patients. MATERIALS AND METHODS: Three major medical databases, PubMed, EMBASE, and ISI web of science were systematically searched to identify all studies on lenvatinib and sorafenib in TC. A meta-analysis was performed to clarify the toxicities and clinical benefits of newly Food and Drug Administration (FDA) approved lenvatinib and sorafenib to thyroid cancer. RESULTS: Ten studies (n = 749) were included which evaluated the toxicities and clinical benefits of newly FDA approved lenvatinib and sorafenib to thyroid cancer. 537 (71.7%) of the 749 patients bearing TC (radioiodine-refractory, differentiated thyroid cancer) clinical benefits from lenvatinib or sorafenib, and serious adverse events occurred in 430 (57.4%) of the 749 patients ([risk ratio (RR) = 1.27, 95% confidence interval (CI) = (1.05-1.53), P = 0.01]). While 31 (4.1%) of the 749 patients died due to various reasons, that mainly accounts for severe bleeding events and cardiac arrest. The clinical benefit is obvious compared to deaths ([RR = 17.06, 95% CI = (12.08-24.11), P < 0.001]). Subgroup analyses were then conducted according to cancer type (radioiodine-refractory thyroid cancer [RR-TC] and TC). We found that in treating RR-TC, the clinical benefits are close to toxicities. While in treating TC, the clinical benefits are better than toxicities. And we found that sorafenib and lenvatinib might be proper to deal with TC (benefits rate 79.7%) compared to RR-TC (benefits rate 69.5%), taking consider of toxicities. CONCLUSIONS: Lenvatinib and sorafenib are useful in the treatment of TC. Although, their toxicities remain high (57.4%) in the patients, the death rate is controlled (4.1%). Take consider of toxicities, lenvatinib, and sorafenib are more useful for TC compared to RR-TC. PMID- 26506874 TI - Meta-analysis of concurrent chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma. AB - BACKGROUND: With radiotherapy (RT) alone, the five-year overall survival (OS) rate for advanced nasopharyngeal carcinoma (NPC) can only reach 40%, the ratio of distant metastasis (DM) is 36-40%. This meta-analysis was performed to compare the clinical efficacy of concurrent chemoradiotherapy (CCRT) with RT alone in the treatment of locoregionally advanced NPC. METHODS: The related literature were retrieved and reviewed by two independent investigators from the followed electronic databases: Review manager 5.3 software (Cochrane Collaboration, London, United Kingdom) was applied for statistical analysis. RESULTS: A total of 16 trials with 2576 patients were recruited according to the criterion. The odds ratios of 3 and 5 years OS was 0.53 (95% confidence interval [95% CI]: 0.44-0.64) and 0.58 (95% CI: 0.48-0.71), which confirmed the significant improvement of CCRT compared with RT alone (P < 0.001). CCRT also reduced the risk of locoregional control failure and DM in locoregionally advanced NPC patients. CONCLUSIONS: The results suggested that CCRT was more beneficial when compared with RT alone in locoregionally advanced NPC patients. Further study is needed to perform to confirm this effect. PMID- 26506875 TI - Radiotherapy with temozolomide provides better survival in the newly diagnosed glioblastoma multiforme: A meta-analysis. AB - BACKGROUND: The optimal treatment for patients with newly diagnosed glioblastoma multiforme (GBM) remains controversial. The purpose of this meta-analysis was to systematically evaluate radiotherapy/temozolomide (TMZ) versus radiotherapy for treating newly diagnosed GBM. MATERIALS AND METHODS: Six electronic databases (PubMed, EMBASE, MEDLINE, Web of Science, Cochrane Library, and CNKI) were searched for relevant publications up to November 05, 2014. RevMan version 5.2 software was used for statistical analysis. RESULTS: A total of 9 studies were identified in this analyses, which included 986 patients. The summary risk ratio (RR) for overall survival and the progression-free survival (PFS) was the measure of interest. Results revealed that the addition of TMZ to radiotherapy resulted in a statistically significant survival benefit in poor prognosis patients with newly diagnosed glioblastoma (RR = 2.93 [95% confidence interval (CI) 2.29, 3.75], P < 0.00001). Moreover, radiotherapy plus TMZ was more beneficial than radiotherapy alone in improving PFS (RR = 3.52, [95% CI 2.53, 4.89], P < 0.00001). However, certain grade 3-4 hematological toxicities were significantly more common with TMZ. CONCLUSIONS: This meta-analysis suggests that radiotherapy/TMZ provides better survival than radiotherapy alone in treating GBM. PMID- 26506876 TI - Dua-energy virtual noncontrast imaging in diagnosis of cervical metastasis lymph nodes. AB - OBJECTIVE: The aim of this study was to evaluate the clinical value of dua-energy virtual noncontrast imaging (DVNCT) in the diagnosis of cervical metastasis lymph nodes. MATERIALS AND METHODS: From February 2014 to January 2015, 41 patients with 98 enlarged cervical lymph nodes were recruited in this study. All the enlarged lymph nodes were pathology confirmed. The patients received DVNCT and conventional noncontrast scan. The difference of average computed tomography (CT) value, signal to noise ratio, a contrast to noise ratio, image subjective assessment, and lesion detectability between virtual noncontrast imaging and conventional noncontrast scan were compared. The radiation dose of virtual noncontrast imaging and real noncontrast imaging of cervical lymph node were also compared. The diagnostic sensitivity and specificity for DVNCT was also evaluated. RESULTS: No statistical difference of average CT value, signal to noise ratio, a contrast to noise ratio, image subjective assessment, and radiation dosage between virtual noncontrast imaging and conventional noncontrast scan were found. However, the radiation dosage of DVNCT was significant lower than that of conventional noncontrast scan (P < 0.05). The diagnostic sensitivity and specificity for malignant metastasis lymph node were 88.6% and 70.3% by DVNCT. CONCLUSION: DVNCT combined with contrast imaging can provide clear images in the diagnosis of enlarged cervical lymph nodes and reduce radiation dosage. PMID- 26506877 TI - A meta-analysis of neoadjuvant chemotherapy plus radiation in the treatment of locally advanced nasopharyngeal carcinoma. AB - OBJECTIVE: We perform this meta-analysis was to evaluate the efficacy of neoadjuvant chemotherapy followed by radiation in the treatment of locally advanced nasopharyngeal carcinoma. MATERIALS AND METHODS: We searched the database of Medline and Wanfang to screen and included the prospective, randomized controlled trials of neoadjuvant chemotherapy plus radiation versus radiotherapy in the treatment of locally advanced nasopharyngeal carcinoma. The pooled 5-year overall survival, 5 years disease free survival, recurrence rate, and metastasis rate were calculated by Stata version 11.0 statistical software. RESULTS: Five prospective clinical studies were included in this meta-analysis. The total number of cases included in this study was 1277. The pooled 5 years overall survival and 5 years disease free survival were not statistical different between the neoadjuvant chemotherapy plus radiation group and radiotherapy group, respectively (P > 0.05). But the recurrence rate (odds ratio [OR] = 0.65, P < 0.05) and metastasis rate (OR = 0.61, P < 0.05) were significantly lower in the neoadjuvant chemotherapy plus radiation group compared to radiotherapy group. CONCLUSION: Neoadjuvant chemotherapy followed by radiation can decrease the risk of recurrence and metastasis but not improve the 5 years overall survival and 5 years disease free survival compared to radiotherapy alone in the patients with locally advanced nasopharyngeal carcinoma. PMID- 26506878 TI - Serum level of interleukin-17 and interleukin-35 as a biomarker for diagnosis of thyroid cancer. AB - OBJECTIVE: The aim of this study was to evaluate the serum level of interleukin 17 (IL-17) and IL-35 in thyroid cancer patients and its diagnostic value as a biomarker. METHODS: Sixty-one thyroid carcinoma patients were recruited from January 2012 to December 2014 in our hospital. Of the 61 included cases, 42 subjects were pathology confirmed with thyroid cancer and other 19 cases were diagnosed with thyroid adenoma. The serum level of IL-17 and IL-35 were compared between the two groups. The diagnosed sensitivity, specificity, and receiver operating characteristic curve (ROC) for serum IL-17 and IL-35 were evaluated according to Bayes theorem. RESULTS: The serum level of IL-17 were 16.3 +/- 4.1 pg/ml and 9.4 +/- 3.6 pg/ml for the thyroid cancer and thyroid adenoma patients respectively, with statistical difference (P < 0.05). The serum level of IL-35 were 48.8 +/- 7.8 pg/ml and 62.3 +/- 9.6 pg/ml for the thyroid cancer and thyroid adenoma patients, respectively, which indicated that the thyroid adenoma group was much higher with statistical difference (P < 0.05). The diagnosis sensitivity and specificity for serum IL-17 were 71.4% and 80.2% at the cutoff value of 12.1 pg/ml with the area under the ROC of 0.8239. The diagnosis sensitivity and specificity for serum IL-35 were 76.8% and 82.4% at the cutoff value of 57.6 pg/ml with the area under the ROC of 0.8722. CONCLUSION: The serum level of IL-17 and IL-35 was significantly different between thyroid cancer and thyroid adenoma patients, which could be a potential biomarker for the diagnosis of malignant thyroid tumor. PMID- 26506879 TI - Genome-wide methylation profiling reveals new biomarkers for prognosis prediction of glioblastoma. AB - OBJECTIVE: To identify a specific hypermethylated molecular biomarker for human malignant glioblastoma prognosis. MATERIALS AND METHODS: Genome-wide methylation profiling was performed on 33 tumors and 3 normal glioblastoma samples using the Infinium HumanMethylation450 microarray. Cluster analysis was carried out in these samples according to the differentiated methylated genes. DNA methylation of selected significant candidates was subsequently validated to analyze the association of methylation status of these genes with overall survival as well as gene expression. RESULTS: We found 217 hypermethylated CpG sites located in 210 respective genes with significant differences in short- and long-term survival (STS and LTS) samples (P < 0.01). Cluster analysis revealed fine clustering of genes with LTS and STS. Of these, we selected 10 most hypermethylated genes, including IL11, RRAD, MS4A6A, SNAPC2, ALDH1A3, ADCY1, MMS19L, NDUFB8, POMC, and THSD4, to perform cluster analysis. It came out with the same fine classification and with survival time of these patients. The top ranking genes were further examined to compare their methylation status with the overall survival rate of patients, as well as with gene expression levels. CONCLUSION: We obtained a featured global profiling of DNA methylation in glioblastoma. Our findings strongly indicate that epigenetic silencing of IL11, RRAD, MS4A6A, SNAPC2, and ALDH1A3 are common events in glioblastoma which could be used as novel biomarkers for the prognosis of glioblastoma. PMID- 26506880 TI - MicoRNA-451 is a novel tumor suppressor via targeting c-myc in head and neck squamous cell carcinomas. AB - OBJECTIVE: Head and neck squamous cell carcinoma (HNSCC) represents as a common malignancy with increasing incidence in the worldwide. The fact of its poor survival rate urgently requires developing efficient predictive biomarkers for clinical use. MicroRNAs (miRNAs) recently represent as a novel direction for early diagnosis and prognosis prediction in HNSCC therapy. In this study, we comprehensively investigated the function and putative target of miRNA-451 in vitro. METHODS: The expression of miRNA-451 was detected in HNSCC tissues and cell lines by real-time PCR. Forced expression or inhibition of miRNA-451 was done by transient transfection of mimics or inhibitor of miRNA-451 into indicated cells, respectively. Cell proliferation was evaluated by cell counting and crystal staining. Afterwards, we perform western blot to verify the expression of the miRNA-451 predicted target, c-myc, after miRNA-451 was overexpressed. RESULTS: We showed that miRNA-451 was downregulated in paired HNSCC tissues as well as in cell lines. And overexpression of miRNA-451 in cells with low endogenous expression of miRNA-451 accelerated proliferation. To the contrast, knockdown of miRNA-451 in cells with high levels of miRNA-451 significantly reduced cell growth rate. Furthermore, we used bioinformatics and cellular methods to predict and prove that c-myc was targeted by miRNA-451, since forced expression of miRNA-451 leaded to decreased c-myc protein expression in HNSCC cells. CONCLUSION: Our findings identify miRNA-451 as a potential biomarker and suggest a key role of miRNA-451-c-myc pathway in HNSCC cell transformation, which could represent a novel therapeutic strategy in HNSCC treatment. PMID- 26506881 TI - Metronidazole amino acidum natrium combined with radiation in the treatment of nasopharyngeal carcinoma: A meta-analysis based on randomized controlled trials. AB - OBJECTIVE: We performed this meta-analysis to assess the metronidazole amino acidum natrium combined with radiation in the treatment of nasopharyngeal carcinoma. MATERIALS AND METHODS: Two reviewers independently reviewed the databases of PubMed and CNKI. The prospective, randomized, controlled trials of metronidazole amino acidum natrium combined with radiation versus radiotherapy alone in the treatment of nasopharyngeal carcinoma were included in this meta analysis. The objective response rate (RR) of 1-, 3-, and 5-year survival rates were pooled by statistical software. The publication bias was evaluated by Begg's funnel plot. RESULTS: Sixteen prospective, randomized, controlled trials were finally included in this meta-analysis. The quality assessment showed that the method's quality was relatively poor. The pooled results showed that the metronidazole amino acidum natrium combined with radiation can significantly improve the objective RR for the primary lesion (RR = 1.37, 95% confidence interval [CI]: 1.23-1.53, P < 0.05) and neck metastasis lesion (RR = 1.36, 95% CI: 1.25-1.49, P < 0.05). For survival analysis, the combined treatment can significantly improve the 1-year survival (RR = 1.57, 95% CI: 1.28-1.93, P < 0.05), 3-year survival (RR = 1.23, 95% CI: 1.06-1.41, P < 0.05), and 5-year survival rates (RR = 1.27, 95% CI: 1.05-1.53, P < 0.05). CONCLUSION: Metronidazole amino acidum natrium combined with radiation can improve the objective RR and long-term survival compared to radiation therapy alone in the treatment of nasopharyngeal carcinoma. PMID- 26506882 TI - Clinical and prognostic analysis in 32 pediatric nasopharyngeal carcinoma. AB - OBJECTIVES: To analyze the clinical outcome and prognostic factors of pediatric nasopharyngeal carcinomas, provide the basis for the rational treatment, and improve the cure rate. MATERIALS AND METHODS: Thirty-two pediatric nasopharyngeal carcinoma patients with pathologically confirmed diagnosis and aged from 11 to 18 years old were retrospectively analyzed. All patients received intensity modulated radiation therapy, dose of GTVnx 6400-7425 cGy, PGTVnx 6400-7050 cGy, PTV 15,400-6000 cGy, PTV 25,000-5490 cGy, and GTVnd 6000-6996 cGy were given. Among these patients, 29 received various chemotherapies. The Kaplan-Meier test and log-rank test of SPSS 17.0 statistic software package were used to calculate survival rate, compare and analyze the survival rates of each group. Cox model was used to analyzing the prognosis factors. RESULTS: In this study, the median survival time was 44.5 months, and the median follow-up time is 62.5 months. The 1-, 3-, and 5-year overall survival rates were 100.0%, 93.2%, 85.7%, respectively, in stage III, and 94.8%, 88.3%, and 64.7% in stage IV. All patients 1-, 3-, and 5-year overall survival rates were 97.2%, 90.5%, and 74.2%. Univariate analysis resulted that N stage (P = 0.043), chemotherapy (P = 0.003) and the radiotherapy dose (P = 0.028) were significant factors for survival. On multivariate analysis, only the N stage influence survival. CONCLUSIONS: In pediatric nasopharyngeal carcinoma, the more important prognostic factors are N stage, chemotherapy, radiotherapy dose. Patients with N2-3 should be treated with combined chemotherapy and radiotherapy. PMID- 26506883 TI - Administration of perivascular cyanoacrylate for the prevention of cellular damage in saphenous vein grafts: an experimental model. AB - OBJECTIVE: The saphenous vein is the most commonly used graft in coronary artery bypass surgery, since no suitable arterial graft is available. However, the frequency of late graft failure is a cause for research into graft protection. The objective of this study was to investigate the effect of synthetic adhesive cyanoacrylate administration on the saphenous vein graft for preventing vascular damage due to internal pressure on the graft. METHODS: In this study we enrolled 20 volunteer subjects who had undergone coronary artery bypass surgery and who had excess saphenous vein grafts. Perivascular cyanoacrylate was administered to one of two saphenous vein grafts explanted from each patient. The other saphenous vein graft from each patient was not treated and was used as the control. A model of the arterial system was created using a saphenous vein cardiopulmonary bypass system. Circulation was maintained at 120 mmHg for 45 minutes. Afterwards, the grafts were subjected to histopathological examination. RESULTS: The cyanoacrylate group of grafts did not develop severe vascular damage compared with many instances of moderate and severe damage due to compression in the control group of grafts (p = 0.003). CONCLUSION: Perivascular administration of cyanoacrylate appeared to be successful in the prevention of early saphenous vein graft injury. No in vivo study has been performed to date to assess endothelial damage in the saphenous vein, in order to demonstrate the long-term effect of cyanoacrylate. Further investigations are needed in this regard. PMID- 26506884 TI - Blood in the T-tube as a side effect of hemosuccus pancreaticus. AB - This study examined a 60-year-old female patient with chronic pancreatitis and hemosuccus pancreaticus (HP), who was once misdiagnosed with biliary bleeding because of choledocholithiasis and T-tube drainage. Bleeding from the T-tube was demonstrated as a side effect of HP. The difficulty in diagnosing this case was attributed to the absence of pseudocysts or obvious aneurysms on CT images. Conclusively, for patients with indirect signs of biliary bleeding, such as bleeding from a T-tube, the possibility of the symptoms being side effects of pancreatic bleeding should be considered. PMID- 26506885 TI - GNAS and KRAS mutational analyses of intraductal papillary neoplasms of the pancreas and bile duct developing in the same individual: A case report. AB - Intraductal papillary mucinous neoplasm (IPMN) of the pancreas and intraductal papillary neoplasm of the bile duct (IPNB) are considered as counterparts of each other, and it is suggested that these two entities have similar molecular alteration pathways. However, the occurrence of IPMN of the pancreas and IPNB in the same patient is rare. We report a surgical case of a 69-year-old woman who developed invasive IPMN of the pancreas and underwent pancreatectomy, 6 months after hepatic resection of invasive IPNB. Molecular analysis revealed GNAS/KRAS mutation in both invasive IPMN of the pancreas and IPNB. This is believed to be the first case report investigating GNAS/KRAS mutational status in both IPMN of the pancreas and IPNB developing in the same patient, and these two entities may show similar molecular alternations. PMID- 26506886 TI - Interactions of a biocompatible water-soluble anthracenyl polymer derivative with double-stranded DNA. AB - We have studied the interaction of a polymeric water soluble anthracenyl derivative () with salmon testes DNA. The results from UV-Vis, fluorescence, Fourier transform infrared (FT-IR) and circular dichroism spectroscopies indicate that the groove binding process regulates the interaction between and DNA. The binding constants, calculated by absorption spectroscopy at 298, 304 and 310 K, were equal to 3.2 * 10(5) M(-1), 4.7 * 10(5) M(-1), and 6.6 * 10(5) M(-1) respectively, proving a relatively high affinity of for salmon testes DNA. Results of Hoechst 33258 displacement assays strongly support the groove binding mode of to DNA. The association stoichiometry of the :DNA adduct was found to be 1 for every 5 base pairs. FT-IR spectra, recorded at different /DNA molar ratios, indicate the involvement of the phosphate groups and adenine and thymine DNA bases in the association process. Thermodynamic results suggest that hydrophobic forces regulate the binding of with DNA without excluding some extent of involvement of van der Waals forces and hydrogen bonding arising due to surface binding between the hydrophilic polymeric arms of the ligand and the functional groups positioned on the edge of the groove. The resulting composite biomaterial could constitute a valuable candidate for future biological and/or photonic applications. PMID- 26506887 TI - Safety performance evaluation of cable median barriers on freeways in Florida. AB - OBJECTIVE: This article aims to evaluate the safety performance of cable median barriers on freeways in Florida. METHOD: The safety performance evaluation was based on the percentages of barrier and median crossovers by vehicle type, crash severity, and cable median barrier type (Trinity Cable Safety System [CASS] and Gibraltar system). Twenty-three locations with cable median barriers totaling about 101 miles were identified. Police reports of 6,524 crashes from years 2005 2010 at these locations were reviewed to verify and obtain detailed crash information. A total of 549 crashes were determined to be barrier related (i.e., crashes involving vehicles hitting the cable median barrier) and were reviewed in further detail to identify crossover crashes and the manner in which the vehicles crossed the barriers; that is, by either overriding, underriding, or penetrating the barriers. RESULTS: Overall, 2.6% of vehicles that hit the cable median barrier crossed the median and traversed into the opposite travel lane. Overall, 98.1% of cars and 95.5% of light trucks that hit the barrier were prevented from crossing the median. In other words, 1.9% of cars and 4.5% of light trucks that hit the barrier had crossed the median and encroached on the opposite travel lanes. There is no significant difference in the performance of cable median barrier for cars versus light trucks in terms of crossover crashes. In terms of severity, overrides were more severe compared to underrides and penetrations. The statistics showed that the CASS and Gibraltar systems performed similarly in terms of crossover crashes. However, the Gibraltar system experienced a higher proportion of penetrations compared to the CASS system. The CASS system resulted in a slightly higher percentage of moderate and minor injury crashes compared to the Gibraltar system. CONCLUSIONS: Cable median barriers are successful in preventing median crossover crashes; 97.4% of the cable median barrier crashes were prevented from crossing over the median. Of all of the vehicles that hit the barrier, 83.6% were either redirected or contained by the cable barrier system. Barrier crossover crashes were found to be more severe compared to barrier noncrossover crashes. In addition, overrides were found to be more severe compared to underrides and penetrations. PMID- 26506888 TI - [Non-bacterial chronic osteomyelitis: Experience in a tertiary hospital]. AB - INTRODUCTION: Non-bacterial chronic osteomyelitis (NBCO) is an autoinflammatory disease that presents with recurrent bouts of bone inflammation in the absence of microbiological isolation. It is a diagnosis of exclusion. Its treatment was classically based on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, although nowadays bisphosphonates or anti-tumour necrosis factor-alpha (anti-TNF) drugs are frequently used with good results. The objective of the study is to describe our experience in the diagnosis and treatment of patients with NBCO. PATIENTS AND METHODS: Retrospective chart review of patients with NBCO followed up in a tertiary centre between 2008 and 2015. RESULTS: A total of 7 patients with NBCO were recorded. Four were female and the median age was 10 years (IQR 2). The most common complaint was pain that interfered with sleep in 5 of the patients. Six patients had multifocal lesions at diagnosis. Bone biopsy demonstrated neutrophilic or lymphocytic infiltration and sclerosis in 6 patients. Four patients received antibiotics and NSAIDs without clinical response. Five received a short course of prednisone with an adequate control of symptoms, but only one of them maintained remission after corticosteroid suspension. Five patients received bisphosphonates with disease remission in 3 of them. The other 2 showed an inadequate response to pamidronate and were started on anti-TNF therapy (etanercept, infliximab or adalimumab), remaining asymptomatic at present. CONCLUSIONS: Our series, although limited, confirms the effectiveness and safety of bisphosphonate and anti-TNF therapy for children with NBCO. PMID- 26506889 TI - [Typical haemolytic uraemic syndrome: Report of the first case due to Escherichia coli O26:H11 in Spain]. PMID- 26506890 TI - Using pilot data to size a two-arm randomized trial to find a nearly optimal personalized treatment strategy. AB - A personalized treatment strategy formalizes evidence-based treatment selection by mapping patient information to a recommended treatment. Personalized treatment strategies can produce better patient outcomes while reducing cost and treatment burden. Thus, among clinical and intervention scientists, there is a growing interest in conducting randomized clinical trials when one of the primary aims is estimation of a personalized treatment strategy. However, at present, there are no appropriate sample size formulae to assist in the design of such a trial. Furthermore, because the sampling distribution of the estimated outcome under an estimated optimal treatment strategy can be highly sensitive to small perturbations in the underlying generative model, sample size calculations based on standard (uncorrected) asymptotic approximations or computer simulations may not be reliable. We offer a simple and robust method for powering a single stage, two-armed randomized clinical trial when the primary aim is estimating the optimal single stage personalized treatment strategy. The proposed method is based on inverting a plugin projection confidence interval and is thereby regular and robust to small perturbations of the underlying generative model. The proposed method requires elicitation of two clinically meaningful parameters from clinical scientists and uses data from a small pilot study to estimate nuisance parameters, which are not easily elicited. The method performs well in simulated experiments and is illustrated using data from a pilot study of time to conception and fertility awareness. PMID- 26506891 TI - The amino acid transporter SLC38A9 regulates MTORC1 and autophagy. AB - The mechanistic target of rapamycin (serine/threonine kinase) complex 1 (MTORC1) is a master regulator of macroautophagy (hereafter autophagy) that responds to different environmental nutrients, including amino acids, glucose, and growth factors. The identity of the amino acid-sensing component of the MTORC1 machinery had remained elusive until a lysosomal low-affinity amino acid transporter, SLC38A9 (solute carrier family 38, member 9), was recently characterized as a novel component of the Ragulator-RRAG GTPase complex by 3 independent research groups. PMID- 26506892 TI - Activation of autophagy in macrophages by pro-resolving lipid mediators. AB - The resolution of inflammation is an active process driven by specialized pro resolving lipid mediators, such as 15-epi-LXA4 and resolvin D1 (RvD1), that promote tissue regeneration. Macrophages regulate the innate immune response being key players during the resolution phase to avoid chronic inflammatory pathologies. Their half-life is tightly regulated to accomplish its phagocytic function, allowing the complete cleaning of the affected area. The balance between apoptosis and autophagy appears to be essential to control the survival of these immune cells within the inflammatory context. In the present work, we demonstrate that 15-epi-LXA4 and RvD1 at nanomolar concentrations promote autophagy in murine and human macrophages. Both compounds induced the MAP1LC3-I to MAP1LC3-II processing and the degradation of SQSTM1 as well as the formation of MAP1LC3(+) autophagosomes, a typical signature of autophagy. Furthermore, 15 epi-LXA4 and RvD1 treatment favored the fusion of the autophagosomes with lysosomes, allowing the final processing of the autophagic vesicles. This autophagic response involves the activation of MAPK1 and NFE2L2 pathways, but by an MTOR-independent mechanism. Moreover, these pro-resolving lipids improved the phagocytic activity of macrophages via NFE2L2. Therefore, 15-epi-LXA4 and RvD1 improved both survival and functionality of macrophages, which likely supports the recovery of tissue homeostasis and avoiding chronic inflammatory diseases. PMID- 26506893 TI - Molecular basis of ubiquitin recognition by the autophagy receptor CALCOCO2. AB - The autophagy receptor CALCOCO2/NDP52 functions as a bridging adaptor and plays an essential role in the selective autophagic degradation of invading pathogens by specifically recognizing ubiquitin-coated intracellular pathogens and subsequently targeting them to the autophagic machinery; thereby it is required for innate immune defense against a range of infectious pathogens in mammals. However, the mechanistic basis underlying CALCOCO2-mediated specific recognition of ubiqutinated pathogens is still unknown. Here, using biochemical and structural analyses, we demonstrated that the cargo-binding region of CALCOCO2 contains a dynamic unconventional zinc finger as well as a C2H2-type zinc-finger, and only the C2H2-type zinc finger specifically recognizes mono-ubiquitin or poly ubiquitin chains. In addition to elucidating the specific ubiquitin recognition mechanism of CALCOCO2, the structure of the CALCOCO2 C2H2-type zinc finger in complex with mono-ubiquitin also uncovers a unique zinc finger-binding mode for ubiquitin. Our findings provide mechanistic insight into how CALCOCO2 targets ubiquitin-decorated pathogens for autophagic degradations. PMID- 26506894 TI - Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer. AB - In spite of adjuvant chemotherapy, a significant fraction of patients with localized breast cancer (BC) relapse after optimal treatment. We determined the occurrence of cytoplasmic MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3B)-positive puncta, as well as the presence of nuclear HMGB1 (high mobility group box 1) in cancer cells within surgical BC specimens by immunohistochemistry, first in a test cohort (152 patients) and then in a validation cohort of localized BC patients who all received adjuvant anthracycline-based chemotherapy (1646 patients). Cytoplasmic LC3B(+) puncta inversely correlated with the intensity of SQSTM1 staining, suggesting that a high percentage cells of LC3B(+) puncta reflects increased autophagic flux. After setting optimal thresholds in the test cohort, cytoplasmic LC3B(+) puncta and nuclear HMGB1 were scored as positive in 27.2% and 28.6% of the tumors, respectively, in the validation cohort, while 8.7% were considered as double positive. LC3B(+) puncta or HMGB1 expression alone did not constitute independent prognostic factors for metastasis-free survival (MFS) in multivariate analyses. However, the combined positivity for LC3B(+) puncta and nuclear HMGB1 constituted an independent prognostic factor significantly associated with prolonged MFS (hazard ratio: 0.49 95% confidence interval [0.26-0.89]; P = 0.02), and improved breast cancer specific survival (hazard ratio: 0.21 95% confidence interval [0.05 0.85]; P = 0.029). Subgroup analyses revealed that within patients with poor prognosis BC, HMGB1(+) LC3B(+) double-positive tumors had a better prognosis than BC that lacked one or both of these markers. Altogether, these results suggest that the combined positivity for LC3B(+) puncta and nuclear HMGB1 is a positive predictor for longer BC survival. PMID- 26506895 TI - Quantitative analysis of autophagic flux by confocal pH-imaging of autophagic intermediates. AB - Although numerous techniques have been developed to monitor autophagy and to probe its cellular functions, these methods cannot evaluate in sufficient detail the autophagy process, and suffer limitations from complex experimental setups and/or systematic errors. Here we developed a method to image, contextually, the number and pH of autophagic intermediates by using the probe mRFP-GFP-LC3B as a ratiometric pH sensor. This information is expressed functionally by AIPD, the pH distribution of the number of autophagic intermediates per cell. AIPD analysis reveals how intermediates are characterized by a continuous pH distribution, in the range 4.5-6.5, and therefore can be described by a more complex set of states rather than the usual biphasic one (autophagosomes and autolysosomes). AIPD shape and amplitude are sensitive to alterations in the autophagy pathway induced by drugs or environmental states, and allow a quantitative estimation of autophagic flux by retrieving the concentrations of autophagic intermediates. PMID- 26506896 TI - BCL2L13 is a mammalian homolog of the yeast mitophagy receptor Atg32. AB - Although Atg32 is essential for mitophagy in yeast, no mammalian homolog has been identified. Here, we demonstrate that BCL2L13 (BCL2-like 13 [apoptosis facilitator]) is a functional mammalian homolog of Atg32. First, we hypothesized that a mammalian mitophagy receptor will share certain molecular features with Atg32. Using the molecular profile of Atg32 as a search tool, we screened public databases for novel Atg32 functional homologs and identified BCL2L13. BCL2L13 induces mitochondrial fragmentation and mitophagy in HEK293 cells. In BCL2L13, the BH domains are important for fragmentation, whereas the WXXI motif, an LC3 interacting region, is needed for mitophagy. BCL2L13 induces mitochondrial fragmentation and mitophagy even in the absence of DNM1L/Drp1 and PARK2/Parkin, respectively. BCL2L13 is indispensable for mitochondrial damage-induced fragmentation and mitophagy. Furthermore, BCL2L13 induces mitophagy in Atg32 deficient yeast. Induction and/or phosphorylation of BCL2L13 may regulate its activity. Our findings thus open a new chapter in mitophagy research. PMID- 26506897 TI - Precision autophagy: Will the next wave of selective autophagy markers and specific autophagy inhibitors feed clinical pipelines? AB - Research presented at the Vancouver Autophagy Symposium (VAS) 2014 suggests that autophagy's influence on health and disease depends on tight regulation and precision targeting of substrates. Discussions recognized a pressing need for robust biomarkers that accurately assess the clinical utility of modulating autophagy in disease contexts. Biomarker discovery could flow from investigations of context-dependent triggers, sensors, and adaptors that tailor the autophagy machinery to achieve target specificity. In his keynote address, Dr. Vojo Deretic (University of New Mexico) described the discovery of a cargo receptor family that utilizes peptide motif-based cargo recognition, a mechanism that may be more precise than generic substrate tagging. The keynote by Dr. Alec Kimmelman (Harvard Medical School) emphasized that unbiased screens for novel selective autophagy factors may accelerate the development of autophagy-based therapies. Using a quantitative proteomics screen for de novo identification of autophagosome substrates in pancreatic cancer, Kimmelman's group discovered a new type of selective autophagy that regulates bioavailable iron. Additional presentations revealed novel autophagy regulators and receptors in metabolic diseases, proteinopathies, and cancer, and outlined the development of specific autophagy inhibitors and treatment regimens that combine autophagy modulation with anticancer therapies. VAS 2014 stimulated interdisciplinary discussions focused on the development of biomarkers, drugs, and preclinical models to facilitate clinical translation of key autophagy discoveries. PMID- 26506898 TI - A new genomic island. PMID- 26506899 TI - Standardized phenotyping enhances Mendelian disease gene identification. AB - Whole-exome sequencing has revolutionized the identification of genes with dominant disease-associated variants for rare clinically and genetically heterogeneous disorders, but the identification of genes with recessive disease associated variants has been less successful. A new study now provides a framework integrating Mendelian variant filtering with statistical assessments of patients' genotypes and phenotypes, thereby catalyzing the discovery of novel mutations associated with recessive disease. PMID- 26506900 TI - Small island, big genetic discoveries. AB - Three new studies have identified new genes and sequence variants implicated in blood lipids, inflammatory markers, hemoglobin levels and adult height variation in Sardinia. These reports highlight the usefulness of large-scale genotype imputation based on whole-genome sequencing, particularly in isolated populations, in studying the genetics of complex human phenotypes. PMID- 26506901 TI - The genomic landscape of adult T cell leukemia/lymphoma. AB - Adult T cell leukemia/lymphoma (ATL) is a neoplasm linked to human T-lymphotropic virus type-1 (HTLV-1) infection and is refractory to current combination chemotherapy. A large genomic and transcriptomic study of ATL now provides detailed insight into the molecular lesions implicated in the development of this T cell malignancy. PMID- 26506902 TI - Evidence for the secondary sexual development of the anal fin in female kokanee salmon Oncorhynchus nerka. AB - This study examines whether the anal fin undergoes secondary sexual development similar to other reproductive traits in salmonids. This hypothesis was tested by comparing the anal-fin size of female kokanee salmon Oncorhynchus nerka that were in the early and late stages of sexual development. Females in an advanced stage of maturation had significantly larger anal fins relative to females in an early state of maturation (+4-7%), indicating that the anal fin undergoes secondary sexual development. The magnitude of this secondary growth was comparable with snout length (+9-10%), which is known to undergo secondary sexual development in female salmonids. When morphological trait dimensions were compared between the sexes, the anal fin was the only morphological trait found to have a female biased sexual size dimorphism. This is the first study to show that the anal fin of female salmonids undergoes secondary sexual development. PMID- 26506903 TI - Case of adult-onset verrucous hemangioma developed after repeated trauma. PMID- 26506905 TI - Differential processing of immediately repeated verbal and non-verbal stimuli: an evoked-potential study. AB - Stimuli are better retained in memory if they are repeated after a delay than if they are immediately repeated. This effect is called the spacing effect (SE). Recent electroencephalographic (EEG) studies showed that delayed repetition of meaningful designs in a continuous recognition task induces an evoked response very similar to new presentations. In contrast, immediately repeated designs induced circumscribed, stronger activation of the left medio-temporal lobe (MTL) at 200-300 ms. In amnesic subjects, this signal was missing, indicating that it has a memory-protective effect. Here, high-density EEG was used in humans to explore whether meaningless verbal (non-words) and non-verbal (geometric designs) stimuli also have a SE associated with such lateralized, temporally limited activation of the left MTL upon immediate repetition. The results revealed a SE for both materials. Timing and localization of brain activity differed as a function of stimulus material. Specific responses to immediate repetitions occurred at 200-285 ms for non-verbal stimuli and at 285-380 ms for verbal material. Source estimations revealed increased activity in right inferior frontal areas for immediate non-verbal repetitions and in left fronto-parietal areas for immediate verbal repetition in comparison to new presentations. These findings show that, while the SE is a ubiquitous phenomenon, the neural processes underlying it vary according to stimulus material. PMID- 26506904 TI - Perampanel for focal epilepsy: insights from early clinical experience. AB - Perampanel is approved for adjunctive therapy of focal epilepsy with or without secondarily generalized seizures in patients aged >12 years. This narrative review uses real-world and clinical trial data to elucidate perampanel's role in the clinic. Audit data show good tolerability with perampanel and higher freedom from-seizure rates in elderly vs younger patients. When using perampanel in elderly patients, special attention should be given to comorbidities and co medication to avoid potential interactions or adverse events. Slower titration is generally recommended, and seizure control should be reassessed at a dose of 4 mg before further dose increases. Perampanel efficacy is similar in adolescents and adults; however, somnolence, nasopharyngitis, and aggression are more frequent in adolescents vs the overall population. Individualized and slow-dose titration can minimize adverse events. Low serum concentrations of perampanel may occur in patients also receiving some enzyme-inducing anti-epileptic drugs; a perampanel dose increase may be required. Adverse events of importance with perampanel include dizziness; anger, aggression, and hostile behavior (particularly in adolescents); and falls (particularly in patients >65 years). An individualized approach to dosing, including slower up-titration and bedtime dosing, reduces dizziness risk. Other drugs may cause or aggravate dizziness; reducing concomitant drugs may be necessary when up-titrating perampanel. It would seem clinically appropriate to give due consideration to avoiding use in patients with a history of anger or hostile/aggressive behavior. The possibility of such behaviors should be discussed with patients before starting perampanel, with monitoring during up-titration. Slower up-titration of perampanel in older patients helps reduce fall risk. PMID- 26506906 TI - Bevacizumab in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine oxaliplatin-based chemotherapy for first-line and maintenance treatment of metastatic colorectal cancer. AB - Despite a slight decrease in mortality rates, recent advances in screening methods, diagnosis and overall improved therapeutic options, colorectal cancer (CRC) remains among the leading causes of cancer-related death worldwide. The major cause is the mortality related to metastatic status of CRC. Increasing clinical evidence derived from randomized trials strongly suggests that the efficacy of standard cytotoxic agents, including various combinations of 5 fluoouracil (5-FU)/leucovorin (LV), capecitabine, irinotecan and oxaliplatin, may be significantly augmented with concomitant administration of molecular agents targeting the vascular endothelial growth factor (VEGF) signaling pathways, such as bevacizumab. Herein, we critically discuss the current data on the efficacy and safety profile of bevacizumab in combination with fluoropyrimidine-based chemotherapy for first-line and maintenance treatment of metastatic CRC and briefly comment on existing controversies and future perspectives. PMID- 26506907 TI - Optical Characterization of Strong UV Luminescence Emitted from the Excitonic Edge of Nickel Oxide Nanotowers. AB - NiO had been claimed to have the potential for application in transparent conducting oxide, electrochromic device for light control, and nonvolatile memory device. However, the detailed study of excitonic transition and light-emission property of NiO has rarely been explored to date. In this work, we demonstrate strong exciton-complex emission of high-quality NiO nanotowers grown by hot filament metal-oxide vapor deposition with photoluminescence as an evaluation tool. Fine and clear emission features coming from the excitonic edge of the NiO are obviously observed in the photoluminescence spectra. A main excitonic emission of ~3.25 eV at 300 K can be decomposed into free exciton, bound excitons, and donor-acceptor-pair irradiations at lowered temperatures down to 10 K. The band-edge excitonic structure for the NiO nanocrystals has been evaluated and analyzed by transmission and thermoreflectacne measurements herein. All the experimental results demonstrate the cubic NiO thin-film nanotower is an applicable direct-band-gap material appropriate for UV luminescence and transparent-conducting-oxide applications. PMID- 26506908 TI - Impact of Perioperative Allogenic Blood Transfusion on Survival After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma. AB - The present retrospective multicenter study analyzed the effect of perioperative blood transfusions (PBTs) on the outcomes in 285 patients with upper tract urothelial carcinoma who had undergone radical nephroureterectomy (RNU). We found that patients receiving PBTs had inferior survival compared with that of patients without PBTs. Future investigations should focus on optimization of preoperative hemoglobin levels, surgical accuracy, and anesthetic management of RNU. BACKGROUND: Preoperative anemia is an independent predictor for unfavorable outcomes in patients with upper tract urothelial carcinoma (UTUC) who undergo radical nephroureterectomy (RNU). The effect of perioperative blood transfusion (PBT) on survival, however, has been insufficiently investigated. We investigated the impact of PBT on the outcomes of patients UTUC treated with RNU. PATIENTS AND METHODS: We analyzed the data from 285 patients with UTUC who had undergone RNU at 3 German academic institutions. PBT administration was analyzed as a dichotomous variable (administered vs. not administered) and the number of PBT units as a continuous and categorical variable (0 vs. <= 2 vs. > 2). Cox regression models were used to analyze the impact of PBT on disease recurrence and survival. RESULTS: A total of 81 patients (28.4%) had received a PBT with a median number of 2 U (interquartile range, 2-4). The administration of PBT was associated with advanced tumor stage, higher tumor grade, and preoperative anemia (P <= .049 for all). At a mean follow-up of 52 months, PBT and an increasing number of PBT units were significantly associated with inferior overall survival (P <= .025). On multivariable analyses adjusted for established UTUC outcome prognosticators, PBT was significantly associated with inferior overall survival (hazard ratio, 1.6; 95% confidence interval, 1.055-2.428; P = .027). CONCLUSION: PBT is an independent risk factor for worse overall survival in patients with UTUC treated with RNU. Continued efforts are warranted to optimize patients' preoperative hemoglobin level, surgical accuracy, and anesthetic management of RNU to reduce the necessity for PBTs. PMID- 26506909 TI - Transcriptome and proteome of Conus planorbis identify the nicotinic receptors as primary target for the defensive venom. AB - Most venomous predators have evolved complex venom primarily to immobilize their prey and secondarily to defend against predators. In a new paradigm, carnivorous marine gastropods of the genus Conus were shown to rapidly and reversibly switch between two types of venoms in response to predatory or defensive stimulus, suggesting that the defensive use of venom may have a more important role in venom evolution and specialization than previously thought. To further investigate this phenomenon, the defensive repertoire of a vermivorous species, Conus planorbis, was deciphered using second-generation sequencing coupled to high-throughput proteomics. The venom gland transcriptome of C. planorbis revealed 182 unique conotoxin precursors from 25 gene superfamilies, with superfamily T dominating in terms of read and paralog numbers. Analysis of the defense-evoked venom revealed that this vermivorous species uses a similarly complex arsenal to deter aggressors as more recently evolved fish- and mollusk hunting species, with MS/MS validating 23 conotoxin sequences from six superfamilies. Pharmacological characterization of the defensive venom on human receptors identified the nicotinic acetylcholine receptors as a primary target. This work provides the first insights into the composition and biological activity of specifically evolved defensive venoms in vermivorous cone snails. PMID- 26506910 TI - Ionizing Radiation Impacts on Cardiac Differentiation of Mouse Embryonic Stem Cells. AB - Little is known about the effects of ionizing radiation on the earliest stages of embryonic development although it is well recognized that ionizing radiation is a natural part of our environment and further exposure may occur due to medical applications. The current study addresses this issue using D3 mouse embryonic stem cells as a model system. Cells were irradiated with either X-rays or carbon ions representing sparsely and densely ionizing radiation and their effect on the differentiation of D3 cells into spontaneously contracting cardiomyocytes through embryoid body (EB) formation was measured. This study is the first to demonstrate that ionizing radiation impairs the formation of beating cardiomyocytes with carbon ions being more detrimental than X-rays. However, after prolonged culture time, the number of beating EBs derived from carbon ion irradiated cells almost reached control levels indicating that the surviving cells are still capable of developing along the cardiac lineage although with considerable delay. Reduced EB size, failure to downregulate pluripotency markers, and impaired expression of cardiac markers were identified as the cause of compromised cardiomyocyte formation. Dysregulation of cardiac differentiation was accompanied by alterations in the expression of endodermal and ectodermal markers that were more severe after carbon ion irradiation than after exposure to X-rays. In conclusion, our data show that carbon ion irradiation profoundly affects differentiation and thus may pose a higher risk to the early embryo than X-rays. PMID- 26506911 TI - Porcine semen as a vector for transmission of viral pathogens. AB - Different viruses have been detected in porcine semen. Some of them are on the list of the World Organization for Animal Health (OIE), and consequently, these pathogens are of socioeconomic and/or public health importance and are of major importance in the international trade of animals and animal products. Artificial insemination (AI) is one of the most commonly used assisted reproductive technologies in pig production worldwide. This extensive use has enabled pig producers to benefit from superior genetics at a lower cost compared to natural breeding. However, the broad distribution of processed semen doses for field AI has increased the risk of widespread transmission of swine viral pathogens. Contamination of semen can be due to infections of the boar or can occur during semen collection, processing, and storage. It can result in reduced semen quality, embryonic mortality, endometritis, and systemic infection and/or disease in the recipient female. The presence of viral pathogens in semen can be assessed by demonstration of viable virus, nucleic acid of virus, or indirectly by measuring serum antibodies in the boar. The best way to prevent disease transmission via the semen is to assure that the boars in AI centers are free from the disease, to enforce very strict biosecurity protocols, and to perform routine health monitoring of boars. Prevention of viral semen contamination should be the primary focus because it is easier to prevent contamination than to eliminate viruses once present in semen. Nevertheless, research and development of novel semen processing treatments such as single-layer centrifugation is ongoing and may allow in the future to decontaminate semen. PMID- 26506912 TI - Female bovine blastocysts are more prone to apoptosis than male ones. AB - Female and male embryos show differences in gene expression and metabolism from the onset of their genome. Those differences are affected by environmental factors. The objective of the study was to compare the apoptotic rates of in vitro-produced female and male bovine blastocysts cultured in different conditions. Day 7 blastocysts obtained after IVF with sex-sorted semen and culture in two synthetic oviductal fluid-based media (containing fetal calf serum [FCS] or BSA, insulin, transferrin, and selenium) were simultaneously evaluated for two markers of apoptosis after 3D reconstruction from confocal images: active caspase 3 by immunofluorescence and DNA fragmentation by terminal deoxynucleotidyl transferase dUTP nick end labeling. Higher levels of apoptotic cells were observed in female embryos whatever the culture condition but with a more pronounced difference in FCS medium. This result was confirmed using the unsexed semen of two bulls. The sex effect on apoptosis was detected in both the inner cell mass and the trophectoderm but was dependent on the embryonic size. In conclusion, this study reported that female bovine blastocysts are more prone to apoptosis than male ones but that culture in FCS exacerbates the differences in apoptosis between sexes, especially in small blastocysts. PMID- 26506913 TI - Combined Analyses of the VHL and Hypoxia Signaling Axes in an Isogenic Pairing of Renal Clear Cell Carcinoma Cells. AB - The loss of function of the Von Hippel-Lindau (VHL) tumor suppressor leads to the development of hypervascular tumors, exemplified by clear-cell-type renal cell carcinoma (RCC). VHL governs the adaptive responses to fluctuation of oxygen levels largely through the regulated suppression of hypoxia inducible factors (HIFs). Here, we combine proteome and phospho-proteomic analysis of isogenic 786 O RCC (+/-VHL) cells to compare signatures that reflect hypoxia and/or loss of VHL. VHL-independent hypoxic responses, notably include up-regulation of phosphorylation at Ser232 on the pyruvate dehydrogenase alpha subunit that is known to promote glycolysis. Hypoxic responses governed by VHL include up regulation of known biomarkers of RCC (e.g., GLUT1, NDRG1) and the signaling adaptor molecule IRS-2. Notably, we also observe down-regulation of linked components associated with the Jacobs-Stewart cycle, including the intracellular carbonic anhydrase II (CA2), which governs cellular response to CO2 fluctuations that often accompany hypoxia in tumors. Further studies indicate an unusual mechanism of control for CA2 expression that, at least in part, reflects enhanced activity of the NFkappaB pathway, which is associated with loss of VHL. PMID- 26506914 TI - Predicting the response of patients with advanced urothelial cancer to methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC) after the failure of gemcitabine and platinum (GP). AB - BACKGROUND: Platinum-based systemic chemotherapy is the treatment of choice for patients with advanced urothelial carcinoma (UC). Although no chemotherapeutic regimen is established as a second-line therapy, recent studies reported that methotrexate, vinblastine, Adriamycin and cisplatin (MVAC) elicited a significant response in patients who failed gemcitabine and platinum (GP) chemotherapy. We investigated the clinical factors useful for predicting a favourable response to MVAC in UC patients who failed GP. METHODS: Forty-five patients with advanced UC who received second-line MVAC chemotherapy after failure with first-line GP chemotherapy were enrolled in this study. Univariate and multivariate analyses based on Cox's regression were performed to identify independent prognostic factors for progression-free survival (PFS) after second-line MVAC chemotherapy. RESULTS: The median follow-up period after the first MVAC administration was 10.0 months. The median PFS and overall survival (OS) were 6.5 months (95% confidence interval [CI]: 5.1-7.9) and 14.5 months (95% CI, 7.4-21.4), respectively. The overall response rate was 57.8%. The response to first-line GP chemotherapy (hazard ratio [HR], 2.500; p = 0.012) and patient age (HR, 1.047; p = 0.033) were predictors of PFS after MVAC chemotherapy. CONCLUSIONS: The response to first line GP chemotherapy and age were independent predictors of PFS in patients who received second-line MVAC chemotherapy. This report is the first to describe independent predictors of PFS after MVAC chemotherapy. PMID- 26506915 TI - Nonpredominant lepidic pattern correlates with better outcome in invasive lung adenocarcinoma. AB - OBJECTIVES: Histologic heterogeneity is a typical feature of pulmonary adenocarcinoma. This study aimed to deconstruct the intratumoral growth pattern composition and to examine the prognostic relevance of the current lung adenocarcinoma classification in a series of Finnish lung cancer patients. MATERIALS AND METHODS: A cohort of 112 patients with surgically operated stage I IV lung adenocarcinoma was retrospectively reviewed. Histologic subtyping was performed according to the classification system established by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS). Systematically collected clinical information including survival data was correlated with the subtype status. In addition, emphasis was placed on the nonpredominant histologic patterns, gender and smoking history. RESULTS: The most common subtype was acinar predominant adenocarcinoma with 56 cases (50%). Most tumors were composed of a mixture of two or more growth patterns, and single pattern tumors were rare (9.8%). Micropapillary predominant adenocarcinoma and solid predominant adenocarcinoma were the subtypes with the lowest disease-specific survival rates (5-year DSS 21.4% and 30.4%; shared mean DSS 46.3 months, p=0.040). A nonpredominant lepidic component was observed in 24 (21.4%) tumors, and its presence predicted a better outcome (mean DSS 127.4 months vs. 55.7 months, p=0.001). This association was confirmed by multivariate analysis (p=0.004). Solid pattern and solid, papillary, micropapillary and cribriform predominant histology associated with smoking (p<0.001), while mucinous pattern was more common in nonsmokers (p<0.001) and in women (p=0.050). CONCLUSIONS: Micropapillary and solid predominant adenocarcinomas showed significantly lower survival rate than other major subtypes, yet the prognostic value of the current lung adenocarcinoma classification is not limited only to the predominant growth patterns. The more favorable outcome associated with the nonpredominant lepidic pattern further emphasizes the importance of histologic subtyping and assessment of tumor heterogeneity in the diagnostics of lung adenocarcinoma. PMID- 26506916 TI - Sleeping posture as a risk factor for retinal vein occlusion. PMID- 26506917 TI - The surgical experience of current non-surgeons gained at medical school: a survey analysis with implications for teaching today's students. AB - BACKGROUND: It is unknown what aspects of undergraduate surgical curricula are useful for future non-surgeons. We aimed to define relevant, enduring learning achievements for this subgroup to enable student-centered teaching. METHODS: An online questionnaire using open ended questions was distributed to physicians of non-surgical specialties at the University Hospital of Tuebingen, Germany and its associated teaching hospitals. Participants were asked to describe knowledge and skills that endured from their surgical clerkship and which of these are used in daily practice. Textual responses were initially coded using content analysis and the frequency of recurrent categories was calculated. RESULTS: Sixty-seven of 153 questionnaires were returned; participants belonged to six different non-surgical specialties and had received their training at 22 different medical schools. Sustaining learning achievements included basic skills (suturing and working under sterile conditions), learning about professionalism and appreciating working conditions in surgery. Two learning techniques were valued: witnessing of rare cases or complications and working autonomously. CONCLUSION: Integration of our findings in undergraduate surgical teaching may focus teaching on students' interests and improve surgical teaching. PMID- 26506918 TI - Dental service use among patients with specific disabilities: A nationwide population-based study. AB - BACKGROUND/PURPOSE: The Taiwan National Health Insurance program has allocated a specific fund for dental services to patients with specific disabilities (PSDs); however, the trends and the quality are unknown. In this study, we conducted quantity analyses and quality assessments of dental service use among PSDs using a nationwide population-based database. METHODS: PSDs were identified according to the codes of diagnosis fee. Quantity analyses included the number of patients receiving dental services, the number of visits, and the percentages of categories of dental service use. Quality assessments included refilling rates for operative dental treatments and unfinished rates for endodontic therapies. RESULTS: For quantity analyses, dental services were accessible to 3-4% of patients with disabilities and were mostly provided to younger PSDs. The general population received more operative and endodontic therapies, and PSDs received more periodontal therapies. For quality assessments, the teeth of PSDs had a 9.74 15.07% refilling rate, which was higher than that of the general population (1.39 6.37%). Furthermore, the teeth of PSDs had a 32.03% unfinished endodontic rate, which was higher than that of the general population (21.42%). CONCLUSION: During 2010-2012, only 3-4% of patients with disabilities had access to dental services, mostly provided to younger PSDs. Teeth of PSDs had higher refilling rates and unfinished endodontic sessions than the general population. We suggest that a more comprehensive dental care system is necessary to improve the quantity and quality of dental services, especially in middle-aged and older PSDs. PMID- 26506919 TI - Serotonin syndrome overlapping with neuroleptic malignant syndrome: A case report and approaches for differentially diagnosing the two syndromes. AB - Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are life threatening adverse reactions caused by serotonergic antidepressants and neuroleptics, respectively. SS and NMS have overlapping clinical features, and thus differentially diagnosing the syndromes can be difficult in patients who are taking both types of drugs. Here, the author reports a unique case of a patient who developed SS that overlapped with NMS after taking imipramine and lithium carbonate with the subsequent addition of metoclopramide. This is the first case report of SS that overlapped with NMS. The author also briefly summarizes the clinical symptoms of each syndrome and describes the approaches that were used to differentially diagnose the two syndromes. PMID- 26506920 TI - Biological surface-active compounds from marine bacteria. AB - Surface-active compounds (SACs) are widely used in different industries as well as in many daily consumption products. However, with the increasing concern for their environmental acceptability, attention has turned towards biological SACs which are biodegradable, less toxic and more environmentally friendly. In this work, 176 marine hydrocarbon-degrading bacterial isolates from petroleum contaminated sites along the Norwegian coastline were isolated and screened for their capacity to produce biological SACs. Among them, 18 isolates were capable of reducing the surface tension of the culture medium by at least 20 mN m(-1) and/or capable of maintaining more than 40% of the emulsion volume after 24 h when growing on glucose or kerosene as carbon and energy source. These isolates were members of the genera Pseudomonas, Pseudoalteromonas, Rhodococcus, Catenovulum, Cobetia, Glaciecola, Serratia, Marinomonas and Psychromonas. Two isolates, Rhodococcus sp. LF-13 and Rhodococcus sp. LF-22, reduced surface tension of culture medium by more than 40 mN m(-1) when growing on kerosene, n hexadecane or rapeseed oil. The biosurfactants were produced by resting cells of the two Rhodococcus strains suggesting the biosynthesis of the biosurfactants was not necessarily associated with their growth on hydrocarbons. PMID- 26506921 TI - Autovideography: The Lived Experience of Recovery for Adults with Serious Mental Illness. AB - Mental health services have been transforming toward a recovery orientation for more than a decade, yet a robust understanding of recovery eludes many providers, and consensus on a conceptual definition has yet to be reached. This article examines mental health consumers' lived experience of recovery and evaluates the usefulness and comprehensiveness of CHIME, a major framework conceptually defining recovery for adults with serious mental illness. Researchers partnered with a mental health association in a major US city to engage in research with graduates of a recovery and education class for adults diagnosed with serious mental illness. Twelve participants were loaned video cameras and invited to "Tell us about your recovery" through autovideography. Of the 12 participants, six produced videos directly responding to the overall research question and were subsequently included in the present analysis. Data were analyzed thematically, and CHIME adequately represented the major domains presented in consumer videos with two notable modifications: subdomains of "reciprocity" within relationships and "contributing to others" were added to comprehensively represent consumer perspectives about recovery. Adding two subdomains to CHIME more effectively represents consumer narratives about recovery, contributes to the social construction of the personhood of people with serious mental illness, and offers a more robust description of the process of recovery. PMID- 26506922 TI - Gentamicin-induced ototoxicity and nephrotoxicity vary with circadian time of treatment and entail separate mechanisms. AB - The aminoglycoside antibiotic gentamicin can cause both ototoxicity and nephrotoxicity, the severity of which varies with circadian time of daily treatment. However, it is not yet resolved if such drug-induced adverse effects are independent or interdependent phenomena. Two groups of 9 female Sprague Dawley rats (200-250 g), each housed separately and entrained to a 12 h light (06:00-18:00 h) - 12 h dark cycle, received a daily subcutaneous injection of 100 mg/kg gentamicin. One group was treated at the beginning of the activity span, 2 Hours After Lights On (HALO), and the other at the beginning of the rest span, 14 HALO. Global toxicity was gauged by both body weight loss relative to the pre treatment baseline and number of deaths. Ototoxicity, i.e., hearing loss, was assessed by changes in auditory brainstem response (ABR) for pure tone stimuli of 8, 16, 24, and 32 kHz before and after 2 and 4 weeks of gentamicin treatment. Renal toxicity was evaluated by changes in urinary N-acetyl-beta-glucosaminidase (NAG)/creatinine (CR) concentration ratio before and after each week of treatment. In a complementary substudy of separate but comparable 2 and 14 HALO groups of rats, blood samples were obtained before and 30, 60, 120, and 240 min post-subcutaneous injection of 100 mg/kg gentamicin. Number of animal deaths was greater in the 2 (4 deaths) than 14 HALO (1 death) group, mirroring more severe initial (first two weeks of treatment) body weight losses from baseline, being more than 2-fold greater in animals of the 2 than 14 HALO group. Ototoxicity progressively worsened during the treatment; although, the extent of hearing loss varied according to circadian time of treatment across all frequencies (p < 0.05), particularly the 24 and 32 kHz ones (both p < 0.005), both at the 2 and 4 week assessments. At 32 kHz after 4 weeks of gentamicin dosing, the 2 HALO group showed an average 42 dB hearing loss, while the 14 HALO group exhibited only an average 10 dB loss. ABR response latencies were longer for the 2 than 14 HALO rats. The time course of nephrotoxicity differed from that of ototoxicity. The mean urinary NAG/CR ratio peaked after the first week of treatment, averaging 13.64-fold greater than baseline for the 2 HALO-treated animals compared to 7.38 fold greater than baseline for the 14 HALO-treated ones. Ratio values declined thereafter; although, even after the second week of dosing, they remained greater in the 2 than 14 HALO group (averaging 8.15-fold greater and 2.23-fold greater than baseline, respectively). Pharmacokinetic analysis of the blood gentamicin values revealed slower clearance, on average by ~25% (p < 0.001), in the rats of the 14 than 2 HALO group (x +/- S.E.: 3.22 +/- 0.49 and 4.53 +/- 0.63 mL/min/kg, respectively). The study findings indicate robust difference of the time course in rats of both treatment groups of gentamicin-induced ototoxicity and nephrotoxicity, supporting the hypothesis these organ toxicities are independent of one another, and further suggest the observed treatment-time differences in gentamicin adverse effects may be more dependent on local cell, tissue, or organ circadian (chrono) pharmacodynamic than (chrono) pharmacokinetic mechanisms. PMID- 26506923 TI - Difficulty eating and significant weight loss in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. AB - Joint Hypermobility Syndrome, also known as Ehlers-Danlos Syndrome Hypermobility Type (JHS/EDS-HT), is a heritable disorder of connective tissue, common but poorly known by the medical community. Although generalized joint hypermobility and fragility of tissues have been described as core features, recent research highlights the multisystemic nature of JHS/EDS-HT, which presents with a wide range of articular and extra-articular symptoms. Among these, gastrointestinal problems, temporomandibular disorders, and smell and taste abnormalities are common among those affected, having significant implications for eating. The present work reviews the literature linking JHS/EDS-HT and eating problems. Two illustrative case reports, in which JHS/EDS-HT manifestations contribute to developing and maintaining disturbed eating behaviors and significant weight loss, are presented. PMID- 26506924 TI - Anorexia nervosa versus bulimia nervosa: differences based on retrospective correlates in a case-control study. AB - OBJECTIVE: This study is the result of two Portuguese case-control studies that examined the replication of retrospective correlates and preceding life events in anorexia nervosa (AN) and bulimia nervosa (BN) development. This study aims to identify retrospective correlates that distinguish AN and BN METHOD: A case control design was used to compare a group of women who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for AN (N = 98) and BN (N = 79) with healthy controls (N = 86) and with other psychiatric disorders (N = 68). Each control group was matched with AN patients regarding age and parental social categories. Risk factors were assessed by interviewing each person with the Oxford Risk Factor Interview. RESULTS: Compared to AN, women with BN reported significantly higher rates of paternal high expectations, excessive family importance placed on fitness/keeping in shape, and negative consequences due to adolescent overweight and adolescent objective overweight. DISCUSSION: Overweight during adolescence emerged as the most relevant retrospective correlate in the distinction between BN and AN participants. Family expectations and the importance placed on keeping in shape were also significant retrospective correlates in the BN group. PMID- 26506925 TI - Does applying postoperative suprapubic catheterisation in urogynecology benefit patients? AB - PURPOSE: The aim of this study was to define groups of women that are at particular risk for postoperative voiding dysfunction (PVD) after surgery for stress urinary incontinence (SUI) and/or pelvic organ prolapse (POP) and to focus on the question if these specific groups would benefit from suprapubic catheter (SPC) insertion. Complications associated with SPC were identified. METHODS: Between 06/2005 and 01/2013, the medical records of N = 4463 patients who underwent POP and/or SUI surgery were reviewed for suprapubic bladder drainage, duration of suprapubic catheterisation and SPC associated complications. 35 women suffering from vesicovaginal (28) and urethrovaginal (7) fistulas at the same time span were enrolled additionally. RESULTS: The results obtained revealed that patients after isolated anterior colporrhaphy, isolated anterior colporrhaphy and TVT, isolated cystocele repair using mesh and TVT, as well as patients with concomitant posterior and/or middle compartment prolapse surgery are at increased risk of developing PVD. Thus, postoperative suprapubic bladder drainage is beneficial. Complications occurred in 4.9 % of patients who received an SPC: urinary tract infection (UTI) (35), catheter dislocation (21), infection at the catheter insertion (2) and small bowel perforation (1). For the patients treated for fistulas we noticed a complication rate related to SPC of 11.4 %: UTI (2) and small bowel perforation (2). CONCLUSIONS: Patients should be counselled about the risk of developing PVD after POP and/or SUI surgery and should be informed about postoperative bladder drainage options related to their surgery. PMID- 26506926 TI - Use of locally delivered dequalinium chloride in the treatment of vaginal infections: a review. AB - BACKGROUND: Vaginal infections are responsible for a large proportion of gynaecological outpatient visits. Those are bacterial vaginosis (BV), vulvovaginal candidosis (VVC), aerobic vaginitis (AV) associated with aerobic bacteria, and mixed infections. Usual treatments show similar acceptable short term efficacy, but frequent recurrences and increasing microbial resistance are unsolved issues. Furthermore, vaginal infections are associated with a variety of serious adverse outcomes in pregnancy and generally have a major impact on quality of life. Identifying the correct therapy can be challenging for the clinician, particularly in mixed infections. FINDINGS: Dequalinium chloride (DQC) is an anti-microbial antiseptic agent with a broad bactericidal and fungicidal activity. Systemic absorption after vaginal application of DQC is very low and systemic effects negligible. Vaginal DQC (Fluomizin vaginal tablets) has been shown to have equal clinical efficacy as clindamycin in the treatment of BV. Its broad antimicrobial activity makes it appropriate for the treatment of mixed vaginal infections and in case of uncertain diagnosis. Moreover, resistance of pathogens is unlikely due to its multiple mode of action, and vaginal DQC provides also a reduced risk for post-treatment vaginal infections. CONCLUSIONS: Vaginal DQC (10 mg) as 6-day therapy offers a safe and effective option for empiric therapy of different vaginal infections in daily practice. This review summarizes the available and relevant pharmacological and clinical data for the therapy of vaginal infections with vaginal DQC and provides the rationale for its use in daily gynaecologic practice. PMID- 26506927 TI - Vitamin D receptor polymorphisms and 25-hydroxyvitamin D in a group of Sicilian multiple sclerosis patients. AB - Multiple sclerosis (MS) is an auto-immune disease whose etiology remains controversial. Both genetic and environmental factors are thought to be involved in the risk of developing the disease. The purpose of our study was to assess the association of Vitamin D receptor (VDR) polymorphisms with MS and to investigate the interaction of these polymorphisms with vitamin D levels. A total of 179 Sicilian subjects, including 104 MS patients and 75 healthy controls, were studied. The most common VDR polymorphisms (Fok-I, Bsm-I, Taq-I and Apa-I) were genotyped by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analyses in both groups and serum 25-hydroxyvitamin D [25(OH)D] levels were determined in MS patients by high-performance liquid chromatography (HPLC). The distribution of genotype and allele frequencies of the four VDR polymorphisms did not differ significantly between MS patients and healthy controls, and were unrelated to the forms and the course of MS. Low serum levels of 25(OH)D were observed in MS patients but no association was observed between VDR and 25(OH)D levels except for Fok-I. Moreover, MS patients with FF and Ff genotype had a significantly lower serum levels of 25(OH)D compared with ff carriers (P < 0.05 FF vs Ff and Ff vs ff). Our findings showed no association between VDR polymorphisms and risk of MS. Interestingly, F allele could confer a genetic predisposition to lower 25(OH)D levels. PMID- 26506928 TI - Milder form of heat-related symptoms and thermal sensation: a study in a Mediterranean climate. AB - Mild heat-related health effects and their potential association with meteorological and personal parameters in relation to subjective and objective thermal sensation were investigated. Micrometeorological measurements and questionnaire surveys were conducted in an urban Mediterranean environment during a warm, cool, and a transitional season. The participants were asked to indicate their thermal sensation based on a seven-point scale and report whether they were experiencing any of the following symptoms: headache, dizziness, breathing difficulties, and exhaustion. Two thermal indices, Actual Sensation Vote (ASV) and Universal Thermal Climate Index (UTCI), were estimated in order to obtain an objective measure of individuals' thermal sensation. Binary logistic regression was applied to identify risk parameters while cluster analysis was used to determine thresholds of air temperature, ASV and UTCI related to health effects. Exhaustion was the most frequent symptom reported by the interviewees. Females and smokers were more likely to report heat-related symptoms than males and nonsmokers. Based on cluster analysis, 35 degrees C could be a cutoff point for the manifestation of heat-related symptoms during summer. The threshold for ASV was 0.85 corresponding to "warm" thermal sensation and for UTCI was about 30.85 degrees C corresponding to "moderate heat stress" according to the Mediterranean assessment scale. PMID- 26506929 TI - Temperature deviation index and elderly mortality in Japan. AB - Few studies have examined how the precedence of abnormal temperatures in previous neighboring years affects the population's health. In the present study, we attempted to quantify the health effects of abnormal weather patterns by creating a metric called the temperature deviation index (TDI) and estimated the effects of TDI on mortality in Japan. We used data from 47 prefectures in Japan to compute the TDI on days between May and September from 1966 to 2010. The TDI is a summed product of an indicator of absence of high temperatures in the neighboring years, and more weights were assigned to the years closest to the current year. To estimate the TDI effects on elderly mortality, we used generalized linear modeling with a Poisson distribution after adjusting for apparent temperature, barometric pressure, day of the week, and time trend. For each prefecture, we estimated the TDI effects and pooled the estimates to yield a national average for 1991-2010 in Japan. The estimated effects of TDI in middle- or high-latitude prefectures were greater than in low-latitude prefectures. The estimated national average of TDI effects was a 0.5 % (95 % confidence intervals [CI], 0.1, 1.0) increase in elderly mortality per 1-unit (around 1 standard deviation) increase in the TDI. The significant pooled estimation of TDI effects was mainly due to the TDI effects on summer days with moderate temperature (25th-49th percentile, mean temperature 22.9 degrees C): a 1.9 % (95 % CI, 1.1, 2.6) increase in elderly mortality per 1-unit increase in the TDI. However, TDI effects were insignificant in other temperature ranges. These findings suggest that elderly deaths increased on moderate temperature days in the summer that differed substantially from days during that time window in the neighboring years. Therefore, not only high temperature itself but also temperature deviation compared to previous years could be considered to be a risk factor for elderly mortality in the summer. PMID- 26506930 TI - The spatial distribution of vulnerability to the health impacts of flooding in the Mekong Delta, Vietnam. AB - Flooding causes significant public health issues. The Mekong Delta has been considered the region to be the most vulnerable to flooding in Vietnam. This study assessed the spatial vulnerability of the health impacts of flooding in the Mekong Delta region, Vietnam. This study applied a vulnerability assessment framework which was computed as the function of three dimensions: exposure, sensitivity, and adaptive capacity. The indicators for each dimension were derived from the relevant literature, consultations with experts, and data availability. An analytic hierarchy process (AHP) and a principal component analysis (PCA) were used to determine the weight of indicators. Vulnerability indexes (VIs) were then computed for each province. A total of 29 indicators (sensitivity index, 14; adaptive capacity index, 13; and exposure index, 2) were employed to evaluate the vulnerability to the health impacts of flooding at a provincial level. The results of AHP revealed that the highest VIs were found in the Dong Thap and An Giang provinces (VI, 1.948 and 1.574, respectively). VIs were distributed with higher indexes in upstream provinces close to a river than in coastal provinces. PCA generated three components from the 29 indicators, and the VIs computed from the PCA method are in substantial agreement with the AHP method (ICC = 0.71, p < 0.05). The vulnerability to the health impacts of flooding varies from province to province in the Mekong Delta region in Vietnam. Individual plans for health preparedness and adaption to flooding should be developed for each province in the Mekong Delta region. PMID- 26506931 TI - A reduced activity model: a relevant tool for the study of ageing muscle. AB - Skeletal muscle mass is in a constant state of turnover, and atrophy is the result of a shift in the balance of muscle protein synthesis and breakdown resulting in net muscle protein loss. Total disuse of skeletal muscle quickly leads to muscle atrophy and loss of strength, and this has been repeatedly demonstrated in studies employing bed rest and lower limb immobilisation methodologies in young healthy participants. Fewer studies have focused on older participants (>65 years of age), but those that have provide evidence that advancing age brings increased vulnerability to rapid and marked loss of muscle size and strength during period of total muscle unloading. Increased systemic inflammation and reduced protein synthetic responses to protein feeding and muscle contraction might influence the severity of muscle protein loss during periods of total unloading compared with younger individuals. Less extreme reductions in muscle loading (e.g., 2 weeks of reducing daily ambulation to <1500 steps/day) have also been shown to result in decreases in muscle mass. This step reduction model may be more relevant than total bed rest or limb immobilisation for examining real-world scenarios that present a physiological challenge to the maintenance of skeletal muscle mass in older individuals. PMID- 26506932 TI - Differential evolution of peripheral cytokine levels in symptomatic and asymptomatic responses to experimental influenza virus challenge. AB - Exposure to influenza virus triggers a complex cascade of events in the human host. In order to understand more clearly the evolution of this intricate response over time, human volunteers were inoculated with influenza A/Wisconsin/67/2005 (H3N2), and then had serial peripheral blood samples drawn and tested for the presence of 25 major human cytokines. Nine of 17 (53%) inoculated subjects developed symptomatic influenza infection. Individuals who will go on to become symptomatic demonstrate increased circulating levels of interleukin (IL)-6, IL-8, IL-15, monocyte chemotactic protein (MCP)-1 and interferon (IFN) gamma-induced protein (IP)-10 as early as 12-29 h post inoculation (during the presymptomatic phase), whereas challenged patients who remain asymptomatic do not. Overall, the immunological pathways of leucocyte recruitment, Toll-like receptor (TLR)-signalling, innate anti-viral immunity and fever production are all over-represented in symptomatic individuals very early in disease, but are also dynamic and evolve continuously over time. Comparison with simultaneous peripheral blood genomics demonstrates that some inflammatory mediators (MCP-1, IP-10, IL-15) are being expressed actively in circulating cells, while others (IL-6, IL-8, IFN-alpha and IFN-gamma) are probable effectors produced locally at the site of infection. Interestingly, asymptomatic exposed subjects are not quiescent either immunologically or genomically, but instead exhibit early and persistent down-regulation of important inflammatory mediators in the periphery. The host inflammatory response to influenza infection is variable but robust, and evolves over time. These results offer critical insight into pathways driving influenza-related symptomatology and offer the potential to contribute to early detection and differentiation of infected hosts. PMID- 26506933 TI - Premorbid function, comorbidity, and frailty predict outcomes after ruptured abdominal aortic aneurysm repair. AB - OBJECTIVE: Strategies to improve outcomes for patients with ruptured abdominal aortic aneurysm (rAAA) are becoming more evident. The aging population, however, continues to make the decision to intervene often difficult, especially given that traditional risk models do not reflect issues of aging and frailty. This study aimed to integrate measures of function alongside comorbidity- and frailty specific factors to determine outcome. METHODS: Patients treated for a rAAA between January 2006 and April 2014 were assessed. Demographics, mortality, and requirement for care after discharge as well as a variety of measures of function (physical, social, and psychological) and comorbidity were recorded. The primary outcome was 1-year mortality. Outcome models were generated using multivariate logistic regression and were compared with models of vascular frailty and AAA related outcome. RESULTS: Of 184 patients treated, 108 (59%) underwent an open surgical repair. The overall 30-day and 1-year mortality were 21.5% and 31.4%, respectively, with an overall median hospital length of stay of 13 days (interquartile range, 6-27 days). An optimal logistic regression model for 12 month mortality used Katz score, Charlson score, number of admission medicines, visual impairment, hearing impairment, hemoglobin level, and statin use as predictors, achieving an area under the receiver operating characteristic curve of 0.84. CONCLUSIONS: This novel rAAA model incorporating function and comorbidity offers good predictive power for mortality. It is quick to calculate and may ultimately become helpful for both counseling and selection of patients and comparative audit at a time when outcome in patients with rAAA increasingly comes under the spotlight. PMID- 26506934 TI - Postoperative urinary retention in men is common after carotid endarterectomy and is associated with advanced age and prior urinary tract infection. AB - OBJECTIVE: This study was undertaken to analyze the occurrence of postoperative urinary retention (POUR) after carotid endarterectomy (CEA) and determine whether there are any associated modifiable risk factors. CEA was chosen to minimize the confounding effects of known risk factors for POUR, including immobilization, regional and severe pain, and neuroaxial anesthesia. METHODS: This was a retrospective record review of 186 male patients undergoing CEA between 2007 and 2011. Demographic, comorbidities, and operative characteristics were compared. Continuous variables are reported as median and interquartile range (IQR) and categoric variables as frequencies and proportions. Pearson chi(2) or Mann Whitney U tests compared categoric and continuous variables, respectively. Logistic regression was used to examine univariate and multivariate odds of POUR. Multivariate analysis controlled for known predictors of urinary retention. Association with other complications was examined with the Pearson correlation coefficient. RESULTS: POUR occurred in 34 patients (18.3%). Median age and history of urinary tract infection (UTI) were significantly associated with POUR: median age was 73.0 years (IQR, 67-80 years) for those with POUR vs 69.5 years (IQR, 63-76 years) for those without (P = .047); 17.6% of patients with a history of UTI developed POUR vs 5.9% without (P = .023). These findings persisted on multivariate analysis controlling for known predictors of POUR (body mass index, history of diabetes, benign prostate hyperplasia, and prior prostate surgery): median age (odds ratio, 1.05; 95% confidence interval, 1-1.1) and history of UTI (odds ratio, 4.16; 95% confidence interval, 1.23-14.05; P = .022). The occurrence of POUR was significantly correlated with postoperative UTI: 18.8% with POUR vs 0.7% without (Pearson r = 0.369; P < .001). CONCLUSIONS: POUR requiring bladder catheterization after CEA predisposes patients to postoperative UTI and is more common in older patients and those with a history of UTI. CEA patients lack inherent risk factors for POUR and would be a useful population for prospective studies involving POUR. PMID- 26506935 TI - Blunt thoracic aortic injury with small pseudoaneurysm may be managed by nonoperative treatment. AB - OBJECTIVE: The efficacy of nonoperative management of blunt thoracic aortic injury (BTAI) was evaluated in patients with pseudoaneurysm. METHODS: A retrospective review was done for patients with BTAI at Fukui Prefectural Hospital during a 9-year period. Charts were reviewed for age, gender, Injury Severity Score, Abbreviated Injury Scale for each body area, initial type of aortic injury, site of aortic injury, type of definitive management, complications, and outcomes. RESULTS: Eighteen patients with BTAI were treated at Fukui Prefectural Hospital. Of 18 patients with pseudoaneurysm, seven patients were hemodynamically unstable and four patients died because of associated injuries; there were no aortic-related deaths. All 14 surviving patients were followed up for an average of 40.9 months. Only two patients with pseudoaneurysm required operative management because of the progression of the pseudoaneurysm. The pseudoaneurysm/normal aortic diameter ratio of those with any intervention was higher than that of those with nonoperative management. CONCLUSIONS: BTAI with pseudoaneurysm can be managed nonoperatively, with about 10% risk of progression to require surgical repair. PMID- 26506936 TI - A randomized controlled trial of interrupted versus continuous suturing techniques for radiocephalic fistulas. AB - OBJECTIVE: Continuous suturing techniques have conventionally been used for the end-to-side anastomoses of radiocephalic fistulas (RCFs); however, primary patency rates are poor. Only 50% to 60% of RCFs ever achieve functional patency. We hypothesized that a hybrid interrupted-continuous suturing technique (as used in many microsurgical procedures) may improve outcomes in fistulas constructed from small vessels. METHODS: A randomized controlled trial comparing hybrid interrupted-continuous (n = 42) with continuous (n = 36) suturing techniques for RCF was undertaken. Patients were excluded if vessels were <1.8 mm in diameter or if previous ipsilateral fistula had been attempted. A priori power calculation indicated that a sample size of 78 patients was required to detect an improvement in patency from 50% to 80% (alpha = .05, beta = .8). The primary end point was primary patency at 6 weeks (assessed by a blinded observer for the presence of thrill and bruit). Secondary end points were immediate patency, functional patency (assessed clinically and by ultrasound) at 6 weeks, and presence of anastomotic stenosis. RESULTS: Groups were comparable for basic patient demographics, operating surgeon, and vessel diameter as measured on preoperative ultrasound (mean age, 58.9 +/- 13 years; 68% male). Primary patency at 6 weeks was higher in the hybrid interrupted-continuous suturing technique group (71% vs 47%; P = .01). Immediate patency was also higher in the hybrid interrupted continuous suturing technique group (93% vs 67%; P < .001). There was no significant difference in functional patency at 6 weeks (52% vs 36%; P = .18). Three patients developed an anastomotic stenosis. All were in the hybrid interrupted-continuous suturing technique group. One patient from the interrupted suturing technique cohort required re-exploration for bleeding. CONCLUSIONS: A hybrid interrupted-continuous suturing technique yielded higher immediate and 6 week primary patency rates for RCF. The hybrid interrupted-continuous suturing technique may improve anastomotic compliance and reduce the narrowing and puckering that can occur on suture tightening in small-caliber vessels. Based on these findings, consideration should be given to performing hybrid interrupted continuous anastomoses for RCFs. PMID- 26506937 TI - Outcome comparison between open and endovascular management of axillosubclavian arterial injuries. AB - BACKGROUND: Endovascular repair (ER) of axillosubclavian arterial injuries is a minimally invasive alternative to open repair (OR). The purpose of this study was to compare the outcomes of ER vs OR. METHODS: A retrospective study was performed of patients who sustained axillosubclavian arterial injuries admitted to two high volume academic trauma centers between 2003 and 2013. Patients undergoing ER and OR were matched according to 25 different demographic and clinical variables in a 1:3 ratio using propensity scores. The primary outcome was in-hospital mortality. Secondary outcomes were complications and length of stay. RESULTS: Among 153 patients (79.7% male; mean age, 32.7 +/- 15.9 years) who sustained axillosubclavian arterial injuries, 18 (11.8%) underwent ER and 135 (88.2%) had OR. Matched cases (ER, n = 18) and controls (OR, n = 54) had similar demographic and clinical data, such as age, gender, admission systolic blood pressure and Glasgow Coma Scale score, body Abbreviated Injury Scale scores, Injury Severity Score, and transfusion requirements. Patients undergoing ER had significantly lower in-hospital mortality compared with patients undergoing OR (5.6% vs 27.8%; P = .040; odds ratio, 0.7; 95% confidence interval, 0.6-0.9). Similarly, patients undergoing ER had substantially lower rates of surgical site infections and a trend toward lower rates of sepsis. Outpatient follow-up was available in 88.2% (n = 15) of the patients at a median time of 8 months (1-30 months). Two ER patients required open reintervention for stent-related complications (one for a type Ia endoleak and another for stent thrombosis). CONCLUSIONS: In our experience with axillosubclavian arterial injuries, ER was associated with improved mortality and lower complication rates. Patient follow-up demonstrates an acceptable reintervention rate after ER. Further multicenter prospective evaluation is warranted to determine long-term outcomes. PMID- 26506938 TI - Safety and utility of total percutaneous endovascular aortic repair with a single Perclose ProGlide closure device. AB - OBJECTIVE: This study evaluated the safety and efficacy of total percutaneous endovascular aortic aneurysm repair (PEVAR) with a single Perclose ProGlide device (Abbot Vascular, Santa Clara, Calif) compared with endovascular aortic repair with surgical cutdown (SEVAR). METHODS: The study included 50 abdominal aortic aneurysm patients who were treated with PEVAR with a single Perclose ProGlide device and 96 patients treated with SEVAR. Technical success was defined as successful arterial closure of the common femoral artery without the need for adjunctive surgical or endovascular procedures. The rates of complications, including bleeding requiring transfusion, infection, pseudoaneurysm, paresthesia, and lymphocele, as well as the operating room time and hospital duration were compared between the PEVAR and SEVAR groups. RESULTS: Technical success was obtained in all patients in the PEVAR group. One patient in the SEVAR group needed surgical repair due to access site bleeding. Complication rates were similar between the groups (4% in the PEVAR vs 8% in the SEVAR; P = .495). The PEVAR group had significantly shorter operating room times (153 +/- 47 minutes vs 211 +/- 88 minutes, P < .001) and hospital lengths of stay (6.7 +/- 6.8 days vs 9.3 +/- 4.5 days, P < .001). CONCLUSIONS: Compared with SEVAR, PEVAR with a single ProGlide device is a safe procedure with a shorter operating room time and hospital stay, without increasing access site complications. PMID- 26506939 TI - Discussion. PMID- 26506940 TI - Digital periarterial sympathectomy in the management of post-traumatic Raynaud syndrome. AB - OBJECTIVE: Among Basque handball players, the repeated impact of a ball on the palms of their hands hundreds of thousands of times throughout their sporting careers produces Raynaud syndrome. Treating this patient group is complex. Our objective was to assess the efficacy of digital periarterial sympathectomy in this patient group. METHODS: The study included all of the federated amateur and professional Basque handball patients who presented with Raynaud syndrome assessed in the vascular surgery service between January 2005 and December 2012. The postoperative assessment included a physical examination, basal photoplethysmography and photoplethysmography after heat hyperemia, and arteriography or magnetic resonance angiography. RESULTS: All 182 digital periarterial sympathectomies in the 114 fingers of 60 patients were in Porter functional class III or IV. All patients were discharged within the first 48 hours. Follow-up results, with a mean of 2 years +/- 5 months, were 100%. All patients presented immediate pain remission, recovery of comfort, normal nail growth, rapid healing of all ulcers, distal anhidrosis, and return to active sport participation. The results remain steady in 58 patients (93.5%). Mean time until return to sports activity was 9.95 +/- 1.61 weeks. CONCLUSIONS: Digital periarterial sympathectomy is a simple, relatively nonaggressive technique without adverse side effects and with excellent medium-term results. In patients with Raynaud syndrome refractory to medical treatment and with threat to the viability of one or several fingers, digital periarterial sympathectomy can be the first treatment option, especially in cases of arteritis associated with very severe spasms. PMID- 26506941 TI - Improved trends in patient survival and decreased major complications after emergency ruptured abdominal aortic aneurysm repair. AB - BACKGROUND: Improved trends in patient survival and decreased major complications after emergency ruptured abdominal aortic aneurysm (AAA) repair. Emergency AAA repair carries a high risk of morbidity and mortality. This study seeks to examine morbidity and mortality trends from the National Surgical Quality Improvement Program (NSQIP) database, and identify potential risk factors. METHODS: All emergency AAA repairs were identified using the NSQIP database from 2005 to 2011. Univariate analysis (using the Student t, chi(2), and Fisher's exact tests) and multivariate logistic regression was performed to examine trends in mortality and morbidity. RESULTS: Out of 2761 patients who underwent emergency AAA repair, 321 (11.6%) died within 24 hours of surgery. Of the remaining 2440 patients, 1133 (46.4%) experienced major complications and 459 (18.8%) died during the postoperative period. From 2005 to 2011, there was a significant decrease in patient mortality, particularly in patients who survived the perioperative period (P = .002). Total complications increased overall (P < .0001); however, major complications decreased from 58.7% in 2005 to 42.6% in 2011 (P < .0001) among patients who survived beyond 24 hours. The use of endovascular aortic repair (EVAR) increased over the study period (P < .0001). On multivariate analysis of patients who survived past the initial 24-hour period, advancing age (odds ratio [OR], 1.1; 95% confidence interval [CI], 1.0-1.1), chronic obstructive pulmonary disease (OR, 2.6; 95% CI, 1.7-4.1), dependent functional status (OR, 2.0; 95% CI, 1.2-3.2), and presence of a major complication (OR, 3.1; 95% CI, 2.0-5.0) were significantly associated with death, whereas presence of a senior resident (OR, 0.4; 95% CI, 0.3-0.6) or fellow (OR 0.3; 95% CI, 0.2-0.6) was inversely associated with death. EVAR was not associated with death, but was associated with 30-day complications (OR, 0.5; 95% CI, 0.3-0.6). CONCLUSIONS: Patient survival has increased from 2005 to 2011 after emergency AAA repair, with a significant improvement particularly in patients who survive past the first 24 hours. EVAR was not associated with mortality, but was protective of 30-day complications. Although the total number of complications increased, the number of major complications decreased over the study period, suggesting that newer techniques and patient care protocols may be improving outcomes. PMID- 26506942 TI - Reduced endothelial progenitor cells in extracranial arterial stenosis but not intracranial arterial stenosis. AB - OBJECTIVE: Endothelial progenitor cells (EPCs) are novel markers of endothelial dysfunction and are related to cardiovascular disease. However, their relationship with cerebral atherosclerosis (CA) has not been investigated extensively. We aim to study the relationship between CA severity and EPC subpopulations levels. METHODS: We enrolled 197 patients in this study. EPCs were measured by flow cytometry. Digital subtraction angiography was used to assess CA. Arterial lesion severity was evaluated among cerebral arteries which showed steno-occlusion change and the extent of that condition. RESULTS: There was a significant inverse correlation between EPCs level and CA prevalence after adjusting for confounders (CD45(-/dim)CD34(+)CD309(+) cells: odds ratio [OR], 0.110; 95% confidence interval [CI], 0.026-0.475; P = .00; CD45( /dim)CD133(+)CD309(+) cells: OR, 0.134; 95% CI, 0.030-0.599; P = .01; CD45(-/dim) CD34(+)CD133(+)CD309(+) cells: OR, 0.010; 95% CI, 0.001-0 .541, P = .02). Multivariate logistic regression analysis showed that only the EPCs level was significantly inversely associated with extracranial atherosclerosis rather than intracranial atherosclerosis (P > .05). CONCLUSIONS: Our data indicated that EPCs subpopulations were independent predictors for CA severity, even after controlling for traditional risk factors. PMID- 26506943 TI - Utility of a tubularized extracellular matrix as an alternative conduit for arteriovenous fistula aneurysm repair. AB - OBJECTIVE: The treatment of segmental arteriovenous fistula aneurysms (AVFAs) remains a challenge in dialysis access preservation. We examined our experience with the use of tubularized extracellular matrix (ECM; CorMatrix, Roswell, Ga) for AVFA repair. METHODS: Between October 2013 and January 2015, we conducted a prospective study of CorMatrix ECM for AVFA repair. All patients underwent intraoperative fistulography. Patients with central venous stenosis or occlusion had simultaneous angioplasty and stenting as indicated. The aneurysm and overlying skin were then resected, and an ECM patch was fashioned into a tube for interposition repair. Patients with multiple AVFAs underwent staged repair. Cannulation of the repaired segments was allowed after 6 weeks. RESULTS: During the study period, 15 patients (40% male; mean age, 49.5 years) underwent 18 AVFA repairs using ECM (3 staged repairs). Six patients (40%) underwent simultaneous treatment of central vein lesions, whereas eight patients (53%) had associated skin erosion. Treated sites included radiocephalic (2), brachiobasilic (1), and brachiocephalic (15) AVFAs. All patients had hemodialysis at an alternative location on the same extremity without the need for catheter placement. Five patients underwent a follow-up ultrasound examination at a mean of 6 weeks. All studies demonstrated patency of the ECM segments without stenosis. At a mean follow-up time of 6.9 months, two thrombosis events were observed, both in patients with known refractory central venous stenosis treated with previous angioplasty (2) and stenting (1). Both patients required new access placement. No complications were attributable to ECM sites. CONCLUSIONS: ECM is an alternative conduit for salvage of an autologous AVFA. This technique may help avoid the use of prosthetic grafts and hemodialysis catheters. Patients with associated central venous stenosis are at risk of thrombosis. PMID- 26506944 TI - Molecular regulation of miRNAs and potential biomarkers in the progression of hepatic steatosis to NASH. AB - Increasing evidence suggests that microRNAs regulate diverse biological functions in the liver and play a very important function in metabolic-related disorders such as nonalcoholic fatty liver disease via regulating their target genes expression. In this review, we summarized the most recent progress in identification of miRNAs involving in the progression of liver steatosis and discussed the possible mechanisms by which miRNAs contribute to the diverse pathogenic liver injuries. We provide insights into the functional network of miRNAs by connecting miRNAs, their targets and biological pathways associated to hepatic steatosis and fibrosis, with important implications for our understanding of phenotypic-based disease pathogenesis. We also discuss the possible roles and challenges of miRNAs as biomarkers for drug-induced liver injury. PMID- 26506945 TI - Posttranslationally caused bioluminescence burst of the Escherichia coli luciferase reporter strain. AB - We continuously monitored bioluminescence from a wild-type reporter strain of Escherichia coli (lacp::luc+/WT), which carries the promoter of the lac operon (lacp) fused with the firefly luciferase gene (luc+). This strain showed a bioluminescence burst when shifted into the stationary growth phase. Bioluminescence profiles of other wild-type reporter strains (rpsPp::luc+ and argAp::luc+) and gene-deletion reporter strains (lacp::luc+/crp- and lacp::luc+/lacI-) indicate that transcriptional regulation is not responsible for generation of the burst. Consistently, changes in the luciferase protein levels did not recapitulate the profile of the burst. On the other hand, dissolved oxygen levels increased over the period across the burst, suggesting that the burst is, at least partially, caused by an increase in intracellular oxygen levels. We discuss limits of the firefly luciferase when used as a reporter for gene expression and its potential utility for monitoring metabolic changes in cells. PMID- 26506946 TI - Polysaccharide from Pleurotus nebrodensis induces apoptosis via a mitochondrial pathway in HepG2 cells. AB - A novel alkali extractable polysaccharide (designated as PNA-2) was purified from Pleurotus nebrodensis and the effects of purified PNA-2 on the proliferation and apoptosis of human hepatic cancer cells (HepG2) were investigated in this study. The results of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that PNA-2 inhibited the proliferation of HepG2 cells by apoptosis induction, which was also characterized using scanning electron microscopy (SEM). Moreover, the expression of apoptosis-associated mRNA, proteins and the cell-cycle arrest at the G0/G1 phase was determined using RT-qPCR, Western blot and flow cytometry, respectively. A notable inhibition of the migration rate of PNA-2-treated HepG2 cells was observed using a cell scratch assay. DNA damage was observed using a comet assay and AO/EB staining in HepG2 cells, which were exposed to PNA-2. Induction of the mitochondria-mediated intrinsic apoptotic pathway by PNA-2 was indicated by the loss of mitochondrial membrane potential (DeltaPsim), Bcl-2 dysregulation and cytochrome c release. All the results suggested that the mitochondria-mediated intrinsic apoptotic pathway could be involved in PNA-2-mediated apoptosis of human liver carcinoma cells HepG2. Finally, the results indicated that PNA-2 significantly suppressed tumor growth in HepG2 tumor-bearing mice, indicating that PNA-2 may be developed as a candidate drug or functional food factor to prevent or treat liver cancer. PMID- 26506947 TI - Paraneoplastic pemphigus associated with fatal bronchiolitis obliterans and intractable mucosal erosions: Treatment with cyclosporin in addition to steroid, rituximab and intravenous immunoglobulin. AB - Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease that presents as severe mucosal erosions and variable cutaneous lesions and is primarily associated with hematologically malignant or benign diseases. A 59-year-old Japanese woman presented with oral, ocular and vaginal mucosal erosions and erythema as well as blistering on her trunk and limbs. She developed bronchiolitis obliterans; lymphadenopathy in the cervical, subclavian, para aortic and intraperitoneal regions; and splenomegaly. PNP with B-cell lymphoma was diagnosed. She was treated with two courses of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) for B-cell lymphoma, rituximab once every 3 weeks for five cycles, steroid pulse therapy, oral prednisolone, cyclosporin and high-dose i.v. immunoglobulin. The B-cell lymphoma was in remission after two courses of R-CHOP treatment. Although her skin erythema and blistering were also improved, the mucosal erosions and bronchiolitis obliterans gradually worsened. The patient died of bronchiolitis obliterans after 6 months of hospitalization. Because a cellular immune response is thought to be involved in the pathogenesis of PNP, cyclosporin therapy is expected to aid in suppressing the cellular response. In this case, however, the patient's mucosal lesions and bronchiolitis obliterans were not improved by regular administration of cyclosporin therapy. PMID- 26506948 TI - Complete chloroplast and ribosomal sequences for 30 accessions elucidate evolution of Oryza AA genome species. AB - Cytoplasmic chloroplast (cp) genomes and nuclear ribosomal DNA (nR) are the primary sequences used to understand plant diversity and evolution. We introduce a high-throughput method to simultaneously obtain complete cp and nR sequences using Illumina platform whole-genome sequence. We applied the method to 30 rice specimens belonging to nine Oryza species. Concurrent phylogenomic analysis using cp and nR of several of specimens of the same Oryza AA genome species provides insight into the evolution and domestication of cultivated rice, clarifying three ambiguous but important issues in the evolution of wild Oryza species. First, cp based trees clearly classify each lineage but can be biased by inter-subspecies cross-hybridization events during speciation. Second, O. glumaepatula, a South American wild rice, includes two cytoplasm types, one of which is derived from a recent interspecies hybridization with O. longistminata. Third, the Australian O. rufipogan-type rice is a perennial form of O. meridionalis. PMID- 26506949 TI - Bifidobacteria exhibit social behavior through carbohydrate resource sharing in the gut. AB - Bifidobacteria are common and frequently dominant members of the gut microbiota of many animals, including mammals and insects. Carbohydrates are considered key carbon sources for the gut microbiota, imposing strong selective pressure on the complex microbial consortium of the gut. Despite its importance, the genetic traits that facilitate carbohydrate utilization by gut microbiota members are still poorly characterized. Here, genome analyses of 47 representative Bifidobacterium (sub)species revealed the genes predicted to be required for the degradation and internalization of a wide range of carbohydrates, outnumbering those found in many other gut microbiota members. The glycan-degrading abilities of bifidobacteria are believed to reflect available carbon sources in the mammalian gut. Furthermore, transcriptome profiling of bifidobacterial genomes supported the involvement of various chromosomal loci in glycan metabolism. The widespread occurrence of bifidobacterial saccharolytic features is in line with metagenomic and metatranscriptomic datasets obtained from human adult/infant faecal samples, thereby supporting the notion that bifidobacteria expand the human glycobiome. This study also underscores the hypothesis of saccharidic resource sharing among bifidobacteria through species-specific metabolic specialization and cross feeding, thereby forging trophic relationships between members of the gut microbiota. PMID- 26506950 TI - Role of tDCS in potentiating poststroke computerized cognitive rehabilitation: Lessons learned from a case study. AB - Cognitive impairment after stroke is quite common and can cause important disability with a relevant impact on quality of life. Cognitive rehabilitation (CR) and related assistive technology may improve functional outcomes. A 30-year old woman came to our research institute for an intensive CR cycle following a right parieto-temporal stroke. Because the patient was in the chronic phase, we decided to use 3 different rehabilitative protocols: (a) traditional cognitive training (TCT), (b) computerized cognitive training (CCT), and (c) CCT combined with transcranial direct stimulation (CCT plus) with a 2-week interval separating each session. Cognitive and language deficits were investigated using an ad-hoc psychometric battery at baseline (T0), post-TCT (T1), post-CCT (T2), and post-CCT plus (T3). Our patient showed the best neuropsychological improvement, with regard to attention processes and language domain, after T3. Our data showed that CCT plus should be considered a promising tool in the treatment of poststroke neuropsychological deficits. PMID- 26506951 TI - Rhamnolipids induce oxidative stress responses in cherry tomato fruit to Alternaria alternata. AB - BACKGROUND: Rhamnolipids showed an antimicrobial activity applicable to a variety of pathogenic microorganisms, but mechanisms were mostly focused on their direct inhibitory effect. RESULTS: This study showed that disease incidence obviously decreased when cherry tomatoes were treated with rhamnolipids, whether before or after Alternaria alternata inoculation. The activities of antioxidant enzymes, including superoxide dismutase and catalase, were increased in rhamnolipid pretreated cherry tomato inoculated with A. alternata within 12 h, while contents of reactive oxygen species decreased. Moreover, resistant response of cherry tomato treated with rhamnolipids and A. alternata was also attributed to activity stimulation of ascorbate peroxidase and glutathione reductase, accompanied with an increase in reduced glutathione, which is beneficial for scavenging excessive H2 O2 . CONCLUSION: Results indicated that rhamnolipids could effectively reduce fungal disease of harvested cherry tomato by inducing fruit resistance and mechanisms involved in elicitation of antioxidative reactions such as the ability to scavenge excess reactive oxygen species. (c) 2015 Society of Chemical Industry. PMID- 26506952 TI - Transurethral Resection of the Prostate (TURP) Versus Original and PErFecTED Prostate Artery Embolization (PAE) Due to Benign Prostatic Hyperplasia (BPH): Preliminary Results of a Single Center, Prospective, Urodynamic-Controlled Analysis. AB - PURPOSE: To compare clinical and urodynamic results of transurethral resection of the prostate (TURP) to original and PErFecTED prostate artery embolization (PAE) methods for benign prostatic hyperplasia. METHODS: We prospectively randomized 30 patients to receive TURP or original PAE (oPAE) and compared them to a cohort of patients treated by PErFecTED PAE, with a minimum of 1-year follow-up. Patients were assessed for urodynamic parameters, prostate volume, international prostate symptom score (IPSS), and quality of life (QoL). RESULTS: All groups were comparable for all pre-treatment parameters except bladder contractility and peak urine flow rate (Q max), both of which were significantly better in the TURP group, and IIEF score, which was significantly higher among PErFecTED PAE patients than TURP patients. All groups experienced significant improvement in IPSS, QoL, prostate volume, and Q max. TURP and PErFecTED PAE both resulted in significantly lower IPSS than oPAE but were not significantly different from one another. TURP resulted in significantly higher Q max and significantly smaller prostate volume than either original or PErFecTED PAE but required spinal anesthesia and hospitalization. Two patients in the oPAE group with hypocontractile bladders experienced recurrence of symptoms and were treated with TURP. In the TURP group, urinary incontinence occurred in 4/15 patients (26.7 %), rupture of the prostatic capsule in 1/15 (6.7 %), retrograde ejaculation in all patients (100 %), and one patient was readmitted for temporary bladder irrigation due to hematuria. CONCLUSIONS: TURP and PAE are both safe and effective treatments. TURP and PErFecTED PAE yield similar symptom improvement, but TURP is associated with both better urodynamic results and more adverse events. PMID- 26506953 TI - Continuing donepezil when Alzheimer symptoms worsen might delay nursing home admission, study indicates. PMID- 26506954 TI - Screening of Glaucoma or Cataract Prevalence in Vitiligo Patients and Its Relationship With Periorbital Steroid Use. AB - BACKGROUND/AIM: There is scarce literature connecting vitiligo and primary open angle glaucoma (POAG). Most literature reports that secondary complications are a direct consequence of corticosteroid treatment of vitiligo. In this study, we aimed to investigate the prevalence of ocular problems in patients with vitiligo and to determine its association with periorbital topical corticosteroid use. METHOD: A cross-sectional study was carried out on 90 patients with vitiligo. The Vitiligo European Task Force questionnaire was completed for each patient. A control group comprising 90 healthy individuals who did not have vitiligo and who were matched on age and gender was used for comparison. A complete ophthalmologic examination was performed. A family history of glaucoma and the use of topical steroids were recorded. RESULTS: Two (2/90, 2.2%) of the patients with vitiligo had glaucoma compared with none of the individuals in the control group (P = .25). Nineteen of the 90 patients with vitiligo used periorbital steroids, and of these patients, 10.5% (2/19) developed glaucoma. The duration of periorbital corticosteroid use was 4.50 +/- 2.1 years. Eighty-nine percent (17/19) of the vitiligo patients who applied the potent topical corticosteroid (class I) clobetasol propionate to the periorbital area did not develop glaucoma. In contrast, glaucoma was not observed in 79% (71/90) of the vitiligo patients who did not use steroids. Cataract, uveitis, or fundus problems were not observed in either group. CONCLUSION: The study suggests that patients who have vitiligo and use topical steroids periorbitally do not have an increased risk of glaucoma or cataracts. Future studies that have a larger sample size and use a detailed steroid use protocol are needed. PMID- 26506955 TI - Functional disruption of human leukocyte antigen II in human embryonic stem cell. AB - BACKGROUND: Theoretically human embryonic stem cells (hESCs) have the capacity to self-renew and differentiate into all human cell types. Therefore, the greatest promise of hESCs-based therapy is to replace the damaged tissues of patients suffering from traumatic or degenerative diseases by the exact same type of cells derived from hESCs. Allograft immune rejection is one of the obstacles for hESCs based clinical applications. Human leukocyte antigen (HLA) II leads to CD4(+) T cells-mediated allograft rejection. Hence, we focus on optimizing hESCs for clinic application through gene modification. RESULTS: Transcription activator like effector nucleases (TALENs) were used to target MHC class II transactivator (CIITA) in hESCs efficiently. CIITA (-/-) hESCs did not show any difference in the differentiation potential and self-renewal capacity. Dendritic cells (DCs) derived from CIITA (-/-) hESCs expressed CD83 and CD86 but without the constitutive HLA II. Fibroblasts derived from CIITA (-/-) hESCs were powerless in IFN-gamma inducible expression of HLA II. CONCLUSION: We generated HLA II defected hESCs via deleting CIITA, a master regulator of constitutive and IFN gamma inducible expression of HLA II genes. CIITA (-/-) hESCs can differentiate into tissue cells with non-HLA II expression. It's promising that CIITA (-/-) hESCs-derived cells could be used in cell therapy (e.g., T cells and DCs) and escape the attack of receptors' CD4(+) T cells, which are the main effector cells of cellular immunity in allograft. PMID- 26506956 TI - TOR1A, THAP1, and GNAL mutational screening in Austrian patients with primary isolated dystonia. PMID- 26506957 TI - Margaret McCartney: Cash as a treatment for poverty. PMID- 26506958 TI - Unknown Risks: Parental Hesitation about Vaccination. AB - OBJECTIVE: This qualitative study of a select sample of vaccine-hesitant parents (VHPs) explores perceived and constructed personal judgments about the risks and uncertainties associated with vaccines and vaccine-preventable diseases (VPDs) and how these subjective risk judgments influence parents' decisions about childhood vaccination. METHODS: The study employed semistructured focus group interviews with 42 VHPs to elicit parents' perceptions and thought processes regarding the risks associated with vaccination and nonvaccination, the sources of these perceptions, and their approach to decision making about vaccination for their children. RESULTS: VHPs engage in various reasoning processes and tend to perceive risks of vaccination as greater than the risks of VPDs. At the same time, VHPs engage in other reasoning processes that lead them to perceive ambiguity in information about the harms of vaccination-citing concerns about the missing, conflicting, changing, or otherwise unreliable nature of information. CONCLUSIONS: VHPs' refusal of vaccination may reflect their aversion to both the risk and ambiguity they perceive to be associated with vaccination. Mitigating this vaccine hesitancy likely requires reconstructing the risks and ambiguities associated with vaccination-a challenging task that requires providing parents with meaningful evidence-based information on the known risks of vaccination versus VPDs and explicitly acknowledging the risks that remain truly unknown. PMID- 26506964 TI - Health equity: the linchpin of sustainable development. PMID- 26506959 TI - Long-term mortality of patients surviving firearm violence. AB - OBJECTIVE: We aim to calculate the 5-year mortality after surviving to hospital discharge after a firearm injury and estimate the association of firearm injury with later mortality. METHODS: We performed a retrospective cohort study of patients from an urban emergency department (ED) and trauma centre in Oakland, California, USA, in 2007. We created three cohorts of patients presenting for (1) gunshot wound (GSW), (2) MVC and (3) assault without a firearm. Demographic and clinical information was obtained from the clinical chart, and the California Department of Public Health Vital Statistics and Social Security Death Master File (2007-2012) were queried to identify patients who died. RESULTS: We analysed 516 GSW patients, 992 MVC patients and 695 non-GSW assault patients. Of the GSW patients, 86.4% were alive at 5 years. All-cause 5-year mortality among GSW victims surviving to discharge after injury was 5.1%. Compared with MVC patients, both GSW and non-GSW assault patients have higher risk of death at 5 years (HR 2.54 (95% CI 1.41 to 4.59) and HR 1.64 (95% CI 1.01 to 2.68), respectively), adjusting for age, sex and race. Risk of death was higher in the first year for the GSW cohort (HR 6.14 (95% CI 2.35 to 16.08) and HR 5.06 (95% CI 1.88 to 13.63) as compared with MVC and non-GSW assault cohorts, respectively). Homicide was the cause of death in 79.2% of GSW patients who died after surviving the index injury. CONCLUSION: Among individuals presenting to the ED after injury or assault and surviving to discharge, firearm injury exposure is an important predictor of death within 5 years and most pronounced in the first year after injury. PMID- 26506965 TI - Schwertmannite formation at cell junctions by a new filament-forming Fe(II) oxidizing isolate affiliated with the novel genus Acidithrix. AB - A new acidophilic iron-oxidizing strain (C25) belonging to the novel genus Acidithrix was isolated from pelagic iron-rich aggregates ('iron snow') collected below the redoxcline of an acidic lignite mine lake. Strain C25 catalysed the oxidation of ferrous iron [Fe(II)] under oxic conditions at 25 degrees C at a rate of 3.8 mM Fe(II) day(-1) in synthetic medium and 3.0 mM Fe(II) day(-1) in sterilized lake water in the presence of yeast extract, producing the rust coloured, poorly crystalline mineral schwertmannite [Fe(III) oxyhydroxylsulfate]. During growth, rod-shaped cells of strain C25 formed long filaments, and then aggregated and degraded into shorter fragments, building large cell-mineral aggregates in the late stationary phase. Scanning electron microscopy analysis of cells during the early growth phase revealed that Fe(III)-minerals were formed as single needles on the cell surface, whereas the typical pincushion-like schwertmannite was observed during later growth phases at junctions between the cells, leaving major parts of the cell not encrusted. This directed mechanism of biomineralization at specific locations on the cell surface has not been reported from other acidophilic iron-oxidizing bacteria. Strain C25 was also capable of reducing Fe(III) under micro-oxic conditions which led to a dissolution of the Fe(III)-minerals. Thus, strain C25 appeared to have ecological relevance for both the formation and transformation of the pelagic iron-rich aggregates at oxic/anoxic transition zones in the acidic lignite mine lake. PMID- 26506966 TI - Initial guidelines for colorectal cancer screening in Saudi Arabia: a beginning. PMID- 26506967 TI - Prevalence of major congenital anomalies at King Fahad Medical City in Saudi Arabia: a tertiary care centre-based study. AB - BACKGROUND AND OBJECTIVES: The prevalence of major congenital anomalies in Saudi Arabia is a largely understudied area. Knowing the prevalence of birth defects and their trends is important in identifying potential factors that are either causative or preventative. Early antenatal diagnosis of major congenital anomalies is important for possible termination of pregnancy, fetal or neonatal. We determined the prevalence of major congenital anomalies in our hospital population since implementation of an improved screening system. PATIENTS AND METHODS: This single-centre prospective cross-sectional study was conducted in a tertiary care hospital in Riyadh. A total of 63452 obstetrical ultrasound examinations were performed for 30632 female Saudi obstetric patients from the period of January 2007 to December 2012. RESULTS: A total of 1598 fetuses were diagnosed with major congenital anomalies, including 1064 (66.6 %) fetuses with isolated major anomalies and 534 (33.4%) fetuses with non-isolated major anomalies. The antenatal prevalence of congenital anomalies was 52.1 per 1000 pregnancies. The median maternal age at diagnosis was 29 years. The median gestational age at diagnosis was 30 weeks of gestation. Two hundred and eighty five cases (17.85%) had a previous family history of similar anomalies. The most commonly diagnosed anomalies involved the genitourinary system (652 cases). The birth prevalence of major congenital anomalies was 46.5 per 1000 live births. CONCLUSION: The prevalence of major congenital anomalies in our hospital population appears to be higher than international prevalences, with a high recurrence rate. Environmental, nutritional and social factors may be contributing to this phenomenon. PMID- 26506968 TI - High-volume hemofiltration plus hemoperfusion for hyperlipidemic severe acute pancreatitis: a controlled pilot study. AB - BACKGROUND AND OBJECTIVES: The evidence for high-volume hemofiltration plus hemoperfusion (HVHF&HP) for hyperlipidemic severe acute pancreatitis (HL-SAP) is anecdotal. The purpose of our study was to evaluate the efficacy of HVHF&HP for HL-SAP in a prospective controlled study. DESIGN AND SETTING: Prospective controlled pilot study between May 2010 and May 2013 in a hospital intensive care unit. PATIENTS AND METHODS: HL-SAP patients chose conventional treatment alone (the control group) or conventional treatment combined with the experimental protocol (the HVHF&HP group) and were prospectively followed in our hospital. APACHE II score, SOFA score, ICU and hospital stay duration, and serum biomarkers were considered endpoints. RESULTS: Ten HL-SAP patients accepted conventional treatment alone (the control group) and 10 patients underwent HVHF&HP combined with conventional treatment (the HVHF&HP group). The APACHE II score, SOFA score, systolic blood pressure, diastolic blood pressure, heart rate, serum amylase, and serum creatinine were significantly reduced after the HVHF&HP treatment. The changes in these variables were significantly different between the HVHF&HP and control group at 48 hours after the initiation of treatment. Patients in the HVHF&HP group had a significantly shorter ICU stay (P=.015). The reduction in serum triglyceride and cholesterol in the HVHF&HP group after 2, 6, 12, 24, and 48 hours was greater than the control group. All of the tested serum cytokines were significantly decreased after HVHF&HP treatment (P < .05). However, in patients who underwent conventional treatment alone, there was no significant change in the serum cytokines. CONCLUSION: This study suggests that the addition of HVHF&HP to conventional treatment for HL-SAP patients may be superior to conventional treatment alone for the improvement of serum biomarkers and clinical outcomes. PMID- 26506969 TI - Psychiatric disorders among infertile men and women attending three infertility clinics in Riyadh, Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: No study has assessed psychiatric disorders among infertile men and women seeking fertility treatment in Saudi Arabia. Therefore, we sought to measure the rate of psychiatric disorders in this population. DESIGN AND SETTING: This was a cross-sectional observational study among patients attending infertility clinics at three referral hospitals in Riyadh, Saudi Arabia, between January 2013 and September 2014. PATIENTS AND METHODS: 406 patients (206 women and 200 men) participated in the study. The approved Arabic version of the MINI tool was used to assess 18 common psychiatric illnesses. RESULTS: The response rate was 81%. Of the men surveyed, only 4.5% self-reported having a psychiatric disorder. Of the women surveyed, only 10.2% reported having a psychiatric disorder. However, using the MINI scale, psychiatric illness was documented in 30% of males and 36.9% of females. The most common diagnoses for both genders were depression (21.7%) and anxiety (21.2%). Significantly more females than males exhibited suicidality and depression. In contrast, significantly more males than females had bipolar disorders and substance-related disorders. A low monthly income among male and female participants and polygamy among female participants were significantly associated with psychiatric disorders. CONCLUSIONS: This study shows that a higher prevalence of psychiatric disorders, particularly depression and anxiety, among infertile men and women in Saudi Arabia is associated with lower income and polygamy. This study highlights the importance of integrated care for alleviating the psychological burden of this unfortunate population and improving outcomes and quality of life. This study also encourages follow-up studies that aim to further understand the complex relationship between fertility and psychological well-being. PMID- 26506970 TI - Exploring quality of life among renal and liver transplant recipients. AB - BACKGROUND AND OBJECTIVES: Despite the worldwide recognition of the importance of quality of life (QOL) assessment, research data on QOL for renal and liver transplant recipients are limited. The main objective of this study was to explore and compare QOL in renal and liver transplant patients. DESIGN AND SETTING: This cross-sectional study was conducted at at King Abdulaziz Medical City, Saudi Arabia. PATIENTS AND METHODS: Saudis 16 years of age or more who received liver or renal transplantation at least three months before the study participated. QOL was evaluated using the World Health Organization QOL instrument (WHOQOL-BREF). RESULTS: Renal and liver transplant patients were highly or moderately satisfied with most circumstances of life. Using data for subjects in all WHO centers, renal and liver transplant patients domain scores in this study were significantly higher in the psychological health domain, social relations and environmental domain (P < .0001). The results also show that renal and liver transplant recipients who were male, or had higher education or who were employed had higher QOL scores. CONCLUSIONS: This study found that both renal and liver transplant recipients achieved very high QOL domain scores as compared with international data. Lower QOL was significantly associated with social disadvantages, suggesting that these patients may require more focused attention and counselling following transplantation. PMID- 26506971 TI - Group A beta-hemolytic streptococcal pharyngitis and carriage rate among Egyptian children: a case-control study. AB - BACKGROUND: Improper prescription of antibiotics for treatment of acute pharyngitis predisposes to emergence of a carrier state and antibiotic-resistant strains of group A streptococci (GAS). We sought to identify the frequency and antimicrobial susceptibility patterns of group A streptococci among Egyptian children with acute pharyngitis compared with asymptomatic children. DESIGN AND SETTING: Case-control study conducted from September 2013 to August 2014 at a pediatric outpatient clinic in Egypt. PATIENTS AND METHODS: Throat swabs were collected from children with acute pharyngitis and from asymptomatic children. We evaluated the accuracy of McIsaac scores and the rapid antigen detection test (RADT) for diagnosis of GAS pharyngitis with throat culture as a reference test. Antimicrobial susceptibility testing of GAS isolates was done by the disc diffusion method. RESULTS: Of 142 children with acute pharyngitis (cases) and 300 asymptomatic children (controls) (age range, 4-16 years), GAS pharyngitis was diagnosed in 60/142 children (42.2%); 48/300 (16%) were found to be carriers. All GAS isolates in the case group were sensitive to penicillin; however, an MIC90 (0.12 micro g/mL) for penicillin is high and an alarming sign. The resistance rate to macrolides was 70% with the cMLSB phenotype in 65.1%. The sensitivities and specificities were 78.3% and 73.2% for McIsaac score of >=4 and 81.1% and 93.9% for RADT, respectively. GAS isolates in the control group were 100% sensitive to penicillin, while 12.5% and 37.5% were resistant to macrolides and tetracycline, respectively. CONCLUSION: An increased MIC90 for GAS isolates to penicillin is an alarming sign. A high frequency of resistance to macrolides was also observed. PMID- 26506972 TI - Current practices for lupus anticoagulant testing at a tertiary care hospital and impact on laboratory resources. AB - BACKGROUND AND OBJECTIVES: The lupus anticoagulant (LA) test is an advanced test that is time consuming and requires a highly trained lab specialist. A high proportion of clinicians do not adhere to international guidelines and request the test inappropriately. DESIGN AND SETTINGS: This descriptive study covered the period from January 2012 and January 2013 at the Hematology Laboratory at King Khalid University Hospital, Riyadh. PATIENTS AND METHODS: The 274 lupus anticoagulant requests were categorized as proper or improper based on the guidelines of the International Society of Thrombosis and Haemostasis (ISTH). Data on numbers of requests and cost are summarized. RESULTS: Of the 274 requests, 222 (81%) were classified as proper while 52 (19%) requests did not satisfy ISTH guidelines. The most frequently encountered incorrect indications were warfarin therapy (46%), heparin therapy (27%), a normal aPTT with no clinical indication (25%) and low serum fibrinogen levels (2%). The total cost of all improper requests was about 41080 SAR (10954 USD). CONCLUSION: A majority of improper requests were related to anticoagulant therapy, which highlights the importance of implementing a comprehensive diagnostic algorithm for patients on warfarin and heparin therapy. PMID- 26506973 TI - Indications and techniques employed for keratoplasty in the Eastern province of Saudi Arabia: 6 years of experience. AB - BACKGROUND AND OBJECTIVES: Keratoplasty services in Saudi Arabia have progressed steadily in the past few decades. We sought to identify the leading indications and types of keratoplasty performed in the Eastern Province of Saudi Arabia over a six-year period and to compare these indications with published data. DESIGN AND SETTING: This was a retrospective descriptive analysis of the records of patients who underwent keratoplasty at four ophthalmology centers in the Eastern Province between 2008 and 2013. PATIENTS AND METHODS: All keratoplasty procedures were included in the analysis. The primary surgical indication and type of surgery were identified for each case. RESULTS: Keratoplasties included 570 penetrating keratoplasty, 217 deep lamellar keratoplasty, 80 triple procedures, 24 descemet stripping automated endothelial keratoplasty and 12 Boston keratoprosthesis implantations. The mean age of all patients was 28.8 years (range 14-72 years), and 58.9% of the patient were males. The lead.ing indication for keratoplasty was keratoconus 53.10%, bullous keratopathy 13.80%, corneal scarring 10.7%, regrafts 9.1%, and stromal dystrophies 4.9%. CONCLUSIONS: In this study, the leading indications for keratoplasty were keratoconus, bullous keratopathy, corneal scarring, regrafts and stromal dystrophies. A significant increasing trend for descemet's stripping automated endothelial keratoplasty surgeries was observed in spite of the number of cases. PMID- 26506974 TI - Accessory lacrimal gland duct cyst: 23 years of experience in the Saudi population. AB - BACKGROUND AND OBJECTIVES: Accessory lacrimal gland ductal cyst is a rare clinical entity that has been reported after trauma, infection, or conjunctival inflammation. Trachoma has been postulated as an etiologic factor for this dacryops in Saudis. We studied the prevalence, demographics, clinicopathological features and surgical approach for these lesions. DESIGN AND SETTING: Retrospective study of 23 consecutive ductal cysts diagnosed clinically and proved histopathologically at King Khaled Eye Specialist Hospital (KKESH) over 23 years (1991-2014). PATIENTS AND METHODS: Data on patient demographics, clinical features, surgery, and outcome were collected by chart review. The histopathologic slides were reviewed by a single pathologist. RESULTS: Of 23 cases of accessory lacrimal gland ductal cysts confirmed histopathologically, 14 were males and 9 females with a median age of 38.8 years. Cysts were located in the upper eyelid in 73.9%. The commonest presentation was a painless eyelid mass in 91.3%. Excision by conjunctival incision was performed in 14 and intra operative perforation occurred in 9. Trachomatous scarring was evident in 39.1% but did not have significance in relation to this rupture. No recurrences have been observed with a mean follow up of 34.6 months. CONCLUSION: The approximate prevalence of accessory lacrimal gland dacryops in the Saudi population is 1/6800. Trachoma does not seem to be a major predisposing factor. They are more frequent in males. Their histopathological appearance is identical regardless of origin. The presence of conjunctival scarring, dacryops size, and the surgical incision type did not seem to have significant correlation with the iatrogenic rupture of the cyst. We recommend careful dissection for complete cyst excision through conjunctival approach with no expected recurrence. PMID- 26506975 TI - Mucoepidermoid carcinoma of the nasal septum (case report). AB - We report an extremely rare case of mucoepidermoid carcinoma of the nasal septum. A patient with a history of right-sided nasal obstruction presented to our clinic. Clinical examination revealed a mass in the right nasal cavity originating from the nasal septum. Biopsy revealed a high-grade mucoepidermoid carcinoma. The patient was treated with surgical resection only. Surgery alone might be suitable for small tumors when direct inspection of the surgical site is feasible to detect early recurrence. PMID- 26506976 TI - Hourglass bladder after ileocystoplasty (case report). AB - Narrowing of the anastomotic area between the bowel segment and urinary bladder is known as "hourglass bladder." This report describes a rare case of hourglass bladder deformity occurring post-ileocystoplasty in a 14-year-old male. We describe the essential steps that should be taken during bladder augmentation to avoid such a complication, along with a discussion of the relevant literature. This case emphasizes the need to strictly adhere to the steps of augmentation cystoplasty to avoid this technical complication. PMID- 26506977 TI - Skin infection on both legs caused by Acremonium strictum (case report). AB - Acremonium species are saprophytic molds widely distributed in nature, existing in soil and decaying vegetation. Penetrating wounds, intravascular catheters and immunosuppression are risk factors for invasive infections of Acremonium. The fungus can also cause cutaneous infections and mycetoma in the immunocompetent; such infections occur in extremities open to trauma. In this paper, a female patient with skin infection due to Acremonium strictum in both legs is described. PMID- 26506978 TI - Invasive pulmonary aspergillosis presenting as thoracic mass causing obstruction of the superior and inferior vena cava in an immunocompetent patient: a diagnostic dilemma. AB - Invasive pulmonary aspergillosis (IPA) is a disease of immunocompromised patients, but its prevalence is increasing in immunocompetent persons. Patients usually present with non-specific symptoms, sometimes consistent with bronchopneumonia. We discuss the case of a 19-year-old boy who presented with constitutional respiratory symptoms along with signs of obstruction of the superior and inferior vena cava. A chest radiograph was suggestive of a thoracic mass raising suspicion of bronchogenic carcinoma/ benign mass, sarcoidosis and tuberculosis, but a diagnosis of invasive aspergillosis was established. The patient showed excellent clinico-radiological improvement with administration of voriconazole. Invasive pulmonary aspergillosis may also present with atypical findings and should be considered in differentials when investigating a case even if the patient does not have a risk factor. PMID- 26506979 TI - Paternal long-term exercise programs offspring for low energy expenditure and increased risk for obesity in mice. AB - Obesity has more than doubled in children and tripled in adolescents in the past 30 yr. The association between metabolic disorders in offspring of obese mothers with diabetes has long been known; however, a growing body of research indicates that fathers play a significant role through presently unknown mechanisms. Recent observations have shown that changes in paternal diet may result in transgenerational inheritance of the insulin-resistant phenotype. Although diet induced epigenetic reprogramming via paternal lineage has recently received much attention in the literature, the effect of paternal physical activity on offspring metabolism has not been adequately addressed. In the current study, we investigated the effects of long-term voluntary wheel-running in C57BL/6J male mice on their offspring's predisposition to insulin resistance. Our observations revealed that fathers subjected to wheel-running for 12 wk produced offspring that were more susceptible to the adverse effects of a high-fat diet, manifested in increased body weight and adiposity, impaired glucose tolerance, and elevated insulin levels. Long-term paternal exercise also altered expression of several metabolic genes, including Ogt, Oga, Pdk4, H19, Glut4, and Ptpn1, in offspring skeletal muscle. Finally, prolonged exercise affected gene methylation patterns and micro-RNA content in the sperm of fathers, providing a potential mechanism for the transgenerational inheritance. These findings suggest that paternal exercise produces offspring with a thrifty phenotype, potentially via miRNA induced modification of sperm. PMID- 26506981 TI - Solubility of n-butane and 2-methylpropane (isobutane) in 1-alkyl-3 methylimidazolium-based ionic liquids with linear and branched alkyl side-chains. AB - The solubility of n-butane and 2-methylpropane (isobutane) in three ionic liquids - 1-(2-methylpropyl)-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [(2mC3)C1im][Ntf2], 1-(3-methylbutyl)-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [(3mC4)C1im][Ntf2] and 1-methyl-3 pentylimidazolium bis(trifluoromethylsulfonyl)imide [C5C1im][Ntf2] - has been measured at atmospheric pressure from 303 to 343 K. Isobutane is less soluble than n-butane in all the ionic liquids. Henry's constant values range from 13.8 * 10(5) Pa for n-butane in [C5C1im][Ntf2] at 303 K to 64.5 * 10(5) Pa for isobutane in [(2mC3)C1im][Ntf2] at 343 K. The difference in solubility between the two gases can be explained by a more negative enthalpy of solvation for n-butane. A structural analysis of the pure solvents and of the solutions of the gases, probed by molecular dynamics simulations, could explain the differences found in the systems: (i) the nonpolar domains of the ionic liquids accommodate better the long and more flexible n-butane solute; (ii) the small differences in solubility of each gas in the ionic liquids with the same number of carbon atoms in the alkyl side-chains are explained by the absence of large structural differences in the pure solvents. In all cases, the structural analysis of the four ionic liquids confirms that the studied gases can act as probes of the molecular structure of the ionic liquids, the simulations being always compatible with the experimental solubility data. PMID- 26506980 TI - Mice with hepcidin-resistant ferroportin accumulate iron in the retina. AB - Because ferroportin (Fpn) is the only known mammalian cellular iron exporter, understanding its localization and regulation within the retina would shed light on the direction of retinal iron flux. The hormone hepcidin may regulate retinal Fpn, as it triggers Fpn degradation in the gut. Immunofluorescence was used to label Fpn in retinas of mice with 4 different genotypes (wild type; Fpn C326S, a hepcidin-resistant Fpn; hepcidin knockout; and ceruloplasmin/hephaestin double knockout). No significant difference in Fpn levels was observed in these retinas. Fpn localized to the abluminal side of the outer plexiform vascular endothelial cells, Muller glia cells, and the basolateral side of the retinal pigment epithelium. Adeno-associated virus (AAV)-hepcidin was injected into the eyes of hepcidin knockout mice, while AAV-lacZ was injected into the contralateral eyes as a control. AAV-hepcidin injected eyes had increased ferritin immunolabeling in retinal vascular endothelial cells. Fpn C326S mice had systemic iron overload compared to wild type and had the fastest retinal iron accumulation of any hereditary model studied to date. The results suggest that physiologic hepcidin levels are insufficient to alter Fpn levels within the retinal pigment epithelium and Muller cells, but may limit iron transport into the retina from vascular endothelial cells. PMID- 26506982 TI - Light-NBI to identify high-risk phenotypes for gastric adenocarcinoma: do we still need biopsies? AB - OBJECTIVE: Early diagnosis of gastric cancer may be achieved through surveillance of patients with extensive gastric intestinal metaplasia (eGIM). However, diagnosis of eGIM generally implies histology. We aimed at determining the accuracy of high-resolution endoscopy with light-narrow band imaging (NBI) to assess the presence of eGIM on a per-patient basis. MATERIAL AND METHODS: Prospective cohort of 60 patients divided into two groups: derivation cohort (n = 25) to evaluate the reliability and validity, and a real-time validation group (n = 35). In the derivation group, six endoscopists with two levels of expertise were asked to estimate the grade of GIM based in endoscopic images (white light endoscopy, light-NBI and amplification/near focus). In the real-time validation set, experienced endoscopists were asked to similarly record their real-time optical diagnosis. Histology was then considered as the gold standard. RESULTS: In the derivation group diagnosis accuracy was 60% with WLE (non-expert 59% vs. 61% experts), increasing to 73% after NBI magnification (non-expert 63% vs. 83% expert, p < 0.05). Moreover, proportion of agreement with histology was 83%, with a correct diagnosis of eGIM in 87% for experienced observers. In the real-time group experts obtained 89% global diagnostic accuracy correctly identifying 91% of the eGIM. The sensitivity, specificity, LR + and LR- of real-time endoscopic diagnosis of eGIM was 0.92 (CI95%:0.67-0.99), 0.96 (0.79-0.99), 21.1 (3.08-144) and 0.09 (0.013-0.57). CONCLUSION: For the first time the reliability of high resolution endoscopy with light-NBI for extension of GIM is described. Our results suggest that more than 90% of individuals at risk could be identified without the need for biopsies, simplifying the current recommendations. PMID- 26506983 TI - Shifting to 4 * 1 intermittent catheterization without an early follow-up urodynamic study is possible in most patients with subacute spinal cord injury. AB - OBJECTIVES: We retrospectively evaluated the frequency of changing to 4/day intermittent catheterization (IC) in patients with subacute spinal cord injury (SCI) who had been initiated on IC 6 times a day and started oral anticholinergic treatment following urodynamic investigation for decreased maximum cystometric capacity and undergone a follow-up urodynamic study within 45 days. The goal of the study was to see if the second urodynamic study was necessary. METHODS: The frequency of shifting to 4/day IC was investigated retrospectively in 27 patients with subacute SCI who were prescribed 6/day IC. RESULTS: In 25 of 27 patients a bladder capacity of 400 ml or more was reached in urodynamic study carried out in the following 45 days and the patients were shifted to 4/day IC. There was a significant difference between the anticholinergic pre-treatment (293 +/- 39 ml) and post-treatment (531 +/- 81 ml) capacities (P < 0.001). The mean increase in bladder capacity in all patients was 237.6 +/- 79.5 ml (83.5 +/- 32.1%). CONCLUSION: Patients with subacute SCI who were prescribed 6/day IC and were given an oral anticholinergic drug can be shifted to 4/day IC after 45 days without performing an early control urodynamic study if the patients use the drug properly. However in the long-run, periodic follow-up urodynamic studies should be carried out at appropriate intervals, according to the patients' clinical findings. PMID- 26506984 TI - Association of IL-4 (intron 3) and IL-10 (-1082) gene polymorphisms with risk of mitral valve disease in children with rheumatic heart disease. AB - Aim Rheumatic heart disease is an inflammatory disease of cardiac tissue. The underlying pathogenic mechanisms highlight a complex interplay of immunological, genetic, and environmental factors. The aim of the present study was to investigate whether IL-4 (intron 3) and IL-10 (-1082) gene polymorphisms could be associated with susceptibility and/or severity of rheumatic heart disease among patients from the Egyptian population. Materials and methods A cohort of 140 Egyptian children with rheumatic heart disease and 100 healthy controls were enrolled in this case-control study. Genotyping for IL-4 (intron 3) and IL-10 ( 1082) gene polymorphisms was carried out for all patients using a polymerase chain reaction-based analysis. RESULTS: No significant difference in the distribution of genotypes and allelic frequencies between rheumatic heart disease cases and controls for IL-4 (intron 3) (p=0.17; OR 1.07, 95% CI 0.82-3.74) and IL 10 (-1082) (p=0.49; OR 1.03, 95% CI 0.65-2.71) gene polymorphisms was observed. Further categorisation of patients into mitral valve disease and combined valve disease subgroups showed that cases with mitral valve disease have significantly higher frequency of the RP2 allele of IL-4 (intron 3) (p=0.03; OR 2.98, 95% CI 1.93-6.15) and the G allele of IL-10 (-1082) (p=0.04; OR 2.14, 95% CI 1.62-4.95) when compared with controls. Discussion Our study shows that IL-4 (intron 3) and IL-10 (-1082) gene polymorphisms are not significantly associated with susceptibility to rheumatic heart disease, but they might play a role in the pathogenesis of patients with mitral valve disease. PMID- 26506985 TI - Tumor heterogeneity-induced signaling regulates SCLC metastasis. PMID- 26506986 TI - Prevalence and characteristics of road traffic injuries among young drivers in Oman, 2009-2011. AB - OBJECTIVES: Studies from different parts of the world have indicated that the impact of road traffic incidents disproportionally affects young adults. Few known studies have been forthcoming from Arabian Gulf countries. Within Oman, a high proportion of the population is under the age of 20. Coupled with the drastic increase in motorization in recent years, there is a need to understand the state of road safety among young people in Oman. The current research aimed to explore the prevalence and characteristics of road traffic injuries among young drivers aged 17-25 years. METHODS: Crash data from 2009 to 2011 were extracted from the Directorate General of Traffic, Royal Oman Police (ROP) database in Oman. The data were analyzed to explore the impact of road crashes on young people (17-25 years), the characteristics of young driver crashes, and how these differ from older drivers and to identify key predictors of fatalities in young driver crashes. RESULTS: Overall, young people were overrepresented in injuries and fatalities within the sample time period. Though it is true that many young people in crashes were driving at the time, it was also evident that young people were often victims in a crash caused by someone else. Thus, to reduce the impact of road crashes on young people, there is a need to generally address road safety within Oman. When young drivers were involved in crashes they were predominantly male. The types of crashes these drivers have can be broadly attributed to risk taking and inexperience. Speeding and nighttime driving were the key risk factors for fatalities. CONCLUSION: The results highlight the need to address young driver safety in Oman. From these findings, the introduction of a graduated driver licensing system with nighttime driving restrictions could significantly improve young driver safety. PMID- 26506987 TI - The mineral phase evolution behaviour in the production of glass-ceramics from municipal solid waste incineration fly ash by melting technology. AB - High energy consumption was the major obstacle to the widespread application of melting technology in the treatment of municipal solid waste incineration fly ash. Aiming to lower the ash-melting temperature (AMT) for energy-saving, differential scanning calorimetry, X-ray diffraction and the scanning electron microscope were used to investigate the relations between AMT and the mineral evolution. The results indicated that the change of AMT was determined by the types and the contents of mineral crystals. The transition from refractory minerals to fluxing minerals was the key. The transition of the main crystalline phase from pseudowollastonite (Ca3(Si3O9)) to wollastonite (CaSiO3) played a significant role in AMT reduction. A quantum chemistry calculation was carried out to investigate the effect of crystal reaction activity on AMT. In the chemical reaction, the highest occupied molecular orbital and the lowest unoccupied molecular orbital played a more important role than any other orbits. Cations (Ca(2+), Mg(2+), Na(+), K(+)) were apt to enter into the crystal lattice of wollastonite and gehlenite mainly through Si (3), O (1), Si (6), O (10) and Al (2), O (10), and broke the covalent bonds of Si (3)-O (7), Al (1)-O (9) and Al (1)-O (15), respectively. This deconstruction behaviour provided convenient conditions for restructuring and promoted the formation of fluxing minerals. In melts, the excess SiO2 monomers which existed in the form of cristobalite and quartz caused AMT increase. PMID- 26506988 TI - Long-term results of chemoradiotherapy for stage II-III thoracic esophageal cancer in a single institution after 2000 -with a focus on comparison of three protocols. AB - BACKGROUND: To evaluate the long-term results of chemoradiotherapy (CRT) for stage II-III thoracic esophageal cancer mainly by comparing results of three protocols retrospectively. METHODS: Between 2000 and 2012, 298 patients with stage II-III thoracic esophageal cancer underwent CRT. Patients in Group A received two cycles of cisplatin (CDDP) at 70 mg/m(2) (day 1 and 29) and 5 fluorouracil (5-FU) at 700 mg/m(2)/24 h (day 1-4 and 29-32) with radiotherapy (RT) of 60 Gy without a break. Patients in Group B received two cycles of CDDP at 40 mg/m(2) (day 1, 8, 36 and 43) and 5-FU at 400 mg/m(2)/24 h (day 1-5, 8-12, 36 40 and 43-47) with RT of 60 Gy with a 2-week break. Patients in Group C received two cycles of nedaplatin at 70 mg/m(2) (day 1 and 29) and 5-FU at 500 mg/m(2)/24 h (day 1-4 and 29-32) with RT of 60-70 Gy without a break. Differences in prognostic factors between the groups were analyzed by univariate and multivariate analyses. RESULTS: The 5-year overall survival rates for patients in Group A, Group B and Group C were 52.4, 45.2 and 37.2%, respectively. The 5-year overall survival rates for patients in Stage II, Stage III (non-T4) and Stage III (T4) were 64.0, 40.1 and 22.5%, respectively. The 5-year overall survival rates for patients who received 1 cycle and 2 cycles of concomitant chemotherapy were 27.9 and 46.0%, respectively. In univariate analysis, stage, performance status and number of concomitant chemotherapy cycles were significant prognostic factors (p < 0.001, p = 0.008 and p < 0.001, respectively). In multivariate analysis, stage, protocol and number of concomitant chemotherapy cycles were significant factors (p < 0.001, p = 0.043 and p < 0.001, respectively). CONCLUSIONS: The protocol used in Group A may be an effective protocol of CRT for esophageal cancer. It may be important to complete the scheduled concomitant chemotherapy with the appropriate intensity of CRT. PMID- 26506989 TI - Circadian rhythms, insomnia and osteoarthritis pain. PMID- 26506990 TI - Participant evaluation of an education module on interprofessional collaboration for students in healthcare studies. AB - BACKGROUND: Interprofessional collaboration is considered a key-factor to deliver the highest quality of care. Interprofessional collaboration (IPC) assumes a model of working together, in particular with awareness of the process of interprofessional collaboration, to develop an integrated and cohesive answer to the needs of the client/family/population. Educational modules are developed in response to a perceived need to improve interprofessional collaboration for the benefit of patientcare. Up until 2005 no explicit module on interprofessional collaboration existed in the education programs of the Antwerp University Association (AUHA). During a decade the 'Interprofessional Collaboration In Healthcare (IPCIHC) - module' is organised and evaluated by its participants. METHODS: One group, post-test design was used to gather data from the participating students using a structured questionnaire. Data was collected between March 2005 and March 2014 from participating final year students in healthcare educational programs. RESULTS: 3568 (84 % overall response) students evaluated the IPCIHC module from 2005 up to 2014. Over 80 % of the participants were convinced the IPCIHC increased their knowledge and changed their understanding that it will impact their future professional relationships, and felt a greater understanding about problem-solving in healthcare teams. Even though the results indicate that the goals of the IPCIHC module were achieved, less than 60 % of the participants experienced a change in attitude towards other professional groups. CONCLUSIONS: Despite the positive outcomes from the participants, the challenge still remains to keep on educating future healthcare providers in interprofessional collaboration in order to achieve an increase in interprofessional behaviour towards other professional groups. Research is needed to investigate the effectiveness of undergraduate programs on the quality and safety of patientcare in practice. PMID- 26506991 TI - Erratum to: Injurious mechanical ventilation affects neuronal activation in ventilated rats. PMID- 26506992 TI - Gender differences in the effect of social support on health-related quality of life: results of a population-based prospective cohort study in old age in Germany. AB - PURPOSE: The causality between social predictors and HRQoL in old age remains almost unclear as only a few studies have examined the influence of social support on HRQoL in a longitudinal setting. Moreover, available studies investigating gender differences in the effect of social support on HRQoL in old age have been solely cross-sectional. Consequently, the aim of this study was to examine whether social support affects health-related quality of life (HRQoL) in old age and whether this effect is moderated by gender. METHODS: In a population based cohort (N = 2443) of people aged 75 years and older in Germany, the development of HRQoL was prospectively observed over a 3-year period. Quality of life was quantified by using the visual analogue scale of the EQ-5D instrument. Social support was assessed by using the 14-item form of the questionnaire for social support (F-SozU K-14). In order to control for unobserved heterogeneity, fixed-effects regression analysis was used. RESULTS: In the total sample (beta = 0.55, p < 0.05) and in men (beta = 1.39, p < 0.001), a strong positive impact of social support on HRQoL was found. There was no significant effect of social support on HRQoL in women. The effect of social support on HRQoL was significantly moderated by gender (p < 0.05). CONCLUSIONS: Findings accentuate the fundamental role of social support in HRQoL in old age. Particularly in men, it is therefore crucial to strengthen the social ties in old age. PMID- 26506993 TI - Trastuzumab-Associated Flagellate Erythema: Report in a Woman with Metastatic Breast Cancer and Review of Antineoplastic Therapy-Induced Flagellate Dermatoses. AB - INTRODUCTION: Flagellate erythema presents as erythematous, individual and intermingled, linear streaks in a whiplash-like pattern. Several conditions, including antineoplastic agents, have been associated with flagellate erythema. A woman with metastatic breast cancer who developed flagellate erythema after receiving trastuzumab is described and the features of flagellate erythema associated with other antineoplastic agents are reviewed. METHODS: PubMed was used to search the following terms, separately and in combination: agent, antineoplastic, bendamustine, bleomycin, breast, cancer, chemotherapy, dermatitis, dermatosis, docetaxel, erythema, flagellate, Herceptin, pigmentation, peplomycin, therapy, and trastuzumab. All papers were reviewed and relevant manuscripts, along with their reference citations, were evaluated. RESULTS: The woman's pruritus and skin lesions promptly resolved after treatment with corticosteroids (oral and topical) and antihistamines (oral); premedication with dexamethasone prior to each subsequent trastuzumab treatment prevented recurrence of flagellate erythema. Chemotherapy-induced flagellate erythema was initially described in oncology patients who received bleomycin. In addition to trastuzumab, other antineoplastic agents that have been associated with the development of flagellate erythema include bendamustine, docetaxel, and peplomycin. CONCLUSION: Cutaneous adverse events to trastuzumab are uncommon. However, flagellate erythema should be added to the potential side effects of trastuzumab. In addition, trastuzumab should be added to the list of antineoplastic agents that may be associated with flagellate erythema. PMID- 26506994 TI - Prognostic Significance of High-Sensitivity Cardiac Troponin T Concentrations between the Limit of Blank and Limit of Detection in Community-Dwelling Adults: A Metaanalysis. AB - BACKGROUND: There is controversy regarding whether to report concentrations of high-sensitivity cardiac troponin T (hs-cTnT) to the limit of blank (LOB) (3 ng/L) or the limit of detection (LOD) (5 ng/L) of the assay in community-based cohorts. We hypothesized that hs-cTnT concentrations between the LOB and LOD would be associated with poorer cardiovascular outcomes compared to concentrations below the LOB. METHODS: hs-cTnT was analyzed in a total of 10 723 participants from the Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities (ARIC) study, and Dallas Heart Study (DHS). Participants were divided into 2 groups, those with hs-cTnT concentrations below the limit of blank (LOB) (<3 ng/L) and those with hs-cTnT between the LOB and limit of detection (LOD) (3 4.99 ng/L). Cross-sectional associations with traditional cardiovascular risk factors and cardiac structural measurements, and longitudinal associations with long-term cardiovascular outcomes of incident heart failure and cardiovascular death, were determined. RESULTS: Participants with hs-cTnT between the LOB and LOD for all 3 cohorts were older, more likely to be male, and have a higher burden of cardiovascular risk factors and structural pathology. A metaanalysis of the 3 cohorts showed participants with hs-cTnT between the LOB and LOD were at increased risk of new-onset heart failure (hazard ratio, 1.18; 95% CI, 1.02-1.38) and cardiovascular mortality (hazard ratio, 1.29; 95% CI, 1.06-1.57). CONCLUSIONS: hs-cTnT concentrations between the LOB and LOD (3-4.99 ng/L) are associated with a higher prevalence of traditional risk factors, more cardiac pathology, and worse outcomes than concentrations below the LOB (<3 ng/L). PMID- 26506995 TI - Reference Values and Release Kinetics of B-Type Natriuretic Peptide Signal Peptide in Patients with Acute Myocardial Infarction. AB - BACKGROUND: The signal peptide for human B-type natriuretic peptide preprohormone (BNPsp), which is released from cardiomyocytes, is increased in plasma of patients with acute myocardial infarction (AMI); however, its exact release kinetics have not been defined. METHODS: We measured BNPsp and high-sensitivity cardiac troponin T (hs-cTnT) in a reference group of individuals without structural heart disease (n = 285) and determined the release kinetics of these biomarkers in patients (n = 29) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH), a procedure allowing exact timing of onset of iatrogenic AMI. Blood samples were collected before TASH and at numerous preselected time points after TASH. RESULTS: The reference median BNPsp concentration was 53.4 pmol/L [interquartile range (IQR) 47.0-61.0; 95th percentile 85.9 pmol/L; 99th percentile 116.3 pmol/L]. Baseline concentrations in patients undergoing TASH were higher than in the reference group [91.9 pmol/L (IQR 62.9-116.4); P < 0.0001]. BNPsp increased significantly, peaking at 15 min after induction of AMI [149.6 pmol/L (109.5-204.9) vs baseline; P = 0.004] and declining slowly thereafter, falling below the preprocedural value after 8 h (P = 0.014). hs-cTnT increased significantly 15 min after induction of AMI [26 ng/L (19-39) vs 18 ng/L (11-29); P = 0.001] and remained high at all later time points. CONCLUSIONS: BNPsp concentrations increased immediately after AMI induction, providing early evidence of myocardial injury. The release kinetics of BNPsp differed from those of hs-cTnT. These findings provide information that should help in establishing the diagnostic value of BNPsp in the setting of early AMI. PMID- 26506996 TI - Long Noncoding RNAs in Urine Are Detectable and May Enable Early Detection of Acute T Cell-Mediated Rejection of Renal Allografts. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) are novel intracellular noncoding ribonucleotides regulating the genome and proteome. They are detectable in the blood of patients with acute kidney injury. We tested whether lncRNAs are present in urine and may serve as new predictors of outcome in renal transplant patients with acute rejection. METHODS: A global lncRNA expression analysis was performed with RNA from urine of patients with acute T cell-mediated renal allograft rejection and control transplant patients. Deregulated lncRNAs were confirmed in kidney biopsies and urine in a validation cohort of 62 patients with acute rejection, 10 of them after successful antirejection therapy, and 31 control transplant patients. RESULTS: A global screen revealed several lncRNAs to be deregulated in urine of patients with acute rejection. Three intergenic lncRNAs, LNC-MYH13-3:1, RP11-395P13.3-001, and RP11-354P17.15-001, were most strongly altered. These were validated in the whole cohort of patients. RP11-395P13.3-001 and RP11-354P17.15-001 were upregulated in patients with acute rejection compared with controls. Only levels of RP11-354P17.15-001 normalized in patients with acute rejection after successful antirejection therapy. RP11-354P17.15-001 was associated with higher decline in glomerular filtration rate 1 year after transplantation. In vitro, in tubular epithelial cells, all lncRNAs were enriched by interleukin-6 treatment, but only RP11-395P13.3-001 and RP11-354P17.15-001 increased in cell culture supernatant, indicating that these lncRNAs might be secreted under inflammatory conditions. CONCLUSIONS: lncRNAs are strongly altered in urine of patients with acute rejection. Urinary RP11-354P17.15-001 may serve as a novel biomarker of acute kidney rejection, identifying patients with acute rejection and predicting loss of kidney function. PMID- 26506997 TI - Biomarker-based drug safety assessment in the age of systems pharmacology: from foundational to regulatory science. AB - Improved biomarker-based assessment of drug safety is needed in drug discovery and development as well as regulatory evaluation. However, identifying drug safety-related biomarkers such as genes, proteins, miRNA and single-nucleotide polymorphisms remains a big challenge. The advances of 'omics' and computational technologies such as genomics, transcriptomics, metabolomics, proteomics, systems biology, network biology and systems pharmacology enable us to explore drug actions at the organ and organismal levels. Computational and experimental systems pharmacology approaches could be utilized to facilitate biomarker-based drug safety assessment for drug discovery and development and to inform better regulatory decisions. In this article, we review the current status and advances of systems pharmacology approaches for the development of predictive models to identify biomarkers for drug safety assessment. PMID- 26506998 TI - Early laryngeal outcome of prolonged intubation using an anatomical tube: a double blind, randomised study. AB - The objective of this study was to study the short-term impact on larynx by a newly designed anatomical tube. A prospective randomised trial of a newly designed anatomical tube versus a standard endotracheal tube in patients operated under general anaesthesia for at least 12 h. Seventy adults were included and randomised to either type of tube. The patients were evaluated by means of fibre optic laryngoscopy and VAS-rating of symptoms on two occasions in the first post operative week. The evaluating investigators and the patients were blinded to the type of tube used. 27 cases and 23 controls had complete data for evaluation. Age, gender and intubation times were comparable. Symptoms such as hoarseness, coughing, and pain were rated above 30 % of maximum during at least one of the first post-operative days by 21 and 19 patients, respectively. At the first examination (within 24 h), 38 % of patients in the anatomical tube group stated no hoarseness; compared to 13 % of the controls (p = 0.057). Fibre-optic laryngoscopy showed some kind of pathology in all the patients examined within 24 h of extubation. After 3-6 days, seven patients with the anatomical tube and four patients in the control group showed complete resolution of the lesions, and the changes were limited to redness in the vocal process area in another seven and four, respectively. The differences between the groups did not attain statistical significance. The study shows considerable short-term laryngeal morbidity after prolonged intubation, and the anatomical tube only showed an advantage concerning hoarseness. Further improvement of the endotracheal tubes and intubation routines are still needed. PMID- 26506999 TI - Translation and validation of EORTC QLQ-H&N 35 into Moroccan Arabic for ENT head and neck cancer patients in Morocco. AB - Disease-specific quality of life (QOL) measures have enhanced the capacity of outcome measures to evaluate subtle changes and differences between groups. As many of the QOL measures have been developed in English, they require translation to ensure their usefulness in a multi-cultural and/or international society. Published guidelines provide formal methods to achieve cross-culturally comparable versions of a QOL tool. The aim of this study was to adapt the head and neck specific module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-H&N 35 questionnaire) into Moroccan Arabic and to determine its psychometric properties. After translation, back translation and pretesting of the pre-final version, the translated version was submitted to a committee of professionals composed by otolaryngologists and epidemiologists. The psychometric properties were tested in patients with ENT cancer. Internal consistency was tested using Cronbach's alpha and the test retest reliability using interclass correlation coefficients. Construct validity was assessed by examining item convergent and divergent validity. It was also tested using Spearman's correlation between QLQ-H&N 35 scales and EQ-5D. The study was conducted in 120 patients. The Moroccan version was internally reliable, Cronbach's alpha ranged from 0.71 for "trouble with social contact" to 0.94 for "senses impairment", indicating good internal consistency. Test-retest reliability was assessed using the intra-class correlation coefficient, which ranged from 0.64 for "speech trouble" to 0.89 for "physical activities". The instrument demonstrated a good construct and concomitant validity. We have developed a semantically equivalent translation with cultural adaptation of EORTC QLQ-H&N 35 questionnaire. The assessment of its measurement properties showed that it is quite reliable and a valid measure of the effect of cancer on the quality of life in Moroccan patients. PMID- 26507000 TI - A systematic review of tongue base suspension techniques as an isolated procedure or combined with uvulopalatopharyngoplasty in obstructive sleep apnea. AB - We aimed to evaluate existing research into the effectiveness and safety of two tongue base suspension (TBS) techniques (Repose((r)) system and modified TBS) with or without uvulopalatopharyngoplasty (UPPP) in obstructive sleep apnea. The literature review was performed using PubMed database. Searched terms used included the keywords "sleep apnea", "surgery", "tongue", "tongue base", "suspension", "Repose", "uvulopalatopharyngoplasty", and "hypopharynx". Levels of evidences and grades of recommendations were determined according to the hierarchy proposed by Oxford Centre for Evidence-based Medicine. Seven studies including 113 patients met the eligibility criteria for TBS as a stand-alone procedure. Four of seven studies including 62 patients used the Repose((r)), and three studies including 51 patients used the modified TBS. The success rates were higher in the studies that used modified technique (74.5 %) than those that used the Repose((r)) (25.8 %), (p < 0.001). Ten studies including 300 patients met the eligibility criteria for TBS combined with UPPP. Seven of ten studies including 176 patients used the Repose((r)), and three studies including 124 patients used the modified TBS. The success rates in this group were similar between the modified TBS (73.4 %) and Repose((r)) (67.6 %), (p = 0.341). When aggregate data of 413 patients were compared, the modified TBS was found to be associated with significantly higher success rates (73.7 vs. 56.7 %, p < 0.001). The evidence supports primarily grade C recommendations for the benefits of both techniques with or without UPPP; although there is a trend toward improved outcome with modified technique. PMID- 26507001 TI - Effects of low-intensity non-coherent light therapy on the inflammatory process in the calcaneal tendon of ovariectomized rats. AB - The aim of this experimental study was to investigate the effects of low intensity light-emitting diode (LED) phototherapy on the inflammatory process in the calcaneal tendon of ovariectomized rats (OVX) through the involvement of the inflammatory mediators interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha (TNF-alpha). Thirty-five female Wistar rats were divided into 4 groups: 3 groups of OVX rats totaling 30 rats (untreated OVX rats [OVX injury group], treated OVX rats [OVX LED group], and control OVX rats; subgroups existed based on the sampling times, which were 3, 7, and 14 days) and 1 group of non-OVX rats (not OVX; n = 5). Tendon injury was induced by trauma using a 208-g mass placed at 20 cm from the right tendon of each animal with energy of 0.70 J. The animals were treated 12 h after tendonitis with LED therapy and every 48 h thereafter until euthanasia (at 3, 7, or 14 days). The tendons were dissected and stored in liquid nitrogen at -196 degrees C, thawed only at the time of immunoenzymatic testing (ELISA). Groups treated with LED showed a decrease in the number of pro inflammatory cells, IL-6, and TNF-alpha (p <0.05), and an increase in IL-10 (p < 0.05) when compared to the not OVX group (p < 0.05). It was concluded that low intensity LED treatment using the parameters and wavelength of 945 nm in the time periods studied reduced the release of IL-6 and TNF-alpha and increased the release of IL-10, thereby improving the inflammatory response in OVX rats. PMID- 26507003 TI - Evaluation of regulatory genetic variants in POU5F1 and risk of congenital heart disease in Han Chinese. AB - OCT4 is a transcription factor of the POU family, which plays a key role in embryonic development and stem cell pluripotency. Previous studies have shown that Oct4 is required for cardiomyocyte differentiation in mice and its depletion could result in cardiac morphogenesis in embryo. However, whether the genetic variations in OCT4 coding gene, POU5F1, confer the predisposition to congenital heart disease (CHD) is unclear. This study sought to investigate the associations between low-frequency (defined here as having minor allele frequency (MAF) between 0.1%-5%) and rare (MAF below 0.1%) variants with potential function in POU5F1 and risk of CHD. We conducted association analysis in a two-stage case control study with a total of 2,720 CHD cases and 3,331 controls in Chinese. The low-frequency variant rs3130933 was observed to be associated with a significantly increased risk of CHD [additive model: adjusted odds ratio (OR) = 2.15, adjusted P = 3.37 * 10(-6)]. Furthermore, luciferase activity assay showed that the variant A allele led to significantly lower expression levels as compared to the G allele. These findings indicate for the first time that low frequency functional variant in POU5F1 may contribute to the risk of congenital heart malformations. PMID- 26507004 TI - The Fort Collins Commuter Study: Impact of route type and transport mode on personal exposure to multiple air pollutants. AB - Traffic-related air pollution is associated with increased mortality and morbidity, yet few studies have examined strategies to reduce individual exposure while commuting. The present study aimed to quantify how choice of mode and route type affects personal exposure to air pollutants during commuting. We analyzed within-person difference in exposures to multiple air pollutants (black carbon (BC), carbon monoxide (CO), ultrafine particle number concentration (PNC), and fine particulate matter (PM2.5)) during commutes between the home and workplace for 45 participants. Participants completed 8 days of commuting by car and bicycle on direct and alternative (reduced traffic) routes. Mean within-person exposures to BC, PM2.5, and PNC were higher when commuting by cycling than when driving, but mean CO exposure was lower when cycling. Exposures to CO and BC were reduced when commuting along alternative routes. When cumulative exposure was considered, the benefits from cycling were attenuated, in the case of CO, or exacerbated, in the case of particulate exposures, owing to the increased duration of the commute. Although choice of route can reduce mean exposure, the effect of route length and duration often offsets these reductions when cumulative exposure is considered. Furthermore, increased ventilation rate when cycling may result in a more harmful dose than inhalation at a lower ventilation rate. PMID- 26507005 TI - Spatial patterning in PM2.5 constituents under an inversion-focused sampling design across an urban area of complex terrain. AB - Health effects of fine particulate matter (PM2.5) vary by chemical composition, and composition can help to identify key PM2.5 sources across urban areas. Further, this intra-urban spatial variation in concentrations and composition may vary with meteorological conditions (e.g., mixing height). Accordingly, we hypothesized that spatial sampling during atmospheric inversions would help to better identify localized source effects, and reveal more distinct spatial patterns in key constituents. We designed a 2-year monitoring campaign to capture fine-scale intra-urban variability in PM2.5 composition across Pittsburgh, PA, and compared both spatial patterns and source effects during "frequent inversion" hours vs 24-h weeklong averages. Using spatially distributed programmable monitors, and a geographic information systems (GIS)-based design, we collected PM2.5 samples across 37 sampling locations per year to capture variation in local pollution sources (e.g., proximity to industry, traffic density) and terrain (e.g., elevation). We used inductively coupled plasma mass spectrometry (ICP-MS) to determine elemental composition, and unconstrained factor analysis to identify source suites by sampling scheme and season. We examined spatial patterning in source factors using land use regression (LUR), wherein GIS-based source indicators served to corroborate factor interpretations. Under both summer sampling regimes, and for winter inversion-focused sampling, we identified six source factors, characterized by tracers associated with brake and tire wear, steel-making, soil and road dust, coal, diesel exhaust, and vehicular emissions. For winter 24-h samples, four factors suggested traffic/fuel oil, traffic emissions, coal/industry, and steel-making sources. In LURs, as hypothesized, GIS based source terms better explained spatial variability in inversion-focused samples, including a greater contribution from roadway, steel, and coal-related sources. Factor analysis produced source-related constituent suites under both sampling designs, though factors were more distinct under inversion-focused sampling. PMID- 26507006 TI - Plasmon-Induced Transparency by Hybridizing Concentric-Twisted Double Split Ring Resonators. AB - As a classical analogue of electromagnetically induced transparency, plasmon induced transparency (PIT) has attracted great attention by mitigating otherwise cumbersome experimental implementation constraints. Here, through theoretical design, simulation and experimental validation, we present a novel approach to achieve and control PIT by hybridizing two double split ring resonators (DSRRs) on flexible polyimide substrates. In the design, the large rings in the DSRRs are stationary and mirror images of each other, while the small SRRs rotate about their center axes. Counter-directional rotation (twisting) of the small SRRs is shown to lead to resonance shifts, while co-directional rotation results in splitting of the lower frequency resonance and emergence of a PIT window. We develop an equivalent circuit model and introduce a mutual inductance parameter M whose sign is shown to characterize the existence or absence of PIT response from the structure. This model attempts to provide a quantitative measure of the physical mechanisms underlying the observed PIT phenomenon. As such, our findings can support the design of several applications such as optical buffers, delay lines, and ultra-sensitive sensors. PMID- 26507007 TI - Production of immunoregulatory polysaccharides from Crassostrea hongkongensis and their positive effects as a nutrition factor in modulating the effectiveness and toxicity of 5-FU chemotherapy in mice. AB - Chemotherapy is generally accompanied by undesirable side effects, such as immunosuppression and malnutrition, which reduce tolerance to cancer therapies. Prior studies have shown that immunonutrition improves the clinical outcomes of cancer patients. In this study, immunoregulatory polysaccharides from Crassostrea hongkongensis were included in a nutrition formula that was administered to S180 tumor-bearing mice in combination with 5-fluorouracil (5-FU) treatment. The C30 60% fraction of the polysaccharides was characterized as a branched polysaccharide, with a high amount of d-glucose (96.76% of the total) and the highest uronic acid and sulfate groups' content among all of the polysaccharide fractions. The C30-60% polysaccharide fraction showed a maximal proliferative effect on RAW264.7 cells and T lymphocytes at a concentration of 0.0391 mg mL(-1) and 0.0781 mg mL(-1), respectively. Moreover, the combination treatment of the C30-60% polysaccharide-based nutrition formula (OPNF) with the administration of 5-FU effectively inhibited the growth of tumors and notably increased the leucocyte and lymphocyte counts in S180 tumor-bearing mice. In addition, a slight increase in the erythrocyte and hemoglobin values was observed in the mice treated with the combination of OPNF and 5-FU. These results suggest that supplementation with a C30-60%-based enteral formula would be beneficial for patients undergoing chemotherapy with 5-FU. PMID- 26507008 TI - Development of High Resolution Melting Analysis for the Diagnosis of Human Malaria. AB - Molecular detection has overcome limitations of microscopic examination by providing greater sensitivity and specificity in Plasmodium species detection. The objective of the present study was to develop a quantitative real-time polymerase chain reaction coupled with high-resolution melting (qRT-PCR-HRM) assay for rapid, accurate and simultaneous detection of all five human Plasmodium spp. A pair of primers targeted the 18S SSU rRNA gene of the Plasmodium spp. was designed for qRT-PCR-HRM assay development. Analytical sensitivity and specificity of the assay were evaluated. Samples collected from 229 malaria suspected patients recruited from Sabah, Malaysia were screened using the assay and results were compared with data obtained using PlasmoNex(TM), a hexaplex PCR system. The qRT-PCR-HRM assay was able to detect and discriminate the five Plasmodium spp. with lowest detection limits of 1-100 copy numbers without nonspecific amplifications. The detection of Plasmodium spp. in clinical samples using this assay also achieved 100% concordance with that obtained using PlasmoNex(TM). This indicated that the diagnostic sensitivity and specificity of this assay in Plasmodium spp. detection is comparable with those of PlasmoNex(TM). The qRT-PCR-HRM assay is simple, produces results in two hours and enables high-throughput screening. Thus, it is an alternative method for rapid and accurate malaria diagnosis. PMID- 26507009 TI - Placenta-derived mesenchymal stem cells possess better immunoregulatory properties compared to their cord-derived counterparts-a paired sample study. AB - Mesenchymal stem cells (MSCs) show immunoregulatory properties. Here, we compared MSCs obtained from placenta (P-MSCs) and umbilical cord (C-MSCs) from the same donor, for their immunomodulatory efficacy. P-MSCs and C-MSCs showed similar morphology and phenotypic profile, but different clonogenic ability. Importantly, they showed a significant difference in their immunosuppressive properties as assessed in mixed leukocyte reaction (MLR). The P-MSCs affected the antigen presenting ability of mononuclear cells (MNCs) and dendritic cells (DCs) significantly as compared to C-MSCs resulting in a reduced T-cell proliferation. P-MSC conditioned medium (CM) showed a significant reduction in T cell proliferation as compared to C-MSC CM, thus suggesting that a cell to cell contact is not essential. We found increased levels of IL-10 and TGFbeta1 and reduction in levels of IFNgamma in P-MSC MLRs as compared to C-MSC MLRs. Furthermore, the CD3(+) CD4(+) CD25(+) T regulatory cells were enriched in case of P-MSCs in both, MSC-MNC and MSC-DC co-cultures. This observation was further supported by increased mRNA expression of FoxP3 in P-MSCs. Presently, cord derived MSCs are being employed in transplantation therapies parallel to the bone marrow-derived MSCs. Our findings suggest that P-MSCs can be a better alternative to C-MSCs, to provide aid in immunological ailments. PMID- 26507010 TI - Neuropsychological performance of a patient suspected of dementia taking lorazepam and retested 1 year later following titration. AB - The effects of medication on neuropsychological performance have yet to be fully investigated, particularly in older patients. As such, the present case study was undertaken to examine the specific impact of benzodiazepine use on neuropsychological performance by providing a comparison of the test-retest data of an 81-year-old patient taking lorazepam. A comprehensive neuropsychological evaluation was conducted: (a) during the initial referral, while the patient had been taking high doses of lorazepam for approximately 3 years; and (b) 6 months after complete titration, which was 1 year after the initial evaluation. Normative scores derived from the 2 trials were compared via calculation of Reliable Change Indexes. Neuropsychological performance during both evaluations was indicative of dementia, including similar degrees of impairment in delayed memory, verbal fluency, and olfaction. However, scores obtained during the second evaluation were somewhat higher, with significant improvements observed in immediate memory, visuospatial/construction abilities, language function, abstract concept formation, and set shifting. Results of the current case study suggest that several neuropsychological domains may be particularly sensitive to chronic benzodiazepine use. Although the overall diagnostic picture in the present study remained unaltered, clinicians should be cognizant of such medication effects and the potential for these neuropsychological alterations to obscure differential diagnosis. PMID- 26507062 TI - [Appropriate choice of drugs in older patients]. AB - Older patients use many drugs, while there is hardly any information about the effect and safety of these in elderly patients. It appears that only 56%, and 20% of the information required by the European Medicines Agency (EMA) concerning use of medication in the elderly is stated in the patient information leaflet and in the Dutch Pharmacotherapeutic Compass, respectively. The Expertise Centre PHarmacotherapy in Old Persons (Ephor) gathered all available information about drug prescribing in older patients for a number of drug groups from national and international literature, and provided prescribing advice. This information will be made available to users of the Dutch Pharmacotherapeutic Compass, for quick accessibility. PMID- 26507063 TI - [Pharmacogenetics in primary health care: implementation and future expectations]. AB - Personalised medicine is a targeted approach to the prevention, diagnosis and treatment of disorders on the basis of the specific genetic profile of the patient. Pharmacogenetics research shows that differences in the genetic profile of patients explain the interindividual differences in efficacy and side effects of medicines. Although there are high expectations of personalised medicine and pharmacogenetics in healthcare, both are only used to a limited extent to date. Pharmacogenetics seems particularly important in diseases with a poor prognosis and treatments with potentially serious side effects. Pharmacogenetics testing is reimbursed in the case of serious side effects or unexpected ineffectiveness. 95% of patients in the Netherlands have at least one abnormality in the panel of genes for which guidance is available. The KNMP (Royal Dutch Pharmacists' Association) provides dosing advice based on genotype for 80 medicines, 27 of which are regularly prescribed in primary health care. PMID- 26507064 TI - [A man with a pedunculated mass]. AB - A 29-year-old man presented with a painless soft mass that was hanging on a string of skin on his upper leg. Physical examination revealed a 5 cm broad, elastic, stalked skin toned mass. On microscopic examination the diagnosis fibrolipoma was objectified. PMID- 26507065 TI - [Erythema after subcutaneous heparin treatment]. AB - BACKGROUND: Heparin-induced skin lesions are common. The majority are delayed type hypersensitivity reactions to heparin or other components of the injection fluid. Differentiation from heparin-induced thrombocytopenia (HIT) skin lesions is important. The Warkentin 4T's score is helpful for assessment of the risk of HIT. CASE DESCRIPTION: A 36-year old female was treated with injections of tinzaparin for a deep vein thrombosis. After 16 days, she developed progressive thrombocytopenia and a skin lesion at one of the injection sites. She was diagnosed with "skin lesion consistent with HIT and caused by the use of low molecular-weight heparin". The platelet count returned to normal and the severity of the skin lesion improved after replacement of tinzaparin with fondaparinux. CONCLUSION: In patients with skin lesions suspected of being caused by the use of heparin, a complete blood count needs to be made as quickly as possible. With a 4T's score >= 4, it is recommended that a skin biopsy and a laboratory HIT-test are performed. Heparin should be replaced by alternative anticoagulants by way of precaution. PMID- 26507066 TI - [A man with an abnormal PET-CT scan]. AB - A 65-year-old patient with rectal carcinoma underwent an 18FDG PET-CT scan. The scan showed nodular foci of 18FDG uptake against the ventral abdominal wall, possibly carcinomatous peritonitis. These abnormalities were caused by a foreign body reaction to a mesh that was placed five months earlier because of an umbilical hernia repair. PMID- 26507067 TI - [The correct mammographic positioning in breast cancer screening]. AB - OBJECTIVE: To compare the positioning quality of mammograms produced by new (NRs) versus experienced (ERs) screening radiographers in the Dutch breast cancer screening programme. DESIGN: Retrospective study. METHOD: NRs must successfully complete an education programme before being allowed to start work in Dutch screening practice. This education programme consists of a theoretical component, a practical component and a final practical examination, including a portfolio review. Furthermore, each unit undergoes an audit once every three years. During the audit, mammograms produced by ERs in the unit are assessed on the basis of criteria relating to the positioning of the breast. In this retrospective study, we analysed 13,520 images from portfolios (NRs) and 14,896 images from audits (ERs) on the basis of pre-specified quality criteria, e.g. depiction of the pectoral muscle. RESULTS: Positioning quality was significantly better by NRs than ERs (CC views: 97% versus 86% adequate, p<0.01; MLO views: 92% versus 84% adequate, p<0.01). NRs scored better for most of the CC criteria but had more difficulty with for example the inframammary angle in MLO views than ERs. Overall, the mammograms from NRs were more often considered adequate, because their errors were less serious. CONCLUSION: NRs perform better than ERs in terms of quality of positioning technique. These results stress the need for continuous monitoring of and feedback into the Dutch breast cancer screening programme to maintain high-quality screening mammography. PMID- 26507068 TI - [Treatment 'to be on the safe side': avoiding every risk in the case of malignancy or pre-malignancy]. AB - In a recent study in JAMA Surgery, Sagara et al. showed that patients with low grade ductal carcinoma in situ who did not receive surgery had a similar prognosis compared to patients who did receive surgical treatment. This paper adds to a growing number of publications demonstrating that overtreatment is common in premalignant diseases. This phenomenon of a strongly-felt need for risk reduction when it comes to malignant disease is not found, for example, in cardiovascular risk management. The same conclusion can be drawn for radiotherapy in older women after breast-conserving surgery. Although multiple studies show that radiotherapy can be avoided in a selected group of patients, 98 per cent of women are still treated according to current guidelines. 'Overly' safe, but with little regard for treatment-related side effects. The study by Sagara and colleagues indicates that it is time to discuss with the patient the very small absolute benefits of our current practice regarding (pre-)malignant diseases. PMID- 26507069 TI - [Impact of a clinical decision model for febrile children at risk for serious bacterial infections at the emergency department: a randomized controlled trial]. AB - OBJECTIVE: To assess the impact of a clinical decision model for febrile children at risk for serious bacterial infections (SBI) attending the emergency department (ED). METHOD: Randomized controlled trial with 439 febrile children, aged 1 month 16 years, attending the pediatric ED of a Dutch university hospital during 2010 2012. Febrile children were randomly assigned to the intervention (clinical decision model; n=219) or the control group (usual care; n=220). The clinical decision model included clinical symptoms, vital signs, and C-reactive protein and provided high/low-risks for "pneumonia" and "other SBI". Nurses were guided by the intervention to initiate additional tests for high-risk children. Primary patient outcome was defined as correct SBI diagnoses. Secondary process outcomes were defined as length of stay; diagnostic tests; antibiotic treatment; hospital admission; revisits and medical costs. RESULTS: The decision model had good discriminative ability for both pneumonia (n=33; AUC 0.83 (95% CI 0.75-0.90)) and other SBI (n=22; AUC 0.81 (95% CI 0.72-0.90)). Compliance to model recommendations was high (86%). No differences in correct SBI determination was observed. Application of the clinical decision model resulted in less full-blood counts (14% vs. 22%, p-value<0.05) and more urine-dipstick testing (71% vs. 61%, p-value<0.05). CONCLUSION: In contrast to our expectations no substantial impact on patient outcome was perceived. The clinical decision model preserved however, good discriminatory ability to detect SBI, achieved good compliance among nurses and resulted in a more standardized diagnostic approach towards febrile children, with less full blood-counts and more rightfully urine-dipstick testing. Trial registration: Trialregister.nl: NTR2381. PMID- 26507070 TI - [Do clinical decision models improve the triage of acutely ill children?]. AB - Acute infection is the most common presentation of children in primary care, with only a few having serious infections. To avoid complications, early recognition and appropriate referral are essential. Clinical decision models have the potential to improve diagnostic decision-making for these serious conditions. Although many models have been developed, few have proven cost-effective. A recent model developed in acutely ill children presenting in Belgian primary care and validated in a new cohort has been shown to adequately identify children that are hospitalised with acute infections. The results are impressive but raise questions about generalisability and cost-effectiveness. In conclusion, clinical decision models appear currently incapable of improving decision-making in acutely ill children. As an alternative, we should consider asking the general practitioner to perform telephone triage. PMID- 26507071 TI - Multiple variations of the renal and testicular vessels: possible embryological basis and clinical importance. AB - During routine dissection of the abdominal cavity of a 55-year-old African male cadaver, multiple anomalies including renal and testicular vessels were encountered. The right kidney was supplied by three right hilar renal arteries arising from the abdominal aorta at different vertebral levels whereas only one left renal artery supplied the left kidney. On the right three renal veins drained the kidney into the inferior vena cava. In contrast, the left kidney was drained by a single renal vein which received a large primary posterior tributary. The primary posterior tributary had three tributaries from the posterior lumbar region. The right testis had two sources of arterial supply; one from the subcostal artery and another from the abdominal aorta. The left testis was supplied normally by a single testicular artery. The right testis was drained by four testicular veins as follows: one drained into the subcostal vein, the other two drained separately for a longer course and joined shortly before draining into the right main renal vein, the fourth one drained into the anterior aspect of the inferior vena cava at the level of the second lumbar vertebra. On the left, the testicle was drained by two testicular veins which travelled separately from the deep inguinal ring and joined shortly before they drain into the left renal vein. This variation may represent an immature form of complicated development of kidneys and testes. Additionally, emphasis must be put on preoperative vascular examination to avoid surgical complications from variant vessels in this region. PMID- 26507072 TI - Regulation of FOXO3 subcellular localization by Kit ligand in the neonatal mouse ovary. AB - PURPOSE: Foxo3 protein is required in the oocyte nucleus for the maintenance of primordial follicles in a dormant state. PI3K/AKT-dependent phosphorylation of Foxo3 leads to its relocalization to the cytoplasm and subsequent follicular activation. However, the nature of the upstream signals controlling Foxo3 activity and subcellular localization remains unknown. We aimed to study the in vitro effects of Kit ligand (stem cell factor) on the subcellular localization of Foxo3 in primordial follicles within the postnatal mouse ovary. METHODS: This was an in vitro study using explants of intact neonatal mouse ovaries. The study was performed in laboratory animal facility and basic science research laboratory at a University Hospital. The animals used for this study were FVB mice. Neonatal FVB mice ovaries at postnatal day 7 (PD7) were harvested and incubated in culture medium (DMEM) at 37 degrees C and 5 % CO(2) for 60-90 min with (n = 3) or without (n = 3) Kit ligand at 150 ng/mL (8 nM). Similar experimental conditions were used to establish a dose-response curve for the effects of Kit ligand and assess the effects of imatinib (small molecule inhibitor of the Kit receptor). Immunofluorescence was used to identify the subcellular location of Foxo3 in oocytes. Proportions of cytoplasmic versus nuclear Foxo3 in primordial follicles were determined. RESULTS: Kit ligand treatment increased the cytoplasmic localization of Foxo3 from 40 % in the untreated ovaries to 74 % in the treated group (p = 0.007 in paired samples and p = 0.03 in unpaired samples). Furthermore, this effect was reversible with imatinib (p = 0.005). A dose response curve for Kit ligand treatment showed that maximum effect was seen at 150 ng/mL. CONCLUSION: Kit ligand treatment in vitro increases the proportion of cytoplasmic Foxo3 in primordial follicles at PD7, lending support to the idea that Kit receptor/ligand controls Foxo3 activity in the context of primordial follicle activation. PMID- 26507073 TI - Current and Emerging Medical Therapies for Gastroparesis. AB - OPINION STATEMENT: Gastroparesis likely involves various pathophysiological disorders and is increasingly prevalent as complications of surgeries, medications, and chronic diabetes. Key to diagnosis is evidence of delayed gastric emptying, generally based on standardized scintigraphy, and ruling out distal obstruction or other dysmotilities. Initial medical management includes reviewing potentially exacerbating medications and ruling out other reversible causes, achieving tighter glucose control in diabetics, and implementing dietary and lifestyle changes. While current available medications are limited, symptomatic control is aimed at improving gastric emptying, alleviating nausea and vomiting, and treating associated abdominal pain. Other potential therapies are aimed at reducing acid production, improving gastric accommodation or pyloric dysfunction, and treating bacterial overgrowth. Future studies should be aimed toward identification of subpopulations of gastroparetics who are better responders to the various medications based on differences in underlying pathophysiology and adopting standardized study end point measures that may allow for comparisons across trials. This chapter will review current treatment options, upcoming promising medications, and some of the hurdles in advancing the field forward. PMID- 26507074 TI - Characterization of Titratable Amphiphiles in Lipid Membranes by Fluorescence Spectroscopy. AB - Understanding the ionization behavior of lipid membranes is a key parameter for successful development of lipid-based drug delivery systems. Accurate determination of the ionization state of a titratable species incorporated in a lipid bilayer however requires special care. Herein we investigated the behavior of titratable lipids in liposomes by fluorescence spectroscopy and determined which extrinsic parameters-i.e., besides those directly related to their molecular structure-determine their ionization state. Two fluorescent dyes, TNS and R18, have been used to investigate basic and acidic titratable lipids, respectively. Our results suggest that the titration behavior of the ionizable lipid in the membrane is more sensitive to the composition of the membrane and to its physical state than to the presence of solutes in the aqueous phase. Essentially overlooked in earlier studies on ionizable lipid assemblies, the concentration of the titratable lipid in the membrane was found to have a major effect on the ionization state of the lipid polar head. This may result in a shift in the apparent pKa value which may be as large as two pKa units and cannot be satisfactorily predicted. PMID- 26507075 TI - Senior citizens were routinely tested for "angel dust" in scam that led to $256m settlement. PMID- 26507076 TI - Patients' goals, resources, and barriers to future change: A qualitative study of patient reflections at hospital discharge after myocardial infarction. AB - BACKGROUND: Myocardial infarction (MI) patients may find it challenging to adhere to lifestyle advice and medications. Understanding motivational factors and barriers to change is crucial. However, empirical evidence on patients' ability to effect lifestyle changes at the time of discharge is limited. AIM: The aim of this study was to identify at the time of hospital discharge the goals, resources, and barriers to future change in MI patients. METHODS: We conducted a qualitative interview study with a purposive sample of 20 MI patients (eight women) in a cardiac department at a university hospital in Norway. All interviews were conducted before hospital discharge, transcribed verbatim, and analysed using qualitative content analysis. FINDINGS: Three themes suggested that, at the time of discharge, patients' views of their MI were complex and diverse. Patients were motivated to change their lifestyle and contemplated taking their life in new directions, adopting a change of life perspective. Frequently, patients struggled to understand the context of living with an MI, manage symptoms, and understand the precipitating causes of MI. There were also patients who wanted to maintain their present lifestyle and live as normal as possible. They just wanted to keep going. CONCLUSIONS AND IMPLICATIONS: There is a need for a different approach to communicating with MI patients at the time of discharge. Person centred care that allows personal narratives to emerge may enable health-care professionals to offer more individualised guidance to MI patients that will help them cope with the everyday challenges they experience after discharge. PMID- 26507077 TI - Tracking the Invasion of Small Numbers of Cells in Paper-Based Assays with Quantitative PCR. AB - Paper-based scaffolds are an attractive material for culturing mammalian cells in a three-dimensional environment. There are a number of previously published studies, which utilize these scaffolds to generate models of aortic valves, cardiac ischemia and reperfusion, and solid tumors. These models have largely relied on fluorescence imaging and microscopy to quantify cells in the scaffolds. We present here a polymerase chain reaction (PCR)-based method, capable of quantifying multiple cell types in a single culture with the aid of DNA barcodes: unique sequences of DNA introduced to the genome of individual cells or cell types through lentiviral transduction. PCR-based methods are highly specific and are amenable to high-throughput and multiplexed analyses. To validate this method, we engineered two different breast cancer lines to constitutively express either a green or red fluorescent protein. These cells lines allowed us to directly compare the ability of fluorescence imaging (of the fluorescent proteins) and qPCR (of the unique DNA sequences of the fluorescent proteins) to quantify known numbers of cells in the paper based-scaffolds. We also used both methods to quantify the distribution of these breast cell lines in homotypic and heterotypic invasion assays. In the paper-based invasion assays, a single sheet of paper containing cells suspended in a hydrogel was sandwiched between sheets of paper containing only hydrogel. The stack was incubated, and the cells invaded the adjacent layers. The individual sheets of the invasion assay were then destacked and the number of cells in each layer quantified. Our results show both methods can accurately detect cell populations of greater than 500 cells. The qPCR method can repeatedly and accurately detect as few as 50 cells, allowing small populations of highly invasive cells to be detected and differentiated from other cell types. PMID- 26507078 TI - The clinical effectiveness and cost-effectiveness of the PROGENSA(r) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation. AB - BACKGROUND: There is no single definitive test to identify prostate cancer in men. Biopsies are commonly used to obtain samples of prostate tissue for histopathological examination. However, this approach frequently misses cases of cancer, meaning that repeat biopsies may be necessary to obtain a diagnosis. The PROGENSA((r)) prostate cancer antigen 3 (PCA3) assay (Hologic Gen-Probe, Marlborough, MA, USA) and the Prostate Health Index (phi; Beckman Coulter Inc., Brea, CA, USA) are two new tests (a urine test and a blood test, respectively) that are designed to be used to help clinicians decide whether or not to recommend a repeat biopsy. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of the PCA3 assay and the phi in the diagnosis of prostate cancer. DATA SOURCES: Multiple publication databases and trial registers were searched in May 2014 (from 2000 to May 2014), including MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science, Medion, Aggressive Research Intelligence Facility database, ClinicalTrials.gov, International Standard Randomised Controlled Trial Number Register and World Health Organization International Clinical Trials Registry Platform. REVIEW METHODS: The assessment of clinical effectiveness involved three separate systematic reviews, namely reviews of the analytical validity, the clinical validity of these tests and the clinical utility of these tests. The assessment of cost-effectiveness comprised a systematic review of full economic evaluations and the development of a de novo economic model. SETTING: The perspective of the evaluation was the NHS in England and Wales. PARTICIPANTS: Men suspected of having prostate cancer for whom the results of an initial prostate biopsy were negative or equivocal. INTERVENTIONS: The use of the PCA3 score or phi in combination with existing tests (including histopathology results, prostate-specific antigen level and digital rectal examination), multiparametric magnetic resonance imaging and clinical judgement. RESULTS: In addition to documents published by the manufacturers, six studies were identified for inclusion in the analytical validity review. The review identified issues concerning the precision of the PCA3 assay measurements. It also highlighted issues relating to the storage requirements and stability of samples intended for analysis using the phi assay. Fifteen studies met the inclusion criteria for the clinical validity review. These studies reported results for 10 different clinical comparisons. There was insufficient evidence to enable the identification of appropriate test threshold values for use in a clinical setting. In addition, the implications of adding either the PCA3 assay or the phi to clinical assessment were not clear. Furthermore, the addition of the PCA3 assay or the phi to clinical assessment plus magnetic resonance imaging was not found to improve discrimination. No published papers met the inclusion criteria for either the clinical utility review or the cost-effectiveness review. The results from the cost-effectiveness analyses indicated that using either the PCA3 assay or the phi in the NHS was not cost-effective. LIMITATIONS: The main limitations of the systematic review of clinical validity are that the review conclusions are over-reliant on findings from one study, the descriptions of clinical assessment vary widely within reviewed studies and many of the reported results for the clinical validity outcomes do not include either standard errors or confidence intervals. CONCLUSIONS: The clinical benefit of using the PCA3 assay or the phi in combination with existing tests, scans and clinical judgement has not yet been confirmed. The results from the cost-effectiveness analyses indicate that the use of these tests in the NHS would not be cost-effective. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014009595. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26507079 TI - Urinary biomarkers are unreliable for diagnosing bladder cancer, study finds. PMID- 26507081 TI - Chemistry and Light: The International Year of Light. PMID- 26507080 TI - Chemical Vapor Deposition of FeOCl Nanosheet Arrays and Their Conversion to Porous alpha-Fe2 O3 Photoanodes for Photoelectrochemical Water Splitting. AB - FeOCl nanosheet arrays were deposited on fluorine-doped tin oxide glass substrates through a chemical vapor deposition method and further converted to hematite porous nanosheet arrays. A much enhanced photocurrent was obtained for such hematite films, which was three times higher than that of a planar hematite film at 1.23 V versus a reversible hydrogen reference electrode. PMID- 26507082 TI - Fe vs. TiO2 Photo-assisted Processes for Enhancing the Solar Inactivation of Bacteria in Water. AB - Batch solar water disinfection (SODIS) is a known, simple and low-cost water treatment technology. SODIS is based on the synergistic action of temperature increase and light-assisted generation of Reactive Oxygen Species (ROS) on bacteria. ROS are generated via the action of solar photons on i) Natural Organic Matter (NOM), ii) some mineral components of water (Fe oxides or Fe-organic complexes, nitrogen compounds) and iii) endogenous bacteria photosensitizers (e.g. cytochrome). SODIS has proven its effectiveness for remote settlements or urban slums in regions with high incident solar radiation. All of the internal and external simultaneous processes are often driven by photoactive Fe-species present in the cell, as well as in the natural water sources. In SODIS, a temperature of 50 degrees C is required and due to this temperature dependence, only 1-2 L can be treated at a time. As required exposure time strongly depends on irradiation intensity and temperature, some SODIS households could be overburdened, leading to inadequate treatment and probable bacterial re-growth. This is why TiO(2) photocatalysis and Fe photo-assisted systems (i.e. photo Fenton reactants) have been considered to enhance the photo-catalytic processes already present in natural water sources when exposed to solar light. Both TiO(2) and Fe-photoassisted processes, when applied to water disinfection aim to improve the performance of solar bacteria inactivation systems by i) enhancing ROS production, ii) making the process independent from the rise in temperature and as a consequence iii) allowing the treatment of larger volumes than 1-2 L of water and iv) prevent bacterial (re)growth, sometimes observed after sole solar treatment. PMID- 26507083 TI - Light in Medicine: The Interplay of Chemistry and Light. AB - Photodynamic therapy (PDT) has had mixed reception in the clinic, with most success stories being based on the ablative capacity of PDT. In these applications, maximal combinations of light and an exogenous photosensitiser are used to generate high levels of reactive oxygen species (ROS) that induce cell death either directly via necrosis or indirectly via vascular damage. However, recent advances in understanding the complex role of ROS in cell signalling have revealed potential new applications for PDT. For example, the proliferative effects of low level ROS could be applied to wound healing or immunomodulation. These effects should also be considered in the ablative applications. With the decades of chemical advances for ablative PDT at hand - including targeting mechanisms to diseased cells and subcellular locations, optimisation of light absorption, and carrier mechanisms that modulate the therapeutic response - the application of PDT to other types of treatment could be relatively rapid. This review serves to summarise some of these developments and suggest future directions. PMID- 26507084 TI - Photoinduced Charge Accumulation in Molecular Systems. AB - Fuel-forming reactions such as CO(2) reduction or water splitting require multiple redox equivalents. When aiming at light-driven production of energy-rich chemicals, nowadays often referred to as solar fuels, it therefore becomes important to master the photoinduced accumulation of electrons or holes on individual molecular components. Featured in this short review are some of the key molecular systems explored in this emerging field of research. This includes for example a trinuclear Ru(II)-Rh(III)-Ru(III) complex or an Ir(III)-sensitized polyoxotungstate hybrid, but also several systems in which electron or hole collection occurs at organic moieties such as perylenebis(dicarboximide), quinone containing or oligotriarylamine-based units. In many cases the photodriven accumulation of charge requires the use of sacrificial electron donors, but there exist also a handful of studies in which redox equivalents can be accumulated without the use of such additives. PMID- 26507085 TI - Photoelectron Spectroscopy for Chemical Analysis. AB - Photoelectron spectroscopy started its modern development in the fifties based on techniques for studies of nuclear decay. Since then, photoelectron spectroscopy has undergone a dramatic expansion of application and is now a prime research tool in basic and applied science. This progress has been largely due to the concomitant development of photon sources, sample handling and electron energy analyzers. The present article describes some of the salient features of modern photoelectron spectroscopy and its applications with particular emphasis on energy relevant issues. PMID- 26507086 TI - Artificial Photosynthesis with Semiconductor-Liquid Junctions. AB - Given the urgent need to develop a sustainable, carbon neutral energy storage system on a global scale, intense efforts are currently underway to advance the field of artificial photosynthesis: i.e. solar fuel engineering. In this review we give an overview of the field of artificial photosynthesis using a semiconductor-electrolyte interface employed in a photoelectrochemical device or as a heterogeneous photocatalyst. First we present a basic description of the operation principles of a semiconductor-liquid junction based device. The role of nanotechnology in the recent advances in the field is highlighted and common material systems under current study are briefly reviewed. The importance of the material surfaces are further scrutinized by presenting recent advances in interfacial engineering. Technical challenges and an outlook towards industrialization of the technology are given. PMID- 26507087 TI - Dye-sensitized Solar Cells: New Approaches with Organic Solid-state Hole Conductors. AB - Solid-state dye-sensitized solar cells (sDSCs) in which a solid organic charge transfer medium, or hole conductor (HC), is interposed between a dye-coated mesoporous oxide electrode and a conductive counter electrode, have attracted considerable interest as viable alternatives to the more ubiquitous mediator electrolyte DSC. Of particular importance to efficient operation are, in addition to the useful processes contributing to current generation (light harvesting, electron injection and current collection), the recombinative deleterious processes. The organic HCs are highly reactive toward electrons in the oxide or the conducting glass support, therefore necessitating the inclusion of a carefully prepared thin blocking oxide underlayer support as well as the molecular design of special dark current-suppressing dyes. Initially (mid-1990s) sDSCs with organic small molecular weight hole conductors have undergone systematic investigation. At the same time the first tests of sDSCs with conducting polymer hole conductors were published, with subsequent emphasis on the in situ generation of the HC inside the pores. For both types of devices a light-to-electricity conversion efficiency, in the 5-10% range for several dye-HC combinations, approaches that of the most efficient DSCs with non-volatile liquid electrolytes, thereby encouraging further efforts for obtaining stable, efficient and inexpensive sDSCs. PMID- 26507089 TI - New President, New Board Member and New Chief Science Officer of the "Platform Chemistry". PMID- 26507088 TI - Scientific Basis for Regulatory Decision-Making of Nanomaterials Report on the Workshop, 20-21 January 2014, Center of Applied Ecotoxicology, Dubendorf. AB - The key findings of a workshop jointly organized by the Swiss Centre of Applied Ecotoxicity, the Swiss Centre for Applied Human Toxicology (SCAHT), and the Federal Office of Public Health (FOPH) are summarized and provide a critical analysis of the current regulatory framework for nanomaterials and a snapshot of some hot topics in nanoscience. PMID- 26507090 TI - 3D Bioprinted Muscle and Tendon Tissues for Drug Development. PMID- 26507094 TI - Two Bronze Medals for Switzerland at the 46th International Chemistry Olympiad in Hanoi, Vietnam. PMID- 26507095 TI - Early Diagnosis- The Value of Knowledge. The 2014 Olten Meeting. AB - The 2014 Olten Meeting of Swiss biotechnet took place under the heading of 'crystal-clear insights', referring to innovations that make prevention, diagnosis and therapy more reliable, faster and cheaper thanks to biotech breakthroughs. The balanced mixture from research and industry generates new impetus and helps to develop key strategies for the future. PMID- 26507096 TI - Atomistic bond relaxation, energy entrapment, and electron polarization of the RbN and CsN clusters (N <= 58). AB - We systematically examined the effect of atomic undercoordination on the performance of bonds and electrons of Rb and Cs atomic clusters and their solid skins using a combination of photoelectron spectrometric analysis and density functional theory calculations. Results show that atomic coordination number reduction shortens the bonds by up to 30% for the Rb13 and Cs13 clusters, which densifies the local electrons and entraps their binding energies. Consistency between predictions and observations revealed that the Rb 4p level shifts from 13.654 eV for an isolated atom to a bulk value of 14.940 eV and the Cs 5p level shifts from 10.284 to 11.830 eV upon bulk formation. Such core-electron densification and entrapment polarize the valence charge from the inner to the outermost layer of skins, which perturbs the local Hamiltonian and hence dictates the unusual behavior of the Rb and Cs solid skins and nanocrystals. PMID- 26507097 TI - Management of polycystic ovarian syndrome with Diane-35 or Diane-35 plus metformin. AB - In this study, we assessed the efficacy and safe usage of the oral contraceptive, Diane-35, in the treatment of polycystic ovary syndrome (PCOS) when combined with the drug metformin. Eighty-two patients with PCOS were randomly divided into two equal groups: Diane-35 treatment group and Diane-35 plus metformin group. Three treatment cycles were administered. Patients' biomedical data such as height, weight, waist circumference, hip circumference, body fat percentage, acne score, hirsutism score and serum hormone levels were selected, which were tested between the second and the fifth day of the menstrual cycle and follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), blood glucose, blood lipids and insulin levels(IR) were analyzed. Significant reduction in body mass index (BMI), acne score, LH and T levels were observed in both groups after three months of treatment; on the other hand, high-density lipoprotein cholesterol (HDL) concentration elevated (p < 0.05). Combined treatment group had a significant change in BMI index and fasting blood glucose levels compared to Diane-35 alone treatment group (p < 0.05). With personalized nutrition and exercise program, Diane-35 only group or Diane-35 plus metformin group had both significantly lowered their serum testosterone levels and had improved acne symptoms. Diane-35 plus metformin combination had shown reduced fat percentage levels in patients with PCOS, and had shown improved glucose and lipid metabolism. PMID- 26507098 TI - Antibiotic prescribing in UK general dental practice: a cross-sectional study. AB - OBJECTIVES: To assess the extent to which antibiotic prescribing in general dental practice conforms to clinical guidelines and to describe factors associated with antibiotic prescription in the absence of spreading infection or systemic involvement. METHODS: A cross-sectional study of the management of adult patients with acute dental conditions by General Dental Practitioners (GDPs) in Wales, UK. Clinical information on the management of patients was compared to clinical and prescribing guidelines published by the Scottish Dental Clinical Effectiveness Programme and the Faculty of General Dental Practice (UK). Multilevel logistic regression was used to identify patient, practitioner and consultation characteristics predictive of antibiotic prescribing in the absence of infection. RESULTS: Antibiotics were prescribed to 57.4% of 568 patients. Over half of antibiotics (65.6%) were prescribed in situations where there was no evidence of spreading infection, and 70.6% were used without the provision of an operative intervention. Only 19.0% of antibiotics were prescribed in situations where their use was indicated by clinical guidelines. Factors associated (P < 0.05) with antibiotic prescription in the absence of infection were failure of previous operative treatment (Odds Ratio (OR) 13.57), shortage of clinical time to undertake treatment (OR 10.21), patients who were unable or unwilling to accept operative treatment (OR 4.89), patient requests for antibiotics (OR 3.69) and acute periodontal conditions (OR 3.37). CONCLUSIONS: A high level of inappropriate antibiotic prescribing was observed amongst the GDPs studied. Features of the healthcare environment, such as clinical time pressures, and patient-related characteristics, such as expectations for antibiotics and refusal of operative treatment, are associated with antibiotic prescribing in the absence of infection. Individuals responsible for the commissioning and delivery of dental services should seek to develop targeted interventions addressing these issues in order to ensure optimal antimicrobial stewardship within dentistry. PMID- 26507099 TI - Cricothyroidotomy catheters: an investigation of mechanisms of failure and the effect of a novel intracatheter stylet. AB - Emergency catheter cricothyroidotomy often fails. Case reports have concentrated on kinking and displacement of the catheter as the major causes. We investigated catheter tip penetration of the trachea. Using insertion angles of 90 degrees , 75 degrees , 60 degrees , 45 degrees and 30 degrees we advanced 14 G intravenous catheters into fresh isolated sheep tracheas during high pressure oxygen insufflation. At all angles, the catheter tip became blocked by pushing into the mucosa with submucosal gas injection on one or more attempts. Full thickness rupture with extratracheal gas also occurred on insertions at 90 degrees and 60 degrees . We then tested a Luer-mounted prototype wire stylet which remains in situ during insufflation. Using the same methodology, the stylet was able to be placed and prevented blockage at all angles of insertion. Mucosal trauma and submucosal gas injection occurred on insertions at 90 degrees and 75 degrees . Our results should guide further stylet design. PMID- 26507100 TI - Retinal development in the gilthead seabream Sparus aurata. AB - The retinal development of the gilthead seabream Sparus aurata has been analysed from late embryonic development to juvenile stages using classical histological and immunohistological methods. Five significant phases were established. Phases 1 and 2 comprise the late embryonic and hatching stages, respectively. The results indicate that during these early stages the retina is composed of a single neuroblastic layer that consists of undifferentiated retinal progenitor cells. Phase 3 (late prolarval stage) is characterized by the emergence of the retinal layers and the appearance of neurochemical profiles in differentiating photoreceptors, amacrine and ganglion cells. Phases 4 and 5 comprise the late larval and juvenile stages. In these stages, all the retinal cell types can be detected immunohistochemically. All the maturational events described are first detected in the central retina and, as development progresses, spread to the rest of the retina following a central-to-peripheral gradient. The results of this study suggest that S. aurata is an altricial teleost species that hatches with a morphologically undifferentiated retina. The most relevant processes involved in retinogenesis occur during the late prolarval stage (phase 3). PMID- 26507101 TI - Identification of lysosomal Npc1-binding proteins: Cathepsin D activity is regulated by NPC1. AB - Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder, characterized by severe neurodegeneration. It is mostly produced by mutations in the NPC1 gene, encoding for a protein of the late endosomes/lysosomes membrane, involved in cholesterol metabolism. However, the specific role of this protein in NPC disease still remains unknown. We aimed to identify Npc1-binding proteins in order to define new putative NPC1 lysosomal functions. By affinity chromatography using an Npc1 peptide (amino acids 1032-1066 of loop I), as bait, we fished 31 lysosomal proteins subsequently identified by LC-MS/MS. Most of them were involved in proteolysis and lipid catabolism and included the protease cathepsin D. Cathepsin D and NPC1 interaction was validated by immunoprecipitation and the functional relevance of this interaction was studied. We found that fibroblasts from NPC patients with low levels of NPC1 protein have high amounts of procathepsin D but reduced quantities of the mature protein, thus showing a diminished cathepsin D activity. The increase of NPC1 protein levels in NPC cells by treatment with the proteasome inhibitor bortezomib, induced an elevation of cathepsin D activity. All these results suggest a new lysosomal function of NPC1 as a regulator of cathepsin D processing and activity. PMID- 26507102 TI - Characterisation of lubricin in synovial fluid from horses with osteoarthritis. AB - REASON FOR PERFORMING STUDY: The glycoprotein lubricin contributes to the boundary lubrication of the articular cartilage surface. The early events of osteoarthritis involve the superficial layer where lubricin is synthesised. OBJECTIVES: To characterise the glycosylation profile of lubricin in synovial fluid from horses with osteoarthritis and study secretion and degradation of lubricin in an in vitro inflammation cartilage model. STUDY DESIGN: In vitro study. METHODS: Synovial fluid samples collected from horses with joints with normal articular cartilage and structural osteoarthritic lesions; with and without osteochondral fragments, were analysed for the lubricin glycosylation profiles. Articular cartilage explants were stimulated with or without interleukin-1beta for 25 days. Media samples collected at 3-day intervals were analysed by quantitative proteomics, western blot and enzyme-linked immunosorbent assay. RESULTS: O-glycosylation profiles in synovial fluid revealed both Core 1 and 2 O-glycans, with Core 1 O-glycans predominating. Synovial fluid from normal joints (49.5 +/- 1.9%) contained significantly lower amounts of monosialylated Core 1 O-glycans compared with joints with osteoarthritis (53.8 +/- 7.8%, P = 0.03) or joints with osteochondral fragments (57.3 +/- 8.8%, P = 0.001). Additionally, synovial fluid from normal joints (26.7 +/- 6.7%) showed higher amounts of disialylated Core 1 O-glycan than from joints with osteochondral fragments (21.2 +/- 4.9%, P = 0.03). A C-terminal proteolytic cleavage site in lubricin was found in synovial fluid from normal and osteochondral fragment joints and in media from interleukin-1beta stimulated and unstimulated articular cartilage explants. CONCLUSIONS: This is the first demonstration of a change in the glycosylation profile of lubricin in synovial fluid from diseased equine joints compared with that from normal joints. We demonstrate an identical proteolytic cleavage site of lubricin both in vitro and in vivo. The reduced sialation of lubricin in synovial fluid from diseased joints may affect the boundary lubricating ability of the superficial layer of articular cartilage and could be one of the early events in the progression of osteoarthritis. PMID- 26507103 TI - Calcification of hydrophilic acrylic intraocular lens in eyes with silicone oil tamponade - an interventional case series report. PMID- 26507104 TI - Biosynthetic Origin of the Antibiotic Pseudopyronines A and B in Pseudomonas putida BW11M1. AB - Within the framework of our effort to discover new antibiotics from pseudomonads, pseudopyronines A and B were isolated from the plant-derived Pseudomonas putida BW11M1. Pseudopyronines are 3,6-dialkyl-4-hydroxy-2-pyrones and displayed high in vitro activities against several human pathogens, and in our hands also towards the plant pathogen Pseudomonas savastanoi. Here, the biosynthesis of pseudopyronine B was studied by a combination of feeding experiments with isotopically labeled precursors, genomic sequence analysis, and gene deletion experiments. The studies resulted in the deduction of all acetate units and revealed that the biosynthesis of these alpha-pyrones occurs with a single PpyS homologous ketosynthase. It fuses, with some substrate flexibility, a 3-oxo-fatty acid and a further unbranched saturated fatty acid, both of medium chain-length and provided by primary metabolism. PMID- 26507105 TI - Bromoderma mimicking pyoderma gangrenosum caused by commercial sedatives. AB - Bromoderma is a rare skin disorder caused by bromide intake. It presents as single or multiple papillomatous nodules or plaques, and ulcers studded with small pustules on the face or limbs. The clinical features of bromoderma are similar to those of pyoderma gangrenosum. A 41-year-old Japanese woman was diagnosed with pyoderma gangrenosum 11 years prior to presentation. Pyoderma had repeatedly appeared over her entire body despite treatment. She also frequently complained of syncopal episodes. She was admitted to our hospital after loss of consciousness and an episode of generalized convulsion. Laboratory tests revealed a negative serum anion gap and hyperchloremia. Her serum bromide level was significantly elevated, suggesting bromide intoxication. The patient had a 10 year history of high serum bromide levels. After the intake of bromide-containing sedatives was stopped, there was no recurrence of pyoderma in the absence of treatment. In conclusion, this case was diagnosed as bromoderma with commercial sedative-induced bromide intoxication. Although the US Food and Drug Administration have banned the use of bromides, over-the-counter (OTC) treatments containing bromides are still used in Japan and other countries. Long-term use of OTC medicines containing bromvalerylurea may result in the development of bromoderma. If unclarified neurological or psychiatric symptoms are associated with pyoderma, we propose measurement of the patient's serum chloride concentration. Determination of hyperchloremia is helpful for the diagnosis of chronic intoxication with bromides. PMID- 26507106 TI - Negative impacts of high temperatures on growth of black spruce forests intensify with the anticipated climate warming. AB - An increasing number of studies conclude that water limitations and heat stress may hinder the capacity of black spruce (Picea mariana (Mill.) B.S.P.) trees, a dominant species of Canada's boreal forests, to grow and assimilate atmospheric carbon. However, there is currently no scientific consensus on the future of these forests over the next century in the context of widespread climate warming. The large spatial extent of black spruce forests across the Canadian boreal forest and associated variability in climate, demography, and site conditions pose challenges for projecting future climate change responses. Here we provide an evaluation of the impacts of climate warming and drying, as well as increasing [CO2 ], on the aboveground productivity of black spruce forests across Canada south of 60 degrees N for the period 1971 to 2100. We use a new extensive network of tree-ring data obtained from Canada's National Forest Inventory, spatially explicit simulations of net primary productivity (NPP) and its drivers, and multivariate statistical modeling. We found that soil water availability is a significant driver of black spruce interannual variability in productivity across broad areas of the western to eastern Canadian boreal forest. Interannual variability in productivity was also found to be driven by autotrophic respiration in the warmest regions. In most regions, the impacts of soil water availability and respiration on interannual variability in productivity occurred during the phase of carbohydrate accumulation the year preceding tree-ring formation. Results from projections suggest an increase in the importance of soil water availability and respiration as limiting factors on NPP over the next century due to warming, but this response may vary to the extent that other factors such as carbon dioxide fertilization, and respiration acclimation to high temperature, contribute to dampening these limitations. PMID- 26507107 TI - Inhibition of Human Hepatic Bile Acid Transporters by Tolvaptan and Metabolites: Contributing Factors to Drug-Induced Liver Injury? AB - Tolvaptan is a vasopressin V(2)-receptor antagonist that has shown promise in treating Autosomal Dominant Polycystic Kidney Disease (ADPKD). Tolvaptan was, however, associated with liver injury in some ADPKD patients. Inhibition of bile acid transporters may be contributing factors to drug-induced liver injury. In this study, the ability of tolvaptan and two metabolites, DM-4103 and DM-4107, to inhibit human hepatic transporters (NTCP, BSEP, MRP2, MRP3, and MRP4) and bile acid transport in sandwich-cultured human hepatocytes (SCHH) was explored. IC(50) values were determined for tolvaptan, DM-4103 and DM-4107 inhibition of NTCP (~41.5, 16.3, and 95.6 MUM, respectively), BSEP (31.6, 4.15, and 119 MUM, respectively), MRP2 (>50, ~51.0, and >200 MUM, respectively), MRP3 (>50, ~44.6, and 61.2 MUM, respectively), and MRP4 (>50, 4.26, and 37.9 MUM, respectively). At the therapeutic dose of tolvaptan (90 mg), DM-4103 exhibited a C(max)/IC(50) value >0.1 for NTCP, BSEP, MRP2, MRP3, and MRP4. Tolvaptan accumulation in SCHH was extensive and not sodium-dependent; intracellular concentrations were ~500 MUM after a 10-min incubation duration with tolvaptan (15 MUM). The biliary clearance of taurocholic acid (TCA) decreased by 43% when SCHH were co-incubated with tolvaptan (15 MUM) and TCA (2.5 MUM). When tolvaptan (15 MUM) was co incubated with 2.5 MUM of chenodeoxycholic acid, taurochenodeoxycholic acid, or glycochenodeoxycholic acid in separate studies, the cellular accumulation of these bile acids increased by 1.30-, 1.68-, and 2.16-fold, respectively. Based on these data, inhibition of hepatic bile acid transport may be one of the biological mechanisms underlying tolvaptan-associated liver injury in patients with ADPKD. PMID- 26507108 TI - Skin Damage Mechanisms Related to Airborne Particulate Matter Exposure. AB - Epidemiological studies suggest a correlation between increased airborne particulate matter (PM) and adverse health effects. The mechanisms of PM-health effects are believed to involve oxidative stress and inflammation. To evaluate the ability of PM promoting skin tissue damage, one of the main organs exposed to outdoor pollutants, we analyzed the effect of concentrated ambient particles (CAPs) in a reconstructed human epidermis (RHE) model. RHE tissues were exposed to 25 or 100 ug/ml CAPs for 24 or 48 h. Data showed that RHE seems to be more susceptible to CAPs-induced toxicity after 48 h exposure than after 24 h. We found a local reactive O(2) species (ROS) production increase generated from metals present on the particle, which contributes to lipids oxidation. Furthermore, as a consequence of altered redox status, NFkB nucleus translocation was increase upon CAPs exposure, as well as cyclooxygenase 2 and cytochrome P450 levels, which may be involved in the inflammatory response initiated by PM. CAPs also triggered an apoptotic process in skin. Surprisingly, by transition electron microscopy analysis we showed that CAPs were able to penetrate skin tissues. These findings contribute to the understanding of the cutaneous pathophysiological mechanisms initiated by CAPs exposure, where oxidative stress and inflammation may play predominant roles. PMID- 26507109 TI - A facile one pot route for the synthesis of imide tethered peptidomimetics. AB - A simple and efficient method for the synthesis of N,N'-orthogonally protected imide tethered peptidomimetics is presented. The imide peptidomimetics were synthesized by coupling the in situ generated selenocarboxylate of N(alpha) protected amino acids with N(alpha)-protected amino acid azides in good yields. The protocol was also successfully applied for the synthesis of hybrid tripeptidomimetics bearing both amide and imide functionalities. In addition, coumarinic imide conjugates of amino acids have been accomplished by employing this protocol. The present method provides a convenient and easy access to imide tethered peptidomimetics and is compatible with common protecting groups employed in peptide chemistry. PMID- 26507110 TI - Solidago altissima differs with respect to ploidy frequency and clinal variation across the prairie-forest biome border in Minnesota. AB - PREMISE OF THE STUDY: Although our awareness of ploidy diversity has expanded with the application of flow cytometry, we still know little about the extent to which cytotypes within mixed-ploidy populations are genetically differentiated across environmental gradients. METHODS: To address this issue, we reared 14 populations of Solidago altissima spanning the prairie-forest ecotone in Minnesota in a common garden with a watering treatment. We assessed ploidy frequencies and measured survival, flowering phenology, and plant architectural traits for 4 years. KEY RESULTS: All populations harbored multiple cytotypes; prairie populations were dominated by tetraploids, forest populations by hexaploids. Diploids and polyploids differed significantly for 84% of the traits. Beyond average differences, the slope of trait values covaried with latitude and longitude, but this relationship was stronger for diploids than the other two polyploid cytotypes as indicated by numerous ploidy * latitude and ploidy * longitude interactions. For example, the timing of flowering of the cytotypes overlapped in populations sampled from the northeastern hemiboreal forest but differed significantly between cytotypes sampled from populations in the southwestern prairie. The watering treatments had weak effects, and there were no ploidy differences for phenotypic plasticity. CONCLUSIONS: Our data show that diploids have diverged genetically to a greater extent than polyploids along the environmental clines sampled in this study. Moreover, different environments favor phenotypic convergence over divergence among cytotypes for some traits. Differences in ploidy frequency and phenotypic divergence among cytotypes across gradients of temperature and precipitation are important considerations for restoration in an age of climate change. PMID- 26507111 TI - Seed morphology and anatomy and its utility in recognizing subfamilies and tribes of Zingiberaceae. AB - PREMISE OF THE STUDY: Recent phylogenetic analyses based on molecular data suggested that the monocot family Zingiberaceae be separated into four subfamilies and four tribes. Robust morphological characters to support these clades are lacking. Seeds were analyzed in a phylogenetic context to test independently the circumscription of clades and to better understand evolution of seed characters within Zingiberaceae. METHODS: Seventy-five species from three of the four subfamilies were analyzed using synchrotron based x-ray tomographic microscopy (SRXTM) and scored for 39 morphoanatomical characters. KEY RESULTS: Zingiberaceae seeds are some of the most structurally complex seeds in angiosperms. No single seed character was found to distinguish each subfamily, but combinations of characters were found to differentiate between the subfamilies. Recognition of the tribes based on seeds was possible for Globbeae, but not for Alpinieae, Riedelieae, or Zingibereae, due to considerable variation. CONCLUSIONS: SRXTM is an excellent, nondestructive tool to capture morphoanatomical variation of seeds and allows for the study of taxa with limited material available. Alpinioideae, Siphonochiloideae, Tamijioideae, and Zingiberoideae are well supported based on both molecular and morphological data, including multiple seed characters. Globbeae are well supported as a distinctive tribe within the Zingiberoideae, but no other tribe could be differentiated using seeds due to considerable homoplasy when compared with currently accepted relationships based on molecular data. Novel seed characters suggest tribal affinities for two currently unplaced Zingiberaceae taxa: Siliquamomum may be related to Riedelieae and Monolophus to Zingibereae, but further work is needed before formal revision of the family. PMID- 26507112 TI - Resolving basal lamiid phylogeny and the circumscription of Icacinaceae with a plastome-scale data set. AB - PREMISE OF THE STUDY: Major relationships within Lamiidae, an asterid clade with ~40000 species, have largely eluded resolution despite two decades of intensive study. The phylogenetic positions of Icacinaceae and other early-diverging lamiid clades (Garryales, Metteniusaceae, and Oncothecaceae) have been particularly problematic, hindering classification and impeding our understanding of early lamiid (and euasterid) character evolution. METHODS: To resolve basal lamiid phylogeny, we sequenced 50 plastid genomes using the Illumina sequencing platform and combined these with available asterid plastome sequence data for more comprehensive phylogenetic analyses. KEY RESULTS: Our analyses resolved basal lamiid relationships with strong support, including the circumscription and phylogenetic position of the enigmatic Icacinaceae. This greatly improved basal lamiid phylogeny offers insight into character evolution and facilitates an updated classification for this clade, which we present here, including phylogenetic definitions for 10 new or converted clade names. We also offer recommendations for applying this classification to the Angiosperm Phylogeny Group (APG) system, including the recognition of a reduced Icacinaceae, an expanded Metteniusaceae, and two orders new to APG: Icacinales (Icacinaceae + Oncothecaceae) and Metteniusales (Metteniusaceae). CONCLUSIONS: The lamiids possibly radiated from an ancestry of tropical trees with inconspicuous flowers and large, drupaceous fruits, given that these morphological characters are distributed across a grade of lineages (Icacinaceae, Oncothecaceae, Metteniusaceae) subtending the core lamiid clade (Boraginales, Gentianales, Lamiales, Solanales, Vahlia). Furthermore, the presence of similar morphological features among members of Aquifoliales suggests these characters might be ancestral for the Gentianidae (euasterids) as a whole. PMID- 26507113 TI - Postpollination discrimination between self and outcross pollen covaries with the mating system of a self-compatible flowering plant. AB - PREMISE OF THE STUDY: Variation in the mating system of hermaphroditic plant populations is determined by interactions between genetic and environmental factors operating via both pre- and postmating processes. Models predicting the maintenance of intermediate outcrossing rates in animal-pollinated plants often assume that the mating system is primarily controlled by floral morphology and pollinator availability, but rarely has the influence of postpollination processes on variation in outcrossing been examined. METHODS: We investigated the influence of stylar discrimination between illegitimate and legitimate pollen tube growth and the pollen-load capacity of stigmas on mating-system variation in the annual, tristylous species Eichhornia paniculata using controlled crosses and genetic markers. This species exhibits an exceptionally broad range of outcrossing rates in natural populations. KEY RESULTS: There was significant variation among populations in the pollen-load capacity of stigmas and the ability of styles to discriminate between illegitimate vs. legitimate pollen. There was strong correspondence between stylar-discrimination ability and variation in outcrossing rate among populations and style morphs. The combination of stigmatic pollen-load capacity and stylar discrimination explained more than 80% of the variation in outcrossing rates among populations. CONCLUSIONS: The finding that stigmatic pollen-load capacity and stylar-discrimination ability contributed significantly to explaining the wide range of outcrossing rates in E. paniculata suggests that postpollination mechanisms play an important role in governing mating patterns in this species. The difference in levels of stylar discrimination between outcrossing and selfing populations may reflect a trade off between selection for increased outcrossing and greater reproductive assurance. PMID- 26507114 TI - Anatomy of fleshy fruits in the monocots. AB - PREMISE OF THE STUDY: An anatomical and developmental study of distantly related fleshy fruits in the monocots was undertaken to better understand the evolution of baccate fruits in the monocot clade as a whole. We studied 14 species with fleshy fruits spanning the Alismatales, Arecales, Asparagales, Commelinales, Dioscoreales, Liliales, and Poales to determine various mechanisms through which baccate fruits attain fleshiness at maturity. METHODS: Flowers and fruits of various stages were collected, sectioned, stained, and examined using light microscopy and scanning electron microscopy. KEY RESULTS: Three basic pathways for attaining fleshiness were identified within the species examined (true berries, with a uniform pericarp; typical drupes, with an endocarp differentiated by the presence of stony pyrenes; and specialized drupes, involving mesocarp and endocarp differentiated by stone pyrenes). Furthermore, developmental characters differentiating basic fruit types were identified. CONCLUSIONS: Fleshy fruits in the monocots do not develop through a single shared pathway, indicating that fleshiness has evolved multiple times within the clade. PMID- 26507115 TI - Patterns of among- and within-species variation in heterospecific pollen receipt: The importance of ecological generalization. AB - PREMISE OF THE STUDY: Coflowering plants are at risk for receiving pollen from heterospecifics as well as conspecifics, yet evidence shows wide variation in the degree that heterospecific pollen transfer occurs. Evaluation of patterns and correlates of among- and within-species variation in heterospecific pollen (HP) receipt is key to understanding its importance for floral evolution and species coexistence; however, the rarity of deeply sampled multispecies comparisons has precluded such an evaluation. METHODS: We evaluated patterns of among- and within species variation in HP load size and diversity in 19 species across three distinct plant communities. We assessed the importance of phenotypic specialization (floral phenotype), ecological specialization (contemporary visitor assemblage), and conspecific flower density as determinants of among species variation. We present hypotheses for different accrual patterns of HP within species based on the evenness and quality of floral visitors and evaluated these by characterizing the relationship between conspecific pollen (CP) and HP receipt. KEY RESULTS: We found that within-species variation in HP receipt was greater than among-species and among-communities variation. Among species, ecological generalization emerged as the strongest driver of variation in HP receipt irrespective of phenotypic specialization. Within-species variation in HP load size and diversity was predicted most often from two CP-HP relationships (linear or exponentially decreasing), suggesting that two distinct types of plant pollinator interactions prevail. CONCLUSIONS: Our results give important insights into the potential drivers of among- and within-species variation in HP receipt. They also highlight the value of explorations of patterns at the intraspecific level, which can ultimately shed light on plant-pollinator-mediated selection in diverse plant communities. PMID- 26507116 TI - Child passengers and driver culpability in fatal crashes by driver gender. AB - OBJECTIVE: Studies based on accident statistics generally suggest that the presence of a passenger reduces adult drivers' accident risk. However, passengers have been reported to be a source of distraction in a remarkable portion of distraction-related crashes. Although the effect of passengers on driving performance has been studied extensively, few studies have focused on how a child passenger affects the driver. A child in a car is a potential distractor for parents, especially for mothers of small children, who often suffer from sleep deficit. The aim of this study was to examine how the presence of child passengers of different ages is associated with a higher driver culpability, which was expected due to child-related distraction and fatigue. METHODS: The analysis was based on the comprehensive data of fatal crashes studied in-depth by multidisciplinary road accident investigation teams in Finland during 1988-2012. Teams determine the primary party who had the most crucial effect on the origin of the event. We define the primary party as culpable and the others involved as nonculpable drivers. The culpability rate was defined as the percentage of culpable drivers and rates were compared for drivers with a child/teen passenger aged 0-17 years (N = 348), with an adult passenger without children (N = 324), and when driving alone (N = 579), grouped by child age and driver gender. Drivers with specific risk-related behavior (substantial speeding, driving when intoxicated, unbelted, or without a license) were excluded from the analyses, in order to make the drivers with and without children comparable. Only drivers 26 47 years old were included, representing parents with children 0-9 years of age. RESULTS: Male drivers were less often culpable with 0- to 17-year-old passengers in the car than alone or with adults. This was not the case with female drivers. The gender difference in culpability was most marked with small children age 0-4 years. Female drivers' culpability rate with a 0- to 4-year-old child passenger was higher and male drivers' culpability rate was lower compared to drivers without passengers or with only adult passengers. CONCLUSION: The results indicate that female drivers are at higher risk of crashes than male drivers when driving with small children. Further research is needed to replicate this finding and to determine causal mechanisms. PMID- 26507117 TI - Results of efforts by the Convention on Biological Diversity to describe ecologically or biologically significant marine areas. AB - In 2004, Parties to the Convention on Biological Diversity (CBD) addressed a United Nations (UN) call for area-based planning, including for marine-protected areas that resulted in a global effort to describe ecologically or biologically significant marine areas (EBSAs). We summarized the results, assessed their consistency, and evaluated the process developed by the Secretariat of the CBD to engage countries and experts in 9 regional workshops held from 2011 to 2014. Experts from 92 countries and 79 regional or international bodies participated. They considered 250 million km(2) of the world's ocean area (two-thirds of the total). The 204 areas they examined in detail differed widely in area (from 5.5 km(2) to 11.1 million km(2) ). Despite the initial focus of the CBD process on areas outside national jurisdiction, only 31 of the areas examined were solely outside national jurisdiction. Thirty-five extended into national jurisdictions, 137 were solely within national jurisdictions, and 28 included the jurisdictions of more than 1 country (1 area lacked precise boundaries). Data were sufficient to rank 88-99% of the areas relative to each of the 7 criteria for EBSAs agreed to previously by Parties to the CBD. The naturalness criterion ranked high for a smaller percentage of the EBSAs (31%) than other criteria (51-70%), indicating the difficulty in finding relatively undisturbed areas in the ocean. The highly participatory nature of the workshops, including easy and consistent access to the relevant information facilitated by 2 technical teams, contributed to the workshop participants success in identifying areas that could be ranked relative to most criteria and areas that extend across jurisdictional boundaries. The formal recognition of workshop results by the Conference of Parties to the CBD resulted in these 204 areas being identified as EBSAs by the 196 Parties. They represent the only suite of marine areas recognized by the international community for their greater importance for biodiversity it is their importance for biodiversity itself not conservation as process explicitly excluded management issues than their surroundings. This comes at a critical juncture in negotiations at the UN that will consider developing a new implementation agreement under UN Convention of the Law of the Sea to support the conservation and sustainable use of marine biological diversity beyond areas of national jurisdiction. The EBSA description process is a good example of how to bring the international community together to build a shared understanding of which ocean areas are particularly valuable to biodiversity. PMID- 26507118 TI - Visuotemporal cues clinically improved walking ability of ambulatory patients with spinal cord injury within 5 days. AB - BACKGROUND/OBJECTIVE: The human movement system uses a variety of inputs to produce movements. The concurrent use of external information, specifically visutemporal cues, while walking could promote the walking ability of ambulatory patients with spinal cord injury (SCI). This study explored the use of visutemporal cues in rehabilitation training by subjecting ambulatory individuals with SCI to walking training with or without visuotemporal cues and then assessing the effects on their functional ability. DESIGN: Quasi-experimental study. SETTING: A tertiary rehabilitation center. PARTICIPANTS: Thirty-two participants were randomly assigned to the experimental or control groups using stage of injury, severity of SCI, and baseline walking ability as criteria for group arrangement (16 participants/group). INTERVENTIONS: The participants were trained to walk over level ground at their fastest safe speed with or without a visuotemporal cue, 30 minutes/day, for 5 consecutive days. OUTCOME MEASURES: The 10-meter walk test, 6-minute walk test, timed up and go test, and five times sit to-stand test. RESULTS: The participants demonstrated significant improvement in all functional tests after the 5 days of training (P < 0.001). In addition, the improvement in the group trained using the visuotemporal cue was significantly better than that trained without using the cue. CONCLUSIONS: Most of these participants were at a chronic stage of SCI, so the findings supported a benefit for incorporating visuotemporal cues in rehabilitation practice, particularly today when the length of rehabilitation has dramatically decreased. PMID- 26507119 TI - Epigenetic instability at imprinting control regions in a Kras(G12D)-induced T cell neoplasm. AB - Although aberrant DNA methylation within imprinted domains has been reported in a variety of neoplastic diseases, it remains largely uncharacterized in the context of carcinogenesis. In this study, we induced T-cell lymphoma in mice by employing a breeding scheme involving mouse strains, LSL-Kras(G12D) and MMTV-Cre. We then systematically surveyed imprinted domains for DNA methylation changes during tumor progression using combined bisulfite restriction analysis and NGS-based bisulfite sequencing. We detected hyper- or hypo-methylation at the imprinting control regions (ICRs) of the Dlk1, Peg10, Peg3, Grb10, and Gnas domains. These DNA methylation changes at ICRs were more prevalent and consistent than those observed at the promoter regions of well-known tumor suppressors, such as Mgmt, Fhit, and Mlh1. Thus, the changes observed at these imprinted domains are the outcome of isolated incidents affecting DNA methylation settings. Within imprinted domains, DNA methylation changes tend to be restricted to ICRs as nearby somatic differentially methylated regions and promoter regions experience no change. Furthermore, detailed analyses revealed that small cis-regulatory elements within ICRs tend to be resistant to DNA methylation changes, suggesting potential protection by unknown trans-factors. Overall, this study demonstrates that DNA methylation changes at ICRs are dynamic during carcinogenesis and advocates that detection of aberrant DNA methylation at ICRs may serve as a biomarker to enhance diagnostic procedures. PMID- 26507120 TI - Helix handedness inversion in arylamide foldamers: elucidation and free energy profile of a hopping mechanism. AB - We report the first atomistic level description of the handedness inversion mechanism for helical arylamide foldamers. The key process in the handedness inversion is the simultaneous unfolding and folding of two adjacent aryl-aryl linkages, propagating from a helix terminus along the strand. Intermediates along the inversion pathway have a common feature - a single unfolded aryl-aryl linkage (through C(aryl)-C(amide) rotation) connecting two helical segments of opposite handedness. This explicit solvent metadynamics study also provides thorough quantitative free energy information for each step of the previously uncharacterized inversion pathway. PMID- 26507121 TI - Nitrification and denitrification in two-chamber microbial fuel cells for treatment of wastewater containing high concentrations of ammonia nitrogen. AB - Simultaneous nitrification and denitrification in the aerated cathode chamber of microbial fuel cells (MFCs) inoculated with nitrifying bacteria were investigated using two-chamber MFCs. Based on the variations of [Formula: see text], [Formula: see text] and [Formula: see text] in the cathode chamber of four MFCs added with different concentrations of [Formula: see text] (50, 65, 130 and 230 mg/L), the occurrence of simultaneous nitrification and denitrification leading to effective removal of nitrogen was confirmed. Electrochemical reaction with electrons transferred from the anode chamber was found to be the major mechanism responsible for the removal of [Formula: see text] in the cathode chamber. The estimated values of the first-order rate constant for nitrification and denitrification varied in the range of 0.3-1.7 day(-1) and 0.2-0.9 day(-1), revealing a decreasing trend with increases in the initial [Formula: see text] concentrations and the detected maximum concentration of the nitrification product of [Formula: see text] in the cathode chamber, respectively. PMID- 26507122 TI - Human umbilical cord derived mesenchymal stem cells promote interleukin-17 production from human peripheral blood mononuclear cells of healthy donors and systemic lupus erythematosus patients. AB - Inflammation instigated by interleukin (IL)-17-producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity. The expansion of IL-17-producing cells from healthy donors is reportedly promoted by mesenchymal stem cells derived from fetal bone marrow. In the present study, human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were examined for their effects on lymphocytes from healthy donors and from patients with systemic lupus erythematosus (SLE). Significantly higher levels of IL-17 were produced when CD4(+) T cells from healthy donors were co cultured with hUC-MSCs than those that were cultured alone. Blocking experiments identified that this effect might be mediated partially through prostaglandin E2 (PGE2 ) and IL-1beta, without IL-23 involvement. We then co-cultured hUC-MSCs with human CD4(+) T cells from systemic lupus erythematosus patients. Ex-vivo inductions of IL-17 by hUC-MSCs in stimulated lymphocytes were significantly higher in SLE patients than in healthy donors. This effect was not observed for IL-23. Taken together, our results represent that hUC-MSCs can promote the IL-17 production from CD4(+) T cells in both healthy donor and SLE patients. PGE2 and IL-1beta might also be partially involved in the promotive effect of hUC-MSCs. PMID- 26507123 TI - Levoatriocardinal vein and partial anomalous pulmonary vein drainage in left sided obstructive CHDs: diagnostic and surgical implications. AB - We report two cases with levoatriocardinal vein and partial anomalous pulmonary venous drainage in left-sided obstructive lesions. This association may be difficult to recognise by echocardiography. Cardiac CT and MRI were crucial to define the diagnosis and to tailor the best therapeutic option. PMID- 26507124 TI - Perceived morningness-eveningness predicts academic adjustment and substance use across university, but social jetlag is not to blame. AB - Past research has consistently found that evening-types typically report poorer academic adjustment and higher levels of substance use compared to morning-types. An important development within the morningness-eveningness and psychosocial adjustment literature has been the hypothesis that social jetlag (i.e. the asynchrony between an individual's "biological" and "social" clocks) is one factor that may explain why evening-types are at a greater risk for negative psychosocial adjustment. Yet, only a handful of studies have assessed social jetlag. Furthermore, the few studies that have assessed social jetlag have done so only with concurrent data, and thus have not been able to determine the direction of effects among morningness-eveningness, social jetlag and psychosocial adjustment. To address this important gap in the literature, the present 3-year longitudinal study employed the use of a cross-lagged auto regressive model to specifically examine the predictive role of perceived morningness-eveningness and social jetlag on two important indices of psychosocial adjustment among university students: academic adjustment and substance use. We also assessed whether there would be an indirect effect between perceived morningness-eveningness and psychosocial adjustment through social jetlag. Participants were 942 (71.5% female; M = 19 years, SD = 0.90) undergraduates at a mid-sized university in Southern Ontario, Canada, who completed a survey at three assessments, each one year apart, beginning in first year university. Measures were demographics (age, gender and parental education), sleep problems, perceived morningness-eveningness, social jetlag, academic adjustment and substance use. As hypothesized, results of path analyses indicated that a greater perceived eveningness preference significantly predicted higher social jetlag, poorer academic adjustment and higher substance use over time. In contrast, we found no support for social jetlag as a predictor of academic adjustment and substance use, indicating that social jetlag did not explain the link between perceived morningness-eveningness and negative psychosocial adjustment. An important finding was the significant predictive effect of higher substance use on social jetlag over time. Results of the present study highlight the importance of employing a longitudinal framework within which to specifically determine the direction of effects among the study variables in order to validate proposed theoretical models that aim to guide our understanding of how perceived morningness-eveningness, social jetlag, academic adjustment and substance use relate to each other. PMID- 26507125 TI - Functional responses and adaptation of mesophilic microbial communities to psychrophilic anaerobic digestion. AB - Psychrophilic (<20 degrees C) anaerobic digestion (AD) represents an attractive alternative to mesophilic wastewater treatment. In order to investigate the AD microbiome response to temperature change, with particular emphasis on methanogenic archaea, duplicate laboratory-scale AD bioreactors were operated at 37 degrees C followed by a temperature drop to 15 degrees C. A volatile fatty acid-based wastewater (composed of propionic acid, butyric acid, acetic acid and ethanol) was used to provide substrates representing the later stages of AD. Community structure was monitored using 16S rRNA gene clone libraries, as well as DNA and cDNA-based DGGE analysis, while the abundance of relevant methanogens was followed using qPCR. In addition, metaproteomics, microautoradiography fluorescence in situ hybridization, and methanogenic activity measurements were employed to investigate microbial activities and functions. Methanomicrobiales abundance increased at low temperature, which correlated with an increased contribution of CH4 production from hydrogenotrophic methanogenesis at 15 degrees C. Methanosarcinales utilized acetate and H2/CO2 as CH4 precursors at both temperatures and a partial shift from acetoclastic to hydrogenotrophic methanogenesis was observed for this archaeal population at 15 degrees C. An upregulation of protein expression was reported at low temperature as well as the detection of chaperones indicating that mesophilic communities experienced stress during long-term exposure to 15 degrees C. Overall, changes in microbial community structure and function were found to underpin the adaptation of mesophilic sludge to psychrophilic AD. PMID- 26507126 TI - Prognostic value of inhibitors of apoptosis proteins (IAPs) and caspases in prostate cancer: caspase-3 forms and XIAP predict biochemical progression after radical prostatectomy. AB - BACKGROUND: The expression status of apoptotic regulators, such as caspases and inhibitors of apoptosis proteins (IAPs), could reflect the aggressiveness of tumors and, therefore, could be useful as prognostic markers. We explored the associations between tumor expression of caspases and IAPs and clinicopathological features of prostate cancer--clinical and pathological T stage, Gleason score, preoperative serum PSA levels, perineural invasion, lymph node involvement, surgical margin status and overall survival--and evaluated its capability to predict biochemical progression after radical prostatectomy. METHODS: Protein expression of caspases (procaspase-8, cleaved caspase-8, procaspase-3, cleaved caspase-3, caspase-7 and procaspase-9) and IAPs (cIAP1/2, cIAP2, NAIP, Survivin and XIAP) was analyzed by immunohistochemistry in radical prostatectomy samples from 84 prostate cancer patients. Spearman's test, Kaplan Meier curves, and univariate and multivariate Cox proportional hazard regression analysis were performed. RESULTS: cIAP1/2, cIAP2, Survivin, procaspase-8, cleaved caspase-8, procaspase-3 and caspase-7 expression correlated with at least one clinicopathological feature of the disease. Patients negative for XIAP, procaspase-3 or cleaved caspase-3 had a significantly worse prognosis. Of note, XIAP, procaspase-3 and cleaved caspase-3 were predictors of biochemical progression independent of Gleason score and pathological T stage. CONCLUSIONS: Our results indicate that alterations in the expression of IAPs and caspases contribute to the malignant behavior of prostate tumors and suggest that tumor expression of XIAP, procaspase-3 and cleaved caspase-3 may help to identify prostate cancer patients at risk of progression. PMID- 26507127 TI - Predictive biomarkers for treatment selection: statistical considerations. AB - Predictive biomarkers are developed for treatment selection to identify patients who are likely to benefit from a particular therapy. This review describes statistical methods and discusses issues in the development of predictive biomarkers to enhance study efficiency for detection of treatment effect on the selected responder patients in clinical studies. The statistical procedure for treatment selection consists of three components: biomarker identification, subgroup selection and clinical utility assessment. Major statistical issues discussed include biomarker designs, procedures to identify predictive biomarkers, classification models for subgroup selection, subgroup analysis and multiple testing for clinical utility assessment and evaluation. PMID- 26507128 TI - CD3epsilon recruits Numb to promote TCR degradation. AB - Modulation of TCR signaling upon ligand binding is achieved by changes in the equilibrium between TCR degradation, recycling and synthesis; surprisingly, the molecular mechanism of such an important process is not fully understood. Here, we describe the role of a new player in the mediation of TCR degradation: the endocytic adaptor Numb. Our data show that Numb inhibition leads to abnormal intracellular distribution and defective TCR degradation in mature T lymphocytes. In addition, we find that Numb simultaneously binds to both Cbl and a site within CD3epsilon that overlaps with the Nck binding site. As a result, Cbl couples specifically to the CD3epsilon chain to mediate TCR degradation. The present study unveils a novel role of Numb that lies at the heart of TCR signaling initiation and termination. PMID- 26507129 TI - Vitamin A deficient mice exhibit increased viral antigens and enhanced cytokine/chemokine production in nasal tissues following respiratory virus infection despite the presence of FoxP3+ T cells. AB - The World Health Organization (WHO) estimates that 250 million children under the age of five suffer from vitamin A deficiencies (VAD). Individuals with VAD experience higher rates of mortality and increased morbidity during enteric and respiratory infections compared with those who are vitamin A sufficient. Previously, our laboratory has demonstrated that VAD mice have significantly impaired virus-specific IgA and CD8(+) T-cell responses in the airways. Here, we demonstrate that VAD mice experience enhanced cytokine/chemokine gene expression and release in the respiratory tract 10 days following virus infection compared with control vitamin A sufficient animals. Cytokines/chemokines that are reproducibly up-regulated at the gene expression and protein levels include IFNgamma and IL-6. Despite previous indications that cytokine dysregulation in VAD animals might reflect low forkhead box P3 (FoxP3)-positive regulatory T-cell frequencies, we found no reduction in FoxP3(+) T cells in VAD respiratory tissues. As an alternative explanation for the high cytokine levels, we found that the extent of virus infection and the persistence of viral antigens were increased on day 10 post-infection in VAD animals compared with controls, and consequently that respiratory tract tissues had an increased potential to activate virus-specific T cells. Results encourage cautious management of viral infections in patients with VAD, as efforts to enhance FoxP3(+) T cell frequencies and quell immune effectors could potentially exacerbate disease if the virus has not been cleared. PMID- 26507130 TI - Diagnosis and management of inhalation injury: an updated review. AB - In this article we review recent advances made in the pathophysiology, diagnosis, and treatment of inhalation injury. Historically, the diagnosis of inhalation injury has relied on nonspecific clinical exam findings and bronchoscopic evidence. The development of a grading system and the use of modalities such as chest computed tomography may allow for a more nuanced evaluation of inhalation injury and enhanced ability to prognosticate. Supportive respiratory care remains essential in managing inhalation injury. Adjuncts still lacking definitive evidence of efficacy include bronchodilators, mucolytic agents, inhaled anticoagulants, nonconventional ventilator modes, prone positioning, and extracorporeal membrane oxygenation. Recent research focusing on molecular mechanisms involved in inhalation injury has increased the number of potential therapies. PMID- 26507131 TI - Early decision-analytic modeling - a case study on vascular closure devices. AB - BACKGROUND: As economic considerations become more important in healthcare reimbursement, decisions about the further development of medical innovations need to take into account not only medical need and potential clinical effectiveness, but also cost-effectiveness. Already early in the innovation process economic evaluations can support decisions on development in specific indications or patient groups by anticipating future reimbursement and implementation decisions. One potential concept for early assessment is value based pricing. METHODS: The objective is to assess the feasibility of value-based pricing and product design for a hypothetical vascular closure device in the pre clinical stage which aims at decreasing bleeding events. A deterministic decision analytic model was developed to estimate the cost-effectiveness of established vascular closure devices from the perspective of the Statutory Health Insurance system. To identify early benchmarks for pricing and product design, three strategies of determining the product's value are explored: 1) savings from complications avoided by the new device; 2) valuation of the avoided complications based on an assumed willingness-to-pay-threshold (the efficiency frontier approach); 3) value associated with modifying the care pathways within which the device would be applied. RESULTS: Use of established vascular closure devices is dominated by manual compression. The hypothetical vascular closure device reduces overall complication rates at higher costs than manual compression. Maximum cost savings of only about ?4 per catheterization could be realized by applying the hypothetical device. Extrapolation of an efficiency frontier is only possible for one subgroup where vascular closure devices are not a dominated strategy. Modifying care in terms of same-day discharge of patients treated with vascular closure devices could result in cost savings of ?400-600 per catheterization. CONCLUSIONS: It was partially feasible to calculate value based prices for the novel closure device which can be used to inform product design. However, modifying the care pathway may generate much more value from the payers' perspective than modifying the device per se. Manufacturers should thus explore the feasibility of combining reimbursement of their product with arrangements that make same-day discharge attractive also for hospitals. Due to the early nature of the product, the results are afflicted with substantial uncertainty. PMID- 26507132 TI - IVC agenesis: a rare cause of deep vein thrombosis. AB - We present the case of a healthy, young Caucasian female who presented to an outside hospital with phlegmasia cerulea dolens of both lower extremities. Computed tomography angiography revealed inferior vena cava (IVC) occlusion. She was initiated on heparin infusion and transferred to University of Virginia Medical Center. Our evaluation revealed aplasia of the IVC from the infrahepatic segment to the confluence of the common iliac veins and acute bilateral iliac vein thromboses. An extensive network of collateral veins was noted. These findings were consistent with IVC agenesis. She was not pregnant or using contraception. Primary thrombophilia workup was negative. She underwent bilateral iliac vein thrombolysis and was started on anticoagulation. While IVC agenesis is rare, it carries risk for development of thrombotic sequelae and bears consideration when evaluating young patients with unexplained deep vein thrombosis, especially if extensive and bilateral. PMID- 26507133 TI - HCV-HIV coinfected pregnant women: data from a multicentre study in Italy. AB - PURPOSE: To provide information about main pregnancy outcomes in HIV-HCV coinfected women and about the possible interactions between HIV and HCV in this particular population. METHODS: Data from a multicenter observational study of pregnant women with HIV, conducted in Italian University and Hospital Clinics between 2001 and 2015, were used. Eligibility criteria for analysis were HCV coinfection and at least one detectable plasma HCV-RNA viral load measured during pregnancy. Qualitative variables were compared using the Chi-square or the Fisher test and quantitative variables using the Mann-Whitney U test. The Spearman's coefficient was used to evaluate correlations between quantitative variables. RESULTS: Among 105 women with positive HCV-RNA, median HCV viral load was substantially identical at the three trimesters (5.68, 5.45, and 5.86 log IU/ml, respectively), and 85.7 % of the women had at least one HCV-RNA value >5 log IU/ml. Rate of preterm delivery was 28.6 % with HCV-RNA <5 log IU/ml and 43.2 % with HCV-RNA >5log (p = 0.309). Compared to women with term delivery, women with preterm delivery had higher median HCV-RNA levels (third trimester: 6.00 vs. 5.62 log IU/ml, p = 0.037). Third trimester HIV-RNA levels were below 50 copies/ml in 47.7 % of the cases. No cases of vertical HIV transmission occurred. Rate of HCV transmission was 9.0 % and occurred only with HCV-RNA levels >5 log IU/ml. CONCLUSIONS: Coinfection with HIV and HCV has relevant consequences in pregnancy: HIV coinfection is associated with high HCV-RNA levels that might favour HCV transmission, and HCV infection might further increase the risk of preterm delivery in women with HIV. HCV/HIV coinfected women should be considered a population at high risk of adverse outcomes. PMID- 26507134 TI - Editorial. PMID- 26507135 TI - Genomics in research and health care with Aboriginal and Torres Strait Islander peoples. AB - Genomics is increasingly becoming an integral component of health research and clinical care. The perceived difficulties associated with genetic research involving Aboriginal and Torres Strait Islander people mean that they have largely been excluded as research participants. This limits the applicability of research findings for Aboriginal and Torres Strait Islander patients. Emergent use of genomic technologies and personalised medicine therefore risk contributing to an increase in existing health disparities unless urgent action is taken. To allow the potential benefits of genomics to be more equitably distributed, and minimise potential harms, we recommend five actions: (1) ensure diversity of participants by implementing appropriate protocols at the study design stage; (2) target diseases that disproportionately affect disadvantaged groups; (3) prioritise capacity building to promote Indigenous leadership across research professions; (4) develop resources for consenting patients or participants from different cultural and linguistic backgrounds; and (5) integrate awareness of issues relating to Indigenous people into the governance structures, formal reviews, data collection protocols and analytical pipelines of health services and research projects. PMID- 26507136 TI - Should patients in a persistent vegetative state be allowed to die? Guidelines for a new standard of care in Australian hospitals. AB - In this article we will be arguing in favour of legislating to protect doctors who bring about the deaths of PVS patients, regardless of whether the death is through passive means (e.g. the discontinuation of artificial feeding and respiration) or active means (e.g. through the administration of pharmaceuticals known to hasten death in end-of-life care). We will first discuss the ethical dilemmas doctors and lawmakers faced in the more famous PVS cases arising in the US and UK, before exploring what the law should be regarding such patients, particularly in Australia. We will continue by arguing in favour of allowing euthanasia in the interests of PVS patients, their families, and finally the wider community, before concluding with some suggestions for how these ethical arguments could be transformed into a set of guidelines for medical practice in this area. PMID- 26507137 TI - Koplin, Titmuss and the social tail that wags the dog: Commentary on Koplin, "From blood donation to kidney sales". AB - This paper is a commentary on Koplin's "From Blood Donation to Kidney Sales". While appreciative of his paper, it argues that an argument from social solidarity to a Titmussian donor system is problematic. It reviews weaknesses in Titmuss, discusses problems about Titmussian blood donation as a vehicle for solidarity, and explores problems about extending a Titmussian approach to organs. PMID- 26507138 TI - Ethics for pandemics beyond influenza: Ebola, drug-resistant tuberculosis, and anticipating future ethical challenges in pandemic preparedness and response. AB - The unprecedented outbreak of Ebola virus disease (EVD) in West Africa has raised several novel ethical issues for global outbreak preparedness. It has also illustrated that familiar ethical issues in infectious disease management endure despite considerable efforts to understand and mitigate such issues in the wake of past outbreaks. To improve future global outbreak preparedness and response, we must examine these shortcomings and reflect upon the current state of ethical preparedness. To this end, we focus our efforts in this article on the examination of one substantial area: ethical guidance in pandemic plans. We argue that, due in part to their focus on considerations arising specifically in relation to pandemics of influenza origin, pandemic plans and their existing ethical guidance are ill-equipped to anticipate and facilitate the navigation of unique ethical challenges that may arise in other infectious disease pandemics. We proceed by outlining three reasons why this is so, and situate our analysis in the context of the EVD outbreak and the threat posed by drug-resistant tuberculosis: (1) different infectious diseases have distinct characteristics that challenge anticipated or existing modes of pandemic prevention, preparedness, response, and recovery, (2) clear, transparent, context-specific ethical reasoning and justification within current influenza pandemic plans are lacking, and (3) current plans neglect the context of how other significant pandemics may manifest. We conclude the article with several options for reflecting upon and ultimately addressing ethical issues that may emerge with different infectious disease pandemics. PMID- 26507139 TI - The cytokinesis-blocked micronucleus assay: dose-response calibration curve, background frequency in the population and dose estimation. AB - An in vitro study of the dose responses of human peripheral blood lymphocytes was conducted with the aim of creating calibrated dose-response curves for biodosimetry measuring up to 4 Gy (0.25-4 Gy) of gamma radiation. The cytokinesis blocked micronucleus (CBMN) assay was employed to obtain the frequencies of micronuclei (MN) per binucleated cell in blood samples from 16 healthy donors (eight males and eight females) in two age ranges of 20-34 and 35-50 years. The data were used to construct the calibration curves for men and women in two age groups, separately. An increase in micronuclei yield with the dose in a linear quadratic way was observed in all groups. To verify the applicability of the constructed calibration curve, MN yields were measured in peripheral blood lymphocytes of two real overexposed subjects and three irradiated samples with unknown dose, and the results were compared with dose values obtained from measuring dicentric chromosomes. The comparison of the results obtained by the two techniques indicated a good agreement between dose estimates. The average baseline frequency of MN for the 130 healthy non-exposed donors (77 men and 55 women, 20-60 years old divided into four age groups) ranged from 6 to 21 micronuclei per 1000 binucleated cells. Baseline MN frequencies were higher for women and for the older age group. The results presented in this study point out that the CBMN assay is a reliable, easier and valuable alternative method for biological dosimetry. PMID- 26507140 TI - Evaluation of the efficacy of palonosetron for prevention of chemotherapy-induced nausea and vomiting in patients with gastric cancer treated with S-1 plus cisplatin. AB - PURPOSE: The purpose of our study was to evaluate the efficacy of a new combination antiemetic therapy consisting of palonosetron, aprepitant, and dexamethasone in gastric cancer patients undergoing chemotherapy with S-1 plus cisplatin. METHODS: This prospective, multi-institutional observational study assessed patient-reported nausea, vomiting, use of rescue therapy, change of dietary intake, and Functional Living Index-Emesis (FLIE) questionnaire results. The percentages of patients showing complete response (CR; no emesis and non-use of any rescue antiemetics) and complete protection (CP; no significant nausea and non-use of any rescue antiemetics), change of dietary intake, and impact of chemotherapy-induced nausea and vomiting on daily life during the overall (0-120 h after cisplatin administration), acute (0-24 h), and delayed (24-120 h) phases were examined. These findings were compared with our previous study, which used granisetron, aprepitant, and dexamethasone, to assess the relative effectiveness of palonosetron versus granisetron in combination antiemetic therapy. RESULTS: Of the 72 included patients, 66 (91.6 %), 70 (97.2 %), and 50 (69.1 %) achieved CR, and 48 (66.7 %), 61 (84.7 %) and 49 (68.1 %) achieved CP during in the overall, acute, and delayed phases of cisplatin administration, respectively. Approximately half of the patients had some degree of anorexia. FLIE results indicated that 78.6 % of patients maintained their quality of life. Palonosetron was not superior to granisetron in combination antiemetic therapy. CONCLUSIONS: Three-drug combination antiemetic therapy with palonosetron, aprepitant, and dexamethasone was tolerable in gastric cancer patients undergoing treatment with S-1 plus cisplatin. The predominance of palonosetron to granisetron was not demonstrated in this study. PMID- 26507141 TI - A retrospective analysis on the utility and complications of upper arm ports in 433 cases at a single institute. AB - BACKGROUND: We have employed upper arm central venous ports (UACVPs) since 2006 for long-term intravenous chemotherapy (CTx) or fluid supplementation. We evaluated the long-term availability of CVPs implanted in the upper arm to determine whether UACVPs could be one of the treatment options besides chest CVPs in terms of CVP-related complications. METHODS: We reviewed the medical records of all patients who underwent subcutaneous implantation of UACVPs at Kyoto University Hospital from 1 April, 2006 to 30 June, 2009. We assessed the indwelling duration of the UACVPs and the incidences of early and late UACVP related complications. RESULTS: A total of 433 patients underwent subcutaneous implantation of UACVPs during this time period. The cumulative follow-up period was 251,538 catheter days, and the median duration of UACVP indwelling was 439.0 days (1-2, 24). There was no UACVP-related mortality throughout the study period. A total of 83 UACVP-related complications occurred (19.2 %), including 43 cases of infection (9.9 %, 0.17/1000 catheter days), ten cases of catheter-related thrombosis (2.3 %, 0.040/1000 catheter days), ten cases of occlusion (2.3 %, 0.040/1000 catheter days), nine cases of catheter dislocation (2.0 %, 0.036/1000 catheter days), five cases of port leakage (1.2 %, 0.019/1000 catheter days), four cases of skin dehiscence (0.9 %, 0.015/1000 catheter days) and two cases of port chamber twist (0.5 %, 0.008/1000 catheter days). The removal-free one-year port availability was estimated at 87.8 %. CONCLUSIONS: UACVPs were of long-term utility, with complication rates comparable to those of chest CVPs previously reported. PMID- 26507142 TI - Maternal TET3 is dispensable for embryonic development but is required for neonatal growth. AB - The development of multicellular organisms is accompanied by reprogramming of the epigenome in specific cells, with the epigenome of most cell types becoming fixed after differentiation. Genome-wide reprogramming of DNA methylation occurs in primordial germ cells and in fertilized eggs during mammalian embryogenesis. The 5-methylcytosine (5mC) content of DNA thus undergoes a marked decrease in the paternal pronucleus of mammalian zygotes. This loss of DNA methylation has been thought to be mediated by an active demethylation mechanism independent of replication and to be required for development. TET3-mediated sequential oxidation of 5mC has recently been shown to contribute to the genome-wide loss of 5mC in the paternal pronucleus of mouse zygotes. We now show that TET3 localizes not only to the paternal pronucleus but also to the maternal pronucleus and oxidizes both paternal and maternal DNA in mouse zygotes, although these phenomena are less pronounced in the female pronucleus. Genetic ablation of TET3 in oocytes had no significant effect on oocyte development, maturation, or fertilization or on pregnancy, but it resulted in neonatal sublethality. Our results thus indicate that zygotic 5mC oxidation mediated by maternal TET3 is required for neonatal growth but is not essential for development. PMID- 26507143 TI - Insulin Resistance in Nondiabetic Peritoneal Dialysis Patients: Associations with Body Composition, Peritoneal Transport, and Peritoneal Glucose Absorption. AB - BACKGROUND AND OBJECTIVES: Insulin resistance has been associated with cardiovascular disease in peritoneal dialysis patients. Few studies have addressed the impact of fast transport status or dialysis prescription on insulin resistance. The aim of this study was to test whether insulin resistance is associated with obesity parameters, peritoneal transport rate, and glucose absorption. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Insulin resistance was evaluated with homeostasis model assessment method (HOMA-IR), additionally corrected by adiponectin (HOMA-AD). Enrolled patients were prevalent nondiabetics attending at Santo Antonio Hospital Peritoneal Dialysis Unit, who were free of hospitalization or infectious events in the previous 3 months (51 patients aged 50.4 +/- 15.9 years, 59% women). Leptin, adiponectin, insulin-like growth factor binding protein 1 (IGFBP-1), and daily glucose absorption were also measured. Lean tissue index, fat tissue index (FTI), and relative fat mass (rel.FM) were assessed using multifrequency bioimpedance. Patients were categorized according to dialysate to plasma creatinine ratio at 4 hours, 3.86% peritoneal equilibration test, and obesity parameters. RESULTS: Obesity was present in 49% of patients according to rel.FM. HOMA-IR correlated better with FTI than with body mass index. Significant correlations were found in obese, but not in nonobese patients, between HOMA-IR and leptin, leptin/adiponectin ratio (LAR), and IGFBP-1. HOMA-IR correlated with HOMA-AD, but did not correlate with glucose absorption or transport rate. There were no significant differences in insulin resistance indices, glucose absorption, and body composition parameters between fast and nonfast transporters. A total of 18 patients (35.3%) who had insulin resistance presented with higher LAR and rel.FM (7.3 [12.3, interquartile range] versus 0.7 [1.4, interquartile range], P<0.001, and 39.4 +/- 10.1% versus 27.2 +/ 11.5%, P=0.002, respectively), lower IGFBP-1 (8.2 +/- 7.2 versus 21.0 +/- 16.3 ng/ml, P=0.002), but similar glucose absorption and small-solute transport compared with patients without insulin resistance. FTI and LAR were independent correlates of HOMA-IR in multivariate analysis adjusted for glucose absorption and small-solute transport (r=0.82, P<0.001). CONCLUSIONS: Insulin resistance in nondiabetic peritoneal dialysis patients is associated with obesity and LAR independent of glucose absorption and small-solute transport status. Fast transport status was not associated with higher likelihood of obesity or insulin resistance. PMID- 26507144 TI - Pancardiac tuberculosis - a case report. AB - Tuberculous involvement of the heart though not common has been reported in literature. Pericardium is commonly involved followed by the myocardium. Endocardial involvement is rare. We would like to report a case of a 14-year-old female with florid and extensive involvement of all the layers of the heart by tuberculosis. PMID- 26507145 TI - To screen or not to screen mothers of preterm infants for extended-spectrum beta lactamase-producing Enterobacteriaceae (ESBL-E). PMID- 26507146 TI - Are current measures of neonatal birth trauma valid indicators of quality of care? PMID- 26507147 TI - Extended-spectrum beta-lactamase-producing Enterobacteriaceae among pregnant women in Norway: prevalence and maternal-neonatal transmission. AB - OBJECTIVE: To study (i) the prevalence and risk factors for carriage of extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) in pregnant women, (ii) the maternal-neonatal transmission rate of ESBL-E at birth and (iii) the prevalence of ESBL-E in expressed breast milk of colonized mothers. STUDY DESIGN: In this cross-sectional, population-based study with case follow-up on maternal neonatal transmission of ESBL-E, women were screened for rectal ESBL-E colonization at 36 weeks of pregnancy and delivery. Possible risk factors for colonization were studied by logistic regression. Infants of ESBL-E-positive mothers were screened for ESBL-E during their first weeks of life. ESBL-encoding genes were detected by PCR and clonal relatedness was investigated by pulsed field gel electrophoreses. RESULTS: In total, 26 out of 901 (2.9%) women were colonized by ESBL-producing Escherichia coli at 36 weeks of pregnancy. One of the women carried an additional ESBL Klebsiella pneumoniae strain. Adjusted for traveling, African or Asian nationality was a risk factor for colonization; OR=5.62 (2.21, 14.27) (LR-p=0.003). Fourteen women remained ESBL-E carriers at delivery. ESBL-E strains indistinguishable from the strains isolated from their respective mothers were detected in 5 (35.7%) infants during their first days of life (median day 3; range=2 to 8). A total of 146 expressed milk samples were cultured from 25 out of 26 colonized mothers, all were ESBL-E negative. CONCLUSIONS: The prevalence of ESBL-E carriage among pregnant women was low in our region, but the high maternal-neonatal transmission rate suggests that colonized mothers represent a substantial risk for infant colonization. PMID- 26507148 TI - Volume guarantee pressure support ventilation in extremely preterm infants and neurodevelopmental outcome at 18 months. PMID- 26507149 TI - Response to: Volume guarantee pressure support ventilation in extremely preterm infants and neurodevelopmental outcome at 18 months. PMID- 26507150 TI - Glucose infusion rates (GIR): shaken, not stirred. PMID- 26507151 TI - Felid Lungworms and Heartworms in Italy: More Questions than Answers? AB - Nematodes infecting the cardiorespiratory system of cats have recently stimulated high scientific interest. Over the past few years, different aspects of these parasites have been clarified and various issues elucidated. This increased knowledge has improved awareness on this topic but, at the same time, some dilemmas have not been solved and new questions have been raised. In this review, we underline and discuss current knowledge of, and new doubts relating to, feline lungworms and heartworms, with the aim of stimulating new studies to fill gaps of basic (i.e., epidemiology and biology) and applied (i.e., clinical aspects) knowledge of the old and new parasites affecting the cardiorespiratory system of cats. PMID- 26507152 TI - Best Practices for Preventing Vector-Borne Diseases in Dogs and Humans. AB - Vector-borne diseases constitute a diversified group of illnesses, which are caused by a multitude of pathogens transmitted by arthropod vectors, such as mosquitoes, fleas, ticks, and sand flies. Proper management of these diseases is important from both human and veterinary medicine standpoints, given that many of these pathogens are transmissible to humans and dogs, which often live in close contact. In this review, we summarize the most important vector-borne diseases of dogs and humans and the best practices for their prevention. The control of these diseases would ultimately improve animal and human health and wellbeing, particularly in developing countries in the tropics, where the risk of these diseases is high and access to health care is poor. PMID- 26507153 TI - Factors That Predict Differences in Childhood Mortality in Nigerian Communities: A Prognostic Model. AB - OBJECTIVE: To identify predictors of variations of childhood mortality between Nigerian communities and to identify high-risk communities where childhood mortality was higher than expected. STUDY DESIGN: Secondary analysis of the 2013 Nigeria Demographic and Health Survey data using prognostic univariable and multivariable mixed Poisson regression models. Likelihood ratio test, Hosmer Lemeshow goodness-of-fit, and variance inflation factor were used to evaluate the fitness of the final model. RESULTS: The final adjusted model revealed that communities with high rating of multiple childhood deprivation (relative risk 1.14, 95% CI 1.09-1.19) and maternal socioeconomic deprivation (relative risk 1.22, 95% CI 1.14-1.29) were associated significantly with the risk of childhood mortality. Communities with enhanced maternal hospital-based health-seeking behaviors and more advantageous environmental conditions had reduced risks of childhood mortality. Similarly, children living in communities with high ethnic diversity were significantly less likely to die before their fifth birthday (relative risk 0.96, 95% CI 0.94-0.97). About 64% of the observed heterogeneity in childhood mortality in these communities was explained by the final model. Eleven of the 896 communities had higher than expected childhood mortality rates during the study period. CONCLUSIONS: Of the 31 482 children included in this survey, 2886 had died before their fifth birthday (128 deaths per 1000 live births). There are variations in childhood mortality across Nigerian communities that are not determined only by health system functions but also by factors beyond the scope of health authorities and healthcare delivery systems. PMID- 26507154 TI - Lingual Osseous Choristoma. PMID- 26507155 TI - A Systematic Review of the Probability of Asphyxia in Children Aged <2 Years with Unexplained Epistaxis. AB - OBJECTIVE: To determine the proportion of children aged <2 years who have been asphyxiated presenting with epistaxis in the absence of trauma or medical explanation and to identify the characteristics of the clinical presentation indicative of asphyxiation. STUDY DESIGN: An all-language systematic review was conducted by searching 10 databases from 1900 to 2015 and gray literature to identify high-quality studies that included children with epistaxis aged <2 years (alive or dead) with explicit confirmation of intentional or unintentional asphyxiation (upper airway obstruction). Studies of traumatic or pathological epistaxis were excluded. For each comparative study, the proportion of children presenting with epistaxis that were asphyxiated is reported with 95% CI. RESULTS: Of 2706 studies identified, 100 underwent full review, resulting in 6 included studies representing 30 children with asphyxiation-related epistaxis and 74 children with non-asphyxiation-related epistaxis. The proportion of children presenting with epistaxis that had been asphyxiated, reported by 3 studies, was between 7% and 24%. Features associated with asphyxiation in live children included malaise, altered skin color, respiratory difficulty, and chest radiograph abnormalities. There were no explicit associated features described among those children who were dead on arrival. CONCLUSION: There is an association between epistaxis and asphyxiation in young children; however, epistaxis does not constitute a diagnosis of asphyxia in itself. In any infant presenting with unexplained epistaxis, a thorough investigation of etiology is always warranted, which must include active exploration of asphyxia as a possible explanation. PMID- 26507156 TI - Coupling between apical tension and basal adhesion allow epithelia to collectively sense and respond to substrate topography over long distances. AB - Epithelial sheets fold into complex topographies that contribute to their function in vivo. Cells can sense and respond to substrate topography in their immediate vicinity by modulating their interfacial mechanics, but the extent to which these mechanical properties contribute to their ability to sense substrate topography across length scales larger than a single cell has not been explored in detail. To study the relationship between the interfacial mechanics of single cells and their collective behavior as tissues, we grew cell-sheets on substrates engraved with surface features spanning macroscopic length-scales. We found that many epithelial cell-types sense and respond to substrate topography, even when it is locally nearly planar. Cells clear or detach from regions of local negative curvature, but not from regions with positive or no curvature. We investigated this phenomenon using a finite element model where substrate topography is coupled to epithelial response through a balance of tissue contractility and adhesive forces. The model correctly predicts the focal sites of cell-clearing and epithelial detachment. Furthermore, the model predicts that local tissue response to substrate curvature is a function of the surrounding topography of the substrate across long distances. Analysis of cell-cell and cell-substrate contact angles suggests a relationship between these single-cell interfacial properties, epithelial interfacial properties, and collective epithelial response to substrate topography. Finally, we show that contact angles change upon activation of oncogenes or inhibition of cell-contractility, and that these changes correlate with collective epithelial response. Our results demonstrate that in mechanically integrated epithelial sheets, cell contractility can be transmitted through multiple cells and focused by substrate topography to affect a behavioral response at distant sites. PMID- 26507157 TI - Time-averaged serum potassium levels and its fluctuation associate with 5-year survival of peritoneal dialysis patients: two-center based study. AB - The time-averaged serum potassium was more comprehensive to reflect the all-time changes of serum potassium levels during peritoneal dialysis (PD). However, the association of fluctuation of time-averaged serum potassium level with long-time survival of PD patients remains unknown. In this retrospective study, we included 357 incident PD patients in 2 centers from January 1, 2007 to October 31, 2012 with follow-up through October 31, 2014. Our data demonstrated that it was the lower time-averaged serum potassium level rather than baseline of serum potassium level that was associated with high risk of death. Patients with higher standard deviation (SD) had significantly poorer all-cause (p = 0.016) and cardiovascular mortality (p = 0.041). Among the patients with time-averaged serum potassium levels below 4.0 mEq/L, a lower mean value was more important than its SD to predict death risk. In contrast, the patients with time-averaged serum potassium levels above 4.0 mEq/L, those with serum potassium SD < 0.54 mEq/L, exhibited a higher 3-year and 5-year survival rate for both all-cause and cardiovascular mortality compared to the control groups. Our data clearly suggested both time averaged serum potassium and its fluctuation contributed disproportionately to the high death risk in PD patients. PMID- 26507158 TI - Reply. PMID- 26507159 TI - Comparison of Contrast Sensitivity and Through Focus in Small-Aperture Inlay, Accommodating Intraocular Lens, or Multifocal Intraocular Lens Subjects. PMID- 26507160 TI - Patients With Impingement Syndrome With and Without Rotator Cuff Tears Do Well 20 Years After Arthroscopic Subacromial Decompression. AB - PURPOSE: To present the long-term outcome of arthroscopic subacromial decompression (ASD) for patients with impingement syndrome with or without rotator cuff tears as well as with or without calcific tendinitis in a follow-up of 20 years. METHODS: We included 95 patients after a mean follow-up of 19.9 (19.5 to 20.5) years. All patients underwent ASD, including acromioplasty, resection of the coracoacromial ligament, and coplaning without cuff repair. The Constant score was used to assess the functioning of the shoulder. In addition, we defined a combined failure end point of a poor Constant score and revision surgery. RESULTS: Revision surgery was performed in14.7% of the patients. The combined end point showed successful results in 78.8% of all cases. All patients with isolated impingement syndrome achieved successful results. Those with partial-thickness tears had successful outcomes in 90.9% of all cases, and patients with full-thickness tears had successful outcomes in 70.6% of all cases. The tendinitis calcarea group showed the poorest results, with a 65.2% success rate. CONCLUSIONS: Our long-term results show that patients with impingement syndrome who received ASD, including acromioplasty, resection of the coracoacromial ligament, and coplaning do well 20 years after the index surgery. ASD without cuff repair even appears to be a safe, efficacious, and sustainable procedure for patients with partial rotator cuff tears. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26507161 TI - The Accuracy of the Lateral Tibial Spine as a Landmark for Lateral Meniscal Allograft Transplantation. AB - PURPOSE: To determine a relationship between the direction of the guide pin for the keyhole in the lateral meniscus (LM) transplantation and the line connecting the centers of both horns of the LM. METHODS: Forty-four resected tibial plateaus during total knee arthroplasty were used for anatomical and radiological evaluations. The inclusion criterion was medial compartment osteoarthritis. Exclusion criteria were osteoarthritic changes, meniscal tear, and previous fracture in the lateral compartment. Resected tibial plateaus were positioned so that the anterior and posterior parts of the lateral tibial spine (LTS) were overlapped accurately on fluoroscopic anteroposterior view. A wire (Pin-F) was drilled along the peak of the LTS. The insertion area of anterior and posterior horns of the LM was dissected carefully. The periphery and the center of the insertion area of both horns were marked. Another wire (Pin-A) was drilled along a line connecting the centers of both horns. An axial radiograph was taken for each prepared tibial plateau. A longitudinal line was drawn along each wire, and the angle between the 2 wires was measured using the imaging software. If the Pin F was externally rotated relative to the Pin-A, the angle was designated as positive, and if the Pin-F was internally rotated, the angle was designated as negative. RESULTS: The mean angle between Pin-F and Pin-A was -7.4 degrees +/- 9.6 degrees . Thirty-three (75%) Pin-Fs were fixed in an internally rotated position, and 11 (25%) were fixed in an externally rotated position. CONCLUSIONS: The direction of most guide pins drilled along the LTS was not coincident with the line connecting the centers of both horns of the LM. CLINICAL RELEVANCE: The axis of the LTS is not a reliable marker for the trough in the LM allograft transplantation. PMID- 26507162 TI - Open and Arthroscopic Treatment of Adult Hip Dysplasia: A Systematic Review. AB - PURPOSE: To compare patient-reported outcome (PRO) and rates of conversion to total hip arthroplasty (THA) after hip arthroscopy, Bernese periacetabular osteotomy (PAO), and a combined approach for the management of patients with different grades of hip dysplasia. METHODS: We searched MEDLINE and PubMed databases for articles published since 2000 using the following terms: (((("hip dysplasia") or "dysplastic") and "arthroscopy")) or ((("hip dysplasia") or "dysplastic") and "osteotomy"). Two authors independently reviewed the literature. Inclusion criteria were English language, relevance to hip dysplasia, surgical outcomes, and sample size of 10 patients or more. We excluded articles that were reviews or techniques; articles that included overlapping populations, patients with a mean age less than 18 years, patients with other hip conditions, patients with genetic or neuromuscular causes of hip dysplasia, and patients with Tonnis grade 2 or greater arthritis; articles on femoral osteotomy, and articles on previous surgical intervention, except hip arthroscopy. Articles were analyzed for PRO scores and rates of conversion to THA. RESULTS: Ten of 759 articles reviewed met the inclusion and exclusion criteria. Of 834 hips treated for dysplasia with a mean age of 31 years, 114 were treated with arthroscopy alone, 703 were treated with PAO alone, and 17 were treated with both procedures. Mean follow-up was 3.2 years, 6.5 years, and 5.6 years, respectively. Conversion rates to THA were 4.8%, 12.0%, and 17.7%, respectively. In studies reporting pre- and postoperative PRO scores, all but one reported improvement. CONCLUSIONS: The management of hip dysplasia may entail hip arthroscopy, PAO, or a combined approach. Arthroscopy has resulted in improved outcomes in borderline dysplastic cases (lateral center edge angle between 18 degrees and 25 degrees ). PAO has primarily been used in true dysplasia with continued success. There were too few combined procedures of arthroscopy with PAO to reach a reliable conclusion in this subgroup. PMID- 26507163 TI - The production mechanism and immunosuppression effect of pulmonary surfactant protein D via toll like receptor 4 signaling pathway in human corneal epithelial cells during Aspergillus fumigatus infection. AB - OBJECTIVE: To observe the production mechanism of surfactant protein D (SP-D) in human corneal epithelial cells (HCECs) when infected by Aspergillus fumigatus (A. fumigatus) hyphae, and explore whether SP-D can inhibit the cell activations through toll-like receptor 4 signaling pathway during fungal infection. METHODS: mRNA and protein expressions of SP-D were evaluated in HCECs after stimulation by A. fumigatus, with or without pretreatment of TLR4 inhibitor (CLI-095) by real time PCR and Western blot. The expression levels of inflammatory cytokines IL 1beta and IL-8 evaluated when pretreated with SP-D antibody or recombinant human SP-D in fungi-stimulated HCECs by real time PCR and ELISA, IL-1beta and IL-8 expressions were also detected in A. fumigatus-stimulated HCECs that pretreated with CLI095 or MyD88 inhibitor (Pepinh-MYD) and recombinant human SP-D. RESULTS: mRNA and protein levels of SP-D increased after stimulation of A. fumigatus for 16h and 20h respectively. The upregulation of SP-D could be inhibited by CLI-095. mRNA and protein expressions of IL-1beta and IL-8 decreased significantly when pretreated HCECs with recombinant human SP-D for 4h before A. fumigatus stimulation, while IL-1beta and IL-8 increased when pretreated with SP-D antibody for 1h. Pretreatment of CLI095 or Pepinh-MYD can increase the expressions of IL 1beta and IL-8 mRNA and protein in HCECs induced by recombinant human SP-D and A. fumigatus. CONCLUSIONS: SP-D can be stimulated by TLR4 during A. fumigatus infection. Recombinant human SP-D can inhibit the expression of inflammatory cytokines through TLR4 signaling pathway. PMID- 26507164 TI - Icariin inhibits TNF-alpha/IFN-gamma induced inflammatory response via inhibition of the substance P and p38-MAPK signaling pathway in human keratinocytes. AB - Pro-inflammatory cytokines play a crucial role in the etiology of atopic dermatitis. We demonstrated that Herba Epimedii has anti-inflammatory potential in an atopic dermatitis mouse model; however, limited research has been conducted on the anti-inflammatory effects and mechanism of icariin, the major active ingredient in Herba Epimedii, in human keratinocytes. In this study, we evaluated the anti-inflammatory potential and mechanisms of icariin in the tumor necrosis factor-alpha (TNF-alpha)/interferon-gamma (IFN-gamma)-induced inflammatory response in human keratinocytes (HaCaT cells) by observing these cells in the presence or absence of icariin. We measured IL-6, IL-8, IL-1beta, MCP-1 and GRO alpha production by ELISA; IL-6, IL-8, IL-1beta, intercellular adhesion molecule 1 (ICAM-1) and tachykinin receptor 1 (TACR1) mRNA expression by real-time PCR; and P38-MAPK, P-ERK and P-JNK signaling expression by western blot in TNF alpha/IFN-gamma-stimulated HaCaT cells before and after icariin treatment. The expression of TNF-alpha-R1 and IFN-gamma-R1 during the stimulation of the cell models was also evaluated before and after icariin treatment. We investigated the effect of icariin on these pro-inflammatory cytokines and detected whether this effect occurred via the mitogen-activated protein kinase (MAPK) signal transduction pathways. We further specifically inhibited the activity of two kinases with 20MUM SB203580 (a p38 kinase inhibitor) and 50MUM PD98059 (an ERK1/2 kinase inhibitor) to determine the roles of the two signal pathways involved in the inflammatory response. We found that icariin inhibited TNF-alpha/IFN-gamma induced IL-6, IL-8, IL-1beta, and MCP-1 production in a dose-dependent manner; meanwhile, the icariin treatment inhibited the gene expression of IL-8, IL-1beta, ICAM-1 and TACR1 in HaCaT cells in a time- and dose-dependent manner. Icariin treatment resulted in a reduced expression of p-P38 and p-ERK signal activation induced by TNF-alpha/IFN-gamma; however, only SB203580, the p38 alpha/beta inhibitor, inhibited the secretion of inflammatory cytokines induced by TNF alpha/IFN-gamma in cultured HaCaT cells. The differential expression of TNF-alpha R1 and IFN-gamma-R1 was also observed after the stimulation of TNF-alpha/IFN gamma, which was significantly normalized after the icariin treatment. Collectively, we illustrated the anti-inflammatory property of icariin in human keratinocytes. These effects were mediated, at least partially, via the inhibition of substance P and the p38-MAPK signaling pathway, as well as by the regulation of the TNF-alpha-R1 and IFN-gamma-R1 signals. PMID- 26507165 TI - Protective effects of polydatin on lipopolysaccharide-induced acute lung injury through TLR4-MyD88-NF-kappaB pathway. AB - The purpose of this study was to investigate the protective effect of PD against lipopolysaccharide (LPS)-induced acute lung injury (ALI) and explore its potential mechanism. In vivo, PD and dexamethasone were intraperitoneally administered 1h before LPS stimulation. Then, mice were sacrificed at 6h post-LPS stimulation. Neutrophil number, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) in bronchoalveolar lavage fluid (BALF) were determined, as well as lung wet to dry ratio (W/D) and polymorphonuclear (MPO) activity. The protein expressions of Toll like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), IL-1R-associated kinases 1 (IRAK1), IRAK4, inhibitor of nuclear factor kappa-B kinase (IKK)alpha, p IKKalpha, IKKbeta, p-IKKbeta, inhibitor of NF-kappaB (IkappaBalpha), p IkappaBalpha and NF-kappaB in lung tissues were assessed. Besides, we detected the IL-6, IL-1beta, IL-8, TNF-alpha levels and TLR4, MyD88, NF-kappaB protein expressions in LPS-induced BEAS-2B cells. Consequently, PD significantly inhibited the levels of W/D, MPO, neutrophils number, TNF-alpha, IL-6, IL-1beta and reversed TLR4-MyD88-NF-kappaB signaling pathway in lung tissues. In vitro assays, PD effectively negatively mediated the inflammatory cytokines and ameliorated the high expressions of TLR4, MyD88, NF-kappaB caused by LPS simulation in Human bronchial epithelial BEAS-2B cells. This study indicated that PD played a protective role in LPS-induced ALI and BEAS-2B cells. The results supported further study of PD as potential candidate for acute lung injury. PMID- 26507166 TI - HO-1 inhibits IL-13-induced goblet cell hyperplasia associated with CLCA1 suppression in normal human bronchial epithelial cells. AB - Mucus hypersecretion and goblet cell hyperplasia are common features that characterize asthma. IL-13 increases mucin (MUC) 5AC, the major component of airway mucus, in airway epithelial cells. According to the literature, IL-13 receptor activation leads to STAT6 activation and consequent induction of chloride channel accessory 1 (CLCA1) gene expression, associated with the induction of MUC5AC. Heme oxygenase-1 (HO-1) is an enzyme that catalyzes oxidation of heme to biliverdin, and has anti-inflammatory and anti-oxidant properties. We examined the effects of HO-1 on mucin production and goblet cell hyperplasia induced by IL-13. Moreover, we assessed the cell signaling intermediates that appear to be responsible for mucin production. Normal human bronchial epithelial (NHBE) cells were grown at air liquid interface (ALI) in the presence or absence of IL-13 and hemin, a HO-1 inducer, for 14 days. Protein concentration was analyzed using ELISA, and mRNA expression was examined by real time PCR. Histochemical analysis was performed using HE staining, andWestern blotting was performed to evaluate signaling transduction pathway. Hemin (4 MUM) significantly increased HO-1 protein expression (p b 0.01) and HO-1 mRNA expression (p b 0.001). IL-13 significantly increased goblet cells, MUC5AC protein secretion (p b 0.01) and MUC5AC mRNA (p b 0.001), and these were decreased by hemin by way of HO-1. Tin protoporphyrin (SnPP)-IX, a HO-1 inhibitor, blocked the effect of hemin restoring MUC5AC protein secretion (p b 0.05) and goblet cell hyperplasia. Hemin decreased the expression of CLCA1 mRNA (p b 0.05) and it was reversed by SnPP-IX, but could not suppress IL-13-induced phosphorylation of STAT6 or SAM pointed domain-containing ETS transcription factor (SPDEF) and Forkhead box A2 (FOXA2) mRNA expression. In summary, HO-1 overexpression suppressed IL-13-induced goblet cell hyperplasia and MUC5AC production, and involvement of CLCA1 in the mechanism was suggested. PMID- 26507167 TI - IL-35 inhibits acute graft-versus-host disease in a mouse model. AB - Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous study found that the novel anti-inflammatory cytokine IL-35 could suppress aGVHD in patients after allo-HSCT. In this study, we used C57BL/6 (B6, H-2b) mice as donors and (B6*DBA/2) F1 (BDF1, H-2b*d) mice as recipients to create a model of aGVHD and explore the relationship between IL-35 and aGVHD. The mice receiving IL-35 survived longer than did the control mice. We observed that treatment with IL-35 and RAPA could reduce the incidence of aGVHD. Additionally, this treatment inhibited intestinal and thymic epithelial cell apoptosis and liver infiltration by the donor T-cells, thereby ameliorating the enteropathy and liver injury caused by aGVHD. We found that IL-35 and RAPA also markedly suppressed TNF-alpha and IL-17A expression and enhanced IFN-gamma expression in the intestine and liver. We measured Tregs in spleen and found that IL-35 and RAPA treatment expanded the number of Tregs in spleen. We found that the phosphorylation of STAT1 and STAT4 were inhibited in mice with aGVHD. In contrast, STAT1 and STAT4 were phosphorylated when the mice were treated with IL-35. IL-35 may have therapeutic potential in the treatment of aGVHD after allo-HSCT. PMID- 26507168 TI - DNA N(6)-methyladenine: a new epigenetic mark in eukaryotes? AB - DNA N(6)-adenine methylation (N(6)-methyladenine; 6mA) in prokaryotes functions primarily in the host defence system. The prevalence and significance of this modification in eukaryotes had been unclear until recently. Here, we discuss recent publications documenting the presence of 6mA in Chlamydomonas reinhardtii, Drosophila melanogaster and Caenorhabditis elegans; consider possible roles for this DNA modification in regulating transcription, the activity of transposable elements and transgenerational epigenetic inheritance; and propose 6mA as a new epigenetic mark in eukaryotes. PMID- 26507169 TI - The systematic analysis of protein-lipid interactions comes of age. AB - Lipids tailor membrane identities and function as molecular hubs in all cellular processes. However, the ways in which lipids modulate protein function and structure are poorly understood and still require systematic investigation. In this Innovation article, we summarize pioneering technologies, including lipid overlay assays, lipid pull-down assays, affinity-purification lipidomics and the liposome microarray-based assay (LiMA), that will enable protein-lipid interactions to be deciphered on a systems level. We discuss how these technologies can be applied to the charting of system-wide networks and to the development of new pharmaceutical strategies. PMID- 26507170 TI - A simple approach to facilitate the use of microdebrider for treatment of fibrous gynaecomastia. PMID- 26507171 TI - How important is the pathological margin distance in vulvar cancer? AB - PURPOSE: The ideal pathological margin in vulvar squamous cell carcinoma (VSCC) is still debated. Our aim was to analyze the value of tumor-free pathological margin distance with regard to local recurrence in VSCC. METHODS: We analyzed a series of 205 patients who were treated for VSCC from January 1980 to November 2007. Patients were categorized into 3 groups, based on pathological free margin (PFM): <3 mm (n = 18); >=3 and <8 mm (n = 61); and >=8 mm (n = 126). RESULTS: The median age was 69 years. The median PFM was 10 mm (range: 1-65). Of 168 patients who underwent lymphadenectomy, 64 (38.1%) developed LN metastasis. After a median follow-up of 36.2 months, 78 (38%) cases recurred-47 (60.2%) experienced a local recurrence (LR). LR occurred in 16.7% of patients with a PFM of <3 mm, 24.6% with a PFM >=3 and <8 mm, and 22.2% of those with a PFM >=8 mm (p = 0.77). PFM did not correlate with LR when analyzed continuously (p = 0.98). The 5-year disease-free survival (DFS) for LR was 79.6%. Margin distance did not negatively impact DFS (p = 0.94); the presence of perineural invasion was the only variable that negatively influenced DFS (p = 0.009). CONCLUSIONS: Although our results suggest no correlation between LR and pathological margin distance, the tumor-free resection margin remains significant with regard to locoregional control in vulvar cancer. A more conservative surgical approach may be considered in certain situations, such as margins near the clitoris, urethra, and anus. PMID- 26507172 TI - Legal changes to increase access to naloxone for opioid overdose reversal in the United States. AB - BACKGROUND: Opioid overdose, which has reached epidemic levels in the United States, is reversible by administration of the medication naloxone. Naloxone requires a prescription but is not a controlled substance and has no abuse potential. In the last half-decade, the majority of states have modified their laws to increase layperson access to the medication. METHODS: We utilized a structured legal research protocol to systematically identify and review all statutes and regulations related to layperson naloxone access in the United States that had been adopted as of September, 2015. Each law discovered via this process was reviewed and coded by two trained legal researchers. RESULTS: As of September, 2015, 43 states and the District of Columbia have passed laws intended to increase layperson naloxone access. We categorized these laws into three domains: (1) laws intended to increase naloxone prescribing and distribution, (2) laws intended to increase pharmacy naloxone access, and (3) laws intended to encourage overdose witnesses to summon emergency responders. These laws vary greatly across states in such characteristics as the types of individuals who can receive a prescription for naloxone, whether laypeople can dispense the medication, and immunity provided to those who prescribe, dispense and administer naloxone or report an overdose emergency. CONCLUSIONS: Most states have now passed laws intended to increase layperson access to naloxone. While these laws will likely reduce overdose morbidity and mortality, the cost of naloxone and its prescription status remain barriers to more widespread access. PMID- 26507173 TI - Perceived relative harm of electronic cigarettes over time and impact on subsequent use. A survey with 1-year and 2-year follow-ups. AB - INTRODUCTION: Media presentations of e-cigarettes may affect perception of the devices which may influence use. OBJECTIVES: To assess in a cohort of past-year smokers (1) if perceived harm of e-cigarettes relative to cigarettes changed over time, (2) predictors of perceived relative harm, (3) if perceived relative harm predicted subsequent e-cigarette use among never-users. METHODS: Longitudinal web based survey of a general population sample of British smokers and ex-smokers, waves in 2012 (n=4553), 2013 and 2014 (44%, 31% response rate, respectively). Changes over time were assessed using Friedman and McNemar tests, n=1204. Perceived relative harm at wave 3 was regressed onto perceived relative harm at waves 1 and 2, while adjusting for socio-demographics and change in smoking and e cigarette status, n=1204. Wave 2 e-cigarette use among 1588 wave 1 never-users was regressed onto wave 1 socio-demographics, smoking status and perceived relative harm. RESULTS: Perceived relative harm changed (chi(2)=20.67, p<0.001); the proportion perceiving e-cigarettes to be less harmful than cigarettes decreased from 2013 to 2014 (chi(2)=16.55, p<0.001). Previous perception of e cigarettes as less harmful, having tried e-cigarettes and having stopped smoking between waves predicted perceiving e-cigarettes as less harmful than cigarettes. Perceiving e-cigarettes to be less harmful than cigarettes predicted subsequent use, adjusting for other characteristics (OR=1.39; 95% CI: 1.08-1.80, p=0.011). CONCLUSION: Among a cohort of smokers and ex-smokers, accurately perceiving e cigarettes as less harmful than smoking predicted subsequent e-cigarette use in never-users; this perception declined over time. Clear information on the relative harm of cigarettes and e-cigarettes is needed. PMID- 26507174 TI - The latent structure of alcohol misuse in young adults: Do taxometric results differ as a function of prior criminal history? AB - BACKGROUND: The purpose of this study was to determine whether the latent structure of alcohol misuse is categorical or continuous in male and female adults with and without a history of prior criminal offending. METHODS: Data from 3452 (1530 male, 1922 female) 27-to-32 year old members of the National Longitudinal Study of Adolescent to Adult Health (Add Health) were subjected to taxometric analysis using three nonredundant taxometric procedures--mean above minus below a cut (MAMBAC), maximum covariance (MAXCOV), and latent mode factor analysis (L-Mode). RESULTS: Analyses produced results consistent with categorical latent structure in males with a previous history of criminal offending but not in males without a previous history of criminal offending or females with or without a history of criminal offending. The findings from the other groups were indeterminate for the most part (i.e., neither categorical nor continuous). The presumptive taxon was validated by testing differences in age of onset and frequency of criminal arrest and drunkenness between the putative taxon and the upper portion of the complement. As predicted, all four validation outcomes were significantly worse in the taxon group. CONCLUSIONS: On the basis of these results it is concluded that alcohol misuse in young adults may have features of both categorical and continuous latent structure and that the categorical aspects are more prominent in males with a history of offending behavior. Additional research is required to determine which aspects and features of alcohol misuse are categorical and which aspects and features are continuous. PMID- 26507175 TI - Time-varying effects of a text-based smoking cessation intervention for urban adolescents. AB - INTRODUCTION: Craving to smoke is understood as an important mechanism for continued smoking behavior. Identifying how smoking interventions operate on craving with particular populations is critical for advancing intervention science. This study's objective was to investigate the time-varying effect of a text-delivered smoking cessation intervention. METHODS: Toward this end, we used ecological momentary assessment (EMA) data collected from a five-day, automated text-messaging smoking cessation randomized clinical trial with 200 urban adolescents. We employed a time-varying effect model (TVEM) to estimate the effects of stress (time-varying covariate) and baseline nicotine dependence level (time-invariant covariate) on craving over six months by treatment condition. The TVEM approach models behavioral change and associations of coefficients expressed dynamically and graphically represented as smooth functions of time. RESULTS: Controlling for gender, age, and current smoking, differences in trajectories of craving between intervention and control conditions were apparent over the course of the study. During months 2 to 3, the association between stress and craving was significantly stronger among the control group, suggesting treatment dampens this association during this time period. The intervention also reduced the salience of baseline dependence among treatment adolescents, with craving being reduced steadily over time, while the control group increased craving over time. CONCLUSIONS: These results provide insight into the time-varying nature of treatment effects for adolescents receiving a text-based smoking cessation intervention. The ability to specify when in the course of an intervention the effect is strongest is important in developing targeted and adaptive interventions that can adjust strategically with time. PMID- 26507176 TI - Effects of artificial sweeteners on breath alcohol concentrations in male and female social drinkers. AB - BACKGROUND: Alcohol is often mixed with various nonalcoholic beverages. While consumption of food with alcohol will decrease peak breath alcohol concentrations (BrAC), recent evidence has suggested that mixing alcohol with diet beverages can result in higher BrAC when compared with mixing the same amount of alcohol with sweetened beverages. The purpose of this study was to examine this phenomenon using two different moderate alcohol doses. METHODS: Twenty participants (10 males) attended five sessions where they received 1 of 5 doses (0.91 ml/kg vodka+3.64 ml/kg of diet soda, 0.91 ml/kg vodka+3.64 of regular soda, 1.82 ml/kg vodka+7.28 ml/kg diet soda, 1.82 ml/kg vodka+7.28 ml/kg regular soda, and a placebo beverage). BrAC was recorded repeatedly up to 180 min after dose administration. RESULTS: Participants had significantly higher BrAC when the mixer was diet as compared to regular for both alcohol dose conditions. No gender differences were observed. CONCLUSIONS: Mixing alcohol with diet beverages can result in higher BrAC when compared to the same amount of alcohol administered with a similar sweetened beverage. Individuals who consume diet mixers with alcohol may reduce caloric intake but increase the harms associated with higher BrACs. PMID- 26507177 TI - Clinical experiences of ultrasound-guided thoracolumbar interfascial plane block: a clinical experience. PMID- 26507178 TI - "Acquired" Dandy-Walker malformation and cerebellar hemorrhage: Usefulness of serial MRI. AB - BACKGROUND/PURPOSE: Neuroimaging plays a fundamental role in the diagnosis of Dandy Walker malformation (DWM), a posterior fossa anomaly that is usually associated with genetic abnormalities, but may rarely be ascribed to acquired causes. Here, we report the clinical history and neuroimaging studies of a child with a complex cardiac malformation, developmental delay, and oculomotor anomalies whose neuroimaging findings were consistent with an acquired form of DWM. METHODS/RESULTS: Fetal MRI at gestational weeks 27 and 31 showed cerebellar and vermis hypoplasia and fourth ventricle enlargement, together with hemosiderin deposits on the cerebellar hemispheric surface, but without significant vermian rotation. Postnatal MRIs at 5 days and 13 months revealed progressive counter clockwise rotation of the hypoplastic cerebellar vermis with cystic dilation of the fourth ventricle, eventually leading to a full-blown DWM. CONCLUSION: This case strengthens the opinion that DWM is a heterogeneous condition, and may support the hypothesis that acquired meningeal abnormalities in the form of cortico-pial hemosiderosis may play a role in the development of DWM. This case also demonstrates that serial neuroimaging plays a key role in the correct diagnosis of posterior fossa malformations, whose prognosis is difficult to establish on second trimester fetal MRI and requires longer clinical follow-up. PMID- 26507179 TI - Fluorescence-Guided Probes of Aptamer-Targeted Gold Nanoparticles with Computed Tomography Imaging Accesses for in Vivo Tumor Resection. AB - Recent development of molecular imaging probes for fluorescence-guided surgery has shown great progresses for determining tumor margin to execute the tissue resection. Here we synthesize the fluorescent gold nanoparticles conjugated with diatrizoic acid and nucleolin-targeted AS1411 aptamer. The nanoparticle conjugates exhibit high water-solubility, good biocompatibility, visible fluorescence and strong X-ray attenuation for computed tomography (CT) contrast enhancement. The fluorescent nanoparticle conjugates are applied as a molecular contrast agent to reveal the tumor location in CL1-5 tumor-bearing mice by CT imaging. Furthermore, the orange-red fluorescence emitting from the conjugates in the CL1-5 tumor can be easily visualized by the naked eyes. After the resection, the IVIS measurements show that the fluorescence signal of the nanoparticle conjugates in the tumor is greatly enhanced in comparison to that in the controlled experiment. Our work has shown potential application of functionalized nanoparticles as a dual-function imaging agent in clinical fluorescence-guided surgery. PMID- 26507181 TI - Anaesthetics, infants, and neurodevelopment: case closed? PMID- 26507182 TI - Molecular detection of Rickettsia conorii and other zoonotic spotted fever group rickettsiae in ticks, Romania. AB - The diverse tick fauna as well as the abundance of tick populations in Romania represent potential risks for both human and animal health. Spotted fever group (SFG) rickettsiae are recognized as important agents of emerging human tick-borne diseases worldwide. However, the epidemiology of rickettsial diseases has been poorly investigated in Romania. In urban habitats, companion animals which are frequently exposed to tick infestation, play a role in maintenance of tick populations and as reservoirs of tick-borne pathogens. Therefore, the aim of the present study was to investigate the occurrence of SFG rickettsiae in ticks infesting dogs in a greater urban area in South-eastern Romania. Adult ixodid ticks (n=205), including Rhipicephalus sanguineus sensu lato (n=120), Dermacentor reticulatus (n=76) and Ixodes ricinus (n=9) were collected from naturally infested dogs and were screened for SFG rickettsiae using conventional PCR followed by sequencing. Additionally, ticks were screened for DNA of Babesia spp., Hepatozoon spp., Ehrlichia canis, and Anaplasma platys. Four zoonotic SFG rickettsiae were identified: Rickettsia raoultii (16%) and Rickettsia slovaca (3%) in D. reticulatus, Rickettsia monacensis (11%) in I. ricinus, and Rickettsia conorii (0.8%) in Rh. sanguineus s.l. Moreover, pathogens of veterinary importance, such as B. canis (21%) in D. reticulatus and E. canis (7.5%) in Rh. sanguineus s.l. were identified. The findings expand the knowledge on distribution of SFG rickettsiae as well as canine pathogens in Romania. Additionally, this is the first report describing the molecular detection of R. conorii in ticks from Romania. PMID- 26507183 TI - Forecasting magma-chamber rupture at Santorini volcano, Greece. AB - How much magma needs to be added to a shallow magma chamber to cause rupture, dyke injection, and a potential eruption? Models that yield reliable answers to this question are needed in order to facilitate eruption forecasting. Development of a long-lived shallow magma chamber requires periodic influx of magmas from a parental body at depth. This redistribution process does not necessarily cause an eruption but produces a net volume change that can be measured geodetically by inversion techniques. Using continuum-mechanics and fracture-mechanics principles, we calculate the amount of magma contained at shallow depth beneath Santorini volcano, Greece. We demonstrate through structural analysis of dykes exposed within the Santorini caldera, previously published data on the volume of recent eruptions, and geodetic measurements of the 2011-2012 unrest period, that the measured 0.02% increase in volume of Santorini's shallow magma chamber was associated with magmatic excess pressure increase of around 1.1 MPa. This excess pressure was high enough to bring the chamber roof close to rupture and dyke injection. For volcanoes with known typical extrusion and intrusion (dyke) volumes, the new methodology presented here makes it possible to forecast the conditions for magma-chamber failure and dyke injection at any geodetically well monitored volcano. PMID- 26507180 TI - Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. AB - BACKGROUND: Preclinical data suggest that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. METHODS: In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks' gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevoflurane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratified by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98.6 (14.2) in the awake-regional group and 98.2 (14.7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0.169, 95% CI -2.30 to 2.64). The median duration of anaesthesia in the general anaesthesia group was 54 min. INTERPRETATION: For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia. FUNDING: Australia National Health and Medical Research Council (NHMRC), Health Technologies Assessment-National Institute for Health Research UK, National Institutes of Health, Food and Drug Administration, Australian and New Zealand College of Anaesthetists, Murdoch Childrens Research Institute, Canadian Institute of Health Research, Canadian Anesthesiologists' Society, Pfizer Canada, Italian Ministry of Heath, Fonds NutsOhra, and UK Clinical Research Network (UKCRN). PMID- 26507184 TI - Associations Between Original and a Reduced Frontal Systems Behavior Scale (FrSBe), Cognition, and Activities of Daily Living in a Large Neurologic Sample. AB - A recent confirmatory factor analysis (CFA) on the Frontal Systems Behavior Scale (FrSBe) indicated that the basic structure of the FrSBe subscales held after removal of 8 weak items. In a replication of previous studies using the original FrSBe, the present study explored associations between a reduced version of the FrSBe, cognition, and activities of daily living (ADLs) in a large mixed outpatient neurologic sample. Consistent with previous findings with the original FrSBe, significant associations existed between reduced FrSBe scores and the Mattis Dementia Rating Scale-Second Edition. Additionally, after controlling for age, gender, and education, reduced FrSBe Apathy was associated with basic ADLs, and reduced FrSBe Disinhibition was associated with instrumental ADLs. These results offer replication in a larger sample of previous findings and statistical support for a reduced FrSBe beyond CFA results alone. PMID- 26507185 TI - Mast Cell Accumulation and Degranulation in Rat Bladder with Partial Outlet Obstruction. AB - INTRODUCTION: Benign prostatic hyperplasia causes partial bladder outlet obstruction (pBOO), and many patients with pBOO are affected by not only voiding symptoms but also storage symptoms. We previously suggested that enhancement of 5 hydroxytryptamine (5-HT)-induced bladder contraction in the pBOO bladder may be one cause of storage symptoms. However, little is known about the presence of 5 HT in rat bladders. In this study, we hypothesized that mast cells are a source of 5-HT and investigated the distribution of mast cells and 5-HT in the bladders of rats with pBOO. METHODS: The bladders of female Sprague-Dawley rats were subjected to pBOO and sham operations for 1 week, were isolated, and were fixed for light or electron microscopy. Mast cells and 5-HT in the bladders were detected by toluidine blue staining and immunohistochemical staining, respectively. The mast cells were counted under a light microscope. Degranulated mast cells were observed under an electron microscope and counted under a light microscope. RESULTS: Mast cells were present in the mucosa/submucosa region in sham rat bladders. Their number was increased in the detrusor muscle/subserosa/serosa region, especially the subserosal layer, in pBOO rat bladders. The localization of mast cells almost matched that of 5-HT-positive cells in consecutive sections. Degranulated mast cells were present in sham and pBOO rat bladders, but the proportion of degranulated mast cells was significantly increased in every region in pBOO rat bladders compared with that in sham rat bladders. CONCLUSION: These results suggest that mast cells contain 5 HT and are more abundant locally in the subserosal layer of pBOO rat bladders. 5 HT released from mast cells could stimulate 5-HT2 receptors on the detrusor muscle, and this may underlie storage symptoms. FUNDING: Asahi Kasei Pharma Corp. PMID- 26507187 TI - Evaluation of Parenteral Nutrition Errors in an Era of Drug Shortages. AB - BACKGROUND: Ingredient shortages have forced many organizations to change practices or use unfamiliar ingredients, which creates potential for error. Parenteral nutrition (PN) has been significantly affected, as every ingredient in PN has been impacted in recent years. MATERIALS AND METHODS: Ingredient errors involving PN that were reported to the national anonymous MedMARx database between May 2009 and April 2011 were reviewed. Errors were categorized by ingredient, node, and severity. Categorization was validated by experts in medication safety and PN. A timeline of PN ingredient shortages was developed and compared with the PN errors to determine if events correlated with an ingredient shortage. This information was used to determine the prevalence and change in harmful PN errors during periods of shortage, elucidating whether a statistically significant difference exists in errors during shortage as compared with a control period (ie, no shortage). RESULTS: There were 1311 errors identified. Nineteen errors were associated with harm. Fat emulsions and electrolytes were the PN ingredients most frequently associated with error. Insulin was the ingredient most often associated with patient harm. On individual error review, PN shortages were described in 13 errors, most of which were associated with intravenous fat emulsions; none were associated with harm. There was no correlation of drug shortages with the frequency of PN errors. CONCLUSION: Despite the significant impact that shortages have had on the PN use system, no adverse impact on patient safety could be identified from these reported PN errors. PMID- 26507186 TI - Early pregnancy vitamin D status and risk for adverse maternal and infant outcomes in a bi-ethnic cohort: the Behaviors Affecting Baby and You (B.A.B.Y.) Study. AB - Vitamin D deficiency is common during pregnancy and higher in Hispanic as compared with non-Hispanic white women. However, the association between vitamin D deficiency and adverse pregnancy outcomes remains unclear and may vary across ethnic groups, in part because of genetic variation in the metabolism of vitamin D. Few studies have included Hispanic women. Therefore, we investigated this association among 237 participants in the Behaviors Affecting Baby and You Study, a randomised trial of an exercise intervention among ethnically diverse prenatal care patients in Massachusetts. Baseline serum 25-hydroxyvitamin D (25(OH)D) was measured at 15.2 (sd 4.7) weeks' gestation. Information on adverse pregnancy outcomes was abstracted from medical records. Mean 25(OH)D was 30.4 (sd 12.0) ng/ml; 53.2 % of participants had insufficient (<30 ng/ml) and 20.7 % had deficient (<20 ng/ml) 25(OH)D levels. After adjusting for month of blood draw, gestational age at blood draw, gestational age at delivery, age, BMI and Hispanic ethnicity, women with insufficient and deficient vitamin D had infants with birth weights 139.74 (se 69.16) g (P=0.045) and 175.52 (se 89.45) g (P=0.051) lower compared with women with sufficient vitamin D levels (>=30 ng/ml). Each 1 ng/ml increase in 25(OH)D was associated with an increased risk for gestational diabetes mellitus among Hispanic women only (relative risk 1.07; 95 % CI 1.03, 1.11) in multivariable analysis. We did not observe statistically significant associations between maternal vitamin D status and other pregnancy outcomes. Our findings provide further support for an adverse impact of vitamin D deficiency on birth weight in Hispanic women. PMID- 26507188 TI - Oral Glutamine in Preventing Treatment-Related Mucositis in Adult Patients With Cancer: A Systematic Review. AB - BACKGROUND: Breakdown of the mucosal barrier resulting in mucositis is a common adverse event in patients with cancer receiving chemotherapy and radiation. Many studies have evaluated the use of oral glutamine to prevent mucositis in these settings, but current guidelines make no recommendations with regard to its use. Our objective was to systematically review the evidence for the use of oral glutamine in preventing mucositis in adult patients with cancer undergoing chemotherapy and/or radiation. MATERIALS AND METHODS: A systematic search of English-language literature was done via MEDLINE using the search terms glutamine, cancer, and mucositis or esophagitis or stomatitis. Fifteen studies conducted in adult patients with cancer receiving chemotherapy and/or radiation comparing single-agent oral glutamine with control were identified. RESULTS: Oral glutamine was shown to be effective in 11 of the 15 studies included in the systematic review. It significantly reduced the incidence of grade 2, 3, or 4 mucositis and/or reduced weight loss as well as the duration, time of onset, and/or maximum grade of mucositis. The most common dosing regimen was 30 g/d in 3 divided doses, with other regimens ranging from 7.5-24 g/d. Rates of nausea, vomiting, dry mouth, and anorexia were similar in the glutamine and control groups. CONCLUSION: In summary, the favorable efficacy and low toxicity of oral glutamine observed in clinical trials we reviewed provide a strong rationale for large randomized placebo-controlled studies to further evaluate its efficacy in preventing mucositis in patients with cancer receiving chemotherapy and/or radiation. PMID- 26507189 TI - Iodine Supplementation for Pediatric Patients Receiving Long-Term Parenteral Nutrition. AB - BACKGROUND: Patients dependent on parenteral nutrition (PN) are among a group at risk of developing iodine deficiency. Supplementation with iodine in this population has been debated in a number of studies, resulting in variable clinical practices. The Committee on Clinical Practice Issues of the American Society for Clinical Nutrition recommends a dose of 1 mcg/kg/d of parenteral iodine for patients receiving PN. At our institution, PN trace elements do not include iodine, although this is not the case internationally. Our study sought to assess iodine levels and thyroid function in a cohort of PN-dependent pediatric patients. METHODS: A retrospective analysis studied 32 pediatric patients with a variety of medical diagnoses who received PN as a primary means of nutrition for 6 months or longer. Patients received variable proportions of their total caloric intake as PN, which ranged from 14%-100%. Iodine and thyroid function levels were obtained by serum sampling. RESULTS: No patient in our cohort of 32 demonstrated thyroid dysfunction or developed iodine deficiency. The length of time on PN and the percentage of total nutrition intake as PN were not associated with iodine levels (P < .89 and P < .73, respectively). There were no significant associations between age (P < .342), clinical diagnosis (P < .46), or sex (P < .43) on iodine status. There were no incidences of abnormal iodine levels in our cohort. Our study suggests that pediatric patients older than 6 months receiving PN may not benefit from iodine supplementation, but further investigation is needed. PMID- 26507190 TI - Zarzio(r), biosimilar of filgrastim, in prophylaxis of chemotherapy-induced neutropenia in routine practice: a French prospective multicentric study. AB - PURPOSE: Chemotherapy-induced neutropenia is a serious and potentially life threatening consequence of cancer treatment. Prophylactic treatment with granulocyte-colony stimulating factor (G-CSF) decreases the incidence of febrile neutropenia, the rate of hospitalization, and the use of antibiotics in patients at risk. The aim of this study was to assess efficacy, safety, and use of Zarzio((r))-biosimilar of Neupogen((r)) (G-CSF; filgrastim)-in prophylaxis of chemotherapy-induced neutropenia in current practice in cancer patients. METHODS: We conducted an observational, prospective, longitudinal, and multicentric study in France. The incidence of neutropenia was evaluated at each cycle of chemotherapy. RESULTS: One hundred eighty-four patients (women, 64.7 %; mean age, 61.7 years) with solid tumor (89.7 %; breast cancer, 50.5 %) or non-Hodgkin lymphoma (10.3 %) were included. The risk of febrile neutropenia based on chemotherapy regimen was >20 % for 32.1 % of patients. No case of febrile neutropenia was reported. Neutropenia was the cause of hospitalization and/or antibiotic therapy in 10 patients. The most frequent adverse events related to Zarzio((r)) were pain, in particular bone pain. No serious adverse event related to Zarzio((r)) was reported. CONCLUSION: The results obtained in real-life conditions confirm that Zarzio((r)) is efficient and well tolerated in cancer patients. PMID- 26507191 TI - A phase II trial of ixabepilone and cyclophosphamide as neoadjuvant therapy for patients with HER2-negative breast cancer: correlation of pathologic complete response with the 21-gene recurrence score. AB - Ixabepilone and the taxanes have similar activity in the first-line treatment of metastatic breast cancer, and ixabepilone is sometimes effective in taxane refractory patients. We conducted a phase 2 trial to evaluate ixabepilone in combination with cyclophosphamide as neoadjuvant treatment for patients with locally advanced HER2-negative breast cancer. Response to neoadjuvant treatment was correlated with the baseline 21-gene Recurrence Score(r) (Oncotype DX; Genomic Health Inc, Redwood City, CA). Eligible women with HER2-negative locally advanced breast cancer received ixabepilone 40 mg/m(2) plus cyclophosphamide 600 mg/m(2) on day 1 of each 21-day cycle. Following 6 cycles, patients underwent definitive surgery. Primary endpoint was rate of pathologic complete response (pCR). Breast biopsy tumor samples were obtained at pretreatment and at surgery in patients with residual disease. Tumor specimens were analyzed using the 21 gene assay. One hundred sixty-eight patients (median age 52 years; 45 % triple negative) were enrolled; 161 (96 %) underwent definitive surgery following neoadjuvant ixabepilone/cyclophosphamide. Overall, 27 patients (17 %) achieved pCR, including 19 of 73 (26 %) triple-negative patients. The most frequently occurring grade 3/4 toxicity was neutropenia (98 patients; 58 %). Recurrence Scores were highly correlated with achievement of pCR (0/36 with low or intermediate Recurrence Scores vs. 19/72 with high Recurrence Scores; p = 0.002). There was high concordance between baseline and post-treatment Recurrence Scores in the 72 patients with paired samples. The combination of ixabepilone and cyclophosphamide yielded a pCR rate of 17 %, similar to other neoadjuvant chemotherapy regimens. Pathologic complete responses occurred only in patients with high-risk baseline Recurrence Scores. PMID- 26507192 TI - Asymmetric Synthesis of Vitamin D3 Analogues: Organocatalytic Desymmetrization Approach toward the A-Ring Precursor of Calcifediol. AB - A novel asymmetric synthesis has been developed for the construction of the A ring of a chiral precursor to calcifediol. The highlights of this synthesis include (i) the introduction of the stereochemistry at the C5-position of the A ring through the organocatalytic enantioselective desymmetrization of a prochiral cyclic anhydride using a bifunctional urea catalyst and (ii) the introduction of the exo-cyclic (Z)-dienol side chain by a tandem Claisen rearrangement/sulfoxide thermolysis of an allylic alcohol. PMID- 26507193 TI - Erratum to: The effects of paroxetine given repeatedly on the 5-HT receptor subpopulations in the rat brain. PMID- 26507194 TI - Effects of clonidine and scopolamine on multiple target detection in rapid serial visual presentation. AB - RATIONALE: The specific role of neuromodulator systems in regulating rapid fluctuations of attention is still poorly understood. OBJECTIVES: In this study, we examined the effects of clonidine and scopolamine on multiple target detection in a rapid serial visual presentation task to assess the role of the central noradrenergic and cholinergic systems in temporal attention. METHOD: Eighteen healthy volunteers took part in a crossover double-dummy study in which they received clonidine (150/175 MUg), scopolamine (1.2 mg), and placebo by mouth in counterbalanced order. A dual-target attentional blink task was administered at 120 min after scopolamine intake and 180 min after clonidine intake. The electroencephalogram was measured during task performance. RESULTS: Clonidine and scopolamine both impaired detection of the first target (T1). For clonidine, this impairment was accompanied by decreased amplitudes of the P2 and P3 components of the event-related potential. The drugs did not impair second-target (T2) detection, except if T2 was presented immediately after T1. The attentional blink for T2 was not affected, in line with a previous study that found no effect of clonidine on the attentional blink. CONCLUSIONS: These and other results suggest that clonidine and scopolamine may impair temporal attention through a decrease in tonic alertness and that this decrease in alertness can be temporarily compensated by a phasic alerting response to a salient stimulus. The comparable behavioral effects of clonidine and scopolamine are consistent with animal studies indicating close interactions between the noradrenergic and cholinergic neuromodulator systems. PMID- 26507195 TI - The 5-HT2C receptor agonist, lorcaserin, and the 5-HT6 receptor antagonist, SB 742457, promote satiety; a microstructural analysis of feeding behaviour. AB - RATIONALE: Whilst the FDA-approved anorectic, lorcaserin and various 5 hydroxytryptamine (5-HT)6 receptor antagonists reduce feeding, a direct assessment of their impact upon feeding behaviour is less clear. We therefore examined the action of lorcaserin and the clinical-stage developmental candidate 5-HT6 receptor antagonist, SB-742457, upon microstructural analysis of licking behaviour. Such analysis provides a rich source of information about the mechanisms controlling food intake. OBJECTIVES: The objective of the present study was to gain insight into the influence upon feeding behaviour of the 5-HT2C receptor agonist, lorcaserin and the developmental 5-HT6 receptor antagonist, SB 742457. METHODS: The impact of lorcaserin and SB-742457 upon licking behaviour of non-deprived rats for a glucose solution was assessed using microstructural analysis. RESULTS: Lorcaserin (0.1-3.0 mg/kg) displayed a dose-dependent ability to reduce glucose consumption via reduction in the number of bouts of licking. A similar action was evident with SB-742457, but only at the lowest dose tested (3.0 mg/kg). CONCLUSIONS: The behavioural actions of both lorcaserin and SB 742457 demonstrate they directly promote satiety. PMID- 26507196 TI - Ghrelin and endocannabinoids participation in morphine-induced effects in the rat nucleus accumbens. AB - RATIONALE AND OBJECTIVES: In addition to dopamine, endocannabinoids are thought to participate in neural reward mechanisms of opioids. Number of recent studies suggests crucial involvement of ghrelin in some addictive drugs effects. Our previous results showed that ghrelin participates in morphine-induced changes in the mesolimbic dopaminergic system associated with reward processing. The goal of the present study was to test whether the growth hormone secretagogue receptor (GHS-R1A) antagonist JMV2959 was able to influence morphine-induced effects on anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) in the nucleus accumbens shell (NACSh). METHODS: We used in vivo microdialysis to determine changes in levels of AEA and 2-AG in the NACSh in rats following (i) an acute morphine dose (5, 10 mg/kg s.c.) with and without JMV2959 pretreatment (3, 6 mg/kg i.p.) or (ii) a morphine challenge dose (5 mg/kg s.c.) with and without JMV2959 (3, 6 mg/kg i.p.) pretreatment, administered during abstinence following repeated doses of morphine (5 days, 10-40 mg/kg). Co-administration of ghrelin (40 ug/kg i.p.) was used to verify the ghrelin mechanisms involvement. RESULTS: Pretreatment with JMV2959 significantly and dose-dependently reversed morphine induced anandamide increases in the NACSh in both the acute and longer-term models, resulting in a significant AEA decrease. JMV2959 significantly intensified acute morphine-induced decreases in accumbens 2-AG levels and attenuated morphine challenge-induced 2-AG decreases. JMV2959 pretreatment significantly reduced concurrent morphine challenge-induced behavioral sensitization. JMV2959 pretreatment effects were abolished by co-administration of ghrelin. CONCLUSIONS: Our results indicate significant involvement of ghrelin signaling in morphine-induced endocannabinoid changes in the NACSh. PMID- 26507197 TI - Phase II study of lapatinib and capecitabine in second-line treatment for metastatic pancreatic cancer. AB - PURPOSE: Patients with metastatic, gemcitabine-refractory pancreatic cancer typically have poor survival. Erlotinib, a targeted therapy that inhibits epidermal growth factor receptor (EGFR) activity (overexpressed in 40-60 % of pancreatic cancers), was FDA approved for the treatment of patients with advanced pancreatic cancer. Human epidermal growth factor receptor 2 (HER-2), another member of the ErbB family of growth factor receptor tyrosine kinases, has also been a therapeutic target of interest in pancreatic cancer; HER-2 overexpression is found in 20 % of pancreatic cancers. Lapatinib is a tyrosine kinase inhibitor that binds to both EGFR and HER-2. We conducted a single-arm phase II study to evaluate the combination of lapatinib and capecitabine in the second-line treatment of metastatic, gemcitabine-refractory pancreatic cancer. METHODS: Seventeen patients with metastatic, unresectable pancreatic cancer whose disease had progressed on first-line gemcitabine-based therapy were selected for this study. Patients were required to have an adequate performance status (ECOG 0-2) and normal hepatic and renal function prior to being enrolled. Patients received lapatinib 1250 mg PO daily 1 h before or after meals, and capecitabine 1000 mg/m(2) PO twice daily on days 1-14 of the 21-day cycle. The primary endpoint was median overall survival (OS), and the secondary endpoints were objective response rate, progression-free survival (PFS) and the safety profile of the combination therapy. Clinical toxicities were assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0. Radiographic response was evaluated by RECIST criteria. RESULTS: Clinically, six of the 17 patients treated had disease progression (PD) after two cycles, six of 17 patients had stable disease (SD) and received more than four cycles (SD, range 4 22 cycles). For all patients, median PFS was 2.6 months (95 % CI 1.3-3.8) and median OS was 5.2 months (95 % CI 3.4-9). Treatment-related toxicities were limited to three (17 %) patients developing grade 3 adverse events such as nausea, vomiting, diarrhea and fatigue. When stratifying patients by treatment response, we found a statistically significant difference in median PFS and OS: median PFS was 1.4 months (95 % CI 1.0-1.8) in the PD group versus 4.0 months (95 % CI 1.8-6.3) in the SD group (P value = 0.001). Median OS was 2.9 months (95 % CI 0-7.3) in the PD group versus 8.3 months (95 % CI 0-21.2) in the SD group (P value = 0.023). CONCLUSIONS: The combination of lapatinib and capecitabine is a tolerable regimen for patients with gemcitabine-refractory pancreatic cancer; however, this observation is based on the small number of patients enrolled in the trial. A subset of the enrolled patients had clinical benefit from treatment. Predictive biomarkers that allow selection of patients that will respond to this regimen should be further investigated. PMID- 26507199 TI - Vascularized composite allotransplantation: a new concept in musculoskeletal regeneration. AB - Over the past 20 years, the fields of biomaterial sciences and tissue engineering have evolved into new clinically relevant applications including regenerative medicine and cell based therapies. Tissue engineering therapies are based on different types of materials and scaffolds combined with cells and submitted to engineering processes in order to create bio-scaffolds which will improve or replace biological functions. Despite the effort, only a few therapies, such as bone, cartilage and nerve, succeeded in clinical applications. Furthermore, the major drawback in standard application of these therapies was the critical size defects which could be covered with engineered materials, as well as inability to provide sustainable vascular supply to the created bio-scaffolds. In 1998, the first successful hand transplantation was performed in France, and the field of vascularized composite allotransplantation (VCA) was introduced into the armamentarium of reconstructive surgery (Dubernard in Am J Transplant 5(6):1580 1, 2005; Petruzzo et al. in Am J Transplant 6(7):1718-24, 2006; Lanzetta et al. in Transplantation 79(9):1210-4, 2005). As a result, a new generation of transplants including hand, face, larynx abdominal wall, lower extremities and penile transplantation became available to patients who had lost these unique organs and were previously unable to achieve restored function using standard reconstructive procedures. Ethical debate on the need for life-long immunosuppressive therapy to prevent rejection of the VCA overshadowed the success of face and hand transplants. Thus, a new, challenging opportunity developed to combine approaches of tissue engineering and regenerative medicine and ultimately restore the framework, function, aesthetics and survival of the VSA transplants. This overview presents the unique opportunities of merging established and new technologies into the burgeoning field of reconstructive transplantation. PMID- 26507198 TI - Biocompatibility of antibacterial Ti-Cu sintered alloy: in vivo bone response. AB - Ti-10Cu sintered alloy has shown very strong in vitro and in vivo antibacterial property and in vitro cell compatibility. In this paper, Ti-10Cu implant (Ti-Cu group) and commercial pure Ti implant (cp-Ti group) were implanted in rabbit femurs to investigate in vivo bone response to the Ti-10Cu alloy. X-ray photo, fluorescent microscopy, routine pathological examination and immunohistochemistry have been used to analyze bone growth, mineral apposition rate (MAR), bone implant contact (BIC), BMP-2 expression and TGF-beta1 expression. In both Ti-Cu and cp-Ti groups, new bone tissue was found at bone/implant interfaces 4 weeks postimplantation and completely filled the interfaces gap bone 12 weeks postimplantation. A significant MOD value in BMP-2 expression was observed at week 1 and week 4 in the Ti-Cu group with lower values of week 2 and 3 in both groups, which indicated strong positive activity. MOD value in TGF-beta1 expression decreased with the extension of implantation. However, no difference can be found in MAR, BIC and TGF-beta1 expression between the two groups at all intervals. It was deduced that Ti-Cu alloy exhibited as good bone response as cp Ti. The good bone compatibility suggests that Ti-10Cu alloy might have potential application in orthopedic surgery and dental implant. PMID- 26507200 TI - Physical vapour deposition of zirconia on titanium: fabrication, characterization and interaction with human osteoblast cells. AB - The physical vapor deposition of zirconia was used to prepare two new titanium based surfaces M1 and M2 with a different layer thickness. These novel surfaces were characterized for chemistry, topography and morphology by surface and solid state techniques. Primary osteoblast cells were used for in vitro studies. DAPI assay was applied for cell proliferation, while for bone sialoprotein (BSP), osteonectin and transforming growth factor-beta (TGF-beta) expression immunohistochemical analyses were employed. Materials M1 and M2 affected cell proliferation accordingly to their surface roughness with their impact on cell number being between the impact of two rough (Ticer, SS) and two smooth surfaces (Ti cp and Cercon). Different influence of the investigated materials on the osteoblastic production of BSP (all materials similar impact), ON (Cercon-higher; SS-lower for others) and TGF-beta (Cercon different) was found. PMID- 26507201 TI - In vitro antimicrobial activity of ZnO based glass-ceramics against pathogenic bacteria. AB - The antibacterial activity of ZnO (0-15.53 mol%) based SiO2-CaO-P2O5-Na2O-CaF2 bioactive glass-ceramics synthesized by controlled crystallisation were studied against eight micro-organisms using modified Kirby Bauer method. The antibacterial activity of the specimens was statistically evaluated using one-way analysis of variance and P < 0.05 was used as the level of significance. In vitro dissolution tests were performed in stimulated body fluid for 48 h at 37 degrees C for different time intervals to correlate the dissolution behaviour of test samples with antibacterial effects. The results illustrate that specimen BZn15.53 having the highest concentration of ZnO (15.53 mol%) demonstrated the strongest effect against Staph.aureus, S. epidermidis, B. subtilis and K. pneumonia. The effectiveness of BZn15.53 in inhibiting bacteria was due to accumulation of Zn(+2) ions around the surface of the bacteria cell release that caused the death of the cell, besides the presence of hydroxyapatite phase was also responsible for damaging the cell membrane of bacteria. PMID- 26507202 TI - Antibiotic-loaded chitosan-Laponite films for local drug delivery by titanium implants: cell proliferation and drug release studies. AB - In this study, chitosan-Laponite nanocomposite coatings with bone regenerative potential and controlled drug-release capacity are prepared by electrophoretic deposition technique. The controlled release of a glycopeptide drug, i.e. vancomycin, is attained by the intercalation of the polymer and drug macromolecules into silicate galleries. Fourier-transform infrared spectrometry reveals electrostatic interactions between the charged structure of clay and the amine and hydroxyl groups of chitosan and vancomycin, leading to a complex positively-charged system with high electrophoretic mobility. By applying electric field the charged particles are deposited on the surface of titanium foils and uniform chitosan films containing 25-55 wt% Laponite and 937-1655 ug/cm(2) vancomycin are obtained. Nanocomposite films exhibit improved cell attachment with higher cell viability. Alkaline phosphatase assay reveals enhanced cell proliferation due the gradual dissolution of Laponite particles into the culture medium. In-vitro drug-release studies show lower release rate through a longer period for the nanocomposite compared to pristine chitosan. PMID- 26507203 TI - Simultaneous Electrodialytic Preconcentration and Speciation of Chromium(III) and Chromium(VI). AB - Large amounts of chromium (Cr) compounds are used for manufacturing of various products and various chemical processes. Some inevitably find their way into the environment. Environmental Cr is dominantly inorganic and is either in the cationic +3 oxidation state or in the anionic oxochromium +6 oxidation state. The two differ dramatically in their implications; Cr(III) is essential to human nutrition and even sold as a supplement, while Cr(VI) is a potent carcinogen. Drinking water standards for chromium may be based on total Cr or Cr(VI) only. Thus, Cr speciation analysis is very important. Despite their high sensitivity, atomic spectrometric techniques or induction coupled plasma-mass spectrometry (ICP-MS) cannot directly differentiate the oxidation states. We present here a new electrodialytic separation concept. Sample analyte ions are quantitatively transferred via appropriately ionically functionalized dialysis membranes into individual receptors that are introduced into the ICP-MS. There was no significant conversion of Cr(VI) to Cr(III) or vice versa during the very short (6 s) separation process. Effects of salinity (up to ~20 mM NaCl) can be eliminated with proper membrane functionalization and receptor optimization. With the ICP-MS detector we used, the limits of detection for either form of Cr was 0.1 MUg/L without preconcentration. Up to 10-fold preconcentration was readily possible by increasing the donor solution flow rate relative to the acceptor solution flow rates. The proposed approach permits simultaneous matrix isolation, preconcentration, and chromium speciation. PMID- 26507204 TI - Multiple Authorship in Scientific Manuscripts: Ethical Challenges, Ghost and Guest/Gift Authorship, and the Cultural/Disciplinary Perspective. AB - Multiple authorship is the universal solution to multi-tasking in the sciences. Without a team, each with their own set of expertise, and each involved mostly in complementary ways, a research project will likely not advance quickly, or effectively. Consequently, there is a risk that research goals will not be met within a desired timeframe. Research teams that strictly scrutinize their modus operandi select and include a set of authors that have participated substantially in the physical undertaking of the research, in its planning, or who have contributed intellectually to the ideas or the development of the manuscript. Authorship is not an issue that is taken lightly, and save for dishonest authors, it is an issue that is decided collectively by the authors, usually in sync with codes of conduct established by their research institutes or national ministries of education. Science, technology and medicine (STM) publishers have, through independent, or sometimes coordinated efforts, also established their own sets of guidelines regarding what constitutes valid authorship. However, these are, for the greater part, merely guidelines. A previous and recent analysis of authorship definitions indicates that the definitions in place regarding authorship and its validity by many leading STM publishers is neither uniform, nor standard, despite several of them claiming to follow the guidelines as set forward by the International Committee of Medical Journal Editors or ICMJE. This disparity extends itself to ghost and guest authorship, two key authorship-related issues that are examined in this paper to assess the extent of discrepancies among the same set of STM publishers and what possible influence they might have on publishing ethics. PMID- 26507205 TI - RETRACTED ARTICLE: Systematic Assessment of Research on Autism Spectrum Disorder and Mercury Reveals Conflicts of Interest and the Need for Transparency in Autism Research. PMID- 26507207 TI - Core Halogenation as a Construction Principle in Tuning the Material Properties of Tetraazaperopyrenes. AB - A detailed study on the effects of core halogenation of tetraazaperopyrene (TAPP) derivatives is presented. Its impact on the solid structure, as well as the photophysical and electrochemical properties, has been probed by the means of X ray crystallography, UV/Vis and fluorescence spectroscopy, high-resolution electron energy loss spectroscopy (HREELS), cyclic voltammetry (CV), and DFT modeling. The aim was to assess the potential of this approach as a construction principle for organic electron-conducting materials of the type studied in this work. Although halogenation leads to a stabilization of the LUMOs compared to the unsubstituted parent compound, the nature of the halide barely affects the LUMO energy while strongly influencing the HOMO energies. In terms of band-gap engineering, it was demonstrated that the HOMO-LUMO gap is decreased by substitution of the TAPP core with halides, the effect being found to be most pronounced for the iodinated derivative. The performance of the recently reported core-fluorinated and core-iodinated TAPP derivatives in organic thin-film transistors (TFTs) was investigated on both a glass substrate, as well as on a flexible plastic substrate (PEN). Field-effect mobilities of up to 0.17 cm(2) Vs(-1) and on/off current ratio of >10(6) were established. PMID- 26507208 TI - US pediatricians call for tougher rule enforcement to reduce football injuries. PMID- 26507209 TI - The amount and duration of smoking is associated with aggravation of hormone and biochemical profile in women with PCOS. AB - We investigated the association between the amount and duration of smoking on biochemical, clinical parameters and the ovarian morphology in women with polycystic ovary syndrome (PCOS). That was a retrospective study. These women were divided into two groups, non-smokers (217) and smokers (92). The amount of cigarettes and duration of smoking was measured in pack-years. Both groups underwent clinical evaluation, biochemical and hormone analysis, transvaginal ultrasound and oral glucose tolerance tests (OGTT). The mean value of the number of cigarettes was 14.8 (+/-8.8) and the median value of pack-years in the smokers group was 4.0 (1.5-7.5). Smokers group has significantly higher free testosterone (F-T), 17-hydroxyprogesterone (17-OHP), delta 4 androstenedione (Delta4-A), T4, low-density lipoprotein (LDL), and white blood cells (WBC). During correlation of all the above parameters and pack-years, there has been significant positive correlation in F-T and Delta4-A. The participants with more pack-years showed statistically higher values of F-T and Delta4-A. There was also a significant positive correlation between total cholesterol, triglycerides, WBC and pack-years of the participants. Prolactin (PRL) has been inversely associated with pack years. We concluded that the increase of pack-years aggravated lipid profile, WBC and decreased PRL levels, in PCOS patients. PMID- 26507206 TI - A randomised controlled trial of the clinical effectiveness and cost effectiveness of the levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia: the ECLIPSE trial. AB - BACKGROUND: Heavy menstrual bleeding (HMB) is a common problem, yet evidence to inform decisions about initial medical treatment is limited. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of the levonorgestrel releasing intrauterine system (LNG-IUS) (Mirena(r), Bayer) compared with usual medical treatment, with exploration of women's perspectives on treatment. DESIGN: A pragmatic, multicentre randomised trial with an economic evaluation and a longitudinal qualitative study. SETTING: Women who presented in primary care. PARTICIPANTS: A total of 571 women with HMB. A purposeful sample of 27 women who were randomised or ineligible owing to treatment preference participated in semistructured face-to-face interviews around 2 and 12 months after commencing treatment. INTERVENTIONS: LNG-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined oestrogen-progestogen or progesterone alone). Women could subsequently swap or cease their allocated treatment. OUTCOME MEASURES: The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS) assessed over a 2-year period and then again at 5 years. Secondary outcomes included general quality of life (QoL), sexual activity, surgical intervention and safety. Data were analysed using iterative constant comparison. A state transition model-based cost-utility analysis was undertaken alongside the randomised trial. Quality-adjusted life-years (QALYs) were derived from the European Quality of Life-5 Dimensions (EQ-5D) and the Short Form questionnaire-6 Dimensions (SF-6D). The intention-to-treat analyses were reported as cost per QALY gained. Uncertainty was explored by conducting both deterministic and probabilistic sensitivity analyses. RESULTS: The MMAS total scores improved significantly in both groups at all time points, but were significantly greater for the LNG-IUS than for usual treatment [mean difference over 2 years was 13.4 points, 95% confidence interval (CI) 9.9 to 16.9 points; p < 0.001]. However, this difference between groups was reduced and no longer significant by 5 years (mean difference in scores 3.9 points, 95% CI -0.6 to 8.3 points; p = 0.09). By 5 years, only 47% of women had a LNG-IUS in place and 15% were still taking usual medical treatment. Five-year surgery rates were low, at 20%, and were similar, irrespective of initial treatments. There were no significant differences in serious adverse events between groups. Using the EQ-5D, at 2 years, the relative cost-effectiveness of the LNG-IUS compared with usual medical treatment was L1600 per QALY, which by 5 years was reduced to L114 per QALY. Using the SF-6D, usual medical treatment dominates the LNG-IUS. The qualitative findings show that women's experiences and expectations of medical treatments for HMB vary considerably and change over time. Women had high expectations of a prompt effect from medical treatments. CONCLUSIONS: The LNG-IUS, compared with usual medical therapies, resulted in greater improvement over 2 years in women's assessments of the effect of HMB on their daily routine, including work, social and family life, and psychological and physical well-being. At 5 years, the differences were no longer significant. A similar low proportion of women required surgical intervention in both groups. The LNG-IUS is cost-effective in both the short and medium term, using the method generally recommended by the National Institute for Health and Care Excellence. Using the alternative measures to value QoL will have a considerable impact on cost-effectiveness decisions. It will be important to explore the clinical and health-care trajectories of the ECLIPSE (clinical effectiveness and cost-effectiveness of levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia) trial participants to 10 years, by which time half of the cohort will have reached menopause. TRIAL REGISTRATION: Current Controlled Trials ISRCTN86566246. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 88. See the NIHR Journals Library website for further project information. PMID- 26507210 TI - This special issue marks a historical moment for CHIMIA in its nearly 70-year history. Introduction. PMID- 26507211 TI - Platinum(IV) Carboxylate Prodrug Complexes as Versatile Platforms for Targeted Chemotherapy. AB - Kinetically-inert Pt(IV) carboxylate complexes have emerged in recent years as candidates for the development of next-generation platinum anticancer drugs. Being native prodrugs of clinically-important Pt(II) chemotherapeutic agents, the Pt(IV) scaffold can be exploited to incorporate additional functionalities while keeping the Pt(II) pharmacophore intact. This mini-review examines recent work performed to illuminate the mechanism of Pt(IV) prodrug activation and their use as versatile platforms for targeted chemotherapy. PMID- 26507212 TI - Modelling Water: A Lifetime Enigma. AB - The first attempt to describe water dates back to 1933 with the Bernal-Fowler model and it would take another forty years before the first computer simulation of liquid water by Barker and Watts in 1969. Since then, over a hundred different water models have been proposed. Despite being widely studied, water remains poorly understood. Examining the evolution of water models, we identified three distinct philosophies in water modelling, namely the employment of effective point charges in pioneering empirical models, the incorporation of polarization to describe many-body inductive effects and the extensive use of ab initio calculations to describe short-range effects. In doing so, we can appraise the current understanding of water and identify attributes that a water model should possess to capture the intricate interactions between water molecules. PMID- 26507213 TI - Characterization of Lipid and Cell Membrane Organization by the Fluorescence Correlation Spectroscopy Diffusion Law. AB - The plasma membrane organization of live cells defines a plethora of cellular processes important for cell functionality. Many membrane structures that define this organization exist at a spatial resolution below the optical diffraction limit and are highly dynamic. Therefore, a method with millisecond time resolution and nanometer spatial resolution is required for the investigation of plasma membrane organization. However, spatial and temporal resolutions of the currently available biophysical techniques are often mutually exclusive. In a novel realization, Lenne and coworkers developed a spot-variation modality of fluorescence correlation spectroscopy (FCS), also known as FCS diffusion law, to harvest nanoscopic information from microscopic measurements. The FCS diffusion law, so far, has been instrumental to decode the physico-chemical origin of membrane organization and its relationship with biological processes. Overall, the structural information of plasma membrane obtained by FCS diffusion law provides a better understanding of its coupling to the underlying cellular processes. PMID- 26507214 TI - Valorization of Renewable Carbon Resources for Chemicals. AB - The overuse of fossil fuels has caused an energy crisis and associated environment issues. It is desirable to utilize renewable resources for the production of chemicals. This review mainly introduces our recent work on the transformation of renewable carbon resources including the conversion of cellulose, lignin, and chitin into sustainable chemicals. Various transformation routes have been established to form value-added chemicals, and accordingly a variety of effective catalytic systems have been developed, either based on metal catalysis and/or acid-base catalysis, to enable the desired transformation. PMID- 26507215 TI - Exposure to Metals Can Be Therapeutic. AB - Because of the widespread epigenetic changes ensuing from carcinogenesis, structural and chemical features of chromatin provide unique targets for developing safer and more effective anticancer drugs. Metal-based agents have a potential advantage over other small molecular species in that characteristics of coordination geometry, redox state and ligand exchange allow one to fine-tune reactivity and affinity properties in a distinct fashion. This intersection of chromatin biology and bioinorganic medicinal chemistry is the subject of multiple collaborations in and between Switzerland and Singapore. PMID- 26507216 TI - Electrocatalysts for the Selective Reduction of Carbon Dioxide to Useful Products. AB - The electrochemical reduction of carbon dioxide (CO(2)) to hydrocarbons and alcohols holds great promise as a sustainable and green method to produce valuable carbon fuels. In this work, we review the catalysts used in the selective reduction of CO(2) to formate, carbon monoxide, methane and ethylene. PMID- 26507217 TI - Evolving P450pyr Monooxygenase for Regio- and Stereoselective Hydroxylations. AB - P450pyr monooxygenase from Sphingomonas sp. HXN-200 catalysed the regio- and stereoselective hydroxylation at a non-activated carbon atom, a useful but challenging reaction in classic chemistry, with unique substrate specificity for a number of alicyclic compounds. New P450pyr mutants were developed by directed evolution with improved catalytic performance, thus significantly extending the application of the P450pyr monooxygenase family in biohydroxylation to prepare useful and valuable chiral alcohols. Directed evolution of P450pyr created new enzymes with improved S-enantioselectivity or R-enantioselectivity for the hydroxylation of N-benzyl pyrrolidine, enhanced regioselectivity for the hydroxylation of N-benzyl pyrrolidinone, and increased enantioselectivity for the hydroxylation of N-benzyl piperidinone, respectively. Directed evolution of P450pyr generated also mutants with fully altered regioselectivity (from terminal to subterminal) and newly created excellent S-enantioselectivity for the biohydroxylation of n-octane and propylbenzene, respectively, providing new opportunities for the regio- and enantioselective alkane functionalization. New P450pyr mutants were engineered as the first catalyst for highly selective terminal hydroxylation of n-butanol to 1,4-butanediol. Several novel, accurate, sensitive, simple, and HTS assays based on colorimetric or MS detection for measuring the enantio- and/or regioselectivity of hydroxylation were developed and proven to be practical in directed evolution. The P450pyr X-ray structure was obtained and used to guide the evolution. In silico modelling and substrate docking provided some insight into the influence of several important amino acid mutations of the engineered P450pyr mutants on the altered or enhanced regio- and enantioselectivity as well as new substrate acceptance. The obtained information and knowledge is useful for further engineering of P450pyr for other hydroxylations and oxidations. PMID- 26507218 TI - Acid Mediated Ring Closing Metathesis: A Powerful Synthetic Tool Enabling the Synthesis of Clinical Stage Kinase Inhibitors. AB - The powerful olefin metathesis reaction was employed for the construction of late phase clinical agents SB1317 and SB1518. In both cases RCM seems to proceed only in the presence of an acid and to predominantly furnish trans isomers. In case of SB1518 it proceeded in the presence of acid HCl, while for SB1317, it mainly proceeds in the presence of TFA (trifluroacetic acid). PMID- 26507219 TI - Skin Concentrations of Topically Applied Substances in Reconstructed Human Epidermis (RHE) Compared with Human Skin Using in vivo Confocal Raman Microscopy. AB - Detailed knowledge about the skin concentration of topically applied substances is important to understand their local pharmacological activity. In particular since in vitro models of reconstructed human epidermis are increasingly used as models for diseased skin. In general, diffusion cell experiments are performed to determine the diffusion flux of test substances through either skin models or excised skin both from humans and animals. Local concentrations of the test substances within the skin are then calculated applying diffusion laws and suitable boundary conditions. In this study we used a direct approach to reveal the local concentrations of test substances within skin using confocal Raman microscopy. This non-invasive method can also be applied in vivo and therefore we directly compared in vivo concentrations with those obtained from commercially available reconstructed human epidermis (RHE). Hydrophilic and lipophilic test substances with log Pow from -0.07 to 5.91 were topically applied on human skin in vivo and RHE from SkinEthic was used as the commercial skin model. Local concentration profiles in the stratum corneum (SC) showed substantial differences between the RHE model and the in vivo situation. Differences between RHE models and human skin in vivo were also observed in their molecular composition, in particular in terms of their water profile, lipid content and the presence of natural moisturizing factor (NMF). Confocal Raman is shown to be a powerful non invasive method for qualitative and quantitative comparative studies between RHE models and human skin in vivo. This method can also be applied to validate RHE models for future use in clinical studies. PMID- 26507223 TI - Balancing the benefits and harms of drug treatments for older men with lower urinary tract symptoms. PMID- 26507224 TI - Antipsychotic prescribing for behavioral disorders in US youth: physician specialty, insurance coverage, and complex regimens. AB - PURPOSE: To assess antipsychotic prescribing patterns according to insurance coverage type and physician specialty in the outpatient treatment of behavioral disorders (BD) in US youth. METHODS: We used 2003-2010 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey data to compare antipsychotic prescribing in the outpatient treatment of BD in youth (6 19 years) according to insurance coverage (public vs. private) and physician specialty (psychiatrist vs. non-psychiatrist) using population-weighted Chi square and multivariable analyses. Also, we examined co-prescribing of antipsychotics with other psychotropic medication classes. Subgroup analyses were conducted in BD visits with no other clinician-reported psychiatric diagnosis (non-comorbid BD visits). RESULTS: A large majority (71.0%) of BD visits were provided by non-psychiatrists. However, psychiatrists prescribed antipsychotics far more frequently than non-psychiatrists (24.2% vs. 4.6%; adjusted odds ratio (AOR) = 5.1 [95% confidence interval (CI), 2.8-9.2]) in total BD visits as well as in non-comorbid BD visits (18.6% vs. 3.6%; AOR = 5.8 [95% CI, 3.2-10.5]). Antipsychotic prescribing was nearly two-fold greater in visits by publicly insured 6-12 year olds (11.3% vs. 5.8%; AOR = 1.9 [95% CI, 1.1-3.5]) and 13-19 year olds (16.2% vs. 8.9%; AOR = 2.0 [95% CI, 1.1-3.6]) compared with their privately insured counterparts. In more than one-third of antipsychotic prescribed BD visits, antipsychotics were prescribed concomitantly with >=2 psychotropic medication classes regardless of age group, insurance coverage, or even in the absence of psychiatric comorbidities. CONCLUSION: In outpatient visits by youth for BD, antipsychotics were primarily prescribed by psychiatrists, concomitantly, and for the publicly insured. These treatment patterns merit further investigation. PMID- 26507225 TI - Therapeutic strategies for cytomegalovirus in allogeneic hematopoietic cell transplantation. AB - Cytomegalovirus (CMV) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation. Advances in surveillance of cytomegalovirus reactivation using sensitive techniques and a preemptive strategy to treat virus reactivation has reduced incidence of cytomegalovirus end organ disease. However, severe immunosuppression associated with extensive T-cell depletion resulting from graft-versus-host disease prevention for cases of mismatched or others such as haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease therapy itself create clinical challenges in managing cytomegalovirus infection. Novel anticytomegalovirus therapies including newer pharmacologic interventions, vaccines, and adoptive cellular therapies to restore anticytomegalovirus immunity appear promising and are expected to continue to shape our treatment armamentarium. Eradication of CMV disease altogether, rather than simply suppressing viremia, should be the ultimate desirable goal. PMID- 26507226 TI - Telangiectasia macularis multiplex acquisita accompanied by hepatitis B infection. AB - We describe two rarely documented cases of telangiectasia macularis multiplex acquisita (TMMA) with a history of hepatitis B infection. Both patients presented with multiple erythematous macules and telangiectasia on bilateral upper arms and the upper part of the trunk. Patient 1 also had spider naevi on the upper part of the chest and palmar erythema; thus we inferred that TMMA, like spider naevi and palmar erythema, might belong to the spectrum of vascular changes of liver diseases. PMID- 26507227 TI - Inactivated Influenza Vaccine That Provides Rapid, Innate-Immune-System-Mediated Protection and Subsequent Long-Term Adaptive Immunity. AB - The continual threat to global health posed by influenza has led to increased efforts to improve the effectiveness of influenza vaccines for use in epidemics and pandemics. We show in this study that formulation of a low dose of inactivated detergent-split influenza vaccine with a Toll-like receptor 2 (TLR2) agonist-based lipopeptide adjuvant (R4Pam2Cys) provides (i) immediate, antigen independent immunity mediated by the innate immune system and (ii) significant enhancement of antigen-dependent immunity which exhibits an increased breadth of effector function. Intranasal administration of mice with vaccine formulated with R4Pam2Cys but not vaccine alone provides protection against both homologous and serologically distinct (heterologous) viral strains within a day of administration. Vaccination in the presence of R4Pam2Cys subsequently also induces high levels of systemic IgM, IgG1, and IgG2b antibodies and pulmonary IgA antibodies that inhibit hemagglutination (HA) and neuraminidase (NA) activities of homologous but not heterologous virus. Improved primary virus nucleoprotein (NP)-specific CD8(+) T cell responses are also induced by the use of R4Pam2Cys and are associated with robust recall responses to provide heterologous protection. These protective effects are demonstrated in wild-type and antibody deficient animals but not in those depleted of CD8(+) T cells. Using a contact dependent virus transmission model, we also found that heterologous virus transmission from vaccinated mice to naive mice is significantly reduced. These results demonstrate the potential of adding a TLR2 agonist to an existing seasonal influenza vaccine to improve its utility by inducing immediate short term nonspecific antiviral protection and also antigen-specific responses to provide homologous and heterologous immunity. IMPORTANCE: The innate and adaptive immune systems differ in mechanisms, specificities, and times at which they take effect. The innate immune system responds within hours of exposure to infectious agents, while adaptive immunity takes several days to become effective. Here we show, by using a simple lipopeptide-based TLR2 agonist, that an influenza detergent-split vaccine can be made to simultaneously stimulate and amplify both systems to provide immediate antiviral protection while giving the adaptive immune system time to implement long-term immunity. Both types of immunity induced by this approach protect against vaccine-matched as well as unrelated virus strains and potentially even against strains yet to be encountered. Conferring dual functionality to influenza vaccines is beneficial for improving community protection, particularly during periods between the onset of an outbreak and the time when a vaccine becomes available or in scenarios in which mass vaccination with a strain to which the population is immunologically naive is imperative. PMID- 26507228 TI - A New Type of YumC-Like Ferredoxin (Flavodoxin) Reductase Is Involved in Ribonucleotide Reduction. AB - The trxB2 gene, which is annotated as a thioredoxin reductase, was found to be essential for growth of Lactococcus lactis in the presence of oxygen. The corresponding protein (TrxB2) showed a high similarity with Bacillus subtilis YumC (E value = 4.0E-88), and YumC was able to fully complement the DeltatrxB2 mutant phenotype. YumC represents a novel type of ferredoxin (flavodoxin) reductase (FdR) with hitherto-unknown biological function. We adaptively evolved the DeltatrxB2 mutant under aerobic conditions to find suppressor mutations that could help elucidate the involvement of TrxB2 in aerobic growth. Genome sequencing of two independent isolates, which were able to grow as well as the wild-type strain under aerated conditions, revealed the importance of mutations in nrdI, encoding a flavodoxin involved in aerobic ribonucleotide reduction. We suggest a role for TrxB2 in nucleotide metabolism, where the flavodoxin (NrdI) serves as its redox partner, and we support this hypothesis by showing the beneficial effect of deoxynucleosides on aerobic growth of the DeltatrxB2 mutant. Finally, we demonstrate, by heterologous expression, that the TrxB2 protein functionally can substitute for YumC in B. subtilis but that the addition of deoxynucleosides cannot compensate for the lethal phenotype displayed by the B. subtilis yumC knockout mutant. IMPORTANCE: Ferredoxin (flavodoxin) reductase (FdR) is involved in many important reactions in both eukaryotes and prokaryotes, such as photosynthesis, nitrate reduction, etc. The recently identified bacterial YumC-type FdR belongs to a novel type, the biological function of which still remains elusive. We found that the YumC-like FdR (TrxB2) is essential for aerobic growth of Lactococcus lactis. We suggest that the YumC-type FdR is involved in the ribonucleotide reduction by the class Ib ribonucleotide reductase, which represents the workhorse for the bioconversion of nucleotides to deoxynucleotides in many prokaryotes and eukaryotic pathogens under aerobic conditions. As the partner of the flavodoxin (NrdI), the key FdR is missing in the current model describing the class Ib system in Escherichia coli. With this study, we have established a role for this novel type of FdR and in addition found the missing link needed to explain how ribonucleotide reduction is carried out under aerobic conditions. PMID- 26507229 TI - Identification of Population Bottlenecks and Colonization Factors during Assembly of Bacterial Communities within the Zebrafish Intestine. AB - The zebrafish, Danio rerio, is a powerful model for studying bacterial colonization of the vertebrate intestine, but the genes required by commensal bacteria to colonize the zebrafish gut have not yet been interrogated on a genome wide level. Here we apply a high-throughput transposon mutagenesis screen to Aeromonas veronii Hm21 and Vibrio sp. strain ZWU0020 during their colonization of the zebrafish intestine alone and in competition with each other, as well as in different colonization orders. We use these transposon-tagged libraries to track bacterial population sizes in different colonization regimes and to identify gene functions required during these processes. We show that intraspecific, but not interspecific, competition with a previously established bacterial population greatly reduces the ability of these two bacterial species to colonize. Further, using a simple binomial sampling model, we show that under conditions of interspecific competition, genes required for colonization cannot be identified because of the population bottleneck experienced by the second colonizer. When bacteria colonize the intestine alone or at the same time as the other species, we find shared suites of functional requirements for colonization by the two species, including a prominent role for chemotaxis and motility, regardless of the presence of another species. IMPORTANCE: Zebrafish larvae, which are amenable to large-scale gnotobiotic studies, comprehensive sampling of their intestinal microbiota, and live imaging, are an excellent model for investigations of vertebrate intestinal colonization dynamics. We sought to develop a mutagenesis and tagging system in order to understand bacterial population dynamics and functional requirements during colonization of the larval zebrafish intestine. We explored changes in bacterial colonization dynamics and functional requirements when bacteria colonize a bacterium-free intestine, one previously colonized by their own species, or one colonized previously or simultaneously with a different species. This work provides a framework for rapid identification of colonization factors important under different colonization conditions. Furthermore, we demonstrate that when colonizing bacterial populations are very small, this approach is not accurate because random sampling of the input pool is sufficient to explain the distribution of inserts recovered from bacteria that colonized the intestines. PMID- 26507230 TI - A Molecular-Level Landscape of Diet-Gut Microbiome Interactions: Toward Dietary Interventions Targeting Bacterial Genes. AB - As diet is considered the major regulator of the gut ecosystem, the overall objective of this work was to demonstrate that a detailed knowledge of the phytochemical composition of food could add to our understanding of observed changes in functionality and activity of the gut microbiota. We used metatranscriptomic data from a human dietary intervention study to develop a network that consists of >400 compounds present in the administered plant-based diet linked to 609 microbial targets in the gut. Approximately 20% of the targeted bacterial proteins showed significant changes in their gene expression levels, while functional and topology analyses revealed that proteins in metabolic networks with high centrality are the most "vulnerable" targets. This global view and the mechanistic understanding of the associations between microbial gene expression and dietary molecules could be regarded as a promising methodological approach for targeting specific bacterial proteins that impact human health. IMPORTANCE: It is a general belief that microbiome-derived drugs and therapies will come to the market in coming years, either in the form of molecules that mimic a beneficial interaction between bacteria and host or molecules that disturb a harmful interaction or proteins that can modify the microbiome or bacterial species to change the balance of "good" and "bad" bacteria in the gut microbiome. However, among the numerous factors, what has proven the most influential for modulating the microbial composition of the gut is diet. In line with this, we demonstrate here that a systematic analysis of the interactions between the small molecules present in our diet and the gut bacterial proteome holds great potential for designing dietary interventions to improve human health. PMID- 26507231 TI - Dendritic Cell Autophagy Contributes to Herpes Simplex Virus-Driven Stromal Keratitis and Immunopathology. AB - Herpetic stromal keratitis (HSK) is a blinding ocular disease that is initiated by HSV-1 and characterized by chronic inflammation in the cornea. Although HSK immunopathology of the cornea is well documented in animal models, events preceding this abnormal inflammatory cascade are poorly understood. In this study, we have examined the activation of pathological CD4(+) T cells in the development of HSK. Dendritic cell autophagy (DC-autophagy) is an important pathway regulating major histocompatibility complex class II (MHCII)-dependent antigen presentation and proper CD4(+) T cell activation during infectious diseases. Using DC-autophagy-deficient mice, we found that DC-autophagy significantly and specifically contributes to HSK disease without impacting early innate immune infiltration, viral clearance, or host survival. Instead, the observed phenotype was attributable to the abrogated activation of CD4(+) T cells and reduced inflammation in HSK lesions. We conclude that DC-autophagy is an important contributor to primary HSK immunopathology upstream of CD4(+) T cell activation. IMPORTANCE: Herpetic stromal keratitis (HSK) is the leading cause of infectious blindness in the United States and a rising cause worldwide. HSK is induced by herpes simplex virus 1 but is considered a disease of inappropriately sustained inflammation driven by CD4(+) T cells. In this study, we investigated whether pathways preceding CD4(+) T cell activation affect disease outcome. We found that autophagy in dendritic cells significantly contributed to the incidence of HSK. Dendritic cell autophagy did not alter immune control of the virus or neurological disease but specifically augmented CD4(+) T cell activation and pathological corneal inflammation. This study broadens our understanding of the immunopathology that drives HSK and implicates the autophagy pathway as a new target for therapeutic intervention against this incurable form of infectious blindness. PMID- 26507232 TI - Toxoplasma gondii Infections Alter GABAergic Synapses and Signaling in the Central Nervous System. AB - During infections with the protozoan parasite Toxoplasma gondii, gamma aminobutyric acid (GABA) is utilized as a carbon source for parasite metabolism and also to facilitate parasite dissemination by stimulating dendritic-cell motility. The best-recognized function for GABA, however, is its role in the nervous system as an inhibitory neurotransmitter that regulates the flow and timing of excitatory neurotransmission. When this pathway is altered, seizures develop. Human toxoplasmosis patients suffer from seizures, suggesting that Toxoplasma interferes with GABA signaling in the brain. Here, we show that while excitatory glutamatergic presynaptic proteins appeared normal, infection with type II ME49 Toxoplasma tissue cysts led to global changes in the distribution of glutamic acid decarboxylase 67 (GAD67), a key enzyme that catalyzes GABA synthesis in the brain. Alterations in GAD67 staining were not due to decreased expression but rather to a change from GAD67 clustering at presynaptic termini to a more diffuse localization throughout the neuropil. Consistent with a loss of GAD67 from the synaptic terminals, Toxoplasma-infected mice develop spontaneous seizures and are more susceptible to drugs that induce seizures by antagonizing GABA receptors. Interestingly, GABAergic protein mislocalization and the response to seizure-inducing drugs were observed in mice infected with type II ME49 but not type III CEP strain parasites, indicating a role for a polymorphic parasite factor(s) in regulating GABAergic synapses. Taken together, these data support a model in which seizures and other neurological complications seen in Toxoplasma infected individuals are due, at least in part, to changes in GABAergic signaling. IMPORTANCE: Infections of the central nervous system can cause seizures. While inflammation in the brain has been proposed to initiate the onset of the seizures, relatively little is known about how inflammation impacts the structure and function of the neurons. Here we used a parasite called Toxoplasma gondii that infects the brain and showed that seizures arise due to a defect in signaling of GABA, which is the neurotransmitter primarily responsible for preventing the onset of seizures. PMID- 26507233 TI - Autophagy-Related Protein ATG8 Has a Noncanonical Function for Apicoplast Inheritance in Toxoplasma gondii. AB - Autophagy is a catabolic process widely conserved among eukaryotes that permits the rapid degradation of unwanted proteins and organelles through the lysosomal pathway. This mechanism involves the formation of a double-membrane structure called the autophagosome that sequesters cellular components to be degraded. To orchestrate this process, yeasts and animals rely on a conserved set of autophagy related proteins (ATGs). Key among these factors is ATG8, a cytoplasmic protein that is recruited to nascent autophagosomal membranes upon the induction of autophagy. Toxoplasma gondii is a potentially harmful human pathogen in which only a subset of ATGs appears to be present. Although this eukaryotic parasite seems able to generate autophagosomes upon stresses such as nutrient starvation, the full functionality and biological relevance of a canonical autophagy pathway are as yet unclear. Intriguingly, in T. gondii, ATG8 localizes to the apicoplast under normal intracellular growth conditions. The apicoplast is a nonphotosynthetic plastid enclosed by four membranes resulting from a secondary endosymbiosis. Using superresolution microscopy and biochemical techniques, we show that TgATG8 localizes to the outermost membrane of this organelle. We investigated the unusual function of TgATG8 at the apicoplast by generating a conditional knockdown mutant. Depletion of TgATG8 led to rapid loss of the organelle and subsequent intracellular replication defects, indicating that the protein is essential for maintaining apicoplast homeostasis and thus for survival of the tachyzoite stage. More precisely, loss of TgATG8 led to abnormal segregation of the apicoplast into the progeny because of a loss of physical interactions of the organelle with the centrosomes. IMPORTANCE: By definition, autophagy is a catabolic process that leads to the digestion and recycling of eukaryotic cellular components. The molecular machinery of autophagy was identified mainly in model organisms such as yeasts but remains poorly characterized in phylogenetically distant apicomplexan parasites. We have uncovered an unusual function for autophagy-related protein ATG8 in Toxoplasma gondii: TgATG8 is crucial for normal replication of the parasite inside its host cell. Seemingly unrelated to the catabolic autophagy process, TgATG8 associates with the outer membrane of the nonphotosynthetic plastid harbored by the parasite called the apicoplast, and there it plays an important role in the centrosome driven inheritance of the organelle during cell division. This not only reveals an unexpected function for an autophagy-related protein but also sheds new light on the division process of an organelle that is vital to a group of important human and animal pathogens. PMID- 26507234 TI - Enzymatic Degradation of Phenazines Can Generate Energy and Protect Sensitive Organisms from Toxicity. AB - Diverse bacteria, including several Pseudomonas species, produce a class of redox active metabolites called phenazines that impact different cell types in nature and disease. Phenazines can affect microbial communities in both positive and negative ways, where their presence is correlated with decreased species richness and diversity. However, little is known about how the concentration of phenazines is modulated in situ and what this may mean for the fitness of members of the community. Through culturing of phenazine-degrading mycobacteria, genome sequencing, comparative genomics, and molecular analysis, we identified several conserved genes that are important for the degradation of three Pseudomonas derived phenazines: phenazine-1-carboxylic acid (PCA), phenazine-1-carboxamide (PCN), and pyocyanin (PYO). PCA can be used as the sole carbon source for growth by these organisms. Deletion of several genes in Mycobacterium fortuitum abolishes the degradation phenotype, and expression of two genes in a heterologous host confers the ability to degrade PCN and PYO. In cocultures with phenazine producers, phenazine degraders alter the abundance of different phenazine types. Not only does degradation support mycobacterial catabolism, but also it provides protection to bacteria that would otherwise be inhibited by the toxicity of PYO. Collectively, these results serve as a reminder that microbial metabolites can be actively modified and degraded and that these turnover processes must be considered when the fate and impact of such compounds in any environment are being assessed. IMPORTANCE: Phenazine production by Pseudomonas spp. can shape microbial communities in a variety of environments ranging from the cystic fibrosis lung to the rhizosphere of dryland crops. For example, in the rhizosphere, phenazines can protect plants from infection by pathogenic fungi. The redox activity of phenazines underpins their antibiotic activity, as well as providing pseudomonads with important physiological benefits. Our discovery that soil mycobacteria can catabolize phenazines and thereby protect other organisms against phenazine toxicity suggests that phenazine degradation may influence turnover in situ. The identification of genes involved in the degradation of phenazines opens the door to monitoring turnover in diverse environments, an essential process to consider when one is attempting to understand or control communities influenced by phenazines. PMID- 26507235 TI - Intrinsic Antimicrobial Resistance Determinants in the Superbug Pseudomonas aeruginosa. AB - Antimicrobial-resistant bacteria pose a serious threat in the clinic. This is particularly true for opportunistic pathogens that possess high intrinsic resistance. Though many studies have focused on understanding the acquisition of bacterial resistance upon exposure to antimicrobials, the mechanisms controlling intrinsic resistance are not well understood. In this study, we subjected the model opportunistic superbug Pseudomonas aeruginosa to 14 antimicrobials under highly controlled conditions and assessed its response using expression- and fitness-based genomic approaches. Our results reveal that gene expression changes and mutant fitness in response to sub-MIC antimicrobials do not correlate on a genomewide scale, indicating that gene expression is not a good predictor of fitness determinants. In general, fewer fitness determinants were identified for antiseptics and disinfectants than for antibiotics. Analysis of gene expression and fitness data together allowed the prediction of antagonistic interactions between antimicrobials and insight into the molecular mechanisms controlling these interactions. IMPORTANCE: Infections involving multidrug-resistant pathogens are difficult to treat because the therapeutic options are limited. These infections impose a significant financial burden on infected patients and on health care systems. Despite years of antimicrobial resistance research, we lack a comprehensive understanding of the intrinsic mechanisms controlling antimicrobial resistance. This work uses two fine-scale genomic approaches to identify genetic loci important for antimicrobial resistance of the opportunistic pathogen Pseudomonas aeruginosa. Our results reveal that antibiotics have more resistance determinants than antiseptics/disinfectants and that gene expression upon exposure to antimicrobials is not a good predictor of these resistance determinants. In addition, we show that when used together, genomewide gene expression and fitness profiling can provide mechanistic insights into multidrug resistance mechanisms. PMID- 26507237 TI - The medicinal chemist's toolbox for late stage functionalization of drug-like molecules. AB - The advent of modern C-H functionalization chemistries has enabled medicinal chemists to consider a synthetic strategy, late stage functionalization (LSF), which utilizes the C-H bonds of drug leads as points of diversification for generating new analogs. LSF approaches offer the promise of rapid exploration of structure activity relationships (SAR), the generation of oxidized metabolites, the blocking of metabolic hot spots and the preparation of biological probes. This review details a toolbox of intermolecular C-H functionalization chemistries with proven applicability to drug-like molecules, classified by regioselectivity patterns, and gives guidance on how to systematically develop LSF strategies using these patterns and other considerations. In addition, a number of examples illustrate how LSF approaches have been used to impact actual drug discovery and chemical biology efforts. PMID- 26507236 TI - Methamphetamine Alters the Antimicrobial Efficacy of Phagocytic Cells during Methicillin-Resistant Staphylococcus aureus Skin Infection. AB - Methamphetamine (METH) is a major drug of abuse in the United States and worldwide. Furthermore, Staphylococcus aureus infections and METH use are coemerging public health problems. S. aureus is the single most important bacterial pathogen in infections among injection drug users, with skin and soft tissue infections (SSTI) being extremely common. Notably, the incidence of SSTI, especially in drug users, is difficult to estimate because such infections are often self-treated. Although there is substantial information on the behavioral and cognitive defects caused by METH in drug users, there is a dearth of knowledge regarding its impact on bacterial infections and immunity. Therefore, we hypothesized that METH exacerbates S. aureus skin infection. Using a murine model of METH administration and wound infection, we demonstrated that METH reduces wound healing and facilitates host-mediated collagen degradation by increased expression and production of matrix metalloproteinase-2 (MMP-2). Additionally, we found that METH induces S. aureus biofilm formation and leads to detrimental effects on the functions of human and murine phagocytic cells, enhancing susceptibility to S. aureus infection. Our findings provide empirical evidence of the adverse impact of METH use on the antimicrobial efficacy of the cells that comprise innate immunity, the initial host response to combat microbial infection. IMPORTANCE: METH is an extremely addictive central nervous system stimulant that is frequently administered by injection. SSTI, common problems among injection drug users, result in serious morbidity for patients and costly hospitalizations for treatment of superficial wounds and incision and drainage of abscesses; however, there has been little etiologic or preventive epidemiological research on this problem. In addition, the evasive nature of injection drug users toward medical care complicates our ability to accurately predict the prevalence of these infections. Hence, this study investigated the impact of METH use on S. aureus skin infection. Our findings demonstrate that this drug of abuse promotes biofilm formation and negatively impacts the wound healing process and innate immune function, exacerbating susceptibility to S. aureus infection. The findings may translate into new knowledge and development of therapeutic and public health strategies to deal with the devastating complications of METH abuse. PMID- 26507238 TI - Comparative and quantitative proteomics reveal the adaptive strategies of oyster larvae to ocean acidification. AB - Decreasing pH due to anthropogenic CO2 inputs, called ocean acidification (OA), can make coastal environments unfavorable for oysters. This is a serious socioeconomical issue for China which supplies >70% of the world's edible oysters. Here, we present an iTRAQ-based protein profiling approach for the detection and quantification of proteome changes under OA in the early life stage of a commercially important oyster, Crassostrea hongkongensis. Availability of complete genome sequence for the pacific oyster (Crassostrea gigas) enabled us to confidently quantify over 1500 proteins in larval oysters. Over 7% of the proteome was altered in response to OA at pHNBS 7.6. Analysis of differentially expressed proteins and their associated functional pathways showed an upregulation of proteins involved in calcification, metabolic processes, and oxidative stress, each of which may be important in physiological adaptation of this species to OA. The downregulation of cytoskeletal and signal transduction proteins, on the other hand, might have impaired cellular dynamics and organelle development under OA. However, there were no significant detrimental effects in developmental processes such as metamorphic success. Implications of the differentially expressed proteins and metabolic pathways in the development of OA resistance in oyster larvae are discussed. The MS proteomics data have been deposited to the ProteomeXchange with identifiers PXD002138 (http://proteomecentral.proteomexchange.org/dataset/PXD002138). PMID- 26507239 TI - Investigating lung responses with functional hyperpolarized xenon-129 MRI in an ex vivo rat model of asthma. AB - PURPOSE: Asthma is a disease of increasing worldwide importance that calls for new investigative methods. Ex vivo lung tissue is being increasingly used to study functional respiratory parameters independent of confounding systemic considerations but also to reduce animal numbers and associated research costs. In this work, a straightforward laboratory method is advanced to probe dynamic changes in gas inhalation patterns by using an ex vivo small animal ovalbumin (OVA) model of human asthma. METHODS: Hyperpolarized (hp) (129) Xe was actively inhaled by the excised lungs exposed to a constant pressure differential that mimicked negative pleural cavity pressure. The method enabled hp (129) Xe MRI of airway responsiveness to intravenous methacholine (MCh) and airway challenge reversal through salbutamol. RESULTS: Significant differences were demonstrated between control and OVA challenged animals on global lung hp (129) Xe gas inhalation with P < 0.05 at MCh dosages above 460 MUg. Spatial mapping of the regional hp gas distribution revealed an approximately three-fold increase in heterogeneity for the asthma model organs. CONCLUSION: The experimental results from this proof of concept work suggest that the ex vivo hp noble gas imaging arrangement and the applied image analysis methodology may be useful as an adjunct to current diagnostic techniques. Magn Reson Med 76:1224-1235, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 26507240 TI - A role of Heat Shock Protein 70 in Photoreceptor Cell Death: Potential as a Novel Therapeutic Target in Retinal Degeneration. AB - Retinal degenerative diseases (RDs) such as retinitis pigmentosa (RP) are a genetically heterogeneous group of disorders characterized by night blindness and peripheral vision loss, which caused by the dysfunction and death of photoreceptor cells. Although many causative gene mutations have been reported, the final common end stage is photoreceptor cell death. Unfortunately, no effective treatments or therapeutic agents have been discovered. Heat shock protein 70 (HSP70) is highly conserved and has antiapoptotic activities. A few reports have shown that HSP70 plays a role in RDs. Thus, we focused on the role of HSP70 in photoreceptor cell death. Using the N-methyl-N-nitrosourea (MNU) induced photoreceptor cell death model in mice, we could examine two stages of the novel cell death mechanism; the early stage, including HSP70 cleavage through protein carbonylation by production of reactive oxygen species, lipid peroxidation and Ca(2+) influx/calpain activation, and the late stage of cathepsin and/or caspase activation. The upregulation of intact HSP70 expression by its inducer is likely to protect photoreceptor cells. In this review, we focus on the role of HSP70 and the novel cell death signaling process in RDs. We also describe candidate therapeutic agents for RDs. PMID- 26507241 TI - Derivatisable Cyanobactin Analogues: A Semisynthetic Approach. AB - Many natural cyclic peptides have potent and potentially useful biological activities. Their use as therapeutic starting points is often limited by the quantities available, the lack of known biological targets and the practical limits on diversification to fine-tune their properties. We report the use of enzymes from the cyanobactin family to heterocyclise and macrocyclise chemically synthesised substrates so as to allow larger-scale syntheses and better control over derivatisation. We have made cyclic peptides containing orthogonal reactive groups, azide or dehydroalanine, that allow chemical diversification, including the use of fluorescent labels that can help in target identification. We show that the enzymes are compatible and efficient with such unnatural substrates. The combination of chemical synthesis and enzymatic transformation could help renew interest in investigating natural cyclic peptides with biological activity, as well as their unnatural analogues, as therapeutics. PMID- 26507242 TI - Prediction model for early biochemical recurrence after radical prostatectomy based on the Cancer of the Prostate Risk Assessment score and the presence of secondary circulating prostate cells. AB - OBJECTIVE: To establish a prediction model for early biochemical recurrence based on the Cancer of the Prostate Risk Assessment (CAPRA) score and the presence of secondary circulating prostate cells (CPCs). PATIENTS AND METHODS: We conducted a prospective single-centre study of men who underwent radical prostatectomy as monotherapy for prostate cancer. Clinicopathological findings were used to calculate the CAPRA score. At 90 days after surgery, blood was taken for CPC detection, mononuclear cells were obtained using differential gel centrifugation, and CPCs were identified using immunocytochemistry. A CPC was defined as a cell expressing prostate-specific antigen (PSA) but not CD45. The CPC test results were defined as positive or negative. Patients were followed up for up to 5 years and biochemical recurrence was defined as a PSA level >0.2 ng/mL. The validity of the CAPRA score was calibrated using partial validation, and Cox proportional hazard regression to build three models: a CAPRA score model, a CPC model and a CAPRA/CPC combined model. RESULTS: A total of 321 men, with a mean age of 65.5 years, participated in the study. After 5 years of follow-up the biochemical recurrence-free survival rate was 98.55%. For the model that included CAPRA score there was a hazard ratio (HR) of 7.66, for the CPC model there was an HR of 34.52 and for the combined model there were HRs of 2.60 for CAPRA score and 22.5 for CPC. Using the combined model, 23% of men changed from the low-risk to the high risk category, or vice versa. CONCLUSION: The incorporation of CPC detection significantly improved the model's discriminative ability in establishing the probability of biochemical recurrence; patients in the high-risk group according to CAPRA score who are negative for CPCs have a much better prognosis. The addition of CPC detection gives clinically significant information to aid the decision on who may be eligible for adjuvant therapy. PMID- 26507243 TI - Case of food-dependent exercise-induced anaphylaxis due to peach with Pru p 7 sensitization. PMID- 26507244 TI - The paracaspase MALT1: biological function and potential for therapeutic inhibition. AB - The paracaspase MALT1 has a central role in the activation of lymphocytes and other immune cells including myeloid cells, mast cells and NK cells. MALT1 activity is required not only for the immune response, but also for the development of natural Treg cells that keep the immune response in check. Exaggerated MALT1 activity has been associated with the development of lymphoid malignancies, and recently developed MALT1 inhibitors show promising anti-tumor effects in xenograft models of diffuse large B cell lymphoma. In this review, we provide an overview of the present understanding of MALT1's function, and discuss possibilities for its therapeutic targeting based on recently developed inhibitors and animal models. PMID- 26507245 TI - Mechanisms of gene targeting in higher eukaryotes. AB - Targeted genome modifications using techniques that alter the genomic information of interest have contributed to multiple studies in both basic and applied biology. Traditionally, in gene targeting, the target-site integration of a targeting vector by homologous recombination is used. However, this strategy has several technical problems. The first problem is the extremely low frequency of gene targeting, which makes obtaining recombinant clones an extremely labor intensive task. The second issue is the limited number of biomaterials to which gene targeting can be applied. Traditional gene targeting hardly occurs in most of the human adherent cell lines. However, a new approach using designer nucleases that can introduce site-specific double-strand breaks in genomic DNAs has increased the efficiency of gene targeting. This new method has also expanded the number of biomaterials to which gene targeting could be applied. Here, we summarize various strategies for target gene modification, including a comparison of traditional gene targeting with designer nucleases. PMID- 26507247 TI - Corrigendum. PMID- 26507248 TI - Electronic Health Record Mid-Parental Height Auto-Calculator for Growth Assessment in Primary Care. AB - Primary care providers are charged with distinguishing children with an underlying growth problem from those with healthy variant short stature. Knowing the heights of the biological parents aids in making that decision. This study sought to determine the feasibility and functionality of an electronic mid parental height (MPH) auto-calculator in the clinical assessment of child growth in a pediatric primary care setting. Clinicians completed surveys for 62% of 6803 children (mean height 13 +/- 7 percentile) with recorded parent heights. Collecting parent height data required <30 seconds in 91% of encounters. The MPH tool confirmed clinicians' initial growth assessment in 79% of cases and changed it in 4%; the remainder did not use the tool. Clinicians who changed assessment were more likely (P < .0001) to pursue more comprehensive evaluation. The MPH tool was a quick, functional resource as a component of an electronic health record system in actual, busy, pediatric primary care practices. PMID- 26507249 TI - Foregut Duplication Cysts in the Head and Neck: A Case Report and Literature Review. PMID- 26507246 TI - Functional roles of HIV-1 Tat protein in the nucleus. AB - Human immunodeficiency virus-1 (HIV-1) Tat protein is one of the most important regulatory proteins for viral gene expression in the host cell and can modulate different cellular processes. In addition, Tat is secreted by the infected cell and can be internalized by neighboring cells; therefore, it affects both infected and uninfected cells. Tat can modulate cellular processes by interacting with different cellular structures and signaling pathways. In the nucleus, Tat might be localized either in the nucleoplasm or the nucleolus depending on its concentration. Here we review the distinct functions of Tat in the nucleoplasm and the nucleolus in connection with viral infection and HIV-induced oncogenesis. PMID- 26507250 TI - Plastic Bronchitis Treated With Topical Tissue-Type Plasminogen Activator and Cryotherapy. PMID- 26507251 TI - "Are you still driving?" Metasynthesis of patient preferences for communication with health care providers. AB - AIM: The aim of this study was to synthesize published qualitative studies to identify older adults' preferences for communication about driving with health care providers. BACKGROUND: Health care providers play a key role in addressing driving safety and driving retirement with older adults, but conversations about driving can be difficult. Guides exist for family members and providers, but to date less is known about the types of communication and messages older drivers want from their health care providers. DESIGN: A qualitative metasynthesis of studies published on or before October 10, 2014, in databases (PubMed, CINAHL, PsycINFO, and Web of Science) and grey literature was performed. REVIEW METHODS: Twenty-two published studies representing 518 older adult drivers met the following inclusion criteria: the study (1) was about driving; (2) involved older drivers; (3) was qualitative (rather than quantitative or mixed methods); and (4) contained information on older drivers' perspectives about communication with health care providers. RESULTS: We identified 5 major themes regarding older adults' communication preferences: (1) driving discussions are emotionally charged; (2) context matters; (3) providers are trusted and viewed as authority figures; (4) communication should occur over a period of time rather than suddenly; and (5) older adults desire agency in the decision to stop driving. CONCLUSION: Various stakeholders involved in older driver safety should consider older drivers' perspectives regarding discussions about driving. Health care providers can respect and empower older drivers-and support their family members through tactful communication about driving safety and mobility transitions during the life course. PMID- 26507252 TI - Cortisol Response in Healthy and Diseased Dogs after Stimulation with a Depot Formulation of Synthetic ACTH. AB - BACKGROUND: The ACTH stimulation test is used to evaluate the adrenocortical reserve. Recently, the availability of the synthetic ACTH formulation was limited, causing major problems in clinical practice. OBJECTIVES: The objective of this study was to evaluate poststimulation peak cortisol concentrations and the duration of the stimulatory effect of a depot ACTH preparation in dogs. ANIMALS: Twenty-two healthy dogs, 10 dogs with suspected hypoadrenocorticism (HA) and 15 dogs with suspected hyperadrenocorticism (HC). METHODS: Prospective study. An ACTH stimulation test using a synthetic depot tetracosactide, administered intramuscularly (5 MUg/kg or at least 0.1 mL) was performed. Blood samples for determination of cortisol were taken immediately before and 1, 2, 3, 4, 6, and 24 hours after stimulation. RESULTS: Peak cortisol concentrations were reached after 2-4 hours in all dogs. Cortisol concentrations 1 hour after stimulation were >9 MUg/dL in all healthy dogs and >5 MUg/dL in all dogs in which HA was excluded. None of the dogs with HA showed a cortisol-increase above the detection-limit of the assay. After 6 hours, cortisol concentrations had decreased in the healthy and HC group and were back to baseline after 24 hours. CONCLUSIONS AND CLINICAL IMPORTANCE: The depot formulation can be used in place of the short-acting ACTH to evaluate the adrenocortical reserve. Blood for peak cortisol concentrations should be drawn 3 hours after stimulation in cases in which HC is suspected; in HA-suspected cases, blood sampling can take place after 1 hour. As the stimulatory effect is gone after 24 hours, interference with other hormonal tests is unlikely after that time. PMID- 26507253 TI - Differentially methylated obligatory epialleles modulate context-dependent LAM gene expression in the honeybee Apis mellifera. AB - Differential intragenic methylation in social insects has been hailed as a prime mover of environmentally driven organismal plasticity and even as evidence for genomic imprinting. However, very little experimental work has been done to test these ideas and to prove the validity of such claims. Here we analyze in detail differentially methylated obligatory epialleles of a conserved gene encoding lysosomal alpha-mannosidase (AmLAM) in the honeybee. We combined genotyping of progenies derived from colonies founded by single drone inseminated queens, ultra deep allele-specific bisulfite DNA sequencing, and gene expression to reveal how sequence variants, DNA methylation, and transcription interrelate. We show that both methylated and non-methylated states of AmLAM follow Mendelian inheritance patterns and are strongly influenced by polymorphic changes in DNA. Increased methylation of a given allele correlates with higher levels of context-dependent AmLAM expression and appears to affect the transcription of an antisense long noncoding RNA. No evidence of allelic imbalance or imprinting involved in this process has been found. Our data suggest that by generating alternate methylation states that affect gene expression, sequence variants provide organisms with a high level of epigenetic flexibility that can be used to select appropriate responses in various contexts. This study represents the first effort to integrate DNA sequence variants, gene expression, and methylation in a social insect to advance our understanding of their relationships in the context of causality. PMID- 26507254 TI - Monitoring development of autonomic dysreflexia during urodynamic investigation in patients with spinal cord injury. AB - OBJECTIVES: We aimed to investigate whether autonomic dysreflexia (AD) develops during urodynamic investigation in patients with spinal cord injury (SCI) with neurological level below thoracic (T) 6 together with the frequency and related factors for AD development. STUDY DESIGN: Prospective study. METHODS: The systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) of 51 SCI patients with a neurological level below T6 were measured and recorded at the beginning and every two minutes during the filling phase of the urodynamic study. The changes between the SBP, DBP and HR values at the beginning and end of the filling phase were analyzed. RESULTS: Autonomic dysreflexia developed only in one of the 51 patients included into the study. The BP of this patient increased from 105/76 mmHg to 145/102 mmHg and the HR dropped from 88 beats/minute (bpm) to 69 bpm together with development of the AD symptoms. The patient was a 47-year old male with a neurological level at T8. A significant difference was found between the mean SBP and the mean DBP values at the beginning and end of the filling phase. CONCLUSIONS: Although rare, AD can be seen during urodynamic investigation in patients with a neurological level below T6, especially when close to the T6 level. Therefore, we suggest that the patients with a neurological level below T6 and especially closer to T6 level should be followed up in terms of development of AD. The clinicians should take into account the HR values in addition to the the SBP and DBP values at follow-ups. PMID- 26507255 TI - A facile palladium catalysed 3-component cascade route to functionalised isoquinolinones and isoquinolines. AB - Palladium catalysed three component cascade process, involving coupling of 2 iodobenzoates, -benzaldehydes, or acetophenones with substituted allenes and ammonium tartrate as an ammonium surrogate, provides a novel and facile route to substituted functionalised isoquinolinones and isoquinolines in good yields. PMID- 26507256 TI - Synthesis of self-assembled IL-1Ra-presenting nanoparticles for the treatment of osteoarthritis. AB - Osteoarthritis is a progressive joint disease that results in degradation of cartilage in load-bearing joints. Pain and inflammation in the joint are the hallmarks of this condition, which further exacerbate the cartilage destruction and health of the patient. It is hence imperative to treat the joint inflammation at the earliest. Interleukin 1 (IL-1) blockade by IL-1 receptor antagonist (IL 1Ra) has shown promise in the clinic but this therapy suffers from rapid clearance, high doses, and frequent intervention. Use of carrier particles that result in longer residence time has been proposed. Here we have synthesized a new class of nanoparticles presenting IL-1Ra on the surface and with tunable size from 300 to 700 nm. These IL-1Ra-poly(2-hydroxyethyl methacrylate)-pyridine nanoparticles are cytocompatible and stable in serum-containing solutions for several days. Our results further demonstrate that these nanoparticles are capable of blocking IL-1beta signaling in an NF-kappaB inducible reporter cell line. These engineered nanoparticles are promising for localized intra-articular delivery in joint space to reduce inflammation in osteoarthritis and other inflammatory diseases. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 595-599, 2016. PMID- 26507257 TI - Effect of operating temperature on transient behaviour of a biofilter treating waste-air containing n-butanol vapour during intermittent loading. AB - Transient-state removal of n-butanol vapour was investigated in a biofilter (BF) packed with compost and lava rock at different operating temperatures in the range of 30-45 degrees C under intermittent loading (8 h per day). Adsorption on the inactive bed and biodegradation in the microbial-active bed were studied separately at an empty bed residence time (EBRT) of 1 min and inlet concentrations of 2.6-3.2 g m(-3), respectively. According to the transient experiments, the highest removal efficiency (RE) around 86% was obtained at 40 degrees C due to a high microbial activity. Comparison of CO2 production and pure adsorption of n-butanol showed that adsorption was the major mechanism in the start-up of BF at each operating condition; although the impact of adsorption declined as temperature increased from 30 degrees C to 45 degrees C. The process was reaction limited at all operating conditions. Based on the determination of stoichiometric coefficients of n-butanol biodegradation, the CO2 production level was significantly lower than that of the chemical oxidation process which resulted in a decrease in environmental pollution. PMID- 26507258 TI - PDGFRB mutation causes autosomal-dominant Penttinen syndrome. AB - A point mutation in PDGFRB causes autosomal-dominant Penttinen syndrome Johnston JJ et al. (2015) American Journal of Human Genetics 97(3): 465-474. PMID- 26507259 TI - Use of three-dimensional mapping in young patients decreases radiation exposure even without a goal of zero fluoroscopy. AB - At present, three-dimensional mapping is often used during cardiac ablations with an explicit goal of decreasing radiation exposure; three-dimensional mapping was introduced in our institution in 2007, but not specifically to decrease fluoroscopy time. We document fluoroscopy use and catheterisation times in this setting. Data were obtained retrospectively from patients who underwent ablation for atrioventricular nodal re-entrant tachycardia from January, 2004 to December, 2011. A total of 93 patients were included in the study. Among them, 18 patients who underwent radiofrequency ablation without three-dimensional mapping were included in Group 1, 13 patients who underwent cryoablation without three dimensional mapping were included in Group 2, and 62 patients who underwent cryoablation with three-dimensional mapping were included in Group 3. Mean fluoroscopy times differed significantly (34.3, 23.4, and 20.3 minutes, p<0.001) when all the groups were compared. Group 3 had a shorter average fluoroscopy time that did not reach significance when compared directly with Group 2 (p=0.29). An unadjusted linear regression model showed a progressive decrease in fluoroscopy time (p=0.002). Mean total catheterisation times differed significantly (180, 211, and 210 minutes, p=0.02) and were related to increased ablation times inherent to cryoablation techniques. Acute success was achieved in 89, 100, and 97% of patients (p=0.25), and chronic success was achieved in 80, 92, and 93% of patients (p=0.38). Complication rates were similar (17, 23, and 7%, p=0.14). In conclusion, three-dimensional mapping systems decrease fluoroscopy times even without an explicit goal of zero fluoroscopy. Efficacy and safety of the procedure have not changed. PMID- 26507260 TI - Facebook use and chronotype: Results of a cross-sectional study. AB - Facebook has become the most popular social networking site round the world. In seeking an explanation for this phenomenon, individual differences in circadian functioning seem to be an interesting issue. The main aim of this study was to examine the potential associations between morningness/eveningness and Facebook use (intrusion and intensity). The participants were 663 Facebook users. The Facebook Intrusion Questionnaire, Facebook Intensity Scale and the Composite Scale of Morningness were used. Our results indicate that chronotype is negatively related with Facebook usage. Eveningness people use Facebook intensively and their Facebook use is more intrusive. Moreover, eveningness in combination with young age predicted Facebook intensity. PMID- 26507261 TI - Circulating mitochondrial biomarkers for drug-induced liver injury. AB - Liver mitochondria affected by drugs can be released into circulation and serve as biomarkers for drug-induced liver injury (DILI). The tissue specificity of ALT was improved by differentiating cytosolic ALT1 and mitochondrial ALT2 isoforms released in circulation. Prior to ALT elevation, mitochondrial cytochrome c, OCT, GLDH, CPS1 and DNA were increased in circulation following DILI. The baseline expression of mt-Nd6 was predictive of individual DILI susceptibility in animals. As mitochondrial DILI biomarkers appeared to be drug or species dependent, they might have value in clinical scenarios when culprit drugs are established, but may not be ideal tools to assess DILI potentials of new drugs. PMID- 26507262 TI - Comparison of femtosecond laser-assisted deep anterior lamellar keratoplasty and penetrating keratoplasty for keratoconus. AB - BACKGROUND: To compare outcomes of femtosecond laser-assisted deep anterior lamellar keratoplasty (FSL-DALK) and penetrating keratoplasty (FSL-PK) for the treatment of keratoconus. METHODS: Twenty eight eyes underwent FSL-DALK (consisted of 12 eyes in the FSL-DALKa subgroup without baring the Descemet's membrane and 16 eyes in the FSL-DALKb subgroup baring the Descemet's membrane using big-bubble technique) were compared with 12 eyes that underwent FSL-PK for keratoconus. These patients underwent an ophthalmic examination preoperatively and 3, 6, 9, and 12 months postoperatively. RESULTS: The postoperative BCVA in the FSL-PK group, and the FSL-DALKb subgroup were significantly better than that in the FSL-DALKa subgroup (P < 0.05), whereas no differences were found between the FSL-DALKb subgroup and the FSL-PK group (P > 0.05). There were no significant differences in the mean spherical equivalent (SE) and astigmatism between the FSL DALK and the FSL-PK groups, nor between the subgroups of FSL-DALK during the follow-up period (P > 0.05). At the last follow-up, the mean endothelial cell loss in the FSL-DALK group (9.12 %) was significantly less than that in the FSL PK group (20.79 %) (P < 0.001), while there was no difference between the FSL DALKa (9.15 %) and the FSL-DALKb (9.10 %) subgroups (P = 0.15). The FSL-DALK group seemed to have fewer graft rejections (1/28 cases) than the FSL-PK group (2/12 cases), although Kaplan-Meier curve showed no significant difference between the two groups (P = 0.144). CONCLUSIONS: In this retrospective study, the results suggested that FSL-DALKb gives better visual outcome, and FSL-DALKb is a better option for keratoconus whose endothelium is not compromised. However, larger and prospective studies are further required. PMID- 26507263 TI - Milk fat globule epidermal growth factor-factor 8-derived peptide attenuates organ injury and improves survival in sepsis. AB - INTRODUCTION: Sepsis involves overwhelming inflammatory responses with subsequent immune-suppression that can lead to multiple organ dysfunction and ultimately death. Milk fat globule epidermal growth factor-factor 8 (MFG-E8) is a secretory protein found to have multiple biological activities against autoimmune and inflammatory diseases. MFG-E8 contains an Arg-Gly-Asp (RGD) motif involved in cell-cell and cell-matrix interactions. In sepsis, excessive neutrophils migration through endothelial cells and matrix to sites of inflammation results in organ damage. We hypothesized that MFG-E8-derived short peptides (MSP) flanking its RGD motif could provide protection against organ injury in sepsis. METHODS: The differentiated human neutrophil-like HL-60 cells (dHL60) were incubated with a series of peptides flanking the RGD motif of human MFG-E8 for a cell adhesion assay to fibronectin or human pulmonary artery endothelial cells (PAECs). For the induction of sepsis, male C57BL/6 mice (20-25 g) were subjected to cecal ligation and puncture (CLP). Peptide MSP68 (1 mg/kg body weight) or normal saline (vehicle) was injected intravenously at 2 h after CLP. Blood and tissue samples were collected at 20 h after CLP for various measurements. RESULTS: After screening, peptide MSP68 (VRGDV) had the highest inhibition of dHL 60 cell adhesion to fibronectin by 55.8 % and to PAEC by 67.7 %. MSP68 treatment significantly decreased plasma levels of organ injury marker AST by 37.1 % and the proinflammatory cytokines IL-6 and TNF-alpha by 61.9 % and 22.1 %, respectively after CLP. MSP68 improved the integrity of microscopic architectures, decreased IL-6 levels in the lungs by 85.1 %, and reduced apoptosis. MSP68 treatment also significantly reduced the total number of neutrophil infiltration by 61.9 % and 48.3 % as well as MPO activity by 40.8 % and 47.3 % in the lungs and liver, respectively, after CLP. Moreover, the number of bacteria translocated to mesenteric lymph nodes was decreased by 57 % with MSP68 treatment. Finally, the 10-day survival rate was increased from 26 % in the vehicle group to 58 % in the MSP68-treated group. CONCLUSIONS: MSP68 effectively inhibits excessive neutrophils infiltrating to organs, leading to moderate attenuation of organ injury and significantly improved survival in septic mice. Thus, MSP68 may be a potential therapeutic agent for treating sepsis. PMID- 26507264 TI - Association of ARNTL and PER1 genes with Parkinson's disease: a case-control study of Han Chinese. AB - Circadian disruptions may result in sleep problems, oxidative stress and an altered inflammatory response. These symptoms may contribute to PD pathogenesis, despite a lack of direct experimental evidence supporting this relationship. Clock genes are essential to drive and maintain circadian rhythm. To elucidate the possible role of circadian disruptions in PD, we investigated 132 tag variants in eight clock genes. We genotyped these tags within 1,394 Chinese cases and 1,342 controls using Illumina GoldenGate chips. We discovered that SNPs in ARNTL (rs900147, P = 3.33 * 10(-5), OR = 0.80) and PER1 (rs2253820, P = 5.30 * 10(-6), OR = 1.31) genes are significantly associated with PD risk. Moreover, the positive association of the ARNTL rs900147 variant was more robust in tremor dominant (TD) (P = 3.44 * 10(-4)) than postural instability and gait difficulty (PIGD) cases (P = 6.06 * 10(-2)). The association of the PER1 rs2253820 variant was more robust in PIGD (P = 5.42 * 10(-5)) than TD cases (P = 4.2 * 10(-2)). Haplotype analysis also showed that ARNTL and PER1 were associated with PD. Imputation analysis identified more SNPs within ARNTL and PER1 associated with PD, some of which may affect gene expression through altering the transcription factor binding site. In summary, our findings suggest that genetic polymorphisms in ARNTL and PER1 genes, as well as circadian disruptions, may contribute to PD pathogenesis. PMID- 26507265 TI - How many operating rooms are needed to manage non-elective surgical cases? A Monte Carlo simulation study. AB - BACKGROUND: Patients often wait to have urgent or emergency surgery. The number of operating rooms (ORs) needed to minimize waiting time while optimizing resources can be determined using queuing theory and computer simulation. We developed a computer program using Monte Carlo simulation to determine the number of ORs needed to minimize patient wait times while optimizing resources. METHODS: We used patient arrival data and surgical procedure length from our institution, a tertiary-care academic medical center that serves a large diverse population. With ~4800 patients/year requiring non-elective surgery, and mean procedure length 185 min (median 150 min) we determined the number of ORs needed during the day and evening (0600-2200) and during the night (2200-0600) that resulted in acceptable wait times. RESULTS: Simulation of 4 ORs at day/evening and 3 ORs at night resulted in median wait time = 0 min (mean = 19 min) for emergency cases requiring surgery within 2 h, with wait time at the 95th percentile = 109 min. Median wait time for urgent cases needing surgery within 8-12 h was 34 min (mean = 136 min), with wait time at the 95th percentile = 474 min. The effect of changes in surgical length and volume on wait times was determined with sensitivity analysis. CONCLUSIONS: Monte Carlo simulation can guide decisions on how to balance resources for elective and non-elective surgical procedures. PMID- 26507266 TI - Educating Residents on Diagnosing Personality Disorders Across Cultures. PMID- 26507267 TI - Cross-Cultural Psychiatry and Implications in Education. PMID- 26507268 TI - Advances in the Generation of Genetically Modified (GM) Animal Models: Meeting report. PMID- 26507269 TI - Targeted modification of storage protein content resulting in improved amino acid composition of barley grain. AB - C-hordein in barley and omega-gliadins in wheat are members of the prolamins protein families. Prolamins are the major component of cereal storage proteins and composed of non-essential amino acids (AA) such as proline and glutamine therefore have low nutritional value. Using double stranded RNAi silencing technology directed towards C-hordein we obtained transgenic barley lines with up to 94.7% reduction in the levels of C-hordein protein relative to the parental line. The composition of the prolamin fraction of the barley parental line cv. Golden Promise was resolved using SDS-PAGE electrophoresis, the protein band were excised and the proteins identified by quadrupole-time-of-flight mass spectrometry. Subsequent SDS-PAGE separation and analysis of the prolamin fraction of the transgenic lines revealed a reduction in the amounts of C hordeins and increases in the content of other hordein family members. Analysis of the AA composition of the transgenic lines showed that the level of essential amino acids increased with a concomitant reduction in proline and glutamine. Both the barley C-hordein and wheat omega-gliadin genes proved successful for RNAi gene mediated suppression of barley C-hordein level. All transgenic lines that exhibited a reduction for C-hordein showed off-target effects: the lines exhibited increased level of B/gamma-hordein while D-hordein level was reduced. Furthermore, the multicopy insertions correlated negatively with silencing. PMID- 26507270 TI - Distribution of coniferin in differentiating normal and compression woods using MALDI mass spectrometric imaging coupled with osmium tetroxide vapor treatment. AB - Matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI MSI) was employed to detect monolignol glucosides in differentiating normal and compression woods of two Japanese softwoods, Chamaecyparis obtusa and Cryptomeria japonica Comparison of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry collision-induced dissociation fragmentation analysis and structural time-of-flight (MALDI-TOF CID-FAST) spectra between coniferin and differentiating xylem also confirmed the presence of coniferin in differentiating xylem. However, as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and MALDI-TOF CID-FAST spectra of sucrose were similar to those of coniferin, it was difficult to distinguish the distribution of coniferin and sucrose using MALDI-MSI and collision-induced dissociation measurement only. To solve this problem, osmium tetroxide vapor was applied to sections of differentiating xylem. This vapor treatment caused peak shifts corresponding to the introduction of two hydroxyl groups to the C=C double bond in coniferin. The treatment did not cause a peak shift for sucrose, and therefore was effective in distinguishing coniferin and sucrose. Thus, it was found that MALDI-MSI combined with osmium tetroxide vapor treatment is a useful method to detect coniferin in differentiating xylem. PMID- 26507271 TI - Whole-plant allocation to storage and defense in juveniles of related evergreen and deciduous shrub species. AB - In evergreen plants, old leaves may contribute photosynthate to initiation of shoot growth in the spring. They might also function as storage sites for carbohydrates and nitrogen (N). We hence hypothesized that whole-plant allocation of carbohydrates and N to storage in stems and roots may be lower in evergreen than in deciduous species. We selected three species pairs consisting of an evergreen and a related deciduous species: Mahonia aquifolium (Pursh) Nutt. and Berberis vulgaris L. (Berberidaceae), Prunus laurocerasus L. and Prunus serotina Ehrh. (Rosaceae), and Viburnum rhytidophyllum Hemsl. and Viburnum lantana L. (Adoxaceae). Seedlings were grown outdoors in pots and harvested on two dates during the growing season for the determination of biomass, carbohydrate and N allocation ratios. Plant size-adjusted pools of nonstructural carbohydrates in stems and roots were lower in the evergreen species of Berberidaceae and Adoxaceae, and the slope of the carbohydrate pool vs plant biomass relationship was lower in the evergreen species of Rosaceae compared with the respective deciduous species, consistent with the leading hypothesis. Pools of N in stems and roots, however, did not vary with leaf habit. In all species, foliage contained more than half of the plant's nonstructural carbohydrate pool and, in late summer, also more than half of the plant's N pool, suggesting that in juvenile individuals of evergreen species, leaves may be a major storage site. Additionally, we hypothesized that concentration of defensive phenolic compounds in leaves should be higher in evergreen than in deciduous species, because the lower carbohydrate pool in stems and roots of the former restricts their capacity for regrowth following herbivory and also because of the need to protect their longer-living foliage. Our results did not support this hypothesis, suggesting that evergreen plants may rely predominantly on structural defenses. In summary, our study indicates that leaf habit has consequences for storage economics at the whole-plant level, with evergreen shrub species storing less carbohydrates (but not N) per unit plant biomass than deciduous species. PMID- 26507272 TI - A carbohydrate quandary. PMID- 26507273 TI - DNA transfer-a never ending story. A study on scenarios involving a second person as carrier. AB - The transfer of DNA directly from one item to another has been shown in many studies with elaborate discussions on the nature of the DNA donor as well as material and surface of the items or surrounding features. Every DNA transfer scenario one can imagine seems to be possible. This evokes more and more intricate scenarios proposed by lawyers or attorneys searching for an explanation of the DNA of a certain person on a distinct item with impact on a crime. At court, the forensic genetic scientist has to comment on the probability of these scenarios thus calling for extensive studies on such settings. Here, the possibility of an involvement of a second person as a carrier of the donor's DNA in a variety of different scenarios including three pairs of people and two kinds of items (textiles and plastic bags) was investigated. All transfer settings were executed with and without gloves on the carrier's hands. DNA left on the items was isolated and analyzed using the Powerplex(r) ESX17 kit. In 21 out of 180 samples, all alleles of the donor DNA could be obtained on the second item (12%), on eight samples, the donor's DNA was dominant compared to all other alleles (38% of samples with complete donor profile). Additionally, 51 samples displayed at least more than half of the donor's alleles (28%). The complete DNA profile of the carrier was found in 47 out of 180 samples (42 partial profiles). In summary, it could be shown that a transfer of donor DNA from epithelial cells through a carrier to a second item is possible, even if the carrier does not wear gloves. PMID- 26507274 TI - Erratum to: Implantation of autologous muscle-derived stem cells in treatment of fecal incontinence: results of an experimental pilot study. PMID- 26507275 TI - Early Pliocene onset of modern Nordic Seas circulation related to ocean gateway changes. AB - The globally warm climate of the early Pliocene gradually cooled from 4 million years ago, synchronous with decreasing atmospheric CO2 concentrations. In contrast, palaeoceanographic records indicate that the Nordic Seas cooled during the earliest Pliocene, before global cooling. However, a lack of knowledge regarding the precise timing of Nordic Seas cooling has limited our understanding of the governing mechanisms. Here, using marine palynology, we show that cooling in the Nordic Seas was coincident with the first trans-Arctic migration of cool water Pacific mollusks around 4.5 million years ago, and followed by the development of a modern-like Nordic Seas surface circulation. Nordic Seas cooling precedes global cooling by 500,000 years; as such, we propose that reconfiguration of the Bering Strait and Central American Seaway triggered the development of a modern circulation in the Nordic Seas, which is essential for North Atlantic Deep Water formation and a precursor for more widespread Greenland glaciation in the late Pliocene. PMID- 26507276 TI - Transarterial bland versus chemoembolization for hepatocellular carcinoma: rethinking a gold standard. AB - BACKGROUND: Transarterial chemoembolization (TACE) is the most common procedure for the treatment of hepatocellular carcinoma (HCC). However, HCC is generally considered chemoresistant and data demonstrating the superiority of TACE over bland embolization (TAE) are lacking. MATERIALS AND METHODS: A nationwide, retrospective cohort study of HCC patients treated with first-line TACE or TAE within the Veterans Affairs health care system (2005-2012) was performed. The primary outcome was overall survival. Risk of death by treatment type (TACE or TAE) was evaluated using multivariate (adjusted for age, presence of cirrhosis, Barcelona Clinic Liver Cancer stage, and Charlson comorbidity score) and propensity score-adjusted Cox regression. RESULTS: The cohort included 405 patients treated with first-line transarterial embolization. Among these patients, 32 (7.9%) underwent TAE. Most of the patients (76.8%) had intermediate or advanced stage at presentation. Similar proportions of patients (TACE 53.3% versus TAE 43.7%; P = 0.30) received more than one embolization procedure. There was no difference in median survival (20.1 versus 23.1 mo, respectively; log-rank P = 0.84). Compared to TACE, there was no difference in risk of death associated with TAE after multivariate (hazard ratio [HR] 0.92; 95% CI, 0.61-1.37) and propensity score adjustment (HR = 0.86; 95% CI = 0.58-1.29). CONCLUSIONS: There is no clear benefit associated with chemotherapy infusion over bland embolization for HCC treatment. Given the rising incidence of HCC in the United States and considering the added costs associated with TACE compared to TAE, future work comparing these competing management strategies is needed. PMID- 26507277 TI - Beneficial effects of dantrolene on sepsis-induced diaphragmatic dysfunction are associated with downregulation of high-mobility group box 1 and calpain-caspase-3 proteolytic pathway. AB - BACKGROUND: Intracellular calcium overload is a major contributing factor to diaphragmatic dysfunction triggered by sepsis. In this study, the possible role of dantrolene, a ryanodine receptor inhibitor, in preventing the release of calcium from the sarcoplasmic reticulum in diaphragmatic dysfunction and weakness was explored. METHODS: A middle-grade severity sepsis rat model was established for the effects of treatment with dantrolene, on diaphragm harvested 24 h after cecal ligation and puncture (CLP), and analyzed using functional, histologic, and biomarker assays. RESULTS: It was found that in septic rats, treatment with dantrolene significantly improved the contractility, relaxation, and fatigue index of the diaphragm in a dose-dependent manner. The benefits are associated with improvement in ultrastructural changes of Z band integrity and myofilament arrangements along with increases both in the ratio of slow-twitch type composition. Moreover, dantrolene effectively inhibits the overexpression of high mobility group box 1 and reduces the calpain-1-caspase-3 proteolytic activity. CONCLUSIONS: Dantrolene can effectively attenuate the dysfunction of diaphragm in septic rats; Furthermore, the beneficial effects were associated with downregulation of high-mobility group box 1 and calpain-1-caspase-3 proteolytic activity. PMID- 26507278 TI - Live birth following early follicular phase oocyte collection and vitrified warmed embryo transfer 8 days later. AB - A 30-year-old woman with premature ovarian insufficiency had two follicles measuring 17 mm and 14 mm on day 3 of her menstrual cycle. Serum oestradiol concentration was 210 pg/ml. Recombinant human chorionic gonadotrophin was given and 5 mg/day letrozole started orally. One metaphase II oocyte was collected 36 h later. A 4-cell embryo was vitrified on the second day after fertilization. Letrozole was stopped on cycle day 8 due to absence of any other visible antral follicles. Oestradiol valerate 6 mg/day was started and the endometrium was 9.2 mm on cycle day 11. The embryo was warmed and transferred on cycle day 13, the 8th day after oocyte retrieval. Luteal phase support with progesterone, oestradiol and low molecular weight heparin was started on the day of transfer and continued until the 10th gestational week. A healthy girl weighing 3200 g was born at term. Early follicular phase oocyte collection did not result in early opening of the implantation window. Apparently secretory transformation was not started until luteal phase support, enabling a cleavage stage embryo transferred 8 days later to implant. Either corpus luteum formation could be disrupted or the endometrium could remain unresponsive to progesterone during the early follicular phase. PMID- 26507279 TI - 'Luteal coasting' after GnRH agonist trigger - individualized, HCG-based, progesterone-free luteal support in 'high responders': a case series. AB - This study reports 21 IVF cases with excessive ovarian response, who received gonadotrophin-releasing hormone agonist (GnRHa) triggering for final oocyte maturation, followed by a human chorionic gonadotrophin (HCG)-based, progesterone free, luteal support, individually timed ('luteal coasting') according to endogenous luteal progesterone concentrations. One patient developed a brief early-onset moderate ovarian hyperstimulation syndrome (OHSS) condition. Six clinical pregnancies were achieved, two of which have resulted in live births thus far. To further individualize the luteal phase support post GnRHa trigger, the same principle that holds for follicular coasting, used in the context of OHSS prevention, may be valid. Monitoring luteal progesterone concentrations from the day of oocyte retrieval, and administering a bolus of HCG (1500 IU) when the concentration drops significantly, seems to facilitate fresh embryo transfer, even in patients with excessive ovarian responses. PMID- 26507280 TI - A preliminary report of successful cleavage after calcium ionophore activation at ICSI in cases with previous arrest at the pronuclear stage. AB - Artificial oocyte activation (AOA) has been previously suggested as a means to overcome the problem of total fertilization failure, which affects about 1-3% of the intracytoplasmic sperm injection (ICSI) cycles. A preliminary study on the application of chemical AOA was conducted using A23187 Ca(2+) ionophore to improve embryonic development in four women with a history of complete fertilization arrest and inability to transit to cleavage stage during previous ICSI trials. Data indicated that activated oocytes resulted in better fertilization, embryonic development and clinical pregnancy in one of the four couples. Therefore, ICSI combined with AOA using Ca(2+) ionophore may be useful in selected patients with cleavage failure, and may help the zygotes to reach more advanced developmental stages. PMID- 26507281 TI - HFEA response to 'A plea for caution and more research in the "experimental" use of ionophores in ICSI'. PMID- 26507282 TI - Transplantation of ovarian tissue to postpone menopause - is it really more advantageous for women's health than menopause hormone therapy? PMID- 26507283 TI - Karyomapping allows preimplantation genetic diagnosis of a de-novo deletion undetectable using conventional PGD technology. AB - Preimplantation genetic diagnosis (PGD) was carried out for a couple carrying a de-novo deletion in the TSC2 gene, responsible for tuberous sclerosis. Karyomapping, a method employing genome-wide analysis of single nucleotide polymorphisms (SNP), was used as PGD protocol. Analysis of DNA from the affected parent using karyomapping confirmed the region covered by the deletion and revealed more than 30 SNP located within the affected region. These SNP were subsequently used for embryo diagnosis (deletion revealed by hemizygosity and/or reduced probe intensity). Seven blastocyst embryos underwent trophectoderm biopsy followed by vitrification. Biopsied cells were subjected to comprehensive aneuploidy screening using microarray comparative genomic hybridization (aCGH), with karyomapping for the detection of embryos carrying the mutant TSC2 gene carried out in tandem. Two embryo transfers were performed, the second of which resulted in the birth of a child. This study highlights that karyomapping may be applicable to a subset of de-novo mutations undetectable using standard PGD strategies. Additionally, karyomapping results were in complete concordance with aCGH, both methods revealing the same aneuploidies in the embryos tested. It was concluded that karyomapping may represent a valuable advance in cases of PGD for monogenic diseases. PMID- 26507284 TI - Response: transplantation of ovarian tissue to postpone menopause - is it really more advantageous for women's health than menopause hormone therapy? PMID- 26507285 TI - PhenoMiner: from text to a database of phenotypes associated with OMIM diseases. AB - Analysis of scientific and clinical phenotypes reported in the experimental literature has been curated manually to build high-quality databases such as the Online Mendelian Inheritance in Man (OMIM). However, the identification and harmonization of phenotype descriptions struggles with the diversity of human expressivity. We introduce a novel automated extraction approach called PhenoMiner that exploits full parsing and conceptual analysis. Apriori association mining is then used to identify relationships to human diseases. We applied PhenoMiner to the BMC open access collection and identified 13,636 phenotype candidates. We identified 28,155 phenotype-disorder hypotheses covering 4898 phenotypes and 1659 Mendelian disorders. Analysis showed: (i) the semantic distribution of the extracted terms against linked ontologies; (ii) a comparison of term overlap with the Human Phenotype Ontology (HP); (iii) moderate support for phenotype-disorder pairs in both OMIM and the literature; (iv) strong associations of phenotype-disorder pairs to known disease-genes pairs using PhenoDigm. The full list of PhenoMiner phenotypes (S1), phenotype-disorder associations (S2), association-filtered linked data (S3) and user database documentation (S5) is available as supplementary data and can be downloaded at http://github.com/nhcollier/PhenoMiner under a Creative Commons Attribution 4.0 license. Database URL: phenominer.mml.cam.ac.uk. PMID- 26507286 TI - Systematic review of medial versus lateral survivorship in unicompartmental knee arthroplasty. AB - BACKGROUND: Unicompartmental knee arthroplasty (UKA) has gained popularity in patients with isolated unicompartmental osteoarthritis. To our knowledge no systematic review has assessed and compared survivorship of medial and lateral UKA. We performed a systematic review assessing medial and lateral UKA survivorship and comparing survivorship in cohort studies and registry-based studies. METHODS: A search was performed using PubMed, Embase and Cochrane systems. Ninety-six eligible studies reported survivorship, of which fifty-eight reported medial and sixteen reported lateral UKA survivorship. Nineteen cohort studies and seven registry-based studies reported combined medial and lateral survivorship. RESULTS: The five-year, ten-year and fifteen-year medial UKA survivorship was 93.9%, 91.7% and 88.9%, respectively. Lateral UKA survivorship was 93.2%, 91.4% and 89.4% at five-year, ten-year and fifteen-year, respectively. No statistical difference between both compartments was found. At twenty years and twenty-five years survivorship of medial UKA was 84.7% and 80%, respectively, but no studies reported lateral UKA survivorship at these follow-up intervals. Survivorship of cohort studies was not significantly higher compared to registry based studies at five years (94.3 vs. 91.7, respectively, p=0.133) but was significantly higher at ten years (90.5 vs. 84.1, p=0.015). CONCLUSION: This is the first systematic review that shows no difference in the five-, ten- and fifteen-year survivorship of medial and lateral UKA. We found a lower survivorship in the registry-based studies compared to cohort studies. PMID- 26507287 TI - Interface control of electronic transport across the magnetic phase transition in SrRuO3/SrTiO3 heterointerface. AB - The emerging material class of complex-oxides, where manipulation of physical properties lead to new functionalities at their heterointerfaces, is expected to open new frontiers in Spintronics. For example, SrRuO3 is a promising material where external stimuli like strain, temperature and structural distortions control the stability of electronic and magnetic states, across its magnetic phase transition, useful for Spintronics. Despite this, not much has been studied to understand such correlations in SrRuO3. Here we explore the influence of electron-lattice correlation to electron-transport, at interfaces between SrRuO3 and Nb:SrTiO3 across its ferromagnetic transition, using a nanoscale transport probe and first-principles calculations. We find that the geometrical reconstructions at the interface and hence modifications in electronic structures dominate the transmission across its ferromagnetic transition, eventually flipping the charge-transport length-scale in SrRuO3. This approach can be easily extended to other devices where competing ground states can lead to different functional properties across their heterointerfaces. PMID- 26507288 TI - A microchannel device tailored to laser axotomy and long-term microelectrode array electrophysiology of functional regeneration. AB - We designed a miniaturized and thin polydimethylsiloxane (PDMS) microchannel device compatible with commercial microelectrode array (MEA) chips. It was optimized for selective axonal ablation by laser microdissection (LMD) to investigate the electrophysiological and morphological responses to a focal injury in distinct network compartments over 45 days in vitro (45 DIV). Low density cortical or hippocampal networks (<3500 neurons per device) were cultured in quasi-closed somal chambers. Their axons were selectively filtered through neurite cavities and guided into the PDMS microchannels aligned over the recording electrodes. The device geometries amplified extracellularly recorded signals in the somal reservoir and the axonal microchannels to detectable levels. Locally extended areas along the microchannel, so-called working stations, forced axonal bundles to branch out and thereby allowed for their repeatable and controllable local, partial or complete dissections. Proximal and distal changes in the activity and morphology of the dissected axons were monitored and compared to those of their parent networks and of intact axons in the control microchannels. Microscopy images confirmed progressive anterograde degeneration of distal axonal segments over four weeks after surgery. Dissection on cortical and hippocampal axons revealed different cell type- and age-dependent network responses. At 17 DIV, network activity increased in both the somal and proximal microchannel compartments of the dissected hippocampal or cortical axons. At later days (24 DIV), the hippocampal networks were more susceptible to axonal injury. While their activity decreased, that in the cortical cultures actually increased. Subsequent partial dissections of the same axonal bundles led to a stepwise activity reduction in the distal hippocampal or cortical axonal fragments. We anticipate that the MEA-PDMS microchannel device for the combined morphological and electrophysiological study of axonal de- and regeneration can be easily merged with other experimental paradigms like molecular or pharmacological screening studies. PMID- 26507289 TI - Surgical management of complicated pancreatic pseudocysts after acute pancreatitis. AB - BACKGROUND: Management of pancreatic pseudocysts (PP) is unclear when located in areas outside the lesser sac, infected, or when portal venous (PV) occlusion is present. METHODS: Patients having internal drainage of PP. Management and outcome were assessed relative to location, presence of infection, and/or PV occlusion. RESULTS: No patient required transfusion, and there were no readmissions in 9 patients with PV occlusion. Eleven patients had infected PP including 5 extending outside the lesser sac. Six had postoperative imaging, 4 readmission, and 3 required adjunct postoperative percutaneous drainage. All but 2 with PP beyond the lesser sac had Roux-en-Y cystjejunostomy including 4 with 2 anastomoses. Nine, 4, and 5 required reimaging, readmission, and postoperative therapeutic intervention, respectively. CONCLUSIONS: (1) Open PP drainage in the face of PV occlusion confers a low risk of bleeding and a minimal need for reimaging or readmission; (2) internal drainage of infected PP is a viable option to external drainage; and (3) PP extending beyond the lesser sac can most often be managed successfully by Roux-en-Y drainage but may require additional intervention. PMID- 26507290 TI - Simulated Trauma and Resuscitation Team Training course-evolution of a multidisciplinary trauma crisis resource management simulation course. AB - BACKGROUND: We previously reported on a pilot trauma multidisciplinary crisis resource course titled S.T.A.R.T.T. (Simulated Trauma and Resuscitative Team Training). Here, we study the course's evolution. METHODS: Satisfaction was evaluated by postcourse survey. Trauma teams were evaluated using the Ottawa global rating scale and an Advanced Trauma Life Support primary survey checklist. RESULTS: Eleven "trauma teams," consisting of physicians, nurses, and respiratory therapists, each completed 4 crisis simulations over 3 courses. Satisfaction remained high among participants with overall mean satisfaction being 4.39 on a 5 point Likert scale. As participants progressed through scenarios, improvements in global rating scale scores were seen between the 1st and 4th (29.8 vs 36.1 of 42, P = .022), 2nd and 3rd (28.2 vs 34.6, P = .017), and 2nd and 4th (28.2 vs 36.1, P = .003) scenarios. There were no differences in Advanced Trauma Life Support checklist with mean scores for each scenario ranging 11.3 to 13.2 of 17. CONCLUSIONS: The evolved Simulated Trauma and Resuscitative Team Training curriculum has maintained high participant satisfaction and is associated with improvement in team crisis resource management skills over the duration of the course. PMID- 26507291 TI - Postoperative sepsis in cancer patients undergoing major elective digestive surgery is associated with increased long-term mortality. AB - BACKGROUND: Major postoperative events (acute respiratory failure, sepsis, and surgical complications) are frequent early after elective gastroesophageal and pancreatic surgery. It is unclear whether these complications impact equally on long-term outcome. METHODS: Prospective observational study including the patients admitted to the surgical intensive care unit between January 2009 and October 2011 after elective gastroesophageal and pancreatic surgery. Risk factors for 30-day major postoperative events and long-term outcome were evaluated. RESULTS: During the study period, 259 patients were consecutively included. Among them, 166 (64%), 54 (21%), and 39 (15%) patients underwent pancreatic surgery, gastric surgery, and esophageal surgery, respectively. Using the Clavien-Dindo classification, 117 patients (45%) developed at least 1 postoperative complication, including 60 (23%) patients with acute respiratory failure, 77 (30%) with sepsis, and 89 (34%) with surgical complications. The median follow-up from the time of intensive care unit admission was 34 months (95% confidence interval, 30-37 months). The 1-year survival was 95% (95% confidence interval, 92 98). Among the perioperative variables, postoperative sepsis and an American Society of Anesthesiologists score higher than 2 were independently associated with long-term mortality. In septic patients, death (n = 16) was significantly associated with cancer recurrence (n = 10; P < .0001). Independent factors associated with postoperative sepsis were a Sequential Organ Failure Assessment score on day 1, a systemic inflammatory response syndrome on day 3, positive intraoperative microbiological samples, Simplified Acute Physiology Score II and an American Society of Anesthesiologists score higher than 2 (P < .005). CONCLUSIONS: Postoperative sepsis was the only major postoperative event associated with long-term mortality. Postoperative sepsis may reflect a deep impairment of immune response, which is potentially associated with cancer recurrence and mortality. PMID- 26507292 TI - Open Reduction Techniques for Supracondylar Humerus Fractures in Children. AB - Supracondylar humerus fractures are the most common elbow fractures in children. Displaced supracondylar humerus fractures that are associated with neurologic and/or vascular injuries are treated with timely reduction through closed techniques. When closed techniques fail, reduction by open methods is indicated. Controversy exists as to which surgical approach yields the best outcomes in terms of cosmetic and functional results, while minimizing postoperative complications. Open reduction, when indicated, has been shown to yield good outcomes when closed reduction methods fail. PMID- 26507293 TI - AAOS Clinical Practice Guideline on the Treatment of Pediatric Diaphyseal Femur Fractures. PMID- 26507294 TI - Learning and memory: Influences from above on memory. PMID- 26507296 TI - Microglia: Tau distributors. PMID- 26507295 TI - Packet-based communication in the cortex. AB - Cortical circuits work through the generation of coordinated, large-scale activity patterns. In sensory systems, the onset of a discrete stimulus usually evokes a temporally organized packet of population activity lasting ~50-200 ms. The structure of these packets is partially stereotypical, and variation in the exact timing and number of spikes within a packet conveys information about the identity of the stimulus. Similar packets also occur during ongoing stimuli and spontaneously. We suggest that such packets constitute the basic building blocks of cortical coding. PMID- 26507297 TI - Guided orthodontic regeneration: A tool to enhance conventional regenerative techniques in implant surgery. AB - A hopeless upper central incisor was subjected to forced eruption before implant substitution to improve and develop the amount of soft tissue. This involved a GBR to insert the implant and a GTR to regenerate the tissue around the dehiscence of the nearby lateral using a "Guided Orthodontic Regeneration" (GOR) approach. The extrusion was performed esthetically in lingual orthodontics. The GOR technique included a Guided Orthodontic "Bone" Regeneration (GOBR) and a Guided Orthodontic "Soft Tissue" Regeneration (GOTR). This developed a 3D implant site while correcting the osseous defects and increasing the amount of soft tissue, which was used for a subsequent regenerative technique. PMID- 26507298 TI - Orthodontic and surgical management of a skeletal Class III case. AB - This article presents a case report on a skeletal Class III associated with transverse maxillary constriction treated using a combined orthodontic and surgical approach. The presurgical orthodontic phase involved decompensation for the malocclusion accompanied by upper arch expansion. After 15 months of orthodontic preparation, the patient underwent mandibular setback surgery. A period of orthodontic stabilization and finishing was undertaken during the three months post-surgery, with final debonding 24 months after the start of treatment. The esthetic and functional results were very satisfactory thanks to this collaboration between orthodontics and surgery. PMID- 26507301 TI - Decomposing Racial Disparities in Obesity Prevalence: Variations in Retail Food Environment. AB - INTRODUCTION: Racial disparities in obesity exist at the individual and community levels. Retail food environment has been hypothesized to be associated with racial disparities in obesity prevalence. This study aimed to quantify how much food environment measures explain racial disparities in obesity at the county level. METHODS: Data from 2009 to 2010 on 3,135 U.S. counties were extracted from the U.S. Department of Agriculture Food Environment Atlas and the Behavioral Risk Factor Surveillance System and analyzed in 2013. Oaxaca-Blinder decomposition was used to quantify the portion of the gap in adult obesity prevalence observed between counties with a high and low proportion of African-American residents is explained by food environment measures (e.g., proximity to grocery stores, per capita fast-food restaurants). Counties were considered to have a high African American population if the percentage of African-American residents was >13.1%, which represents the 2010 U.S. Census national estimate of percentage African American citizens. RESULTS: There were 665 counties (21%) classified as a high African-American county. The total gap in mean adult obesity prevalence between high and low African-American counties was found to be 3.35 percentage points (32.98% vs 29.63%). Retail food environment measures explained 13.81% of the gap in mean age-adjusted adult obesity prevalence. CONCLUSIONS: Retail food environment explains a proportion of the gap in adult obesity prevalence observed between counties with a high proportion of African-American residents and counties with a low proportion of African-American residents. PMID- 26507302 TI - Primary PCI is associated with different cardiac autonomic patterns in relation to the site of myocardial infarction. AB - AIM: Reflex alterations of cardiac autonomic modulation have been described after acute myocardial infarction (AMI). The non-homogeneous autonomic innervation of the heart gives reason of different patterns of autonomic modulation depending upon the site of AMI. Conflicting data are available on cardiac autonomic modifications after primary percutaneous coronary intervention (pPCI). We evaluated cardiac autonomic changes in patients with ST-elevation myocardial infarction (STEMI) after pPCI, either within 24h after revascularization (T0) and at clinical stability (T1, 6+/-2days), taking into account the site of infarction. METHODS AND RESULTS: We enrolled 33 consecutive patients with STEMI treated with pPCI (25 males, mean age 61+/-12.1yr); 15 had an anterior wall STEMI (ANT) and 18 had an inferior wall STEMI (INF). ECG and respiration were recorded at T0 and at T1. Cardiac autonomic modulation was evaluated by means of symbolic analysis of heart rate variability. At T0, At T0, 0V% (marker of sympathetic modulation) was higher in INF compared to ANT [31% (18-43) vs 18% (7-32), p=0.014]. Moreover, ANT had a higher 2LV%, index of vagal modulation, compared to INF [8% (7-15) vs 5% (2-8), p=0.006]. CONCLUSION: After pPCI, these preliminary results suggest that patients with INF were characterized by a sympathetic predominance, while ANT by a predominant vagal modulation. Our data suggest that pPCI can be associated with specific autonomic patterns, which are different for ANT and INF STEMI, according to the different autonomic innervation. Future ad hoc studies are needed to confirm these preliminary observations. PMID- 26507303 TI - Is diabetes mellitus a risk factor for venous thromboembolism? A systematic review and meta-analysis of case-control and cohort studies. AB - OBJECTIVE: Diabetes mellitus is a well-established risk factor for atherosclerotic disease, but its role in the occurrence of venous thromboembolism (VTE) has not been elucidated. We conducted a meta-analysis of published cohort and case-control studies to assess whether diabetes mellitus is a risk factor for VTE. RESEARCH DESIGN AND METHODS: We systematically searched MEDLINE and EMBASE for case-control and prospective cohort studies assessing association between the risk of venous thromboembolism and diabetes. Odds ratios (OR) from case-control studies were combined while for prospective studies hazard ratios (HR) were combined. Models with random effects were used. Meta-analyses were conducted separately for raw and adjusted measures of association. RESULTS: 24 studies were identified including 10 cohort studies (274,501 patients) and 14 case-control studies (1,157,086 patients). Meta-analysis of the prospective cohort studies demonstrated a significant association between diabetes and VTE (HR 1.60; 95% CI 1.35 to 1.89). This association was no longer present after analysis of multi adjusted HRs (HR 1.10; 95% CI 0.77 to 1.56). Meta-analysis of case-control studies showed a significant association between diabetes and VTE (OR 1.57; 95%CI 1.17 to 2.12), but this association was no longer present when adjusted ORs were used (OR 1.18; 95%CI 0.89 to 1.56). CONCLUSIONS: The increased risk of VTE associated with diabetes mainly results from confounders rather than an intrinsic effect of diabetes on venous thrombotic risk. Therefore, no specific recommendations should apply for the management of diabetic patients at risk for VTE. PMID- 26507304 TI - Vandenbroucke and Pearce respond to "incident and prevalent exposures and causal inference". PMID- 26507305 TI - Point: incident exposures, prevalent exposures, and causal inference: does limiting studies to persons who are followed from first exposure onward damage epidemiology? AB - The idea that epidemiologic studies should start from first exposure onward has been advocated in the past few years. The study of incident exposures is contrasted with studies of prevalent exposures in which follow-up may commence after first exposure. The former approach is seen as a hallmark of a good study and necessary for causal inference. We argue that studying incident exposures may be necessary in some situations, but it is not always necessary and is not the preferred option in many instances. Conducting a study involves decisions as to which person-time experience should be included. Although studies of prevalent exposures involve left truncation (missingness on the left), studies of incident exposures may involve right censoring (missingness on the right) and therefore may not be able to assess the long-term effects of exposure. These considerations have consequences for studies of dynamic (open) populations that involve a mixture of prevalent and incident exposures. We argue that studies with prevalent exposures will remain a necessity for epidemiology. The purpose of this paper is to restore the balance between the emphasis on first exposure cohorts and the richness of epidemiologic information obtained when studying prevalent exposures. PMID- 26507306 TI - Counterpoint: epidemiology to guide decision-making: moving away from practice free research. AB - Analyses of observational data aimed at supporting decision-making are ideally framed as a contrast between well-defined treatment strategies. These analyses compare individuals' outcomes from the start of the treatment strategies under consideration. Exceptions to this synchronizing of the start of follow-up and the treatment strategies may be justified on a case-by-case basis. PMID- 26507307 TI - Counterpoint: the treatment decision design. AB - The comparative new-user design is a principled approach to learning about the relative risks and benefits of starting different treatments in patients who have no history of use of the treatments being studied. Vandenbroucke and Pearce (Am J Epidemiol. 2015;182(10):826-833) discuss some problems inherent in incident exposure designs and argue that epidemiology may be harmed by a rigid requirement that follow-up can only begin at first exposure. In the present counterpoint article, a range of problems in pharmacoepidemiology that do not necessarily require that observation begin at first exposure are discussed. For example, among patients who are past or current users of a medication, we might want to know whether treatment should be augmented, switched, restarted, or discontinued. To answer these questions, a generalization of the new-user design, the treatment decision design, which identifies cohorts anchored at times when treatment decisions are being made, such as the evaluation of laboratory parameters, is discussed. The design aims to provide estimates that are directly relevant to physicians and patients, helping them to better understand the risks and benefits of the different treatment choices that they are considering. PMID- 26507308 TI - Active cancellation - A means to zero dead-time pulse EPR. AB - The necessary resonator employed in pulse electron paramagnetic resonance (EPR) rings after the excitation pulse and creates a finite detector dead-time that ultimately prevents the detection of signal from fast relaxing spin systems, hindering the application of pulse EPR to room temperature measurements of interesting chemical or biological systems. We employ a recently available high bandwidth arbitrary waveform generator (AWG) to produce a cancellation pulse that precisely destructively interferes with the resonant cavity ring-down. We find that we can faithfully detect EPR signal at all times immediately after, as well as during, the excitation pulse. This is a proof of concept study showcasing the capability of AWG pulses to precisely cancel out the resonator ring-down, and allow for the detection of EPR signal during the pulse itself, as well as the dead-time of the resonator. However, the applicability of this approach to conventional EPR experiments is not immediate, as it hinges on either (1) the availability of low-noise microwave sources and amplifiers to produce the necessary power for pulse EPR experiment or (2) the availability of very high conversion factor micro coil resonators that allow for pulse EPR experiments at modest microwave power. PMID- 26507309 TI - Lack of association between TDP-43 pathology and tau mis-splicing in Alzheimer's disease. AB - A proportion of Alzheimer's disease cases displays inclusions of the RNA-binding protein, TDP-43. Considering the pathogenic role of tau mis-splicing, we compared tau isoform expression between Alzheimer's disease cases with or without TDP-43 inclusions. The average ratio of tau isoforms containing or lacking exon 10 (4R/3R ratio) or the total level of tau mRNA was not significantly different between cases with or without TDP-43 pathology in any of the brain regions examined. Although TDP-43 functions may be affected, TDP-43 does not critically regulate expression or splicing of tau in Alzheimer's disease suggesting that TDP 43 contributes to Alzheimer's disease through mechanisms independent of tau. PMID- 26507310 TI - Evaluating pathogenic dementia variants in posterior cortical atrophy. AB - Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ~ 4300 European-American population controls from the NHLBI Exome Sequencing Project. We identified 2 rare variants not previously reported in PCA, TREM2 Arg47His, and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report 2 rare mutations in TREM2 and PSEN2, validate our previously reported APOE epsilon4 association, and demonstrate the utility of NeuroX. PMID- 26507311 TI - HDAC6 alleviates prion peptide-mediated neuronal death via modulating PI3K-Akt mTOR pathway. AB - Histone deacetylase 6 (HDAC6) controls several major cellular responses to stress that play a role in neurodegenerative diseases, including aggresome formation, autophagy, and apoptosis. However, the specific role of HDAC6 in prion diseases is not known. In this study, we examined the relationship between HDAC6 and cellular response to the neurotoxic synthetic prion protein fragment PrP106-126. We determined that exposure of cerebral cortical neurons to this fragment alters the expression and localization of HDAC6. Suppression of HDAC6 activity or knockdown of HDAC6 expression exacerbates the neuronal cell death induced by PrP106-126, but that overexpression of HDAC6 alleviates PrP106-126-induced neuronal death. We also found that this protective effect of HDAC6 involves the activation of autophagy and modulation of PI3K-Akt-mammalian target of rapamycin (mTOR) signaling. Overexpression of HDAC6 in neurons-induced autophagy correlated with a reduction in phosphorylated mTOR and phosphorylated p70S6K in response to PrP106-126 stimulation, conversely, HDAC6 deficiency interfered with autophagy and increased phosphorylated mTOR and phosphorylated 70S6K. In addition, HDAC6 also appears to modulate the phosphorylation of Akt; overexpression of HDAC6 increased the phosphorylated Akt, but HDAC6 deficiency resulted in further reduction of phosphorylated Akt. Overall, we demonstrate that HDAC6 protects neurons from toxicity of prion peptide, and that this protection occurs at through the regulation of the PI3k-Akt-mTOR axis. PMID- 26507312 TI - Effect of Heat-Inactivated Clostridium sporogenes and Its Conditioned Media on 3 Dimensional Colorectal Cancer Cell Models. AB - Traditional cancer treatments, such as chemotherapy and radiation therapy continue to have limited efficacy due to tumor hypoxia. While bacterial cancer therapy has the potential to overcome this problem, it comes with the risk of toxicity and infection. To circumvent these issues, this paper investigates the anti-tumor effects of non-viable bacterial derivatives of Clostridium sporogenes. These non-viable derivatives are heat-inactivated C. sporogenes bacteria (IB) and the secreted bacterial proteins in culture media, known as conditioned media (CM). In this project, the effects of IB and CM on CT26 and HCT116 colorectal cancer cells were examined on a 2-Dimensional (2D) and 3-Dimensional (3D) platform. IB significantly inhibited cell proliferation of CT26 to 6.3% of the control in 72 hours for the 2D monolayer culture. In the 3D spheroid culture, cell proliferation of HCT116 spheroids notably dropped to 26.2%. Similarly the CM also remarkably reduced the cell-proliferation of the CT26 cells to 2.4% and 20% in the 2D and 3D models, respectively. Interestingly the effect of boiled conditioned media (BCM) on the cells in the 3D model was less inhibitory than that of CM. Thus, the inhibitive effect of inactivated C. sporogenes and its conditioned media on colorectal cancer cells is established. PMID- 26507313 TI - The state of the fishery, conservation and management of the stalked barnacle Pollicipes pollicipes in Portugal. AB - The stalked barnacle Pollicipes pollicipes is the most important intertidal economical resource in Portugal. The assessment of the state of the fishery, conservation and management of P. pollicipes in Portugal was made for the first time in three regions with different regulations regarding this fishery: two marine protected areas ("Reserva Natural das Berlengas", RNB; and "Parque Natural do Sudoeste Alentejano e Costa Vicentina", PNSACV); and the Center coast. Different approaches (independent observations, inquiries, logbooks) and sources of data (past and recent) were used. An overall negative tendency of the state of the fishery and conservation of this resource was observed in all regions, with the exception of the stable tendency detected in PNSACV when using the inquiries approach. A weak management was considered to be in practice at Center and at PNSACV, while an acceptable management was inferred for RNB. We recommend a change into a co-management system that should be tested in pilot regions as RNB and/or PNSACV. PMID- 26507314 TI - High-Gain High-Field Fusion Plasma. AB - A Faraday wheel (FW)-an electric generator of constant electrical polarity that produces huge currents-could be implemented in an existing tokamak to study high gain high-field (HGHF) fusion plasma, such as the Experimental Advanced Superconducting Tokamak (EAST). HGHF plasma can be realized in EAST by updating its pulsed-power system to compress plasma in two steps by induction fields; high gains of the Lawson trinity parameter and fusion power are both predicted by formulating the HGHF plasma. Both gain rates are faster than the decrease rate of the plasma volume. The formulation is checked by earlier ATC tests. Good agreement between theory and tests indicates that scaling to over 10 T at EAST may be possible by two-step compressions with a compression ratio of the minor radius of up to 3. These results point to a quick new path of fusion plasma study, i.e., simulating the Sun by EAST. PMID- 26507315 TI - Association of dietary and serum vitamin E with bone mineral density in middle aged and elderly Chinese adults: a cross-sectional study. AB - Previous studies have suggested that vitamin E (VE) may affect bone health, but the findings have been inconclusive. We examined the relationship between VE status (in both diet and serum) and bone mineral density (BMD) among Chinese adults. This community-based study included 3203 adults (2178 women and 1025 men) aged 40-75 years from Guangzhou, People's Republic of China. General and dietary intake information were collected using structured questionnaire interviews. The serum alpha-tocopherol (TF) level was quantified by reversed-phase HPLC. The BMD of the whole body, the lumbar spine and left hip sites (total, neck, trochanter, intertrochanter and Ward's triangle) were measured using dual-energy X-ray absorptiometry. In women, the dietary intake of VE was significantly and positively associated with BMD at the lumbar spine, total hip, intertrochanter and femur neck sites after adjusting for covariates (P(trend): 0.001-0.017). Women in quartile 3 of VE intake typically had the highest BMD; the covariate adjusted mean BMD were 2.5, 3.06, 3.41 and 3.54% higher, respectively, in quartile 3 (v. 1) at the four above-mentioned sites. Similar positive associations were observed between cholesterol-adjusted serum alpha-TF levels and BMD at each of the studied bone sites (P(trend): 0.001-0.022). The covariate adjusted mean BMD were 1.24-4.83% greater in quartile 4 (v. 1) in women. However, no significant associations were seen between the VE levels (dietary or serum) and the BMD at any site in men. In conclusion, greater consumption and higher serum levels of VE are associated with greater BMD in Chinese women but not in Chinese men. PMID- 26507316 TI - The Rey Auditory Verbal Learning Test forced-choice recognition task: Base-rate data and norms. AB - The present study describes a novel Forced-Choice Response (FCR) index for detecting poor effort on the Rey Auditory Verbal Learning Test (RAVLT). This retrospective study analyzes the performance of 4 groups on the new index: clinically referred patients with suspected dementia, forensic patients identified as not exhibiting adequate effort on other measures of response bias, students who simulated poor effort, and a large normative sample collected in the Gulf State of Oman. Using sensitivity and specificity analyses, the study shows that much like the California Verbal Learning Test-Second Edition FCR index, the RAVLT FCR index misses a proportion of individuals with inadequate effort (low sensitivity), but those who fail this measure are highly likely to be exhibiting poor effort (high specificity). The limitations and benefits of utilizing the RAVLT FCR index in clinical practice are discussed. PMID- 26507317 TI - Knowledge of the anatomy and physiology of the spleen throughout Antiquity and the Early Middle Ages. AB - The evolution of knowledge regarding the anatomy and physiology of the spleen throughout Antiquity and the Early Middle Ages is described, and general perceptions about this organ during different eras along this time line are presented. The original words of great physicians from the period of time stretching from Ancient Egypt to the Avicennan era are quoted and discussed to demonstrate how knowledge of the spleen has evolved and to present the theories that dominated each era. Furthermore, theories about illnesses relating to the spleen are reported, which show how this organ was perceived-in terms of its function and anatomy-during each era. PMID- 26507318 TI - Can Palladium Acetate Lose Its "Saltiness"? Catalytic Activities of the Impurities in Palladium Acetate. AB - Commercially available palladium acetate often contains two major impurities, whose presence can impact the overall catalytic efficacy. This systematic study provides a comparison of the differences in catalytic activity of pure palladium acetate, Pd3(OAc)6, with the two impurities: Pd3(OAc)5(NO2) and polymeric [Pd(OAc)2]n in a variety of cross-coupling reactions. The solid state (13)C NMR spectra of all three compounds in conjunction with DFT calculations confirm their reported geometries. PMID- 26507319 TI - Single- versus Multiple-Pest Infestation Affects Differently the Biochemistry of Tomato (Solanum lycopersicum 'Ailsa Craig'). AB - Tomato is susceptible to pest infestations by both spider mites and aphids. The effects of each individual pest on plants are known, whereas multiple-pest infestations have received little interest. We studied the effects of single- versus multiple-pest infestation by Tetranychus urticae and Myzus persicae on tomato biochemistry (Solanum lycopersicum) by combining a metabolomic approach and analyses of carotenoids using UHPLC-ToF-MS and volatiles using GC-MS. Plants responded differently to aphids and mites after 3 weeks of infestation, and a multiple infestation induced a specific metabolite composition in plants. In addition, we showed that volatiles emissions differed between the adaxial and abaxial leaf epidermes and identified compounds emitted particularly in response to a multiple infestation (cyclohexadecane, dodecane, aromadendrene, and beta elemene). Finally, the carotenoid concentrations in leaves and stems were more affected by multiple than single infestations. Our study highlights and discusses the interplay of biotic stressors within the terpenoid metabolism. PMID- 26507320 TI - Letter to the Editor concerning "Systematic review of the effect of dynamic fixation systems compared with rigid fixation in the anterior cervical spine" by Campos RR, Botelho RV (Eur Spine J. 2014 Feb; 23(2):298-304). PMID- 26507321 TI - Letter to the Editor concerning "Risk factors for adjacent segment pathology requiring additional surgery after single-level spinal fusion: impact of pre existing spinal stenosis demonstrated by preoperative myelography" by I. Yugue et al. (2015) Eur Spine J Aug 14 [Epub ahead of print]. PMID- 26507322 TI - Answer to the Letter to the Editor of Yi Shen et al. concerning "Risk factors for adjacent segment pathology requiring additional surgery after single-level spinal fusion: impact of pre-existing spinal stenosis demonstrated by preoperative myelography" by I. Yugue et al. (2015) Eur Spine J Aug 14 doi:10.1007/s00586-015 4291-5. PMID- 26507323 TI - A validated preoperative score predicting survival and functional outcome in lung cancer patients operated with posterior decompression and stabilization for metastatic spinal cord compression. AB - PURPOSE: This study aims to create and validate a score for survival and functional outcome of lung cancer patients with metastatic spinal cord compression (MSCC) after posterior decompressive surgery. METHODS: The entire cohort of 73 consecutive patients was randomly assigned to a test group (N = 37) and a validation group (N = 36). In the test group, we retrospectively analyzed 10 preoperative characteristics. Characteristics significantly associated with survival on multivariate analysis were included in the score. Patients in the validation group were used to confirm whether the score was reproducible. Postoperative functional outcome was analyzed both in the test and validation groups. RESULTS: On multivariate analysis, preoperative ambulatory status (P = 0.0017), visceral metastases (P = 0.0002), and time developing motor deficits (P = 0.0004) had significant impact on survival and were included in the scoring system. According to the prognostic scores, which ranged from 0 to 6 points, two risk groups were designed: 0-2 and 3-6 points and the median survival was 2.6 months (95 % CI, 1.0-3.8 months) and 10.7 months (95 % CI, 7.1-13.7 months), respectively (P < 0.0001). In the validation group, the corresponding median survival was 2.7 months (95 % CI, 1.6-5.5 months) and 10.8 months (5.8-13.6 months), respectively (P < 0.0001). In addition, the functional outcome was worse in patients with 0-2 points than in patients with 3-6 points both in the test (P = 0.0023) and validation groups (P = 0.0298). CONCLUSION: Patients with scores of 0-2 points, who have short survival time (life expectancy less than 3 months) and poor functional outcome, appear best treated with radiotherapy or best supportive care alone. Surgery may be no longer in consideration in most of the patients in this group. Patients with score of 3-6 points should be surgical candidates, because survival prognosis (life expectancy more than 10 months) and functional outcome are favorable after surgery. PMID- 26507324 TI - Predicting the image noise level of prospective ECG-triggered coronary computed tomography angiography: quantitative measurement of thoracic component versus body mass index. AB - We evaluated the feasibility of using quantitatively measured thoracic components, as compared to body mass index (BMI), for predicting the image noise of coronary computed tomography angiography (CCTA). One hundred subjects (M:F = 64:36; mean age, 55 +/- 8.8 years) who underwent prospective electrocardiography gated CCTA and low-dose chest computed tomography (CT) were analyzed retrospectively. The image noise of the CCTA was determined by the standard deviation of the attenuation value in a region of interest on the aortic root level. On the low-dose chest CT, the areas of the thoracic components were measured at the aortic root level. An auto-segmentation technique with the following threshold levels was used: quantitatively measured area of total thorax [QMAtotal: -910 to 1000 Hounsfield units (HU)], lung (QMAlung: -910 to -200 HU), fat (QMAfat: -200 to 0 HU), muscle (QMAmuscle: 0-300 HU), soft tissue (fat + muscle, QMAsoft tissue: -200 to 300 HU), bone (QMAbone: 300-1000 HU) and solid tissue (fat + muscle + bone, QMAsolid tissue: -200 to 1000 HU). The relationship between image noise and variable biometric parameters including QMA was analyzed, and the linear correlation coefficients were used as indicators of the strength of association. Among the variable biometric parameters, including BMI, QMAsolid tissue showed the highest correlation coefficient with image noise in all subjects (r = 0.804), males (r = 0.716), females (r = 0.889), the overweight (r = 0.556), and the non-overweight subgroups (r = 0.783). QMAsolid tissue can be used as a potential surrogate predictor of the image noise level in low tube voltage CCTA. PMID- 26507325 TI - Greetings from President of ASCI. PMID- 26507326 TI - The impact of image resolution on computation of fractional flow reserve: coronary computed tomography angiography versus 3-dimensional quantitative coronary angiography. AB - Calculation of fractional flow reserve (FFR) based on computational fluid dynamics (CFD) requires reconstruction of patient-specific coronary geometry and estimation of hyperemic flow rate. Coronary computed tomography angiography (CCTA) and invasive coronary angiography (ICA) are two dominating imaging modalities used for the geometrical reconstruction. Our aim was to investigate the impact of image resolution as inherently associated with these two imaging modalities on geometrical reconstruction and subsequent FFR calculation. Patients with mild or intermediate coronary stenoses who underwent both CCTA and ICA were included. CCTA images were acquired either by 320-row area detector CT or by 128 slice dual-source CT. Two geometrical models were reconstructed separately from CCTA and ICA, from which FFRCTA and FFRQCA were subsequently calculated using CFD simulations, applying the same hyperemic flow rate derived from the ICA images at the inlet boundaries. A total of 57 vessels in 41 patients were analyzed. Average diameter stenosis was 43.4 +/- 10.8 % by 3D QCA. Reasonably good correlation between FFRCTA and FFRQCA was observed (r = 0.71, p < 0.001). The difference between FFRCTA and FFRQCA was correlated with the deviation between minimal lumen areas by CCTA and by ICA (rho = 0.34, p = 0.01), but not with plaque volume (rho = -0.09, p = 0.51) or calcified plaque volume (rho = 0.01, p = 0.95). Applying the cutoff value of <=0.8 to both FFRCTA and FFRQCA, the agreement between FFRCTA and FFRQCA in discriminating functional significant stenoses was moderate (kappa 0.47, p < 0.001). Disagreement was found in 10 (17.5 %) vessels. Acceptable correlation between FFRCTA and FFRQCA was observed, while their agreement in distinguishing functional significant stenosis was moderate. Our results suggest that image resolution has a significant impact on FFR computation. PMID- 26507327 TI - Label-Free and Sensitive Detection of Thrombomodulin, a Marker of Endothelial Cell Injury, Using Quartz Crystal Microbalance. AB - Thrombomodulin (TM), an integral glycoprotein on the surface of endothelial cells, can be released during endothelial cell injury and the levels of serum TM are regarded as an important parameter of activity in vasculitides in vivo. Quantitative detection of TM and investigation on the release of soluble thrombomodulin (sTM) by the injured HUVEC-C cells using quartz crystal microbalance (QCM) were achieved in this work. Anti-antibody (AAb) and bovine serum albumin (BSA) were bound on gold nanoparticles (GNPs) to construct BSA-GNPs AAb nanocomposites and they were characterized by transmission electron microscope, UV-vis, and infrared spectrophotometry, respectively. The capture of the nanocomposites on the TM antibody modified electrode, which was tested by scanning electron microscope, could result in a great decrease of the resonant frequency (f0). This binding was effectively inhibited by the beforehand immobilized TM proteins on the electrode surface due to the strong steric hindrance effect. It led to the decrease of the frequency changing extent. The relative frequency-shift was found to be proportional to the logarithm of the TM concentration from 10 to 5000 ng mL(-1) with a detection limit of 2 ng mL(-1). By analyzing the growth medium used for cell incubation, the release of sTM by the injured HUVEC-C cells in the presence of H2O2 was confirmed. The sTM amount in the growth medium was increased with the enhancement of contact time of the cells with H2O2, proving that sTM may serve as a specific marker of endothelial cell injury. PMID- 26507328 TI - Sensitive detection of cyanide using bovine serum albumin-stabilized cerium/gold nanoclusters. AB - A simple, sensitive, and selective fluorescence assay for the detection of CN(-) has been demonstrated using bovine serum albumin-stabilized cerium/gold nanoclusters (BSA-Ce/Au NCs). When excited at 325 nm, BSA-Ce/Au NCs have two fluorescence bands centered at 410 and 658 nm, which are assigned to BSA-Ce/Au complexes and Au NCs, respectively. Each BSA-Ce/Au NC contains 22 Au atoms and 8 Ce ions. Through etching of the Au core in BSA-Ce/Au NCs by CN(-), the fluorescence at 658 nm is quenched, while that at 410 nm enhances during the formation of complexes among BSA, Ce(4+), and [Au(CN)2](-). The circular dichroism spectra reveal that relative to BSA-Au NCs, BSA-Ce/Au NCs have looser structures of the BSA templates. As a result, it is easier for CN(-) to access the Au cores in BSA-Ce/Au NCs, allowing faster (within 15 min) etching of the Au cores by CN(-). At pH 12.0, this assay allows the detection of CN(-) down to 50 nM, with linearity over 0.1-15 MUM. This assay has been applied to the determination of the concentrations of CN(-) in spiked drinking water and pond water samples. PMID- 26507329 TI - Comparative study on occurrence characteristics of matrix water in static and gas double-dynamic solid-state fermentations using low-field NMR and MRI. AB - The water in a solid substrate is generally divided into three forms: hygroscopic, capillary, and free. However, there are few methods available for detecting the contents of different states of water in substrates. In this paper, low-field NMR and MRI were used to analyze the water occurrence characteristics of steam-exploded corn straw in solid-state fermentation (SSF). A significant linear relationship was found between the total NMR peak areas and the total water contents with a correlation coefficient of 0.993. It was further proved to be successful in comparing the contents and distributions of different states of water in static SSF and gas double-dynamic SSF (GDD-SSF). The results showed that among the three states of water, capillary water was the main form of water present and lost in substrates during fermentation. Total water and capillary water contents did not significantly differ as a result of different sample treatments, but hygroscopic water and free water contents in static SSF were respectively 0.38 and 2.98 times that in GDD-SSF with a packing height of 3 cm after fermentation. A relatively uniform water distribution and deep-depth region for microbial growth were found in GDD-SSF, suggesting that GDD-SSF was more suitable for industrialization. This technology has great potential for achieving efficient on-line water supply through water loss detection in SSF. PMID- 26507330 TI - Feather segmentation to discriminate between different enrofloxacin treatments in order to monitor off-label use in the poultry sector. AB - Antibiotics are commonly used in the poultry industry to treat bacterial infections. In the combat against bacterial resistance, policies require, besides a reduction of antibiotic usage in humans and animals, an up-to-date farmer registration mentioning all treatments. For enforcement of such policies, tests are needed to antedate administration and to determine the type of treatment so as to prevent off-label use and the supervacaneous use of last-resort antibiotics like cephalosporins and fluoroquinolones. After poultry treatment, high amounts of enrofloxacin and its metabolite ciprofloxacin are deposited in chicken feathers. A method is presented to discriminate different treatments based on differentiating extractable and non-extractable enrofloxacin and ciprofloxacin in chicken feathers. With this approach, we show it is possible to distinguish between a registered therapeutic oral treatment, an off-label spray treatment and an illegal prolonged sub-therapeutic treatment with enrofloxacin. This approach is a new and strong tool in the enforcement of new policies in the fight against off-label and supervacaneous antibiotic use. PMID- 26507331 TI - Physicochemical and toxicological evaluation of silica nanoparticles suitable for food and consumer products collected by following the EC recommendation. AB - Specific information about the particle size distribution, agglomeration state, morphology, and chemical composition of four silica samples, used as additives in food and in personal care products, were achieved with a combination of analytical techniques. The combined use of differential centrifugal sedimentation (DCS), sedimentation field flow fractionation (SdFFF), and scanning and transmission electron microscopy (SEM and TEM) allows to classify the water dispersed samples as "nanomaterials" according to the EC definition. The mechanical stirring and the ultrasound treatment were compared as dispersion methods. The particle surface chemical composition, determined by particle induced X-ray emission (PIXE) and X-ray photoelectron spectroscopy (XPS), assessed the different levels of purity between the pyrogenic and the precipitated silica and highlighted particle surface chemical composition modifications in the outer shell when dispersed by mechanical stirring. The potential toxic effects of silica on intestinal Caco-2 cells were investigated using MTS assay and by measuring lactate dehydrogenase (LDH) release and caspases 3/7 activity after 24 h of incubation. No or limited decrease of cell viability was observed for all particles regardless of dispersion procedure, suggesting a relative innocuity of these silica samples. PMID- 26507332 TI - A simple and fast method based on mixed hemimicelles coated magnetite nanoparticles for simultaneous extraction of acidic and basic pollutants. AB - One of the considerable and disputable areas in analytical chemistry is a single step simultaneous extraction of acidic and basic pollutants. In this research, a simple and fast coextraction of acidic and basic pollutants (with different polarities) with the aid of magnetic dispersive micro-solid phase extraction based on mixed hemimicelles assembly was introduced for the first time. Cetyltrimethylammonium bromide (CTAB)-coated Fe3O4 nanoparticles as an efficient sorbent was successfully applied to adsorb 4-nitrophenol and 4-chlorophenol as two acidic and chlorinated aromatic amines as basic model compounds. Using a central composite design methodology combined with desirability function approach, the optimal experimental conditions were evaluated. The opted conditions were pH = 10; concentration of CTAB = 0.86 mmol L(-1); sorbent amount = 55.5 mg; sorption time = 11.0 min; no salt addition to the sample, type, and volume of the eluent = 120 MUL methanol containing 5% acetic acid and 0.01 mol L( 1) HCl; and elution time = 1.0 min. Under the optimum conditions, detection limits and linear dynamic ranges were achieved in the range of 0.05-0.1 and 0.25 500 MUg L(-1), respectively. The percent of extraction recoveries and relative standard deviations (n = 5) were in the range of 71.4-98.0 and 4.5-6.5, respectively. The performance of the optimized method was certified by coextraction of other acidic and basic compounds. Ultimately, the applicability of the method was successfully confirmed by the extraction and determination of the target analytes in various water samples, and satisfactory results were obtained. PMID- 26507333 TI - Fourier transform infrared spectroscopy (FTIR) characterization of the interaction of anti-cancer photosensitizers with dendrimers. AB - The systemic or local administration of a photosensitizer for photodynamic therapy is highly limited by poor selectivity, rapid deactivation and long lasting skin toxicity due to unfavorable biodistribution. Drug delivery systems based on nanocarriers may help specific and effective delivery of photosensitizers. In the present paper, the interaction of two photosensitizers, methylene blue and rose bengal, with phosphorous cationic and anionic dendrimers as potential nanocarriers, has been characterized. A novel method is presented based on the analysis of the infrared spectra of mixtures of photosensitizer and dendrimer. The capacity of dendrimers to bind the photosensitizers has been evaluated by obtaining the corresponding binding curves. It is shown that methylene blue interacts with both cationic and anionic dendrimers, whereas rose bengal only binds to the cationic ones. Dendrimers are shown to be potential nanocarriers for a specific delivery of both photosensitizers. PMID- 26507334 TI - Cross-correlated relaxation measurements under adiabatic sweeps: determination of local order in proteins. AB - Adiabatically swept pulses were originally designed for the purpose of broadband spin inversion. Later, unexpected advantages of their utilization were also found in other applications, such as refocusing to excite spin echoes, studies of chemical exchange or fragment-based drug design. Here, we present new experiments to characterize fast (ps-ns) protein dynamics, which benefit from little-known properties of adiabatic pulses. We developed a strategy for measuring cross correlated cross-relaxation (CCCR) rates during adiabatic pulses. This experiment provides a linear combination of longitudinal and transverse CCCR rates, which is offset-independent across a typical amide (15)N spectrum. The pulse sequence can be recast to provide accurate transverse CCCR rates weighted by the populations of exchanging states. Sensitivity can be improved in systems in slow exchange. Finally, the experiments can be easily modified to yield residue-specific correlation times. The average correlation time of motions can be determined with a single experiment while at least two different experiments had to be recorded until now. PMID- 26507335 TI - Hemicellulosic Ethanol Production by Immobilized Wild Brazilian Yeast Scheffersomyces shehatae UFMG-HM 52.2: Effects of Cell Concentration and Stirring Rate. AB - The use of sugarcane bagasse hemicellulosic hydrolysates presents an interesting alternative to second generation (2G) ethanol production. Techniques to enhance the fermentation process, e.g., the use of immobilized cells, is one of the key factors for efficient production. Here, the effect of two important parameters (cell concentration in immobilized system and stirring rate) on the 2G ethanol production using the wild Brazilian yeast S. shehatae UFMG-HM 52.2 immobilized in calcium alginate matrix are presented. A 2(2) full factorial design of experiments was carried out to evaluate the effect of cell concentrations in sodium alginate solution for immobilized bead production (3.0, 6.0, and 9.0 g/L) and stirring rate (150, 200, and 250 rpm) for 2G ethanol production. Statistical analysis showed that the use of both variables at low levels enhanced ethanol yield (YP/S). Under these process conditions, YP/S of 0.31 g/g and ethanol productivity (Qp) of 0.12 g/L h were achieved. Results showed the potential of this immobilized yeast in 2G ethanol production from C5 sugars and demonstrate the importance of adequate cell concentration in immobilized systems, a finding that stands to increase bioprocesses yields and productivity. PMID- 26507336 TI - Effect of myo-inositol and melatonin versus myo-inositol, in a randomized controlled trial, for improving in vitro fertilization of patients with polycystic ovarian syndrome. AB - Polycystic ovarian syndrome (PCOS) induces anovulation in women of reproductive age, and is one of the pathological factors involved in the failure of in vitro fertilization (IVF). Indeed, PCOS women are characterized by poor quality oocytes. Therefore, a treatment for enhancing oocyte quality becomes crucial for these patients. Myo-Inositol and melatonin proved to be efficient predictors for positive IVF outcomes, correlating with high oocyte quality. We tested the synergistic effect of myo-inositol and melatonin in IVF protocols with PCOS patients in a randomized, controlled, double-blind trial. Five-hundred twenty-six PCOS women were divided into three groups: Controls (only folic acid: 400 mcg), Group A (Inofolic(r) plus, a daily dose of myo-inositol: 4000 mg, folic acid: 400 mcg, and melatonin: 3 mg), and Group B (Inofolic(r), a daily dose of myo inositol: 4000 mg, and folic acid: 400 mcg). The main outcome measures were oocyte and embryo quality, clinical pregnancy and implantation rates. The treatment lasted from the first day of the cycle until 14 days after embryo transfer. Myo-inositol and melatonin have shown to enhance, synergistically, oocyte and embryo quality. In consideration of the beneficial effect observed in our trial and on the bases of previous studies, we decided to integrate routinely MI and M supplementation in the IVF protocols. The same treatment should be taken carefully in consideration in all procedures of this kind. PMID- 26507337 TI - CORR Insights((r)): Are Patient-reported Outcome Measures in Orthopaedics Easily Read by Patients? PMID- 26507338 TI - Reamed Intramedullary Nailing has an Adverse Effect on Bone Regeneration During the Distraction Phase in Tibial Lengthening. AB - BACKGROUND: The lengthening over nail (LON) technique has gained popularity because it enables shorter periods of external fixation, prevents deformities during lengthening, and reduces the risk of refracture after removal of the frame compared with the classic Ilizarov method. However, it is not clear if the violation of endosteal blood supply by reamed intramedullary nailing in the LON technique has a negative effect on bone regeneration or a positive effect by compensatory enhancement of periosteal circulation. QUESTIONS/PURPOSES: The purposes of this study were to (1) compare the amount of regenerate bone during the distraction phase between two tibial lengthening techniques, the LON technique and lengthening and then nail (LATN) technique; and (2) compare callus shape at the end of the distraction phase using the classification of Li et al. METHODS: This is a retrospective study comparing two treatment groups. Between September 2011 and June 2013, 120 patients underwent bilateral lower leg lengthening for familial short stature with either the LON or LATN technique, and were considered potentially eligible for inclusion in this retrospective, comparative study. During this same period, LON and LATN techniques were used in other patient populations, but all patients with familial short stature were considered for inclusion in the study. The specific contraindications for LON were diameter of the isthmus of the tibia narrower than 8 mm, length of the tibia shorter than 270 mm, and alignment of the lower extremity in valgus; in patients without these specific contraindications to LON, patients were offered either LATN or LON after counseling regarding the advantages and disadvantages of each procedure. The proposed advantages of LATN were shorter healing index and more stable internal fixation which might lead to earlier full weightbearing, whereas proposed disadvantages were a greater chance for deep infection, more deformity during lengthening, and subsequently longer external fixator period for correction. The groups were comparable in terms of age, sex distribution, smoking history, BMI, distraction rate, and final length gain. A longer period of external fixation was necessary in the LATN group, related to the relative stability of the segment without an intramedullary nail. Patients with tibial lengthening with the LON technique (31 patients, 62 tibiae) were compared with patients who had the LATN technique (89 patients, 178 tibiae) regarding the amount of bone regeneration at the anterior, posterior, medial, and lateral cortices of the lengthened area for each at 4, 8, and 12 weeks postoperatively using a pixel value ratio method. In addition, both groups were compared for callus shape and type at the end of the distraction phase (LON, 3.4 +/- 0.06 months; LATN, 4.2 +/- 0.05 months). RESULTS: The pixel value ratios of the anterior, posterior, medial, and lateral cortices in the LON and LATN groups were 0.78 +/- 0.06 and 0.74 +/- 0.05; 0.82 +/- 0.08 and 0.76 +/- 0.05; 0.75 +/- 0.06 and 0.72 +/- 0.05; and 0.85 +/- 0.06 and 0.82 +/- 0.06, respectively at 4 weeks postoperatively(p value > 0.500 for all); 0.75 +/- 0.05 and 0.77 +/- 0.04; 0.78 +/- 0.05 and 0.89 +/- 0.04; 0.73 +/- 0.05 and 0.82 +/- 0.05; and 0.78 +/- 0.06 and 0.88 +/- 0.03, respectively at 8 weeks postoperatively (p value < 0.001 for the posterior, medial, and lateral cortices); 0.72 +/- 0.05 and 0.76 +/- 0.03; 0.75 +/- 0.07 and 0.89 +/- 0.03; 0.71 +/- 0.05 and 0.82 +/- 0.03; and 0.78 +/- 0.06 and 0.91 +/- 0.03, respectively at 12 weeks postoperatively (p value < 0.001 for the posterior, medial, and lateral cortices). A greater percentage of tibiae having the generally favored fusiform-shaped callus were seen with the LATN technique (61 of 178 segments) than with the LON technique (four of 62 segments; p < 0.001). There were no tibia showing the inferior concave, lateral, or central shaped callus with the LATN technique, whereas eight tibiae (eight of 62 segments) showed concave-shaped callus with the LON technique (p < 0.001). CONCLUSIONS: The potentially negative effect on callus regeneration from the concomitant use of reamed intramedullary nailing during the LON technique should not be overlooked. Based on our study, LATN may be a better choice for patients willing to accept the longer period of external fixation. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26507339 TI - Obituary: A Remembrance of Gordon Andrew Hunter (1937-2015). PMID- 26507341 TI - Energypolis: Chemistry for Energy. PMID- 26507340 TI - Mental health professionals' attitudes toward patients with PTSD and depression. AB - BACKGROUND: To date, mental health professionals' attitudes toward posttraumatic stress disorder (PTSD), compared to other psychiatric disorders such as schizophrenia or depression, have rarely been studied. OBJECTIVE: We assessed mental health professionals' attitudes toward patients with PTSD compared to patients suffering from depression. METHOD: Case vignettes of a patient with either PTSD or depression were presented to two samples of mental health professionals: attendees of a conference on posttraumatic stress (N=226) or of a lecture for psychiatry residents (N=112). Participants subsequently completed a questionnaire that assessed their attitude reactions to the presented case. RESULTS: Participants showed similarly positive attitudes toward depression and PTSD. PTSD elicited a more favorable attitude with regard to prosocial reactions, estimated dependency, attributed responsibility, and interest in the case, particularly in mental health professionals specializing in psychotraumatology. Across diagnoses, higher age and longer professional experience were associated with more positive attitudes toward patients. CONCLUSIONS: Mental health professionals' positive attitudes toward patients with depression and PTSD correlate with their specific knowledge about the disorder, their level of professional training, and their years of professional experience. LIMITATIONS: The instruments used, although based on established theoretical concepts in attitude research, were not validated in their present versions. PMID- 26507342 TI - Screening Materials Relevant for Energy Technologies. AB - In this short review, some recent advances are discussed in the development of computational techniques to perform large-scale screening of materials for energy related applications. We focus on carbon capture and methane storage in different classes of nanoporous materials. We show how these screening studies can identify whether economic targets for particular processes can be reached. PMID- 26507343 TI - Molecular Engineering of Functional Materials for Energy and Opto-Electronic Applications. AB - This review presents an overview of the dedicated research directions of the Group for Molecular Engineering of Functional Materials (GMF). This includes molecular engineering aspects of sensitizers constructed from ruthenium complexes, organic molecules, porphyrins and phthalocyanines. Manipulation of organometal trihalide perovskites, and charge transporting materials for high performance perovskite solar cells and photo-detectors are also described. Controlling phosphorescence color, and quantum yields in iridium complexes by tailoring ligands for organic light emitting diodes are demonstrated. Efficient reduction of CO(2) to CO using molecular catalyst on a protected Cu(2)O photocathode, and cost-effective water-splitting cell using a high efficiency perovskite solar cell are presented. PMID- 26507344 TI - Storage of Renewable Energy by Reduction of CO2 with Hydrogen. AB - The main difference between the past energy economy during the industrialization period which was mainly based on mining of fossil fuels, e.g. coal, oil and methane and the future energy economy based on renewable energy is the requirement for storage of the energy fluxes. Renewable energy, except biomass, appears in time- and location-dependent energy fluxes as heat or electricity upon conversion. Storage and transport of energy requires a high energy density and has to be realized in a closed materials cycle. The hydrogen cycle, i.e. production of hydrogen from water by renewable energy, storage and use of hydrogen in fuel cells, combustion engines or turbines, is a closed cycle. However, the hydrogen density in a storage system is limited to 20 mass% and 150 kg/m(3) which limits the energy density to about half of the energy density in fossil fuels. Introducing CO(2) into the cycle and storing hydrogen by the reduction of CO(2) to hydrocarbons allows renewable energy to be converted into synthetic fuels with the same energy density as fossil fuels. The resulting cycle is a closed cycle (CO(2) neutral) if CO(2) is extracted from the atmosphere. Today's technology allows CO(2) to be reduced either by the Sabatier reaction to methane, by the reversed water gas shift reaction to CO and further reduction of CO by the Fischer-Tropsch synthesis (FTS) to hydrocarbons or over methanol to gasoline. The overall process can only be realized on a very large scale, because the large number of by-products of FTS requires the use of a refinery. Therefore, a well-controlled reaction to a specific product is required for the efficient conversion of renewable energy (electricity) into an easy to store liquid hydrocarbon (fuel). In order to realize a closed hydrocarbon cycle the two major challenges are to extract CO(2) from the atmosphere close to the thermodynamic limit and to reduce CO(2) with hydrogen in a controlled reaction to a specific hydrocarbon. Nanomaterials with nanopores and the unique surface structures of metallic clusters offer new opportunities for the production of synthetic fuels. PMID- 26507345 TI - Surface Reactions are Crucial for Energy Storage. AB - Reactions between gas molecules, e.g. H2 and CO2 and solids take place at the surface. The electronic states and the local geometry of the atomic arrangement determine the energy of the adsorbate, i.e. the initial molecule and the transition state. Here we review our research to identify the surface species, their chemical state and orientation, the interaction with the neighbouring molecules and the mobility of the adsorbed species and complement the experimental results with thermodynamic modelling. The role of the Ti was found to be a bridge between the charged species preventing the individual movement of the ions including charge separation. The Ti has no catalytic effect on the hydrogen sorption reaction in borohydrides. The physisorption of molecular hydrogen is too weak at ambient temperature to reach a significant hydrogen storage density. The addition of a hydrogen dissociation catalyst to a nanoporous material with a large specific surface area may potentially enable the spillover of hydrogen atoms from the metal catalyst to the surface of the porous material and chemisorb on specific sites with a much higher binding energy compared to physisorption. The intercalation of alkali metals in C60 fullerenes increases the interaction energy of hydrogen with the so-called metal fullerides significantly. Sterical diffusion barriers by partial oxidation of the surface of borohydrides turned out to redirect the reaction path towards pure hydrogen desorption and suppress the formation of diborane, a by-product of the hydrogen evolution reaction from borohydrides previously undetected. The combination of a newly developed gas controlling system with microreactors allows us to investigate complex reactions with small quantities of nano designed new catalytic materials. Furthermore, tip-enhanced Raman spectroscopy (TERS) will allow the investigation of the reactions locally on the surface of the catalyst and the near ambient pressure photoelectron spectroscopy enables analysis of the surfaces in ultra high vacuum and in situ interaction with the adsorbates i.e. while the reaction takes place. This brings us in a unique position for the investigation of the heterogeneous reactive systems. The mechanism of the Ti catalysed hydrogen sorption reactions in alanates was recently established based on spectroscopic investigations combined with thermodynamic analysis of the transition states. PMID- 26507346 TI - Recent Advances in Carbon Capture with Metal-Organic Frameworks. AB - The escalating level of CO(2) in the atmosphere is one of the most critical environmental issues of our age. The carbon capture and storage from pilot test plants represents an option for reducing CO(2) emissions, however, the energy cost associated with post-combustion carbon capture process alone is ~30% of the total energy generated by the power plant. Thus, the generation of carbon capture adsorbents with high uptake capacities, great separation performance and low cost is of paramount importance. Metal-organic frameworks are infinite networks of metal-containing nodes bridged by organic ligands through coordination bonds into porous extended structures and several reports have revealed that they are ideal candidates for the selective capture of CO(2). In this review we summarize recent advances related to the synthesis of porous MOFs and the latest strategies to enhance the CO(2) adsorption enthalpies and capacities at low-pressures, increase hydrolytic and mechanical stabilities, and improve the ease of regeneration. Although they show great promise for post-combustion carbon capture, there are still major challenges that must be overcome before they can be used for such a large-scale application. PMID- 26507347 TI - Inkjet Printing Meets Electrochemical Energy Conversion. AB - Inkjet printing is a very powerful digital and mask-less microfabrication technique that has attracted the attention of several research groups working on electrochemical energy conversion concepts. In this short review, an overview is given about recent efforts to employ inkjet printing for the search of new electrocatalyst materials and for the preparation of catalyst layers for polymer electrolyte membrane fuel cell applications. Recent approaches of the Laboratory of Physical and Analytical Electrochemistry (LEPA) at the Ecole Polytechnique Federale de Lausanne for the inkjet printing of catalyst layers and membrane electrode assemblies are presented and future energy research directions of LEPA based on inkjet printing in the new Energypolis campus in the Canton of Valais are summarized. PMID- 26507348 TI - Analytical Chemistry at the Laboratoire d'Electrochimie Physique et Analytique. AB - The Laboratoire d'Electrochimie Physique et Analytique (LEPA) has moved to the new Energypolis campus in Sion. This laboratory is involved in energy research in particular by studying charge transfer reactions at soft interfaces and developing interfacial redox electrocatalysis, by pioneering the concept of photo ionic cells and by integrating redox flow batteries for the production of hydrogen at the pilot scale. Nonetheless, this laboratory has a long tradition in analytical chemistry with the development of microfabrication techniques such as laser photo-ablation, screen-printing and more recently inkjet printing for the design and fabrication of biosensors and immunosensors. As shown in the present review, the laboratory has recently pioneered new technologies for electrochemical and mass spectrometry imaging and for the screening of allergy in patients. The role of the laboratory in the Valais landscape will be to foster the collaboration with the HES to develop teaching and research in analytical chemistry as this field is a major source of employment for chemists. PMID- 26507349 TI - Novel Analytical Workflow for Comprehensive Non-targeted Phytochemical Metabolic Profiling. AB - The understanding and interpretation of pharmacological properties on a molecular level is of great importance for many different fields of research. Our study provides a novel model work-flow for comprehensive metabolic profiling by structural identification of relevant metabolites not limited to phytochemistry applications. High resolution liquid chromatography mass spectrometry LC-MS/MS data can be directly correlated with pharmacological test results on a molecular level. Thus the understanding and interpretation of pharmacological properties is supported by structural and chemical information. PMID- 26507350 TI - Recovering Valuable Phosphates: Chemical Biotechnology as a Problem Solver for the Environment. AB - Researchers from the HES-SO Valais/Wallis have demonstrated how to extract phosphate from sewage sludge on the laboratory scale using renewable energy sources from a microbial fuel cell. The mobilized phosphate barely contains heavy metals and can be used to produce fertilizer of marketable quality. The necessary energy comes from a sewage treatment plant and causes no additional costs. PMID- 26507351 TI - Biotech Meets Chemistry: Roche Invests in Customized Training. AB - In response to current needs, Roche is offering its employees an intensive course in biotechnology under the auspices of biotechnet Switzerland. Lecturers from ZHAW Wadenswil [university of applied science] give participants the benefit of their expertise in theory and laboratory practice. One valuable spin-off from this is that this extra-mural course will allow participants to create a permanent network. PMID- 26507356 TI - Obesity-related behaviours and BMI in five urban regions across Europe: sampling design and results from the SPOTLIGHT cross-sectional survey. AB - OBJECTIVES: To describe the design, methods and first results of a survey on obesity-related behaviours and body mass index (BMI) in adults living in neighbourhoods from five urban regions across Europe. DESIGN: A cross-sectional observational study in the framework of an European Union-funded project on obesogenic environments (SPOTLIGHT). SETTING: 60 urban neighbourhoods (12 per country) were randomly selected in large urban zones in Belgium, France, Hungary, the Netherlands and the UK, based on high or low values for median household income (socioeconomic status, SES) and residential area density. PARTICIPANTS: A total of 6037 adults (mean age 52 years, 56% female) participated in the online survey. OUTCOME MEASURES: Self-reported physical activity, sedentary behaviours, dietary habits and BMI. Other measures included general health; barriers and motivations for a healthy lifestyle, perceived social and physical environmental characteristics; the availability of transport modes and their use to specific destinations; self-defined neighbourhood boundaries and items related to residential selection. RESULTS: Across five countries, residents from low-SES neighbourhoods ate less fruit and vegetables, drank more sugary drinks and had a consistently higher BMI. SES differences in sedentary behaviours were observed in France, with residents from higher SES neighbourhoods reporting to sit more. Residents from low-density neighbourhoods were less physically active than those from high-density neighbourhoods; during leisure time and (most pronounced) for transport (except for Belgium). BMI differences by residential density were inconsistent across all countries. CONCLUSIONS: The SPOTLIGHT survey provides an original approach for investigating relations between environmental characteristics, obesity-related behaviours and obesity in Europe. First descriptive results indicate considerable differences in health behaviours and BMI between countries and neighbourhood types. PMID- 26507355 TI - Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update. AB - Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ~27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2). PMID- 26507357 TI - Safety and efficacy of ruxolitinib in myelofibrosis patients without splenomegaly. PMID- 26507358 TI - It's important to see death and dying in a broad cultural context. PMID- 26507359 TI - Toward improved effectiveness of bladder cancer immunotherapy. PMID- 26507361 TI - Selective spectroscopic imaging of hyperpolarized pyruvate and its metabolites using a single-echo variable phase advance method in balanced SSFP. AB - PURPOSE: In balanced steady state free precession (bSSFP), the signal intensity has a well-known dependence on the off-resonance frequency, or, equivalently, the phase advance between successive radiofrequency (RF) pulses. The signal profile can be used to resolve the contributions from the spectrally separated metabolites. This work describes a method based on use of a variable RF phase advance to acquire spatial and spectral data in a time-efficient manner for hyperpolarized 13C MRI. THEORY AND METHODS: The technique relies on the frequency response from a bSSFP acquisition to acquire relatively rapid, high-resolution images that may be reconstructed to separate contributions from different metabolites. The ability to produce images from spectrally separated metabolites was demonstrated in vitro, as well as in vivo following administration of hyperpolarized 1-13C pyruvate in mice with xenograft tumors. RESULTS: In vivo images of pyruvate, alanine, pyruvate hydrate, and lactate were reconstructed from four images acquired in 2 s with an in-plane resolution of 1.25 * 1.25 mm(2) and 5 mm slice thickness. CONCLUSION: The phase advance method allowed acquisition of spectroscopically selective images with high spatial and temporal resolution. This method provides an alternative approach to hyperpolarized 13C spectroscopic MRI that can be combined with other techniques such as multiecho or fluctuating equilibrium bSSFP. Magn Reson Med 76:1102-1115, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26507362 TI - Detection of CD28/CD86 co-stimulatory molecules and surface properties of T and dendritic cells: An AFM study. AB - Although the importance of B7/CD28 co-stimulation has been widely studied, little is known about their nano-spatial localization and their corresponding cells' biophysical and biomechanical properties. Here, we investigated the morphological, biophysical, and biomechanical properties of T cells and dendritic cells (DCs) by atomic force microscopy (AFM) and force curves. The nano-spatial distribution of CD28 and CD86 antigen on T cells and DCs was detected by CD86 or CD28 antibody-functionalized AFM tip. Single-molecule force spectroscopy (SMFS) based force volumes and quantum dots (QDs)-based fluorescence imaging demonstrated that the co-stimulatory molecules were not randomly distributed over the cells' surface, but more than 80% of CD28 and CD86 molecules appeared to be expressed as 100-200 nm nanoclusters and polarize dominantly in the peak of the cell membrane fluctuations. AFM imaging and quantitative analysis showed that the roughness of mature DCs (mDCs) was higher than that of immature DCs (iDCs). The adhesion force distribution of iDCs and mDCs was heterogeneous while the elasticity distribution was homogeneous locally. In addition, mDCs had a fourfold increase of Young's modulus of iDCs, indicating the contribution of the actin cytoskeleton to the elastic properties of the cells. Taken together, the nano cluster distribution of CD28 and CD86, the rough mDCs surface, the higher adhesion force and elasticity of mDCs may facilitate to the occurrence of B7/CD28 co-stimulation signals and the formation of immune synapse. These nanoscale findings provide new insights into the antigen-presenting function of DCs, the T cell activation and ultimate immune response. SCANNING 38:365-375, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26507363 TI - Right lateral mini-thoracotomy for mitral valve surgery. AB - Since the 1990 s, minimally invasive cardiac surgery has gained wide acceptance due to patient and economic demand. The advantages are less trauma, less bleeding, less wound infections, less pain and faster recovery. Many studies showed that the outcomes are comparable with those of conventional sternotomy. Right lateral mini-thoracotomy evolved into a routine and safe access in specialized centres for minimally invasive mitral valve surgery. The 6-cm incision is performed over the fifth intercostal space in the inframammary groove. With a double-lumen tube, the right lung is deflated before entering the pleural cavity. A soft tissue retractor is used to minimize rib spreading. The stab incisions for the endoscopic camera and the transthoracic clamp are performed in the right anterior and posterior axillary line in the third intercostal space. Surgery on the mitral valve is performed in a standard fashion under a direct vision with video assistance. One chest tube is inserted. The intercostal space is adapted with braided sutures to prevent lung herniation. Ropivacaine is used for local infiltration. The pectoral muscle, subcutaneous tissue and skin are adapted with running sutures. Complications of a right lateral mini-thoracotomy are rare (conversion to sternotomy, rethoracotomy, phrenic nerve palsy, wound infection and thoracic wall hernia) and well manageable. PMID- 26507364 TI - Putative zeatin O-glucosyltransferase OscZOG1 regulates root and shoot development and formation of agronomic traits in rice. AB - As a ubiquitous reaction, glucosylation controls the bioactivity of cytokinins in plant growth and development. Here we show that genetic manipulation of zeatin-O glucosylation regulates the formation of important agronomic traits in rice by manipulating the expression of OscZOG1 gene, encoding a putative zeatin O glucosyltransferase. We found that OscZOG1 was preferentially expressed in shoot and root meristematic tissues and nascent organs. The growth of lateral roots was stimulated in the overexpression lines, but inhibited in RNA interference lines. In shoots, knockdown of OscZOG1 expression by RNA interference significantly improved tillering, panicle branching, grain number per panicle and seed size, which are important agronomic traits for grain yield. In contrast, constitutive expression of OscZOG1 leads to negative effects on the formation of the grain yielding traits with a marked increase in the accumulation levels of cis-zeatin O glucoside (cZOG) in the transgenic rice plants. In this study, our findings demonstrate the feasibility of improving the critical yield-determinant agronomic traits, including tiller number, panicle branches, total grain number per panicle and grain weight by downregulating the expression level of OscZOG1. Our results suggest that modulating the levels of cytokinin glucosylation can function as a fine-tuning switch in regulating the formation of agronomic traits in rice. PMID- 26507366 TI - Efficient disruption and replacement of an effector gene in the oomycete Phytophthora sojae using CRISPR/Cas9. AB - Phytophthora sojae is an oomycete pathogen of soybean. As a result of its economic importance, P. sojae has become a model for the study of oomycete genetics, physiology and pathology. The lack of efficient techniques for targeted mutagenesis and gene replacement have long hampered genetic studies of pathogenicity in Phytophthora species. Here, we describe a CRISPR/Cas9 system enabling rapid and efficient genome editing in P. sojae. Using the RXLR effector gene Avr4/6 as a target, we observed that, in the absence of a homologous template, the repair of Cas9-induced DNA double-strand breaks (DSBs) in P. sojae was mediated by non-homologous end-joining (NHEJ), primarily resulting in short indels. Most mutants were homozygous, presumably as a result of gene conversion triggered by Cas9-mediated cleavage of non-mutant alleles. When donor DNA was present, homology-directed repair (HDR) was observed, which resulted in the replacement of Avr4/6 with the NPT II gene. By testing the specific virulence of several NHEJ mutants and HDR-mediated gene replacements in soybean, we have validated the contribution of Avr4/6 to recognition by soybean R gene loci, Rps4 and Rps6, but also uncovered additional contributions to resistance by these two loci. Our results establish a powerful tool for the study of functional genomics in Phytophthora, which provides new avenues for better control of this pathogen. PMID- 26507365 TI - Dimeric bis (heptyl)-Cognitin Blocks Alzheimer's beta-Amyloid Neurotoxicity Via the Inhibition of Abeta Fibrils Formation and Disaggregation of Preformed Fibrils. AB - AIMS: Fibrillar aggregates of beta-amyloid protein (Abeta) are the main constituent of senile plaques and considered to be one of the causative events in the pathogenesis of Alzheimer's disease (AD). Compounds that could inhibit Abeta fibrils formation, disaggregate preformed Abeta fibrils as well as reduce their associated neurotoxicity might have therapeutic values for treating AD. In this study, the inhibitory effects of bis (heptyl)-cognitin (B7C), a multifunctional dimer derived from tacrine, on aggregation and neurotoxicity of Abeta1-40 were evaluated both in vitro and in vivo. METHODS: Thioflavin T fluorescence assay was carried out to evaluate Abeta aggregation, MTT and Hoechst-staining assays were performed to investigate Abeta-associated neurotoxicity. Fluorescent probe DCFH DA was used to estimate the accumulation of intracellular reactive oxygen stress (ROS). Morris water maze was applied to determine learning and memory deficits induced by intracerebroventricular infusion of Abeta in rats. RESULTS: B7C (0.1 10 MUM), but not tacrine, effectively inhibited Abeta fibrils formation and disaggregated preformed Abeta fibrils following co-incubation of B7C and Abeta monomers or preformed fibrils, respectively. In addition, B7C markedly reduced Abeta fibrils-associated neurotoxicity in SH-SY5Y cell line, as evidenced by the increase in cell survival, the decrease in Hoechst-stained nuclei and in intracellular ROS. Most encouragingly, B7C (0.1 and 0.2 mg/kg), 10 times more potently than tacrine (1 and 2 mg/kg), inhibited memory impairments after intracerebroventricular infusion of Abeta in rats, as evidenced by the decrease in escape latency and the increase in the spatial bias in Morris water maze test along with upregulation of choline acetyltransferase activity and downregulation of acetylcholinesterase activity. CONCLUSION: These findings provide not only novel molecular insight into the potential application of B7C in treating AD, but also an effective approach for screening anti-AD agents. PMID- 26507367 TI - Prognosis of 234 rosacea patients according to clinical subtype: The significance of central facial erythema in the prognosis of rosacea. AB - Rosacea has a wide spectrum of clinical features, which include persistent facial redness, flushing, telangiectasia, inflammatory papules/pustules, hypertrophy and/or ocular features. The prognosis of rosacea according to clinical subtype has not been evaluated. We analyzed the prognosis of rosacea in 234 patients, which included 120 patients with mixed subtype, 75 with the erythematotelangiectatic rosacea subtype and 39 with the papulopustular rosacea (PPR) subtype. The prognosis of rosacea was classified as: (i) no improvement; (ii) partial remission; and (iii) complete remission. The frequencies of complete remission, time to complete remission and 1-year complete remission rate were compared between subtypes. Follow-up periods ranged 2-72 months (median follow up, 17.5). Aggravation of the disease was found in 50.4% of patients during follow up. Partial or complete remission was noted in 61.5% and 20.9% of patients, respectively. The median time to complete remission was 56.0 months. The prognosis of disease was more favorable for patients with the PPR subtype than for patients with other subtypes with respect to the frequency of complete remission, median time to complete remission and the 2-year complete remission rate. In conclusion, papulopustular rosacea without remarkable centrofacial erythema showed a more favorable prognosis than other subtypes. Erythematotelangiectatic lesions in rosacea patients present a challenge for the treatment of rosacea. PMID- 26507368 TI - A systematic review of health service interventions to reduce use of unplanned health care in rural areas. AB - RATIONALE, AIMS AND OBJECTIVES: Use of unplanned health care has long been increasing, and not enough is known about which interventions may reduce use. We aimed to review the effectiveness of interventions to reduce the use of unplanned health care by rural populations. METHODS: The method used was systematic review. Scientific databases (Medline, Embase and Central), grey literature and selected references were searched. Study quality and bias was assessed using Cochrane Risk of Bias and modified Newcastle Ottawa Scales. Results were summarized narratively. RESULTS: A total of 2708 scientific articles, reports and other documents were found. After screening, 33 studies met the eligibility criteria, of which eight were randomized controlled trials, 13 were observational studies of unplanned care use before and after new practices were implemented and 12 compared intervention patients with non-randomized control patients. Eight of the 33 studies reported modest statistically significant reductions in unplanned emergency care use while two reported statistically significant increases in unplanned care. Reductions were associated with preventative medicine, telemedicine and targeting chronic illnesses. Cost savings were also reported for some interventions. CONCLUSION: Relatively few studies report on unscheduled medical care by specifically rural populations, and interventions were associated with modest reductions in unplanned care use. Future research should evaluate interventions more robustly and more clearly report the results. PMID- 26507369 TI - Development and usability testing of a web-based self-management intervention for oral cancer survivors and their family caregivers. AB - Oral cancer (OC) survivors experience debilitating side effects that affect their quality of life (QOL) and that of their caregivers. This study aimed to develop and evaluate a dyadic, web-based intervention to improve survivor self-management and survivor/caregiver QOL. A qualitative needs assessment (semi-structured interviews) with 13 OC survivors and 12 caregivers was conducted to discern information and support needs as well as preferences regarding website features and tools. Results using Grounded Theory analysis showed that OC survivors and caregivers: (1) want and need practical advice about managing side effects; (2) want to reach out to other survivors/caregivers for information and support; and (3) have both overlapping and unique needs and preferences regarding website features. Usability testing (N = 6 survivors; 5 caregivers) uncovered problems with the intuitiveness, navigation and design of the website that were subsequently addressed. Users rated the website favourably on the dimensions of attractiveness, controllability, efficiency, intuitiveness and learnability, and gave it a total usability score of 80/100. Overall, this study demonstrates that OC survivors and caregivers are interested in using an online programme to improve QOL, and that providing tailored website content and features based on the person's role as survivor or caregiver is important in this population. PMID- 26507370 TI - Evaluation of Pseudoenantiomeric Mixed Carbonates as Efficient Fluorogenic Probes for Enantioselectivity Screening. AB - We report mixed carbonates as enzyme substrates and demonstrate their application as fluorogenic probes for lipase and esterase enantiopreference screening. By the application of pseudoenantiomers with distinct fluorescence behaviors, it is possible to evaluate the activity and enantiopreference of hydrolytic enzymes. In order to validate our method, enantioselectivities calculated from fluorometric measurements were compared with the results obtained from larger-scale kinetic resolution. PMID- 26507371 TI - Circumstances and causes of fatal cycling crashes in the Czech Republic. AB - OBJECTIVES: The circumstances and causes of death of 129 cyclists registered in the Olomouc and the Zlin regions, the Czech Republic, between 2005 and 2013 were the subject of this study. METHODS: We analyzed the autopsy reports, where the principal cause of death was stated, and obtained a detailed description of the circumstances recorded by the police officers. RESULTS: Eighty-three cases (64.3% of the set) were collisions involving a motor vehicle. The driver was the guilty party in 57 cases (68.7%) and the cyclist in the remaining 26 cases (31.3%). The most frequent cause of the crash was connected with right of way (29 cases). Cars were involved in 52 cases; heavy vehicles, including buses, in 26 cases; and motorcycles in 5 cases. Single-vehicle crashes consisted of 43 (33.3%) cases. We divided this group into 3 subgroups based on whether the particular case could be attributed to a cyclist having lost control of the bicycle (31 cases) or to other particular causes. Sixty-eight cases (52.7%) of fatal outcomes were directly linked to intracranial injuries. Multiple injuries were the principal cause of death in 19 cases (14.7%), followed by hemorrhagic traumatic shock (12 cases, 9.3%). Seventy-two (55.8%) cyclists died immediately after the crash and 23 (17.8%) cyclists died within a day of the accident. CONCLUSIONS: Trucks were more dangerous to cyclists than cars at intersections, whereas cars were more dangerous on straight sections. The most important pattern was identified as a motor vehicle hitting a cyclist from behind on a straight road section. We identified a strong underestimation of natural death as a cause of cycling fatalities in the official police reports. PMID- 26507374 TI - Interrupting Rivaling Access-flow with Nonsurgical Image-guided ligation: the "IRANI" Procedure. AB - The presence of collateral veins is one of the most common causes of fistula failure to mature. The traditional approach to eliminate collateral vessel flow is coil embolization under fluoroscopy or surgical cut down and branch vessel ligation. However, both approaches are expensive and time consuming. Here, we described an image-guided nonsurgical method to ligate collateral veins. The collateral veins were ligated using Hawkins-Akins needle under ultrasound guidance. The average time for one ligation procedure was 17 minutes. There was a significant increase of blood flow in the venous outflow postligation procedure. Four weeks postprocedure ultrasound demonstrated occlusion of the target vessels. This procedure was well tolerated without major complications. In summary, the novel procedure described here offers an image-guided nonsurgical approach for collateral vein occlusion. PMID- 26507375 TI - Chronically Occluded Arteriovenous Fistula Salvaged by Sharp Needle Recanalization. AB - Salvage of a failed arteriovenous access with occlusion of the venous outflow and no alternative for a secondary arteriovenous fistula that would provide for immediate dialysis is a difficult problem for which there is no ideal solution. The present report is such a patient. The patient had a radial-cephalic fistula represented by only a very short segment, inadequate for effective dialysis. Salvage was accomplished using the sharp needle revascularization technique in order to avoid a prolonged period of central venous catheter use. PMID- 26507376 TI - Clinical Importance of Intraoperative Cephalic Vein Distensibility as a Predictor of Radiocephalic Arteriovenous Fistula Maturation. AB - Radiocephalic arteriovenous fistula (RCAVF) is the preferred vascular access, but the maturation failure rate is high. Poor vein distensibility is the main cause of maturation failure. There have been several studies regarding vein distensibility, but vein dilation protocol and the cut-off value predicting maturation failure were inconsistent. We were doubtful that the vein distensibility had been appropriately evaluated, and sought to determine a more clinically applicable parameter. The cephalic vein was dilated via intraluminal hydrostatic pressure during the surgery and the vein size was measured. Maturation failure occurred in 30 patients (22.4%) and was more common in females and in patients who had a previous history of arteriovenous access formation (p = 0.0095 and p = 0.014). The intraoperative postdilation diameter, and the difference between pre and postdilation diameters differed between the two groups (p = 0.0004 and p = 0.0004). The cut-off value of the postdilation diameter, which indicated a high probability of maturation success, was >4 mm, and the cut off value which indicated a higher probability of maturation failure; that is, the difference between the pre and postdilation diameter, was <=2.2 mm. The degree of distensibility of the cephalic vein may be an important determinant of RCAVF maturation. PMID- 26507377 TI - Lysine-acetylation as a fundamental regulator of Ran function: Implications for signaling of proteins of the Ras-superfamily. AB - The small GTP-binding protein Ran is involved in the regulation of essential cellular processes in interphase but also in mitotic cells: Ran controls the nucleocytoplasmic transport of proteins and RNA, it regulates mitotic spindle formation and nuclear envelope assembly. Deregulations in Ran dependent processes were implicated in the development of severe diseases such as cancer and neurodegenerative disorders. To understand how Ran-function is regulated is therefore of highest importance. Recently, several lysine-acetylation sites in Ran were identified by quantitative mass-spectrometry, some being located in highly important regions such as the P-loop, switch I, switch II and the G5/SAK motif. We recently reported that lysine-acetylation regulates nearly all aspects of Ran-function such as RCC1 catalyzed nucleotide exchange, intrinsic nucleotide hydrolysis, its interaction with NTF2 and the formation of import- and export complexes. As a hint for its biological importance, we identified Ran-specific lysine-deacetylases (KDACs) and -acetyltransferases (KATs). Also for other small GTPases such as Ras, Rho, Cdc42, and for many effectors and regulators thereof, lysine-acetylation sites were discovered. However, the functional impact of lysine-acetylation as a regulator of protein function has only been marginally investigated so far. We will discuss recent findings of lysine-acetylation as a novel modification to regulate Ras-protein signaling. PMID- 26507378 TI - [The Roots of Idiographic Paleontology: Karl Alfred von Zittel's Methodology and Conception of the Fossil Record]. AB - This paper examines Karl Alfred von Zittel's practice in order to uncover the roots of so-called idiographic paleontology.The great American paleontologist Stephen Jay Gould (1941-2002) defined the discipline of idiographic paleontology as illustration and description of the morphological features of extinct species. However, this approach does not investigate macroevolutionary patterns and processes. On the contrary, the paleobiological revolution of the 1970s implemented an epistemic methodology that illustrates macrovelutionary patterns and laws by combining idiographic data with a nomothetic form of explanation. This article elucidates the features of the idiographic data as well as the acquired knowledge coupled with this approach. First of all, Heinrich G. Bronn's (1800-1862) statistical method is analyzed. Zittel's practice arose as a reaction against the approximate conclusions reached by Bronn's quantitative approach. Second, the details of Zittel's methodology are described in order to bring out its peculiarities.The microscope played a pivotal role in creating and forming Zittel's morphological data. This analysis sheds new light on the reasons behind the so-called ideographic paleontology, thus revising Gould's historical reconstruction, as well as on the notion of paleontological data. However, even though Zittel aimed at reaching precise and stable conclusions,his data cannot be used for elucidating evolutionary mechanisms: they are scientific in a purely descriptive sense, but completely useless for biological investigations. Finally, this paper examines how Zittel's methodology affects the contemporary paleobiological enterprise and thereby reflects upon the notion of natural history. PMID- 26507379 TI - [Physicians as Experts of the Integration of war invalids of WWI and WWII]. AB - After the First World War the large number of war invalids posed a medical as well as a socio-political problem. This needed to be addressed, at least to some extent, through healthcare providers (Versorgungsbehorden) and reintegration into the labour market. Due to the demilitarization of Germany, this task was taken on by the civil administration, which was dissolved during the time of National Socialism. In 1950, the Federal Republic of Germany enacted the Federal War Victims Relief Act (Bundesversorgungsgesetz), which created a privileged group of civil and military war invalids, whereas other disabled people and victims of national socialist persecution were initially excluded. This article examines the continuities and discontinuities of the institutions following the First World War. A particular focus lies on the groups of doctors which structured this field. How did doctors become experts and what was their expertise? PMID- 26507380 TI - Rhenium(V)-oxo corrolazines: isolating redox-active ligand reactivity. AB - The synthesis of the first example of a third-row metallocorrolazine characterized by single crystal X-ray diffraction is reported. This Re(V)(O) porphyrinoid complex shows an exclusively ligand-based reactivity with strong acids and oxidizing agents. The one-electron oxidized pi-radical-cation complex is capable of H-atom abstraction. PMID- 26507381 TI - The effect of alendronate on biomineralization at the bone/implant interface. AB - A recent approach to improve the osseointegration of implants is to utilize local drug administration. The presence of an osteoporosis drug may influence both bone quantity and quality at the bone/implant interface. Despite this, the performance of bone-anchoring implants is traditionally evaluated only by quantitative measurements. In the present study, the osteoporosis drug alendronate (ALN) was administrated from mesoporous titania thin films that were coated onto titanium implants. The effect that the drug had on biomineralization was explored both in vitro using simulated body fluid (SBF) and in vivo in a rat tibia model. The SBF study showed that the apatite formation was completely hindered at a high concentration of ALN (0.1 mg/mL). However, when ALN was administrated from the mesoporous coating the surface became completely covered with apatite. Ex vivo characterization of the bone/implant interface using Raman spectroscopy demonstrated that the presence of ALN enhanced the bone mineralization, and that the chemical signature of newly formed bone in the presence of ALN had a higher resemblance to the pre-existing mature bone than to the bone formed without drug. Taken together, this study demonstrates the importance of evaluating the quality of the formed bone to better understand the performance of implants. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A 104A: 620-629, 2016. PMID- 26507382 TI - Fenton's treatment as an effective treatment for elderberry effluents: economical evaluation. AB - The utilization of Fenton's oxidation for the depuration of elderberry juice wastewater was studied. The aim was to select the adequate cost-effective operating conditions suitable to lead to an effluent within the legal thresholds to be discharged into the natural water courses. The treatment efficacy was assessed by chemical oxygen demand (COD), colour, phenolic content and total solids removal besides its ability to improve biodegradability (biochemical oxygen demand (BOD5)/COD). Moreover, the costs of the applied reactants were also considered. Fenton's reaction was able to abate at least 70% of COD (corresponding to a final value below 150 mg O2 L(-1)). Besides, total phenolic content degradation was always achieved. Within these conditions, the resulting effluent is able to be directly discharged into the natural hydric channels. Fenton oxidation could be successfully applied as a single treatment method with a reactant cost of 4.38 ? m(-3) ([Fe(2+)] = 20 mmol L(-1), [H2O2] = 100 mmol L( 1), pH = 3 and 4 h of oxidation procedure). PMID- 26507383 TI - Psychometric properties of a revised version of the Assisting Hand Assessment (Kids-AHA 5.0). AB - AIM: The aim of this study was to scrutinize the Assisting Hand Assessment (AHA) version 4.4 for possible improvements and to evaluate the psychometric properties regarding internal scale validity and aspects of reliability of a revised version of the AHA. METHOD: In collaboration with experts, scoring criteria were changed for four items, and one fully new item was constructed. Twenty-two original, one new, and four revised items were scored for 164 assessments of children with unilateral cerebral palsy aged 18 months to 12 years. Rasch measurement analysis was used to evaluate internal scale validity by exploring rating-scale functioning, item and person goodness-of-fit, and principal component analysis. Targeting and scale reliability were also evaluated. RESULTS: After removal of misfitting items, a 20-item scale showed satisfactory goodness-of-fit. Unidimensionality was confirmed by principal component analysis. The rating scale functioned well for the 20 items, and the item difficulty was well suited to the ability level of the sample. The person reliability coefficient was 0.98, indicating high separation ability of the scale. A conversion table of AHA scores between the previous version (4.4) and the new version (5.0) was constructed. INTERPRETATION: The new, 20-item version of the Kids-AHA (version 5.0), demonstrated excellent internal scale validity, suggesting improved responsiveness to changes and shortened scoring time. For comparison of scores from version 4.4 to 5.0, a transformation table is presented. PMID- 26507384 TI - Effect of First Aid Education on First Aid Knowledge and Skills of Commercial Drivers in South West Nigeria. AB - BACKGROUND: Prompt prehospital care is essential for improving outcomes of road crash victims; however, this service is sub-optimal in developing countries because Emergency Medical Services (EMS) are not readily available. Training of lay responders in first aid has been suggested as a means of filling this gap in settings with inadequate EMS. This study was conducted to determine the effect of first aid training on the first aid knowledge and skills of commercial drivers. METHODS: A before-and-after study was conducted among 128 commercial drivers (62 intervention and 66 controls) selected by multi-stage sampling. Drivers' first aid knowledge and skills were assessed at baseline, immediate, and three months post-intervention. The intervention involved a 2-day training session in first aid. Repeated measures ANOVA was used to test for differences in respondents' pre and post-intervention scores over the three assessment points. RESULTS: Mean first aid knowledge scores for intervention drivers were 48.9% (SD=12.0), 57.8% (SD=11.2), and 59.2% (SD=9.0) at baseline, immediate, and three months post intervention. Corresponding scores for the controls were 48.3% (SD=12.8), 39.2% (SD=15.3), and 46.8% (SD=15.3). Mean first aid skill scores for intervention drivers were 17.5% (SD=3.8), 80.7% (SD=8.3), and 72.3% (SD=16.8). Scores for control drivers were 16.5% (SD=4.5), 16.3% (SD=4.7), and 20.4% (SD=9.1), respectively. Repeated measures ANOVA showed significant differences in first aid knowledge and skills scores over the three phases. Independent t-test revealed significant differences in scores between the intervention and control groups post-intervention. CONCLUSION: The training led to significant improvement in first aid knowledge and skills of intervention drivers. This confirms that lay responders can be trained in provision of first aid. The slight drop in skills scores, which occurred three months post-intervention, highlights the need for periodic refresher trainings to be conducted for the drivers in order to maintain the knowledge and skills acquired. PMID- 26507385 TI - Volume depletion provided by blood donation alters twist mechanics of the heart: Preload dependency of left ventricular torsion. AB - OBJECTIVES: The crucial role of twisting motion on both left ventricular (LV) contraction and relaxation has been clearly identified. However, the reports studying the association between LV torsion and loading conditions have revealed conflicting outcomes. Previously normal saline infusion was shown to increase LV rotation. Our aim was to test this phenomenon after volume depletion in healthy volunteer blood donors. DESIGN: A total of 26 healthy male volunteers were included in the study. LV end-diastolic and end-systolic diameter, LV ejection fraction, LV diastolic parameters, LV apical and basal rotation and peak systolic LV torsion were measured by speckle-tracking echocardiography before and after 450 mL blood donation. RESULTS: Blood donation led to a significant decrease in end-diastolic LV internal diameter (48.7 +/- 0.4 versus 46.4 +/- 0.4 mm; p < 0.001) and cardiac output (6.2 +/- 1.0 versus 5.1 +/- 0.7 L/min; p < 0.001). There was a significant decrease in the magnitude of peak systolic apical rotation (4.4 +/- 1.9 degrees versus 2.9 +/- 1.5 degrees ; p < 0.001) but no change in basal rotation (2.6 +/- 1.4 degrees versus 2.7 +/- 1.6 degrees ; p = 0.81). Peak systolic LV Torsion decreased after blood donation (6.9 +/- 1.9 degrees versus 5.7 +/- 2.1 degrees ; p = 0.028). CONCLUSIONS: LV apical rotation and peak systolic LV torsion seem to be preload dependent. Preload reduction provided by 450-mL blood donation decreased LV torsion in healthy male volunteers. Volume dynamics should be taken into account in the evaluation of LV torsion. PMID- 26507386 TI - Dose-dependent protective effect of nicotine in a murine model of viral myocarditis induced by coxsackievirus B3. AB - The alpha 7 nicotinic acetylcholine receptor (alpha7 nAChR) was recently described as an anti-inflammatory target in various inflammatory diseases. The aim of this study was to investigate the dose-related effects of nicotine, an alpha7 nAChR agonist, in murine model of viral myocarditis. BALB/C mice were infected by an intraperitoneally injection with coxsackievirus B3. Nicotine was administered at doses of 0.1, 0.2 or 0.4 mg/kg three times per day for 7 or 14 consecutive days. The effects of nicotine on survival, myocardial histopathological changes, cardiac function, and cytokine levels were studied. The survival rate on day 14 increased in a dose-dependent fashion and was markedly higher in the 0.2 and 0.4 mg/kg nicotine groups than in the infected untreated group. Treatment with high-dose nicotine reduced the myocardial inflammation and improved the impaired left ventricular function in infected mice. The mRNA expressions and protein levels of TNF-alpha, IL-1beta, IL-6, and IL-17A were significantly downregulated in dose-dependent manners in the nicotine treatment groups compared to the infected untreated group. Nicotine dose dependently reduced the severity of viral myocarditis through inhibiting the production of proinflammatory cytokines. The findings suggest that alpha7 nAChR agonists may be a promising new strategy for patients with viral myocarditis. PMID- 26507387 TI - Long-term follow-up of retropupillary iris-claw intraocular lens implantation: a retrospective analysis. AB - BACKGROUND: The ideal intraocular lens in cases of aphakia without capsular support is debated. Choices include anterior chamber lenses, iris- or scleral sutured lenses, and iris-claw lenses. Our aim was to report our long-term evaluation of the use of retropupillary implantation of the Artisan iris-claw intraocular lens (RPICIOL) in several aphakic conditions without capsular support. METHODS: A retrospective analysis of consecutive 320 eyes of 320 patients (222 males and 98 females) without capsular support in which we performed RPICIOL implantation in post-traumatic aphakia (141 eyes, group 1), post-cataract surgery aphakia (122 eyes, group 2), and in cases in which penetrating keratoplasty was associated with vitrectomy (57 eyes, group 3). Either anterior or posterior vitrectomy procedures were performed with 20-, 23-, or 25-gauge techniques for different associated anterior or posterior segment indications. We reviewed the refractive outcome, anatomical outcome, long-term stability of the implants, and possible long-term complications. RESULTS: The mean patient age was 59.7 years (range, 16-84 years) in group 1; 60.1 years (range, 14-76 years) in group 2; and 65.8 years (range, 25-71.5 years) in group 3. The mean follow-up time was 5.3 years (range, 1 month to 8 years). At the end of the follow-up period, the mean post-operative best-corrected LogMAR visual acuity was 0.6 (range, perception of light to 0.3) in group 1; 0.3 (range, 0.5 0.1) in group 2; and 0.6 (range, hand movement to 0.2) in group 3. Disenclavation of RPICIOLs occurred in three cases because of slippage of one of the iris-claw haptics and spontaneous complete posterior dislocation occurred in one case. One case presented with retinal detachment, and no cases of uveitis were observed. Eight cases complained of chronic dull pain, and severe iridodonesis was seen in five cases. One case of post-operative macular edema was observed without post operative increase in the mean intraocular pressure. There was no statistically different change in the endothelial cell density (cells/mm(2)) at the end of the follow-up period. CONCLUSIONS: RPICIOL for secondary implantations is a valid alternative strategy to scleral-fixated or angle-supported IOL implantation. PMID- 26507388 TI - Effects of a prehabilitation program on patients' recovery following spinal stenosis surgery: study protocol for a randomized controlled trial. AB - BACKGROUND: Degenerative lumbar spinal stenosis is a prevalent condition in adults over the age of 65 and often leads to deconditioning. Although the benefits of surgery outweigh those of conservative approaches, physical rehabilitation may be used to improve function and to minimize the risk of persistent dysfunction. This study protocol was designed to establish the feasibility of a full-scale randomized controlled trial and to assess the efficacy of an active preoperative intervention program on the improvement of clinical parameters and functional physical capacity in patients undergoing surgery for lumbar spinal stenosis. METHODS/DESIGN: Forty patients will be recruited and randomly allocated to one of the 2 treatment arms: 6 weeks supervised preoperative rehabilitation program (experimental group) or hospital standard preoperative management (control group). The intervention group will be trained three times per week, with each session aiming to improve strength, muscular endurance, spinal stabilization and cardiovascular fitness. Intensity and complexity of exercises will be gradually increased throughout the sessions, depending on each participant's individual progress. Primary outcomes are level of low back disability and level of pain. Secondary outcomes include the use of pain medication, quality of life, patient's global impression of change, lumbar extensor muscles endurance, maximum voluntary contraction of lumbar flexor and extensor muscles, maximum voluntary contraction of knee extensors, active lumbar ranges of motion, walking abilities, and cardiovascular capacity. Both the primary and secondary outcomes will be measured at baseline, at the end of the training program (6 weeks after baseline evaluation for control participants), and at 6 weeks, 3 and 6 months postoperatively. DISCUSSION: This study will inform the design of a future large-scale trial. Improvements of physical performances before undergoing lumbar surgery may limit functional limitations occurring after a surgical intervention. Results of this study will provide opportunity to efficiently improve spinal care and advance our knowledge of favorable preoperative strategies to optimize postoperative recovery. TRIAL REGISTRATION: US National Institutes of Health Clinical Trials registry NCT02258672 , 10 February 2014. PMID- 26507389 TI - The future of pediatric and adolescent urologic oncology as a subspecialty: Gains and growth via research, education, and quality improvement. PMID- 26507390 TI - Diversity of pigmented Gram-positive bacteria associated with marine macroalgae from Antarctica. AB - Little is known about the diversity and roles of Gram-positive and pigmented bacteria in Antarctic environments, especially those associated with marine macroorganisms. This work is the first study about the diversity and antimicrobial activity of culturable pigmented Gram-positive bacteria associated with marine Antarctic macroalgae. A total of 31 pigmented Gram-positive strains were isolated from the surface of six species of macroalgae collected in the King George Island, South Shetland Islands. On the basis of 16S rRNA gene sequence similarities >=99%, 18 phylotypes were defined, which were clustered into 11 genera of Actinobacteria (Agrococcus, Arthrobacter, Brachybacterium, Citricoccus, Kocuria, Labedella, Microbacterium, Micrococcus, Rhodococcus, Salinibacterium and Sanguibacter) and one genus of the Firmicutes (Staphylococcus). It was found that five isolates displayed antimicrobial activity against a set of macroalgae associated bacteria. The active isolates were phylogenetically related to Agrococcus baldri, Brachybacterium rhamnosum, Citricoccus zhacaiensis and Kocuria palustris. The results indicate that a diverse community of pigmented Gram positive bacteria is associated with Antartic macroalgae and suggest its potential as a promising source of antimicrobial and pigmented natural compounds. PMID- 26507391 TI - Anastrozole plus leuprorelin in early maturing girls with compromised growth: the "GAIL" study. AB - PURPOSE: Aromatase inhibitors have been used to increase predicted adult height (PAH) in boys but in girls only in McCune-Albright syndrome. We investigated whether anastrozole combined with leuprorelin for up to 2 years is safe and effective in improving PAH in girls with early puberty and compromised growth, compared to leuprorelin alone. METHODS: The "GAIL" study: girls treated with an aromatase inhibitor and an LHRH analogue, ISRCTN11469487, was a 7-year prospective phase IIa study with parallel design, performed at Athens Medical Center (C-A), and Attikon University Hospital, Athens, Greece (C-B). Forty girls, consecutively referred for early puberty (onset 7.5-9 years) with a PAH <-2 or >1.5 SD lower than their target height (TH), were included. Twenty started on leuprorelin sc/im 0.3 mg/kg/month plus anastrozole 1 mg/d p.o. (group-A, C-A) and 20 on leuprorelin (group-B, C-B) for 2 years or until the age of 10 years. Groups did not differ in age, height, BMI, bone age advancement (BAA), and distance of PAH from TH. Follow-up was at 6, 12, 18, and 24 m. RESULTS: Reduction in BAA was significantly higher in group-A compared to group-B already by 6 m. Despite the transiently significant decrease in height velocity in group-A, gain in PAH SD was almost double by 12 and 18 m vs group-B and reached the maximum of +1.21 +/- 0.45 (7.51 cm) vs +0.31 +/- 0.37 (1.92 cm, p = 0.001) in group-B at 24 m. Group-A had no clinical or biochemical hyperandrogenism, unchanged normal bone density, and lumbar spine X-rays. CONCLUSION: The co-administration of anastrozole with leuprorelin safely improves PAH in girls with compromised growth. PMID- 26507392 TI - Sperm competition risk drives plasticity in seminal fluid composition. AB - BACKGROUND: Ejaculates contain a diverse mixture of sperm and seminal fluid proteins, the combination of which is crucial to male reproductive success under competitive conditions. Males should therefore tailor the production of different ejaculate components according to their social environment, with particular sensitivity to cues of sperm competition risk (i.e. how likely it is that females will mate promiscuously). Here we test this hypothesis using an established vertebrate model system, the house mouse (Mus musculus domesticus), combining experimental data with a quantitative proteomics analysis of seminal fluid composition. Our study tests for the first time how both sperm and seminal fluid components of the ejaculate are tailored to the social environment. RESULTS: Our quantitative proteomics analysis reveals that the relative production of different proteins found in seminal fluid--i.e. seminal fluid proteome composition--differs significantly according to cues of sperm competition risk. Using a conservative analytical approach to identify differential expression of individual seminal fluid components, at least seven of 31 secreted seminal fluid proteins examined showed consistent differences in relative abundance under high versus low sperm competition conditions. Notably three important proteins with potential roles in sperm competition--SVS 6, SVS 5 and CEACAM 10--were more abundant in the high competition treatment groups. Total investment in both sperm and seminal fluid production also increased with cues of heightened sperm competition risk in the social environment. By contrast, relative investment in different ejaculate components was unaffected by cues of mating opportunities. CONCLUSIONS: Our study reveals significant plasticity in different ejaculate components, with the production of both sperm and non-sperm fractions of the ejaculate strongly influenced by the social environment. Sperm competition risk is thus shown to be a key factor in male ejaculate production decisions, including driving plasticity in seminal fluid composition. PMID- 26507393 TI - The effects of concentrate supplementation on growth performance and behavioral activities of cattle grazed on natural pasture. AB - The study was conducted in Manyara Region, to determine the effect of concentrate supplementation on growth performance and foraging behavior of zebu steers. Twenty zebu steers were distributed equally into two dietary groups: pasture + concentrate (PS) and natural pasture alone (NP). The animals' body weight and body condition scores were estimated every 2 weeks. The focal observation technique was used to determine grazing behavior. The average daily gain (ADG) was significantly higher (P <= 0.05) in the PS than in the NP. Significant less time (P <= 0.05) was spent in feeding by animals in the PS than those in the NP. Significant less bite rates (P <= 0.05) were also observed in the PS than in the NP. The most highly abundant forage species exhibited low CP contents but were most frequently eaten by the focal animals. Strategic supplementation with locally available concentrates is recommended for profitable ruminant productivity and environmentally friendly grazing strategy. PMID- 26507394 TI - Replacing soybean meal for cottonseed meal on performance of lactating dairy cows. AB - Cottonseed meal (CSM) is an alternative source of protein, and previous studies have been shown that it can replace soybean meal (SBM) without decrease animal performance. However, Brazilian CSM has a different chemical composition compared with the usual CSM reported in the literature. The objective of this experiment was to evaluate the effects of replacing SBM for Brazilian CSM on performance and energy balance of mid-lactating dairy cows. Forty-two Holstein cows were used in a replicate 3 * 3 Latin square design. Increasing contents of CSM (0, 15, and 30% of dry matter (DM)) were fed in diets to replace SBM. Milk yield and feed efficiency were linearly reduced with the replacement of CSM for SBM (P = 0.001). Milk fat content tended to increase quadratically (P = 0.07) with CSM addition. Replacing SBM for CSM affected milk protein content quadratically (P = 0.05). Milk urea nitrogen and plasma urea nitrogen (PUN) tended to respond quadratically (P = 0.06 and 0.10) when CSM replaced SBM to the diets. Variation in body weight (BW) also responded quadratically as CSM replaced SBM (P = 0.05). Altogether, the findings suggest better performance when cows receive SBM diet compared with the Brazilian CSM diet. PMID- 26507395 TI - Antimicrobial Resistance of Escherichia coli Causing Uncomplicated Urinary Tract Infections: A European Update for 2014 and Comparison with 2000 and 2008. AB - INTRODUCTION: The objective of this study was to provide an update on the resistance of Escherichia coli in women with acute uncomplicated urinary tract infections (UTIs) in France, Germany, Spain, Sweden, and the United Kingdom (UK) to mecillinam [amdinocillin (United States Adopted Name)], amoxicillin-clavulanic acid, cefadroxil, nitrofurantoin, ciprofloxacin, and trimethoprim, and to compare the results with resistance in the ECO.SENS I and II surveys in 2000 and 2008, respectively. METHODS: The susceptibility of E. coli in France (166 isolates), Germany (133 isolates), Spain (169 isolates), Sweden (137 isolates), and the UK (124 isolates) was determined by disc diffusion according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints and methodology. Resistance rates were compared using Fisher's exact test, 2-tailed, with P < 0.05 indicating statistical significance. RESULTS: Since 2000, there has been a significant increase in resistance to cefadroxil in Germany (1% to 12%) and Spain (3% to 8%), to ciprofloxacin in Germany (2% to 21%), Spain (15% to 31%), Sweden (0% to 7%), and the UK (1% to 15%), to trimethoprim in Germany (23% to 37%), Spain (25% to 37%), Sweden (9% to 17%), and the UK (13% to 46%), to mecillinam in Spain (1% to 6.5%), and to nitrofurantoin in the UK (0% to 6%); there was also a significant decrease in resistance to nitrofurantoin in Spain (4% to 0%). Since 2008, there has been a significant increase in resistance to ciprofloxacin in Sweden (3% to 15%) and the UK (1% to 15%), and to trimethoprim (13% to 46%) and nitrofurantoin (0% to 6%) in the UK. CONCLUSION: E. coli isolates from women with acute uncomplicated UTIs have increasing antimicrobial resistance, particularly to ciprofloxacin and trimethoprim. However, resistance to mecillinam and nitrofurantoin mostly remains low. FUNDING: LEO Pharma. PMID- 26507396 TI - Are the effects of Kinesio Taping clinically meaningful in patients with acute low back pain? PMID- 26507397 TI - Validity and reliability of a simple 'low-tech' test for measuring choice stepping reaction time in older people. AB - OBJECTIVE: To establish the psychometric properties of a simple 'low-tech' choice stepping reaction time test (CSRT-M) by investigating its validity and test retest reliability. DESIGN: Cross-sectional. SETTING: Community. SUBJECTS: A total of 169 older people from the control arm of a clinical trial and a convenience sample of 30 older people. MAIN MEASURES: Demographic, physical, cognitive and prospective falls data were collected in addition to CSRT-M. The CSRT-M time was taken as the total time to complete 20 steps onto four targets printed on a portable rubber mat. Assessment of the original electronic version (CSRT-E) and re-administration of the CSRT-M the next day was done in 30 participants. RESULTS: Multivariate regression analysis showed that the CSRT-M time was best explained by leaning balance control, quadriceps strength and cognitive functioning (R2 = 0.44). Performance on the CSRT-M was worse in older participants and participants with a presence of fall risk factors, supporting good discriminant validity. The odds of suffering multiple future falls increased by 74% (odds ratio (OR) = 1.74, 95% CI (confidence interval) = 1.14-2.65, p = 0.010) for each standard deviation increase in CSRT-M, supporting good predictive validity. Criterion validity was confirmed by a strong bivariate correlation between CSRT-M and CSRT-E (0.81, p < 0.001). Test-retest reliability for the CSRT M was good (intraclass correlation coefficient = 0.74, 95% CI = 0.45-0.88, p < 0.001). CONCLUSIONS: A simple test of unplanned volitional stepping (CSRT-M) has excellent predictive validity for future falls, good inter-day test-retest reliability and excellent criterion validity with respect to the well-validated CSRT-E. The CSRT-M, therefore, may be a useful fall risk screening tool for older people. PMID- 26507398 TI - Rituximab in the treatment of refractory scleritis in patients with granulomatosis with polyangiitis (Wegener's). AB - PURPOSE: The purpose of this descriptive study was to evaluate the clinical response to rituximab (RTX) in patients with scleritis due to granulomatosis with polyangiitis (GPA), in patients who had proved refractory to treatment with systemic glucocorticoids and immunosuppressive agents. METHODS: Retrospective analysis of interventional case series. Single referral center study. Eight patients (12 affected eyes) due to scleritis secondary to GPA, refractory to conventional treatment were included to receive RTX as therapy for remission induction. RTX was administered as a 1-g infusion every 2 weeks, for a total of 2 g. Patient follow-up included clinical evaluation (systemic and ophthalmologic), B-cell subset (CD19, CD20, CD22) counts, proteinase-3 anti-neutrophil cytoplasmic antibody (PR-3 ANCA), and Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS-WG). Outcomes were response to treatment and achievement of remission, as well as number of ocular relapses. RESULTS: The main indication for treatment was refractory necrotising anterior scleritis. Four weeks after completion of treatment with RTX, all patients showed clear clinical improvement, with no further progression. In all patients, an absolute depletion of B cells was confirmed in the first 6 weeks after treatment. Seven patients (87.5 %) achieved remission of inflammatory activity in 7 months or less. However, three patients experienced ocular relapse, which comprised reactivation of the anterior scleritis, uveitis, and posterior scleritis, and two patients required a second dose of RTX, with immediate improvement. CONCLUSIONS: RTX is useful in the treatment of refractory necrotising scleritis in patients with GPA. Of note, in those who relapse after remission, RTX can be successfully used for retreatment. PMID- 26507399 TI - Minimally fibrotic stage 5 ROP: a clinical prognostic factor in eyes undergoing vitrectomy for stage 5 retinopathy of prematurity. AB - TITLE: Minimally fibrotic Stage 5: A clinical prognostic factor in eyes undergoing vitrectomy for stage 5 retinopathy of prematurity (ROP). PURPOSE: To define minimally fibrotic stage 5 ROP and to demonstrate better surgical outcomes in this subgroup. METHODS: A cohort of eligible eyes with stage 5 ROP undergoing vitrectomy were further divided into those with minimally fibrotic stage 5 and others. Minimally fibrotic stage 5 ROP was defined as those stage 5 eyes having a translucent retrolental membrane with visibility of the underlying retinal vessels and absence of anteriorly rotated ciliary processes. We reported on anatomic and visual outcomes in eyes with defined characteristics of this subgroup identified before surgery and then observing them post vitrectomy over a period of time as compared to others. RESULTS: Minimally fibrotic stage 5 eyes had better visual (p = .0068) and anatomical outcomes (p = .0001). CONCLUSION: Minimally fibrotic stage 5 ROP shows ridge to ridge traction that has resulted in a traction retinal detachment with a retrolental membrane, but fibrotic change has just begun. This stage 5 ROP with limited fibrosis represents a subset of this stage 5 ROP with a positive anatomic and visual prognosis. PMID- 26507400 TI - Synthesis of large-area multilayer hexagonal boron nitride for high material performance. AB - Although hexagonal boron nitride (h-BN) is a good candidate for gate-insulating materials by minimizing interaction from substrate, further applications to electronic devices with available two-dimensional semiconductors continue to be limited by flake size. While monolayer h-BN has been synthesized on Pt and Cu foil using chemical vapour deposition (CVD), multilayer h-BN is still absent. Here we use Fe foil and synthesize large-area multilayer h-BN film by CVD with a borazine precursor. These films reveal strong cathodoluminescence and high mechanical strength (Young's modulus: 1.16 +/- 0.1 TPa), reminiscent of formation of high-quality h-BN. The CVD-grown graphene on multilayer h-BN film yields a high carrier mobility of ~ 24,000 cm(2) V(-1) s(-1) at room temperature, higher than that (~ 13,000 (2) V(-1) s(-1)) with exfoliated h-BN. By placing additional h-BN on a SiO2/Si substrate for a MoS2 (WSe2) field-effect transistor, the doping effect from gate oxide is minimized and furthermore the mobility is improved by four (150) times. PMID- 26507401 TI - Predictive Validity of Self-Reported Measures of Adherence to Noninsulin Antidiabetes Medication against Control of Glycated Hemoglobin Levels. AB - OBJECTIVE: To assess and compare the predictive validity of 4 self-reported adherence measures. METHODS: A convenience sample of 153 patients with type 2 diabetes completed a self-report with 4 items (SR-4) and a French version of the Morisky Medication Adherence Scale with 8 items (MMAS-8), reported the proportion of pills missed, and answered a single-item scale regarding their antidiabetes drug treatments. They also provided measures of glycated hemoglobin (A1C) taken between 3 and 6 months after the adherence measurements. We examined the relationship between self-reported adherence and glycemic control using the area under the receiver operating characteristics curve (AUC) and linear regression analyses. RESULTS: AUCs were 0.51, 0.52, 0.53 and 0.52 for the SR-4, MMAS-8, self reported proportion of pills missed and single-item scale, respectively. AUCs stratified according to median duration of diabetes ranged from 0.55 to 0.63. Based on linear regression analyses adjusted for diabetes duration, the association measured in the total sample between adherence measures and A1C levels was not statistically significant. When regression analyses were performed among participants with A1C levels >=7% only, SR-4, MMAS-8 and the single-item scale scores were significantly associated with A1C levels, and beta coefficients were associated with a 1-unit increase in adherence scores of -0.46, -0.20 and 0.38, respectively. CONCLUSION: The results support the predictive validity of all measures except the self-reported proportion of missed pills. PMID- 26507402 TI - Current Perspectives on Long-term Obesity Pharmacotherapy. AB - Approximately 1 in 4 adult Canadians are obese and, thus, are at an elevated risk for developing type 2 diabetes, cardiovascular disease and other conditions. Current treatment guidelines recommend that obese individuals lose 5% to 10% of their starting weights to minimize the risk factors for cardiovascular disease and reduce the risk for developing type 2 diabetes or hypertension. All obesity management strategies involve lifestyle management, but few patients will lose a significant amount of weight and manage to keep it off over the long term using just this strategy. Bariatric surgery is associated with significant long-term weight loss but is restricted to subjects with very high body mass indices, who often wait many years to undergo the procedure. Recent breakthroughs in understanding the mechanisms underlying the development and maintenance of elevated body fat have led to the arrival of new obesity pharmacotherapies. These novel antiobesity therapies, which work by reducing energy intake or through increasing satiety, decreasing hunger, or reducing absorption of calories, may be used indefinitely once patients have demonstrated significant responses (usually defined as >=5% weight loss) over the first 12 weeks of treatment. To date, 2 long-term obesity pharmacotherapies have been approved and are available in Canada: liraglutide and orlistat. Here, I summarize the mechanisms and clinical features of medications for long-term obesity management that are available in Canada, as well as those available in other jurisdictions or are currently in development. PMID- 26507403 TI - Complex instability of axially compressed tubular lipid membrane with controlled spontaneous curvature. AB - Tubular lipid membranes (TLMs) are formed by an external pulling force from artificial or biological bilayer vesicles and can be subsequently stabilized by incorporating proteins or amphiphilic polymers into the lipid bilayer. The arising spontaneous curvature of the lipid sheet allows switching off the pulling force without TLM destabilization. However, here we show that during this process two different thermal fluctuation modes drastically increase their amplitudes making fluctuations of the TLM much greater than its radius. Due to the system's proximity to the critical fluctuation point, a weak axial compressive force is sufficient to destabilize the TLM. Its absolute value is shown to be much smaller than that of the pulling force required for the initial lipid nanotube formation. Induced complex instability was studied in the frame of Landau phase transition theory. The process involves two consecutive second-order phase transitions and leads to the tube deformation combining annular corrugation with completely unconventional chiral buckling. PMID- 26507404 TI - Gender differences in outcomes after surgical ablation of atrial fibrillation. AB - BACKGROUND: Gender disparities have been established in patients who have atrial fibrillation (AF), and in their outcomes after medical treatment for AF. This study evaluated differences in outcome by gender in patients who underwent surgical treatment for AF. METHODS: From April 2004 to December 2012, a total of 936 patients had surgical treatment for AF. Outcomes were analyzed by gender using propensity score-matching methods. RESULTS: Of the 936 subjects, 571 (61%) were men; women were older (aged 68.6 +/- 11.3 vs 66.9 +/- 11.9 years; P = .033), had more heart failure (44% vs 37%; P = .024), more mitral valve surgery (72% vs 50%; P < .001) and more tricuspid valve surgery (41% vs 18%; P < .001). Men underwent more coronary artery bypass surgery (37% vs 19%; P < .001) and aortic valve surgery (38% vs 31%; P = .029). Women had higher late stroke rate per 10 person-years (0.15 vs 0.07; P = .035), fewer catheter ablations (6.0% vs 9.8%; P = .017), and a trend toward fewer cardioversions for recurrent AF (15.7% vs 19.2%; P = .20). After propensity-score matching, late stroke rates per 10 person years trended higher in women (0.12 vs 0.04; P = .13). No significant gender differences were found in overall survival (5-year survival: 78.8% in men, and 81.0% in women; P = .40) or freedom from AF without antiarrhythmic drugs at last follow-up (71.8% in men vs 73.6% in women, P = .59). CONCLUSIONS: Women sought surgery treatment at older ages and with more heart failure. No gender-based differences were found in stroke, overall survival, or procedure success, after propensity-score matching. PMID- 26507405 TI - Risk factors for mechanical ventilation and reintubation after pediatric heart surgery. AB - OBJECTIVE: To determine the prevalence of and risk factors associated with the need for mechanical ventilation in children following cardiac surgery and the need for subsequent reintubation after the initial extubation attempt. METHODS: Patients younger than 18 years who underwent cardiac operations for congenital heart disease at one of the participating pediatric intensive care units (ICUs) in the Virtual PICU Systems (VPS), LLC, database were included (2009-2014). Multivariable logistic regression models were fitted to identify factors likely associated with mechanical ventilation and reintubation. RESULTS: A total of 27,398 patients from 62 centers were included. Of these, 6810 patients (25%) were extubated in the operating room (OR), whereas 20,588 patients (75%) arrived intubated in the ICU. Of the patients who were extubated in the OR, 395 patients (6%) required reintubation. In contrast, 2054 patients (10%) required reintubation among the patients arriving intubated postoperatively in the ICU. In adjusted models, patient characteristics, patients undergoing high-complexity operations, and patients undergoing operations in lower-volume centers were associated with higher likelihood for the need for postoperative mechanical ventilation and need for reintubation. Furthermore, the prevalence of mechanical ventilation and reintubation was lower among the centers with a dedicated cardiac ICU in propensity-matched analysis among centers with and without a dedicated cardiac ICU. CONCLUSIONS: This multicenter study suggests that proportion of patients extubated in the OR after heart operation is low. These data further suggest that extubation in the OR can be done successfully with a low complication rate. PMID- 26507406 TI - The importance of standardization in surgical ablation for atrial fibrillation. PMID- 26507407 TI - Cytogenetic Studies of Rwandan Pediatric Patients Presenting with Global Developmental Delay, Intellectual Disability and/or Multiple Congenital Anomalies. AB - Global developmental delay (GDD) is defined as a significant delay in two or more developmental domains: gross or fine motor, speech/language, cognitive, social/personal and activities of daily living. Many of these children will go on to be diagnosed with intellectual disability (ID), which is most commonly defined as having an IQ <75 in addition to impairment in adaptive functioning. Cytogenetic studies have been performed in 664 Rwandan pediatric patients presenting GDD/ID and/or multiple congenital abnormalities (MCA). Karyotype analysis was performed in all patients and revealed 260 chromosomal abnormalities. The most frequent chromosomal abnormality was Down syndrome and then Edward syndrome and Patau syndrome. Other identified chromosomal abnormalities included 47,XX,+del(9)(q11), 46,XY,del(13)(q34) and 46,XX,der(22)t(10;22)(p10;p10)mat. In conclusion, our results highlight the high frequency of cytogenetically detectable abnormalities in this series, with implications for the burden on the healthcare. This study demonstrates the importance of cytogenetic analysis in patients with GDD/ID and MCA. PMID- 26507408 TI - Poor Infant Feeding Practices and High Prevalence of Malnutrition in Urban Slum Child Care Centres in Nairobi: A Pilot Study. AB - Little is known about the style and quality of feeding and care provided in child day-care centres in slum areas. This study purposively sampled five day-care centres in Nairobi, Kenya, where anthropometric measurements were collected among 33 children aged 6-24 months. Mealtime interactions were further observed in 11 children from four centres, using a standardized data collection sheet. We recorded the child actions, such as mood, interest in food, distraction level, as well as caregiver actions, such as encouragement to eat, level of distraction and presence of neutral actions. Of the 33 children assessed, with a mean age of 15.9 +/- 4.9 months, 14 (42%) were female. Undernutrition was found in 13 (39%) children with at least one Z score <-2 or oedema (2): height for age <-2 (11), weight for age <-2 (11), body mass index for age <-2 (4). Rates of undernutrition were highest (9 of 13; 69%) in children aged 18-24 months. Hand-washing before the meal was lacking in all centres. Caregivers were often distracted and rarely encouraged children to feed, with most children eating less than half of their served meal. Poor hygiene coupled with non-responsive care practices observed in the centres is a threat to child health, growth and development. PMID- 26507409 TI - Dramatic increase in SHP2 binding activity of Helicobacter pylori Western CagA by EPIYA-C duplication: its implications in gastric carcinogenesis. AB - Infection with cagA-positive Helicobacter pylori is critically associated with the development of gastric cancer. The cagA-encoded CagA is delivered into gastric epithelial cells via type IV secretion, where it interacts with and thereby deregulates the pro-oncogenic phosphatase SHP2. East Asian CagA and Western CagA are two major CagA species produced by H. pylori circulating in East Asian countries and in the rest of the world, respectively. The SHP2 binding site of Western CagA, termed the EPIYA-C segment, variably duplicates and infection with H. pylori carrying Western CagA with multiple EPIYA-C segments is a distinct risk factor of gastric cancer. Here we show that duplication of EPIYA-C from one to two or more increases SHP2 binding of Western CagA by more than one hundredfold. Based on the decisive difference in SHP2 binding, Western CagA can be divided into two types: type I CagA carrying a single EPIYA-C segment and type II CagA carrying multiple EPIYA-C segments. Gastric epithelial cells expressing type II CagA acquire the ability to invade extracellular matrices, a malignant cellular trait associated with deregulated SHP2. A big leap in SHP2 binding activity may therefore provide molecular basis that makes type II Western CagA a distinct gastric cancer risk. PMID- 26507410 TI - Biomechanical Effects of Acromioplasty on Superior Capsule Reconstruction for Irreparable Supraspinatus Tendon Tears. AB - BACKGROUND: Acromioplasty is increasingly being performed for both reparable and irreparable rotator cuff tears. However, acromioplasty may destroy the coracoacromial arch, including the coracoacromial ligament, consequently causing a deterioration in superior stability even after superior capsule reconstruction. PURPOSE/HYPOTHESIS: The purpose of this study was to investigate the effects of acromioplasty on shoulder biomechanics after superior capsule reconstruction for irreparable supraspinatus tendon tears. The hypothesis was that acromioplasty with superior capsule reconstruction would decrease the area of subacromial impingement without increasing superior translation and subacromial contact pressure. STUDY DESIGN: Controlled laboratory study. METHODS: Seven fresh-frozen cadaveric shoulders were evaluated using a custom shoulder testing system. Glenohumeral superior translation, the location of the humeral head relative to the glenoid, and subacromial contact pressure and area were compared among 4 conditions: (1) intact shoulder, (2) irreparable supraspinatus tendon tear, (3) superior capsule reconstruction without acromioplasty, and (4) superior capsule reconstruction with acromioplasty. Superior capsule reconstruction was performed using the fascia lata. RESULTS: Compared with the intact shoulder, the creation of an irreparable supraspinatus tear significantly shifted the humeral head superiorly in the balanced muscle loading condition (without superior force applied) (0 degrees of abduction: 2.8-mm superior shift [P = .0005]; 30 degrees of abduction: 1.9-mm superior shift [P = .003]) and increased both superior translation (0 degrees of abduction: 239% of intact [P = .04]; 30 degrees of abduction: 199% of intact [P = .02]) and subacromial peak contact pressure (0 degrees of abduction: 308% of intact [P = .0002]; 30 degrees of abduction: 252% of intact [P = .001]) by applying superior force. Superior capsule reconstruction without acromioplasty significantly decreased superior translation (0 degrees of abduction: 86% of intact [P = .02]; 30 degrees of abduction: 75% of intact [P = .002]) and subacromial peak contact pressure (0 degrees of abduction: 47% of intact [P = .0002]; 30 degrees of abduction: 83% of intact [P = .0005]; 60 degrees of abduction: 38% of intact [P = .04]) compared with after the creation of a supraspinatus tear. Adding acromioplasty significantly decreased the subacromial contact area compared with superior capsule reconstruction without acromioplasty (0 degrees of abduction: 26% decrease [P = .01]; 30 degrees of abduction: 21% decrease [P = .009]; 60 degrees of abduction: 61% decrease [P = .003]) and did not alter humeral head position, superior translation, or subacromial peak contact pressure. CONCLUSION: Superior capsule reconstruction repositioned the superiorly migrated humeral head and restored superior stability in the shoulder joint. Adding acromioplasty decreased the subacromial contact area without increasing the subacromial contact pressure. CLINICAL RELEVANCE: When superior capsule reconstruction is performed for irreparable rotator cuff tears, acromioplasty may help to decrease the postoperative risk of abrasion and tearing of the graft beneath the acromion. PMID- 26507411 TI - Reusable acoustic tweezers for disposable devices. AB - We demonstrate acoustic tweezers used for disposable devices. Rather than forming an acoustic resonance, we locally transmitted standing surface acoustic waves into a removable, independent polydimethylsiloxane (PDMS)-glass hybridized microfluidic superstrate device for micromanipulation. By configuring and regulating the displacement nodes on a piezoelectric substrate, cells and particles were effectively patterned and transported into said superstrate, accordingly. With the label-free and contactless nature of acoustic waves, the presented technology could offer a simple, accurate, low-cost, biocompatible, and disposable method for applications in the fields of point-of-care diagnostics and fundamental biomedical studies. PMID- 26507412 TI - Diagnosis and management of pulmonary embolism in critical situations: A cardiac challenge. PMID- 26507413 TI - A very rare coronary artery anomaly, intercoronary communication, that may be lucky for some patients. PMID- 26507414 TI - Reply to the comment on "Cost-effectiveness of rivaroxaban for stroke prevention in atrial fibrillation in the Portuguese setting". PMID- 26507415 TI - Anterolateral papillary muscle rupture after intervention of the right coronary artery. AB - Rupture of the anterolateral papillary muscle following a right coronary artery occlusion is extremely rare, and when complicated by a right ventricular infarction, can be fatal. The literature on optimal management of this complication is limited. We present an unusual case of anterolateral papillary muscle rupture following intervention of the right coronary artery. PMID- 26507416 TI - Cochrane Corner: Colchicine in acute and recurrent pericarditis. AB - The potential anti-inflammatory effect of colchicine has been explored in many conditions, including pericarditis. The Cochrane Collaboration Systematic Review included four randomized controlled trials enrolling 564 patients with acute pericarditis (two studies) or recurrent pericarditis (two studies), followed for a period of 20-24 months. Colchicine was associated with a significant reduction in short-term persistence of chest pain and in long-term risk of recurrence of pericarditis. No significant increase in overall adverse events was observed. Despite the available evidence, the use of colchicine in this context remains strictly off-label. PMID- 26507417 TI - Mechanisms of astrocytic K(+) clearance and swelling under high extracellular K(+) concentrations. AB - In response to the elevation of extracellular K(+) concentration ([K(+)]out), astrocytes clear excessive K(+) to maintain conditions necessary for neural activity. K(+) clearance in astrocytes occurs via two processes: K(+) uptake and K(+) spatial buffering. High [K(+)]out also induces swelling in astrocytes, leading to edema and cell death in the brain. Despite the importance of astrocytic K(+) clearance and swelling, the underlying mechanisms remain unclear. Here, we report results from a simulation analysis of astrocytic K(+) clearance and swelling. Astrocyte models were constructed by incorporating various mechanisms such as intra/extracellular ion concentrations of Na(+), K(+), and Cl( ), cell volume, and models of Na,K-ATPase, Na-K-Cl cotransporter (NKCC), K-Cl cotransporter, inwardly-rectifying K(+) (KIR) channel, passive Cl(-) current, and aquaporin channel. The simulated response of astrocyte models under the uniform distribution of high [K(+)]out revealed significant contributions of NKCC and Na,K-ATPase to increases of intracellular K(+) and Cl(-) concentrations, and swelling. Moreover, we found that, under the non-uniform distribution of high [K(+)]out, KIR channels localized at synaptic clefts absorbed excess K(+) by depolarizing the equivalent potential of K(+) (E K) above membrane potential, while K(+) released through perivascular KIR channels was enhanced by hyperpolarizing E K and depolarizing membrane potential. Further analysis of simulated drug effects revealed that astrocyte swelling was modulated by blocking each of the ion channels and transporters. Our simulation analysis revealed controversial mechanisms of astrocytic K(+) clearance and swelling resulting from complex interactions among ion channels and transporters. PMID- 26507418 TI - Ion channels, guidance molecules, intracellular signaling and transcription factors regulating nervous and vascular system development. AB - Our sophisticated thoughts and behaviors are based on the miraculous development of our complex nervous network system, in which many different types of proteins and signaling cascades are regulated in a temporally and spatially ordered manner. Here we review our recent attempts to grasp the principles of nervous system development in terms of general cellular phenomena and molecules, such as volume-regulated anion channels, intracellular Ca(2+) and cyclic nucleotide signaling, the Npas4 transcription factor and the FLRT family of axon guidance molecules. We also present an example illustrating that the same FLRT family may regulate the development of vascular networks as well. The aim of this review is to open up new vistas for understanding the intricacy of nervous and vascular system development. PMID- 26507419 TI - The effect of PrP(Sc) accumulation on inflammatory gene expression within sheep peripheral lymphoid tissue. AB - Accumulation of the misfolded prion protein, PrP(Sc) in the central nervous system (CNS) is strongly linked to progressive neurodegenerative disease. For many transmissible spongiform encephalopathies (TSEs), peripheral lymphoid tissue is an important site of PrP(Sc) amplification but without gross immunological consequence. Susceptible VRQ homozygous New Zealand Cheviot sheep were infected with SSBP/1 scrapie by inoculation in the drainage area of the prescapular lymph nodes. The earliest time that PrP(Sc) was consistently detected by immunohistology in these nodes was D50 post infection. This transcriptomic study of lymph node taken before (D10) and after (D50) the detection of PrP(Sc), aimed to identify the genes and physiological pathways affected by disease progression within the nodes as assessed by PrP(Sc) detection. Affymetrix Ovine Gene arrays identified 75 and 80 genes as differentially-expressed at D10 and D50, respectively, in comparison with control sheep inoculated with uninfected brain homogenate. Approximately 70% of these were repressed at each time point. RT-qPCR analysis of seven genes showed statistically significant correlation with the array data, although the results for IL1RN and TGIF were different between the two technologies. The ingenuity pathway analysis (IPA) and general low level of repression of gene expression in lymphoid tissue, including many inflammatory genes, contrasts with the pro-inflammatory and pro-apoptotic events that occur within the CNS at equivalent stages of disease progression as assessed by PrP(Sc) accumulation. PMID- 26507420 TI - Molecular characterization and antimicrobial susceptibility of Clostridium difficile isolated from rabbits raised for meat production. AB - Clostridium difficile is an important cause of enteric disease in humans and animals. Recent studies demonstrated a genetic overlap between C. difficile isolated from animals and humans suggesting animals as possible reservoir for human pathogenic strains. This study was a preliminary investigation on the occurrence of C. difficile in rabbits raised in industrial holdings for food production and aimed to characterise isolates and estimate their antimicrobial susceptibility. C. difficile isolates were characterized by toxin profiles, toxinotyping and PCR-ribotyping. The MICs of six antibiotics were determined using E-test. Between 2007 and 2013, 285 industrial holdings (representing 40% of the national census) submitted rabbits to our laboratory for diagnostic purposes, among these holdings, groups of three to five post-weaned rabbits were sampled once by convenience. 1279 samples of caecal content were collected. The overall isolation rate of C. difficile from the enteric specimen was 3% (38/1279), with no difference among animals affected or not by enteric disorders. Among isolates 66% (25/38) were toxigenic. Sixteen different PCR-ribotypes (RTs) were identified. Among the toxigenic strains RT-014/020, RT-078 and RT-012 were found in at least three rabbit holdings. According to the ECOFF threshold, 82% (31/38) C. difficile isolates displayed a reduced susceptibility to at least one and 18% (7/38) to three tested antimicrobials. Rabbits are colonized by heterogeneous C. difficile ribotypes many of which are commonly isolated in humans. One third of isolates displayed a reduced susceptibility to MTZ, the first choice antimicrobial for human CDI treatment. According to our findings rabbits are a potential source of C. difficile for humans. PMID- 26507421 TI - Effect of the thin-film limit on the measurable optical properties of graphene. AB - The fundamental sheet conductance of graphene can be directly related to the product of its absorption coefficient, thickness and refractive index. The same can be done for graphene's fundamental opacity if the so-called thin-film limit is considered. Here, we test mathematically and experimentally the validity of this limit on graphene, as well as on thin metal and semiconductor layers. Notably, within this limit, all measurable properties depend only on the product of the absorption coefficient, thickness, and refractive index. As a direct consequence, the absorptance of graphene depends on the refractive indices of the surrounding media. This explains the difficulty in determining separately the optical constants of graphene and their widely varying values found in literature so far. Finally, our results allow an accurate estimation of the potential optical losses or gains when graphene is used for various optoelectronic applications. PMID- 26507422 TI - Operative Intercostal Nerve Blocks With Long-Acting Bupivacaine Liposome for Pain Control After Thoracotomy. AB - BACKGROUND: Postthoracotomy pain is quite intense. Epidural analgesia (EPI) has long been the gold standard but is often associated with hypotension and urinary retention. The recent availability of liposomal bupivacaine formulation (Exparel) stimulated us to use it for multilevel intercostal nerve blocks (IB) injected during open thoracotomy. METHODS: We reviewed the records of 85 patients who had open thoracotomies for lung, pleural, or mediastinal pathologies between March 2010 and December 2013. Clinical variables; pain score; supplemental narcotic utilization on day 1, 2, and 3; postoperative pulmonary complications; and hospital length of stay were compared in the 2 groups. RESULTS: In all, 53 patients in the IB group had similar clinical data compared to 32 in the EPI group. There were statistically significant lower mean pain scores on days 1 and 3, but no significant difference in pain score on day 2. Supplemental narcotic utilization was not different between the 2 groups. There was a significant decrease in pulmonary complications in the IB group (4 of 53) compared to the EPI group (8 of 32).The total length of hospital stay was 7.4 days in the IB group versus 9.3 days in EPI group (p < 0.05). CONCLUSIONS: It appears that intraoperative IB with bupivacaine liposome at 6 levels during thoracotomy provided significantly better pain control in postoperative days 1 and 3, compared to EPI in this retrospective study. This technique is simple, safe, and reproducible. It does not require epidural space invasion, infusion pumps, or another service to comanage the postoperative pain therapy. PMID- 26507423 TI - Bilateral Internal Thoracic Artery Composite Y Grafts: Analysis of 464 Angiograms in 296 Patients. AB - BACKGROUND: The use of bilateral internal thoracic arteries (BITA) in coronary artery bypass graft surgery improves patient survival. The optimum BITA graft configuration is unknown. This study evaluates outcomes after the use of bilateral internal mammary Y grafting as the primary grafting strategy. METHODS: Patients who underwent BITA composite Y grafting (n = 1,011) between October 1994 and March 2009 were identified from a cardiac surgical database. Follow-up (mean 12 years) was obtained by cross-reference with the state death registry and local cardiology databases. RESULTS: Perioperative mortality was 1.6%. Kaplan-Meier 10 year survival was 87.2%. There were 464 episodes of postdischarge angiography in 296 patients, at an average of 5.5 years to first angiography. Graft failure occurred in 151 patients, predominately affecting the right ITA limb (n = 139). Degree of native vessel stenosis (odds ratio [OR] 0.66 per 10% increase), anatomic territory grafted (circumflex OR 2.64, right coronary OR 6.73 versus anterior), and end-to-side free wall anastomoses (OR 1.98) predicted anastomotic occlusion. The left anterior descending artery graft patency was unaffected by sequential grafting. Progression to graft failure after the first angiogram was rarely seen in the 111 patients who had serial angiography. CONCLUSIONS: Outcomes of BITA Y grafting are similar to those for other BITA configurations. The rate of presentation with arterial graft dysfunction decreases over time. Although competitive flow affects anastomotic patency, there is no threshold at which risk of occlusion substantially increases. PMID- 26507424 TI - Adjuvant Therapy for Positive Nodes After Induction Therapy and Resection of Esophageal Cancer. AB - BACKGROUND: The value of adjuvant chemotherapy for patients with positive lymph nodes (+LNs) after induction therapy and resection of esophageal cancer is controversial. This study assesses survival benefit of adjuvant chemotherapy in this cohort. METHODS: We analyzed our single-institution database for patients with +LNs after induction therapy and resection of primary esophageal cancer between 2000 and 2013. Factors associated with survival were analyzed using a Cox proportional hazards model. RESULTS: A total of 101 of 764 esophagectomy patients received induction and had +LNs on final pathologic examination. Forty-five also received adjuvant therapy: 37 of 45 (82%) received chemotherapy alone, 1 of 45 (2%) received radiation alone, and 7 of 45 (16%) received both. Pathologic stage was IIB in 21 (47%), IIIA in 19 (42%), and IIIB in 5 (11%). In 56 node-positive patients with induction but not adjuvant therapy, pathologic stage was IIB in 28 (50%), IIIA in 18 (32%), IIIB in 7 (13%), and IIIC in 3 (5%). Neither age nor comorbidity score differed between cohorts. Adjuvant patients experienced a shorter hospital length of stay (mean, 10 days [range, 6 to 33 days] versus 11 days [range, 7 to 67 days]; p = 0.03]. Median survival favored the adjuvant group: 24.0 months (95% confidence interval, 16.6 to 32.2 months) versus 18.0 months (95% confidence interval, 11.1 to 25.0 months); p = 0.033). Multivariate Cox regression identified adjuvant therapy, length of stay, and number of +LNs as influential for survival. CONCLUSIONS: Optimal management of node-positive patients after induction therapy and esophagectomy remains unclear, but in this series, adjuvant therapy, length of stay, and number of +LNs impacted survival. A prospective trial may reduce potential bias and guide the evaluation of adjuvant therapy in this patient population. PMID- 26507425 TI - Gaps in Guideline-Concordant Use of Diagnostic Tests Among Lung Cancer Patients. AB - BACKGROUND: Practice guidelines recommend routine use of pulmonary function tests (PFTs), computed tomography (CT), and positron emission tomography (PET) for the workup of resectable lung cancer patients. Little is known about the frequency of guideline concordance in routine practice. METHODS: A cohort study (2007 to 2013) of 15,951 lung cancer patients undergoing lobectomy or pneumonectomy was conducted with MarketScan, a claims database of individuals with employer provided health insurance. Guideline concordance was defined by claims for PFT within 180 days of resection and for CT and PET within 90 days of resection. Generalized linear models were used to evaluate temporal trends, patient characteristics, and costs associated with guideline-concordant care. RESULTS: Overall, 61% of patients received guideline-concordant care, increasing from 57% in 2007 to 66% in 2013 (p < 0.001). Compared with patients who received guideline discordant care, patients with guideline-concordant care more frequently underwent repeat testing (PFT: 21% versus 12%, p < 0.001; CT: 46% versus 22%, p < 0.001; PET: 2.3% versus 1.1%, p < 0.001). Health plan-adjusted mean total test related costs were higher among guideline-concordant patients who underwent repeat testing than patients who did not ($4,304 versus $3,454, p < 0.001). CONCLUSIONS: Forty percent of lung cancer patients treated with surgical procedures did not receive recommended noninvasive cancer staging and physiologic assessment before resection. Guideline concordance was associated with repeat testing, and repeat testing was associated with higher costs. These findings support the need for quality improvement interventions that can increase guideline concordance while curbing potential excess use of diagnostic tests. PMID- 26507426 TI - Detection of Atrial Fibrillation After Surgical Ablation: Conventional Versus Continuous Monitoring. AB - BACKGROUND: Current guidelines recommend at least 24-hour Holter monitoring at 6 month intervals to evaluate the recurrence of atrial fibrillation (AF) after surgical ablation. In this prospective multicenter study, conventional intermittent methods of AF monitoring were compared with continuous monitoring using an implantable loop recorder (ILR). METHODS: From August 2011 to January 2014, 47 patients receiving surgical treatment for AF at 2 institutions had an ILR placed at the time of operation. Each atrial tachyarrhythmia (ATA) of 2 minutes or more was saved. Patients transmitted ILR recordings bimonthly or after any symptomatic event. Up to 27 minutes of data was stored before files were overwritten. Patients also underwent electrocardiography (ECG) and 24-hour Holter monitoring at 3, 6, and 12 months. ILR compliance was defined as any transmission between 0 and 3 months, 3 and 6 months, or 6 and 12 months. Freedom from ATAs was calculated and compared. RESULTS: ILR compliance at 12 months was 93% compared with ECG and Holter monitoring compliance of 85% and 76%, respectively. ILR devices reported a total of 20,878 ATAs. Of these, 11% of episodes were available for review and 46% were confirmed as AF. Freedom from ATAs was no different between continuous and intermittent monitoring at 1 year. Symptomatic events accounted for 187 episodes; however, only 10% were confirmed as AF. CONCLUSIONS: ILR was equivalent at detecting ATAs when compared with Holter monitoring or ECG. However, the high rate of false-positive readings and the limited number of events available for review present barriers to broad implementation of this form of monitoring. Very few symptomatic events were AF on review. PMID- 26507427 TI - Patterns and Predictors of Chemotherapy Use for Resected Non-Small Cell Lung Cancer. AB - BACKGROUND: Chemotherapy combined with surgical resection improves survival in patients with stage II to IIIA non-small cell lung cancer (NSCLC) and may benefit selected patients with stage IB disease. We sought to evaluate chemotherapy use in resected stage IB to IIIA NSCLC over time and to identify predictors of perioperative chemotherapy administration. METHODS: Patients with resected stage IB to IIIA NSCLC were identified from the National Cancer Data Base (2002 to 2011). Administration of chemotherapy was assessed over time. Hierarchical regression models were developed to assess patient, hospital, and tumor-level characteristics predicting perioperative chemotherapy administration. RESULTS: In 55,016 stage IB patients, chemotherapy use significantly increased between 2002 and 2011 from 5.3% to 15.1% (p < 0.001). In 57,033 patients with stage II to IIIA disease, perioperative chemotherapy administration also significantly increased from 29.3% to 58.4% (p < 0.001). Multivariable analyses demonstrated stage IB and II to IIIA patients were less likely to receive chemotherapy if they were older, treated at an academic center (vs community), had more comorbidities, or had lower-grade tumors (all p < 0.05). Stage IB patients with tumors sized 4 cm or larger were more likely to receive chemotherapy (odds ratio, 3.16; 95% confidence interval, 2.73 to 3.65) than those with tumors smaller than 4 cm. Compared with stage IIA patients, stage IIB patients were no more likely to receive perioperative chemotherapy (odds ratio, 1.06; 95% confidence interval, 0.96 to 1.17), whereas stage IIIA patients received chemotherapy significantly more often (odds ratio, 2.82; 95% confidence interval, 2.55 to 3.11). CONCLUSIONS: The use of chemotherapy has significantly increased in patients with resected stage IB to IIIA NSCLC. Although clinicians have increasingly adopted evidence-based recommendations, significant treatment gaps persist and represent areas for quality improvement. PMID- 26507428 TI - Randomized, placebo-controlled, double-blind clinical trial to evaluate the efficacy of polyhexanide for topical decolonization of MRSA carriers. AB - OBJECTIVES: The objective of this study was to evaluate the efficacy of polyhexanide (Prontoderm((r))) in eliminating MRSA carriage. METHODS: In a 1900 bed teaching hospital, MRSA-colonized patients were randomized into a double blind, placebo-controlled superiority trial between January 2011 and July 2014. Patients were treated with either polyhexanide or placebo applied to the anterior nares (thrice daily) and skin (once daily) for 10 days. The primary outcome was MRSA decolonization at day 28 (D28) after the end of treatment assessed by ITT responder and PP analyses (microbiological follow-up +/- 7 days and topical treatment >= 5 days). Secondary outcomes included safety, emergence of resistance and MRSA genotype changes. Registered trial number ISRCTN02288276. RESULTS: Of 2590 patients screened, 146 (polyhexanide group, 71; placebo group, 75) were included. ITT analysis showed that 24/71 (33.8%) patients in the polyhexanide group versus 22/75 (29.3%) in the placebo group were MRSA-free at D28 (risk difference, 4.5%; 95% CI, -10.6% to 19.5%; P = 0.56). PP analysis confirmed the results with 19/53 (35.8%) decolonized polyhexanide-treated patients versus 17/56 (30.4%) in the placebo arm (risk difference, 5.5%; 95% CI, -12.2% to 23%; P = 0.54). Nine serious adverse events occurred in the polyhexanide group versus 12 in the placebo group; none was attributable to study medication. Emergence of polyhexanide resistance or cross-resistance between polyhexanide and chlorhexidine was not observed. No case of exogenous recolonization by a genotypically different MRSA strain was documented. CONCLUSIONS: This study suggests that under real-life conditions, a single polyhexanide decolonization course is not effective in eradicating MRSA carriage. PMID- 26507429 TI - Personalized medicine for patients with MDR-TB. AB - The emergence of MDR-TB is a cause of great concern due to difficulties in patient management and poor treatment outcomes. Currently the duration of treatment and the choice of drugs for patients with MDR-TB are standardized in many countries. This might not be the best approach since the optimal therapy may depend on different pathogen- and host-related features. Combining the introduction of technological innovations such as whole bacillary genome sequencing for the identification of drug-resistance-associated mutations, therapeutic drug monitoring and host-directed therapies with an individualized approach to MDR-TB management will likely lead to more tolerable, shorter and more efficient treatment regimens and an increase in the quality of life of those affected by MDR-TB. PMID- 26507430 TI - Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase. AB - Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase (sEH) were investigated. First, a series of alkyl or aryl groups were substituted on the carbon alpha to the phosphonate function in amide compounds to see whether substituted phosphonates can act as a secondary pharmacophore. A tert-butyl group (16) on the alpha carbon was found to yield most potent inhibition on the target enzyme. A 4-50-fold drop in inhibition was induced by other substituents such as aryls, substituted aryls, cycloalkyls, and alkyls. Then, the modification of the O-substituents on the phosphonate function revealed that diethyl groups (16 and 23) were preferable for inhibition to other longer alkyls or substituted alkyls. In amide compounds with the optimized diethylphosphonate moiety and an alkyl substitution such as adamantane (16), tetrahydronaphthalene (31), or adamantanemethane (36), highly potent inhibitions were gained. In addition, the resulting potent amide-phosphonate compounds had reasonable water solubility, suggesting that substituted phosphonates in amide inhibitors are effective for both inhibition potency on the human sEH and water solubility as a secondary pharmacophore. PMID- 26507431 TI - Synthesis of potent urease inhibitors based on disulfide scaffold and their molecular docking studies. AB - Disulfide analogs (1-20) have been synthesized, characterized by HR-MS, (1)H NMR and (13)C NMR and screened for urease inhibitory potential. All compounds were found to have varied degree of urease inhibitory potential ranging in between 0.4 +/- 0.01 and 18.60 +/- 1.24 MUM when compared with standard inhibitor thiourea with IC50 19.46 +/- 1.20 MUM. Structure activity relationship has been established. The binding interactions of compounds with enzyme were confirmed through molecular docking. All the synthesized compounds 1-20 are new. Our compounds are cheaply synthesizable with high yield and can further be studied to discovery lead compounds. We further, tested for carbonic anhydrase, PDE1 and butyrylcholinesterase but they show no activity. On the other hand we evaluated all compounds for cytotoxicity they showed no toxicity. PMID- 26507432 TI - Targeted Shiga toxin-drug conjugates prepared via Cu-free click chemistry. AB - The main drawback of the anticancer chemotherapy consists in the lack of drug selectivity causing severe side effects. The targeted drug delivery appears to be a very promising strategy for controlling the biodistribution of the cytotoxic agent only on malignant tissues by linking it to tumor-targeting moiety. Here we exploit the natural characteristics of Shiga toxin B sub-unit (STxB) as targeting carrier on Gb3-positive cancer cells. Two cytotoxic conjugates STxB-doxorubicin (STxB-Doxo) and STxB-monomethyl auristatin F (STxB-MMAF) were synthesised using copper-free 'click' chemistry. Both conjugates were obtained in very high yield and demonstrated strong tumor inhibition activity in a nanomolar range on Gb3 positive cells. PMID- 26507433 TI - Preliminary findings demonstrating latent effects of early adolescent marijuana use onset on cortical architecture. AB - BACKGROUND: As the most commonly used illicit substance during early adolescence, long-term or latent effects of early adolescent marijuana use across adolescent developmental processes remain to be determined. METHODS: We examined cortical thickness, gray/white matter border contrast (GWR) and local gyrification index (LGI) in 42 marijuana (MJ) users. Voxelwise regressions assessed early-onset (age <16) vs. late-onset (>=16 years-old) differences and relationships to continued use while controlling for current age and alcohol use. RESULTS: Although groups did not differ by onset status, groups diverged in their correlations between cannabis use and cortical architecture. Among early-onset users, continued years of MJ use and current MJ consumption were associated with thicker cortex, increased GWR and decreased LGI. Late-onset users exhibited the opposite pattern. This divergence was observed in all three morphological measures in the anterior dorsolateral frontal cortex (p<.05, FWE-corrected). CONCLUSIONS: Divergent patterns between current MJ use and elements of cortical architecture were associated with early MJ use onset. Considering brain development in early adolescence, findings are consistent with disruptions in pruning. However, divergence with continued use for many years thereafter suggests altered trajectories of brain maturation during late adolescence and beyond. PMID- 26507434 TI - Development of chronic pulmonary aspergillosis in adult asthmatics with ABPA. AB - BACKGROUND: Chronic pulmonary aspergillosis (CPA) is an occasional complication of allergic bronchopulmonaryaspergillosis (ABPA) but the transition is poorly understood. METHODS: All patients referred to the UK's National Aspergillosis Centre with CPA between May 2009 and June 2012 were screened with serum total IgE and anti-Aspergillus IgE for a dual diagnosis of ABPA and CPA. Those patients suspected of having both conditions were re-evaluated and their imaging reviewed. RESULTS: Of 407 referred patients, 42 screened positive and 22 were confirmed as having both ABPA and CPA. Asthma was present from early childhood in 19 (86%), the median interval between ABPA and onset of CPA was 7.5 years; one patient developed ABPA and CPA simultaneously. Aspergillus IgG levels varied from 23 to 771 mg/L, median 82 mg/L. All 22 patients had bronchiectasis. In patients with ABPA, CT typically demonstrated varicose or cystic bronchiectasis primarily affecting segmental and proximal subsegmental upper lobe bronchi. Other findings included mucoid impaction and centrilobular nodules. Radiological changes associated with CPA included pleural thickening which was often bilateral and accentuated by adjacent hypertrophied extrapleural fat, upper lobe volume loss, thick walled apical cavities, some of which contained aspergillomas, and cavitating pulmonary nodules. CPA secondary to ABPA has more subtle radiological appearances than when due to other underlying diseases. CONCLUSIONS: CPA may complicate ABPA and have distinct radiology features, in addition to bronchiectasis. A novel biomarker is required to anticipate this serious complication, as current serology is not specific enough. PMID- 26507435 TI - Effect of the loading rate on compressive properties of goose eggs. AB - The resistance of goose (Anser anser f. domestica) eggs to damage was determined by measuring the average rupture force, specific deformation and rupture energy during their compression at different compression speeds (0.0167, 0.167, 0.334, 1.67, 6.68 and 13.36 mm/s). Eggs have been loaded between their poles (along X axis) and in the equator plane (Z axis). The greatest amount of force required to break the eggs was required when eggs were loaded along the X axis and the least compression force was required along the Z axis. This effect of the loading orientation can be described in terms of the eggshell contour curvature. The rate sensitivity of the eggshell rupture force is higher than that observed for the Japanese quail's eggs. PMID- 26507437 TI - Does Poststroke Lower-Limb Spasticity Influence the Recovery of Standing Balance Control? A 2-Year Multilevel Growth Model. AB - Background Poststroke lower-limb spasticity (LLS) has been shown to degrade standing balance control by disrupting the temporal synchronization between individual limb centers of pressure (COPs). Time-varying changes in standing balance control associated with alterations in the extent of LLS have yet to be documented and are important to informing treatment strategies to improve such functional outcomes. Objective The present work aimed to understand the natural recovery of standing balance control among stroke survivors with LLS using limb specific indices of standing balance control. Furthermore, we sought to understand if time-varying changes in LLS were associated with alterations in standing balance control. Methods A retrospective analysis of 92 participants was performed; 47 participants never exhibited LLS during the study (No_LLS), and 45 participants exhibited LLS during at least 1 testing session (LLS). Quiet standing for a duration of 30 s on 2 force platforms was recorded. Temporal synchrony and spatial symmetry of COP displacements were assessed, along with interlimb weight-bearing symmetry. Results All variables, except spatial symmetry, indicated initial improvement followed by deceleration in the rate of balance control recovery. Limb-specific measures indicated that individuals with LLS exhibited deficits in balance control. The recovery trajectories were not different between groups, suggesting a similar rate, but reduced extent, of balance control recovery among the LLS relative to the No_LLS group. Only temporal synchrony was altered by time-varying changes in spasticity. Conclusions The present results suggest that the reduction in spasticity may be beneficial to balance control recovery. PMID- 26507436 TI - Evaluating markers of epithelial-mesenchymal transition to identify cancer patients at risk for metastatic disease. AB - Most cancer deaths are due to metastases. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells could be helpful to assess patient risk of metastatic disease, even among those otherwise diagnosed with local disease. Previous studies of EMT markers and patient outcomes used inconsistent methods and did not compare the clinical impact of different expression cut points for the same marker. Using digital image analysis, we measured the EMT markers Snail and E-cadherin in primary tumor specimens from 190 subjects in tissue microarrays from a population-based prospective cohort of colorectal cancer patients and estimated their associations with time-to-death. After measuring continuous marker expression data, we performed a systematic search for the cut point for each marker with the best model fit between dichotomous marker expression and time-to-death. We also assessed the potential clinical impact of different cut points for the same marker. After dichotomizing expression status at the statistically-optimal cut point, we found that Snail expression was not associated with time-to-death. When measured as a weighted average of tumor cores, low E-cadherin expression was associated with a greater risk of dying within 5 years of surgery than high expression (risk difference = 33 %, 95 % confidence interval 3-62 %). Identifying a clinically-optimal cut point for an EMT marker requires trade-offs between strength and precision of the association with patient outcomes, as well as consideration of the number of patients whose treatments might change based on using the marker at a given cut point. PMID- 26507438 TI - Dosage Effect of Zinc Glycine Chelate on Zinc Metabolism and Gene Expression of Zinc Transporter in Intestinal Segments on Rat. AB - Zinc plays an essential role in various fundamental biological processes. The focus of this research was to investigate the dosage effect of zinc glycine chelate (Zn-Gly) on zinc metabolism and the gene expression of zinc transporters in intestinal segments. A total of 30 4-week-old SD rats were randomized into five treatment groups. The basal diets for each group were supplemented with gradient levels of Zn (0, 30, 60, 90, and 180 mg/kg) from Zn-Gly. After 1-week experiment, the results showed that serum and hepatic zinc concentration were elevated linearly with supplemental Zn levels from 0 to 180 mg Zn/kg. Serum Cu-Zn SOD activities resulted in a significant (P < 0.01) quadratic response and reached the peak when fed 60 mg Zn/kg. There were linear responses to the addition of Zn-Gly from 0 to 180 mg Zn/kg on Cu-Zn SOD and AKP activities in the liver. In the duodenum, MT1 mRNA was upregulated with the increasing dietary Zn Gly levels and reached the peak of 180 mg Zn/kg (P < 0.05). Zip4 mRNA expression was downregulated with the increasing zinc levels (P < 0.05) in both duodenum and jejunum. In the jejunum, Zip5 mRNA expression in 60 mg Zn/kg was higher compared with other groups (P < 0.05). ZnT1 mRNA in duodenum was numerically increased with the rising levels of zinc content and was significantly higher (P < 0.05) with 180 mg Zn/kg. In the duodenum, adding 60 or 90 mg Zn/kg increased PepT1 expression, but in the jejunum, 60 mg Zn/kg did not differ from 0 added Zn. In summary, there is a dose-dependent effect of dietary Zn-Gly on serum and hepatic zinc levels and the activities of Cu-Zn SOD and AKP on rats. Dietary Zn-Gly has a certain effect on MT1, Zip4, Zip5, and ZnT1 expression, which expressed differently in intestinal segments with different levels of Zn-Gly load. Besides, Zn-Gly also could regulate PepT1 expression in intestinal segments. PMID- 26507439 TI - Selenium Induces an Anti-tumor Effect Via Inhibiting Intratumoral Angiogenesis in a Mouse Model of Transplanted Canine Mammary Tumor Cells. AB - Selenium (Se) has been widely reported to possess anti-tumor effects. Angiogenesis is the formation of new blood vessels and is required to supply oxygen, nutrients, and growth factors for tumor growth, progression, and metastasis. To explore whether the anti-tumor effect of Se was associated with angiogenesis in vivo, we studied the effects of sodium selenite (Sel) and methylseleninic acid (MSA) on tumors induced by canine mammary tumor cells (CMT1211) in mice; cyclophosphamide (CTX) served as a positive control. The results showed that the Se content was significantly increased in the Sel and MSA groups. Se significantly inhibited the tumor weights and volumes. Large necrotic areas and scattered and abnormal small necrotic areas were observed in the Se treatment group. Immunofluorescence double staining showed a reduction in the microvessel density (MVD) and increment in the vessel maturation index (VMI) compared with the untreated control group. As expected, the protein and mRNA levels of the angiogenesis factors angiopoietin-2 (Ang-2), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) were decreased in the Se-treated tumors by IHC, as shown by western blotting and RT QPCR. We also found that organic Se MSA provided stronger inhibition of tumor growth compared with inorganic sodium selenite (Sel). Altogether, our results indicated that Se exerted anti-tumor effects in vivo at least partially by inhibiting angiogenic factors. PMID- 26507440 TI - Effect of Dietary Selenium Deficiency on the Cell Apoptosis and the Level of Thyroid Hormones in Chicken. AB - This study assessed the effect of dietary selenium (Se) deficiency on male reproductive function in chicken. A total of 180 Hy-line laying cocks (1 day old; Weiwei) were randomly divided into 2 groups (n = 90) of Se-deficient chickens and control chickens. The control group was fed a basic diet (containing 0.15 mg of Se/kg). The Se-deficient group was fed a Se-deficient corn-soy basal diet (containing 0.033 mg of Se/kg). Fifteen chickens were killed in each group on days 30, 60, and 90, respectively. Then, serum and testes were collected and used in the detection of experimental index. Results indicated that GSH-Px activity and Bcl-2 mRNA level in the testes and thyroidal triiodothyronine (T3) and free triiodothyronine (FT3) levels in serum by dietary Se deficiency were significantly decreased compared to the corresponding control groups. Se deficiency-treated group showed a significant increase in MDA concent, TUNEL positive cells, and mRNA level of Bax, Caspase3, and p53 in the testes and thyroidal thyroxine (T4), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) levels in serum. Histopathologically, Se deficiency caused impairments in the testes. These results suggested that dietary Se deficiency exerts significant harmful effects on male reproductive organ and that the intrinsic and extrinsic pathways and the upstream regulators such as p53, Bax, and Bcl-2 were all involved in Se deficiency-induced testicular apoptosis. PMID- 26507441 TI - Acceptance and commitment therapy as a nonpathologizing intervention approach for survivors of trauma. AB - Acceptance and commitment therapy (ACT; Hayes, Strosahl, & Wilson, 2012) is proposed as a nonpathologizing approach to trauma-related problems. ACT has at its core a functional approach to understanding the human condition such that problems are maintained by functional processes, such as avoidance. Treatment focuses on these processes to institute change, stepping away from directly pursuing symptoms as an evaluative outcome. A collaborative, client-centered approach is used in defining valued life directions and committing to action based on those values. ACT presents a method of approaching trauma-related problems that is structured to support a client in finding a life beyond trauma that has value. PMID- 26507442 TI - Dynamics of HIV infection in lymphoid tissue network. AB - Human immunodeficiency virus (HIV) is a fast replicating ribonucleic acid virus, which can easily mutate in order to escape the effects of drug administration. Hence, understanding the basic mechanisms underlying HIV persistence in the body is essential in the development of new therapies that could eradicate HIV infection. Lymphoid tissues are the primary sites of HIV infection. Despite the recent progress in real-time monitoring technology, HIV infection dynamics in a whole body is unknown. Mathematical modeling and simulations provide speculations on global behavior of HIV infection in the lymphatic system. We propose a new mathematical model that describes the spread of HIV infection throughout the lymphoid tissue network. In order to represent the volume difference between lymphoid tissues, we propose the proportionality of several kinetic parameters to the lymphoid tissues' volume distribution. Under this assumption, we perform extensive numerical computations in order to simulate the spread of HIV infection in the lymphoid tissue network. Numerical computations simulate single drug treatments of an HIV infection. One of the important biological speculations derived from this study is a drug saturation effect generated by lymphoid network connection. This implies that a portion of reservoir lymphoid tissues to which drug is not sufficiently delivered would inhibit HIV eradication despite of extensive drug injection. PMID- 26507443 TI - Historical perspective on the DNA damage response. AB - The DNA damage response (DDR) has been broadly defined as a complex network of cellular pathways that cooperate to sense and repair lesions in DNA. Multiple types of DNA damage, some natural DNA sequences, nucleotide pool deficiencies and collisions with transcription complexes can cause replication arrest to elicit the DDR. However, in practice, the term DDR as applied to eukaryotic/mammalian cells often refers more specifically to pathways involving the activation of the ATM (ataxia-telangiectasia mutated) and ATR (ATM-Rad3-related) kinases in response to double-strand breaks or arrested replication forks, respectively. Nevertheless, there are distinct responses to particular types of DNA damage that do not involve ATM or ATR. In addition, some of the aberrations that cause replication arrest and elicit the DDR cannot be categorized as direct DNA damage. These include nucleotide pool deficiencies, nucleotide sequences that can adopt non-canonical DNA structures, and collisions between replication forks and transcription complexes. The response to these aberrations can be called the genomic stress response (GSR), a term that is meant to encompass the sensing of all types of DNA aberrations together with the mechanisms involved in coping with them. In addition to fully functional cells, the consequences of processing genomic aberrations may include mutagenesis, genomic rearrangements and lethality. PMID- 26507444 TI - Chemical Characterization of Beer Aging Products Derived from Hard Resin Components in Hops (Humulus lupulus L.). AB - The bitter taste of beer originates from resins in hops (Humulus lupulus L.), which are classified into two subtypes (soft and hard). Whereas the nature and reactivity of soft-resin-derived compounds, such as alpha-, beta-, and iso-alpha acids, are well studied, there is only a little information on the compounds in hard resin. For this work, hard resin was prepared from stored hops and investigated for its compositional changes in an experimental model of beer aging. The hard resin contained a series of alpha-acid oxides. Among them, 4' hydroxyallohumulinones were unstable under beer storage conditions, and their transformation induced primary compositional changes of the hard resin during beer aging. The chemical structures of the products, including novel polycyclic compounds scorpiohumulinols A and B and dicyclohumulinols A and B, were determined by HRMS and NMR analyses. These compounds were proposed to be produced via proton-catalyzed cyclization reactions of 4'-hydroxyallohumulinones. Furthermore, they were more stable than their precursor 4'-hydroxyallohumulinones during prolonged storage periods. PMID- 26507445 TI - Impartial information about alcohol during pregnancy or another modern day witch hunt? PMID- 26507446 TI - Poor Sleep Is Related to Lower Emotional Competence Among Adolescents. AB - The aim of the present study was to explore the association between subjective insomnia and self-reported emotional competence in areas such as regulating and perceiving one's own emotions and empathy, in a sample of adolescents. Gender differences were also explored. 366 adolescents in 10th to 12th grade (mean age: M = 16.9 years) took part in this cross-sectional study. They completed questionnaires related to emotional competencies, empathy, and sleep. Higher scores for insomnia were associated with lower scores for some aspects of emotional competence and empathy. Compared to males, females generally had higher scores for emotional competence. Poor sleep as subjectively experienced among adolescents is associated with specific impairments in emotional competence and empathy. Gender-related patterns were also observed. PMID- 26507447 TI - Possible paraneoplastic syndrome case of bullous pemphigoid with immunoglobulin G anti-BP180 C-terminal domain antibodies associated with psoriasis and primary macroglobulinemia. AB - A 61-year-old Japanese man developed bullous skin lesions during topical therapy for psoriasis vulgaris. Physical examination demonstrated numerous tense bullae and scaly erythemas on the trunk and extremities. Histopathology of the skin biopsy demonstrated subepidermal bullae and lymphocytic infiltration with eosinophils in the dermis. Direct immunofluorescence revealed linear deposits of immunoglobulin (Ig)G, IgA and C3 along the basement membrane zone. Indirect immunofluorescence of 1 mol/L NaCl-split skin showed IgG reactivity with both epidermal and the dermal sides. IgM reactivity with both the epidermal and dermal sides was also detected. Enzyme-linked immunosorbent assays showed negative results for both BP180 and BP230. Immunoelectrophoresis of serum and bone marrow aspiration revealed underlying primary macroglobulinemia with M-proteinemia of IgM-kappa type. Immunoblot analysis revealed IgG, but not IgM, antibodies to recombinant protein of BP180 C-terminal domain. We diagnosed the present case as bullous pemphigoid with IgG anti-BP180 C-terminal domain autoantibodies associated with primary macroglobulinemia and psoriasis vulgaris. Systemic administration of prednisolone 30 mg/day resulted in dramatic improvement of both bullous and psoriatic skin lesions. When the bullous and psoriatic lesions relapsed, DRC chemotherapy (dexamethasone, rituximab and cyclophosphamide) for macroglobulinemia was performed. Then, the psoriatic lesions improved and the bullous lesions disappeared. We suggested that the present case may be paraneoplastic syndrome of bullous pemphigoid associated with primary macroglobulinemia and psoriasis vulgaris. PMID- 26507448 TI - Attitudes toward and willingness to work with older people among undergraduate nursing students in a public university in Sri Lanka: A cross sectional study. AB - BACKGROUND: With the increased number of older people globally, caring for older people has become a challenge for many countries. Nurses have a pivotal role in providing quality care for older people and care is affected by their attitudes. The preparation of nurses to deliver quality care needs to be instilled during their studying in the Schools of Nursing. OBJECTIVE: To examine the attitudes of nursing students toward and their willingness to work with older people in Sri Lanka. METHODOLOGY: A purposive sample of 98 first to fourth year undergraduate nursing students in the Department of Nursing, University of Peradeniya completed a self-administered questionnaire consisting of socio-demographic variables, Kogan's Attitudes toward Older People Scale, and questions related to willingness to work with older people. RESULTS: Fifty percent of the respondents (n=49) held slightly positive attitudes toward older people while 45% (n=44) held slightly negative attitudes. About one-third of the respondents (29.9%, n=29) selected the elderly group as the least preferred group for their future career from the categorized seven age groups. Only 5.1% (n=5) of the respondents ranked the elderly group as the first preferred group. There was a significant difference in attitudes between students who lived with older people and students who did not live with older people (t=2.565, p=.012). There was a positive relationship between attitudes and preference for working with older people (r=.342, p=.001). CONCLUSION: Nursing students have moderately positive attitudes toward older people; however, they show little interest in working with older people. Living with older people develops positive attitudes of young people toward older people. Attitudes are related to the selection in area of specialty in nursing. Nursing curricula need to include Gerontological Nursing as a major area. PMID- 26507449 TI - Undergraduate nursing students and cross-cultural care: A program evaluation. AB - OBJECTIVE: The purpose of this study was to evaluate baccalaureate nursing students' perspectives on their acquired cultural competency following the integration of a transcultural nursing thread throughout the curriculum. This research is as part of an ongoing program evaluation. DESIGN: A cross-sectional survey design utilizing The Residents Physicians' Preparedness to Provide Cross Cultural Care Survey (Weissman et al., 2005). The instrument was adapted and used as the Nursing Education in Cross-Cultural Care Survey. This survey consisted of five sections: training, cross-cultural experiences, resources, specialty areas, and personal and professional characteristics. SETTING: The setting for this research was a baccalaureate school of nursing at a small university in rural Hawaii. PARTICIPANTS: A convenience sample of 56 graduating senior nursing students over a 2-year period participated in the study. RESULTS: Students perceived themselves as somewhat prepared to provide cultural competent care. Limited exposure and utilization of interpreters, lack of role models and mentors, and unpreparedness to counsel different cultures in the area of terminal health were the lowest scoring subsections. Students learned best in the clinical setting compared to classroom setting. CONCLUSIONS: Nursing program evaluation needs to be systematic and ongoing. All programs need to determine whether program goals were met. This survey tool assisted faculty to evaluate the integration of the transcultural thread throughout the nursing curriculum. At the end of the nursing program, students were somewhat prepared to deliver cross cultural care. Areas were identified for program improvement. PMID- 26507450 TI - The Courage to Care-An innovative arts-based event to engage students and the local community to reflect on Australian nurses' roles in the First World War and after. AB - There is a large body of work that documents the history of the nursing profession and the experiences of nurses during significant historical eras such as the First World War. Yet learning about nursing history is commonly a tiny, or absent, component in the undergraduate nursing curriculum. This paper discusses an innovative project that had multiple aims. A primary aim was to engage nursing students and educators in a project that valued nursing history by integrating it into an event to celebrate International Nurses Day. As the paper will explain, other aims were in organising the event so that it capitalised on particular creative arts strengths within the faculty, offering cross-disciplinary connections, engagement and appreciation. A Readers' Theatre event, involving academics and students in nursing, creative arts and education, was conceived, developed and performed for the community. The theme was the experiences of First World War nurses and how they encapsulated values important to nursing today - the 6 Cs - which guide high standards of nursing. The 6 Cs are care, compassion, competence, communication, courage and commitment. We called the Readers' Theatre "The Courage to Care", and this involved a 4month process of script development, event planning and a performance. This process and outcomes were evaluated, prompting a reflection on the strengths and challenges of working in this creative way to engage a wide group of stakeholders to advance the profession of nursing. PMID- 26507451 TI - Dietary inflammatory index and endometrial cancer risk in an Italian case-control study. AB - The relation between inflammation deriving from diet and endometrial cancer risk has not yet been investigated. In this study, we explored the association between the dietary inflammatory index (DII) and endometrial cancer risk in an Italian case-control study. Cases comprised 454 patients with incident, histologically confirmed carcinoma of the endometrium, and controls comprised 908 subjects admitted to the same network of hospitals as cases for a wide spectrum of acute, non-neoplastic conditions. DII scores were computed on the basis of dietary intake assessed using a reproducible and valid seventy-eight-item FFQ. OR were calculated through logistic regression models conditioned on age and study centre and adjusted for recognised confounding factors, including total energy intake. Women with the most pro-inflammatory diet had a higher risk for endometrial cancer compared with women with the most anti-inflammatory diet (OR(Quartile) 4 v. 1 1.46; 95% CI 1.02, 2.11; P(trend)=0.04). A pro-inflammatory diet may increase the risk for endometrial cancer. PMID- 26507452 TI - Tunnel technique versus coronally advanced flap with acellular dermal matrix graft in the treatment of multiple gingival recessions. AB - AIM: The aim of this randomized controlled clinical study was to evaluate the outcomes of acellular dermal matrix (ADM) graft in combination with tunnel technique (TUN) on root coverage, aesthetics, and patient satisfaction and to compare with coronally advanced flap (CAF)+ADM in the treatment of multiple gingival recessions. MATERIAL AND METHODS: A total of 20 patients with 58 Miller Class I multiple recessions >=3 mm were included and divided into TUN+ADM and CAF+ADM groups. At baseline and 12 months, probing depth (PD), clinical attachment level (CAL), recession height (RH) and width (RW), keratinized tissue height (KT), gingival thickness, and complete and mean root coverage (CRC, MRC) were evaluated. Patient satisfaction and root coverage aesthetic scores (RES) were also assessed. RESULTS: Mean root coverage was 75.72% in TUN+ADM and 93.81% in CAF+ADM. Intragroup comparisons revealed significant differences at 12 months for all parameters in both groups (p < 0.05). Intergroup differences were found to be statistically significant for RH and RW reduction, KT increase, CAL gain, MRC, CRC, and RES in favour of CAF+ADM group (p < 0.05). CONCLUSION: Both techniques were effective in root coverage of multiple recessions; however, better clinical results were achieved with CAF and ADM combination. PMID- 26507454 TI - miR-346 and miR-138 competitively regulate hTERT in GRSF1- and AGO2-dependent manners, respectively. AB - miRNAs typically downregulate the expression of target genes by binding to their 3'UTR, and dysregulation of miRNAs may contribute to tumorigenesis. Here, we found that miR-346 and miR-138 competitively bind to a common region in the 3'UTR of hTERT mRNA and have opposite effects on the expression and function of hTERT in human cervical cancer cells. Furthermore, G-rich RNA sequence binding factor 1 (GRSF1) mediates the miR-346-dependent upregulation of hTERT by binding to the miR-346 middle sequence motif (CCGCAU) which forms a "bulge loop" when miR-346 is bound to the hTERT 3'UTR, facilitating the recruitment of hTERT mRNA to ribosomes to promote translation in an AGO2-independent manner. Conversely, miR-138 suppresses hTERT expression in an AGO2-dependent manner. Interestingly, replacement of the miR-138 middle sequence with that of miR-346 results in an upregulation of hTERT expression in a GRSF1-dependent manner. Moreover, miR-346 depends on GRSF1 to upregulate another target gene, activin A receptor, type IIB (ACVR2B), in which miR-346 "CCGCAU" motif is essential. These findings reveal novel mechanisms of miRNA-mediated upregulation of target gene expression and describe the coordinated action of multiple miRNAs to control the fate of a single target mRNA through binding to its 3'UTR. PMID- 26507455 TI - Pressure-dependent regulation of Ca2+ signalling in the vascular endothelium. AB - KEY POINTS: Increased pressure suppresses endothelial control of vascular tone but it remains uncertain (1) how pressure is sensed by the endothelium and (2) how the vascular response is inhibited. This study used a novel imaging method to study large numbers of endothelial cells in arteries that were in a physiological configuration and held at normal blood pressures. Increased pressure suppressed endothelial IP3 -mediated Ca(2+) signals. Pressure modulated endothelial cell shape. The changes in cell shape may alter endothelial Ca(2+) signals by modulating the diffusive environment for Ca(2+) near IP3 receptors. Endothelial pressure-dependent mechanosensing may occur without a requirement for a conventional molecular mechanoreceptor. ABSTRACT: The endothelium is an interconnected network upon which haemodynamic mechanical forces act to control vascular tone and remodelling in disease. Ca(2+) signalling is central to the endothelium's mechanotransduction and networked activity. However, challenges in imaging Ca(2+) in large numbers of endothelial cells under conditions that preserve the intact physical configuration of pressurized arteries have limited progress in understanding how pressure-dependent mechanical forces alter networked Ca(2+) signalling. We developed a miniature wide-field, gradient-index (GRIN) optical probe designed to fit inside an intact pressurized artery that permitted Ca(2+) signals to be imaged with subcellular resolution in a large number (~200) of naturally connected endothelial cells at various pressures. Chemical (acetylcholine) activation triggered spatiotemporally complex, propagating inositol trisphosphate (IP3 )-mediated Ca(2+) waves that originated in clusters of cells and progressed from there across the endothelium. Mechanical stimulation of the artery, by increased intraluminal pressure, flattened the endothelial cells and suppressed IP3 -mediated Ca(2+) signals in all activated cells. By computationally modelling Ca(2+) release, endothelial shape changes were shown to alter the geometry of the Ca(2+) diffusive environment near IP3 receptor microdomains to limit IP3 -mediated Ca(2+) signals as pressure increased. Changes in cell shape produce a geometric microdomain regulation of IP3 -mediated Ca(2+) signalling to explain macroscopic pressure-dependent, endothelial mechanosensing without the need for a conventional mechanoreceptor. The suppression of IP3 -mediated Ca(2+) signalling may explain the decrease in endothelial activity as pressure increases. GRIN imaging provides a convenient method that gives access to hundreds of endothelial cells in intact arteries in physiological configuration. PMID- 26507456 TI - A Combined Crystallographic and Theoretical Study Explains the Capability of Carboxylic Acids to Adopt Multiple Binding Modes in the Active Site of Carbonic Anhydrases. AB - Carboxylates are the least investigated class of inhibitors of carbonic anhydrases (CAs). Here we explain the versatility of binding of these molecules to CAs by examining a new adduct of hCA II with N-carboxymethyl-saccharin. PMID- 26507457 TI - Neofunctionalization of Androgen Receptor by Gain-of-Function Mutations in Teleost Fish Lineage. AB - Steroid hormone receptor family provides an example of evolution of diverse transcription factors through whole-genome duplication (WGD). However, little is known about how their functions have been evolved after the duplication. Teleosts present a good model to investigate an accurate evolutionary history of protein function after WGD, because a teleost-specific WGD (TSGD) resulted in a variety of duplicated genes in modern fishes. This study focused on the evolution of androgen receptor (AR) gene, as two distinct paralogs, ARalpha and ARbeta, have evolved in teleost lineage after TSGD. ARalpha showed a unique intracellular localization with a higher transactivation response than that of ARbeta. Using site-directed mutagenesis and computational prediction of protein-ligand interactions, we identified two key substitutions generating a new functionality of euteleost ARalpha. The substitution in the hinge region contributes to the unique intracellular localization of ARalpha. The substitution on helices 10/11 in the ligand-binding domain possibly modulates hydrogen bonds that stabilize the receptor-ligand complex leading to the higher transactivation response of ARalpha. These substitutions were conserved in Acanthomorpha (spiny-rayed fish) ARalphas, but not in an earlier branching lineage among teleosts, Japanese eel. Insertion of these substitutions into ARs from Japanese eel recapitulates the evolutionary novelty of euteleost ARalpha. These findings together indicate that the substitutions generating a new functionality of teleost ARalpha were fixed in teleost genome after the divergence of the Elopomorpha lineage. Our findings provide a molecular explanation for an adaptation process leading to generation of the hyperactive AR subtype after TSGD. PMID- 26507458 TI - The effect of modulated electro-hyperthermia on the pharmacokinetic properties of nefopam in healthy volunteers: A randomised, single-dose, crossover open-label study. AB - PURPOSE: Nefopam is a widely available analgesic for the management of pain. The aim of this study was to reveal the effect of regional hyperthermia of the abdominal area on the pharmacokinetics of nefopam. MATERIALS AND METHODS: A randomised, single-dose, crossover, open-label study was conducted to reveal the effect of hyperthermia using modulated electro-hyperthermia on the pharmacokinetics of nefopam. The pharmacokinetics of orally administered nefopam without hyperthermia was studied in 12 healthy volunteers and then 7 days later they were treated with nefopam plus modulated electro-hyperthermia to the abdominal area for 1 h. Blood samples were collected up to 24 h after the drug administration. From the blood concentration-time curve, the maxinum plasma concentration (C(max)), time to C(max) (T(max)) and the area under the curve (AUC) were obtained. The safety and tolerability of these treatments were also assessed. RESULTS: The geometric mean ratios (GMRs) ((nefopam + modulated electro hyperthermia)/nefopam) and the associated 90% confidence intervals (CIs) for C(max), AUC(last) and AUC(inf) were 1.2804 (1.1155~1.4696), 1.0512 (0.9555~1.1566) and 1.0612 (0.9528~1.1819), respectively. The increase in C(max) was statistically significant, and T(max) was significantly shortened. CONCLUSIONS: The significant increase in C(max) and decrease in T(max) indicated that modulated electro-hyperthermia increased the absorption of the orally administered nefopam, thereby transitionally increasing the blood concentration of the drug. The AUC is an important parameter that contributes to the therapeutic effect of drugs. The lack of significant change in AUC suggests that modulated electro-hyperthermia may increases the absorption of orally administered drugs without increasing the systemic adverse effect of the drugs. PMID- 26507459 TI - Mitochondrial superoxide dismutase deficiency accelerates chronological aging in the fission yeast Schizosaccharomyces pombe. AB - A mitochondrial superoxide dismutase (SOD2) is the first line of antioxidant defense against mitochondrial superoxide. Even though the involvement of SOD2 in lifespan has been studied extensively in several organisms, characterization of the aging process has not been performed for the sod2 mutant (sod2Delta) of a prominent model Schizosaccharomyces pombe. In this study, we measured the chronological lifespan of sod2Delta cells by their ability to survive in long term culture. SOD2 deficiency drastically decreased cell viability in the stationary phase. The mutation frequency of nuclear DNA in sod2Delta was elevated in the stationary phase, and cellular proteins and nuclear DNA were extensively degraded, concurrent with cell death. The sod2 gene in wild-type cells could be induced by an increase in endogenous oxidative stresses, after which, SOD2 activity was substantially elevated during the stationary phase. Culture in a lower glucose concentration (calorie restriction) prominently extended the sod2Delta lifespan. Therefore, S. pombe SOD2 plays a critical role in longevity through its upregulation in the non-dividing phase. PMID- 26507460 TI - Appraisal of guidelines for androgenetic alopecia using the Appraisal of Guidelines for Research and Evaluation II instrument. AB - RATIONALE, AIMS AND OBJECTIVES: The purpose of this study is to systematically evaluate the quality of methodological guidelines for androgenetic alopecia (AGA) using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument by searching and analysing the available worldwide guidelines. This could provide a reference for selecting clinical guidelines and for developing new guidelines in the future. METHODS: We searched PubMed and other electronic databases for any AGA guidelines published until 2014. The AGREE II instrument was used by two researchers to create a systematic appraisal in six domains to determine the guidelines fulfilling the inclusion and exclusion criteria. RESULTS: Five guidelines associated with the therapy of AGA were identified. The mean scores for the six AGREE II domains were as follows: 89.45% for 'scope and purpose', 53.88% for 'stakeholder involvement', 53.96% for 'rigour of development', 87.22% for 'clarity of presentation', 42.92% for 'applicability' and 59.16% for 'editorial independence'. The European guideline ranked the highest, whereas the American guideline of 1996 ranked the lowest. The Asian, European and Japanese guidelines were strongly recommended, and the two from America were recommended with modifications. CONCLUSIONS: Guidelines should provide accurate and evidence-based recommendations. The AGREE II instrument is a useful tool to improve the quality of guidelines, and high-quality guidelines for clinical practice can be provided by using it. PMID- 26507461 TI - Restraint use in the Eastern Province of the Kingdom of Saudi Arabia. AB - OBJECTIVES: This study set out to examine seat belt and child restraint use in the Dammam Municipality of the Kingdom of Saudi Arabia, based on the premise that an increase in seat belt use would significantly reduce personal injury in traffic crashes. It was expected that local data would help identify intervention strategies necessary to improve seat belt use in the region. METHODS: The research involved 2 methodologies. First, 1,389 face-to-face interviews were conducted with male and female adults in regional shopping plazas regarding their own and their children's restraint use in their vehicles and reasons for these attitudes and beliefs. Second, 2 on-road observation studies of adult and child restraint use were conducted by trained observers. Occupants of approximately 5,000 passenger vehicles were observed while stopped at representative signalized traffic intersections. RESULTS: The findings showed front seat belt use rates of between 43 and 47% for drivers and 26 to 30% for front seat passengers; rear seat belt use rates were lower. While there seemed to be some knowledge about the purpose and reasons for restraining both adults and children in suitable restraints, this failed to be confirmed in the on-road observations. CONCLUSIONS: Reasons for these rates and findings are discussed fully, and recommendations for improving seat belt use in the Dammam Municipality are included. PMID- 26507462 TI - Elution of Clindamycin and Enrofloxacin From Calcium Sulfate Hemihydrate Beads In Vitro. AB - OBJECTIVE: To compare the in vitro elution characteristics of clindamycin and enrofloxacin from calcium sulfate hemihydrate beads containing a single antibiotic, both antibiotics, and each antibiotic incubated in the same eluent well. STUDY DESIGN: Experimental in vitro study. METHODS: Calcium sulfate hemihydrate beads were formed by mixing with clindamycin and/or enrofloxacin to create 4 study groups: (1) 160 mg clindamycin/10 beads; (2) 160 mg enrofloxacin/10 beads; (3) 160 mg clindamycin + 160 mg enrofloxacin/10 beads; and (4) 160 mg clindamycin/5 beads and 160 mg enrofloxacin/5 beads. Chains of beads were formed in triplicate and placed in 5 mL phosphate buffered saline (PBS; pH 7.4 and room temperature) with constant agitation. Antibiotic-conditioned PBS was sampled at 14 time points from 1 hour to 30 days. Clindamycin and enrofloxacin concentrations in PBS were determined using high-performance liquid chromatography. RESULTS: Eluent concentrations from clindamycin-impregnated beads failed to remain sufficiently above minimum inhibitory concentration (MIC) for common infecting bacteria over the study period. Enrofloxacin eluent concentrations remained sufficiently above MIC for common wound pathogens of dogs and cats and demonstrated an atypical biphasic release pattern. No significant differences in elution occurred as a result of copolymerization of the antibiotics into a single bead or from individual beads co-eluting in the same eluent well. CONCLUSION: Clindamycin-impregnated beads cannot be recommended for treatment of infection at the studied doses; however, use of enrofloxacin impregnated beads may be justified when susceptible bacteria are cultured. PMID- 26507463 TI - Functional organization of an Mbp enhancer exposes striking transcriptional regulatory diversity within myelinating glia. AB - In mammals, large caliber axons are ensheathed by myelin, a glial specialization supporting axon integrity and conferring accelerated and energy-efficient action potential conduction. Myelin basic protein (MBP) is required for normal myelin elaboration with maximal mbp transcription in oligodendrocytes requiring the upstream M3 enhancer. To further characterize the mechanism regulating mbp transcription, we defined M3 structure/function relationships by evaluating its evolutionary conservation, DNA footprints and the developmental programing conferred in mice by M3 derivatives. Multiple M3 regulatory element combinations were found to drive expression in oligodendrocytes and Schwann cells with a minimal 129 bp sequence conferring expression in oligodendrocytes throughout myelin elaboration, maintenance and repair. Unexpectedly, M3 derivatives conferred markedly different spatial and temporal expression programs thus illuminating striking transcriptional heterogeneity within post-mitotic oligodendrocytes. Finally, one M3 derivative engaged only during primary myelination, not during adult remyelination, demonstrating that transcriptional regulation in the two states is not equivalent. PMID- 26507464 TI - Sublingual immunotherapy for allergic rhinitis: where are we now? AB - Sublingual immunotherapy (SLIT) was introduced in the 1980s as a safer option to subcutaneous immunotherapy and in the latest decade achieved significant advances. Its efficacy in allergic rhinitis is supported by a number of meta analyses. The development of SLIT preparations in tablets to fulfill the requirements of regulatory agencies for quality of allergen extracts made available optimal products for grass-pollen-induced allergic rhinitis. Preparations of other allergens based on the same production methods are currently in progress. A notable outcome of SLIT, that is shared with subcutaneous immunotherapy, is the evident cost-effectiveness, showing significant cost savings as early as 3 months from starting the treatment, that become as high as 80% compared with drug treatment in the ensuing years. PMID- 26507465 TI - Oxidation resistance 1 (OXR1) participates in silkworm defense against bacterial infection through the JNK pathway. AB - Bacterial infection causes enhanced reactive oxygen species (ROS) levels in insects. Oxidation resistance 1 (OXR1) plays an antioxidant role in eukaryotic organisms, including insects. In this report, we demonstrated that Pseudomonas aeruginosa and Staphylococcus aureus infection and hydrogen peroxide (H2 O2 ) injection induced the expression of specific transcriptional isoforms of OXR1 in larval silkworms. We further showed that a Jun kinase (JNK) pathway inhibitor, SP600125, down-regulated expression of OXR1 during infection, leading to elevated H2 O2 levels in the hemolymph, resulting in lower viability of the injected bacteria inside the silkworm larvae. Our study suggests that OXR1 participates in protecting larval silkworms from oxidative stress and bacterial infection through the JNK pathway. PMID- 26507466 TI - Coupling spindle position with mitotic exit in budding yeast: The multifaceted role of the small GTPase Tem1. AB - The budding yeast S. cerevisiae divides asymmetrically and is an excellent model system for asymmetric cell division. As for other asymmetrically dividing cells, proper spindle positioning along the mother-daughter polarity axis is crucial for balanced chromosome segregation. Thus, a surveillance mechanism named Spindle Position Checkpoint (SPOC) inhibits mitotic exit and cytokinesis until the mitotic spindle is properly oriented, thereby preventing the generation of cells with aberrant ploidies. The small GTPase Tem1 is required to trigger a Hippo-like protein kinase cascade, named Mitotic Exit Network (MEN), that is essential for mitotic exit and cytokinesis but also contributes to correct spindle alignment in metaphase. Importantly, Tem1 is the target of the SPOC, which relies on the activity of the GTPase-activating complex (GAP) Bub2-Bfa1 to keep Tem1 in the GDP bound inactive form. Tem1 forms a hetero-trimeric complex with Bub2-Bfa1 at spindle poles (SPBs) that accumulates asymmetrically on the bud-directed spindle pole during mitosis when the spindle is properly positioned. In contrast, the complex remains symmetrically localized on both poles of misaligned spindles. We have recently shown that Tem1 residence at SPBs depends on its nucleotide state and, importantly, asymmetry of the Bub2-Bfa1-Tem1 complex does not promote mitotic exit but rather controls spindle positioning. PMID- 26507467 TI - Multitarget Strategy to Address Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and Computational Studies of Coumarin-Based Derivatives. AB - Alzheimer's disease (AD) is a major public health challenge that faces an aging global population. Current drug treatment has demonstrated only symptomatic efficacy, leaving an unmet medical need for a new generation of disease-modifying therapies. Following the multitarget-directed ligand approach, a small library of coumarin-based derivatives was designed and synthesized as a follow-up to our studies on AP2238, aimed at expanding its biological profile. The coumarin substitution pattern at the 6- or 7-position was modified by introducing alkyl chains of variable lengths and with different terminal amino functional groups. 3 (4-{[Benzyl(ethyl)amino]methyl}phenyl)-6-({5-[(7-methoxy-6H-indeno[2,1-b]quinolin 11-yl)amino]pentyl}oxy)-2H-chromen-2-one, bearing the bulkiest amine, emerged as a non-neurotoxic dual acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) inhibitor, potentially suitable for the treatment of the middle stage of AD. Furthermore, the introduction of a diethylamino spacer, as in 3-(4 {[benzyl(ethyl)amino]methyl}phenyl)-6-{[5-(diethylamino)pentyl]oxy}-2H-chromen-2 one and 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H chromen-2-one, led to nanomolar human AChE inhibitors endowed with significant inhibitory activity toward Abeta42 self-aggregation, whereas the reference compound was completely ineffective. Furthermore, 3-(4 {[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one also showed promising neuroprotective behavior, which makes it a potential candidate for development into a disease-modifying agent. PMID- 26507468 TI - Editors' note. PMID- 26507469 TI - Advancing SCI health care to avert rehospitalization. AB - This commentary reflects on the high rate of health care utilization among individuals with traumatic spinal cord injury (SCI) in the first year of injury as reported by Skelton et al. in the current issue of this journal. Commentary argues that the variation in risk-adjusted rehospitalization rates suggests that there is considerable opportunity for improvement. Authors note that we need better strategies to prevent the onset of the 3 conditions that drive most of the rehospitalization, namely, urinary tract infections, pneumonia, and pressure ulcers. Commentary also urges providers to rethink and reinvent the process of care in acute, rehabilitation, and post-discharge phases of care. It recommends that SCI centers take greater advantage data resources already available such as the National Spinal Cord Injury Database to openly share and compare center-to center differences in practice and outcomes. It also urges SCI centers to reinvent their systems of care in ways being made possible under health care reform, especially systems that make all providers in a given episode of care from acute to rehabilitation to post-discharge care, mutually and financially accountable for both outcomes and costs including emergency room use and rehospitalization. PMID- 26507472 TI - Correction: NanoSIMS analysis of an isotopically labelled organometallic ruthenium(II) drug to probe its distribution and state in vitro. AB - Correction for 'NanoSIMS analysis of an isotopically labelled organometallic ruthenium(II) drug to probe its distribution and state in vitro' by Ronald F. S. Lee et al., Chem. Commun., 2015, DOI: 10.1039/c5cc06983a. PMID- 26507471 TI - Velocity-selective-inversion prepared arterial spin labeling. AB - PURPOSE: To develop a Fourier-transform based velocity-selective inversion (FT VSI) pulse train for velocity-selective arterial spin labeling (VSASL). METHODS: This new pulse contains paired and phase cycled refocusing pulses. Its sensitivities to B0/B1 inhomogeneity and gradient imperfections such as eddy currents were evaluated through simulation and phantom studies. Cerebral blood flow (CBF) quantification using FT-VSI prepared VSASL was compared with conventional VSASL and pseudocontinuous ASL (PCASL) at 3 Tesla. RESULTS: Simulation and phantom results of the proposed FT-VSI pulse train demonstrated excellent robustness to B0/B1 field inhomogeneity and eddy currents. The estimated CBF of gray matter and white matter for the FT-VSI prepared VSASL, averaged among eight healthy volunteers, were 49.5 +/- 7.5 mL/100 g/min and 14.8 +/- 2.4 mL/100 g/min, respectively. Excellent correlation and agreement between the FT-VSI method and conventional VSASL and PCASL were found. The averaged signal-to-noise ratio (SNR) value in gray matter of the FT-VSI method was 39% higher than VSASL using conventional double refocused hyperbolic tangent pulses and 9% lower than PCASL. CONCLUSION: A novel FT-VSI pulse train was demonstrated to be a suitable labeling module for VSASL with robustness of velocity-selective profile to B0/B1 field inhomogeneity and gradient imperfections. Compared with conventional VSASL, FT-VSI prepared VSASL produced consistent CBF maps with higher SNR values. Magn Reson Med 76:1136-1148, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26507473 TI - Evaluation and comparison of the in vitro characteristics and chondrogenic capacity of four adult stem/progenitor cells for cartilage cell-based repair. AB - Cell-based therapy is being considered as a promising approach to regenerate damaged cartilage. Though, autologous chondrocyte implantation is the most effective strategy currently in use, but is hampered by some drawbacks seeking comprehensive research to surmount existing limitations or introducing alternative cell sources. In this study, we aimed to evaluate and compare the in vitro characteristics and chondrogenic capacity of some easily available adult cell sources for use in cartilage repair which includes: bone marrow-derived mesenchymal stem cells (MSC), adipose tissue-derived MSC, articular chondrocyte progenitors, and nasal septum-derived progenitors. Human stem/progenitor cells were isolated and expanded. Cell's immunophenotype, biosafety, and cell cycle status were evaluated. Also, cells were seeded onto aligned electrospun poly (l lactic acid)/poly (epsilon-caprolactone) nanofibrous scaffolds and their proliferation rate as well as chondrogenic potential were assessed. Cells were almost phenotypically alike as they showed similar cell surface marker expression pattern. The aligned nanofibrous hybrid scaffolds could support the proliferation and chondrogenic differentiation of all cell types. However, nasal cartilage progenitors showed a higher proliferation potential and a higher chondrogenic capacity. Though, mostly similar in the majority of the studied features, nasal septum progenitors demonstrated a higher chondrogenic potential that in combination with their higher proliferation rate and easier access to the source tissue, introduces it as a promising cell source for cartilage tissue engineering and regenerative medicine. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 600-610, 2016. PMID- 26507474 TI - Catalysis is the science of controlling reactivity on a molecular level. Introduction. PMID- 26507475 TI - Iridium-mediated Bond Activation and Water Oxidation as an Exemplary Case of CARISMA, A European Network for the Development of Catalytic Routines for Small Molecule Activation. AB - CARISMA is a currently running COST Action that pools leading European experts in computational and experimental chemistry to foster synergies for developing new catalytic processes for the transformation of abundant small molecules such as water, carbon dioxide, or ammonia into high-value chemicals and energy-relevant products. CARISMA promotes new collaborations, exchange of knowledge and skills, frontier training to young as well as established researchers, and a platform for the advancement of theoretical and experimental research in an iterative process, comprised of expertise in various connate domains including synthesis, catalysis, spectroscopy, kinetics, and computational chemistry. These interactions stimulate the discovery of new and efficient catalytic processes, illustrated in the second part of this contribution with the collaborative development of powerful iridium based complexes for bond activation and water oxidation catalysis. PMID- 26507476 TI - The Role of Proton Transfer in Heterogeneous Transformations of Hydrocarbons. AB - Heterogeneous catalysis is essential for the transformation of light hydrocarbons into chemical feedstocks. Many of the catalysts that mediate these transformations consist of isolated metal ions on the surface of a metal oxide support, such as silica or alumina. Due to the complexity of these catalysts, studying the active site and mechanism of these reactions is difficult. Surface organometallic chemistry (SOMC) could offer a solution to this problem by allowing the synthesis of well-defined surface organometallic species. This approach has been used to study the reactions of light hydrocarbons with isolated metal species on silica and alumina surfaces. These studies showed that proton transfers play a key role in the reactions of many hydrocarbons. The mechanisms of these reactions and their role in some common catalytic cycles are discussed. PMID- 26507477 TI - Nitrous Oxide-dependent Iron-catalyzed Coupling Reactions of Grignard Reagents. AB - The formation of carbon-carbon bonds is one of the fundamental transformations in chemistry. In this regard the application of palladium-based catalysts has been extensively investigated during recent years, but nowadays research focuses on iron catalysis, due to sustainability, costs and toxicity issues; hence numerous examples for iron-catalyzed cross-coupling reactions have been established, based on the coupling of electrophiles (R(1)-X, X = halide) with nucleophiles (R(2) MgX). Only a small number of protocols deals with the iron-catalyzed oxidative coupling of nucleophiles (R(1)-MgX + R(2)-MgX) with the aid of oxidants (1,2 dihaloethanes). However, some issues arise with these oxidants; hence more recently the potential of the industrial waste product nitrous oxide (N(2)O) was investigated, because the unproblematic side product N(2) is formed. Based on that, we demonstrate the catalytic potential of easily accessible iron complexes in the oxidative coupling of Grignard reagents. Importantly, nitrous oxide was essential to obtain yields up to >99% at mild conditions (e.g. 1 atm, ambient temperature) and low catalyst loadings (0.1 mol%) Excellent catalyst performance is realized with turnover numbers of up to 1000 and turnover frequencies of up to 12000 h(-1). Moreover, a good functional group tolerance is observed (e.g. amide, ester, nitrile, alkene, alkyne). Afterwards the reaction of different Grignard reagents revealed interesting results with respect to the selectivity of cross coupling product formation. PMID- 26507478 TI - New Wind in Old Sails: Novel Applications of Triphos-based Transition Metal Complexes as Homogeneous Catalysts for Small Molecules and Renewables Activation. AB - Recent developments in the coordination chemistry and applications of Ru-triphos [triphos = 1,1,1-tris-(diphenylphosphinomethyl)ethane] systems are reviewed, highlighting their role as active and selective homogenous catalysts for small molecule activation, biomass conversions and in carbon dioxide utilization related processes. PMID- 26507479 TI - Effect of 2-Propanol on the Transfer Hydrogenation of Aldehydes by Aqueous Sodium Formate using a Rhodium(I)-sulfonated Triphenylphosphine Catalyst. AB - In water/2-propanol mixtures [RhCl(mtppms)(3)] (mtppms = monosulfonated triphenylphosphine) was an efficient catalyst for the selective C=C reduction of trans-3-phenyl-2-propenal (trans-cinnamaldehyde) by hydrogen transfer from formate at temperatures as low as 30 degrees C. An outstandingly high catalyst turnover frequency of 1214 h(-1) was determined at 70 degrees C. A possible mechanism of the reaction is suggested on the basis of kinetic studies and (1)H- and (31)P-NMR spectroscopic identification of the major Rh(I) species in the reaction mixtures as cis-mer-[H(2)RhX(mtppms)(3)] (X = HCOO(-) or H(2)O). It was established that a large part but not all of the rate increase observed in water/2-propanol mixtures in comparison with systems with neat water as solvent was the consequence of complete dissolution of trans-cinnamaldehyde on the effect of the co-solvent. Nevertheless, the rate showed a significant further increase with increasing 2-propanol concentration even in homogeneous solution and this was ascribed to changes in the solvent structure. The high catalyst activity in this solvent mixture allowed the transfer hydrogenation of citral. Although good to excellent conversions were observed at 30-70 degrees C, a useful degree of selectivity in hydrogenation of C=C vs. C=O bonds could not be achieved. PMID- 26507480 TI - Transition Metal-free Methylation of Amines with Formaldehyde as the Reductant and Methyl Source. AB - A simple transition metal-free procedure using formal dehyde for the N,N dimethylation and N-methylation of primary and secondary anilines is reported. The reaction showed limitations on sterically hindered and electron-withdrawing anilines, but is successful on amines with electron-donating substituents. Formaldehyde acts as both the reducing agent and the carbon source in the reaction. PMID- 26507481 TI - Dehydrogenation of Formic Acid by Heterogeneous Catalysts. AB - Formic acid has recently been considered as one of the most promising hydrogen storage materials. The basic concept is briefly discussed and the research progress is detailledly reviewed on the dehydrogenation of aqueous formic acid by heterogeneous catalysts. PMID- 26507482 TI - Conditions for the Use of CO2. AB - This review presents several aspects of the utilization of carbon dioxide. In particular, it will consider the conditions for its correct utilization in order to reduce its emission into atmosphere and to size the demand of CO(2) that may be used within several different industrial sectors, spanning from fine chemicals to bulk chemicals, intermediates and fuels. PMID- 26507483 TI - The Management Centre Innsbruck Keeping one step ahead with algae innovation. AB - MCI - Management Center Innsbruck is an innovative breeding ground for making algae biotechnological concepts economically attractive, useful for society and environmentally friendly. For biotechnet Switzerland there are solid reasons for entering into a strategic partnership with the MCI in the domain of bioresource technologies at the international level. PMID- 26507484 TI - ORION - A Global Approach to Waste Management. AB - In the ORION project supported by the European Commission, 20 partners work together to manage organic waste from agro-food industries. The goal is to develop a small, automatic and user-friendly digestion machine to facilitate the domestic on-site treatment of a wide range of organic waste from around 100 and up to 5000 tonnes per year at low cost and with limited maintenance. Simon Crelier at the HES-SO Valais/Wallis is part of the network. PMID- 26507489 TI - Research on the drying kinetics of household food waste for the development and optimization of domestic waste drying technique. AB - Domestic food waste drying foresees the significant reduction of household food waste mass through the hygienic removal of its moisture content at source. In this manuscript, a new approach for the development and optimization of an innovative household waste dryer for the effective dehydration of food waste at source is presented. Food waste samples were dehydrated with the use of the heated air-drying technique under different air-drying conditions, namely air temperature and air velocity, in order to investigate their drying kinetics. Different thin-layer drying models have been applied, in which the drying constant is a function of the process variables. The Midilli model demonstrated the best performance in fitting the experimental data in all tested samples, whereas it was found that food waste drying is greatly affected by temperature and to a smaller scale by air velocity. Due to the increased moisture content of food waste, an appropriate configuration of the drying process variables can lead to a total reduction of its mass by 87% w/w, thus achieving a sustainable residence time and energy consumption level. Thus, the development of a domestic waste dryer can be proved to be economically and environmentally viable in the future. PMID- 26507490 TI - Cudrania tricuspidata water extract improved obesity-induced hepatic insulin resistance in db/db mice by suppressing ER stress and inflammation. AB - BACKGROUND: Obesity can play a role in the development of hepatic insulin resistance. Although the molecular mechanism of the association between obesity and hepatic insulin resistance is unclear, it has been reported that obesity leads to hepatic endoplasmic reticulum (ER) stress and inflammation, which can induce the development of insulin resistance in several tissues. OBJECTIVE: In this study, we investigated the associations between hepatic insulin resistance, ER, and inflammation in obesity and the effect of water extract from Cudrania tricuspidata leaves (CTL) on hepatic insulin resistance induced by ER stress and inflammation in db/db mice. DESIGN: The mice were randomly divided into four groups: a normal control group (C57BL/6J), a control group (C57BL/6J-db/db), a CTL 100 group (C57BL/6J-db/db mice fed a dietary supplement of 100 mg/kg of CTL), and a CTL 300 group (C57BL/6J-db/db mice fed a dietary supplement of 300 mg/kg of CTL). After 8 weeks, we performed an oral glucose tolerance test and the mice were sacrificed. RESULTS: The C57BL/6J-db/db mice developed obesity and hyperglycemia, and the ER stress response and inflammation were activated in their livers. Interestingly, there was a marked decrease in the activation of the ER stress response and insulin resistance in the livers of the C57BL/6J-db/db mice treated with CTL due to decreases in the phosphorylation of eIF2alpha, IRE1alpha, and IRS-1 serine and decreases in the mRNA expression of ATF4, c-Jun N terminal kinase, C/EBPalpha, and C/EBP homologous protein. Dietary supplementation with CTL also induced a statistically significant decrease in the expression of pro-inflammatory cytokines, C-reactive protein (CRP), and NF-kappaB phosphorylation. CONCLUSIONS: Overall, these results suggest that CTL can improve hepatic insulin resistance and hyperglycemia by controlling obesity-induced ER stress and inflammation in the liver and that CTL may be a useful agent in treating hyperglycemia. PMID- 26507491 TI - Nutritional assessment methods for zinc supplementation in prepubertal non-zinc deficient children. AB - BACKGROUND: Zinc is an essential nutrient that is required for numerous metabolic functions, and zinc deficiency results in growth retardation, cell-mediated immune dysfunction, and cognitive impairment. OBJECTIVE: This study evaluated nutritional assessment methods for zinc supplementation in prepubertal non-zinc deficient children. DESIGN: We performed a randomised, controlled, triple-blind study. The children were divided into a control group (10% sorbitol, n=31) and an experimental group (10 mg Zn/day, n=31) for 3 months. Anthropometric and dietary assessments as well as bioelectrical measurements were performed in all children. RESULTS: Our study showed (1) an increased body mass index for age and an increased phase angle in the experimental group; (2) a positive correlation between nutritional assessment parameters in both groups; (3) increased soft tissue, and mainly fat-free mass, in the body composition of the experimental group, as determined using bioelectrical impedance vector analysis; (4) increased consumption of all nutrients, including zinc, in the experimental group; and (5) an increased serum zinc concentration in both groups (p<0.0001). CONCLUSIONS: Given that a reference for body composition analysis does not exist for intervention studies, longitudinal studies are needed to investigate vector migration during zinc supplementation. These results reinforce the importance of employing multiple techniques to assess the nutritional status of populations. PMID- 26507492 TI - Infant and adult pupil dilation in response to unexpected sounds. AB - Surprisingly occurring sounds outside the focus of attention can involuntarily capture attention. This study focuses on the impact of deviant sounds on the pupil size as a marker of auditory involuntary attention in infants. We presented an oddball paradigm including four types of deviant sounds within a sequence of repeated standard sounds to 14-month-old infants and to adults. Environmental and noise deviant sounds elicited a strong pupil dilation response (PDR) in both age groups. In contrast, moderate frequency deviants elicited a significant PDR in adults only. Moreover, a principal component analysis revealed two components underlying the PDR. Component scores differ, depending on deviant types, between age groups. Results indicate age effects of parasympathetic inhibition and sympathetic activation of the pupil size caused by deviant sounds with a high arousing potential. Results demonstrate that the PDR is a sensitive tool for the investigation of involuntary attention to sounds in preverbal children. PMID- 26507493 TI - A rational approach to fluid therapy in sepsis. AB - Aggressive fluid resuscitation to achieve a central venous pressure (CVP) greater than 8 mm Hg has been promoted as the standard of care, in the management of patients with severe sepsis and septic shock. However recent clinical trials have demonstrated that this approach does not improve the outcome of patients with severe sepsis and septic shock. Pathophysiologically, sepsis is characterized by vasoplegia with loss of arterial tone, venodilation with sequestration of blood in the unstressed blood compartment and changes in ventricular function with reduced compliance and reduced preload responsiveness. These data suggest that sepsis is primarily not a volume-depleted state and recent evidence demonstrates that most septic patients are poorly responsive to fluids. Furthermore, almost all of the administered fluid is sequestered in the tissues, resulting in severe oedema in vital organs and, thereby, increasing the risk of organ dysfunction. These data suggest that a physiologic, haemodynamically guided conservative approach to fluid therapy in patients with sepsis would be prudent and would likely reduce the morbidity and improve the outcome of this disease. PMID- 26507494 TI - Dexamethasone alone vs in combination with transcutaneous electrical acupoint stimulation or tropisetron for prevention of postoperative nausea and vomiting in gynaecological patients undergoing laparoscopic surgery. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is commonly reported after surgery and anaesthesia. We compared the effects of combinations of electrical acupoint stimulation or tropisetron with dexamethasone with the effects of dexamethasone alone, for inhibition of PONV in gynaecological patients undergoing laparoscopic surgery. METHODS: We randomized 157 patients undergoing elective gynaecological laparoscopic surgery under general anaesthesia into the following three groups: acupoint stimulation+dexamethasone (Group Acu, n=53), tropisetron+dexamethasone (Group Trp, n=53), and dexamethasone alone (Group Dxm, n=51). The incidence of nausea, vomiting, and need for rescue antiemetics was recorded 2, 6, 24, and 48 h after surgery. RESULTS: We found significant differences in the incidence of PONV during 24 h after surgery between the combination therapy groups and the dexamethasone-alone group (P=0.021). In the first 24 h, 28% of patients in Group Acu, 26% of patients in Group Trp, and 50% of patients in Group Dxm experienced nausea, vomiting, or both. The incidence of 24 h PONV in Group Acu was significantly lower than that in Group Dxm (P=0.048; odds ratio 0.389; 95% CI 0.170-0.891). The incidence of 24 h PONV in Group Trp was also significantly lower than that in Group Dxm (P=0.042; odds ratio 0.359; 95% CI 0.157-0.819). There was no significant difference between Group Acu and Group Trp (P=0.857). The need for antiemetic rescue medication was similar in the three groups. All groups expressed similar patient satisfaction. CONCLUSIONS: Combined with dexamethasone, electrical acupoint stimulation or tropisetron is more effective in PONV prophylaxis than dexamethasone alone in gynaecological patients undergoing laparoscopic surgery. CLINICAL TRIAL REGISTRATION: NCT 02096835. PMID- 26507495 TI - Potential Exposure to Ebola Virus from Body Fluids due to Ambulance Compartment Permeability in Sierra Leone. AB - INTRODUCTION: Prehospital care, including patient transport, is integral in the patient care process during the Ebola response. Transporting ill persons from the community to Ebola care facilities can stop community spread. Vehicles used for patient transport in infectious disease outbreaks should be evaluated for adequate infection prevention and control. PROBLEM: An ambulance driver in Sierra Leone attributed his Ebola infection to exposure to body fluids that leaked from the patient compartment to the driver cabin of the ambulance. METHODS: A convenience sample of 14 vehicles used to transport patients with suspected or confirmed Ebola in Sierra Leone were assessed. The walls separating the patient compartment and driver cabin in these vehicles were evaluated for structural integrity and potential pathways for body fluid leakage. Ambulance drivers and other staff were asked to describe their cleaning and decontamination practices. Ambulance construction and design standards from the National Fire Protection Association, US General Services Administration, and European Committee on Standardization (CEN) were reviewed. RESULTS: Many vehicles used by ambulance staff in Sierra Leone were not traditional ambulances, but were pick-up trucks or sport-utility vehicles that had been assembled or modified for patient transport. The wall separating the patient compartment and driver cabin in many vehicles did not have a waterproof seal around the edges. Staff responsible for cleaning and disinfection did not thoroughly clean bulk body fluids with disposable towels before disinfection of the patient compartment. Pressure from chlorine sprayers used in the decontamination process may have pushed body fluids from the patient compartment into the driver cabin through gaps around the wall. Ambulance design standards do not require a waterproof seal between the patient compartment and driver cabin. Sealing the wall by tightening or replacing existing bolts is recommended, followed by caulking of all seams with a sealant. CONCLUSION: Waterproof separation between the patient compartment and driver cabin may be essential for patient transport vehicles in infectious disease outbreaks, especially when chlorine sprayers are used for decontamination or in resource limited settings where cleaning supplies may be limited. PMID- 26507496 TI - [Early goal-directed therapy for septic shock : Systematic review and meta analysis]. PMID- 26507497 TI - Lung protective ventilation and hospital survival of cardiac intensive care patients. AB - OBJECTIVE: To detect connections between parameters of ventilation and outcomes of cardiac intensive care patients. DESIGN AND SETTING: Noninterventional study. Between 05/11 and 05/12 all patients with acute heart failure and post cardiopulmonary resuscitation were registered. Lung protective ventilation was defined as peak inspiratory pressure (PIP) < 30 mmHg and tidal volume (Vt) < = 6 ml/kg. RESULTS: In total, 129 patients were included in the study, 68.2 % male, age 67.9 +/- 13.4 years, weight 71.4 +/- 37.2 kg, predictive body weight 66.9 +/- 8.8 kg, mortality 47.3 %. Lung protective ventilated patients at day 1: 17.3 % with a significant difference between surviving and nonsurviving patients (24.1 % vs. 9.6 %; p < 0.05). Logistic regression models showed a strong connection between PIP and survival (odds ratio 1.13; p < 0.05). Vt showed no significant influence on survival. CONCLUSION: Our data recommends a strict observance of a low PIP for cardiac intensive care patients, whereas Vt seems to be of secondary importance. PMID- 26507498 TI - Metabolic syndrome and the risk of breast cancer among postmenopausal women in North-West China. AB - OBJECTIVE: To determine whether metabolic syndrome (MetS) and its components are risk factors for breast cancer among postmenopausal women in China. METHODS: Based on the baseline data of the Jinchang Cohort, a case-control study was carried out among postmenopausal women, including 43 cases and 86 controls. Both MetS and its components were evaluated. Odds ratios and 95% confidence intervals (CI) for the association were estimated by conditional logistic regression analysis. RESULTS: The odds ratio of postmenopausal breast cancer was 3.505 (95% CI 1.282-9.583) for MetS, 3.016 (95% CI 1.044-8.715) for body mass index (BMI) >= 25 kg/m(2), and 3.191 (95% CI 1.253-8.125) for dyslipidemia. There was no significant association between postmenopausal breast cancer and hypertension as well as diabetes. Women with four metabolic factors showed greater risk for postmenopausal breast cancer (p(trend) < 0.05). Dyslipidemia and BMI >= 25 kg/m(2) showed most significant interaction on breast cancer (odds ratio = 11.359; 95% CI 2.663-48.450). With BMI >= 25 kg/m(2), the interaction of dyslipidemia and other metabolic factors on breast cancer was higher than that without BMI >= 25 kg/m(2). CONCLUSION: This case-control study suggested that MetS was associated with an elevated risk of breast cancer among postmenopausal women in north-west China. Overweight and dyslipidemia had the strongest adverse effects on postmenopausal breast cancer. PMID- 26507499 TI - Is there hope to treat glioblastoma effectively? AB - Thomas Mehrling was appointed Managing Director of Mundipharma EDO GmbH, Basel, in January 2013 and brings extensive experience with more than 17 years in the industry to this role. During his career, he has held various senior positions in different companies across almost all functions in drug development and commercialization. Most recently, he held the position of International Director Oncology Strategy (2011-2013). From 2004 to 2011 he served as European Director Oncology at Mundipharma International Ltd. During his tenure the oncology business of the European Mundipharma network of independent associated companies was set up and two major products were launched in Europe, DepoCyte(r) and Levact(r) (Ribomustin(r), Treanda(r)). He joined Mundipharma in 2000 as Head of Business Development. Prior to Mundipharma, he was Senior Vice President of the global CRO Medical Affairs at Staticon International, and prior to this he acted as Medical Leader at Takeda European R&D center. Dr. Mehrling is a certified Pharmacist with a PhD in pharmacology and a certified Physician trained in haemato-oncology. He obtained his PhD from Frankfurt University following work on developing a new 5-HT3 antagonist to treat nausea and vomiting and developed a particular interest in mechanisms of multidrug resistance into chemotherapy. Dr. Mehrling earned his MD degree through his work in the Department of Internal medicine at Frankfurt University (Hemato-oncology and Cardiology) where he worked for several years before starting his career in the pharmaceutical industry. PMID- 26507500 TI - A feedback regulatory loop involving p53/miR-200 and growth hormone endocrine axis controls embryo size of zebrafish. AB - In vertebrates, growth hormone/insulin-like growth factor (GH/IGF) axis signaling plays a critical role in regulating somatic growth. Understanding the direct upstream regulators of GH/IGF axis remains a major challenge. Our studies of the zebrafish reveal that the conserved miR-200 family members are critical regulators of embryo size by targeting several GH/IGF axis genes, including GH, GHRa, GHRb and IGF2a. Overexpression of miR-200s led to cell cycle arrest in the G1 phase and induced apoptotic responses during embryo development, thereby inhibiting somatic growth of zebrafish embryos. Intriguingly, GH induced expression of both p53 and miR-200s, and miR-200s is a potential p53 transcriptional target, thus forming a negative feedback loop. Significantly, the up-regulation of miR-200s associated with GH activation is abolished in embryos with p53 mutation. By integrating these studies, we conclude that p53/miR-200 and GH/IGF signaling pathway form a negative regulatory loop to control embryo size, that provide critical insights into the long-standing puzzle of how body growth is determined during early development of teleosts. PMID- 26507501 TI - The Awakening of Alice. PMID- 26507502 TI - Accurate Clinical Data is Vital in the Age of Surgeon Level Outcome Reporting. PMID- 26507503 TI - Association Between Fibulin-1 and Aortic Augmentation Index in Male Patients with Peripheral Arterial Disease. AB - BACKGROUND: Fibulin-1 (FBLN-1), a newly identified biomarker for vascular stiffness in type 2 diabetes, may participate in the pathophysiological processes leading to progression of arterial stiffness in atherosclerosis. In the present study, the relationship between FBLN-1 and arterial stiffness was examined in patients with atherosclerosis and in healthy subjects. METHODS: Thirty-eight patients with peripheral arterial disease (PAD) (age 62.4 +/- 9.0 years), 38 patients with coronary artery disease (CAD) (age 64.0 +/- 9.5 years), and 30 apparently healthy controls (age 61.1 +/- 6.4 years) were studied. Serum FBLN-1, oxidized low density lipoprotein (oxLDL), resistin and plasminogen activator inhibitor-1 (PAI-1) levels were measured using the enzyme linked immunosorbent assay method. The technique of applanation tonometry was used for non-invasive pulse wave analysis and pulse wave velocity assessments. RESULTS: The levels of FBLN-1 (PAD = 9.4 [4.9-17.8] vs. CAD = 7.1 [4.8-11.8] vs. controls = 5.6 [4.1 8.4] MUg/mL; p = .005), carotid-femoral pulse wave velocity (cf-PWV) (9.8 +/- 2.2 vs. 9.5 +/- 2.2 vs. 8.3 +/- 2.2 m/s; p = .023) and the heart rate corrected augmentation index (AIx@75) (29.4 +/- 7.2 vs. 19.2 +/- 7.2 vs. 15.4 +/- 7.1%; p < .001), differed among the three groups. A correlation between FBLN-1 and AIx@75 was observed only in patients with PAD (rho = 0.37, p = .021). The relationship retained statistical significance in a multiple regression model after adjustment for potential confounders. CONCLUSIONS: An independent association was demonstrated between serum FBLN-1 and AIx@75 in the PAD group. Thus, the findings suggest that FBLN-1 may play a role in arterial stiffening in patients with atherosclerosis. PMID- 26507504 TI - Evaluation of interventions for informed consent for randomised controlled trials (ELICIT): protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey. AB - BACKGROUND: The process of obtaining informed consent for participation in randomised controlled trials (RCTs) was established as a mechanism to protect participants against undue harm from research and allow people to recognise any potential risks or benefits associated with the research. A number of interventions have been put forward to improve this process. Outcomes reported in trials of interventions to improve the informed consent process for decisions about trial participation tend to focus on the 'understanding' of trial information. However, the operationalization of understanding as a concept, the tools used to measure it and the timing of the measurements are heterogeneous. A lack of clarity exists regarding which outcomes matter (to whom) and why. This inconsistency between studies results in difficulties when making comparisons across studies as evidenced in two recent systematic reviews of informed consent interventions. As such, no optimal method for measuring the impact of these interventions aimed at improving informed consent for RCTs has been identified. METHODS/DESIGN: The project will adopt and adapt methodology previously developed and used in projects developing core outcome sets for assessment of clinical treatments. Specifically, the work will consist of three stages: 1) A systematic methodology review of existing outcome measures of trial informed consent interventions; 2) Interviews with key stakeholders to explore additional outcomes relevant for trial participation decisions; and 3) A Delphi study to refine the core outcome set for evaluation of trial informed consent interventions. All stages will include the stakeholders involved in the various aspects of RCT consent: users (that is, patients), developers (that is, trialists), deliverers (focusing on research nurses) and authorisers (that is, ethics committees). A final consensus meeting including all stakeholders will be held to review outcomes. DISCUSSION: The ELICIT study aims to develop a core outcome set for the evaluation of interventions intended to improve informed consent for RCTs for use in future RCTs and reviews, thereby improving the reliability and consistency of research in this area. PMID- 26507505 TI - Insufficient access to harm reduction measures in prisons in 5 countries (PRIDE Europe): a shared European public health concern. AB - BACKGROUND: Prisoners constitute a high-risk population, particularly for infectious diseases. The aim of this study was to estimate the level of infectious risk in the prisons of five different European countries by measuring to what extent the prison system adheres to WHO/UNODC recommendations. METHODS: Following the methodology used in a previous French survey, a postal/electronic questionnaire was sent to all prisons in Austria, Belgium, Denmark and Italy to collect data on the availability of several recommended HIV-HCV prevention interventions and HBV vaccination for prisoners. A score was built to compare adherence to WHO/UNODC recommendations (considered a proxy of environmental infectious risk) in those 4 countries. It ranged from 0 (no adherence) to 12 (full adherence). A second score (0 to 9) was built to include data from a previous French survey, thereby creating a 5-country comparison. RESULTS: A majority of prisons answered in Austria (100 %), France (66 %) and Denmark (58 %), half in Belgium (50 %) and few in Italy (17 %), representing 100, 74, 89, 47 and 23 % coverage of the prison populations, respectively. Availability of prevention measures was low, with median adherence scores ranging from 3.5 to 4.5 at the national level. These results were confirmed when using the second score which included France in the inter-country comparison. Overall, the adherence score was inversely associated with prison overpopulation rates (p = 0.08). CONCLUSIONS: Using a score of adherence to WHO/UNODC recommendations, the estimated environmental infectious risk remains extremely high in the prisons of the 5 European countries assessed. Public health strategies should be adjusted to comply with the principle of equivalence of care and prevention with the general community. PMID- 26507506 TI - Integrin-beta3 clusters recruit clathrin-mediated endocytic machinery in the absence of traction force. AB - The turnover of integrin receptors is critical for cell migration and adhesion dynamics. Here we find that force development at integrins regulates adaptor protein recruitment and endocytosis. Using mobile RGD (Arg-Gly-Asp) ligands on supported lipid membranes (RGD membranes) and rigid RGD ligands on glass (RGD glass), we find that matrix force-dependent integrin signals block endocytosis. Dab2, an adaptor protein of clathrin-mediated endocytosis, is not recruited to activated integrin-beta3 clusters on RGD-glass; however, it is recruited to integrin-mediated adhesions on RGD membranes. Further, when force generation is inhibited on RGD-glass, Dab2 binds to integrin-beta3 clusters. Dab2 binding to integrin-beta3 excludes other adhesion-related adaptor proteins, such as talin. The clathrin-mediated endocytic machinery combines with Dab2 to facilitate the endocytosis of RGD-integrin-beta3 clusters. From these observations, we propose that loss of traction force on ligand-bound integrin-beta3 causes recruitment of Dab2/clathrin, resulting in endocytosis of integrins. PMID- 26507507 TI - Dosing and Safety Implications for Oncologists When Administering Everolimus to Patients With Hormone Receptor-Positive Breast Cancer. AB - Aberrations in the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway are common abnormalities in breast cancer and are associated with the development of resistance to endocrine- and human epidermal growth factor receptor (HER)2-targeted therapies. Because of the significant improvement in progression-free survival for everolimus plus exemestane compared with exemestane plus placebo, everolimus, an mTOR inhibitor, was approved in the United States for the treatment of patients with hormone receptor-positive (HR+), HER-negative, advanced breast cancer whose disease had progressed while receiving letrozole or anastrozole. To provide optimal prevention and management strategies, it is crucial that clinicians are aware of the adverse events (AEs) associated with mTOR inhibition. Understanding the appropriate dose modifications will help reduce toxicity and improve drug tolerance, thus achieving the optimal benefit from everolimus. Analyses of data from the Breast Cancer Trials of Oral Everolimus 2 trial have shown that, despite a greater frequency of AEs in the everolimus plus exemestane treatment arm, the AEs were effectively managed with temporary dose reductions or interruptions. In some cases, the full dose of everolimus could be resumed. Despite a lower mean dose and duration of exposure in patients aged >= 70 versus < 70 years, everolimus plus exemestane was similarly efficacious, suggesting that appropriate dose reductions for toxicity will not adversely impact efficacy. Appropriate modification of the everolimus dose and dose delay according to the severity of AEs, with resumption of the optimal dose of everolimus when toxicity has improved, will positively affect patient outcomes in HR+ advanced breast cancer. PMID- 26507508 TI - Biological Network Inference from Microarray Data, Current Solutions, and Assessments. AB - Currently in bioinformatics and systems biology there is a growing interest for the analysis of associations among biological molecules at a network level. A main research in this area is represented by the inference of biological networks from experimental data. Biological network inference aims to reconstruct network of interactions (or associations) among biological molecules (e.g., genes or proteins) starting from experimental observations. The current scenario is characterized by a growing number of algorithms for the inference, while few attention has been posed on the determination of fair assessments and comparisons. Current assessments are usually based on the comparison of the algorithms using reference networks or gold standard datasets. Here we survey some selected inference algorithms and we compare current assessments. We also present a systematic listing of freely available inference and assessment tools for easy reference. Finally we outline some possible future directions of research, such as the use of a prior knowledge into the assessment process. PMID- 26507509 TI - The relevance of timing of illness and death events in the household life cycle for coping outcomes in rural Uganda in the era of HIV. AB - INTRODUCTION: Predicting the household's ability to cope with adult illness and death can be complicated in low-income countries with high HIV prevalence and multiple other stressors and shocks. This study explored the link between stage of the household in the life cycle and the household's capacity to cope with illness and death of adults in rural Uganda. METHODS: Interviews focusing on life histories were combined with observations during monthly visits to 22 households throughout 2009, and recorded livelihood activities and responses to illness and death events. For the analysis, households were categorised into three life cycle stages ('Young', 'Middle-aged' and 'Old') and the ability to cope and adapt to recorded events of prolonged illness or death was assessed. RESULTS: In 16 of the 26 recorded events, a coping or struggling outcome was found to be related to household life cycle stage. 'Young' households usually had many dependants too young to contribute significantly to livelihoods, so were vulnerable to illness or death of the household head specifically. 'Middle-aged' households had adult children who participated in activities that contributed to livelihoods at home or sent remittances. More household members meant livelihood diversification, so these households usually coped best. Worst off were 'Old' households, where members were unable to work hard and often supported young grandchildren, while their adult children had stopped sending remittances as they had established households of their own. CONCLUSIONS: While households may adopt diverse coping mechanisms, the stage in the household life cycle when stressful events occur is important for coping outcomes. Households of the elderly and households with many young dependents are clearly vulnerable. These results demonstrate that household life cycle analysis can be useful in assessing ability to respond to stressors and shocks, including AIDS-related illness and death. PMID- 26507510 TI - Treatments for Cutaneous Lichen Planus: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Cutaneous lichen planus (CLP) is an inflammatory dermatosis. Its chronic relapsing course and frequently spontaneous regression hamper the assessment of treatment effectiveness. OBJECTIVE: To evaluate the efficacy of available treatment modalities for CLP. DATA SOURCES: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov registry. METHODS: We performed a systematic review of the current literature. All randomized controlled trials, nonrandomized case-control studies, and cohort studies with more than one treatment arm were included. The primary outcomes were complete response and time to complete response. The secondary outcomes were partial response, relapse, time to relapse, reduction of itch, the adverse event rate, and withdrawal due to adverse events. DATA SYNTHESIS: Sixteen studies met the inclusion criteria, of which 11 were randomized controlled trials. Most trials had a small sample size. In the rare studies in which variants other than generalized or classic lichen planus were included, they could not be analyzed separately. Body-of-evidence quality ranged from very low to moderate. Acitretin, sulfasalazine, and griseofulvin were associated with increased overall response rates in comparison with placebo. Narrow-band ultraviolet B radiation (NBUVB) was more effective than 6 weeks' low-dose prednisolone in achieving a complete response, and prednisolone was more effective than enoxaparin. Hydroxychloroquine was more effective than griseofulvin in achieving an overall response. Betamethasone valerate 0.1% ointment had comparable efficacy to calcipotriol ointment. Methotrexate was effective, with a nonsignificant difference in the complete response rate in comparison with oral betamethasone. In nonrandomized controlled trials, oral psoralen plus ultraviolet A photochemotherapy (PUVA) had comparable efficacy to a PUVA bath and NBUVB. Psoralen plus sunlight exposure (PUVASOL) and betamethasone dipropionate 0.05% cream were effective relative to a short course of oral metronidazole. CONCLUSIONS: Several effective treatment options are available for CLP. Further well-designed studies are warranted to investigate the efficacy of topical glucocorticoids-the current first-line therapy-as well as other treatment modalities, and the treatment of different variants of CLP. PMID- 26507511 TI - Determination of typical lipophilic marine toxins in marine sediments from three coastal bays of China using liquid chromatography-tandem mass spectrometry after accelerated solvent extraction. AB - A method based on sample preparation by accelerated solvent extraction and analysis by liquid chromatography-tandem mass spectrometry was validated and used for determination of seven typical lipophilic marine toxins (LMTs) in marine sediment samples collected from three typical coastal bays in China. Satisfactory specificity, reproducibility (RSDs <= 14.76%), stability (RSDs <= 17.37%), recovery (78.0%-109.0%), and detection limit (3.440 pg/g-61.85 pg/g) of the developed method were achieved. The results obtained from the analysis of samples from Hangzhou Bay revealed okadaic acid as the predominant LMT with concentrations ranging from 186.0 to 280.7 pg/g. Pecenotoxin-2 was quantified in sediment samples from Laizhou Bay at the concentrations from 256.4 to 944.9 pg/g. These results suggested that the proposed method was reliable for determining the typical LMTs in marine sediments and that the sediments obtained from Hangzhou Bay, Laizhou Bay and Jiaozhou Bay were all contaminated by certain amounts of LMTs. PMID- 26507512 TI - Surface oil footprint and trajectory of the Ixtoc-I oil spill determined from Landsat/MSS and CZCS observations. AB - The Ixtoc-I oil spill occurred in 1979 in shallow waters (50 m) of the Bay of Campeche, Mexico. Although it is known that a large portion of the released oil from this second largest accidental marine oil spill in history reached the surface, to date there has been no attempt to document the surface footprint and trajectory of the released oil. Our study attempts to fill this knowledge gap using remote sensing data collected by Landsat/MSS and CZCS. Both showed the same general patterns of oil trajectory to the northwest and north, nearly parallel to the coastline of the western Gulf of Mexico (GoM) with possible oil landing on Mexican and Texas beaches. Field observations at selected beaches and islands along the coast of the western and southern GoM during and after the spill confirmed these satellite-based findings, which were also used to help in planning a recent field campaign to collect sediment samples in the southern GoM. PMID- 26507513 TI - Congruency analysis of biofilm-dwelling ciliates as a surrogate of eukaryotic microperiphyton for marine bioassessment. AB - Biofilm-dwelling ciliates are primary components of the eukaryotic microperiphyton in both species composition and community structure. To evaluate the congruency of biofilm-dwelling ciliates as potential surrogates of the eukaryotic microperiphyton, a dataset was collected every month at four stations from the coastal waters of the Yellow Sea, northern China, and assessed. Sufficient species abundance data were obtained for ciliated protozoans at high taxonomic levels up to the family level, indicating a significant variation along the gradient of contamination. Correlation analyses revealed that the taxa richness of these matrices can explain > 85% of the variance in that of the full species dataset. The cost/benefit analysis showed that the protozoan subset at low resolutions up to the family level may be used as a potential surrogate of the original dataset. Thus, we suggest that the protozoan assemblages at genus- and/or family-level resolutions may be useful, cost-efficient surrogates of the original dataset for bioassessment in marine ecosystems. PMID- 26507514 TI - Coral reef fish assemblages along a disturbance gradient in the northern Persian Gulf: A seasonal perspective. AB - Seasonal dynamics of coral reef fish assemblages were assessed along a gradient of potential anthropogenic disturbance in the Northern Persian Gulf. Overall, the attributes of coral reef fish assemblages showed seasonality at two different levels: seasonal changes irrespective of the magnitude of disturbance level (e.g. species richness), and seasonal changes in response to disturbance level (e.g. total abundance and assemblage composition). The examined parameters mostly belonged to the second group, but the interpretation of the relationship between patterns of seasonal changes and the disturbance level was not straightforward. The abundance of carnivorous fishes did not vary among seasons. SIMPER identified the family Nemipteridae as the major contributor to the observed spatiotemporal variations in the composition of coral reef fish assemblages in the study area. PMID- 26507515 TI - Identification and validation of immunogenic potential of India specific HPV-16 variant constructs: In-silico &in-vivo insight to vaccine development. AB - Cervical cancer is one of the most common gynecological cancers in the world but in India, it is the top most cancer among women. Persistent infection with high risk human papillomaviruses (HR-HPVs) is the most important risk factor. The sequence variation(s) in the most common HR-HPV i.e. HPV type 16 leads to altered biological functions with possible clinical significance in the different geographical locations. Sixteen major variants (V1-V16) in full length L1 gene of HPV-16 were identified following analysis of 250 prospectively collected cervical cancer tissue biopsies and their effect on immunogenicity was studied. The effect of these major variations on the epitopes were predicted by in silico methods and the immunogenicity of variants and respective reference DNA vaccine constructs were evaluated by administration of prepared DNA vaccine constructs in female BALB/c mice to evaluate antibody titer. In the present study, L500F (V16) variation showed a significant ~2.7 fold (p < 0.002) increase in antibody titer, whereas T379P (V8) showed ~0.4 fold (p < 0.328) decrease after final injection. These results showed a promising roadmap for the development of DNA based vaccine and for the generation of effective response, though there is a need to study more prevalent variants of HPV in the Indian population. PMID- 26507516 TI - Effect of preoperative urodynamic detrusor overactivity on post-prostatectomy incontinence: a systematic review and meta-analysis. AB - PURPOSE: To investigate whether preoperative urodynamic detrusor overactivity (DO) contributes to post-prostatectomy incontinence (PPI). METHODS: We systematically searched the online PubMed, Embase, and Cochrane Library databases spanning the period of January 1989 to December 2014. RESULTS: A total of nine articles met the eligibility criteria for this systematic review. The eligible studies included a total of 457 patients with a median number of 58 patients per study (range 17-92). Of the nine studies, five conducted open retropubic radical prostatectomy (RRP), two performed robot-assisted laparoscopic prostatectomy (RALP), and two others utilized multiple modalities. PPI was more likely to occur in patients with preoperative DO [pooled odds ratio (OR) 2.30; 95 % confidence interval (CI) 1.39-3.82; studies 9; participants 419], as compared to patients who were DO negative. Sensitivity analysis using the subgroups of RRP (OR 2.32; 95 % CI 1.11-4.85), RALP (OR 3.41; 95 % CI 1.55-7.47), DO defined as any amplitude of involuntary contraction (OR 2.32; 95 % CI 1.11-4.85), no postoperative intervention (OR 2.32; 95 % CI 1.11-4.85), and outcome evaluation after 6 months (OR 2.32; 95 % CI 1.11-4.85) demonstrated consistent results. Although some comparisons showed inter-study heterogeneity, there was no clear evidence of publication bias in this meta-analysis. CONCLUSIONS: Our meta analysis results suggest that preoperative DO is another possible underlying mechanism for PPI. PMID- 26507517 TI - Genetic variation in APE1 gene promoter is associated with noise-induced hearing loss in a Chinese population. AB - OBJECTIVE: To investigate whether the apurinic/apyrimidinic endonuclease 1 (APE1) 1349 T>G and -656 T>G polymorphisms were associated with the risk of noise induced hearing loss (NIHL) in a Chinese population. METHODS: The two APE1 polymorphisms were analyzed among 613 NIHL workers and 613 normal hearing workers using the minor groove binder TaqMan probe assay. RESULTS: We found that the APE1 -656 TT genotype was associated with a increased risk of NIHL [adjusted odds ratio (OR) 1.46, 95% confidence interval (CI) 1.05-2.06]. This increased risk was more pronounced in the stratification analysis. Furthermore, we found that subjects with two risk genotypes (hOGG1 Cys/Cys, APE1 -656 TT) had a significantly increased risk of NIHL (adjusted OR 1.91, 95% CI 1.27-2.88). CONCLUSION: Our study identified that the APE1 -656 T>G polymorphism may contribute to the susceptibility of NIHL. PMID- 26507518 TI - Effects of burn location and investigator on burn depth in a porcine model. AB - INTRODUCTION: In order to be useful, animal models should be reproducible and consistent regardless of sampling bias, investigator creating burn, and burn location. We determined the variability in burn depth based on biopsy location, burn location and investigator in a porcine model of partial thickness burns. METHODS: 24 partial thickness burns (2.5 cm by 2.5 cm each) were created on the backs of 2 anesthetized pigs by 2 investigators (one experienced, one inexperienced) using a previously validated model. In one of the pigs, the necrotic epidermis covering each burn was removed. Five full thickness 4mm punch biopsies were obtained 1h after injury from the four corners and center of the burns and stained with Hematoxylin and Eosin and Masson's trichrome for determination of burn depth by a board certified dermatopathologist blinded to burn location and investigator. Comparisons of burn depth by biopsy location, burn location and investigator were performed with t-tests and ANOVA as appropriate. RESULTS: The mean (SD) depth of injury to blood vessels (the main determinant of burn progression) in debrided and non-debrided pigs pooled together was 1.8 (0.3)mm, which included 75% of the dermal depth. Non-debrided burns were 0.24 mm deeper than debrided burns (P<0.001). Burn depth increased marginally from cephalic to caudal in non-debrided burns, but showed no statistical differences for these locations, in debrided burns. Additionally, there were also no statistical differences in burn depths from midline to lateral in either of these burn types. Burn depth was similar for both investigators and among biopsy locations. CONCLUSIONS: Burn depth was greater for caudal locations in non-debrided burns and overall non-debrided burns were deeper than debrided burns. However, burn depth did not differ based on investigator, biopsy site, and medial-lateral location. PMID- 26507519 TI - Inclusion of coexisting morbidity in a TBSA% and age based model for the prediction of mortality after burns does not increase its predictive power. AB - INTRODUCTION: Several models for predicting mortality have been developed for patients with burns, and the most commonly used are based on age and total body surface area (TBSA%). They often show good predictive precision as depicted by high values for area under the receiver operating characteristic curves (AUC). However the effect of coexisting morbidity on such prediction models has not to our knowledge been thoroughly examined. We hypothesised that adding it to a previously published model (based on age, TBSA%, full thickness burns, gender, and need for mechanical ventilation) would further improve its predictive power. METHODS: We studied 772 patients admitted during the period 1997-2008 to the Linkoping University Hospital, National Burn Centre with any type of burns. We defined coexisting morbidity as any of the medical conditions listed in the Charlson list, as well as psychiatric disorders or drug or alcohol misuse. We added coexisting medical conditions to the model for predicting mortality (age, TBSA%, and need for mechanical ventilation) to determine whether it improved the model as assessed by changes in deviances between the models. RESULTS: Mean (SD) age and TBSA% was 35 (26) years and 13 (17) %, respectively. Among 725 patients who survived, 105 (14%) had one or more coexisting condition, compared with 28 (60%) among those 47 who died. The presence of coexisting conditions increased with age (p<0.001) among patients with burns. The AUC of the mortality prediction model in this study, based on the variables age, TBSA%, and need for mechanical ventilation was 0.980 (n=772); after inclusion of coexisting morbidity in the model, the AUC improved only marginally, to 0.986. The model was not significantly better either. CONCLUSION: Adding coexisting morbidity to a model for prediction of mortality after a burn based on age, TBSA%, and the need for mechanical ventilation did not significantly improve its predictive value. This is probably because coexisting morbidity is automatically adjusted for by age in the original model. PMID- 26507520 TI - Moments of homecoming among people with advanced dementia disease in a residential care facility. AB - This study concerns moments of homecoming among people with advanced dementia disease living in a residential care facility. Our main finding from participant observations with nine residents was that the residents showed moments of homecoming, i.e. they alternated between verbal and/or nonverbal expressions of feeling at home and of not feeling at home. If care providers understand that they can help people with advanced dementia disease experience moments of homecoming, they can focus on aspects of care that can promote these experiences. PMID- 26507521 TI - Outcomes of intramedullary nailing for acute proximal humerus fractures: a systematic review. AB - BACKGROUND: While proximal humerus fractures remain common within the elderly population, the optimal treatment method remains controversial. Intramedullary nailing has been advocated as an effective and less invasive surgical technique. The purpose of this study is to elucidate the demographics, outcomes, and complications of intramedullary nailing for acute, displaced proximal humerus fractures. MATERIALS AND METHODS: Multiple computerized literature databases were used to perform a systematic review of English-language literature. Studies that met our stated criteria were further assessed for the requisite data, and when possible, similar outcome data were combined to generate frequency-weighted means. RESULTS: Fourteen studies with 448 patients met our inclusion criteria. The frequency-weighted mean age was 64.3 years, and mean follow-up was 22.6 months. Females accounted for 71 % of the included patients. Three-part fractures (51 %) were most commonly treated. The overall frequency-weighted mean Constant score was 72.8, and American Shoulder and Elbow Surgeons (ASES) score was 84.3. Frequency-weighted mean forward elevation, abduction, extension, and external rotation were 137.3 degrees , 138.4 degrees , 33.8 degrees , and 43.1 degrees , respectively. The Constant score for two- and three-part fractures was significantly higher than for four-part fractures (p = 0.007 and p = 0.0009, respectively). The reoperation rate for two-, three-, and four-part fractures was 13.6, 17.4, and 63.2 %, respectively. CONCLUSIONS: Intramedullary nailing of acute, displaced two- and three-part proximal humerus fractures yields satisfactory clinical outcomes, although reoperation and complication rates remain high. Use of this implant for four-part fractures cannot be recommended until further clinical studies with larger patient numbers are available. LEVEL OF EVIDENCE: Level IV, Systematic review. PMID- 26507522 TI - Understanding the impact of Fc glycosylation on its conformational changes by molecular dynamics simulations and bioinformatics. AB - N-linked glycosylation of Fc at N297 plays an important role in its effector function, aberrance of which would cause disease pathogenesis. Here, we performed all-atom molecular dynamics simulations to explore the effects of Fc glycosylation on its dynamics behaviors. Firstly, equilibrium simulations suggested that Fc deglycosylation was able to induce residual flexibility in its CH2 domain. Besides, the free energy landscape revealed three minimum energy wells in deglycosylated Fc, representing its "open", "semi-closed" and "closed" states. However, we could only observe the "open" state of glycosylated Fc. Supportively, principal component analysis emphasized the prominent motion of delyclosylated Fc and dynamically depicted how it changed from the "open" state to its "closed" state. Secondly, we studied the recognition mechanism of the Fc binding to its partners. Energy decomposition analysis identified key residues of Fc to recognize its two partners P13 and P34. Evidently, electrostatic potential surfaces showed that electrostatic attraction helped to stabilize the interaction between Fc and its partners. Also, relative binding free energies explained different binding affinities in Fc-P13 and Fc-P34. Collectively, these results together provided the structural basis for understanding conformational changes of deglycosylated Fc and the recognition mechanism of the Fc binding to its partners. PMID- 26507523 TI - Impact of the Femoral Head Position on Moment Arms in Total Hip Arthroplasty: A Parametric Finite Element Study. AB - BACKGROUND: Although the importance of accurate femoral reconstruction to achieve a good functional outcome is well documented, quantitative data on the effects of a displacement of the femoral center of rotation on moment arms are scarce. The purpose of this study was to calculate moment arms after nonanatomical femoral reconstruction. METHODS: Finite element models of 15 patients including the pelvis, the femur, and the gluteal muscles were developed. Moment arms were calculated within the native anatomy and compared to distinct displacement of the femoral center of rotation (leg lengthening of 10 mm, loss of femoral offset of 20%, anteversion +/-10 degrees , and fixed anteversion at 15 degrees ). Calculations were performed within the range of motion observed during a normal gait cycle. RESULTS: Although with all evaluated displacements of the femoral center of rotation, the abductor moment arm remained positive, some fibers initially contributing to extension became antagonists (flexors) and vice versa. A loss of 20% of femoral offset led to an average decrease of 15% of abductor moment. Femoral lengthening and changes in femoral anteversion (+/-10 degrees , fixed at 15 degrees ) led to minimal changes in abductor moment arms (maximum change of 5%). Native femoral anteversion correlated with the changes in moment arms induced by the 5 variations of reconstruction. CONCLUSION: Accurate reconstruction of offset is important to maintaining abductor moment arms, while changes of femoral rotation had minimal effects. Patients with larger native femoral anteversion appear to be more susceptible to femoral head displacements. PMID- 26507524 TI - In Reply. PMID- 26507525 TI - A Comparison of Short-Term Outcomes of Minimally Invasive Computer-Assisted vs Minimally Invasive Conventional Instrumentation for Primary Total Knee Arthroplasty: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Median parapatellar approach is the most used for total knee arthroplasty (TKA). With the advent of enhanced recovery and shorter length of hospital stay, there is an increasing pressure on surgeons to perform surgery through smaller incisions. Minimally invasive (MIS) TKA allows earlier functional recovery; it is not clear if this is associated with more complications. It is also unclear if computer-assisted minimally invasive (MIS CA) TKA has any affect on improving patient outcomes. We performed a systematic review and meta-analysis comparing MIS CA vs MIS TKA. METHODS: We performed an extensive literature search including both randomized controlled studies and prospective cohort studies. All data reported on component alignment, surgical time, complications, knee flexion, and postoperative functional knee scores were included for analysis. RESULTS: Ten studies were suitable for inclusion resulting in 490 patients with MIS CA and 503 MIS patients. There was no significant difference in the outliers on complications, knee flexion, and postoperative functional scores. Coronal plane tibial component showed statistically significant number of outliers in the MIS group demonstrating superior component positioning in the MIS CA group. Operative time was significantly longer in the MIS CA group with a mean increase of 32 minutes. CONCLUSIONS: Computer-assisted minimally invasive TKA is superior than the standard MIS TKA in terms of component positioning; however, it is unclear if this will have any long-term clinical implications. The increased operative time, although clinically relevant, does not appear to be associated with an increase in complications. PMID- 26507526 TI - Combined Administration of Systemic and Topical Tranexamic Acid for Total Knee Arthroplasty: Can It Be a Better Regimen and Yet Safe? A Randomized Controlled Trial. AB - BACKGROUND: Total knee arthroplasty (TKA) is associated with substantial blood loss in postoperative period. Tranexamic acid (TXA) is potent antifibrinolytic agent, routinely administered by intravenous (IV) and topical route, which can possibly interrupt cascade of events due to hemostatic irregularities close to source of bleeding. However, scientific evidence of combined administration of TXA in TKA is still meagre. The present study aimed to compare efficacy of combined IV and topical TXA with IV use alone in terms of blood loss, transfusion rate, and incidence of deep vein thrombosis and thromboembolism. PATIENTS AND METHODS: 119 patients undergoing unilateral TKA were randomized into IV alone and combined group. Patients assigned to IV group were given IV TXA as a preoperative and postoperative dose given 3 and 6 hours after surgery, whereas in combined group, topical TXA solution was applied intraarticularly about 5 minutes before closure of arthrotomy in addition to IV doses. RESULTS: Combined use of IV and topical TXA provided better results than IV use alone with mean calculated total blood loss (590.69+/-191.1 vs 385.68+/-182.5, P<.001), blood transfusion rate (6.6% vs 1.6%, P = .364), hemoglobin drop (1.82+/-0.6 vs 1.14+/-0.5, P<.001). No case of DVT or TE was noted among the 2 study groups. CONCLUSION: Combined use of IV and intraarticular TXA provided significantly better results compared with IV use alone with respect to all variables related to postoperative blood loss in TKA. Moreover, TXA use is safe in terms of incidence of symptomatic DVT and TE. PMID- 26507527 TI - How Much Do Adverse Event Rates Differ Between Primary and Revision Total Joint Arthroplasty? AB - BACKGROUND: It is not known which adverse events occur more commonly following revision than following primary total joint arthroplasty. METHODS: Patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) during 2011 to 2013 as part of the America College of Surgeons National Surgical Quality Improvement Program were identified. Rates of adverse events were compared between patients undergoing primary and patients undergoing revision procedures with adjustments for demographic and comorbidity characteristics. RESULTS: In total, 48307 THA patients and 70605 TKA patients met inclusion criteria. Of the THA patients, 43247 (89.5%) underwent primary procedures, while 5060 (10.5%) underwent revision procedures. Of the TKA patients, 65694 (93.0%) underwent primary procedures, while 4911 (7.0%) underwent revision procedures. Patients undergoing revision procedures had higher rates of systemic sepsis (for THA, 0.3% vs 0.1%, adjusted relative risk [RR], 3.5; 95% confidence interval [CI], 1.7-7.0; P < .001; for TKA, 0.3% vs 0.1%, adjusted RR, 3.0; 95% CI, 1.7-5.2, P < .001), deep incisional surgical site infection (for THA, 1.3% vs 0.3%, adjusted RR, 4.3; 95% CI, 3.2-5.8, P < .001; for TKA, 0.7 vs 0.2%, RR, 4.0; 95% CI, 2.7-5.9, P < .001), and organ/space infection (for THA, 1.8% vs 0.2%, RR, 7.4; 95% CI, 5.4 10.0, P < .001; for TKA, 1.1% vs 0.1%, adjusted RR, 7.5; 95% CI, 5.4-10.6, P < .001). Patients undergoing revision procedures did not have higher rates of pulmonary embolism or deep vein thrombosis (P >= .05 for each). CONCLUSIONS: Public reporting of adverse events should be interpreted in the context of the differences between primary and revision procedures, and reimbursement systems should reflect the greater amount of postoperative care that patients undergoing revision procedures require. PMID- 26507528 TI - Effect of ovine luteinizing hormone (oLH) charge isoforms on VEGF and cAMP production. AB - Although an increase in VEGF expression and synthesis in association with LH has been established; it is unknown if all LH isoforms act similarly. This study evaluated the production of cAMP and VEGF among LH isoforms in two in vitro bioassays. The LH was obtained from hypophyses and the group of isoforms was isolated by chromatofocusing. cAMP production was assessed using the in vitro bioassay of HEK-293 cells and VEGF production was evaluated in granulosa cells. Immunological activity was measured with a homologous RIA. Immunoactivity and bioactivity for each isoform were compared against a standard, by estimating the IC50 and the EC50. The basic isoforms were more immunoactive than the standard. The neutral and the moderately acidic had an immunological activity similar to the standard. The acidic isoform was the least immunoreactive. cAMP production at the EC50 dose was similar among the basic isoforms, the moderately acidic and the standard; for the neutral and the acidic, the EC50 dose was higher. It was observed that compared with the control, VEGF production at the lowest LH dose was no different in the standard and each isoform. In the intermediate dose, a positive response was caused in the standard and the neutral and basic isoforms. Although the acidic isoform showed a dose-dependent response, it was not significant relative to the control. In conclusion, the basic isoform generated the greatest cAMP and VEGF production, similar to the reference standard, and the acidic the smallest. PMID- 26507529 TI - Persistent dengue emergence: the 7 years surrounding the 2010 epidemic in Nepal. AB - BACKGROUND: Dengue fever (DF) is an emerging public health problem in Nepal, and yet neither the magnitude of the DF burden or its epidemiological trends are well understood. METHODS: We conducted a sero-epidemiological, seasonal trend and demographic analysis of the trends in DF in the Terai region of Nepal, from 2007 to 2013. In that period, 2002 serum samples were collected from febrile patients suspected of dengue virus infection. Samples were screened by IgM antibody ELISA analysis for the presence of anti-dengue IgM antibodies. RESULTS: The overall prevalence of DF cases was found to range from 26.1 to 55.4%. Infection was found to be more common among adults and males. Seasonal trends revealed that cases peaked in October and November. CONCLUSIONS: The study offers perspective on the dengue fever burden before, during and after a major epidemic and can now be used as a basis for formulating strategies by policy makers that will enhance and develop relevant control and preventive measures against dengue fever. The findings of this study reinforce the perceived need for urgent dengue virus surveillance to enhance dengue control strategies that need to be developed for future preparedness. In the light of the recent earthquakes, future major outbreaks of vector borne disease are likely to recur. PMID- 26507530 TI - Discovery of Small Molecules that Inhibit the Disordered Protein, p27(Kip1). AB - Disordered proteins are highly prevalent in biological systems, they control myriad signaling and regulatory processes, and their levels and/or cellular localization are often altered in human disease. In contrast to folded proteins, disordered proteins, due to conformational heterogeneity and dynamics, are not considered viable drug targets. We challenged this paradigm by identifying through NMR-based screening small molecules that bound specifically, albeit weakly, to the disordered cell cycle regulator, p27(Kip1) (p27). Two groups of molecules bound to sites created by transient clusters of aromatic residues within p27. Conserved chemical features within these two groups of small molecules exhibited complementarity to their binding sites within p27, establishing structure-activity relationships for small molecule:disordered protein interactions. Finally, one compound counteracted the Cdk2/cyclin A inhibitory function of p27 in vitro, providing proof-of-principle that small molecules can inhibit the function of a disordered protein (p27) through sequestration in a conformation incapable of folding and binding to a natural regulatory target (Cdk2/cyclin A). PMID- 26507531 TI - In-hospital and long-term outcomes after percutaneous coronary intervention for chronic total occlusion in elderly patients: A consecutive, prospective, single centre study. AB - BACKGROUND: Elderly patients are increasingly referred for complex percutaneous coronary interventions (PCI), including recanalization of chronic total occlusion (CTO). AIMS: To assess the feasibility, safety and clinical benefits associated with CTO-PCI in elderly patients. METHODS: Consecutive patients (n=356) who underwent CTO-PCI in our institution between January 2008 and December 2011 were prospectively included. The short-term outcomes of CTO-PCI were assessed by comparing the rates of successful recanalization and postoperative complications in patients aged >= 75 years and those < 75 years. The clinical effect of successful recanalization was evaluated in a 20-month follow-up analysis in patients >= 75 years. RESULTS: Although patients >= 75 years (n = 93) had more complex coronary artery disease, the procedural success rate was similar to that in younger patients (78.2% vs. 74.3%, respectively; P = 0.41). Postoperative complications were more frequent in older patients (5.4% vs. 0.4%; P = 0.005). Major adverse cardiac event-free survival analysis at 20 months revealed that successful revascularization was indicative of a better prognosis in older patients (hazard ratio: 0.43, 95% confidence interval: 0.19-0.96; P = 0.039). CONCLUSION: Elderly patients have more complex coronary disease and are at a higher risk of postoperative complications. Nevertheless, we observed a similar success rate for CTO-PCI in elderly patients as for younger patients. Successful CTO recanalization improved the event-free survival rate at 20 months. Thus, CTO PCI constitutes an alternative strategy for treating selected elderly patients. PMID- 26507532 TI - Management of Takotsubo cardiomyopathy in non-academic hospitals in France: The Observational French SyndromEs of TakoTsubo (OFSETT) study. AB - BACKGROUND: Takotsubo cardiomyopathy (TTC) is a rare condition characterized by a sudden temporary weakening of the heart. TTC can mimic acute myocardial infarction and is associated with a minimal release of myocardial biomarkers in the absence of obstructive coronary artery disease. AIMS: To provide an extensive description of patients admitted to hospital for TTC throughout France and to study the management and outcomes of these patients. METHODS: In 14 non-academic hospitals, we collected clinical, electrocardiographic, biological, psychological and therapeutic data in patients with a diagnosis of TTC according to the Mayo Clinic criteria. RESULTS: Of 117 patients, 91.5% were women, mean +/- SD age was 71.4 +/- 12.1 years and the prevalence of risk factors was high (hypertension: 57.9%, dyslipidaemia: 33.0%, diabetes: 11.5%, obesity: 11.5%). The most common initial symptoms were chest pain (80.5%) and dyspnoea (24.1%). A triggering psychological event was detected in 64.3% of patients. ST-segment elevation was found in 41.7% of patients and T-wave inversion in 71.6%. Anterior leads were most frequently associated with ST-segment elevation, whereas T-wave inversion was more commonly associated with lateral leads, and Q-waves with septal leads. The ratio of peak B-type natriuretic peptide (BNP) or N-terminal prohormone BNP (NT-proBNP) level to peak troponin level was 1.01. No deaths occurred during the hospital phase. After 1 year of follow-up, 3 of 109 (2.8%) patients with available data died, including one cardiovascular death. Rehospitalizations occurred in 17.4% of patients: 2.8% due to acute heart failure and 14.7% due to non-cardiovascular causes. There was no recurrence of TTC. CONCLUSIONS: This observational study of TTC included primarily women with atherosclerotic risk factors and mental stress. T-wave inversion was more common than ST-segment elevation. There were few adverse cardiovascular outcomes in these patients after 1-year follow-up. PMID- 26507533 TI - The prescription of medical cannabis by a transitional pain service to wean a patient with complex pain from opioid use following liver transplantation: a case report. AB - PURPOSE: The purpose of this case report is to describe a patient with a preoperative complex pain syndrome who underwent liver transplantation and was able to reduce his opioid consumption significantly following the initiation of treatment with medical cannabis. CLINICAL FEATURES: A 57-yr-old male with a history of hepatitis C cirrhosis underwent liver transplantation. Preoperatively, he was taking hydromorphone 2-8 mg?day(-1) for chronic abdominal pain. Postoperatively, he was given intravenous patient-controlled analgesia through which he received hydromorphone 30 mg?day(-1). Our multidisciplinary Transitional Pain Service was involved with managing his moderate to severe acute postsurgical pain in hospital and continued with weaning him from opioid medications after discharge. It was difficult to wean the patient from opioids, and he was subsequently given medical cannabis at six weeks postoperatively with remarkable effect. By the fifth postoperative month, his use of opioids had tapered to 6 mg?day(-1) of hydromorphone, and his functional status was excellent on this regimen. CONCLUSION: Reductions in opioid consumption were achieved with the administration of medical cannabis in a patient with acute postoperative pain superimposed on a chronic pain syndrome and receiving high doses of opioids. Concurrent benefits of initiating medical cannabis may include improvements in pain profile and functional status along with reductions in opioid-related side effects. This highlights the potential for medical cannabis as an adjunct medication for weaning patients from opioid use. PMID- 26507534 TI - Ultrasound-guided internal jugular vein cannulation: a novel technique for confirming that the guidewire is directed towards the right atrium. PMID- 26507535 TI - The prescription opioid epidemic: an overview for anesthesiologists. AB - PURPOSE: The objectives for preparing this article were to review the historical context and epidemiology surrounding the North American prescription opioid crisis, to summarize the evidence regarding the benefits and harms of long-term opioid therapy for non-cancer pain, and to outline ways in which anesthesiologists may help ameliorate the problem. SOURCE: We searched PubMed, Google Scholar, and EMBASETM for relevant articles using various search terms, including pain, opioid epidemic, history of opioid use, perioperative care, and addiction. Related citations were further explored and searched depending on the specific subtopic of interest. PRINCIPAL FINDINGS: In the 1980s and early 1990s, opioids were infrequently used for the treatment of chronic pain. Thereafter, however, physicians were gradually inculcated with the message that long-term opioid therapy was a safe and effective treatment option for patients with chronic non-cancer pain. Pharmaceutical companies supported this growing movement and employed aggressive and sometimes misleading marketing strategies for new opioid formulations. As a result, the practice of prescribing opioids flourished in the late 1990s. The surge in prescribing opioids was accompanied by a marked increase in opioid-related morbidity and mortality. This change in practice transpired despite the absence of randomized trials showing clinically significant benefit from the long-term use of opioids. Subsequently, however, a large and growing body of evidence has emerged quantifying the harms associated with long-term opioid therapy. Anesthesiologists widely prescribe opioids for acute and chronic pain; yet, as a group, they may be largely unaware of the current state of this growing epidemic and what role they can play to rectify this problem. CONCLUSION: Anesthesiologists are well positioned to take a leadership role in the management of postoperative discharge opioid therapy in an effort to curb the overutilization of opioids. Furthermore, anesthesiologists who regularly prescribe opioids for chronic pain patients should appreciate the limited evidence base for this practice and communicate the risks of opioid therapy to their patients. PMID- 26507536 TI - Preclinical neuroprotective actions of xenon and possible implications for human therapeutics: a narrative review. AB - PURPOSE: The purpose of this report is to facilitate an understanding of the possible application of xenon for neuroprotection in critical care settings. This narrative review appraises the literature assessing the efficacy and safety of xenon in preclinical models of acute ongoing neurologic injury. SOURCE: Databases of the published literature (MEDLINE(r) and EMBASETM) were appraised for peer reviewed manuscripts addressing the use of xenon in both preclinical models and disease states of acute ongoing neurologic injury. For randomized clinical trials not yet reported, the investigators' declarations in the National Institutes of Health clinical trials website were considered. PRINCIPAL FINDINGS: While not a primary focus of this review, to date, xenon cannot be distinguished as superior for surgical anesthesia over existing alternatives in adults. Nevertheless, studies in a variety of preclinical disease models from multiple laboratories have consistently shown xenon's neuroprotective properties. These properties are enhanced in settings where xenon is combined with hypothermia. Small randomized clinical trials are underway to explore xenon's efficacy and safety in clinical settings of acute neurologic injury where hypothermia is the current standard of care. CONCLUSION: According to the evidence to date, the neuroprotective efficacy of xenon in preclinical models and its safety in clinical anesthesia set the stage for the launch of randomized clinical trials to determine whether these encouraging neuroprotective findings can be translated into clinical utility. PMID- 26507537 TI - Clinical and Prognostic Profiles of Cardiomyopathies Caused by Mutations in the Troponin T Gene. AB - INTRODUCTION AND AIMS: Mutations in the troponin T gene (TTNT2) have been associated in small studies with the development of hypertrophic cardiomyopathy characterized by a high risk of sudden death and mild hypertrophy. We describe the clinical course of patients carrying mutations in this gene. METHODS: We analyzed the clinical characteristics and prognosis of patients with mutations in the TNNT2 gene who were seen in an inherited cardiac disease unit. RESULTS: Of 180 families with genetically studied cardiomyopathies, 21 families (11.7%) were identified as having mutations in TNNT2: 10 families had Arg92Gln, 5 had Arg286His, 3 had Arg278Cys, 1 had Arg92Trp, 1 had Arg94His, and 1 had Ile221Thr. Thirty-three additional genetic carriers were identified through family assessment. The study included 54 genetic carriers: 56% were male, and the mean average age was 41 +/- 17 years. There were 33 cases of hypertrophic cardiomyopathy, 9 of dilated cardiomyopathy, and 1 of noncompaction cardiomyopathy, and maximal myocardial thickness was 18.5 +/- 6mm. Ventricular dysfunction was present in 30% of individuals and a history of sudden death in 62%. During follow-up, 4 patients died and 14 (33%) received a defibrillator (8 probands, 6 relatives). Mean survival was 54 years. Carriers of Arg92Gln had early disease development, high penetrance, a high risk of sudden death, a high rate of defibrillator implantation, and a high frequency of mixed phenotype. CONCLUSIONS: Mutations in the TNNT2 gene were more common in this series than in previous studies. The clinical and prognostic profiles depended on the mutation present. Carriers of the Arg92Gln mutation developed hypertrophic or dilated cardiomyopathy and had a significantly worse prognosis than those with other mutations in TNNT2 or other sarcomeric genes. PMID- 26507538 TI - Control of Anticoagulation With Warfarin or Acenocoumarol in Spain. Do They Differ? PMID- 26507539 TI - What's New in Constrictive Pericarditis? A European Perspective. PMID- 26507540 TI - Antihypertensive Medication: On the Right Path? PMID- 26507541 TI - Macronutrient composition determines accumulation of persistent organic pollutants from dietary exposure in adipose tissue of mice. AB - Accumulation of persistent organic pollutants (POPs) has been linked to adipose tissue expansion. As different nutrients modulate adipose tissue development, we investigated the influence of dietary composition on POP accumulation, obesity development and related disorders. Lifespan was determined in mice fed fish-oil based high fat diets during a long-term feeding trial and accumulation of POPs was measured after 3, 6 and 18months of feeding. Further, we performed dose response experiments using four abundant POPs found in marine sources, PCB-153, PCB-138, PCB-118 and pp'-DDE as single congeners or as mixtures in combination with different diets: one low fat diet and two high fat diets with different protein:sucrose ratios. We measured accumulation of POPs in adipose tissue and liver and determined obesity development, glucose tolerance, insulin sensitivity and hepatic expression of genes involved in metabolism of xenobiotics. Compared with mice fed diets with a low protein:sucrose ratio, mice fed diets with a high protein:sucrose ratio had significantly lower total burden of POPs in adipose tissue, were protected from obesity development and exhibited enhanced hepatic expression of genes involved in metabolism and elimination of xenobiotics. Exposure to POPs, either as single compounds or mixtures, had no effect on obesity development, glucose tolerance or insulin sensitivity. In conclusion, this study demonstrates that the dietary composition of macronutrients profoundly modulates POP accumulation in adipose tissues adding an additional parameter to be included in future studies. Our results indicate that alterations in macronutrient composition might be an additional route for reducing total body burden of POPs. PMID- 26507542 TI - Molecular mechanisms of gastrointestinal protection by quercetin against indomethacin-induced damage: role of NF-kappaB and Nrf2. AB - The aim of this study was to determine the gastrointestinal protection by quercetin against indomethacin-induced oxidative stress and inflammation, with specific interest in studying the underlying molecular mechanisms. We hypothesized that the quercetin-protective effect relies on its antioxidant and antiinflammatory properties. Rats were pretreated with quercetin (50- or 100 mg/kg, ig single dose), 30 min before INDO administration (40-mg/kg ig single dose). Caco-2 cells were treated with INDO (250 and 500 MUM) in the absence or presence of quercetin (10 MUg/ml). Quercetin prevented the decrease in nuclear translocation of Nrf2, a key regulator of the antioxidant response, and the increase in reactive oxygen species levels induced by INDO by inhibiting the enhancement of NADPH oxidase and xanthine oxidase activities as well as the reduction in superoxide dismutase and glutathione peroxidase activities in gastric and ileal tissues. Quercetin also prevented INDO-induced ICAM-1 and P selectin expressions and the increase of myeloperoxidase activity in gastric and ileal tissues and NF-kappaB activation and IL-8 production in Caco-2 cells. Quercetin did not affect the inhibition of TNFalpha-mediated production of prostaglandin E2 induced by INDO in Caco-2 cells. The protective effects of quercetin observed in the gastric and ileal mucosa of rats as well as in Caco-2 cells relied on the ability of this flavonol to prevent NF-kappaB activation and increase Nrf2 translocation. This study supports the concept that quercetin may be useful in the prevention and/or treatment of nonsteroidal antiinflammatory drug-associated side effects, without interfering with their therapeutic efficacy. PMID- 26507543 TI - Antiproliferative effects of gamma-tocotrienol are associated with lipid raft disruption in HER2-positive human breast cancer cells. AB - A large percentage of human breast cancers are characterized by excessive or aberrant HER2 activity. Lipid rafts are specialized microdomains within the plasma membrane that are required for HER2 activation and signal transduction. Since the anticancer activity of gamma-tocotrienol is associated with suppression in HER2 signaling, studies were conducted to examine the effects of gamma tocotrienol on HER2 activation within the lipid raft microdomain in HER2-positive SKBR3 and BT474 human breast cancer cells. Treatment with 0-5MUM gamma tocotrienol induced a significant dose-dependent inhibition in cancer cell growth after a 5-day culture period, and these growth inhibitory effects were associated with a reduction in HER2 dimerization and phosphorylation (activation). Phosphorylated HER2 was found to be primarily located in the lipid raft microdomain of the plasma membrane in vehicle-treated control groups, whereas gamma-tocotrienol treatment significantly inhibited this effect. Assay of plasma membrane subcellular fractions showed that gamma-tocotrienol also accumulates exclusively within the lipid raft microdomain. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) is an agent that disrupts lipid raft integrity. Acute exposure to 3mM HPbetaCD alone had no effect, whereas an acute 24-h exposure to 20MUM gamma tocotrienol alone significantly decreased SKBR3 and BT474 cell viability. However, combined treatment with these agents greatly reduced gamma-tocotrienol accumulation in the lipid raft microdomain and cytotoxicity. In summary, these findings demonstrate that the anticancer effects of gamma-tocotrienol are associated with its accumulation in the lipid raft microdomain and subsequent interference with HER2 dimerization and activation in SKBR3 and BT474 human breast cancer cells. PMID- 26507544 TI - Mono-2-ethylhexyl phthalate (MEHP) alters histiotrophic nutrition pathways and epigenetic processes in the developing conceptus. AB - Histiotrophic nutrition pathways (HNPs) are processes by which the organogenesis stage conceptus obtains nutrients, amino acids, vitamins and cofactors required for protein biosynthesis and metabolic activities. Nutrients are captured from the maternal milieu as whole proteins and cargoes via receptor-mediated endocytosis in the visceral yolk sac (VYS), degraded by lysosomal proteolysis and delivered to the developing embryo (EMB). Several nutrients obtained by HNPs are required substrates for one-carbon (C1) metabolism and supply methyl groups required for epigenetic processes, including DNA and histone methylation. Increased availability of methyl donors has been associated with reduced risk for neural tube defects (NTDs). Here, we show that mono-2-ethylhexyl phthalate (MEHP) treatment (100 or 250MUM) alters HNPs, C1 metabolism and epigenetic programming in the organogenesis-stage conceptus. Specifically, 3-h MEHP treatment of mouse EMBs in whole culture resulted in dose-dependent reduction of HNP activity in the conceptus. To observe nutrient consequences of decreased HNP function, C1 components and substrates and epigenetic outcomes were quantified at 24h. Treatment with 100-MUM MEHP resulted in decreased dietary methyl donor concentrations, while treatment with 100- or 250-MUM MEHP resulted in dose dependent elevated C1 products and substrates. In MEHP-treated EMBs with NTDs, H3K4 methylation was significantly increased, while no effects were seen in treated VYS. DNA methylation was reduced in MEHP-treated EMB with and without NTDs. This research suggests that environmental toxicants such as MEHP decrease embryonic nutrition in a time-dependent manner and that epigenetic consequences of HNP disruption may be exacerbated in EMB with NTDs. PMID- 26507545 TI - Comparative effects of whey protein versus L-leucine on skeletal muscle protein synthesis and markers of ribosome biogenesis following resistance exercise. AB - We compared immediate post-exercise whey protein (WP, 500 mg) versus L-leucine (LEU, 54 mg) feedings on skeletal muscle protein synthesis (MPS) mechanisms and ribosome biogenesis markers 3 h following unilateral plantarflexor resistance exercise in male, Wistar rats (~250 g). Additionally, in vitro experiments were performed on differentiated C2C12 myotubes to compare nutrient (i.e., WP, LEU) and 'exercise-like' treatments (i.e., caffeine, hydrogen peroxide, and AICAR) on ribosome biogenesis markers. LEU and WP significantly increased phosphorylated rpS6 (Ser235/236) in the exercised (EX) leg 2.4-fold (P < 0.01) and 2.7-fold (P < 0.001) compared to the non-EX leg, respectively, whereas vehicle-fed control (CTL) did not (+65 %, P > 0.05). Compared to the non-EX leg, MPS levels increased 32 % and 52 % in the EX leg of CTL (P < 0.01) and WP rats (P < 0.001), respectively, but not in LEU rats (+15 %, P > 0.05). Several genes associated with ribosome biogenesis robustly increased in the EX versus non-EX legs of all treatments; specifically, c-Myc mRNA, Nop56 mRNA, Bop1 mRNA, Ncl mRNA, Npm1 mRNA, Fb1 mRNA, and Xpo-5 mRNA. However, only LEU significantly increased 45S pre-rRNA levels in the EX leg (63 %, P < 0.001). In vitro findings confirmed that 'exercise-like' treatments similarly altered markers of ribosome biogenesis, but only LEU increased 47S pre-rRNA levels (P < 0.01). Collectively, our data suggests that resistance exercise, as well as 'exercise-like' signals in vitro, acutely increase the expression of genes associated with ribosome biogenesis independent of nutrient provision. Moreover, while EX with or without WP appears superior for enhancing translational efficiency (i.e., increasing MPS per unit of RNA), LEU administration (or co-administration) may further enhance ribosome biogenesis over prolonged periods with resistance exercise. PMID- 26507547 TI - Dissociative experiences and dissociative minds: Exploring a nomological network of dissociative functioning. AB - In this study, the psychometric properties of the Dissociative Experiences Scale II (DES-II) were tested in a sample of Italian adults, and a nomological network of dissociative functioning based on current psychodynamic research was examined. A total of 794 participants (55% females) ranging in age from 18 to 64 completed the DES-II and other measures of theory of mind, alexithymia, attachment style, and empathy. The Italian translation of the DES-II showed high internal consistency, adequate item-to-scale homogeneity, and good split-half reliability. A single-factor solution including the 8 items of pathological dissociation (DES T) adequately fit the data. Participants who reported higher levels of dissociative experiences showed significantly lower scores on theory of mind and empathy than other participants. They also showed significantly higher scores on alexithymia, preoccupied attachment, and fearful attachment. Results of the study support the view that people who suffer from severe dissociative experiences may also have difficulties mentalizing and regulating affects and that they may feel uncomfortable in close relationships because they have a negative view of the self. This can inform clinical work with dissociative individuals, who could benefit from therapies that consider their potential problems with mentalization, empathy, affect regulation, and attachment. PMID- 26507546 TI - Pharmacokinetics and pharmacodynamics of dasatinib in the chronic phase of newly diagnosed chronic myeloid leukemia. AB - PURPOSE: Dasatinib is a novel, oral, multi-targeted kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL) and Src family kinases. The study investigated pharmacokinetic (PK) and pharmacodynamic (PD) analyses of dasatinib in 51 newly diagnosed, chronic phase, chronic myeloid leukemia patients. METHODS: The dasatinib concentration required to inhibit 50 % of the CrkL (CT10 regulator of kinase like) phosphorylation in bone marrow CD34+ cells (half maximal (50 %) inhibitory concentration (IC50)CD34+cells) was calculated from each patient's dose-response curve using flow cytometry. PK parameters were obtained from the population pharmacokinetic analysis of dasatinib concentrations in plasma on day 28 after administration. RESULTS: Early molecular responses were not significantly associated with PK or PD (IC50 CD34+cells) parameters. However, the PK/PD parameter-time above IC50 CD34+cells-significantly correlated with BCR-ABL transcript level at 3 months (correlation coefficient (CC) = -0.292, P = 0.0375) and the reduction of BCR-ABL level at 1 or 3 months (CC = -0.404, P = 0.00328 and CC = -0.356, P = 0.0104, respectively). Patients with more than 12.6 h at time above IC50 CD34+cells achieved a molecular response of 3.0 log reduction at 3 months and those more than 12.8 h achieved a deep molecular response less than 4.0 log reduction at 6 months at a significantly high rate (P = 0.013, odds ratio = 4.8 and P = 0.024, odds ratio = 4.3, respectively). CONCLUSION: These results suggest that the anti-leukemic activity of dasatinib exhibits in a time-dependent manner and that exposure for more than 12.8 h at time above IC50 CD34+cells could significantly improve prognosis. PMID- 26507548 TI - Comparison of the accuracy of hemoglobin point of care testing using HemoCue and GEM Premier 3000 with automated hematology analyzer in emergency room. AB - The laboratory analysis provides accurate, but time consuming hemoglobin level estimation especially in the emergency setting. The reliability of time-sparing point of care devices (POCT) remains uncertain. We tested two POCT devices accuracy (HemoCue(r)201+ and Gem(r)PremierTM3000) in routine emergency department workflow. Blood samples taken from patients admitted to the emergency department were analyzed for hemoglobin concentration using a laboratory reference Beckman Coulter LH 750 (HBLAB), the HemoCue (HBHC) and the Gem Premier 3000 (HBGEM). Pairwise comparison for each device and HbLAB was performed using correlation and the Bland-Altman methods. The reliability of transfusion decision was assessed using three-zone error grid. A total of 292 measurements were performed in 99 patients. Mean hemoglobin level were 115 +/- 33, 110 +/- 28 and 111 +/- 30 g/l for HbHC, HbGEM and HbLAB respectively. A significant correlation was observed for both devices: HbHC versus HbLAB (r2 = 0.93, p < 0.001) and HBGEM versus HBLAB (r2 = 0.86, p < 0.001). The Bland-Altman method revealed bias of -3.7 g/l (limits of agreement -20.9 to 13.5) for HBHC and HBLAB and 2.5 g/l (-18.6 to 23.5) for HBGEM and HBLAB, which significantly differed between POCT devices (p < 0.001). Using the error grid methodology: 94 or 91 % of values (HbHC and HbGEM) fell in the zone of acceptable difference (A), whereas 0 and 1 % (HbHC and HbGEM) were unacceptable (zone C). The absolute accuracy of tested POCT devices was low though reaching a high level of correlation with laboratory measurement. The results of the Morey's error grid were unfavorable for both POCT devices. PMID- 26507549 TI - Capitalizing on Community Resources to Build Specialized Behavioral Health Services Together with Persons who are Deaf, Deafblind or Hard of Hearing. AB - There are relatively few counselors, psychologists, psychiatrists, and social workers who specialize in serving people who are Deaf, Deafblind or hard of hearing in the United States. Professionals that serve minority populations are often an insular group. They tend to network most often with fellow professionals who understand the language and cultural needs of their service population. Such specialized behavioral health providers rarely have the opportunity to interface with "mainstream" program planners, funders and administrators. Consequently, new recovery agendas, best practice models and community reintegration ideas are only slowly integrated into the care of persons who are Deaf, Deafblind or hard of hearing. We describe the development and implementation of a task force comprised of "front line" providers, administrators, county government officials, advocates and consumers that has made strides toward effective change in a local behavioral health care system. Methods employed, successes, barriers and other reflections on the task force's efforts also are described. PMID- 26507550 TI - Needs Assessment of Hurricane Katrina Evacuees Residing Temporarily in Dallas. AB - This study assessed the psychosocial needs of Hurricane Katrina evacuees temporarily residing in Dallas, TX, after sheltering but prior to their permanent resettlement. Common trauma exposures were physical exposure to flood water, seeing corpses, witnessing death, and loss of family, friends, or home. Fewer than 10 % met symptom criteria for disaster-related posttraumatic stress disorder (PTSD). More than one-fourth met major depressive disorder (MDD) symptom criteria post-disaster but only 15 % had a new (incident) MDD episode after the disaster. Specific trauma exposures and some hurricane-related stressors contributed to risk for both Katrina-related PTSD symptom criteria and incident MDD, but other hurricane-related stressors were uniquely associated with incident MDD. Referral to mental health services was associated with meeting symptom criteria for PTSD and with incident MDD, but only about one-third of these individuals received a referral. Understanding the needs of disaster-exposed population requires assessing trauma exposures and identifying pre-disaster and post-disaster psychopathology. PMID- 26507551 TI - Genome-wide association study identifies African-ancestry specific variants for metabolic syndrome. AB - The metabolic syndrome (MetS) is a constellation of metabolic disorders that increase the risk of developing several diseases including type 2 diabetes and cardiovascular diseases. Although genome-wide association studies (GWAS) have successfully identified variants associated with individual traits comprising MetS, the genetic basis and pathophysiological mechanisms underlying the clustering of these traits remain unclear. We conducted GWAS of MetS in 1427 Africans from Ghana and Nigeria followed by replication testing and meta-analysis in another continental African sample from Kenya. Further replication testing was performed in an African American sample from the Atherosclerosis Risk in Communities (ARIC) study. We found two African-ancestry specific variants that were significantly associated with MetS: SNP rs73989312[A] near CA10 that conferred increased risk (P=3.86 * 10(-8), OR=6.80) and SNP rs77244975[C] in CTNNA3 that conferred protection against MetS (P=1.63 * 10(-8), OR=0.15). Given the exclusive expression of CA10 in the brain, our CA10 finding strengthens previously reported link between brain function and MetS. We also identified two variants that are not African specific: rs76822696[A] near RALYL associated with increased MetS risk (P=7.37 * 10(-9), OR=1.59) and rs7964157[T] near KSR2 associated with reduced MetS risk (P=4.52 * 10(-8), Pmeta=7.82 * 10(-9), OR=0.53). The KSR2 locus displayed pleiotropic associations with triglyceride and measures of blood pressure. Rare KSR2 mutations have been reported to be associated with early onset obesity and insulin resistance. Finally, we replicated the LPL and CETP loci previously found to be associated with MetS in Europeans. These findings provide novel insights into the genetics of MetS in Africans and demonstrate the utility of conducting trans-ethnic disease gene mapping studies for testing the cosmopolitan significance of GWAS signals of cardio-metabolic traits. PMID- 26507552 TI - Action of multiple intra-QTL genes concerted around a co-localized transcription factor underpins a large effect QTL. AB - Sub-QTLs and multiple intra-QTL genes are hypothesized to underpin large-effect QTLs. Known QTLs over gene families, biosynthetic pathways or certain traits represent functional gene-clusters of genes of the same gene ontology (GO). Gene clusters containing genes of different GO have not been elaborated, except in silico as coexpressed genes within QTLs. Here we demonstrate the requirement of multiple intra-QTL genes for the full impact of QTL qDTY12.1 on rice yield under drought. Multiple evidences are presented for the need of the transcription factor 'no apical meristem' (OsNAM12.1) and its co-localized target genes of separate GO categories for qDTY12.1 function, raising a regulon-like model of genetic architecture. The molecular underpinnings of qDTY12.1 support its effectiveness in further improving a drought tolerant genotype and for its validity in multiple genotypes/ecosystems/environments. Resolving the combinatorial value of OsNAM12.1 with individual intra-QTL genes notwithstanding, identification and analyses of qDTY12.1has fast-tracked rice improvement towards food security. PMID- 26507553 TI - Maternal antibodies and developing blood-brain barrier. AB - We briefly review the protective role of maternal antibodies during fetal development and at early postnatal stages. We describe antibody delivery to fetuses, particularly in the context of the developing blood-brain barrier (BBB), and present the essential concepts regarding the adult BBB, together with existing information on the prenatal developing BBB. We focus on maternal antibody transfer to the developing brain and the consequences of the presence of pathogenic antibodies at early stages of brain development on subsequent brain dysfunction. PMID- 26507554 TI - What is the potential for interventions designed to prevent violence against women to reduce children's exposure to violence? Findings from the SASA! study, Kampala, Uganda. AB - Intimate partner violence (IPV) and child maltreatment often co-occur in households and lead to negative outcomes for children. This article explores the extent to which SASA!, an intervention to prevent violence against women, impacted children's exposure to violence. Between 2007 and 2012 a cluster randomized controlled trial was conducted in Kampala, Uganda. An adjusted cluster level intention to treat analysis, compares secondary outcomes in intervention and control communities at follow-up. Under the qualitative evaluation, 82 in depth interviews were audio recorded at follow-up, transcribed verbatim, and analyzed using thematic analysis complemented by constant comparative methods. This mixed-methods article draws mainly on the qualitative data. The findings suggest that SASA! impacted on children's experience of violence in three main ways. First, quantitative data suggest that children's exposure to IPV was reduced. We estimate that reductions in IPV combined with reduced witnessing by children when IPV did occur, led to a 64% reduction in prevalence of children witnessing IPV in their home (aRR 0.36, 95% CI 0.06-2.20). Second, among couples who experienced reduced IPV, qualitative data suggests parenting and discipline practices sometimes also changed-improving parent-child relationships and for a few parents, resulting in the complete rejection of corporal punishment as a disciplinary method. Third, some participants reported intervening to prevent violence against children. The findings suggest that interventions to prevent IPV may also impact on children's exposure to violence, and improve parent-child relationships. They also point to potential synergies for violence prevention, an area meriting further exploration. PMID- 26507555 TI - [Report from the cardiac, vascular, renal, and transplantation pathology working group]. PMID- 26507556 TI - Voluntary Sleep Choice and Its Effects on Bayesian Decisions. AB - This study examines whether voluntary sleep restriction at commonly experienced levels impacts decision making in a Bayesian choice task. Participants recruited were largely traditional age college students from a regional state university (n = 100) and a federal military academy (n = 99; n = 56 and 43, respectively, used in final analysis). Sleep was measured by actigraphy over a one-week period, followed by performance of a decision task. The task involved two sources of information, base rate odds and sample evidence, with subjects asked to make a probability judgment. Results found that subjects with nightly sleep < 6 hr (sleep deprived = SD), relative to those with > 7 hr, placed less decision weight on new evidence, relative to base rate information, in making difficult choices. This result is strongest among female subjects. For easier choices, voluntary SD did not affect relative decision weights placed on the two sources of available information. PMID- 26507557 TI - Esophagitis dissecans superficialis associated with pemphigus vulgaris. PMID- 26507558 TI - beta-Arrestin 2 dependence of delta opioid receptor agonists is correlated with alcohol intake. AB - BACKGROUND AND PURPOSE: delta Opioid receptor agonists are being developed as potential treatments for depression and alcohol use disorders. This is particularly interesting as depression is frequently co-morbid with alcohol use disorders. Yet we have previously shown that delta receptor agonists range widely in their ability to modulate alcohol intake; certain delta receptor agonists actually increase alcohol consumption in mice. We propose that variations in beta arrestin 2 recruitment contribute to the differential behavioural profile of delta receptor agonists. EXPERIMENTAL APPROACH: We used three diarylmethylpiperazine-based non-peptidic delta receptor selective agonists (SNC80, SNC162 and ARM390) and three structurally diverse delta receptor agonists (TAN-67, KNT127 and NIH11082). We tested these agonists in cAMP and beta-arrestin 2 recruitment assays and a behavioural assay of alcohol intake in male C57BL/6 mice. We used beta-arrestin 2 knockout mice and a model of depression-like behaviour to further study the role of beta-arrestin 2 in delta receptor pharmacology. KEY RESULTS: All six tested delta receptor agonists were full agonists in the cAMP assay but displayed distinct beta-arrestin 2 recruitment efficacy. The efficacy of delta receptor agonists to recruit beta-arrestin 2 positively correlated with their ability to increase alcohol intake (P < 0.01). The effects of the very efficacious recruiter SNC80 on alcohol intake, alcohol place preference and depression-like behaviour were beta-arrestin 2-dependent. CONCLUSIONS AND IMPLICATIONS: Our finding that delta receptor agonists that strongly recruit beta-arrestin 2 can increase alcohol intake carries important ramifications for drug development of delta receptor agonists for treatment of alcohol use disorders and depressive disorders. PMID- 26507559 TI - Effect of sardine proteins on hyperglycaemia, hyperlipidaemia and lecithin:cholesterol acyltransferase activity, in high-fat diet-induced type 2 diabetic rats. AB - Type 2 diabetes (T2D) is a major risk factor of CVD. The effects of purified sardine proteins (SP) were examined on glycaemia, insulin sensitivity and reverse cholesterol transport in T2D rats. Rats fed a high-fat diet (HFD) for 5 weeks, and injected with a low dose of streptozotocin, were used. The diabetic rats were divided into four groups, and they were fed casein (CAS) or SP combined with 30 or 5% lipids, for 4 weeks. HFD-induced hyperglycaemia, insulin resistance and hyperlipidaemia in rats fed HFD, regardless of the consumed protein. In contrast, these parameters lowered in rats fed SP combined with 5 or 30% lipids, and serum insulin values reduced in SP v. CAS. HFD significantly increased total cholesterol and TAG concentrations in the liver and serum, whereas these parameters decreased with SP, regardless of lipid intake. Faecal cholesterol excretion was higher with SP v. CAS, combined with 30 or 5% lipids. Lecithin:cholesterol acyltransferase (LCAT) activity and HDL3-phospholipids (PL) were higher in CAS-HF than in CAS, whereas HDL2-cholesteryl esters (CE) were lower. Otherwise, LCAT activity and HDL2-CE were higher in the SP group than in the CAS group, whereas HDL3-PL and HDL3-unesterified cholesterol were lower. Moreover, LCAT activity lowered in the SP-HF group than in the CAS-HF group, when HDL2-CE was higher. In conclusion, these results indicate the potential effects of SP to improve glycaemia, insulin sensitivity and reverse cholesterol transport, in T2D rats. PMID- 26507561 TI - Adding the 'medicines' back into personalized medicine to improve cancer treatment outcomes. PMID- 26507563 TI - On-chip plasmonic waveguide optical waveplate. AB - Polarization manipulation is essential in almost every photonic system ranging from telecommunications to bio-sensing to quantum information. This is traditionally achieved using bulk waveplates. With the developing trend of photonic systems towards integration and miniaturization, the need for an on-chip waveguide type waveplate becomes extremely urgent. However, this is very challenging using conventional dielectric waveguides, which usually require complex 3D geometries to alter the waveguide symmetry and are also difficult to create an arbitrary optical axis. Recently, a waveguide waveplate was realized using femtosecond laser writing, but the device length is in millimeter range. Here, for the first time we propose and experimentally demonstrate an ultracompact, on-chip waveplate using an asymmetric hybrid plasmonic waveguide to create an arbitrary optical axis. The device is only in several microns length and produced in a flexible integratable IC compatible format, thus opening up the potential for integration into a broad range of systems. PMID- 26507564 TI - Scotland's projected changes to general practice. PMID- 26507565 TI - A Robust, Eco-Friendly Access to Secondary Thioamides through the Addition of Organolithium Reagents to Isothiocyanates in Cyclopentyl Methyl Ether (CPME). AB - The nucleophilic addition of widely available and variously functionalized organolithium reagents to isothiocyanates represents a straightforward, high yielding, one-pot method to access secondary thioamides. The simple reaction conditions required and the broad scope (>50 cases examples) makes it a robust and reliable method to access both simple and complex thioamides, including enantiopure ones. Noxious and unpleasant-smelling sulfurating agents, usually employed in the literature established methods, are avoided during the whole synthetic procedure thus, rendering the protocol highly attractive, also for sustainability aspects. PMID- 26507566 TI - The effect of traditional stir-frying process on hydrophilic and lipophilic antioxidant capacities of pine nut kernels. AB - The effect of traditional stir-frying process at different heating temperatures (50-150 degrees C) and time periods (5-20 min) on hydrophilic part (total and individual phenolics), lipophilic part (tocopherol and phytosterol compounds) and their corresponding antioxidant capacities in pine nut kernels were investigated. The concentrations of total phenolics, phenolic acids, tocopherols and phytosterols in raw pine nut kernels were 15.76 mg gallic acid equivalents/100 g dry weight (mg GAE/100 g DW), 12.15 mg/100 g DW, 28.67 mg/100 g DW and 198.81 mg/100 g DW, respectively. Stir-frying at low temperatures over short time periods led to an increase of phenolics, phytosterols and hydrophiliic antioxidant capacities. However, these values decreased under the longer heating time and the higher temperature. Tocopherols and lipophilic antioxidant capacities did not show clear changes at lower heating temperatures or shorter heating times, while they had an apparent decreasing trend at higher heating temperatures or longer heating times. Gallic acid might be the main component, which is responsible for the hydrophilic antioxidant capacity (R(2 )= 0.84, 0.81 and 0.81 using DPPH, FRAP and H-ORAC assays), and tocopherols might be the main antioxidant components in the lipophilic part (R(2 )= 0.87 and 0.89 using DPPH and L-ORAC assays). PMID- 26507567 TI - Increased heterosis in selfing populations of a perennial forb. AB - Quantifying the importance of random genetic drift in natural populations is central to understanding the potential limits to natural selection. One approach is to estimate the magnitude of heterosis, the increased fitness of progeny derived from crosses between populations relative to crosses within populations caused by the heterozygous masking of deleterious recessive or nearly recessive alleles that have been fixed by drift within populations. Self-fertilization is expected to reduce the effective population size by half relative to outcrossing, and population bottlenecks may be common during the transition to selfing. Therefore, chance fixation of deleterious alleles due to drift in selfing populations should increase heterosis between populations. Increased homozygosity due to fixation or loss of alleles should also decrease inbreeding depression within populations. Most populations of the perennial herb Arabidopsis lyrata ssp. lyrata are self-incompatible (SI), but several have evolved self compatibility and are highly selfing. We quantified heterosis and inbreeding depression in two predominantly self-compatible (SC) and seven SI populations in a field common garden experiment within the species' native range and examined the correlation between these metrics to gauge the similarity in their genetic basis. We measured proportion germination in the lab, and survival and fecundity (flower and seed production) for 2 years in the field, and calculated estimates of cumulative fitness. We found 7.2-fold greater heterosis in SC compared with SI populations, despite substantial heterosis in SI populations (56 %). Inbreeding depression was >61 %, and not significantly different between SC and SI populations. There was no correlation between population estimates of heterosis and inbreeding depression, suggesting that they have somewhat different genetic bases. Combined with other sources of information, our results suggest a history of bottlenecks in all of these populations. The bottlenecks in SC populations may have been severe, but their strong inbreeding depression remains enigmatic. PMID- 26507568 TI - Performance of hybrid progeny formed between genetically modified herbicide tolerant soybean and its wild ancestor. AB - Gene flow from genetically modified (GM) crops to wild relatives might affect the evolutionary dynamics of weedy populations and result in the persistence of escaped genes. To examine the effects of this gene flow, the growth of F1 hybrids that were formed by pollinating wild soybean (Glycine soja) with glyphosate tolerant GM soybean (G. max) or its non-GM counterpart was examined in a greenhouse. The wild soybean was collected from two geographical populations in China. The performance of the wild soybean and the F2 hybrids was further explored in a field trial. Performance was measured by several vegetative and reproductive growth parameters, including the vegetative growth period, pod number, seed number, above-ground biomass and 100-seed weight. The pod setting percentage was very low in the hybrid plants. Genetically modified hybrid F1 plants had a significantly longer period of vegetative growth, higher biomass and lower 100-seed weight than the non-GM ones. The 100-seed weight of both F1 and F2 hybrids was significantly higher than that of wild soybean in both the greenhouse and the field trial. No difference in plant growth was found between GM and non GM F2 hybrids in the field trial. The herbicide-resistant gene appeared not to adversely affect the growth of introgressed wild soybeans, suggesting that the escaped transgene could persist in nature in the absence of herbicide use. PMID- 26507569 TI - Effects of disturbance regime on carbohydrate reserves in meadow plants. AB - Carbohydrate storage enables plants to tolerate both seasonally unfavourable conditions and recover from disturbance. Although short-term changes in storage levels due to disturbance are fairly well known, less is known about long-term changes in storage levels, especially in response to cessation of repeated disturbance. Additionally, whereas it is presumably the total amount (pool) of storage carbohydrate reserves that is of importance, typically carbohydrate concentrations are measured instead, as a proxy. We assessed changes in carbohydrate concentrations and pools in storage organs and changes in above- versus belowground biomass in response to mowing cessation in nine herbs from two meadows (dry and wet) at the (June) peak of vegetation development and the (October) growing season end 1 and 3 years after the change in the disturbance regime. We tested three hypotheses: (1) storage will increase with abandonment of mowing only in the first year after disturbance cessation, but not further increase subsequently, as high storage would hinder competitive ability; (2) storage will increase towards the end of the season in both disturbed and undisturbed plants; and (3) changes in carbohydrate concentrations are accurate predictors of changes in pools. Although species-specific changes in carbohydrate reserves occurred in the wet meadow, more general trends appeared in the dry meadow. There, plants accumulated higher carbohydrate reserves at the end of the season, especially in unmown plots. However, the reserves for plants in both disturbance regimes were the same at the growing season peak (June) in both examined years. The increase in storage of carbohydrates on unmown plots in October was manifested by increases of both storage organ biomass and carbohydrate concentration, whereas in mown plots, it was due only to increased carbohydrate concentration. Although concentrations and pools represent different aspects of plant carbohydrate economy, concentrations will represent short-term responses to changed disturbance regimes. PMID- 26507570 TI - DNA barcodes reveal microevolutionary signals in fire response trait in two legume genera. AB - Large-scale DNA barcoding provides a new technique for species identification and evaluation of relationships across various levels (populations and species) and may reveal fundamental processes in recently diverged species. Here, we analysed DNA sequence variation in the recently diverged legumes from the Psoraleeae (Fabaceae) occurring in the Cape Floristic Region (CFR) of southern Africa to test the utility of DNA barcodes in species identification and discrimination. We further explored the phylogenetic signal on fire response trait (reseeding and resprouting) at species and generic levels. We showed that Psoraleoid legumes of the CFR exhibit a barcoding gap yielding the combination of matK and rbcLa (matK + rbcLa) data set as a better barcode than single regions. We found a high score (100 %) of correct identification of individuals to their respective genera but a very low score (<50 %) in identifying them to species. We found a considerable match (54 %) between genetic species and morphologically delimited species. We also found that different lineages showed a weak but significant phylogenetic conservatism in their response to fire as reseeders or resprouters, with more clustering of resprouters than would be expected by chance. These novel microevolutionary patterns might be acting continuously over time to produce multi-scale regularities of biodiversity. This study provides the first insight into the DNA barcoding campaign of land plants in species identification and detection of the phylogenetic signal in recently diverged lineages of the CFR. PMID- 26507571 TI - Biopolymers from Composted Biowaste as Stabilizers for the Synthesis of Spherical and Homogeneously Sized Silver Nanoparticles for Textile Applications on Natural Fibers. AB - The use of bio-based substances (BBS) obtained from composted biowaste as stabilizers for the production of silver nanoparticles (AgNPs) in substitution to citrate is investigated herein, evaluating the functionalization of natural fibers for textile antibacterial applications. The results obtained evidenced that BBS can substitute citrate as reducing/stabilizing agent in the synthesis, inducing a geometrical control (in shape and size) of the AgNPs. Two different substrates were selected (wool and cotton) and two dip-coating deposition techniques investigated. The release of AgNPs from the supports in water was evaluated under two different experimental conditions: 1) soaking (static conditions) for 7 and 15 days, simulating the contact with sweat, and 2) centrifugation (dynamic conditions), simulating a washing machine treatment. A wide physicochemical characterization was carried out to evaluate the effects of BBS on the morphology and stability of AgNPs suspensions as well as the functionalization effectiveness. PMID- 26507572 TI - Assessment of post-operative pain management among acutely and electively admitted patients - a Swedish ward perspective. AB - RATIONALE, AIMS AND OBJECTIVES: Swedish health care is regulated to involve the patient in every intervention process. In the area of post-operative pain, it is therefore important to evaluate patient experience of the quality of pain management. Previous research has focused on mapping this area but not on comparing experiences between acutely and electively admitted patients. Hence, the aim of this study was to investigate the experiences of post-operative pain management quality among acutely and electively admitted patients at a Swedish surgical department performing soft-tissue surgery. METHODS: A survey study design was used as a method based on a multidimensional instrument to assess post operative pain management: Strategic and Clinical Quality Indicators in Postoperative Pain Management (SCQIPP). Consecutive patients at all wards of a university hospital's surgical department were included. Data collection was performed at hospital discharge. RESULTS: In total, 160 patients participated, of whom 40 patients were acutely admitted. A significant difference between acutely and electively admitted patients was observed in the SCQIPP area of environment, whereas acute patients rated the post-operative pain management quality lower compared with those who were electively admitted. CONCLUSIONS: There may be a need for improvement in the areas of post-operative pain management in Sweden, both specifically and generally. There may also be a difference in the experience of post-operative pain quality between acutely and electively admitted patients in this study, specifically in the area of environment. In addition, low levels of the perceived quality of post-operative pain management among the patients were consistent, but satisfaction with analgesic treatment was rated as good. PMID- 26507573 TI - MiR-375 is Essential for Human Spinal Motor Neuron Development and May Be Involved in Motor Neuron Degeneration. AB - The transcription factor REST is a key suppressor of neuronal genes in non neuronal tissues. REST has been shown to suppress proneuronal microRNAs in neural progenitors indicating that REST-mediated neurogenic suppression may act in part via microRNAs. We used neural differentiation of Rest-null mouse ESC to identify dozens of microRNAs regulated by REST during neural development. One of the identified microRNAs, miR-375, was upregulated during human spinal motor neuron development. We found that miR-375 facilitates spinal motor neurogenesis by targeting the cyclin kinase CCND2 and the transcription factor PAX6. Additionally, miR-375 inhibits the tumor suppressor p53 and protects neurons from apoptosis in response to DNA damage. Interestingly, motor neurons derived from a spinal muscular atrophy patient displayed depressed miR-375 expression and elevated p53 protein levels. Importantly, SMA motor neurons were significantly more susceptible to DNA damage induced apoptosis suggesting that miR-375 may play a protective role in motor neurons. PMID- 26507574 TI - Therapeutic Potential of Temperate Forage Legumes: A Review. AB - The discovery of bioactive molecules from botanical sources is an expanding field, preferentially oriented to plants having a tradition of use in medicine and providing high yields and availability. Temperate forage legumes are Fabaceae species that include worldwide-important crops. These plants possess therapeutic virtues that have not only been used in veterinary and folk medicine, but have also attracted the interest of official medicine. We have examined here Medicago sativa (alfalfa), Trifolium pratense and T. repens (clovers), Melilotus albus and M. officinalis (sweet clovers), Lotus corniculatus (birdsfoot trefoil), Onobrychis viciifolia (sainfoin), Lespedeza capitata (roundhead lespedeza), and Galega officinalis (goat's rue). The phytochemical complexes of these species contain secondary metabolites whose pharmacological potentials deserve investigation. Major classes of compounds include alkaloids and amines, cyanogenic glycosides, flavonoids, coumarins, condensed tannins, and saponins. Some of these phytochemicals have been related to antihypercholesterolemia, antidiabetic, antimenopause, anti-inflammatory, antiedema, anthelmintic, and kidney protective effects. Two widely prescribed drugs have been developed starting from temperate forage legumes, namely, the antithrombotic warfarin, inspired from sweet clover's coumarin, and the antidiabetic metformin, a derivative of sainfoin's guanidine. Available evidence suggests that temperate forage legumes are a potentially important resource for the extraction of active principles to be used as nutraceuticals and pharmaceuticals. PMID- 26507575 TI - Tumor Cell-Derived Periostin Regulates Cytokines That Maintain Breast Cancer Stem Cells. AB - Basal-like breast cancer (BLBC) is an aggressive subtype of breast cancer which is often enriched with cancer stem cells (CSC), but the underlying molecular basis for this connection remains elusive. We hypothesized that BLBC cells are able to establish a niche permissive to the maintenance of CSCs and found that tumor cell-derived periostin (POSTN), a component of the extracellular matrix, as well as a corresponding cognate receptor, integrin alpha(v)beta(3), are highly expressed in a subset of BLBC cell lines as well as in CSC-enriched populations. Furthermore, we demonstrated that an intact periostin-integrin beta3 signaling axis is required for the maintenance of breast CSCs. POSTN activates the ERK signaling pathway and regulates NF-kappaB-mediated transcription of key cytokines, namely IL6 and IL8, which in turn control downstream activation of STAT3. In summary, these findings suggest that BLBC cells have an innate ability to establish a microenvironmental niche supportive of CSCs. IMPLICATIONS: The findings reported here indicate that POSTN produced by CSCs acts to reinforce the stem cell state through the activation of integrin receptors and the production of key cytokines. PMID- 26507576 TI - Biofidelity assessment of the 6-year-old ATDs in lateral impact. AB - OBJECTIVES: The objective of this study was to assess and compare the current lateral impact biofidelity of the shoulder, thorax, abdomen, and pelvis of the Q6, Q6s, and Hybrid III (HIII) 6-year-old anthropomorphic test devices (ATDs) through lateral impact testing. METHODS: A series of lateral impact pendulum tests, vertical drop tests, and Wayne State University (WSU) sled tests was performed, based on the procedures detailed in ISO/TR 9790 (1999) and scaling to the 6-year-old using Irwin et al. ( 2002 ). The HIII used in this study was tested with the Ford-designed abdomen described in Rouhana ( 2006 ) and Elhagediab et al. ( 2006 ). The data collected from the 3 different ATDs were filtered using SAE J211 (SAE International 2003 ), aligned using the methodology described by Donnelly and Moorhouse ( 2012 ), and compared for each body region tested (shoulder, thorax, abdomen, and pelvis). The biofidelity performance in lateral impact for the 3 ATDs was assessed against the scaled biofidelity targets published in Irwin et al. ( 2002 ), the abdominal biofidelity target suggested in van Ratingen et al. ( 1997 ), and the biofidelity targets published in Rhule et al. ( 2013 ). Regional and overall biofidelity rankings for each of the 3 ATDs were performed using both the ISO 9790 biofidelity rating system (ISO/TR 9790 1999) and the NHTSA's external biofidelity ranking system (BRS; Rhule et al. 2013 ). RESULTS: All 3 6-year-old ATD's pelvises were rated as least biofidelic of the 4 body regions tested, based on both the ISO and BRS biofidelity rating systems, followed by the shoulder and abdomen, respectively. The thorax of all 3 ATDs was rated as the most biofidelic body region using the aforementioned biofidelity rating systems. The HIII 6-year-old ATD was rated last in overall biofidelity of the 3 tested ATDs, based on both rating systems. The Q6s ATD was rated as having the best overall biofidelity using both rating systems. CONCLUSIONS: All 3 ATDs are more biofidelic in the thorax and abdomen than the shoulder and pelvis, with the pelvis being the least biofidelic of all 4 tested body regions. None of the 3 tested 6-year-old ATDs had an overall ranking of 2.0 or less, based on the BRS ranking. Therefore, it is expected that none of the 3 ATDs would mechanically respond like a postmortem human subject (PMHS) in a lateral impact crash test based on this ranking system. With respect to the ISO biofidelity rating, the HIII dummy would be considered unsuitable and the Q-series dummies would be considered marginal for assessing side impact occupant protection. PMID- 26507577 TI - Highly Comminuted, Articular Fractures of the Distal Antebrachium Managed by Pancarpal Arthrodesis in 8 Dogs. AB - OBJECTIVE: To describe the surgical management by pancarpal arthrodesis for highly comminuted articular fractures of the distal antebrachium in 8 dogs. STUDY DESIGN: Retrospective clinical case series. ANIMALS: Eight dogs. METHODS: Medical records (2001-2014) of dogs with antebrachial fractures were reviewed and dogs with highly comminuted distal antebrachial fractures were identified. The nature of the injury, surgical management by pancarpal arthrodesis, outcome, and complications were recorded. RESULTS: Nine fractures occurred in 8 dogs. Seven dogs were ex-racing greyhounds (8 fractures) and of these, 6/7 dogs had fractures of the right thoracic limb. Compared with the hospital population of dogs with antebrachial fractures, greyhounds were over-represented for the antebrachial injury (odds ratio 117, 95% confidence interval 13-1022). Five dogs sustained injury during exertional exercise or with relatively minor trauma. Submitted bone samples (n = 4) showed no evidence of underlying neoplasia. Mean followup was 15.5 months with 11 complications recorded in 7/8 dogs, including 1 catastrophic, 5 major, and 5 minor complications. Pancarpal arthrodesis allowed a full functional outcome in 3 dogs and an acceptable outcome in 3. CONCLUSION: Comminuted articular fractures of the distal radius and ulna are complex injuries and have a similar presentation to pathologic fractures. Surgical management by pancarpal arthrodesis is associated with a high risk of complication and a guarded prognosis for a full functional outcome. PMID- 26507578 TI - The impact of dendritic cell-tumor fusion cells on cancer vaccines - past progress and future strategies. AB - Dendritic cells (DCs) are potent antigen-presenting cells that can be used in cancer vaccines. Thus, various strategies have been developed to deliver tumor associated antigens via DCs. One strategy includes administering DC-tumor fusion cells (DC-tumor FCs) to induce antitumor immune responses in cancer patients. However, clinical trials using this strategy have fallen short of expectations. Several factors might limit the efficacy of these anticancer vaccines. To induce efficient antitumor immune responses and enhance potential clinical benefits, DC tumor FC-based cancer vaccines require manipulations that improve immunogenicity for both DCs and whole tumor cells. This review addresses recent progress in improving clinical outcomes using DC-tumor FC-based cancer vaccines. PMID- 26507579 TI - Transvaginal ultrasound cervical length for prediction of spontaneous labour at term: a systematic review and meta-analysis. AB - BACKGROUND: The possibility to predict the delivery date is a question frequently raised by pregnant women. However, a clinician has currently little to predict when a woman at term will deliver. OBJECTIVE: To evaluate the predictive accuracy of transvaginal ultrasound (TVU) cervical length (CL) for spontaneous onset of labour in singleton gestation enrolled at term by a meta-analysis. SEARCH STRATEGY: We performed a literature search in electronic databases. SELECTION CRITERIA: We included only studies assessing the accuracy of TVU CL in prediction of spontaneous onset of labour in singleton gestations with vertex presentation who were enrolled at term. DATA COLLECTION AND ANALYSIS: The primary outcome was the accuracy of CL for prediction of spontaneous labour within 7 days. Pooled sensitivities and specificities were calculated. MAIN RESULTS: Five studies including 735 singleton gestations were included. For the prediction of spontaneous labour within 7 days for CL <30 mm the pooled sensitivity was 64% and pooled specificity was 60%. The higher the CL, the better the sensitivity; the lower the CL, the better the specificity. A woman with a singleton gestation at term and a TVU CL of 30 mm has a <50% chance of delivering within 7 days, while one with a TVU CL of 10 mm has an over 85% chance of delivery within 7 days. CONCLUSIONS: TVU CL at term has moderate value in predicting the onset of spontaneous labour. A woman with a TVU CL of 10 mm or less has a high chance of delivering within a week. TWEETABLE ABSTRACT: Cervical length at term has moderate value in predicting the onset of spontaneous labour. PMID- 26507580 TI - HIF3alpha: the little we know. AB - Hypoxia-inducible factors (HIFs) are key regulators of the transcriptional response to hypoxic stress. Three inducible isoforms of HIF are present in mammals. HIF1alpha and HIF2alpha are the best characterized and structurally similar isoforms, while HIF3alpha is the most distantly related and is less studied. The HIF3alpha gene undergoes complex regulation and produces a large number of long and short mRNA splice variants, which are translated into different polypeptides. These molecules primarily act as negative regulators of HIF1alpha and HIF2alpha activity and transcriptional activators of target genes, according to the variant and the biological context. The present review provides an overview of the available, fragmented and sometimes contradictory information concerning the structure, expression and distinct roles of the HIF3alpha variants, in both hypoxic adaptation and in hypoxia-unrelated activities. The pathological consequences of HIF3alpha deregulation are also illustrated. PMID- 26507581 TI - BEND3 mediates transcriptional repression and heterochromatin organization. AB - Transcription repression plays a central role in gene regulation. Transcription repressors utilize diverse strategies to mediate transcriptional repression. We have recently demonstrated that BEND3 (BANP, E5R and Nac1 domain) protein represses rDNA transcription by stabilizing a NoRC component. We discuss the role of BEND3 as a global regulator of gene expression and propose a model whereby BEND3 associates with chromatin remodeling complexes to modulate gene expression and heterochromatin organization. PMID- 26507582 TI - We Need 2C but Not 2B: Developing Serotonin 2C (5-HT2C) Receptor Agonists for the Treatment of CNS Disorders. AB - The serotonin 2C (5-HT2C ) receptor has been identified as a potential drug target for the treatment of a variety of central nervous system (CNS) disorders, such as obesity, substance abuse, and schizophrenia. In this Viewpoint article, recent progress in developing selective 5-HT2C agonists for use in treating these disorders is summarized, including the work of our group. Challenges in this field and the possible future directions are described. Homology modeling as a method to predict the binding modes of 5-HT2C ligands to the receptor is also discussed. Compared to known ligands, the improved pharmacological profiles of the 2-phenylcyclopropylmethylamine-based 5-HT2C agonists make them preferred candidates for further studies. PMID- 26507583 TI - Photocontrol of ion permeation in lipid vesicles with (bola)amphiphilic spirooxazines. AB - Three (bola)amphiphilic spirooxazines have been synthesized and their photochromism has been characterized. The large biphotochromic structure of 2 significantly affects its conformational flexibility and the rate constants for thermal ring closure are particularly dependent on the lipid phase state. Two comprehensive ion permeation studies were performed to examine the effect of spirooxazine inclusion and isomerization on membrane permeability. In all cases, the open-ring isomers of these spirooxazines are more disruptive in bilayer membranes than their closed-ring isomers. Further, the rate of ion permeation and net release are highly dependent on the lipid bilayer phase state and the relative position of the photochromic moiety in the bilayer membrane. Moreover, the difference in potassium ion permeability under UV and visible irradiation is more pronounced than previously reported photoresponsive membrane disruptors with reversible photocontrols. PMID- 26507584 TI - Biochemical characteristics and antioxidant activity of crude and purified sulfated polysaccharides from Gracilaria fisheri. AB - Sulfated polysaccharides (SPs) from Gracilaria fisheri of Thailand, which were extracted in low-temperature (25 degrees C) water showed the highest content of phenolic compounds compared with those extracted at high temperature (55 degrees C). Crude SP antioxidant activity was evaluated by measuring the DPPH free radical scavenging effect which is directly related to the level of phenolic compounds. The sulfate content, total sugar, and SPs yield were also directly related to the extraction temperature. All extracts contained galactose as a major monosaccharide. High antioxidant activity of crude SP, positively correlated with the phenolic compound contents (R(2) = 0.996) contributed by the existence of sulfate groups and phenolic compounds. In purified SP, F1 fraction exhibited strong radical scavenging ability, but it was not significantly different compared to crude SP extracted at 25 degrees C. This indicated that the appropriate density and distribution of sulfate groups in the SP extract showed the best antioxidant activity. PMID- 26507585 TI - Infrared study of matrix-isolated ethyl cyanide: simulation of the photochemistry in the atmosphere of Titan. AB - Low-temperature Ar matrix isolation has been carried out to investigate the infrared spectrum of ethyl cyanide (CH3CH2CN), a molecule present in the atmosphere of Titan. The lambda > 120 nm and lambda > 230 nm photolysis reactions of ethyl cyanide in an Ar matrix were also performed in order to compare the behaviour of this compound when it is submitted to high and low energetic radiations. These different wavelengths have been used with the aim to reproduce the radiation reaching the various parts of the atmosphere. Several photoproducts have been identified during photolysis such as vinyl cyanide (CH2[double bond, length as m-dash]CHCN), cyanoacetylene (HC3N), and ethylene/hydrogen cyanide (C2H4/HCN), ethylene/hydrogen isocyanide (C2H4/HNC), acetylene/hydrogen cyanide (C2H2/HCN), acetylene/hydrogen isocyanide (C2H2/HNC), and acetylene:methylenimine (C2H2:HNCH2) complexes. Ethyl isocyanide (CH3CH2NC) and a ketenimine form (CH3CH[double bond, length as m-dash]C[double bond, length as m-dash]NH) have been identified as well. Photoproduct identification and spectral assignments were done using previous studies and density functional theory (DFT) calculations with the B3LYP/cc-pVTZ basis set. PMID- 26507586 TI - Rapid inner-volume imaging in the steady-state with 3D selective excitation and small-tip fast recovery imaging. AB - PURPOSE: Develop a method for rapid three-dimensional inner-volume (IV), or reduced field-of-view, steady-state imaging. METHODS: Tailored radiofrequency pulses for exciting a three-dimensional IV were designed using a recently proposed algorithm and used in three different sequences: spoiled gradient echo, balanced steady-state free precession, and "small-tip fast recovery" (STFR) which uses a "tip-up" RF pulse after the readout to fast recover spins to the longitudinal axis. The inner- and outer-volume (OV) steady-state signals were analyzed. To demonstrate the potential utility of the proposed method, segmented stack-of-spirals reduced field-of-view images in a volunteer were acquired. RESULTS: For a given three-dimensional IV excitation pulse, STFR can achieve higher IV/OV signal ratio compared with spoiled gradient echo and balanced steady state free precession. For spoiled gradient echo and balanced steady-state free precession, this ratio is significantly lower than that produced by a single IV excitation. For STFR, this ratio exceeds that produced by a single IV excitation, due to partial OV saturation produced by the nonspatially selective tip-up pulse. Reduced FOV STFR stack-of-spirals imaging with 2-fold under-sampling in both x-y and z is demonstrated. CONCLUSION: STFR provides an effective mechanism for OV suppression in steady-state IV imaging. The recently proposed joint pulse design method can be used in the STFR sequence to achieve fast reduced field-of-view imaging. Magn Reson Med 76:1217-1223, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26507587 TI - Interactions between RAD51 rs1801321 and maternal cigarette smoking as risk factor for nonsyndromic cleft lip with or without cleft palate. PMID- 26507589 TI - We are very pleased to offer you again a very exciting issue of CHIMIA. Introduction. PMID- 26507588 TI - Characteristics and biodegradability of olive mill wastewaters. AB - Olive mill wastewaters (OMWs) are mostly characterized by their high-organic content and complex organic compounds in addition to the phenolic compounds. European olive oil manufacturers have to cope up with the same wastewater treatment problem and the applied conventional treatment technologies for OMW were not proved to be very successful in each case. Olive mills are mostly small and medium-sized installations and OMW is generated during the three-four-month long manufacturing season. The problem is not only the complex wastewater to be treated but also the scattered positioning of the olive mills, the seasonal wastewater generation and the size of the manufacturing facilities. The aim of the study is to identify the organic content of OMW and to assess the biological and chemical treatability of OMWs, in order to assist the development of integrated chemical-biological treatment schemes for best appropriate techniques implementation. The experimental studies show that separation of the particulate fraction improved the biodegradability or reduced the refractory and inhibitory effects of particulate organics. PMID- 26507590 TI - Metathesis by Molybdenum and Tungsten Catalysts. AB - Carbon-carbon double bonds are an integral part of the chemical industry and are widely found in natural products, from the small and simple (ethylene) to the large and complex. The ability to manipulate carbon-carbon double bonds to make other carbon-carbon double bonds in a catalytic and stereospecific fashion has revolutionized the way organic molecules and polymers are made today. This article outlines the development of modern molybdenum and tungsten alkylidene catalysts that can be designed at a molecular level to achieve a given result. Carbon-carbon triple bonds also can be manipulated in a similar manner with the appropriate alkylidyne catalyst. Although the 'alkene metathesis' and 'alkyne metathesis' reactions are now fifty to sixty years old, many problems remain that will require an even more detailed understanding of these most intricate, superficially simple reactions. PMID- 26507591 TI - Looking Back on 35 Years of Industrial Catalysis. AB - This article is an account of my 35 years in the Basel Chemical Industry, starting in 1976 as a young research chemist in the Central Research Laboratories of Ciba-Geigy until my retirement as Chief Scientific Officer of Solvias in 2011. In the first section, important aspects of industrial research are commented from my personal point of view with particular emphasis on the importance of team work and the situation of catalysis in the (Swiss) fine chemicals industry. In the next sections, the three most important areas of catalytic research are described where my colleagues and I could not only solve specific Ciba-Geigy / Novartis / Solvias problems, but also developed industrially relevant, generally applicable catalytic methodologies and contributed to the understanding of these complex catalytic transformations: i) Catalytic C-C and C-N coupling catalysis where we developed highly efficient catalysts for the Heck, Suzuki, Buchwald-Hartwig reactions; ii) Hydrogenations using modified heterogeneous catalysts, especially the chemoselective reduction of functionalized nitro arenes and the enantioselective hydrogenation of substituted ketones using Pt catalysts modified with chinchona alkaloids where mechanistic studies led to a working understanding of this fascinating reaction; iii) Enantioselective homogeneous hydrogenation and chiral ligands. The process development for the production of (S)-metolachlor, an important herbicide via an iridium-Josiphos catalyzed C=N hydrogenation is described in some detail, followed by a brief description how the Solvias Ligand Portfolio was developed. PMID- 26507592 TI - Challenges and Rewards in Medicinal Chemistry Targeting Cardiovascular and Metabolic Diseases. AB - Medicinal chemistry has been transformed by major technological and conceptual innovations over the last three decades: structural biology and bioinformatics, structure and property based molecular design, the concepts of multidimensional optimization (MDO), in silico and experimental high-throughput molecular property analysis. The novel technologies advanced gradually and in synergy with biology and Roche has been at the forefront. Applications in drug discovery programs towards new medicines in cardiovascular and metabolic diseases are highlighted to show impact and advancement: the early discovery of endothelin antagonists for endothelial dysfunction (Bosentan), 11-beta hydroxysteroid dehydrogenase (11beta HSD1) inhibitors for dysregulated cellular glucocorticoid tonus (type 2 diabetes and metabolic syndrome) and non-covalent hormone sensitive lipase (HSL) inhibitors to study the scope of direct inhibition of lipolysis in the conceptual frame of lipotoxicity and type 2 diabetes. PMID- 26507593 TI - What Makes Us Smell: The Biochemistry of Body Odour and the Design of New Deodorant Ingredients. AB - Today, axilla odours are socially stigmatized and are targeted with deodorants and antiperspirants representing a multi-billion market. Axilla odours aren't simple byproducts of our metabolism but specifically formed by an intricate interplay between i) specific glands, ii) secreted amino acid conjugates of highly specific odorants and iii) selective enzymes present in microorganisms colonizing our skin, providing a natural 'controlled-release' mechanism. Within a multidisciplinary research project, we were able to elucidate the structure of key body odorants, isolate and characterize secreted amino acid conjugates and identify the enzymes responsible for odour release. These enzymes then served as targets for the development of specific active compounds in an almost medicinal chemistry approach, an approach rarely used in the cosmetic field so far. Here we review the key new insights into the biochemistry of human body odour formation, with some remarks on the experimental steps undertaken and hurdles encountered. The development of deodorant actives and the difficult path to market for such specifically acting cosmetic actives is discussed. The basic insights into the biochemistry also opened the way to address some questions in population genetics: Why have large proportions of Asians lost the 'ability' to form body odours? Do twins smell the same? Are our typical body odours indeed influenced by the immune system as often claimed? After addressing these questions, I'll conclude with the key remaining challenges in this field on an ecological niche that is 'anatomically very close to our heart'. PMID- 26507594 TI - Contributions of Biomolecular NMR to Allosteric Drug Discovery. AB - Drug discovery is a complex process, and a variety of technologies contribute to its success. Biophysical methods have gained widespread attention within the last decade, and in particular NMR spectroscopy as the most versatile biophysical method has seen numerous applications and significant impact to drug discovery. Here we summarize the potential of NMR to support drug discovery, and highlight a number of recent applications. PMID- 26507595 TI - Sedaxane, Isopyrazam and SolatenolTM: Novel Broad-spectrum Fungicides Inhibiting Succinate Dehydrogenase (SDH) - Synthesis Challenges and Biological Aspects. AB - Sedaxane (SDX) 1, isopyrazam (IZM) 2 and SolatenolTM (STL) 3 are broad-spectrum pyrazole carboxamides, which originate from novel chemical classes of fungicides. Their mode of action (MoA) is inhibition of succinate dehydrogenase (SDH), which was recognized for a long time to deliver only compounds with a narrow biological spectrum. This view changed with the market introduction of BASF's boscalid in 2003. All major agro-companies subsequently worked in parallel on this MoA successfully and recently introduced new compounds to the market. Syngenta entered the SDHI area in 1998 and was able to introduce three complementary compounds to the market between 2010 and 2012. In this short review some synthesis challenges and biological effects of SDX 1, IZM 2 and STL 3 will be covered. New cost-efficient synthesis strategies for the preparation of o biscyclopropyl-aniline, new benzonorbornene intermediates and the key pyrazole carboxylic acid intermediate which is essential for all three Syngenta SDHIs, will be in the focus of this review. PMID- 26507596 TI - Heterogenised Molecular Catalysts for the Reduction of CO2 to Fuels. AB - CO(2) conversion provides a possible solution to curtail the growing CO(2) levels in our atmosphere and reduce dependence on fossil fuels. To this end, it is essential to develop efficient catalysts for the reduction of CO(2). The structure and activity of molecular CO(2) reduction catalysts can be tuned and they offer good selectivity with reasonable stability. Heterogenisation of these molecules reduces solvent restrictions, facilitates recyclability and can dramatically improve activity by preventing catalyst inactivation and perturbing the kinetics of intermediates. The nature and morphology of the solid-state material upon which the catalyst is immobilised can significantly influence the activity of the hybrid assembly. Although work in this area began forty years ago, it has only drawn substantial attention in recent years. This review article gives an overview of the historical development of the field. PMID- 26507597 TI - Metal Complexes and Medicine: A Successful Combination. AB - Since the start of our independent research at the Department of Chemistry of the University of Zurich in 2009, our group has been, among other topics, working on the use of metal complexes in medicinal chemistry. In this short review article, we highlight our recent achievements in the use of such compounds to fight the parasitic disease schistosomiasis. PMID- 26507598 TI - Molecular Engineering of Functional Materials for Energy and Opto-Electronic Applications. PMID- 26507599 TI - PAT at the Universities of Applied Sciences. AB - An overview of activities in the field of Process Analytical Technologies (PAT) at the Universities of Applied Sciences in Switzerland is presented. PMID- 26507600 TI - The 50th EUCHEM Conference on Stereochemistry (Burgenstock Conference 2015), Brunnen, April 26th-Mai 1st, 2015. PMID- 26507601 TI - International Conference on Contaminated Sediments - ContaSed 2015 8-13 March 2015, Monte Verita, Ascona, Switzerland. AB - About 80 participants from 22 countries from industry and academia gathered at the International Conference on Contaminated Sediments (ContaSed 2015) held at the Congressi Stefano Franscini (CSF), the conference center of ETH Zurich, located at Monte Verita, Ascona, Switzerland. ContaSed 2015 provided a platform for top experts as well as for junior researchers from different scientific disciplines to present recent results and novel approaches on the analysis, assessment and remediation of contaminated sediments. ContaSed 2015 served as a unique communication and discussion opportunity for environmental scientists with an emphasis on chemistry, sedimentology, ecotoxicology or remediation engineering. PMID- 26507602 TI - 7th Waedenswil Day of Chemistry Personalized Medicine: Full Speed Ahead! AB - The aim of Personalized Medicine in disease treatment and prevention is to take account of the individual variability in genes, environment and lifestyle for each person. This approach is applied to certain tumours but is still not common for most diseases. On June 18, 2015 the TEDD network (Tissue Engineering for Drug Development and Substance Testing) invited a total of 130 academic and industrial partners to Waedenswil to exchange ideas and discuss promising approaches. PMID- 26507606 TI - Doing their best: strategies used by South African clinicians in working with psychiatric inpatients across a language barrier. AB - BACKGROUND AND OBJECTIVES: South Africa has 11 official languages, but most psychiatrists can speak only English and Afrikaans and there are no formal interpreter posts in the mental healthcare system. As a result clinicians communicate with patients who have limited English language proficiency (LEP) without the use of interpreters. We present case material, constituting recordings of interactions between clinicians and LEP patients in a public psychiatric institution. The aim is to have a better understanding of how these clinical encounters operated and what communicative strategies clinicians used. DESIGN: We used the Roter interaction analysis system (RIAS) to evaluate clinicians' conversational strategies and to analyze interactions between clinicians and patients. RESULTS: Clinicians showed a high degree of tenacity in trying to engage patients in the clinical conversation, build rapport, and gather crucial diagnostic information. However, patients often responded briefly and monosyllabically, or kept quiet. In psychiatry where commonality of language cannot be assumed, it is not possible to determine the clinical significance of these responses. DISCUSSION: Clinicians went to great lengths to understand LEP patients. It is also clear that patients were often not optimally understood. Clinicians would try to gain valid information in a polite manner, but would abandon these attempts repeatedly as it became clear that proper communication was not possible. CONCLUSIONS: Our findings suggest that in the absence of interpreter services, the communication between clinicians and LEP patients is sparse and yields limited clinical information. The lack of proper language services stands in the way of optimal clinical care and requires urgent attention. PMID- 26507607 TI - Strategies to reduce plate waste in primary schools - experimental evaluation. AB - OBJECTIVE: To determine and compare the effect of two interventions in reducing the plate waste of school lunches. DESIGN: A between-group analysis was conducted among children from three primary schools: (i) a group receiving intervention A, designed for children and focusing on nutrition education and food waste; (ii) a group receiving intervention B, intended for teachers and focusing on the causes and consequences of food waste; and (iii) a control group with no intervention. For each child, physical weighing of individual meals and leftovers was performed on three non-consecutive weeks at baseline (T0), 1 week (T1, short term) and 3 months (T2, medium term) following the intervention. Plate waste was recorded for a total of 1742 lunches during 14 d over eight different menus. SETTING: Portuguese public primary schools in the city of Porto. SUBJECTS: All fourth grade children (n 212) attending the three preselected schools. RESULTS: After intervention A focusing on nutrition education designed for children, a decrease in soup waste was observed compared with the control group. The effect was greater at T1 (-11.9 (se 2.8) %; P<0.001) than at T2 (-5.8 (se 4.4) %; P=0.103). The plate waste of identical main dishes decreased strongly at T1 (-33.9 (se 4.8) %; P<0.001). However, this effect was not found at T2 (-13.7 (se 3.2) %; P<0.001). After intervention B involving teachers, plate waste decreased at T2 ( 5.5 (se 1.9) % for soup; -5.4 (se 2.4) % for identical main dishes). CONCLUSIONS: Nutrition education designed for children was more effective in the short than the medium term. Thus, this kind of intervention was not effective in reducing food waste in the medium term. In contrast, an intervention focusing on teachers revealed better results in the medium term than in the short term. PMID- 26507608 TI - Bisphosphonate drug holidays--when, why and for how long? AB - Bisphosphonates are first-line agents used for the treatment of osteoporosis in postmenopausal women and men. Although their efficacy in the reduction of vertebral, non-vertebral and hip fracture risk has been established, some concerns have arisen associated with their long-term use. These include osteonecrosis of the jaw and atypical (subtrochanteric and femoral shaft) fractures. The latter may result from accumulation of fatigue damage due to oversuppression of bone turnover in susceptible individuals. In this respect, the concept of a 'drug holiday' after completion of a reasonable period of bisphosphonate therapy has emerged. Theoretically, this allows bone turnover to increase and permits normal skeletal maintenance and repair, although there is as yet no good evidence that bisphosphonate discontinuation will reduce the risk of these adverse events. Current data derive from studies in postmenopausal women and support a beneficial effect of alendronate or zolendronate continuation in high-risk groups, such as those with T-score < -2.5 or prevalent vertebral fractures after completion of 5 or 3 years, respectively. The optimal length of a 'drug holiday' has not been established but existing data suggest up to 5 years with alendronate, 3 years with zoledronate and 1 year with risedronate. A decision to recommence therapy should then probably be based on regular reassessment of bone mineral density and fracture risk. PMID- 26507609 TI - Late relapses in primary CNS lymphoma after complete remissions with high-dose methotrexate monotherapy. AB - Treatment of patients with newly diagnosed primary CNS lymphomas using high dose methotrexate regimens is reported to yield about 30% long term survivors with minimal neurotoxicity. As in other systemic large cell lymphomas, it is generally assumed that most relapses occur within 5 years of diagnosis. A retrospective review of the Johns Hopkins experience in 52 patients treated between 1995 and 2008 yielded 19 patients (37%) who achieved a complete response and were followed for over 5 years. Four of these patients remained progression-free for over 10 years. However, two of these long-term survivors have now relapsed over 10 years after their initial diagnosis. An analysis of progression and overall survival does not reveal a plateau suggesting that even patients who have not recurred for over 10 years remain at high risk for relapse after treatment with single agent high dose methotrexate. PMID- 26507610 TI - In Reply to Drs Mullins and Ali. PMID- 26507611 TI - Coca: High Altitude Remedy of the Ancient Incas. AB - The use of coca leaf for medicinal purposes is a centuries-old tradition of the native peoples of South America. Coca products are thought by many laypersons to provide risk-free benefits to users participating in strenuous activities at high altitude. Physiologic studies of coca have increased understanding of its possible mechanism of action as well as its potential impact on high altitude activities. This present work explores the role of coca throughout the history of the Andean peoples and explores whether this ancient remedy has a place in modern medicine. A focused summary of research articles with particular relevance to the field of wilderness medicine is also included to better provide the reader with lessons not only from history but also from another culture. PMID- 26507612 TI - California Sea Lion (Zalophus californianus) and Harbor Seal (Phoca vitulina richardii) Bites and Contact Abrasions in Open-Water Swimmers: A Series of 11 Cases. AB - OBJECTIVE: To review cases of bites and contact abrasions in open-water swimmers from California sea lions (Zalophus californianus) and harbor seals (Phoca vitulina richardii). METHODS: Open-water swimmers from a San Francisco swimming club were questioned about encounters with pinnipeds (seals and sea lions) that resulted in bites or contact abrasions. When possible, wounds were documented with photographs. Medical follow-up and treatment complications were also reviewed. RESULTS: From October 2011 to December 2014, 11 swimmers reported bites by a sea lion (n = 1), harbor seal (n = 7), or unidentified pinniped (n = 3). Ten of the encounters occurred in San Francisco Bay; 1 occurred in the Eld Inlet, in Puget Sound, near Olympia, WA. None of the swimmers were wearing wetsuits. All bites involved the lower extremities; skin was broken in 4 of 11 bites and antibiotics were prescribed in 3 cases. One swimmer, who was bitten by a harbor seal, also had claw scratches. A treatment failure occurred with amoxicillin/clavulanate in another swimmer who was bitten by an unidentified pinniped; the wound healed subsequently with doxycycline, suggesting an infection with Mycoplasma spp. There were no long-lasting consequences from any of the bites. The majority of cases occurred at low tide, and bumping of the swimmer by the animal before or after a bite was common, but no clear tide or attack pattern was identified. CONCLUSIONS: Bites and contact abrasions from sea lions and harbor seals are reported infrequently in open-water swimmers and typically involve the lower extremities. Because of the risk of Mycoplasma infection, treatment with a tetracycline is recommended in pinniped bites with signs of infection or serious trauma. Attempting to touch or pet sea lions or seals is inadvisable and prohibited by the Marine Mammal Protection Act. Swimmers should leave the water as soon as possible after a bite or encounter. PMID- 26507613 TI - Uniform yolk-shell iron sulfide-carbon nanospheres for superior sodium-iron sulfide batteries. AB - Sodium-metal sulfide battery holds great promise for sustainable and cost effective applications. Nevertheless, achieving high capacity and cycling stability remains a great challenge. Here, uniform yolk-shell iron sulfide-carbon nanospheres have been synthesized as cathode materials for the emerging sodium sulfide battery to achieve remarkable capacity of ~ 545 mA h g(-1) over 100 cycles at 0.2 C (100 mA g(-1)), delivering ultrahigh energy density of ~ 438 Wh kg(-1). The proven conversion reaction between sodium and iron sulfide results in high capacity but severe volume changes. Nanostructural design, including of nanosized iron sulfide yolks (~ 170 nm) with porous carbon shells (~ 30 nm) and extra void space (~ 20 nm) in between, has been used to achieve excellent cycling performance without sacrificing capacity. This sustainable sodium-iron sulfide battery is a promising candidate for stationary energy storage. Furthermore, this spatially confined sulfuration strategy offers a general method for other yolk shell metal sulfide-carbon composites. PMID- 26507614 TI - Four New SPORE Grants Awarded. AB - Despite an economic climate shaped by tight budgets, the NCI recently announced four new Specialized Program of Research Excellence awards that emphasize translation research. In total, the NCI doled out $106 million to fund these new awards and 48 renewed or continuing grants. PMID- 26507615 TI - How accurate is anatomic limb alignment in predicting mechanical limb alignment after total knee arthroplasty? AB - BACKGROUND: Anatomic limb alignment often differs from mechanical limb alignment after total knee arthroplasty (TKA). We sought to assess the accuracy, specificity, and sensitivity for each of three commonly used ranges for anatomic limb alignment (3-9 degrees , 5-10 degrees and 2-10 degrees ) in predicting an acceptable range (neutral +/- 3 degrees ) for mechanical limb alignment after TKA. We also assessed whether the accuracy of anatomic limb alignment was affected by anatomic variation. METHODS: This retrospective study included 314 primary TKAs. The alignment of the limb was measured with both anatomic and mechanical methods of measurement. We also measured anatomic variation, including the femoral bowing angle, tibial bowing angle, and neck-shaft angle of the femur. All angles were measured on the same full-length standing anteroposterior radiographs. The accuracy, specificity, and sensitivity for each range of anatomic limb alignment were calculated and compared using mechanical limb alignment as the reference standard. The associations between the accuracy of anatomic limb alignment and anatomic variation were also determined. RESULTS: The range of 2-10 degrees for anatomic limb alignment showed the highest accuracy, but it was only 73 % (3-9 degrees , 65 %; 5-10 degrees , 67 %). The specificity of the 2-10 degrees range was 81 %, which was higher than that of the other ranges (3-9 degrees , 69 %; 5-10 degrees , 67 %). However, the sensitivity of the 2-10 degrees range to predict varus malalignment was only 16 % (3-9 degrees , 35 %; 5-10 degrees , 68 %). In addition, the sensitivity of the 2-10 degrees range to predict valgus malalignment was only 43 % (3-9 degrees , 71 %; 5-10 degrees , 43 %). The accuracy of anatomical limb alignment was lower for knees with greater femoral (odds ratio = 1.2) and tibial (odds ratio = 1.2) bowing. CONCLUSIONS: Anatomic limb alignment did not accurately predict mechanical limb alignment after TKA, and its accuracy was affected by anatomic variation. Thus, alignment after TKA should be assessed by measuring mechanical alignment rather than anatomic alignment. PMID- 26507616 TI - Fatty acid and cholesterol profiles and hypocholesterolemic, atherogenic, and thrombogenic indices of table eggs in the retail market. AB - BACKGROUND: Eggs are an important source of food due to its favorable effects on human health derived from the protein, fats, minerals, vitamins and bioactive components. We studied the effects of source of eggs in the retail market on fatty acids, lipid profiles and antioxidant status in eggs. METHODS: Eggs from four sources named A, B, C, and D in the retail market were collected to determine fatty acid, total lipid, and cholesterol profiles; hypocholesterolemic, atherogenic and thrombotic indices; antioxidant status (e.g., of malondialdehyde); and total antioxidant capacity in the whole edible parts of eggs (albumen + yolk) and egg yolk. Samples were collected four times and pooled over times to represent 5 and 10 samples per source for determinations of fatty acids and determinations of lipid profiles and antioxidant status, respectively. RESULTS: Fatty acid, total lipid, and cholesterol profiles; hypocholesterolemic, atherogenic and thrombotic indices; presence of malondialdehyde; and total antioxidant capacity in the whole edible parts of eggs and egg yolk showed significant differences (P >= 0.05) among different sources of eggs in retail market. Source D showed higher levels of saturated fatty acids (SFA) and linoleic and monounsaturated fatty acid (MUFA)/polyunsaturated fatty acid (PUFA) ratio but lower levels of MUFA and linolenic, arachidonic, eicosapentaeonic (EPA), decohexaenoic (DHA), and total omega9 fatty acids and lower unsaturated fatty acids (UFA)/SFA ratio. Similar trend was shown in fatty acids profiles of the whole edible parts of eggs. On the other hand, total cholesterol, low density lipoprotein (LDL), LDL/high density lipoprotein (HDL) ratio, and atherogenic and thrombogenic indices and total antioxidant capacity of source D were significantly higher than those of other source, but levels of hypocholesterolemic index, and malondialdehyde levels were lower for source D. CONCLUSION: Eggs in the retail market in Jeddah city, Saudi Arabia, from May to August 2015 showed a different pattern of fatty acid and cholesterol profiles; hypocholesterolemic, atherogenic, and thrombogenic indices; and antioxidant status, which might reflect the nutritional and husbandry practice of laying hens. This can affect the nutritional values of eggs, and hence, customer benefits, suggesting the need for standardization and quality control based on nutrient index values. PMID- 26507617 TI - Sublingual Fentanyl Tablets for Relief of Breakthrough Pain in Cancer Patients and Association with Quality-of-Life Outcomes. AB - BACKGROUND AND OBJECTIVE: Breakthrough pain (BTP) is highly prevalent in patients with cancer and is strongly associated with adverse outcomes related to health status, mood, anxiety and depression. However, studies on the effect of BTP medication on quality of life (QOL) are lacking. The purpose of this study was to provide a qualitative evaluation of the effect of sublingual fentanyl tablets (SFT), a therapy specifically developed for BTP, on the QOL of cancer pain patients. METHODS: We conducted a multicentre, prospective observation post authorisation, open-label study between March and December 2013. The study consisted of a screening visit and four assessment points at 3, 7, 15 and 30 days. Pain intensity (PI), frequency of BTP, onset of pain relief and adverse events (AEs) were assessed at each visit. Anxiety and depression were evaluated using the validated Hospital Anxiety and Depression Scale (HADS) and health status using the Short Form 12, version 2 (SF-12v2) Health Survey. RESULTS: Of the 102 patients considered eligible, 81 (79.4 %) were enrolled; of these, 69 (85.1 %) completed the study. Significant pain reduction was achieved for average PI (p < 0.001) compared with baseline. At the end of the observational period, HADS scores showed significant improvement in the depression subscale (p = 0.005) and the anxiety subscale (p < 0.001). Similarly, SF-12 scores showed significant improvement, both in the mental component score (p < 0.001) and the physical component score (p = 0.002). SFT was well-tolerated and only one patient withdrew from the study due to drug-related AEs. CONCLUSION: SFT represents an effective, well-tolerated treatment for cancer BTP. Results provide consistent evidence for the positive impact of SFT on health-related QOL and physical functioning as well as other co-morbidities of cancer BTP such as anxiety and depression. PMID- 26507618 TI - Antiplatelet Efficacy of Fixed-Dose Aspirin-Clopidogrel Combination in Patients with Stable Coronary Artery Disease Treated with Drug-Eluting Stent Implantation. AB - BACKGROUND AND OBJECTIVES: A fixed-dose combination (FDC) of aspirin and clopidogrel bisulfate may improve medication adherence. However, the absence of data on the relative antiplatelet efficacy of FDC and separate dual pills (SDP) of aspirin and clopidogrel in real-world patients with stable coronary artery disease is a major factor retarding clinical introduction of such an FDC. METHODS: This was a single-centre, randomized, open-label, parallel-group, non inferiority trial. Patients who maintained a regimen of separate aspirin and clopidogrel pills for at least 1 year after drug-eluting stent implantation without adverse events were enrolled. Patients were randomly assigned to either the FDC group or the SDP group. Antiplatelet efficacy and tolerability were assessed at baseline and at 4 weeks. RESULTS: Of the 93 enrolled patients, 83 (FDC group: n = 42; SDP group: n = 41) completed the study. The difference in the changes in P2Y12 percentage inhibition did not exceed the predetermined value for inferiority [mean difference -1.7; 95 % confidence interval (CI) -6.9 to 4.5, p < 0.001 for non-inferiority]. The changes from baseline to 4 weeks in P2Y12 reaction units (PRU) (mean difference 9.7 PRU, p = 0.46), maximal platelet aggregation (mean difference 2.0 %, p = 0.44) and aspirin reaction units (ARU) (mean difference -2.3 ARU, p = 0.88) did not differ significantly between the treatment groups. The tolerability of the FDC formulation was similar to that of SDP therapy (p = 0.68). CONCLUSION: In patients with prior percutaneous coronary intervention, the antiplatelet efficacy of the aspirin/clopidogrel FDC was non inferior to that of SDP and the tolerability of the two regimens was similar after 4 weeks of treatment. PMID- 26507619 TI - Thrombocytopenia in Patients Receiving Prolonged Linezolid May be Caused by Oxidative Stress. AB - BACKGROUND AND OBJECTIVES: Oxidative stress in drug-induced thrombocytopenia (TP) has been discussed. This study was carried out to assess the oxidative stress in patients with normal platelet count (NPC) and TP after linezolid (LZD) treatment and to evaluate if TP caused by LZD is associated with a reduction in antioxidation ability and an increase in lipid peroxidative product in platelets. METHODS: After LZD treatment for 20 days, 44 patients with TP and 73 patients with NPC were included in this study. Blood samples were collected on the day before medicine treatment and day 7, 14, and 20 after LZD therapy. Levels of reactive oxygen species (ROS), malondialdehyde (MDA), and cholesterol as well as the activities of antioxidative enzyme were estimated. In addition, we identified 37 patients with TP caused by low-dose methotrexate (7.5-25 mg/week) therapy as a positive control group. RESULTS: In total, 37.60% of cases presented with TP on the 20th day of LZD administration. Individuals with TP had significantly elevated levels of ROS and MDA, low levels of superoxide dismutase (SOD) and catalase (CAT), significantly decreased high-density lipoprotein-cholesterol, low density lipoprotein (LDL)-cholesterol levels, and increased oxidized-LDL levels in comparison to individuals with NPC. However, no significant changes in the levels of glutathione-peroxidase were found in the course of time. In all cases with LZD, significant increases in levels of ROS, MDA, and ox-LDL were found in the 20-day samples compared with their respective samples before LZD treatment. Correlation analysis revealed a positive association between platelet count and levels of SOD on day 20 and CAT on days 14 and 20 in plasma, a negative association between platelet count and level of MDA and ROS on days 14 and 20 in patients with LZD-induced TP. CONCLUSIONS: The oxidative stress markers were increased in LZD-induced TP, suggesting that oxidative damage might be the underlying mechanism. PMID- 26507620 TI - Safety of Overnight Switch from Brand-Name to Generic Levetiracetam. AB - BACKGROUND AND OBJECTIVE: Concerns that antiepileptic brand-to-generic interchange results in disruption of seizure control are widespread. The objective of this study was to evaluate the safety and tolerability of the brand to-generic levetiracetam switch in patients with focal or generalized epilepsy. METHODS: A prospective study in patients with primary, cryptogenic or symptomatic epilepsy, who were taking branded levetiracetam and were switched to generic levetiracetam. Patients were consecutively recruited from January 2013 to January 2015. We evaluated efficacy, tolerability and compliance before switching (T0) and after 6 months of therapy (T1). Evaluations were scheduled as follows: baseline, 7 and 15 days, 1, 3 and 6 months. At each visit clinical diary seizures, physical and neurological examination, laboratory parameters and electroencephalogram were evaluated. RESULTS: Fifty-nine patients, equally mixed by sex, were included in the study. Mean age was 26.1 years. Forty-seven per cent of the patients enrolled received levetiracetam as monotherapy. One patient was lost during the follow-up: so at T1 we had 58 patients (28 monotherapy and 30 polytherapy). At T0 and at T1, there was no statistically significant difference in terms of seizure frequency and intensity, occurrence of adverse events, laboratory parameters and electroencephalographic features. Two patients stopped treatment with the generic (both at 3 months after the switch) and restarted therapy with brand levetiracetam because of seizure increase. At the end of the study, the switchback rate was 3.4%. CONCLUSIONS: No increase of seizures and adverse effects were observed when branded levetiracetam was interchanged to a generic equivalent. More studies should be conducted with a larger series of patients to confirm these results. PMID- 26507621 TI - [The Role Development and Future of Dementia Nurse Specialists]. AB - The impact of aging on society is comprehensive and profound. Dementia is a key representative disease / condition of aging societies. The complexity of the course, behavior, and psychiatric symptoms of this disease often burdens families and challenges professional caregivers. Thus, dementia is a growing problem in healthcare that cannot be ignored. As nurses are the healthcare professionals that are most frequently in contact with dementia patients and their families, they occupy a pivotal position in the dementia care team. The present study analyzes the current problems encountered in caring for dementia patients in different care settings, highlights the current difficulties encountered in dementia-care policy and practice in Taiwan, and reviews the development and role of clinical nurse specialists in dementia care in several developed countries. Finally, we propose relevant policy, practice, organizational, and future research recommendations. The content of this paper may be used as a reference for related policymaking and in the promotion of the advanced nursing care role in dementia care. PMID- 26507622 TI - [The Development of Long-Term Care Policies and the Impact on Nursing]. AB - The government must reform and enhance current medical and long-term care services in order to respond effectively to societal ageing and labor shortage trends and to ensure sustainable operations. The post-acute care system should be reoriented on the home and community instead of the hospital. The Long Term Care Service Act integrates long-term care services that were previously dispersed amongst different departments, sets up a long-term care development fund, and improves the quality and allocation of long-term care services. Moreover, the Long Term Care Insurance Act will implement a bundle payment system to assist disabled families. The integration of automation and information technology will make long-term care more efficient. Although nurses are more skilled at elderly care and counseling than other community care professionals, nurses generally lack training in business management. Home and community-based services thus require better-trained manpower, opportunities to set care agents, and opportunities to offer flexible caring jobs. Therefore, nurses should strengthen their capabilities in post-acute care, business management, cooperation, and coordination. PMID- 26507623 TI - [The Legal Duties of Long-Term Care Providers in Long-Term Care Institutions Using the Example of Fall Accidents Among Elderly Patients]. AB - Two reasons may explain a majority of neglect-related falls that are experienced by the elderly living in senior welfare institutions. Firstly, the supervisors may not manage these institutions in accordance with the law or with the Senior Citizens Welfare Act and the Establishment Standards of Senior Citizens' Welfare Institutions. This situation may compromise the facilities and nursing manpower of these institutions. Secondly, nurses may be negligent in their care of the elderly. Healthcare professionals are responsible to implement their care duties. Failure to implement these duties that result in care-recipient injury or death will expose these professionals to charges of negligent homicide or negligent assault. In order to help supervisors and nurses who work in senior welfare institutions better understand their care duties, the present article introduces relevant laws and regulations, including the Senior Citizens Welfare Act and the Establishment Standards of Senior Citizens' Welfare Institutions. In addition, we introduce three judicial decisions that highlight the domestic judicial practice related to the care duties of long-term care providers. As a result, we hope that long-term care providers may better implement their duties properly and thus avoid negligent harm to those in their care and help better protect and promote the rights and welfare of the elderly. PMID- 26507624 TI - [Healthcare Services for Older People: From Fragmentation to Integration]. AB - The percentage of people aged 65 years and older is estimated to exceed 20% of the total population in Taiwan, which makes Taiwan a "super-aged" country. This rapid demographic transition, unprecedented in human history, presents unique challenges. The health characteristics of older people differ fundamentally from their younger adult peers, especially in terms of the critical impact of disability on health. Therefore, special attention to the interrelationship between multimorbidity and disability is required in order to provide healthcare services that are appropriate and effective. The integrated care approach of Europe, which concurrently addresses the needs of health and social care, has become the important foundation of social security in the European Union. The healthcare services available to older people in Taiwan, including outpatient, inpatient and intermediate care, are far from satisfactory and extensively fragmented. For older people with multimorbidities and / or disabilities, these fragmented healthcare services result in inconvenient access to healthcare and impaired quality of care and quality of life. At present, Taiwan has developed various healthcare models such as integrated outpatient services, age-friendly healthcare facilities, post-acute care, and a 10-year long-term care program. However, the development of these healthcare models clearly demonstrates the need for service integration. Integrated care promotes seamless case management, which aims to provide smooth access for older people with multiple, complex care needs to essential services and comprehensive healthcare benefits. During the process, the integration of services per se should be prioritized over the prompt merging of departments or facilities. The development and success of integrated care depend on the complete understanding of and promotion by the frontline working staff. PMID- 26507625 TI - [A Study of the Evidence-Based Nursing Practice Competence of Nurses and Its Clinical Applications]. AB - BACKGROUND: Nurses must develop competence in evidence-based nursing in order to provide the best practice medical care to patients. Evidence-based nursing uses issue identification, data mining, and information consolidation from the related medical literature to help nurses find the best evidence. Therefore, for medical institutions to provide quality clinical care, it is necessary for nurses to develop competence in evidence-based nursing. PURPOSE: This study aims to explore the effect of a fundamental evidence-based nursing course, as a form of educational intervention, on the development of evidence-based nursing knowledge, self-efficacy in evidence-based practice activities, and outcome expectations of evidence-based practice in nurse participants. Further the competence of these nurses in overcoming obstacles in evidence-based nursing practice. METHODS: This quasi-experimental study used a pre-post test design with a single group of participants. A convenience sample of 34 nurses from a municipal hospital in northern Taiwan received 8 hours of a fundamental evidence-based nursing course over a two-week period. Participants were asked to complete four questionnaires before and after the intervention. The questionnaires measured the participants' basic demographics, experience in mining the medical literature, evidence-based nursing knowledge, self-efficacy in evidence-based practice activities, outcome expectations of evidence-based practice, competence in overcoming obstacles in evidence-based nursing practice, and learning satisfaction. Collected data was analyzed using paired t, Wilcoxon Signed Rank, and McNemar tests to measure the differences among participants' evidence-based nursing knowledge and practice activities before and after the workshop. RESULTS: The nurses demonstrated significantly higher scores from pre-test to post-test in evidence-based nursing knowledge II, self-efficacy in evidence-based nursing practice activities, and outcome expectations of evidence-based practice. Although the differences did not reach statistical significance, the post-test scores were significantly lower than pre-test scores in terms of the measurement of the nurses' obstacles in evidence-based nursing practice, which indicates significant improvements from pre-test to post-test in terms of the competence of participants in overcoming obstacles in evidence-based nursing practice. CONCLUSIONS: The intervention was found to be effective in improving the evidence-based nursing knowledge, self efficacy in evidence-based nursing practice activities, and outcome expectations of evidence-based practice of participants and effective in reducing their obstacles in evidence-based nursing practice. Medical institutions should provide evidence-based nursing courses on a regular basis as a part of in-service education for nurses in order to help nurses develop the evidence-based nursing knowledge and practical competence required to provide quality clinical care. PMID- 26507626 TI - [Correlation Between Job Characteristics and Occupational Fatigue in Nurses]. AB - BACKGROUND: Occupational fatigue in nurses has earned much attention in recent years. This phenomenon affects the health of nurses and threatens the safety of patients. However, few studies have reported on the correlation between job characteristics and occupational fatigue in China. PURPOSE: The present study describes the nursing job characteristics and nursing occupational fatigue situation at general hospitals in Chengdu in China and explores the correlations between job characteristics and occupational fatigue. METHODS: A cross-sectional descriptive correlation design with systematic sampling was used to recruit 923 nurses from general hospitals in Chengdu. The structural questionnaires used in this study included a personal data-sheet, Occupational Fatigue Exhaustion Recovery Scale (OFER), and Job Content Questionnaire (JCQ). Mean, percentage, independent t test, Chi-square test, Pearson correlation, and multiple linear regression analysis were employed to analyze data. RESULTS: Nurses' acute fatigue level and chronic fatigue level were high, with average scores of 60.30 +/- 22.02 and 46.44 +/- 23.33, respectively. All dimensions (with the exception of colleague support) correlated significantly with job characteristics and occupational fatigue. Job control, job demand, and amount of shiftwork were important predictors of both acute fatigue and chronic fatigue. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The results of the study may help the managers better understand the current situation of nurses' occupational fatigue and formulate effective measures that consider the individual characteristics of nurses and the differences in perceived job control and job demand. Furthermore, the results may help nurses better assess the causes of their work-related fatigue and facilitate coping measures in order to reduce acute and chronic fatigue. PMID- 26507627 TI - [The Design Requirements for an E-Health Management Platform: Addressing the Needs of Adolescent Girls at High Risk of Metabolic Syndrome]. AB - BACKGROUND: The rising prevalence of metabolic syndrome among adolescents has not been effectively addressed by current campus-based health promotions. Using the Internet in these promotions may help health professionals achieve better healthcare management. PURPOSE: The purpose of the present study was to explore the design requirements of an e-health management platform from the subjective perspective of adolescent girls who were at a high risk of metabolic syndrome. The findings may provide a reference for designing nursing interventions that more effectively promote healthly lifestyle habits to adolescents. METHODS: This qualitative study employed a snowball approach and used a semi-structured interview guide to collect data. A total of 20 Taiwanese adolescent females who were at a high risk of metabolic syndrome, aged 16-20 years, able to speak Mandarin or Taiwanese, and willing to participate and to have their sessions tape recorded were enrolled as participants and engaged individually in in-depth interviews. The constant comparative method was used to inductively analyze the interview data. RESULTS: Five main themes related to the e-health management platform emerged from the data. These themes included: an attractive and user friendly website interface, access to reliable information and resources, provision of tailored health information, access to peer support, and self monitoring and learning tools. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The findings highlight the key design needs of an e-Health management platform from the perspective of adolescent girls who are at a high risk of metabolic syndrome. The identified themes may be addressed in future revisions / developments of these platforms in order to better address the needs of this vulnerable population and to effectively reduce the incidence of metabolic syndrome. The authors hope that the results of the present study may be used to provide better healthcare and support for adolescent girls with metabolic syndrome. PMID- 26507628 TI - [The Comparison of the Difference Between the Emphasis on and the Receipt of Patient Privacy in the Hospital Setting]. AB - BACKGROUND: Privacy is a unique privilege for humans. Enhancing the balance between the importance given to patient privacy and the receipt of this privacy by patients is one key approach to improving the relationship between patients and the hospital. PURPOSE: This study compared the difference between the importance of patient privacy and receipt of this privacy by patients as a reference for future patient privacy policy planning. METHODS: This study was a cross-sectional design. We randomly sampled three hospitals in northern Taiwan and investigated patients using a questionnaire. The questionnaire was self designed and verified for reliability and validity. We used frequency and percentage to describe demographic data and used a t-test to compare the deviation between the emphasis on and receipt of patient privacy. RESULTS: There were 296 valid samples in this study and the effective rate was 84.57%. The highest degree of importance was information privacy and the lowest was physical privacy. Physical privacy (t = 3.04, p < .001) and mental privacy (t = 2.42, p < .01) exhibited significant differences between emphasis and receipt. Demographic data on gender, age, education level, marital status, and occupation. Type of hospital and ward level correlated with the emphasis and receipt of privacy. CONCLUSIONS: The importance of privacy for physical and mental wellbeing was higher than the actual receipt of this privacy among the patient sample. The importance of privacy for married individuals and young women with high education levels was higher, while males and less-educated individuals scored lower in terms of privacy receipt. Medical agencies must provide higher levels of physical and mental privacy in order to enhance patient satisfaction. PMID- 26507629 TI - [Quality Improvement Project: Increasing the Rate of Proper Use of Infant Transferring Warmers]. AB - BACKGROUND & PROBLEMS: Infant-transferring warmers provide a warm environment and emergency care facilities such ventilators for high-risk infants during transport. Accurate use of this warmer has been demonstrated to reduce rates of neonatal complications and increase rates of survival. This project found that, despite the complaints of nurses that warmers occasionally malfunctioned during the transfer process, warmer functions nearly always tested normal after use. Therefore, the researchers surveyed ward nurses to better understand the underlying reasons for these complaints. Results found that only 68.4% of those surveyed operated the warmer correctly. The reasons for improper use were analyzed and categorized as: Nurse-related factors - lack of warmer operating knowledge and experience in the clinic; System-related factors - lack of a standard operating procedure (SOP) and monitor/audit practices and an incomplete training protocol; Equipment-related factors - lack of an equipment preparation SOP and difficulties in setting the ventilator properly. PURPOSE: The purpose of this project was to achieve a 100% rate of proper warmer use among nurses. RESOLUTION: Through continuous clinical education, we created a standard operating procedure for warmer operation, created a video and poster for warmer users, simplified the equipment preparation SOP, and periodically monitored and checked results. RESULTS: After the intervention, 100% of the nurses were able to use the warmers correctly. Additionally, the rate of satisfaction for nursing warmer use among the participating nurses increased from 51.4% to 80.6%. CONCLUSIONS: This project effectively increased the rate for correctly using transferring warmers among participating nurses and improved the quality of medical care. PMID- 26507630 TI - [A Project to Improve the Time-Effectiveness of Routine Morning Blood Tests]. AB - BACKGROUND & PROBLEMS: Morning blood sampling, conducted around 4am to 5am, is routinely ordered due to nothing-by-mouth (NPO) requirements and clinical practice norms. However, this routine may interrupt the normal sleep of patients and decrease the satisfaction of patients with the care received. However, our night-shift staff is not able to take all blood samples during this time, resulting in a high rate of overdue reporting. PURPOSE: To reduce the overdue rate of laboratory result from 62.3% to less than 19.3%. RESOLUTION: In 2013, we performed interventions including the process reengineering of blood sampling to meet the needs of laboratory result flows and the upgrading of equipment in our neurology ward. The reengineering strategies used included the redistribution of blood sampling times in order to decrease testing for unnecessary items. The equipment upgrades improved the ability of the carrier in the pneumatic tube systems to carry the chilled blood samples. An independent two-sample t-test was used to compare the overdue rate before and after the interventions. RESULTS: The overall overdue rate for the blood sampling to laboratory flow improved from 62.3% before the intervention to 18.0% (t = 7.07, p < .001) after the intervention. Furthermore, the overdue rate for the testing done at the stat laboratory improved from 66.9% to 21.3% (t = 7.36, p < .001), while the overdue rate for the testing done at the non-stat laboratory improved from 52.4% to 17.8% (t = 5.37, p < .001). Besides, the satisfaction of both inpatients and nurses with regard to blood-sampling flow improved from 51% and 54.2%, respectively to 93% (t = 51.10, p < .001) and 94% (t = 12.26, p <.001). CONCLUSIONS: Our process reengineering strategies and the upgrading of the pneumatic tube system successfully reduced the overdue rate for the blood sampling and increased the satisfaction of inpatients. PMID- 26507631 TI - [Theoretical Development and Research Trends in Developmental Care]. AB - The Newborn Individualized Developmental Care and Assessment Program (NIDCAP), based on the Synactive Theory, is applied to improve brain development in premature and illness infants within a supportive environment. The NIDCAP has been used widely in the clinical setting. The aim of this article was to systematically review research published between 2000 and 2013 that relates to the evidence and application of developmental care. Most studies support the effectiveness of developmental care in terms of facilitating the healthy growth of premature infants, reducing oxygen dependence, reducing hospitalization times, and improving neurodevelopmental outcomes at two years of age. However, research results related to the effects of developmental care on neurodevelopmental outcomes from 2 years old to school age are not consistent. The heterogeneity of interventions, outcome indicators, and measurements in studies may contribute to these mixed results. In addition, as developmental care has been applied for many years, the contamination of participants in the supportive environment should be considered. Based on current evidence, neonatal healthcare professionals must recognize the core value of developmental care in dealing with premature infants and their families. In order to provide effective interventions for infants, further research is needed to assess the comparative effects of the single intervention and the holistic approach in developmental care. PMID- 26507632 TI - [Using Acupressure to Improve Abdominal Bloating in a Hemicolectomy Patient: A Nursing Experience]. AB - This article describes a nursing experience applying the protocol of bilateral Zusanli (ST-36) acupressure to reduce abdominal bloating in a colon cancer patient who had undergone a right hemicolectomy. The period of care was between November 13 and November 23, 2014. Data were collected through direct care, interviews, observation, and physical assessment. The main health problems of the patient included anxiety, surgical wound pain, and abdominal bloating. We provided pre- and postoperative routine nursing care, wound pain management, and the protocol of Zusanli (ST-36) acupressure for reducing abdominal bloating. Results of care recorded the first passage of flatus and intestinal motility during the second postoperative day, with no complaints of bloating from the fourth postoperative day. The subject exhibited a relaxed mood and slept soundly following each acupressure session. Furthermore, the subject reported experiencing no abdominal bloating during the week following discharge, during which he continued to follow the acupressure protocol. This article provides support via an instance of nursing care for the effectiveness of the Zusanli (ST 36) acupressure in improving abdominal bloating and thus reducing the complications of hemicolectomy surgery. PMID- 26507633 TI - Genotyping and study of the pauA and sua genes of Streptococcus uberis isolates from bovine mastitis. AB - This study aimed to determine the clonal relationship among 137 Streptococcus uberis isolates from bovine milk with subclinical or clinical mastitis in Argentina and to assess the prevalence and conservation of pauA and sua genes. This information is critical for the rational design of a vaccine for the prevention of bovine mastitis caused by S. uberis. The isolates were typed by random amplified polymorphic DNA (RAPD) analysis and by pulsed-field gel electrophoresis (PFGE). The 137 isolates exhibited 61 different PFGE types and 25 distinct RAPD profiles. Simpson's diversity index was calculated both for PFGE (0.983) and for RAPD (0.941), showing a high discriminatory power in both techniques. The analysis of the relationship between pairs of isolates showed 92.6% concordance between both techniques indicating that any given pair of isolates distinguished by one method tended to be distinguished by the other. The prevalence of the sua and pauA genes was 97.8% (134/137) and 94.9% (130/137), respectively. Nucleotide and amino acid sequences of the sua and pauA genes from 20 S. uberis selected isolates, based on their PFGE and RAPD types and geographical origin, showed an identity between 95% and 100% with respect to all reference sequences registered in GenBank. These results demonstrate that, in spite of S. uberis clonal diversity, the sua and pauA genes are prevalent and highly conserved, showing their importance to be included in future vaccine studies to prevent S. uberis bovine mastitis. PMID- 26507634 TI - [Isolated yeast species in urine samples in a Spanish regional hospital]. AB - Candiduria detection in hospitalized or immunocompromised patients is of great clinical significance. The aim of our study was to describe the isolation frequency of significant species of yeasts in urine samples processed in our hospital during the period 2010- 2013, and to analyze their susceptibility to commonly used antifungal agents. Species identification was performed by seeding on a chromogenic medium, the filamentation test and automated systems (ASM Vitek and MALDI Biotyper), while susceptibility was determined using the ASM Vitek system. Of the 632 yeast isolates in urine, 371 were Candida albicans species and 261 non-C. albicans Candida spp. The species with the highest number of resistant isolates were Candida glabrata and Candida krusei. Based on the results obtained, we believe that species identification and the susceptibility study should be current practice in the laboratories when species other than C. albicans are isolated. PMID- 26507635 TI - Ordering Individuals with Sum Scores: The Introduction of the Nonparametric Rasch Model. AB - When a simple sum or number-correct score is used to evaluate the ability of individual testees, then, from an accountability perspective, the inferences based on the sum score should be the same as the inferences based on the complete response pattern. This requirement is fulfilled if the sum score is a sufficient statistic for the parameter of a unidimensional model. However, the models for which this holds true are known to be restrictive. It is shown that the less restrictive nonparametric models could result in an ordering of persons that is different from an ordering based on the sum score. To arrive at a fair evaluation of ability with a simple number-correct score, ordinal sufficiency is defined as a minimum condition for scoring. The monotone homogeneity model, together with the property of ordinal sufficiency of the sum score, is introduced as the nonparametric Rasch model. A basic outline for testable hypotheses about ordinal sufficiency, as well as illustrations with real data, is provided. PMID- 26507636 TI - Tunable magnetocaloric effect in transition metal alloys. AB - The unpredictability of geopolitical tensions and resulting supply chain and pricing instabilities make it imperative to explore rare earth free magnetic materials. As such, we have investigated fully transition metal based "high entropy alloys" in the context of the magnetocaloric effect. We find the NiFeCoCrPdx family exhibits a second order magnetic phase transition whose critical temperature is tunable from 100 K to well above room temperature. The system notably displays changes in the functionality of the magnetic entropy change depending on x, which leads to nearly 40% enhancement of the refrigerant capacity. A detailed statistical analysis of the universal scaling behavior provides direct evidence that heat treatment and Pd additions reduce the distribution of exchange energies in the system, leading to a more magnetically homogeneous alloy. The general implications of this work are that the parent NiFeCoCr compound can be tuned dramatically with FCC metal additives. Together with their relatively lower cost, their superior mechanical properties that aid manufacturability and their relative chemical inertness that aids product longevity, NiFeCoCr-based materials could ultimately lead to commercially viable magnetic refrigerants. PMID- 26507637 TI - Trends in standardized mortality rates for select groups of cardiovascular diseases in Slovakia between 1980 and 2010. AB - OBJECTIVES: Reducing mortality due to cardiovascular diseases especially in people less than 65 years is one of the main targets of WHO preventive programs. This work aimed to analyse recent trends in cardiovascular mortality rates in Slovakia. STUDY DESIGN: A descriptive study was implemented with a Joinpoint analysis. METHODS: Analysis was of annual all circulatory, acute myocardial infarction mortality, and cerebrovascular disease mortality rates, between 1980 and 2010 for Slovakia. Data were stratified by sex and 10-year age group (age 25 85 years). The annual percentage change (APC) and significant changes in the trend were identified using joinpoint Poisson regression. RESULTS: The standardized mortality rate for all cardiovascular diseases declined in Slovakia between 1980 and 2010 by 25.7% and 30.5% for men and women, respectively. Joinpoint analysis of all cardiovascular disease mortality rates demonstrated statistically significant changes in trends of APC decline for both genders. For men, acceleration in the rate of decline between 2001 and 2010 was observed APC 2.2 (95% CI = -3.5, -1.2) following a slowing of the rate of decline between 1980 and 2001, when the APC reached -0.5 (95% CI = -0.8, -0.3). For women the trend was similar. Between 2003 and 2010 acceleration in the decline was demonstrated APC -2.8 (95% CI = -4.3, -1.4). CONCLUSION: The results of our analysis demonstrate the need to constantly address issues of cardiovascular diseases, as mortality rates in Slovakia are among the highest within the European Union countries in the long term. PMID- 26507638 TI - Psychotic like experiences (PLE's) in middle-aged adults. PMID- 26507639 TI - Effects of oxaliplatin-based chemotherapy on liver function--an analysis of impact and functional recovery using the LiMAx test. AB - PURPOSE: Chemotherapy-associated liver injury of patients undergoing therapy for colorectal liver metastases stimulates concerns on surgical safety. No common guidelines for the optimal timing of liver surgery after the application of systemic chemotherapy (chemotherapy-free interval) have been established and effects on individual liver function remain unexplored. METHODS: Maximum liver function capacity (LiMAx) and indocyanine green plasma disappearance rate (ICG PDR) were measured in 20 patients with colorectal cancer receiving adjuvant oxaliplatin-based chemotherapy (OBC) prior to the first and after the last treatment course as well as 4 and 8 weeks thereafter. RESULTS: Comparison of pre- and post-chemotherapy test results demonstrated a significant decrease of LiMAx to 73.2 % +/- 19.0 % (p = 0.001) and ICG-PDR to 78.2 % +/- 21.3 % (p = 0.001) after cessation of OBC. The dynamics of LiMAx indicate an interindividual effect on vulnerability to systemic chemotherapy with subsequent functional regeneration after 8 weeks (pre-OBC 530 +/- 144 MUg/kg/h vs. 4 weeks post-OBC 463 +/- 111 MUg/kg/; p = 0.012 and vs. 8 weeks post-OBC 494 +/- 138 MUg/kg/h; p = 0.134). An analysis of individual regeneration after chemotherapy yielded a highly different course of functional recovery with patients regaining pre-chemotherapy function within 4 weeks, whereas others still showed deterioration after 8 weeks after cessation of chemotherapy. DISCUSSION AND CONCLUSION: Enzymatic liver function (LiMAx) is significantly reduced after oxaliplatin-based chemotherapy and subsequently recovers within 8 weeks after cessation of chemotherapy. However, pace of regeneration appears to be highly different among patients suggesting patient individual chemotherapy-free interval monitored by LiMAx. PMID- 26507640 TI - Prognosis of patients presenting extreme acidosis (pH <7) on admission to intensive care unit. AB - PURPOSE: The purpose was to determine prognosis of patients presenting extreme acidosis (pH <7) on admission to the intensive care unit (ICU) and to identify mortality risk factors. MATERIALS AND METHODS: We retrospectively analyzed all patients who presented with extreme acidosis within 24 hours of admission to a polyvalent ICU in a university hospital between January 2011 and July 2013. Multivariate analysis and survival analysis were used. RESULTS: Among the 2156 patients admitted, 77 patients (3.6%) presented extreme acidosis. Thirty (39%) patients suffered cardiac arrest before admission. Although the mortality rate predicted by severity score was 93.6%, death occurred in 52 cases (67.5%) in a median delay of 13 (5-27) hours. Mortality rate depended on reason for admission, varying between 22% for cases linked to diabetes mellitus and 100% for cases of mesenteric infarction (P = .002), cardiac arrest before admission (P < .001), type of lactic acidosis (P = .007), high Simplified Acute Physiology Score II (P = .008), and low serum creatinine (P = .012). CONCLUSIONS: Patients with extreme acidosis on admission to ICU have a less severe than expected prognosis. Whereas mortality is almost 100% in cases of cardiac arrest before admission, mortality is much lower in the absence of cardiac arrest before admission, which justifies aggressive ICU therapies. PMID- 26507641 TI - Palliative and end-of-life educational practices in US pulmonary and critical care training programs. AB - PURPOSE: To describe educational features in palliative and end-of-life care (PEOLC) in pulmonary/critical care fellowships and identify the features associated with perceptions of trainee competence in PEOLC. METHODS: A survey of educational features in 102 training programs and the perceived skill and comfort level of trainees in 6 PEOLC domains: communication, symptom control, ethical/legal, community/institutional resources, specific syndromes, and ventilator withdrawal. We evaluated associations between perceived trainee competence/comfort in PEOLC and training program features, using regression analyses. RESULTS: Fifty-five percent of program directors (PDs) reported faculty with training in PEOLC; 30% had a written PEOLC curriculum. Neither feature was associated with trainee competence/comfort. Program directors and trainees rated bedside PEOLC teaching highly. Only 20% offered PEOLC rotations; most trainees judged these valuable. Most PDs and trainees reported that didactic teaching was insufficient in communication, although sufficient teaching of this was associated with perceived trainee competence in communication. Perceived trainee competence in managing institutional resources was rated poorly. Program directors reporting significant barriers to PEOLC education also judged trainees less competent in PEOLC. Time constraint was the greatest barrier. CONCLUSION: This survey of PEOLC education in US pulmonary/critical care fellowships identified associations between certain program features and perceived trainee skill in PEOLC. These results generate hypotheses for further study. PMID- 26507642 TI - Sugar sweetened beverages are associated with greater incidence of diabetes but there is a paucity of evidence on healthfulness of artificially-sweetened beverages and fruit juices. PMID- 26507643 TI - The simultaneous effects of pharmaceutical policies from payers' and patients' perspectives: Italy as a case study. AB - OBJECTIVES: This paper aims at covering a literature gap on the effects of copayments, prescription quotas and therapeutic reference pricing on public and private expenditures and volumes (1) When these policies are implemented in different areas at different times, (2) estimating their impact in the short and long run, (3) assessing the extent to which these impacts are interdependent, (4) scrutinising the extent to which the effects are mediated by prescribers' and patients' behaviours. METHODS: Monthly regional data on pharmaceutical expenditures, volumes and policies in Italy from 2000 to 2014 are analysed using a difference-in-differences model enriched to capture short- versus long-term effects and simultaneous and interactive effects. Sobel-Goodman test and bootstrap analyses were used to test for mediation. RESULTS: The three policies have different short- and long-run effects. Interactions support the hypothesis of reinforcing effects. Behavioural reactions to policies such as reducing the demand or total per capita expenditures mediate the impact of policies, thus explaining the different effects between the short and long term. CONCLUSIONS: Evidence on the impact over time of regional policies diversely introduced in different times have important policy implications. First, pharmaceutical policies interact with each other, and the combined effect may be different from what we would expect from the sum of each single policy. Hence, policymakers should be very careful in designing mixed policies for their unexpected combined effects. Second, the impact of policies tends to reduce over time. If longer-term impact is desired, it would be appropriate to introduce some adjustments over time. Third, policies have multiple effects, and this should be considered when they are designed. Finally, pharmaceutical policies may have an unintended impact on health and health care. PMID- 26507644 TI - Targeted delivery of HGF to the skeletal muscle improves glucose homeostasis in diet-induced obese mice. AB - Hepatocyte growth factor (HGF) is a cytokine that increases glucose transport ex vivo in skeletal muscle. The aim of this work was to decipher the impact of whether conditional overexpression of HGF in vivo could improve glucose homeostasis and insulin sensitivity in mouse skeletal muscle. Following tetracyclin administration, muscle HGF levels were augmented threefold in transgenic mice (SK-HGF) compared to control mice without altering plasma HGF levels. In conditions of normal diet, SK-HGF mice showed no differences in body weight, plasma triglycerides, blood glucose, plasma insulin and glucose tolerance compared to control mice. Importantly, obese SK-HGF mice exhibited improved whole body glucose tolerance independently of changes in body weight or plasma triglyceride levels compared to control mice. This effect on glucose homeostasis was associated with significantly higher (~80%) levels of phosphorylated protein kinase B in muscles from SK-HGF mice compared to control mice. In conclusion, muscle expression of HGF counteracts obesity-mediated muscle insulin resistance and improves glucose tolerance in mice. PMID- 26507645 TI - The association among peri-aortic root adipose tissue, metabolic derangements and burden of atherosclerosis in asymptomatic population. AB - AIM: To describe the relationship between a novel measurement of peri-arotic root fat and ultrasound measures of carotid artery remodeling. MATERIALS AND METHODS: We studied 1492 consecutive subjects (mean age: 51.04 +/- 8.97 years, 27% females) who underwent an annual cardiovascular risk survey in Taiwan. Peri aortic root fat (PARF) was assessed by cardiac CT using three-dimensional (3D) volume assessment. Carotid artery morphology and remodeling were assessed by ultrasound. We explored the relationships between PARF volumes, cardiometabolic risk profiles and carotid morphology and remodeling. RESULTS: Mean PARF volume in current study was 20.8 +/- 10.6 ml. PARF was positively correlated with measures of general adiposity, systemic inflammation, and several traditional cardiometabolic risk profiles (all p < 0.001) and successfully predicted metabolic syndrome (MetS) (AUROC: 0.75, 95%, confidence interval: 0.72-0.77). Higher PARF was independently associated with increased carotid artery intima media thickness (IMT) (beta-coef.: 0.08) and diameter (beta-coef.: 0.08, both p < 0.05) after accounting for age, sex, BMI and other cardiovascular risk factors. The addition of PARF beyond metabolic syndrome components significantly provided incremental prediction value for abnormal IMT (DeltaAUROC: 0.053, p = 0.0021). CONCLUSION: Peri-aortic root fat is associated with carotid IMT, even after adjustment for cardiometabolic risks, age and coronary atherosclerosis. Further research studies are warranted to identify the mediators of downstream pathophysiologic effects on carotid arteries by PARF and understand the mechanisms related to this correlation. PMID- 26507646 TI - Treatment study of distal femur for parathyroid hormone (1-34) and beta tricalcium phosphate on bone formation in critical-sized defects in osteopenic rats. AB - The objective of this study was to evaluate the effect of following combined treatment with parathyroid hormone (1-34) (PTH) and beta-tricalcium phosphate (beta-TCP) on local bone formation in a rat 3-mm critical-sized defect at the distal femur. Fourteen weeks were allowed to pass before defect surgery for the establishment of osteopenic animal models chronically fed a low-protein diet. All animals were randomly divided into four groups: group PTH; group beta-TCP, group PTH + beta-TCP, and a control group. All rats then underwent a surgical procedure to create bone defects in the bilateral distal femurs, and beta-TCP was implanted into critical-sized defects for the groups designated as beta-TCP and group PTH + beta-TCP. After the defect operation, all animals from group PTH and group PTH + beta-TCP received following subcutaneous injections with PTH (60 MUg/kg, three times per week) until euthanasia at 4 and 8 weeks. The distal femurs and blood were collected for evaluation. The results of study showed the strongest effect on accelerating the local bone formation with treatment beta-TCP and PTH at 4 weeks and 8 weeks. The results from our study demonstrate that a combination of PTH and beta-TCP had an additive effect on local bone formation in osteopenic rats chronically fed a low-protein diet. PMID- 26507647 TI - Osseointegration of titanium implants with SLAffinity treatment: a histological and biomechanical study in miniature pigs. AB - PURPOSE: Electrochemical oxidation following sandblasting and acid-etching (SLA) treatment has received interest as a surface modification procedure for titanium (Ti) implants (denoted as an SLAffinity surface); however, little information is available on its impacts on the in vivo performance of SLAffinity-Ti implants. The present study evaluated the osseointegration and biomechanical bone-tissue response to SLAffinity-Ti implants with micro- and nanoporous oxide layers. MATERIALS AND METHODS: The interaction between blood and the tested implants was examined. In total, 144 implants with the following surfaces were used: a standard machined (M-Ti), an SLA-Ti, and an SLAffinity-Ti surface. For each animal, four implants (one M-Ti, one SLA-Ti, and two SLAffinity-Ti) were inserted into the mandibular canine-premolar area for histomorphometric observations and another four implants were inserted into the flat surface on the anteromedial aspect of the rear tibia for removal torque (RT) tests. After 2, 4, and 8 weeks of implantation, histomorphometric and RT tests were conducted. RESULTS: Interactions between blood and implants were better for implants with the SLAffinity-Ti surface. RT tests showed a significant improvement in fixation strength for SLAffinity-Ti implants (84.5 +/- 8.7 N-cm) after 8 weeks compared to M-Ti (62.95 +/- 11.5 N-cm) and SLAffinity-Ti (76.1 +/- 6.6 N-cm) implants. A histological evaluation showed that osseous integration had occurred with all implants after 8 weeks. SLAffinity-Ti implants exhibited 28.5 +/- 6.2 % bone-to implant contact (BIC) at 2 weeks and 84.3 +/- 8.1 % at 8 weeks. M-Ti implants exhibited BIC levels of 17.0 +/- 5.4 and 76.5 +/- 6.3 %, whereas SLA-Ti implants exhibited BIC levels of 28.5 +/- 6.2 and 81.1 +/- 8.4 % at corresponding time intervals. In terms of the peri-implant bone area (BA), values for SLAffinity-Ti implants ranged from 29.5 +/- 4.1 to 88.3 +/- 3.0 %. For M-Ti implants, values ranged from 20.3 +/- 5.5 to 81.7 +/- 4.2 %. For SLA-Ti implants, values ranged from 23.0 +/- 3.5 to 84.0 +/- 3.6 %. CONCLUSIONS: Electrochemical oxidation increased the oxide layers and improved the blood interaction with SLAffinity-Ti implants, resulting in significantly higher bone apposition with the SLAffinity Ti implants after 2 and 8 weeks of healing. An increase in resistance for the RT of SLAffinity-Ti implants over the 8-week healing period was also observed. CLINICAL RELEVANCE: The use of SLAffinity-Ti implants has potential for improvement of early osseointegration. PMID- 26507648 TI - Prehospital triage accuracy in a criteria based dispatch centre. AB - BACKGROUND: Priority dispatch accuracy is a key issue in optimizing the match between patients' medical needs and pre-hospital resources. This study measures the accuracy of a Criteria Based Dispatch (CBD) system, by evaluating discrepancies between dispatch priorities and ambulance crews' severity evaluations. METHODS: This is a retrospective study conducted from January 2011 to December 2011. We ruled that a National Advisory Committee for Aeronautics (NACA) score > 3 (injuries/diseases which can possibly lead to deterioration of vital signs) to 7 (lethal injuries/ diseases) should require a priority dispatch with lights and siren (L&S), while NACA scores < 4 should require a priority dispatch without L&S. Over triage was defined as the proportion of L&S dispatches with a NACA score < 4, and under triage as the proportion of dispatches without L&S with a NACA score > 3. RESULTS: There were 29,008 primary missions in 2011, 1122 were excluded. Of the 15,749 L&S missions, 12,333 patients had a NACA score < 4, leading to an over triage rate of 78 %; 561 missions out of 12,137 missions without L&S had a NACA score > 3, leading to an under triage rate of 4.6 %. Sensitivity was 86 % (95 % confidence interval: 85.6-86.4 %), specificity 48 % (47.4-48.6 %), positive predictive value 21.7 % (21.2-22.2 %), and negative predictive value 95.4 % (95.2-95.6 %). CONCLUSION: The rates of over triage and under triage in our CBD are 78 and 4.6 % respectively. The lack of consistent or universal metrics is perhaps the most important limitation in dispatch accuracy research. This is mainly due to the large heterogeneity of dispatch systems and prehospital emergency system. PMID- 26507649 TI - Cytotoxicity and antimicrobial activity of marine macro algae (Dictyotaceae and Ulvaceae) from the Persian Gulf. AB - Pharmaceutical industry now accept the worlds ocean which contains a vast array of organisms with unique biological properties, as a major frontier for medical investigation. Bioactive compounds with different modes of action, such as, antiproliferative, antioxidant, antimicrotubule, have been isolated from marine sources, specifically macro and micro algae, and cyanobacteria. The aim of this work was to investigate antimicrobial and cytotoxic activities of the extracts of marine macro algae Ulva flexuosa, Padina antillarum and Padina boergeseni from the northern coasts of the Persian Gulf, Qeshm Island, Iran, against three cell lines including MCF7, HeLa and Vero, as well as their inhibitory effects against a wide array (i.e. n = 11) of pathogenic bacteria and fungi. Antimicrobial activity of the marine macro algal extracts was assessed using a disc diffusion method; an MTT cytotoxicity assay was employed to test the effects of the extracts on each cancer cell line. The algal extracts showed considerable antimicrobial activity against the majority of the tested bacteria and fungi. Both ethyl acetate and methanol extracts at the highest concentration (100 ug/ml) caused cell death, with the IC50 values calculated for each cell type and each algal extracts. Results are exhibited a higher decrease in the viability of the cells treated at the highest concentration of marine macro algal ethyl acetate extracts compared to the methanol extracts (78.9 % death in Vero cells by ethyl acetate extracts from U. flexuosa). Despite, the ethyl acetate extracts with lower dose- response of cells, exhibited better cytotoxic activity than methanol extracts (IC50: 55.26 MUg/ml in Vero cells by ethyl acetate extracts from U. flexuosa). Based on the findings, it is concluded that the marine macro algal extracts from the Persian Gulf possess antibacterial and cytotoxic potential, which could be considered for future applications in medicine and identifying novel drugs from the marine resources. PMID- 26507650 TI - Determinants of Utilization and Community Experiences with Community Health Volunteers for Treatment of Childhood Illnesses in Rural Sierra Leone. AB - In 2010, at the same time as the national roll out of the Free Health Care Initiative (FHCI), which removed user fees for facility based health care, trained community health volunteers (CHVs) were deployed to provide integrated community case management of diarrhea, malaria and pneumonia to children under 5 years of age (U5) in Kambia and Pujehun districts, Sierra Leone. After 2 years of implementation and in the context of FHCI, CHV utilization rate was 14.0 %. In this study, we examine the factors associated with this level of CHV utilization. A cross-sectional household-cluster survey of 1590 caregivers of 2279 children U5 was conducted in 2012; with CHV utilization assessed using a multiple logistic regression model. Focus groups and in-depth interviews were also conducted to understand communities' experiences with CHVs. Children with diarrhea (OR = 3.17, 95 % CI: 1.17-8.60), from female-headed households (OR = 4.55, 95 % CI: 1.88 11.00), and whose caregivers reported poor quality of care as a barrier to facility care-seeking (OR = 8.53, 95 % CI: 3.13-23.16) were more likely to receive treatment from a CHV. Despite low utilization, caregivers were highly familiar and appreciative of CHVs, but were concerned about the lack of financial remuneration for CHVs. CHVs remained an important source of care for children from female-headed households and whose caregivers reported poor quality of care at health facilities. CHVs are an important strategy for certain populations even when facility utilization is high or when facility services are compromised, as has happened with the recent Ebola epidemic in Sierra Leone. PMID- 26507651 TI - Reactions to Thirdhand Smoke are Associated with Openness to Smoking in Young Never Smoking Children. AB - To investigate the associations between reactions to thirdhand smoke (THS) and openness to smoking in young children. In a school-based survey in Hong Kong, 4762 Chinese primary school students reported their reactions to THS (one or more of 'pleasant/happy', 'nausea', 'excited', 'heart beat faster', 'relaxed', 'dislike the smell', 'like the smell', 'dizzy', 'coughing/choking', 'eye uncomfortable' and 'none of the above'), smoking status and openness to smoking (lack of a firm intention not to smoke). Factor structure of reactions to THS was investigated with factor scores calculated and categorised. Logistic regression yielded adjusted odds ratio (AOR) of openness to smoking for reactions to THS. Factor analysis yielded two factors including 5 and 4 reactions, which were generally deemed negative and positive, respectively. The proportions of students with factor scores >=1 for negative and positive reactions were 51.3 and 6.3 %, respectively. In never smokers, openness to smoking was negatively associated with 'dislike the smell' (AOR 0.52, 95 % CI 0.39-0.68), 'coughing/choking' (0.53, 0.38-0.75), 'eye uncomfortable' (0.62, 0.40-0.95) and negative reaction factor score of 2-5 (vs. 0) (0.59, 0.40-0.88), and was positively associated with 'pleasant/happy' (2.80, 1.54-5.09), 'excited' (2.83, 1.17-6.87), 'like the smell' (3.06, 1.49-6.26) and positive reaction factor score of 1-4 (vs. 0) (2.86, 1.83 4.48). In experimental or former smokers, fewer associations reached statistical significance. Negative and positive reactions to THS were negatively and positively associated with openness to smoking, respectively, in young never smoking children. PMID- 26507652 TI - Selective cytotoxicity and cell death induced by human amniotic membrane in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) has a worldwide high incidence and mortality. For this reason, it is essential to invest in new therapies for this type of cancer. Our team already proved that human amniotic membrane (hAM) is able to inhibit the metabolic activity of several human cancer cell lines, including HCC cell lines. Taking into account the previously performed work, this experimental study aimed to investigate the pathways by which hAM protein extracts (hAMPEs) act on HCC. Our results showed that hAMPE reduce the metabolic activity, protein content and DNA content in a dose- and time-dependent manner in all HCC cell lines. This therapy presents selective cytotoxicity, since it was not able to inhibit a non tumorigenic human cell line. In addition, hAMPE induced cell morphology alterations in all HCC cell lines, but death type is cell line dependent, as proved by in vitro and in vivo studies. In conclusion, hAMPE have a promising role in HCC therapy, since it is capable of inducing HCC cytotoxicity and cell death. PMID- 26507653 TI - A real-time PCR assay for detection of the Ehrlichia muris-like agent, a newly recognized pathogen of humans in the upper Midwestern United States. AB - The Ehrlichia muris-like agent (EMLA) is an emerging, tick-transmitted human pathogen that occurs in the upper Midwestern United States. Here, we describe the development and validation of a p13-based quantitative real-time PCR TaqMan assay to detect EMLA in blood or tissues of ticks, humans, and rodents. The primer and probe specificities of the assay were ascertained using a large panel of various Ehrlichia species and other members of Rickettsiales. In addition to control DNA, both non-infected and EMLA-infected human blood, Mus musculus blood, and M. musculus tissue extracts were evaluated, as were non-infected and EMLA-infected Ixodes scapularis and uninfected Dermacentor variabilis DNA lysates. The specificity of the probe was determined via real-time PCR. An EMLA p13 control plasmid was constructed, and serial dilutions were used to determine the analytical sensitivity, which was found to be 1 copy per 4MUl of template DNA. The sensitivity and specificity of this assay provides a powerful tool for ecological studies involving arthropod vectors and their mammalian hosts. PMID- 26507654 TI - Structure-Function Analysis of a Mixed-linkage beta-Glucanase/Xyloglucanase from the Key Ruminal Bacteroidetes Prevotella bryantii B(1)4. AB - The recent classification of glycoside hydrolase family 5 (GH5) members into subfamilies enhances the prediction of substrate specificity by phylogenetic analysis. However, the small number of well characterized members is a current limitation to understanding the molecular basis of the diverse specificity observed across individual GH5 subfamilies. GH5 subfamily 4 (GH5_4) is one of the largest, with known activities comprising (carboxymethyl)cellulases, mixed linkage endo-glucanases, and endo-xyloglucanases. Through detailed structure function analysis, we have revisited the characterization of a classic GH5_4 carboxymethylcellulase, PbGH5A (also known as Orf4, carboxymethylcellulase, and Cel5A), from the symbiotic rumen Bacteroidetes Prevotella bryantii B14. We demonstrate that carboxymethylcellulose and phosphoric acid-swollen cellulose are in fact relatively poor substrates for PbGH5A, which instead exhibits clear primary specificity for the plant storage and cell wall polysaccharide, mixed linkage beta-glucan. Significant activity toward the plant cell wall polysaccharide xyloglucan was also observed. Determination of PbGH5A crystal structures in the apo-form and in complex with (xylo)glucan oligosaccharides and an active-site affinity label, together with detailed kinetic analysis using a variety of well defined oligosaccharide substrates, revealed the structural determinants of polysaccharide substrate specificity. In particular, this analysis highlighted the PbGH5A active-site motifs that engender predominant mixed-linkage endo-glucanase activity vis a vis predominant endo-xyloglucanases in GH5_4. However the detailed phylogenetic analysis of GH5_4 members did not delineate particular clades of enzymes sharing these sequence motifs; the phylogeny was instead dominated by bacterial taxonomy. Nonetheless, our results provide key enzyme functional and structural reference data for future bioinformatics analyses of (meta)genomes to elucidate the biology of complex gut ecosystems. PMID- 26507655 TI - Mapping the Binding Site of the Inhibitor Tariquidar That Stabilizes the First Transmembrane Domain of P-glycoprotein. AB - ABC (ATP-binding cassette) transporters are clinically important because drug pumps like P-glycoprotein (P-gp, ABCB1) confer multidrug resistance and mutant ABC proteins are responsible for many protein-folding diseases such as cystic fibrosis. Identification of the tariquidar-binding site has been the subject of intensive molecular modeling studies because it is the most potent inhibitor and corrector of P-gp. Tariquidar is a unique P-gp inhibitor because it locks the pump in a conformation that blocks drug efflux but activates ATPase activity. In silico docking studies have identified several potential tariquidar-binding sites. Here, we show through cross-linking studies that tariquidar most likely binds to sites within the transmembrane (TM) segments located in one wing or at the interface between the two wings (12 TM segments form 2 divergent wings). We then introduced arginine residues at all positions in the 12 TM segments (223 mutants) of P-gp. The rationale was that a charged residue in the drug-binding pocket would disrupt hydrophobic interaction with tariquidar and inhibit its ability to rescue processing mutants or stimulate ATPase activity. Arginines introduced at 30 positions significantly inhibited tariquidar rescue of a processing mutant and activation of ATPase activity. The results suggest that tariquidar binds to a site within the drug-binding pocket at the interface between the TM segments of both structural wings. Tariquidar differed from other drug substrates, however, as it stabilized the first TM domain. Stabilization of the first TM domain appears to be a key mechanism for high efficiency rescue of ABC processing mutants that cause disease. PMID- 26507656 TI - The T210M Substitution in the HLA-a*02:01 gp100 Epitope Strongly Affects Overall Proteasomal Cleavage Site Usage and Antigen Processing. AB - MHC class I-restricted epitopes, which carry a tumor-specific mutation resulting in improved MHC binding affinity, are preferred T cell receptor targets in innovative adoptive T cell therapies. However, T cell therapy requires efficient generation of the selected epitope. How such mutations may affect proteasome mediated antigen processing has so far not been studied. Therefore, we analyzed by in vitro experiments the effect on antigen processing and recognition of a T210M exchange, which previously had been introduced into the melanoma gp100209 217 tumor epitope to improve the HLA-A*02:01 binding and its immunogenicity. A quantitative analysis of the main steps of antigen processing shows that the T210M exchange affects proteasomal cleavage site usage within the mutgp100201-230 polypeptide, leading to the generation of an unique set of cleavage products. The T210M substitution qualitatively affects the proteasome-catalyzed generation of spliced and non-spliced peptides predicted to bind HLA-A or -B complexes. The T210M substitution also induces an enhanced production of the mutgp100209-217 epitope and its N-terminally extended peptides. The T210M exchange revealed no effect on ERAP1-mediated N-terminal trimming of the precursor peptides. However, mutant N-terminally extended peptides exhibited significantly increased HLA A*02:01 binding affinity and elicited CD8(+) T cell stimulation in vitro similar to the wtgp100209-217 epitope. Thus, our experiments demonstrate that amino acid exchanges within an epitope can result in the generation of an altered peptide pool with new antigenic peptides and in a wider CD8(+) T cell response also towards N-terminally extended versions of the minimal epitope. PMID- 26507657 TI - Oligomerization and GTP-binding Requirements of MxA for Viral Target Recognition and Antiviral Activity against Influenza A Virus. AB - The IFN-induced human myxovirus resistance protein A (MxA) exhibits a broad antiviral activity against many viruses, including influenza A virus (IAV). MxA belongs to the family of dynamin-like GTPases and assembles in vitro into dimers, tetramers, and oligomeric ring-like structures. The molecular mechanism of action remains to be elucidated. Furthermore, it is not clear whether MxA exerts its antiviral activity in a monomeric and/or multimeric form. Using a set of MxA mutants that form complexes with defined stoichiometry, we observed that, in the presence of guanosine 5'-O-(thiotriphosphate), purified MxA disassembled into tetramers and dimers. Dimeric forms did not further disassemble into monomers. Infection experiments revealed that besides wild-type MxA, dimeric and monomeric variants of MxA also efficiently restricted IAV at a replication step after primary transcription. Moreover, only dimeric MxA was able to form stable complexes with the nucleoprotein (NP) of IAV. MxA interacted with NP independently of other viral components. Interestingly, the dimeric form of MxA was able to efficiently bind to NP from several MxA-sensitive strains but interacted much more weakly with NP from the MxA-resistant PR8 strain derived from the H1N1 1918 lineage. Taken together, these data suggest that, during infection, a fraction of MxA disassembles into dimers that bind to NP synthesized following primary transcription in the cytoplasm, thereby preventing viral replication. PMID- 26507658 TI - USP11 Is a Negative Regulator to gammaH2AX Ubiquitylation by RNF8/RNF168. AB - Ubiquitin modification at double strand breaks (DSB) sites is an essential regulator of signaling and repair. gammaH2AX extends from DSB sites and provides a platform for subsequent recruitment and amplification of DNA repair proteins and signaling factors. Here, we found that RNF8/RNF168 ubiquitylates gammaH2AX. We identified that USP11 is a unique deubiquitylation enzyme for gammaH2AX. USP11 deubiquitylates gammaH2AX both in vivo and in vitro but not the canonical (ub) K119-H2A and (ub)-K120-H2B in vitro, and USP11 ablation enhances the levels of gammaH2AX ubiquitylation. We also found that USP11 interacts with gammaH2AX both in vivo and in vitro. We found that 53BP1 and ubiquitin-conjugated proteins are misregulated to be retained longer and stronger at DSB sites after knockdown of USP11. We further found that cells are hypersensitive to gamma-irradiation after ablation of USP11. Together, our findings elucidate deeply and extensively the mechanism of RNF8/RNF168 and USP11 to maintain the proper status of ubiquitylation gammaH2AX to repair DSB. PMID- 26507659 TI - Molecular Basis of Regulating High Voltage-Activated Calcium Channels by S Nitrosylation. AB - Nitric oxide (NO) is involved in a variety of physiological processes, such as vasoregulation and neurotransmission, and has a complex role in the regulation of pain transduction and synaptic transmission. We have shown previously that NO inhibits high voltage-activated Ca(2+) channels in primary sensory neurons and excitatory synaptic transmission in the spinal dorsal horn. However, the molecular mechanism involved in this inhibitory action remains unclear. In this study, we investigated the role of S-nitrosylation in the NO regulation of high voltage-activated Ca(2+) channels. The NO donor S-nitroso-N-acetyl-DL penicillamine (SNAP) rapidly reduced N-type currents when Cav2.2 was coexpressed with the Cavbeta1 or Cavbeta3 subunits in HEK293 cells. In contrast, SNAP only slightly inhibited P/Q-type and L-type currents reconstituted with various Cavbeta subunits. SNAP caused a depolarizing shift in voltage-dependent N-type channel activation, but it had no effect on Cav2.2 protein levels on the membrane surface. The inhibitory effect of SNAP on N-type currents was blocked by the sulfhydryl-specific modifying reagent methanethiosulfonate ethylammonium. Furthermore, the consensus motifs of S-nitrosylation were much more abundant in Cav2.2 than in Cav1.2 and Cav2.1. Site-directed mutagenesis studies showed that Cys-805, Cys-930, and Cys-1045 in the II-III intracellular loop, Cys-1835 and Cys 2145 in the C terminus of Cav2.2, and Cys-346 in the Cavbeta3 subunit were nitrosylation sites mediating NO sensitivity of N-type channels. Our findings demonstrate that the consensus motifs of S-nitrosylation in cytoplasmically accessible sites are critically involved in post-translational regulation of N type Ca(2+) channels by NO. S-Nitrosylation mediates the feedback regulation of N type channels by NO. PMID- 26507660 TI - Protein Kinase D2 Assembles a Multiprotein Complex at the Trans-Golgi Network to Regulate Matrix Metalloproteinase Secretion. AB - Vesicle formation and fission are tightly regulated at the trans-Golgi network (TGN) during constitutive secretion. Two major protein families regulate these processes: members of the adenosyl-ribosylation factor family of small G-proteins (ARFs) and the protein kinase D (PKD) family of serine/threonine kinases. The functional relationship between these two key regulators of protein transport from the TGN so far is elusive. We here demonstrate the assembly of a novel functional protein complex at the TGN and its key members: cytosolic PKD2 binds ARF-like GTPase (ARL1) and shuttles ARL1 to the TGN. ARL1, in turn, localizes Arfaptin2 to the TGN. At the TGN, where PKD2 interacts with active ARF1, PKD2, and ARL1 are required for the assembly of a complex comprising of ARF1 and Arfaptin2 leading to secretion of matrix metalloproteinase-2 and -7. In conclusion, our data indicate that PKD2 is a core factor in the formation of this multiprotein complex at the TGN that controls constitutive secretion of matrix metalloproteinase cargo. PMID- 26507661 TI - Cyclic Nucleotide-dependent Protein Kinases Target ARHGAP17 and ARHGEF6 Complexes in Platelets. AB - Endothelial cells release prostacyclin (PGI2) and nitric oxide (NO) to inhibit platelet functions. PGI2 and NO effects are mediated by cyclic nucleotides, cAMP- and cGMP-dependent protein kinases (PKA, PKG), and largely unknown PKA and PKG substrate proteins. The small G-protein Rac1 plays a key role in platelets and was suggested to be a target of cyclic nucleotide signaling. We confirm that PKA and PKG activation reduces Rac1-GTP levels. Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. We show that ARHGAP17 binds to the actin-regulating CIP4 protein in platelets and that Ser-702 phosphorylation interferes with this interaction. Reduced CIP4 binding results in enhanced inhibition of cell migration by ARHGAP17. Furthermore, we show that ARHGEF6 is constitutively linked to GIT1, a GAP of Arf family small G proteins, and that ARHGEF6 phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex. PKA and PKG induced rearrangement of ARHGAP17- and ARHGEF6-associated protein complexes might contribute to Rac1 regulation and platelet inhibition. PMID- 26507662 TI - Characterization of the Functional Roles of Amino Acid Residues in Acceptor binding Subsite +1 in the Active Site of the Glucansucrase GTF180 from Lactobacillus reuteri 180. AB - alpha-Glucans produced by glucansucrase enzymes hold strong potential for industrial applications. The exact determinants of the linkage specificity of glucansucrase enzymes have remained largely unknown, even with the recent elucidation of glucansucrase crystal structures. Guided by the crystal structure of glucansucrase GTF180-DeltaN from Lactobacillus reuteri 180 in complex with the acceptor substrate maltose, we identified several residues (Asp-1028 and Asn-1029 from domain A, as well as Leu-938, Ala-978, and Leu-981 from domain B) near subsite +1 that may be critical for linkage specificity determination, and we investigated these by random site-directed mutagenesis. First, mutants of Ala-978 (to Leu, Pro, Phe, or Tyr) and Asp-1028 (to Tyr or Trp) with larger side chains showed reduced degrees of branching, likely due to the steric hindrance by these bulky residues. Second, Leu-938 mutants (except L938F) and Asp-1028 mutants showed altered linkage specificity, mostly with increased (alpha1 -> 6) linkage synthesis. Third, mutation of Leu-981 and Asn-1029 significantly affected the transglycosylation reaction, indicating their essential roles in acceptor substrate binding. In conclusion, glucansucrase product specificity is determined by an interplay of domain A and B residues surrounding the acceptor substrate binding groove. Residues surrounding the +1 subsite thus are critical for activity and specificity of the GTF180 enzyme and play different roles in the enzyme functions. This study provides novel insights into the structure-function relationships of glucansucrase enzymes and clearly shows the potential of enzyme engineering to produce tailor-made alpha-glucans. PMID- 26507663 TI - Unmasking of CD22 Co-receptor on Germinal Center B-cells Occurs by Alternative Mechanisms in Mouse and Man. AB - CD22 is an inhibitory B-cell co-receptor whose function is modulated by sialic acid (Sia)-bearing glycan ligands. Glycan remodeling in the germinal center (GC) alters CD22 ligands, with as yet no ascribed biological consequence. Here, we show in both mice and humans that loss of high affinity ligands on GC B-cells unmasks the binding site of CD22 relative to naive and memory B-cells, promoting recognition of trans ligands. The conserved modulation of CD22 ligands on GC B cells is striking because high affinity glycan ligands of CD22 are species specific. In both species, the high affinity ligand is based on the sequence Siaalpha2-6Galbeta1-4GlcNAc, which terminates N-glycans. The human ligand has N acetylneuraminic acid (Neu5Ac) as the sialic acid, and the high affinity ligand on naive B-cells contains 6-O-sulfate on the GlcNAc. On human GC B-cells, this sulfate modification is lost, giving rise to lower affinity CD22 ligands. Ligands of CD22 on naive murine B-cells do not contain the 6-O-sulfate modification. Instead, the high affinity ligand for mouse CD22 has N-glycolylneuraminic acid (Neu5Gc) as the sialic acid, which is replaced on GC B-cells with Neu5Ac. Human naive and memory B-cells express sulfated glycans as high affinity CD22 ligands, which are lost on GC B-cells. In mice, Neu5Gc-containing glycans serve as high affinity CD22 ligands that are replaced by Neu5Ac-containing glycans on GC B cells. Our results demonstrate that loss of high affinity CD22 ligands on GC B cells occurs in both mice and humans through alternative mechanisms, unmasking CD22 relative to naive and memory B-cells. PMID- 26507664 TI - A competing risk analysis of sequential complication development in Asian type 2 diabetes mellitus patients. AB - This retrospective cohort study investigated the progression risk of sequential complication in Asian type 2 diabetes (T2D) patients using the Taiwan Pay-for Performance Diabetes Registry and claim data from November 2003 to February 2009. 226,310 adult T2D patients without complication were followed from diagnosis to complications, including myocardial infarction (MI), other ischemic heart disease (IHD), congestive heart failure (CHF), stroke, chronic kidney disease (CKD), retinopathy, amputation, death or to the end of study. Cumulative incidences (CIs) of first and second complications were analyzed in 30 and 4 years using the cumulative incidence competing risk method. IHD (29.8%), CKD (24.5%) and stroke (16.0%) are the most common first complications. The further development of T2D complications depends on a patient's existing complication profiles. Patients who initially developed cardiovascular complications had a higher risk (9.2% to 24.4%) of developing IHD or CKD, respectively. All-cause mortality was the most likely consequence for patients with a prior MI (12.0%), so as stroke in patients with a prior MI (10.8%) or IHD (8.9%). Patients with CKD had higher risk of developing IHD (16.3%), stroke (8.9%) and all-cause mortality (8.7%) than end stage renal disease (4.0%). Following an amputation, patients had a considerable risk of all-cause mortality (42.1%). PMID- 26507665 TI - North Carolina Macular Dystrophy Is Caused by Dysregulation of the Retinal Transcription Factor PRDM13. AB - PURPOSE: To identify specific mutations causing North Carolina macular dystrophy (NCMD). DESIGN: Whole-genome sequencing coupled with reverse transcription polymerase chain reaction (RT-PCR) analysis of gene expression in human retinal cells. PARTICIPANTS: A total of 141 members of 12 families with NCMD and 261 unrelated control individuals. METHODS: Genome sequencing was performed on 8 affected individuals from 3 families affected with chromosome 6-linked NCMD (MCDR1) and 2 individuals affected with chromosome 5-linked NCMD (MCDR3). Variants observed in the MCDR1 locus with frequencies <1% in published databases were confirmed using Sanger sequencing. Confirmed variants absent from all published databases were sought in 8 additional MCDR1 families and 261 controls. The RT-PCR analysis of selected genes was performed in stem cell-derived human retinal cells. MAIN OUTCOME MEASURES: Co-segregation of rare genetic variants with disease phenotype. RESULTS: Five sequenced individuals with MCDR1-linked NCMD shared a haplotype of 14 rare variants spanning 1 Mb of the disease-causing allele. One of these variants (V1) was absent from all published databases and all 261 controls, but was found in 5 additional NCMD kindreds. This variant lies in a DNase 1 hypersensitivity site (DHS) upstream of both the PRDM13 and CCNC genes. Sanger sequencing of 1 kb centered on V1 was performed in the remaining 4 NCMD probands, and 2 additional novel single nucleotide variants (V2 in 3 families and V3 in 1 family) were identified in the DHS within 134 bp of the location of V1. A complete duplication of the PRDM13 gene was also discovered in a single family (V4). The RT-PCR analysis of PRDM13 expression in developing retinal cells revealed marked developmental regulation. Next-generation sequencing of 2 individuals with MCDR3-linked NCMD revealed a 900-kb duplication that included the entire IRX1 gene (V5). The 5 mutations V1 to V5 segregated perfectly in the 102 affected and 39 unaffected members of the 12 NCMD families. CONCLUSIONS: We identified 5 rare mutations, each capable of arresting human macular development. Four of these strongly implicate the involvement of PRDM13 in macular development, whereas the pathophysiologic mechanism of the fifth remains unknown but may involve the developmental dysregulation of IRX1. PMID- 26507666 TI - Alternative application of Tau protein in Creutzfeldt-Jakob disease diagnosis: Improvement for weakly positive 14-3-3 protein in the laboratory. AB - The 14-3-3 protein has been used as a biomarker for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). However, weakly positive 14-3-3 leads to false positive results and an incorrect diagnosis. We attempted to use quantitative data for tau protein to provide an accurate diagnosis based on weak 14-3-3 protein. Sixty-two patients with sCJD, including pathologically confirmed, clinically definite, and probable cases, and 89 non-CJD patients were investigated based on a Korean population. Among them, 20 sCJD and 14 non-CJD showed weakly positive 14-3-3. The total tau (t-tau) and phosphorylated tau (p tau) protein levels were measured by ELISA, and the p-tau to t-tau ratio (p/t ratio) was calculated. The combined use of the 14-3-3 protein assay, t-tau levels, and p/t ratio improved the specificity of diagnosis compared with the use of the 14-3-3 protein assay alone (47% for 14-3-3 alone; 85.94% for 14-3-3 combined with t-tau; 90.62% for 14-3-3 combined with the p/t ratio). In addition, 18 of 20 sCJD and 12 of 14 non-CJD who were weakly positive for 14-3-3 were positive for the p/t ratio and negative for the p/t ratio, respectively. When used in combination with the 14-3-3 protein, the tau protein is useful as a biomarker for the precise diagnosis of sCJD. PMID- 26507667 TI - Piezometric biosensors for anti-apoptotic protein survivin based on buried positive-potential barrier and immobilized monoclonal antibodies. AB - The anti-apoptotic protein survivin (Sur) plays an important role in the regulation of cell division and inducing the chemotherapeutic drug resistance. The Sur protein and its mRNA have recently been studied as cancer biomarkers and potential targets for cancer therapy. In this work, we have focused on the design of immunosensors for the detection of Sur based on buried positive-potential barrier layer structure and anti-survivin antibody. The modification of solid AuQC piezoelectrodes was monitored by recording the resonance frequency shift and electrochemical measurements during each step of the sensor preparation. Our results indicate that the immunosensor with covalently bound monoclonal anti survivin antibody can detect Sur with the limit of detection, LOD=1.7nM (S/N=3sigma). The immunosensor applicability for the analysis of real samples was assessed by testing samples of cell lysate solutions obtained from human astrocytoma (glioblastoma) U-87MG cell line, with the experiments performed using the standard addition method. The good linearity of the calibration curves for PBS and lysate solutions at low Sur concentrations confirm the high specificity of the proposed biosensor and good discrimination against nonspecific interactions with lysate components. The calculations indicate that there is still room to increase the Sur capture capacity for Sur while miniaturizing the sensor. The important advantage of the sensor is that it can be reused by a simple regeneration procedure. PMID- 26507668 TI - Interethnic differences of cytochrome P450 gene polymorphisms may influence outcome of taxane therapy in Roma and Hungarian populations. AB - Taxanes are widely used microtubule-stabilizing chemotherapeutic agents in the treatment of cancers. Several cytochrome P450 gene variants have been proven to influence taxane metabolism and therapy. The purpose of this work was to determine the distribution of genetic variations of CYP1B1, CYP2C8 and CYP3A5 genes as the first report on taxane metabolizer cytochrome P450 gene polymorphisms in Roma and Hungarian populations. A total of 397 Roma and 412 Hungarian healthy subjects were genotyped for CYP1B1 c.4326C > G, CYP2C8 c.792C > G and CYP3A5 c.6986A > G variant alleles by PCR-RFLP assay and direct sequencing. We found significant differences in the frequencies of homozygous variant genotypes of CYP1B1 4326 GG (p = 0.002) and CYP3A5 6986 GG (p < 0.001) between Roma and Hungarian populations. Regarding minor allele frequencies, for CYP2C8 a significantly increased prevalence was found in 792G allele frequency in the Hungarian population compared to the Roma population (5.83% vs. 2.14%, p = 0.001). Our results can be used as possible predictive factors in population specific treatment algorithms to developing effective programs for a better outcome in patients treated with taxanes. PMID- 26507669 TI - Utilization of the Newest Vital Sign (NVS) in Practice in the United States. AB - Health literacy refers to the ability of a patient to obtain, communicate, process, and understand basic information related to health and services. It is estimated that the majority of adult Americans may have difficulty understanding health information. In addition, limited health literacy of patients is linked to over $100 billion in health care costs. Measurement of health literacy may aid in improving communication with patients, and thus to improving outcomes and decreasing costs. The Newest Vital Sign (NVS) is a tool that has been used to assess health literacy in a variety of patients. It has been validated against other measures including the Test of Functional Health Literacy in Adults (TOFHLA). Patients are categorized as high likelihood of limited health literacy, possible limited health literacy, or adequate literacy. The NVS has been used in a variety of settings and tested among a wide range of patient groups. The most common setting for use is in primary care, probably due to the relatively quick assessment of health literacy (within 3 minutes). The NVS has been used in Caucasians, African Americans, Hispanics, and several other ethnicities. Assessment with the NVS has been conducted in adult patients across the age continuum, and with several different health conditions, including diabetes, kidney disease, and pain. This article seeks to review the published uses to date and to provide suggestions for potential uses of the NVS. PMID- 26507670 TI - Paraneoplastic eosinophilic fasciitis with generalized morphea and vitiligo in a patient working with organic solvents. PMID- 26507671 TI - Deep neck infections in children. AB - BACKGROUND/PURPOSE: Deep neck infections (DNIs) often have a rapid onset and can progress to life-threatening complications. There are only a few reports on pediatric DNIs' clinical manifestations, diagnostic clues, and etiology in Taiwan. METHODS: A retrospective chart review of patients (aged <= 18 years) diagnosed with DNI from January 2005 to December 2014 was performed. DNIs were classified into retropharyngeal, parapharyngeal, peritonsillar, submandibular, and multispace abscesses. RESULTS: A total of 52 patients with DNI were identified. The most common site of DNI was the parapharyngeal space (n = 22, 42.3%). The most commonly associated antecedent illness was preceding upper respiratory tract infection (30.8%). The most common clinical presentation was neck mass or swelling (82.7%) and fever (75%). Pus drainage or needle aspiration was performed to obtain pus samples from the infection site for pus culture (n = 31). The most commonly isolated pathogen was Staphylococcus aureus (n = 7). Amoxicillin-clavulanic acid (56.6%) was the most commonly used antibiotics, followed by penicillin (15.1%). There was no long-term morbidity or mortality. CONCLUSION: When a patient (regardless of age) presents with neck mass or swelling, the DNI should always be included in the differential diagnosis. The low culture rate in Taiwan and previous partial treatment of infections may have affected identification of pathogens in cultures. Performing Gram staining and acid-fast staining of pus, instead of culture alone, as early as possible before initiating the initial antimicrobial therapy are thus crucial. The recurrence of DNI should alert the physician to the possibility of an underlying bronchogenic cyst. Excision surgery is required to cure recurrent infections. PMID- 26507672 TI - The effect of immunization with pneumococcal conjugated vaccines on Streptococcus pneumoniae resistance patterns in acute otitis media. AB - Following the introduction of 7- and 13-pneumococcal conjugate vaccines (PCVs) in Israel, we demonstrated that within Streptococcus pneumoniae (Sp) positive middle ear cultures, obtained from young children with severe acute otitis media (AOM) episodes, there were more penicillin-susceptible and less multi-drug resistant Sp isolates in PCV immunized children. PMID- 26507674 TI - Oral lipoma associated with multiple endocrine neoplasia (MEN) type 1. PMID- 26507673 TI - Blood-brain and retinal barriers show dissimilar ABC transporter impacts and concealed effect of P-glycoprotein on a novel verapamil influx carrier. AB - BACKGROUND AND PURPOSE: The respective impact and interplay between ABC (P glycoprotein/P-gp/Abcb1a, BCRP/ABCG2, MRP/ABCC) and SLC transporter functions at the blood-brain barrier (BBB) and blood-retinal barriers (BRB) are incompletely understood. EXPERIMENTAL APPROACH: We measured the initial cerebral and retinal distribution of selected ABC substrates by in situ carotid perfusion using P gp/Bcrp knockout mice and chemical ABC/SLC modulation strategies. P-gp, Bcrp, Mrp1 and Mrp4 were studied by confocal retina imaging. KEY RESULTS: Chemical or physical disruption of P-gp increased [(3) H]-verapamil transport by ~10-fold at the BBB and ~1.5-fold at the BRB. [(3) H]-Verapamil transport involved influx mediated by an organic cation clonidine-sensitive/diphenhydramine-sensitive proton antiporter at both barriers; this effect was unmasked when P-gp was partially or fully inhibited/disrupted at the BBB. Studies of [(3) H] mitoxantrone and [(3) H]-zidovudine transport suggested, respectively, that Bcrp efflux was less involved at the BRB than BBB, whereas Mrps were significantly and similarly involved at both barriers. Confocal imaging showed that P-gp and Bcrp were expressed in intra-retinal vessels (inner BRB/iBRB) but absent from the blood/basal membrane of cells of the retinal pigment epithelium (outer BRB/oBRB/RPE) where, in contrast, Mrp1 and Mrp4 were localized. CONCLUSIONS AND IMPLICATIONS: P-gp, Bcrp, Mrp1 and Mrp4 are differentially expressed at the outer and inner BRB, resulting in an altered ability to limit substrate distribution at the retina as compared with the BBB. [(3) H]-Verapamil distribution is not P-gp specific and involves a proton antiporter at both the BBB and BRB. However, this transport is concealed by P-gp at the BBB, but not at the BRB, where P-gp activity is reduced. PMID- 26507675 TI - Use of thermoplasticised nasal splint in naso-orbitoethmoid fractures: a technical note. PMID- 26507676 TI - Accidental displacement of a dental implant into the submandibular space during explantation. AB - Dental implants are reliable and widely used, but complications such as peri implantitis occasionally necessitate their removal. Accidents during removal are similar to those that may occur during extraction, including displacement into another structure in the maxillofacial region. We present a rare case of accidental displacement into the submandibular space, which happened during an attempt to remove an implant. PMID- 26507677 TI - DOES RURAL-TO-URBAN MIGRATION PLACE ADOLESCENTS AT RISK OF DELETERIOUS SEXUAL AND REPRODUCTIVE HEALTH OUTCOMES? EVIDENCE FROM HAITI. AB - This study examines the links between migration and sexual and reproductive health among rural-to-urban migrant youth in Haiti. It evaluates behavioural, knowledge and attitudinal components from the perspective of three competing explanations for migrants' behaviours: adaptation, disruption and selection. Discrete-time event history analysis is employed to compare these hypotheses using Haiti Demographic and Health Survey data (N=1215 adolescent girls, N=829 adolescent boys). Multi-level models are used to compare changes in knowledge and attitudes in individuals using data from the Haiti Youth Transitions Study (N=223). The findings reveal that disruption is the most plausible explanation for the timing of migration and first sex among girls. However, contrary to the assumption that migrant youth risk experiencing first sex earlier, girls are less likely to experience first sex near the time they migrate, and rural-to-urban migrant boys may experience first sex at later ages. The high aspirations of migrant youth provide a likely explanation for these findings. Furthermore, male migrants accumulate less protective knowledge, which is consistent with the disruption hypothesis, and migrants endorse premarital sex similarly to non migrants. Sexual and reproductive health curricula should be adapted to the unique needs of migrant youth, and youth should be targeted before they migrate. PMID- 26507679 TI - Defective mutations within the translocation domain of Clostridium difficile toxin B impair disease pathogenesis. AB - The Clostridium difficile toxin B is one of the main virulence factors and plays an important role in the pathogenesis of C. difficile infection (CDI). We recently revealed crucial residues in the translocation domain of TcdB for the pore formation and toxin translocation. In this study, we investigated the effects of mutating a critical site involved in pore formation, Leu-1106, to residues that differ in size and polarity (Phe, Ala, Cys, Asp). We observed a broad range of effects on TcdB function in vitro consistent with the role of this site in pore formation and translocation. We show that mice challenged systemically with a lethal dose (LD100) of the most defective mutant (L1106K) showed no symptoms of disease highlighting the importance of this residue and the translocation domain in disease pathogenesis. These findings offer insights into the structure function of the toxin translocation pore, and inform novel therapeutic strategies against CDI. PMID- 26507680 TI - High sensitive space electric field sensing based on micro fiber interferometer with field force driven gold nanofilm. AB - The traditional electrical field sensing can be realized by utilizing electro optic materials or liquid crystals, and has limitations of easy breakdown, free assembly and difficult measurement of low-frequency. Here, we propose a new method to realize safe measurement of spatial dynamic electric field by using a micro fiber interferometer integrated with gold nanofilm. The energy of the electric charge received through antenna forms the intrinsic electric field with two micro electrodes, one of which is the 120 nm gold film vibration beam micromachined by femtosecond lasers and integrated with the micro fiber. The change of the intrinsic electric field force due to the spatial electric field will cause the vibration of the film beam. By demodulating the output signal of the micro fiber interferometer, the electric field can be measured. We demonstrate the detectable frequency ranges from tens of Hz to tens of KHz, and the minimum electric field intensity is ~200 V/m at 1 KHz. Our electric field measurement technology combining optical fiber interference with gold nanostructures shows the advantages of security, high sensitivity, compact size, and multiplexed multi-point and remote detection. PMID- 26507681 TI - IL-21 and IL-21 receptor in the immunopathogenesis of multiple sclerosis. AB - Cytokines are considered important factors in the modulation of various immune responses. Among them, interleukin (IL)-21 is one of the major immune modulators, adjusting various immune responses by affecting various immune cells. It has been suggested that IL-21 may enhance autoimmunity through different mechanisms, such as development and activation of helper T (TH)-17 and follicular helper T (TFH) cells, activation of natural killer (NK) cells, enhancing B-cell differentiation and antibody secretion and suppression of regulatory T (Treg) cells. Moreover, IL 21 has also been suggested to be an inducer of autoimmunity when following treatment of MS patients with some therapeutics such as alemtuzumab. This review will seek to clarify the precise role of IL-21/IL-21R in the pathogenesis of MS and, in its animal model, experimental autoimmune encephalomyelitis (EAE). PMID- 26507682 TI - Oxidative Coupling of Terminal Alkynes with Aldehydes Leading to Alkynyl Ketones by Using Indium(III) Bromide. AB - An indium(III)-promoted direct acylation of terminal alkynes using aldehydes leading to ynones was developed. In contrast to the previous addition reactions of alkynes to aldehydes, which provide propargylic alcohols, the oxidative coupling proceeded exclusively to afford alkynyl ketones. The products were likely generated through an Oppenauer oxidation of the indium propargylic alkoxide species by excess amounts of aldehydes. PMID- 26507683 TI - Preschool children's control of action outcomes. AB - Naturalistic goal-directed behaviours require the engagement and maintenance of appropriate levels of cognitive control over relatively extended intervals of time. In two experiments, we examined preschool children's abilities to maintain top-down control throughout the course of a sequential task. Both 3- and 5-year olds demonstrated good abilities to access goals at the lowest level of the representational hierarchy. However, only 5-year-olds consistently aligned their response choices with goals at superordinate levels. These findings suggest that the ability to maintain top-down control and adjust behavioural responses according to goals at multiple levels of abstraction undergoes a marked improvement throughout the preschool period. Results are discussed in relation to current accounts of cognitive control and the monitoring of conflict in sequential action. PMID- 26507684 TI - The Role of Heterotrophic Microbial Communities in Estuarine C Budgets and the Biogeochemical C Cycle with Implications for Global Warming: Research Opportunities and Challenges. AB - Estuaries are among the most productive and economically important marine ecosystems at the land-ocean interface and contribute significantly to exchange of CO2 with the atmosphere. Estuarine microbial communities are major links in the biogeochemical C cycle and flow of C in food webs from primary producers to higher consumers. Considerable attention has been given to bacteria and autotrophic eukaryotes in estuarine ecosystems, but less research has been devoted to the role of heterotrophic eukaryotic microbes. Current research is reviewed here on the role of heterotrophic eukaryotic microbes in C biogeochemistry and ecology of estuaries, with particular attention to C budgets, trophodynamics, and the metabolic fate of C in microbial communities. Some attention is given to the importance of these processes in climate change and global warming, especially in relation to sources and sinks of atmospheric CO2 , while also documenting the current paucity of research on the role of eukaryotic microbes that contribute to this larger question of C biogeochemistry and the environment. Some recommendations are made for future directions of research and opportunities of applying newer technologies and analytical approaches to a more refined analysis of the role of C in estuarine microbial community processes and the biogeochemical C cycle. PMID- 26507685 TI - Efficacy and safety of oral alitretinoin in severe oral lichen planus--results of a prospective pilot study. AB - BACKGROUND: Patients with severe oral lichen planus refractory to standard topical treatment currently have limited options of therapy suitable for long term use. Oral alitretinoin (9-cis retinoic acid) was never systematically investigated in clinical trials, although case reports suggest its possible efficacy. OBJECTIVES: To assess the efficacy and safety of oral alitretinoin taken at 30 mg once daily for up to 24 weeks in the treatment of severe oral lichen planus refractory to standard topical therapy. METHODS: We conducted a prospective open-label single arm pilot study to test the efficacy and safety of 30 mg oral alitretinoin once daily for up to 24 weeks in severe oral lichen planus. Ten patients were included in the study. Primary end point was reduction in signs and symptoms measured by the Escudier severity score. Secondary parameters included pain and quality of life scores. Safety parameters were assessed during a follow-up period of 5 weeks. RESULTS: A substantial response at the end of treatment, i.e. >50% reduction in disease severity measured by the Escudier severity score, was apparent in 40% of patients. Therapy was well tolerated. Adverse events were mild and included headache, mucocutaneous dryness, musculoskeletal pain, increased thyroid-stimulating hormone and dyslipidaemia. CONCLUSIONS: Alitretinoin given at 30 mg daily reduced disease severity of severe oral lichen planus in a substantial proportion of patients refractory to standard treatment, was well tolerated and may thus represent one therapeutic option for this special group of patients. PMID- 26507686 TI - Role of plant growth promoting rhizobacteria and Ag-nano particle in the bioremediation of heavy metals and maize growth under municipal wastewater irrigation. AB - The investigation evaluated the role of plant growth promoting rhizobacteria (PGPR) and Ag-nano particle on the growth and metabolism of maize irrigated with municipal wastewater (MW). Three PGPR isolated from MW were identified on the basis of 16S-rRNA gene sequence analyses as Pseudomonas sp., Pseudomonas fluorescence, and Bacillus cereus. The municipal waste water was used to irrigate the maize seeds inoculated with 3 isolated PGPR. The isolated PGPR had catalase and oxidase enzymes, solubilize insoluble bound phosphate and exhibit antifungal and antibacterial activities. The colony forming unit (cfu) of the PGPR was inhibited by Ag-nano particle, but was stimulated by the municipal wastewater. The Ag-nano particles augmented the PGPR induced increase in root area and root length. The root-shoot ratio was also changed with the Ag-nano particles. The plants irrigated with municipal wastewater had higher activities of peroxidase and catalase which were further augmented by Ag-nano particle. The Ag- nano particle application modulated level of ABA (34%), IAA (55%), and GA (82%), increased proline production (70%) and encountered oxidative stress and augmented the bioremediation potential of PGPR for Pb, Cd, and Ni. Municipal wastewater needs to be treated with PGPR and Ag nano particle prior to be used for irrigation. This aims for the better growth of the plant and enhanced bioremediation of toxic heavy metals. PMID- 26507687 TI - From efficacy to effectiveness in smoking cessation in severe mental illness. PMID- 26507688 TI - Predicting vehicle belt fit for children ages 6-12. AB - OBJECTIVE: To predict shoulder belt fit and lap belt fit as a function of child age, vehicle seat characteristics, and belt geometry. METHODS: In a previous study, the lap belt and shoulder belt fit of 44 children aged 5-12 were measured in a simulated vehicle seat while varying cushion length, cushion angle, seatback angle, and belt anchorage geometry. A regression model was developed to predict lap belt fit and shoulder belt fit as a function of vehicle parameters and child stature. These regression models were applied to the stature distribution of 6- to 12-year-olds using a range of vehicle geometry data to predict the proportion of children expected to achieve good belt fit in the second-row, outboard seating positions of 46 vehicles when not using belt-positioning boosters. RESULTS: Across the ranges observed in vehicles, lap belt angle had the strongest effect on lap belt fit, although vehicle cushion length also contributed. Shoulder belt fit was most strongly affected by D-ring location. Vehicles with the geometric conditions most suitable for children are estimated to provide good lap belt fit for 25% of children aged 6 to 12. In 20% of vehicles, the shoulder belt is too far inboard for the target child population; 20% of vehicles are estimated to have shoulder belt fit too far outboard for children ages 6 to 12. CONCLUSIONS: Based on this geometric analysis, the rear seats of most vehicles are unlikely to provide good lap belt fit for up to 75% of children ages 6-12. Shoulder belt fit is outside the target range for 40% of children. Consequently, children under 12 years of age are likely to experience markedly poorer belt fit when transitioning out of a booster seat. PMID- 26507689 TI - Coping and rehabilitation in alcoholic liver disease patients after hepatic encephalopathy--in interaction with professionals and relatives. AB - AIMS AND OBJECTIVES: To identify and describe conditions that limit or support patients, with alcoholic liver disease after surviving alcohol-induced hepatic encephalopathy, ability to cope with current and potential physical and psychosocial problems--in interaction with professionals and relatives--and to recommend appropriate interventions. BACKGROUND: Alcoholic liver disease patients surviving alcohol-induced hepatic encephalopathy have significantly impaired quality of life. Internationally, there is a lack of knowledge about the conditions that affect alcoholic liver disease patients' coping and rehabilitation. DESIGN: A grounded theory study. METHODS: Semi-structured interviews, conducted with 11 alcoholic liver disease patients who were diagnosed with hepatic encephalopathy. The interview guide was inspired by Richard S. Lazarus's theory of stress and coping. RESULTS: The elements that support or limit alcoholic liver disease patients' ability to cope with physical and psychosocial problems in interaction with professionals and relatives were represented by the core category 'Struggle for preservation of identity as a significant individual'. It was characterised by three categories, which are interrelated and impact upon each other: 'Acknowledgement', 'Struggle to maintain control' and 'Achieving a sense of security'. CONCLUSION: Alcoholic liver disease patients experience a struggle to preserve their identity as a significant individual. It can be assumed that professionals and relatives in their interaction with, and support of, patients should focus on strengthening and preserving patients' identity in the form of acknowledgement, helping alcoholic liver disease patients maintain self-control and providing a safety net so patients feel a sense of security. RELEVANCE TO CLINICAL PRACTICE: It can be assumed that professionals should support alcoholic liver disease patients' appraisal of, and coping with, physical and psychosocial problems based on acknowledgment, understanding and a sympathetic attitude. Professionals should proactively approach patients when they withdraw. It may be useful for professionals to be aware of alcoholic liver disease patients' individual coping strategies and thereby their individual requirements for professional supportive intervention. PMID- 26507690 TI - Early sponges and toxic protists: possible sources of cryostane, an age diagnostic biomarker antedating Sturtian Snowball Earth. AB - The period 800-717 million years (Ma) ago, in the lead-up to the Sturtian Snowball glaciation, saw an increase in the diversity of eukaryotic microfossils. To afford an independent and complementary view of this evolutionary period, this study presents the distribution of eukaryotic biomarkers from three pre-Sturtian successions across the supercontinent Rodinia: the ca. 780 Ma Kanpa Formation of the Western Australian Officer Basin, the ca. 800-740 Ma Visingso Group of Sweden, and the 740 Ma Chuar Group in Arizona, USA. The distribution of eukaryotic steranes is remarkably similar in the three successions but distinct from all other known younger and older sterane assemblages. Cholestane was the only conventional structure, while indigenous steranes alkylated in position C 24, such as ergostane, stigmastane, dinosterane and isopropylcholestane, and n propylcholestane, were not observed. This sterane distribution appears to be age diagnostic for the pre-Sturtian Neoproterozoic. It attests to the distinct evolutionary state of pre-Snowball eukaryotes, pointing to a taxonomic disparity that was still lower than in the Ediacaran (635-541 Ma). All three basins also show the presence of a new C28 sterane that was tentatively identified as 26 methylcholestane, here named cryostane. The only known extant organisms that can methylate sterols in the 26-position are demosponges. This assignment is plausible as molecular clocks place the appearance of the earliest animals into the pre-Sturtian Neoproterozoic. The unusual 26-methylsterol may have protected sponges, but also other eukaryotes, against their own membranolytic toxins. Some protists release lytic toxins to deter predators and kill eukaryotic prey. As conventional membrane sterols can be the site of attack for these toxins, sterols with unusual side-chain modification protect the cell. This interpretation of cryostane supports fossil evidence of predation in the Chuar Group and promotes hypotheses about the proliferation of eukaryophagy in the lead-up to the Cryogenian. PMID- 26507692 TI - Triplet State Aromaticity: NICS Criterion, Hyperconjugation, and Charge Effects. AB - Aromaticity, one of the most important concepts in organic chemistry, has attracted considerable interest from both experimentalists and theoreticians. It remains unclear which NICS index is best to evaluate the triplet-state aromaticity. Here, we carry out thorough density functional theory (DFT) calculations to examine this issue. Our results indicate that among the various computationally available NICS indices, NICS(1)zz is the best for the triplet state. The correlations can be improved from 0.840 to 0.938 when only neutral species are considered, demonstrating the significant effect of the charge on the triplet-state aromaticity. In addition, calculations suggest that five-membered cyclic species with "hyperconjugative" aromaticity (and antiaromaticity) in the S0 state will become antiaromatic (and aromatic) in the T1 state, indicating an important role of hyperconjugation. Finally, a moderate correlation (r(2) =0.708) is identified between the NICS(1)zz values and spin distributions. PMID- 26507693 TI - Chemical chain termination resolves the timing of ketoreduction in a partially reducing iterative type I polyketide synthase. AB - Synthetic chain terminators were used to capture the biosynthetic intermediates from a partially reducing iterative type I polyketide synthase, which is integrated into a multimodular biosynthesis enzyme. The off-loaded metabolites clarified the timing of ketoreduction and aromatization in the assembly of the antibiotic micacocidin. PMID- 26507691 TI - All roads lead to PP2A: exploiting the therapeutic potential of this phosphatase. AB - Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase involved in the regulation of many cellular processes. A confirmed tumor suppressor protein, PP2A is genetically altered or functionally inactivated in many cancers highlighting a need for its therapeutic reactivation. In this review we discuss recent literature on PP2A: the elucidation of its structure and the functions of its subunits, and the identification of molecular lesions and post-translational modifications leading to its dysregulation in cancer. A final section will discuss the proteins and small molecules that modulate PP2A and how these might be used to target dysregulated forms of PP2A to treat cancers and other diseases. PMID- 26507694 TI - Clinical Importance and Sonographic Features of Nonpalpable Axillary Lymphadenopathy Identified on Breast Sonography in Patients Without Malignancy. AB - OBJECTIVES: The purpose of this study was to evaluate the clinical importance and sonographic features of nonpalpable axillary lymphadenopathy identified on breast sonography in patients without malignancy. METHODS: Our study included 71 women and 2 men (mean age, 47.5 years; range, 16-69 years) with axillary lymphadenopathy identified on breast sonography. None of the 73 patients had known malignancy or presented with palpable lymph nodes or symptoms of mastitis. The lesions were pathologically diagnosed in 53 patients by surgical biopsy (n = 8), ultrasound-guided core needle biopsy (n = 17), or ultrasound -guided fine needle aspiration (n = 28). Twenty patients underwent follow-up imaging for 6 to 60 months (mean, 17 months). The sonographic features of the axillary lymph nodes were analyzed for all patients. RESULTS: The final diagnoses included benign reactive hyperplasia (n = 45), Kikuchi disease (n = 4), tuberculosis (n = 3), and sarcoidosis (n = 1). None of the 20 patients who underwent follow-up imaging developed malignancy. Suspicious sonographic features were frequently observed (loss of the fatty hilum, round shape, abnormal cortical thickening, and marked hypoechogenicity: 79.5%, 75.3%, 82.1%, and 9.6%, respectively) and were mostly complex, with the most common combination being a round shape and loss of the fatty hilum in 61.6% patients. CONCLUSIONS: No malignancy was detected in all 73 patients, despite frequent manifestations of complex and extremely suspicious sonographic features. Short-term follow-up imaging rather than immediate biopsy can be recommended for nonpalpable lymphadenopathy in patients without known malignancy. PMID- 26507695 TI - Accuracy of Spleen Measurement by Medical Residents Using Hand-Carried Ultrasound. AB - OBJECTIVES: Easily palpable splenomegaly can be identified on physical examination, but it is difficult to detect lesser degrees of splenomegaly. Rapid bedside assessment can be conducted with hand-carried ultrasound. We performed this study to determine whether medical residents could reliably assess spleen size using hand-carried ultrasound after a brief educational intervention. METHODS: Postgraduate year 1 internal medicine residents were shown a brief (45 minute) presentation on ultrasound basics, the use of hand-carried ultrasound, and principles of splenic ultrasound imaging. They practiced on each other, using hand-carried ultrasound to assess spleen size, for 1 hour in the presence of an instructor. Patients with varying degrees of splenomegaly and hospital staff were recruited at Vancouver General Hospital. A sonographer measured spleen size in each participant using conventional ultrasound. Subsequently, the trained residents scanned the participants using hand-carried ultrasound, blinded to the sonographer's measurements and the participants' diagnoses. The instructor was not present during scanning. RESULTS: Twelve first-year residents (8 male and 4 female; mean age +/- SEM, 28 +/- 1 years; all with limited prior ultrasound training) and 19 patients and staff members (10 male and 9 female; mean age, 60 +/- 4 years; body mass index, 24 +/- 2 kg/m(2)) were recruited. The greatest longitudinal measurements were 14.0 +/- 0.7 cm with conventional ultrasound administered by the sonographer and 13.2 +/- 0.9 cm with hand-carried ultrasound administered by the residents (P > .05, not significant). The correlation between conventional and hand-carried ultrasound was r = 0.81 (P < .001). CONCLUSIONS: Internal medicine residents can reliably assess spleen size at the point of care using hand-carried ultrasound with minimal training. Our findings, if replicated in other centers and in different clinical scenarios, may change the way that clinicians examine the spleen. PMID- 26507696 TI - What Is the Rate of Incomplete Fetal Anatomic Surveys During a Second-Trimester Scan? Retrospective Observational Study of 4000 Nonobese Pregnant Women. AB - OBJECTIVES: The purpose of this study was to estimate the rate of incomplete fetal anatomic surveys during a second-trimester scan due to an unfavorable fetal position in a nonobese population. METHODS: All pregnant women who came to the Altamedica Fetal-Maternal Medical Center, a specialized center for prenatal diagnosis, for a routine second-trimester scan between January 2012 and April 2013 were retrospectively included in the analysis. Patients with a body mass index higher than 30.0 kg/m(2) or anterior fibroids larger than 5 cm were not included in the study. RESULTS: Of 4000 pregnant women admitted for a second trimester scan, 169 (4.2%) came back within 2 weeks to complete the examination because of an unfavorable fetal position. In particular, 104 (2.6%) needed visualization of only 1 view, and 65 (1.6%) needed more than 1 view. The most difficult organ to visualize was the corpus callosum, in 73 cases (1.8%); the face was not visualized in 69 cases (1.7%); the cerebellar vermis was not seen in 47 fetuses (1.1%); and the heart could not be completely examined in 40 fetuses (1.0%). Of the 4000 women, 169 (4.2%) had a nonexhaustive scan; 149 (3.7%) needed a second scan to complete the second-trimester survey; 14 (0.35%) needed a third scan; and 2 (0.05%) remained with a not completely exhaustive scan. CONCLUSIONS: There is always a small percentage of incomplete fetal anatomic surveys during a second-trimester scan, which cannot be modified by the sonographer's skill or by technical sonographic innovations. PMID- 26507697 TI - HDlive Imaging of a Giant Fetal Hemangioma. PMID- 26507698 TI - Pulmonary Atresia With an Intact Ventricular Septum in the Setting of D Transposition of the Great Arteries With a Hypoplastic Left Ventricle: Fetal Diagnosis. PMID- 26507699 TI - Evaluation of Thyroid Nodules by a Scoring and Categorizing Method Based on Sonographic Features. AB - OBJECTIVES: To assess sonographic features of thyroid nodules associated with malignancy and to establish a scoring and categorizing method based on sonographic features. METHODS: A total of 2445 patients with 2445 thyroid nodules were included and divided into 2 groups: benign (1493 cases) and malignant (952 cases). First, 10 sonographic features, including shape, border, margin, internal content, echogenicity, microcalcifications, posterior echo, halo, vascularization distribution, and vascularization degree, were defined, and all nodules were retrospectively evaluated. Second, the features associated with malignancy were selected by statistical analysis and were assigned weightings according to their odds ratios. Third, a total score for each nodule was obtained after the assigned weightings of the suspicious features were summed. Fourth, the malignancy rate of each total score was calculated. Then a modified version of the Thyroid Imaging Reporting and Data System (TI-RADS) was established with reference to the American College of Radiology's Breast Imaging Reporting and Data System. RESULTS: Seven independent features associated with malignancy were a taller-than wide shape, an obscure border, an irregular margin, solid internal content, marked hypoechogenicity and hypoechogenicity, microcalcifications, and an internal vascularization distribution. The TI-RADS included 5 categories with different malignancy rates: category 3 (<2%), 4A (2%-5%), 4B (5%-50%), 4C (50% 90%), and 5 (>= 90%). CONCLUSIONS: A modified version of TI-RADS was established on the basis of the sonographic features with different weightings according to the relative risk of malignancy. This system could be of great use in predicting the nature of thyroid nodules in a quantified and standardized way and also helping clinicians decide on the clinical management. PMID- 26507700 TI - Particularly strong C-H...pi interactions between benzene and all-cis 1,2,3,4,5,6 hexafluorocyclohexane. AB - We present the first high-level ab initio benchmark study of the interaction energy between fluorocyclohexanes and benzene. These compounds form CH...pi interactions with aromatic solvents which causes notable shielding of the axial cyclohexane protons. For the recently synthesised all-cis 1,2,3,4,5,6 hexafluorocyclohexane the interaction energy with benzene amounts to -7.9 kcal mol(-1) and -6.4 kcal mol(-1) at the MP2 and SCS-MP2 levels, respectively (extrapolated to the complete basis set limit), which according to dispersion corrected density functional calculations, is largely due to dispersion. PMID- 26507701 TI - Comment on: 'Ultra-processed foods have the worst nutrient profile, yet they are the most available packaged products in a sample of New Zealand supermarkets' by Luiten et al. PMID- 26507702 TI - Kinetic investigations of quinoline oxidation by ferrate(VI). AB - Quinoline is considered as one of the most toxic and carcinogenic compounds and is commonly found in industrial wastewaters, which require treatment before being discharged. Removal of quinoline by the use of an environmentally friendly oxidant, potassium ferrate(VI) (K2FeO4), was assessed by studying the kinetics of the oxidation of quinoline by ferrate(VI) (Fe(VI)) as a function of pH (8.53 10.53) and temperature (21-36 degrees C) in this work. The reaction of quinoline with Fe(VI) was found to be first order in Fe(VI), half order in quinoline, and 1.5 order overall. The observed rate constant at 28 degrees C decreased non linearly from 0.5334 to 0.2365 M(-0.5) min(-1) with an increase in pH from 8.53 to 10.03. Considering the equilibria of Fe(VI) and quinoline, the reaction between quinoline and Fe(VI) contained two parallel reactions under the given pH conditions. The individual rate constants of these two reactions were determined. The results indicate that the protonated species of Fe(VI) reacts more quickly with quinoline than the deprotonated form of Fe(VI). The reaction activation energy Ea was obtained to be 51.44 kJ.mol(-1), and it was slightly lower than that of conventional chemical reaction. It reveals that the oxidation of quinoline by Fe(VI) is feasible in the routine water treatment. PMID- 26507703 TI - Immunoactivation induced by chronic viral infection inhibits viral replication and drives immunosuppression through sustained IFN-I responses. AB - Acute or chronic viral infections can lead to generalized immunosuppression. Several mechanisms, such as immunopathology of CD8(+) T cells, inhibitory receptors, or regulatory T (Treg) cells, contribute to immune dysfunction. Moreover, patients with chronic viral infections usually do not respond to vaccination, a finding that has not been previously explained. Recently, we reported that CD169(+) macrophages enforce viral replication, which is essential for guaranteeing antigen synthesis and efficient adaptive immune responses. In the present study, we used a chronic lymphocytic choriomeningitis virus infection mouse model to determine whether this mechanism is affected by chronic viral infection, which may impair the activation of adaptive immunity. We found that enforced viral replication of a superinfecting virus is completely blunted in chronically infected mice. This absence of enforced viral replication in CD169(+) macrophages is not explained by CD8(+) T-cell-mediated immunopathology but rather by prolonged IFN-I responses. Consequently, the absence of viral replication impairs both antigen production and the adaptive immune response against the superinfecting virus. These findings indicate that chronic infection leads to sustained IFN-I action, which is responsible for the absence of an antiviral immune response against a secondary viral infection. PMID- 26507704 TI - Role of biochemical markers in the management of osteoporosis. AB - Estrogen and bone health form a cornerstone of osteoporosis management. Diagnosis of osteoporosis is performed using bone mineral density (BMD), despite the limitations associated with this. Within the last 25 years, numerous bone turnover markers (BTM) have been developed, and this has led to a marked improvement in drug development for osteoporosis and understanding of fast bone losers. Estrogen research has provided landmark research on understanding the relationship between osteoporosis and BTMs. Clinical studies have illustrated how measurement of BTMs can assist in prediction of rapid bone loss, future fractures and, most importantly, the fracture efficacy of drugs. The BTMs provide information independent of BMD and fracture history. In addition, changes in bone turnover within 1 month predict later changes in BMD, which allows for early efficacy and prognostic measures. The aim is to provide a careful review of the possibilities that implementation of BTMs into clinical practice have provided, while placed in a historical context. The primary focus is on how the BTMs have revolutionized clinical trials on osteoporosis drugs through their ability to supplement bone mass measurements and fracture efficacy endpoints. PMID- 26507705 TI - Coil compression in simultaneous multislice functional MRI with concentric ring slice-GRAPPA and SENSE. AB - PURPOSE: Simultaneous multislice (SMS) imaging is a useful way to accelerate functional magnetic resonance imaging (fMRI). As acceleration becomes more aggressive, an increasingly larger number of receive coils are required to separate the slices, which significantly increases the computational burden. We propose a coil compression method that works with concentric ring non-Cartesian SMS imaging and should work with Cartesian SMS as well. We evaluate the method on fMRI scans of several subjects and compare it to standard coil compression methods. METHODS: The proposed method uses a slice-separation k-space kernel to simultaneously compress coil data into a set of virtual coils. Five subjects were scanned using both non-SMS fMRI and SMS fMRI with three simultaneous slices. The SMS fMRI scans were processed using the proposed method, along with other conventional methods. Code is available at https://github.com/alcu/sms. RESULTS: The proposed method maintained functional activation with a fewer number of virtual coils than standard SMS coil compression methods. Compression of non-SMS fMRI maintained activation with a slightly lower number of virtual coils than the proposed method, but does not have the acceleration advantages of SMS fMRI. CONCLUSION: The proposed method is a practical way to compress and reconstruct concentric ring SMS data and improves the preservation of functional activation over standard coil compression methods in fMRI. Magn Reson Med 76:1196-1209, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26507706 TI - Ureteral Avulsion Associated with Ureteroscopy: Insights from the MAUDE Database. AB - BACKGROUND: Flexible and semirigid ureteroscopy (URS) are widely performed for the treatment of upper tract calculi and tumors. Ureteral avulsion is a rare, but devastating complication of endoscopic stone removal having multiple possible etiologies. Awareness and avoidance of this rare complication depend on identifying responsible mechanisms. This study examines the situations in which ureteral avulsion occurs as described anonymously in the Manufacturer and User facility Device Experience (MAUDE) database. MATERIALS AND METHODS: The MAUDE database was systematically reviewed to account for all reported complications of flexible and semirigid URS. Keywords "ureteroscopy, injury, death, malfunction and other" were entered in the database and medical device reports were reviewed to capture any cases resulting in ureteral avulsion. Attention was paid to the type of ureteroscope involved and the mechanism for avulsion. RESULTS: A total of 104 entries were found detailing the reported complications of flexible and semirigid URS. Ureteral avulsion was clearly noted in six reports with flexible (2) and semirigid ureteroscopes (4). Potential mechanisms included locked deflection of a flexible ureteroscope (1), bunching of the distal bending rubber in a flexible ureteroscope (1), scabbard avulsion (3), and stone basketing (1). CONCLUSIONS: Although the incidence of ureteral avulsion cannot truly be determined from this study, some potentially novel mechanisms for this rare complication are observed. This may target future educational efforts to maximize awareness and avoidance of this complication. PMID- 26507707 TI - Multicolor flow-cytometric analysis of milk allergen-specific T-helper type 2 cells revealed coexpression of interleukin-4 with Foxp3. AB - BACKGROUND: Allergen-specific T-helper type 2 (TH2) cells play an important role in the development of allergic inflammation; however, investigations of the properties of allergen-specific T cells have been challenging in humans. Despite clear evidence that forkhead box p3 (Foxp3) is expressed in conventional effector T cells, its function has remained unknown. OBJECTIVE: To characterize allergen specific TH2 cells in milk allergy, with particular focus on the expression of Foxp3. METHODS: Twenty-one children with milk allergy and 11 children without milk allergy were studied. Peripheral blood mononuclear cells from subjects were stimulated with milk allergen for 6 hours and analyzed using multicolor flow cytometry to identify CD154(+) allergen-specific T-helper cells. Simultaneously, the expression of intracellular cytokines and Foxp3 was analyzed. RESULTS: The milk allergy group had significantly larger numbers of milk allergen-specific interleukin (IL)-4- and IL-5-producing CD4(+) T cells than the control group. Subjects in the milk allergy group had significantly more CD154(+)CD4(+) IL-10 producing cells and CD154(+)Foxp3(+)CD4(+) cells than those in the control group. In addition, the number of milk allergen-specific CD154(+)Foxp3(+)CD4(+) cells strongly correlated with that of CD154(+)IL4(+)CD4(+) cells. Bcl-2 expression in CD154(+)IL-4(+)Foxp3(+) T-helper cells was significantly lower compared with that in total CD4 cells. CONCLUSION: Increased numbers of IL-4-producing allergen specific T-helper cells were found in patients with milk allergy. In addition, Foxp3 was coexpressed with IL-4 in allergen-specific TH2 cells from patients. This coexpression was associated with lower Bcl-2 levels and could contribute to the phenotype and function of TH2 cells. PMID- 26507708 TI - Short ragweeds is highly cross-reactive with other ragweeds. AB - BACKGROUND: The most widespread ragweed (Ambrosia) species in North America are short ragweed (Ambrosia artemisiifolia; Amb a), giant ragweed (Ambrosia trifida; Amb t), and western ragweed (Ambrosia psilostachya; Amb p). Varied geographic distributions of ragweed species raise questions regarding the need for ragweed species-specific allergen immunotherapy. OBJECTIVE: To determine allergenic cross reactivity among ragweed species by immunologic analyses of sera from subjects allergic to ragweed from North America and Europe. METHODS: Sera were collected from 452 subjects allergic to ragweed who participated in Amb a sublingual immunotherapy tablet clinical trials. All subjects had positive skin prick test and serum IgE against Amb a. Ragweed-specific IgE (pre treatment) and IgG4 (post treatment) were measured by ImmunoCAP. IgE inhibition studies among Amb a, Amb t, and Amb p were conducted. Using pooled sera from another ragweed-allergic population, IgE inhibition studies of 7 less widespread Ambrosia species also were conducted. RESULTS: A strong correlation between Amb a vs Amb p and Amb t serum IgE levels was observed. In the vast majority of pretreatment sera, Amb a inhibited Amb a, Amb p, and Amb t IgE reactivity by more than 90%. Strong correlations were observed between Amb a vs Amb p and Amb t post-treatment IgG4 levels. In pooled sera, Amb a extract inhibited the binding of serum IgE to all 10 ragweed species by 98%-100%. CONCLUSION: In a population of subjects allergic to Amb a, substantial allergenic cross-reactivity among Amb a, Amb p, and Amb t was demonstrated. These in vitro data suggest that an Amb a-based single-species ragweed allergen immunotherapy may be therapeutically active in patients exposed to diverse ragweed pollens. TRIAL REGISTRY: Clinicaltrials.gov, NCT00770315, NCT00783198, and NCT00330083. PMID- 26507709 TI - Timothy specific IgE levels are associated with efficacy and safety of timothy grass sublingual immunotherapy tablet. AB - BACKGROUND: Regional pollen allergen exposure differences may induce variable sensitization profiles that could affect allergen immunotherapy efficacy and safety. OBJECTIVE: To describe sensitization profiles against timothy grass allergen components (Phl p) in North American subjects screened for a timothy grass sublingual immunotherapy (SLIT) tablet trial and evaluate grass SLIT tablet efficacy and safety based on pretreatment Phl p IgE levels. METHODS: Serum specific IgE was measured post hoc by ImmunoCAP ISAC from subjects screened (N = 1,905) for study P08067 (NCT01385371) conducted in Canada and 5 US regions. Subjects exhibited positivity for timothy grass by skin prick testing and serum IgE. Average total combined symptom plus medication score during the entire pollen season and treatment-related adverse events (TRAEs) were determined in randomized subjects (n = 1,140) by pretreatment Phl p IgE levels (group 1, <=33rd percentile; group 2, >33rd-67th percentile; group 3, >67th percentile; or undetectable). RESULTS: Most screened subjects were sensitized to Phl p 1 (73%) and Phl p 5 (51%). The highest mean IgE levels and largest proportions of subjects with positive reactions for Phl p 1 and Phl p 5 were found in Canada and the western United States. Improvements in total combined symptom plus medication score vs placebo by Phl p 5 IgE groups 1 to 3 were 7.7%, 23.9%, and 35.4%, respectively, and 18.7% for subjects with undetectable Phl p 5 IgE. TRAE incidences with the grass SLIT tablet by Phl p 5 IgE groups 1 to 3 were 56.1%, 66.4%, and 74.5%, respectively, and 49.7% in subjects with undetectable Phl p 5 IgE. Similar, but less pronounced, trends for efficacy and TRAEs were observed for Phl p 1 and Phl p 6 IgE. CONCLUSION: Sensitization profiles varied by region. Trends toward higher efficacy and increased TRAE incidence in subjects with higher pretreatment Phl p IgE levels were observed. TRIAL REGISTRY: www.clinicaltrials.gov, identifier NCT01385371. PMID- 26507710 TI - Are fish tropomyosins allergens? PMID- 26507711 TI - High rate of failure to thrive in a pediatric cohort with eosinophilic esophagitis. PMID- 26507712 TI - Ndrg1 is a T-cell clonal anergy factor negatively regulated by CD28 costimulation and interleukin-2. AB - Induction of T-cell clonal anergy involves serial activation of transcription factors, including NFAT and Egr2/3. However, downstream effector mechanisms of these transcription factors are not fully understood yet. Here we identify Ndrg1 as an anergy factor induced by Egr2. Ndrg1 is upregulated by anergic signalling and maintained at high levels in resting anergic T cells. Overexpression of Ndrg1 mimics the anergic state and knockout of the gene prevents anergy induction. Interestingly, Ndrg1 is phosphorylated and degraded by CD28 signalling in a proteasome-dependent manner, explaining the costimulation dependence of anergy prevention. Similarly, IL-2 treatment of anergic T cells, under conditions that lead to the reversal of anergy, also induces Ndrg1 phosphorylation and degradation. Finally, older Ndrg1-deficient mice show T-cell hyperresponsiveness and Ndrg1-deficient T cells aggravate inducible autoimmune inflammation. Thus, Ndrg1 contributes to the maintenance of clonal anergy and inhibition of T-cell mediated inflammation. PMID- 26507713 TI - [Submental artery island flaps for reconstruction in the head and neck region]. AB - BACKGROUND: Reconstruction of defects after extirpation of head and neck neoplasms is a highly challenging and complex surgical undertaking. Commonly used techniques, such as the radial forearm flap or anterior lateral thigh flap, have numerous disadvantages, e.g., donor-site morbidity, poor color match for cutaneous reconstruction, and excessive tissue bulk for intraoral reconstruction. Use of a submental artery island flap is a relatively new and increasingly performed option for reconstruction in the head and neck region. MATERIALS AND METHODS: From March 2013 to August 2015, 12 patients were treated with a submental island flap after surgical resection of intraoral carcinomas or cutaneous neoplasms of the lower half of the face. CASE DESCRIPTION: This paper reports on two cases. The first case describes reconstruction of the floor of the mouth using a pull-through technique after resection of a squamous cell carcinoma. The submental flap was pedicled on the contralateral side, since neck dissection of regions I-V had been performed on the ipsilateral side. The second case is a reconstruction of the lower midface with parts of the upper lip, after removal of a cutaneous spinalioma. In a N0 neck, no neck dissection was performed. The flap healed without problems in both patients, leading to a very good functional and cosmetic outcome. CONCLUSION: The submental island flap demonstrates reliability and versatility for head and neck reconstructions. Its minimal donor site morbidity, excellent cosmetic match, pliability, and relative ease of dissection and application confer a definite advantage over distant flaps. PMID- 26507714 TI - [HPV infection in oral, pharyngeal and laryngeal papillomas]. AB - BACKGROUND: HPV infections play a major role in the pathogenesis of squamous cell carcinomas of the head and neck. Regarding benign papillomas, the role of HPV is still uncertain. MATERIALS AND METHODS: To clarify this issue, 100 exophytic papillomas of the oral cavity, pharynx and larynx were subjected to histopathological and molecular pathological examination. Excision biopsies were taken from 62 male and 38 female patients with an age range of 18 to 87 years. Biopsies were tested for p16 expression by immunohistochemistry and analyzed for HPV subtypes 6/11 (low-risk), 16/18 and 31/33/53 (high-risk) by chromogenic in situ hybridization. RESULTS: HPV infections were verified molecularly in 34 % of biopsies; in all cases with the low-risk HPV subtypes 6/11. Only one case showed infection with both 6/11 and 31/33/53 subtypes, but not subtype 16/18; whereas expression of p16 was found in 67 %. The rate of positive molecular verification of HPV infection (in situ hybridization) was highest in the laryngeal lesions with 61.1 %, followed by the oral cavity with 52.9 %, and lowest in pharyngeal lesions (21.5 %). Recurrent papillomas were seen in 18 cases (18 %), of which 14 were molecularly positive for HPV (in situ hybridization). A correlation between inflammatory infiltration and HPV infection could be verified in 82 %. CONCLUSION: Our data demonstrate an important role of HPV infection for the development of benign papillomas of the head and neck region. Furthermore, there is a positive correlation between HPV infection and recurrent papillomas. Therefore, a molecular morphological HPV analysis of papillomas could provide important prognostic data. PMID- 26507715 TI - [HPV-associated head and neck cancer : mutational signature and genomic aberrations]. AB - A significantly increasing proportion of oropharyngeal head and neck carcinomas (OSCC) in North America and Europe are associated with human papillomavirus (HPV) infections. HPV-related OSCC is regarded as a distinct tumor type with regard to its cellular, biologic, and clinical characteristics. Patients with HPV-related OSCC have significantly better local control, but higher rates of regional lymph node and distant metastases as compared to patients with HPV-negative OSCC. Classical molecular genetic investigations demonstrated specific chromosomal aberration signatures in HPV-related OSCC, and recent developments in next generation sequencing (NGS) technology have rendered possible the sequencing of entire genomes, and thus detection of specific mutations, in just a few days. Initial data from The Cancer Genome Atlas (TCGA) project obtained by using genome wide high throughput methods have confirmed that HPV-related OSCC contain fewer, albeit more specific mutations than HPV-negative tumors. Additionally, these data revealed the presence of specific-potentially therapeutically targetable activating driver mutations in subgroups of HPV-positive OSCC, some of which have a prognostic impact. Specific targeted NGS technologies provide new possibilities for identification of diagnostic, prognostic, and predictive biomarkers and the development of personalized cancer treatment. Patients with HPV-positive tumors are likely to profit from these developments in the future, since the genetic alterations are relatively homogenous and frequently lead to signal pathway activation. There is an urgent need for network research activities to carry out the necessary basic research in prospective cohort studies. PMID- 26507716 TI - Whiteboard animation for knowledge mobilization: a test case from the Slave River and Delta, Canada. AB - OBJECTIVE: To present the co-creation of a whiteboard animation video, an enhanced e-storytelling technique for relaying traditional knowledge interview results as narratives. DESIGN: We present a design for translating interview results into a script and accompanying series of figures, followed by technical steps to create a whiteboard animation product. METHOD: Our project used content analysis and researcher triangulation, followed by a collaborative process to develop an animated video to disseminate research findings. A 13-minute long whiteboard animation video was produced from a research study about changing environments in northern Canadian communities and was distributed to local people. Three challenging issues in the video creation process including communication issues, technical difficulties and contextual debate were resolved among the supporting agencies and researchers. CONCLUSIONS: Dissemination of findings is a crucial step in the research process. Whiteboard animation video products may be a viable and culturally-appropriate form of relaying research results back to Indigenous communities in a storytelling format. PMID- 26507717 TI - Primary health care accessibility challenges in remote indigenous communities in Canada's North. AB - BACKGROUND: Despite many improvements, health disparities between indigenous and non-indigenous populations in Canada's North persist. While a strong primary health care (PHC) system improves the health of a population, the majority of indigenous communities are very remote, and their access to PHC services is likely reduced. Understanding the challenges in accessing PHC services in these communities is necessary to improve the health of the population. OBJECTIVE: The objective of the study was to document and analyze the challenges in accessing PHC services by indigenous people in remote communities in Canada's Northwest Territories (NWT) from the perspectives of users and providers of PHC services. METHODS: Using explorative, qualitative methods, our study involved 14 semi structured interviews with PHC service providers (SPs) and service users (SUs) in 5 communities across the NWT which varied according to population, remoteness, ethnic composition and health care resources. The interview guide was developed after key informant consultations. RESULTS: Both SPs and SUs understood the constraints in providing equitable access to PHC services in remote communities. The provision of emergency care was found to be particularly challenging, because of the lack of qualified staff in the community and the dependence on aeromedical evacuations. Wider dissemination of first aid skills among community members was seen to cover some gaps and also increase self-confidence. For non-emergency care, the need to travel outside the community was generally disliked. All recognized the need for more preventive services which were often postponed or delayed because of the overwhelming demand for acute care. As long as services were provided in a community, the satisfaction was high among SUs. SPs appreciated the orientation they received and the ability to build rapport with the community. CONCLUSIONS: Northern SUs and SPs generally acknowledge the health consequences of living in remote communities. The generally high level of satisfaction attests to the overall effectiveness of PHC in the region despite geographical remoteness. Many improvements could be made in terms of upgrading the clinical skills of SPs and community members, improving staff retention, extending the frequency and duration of community visits and providing more attention to preventive services. PMID- 26507718 TI - SOFIE: Surgery for Olecranon Fractures in the Elderly: a randomised controlled trial of operative versus non-operative treatment. AB - BACKGROUND: Displaced olecranon fractures after a simple fall are common in elderly patients. This patient group often has multiple medical co-morbidities and low functional demands. Standard treatment for these fractures has been operative fixation, using either wires or a plate. Recent case series suggest that such injuries can be managed without surgery with good functional outcomes. There has been no published trial comparing operative to non-operative treatment for displaced olecranon fractures. This project aims to test for superiority of operative treatment versus non-operative treatment for displaced olecranon fractures in the elderly, by comparing pain and function in the affected limb up to one year after the injury. METHODS/DESIGN: SOFIE is an international study with a multicentre pragmatic randomised controlled trial design. The primary objective of the study is to compare a patient related outcome, the Disability of the Arm Shoulder and Hand (DASH) Score, between patients treated operatively and non-operatively at twelve months. Patients will be considered for the study if they are 75 years of age or older, medically fit for surgery, have an isolated displaced olecranon fracture, and present within 14 days of injury. Eligible patients willing to participate will be randomised either to operative fixation, with surgery using the preferred technique of the treating orthopaedic surgeon (tension band wiring or plate fixation), or to non-operative treatment involving early range of motion as tolerated. Secondary outcome measures will include pain, active range of motion, elbow extension strength, and any adverse events (infection, secondary interventions) at 3 and 12 months. DISCUSSION: The study will answer an important clinical question about the effectiveness of a commonly performed orthopaedic procedure, and will guide future treatment for displaced olecranon fractures in the elderly. TRIAL REGISTRATION NUMBER: World Health Organisation Universal Trial Number (WHO UTN) - U111111574090 . Australian and New Zealand Clinical Trials Registry (ANZCTR) - ACTRN12614000588695 . PMID- 26507719 TI - Expression of CD147 and matrix metalloproteinase-11 in colorectal cancer and their relationship to clinicopathological features. AB - BACKGROUND: This study aimed to investigate the expression of CD147 and MMP-11 in human colorectal cancer (CRC) and to evaluate their clinical significance. METHODS: Real-time polymerase chain reaction was used to evaluate CD147 and MMP 11 mRNA level in 56 pairs of fresh CRC samples matched with adjacent normal mucosa. The protein expression of CD147 and MMP-11 in CRC specimens and corresponding normal colorectal mucosa were evaluated by immunohistochemistry on CRC tissue microarrays. Expression and co-localization of these two proteins in human colorectal cancer tissue were also evaluated by laser scanning confocal microscopy. Furthermore, their correlations with clinicopathological factors and overall survival after surgery were evaluated. RESULTS: Both CD147 and MMP-11 were demonstrated to be over-expressed at mRNA level (P < 0.001, both) and protein level (P < 0.001, both) in CRC tissue than paired normal mucosa. Spearman rank test showed a positive correlation between these two proteins (P = 0.025). Immunofluorescence double staining confirmed the co-localization of CD147 and MMP 11 in paraffin-embedded tissues of CRC patients. Expression of CD147 and MMP-11 were both correlated with CRC lymph node metastasis (P = 0.021 and P = 0.031, respectively), distant metastasis (P < 0.001 and P = 0.013, respectively) and TNM stage (P = 0.006 and P = 0.049, respectively). Univariate survival analysis showed that both CD147 and MMP11 expression was significantly associated with shorter survival time (P = 0.001 and P = 0.009, respectively). Additionally, in multivariate analysis, both CD147 and MMP-11 were proved to be independent prognostic factors (P = 0.009, 0.028, respectively). CONCLUSIONS: These results indicated that both CD147 and MMP-11 may be involved in the progression of colorectal cancer, and they are potential prognostic factors and might become new therapeutic targets for CRC patients. PMID- 26507720 TI - Pharmacokinetics of the Soluble Guanylate Cyclase Stimulator Riociguat in Healthy Young Chinese Male Non-Smokers and Smokers: Results of a Randomized, Double Blind, Placebo-Controlled Study. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the pharmacokinetics, safety, and tolerability of riociguat after single and multiple oral doses of 1 or 2 mg three times daily (tid), and to determine the effect of smoking on riociguat pharmacokinetics in Chinese men. METHODS: In a randomized, double-blind, placebo-controlled, single-center study stratified for smokers and non-smokers, healthy Chinese men aged 18-45 years received two riociguat doses: Dose Step 1 (1 mg) then Dose Step 2 (2 mg) conducted after the safety and tolerability at Dose Step 1 was confirmed. For each step, 12 subjects received riociguat and six received placebo. A single dose was given on Day 1, followed by a 48-h pharmacokinetic profile. Multiple-dose treatment tid was then given for 6 days (Days 3-8), with a last single dose on Day 9, followed by a 72-h pharmacokinetic profile. Primary outcomes were pharmacokinetic parameters for riociguat after single and multiple dosing. RESULTS: Thirty-six subjects (18 smokers; 18 non-smokers) were randomized and provided valid pharmacokinetic data. Riociguat and its pharmacologically active metabolite M1 (BAY 60-4552) showed nearly dose-proportional pharmacokinetics. Accumulation was minimal in smokers and approximately two-fold in non-smokers. Exposure for riociguat was decreased by >=60% in smokers. No serious or significant adverse events occurred during the study. CONCLUSIONS: Riociguat pharmacokinetics showed dose proportionality in healthy Chinese men, as previously demonstrated in healthy white male individuals. Exposure to riociguat was substantially decreased in smokers compared with non-smokers. Riociguat was well tolerated in Chinese men. PMID- 26507721 TI - Clinical Pharmacokinetics of Dulaglutide in Patients with Type 2 Diabetes: Analyses of Data from Clinical Trials. AB - BACKGROUND AND OBJECTIVE: Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist administered as once-weekly subcutaneous injections for the treatment of type 2 diabetes (T2D). The clinical pharmacokinetics of dulaglutide were characterized in patients with T2D and healthy subjects. METHODS: The pharmacokinetics of dulaglutide were assessed throughout clinical development, including conventional pharmacokinetic analysis in clinical pharmacology studies and population pharmacokinetic analyses of data from combined phase 2 and phase 3 studies in patients with T2D. The effects of potential covariates on dulaglutide population pharmacokinetics were evaluated using nonlinear mixed-effects models. RESULTS: Dulaglutide gradually reached the maximum concentration in 48 h and had a terminal elimination half-life of 5 days. Steady state was achieved between the second and fourth doses. The accumulation ratio was 1.56 for the 1.5 mg dose. Intra-individual variability estimates for the area under the plasma concentration-time curve and the maximum concentration were both <17% [coefficient of variation (CV)]. There was no difference in pharmacokinetics between injection sites (arm, thigh or abdomen). Dulaglutide pharmacokinetics were well described by a two-compartment model with first-order absorption and elimination. The population clearance was estimated at 0.126 L/h [inter individual variability (CV) 33.8%]. Age, body weight, sex, race and ethnicity did not influence dulaglutide pharmacokinetics to any clinically relevant degree. CONCLUSION: The pharmacokinetics of dulaglutide support once-weekly administration in patients with T2D. The pharmacokinetic findings suggest that dose adjustment is not necessary on the basis of body weight, sex, age, race or ethnicity or site of injection. PMID- 26507722 TI - Effects of Age, Sex, and Race on the Safety and Pharmacokinetics of Single and Multiple Doses of Azilsartan Medoxomil in Healthy Subjects. AB - BACKGROUND AND OBJECTIVE: Azilsartan medoxomil (AZL-M) is an angiotensin II receptor blocker approved to treat hypertension. After oral dosing, AZL-M is quickly hydrolyzed to azilsartan (AZL). The aims of this study were to assess the effects of age, sex, and race on the pharmacokinetics of AZL-M in healthy subjects, as well as safety and tolerability. METHODS: Sixty-one healthy adults were enrolled in this phase I, single-blind, randomized placebo-controlled study (placebo control was for assessment of safety/tolerability only). Subjects were stratified by age (18-45 vs. 65-85 years), sex, and race (black vs. white) and given oral AZL-M 60 mg (3 * 20 mg capsules) or placebo as a single dose (Day 1) and consecutive daily doses (Days 4-8) (6:2 ratio for AZL-M:placebo per group). Pharmacokinetics were evaluated (AZL-M patients only) on Days 1-3 and 8-9 and safety/tolerability was monitored. RESULTS: Age, sex, and race had no clinically meaningful effect on AZL exposures after single or multiple dosing. Pharmacokinetic parameters remained similar between Days 1 and 8 for each age, sex, and race subgroup. The frequency of adverse events was similar for AZL-M (32%) and placebo (29%). No discontinuations or serious adverse events occurred. CONCLUSIONS: Based on these pharmacokinetic and safety/tolerability findings, no AZL-M dose adjustments are required based on age, sex, or race (black/white). PMID- 26507723 TI - The Effect of Nizatidine, a MATE2K Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Volunteers. AB - BACKGROUND AND OBJECTIVES: In the proximal tubule, basic drugs are transported from the renal cells to the tubule lumen through the concerted action of the H(+)/organic cation antiporters, multidrug and toxin extrusion (MATE) 1 and MATE2K. Dual inhibitors of the MATE transporters have been shown to have a clinically relevant effect on the pharmacokinetics of concomitantly administered basic drugs. However, the clinical impact of selective renal organic cation transport inhibition on the pharmacokinetics and pharmacodynamics of basic drugs, such as metformin, is unknown. This study sought to identify a selective MATE2K inhibitor in vitro and to determine its clinical impact on the pharmacokinetics and pharmacodynamics of metformin in healthy subjects. METHODS: Strategic cell based screening of 71 US Food and Drug Administration (FDA)-approved medications was conducted to identify selective inhibitors of renal organic cation transporters that are capable of inhibiting at clinically relevant concentrations. From this screen, nizatidine was identified and predicted to be a clinically potent and selective inhibitor of MATE2K-mediated transport. The effect of nizatidine on the pharmacokinetics and pharmacodynamics of metformin was evaluated in 12 healthy volunteers in an open-label, randomized, two-phase crossover drug-drug interaction (DDI) study. RESULTS: In healthy volunteers, the MATE2K-selective inhibitor nizatidine significantly increased the apparent volume of distribution, half-life, and hypoglycemic activity of metformin. However, despite achieving unbound maximum concentrations greater than the in vitro inhibition potency (concentration of drug producing 50% inhibition [IC50]) of MATE2K-mediated transport, nizatidine did not affect the renal clearance (CLR) or net secretory clearance of metformin. CONCLUSION: This study demonstrates that a selective inhibition of MATE2K by nizatidine affected the apparent volume of distribution, tissue concentrations, and peripheral effects of metformin. However, nizatidine did not alter systemic concentrations or the CLR of metformin, suggesting that specific MATE2K inhibition may not be sufficient to cause renal DDIs with metformin. PMID- 26507724 TI - Characteristics of ammonia, acid gases, and PM2.5 for three typical land-use types in the North China Plain. AB - Air pollution is one of the most serious environmental problems in China due to its rapid economic development alongside a very large consumption of fossil fuel, particularly in the North China Plain (NCP). During the period 2011-2014, we integrated active and passive sampling methods to perform continuous measurements of NH3, HNO3, NO2, and PM2.5 at two urban, one suburban, and two rural sites in the NCP. The annual average concentrations of NH3, NO2, and HNO3 across the five sites were in the ranges 8.5-23.0, 22.2-50.5, and 5.5-9.7 MUg m(-3), respectively, showing no significant spatial differences for NH3 and HNO3 but significantly higher NO2 concentration at the urban sites. At each site, annual average concentrations of NH3 and NO2 showed increasing and decreasing trends, respectively, while there was no obvious trend in annual HNO3 concentrations. Daily PM2.5 concentrations ranged from 11.8 to 621.0 MUg m(-3) at the urban site, from 19.8 to 692.9 MUg m(-3) at the suburban site, and from 23.9 to 754.5 MUg m( 3) at the two rural sites, with more than 70% of sampling days exceeding 75 MUg m(-3). Concentrations of water-soluble ions in PM2.5 ranked differently between the non-rural and rural sites. The three dominant ions were NH4(+), NO3(-), and SO4(2-) and mainly existed as (NH4)2SO4, NH4HSO4, and NH4NO3, and their concentrations averaged 48.6 +/- 44.9, 41.2 +/- 40.8, and 49.6 +/- 35.9 MUg m(-3) at the urban, suburban, and rural sites, respectively. Ion balance calculations indicated that PM2.5 was neutral at the non-rural sites but acidic at the rural sites. Seasonal variations of the gases and aerosols exhibited different patterns, depending on source emission strength and meteorological conditions. Our results suggest that a feasible pathway to control PM2.5 pollution in the NCP should target ammonia and acid gases together. PMID- 26507725 TI - Geochemical background and ecological risk of heavy metals in surface sediments from the west Zhoushan Fishing Ground of East China Sea. AB - Surface sediment grain size as well as the spatial distribution, pollution status, and source identification of heavy metals in the west Zhoushan Fishing Ground (ZFG) of the East China Sea were analyzed to study the geochemical background concentrations of heavy metals and to assess their potential ecological risk. Our results show that surface sediments in the eastern part of study area were mainly composed of sand-sized components. Spatial distributions of heavy metals were mainly controlled by grain size and terrigenous materials, and their concentrations in the coarsest grain sediments formed primarily during the Holocene transgressive period could represent the element background values of our study area. Contamination factor suggests that there was no pollution of Pb, Zn, and Cr generally in our study area and slight pollution of Cu, Cd, and As (especially Cu) at some stations. In addition, ecological harm coefficient indicates that the ecological risk of each heavy metal, except for Cd, at two stations was low as well. These results are consistent with the pollution load index and ecological risk index, which suggest both the overall level of pollution and the overall ecological risk of six studied metals in sediment were relatively low in our study area. Enrichment factor indicates that the heavy metals came mostly from the natural source. Summarily, the quality level of sediment in our study area was relatively good, and heavy metals in sediments could not exert threat to aquatic lives in the ZFG until now. PMID- 26507726 TI - Enrofloxacin degradation in broiler chicken manure under various laboratory conditions. AB - The rate of degradation of enrofloxacin in broiler chicken manure has been characterized in the laboratory according to the CVMP guideline on determining the fate of veterinary medicinal products in manure. Degradation was followed in a flow-through system under aerobic and anaerobic conditions, in the dark and in the presence of light. The rate of degradation of enrofloxacin and the formation of its degradation products are dependent on laboratory conditions. A rapid degradation of enrofloxacin in the dark was noticed, where a shorter degradation half-life under aerobic (DT50 = 59.1 days), comparing to anaerobic conditions (DT50 = 88.9 days), was determined. The presence of light slowed down the enrofloxacin degradation half-life, which was significantly shorter under aerobic (DT50 = 115.0 days), comparing to anaerobic conditions (DT50 = 190.8 days). Desethylene-enrofoxacin was the only degradation product formed, its concentrations ranged from 2.5 to 14.9 %. The concentration of the degradation product was approximately 2.5-fold higher under aerobic conditions. Enrofloxacin degradation in sterile manure incubated under sterile conditions was marginal comparing to non-sterile conditions; after 120 days of incubation, approximately 80 % of enrofloxacin was still present in manure and only 1 % of desethylene enrofloxacin was formed. The present work demonstrates that enrofloxacin degradation in chicken manure is relatively fast when incubated in the dark under aerobic conditions which is the recommended incubation system for chicken manure according to CVMP guideline. PMID- 26507727 TI - Degradation of artificial sweetener saccharin in aqueous medium by electrochemically generated hydroxyl radicals. AB - The removal of artificial sweetener saccharin (SAC) in aqueous solution by electrochemical advanced oxidation using electro-Fenton process was performed. Experiments were carried out in an undivided cylindrical glass cell with a carbon felt cathode and a Pt or boron-doped diamond (BDD) anode. The removal of SAC by electrochemically generated hydroxyl radicals followed pseudo-first-order kinetics with both Pt and BDD anode. The absolute rate constant of the SAC hydroxylation reaction was determined for the first time using the competition kinetic method and found to be (1.85 +/- 0.01) * 10(9) M(-1) s(-1). The comparative study of TOC removal efficiency during electro-Fenton treatment indicated a higher mineralization rate with BDD than Pt anode. The identification and evolution of short-chain carboxylic acids and inorganic ions formed during oxidation process were monitored by ion-exchange chromatography and ion chromatography, respectively. The assessment of toxicity of SAC and/or its reaction by-products during treatment was performed using Microtox(r) method based on the Vibrio fischeri bacteria luminescence inhibition. Results showed that the process was able to efficiently detoxify the treated solution. PMID- 26507728 TI - Sources appointment and ecological risk assessment of polycyclic aromatic hydrocarbons (PAHs) in sediments of Erhai Lake, a low-latitude and high-altitude lake in southwest China. AB - Sixteen polycyclic aromatic hydrocarbons (PAHs) were analyzed from the surficial sediments in Erhai Lake, a plateau lake in China. The results showed that except for acenaphthylene (Ace) Ace and Dibenz(a,h)anthracene (DBA), the central region contained individual PAHs at concentrations lower than those in other lake regions. Total concentration of the PAHs (SigmaPAHs) in the sediments from Erhai Lake ranged from 32.42 to 558.53 mg/kg with a mean value of 256.70 mg/kg. The maximum value of SigmaPAHs was observed in the north region of the lake and more than 10-fold higher than the minimum values. Moreover, high molecular weight (HMW) PAHs, especially 5-ring PAHs, accounted for higher ratios up to 76 % relative to other PAHs compound in almost all sampling sites. Molecular diagnostic ratios including anthtacene (Ant)/(Ant + phenanthrene (Phe)), fluoranthene (Flt)/(Flt + pyrene (Pyr)), benz(a)anthracene (BaA)/(BaA + chrysene (Chr)), and indeno(1,2,3-cd)pyrene (IPY)/(IPY + benz(g,h,i)perylene (BPE)) were recorded at all sampling sites and indicated that the origin of PAHs in Erhai Lake was predominately pyrolytic. Furthermore, principal component analysis with component dominating by HMW PAHs showed that combustion origins were the primary contamination sources of PAHs in the sediments of Erhai Lake. Finally, ecological risk assessment indicated that the sediments from Erhai Lake are exposed to potential low risk for SigmaPAHs, and the ecological risk decreases in the order of northern region > southern region > central region. PMID- 26507729 TI - The spatiotemporal distribution of dissolved carbon in the main stems and their tributaries along the lower reaches of Heilongjiang River Basin, Northeast China. AB - The Heilongjiang River Basin in the eastern Siberia, one of the largest river basins draining to the North Pacific Ocean, is a border river between China, Mongolia, and Russia. In this study, we examined the spatial and seasonal variability in dissolved organic carbon (DOC), dissolved inorganic carbon (DIC), and dissolved total carbon (DTC) concentrations along lower reaches of Heilongjiang River Basin, China. Water samples were collected monthly along the mouths of main rivers (Heilongjiang River, Wusuli River, and Songhua River) and their ten tributary waters for 2 years. The DOC concentrations of waters ranged from 1.74 to 16.64 mg/L, with a mean value of 8.90 +/- 0.27 mg/L (n = 165). Notably, mean DIC concentrations were 9.08 +/- 0.31 mg/L, accounting for 13.26~83.27% of DTC. DIC concentrations increased significantly after the Heilongjiang River passed through Northeast China, while DOC concentrations decreased. Over 50% of DIC concentrations were decreased during exports from groundwater to rice fields and from rice fields to ditches. Water dissolved carbon showed large spatial and temporal variations during the 2-year measurement, suggesting that more frequently samplings were required. Carbon (DIC + DOC) loads from the Heilongjiang River to the Sea of Okhotsk were estimated to be 3.26 Tg C/year in this study, accounting for 0.64% of the global water dissolved carbon flux. DIC export contributed an average of 51.84% of the estimated carbon load in the Heilongjiang River, acting as an important carbon component during riverine transport. Our study could provide some guides on agricultural water management and contribute to more accurately estimate global carbon budgets. PMID- 26507730 TI - Mercury toxicity to terrestrial snails in a partial life cycle experiment. AB - Despite growing concerns about the potential adverse effects of elevated mercury (Hg) concentrations in the terrestrial environment, only a few toxicity data are available for soil invertebrates. The chronic toxicity of inorganic Hg-Hg(II)- through food or soil contaminations was therefore assessed for the snail Cantareus aspersus, a well-recognized soil quality bioindicator. The 28-day EC50s (the concentrations causing 50% effect) for the snail growth were 600 and 5048 mg Hg kg(-1) for food and soil, respectively. A survey of growth over its entire duration (91 days) allowed to show that the effects took place rapidly after the beginning of exposure and persisted in the long term. Reproduction was also impaired, and we established 28-day EC50s for sexual maturation and fecundity of 831 and 339 mg Hg kg(-1), respectively, for food and 1719 and 53 mg Hg kg(-1), respectively, for soil. Total Hg analyses in snails exposed to contaminated matrices revealed important bioaccumulation capacities up to 2000 mg Hg kg(-1) viscera. Critical limits in internal Hg concentration of about 500 and 1000 mg Hg kg(-1) were determined as thresholds for the induction of growth toxicity through food and soil exposure, respectively. These different values underlined differences in the uptake and toxicological dynamics of Hg according to its bioavailability in the source of exposure. PMID- 26507731 TI - Molecular and cellular effects of contamination in aquatic ecosystems. PMID- 26507732 TI - Long-term use of biosolids as organic fertilizers in agricultural soils: potentially toxic elements occurrence and mobility. AB - The presence of potentially toxic elements (PTEs) may hinder a more widespread application of biosolids in agriculture. At present, the European Directive 86/278/CEE limit the total concentrations of seven metals (Cu, Cr, Ni, Pb, Zn, Cd and Hg) in agricultural soils and in sewage sludges used as fertilizers but it has not taken into consideration the potential impacts of other emerging micropollutants that may be present in the biosolids as well as their mobility. The aim of this study was to evaluate the accumulation and mobility of 13 elements (including regulated metals and other inorganic species) in agricultural soils repeatedly amended with biosolids for 15 years. Firstly, three digestions programs using different acid mixtures were tested to evaluate the most accurate and efficient method for analysis of soil and sludge. Results demonstrated that sewage sludge application increased concentrations of Pb and Hg in soil, but values did not exceed the quality standard established by legislation. In addition, other elements (As, Co, Sb, Ag, Se and Mn) that at present are not regulated by the Spanish and European directives were identified in the sewage sludge, and significant differences were found between Ag content in soils amended with biosolids in comparison with control soils. This fact can be related to the increasing use of silver nanoparticles in consumer products due to their antibacterial properties. Results from the leaching tests show up that, in general, the mobility degree for both regulated and non-regulated elements in soils amended with biosolids was quite low (<10 %). PMID- 26507733 TI - Toxic heavy metals in the muscle of roe deer (Capreolus capreolus)--food toxicological significance. AB - The study was performed on 20 (10 males, 10 females) roe deer (Capreolus capreolus) to investigate the concentration of cadmium, lead, mercury, and arsenic in the muscle tissue. They reside in forest and meadow, about 50 km distance from industrial activities and traffic. Samples were taken from the musculus biceps femoris of each deer without external contamination after shooting during the regular hunting season on a hunting area close to Eger in Hungary. The determination of heavy metal contents was carried out by inductively coupled plasma optical emission spectrometry (ICP-OES). The statistical analysis was performed by statistical package for the social sciences (SPSS) version 11.0. The measured residue concentration of cadmium was below the limit of detection in the roe deer meat indicating no health risk for the consumers. The average lead concentration (0.48 +/- 0.21 mg/kg wet weight) exceeded the regulated maximum limit, but its calculated weekly intake was below the provisional tolerable weekly intake (PTWI). The residue level of mercury is not regulated and the average mercury content of roe deer meat (0.87 +/- 0.40 mg/kg wet weight) was about half of PTWI, but the consumption of meat with the highest detected concentrations results in higher PTWI than recommended. The measured concentration of arsenic (0.27 +/- 0.20 mg/kg wet weight) in the roe deer meat may not pose any health risk for the human consumers according to the PTWI set by the World Health Organization. PMID- 26507734 TI - Endocrine-disrupting chemicals in coastal lagoons of the Po River delta: sediment contamination, bioaccumulation and effects on Manila clams. AB - The large estuary that the River Po forms at its confluence into the Adriatic Sea comprises a multitude of transitional environments, including coastal lagoons. This complex system receives the nutrients transported by the River Po but also its load of chemical contaminants, which may pose a substantial (eco)toxicological risk. Despite the high ecological and economic importance of these vulnerable environments, there is a substantial lack of information on this risk. In light of the recent amendments of the European Water Framework Directive (2013/39/EU), the present study investigated the sediment contamination of six coastal lagoons of the Po delta and its effects on Manila clams (Ruditapes philippinarum), exposed in situ for 3 months. Sediment contamination and clam bioaccumulation of a wide range of chemicals, i.e. trace metals (Cd, Cr, Ni, Hg, Pb, As), polybrominated diphenyl ethers (PBDEs), alkylphenols (APs), organochlorine compounds (PCBs, DDTs), polycyclic aromatic hydrocarbons (PAHs) and organotins (TPhT, TBT), suggested a southward increase related to the riverine transports. Where the River Po influence was more direct, the concentrations of contaminants were higher, with nonylphenol and BDE-209 exceeding sediment quality guidelines. Biometric indicators suggested the influence of contamination on organism health; an inverse relationship between PBDEs in sediments and clam condition index has been found, as well as different biota-sediment accumulation factors (BSAFs) in the lagoons. PMID- 26507735 TI - Biohythane production from organic wastes: present state of art. AB - The economy of an industrialized country is greatly dependent on fossil fuels. However, these nonrenewable sources of energy are nearing the brink of extinction. Moreover, the reliance on these fuels has led to increased levels of pollution which have caused serious adverse impacts on the environment. Hydrogen has emerged as a promising alternative since it does not produce CO2 during combustion and also has the highest calorific value. The biohythane process comprises of biohydrogen production followed by biomethanation. Biological H2 production has an edge over its chemical counterpart mainly because it is environmentally benign. Maximization of gaseous energy recovery could be achieved by integrating dark fermentative hydrogen production followed by biomethanation. Intensive research work has already been carried out on the advancement of biohydrogen production processes, such as the development of suitable microbial consortium (mesophiles or thermophiles), genetically modified microorganism, improvement of the reactor designs, use of different solid matrices for the immobilization of whole cells, and development of two-stage process for higher rate of H2 production. Scale-up studies of the dark fermentation process was successfully carried out in 20- and 800-L reactors. However, the total gaseous energy recovery for two stage process was found to be 53.6 %. From single-stage H2 production, gaseous energy recovery was only 28 %. Thus, two-stage systems not only help in improving gaseous energy recovery but also can make biohythane (mixture of H2 and CH4) concept commercially feasible. PMID- 26507736 TI - Cu(2+) and Fe(2+) mediated photodegradation studies of soil-incorporated chlorpyrifos. AB - The influences of Cu(2+) and Fe(2+) on the photodegradation of soil-incorporated chlorpyrifos were investigated in the present study. The soil samples spiked with chlorpyrifos and selected metal ions were irradiated with UV light for different intervals of time and analyzed by HPLC. The unsterile and sterile control soil samples amended with pesticides and selected metals were incubated in the dark at 25 degrees C for the same time intervals. The results of the study evidenced that photodegradation of chlorpyrifos followed the first-order kinetics. The dissipation t0.5 of chlorpyrifos was found to decrease from 41 to 20 days under UV irradiation. The rate of chlorpyrifos photodegradation was increased in the presence of both metals, i.e., Cu(2+) and Fe(2+). Thus, initially observed t0.5 of 19.8 days was decreased to 4.39 days in the case of Cu(+2) and 19.25 days for Fe(+2). Copper was found to increase the rate of photodegradation by 4.5 orders of magnitude while the microbial degradation of chlorpyrifos was increased only twofold. The microbial degradation of chlorpyrifos was only negligibly affected by Fe(2+) amendment. The studied trace metals also affected the abiotic degradation of the pesticide in the order Cu(2+) > Fe(2+). PMID- 26507737 TI - What 'a good death' means for bereaved family carers. PMID- 26507738 TI - Non-invasive mapping of calculation function by repetitive navigated transcranial magnetic stimulation. AB - Concerning calculation function, studies have already reported on localizing computational function in patients and volunteers by functional magnetic resonance imaging and transcranial magnetic stimulation. However, the development of accurate repetitive navigated TMS (rTMS) with a considerably higher spatial resolution opens a new field in cognitive neuroscience. This study was therefore designed to evaluate the feasibility of rTMS for locating cortical calculation function in healthy volunteers, and to establish this technique for future scientific applications as well as preoperative mapping in brain tumor patients. Twenty healthy subjects underwent rTMS calculation mapping using 5 Hz/10 pulses. Fifty-two previously determined cortical spots of the whole hemispheres were stimulated on both sides. The subjects were instructed to perform the calculation task composed of 80 simple arithmetic operations while rTMS pulses were applied. The highest error rate (80 %) for all errors of all subjects was observed in the right ventral precentral gyrus. Concerning division task, a 45 % error rate was achieved in the left middle frontal gyrus. The subtraction task showed its highest error rate (40 %) in the right angular gyrus (anG). In the addition task a 35 % error rate was observed in the left anterior superior temporal gyrus. Lastly, the multiplication task induced a maximum error rate of 30 % in the left anG. rTMS seems feasible as a way to locate cortical calculation function. Besides language function, the cortical localizations are well in accordance with the current literature for other modalities or lesion studies. PMID- 26507739 TI - Developing 'high impact' guideline-based quality indicators for UK primary care: a multi-stage consensus process. AB - BACKGROUND: Quality indicators (QIs) are an important tool for improving clinical practice and are increasingly being developed from evidence-based guideline recommendations. We aimed to identify, select and apply guideline recommendations to develop a set of QIs to measure the implementation of evidence-based practice using routinely recorded clinical data in United Kingdom (UK) primary care. METHODS: We reviewed existing national clinical guidelines and QIs and used a four-stage consensus development process to derive a set of 'high impact' QIs relevant to primary care based upon explicit prioritisation criteria. We then field tested the QIs using remotely extracted, anonymised patient records from 89 randomly sampled primary care practices in the Yorkshire region of England. RESULTS: Out of 2365 recommendations and QIs originally reviewed, we derived a set of 18 QIs (5 single, 13 composites - comprising 2-9 individual recommendations) for field testing. QIs predominantly addressed chronic disease management, in particular diabetes, cardiovascular and renal disease, and included both processes and outcomes of care. Field testing proved to be critical for further refinement and final selection. CONCLUSIONS: We have demonstrated a rigorous and transparent methodology to develop a set of high impact, evidence based QIs for primary care from clinical guideline recommendations. While the development process was successful in developing a limited set of QIs, it remains challenging to derive robust new QIs from clinical guidelines in the absence of established systems for routine, structured recording of clinical care. PMID- 26507740 TI - Low ERCP Volume Is Associated with More Industry Representative Interactions but Similar Training of Nurses. AB - BACKGROUND: Data on ERCP nurses and associate (ERCP-NA) training and comfort are lacking. Healthcare industry representative (HCIR) influence may be greater in low-volume units (LVUs) due to decreased procedure and device familiarity. AIM: The aim of this study was to compare ERCP-NA training, safety, and HCIR relationships between LVU and high-volume unit (HVU) ERCP facilities. METHODS: We conducted an electronic survey of all Society of Gastroenterology Nurses and Associates (SGNA) members assessing: (1) demographics and procedure volume, (2) ERCP training and radiation safety, and (3) HCIR interactions. Responses were stratified by ERCP volume. RESULTS: Among 832 SGNA member respondents (median age 55), 615 (74%) worked as an ERCP-NA; 41% derived from LVUs. The majority of ERCP NAs, irrespective of unit volume, had observed <50 ERCPs before starting. Except for lead glasses, the majority (>80%) adhered to basic radiation safety, irrespective of unit volume. LVUs were more likely than HVU ERCP-NAs to agree that HCIRs were requested for intra-procedure assistance (24 vs. 19%, p = 0.008), asked for input on the next choice of device (22 vs. 15%, p = 0.01), and assist in device usage (27 vs. 22%, p = 0.04). Irrespective of volume, 30% agreed that they were more likely to utilize a company's devices if that HCIR was present. CONCLUSIONS: ERCP-NA training before independent participation in ERCP is suboptimal. HCIRs are frequently requested for assistance during ERCPs, especially in LVUs. HCIR impact on ERCP outcomes and device utilization and whether enhanced ERCP-NA training will impact the role of HCIR, require further study. PMID- 26507741 TI - Vitamin D Deficiency and Gallbladder Stasis. AB - Cholelithiasis or presence of calculi/gallstones in the gallbladder occurs more frequently in pregnant women. Vitamin D deficiency is suggested to be associated with gallbladder stasis, and a role for vitamin D supplementation is thought to have potential to prevent gallstones in this special population. PMID- 26507742 TI - Assessing Needs for Cancer Education and Support in American Indian and Alaska Native Communities in the Northwestern United States. AB - American Indians and Alaska Natives (AI/ANs) experience significant cancer disparities. To inform future public health efforts, a web-based needs assessment survey collected quantitative and qualitative data from AI/AN community health workers and cancer survivors in the northwestern United States. Content analysis of qualitative responses identified themes to contextualize quantitative results. Seventy-six AI/AN respondents (93% female) described substantial unmet needs for education and resources to assist cancer survivors, including a shortage of patient navigators, support groups, and home health care workers. Fear of negative outcomes, a culturally rooted avoidance of discussing illness, and transportation difficulties were cited as major barriers to participation in cancer education and receipt of health services. Face-to-face contact was overwhelmingly preferred for community education and support, but many respondents were receptive to other communication channels, including e-mail, social media, and webinars. Survey results highlight the importance of culturally sensitive approaches to overcome barriers to cancer screening and education in AI/AN communities. Qualitative analysis revealed a widespread perception among respondents that available financial and human resources were insufficient to support AI/AN cancer patients' needs. PMID- 26507743 TI - Evaluation of the Effect of a Promotora-led Educational Intervention on Cervical Cancer and Human Papillomavirus Knowledge Among Predominantly Hispanic Primary Care Patients on the US-Mexico Border. AB - Despite declining cervical cancer rates, ethnic minorities continue to bear an unequal burden in morbidity and mortality. While access to screening is a major barrier, low levels of knowledge and cultural influences have been found to play a part in underutilization of preventive services. The aim of our study was to evaluate the effect of a promontora-led educational intervention on cervical cancer and human papillomavirus knowledge in mainly Hispanic females attending a primary care clinic. One hundred ten females were recruited from the waiting room of a busy primary care clinic and invited to attend individual or small group educational sessions. Participants completed knowledge surveys pre- and post intervention. An overall evaluation of the educational session was also completed. Following the educational intervention, participants showed an improvement in knowledge scores from a mean score of 10.8 (SD 3.43) out of a possible score of 18 to a mean score of 16.0 (SD1.51) (p < 0.001). 94.5 % of participants rated as excellent, the presentation of information in a way that was easy to understand, most reported that it was a good use of their time and that it lowered their anxiety about testing for early detection of cervical cancer. An educational intervention delivered by well-trained Promotora/Lay health care worker significantly improves patient's cervical cancer and HPV knowledge and can be a useful tool in patient education in the clinical setting especially with high risk populations. PMID- 26507744 TI - Novel Method for Recruiting Representative At-Risk Individuals into Cancer Prevention Trials: Online Health Risk Assessment in Employee Wellness Programs. AB - Participation in cancer prevention trials (CPT) is lower than 3 % among high-risk healthy individuals, and racial/ethnic minorities are the most under-represented. Novel recruitment strategies are therefore needed. Online health risk assessment (HRA) serves as a gateway component of nearly all employee wellness programs (EWPs) and may be a missed opportunity. This study aimed to explore employees' interest, willingness, motivators, and barriers of releasing their HRA responses to an external secure research database for recruitment purpose. We used qualitative research methods (focus group and individual interviews) to examine employees' interest and willingness in releasing their online HRA responses to an external, secure database to register as potential CPT participants. Fifteen structured interviews (40 % of study participants were of racial/ethnic minority) were conducted, and responses reached saturation after four interviews. All employees showed interest and willingness to release their online HRA responses to register as a potential CPT participant. Content analyses revealed that 91 % of participants were motivated to do so, and the major motivators were to (1) obtain help in finding personally relevant prevention trials, (2) help people they know who are affected by cancer, and/or (3) increase knowledge about CPT. A subset of participants (45 %) expressed barriers of releasing their HRA responses due to concerns about credibility and security of the external database. Online HRA may be a feasible but underutilized recruitment method for cancer prevention trials. EWP-sponsored HRA shows promise for the development of a large, centralized registry of racially/ethnically representative CPT potential participants. PMID- 26507745 TI - Astrocytes Regulate Angiogenesis Through the Jagged1-Mediated Notch1 Pathway After Status Epilepticus. AB - Vascular disruptions including blood-brain barrier breakdown and pathologic angiogenesis contribute to the development of epilepsy in normal brains. The Notch signaling pathway is activated in response to seizure activity, and its activation promotes seizures, although its exact role in angiogenesis is poorly understood. Here, we have examined the role of Notch signaling in angiogenesis in a kainic acid-induced mouse model of epilepsy. We show that following seizures, expression of the Notch ligand Jagged1 in the hippocampus is upregulated in astrocytes and levels of activated Notch1 are increased in endothelial cells. Using an in vitro model of angiogenesis, we provide evidence that brain endothelial tube formation is promoted in the presence of astrocytes. Isolated primary brain endothelial cells develop significantly longer vascular sprouts when cultured in the presence of astrocytes. Notch1 signaling is activated in brain endothelial cells cocultured with astrocytes, and astrocytic Jagged1 expression is required for angiogenic enhancement, as shown by the inhibitory effect of Jagged1 small interfering RNA (siRNA) expression in astrocytes on endothelial cell vascular sprouting in vitro. Therapies targeting the Jagged1/Notch1 signaling pathway may therefore be effective in limiting aberrant angiogenesis following status epilepticus. PMID- 26507747 TI - What's in a name? Borderline personality disorder in adolescence. PMID- 26507746 TI - The influence of comorbid oppositional defiant disorder on white matter microstructure in attention-deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) are highly comorbid disorders. ADHD has been associated with altered white matter (WM) microstructure, though the literature is inconsistent, which may be due to differences in the in- or exclusion of participants with comorbid ODD. WM abnormalities in ODD are still poorly understood, and it is unclear whether comorbid ODD in ADHD may have confounded the current ADHD literature. Diffusion Tensor Imaging (DTI) was used to compare fractional anisotropy (FA) and mean diffusivity (MD) between ADHD patients with (n = 42) and without (n = 117) comorbid ODD. All participants were between 8-25 years and groups did not differ in mean age or gender. Follow-up analyses were conducted to examine the role of antisocial behaviour (conduct problems) on FA and MD values in both groups. Comorbid ODD in ADHD was associated with lower FA in left frontotemporal WM, which appeared independent of ADHD symptoms. FA was negatively associated with antisocial behaviour in ADHD + ODD, but not in ADHD-only. Comorbid ODD is associated with WM abnormalities in individuals with ADHD, which appears to be independent of ADHD symptoms. Altered WM microstructure in comorbid ODD may play a role in inconsistencies in the current DTI literature in ADHD. Altered development of these tracts may contribute to social-emotional and cognitive problems in children with oppositional and antisocial behaviour. PMID- 26507748 TI - Safety and efficacy of composite collagen-silver nanoparticle hydrogels as tissue engineering scaffolds. AB - The increasing number of multidrug resistant bacteria has revitalized interest in seeking alternative sources for controlling bacterial infection. Silver nanoparticles (AgNPs), are amongst the most promising candidates due to their wide microbial spectrum of action. In this work, we report on the safety and efficacy of the incorporation of collagen coated AgNPs into collagen hydrogels for tissue engineering. The resulting hybrid materials at [AgNPs] < 0.4 MUM retained the mechanical properties and biocompatibility for primary human skin fibroblasts and keratinocytes of collagen hydrogels; they also displayed remarkable anti-infective properties against S. aureus, S. epidermidis, E. coli and P. aeruginosa at considerably lower concentrations than silver nitrate. Further, subcutaneous implants of materials containing 0.2 MUM AgNPs in mice showed a reduction in the levels of IL-6 and other inflammation markers (CCL24, sTNFR-2, and TIMP1). Finally, an analysis of silver contents in implanted mice showed that silver accumulation primarily occurred within the tissue surrounding the implant. PMID- 26507749 TI - The scientific bases to consider Parkinson's disease an occupational disease in agriculture professionals exposed to pesticides in France. PMID- 26507750 TI - Magnesium and phase angle: a prognostic tool for monitoring cellular integrity in judo athletes. AB - Adequate magnesium (Mg) levels play a vital role in membrane excitability, cell contractility and metabolism, being a key nutrient for sustaining appropriate muscular contraction and performance levels in athletes. Phase angle (PhA), assessed by bioimpedance analysis (BIA), has been reported to be positively associated with most nutritional markers and is an indicator of membrane integrity and water distribution between intra- and extracellular spaces. The aim of the present study was to verify the association between Mg status and PhA as a predictor of cellular health, in a sample of judo athletes from a period of weight stability to prior to competition. Judo athletes (n = 20) from the national team were evaluated on two occasions: during a period when body weight was stable (M1), and prior to competition (M2). Changes between these occasions were calculated as M2-M1. PhA was obtained by bioelectrical impedance spectroscopy at a frequency of 50 KHz. Mg was measured in serum and red blood cells (RBC) by atomic absorption spectrophotometry, and Mg in the diet was assessed from a 24-h diet record over a seven-day period, after an assessment of body composition. Mean PhA did not differ from M1 to M2. However, individual changes in PhA were positively associated with individual changes in serum (r = 0.62, p = 0.004) and RBC Mg (r = 0.45, p = 0.048). This association was independent of weight changes between assessments, but when adjusted for Mg intake changes, only the association between PhA and serum Mg remained significant. These results highlight that in elite athletes PhA may be an indirect indicator of muscular function. PMID- 26507751 TI - Relationship between serum magnesium concentration and metabolic and hormonal disorders in middle-aged and older men. AB - The aim of this study was to determine the relationship between serum magnesium (Mg) concentrations in middle-aged and older men, and the occurrence of selected metabolic and hormonal disorders. The study involved a total of 313 men aged 50 75 years, and who underwent standard anthropometric measurements. Also determined were blood serum Mg, lipid parameters - total cholesterol (TCh), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG) and carbohydrate metabolism parameters - glucose, insulin (I). In men with a normal total testosterone (TT) concentration, serum Mg was significantly higher compared to patients with a total testosterone deficiency. The subjects with metabolic syndrome had lower serum Mg compared to patients without metabolic syndrome. Serum Mg concentration in type 2 diabetes mellitus was lower compared to men without diabetes. In patients with arterial hypertension, serum Mg concentration was lower than in patients without hypertension. Statistically significant negative correlations were found for the relationships between Mg concentration and body mass index, waist-to-hip ratio, abdominal circumference, arterial blood pressure. Statistically significant, positive correlations were found for the relationships between Mg concentration and TT, TCh, LDL concentrations. The lower serum Mg level may be conducive to the development of total testosterone deficiency, arterial hypertension, diabetes, and therefore metabolic syndrome. PMID- 26507753 TI - Revisiting the Hippocratic Oath. PMID- 26507752 TI - Molecular developmental evidence for a subcoxal origin of pleurites in insects and identity of the subcoxa in the gnathal appendages. AB - Pleurites are chitinous plates in the body wall of insects and myriapods. They are believed to be an adaptation to locomotion on land but their developmental and evolutionary origins are unclear. A widely endorsed explanation for their origin is through toughening pre-existing parts of the body wall; in contrast, the subcoxal theory suggests pleurites derive from a redeployment of the proximal most section of the leg, the subcoxa. Here, by studying expression of appendage patterning genes in embryos and larvae of the beetle Tribolium castaneum, we provide the first molecular evidence for the existence of a cryptic subcoxal segment in developing legs. We follow this structure during development and show that the embryonic subcoxa later forms the pleurites of the larva as predicted by the subcoxal theory. Our data also demonstrate that subcoxal segments are present in all post-antennal appendages, including the first molecular evidence of a two segmented mandible with a subcoxal segment in insects. PMID- 26507754 TI - Commentary on: Trans-diaphragmatic left ventricular venting during peripheral venous-arterial extracorporeal membrane oxygenation. PMID- 26507755 TI - Review of Cardiac Disease in Nemaline Myopathy. AB - OBJECTIVES: Little is known about the type, frequency, severity, treatment, and outcome of cardiac disease in nemaline myopathy. This review summarizes and discusses findings concerning the type, prevalence, diagnosis, treatment, and outcome of cardiac involvement in nemaline myopathy. METHODS: Review of publications about nemaline myopathy and cardiac disease. RESULTS: Altogether, 35 patients with nemaline myopathy with cardiac disease were identified. Age at presentation ranged from 0 to 62 years. In 30 individuals whose gender was described, 22 were male and eight were female. Onset was congenital in 16 patients, infantile in five, and adult in four. Nine patients presented with dilated cardiomyopathy, six with hypertrophic cardiomyopathy, and one with nonspecific cardiomyopathy. Among those with cardiomyopathy, four developed heart failure. One patient experienced sudden cardiac death. A ventricular septal defect was described in two patients. Cardiac treatment included drugs for heart failure (eight patients), implantable cardioverter-defibrillator implantation (one patient), and heart transplant (three patients). Four patients received noninvasive positive-pressure ventilation and two continuous positive-pressure ventilation. The outcome was fatal in 11 patients. CONCLUSIONS: Cardiac disease in nemaline myopathy manifests as cardiomyopathy leading to heart failure. If respiratory muscles are affected, the right side of the heart may be secondarily involved. Early detection of cardiac involvement is essential since effective treatment for cardiac disease in nemaline myopathy may be available. PMID- 26507756 TI - Cupcakes, like supramolecular chemistry, are in reality just variations. Introduction. PMID- 26507757 TI - A Convenient Synthetic Route to Partial-Cone p-Carboxylatocalix[4]arenes. AB - p-Carboxylatocalix[n]arenes have emerged as useful building blocks for the construction of a diverse range of supramolecular assemblies. A convenient route to a p-carboxylatocalix[4]arene that is locked in a partial-cone conformation is presented. The conformation gives the molecule markedly different topological directionality relative to those previously used in self- and metal-directed assembly studies. PMID- 26507758 TI - UV-visible Absorption Study of the Self-association of Non-ionic Chromonic Triphenylenes TP6EOnM (n = 2, 3, 4) in Dilute Aqueous Solutions: Impact of Chain Length on Aggregation. AB - A series of triphenylenes with oligoethoxy chains of various length, TP6EOnM with n = 2, 3, 4, has been synthesised and purified by HPLC. The self-association of these disc-shaped molecules in dilute aqueous solutions (~10(-7) to ~4 * 10(-4) M) has been studied by UV-visible absorption spectroscopy. The free energy of association decreases as the length of the chains increases. As a result, for a given concentration, the average size of aggregate diminishes as the chain length increases. While the absorption properties of the monomer are identical for the three molecules, the extinction coefficients of solutions of the three triphenylenes at a given concentration are significantly different and are directly linked to the average size of the aggregates. The change of epsilon values upon aggregation could explain the trend generally observed with dyes for solar cells substituted with chains of increasing length showing increasing extinction coefficient values. PMID- 26507759 TI - Triplet-Triplet Energy Transfer Study in Hydrogen Bonding Systems. AB - The 2,6-diiodoBodipy-styrylBodipy hydrogen bonding system was prepared to study the effect of hydrogen bonding on the triplet-triplet-energy-transfer (TTET) process. 2,6-DiiodoBodipy linked with N-acetyl-2,6-diaminopyridine (D-2) was used as the triplet energy donor, and the styrylBodipy connected with thymine (A-1) was used as triplet energy acceptor, thus the TTET process was established upon photoexcitation. The photophysical processes of the hydrogen bonding system were studied with steady-state UV-vis absorption spectroscopy, fluorescence spectroscopy, fluorescence lifetime measurement and nanosecond time-resolved transient absorption spectroscopies. The TTET of the intramolecular/hydrogen bonding/intermolecular systems were compared through nanosecond transient absorption spectroscopy. The TTET process of the hydrogen bonding system is faster and more efficient (kTTET = 6.9 * 10(4) s(-1), PhiTTET = 94.0%) than intermolecular triplet energy transfer (kTTET = 6.0 * 10(4) s(-1), PhiTTET = 90.9%), but slower and less efficient than intramolecular triplet energy transfer (kTTET > 10(8) s(-1)). These results are valuable for designing self-assembly triplet photosensitizers and for the study of the TTET process of hydrogen bonding systems. PMID- 26507760 TI - Synthetic G-Quartets as Versatile Nanotools for the Luminescent Detection of G Quadruplexes. AB - Recent years have witnessed a tremendous increase in the biotechnological applications of nucleic acid-based nanotools. Beyond their biological relevance, nucleobases have indeed found new scopes of applications in bionanotechnology, which are expanding nowadays at an accelerated pace. Among the four canonical nucleobases (adenine, guanine, cytosine and thymine), guanine is certainly the most useful and used base, thanks to its versatile H-bond donating/accepting properties that make it suitable for being involved in various assemblies ranging from base-pairs to base-quartets. Here, we would like to report on an innovative guanine-based molecular tool named Tb. Pyro-DOTASQ: this metal complex has a sophisticated chemical structure that allows formation of an intramolecular G quartet upon interaction with alternative secondary structures known as G quadruplexes. This target-promoted molecular switch triggers a luminescence response that would permit the use of Tb. Pyro-DOTASQ to search and detect quadruplex-forming DNA and RNA sequences: its unique design indeed allows it i) to create specific interaction with quadruplexes, ii) to provide an easily readable luminescent output to monitor this association and iii) to be readily immobilized on graphene surface, thus making Tb. Pyro-DOTASQ a high-value molecular device. Results obtained in the course of in-depth biophysical analyses raise questions about the actual supramolecular structure of Tb. Pyro-DOTASQ: these results thus shed a bright light on the care that must be exercised when using intricate molecular architectures to construct elaborated supramolecular metal complexes. PMID- 26507761 TI - Synthesis and Structure of Hexatungstochromate(III), [H3Cr(III)W6O24]6-. AB - The hexatungstochromate(III) [H(3)Cr(III)W(6)O(24)](6-) (1) was synthesized in aqueous, basic medium by simple reaction of chromium(III) nitrate nonahydrate and sodium tungstate dihydrate in a 1:6 ratio. Polyanion 1 represents the first Anderson-Evans type heteropolytungstate with a trivalent hetero element. The sodium salt of 1 with the formula Na(6)[H(3)Cr(III)W(6)O(24)].22H(2)O (1a) was fully characterized in the solid state by single crystal XRD, FT-IR spectroscopy, and thermogravimetric analysis. PMID- 26507762 TI - Self-assembly of Metallamacrocycles Employing a New Benzil-based Organometallic Bisplatinum(II) Acceptor. AB - A benzil-based semi-rigid dinuclear-organometallic acceptor 4,4'-bis[trans Pt(PEt(3))(2)(NO(3))(ethynyl)]benzil (bisPt-NO(3)) containing a Pt-ethynyl functionality was synthesized in good yield and characterized by multinuclear NMR ((1)H, (31)P, and (13)C), electrospray ionization mass spectrometry (ESI-MS), and single-crystal X-ray diffraction analysis of the iodide analogue bisPt-I. The stoichiometric (1:1) combination of the acceptor bisPt-NO(3) separately with four different ditopic donors (L(1)-L(4); L(1) = 9-ethyl-3,6-di(1H-imidazol-1-yl)-9H carbazole, L(2) = 1,4-bis((1H-imidazol-1-yl)methyl)benzene, L(3) = 1,3-bis((1H imidazol-1-yl)methyl)benzene and L(4) = 9,10-bis((1H-imidazol-1-yl) methyl)anthracene) yielded four [2 + 2] self-assembled metallacycles M(1)-M(4) in quantitative yields, respectively. All these newly synthesized assemblies were characterized by various spectroscopic techniques (NMR, IR, ESI-MS) and their sizes/shapes were predicted through geometry optimization employing the PM6 semi empirical method. The benzil moiety was introduced in the backbone of the acceptor bisPt-NO(3) due to the interesting structural feature of long carbonyl C C bond (~1.54 A), which enabled us to probe the role of conformational flexibility on size and shapes of the resulting coordination ensembles. PMID- 26507767 TI - The commensal infant gut meta-mobilome as a potential reservoir for persistent multidrug resistance integrons. AB - Despite the accumulating knowledge on the development and establishment of the gut microbiota, its role as a reservoir for multidrug resistance is not well understood. This study investigated the prevalence and persistence patterns of an integrase gene (int1), used as a proxy for integrons (which often carry multiple antimicrobial resistance genes), in the fecal microbiota of 147 mothers and their children sampled longitudinally from birth to 2 years. The study showed the int1 gene was detected in 15% of the study population, and apparently more persistent than the microbial community structure itself. We found int1 to be persistent throughout the first two years of life, as well as between mothers and their 2 year-old children. Metagenome sequencing revealed integrons in the gut meta mobilome that were associated with plasmids and multidrug resistance. In conclusion, the persistent nature of integrons in the infant gut microbiota makes it a potential reservoir of mobile multidrug resistance. PMID- 26507768 TI - Differences in protein binding and excretion of Triapine and its Fe(III) complex. AB - Triapine has been investigated as anticancer drug in multiple clinical phase I/II trials. Although promising anti-leukemic activity was observed, Triapine was ineffective against solid tumors. The reasons are currently widely unknown. The biological activity of Triapine is strongly connected to its iron complex (Fe Triapine) which is pharmacologically not investigated. Here, novel analytical tools for Triapine and Fe-Triapine were developed and applied for cell extracts and body fluids of treated mice. Triapine and its iron complex showed a completely different behavior: for Triapine, low protein binding was observed in contrast to fast protein adduct formation of Fe-Triapine. Notably, both drugs were rapidly cleared from the body (serum half-life time <1h). Remarkably, in contrast to Triapine, where (in accordance to clinical data) basically no renal excretion was found, the iron complex was effectively excreted via urine. Moreover, no Fe-Triapine was detected in serum or cytosolic extracts after Triapine treatment. Taken together, our study will help to further understand the biological behavior of Triapine and its Fe-complex and allow the development of novel thiosemicarbazones with pronounced activity against solid tumor types. PMID- 26507769 TI - What technical platform is needed for non-traumatic abdominal emergencies? Can we be realistic yet effective? PMID- 26507770 TI - Dissection technique for selective liver harvesting. PMID- 26507771 TI - Efficacy and tolerability of high-dose phenobarbital in children with focal seizures. AB - OBJECTIVE: We retrospectively reviewed the outcomes of children with focal epilepsy treated with oral high-dose phenobarbital. METHODS: We reviewed data on children (aged<15 years) with focal seizures treated with high-dose phenobarbital (>5 mg/kg/day to maintain a target serum level >40 MUg/mL) for at least 6 months. Seizure frequency was evaluated after phenobarbital titration, and 1 and 2 years after high-dose phenobarbital treatment commenced. Treatment was judged effective when seizure frequencies fell by ?75%. RESULTS: Seven boys and eight girls were treated. The median age at commencement of high-dose phenobarbital therapy was 30 months. The maximal serum phenobarbital level ranged from 36.5 to 62.9 MUg/mL. High-dose PB was effective in seven. In two patients, treatment was transiently effective, but seizure frequency later returned to the baseline. High-dose PB was ineffective in six. No significant association between effectiveness and any clinical variable was evident. Drowsiness was recorded in nine patients, but no patient developed a behavioral problem or hypersensitivity. CONCLUSION: Oral high dose phenobarbital was effective in 7 of 15 patients with focal epilepsy and well tolerated. High-dose PB may be useful when surgical treatment is difficult. PMID- 26507772 TI - Tourette syndrome: Update. PMID- 26507773 TI - Chronic papillomatous dermatitis around an ileostoma. PMID- 26507774 TI - All-trans retinoic acid protects against doxorubicin-induced cardiotoxicity by activating the ERK2 signalling pathway. AB - BACKGROUND AND PURPOSE: Doxorubicin is a powerful antineoplastic agent for treating a wide range of cancers. However, doxorubicin cardiotoxicity of the heart has largely limited its clinical use. All-trans retinoic acid (ATRA) plays an important role in many cardiac biological processes, but its protective effects on doxorubicin-induced cardiotoxicity remain unknown. Here, we studied the effect of ATRA on doxorubicin cardiotoxicity and the underlying mechanisms. EXPERIMENTAL APPROACHES: Cellular viability assays, Western blotting and mitochondrial respiration analyses were employed to evaluate the cellular response to ATRA in H9c2 cells and primary cardiomyocytes. Quantitative PCR and gene knockdown were performed to investigate the underlying molecular mechanisms of ATRA's effects on doxorubicin cardiotoxicity. KEY RESULTS: ATRA significantly inhibited doxorubicin-induced apoptosis in H9c2 cells and primary cardiomyocytes. ATRA was more effective against doxorubicin cardiotoxicity than resveratrol and dexrazoxane. ATRA also suppressed reactive oxygen species generation and restored expression levels of mRNA and proteins in the phase II detoxifying enzyme system: nuclear factor-E2-related factor 2, manganese superoxide dismutase, haem oxygenase-1, and mitochondrial function (mitochondrial membrane integrity, mitochondrial DNA copy numbers and mitochondrial respiration capacity, biogenesis and dynamics). Both a ERK1/2 inhibitor (U0126) and ERK2 siRNA, but not ERK1 siRNA, abolished the protective effect of ATRA against doxorubicin-induced toxicity in H9c2 cells. Remarkably, ATRA did not compromise the anticancer efficacy of doxorubicin in gastric carcinoma cells. CONCLUSIONS AND IMPLICATIONS: ATRA protected cardiomyocytes against doxorubicin-induced toxicity, by activating the ERK2 pathway, without compromising its anticancer efficacy. Therefore, ATRA is a promising candidate as a cardioprotective agent against doxorubicin cardiotoxicity. PMID- 26507775 TI - Computed tomographic-guided percutaneous radiofrequency ablation with hydrodissection of hepatic malignancies in the subcapsular location: Evaluation of safety and technical efficacy. AB - BACKGROUND: Image-guided percutaneous radiofrequency ablation (RFA) has been the most commonly used modality in the treatment of nonresectable hepatic malignancies. However, tumors in the subcapsular location are still technically challenging. This study was undertaken to evaluate the feasibility, safety, and efficacy of computed tomographic-guided percutaneous RFA with hydrodissection for hepatic malignancies in the subcapsular location. METHODS: A total of 103 patients with 253 hepatic lesions were treated with computed tomographic-guided percutaneous RFA. Computed tomographic-guided percutaneous RFA with hydrodissection was performed in 15 patients with 15 hepatic nodules. All tumors located in the hepatic subcapsular location were considered difficult to treat on planning sonography. Hydrodissection was performed with 5% dextrose in water or saline solution in displacing adjacent structures >= 10 mm away from the liver capsule. Two RFA systems with multitined expandable electrodes or straight internally cooled single electrodes were used for treatment of hepatic malignancies. The feasibility, safety, and efficacy of this technique were analyzed on follow-up contrast-enhanced computed tomography or magnetic resonance imaging. RESULTS: Hydrodissection was successfully achieved in 15 (100%) patients, displacing the adjacent structures >= 10 mm that were originally < 10 mm away from the liver capsule with administration of a mean of 376 mL of dextrose in water or saline solution. The average distance between an adjacent structure and the liver capsule after hydrodissection was 1.50 +/- 0.40 cm and 0.11 +/- 0.15 cm prior to hydrodissection, which was statistically significant (p < 0.001). No complication related to hydrodissection occurred during the follow up period. The primary technical success rate of percutaneous RFA for tumor was 100% (15/15) at 1-month follow-up imaging. There were three minor complications (20%, 3/15) related to the RFA procedure. CONCLUSION: Computed tomographic-guided percutaneous RFA with hydrodissection is a feasible, safe, and effective technique in the treatment of hepatic malignancies in the subcapsular location. PMID- 26507776 TI - UDP-galactose transporter gene hUGT1 expression in tobacco plants leads to hyper galactosylated cell wall components. AB - We reported previously that tobacco plants transformed with the human UDP galactose transporter 1 gene (hUGT1-transgenic plants) displayed morphological, architectural, and physiological alterations, such as enhanced growth, increased accumulation of chlorophyll and lignin, and a gibberellin-responsive phenotype. In the present study, we demonstrated that hUGT1 expression altered the monosaccharide composition of cell wall matrix polysaccharides, such as pectic and hemicellulosic polysaccharides, which are biosynthesized in the Golgi lumen. An analysis of the monosaccharide composition of the cell wall matrix polysaccharides revealed that the ratio of galactose to total monosaccharides was significantly elevated in the hemicellulose II and pectin fractions of hUGT1 transgenic plants compared with that of control plants. A hyper-galactosylated xyloglucan structure was detected in hemicellulose II using oligosaccharide mass profiling. These results indicated that, because of the enhanced UDP-galactose transport from the cytosol to the Golgi apparatus by hUGT1, galactose incorporation in the cell wall matrix polysaccharides increased. This increased galactose incorporation may have contributed to increased galactose tolerance in hUGT1-transgenic plants. PMID- 26507777 TI - Support Seeking or Familial Obligation: An Investigation of Motives for Disclosing Genetic Test Results. AB - Genetic test results reveal not only personal information about a person's likelihood of certain medical conditions but also information about the person's genetic relatives. Given the familial nature of genetic information, one's obligation to protect family members may be a motive for disclosing genetic test results, but this claim has not been methodically tested. Existing models of disclosure decision making presume self-interested motives, such as seeking social support, instead of other-interested motives, like familial obligation. This study investigated young adults' (N = 173) motives to share a genetic-based health condition, alpha-1 antitrypsin deficiency, after reading a hypothetical vignette. Results show that social support and familial obligation were both reported as motives for disclosure. In fact, some participants reported familial obligation as their primary motivator for disclosure. Finally, stronger familial obligation predicted increased likelihood of disclosing hypothetical genetic test results. Implications of these results were discussed in reference to theories of disclosure decision-making models and the practice of genetic disclosures. PMID- 26507778 TI - Aged garlic extract enhances heme oxygenase-1 and glutamate-cysteine ligase modifier subunit expression via the nuclear factor erythroid 2-related factor 2 antioxidant response element signaling pathway in human endothelial cells. AB - The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway defends cells against oxidative stress and regulates the cellular redox balance. Activation of this pathway induces a variety of antioxidant enzymes, resulting in the protection of our bodies against oxidative damage. It has been reported that aged garlic extract (AGE), a garlic preparation that is rich in water-soluble cysteinyl moieties, reduces oxidative stress and helps to ameliorate of cardiovascular, renal and hepatic diseases. We hypothesized that AGE enhances the expression of antioxidant enzymes via the Nrf2 ARE pathway in human umbilical vein endothelial cells in culture. Gene expression of antioxidant enzymes was measured using real-time polymerase chain reaction. Nuclear accumulation of Nrf2 and antioxidant enzymes expression were evaluated using western blotting analyses. We found that AGE promoted the accumulation of Nrf2 into the nucleus in a time- and dose-dependent manner and increased the gene expression and polypeptide level of heme oxygenase-1 (HO-1) and glutamate cysteine ligase modifier subunit (GCLM). Moreover, the effect of AGE in elevating the gene expression of HO-1 and GCLM was found to be mediated via Nrf2 activation in human umbilical vein endothelial cells. Taken together, these observations suggest that AGE induces the expression of HO-1 and GCLM, which are antioxidant enzymes, via activation of the Nrf2-ARE signaling pathway. PMID- 26507779 TI - Reinforcing endothelial junctions prevents microvessel permeability increase and tumor cell adhesion in microvessels in vivo. AB - Tumor cell adhesion to the microvessel wall is a critical step during tumor metastasis. Vascular endothelial growth factor (VEGF), a secretion of tumor cells, can increase microvessel permeability and tumor cell adhesion in the microvessel. To test the hypothesis that inhibiting permeability increase can reduce tumor cell adhesion, we used in vivo fluorescence microscopy to measure both microvessel permeability and adhesion rates of human mammary carcinoma MDA MB-231 cells in post-capillary venules of rat mesentery under the treatment of VEGF and a cAMP analog, 8-bromo-cAMP, which can decrease microvessel permeability. By immunostaining adherens junction proteins between endothelial cells forming the microvessel wall, we further investigated the structural mechanism by which cAMP abolishes VEGF-induced increase in microvessel permeability and tumor cell adhesion. Our results demonstrate that 1) Pretreatment of microvessels with cAMP can abolish VEGF-enhanced microvessel permeability and tumor cell adhesion; 2) Tumor cells prefer to adhere to the endothelial cell junctions instead of cell bodies; 3) VEGF increases microvessel permeability and tumor cell adhesion by compromising endothelial junctions while cAMP abolishes these effects of VEGF by reinforcing the junctions. These results suggest that strengthening the microvessel wall integrity can be a potential approach to inhibiting hematogenous tumor metastasis. PMID- 26507780 TI - Respiratory modulated sympathetic activity: a putative mechanism for developing vascular resistance? AB - KEY POINTS: Sympathetic activity exhibits respiratory modulation that is amplified in hypertensive rats. Respiratory modulated sympathetic activity produces greater changes in vascular resistance than tonic stimulation of the same stimulus magnitude in normotensive but not hypertensive rats. Mathematical modelling demonstrates that respiratory modulated sympathetic activity may fail to produce greater vascular resistance changes in hypertensive rats because the system is saturated as a consequence of a dysfunctional noradrenaline reuptake mechanism. Respiratory modulated sympathetic activity is an efficient mechanism to raise vascular resistance promptly, corroborating its involvement in the ontogenesis of hypertension. ABSTRACT: Sympathetic nerve activity (SNA) exhibits respiratory modulation. This component of SNA is important - being recruited under cardiorespiratory reflex conditions and elevated in the spontaneously hypertensive (SH) rat - and yet the exact influence of this modulation on vascular tone is not understood, even in normotensive conditions. We constructed a mathematical model of the sympathetic innervation of an arteriole, and used it to test the hypothesis that respiratory modulation of SNA preferentially increases vasoconstriction compared to a frequency-matched tonic pattern. Simulations supported the hypothesis, where respiratory modulated increases in vasoconstriction were mediated by a noradrenergic mechanism. These predictions were tested in vivo in adult Wistar rats. Stimulation of the sympathetic chain (L3) with respiratory modulated bursting patterns, revealed that bursting increases vascular resistance (VR) more than tonic stimulation (57.8 +/- 3.3% vs. 44.8 +/- 4.2%; P < 0.001; n = 8). The onset of the VR response was also quicker for bursting stimulation (rise time constant = 1.98 +/- 0.09 s vs. 2.35 +/- 0.20 s; P < 0.01). In adult SH rats (n = 8), the VR response to bursting (44.6 +/- 3.9%) was not different to tonic (37.4 +/- 3.5%; P = 0.57). Using both mathematical modelling and in vivo techniques, we have shown that VR depends critically on respiratory modulation and revealed that this pattern dependency in Wistar rats is due to a noradrenergic mechanism. This respiratory component may therefore contribute to the ontogenesis of hypertension in the pre-hypertensive SH rat - raising VR and driving vascular remodelling. Why adult SH rats do not exhibit a pattern-dependent response is not known, but further modelling revealed that this may be due to dysfunctional noradrenaline reuptake. PMID- 26507781 TI - Messenger RNA-based therapeutics for the treatment of apoptosis-associated diseases. AB - Gene therapy is a promising approach for treating diseases that are closely associated with excessive apoptosis, because the gene can effectively and sustainably introduce anti-apoptotic factors into cells. However, DNA delivery poses the risk of random genomic integration, leading to overexpression of the delivered gene and cancer development. Messenger RNA (mRNA) can evade integration events in target cells. We examined the use of mRNA-based therapeutics for introducing anti-apoptotic factors by using a mouse model of fulminant hepatitis. For introducing mRNA into the liver, a synthesised polymer-based carrier of polyplex nanomicelles was used for hydrodynamic intravenous injection. Using GFP as a reporter, we demonstrate that mRNA delivery induced efficient protein expression in almost 100% of liver cells, while plasmid DNA (pDNA) delivery provided a smaller percentage of GFP-positive cells. Analyses using Cy5-labelled mRNA and pDNA revealed that efficient expression by mRNA was attributed to a simple intracellular mechanism, without the need for nuclear entry. Consistent with this observation, Bcl-2 mRNA was more effective on reducing apoptosis in the liver of mice with fulminant hepatitis than Bcl-2 pDNA. Therefore, mRNA-based therapeutics combined with an effective delivery system such as polyplex nanomicelles is a promising treatment for intractable diseases associated with excessive apoptosis. PMID- 26507782 TI - COMMUNICATION IN THE CONTEXT OF FAMILY CAREGIVING: AN EXPLORATORY STUDY OF UGANDAN CHILDREN ON ANTIRETROVIRAL THERAPY. AB - It is important to consider the complexities of family dynamics when deciding when and how to communicate with HIV-infected children about their illness and treatment. Previous research has focused on providers' and caregivers' perspectives on whether, when and how to disclose HIV/AIDS diagnosis and treatment to HIV-infected children. From the perspective of HIV-infected children, communication does not mean just giving information about illness and treatment, but also encompasses emotional and material care. This paper places communication within the broader framework of caregiving in family situations. This exploratory study was conducted in Jinja district, Uganda, between November 2011 and December 2012. Through participant observation and in-depth interviews, communication by, and with, HIV-infected children in the context of family situations was explored from the perspectives of 29 HIV-infected children aged 8 17 years on antiretroviral therapy (ART) using content thematic analysis. Children's communication with caregivers about their illness and treatment varied depending on whom they were living with and the nature of caregiving. Although a mother's care was considered best, children described others who cared 'like a mother'. For some, caregiving was distributed among several relatives and non relatives, while others felt they had hardly anyone to care for them. Caregiving from the children's perspective involved emotional support, expressed verbally and explicitly in messages of concern, encouragement conveyed in reminders to take medicines, attention when sick and confidential conversations about the challenges of having HIV and taking ART. Caregiving was also communicated implicitly in acts of provision of food/drinks to take with medicines, counting pills to confirm they had taken the medicines and accompanying children to treatment centres. Children's communication about their health and medicines and the care they received was to a large extent shaped by the nature of their relatedness to their caregivers, the extent to which caregiving was dispersed among several people and who else in the household was infected with HIV and on medication. PMID- 26507783 TI - [Recently recognized ophthalmic complications of systemic treatments]. AB - The ocular side effects of systemic treatments are numerous and sometimes severe. The prescriber and the ophthalmologist should be aware of ocular side effects of systemic treatments in order to inform their patients accordingly, implement appropriate ophthalmological monitoring and/or treatment and if necessary, adapt the therapeutic management. In this review, we describe the recently recognized ophthalmic complications of systemic treatments, except for optic neuropathies. PMID- 26507784 TI - [Diabetic macular edema: Diagnosis and pre-treatment work-up]. PMID- 26507785 TI - Two cases of non-prosthetic bone and joint infection due to Propionibacterium acnes. PMID- 26507786 TI - Institutionally based videoconferencing. AB - The delivery of psychiatric care via video-teleconferencing (VTC) technology is thought to have reached a tipping point. As a medical speciality with relatively few material or technical requirements for service delivery, psychiatry has been one of the earliest to embrace the possibility of providing evaluations and treatment at a distance. Such technical infrastructure as is necessary can often be found in the institutions already in existence. It was natural therefore that institutionally based telepsychiatry would lay the foundation for the development of the field. In this article we review the history and development of institutional VTC in a wide variety of clinically supervised settings such as hospitals, outpatient clinics, and forensic settings. We cite evidence supporting institutionally sponsored use and expand on key takeaways for the development and expansion of videoconferencing in these settings. We also speculate on the future direction and development of psychiatric care provided by these arrangements. PMID- 26507787 TI - Increased cytoplasm viscosity hampers aggregate polar segregation in Escherichia coli. AB - In Escherichia coli, under optimal conditions, protein aggregates associated with cellular aging are excluded from midcell by the nucleoid. We study the functionality of this process under sub-optimal temperatures from population and time lapse images of individual cells and aggregates and nucleoids within. We show that, as temperature decreases, aggregates become homogeneously distributed and uncorrelated with nucleoid size and location. We present evidence that this is due to increased cytoplasm viscosity, which weakens the anisotropy in aggregate displacements at the nucleoid borders that is responsible for their preference for polar localisation. Next, we show that in plasmolysed cells, which have increased cytoplasm viscosity, aggregates are also not preferentially located at the poles. Finally, we show that the inability of cells with increased viscosity to exclude aggregates from midcell results in enhanced aggregate concentration in between the nucleoids in cells close to dividing. This weakens the asymmetries in aggregate numbers between sister cells of subsequent generations required for rejuvenating cell lineages. We conclude that the process of exclusion of protein aggregates from midcell is not immune to stress conditions affecting the cytoplasm viscosity. The findings contribute to our understanding of E. coli's internal organisation and functioning, and its fragility to stressful conditions. PMID- 26507788 TI - An isolated Amycolatopsis sp. GDS for cellulase and xylanase production using agricultural waste biomass. AB - AIM: The aim of this study was to evaluate an isolate of Amycolatopsis sp. GDS for cellulase and xylanase production, their characterization, and its application to the preparation of biomass feedstock for ethanol production. METHODS AND RESULTS: A novel potent cellulolytic bacterial strain was isolated and identified as Amycolatopsis sp. GDS. The strain secreted high levels of cellulase and xylanase in the presence of agricultural waste biomass. The enzymes were thermostable and active up to 70 degrees C. Interestingly, the enzymes were expressed well at higher NaCl (up to 2.5 mol l(-1) ) and ionic liquid (10%) concentrations, so that they could be used during the pretreatment of biomass. Enzyme stability in the presence of organic solvents, surfactants and oxidizing agents was also noted. Crude enzymes from Amycolatopsis sp. GDS resulted in comparable saccharification (60%) of wheat straw to commercial enzymes (64%). CONCLUSIONS: The cellulolytic enzymes from Amycolatopsis sp. GDS were stable, expressed well under conditions with various chemicals, and yielded significant amounts of hydrolysates from the biomass. The high bioethanol production using yeast co-cultures with enzymatic hydrolysates highlights the significance of selecting the strain and substrate for biofuel production. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates the importance of the isolate Amycolatopsis sp. GDS that secretes high levels of cellulase and hemicellulase by utilizing agricultural waste biomass and its application in the preparation of biomass feedstock and sequential ethanol fermentation. PMID- 26507790 TI - Validation of a fast UPLC-MS/MS method for quantitative analysis of opioids, cocaine, amphetamines (and their derivatives) in human whole blood. AB - BACKGROUND: Conventional methods for analysis of drugs of abuse require multiple assays which can be both expensive and time-consuming. This work describes a novel, rapid, simple and sensitive method for the quantification of 14 illicit drugs and their metabolites in whole blood. Results/methodology: This method employed a rapid liquid-liquid sample extraction of whole blood followed by UPLC MS/MS analysis. Calibration curves were validated for analysis of appropriate concentrations. Inter- and intra-assay variations were <14.8%. Deviation of accuracy was <14.9% from target concentration for each quality control level. CONCLUSION: This work described the development and the full validation of a precise, sensitive and accurate assay. After validation, this new assay was successfully applied to routine toxicological analysis. PMID- 26507789 TI - A Rigid Hinge Region Is Necessary for High-Affinity Binding of Dimannose to Cyanovirin and Associated Constructs. AB - Mutations in the hinge region of cyanovirin-N (CVN) dictate its preferential oligomerization state. Constructs with the Pro51Gly mutation preferentially exist as monomers, whereas wild-type cyanovirin can form domain-swapped dimers under certain conditions. Because the hinge region is an integral part of the high affinity binding site of CVN, we investigated whether this mutation affects the shape, flexibility, and binding affinity of domain B for dimannose. Our studies indicate that the capability of monomeric wild-type CVN to resist mechanical perturbations is enhanced when compared to that of constructs in which the hinge region is more flexible. Our computational results also show that enhanced flexibility leads to blocking of the binding site by allowing different rotational isomeric states of Asn53. Moreover, at higher temperatures, this observed flexibility leads to an interaction between Asn53 and Asn42, further hindering access to the binding site. On the basis of these results, we predicted that binding affinity for dimannose would be more favorable for cyanovirin constructs containing a wild-type hinge region, whereas affinity would be impaired in the case of mutants containing Pro51Gly. Experimental characterization by isothermal titration calorimetry of a set of cyanovirin mutants confirms this hypothesis. Those possessing the Pro51Gly mutation are consistently inferior binders. PMID- 26507791 TI - Medical Eschatologies: The Christian Spirit of Hospital Protocol. AB - If much has been written of the forms of bodiliness reinforced by hospitals, less attention has been paid to the medicalization of the soul. The medical management of death institutionalizes divisions between body and soul, and matter and spirit, infusing end-of-life care with latent Christian theological presumptions. The invisibility of these presumptions is partly sustained by projecting religiosity on those who endorse other cosmologies, while retaining for medicine a mask of secular science. Stories of conflict with non-Christian patients force these presumptions into visibility, suggesting alternative ethics of care and mourning rooted in other understandings. In this article, I explore one such story. Considering the story as an allegory for how matter and spirit figure in contemporary postmortem disciplines, I suggest that it exposes both the operation of a taboo against mixing material and spiritual agendas, and an assumption that appropriate mourning is oriented toward symbolic homage, rather than concern for the material welfare of the dead. PMID- 26507792 TI - A systematic review and meta-analysis of factors that relate to aggression perpetrated against nurses by patients/relatives or staff. AB - AIMS AND OBJECTIVES: The aim of this meta-analysis was to identify the factors that related to aggression (verbal abuse or physical abuse/assault) perpetrated against the nurse or other health professionals by patients/relatives or staff. In the light of the paucity of systematic reviews on this common issue in nursing, the objective was to present a comprehensive systematic review and meta analysis of these papers. BACKGROUND: Aggression towards nurses is common around the world and can be the impetus for nurses leaving the profession or developing anxiety when working in particular settings. DESIGN: Systematic review with meta analysis. METHODS: Meta-analyses were conducted to assess the effect of the factors of gender and context (dichotomised as mental health/psychiatric or nonmental health/psychiatric). The databases of Medline (1966-2015), CINAHL (1982 2015) and PsychInfo (1920-2015). RESULTS: A total of 1571 papers were screened by two reviewers. At the final decision 14 were selected for analysis. A higher proportion of female nurses than male nurses were reported to be the victims of verbal abuse, with the difference in proportions being statistically significant. A statistically significant higher proportion of male nurses than female nurses were reported to be the victims of physical abuse. There was a significantly higher proportion of mental health nurses reported experiencing physical abuse as compared to nonmental health nurses. CONCLUSIONS: The analysis reveal female nurses have greater odds of verbal abuse than male nurses and male nurses have greater odds of physical abuse than female nurses. Overall mental health nurses had three times higher odds of physical assault than other nurses. RELEVANCE TO CLINICAL PRACTICE: In the light of the findings it is recommended organisational support improve in high aggression potential clinical areas and for nursing curriculums to incorporate education about the management of challenging behaviours in undergraduate programmes. PMID- 26507793 TI - The clinical characteristics of congenital laryngeal saccular cysts. AB - CONCLUSION: The first step when treating newborns and infants with hoarseness and dyspnea is to consider the possibility of CLSCs. The appropriate operation can then be chosen based on the cyst sub-type. Complete resection of the cyst wall is the key to preventing recurrence. BACKGROUND: A laryngeal saccular cyst is an unusual congenital lesion that appears clinically during the neonatal period or early infancy. Because few reports on congenital laryngeal saccular cysts (CLSCs) exist, this study investigated the clinical features of patients with a history of CLSCs to determine the clinical characteristics of this disease. METHODS: The data from 28 CLSC patients admitted to Beijing Tongren Hospital from July 2004 to September 2014 were reviewed. Gender, age at onset of symptoms, number of surgical procedures performed, effect of the operation, and CLSC classification were analyzed. RESULTS: CLSCs accounted for 0.79% of laryngeal operations during the study period. Of the cases examined, 35.7% (10/28) had first been treated as laryngomalacia. With respect to cyst type, 17.9% (5/28) were anterior laryngeal saccular cysts, and 82.1% (23/28) were lateral saccular cysts. The patients underwent a total of 53 surgeries, including 21 procedures performed at other hospitals. The time to recurrence of the cysts following needle aspiration ranged from 5-10 days. The time to recurrence after the roof of the cyst was excised ranged from 1-10 months. There were no recurrences after the complete resection of the cyst wall using a CO2 laser and microsuturing of the wound surfaces via an endoscopic procedure, which is much better than the 41% of endoscopic de-roofing cases which recurred reported by Mitchell et al. PMID- 26507794 TI - Care Quality Commission's unfair treatment of Addenbrooke's Hospital. PMID- 26507795 TI - Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD-deficient IGFBP-2 variant in female transgenic mice. AB - Impaired growth is often associated with an extension of lifespan. However, the negative correlation between somatic growth and life expectancy is only true within, but not between, species. This can be observed because smaller species have, as a rule, a shorter lifespan than larger species. In insects and worms, reduced reproductive development and increased fat storage are associated with prolonged lifespan. However, in mammals the relationship between the dynamics of reproductive development, fat metabolism, growth rate, and lifespan are less clear. To address this point, female transgenic mice that were overexpressing similar levels of either intact (D-mice) or mutant insulin-like growth factor binding protein-2 (IGFBP-2) lacking the Arg-Gly-Asp (RGD) motif (E- mice) were investigated. Both lines of transgenic mice exhibited a similar degree of growth impairment (-9% and -10%) in comparison with wild-type controls (C-mice). While in D-mice, sexual maturation was found to be delayed and life expectancy was significantly increased in comparison with C-mice, these parameters were unaltered in E-mice in spite of their reduced growth rate. These observations indicate that the RGD-domain has a major influence on the pleiotropic effects of IGFBP-2 and suggest that somatic growth and time of sexual maturity or somatic growth and life expectancy are less closely related than thought previously. PMID- 26507796 TI - Targeting DNA repair, DNA metabolism and replication stress as anti-cancer strategies. AB - Anti-cancer therapies targeting and damaging the DNA have been extensively used in the last 50 years since the discovery of nitrogen mustards, antimetabolites and platin agents. The use of these drugs is often limited by dose-limiting side effects related to their poor specificity. In recent years, much effort has been put on the discovery and development of compounds that would exploit defects in DNA repair in cancer cells such as Wee1, Chk1 or PARP1 inhibitors. However, not all cancers respond to these inhibitors. Recently, new developments towards specifically targeting broader characteristics of cancer such as replication stress (RS) and lost redox homeostasis have emerged. Oncogenes induce proliferation signals, which also result in replication-associated DNA damage, i.e. RS. Our knowledge into overall causes of RS, lesions produced and how these are signalled in cells to activate cell cycle checkpoints is evolving. Inhibition of ATR, which would normally keep non-deleterious levels of RS, induces intolerable RS levels for cancer cells. Interestingly, links between replication and transcription appear to underlie RS along with a reduction of the dNTP pool. Remarkably, sanitization of the dNTP pool by MutT homologue 1, impeding incorporation of oxidized dNTPs into the DNA, seems to be crucial for cancer cell survival. In this minireview we present an overview of current and novel strategies to target DNA repair and exploit DNA damage to treat cancer. We present the current models for cancer-associated RS as well as cancer phenotypic lethality. Both strategies are poised to better target cancer cells and reduce side effects. PMID- 26507797 TI - Molecular Evolution of Drosophila Germline Stem Cell and Neural Stem Cell Regulating Genes. AB - Here, we study the molecular evolution of a near complete set of genes that had functional evidence in the regulation of the Drosophila germline and neural stem cell. Some of these genes have previously been shown to be rapidly evolving by positive selection raising the possibility that stem cell genes as a group have elevated signatures of positive selection. Using recent Drosophila comparative genome sequences and population genomic sequences of Drosophila melanogaster, we have investigated both long- and short-term evolution occurring across these two different stem cell systems, and compared them with a carefully chosen random set of genes to represent the background rate of evolution. Our results showed an excess of genes with evidence of a recent selective sweep in both germline and neural stem cells in D. melanogaster. However compared with their control genes, both stem cell systems had no significant excess of genes with long-term recurrent positive selection in D. melanogaster, or across orthologous sequences from the melanogaster group. The evidence of long-term positive selection was limited to a subset of genes with specific functions in both the germline and neural stem cell system. PMID- 26507798 TI - Methylated Cytosines Mutate to Transcription Factor Binding Sites that Drive Tetrapod Evolution. AB - In mammals, the cytosine in CG dinucleotides is typically methylated producing 5 methylcytosine (5mC), a chemically less stable form of cytosine that can spontaneously deaminate to thymidine resulting in a T*G mismatched base pair. Unlike other eukaryotes that efficiently repair this mismatched base pair back to C*G, in mammals, 5mCG deamination is mutagenic, sometimes producing TG dinucleotides, explaining the depletion of CG dinucleotides in mammalian genomes. It was suggested that new TG dinucleotides generate genetic diversity that may be critical for evolutionary change. We tested this conjecture by examining the DNA sequence properties of regulatory sequences identified by DNase I hypersensitive sites (DHSs) in human and mouse genomes. We hypothesized that the new TG dinucleotides generate transcription factor binding sites (TFBS) that become tissue-specific DHSs (TS-DHSs). We find that 8-mers containing the CG dinucleotide are enriched in DHSs in both species. However, 8-mers containing a TG and no CG dinucleotide are preferentially enriched in TS-DHSs when compared with 8-mers with neither a TG nor a CG dinucleotide. The most enriched 8-mer with a TG and no CG dinucleotide in tissue-specific regulatory regions in both genomes is the AP-1 motif ( TG: A(C)/GT CA: N), and we find evidence that TG dinucleotides in the AP-1 motif arose from CG dinucleotides. Additional TS-DHS enriched TFBS containing the TG/CA dinucleotide are the E-Box motif (G CA: GC TG: C), the NF-1 motif (GG CATG: CC), and the GR (glucocorticoid receptor) motif (G-A CATG: T-C). Our results support the suggestion that cytosine methylation is mutagenic in tetrapods producing TG dinucleotides that create TFBS that drive evolution. PMID- 26507799 TI - Chlamydiaceae Genomics Reveals Interspecies Admixture and the Recent Evolution of Chlamydia abortus Infecting Lower Mammalian Species and Humans. AB - Chlamydiaceae are obligate intracellular bacteria that cause a diversity of severe infections among humans and livestock on a global scale. Identification of new species since 1989 and emergence of zoonotic infections, including abortion in women, underscore the need for genome sequencing of multiple strains of each species to advance our knowledge of evolutionary dynamics across Chlamydiaceae. Here, we genome sequenced isolates from avian, lower mammalian and human hosts. Based on core gene phylogeny, five isolates previously classified as Chlamydia abortus were identified as members of Chlamydia psittaci and Chlamydia pecorum. Chlamydia abortus is the most recently emerged species and is a highly monomorphic group that lacks the conserved virulence-associated plasmid. Low level recombination and evidence for adaptation to the placenta echo evolutionary processes seen in recently emerged, highly virulent niche-restricted pathogens, such as Bacillus anthracis. In contrast, gene flow occurred within C. psittaci and other Chlamydiaceae species. The C. psittaci strain RTH, isolated from a red tailed hawk (Buteo jamaicensis), is an outlying strain with admixture of C. abortus, C. psittaci, and its own population markers. An average nucleotide identity of less than 94% compared with other Chlamydiaceae species suggests that RTH belongs to a new species intermediary between C. psittaci and C. abortus. Hawks, as scavengers and predators, have extensive opportunities to acquire multiple species in their intestinal tract. This could facilitate transformation and homologous recombination with the potential for new species emergence. Our findings indicate that incubator hosts such as birds-of-prey likely promote Chlamydiaceae evolution resulting in novel pathogenic lineages. PMID- 26507800 TI - Hypothalamus-Pituitary-Adrenal Axis Hypersuppression Is Associated with Gastrointestinal Symptoms in Major Depression. AB - BACKGROUND/AIMS: Gastrointestinal symptoms and hypothalamus-pituitary-adrenal (HPA) axis dysfunction are frequently observed in patients with major depression. The primary aim of the study was to investigate the relationship between HPA-axis function and self-perceived functional gastrointestinal symptoms in major depression. METHODS: Patients with major depression (n = 73) and controls representative of the general population (n = 146) underwent a weight adjusted very low dose dexamethasone suppression test (DST). Patients and controls completed the gastrointestinal symptom rating scale-iritable bowel syndrome (GSRS IBS) and the hospital anxiety depression scale. Medical records of the patients were screened over a ten year period for functional gastrointestinal disorder and pain conditions. RESULTS: Patients with high GSRS-IBS scores (above median) exhibited HPA-axis hypersuppression more often than controls (defined by the lowest 10% cutoff of the post-DST cortisol values among controls, adjusted OR 7.25, CI 1.97-26.7) whereas patients with low GSRS-IBS scores did not differ from controls concerning their post-DST cortisol values. Patients who had consulted primary care for functional gastrointestinal disorder (P = 0.039), lumbago (P = 0.006) and chronic multifocal pain (P = 0.057) also exhibited an increased frequency of hypersuppression. CONCLUSIONS: HPA-axis hypersuppression is associated with functional gastrointestinal symptoms in patients with major depression. PMID- 26507801 TI - Comment on: 'Anthropometric parameters in relation to glycaemic status and lipid profile in a multi-ethnic sample in Italy' by Gualdi-Russo et al. PMID- 26507802 TI - Aquation Is a Crucial Activation Step for Anticancer Action of Ruthenium(II) Polypyridyl Complexes to Trigger Cancer Cell Apoptosis. AB - Aquation has been proposed as crucial chemical action step for ruthenium (Ru) complexes, but its effects on the action mechanisms remain elusive. Herein, we have demonstrated the aquation process of a potent Ru polypyridyl complex (RuBmp=[Ru(II) (bmbp)(phen)Cl]ClO4 , bmbp=2,6-bis(6-methylbenzimidazol-2-yl) pyridine, phen=phenanthroline) with a chloride ligand, and revealed that aquation of RuBmp effectively enhanced its hydrophilicity and cellular uptake, thus significantly increasing its anticancer efficacy. The aquation products (H RuBmp=[Ru(II) (bmbp)(phen)Cl]ClO4 , [Ru(II) (bmbp)(phen)(H2 O)]ClO4 , bmbp) exhibited a much higher apoptosis-inducing ability than the intact complex, with involvement of caspase activation, mitochondria dysfunction, and interaction with cell membrane death receptors. H-RuBmp demonstrated a higher interaction potency with the cell membrane and induced higher levels of ROS overproduction in cancer cells to regulate the AKT, MAPK, and p53 signaling pathways. Taken together, this study could provide useful information for fine-tuning the rational design of next-generation metal medicines. PMID- 26507804 TI - Letter in reply to Riggan et al. Re: External validation of the paracetamol aminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose. PMID- 26507805 TI - Intrathecal CD4(+) and CD8(+) T-cell responses to endogenously synthesized candidate disease-associated human autoantigens in multiple sclerosis patients. AB - MS pathology is potentially orchestrated by autoreactive T cells, but the antigens recognized remain unknown. A novel APC/T-cell platform was developed to determine intrathecal CD4(+) and CD8(+) T-cell responses to candidate MS associated autoantigens (cMSAg) in clinically isolated syndrome (CIS, n = 7) and MS (n = 6) patients. Human cMSAg encoding open reading frames (n = 8) were cloned into an Epstein-Barr virus (EBV)-based vector to express cMSAg at high levels in EBV-transformed B-cells (BLCLs). Human cMSAg cloned were myelin-associated and oligodendrocyte glycoprotein, myelin basic protein, proteolipid protein, ATP dependent potassium channel ATP-dependent inwards rectifying potassium channel 4.1, S100 calcium-binding protein B, contactin-2, and neurofascin. Transduced BLCLs were used as autologous APC in functional T-cell assays to determine cMSAg specific T-cell frequencies in cerebrospinal fluid derived T-cell lines (CSF TCLs) by intracellular IFN-gamma flow cytometry. Whereas all CSF-TCL responded strongly to mitogenic stimulation, no substantial T-cell reactivity to cMSAg was observed. Contrastingly, measles virus fusion protein-specific CD4(+) and CD8(+) T-cell clones, used as control of the APC/T-cell platform, efficiently recognized transduced BLCL expressing their cognate antigen. The inability to detect substantial T-cell reactivity to eight human endogenously synthesized cMSAg in autologous APC do not support their role as prominent intrathecal T-cell target antigens in CIS and MS patients early after onset of disease. PMID- 26507806 TI - Stacking of the mutagenic base analogue 5-bromouracil: energy landscapes of pyrimidine dimers in gas phase and water. AB - The potential energy surfaces of stacked base pairs consisting of cytosine (C), thymine (T), uracil (U) and the mutagenic thymine analogue 5-bromouracil (BrU) have been searched to obtain all possible minima. Minima and transition states were optimised at the counterpoise-corrected M06-2X/6-31+G(d) level, both in the gas phase and in water, modelled by the polarizable continuum model. The stacked dimers studied are BrU/BrU, C/BrU, C/C, C/T, C/U, T/BrU and T/U. Both face-to back and face-to-face structures were considered. Free energies were calculated at 298.15 K. Together with U/U, T/T and BrU/U results from previous work, these results complete the family consisting of every stacked dimer combination consisting of C, T, U and BrU. The results were used to assess the hypothesis suggested in the literature that BrU stacks stronger than T, which could stabilise the mispair formed by BrU and guanine. In the gas phase, structures of C/BrU, T/BrU and U/BrU with greater zero-point-corrected binding energies than C/T, T/T and U/T, respectively, were found, with differences in favour of BrU of 3.1 kcal mol(-1), 1.7 kcal mol(-1) and 0.5 kcal mol(-1), respectively. However, the structure of these dimers differed considerably from anything encountered in DNA. When only the dimers with the most "DNA-like" twist (+/-36 degrees ) were considered, C/BrU and T/BrU were still more strongly bound than C/T and T/T, by 0.5 kcal mol(-1) and 1.7 kcal mol(-1), respectively. However, when enthalpic and/or solvent contributions were taken into account, the stacking advantage of BrU was reversed in the gas phase and mostly nullified in water. Enhanced stacking therefore does not seem a plausible mechanism for the considerably greater ability of BrU-G mispairs over T-G mispairs to escape enzymatic repair. PMID- 26507807 TI - A compact process for treating oilfield wastewater by combining hydrolysis acidification, moving bed biofilm, ozonation and biologically activated carbon techniques. AB - A lab-scale hybrid system integrating a hybrid hydrolysis acidification (HA) reactor, a moving bed biofilm reactor (MBBR) and an ozonation-biologically activated carbon (O3-BAC) unit was used in the treatment of heavy oil wastewater with high chemical oxygen demand (COD) and low biodegradability. The effects of hydraulic retention time and ozonation time were investigated. The results show that under the optimal conditions, the effluent concentrations of COD, oil and ammonia were 48, 1.3 and 3.5 mg/L, respectively, corresponding to total removal efficiencies of 95.8%, 98.9% and 94.4%, respectively. The effluent could meet the grade I as required by the national discharge standard of China. The HA process remarkably improved the biodegradability of the wastewater, while the MBBR process played an important role in degrading COD. The ozonation process further enhanced the biodegradability of the MBBR effluent, and finally, deep treatment was completed in the BAC reactor. This work demonstrates that the hybrid HA/MBBR/O3-BAC system has the potential to be used for the treatment of high strength oilfield wastewater. PMID- 26507808 TI - Tunable Microfibers Suppress Fibrotic Encapsulation via Inhibition of TGFbeta Signaling. AB - Fibrotic encapsulation limits the efficacy and lifetime of implantable biomedical devices. Microtopography has shown promise in the regulation of myofibroblast differentiation, a key driver of fibrotic encapsulation. However, existing studies have not systematically isolated the requisite geometric parameters for suppression of myofibroblast differentiation via microtopography, and there has not been in vivo validation of this technology to date. To address these issues, a novel lamination method was developed to afford more control over topography dimensions. Specifically, in this study we focus on fiber length and its effect on myofibroblast differentiation. Fibroblasts cultured on films with microfibers exceeding 16 MUm in length lost the characteristic morphology associated with myofibroblast differentiation, while shorter microfibers of 6 MUm length failed to produce this phenotype. This increase in length corresponded to a 50% decrease in fiber stiffness, which acts as a mechanical cue to influence myofibroblast differentiation. Longer microfiber films suppressed expression of myofibroblast specific genes (alphaSMA, Col1alpha2, and Col3alpha1) and TGFbeta signaling components (TGFbeta1, TbetaR2, and Smad3). About 16 MUm long microfiber films subcutaneously implanted in a mouse wound-healing model generated a substantially thinner fibrotic capsule and less deposition of collagen in the wound bed. Together, these results identify a critical feature length threshold for microscale topography-mediated repression of fibrotic encapsulation. This study also demonstrates a simple and powerful strategy to improve surface biocompatibility and reduce fibrotic encapsulation around implanted materials. PMID- 26507810 TI - Utility of Isovolumic Contraction Peak Velocity for Evaluation of Adult Patient Status after Transcatheter Closure of Atrial Septal Defect. PMID- 26507811 TI - Reply. PMID- 26507813 TI - Hepatoprotective iridoid glucosides from Callicarpa nudiflora. AB - Two new iridoid glucosides, callicoside A (1) and callicoside B (2), were isolated from the leaves of Callicarpa nudiflora. Their structures were elucidated by means of spectroscopic methods and chemical evidences. In an in vitro bioassay, compound 1 showed pronounced hepatoprotective activity against D galactosamine-induced toxicity in WB-F344 rat hepatic epithelial stem-like cells. PMID- 26507814 TI - Auditory feedback blocks memory benefits of cueing during sleep. AB - It is now widely accepted that re-exposure to memory cues during sleep reactivates memories and can improve later recall. However, the underlying mechanisms are still unknown. As reactivation during wakefulness renders memories sensitive to updating, it remains an intriguing question whether reactivated memories during sleep also become susceptible to incorporating further information after the cue. Here we show that the memory benefits of cueing Dutch vocabulary during sleep are in fact completely blocked when memory cues are directly followed by either correct or conflicting auditory feedback, or a pure tone. In addition, immediate (but not delayed) auditory stimulation abolishes the characteristic increases in oscillatory theta and spindle activity typically associated with successful reactivation during sleep as revealed by high-density electroencephalography. We conclude that plastic processes associated with theta and spindle oscillations occurring during a sensitive period immediately after the cue are necessary for stabilizing reactivated memory traces during sleep. PMID- 26507815 TI - Flu vaccine and egg allergy. PMID- 26507816 TI - Fighting Ebola in Sierra Leone: a view from the frontline. AB - The largest and most complex Ebola epidemic in history is believed to have started with the infection of a 2-year-old boy in South-eastern Guinea in late 2013. Within a year, thousands of children and their families had contracted the virus, many had died and many more were orphaned. We reflect on our experiences of volunteering at the Kerry Town Ebola Treatment Centre in Sierra Leone between January and February 2015, where we were deployed to care for just a few of these children as part of the Save The Children team. PMID- 26507817 TI - [Antimicrobial resistance]. PMID- 26507821 TI - Impact of the Professional Component MPPR Policy on Interdivisional Finances in an Academic Radiology Department. AB - PURPOSE: The professional component (PC) Multiple Procedure Payment Reduction (MPPR) policy reduces reimbursement for two or more imaging services rendered by the same group practice for a single patient in a single session. The purpose of this study was to analyze the impact of the PC MPPR on interdivisional finances in an academic radiology department. METHODS: A retrospective analysis of Medicare collections from imaging services rendered by a single academic radiology department in a tertiary care medical center for calendar year 2014 was performed. The impact of the PC MPPR on each division was calculated as the fraction of the total departmental PC MPPR, and as the proportion of the divisional revenue. RESULTS: The total decrease in Medicare collections as a result of the PC MPPR was 5.35%. The impact of the PC MPPR on each division as a fraction of the total departmental PC MPPR was: abdominal division (16.63%); thoracic division (23.56%); breast division (0.03%); musculoskeletal division (11.92%); neuroradiology division (34.40%); and noninvasive cardiovascular division (13.46%). The impact of the PC MPPR on each division as a fraction of the divisional revenue was: abdominal (2.82%); thoracic (11.83%); breast (0.66%); musculoskeletal (6.01%); neuroradiology (5.31%); and noninvasive cardiovascular (5.85%). CONCLUSIONS: The PC MPPR differentially affects divisions within an academic radiology department. The neuroradiology and thoracic divisions of our department were the most adversely affected, owing to the high frequency of combined examinations. We speculate that this impact has implications for divisional self-sufficiency, interdivisional relationships, and resident decision making regarding subspecialty training. PMID- 26507822 TI - Emergency Department CT Expediency: A Time Reduction by Redesign. PMID- 26507823 TI - Lung CT Screening Reporting and Data System Speed and Accuracy Are Increased With the Use of a Semiautomated Computer Application. AB - PURPOSE: The Lung CT Screening Reporting and Data System (Lung-RADSTM) is an algorithm that can be used to classify lung nodules in patients with significant smoking histories. It is published in table format but can be implemented as a computer program. The aim of this study was to assess the efficiency and accuracy of the use of a computer program versus the table in categorizing lung nodules. METHODS: The Lung-RADS algorithm was implemented as a computer program. Through the use of a survey tool, respondents were asked to categorize 13 simulated lung nodules using the computer program and the Lung-RADS table as published. Data were gathered regarding time to completion, accuracy of each nodule's categorization, users' subjective categorization confidence, and users' perceived efficiency using each method. RESULTS: The use of a computer program to categorize lung nodules resulted in significantly increased interpretation speed (80.8 +/- 37.7 vs 156 +/- 105 seconds, P < .0001), lung nodule classification accuracy (99.6% vs 76.5%, P < .0001), and perceived confidence and efficiency compared with the use of the table. There were no significant differences in accuracy when comparing thoracic radiologists with the remainder of the group. CONCLUSIONS: Radiologists were both more efficient and more accurate in lung nodule categorization when using computerized decision support tools. The authors propose that other institutions use computerized implementations of Lung-RADS in the interests of both efficiency and patient outcomes through proper management. Furthermore, they suggest the ACR design future iterations of the Lung-RADS algorithm with computerized decision support in mind. PMID- 26507824 TI - The clock is ticking: the rate and timeliness of antiretroviral therapy initiation from the time of treatment eligibility in Kenya. AB - INTRODUCTION: Understanding the determinants of timely antiretroviral therapy (ART) initiation is useful for HIV programmes intent on developing models of care that reduce delays in treatment initiation while maintaining a high quality of care. We analysed patient- and facility-level determinants of time to ART initiation among patients who initiated ART in Kenya. METHODS: We collected facility-level information and conducted a retrospective chart review of adults initiating ART between 2007 and 2012 at 51 health facilities in Kenya. We evaluated the association between patient- and facility-level covariates at the time of ART eligibility and time to ART initiation. We also explored the determinants associated with timeliness of ART initiation. RESULTS: The analysis included 11,942 patients. The median age at the time eligibility was first determined was 37 years (interquartile range [IQR] 31-45). Overall, 75% of patients initiated ART within two months of eligibility. The median CD4 cell count at the time eligibility was first determined rose from 132 (IQR 51-217) in 2007 to 195 (IQR 91-286) in 2011 to 2012 (p<0.001). The cumulative probability of ART initiation among treatment-eligible patients increased over time: 87.1% (95% confidence interval [CI] 85.1-89.0%) in 2007; 96.8% (96.0-97.5%) in 2008; 97.1% (96.3-97.7%) in 2009; 98.5% (98.0 -98.9%) in 2010; and 99.7% (95% CI 99.4 -99.8%) in 2011 to 2012 (p<0.0001). In multivariate analyses, attending a health facility with high ART patient volumes within two months of eligibility was considered the key facility-level determinant of ART initiation (adjusted odds ratio 0.57, 95% CI 0.45-0.72, p<0.001). Patient-level determinants included being eligible for ART in the years subsequent to 2007, advanced World Health Organization clinical stage and low CD4 cell count at the time eligibility was first determined. CONCLUSIONS: Overall, the time between treatment eligibility and ART initiation decreased substantially in Kenya between 2007 and 2012, with uniform gains across different types of health facilities. Our findings highlight the slow increase in CD4 cell counts at the time of ART eligibility over time, indicating that a large number of patients are still beginning ART with advanced HIV disease. Our findings also support the decentralisation of ART services at all health facilities that have the capacity to initiate treatment. Continued evaluation of programme- and country-level data is needed to monitor timeliness of ART initiation as countries continue to expand treatment access. PMID- 26507825 TI - The Cancer Genome Atlas Clinical Explorer: a web and mobile interface for identifying clinical-genomic driver associations. AB - BACKGROUND: The Cancer Genome Atlas (TCGA) project has generated genomic data sets covering over 20 malignancies. These data provide valuable insights into the underlying genetic and genomic basis of cancer. However, exploring the relationship among TCGA genomic results and clinical phenotype remains a challenge, particularly for individuals lacking formal bioinformatics training. Overcoming this hurdle is an important step toward the wider clinical translation of cancer genomic/proteomic data and implementation of precision cancer medicine. Several websites such as the cBio portal or University of California Santa Cruz genome browser make TCGA data accessible but lack interactive features for querying clinically relevant phenotypic associations with cancer drivers. To enable exploration of the clinical-genomic driver associations from TCGA data, we developed the Cancer Genome Atlas Clinical Explorer. DESCRIPTION: The Cancer Genome Atlas Clinical Explorer interface provides a straightforward platform to query TCGA data using one of the following methods: (1) searching for clinically relevant genes, micro RNAs, and proteins by name, cancer types, or clinical parameters; (2) searching for genomic/proteomic profile changes by clinical parameters in a cancer type; or (3) testing two-hit hypotheses. SQL queries run in the background and results are displayed on our portal in an easy-to-navigate interface according to user's input. To derive these associations, we relied on elastic-net estimates of optimal multiple linear regularized regression and clinical parameters in the space of multiple genomic/proteomic features provided by TCGA data. Moreover, we identified and ranked gene/micro RNA/protein predictors of each clinical parameter for each cancer. The robustness of the results was estimated by bootstrapping. Overall, we identify associations of potential clinical relevance among genes/micro RNAs/proteins using our statistical analysis from 25 cancer types and 18 clinical parameters that include clinical stage or smoking history. CONCLUSION: The Cancer Genome Atlas Clinical Explorer enables the cancer research community and others to explore clinically relevant associations inferred from TCGA data. With its accessible web and mobile interface, users can examine queries and test hypothesis regarding genomic/proteomic alterations across a broad spectrum of malignancies. PMID- 26507826 TI - Craniula: A cranial window technique for prolonged imaging of brain surface vasculature with simultaneous adjacent intracerebral injection. AB - BACKGROUND: Imaging of the brain surface vasculature following inflammatory insults is critical to study structural and functional changes in the living brain under normal and pathological conditions. Although there have been published reports relating to the changes that occur in the blood brain barrier (BBB) during the inflammatory process, the ability to visualize and track such changes in vivo and over time has proven to be problematic. Different techniques have been used to achieve visualization of pial vessels, but the approach has limits, which can jeopardize the well-being of the animals. Development of the cranial window technique provided a major advance in the acquisition of live images of the brain vasculature and its response to different insults and treatments. METHODS: We describe in detail a protocol for delivery of a localized inflammatory insult to the mouse brain via a craniula (cranial window and adjacent cannula) and subsequent imaging of the mouse brain vasculature by intravital microscopy and two-photon laser scanning microscopy. The surgical implantation of the craniula can be completed in 30-45 min and images can be acquired immediately and for several months thereafter. The technique is minimally invasive and permits serial injections directly to the brain, thereby allowing longitudinal imaging studies. The craniula technique permits the study of structural and functional changes of the BBB following inflammatory insult and as such has wide application to neuroscience research. PMID- 26507827 TI - Implementation of the trans-abdominal partial extra-peritoneal (TAPE) technique in laparoscopic lumbar hernia repair. AB - BACKGROUND: There is still not any standardized operative strategy that is well accepted all over the world for lumbarhernia. We are here to investigate the feasibility of the trans-abdominal partial extra-peritoneal (TAPE) technique in lumbar hernia repair. METHODS: The TAPE technique was applied to 14 patients with lumbar hernia from May 2009 until January 2014. The surgical technique was described in details and follow-ups were performed for further evaluation. RESULTS: The mean age of the 14 patients was 68 +/- 8 years, with the average BMI 25.5 +/- 2.1 kg/m(2). The etiology study showed that 13 cases after surgical operations and one case after trauma. The average size of the hernia defect was 86.8 +/- 46.4 cm(2), while the mean size of the mesh implanted was 275 +/- 61.2 cm(2). The mean operative time was 59.2 +/- 8.2 min. There was no intra-operative visceral injury in this serial of cases. There was no conversion case and all patients accepted the TAPE technique successfully. The VAS was 3.8 +/- 1.9 and 2.2 +/- 1.6 on POD1 and POD3, respectively. The mean post-operative hospital stay was 4.0 +/- 1.3 days. The median follow-up time was 33 months. All patients returned to unrestricted movement within 2 weeks after surgery. During the follow ups, no complication as bulge, seroma, hematoma, wound infection, abscess in surgical area and chronic pain, nor recurrence was observed. CONCLUSIONS: According to our experience in this series of investigations, the TAPE could be a feasible and easy-to-learn technique which can be applied to most of the lumbar hernia repairs. PMID- 26507828 TI - A longitudinal assessment of changes in bacterial community composition associated with the development of periodontal disease in dogs. AB - Periodontal disease is the most widespread oral disease in dogs. Whilst the involvement of bacteria in the aetiology of periodontitis is well established the role of individual species and their complex interactions with the host is not well understood. The objective of this research was therefore to perform a longitudinal study in dogs to identify the changes that occur in subgingival bacterial communities during the transition from mild gingivitis to the early stages of periodontitis (<25% attachment loss). Subgingival plaque samples were collected from individual teeth of 52 miniature schnauzer dogs every six weeks for up to 60 weeks. The microbial composition of plaque samples was determined using 454-pyrosequencing of the 16S rDNA. A group of aerobic Gram negative species, including Bergeyella zoohelcum COT-186, Moraxella sp. COT-017, Pasteurellaceae sp. COT-080, and Neisseria shayeganii COT-090 decreased in proportion as teeth progressed to mild periodontitis. In contrast, there was less evidence that increases in the proportion of individual species were associated with the onset of periodontitis, although a number of species (particularly members of the Firmicutes) became more abundant as gingivitis severity increased. There were small increases in Shannon diversity, suggesting that plaque community membership remains relatively stable but that bacterial proportions change during progression into periodontitis. This is the first study to demonstrate the temporal dynamics of the canine oral microbiota; it showed that periodontitis results from a microbial succession predominantly characterised by a reduction of previously abundant, health associated taxa. PMID- 26507829 TI - Emergence of a Pseudorabies virus variant with increased virulence to piglets. AB - Pseudorabies virus (PRV) causes Pseudorabies (PR), an economically important disease in domestic swine. PR outbreaks on pig farms caused by PRV variant strains in Bartha-K61-vaccinated pigs have resulted in considerable economic losses in China since 2011. In this study, the pathogenicity of the PRV variant JS-2012 strain to pigs was investigated by experimentally inoculating piglets of different ages in comparison with a classic virulent PRV SC strain. The JS-2012 strain caused an earlier onset of clinical signs and higher mortality in 15, 30, and 60-day-old pigs, as compared with a classic virulent PRV SC strain. The Bartha-K61 vaccination provided complete protection against challenge with classical virulent PRV, but only partial protection against challenge with the JS 2012 strain in piglets. In conclusion, the increased virulence of the PRV variant may have partly contributed to the PR outbreak in China. PMID- 26507830 TI - Biofilm formation of Francisella noatunensis subsp. orientalis. AB - Francisella noatunensis subsp. orientalis (Fno) is an emergent fish pathogen in both marine and fresh water environments. The bacterium is suspected to persist in the environment even without the presence of a suitable fish host. In the present study, the influence of different abiotic factors such as salinity and temperature were used to study the biofilm formation of different isolates of Fno including intracellular growth loci C (iglC) and pathogenicity determinant protein A (pdpA) knockout strains. Finally, we compared the susceptibility of planktonic and biofilm to three disinfectants used in the aquaculture and ornamental fish industry, namely Virkon((r)), bleach and hydrogen peroxide. The data indicates that Fno is capable of producing biofilms within 24 h where both salinity as well as temperature plays a role in the growth and biofilm formation of Fno. Mutations in the iglC or pdpA, both known virulence factors, do not appear to affect the capacity of Fno to produce biofilms, and the minimum inhibitory concentration, and minimum biocidal concentration for the three disinfectants were lower than the minimum biofilm eradication concentration values. This information needs to be taken into account if trying to eradicate the pathogen from aquaculture facilities or aquariums. PMID- 26507831 TI - Pharmacological Options for Smoking Cessation in Heavy-Drinking Smokers. AB - There is a high prevalence of comorbid tobacco use and alcohol use disorder (AUD), affecting more than 6 million people in the US. Globally, tobacco and alcohol use rank fourth and fifth, respectively, for disability-adjusted life years lost. Levels of alcohol use are higher in smokers than nonsmokers, and the prevalence of smoking is higher in heavy drinkers compared with nondrinkers. This relationship is driven by many different factors, including genetics, neurobiological mechanisms, conditioning processes, and psychosocial influences. Although this unique population tends to experience more negative health consequences, more severe AUD, and poorer response to treatment than those with either AUD or tobacco use disorder alone, there are currently no available treatment protocols tailored to this comorbid condition. In this review, we provide a comprehensive review of ongoing clinical research into smoking cessation options for heavy-drinking smokers (HDS) through an evaluation of the effect of promising novel pharmacotherapies as well as combination therapies, including varenicline, naltrexone, the combination of varenicline and naltrexone, and the combination of naltrexone and nicotine replacement therapy (NRT). These treatments are considered in light of the standard of care for smoking cessation, and seek to improve upon the available guidelines for this sizeable subgroup of smokers, namely those smokers who drink heavily. PMID- 26507832 TI - Practical Use of Newer Antiepileptic Drugs as Adjunctive Therapy in Focal Epilepsy. AB - This article lays the background for, and discusses the practical issues surrounding, the adjunctive use of the last four antiepileptic drugs (AEDs) to be licensed for the treatment of pharmacoresistant focal seizures in the UK and elsewhere. More than 30% of adolescent and adult patients will not be fully controlled on the currently available therapeutic armamentarium. After not responding to their first three AED schedules, only a handful of patients attained seizure freedom on subsequent regimens. To optimise the response to any new AED in this setting, it is often necessary to reduce the existing drug burden. The pharmacology, tolerability and safety, and everyday use of lacosamide, eslicarbazepine acetate, retigabine (ezogabine) and perampanel will be reviewed and discussed. This will be accompanied by data from prospective audits with each drug undertaken at the Western Infirmary in Glasgow, Scotland, and a report of their successful introduction in an illustrative case. Overall, there is a large variation in the course of refractory epilepsy and the effect of AED therapy on this process seems minimal. Nevertheless, a number of patients will benefit from the introduction of each new AED, with some becoming seizure free. PMID- 26507833 TI - Drug-Induced Progressive Multifocal Leukoencephalopathy: A Comprehensive Analysis of the WHO Adverse Drug Reaction Database. AB - OBJECTIVE: To identify safety signals concerning the association between the use of various drug classes and the onset of progressive multifocal leukoencephalopathy (PML). METHODS: All reports containing suspected or interacting PML-related or leukoencephalopathy-related drugs, held in the World Health Organization spontaneous individual case safety reports database as at 1 September 2014, were retrieved. We identified safety signals by analysing the drug-reaction pairs, using the reporting odds ratio as a measure of disproportionality. A safety signal was defined if a drug was reported more than twice in PML cases with a reporting odds ratio >2 and a lower 95 % confidence limit >1. RESULTS: We retrieved 2452 reports associated with PML (N = 1612), leukoencephalopathy (N = 835) or both (N = 5), corresponding to 343 different drugs. PML was reported similarly in male and female adults (18-64 years), and almost 30 % of the cases had a fatal outcome. The most frequent Anatomical Therapeutic Chemical (ATC) classification groups concerned antineoplastic agents (23.5 %), antivirals for systemic use (10.1 %) or immunostimulants (4.6 %). Significant disproportionality was found for 88 drugs in the overall analysis (of cases with 'progressive multifocal leukoencephalopathy' or 'leukoencephalopathy' as the Preferred Term), and a new safety signal was identified for 59 active substances (e.g. muromonab-CD3, basiliximab and antithymocyte Ig), as no information on a possible risk of PML was acknowledged in their Summary of Product Characteristics documents. Some safety signals were confirmed also after sensitivity analysis adjustment for several confounding factors (underlying diseases and considering only 'progressive multifocal leukoencephalopathy' as the Preferred Term). CONCLUSION: We report a possible association between several drugs and PML that has not been previously described. In addition, we have confirmed previously reported signals in a number of drugs. We highlight the need for follow-up by regulatory agencies. PMID- 26507834 TI - A new computer-controlled air-liquid interface cultivation system for the generation of differentiated cell cultures of the airway epithelium. AB - The increased application of in vitro systems in pharmacology and toxicology requires cell culture systems that facilitate the cultivation process and ensure stable, reproducible and controllable cultivation conditions. Up to now, some devices have been developed for the cultivation of cells under submersed conditions. However, systems meeting the requirements of an air-liquid interface (ALI) cultivation for the special needs of bronchial epithelial cells for example are still lacking. In order to obtain in vivo like organization and differentiation of these cells they need to be cultivated under ALI conditions on microporous membranes in direct contact with the environmental atmosphere. For this purpose, a Long-Term-Cultivation system was developed (CULTEX((r)) LTC-C system) for the computer-controlled cultivation of such cells. The transwell inserts are placed in an incubator module (24 inserts), which can be adjusted for the medium level (ultrasonic pulse-echosensor), time and volume-dependent medium exchange, and frequency for mixing the medium with a rotating disc for homogeneous distribution of medium and secretion components. Normal primary freshly isolated bronchial epithelial cells were cultivated for up to 38 days to show the efficiency of such a cultivation procedure for generating 3D cultures exhibiting in vivo-like pseudostratified organization of the cells as well as differentiation characteristics like mucus-producing and cilia-forming cells. PMID- 26507835 TI - Immunohistochemical patterns in different stromal variants of pleomorphic adenomas: literature review. AB - Pleomorphic adenoma is the most frequent type of benign salivary neoplasm located in the mouth and is characterized by its significant histopathological diversity. The histogenesis of the pleomorphic adenoma is uncertain; so far several studies suggest that myoepithelial cells are responsible for the variable histomorphology of this type of neoplasm. At times, stroma is the predominant element. The purpose of the present review is to analyze the results reported in the scientific literature concerning immunomarkers expressed in the different stromal elements of pleomorphic adenoma. PMID- 26507836 TI - Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody, in Patients with Advanced Cancer. AB - BACKGROUND: KHK2866 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed at heparin-binding epidermal growth factor-like growth factor (HB-EGF). OBJECTIVE: To determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, potential immunogenicity, and preliminary clinical efficacy of KHK2866 monotherapy in patients with advanced and refractory cancer in a first-in-human, phase 1 study. MATERIALS AND METHODS: Using a standard 3 + 3 dose-escalation design, 20 patients received KHK2866 (0.3, 1, and 3 mg/kg) intravenously once weekly. Two additional patients received 0.1 mg/kg in a cohort which was subsequently added following protocol amendment. RESULTS: The first three patients enrolled experienced grade 2 hypersensitivity (acute infusion reactions) after the first dose of KHK2866. After prophylactic treatment with an H1-blocker and corticosteroids in subsequently recruited patients, two grade 2 hypersensitivity reactions were observed in the remaining 19 patients. Grade 2/3 neurotoxicity appeared to be dose-limiting at 3 mg/kg in the original dose-escalation cohorts (n = 2), at 1 mg/kg in the MTD dose expansion cohort (n = 1), and at 0.1 mg/kg (n = 1). Neurotoxicity was manifested as complex partial seizure activity, aphasia, and confusion after first-dose administration. Pharmacokinetic exposure to KHK2866 increased proportionally to dose. Mean elimination half-life was 71.9-118 h over the dose range from 0.3 to 3 mg/kg. All KHK2866 doses decreased serum free HB-EGF levels, generally below the lower limit of quantification. CONCLUSIONS: The study was terminated because of neuropsychiatric toxicity. The only predictive factor for neuropsychiatric toxicity was administration of KHK2866. These effects were reversible, but were not predictable. Their etiology is not presently understood. [Study registered at ClinicalTrials.gov #NCT0179291]. PMID- 26507837 TI - Changes in Renal Function of Patients with Metastatic Renal Cell Carcinoma During Treatment with Molecular-Targeted Agents. AB - BACKGROUND: Impairment of renal function is a serious issue that should be considered in patients undergoing treatment with molecular-targeted agents for metastatic renal cell carcinoma (mRCC). AIMS: The objective of this study was to assess the impact of molecular-targeted therapy on changes in renal function among patients with mRCC. PATIENTS AND METHODS: The study included 408 mRCC patients treated with sunitinib, sorafenib, axitinib, everolimus and/or temsirolimus. Among these, 185, 128 and 95 received molecular-targeted agents as first-line (group 1), second-line (group 2) and third-line (group 3) therapy, respectively. RESULTS: No significant differences between the estimated glomerular filtration rate (eGFR) at baseline and that at the end of molecular targeted therapy were noted among the three groups of patients. In addition, there were no significant differences between eGFR prior to the introduction of molecular-targeted therapy and that at the end of therapy across agents and lines of targeted therapy, with the exception of patients treated with axitinib and everolimus in second-line and third-line therapy, respectively. In group 1, a reduction in eGFR of >10 % from baseline was independently associated with performance status, hypertension and treatment duration, while in groups 2 and 3, only treatment duration was independently related to a reduction in eGFR of >10 %. CONCLUSIONS: It appears that renal function in patients with mRCC is not markedly impaired by molecular-targeted therapies, irrespective of the specific agents introduced; however, it may be necessary to pay special attention to deterioration in renal function when molecular-targeted therapy is continued for longer periods. PMID- 26507838 TI - Biosynthesis of mercapturic acid derivative of the labdane-type diterpene, cyslabdan that potentiates imipenem activity against methicillin-resistant Staphylococcus aureus: cyslabdan is generated by mycothiol-mediated xenobiotic detoxification. AB - Genome mining of cyslabdan-producing Streptomyces cyslabdanicus K04-0144 revealed that a set of four genes, cldA, cldB, cldC, and cldD (the cld cluster), which formed a single transcriptional unit, were involved in the biosynthesis of cyslabdan that potentiates imipenem activity against methicillin-resistant Staphylococcus aureus. Experimental studies supported the heterologous expression of the cld cluster of S. cyslabdanicus K04-0144 in S. avermitilis SUKA22, and transformants carrying the cld cluster produced not only cyslabdan A (1), but also its new derivatives, 17-hydroxyl-1 (2) and 2-hydroxyl-1 (3), in the culture broth. An analysis of diterpene metabolites in the mycelia showed that a large amount of a novel intermediate had accumulated and its structure was elucidated as (7S, 8S, 12E)-8,17-epoxy-7-hydroxylabda-12,14-diene (4). The cld-like cluster (rmn cluster) was also detected in the genome of S. anulatus GM95 by searching our in-house genome databases, and the heterologous expression of the rmn cluster in S. avermitilis SUAK22 demonstrated that the rmn cluster was involved in the biosynthesis of the labdane-type bicyclic diterpene, raimonol (7). CldA/RmnA catalyzed the generation of geranylgeranyl diphosphate (GGPP) from dimethylallyl diphosphate and isopentenyl diphosphate. CldB/RmnB converted GGPP to (+)-copalyl diphosphate, and CldD/RmnD generated labda-8(17),12(E),14-triene (5). CldC introduced two oxygen atoms at C-7 and C-8,17 to generate 4, while RmnC hydroxylated 5 at C-7 to generate 7. The heterologous expression of the cld cluster suggested that four gene products catalyzed to generate 4, but not 1. The deletion mutant of the gene encoding the mycothiol (MSH)-S-conjugate amidase (mca) of S. avermitilis SUKA22 carrying the cld cluster failed to produce 1, but accumulated 4 in the mycelia, whereas S. avermitilis SUKA22 and its mca-deletion mutant carrying the cld cluster both produced the MSH-S-conjugate of 4. The intermediate 4 was converted into the MSH-S-conjugate with MSH, which was achieved through a non-enzymatic nucleophilic reaction. The MSH-S-conjugate of 4 generated was further hydrolyzed to generate the mercapturic acid derivative, 1, by MSH-S-conjugate amidase and 1 was excreted from the mycelia. PMID- 26507839 TI - The effect of electronic medical record system use on communication between pharmacists and prescribers. AB - BACKGROUND: The Electronic Medical Record (EMR) is becoming increasingly common in health care settings. Research shows that EMRs have the potential to reduce instances of medication errors and improve communication between pharmacists and prescribers; however, more research is required to demonstrate whether this is true. This study aims to determine the effect of a newly implemented EMR system on communication between pharmacists and primary care clinicians. METHODS: A retrospective chart analysis of primary care EMR data comparing faxed pharmacy communications captured before and after the implementation of an EMR system at an academic family medicine clinic. Communication requests were classified into the following various categories: refill accepted, refill denied, clarification, incorrect dose, interaction, drug insurance/coverage application, new prescription request, supplies request, continued care information, duplicate fax substitution, opioid early release request, confirmation by phone call, and other. RESULTS: The number and percentage of clarification requests, interaction notifications, and incorrect dose notifications were lower after the implementation of the EMR system. The number and percentage of refills accepted and new prescription requests increased after the implementation of the EMR system. CONCLUSION: The implementation of an EMR in an academic family medicine clinic had a significant effect on the volume of communication between pharmacists and prescribers. The amount of clarification requests and incorrect dosing communications decreased after EMR implementation. This suggests that EMRs improve prescribing safety. The increased amount of refills accepted and new prescription requests post EMR implementation suggests that the EMR is capable of changing prescription patterns. PMID- 26507840 TI - Recurrent episodes of night blindness in a patient with short bowel syndrome. AB - PURPOSE: To describe clinical characteristics in a patient with recurrent episodes of night blindness due to vitamin A deficiency caused by short bowel syndrome in Crohn disease. METHODS: Retrospective analysis of best-corrected visual acuity (BCVA), kinetic perimetry, slit-lamp biomicroscopy, ophthalmoscopy, fundus photography, fundus autofluorescence (FAF), spectral domain optical coherence tomography (SD-OCT), dark adaptometry (DA) and electroretinography (ERG). Serum vitamin A level was measured. RESULTS: A 44-year-old man with a 3 year history of night blindness suffered from a short bowel syndrome with chronic malabsorption due to ileocecal resection in Crohn disease. Both eyes had a BCVA of 0.9, Bitot's spots of the conjunctiva and no significant fundus abnormalities. SD-OCT showed no remarkable changes, whereas FAF was brighter than normal in the center of the fovea. DA showed normal cone and a lack of rod function. The dark adapted 0.01 ERG was non-detectable, the dark-adapted 3.0 ERG severely diminished, but the light-adapted 3.0 and 30 Hz flicker ERGs were within normal limits. Serum vitamin A level was 0.11 ug/ml (normal 0.30-0.65 ug/ml). Treatment with intravenous vitamin A caused a rapid recovery of night vision and ERG. However, during the following 3 years, he had three further episodes of night blindness with loss of rod function. During each period, parenteral vitamin A substitution brought complete recovery of night vision and rod function. BCVA, fundus, FAF findings and SD-OCT remained unchanged during the course. CONCLUSIONS: In patients with known chronic malabsorption serum vitamin A level should be regularly checked to avoid recurrent night blindness episodes. ERG might be more sensitive than serum vitamin A level and is recommended in case of night blindness but still normal vitamin A level. PMID- 26507841 TI - Analysis of the preferences for splice codes across tissues. PMID- 26507842 TI - MiR-33a suppresses breast cancer cell proliferation and metastasis by targeting ADAM9 and ROS1. AB - MicroRNAs (miRNAs) are small noncoding RNAs that have a pivotal role in the post transcriptional regulation of gene expression by sequence-specifically targeting multiple mRNAs. Although miR-33a was recently reported to play an important role in lipid homeostasis, atherosclerosis, and hepatic fibrosis, the functions of miR 33a in tumor progression and metastasis are largely unknown. Here, we found that downregulated miR-33a in breast cancer tissues correlates with lymph node metastasis. MiR-33a expression is significantly lower in the highly metastatic breast cancer cell lines than the noncancerous breast epithelial cells and non metastatic breast cancer cells. Moreover, the overexpression of miR-33a in metastatic breast cancer cells remarkably decreases cell proliferation and invasion in vitro and significantly inhibits tumor growth and lung metastasis in vivo, whereas its knockdown in non-metastatic breast cancer cells significantly enhances cell proliferation and invasion in vitro and promotes tumor growth and lung metastasis in vivo. Combining bioinformatics prediction and biochemical analyses, we showed that ADAM9 and ROS1 are direct downstream targets of miR-33a. These findings identified miR-33a as a negative regulator of breast cancer cell proliferation and metastasis. PMID- 26507843 TI - An improved method for phasing crystal structures with low non-crystallographic symmetry using cryo-electron microscopy data. PMID- 26507844 TI - Nurse Family Partnership: Comparing Costs per Family in Randomized Trials Versus Scale-Up. AB - The literature that addresses cost differences between randomized trials and full scale replications is quite sparse. This paper examines how costs differed among three randomized trials and six statewide scale-ups of nurse family partnership (NFP) intensive home visitation to low income first-time mothers. A literature review provided data on pertinent trials. At our request, six well-established programs reported their total expenditures. We adjusted the costs to national prices based on mean hourly wages for registered nurses and then inflated them to 2010 dollars. A centralized data system provided utilization. Replications had fewer home visits per family than trials (25 vs. 31, p = .05), lower costs per client ($8860 vs. $12,398, p = .01), and lower costs per visit ($354 vs. $400, p = .30). Sample size limited the significance of these differences. In this type of labor intensive program, costs probably were lower in scale-up than in randomized trials. Key cost drivers were attrition and the stable caseload size possible in an ongoing program. Our estimates reveal a wide variation in cost per visit across six state programs, which suggests that those planning replications should not expect a simple rule to guide cost estimations for scale-ups. Nevertheless, NFP replications probably achieved some economies of scale. PMID- 26507845 TI - Epithelioid Multinodular Osteoblastoma of the Mandible: A Case Report and Review of Literature. AB - Epithelioid multinodular osteoblastoma is a rare variant of osteoblastoma characterized by numerous nodules of epithelioid osteoblasts surrounding bony trabeculae, as well as clusters of epithelioid osteoblasts without osteoid formation. It commonly occurs in the gnathic bones of the face and spine, and has a male predominance. To date, only 26 cases of epithelioid multinodular osteoblastoma have been reported and described in detail in the literature. Lucas et al. (Hum Pathol 25:117-134, 1994) described 43 cases of a variant of osteoblastoma that he termed epithelioid multifocal osteoblastoma. These both likely represent the same entity. Here, we report another case of this rare variant of osteoblastoma. An 18-year-old male patient presents with a periapical radiolucency in the region of vital tooth #30. The surgeon's differential diagnosis for this radiolucent lesion was ameloblastoma versus cyst. An incisional biopsy of the lesion revealed well-vascularized fibrous connective tissue containing a multinodular tumor composed of collections of epithelioid cells with osteoblastic differentiation surrounding zones of hyalinization and bony trabeculae. Multinucleated giant cells and rare typical mitotic figures were noted. Additionally present within the tumor were clusters of epithelioid osteoblasts without bony trabeculae. Residual immature viable bone trabeculae were noted surrounding the tumor. A diagnosis of epithelioid multinodular osteoblastoma was rendered. In this paper we present a rare case of epithelioid multinodular osteoblastoma of the mandible, provide a general review of the literature, and highlight the unique histological features that help differentiate this tumor from tumors classified as conventional osteoblastoma, aggressive osteoblastoma, pseudoanaplastic osteoblastoma and, most importantly, low-grade or osteoblastoma-like osteosarcoma. PMID- 26507846 TI - Biological Soil Crusts from Coastal Dunes at the Baltic Sea: Cyanobacterial and Algal Biodiversity and Related Soil Properties. AB - Biological soil crusts (BSCs) are known as "ecosystem-engineers" that have important, multifunctional ecological roles in primary production, in nutrient and hydrological cycles, and in stabilization of soils. These communities, however, are almost unstudied in coastal dunes of the temperate zone. Hence, for the first time, the biodiversity of cyanobacterial and algal dominated BSCs collected in five dunes from the southern Baltic Sea coast on the islands Rugen and Usedom (Germany) was investigated in connection with physicochemical soil parameters. The species composition of cyanobacteria and algae was identified with direct determination of crust subsamples, cultural methods, and diatom slides. To investigate the influence of soil properties on species composition, the texture, pH, electrical conductivity, carbonate content, total contents of carbon, nitrogen, phosphorus, and the bioavailable phosphorus-fraction (PO4 (3-)) were analyzed in adjacent BSC-free surface soils at each study site. The data indicate that BSCs in coastal dunes of the southern Baltic Sea represent an ecologically important vegetation form with a surprisingly high site-specific diversity of 19 cyanobacteria, 51 non-diatom algae, and 55 diatoms. All dominant species of the genera Coleofasciculus, Lyngbya, Microcoleus, Nostoc, Hydrocoryne, Leptolyngbya, Klebsormidium, and Lobochlamys are typical aero-terrestrial cyanobacteria and algae, respectively. This first study of coastal sand dunes in the Baltic region provides compelling evidence that here the BSCs were dominated by cyanobacteria, algae, or a mixture of both. Among the physicochemical soil properties, the total phosphorus content of the BSC-free sand was the only factor that significantly influenced the cyanobacterial and algal community structure of BSCs in coastal dunes. PMID- 26507847 TI - Fabrication of anisotropically arrayed nano-slots metasurfaces using reflective plasmonic lithography. AB - Nanofabrication technology with high-resolution, high-throughput and low-cost is essential for the development of nanoplasmonic and nanophotonic devices. At present, most metasurfaces are fabricated in a point by point writing manner with electron beam lithography or a focused ion beam, which imposes a serious cost barrier with respect to practical applications. Near field optical lithography, seemingly providing a high-resolution and low-cost way, however, suffers from the ultra shallow depth and poor fidelity of obtained photoresist patterns due to the exponential decay feature of evanescent waves. Here, we propose a method of surface plasmonic imaging lithography by introducing a reflective plasmonic lens to amplify and compensate evanescent waves, resulting in the production of nano resist patterns with high fidelity, contrast and enhanced depth beyond that usually obtained by near field optical lithography. As examples, a discrete and anisotropically arrayed nano-slots mask pattern with different orientations and a size of 40 nm * 120 nm could be imaged in photoresist and transferred successfully onto a metal layer through an etching process. Evidence for the pattern quality is given by virtue of the fabricated metasurface lens devices showing good focusing performance in experiments. It is believed that this method provides a parallel, low-cost, high-throughput and large-area nanofabrication route for fabricating nanostructures of holograms, vortex phase plates, bio sensors and solar cells etc. PMID- 26507848 TI - Mallory-Denk bodies: Correlation with steatosis, severity, zonal distribution, and identification with ubiquitin. AB - BACKGROUND/AIMS: Intermediate filament proteins contain few aggregates as their main component. Among those, Mallory-Denk bodies (MDBs) are by far the best recognized component. To identify the presence of MDBs in individuals having chronic liver disease and to evaluate the correlation among MDBs and steatosis as well as the severity and zonal distribution of hepatocyte balloon degeneration. Tertiary reference hospital. MATERIALS AND METHODS: Three hundred consecutive liver specimens derived from our patients with chronic liver disease were included in the current study. Immunohistochemistry analysis was conducted on frozen liver biopsies fixed at room temperature with acetone anti-rabbit antibody to ubiquitin. In addition, histological activity was evaluated by the routine staining of liver biopsy sections with hematoxylin-eosin and periodic staining by acid-Schiff stain, reticulin, Masson trichrome, and iron. The presence of MDBs, steatosis, severity, and the zonal distribution of hepatocyte balloon degeneration were evaluated in every patient. RESULTS: Histopathologic diagnosis were chronic hepatitis B (n=219), alcoholic steatohepatitis (n=23), non-alcoholic steatohepatitis (n=20), chronic hepatitis C (n=20), overlap syndrome (n=10), and primary biliary cirrhosis (n=8). The distribution of MDBs stained positive for ubiquitin was 80% in the overlap syndrome, 86% in chronic hepatitis B, and 100% in alcoholic steatohepatitis, NASH, chronic hepatitis C, and primary biliary cirrhosis. There was a correlation between the severity of steatosis and ubiquitin positivity, particularly in zone 2. A conspicuous correlation existed between the severity of hepatocyte balloon degeneration and ubiquitin positivity. CONCLUSION: These findings have demonstrated that the observation of MDB together with ubiquitin positivity will be helpful in the evaluation of the models of diagnosis, staging, and therapy in patients with chronic liver disease. PMID- 26507849 TI - Systemic Risk Analysis on Reconstructed Economic and Financial Networks. AB - We address a fundamental problem that is systematically encountered when modeling real-world complex systems of societal relevance: the limitedness of the information available. In the case of economic and financial networks, privacy issues severely limit the information that can be accessed and, as a consequence, the possibility of correctly estimating the resilience of these systems to events such as financial shocks, crises and cascade failures. Here we present an innovative method to reconstruct the structure of such partially-accessible systems, based on the knowledge of intrinsic node-specific properties and of the number of connections of only a limited subset of nodes. This information is used to calibrate an inference procedure based on fundamental concepts derived from statistical physics, which allows to generate ensembles of directed weighted networks intended to represent the real system-so that the real network properties can be estimated as their average values within the ensemble. We test the method both on synthetic and empirical networks, focusing on the properties that are commonly used to measure systemic risk. Indeed, the method shows a remarkable robustness with respect to the limitedness of the information available, thus representing a valuable tool for gaining insights on privacy protected economic and financial systems. PMID- 26507850 TI - Minimal invasive lung support via umbilical vein with a double-lumen cannula in a neonatal lamb model: a proof of principle. AB - PURPOSE: Acute respiratory distress syndrome, with the need for invasive mechanical ventilation (MV) remains a major cause of neonatal mortality and morbidity. Although venovenous extracorporeal lung support (VV-ECLS) has become a standard of care procedure in neonatal patients with acute pulmonary failure there are no reports regarding the use of a double-lumen cannula for extracorporeal minimal invasive lung support via the umbilical vein. METHODS: A neonatal lamb model was used (n = 3). Umbilical vein was cannulated with a double lumen catheter allowing venovenous extracorporeal gas exchange. Cannula was positioned with its tip in the right atrium. VV-ECLS was started and ventilation was stopped. Providing oxygenation and CO2 removal solely through VV-ECLS hemodynamics, blood gases were measured. RESULTS: Total VV-ECLS without MV was applied to all three neonatal lambs. Time on venovenous ECLS was 60, 120 and 120 min. Initial pCO2 was 60, 56 and 65 mmHg compared to 31, 32 and 32 mmHg at the end of VV-ECLS. Initial pO2 was 30, 27 and 26 mmHg compared to 22, 19 and 23 mmHg. Initial lactate was 5, 10 and 3.7 mmol/l compared to 13.3, 12.6 and 11.3 mmol/l at the end of VV-ECLS. MAP at baseline was 51, 52 and 65 mmHg compared to 36, 38 and 41 mmHg at the end of VV-ECLS. In all three lambs inotropes were admitted to maintain MAD >35 mmHg. CONCLUSION: Even without mechanical ventilation we were able to sufficiently remove pCO2 with our new minimal invasive VV-ECLS using a double-lumen catheter via the umbilical vein, supporting the idea of a lung protective strategy in neonatal acute respiratory failure. pO2 was measured 22, 19 and 23 mmHg, respectively, at the end of VV-ECLS, at least partially caused by recirculation phenomenon, which could possibly be improved by different cannula design. Inotropic support was necessary during VV-ECLS to achieve targeted MAD > 35 mmHg. While technically feasible, this new approach might allow further research in the field of extracorporeal lung support and therefore will follow the concept of a lung protective strategy in acute neonatal respiratory failure. PMID- 26507852 TI - Risk of cancer in patients with irritable bowel syndrome: a nationwide population based study. AB - PURPOSE: The aim of our study was to evaluate the overall cancer risk among patients with the irritable bowel syndrome (IBS) by using a nationwide population based data set. METHODS: We obtained data on newly diagnosed IBS patients (age >= 20 years) without antecedent cancer from the Taiwan National Health Insurance Research Database for the period between 2000 and 2010. Standardized incidence ratios (SIRs) were calculated for various types of cancer in the IBS patients. RESULTS: A total of 1,043 people among the 29,838 IBS patients had developed cancer, and the follow-up was 139,185 person-years (median, 4.56 years), leading to a significantly increased SIR (1.18; 95% confidence interval [CI]) = 1.11 1.26) among all cancer types. However, after excluding cancer that developed within the first year after IBS diagnosis, the increased SIR of overall cancer was nonsignificant. In particular, the IBS patients exhibited an increased risk of cancers of the colon and rectum (SIR = 1.51; 95% CI = 1.31-1.73), liver and biliary tract (SIR = 1.40; 95% CI = 1.21-1.62), pancreas (SIR = 1.56; 95% CI = 1.02-2.28), and kidney (SIR = 1.56; 95% CI = 1.10-2.15). CONCLUSIONS: An increased SIR in IBS patients was observed only within the first year of IBS diagnosis. The findings of this study might have resulted from detection bias, localized symptoms, or paraneoplastic syndromes associated with IBS-like symptoms. Additional prospective studies are necessary to confirm these findings. PMID- 26507853 TI - In-vitro Optimization of Nanoparticle-Cell Labeling Protocols for In-vivo Cell Tracking Applications. AB - Recent advances in theranostic nanomedicine can promote stem cell and immune cell based therapy. Gold nanoparticles (GNPs) have been shown to be promising agents for in-vivo cell-tracking in cell-based therapy applications. Yet a crucial challenge is to develop a reliable protocol for cell upload with, on the one hand, sufficient nanoparticles to achieve maximum visibility of cells, while on the other hand, assuring minimal effect of particles on cell function and viability. Previous studies have demonstrated that the physicochemical parameters of GNPs have a critical impact on their efficient uptake by cells. In the current study we have examined possible variations in GNP uptake, resulting from different incubation period and concentrations in different cell-lines. We have found that GNPs effectively labeled three different cell-lines - stem, immune and cancer cells, with minimal impairment to cell viability and functionality. We further found that uptake efficiency of GNPs into cells stabilized after a short period of time, while GNP concentration had a significant impact on cellular uptake, revealing cell-dependent differences. Our results suggest that while heeding the slight variations within cell lines, modifying the loading time and concentration of GNPs, can promote cell visibility in various nanoparticle dependent in-vivo cell tracking and imaging applications. PMID- 26507854 TI - Molecular Simulations of Anion and Temperature Dependence on Structure and Dynamics of 1-Hexyl-3-methylimidazolium Ionic Liquids. AB - In this study, we examine the effect of various anions and temperature on structure and dynamics of 1-hexyl-3-methylimidazolium ionic liquids (ILs) from molecular dynamics simulations. The structural properties show that ILs containing smaller anions like Cl(-) and Br(-) are relatively higher cation-anion interactions, compared to ILs containing larger anions like OTf(-) and NTf2(-). In all ILs, the spatial distribution of anions is closer to the acidic hydrogen atom of the cation compared to the two nonacidic hydrogen atoms of the cation. The diffusion coefficients of cations and anions (ionic conductivity) increase with anionic size. At each temperature, the cationic and anionic diffusions and ionic conductivity are lowest in ILs containing anions like Cl(-) and Br(-) and highest in ILs containing anions like BF4(-), OTf(-), and NTf2(-). Consistent with experiments, simulations predict that ILs with an intermediate size BF4(-) anion show the highest cationic and anionic diffusion (and ionic conductivity). At each temperature, the interactions between ion pairs of each IL show that a decrease in ion-pair lifetimes is directly related to the increase in diffusion coefficients and conductivity in ILs, suggesting that characterization of ion pair lifetimes is sufficient to validate the trends seen in dynamical properties of ILs. PMID- 26507855 TI - Mapping DNA cleavage by the Type ISP restriction-modification enzymes following long-range communication between DNA sites in different orientations. AB - The prokaryotic Type ISP restriction-modification enzymes are single-chain proteins comprising an Mrr-family nuclease, a superfamily 2 helicase-like ATPase, a coupler domain, a methyltransferase, and a DNA-recognition domain. Upon recognising an unmodified DNA target site, the helicase-like domain hydrolyzes ATP to cause site release (remodeling activity) and to then drive downstream translocation consuming 1-2 ATP per base pair (motor activity). On an invading foreign DNA, double-strand breaks are introduced at random wherever two translocating enzymes form a so-called collision complex following long-range communication between a pair of target sites in inverted (head-to-head) repeat. Paradoxically, structural models for collision suggest that the nuclease domains are too far apart (>30 bp) to dimerise and produce a double-strand DNA break using just two strand-cleavage events. Here, we examined the organisation of different collision complexes and how these lead to nuclease activation. We mapped DNA cleavage when a translocating enzyme collides with a static enzyme bound to its site. By following communication between sites in both head-to-head and head-to-tail orientations, we could show that motor activity leads to activation of the nuclease domains via distant interactions of the helicase or MTase-TRD. Direct nuclease dimerization is not required. To help explain the observed cleavage patterns, we also used exonuclease footprinting to demonstrate that individual Type ISP domains can swing off the DNA. This study lends further support to a model where DNA breaks are generated by multiple random nicks due to mobility of a collision complex with an overall DNA-binding footprint of ~30 bp. PMID- 26507856 TI - Nucleotide binding database NBDB--a collection of sequence motifs with specific protein-ligand interactions. AB - NBDB database describes protein motifs, elementary functional loops (EFLs) that are involved in binding of nucleotide-containing ligands and other biologically relevant cofactors/coenzymes, including ATP, AMP, ATP, GMP, GDP, GTP, CTP, PAP, PPS, FMN, FAD(H), NAD(H), NADP, cAMP, cGMP, c-di-AMP and c-di-GMP, ThPP, THD, F 420, ACO, CoA, PLP and SAM. The database is freely available online at http://nbdb.bii.a-star.edu.sg. In total, NBDB contains data on 249 motifs that work in interactions with 24 ligands. Sequence profiles of EFL motifs were derived de novo from nonredundant Uniprot proteome sequences. Conserved amino acid residues in the profiles interact specifically with distinct chemical parts of nucleotide-containing ligands, such as nitrogenous bases, phosphate groups, ribose, nicotinamide, and flavin moieties. Each EFL profile in the database is characterized by a pattern of corresponding ligand-protein interactions found in crystallized ligand-protein complexes. NBDB database helps to explore the determinants of nucleotide and cofactor binding in different protein folds and families. NBDB can also detect fragments that match to profiles of particular EFLs in the protein sequence provided by user. Comprehensive information on sequence, structures, and interactions of EFLs with ligands provides a foundation for experimental and computational efforts on design of required protein functions. PMID- 26507857 TI - BloodSpot: a database of gene expression profiles and transcriptional programs for healthy and malignant haematopoiesis. AB - Research on human and murine haematopoiesis has resulted in a vast number of gene expression data sets that can potentially answer questions regarding normal and aberrant blood formation. To researchers and clinicians with limited bioinformatics experience, these data have remained available, yet largely inaccessible. Current databases provide information about gene-expression but fail to answer key questions regarding co-regulation, genetic programs or effect on patient survival. To address these shortcomings, we present BloodSpot (www.bloodspot.eu), which includes and greatly extends our previously released database HemaExplorer, a database of gene expression profiles from FACS sorted healthy and malignant haematopoietic cells. A revised interactive interface simultaneously provides a plot of gene expression along with a Kaplan-Meier analysis and a hierarchical tree depicting the relationship between different cell types in the database. The database now includes 23 high-quality curated data sets relevant to normal and malignant blood formation and, in addition, we have assembled and built a unique integrated data set, BloodPool. Bloodpool contains more than 2000 samples assembled from six independent studies on acute myeloid leukemia. Furthermore, we have devised a robust sample integration procedure that allows for sensitive comparison of user-supplied patient samples in a well-defined haematopoietic cellular space. PMID- 26507858 TI - The Swedish Crohn Trial: A Prematurely Terminated Randomized Controlled Trial of Thiopurines or Open Surgery for Primary Treatment of Ileocaecal Crohn's Disease. AB - BACKGROUND AND AIMS: The importance of efficient and safe treatment of Crohn's disease is highlighted by its chronicity. Both medical and surgical treatments have shown good results in the symptomatic control of limited ileocaecal Crohn's disease. The aim of this study was to compare medical treatment with surgical treatment of ileocaecal Crohn's disease. METHODS: Thirty-six patients from seven hospitals with primary ileocaecal Crohn's disease were randomized to either medical or surgical treatment. The medical treatment was induction of remission with budesonide and thereafter maintenance treatment with azathioprine. The surgical treatment was open ileocaecal resection. Crohn's disease activity index over time, expressed as area under the curve at 1, 3 and 5 years, was the primary endpoint. Subjective health measured with the 36-item Short Form Survey Instrument (SF36) and a visual analogue scale (VAS) were secondary endpoints. RESULTS: There were no differences between the treatment groups in Crohn's disease activity index over time. General health, measured as SF36 score, was higher in patients receiving surgical treatment than in those receiving medical treatment at 1 year, but there was no corresponding difference in VAS. Due to the slow inclusion rate and changes in clinical practice, the study was t=erminated prematurely. CONCLUSION: The study ended up being underpowered and should be interpreted with caution, but there was no clinically significant difference between the two treatment arms. Further studies are needed to address this important clinical question. PMID- 26507859 TI - Food-related Quality of Life in Inflammatory Bowel Disease: Development and Validation of a Questionnaire. AB - BACKGROUND: Psychosocial factors surrounding eating and drinking, such as enjoying food, managing restrictions, and maintaining social relationships, remain under-researched in inflammatory bowel disease [IBD]. This study aimed to develop and validate a food-related quality of life [FR-QoL] questionnaire to systematically measure these issues in the IBD population. METHODS: Following semi-structured interviews with 28 IBD patients, 150 potential questionnaire items were generated. These were ranked by 100 IBD patients, and items were removed based on ceiling/floor effects and high inter-item correlations [> 0.7], with 41 items being retained. In total, 323 IBD patients, 100 asthma patients [chronic disease control], and 117 healthy controls completed the FR-QoL questionnaire, alongside generic and disease-specific QoL and food satisfaction questionnaires. Principal components analysis [PCA], construct and discriminant validity, and test-retest reliability were calculated. RESULTS: Twelve items were removed following PCA. The reduced questionnaire [FR-QoL-29] explained 63.9% of the variance [Cronbach's alpha = 0.96]. FR-QoL-29 correlated significantly with generic QoL [r = 0.697], depression [r = -0.519], anxiety [r = -0.531], and food satisfaction [r = 0.701]. The FR-QoL-29 sumscores were significantly lower for IBD (89.5, standard deviation [SD] 28.6) than asthma [125.4, SD 24.1; p < 0.001] and healthy volunteers [123.0, SD 16.5; p<0.001]. Within IBD, worse food-related QoL was found in those with moderate/high disease activity [66.7, SD 22.1] compared with remission/low disease activity [92.5, SD 28.1]. Test-retest reliability was good (intra-class correlation [ICC] = 0.83, 95% confidence interval [CI] = 0.76:0.88). CONCLUSIONS: The FR-QoL-29 shows good reliability and validity across a range of IBD characteristics. This easily administered questionnaire is a useful tool in identifying poor food-related QoL and in the future may identify areas for intervention. PMID- 26507860 TI - Inflammatory Bowel Disease and the Risk of Autoimmune Diseases. AB - BACKGROUND: An increased risk of autoimmune disease has been reported in patients with inflammatory bowel disease [IBD]. Using data from the Clinical Practice Research Datalink [CPRD], this study set out to further examine this relationship. METHODS: Patients with a first-time IBD diagnosis were randomly matched to an equal-sized IBD-free comparison group. Incidence rates for new onset autoimmune diseases were estimated. A nested case-control analysis comprising IBD patients was conducted, using conditional logistic regression to assess whether IBD severity, duration, or treatment influences the risk of developing autoimmune diseases. RESULTS: During follow-up, 1069 IBD and 585 IBD free patients developed an incident autoimmune disease. An increased incidence of autoimmune disease was observed in IBD patients (incidence rate [IR] 9.65, 95% confidence interval [CI] 9.09-10.24) compared with the non-IBD comparison group [IR 5.22, 95% CI 4.82-5.66]. In IBD patients, increased disease severity was associated with an increased risk of autoimmune disease development (odds ratio [OR] 1.62, 95% CI 1.28-2.05). Current antibiotic use was also associated with an increased risk [adjusted OR 1.72, 95% CI 1.07-2.78]. A reduced risk of incident autoimmune diseases was observed for current long-term users of aminosalicylates [adjusted OR 0.72, 95% CI 0.57-0.91]. CONCLUSIONS: Individuals with IBD had an increased risk of developing an autoimmune disease. Increased disease severity and current antibiotic use were associated with an increased relative risk of developing additional autoimmune diseases in IBD patients. Long-term current aminosalicylate use was associated with a reduced risk. PMID- 26507861 TI - Contrast-enhanced Ultrasound for Detection of Crohn's Disease Activity: Systematic Review and Meta-analysis. AB - BACKGROUND AND AIMS: Reports on imaging of active Crohn's disease (aCD) using contrast-enhanced ultrasound (CEUS) are encouraging. However, the statistical power of most published papers is limited due to the small size of the patient groups included. This study was performed to verify the diagnostic value of CEUS in detecting aCD. METHODS: A systematic literature search was performed by two independent reviewers for articles on the test characteristics of CEUS for the identification of aCD. The quality of the analysed studies was evaluated using a quality assessment tool for diagnostic accuracy studies (QUADAS-2). Pooling was performed using a diagnostic random-effect model and bivariate analysis. RESULTS: Eight articles were included in the final analysis, with a total of 332 patients. There was no significant publication bias. Significant heterogeneity was found regarding CEUS methodology and sonographic definitions of aCD. In a bivariate analysis, pooled sensitivity was 0.94 (95% CI 0.87-0.97) and pooled specificity was 0.79 (95% CI 0.67-0.88). Spearman correlation statistics presented no significant diagnostic threshold effect (r = 0.12, p > 0.9). Subgroup analysis showed that relative intestine wall enhancement had the highest diagnostic value (area under the curve 94%), while the presence of enhancement and analysis of the slope were less useful (area under the curve 91 and 90%, respectively). CONCLUSIONS: CEUS presents good sensitivity and moderate specificity in the detection of the aCD. Large-scale randomized trials with quantitative evaluation of CEUS images are necessary to promote this technique in clinical practice. PMID- 26507862 TI - The clinical application of rhBMP-7 for the reconstruction of alveolar cleft. AB - In this study, radiographic assessment was performed to find out the effectiveness of bone regeneration following the application of recombinant human bone morphogenetic protein 7 (rhBMP-7) for the reconstruction of alveolar cleft defects in 11 cases: nine unilateral and two bilateral alveolar clefs. Reconstruction of the alveolar cleft was performed by using 3.5 mg of rhBMP-7 (Osigraft OP1) on a type I collagen carrier. Radiographs were taken 6 months post operation using a Gendex Intraoral Unit with Agfa Dentus M2 Comfort occlusal film. The amount of bony infill was graded on a Kindelan four-point scale. The patients were followed up for an average of 6.6 years. Based on the radiographic analysis, eight out of the nine unilateral alveolar cleft cases received a score of grade I and one patient had a grade II score, using the Kindelan scale. In the two bilateral alveolar clefts, only one side had bone formation. The radiographic appearance showed a normal trabecular pattern similar to the adjacent bone. Thus, rhBMP-7 was radiographically and clinically successful in regenerating the bone at the alveolar cleft which resulted in shortening of the operation time, absence of donor-site morbidity and a shorter hospital stay. The promising results of this preliminary study should encourage a phase II trial to compare bone grafts with BMP for the reconstruction of alveolar defects. PMID- 26507863 TI - Efficacy of custom-made pressure clips for ear keloid treatment after surgical excision. AB - BACKGROUND: Mechanical pressure is increasingly applied as a means to prevent or treat keloid scars. AIM: The aim of this study is to analyze the long-term efficacy of our custom-molded pressure-adjustable earclips to prevent keloid recurrence after surgical excision. METHODS: Using our custom-molded earclip, 88 patients who had undergone ear surgery for keloid scars were treated for 12 h a day for 6-18 months. The mean follow-up was 6.5 years. The primary outcome was the recurrence of keloids with patient satisfaction being the secondary outcome as assessed by Patient and Observer Scale (POSAS). RESULTS: Keloid scars did not recur in 70.5% of treated patients. The Fitzpatrick scale, which classifies human skin by type, was significantly different between the recurrence and nonrecurrence group. Differences in other patient characteristics were not found between both groups. All parameters mentioned in the POSAS patient scale drastically improved after therapy. There were no severe side effects observed after the therapy. CONCLUSION: Our pressure-adjustable earclip model is an effective tool in the prevention of ear keloid recurrence and is associated with high patient satisfaction. Its benefits should prompt further studies on its value as an adjuvant therapy to surgery in keloid treatment. LEVEL OF EVIDENCE: Level III on the Evidence Rating Scale for Therapeutic Studies. PMID- 26507864 TI - T1 mapping for assessment of myocardial injury and microvascular obstruction at one week post myocardial infarction. AB - OBJECTIVES: To compare 3T T1 mapping to conventional T2-weighted (T2W) imaging for delineating myocardial oedema one week after ST-elevation myocardial infarction (STEMI), and to explore the confounding effects of microvascular obstruction (MVO) on each technique. METHODS: T2W spectral attenuated inversion recovery and native T1 mapping were applied in 10 healthy volunteers and 62 STEMI patients, and late gadolinium enhancement was included for infarct localisation at 1 week and at 6 months post-STEMI. Segmental T1 values and T2W signal intensity ratios were calculated; oedema volumes and salvage indices were determined in patients using image thresholding-a receiver operator characteristic (ROC) derived T1 threshold, and a 2SD T2W threshold; and the results were compared between patients with/without MVO (n=35/27). RESULTS: Native T1 mapping delineated oedema with significantly better discriminatory power than T2W-as indicated by ROC analysis (area-under-the-curve, AUC=0.89 versus 0.83, p=0.009; and sensitivity/specificity=83/83% versus 73/73%). The optimal ROC threshold derived for T1 mapping was 1241ms, which gave significantly larger oedema volumes than 2SD T2W (p=0.006); with this threshold, patients with and without MVO showed similar oedema volumes, but patients with MVO had significantly poorer salvage indices (p<0.05) than those without. Neither method was significantly affected by MVO, the volume of which was seen to increase exponentially with infarct size. CONCLUSIONS: Native T1 mapping at 3T can delineate oedema one week post-STEMI, showing larger oedema volumes and better discriminatory power than T2W imaging, and it is suitable for quantitative thresholding. Both techniques are robust against MVO-related magnetic susceptibility. PMID- 26507865 TI - Case of widespread purpura due to emboli of Candida parapsilosis. PMID- 26507866 TI - Prevalence of emm types and antimicrobial susceptibility of Streptococcus dysgalactiae subsp. equisimilis in Austria. AB - OBJECTIVES: An increase of severe infections caused by Streptococcus dysgalactiae subsp. equisimilis (SDSE) similar to infections caused by Streptococcus pyogenes has been reported over the last years. Little is known about infections with SDSE in Austria. Therefore, we investigated a collection of 113 SDSE invasive and non invasive isolates from different infection sites and type of infections as well as patients' characteristics. METHODS: The isolates were phenotypically identified and emm typed using the enlarged emm database from the Centers for Disease Control and Prevention. Additionally, 13 antimicrobial agents were tested using EUCAST guidelines and virulence genes were investigated. RESULTS: Severe SDSE infections were most common in elderly men with underlying diseases especially diabetes mellitus. With VitekMS identification of SDSE isolates was successful to the species level only. Emm typing revealed 24 different emm types, one new type and one new subtype. StG485, stG6, stC74a, stG643, and stG480 were the predominant types in this study, stC74a and stG652 in invasive infections and stG643, stC74a and stG485 in non-invasive infections. Resistance was observed to tetracycline (62%), macrolides (13%) with one M phenotype, and clindamycin (12%) presenting 6 constitutive MLS(B) phenotypes and 8 inducible MLS(B) phenotypes. Levofloxacin resistance was detected only in one isolate. All isolates tested for virulence genes were positive for scpA, ska, saga and slo. Superantigenic genes were negative except speG(dys) (positive 17/34; 50%). CONCLUSION: This paper presents the first report of SDSE infections in Austria. Severe SDSE infections were found mainly in elderly men with underlying diseases. SDSE isolates demonstrated substantial emm type diversity without association with infections site or invasiveness. Analysis of virulence genes showed no significant difference between invasive and non-invasive infections. PMID- 26507867 TI - PPARgamma agonists regulate bidirectional transport of amyloid-beta across the blood-brain barrier and hippocampus plasticity in db/db mice. AB - BACKGROUND AND PURPOSE: There is emerging evidence suggesting that abnormal transport of amyloid-beta (Abeta) across the blood-brain barrier (BBB) is involved in diabetes-associated cognitive decline. We investigated whether PPARgamma agonists restore Abeta transport across the BBB and hippocampal plasticity in db/db mice. EXPERIMENTAL APPROACH: Efflux and influx of Abeta across the BBB were determined by stereotaxic intra-cerebral or i.a. infusion of [(125) I]-Abeta1-40 respectively. Receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein 1 (LRP1), which are involved in Abeta influx and efflux, PPARgamma and NF-kappaB p65 at the BBB, as well as hippocampal Abeta, caspase-3, Bax and Bcl-2 were assayed by Western blot, immunohistochemistry and RT-PCR. In vivo, hippocampal LTP was recorded, and Morris water maze and Y-maze tasks were performed. KEY RESULTS: Treatment with PPARgamma agonists, rosiglitazone (0.8 mg.kg(-1) ) and pioglitazone (9.0 mg.kg( 1) ), for 6 weeks significantly increased Abeta efflux and decreased Abeta influx across the BBB in db/db mice. Concomitantly, they decreased hippocampal Abeta1-40 and Abeta1-42 , suppressed neuronal apoptosis, as indicated by decreased caspase 3 activity and increased ratio of Bcl-2/Bax, and increased hippocampal plasticity, characterized by an enhanced in vivo LTP and better performance in behavioural tests. Furthermore, the PPARgamma agonists induced the expression of LRP1 gene by activation of PPARgamma and suppressed RAGE gene expression by inactivation of NF-kappaB signalling at the BBB of db/db mice. CONCLUSIONS AND IMPLICATIONS: PPARgamma agonists modify abnormal Abeta transport across the BBB and this is accompanied by amelioration of beta-amyloidosis and an improvement in hippocampal plasticity in diabetic mice. PMID- 26507868 TI - Why the Care Quality Commission rated Addenbrooke's as inadequate. PMID- 26507869 TI - Promoter Hypermethylation of FANCF and Susceptibility and Prognosis of Epithelial Ovarian Cancer. AB - OBJECTIVE: To assess the 5' CpG island methylation of Fanconi anemia, complementation group F (FANCF) gene in epithelial ovarian cancer (EOC) tissues and normal ovarian tissues and to investigate the relationship between FANCF methylation and clinicopathologic features and prognosis of EOC. METHODS: The experiment was performed with 112 EOC tissue samples (case group) and 60 normal ovarian tissues (control group). With methylation-specific polymerase chain reaction (MSP), FANCF methylation status of cases and controls was assessed. And the association between FANCF methylation and the clinicopathological features of EOC was investigated with univariate survival analysis and Cox regression model analysis. RESULTS: The methylation-positive rate of the case group was significantly higher than that of the control group (P = 0.015). The FANCF promoter methylation rates showed significant differences in the comparisons stratified by age, International Federation of Gynecology and Obstetrics (FIGO) staging, histopathological classification, and lymph node metastasis (all P < .05). Univariate survival analysis showed there were significant differences in mean survival time between the groups based on FIGO staging, histopathological classification, lymph node metastasis, and FANCF methylation (all P < .05). Cox regression model analysis suggested that FIGO staging and FANCF methylation were independent risk factors for EOC prognosis. CONCLUSION: CpG island methylation of FANCF gene promoter region is strongly associated with the susceptibility and clinicopathologic features of EOC. The FIGO staging and FANCF methylation are independent risk factors for EOC prognosis. PMID- 26507870 TI - Environmental Tobacco Smoke Exposure in Pregnancy is Associated With Earlier Delivery and Reduced Birth Weight. AB - The association between maternal smoking and preterm birth (PTB) has been known for more than 50 years but the effect of passive smoking is controversial. This retrospective cohort study in Bristol, United Kingdom, examines the effect of environmental tobacco smoke exposure (ETSE) on gestational age at delivery, birth weight, PTB, and being small-for-gestational age (SGA). Environmental tobacco smoke exposure was defined by either self-report or exhaled carbon monoxide (eCO) levels, and exposed women were compared with unexposed controls. Two models were used: The first included all women with adjustment for maternal smoking, and the second considered nonsmokers alone. Both models were further adjusted for maternal age, body mass index, parity, ethnicity, employment status, socioeconomic position, asthma, preeclampsia, and offspring sex. Logistic regression and likelihood ratio tests were used to test for any association between exposure and the binary outcomes (PTB and SGA), while linear regression and F tests were used to test for associations between exposure and the continuous outcomes. There were 13 359 deliveries in 2012 to 2014, with complete data for 5066 and 4793 women in the self-reported and eCO-measured exposure groups, respectively. Self-reported exposure was associated with earlier delivery (-0.19 weeks; 95% confidence interval [CI]: -0.32 to -0.05) and reduced birth weight (-56 g, 95% CI: -97 to -16 g) but no increase in the risk of PTB or SGA. There was no evidence for an association between eCO-measured exposure and any of the outcome measures. This information is important when advising women and their families and adds further support to continued public health efforts to reduce exposure to tobacco smoke. PMID- 26507871 TI - Steroid Pathway Genes and Neonatal Respiratory Distress After Betamethasone Use in Anticipated Preterm Birth. AB - OBJECTIVE: To test several key glucocorticoid genes that are enhanced in lung development for associations with respiratory distress syndrome (RDS) after antenatal corticosteroid use. METHODS: A prospective cohort of women received betamethasone to accelerate fetal lung maturity for threatened preterm delivery. DNA was obtained from mothers and newborns. Neonatal RDS was the primary outcome. Genotyping for single-nucleotide polymorphisms (SNPs) in 68 glucocorticoid genes found to be differentially expressed during lung development was performed. Multivariable analysis tested for associations of SNPs in the candidate genes with RDS. RESULTS: Genotypic results for 867 SNPs in 96 mothers and 73 babies were included. Thirty-nine (53.4%) babies developed RDS. Maternal SNPs in the centromeric protein E (CENPE), GLRX, CD9, and AURKA genes provided evidence of association with RDS (P < .01). In newborns, SNPs in COL4A3, BHLHE40, and SRGN provided evidence of association with RDS (P < .01). CONCLUSION: Single nucleotide polymorphisms in several glucocorticoid responsive genes suggest association with neonatal RDS after antenatal corticosteroid use. PMID- 26507872 TI - Candidate Gene and MicroRNA Expression in Fetal Membranes and Preterm Delivery Risk. AB - We investigated candidate gene and microRNA (miRNA) expression in amnion and chorion in relation to risk of preterm delivery (PTD). Amnion and chorion were separated from placenta and collected at delivery from participants who delivered at term (N = 10) and from participants who delivered preterm following spontaneous labor (sPTL-PTD; N = 10), premature rupture of membranes (PPROM-PTD; N = 10), and preeclampsia (PE-PTD; N = 10). Expression of genes (metalloproteinase [MMP] 2, MMP-9, and tissue inhibitors of MMP-1) and miRNAs (miR-199a*, -202*, -210, -214, -223, and -338) was profiled using quantitative real-time polymerase chain reaction approaches. Adjusted multinomial logistic regression models were used to calculate relative risk ratios (RRR), 95% confidence intervals, and P values. Among controls, the expression of miR-199a*, 202*, and -214 was lower in the amnion compared with their expression in the chorion, whereas the expression of miR-210 was higher in the amnion compared with its expression in the chorion (all P values < .05). In the amnion, MMP-9 expression was associated with PTD risk (overall P value = .0092), and MMP-9 expression was positively associated with the risk of PPROM-PTD (RRR: 31.10) and inversely associated with the risk of PE-PTD (RRR:6.55e-6), although individual associations were not statistically significant. In addition, in the amnion, the expression of miR-210 (RRR: 0.45; overall P value = .0039) was inversely associated with the risk of PE-PTD, and miR-223 was inversely associated with all subtypes of PTD (overall P value = .0400). The amnion and chorion differ in their miRNA expression. The expression of MMP-9, miR-210, and -223 in the amnion is associated with PTD risk. PMID- 26507873 TI - Expression of Endometrial Receptivity Genes Increase After Myomectomy of Intramural Leiomyomas not Distorting the Endometrial Cavity. AB - This study was designed to investigate whether endometrial receptivity genes are altered in infertile patients with intramural leiomyomas (IM) not distorting the endometrial cavity undergoing myomectomy. We measured endometrial HOXA-10, HOXA 11, LIF, ITGB3, and ITGAV messenger RNA (mRNA) expressions levels before and after myomectomy/metroplasty during mid-luteal phase in participants with IM, submucosal leiomyomas (SM), and septate uterus and fertile participants without fibroids. Initial endometrial sampling was obtained at the time of surgery, and second sampling was obtained 3 months after myomectomy/metroplasty. Expressions of each gene were evaluated using real-time reverse transcriptase polymerase chain reaction (RT-PCR). A trend toward decreased endometrial HOXA-10, HOXA-11, and ITGAV mRNA expression was detected in both SM and IM groups before myomectomy when compared to both fertile group and septate uterus. However, the differences failed to show statistical significance. After myomectomy of IM, we have detected 12.8-fold increase in endometrial HOXA-10 mRNA expression and 9.0-fold increase in endometrial HOXA-11 mRNA expression. This increase in endometrial HOXA-10 and 11 mRNA expression was significant. Accordingly, 2 patients having intramural fibroids greater than 5 cm were able to remain pregnant after myomectomy. Conversely, submucosal myomectomy did not cause any significant effect on endometrial receptivity markers. Likewise, all markers of endometrial receptivity remained unchanged after metroplasty. Myomectomy of IM have favorable effect on endometrial HOXA-10 and 11 mRNA expression. PMID- 26507874 TI - Erratum to: Functional signatures of oral dysbiosis during periodontitis progression revealed by microbial metatranscriptome analysis. PMID- 26507875 TI - Effects of Metoclopramide on Esophageal Motor Activity and Esophagogastric Junction Compliance in Healthy Volunteers. AB - BACKGROUND/AIMS: Prokinetic drugs such as metoclopramide are frequently used as second-line therapy for patients with gastroesophageal reflux disease. However, their beneficial effects remain unclear. Esophageal motor activities and compliance of the esophagogastric junction (EGJ) are important for prevention of gastroesophageal reflux. Although metoclopramide has been reported to increase lower esophageal sphincter (LES) pressure, its effects on EGJ compliance have not been evaluated. In the present study, we investigated the effects of metoclopramide on esophageal motor activities and EGJ compliance. METHODS: Nine healthy male volunteers without abdominal symptoms were enrolled. Peristaltic esophageal contractions and LES pressure were examined using high-resolution esophageal manometry, while EGJ compliance was evaluated with an endoluminal functional lumen-imaging probe. After obtaining baseline values for esophageal motor activities and EGJ compliance, metoclopramide (10 mg) was intravenously administered, then all measurements were repeated at 15 minutes after administration in each subject. RESULTS: Following administration of metoclopramide, mean resting LES pressure was significantly increased as compared with the baseline (13.7 +/- 9.2 vs 26.7 +/- 8.8 mmHg, P < 0.05). In addition, metoclopramide significantly augmented peristaltic contractions, especially in the distal esophageal segment (P < 0.05). On the other hand, distensibility index did not change after administration (4.5 +/- 0.5 vs 4.1 +/- 0.5 mm(2)/mmHg), suggesting no significant effect of metoclopramide on EGJ compliance. CONCLUSIONS: Metoclopramide augmented esophageal contractions without changing EGJ compliance in healthy adults. PMID- 26507876 TI - Comparison of socio-demographic characteristics, substance, and depression among male heroin users attending therapeutic community and methadone maintenance treatment program in Nantou, Taiwan. AB - BACKGROUND: Little is known about differences between the characteristics and psychopathological symptoms of heroin users attending TC or MMT in Asia. This study aimed to compare characteristics and prevalence of depressive disorders among male heroin users in TC and MMT program in Nantou, Taiwan. METHODS: The study sample (n = 705) comprised male heroin users with heroin dependence recruited from the MMT program and TC program at a psychiatric center in Nantou, Taiwan between 2006 and 2014. Socio-demographic and heroin-related characteristics were obtained from self-report questionnaires. DSM-IV diagnoses of heroin dependence, major depressive disorder, and dysthymic disorder were evaluated by trained interviewers. T-test and chi-square test and multivariate logistic regression were performed to measure the differences on variables between samples of TC and MMT. RESULTS: Compared to MMT, TC participants had poorer family support, higher rate of unmarried, higher rate of unemployment, earlier onset of heroin use, longer length of heroin use, and lower daily dosage of heron. MMT heroin users had higher 1-month prevalence of major depressive disorder than TC participants. We found the distribution of current major depression disorder differed between heroin users choosing different treatment models even controlling for other demographic factors, substance related factors and psychosocial factors. The underlying explanations require further investigation. CONCLUSIONS: This study found differences in the characteristics and prevalence of psychopathology. Further study to explore the effect of these differences on the outcome between MMT and TC is warranted. PMID- 26507877 TI - Sustained weight loss in patients treated with mifepristone for Cushing's syndrome: a follow-up analysis of the SEISMIC study and long-term extension. AB - BACKGROUND: Overweight and obesity are common among patients with Cushing's syndrome (CS) and may persist in some patients even after ostensibly curative surgery, contributing to cardiometabolic dysfunction and increased cardiovascular risk. Mifepristone, a selective glucocorticoid receptor antagonist, was effective in controlling hyperglycemia in a 24-week trial of adults (N = 50) with endogenous CS and associated type 2 diabetes mellitus/impaired glucose tolerance or hypertension who had failed or were not candidates for surgery (SEISMIC, Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome). This analysis examines long-term weight change among patients who received mifepristone in SEISMIC and enrolled in a long-term safety extension (LTE) study. METHODS: Patients completing the 24-week SEISMIC study and subsequent 6-week off-drug safety evaluation were invited to enroll in the LTE study. Mifepristone doses at the end of SEISMIC were the LTE starting doses. Body weight measures were reviewed at baseline and week 24 of SEISMIC and at LTE month 6, 12, 18, 24, and final visit (last observation collected during the LTE study). RESULTS: Of the 30 patients enrolled in the LTE, evaluable weight data were available for 29 (20/29 female; mean age of 44.7 +/- 11.2 years). These patients received mifepristone for a median of 29.2 months (range 8.4-41.9). Mean +/- SD weight from SEISMIC baseline to LTE final visit decreased by 10.3 +/- 16.3 kg (mean 105.4 +/- 34.3 kg to 95.1 +/- 32.9 kg), a 9.3 % decrease from baseline weight (P = 0.0008). Of the 29 LTE patients, 18 (62.1 %) lost >= 5 % of body weight by the end of the initial 24-week treatment period; this >=5 % weight loss persisted in 83.3 % (15/18) at LTE final visit. Ten patients (34.5 %) lost >= 10 % of initial body weight by week 24 of SEISMIC, which persisted in 80 % at LTE final visit. No new safety signals were detected with long-term mifepristone use. CONCLUSION: Clinically meaningful weight loss achieved during a 24-week study of mifepristone for CS persisted for two additional years in patients who remained on therapy. Long-term treatment with mifepristone appears to have a beneficial effect on weight in patients with endogenous CS. TRIAL REGISTRATION: NCT00569582 (SEISMIC); NCT00936741 (Long-Term Extension). PMID- 26507878 TI - Effects of Panax ginseng extract on human dermal fibroblast proliferation and collagen synthesis. AB - Current studies of Panax ginseng (or Korean ginseng) have demonstrated that it has various biological effects, including angiogenesis, immunostimulation, antimicrobial and anti-inflammatory effects. Therefore, we hypothesised that P. ginseng may also play an important role in wound healing. However, few studies have been conducted on the wound-healing effects of P. ginseng. Thus, the purpose of this in vitro pilot study was to determine the effects of P. ginseng on the activities of fibroblasts, which are key wound-healing cells. Cultured human dermal fibroblasts were treated with one of six concentrations of P. ginseng: 0, 1, 10 and 100 ng/ml and 1 and 10 ug/ml. Cell proliferation was determined 3 days post-treatment using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay, and collagen synthesis was evaluated by the collagen type I carboxy-terminal propeptide method. Cell proliferation levels and collagen synthesis were compared among the groups. The 10 ng/ml to 1 ug/ml P. ginseng treatments significantly increased cell proliferation, and the 1 ng/ml to 1 ug/ml concentrations significantly increased collagen synthesis. The maximum effects for both parameters were observed at 10 ng/ml. P. ginseng stimulated human dermal fibroblast proliferation and collagen synthesis at an optimal concentration of 10 ng/ml. PMID- 26507879 TI - Evolutionary Stability of Minimal Mutation Rates in an Evo-epidemiological Model. AB - We consider the evolution of mutation rate in a seasonally forced, deterministic, compartmental epidemiological model with a transmission-virulence trade-off. We model virulence as a quantitative genetic trait in a haploid population and mutation as continuous diffusion in the trait space. There is a mutation rate threshold above which the pathogen cannot invade a wholly susceptible population. The evolutionarily stable (ESS) mutation rate is the one which drives the lowest average density, over the course of one forcing period, of susceptible individuals at steady state. In contrast with earlier eco-evolutionary models in which higher mutation rates allow for better evolutionary tracking of a dynamic environment, numerical calculations suggest that in our model the minimum average susceptible population, and hence the ESS, is achieved by a pathogen strain with zero mutation. We discuss how this result arises within our model and how the model might be modified to obtain a nonzero optimum. PMID- 26507880 TI - Valproic acid suppresses collagen by selective regulation of Smads in conjunctival fibrosis. AB - Overproduction of type I collagen is associated with a wide range of fibrotic diseases as well as surgical failure such as in glaucoma filtration surgery (GFS). Its modulation is therefore of clinical importance. Valproic acid (VPA) is known to reduce collagen in a variety of tissues with unclear mechanism of action. In this report, we demonstrate that VPA inhibited collagen production in both conjunctival fibroblasts and the mouse model of GFS. In fibroblasts, VPA decreased type I collagen expression which intensified with longer drug exposure and suppressed steady-state type I collagen promoter activity. Moreover, VPA decreased Smad2, Smad3 and Smad4 but increased Smad6 expression with a similar intensity-exposure profile. Reduction of Smad3 using small hairpin RNA and/or overexpression of Smad6 resulted in decreased collagen expression which was exacerbated when VPA was simultaneously present. Furthermore, fibrogenic TGF beta2 failed to induce collagen when VPA was present, as opposed to the myofibroblast markers, beta-actin, alpha-smooth muscle actin and tenascin-C, which were elevated by TGF-beta2. VPA suppressed p3TP-Lux luciferase activity and selectively rescued Smad6 expression from suppression by TGF-beta2. Notably, SMAD6 overexpression reduced the effectiveness of TGF-beta2 in inducing collagen expression. In corroboration, VPA inhibited type I collagen but increased Smad6 expression in the late phase of wound healing in the mouse model of GFS. Taken together, our data indicate that VPA has the capacity to effectively suppress both steady-state and fibrogenic activation of type I collagen expression by modulating Smad expression. Hence, VPA is potentially applicable as an anti fibrotic therapeutic by targeting collagen. Key message: * VPA modulates type I collagen expression via members of the Smad family. * VPA suppresses Smad2, Smad3 and Smad4 but upregulates Smad6. * Smad3 and Smad6 are involved in VPA regulation of steady-state collagen expression. * Smad6 is involved in VPA modulation of TGF beta-stimulated collagen expression. * VPA reduces collagen and upregulates Smad6 in the mouse model of glaucoma filtration surgery. PMID- 26507881 TI - Did natural selection make the Dutch taller? A cautionary note on the importance of quantification in understanding evolution. AB - One of the main achievements of the modern synthesis is a rigorous mathematical theory for evolution by natural selection. Combining this theory with statistical models makes it possible to estimate the relevant parameters so as to quantify selection and evolution in nature. Although quantification is a sign of a mature science, statistical models are unfortunately often interpreted independently of the motivating mathematical theory. Without a link to theory, numerical results do not represent proper quantifications, because they lack the connections that designate their biological meaning. Here, we want to raise awareness and exemplify this problem by examining a recent study on natural selection in a contemporary human population. Stulp et al. (2015) concluded that natural selection may partly explain the increasing stature of the Dutch population. This conclusion was based on a qualitative assessment of the presence of selection on height. Here, we provide a quantitative interpretation of these results using standard evolutionary theory to show that natural selection has had a minuscule effect. PMID- 26507883 TI - Comment on: "Indigenous Medicine Use for Sex Selection During Pregnancy and Risk of Congenital Malformations: A Population-Based Case-Control Study in Haryana, India". PMID- 26507882 TI - Identification of MltG as a potential terminase for peptidoglycan polymerization in bacteria. AB - Bacterial cells are fortified against osmotic lysis by a cell wall made of peptidoglycan (PG). Synthases called penicillin-binding proteins (PBPs), the targets of penicillin and related antibiotics, polymerize the glycan strands of PG and crosslink them into the cell wall meshwork via attached peptides. The average length of glycan chains inserted into the matrix by the PBPs is thought to play an important role in bacterial morphogenesis, but polymerization termination factors controlling this process have yet to be discovered. Here, we report the identification of Escherichia coli MltG (YceG) as a potential terminase for glycan polymerization that is broadly conserved in bacteria. A clone containing mltG was initially isolated in a screen for multicopy plasmids generating a lethal phenotype in cells defective for the PG synthase PBP1b. Biochemical studies revealed that MltG is an inner membrane enzyme with endolytic transglycosylase activity capable of cleaving at internal positions within a glycan polymer. Radiolabeling experiments further demonstrated MltG-dependent nascent PG processing in vivo, and bacterial two-hybrid analysis identified an MltG-PBP1b interaction. Mutants lacking MltG were also shown to have longer glycans in their PG relative to wild-type cells. Our combined results are thus consistent with a model in which MltG associates with PG synthetic complexes to cleave nascent polymers and terminate their elongation. PMID- 26507884 TI - Authors' Reply to Sibel Yontem and Colleagues' Comment on "Indigenous Medicine Use for Sex Selection During Pregnancy and Risk of Congenital Malformations: A Population-Based Case-Control Study in Haryana, India". PMID- 26507885 TI - An Empirical Approach to Explore the Relationship Between Measures of Disproportionate Reporting and Relative Risks from Analytical Studies. AB - INTRODUCTION: Although it seems reasonable to suppose that a drug that increases the risk of an adverse event might tend to show increased disproportionality statistics in spontaneous reporting databases, that relationship is not clear. Therefore, an empirical approach was taken to investigate the relationship between proportional reporting ratios (PRRs) and relative risk (RR) estimates from formal studies in a set of known adverse drug reactions (ADRs). METHODS: Drug-event pairs that were the subject of pharmacovigilance-driven European regulatory actions from 2007 to 2010 were selected. Only pairs having RR derived from formal studies and where it was considered that there was well-established evidence supporting the actions were included. A best estimate of the RR for each ADR was chosen based on pre-specified rules. PRRs were then calculated in Eudravigilance using only those cases reported before the date of first recognition of the ADR in the medical community. An additional analysis was carried out in FEDRA, the Spanish spontaneous reports database. A descriptive analysis and an orthogonal regression model were performed. RESULTS: From an initial dataset of 78 drug-event pairs, 15 were selected. The regression model (ln RR = 0.203 + 0.463 * ln PRR) showed a significant (p < 0.001) correlation between RR and PRR in Eudravigilance. None of the ADR-related variables analysed modified the relationship. Exploratory results in FEDRA went in the same direction. CONCLUSIONS: Disproportionality measures should not replace formal studies but could provide an initial indication of the likely clinical importance of an ADR, should the signal be confirmed subsequently. Whether the same conclusions can be applied to other datasets should be further studied. PMID- 26507886 TI - Patients' experiences of living with varicose veins and management of the disease in daily life. AB - AIMS AND OBJECTIVES: The aim was to describe the experience of living with varicose veins classified according CEAP (clinical class, aetiology, anatomy, pathophysiology) as C4 (eczema or thrombophlebitis) and management of the disease in daily life. BACKGROUND: Primary chronic venous insufficiencies with varicose veins are a relatively common condition among both men and women. Several studies have shown that quality of life improved after treatment of varicose veins compared to before treatment. This suggests that patients with a milder form of varicose veins such as C4 experience a negative influence on their quality of life before treatment. DESIGN: This is an explorative qualitative study with a phenomenological approach. METHOD: A purposive sample was used, and 12 in-depth interviews were conducted with persons having superficial venous insufficiency classified C4. A descriptive phenomenological analysis was performed. RESULTS: The essence of the phenomenon of living with varicose veins classified C4 and management of the disease in daily life meant adapting to a life with varicose veins and relieve discomfort from legs with an unfavourable appearance. Coping with discomfort involved dealing with the disease emotionally and finding strategies that helped to relieve symptoms; however, living with 'repulsive' legs was seen as embarrassing, and many found the need to hide their condition. CONCLUSION: Patients with varicose veins classified C4 had notable symptoms of the disease that affected daily living. This in turn required the use of different coping strategies to manage symptoms, and significant adjustments related to activities and social life were made. RELEVANCE TO CLINICAL PRACTICE: It seems desirable that patients with varicose veins receive treatment at an earlier stage of the disease and are familiar with the tools and solutions available to alleviate symptoms and avoid a negative impact on daily life. PMID- 26507887 TI - Hot topics and networks in Cardiovascular Research. PMID- 26507888 TI - Outcome and fewer indications for adjuvant therapy for patients with oral squamous cell carcinomas under standardized tumor board conditions. AB - PURPOSE: The aim of our study was to review the outcome of patients with oral squamous cell carcinoma (OSCC) treated according to the current diagnostic and treatment protocols ["Tumor Board Group" (TBG)] compared to patients diagnosed before the introduction of standardized and certified guidelines ["Conventional Group" (CG)]. We also analyzed the influence of prognostic factors on overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) rates. METHODS: A total of 321 patients (TBG 95 patients and CG 226 patients) with histologically confirmed OSCC were included in our study. RFS, DFS and OS rates were analyzed by Kaplan-Meier estimates. Cox regression was performed for multivariate analysis of prognostic factors. Results were statistically significant with a p value of <0.05. RESULTS: T, N, AJCC stage, age and therapy resulted to be independent risk factors for OS and DFS. We were not able to identify statistically significant prognostic factors for RFS apart from grading. 31.58% of patients from the TBG received postoperative adjuvant treatment compared to 74.78% within the CG. The OS rate was 79.63% at 30 months for patients from the TBG in comparison with 65.54% for patients from the CG. CONCLUSION: The implementation of standardized guidelines including the establishment of the "Tumor Board Conference" results in a higher percentage of patients receiving surgery as only treatment and in better OS rates. To further support this positive trend, patients shall be followed longer and analyzed in future. T, N and M as well as AJCC stage were identified as most important prognostic factors for OS and DFS in our study. PMID- 26507889 TI - Race and sex disparities in long-term survival of oral and oropharyngeal cancer in the United States. AB - PURPOSE: To investigate the effect of race and sex on long-term survival of oral and oropharyngeal cancer. METHODS: The Surveillance, Epidemiology and End Results database was queried for adult oral and oropharyngeal cancer patients with at least 25-year follow-up. Kaplan-Meier survival curves and cox proportional hazards model were used to identify differences. RESULTS: Of the 22,162 patients identified, 70.3% were males. Only 8.9% were alive at 25 years post-diagnosis. Black males show the poorest overall and disease-specific survival rates (p < 0.001). After controlling for covariates, Blacks had a 40% higher hazard of mortality compared with Whites (HR 1.40, 95% CI 1.35-1.46), while females had a 9% reduction in mortality risk (HR 0.91, 95% CI 0.88-0.94). CONCLUSIONS: Overall and disease-specific survival is poor for oral and oropharyngeal cancer patients, and Black men fare worst. This illustrates the need for long-term cancer survival plans incorporating disparity effects in overall cancer outcomes. PMID- 26507890 TI - Facile preparation of hyaluronic acid and transferrin co-modified Fe3O4 nanoparticles with inherent biocompatibility for dual-targeting magnetic resonance imaging of tumors in vivo. AB - Clinical diagnosis of malignant tumors using nanoprobes needs severe improvements in the aspects of sensitivity and biocompatibility. Integrating a dual-targeting strategy with the selection of human-inherent elements and molecules as raw materials shows great potential in the development of a biosafe and sensitive nanoplatform. To carry out the proposed design, we constructed a biocompatible, dual-targeting MR imaging nanoprobe, based on Fe3O4 nanoparticles (NPs) co modified with inherently innoxious hyaluronic acid (HA) and transferrin (Tf). HA was used as both a template and a targeting molecule to form Fe3O4@HA NPs through a one-step co-precipitation method, which were then further modified with Tf to obtain the dual-targeting Fe3O4@HA@Tf NPs at room temperature. The excellent biocompatibility of the nanoprobe was demonstrated via toxicity assays in vitro and in vivo. The desirable dual-targeting ability towards tumor cells was confirmed by a cellular uptake test (Hela cells, overexpressing both CD44 and transferrin receptors), and the developed nanoprobe was successfully applied in tumor-targeted MR imaging in vivo. In summation, we developed a dual-targeting Fe3O4 nanoprobe, following a facile procedure at room temperature. The nanoprobe showed a high targeting ability towards tumor cells and excellent biocompatibility, which showed its great potential to be applied in the clinical diagnosis of tumors. PMID- 26507891 TI - On a quest for stress tolerance genes: membrane transporters in sensing and adapting to hostile soils. AB - Abiotic stresses such as salinity, drought, and flooding severely limit food and fibre production and result in penalties of in excess of US$100 billion per annum to the agricultural sector. Improved abiotic stress tolerance to these environmental constraints via traditional or molecular breeding practices requires a good understanding of the physiological and molecular mechanisms behind roots sensing of hostile soils, as well as downstream signalling cascades to effectors mediating plant adaptive responses to the environment. In this review, we discuss some common mechanisms conferring plant tolerance to these three major abiotic stresses. Central to our discussion are: (i) the essentiality of membrane potential maintenance and ATP production/availability and its use for metabolic versus adaptive responses; (ii) reactive oxygen species and Ca(2+) 'signatures' mediating stress signalling; and (iii) cytosolic K(+) as the common denominator of plant adaptive responses. We discuss in detail how key plasma membrane and tonoplast transporters are regulated by various signalling molecules and processes observed in plants under stress conditions (e.g. changes in membrane potential; cytosolic pH and Ca(2+); reactive oxygen species; polyamines; abscisic acid) and how these stress-induced changes are related to expression and activity of specific ion transporters. The reported results are then discussed in the context of strategies for breeding crops with improved abiotic stress tolerance. We also discuss a classical trade-off between tolerance and yield, and possible avenues for resolving this dilemma. PMID- 26507892 TI - Cell wall-associated kinases and pectin perception. AB - The pectin matrix of the angiosperm cell wall is regulated in both synthesis and modification and greatly influences the direction and extent of cell growth. Pathogens, herbivory and mechanical stresses all influence this pectin matrix and consequently plant form and function. The cell wall-associated kinases (WAKs) bind to pectin and regulate cell expansion or stress responses depending upon the state of the pectin. This review explores the WAKs in the context of cell wall biology and signal transduction pathways. PMID- 26507893 TI - Mitogen-activated protein kinase 6 mediates nuclear translocation of ORE3 to promote ORE9 gene expression in methyl jasmonate-induced leaf senescence. AB - Methyl jasmonate (MeJA) is a potent promoter of plant senescence. ORESARA3 (ORE3)/ETHYLENE INSENSITIVE2 (EIN2), a protein similar to the members of the disease-related Nramp metal transporter family, is involved in cross-talk among several senescence processes related to abscisic acid, ethylene, MeJA, age and darkness. Nevertheless, the mechanism involved in the regulation of ORE3/EIN2 in exogenous MeJA-induced leaf senescence remains unclear. The C-terminal end of ORE3/EIN2 (CEND) was cleaved from ORE3/EIN2 located in the endoplasmic reticulum and then transferred to the nucleus during MeJA-induced senescence. Further analyses showed that mitogen-activated protein kinase 6 (MPK6) promoted CEND cleavage and nuclear translocation. Nuclear CEND accumulated ETHYLENE INSENSITIVE3 (EIN3), a transcription factor that accelerates MeJA-induced leaf senescence wherein ORESARA9 (ORE9) expression was suppressed in ein3, ore3, and mpk6 mutant plants. ChIP experiments revealed that EIN3 bound directly to the ORE9 promoter and this binding was enhanced in MeJA-induced leaf senescence. This study revealed the effect of the signalling pathway involving MPK6-ORE3-EIN3-ORE9 on regulating leaf senescence and provided insights into the mechanism of MeJA in promoting leaf senescence in Arabidopsis thaliana. PMID- 26507894 TI - ABSCISIC ACID-INSENSITIVE 4 negatively regulates flowering through directly promoting Arabidopsis FLOWERING LOCUS C transcription. AB - During the life cycle of a plant, one of the major biological processes is the transition from the vegetative to the reproductive stage. In Arabidopsis, flowering time is precisely controlled by extensive environmental and internal cues. Gibberellins (GAs) promote flowering, while abscisic acid (ABA) is considered as a flowering suppressor. However, the detailed mechanism through which ABA inhibits the floral transition is poorly understood. Here, we report that ABSCISIC ACID-INSENSITIVE 4 (ABI4), a key component in the ABA signalling pathway, negatively regulates floral transition by directly promoting FLOWERING LOCUS C (FLC) transcription. The abi4 mutant showed the early flowering phenotype whereas ABI4-overexpressing (OE-ABI4) plants had delayed floral transition. Consistently, quantitative reverse transcription-PCR (qRT-PCR) assay revealed that the FLC transcription level was down-regulated in abi4, but up-regulated in OE-ABI4. The change in FT level was consistent with the pattern of FLC expression. Chromatin immunoprecipitation-qPCR (ChIP-qPCR), electrophoretic mobility shift assay (EMSA), and tobacco transient expression analysis showed that ABI4 promotes FLC expression by directly binding to its promoter. Genetic analysis demonstrated that OE-ABI4::flc-3 could not alter the flc-3 phenotype. OE FLC::abi4 showed a markedly delayed flowering phenotype, which mimicked OE FLC::WT, and suggested that ABI4 acts upstream of FLC in the same genetic pathway. Taken together, these findings suggest that ABA inhibits the floral transition by activating FLC transcription through ABI4. PMID- 26507895 TI - PIXE-electrophoresis shows starving collembolan reallocates protein-bound metals. AB - One of multiple functions of metalloproteins is to provide detoxification to excess metal levels in organisms. Here we address the induction and persistence of a range of low to high molecular weight copper- and zinc binding proteins in the collembolan species Tetrodontophora bielanensis exposed to copper- and zinc enriched food, followed by a period of recovery from metal exposure, in absence and presence of food. After 10 days of feeding copper and zinc contaminated yeast, specimens were either moved to ample of leaf litter material from their woodland stand of origin or starved (no food offered). The molecular weight distribution of metal binding proteins was determined by native polyacryl gel electrophoresis. One gel was stained with Comassie brilliant blue and a duplicate gel dried and scanned for the amount of copper and zinc by particle-induced X-ray emission. Specimens exposed to copper and recovered from it with ample of food had copper bound to two groups of rather low molecular weight proteins (40-50 kDa) and two of intermediate size (70-80 kDa). Most zinc in specimens from the woodland stand was bound to two large proteins of about 104 and 106 kDa. The same proteins were holding some zinc in metal-exposed specimens, but most zinc was found in proteins <40 kDa in size. Specimens recovered from metal exposure in presence of ample of food had the same distribution pattern of zinc binding proteins, whereas starved specimens had zinc as well as copper mainly bound to two proteins of 8 and 10 kDa in size. Thus, the induction and distribution of copper- and zinc-binding proteins depend on exposure conditions, and the presence of low molecular weight binding proteins, characteristic of metallothioneins, was mainly limited to starving conditions. PMID- 26507896 TI - A Relational Turbulence Model Perspective on Communication in Intimate Relationships Post-HPV Testing. AB - The Relational Turbulence Model (RTM) is a theoretical tool designed to understand how romantic partners navigate tumultuous events. In this article, we explore two RTM constructs, relational uncertainty and partner interference, in the context of romantic partners' human papillomavirus (HPV) diagnosis outcomes. We examine whether self-reported relational uncertainty and partner interference were differentially associated with a negative self-HPV diagnosis, a positive self-diagnosis, or a partner's positive diagnosis. Findings suggest that diagnosis type predicts relational uncertainty and partner interference in different ways. We also argue that partners' reported expression of affect after experiencing a relationally-relevant transition may manifest in both positive and negative ways. Our results support the contention that partners may express both positive and negative affect toward one another, particularly based on the type of HPV diagnosis outcome they receive. PMID- 26507897 TI - Choroidal neovascularization is inhibited via an intraocular decrease of inflammatory cells in mice lacking complement component C3. AB - In early age-related macular degeneration (AMD), complement component C3 can be observed in drusen, which is the accumulation of material beneath the retinal pigment epithelium. The complement pathways, via the activation of C3, can upregulate the expression of cytokines and their receptors and the recruitment of inflammatory leukocytes, both of which play an important role in the development of choroidal neovascularization (CNV) in exudative AMD. Laser-induced CNV lesions were found to be significantly smaller in C3(-/-) mice than in wild-type mice. By using flow cytometry, we demonstrated that the proportions of intraocular granulocytes, CD11b(+)F4/80(+)Ly6C(hi) and CD11b(+)F4/80(+)Ly6C(lo) cells, were lower in C3(-/-) mice than in wild-type mice as early as day 1 after laser injury, and the proportions of granulocytes and three macrophage/monocyte subsets were significantly lower on day 3. In contrast, C3(-/-) mice had more granulocytes and CD11b(+)F4/80(+)Ly6C(hi) cells in peripheral blood than wild type mice after injury. Further, the expression levels of Vegfa164 were upregulated in intraocular Ly6C(hi) macrophages/monocytes of C3(-/-) mice, but not as much as in wild-type mice. Collectively, our data demonstrate that despite a more pronounced induction of systemic inflammation, inhibition of complement factor C3 suppresses CNV by decreasing the recruitment of inflammatory cells to the lesion. PMID- 26507898 TI - Establishment of diagnostic reference levels for common multi-detector computed tomography examinations in Iran. AB - In order to establish diagnostic reference levels (DRLs) for multi-detector computed tomography (MDCT), four routine CT examinations were identified and a computer program was developed to collect data from 19 MDCT scanners in Iran. Mean values of Volume computed tomography dose index (CTDIvol) and dose-length product (DLP) in each site were calculated and the DRLs were defined as the 75th percentile of the distribution of the CTDIvol/DLP values for each examination. In terms of DLP, the DRLs of adult age group are 700, 290, 330, and 550 mGy cm for the Brain, Sinus, Chest, and Abdomen and Pelvis protocols, respectively. Although DRLs of this study are comparable to other international DRLs and in most cases are less than the international reference values, the great extent of dose distributions indicates that the CT imaging procedures in Iran should be optimized by applying diagnostic reference levels in order to decrease the radiation dose to patient undergoing CT examination. PMID- 26507899 TI - Heart rate variability helps tracking time more accurately. AB - Adequate temporal abilities are crucial for adaptive behavior. In time processing, variations in the rate of pulses' emission by the pacemaker are often reported to be an important cause of temporal errors. These variations are often associated with physiological changes, and recently it has also been proposed that physiological changes may not just vary the pulses' emission, but they can work as a timekeeper themselves. In the present study we further explore the relationship between temporal abilities with autonomic activity and interoceptive awareness in a group of thirty healthy young adults (mean age 24.18 years; SD=2.1). Using electrocardiogram, impedance cardiography and skin conductance measures, we assessed the relationship between the autonomic profile at rest and temporal abilities in two temporal tasks (time bisection and finger tapping tasks). Results showed that heart rate variability affects time perception. We observed that increased heart rate variability (HRV) was associated with higher temporal accuracy. More specifically, we found that higher vagal control was associated with lower error in producing 1-s tempo, whereas higher overall HRV was related with lower error (measured by the constant error) in the time bisection task. Our results support the idea that bodily signals may shape our perception of time. PMID- 26507900 TI - Region-specific reduction of auditory sensory gating in older adults. AB - Aging has been associated with declines in sensory-perceptual processes. Sensory gating (SG), or repetition suppression, refers to the attenuation of neural activity in response to a second stimulus and is considered to be an automatic process to inhibit redundant sensory inputs. It is controversial whether SG deficits, as tested with an auditory paired-stimulus protocol, accompany normal aging in humans. To reconcile the debates arising from event-related potential studies, we recorded auditory neuromagnetic reactivity in 20 young and 19 elderly adult men and determined the neural activation by using minimum-norm estimate (MNE) source modeling. SG of M100 was calculated by the ratio of the response to the second stimulus over that to the first stimulus. MNE results revealed that fronto-temporo-parietal networks were implicated in the M100 SG. Compared to the younger participants, the elderly showed selectively increased SG ratios in the anterior superior temporal gyrus, anterior middle temporal gyrus, temporal pole and orbitofrontal cortex, suggesting an insufficient age-related gating to repetitive auditory stimulation. These findings also highlight the loss of frontal inhibition of the auditory cortex in normal aging. PMID- 26507901 TI - Monitoring the concentration of flowing pharmaceutical powders in a tableting feed frame. AB - The use of process analytical technology (PAT) tools is increasing steadily in the pharmaceutical industry. Such tools are now located throughout the process. When producing tablets, the tableting step itself may be the ideal moment to assess final product composition. Being the last unit operation in tablet production where the elements are still free flowing, it is relatively straightforward to ascertain the composition of the blend in real time. However, a single probe cannot be expected to monitor the composition of every component of a multicomponent blend. In this study, three PAT tools (light-induced fluorescence spectroscopy, near-infrared spectroscopy and color (RGB) imaging) simultaneously checked the composition of powder blends flowing through the feeding unit (feed frame) of a tablet press. The results demonstrate the potential of these tools in monitoring changes in the concentration of a multicomponent mixture in real time, providing users with means to both scrutinize the process and better understand phenomena occurring inside the feed frame. PMID- 26507902 TI - THE CORRELATION BETWEEN g LOADINGS AND HERITABILITY IN RUSSIA. AB - The study focused on the extent to which the general factor of intelligence g and heritability coefficients of the subtests of an IQ battery correlate. Modest to strong positive correlations were found in five studies from Western countries and six studies from a Japanese meta-analysis. The results for Russian twins were compared with those of the Western and Japanese studies. Data from 402 twins aged 13 and 296 twins aged 16 showed correlations of r=-0.45 and r=-0.60, respectively. It is concluded that the two data points are clearly not in line with established findings. It may be that the link between g loadings and heritabilities is more complex than previously thought. PMID- 26507903 TI - Comparative analysis of clinical profile: Chronic cough vs paradoxical vocal fold motion. AB - BACKGROUND: Ongoing contention surrounding typical demographic and clinical attributes of chronic cough (CC) and paradoxical vocal fold motion (PVFM) impedes timely diagnosis and optimum patient care. Designed to reduce preventable patient morbidity through improved recognition and differentiation, the current study aimed to determine representative clinical profiles for CC and PVFM, with identification of distinctive attributes from the general population and risk factors associated with each diagnosis. METHODS: Self-reported medical questionnaires, demographic and lifestyle attributes of CC and PVFM cases from a disease-specific outcomes database were compared to US population data and published normative values. Univariate comparison and multivariate regression modelling of age, sex, alcohol intake, smoking, Reflux Symptom Index (RSI), Voice Handicap Index (VHI), and Generalized Anxiety Disorder 7-item Scale (GAD-7) determined distinguishing features between the clinical groups, including odds ratios for presenting with CC versus PVFM. RESULTS: Clinical profiles developed from 283 (128 CC, 155 PVFM) adults (18-91 years) were significantly different from the general population across each demographic, lifestyle and clinical variable (all p < .01), with the exception of obesity. Age (55.39 +/- 13.54 vs 45.07 +/- 16.51 years, p < .01) and mean RSI score (21.5 +/- 9.02 vs 18.1 +/- 9.08, p < .01) most reliably distinguished CC from PVFM, with those aged 60-69 years (OR = 9.45) most likely to be diagnosed with CC. CONCLUSIONS: Standard clinical profiles of CC and PVFM are distinct from the general population, aiding determination of relative probabilities and risk factors in the differential diagnostic process. Variations between CC and PVFM were subtle, reliably distinguished by age and relative severity of laryngopharyngeal reflux symptomatology. PMID- 26507904 TI - Coronary Computed Tomography Angiography Versus Traditional Care: Comparison of One-Year Outcomes and Resource Use. AB - STUDY OBJECTIVE: Three large, multicenter, randomized, clinical trials have shown that coronary computed tomography (CT) angiography allows efficient evaluation and safe discharge of patients with low- to intermediate-risk chest pain who present to the emergency department (ED). We report 1-year event rates and resource use from the American College of Radiology Imaging Network-Pennsylvania 4005 multicenter trial. METHODS: Patients with low- to intermediate-risk chest pain and presenting to the ED were randomized in a 2:1 ratio to a coronary CT angiography care pathway or traditional care. Subjects were contacted by telephone at least 1 year after ED presentation. Medical record review was performed for all cardiac hospitalizations, procedures and diagnostic tests, and adverse cardiac events. Our main outcome was the composite of cardiac death and myocardial infarction within 1 year. The secondary outcome was resource use. RESULTS: One thousand three hundred sixty-eight patients enrolled and 1,285 (94%) had direct participant or proxy contact at 1 year. All others had record review or death index search. From index presentation through 1 year, there was no difference between patients in the coronary CT angiography arm versus traditional care with respect to major adverse cardiac event (1.4% versus 1.1%; difference 0.3%; 95% CI -5.5% to 6.0%). From hospital discharge through 1 year, there was also no difference in ED revisits (36% versus 38%; difference -2.1%; 95% CI -7.9% to 3.7%), hospital admissions (16% versus 17%; difference -0.9%; 95% CI -6.7% to 4.9%), or subsequent cardiac testing (13% versus 13%; difference -0.4%; 95% CI 6.2% to 5.5%). One of 640 subjects with a negative coronary CT angiography result had a major adverse cardiac event within 1 year of presentation (0.16%; 95% CI 0.004% to 0.87%). CONCLUSION: A coronary CT angiography-based strategy for evaluation of patients with low- to intermediate-risk chest pain who present to the ED does not result in increased resource use during 1 year. A negative coronary CT angiography result is associated with a less than 1% major adverse cardiac event rate during the first year after testing. PMID- 26507905 TI - Design Trumps Training. PMID- 26507906 TI - Effect Sizes and Primary Outcomes in Large-Budget, Cardiovascular-Related Behavioral Randomized Controlled Trials Funded by NIH Since 1980. AB - PURPOSE: We reviewed large-budget, National Institutes of Health (NIH)-supported randomized controlled trials (RCTs) with behavioral interventions to assess (1) publication rates, (2) trial registration, (3) use of objective measures, (4) significant behavior and physiological change, and (5) effect sizes. METHODS: We identified large-budget grants (>$500,000/year) funded by NIH (National Heart Lung and Blood Institute (NHLBI) or National Institute of Diabetes & Digestive and Kidney Diseases (NIDDK)) for cardiovascular disease (dates January 1, 1980 to December 31, 2012). Among 106 grants that potentially met inclusion criteria, 20 studies were not published and 48 publications were excluded, leaving 38 publications for analysis. ClinicalTrials.gov abstracts were used to determine whether outcome measures had been pre-specified. RESULTS: Three fourths of trials were registered in ClinicalTrials.gov and all published pre-specified outcomes. Twenty-six trials reported a behavioral outcome with 81 % reporting significant improvements for the target behavior. Thirty-two trials reported a physiological outcome. All were objectively measured, and 81 % reported significant benefit. Seventeen trials reported morbidity outcomes, and seven reported a significant benefit. Nine trials assessed mortality, and all were null for this outcome. CONCLUSIONS: Behavioral trials complied with trial registration standards. Most reported a physiological benefit, but few documented morbidity or mortality benefits. PMID- 26507907 TI - Acute Stress Disorder Symptoms Predict All-Cause Mortality Among Myocardial Infarction Patients: a 15-Year Longitudinal Study. AB - BACKGROUND: Studies have recognized myocardial infarction (MI) as a risk for acute stress disorder (ASD), manifested in dissociative, intrusive, avoidant, and hyperarousal symptoms during hospitalization. PURPOSE: This study examined the prognostic role of ASD symptoms in predicting all-cause mortality in MI patients over a period of 15 years. METHODS: One hundred and ninety-three MI patients filled out questionnaires assessing ASD symptoms during hospitalization. Risk factors and cardiac prognostic measures were collected from patients' hospital records. All-cause mortality was longitudinally assessed, with an endpoint of 15 years after the MI. RESULTS: Of the participants, 21.8 % died during the follow up period. The decedents had reported higher levels of ASD symptoms during hospitalization than had the survivors, but this effect became nonsignificant when adjusting for age, sex, education, left ventricular ejection fraction, and depression. A series of analyses conducted on each of the ASD symptom clusters separately indicated that-after adjusting for age, sex, education, left ventricular ejection fraction, and depression-dissociative symptoms significantly predicted all-cause mortality, indicating that the higher the level of in hospital dissociative symptoms, the shorter the MI patients' survival time. CONCLUSION: These findings suggest that in-hospital dissociative symptoms should be considered in the risk stratification of MI patients. PMID- 26507908 TI - Exploring risk profiles and emergency frequency of purchasers and non-purchasers of personal emergency alarms: a prospective cohort study. AB - BACKGROUND: Personal alarms support independent living and have the potential to reduce serious consequences after a fall or during a medical emergency. While some Australian states have government funded personal alarm programs, others do not; but user-pays services are available. Although several studies have examined the profiles of alarm users, little is known about the risk profile of non-users. Specifically, whether there are "at risk" individuals who are unable, or choose not to purchase a service, who experience a home-based emergency in which an alarm could have mitigated an adverse outcome. This study aimed to describe the 'risk profile' of purchasers and non-purchasers of alarms; explore the reasons behind the decision to purchase or not to purchase and identify how often emergency assistance was needed and why. METHODS: Purchasers and non-purchasers were followed for one year in this prospective cohort study. Demographic, decision-making and risk factor data were collected at an initial face-to-face interview, while information about emergencies was collected by monthly calls. RESULTS: One hundred and fifty-seven purchasers and sixty-five non-purchasers completed the study. The risk profiles between the groups were similar in terms of gender, living arrangements, fall history and medical conditions. Purchasers (Mean = 82.6 years) were significantly older than non-purchasers (Mean = 79.3 years), (t(220) = -3.38, p = 0.000) and more functionally dependent on the IADL (z = -2.57, p = 0.010) and ADL (z = -2.45 p = 0.014) function scores. Non purchasers (Mean = 8.04, SD = 3.57) were more socially isolated with significantly fewer family networks than purchasers (Mean = 9.46, SD = 3.25) (t(220) = -2.86, p = 0.005). Both groups experienced similarly high numbers of emergencies, 38.2 % of purchasers and 41.5 % of non-purchasers had at least one emergency where an alarm could have assisted. Main reasons for non-purchase were: cost (77 %), limited alarm range (51 %), no need (39 %) and lack of suitable contacts (30 %). CONCLUSION: There are older individuals who are at high risk of an emergency who are choosing, often for financial and lack of family support reasons, not to purchase a personal alarm service. Greater availability of government funded subsidy schemes would enable these individuals to access a service. Increasing the range over which alarms work could increase their appeal to a broader range of older persons living in the community. Future research should consider how strategies that improve social isolation from family and challenge clients' beliefs about their own health and independence can support increased access to personal alarm services. PMID- 26507909 TI - Mass spectrometry-guided isolation of two new benzoquinoline alkaloids from Macleaya cordata. AB - Two new alkaloids, named 2,3-methylenedioxy-7,10-dimethyl-7,8,9,10-tetrahydro benzoquinoline (1) and 2,3-methylenedioxy-7,10-dimethyl-8-carboxyl-benzoquinoline (2), were detected primarily from the fruits of Macleaya cordata by their different fragmentation pathways. And then isolation of the two compounds was performed by column chromatography and preparative HPLC under the guiding of mass spectrometry. Finally, their structures were determined by spectroscopic analysis. PMID- 26507910 TI - Anti-inflammatory effect of curcumin on mast cell-mediated allergic responses in ovalbumin-induced allergic rhinitis mouse. AB - Curcumin has commonly been used for the treatment of various allergic diseases. However, its precise anti-allergic rhinitis effect and mechanism remain unknown. In the present study, the effect of curcumin on allergic responses in ovalbumin (OVA)-induced allergic rhinitis mouse was investigated. We explored the effect of curcumin on the release of allergic inflammatory mediators, such as histamine, OVA-specific IgE, and inflammatory cytokines. Also, we found that curcumin improved rhinitis symptoms, inhibited the histopathological changes of nasal mucosa, and decreased the serum levels of histamine, OVA-specific IgE and TNF alpha in OVA-induced allergic rhinitis mice. In addition, curcumin suppressed the production of inflammatory cytokines, such as TNF-alpha, IL-1beta, IL-6 and IL-8. Moreover, curcumin significantly inhibited PMA-induced p-ERK, p-p38, p-JNK, p Ikappa-Balpha and NF-kappaB. These findings suggest that curcumin has an anti allergic effect through modulating mast cell-mediated allergic responses in allergic rhinitis, at least partly by inhibiting MAPK/NF-kappaB pathway. PMID- 26507911 TI - Mycobacterium tuberculosis MmsA, a novel immunostimulatory antigen, induces dendritic cell activation and promotes Th1 cell-type immune responses. AB - Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is an outstanding pathogen that modulates the host immune response. This inconvenient truth drives the continual identification of antigens that generate protective immunity, including Th1-type T cell immunity. Here, the contribution of methylmalonate semialdehyde dehydrogenase (MmsA, Rv0753c) of Mtb to immune responses was examined in the context of dendritic cell (DC) activation and T cell immunity both in vitro and in vivo. The results showed that MmsA induced DC activation by activating the MAPK and NF-kappaB signaling pathways. Additionally, MmsA-treated DCs activated naive T cells, effectively polarized CD4(+) and CD8(+) T cells to secrete IFN-gamma and IL-2, and induced T cell proliferation. These results indicate that MmsA is a novel DC maturation-inducing antigen that drives the Th1 immune response. Thus, MmsA was found to potentially regulate immune responses via DC activation toward Th1-type T cell immunity, enhancing our understanding of Mtb pathogenesis. PMID- 26507913 TI - ZnO nanoflowers with single crystal structure towards enhanced gas sensing and photocatalysis. AB - In this paper, ZnO nanoflowers (NFs) were fabricated by thermal decomposition in an organic solvent and their application in gas sensors and photocatalysis was investigated. These single crystal ZnO NFs, which were observed for the first time, with an average size of ~60 nm and were grown along the {100} facet. It was suggested that oleylamine used in the synthesis inhibited the growth and agglomeration of ZnO through the coordination of the oleylamine N atoms. The NFs exhibited excellent selectivity to acetone with a concentration of 25 ppm at 300 degrees C because they had a high specific surface area that provided more active sites and the surface adsorbed oxygen species for interaction with acetone. In addition, the ZnO NFs showed enhanced gas sensing response which was also ascribed to abundant oxygen vacancies at the junctions between petals of the NFs. Furthermore, ZnO-reduced graphene oxide (RGO) composites were fabricated by loading the ZnO NFs on the surface of the stratiform RGO sheet. In the photodegradation of rhodamine B tests, the composite revealed an enhanced photocatalytic performance compared with ZnO NFs under UV light irradiation. PMID- 26507912 TI - Deficiency of GABAergic synaptic inhibition in the Kolliker-Fuse area underlies respiratory dysrhythmia in a mouse model of Rett syndrome. AB - KEY POINTS: Life threatening breathing irregularity and central apnoeas are highly prevalent in children suffering from Rett syndrome. Abnormalities in inhibitory synaptic transmission have been associated with the physiopathology of this syndrome, and may underlie the respiratory disorder. In a mouse model of Rett syndrome, GABAergic terminal projections are markedly reduced in the Kolliker-Fuse nucleus (KF) in the dorsolateral pons, an important centre for control of respiratory rhythm regularity. Administration of a drug that augments endogenous GABA localized to this region of the pons reduced the incidence of apnoea and the respiratory irregularity of Rett female mice. Conversely, the respiratory disorder was recapitulated by blocking GABAergic transmission in the KF area of healthy rats. This study helps us understand the mechanism for generation of respiratory abnormality in Rett syndrome, pinpoints a brain site responsible and provides a clear anatomical target for the development of a translatable drug treatment. Central apnoeas and respiratory irregularity are a common feature in Rett syndrome (RTT), a neurodevelopmental disorder most often caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2). We used a MECP2 deficient mouse model of RTT as a strategy to obtain insights into the neurobiology of the disease and into mechanisms essential for respiratory rhythmicity during normal breathing. Previously, we showed that, systemic administration of a GABA reuptake blocker in MECP2 deficient mice markedly reduced the occurrence of central apnoeas. Further, we found that, during central apnoeas, post-inspiratory drive (adductor motor) to the upper airways was enhanced in amplitude and duration in Mecp2 heterozygous female mice. Since the pontine Kolliker-Fuse area (KF) drives post-inspiration, suppresses inspiration, and can reset the respiratory oscillator phase, we hypothesized that synaptic inhibition in this area is essential for respiratory rhythm regularity. In this study, we found that: (i) Mecp2 heterozygous mice showed deficiency of GABA perisomatic bouton-like puncta and processes in the KF nucleus; (ii) blockade of GABA reuptake in the KF of RTT mice reduced breathing irregularity; (iii) conversely, blockade of GABAA receptors in the KF of healthy rats mimicked the RTT respiratory phenotype of recurrent central apnoeas and prolonged post inspiratory activity. Our results show that reductions in synaptic inhibition within the KF induce rhythm irregularity whereas boosting GABA transmission reduces respiratory arrhythmia in a murine model of RTT. Our data suggest that manipulation of synaptic inhibition in KF may be a clinically important strategy for alleviating the life threatening respiratory disorders in RTT. PMID- 26507915 TI - A blood transfusion can save a child's life or threaten it. PMID- 26507916 TI - A smartphone version of the Faces Pain Scale-Revised and the Color Analog Scale for postoperative pain assessment in children. AB - BACKGROUND: Effective pain assessment is essential during postoperative recovery. Extensive validation data are published supporting the Faces Pain Scale-Revised (FPS-R) and the Color Analog Scale (CAS) in children. Panda is a smartphone-based application containing electronic versions of these scales. OBJECTIVES: To evaluate agreement between Panda and original paper/plastic versions of the FPS-R and CAS and to determine children's preference for either Panda or original versions of these scales. METHODS: ASA I-III children, 4-18 years, undergoing surgery were assessed using both Panda and original versions of either the FPS-R or CAS. Pain assessments were conducted within 10 min of waking from anesthesia and 30 min later. RESULTS: Sixty-two participants, median (range) age 7.5 (4-12) years, participated in the FPS-R trial; Panda scores correlated strongly with the original scores at both time points (Pearson's r > 0.93) with limits of agreement within clinical significance (80% CI). Sixty-six participants, age 13 (5-18) years, participated in the CAS trial. Panda scores correlated strongly with the original scores at both time points (Pearson's r > 0.87); mean pain scores were higher (up to +0.47 out of 10) with Panda than with the original tool, representing a small systematic bias, but limits of agreement were within clinical significance. Most participants who expressed a preference preferred Panda over the original tool (81% of FPS-R, 76% of CAS participants). CONCLUSION: The Panda smartphone application can be used in lieu of the original FPS-R and CAS for assessment of pain in children. Children's preference for Panda may translate to improved cooperation with self-report of pain. PMID- 26507917 TI - Changes in QTc associated with a rapid bolus dose of dexmedetomidine in patients receiving TIVA: a retrospective study. AB - BACKGROUND: Clinical indications for the perioperative use of dexmedetomidine in pediatric anesthesia are accumulating. However, in 2013, dexmedetomidine was added to the list of medications with possible risk of prolonging the QT interval and/or inducing Torsades de Pointes. Unfortunately, current evidence for dexmedetomidine-induced QT prolongation is sparse and somewhat contradictory. OBJECTIVE: The purpose of this study was to evaluate temporal changes in corrected QT interval (QTc) after a rapid bolus administration of dexmedetomidine under total intravenous anesthesia (TIVA) with a standardized propofol and remifentanil administration. METHODS: Electrocardiography (ECG) and corresponding trend data were extracted from automated electronic data capture of physiological monitoring. Ten-second epochs of ECG data were extracted in 1-min intervals for 12 min, starting 1 min before dexmedetomidine bolus administration, and ending 10 min after. QT intervals were extracted using an automated routine in MATLAB, and corrected for heart rate (HR) using Bazett's (QTcB) and Fridericia's formulas (QTcF). QTcB and QTcF were compared using Wilcoxon signed-rank test between baseline measurements and the subsequent four interval values. RESULTS: Data from 21 subjects (17 male) with median (range) age 7.1 (5.4-9.5) yr, weight 23.6 (16.2 36.7) kg, and height 121 (103-140) cm were analyzed. Bolus administration of dexmedetomidine reduced HR in all subjects (median 22%), and caused transient reduction of QT interval, with its peak at 1-min postbolus administration: QTcB (median reduction 30.7 ms, P < 0.001) or QTcF (median reduction 15.4 ms, P = 0.001); QT shortening became statistically insignificant 4 min following dexmedetomidine bolus administration for QTcB and 2 min for QTcF. CONCLUSION: In this study, a rapid bolus of dexmedetomidine transiently shortened corrected QT intervals. However, these effects are confounded by dexmedetomidine-induced bradycardia. These findings should be confirmed in pediatric studies without concomitant TIVA administration and with optimized correction of baseline HR. PMID- 26507918 TI - The Guedel airway: too large is too bad. PMID- 26507919 TI - Should awake caudals and epidurals be used more frequently in neonates and infants? PMID- 26507920 TI - Let them drink! PMID- 26507921 TI - Is atropine premedication during ketamine-dexmedetomidine sedation is necessary? PMID- 26507922 TI - Lung ultrasound assessment of influenza A(H1N1)-associated ARDS in a child with acute lymphoblastic leukemia outbreak undergoing extracorporeal membrane oxygenation. PMID- 26507924 TI - A systematic review of the safety and efficacy of hepatopancreatoduodenectomy for biliary and gallbladder cancers. AB - OBJECTIVES: To review the evidence on the safety and efficacy of hepatopancreatoduodenectomy for biliary and gallbladder cancers. METHODS: Medline and EMBASE were systematically searched for papers describing hepatopancreatoduodenectomy in patients with biliary and gallbladder cancers. RESULTS: Eighteen studies involving 397 patients were reviewed. A major hepatectomy was undertaken in 81.3% of the 397 patients, and the R0 resection rate was 71.3%. The morbidity and mortality rates were 78.9% and 10.3%, respectively. The 5-year overall survival rate ranged from 3% to 50% (median = 31%). The 5-year survival rate in patients who underwent a curative resection was 18-68.8% (median = 51.3%), and 0% in patients who received a non-curative resection. CONCLUSIONS: A hepatopancreatoduodenectomy is a challenging procedure with high morbidity and mortality rates. However, this procedure can provide a chance of long-term survival in patients in whom a curative resection is feasible. PMID- 26507925 TI - The Role of Emotion and Reason in Criminal Decision Making. PMID- 26507926 TI - Adjuvant eflornithine to maintain IPL-induced hair reduction in women with facial hirsutism: a randomized controlled trial. AB - BACKGROUND: Photoepilation is the treatment of choice for hair removal in patients with hirsutism, but it remains a challenge to prevent regrowth of hairs. OBJECTIVES: The objective of this study was to investigate whether topical eflornithine maintains hair reduction in hirsute patients after cessation of intense pulsed light (IPL) therapy. METHODS: A randomized, split-face, single blinded controlled trial on topical eflornithine vs. no eflornithine treatment (control) after 5-6 IPL-treatments in 22 women with facial hirsutism. Application of eflornithine was initiated after the final IPL-treatment (baseline) and applied twice daily for 6 months to half of the face. Patients were assessed at baseline and 1, 3 and 6 months after the final IPL-treatment. The primary endpoint was difference in facial hair counts between eflornithine vs. no treatment. Secondary endpoints were patient-evaluated efficacy, patient satisfaction and safety. RESULTS: A total of 18 patients completed the study protocol. At 1 month after final IPL-treatment, eflornithine reduced hair regrowth by 14% (P = 0.007, n = 20 patients), at 3 months by 9% (P = 0.107, n = 19) and at 6 months by 17% (P = 0.048, n = 18) compared to no treatment. Patient evaluated efficacy supported blinded hair counts and patients were satisfied with eflornithine treatment throughout the study (median VAS 5-6). Eflornithine was generally well tolerated, but blinded evaluation demonstrated deterioration of acne in two patients at final assessment. CONCLUSION: Topical eflornithine provides a self-administered treatment with a potential to maintain IPL-induced hair reduction in hirsute patients. PMID- 26507927 TI - Monolithic lithium-disilicate single crowns supported by zirconia oral implants: three-year results of a prospective cohort study. AB - OBJECTIVE: To determine the survival and success rate of CAD/CAM-fabricated monolithic lithium-disilicate crowns supported by zirconia oral implants after 3 years. MATERIAL AND METHODS: Twenty-four patients in need of a single tooth replacement received a zirconia implant and were finally restored with 24 single crowns (SCs) ground out of pre-crystallized lithium-disilicate blanks. The restorations were adhesively cemented and evaluated using modified United States Public Health Service (USPHS) criteria. In case of clinically relevant defects that could be repaired to an acceptable level, SCs were regarded as surviving. Restorations with minor chippings, a small-area roughness (o <2 mm), slightly soundable marginal gaps, minimal under-/overcontours, and tolerable color deviations (<1 Vitashade) were regarded as success. The Kaplan-Meier method and log-rank tests were used for the success/survival analyses and the calculation of potential group differences (gender, location, jaw). Additionally, several patient-reported outcome measures (PROMs) were evaluated. RESULTS: Twenty-three patients were seen 3 years after implant placement. No SC had to be replaced, resulting in 100% survival. No chippings were observed. As one SC showed a major occlusal roughness, the Kaplan-Meier success rate after a mean observation period of 31 months was 95.7%. No group differences could be calculated. Compared with the pre-treatment surveys, the further PROMs showed a permanently improved perception of function, esthetics, sense, and speech. CONCLUSION: Monolithic lithium-disilicate SCs supported by zirconia implants showed promising survival and success rates after an observation period of 3 years. It remains to be seen whether the further observation period confirms this positive results. PMID- 26507928 TI - Bioanalysis of ibrutinib and its active metabolite in human plasma: selectivity issue, impact assessment and resolution. AB - Ronald de Vries graduated in Organic and Analytical Chemistry at the Free University of Amsterdam, The Netherlands. After working in a Contract Laboratory (CRO) for 7 years, he joined Janssen R&D in 1998. At Janssen R&D, Belgium, Ronald worked in the bioanalytical department that supports both clinical and nonclinical bioanalysis. In this department he had several roles, such as providing the bioanalytical support for various drug development programs and leading the method establishment group. He has done numerous global assay transfers to/from Janssen from/to other laboratories and plays an important role in the introduction and application of new technologies and applied innovation in the department. In 2014 he started in the drug metabolism and pharmacokinetics department of Janssen R&D, where his main tasks are in vivo and in vitro metabolite identification using high resolution MS and Radiodetection. PMID- 26507929 TI - Pioglitazone Suppresses CXCR7 Expression To Inhibit Human Macrophage Chemotaxis through Peroxisome Proliferator-Activated Receptor gamma. AB - Cardiovascular disease is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Pioglitazone, the widely used thiazolidinedione, is shown to be efficient in the prevention of cardiovascular complications of T2DM. In this study, we report that pioglitazone inhibits CXCR7 expression and thus blocks chemotaxis in differentiated macrophage without perturbing cell viability or macrophage differentiation. In addition, pioglitazone-mediated CXCR7 suppression and chemotaxis inhibition occur via activating peroxisome proliferator-activated receptor gamma (PPARgamma) but not PPARalpha in differentiated macrophage. More importantly, pioglitazone therapy induced PPARgamma activation suppresses CXCR7 expression in human carotid atherosclerotic lesions. Collectively, our data demonstrate that pioglitazone suppresses CXCR7 expression to inhibit human macrophage chemotaxis through PPARgamma. PMID- 26507931 TI - The influence of motor function on processing speed in preterm and term-born children. AB - This study investigates the relationship between motor function and processing speed in preterm children. Processing speed was compared in 145 adolescents, born 25-41 weeks gestational age, utilizing tasks including differing motor demands. The influence of motor cortex excitability and functional motor skills on task performance was assessed. For tasks with motoric demands, differences in performance between preterm and term-born children were mediated by the relationship between gestational age, corticomotor excitability, and motor function. There were no differences in non-motor processing speed task performance between preterm and term-born children. Measures of processing speed may be confounded by a timed motor component. PMID- 26507932 TI - Investigation of the phosphorus removal capacities of basic oxygen furnace slag under variable conditions. AB - Effects of reaction time, initial phosphorus concentration, basic oxygen furnace slag (BOF-slag) dosage and size, and temperature on the phosphorus removal capacities (PRCs) of BOF-slag have been investigated in detail through batch tests. Weakly bound phosphorus, Fe- and Al-associated phosphorus, and Ca associated phosphorus from fresh and reacted BOF-slag were analysed using sequential chemical extraction processes. It was determined that the PRCs of BOF slag increased with the increase of initial phosphorus concentration and temperature while it decreased with the increase of BOF-slag dosage and size. The phosphorus removed by BOF-slag was primarily assigned to weakly bound phosphorus and Ca-associated phosphorus. Weakly bound phosphorus showed a significant decrease with the increase in all experimental parameter values. However, Ca associated phosphorus exhibited a prominent increase with increasing reaction time, initial phosphorus concentration, and temperature. These demonstrate that experimental parameters can simultaneously affect the PRCs of BOF-slag and the ways of phosphorus removal by BOF-slag. PMID- 26507933 TI - Monitoring Healing Progression and Characterizing the Mechanical Environment in Preclinical Models for Bone Tissue Engineering. AB - The treatment of large segmental bone defects remains a significant clinical challenge. Due to limitations surrounding the use of bone grafts, tissue engineered constructs for the repair of large bone defects could offer an alternative. Before translation of any newly developed tissue engineering (TE) approach to the clinic, efficacy of the treatment must be shown in a validated preclinical large animal model. Currently, biomechanical testing, histology, and microcomputed tomography are performed to assess the quality and quantity of the regenerated bone. However, in vivo monitoring of the progression of healing is seldom performed, which could reveal important information regarding time to restoration of mechanical function and acceleration of regeneration. Furthermore, since the mechanical environment is known to influence bone regeneration, and limb loading of the animals can poorly be controlled, characterizing activity and load history could provide the ability to explain variability in the acquired data sets and potentially outliers based on abnormal loading. Many approaches have been devised to monitor the progression of healing and characterize the mechanical environment in fracture healing studies. In this article, we review previous methods and share results of recent work of our group toward developing and implementing a comprehensive biomechanical monitoring system to study bone regeneration in preclinical TE studies. PMID- 26507934 TI - Neonatal outcomes in subgroups of women with preterm prelabor rupture of membranes before 34 weeks. AB - OBJECTIVE: To evaluate the influence of microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (HCA) on short-term neonatal outcome in women with preterm prelabor rupture of membranes before 34 weeks of gestation. METHODS: A prospective observational cohort study including 122 pregnant women with PPROM between 24+0 and 34+0. MIAC was defined as a positive PCR result for Ureaplasma species, Mycoplasma hominis and Chlamydia trachomatis and/or positive PCR result for the 16S rRNA gene in the amniotic fluid. HCA was defined according to the Salafia classification. Maternal and short-term neonatal outcomes were evaluated according to the presence or absence of MIAC and/or HCA. RESULTS: The presence of both MIAC and HCA was observed in 36% (45/122) of women, HCA alone in 34% (41/122) and MIAC in 5% (6/122). A significantly higher incidence of early onset sepsis was observed in newborns born from women with both MIAC and HCA [33% (15/45)] compared with women with HCA alone [12% (5/41)] or MIAC alone [0% (0/6)] or women without MIAC or HCA detected [0% (0/30); p = 0.001]. CONCLUSIONS: The presence of both MIAC and HCA increases the risk of early onset sepsis in pregnancies complicated by preterm prelabor rupture of membranes before 34 weeks of gestation. PMID- 26507935 TI - Effect of pore size of three-dimensionally ordered macroporous chitosan-silica matrix on solubility, drug release, and oral bioavailability of loaded nimodipine. AB - OBJECTIVE: To explore the effect of the pore size of three-dimensionally ordered macroporous chitosan-silica (3D-CS) matrix on the solubility, drug release, and oral bioavailability of the loaded drug. METHODS: 3D-CS matrices with pore sizes of 180 nm, 470 nm, and 930 nm were prepared. Nimodipine (NMDP) was used as the drug model. The morphology, specific surface area, and chitosan mass ratio of the 3D-CS matrices were characterized before the effect of the pore size on drug crystallinity, solubility, release, and in vivo pharmacokinetics were investigated. RESULTS: With the pore size of 3D-CS matrix decreasing, the drug crystallinity decreased and the aqueous solubility increased. The drug release was synthetically controlled by the pore size and chitosan content of 3D-CS matrix in a pH 6.8 medium, while in a pH 1.2 medium the erosion of the 3D-CS matrix played an important role in the decreased drug release rate. The area under the curve of the drug-loaded 3D-CS matrices with pore sizes of 930 nm, 470 nm, and 180 nm was 7.46-fold, 5.85-fold, and 3.75-fold larger than that of raw NMDP respectively. CONCLUSION: Our findings suggest that the oral bioavailability decreased with a decrease in the pore size of the matrix. PMID- 26507936 TI - alpha-Melanocyte-stimulating hormone prevents glutamate excitotoxicity in developing chicken retina via MC4R-mediated down-regulation of microRNA-194. AB - Glutamate excitotoxicity is a common pathology to blinding ischemic retinopathies, such as diabetic retinopathy, glaucoma, and central retinal vein or artery occlusion. The development of an effective interventional modality to glutamate excitotoxicity is hence important to preventing blindness. Herein we showed that alpha-melanocyte-stimulating hormone (alpha-MSH) time-dependently protected against glutamate-induced cell death and tissue damage in an improved embryonic chicken retinal explant culture system. alpha-MSH down-regulated microRNA-194 (miR-194) expression during the glutamate excitotoxicity in the retinal explants. Furthermore, pharmacological antagonists to melanocortin 4 receptor (MC4R) and lentivirus-mediated overexpression of pre-miR-194 abrogated the suppressing effects of alpha-MSH on glutamate-induced activities of caspase 3 or 7, the ultimate enzymes for glutamate-induced cell death. These results suggest that the protective effects of alpha-MSH may be due to the MC4R mediated down-regulation of miR-194 during the glutamate-induced excitotoxicity. Finally, alpha-MSH attenuated cell death and recovered visual functions in glutamate stimulated post-hatch chick retinas. These results demonstrate the previously undescribed protective effects of alpha-MSH against glutamate-induced excitotoxic cell death in the cone-dominated retina both in vitro and in vivo, and indicate a novel molecular mechanism linking MC4R-mediated signaling to miR-194. PMID- 26507937 TI - Gastric carcinoid tumor after laparoscopic sleeve gastrectomy. PMID- 26507938 TI - A new look at weight loss surgery for children and adolescents with Prader-Willi syndrome. PMID- 26507939 TI - Laparoscopic hand-assisted versus robotic-assisted laparoscopic sleeve gastrectomy: experience of 103 consecutive cases. AB - BACKGROUND: Laparoscopic sleeve gastrectomy has become a stand-alone procedure in the treatment of morbid obesity. There are very few reports on the use of robotic approach in sleeve gastrectomy. OBJECTIVES: The purpose of this retrospective study is to report our early experience of robotic-assisted laparoscopic sleeve gastrectomy (RALSG) using a proctored training model with comparison to an institutional cohort of patients who underwent laparoscopic hand-assisted sleeve gastrectomy (LASG). SETTINGS: University hospital. METHODS: The study included 108 patients who underwent sleeve gastrectomy either via the laparoscopic assisted or robot-assisted approach during the study period. Of these 108 patients, 62 underwent LASG and 46 underwent RALSG. The console surgeon in the RALSG is a clinical year 4 (CY4) surgery resident. All CY4 surgery residents received targeted simulation training before their rotation. The console surgeon is proctored by the primary surgeon with assistance as needed by the second surgeon. RESULTS: The patients in the robotic and laparoscopic cohorts did not have a statistical difference in their demographic characteristics, preoperative co-morbidities, or complications. The mean operating time did not differ significantly between the 2 cohorts (121 min versus 110 min, P = .07). Patient follow-up in the LSG and RALSG were 91% and 90% at 3 months, 62% and 64% at 6 months, and 60% and 55% at 1 year, respectively. The mean percentage estimated weight loss (EWL%) at 3 months, 6 months, and 1 year was greater in the robotic group but not statistically significant (27 versus 22 at 3 mo [P = .05] and 39 versus 34 at 6 mo [P = .025], 57 versus 48 at 1 yr [P = .09]). There was no mortality in either group. CONCLUSION: Early results of our experience with RALSG indicate low perioperative complication rates and comparable weight loss with LASG. The concept of a stepwise education model needs further validation with larger studies. PMID- 26507940 TI - Interpretation of results from the effect of surgically induced weight loss on nonalcoholic fatty liver disease patients. PMID- 26507941 TI - Bariatric surgery reduces risk of endometrial cancer. PMID- 26507942 TI - Lignin Modification for Biopolymer/Conjugated Polymer Hybrids as Renewable Energy Storage Materials. AB - Lignin derivatives, which arise as waste products from the pulp and paper industry and are mainly used for heating, can be used as charge storage materials. The charge storage function is a result of the quinone groups formed in the lignin derivative. Herein, we modified lignins to enhance the density of such quinone groups by covalently linking monolignols and quinones through phenolation. The extra guaiacyl, syringyl, and hydroquinone groups introduced by phenolation of kraft lignin derivatives were monitored by (31) P nuclear magnetic resonance and size exclusion chromatography. Electropolymerization in ethylene glycol/tetraethylammonium tosylate electrolyte was used to synthesize the kraft lignin/polypyrrole hybrid films. These modifications changed the phenolic content of the kraft lignin with attachment of hydroquinone units yielding the highest specific capacity (around 70 mA h g(-1) ). The modification of softwood and hardwood lignin derivatives yielded 50 % and 23 % higher charge capacity than the original lignin, respectively. PMID- 26507943 TI - Influence of chemical disorder on energy dissipation and defect evolution in concentrated solid solution alloys. AB - A grand challenge in materials research is to understand complex electronic correlation and non-equilibrium atomic interactions, and how such intrinsic properties and dynamic processes affect energy transfer and defect evolution in irradiated materials. Here we report that chemical disorder, with an increasing number of principal elements and/or altered concentrations of specific elements, in single-phase concentrated solid solution alloys can lead to substantial reduction in electron mean free path and orders of magnitude decrease in electrical and thermal conductivity. The subsequently slow energy dissipation affects defect dynamics at the early stages, and consequentially may result in less deleterious defects. Suppressed damage accumulation with increasing chemical disorder from pure nickel to binary and to more complex quaternary solid solutions is observed. Understanding and controlling energy dissipation and defect dynamics by altering alloy complexity may pave the way for new design principles of radiation-tolerant structural alloys for energy applications. PMID- 26507944 TI - Pre-translational regulation of luteinizing hormone receptor in follicular somatic cells of cattle. AB - Differential regulation of LHR in theca cells (TC) and granulosa cells (GC) is important for normal follicular development. Unlike TC, GC only acquire LH responsiveness during the later stages of antral follicle development. This study tested the hypothesis that differential LH-responsiveness in these two cell types may be due, in part, to shifts in cellular patterns of alternatively spliced LHR mRNA transcripts which may not be obvious from analysis of total LHR gene expression. It also further explored the role of translation inhibition by an LHR binding protein (LHBP), normally associated with the production of endogenous cholesterol. LHR mRNA variation arises as a result of the alternative splicing of two variable deletion sites (VDS) designated 5' VDS and 3' VDS, and it was proposed that differences in cell sensitivity to LH may be due in part to variations in the pattern of the mRNA expression of the receptor variants. The outcomes of the present study support a dynamic multi-facetted regulation of LHR during pre-translation. Not only did the ratio between variants change during antral follicle growth and in vitro cell differentiation but also between TC and GC. Regulation could also be linked to LH concentration feedback mechanisms as the absence of LH caused cultured TC to markedly up-regulate amounts of LHR mRNA. In both TC and GC, LHR mRNA was greatly reduced after treatment to block mevalonate production in the de novo cholesterol pathway, adding further support for a regulatory mechanism linked to enriched cellular amounts of mevalonate kinase. PMID- 26507945 TI - Predictive capacity of sperm quality parameters and sperm subpopulations on field fertility after artificial insemination in sheep. AB - This study was designed to evaluate the relevance of several sperm quality parameters and sperm population structure on the reproductive performance after cervical artificial insemination (AI) in sheep. One hundred and thirty-nine ejaculates from 56 adult rams were collected using an artificial vagina, processed for sperm quality assessment and used to perform 1319 AI. Analyses of sperm motility by computer-assisted sperm analysis (CASA), sperm nuclear morphometry by computer-assisted sperm morphometry analysis (CASMA), membrane integrity by acridine orange-propidium iodide combination and sperm DNA fragmentation using the sperm chromatin dispersion test (SCD) were performed. Clustering procedures using the sperm kinematic and morphometric data resulted in the classification of spermatozoa into three kinematic and three morphometric sperm subpopulations. Logistic regression procedures were used, including fertility at AI as the dependent variable (measured by lambing, 0 or 1) and farm, year, month of AI, female parity, female lambing-treatment interval, ram, AI technician and sperm quality parameters (including sperm subpopulations) as independent factors. Sperm quality variables remaining in the logistic regression model were viability and VCL. Fertility increased for each one-unit increase in viability (by a factor of 1.01) and in VCL (by a factor of 1.02). Multiple linear regression analyses were also performed to analyze the factors possibly influencing ejaculate fertility (N=139). The analysis yielded a significant (P<0.05) relationship between sperm viability and ejaculate fertility. The discriminant ability of the different semen variables to predict field fertility was analyzed using receiver operating characteristic (ROC) curve analysis. Sperm viability and VCL showed significant, albeit limited, predictive capacity on field fertility (0.57 and 0.54 Area Under Curve, respectively). The distribution of spermatozoa in the different subpopulations was not related to fertility. PMID- 26507946 TI - Dual-Responsive Mechanized Mesoporous Silica Nanoparticles Based on Sulfonatocalixarene Supramolecular Switches. AB - Mesoporous silica nanoparticles (MSNs) have been functionalized with supramolecular switches, composed of cleavable disulfide bond-containing alkylammonium stalks encircled by water-soluble sulfonatocalix[4,6]arenes, to result in smart mechanized MSNs. Cargo can be encased tightly in the nanopores of these mechanized MSNs in their closed state, but are released efficiently either in response to L-glutathione (GSH), by cleaving the disulfide bonds in the stalks, or in response to pH variation, by turning on the calixarene-based supramolecular switches. The higher concentration of GSH in cancer cell cytosol and the relatively lower pH value of cancer cell lysosome can simultaneously activate the mechanized MSNs, enabling them to release the pre-loaded cargo in place. This sufficient use of the different environment of cancer cells and normal healthy cells can enhance the targeting effect of delivery vehicles and effectively lower the side effects of delivered anti-cancer drugs. In vitro cytotoxicity tests suggest good biocompatibility and low toxicity of these newly developed drug-delivery systems. PMID- 26507947 TI - Thermal control of ionic transport and fluid flow in nanofluidic channels. AB - In this work, we report a nanofluidic gating mechanism that uses the thermal effect for modulating the ionic transport inside nanofluidic channels. The control of the ionic transport inside a nanochannel is demonstrated using electrical conductivity. A thermal gate controls the ionic transport more effectively than most of the other gating mechanisms previously described in the scientific literature. Gating in both bulk and overlapping electric double layer regimes can be obtained. The relatively short response time of opening and closing processes makes it a good candidate for manipulating small molecules in micro- and nanoscale devices. PMID- 26507948 TI - Anti-N-Methyl-D-Aspartate Receptor Encephalitis in Children and Adolescents. AB - Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease that is becoming increasingly recognized in the pediatric population. It may be the most common cause of treatable autoimmune encephalitis. The majority of cases of anti-NMDAR encephalitis are idiopathic in etiology, but a significant minority can be attributed to a paraneoplastic origin. Children with anti-NMDAR encephalitis initially present with a prodrome of neuropsychiatric symptoms, often with orofacial dyskinesias followed by progressively worsening seizures, agitation, and spasticity, which may result in severe neurologic deficits and even death. Definitive diagnosis requires detection of NMDAR antibodies in the cerebrospinal fluid. Optimal outcomes are associated with prompt removal of the tumor in paraneoplastic cases, as well as aggressive immunosuppressive therapy. Early detection is essential for increasing the chances for a good outcome. Close follow-up is required to screen for relapse and later onset tumor presentation. The nurse practitioner plays a major role in the research, screening, diagnosis, treatment, follow-up, and rehabilitation of a child or adolescent with anti-NMDAR encephalitis. PMID- 26507949 TI - Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities. AB - The Rho/ROCK pathway is involved in numerous pivotal cellular processes that have made it an area of intense study in cancer medicine, however, Rho-associated coiled-coil containing protein kinase (ROCK) inhibitors are yet to make an appearance in the clinical cancer setting. Their performance as an anti-cancer therapy has been varied in pre-clinical studies, however, they have been shown to be effective vasodilators in the treatment of hypertension and post-ischaemic stroke vasospasm. This review addresses the various roles the Rho/ROCK pathway plays in angiogenesis, tumour vascular tone and reciprocal feedback from the tumour microenvironment and explores the potential utility of ROCK inhibitors as effective vascular normalising agents. ROCK inhibitors may potentially enhance the delivery and efficacy of chemotherapy agents and improve the effectiveness of radiotherapy. As such, repurposing of these agents as adjuncts to standard treatments may significantly improve outcomes for patients with cancer. A deeper understanding of the controlled and dynamic regulation of the key components of the Rho pathway may lead to effective use of the Rho/ROCK inhibitors in the clinical management of cancer. PMID- 26507950 TI - Running and tumbling with E. coli in polymeric solutions. AB - Run-and-tumble motility is widely used by swimming microorganisms including numerous prokaryotic and eukaryotic organisms. Here, we experimentally investigate the run-and-tumble dynamics of the bacterium E. coli in polymeric solutions. We find that even small amounts of polymer in solution can drastically change E. coli dynamics: cells tumble less and their velocity increases, leading to an enhancement in cell translational diffusion and a sharp decline in rotational diffusion. We show that suppression of tumbling is due to fluid viscosity while the enhancement in swimming speed is mainly due to fluid elasticity. Visualization of single fluorescently labeled DNA polymers reveals that the flow generated by individual E. coli is sufficiently strong to stretch polymer molecules and induce elastic stresses in the fluid, which in turn can act on the cell in such a way to enhance its transport. Our results show that the transport and spread of chemotactic cells can be independently modified and controlled by the fluid material properties. PMID- 26507951 TI - Chassidic Teachings and Modern Psychology: Toward a More Unified Approach. AB - This article describes how many modern psychological constructs and theories exist in older as well as newer Chassidic and Jewish teachings, particularly those of Chabad Lubavitch. This exploration points toward a potential benefit for a unification of psychology and Chassidic teachings. Psychological theories and constructs explored are Freudian psychoanalysis, cognitive dissonance, cognitive restructuring/reframing, self-efficacy/planned behavior, and logotherapy/existentialism. The article then concludes with a discussion of possible implications of moving toward a unified approach for clinical practitioners. PMID- 26507952 TI - Binding of glutathione and melatonin to pepsin occurs via different binding mechanisms. AB - Glutathione is a hydrophilic antioxidant and melatonin is a hydrophobic antioxidant, thus, the binding mechanism of the two antioxidants interacting with protease may be different. In this study, binding of glutathione and melatonin to pepsin has been studied using isothermal titration calorimetry (ITC), equilibrium microdialysis, UV-Vis absorption spectroscopy, circular dichroism (CD) spectroscopy, and molecular modeling. Thermodynamic investigations reveal that the binding of glutathione/melatonin to pepsin is driven by favorable enthalpy and unfavorable entropy, and the major driving forces are hydrogen bond and van der Waals force. ITC, equilibrium microdialysis, and molecular modeling reveal that the binding of glutathione to pepsin is characterized by a high number of binding sites. For melatonin, one molecule of melatonin combines with one molecule of pepsin. These results confirm that glutathione/melatonin interact with pepsin through two different binding mechanisms. In addition, the UV-Vis absorption and CD experiments indicate that glutathione and melatonin may induce conformational and microenvironmental changes of pepsin. The conformational changes of pepsin may affect its biological function as protease. PMID- 26507953 TI - How we remember what we can do. AB - According to the motor simulation theory, the knowledge we possess of what we can do is based on simulation mechanisms triggered by an off-line activation of the brain areas involved in motor control. Action capabilities memory does not work by storing some content, but consists in the capacity, rooted in sensory-motor systems, to reenact off-line action sequences exhibiting the range of our powers. In this paper, I present several arguments from cognitive neuropsychology, but also first-person analysis of experience, against this hypothesis. The claim that perceptual access to affordances is mediated by motor simulation processes rests on a misunderstanding of what affordances are, and comes up against a computational reality principle. Motor simulation cannot provide access to affordances because (i) the affordances we are aware of at each moment are too many for their realization to be simulated by the brain and (ii) affordances are not equivalent to currently or personally feasible actions. The explanatory significance of the simulation theory must then be revised downwards compared to what is claimed by most of its advocates. One additional challenge is to determine the prerequisite, in terms of cognitive processing, for the motor simulation mechanisms to work. To overcome the limitations of the simulation theory, I propose a new approach: the direct content specification hypothesis. This hypothesis states that, at least for the most basic actions of our behavioral repertoire, the action possibilities we are aware of through perception are directly specified by perceptual variables characterizing the content of our experience. The cognitive system responsible for the perception of action possibilities is consequently far more direct, in terms of cognitive processing, than what is stated by the simulation theory. To support this hypothesis I review evidence from current neuropsychological research, in particular data suggesting a phenomenon of 'fossilization' of affordances. Fossilization can be defined as a gap between the capacities that are treated as available by the cognitive system and the capacities this system really has at its disposal. These considerations do not mean that motor simulation cannot contribute to explain how we gain perceptual knowledge of what we can do based on the memory of our past performances. However, when precisely motor simulation plays a role and what it is for exactly currently remain largely unknown. PMID- 26507954 TI - Expression and functioning of retinal-based proton pumps in a saltern crystallizer brine. AB - We examined the presence of bacteriorhodopsin and other retinal protein pigments in the microbial community of the saltern crystallizer ponds in Eilat, Israel, and assessed the effect of the retinal-based proton pumps on the metabolic activity. The biota of the hypersaline (~309 g salts l(-1)) brine consisted of ~2200 beta-carotene-rich Dunaliella cells and ~3.5 * 10(7) prokaryotes ml(-1), most of which were flat, square or rectangular Haloquadratum-like archaea. No indications were obtained for massive presence of Salinibacter. We estimated a concentration of bacteriorhodopsin and bacteriorhodopsin-like pigments of 3.6 nmol l(-1). When illuminated, the community respiration activity of the brine samples in which oxygenic photosynthesis was inhibited by 3-(3-4-dichlorophenyl) 1,1-dimethylurea, decreased by 40-43 %. This effect was interpreted to be the result of competition between two energy yielding systems: the bacteriorhodopsin proton pump and the respiratory chain. The results presented have important implications for the interpretation of many published data on photosynthetic and respiratory activities in hypersaline environments. PMID- 26507955 TI - Transcriptional regulation of dimethyl sulfoxide respiration in a haloarchaeon, Haloferax volcanii. AB - The halophilic euryarchaeon Haloferax volcanii can grow anaerobically by DMSO respiration. DMSO reductase was induced by DMSO respiration not only under anaerobic growth conditions but also in denitrifying cells of H. volcanii. Deletion of the dmsR gene, encoding a putative regulator for the DMSO reductase, resulted in the loss of anaerobic growth by DMSO respiration. Reporter experiments revealed that only the anaerobic condition was essential for transcription of the dmsEABCD genes encoding DMSO reductase and that transcription was enhanced threefold by supplementation of DMSO. In the ?dmsR mutant, transcription of the dmsEABCD genes induced by the anaerobic condition was not enhanced by DMSO, suggesting that DmsR is a DMSO-responsive regulator. Transcriptions of the dmsR and mgd genes for Mo-bisMGD biosynthesis were regulated in the same manner as the dmsEABCD genes. These results suggest that the genetic regulation of DMSO respiration in H. volcanii is controlled by at least two systems: one is the DMSO-responsive DmsR, and the other is an unknown anaerobic regulator. PMID- 26507956 TI - Pcal_1699, an extremely thermostable malate dehydrogenase from hyperthermophilic archaeon Pyrobaculum calidifontis. AB - Two malate dehydrogenase homologs, Pcal_0564 and Pcal_1699, have been found in the genome of Pyrobaculum calidifontis. The gene encoding Pcal_1699 consisted of 927 nucleotides corresponding to a polypeptide of 309 amino acids. To examine the properties of Pcal_1699, the structural gene was cloned, expressed in Escherichia coli and the purified gene product was characterized. Pcal_1699 was NADH specific enzyme exhibiting a high malate dehydrogenase activity (886 U/mg) at optimal pH (10) and temperature (90 degrees C). Unfolding studies suggested that urea could not induce complete unfolding and inactivation of Pcal_1699 even at a final concentration of 8 M; however, in the presence of 4 M guanidine hydrochloride enzyme structure was unfolded with complete loss of enzyme activity. Thermostability experiments revealed that Pcal_1699 is the most thermostable malate dehydrogenase, reported to date, retaining more than 90 % residual activity even after heating for 6 h in boiling water. PMID- 26507957 TI - Sexual behavior, risk perception, and HIV transmission can respond to HIV antiviral drugs and vaccines through multiple pathways. AB - There has been growing use of highly active antiretroviral treatment (HAART) for HIV and significant progress in developing prophylactic HIV vaccines. The simplest theories of counterproductive behavioral responses to such interventions tend to focus on single feedback mechanisms: for instance, HAART optimism makes infection less scary and thus promotes risky sexual behavior. Here, we develop an agent based, age-structured model of HIV transmission, risk perception, and partner selection in a core group to explore behavioral responses to interventions. We find that interventions can activate not one, but several feedback mechanisms that could potentially influence decision-making and HIV prevalence. In the model, HAART increases the attractiveness of unprotected sex, but it also increases perceived risk of infection and, on longer timescales, causes demographic impacts that partially counteract HAART optimism. Both HAART and vaccination usually lead to lower rates of unprotected sex on the whole, but intervention effectiveness depends strongly on whether individuals over- or under estimate intervention coverage. Age-specific effects cause sexual behavior and HIV prevalence to change in opposite ways in old and young age groups. For complex infections like HIV-where interventions influence transmission, demography, sexual behavior and risk perception-we conclude that evaluations of behavioral responses should consider multiple feedback mechanisms. PMID- 26507958 TI - Skin Necrosis Following Adipocitolitic Solution Injections. PMID- 26507959 TI - Characterizing the Lateral Border of the Frontalis for Safe and Effective Injection of Botulinum Toxin. AB - BACKGROUND: The forehead is a common site for injection of botulinum neurotoxin type A (BoNT-A) to treat hyperactive facial muscles. Unexpected side effects of BoNT-A injection may occur because the anatomy of the forehead musculature is not fully characterized. OBJECTIVES: The authors described the lateral border of the frontalis in terms of facial landmarks and reference lines to determine the safest and most effective forehead injection sites for BoNT-A. METHODS: The hemifaces of 49 embalmed adult Korean cadavers were dissected in a morphometric analysis of the frontalis. L2 was defined in terms of FT (the most protruding point of the frontotemporal region), L0 (the line connecting the infraorbital margin with the tragus), and L1 (the line parallel to L0 and passing through FT) such that L2 was positioned 45 degrees from L1 and passed through FT. RESULTS: The distance from FT to the superior margin of the orbicularis oculi was 12.3 +/- 3.3 mm. The frontalis extended more than 5 cm along L2 in 49 of 49 cases (100%), more than 6 cm in 47 cases (95.9%), more than 7 cm in 34 cases (69.4%), more than 8 cm in 11 cases (22.4%), and more than 9 cm in 3 cases (6.1%). The lateral border of the frontalis ran parallel to and within 1 cm of the medial side of L2. CONCLUSIONS: Surface anatomy mapping can assist with predicting the lateral border of the frontalis to minimize the side effects and maximize the efficiency of BoNT-A injections into the forehead. PMID- 26507961 TI - Cardiac Sarcoidosis Detected by (18)F-Fluorodeoxyglucose Positron Emission Tomography. PMID- 26507960 TI - Spanish Catheter Ablation Registry. 14th Official Report of the Spanish Society of Cardiology Working Group on Electrophysiology and Arrhythmias (2014). AB - INTRODUCTION AND OBJECTIVES: This report presents the findings of the 2014 Spanish Catheter Ablation Registry. METHODS: For data collection, each center was allowed to choose freely between 2 systems: retrospective, requiring the completion of a standardized questionnaire, and prospective, involving reporting to a central database. RESULTS: Data were collected from 85 centers. A total of 12 871 ablation procedures were performed, for a mean of 149.5+/-103 procedures per center. The ablation targets most frequently treated were atrioventricular nodal reentrant tachycardia (n=3026; 23.5%), cavotricuspid isthmus (n=2833; 22.0%), and atrial fibrillation (n=2498; 19.4%). The number of ablation procedures for ventricular arrhythmias was similar to that of 2013, but there was a slight increase in the treatment of all the ventricular substrates, especially those associated with idiopathic ventricular tachycardia and scarring following myocardial infarction. The overall success rate was 95%, the rate of major complications was 1.3%, and the mortality rate was 0.02%. CONCLUSIONS: The 2014 registry shows that the number of ablation procedures performed continued its upward trend and that, overall, the success rate was high and the number of complications low. Ablation of complex conditions continued to increase. PMID- 26507962 TI - Prediction of anastomotic leak in colorectal cancer surgery based on a new prognostic index PROCOLE (prognostic colorectal leakage) developed from the meta analysis of observational studies of risk factors. AB - PURPOSE: To obtain a prognostic index, which has been named PROCOLE (prognostic colorectal leakage), it can predict the risk that a certain individual may suffer anastomotic leakage. METHODS: The methodology consists of a systematic review to identify potential risk factors for anastomotic leakage and a meta-analysis of studies of each of these factors. In the meta-analysis, the prognostic index integrates factors that are statistically significant, which are weighted according to the estimated value of the effect size. The prognostic index was validated using retrospectively collected data from patients who underwent colorectal cancer surgery anastomosis at our institution. RESULTS: The mean and standard deviation of the PROCOLE prognostic index in patients with anastomotic leakage is 1.9 +/- 6.13, whereas in controls, it is 3.63 +/- 2.1. The predictive ability of the PROCOLE, assessed by calculating the area under the curve (AUC) of the receiver operating characteristic (ROC), results in an AUC of 0.82 with a 95% confidence interval (CI) (0.75, 0.89) of the AUC, and it can be considered a good prognostic indicator. CONCLUSIONS: The PROCOLE prognostic index predicts the risk of a certain individual developing anastomotic leakage after colorectal cancer surgery. Specifically, the PROCOLE prognostic index establishes a discrimination value threshold of 4.83 for recommending the implementation of a protective stoma. We have developed free software with a simple interface that only requires the selection of risk factors to obtain the PROCOLE value. PMID- 26507963 TI - Risk factors for surgical site infection following colorectal resection: a multi institutional study. AB - INTRODUCTION: Surgical site infection (SSI) is an infection occurring in an incisional wound within 30 days of surgery and significantly affects patients undergoing colorectal surgery. This study examined a multi-institutional dataset to determine risk factors for SSI following colorectal resection. METHODS: Data on 386 patients who underwent colorectal resection in three institutions were accrued. Patients were identified using a prospective SSI database and hospital records. Data are presented as median (interquartile range), and logistic regression analysis was used to identify risk factors. RESULTS: Patients (21.5%) developed a postoperative SSI. The median time to the development of SSI was 7 days (5-10). Of all infections, 67.5% were superficial, 22.9% were deep and 9.6% were organ space. In univariate analysis, an ASA grade of II (RR 0.6, CI 0.3-0.9, P = 0.019), having an elective procedure (RR 0.4, CI 0.2-0.6, P < 0.001), using a laparoscopic approach (RR 0.5, CI 0.3-0.9, P = 0.019), having a daytime procedure (RR 0.3, CI 0.1-0.7, P = 0.006) and having a clean/contaminated wound (RR 0.4, CI 0.2-0.7, P = 0.001) were associated with reduced risk of SSI. In multivariate analysis, an ASA grade of IV (RR 3.9, CI 1.1-13.7, P = 0.034), a procedure duration over 3 h (RR 4.3, CI 2.3-8.2, P < 0.001) and undergoing a panproctocolectomy (RR 6.5, CI 1.0-40.9, P = 0.044) were independent risk factors for SSI. Those who developed an SSI had a longer duration of inpatient stay (22 days [16-31] vs 15 days [10-26], P < 0.001). CONCLUSIONS: Patients who develop an SSI have a longer duration of inpatient stay. Independent risk factors for SSI following colorectal resection include being ASA grade IV, having a procedure duration over 3 h, and undergoing a panproctocolectomy. PMID- 26507964 TI - Catenulispora fulva sp. nov., isolated from forest soil. AB - An actinomycete strain, designated SA-246T, was isolated from a forest soil sample collected from Chungnam, South Korea. Applying a polyphasic approach, the isolate was identified as a member of the genus Catenulispora using morphological and chemotaxonomic characteristics, including the presence of ll-diaminopimelic acid, glutamic acid, alanine and glycine in the peptidoglycan. Whole-cell hydrolysates contained predominantly rhamnose, mannose, ribose, arabinose, galactose and glucose. The major menaquinones were MK-9(H4), MK-9(H6) and MK 9(H8). 16S rRNA gene sequence analysis revealed that strain SA-246T belongs to the genus Catenulispora, showing the highest sequence similarity to Catenulispora yoronensis TT N02-20T (98.7 % 16S rRNA gene sequence similarity), Catenulispora subtropica TT 99-48T (98.2 %), Catenulispora graminis BR-34T (97.4 %), Catenulispora rubra Aac-30T (97.4 %) and Catenulispora acidiphila ID139908T (97.3 %). On the basis of polyphasic analysis from this study, strain SA-246T represents a novel species of the genus Catenulispora, for which the name Catenulispora fulva sp. nov. is proposed. The type strain is SA-246T ( = KACC 17878T = NBRC 110074T). PMID- 26507966 TI - Prevalence of the use of anchorage miniscrews among French orthodontists. AB - Since always, anchorage has raised frequent problems for orthodontists. Since the early 2000s, the use of anchorage miniscrews has spread on a vast scale among practitioners. For the first time, a broad epidemiological survey (733 exploitable responses) has looked into the habits of French orthodontists regarding the use of anchorage miniscrews. The survey reveals that the majority of French practitioners have adopted miniscrews in their daily practice (66%), particularly among those using the lingual technique. However, the number of patients concerned still remains small for most practitioners (fewer than 10 patients for 65% of users). Seventy-four percent of users are satisfied with their experience with miniscrews although a majority uses them exclusively in adults (64%). The movements most sought by miniscrew users are mesialization/distalization and intrusion/extrusion. Among non-users, 60% have never placed an anchorage miniscrew but are thinking about doing so, whereas 20% of practitioners have used them but have since abandoned them. Finally, 20% of non-users have never used anchorage miniscrews and do not intend to do so. PMID- 26507967 TI - Analysis of recombinase A (recA/RecA) in the actinobacterial family Streptosporangiaceae and identification of molecular signatures. AB - The family Streptosporangiaceae (suborder Streptosporangineae) comprises 13 genera and 100 species with validly published names. In a recent study, gyrB gene sequences were obtained for members of the family Streptosporangiaceae and the GyrB amino acid sequences were analysed for molecular signatures. In this study, recA gene sequences (895nt) were determined for the type strains of members of the family Streptosporangiaceae. The sequences used represent 81% of the full length recA gene of Streptosporangium roseum DSM 43021(T). The recA gene sequences were used for phylogenetic analyses and the trees were compared to the corresponding 16S-rRNA and gyrB gene trees. RecA amino acid alignments (298 amino acids) were generated and inspected for unique amino acid signatures to distinguish the genera in the family from each other. As was observed for the gyrB gene trees, the recA gene trees generally supported the division of the members of the family Streptosporangiaceae into 13 genera. The genus Nonomuraea was not monophyletic in any of the recA gene trees, while the genera Planomonospora and Streptosporangium were not monophyletic in the maximum likelihood and maximum parsimony trees. The gyrB-recA concatenated-gene tree was more robust than the recA gene tree, with 63 nodes in the gyrB-recA tree having bootstrap values >=95%. The only insertions in the recA gene sequences were inteins identified in the type strains of Acrocarpospora phusangensis, Acrocarpospora pleiomorpha and Microbispora mesophila. Examination of the RecA sequence alignments for genus-specific amino acid sequences showed that the genera Herbidospora, Planobispora, Planomonospora and Streptosporangium contain unique amino acid sequences that distinguish these genera from all other genera in the family Streptosporangiaceae. The results of this investigation extend the results of the GyrB study and will be useful in future taxonomic studies in the family Streptosporangiaceae by providing additional genus-specific molecular signatures. PMID- 26507968 TI - Enhanced CCR9 expression levels in psoriatic skin are associated with poor clinical outcome to infliximab treatment. AB - Infliximab is an anti-tumor necrosis factor (TNF)-alpha antibody drug that suppresses TNF-alpha and its associated inflammatory responses. Although infliximab therapy generally results in a 75% or greater improvement in the Psoriasis Area and Severity Index from baseline in psoriasis patients, there is the heterogeneity of therapeutic efficacy in psoriasis patients among patients of a similar PASI baseline score. However, there are few published reports about the predictors of the clinical response among psoriasis patients who undergo biologic therapies. We thus evaluated the possible existence of biologic markers that would indicate poor prognosis of infliximab using skin biopsy specimens. This was because we assumed that the inhibitors for upregulated chemokine/chemokine receptors in non-responders may have the ability to reduce the occurrence of psoriatic eruptions. PCR array analyses identified that the levels of various chemokines and chemokine receptors were increased in non-responders in comparison to responders. Immunohistochemical analyses revealed that upregulation of the CCR9 protein levels was not associated with the pretherapeutic PASI score, but with poor response to infliximab. Our results indicated that the expression levels of CCR9 in lesional skin may be a useful biologic marker of the clinical efficacy of infliximab therapy in psoriasis patients. PMID- 26507969 TI - Decrease in the urine cotinine concentrations of Korean non-smokers between 2009 and 2011 following implementation of stricter smoking regulations. AB - This study aimed to determine if there was an association between the implementation of smoking regulation policies and the urine cotinine concentrations of Korean non-smokers. The subjects of this study were 4612 non smoking Korean citizens (aged 19 or older) selected from the first stage of the Korean National Environmental Health Survey conducted by the National Institute of Environmental Research from 2009 to 2011. Cotinine concentrations in urine were measured by GC-MS (limit of detection: 0.05 ng/mL). Changes in the urine cotinine concentration were analyzed using a weighted general linear model and linear regression and values were shown as geometric mean (GM). The GM urine cotinine concentration decreased over time (2.92 ng/mL in 2009, 1.93 ng/mL in 2010, and 1.25 ng/mL in 2011). The total decrease in the subjects' urine cotinine concentration between 2009 and 2011 was 2.79 ng/mL, representing a relative decrease of 54.7%. The decrease in GM urine cotinine concentration in each subgroup ranged from 2.17 ng/mL to 3.29 ng/mL (relative decreases of 46.4% and 62.8%, respectively), with the largest absolute reductions in subjects in the following groups: females, aged 40-49 years, detached residence type, no alcohol consumption, employed, secondhand smoke exposure. All groups had negative regression coefficients, all of which were significant (p < 0.001). Our results provide indirect indicators of the effectiveness of smoking regulation policies including the revision of the National Health Promotion Act in Korea. PMID- 26507970 TI - Genetic testing in steroid-resistant nephrotic syndrome: when and how? AB - Steroid-resistant nephrotic syndrome (SRNS) represents the second most frequent cause of chronic kidney disease in the first three decades of life. It manifests histologically as focal segmental glomerulosclerosis (FSGS) and carries a 33% risk of relapse in a renal transplant. No efficient treatment exists. Identification of single-gene (monogenic) causes of SRNS has moved the glomerular epithelial cell (podocyte) to the center of its pathogenesis. Recently, mutations in >30 recessive or dominant genes were identified as causing monogenic forms of SRNS, thereby revealing the encoded proteins as essential for glomerular function. These findings helped define protein interaction complexes and functional pathways that could be targeted for treatment of SRNS. Very recently, it was discovered that in the surprisingly high fraction of ~30% of all individuals who manifest with SRNS before 25 years of age, a causative mutation can be detected in one of the ~30 different SRNS-causing genes. These findings revealed that SRNS and FSGS are not single disease entities but rather are part of a spectrum of distinct diseases with an identifiable genetic etiology. Mutation analysis should be offered to all individuals who manifest with SRNS before the age of 25 years, because (i) it will provide the patient and families with an unequivocal cause-based diagnosis, (ii) it may uncover a form of SRNS that is amenable to treatment (e.g. coenzyme Q10), (iii) it may allow avoidance of a renal biopsy procedure, (iv) it will further unravel the puzzle of pathogenic pathways of SRNS and (v) it will permit personalized treatment options for SRNS, based on genetic causation in way of 'precision medicine'. PMID- 26507971 TI - Mechanisms of formation of chemical bonding and defect formation at the a SiO2/BaTiO3 interfaces. AB - The structure and mechanisms of bonding and defect formation at the interfaces between amorphous silica (a-SiO2) and BaTiO3(0 0 1) were investigated using ab initio molecular dynamics. It was found that the nature of interfacial bonds crucially depends on the BaTiO3 surface termination. In particular, the interface between silica and TiO2-terminated BaTiO3 (BTO) slab is characterised by strong covalent Ti-O-Si bonds, while the interface between silica and BaO-terminated BTO demonstrates ionic character of interfacial bonds and exhibits bond instability. In both cases, the dynamics of oxygen species at oxide interfaces is a driving force of the formation of interfacial bonds and defects. PMID- 26507972 TI - The application of phenytoin in the treatment of diabetic ulcers. PMID- 26507974 TI - Direct effects of HP Acthar Gel on human B lymphocyte activation in vitro. AB - INTRODUCTION: Both clinical experience and experimental evidence have suggested that Adrenocorticotropic hormone (ACTH) might directly exert immunomodulatory effects not dependent on adrenal steroidogenesis. METHODS: The direct effects of H.P. Acthar Gel (Acthar), a repository preparation containing a porcine ACTH analogue, on human B lymphocyte function were studied in vitro using peripheral blood B cells isolated using anti-CD19 coated magnetic beads and activated by interleukin 4 (IL-4) and CD40 ligand (CD40L). Analysis of expression of messenger RNA (mRNA) encoding activation-induced cytidine deaminase (AICDA) was carried out by quantitative real-time polymerase chain reaction (PCR). Cellular proliferation was assessed by a flow cytometric technique using intracellular staining with carboxyfluorescein succinimidyl ester (CFSE). Immunoglobulin G (IgG) production was measured in cell supernatants using an immunoassay. RESULTS: Acthar was found to exert acute, dose-dependent inhibitory effects on IL-4/CD40L-mediated induction of the expression of activation-induced cytidine deaminase (AICDA) after 24 hours, as well as sustained inhibition of B cell proliferation and IgG production during five more days of culture, without deleterious effects on B cell viability. CONCLUSIONS: These experiments demonstrate that Acthar can exert direct effects on the humoral immune system independent of any role in the regulation of adrenal steroidogenesis. Although the impact of these findings on clinical disease was not evaluated in this study, these data support the therapeutic potential of Acthar for the management of autoimmune diseases characterized by B cell activation and aberrant humoral immune function. PMID- 26507975 TI - Problems at Addenbrooke's caused by failure to implement electronic patient record system effectively. PMID- 26507977 TI - Mutuality in the provision of Scottish healthcare. AB - The backdrop to this article is provided by the Better Health, Better Care Action Plan (Scottish Government, 2007), Section 1 of which is entitled 'Towards a Mutual NHS'. According to Better Health, Better Care (Scottish Government, 2007: 5): 'Mutual organisations are designed to serve their members. They are designed to gather people around a common sense of purpose. They are designed to bring the organisation together in what people often call "co-production."' The aim of this article is to precis the current knowledge of mutuality in the provision of Scottish healthcare. In detail, it will: introduce the 'mutual' organisation; offer a historical perspective of mutuality; suggest why healthcare mutuality is important; and briefly, detail the differences in mutual health-care policy in England and Scotland. It is hoped that this analysis will help researchers and practitioners alike appreciate further the philosophy of mutuality in the provision of Scottish healthcare. PMID- 26507976 TI - Regulation of CsrB/C sRNA decay by EIIA(Glc) of the phosphoenolpyruvate: carbohydrate phosphotransferase system. AB - Csr is a conserved global regulatory system, which uses the sequence-specific RNA binding protein CsrA to activate or repress gene expression by binding to mRNA and altering translation, stability and/or transcript elongation. In Escherichia coli, CsrA activity is regulated by two sRNAs, CsrB and CsrC, which bind to multiple CsrA dimers, thereby sequestering this protein away from its mRNA targets. Turnover of CsrB/C sRNAs is tightly regulated by a GGDEF-EAL domain protein, CsrD, which targets them for cleavage by RNase E. Here, we show that EIIA(Glc) of the glucose-specific PTS system is also required for the normal decay of these sRNAs and that it acts by binding to the EAL domain of CsrD. Only the unphosphorylated form of EIIA(Glc) bound to CsrD in vitro and was capable of activating CsrB/C turnover in vivo. Genetic studies confirmed that this mechanism couples CsrB/C sRNA decay to the availability of a preferred carbon source. These findings reveal a new physiological influence on the workings of the Csr system, a novel function for the EAL domain, and an important new way in which EIIA(Glc) shapes global regulatory circuitry in response to nutritional status. PMID- 26507978 TI - Taking hospital treatments home: a mixed methods case study looking at the barriers and success factors for home dialysis treatment and the influence of a target on uptake rates. AB - BACKGROUND: Despite healthcare policies and evidence which promote home dialysis, uptake rates have been falling for over 10 years in England. A target introduced by commissioners in the West Midlands provided a unique opportunity to study how hospitals can increase home-based treatment for a group of patients with complex life-threatening conditions. METHODS: Quantitative changes in home treatment uptake rates in seven hospitals in the West Midlands were compared with the rest of England for 3 years pre and post the introduction of the target in 2010, using a logistic regression model. Qualitative interviews in four hospitals with 96 clinical and managerial staff and 93 dialysis patients explored the barriers and facilitators to increasing the uptake of home treatment and the impact of the target. RESULTS: Home treatment uptake rates increased significantly in the seven study hospitals compared with the 3 years prior to the introduction of the target and compared with the rest of England where rates remained static. The four main factors facilitating increased uptake were as follows: the commissioner's target, linked to financial penalties; additional funding for specialist staff and equipment; committed, visible clinical champions and good systems for patient training and ongoing healthcare support at home. The three main barriers were as follows: lack of training for non-specialist staff, poorly developed patient education and considerable unrecognised and unmet emotional and psychological patient needs. CONCLUSIONS: This study shows the impact of using targets with financial penalties to achieve change and how hospitals can increase significantly the uptake of home-based self-care for a group of patients with complex medical needs. It provides useful pointers to the main barriers and facilitators, which are likely to be relevant to other groups of patients who could be treated at home. It also highlights two neglected areas which need to improve if patients with life-threatening long-term conditions are to be encouraged to take up home treatment: individualised patient education which allows exploration of the impacts of treatment options and the provision of ongoing emotional support. PMID- 26507979 TI - Serum and urine concentrations of morphine and morphine metabolites in patients with advanced cancer receiving continuous intravenous morphine: an observational study. AB - BACKGROUND: The feasibility and clinical implication of drug monitoring of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) need further investigation. This study aimed to determine what predicts serum concentrations of morphine in cancer patients receiving continuously intravenous morphine, the relationships between serum concentration of morphine/its metabolites and urinary concentrations, and the relation between morphine concentrations and with clinical outcomes. METHODS: We collected serum and urine samples from 24 patients with advanced cancer undergoing continuously intravenous morphine therapy. Serum samples were obtained at day one. Spot urine samples were collected once daily on three consecutive days. Pain and adverse drug events were assessed using the Korean version of MD Anderson Symptom Inventory. RESULTS: A total of 96 samples (72 urine and 24 serum samples) were collected. Median dose of morphine was 82.0 mg/24 h. In a multivariate analysis, total daily morphine dose was the most significant predictors of both serum and urine concentration of morphine. Morphine, M6G, and M3G in serum and urine were statistical significantly correlated (correlation coefficient = 0.81, 0.44, 0.56; p values < 0.01, 0.03, 0.01, respectively). CONCLUSION: Spot urine concentrations of morphine and its metabolites were highly correlated to those of serum. Total dose of daily morphine was related to both serum and urine concentration of morphine and its metabolites. PMID- 26507980 TI - Species turnover (beta-diversity) in ectomycorrhizal fungi linked to NH4+ uptake capacity. AB - Ectomycorrhizal (EcM) fungal communities may be shaped by both deterministic and stochastic processes, potentially influencing ecosystem development and function. We evaluated community assembly processes for EcM fungi of Pseudotsuga menziesii among 12 sites up to 400 km apart in southwest British Columbia (Canada) by investigating species turnover (beta-diversity) in relation to soil nitrogen (N) availability and physical distance. We then examined functional traits for an N related niche by quantifying net fluxes of NH4+, NO3- and protons on excised root tips from three contrasting sites using a microelectrode ion flux measurement system. EcM fungal communities were well aligned with soil N availability and pH, with no effect of site proximity (distance-decay curve) on species assemblages. Species turnover was significant (beta(1/2) = 1.48) along soil N gradients, with many more Tomentella species on high N than low N soils, in contrast to Cortinarius species. Ammonium uptake was greatest in the spring on the medium and rich sites and averaged over 190 nmol/m(2)/s for Tomentella species. The lowest uptake rates of NH4+ were by nonmycorrhizal roots of axenically grown seedlings (10 nmol/m(2)/s), followed by Cortinarius species (60 nmol/m(2)/s). EcM roots from all sites displayed only marginal uptake of nitrate (8.3 nmol/m(2)/s). These results suggest NH4+ uptake capacity is an important functional trait influencing the assembly of EcM fungal communities. The diversity of EcM fungal species across the region arguably provides critical belowground adaptations to organic and inorganic N supply that are integral to temperate rainforest ecology. PMID- 26507981 TI - Diffusion-weighted MR imaging for characterizing mediastinal lymph nodes in children. PMID- 26507983 TI - Bilateral duplication of the abducens nerves: an incidental finding on magnetic resonance imaging. AB - Although anomaly of the abducens nerve, including duplication, has been reported in anatomical papers, no radiological report exists regarding a duplicated abducens nerve observed on magnetic resonance (MR) imaging. We encountered a case of bilateral duplication of the abducens nerves, which was found incidentally on MR scans from an 11-year-old boy. He did not have any symptoms of eye movement related to abducens nerve abnormality; thus, the duplication was considered to be a normal variant in this patient. Radiologists should be aware that duplication of the abducens nerve may occur and can be diagnosed on MR, particularly when diagnosing symptomatic patients or as a preoperative assessment for microsurgery of the nerve. PMID- 26507982 TI - Present and future role of FDG-PET/CT imaging in the management of head and neck carcinoma. AB - Integrated positron emission tomography/computed tomography (PET/CT) with 2 [(18)F]fluoro-2-deoxy-D-glucose (FDG) is a useful technique for acquisition of both glucose metabolic and anatomic imaging data using a single device in a single diagnostic session, and has opened a new field in clinical oncologic imaging. FDG-PET/CT has been used successfully for the initial staging, restaging, monitoring of the response to therapy, and prognostication of head and neck carcinoma. The present review discusses the current role of FDG-PET/CT in the management of head and neck carcinoma, focusing on its usefulness and limitations for imaging in these patients. PMID- 26507984 TI - Three-dimensional conformal fractionated radiotherapy for spinal schwannoma with a paravertebral or an intraosseous component. AB - INTRODUCTION: We retrospectively evaluated the efficacy of three-dimensional conformal radiotherapy (3D-CRT) for spinal schwannoma. METHODS: Nine patients with spinal schwannoma were treated with 3D-CRT. All patients had a paravertebral or intraosseous component. Tumor sizes ranged from 0.8 to 8.7 cm, with a median of 3.5 cm. The prescribed dose was 50 Gy in 25 fractions at the isocenter, except for 1 patient who received 66 Gy in 33 fractions for a large sacral tumor. The follow-up period ranged from 20 to 137 months, with a median of 72 months. RESULTS: Tumor shrinkage within 3 mm occurred in 4 patients and tumor expansion within 3 mm occurred in 3. One tumor showed neither expansion nor shrinkage at the last follow-up. One patient experienced transient expansion by 8 mm in diameter at 12 months after the completion of radiotherapy (35-43 mm), and then the tumor size remained unchanged for 7 years. No severe late toxicity >= grade 3 was observed. CONCLUSIONS: Only 1 of 9 tumors showed transit expansion over 3 mm after 3D-CRT, and severe late radiation toxicity was not observed. Use of 3D-CRT should be considered a treatment option for spinal schwannoma. PMID- 26507985 TI - CT evaluation and clinical factors predicting delayed colonic perforation following acute pancreatitis. AB - PURPOSE: Delayed colonic perforation after acute pancreatitis (AP) is a potentially lethal complication. This study investigated the frequency and predictors of delayed colonic perforation (DCP) following AP by reviewing the earliest laboratory data and computed tomography (CT) examination findings after pancreatitis onset. MATERIALS AND METHODS: This retrospective study examined 75 consecutive cases of AP treated between April 2009 and April 2014. Laboratory data after onset and imaging features from earliest CT examinations (Balthazar grade, CT Severity Index) were reviewed. To clarify relationships between these data and DCP, univariate analyses were undertaken between perforated and nonperforated groups. RESULTS: Delayed colonic perforation occurred in four of the 75 patients (5.3 %). Median duration to perforation after onset was 13 days (range 6-47). All four patients with DCP showed grade E according to Balthazar grade (>=2 peripancreatic collections and/or gas bubbles in or adjacent to pancreas). Univariate analyses identified Balthazar grade E as a risk factor for DCP (p = 0.0087). CONCLUSION: Delayed colonic perforation is not uncommon and can occur a week or more after AP. Balthazar grade E on earliest CT after onset represents a risk factor for DCP. PMID- 26507986 TI - [Fixed angle carbon fiber reinforced polymer composite plate for treatment of distal radius fractures : Pilot study on clinical applications]. AB - BACKGROUND: The clinical implementation of a new carbon-fiber-reinforced polyetheretherketon (PEEK) plate for distal radius fractures might offer advantageous properties over the conventional metallic devices. This includes similar elastic modulus to cortical bone, radiolucency, low artifacts on MRI scans and the lack of metal allergies. OBJECTIVE: The aim of this study was to evaluate the clinical results at 6-week and 12-month follow-up using either a new fixed angle (monoaxial) PEEK plate system or a fixed angle (polyaxial) titanium plate. METHODES: We included 26 patients (mean age 59.3) with displaced fractures of the distal radius (all AO types). Radiological and functional outcomes were measured prospectively at a 6-week and 12 month follow-up. RESULTS: We documented no cases of hardware breakage or significant loss of the surgically achieved fracture reduction with the usage oft the new PEEK device. Operating time was 101.0 min using PEEK versus 109.3 min in titanium plates, recorded times were including preparation, draping, and postoperative processing (ns, p 0.156). At the 6-week follow up the PEEK plate showed a trend for better range of motion and functional results (DASH-score, Mayo-wrist score, VAS) with no statistical significance. Results of 12 month follow up with PEEK showed comparable results with corresponding studies examining titanium plate after this period. CONCLUSION: First experience with PEEK plate osteosynthesis demonstrate quick clinical implementation with good clinical outcome and the advantage of excellent postoperative radiological assessment. At early follow-up PEEK even showed a trend for improved functional results. PMID- 26507987 TI - Luminescent europium and terbium complexes of dipyridoquinoxaline and dipyridophenazine ligands as photosensitizing antennae: structures and biological perspectives. AB - The europium(III) and terbium(III) complexes, namely [Eu(dpq)(DMF)2(NO3)3] (1), [Eu(dppz)2(NO3)3] (2), [Tb(dpq)(DMF)2Cl3] (3), and [Tb(dppz)(DMF)2Cl3] (4), where dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 1 and 3), dipyrido[3,2-a:2',3' c]phenazine (dppz in 2 and 4) and N,N'-dimethylformamide (DMF) have been isolated, characterized from their physicochemical data, luminescence studies and their interaction with DNA, serum albumin protein and photo-induced DNA cleavage activity are studied. The X-ray crystal structures of complexes 1-4 show discrete mononuclear Ln(3+)-based structures. The Eu(3+) in [Eu(dpq)(DMF)2(NO3)3] (1) and [Eu(dppz)2(NO3)3] (2) as [Eu(dppz)2(NO3)3].dppz (2a) adopts a ten-coordinated bicapped dodecahedron structure with a bidentate N,N-donor dpq ligand, two DMF and three NO3(-) anions in 1 and two bidentate N,N-donor dppz ligands and three NO3(-) anions in 2. Complexes 3 and 4 show a seven-coordinated mono-capped octahedron structure where Tb(3+) contains bidentate dpq/dppz ligands, two DMF and three Cl(-) anions. The complexes are highly luminescent in nature indicating efficient photo-excited energy transfer from the dpq/dppz antenna to Ln(3+) to generate long-lived emissive excited states for characteristic f -> f transitions. The time-resolved luminescence spectra of complexes 1-4 show typical narrow emission bands attributed to the (5)D0 -> (7)F(J) and (5)D4 -> (7)F(J) f-f transitions of Eu(3+) and Tb(3+) ions respectively. The number of inner-sphere water molecules (q) was determined from luminescence lifetime measurements in H2O and D2O confirming ligand-exchange reactions with water in solution. The complexes display significant binding propensity to the CT-DNA giving binding constant values in the range of 1.0 * 10(4)-6.1 * 10(4) M(-1) in the order 2, 4 (dppz) > 1, 3 (dpq). DNA binding data suggest DNA groove binding with the partial intercalation nature of the complexes. All the complexes also show binding propensity (K(BSA) ~ 10(5) M(-1)) to the bovine serum albumin (BSA) protein. The intensity of the time-gated luminescence spectral bands enhances significantly with the increasing DNA concentration in aqueous buffer medium due to displacement of bound water upon interaction with DNA, thus reducing non radiative quenching through the O-H oscillator. Complexes 1-4 efficiently cleave supercoiled (SC) ds-DNA to its nicked circular (NC) form on exposure to UV-A light of 365 nm via formation of singlet oxygen ((1)O2) and hydroxyl radicals (HO) as the reactive oxygen species at micromolar concentrations under physiological conditions. PMID- 26507988 TI - Omarigliptin: first global approval. AB - Omarigliptin [Marizev((r)) (Japan)] is a small-molecule dipeptidyl peptidase-4 (DPP-4) inhibitor developed by Merck for the oral treatment of type 2 diabetes (T2DM). Unlike the majority of other approved agents of its class, which are usually administered once daily, omarigliptin can be administered once weekly. Once-weekly omarigliptin has received its first global approval in this indication in Japan, for use in adults. Phase III clinical development of the product is underway in several other countries. This article summarizes the milestones in the development of omarigliptin leading to this first approval for the treatment of T2DM. PMID- 26507989 TI - Letter from the Editor - Let's Talk .... PMID- 26507990 TI - An Extended Validity Argument for Assessing Feedback Culture. AB - NEGEA 2015 CONFERENCE ABSTRACT (EDITED): Measuring an Organization's Culture of Feedback: Can It Be Done? Steven Rougas and Brian Clyne. CONSTRUCT: This study sought to develop a construct for measuring formative feedback culture in an academic emergency medicine department. Four archetypes (Market, Adhocracy, Clan, Hierarchy) reflecting an organization's values with respect to focus (internal vs. external) and process (flexibility vs. stability and control) were used to characterize one department's receptiveness to formative feedback. The prevalence of residents' identification with certain archetypes served as an indicator of the department's organizational feedback culture. BACKGROUND: New regulations have forced academic institutions to implement wide-ranging changes to accommodate competency-based milestones and their assessment. These changes challenge residencies that use formative feedback from faculty as a major source of data for determining training advancement. Though various approaches have been taken to improve formative feedback to residents, there currently exists no tool to objectively measure the organizational culture that surrounds this process. Assessing organizational culture, commonly used in the business sector to represent organizational health, may help residency directors gauge their program's success in fostering formative feedback. The Organizational Culture Assessment Instrument (OCAI) is widely used, extensively validated, applicable to survey research, and theoretically based and may be modifiable to assess formative feedback culture in the emergency department. APPROACH: Using a modified Delphi technique and several iterations of focus groups amongst educators at one institution, four of the original six OCAI domains (which each contain 4 possible responses) were modified to create a 16-item Formative Feedback Culture Tool (FFCT) that was administered to 26 residents (response rate = 55%) at a single academic emergency medicine department. The mean score of each item on the FFCT (range = 0-100) was analyzed. Convergent and divergent properties of the four archetypes were assessed using a multitrait-multimethod matrix of Pearson's coefficients. Expecting that items in one archetype would diverge from the others, whereas items within an archetype should have strong convergent properties, convergent validity was assessed by comparing items across domains that all related to the same archetype. Similarly, divergent validity was assessed by comparing the correlation of items within an archetype to the correlations of those items within a hetero-domain block (i.e., to other items within the same domain). RESULTS: Three of the four domains of the FFCT (Overall Departmental Characteristics 35.4 +/- 15.4, Departmental Foundation of Feedback 46.1 +/- 16.7, and Departmental Emphasis of Feedback 30.3 +/- 17.7) had the highest mean in the Market archetype (results/achievement oriented), whereas the final domain (Departmental Definition of Successful Feedback 34.8 +/- 22.1) had the highest mean in the Clan archetype (personal growth/team achievement). Item responses in the Clan and Hierarchy archetypes had the strongest convergent and divergent validity, respectively. Item responses in the Adhocracy archetype had the weakest convergent and divergent validity. CONCLUSIONS: Although the sample size was small, this initial study demonstrates that a modified organizational culture assessment tool can feasibly be utilized to identify the primary formative feedback archetype of a cohort of residents. This may have future implications for measuring changes in culture after the implementation of strategic programs to address formative feedback. Future studies should examine the generalizability of the FFCT to other institutions, as well as address the weak validity evidence of the Adhocracy archetype in the FFCT. PMID- 26507991 TI - A Proposed Conceptual Framework and Investigation of Upward Feedback Receptivity in Medical Education. AB - WGEA 2015 CONFERENCE ABSTRACT (EDITED). Faculty Perceptions of Receiving Feedback From Third-Year Clerkship Students. Amanda Kost, Heidi Combs, Sherilyn Smith, Eileen Klein, Patricia Kritek, and Lynne Robins. PHENOMENON: In addition to giving feedback to 3rd-year clerkship students, some clerkship instructors receive feedback, requested or spontaneous, from students prior to the clerkship's end. The concept of bidirectional feedback is appealing as a means of fostering a culture of respectful communication and improvement. However, little is known about how teachers perceive this feedback in practice or how it impacts the learning environment. APPROACH: We performed 24 semistructured 30-minute interviews with 3 to 7 attending physician faculty members each in Pediatrics, Internal Medicine, Family Medicine, Surgery, Psychiatry, and Obstetrics and Gynecology who taught in 3rd-year required clerkships during the 2012-2013 academic year. Questions probed teachers' experience with and attitudes toward receiving student feedback. Prompts were used to elicit stories and obtain participant demographics. Interviews were audio-recorded, transcribed, and entered into Dedoose for qualitative analysis. Researchers read transcripts holistically for meaning, designed a coding template, and then independently coded each transcript. A constant comparative approach and regular meetings were used to ensure consistent coding between research team members. FINDINGS: Participants ranged in age from 37 to 74, with 5 to 35 years of teaching experience. Seventy-one percent were male, and 83% identified as White. In our preliminary analysis, our informants reported a range of experience in receiving student feedback prior to the end of a clerkship, varying from no experience to having developed mechanisms to regularly request specific feedback about their programs. Most expressed openness to actively soliciting and receiving student feedback on their teaching during the clerkship although many questioned whether this process was feasible. Actual responses to receiving student feedback were mixed. Some reported having received feedback that motivated change, and others rejected the feedback they received on the grounds that it lacked validity or was inappropriate. Others expressed uncertainty about how they would react to student feedback. Faculty expressed a preference for receiving feedback about behaviors and items that were within their control. INSIGHTS: These findings suggest there is opportunity to pilot implementation of a structured student feedback mechanism, separate from teacher evaluations, in selected 3rd-year clerkships. Materials should developed to help faculty solicit, understand, and respond to student feedback and to help students frame and provide the kinds of feedback to teachers that will lead to suggested improvements. Both these endeavors have the potential to improve the clinical learning environment during 3rd-year clerkships through the cultivation of respectful communication and the encouragement of improvement in teaching efforts. PMID- 26507992 TI - Developing Professionalism via Multisource Feedback in Team-Based Learning. AB - CGEA 2015 CONFERENCE ABSTRACT (EDITED). A Novel Approach to Assessing Professionalism in Preclinical Medical Students Using Paired Self- and Peer Evaluations. Amanda R. Emke, Steven Cheng, and Carolyn Dufault. CONSTRUCT: This study sought to assess the professionalism of 2nd-year medical students in the context of team-based learning. BACKGROUND: Professionalism is an important attribute for physicians and a core competency throughout medical education. Preclinical training often focuses on individual knowledge acquisition with students working only indirectly with faculty assessors. As such, the assessment of professionalism in preclinical training continues to present challenges. We propose a novel approach to preclinical assessment of medical student professionalism to address these challenges. APPROACH: Second-year medical students completed self- and peer assessments of professionalism in two courses (Pediatrics and Renal/Genitourinary Diseases) following a series of team-based learning exercises. Assessments were composed of nearly identical 9-point rating scales. Correlational analysis and linear regression were used to examine the associations between self- and peer assessments and the effects of predictor variables. Four subgroups were formed based on deviation from the median ratings, and logistic regression was used to assess stability of subgroup membership over time. A missing data analysis was conducted to examine differences between average peer-assessment scores as a function of selective nonparticipation. RESULTS: There was a significant positive correlation (r = .62, p < .0001) between self-assessments completed alone and those completed at the time of peer assessment. There was also a significant positive correlation between average peer-assessment and self-assessment alone (r = .19, p < .0002) and self assessment at the time of peer assessment (r = .27, p < .0001). Logistic regression revealed that subgroup membership was stable across measurement at two time points (T1 and T2) for all groups, except for members of the high self assessment/low peer assessment at T1, who were significantly more likely to move to a new group at T2, chi(2)(3, N = 129) = 7.80, p < .05. Linear regression revealed that self-assessment alone and course were significant predictors of self-assessment at the time of peer assessment (Fself_alone = 144.74, p < .01 and Fcourse = 4.70, p < .05), whereas average peer rating, stage (T1, T2) and academic year (13-14, 14-15) were not. Linear regression also revealed that students who completed both self-assessments had significantly higher average peer assessment ratings (average peer rating in students with both self assessments = 8.42, no self-assessments = 8.10, self_at_peer = 8.37, self_alone = 8.28) compared to students who completed one or no self-assessments (F = 5.34, p < .01). CONCLUSIONS: When used as a professionalism assessment within team-based learning, stand-alone and simultaneous peer and self-assessments are highly correlated within individuals across different courses. However, although self assessment alone is a significant predictor of self-assessment made at the time of assessing one's peers, average peer assessment does not predict self assessment. To explore this lack of predictive power, we classified students into four subgroups based on relative deviation from median peer and self-assessment scores. Group membership was found to be stable for all groups except for those initially sorted into the high self-assessment/low peer assessment subgroup. Members of this subgroup tended to move into the low self-assessment/low peer assessment group at T2, suggesting they became more accurate at self-assessing over time. A small group of individuals remained in the group that consistently rated themselves highly while their peers rated them poorly. Future studies will track these students to see if similar deviations from accurate professional self assessment persist into the clinical years. In addition, given that students who fail to perform self-assessments had significantly lower peer assessment scores than their counterparts who completed self-assessments in this study, these students may also be at risk for similar professionalism concerns in the clinical years; follow-up studies will examine this possibility. PMID- 26507993 TI - Conceptualizing Interprofessional Teams as Multi-Team Systems-Implications for Assessment and Training. AB - SGEA 2015 CONFERENCE ABSTRACT (EDITED). Evaluating Interprofessional Teamwork During a Large-Scale Simulation. Courtney West, Karen Landry, Anna Graham, and Lori Graham. CONSTRUCT: This study investigated the multidimensional measurement of interprofessional (IPE) teamwork as part of large-scale simulation training. BACKGROUND: Healthcare team function has a direct impact on patient safety and quality of care. However, IPE team training has not been the norm. Recognizing the importance of developing team-based collaborative care, our College of Nursing implemented an IPE simulation activity called Disaster Day and invited other professions to participate. The exercise consists of two sessions: one in the morning and another in the afternoon. The disaster scenario is announced just prior to each session, which consists of team building, a 90-minute simulation, and debriefing. Approximately 300 Nursing, Medicine, Pharmacy, Emergency Medical Technicians, and Radiology students and over 500 standardized and volunteer patients participated in the Disaster Day event. To improve student learning outcomes, we created 3 competency-based instruments to evaluate collaborative practice in multidimensional fashion during this exercise. APPROACH: A 20-item IPE Team Observation Instrument designed to assess interprofessional team's attainment of Interprofessional Education Collaborative (IPEC) competencies was completed by 20 faculty and staff observing the Disaster Day simulation. One hundred sixty-six standardized patients completed a 10-item Standardized Patient IPE Team Evaluation Instrument developed from the IPEC competencies and adapted items from the 2014 Henry et al. PIVOT Questionnaire. This instrument assessed the standardized or volunteer patient's perception of the team's collaborative performance. A 29-item IPE Team's Perception of Collaborative Care Questionnaire, also created from the IPEC competencies and divided into 5 categories of Values/Ethics, Roles and Responsibilities, Communication, Teamwork, and Self Evaluation, was completed by 188 students including 99 from Nursing, 43 from Medicine, 6 from Pharmacy, and 40 participants who belonged to more than one component, were students at another institution, or did not indicate their institution. The team instrument was designed to assess each team member's perception of how well the team and him- or herself met the competencies. Five of the items on the team perceptions questionnaire mirrored items on the standardized patient evaluation: demonstrated leadership practices that led to effective teamwork, discussed care and decisions about that care with patient, described roles and responsibilities clearly, worked well together to coordinate care, and good/effective communication. RESULTS: Internal consistency reliability of the IPE Team Observation Instrument was 0.80. In 18 of the 20 items, more than 50% of observers indicated the item was demonstrated. Of those, 6 of the items were observed by 50% to 75% of the observers, and the remaining 12 were observed by more than 80% of the observers. Internal consistency reliability of the IPE Team's Perception of Collaborative Care Instrument was 0.95. The mean response score-1 (strongly disagree) to 4 (strongly agree)-was calculated for each section of the instrument. The overall mean score was 3.57 (SD = .11). Internal consistency reliability of the Standardized Patient IPE Team Evaluation Instrument was 0.87. The overall mean score was 3.28 (SD = .17). The ratings for the 5 items shared by the standardized patient and team perception instruments were compared using independent sample t tests. Statistically significant differences (p < .05) were present in each case, with the students rating themselves higher on average than the standardized patients did (mean differences between 0.2 and 0.6 on a scale of 1-4). CONCLUSIONS: Multidimensional, competency based instruments appear to provide a robust view of IPE teamwork; however, challenges remain. Due to the large scale of the simulation exercise, observation based assessment did not function as well as self- and standardized patient-based assessment. To promote greater variation in observer assessments during future Disaster Day simulations, we plan to adjust the rating scale from "not observed," "observed," and "not applicable" to a 4-point scale and reexamine interrater reliability. PMID- 26507994 TI - Investigation of Unethical and Unprofessional Behavior in Korean Residency Training. AB - PHENOMENON: Medical ethics and professionalism are fundamental competencies for all physicians, and resident physicians have to develop these competencies during their training. Although Korea has a reputation for having the highest quality medical practice in East Asia, improvements in the technological aspects of care have outpaced the developments in institutional systems and education needed to fulfill social responsibility. Enhancing professionalism education during postgraduate training requires thorough exposition of this situation. APPROACH: Twenty residents from 17 clinical departments at 1 Korean tertiary university affiliated hospital were recruited, and in-depth interviews were conducted in person by an interviewer who was a fellow resident with participants. Interviewees recalled and described personal experiences or observations of misbehaviors that had occurred during their residency training. Researchers recorded and transcribed all interviews, and 4 researchers conducted a thematic analysis. FINDINGS: Authors extracted 48 descriptors representing 8 categories of unethical and unprofessional behaviors from the transcripts: (a) substandard practice, (b) violation of work ethics, (c) misconduct related to conflict of interest, (d) dishonesty with patients, (e) violation of patient confidentiality, (f) lack of respect for patients, (g) lack of respect for colleagues, and (h) misconduct in research. Each of the interviewees mentioned between 3 and 18 descriptors. "Not fulfilling basic duties for patient care" was the most frequently mentioned misconduct, followed by "fabricating patient medical status or test results to meet preoperative criteria for anesthesia" and "verbal or physical abuse of junior doctors." INSIGHTS: Residents reported a diverse variety of unethical and unprofessional behaviors throughout their training and described the ethical distress they suffered in the real clinical situations. The results of this study support the notion that reinforcing ethics and professionalism education during postgraduate medical training in a practical and authentic way will help trainees manage the ethical conflicts or dilemmas they will inevitably encounter. PMID- 26507995 TI - Is the Front Line Prepared for the Changing Faces of Patients? Predictors of Cross-Cultural Preparedness Among Clinical Nurses and Resident Physicians in Lausanne, Switzerland. AB - PHENOMENON: Assuring quality medical care for all persons requires that healthcare providers understand how sociocultural factors affect a patient's health beliefs/behaviors. Switzerland's changing demographics highlight the importance of provider cross-cultural preparedness for all patients-especially those at risk for social/health precarity. We evaluated healthcare provider cross cultural preparedness for commonly encountered vulnerable patient profiles. APPROACH: A survey on cross-cultural care was mailed to Lausanne University hospital's "front-line healthcare providers": clinical nurses and resident physicians at our institution. Preparedness items asked "How prepared do you feel to care for ... ?" (referring to example patient profiles) on an ascending 5 point Likert scale. We examined proportions of "4 - well/5 - very well prepared" and the mean composite score for preparedness. We used linear regression to examine the adjusted effect of demographics, work context, cultural-competence training, and cross-cultural care problem awareness, on preparedness. FINDINGS: Of 885 questionnaires, 368 (41.2%) were returned: 124 (33.6%) physicians and 244 (66.4%) nurses. Mean preparedness composite was 3.30 (SD = 0.70), with the lowest proportion of healthcare providers feeling prepared for patients "whose religious beliefs affect treatment" (22%). After adjustment, working in a sensitized department (beta = 0.21, p = .01), training on the history/culture of a specific group (beta = 0.25, p = .03), and awareness regarding (a) a lack of practical experience caring for diverse populations (beta = 0.25, p = .004) and (b) inadequate cross-cultural training (beta = 0.18, p = .04) were associated with higher preparedness. Speaking French as a dominant language and physician role (vs. nurse) were negatively associated with preparedness (beta = -0.26, p = .01; beta = -0.22, p = .01). INSIGHTS: The state of cross-cultural care preparedness among Lausanne's front-line healthcare providers leaves room for improvement. Our study points toward institutional strategies to improve preparedness: notably, making sure departments are sensitized to cross-cultural care resources and increasing provider diversity to reflect the changing Swiss demographic. PMID- 26507996 TI - Challenges Facing Medical Residents' Satisfaction in the Middle East: A Report From United Arab Emirates. AB - PHENOMENON: Medical residents' satisfaction with the quality of training for medical residency training specialists is one of the core measures of training program success. It will also therefore contribute to the integrity of healthcare in the long run. Yet there is a paucity of research describing medical residents' satisfaction in the Middle East, and there are no published studies that measure the satisfaction of medical residents trained within the United Arab Emirates (UAE). This makes it difficult to develop a quality residency training program that might meet the needs of both physicians and society. APPROACH: The authors designed a questionnaire to assess medical residents' satisfaction with the Dubai residency training program in order to identify insufficiencies in the training, clinical, and educational aspects. The survey was a self-report questionnaire composed of different subscales covering sociodemographic and educational/academic profile of the residents along with their overall satisfaction of their training, curriculum, work environment, peer teamwork, and their personal opinion on their medical career. FINDINGS: Respondents showed a substantial level of satisfaction with the residency training. The vast majority of residents (80%, N = 88) believe that their residency program curriculum and rotation was "good," "very good," or "excellent." Areas of dissatisfaction included salary, excessive paperwork during rotations, and harassment. INSIGHTS: This is the first report that studies the satisfaction of medical residents in all specialties in Dubai, UAE. Our findings provide preliminary evidence on the efficiency of different modifications applied to the residency program in UAE. To our knowledge, there has not been any previous study in the Middle East that has analyzed this aspect of medical residents from different specialties. The authors believe that this report can be used as a baseline to monitor the effectiveness of interventions applied in the future toward improving residency training programs in this region. PMID- 26507997 TI - How Many Responses Do We Need? Using Generalizability Analysis to Estimate Minimum Necessary Response Rates for Online Student Evaluations. AB - CONSTRUCT: The study compares paper and online ratings of instructional units and analyses, with the G-study using the symmetry principle, the response rates needed to ensure acceptable precision of the measure when compliance is low. BACKGROUND: Students' ratings of teaching contribute to the quality of medical training programs. To date, many schools have replaced pen-and-paper questionnaires with electronic forms, despite the lower response rates consistently reported with the latter. Few available studies have examined the effects of low response rates on the reliability and precision of the evaluation measure. Moreover, the minimum number of raters to target when response rates are low remains unclear. APPROACH: Descriptive data were derived from 799 students' paper and online ratings of 11 preclinical instructional units (PIUs). Reliability was assessed by Cronbach's alpha coefficients. The generalizability method applying the symmetry principle approach was used to analyze the precision of the measure with a reference standard error of mean (SEM) set at 0.10; optimization models were built to estimate minimum response rates. RESULTS: Overall, response rates were 74% and 30% (p < .001) and PIUs ratings were 3.8 +/- 0.5 and 3.6 +/- 0.5 (p = .02), respectively in paper and online questionnaires. Higher SEM levels and significantly larger 95% confidence intervals of PIUs rating scores were observed with online evaluations. To keep the SEM within preset limits of precision, a minimum of 48% response rate was estimated for online formats. CONCLUSIONS: The proposed generalizability analysis allowed estimating the minimum response needed to maintain acceptable precision in online evaluations. The effects of response rates on accuracy are discussed. PMID- 26507998 TI - The Impact of Repeated Exposure to Items. AB - THEORY: When test developers have a limited number of test questions available or when the equating design requires some item overlap across forms, psychometricians worry that examinees who encounter previously seen questions on subsequent test forms may be able to inflate their test score due to their familiarity with the repeated test questions. HYPOTHESES: Prior exposure to test questions may lead to contamination and inflated scores. This research seeks to detect if examinees' scores were inflated due to prior exposure to test questions and, if so, whether those increases were significant. METHOD: The sample for this study consisted of candidates who took the American Board of Family Medicine's certification examination twice in a single year (n = 988). Examinees were randomly assigned one of two forms for their first attempt and received the other form for their repeat test. There were 99 questions in common across both forms. The Rasch model was used to estimate examinee ability. Performance changes on the common questions and unique questions were compared and repeated measures t tests were performed to establish whether score changes were likely to have occurred by chance. RESULTS: On average, the examinees increased their overall ability estimate by .187 logits on the repeat attempt. The repeated measures t tests indicate this difference was statistically significant, t(987) = -25.298, p < .001, alpha = .05. The mean difference between the examinees' ability estimate on common and unique items for their first attempt was not statistically significant, t(987) = .264, p = .792, alpha = .05; however, the mean difference between common and unique items on the second attempt (0.029 logits) was statistically significant, t(987) = 3.28, p = .001, alpha = .05. CONCLUSIONS: Some of the increase in the examinees' overall ability estimate may attributed to a general increase in the latent trait; however, there was a small but detectable increase that could be attributed to prior exposure to the questions. On average, about 15% of the repeated questions were changed from wrong to right, but about 11% of questions were changed from right to wrong, suggesting that examinees may occasionally be using prior exposure to their benefit but general guessing accounts for more of the changes. The impact of the mean difference between the common and unique item scores (0.029 logits) is trivial at the individual level; however, such a bias among the population of repeat testers could be problematic if a small subset of examinees were using a "remember-research-retest" strategy to obtain nontrivial score increases. PMID- 26507999 TI - Teaching Medical Students to Reflect More Deeply. AB - PROBLEM: Although many studies have examined the importance of reflective writing in medical education, there is a scarcity of evidence for any particular intervention to improve the quality of reflection among medical students. Historically, students on our Internal Medicine clerkship were given a written reflection assignment without explanation of critical reflection. To facilitate the development of deeper reflection, a new curriculum was introduced. INTERVENTION: A 90-minute workshop on critical reflection was introduced at the start of the Internal Medicine rotation. Key components included a video clip stimulating reflection, small- and large-group exercises, and a faculty member's personal reflection. Students were then asked to write two reflection papers. To minimize bias, the names and dates were removed from each reflection paper and combined with reflection papers from a historical control group. Four faculty used a previously validated tool, the REFLECT rubric, to independently grade the written reflection papers as nonreflective (as a 1), thoughtful action (2), reflection (3), or critical reflection (4). The final grade of each paper was determined by consensus among the graders. CONTEXT: The 90-minute workshop was given once at the beginning of each 10-week requisite Internal Medicine clerkship to 3rd-year medical students. OUTCOME: One hundred fifty-five papers written after the workshop were compared to 155 papers from a preworkshop historical control group. The primary analysis showed the number of students writing "critical reflection" papers increased after the educational intervention, from 14% to 47% (p = .0002). The effect size using Cohen's d was 0.62. The kappa statistic used to measure interrater reliability among the four graders was 0.37. LESSONS LEARNED: Through a 90-minute reflection workshop more 3rd-year students were able to demonstrate the potential for "critical reflection" compared to previous students not exposed to this teaching. Strengths include the large sample size of written reflection papers submitted throughout an entire academic year and blinded grading of papers that minimized bias. The low interrater reliability is a limitation. We believe this curriculum could readily be adapted to a clerkship seeking to enhance learner reflection. PMID- 26508000 TI - Increasing Medical Students' Confidence in Procedural Skills Using a Junior Doctor-Delivered Bedside Supervision Program. AB - PROBLEM: Clinical procedural skills are formally taught to medical students in clinical skills centers using mannequins. Exposure to procedural skills involving patients and opportunities to practice under the supervision of doctors are limited. INTERVENTION: A bedside supervision program was piloted at a district general hospital in the United Kingdom. The supervision model was chosen as the method to increase medical students' practice in basic procedural skills because it allowed safe practice with patients. CONTEXT: The program was an optional component of the medical students' clinical clerkships. Off-duty junior doctors were recruited as voluntary trainers. The trainers obtained requests for procedural tasks from the on-call doctors and ward nurses, following which the trainers supervised medical students performing the basic procedures with patient consent. OUTCOME: The pilot program was successfully run for 4 weeks. Fourteen students took part, and 9 (64%) completed a postintervention feedback questionnaire. The students' confidence (rating scale = 1-5) in performing procedural skills improved from a mean of 3.0 (SD +/- 0.9) to 4.7 (SD +/- 0.5) following a supervision session. Although the range of skills was limited to opportunistic encounters, the students reported high satisfaction and felt supervision enabled them to identify areas for improvement. LESSONS LEARNED: It is feasible to implement a junior doctor-delivered bedside program to supplement procedural skills training provided by medical schools. The challenges include reconciling the tension between junior doctors' service work and their teaching commitment, logistical issues such as recruiting a sufficient number of trainers and ensuring adequate coverage of training tasks. PMID- 26508001 TI - A Medical School Prematriculation Program for Rural Students: Staying Connected With Place, Cultivating a Special Connection With People. AB - PROBLEM: Rural medical students who attend urban medical schools experience urban disruption that may make it less likely that they will return to rural practice. Most prematriculation programs focus on academic preparation and are in urban areas, potentially adding to urban disruption. Most initial learning experiences concerning communication with patients are also in urban areas. INTERVENTION: Fifty-nine rural preclinical students completed a 3-week summer rural prematriculation program from 2009 to 2014. The focus was on learning a holistic approach to interviewing patients and experiential learning based in a rural practice. Group reflection sessions focused on understanding health beliefs, psychosocial details of the patient's life, and the importance of the sense of place. Measures included student reports, program evaluations, and a pre- and post- 10-item opinion survey focused on the students' perceived importance of traditional biomedical and psychosocial knowledge. CONTEXT: The program was based at the Trover Campus, a regional clinical campus of the University of Louisville School of Medicine, in a town of 20,000 in the western Kentucky coalfields that is 150 miles from the main urban campus. Practice site assignments were in surrounding medically underserved towns in family medicine practices. OUTCOME: After the 3-week experience, students became comfortable with interviews concerning health habits using the Prochaska model of lifestyle modification and expressed an increased importance of some psychosocial factors and a corresponding decrease in importance of traditional biomedical factors in choosing treatment for an individual patient (significant results by Mann Whitney, two-tailed, ranged U = 1136.0, p = .001 to U = 1377.5, p <= .05). Student reports showed that the students gained a new detailed understanding of rural practice. Students also expressed an appreciation for having developed a support network of fellow rural students with whom they would begin medical school on the urban campus. LESSONS LEARNED: These results support the value of a summer prematriculation program for rural students based in a rural area. New appreciation for psychosocial patient factors, new skills in communication with patients, new understanding of the details of rural practice, and new relationships with other rural classmates were perceived as positive aspects of the program. Longer term measures of whether the program decreased urban disruption significantly will require continued tracking of the students until they make a practice choice 7 to 9 years later. Wider collaboration with other medical school rural programs is necessary to determine which aspects of rural focused training are most effective. PMID- 26508002 TI - When Professors Don't Return Essays. AB - ISSUE: Students devote hundreds of hours to writing notes during medical school clerkships but receive very limited feedback on that work. Medical student notes are like college essays-both are persuasive compositions. But attending physicians rarely scrutinize student notes like college professors analyze essays. This is a missed opportunity to teach clinical reasoning. EVIDENCE: A survey at our institution showed that only 16% of students received written feedback and 31% received oral feedback on their notes from more than 3 attending physicians during the first 8 months of 3rd-year clerkships. Many studies have reported a paucity of feedback across multiple domains and a sense among students that clinical reasoning is not being adequately taught during clerkships. Meanwhile, college professors teach written composition and reasoning through interactive methods that help students to develop structured, well-reasoned arguments. A recent study showed that 85% of Oxford undergraduates favored these demanding and time-intensive tutorials. IMPLICATIONS: Attending physicians who adopt a tutorial-based approach toward their students' notes would have a forum to teach clinical reasoning and emphasize the importance of written composition in medical practice. PMID- 26508007 TI - Specific K39 antibody response and its persistence after treatment in patients with imported leishmaniasis. AB - The sensitivity of a K39 ELISA (Leishmania IgG, Virion/Serion) for the detection of antibodies in patients with imported leishmaniasis was compared with an immunofluorescence assay (IFA), which was applied as "golden standard". The retrospective study comprised 93 IFA-positive or borderline sera from 42 patients with visceral (n = 16) or cutaneous (n = 26) leishmaniasis. Patients had acquired infection predominately in the Mediterranean area or the Middle East. The Leishmania species (Leishmania donovani/infantum, Leishmania tropica, Leishmania major) were identified by real-time PCR. The majority (94%) of first samples from patients with visceral leishmaniasis (VL) tested positive by K39 ELISA. Antibody levels ranged from low to very high (33.19-1990.00 U/ml; median 596.66 U/ml) but did not correlate with the respective IFA titers. High K39 ELISA values correlated with acute infection in immunocompetent individuals. K39 antibodies declined in all individuals after clinically successful therapy, but time to seronegativity varied considerably (51 weeks to >6 years). In patients with cutaneous leishmaniasis (CL), the sensitivity of the K39 ELISA was low (23%) compared to IFA (92% positive). Antibody levels ranged from low to medium (10.85 524.77 U/ml; median 19.77 U/ml). The highest antibody concentrations were seen in L. infantum-infected individuals. Summarizing, a high K39 ELISA value indicates active VL. The assay is, like IFA, not a measure for effective therapy but may support post-treatment monitoring. Low level positivity can indicate subclinical, previous or clinically cured VL or even CL. The K39 ELISA can supplement highly sensitive screening tests in the diagnosis and follow-up of imported leishmaniasis. PMID- 26508008 TI - Transcriptomic analysis of global changes in cytokine expression in mouse spleens following acute Toxoplasma gondii infection. AB - Toxoplasma gondii is a global pathogen that infects a wide range of animals and humans. During T. gondii infection, the spleen plays an important role in coordinating the adaptive and innate immune responses. However, there is little information regarding the changes in global gene expression within the spleen following T. gondii infection. To address this gap in knowledge, we examined the transcriptome of the mouse spleen following T. gondii infection. We observed differential expression of 2310 transcripts under these conditions. Analysis of KEGG and GO enrichment indicated that T. gondii alters multiple immune signaling cascades. Most of differentially expressed GO terms and pathways were downregulated, while immune-related GO terms and pathways were upregulated with response to T. gondii infection in mouse spleen. Most cytokines were upregulated in infected spleens, and all differentially expressed chemokines were upregulated which enhanced the immune cells chemotaxis to promote recruitment of immune cells, such as neutrophils, eosinophils, monocytes, dendritic cells, macrophages, NK cells, basophils, B cells, and T cells. Although IFN-gamma-induced IDO (Ido1) was upregulated in the present study, it may not contribute a lot to the control of T. gondii because most differentially expressed genes involved in tryptophan metabolism pathway were downregulated. Innate immunity pathways, including cytosolic nucleic acid sensing pathway and C-type lectins-Syk-Card9 signaling pathways, were upregulated. We believe our study is the first comprehensive attempt to define the host transcriptional response to T. gondii infection in the mouse spleen. PMID- 26508009 TI - A new coccidian, Isospora parnaitatiaiensis n. sp. (Apicomplexa, Eimeriidae), from the white-shouldered fire-eye Pyriglena leucoptera (Passeriformes, Thamnophilidae) from South America. AB - A new coccidian species (Protozoa: Apicomplexa: Isospora) parasitizing the white shouldered fire-eye Pyriglena leucoptera (Vieillot, 1818) is described in the Parque Nacional do Itatiaia. This park is a protected area in southeastern Brazil with a high degree of vulnerability, representing a "conservation island" of biodiversity. Isospora parnaitatiaiensis n. sp. has oocysts that are ellipsoidal, 23.8 * 19.4 MUm, with smooth, bilayered wall, ~1.1 MUm thick. Micropyle and oocyst residuum are absent, but one or two polar granules are present. Sporocysts are ellipsoidal, 14.6 * 9.3 MUm. The Stieda body is nipple- to knob-like and sub Stieda body rounded to rectangular. Sporocyst residuum is present, usually as a cluster of numerous granules. Sporozoites are vermiform with two refractile bodies and a nucleus. This is the second isosporoid coccidian described from antbirds (Thamnophilidae). PMID- 26508010 TI - Sources of plutonium in the atmosphere and stratosphere-troposphere mixing. AB - Plutonium isotopes have primarily been injected to the stratosphere by the atmospheric nuclear weapon tests and the burn-up of the SNAP-9A satellite. Here we show by using published data that the stratospheric plutonium exponentially decreased with apparent residence time of 1.5 +/- 0.5 years, and that the temporal variations of plutonium in surface air followed the stratospheric trends until the early 1980s. In the 2000s, plutonium and its isotope ratios in the atmosphere varied dynamically, and sporadic high concentrations of (239,240)Pu reported for the lower stratospheric and upper tropospheric aerosols may be due to environmental events such as the global dust outbreaks and biomass burning. PMID- 26508011 TI - Cavitating lung cancer as response to bevacizumab treatment. PMID- 26508012 TI - Variation in dielectric properties due to pathological changes in human liver. AB - Dielectric properties of freshly excised human liver tissues (in vitro) with several pathological conditions including cancer were obtained in frequency range 100 MHz-5 GHz. Differences in dielectric behavior of normal and pathological tissues at microwave frequencies are discussed based on histological information for each tissue. Data presented are useful for many medical applications, in particular nanosecond pulsed electroporation techniques. Knowledge of dielectric properties is vital for mathematical calculations of local electric field distribution inside electroporated tissues and can be used to optimize the process of electroporation for treatment planning procedures. PMID- 26508013 TI - Comparison of pencil-type ionization chamber calibration results and methods between dosimetry laboratories. AB - A comparison of calibration results and procedures in terms of air kerma length product, PKL, and air kerma, K, was conducted between eight dosimetry laboratories. A pencil-type ionization chamber (IC), generally used for computed tomography dose measurements, was calibrated according to three calibration methods, while its residual signal and other characteristics (sensitivity profile, active length) were assessed. The results showed that the "partial irradiation method" is the preferred method for the pencil-type IC calibration in terms of PKL and it could be applied by the calibration laboratories successfully. Most of the participating laboratories achieved high level of agreement (>99%) for both dosimetry quantities (PKL and K). Estimated relative standard uncertainties of comparison results vary among laboratories from 0.34% to 2.32% depending on the quantity, beam quality and calibration method applied. Detailed analysis of the assigned uncertainties have been presented and discussed. PMID- 26508014 TI - Hypofractionation of partial breast irradiation using radiobiological models. AB - PURPOSE: To reduce the fraction number in Partial Breast Irradiation (PBI) with initial prescription of 40 Gy in 10 fractions using radiobiological models with specific focus on risk of moderate/severe radiation-induced fibrosis (RIF) and report clinical results. METHODS AND MATERIALS: 68 patients (patient group A) were treated with 40 Gy in 10 fractions delivered by field-in-field, forward planned IMRT. Isotoxic regimens with decreasing number of fractions were calculated using Biological Effective Dose (BED) to the breast. Risk for RIF in hypofractionated treatment was predicted by calculating NTCP from DVHs of group A rescaled to fractions and dose of novel regimens. Moderate/severe RIF was prospectively scored during follow-up. Various NTCP models, with and without incomplete repair correction, were assessed from difference to observed incidence of RIF. In order to verify the value for alpha/beta of 3 Gy assumed for breast, we fitted alpha/beta to observed incidences of moderate/severe RIF. RESULTS: Treatments with 35 Gy/7f and 28 Gy/4f were selected for the fraction reduction protocol. 75 patients (group B) were treated in 35 Gy/7f. Incidence of moderate/severe RIF was 5.9% in group A, 5.3% in group B. The NTCP model with correction for incomplete repair had lowest difference from observed RIF. The alpha/beta obtained from fitting was 2.8 (95%CIs 1.1-10.7) Gy. CONCLUSIONS: The hypofractionated regimen was well tolerated. The model for NTCP corrected for incomplete repair was the most accurate and an assumed alpha/beta value of 3 Gy is consistent with our patient data. The hypofractionation protocol is continuing with patients treated with 28 Gy/4f. PMID- 26508015 TI - Limitations of Poisson statistics in describing radioactive decay. AB - OBJECTIVES: The assumption that nuclear decays are governed by Poisson statistics is an approximation. This approximation becomes unjustified when data acquisition times longer than or even comparable with the half-lives of the radioisotope in the sample are considered. In this work, the limits of the Poisson-statistics approximation are investigated. METHODS: The formalism for the statistics of radioactive decay based on binomial distribution is derived. The theoretical factor describing the deviation of variance of the number of decays predicated by the Poisson distribution from the true variance is defined and investigated for several commonly used radiotracers such as (18)F, (15)O, (82)Rb, (13)N, (99m)Tc, (123)I, and (201)Tl. RESULTS: The variance of the number of decays estimated using the Poisson distribution is significantly different than the true variance for a 5-minute observation time of (11)C, (15)O, (13)N, and (82)Rb. CONCLUSIONS: Durations of nuclear medicine studies often are relatively long; they may be even a few times longer than the half-lives of some short-lived radiotracers. Our study shows that in such situations the Poisson statistics is unsuitable and should not be applied to describe the statistics of the number of decays in radioactive samples. However, the above statement does not directly apply to counting statistics at the level of event detection. Low sensitivities of detectors which are used in imaging studies make the Poisson approximation near perfect. PMID- 26508016 TI - Characterizing 3D printing in the fabrication of variable density phantoms for quality assurance of radiotherapy. AB - PURPOSE: To present characterization, process flow, and applications of 3D fabricated low density phantoms for radiotherapy quality assurance (QA). MATERIAL AND METHODS: A Rostock 3D printer using polystyrene was employed to print slabs of varying relative electron densities (0.18-0.75). A CT scan was used to calibrate infill-to-density and characterize uniformity of the print. Two printed low relative density rods (0.18, 0.52) were benchmarked against a commercial CT electron-density phantom. Density scaling of Anisotropic Analytical Algorithm (AAA) was tested with EBT3 film for a 0.57 slab. Gamma criterion of 3% and 3 mm was used for analysis. RESULTS: 3D printed slabs demonstrated uniformity for densities 0.4-0.75. The printed 0.52 rod had close agreement with the commercial phantom. Dosimetric comparison for 0.57 density slab showed >95% agreement between calculation and measurements. CONCLUSION: 3D printing allows fabrication of variable density phantoms for QA needs of a small clinic. PMID- 26508017 TI - Radiation dose to the fetus during CyberKnife radiosurgery for a brain tumor in pregnancy. AB - PURPOSE: Pregnancy during radiosurgery is extremely rare in clinical practice. We report fetal dose results during CyberKnife radiosurgery for a brain tumor in pregnancy. METHODS AND MATERIALS: A 26 year old pregnant woman with a rapidly growing deep-seated grade-III glioma was treated during the third trimester of gestation using CyberKnife. Ultrasound imaging was used to determine the position of the embryo prior to treatment. A dose of 1400 cGy was prescribed aiming to control tumor growth until delivery of the child. Prior to radiosurgery, the treatment was simulated on an anthropomorphic phantom. Radiation dose to the embryo was measured using a Farmer chamber and EBT3 films. RESULTS: Fetal doses of 4.4 cGy and 4.1 cGy were measured for the embryo's head and legs, lying at 56 cm and 72 cm from the isocenter, respectively, using the Farmer chamber situated at 8.5 cm depth beneath the phantom surface. Dose results of 4.4 cGy, 3.5 cGy and 2.0 cGy were measured with the films situated at depths of 6.5 cm, 9.5 cm and 14.5 cm, respectively. An average dose of 4.2 cGy to the fetus was derived from the above values. A corresponding dose of 3.2 cGy was also calculated based on results obtained using EBT3 films situated upon the patient skin. CONCLUSIONS: The measured fetal doses are below the threshold of 10 cGy for congenital malformations, mental and growth retardation effects. The radiogenic cancer risk to the live-born embryo was estimated less than 0.3% over the normal incidence. The treatment was administered successfully, allowing the patient to deliver a healthy child. PMID- 26508018 TI - Farmyard manures: the major agronomic sources of heavy metals in the Philippi Horticultural Area in the Western Cape Province of South Africa. AB - Heavy metal toxicity in agro-ecosystems is a global problem. Recently, it has been indicated that the soils used for agriculture and the fresh produce grown on these soils in the Philippi Horticultural Area (PHA) contains heavy metals exceeding the maximum permissible concentrations thereof in South Africa. This study was therefore aimed at evaluating the concentrations of heavy metals in the soils and vegetables produced in the PHA, as well as to determine the major agronomic sources of these metals in this area. Cu, Pb, and Zn concentrations in the soils exceeded the maximum permissible concentrations of 6.6, 6.6, and 46 mg/kg, respectively. Cd, Pb, and Zn concentrations in the vegetables also exceeded the maximum permissible concentrations of 0.1, 0.5, and 40 mg/kg, respectively. The biggest agronomic contributors of these heavy metals to the soils in the PHA were found to be the farmyard manures. Knowing what the major sources of these heavy metals are, it is important to determine ways to mitigate the inputs thereof, as well as to remove existing concentrations from the soils without contaminating the groundwater resources in the area. PMID- 26508019 TI - Sewage sludge composting: quality assessment for agricultural application. AB - In order to use sewage sludge (SS) composts in agriculture, it is extremely important to estimate the quality of compost products. The aim of this study was to investigate the quality of composted SS as a fertilizer and soil amendment especially in semi-arid areas. To determine the quality and agronomic value of the SS compost products, analyses on pH, electrical conductivity, organic matter content, C/N ratio, phytotoxicity, microbial load, and heavy metal content of composted anaerobically digested SS, with different proportions (1:1, 1:2, and 1:3 v/v) of green and dry plant waste, as bulking agents, were performed. The 1:2 and 1:3 mixtures of SS and green/dry plant waste were the most beneficial for composting, with final composts attaining high organic matter degradation and exhibiting low amounts of heavy metals, a relatively high germination index, and significant reduction of pathogens, suggesting the agricultural relevance of composted SS and green/dry plant waste at 1:2 and 1:3 (v/v) proportions. pH and electrical conductivity were also within the permissible limits. With respect to international standards, it appears that composted SS and green/dry plant waste at 1:2 and 1:3 proportions pose no threat to soil or plant quality if used in agriculture or land restoration. PMID- 26508020 TI - Potential involvement of NET polymorphism in serotonin/norepinephrine reuptake inhibitor response in panic disorder. AB - BACKGROUND: This is a pilot study assessing the impact of polymorphisms of serotonin transporter (5-HTT; 5-HTTLPR (S/L)) and norepinephrine transporter (NET; rs2242446 (T/C)) genes on selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) response in Korean panic disorder (PD) patients. METHODS: PD patients were treated with SSRI (n = 18) or SNRI (n = 6) for 4 weeks. Panic Disorder Severity Scale (PDSS) was rated to evaluate the treatment response. Wilcoxon signed-rank test was used to compare PDSS scores before and after medication (SSRI or SNRI) as well as to compare those according to genotypes. Mann-Whitney U test was used to compare those between the two groups (SSRI or SNRI). RESULTS: Both SSRI and SNRI treatments for 4 weeks significantly reduced PDSS scores. We assessed the impact of rs2242446 on this effect of SSRI and SNRI. The scores were significantly decreased after 4 weeks in the SSRI-treated group regardless of genotypes of rs2242446, whereas they were significantly decreased in the SNRI-treated group with only non-C carrier (TT) of rs2242446. On 5-HTTLPR we could not analyse because 22 patients had SS genotype. CONCLUSIONS: These results suggest that NET polymorphism may affect the SNRI response in Korean PD patients. PMID- 26508021 TI - Expression of cholecystokinin receptors in colon cancer and the clinical correlation in Taiwan. AB - Cholecystokinin and gastrin receptors are upregulated in many human digestive malignancies; however, the correlation of their expressions with severity of colon carcinoma remains sketchy. Here, we determined the expression of cholecystokinin-1 and cholecystokinin-2 receptor, CCK1R and CCK2R, in colon carcinomas and investigated their correlations with clinicopathological characteristics and 1-year survival rate. Expression of CCK1R and CCK2R was determined by immunohistochemical assay in tissue samples obtained from 97 surgical specimens. Clinicopathological character analysis revealed that higher expression of cytoplasmic CCK1R and CCK2R was significantly associated with several variables including the depth of tumor invasion (P = 0.001), venous invasion (P = 0.023), and progression stage (P = 0.013). In addition, immunohistochemical staining revealed statistically significant associations of nuclear CCK1R expression with higher lymphatic invasion (P = 0.042), progression stage (P = 0.025), and unfavorable survival (P = 0.025). Interestingly, we found no link between nuclear CCK2R expression and all the clinicopathological characteristics examined. Taken these, our findings indicate that nuclear CCK1R represents a potential biomarker for poor prognosis, and CCK1R may play a role differing from CCK2R in colon carcinogenesis. PMID- 26508022 TI - Novel MicroRNA signatures in HPV-mediated cervical carcinogenesis in Indian women. AB - This study aimed to investigate the role of miRNAs in HPV-mediated cervical pre cancer and cancer cases in Indian population. We analysed the HPV infection and its genotypes in uterine cervical pre-cancer (n = 80), cancer (n = 200) and normal cervical samples (n = 150) by consensus sequence PCR followed by type specific PCRs. Also, microRNA profiling was done in a subset of cervical pre cancer (n = 20), cancer cases (n = 50) and normal samples (n = 30) by real-time quantitative PCR (qRT-PCR). The prevalence of HPV infection in pre-cancer was found to be 81 % (65/80) and 94 % (188/200) in cancer cases, with most predominant high-risk HPV type-16 (HR-HPV-16) in 83 % of cancer and 91 % of pre- cancer cases, respectively. Whereas in controls, the HPV infection was found to be very low (5 %). The miRNA profiling revealed that in cervical pre-cancer, 100 miRNAs were significantly (p < 0.001) differentially expressed with 70 miRNAs upregulated and 30 miRNAs downregulated. In cervical cancer cases, 383 miRNA were found to be differentially expressed (p < 0.001), of which 350 miRNAs were upregulated and 33 miRNAs were downregulated. We also observed that 182 miRNAs were differentially expressed (p < 0.001) in HPV-16/18-positive (SiHa/HeLa) cell lines compared with HPV-negative (C33A) cell line. In addition, we identified the novel microRNAs such as miR-892b, miR-500, miR-888, miR-505 and miR-711 in cervical precancerous lesions and cervical cancer cases in Indian population. Taken together, the study demonstrates a crucial role of microRNAs in cervical cancer, which may serve as potential early diagnostic markers for cervical carcinogenesis. PMID- 26508023 TI - SATB2 suppresses gastric cancer cell proliferation and migration. AB - Gastric cancer is one of the death-related malignant tumors worldwide. It remains a challenge for the diagnosis and treatment of gastric cancer. Special AT-rich sequence-binding protein 2 (SATB2) is a new tumor suppressive gene and plays important roles in many cancers. However, the role of SATB2 in gastric cancer is still unknown. In the present study, we demonstrated that downregulation of SATB2 was associated with shortened survival in patients with gastric cancer. Ectopic expression of SATB2 inhibited gastric cancer cell proliferation, colony formation, and migration. Overexpression of SATB2 repressed the expression of extracellular signal-regulated kinase 5 (ERK5), and activation of ERK5 restored the SATB2-induced inhibition of proliferation and migration in gastric cancer. This study provided evidence that SATB2 acted as a tumor suppressive gene gastric cancer, serving as a potential therapeutic target. PMID- 26508024 TI - Epigenetic regulation and anti-tumorigenic effects of SH2-containing protein tyrosine phosphatase 1 (SHP1) in human gastric cancer cells. AB - SH2-containing protein tyrosine phosphatase 1 (SHP1) is an important negative regulator in cytokine-mediated signal transduction and cell cycling. Recent studies have demonstrated that SHP1 promoter methylation is frequently observed in gastric adenocarcinoma tissues. In this in vitro study, we attempted to reveal promoter hypermethylation and to investigate effects of SHP1 in gastric carcinoma cell lines. We observed that both gene and protein expression of SHP1 were negative in 8 of 10 gastric cancer cell lines (SNU-1, SNU-5, SNU-16, SNU-638, SNU 719, MKN-28, MKN-45, AGS). Methylation-specific PCR (MSP) showed a methylation specific band only in the 10 gastric cancer lines. Bisulfite pyrosequencing in AGS, MKN-28, and SNU-719 cells indicated that methylation frequency was as high as 94.4, 92.6, and 94.5 %, respectively, in the three cell lines. Treatment of SNU-719, MKN-28, and AGS cells with 5-Aza-2'-deoxycytidine (5-Aza-dc) led to re expression of SHP1 in these cells. Introduction of exogenous SHP1 in SNU-719 and MKN-28 cells by transient transfection substantially downregulated protein expression of constitutive phosphor-Janus kinase 2 (JAK2) (tyrosine 1007/1008) and phosphor-signal transducers and activators of transcription 3 (STAT3) (tyrosine 705), which in turn decreased expression of STAT3 target genes including those encoding cyclin D1, MMP-9, VEGF-1, and survivin. Induction of SHP1 significantly inhibited cell proliferation, migration and invasion in SNU 719 and MKN-28 cells. Taken together, epigenetic silencing of SHP1 is frequently caused by promoter hypermethylation in gastric carcinoma cells. Overexpression of SHP1 downregulates the JAK2/STAT3 pathway to modulate various target genes and inhibit cell proliferation, migration, and invasion in gastric cancer cells. PMID- 26508025 TI - Prognostic value of preoperative lymphocyte to monocyte ratio in patients with nonmetastatic clear cell renal cell carcinoma. AB - Growing evidence indicates that systemic inflammation involves in cancer development and progression. Preoperative lymphocyte to monocyte ratio (LMR) has been estimated as an independent prognostic factor of various cancers. We investigated the prognostic value of LMR in nonmetastatic clear cell renal cell carcinoma (ccRCC) patients after surgery. We retrospectively recruited 430 consecutive patients with nonmetastatic ccRCC (T1-3N0M0) who underwent curative nephrectomy between 2008 and 2009 at a single center in China. Lymphocyte and monocyte counts were obtained at hospitalization before surgery. Preoperative LMR as a continuous variable and as a dichotomized variable at a level of 3.25, which was the 25th percentile value, were analyzed in unvariable and multivariable Cox regression models, respectively. Concordance index (C-index) was calculated to assess predictive accuracy. Kaplan-Meier method was applied to compare survival curves. As both of the continuous and dichotomized variable, decreased preoperative LMR was proven to be independent prognostic factors of recurrence free survival (P = 0.039 and P = 0.003, respectively) and overall survival (P = 0.002 and P < 0.001, respectively). Further examination revealed that the dichotomized LMR could enhance the predictive accuracy of each of the existing prognostic models among intermediate-risk to high-risk patients. The preoperative LMR is an independent prognostic factor of recurrence-free survival and overall survival for nonmetastatic ccRCC patients after surgery, and it can be used in tandem with established prognostic systems to further enhance outcome prediction in intermediate-risk to high-risk patients. PMID- 26508026 TI - Evaluation and screening of mRNA S100A genes as serological biomarkers in different stages of bladder cancer in Egypt. AB - Calcium-binding proteins S100A are multifunctional proteins that show altered expression in various diseases and cancers. This study aimed at validating an easier and less time-consuming technique to evaluate the value of combined use of messenger RNA (mRNA) S100A genes in comparison and combination with voided urine cytology in detection of bladder cancer patients. Blood and urine specimens were collected from patients (n = 120) with histologically confirmed bladder carcinoma who are classified according to bladder cancer stage into four groups and from healthy volunteers (n = 30). Histopathology examination, bilharzias antibody detection, urine cytology, and mRNA expression of S100A genes were estimated for all subjects by real time polymerase chain reaction (RT-PCR). Results indicate that each of the investigated S100A genes can be used as diagnostic marker for bladder cancer. Both S100A4 and S100A6 can be used to differentiate between different stages of bladder cancer. S100A7 can be used for the diagnosis of squamous cell carcinoma. Both S100A8 and S100A9 can be used for detection of invasive bladder carcinoma while S100A11 can be used for early detection of superficial bladder carcinoma. The overall sensitivity and specificity for the studied S100A genes ranged from 73 to 90 and 84 to 92, respectively. The combined use of urine cytology with the investigated S100A genes increased sensitivity from 56 % up to a range of 87-96 %. In conclusion, serum S100A genes can be useful as potential serological biomarkers for bladder cancer, and combined use of urine cytology with S100A genes can improve the sensitivity for detection of bladder cancer. PMID- 26508027 TI - Genetic landscape of recurrent ASXL1, U2AF1, SF3B1, SRSF2, and EZH2 mutations in 304 Chinese patients with myelodysplastic syndromes. AB - We determined the biological and prognostic significance of five recurrent genetic aberrations in Chinese patients with myelodysplastic syndromes (MDS). A total of 304 Chinese MDS patients were screened for known mutations in five genes (ASXL1, U2AF1, SF3B1, SRSF2, and EZH2) using next-generation sequencing. Of these, 97 patients (31.9 %) harbored at least one mutation in the five genes, and patients harboring these mutations had distinct clinical features. Incidence ratios for mutations in ASXL1, U2AF1, SF3B1, SRSF2, and EZH2 were 11.8, 8.6, 8.2, 4.3, and 3.6 %, respectively. Patients with U2AF1, SRSF2, and EZH2 mutations more commonly had high-risk than low-risk subtypes, while SF3B1 mutations were frequently confirmed in MDS subtypes with increased ring sideroblasts. Cases with ASXL1 mutations had a higher percentage of complex karyotypes, while U2AF1 mutations were more common in patients with trisomy 8 or 20q deletions. Notably, among 124 patients with a normal karyotype, 48 (38.7 %) had at least one mutation. Patients with U2AF1 or SRSF2 mutations had significantly shorter overall survival (OS) times compared with patients without these mutations (U2AF1 mutations: median OS, 18 vs 54 months, p = 0.032; SRSF2 mutations: median OS 11 vs 54 months, p = 0.005, respectively). Multivariate analysis showed that the presence of SRSF2 mutations was an independent unfavorable prognostic factor for OS (hazard ratio 2.039; 95 % confidence interval 1.040-4.000; p = 0.038). These data suggest that mutations in epigenetic modification and splicesome genes are common in Chinese patients with MDS, while mutations in U2AF1 and SRSF2 appear to predict an unfavorable prognosis. PMID- 26508028 TI - The upregulation of miRNA-146a inhibited biological behaviors of ESCC through inhibition of IRS2. AB - In recent years, microRNAs, also called as miRNAs, play an important role in carcinogenesis, and the dysregulation of miRNAs is closely associated with cancer progression. Till now, little has been known about the role of miRNA-146a in the esophageal squamous cell carcinomas (ESCC). In the present study, we used in vitro assays to investigate the mechanisms of miRNA-146a in ESCC cell lines and 60 ESCC tissues. Here, we found that miRNA-146a expression is downregulated in both ESCC cell lines and tissues and obviously associated with pathological indicators, such as metastasis and stage of ESCC. In addition, the overexpression of miRNA-146a suppressed EC109 and TE8 cell proliferation and invasion. Meanwhile, miRNA-146a overexpression extremely inhibited the protein expression of insulin receptor substrate 2 (IRS2). Notably, the enforced expression of IRS2 in EC109 cells with miRNA-146a overexpression attenuated the inhibitory effects of miRNA-146a. In conclusion, our findings suggest that miRNA-146a may function as a useful clinical tool in the treatment and diagnosis of ESCC, and its overexpression suppressed cell growth through inhibition of IRS2. Thus, miRNA 146a pathway may be recommended as potential makers for drug design. PMID- 26508029 TI - Overexpression of OCT4 contributes to progression of hepatocellular carcinoma. AB - The abnormal change of octamer transcription factor 4 (OCT4) is associated with tumor progression; however, its effect on hepatocellular carcinoma (HCC) behavior remains unclear. The purpose of this study was to determine the correlation between HCC and OCT4. In the present study, IHC, western blot analysis, and QRT PCR were performed to identify differentially expressed OCT4 in a series of HCC tissues and adjacent non-cancerous tissues. In addition, the functions of OCT4 on HCC progression were studied in vitro. Silencing of OCT4 with siRNA was performed in HCC cell lines, and the impact on proliferation, migration, and the EMT marker of HCC was analyzed. Our results found that OCT4 levels were significantly higher in HCC tissues compared with the adjacent non-cancerous tissues. Furthermore, OCT4 siRNA significantly reduced the proliferation rate of SMMC-7721 and HepG2 cells, inhibited the migration and inversion, and could reverse EMT in HCC cells, indicating that OCT4 plays a critical role in HCC progression. Our data suggest that the pathogenesis of human HCC may be mediated by OCT4, and thus, OCT4 could represent selective targets for the molecularly targeted treatments of HCC. PMID- 26508030 TI - Overexpression of HPV16 E6/E7 mediated HIF-1alpha upregulation of GLUT1 expression in lung cancer cells. AB - High-risk human papillomavirus (HPV) infection may play an important role in non small cell lung carcinoma (NSCLC) development. However, some recent studies have proved that it was not directly associated with lung cancer. The aim of this study was to evaluate the underlying molecular mechanism that HPV16 regulate the expression of GLUT1 and may promote the development of lung cancer. HPV16, HIF 1alpha, and GLUT1 were detected in pleural effusions of patients with lung cancer (n = 95) and with benign lung disease (n = 55) by immunocytochemistry. Western blotting and qRT-PCR were used to detect the expression chances of HPV16 E6/E7, HIF-1alpha, and GLUT1 in lung cancer cells. HPV16, HIF-1alpha, and GLUT1 were significantly more likely to be expressed in the malignant group than in the benign group as detected by immunocytochemistry (ICC), and HIF-1alpha was significantly correlated with HPV16 or GLUT1 in the malignant group (P < 0.01). Expression changes of E6 and E7 significantly promoted the protein expression of HIF-1alpha, the expression of both protein and mRNA of GLUT1, but had no effect on the expression of HIF-1alpha mRNA in lung cancer cells. After inhibition of HIF-1alpha, it obviously downregulated the expression of both protein and mRNA of GLUT1 in lung cancer cells. E6 and E7 regulated the expression of GLUT1 may be due to the mediation of HIF-1alpha in lung cancer cells. These results suggest that both E6 and E7 play the important role in the regulation of Warburg effect and may be a valuable therapeutic target for HPV-related cancer. PMID- 26508032 TI - An integrative taxonomic study reveals a new species of Tylodelphys Diesing, 1950 (Digenea: Diplostomidae) in central and northern Mexico. AB - Tylodelphys aztecae n. sp. (Digenea: Diplostomidae) is described from adult specimens obtained from the intestine of the pied-billed grebe (Podilymbus podiceps) and the metacercariae found in the body cavity of freshwater fishes of the families Goodeidae and Cyprinidae in eight localities across central and northern Mexico. The new species is mainly distinguished from the other four described species of Tylodelphys from the Americas (T. adulta, T. americana, T. elongata and T. brevis) by having a forebody slightly concave, a larger ventral sucker, two larger pseudosuckers and by having between 2 and 7 eggs in the uterus. Partial DNA sequences of the mitochondrial gene cytochrome c oxidase subunit I (cox1), and the internal transcribed spacers (ITS1+5.8S+ ITS2) of the ribosomal DNA, were generated for both developmental stages and compared with available sequences in GenBank of other congeners. The genetic divergence estimated among Tylodelphys aztecae n. sp. and other congeneric species varied from 12 to 15% for cox1, and from 3 to 11% for ITS. In contrast, the genetic divergence among metacercariae and adults of the new species was very low, ranging between 0 and 1% for cox1 and between 0 and 0.3% for ITS. Phylogenetic analyses inferred with both molecular markers using maximum likelihood and Bayesian inference placed the adults and their metacercariae in a single clade, confirming that both stages are conspecific. The morphological evidence and the genetic divergence, in combination with the reciprocal monophyly in both phylogenetic trees, support the hypothesis that the diplostomids found in the intestines of the pied-billed grebe bird and the body cavity from goodeid and cyprinid fishes in central and northern Mexico represent a new species. PMID- 26508031 TI - Esculetin, a natural coumarin compound, evokes Ca(2+) movement and activation of Ca(2+)-associated mitochondrial apoptotic pathways that involved cell cycle arrest in ZR-75-1 human breast cancer cells. AB - Esculetin (6,7-dihydroxycoumarin), a derivative of coumarin compound, is found in traditional medicinal herbs. It has been shown that esculetin triggers diverse cellular signal transduction pathways leading to regulation of physiology in different models. However, whether esculetin affects Ca(2+) homeostasis in breast cancer cells has not been explored. This study examined the underlying mechanism of cytotoxicity induced by esculetin and established the relationship between Ca(2+) signaling and cytotoxicity in human breast cancer cells. The results showed that esculetin induced concentration-dependent rises in the intracellular Ca(2+) concentration ([Ca(2+)]i) in ZR-75-1 (but not in MCF-7 and MDA-MB-231) human breast cancer cells. In ZR-75-1 cells, this Ca(2+) signal response was reduced by removing extracellular Ca(2+) and was inhibited by the store-operated Ca(2+) channel blocker 2-aminoethoxydiphenyl borate (2-APB). In Ca(2+)-free medium, pre-treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) abolished esculetin-induced [Ca(2+)]i rises. Conversely, incubation with esculetin abolished TG-induced [Ca(2+)]i rises. Esculetin induced cytotoxicity that involved apoptosis, as supported by the reduction of mitochondrial membrane potential and the release of cytochrome c and the proteolytic activation of caspase-9/caspase-3, which were partially reversed by pre-chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N' tetraacetic acid-acetoxymethyl ester (BAPTA-AM). Moreover, esculetin increased the percentage of cells in G2/M phase and regulated the expressions of p53, p21, CDK1, and cyclin B1. Together, in ZR-75-1 cells, esculetin induced [Ca(2+)]i rises by releasing Ca(2+) from the ER and causing Ca(2+) influx through 2-APB sensitive store-operated Ca(2+) entry. Furthermore, esculetin activated Ca(2+) associated mitochondrial apoptotic pathways that involved G2/M cell cycle arrest. Graphical abstract The summary of esculetin-evoked [Ca(2+)]i rises and -activated Ca(2+)-associated mitochondrial apoptotic pathways that involved cell cycle arrest. The natural coumarin derivative esculetin caused Ca(2+) influx via 2-APB sensitive store-operated Ca(2+) entry and induced Ca(2+) release from the endoplasmic reticulum. Moreover, esculetin activated the mitochondrial pathway of apoptosis in a Ca(2+)-associated manner that involved G2/M arrest. PMID- 26508033 TI - Exploring the life-saving potential of naloxone: A systematic review and descriptive meta-analysis of take home naloxone (THN) programmes for opioid users. AB - BACKGROUND: The epidemic of drug-related mortality continues to endure. The most common cause of death associated with drugs is overdose and opioids are consistently the substances most prominently involved. As well as efforts to control the availability of illicit drugs and increase engagement in treatment services, the use of naloxone for peer administration has increasingly been championed as a mechanism for addressing the DRD epidemic. Despite increasing adoption and use of take-home naloxone (THN) as a primary response to DRD internationally the evidence base remains limited. METHODS: A systematic review and descriptive meta-analysis of the international THN literature was undertaken to determine an effect size for THN programmes. For each study, a proportion of use (PoU) was calculated using the number of 'peer administered uses' and the 'total number of participant/clients' trained and supplied with naloxone with a specific focus on people who use drugs (PWUD). This was constrained to a three month period as the lowest common denominator. As a percentage this gives the three month rate of use (per 100 participants). RESULTS: From twenty-five identified THN evaluations, nine studies allowed a PoU to be determined. Overall, the model shows a range of 5.2-13.1 (point estimate 9.2) naloxone uses every three months for every 100 PWUD trained. CONCLUSION: Our model estimates that around 9% of naloxone kits distributed are likely to be used for peer administration within the first three months of supply for every 100 PWUD trained. Future evaluations should directly compare different training structures to test relative effectiveness and use a series of fixed time periods (3, 6 and 12 months) to determine whether time since training affects rate of naloxone use. PMID- 26508034 TI - Antimicrobial flavonoids isolated from Indian medicinal plant Scutellaria oblonga inhibit biofilms formed by common food pathogens. AB - Scutellaria oblonga Benth., a hitherto phytochemically unexplored Indian medicinal folklore plant was extracted with acetone and subjected to chromatography to yield nine flavonoids, for the first time from this plant. Antimicrobial assays were performed against 11 foodborne pathogens, and three molecules (Techtochrysin, Negletein and Quercitin-3-glucoside) depicted significant activity. These molecules were assessed for their rate of antibacterial action using time-kill curves which depicted complete inhibition of most of the bacteria within 12-16 h. The significant biofilm-reducing capability exhibited by these three molecules formed a significant finding of the current study. In most of the experiments, a 90-95% reduction in biofilms was observed. Thus, flavonoids as natural molecules from S. oblonga could be further researched to be used as potent antimicrobial and antibiofilm agents. PMID- 26508035 TI - Ethical principles for novel therapies in veterinary practice. AB - OBJECTIVES: To present insights to aid decision-making about novel veterinary treatments from regulations concerning animal experimentation and human clinical medical trials. MATERIALS AND METHODS: EU Directive 2010/63/EU on the protection of animals used for scientific purposes and EU Regulation 536/2014 on clinical trials on medicinal products for human use were analysed, evaluated and "translated" into relevant principles for veterinary surgeons. RESULTS: A number of principles are relevant, relating to treatment expectations, thresholds and objectives; client consent; minimising harms; personnel; review committees; assessment and publication. CLINICAL SIGNIFICANCE: These principles should assist veterinary surgeons to make good ethical decisions about novel treatments. PMID- 26508036 TI - Dynamic atomic contributions to infrared intensities of fundamental bands. AB - Dynamic atomic intensity contributions to fundamental infrared intensities are defined as the scalar products of dipole moment derivative vectors for atomic displacements and the total dipole derivative vector of the normal mode. Intensities of functional group vibrations of the fluorochloromethanes can be estimated within 6.5 km mol(-1) by displacing only the functional group atoms rather than all the atoms in the molecules. The asymmetric CF2 stretching intensity, calculated to be 126.5 km mol(-1) higher than the symmetric one, is accounted for by an 81.7 km mol(-1) difference owing to the carbon atom displacement and 40.6 km mol(-1) for both fluorine displacements. Within the Quantum Theory of Atoms in Molecules (QTAIM) model differences in atomic polarizations are found to be the most important for explaining the difference in these carbon dynamic intensity contributions. Carbon atom displacements almost completely account for the differences in the symmetric and asymmetric CCl2 stretching intensities of dichloromethane, 103.9 of the total calculated value of 105.2 km mol(-1). Contrary to that found for the CF2 vibrations intramolecular charge transfer provoked by the carbon atom displacement almost exclusively explains this difference. The very similar intensity values of the symmetric and asymmetric CH2 stretching intensities in CH2F2 arise from nearly equal carbon and hydrogen atom contributions for these vibrations. All atomic contributions to the intensities for these vibrations in CH2Cl2 are very small. Sums of dynamic contributions of the individual intensities for all vibrational modes of the molecule are shown to be equal to mass weighted atomic effective charges that can be determined from atomic polar tensors evaluated from experimental infrared intensities and frequencies. Dynamic contributions for individual intensities can also be determined solely from experimental data. PMID- 26508037 TI - Cryosurgery/cryoablation in musculoskeletal neoplasms: history and state of the art. AB - The field of cryosurgery began nearly 40 years ago with the open application of liquid nitrogen to ablate tumors. Recent developments in imaging and cryoprobe technology allow for percutaneous ablation of tumors. Computed tomography (CT) guided cryoablation has particular use in treating musculoskeletal neoplasms because of the ability to image the lethal ice zone around both bone and soft tissue structures. This manuscript will review the development, indications, and results of cryoablation as applied to musculoskeletal neoplasms. This technique holds promise for the treatment of benign conditions as well as the palliation and durable treatment of musculoskeletal metastases; it is not commonly indicated in the curative treatment of primary malignant bone or soft tissue sarcomas. PMID- 26508038 TI - Influx of multidrug-resistant organisms by country-to-country transfer of patients. AB - BACKGROUND: Multidrug-resistant organisms (MDRO) are a worldwide problem. International migration and travel facilitate the spread of MDRO. Therefore the goal of our study was to assess the risk of influx of MDRO from patients transferred to one of Central Europe's largest hospitals from abroad. METHODS: A mono-centre study was conducted. All patients transferred from other countries were screened; additional data was collected on comorbidities, etc. Presence of carbapenemases of multidrug-resistant Gram-negatives was confirmed by PCR. The association between length of stay, being colonized and/or infected by a MDRO, country of origin, diagnosis and other factors was assessed by binomial regression analyses. RESULTS: From 2012 to 2013, one fifth of all patients were colonized with MDRO (Methicillin-resistant Staphylococcus aureus [4.1 %], Vancomycin-resistant Enterococci [2.9 %], multidrug-resistant Gram-negatives [12.8 %] and extensively drug-resistant Gram-negatives [3.4 %]). The Gram negatives carried a variety of carbapenemases including OXA, VIM, KPC and NDM. The length of stay was significantly prolonged by 77.2 % in patients colonized with a MDRO, compared to those not colonized (p<0.0001). CONCLUSIONS: Country-to Country transfer of patients to European hospitals represents a high risk of introduction of MDRO and infection control specialists should endorse containment and screening measures. PMID- 26508039 TI - Sex-specific and race/ethnicity-specific disparities in cholangiocarcinoma incidence and prevalence in the USA: An updated analysis of the 2000-2011 Surveillance, Epidemiology and End Results registry. AB - AIM: Cholangiocarcinoma (CCA) is an uncommon but lethal malignancy with an increasing worldwide incidence of intrahepatic cholangiocarcinoma (ICC), but decreasing incidence of extrahepatic cholangiocarcinoma (ECC). To evaluate age specific, sex-specific, race/ethnicity-specific variations in CCA incidence in the USA. METHODS: Using population-based cancer registry data from the 2000-2011 Surveillance, Epidemiology and End Results registry, we retrospectively evaluated age-specific, sex-specific, race/ethnicity-specific variations in incidence and prevalence of CCA stratified by ICC and ECC subtypes among adults in the USA. RESULTS: A total of 11 296 patients with ICC and 8672 patients with ECC were identified. ICC incidence was significantly higher than ECC incidence (1.6 vs 1.3 per 100 000/year, P < 0.01). Among all race/ethnic groups and among both ICC and ECC, Asians had the highest cancer incidence. When stratified by age, CCA incidence increased with age among all groups; however, the rising incidence was most rapid among Asians. For example, among patients aged 80 years and over, the incidence of ICC among Asians was nearly twice the incidence among non-Hispanic whites (13.8 vs 7.2 per 100 000/year). Overall, CCA incidence was higher among men compared with women, and with increasing age, this sex-specific disparity was more pronounced. For example, among patients aged 80 years and over, the incidence of ICC was 9.8 per 100 000/year among men and 6.9 per 100 000/year among women. CONCLUSION: Among adults with CCA in the USA, increasing age was associated with increasing incidence of CCA. In addition, sex-specific and race/ethnicity-specific disparities were seen with the highest incidence of CCA among men and among Asians. PMID- 26508040 TI - Retrospective analysis evaluating the effect of a keratolytic and physical pretreatment with salicylic acid, urea and curettage on the efficacy and safety of photodynamic therapy of actinic keratoses with methylaminolaevulinate. AB - BACKGROUND: Photodynamic therapy (PDT) is a highly effective treatment option for actinic keratosis (AK). Hyperkeratosis of the AK impairs penetration of the photosensitizer and light and leads to a reduced efficacy of PDT. Therefore, it is commonly recommended to perform curettage of the AK prior to treatment. OBJECTIVE: This observational, monocentric, retrospective study sets out to compare the effects of curettage (CUR), chemical keratolytic pretreatment with salicylic acid 10% (SA), and urea cream 40% (UR) on the efficacy and tolerability of PDT. METHOD: A total of 44 subjects aged 73.2 +/- 7.7 years (mean +/- SD) with multiple AKs (mean 11.1 per patient) in face and scalp were analysed. In 15 patients, CUR was performed prior to PDT while 15 and 14 patients underwent keratolytic pretreatment with SA and UR, respectively, 1 day prior to PDT. All patients underwent one session of methylaminolaevulinate (MAL) PDT using a 630-nm LED lamp at 37 J/cm(2) , pain was measured using a visual analogue scale. The response rate was calculated using the documented number of AKs prior and 4 weeks after PDT. RESULTS: Mean lesion response rates were 68.5%, 61.4% and 60.8% for CUR, SA and UR respectively. Differences were not significant. Patients with SA or UR experienced significantly more pain (SA: 6.3 +/- 2.7, P = 0.02; UR: 6.1 +/- 1.8, P = 0.04) than patients with curettage (4.4 +/- 2.1). The cosmetic result and the patients' satisfaction 4 weeks after PDT were good to excellent in all three groups without a significant difference. However, pretreatment with SA or UR led to pronounced local reactions compared to CUR. CONCLUSION: Keratolytic therapy with SA or UR is an effective pretreatment for PDT. However, it leads to an increase in pain during PDT and pronounced local reactions. PMID- 26508041 TI - Metal elements in tissue with dental peri-implantitis: a pilot study. AB - OBJECTIVES: Dental peri-implantitis is characterized by a multifactorial etiology. The role of metal elements as an etiological factor for peri implantitis is still unclear. The aim of this study was to investigate the incidence of metal elements in bone and mucosal tissues around dental Grade 4 CP titanium implants with signs of peri-implantitis in human patients. METHODS: In this prospective pilot study, all patients were enrolled consecutively in two study centers. Bone and soft tissue samples of patients with peri-implantitis with indication for explantation were analyzed for the incidence of different elements (Ca, P, Ti, Fe) by means of synchrotron radiation X-ray fluorescence spectroscopy (SRXRF) and polarized light microscopy (PLM). The existence of macrophages and lymphocytes in the histologic specimens was analyzed. RESULTS: Biopsies of 12 patients (seven bone samples, five mucosal samples) were included and analyzed. In nine of the 12 samples (75%), the SRXRF examination revealed the existence of titanium (Ti) and an associated occurrence with Iron (Fe). Metal particles were detected in peri-implant soft tissue using PLM. In samples with increased titanium concentration, lymphocytes were detected, whereas M1 macrophages were predominantly seen in samples with metal particles. CONCLUSION: Titanium and Iron elements were found in soft and hard tissue biopsies retrieved from peri-implantitis sites. Further histologic and immunohistochemical studies need to clarify which specific immune reaction metal elements/particles induce in dental peri-implant tissue. PMID- 26508042 TI - Microfluidic devices in diagnostics: what does the future hold? PMID- 26508044 TI - Who will you nominate? PMID- 26508045 TI - Pay Review Body data show nurses are on the brink of quitting. PMID- 26508046 TI - Government says that 90% of nursing time should be at bedsides. PMID- 26508048 TI - Heartfelt comments on hospital ward's feedback wall are 'better than chocolates'. PMID- 26508049 TI - Experts highlight six issues to ensure workplace safety. PMID- 26508050 TI - CNO to unveil draft plans at summit next month. PMID- 26508051 TI - New 'vanguards' to bring hospitals together. PMID- 26508052 TI - Giving sorrow words. PMID- 26508060 TI - Vantage point--Refugee response. PMID- 26508061 TI - A workforce for the future. PMID- 26508062 TI - Rewarding experience. PMID- 26508069 TI - Introducing students to clinical audit. AB - It is more than a decade since the UK Central Council for Nursing Midwifery and Health Visiting said that engaging with clinical audit is 'the business of every registered practitioner', yet there appears to be little evidence that nursing has embraced the process. To address this issue, Northampton General Hospital and the University of Northampton implemented a pilot project in which two third-year adult nursing students worked on a 'real life' audit. Supported by the hospital's audit department, and supervised by academic tutors with the relevant experience, the students worked on a pressure-ulcer care audit for their final year dissertation. This article describes the process undertaken by the hospital audit team and the university academic team to develop the pilot project and support the students. Based on the positive evaluations, the university has extended the project to a second phase, incorporating two new partner organisations. PMID- 26508070 TI - Developing from within: ensuring the ambulatory emergency care workforce is fit for purpose. AB - Emergency healthcare provision is changing, and services need to respond to evolving health economies while providing safe, effective, patient-centred care. Ambulatory care is developing to meet these needs, but workforce planners need to ensure that staff are fit for purpose. To address this, one trust, in partnership with a local university, designed a bespoke in-house, work-based learning package on ambulatory care, which was delivered to registered nurses by practice experts. This article describes the project and discusses the evaluation, which highlighted the benefits of this way of learning for the nurses, the trust and the university, and identified some areas that require development. PMID- 26508071 TI - Perceptions of managerial support after workplace violence. AB - Workplace violence against nurses perpetrated by patients is a global problem, and healthcare organisations must take steps to ensure that staff feel safe at work and supported when incidents occur. A study was undertaken in a US teaching hospital to determine nurses' perceptions of management support following violent workplace incidents. This article describes the study and reports the results, which suggest that nurses want better implementation and enforcement of anti violence policies, as well as more visible and immediate support from managers. PMID- 26508072 TI - The personal touch. PMID- 26508073 TI - Use of agave bagasse for production of an organic fertilizer by pretreatment with Bjerkandera adusta and vermicomposting with Eisenia fetida. AB - Agave tequilana Weber is used in tequila and fructans production, with agave bagasse generated as a solid waste. The main use of bagasse is to produce compost in tequila factories with a long traditional composting that lasts 6-8 months. The aim of this study was to evaluate the degradation of agave bagasse by combining a pretreatment with fungi and vermicomposting. Experiments were carried out with fractionated or whole bagasse, sterilized or not, subjecting it to a pretreatment with Bjerkandera adusta alone or combined with native fungi, or only with native bagasse fungi (non-sterilized), for 45 days. This was followed by a vermicomposting with Eisenia fetida and sewage sludge, for another 45 days. Physicochemical parameters, lignocellulose degradation, stability and maturity changes were measured. The results indicated that up to 90% of the residual sugars in bagasse were eliminated after 30 days in all treatments. The highest degradation rate in pretreatment was observed in non-sterilized, fractionated bagasse with native fungi plus B. adusta (BNFns) (71% hemicellulose, 43% cellulose and 71% lignin) at 45 days. The highest total degradation rates after vermicomposting were in fractionated bagasse pre-treated with native fungi (94% hemicellulose, 86% cellulose and 91% lignin). However, the treatment BNFns showed better maturity and stability parameters compared to that reported for traditional composts. Thus, it seems that a process involving vermicomposting and pretreatment with B. adusta could reduce the degradation time of bagasse to 3 months, compared to the traditional composting process, which requires from 6 to 8 months. PMID- 26508074 TI - Resource utilization for transfemoral transcatheter aortic valve replacement: An international comparison. AB - BACKGROUND: Transfemoral transcatheter aortic valve replacement (TF-TAVR) has enjoyed a rapid diffusion in the US and Europe, but the procedure is resource intensive. OBJECTIVES: We sought to identify differences in resource utilization between a US and European center to ascertain opportunities for improvement in the performance of TF-TAVR. METHODS: All patients undergoing TF-TAVR using the Edwards SAPIEN valve series at the San Raffaele Hospital (Milan, Italy) and the Cleveland Clinic Foundation (Cleveland, OH) between January 2011 and December 2012 were included. Resource utilization was defined as preprocedural imaging, intraprocedural imaging, and personnel present during the procedure. RESULTS: A total of 158 patients from Cleveland and 113 from Milan were analyzed. Median logistic EuroScore (22.1 vs. 15.5, P = 0.013) and STS-PROM (8.9 vs. 5.0%, P < 0.001) were higher in Cleveland. Thirty-day outcomes were similar. Majority of procedures in Milan were conducted without a cardiac surgeon (79%) or an imaging specialist (99%) present during the case. There was greater reliance on endotracheal intubation (94.3 vs. 3.5%), general anesthesia (GA: 94.3 vs. 4.4%), and intraprocedural TEE (93 vs. 12.4%) in Cleveland, but shorter length of stay (mean: 6.42 vs. 11.16 days). CONCLUSIONS: We characterized resources used for patients undergoing TF-TAVR in Cleveland and Milan. Important differences included less reliance on GA and TEE and streamlining of procedural personnel in Milan, and reduced length-of-stay in Cleveland. Evolution of TF-TAVR to involve fewer operators must be balanced with the need for ready access to a comprehensive group of specialists in case of emergencies. (c) 2015 Wiley Periodicals, Inc. PMID- 26508075 TI - Catalytic oxidation of pulping effluent by activated carbon-supported heterogeneous catalysts. AB - The present study deals with the non-catalytic and catalytic wet oxidation (CWO) for the removal of persistent organic compounds from the pulping effluent. Two activated carbon-supported heterogeneous catalysts (Cu/Ce/AC and Cu/Mn/AC) were used for CWO after characterization by the following techniques: temperature programmed reduction, Fourier transform infrared spectroscopy and thermo gravimetric analysis. The oxidation reaction was performed in a batch high pressure reactor (capacity = 0.7 L) at moderate oxidation conditions (temperature = 190 degrees C and oxygen pressure = 0.9 MPa). With Cu/Ce/AC catalyst, the maximum chemical oxygen demand (COD), total organic carbon (TOC) and lignin removals of 79%, 77% and 88% were achieved compared to only 50% removal during the non-catalytic process. The 5-day biochemical oxygen demand (BOD5) to COD ratio (a measure for biodegradability) of the pulping effluent was improved to 0.52 from an initial value of 0.16. The mass balance calculations for solid recovered after CWO reaction showed 8% and 10% deduction in catalyst mass primarily attributed to the loss of carbon and metal leaching. After the CWO process, carbon deposition was also observed on the recovered catalyst which was responsible for around 3-4% TOC reduction. PMID- 26508077 TI - Upper limb functional electrical stimulation devices and their man-machine interfaces. AB - Functional Electrical Stimulation (FES) is a technique that uses electricity to activate the nerves of a muscle that is paralysed due to hemiplegia, multiple sclerosis, Parkinson's disease or spinal cord injury (SCI). FES has been widely used to restore upper limb functions in people with hemiplegia and C5-C7 tetraplegia and has improved their ability to perform their activities of daily living (ADL). At the time of writing, a detailed literature review of the existing upper limb FES devices and their man-machine interfaces (MMI) showed that only the NESS H200 was commercially available. However, the rigid arm splint doesn't fit everyone and prevents the use of a tenodesis grip. Hence, a robust and versatile upper limb FES device that can be used by a wider group of people is required. PMID- 26508076 TI - Comparative metabolomic analysis highlights the involvement of sugars and glycerol in melatonin-mediated innate immunity against bacterial pathogen in Arabidopsis. AB - Melatonin is an important secondary messenger in plant innate immunity against the bacterial pathogen Pseudomonas syringe pv. tomato (Pst) DC3000 in the salicylic acid (SA)- and nitric oxide (NO)-dependent pathway. However, the metabolic homeostasis in melatonin-mediated innate immunity is unknown. In this study, comparative metabolomic analysis found that the endogenous levels of both soluble sugars (fructose, glucose, melibose, sucrose, maltose, galatose, tagatofuranose and turanose) and glycerol were commonly increased after both melatonin treatment and Pst DC3000 infection in Arabidopsis. Further studies showed that exogenous pre-treatment with fructose, glucose, sucrose, or glycerol increased innate immunity against Pst DC3000 infection in wild type (Col-0) Arabidopsis plants, but largely alleviated their effects on the innate immunity in SA-deficient NahG plants and NO-deficient mutants. This indicated that SA and NO are also essential for sugars and glycerol-mediated disease resistance. Moreover, exogenous fructose, glucose, sucrose and glycerol pre-treatments remarkably increased endogenous NO level, but had no significant effect on the endogenous melatonin level. Taken together, this study highlights the involvement of sugars and glycerol in melatonin-mediated innate immunity against bacterial pathogen in SA and NO-dependent pathway in Arabidopsis. PMID- 26508078 TI - Xingnaojing mPEG2000-PLA modified microemulsion for transnasal delivery: pharmacokinetic and brain-targeting evaluation. AB - Xingnaojing microemulsion (XNJ-M) administered intranasally is used for stroke treatment. In order to decrease the XNJ-M-induced mucosal irritation, XNJ-M modified by mPEG2000-PLA (XNJ-MM) were prepared in a previous work. The present work aimed to assess the impact of mPEG2000-PLA on pharmacokinetic features and brain-targeting ability of XNJ-M. The bioavailability and brain-target effects of borneol and geniposide in XNJ-M and XNJ-MM were compared in mice after intravenous (i.v.) and intranasal (i.n.) administrations. Gas chromatography, high-performance liquid chromatography, and ultra-performance liquid chromatography/tandem mass spectrometry methods were developed for the quantification of borneol and geniposide. Blood and brain samples were collected from mice at different time points after i.v. and i.n. treatments with borneol at 8.0 mg/kg, geniposide at 4.12 mg/kg. In addition, near-infrared fluorescence dye, 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide was loaded into microemulsions to evaluate the brain-targeting ability of XNJ-M and XNJ-MM by near-infrared fluorescence imaging in vivo and ex vivo. For XNJ-M and XNJ-MM, the relative brain targeted coefficients (Re) were 134.59% and 198.09% (borneol), 89.70% and 188.33% (geniposide), respectively. Besides, significant near-infrared fluorescent signal was detected in the brain after i.n. administration of microemulsions, compared with that of groups for i.v. administration. These findings indicated that mPEG2000-PLA modified microemulsion improved drug entry into blood and brain compared with normal microemulsion: the introduction of mPEG2000-PLA in microemulsion resulted in brain-targeting enhancement of both fat soluble and water-soluble drugs. These findings provide a basis for the significance of mPEG2000-PLA addition in microemulsion, defining its effects on the drugs in microemulsion. PMID- 26508079 TI - Highly Efficient Polymer-Supported Catalytic System for the Valorization of Carbon Dioxide. AB - Polydibenzo-18-crown-6 was utilized as a co-catalyst and polymeric support in combination with potassium iodide for the synthesis of cyclic carbonates from carbon dioxide and epoxides under mild and solvent-free conditions. The efficiency of this catalytic system can be easily increased by loading the polymer with KI prior to the reaction. The influence of various reaction parameters were studied thoroughly. The scope and limitation of the catalyst system was studied at 80 degrees C and 100 degrees C. A large number of terminal epoxides (14) were converted to the desired cyclic carbonates in yields up to 99%. We could successfully recover and reuse the catalyst >20 times with excellent yields up to 99%. Although, we observed that the activity gradually decreased after repetitive cycles. This decrease was attributed to KI leaching and partial degradation caused by mechanical stirring. This assumption is supported by scanning electron microscopy and energy dispersive X-ray spectroscopy. PMID- 26508080 TI - Mussel adhesion is dictated by time-regulated secretion and molecular conformation of mussel adhesive proteins. AB - Interfacial water constitutes a formidable barrier to strong surface bonding, hampering the development of water-resistant synthetic adhesives. Notwithstanding this obstacle, the Asian green mussel Perna viridis attaches firmly to underwater surfaces via a proteinaceous secretion (byssus). Extending beyond the currently known design principles of mussel adhesion, here we elucidate the precise time regulated secretion of P. viridis mussel adhesive proteins. The vanguard 3,4 dihydroxy-L-phenylalanine (Dopa)-rich protein Pvfp-5 acts as an adhesive primer, overcoming repulsive hydration forces by displacing surface-bound water and generating strong surface adhesion. Using homology modelling and molecular dynamics simulations, we find that all mussel adhesive proteins are largely unordered, with Pvfp-5 adopting a disordered structure and elongated conformation whereby all Dopa residues reside on the protein surface. Time-regulated secretion and structural disorder of mussel adhesive proteins appear essential for optimizing extended nonspecific surface interactions and byssus' assembly. Our findings reveal molecular-scale principles to help the development of wet resistant adhesives. PMID- 26508081 TI - Age-related eye disease and gender. AB - Worldwide, the prevalence of moderate to severe visual impairment and blindness is 285 millions, with 65% of visually impaired and 82% of all blind people being 50 years and older. Meta-analyses have shown that two out of three blind people are women, a gender discrepancy that holds true for both developed and developing countries. Cataract accounts for more than half of all blindness globally and gender inequity in access to cataract surgery is the major cause of the higher prevalence of blindness in women. In addition to gender differences in cataract surgical coverage, population-based studies on the prevalence of lens opacities indicate that women have a higher risk of developing cataract. Laboratory as well as epidemiologic studies suggest that estrogen may confer antioxidative protection against cataractogenesis, but the withdrawal effect of estrogen in menopause leads to increased risk of cataract in women. For the other major age related eye diseases; glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy, data are inconclusive. Due to anatomic factors, angle closure glaucoma is more common in women, whereas the dominating glaucoma type; primary open-angle glaucoma (POAG), is more prevalent in men. Diabetic retinopathy also has a male predominance and vascular/circulatory factors have been implied both in diabetic retinopathy and in POAG. For AMD, data on gender differences are conflicting although some studies indicate increased prevalence of drusen and neovascular AMD in women. To conclude, both biologic and socioeconomic factors must be considered when investigating causes of gender differences in the prevalence of age-related eye disease. PMID- 26508082 TI - Increase in circulating sclerostin at the early stage of menopausal transition in Japanese women. AB - OBJECTIVE: We examined the change in circulating sclerostin level during the menopausal transition and we investigated the associations of sclerositin with hormones and bone turnover markers according to each menopausal stage in cross sectional and longitudinal studies. METHODS: We conducted a cross-sectional study in 200 healthy Japanese women and divided them into 4 stages (reproductive, menopausal transition, early postmenopause and late postmenopause) by menstrual regularity, follicle-stimulating hormone level and years since menopause. Serum levels of sclerostin, bone turnover markers and reproductive hormones were measured. In addition, we examined changes in sclerostin level from the reproductive stage to menopausal transition and from menopausal transition to early postmenopause in a longitudinal study. RESULTS: In the cross-sectional study, sclerostin level gradually increased with progression of menopausal stages and showed a significant change during the menopausal transition. Sclerostin levels significantly increased from the reproductive stage to menopausal transition and from menopausal transition to early postmenopause in the longitudinal study. A negative correlation of sclerostin with estradiol was found in early postmenopause. Sclerostin levels were negatively correlated with bone specific alkaline phosphatase levels in the reproductive stage and menopausal transition and with tartrate-resistant acid phosphatase-5b in menopausal transition. CONCLUSION: The change in sclerostin has already occurred in the early stage of menopausal transition and sclerostin level increases with progression of menopausal stages. Elevated sclerostin levels during the menopausal transition may be involved in relative decline in bone formation against increase in bone resorption. PMID- 26508083 TI - Electron Density Analysis of Hyperconjugation. AB - Hyperconjugation is analyzed through the electron density of orbitals responsible for hyperconjugative interactions, which cannot be detected by means of conventional electron-density-based calculations. This interaction is detected through the pi electron density topology, by excluding sigma electron density from the total. As the presence of the hyperconjugation phenomenon in carbocation systems is well understood, several carbocations are benchmarked, and the results show that the positive carbon atom establishes a hyperconjugative critical point with the adjacent methyl group(s). Also, pi localization and delocalization indices are employed to support the conclusions made by the topological analysis. PMID- 26508084 TI - Two-dimensional transition metal dichalcogenide alloys: preparation, characterization and applications. AB - Engineering electronic structure of atomically thin two-dimensional (2D) materials is of great importance to their potential applications. In comparison to numerous other approaches, such as strain and chemical functionization, alloying can continuously tune the band gaps in a wide energy range. Atomically thin 2D alloys have been prepared and studied recently due to their potential use in electronic and optoelectronic applications. In this review, we first summarize the preparation methods of 2D alloys (mainly on transition metal dichalcogenide (TMD) monolayer alloys), including mechanical exfoliation, physical vapor deposition (PVD), chemical vapor deposition (CVD) and chalcogen exchange. Then, atomic-resolution imaging, Raman and photoluminescence (PL) spectroscopy characterization of 2D alloys are reviewed, in which band gap tuning is discussed in detail based on the PL experiments and theoretical calculations. Finally, applications of 2D alloys in field-effect transistors (FETs), photocurrent generation and hydrogen evolution catalysis are reviewed. PMID- 26508085 TI - Semi-analytical modeling of acoustic beam divergence in homogeneous anisotropic half-spaces. AB - Beam divergences of acoustical fields in semi-infinite homogeneous anisotropic media are calculated based on a semi-analytical model. The model for a plane source in a semi-infinite homogeneous anisotropic medium is proposed as an extended model for a point source in an infinite medium. Beam divergences propagating along crystallographic axes <100>, <110>, and <111> in a cubic crystal, a single crystalline Ni-based alloy, are measured and compared to calculation results for verifying the model. The contribution of beam divergence attenuation to the total attenuation for propagating in anisotropic polycrystalline materials is quantitatively evaluated in isolation from scattering attenuation effects. PMID- 26508086 TI - a-SiNx:H-based ultra-low power resistive random access memory with tunable Si dangling bond conduction paths. AB - The realization of ultra-low power Si-based resistive switching memory technology will be a milestone in the development of next generation non-volatile memory. Here we show that a high performance and ultra-low power resistive random access memory (RRAM) based on an Al/a-SiNx:H/p(+)-Si structure can be achieved by tuning the Si dangling bond conduction paths. We reveal the intrinsic relationship between the Si dangling bonds and the N/Si ratio x for the a-SiNx:H films, which ensures that the programming current can be reduced to less than 1 MUA by increasing the value of x. Theoretically calculated current-voltage (I-V) curves combined with the temperature dependence of the I-V characteristics confirm that, for the low-resistance state (LRS), the Si dangling bond conduction paths obey the trap-assisted tunneling model. In the high-resistance state (HRS), conduction is dominated by either hopping or Poole-Frenkel (P-F) processes. Our introduction of hydrogen in the a-SiNx:H layer provides a new way to control the Si dangling bond conduction paths, and thus opens up a research field for ultra-low power Si based RRAM. PMID- 26508087 TI - Specialist teams for neonatal transport to neonatal intensive care units for prevention of morbidity and mortality. AB - BACKGROUND: Maternal antenatal transfers provide better neonatal outcomes. However, there will inevitably be some infants who require acute transport to a neonatal intensive care unit (NICU). Because of this, many institutions develop services to provide neonatal transport by specially trained health personnel. However, few studies report on relevant clinical outcomes in infants requiring transport to NICU. OBJECTIVES: To determine the effects of specialist transport teams compared with non-specialist transport teams on the risk of neonatal mortality and morbidity among high-risk newborn infants requiring transport to neonatal intensive care. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 7), MEDLINE (1966 to 31 July 2015), EMBASE (1980 to 31 July 2015), CINAHL (1982 to 31 July 2015), conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: STUDY DESIGN: randomised, quasi randomised or cluster randomised controlled trials. POPULATION: neonates requiring transport to a neonatal intensive care unit. INTERVENTION: transport by a specialist team compared to a non-specialist team. OUTCOMES: any of the following outcomes - death; adverse events during transport leading to respiratory compromise; and condition on admission to the neonatal intensive care unit. DATA COLLECTION AND ANALYSIS: The methodological quality of the trials was assessed using the information provided in the studies and by personal communication with the author. Data on relevant outcomes were extracted and the effect size estimated and reported as risk ratio (RR), risk difference (RD), number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH) and mean difference (MD) for continuous outcomes. Data from cluster randomised trials were not combined for analysis. MAIN RESULTS: One trial met the inclusion criteria of this review but was considered ineligible owing to serious bias in the reporting of the results. AUTHORS' CONCLUSIONS: There is no reliable evidence from randomised trials to support or refute the effects of specialist neonatal transport teams for neonatal retrieval on infant morbidity and mortality. Cluster randomised trial study designs may be best suited to provide us with answers on effectiveness and clinical outcomes. PMID- 26508088 TI - Epigenome-Wide Association Study of Aggressive Behavior. AB - Aggressive behavior is highly heritable, while environmental influences, particularly early in life, are also important. Epigenetic mechanisms, such as DNA methylation, regulate gene expression throughout development and adulthood, and may mediate genetic and environmental effects on complex traits. We performed an epigenome-wide association study (EWAS) to identify regions in the genome where DNA methylation level is associated with aggressive behavior. Subjects took part in longitudinal survey studies from the Netherlands Twin Register (NTR) and participated in the NTR biobank project between 2004 and 2011 (N = 2,029, mean age at blood sampling = 36.4 years, SD = 12.4, females = 69.2%). Aggressive behavior was rated with the ASEBA Adult Self-Report (ASR). DNA methylation was measured in whole blood by the Illumina HM450k array. The association between aggressive behavior and DNA methylation level at 411,169 autosomal sites was tested. Association analyses in the entire cohort showed top sites at cg01792876 (chr8; 116,684,801, nearest gene = TRPS1, p = 7.6 * 10(-7), False discovery rate (FDR) = 0.18) and cg06092953 (chr18; 77,905,699, nearest gene = PARD6G-AS1, p = 9.0 *10(-7), FDR = 0.18). Next, we compared methylation levels in 20 pairs of monozygotic (MZ) twins highly discordant for aggression. Here the top sites were cg21557159 (chr 11; 107,795,699, nearest gene = RAB39, p = 5.7 * 10(-6), FDR = 0.99), cg08648367 (chr 19; 51,925,472, nearest gene = SIGLEC10, p = 7.6 * 10(-6), FDR = 0.99), and cg14212412 (chr 6; 105,918,992, nearest gene = PREP, p = 8.0 * 10(-6), FDR = 0.99). The two top hits based on the entire cohort showed the same direction of effect in discordant MZ pairs (cg01792876, P(discordant twins) = 0.09 and cg06092953, P(discordant twins) = 0.24). The other way around, two of the three most significant sites in discordant MZ pairs showed the same direction of effect in the entire cohort (cg08648367, P(entire EWAS) = 0.59 and cg14212412, P(entire EWAS) = 3.1 * 10(-3)). Gene ontology analysis highlighted significant enrichment of various central nervous system categories among higher-ranking methylation sites. Higher-ranking methylation sites also showed enrichment for DNase I hypersensitive sites and promoter regions, showing that DNA methylation in peripheral tissues is likely to be associated with aggressive behavior. PMID- 26508089 TI - Social Listening: A Content Analysis of E-Cigarette Discussions on Twitter. AB - BACKGROUND: Electronic cigarette (e-cigarette) use has increased in the United States, leading to active debate in the public health sphere regarding e cigarette use and regulation. To better understand trends in e-cigarette attitudes and behaviors, public health and communication professionals can turn to the dialogue taking place on popular social media platforms such as Twitter. OBJECTIVE: The objective of this study was to conduct a content analysis to identify key conversation trends and patterns over time using historical Twitter data. METHODS: A 5-category content analysis was conducted on a random sample of tweets chosen from all publicly available tweets sent between May 1, 2013, and April 30, 2014, that matched strategic keywords related to e-cigarettes. Relevant tweets were isolated from the random sample of approximately 10,000 tweets and classified according to sentiment, user description, genre, and theme. Descriptive analyses including univariate and bivariate associations, as well as correlation analyses were performed on all categories in order to identify patterns and trends. RESULTS: The analysis revealed an increase in e-cigarette related tweets from May 2013 through April 2014, with tweets generally being positive; 71% of the sample tweets were classified as having a positive sentiment. The top two user categories were everyday people (65%) and individuals who are part of the e-cigarette community movement (16%). These two user groups were responsible for a majority of informational (79%) and news tweets (75%), compared to reputable news sources and foundations or organizations, which combined provided 5% of informational tweets and 12% of news tweets. Personal opinion (28%), marketing (21%), and first person e-cigarette use or intent (20%) were the three most common genres of tweets, which tended to have a positive sentiment. Marketing was the most common theme (26%), and policy and government was the second most common theme (20%), with 86% of these tweets coming from everyday people and the e-cigarette community movement combined, compared to 5% of policy and government tweets coming from government, reputable news sources, and foundations or organizations combined. CONCLUSIONS: Everyday people and the e cigarette community are dominant forces across several genres and themes, warranting continued monitoring to understand trends and their implications regarding public opinion, e-cigarette use, and smoking cessation. Analyzing social media trends is a meaningful way to inform public health practitioners of current sentiments regarding e-cigarettes, and this study contributes a replicable methodology. PMID- 26508090 TI - The combinational use of dual microcatheter technique and new hypersoft helical coil for endovascular treatment of tiny intracranial aneurysm with difficult geometry. AB - The endovascular coiling of very small ruptured aneurysms with difficult geometry presents a significant treatment challenge because of potential dangerous complications, such as intraprocedural ruptures. We report our initial experience with the use of a dual microcatheter technique, combined with new hypersoft helical coils, for the treatment of these difficult lesions. Fourteen very small aneurysms with a maximum diameter of <=3 mm that presented difficult configurations, such as a wide neck or an important branch vessel arising from the fundus, were identified using digital subtraction angiography. These lesions were successfully treated using a dual microcatheter technique and new hypersoft helical coils. There were no intraprocedural ruptures or procedure-related thromboembolisms. Complete or near-complete occlusions were achieved in all of the lesions. A Raymond score of RS 1 was achieved in eight of the aneurysms (57.1%) and an RS 2 was achieved in six of the aneurysms (42.9%). The mean packing density was 35.5%. At the last post-procedure clinical follow-up, a good clinical outcome (a modified Rankin scale score of 0-2) was observed in 11 of the patients (91.7%). The result of angiographic follow up in 11 cases showed two recanalized aneurysms. The use of the dual microcatheter technique and new hypersoft helical coil allowed for stable coil framing and good packing in geometrically difficult tiny aneurysms and presented a low rate of adverse events related to the procedure. The technique provided an efficient strategy for treating very small aneurysms with difficult configurations and high risks. PMID- 26508091 TI - Endovascular glue embolization of dissecting aneurysm of type-3 accessory middle cerebral artery: A contralateral approach. AB - Pediatric intracranial aneurysms are rare with a reported prevalence of 0.5-4.6%. Likewise, anomalous arterial patterns are uncommon in the cerebral circulation. Recognition of these variations and knowledge of vascular territory forms the key to managing pathological conditions associated with these anomalous vessels. Ruptured dissecting aneurysm of type-3 accessory middle cerebral artery (aMCA) has not been reported in the pediatric age group. In addition to type-3 aMCA, the child in this case report had an ipsilateral type-1 aMCA with cortical supply. We describe the patterns of accessory MCA and their vascular territory, state the perplexity involved in deciding the best management strategy, and describe the technical approach we undertook to catheterize this small caliber recurrent artery (type-3 aMCA) originating at an acute angle from the anterior cerebral artery. PMID- 26508092 TI - CT-guided percutaneous skull biopsy using a drill-assisted system: Technical report of two cases. AB - The OnControl coaxial biopsy system (Vidacare Corporation, Shavano Park, TX) includes an inner diamond-tipped access needle and hollow biopsy needle that engage with a battery-powered hand drill. Herein, we report the use of this novel device to perform two CT-guided percutaneous skull biopsies. Both procedures were performed without complication and facilitated a pathologic diagnosis. PMID- 26508093 TI - Complementary and Alternative Medicine Use among Women of Reproductive Age in the United States. AB - BACKGROUND: The purpose of this study was to examine the prevalence of complementary and alternative medicine (CAM) use, types of CAM used, and reasons for CAM use among reproductive-age women in the United States. METHODS: Data are from the 2007 National Health Interview Survey. We examined a nationally representative sample of U.S. women ages 18 to 44 (n = 5,764 respondents). Primary outcomes were past year CAM use, reasons for CAM use, and conditions treated with CAM by pregnancy status (currently pregnant, gave birth in past year, neither). Multivariate logistic regression was used to estimate the odds of CAM use by pregnancy status. FINDINGS: Overall, 67% of reproductive-age U.S. women reported using any CAM in the past year. Excluding vitamins, 42% reported using CAM. Significant differences in use of biologically based (p = .03) and mind-body therapies (p = .012) by pregnancy status were found. Back pain (17.1%), neck pain (7.7%), and anxiety (3.7%) were the most commonly reported conditions treated with CAM among reproductive-age women. However, 20% of pregnant and postpartum women used CAM for pregnancy-related reasons, making pregnancy the most common reason for CAM use among pregnant and postpartum women. CONCLUSIONS: CAM use during the childbearing year is prevalent, with one-fifth of currently or recently pregnant women reporting CAM use for pregnancy-related reasons. Policymakers should consider how public resources may be used to support appropriate, effective use of alternative approaches to managing health during pregnancy and postpartum. Providers should be aware of the changing needs and personal health practices of reproductive age women. PMID- 26508094 TI - A randomized phase I/II study of ABT-888 in combination with temozolomide in recurrent temozolomide resistant glioblastoma: an NRG oncology RTOG group study. AB - This study tested the hypothesis that ABT-888 (velparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, can modulate temozolomide (TMZ) resistance in recurrent TMZ refractory glioblastoma patients. The combination regimen (TMZ/ABT 888) was tested using two randomized schedules (5 vs. 21 days), with 6-month progression free survival (PFS6) as the primary endpoint. The maximum tolerated dose (MTD) for TMZ using the 21 day of 28 TMZ schedule, in concert with 40 mg BID ABT-888 was determined in a phase I portion of this study, and previously reported to be 75 mg/m(2) (arm1). The MTD for ABT-888 (40 mg BID) and the 5 of 28 day TMZ (150-200 mg/m(2)) schedule was known from prior trials (arm2). Two cohorts were studied: bevacizumab (BEV) naive (n = 151), and BEV refractory (n = 74). Overall ten patients were ineligible. The incidence rate of grade 3/4 myelosuppression over all was 20.0 %. For the BEV refractory cohort, the PFS 6 was 4.4 %; for the BEV naive cohort, PFS6 was 17 %. Overall survival was similar for both arms in both the BEV naive [median survival time (MST) 10.3 M; 95 % CI 8.4-12] and BEV refractory cohort (MST 4.7 M; 95 %CI 3.5-5.6). The median PFS was essentially the same for both arms and both cohorts at ~2.0 M (95 % CI 1.9-2.1). PMID- 26508095 TI - Therapeutic potential of cyclooxygenase-3 inhibitors in the management of glioblastoma. AB - In this study we investigated the expression of COX-1, COX-2 and COX-3 mRNA in C6 glioblastoma and normal brain tissues and the effects of acetaminophen, indomethacin or metamizole treatments on the development of C6 glioblastoma in relation with COX inhibition. Glioblastoma cells were inoculated intracerebrally into frontal lobe of adult male Wistar albino rats. 10 days after inoculation, rats were treated with 150 mg/kg acetaminophen, 10 mg/kg indomethacin or 150 mg/kg metamizole. The tumor size was measured histologically and total RNA was isolated from tumor or normal brain tissue and mRNA levels of COX isoforms were determined by qRT-PCR. Our results showed the presence of COX-1, COX-2 and COX-3 expressions in both C6 glioblastoma and normal brain tissues. In tumor tissues COX-3 expression was significantly higher than normal brain tissue (p < 0.05) while there was no significant difference in COX-1 and COX-2 expressions. Acetaminophen and indomethacin decreased the tumor size by 71 and 43 % by inhibiting COX-3 mRNA expression around 87 and 91 % respectively. For the first time our study proposes a possible relationship between COX-3 mRNA expression and C6 glioblastoma development. We also suggested that the inhibition of COX-3 enzyme may be responsible for decrease in tumor size in part, the mechanism by which acetaminophen and indomethacin decreased rat C6 glioblastoma growth. However, the molecular events responsible for COX-3 effects on tumor development are still unresolved as these drugs exert their anti-cancer effect via both COX-3 dependent and independent mechanisms. PMID- 26508096 TI - M2-polarized macrophages in keratocystic odontogenic tumor: relation to tumor angiogenesis. AB - The purpose of this study was to evaluate the presence of M2-polarized macrophages and their relationships to angiogenesis in keratocystic odontogenic tumor (KCOT). M2-polarized macrophages were detected in KCOT samples by immunohistochemistry and immunofluorescence. Meanwhile, microvessel density measured with antibody against CD31 was closely correlated with the presence of M2-polarized macrophages. In addition, macrophage colony-stimulating factor (M CSF) significantly contributed to the activation of M2-polarized macrophages. Moreover, the results of in vitro wound healing, cell migration and tube formation assays further revealed the pro-angiogenic function of M2-polarized macrophage-like cells. This function might be associated with secretion of angiogenic cytokines, such as vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-beta) and matrix metalloprotein-9 (MMP-9). This study demonstrates for the first time that M2-polarized macrophages are prevalent in KCOT, and their presence is dependent on M-CSF expression. More importantly, these tumor-supportive cells can also promote tumor angiogenesis by secreting angiogenic cytokines. PMID- 26508098 TI - The effect of dual task and executive training on pattern of gait in older adults with balance impairment: A Randomized controlled trial. AB - OBJECTIVE: The purpose of this study was to compare the effect of two different approaches of dual-task training and executive training on pattern of gait in older adults with balance impairment. METHODS: Thirty older adults with the mean age of 73.8 participated in the study. They scored 52 or less on the Berg Balance Scale (BBS), and walked with a self-selected gait speed of 1.1m/s or less. Participants were randomly assigned to one of the three groups: experimental group one (cognitive dual-task (CDT) training) that focused on gait performance under dual task condition; experimental group two (executive function (EF) training) who underwent 3 types of training on working memory, inhibition, speed of processing; and a control group. Subjects walked 10 m, under single-task and dual-task (DT) conditions where kinematics parameters were recorded. Participants in experimental groups received 45-min training sessions, 3 times a week for 8 weeks. The data obtained was analyzed using repeated measure at a criterion p value of 0.05. RESULTS: The results showed that after training, changes of walking speed, length of stride and step, times of stride, step, single support, and double support, were significant at p<0.05. Asymmetry index in walking with dual task condition increased significantly, but after training asymmetry in DT condition decreased significantly in EF group. CONCLUSIONS: Both training groups showed improvements in gait parameters in the post test compared with that in the control group; however, in EF training group, symmetry of limbs and inter coordination, improved more than that in CDT group. PMID- 26508099 TI - Prevalence of metabolic syndrome among Iranian occupational drivers. AB - AIMS: Compared with other members of a society, drivers are under more periodic and constant surveillance due mainly to this fact that their type of work requires them to spend most of their times in a sedentarily position. The recent survey had done to evaluate the prevalence of Met Syn among professional drivers in northeast area of Iran. MATERIALS AND METHODS: To evaluate the prevalence of Met Syn among long-haul drivers, 1018 male drivers were studied. Definition of Met Syn was based on ATP III, IDF and AHA. The statistical tests were composed of chi-square and independent t tests. RESULTS AND CONCLUSION: The participants' mean age was 42.17+/-10.65 years. The prevalence of Met Syn according to ATP III, IDF and AHA criteria was 26.1%, 35.2% and 31.6% respectively. 6.6% of drivers were impaired fasting glucose. The drivers with the bus, minibus, taxi formed the greatest number of smokers (82.9%) among all drivers (p=0.023). The average of body mass index (BMI) was 26.2+/-4.06. The most prevalence of Mets according to IDF criteria were observed in drivers of heavy vehicles and also the ones of passenger vehicles, with 36.7% and 43.9% respectively. Based on high prevalence of Met Syn and other risk factors in this study, and considering these factors, should be more careful about this point. It is recommended to control risk factors such as, control of high BMI and TG, LDL, waist circumfernce, education. PMID- 26508100 TI - Prominent apical cytoplasmic bleb formation in metanephric adenoma: report of a case. AB - In a case of metanephric adenoma of the kidney, many apical cytoplasmic blebs were found on the luminal surface of tumor cells. The tumor, measuring 15 mm in diameter, was found incidentally in the right kidney of a 40-year-old woman. It consisted of a dense proliferation of cuboidal cells forming small tubules of round or irregular shape. The apical portion of the cytoplasm of tumor cells exhibited club-shaped expansion or dome-like protrusion which was largely occupied by numerous free ribosomes. The neck portion of the protruded apical cytoplasm was constricted, and the apical cytoplasm appeared to have been "pinched-off" and shed into the lumen. The prominent formation of apical cytoplasmic blebs has, to our knowledge, not been documented in renal tumors except in angiomyoadenomatous tumors. Its pathological significance is unknown, but it most likely represents a response of tumor cells to some hypoxic or toxic cellular injuries. PMID- 26508101 TI - Case of extensive pyoderma gangrenosum with a neutrophilic leukemoid reaction. PMID- 26508102 TI - Molecular method for the detection of Andes hantavirus infection: validation for clinical diagnostics. AB - Hantavirus cardiopulmonary syndrome is a severe disease caused by exposure to New World hantaviruses. Early diagnosis is difficult due to the lack of specific initial symptoms. Antihantavirus antibodies are usually negative until late in the febrile prodrome or the beginning of cardiopulmonary phase, while Andes hantavirus (ANDV) RNA genome can be detected before symptoms onset. We analyzed the effectiveness of quantitative reverse transcription polymerase chain reaction (RT-qPCR) as a diagnostic tool detecting ANDV-Sout genome in peripheral blood cells from 78 confirmed hantavirus patients and 166 negative controls. Our results indicate that RT-qPCR had a low detection limit (~10 copies), with a specificity of 100% and a sensitivity of 94.9%. This suggests the potential for establishing RT-qPCR as the assay of choice for early diagnosis, promoting early effective care of patients, and improving other important aspects of ANDV infection management, such as compliance of biosafety recommendations for health personnel in order to avoid nosocomial transmission. PMID- 26508103 TI - Infectious cause of death determination using minimally invasive autopsies in developing countries. AB - In developing countries, the knowledge of the microorganisms causing fatal infections is critical and could help designing and implementing more effective preventive interventions and treatment guidelines. We aimed to develop and validate protocols for microbiological analysis in post-mortem samples obtained during minimally invasive autopsy (MIA) procedures and to assess their performance. Thirty MIAs performed in adults at Maputo Central Hospital in Southern Mozambique were included in the analysis. Microbiological tests included a universal screening for HIV, hepatitis B and C viruses, Plasmodium falciparum, and bacterial/fungal culture. In addition, a variety of molecular microbiology assays guided by the histological results were performed in blood, cerebrospinal fluid and a variety of tissue samples including liver, lung and central nervous system. The combination of culture-based methods together with molecular microbiological assays led to the identification of 17 out of 19 (89.5%) of the infectious deaths. Microorganisms identified included Mycobacterium tuberculosis, Toxoplasma gondii, Pneumocystis jiroveci, Cryptococcus neoformans, hepatitis B virus, human herpesvirus 8, cytomegalovirus, Streptococcus pneumoniae, Streptococcus dysgalactiae, Ryzopus oryzae, and Acinetobacter baumannii. The combination of classical cultures, serological tests and molecular assays performed in samples obtained through MIA allows the identification of most infectious agents causing death. PMID- 26508104 TI - MALDI-TOF is not useful in the diagnosis of catheter colonization based on superficial cultures: results from an in vitro study. AB - We compared in an vitro model the yields of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and conventional culture (CC) for the detection of catheter colonization with superficial catheter samples (SS). We used blood culture bottles (BCB) with an inserted cannula and incubated at 37 degrees C. The BCB were manipulated with different contaminations and when a BCB turned positive, SS were obtained to perform both techniques. To compare both techniques we analyzed the mean time to colonization (MTC) and the mean time to a result (MTR). The MTC (SD, days) by CC and MALDI-TOF was as follows: hub, 0.59 (0.79) versus 1.07 (1.39), P=0.06; surface: 0.62 (0.67) versus 0.82 (0.81), P<0.001. The MTR (SD, days) of CC and MALDI-TOF was as follows: hub: 1.58 (0.79) versus 2.25 (1.48), P=0.04; surface: 1.62 (0.67) versus 1.95 (0.80), P<0.001. In general, the use of MALDI-TOF performed directly with SS was no better than CC and did not anticipate colonization results. PMID- 26508105 TI - Improvement of identification of Capnocytophaga canimorsus by matrix-assisted laser desorption ionization-time of flight mass spectrometry using enriched database. AB - Capnocytophaga canimorsus and Capnocytophaga cynodegmi can be transmitted from dogs or cats and cause serious human infections. We aimed to evaluate the ability of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) to identify these two Capnocytophaga species. Ninety-four C. canimorsus and 10 C. cynodegmi isolates identified by 16S rRNA gene sequencing were analyzed. Using the MALDI BioTyper database, correct identification was achieved for only 16 of 94 (17%) C. canimorsus and all 10 C. cynodegmi strains, according to the manufacturer's log score specifications. Following the establishment of a complementary homemade reference database by addition of 51 C. canimorsus and 8 C. cynodegmi mass spectra, MALDI-TOF MS provided reliable identification to the species level for 100% of the 45 blind-coded Capnocytophaga isolates tested. MALDI-TOF MS can accurately identify C. canimorsus and C. cynodegmi using an enriched database and thus constitutes a valuable diagnostic tool in the clinical laboratory. PMID- 26508106 TI - Performance of the NG OligoGen kit for the diagnosis of Neisseria gonorrhoeae: comparison with cobas 4800 assay. AB - PCR assays are nowadays between the most sensitive and reliable methods for screening and diagnosing sexually transmitted infections (STIs). The aim of this study was to analyze the reliability, accuracy, and usefulness of the new NG OligoGen kit in comparison with the cobas 4800 assay for the detection of Neisseria gonorrhoeae in clinical samples. A prospective study was designed for detection of N. gonorrhoeae including urine samples (n=152), rectal (n=80), endocervical (n=67), pharyngeal (n=41), and urethral swabs (n=5) that were sent from a regional STI clinic in Seville, Spain. Samples were collected from 255 (73.9%) men and 90 women. Sensitivity, specificity, positive and negative predicative values, and kappa value for N. gonorrhoeae detection using the NG OligoGen kit were 99.6%, 100%, 100%, 99.1%, and 0.99, respectively. Statistical data obtained in this study confirm the usefulness and reliable results of this new assay. PMID- 26508107 TI - The within-day and between-day reliability of using sacral accelerations to quantify balance performance. AB - OBJECTIVES: To investigate the between-day and within-day reliability of a sacral mounted accelerometer to quantify balance performance and different balance metrics. DESIGN: Experimental, cross-sectional. SETTING: Laboratorial experiment. PARTICIPANTS: Thirty healthy volunteers. MAIN OUTCOME MEASURES: Balance tasks were double leg stance, tandem stance and single leg stance with eyes open and closed. Performance was measured by converting accelerations into path length (PL, length of the sway trace), jerk (jerkiness of sway trace) and root mean square (RMS) of the accelerations. RESULTS: Within-day ICC for PL were excellent (mean 0.78 95%CI 0.68-0.89), with Jerk and RMS demonstrating means of 0.60 and 0.47, respectively. The mean percentage minimal detectable change (MDC) within day were small for PL (mean 6.7%, 95%CI 5.3-8.1). Between-day ICC were good for PL (mean 0.61, 95%CI 0.50-0.71), but more varied for Jerk and RMS. The mean percentage MDC was small for PL (mean 6.1%, 95%CI 5.0-7.2). No significant differences were determined for measurements between-days for any metric or task. PL had the highest discriminatory value between the 8 tasks. CONCLUSIONS: The sacral mounted accelerometer reliably measured balance performance within- and between-days. The PL is the recommended metric as it was the most reliable, most discriminatory and most sensitive to change. PMID- 26508108 TI - Lung function in elderly subjects with metabolic syndrome and type II diabetes : Data from the Berlin Aging Study II. AB - BACKGROUND: Previous studies have indicated a relationship between type II diabetes (T2D), metabolic syndrome (MetS) and pulmonary function but the pathological mechanism responsible remains unclear. The aim of the current analysis within the Berlin Aging Study II (BASE-II) was to investigate the influence of abdominal obesity and muscle mass on pulmonary function in subjects with T2D and MetS. MATERIAL AND METHODS: A prebronchodilator pulmonary function test was carried out in 1369 subjects from the BASE-II (mean age 69 +/- 4 years, 51.6 % women) where T2D was defined according to the German Diabetes Association (DDG) criteria, MetS according to the criteria of the International Diabetes Foundation (IDF), American Heart Association (AHA) and National Heart, Lung and Blood Institute (NHLBI) criteria from 2009 and pulmonary obstruction (obstructive lung disease, OLD) by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria of a forced expiratory volume in 1 s (FEV1 and forced vital capacity (FVC) ratio < 70 %. RESULTS: Of the subjects 50.9 % achieved a sufficient level of quality according to the GOLD guidelines and were analyzed with respect to the research question. The FEV1 and FVC were decreased in study participants with T2D and MetS and the lung volume decreased with an increasing number of MetS criteria. Parameters of body composition, such as waist circumference and muscle mass had a significant influence on lung volumes, independent of MetS or T2D. DISCUSSION: In this study MetS and T2D were associated with decreased lung volumes; however, muscle mass and abdominal obesity proved to be the most important factors influencing pulmonary function and could thus form the link between pulmonary function and MetS or T2D. Measurement of grip strength for the determination of muscle mass and waist circumference for determining abdominal obesity could contribute to the interpretation of the results of pulmonary function tests. PMID- 26508109 TI - [Pulmonary function in elderly subjects with metabolic syndrome and type II diabetes : Data from the Berlin Aging Study II]. AB - BACKGROUND: Previous studies have indicated a relationship between type II diabetes (T2D), metabolic syndrome (MetS) and pulmonary function but the pathological mechanism responsible remains unclear. The aim of the current analysis within the Berlin Aging Study II (BASE-II) was to investigate the influence of abdominal obesity and muscle mass on pulmonary function in subjects with T2D and MetS. MATERIAL AND METHODS: A prebronchodilator pulmonary function test was carried out in 1369 subjects from the BASE-II (mean age 69 +/- 4 years, 51.6 % women) where T2D was defined according to the German Diabetes Association (DDG) criteria, MetS according to the criteria of the International Diabetes Federation (IDF), American Heart Association (AHA) and National Heart, Lung and Blood Institute (NHLBI) criteria from 2009 and pulmonary obstruction (obstructive lung disease, OLD) by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria of a forced expiratory volume in 1 s (FEV1 and forced vital capacity (FVC) ratio < 70 %. RESULTS: Of the subjects 50.9 % achieved a sufficient level of quality according to the GOLD guidelines and were analyzed with respect to the research question. The FEV1 and FVC were decreased in study participants with T2D and MetS and the lung volume decreased with an increasing number of MetS criteria. Parameters of body composition, such as waist circumference and muscle mass had a significant influence on lung volumes, independent of MetS or T2D. DISCUSSION: In this study MetS and T2D were associated with decreased lung volumes; however, muscle mass and abdominal obesity proved to be the most important factors influencing pulmonary function and could thus form the link between pulmonary function and MetS or T2D. Measurement of grip strength for the determination of muscle mass and waist circumference for determining abdominal obesity could contribute to the interpretation of the results of pulmonary function tests. PMID- 26508110 TI - [Xerostomia and its impact on oral health-related quality of life]. AB - BACKGROUND: Dry mouth is a frequently occurrence in elderly people and causes numerous clinical and social problems. OBJECTIVE: To investigate the quality of life in geriatric patients living in nursing homes depending on the subjective sensation of dry mouth and associated oral parameters. MATERIAL AND METHODS: A total of 62 male and female elderly patients living in 7 cooperating nursing homes were interviewed employing questionnaires with regard to their oral health related quality of life (GOHAI) and their subjective perception of dry mouth (sXI D). Dental status, drinking habits and current medication were documented. RESULTS: The mean GOHAI score was 53.6 and the mean sXI-D score was 7.9. Oral health-related quality of life was significantly influenced by the subjective sensation of dry mouth (p < 0.001), whereas no significant impact of the number of residual teeth or implants or the character of prosthetic restorations could be identified. Xerostomia was significantly influenced by the number of medications consumed (p = 0.039). CONCLUSION: Xerostomia has a significant impact on the oral health-related quality of life of elderly people living in nursing homes. Thus, dental treatment should focus on the alleviation of xerostomia to improve the oral health-related quality of life in the elderly population. PMID- 26508111 TI - Group 16SrXI phytoplasma strains, including subgroup 16SrXI-B and a new subgroup, 16SrXI-D, are associated with sugar cane white leaf. AB - Sugar cane white leaf (SCWL) is a serious disease caused by phytoplasmas. In this study, we performed nested PCR with phytoplasma universal primer pairs (P1/P7 and R16F2n/R16R2) for the 16S rRNA gene to detect SCWL phytoplasmas in 31 SCWL samples collected from Baoshan and Lincang, Yunnan, China. We cloned and sequenced the nested PCR products, revealing that the 16S rRNA gene sequences from 31 SCWL samples were all 1247 bp in length and shared more than 99 % nucleotide sequence similarity with the 16S rRNA gene sequences of SCWL phytoplasmas from various countries. Based on the reported 16S rRNA gene sequence data from SCWL isolates of various countries, we conducted phylogenetic and virtual RFLP analysis. In the resulting phylogenetic tree, all SCWL isolates clustered into two branches, with the Lincang and Baoshan SCWL phytoplasma isolates belonging to different branches. The virtual RFLP patterns show that phytoplasmas of the Lincang branch belong to subgroup 16SrXI-B. However, the virtual RFLP patterns revealed by HaeIII digestion of phytoplasmas of the Baoshan branch differed from those of subgroup 16SrXI-B. According to the results of phylogenetic and virtual RFLP analysis, we propose that the phytoplasmas of the Baoshan branch represent a new subgroup, 16SrXI-D. These findings suggest that SCWL is caused by phytoplasmas from group 16SrXI, including subgroup 16SrXI-B and a new subgroup, 16SrXI-D. PMID- 26508112 TI - The nucleotide-dependent interaction of FlaH and FlaI is essential for assembly and function of the archaellum motor. AB - The motor of the membrane-anchored archaeal motility structure, the archaellum, contains FlaX, FlaI and FlaH. FlaX forms a 30 nm ring structure that acts as a scaffold protein and was shown to interact with the bifunctional ATPase FlaI and FlaH. However, the structure and function of FlaH has been enigmatic. Here we present structural and functional analyses of isolated FlaH and archaellum motor subcomplexes. The FlaH crystal structure reveals a RecA/Rad51 family fold with an ATP bound on a conserved and exposed surface, which presumably forms an oligomerization interface. FlaH does not hydrolyze ATP in vitro, but ATP binding to FlaH is essential for its interaction with FlaI and for archaellum assembly. FlaH interacts with the C-terminus of FlaX, which was earlier shown to be essential for FlaX ring formation and to mediate interaction with FlaI. Electron microscopy reveals that FlaH assembles as a second ring inside the FlaX ring in vitro. Collectively these data reveal central structural mechanisms for FlaH interactions in mediating archaellar assembly: FlaH binding within the FlaX ring and nucleotide-regulated FlaH binding to FlaI form the archaellar basal body core. PMID- 26508113 TI - Evolutionary consequence of a change in life cycle complexity: A link between precocious development and evolution toward female-biased sex allocation in a hermaphroditic parasite. AB - The evolutionary consequences of changes in the complex life cycles of parasites are not limited to the traits that directly affect transmission. For instance, mating systems that are altered due to precocious sexual maturation in what is typically regarded as an intermediate host may impact opportunities for outcrossing. In turn, reproductive traits may evolve to optimize sex allocation. Here, we test the hypothesis that sex allocation evolved toward a more female biased function in populations of the hermaphroditic digenean trematode Alloglossidium progeneticum that can precociously reproduce in their second hosts. In these precocious populations, parasites are forced to self-fertilize as they remain encysted in their second hosts. In contrast, parasites in obligate three-host populations have more opportunities to outcross in their third host. We found strong support that in populations with precocious development, allocation to male resources was greatly reduced. We also identified a potential phenotypically plastic response in a body size sex allocation relationship that may be driven by the competition for mates. These results emphasize how changes in life cycle patterns that alter mating systems can impact the evolution of reproductive traits in parasites. PMID- 26508114 TI - Wavelength-band-tuning photodiodes by using various metallic nanoparticles. AB - Wavelength-band tuning was easily achieved in this work by depositing various metallic nanoparticles (NPs) on silicon p-n junction photodiodes (PDs). The normalization spectrum of the PDs deposited with gold (Au) NPs reveals a high wavelength pass characteristic; the PDs with silver (Ag) NPs coating behave as a low-wavelength pass, and the PDs with Au/Ag bimetallic NPs appear as a band wavelength pass PD with a full width at half maximum of 450 ~ 630 nm. The issue of wavelength-band tuning is due to the different plasmonic resonance wavelengths associated with various metallic NPs. The extinction plot shows the Au NPs have a longer resonant wavelength of about 545 nm, leading to the incident light with a wavelength near or longer than 545 nm scattered by the Au NPs, hence a high wavelength pass PD. The PDs with Ag NPs, due to the Ag NPs, exhibit a short resonant wavelength of 430 nm, and the short-wavelength incident light is absorbed near the silicon (Si) surface, where the Ag NPs is atop it. The shorter wavelength incident light is enhanced by the plasmonic resonance of Ag NPs, making a low-wavelength PD. The Au/Ag NPs presents a resonant wavelength of 500 nm between the Au and Ag NPs. For the incident light with a wavelength close to 500 nm, a constructive interference causes a substantial increase in the local electromagnetic field, hence leading to a band-wavelength pass PD. PMID- 26508115 TI - Donohue syndrome and use of continuous subcutaneous insulin pump therapy. AB - Donohue syndrome is a rare autosomal recessive condition caused by severe loss-of function mutations in the insulin receptor (INSR) gene. The diagnosis is made on clinical, biochemical and genetic grounds. Mutations are found on chromosome 19p13.2, and code for mutations in the INSR gene. Treatment is challenging and often unsuccessful, and relies on maintaining normoglycaemia and avoiding fasting; in some patients, recombinant human insulin-like growth factor (rhIGF-1) has been trialled. The prognosis is poor, with most babies dying in infancy. Ethically, it is important to consider the benefit versus burden of treatment, the quality of life of the surviving patient and the parents' wishes, when making decisions regarding withholding or withdrawing care. PMID- 26508116 TI - Severe acute measles pneumonitis: virus isolation in bronchoalveolar lavage fluid. AB - In the past few years, several endemic outbreaks of measles have been recognised, not only in children but also in adults, with severe and, occasionally, even fatal complications, possibly due to delayed diagnosis of the disease in adult medicine and decreasing vaccination rates. Furthermore, the treatment consists of supportive measures only. We present a case of severe measles pneumonitis in a 42 year-old man, a travel returnee, proven by direct virus isolation with PCR from bronchoalveolar lavage fluid. CT findings and pulmonary function testing revealed features of obstructive bronchiolitis; the patient was successfully treated with corticosteroids. He fully recovered, and lung function measurement returned to normal values. We conclude that acute measles can present as obstructive bronchiolitis and may be successfully treated with corticosteroids. PMID- 26508117 TI - Swallow syncope caused by third-degree atrioventricular block. AB - We report a case of a patient with more than 30 years of repeated syncopes, always following food intake. The patient was diagnosed with a swallow-related third-degree atrioventricular block and successfully treated with an artificial pacemaker. PMID- 26508118 TI - Laparoscopic treatment of intestinal obstruction caused by an uncommon congenital band. AB - Congenital bands represent a rare cause of small bowel obstruction. We report a case of intestinal obstruction caused by an uncommon form of congenital band in a 16-year-old girl. The diagnosis was strongly evoked preoperatively by CT scan and the intestinal obstruction was successfully treated using a laparoscopic approach. PMID- 26508119 TI - Sheathless transradial coronary angioplasty in an achondroplasic patient with ST elevation myocardial infarction. AB - We present a case of a 50-year-old man with achondroplasia, who presented with anterior ST segment myocardial infarction (STEMI). He was taken urgently to the catheterisation laboratory. Owing to his short stature, it was not possible to insert a radial artery sheath so he underwent a sheathless primary percutaneous coronary intervention (PCI) through the right radial artery, with no complication. He was shifted to the coronary care unit and had an uneventful hospital course. He was discharged in stable condition and follows up regularly as an outpatient. PMID- 26508120 TI - What the mind does not know, the eyes do not see: a rare congenital fusion of the odontoid process to the atlantal hemiarch. AB - Congenital spinal fusion of an odontoid process to an atlantal hemiarch is very rare. The unfamiliarity of the medical fraternity with this congenital malformation can easily be mistaken for an acute fracture, chronic infection or inflammatory disease. We present our experience of managing an adult who presented with neck pain after a motor vehicle accident. Radiological investigation revealed congenital fusion of the odontoid process to the atlantal hemiarch. The prevalence, embryology and clinical significance of this anomaly are discussed. As the natural progression of this anomaly is not well documented, we suggest periodic follow-up to monitor the progression of degenerative changes and instability of the occipitoatlantal junction. PMID- 26508121 TI - Pedunculated mobile aortic arch thrombus as a cause for acute stroke. PMID- 26508122 TI - Knowledge seeking behaviours of pre interns and early career doctors in Sri Lanka: a cross sectional study. AB - BACKGROUND: Use of reference sources for medical knowledge has changed dramatically over the last two decades with the introduction of online sources of information. This study analyses the medical knowledge seeking behaviours of pre interns and early career doctors in Sri Lanka. METHODS: This cross sectional survey with a convenience sample was conducted at two sites targeting two groups; pre-intern doctors graduated from the Faculty of Medicine, University of Colombo and early career doctors following a postgraduate course at the National Hospital of Sri Lanka. The data collection tool was an online self-administered questionnaire (paper based questionnaires used on request) that probed the patterns of using reference sources for medical knowledge. RESULTS AND DISCUSSION: The respondents comprised of 52 pre-interns and 34 early career doctors. A majority (98 %) had internet access. Early career doctors preferred online resources significantly more than the pre-interns. However, the utilization of online resources for evidence synthesis and planning research was unsatisfactory in both groups. A significant proportion (35 %) responded that they had never read a systematic review. Only one person in the entire sample had co-authored a review article. CONCLUSION: The use of online resources by participants seems to be satisfactory with a majority shifting to reliable online resources as a reference point for medical knowledge. However, a closer look at the usage patterns reveal that online resources that can be used for more innovative tasks such as evidence synthesis are grossly under-utilized. PMID- 26508123 TI - The need for support and education for parents of children with reproductive differences. PMID- 26508124 TI - Virus Type and Genomic Load in Acute Bronchiolitis: Severity and Treatment Response With Inhaled Adrenaline. AB - BACKGROUND: Acute bronchiolitis frequently causes infant hospitalization. Studies on different viruses or viral genomic load and disease severity or treatment effect have had conflicting results. We aimed to investigate whether the presence or concentration of individual or multiple viruses were associated with disease severity in acute bronchiolitis and to evaluate whether detected viruses modified the response to inhaled racemic adrenaline. METHODS: Nasopharyngeal aspirates were collected from 363 infants with acute bronchiolitis in a randomized, controlled trial that compared inhaled racemic adrenaline versus saline. Virus genome was identified and quantified by polymerase chain reaction analyses. Severity was assessed on the basis of the length of stay and the use of supportive care. RESULTS: Respiratory syncytial virus (83%) and human rhinovirus (34%) were most commonly detected. Seven other viruses were present in 8%-15% of the patients. Two or more viruses (maximum, 7) were detected in 61% of the infants. Virus type or coinfection was not associated with disease severity. A high genomic load of respiratory syncytial virus was associated with a longer length of stay and with an increased frequency of oxygen and ventilatory support use. Treatment effect of inhaled adrenaline was not modified by virus type, load or coinfection. DISCUSSION: In infants hospitalized with acute bronchiolitis, disease severity was not associated with specific viruses or the total number of viruses detected. A high RSV genomic load was associated with more-severe disease. CLINICAL TRIALS REGISTRATION: NCT00817466 and EudraCT 2009-012667-34. PMID- 26508125 TI - Primary Versus Nonprimary West Nile Virus Infection: A Cohort Study. AB - BACKGROUND: Since 2001, we have observed patients with a clinical picture consistent with West Nile virus (WNV) infection, which was defined as nonprimary infection (NPI) owing to the presence of highly elevated serum immunoglobulin G antibody titers with a high avidity index (>= 55%), absent or low titers of serum and cerebrospinal fluid (CSF) immunoglobulin M, and occasionally positive results of WNV-specific real-time reverse-transcription polymerase chain reaction analysis of CSF and/or blood specimens. METHODS: We investigated 124 patients with a diagnosis of primary WNV infection (PI) or NPI during 2005-2007 at Sheba Medical Center (Tel-Hashomer, Israel). Logistic regression was used to evaluate the association of variables with PI and NPI and with in-hospital mortality. RESULTS: A total of 68 and 50 patients with PI and NPI, respectively were included; 6 patients had incomplete data. In multivariate models, NPI was significantly associated with underlying psychiatric disorders (adjusted odds ratio [aOR], 13.73; 95% confidence interval [CI], 2.28-82.56; P = .004), hospitalization during winter and spring (aOR, 8.82; 95% CI, 1.59-48.87; P = .013), and fever (aOR, 0.61; 95% CI, .39-.95; P = .031). In-hospital mortality was significantly associated with NPI (aOR, 3.86; 95% CI, 1.12-13.28; P = .032) and a higher Charlson comorbidity index (aOR, 1.37; 95% CI, 1.03-1.83; P = .032). CONCLUSIONS: The possibility that NPI may be an emerging clinical entity with a high mortality rate must be considered seriously. PMID- 26508126 TI - Poor Outcomes of Complicated Pouch-Related Fistulas after Ileal Pouch-Anal Anastomosis Surgery. AB - BACKGROUND AND AIMS: Development of a pouch-related fistula tract is an uncommon but highly morbid complication to restorative proctocolectomy with ileal pouch anal anastomosis. Pouch failure with permanent ileostomy is reported in 21%-30% of patients, yet the factors contributing to pouch excision remain poorly defined. The aim of this study was to determine the incidence and treatment results of complicated pouch-related fistula, as well as to evaluate factors involved in excision after pouch failure. MATERIAL AND METHODS: The study was conducted as a retrospective study. All patients with diagnosed pouch-related fistulas were registered with information related to fistula classification, treatments, and outcome. RESULTS AND CONCLUSION: The final analysis included 48 (10.7%) of the 447 total ileal pouch-anal anastomosis patients with complicated pouch-related fistulas. Pouch-vaginal fistulas, pouch-perianal fistulas, and other pouch-related fistulas were observed in 19 (63%), 29 (60%), and 10 (21%) patients, respectively, corresponding to an accumulated risk of 8%, 6%, and 2%, respectively. Time from ileal pouch-anal anastomosis surgery to fistula presentation was 24 (0.2-212) months. Overall pouch failure, defined as pouch excision or a diverting stoma, was seen in 34 (71%) patients, while pouch excision was seen in 23 (48%) of the patients. Patients who developed Crohn's disease had a significantly higher risk of pouch excision, as did patients with an early onset of the fistula after ileal pouch-anal anastomosis (P = 0.006 and P = 0.007, respectively). In conclusion, the present study demonstrated a high risk of pouch failure in patients with complicated pouch-related fistulas. Furthermore, it showed that Crohn's disease and the development of early onset fistulas are associated with pouch excision. PMID- 26508128 TI - Two Ti13-oxo-clusters showing non-compact structures, film electrode preparation and photocurrent properties. AB - Two benzene dicarboxylate (BDC) and salicylate (SAL) substituted titanium-oxo clusters, Ti13O10(o-BDC)4(SAL)4(O(i)Pr)16 (1) and Ti13O10(o-BDC)4(SAL Cl)4(O(i)Pr)16 (2), are prepared by one step in situ solvothermal synthesis. Single crystal analysis shows that the two Ti13 clusters take a paddle arrangement with an S4 symmetry. The non-compact (non-sphere) structure is stabilized by the coordination of BDC and SAL. Film photoelectrodes are prepared by the wet coating process using the solution of the clusters and the photocurrent response properties of the electrodes are studied. It is found that the photocurrent density and photoresponsiveness of the electrodes are related to the number of coating layers and the annealing temperature. Using ligand coordinated titanium-oxo-clusters as the molecular precursors of TiO2 anatase films is found to be effective due to their high solubility, appropriate stability in solution and hence the easy controllability. PMID- 26508127 TI - Resource base influences genome-wide DNA methylation levels in wild baboons (Papio cynocephalus). AB - Variation in resource availability commonly exerts strong effects on fitness related traits in wild animals. However, we know little about the molecular mechanisms that mediate these effects, or about their persistence over time. To address these questions, we profiled genome-wide whole-blood DNA methylation levels in two sets of wild baboons: (i) 'wild-feeding' baboons that foraged naturally in a savanna environment and (ii) 'Lodge' baboons that had ready access to spatially concentrated human food scraps, resulting in high feeding efficiency and low daily travel distances. We identified 1014 sites (0.20% of sites tested) that were differentially methylated between wild-feeding and Lodge baboons, providing the first evidence that resource availability shapes the epigenome in a wild mammal. Differentially methylated sites tended to occur in contiguous stretches (i.e., in differentially methylated regions or DMRs), in promoters and enhancers, and near metabolism-related genes, supporting their functional importance in gene regulation. In agreement, reporter assay experiments confirmed that methylation at the largest identified DMR, located in the promoter of a key glycolysis-related gene, was sufficient to causally drive changes in gene expression. Intriguingly, all dispersing males carried a consistent epigenetic signature of their membership in a wild-feeding group, regardless of whether males dispersed into or out of this group as adults. Together, our findings support a role for DNA methylation in mediating ecological effects on phenotypic traits in the wild and emphasize the dynamic environmental sensitivity of DNA methylation levels across the life course. PMID- 26508129 TI - Histological examination of vascular damage caused by stent retriever thrombectomy devices. AB - BACKGROUND AND OBJECTIVES: Although the recently marketed stent retriever thrombectomy devices have demonstrated a high recanalization rate and favorable clinical outcomes, there is a concern about the risks of intimal injuries when pulling out the stent in the unfolded position. In this study, the Solitaire Flow Restoration System and the Trevo retriever were used in a histopathological comparison of vascular injuries caused by stent retriever thrombectomy devices. METHODS: Rabbit carotid arteries were used in the experiments with stent retriever thrombectomy devices. Carotid artery samples were harvested either 1 or 2 weeks postoperatively for histological examination. RESULTS: Histological changes caused by the use of stent retriever thrombectomy devices were observed from the intimal to medial layers. With the Solitaire FR 4 mm, intimal and medial thickening was observed 1 week postoperatively, and progression of intimal thickening was observed 2 weeks postoperatively. The extent of intimal thickening tended to be greater with the Solitaire FR 6 mm than with the Solitaire FR 4 mm, but this difference was not significant. Compared with the Solitaire FR 4 mm, the Trevo had a significantly smaller area of intimal thickening. CONCLUSIONS: Although there are some differences among devices, results from this study indicate that stent retriever thrombectomy devices induce vascular damage that extends to the medial layer. PMID- 26508130 TI - Effect of stenting on progressive occlusion of small unruptured saccular intracranial aneurysms with residual sac immediately after coil embolization: a propensity score analysis. AB - BACKGROUND: To examine the effect of stenting on progressive occlusion of small and incompletely occluded unruptured intracranial aneurysms (UIAs) <=10 mm in size using a propensity score matched case controlled analysis. METHODS: 715 small UIAs consecutively treated by coiling between 2008 and 2010 were eligible for study. Time of flight MR angiography and/or catheter angiography were used to estimate extent of occlusion after coiling. Complete occlusion at 6 months post embolization of a sac filled with contrast immediately after coiling constituted progressive occlusion. A propensity score matched analysis was conducted, based on the probability of stent deployment. RESULTS: 206 (28.8%) small UIAs showed residual sac filling directly after coiling. Of these, 182 (88.3%) displayed progressive occlusion at 6 months. Aneurysm size (p<0.01), neck size (p<0.01), and embolization attempt (p<0.01) differed significantly for stented and non stented lesions, but the incidence of progressive occlusion did not differ (p=0.78) between the groups. After 1:1 propensity score matching, however, the rate of complete occlusion in stented subjects (97.5%) surpassed that of the non stented counterparts (OR=9.75, p=0.01). CONCLUSIONS: Small UIAs with residual sac filling after coiling showed a complete occlusion rate of 88.3% at 6 months post embolization. Stent deployment seems to promote complete occlusion in such lesions. PMID- 26508131 TI - A randomized study of the effect of patient positioning on setup reproducibility and dose distribution to organs at risk in radiotherapy of rectal cancer patients. AB - BACKGROUND: The patient positioning in pelvic radiotherapy (RT) should be decided based on both reproducibility and on which position that yields the lowest radiation dose to the organs at risk (OAR), and thereby less side effects to patients. The present randomized study aimed to evaluate the influence of patient positioning on setup reproducibility and dose distribution to OAR in rectal cancer patients. METHODS: Ninety-one patients were randomized into receiving RT in either supine or prone position. The recruitment period was from 2005 to 2008. Position deviations were derived from electronic portal image registrations, and setup errors were defined as deviations between the expected and the actual position of bony landmarks. Setup deviations were expressed into three table shift values (?x, ?y, ?z) from which the deviation vector [Formula: see text] were calculated. The estimated lengths of [Formula: see text] defined the main outcome and were compared between prone and supine positions using linear mixed model statistics. The mean volume of each 5 Gy increments between 5 and 45 Gy was calculated for the small bowel and the total bowel, and the dose volumes were compared between prone and supine position. RESULTS AND CONCLUSION: Data from 83 patients was evaluable. The mean [Formula: see text] was 5.8 mm in supine position and 7.1 mm in prone position (p = 0.024), hence the reproducibility was significantly superior in supine position. However, the difference was marginal and may have borderline clinical importance. The irradiated volumes of the small bowel and the total bowel were largest in the supine position for all dose levels, but none of those were significantly different. The patient positioning in RT of rectal cancer patients may therefore be decided based on other factors such as the most comfortable position for the patients. PMID- 26508132 TI - A Qualitative Study of Multidisciplinary ALS Clinic Use in the United States. AB - OBJECTIVES: The multidisciplinary clinic (MDC) has become the standard of care for individuals with amyotrophic lateral sclerosis (ALS) in the United States, yet many patients choose not to receive care at MDCs. We undertook a qualitative study of individuals with ALS to explore patients' perceptions of this form of service delivery. METHODS: Participants completed an online survey that posed open-ended questions about their attitudes and behaviors surrounding MCDs. Qualitative analysis was performed whereby response data was evaluated and grouped into themes. RESULTS: The unique aspect of MDCs most commonly cited by patients was integrated care. Other reasons for attending MDC included those common to specialist centers, such as expertise, access to clinical trials, and participation in research. Perceived disadvantages unique to the MDC model were long and tiring visits. In common with many specialist centers, long travel times were cited as a disadvantage of MDCs. CONCLUSIONS: This information provides a foundation for improving ALS care. For those able to travel, the MDC model has much to offer, but patients' time should be respected. For those patients who cannot travel, alternative models of care should be devised to provide integrated care, clinical expertise, and access to research. PMID- 26508133 TI - The histone deacetylase HDA19 controls root cell elongation and modulates a subset of phosphate starvation responses in Arabidopsis. AB - The length of root epidermal cells and their patterning into files of hair bearing and non-hair cells are genetically determined but respond with high plasticity to environmental cues. Limited phyto-availability of the essential mineral nutrient phosphate (Pi) increases the number of root hairs by longitudinal shortening of epidermal cells and by reprogramming the fate of cells in positions normally occupied by non-hair cells. Through analysis of the root morphology and transcriptional profiles from transgenic Arabidopsis lines with altered expression of the histone deacetylase HDA19, we show that in an intricate interplay of Pi availability and intrinsic factors, HDA19 controls the epidermal cell length, probably by altering the positional bias that dictates epidermal patterning. In addition, HDA19 regulates several Pi-responsive genes that encode proteins with important regulatory or metabolic roles in the acclimation to Pi deficiency. In particular, HDA19 affects genes encoding SPX (SYG1/Pho81/XPR) domain-containing proteins and genes involved in membrane lipid remodeling, a key response to Pi starvation that increases the free Pi in plants. Our data add a novel, non-transcriptionally regulated component of the Pi signaling network and emphasize the importance of reversible post-translational histone modification for the integration of external signals into intrinsic developmental and metabolic programs. PMID- 26508134 TI - XiangshaLiujunzi decoction alleviates the symptoms of functional dyspepsia by regulating brain-gut axis and production of neuropeptides. AB - BACKGROUND: Chinese medicine xiangshaliujunzi decoction (XSLJZD) plays a key role in treating functional dyspepsia (FD), a common clinical gastrointestinal disorder. However, the mechanism of this disease is unclear. Brain-gut axis regulates food intake behaviour, and this regulatory mechanism is mediated by neuropeptides. Brain-gut axis impairment and neuropeptide alteration may be the pathological mechanisms of FD, and brain-gut axis regulation may influence the action of medicine. METHODS: In our experiment, the effect of XSLJZD on FD was evaluated in terms of food intake, sucrose preference test and electromyogram. Changes in neuropeptides [ghrelin, cholecystokinin (CCK) and vasoactive intestinal polypeptide (VIP)] were detected through immunohistochemistry, real time PCR and ELISA. RESULTS: XSLJZD increased food intake and the percentage of sucrose preference (>75 %). However, the response to gastric detention decreased. Furthermore, XSLJZD increased ghrelin, CCK, VIP proteins and genes in the stomach. XSLJZD also increased ghrelin, CCK and VIP proteins in serum. By contrast, XSLJZD decreased the mRNA expression of these neuropeptides in the hypothalamus. CONCLUSIONS: XSLJZD alleviated the symptoms of FD by upregulating the production of ghrelin, CCK and VIP and by increasing the levels of these neuropeptides in circulation. This finding can help elucidate the mechanism of FD and can provide further insight into the pharmacokinetics of XSLJZD. PMID- 26508135 TI - [Treatment planning with functional MRI]. AB - CLINICAL/METHODICAL ISSUE: The aim of magnetic resonance imaging (MRI) guided radiotherapy is high precision in treatment delivery. With new developments it is possible to focus the high dose irradiation on the tumor while sparing the surrounding tissue. The achievements in precision of the treatment planning and delivery warrant equally precise tumor definition. STANDARD RADIOLOGICAL METHODS: In conventional radiation therapy it is necessary to carry out a planning computed tomography (CT). For many tumors there is also need for an additional morphological MRI because of more accurate tumor definition. In standard radiotherapy the tumor volume is irradiated with a homogeneous dose. METHODICAL INNOVATIONS: The aim of functional multiparametric MRI is to visualize and quantify biological, physiological and pathological processes at the cellular and molecular levels. Based on this information it is possible to elucidate tumor biology and identify subvolumes of more aggressive behavior. They are often radiotherapy-resistant, leading to tumor recurrence thus requiring further dose escalation. The concept of inhomogeneous tumor irradiation according to its biological behavior is called dose painting. PERFORMANCE: Dose painting is technically feasible. The expected clinical benefit is motivated by selective treatment adaptations based on biological tumor characteristics. Tumors show variable response to therapy underlining the need for individual treatment plans. This approach may lead not only to higher local control but also to better sparing of normal surrounding tissue. ACHIEVEMENTS: With the clinical implementation of dose painting, improvements in the therapeutic outcome can be expected. PRACTICAL RECOMMENDATIONS: Due to the existing technical challenges, extensive collaboration between radiation oncologists, radiologists, medical physicists and radiation biologists is needed. PMID- 26508136 TI - [Recurrent migratory knee pain]. PMID- 26508137 TI - Erratum to: Antidiabetic Treatment Patterns in a Medicare Advantage Population in the United States. PMID- 26508138 TI - Pharmacokinetics of Tramadol and O-Desmethyltramadol Enantiomers Following Administration of Extended-Release Tablets to Elderly and Young Subjects. AB - BACKGROUND: Tramadol is frequently used in geriatric patients; however, pharmacokinetic (PK) publications on tramadol and O-desmethyltramadol (ODM) in elderly patients are rare. OBJECTIVE: Our objective was to characterize the PK of tramadol and ODM, including absorption processes and covariates for tramadol, in elderly and young subjects after single-dose administration of 200-mg extended release tablets. METHODS: We conducted a PK study in 15 elderly (aged >=75 years) subjects with mild renal insufficiency and 20 young (18-40 years) subjects; blood and urine samples were collected for 48 h post-dose. Non-compartmental analysis (NCA) of each tramadol and ODM enantiomer included area under the concentration time curve (AUC), terminal elimination rate (k el), total body clearance, volume of distribution (V area/ F), and renal clearance (Clr0-48). A one-compartment population model of total tramadol concentration was parameterized with clearance (CL/F), volume of distribution (V/F), and mixed order absorption (first-order and zero-order absorption rate constants with lag times). RESULTS: NCA demonstrated comparable maximum plasma concentration (C max) and AUC between age groups for tramadol enantiomers, but significant differences in V area/ F (mean 34% higher) and k el (mean 28% lower) in the elderly. PK of ODM were significantly different in the elderly for AUC0-inf (mean 35% higher), Clr0-48 (mean 29% lower), and k el (mean 33% lower). The population analysis identified age as a covariate of V/F (young 305 L; elderly 426 L), with a 50% longer mean elimination half-life in the elderly. No differences in absorption processes were observed. CONCLUSIONS: Tramadol exposure was similar between the age groups; exposure to ODM was higher in elderly subjects. PMID- 26508151 TI - Superfetation in live-bearing fishes is not always the result of a morphological constraint. AB - Superfetation is an unusual reproductive strategy that consists of the presence of multiple broods at different developmental stages within a single female. One hypothesis that was proposed to explain its adaptive significance suggests that, in fishes, superfetation is a response to selective pressures that promote a thin and streamlined body shape, such as high-velocity water systems. Superfetation may allow for reduction in ovary size and hence improve streamlining because superfetating females carry few large, full-term embryos at any given time. We tested this morphological constraint hypothesis using reproductive and morphological data from several populations of two viviparous fishes of the family Poeciliidae (Poeciliopsis gracilis and Poeciliopsis infans). We found no evidence to support the morphological constraint hypothesis. In both species the degree of superfetation varied as a function of a complex interaction between source population and female size, and this interpopulation variation was not associated with the velocity of the water current. Contrary to what we expected, females of P. gracilis with more streamlined bodies were observed in rivers where water velocity is slow or moderate. In P. infans the velocity of the water current did not predict variation in body shape. Our results are noteworthy because a previous study which focused on a congeneric species (Poeciliopsis turrubarensis) demonstrated strong support for this hypothesis. However, based on our evidence we conclude that the association among increased superfetation, streamlined morphologies, and fast-flowing environments is not a general rule and that the adaptive value of superfetation may differ among species. PMID- 26508152 TI - Inflammatory and Non-inflammatory Breast Cancer: A Potential Role for Detection of Multiple Viral DNAs in Disease Progression. AB - BACKGROUND: Inflammatory breast cancer (IBC) is the most lethal form of breast cancer. Multiple viral infections in IBC tissues were found to be associated with disease pathogenesis. OBJECTIVE: The aim of the present study was to correlate the incidence of viral DNA with breast cancer progression. MATERIALS AND METHODS: Overall, 135 women diagnosed with breast cancer were enrolled in this study. Using polymerase chain reaction and sequencing assays, we determined the incidence of human papillomavirus types 16 and 18 (HPV-16 and -18), human cytomegalovirus (HCMV), Epstein-Barr virus, human herpes simplex virus type 1 and 2, and human herpes virus type 8 (HHV-8) in breast carcinoma tissue biopsies. We also assessed the expression of the cell proliferation marker Ki-67 by immunohistochemistry in association with the incidence of viral DNA. RESULTS: HCMV and HPV-16 were the most detected viral DNAs in breast carcinoma tissues; however, the frequency of HCMV and HHV-8 DNA were significantly higher in IBC than non-IBC tissues. Moreover, the prevalence of multiple viral DNAs was higher in IBC than non-IBC tissues. The incidence of multiple viral DNAs positively correlates with tumor size and number of metastatic lymph nodes in both non-IBC and IBC patients. The expression of Ki-67 was found to be significantly higher in both non-IBC and IBC tissues in which multiple viral DNAs were detected. CONCLUSIONS: The incidence of multiple viral DNAs in IBC tissues was higher compared with non-IBC tissues. The present results suggest the possibility of a functional relationship between the presence of multiple viral DNAs and disease pathogenesis. PMID- 26508153 TI - Outcomes of Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma in the Netherlands: A Nationwide Retrospective Analysis. AB - BACKGROUND: Large multicenter series on outcomes and predictors of survival after distal pancreatectomy (DP) for pancreatic ductal adenocarcinoma (PDAC) are scarce. METHODS: Adults who underwent DP for PDAC in 17 Dutch pancreatic centers between January 2005 and September 2013 were analyzed retrospectively. The primary outcome was survival, and predictors of survival were identified using Cox regression analysis. RESULTS: In total, 761 consecutive patients after DP were assessed, of whom 620 patients were excluded because of non-PDAC histopathology (n = 616) or a lack of data (n = 4), leaving a total of 141 patients included in the study [45 % (n = 63) male, mean age 64 years (SD = 10)]. Multivisceral resection was performed in 43 patients (30 %) and laparoscopic resection was performed in 7 patients (5 %). A major complication (Clavien-Dindo score of III or higher) occurred in 46 patients (33 %). Mean tumor size was 44 mm (SD 23), and histopathological examination showed 70 R0 resections (50 %), while 30-day and 90-day mortality was 3 and 6 %, respectively. Overall, 63 patients (45 %) received adjuvant chemotherapy. Median survival was 17 months [interquartile range (IQR) 13-21], with a median follow-up of 17 months (IQR 8-29). Cumulative survival at 1, 3 and 5 years was 64, 29, and 22 %, respectively. Independent predictors of worse postoperative survival were R1/R2 resection [hazard ratio (HR) 1.6, 95 % confidence interval (CI) 1.1-2.4], pT3/pT4 stage (HR 1.9, 95 % CI 1.3-2.9), a major complication (HR 1.7, 95 % CI 1.1-2.5), and not receiving adjuvant chemotherapy (HR 1.5, 95 % CI 1.0-2.3). CONCLUSION: Survival after DP for PDAC is poor and is related to resection margin, tumor stage, surgical complications, and adjuvant chemotherapy. Further studies should assess to what extent prevention of surgical complications and more extensive use of adjuvant chemotherapy can improve survival. PMID- 26508154 TI - Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome: a mimicker of juvenile idiopathic arthritis. PMID- 26508155 TI - Persistence of impaired health status of Q fever patients 4 years after the first Dutch outbreak. AB - A significant proportion of Q fever patients from the first Dutch Q fever outbreak in 2007 showed impairment in health status up to 1 year after infection. Interested in whether this decrease in health status persisted, we set out to determine the health status in the same cohort of patients, 4 years after primary infection and to compare health status scores at the individual patient level between 1 and 4 years follow-up. Health status was assessed with the Nijmegen Clinical Screening Instrument (NCSI). Patients were serologically tested to exclude patients with possible, probable or proven chronic Q fever. Results on the NCSI sub-domains at group level [2008 (n = 54) and 2011 (n = 46)] showed a persistent significant percentage of patients exhibiting clinically relevant ('severe') scores for all NCSI sub-domains. After 4 years, undue fatigue was present in 46% and exactly half of all patients experienced a severely impaired general quality of life. Patients with NCSI scores available in both 2008 and 2011 (n = 37) showed no difference in all sub-domain scores, except for a small decrease in dyspnoea emotions in 2011. In this group, a significant proportion of patients either improved or worsened in one or more sub-domains of health status. We conclude that at the group level, health status of Q fever patients remained impaired 4 years after primary infection. At the individual patient level, health status may change. PMID- 26508156 TI - Clinical utility of KRAS status in circulating plasma DNA compared to archival tumour tissue from patients with metastatic colorectal cancer treated with anti epidermal growth factor receptor therapy. AB - BACKGROUND: Circulating cell-free DNA (cfDNA) in plasma is a mixture of DNA from malignant and normal cells, and can be used as a liquid biopsy to detect and quantify tumour specific mutations e.g. KRAS. We investigated the clinical value of KRAS mutations when detected in plasma compared to tumour in patients from metastatic colorectal cancer (mCRC) prior to anti-epidermal growth factor receptor (anti-EGFR) therapy. Secondly, we investigated the concentration of total cfDNA in relation to clinical outcome. PATIENTS AND METHODS: Patients were resistant to 5-FU, oxaliplatin and irinotecan and treated with 3rd line irinotecan (180 mg/m(2)) and cetuximab (500 mg/m(2)) q2w in a prospective phase II trial. The study was conducted prior to implementation of KRAS as selection criteria. Plasma was obtained from a pre-treatment EDTA blood-sample, and the total cfDNA, and KRAS mutations were quantified by an in-house qPCR method. Results are presented according to REMARK. RESULTS: One-hundred-and-forty patients were included. Thirty-four percent had detectable KRAS mutations in the tumour, compared to 23% in plasma. KRAS detection in archival tumour tissue showed no correlation to survival, whereas plasma KRAS status remained a strong predictive and prognostic factor in multivariate analysis (Hazard Ratio (HR)=2.98 (95% CI 1.53-5.80, p=0.001) and 2.84 (1.46-5.53, p=0.002), for OS and PFS, respectively). Combining the information of total cell free DNA levels and plasma KRAS mutation status, produced an additional prognostic effect. CONCLUSION: The value of clinically relevant mutations could be improved by performing the analysis on circulation plasma DNA rather than archival tumour tissue. PMID- 26508157 TI - Detecting tau in serum of transgenic animal models after tau immunotherapy treatment. AB - In the attempt to elucidate if the "peripheral sink hypothesis" could be a potential mechanism of action for tau removal in passive immunotherapy experiments, we have examined tau levels in serum of chronically injected JNPL3 and Tg4510 transgenic animals. Measurement of tau in serum of mice treated with tau antibodies is challenging because of the antibody interference in sandwich enzyme-linked immunosorbent assays. To address this issue, we have developed a heat-treatment protocol at acidic pH to remove interfering molecules from serum, with excellent recovery of tau. The present data show that pan-tau and conformational antibodies do increase tau in mouse sera. However, these concentrations in serum do not consistently correlate with reductions of tau pathology in brain, suggesting that large elevations of tau species measured in serum are not predictive of efficacy. Here, we describe a reliable method to detect tau in serum of transgenic animals that have undergone tau immunotherapy. Levels of tau in human serum are less than the sensitivity of current assays, although artifactual signals are common. The method may be useful in similarly treated humans, a situation in which false positive signals are likely. PMID- 26508158 TI - Unusual molecular pattern in Ajugoideae subfamily: the case of Ajuga genevensis L. from Dolomites. AB - We analysed the ethanolic extract from Ajuga genevensis L. (Lamiaceae) growing in Dolomites, part of Italian Alps. Three new compounds for this species were identified: rosmarinic acid (1), oleanolic acid (2) and maslinic acid (3), representative of two different classes of chemical compounds (phenylpropanoids and pentacyclic triterpenes). A. genevensis resulted to be a valuable source of these compounds endowed with interesting biological activities (i.e. antioxidant, neuroprotective, anti-inflammatory, antiproliferative). The recognition of compounds (1), (2) and (3) may also confirm the ethnomedicinal uses of this plant. From a chemotaxonomical point of view, it is worth noting that iridoids were not evidenced in this accession. Iridoids are considered chemotaxonomic marker in Lamiales, and, in contrast with a previous study on this species, the presence of aucubin was not confirmed. In addition, the presence of large amounts of rosmarinic acid (1) was unexpected for a species that does not belong to subfamily Nepetoideae. PMID- 26508159 TI - Sex-related differences in calcific aortic stenosis: correlating clinical and echocardiographic characteristics and computed tomography aortic valve calcium score to excised aortic valve weight. AB - AIMS: Calcific aortic valve stenosis (AS) is purportedly associated with less calcium burden in women than in men. We sought to examine sex-related differences and correlates of surgically excised aortic valve weight (AVW) in pure AS. METHODS AND RESULTS: Clinical and echocardiographic characteristics of 888 consecutive patients who underwent aortic valve replacement for severe AS were correlated to AVW, and in 126 patients, AVW was also correlated to computed tomography aortic valve calcium (AVC) score. Women and men had similar indexed valve area (0.42 +/- 0.09 vs. 0.42 +/- 0.07 cm (2)/m(2), P = 0.95) and mean systolic gradient (53 +/- 15 vs. 52 +/- 13 mmHg, P = 0.11), but women had higher New York Heart Association class (2.63 +/- 0.70 vs. 2.50 +/- 0.70, P = 0.01) and less prevalent coronary artery disease (38 vs. 52%, P < 0.0001). Aortic valve weight was lower in women (1.94 +/- 0.88 vs. 3.08 +/- 1.32 g, P < 0.0001) even when indexed to body surface area (1.09 +/- 0.48 vs. 1.48 +/- 0.62 g/m(2), P < 0.0001) or left ventricular outflow tract (LVOT) area (0.54 +/- 0.23 vs. 0.71 +/- 0.29 g/cm(2), P < 0.0001). Using multivariate analysis, male sex (P < 0.0001), bicuspid valve (P < 0.0001), and larger LVOT area (P < 0.0001) were the major determinants of increased AVW, along with current cigarette smoking (P = 0.007). Diabetes (P = 0.004) and hypertension (P = 0.03) were independently associated with lower AVW. Aortic valve calcium correlated well with AVW (r = 0.81, P < 0.0001) and was lower in women than in men (2520 +/- 1199 vs. 3606 +/- 1632 arbitrary units, P < 0.0001). CONCLUSIONS: Despite the same degree of AS severity, women have less AVC and lower AVW compared with men, irrespective of valve morphology. Aortic valve calcium is correlated to excised AVW. Hypertension, diabetes, and current cigarette smoking were independently associated with AVW. PMID- 26508160 TI - ERICCA and RIPHeart: two nails in the coffin for cardioprotection by remote ischemic conditioning? Probably not! PMID- 26508161 TI - Antithrombotic therapy for stable coronary artery disease: the difficult quest for the holy balance. PMID- 26508162 TI - Hypertrophic cardiomyopathy: single gene disease or complex trait? PMID- 26508163 TI - Plasma proprotein convertase subtilisin/kexin type 9 levels and the risk of first cardiovascular events. AB - AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that enhances degradation of the LDL receptor. While agents that inhibit PCSK9 markedly reduce atherogenic lipoproteins and show great promise for event reduction, it is unknown whether plasma PCSK9 levels predict incident cardiovascular events. METHODS AND RESULTS: In a nested case-control evaluation conducted in a prospective cohort of >28 000 initially healthy American women, we measured plasma concentrations of PCSK9 at baseline among 358 participants who subsequently developed major cardiovascular events (cases) and among 358 age, smoking, and hormone replacement therapy matched participants who remained free of disease during 17 years of follow-up (controls). Proprotein convertase subtilisin/kexin type 9 level was not significantly related to smoking status, hypertension, obesity, or a family history of premature cardiovascular disease but was positively associated with apolipoprotein B-100 (r = 0.20, P< 0.001), and triglycerides (r = 0.13, P = 0.004). No associations were observed between PCSK9 and apo A1, HDLC, lipoprotein(a), or high-sensitivity C-reactive protein. Despite modest positive association with atherogenic lipids, baseline levels of PCSK9 did not predict the first cardiovascular events; the odds ratios (ORs) for future vascular events for the lowest (referent) to highest baseline quartiles of PCSK9 were 1.0, 0.94, 0.98, and 1.15 (P-trend = 0.53). In contrast, the corresponding ORs for baseline apo B levels were 1.0, 1.14, 1.34, and 1.94 (P-trend = 0.002). CONCLUSIONS: In a large-scale primary prevention cohort, plasma levels of PCSK9 measured at baseline did not predict future cardiovascular events. PMID- 26508164 TI - Peri-infarct pacing to prevent left reverse remodelling: an unvalidated concept? PMID- 26508165 TI - Preoperative thresholds for mid-to-late haemodynamic and clinical outcomes after pulmonary valve replacement in tetralogy of Fallot. AB - AIMS: The right ventricle (RV) remodels early after pulmonary valve replacement (PVR) in tetralogy of Fallot (TOF) patients. Previously reported preoperative thresholds to achieve early postoperative RV normalization were consistently close to 80 mL/m(2) for end-systolic volume (ESV) and 160 mL/m(2) for end diastolic volume (EDV). Our objective was to determine whether these thresholds were also associated with mid-to-late RV normalization and clinical events. METHODS AND RESULTS: Out of a multicentre cohort of 157 TOF patients who had undergone PVR, in 65 patients (62% male, age 29 +/- 8 years, homograft in 98%) cardiovascular magnetic resonance (CMR) imaging was performed preoperatively and >3 years (6.3 years, interquartile range: 4.9-9.5) postoperatively. Mid-to-late haemodynamic outcome was classified as: 'RV normalization' [RV ejection fraction (EF) > 48% and RV EDV < 108 mL/m(2)] in 14 of 65 (22%) patients, 'intermediate' in 34 of 65 (52%) patients, and 'suboptimal' (RV EF < 45% and RV EDV > 120 mL/m(2)) in 17 of 65 (26%) patients. Preoperative RV ESV < 80 mL/m(2) was strongly associated with favourable mid-to-late haemodynamic outcome in a proportional odds model [common odds ratio (OR): 0.04 for worse class, 95% confidence interval (CI): 0.01-0.17]. During 7.8 +/- 4.0 years follow-up after PVR, adverse clinical events (death, sustained ventricular tachycardia, or heart failure) occurred in 18 of 106 (17%) patients with preoperative CMR available. Patients with preoperative RV ESV > 95 mL/m(2) were at increased risk for unfavourable mid-to-late haemodynamic outcome (common OR: 25.5, 95% CI: 5.35-122) and events (hazard ratio: 2.89, 95% CI: 1.03-8.11). CONCLUSION: In TOF patients who had undergone PVR, the best preoperative threshold to achieve mid-to-late RV normalization was RV ESV < 80 mL/m(2). Patients with preoperative RV ESV > 95 mL/m(2) were at increased risk for suboptimal haemodynamic outcome and adverse clinical events. Our findings may assist in timing of PVR. PMID- 26508166 TI - Unintentional extraction of a platinum-chromium everolimus-eluting stent by entanglement with a covered stent. PMID- 26508167 TI - Contrasting mortality risks among subgroups of treated hypertensive patients developing new-onset diabetes. AB - AIMS: Hypertension and diabetes mellitus (DM) frequently cluster together and synergistically increase cardiovascular risk. Among those who develop DM during treatment for hypertension (new-onset diabetes, NOD), it is unclear whether NOD reflects a separate entity associated with increased risk or merely reflects accelerated presentation of DM. METHODS AND RESULTS: We analysed data on 15 089 hypertensive patients attending the Glasgow Blood Pressure Clinic. The date at first hospital encounter either with diagnosis of diabetes or prescription of anti-hyperglycaemic medication were considered as the onset of diabetes. Cox proportional hazard models (including propensity score matching) were employed to study associations between diabetes status, early and late NOD (diagnosis <10 years or >10 years from first clinic visit) and cause-specific mortality. There were 2516 patients (16.7%) with DM, of whom 1862 (12.3%) had NOD [early NOD = 705 (4.6%); late NOD = 1157 (7.6%)]. The incidence rate of NOD was 8.2 per 1000 person-years. The total time at risk was 239 929 person-years [median survival: 28.1 years (inter-quartile range: 16.2-39.9)]. Compared with non-diabetic individuals, prevalent DM [hazard ratio (HR) = 1.8, 95% confidence interval (CI): 1.4-2.2] and time varying NOD status (HR: 1.09, 95% CI: 1.06-1.17) were associated with increased adjusted all-cause mortality. Early NOD (HR: 1.39, 95% CI: 1.2-1.6) was associated with increased in mortality risk, but not late NOD (HR: 0.92, 95% CI: 0.83-1.01). Results were consistent in the propensity score matched analyses. CONCLUSION: Although 1-in-8 hypertensive patients develop NOD, mortality is increased only in the 1-in-20 who develop early NOD. Further studies are warranted to determine if early identification of such individuals should provide an alert for intensification of therapeutic interventions. PMID- 26508168 TI - Myocardial strain imaging: how useful is it in clinical decision making? AB - Myocardial strain is a principle for quantification of left ventricular (LV) function which is now feasible with speckle-tracking echocardiography. The best evaluated strain parameter is global longitudinal strain (GLS) which is more sensitive than left ventricular ejection fraction (LVEF) as a measure of systolic function, and may be used to identify sub-clinical LV dysfunction in cardiomyopathies. Furthermore, GLS is recommended as routine measurement in patients undergoing chemotherapy to detect reduction in LV function prior to fall in LVEF. Intersegmental variability in timing of peak myocardial strain has been proposed as predictor of risk of ventricular arrhythmias. Strain imaging may be applied to guide placement of the LV pacing lead in patients receiving cardiac resynchronization therapy. Strain may also be used to diagnose myocardial ischaemia, but the technology is not sufficiently standardized to be recommended as a general tool for this purpose. Peak systolic left atrial strain is a promising supplementary index of LV filling pressure. The strain imaging methodology is still undergoing development, and further clinical trials are needed to determine if clinical decisions based on strain imaging result in better outcome. With this important limitation in mind, strain may be applied clinically as a supplementary diagnostic method. PMID- 26508169 TI - Left ventricular heart failure and pulmonary hypertension. AB - In patients with left ventricular heart failure (HF), the development of pulmonary hypertension (PH) and right ventricular (RV) dysfunction are frequent and have important impact on disease progression, morbidity, and mortality, and therefore warrant clinical attention. Pulmonary hypertension related to left heart disease (LHD) by far represents the most common form of PH, accounting for 65-80% of cases. The proper distinction between pulmonary arterial hypertension and PH-LHD may be challenging, yet it has direct therapeutic consequences. Despite recent advances in the pathophysiological understanding and clinical assessment, and adjustments in the haemodynamic definitions and classification of PH-LHD, the haemodynamic interrelations in combined post- and pre-capillary PH are complex, definitions and prognostic significance of haemodynamic variables characterizing the degree of pre-capillary PH in LHD remain suboptimal, and there are currently no evidence-based recommendations for the management of PH-LHD. Here, we highlight the prevalence and significance of PH and RV dysfunction in patients with both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), and provide insights into the complex pathophysiology of cardiopulmonary interaction in LHD, which may lead to the evolution from a 'left ventricular phenotype' to a 'right ventricular phenotype' across the natural history of HF. Furthermore, we propose to better define the individual phenotype of PH by integrating the clinical context, non-invasive assessment, and invasive haemodynamic variables in a structured diagnostic work up. Finally, we challenge current definitions and diagnostic short falls, and discuss gaps in evidence, therapeutic options and the necessity for future developments in this context. PMID- 26508170 TI - Exposure to different glyphosate formulations on the oxidative and histological status of Rhamdia quelen. AB - Due to the wide use of glyphosate (GLY) in soybean cultivation, their residues in the environment may affect non-target organisms such as fish, developing toxic effects. Despite GLY being widely used in Brazil, there are few studies comparing the effects of commercial formulations in native freshwater fish species. Silver catfish (Rhamdia quelen) were exposed to three different commercial formulations of GLY 48% (Orium((r)), Original((r)) and Biocarb((r))) at 0.0, 2.5 and 5.0 mg/L for 96 h. The effects in thiobarbituric acid-reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST) and histological alterations were analysed in the liver, whereas alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were studied in the plasma. In the liver, TBARS levels increased and CAT decreased in all treatments and herbicides tested in comparison with the control group. The SOD increased at 2.5 mg/L of Orium((r)), Original((r)) and 5.0 mg/L Orium((r)) and Biocarb((r)), whereas GST increased at 2.5 mg/L Orium((r)) and decreased at 2.5 mg/L Biocarb((r)) when compared to the control group. The main histopathological alterations in hepatic tissue were vacuolisation, leucocyte infiltration, degeneration of cytoplasm and melanomacrophage in all GLY treatments. The ALT decreased after exposure to 2.5 mg/L of Biocarb((r)) and AST increased at 2.5 mg/L of Orium((r)), Original((r)) and 5.0 mg/L of Biocarb((r)) in comparison with the control group. In summary, the oxidative damage generated by GLY may have caused the increased formation of free radicals that led to the histological alterations observed in hepatocytes. PMID- 26508171 TI - Acyl-coenzyme A oxidases 1 and 3 in brown trout (Salmo trutta f. fario): Can peroxisomal fatty acid beta-oxidation be regulated by estrogen signaling? AB - Acyl-coenzyme A oxidases 1 (Acox1) and 3 (Acox3) are key enzymes in the regulation of lipid homeostasis. Endogenous and exogenous factors can disrupt their normal expression/activity. This study presents for the first time the isolation and characterization of Acox1 and Acox3 in brown trout (Salmo trutta f. fario). Additionally, as previous data point to the existence of a cross-talk between two nuclear receptors, namely peroxisome proliferator-activated receptors and estrogen receptors, it was here evaluated after in vitro exposures of trout hepatocytes the interference caused by ethynylestradiol in the mRNA levels of an inducible (by peroxisome proliferators) and a non-inducible oxidase. The isolated Acox1 and Acox3 show high levels of sequence conservation compared to those of other teleosts. Additionally, it was found that Acox1 has two alternative splicing isoforms, corresponding to 3I and 3II isoforms of exon 3 splicing variants. Both isoforms display tissue specificity, with Acox1-3II presenting a more ubiquitous expression in comparison with Acox1-3I. Acox3 was expressed in almost all brown trout tissues. According to real-time PCR data, the highest estrogenic stimulus was able to cause a down-regulation of Acox1 and an up regulation of Acox3. So, for Acox1 we found a negative association between an estrogenic input and a directly activated PPARalpha target gene. In conclusion, changes in hormonal estrogenic stimulus may impact the mobilization of hepatic lipids to the gonads, with ultimate consequences in reproduction. Further studies using in vivo assays will be fundamental to clarify these issues. PMID- 26508172 TI - Sequences analyses and expression profiles in tissues and embryos of Japanese flounder (Paralichthys olivaceus) PRDM1. AB - PRDM1 (PRDI-BF1-RIZ1 homologous domain containing 1) appears to be a pleiotropic regulatory factor in various processes. It contains a PR (PRDI-BF1-RIZ1 homologous) domain protein and five zinc fingers. In the present study, a gene coding the homolog of prdm1 and the 5' regulatory region of prdm1 was identified from the Paralichthys olivaceus (denoted Po-prdm1). Results of real-time quantitative polymerase chain reaction amplification (RT-qPCR) and in situ hybridization (ISH) in embryos revealed that Po-prdm1 was highly expressed between the early gastrula and tail bud stages, with its expression peaking in the mid-gastrula stage, whereas the results of RT-qPCR and ISH in tissues demonstrated that Po-prdm1 transcripts were ubiquitously detected in all tissues, which indicates its pleiotropic function in multiple processes. ISH of gonadal tissues revealed that the transcripts were located in the nucleus and cytoplasm of the oocytes in the ovaries but only in the spermatogonia and not in the spermatocytes in the testes. The Po-prdm1 transcription factor binding sites and their conserved binding region among vertebrates were analyzed in this study. The combined results suggest that Po-PRDM1 has a conserved function in teleosts and mammals. PMID- 26508173 TI - Prevalence and characteristics of child victims in motor vehicle collisions in Panama. AB - OBJECTIVE: Fatalities from motor vehicle collisions are one of the leading causes of death among children in developed countries. Previous publications have shown that the rate is approximately 4 times higher in Latin American countries. We aimed to determine the prevalence and characteristics of child victims of motor vehicle collisions in Panama and to compare them with data from a more developed country. In this study, Spain was the country chosen for such comparison. METHODS: A descriptive and retrospective study on the prevalence and characteristics of child victims from motor vehicle collisions that occurred from 2005 to 2012 in Panama was performed. To carry out this study, the records pertaining to victims of motor vehicle collisions in Panama were obtained from the National Institute of Statistics and Census and the Spanish data were obtained from the Road Accident Report. The variables analyzed were age, sex, number of victims, number of injuries, number of fatalities, and type of motor vehicle collision. RESULTS: The child mortality rate in Panama by motor vehicle collisions during the evaluated time period ranged from 2.11 to 3.63, whereas mortality rates in Spain ranged from 0.6 to 1.9, making rates in Panama 3 to 4 times higher than the rates observed in Spain. Children under 5 years old were the group with the highest number of fatalities in Panama. CONCLUSIONS: In Panama, a lack of specific legislation on the use of child restraints (car seats) as well as a lack of information and awareness campaigns could be responsible for the high toll of child victims associated with motor vehicle collisions. PMID- 26508174 TI - Sustainable farming practices of the Chinese mitten crab (Eriocheir sinensis) around Hongze Lake, lower Yangtze River Basin, China. AB - Results of a survey of 156 Chinese mitten crab (Eriocheir sinensis) grow-out farms around Hongze Lake (118.48-118.72 degrees E; 33.36-33.38 degrees N) are reported. Area farmed has remained relatively unchanged but production (59 932 t in 2012) increased steadily over the last 7 years, indicative of the viability and sustainability of the farming system that has gradually replaced intensive Chinese major carp polyculture around Hongze Lake. Results showed that production range was 135-2400 kg ha(-1) cycle(-1) (mean 1144 +/- 34). Crab yields correlated linearly to stocking density and conformed to a normal distribution curve, with 66.7 % of farms yielding 900 kg ha(-1) cycle(-1) or more. Yield was negatively correlated to pond size and capture size (p < 0.01), and farms with macrophyte coverage rate lower than 30 % of water surface were significantly (p < 0.05) lower than those exceeding 30 %. PMID- 26508175 TI - Understanding the conflicting values associated with motorized recreation in protected areas. AB - The International Union for the Conservation of Nature World Parks Congress in 2014 reported that the quality of management of protected areas is crucial in halting the loss of the world's biodiversity and meeting global environmental challenges. However, increasingly high-impact activities, including motorized recreation are occurring in protected areas such as national parks, creating an ongoing clash of values and further compromising protected area management. This paper discusses the values of protected areas in the context of increasingly high impact motorized usage, the impact of divergent values placed on green spaces such as national parks, and perceptions about these spaces. Given the changing global context of this millennium, and increasing populations requiring space for high-impact activities including motorized recreation, rethinking recreation in protected areas is needed. A protected area classification to accommodate high impact activities away from vulnerable natural areas may assist in maintaining protected area quality. PMID- 26508176 TI - Influence of the size and charge of gold nanoclusters on complexation with siRNA: a molecular dynamics simulation study. AB - The complexation of small interfering RNA (siRNA) with positively charged gold nanoclusters has been studied in the present investigation with the help of classical molecular dynamics and steered molecular dynamics simulations accompanied by free energy calculations. The results show that gold nanoclusters form a stable complex with siRNA. The wrapping of siRNA around the gold nanocluster depends on the size and charge on the surface of the gold cluster. The binding pattern of the gold nanocluster with siRNA is also influenced by the presence of another cluster. The interaction between the positively charged amines in the gold nanocluster and the negatively charged phosphate group in the siRNA is responsible for the formation of complexes. The binding free energy value increases with the size of the gold cluster and the number of positive charges present on the surface of the gold nanocluster. The results reveal that the binding energy of small gold nanoclusters increases in the presence of another gold nanocluster while the binding of large gold nanoclusters decreases due to the introduction of another gold nanocluster. Overall, the findings have clearly demonstrated the effect of size and charge of gold nanoclusters on their interaction pattern with siRNA. PMID- 26508177 TI - New ATP-binding cassette A3 mutation causing surfactant metabolism dysfunction pulmonary type 3. AB - Respiratory distress syndrome (RDS) may occur in term and near-term infants because of mutations in surfactant-related genes. ATP-binding cassette A3 (ABCA3), a phospholipid carrier specifically expressed in the alveolar epithelium, is the most frequently involved protein. We report the case of a couple of late-preterm fraternal twin infants of opposite sex carrying the same compound heterozygous ABCA3 mutations, one of which has never been previously reported, with different disease severity, suggesting variable penetrance or sex related differences. ABCA3 deficiency should be considered in term or near-term babies who develop unexplained RDS. PMID- 26508178 TI - Adenovirus necrotizing hepatitis complicating atypical teratoid rhabdoid tumor. AB - Adenovirus-induced fulminant hepatitis is rare. It has been reported in children with primary immunodeficiency, following transplantation or while receiving chemotherapy for hematological malignancy. We present the case of an infant recovering from chemotherapy for atypical teratoid rhabdoid tumor (ATRT) in whom a diagnosis of hepatic necrosis due to adenovirus was made. PMID- 26508179 TI - Radionuclide cholescintigraphy in genetically confirmed Rotor syndrome. AB - A 7-year-old girl had been followed up for persistent conjugated hyperbilirubinemia since birth. Alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transpeptidase activity was within the normal range, and liver protein synthesis had always been normal. Infectious etiology of jaundice, autoimmune diseases, drug-induced liver injury, hemolytic anemia, alpha 1 anti-trypsin deficiency, Wilson disease and Gilbert syndrome were ruled out. At the age of 8 years the patient underwent radionuclide dynamic cholescintigraphy, indicating poor accumulation of the radiotracer in the liver on one hand, and severe retention of the radiopharmaceutical in the blood pool (including the heart) on the other hand. Rotor syndrome was suspected and finally confirmed on molecular analysis. This case represents the first cholescintigraphy report in a pediatric patient with genetically proven Rotor syndrome. PMID- 26508180 TI - Acute Raoultella planticola cystitis in a child with rhabdomyosarcoma of the bladder neck. AB - Raoultella planticola is a Gram-negative, non-motile, aerobic bacillus. It is an environmental bacteria found in soil and water, and a very rare cause of local or systemic infection in humans. Although some adult cases of R. planticola infection have been reported, childhood local or systemic infection caused by R. planticola is very rare. Reported herein is a rare case of acute cystitis due to R. planticola in a 16-month-old boy with rhabdomyosarcoma of the bladder neck, and a review of the literature. PMID- 26508181 TI - Surgical complications due to postnatal cytomegalovirus infection in a preterm infant with malrotation. AB - We report a case of an extremely preterm infant with intestinal malrotation who contracted postnatal systemic cytomegalovirus (CMV) infection with a complicated intestinal evolution requiring repeated surgical interventions and antiviral treatment. This report is to emphasize that prolonged gastrointestinal symptoms in extremely preterm infants fed with non-pasteurized breast milk should lead to suspicion of CMV infection. The importance of preventive measures when feeding very preterm infants with breast milk needs to be considered. Furthermore, the indications for antiviral treatment, in particular in preterm infants, need to be clarified. PMID- 26508182 TI - Pediatric myositis ossificans mimicking osteosarcoma. AB - Myositis ossificans (MO) is a rare benign cause of heterotopic bone formation in soft tissue that most commonly affects young adults, typically following trauma. We report the case of an 11-year-old girl who developed MO mimicking osteosarcoma in her right shoulder. Plain radiography and computed tomography showed poorly defined flocculated densities in the soft tissue and a periosteal reaction along the proximal humerus. On magnetic resonance imaging, the mass displayed an ill defined margin and inhomogeneous signal change. Histologically, the mass had a pseudosarcomatous appearance. Based on these findings, the patient was initially misdiagnosed with osteosarcoma at another hospital. The diagnosis was difficult because the patient was 11 years old and had no trauma history, with atypical radiographic changes and a predilection for the site of origin for osteosarcomas. We finally made the correct diagnosis of MO by carefully reviewing and reflecting on the pathological differences between stages. PMID- 26508183 TI - Escherichia coli O121:H19 infection identified on microagglutination assay and PCR. AB - Non-O157 Shiga toxin-producing Escherichia coli (STEC) strains are increasingly recognized as foodborne pathogens that trigger hemolytic uremic syndrome (HUS). The detection and isolation of these strains is important, but distinguishing their bacteriological profiles is difficult. A 2-year-old girl developed HUS with mild renal involvement 22 days after consuming barbecued meat. Clinical and laboratory findings gradually improved without specific treatment. Because neither enterohemorrhagic E. coli (EHEC) nor Shiga toxins were detected in stool cultures in a clinical laboratory and the patient tested negative for circulating antibodies to O157 lipopolysaccharide, the case was initially diagnosed as probable atypical HUS. Subsequent serodiagnostic microagglutination assay and polymerase chain reaction-based molecular testing, however, indicated the presence of the EHEC O121:H19 strain with stx2. Thus, to correctly diagnose and treat HUS, a system for detecting non-O157 STEC in a clinical setting is urgently needed. PMID- 26508184 TI - Idiopathic pulmonary hemosiderosis complicated by Down syndrome. AB - We report the case of a 9-year-old girl with Down syndrome (DS) diagnosed with idiopathic pulmonary hemosiderosis (IPH). Although acute pneumonia complicated by hemolytic anemia was suspected, IPH was finally diagnosed on bronchoscopy. Treatment with prednisolone achieved good clinical response. An association between IPH and DS was not able to be identified, but immunological issues in DS may contribute to the onset of IPH. Recurrent and intractable respiratory symptoms with marked infiltrative shadows in the bilateral lungs and complicated by severe anemia in patients with DS should suggest IPH. PMID- 26508185 TI - Remission of autoimmune neutropenia after development of Kawasaki disease. AB - We report the second case of the association of Kawasaki disease (KD) and autoimmune neutropenia (AIN). A 21-month-old female diagnosed as having AIN of infancy developed a complete KD when severe neutropenia continued. The patient suffered from no coronary artery lesions, and well responded to a single high dose gamma-globulin therapy. The cytokine profile of the neutropenic infant was representative of the typical KD. Neutrophil counts notably increased during the convalescent phase of KD, and were then normalized forthwith. The prompt resolutions of KD and AIN paralleled the increase of circulating transforming growth factor (TGF)-beta1 levels. The clinical course of the patient was contrasted to that of the first reported case of a patient who developed severe and refractory KD after the high dose granulocyte-colony stimulating factor (G CSF) therapy. PMID- 26508186 TI - Infective endocarditis associated with acute leukemia: Report of two cases. AB - There have been few reports regarding infective endocarditis (IE) in patients with leukemia. In the first case, a 15-year-old girl with Down syndrome was diagnosed with acute lymphoblastic leukemia. On admission, methicillin-sensitive Staphylococcus aureus (MSSA) was detected on blood culture. Echocardiography was performed because MSSA was detected repeatedly even after treatment. Vegetation in all of the atria and ventricles met the Duke criteria defining IE. She died of multiple organ failure 21 days after diagnosis. In the second case, an 11-year old boy with acute myeloid leukemia underwent peripheral blood stem cell transplantation (PBSCT). He had fever 68 days after PBSCT, and methicillin resistant S. aureus (MRSA) was detected on blood culture. Echocardiography showed vegetation in the right atrium and ventricle. Daptomycin was administered for 7 weeks, and recurrence was not observed. IE should be considered when S. aureus bacteremia is documented even in patients with leukemia. PMID- 26508187 TI - Effects of tolvaptan on congestive heart failure complicated with chylothorax in a neonate. AB - Tolvaptan is an oral vasopressin type 2 receptor antagonist that can be used for heart failure patients with hyponatremia or symptomatic congestion. Although the effects of tolvaptan in adults have been well documented, only limited information is available in children. The case of a neonate with congestive heart failure complicated with chylothorax after palliative surgery for transposition of the great arteries treated with tolvaptan is reported. Slow up-titration to 0.1 mg/kg successfully increased urine output and improved refractory congestive heart failure without hypernatremia. Subsequently, bodyweight and chylothorax decreased gradually. Moreover, the use of tolvaptan reduced the dosage of furosemide. Tolvaptan could be an alternative drug for neonates with congestive heart failure. Further large studies are needed to confirm the efficacy and identify the appropriate dose of tolvaptan in neonates. PMID- 26508188 TI - Adrenocortical tumor with precocious puberty in a 2-month-old girl. AB - Adrenocortical tumor is a rare childhood tumor with a median age at onset of 3.2 years. Virilization is the most common sign. Laparotomy is the reference treatment and has a favorable course. The diagnosis of adrenal tumor can be difficult. The main parameters of malignant tumors are size and metastasis. Analysis of TP53 mutation can facilitate final diagnosis. We report a case of virilizing adrenal tumor that developed in a 2-month-old girl, and which was treated with laparoscopic adrenalectomy. PMID- 26508189 TI - Features of children with positive celiac serology and type 1 diabetes mellitus. AB - Prior studies have reported disparate clinical presentations between children with celiac disease and type 1 diabetes mellitus and those with celiac disease alone. Studies focusing on differences in endoscopic and histopathological findings, however, are limited. We reviewed children aged 2-18 years, presenting for an initial evaluation between January 2000 and December 2010. Data on medical history, serologic markers, upper endoscopy, and histopathology were collected. Only the children with positive celiac serology who had upper endoscopy performed within 3 months of the initial visit were included. We identified 294 children who fulfilled the criteria, 21 of whom had diagnosed type 1 diabetes mellitus. Diabetic children were more likely to have absence of gastrointestinal symptoms. Erythematous duodenal and esophageal mucosa on endoscopy, and histopathology suggestive of reflux esophagitis were more common in the diabetes group. Diabetic children with positive celiac serology had different histopathological features as compared with their non-diabetic counterparts. PMID- 26508190 TI - Eligibility for palivizumab prophylaxis in a cohort of children with severe bronchiolitis. AB - In 2014, the American Academy of Pediatrics (AAP) updated their recommendations for palivizumab prophylaxis for children who are at high risk for severe respiratory syncytial virus (RSV) infection. To investigate the potential impact of the more restrictive 2014 criteria on the eligibility for palivizumab prophylaxis, we applied the 2012 and 2014 AAP recommendations for palivizumab prophylaxis to a multicenter cohort of 2207 US children hospitalized for bronchiolitis. According to the 2012 AAP recommendations, 215 children (9.7%) were eligible for palivizumab prophylaxis, while 140 children (6.3%) would have been eligible based on the 2014 updated recommendations (34.9% relative decrease; 95%CI: 28.5-41.7%). The decrease was largely driven by the restriction of eligibility to preterm infants with gestational age <29 weeks. Further development of and refinement of cost-effective approaches for the prevention of severe RSV infection are needed. PMID- 26508191 TI - Spontaneous improvement in a pediatric patient with peripheral T-cell lymphoma. AB - Peripheral T-cell lymphoma (PTCL) is rare in children, and it has a poor prognosis compared with other types of lymphoma. We report the case of a 7-year old boy with spontaneous improvement of PTCL complicated by hemophagocytic syndrome as the initial symptom. He complained of pain and swelling of the right neck and presented with high fever. Pancytopenia, liver dysfunction, elevated ferritin and soluble interleukin 2 receptor were noted on laboratory tests. Peripheral blood plasma and white blood cells were positive for Epstein-Barr virus (EBV) genome but, after several days, the fever abated and laboratory data improved. On histopathology of lymph node biopsy, he was diagnosed as having PTCL not otherwise specified (PTCL-NOS) with EBV infection. He received no chemotherapy and was disease free at the last follow up, 6 years 8 months after onset. This is probably the first case of spontaneous improvement in PTCL-NOS. Careful treatment planning is therefore necessary in PTCL-NOS, given the possibility of spontaneous improvement of symptoms. PMID- 26508192 TI - Pneumomediastinum, pneumorrhachis and subcutaneous emphysema associated with viral infections: Report of three cases. AB - Spontaneous pneumomediastinum is usually secondary to alveolar rupture in the pulmonary interstitium, associated with subcutaneous emphysema and occasionally with pneumothorax, but is rarely associated with pneumorrhachis. The leaked air into the pulmonary perivascular interstitium follows the path of least resistance from the mediastinum to the fascial planes of the neck. Air freely communicates via the neural foramina and collects in the epidural space. Pneumorrhachis is defined as the presence of air in the spinal canal, either in the intradural and/or extradural spaces. It is a very rare clinical entity and mostly asymptomatic, hence most probably underdiagnosed. Many pathological and physiological events can lead to alveolar rupture, and these clinical findings can be related to various, mainly traumatic and iatrogenic etiologies. Herein we report three cases of pneumomediastinum, subcutaneous emphysema, interstitial emphysema and pneumorrhachis in two cases, which were related to rhinovirus, human bocavirus and respiratory syncytial virus infection. PMID- 26508193 TI - Incidence of childhood primary immune thrombocytopenic purpura. AB - There is a discrepancy in the reported incidence of childhood immune thrombocytopenic purpura (ITP) between Europe (2.9-5.3 per 100 000 persons) and Japan (1.91). Ise district is a suitable area in which to conduct epidemiological study because there is little fluctuation in the sociodemographic factors. We performed a retrospective population-based study to clarify the incidence of primary childhood ITP. We calculated person-years for children aged <15 years based on the Ise district demographics between 2002 and 2012. The calculated person-years were 298 533. The number of hospitalized patients in Ise district was 25 (M/F, 14/11) during the study period. The calculated incidence was therefore 8.4 per 100 000 person-years. It is possible that the difference in incidence between the present calculation and that of the European studies is due to variation in accuracy and/or registration criteria between the studies. PMID- 26508194 TI - Relieving pain and distress during venipuncture: Pilot study of the Japan Environment and Children's Study (JECS). AB - Pain management for needle-related procedures is poor in Japan. In many countries the use of lidocaine/prilocaine cream for the relief of pain associated with venipuncture has been approved. In children, a psychological approach has also been shown to be effective in reducing pain with venipuncture. We developed a multidisciplinary procedure that combines a cream (2.5% lidocaine and 2.5% prilocaine) and pharmacological approaches such as preparation, education, positioning and distraction. We evaluated the feasibility and acceptability of the procedure for young children. Among 132 pediatric participants, 58.3% did not cry during venipuncture. According to caregiver questionnaire, 71.9% felt that the multidisciplinary procedure eliminated the fear of needle-related procedures in the children; 90.9% were satisfied with it and 75.8% thought it should be applied to all children undergoing venipuncture. The present results suggest that the multidisciplinary procedure is feasible, acceptable and suitable for use in children undergoing venipuncture. PMID- 26508195 TI - Ingested large fish hook in the stomach of a 2-year-old boy. PMID- 26508196 TI - Suction entrapment of an upper limb in a swimming pool. PMID- 26508197 TI - Giant thymolipoma in a young child initially diagnosed as cardiomegaly. PMID- 26508198 TI - Pyomyositis and bacteremia due to Staphylococcus aureus as onset of acute promyelocytic leukemia. PMID- 26508199 TI - How long is transient tachypnea of the newborn dependent on oxygen supplementation? PMID- 26508200 TI - Iodine-induced non-autoimmune hypothyroidism in a patient with steroid-resistant nephrotic syndrome. PMID- 26508201 TI - Characteristics and prognosis of hepatocellular carcinoma detected in patients with chronic hepatitis C after the eradication of hepatitis C virus: A multicenter study from Japan. AB - AIM: We investigated the characteristics and prognosis of patients with hepatocellular carcinoma (HCC) diagnosed after sustained virological response (SVR) to antiviral therapy for chronic hepatitis C virus (HCV) infection, namely, the eradication of HCV, according to surveillance status after SVR. METHODS: In this multicenter study, liver function at HCC diagnosis and progression of HCC among patients with HCC diagnosed after SVR were compared. Outcomes were also investigated. RESULTS: In patients not under surveillance after SVR, HCC was significantly more advanced at diagnosis, with tumors that were larger in size and of higher stage than in patients who continued under surveillance after SVR. Survival rates were significantly lower in patients not under surveillance (P < 0.0001). Among patients who were under surveillance, those with a 6-month surveillance interval had larger and higher stage HCC than patients with a 3 month interval. Recurrence rates in patients with a 6-month surveillance interval were significantly higher than in patients with a 3-month surveillance interval (P = 0.0417). CONCLUSION: Lack of surveillance after SVR was obviously associated with more advanced HCC at detection, resulting in poor prognosis. More importantly, there may be a difference in the severity of HCC at diagnosis and prognosis based on the surveillance interval after SVR. Establishing guidelines how to survey patients with chronic hepatitis C after SVR is necessary. PMID- 26508202 TI - Platform Technologies for Directly Reconstructing 3D Living Biomaterials. AB - Bio-electrospraying and cell electrospinning is explored for reconstructing living biomaterials for regenerative biology and medicine. The investigations carried out in this study demonstrate these approaches as platform biotechnologies for tissue reconstruction for repair, replacement, and rejuvenation of damaged and/or ageing tissues and/or organs. PMID- 26508203 TI - Ex vivo confocal microscopy: a new diagnostic technique for mucormycosis. AB - BACKGROUND: Skin-dedicated ex vivo confocal microscopy (EVCM) has so far mainly been employed to identify cutaneous tumours on freshly excised samples. We present two cases where EVCM has been used to diagnose cutaneous mucormycosis. METHODS: The skin biopsies were evaluated by the skin-dedicated ex vivo confocal microscope VivaScope 2500((r)) (MAVIG GmbH, Munich Germany) under both reflectance and fluorescence mode. Conventional direct optical examination on skin scraping and histological examination were later performed. RESULTS: Mucormycetes observed by EVCM presented as hyper-reflective elongated 20 MUm in diameter structures with perpendicular ramifications. Fungi were found both under reflectance and fluorescence mode and were better visible with acridine orange under fluorescence EVCM. Conventional direct optical examination on skin scraping and histological examination found the same elongated and branching structures confirming the presence of Mucormycetes. CONCLUSIONS: Ex vivo confocal microscopy has both the advantages of being fast as the direct optical examination, and to be able to show the localisation of the fungi in the tissue like the histological examination. In our cases, EVCM allowed to rapidly confirm the clinical diagnosis of mucormycosis, which is essential for the treatment of this fungal infection. Further studies are needed to compare the performance of EVCM with the findings of conventional histological and mycological examinations. PMID- 26508204 TI - Somatic mosaic mutations of IDH1 and NPM1 associated with cup-like acute myeloid leukemia in a patient with Maffucci syndrome. AB - Maffucci syndrome is a nonhereditary congenital disorder characterized by multiple enchondromas and with soft-tissue hemangiomas. Somatic mutations of the isocitrate dehydrogenase (IDH) gene have been detected in enchondroma and hemangioma tissue from patients with Maffucci syndrome. The rate of malignant transformation in Maffucci syndrome is high, with enchondromas transforming into chondrosarcomas and the development of secondary neoplasms, including pancreatic and hepatic adenocarcinoma, mesenchymal ovarian tumors, and brain tumors such as glioma. However, hematopoietic malignancies arising in Maffucci syndrome are rare. We report a 7-year-old girl with Maffucci syndrome in whom acute myeloid leukemia (AML) with cup-like nuclear invagination developed. Both leukemic cells and hemangioma had the same gene mutations: an insertion frameshift c.863_864insTCTG (p.W288 fs) in the nucleophosmin (NPM1) gene and a missense mutation c.392_395GTCG > CTCT (p.G131_R132 > AL) in the IDH1 gene. However, buccal mucosa cells and peripheral blood mononuclear cells harvested after two cycles of chemotherapy showed wild-type genotypes. These results suggest that the multiple somatic mutations of the IDH1 and NPM1 genes in hemangioblasts are related to the development of cup-like AML associated with Maffucci syndrome. However, further studies are needed to identify additional molecular events in AML but not in hemangioma. PMID- 26508205 TI - Discovery of the magnetic behavior of hemoglobin: A beginning of bioinorganic chemistry. AB - Two articles published by Pauling and Coryell in PNAS nearly 80 years ago described in detail the magnetic properties of oxy- and deoxyhemoglobin, as well as those of closely related compounds containing hemes. Their measurements revealed a large difference in magnetism between oxygenated and deoxygenated forms of the protein and, along with consideration of the observed diamagnetism of the carbonmonoxy derivative, led to an electronic structural formulation of oxyhemoglobin. The key role of hemoglobin as the main oxygen carrier in mammalian blood had been established earlier, and its allosteric behavior had been described in the 1920s. The Pauling-Coryell articles on hemoglobin represent truly seminal contributions to the field of bioinorganic chemistry because they are the first to make connections between active site electronic structure and the function of a metalloprotein. PMID- 26508206 TI - News Feature: Beyond graphene. PMID- 26508208 TI - Quantification of excretory renal function and urinary protein excretion by determination of body cell mass using bioimpedance analysis. AB - BACKGROUND: Creatinine clearance (CrCl) based on 24 h urine collection is an established method to determine glomerular filtration rate (GFR). However, its measurement is cumbersome and the results are frequently inaccurate. The aim of this study was to develop an alternative method to predict CrCl and urinary protein excretion based on plasma creatinine and the quantification of muscle mass through bioimpedance analysis (BIA). METHODS: In 91 individuals with normal and impaired renal function CrCl was measured from 24 h urine excretion and plasma creatinine concentration. A model to predict 24 h-creatininuria was developed from various measurements assessing muscle mass such as body cell mass (BCM) and fat free mass (FFM) obtained by BIA, skinfold caliper and other techniques (training group, N = 60). Multivariate regression analysis was performed to predict 24 h-creatininuria and to calculate CrCl. A validation group (N = 31) served to compare predicted and measured CrCl. RESULTS: Overall (accuracy, bias, precision, correlation) the new BIA based prediction model performed substantially better compared with measured CrCl (P15 = 87 %, bias = 0, IQR of differences = 7.9 mL/min/1.73 m(2), R = 0.972) versus established estimation formulas such as the 4vMDRD (P15 = 6 %, bias = -8.3 mL/min/1.73 m(2), IQR = 13.7 mL/min/1.73 m(2), R = 0.935), CKD-EPI (P15 = 29 %, bias = -7.0 mL/min/1.73 m(2), IQR = 12.1 mL/min/1.73 m(2), R = 0.932, Cockcroft-Gault equations (P15 = 55 %, bias = -4.4 mL/min/1.73 m(2), IQR = 9.0 mL/min/1.73 m(2), R = 0.920). The superiority of the new method over established prediction formulas was most obvious in a subgroup of individuals with BMI > 30 kg/m(2) and in a subgroup with CrCl > 60 mL/min/1.73 m(2). Moreover, 24 h urinary protein excretion could be estimated accurately by normalization with 24 h-creatininuria derived from BIA based BCM. CONCLUSION: Prediction of CrCl based on estimated urinary creatinine excretion determined from measurement of BCM by BIA technique is both accurate and convenient to quantify renal function in normal and diseased states. This new method may become particularly helpful for the evaluation of patients with borderline renal insufficiency and/or with abnormal body composition. PMID- 26508209 TI - Semisynthetic photoprotein reporters for tracking fast Ca(2+) transients. AB - Changes in the intracellular concentration of free ionized calcium ([Ca(2+)]i) control a host of cellular processes as varied as vision, muscle contraction, neuronal signal transmission, proliferation, apoptosis etc. The disturbance in Ca(2+)-signaling causes many severe diseases. To understand the mechanisms underlying the control by calcium and how disorder of this regulation relates to pathological conditions, it is necessary to measure [Ca(2+)]i. The Ca(2+) regulated photoproteins which are responsible for bioluminescence of marine coelenterates have been successfully used for this purpose over the years. Here we report the results on comparative characterization of bioluminescence properties of aequorin from Aequorea victoria, obelin from Obelia longissima, and clytin from Clytia gregaria charged by native coelenterazine and coelenterazine analogues f, i, and hcp. The comparison of specific bioluminescence activity, stability, emission spectra, stopped-flow kinetics, sensitivity to calcium, and effect of physiological concentrations of Mg(2+) establishes obelin-hcp as an excellent semisynthetic photoprotein to keep track of fast intracellular Ca(2+) transients. The rate of rise of its light signal on a sudden change of [Ca(2+)] is almost 3- and 11-fold higher than those of obelin and aequorin with native coelenterazine, respectively, and 20 times higher than that of the corresponding aequorin-hcp. In addition, obelin-hcp preserves a high specific bioluminescence activity and displays higher Ca(2+)-sensitivity as compared to obelin charged by native coelenterazine and sensitivity to Ca(2+) comparable with those of aequorin f and aequorin-hcp. PMID- 26508210 TI - HPLC 2015. AB - The HPLC 2015 Conference was held from 21 to 25 June at the International Conference Center in Geneva, Switzerland. The emphasis of the meeting was around fundamental aspects of separations, sample preparation, novel developments and applications and hyphenation with MS. In this conference report, a selection of highlights of the Conference is given, based on the sessions attended by the authors, and focusing on subjects with possible relevance in the field of drug metabolism and bioanalysis. Selected papers from HPLC 2015 will be published in a virtual special issue of the Journal of Chromatography. PMID- 26508211 TI - GPs should wake up to their workforce's woes. PMID- 26508212 TI - Burns nurses highlight fancy dress fire risk. PMID- 26508214 TI - Give support staff band 5 roles, says Skills for Health. PMID- 26508213 TI - RCN welcomes guidance on safe staffing in Labour peer's review. PMID- 26508215 TI - Ombudsman's report outlining service failures prompts NHS trusts to improve. PMID- 26508216 TI - Use of temporary nurses up by 15% in Scotland. PMID- 26508217 TI - Seacole award winners announced. PMID- 26508218 TI - Urgent funding needed if vision for neonatal care is to become a reality. PMID- 26508220 TI - Better action plans could reduce deaths from asthma. PMID- 26508219 TI - Liverpool faces practice nursing crisis as 80% are soon to retire. PMID- 26508221 TI - Booklet focuses on dementia patients' hospital care needs. PMID- 26508222 TI - Depression during pregnancy--alert. PMID- 26508230 TI - Birth after caesarean section. PMID- 26508224 TI - Relief for staff and employers as visa threat lifts for overseas nurses. PMID- 26508231 TI - Paving the way for safe discharge. PMID- 26508232 TI - Keep score and help to ensure fair play. PMID- 26508243 TI - Jointly. PMID- 26508245 TI - Care for the older person should be all about the individual, not the age. PMID- 26508246 TI - Building care facilities at acute hospitals is a retrograde step. PMID- 26508247 TI - Age discrimination does persist, and nurses can challenge it. PMID- 26508248 TI - We can be trusted to judge how best to interact with patients. PMID- 26508251 TI - How useful are defibrillators installed in community settings? PMID- 26508253 TI - How to remove a tracheostomy tube. PMID- 26508254 TI - Attitudes to smoking and smoking cessation among nurses. AB - This article presents a literature review on smoking rates among nurses and the nursing role in promoting smoking cessation worldwide. Findings included wide variations between countries in smoking rates among nurses, and the important influence of peers and family members on smoking behaviours. Several studies indicated that nurses would value more education on techniques to promote smoking cessation. PMID- 26508255 TI - Pain management: a fundamental component of dementia care. AB - Pain is a multifaceted experience with physical, psychological, social and spiritual components. Dementia, which is often accompanied by impaired communication, complicates the assessment and treatment of pain. Although older people with dementia share the same age-related pathology as other older people, they do not experience the same access to pain relief as their cognitively unimpaired counterparts. Tools have been developed to enhance self-reporting of pain by people with dementia and the objective observation of non-verbal signs of pain. The first step, however, is awareness that pain might be present and can be responsible for otherwise unexplained distress and behaviour change. Recognition of pain should trigger the appropriate and timely use of pain assessment tools. Pharmaceutical and non-pharmaceutical measures to relieve pain should be used as appropriate. Evaluation of the efficacy of these methods is needed on an ongoing basis. People living with dementia deserve to be listened to, no matter how they choose to express pain, and to have their pain minimised effectively and efficiently. PMID- 26508256 TI - Paediatric anaesthesia: an overview. AB - This article provides an overview of the nursing considerations for paediatric anaesthesia. It is aimed at newly qualified operating department practitioners and anaesthetic nurses, and those with limited experience in the care of paediatric patients. It explores the ways in which paediatric anatomy and physiology differ from those of adults and looks at the implications for treatment in the anaesthetic environment. It also discusses the equipment required and the rationale for its use. PMID- 26508257 TI - 6Cs in mentorship. PMID- 26508258 TI - Delivering the goods. PMID- 26508259 TI - Time to kickstart your career. PMID- 26508262 TI - How to get the best from mentoring. PMID- 26508263 TI - Mineralization of the antibiotic levofloxacin in aqueous medium by electro-Fenton process: kinetics and intermediate products analysis. AB - The present study investigates the feasibility of using electro-Fenton (EF) process for the oxidative degradation of antibiotic levofloxacin (LEV). The EF experiments have been performed in an electrochemical cell using a carbon-felt cathode. The effect of applied current in the range 60-500 mA and catalyst concentration in the range 0.05-0.5 mM on the kinetics of oxidative degradation and mineralization efficiency have been investigated. Degradation of LEV by hydroxyl radicals was found to follow pseudo-first-order reaction kinetics. The absolute rate constant for oxidative degradation of LEV by hydroxyl radical has been determined by a competition kinetics method and found to be (2.48 +/- 0.18) * 10(9) M(-1) s(-1). An optimum current value of 400 mA and a catalyst (Fe(2+)) concentration of 0.1 mM were observed to be optimal for an effective degradation of LEV under our operating conditions. Mineralization of aqueous solution of LEV was performed by the chemical oxygen demand analysis and an almost mineralization degree (>91%) was reached at the end of 6 h of electrolysis. A number of intermediate products have been identified using high performance liquid chromatography and liquid chrmatography-mass spectrometry analyses. Based on these identified reaction intermediates, a plausible reaction pathway has been suggested for the mineralization process. The formation and evolution of [Formula: see text] and [Formula: see text] ions released to the medium during the process were also discussed. PMID- 26508264 TI - Retrograde percutaneous repair of aortic coarctation utilizing trans-septal puncture in patients with complex anatomy. AB - Coarctation of the aorta (COA) is one of the more common congenital anomalies, occurring in four in ten thousand live births and accounting for five to eight percent of all congenital heart defects. COA lesions can be challenging to treat percutaneously, especially if complex vascular anatomy is a barrier to crossing the lesion. We present two cases of COA that utilized a trans-septal approach to cross the lesion in anterograde fashion, subsequently facilitating retrograde stenting of the lesions after snaring and externalizing the wire. In both cases, the trans-septal approach was employed because traditional femoral and radial approaches failed due to complex anatomy, and the trans-septal approach allowed for effective intervention without the need for surgery. PMID- 26508265 TI - Application of nitrate to enhance biodegradation of gasoline components in soil by indigenous microorganisms under anoxic condition. AB - Anaerobic/anoxic biodegradation of hydrocarbons offers an attractive approach to the removal of these compounds from polluted environments such as aquifers, aquatic sediments, submerged soils and subsurface soils. The application of nitrate was investigated to accelerate the degradation of gasoline components such as mono-aromatic hydrocarbons and total petroleum hydrocarbons (TPH) in soil by indigenous microorganisms under anoxic condition. The addition of nitrate had little effect on the degradation of mono-aromatic hydrocarbons m- & p-xylene, o xylene, sec-butylbenzene and 1,2,4-trimethylbenzene, but facilitated the degradation of TPH (C6-C12) and mono-aromatic hydrocarbons toluene and ethylbenzene markedly. Furthermore, the more nitrate added, the higher the percentage of toluene, ethylbenzene and TPH (C6-C12) degraded after 180 days of anoxic incubation. Microorganisms capable of degrading toluene, ethylbenzene and TPH (C6-C12) with nitrate as the electron acceptor under anaerobic/anoxic condition are composed predominantly of Alpha-, Beta-, Gamma- or Delta proteobacteria. Beta- and Gamma-proteobacteria were the main components of indigenous microorganisms, and accounted for 83-100% of the total amount of indigenous microorganisms in soil used in this study. Furthermore, the total amount of indigenous microorganisms increased with nitrate added. The addition of nitrate stimulated the growth of indigenous microorganisms, and therefore facilitated the degradation of toluene, ethylbenzene and TPH (C6-C12). PMID- 26508266 TI - Inferring Infection Patterns Based on a Connectivity Map of Host Transcriptional Responses. AB - Host responses to infections represent an important pathogenicity determiner, and delineation of host responses can elucidate pathogenesis processes and inform the development of anti-infection therapies. Low cost, high throughput, easy quantitation, and rich descriptions have made gene expression profiling generated by DNA microarrays an optimal approach for describing host transcriptional responses (HTRs). However, efforts to characterize the landscape of HTRs to diverse pathogens are far from offering a comprehensive view. Here, we developed an HTR Connectivity Map based on systematic assessment of pairwise similarities of HTRs to 50 clinically important human pathogens using 1353 gene-expression profiles generated from >60 human cells/tissues. These 50 pathogens were further partitioned into eight robust "HTR communities" (i.e., groups with more consensus internal HTR similarities). These communities showed enrichment in specific infection attributes and differential gene expression patterns. Using query signatures of HTRs to external pathogens, we demonstrated four distinct modes of HTR associations among different pathogens types/class, and validated the reliability of the HTR community divisions for differentiating and categorizing pathogens from a host-oriented perspective. These findings provide a first generation HTR Connectivity Map of 50 diverse pathogens, and demonstrate the potential for using annotated HTR community to detect functional associations among infectious pathogens. PMID- 26508267 TI - Pharmacokinetic and therapeutic efficacy of intrapulmonary administration of zoledronate for the prevention of bone destruction in rheumatoid arthritis. AB - Zoledronate, a third-generation nitrogen-containing bisphosphonate, is a new therapeutic agent for the prevention of joint destruction in rheumatoid arthritis (RA). Due to the poor oral absorption of zoledronate, the intravenous route has been the preferred method of administration. To evaluate whether the lung is a promising alternative route of zoledronate administration for the prevention of joint destruction in RA, we examined the pharmacokinetics, safety and therapeutic potential of zoledronate after intrapulmonary administration. The bioavailability of zoledronate was 55% after intrapulmonary administration in rats. In a collagen induced RA mouse model, an intrapulmonary administration of zoledronate given 7 d before the 2nd collagen immunization effectively suppressed bone loss and joint destruction to a level similar to that achieved with intravenous injection at 21 d after the 2nd collagen immunization. Zoledronate only slightly affected lactate dehydrogenase activity in bronchoalveolar lavage fluid 4 h after intrapulmonary administration of the therapeutic dose in rats. Moreover, zoledronate only slightly changed the plasma level of creatinine after intrapulmonary administration while creatinine significantly increased after intravenous injection of zoledronate in mice. These results indicate that the lung is a promising alternative route of zoledronate administration for the treatment and prevention of joint destruction in RA. PMID- 26508268 TI - U.S. community pharmacies as CLIA-waived facilities: Prevalence, dispersion, and impact on patient access to testing. AB - BACKGROUND: The Clinical Laboratory Improvement Amendments of 1988 (CLIA) enabled greater access to low-risk tests by allowing their use in facilities with a Certificate of Waiver in the U.S. Community pharmacies are among the most accessible health professionals, and they are increasingly offering CLIA-waived tests. This manuscript aims to determine: 1) the current number of pharmacies in the United States with CLIA-waivers; 2) the uptake of CLIA-waivers by different pharmacy store types; and 3) the state-by-state differences in the percentage of pharmacies with a CLIA-waiver. METHODS: Data were collected from the U.S. Centers for Disease Control and Prevention CLIA Laboratory Search website on May 3rd, 2015. The website allows for exportation of demographic data on all CLIA-waived facilities by state. RESULTS: Pharmacies are currently the fourth highest-ranking facility of CLIA-waived laboratories with 10,838 locations. Supermarkets had the highest percentage of pharmacies with a CLIA-waiver (43.16%). States demonstrated considerable variability in the percentage of pharmacies with a CLIA-waiver, with a median percentage of 19.56% (0%-60.00% range). CONCLUSIONS: Community pharmacies are currently a leading facility for CLIA-waived laboratories. Substantial state-level variation is observed in the percentage of pharmacies with CLIA-waivers, and these differences may be driven by restrictions in state law or regulations. PMID- 26508269 TI - Med Wise: A theory-based program to improve older adults' communication with pharmacists about their medicines. AB - BACKGROUND: The health and economic toll of medication errors by older adults is well documented. Poor communication and medication coordination problems increase the likelihood of adverse drug events (ADEs). Older adults have difficulty communicating with health care professionals, including pharmacists. As such, the theory-based Med Wise program was designed. Building on the Self-efficacy Framework and the Chronic Care Model, this program was tested with community dwelling older adults. OBJECTIVES: This study and its resultant paper: (1) describe the theory-based design of the Med Wise program; (2) describe the collaboration of multiple community partners to develop a sustainable model for implementing Med Wise; and (3) present findings from the Med Wise course evaluation. METHODS: Med Wise was designed to be a sustainable, skill-based educational and behavior change program consisting of two, 2-h interactive classes to enhance participants' medication communication skills and self efficacy. To explore the potential to disseminate Med Wise throughout the state, a partnership was formed between the pharmacy team and the statewide Aging & Disability Resource Centers (ADRCs), as well as the Community-Academic Aging Research Network (CAARN). Over 30 lay volunteer leaders in 8 Wisconsin (U.S. State) counties were trained, and they delivered Med Wise through ADRC community centers. The CAARN staff evaluated the fidelity of the course delivery by leaders. To evaluate Med Wise, a quasi-experimental design using pre/post surveys assessed knowledge, worry and self-efficacy. A telephone follow-up three months later assessed self-efficacy and translation of medication management skills and behaviors. RESULTS: Med Wise programs were presented to 198 community-dwelling older adults while maintaining program fidelity. This evaluation found significant increases in older adults' knowledge about pharmacists' roles and responsibilities, likelihood of talking with a pharmacist about medication concerns, and self-efficacy for communicating with pharmacists. At the 3 month follow-up, participants reported increased interactions with pharmacists, with 29.2% of participants reported seeking medication reviews and 28.5% medication schedule reviews. CONCLUSIONS: The two-class Med Wise program showed sustained impact at 3 months on key outcomes. Further, the community partners successfully implemented the program with fidelity across 8 counties suggesting its ability to be disseminated and sustained. Future directions include expanding the program to examine wider adoption, and measuring program impact on regimen safety and health outcomes linked to increases in patient engagement. PMID- 26508270 TI - Quality of life of patients with Parkinson's disease and neurodegenerative dementia: A nationally representative study. AB - BACKGROUND: The disability inherent to Parkinson's disease and dementia would suggest poor health-related quality of life for patients with these neurodegenerative conditions; however, the extent of disability from a nationally representative data has not been previously available. OBJECTIVES: This study examined factors associated with the health-related quality of life in patients with Parkinson's disease and dementia using nationally representative samples. METHODS: The study used data from 2002 to 2011 Medical Expenditure Panel Survey (MEPS), a nationally representative survey of households in the United States. The quality of life of patients was captured based on Physical Component Summary (PCS), Mental Component Summary (MCS), Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL). Multivariate regression models were used to compare PCS, MCS, ADL and IADL across the two neurodegenerative conditions after controlling for various sociodemographic and clinical characteristics. RESULTS: The weighted study population included 0.80 million (95% Confidence Interval, CI: 0.75-0.85) patients; those with Parkinson's disease accounted for 40.23% and remaining 59.77% were diagnosed with dementia. Mean age of the study population was 74.32 years (Standard Deviation, SD = 11.36). Most of the Parkinson's patients were male (57.70%), whereas most of the dementia patients were females (58.10%). The unadjusted mean PCS was 33.66 and 35.31 in Parkinson's and dementia patients, respectively (P < 0.01). Patients with Parkinson's disease were less likely to seek help for IADL than neurodegenerative dementia (Odds Ratio, OR = 0.68, P = 0.02). Various other individual, biological and environmental factors were also associated with quality of life in patients with Parkinson's disease and neurodegenerative dementia. CONCLUSIONS: This study found that patients with Parkinson's disease had lower PCS and were less likely to seek help for IADL when compared to the patients with neurodegenerative dementia. Knowledge of these factors can be helpful in improving quality of life of patients with neurodegenerative diseases. PMID- 26508272 TI - Enhanced Hydrogen Transport over Palladium Ultrathin Films through Surface Nanostructure Engineering. AB - Palladium ultrathin films (around 2 MUm) with different surface nanostructures are characterized by TEM, SEM, AFM, and temperature programmed reduction (TPR), and evaluated in terms of H2 permeability and H2-N2 separation. A change in the characteristics of Pd seeds by controlled oxidation-reduction treatments produces films with the same thickness, but different surface and bulk nanostructure. In particular, the films have finer and more homogeneous Pd grains, which results in lower surface roughness. Although all samples show high permeo-selectivity to H2 , the samples with finer grains exhibit enhanced permeance and lower activation energy for H2 transport. The analysis of the data suggests that grain boundaries between the Pd grains at the surface favor H2 transfer from surface to subsurface. Thus, the surface nanostructure plays a relevant role in enhancing the transport of H2 over the Pd ultrathin film, which is an important aspect to develop improved membranes that function at low temperatures and toward new integrated process architectures in H2 and syngas production with enhanced sustainability. PMID- 26508273 TI - The role of miRNAs in cutaneous squamous cell carcinoma. AB - MicroRNAs (miRs) are small, noncoding RNAs that negatively regulate gene expressions at posttranscriptional level. Each miR can control hundreds of gene targets and play important roles in various biological and pathological processes such as hematopoiesis, organogenesis, cell apoptosis and proliferation. Aberrant miR expression contributes to initiation and cell progression of cancers. Accumulating studies have found that miRs play a significant role in cutaneous squamous cell carcinoma (cSCC). Deregulations of miRs may contribute to cSCC carcinogenesis is through acting as oncogenic or tumour suppressive miRs. In this study, we summarized the recent data available on cSCC-associated miRs. In particular, we will discuss the contribution of miR to the initiation and progression of cSCCs. Although there are many obstacles to be overcome, clinical use of miRs as biomarkers for diagnosis, prediction of prognosis and target for therapies, will be a promising area in the future with more expression and functional role of miRs revealed. PMID- 26508274 TI - Torso-like mediates extracellular accumulation of Furin-cleaved Trunk to pattern the Drosophila embryo termini. AB - Patterning of the Drosophila embryonic termini is achieved by localized activation of the Torso receptor by the growth factor Trunk. Governing this event is the perforin-like protein Torso-like, which is localized to the extracellular space at the embryo poles and has long been proposed to control localized proteolytic activation of Trunk. However, a protease involved in terminal patterning remains to be identified, and the role of Torso-like remains unknown. Here we find that Trunk is cleaved intracellularly by Furin proteases. We further show that Trunk is secreted, and that levels of extracellular Trunk are greatly reduced in torso-like null mutants. On the basis of these and previous findings, we suggest that Torso-like functions to mediate secretion of Trunk, thus providing the mechanism for spatially restricted activation of Torso. Our data represent an alternative mechanism for the spatial control of receptor signalling, and define a different role for perforin-like proteins in eukaryotes. PMID- 26508275 TI - Reprint of The improvement of the energy resolution in epi-thermal neutron region of Bonner sphere using boric acid water solution moderator. AB - Bonner sphere is useful to evaluate the neutron spectrum in detail. We are improving the energy resolution in epi-thermal neutron region of Bonner sphere, using boric acid water solution as a moderator. Its response function peak is narrower than that for polyethylene moderator and the improvement of the resolution is expected. The resolutions between polyethylene moderator and boric acid water solution moderator were compared by simulation calculation. Also the influence in the uncertainty of Bonner sphere configuration to spectrum estimation was simulated. PMID- 26508276 TI - Reprint of Inter-comparison of boron concentration measurements at INFN University of Pavia (Italy) and CNEA (Argentina). AB - An inter-comparison of three boron determination techniques was carried out between laboratories from INFN-University of Pavia (Italy) and CNEA (Argentina): alpha spectrometry (alpha-spect), neutron capture radiography (NCR) and quantitative autoradiography (QTA). Samples of different nature were analysed: liquid standards, liver homogenates and tissue samples from different treatment protocols. The techniques showed a good agreement in a concentration range of interest in BNCT (1-100 ppm), thus demonstrating their applicability as precise methods to quantify boron and determine its distribution in tissues. PMID- 26508277 TI - Theranostic potential of gold nanoparticle-protein agglomerates. AB - Owing to the ever-increasing applications, glittered with astonishing success of gold nanoparticles (Au NPs) in biomedical research as diagnostic and therapeutic agents, the study of Au NP-protein interaction seems critical for maximizing their theranostic efficiency, and thus demands comprehensive understanding. The mutual interaction of Au NPs and proteins at physiological conditions may result in the aggregation of protein, which can ultimately lead to the formation of Au NP-protein agglomerates. In the present article, we try to appreciate the plausible steps involved in the Au NP-induced aggregation of proteins and also the importance of the proteins' three-dimensional structures in the process. The Au NP-protein agglomerates can potentially be exploited for efficient loading and subsequent release of various therapeutically important molecules, including anticancer drugs, with the unique opportunity of incorporating hydrophilic as well as hydrophobic drugs in the same nanocarrier system. Moreover, the Au NP protein agglomerates can act as 'self-diagnostic' systems, allowing investigation of the conformational state of the associated protein(s) as well as the protein protein or protein-Au NP interaction within the agglomerates. Furthermore, the potential of these Au NP-protein agglomerates as a novel platform for multifunctional theranostic application along with exciting future-possibilities is highlighted here. PMID- 26508278 TI - One year at Chemosphere: Reflections on the peer review process. PMID- 26508279 TI - Electronic transport properties of Ir-decorated graphene. AB - Graphene decorated with 5d transitional metal atoms is predicted to exhibit many intriguing properties; for example iridium adatoms are proposed to induce a substantial topological gap in graphene. We extensively investigated the conductivity of single-layer graphene decorated with iridium deposited in ultra high vacuum at low temperature (7 K) as a function of Ir concentration, carrier density, temperature, and annealing conditions. Our results are consistent with the formation of Ir clusters of ~100 atoms at low temperature, with each cluster donating a single electronic charge to graphene. Annealing graphene increases the cluster size, reducing the doping and increasing the mobility. We do not observe any sign of an energy gap induced by spin-orbit coupling, possibly due to the clustering of Ir. PMID- 26508280 TI - Differentiation between hepatic hemangioma and metastases on diffusion-weighted MRI. PMID- 26508281 TI - Consumption of and satisfaction with health care among opioid users with chronic non-malignant pain. PMID- 26508282 TI - Electronic Dietary Intake Assessment (e-DIA): Comparison of a Mobile Phone Digital Entry App for Dietary Data Collection With 24-Hour Dietary Recalls. AB - BACKGROUND: The electronic Dietary Intake Assessment (e-DIA), a digital entry food record mobile phone app, was developed to measure energy and nutrient intake prospectively. This can be used in monitoring population intakes or intervention studies in young adults. OBJECTIVE: The objective was to assess the relative validity of e-DIA as a dietary assessment tool for energy and nutrient intakes using the 24-hour dietary recall as a reference method. METHODS: University students aged 19 to 24 years recorded their food and drink intake on the e-DIA for five days consecutively and completed 24-hour dietary recalls on three random days during this 5-day study period. Mean differences in energy, macro-, and micronutrient intakes were evaluated between the methods using paired t tests or Wilcoxon signed-rank tests, and correlation coefficients were calculated on unadjusted, energy-adjusted, and deattenuated values. Bland-Altman plots and cross-classification into quartiles were used to assess agreement between the two methods. RESULTS: Eighty participants completed the study (38% male). No significant differences were found between the two methods for mean intakes of energy or nutrients. Deattenuated correlation coefficients ranged from 0.55 to 0.79 (mean 0.68). Bland-Altman plots showed wide limits of agreement between the methods but without obvious bias. Cross-classification into same or adjacent quartiles ranged from 75% to 93% (mean 85%). CONCLUSIONS: The e-DIA shows potential as a dietary intake assessment tool at a group level with good ranking agreement for energy and all nutrients. PMID- 26508283 TI - Shortcuts to adiabatic passage for fast generation of Greenberger-Horne-Zeilinger states by transitionless quantum driving. AB - Berry's approach on "transitionless quantum driving" shows how to set a Hamiltonian which drives the dynamics of a system along instantaneous eigenstates of a reference Hamiltonian to reproduce the same final result of an adiabatic process in a shorter time. In this paper, motivated by transitionless quantum driving, we construct shortcuts to adiabatic passage in a three-atom system to create the Greenberger-Horne-Zeilinger states with the help of quantum Zeno dynamics and of non-resonant lasers. The influence of various decoherence processes is discussed by numerical simulation and the result proves that the scheme is fast and robust against decoherence and operational imperfection. PMID- 26508284 TI - Vertex Stimulation as a Control Site for Transcranial Magnetic Stimulation: A Concurrent TMS/fMRI Study. AB - BACKGROUND: A common control condition for transcranial magnetic stimulation (TMS) studies is to apply stimulation at the vertex. An assumption of vertex stimulation is that it has relatively little influence over on-going brain processes involved in most experimental tasks, however there has been little attempt to measure neural changes linked to vertex TMS. Here we directly test this assumption by using a concurrent TMS/fMRI paradigm in which we investigate fMRI blood-oxygenation-level-dependent (BOLD) signal changes across the whole brain linked to vertex stimulation. METHODS: Thirty-two healthy participants to part in this study. Twenty-one were stimulated at the vertex, at 120% of resting motor threshold (RMT), with short bursts of 1 Hz TMS, while functional magnetic resonance imaging (fMRI) BOLD images were acquired. As a control condition, we delivered TMS pulses over the left primary motor cortex using identical parameters to 11 other participants. RESULTS: Vertex stimulation did not evoke increased BOLD activation at the stimulated site. By contrast we observed widespread BOLD deactivations across the brain, including regions within the default mode network (DMN). To examine the effects of vertex stimulation a functional connectivity analysis was conducted. CONCLUSION: The results demonstrated that stimulating the vertex with suprathreshold TMS reduced neural activity in brain regions related to the DMN but did not influence the functional connectivity of this network. Our findings provide brain imaging evidence in support of the use of vertex simulation as a control condition in TMS but confirm that vertex TMS induces regional widespread decreases in BOLD activation. PMID- 26508285 TI - Refusal of postoperative radiotherapy and its association with survival in head and neck cancer. AB - BACKGROUND AND PURPOSE: Administering postoperative radiotherapy (PORT) is associated with improved survival and slower disease progression in select head and neck cancer patients. Predictive factors for PORT refusal have not been described in this population. MATERIALS AND METHODS: Retrospective analysis of 6127 head and neck cancer patients who received or refused PORT in the National Cancer Database (2003-2006) was performed. Statistical analysis included Chi square, multivariable logistic regression, Kaplan-Meier, and Cox proportional hazards analysis. RESULTS: In total, 247 patients (4.0%) refused PORT. Three-year overall survival was 62.8% versus 53.4% for those who received and refused PORT, respectively. PORT refusers were more likely to have negative nodes than those who underwent PORT (37.4% versus 20.1%, p<.001). In multivariate analysis, predictive factors for refusing PORT included living far from the treatment facility (OR 1.92), having negative nodes (OR 2.14), and Charlson score of ? 2 (OR 2.14) (all p ?.001). PORT refusal was associated with increased mortality (hazard ratio 1.20, p=.044). CONCLUSIONS: A significant proportion of head and neck cancer patients refused PORT; this was associated with compromised overall survival. Predictive factors for PORT refusal included socioeconomic, demographic, and pathologic variables. Elucidating root causes of refusal may lead to interventions that improve long-term outcomes. PMID- 26508286 TI - Binge eating in adults with mood disorders: Results from the International Mood Disorders Collaborative Project. AB - A post hoc analysis was conducted using data from participants (N=631) with a DSM IV-TR defined diagnosis of major depressive disorder (MDD) or bipolar disorder (BD) who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. It was determined that 20.6% of adults with mood disorders as part of the IMDCP fulfilled criteria for binge eating behaviour (BE). A higher percentage of individuals with BD met criteria for BE when compared to MDD (25.4% vs. 16%; p=0.004) Univariate analyses indicated that individuals with a mood disorder (i.e., MDD or BD) and BE had greater scores on measures of anxiety severity (p=0.013) and higher rates of lifetime and current substance dependence, lifetime alcohol abuse (p=0.007, p=0.006, and p=0.015, respectively), Attention Deficit Hyperactivity Disorder (ADHD) (p=0.018) and measures of neuroticism (p=0.019). Individuals with a mood disorder and concurrent BE had lower scores on measures of conscientiousness (p=0.019). Individuals meeting criteria for BE were also significantly more likely to be obese (i.e., BMI>=30kg/m2) (50% vs. 25.5%; p<0.001). Binge eating is common amongst adults utilising tertiary care services principally for a mood disorder. The presence of BE identifies a subset of adults with mood disorders who have greater illness complexity as evidenced by course of illness variables and comorbidity. Screening for BE amongst individuals with mood disorders is warranted; parsing neurobiological substrates subserving non-homeostatic eating behaviour amongst individuals with mood disorders is a future research vista. PMID- 26508287 TI - The effect of controlled microrobotized blasting on implant surface texturing and early osseointegration. AB - Surface topography modifications have become a key strategy for hastening the host-to-implant response to implantable materials. The present study evaluated the effect of three different carefully controlled surface texture patterns achieved through microrobotized blasting (controlled to high, medium and low roughness) relative to a larger scale blasting procedure (control) in early osseointegration in a canine model. Four commercially pure grade 2 titanium alloy implants (one of each surface) were bilaterally placed in the radii of six beagle dogs and allowed end points of 1 and 6 weeks in vivo. Following sacrifice, implants in bone were non-decalcified processed for bone morphologic and histometric (bone-to-implant contact; bone area fraction occupancy) evaluation. Surface topography was characterized by scanning electron microscopy and optical interferometry. Results showed initial osteogenic tissue interaction at one week and new bone in intimate contact with all implant surfaces at 6 weeks. At 1 and 6 weeks in vivo, higher bone-to-implant and bone area fraction occupancy were observed for the high texture pattern microrobotized blasted surface relative to others. PMID- 26508289 TI - Macular pigmentation complicating irritant contact dermatitis and viral warts in Laugier-Hunziker syndrome. AB - Laugier-Hunziker syndrome (LHS) is a rare acquired disorder characterized by macu lar pigmentation of the lips and oral mucosa, with frequent longitudinal melanonychia. Involvement of other areas, such as the genitalia and fingers, has rarely been described. LHS is a benign condition with no known systemic manifestations. We report the case of a woman who developed melanotic macules on her fingers and elbow 16 years after the onset of pigmentation of her lips. This unusual feature of LHS in our patient was associated with irritant contact dermatitis and viral warts. Only two cases of an association with an inflammatory dermatosis have been reported previously in the literature. PMID- 26508288 TI - Competition, Selectivity and Efficacy of Analogs of A-84543 for Nicotinic Acetylcholine Receptors with Repositioning of Pyridine Nitrogen. AB - Nicotinic acetylcholine receptors (nAChRs) play a crucial role in a number of clinically relevant mental and neurological pathways, as well as autonomic and immune functions. The development of subtype-selective ligands for nAChRs therefore is potentially useful for targeted therapeutic management of conditions where nAChRs are involved. We tested if selectivity for a particular nAChR subtype can be achieved through small structural modifications of a lead compound containing the nicotinic pharmacophore by changing the distance between the electronegative elements. For this purpose, analogs of A-84543 were designed, synthesized and characterized as potentially new nAChR subtype-selective ligands. Compounds were tested for their binding properties in rat cerebral cortical tissue homogenates, and subtype-selectivity was determined using stably transfected HEK cells expressing different nAChR subtypes. All compounds synthesized were found to competitively displace [(3)H]-epibatidine ([(3)H]EB) from the nAChR binding site. Of all the analogues, H-11MNH showed highest affinity for nAChRs compared to a ~ fivefold to tenfold lower affinity of A 84543. All other compounds had affinities >10,000 nM. Both A-84543 and H-11MNH have highest affinity for alpha2beta2 and alpha4beta2 nAChRs and show moderate affinity for beta4- and alpha7-containing receptors. H-11MNH was found to be a full agonist with high potency at alpha3beta4, while A-84543 is a partial agonist with low potency. Based on their unique pharmacological binding properties we suggest that A-84543 and its desmethylpyrrolidine analog can be useful as pharmacological ligands for studying nAChRs if selective pharmacological and/or genetic tools are used to mask the function of other receptors subtypes. PMID- 26508290 TI - Comparison of hybrid (68)Ga-PSMA PET/MRI and (68)Ga-PSMA PET/CT in the evaluation of lymph node and bone metastases of prostate cancer. AB - PURPOSE: To evaluate the reproducibility of the combination of hybrid PET/MRI and the (68)Ga-PSMA-11 tracer in depicting lymph node (LN) and bone metastases of prostate cancer (PC) in comparison with that of PET/CT. MATERIALS AND METHODS: A retrospective analysis of 26 patients who were subjected to (68)Ga-PSMA PET/CTlow dose (1 h after injection) followed by PET/MRI (3 h after injection) was performed. MRI sequences included T1-w native, T1-w contrast-enhanced, T2-w fat saturated and diffusion-weighted sequences (DWIb800). Discordant PET-positive and morphological findings were evaluated. Standardized uptake values (SUV) of PET positive LNs and bone lesions were quantified and their morphological size and conspicuity determined. RESULTS: Comparing the PET components, the proportion of discordant PSMA-positive suspicious findings was very low (98.5 % of 64 LNs concordant, 100 % of 28 bone lesions concordant). Two PET-positive bone metastases could not be confirmed morphologically using CTlow-dose, but could be confirmed using MRI. In 12 of 20 patients, 47 PET-positive LNs (71.9 %) were smaller than 1 cm in short axis diameter. There were significant linear correlations between PET/MRI SUVs and PET/CT SUVs in the 64 LN metastases (p < 0.0001) and in the 28 osseous metastases (p < 0.0001) for SUVmean and SUVmax, respectively. The LN SUVs were significantly higher on PET/MRI than on PET/CT (p SUVmax < 0.0001; p SUVmean < 0.0001) but there was no significant difference between the bone lesion SUVs (p SUVmax = 0.495; p SUVmean = 0.381). Visibility of LNs was significantly higher on MRI using the T1-w contrast-enhanced fat saturated sequence (p = 0.013), the T2-w fat-saturated sequence (p < 0.0001) and the DWI sequence (p < 0.0001) compared with CTlow-dose. For bone lesions, only the overall conspicuity was higher on MRI compared with CTlow-dose (p < 0.006). CONCLUSION: Nodal and osseous metastases of PC are accurately and reliably depicted by hybrid PET/MRI using (68)Ga-PSMA-11 with very low discordance compared with PET/CT including PET-positive LNs of normal size. The correlation between PET/MRI SUVs and PET/CT SUVs was linear in LN and bone metastases but was significantly lower in control (non-metastatic) tissue. PMID- 26508291 TI - FDG uptake at the bronchial stump after curative lobectomy for non-small cell lung cancer. AB - PURPOSE: Focal areas of FDG uptake may occur at the bronchial stump following curative lobectomy for non-small-cell lung carcinoma (NSCLC), even in the absence of suspicious CT changes. The purpose of our study was to investigate the significance of such PET/CT findings. METHODS: FDG-PET/CT scans performed in 54 patients after lobectomy for NSCLC were reviewed. The presence of focal areas of FDG uptake at the bronchial stump, associated CT abnormalities, SUVmax, and normalized SUV (SUVnorm = SUVmax/mean liver SUV) were recorded. Final diagnosis was based on biopsy or imaging follow-up. RESULTS: Focal areas of FDG uptake at the bronchial stump were detected in 30 patients (56 %). Mean SUVmax was 4.0 +/- 1.9 (range; 2.2-12.1) and mean SUVnorm was 1.8 +/- 0.8 (range; 0.9-4.5). Biopsy showed recurrence in two patients. In these patients, SUVnorm was respectively 4.4 and 4.5 (with SUVmax of 8.8 and 12.1), whereas SUVnorm was lower than 4.0 in those without recurrence, with mean SUVnorm of 1.6 +/- 0.5 (range; 0.9-3.4) and mean SUVmax of 3.6 +/- 0.9 (range; 2.2-5.8). The CT component of the PET/CT revealed ill-defined peribronchial soft tissue opacity only in both patients with recurrence. CONCLUSION: FDG uptake at the bronchial stump is a frequent finding after pulmonary lobectomy. Moderate levels of FDG uptake (i.e., SUVnorm < 4.0) without corresponding abnormal CT findings might be a dual criterion for diagnosing benign post-surgical changes. PMID- 26508292 TI - Postoperative gluteal skin damage associated with latent development of gluteal muscle damage. AB - Preceding this study, we observed two cases of concurrent postoperative gluteal skin and muscle damage with extremely high serum creatine kinase (CK) levels, both of which were unrelated to pressure-induced tissue injury. However, postoperative gluteal skin damage accompanied by gluteal muscle damage has not been previously reported and the association between gluteal skin damage, gluteal muscle damage and pressure-induced tissue injury has not previously been investigated. Therefore, we conducted this study to determine the postoperative incidence of gluteal skin damage associated with gluteal muscle damage and assess associations with postoperative serum CK levels and pressure-induced tissue injury. We prospectively evaluated postoperative incidence of gluteal skin damage and measured serum CK levels in 929 consecutive patients who underwent abdominal, urological or gynecological surgery at our hospital. Magnetic resonance imaging (MRI) of the pelvis was performed in 67 patients who consented. As a result, two of 929 patients developed postoperative gluteal skin damage accompanied by gluteal muscle damage. Gluteal muscle damage without gluteal skin damage was observed in 23 of the 67 patients who underwent MRI, and volumes of damaged gluteal muscle and postoperative serum CK levels were positively correlated. Both gluteal skin and muscle damage were distinguishable from pressure-induced tissue injury. Based on the results of this study, we could confirm the occurrence of postoperative gluteal skin damage, distinct from pressure sores, accompanied by gluteal muscle damage. We also revealed latent development of postoperative gluteal muscle damage, distinguishable from compression-induced tissue injury, without accompanying gluteal skin damage. PMID- 26508293 TI - Bioinformatic and Statistical Analysis of Adaptive Immune Repertoires. AB - High-throughput sequencing (HTS) of immune repertoires has enabled the quantitative analysis of adaptive immune responses and offers the potential to revolutionize research in lymphocyte biology, vaccine profiling, and monoclonal antibody engineering. Advances in sequencing technology coupled to an exponential decline in sequencing costs have fueled the recent overwhelming interest in immune repertoire sequencing. This, in turn, has sparked the development of numerous methods for bioinformatic and statistics-driven interpretation and visualization of immune repertoires. Here, we review the current literature on bioinformatic and statistical analysis of immune repertoire HTS data and discuss underlying assumptions, applicability, and scope. We further highlight important directions for future research, which could propel immune repertoire HTS to becoming a standard method for measuring adaptive immune responses. PMID- 26508294 TI - Investigation of the antioxidant and radical scavenging activities of some phenolic Schiff bases with different free radicals. AB - The antioxidant properties of some phenolic Schiff bases in the presence of different reactive particles such as (*)OH, (*)OOH, (CH2=CH-O-O(*)), and (-*)O2 were investigated. The thermodynamic values, DeltaH BDE, DeltaH IP, and DeltaH PA, were used for this purpose. Three possible mechanisms for transfer of hydrogen atom, concerted proton-electron transfer (CPET), single electron transfer followed by proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET) were considered. These mechanisms were tested in solvents of different polarity. On the basis of the obtained results it was shown that SET-PT antioxidant mechanism can be the dominant mechanism when Schiff bases react with radical cation, while SPLET and CPET are competitive mechanisms for radical scavenging of hydroxy radical in all solvents under investigation. Examined Schiff bases react with the peroxy radicals via SPLET mechanism in polar and nonpolar solvents. The superoxide radical anion reacts with these Schiff bases very slowly. PMID- 26508295 TI - Response to comment on Analysis of the influence of dabigatran on coagulation factors and inhibitors. PMID- 26508296 TI - Association Rules Analysis of Comorbidity and Multimorbidity: The Concord Health and Aging in Men Project. AB - BACKGROUND: Comorbidity and multimorbidity are common in older people. Here we used a novel analytic approach called Association Rules together with network analysis to evaluate multimorbidity (two or more disorders) and comorbidity in old age. METHODS: A population-based cross-sectional study was undertaken where 17 morbidities were analyzed using network analysis, cluster analysis, and Association Rules methodology. A comorbidity interestingness score was developed to quantify the richness and variability of comorbidities associated with an index condition. The participants were community-dwelling men aged 70 years or older from the Concord Health and Ageing in Men Project, Sydney, Australia, with complete data (n = 1,464). RESULTS: The vast majority (75%) of participants had multimorbidity. Several morbidity clusters were apparent (vascular cluster, metabolic cluster, neurodegenerative cluster, mental health and other cluster, and a musculoskeletal and other cluster). Association Rules revealed unexpected comorbidities with high lift and confidence linked to index diseases. Anxiety and heart failure had the highest comorbidity interestingness scores while obesity, hearing impairment, and arthritis had the lowest (zero) scores. We also performed Association Rules analysis for the geriatric syndromes of frailty and falls to determine their association with multimorbidity. Frailty had a very complex and rich set of frequent and interesting comorbidities, while there were no frequent and interesting sets associated with falls. CONCLUSIONS: Old age is characterized by a complex pattern of multimorbidity and comorbidity. Single disease definitions do not account for the prevalence and complexity of multimorbidity in older people and a new lexicon may be needed to underpin research and health care interventions for older people. PMID- 26508297 TI - Age-related Decline of Abiotic Stress Tolerance in Young Drosophila melanogaster Adults. AB - Stress tolerance generally declines with age as a result of functional senescence. Age-dependent alteration of stress tolerance can also occur in early adult life. In Drosophila melanogaster, evidence of such a decline in young adults has only been reported for thermotolerance. It is not known whether early adult life entails a general stress tolerance reduction and whether the response is peculiar to thermal traits. The present work was designed to investigate whether newly eclosed D melanogaster adults present a high tolerance to a range of biotic and abiotic insults. We found that tolerance to most of the abiotic stressors tested (desiccation, paraquat, hydrogen peroxide, deltamethrin, and malathion) was high in newly eclosed adults before dramatically declining over the next days of adult life. No clear age-related pattern was found for resistance to biotic stress (septic or fungal infection) and starvation. These results suggest that newly eclosed adults present a culminating level of tolerance to extrinsic stress which is likely unrelated to immune process. We argue that stress tolerance variation at very young age is likely a residual attribute from the previous life stage (ontogenetic carryover) or a feature related to the posteclosion development. PMID- 26508298 TI - Effects of 6-Month Folic Acid Supplementation on Cognitive Function and Blood Biomarkers in Mild Cognitive Impairment: A Randomized Controlled Trial in China. AB - BACKGROUND: This study is to examine the effects of folic acid supplementation on cognitive function in Chinese older adults with mild cognitive impairment who are unexposed to folic acid fortification and assess cognitive functioning in relation to folate, homocysteine, and vitamin B12 values at baseline. METHODS: This was a single-center, randomized, controlled trial in Tianjin, China; 180 individuals aged 65 years and older who had mild cognitive impairment were assigned randomly to one of two groups: (a) those treated with oral folic acid (400 ug/day) and (b) those treated via conventional treatment. Tests of cognitive performance and biomarkers were measured at baseline, 3 months, and 6 months. Analysis was by intention-to-treat. Changes in cognitive or clinical function were analyzed by repeated-measure analysis of variance or mixed-effects models. This trial has been registered with the trial number ChiCTR-TRC-13003227. RESULTS: Total of 159 participants (intervention group: 80; control group: 79) completed the trial. Repeated-measure analysis of variance showed significant improvements in serum folate (etap (2) = 0.712, p = .009), homocysteine (etap (2) = 0.119, p = .017), serum vitamin B12 (etap (2) = 0.144, p = .022), and S adenosylmethionine (etap (2) = 0.117, p = .033) in the intervention group over the control group. Folic acid supplementation improved Full Scale IQ (p = .031; effect size d = 0.168), Digit Span (p = .009; d = 0.176), and Block Design (p = .036; effect size d = 0.146) scores at 6 months in comparison to the control. There were no significant findings for all other cognitive measures. CONCLUSION: There was a beneficial effect from relatively short-term folate supplementation on cognitive functioning in later life. Larger-scale, randomized, controlled trials of longer duration in selected age groups are needed. PMID- 26508299 TI - Color control of nanowire InGaN/GaN light emitting diodes by post-growth treatment. AB - Core/shell InGaN/GaN nanowire light emitting diodes (LEDs) based on vertically standing single nanowires and nanowire arrays were fabricated and extensively characterized. The emission of single wire LEDs with the same conformal contact geometry as the array device exhibits the same broadening as the array LED electroluminescence, which proves an excellent wire-to-wire homogeneity. The electroluminescence spectra present two peaks corresponding to the m-plane InGaN quantum well (blue emission) and to an In-rich region at the m-plane-semipolar plane junction (green emission), in agreement with structural characterizations. Modification of the contact layout and a post-growth plasma treatment enable strongly suppressing the unwanted green electroluminescence while increasing the intensity in the blue spectral range for the same injected electrical power. Electron beam induced current mapping proves the inhibition of the electrical activity of the top part of the nanowire after plasma treatment. Inductively coupled plasma etching of the In-rich region permits one to completely remove the green emission for all injection currents, but loss of intensity in the blue spectral range is observed. Selectively contacting the m-plane and plasma treatment of the top part of the nanowire appear as a viable solution for controlling the color of core/shell nanowire LEDs with an inhomogeneous indium composition. PMID- 26508300 TI - Rhabdobacter roseus gen. nov., sp. nov., isolated from soil. AB - An aerobic, Gram-stain-negative, oxidase- and catalase-positive, non-motile, non spore-forming, rod-shaped, pink-pigmented bacterium, designated strain R49T, was isolated from soil. Flexirubin-type pigments were absent. Phylogenetic analysis based on its 16S rRNA gene sequence revealed that strain R49T formed a lineage within the family Cytophagaceae of the phylum Bacteroidetes that was distinct from the most closely related genera Dyadobacter (91.98-93.85 % sequence similarity), Persicitalea (88.69 %) and Runella (84.79-85.81 %). The major isoprenoid quinone was menaquinone-7 (MK-7) and the major polar lipid was phosphatidylethanolamine. The major cellular fatty acids were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), iso-C15 : 0, C16 : 1omega5c, C16 : 0 and iso-C17 : 0 3-OH. The DNA G+C content of strain R49T was 53.9 mol%. On the basis of phenotypic, genotypic and phylogenetic analysis, strain R49T represents a novel species of a new genus in the family Cytophagaceae, for which the name Rhabdobacter roseus gen. nov., sp. nov. is proposed. The type strain of Rhabdobacter roseus is R49T ( = KEMB 9005-318T = KACC 18395T = JCM 30685T). PMID- 26508301 TI - Reviewing and interpreting the effects of brief alcohol interventions: comment on a Cochrane review about motivational interviewing for young adults. AB - BACKGROUND: Cochrane recently published a systematic review on motivational interviewing (MI) for alcohol misuse in young adults. The review authors concluded that 'there are no substantive, meaningful benefits of MI interventions for the prevention of alcohol misuse' (p. 2), as effect sizes were 'small and unlikely to be of any meaningful benefit in practice' (p. 27). As most of these interventions were quite brief, we wish to open a dialogue about interpreting effect sizes in this review and of (brief) alcohol interventions more generally. ANALYSIS: We analyze four methodological aspects of the review that likely influenced the author's conclusions about intervention effects: (1) risk of bias assessments, (2) search strategies, (3) assessing the quality of the body of evidence and (4) definitions of sustainability and clinical significance. CONCLUSIONS: We interpret the effect sizes found in this review to indicate modest yet beneficial and potentially meaningful effects of these interventions, given their brevity and low cost. This interpretation is consistent with other reviews on brief, MI-based interventions and brief interventions more generally. We therefore encourage the field to re-open dialogue about the clinical importance of the effects of MI on alcohol misuse by young adults. Rather than dismissing interventions with small effects, we believe a more fruitful way forward for the field would be to catalogue effect sizes for various alcohol interventions. Such a catalogue would help stakeholders themselves to choose which interventions meet their minimum desired impact, and thus may be suitable given their targeted populations, setting and resources. PMID- 26508302 TI - Magnetically separable Ag3PO4/NiFe2O4 composites with enhanced photocatalytic activity. AB - Magnetically separable Ag3PO4/NiFe2O4 (APO/NFO) composites were prepared by an in situ precipitation method. The photocatalytic activity of photocatalysts consisting of different APO/NFO mass ratios was evaluated by degradation of methylene blue (MB) under visible light irradiation. The excellent photocatalytic activity was observed using APO/NFO5 (5% NFO) composites with good cycling stability which is higher than that of pure Ag3PO4 and NiFe2O4. All the APO/NFO composites showed good magnetic behavior, which makes them magnetically separable after reaction and reusable for several experiments. Photoconductivities of pure and composite samples were examined to study the photoresponse characteristics. The current intensity greatly enhanced by loading NFO to APO. Furthermore, the photocatalytic performance of the samples is correlated with the conductivity of the samples. The enhancement in the photocatalytic activity of APO/NFO composites for MB degradation is attributed to the excellent conductivity of APO/NFO composites through the co-catalytic effect of NFO by providing accelerated charge separation through the n-n interface. PMID- 26508303 TI - Prevalence and antimicrobial susceptibility patterns of Shigella among acute diarrheal outpatients in Mekelle hospital, Northern Ethiopia. AB - BACKGROUND: Emergence of increased antimicrobial resistance of Shigella species is a global challenge, particularly in developing countries where increased misuse of antimicrobial agents occurs. There is no published data in the study area on the prevalence and antimicrobial susceptibility patterns of Shigella among acute diarrheal patients. This study was therefore, under taken to fill this gap. METHODS: Using cross sectional study method, stool specimens were collected from 216 patients with acute diarrhea at Mekelle Hospital from August to November 2014. Standard bacteriological methods were used to isolate and determine the antimicrobial susceptibility patterns of the isolates, and data were analyzed using SPSS version 20. RESULTS: Out of the total 216 participants, Shigella was isolated from 15 (6.9 %) of the participants. Ten (66.7 %) of the positive isolates were from children <15 years (p = 0.005). Latrine availability, source of drinking water and hand washing habits before meal were statistically significant with shigellosis (p < 0.05). Isolates of Shigella showed 100, 86.7 and 66.7 % resistance to amoxicillin, amoxicillin and cotrimoxazole respectively. Low levels of resistance were observed for norfloxacin and ciprofloxacin (6.7 % each). Overall, 80 % of the isolates showed multidrug resistance. CONCLUSION: Shigella isolates were highly resistant to amoxicillin, amoxicillin and cotrimoxazole. However, ciprofloxacin and norfloxacin were effective. Antibiotic surveillance is needed to prevent further emergence of drug resistant Shigella strains. More has to be done in the availability of latrine, supply of safe drinking water to the community to reduce the disease burden. PMID- 26508304 TI - Gelatin-loaded p(HEMA-GMA) cryogel for high-capacity immobilization of horseradish peroxidase. AB - Poly(2-hydroxyethyl methacrylate-glycidyl methacrylate) [p(HEMA-GMA)] cryogel discs were prepared under sub-zero temperatures. Gelatin was attached covalently on the p(HEMA-GMA) cryogel discs and reversible immobilization of horseradish peroxidase (HRP) was performed. The p(HEMA-GMA) cryogel discs were characterized by swelling tests, scanning electron microscopy, and surface area measurements. HRP immobilization capacity of p(HEMA-GMA)/gelatin cryogel discs was 24.8 mg/g. Removal of phenol from aqueous solutions was performed using HRP immobilized p(HEMA-GMA)/gelatin cryogel. It was observed that within 2 h of contact time, the percentage of phenol removal reaches up to 91% in the presence of H2O2. PMID- 26508305 TI - People die everywhere, so care should be optimised in all settings and all along the way. PMID- 26508306 TI - Synergistic anti-tumor therapy by a comb-like multifunctional antibody nanoarray with exceptionally potent activity. AB - Simultaneously blocking multiple mediators offers new hope for the treatment of complex diseases. However, the curative potential of current combination therapy by chronological administration of separate monoclonal antibodies (mAbs) or multi specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. Here, we describe a facile strategy that arms distinct mAbs with cooperative effectors onto a long chain to form a multicomponent comb-like nano mAb. Unlike dissociative parental mAbs, the multifunctional mAb nanoarray (PL-RB) constructed from type I/II anti-CD20 mAbs shows good pharmacokinetics. This PL-RB simultaneously targets distinct epitopes on a single antigen (Ag) and neighboring Ags on different lymphocytes. This unique intra- and intercellular Ag cross linking endows the multifunctional mAb nanoarray with potent apoptosis activity. The exceptional apoptosis, complement-dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC) that are synchronously evoked by the nano PL-RB are further synergistically promoted via enhanced permeability and retention (EPR), which resulted in high intratumor accumulation and excellent anti-lymphoma efficiency. PMID- 26508307 TI - Utility of Indocyanine Green Fluorescence Imaging for Intraoperative Localization in Reoperative Parathyroid Surgery. AB - BACKGROUND: Due to the variations in anatomic location, the identification of parathyroid glands may be challenging. Although there have been advances in preoperative imaging modalities, there is still a need for an accurate intraoperative guidance. Indocyanine green (ICG) is a new agent that has been used for intraoperative fluorescence imaging in a number of general surgical procedures. Its utility for parathyroid localization in humans has not been reported in the literature. RESULTS: We report 3 patients who underwent reoperative neck surgery for primary hyperparathyroidism. Using a video-assisted technique with intraoperative ICG fluorescence imaging, the parathyroid glands were recognized and removed successfully in all cases. Surrounding soft tissue structures remained nonfluorescent, and could be distinguished from the parathyroid glands. CONCLUSIONS: This report suggests a potential utility of ICG imaging in intraoperative localization of parathyroid glands in reoperative neck surgery. Future work is necessary to assess its benefit for first-time parathyroid surgery. PMID- 26508308 TI - Economic Burden of Bladder Cancer Across the European Union. AB - BACKGROUND: More than 120,000 people are diagnosed annually with bladder cancer in the 28 countries of the European Union (EU). With >40,000 people dying of it each year, it is the sixth leading cause of cancer. However, to date, no systematic cost-of-illness study has assessed the economic impact of bladder cancer in the EU. OBJECTIVE: To estimate the annual economic costs of bladder cancer in the EU for 2012. DESIGN, SETTING, AND PARTICIPANTS: Country-specific cancer cost data were estimated using aggregate data on morbidity, mortality, and health care resource use, obtained from numerous international and national sources. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Health care costs were estimated from expenditures on primary, outpatient, emergency, and inpatient care, as well as medications. Costs of unpaid care and lost earnings due to morbidity and early death were estimated. RESULTS AND LIMITATIONS: Bladder cancer cost the EU ?4.9 billion in 2012, with health care accounting for ?2.9 billion (59%) and representing 5% of total health care cancer costs. Bladder cancer accounted for 3% of all cancer costs in the EU (?143 billion) in 2012 and represented an annual health care cost of ?57 per 10 EU citizens, with costs varying >10 times between the country with the lowest cost, Bulgaria (?8 for every 10 citizens), and highest cost, Luxembourg (?93). Productivity losses and informal care represented 23% and 18% of bladder cancer costs, respectively. The quality and availability of comparable cancer-related data across the EU need further improvement. CONCLUSIONS: Our results add to essential public health and policy intelligence for delivering affordable bladder cancer care systems and prioritising the allocation of public research funds. PATIENT SUMMARY: We looked at the economic costs of bladder cancer across the European Union (EU). We found bladder cancer to cost ?4.9 billion in 2012, with health care accounting for ?2.9 billion. Our study provides data that can be used to inform affordable cancer care in the EU. PMID- 26508309 TI - Prior Endocrine Therapy Impact on Abiraterone Acetate Clinical Efficacy in Metastatic Castration-resistant Prostate Cancer: Post-hoc Analysis of Randomised Phase 3 Studies. AB - BACKGROUND: The duration of prior hormonal treatment can predict responses to subsequent therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: To determine if prior endocrine therapy duration is an indicator of abiraterone acetate (AA) sensitivity. DESIGN, SETTING, AND PARTICIPANTS: Post-hoc exploratory analysis of randomised phase 3 studies examining post-docetaxel (COU-AA-301) or chemotherapy-naive mCRPC (COU-AA-302) patients receiving AA. The treatment effect on overall survival (OS), radiographic progression-free survival (rPFS), and prostate-specific antigen (PSA) response analysed by quartile duration of prior gonadotropin-releasing hormone agonists (GnRHa) or androgen receptor (AR) antagonist. INTERVENTION: Patients were randomised to AA (1000mg, orally once daily) plus prednisone (5mg, orally twice daily) or placebo plus prednisone. Prior endocrine therapy was GnRHa (COU-AA-301, n=1127 [94%]; COU-AA-302, n=1057 [97%], 45.1 mo or 36.7 mo median duration, respectively) and/or orchiectomy (COU-AA-301, n=78 [7%] COU-AA-302, n=44 [4%]); castrated patients received prior AR antagonists (COU-AA-301, n=1015 [85%]; COU-AA-302, n=1078 [99%], 15.7 mo or 16.1 mo median duration, respectively). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox model was used to obtain hazard ratio and associated 95% confidence interval with statistical inference by log rank statistic. RESULTS AND LIMITATIONS: Clinical benefit with AA was observed for OS, rPFS, and PSA response for nearly all quartiles with GnRHa or AR antagonists in both COU-AA-301 and COU-AA-302. In COU-AA-301, patients with a longer duration of prior endocrine therapy tended to have greater AA OS, rPFS, and PSA response benefit, with lead-time chemotherapy bias potentially impacting COU-AA-301 results. Time to castration resistance was not captured. This analysis is limited as a post-hoc exploratory analysis. CONCLUSIONS: In the COU-AA-301 and COU-AA-302 studies, AA produced clinical benefits regardless of prior endocrine therapy duration in patients with mCRPC. PATIENT SUMMARY: Metastatic castration-resistant prostate cancer patients derived clinical benefits with abiraterone acetate regardless of prior endocrine therapy duration. PMID- 26508310 TI - Reply from Authors re: Alexandre Mottrie, Giorgio Gandaglia. Do We Need a Novel Nephrometry Scoring System in Partial Nephrectomy? Eur Urol 2016;69:80-1: Nephrometry Scores for Partial Nephrectomy: The Importance of Defining a Context of Use. PMID- 26508311 TI - Re: William C. Jackson, Matthew J. Schipper, Skyler B. Johnson, et al. Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy. Eur Urol 2016;69:50-7. Re: Ronald C. Chen. Postprostatectomy Radiotherapy: Whether and How Long to Give Concurrent Androgen Deprivation Therapy. Eur Urol 2016;69:58-9: Which patients need treatment intensification? PMID- 26508312 TI - Updated EAU Guidelines for Clear Cell Renal Cancer Patients Who Fail VEGF Targeted Therapy. AB - The European Association of Urology renal cancer guidelines have been updated to recommend nivolumab and cabozantinib over the previous standard of care in patients who have failed one or more lines of VEGF targeted therapy. PMID- 26508313 TI - Placement of a modified cannula in the innominate vein for sufficient drainage during the bidirectional Glenn shunt procedure without cardiopulmonary bypass. AB - During the bidirectional Glenn shunt procedure in small infants, the standard right-angle venous cannula is frequently placed in the innominate vein for establishing the temporary veno-atrial bypass without cardiopulmonary bypass, but it should be small enough to allow flow to pass around it from the internal jugular vein opposite to the side the cannula is directed. Small cannula may induce the inadequacy of venous drainage. We developed a modified right-angle venous cannula and placed it within the innominate vein for sufficient venous drainage. The standard right-angle venous cannula was simply modified by an oval open on the top of the external curvature. Our initial application demonstrated that this modified venous cannula provides better venous drainage during the bidirectional Glenn shunt procedure without cardiopulmonary bypass in small infants. PMID- 26508314 TI - A lateralized top-down network for visuospatial attention and neglect. AB - The lateralization of visuospatial attention has been well investigated and demonstrated to be primarily resulting from unbalanced interaction between interhemispheric fronto-parietal networks in previous studies. Many recent studies of top-down attention have reported the neural signatures of its effects within visual cortex and identified its causal basis. However, the relationship between top-down networks and asymmetric visuospatial attention has not been well studied. In the current study, we aimed to explore the relationship between top down connectivity and asymmetric visuospatial ability by using repetitive transcranial magnetic stimulation (rTMS) and resting-state functional connectivity (RSFC) analyses. We used rTMS and RSFC to model the virtual lesion to assess the behavioral performances in visuospatial attention shifting and to identify the behavior-related top-down functional connectivities, respectively. Furthermore, we also investigated the top-down connectivity in neglect patients to validate the RSFC findings. RSFC analyses in healthy subjects and neglect patients consistently revealed that asymmetric visuospatial ability and visuospatial neglect were closely related to the bias of top-down functional connectivity between posterior superior parietal lobule (SPL) and V1. Our findings indicate that stronger top-down connectivity has stronger dominance on its corresponding visual field. We argue that an asymmetric top-down network may represent a possible neurophysiological substrate for the ongoing functional asymmetry of visuospatial attention, and its interhemispheric unbalanced interaction could contribute to the clinical manifestations of visuospatial neglect. PMID- 26508315 TI - Policing the epidemic: High burden of workplace violence among female sex workers in conflict-affected northern Uganda. AB - Sex workers in sub-Saharan Africa experience a high burden of HIV with a paucity of data on violence and links to HIV risk among sex workers, and even less within conflict-affected environments. Data are from a cross-sectional survey of female sex workers in Gulu, northern Uganda (n = 400). Logistic regression was used to determine the specific association between policing and recent physical/sexual violence from clients. A total of 196 (49.0%) sex workers experienced physical/sexual violence by a client. From those who experienced client violence the most common forms included physical assault (58.7%), rape (38.3%), and gang rape (15.8%) Police harassment was very common, a total of 149 (37.3%) reported rushing negotiations with clients because of police presence, a practice that was significantly associated with increased odds of client violence (adjusted odds ratio: 1.61, 95% confidence intervals: 1.03-2.52). Inconsistent condom use with clients, servicing clients in a bar, and working for a manager/pimp were also independently associated with recent client violence. Structural and community led responses, including decriminalisation, and engagement with police and policy stakeholders, remain critical to addressing violence, both a human rights and public health imperative. PMID- 26508316 TI - Protective effects of extracts from Pomegranate peels and seeds on liver fibrosis induced by carbon tetrachloride in rats. AB - BACKGROUND: Liver fibrosis is a feature in the majority of chronic liver diseases and oxidative stress is considered to be its main pathogenic mechanism. Antioxidants including vitamin E, are effective in preventing liver fibrogenesis. Several plant-drived antioxidants, such as silymarin, baicalin, beicalein, quercetin, apigenin, were shown to interfere with liver fibrogenesis. The antioxidans above are polyphenols, flavonoids or structurally related compounds which are the main chemical components of Pomegranate peels and seeds, and the antioxidant activity of Pomegranate peels and seeds have been verified. Here we investigated whether the extracts of pomegranate peels (EPP) and seeds (EPS) have preventive efficacy on liver fibrosis induced by carbon tetrachloride (CCl4) in rats and explored its possible mechanisms. METHODS: The animal model was established by injection with 50 % CCl4 subcutaneously in male wistar rats twice a week for four weeks. Meanwhile, EPP and EPS were administered orally every day for 4 weeks, respectively. The protective effects of EPP and EPS on biochemical metabolic parameters, liver function, oxidative markers, activities of antioxidant enzymes and liver fibrosis were determined in CCl4-induced liver toxicity in rats. RESULTS: Compared with the sham group, the liver function was worse in CCl4 group, manifested as increased levels of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin. EPP and EPS treatment significantly ameliorated these effects of CCl4. EPP and EPS attenuated CCl4-induced increase in the levels of TGF-beta1, hydroxyproline, hyaluronic acid laminin and procollagen type III. They also restored the decreased superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and inhibited the formation of lipid peroxidized products in rats treated with CCl4. CONCLUSION: The EPP and EPS have protective effects against liver fibrosis induced by CCl4, and its mechanisms might be associated with their antioxidant activity, the ability of decreasing the level of TGF-beta1 and inhibition of collagen synthesis. PMID- 26508317 TI - Armigeres subalbatus colonization of damaged pit latrines: a nuisance and potential health risk to residents of resettlement villages in Laos. AB - During the resettlement of 6500 persons living around the Nam Theun 2 hydroelectric project in Laos, more than 1200 pour-flush latrines were constructed. To assess the role of these latrines as productive larval habitats for mosquitoes, entomological investigations using Centers for Disease Control (CDC) light traps, visual inspection and emergence trapping were carried out in over 300 latrines during the rainy seasons of 2008-2010. Armigeres subalbatus (Diptera: Culicidae) were nine times more likely to be found in latrines (mean catch: 3.09) than in adjacent bedrooms (mean catch: 0.37) [odds ratio (OR) 9.08, 95% confidence interval (CI) 6.74-15.11] and mosquitoes were active in and around 59% of latrines at dusk. Armigeres subalbatus was strongly associated with latrines with damaged or improperly sealed septic tank covers (OR 5.44, 95% CI 2.02-14.67; P < 0.001). Armigeres subalbatus is a nuisance biter and a putative vector of Japanese encephalitis and dengue viruses. Dengue virus serotype 3 was identified from a single pool of non-blood-fed female A. subalbatus using reverse transcription polymerase chain reaction. Maintaining a good seal around septic tanks by covering them with a layer of soil is a simple intervention to block mosquito exit/entry and contribute to vector control in resettlement villages. The scale-up of this simple, cheap intervention would have global impact in preventing the colonization of septic tanks by nuisance biting and disease transmitting mosquitoes. PMID- 26508318 TI - Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy. AB - AIMS/HYPOTHESIS: Changes in podocyte morphology and function are associated with albuminuria and progression of diabetic nephropathy. NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and Nox4 is upregulated in podocytes in response to high glucose. We assessed the role of NOX4-derived ROS in podocytes in vivo in a model of diabetic nephropathy using a podocyte-specific NOX4-deficient mouse, with a major focus on the development of albuminuria and ultra-glomerular structural damage. METHODS: Streptozotocin induced diabetes-associated changes in renal structure and function were studied in male floxedNox4 and podocyte-specific, NOX4 knockout (podNox4KO) mice. We assessed albuminuria, glomerular extracellular matrix accumulation and glomerulosclerosis, and markers of ROS and inflammation, as well as glomerular basement membrane thickness, effacement of podocytes and expression of the podocyte-specific protein nephrin. RESULTS: Podocyte-specific Nox4 deletion in streptozotocin-induced diabetic mice attenuated albuminuria in association with reduced vascular endothelial growth factor (VEGF) expression and prevention of the diabetes-induced reduction in nephrin expression. In addition, podocyte specific Nox4 deletion reduced glomerular accumulation of collagen IV and fibronectin, glomerulosclerosis and mesangial expansion, as well as glomerular basement membrane thickness. Furthermore, diabetes-induced increases in renal ROS, glomerular monocyte chemoattractant protein-1 (MCP-1) and protein kinase C alpha (PKC-alpha) were attenuated in podocyte-specific NOX4-deficient mice. CONCLUSIONS/INTERPRETATION: Collectively, this study shows the deleterious effect of Nox4 expression in podocytes by promoting podocytopathy in association with albuminuria and extracellular matrix accumulation in experimental diabetes, emphasising the role of NOX4 as a target for new renoprotective agents. PMID- 26508319 TI - Factors Modulating Post-Activation Potentiation of Jump, Sprint, Throw, and Upper Body Ballistic Performances: A Systematic Review with Meta-Analysis. AB - BACKGROUND: Although post-activation potentiation (PAP) has been extensively examined following the completion of a conditioning activity (CA), the precise effects on subsequent jump, sprint, throw, and upper-body ballistic performances and the factors modulating these effects have yet to be determined. Moreover, weaker and stronger individuals seem to exhibit different PAP responses; however, how they respond to the different components of a strength-power-potentiation complex remains to be elucidated. OBJECTIVES: This meta-analysis determined (1) the effect of performing a CA on subsequent jump, sprint, throw, and upper-body ballistic performances; (2) the influence of different types of CA, squat depths during the CA, rest intervals, volumes of CA, and loads during the CA on PAP; and (3) how individuals of different strength levels respond to these various strength-power-potentiation complex components. METHODS: A computerized search was conducted in ADONIS, ERIC, SPORTDiscus, EBSCOhost, Google Scholar, MEDLINE, and PubMed databases up to March 2015. The analysis comprised 47 studies and 135 groups of participants for a total of 1954 participants. RESULTS: The PAP effect is small for jump (effect size [ES] = 0.29), throw (ES = 0.26), and upper-body ballistic (ES = 0.23) performance activities, and moderate for sprint (ES = 0.51) performance activity. A larger PAP effect is observed among stronger individuals and those with more experience in resistance training. Plyometric (ES = 0.47) CAs induce a slightly larger PAP effect than traditional high-intensity (ES = 0.41), traditional moderate-intensity (ES = 0.19), and maximal isometric (ES = -0.09) CAs, and a greater effect after shallower (ES = 0.58) versus deeper (ES = 0.25) squat CAs, longer (ES = 0.44 and 0.49) versus shorter (ES = 0.17) recovery intervals, multiple- (ES = 0.69) versus single- (ES = 0.24) set CAs, and repetition maximum (RM) (ES = 0.51) versus sub-maximal (ES = 0.34) loads during the CA. It is noteworthy that a greater PAP effect can be realized earlier after a plyometric CA than with traditional high- and moderate-intensity CAs. Additionally, shorter recovery intervals, single-set CAs, and RM CAs are more effective at inducing PAP in stronger individuals, while weaker individuals respond better to longer recovery intervals, multiple-set CAs, and sub-maximal CAs. Finally, both weaker and stronger individuals express greater PAP after shallower squat CAs. CONCLUSIONS: Performing a CA elicits small PAP effects for jump, throw, and upper-body ballistic performance activities, and a moderate effect for sprint performance activity. The level of potentiation is dependent on the individual's level of strength and resistance training experience, the type of CA, the depth of the squat when this exercise is employed to elicit PAP, the rest period between the CA and subsequent performance, the number of set(s) of the CA, and the type of load used during the CA. Finally, some components of the strength-power-potentiation complex modulate the PAP response of weaker and stronger individuals in a different way. PMID- 26508320 TI - What to expect from immediate salvage hysterectomy following concomitant chemoradiation and image-guided adaptive brachytherapy in locally advanced cervical cancer. AB - PURPOSE: Concomitant chemoradiation followed by brachytherapy is the standard treatment for locally advanced cervical cancers. The place of adjuvant hysterectomy remains unclear but tends to be limited to incomplete responses to radiotherapy or local relapse. The aim was to analyse the benefit from immediate salvage surgery following radiation therapy in incomplete responders. METHODS: Among the patients with locally advanced cervical cancer treated with concomitant chemoradiation followed by 3D image-guided adaptive brachytherapy and hysterectomy, cases with genuine macroscopic remnant, defined as at least 1cm in width, were identified. Their clinical data and outcomes were retrospectively reviewed and compared to the patients treated with the same modalities. RESULTS: Fifty-eight patients were included, with a median follow-up of 4.2 years. After hysterectomy, 9 patients had macroscopic residual disease, 10 microscopic and the remaining 39 patients were considered in complete histological response. The 4 year overall survival and disease-free survival rates were significantly decreased in patients with macroscopic residual disease: 50 and 51% versus 92% and 93%, respectively. Intestinal grades 3-4 toxicities were reported in 10.4% and urinary grades 3-4 in 8.6% in the whole population without distinctive histological features. Planning aims were reached in only one patient with macroscopic residuum (11.1%). In univariate analysis, overall treatment time (>55 days) and histological subtype (adenocarcinomas or adenosquamous carcinomas) appeared to be significant predictive factors for macroscopic remnant after treatment completion (P=0.021 and P=0.017, respectively). In multivariate analysis, treatment time was the only independent factor (P=0.046, odds ratio=7.0). CONCLUSIONS: Although immediate salvage hysterectomy in incomplete responders provided a 4-year disease-free survival of 51%, its impact on late morbidity is significant. Efforts should focus on respect of treatment time and dose escalation. Adenocarcinoma might require higher high-risk clinical target volume planning aims. PMID- 26508321 TI - [Malignant tumours of the eye: Epidemiology, diagnostic methods and radiotherapy]. AB - Malignant tumours of the eye are not common, barely representing 1 % of all cancers. This article aims to summarise, for each of the main eye malignant diseases, aspects of epidemiology, diagnostic methods and treatments, with a focus on radiation therapy techniques. The studied tumours are: eye metastasis, intraocular and ocular adnexal lymphomas, uveal melanomas, malignant tumours of the conjunctive, of the lids, and retinoblastomas. The last chapter outlines ocular complications of radiation therapy and their management. PMID- 26508322 TI - Neural response during anticipation of monetary loss is elevated in adult attention deficit hyperactivity disorder. AB - OBJECTIVES: Risky behaviour seriously impacts the life of adult patients with attention deficit hyperactivity disorder (ADHD). Such behaviours have often been attributed to their exaggerated reward seeking, but dysfunctional anticipation of negative outcomes might also play a role. METHODS: The present study compared adult patients with ADHD (n = 28) with matched healthy controls (n = 28) during anticipation of monetary losses versus gains while undergoing functional magnetic resonance imaging (fMRI) and skin conductance recording. RESULTS: Skin conductance was higher during anticipation of losses compared to gains in both groups. Affective ratings of predictive cues did not differ between groups. ADHD patients showed increased activity in bilateral amygdalae, left anterior insula (region of interest analysis) and left temporal pole (whole brain analysis) compared to healthy controls during loss versus gain anticipation. In the ADHD group higher insula and temporal pole activations went along with more negative affective ratings. CONCLUSIONS: Neural correlates of loss anticipation are not blunted but rather increased in ADHD, possibly due to a life history of repeated failures and the respective environmental sanctions. Behavioural adaptations to such losses, however, might differentiate them from controls: future research should study whether negative affect might drive more risk seeking than risk avoidance. PMID- 26508323 TI - Systematic review of brucellosis in the Middle East: disease frequency in ruminants and humans and risk factors for human infection. AB - A systematic review of studies providing frequency estimates of brucellosis in humans and ruminants and risk factors for Brucella spp. seropositivity in humans in the Middle East was conducted to collate current knowledge of brucellosis in this region. Eight databases were searched for peer-reviewed original Arabic, English, French and Persian journal articles; the search was conducted on June 2014. Two reviewers evaluated articles for inclusion based on pre-defined criteria. Of 451 research articles, only 87 articles passed the screening process and provided bacteriological and serological evidence for brucellosis in all Middle Eastern countries. Brucella melitensis and B. abortus have been identified in most countries in the Middle East, supporting the notion of widespread presence of Brucella spp. especially B. melitensis across the region. Of the 87 articles, 49 were used to provide evidence of the presence of Brucella spp. but only 11 provided new knowledge on the frequency of brucellosis in humans and ruminants or on human risk factors for seropositivity and were deemed of sufficient quality. Small ruminant populations in the region show seroprevalence values that are among the highest worldwide. Human cases are likely to arise from subpopulations occupationally exposed to ruminants or from the consumption of unpasteurized dairy products. The Middle East is in need of well-designed observational studies that could generate reliable frequency estimates needed to assess the burden of disease and to inform disease control policies. PMID- 26508324 TI - Further improvement in ganoderic acid production in static liquid culture of Ganoderma lucidum by integrating nitrogen limitation and calcium ion addition. AB - To further improve the ganoderic acid (GA) production, a novel integrated strategy by combining nitrogen limitation and calcium ion addition was developed. The effects of the integrated combination on the content of GA-T (one powerful anticancer compound), their intermediates (squalene and lanosterol) and on the transcription levels of GA biosynthetic genes in G. lucidum fermentation were investigated. The maximum GA-T content with the integrated strategy were 1.87 mg/ 100 mg dry cell weight, which was 2.1-4.2 fold higher than that obtained with either calcium ion addition or nitrogen limitation alone, and it is also the highest record as ever reported in submerged fermentation of G. lucidum. The squalene content was increased by 3.9- and 2.2-fold in this case compared with either individual strategy alone. Moreover, the transcription levels of the GA biosynthetic genes encoding 3-hydroxy-3-methyglutaryl coenzyme A reductase and lanosterol synthase were also up-regulated by 3.3-7.5 and 1.3-2.3 fold, respectively. PMID- 26508325 TI - Pretreatment of microalgal biomass for enhanced recovery/extraction of reducing sugars and proteins. AB - Microalgae species including Chlamydomonas mexicana, Micractinium reisseri, Scenedesmus obliquus and Tribonema aequale were cultivated in batch cultures, and their biochemical composition was determined. C. mexicana showed the highest carbohydrate content of 52.6% and was selected for further study. Sonication pretreatment under optimum conditions (at 40 kHz, 2.2 Kw, 50 degrees C for 15 min) released 74 +/- 2.7 mg g(-1) of total reducing sugars (TRS) of dry cell weight, while the combined sonication and enzymatic hydrolysis treatment enhanced the TRS yield by fourfold (280.5 +/- 4.9 mg g(-1)). The optimal ratio of enzyme [E]:substrate [S] for maximum TRS yield was [1]:[5] at 50 degrees C and pH 5. Combined sonication and hydrolysis treatment released 7.3% (27.1 +/- 0.9 mg g( 1)) soluble protein of dry cell weight, and further fermentation of the dissolved carbohydrate fraction enhanced the soluble protein content up to 56% (228.4 mg g( 1)) of total protein content. Scanning and transmission electron microscopic analyses indicated that microalgae cells were significantly disrupted by the combined sonication and enzyme hydrolysis treatment. This study indicates that pretreatment and subsequent fermentation of the microalgal biomass enhance the recovery of carbohydrates and proteins which can be used as feedstocks for generation of biofuels. PMID- 26508326 TI - Comment on "Survival of patients with chronic respiratory failure on long-term oxygen therapy and or non-invasive ventilation at home". PMID- 26508327 TI - Plasma total and unacylated ghrelin predict 5-year changes in insulin resistance. AB - BACKGROUND & AIMS: Ghrelin is a gastric hormone circulating in acylated (AG) and unacylated (UG) forms, and higher plasma total ghrelin (TG) and UG may be cross sectionally associated with lower insulin resistance in metabolic syndrome patients. The potential value of ghrelin forms in predicting insulin resistance and its time-related changes in community-based population cohorts remains unknown. METHODS: We measured TG, AG and calculated UG (TG-AG) in 716 individuals from the North-East-Italy MoMa study (age: 55 +/- 9 years, BMI: 29 +/- 5 kg/m(2), M/F:349/367) to test the hypothesis that circulating TG and UG, but not AG are negatively associated with insulin resistance (HOMA). We further hypothesized that baseline TG and UG negatively predict 5-year HOMA changes in a 350 individual subgroup. RESULTS: Baseline TG and UG were associated negatively with HOMA after adjusting for gender and body mass index (BMI). Baseline gender- and BMI-adjusted TG and UG were also negatively associated with HOMA at 5-year follow up (n = 350), and changes in TG and UG were negatively associated with changes in HOMA (P < 0.05) after adjustment for anthropometric and metabolic confounders. No statistically significant correlations were observed between AG and baseline or 5 year HOMA. CONCLUSIONS: In a North-East Italy community-based population cohort, plasma TG and UG but not AG are negatively associated with HOMA. TG and UG and their changes also independently predict 5-year HOMA changes. TG and UG are therefore novel potential modulators of insulin resistance and may contribute to predict its time-related changes in humans. PMID- 26508328 TI - The Temporal Dynamics of Visual Processing in Multiple Sclerosis. AB - Although the integrity of the visual system is often affected in multiple sclerosis (MS), the potential relationship between the temporal dynamics of visual processing and performance on neuropsychological tests assessing processing speed (PS) remains relatively unexplored. Here, we test if a PS deficit is related to abnormalities within the visual system, rather than impaired higher-level cognitive function. Two groups of participants with MS (1 group with PS deficits and another without) and a healthy control group, matched for age and education, were included. To explore the temporal dynamics of visual processing, we used 2 psychophysical paradigms: attention enhancement/prioritization and rapid serial visual presentation. Visual PS deficits were associated with a decreased capability to detect visual stimuli and a higher limitation in visual temporal-processing capacity. These results suggest that a latent sensorial temporal limitation of the visual system is significantly associated to PS deficits in MS. PMID- 26508329 TI - Niche dynamics of alien species do not differ among sexual and apomictic flowering plants. AB - Biological invasions can be associated with shifts of the species' climatic niches but the incidence of such shifts is under debate. The reproductive system might be a key factor controlling such shifts because it influences a species' evolutionary flexibility. However, the link between reproductive systems and niche dynamics in plant invasions has been little studied so far. We compiled global occurrence data sets of 13 congeneric sexual and apomictic species pairs, and used principal components analysis (PCA) and kernel smoothers to compare changes in climatic niche optima, breadths and unfilling/expansion between native and alien ranges. Niche change metrics were compared between sexual and apomictic species. All 26 species showed changes in niche optima and/or breadth and 14 species significantly expanded their climatic niches. However, we found no effect of the reproductive system on niche dynamics. Instead, species with narrower native niches showed higher rates of niche expansion in the alien ranges. Our results suggest that niche shifts are frequent in plant invasions but evolutionary potential may not be of major importance for such shifts. Niche dynamics rather appear to be driven by changes of the realized niche without adaptive change of the fundamental climatic niche. PMID- 26508330 TI - Novel Balloon Surface Scanning Device for Intraoperative Breast Endomicroscopy. AB - Recent advances in fluorescence confocal endomicroscopy have allowed real-time identification of residual tumour cells on the walls of the cavity left by breast conserving surgery. However, it is difficult to systematically survey the surgical site because of the small imaging field-of-view of these probes, compounded by tissue deformation and inconsistent probe-tissue contact when operated manually. Therefore, a new robotized scanning device is required for controlled, large area scanning and mosaicing. This paper presents a robotic scanning probe with an inflatable balloon, providing stable cavity scanning over undulating surfaces. It has a compact design, with an outer diameter of 4 mm and a working channel of 2.2 mm, suitable for a leached flexible fibre bundle endomicroscope probe. With the probe inserted, the tip positioning accuracy measured to be 0.26 mm for bending and 0.17 mm for rotational motions. Large area scanning was achieved (25-35 mm(2)) and the experimental results demonstrate the potential clinical value of the device for intraoperative cavity tumour margin evaluation. PMID- 26508331 TI - Quantitative Imaging Assessment of an Alternative Approach to Surgical Mitral Valve Leaflet Resection: An Acute Porcine Study. AB - This study reports the initial in vivo use of a combined radiofrequency ablation and cryo-anchoring (RFC) catheter as an alternative to surgical mitral valve (MV) leaflet resection. Radiofrequency ablation thermally shrinks enlarged collagenous tissues, providing an alternative to leaflet resection, and cryo-anchoring provides reversible attachment of a catheter to freely mobile MV leaflets. Excised porcine MVs (n = 9) were tested in a left heart flow simulator to establish treatment efficacy criteria. Resected leaflet area was quantified by tracking markers on the leaflet surface, and leaflet length reductions were directly measured on echocardiography. Leaflet area decreased by 38 +/- 2.7%, and leaflet length decreased by 9.2 +/- 1.8% following RFC catheter treatment. The RFC catheter was then tested acutely in healthy pigs (n = 5) under epicardial echocardiographic guidance, open-chest without cardiopulmonary bypass, using mid ventricular free wall access. Leaflet length was quantified using echocardiography. Quantitative assessment of MV leaflet length revealed that leaflet resection was successful in 4 of 5 pigs, with a leaflet length reduction of 13.3 +/- 4.6%. Histological, mechanical, and gross pathological findings also confirmed that RFC catheter treatment was efficacious. The RFC catheter significantly reduces MV leaflet size in an acute animal model, providing a possible percutaneous alternative to surgical leaflet resection. PMID- 26508332 TI - Crash risk perception of sleepy driving and its comparisons with drink driving and speeding: Which behavior is perceived as the riskiest? AB - OBJECTIVE: Driver sleepiness is a major crash risk factor but may be underrecognized as a risky driving behavior. Sleepy driving is usually rated as less of a road safety issue than more well-known risky driving behaviors, such as drink driving and speeding. The objective of this study was to compare perception of crash risk of sleepy driving, drink driving, and speeding. METHODS: Three hundred Australian drivers completed a questionnaire that assessed crash risk perceptions for sleepy driving, drink driving, and speeding. Additionally, the participants' perceptions of crash risk were assessed for 5 different contextual scenarios that included different levels of sleepiness (low, high), driving duration (short, long), and time of day/circadian influences (afternoon, nighttime) of driving. RESULTS: The analysis confirmed that sleepy driving was considered a risky driving behavior but not as risky as high levels of speeding (P < .05). Yet, the risk of crashing at 4 a.m. was considered as equally risky as low levels of speeding (10 km over the limit). The comparisons of the contextual scenarios revealed driving scenarios that would arguably be perceived as quite risky because time of day/circadian influences were not reported as high risk. CONCLUSIONS: The results suggest a lack of awareness or appreciation of circadian rhythm functioning, particularly the descending phase of circadian rhythm that promotes increased sleepiness in the afternoon and during the early hours of the morning. Yet, the results suggested an appreciation of the danger associated with long-distance driving and driver sleepiness. Further efforts are required to improve the community's awareness of the impairing effects from sleepiness and, in particular, knowledge regarding the human circadian rhythm and the increased sleep propensity during the circadian nadir. PMID- 26508333 TI - On the energetics of cation ordering in tungsten-bronze-type oxides. AB - Oxides with the tetragonal tungsten bronze (TTB) structure are well-known ferroelectrics that show a large flexibility both with respect to chemical composition and cation ordering. Two of the simplest compounds in this family are lead metaniobate (PbNb2O6 or PN) and strontium barium niobate (SrxBa1-xNb2O6 or SBN). While PN is a classical ferroelectric, SBN goes from ferroelectric to relaxor-like with increasing Sr content, with a polar direction different from that in PN. The partially occupied sublattices in both systems give the possibility for cation order-disorder phenomena, but it is not known if or how this influences the polarization and ferroelectricity. Here, we use density functional theory (DFT) calculations to investigate how cation and cation vacancy ordering influences the energetics of these compounds, by comparing both the energy differences and the barriers for transition between different cation configurations. We extend the thermodynamic model of O'Neill and Navrotsky, originally developed for cation interchange in spinels, to describe the order disorder phenomenology in TTB oxides. The influence of order-disorder processes on the functional properties of PN and SBN is discussed. PMID- 26508334 TI - Functional Specialization and Flexibility in Human Association Cortex. PMID- 26508335 TI - Frequency-Dependent Corticostriatal Disinhibition Resulting from Chronic Dopamine Depletion: Role of Local Striatal cGMP and GABA-AR Signaling. AB - The onset of motor deficits in parkinsonism is thought to result from dopamine (DA) loss-induced corticostriatal disruption and the development of excessive cortico-basal ganglia synchronization. To gain insights into the mechanisms underlying such corticostriatal dysfunction, we conducted local field potential (LFP) recordings in rats and measured how striatal manipulations of DA, cyclic guanosine monophosphate (cGMP), and gamma-aminobutyric acid- A receptor (GABA-AR) signaling impact corticostriatal transmission at specific oscillatory frequencies. Results indicate that the degree of 6-hydroxydopamine-induced DA lesion and subsequent changes in striatal DA, cGMP, and GABA-AR signaling contribute to impair LFP suppression such that the DA-depleted striatum becomes more permissive to cortically driven oscillations at 10-20 Hz, and to a lesser extent, at 40 Hz. Notably, the corticostriatal dysfunction at 40 Hz emerged only when the degree of chronic DA lesion surpassed 90%, which coincides with the appearance of severe forelimb stepping deficits. Collectively, these results indicate that several mechanisms contribute to suppress LFP within the 10-20 Hz range, yet a critical level of striatal GABAergic activity is required for sustaining corticostriatal inhibition at 40 Hz. Both the degree and chronicity of DA lesion are major contributing factors to the severity of motor and striatal GABAergic deficits that could only be reversed by strengthening local GABA-AR function. PMID- 26508336 TI - Cortico-Cerebellar Structural Connectivity Is Related to Residual Motor Output in Chronic Stroke. AB - Functional imaging studies have argued that interactions between cortical motor areas and the cerebellum are relevant for motor output and recovery processes after stroke. However, the impact of the underlying structural connections is poorly understood. To investigate this, diffusion-weighted brain imaging was conducted in 26 well-characterized chronic stroke patients (aged 63 +/- 1.9 years, 18 males) with supratentorial ischemic lesions and 26 healthy participants. Probabilistic tractography was used to reconstruct reciprocal cortico-cerebellar tracts and to relate their microstructural integrity to residual motor functioning applying linear regression modeling. The main finding was a significant association between cortico-cerebellar structural connectivity and residual motor function, independent from the level of damage to the cortico spinal tract. Specifically, white matter integrity of the cerebellar outflow tract, the dentato-thalamo-cortical tract, was positively related to both general motor output and fine motor skills. Additionally, the integrity of the descending cortico-ponto-cerebellar tract contributed to rather fine motor skills. A comparable structure-function relationship was not evident in the controls. The present study provides first tract-related structural data demonstrating a critical importance of distinct cortico-cerebellar connections for motor output after stroke. PMID- 26508337 TI - Daclatasvir and asunaprevir for recurrent hepatitis C following living donor liver transplantation with HIV co-infection. AB - Antiviral treatment in liver transplant recipients co-infected with hepatitis C virus (HCV) and HIV remains a challenge. We herein report a case of HCV recurrence that was successfully treated using interferon-free anti-HCV therapy with daclatasvir and asunaprevir. A 48-year-old man underwent antiviral therapy with a 24-week course of daclatasvir and asunaprevir for biopsy-proven recurrent HCV 15 months after living donor liver transplantation, following non-response to pre-emptive antiviral treatment with pegylated interferon plus ribavirin. Anti HIV and immunosuppressive regimens were modified safely. Renal function was feasibly preserved. The anti-HCV effect was remarkable with an undetectable viral load confirmed within 2 weeks, and this patient achieved a sustained virological response after 12 weeks of post-transplantation treatment. No serious adverse events were observed. This case indicates that daclatasvir and asunaprevir for recurrent HCV in a HIV co-infected recipient after liver transplantation is safe and effective. PMID- 26508338 TI - Disrupted Tryptophan Metabolism Induced Cognitive Impairment in a Mouse Model of Sepsis-associated Encephalopathy. AB - Sepsis-associated encephalopathy (SAE) is a common complication in critically ill patients and is associated with a poor prognosis. However, the precise mechanisms underlying sepsis-induced cognitive impairment remain largely to be elucidated. The aim of the present study was to investigate whether indoleamine 2, 3 dioxygenase (IDO) activation-mediated neurotoxicity is involved in the pathophysiology of sepsis-induced cognitive impairment. Sepsis was induced by cecal ligation/perforation (CLP). The animals were randomly divided into the following five groups: Sham + vehicle group; Sham + 1-methyl-D, L-tryptophan group; Sham + L-Kynurenine group; CLP + vehicle group; or CLP + 1-methyl-D, L tryptophan group. The survival rate was estimated by the Kaplan-Meier method. Behavioral tests were performed by the open field and fear conditioning tests at days 13 and 14 after operation. In the present study, we demonstrated that sepsis induced a deficit in hippocampus-dependent cognitive impairment in a mouse model of SAE. Furthermore, a single peripheral kynurenine administration, the metabolic product of IDO, induced a deficit in the cognitive impairment in the sham mice. However, mice treated with IDO inhibitor 1-methyl-D, L-tryptophan were protected from sepsis-induced cognitive impairment. In conclusion, our study implicates IDO dependent neurotoxic kynurenine metabolism as a critical factor responsible for the sepsis-induced cognitive impairment and a potential novel target for the treatment of SAE. PMID- 26508339 TI - Digital conservation: an introduction. PMID- 26508340 TI - Technology for nature conservation: an industry perspective. AB - Information age technology has the potential to change the game for conservation by continuously monitoring the pulse of the natural world. Whether or not it will depends on the ability of the conservation sector to build a community of practice, come together to define key technology challenges and work with a wide variety of partners to create, implement, and sustain solutions. I describe why these steps are necessary, outline the latest developments in the field and offer actionable ways forward for conservation agencies, universities, funding bodies, professional societies, and technology corporations to come together to realize the revolution that computational technologies can bring for biodiversity conservation. PMID- 26508341 TI - Digital technology and human development: a charter for nature conservation. AB - The application of digital technology in conservation holds much potential for advancing the understanding of, and facilitating interaction with, the natural world. In other sectors, digital technology has long been used to engage communities and share information. Human development-which holds parallels with the nature conservation sector-has seen a proliferation of innovation in technological development. Throughout this Perspective, we consider what nature conservation can learn from the introduction of digital technology in human development. From this, we derive a charter to be used before and throughout project development, in order to help reduce replication and failure of digital innovation in nature conservation projects. We argue that the proposed charter will promote collaboration with the development of digital tools and ensure that nature conservation projects progress appropriately with the development of new digital technologies. PMID- 26508342 TI - Digital innovation through partnership between nature conservation organisations and academia: a qualitative impact assessment. AB - Nature conservation organisations increasingly turn to new digital technologies to help deliver conservation objectives. This has led to collaborative forms of working with academia to spearhead digital innovation. Through in-depth interviews with three UK research-council-funded case studies, we show that by working with academics conservation organisations can receive positive and negative impacts, some of which cut across their operations. Positive impacts include new ways of engaging with audiences, improved data workflows, financial benefits, capacity building and the necessary digital infrastructure to help them influence policy. Negative impacts include the time and resources required to learn new skills and sustain new technologies, managing different organisational objectives and shifts in working practices as a result of the new technologies. Most importantly, collaboration with academics was shown to bring the opportunity of a profound change in perspectives on technologies with benefits to the partner organisations and individuals therein. PMID- 26508343 TI - Wildlife in the cloud: a new approach for engaging stakeholders in wildlife management. AB - Research in wildlife management increasingly relies on quantitative population models. However, a remaining challenge is to have end-users, who are often alienated by mathematics, benefiting from this research. I propose a new approach, 'wildlife in the cloud,' to enable active learning by practitioners from cloud-based ecological models whose complexity remains invisible to the user. I argue that this concept carries the potential to overcome limitations of desktop-based software and allows new understandings of human-wildlife systems. This concept is illustrated by presenting an online decision-support tool for moose management in areas with predators in Sweden. The tool takes the form of a user-friendly cloud-app through which users can compare the effects of alternative management decisions, and may feed into adjustment of their hunting strategy. I explain how the dynamic nature of cloud-apps opens the door to different ways of learning, informed by ecological models that can benefit both users and researchers. PMID- 26508344 TI - Developing an automated risk management tool to minimize bird and bat mortality at wind facilities. AB - A scarcity of baseline data is a significant barrier to understanding and mitigating potential impacts of offshore development on birds and bats. Difficult and sometimes unpredictable conditions coupled with high expense make gathering such data a challenge. The Acoustic and Thermographic Offshore Monitoring (ATOM) system combines thermal imaging with acoustic and ultrasound sensors to continuously monitor bird and bat abundance, flight height, direction, and speed. ATOM's development and potential capabilities are discussed, and illustrated using onshore and offshore test data obtained over 16 months in the eastern USA. Offshore deployment demonstrated birds tending to fly into winds and activity declining sharply in winds >10 km h(-1). Passerines showed distinct seasonal changes in flight bearing and flew higher than non-passerines. ATOM data could be used to automatically shut down wind turbines to minimize collision mortality while simultaneously providing information for modeling activity in relation to weather and season. PMID- 26508345 TI - Utilizing the Cyberforest live sound system with social media to remotely conduct woodland bird censuses in Central Japan. AB - We have developed a system that streams and archives live sound from remote areas across Japan via an unmanned automatic camera. The system was used to carry out pilot bird censuses in woodland; this allowed us to examine the use of live sound transmission and the role of social media as a mediator in remote scientific monitoring. The system has been streaming sounds 8 h per day for more than five years. We demonstrated that: (1) the transmission of live sound from a remote woodland could be used effectively to monitor birds in a remote location; (2) the simultaneous involvement of several participants via Internet Relay Chat to listen to live sound transmissions could enhance the accuracy of census data collection; and (3) interactions through Twitter allowed members of the public to engage or help with the remote monitoring of birds and experience inaccessible nature through the use of novel technologies. PMID- 26508346 TI - Mapping species distributions: a comparison of skilled naturalist and lay citizen science recording. AB - To assess the ability of traditional biological recording schemes and lay citizen science approaches to gather data on species distributions and changes therein, we examined bumblebee records from the UK's national repository (National Biodiversity Network) and from BeeWatch. The two recording approaches revealed similar relative abundances of bumblebee species but different geographical distributions. For the widespread common carder (Bombus pascuorum), traditional recording scheme data were patchy, both spatially and temporally, reflecting active record centre rather than species distribution. Lay citizen science records displayed more extensive geographic coverage, reflecting human population density, thus offering better opportunities to account for recording effort. For the rapidly spreading tree bumblebee (Bombus hypnorum), both recording approaches revealed similar distributions due to a dedicated mapping project which overcame the patchy nature of naturalist records. We recommend, where possible, complementing skilled naturalist recording with lay citizen science programmes to obtain a nation-wide capability, and stress the need for timely uploading of data to the national repository. PMID- 26508347 TI - Taking a 'Big Data' approach to data quality in a citizen science project. AB - Data from well-designed experiments provide the strongest evidence of causation in biodiversity studies. However, for many species the collection of these data is not scalable to the spatial and temporal extents required to understand patterns at the population level. Only data collected from citizen science projects can gather sufficient quantities of data, but data collected from volunteers are inherently noisy and heterogeneous. Here we describe a 'Big Data' approach to improve the data quality in eBird, a global citizen science project that gathers bird observations. First, eBird's data submission design ensures that all data meet high standards of completeness and accuracy. Second, we take a 'sensor calibration' approach to measure individual variation in eBird participant's ability to detect and identify birds. Third, we use species distribution models to fill in data gaps. Finally, we provide examples of novel analyses exploring population-level patterns in bird distributions. PMID- 26508348 TI - Automated data analysis to rapidly derive and communicate ecological insights from satellite-tag data: a case study of reintroduced red kites. AB - Analysis of satellite-telemetry data mostly occurs long after it has been collected, due to the time and effort needed to collate and interpret such material. Delayed reporting reduces the usefulness of such data for nature conservation where timely information about animal movements is required. To counter this problem, we present a novel approach which combines automated analysis of satellite-telemetry data with rapid communication of insights derived from such data. A relatively simple algorithm (based on radial and angular velocity calculated from fixes) allowed instantaneous detection of excursions away from settlement areas and automated calculation of home ranges on the remaining data. Automating the detection of both excursions and home-range calculations enabled us to disseminate ecological insights from satellite-tag data instantaneously through a dedicated web portal. The automated analysis, interpretation, and communication of satellite-tag and other ecological data offer clear benefits to nature conservation research and practice. PMID- 26508349 TI - Limitations of recreational camera traps for wildlife management and conservation research: a practitioner's perspective. AB - The availability of affordable 'recreational' camera traps has dramatically increased over the last decade. We present survey results which show that many conservation practitioners use cheaper 'recreational' units for research rather than more expensive 'professional' equipment. We present our perspective of using two popular models of 'recreational' camera trap for ecological field-based studies. The models used (for >2 years) presented us with a range of practical problems at all stages of their use including deployment, operation, and data management, which collectively crippled data collection and limited opportunities for quantification of key issues arising. Our experiences demonstrate that prospective users need to have a sufficient understanding of the limitations camera trap technology poses, dimensions we communicate here. While the merits of different camera traps will be study specific, the performance of more expensive 'professional' models may prove more cost-effective in the long-term when using camera traps for research. PMID- 26508350 TI - The social implications of using drones for biodiversity conservation. AB - Unmanned aerial vehicles, or 'drones', appear to offer a flexible, accurate and affordable solution to some of the technical challenges of nature conservation monitoring and law enforcement. However, little attention has been given to their possible social impacts. In this paper, I review the possible social impacts of using drones for conservation, including on safety, privacy, psychological wellbeing, data security and the wider understanding of conservation problems. I argue that negative social impacts are probable under some circumstances and should be of concern for conservation for two reasons: (1) because conservation should follow good ethical practice; and (2) because negative social impacts could undermine conservation effectiveness in the long term. The paper concludes with a call for empirical research to establish whether the identified social risks of drones occur in reality and how they could be mitigated, and for self regulation of drone use by the conservation sector to ensure good ethical practice and minimise the risk of unintended consequences. PMID- 26508351 TI - Microscope and spectacle: on the complexities of using new visual technologies to communicate about wildlife conservation. AB - Wildlife conservation-related organisations increasingly employ new visual technologies in their science communication and public engagement efforts. Here, we examine the use of such technologies for wildlife conservation campaigns. We obtained empirical data from four UK-based organisations through semi-structured interviews and participant observation. Visual technologies were used to provide the knowledge and generate the emotional responses perceived by organisations as being necessary for motivating a sense of caring about wildlife. We term these two aspects 'microscope' and 'spectacle', metaphorical concepts denoting the duality through which these technologies speak to both the cognitive and the emotional. As conservation relies on public support, organisations have to be seen to deliver information that is not only sufficiently detailed and scientifically credible but also spectacular enough to capture public interest. Our investigation showed that balancing science and entertainment is a difficult undertaking for wildlife-related organisations as there are perceived risks of contriving experiences of nature and obscuring conservation aims. PMID- 26508352 TI - Digital technology and the conservation of nature. AB - Digital technology is changing nature conservation in increasingly profound ways. We describe this impact and its significance through the concept of 'digital conservation', which we found to comprise five pivotal dimensions: data on nature, data on people, data integration and analysis, communication and experience, and participatory governance. Examining digital innovation in nature conservation and addressing how its development, implementation and diffusion may be steered, we warn against hypes, techno-fix thinking, good news narratives and unverified assumptions. We identify a need for rigorous evaluation, more comprehensive consideration of social exclusion, frameworks for regulation and increased multi-sector as well as multi-discipline awareness and cooperation. Along the way, digital technology may best be reconceptualised by conservationists from something that is either good or bad, to a dual-faced force in need of guidance. PMID- 26508353 TI - How biophysical in vivo testing techniques can be used to characterize full thickness skin equivalents. AB - BACKGROUND: The reliability of the biophysical properties of skin equivalents (SEs) remains a challenge for medical applications and for product efficacy tests following the European Directive 2003/15/EC2 on the prohibition of animal experiments for cosmetic products. METHODS: We propose to adapt the biophysical in vivo testing techniques to compare full thickness model growth vs. time. The interest in using such techniques lies in possible comparisons between in vivo and in vitro skin as well as monitoring samples over the culture time. RESULTS: High frequency ultrasound technique, optical coherence tomography (OCT), and laser scanning microscopy were used to analyze SEs morphology at days D42 and D60 whereas their microstructure was assessed through transmission electron microscopy and classical histology. A correlation between these observations and mechanical measurements has been proposed so as to underline the consequence of both the development of the dermis elastic fibers and the epidermis differentiation. CONCLUSION: Ultrasounds measurements show a highly homogeneous dermis whereas the OCT technique clearly distinguishes the stratum corneum and the living epidermis. The increase in the thicknesses of these layers as well as the growth in elastin and collagen fibers results in strong modifications of the samples mechanical properties. PMID- 26508354 TI - Structure of DPPC-hyaluronan interfacial layers - effects of molecular weight and ion composition. AB - Hyaluronan and phospholipids play an important role in lubrication in articular joints and provide in combination with glycoproteins exceptionally low friction coefficients. We have investigated the structural organization of 1,2-dipalmitoyl sn-glycero-3-phosphocholine (DPPC) Langmuir layers at the solution-air interface at different length scales with respect to the adsorption of hyaluronan (HA). This allows us to assemble a comprehensive picture of the adsorption and the resulting structures, and how they are affected by the molecular weight of HA and the presence of calcium ions. Brewster angle microscopy and grazing incident diffraction were used to determine the lateral structure at the micro- and macro scale. The data reveals an influence of HA on both the macro and micro structure of the DPPC Langmuir layer, and that the strength of this effect increases with decreasing molecular weight of HA and in presence of calcium ions. Furthermore, from X-ray reflectivity measurements we conclude that HA adsorbs to the hydrophilic part of DPPC, but data also suggest that two types of interfacial structures are formed at the interface. We argue that hydrophobic forces and electrostatic interactions play important rules for the association between DPPC and HA. Surface pressure area isotherms were used to determine the influence of HA on the phase behavior of DPPC while electrophoretic mobility measurements were used to gain insight into the binding of calcium ions to DPPC vesicles and hyaluronan. PMID- 26508355 TI - Compliance with established guidelines for the radiological reporting of atypical femoral fractures. AB - OBJECTIVE: Atypical femoral fractures (AFFs) are important to diagnose early to avoid progression to complete fracture. We set out to determine the reporting accuracy of AFFs. METHODS: We conducted a retrospective analysis of imaging performed between November 2010 and June 2013 to analyse the X-ray reporting of AFFs and to describe the key clinical considerations. Radiological reports were reviewed from the 3805 separate femoral images for search terms thought likely to identify AFFs. This identified 1558 patients. The identified radiographs were reviewed by radiologists with reference to the 2010 American Society of Bone and Mineral Research (ASBMR) criteria. RESULTS: Within these 1558 patients, 16 patients met the radiological criteria for AFF according to the 2010 ASBMR task force statement of which, although all were identified as fractures, 15 were not reported as "atypical" by the original reporting author and none was formally classified as AFF by the original reporting author. Within the 1558 patients, there were an additional 17 patients labelled as having "atypical" fracture features originally, although only 1 patient met the 2010 ASBMR task force criteria for AFF. Only 13 of 16 patients had imaging of the contralateral femur, and there was a significant delay for those who were imaged (111 +/- 44 days). Furthermore, two of the patients with an AFF had previous radiographs demonstrating cortical changes indicative of AFFs prior to formal diagnosis. CONCLUSION: Whilst AFFs are rare diagnoses, the compliance with published guidelines for their radiological classification is low. ADVANCES IN KNOWLEDGE: We have raised awareness of the importance of recognizing AFFs to guide management. PMID- 26508356 TI - Emotional language is all right: Emotional prosody reduces hemispheric asymmetry for linguistic processing. AB - In an influential paper, Bryden and MacRae [(1989). Dichotic laterality effects obtained with emotional words. Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 1, 171-176] introduced a dichotic listening task that allowed for the assessment of linguistic and prosodic processing asymmetries using the same stimuli. The task produces a robust right ear advantage (REA) for linguistic processing (identifying a target word), and a left ear advantage for emotional processing (identifying a target prosody). Here, we adapted this paradigm to determine whether and how the presence of emotional prosody might modulate hemispheric asymmetry for linguistic processing. Participants monitored for a target word among dichotic stimuli consisting of two different words, but spoken in the same emotional prosody-neutral, angry, happy, sad, or fearful. A strong REA was observed when the words were spoken in neutral prosody, which was attenuated for all the emotional prosodies. There were no differences in the ear advantage as a function of valence or discrete emotion, indicating that all emotions had similar effects. Findings are consistent with the hypothesis that the right hemisphere is better able to process speech when it carries emotional prosody. Implications for understanding of right hemisphere language functions are discussed. PMID- 26508357 TI - Evaluation of AutoCAL for electronic portal imaging device-based multi-leaf collimator quality assurance. AB - Modern radiotherapy treatment techniques commonly include multi-leaf collimators (MLCs) to shape the treatment fields and to conform the radiation dose to the target volume. MLCs require accurate and frequent quality assurance (QA) to ensure spatial and temporal accuracy of the leaves in order to allow optimal dose delivery to the patient. In this study, the accuracy and efficacy of AutoCAL, a commercial software for MLC QA, were evaluated. The software was found to be reproducible to within 0.2 mm and to correspond with conventional QA methods (within 1.2 and 0.9 mm of film and water tank measurements, respectively.) Thus, AutoCAL was found to be an accurate and efficient tool for routine MLC QA and calibration. PMID- 26508358 TI - Use of diluted urine for cultivation of Chlorella vulgaris. AB - Our aim was to study the biomass growth of microalga Chlorella vulgaris using diluted human urine as a sole nutrient source. Batch cultivations (21 days) were conducted in five different urine dilutions (1:25-1:300), in 1:100-diluted urine as such and with added trace elements, and as a reference, in artificial growth medium. The highest biomass density was obtained in 1:100-diluted urine with and without additional trace elements (0.73 and 0.60 g L(-1), respectively). Similar biomass growth trends and densities were obtained with 1:25- and 1:300-diluted urine (0.52 vs. 0.48 gVSS L(-1)) indicating that urine at dilution 1:25 can be used to cultivate microalgal based biomass. Interestingly, even 1:300-diluted urine contained sufficiently nutrients and trace elements to support biomass growth. Biomass production was similar despite pH-variation from < 5 to 9 in different incubations indicating robustness of the biomass growth. Ammonium formation did not inhibit overall biomass growth. At the beginning of cultivation, the majority of the biomass consisted of living algal cells, while towards the end, their share decreased and the estimated share of bacteria and cell debris increased. PMID- 26508359 TI - Balloon valvuloplasty treatment of an infolded CoreValve. AB - Transcatheter aortic valve replacement is an approved treatment for select patients with severe aortic stenosis. A rare complication of self-expanding transcatheter heart valves (THVs) is infolding of the valve stent frame, which results in a malopposed segment, perivalvular aortic insufficiency, and possibly leaflet dysfunction. We report here a successful case of balloon valvuloplasty treatment for severe infolding of a self-expandable THV in the aortic position, restoring stent frame geometry and leaflet function. (c) 2015 Wiley Periodicals, Inc. PMID- 26508360 TI - Ambient levels of volatile organic compounds and criteria pollutants in the most industrialized area of central Iberian Peninsula: intercomparison with an urban site. AB - This work presents observations of volatile organic compounds (VOCs), including carbonyls, particulate matter 2.5 (PM2.5) (included in the most recent ambient air quality standards because of its harmful effect on health), PM10 and other important pollutants, CO, SO2, NOx and ozone, over the most industrialized area in the central Iberian Peninsula. Nearly two years of data obtained through a mobile laboratory are used for this purpose. Different concentration ratios and correlations were calculated to assess the effect of the anthropogenic or biogenic processes on the observed VOC levels. The diurnal profile for SO2 is different in Puertollano and it does not coincide with the maxima of the other primary pollutants such as benzene, toluene and xylenes (BTX), CO and NO. This behaviour could be attributed to the fact that SO2 mainly comes from industrial activities. However, an impact of the industry on air quality was detected not only by the results obtained for SO2, but also by the toluene/benzene, T/B, ratio (7.5). Finally, correlations between meteorological conditions and pollution distribution have been considered; also, the analysis of the back trajectories together with Spearman correlation coefficients have been carried out to understand the origin and pathway in some events with unusual high pollutant values. PMID- 26508361 TI - Management of Foley catheter induction among nulliparous women: a retrospective study. AB - BACKGROUND: Induction of labour is associated with increased risk for caesarean delivery among nulliparous women. The aims of this study were to evaluate the risk factors for caesarean delivery and to investigate the risk of maternal and neonatal infections in nulliparous women undergoing induction of labour by Foley catheter. METHODS: This clinical retrospective study of 432 nulliparous women with singleton pregnancy and intact amniotic membranes at or beyond 37 gestational weeks scheduled for induction of labour by Foley catheter was conducted over the course of one year, between January 2012 and January 2013, in Helsinki University Hospital. The main outcome measures were caesarean section rate and maternal and neonatal infections. Univariate and multivariate logistic regressions were used to estimate relative risks by odds ratios with 95% confidence intervals. RESULTS: The caesarean section rate was 39.1% (n = 169). In multivariate regression analysis, the factors associated with caesarean section were the need for oxytocin for labour induction [OR 2.9 (95% CI 1.8-4.5) p < 0.001] and early epidural analgesia [OR 9.9 (95% CI 2.1-47.5), p = 0.004]. The maternal intrapartum infection rate was 6.3%, and the clinical neonatal infection rate was 2.8%. In multivariate analysis, gestational diabetes was associated with maternal intrapartum infection [OR 4.3 (95% CI 1.7-11.0, p = 0.002] and early epidural analgesia with neonatal clinical sepsis [OR 10.5 (95% CI 1.4-76), p = 0.02]. CONCLUSIONS: Oxytocin induction and early epidural analgesia were associated with caesarean delivery. Gestational diabetes and early epidural analgesia were associated with infectious morbidity. Since the first caesarean delivery has a major impact on subsequent pregnancies, optimising labour induction among nulliparous women is important. PMID- 26508363 TI - Schistosomiasis therapeutics: whats in the pipeline? AB - Schistosomiasis is a debilitating neglected tropical disease caused by schistosome worms. Global efforts to control schistosomiasis rely predominantly on mass drug administration of the drug praziquantel to populations at risk of infection. We review the history of schistosome drug development and the current position of schistosome drug research. We conclude that with no additional candidates currently in the anti-schistosome drug clinical trial pipeline, a practical and necessary approach is to optimise the health benefits from praziquantel. We offer suggestions of where and how this can be achieved. We also highlight knowledge gaps in the utility of praziquantel particularly in the treatment of chronic schistosomiasis, which includes fibrosis, organomegaly and cervical lesions associated with female genital schistosomiasis. PMID- 26508362 TI - Alteration of intracellular protein expressions as a key mechanism of the deterioration of bacterial denitrification caused by copper oxide nanoparticles. AB - The increasing production and utilization of copper oxide nanoparticles (CuO NPs) result in the releases into the environment. However, the influence of CuO NPs on bacterial denitrification, one of the most important pathways to transform nitrate to dinitrogen in environment, has seldom been studied. Here we reported that CuO NPs caused a significant alteration of key protein expressions of a model denitrifier, Paracoccus denitrificans, leading to severe inhibition to denitrification. Total nitrogen removal efficiency was decreased from 98.3% to 62.1% with the increase of CuO NPs from 0.05 to 0.25 mg/L. Cellular morphology and integrity studies indicated that nanoparticles entered the cells. The proteomic bioinformatics analysis showed that CuO NPs caused regulation of proteins involved in nitrogen metabolism, electron transfer and substance transport. The down-regulation of GtsB protein (responsible for glucose transport) decreased the production of NADH (electron donor for denitrification). Also, the expressions of key electron-transfer proteins (including NADH dehydrogenase and cytochrome) were suppressed by CuO NPs, which adversely affected electrons transfer for denitrification. Further investigation revealed that CuO NPs significantly inhibited the expressions and catalytic activities of nitrate reductase and nitrite reductase. These results provided a fundamental understanding of the negative influences of CuO NPs on bacterial denitrification. PMID- 26508364 TI - Predictors of Complete Pathologic Response (pT0) to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Carcinoma. AB - No predictors of a complete pathologic response (pT0) to neoadjuvant chemotherapy (NAC) in muscle-invasive bladder carcinoma have been established. We performed a retrospective analysis of 50 patients to identify potential predictors. Our results showed that the presence of additional transitional cell variants on pathologic examination (mixed tumors) predicted against pT0, suggesting the avoidance of NAC and its morbidity in these patients with mixed tumors. BACKGROUND: Randomized trials have supported the use of cisplatin-based neoadjuvant chemotherapy (NAC) in muscle-invasive bladder carcinoma (MIBC) owing to the survival advantage, which has correlated with downstaging of the cancer to pT0. Only 30% to 40% of patients receiving NAC have attained a pT0 response at cystectomy; the remaining have either residual disease or progression. We aimed to identify the factors that could predict a pT0 response to NAC. PATIENTS AND METHODS: Of 336 patients who had undergone robotic cystectomy at our institute from May 2007 to March 2014, we identified 50 patients who had undergone NAC for MIBC. We conducted a retrospective study, dividing these 50 patients into 2 groups, those with and without a pT0. Factors, including age, histologic features, hydronephrosis at initial presentation, and chemotherapy type, were examined by both univariate and multivariate logistic regression analysis. RESULTS: Of the 50 patients, 14 (28%) had pT0 at cystectomy, 20 (40%) had progressive disease, and 16 (32%) had residual disease. The median age was 67.5 years, the median glomerular filtration rate at presentation was 87.5 mL/min, the patients had undergone a median of 3 NAC cycles, and the median time from the end of chemotherapy to surgery was 4 weeks. The odds of a pT0 response for pure urothelial carcinoma (UC) were approximately 11 times greater relative to cancers with transitional cell variant histologic features or mixed tumors (odds ratio 0.09, 95% confidence interval 0.021-0.380; P = .0011), including squamous, glandular differentiation, small cell, micropapillary, sarcomatoid, nested component, lymphoepithelioma-like, and plasmacytoid variants. CONCLUSION: The presence of pure UC favored a pT0 response to NAC compared with those with variant histologic features or mixed tumors. These potential predictors warrant prospective validation to allow the ideal selection of patients for NAC. PMID- 26508365 TI - Dramatic PSA Increase With Tumor Shrinkage After Initiating Degarelix in Advanced Prostate Cancer. PMID- 26508367 TI - A proposal for alternate naming of the common and proper hepatic arteries: the "hepatogastroduodenal artery" and the "hepatic artery". PMID- 26508368 TI - Capillary zone electrophoresis for bottom-up analysis of complex proteomes. AB - Capillary zone electrophoresis (CZE) is emerging as a useful tool in proteomic analysis. Interest arises from dramatic improvements in performance that result from improvements in the background electrolyte used for the separation, the incorporation of advanced sample injection methods, the development of robust and sensitive electrospray interfaces, and the coupling with Orbitrap mass spectrometers with high resolution and sensitivity. The combination of these technologies produces performance that is rapidly approaching the performance of UPLC-based methods for microgram samples and exceeds the performance of UPLC based methods for mid- to low nanogram samples. These systems now produce over 10 000 peptide IDs in a single 100-min analysis of the HeLa proteome. PMID- 26508369 TI - Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes. AB - Monocytes promote the early host response to infection releasing key pro inflammatory cytokines, such as IL-1beta. The biologically inactive IL-1beta precursor is processed to active form by inflammasomes, multi-protein complexes activating caspase-1. Human monocytes exhibit an unconventional one-step pathway of inflammasome activation in response to lipopolysaccharide (LPS) alone. Although this lineage-restricted mechanism is likely to contribute to the pathology of endotoxin shock, signalling pathways regulating this mechanism are currently unknown. Here we report that caspase-4 and caspase-5 mediate IL-1alpha and IL-1beta release from human monocytes after LPS stimulation. Although caspase 4 remains uncleaved, caspase-5 undergoes rapid processing upon LPS treatment. We also identify an additional caspase-5 cleavage product in LPS-stimulated monocytes, which correlates with IL-1 secretion. This one-step pathway requires Syk activity and Ca(2+) flux instigated by CD14/TLR4-mediated LPS internalization. Identification of caspase-4/5 as the key determinants of one step inflammasome activation in human monocytes provides potential targets for therapeutic intervention in endotoxin shock. PMID- 26508370 TI - Effect of Obesity and Leptin Level on Migraineurs. AB - BACKGROUND: The aim of this study was to analyze the effects of obesity and leptin levels on patients with migraine, and to observe the change of leptin levels in migraineurs. MATERIAL AND METHODS: We enrolled 52 migraine patients from the Headache Clinic in Shandong Provincial Hospital into a randomized controlled trial with another 52 age-, sex-, and BMI-matched healthy subjects as controls. Leptin levels in all subjects were determined by radioimmunoassay. RESULTS: Compared with the control group, the migraineurs revealed no significant change in leptin levels (P>0.05). Multivariate Logistic regression analysis showed that neither abdominal obesity nor leptin had significant impact on migraine clinical features. Total body obesity had a significant effect on the frequency (OR=4.248), duration (OR=3.167), and intensity (OR=5.225) of the headache. CONCLUSIONS: Total body obesity affected headache frequency, intensity, and duration, while leptin levels did not. PMID- 26508371 TI - Conductive polymer-mediated 2D and 3D arrays of Mn3O4 nanoblocks and mesoporous conductive polymers as their replicas. AB - Orientation-controlled 2D and 3D microarrays of Mn3O4 nanocuboids that were mediated by a conductive polymer were fabricated by evaporation-induced self assembly of the oxide nanoblocks and subsequent polymerization of pyrrole in the interparticle spaces. Free-standing mesoporous polypyrroles (PPy) having chain- and square-grid-like nanovoid arrays were obtained as replicas of the composite assemblies by dissolving the oxide nanoblocks. The PPy-mediated manganese oxide arrays exhibited stable electrochemical performance as an ultrathin anode of a lithium-ion secondary battery. PMID- 26508372 TI - Primary invasive extramammary Paget disease on penoscrotum: a clinicopathological analysis of 41 cases. AB - To investigate the clinicopathological and immunohistochemical features and prognostic factors for invasive extramammary Paget disease (EMPD) on penoscrotum, we described the clinical presentations, histopathology, and follow-up courses of 41 cases. The age of the patients ranged from 42 to 84 years. All the patients were treated with wide surgical excision, and 14 were confirmed to have lymph node metastasis. During follow-up, 18 patients (43.9%) developed local or distant recurrence, and 13 patients (31.7%) died of the disease. Histologically, glandular formation with true lumina within the epidermis was found in 29 cases, and signet ring cells were seen in 11 cases. In invasive components, nodular/micronodular growth pattern, glandular formation, and strands/solid sheets existed in 95.1% (39/41), 43.9% (18/41), and 24.4% (10/41) of the cases, respectively. More than half of the cases had at least 2 different types of invasive growth pattern. CK7 was diffusely positive in all cases, whereas CK20 was focally positive in 8 cases. GCDFP-15 was expressed to a variable degree in 24 cases. Presence of strands/solid sheets, lymphovascular invasion, and perineural invasion in invasive EMPD were found to be correlated with higher lymph node metastatic rate. Univariate analysis revealed that patients with one of the following prognostic factors: delay in diagnosis more than 7.5 years, depth of invasion more than 1 mm, invasive pattern of strands/solid sheets, marked inflammation, lymphovascular invasion, and lymph node metastasis at diagnosis, had significantly shorter cancer-specific survival. We concluded that invasive EMPD is a rare malignant skin neoplasm with morphological diversity. Invasive pattern of strands/solid sheets is significantly associated with both lymph node metastasis and worse prognosis. Delay in diagnosis, depth of invasion, marked inflammation, lymphovascular invasion, and regional lymph node status are important prognostic factors. PMID- 26508373 TI - Opposing prognostic roles of nuclear and cytoplasmic RACGAP1 expression in colorectal cancer patients. AB - Rac GTPase activating protein 1 (RACGAP1) plays a regulatory role in initiation of cytokinesis, control of cell growth and differentiation, and tumor malignancy, making it a potential prognostic biomarker. RACGAP1 is present in the nucleus, but a diffuse distribution in the cytoplasm also occurs. The aim of this study was to determine the impact of nuclear and cytoplasmic expression of RACGAP1 on clinical outcome to provide further evidence of a role in colorectal cancer. RACGAP1 expression was analyzed by immunohistochemistry in 166 cancer specimens from primary colorectal cancer patients. The mean follow-up time after surgery was 5.4 years (range, 0.01-13.10 years). The prognostic value of RACGAP1 on overall survival was validated by Kaplan-Meier analysis and Cox regression models. RACGAP1 is expressed in colorectal specimen and is present in both the nucleus and cytoplasm in different amounts. Colorectal cancer patients had opposite prognoses depending on the site of RACGAP1 expression. Patients with high nuclear RACGAP1 expression had poor outcomes, whereas those with high cytoplasmic RACGAP1 expression had favorable prognosis (P = .003 and P = .001, respectively). Patients with low nuclear but high cytoplasmic RACGAP1 expression had better survival compared with those with other combinations (P < .001). We suggest that RACGAP1 expression levels in the nucleus and cytoplasm, determined by immunohistochemical staining, predict opposite clinical outcomes and that both could be independent prognostic markers for colorectal cancer. PMID- 26508374 TI - Hypoglycaemia after gastric bypass: mechanisms and treatment. AB - Hypoglycaemia after gastric bypass can be severe, but is uncommon, and is sometimes only revealed through monitoring glucose concentrations. The published literature is limited by the heterogeneity of the criteria used for diagnosis, arguing in favour of the Whipple triad with a glycaemia threshold of 55 mg/dl as the diagnostic reference. Women who lost most of their excess weight after gastric bypass, long after the surgery was performed, and who did not have diabetes before surgery are at the greatest risk. In this context, hypoglycaemia results from hyperinsulinism, which is either generated by pancreas anomalies (nesidioblastosis) and/or caused by an overstimulation of beta cells by incretins, mainly glucagon-like peptide-1 (GLP-1). Glucose absorption is both accelerated and increased because of the direct communication between the gastric pouch and the jejunum. This is a post-surgical exaggeration of a natural adaptation that is seen in patients who have not undergone surgery in whom glucose is infused directly into the jejunum. There is not always a correspondence between symptoms and biological traits; however, hyperinsulinism is constant if hypoglycaemia is severe and there are neuroglucopenic symptoms. The treatment relies firstly on changes in eating habits, splitting food intake into five to six daily meals, slowing gastric emptying, reducing the glycaemic load and glycaemic index of foods, using fructose and avoiding stress at meals. Pharmacological treatment with acarbose is efficient, but other drugs still need to be validated in a greater number of subjects (insulin, glucagon, calcium channel blockers, somatostatin analogues and GLP-1 analogues). Lastly, if the surgical option has to be used, the benefits (efficient symptom relief) and the risks (weight regain, diabetes) should be weighed carefully. PMID- 26508375 TI - Topological computation based on direct magnetic logic communication. AB - Non-uniform magnetic domains with non-trivial topology, such as vortices and skyrmions, are proposed as superior state variables for nonvolatile information storage. So far, the possibility of logic operations using topological objects has not been considered. Here, we demonstrate numerically that the topology of the system plays a significant role for its dynamics, using the example of vortex antivortex pairs in a planar ferromagnetic film. Utilising the dynamical properties and geometrical confinement, direct logic communication between the topological memory carriers is realised. This way, no additional magnetic-to electrical conversion is required. More importantly, the information carriers can spontaneously travel up to ~300 nm, for which no spin-polarised current is required. The derived logic scheme enables topological spintronics, which can be integrated into large-scale memory and logic networks capable of complex computations. PMID- 26508376 TI - The effects of hypoxia-inducible factor (HIF)-1alpha protein on bone regeneration during distraction osteogenesis: an animal study. AB - The aim of this study was to observe the effect of hypoxia-inducible factor (HIF) 1alpha on bone regeneration during distraction osteogenesis (DO). Fifty-one New Zealand white rabbits underwent mandibular lengthening with a distraction rate of 2mm/day, and were divided randomly into three groups (17 in each). Group C rabbits received 20 MUg rHIF-1alpha, group B received 10 MUg rHIF-1alpha, and group A received 100 MUl saline injection in the distraction gap every day for 10 days. Radionuclide bone imaging (RBI), computed tomography, dual energy X-ray absorptiometry, radiography, histology, and three-point bend testing were performed. RBI showed that the uptake ratio in group B (1.41 +/- 0.25, P=0.013) and group C (1.64 +/- 0.37, P<0.001) was higher than that in group A (1.01 +/- 0.26). The bone mineralization density and bone mineralization content in group C were highest among the three groups. Radiology and histology findings indicated more callus regeneration in groups C and B. Mechanical testing demonstrated that the ultimate force in group C (289.71 +/- 43.31N, n=6) was 1.49-fold (P<0.001) that of group A and 1.20-fold (P=0.012) that of group B. HIF-1alpha may represent a new agent to promote DO by accelerating osteogenesis and mineralization. PMID- 26508377 TI - Multi-drug intoxication fatality involving atorvastatin: A case report. AB - Mixed antihypertensive drug intoxication poses a significant risk for patient mortality. In tandem to antihypertensives, hypolipidemic medicines (especially statins) are often prescribed. Among their well-known adverse effects belongs rhabdomyolysis. We report a case of fatal multi-drug overdose in a 65-year-old female alcoholic. The patient was unconscious at admission. Empty blister packs indicated the abuse of 250 tablets of urapidil, 42 tablets of verapamil/trandolapril, 50 tablets of moxonidin, 80 tablets of atorvastatin and 80 tablets of diacerein. Standard measures (gastric lavage, activated charcoal, mechanical ventilation, massive doses of vasopressors, volume expansion, diuretics and alkalinization) failed to provide sufficient drug elimination and hemodynamic support and the sufferer deceased on the fourth day. Dramatic elevations of serum myoglobin (34,020 MUg/L) and creatine kinase (219 MUkat/L) were accompanied by rise in cardiac troponin I and creatinine. Gas chromatography revealed ethanol 1.17 g/kg (blood) and 2.81 g/kg (urine). Thin layer chromatography and gas chromatography of gastric content and urine verified verapamil, moxonidin and urapidil fragment (diacerein method was unavailable). Atorvastatin and trandolapril concentrations (LC-MS(n)) equaled 277.7 MUg/L and 57.5 MUg/L, resp. (serum) and 8.15 MUg/L and 602.3 MUg/L, resp. (urine). Histology confirmed precipitates of myoglobin with acute necrosis of proximal renal tubules in association with striated muscle rhabdomyolysis and myocardial dystrophy. Cardiogenic-distributive shock in conjunction with acute renal failure due to the combined self-poisoning with vasoactive agents and atorvastatin were determined to be this decedent's immediate cause of death. The manner of death was assigned to be suicidal. PMID- 26508378 TI - Fluoroscopy-assisted epidural catheter placement: an exploratory analysis of 303 pre-operative epidurograms. AB - BACKGROUND: Epidural catheters that are placed for post-operative analgesia have a significant failure rate in the first 24 hours. Beginning in 2011, we have used fluoroscopic guidance to place all non-obstetrical epidural catheters. In this retrospective analysis, we hypothesized that the characteristics of dye distribution on an epidurogram obtained immediately after catheter placement would predict clinical catheter function after surgery. METHODS: The epidurograms and medical records of 303 consecutive patients who had epidural catheters placed for post-operative analgesia were reviewed. We extracted data on epidural dye distribution on the epidurograms and compared these results to the clinical function of the epidural catheters assessed on post-operative day 1 (POD1). RESULTS: The three-dimensional pattern of epidural dye distribution (cephalad caudad, right-left, anterior-posterior) had significant correlations with clinical function of an epidural catheter after surgery. Increased cephalad caudad and anterior dye spread both correlated with decreased epidural solution infusion rates on POD1, whereas right- or left-sided dye distribution correlated with unilateral sensory deficits. A higher catheter placement on the neuraxis correlated with lower pain scores after thoracic surgery. CONCLUSIONS: An epidurogram obtained immediately after epidural catheter placement may have clinical utility for predicting clinical function of the catheter after surgery. PMID- 26508379 TI - A Novel Health Information Technology Communication System to Increase Caregiver Activation in the Context of Hospital-Based Pediatric Hematopoietic Cell Transplantation: A Pilot Study. AB - BACKGROUND: Pediatric hematopoietic cell transplantation (HCT), commonly referred to as blood and marrow transplantation (BMT), is an intense treatment modality that requires the involvement of engaged caregivers during the patient's (child's) prolonged hospitalization. The ubiquity of electronic health records (EHRs) and a trend toward patient-centered care could allow a novel health information technology (IT) system to increase parental engagement. The paucity of research on acute care, hospital-based (inpatient) health IT applications for patients or caregivers provides an opportunity for testing the feasibility of such applications. The pediatric BMT population represents an ideal patient group to conduct an evaluation due to the lengthy inpatient stays and a heightened need for patient activation. OBJECTIVE: The primary objective of this study is to assess the feasibility of implementing the BMT Roadmap in caregivers as an intervention during their child's inpatient hospitalization. The BMT Roadmap is an inpatient portal prototype optimized for tablet with a user-centered design. It integrates patient-specific laboratory and medication data from the EHR in real-time and provides support in terms of discharge goals, home care education, and other components. Feasibility will be proven if (1) the BMT Roadmap functions and can be managed by the study team without unexpected effort, (2) the system is accessed by users at a defined minimum threshold, and (3) the qualitative and quantitative research conducted provides quality data that address the perceived usefulness of the BMT Roadmap and could inform a study in a larger sample size. METHODS: This will be a single-arm, nonrandomized feasibility study. We aim to enroll 10 adult caregivers (age >= 18 years) of pediatric patients (aged 0-25 years) undergoing autologous (self-donor) or allogeneic (alternative donor) BMT. Assenting minors (aged 10-18) will also be invited to participate. Recruitment of study participants will take place in the outpatient pediatric BMT clinic. After signing an informed consent, the research study team will provide participants with the BMT Roadmap, available on an Apple iPad, which will used throughout the inpatient hospitalization. To measure the study outcomes, approximately 6-8 semistructured qualitative interviews will be conducted periodically from pre-BMT to 100 days post-BMT and an additional 15-20 semistructured interviews will be conducted among BMT health care providers to assess perceived usefulness and usability of the system, as well as any associated workflow impacts. Quantitative survey instruments will only be administered to adult participants (age >= 18 years). RESULTS: Recruitment will begin in September 2015, and preliminary findings are expected in 2016. CONCLUSIONS: This protocol offers a framework for the design and analysis of a personalized health IT system that has the potential to increase patient and caregiver engagement in acute care, hospital-based contexts. PMID- 26508385 TI - Analyzing large-scale samples confirms the association between the rs1051730 polymorphism and lung cancer susceptibility. AB - The early genome-wide association studies (GWAS) found a significant association between lung cancer and rs1051730 (15q25) polymorphism. However, the subsequent studies reported consistent and inconsistent results in different populations. Three meta-analysis studies were thus performed to reevaluate the association. But their results remain inconsistent. After that, some new GWAS studies reported conflicting results again. We think that the divergence of these results may be due to small-scale samples or heterogeneity among different populations. Therefore, we reevaluated the association by collecting more samples (N = 33,617 cases and 116,639 controls) from 31 studies, which incorporate 8 new studies and 23 previous studies used by one or more of the three meta-analysis studies. We observed a significant association between lung cancer and rs1051730 in pooled population by using allele (OR = 1.30, 95% CI = 1.27-1.34, P < 0.0001), dominant (OR = 1.41, 95% CI = 1.29-1.55, P < 0.0001), recessive (OR = 1.53, 95% CI = 1.42 1.65, P < 0.0001) and additive (OR = 1.75, 95% CI = 1.61-1.90, P < 0.0001) models. Through the subgroup analysis, we observed a significant heterogeneity only in East Asian population (P = 0.006, I(2) = 66.9%), and the association is significant in all subgroups (OR = 1.2976, 95% CI = 1.2622-1.3339 (European ancestry), OR = 1.5025, 95% CI = 1.2465-1.8110 (African), OR = 1.7818, 95% CI = 1.3915-2.2815 (East Asian), P < 0.0001). We believe that these results will contribute to understanding the genetic mechanism of lung cancer. PMID- 26508386 TI - Regression of Paravalvular Aortic Regurgitation and Remodeling of Self-Expanding Transcatheter Aortic Valve: An Observation From the CoreValve U.S. Pivotal Trial. AB - OBJECTIVES: The aim of this study was to describe the natural history and clinical importance of paravalvular aortic regurgitation (PVAR) after CoreValve transcatheter aortic valve replacement (TAVR) and to relate these findings to the structural and hemodynamic changes documented by serial echocardiographic analysis. BACKGROUND: PVAR after TAVR with the self-expanding CoreValve bioprosthesis has been shown to regress over time, but the time course and the mechanism of PVAR regression has not been completely characterized. METHODS: Patients with severe aortic stenosis who underwent CoreValve TAVR and followed up to 1 year in the multicenter CoreValve U.S. Pivotal Trial (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement) were studied. Serial echocardiography studies were analyzed by an echocardiographic core laboratory. Annular sizing ratio was calculated from computed tomography measurements. Paired, as well as total, data were compared. RESULTS: The CoreValve was implanted in 634 patients with a mean age of 82.7 +/- 8.4 years. After a marked improvement noted at discharge, aortic valve velocity, mean gradient, and effective orifice area further improved significantly at 1 month (2.08 +/- 0.45 m/s vs. 1.99 +/- 0.46 m/s, p < 0.0001, 9.7 +/- 4.4 mm Hg vs. 8.9 +/- 4.6 mm Hg, p < 0.0001, and 1.78 +/- 0.51 cm(2) vs. 1.85 +/- 0.58 cm(2), p = 0.03, respectively). The improvement was sustained through 1 year. PVAR was moderate or severe in 9.9%, and of 36 patients with moderate PVAR at discharge and paired data, 30 (83%) improved at least 1 grade of regurgitation at 1 year. Annular sizing ratio was significantly associated with the degree of PVAR. CONCLUSIONS: There was further improvement in aortic prosthetic valve hemodynamics and regression of PVAR up to 1 year compared with discharge after TAVR with CoreValve. These changes are possibly due to remodeling and outward expansion of the self-expandable CoreValve with nitinol frame. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement [Medtronic CoreValve U.S. Pivotal Trial]; NCT01240902). PMID- 26508387 TI - Accuracy of Echocardiography to Evaluate Pulmonary Vascular and RV Function During Exercise. AB - OBJECTIVES: The authors have compared exercise echocardiography and exercise cardiac magnetic resonance imaging with simultaneous invasive pressure registration (ExCMRip) for the assessment of pulmonary vascular and right ventricular (RV) function. BACKGROUND: Exercise echocardiography may enable early diagnosis of pulmonary vascular disease, but its accuracy is untested. METHODS: Exercise imaging was performed in 61 subjects (19 athletes, 9 healthy nonathletes, 8 healthy BMPR2 [bone morphogenetic protein receptor type II] mutation carriers, 5 patients with new or worsening dyspnea after acute pulmonary embolism, and 20 patients with chronic thromboembolic pulmonary hypertension). Echocardiographic variables included mean pulmonary artery pressure (mPAP) and systolic pulmonary artery pressure (sPAP), cardiac output (CO), RV fractional area change, tricuspid annular systolic excursion, and RV end-systolic pressure area ratio as a surrogate measure of RV contractile reserve. ExCMRip provided measurements of CO, RV ejection fraction, mPAP, sPAP, and RV end-systolic pressure-volume ratio at rest and during exercise. Abnormal pulmonary vascular reserve was defined as mPAP/CO slope >3 mm Hg/l/min by ExCMRip. RESULTS: Echocardiographic determination of mPAP/CO was possible in 53 of 61 subjects (87%). mPAP/CO by echocardiography was higher than that obtained by ExCMRip (+0.9 mm Hg/l/min; 95% limits of agreement, -3.6 to 5.4), but enabled accurate identification of patients with abnormal pulmonary vascular reserve (area under the receiver-operating characteristic curve, 0.88 [95% confidence interval (CI): 0.77 to 1.00; p < 0.0001]). Simplified relationships between sPAP and exercise intensity had similar accuracy in identifying subjects with pulmonary vascular disease (area under the receiver-operating characteristic curve, 0.95 [95% CI: 0.88 to 1.01]; p < 0.0001). RV fractional area change by echocardiography correlated strongly with RV ejection fraction by ExCMRip, whereas a moderate correlation was found between tricuspid annular systolic excursion and RV ejection fraction. A moderate correlation was found between ratios of peak exercise to resting RV end-systolic pressure-area ratio and RV end-systolic pressure-volume ratio (r = 0.64; p < 0.0001). CONCLUSIONS: Echocardiographic estimates of RV and pulmonary vascular function are feasible during exercise and identify pathology with reasonable accuracy. They represent valid screening tools for the identification of pulmonary vascular disease in routine clinical practice. PMID- 26508388 TI - Calcified Constrictive Pericarditis: Prevalence, Distribution Patterns, and Relationship to the Myocardium. PMID- 26508389 TI - Postnatal and neonatal care after home birth: A community-based study in Nepal. AB - BACKGROUND: In Nepal, the majority of women who give birth at home do not visit a health facility for postnatal and neonatal care. OBJECTIVES: This study investigated postnatal and neonatal care practices of women who give birth at home in a central hills district of Nepal. DESIGN: This study is a part of community-based prospective study in the Kaski district of Nepal. Postnatal and neonatal care practices were collected via structured questionnaires. SETTING: Kaski district of Nepal. PARTICIPANTS: 92 postpartum women who gave birth at home. OUTCOME MEASURES: Postnatal care at a health facility and neonatal care practices. FINDINGS: Approximately 90% (83/92) of women who gave birth at home were assisted by non-skilled birth attendants, and 67% (62/92) received no postnatal care at a health facility within a week post delivery. The main reason for not having postnatal care at a health facility was 'no perceived need' (52/62, 83.9%). With regard to neonatal care practices, 67% (62/92) used a delivery kit, 79% (73/92) washed their hands before handling their babies, 70% (64/92) bathed their babies on the second day of birth, while all dried and wrapped their babies with a cloth within half an hour of the birth. However, only 46% (42/92) reported skin-to-skin contact within one hour after birth. CONCLUSIONS: The results suggest that there is great scope to strengthen community-based postnatal and neonatal care to screen for and identify postnatal and neonatal problems, especially at home birth. PMID- 26508390 TI - Prognostic factors of Streptococcus pneumoniae infection in adults. AB - OBJECTIVES: The mortality of severe sepsis has markedly decreased since the implementation of the Surviving Sepsis Campaign guidelines. The next logical step is to examine the necessity of individualized management guidelines for targeted therapy against specific bacteria. Streptococcus pneumoniae is the leading cause of community-acquired severe sepsis; however, little is known regarding the prognostic factors in adult patients with S pneumoniae sepsis. We aimed to identify prognostic factors in patients with S pneumoniae sepsis and to explore a subgroup of patients at high risk for death with detailed Sequential Organ Failure Assessment (SOFA) score analysis. METHODS: We retrospectively reviewed the records of patients with S pneumoniae infection treated between 1st January 2006 and 31st July 2012. We identified prognostic factors for 28-day mortality using univariate and multivariate logistic regression models. RESULTS: Of 171 patients (median age, 72 years) with S pneumoniae infection who were included in this study, the 28-day mortality was 17% (29/171). The SOFA score (odds ratio, 2.25; 95% confidence interval, 1.60-3.18; P < .001) and bacteremia (odds ratio, 19.0; 95% confidence interval, 4.06-90.20; P < .001) were identified as prognostic factors for the 28-day mortality. In a subgroup analysis with a cutoff value of the SOFA score determined by receiver operating characteristic analysis, patients with bacteremia and a SOFA score of at least 7 had a significantly higher mortality than did patients without bacteremia and a SOFA score lower than 7 (84% vs 0%, respectively). CONCLUSIONS: Bacteremia and a SOFA score at least 7 were independent prognostic factors of poor outcome in S pneumoniae sepsis. PMID- 26508391 TI - The meaning of elevated troponin I levels: not always acute coronary syndromes. AB - BACKGROUND: Troponin elevation can be caused by etiologies other than acute coronary syndromes (ACS). Our hypothesis was that elevated troponins occur more frequently in non-ACS cases but that ACS cases (type 1 ST-elevation myocardial infarction [STEMI] and type 1 non-STEMI [NSTEMI]) have significantly higher troponin elevations. METHODS: This was a cross-sectional cohort analysis of a random subset of all patients with elevated troponins (defined as >=0.06 ng/mL) over a 1-year period from July 2013 to June 2014. The first positive troponin I and the peak were used in this study. All included patients had medical record reviews looking for whether our cardiologists or hospitalists attributed the elevated troponin to an ACS (NSTEMI or STEMI) or non-ACS cause. Non-ACS causes were categorized as infection, cancer, renal diseases, cardiovascular disease, pulmonary disease, trauma, cardiac arrest, neurologic disease, hypertension, or other. Data were extracted by 2 investigators on the cause of the elevated troponin. Three sessions to educate data extractors were arranged and methods of data extraction discussed, then a 5% sample was reevaluated by the other extractor to determine interrater agreement measures. Parametric data were evaluated with t test and analysis of variance. Dichotomous variables were compared using chi(2) test. Troponin data were evaluated using nonparametric Kruskal-Wallis or Mann-Whitney U. A logistic regression model was created with variables selected a priori to evaluate the predictive ability of these variables in differentiating ACS vs non-ACS causes of elevated troponin. RESULTS: We evaluated 458 randomly selected patients from 1317 unique cases of all patients with initial elevated troponins at least 0.06 mg/mL during the study period. There was 84% interrater agreement in the 5% sampling. Seventy-nine percent had a non-ACS cause of elevated troponin, and the average initial positive troponin I level was significantly lower in the non-ACS cases (0.14; 95% confidence interval [CI], 0.08-0.37) than those with documented STEMI (10.2; 95% CI, 0.75-20.1) or NSTEMIs (0.4; 95% CI, 0.13-1.7). In the non-ACS group, the median initial troponin was 0.14 ng/mL (0.08-0.37 ng/mL). Peak troponin levels were highest in STEMI, next NSTEMI, and lowest in non ACS causes. The most frequent subgroups in the non-ACS group were non-ACS cardiovascular, infectious, renal, or hypertensive causes. In a linear regression model adjusting for age and sex, higher troponin levels had higher odds of being related to ACS causes (adjusted odds ratio, 1.4; 95% CI, 1.2-1.6) than non-ACS causes. CONCLUSION: The etiology for most initial elevated troponin I levels in a randomly selected population is the result of non ACS causes. As initial + troponin levels increased, they were more likely associated with ACS causes than with non-ACS causes. Average initial + and peak troponin values were highest in STEMIs, next highest in NSTEMIs, and lowest overall in non-ACS causes. PMID- 26508392 TI - Therapeutic effects and prevention of recurrence of acquired idiopathic generalized anhidrosis via i.v. immunoglobulin treatment. PMID- 26508393 TI - Posttraumatic Stress Symptoms and Their Association With Smoking Outcome Expectancies Among Homeless Smokers in Boston. AB - INTRODUCTION: Cigarette smoking and traumatic life experiences are each common among homeless adults, but the prevalence and correlates of posttraumatic stress disorder (PTSD) symptoms among homeless smokers are not known. We assessed symptoms of PTSD and their association with smoking outcome expectancies in a sample of homeless smokers in Boston. METHODS: We used time-location sampling to conduct an in-person survey of homeless adult smokers using Boston Health Care for the Homeless Program clinical services. We assessed symptoms of PTSD with the PTSD Checklist-Civilian version and considered scores at least 14 as positive. We used the Smoking Effects Questionnaire to assess positive and negative smoking outcome expectancies. We modeled the associations between PTSD screening status and smoking expectancies using design-adjusted linear regression. RESULTS: Eighty six percent of eligible individuals participated (N = 306). Sixty-eight percent of participants screened positive for PTSD. Screen-positive respondents were younger (P = .001), more likely to report fair/poor health (P = .01), chronic obstructive pulmonary disease (P = .02), and past-month hallucinations (P = .004), and had greater drug (P < .001) and alcohol (P < .001) use severity and cigarette dependence (P = .002). In analyses controlling for these confounders, PTSD screen-positive participants more strongly endorsed smoking to reduce negative affect (P = .01), smoking for social benefits (P = .002), and smoking for weight control (P = .03). Exploratory analyses suggested that these associations were driven by avoidance/numbing and re-experiencing symptoms. CONCLUSIONS: Symptoms of posttraumatic stress are common among homeless smokers and strongly associated with positive smoking outcome expectancies. Tobacco cessation programs for this population should consider screening for PTSD and fostering a trauma-sensitive treatment environment. IMPLICATIONS: In this study of homeless cigarette smokers in Boston, over two-thirds of participants screened positive for PTSD. PTSD screen-positive respondents more strongly endorsed multiple positive smoking outcome expectancies than screen-negative individuals. These findings suggest that the psychological sequelae of trauma may be a pervasive but under-recognized factor impacting the persistence of smoking among homeless people. Tobacco cessation programs for this population should consider screening for PTSD, fostering a trauma-sensitive treatment environment, and incorporating strategies that have shown promise in smokers with PTSD. PMID- 26508394 TI - Efficacy of a Brief Tobacco Intervention for Tobacco and Nicotine Containing Product Use in the US Air Force. AB - INTRODUCTION: While effective Brief Tobacco Interventions (BTIs) are available for cigarette smoking and smokeless tobacco, given the changing prevalence of tobacco and nicotine containing products (TNCPs), there is a need for interventions targeting a broader range of TNCPs (eg, cigarettes, smokeless tobacco, electronic cigarettes, and hookah). The purpose of the current investigation was to evaluate the efficacy of a BTI, a 40-minute intervention designed to intervene on four TNCPs in a sample of US military personnel during an 11-week period of involuntary tobacco abstinence, for reducing intentions to use TNCPs and increasing perceptions of harm of TNCPs. METHODS: The BTI was administered to 1055 Airmen enrolled in Technical Training in the US Air Force. Assessments of perceived harm and intentions to use nine TNCPs (cigarettes, smokeless tobacco, snus, cigars, cigarillos, pipe, e-cigarettes, roll your own cigarettes, and hookah), were assessed at pretest and posttest (immediately following the BTI). RESULTS: Significant increases in perceived harm were observed across all nine TNCPs (all P < .0001) for both users and nonusers. Intentions to use TNCPs were significantly reduced for most products but mainly among users. CONCLUSIONS: Results suggested that a BTI shows promise for impacting TNCP use in a military population. Further research should evaluate the behavioral outcomes (tobacco use) as a result of the intervention. IMPLICATIONS: Given that there are 220 000 new trainees in the military every year, the public health implications of an effective BTI targeting the most commonly used TNCPs for military trainees is considerable. PMID- 26508395 TI - Contractile Changes in the Vasculature After Subchronic Smoking: A Comparison Between Wild Type and Surfactant Protein D Knock-Out Mice. AB - INTRODUCTION: Cigarette smoking is a well-known risk factor for developing cardiovascular diseases, but the underlying mechanisms are largely unknown. Recent data suggest that vasocontractile receptor modulation could be an important factor. Surfactant protein D (SP-D) is important in the particle clearance in the lungs and knock-out (KO) mice for this protein develop emphysema. SP-D is also weakly expressed in the vasculature. We aimed to investigate whether SP-D was important in the cardiovascular response to cigarette smoke exposure (CSE), by utilizing SP-D KO mice and a myograph setup. METHODS: Wild type (WT) and SP-D KO mice were exposed to cigarette smoke (CS) or room air for 12 weeks. The pulmonary artery, left anterior descending coronary artery, and basilar artery (BA) were isolated and mounted in wire myographs. Contractile concentration response curves to endothelin-1 and UDP were obtained. RESULTS: CSE caused a leftward shift in the concentration response curves for endothelin-1 in the BA for both WT and SP-D KO. UDP, acting on the purinergic P2Y6 receptor, caused reduced contraction in the left descending artery and increased contraction in the BA in the CSE WT mice. SP-D KO mice displayed no smoke induced changes, but were surprisingly similar to the CSE WT. CONCLUSION: The contractility to UDP was altered in the brain and heart vasculature of CSE mice. SP-D KO (both control and CSE) and CSE WT had similar changes in contractility compared to control WT. IMPLICATIONS: These results show that sub chronic smoking induces vascular changes in the WT, mainly for the purinergic P2Y6 receptor together with minor changes for the endothelin-1 receptor. SP-D KO (both control and CSE) does not show any further changes compared to CSE WT. PMID- 26508396 TI - Contribution of Monoamine Oxidase Inhibition to Tobacco Dependence: A Review of the Evidence. AB - BACKGROUND: There is a hypothesis that substances present in, or derived from, tobacco smoke inhibit monoamine oxidase (MAO) in the brains of smokers, reducing the degradation of catecholamine neurotransmitters involved in central reward pathways and acting synergistically with nicotine to increase its addictive effects. OBJECTIVE: The objective of this review was to evaluate the evidence for a role of MAO inhibition by tobacco-derived substances in tobacco dependence. INVESTIGATIONAL PLAN: Relevant studies on the effects of tobacco use on MAO levels or activity in humans were identified by electronic searches. RESULTS: The identified data show a clear association between smoking and lower density of MAO A and MAO-B binding sites in the brains of smokers and strong evidence that MAO is inhibited by a substance or substances in, or derived from, tobacco smoke. There was little evidence to support the hypothesis that low MAO levels/activity is a predictive factor for tobacco use. Substances that inhibit MAO in in vitro assays have been isolated from tobacco leaves and tobacco smoke; however, no single substance has been shown to be absorbed from tobacco smoke and to inhibit MAO in the brains of human smokers. Nevertheless, it is possible that MAO inhibition in smokers could result from additive or synergistic effects of several tobacco-derived substances. MAO inhibition potentiates the reinforcing effects of intravenous nicotine in rodents; however, no data were identified to support the hypothesis that MAO inhibitors in or derived from tobacco or tobacco additives affect tobacco dependence in human smokers. IMPLICATIONS: This comprehensive review describes the available evidence for the role of MAO inhibition in tobacco dependence and points the way for further research in this field. In view of the large number of MAO inhibitors identified in tobacco and tobacco smoke, identification of the putative inhibitors responsible for the lower level/activity of MAO in smokers may be impractical. Future studies must address whether the lower level/activity of MAO observed in smokers is also seen in users of other tobacco products and if this change is implicated in their dependence-inducing effects. PMID- 26508397 TI - Assessment of Residents' Attitudes and Satisfaction Before and After Implementation of a Smoke-Free Policy in Boston Multiunit Housing. AB - INTRODUCTION: In 2012, the Boston Housing Authority (BHA) in Massachusetts implemented a smoke-free policy prohibiting smoking within its residences. We sought to characterize BHA resident experiences before and after the smoke-free policy implementation, and compare them to that of nearby residents of the Cambridge Housing Authority, which had no such policy. METHODS: We recruited a convenience sample of nonsmoking residents from the BHA and Cambridge Housing Authority. We measured residents' awareness and support of their local smoking policies before and 9-12 months after the BHA's policy implementation, as well as BHA respondents' attitudes towards the smoke-free policy. We assessed tobacco smoke exposure via saliva cotinine, airborne apartment nicotine, and self reported number of days smelling smoke in the home. We evaluated predictors of general satisfaction at follow-up using linear regression. RESULTS: At follow-up, 91% of BHA respondents knew that smoking was not allowed in apartments and 82% were supportive of such a policy in their building. BHA residents believed enforcement of the smoke-free policy was low. Fifty-one percent of BHA respondents indicated that other residents "never" or "rarely" followed the new smoke-free rule and 41% of respondents were dissatisfied with policy enforcement. Dissatisfaction with enforcement was the strongest predictor of general housing satisfaction, while objective and self-reported measures of tobacco smoke exposure were not predictive of satisfaction. At follow-up, 24% of BHA participants had complained to someone in charge about policy violations. CONCLUSIONS: Resident support for smoke-free policies is high. However, lack of enforcement of smoke-free policies may cause frustration and resentment among residents, potentially leading to a decrease in housing satisfaction. IMPLICATIONS: Smoke-free housing laws are becoming increasingly prevalent, yet little is known about satisfaction and compliance with such policies post implementation. We evaluated nonsmoking residents' attitudes about smoke-free rules and their satisfaction with enforcement 1 year after the BHA implemented its comprehensive smoke-free policy. We found that while residents were supportive of the policy, they believed enforcement was low, a perception that was associated with a drop in housing satisfaction. Our findings point to a desire for smoke-free housing among public housing residents, and the importance of establishing systems and guidelines to help landlords monitor and enforce these policies effectively. PMID- 26508398 TI - Changes in Cigarette Smoking Behavior Among US Young Workers From 2005 to 2010: The Role of Occupation. AB - INTRODUCTION: Young adult workers (18-24 years) in the United States have been identified as a high-risk group for smoking. This study compares changes in smoking behavior by occupational class among this group between 2005 and 2010. METHODS: Data were pooled from the Tobacco Supplement in the 2005 and 2010 National Health Interview Survey. All respondents 18-24 years who reported that they were employed during the two surveys were selected (n = 1880 in 2005; and n = 1531 in 2010). Weighted percentages and 95% confidence interval were reported. Logistic regression analyses were performed to compare smoking behavior between occupational groups (white-collar, blue-collar, and service) and between years (2005-2010), and to examine correlates of smoking, successful quit attempt, and heavy smoking. RESULTS: Smoking prevalence and daily smoking declined in 2010 in white-collar. Smoking prevalence and intensity decreased while age of smoking initiation increased in blue-collar workers. Young workers were more likely to smoke in 2005 than 2010. Service and blue-collar workers were more likely to smoke than white-collar workers. Older young adults, whites, individuals with a high school/or less education, those without health insurance were more likely to smoke. White workers and individuals with a high school/or less education were more likely to be heavy smokers. CONCLUSIONS: White-collar workers have benefited the most from tobacco control efforts. Although improvements were seen in smoking behavior among blue-collar workers, smoking prevalence remained the highest in this group. Smoking behavior among service workers did not change. Young service workers and blue-collar are priority populations for workplace tobacco control efforts. IMPLICATIONS: The current study examines changes in smoking behavior among young adult workers (18-24 years) by occupational class (white-collar, blue collar, and service workers) between 2005 and 2010. Data were pooled from the Tobacco Supplement in the 2005 and 2010 National Health Interview Survey. Smoking prevalence and daily smoking declined significantly in white-collar workers. No change in smoking behavior was observed among service workers. Positive changes in smoking behavior were observed among blue-collar workers, but smoking prevalence remained the highest in this group. Blue-collar and service workers are priority groups for future workplace tobacco control efforts. PMID- 26508399 TI - A Proposed Collaboration Against Big Tobacco: Common Ground Between the Vaping and Public Health Community in the United States. AB - An unfortunate conflict is underway between the public health community and the vaping community over e-cigarettes' harmfulness or lack thereof. This conflict is made worse by an information vacuum that is being filled by vocal members on both sides of the debate; a perceived lack of credibility of public health officials by those in the vaping community; the tobacco industry's recent involvement in e cigarettes; and the constant evolution of different styles and types of e cigarettes. This conflict is avoidable; common ground exists. If both groups rally around what is in their own and the public's best interest-the end of combustible tobacco--all will benefit significantly. If not, the result may be missed opportunities, misguided alliances, and--ultimately-poorer public health. IMPLICATIONS: This study brings light to the contentious debate between the vaping and public health communities. It addresses how both sides are responsible for bringing misleading information to the public and vocal leaders on both sides are unknowingly intensifying and polarizing the debate-likely at the expense of public health. It also describes how this conflict is avoidable, and provides a starting point for potential positions of common ground against Big Tobacco. PMID- 26508401 TI - Chemical Analysis of a "Miller-Type" Complex Prebiotic Broth: Part I: Chemical Diversity, Oxygen and Nitrogen Based Polymers. AB - In a famous experiment Stanley Miller showed that a large number of organic substances can emerge from sparking a mixture of methane, ammonia and hydrogen in the presence of water (Miller, Science 117:528-529, 1953). Among these substances Miller identified different amino acids, and he concluded that prebiotic events may well have produced many of Life's molecular building blocks. There have been many variants of the original experiment since, including different gas mixtures (Miller, J Am Chem Soc 77:2351-2361, 1955; Oro Nature 197:862-867, 1963; Schlesinger and Miller, J Mol Evol 19:376-382, 1983; Miyakawa et al., Proc Natl Acad Sci 99:14,628-14,631, 2002). Recently some of Miller's remaining original samples were analyzed with modern equipment (Johnson et al. Science 322:404-404, 2008; Parker et al. Proc Natl Acad Sci 108:5526-5531, 2011) and a total of 23 racemic amino acids were identified. To give an overview of the chemical variety of a possible prebiotic broth, here we analyze a "Miller type" experiment using state of the art mass spectrometry and NMR spectroscopy. We identify substances of a wide range of saturation, which can be hydrophilic, hydrophobic or amphiphilic in nature. Often the molecules contain heteroatoms, with amines and amides being prominent classes of molecule. In some samples we detect ethylene glycol based polymers. Their formation in water requires the presence of a catalyst. Contrary to expectations, we cannot identify any preferred reaction product. The capacity to spontaneously produce this extremely high degree of molecular variety in a very simple experiment is a remarkable feature of organic chemistry and possibly prerequisite for Life to emerge. It remains a future task to uncover how dedicated, organized chemical reaction pathways may have arisen from this degree of complexity. PMID- 26508402 TI - Comparative study of quantitative performances between the new Sysmex XN-L (XN 550) haematology analyser and the XN-9000 in a routine laboratory. PMID- 26508403 TI - Conditions for high yield of selective-area epitaxy InAs nanowires on SiO x /Si(111) substrates. AB - Experimental data and a model are presented which define the boundary values of V/III flux ratio and growth temperature for droplet-assisted nucleation of InAs semiconductor nanowires in selective-area epitaxy on SiO(x)/Si (111) substrates by molecular beam epitaxy. Within these boundaries, the substrate receives a balanced flux of group III and V materials allowing the growth of vertically oriented nanowires as compared to the formation of droplets or crystallites. PMID- 26508404 TI - Hearing Outcomes After Stereotactic Radiosurgery for Vestibular Schwannomas : Mechanism of Hearing Loss and How to Preserve Hearing. AB - The use of stereotactic radiosurgery (SRS) expanded to include the treatment of vestibular schwannomas (VSs) in 1969; since then, efforts to increase tumour control and to reduce cranial neuropathy have continued. Using the currently recommended marginal dose of 12-13 Gy, long-term reported outcomes after SRS include not only excellent tumour control rates of 92-100 % but also outstanding functional preservation of the trigeminal and facial nerves, with values of 92 100 % and 94-100 %, respectively. Nonetheless, hearing preservation remains in the range of 32-81 %. Previous studies have suggested possible prognostic factors of hearing preservation such as the Gardner-Robertson grade, radiation dose to the cochlea, transient volume expansion (TVE) after SRS, length of irradiated cochlear nerve, marginal dose to the tumour, and age. However, we still do not clearly understand why patients lose their hearing after SRS for VS.Relevant to these considerations, one study recently reported that the auditory brainstem response (ABR) wave V latency and waves I and V interval (IL_I-V) correlated well with intracanalicular pressure values and even with hearing level. The demonstration that ABR values, especially wave V latency and IL_I-V, correlate well with intracanalicular pressure suggests that patients with previously elevated intracanalicular pressure might have an increased chance of hearing loss on development of TVE, which has been recognised as a common phenomenon after SRS or stereotactic radiotherapy (SRT) for intracranial schwannomas.In our experience, the ABR IL_I-V increased during the first 12 months after SRS for VSs in patients who lost their serviceable hearing. The effect of increased ABR IL_I V on hearing outcome also became significant over time, especially at 12 months after SRS, and was more prominent in patients with poor initial pure-tone average (PTA) and/or ABR values. We hypothesise that patients with considerable intracanalicular pressure at the time of SRS are prone to lose their serviceable hearing due to the added intracanalicular pressure induced by TVE, which usually occurs within the first 12 months after SRS for VSs. Using these findings, we suggested a classification system for the prediction of hearing outcomes after SRS for VSs. This classification system could be useful in the proper selection of management modalities for hearing preservation, especially in patients with only hearing ear schwannoma or neurofibromatosis type 2.Advances in diagnostic tools, treatment modalities, and optimisation of radiosurgical dose have improved clinical outcomes, including tumour control and cranial neuropathies, in patients with VSs. However, the preservation of hearing function still falls short of our expectation. A prediction model for hearing preservation after each treatment modality will guide the proper selection of treatment modalities and permit the appropriate timing of active treatment, which will lead to the preservation of hearing function in patients with VSs. PMID- 26508405 TI - Merits and Limits of Tractography Techniques for the Uninitiated. AB - The implementation of fiber tracking or tractography modules in commercial navigation systems resulted in a broad availability of visualization possibilities for major white matter tracts in the neurosurgical community. Unfortunately the implemented algorithms and tracking approaches do not represent the state of the art of tractography strategies and may lead to false tracking results. The application of advanced tractography techniques for neurosurgical procedures poses even additional challenges that relate to effects of the individual anatomy that might be altered by edema and tumor, to stereotactic inaccuracies due to image distortion, as well as to registration inaccuracies and brain shift. PMID- 26508406 TI - 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review. AB - The current first-line treatment of malignant gliomas consists in surgical resection (if possible) as large as possible. The existing tools don't permit to identify the limits of tumor infiltration, which goes beyond the zone of contrast enhancement on MRI. The fluorescence-guided malignant gliomas surgery was started 15 years ago and had become a standard of care in many countries. The technique is based on fluorescent molecule revelation using the filters, positioned within the surgical microscope. The fluorophore, protoporphyrin IX (PpIX), is converted in tumoral cells from 5-aminolevulinic acid (5-ALA), given orally before surgery. Many studies have shown that the ratio of gross total resections was higher if the fluorescence technique was used. The fluorescence signal intensity is correlated to the cell density and the PpIX concentration. The current method has a very high specificity but still lower sensibility, particularly regarding the zones with poor tumoral infiltration. This book reviews the principles of the technique and the results (extent of resection and survival). PMID- 26508407 TI - Clinical Relevance of Prognostic and Predictive Molecular Markers in Gliomas. AB - Sorting and grading of glial tumors by the WHO classification provide clinicians with guidance as to the predicted course of the disease and choice of treatment. Nonetheless, histologically identical tumors may have very different outcome and response to treatment. Molecular markers that carry both diagnostic and prognostic information add useful tools to traditional classification by redefining tumor subtypes within each WHO category. Therefore, molecular markers have become an integral part of tumor assessment in modern neuro-oncology and biomarker status now guides clinical decisions in some subtypes of gliomas. The routine assessment of IDH status improves histological diagnostic accuracy by differentiating diffuse glioma from reactive gliosis. It carries a favorable prognostic implication for all glial tumors and it is predictive for chemotherapeutic response in anaplastic oligodendrogliomas with codeletion of 1p/19q chromosomes. Glial tumors that contain chromosomal codeletion of 1p/19q are defined as tumors of oligodendroglial lineage and have favorable prognosis. MGMT promoter methylation is a favorable prognostic marker in astrocytic high grade gliomas and it is predictive for chemotherapeutic response in anaplastic gliomas with wild-type IDH1/2 and in glioblastoma of the elderly. The clinical implication of other molecular markers of gliomas like mutations of EGFR and ATRX genes and BRAF fusion or point mutation is highlighted. The potential of molecular biomarker-based classification to guide future therapeutic approach is discussed and accentuated. PMID- 26508408 TI - Spinal Dural Arteriovenous Fistula: A Review. AB - Spinal dural arteriovenous fistula (SDAVF) is a rare disease, the etiology of which is not entirely clear. It is the most common vascular malformation of the spinal cord, comprising 60-80 % of the cases. The clinical presentation and imaging findings may be nonspecific and misleading, often mistaking it for other entities like demyelinating or degenerative diseases of the spine.This chapter describes the imaging findings, clinical signs, and symptoms of this disease and also the available treatment options according to the current literature.Angiography is still considered the gold standard for diagnosis; however, MRI/MRA is increasingly used as a screening tool. Modern endovascular techniques are becoming increasingly more effective in treating SDAVF offering a less invasive treatment option; however, they still lag behind surgical success rates which approach 100 %. The outcome of both treatment options is similar if complete obliteration of the fistula is obtained and depends mainly on the severity of neurological dysfunction before treatment.Heightened awareness by radiologists and clinicians to this rare entity is essential to make a timely diagnosis of this treatable disease. A multidisciplinary treatment approach is required in order to make appropriate treatment decisions. PMID- 26508409 TI - Intracranial Meningiomas: A 30-Year Experience and Literature Review. AB - Intracranial meningiomas are tumors arising from the covering cells of the arachnoid layer of the dura mater or from the intraventricular choroid plexus. While mostly benign tumors, they still represent a major challenge to neurosurgeons and other medical disciplines involved in their diagnostic and therapeutic management. Although this review intends to give some state-of-the art information from the literature, it is mainly based on personal experiences since more than 30 years caring for more than 1500 meningioma patients and point to a few new strategies to further improve on patient outcome.Diagnostics are based on magnetic resonance imaging which shows the relationship between tumor and surrounding intracranial structures, particularly the brain but also the vasculature and to some extent the cranial nerves. Furthermore, it may suggest the grading of the tumor and is very helpful in the postoperative diagnosis of complications and later follow-up course.Surgery still is the main treatment with the aim to completely remove the tumor; also in cases of recurrence, other additional options include radiotherapy and radiosurgery for incompletely removed or recurrent meningiomas. Postoperative chemotherapy has not been shown to provide substantial benefit to the patient especially in highly malignant meningiomas.All therapy options should be intended to provide the patient with the best possible functional outcome. Patients' perspective is not always equivalent to surgeons' perspectives. Neuropsychological evaluation and additional guidance of patients harboring meningiomas have proven to be important in modern neurosurgical intracranial tumor treatment. Their help beyond neurosurgical care facilitates the patients to lead an independent postoperative life. PMID- 26508410 TI - Arteries and Veins of the Sylvian Fissure and Insula: Microsurgical Anatomy. AB - We present a vascular anatomical study of the arteries and veins of the sylvian fissure and insula.A good knowledge of the sylvian fissure, the insula, and their vascular relationship would seem mandatory before performing surgery in this area, whatever the type of surgery (aneurysms, arteriovenous malformations, insular tumors).We start with the sylvian fissure and insula morphology, followed by the MCA description and its perforators, with special attention paid to the insular perforators. We demonstrate that the long insular perforators penetrating in the superior part of the posterior short gyrus and long gyri vascularize, respectively, the corticonuclear and corticospinal fasciculi. We particularly insist too on three anatomical constants regarding the vascularization of the insula, already described in the literature: The superior periinsular sulcus is the only sulcus on the lateral surface of the brain without an artery along its axis; the superior branch of the MCA supplies the anterior insular pole and both the anterior and middle short gyri in 100 % of cases; in at least 90 % of cases, the artery that supplied the central insular sulcus continued on to become the central artery.We end with the anatomical study of the veins and cisterns. PMID- 26508411 TI - Neutral N-donor ligand based flexible metal-organic frameworks. AB - This short review gives a focussed discussion on metal-organic frameworks (MOFs) made of neutral N-donor ligands which show structural flexibility under various exogenous stimuli. Chemical stimuli such as presence of anions, free guests, coordinated guests and physical stimuli (light, heat and so on) render structural flexibility in MOFs. Single-crystal-to-single-crystal transformation studies have attracted a lot of attention for the understanding of such flexible MOF materials. Such a dynamic structural behavior with proper host-guest interactions gives very interesting functions such as chemical separation, sensing and magnetic properties and so on. PMID- 26508412 TI - Targeted anticancer drug delivery through anthracycline antibiotic bearing functionalized quantum dots. AB - We herein first report a method for the synthesis of chitosan (CHI)-folate conjugated colloidal ZnO-Mn(+2) quantum dots (QDs) bearing doxorubicin through chemical method (DOX/FA-CHI-QDs) for cancer therapy as well imaging purpose. The entrapment efficiency was determined to be 99.98 +/- 0.012% (DOX/FA-CHI-QDs) and 92.0 +/- 2.62% (DOX-QDs). The developed DOX/FA-CHI-QDs formulations depict the sustained release pattern at the lysosomal pH (pH 5.0). The DOX/FA-CHI-QDs showed enhanced cytotoxicity, cellular uptake and were most preferentially taken up by the cancerous cells via receptor-mediated endocytosis (RME) mechanism. Hence, the QD-based formulation is capable of targeting drug delivery and imaging the delivery process. PMID- 26508413 TI - The effect of environmental heterogeneity on species richness depends on community position along the environmental gradient. AB - Environmental heterogeneity is among the most important factors governing community structure. Besides the widespread evidence supporting positive relationships between richness and environmental heterogeneity, negative and unimodal relationships have also been reported. However, few studies have attempted to test the role of the heterogeneity on species richness after removing the confounding effect of resource availability or environmental severity. Here we constructed an individual-based spatially explicit model incorporating a long-recognized tradeoff between competitive ability and stress tolerance ability of species. We explored the impact of the level of resource availability (i.e. the position of the community along a gradient of environmental severity) on the heterogeneity-diversity relationship (HDR). The results indicate that the shape of HDR depends on the community position along the environmental gradient: at either end of the gradient of environmental severity, a positive HDR occurred, whereas at the intermediate levels of the gradient, a unimodal HDR emerged. Our exploration demonstrates that resource availability/environmental severity should be considered as a potential factor influencing the shape of the HDR. Our theoretical predictions represent hypotheses in need of further empirical study. PMID- 26508414 TI - Efficacy of enteral ticagrelor in hypothermic patients after out-of-hospital cardiac arrest. AB - INTRODUCTION: Delivery of crushed ticagrelor via a nasogastric tube is a widely spread off-label use in unconscious patients following out-of-hospital cardiac arrest (OHCA). Notwithstanding the importance of a potent dual antiplatelet therapy in these patients, the efficacy of crushed ticagrelor after OHCA has not been established yet. METHODS: In a prospective, single-center, observational trial, 38 consecutive MI patients after OHCA were included. 27 patients (71.1 %) underwent mild induced hypothermia. The primary outcome was platelet inhibition at 24h measured by impedance aggregometry. RESULTS: There was sufficient platelet inhibition in most patients after OHCA. In all hypothermic patients, there was an adequate platelet inhibition by ticagrelor at 24 h (p < 0.001). 15 patients (39.5 %) had significant gastroesophageal reflux and one patient with significant reflux had inadequate platelet inhibition at 24 h. There were no stent thrombosis or recurrent atherothrombotic events in these patients. CONCLUSION: Administration of crushed ticagrelor via a nasogastric tube reliably inhibited platelet function in vitro and in vivo regardless of the presence of hypothermia in MI patients. Thus, platelet inhibition can be reliably achieved in MI patients during neuroprotective hypothermia following OHCA. PMID- 26508415 TI - Description of a Heart Team approach to coronary revascularization and its beneficial long-term effect on clinical events after PCI. AB - OBJECTIVE AND BACKGROUND: We present a first description of a Heart Team (HT) guided approach to coronary revascularization and its long-term effect on clinical events after percutaneous coronary intervention (PCI). The HT approach is a structured process to decide for coronary bypass grafting (CABG), PCI or conservative therapy in ad hoc situations as well as in HT conferences. As a hypothesis, during the long-term course after a PCI performed according to HT rules, a low number of late revascularizations, especially CABGs, are expected (F PCI study). METHODS: In this monocentric study, the HT approach to an all-comer population was first analyzed and described in general with the help of a database. Next the use of a HT approach was described for a more homogeneous subgroup with newly detected CAD (1.CAD). Those patients in whom the HT decision was PCI (which was a 1.PCI) were then studied with the help of questionnaires for clinical events during a very long-term follow-up. Events were CABG, PCI, diagnostic catheterization (DCath) and death. RESULTS: A significant number of patients were presented to HT conferences: 22 % out of all 11,174 catheterizations, 24 % out of all 7867 CAD cases and 35 % out of 3408 1.CAD cases. Most of these patients had multi-vessel disease (MVD). Conference decisions were isolated CABG in 46-66 %, PCI in 10-14 %, valvular surgery in 9-16 %, HTx in 10-21 % (Endstage heart failure candidates for surgery) and conservative therapy (Medical or no therapy, additional diagnostic procedures or no adherence to recommended therapy) in 2-3 %. However, most PCIs, ad hoc and elective, were performed under Heart Team rules, but without conference. During follow-up of 1.PCI patients (Kaplan-Meier analysis), CABG occurred in only 15 % of patients, PCI in 37 % and DCath in 65 %; mortality of any course was 51 %. Mortalities were similar in one-vessel disease and in a population of the same year, matched for age and sex (p < 0.057), but mortality was higher in 1.PCI patients with MVD (p < 0.001). Beyond 2 years, Kaplan-Meier curves were linear. CONCLUSION: The structured Heart Team approach is an effective tool for ad hoc and conference-based clinical decision-making with a sustained clinical benefit. This is demonstrated in low late CABG (and PCI) rates after a 1.PCI, without elevated mortality. The all-comer population supports the universal value of these data. Stable annual event rates late after PCI suggest a conversion to stable CAD. Heart Team conferences are also important tools in cases of valvular and end-stage heart disease. PMID- 26508417 TI - Immunohistochemical study and mRNA cytokine profile of the local immune response in cattle naturally infected with Calicophoron daubneyi. AB - In order to recognize the local immune response of the definitive host to Calicophoron daubneyi natural infection, an immunohistochemical study was carried out in the reticulum and rumen in 49 naturally infected cattle. The role of cytokines (IL-4 and IL-10 interleukins and IFN-gamma) in the activation of specific defence mechanisms was evaluated by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) assays to study cytokine mRNA expression. In all infected animals, CD3+ T lymphocytes seemed to be the main element of the inflammatory infiltrate in the reticular and ruminal lamina propria at the point of the parasite adhesion. Intraepithelial globule leukocytes also showed immunolabelling for CD3. Most CD3+ cells also expressed CD4 (T cell helper) antigen although sporadic CD8+-cytotoxic lymphocytes were observed. Local expression of IFN-gamma was observed in damaged papillae at the site of parasite attachment and in scattered cells in the lamina propria. B cells (CD79alphacy+, CD45+ and IgG+) were found constantly in relation to lymphoid aggregates. MAC387 was expressed in squamous epithelium and in macrophages of the lamina propria of affected papillae. Macrophages in this location also stained positively for CD163 and CD68. Intraepithelial Langerhans cells and macrophages located in the lamina propria showed immunopositivity for MHCII in the affected areas. RT-qPCR analysis confirmed a statistical significant increase of IFN-gamma, and IL-10 expression (p<0.01) in the rumen associated with the presence of flukes. These findings suggest a predominant Th1 polarized local immune response with the probable involvement of Th regulatory cells in cattle C. daubneyi natural infection. PMID- 26508418 TI - Octadecabacter ascidiaceicola sp. nov., isolated from a sea squirt (Halocynthia roretzi). AB - A Gram-stain-negative, non-spore-forming, non-flagellated and coccoid, ovoid or rod-shaped bacterial strain, RA1-3T, was isolated from a sea squirt (Halocynthia roretzi) collected from the South Sea, South Korea, and subjected to a taxonomic study using a polyphasic approach. Strain RA1-3T grew optimally at 25 degrees C, at pH 7.0-8.0 and in the presence of 2.0-3.0 % (w/v) NaCl. Neighbour-joining, maximum-likelihood and maximum-parsimony phylogenetic trees based on 16S rRNA gene sequences revealed that strain RA1-3T clustered with the type strains of three species of the genus Octadecabacter, showing 97.54-98.41 % 16S rRNA gene sequence similarity. Sequence similarities to other recognized species were less than 96.97 %. Strain RA1-3T contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the major fatty acid. The major polar lipids of strain RA1-3T were phosphatidylcholine, phosphatidylglycerol, one unidentified aminolipid and one unidentified lipid. The DNA G+C content of strain RA1-3T was 56 mol% and DNA-DNA relatedness values with the type strains of Octadecabacter temperatus, Octadecabacter antarcticus and Octadecabacter arcticus were 13-24 %. The differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain RA1-3T is separated from other recognized species of the genus Octadecabacter. On the basis of the data presented, strain RA1-3T is considered to represent a novel species of the genus Octadecabacter, for which the name Octadecabacter ascidiaceicola sp. nov. is proposed. The type strain is RA1-3T ( = KCTC 42605T = CECT 8868T). PMID- 26508419 TI - Tactical metrics that discriminate winning, drawing and losing teams in UEFA Euro 2012(r). AB - The objectives of this article are twofold: first, an innovative approach to notational analysis in football is outlined. By considering the important theoretical requirements for the analysis of sports games (like the interaction between two parties, the procedural sequence of action or the significance of tactical behaviour) the meaning of the introduced parameters, called tactical metrics, is illustrated. In a second step, the validity of this approach is tested using matches of the Union of European Football Associations (UEFA) Euro 2012(r) to investigate a connection between these metrics and success. The results show that 11 tactical metrics model tactical behaviour in 4 different dimensions (game speed, transition play after ball recovery, transition play after ball loss and offence efficiency (OE)). Discriminant analysis based on the factor values leads to a correct classification of 64.8% identifying winners, losers and drawers. This successful discrimination reveals a connection between match success and the presented metrics. Especially, the transition play after losing the ball and the OE seem to be factors connected directly with the result of a match, since those were important values for a successful discrimination. Furthermore, the procedural description of tactical behaviour provides the opportunity to conduct meaningful recommendations for the training and coaching process. PMID- 26508420 TI - Swarming and mating activity of Anopheles gambiae mosquitoes in semi-field enclosures. AB - Anopheles gambiae Giles sensu stricto (Diptera: Culicidae) is the major Afro tropical vector of malaria. Novel strategies proposed for the elimination and eradication of this mosquito vector are based on the use of genetic approaches, such as the sterile insect technique (SIT). These approaches rely on the ability of released males to mate with wild females, and depend on the application of effective protocols to assess the swarming and mating behaviours of laboratory reared insects prior to their release. The present study evaluated whether large semi-field enclosures can be utilized to study the ability of males from a laboratory colony to respond to natural environmental stimuli and initiate normal mating behaviour. Laboratory-reared males exhibited spatiotemporally consistent swarming behaviour within the study enclosures. Swarm initiation, peak and termination time closely tracked sunset. Comparable insemination rates were observed in females captured in copula in the semi-field cages relative to females in small laboratory cages. Oviposition rates after blood feeding were also similar to those observed in laboratory settings. The data suggest that outdoor enclosures are suitable for studying swarming and mating in laboratory bred males in field-like settings, providing an important reference for future studies aimed at assessing the comparative mating ability of strains for SIT and other vector control strategies. PMID- 26508421 TI - Snake bite: a global failure to act costs thousands of lives each year. PMID- 26508422 TI - Acute arsenic poisoning diagnosed late. AB - Acute arsenicosis, although having a 'historical' background, is not common in our times. This report describes a case of acute arsenic poisoning, missed initially due to its gastroenteritis-like presentation, but suspected and confirmed much later, when the patient sought medical help for delayed complications after about 2 months. PMID- 26508423 TI - Long-term Effects of Nutrition Education in Bariatric Surgery Patients. PMID- 26508424 TI - A peripheral pathway to restless legs syndrome? Clues from familial amyloid polyneuropathy. AB - BACKGROUND: The relationship between restless legs syndrome (RLS) and peripheral neuropathy remains unclear. In order to clarify this relationship, we investigated if RLS is increased in familial amyloid polyneuropathy related to transthyretin (TTR-FAP) and investigated factors associated with RLS in this population. METHODS: RLS frequency was compared between TTR-FAP patients and controls. Secondly, TTR-FAP patients with and without RLS were compared regarding demographic and clinical characteristics. RESULTS: RLS frequency was significantly increased in TTR-FAP, with 18/98 (18.4%) cases contrasting with 5/104 (4.8%) controls (p-value 0.002). This difference remained significant after adjusting for confounders. In TTR-FAP patients, female sex (p-value 0.037), obesity (p-value 0.036) and weight excess (p-value 0.048) were associated with RLS, contrary to other classical RLS risk factors. CONCLUSIONS: RLS frequency is increased in TTR-FAP, thus supporting an association between RLS and neuropathy. This may represent a peripheral pathway in RLS pathogenesis. Furthermore, our results suggest that female sex and obesity/weight excess may be risk factors for RLS development among TTR-FAP patients. PMID- 26508425 TI - Detecting shifts in gene regulatory networks during time-course experiments at single-time-point temporal resolution. AB - Comprehensively understanding the dynamics of biological systems is one of the greatest challenges in biology. Vastly improved biological technologies have provided vast amounts of information that must be understood by bioinformatics and systems biology researchers. Gene regulations have been frequently modeled by ordinary differential equations or graphical models based on time-course gene expression profiles. The state-of-the-art computational approaches for analyzing gene regulations assume that their models are same throughout time-course experiments. However, these approaches cannot easily analyze transient changes at a time point, such as diauxic shift. We propose a score that analyzes the gene regulations at each time point. The score is based on the information gains of information criterion values. The method detects the shifts in gene regulatory networks (GRNs) during time-course experiments with single-time-point resolution. The effectiveness of the method is evaluated on the diauxic shift from glucose to lactose in Escherichia coli. Gene regulation shifts were detected at two time points: the first corresponding to the time at which the growth of E. coli ceased and the second corresponding to the end of the experiment, when the nutrient sources (glucose and lactose) had become exhausted. According to these results, the proposed score and method can appropriately detect the time of gene regulation shifts. The method based on the proposed score provides a new tool for analyzing dynamic biological systems. Because the score value indicates the strength of gene regulation at each time point in a gene expression profile, it can potentially infer hidden GRNs from time-course experiments. PMID- 26508426 TI - Basis set dependence using DFT/B3LYP calculations to model the Raman spectrum of thymine. AB - Raman spectroscopy (including surface enhanced Raman spectroscopy (SERS) and tip enhanced Raman spectroscopy (TERS)) is a highly promising experimental method for investigations of biomolecule damage induced by ionizing radiation. However, proper interpretation of changes in experimental spectra for complex systems is often difficult or impossible, thus Raman spectra calculations based on density functional theory (DFT) provide an invaluable tool as an additional layer of understanding of underlying processes. There are many works that address the problem of basis set dependence for energy and bond length consideration, nevertheless there is still lack of consistent research on basis set influence on Raman spectra intensities for biomolecules. This study fills this gap by investigating of the influence of basis set choice for the interpretation of Raman spectra of the thymine molecule calculated using the DFT/B3LYP framework and comparing these results with experimental spectra. Among 19 selected Pople's basis sets, the best agreement was achieved using 6-31[Formula: see text](d,p), 6 31[Formula: see text](d,p) and 6-11[Formula: see text]G(d,p) sets. Adding diffuse functions or polarized functions for small basis set or use of a medium or large basis set without diffuse or polarized functions is not sufficient to reproduce Raman intensities correctly. The introduction of the diffuse functions ([Formula: see text]) on hydrogen atoms is not necessary for gas phase calculations. This work serves as a benchmark for further research on the interaction of ionizing radiation with DNA molecules by means of ab initio calculations and Raman spectroscopy. Moreover, this work provides a set of new scaling factors for Raman spectra calculation in the framework of DFT/B3LYP method. PMID- 26508427 TI - Distribution and Health Risk Assessment of Polycyclic Aromatic Hydrocarbons in Soil from a Typical Contaminated Urban Coking Sites in Shenyang City. AB - This study evaluated the level of PAH pollution in typical contaminated coking sites in Shenyang. Sixty surface soil samples were collected from an area of 1.3 * 10(5) m(2) polluted by PAHs. The concentrations, sources and possible health risks of 16 PAHs in the area were analyzed. The average content of Sigma16 PAHs was 6.1 * 10(3) mg/kg. In oral intake, benzo(a)pyrene (BaP) presented the largest exposure risk (hazard quotient HQ = 1.17 * 10(-5)), followed by dibenz(a,h)anthracene (DbA) (HQ = 1.14 * 10(-5)). The non-carcinogenic hazard indices and carcinogenic risks of the PAHs were arranged in the order of BaP > DbA > benzo(b)fluoranthene (BbF) > benz(a)anthracene (BaA) > indeno(1,2,3 cd)pyrene (InP) > benzo(k)fluoranthene (BkF) > chrysene (Chr). Bap and DbA were the principal pollution sources, followed by BbF, BaA, InP, BkF and Nap successively. Oral intake was the main route of PAH entry into the human body. PMID- 26508428 TI - Enantioselective Phytotoxicity of Imazamox Against Maize Seedlings. AB - There is increasing concern about the enantioselective effects of chiral herbicides. To study the enantioselective toxicity of the chiral herbicide imazamox on maize, maize seedlings (Zhengda 619, Zea mays L.) were exposed to imazamox racemate and enantiomers in hydroponic experiments. The results showed that imazamox enantiomers selectively affected maize. The effective concentration of Rac-, S- and R-imazamox that caused 50 % inhibition after 5 days treatments (EC50,5d) were 0.4212, 1.2142 and 0.2460 mg L(-1), respectively, for maize root length; 0.0002, 0.1005, 0.0032 mg L(-1), respectively, for maize root fresh weight; 0.7114, 1.4056 and 0.4530 mg L(-1), respectively, for maize shoot height; 0.6220, 1.5418, 0.2286 mg L(-1), respectively, for maize shoot fresh weight; and 0.1100, 0.3306, 0.0307 mg L(-1), respectively, for the total chlorophyll content of leaves. The root morphological parameters and root activity reflected the toxicity effects in the order R-imazamox > Rac-imazamox > S-imazamox. Maize roots were more sensitive to imazamox than maize shoots. The chiral herbicide imazamox poses enantioselective phytotoxicity on maize seedlings: the order of toxicity is R-imazamox > Rac-imazamox > S-imazamox. PMID- 26508429 TI - A Study of 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induced Liver Injury in Jian Carp (Cyprinus carpio var. Jian) Using Precision-Cut Liver Slices. AB - The aim of this study was to establish a model for the study of liver injury induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Jian carp using precision-cut liver slices (PCLS). PCLS were treated with TCDD at concentrations of 0, 0.05, 0.1, 0.3, and 0.6 MUg/L for 6 h, followed by collection of the culture supernatant and PCLS for analysis. Several biochemical indices were analyzed, including glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA). Expression of mRNA was also estimated for cytochrome P4501A (CYP1A), aryl hydrocarbon receptor2 (AhR2), and aryl hydrocarbon receptor nuclear translocator2 (ARNT2). Results showed that some significant effects (p < 0.05) in MDA, GSH-Px and PCLS viability were observed at a TCDD concentration as low as 0.05 ug/L, and the observed effects increased with exposure concentration. Following exposure to TCDD for 6 h at a concentration of 0.3 MUg/L, significant increases (p < 0.01) in the content of GPT, GOT, MDA, and LDH were observed, while SOD activity, GSH-Px activity, and PCLS viability were decreased (p < 0.01 or p < 0.05). Exposure to 0.3 MUg/L TCDD also resulted in increased expression of mRNA for CYP1A, AhR2, and ARNT2. Overall, these results provide evidence of TCDD-induced liver injury and oxidative stress in Jian carp. These results also support the use of PCLS as an in vitro model for the evaluation of hepatotoxicity in Jian carp. PMID- 26508430 TI - Pollution Response Score of Tree Species in Relation to Ambient Air Quality in an Urban Area. AB - Multivariate statistical techniques were employed on twelve leaf traits in four selected common tree species (Mangifera indica L., Polyalthia longifolia Sonn., Ficus benghalensis L. and Psidium guajava L.) to evaluate their responses with respect to major air pollutants in an urban area. Discriminant analysis (DA) identified chlorophyll/carotenoid ratio, leaf dry matter content, carotenoids, net water content and ascorbic acid as the major discriminating leaf traits, which varied maximally with respect to the pollution status. Pollution response score (PRS), calculated on the basis of discriminate functional coefficient values, increased with an increase in air pollution variables for all the tested species, with the highest increase in P. longifolia and the lowest in F. benghalensis. The study highlights the usefulness of DA for evaluation of plant specific traits and PRS for selection of tolerant species. PMID- 26508431 TI - A 74-year-old unoperated univentricular heart: the oldest reported survival. AB - Univentricular heart is a rare congenital heart malformation. Nowadays prognosis is considered to be strictly linked to surgical intervention, and survival into late adulthood is unusual. In some patients native haemodynamic circulation balances pulmonary and systemic blood flow, allowing long-term survival without the need for surgery. We report the case of a 74-year-old man with a univentricular heart in natural history, and we discuss the factors that might contribute to his extraordinary long-term survival. PMID- 26508432 TI - Unusual extrinsic staining following microabrasion in a girl with amelogenesis imperfecta. AB - BACKGROUND: Developmental defects of enamel (DDE), such as amelogenesis imperfecta (AI), may present with tooth discolouration that is of aesthetic concern to the affected individual. Children and young people with DDE may therefore seek dental interventions to improve their dental appearance. The most commonly employed approaches include microabrasion, bleaching and/or placement of composite resin veneers. CASE REPORT: A 13-year-old girl with hypomature AI requested treatment for the 'marks' on her teeth which were having a negative impact on her social interactions. Clinical examination revealed generalised dense white opacities, and a microabrasion approach was performed on 11, 12 and 13 using a commercial preparation of 6.6 % hydrochloric acid. Concerningly, the girl's father phoned the next day reporting that his daughter's teeth had turned 'orange'. An urgent review revealed that the treated teeth had indeed become an orange colour. Further enquiry found that the patient had eaten a tomato pizza immediately after her dental treatment and this was believed to have caused the severe extrinsic staining. The patient was provided with a 16 % carbamide peroxide preparation for night-time use in a laboratory-made tray. A 2-week review revealed complete resolution of the staining. FOLLOW-UP: Direct composite resin restorations were subsequently provided for the girl's maxillary anterior teeth to achieve an optimal cosmetic result and she has remained pleased with her dental appearance. CONCLUSION: Clinicians should be aware of the potential for extrinsic staining following microabrasion or tooth bleaching. Patients should be advised against consuming coloured food and drink for at least 48 h after their treatment. PMID- 26508433 TI - Promotion of microalgal growth by co-culturing with Cellvibrio pealriver using xylan as feedstock. AB - In this work, a Cellvibrio pealriver-microalga co-cultivation mode was used to promote the growths of four microalgae by using xylan as feedstock. After 12days of cultivation, the biomass concentrations of Chlorella sacchrarophila, Chlorella pyrenoidosa and Chlamydomonas reinhardtii in co-cultivation were equal to those in mixotrophic growth on glucose, and the Dunaliella was about 1.6-fold higher than that on glucose. The comparative transcriptomes analysis demonstrated that the xylose and xylan hydrolysates were catalyzed to some active substrates by C. pealriver via some functional enzymes; these active substrates are possibly responsible for the promotion of microalgal growth. This C. pealriver-microalga co-cultivation mode is a potential method to produce low-cost microalgal biodiesel by using hemicellulose as feedstock. PMID- 26508434 TI - Deterioration of semantic associative relationships in mild cognitive impairment and Alzheimer Disease. AB - The aim of this research was to study semantic abilities and their loss in mild cognitive impairment (MCI) and in dementia, while analyzing efficiency in the use of associative relations, within verbal and visuoperceptual modalities. Participants were split into 4 groups: 19 participants with amnestic MCI, 16 patients with mild Alzheimer disease (AD), 20 patients with moderate AD, and 20 healthy controls (HCs). All participants performed standardized neuropsychological tests and experimental (naming and semantic associations) tasks to evaluate verbal and visuoperceptual semantic abilities. We analyzed 4 associative relations (part/whole, function, superordinate, and contiguity) in both verbal and visuoperceptual code. Our results suggest a progressive impairment in semantic categorization knowledge, with worse performance in the AD groups relative to the MCI and HC groups. Our data show a different pattern in the 4 associative relations and the involvement of associative semantic relations already in the early stage of disease, as well as a different pattern of deterioration between verbal and visuoperceptual modalities. Our data indicate that the visuoperceptual semantic network appears to be less deteriorated than the verbal network in AD. The verbal semantic network may be more sensitive in detecting patients at an early stage of the disease. PMID- 26508435 TI - Extreme nickel hyperaccumulation in the vascular tracts of the tree Phyllanthus balgooyi from Borneo. AB - Phyllanthus balgooyi (Phyllanthaceae), one of > 20 nickel (Ni) hyperaccumulator plant species known in Sabah (Malaysia) on the island of Borneo, is remarkable because it contains > 16 wt% Ni in its phloem sap, the second highest concentration of Ni in any living material in the world (after Pycnandra acuminata (Sapotaceae) from New Caledonia with 25 wt% Ni in latex). This study focused on the tissue-level distribution of Ni and other elements in the leaves, petioles and stem of P. balgooyi using nuclear microprobe imaging (micro-PIXE). The results show that in the stems and petioles of P. balgooyi Ni concentrations were very high in the phloem, while in the leaves there was significant enrichment of this element in the major vascular bundles. In the leaves, cobalt (Co) was codistributed with Ni, while the distribution of manganese (Mn) was different. The highest enrichment of calcium (Ca) in the stems was in the periderm, the epidermis and subepidermis of the petiole, and in the palisade mesophyll of the leaf. Preferential accumulation of Ni in the vascular tracts suggests that Ni is present in a metabolically active form. The elemental distribution of P. balgooyi differs from those of many other Ni hyperaccumulator plant species from around the world where Ni is preferentially accumulated in leaf epidermal cells. PMID- 26508436 TI - Retroperitoneal packing or angioembolization for haemorrhage control of pelvic fractures--Quasi-randomized clinical trial of 56 haemodynamically unstable patients with Injury Severity Score >=33. AB - AIMS: Both retroperitoneal pelvic packing and primary angioembolization are widely used to control haemorrhage related to pelvic fractures. It is still unknown which protocol is the safest. The primary aim of this study is to compare survival and complications of pelvic packing and angioembolization in massive haemorrhage related to pelvic fractures. METHODS: Patients with haemodynamically unstable pelvic fractures were quasi-randomized to either pelvic packing (PACK) or angiography (ANGIO) using the time of admission as separator. Physiological markers of haemorrhage, time to intervention, procedure/surgical time, transfusion requirements, complications and early mortality were recorded and analyzed. RESULTS: 29 patients were randomized to PACK and 27 patients to ANGIO. The Injury Severity Score (ISS) in the ANGIO group was lower than in the PACK group (43 +/- 7 vs 48 +/- 6) (p<0.01). The median time from admission to angiography for the ANGIO group was 102 min (range 76-214), and longer than 77 min (range 43-125) from admission to surgery for the PACK group (p<0.01). The procedure time for the ANGIO group was 84 min (range 62-105); while the surgical time was 60 min (range 41-92) for the PACK group (p<0.001). The ANGIO group received 6.4 units packed red blood cells (range 4-10) in the first 24h after angiography. The PACK group required 5.2 units (range 3-10) in the first 24h after leaving the operating theatre (p=0.124). 9 patients in the ANGIO group underwent pelvic packing for persistent bleeding. 6 patients in the PACK group required pelvic angiography after pelvic packing for ongoing hypotension following packing (p=0.353). 5 patients in the ANGIO group died (2 from exsanguination), while 4 in the PACK group died (none from exsanguination) (p=0.449). Complications occurred without differences in both groups. CONCLUSIONS: Compared with angioembolization, pelvic packing has shorter time to intervention and surgical time. Thus pelvic packing is the more rapid treatment of severe pelvic trauma than pelvic angioembolization. It is suitable for patients with haemodynamic instability at centers where the interventional radiology staff is not in-house at all times. REGISTRATION: ClinicalTrials.gov (NCT02535624) and ISRCTN registry (ISRCTN91713422). PMID- 26508437 TI - Hybrid treatment combining emergency surgery and intraoperative interventional radiology for severe trauma. AB - OBJECT: To evaluate the efficacy of hybrid treatment combining emergency surgery and intraoperative interventional radiology (IVR) for severe trauma. PATIENTS AND METHODS: The records of 63 severely injured patients who underwent concurrent emergency surgery and IVR at our emergency centre from 1999 through 2013 were retrospectively reviewed. Mobile digital subtraction angiography device was used in the operating room when performing IVR. Patients undergoing hybrid treatment combining intraoperative IVR and emergency surgery (intraoperative IVR group) were compared with those undergoing IVR in the angiography suite before or after emergency surgery (control group). RESULTS: Thirteen patients underwent hybrid treatment (intraoperative IVR group). Of these 13 patients, 7 underwent treatment for abdominal organ injuries, and 6 for multiregional injuries. Emergency operations were laparotomy (n=12), thoracotomy (n=1), craniotomy (n=1), and haemostasis of the lower extremities (n=1). Five patients underwent damage control surgery. IVR included transarterial embolisation (n=12), endovascular stent or stent-graft placement (n=2), and embolisation of a portal vein by laparotomy (n=2). The mean ISS was 40. The actual overall survival rate was 85%, and the probability of survival (Ps) was 62%. The control group included 45 patients. Five patients who met exclusion criteria were not included in the control group. Age, ISS, RTS, Ps, pH and base excess on arrival, and blood transfusion volume during operation and IVR did not differ significantly between the groups. Total time during operation and IVR was significantly shorter in the intraoperative IVR group than in the control group (229 [SD 72]min vs. 355 [SD 169]min; p=0.007). The mortality were 15 (95% CI 2-45) % in the intraoperative IVR group vs. 36 (95% CI 22-51) % in the control group. CONCLUSION: Hybrid treatment combining emergency surgery and intraoperative IVR can be a novel treatment strategy for severe trauma, and it will improve patient outcomes due to reduction of the time for resuscitation. PMID- 26508438 TI - Exploratory multinomial logit model-based driver injury severity analyses for teenage and adult drivers in intersection-related crashes. AB - OBJECTIVE: Teenage drivers are more likely to be involved in severely incapacitating and fatal crashes compared to adult drivers. Moreover, because two thirds of urban vehicle miles traveled are on signal-controlled roadways, significant research efforts are needed to investigate intersection-related teenage driver injury severities and their contributing factors in terms of driver behavior, vehicle-infrastructure interactions, environmental characteristics, roadway geometric features, and traffic compositions. Therefore, this study aims to explore the characteristic differences between teenage and adult drivers in intersection-related crashes, identify the significant contributing attributes, and analyze their impacts on driver injury severities. METHODS: Using crash data collected in New Mexico from 2010 to 2011, 2 multinomial logit regression models were developed to analyze injury severities for teenage and adult drivers, respectively. Elasticity analyses and transferability tests were conducted to better understand the quantitative impacts of these factors and the teenage driver injury severity model's generality. RESULTS: The results showed that although many of the same contributing factors were found to be significant in the both teenage and adult driver models, certain different attributes must be distinguished to specifically develop effective safety solutions for the 2 driver groups. CONCLUSIONS: The research findings are helpful to better understand teenage crash uniqueness and develop cost-effective solutions to reduce intersection-related teenage injury severities and facilitate driver injury mitigation research. PMID- 26508439 TI - Hypertension in late adolescence and cardiovascular mortality in midlife: a cohort study of 2.3 million 16- to 19-year-old examinees. AB - BACKGROUND: The effect of early hypertension on midlife cardiovascular (CV) mortality remains controversial. We assessed the association of established hypertension in late adolescence with subsequent CV mortality. METHODS: Of 2,298,130 Israeli adolescents (60% males; age 17.4 +/- 0.3 years) who underwent a compulsory medical examination prior to military service between 1967 and 2010, 8720 teenagers (0.4%) were formally diagnosed with persistent hypertension. Using Cox proportional hazards modeling, we compared the hypertensive group to the large normotensive group with regard to time to event analysis of midlife mortality due to cerebrovascular accidents (CVA), coronary heart disease (CHD), sudden death (SD) and their summation as cardiovascular disease (CVD). RESULTS: During 45,729,521 person-years of follow-up, we identified 2918 CV deaths-2879 and 39 among the 2,289,410 normotensive and 8720 hypertensive adolescents, respectively. Hypertension at a young age was associated with a threefold elevation of stroke mortality compared to normotension when adjusted for sex, age at examination, birth year, country of origin, socioeconomic status, education, body mass index (BMI) and height [hazard ratio (HR) 3.12; 95% confidence interval (CI) 1.76-5.54; p < 0.001]. There was no significant association of hypertension with CHD mortality or SD. An increased risk for overall CVD mortality among hypertensive youngsters (HR 1.51; 95 % CI 1.10-2.07) was attenuated after adjusting for BMI and other covariates (HR 1.24; 95% CI 0.90-1.72). CONCLUSIONS: Established hypertension at a young age was independently associated with elevated stroke mortality in midlife. This finding warrants confirmatory large scale long-term follow-up studies to address the distant effects of adolescent hypertension. PMID- 26508440 TI - Periodic Hartree-Fock and hybrid density functional calculations on the metallic and the insulating phase of (EDO-TTF)2PF6. AB - The insulating and conducting phases of (EDO-TTF)2PF6 were studied by all electron, periodic Hartree-Fock and hybrid density functional calculations. Electronic properties, such as the electronic band structure, the density of states and the Fermi surface are discussed in relation to the metal-insulator transition in this material. The nature of conduction is confirmed in both phases from their band structures and density of states. The hybrid DFT band gaps are in good agreement with experiment. Interactions are discussed on the basis of band dispersion in the inter-stack, intra-stack and inter-sheet directions. We discuss the phase transition in terms of the Peierls mechanism and our results fully support this view. PMID- 26508441 TI - Incidence of heart failure in 6083 elderly hypertensive patients: the Second Australian National Blood Pressure Study (ANBP2). AB - AIMS: Hypertension is a known risk factor for the development of heart failure (HF); however, few data are available on the magnitude of short- and long-term progression from hypertension to HF. The present study aims to determine the short- and long-term incidence of HF, and identify factors associated with onset of HF in elderly hypertensive patients. METHODS AND RESULTS: The incidence of HF was measured in 6083 hypertensive patients, in the Second Australian National Blood Pressure Study (ANBP2), followed for a median of 10.8 years (4.1 years during the trial and 6.7 years during post-trial follow-up). A total of 373 cases of HF were identified over 59 581 person-years of follow-up (PY). The overall cumulative incidence of HF was 6.26 per 1000 PY; 5.33 per 1000 PY during the ANBP2 clinical trial and 7.04 per 1000 PY during the post-trial follow-up. HF was 63% higher among men [incidence rate ratios (IRR) 1.63, P < 0.01]. Older age, male sex, obesity, and history of cardiovascular disease independently predicted HF during both the short- and long-term follow-up. In addition, diabetes and smoking were associated with onset of HF in the short-term follow-up, and higher systolic blood pressure in the long-term follow-up. Median survival following diagnosis with HF was 3.94 years, and women (6.06 years) had a survival advantage over men (3.32 years). CONCLUSION: Heart failure is a frequent long-term outcome in treated elderly hypertensive patients. Development of HF was predicted by patient characteristics and co-morbidities, with the effect of some predictors varying over the short- and long-term follow-up. PMID- 26508442 TI - Biomarkers in amyotrophic lateral sclerosis: combining metabolomic and clinical parameters to define disease progression. AB - BACKGROUND AND PURPOSE: The objectives of this study were to define the metabolomic profile of cerebrospinal fluid in amyotrophic lateral sclerosis (ALS) patients, to model outcome through combined clinical and metabolomic parameters and independently to validate predictive models. METHODS: In all, 74 consecutive newly diagnosed patients were enrolled into training (Tr, n = 49) and test (Te, n = 25) cohorts. Investigators recorded clinical data and the metabalomic profile of cerebrospinal fluid at baseline was analyzed with (1)H nuclear magnetic resonance spectroscopy. Markers of disease progression, collected in 1-year prospective follow-up, included change in ALS Functional Rating Scale (var_ALSFRS), change in weight (var_weight) and survival time. Stepwise multiple regression selected from metabolomic and clinical parameters to model rate of progression in the Tr cohort. Best fit models were validated independently in the Te cohort. RESULTS: The best-fit statistical models, using both metabolomic and clinical covariates, predicted outcome with 70.8% (var_weight), 72% (var_ALSFRS) and 76% (survival) accuracy in the Te cohort. Models that used metabolomics or clinical data alone predicted outcome less well. Highlighted metabolites are involved in pathophysiological pathways previously described in ALS. CONCLUSION: Cerebrospinal fluid metabolomics can aid in predicting the clinical course of ALS and tap into pathophysiological processes. The precision of predictive models, independently reproduced in this study, is enhanced through inclusion of both metabolomic and clinical parameters. The findings bring the field closer to a clinically meaningful disease marker. PMID- 26508443 TI - DetectTLC: Automated Reaction Mixture Screening Utilizing Quantitative Mass Spectrometry Image Features. AB - Full characterization of complex reaction mixtures is necessary to understand mechanisms, optimize yields, and elucidate secondary reaction pathways. Molecular level information for species in such mixtures can be readily obtained by coupling mass spectrometry imaging (MSI) with thin layer chromatography (TLC) separations. User-guided investigation of imaging data for mixture components with known m/z values is generally straightforward; however, spot detection for unknowns is highly tedious, and limits the applicability of MSI in conjunction with TLC. To accelerate imaging data mining, we developed DetectTLC, an approach that automatically identifies m/z values exhibiting TLC spot-like regions in MS molecular images. Furthermore, DetectTLC can also spatially match m/z values for spots acquired during alternating high and low collision-energy scans, pairing product ions with precursors to enhance structural identification. As an example, DetectTLC is applied to the identification and structural confirmation of unknown, yet significant, products of abiotic pyrazinone and aminopyrazine nucleoside analog synthesis. Graphical Abstract ?. PMID- 26508444 TI - Main photoautotrophic components of biofilms in natural draft cooling towers. AB - While photoautotrophic organisms are an important component of biofilms that live in certain regions of natural draft cooling towers, little is known about these communities. We therefore examined 18 towers at nine sites to identify the general patterns of community assembly in three distinct tower parts, and we examined how community structures differ depending on geography. We also compared the newly acquired data with previously published data. The bottom sections of draft cooling towers are mainly settled by large filamentous algae, primarily Cladophora glomerata. The central portions of towers host a small amount of planktic algae biomass originating in the cooling water. The upper fourths of towers are colonized by biofilms primarily dominated by cyanobacteria, e.g., members of the genera Gloeocapsa and Scytonema. A total of 41 taxa of phototrophic microorganisms were identified. Species composition of the upper fourth of all towers was significantly affected by cardinal position. There was different species composition at positions facing north compared to positions facing south. West- and east-facing positions were transitory and highly similar to each other in terms of species composition. Biofilms contribute to the degradation of paint coatings inside towers. PMID- 26508445 TI - GLI3 mutations in syndromic and non-syndromic polydactyly in two Indian families. AB - The GLI3 protein is a zinc finger transcription factor, expressed early in development. The GLI3 gene exhibits allelic heterogeneity as mutations in this gene are associated with several developmental syndromic and non-syndromic polydactyly. The present study reports two cases: first, a familial case of Greig Cephalopolysyndactyly Syndrome (GCPS); the second is a sporadic case with both postaxial polydactyly (PAP) type A and B. Resequencing of GLI3 gene reveals a previously reported nonsense truncation mutation g.42007251G > A (p.R792X; rs121917714) in the GCPS family and a novel single nucleotide insertion g.42004239_42004240insA (p.E1478X) in the sporadic case of postaxial polydactyly (PAP). Both nonsense truncation mutations; p.R792X (GCPS) and p.E1478X (PAP) introduce a premature stop codon leading to loss of C-terminal domains. PMID- 26508446 TI - Prediction of response to anti-EGFR antibody-based therapies by multigene sequencing in colorectal cancer patients. AB - BACKGROUND: The anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (moAbs) cetuximab or panitumumab are administered to colorectal cancer (CRC) patients who harbor wild-type RAS proto-oncogenes. However, a percentage of patients do not respond to this treatment. In addition to mutations in the RAS genes, mutations in other genes, such as BRAF, PI3KCA, or PTEN, could be involved in the resistance to anti-EGFR moAb therapy. METHODS: In order to develop a comprehensive approach for the detection of mutations and to eventually identify other genes responsible for resistance to anti-EGFR moAbs, we investigated a panel of 21 genes by parallel sequencing on the Ion Torrent Personal Genome Machine platform. We sequenced 65 CRCs that were treated with cetuximab or panitumumab. Among these, 37 samples were responsive and 28 were resistant. RESULTS: We confirmed that mutations in EGFR-pathway genes (KRAS, NRAS, BRAF, PI3KCA) were relevant for conferring resistance to therapy and could predict response (p = 0.001). After exclusion of KRAS, NRAS, BRAF and PI3KCA combined mutations could still significantly associate to resistant phenotype (p = 0.045, by Fisher exact test). In addition, mutations in FBXW7 and SMAD4 were prevalent in cases that were non-responsive to anti-EGFR moAb. After we combined the mutations of all genes (excluding KRAS), the ability to predict response to therapy improved significantly (p = 0.002, by Fisher exact test). CONCLUSIONS: The combination of mutations at KRAS and at the five gene panel demonstrates the usefulness and feasibility of multigene sequencing to assess response to anti EGFR moAbs. The application of parallel sequencing technology in clinical practice, in addition to its innate ability to simultaneously examine the genetic status of several cancer genes, proved to be more accurate and sensitive than the presently in use traditional approaches. PMID- 26508447 TI - Identification of the Streptococcus pyogenes surface antigens recognised by pooled human immunoglobulin. AB - Immunity to common bacteria requires the generation of antibodies that promote opsonophagocytosis and neutralise toxins. Pooled human immunoglobulin is widely advocated as an adjunctive treatment for clinical Streptococcus pyogenes infection however, the protein targets of the reagent remain ill defined. Affinity purification of the anti-streptococcal antibodies present within pooled immunoglobulin resulted in the generation of an IgG preparation that promoted opsonophagocytic killing of S. pyogenes in vitro and provided passive immunity in vivo. Isolation of the streptococcal surface proteins recognised by pooled human immunoglobulin permitted identification and ranking of 94 protein antigens, ten of which were reproducibly identified across four contemporary invasive S. pyogenes serotypes (M1, M3, M12 and M89). The data provide novel insight into the action of pooled human immunoglobulin during invasive S. pyogenes infection, and demonstrate a potential route to enhance the efficacy of antibody based therapies. PMID- 26508448 TI - Randomized Trial Comparing the Primary Patency following Cutting Versus High Pressure Balloon Angioplasty for Treatment of de Novo Venous Stenoses in Hemodialysis Arteriovenous Fistulae. AB - PURPOSE: A single-center randomized clinical trial was performed to compare postinterventional primary patency rates achieved by cutting balloon angioplasty and high-pressure balloon angioplasty in the treatment of de novo stenoses within autogenous arteriovenous (AV) fistulae for hemodialysis. MATERIALS AND METHODS: Forty-eight patients undergoing their first angioplasty were prospectively randomized to undergo angioplasty with a cutting balloon or high-pressure balloon 4-8 mm in diameter because cutting balloons larger than 8 mm are not available. Nine patients were excluded after angiography, with seven requiring balloons larger than 8 mm. In the remaining 39 patients, there were 42 stenoses in the following regions: juxtaanastomotic (38%), perianstomotic (38%), midcephalic (9%), and cephalic arch (14%). Patients in the cutting balloon group were younger (mean age difference, 9 y; P = .04), but other demographic variables were comparable (range, P = .08-.89). The mean follow-up period was 8.5 mo (range, 24 d to 32 mo). Kaplan-Meier analysis was used to compare duration of patency. Mann Whitney rank-sum t test and chi2/Fisher exact tests were used to compare continuous and categoric variables, respectively. RESULTS: Technical success was achieved in all 39 patients. At 3, 6, and 12 months, the postinterventional primary patency rates for the cutting balloon group were 61.1% (95% confidence interval [CI], 35.75%-82.70%), 27.7% (95% CI, 9.69%-53.48%), and 11.1% (95% CI, 1.38%-34.71%), respectively, compared with 70.0% (95% CI, 45.72%-88.11%), 42.1% (95% CI, 20.25%-66.50%), and 26.3% (95% CI, 9.15%-51.20%), respectively, for the high-pressure balloon group (P < .3 at each interval). CONCLUSIONS: Compared with high-pressure balloon angioplasty, cutting balloon angioplasty does not improve postinterventional primary patency of de novo stenotic lesions in autogenous arteriovenous fistulae. PMID- 26508449 TI - Effectiveness of Transarterial Embolization of Hepatocellular Carcinoma as a Bridge to Transplantation. AB - PURPOSE: To assess the effectiveness of bland transarterial embolization of hepatocellular carcinoma (HCC) as a "bridge" to transplantation. MATERIALS AND METHODS: In this retrospective study, 117 patients with HCC that met Milan criteria underwent bland embolization as their initial and sole therapy for treatment of HCC (88 men and 29 women; mean age, 60.4 y; range, 35-88 y). Subsequent postembolization contrast-enhanced computed tomography or magnetic resonance imaging studies were reviewed to determine whether Milan criteria were met in an intent-to-transplant analysis. Freedom from progression beyond Milan criteria and survival were calculated by Kaplan-Meier technique. Predictors of progression and survival were also assessed. RESULTS: After embolization, 87% and 78% of patients' disease still met Milan criteria at 6 and 12 months, respectively. The median time until disease progression beyond Milan criteria was 22.6 months (95% confidence interval, 16.2-29 mo). alpha-Fetoprotein levels, number of lesions, United Network for Organ Sharing stage, Model for End-stage Liver Disease score, and cirrhosis etiology did not correlate significantly with stability within Milan criteria. A total of 34 patients (29%) underwent eventual liver transplantation at a median of 3.3 months (range, 0.5-20.9 mo). Liver transplantation was a significant independent predictor of longer survival (6.9 y vs 2.6 y; P < .001). The major complication rate within 30 days of embolization was 2.6%, including one mortality. CONCLUSIONS: Bland transarterial embolization as a bridging strategy to maintain HCC within Milan criteria was successful in 78% of patients at 1 year, which compares favorably with other locoregional embolotherapies. PMID- 26508450 TI - Facilely assess the soluble behaviour of the beta-nucleating agent by gradient temperature field for the construction of heterogeneous crystalline-frameworks in iPP. AB - Nucleating agent (NA) species with solubility and self-assembly abilities can readily and effectively manipulate the crystalline morphology of semicrystalline polymers through the construction of heterogeneous frameworks prior to the primary crystallization of basal resins. However, the solubility of NA species is difficult to assess by the current traditional methods. In this study, gradient temperature field (g-T field) was utilized for the first time to ascertain the dissolution and self-assembly behaviors of beta-NA in the melts of isotactic polypropylene (iPP). The g-T field technique can facilely assess the soluble behavior of beta-NA by determining the transformation between several NA frameworks, namely the needle-, flower- and dendrite-like supramolecular structures. Clarifying the soluble behavior of beta-NA is of great significance to guide the formation of various crystalline frameworks under the homo temperature fields and control the resultant crystalline morphology of beta modified iPP. Some interesting findings are summarized as follows: (1) an in situ observation under the g-T field clearly indicates the sequential occurrence of various nucleation and crystallization events in the same observed window, and proves the migration of well molten beta-NA, (2) the exact correlation between Tf and framework type reveals that an abrupt transformation (over the narrow temperature range of 1 degrees C) occurred between needle-like and dendrite-like frameworks, (3) the primary crystallization of iPP is strongly dependent on the construction mode of the beta-NA framework. PMID- 26508451 TI - The "busy life" of unliganded estrogen receptors. AB - Understanding of the role of estrogen receptors (ERalpha and ERbeta) in the pathophysiology of breast cancer (BC) has considerably increased in last decades. Despite sharing a similar structure, these two transcription factors often exert opposite roles in BC. In addition, it has been shown that their transcriptional activity is not strictly associated to ligand activation and that unliganded ERs are able to "have a life on their own." This appears to be mainly due to ligand independent mechanisms leading to ERs PTMs or to their recruitment to specific protein complexes, dependent on cellular context. Furthermore, a significant unliganded ER activity, probably independent by the activation of other pathways, has been recently reported to affect gene transcription, microRNA expression, and downstream proteome. In this review, we describe recent findings on nuclear and cytoplasmic unliganded ERalpha and ERbeta activity. We focus on functional genomics, epigenomics, and interaction proteomics data, including PTM induced by ERs-modulated miRNAs in the BC context. A better comprehension of the molecular events controlled by unliganded ERs activity in BC pathogenesis is crucial since it may impact the therapeutic approach to the initial or acquired resistance to endocrine therapies, frequently experienced in the treatment of BC. PMID- 26508452 TI - Correlation between myeloid-derived suppressor cells and S100A8/A9 in tumor and autoimmune diseases. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that constitute an important component of immune regulatory system. Two calcium binding proteins S100A8 and S100A9 act as important mediators in acute and chronic inflammation. In recent years, many researchers have found that MDSCs and S100A8/A9 operated with one another through a positive feedback loop to promote tumor development and metastasis. However, the correlation between MDSCs and S100A8/A9 in autoimmune diseases (AIDs) remains unknown. In this review, we discussed the co-operation of MDSCs and S100A8/A9 in tumor environment, and also, the role of these two components in AIDs. PMID- 26508453 TI - Long-term evaluation of different strategies of cationic polyelectrolyte dosage to control fouling in a membrane bioreactor treating refinery effluent. AB - In this article, the long-term use of cationic polyelectrolyte to improve the sludge filterability and to control membrane fouling in bioreactor membrane while treating refinery effluents have been evaluated in pilot scale. Corrective and preventive cationic polyelectrolyte dosages have been added to the membrane bioreactor (MBR) to evaluate the membrane fouling mitigation in both strategies. The results have confirmed that the use of the Membrane performance enhancer (MPE) increased the sludge filterability and reduced the membrane fouling. During the monitoring period, stress events occurred due to the increase in oil and grease and phenol concentrations in the MBR feeds. The preventive use of cationic polyelectrolyte allowed for a more effective and stable sludge filterability, with lower cationic polyelectrolyte consumption and without decreasing MBR's overall pollutant removal performance. PMID- 26508454 TI - Links Among Cognitive Empathy, Theory of Mind, and Affective Perspective Taking by Young Children. AB - The authors investigated the development of the affective, cognitive, and behavioral components of empathy in preschoolers, specifically examining how cognitive empathy is linked to theory of mind and affective perspective taking. Participants were 158 children aged 4-6 years. They listened to narratives and then answered questions about the protagonists' emotions. The affective component was probed with the question, "How do you feel seeing the little girl/boy?"; the cognitive component with the question, "Why do you feel [emotion shared with the character]?"; and the behavioral one with the question, "What would you do if you were next to the little boy/girl [experiencing an emotional scenario]?" Results revealed a developmental sequence in the self-focused attribution of cognitive empathy, and a trend toward a developmental sequence for behavioral empathy, which underwent a slight linear increase between 4 and 6 years old. Affective empathy remained stable. More interestingly, they showed that cognitive empathy is linked to both theory of mind and affective perspective taking. PMID- 26508455 TI - Aortic rupture following an EVAR secondary to graft erosion. AB - Significant type 3 endoleak as a defect in the graft material, especially associated with endograft rupture, is a rare complication. A 68-year-old male patient with aortic plaque rupture was treated with endovascular graft placement. The patient was readmitted two years later with severe abdominal pain, a large retroperitoneal hematoma and contrast extravasation below the location where the aortic plaque had presented. Before an aortic infrarenal cuff could be placed during a control angiography, a large graft hole and a significant type 3 endoleak were observed. The sharp aortic plaque may have been responsible for the endograft tear. PMID- 26508456 TI - Assigning glycemic index to foods in a recent Australian food composition database. AB - This paper describes the compilation of a special edition of the AUSNUT2011-2013 food composition database that includes glycemic index (GI) values. A 6-step, systematic methodology was used to assign GI to 5644 foods included in AUSNUT2011 2013. A total of 1752 (31%) foods were assigned a GI of 0 owing to low carbohydrate content; 363 (6%) had a direct match in 1 of the 4 data tables used; 1738 (31%) were assigned the GI of a 'closely related' food item; 1526 (27%) were assigned the weighted mean GI of ingredients; 205 (4%) were assigned the median GI of their corresponding food subgroup; 49 (<1%) were assigned a GI of 0 because they were not a significant source of carbohydrate in typical diets; and 5 (<1%) were assigned a default GI. We propose that this database should be used for all future Australian GI research until a subsequent version/update is compiled. PMID- 26508457 TI - Prevalence of vitamin D deficiency and its association with nutrition, travelling and clothing habits in an immigrant population in Northern Sweden. AB - OBJECTIVES: To study prevalence and determinants of vitamin D deficiency in immigrants from Africa and the Middle East living in Umea, Sweden. DESIGN: Cross sectional population based. SETTING: Umea, Sweden (63 degrees N). SUBJECTS/METHODS: Immigrants aged 25-65 years from nine countries in Africa or the Middle East (n=1306) were invited. A total of 111 men and 106 women (16.5%) completed the study. S-25-hydroxyvitamin D3 was measured with HPLC. Anthropometry, medical, socioeconomic and lifestyle data were registered. RESULTS: Vitamin D status was insufficient or deficient in 73% of the participants. Specifically, 12% had vitamin D deficiency (25(OH)D3<25 nmol/l), and only 3.7% had optimal vitamin D status (25(OH)D3 75-125 nmol/l). Mean 25(OH)D3 level was 41.0 nmol/l (+/- 16.6) with no difference between sexes. Levels of 25(OH)D3 were lower (P=0.030) and vitamin D deficiency was twice as common in immigrants from Africa compared with those from the Middle East. In the multiple regression analysis, vitamin D deficiency was significantly associated with low fatty fish intake (OR 4.31, 95% CI 1.61-11.55), not travelling abroad (OR 3.76, 95% CI 1.18-11.96) and wearing long-sleeved clothes in summer (OR 3.15, 95% CI 1.09-9.12). CONCLUSIONS: The majority of immigrants from Africa and the Middle East who live in northern Sweden have vitamin D deficiency or insufficiency. Our results are consistent with sun exposure and a diet with high intake of fatty fish being most important in avoiding vitamin D deficiency. PMID- 26508458 TI - Changes in body weight and obesity status in German adults: results of seven population-based prospective studies. AB - BACKGROUND/OBJECTIVES: The objective of this study was to quantify body weight changes in German adult populations during the past decades. SUBJECTS/METHODS: Longitudinal analysis of seven cohort studies covering different age ranges between 18 and 83 years. Baseline examinations were between 1994 and 2007 and follow-up durations between 4.0 and 11.9 years. For each study, mean change in body weight per year and 10-year change in body mass index (BMI) classification were analyzed. For the middle age group of 45-64 years, meta-analysis was conducted to obtain an overall estimate for Germany. RESULTS: Among men weight gain was highest in the youngest participants and decreased with advancing age. Among women weight gain was on a stable high level among those younger than 45 years and decreased at older age. Within 10 years, 30-40% of middle-aged participants with normal baseline weight became pre-obese or obese and 20-25% of those with pre-obesity at baseline became obese, whereas >80% of persons who were obese at baseline remained obese over time. The estimated average weight change in adults aged 45-64 years was 0.25 (95% confidence interval (CI): 0.18-0.33) kg/year among men and 0.24 (0.17-0.30) kg/year among women. CONCLUSIONS: We could observe a moderate weight gain over the past years in German middle-aged populations of 0.25 kg/year. Obesity prevention needs to be targeted to specific subgroups in the population, especially to younger adults, who seem to be most vulnerable for gaining weight. Obesity intervention needs to be improved, as the majority of obese adults remained obese over time. PMID- 26508459 TI - The overweight: a rare presentation of celiac disease. AB - We describe the nutritional status of a cohort of celiac disease (CD) children at presentation and during follow-up on gluten-free diet (GFD). Two Italian centers (Rome and Bari) prospectively enrolled 445 biopsy-confirmed CD children, diagnosed between 2009 and 2013. Body Mass Index was used as a measure of nutritional status according to Italian growth charts of Cacciari. The overweight/obese subject was 7.8% at onset and did not significantly increase during follow-up (9.8% at final assessment). The prevalence of overweight/obesity was significantly higher among males than females. Furthermore, overweight/obesity children as compared with those with normal weight were significantly older and had significantly lower levels of tTG antibodies. This study shows that some CD children are obese/overweight at diagnosis; therefore, overweight/obesity can be considered a rare but a possible mode of CD presentation. Thus, CD diagnosis must be considered even in overweight/obese children where this diagnosis can be easily missed. PMID- 26508460 TI - Bone status measured by quantitative ultrasound: a comparison with DXA in Thai children. AB - BACKGROUND/OBJECTIVES: Quantitative ultrasound (QUS) is used to measure bone quality and is known to be safe, radiation free and relatively inexpensive compared with dual-energy X-ray absorptiometry (DXA) that is considered the gold standard for bone status assessments. However, there is no consensus regarding the validity of QUS for measuring bone status. The aim of this study was to compare QUS and DXA in assessing bone status in Thai children. SUBJECTS/METHODS: A total of 181 Thai children (90 boys and 91 girls) aged 6 to 12 years were recruited. Bone status was measured by two different techniques in terms of the speed of sound (SOS) using QUS and bone mineral density (BMD) using DXA. Calcium intake was assessed by 24 h diet recall. Pearson's correlation, kappa-statistic and Bland and Altman analysis were used to assess the agreement between the methods. RESULTS: There was no correlation between the two different techniques. Mean difference (s.d.) of the Z-scores of BMD and SOS was -0.61 (1.27) that was different from zero (P<0.05). Tertiles of Z-scores of BMD and QUS showed low agreement (kappa 0.022, P=0.677) and the limits of agreement in Bland and Altman statistics were wide. CONCLUSIONS: Although QUS is easy and convenient to use, the SOS measurements at the radius seem not appropriate for assessing bone quality status. PMID- 26508461 TI - The co-occurrence of anemia and cardiometabolic disease risk demonstrates sex specific sociodemographic patterning in an urbanizing rural region of southern India. AB - BACKGROUND/OBJECTIVES: To determine the extent and sociodemographic determinants of anemia, overweight, metabolic syndrome (MetS) and the co-occurrence of anemia with cardiometabolic disease risk factors among a cohort of Indian adults. SUBJECT/METHODS: Cross-sectional survey of adult men (n=3322) and nonpregnant women (n=2895) aged 18 years and older from the third wave of the Andhra Pradesh Children and Parents Study that assessed anemia, overweight based on body mass index, and prevalence of MetS based on abdominal obesity, hypertension and blood lipid and fasting glucose measures. We examined associations of education, wealth and urbanicity with these outcomes and their co-occurrence. RESULTS: The prevalence of anemia and overweight was 40% and 29% among women, respectively, and 10% and 25% among men (P<0.001), respectively, whereas the prevalence of MetS was the same across sexes (15%; P=0.55). The prevalence of concurrent anemia and overweight (9%), and anemia and MetS (4.5%) was highest among women. Household wealth was positively associated with overweight and MetS across sexes (P<0.05). Independent of household wealth, higher education was positively correlated with MetS among men (odds ratio (95% confidence interval): MetS: 1.4 (0.99, 2.0)) and negatively correlated with MetS among women (MetS: 0.54 (0.29, 0.99)). Similar sex-specific associations were observed for the co-occurrence of anemia with overweight and MetS. CONCLUSIONS: Women in this region of India may be particularly vulnerable to co-occurring anemia and cardiometabolic risk, and associated adverse health outcomes as the nutrition transition advances in India. PMID- 26508462 TI - Skipping breakfast in early childhood and its associations with maternal and child BMI: a study of 2-5-year-old Australian children. AB - BACKGROUND/OBJECTIVES: Evidence supporting the association between skipping breakfast and children's body mass index (BMI) has been widely reported, and some consideration has been given to children aged 2-5 years. However, no evidence has considered an association between children skipping breakfast and mother's BMI. This study therefore investigated associations between skipping breakfast, child's BMI and mother's BMI in a large cohort of Australian children. SUBJECTS/METHODS: Data were drawn from wave 2 (2-3 years, n=4601) and wave 3 (4-5 years, n=4381) of the Longitudinal Study of Australian Children. The primary outcome was skipping breakfast. Child's and mother's BMI was assessed by trained professionals. RESULTS: Girls at 4-5 years were significantly more likely to skip breakfast compared with boys (56.9% versus 43.1%; P=0.031). In cross-sectional data analysis, obese boys at 2-3 years (odds ratio (OR) 2.38; P=0.039) and at 4-5 years (OR 2.32; P=0.046), and also obese girls at 4-5 years (OR 2.26; P=0.018), were more likely to skip breakfast. Skipping breakfast was positively associated with boys at 2-3 years (OR 2.04; P=0.042) whose mothers were overweight and with girls at 4-5 years (OR 2.60; P=0.001) whose mothers were obese. In longitudinal cross-lagged analysis, boys at 2-3 years whose mothers were obese were more likely to skip breakfast 2 years later at age 4-5 years (OR 2.36; P=0.045). CONCLUSIONS: Skipping breakfast was associated with higher BMI in children and mothers. Future interventions should target obese mothers to promote breakfast intake among children. The interventions may involve changes to dietary and lifestyle habits and provision of education on the benefits of breakfast intake. PMID- 26508463 TI - Plasma acyl-ghrelin increases after meal initiation: a new insight. AB - BACKGROUND/OBJECTIVES: Plasma ghrelin secretion over time in humans is characterized by pre-prandial increases and by post-prandial decreases all day long. However, some authors who measured ghrelin concentrations around meals showed a rise in plasma ghrelin concentration after meal initiation followed by the typical post-prandial decrease. In order to confirm this observation that has never been discussed, we described ghrelin profiles around four eating episodes in the morning in adult men. SUBJECTS/METHODS: Twenty normal-weight and 17 obese men were instructed to eat four fixed meals (706 kJ) 10 min long at 0800 h, 0900 h, 1000 h and 1100 h. Using frequent blood sampling, we determined plasma acyl ghrelin concentrations around those eating episodes. Glucose, insulin and GLP-1 concentrations were also measured. RESULTS: The meals consumption induced a significant increase in plasma acyl-ghrelin concentrations 10 min after meal initiation (P<0.0001): +20.9+/-5.8 and +10.7+/-3.3 pg/ml in normal-weight and obese subjects for the first meal; +10.4+/-3.0 and +5.5+/-3.9 pg/ml in normal weight and obese subjects for the second meal; +12.4+/-3.6 and +4.2+/-2.1 pg/ml in normal-weight and obese subjects for the third meal; and +4.4+/-4.1 and +3.3+/ 2.61 pg/ml in normal-weight and obese subjects for the fourth meal. CONCLUSIONS: This study is the first to describe and discuss the post-meal initiation ghrelin increase. This finding is consistent in normal-weight and obese individuals. PMID- 26508464 TI - Gastrointestinal bleeding in patients receiving oral anticoagulation: Current treatment and pharmacological perspectives. AB - Gastrointestinal bleeding (GIB) is a potentially fatal and avoidable medical condition that poses a burden on global health care costs. The rate of major GIB related to the use of some direct acting oral anticoagulant drugs (DOACs), is higher than that detected in warfarin users. Current strategies in the treatment of GIBs in patients receiving warfarin or DOACs (vitamin K, activated charcoal; hemodialysis; recombinant factor VIIa; [activated] prothrombin complex concentrates) including indications for the treatment of bleeding based on different degrees of severity of the episodes, is reported in this article. Potential preventive strategies to mitigate the risk of GIBs (e.g. upper endoscopy/biopsy, colon cancer screening; eradication of Helicobacter pylori prior to starting anticoagulation; use of proton-pump inhibitors, identification of risk factors for bleeding) are also reported as well as the fact that some of them have not been tested so far in patients receiving DOACs. Antidotes that experimentally reverse the anti-coagulant effect of dabigatran (Idarucizumab; BI 655075; Boehringer Ingelheim); of rivaroxaban, apixaban, or edoxaban (Andexanet alfa, r-Antidote, PRT064445; Portola Pharmaceuticals) or of all DOACs (Aripazine, PER-977, ciraparantag; Perosphere Inc.) are discussed. Likewise, population pharmacokinetics modeling related to the rate of major DOACs-related GIBs is presented. It is also emphasized that the occurrence of GIB reflects the presence of patients at the highest risk for adverse outcomes. Finally, the implications of the concept that patient characteristics and the severity of illness (i.e. comorbidities) exert a greater impact on the risk of GIB than the type of antithrombotic agent employed, are analyzed. PMID- 26508465 TI - Warfarin treatment complications do not correlate to cTTR when above 70. AB - BACKGROUND: The mean time in target range for each centre, cTTR, has previously been shown to correlate to the rate of complications in poorly managed warfarin treatment. However less is known about the correlation when warfarin treatment is well managed. OBJECTIVES: The aim of this study was to examine the correlation between cTTR and the rate of complications in a real life setting with cTTR above 70%, with focus on patients with warfarin due to atrial fibrillation or secondary prevention of a VTE. PATIENTS/METHODS: In total 66,605 patients with 89,293 treatment periods, corresponding to 179,624 treatment years, with warfarin treatment due to VTE or AF between January 1st 2006 and December 31th 2011, was retrieved from the national quality register AuriculA. The cohort was matched with the National Patient Register in Sweden for complications and background characteristics. RESULTS: We found 172 centres and 68,797 treatment periods for AF and 166 centres and 20,496 treatment periods for VTE. Over 90% of the patients had a target range between INR 2-3. We found no correlation between increasing cTTR and reduction in the rate of complications for the AF patients. However, for VTE patients we saw a correlation between increasing cTTR and a reduced complication rate. CONCLUSIONS: Our results show that at very high cTTR levels, above 70%, further improvements in cTTR do not correlate to less treatment complications at least for patients with AF. PMID- 26508466 TI - In memoriam: Ephraim P. Engleman, MD, 1911-2015. PMID- 26508467 TI - Amended 95% confidence intervals in tables in the article by Jani et al (Arthritis Rheumatol, August 2015). PMID- 26508469 TI - Increased risk of brain tumor in patients with Parkinson's disease: a nationwide cohort study in Taiwan. AB - OBJECTIVES: Parkinson's disease (PD) is a neurodegenerative disease. A decreased risk of cancer, except for melanoma, has been observed in patients with PD. The aim of this study was to evaluate the association between brain tumor and PD in a Taiwanese population. MATERIALS AND METHODS: We used data from the National Health Insurance program of Taiwan. The PD cohort contained 2998 patients, and each patient was frequency-matched, based on age and sex, with 4 people without PD, who were randomly selected from the general population. Cox's proportional hazard regression analysis was conducted to estimate the effects of PD on the risk of brain tumor. RESULTS: The risk of developing brain tumor was significantly higher in patients with PD than in those without PD (adjusted hazard ratio = 2.11; 95% confidence interval (CI) = 1.24-3.59), and benign brain tumor exhibited a particularly elevated risk of 2.16-fold (95% CI = 1.26-3.68). The hazard ratio (HR) for developing a benign brain tumor was higher in female patients with PD than in female patients without PD, with the risk being 2.65 fold (95% CI = 1.30-5.43). An analysis of the two age groups, 50-64 years and >=65 years, showed that the HR of only the 50-64-year group was significantly higher between the PD and non-PD groups (HR = 2.77, 95% CI = 1.07-7.14). CONCLUSION: The present study showed that Taiwanese patients with PD are at a higher risk of developing brain tumor than the general population. The exact underlying etiologies require further investigation. PMID- 26508470 TI - Compressed porous graphene particles for use as supercapacitor electrodes with excellent volumetric performance. AB - This work presents a new class of porous graphene particles with a three dimensional microscale network and an ultrahigh specific surface area (2590 m(2) g(-1)), which is obtained by the KOH activation of a compact graphene hydrogel. As supercapacitor electrodes, such porous graphene particles show high compressibility and little capacitance loss when subjected to a compressive force up to 40 MPa, yielding an excellent volumetric performance with an ionic liquid electrolyte. Such carbon materials show great promise for applications needing high volumetric energy. PMID- 26508471 TI - Formation of bimetallic clusters in superfluid helium nanodroplets analysed by atomic resolution electron tomography. AB - Structure, shape and composition are the basic parameters responsible for properties of nanoscale materials, distinguishing them from their bulk counterparts. To reveal these in three dimensions at the nanoscale, electron tomography is a powerful tool. Advancing electron tomography to atomic resolution in an aberration-corrected transmission electron microscope remains challenging and has been demonstrated only a few times using strong constraints or extensive filtering. Here we demonstrate atomic resolution electron tomography on silver/gold core/shell nanoclusters grown in superfluid helium nanodroplets. We reveal morphology and composition of a cluster identifying gold- and silver-rich regions in three dimensions and we estimate atomic positions without using any prior information and with minimal filtering. The ability to get full three dimensional information down to the atomic scale allows understanding the growth and deposition process of the nanoclusters and demonstrates an approach that may be generally applicable to all types of nanoscale materials. PMID- 26508472 TI - Stability and reliability of glycated haemoglobin measurements in blood samples stored at -20 degrees C. AB - AIM: To validate the stability of glycated haemoglobin (HbA1c) measurements in blood samples stored at -20 degrees C for up to one month. METHODS: The study group comprised 142 type 2 diabetic subjects visiting a tertiary centre for diabetes at Chennai city in south India. The HbA1c assay was done on a fasting blood sample using the Bio-Rad Variant machine on Day 0 (day of blood sample collection). Several aliquots were stored at -20 degrees C and the assay was repeated on the 3rd, 7th, 15th, and 30th day after the sample collection. Bland Altman plots were constructed and variation in the HbA1c levels on the different days was compared with the day 0 level. RESULTS: The median differences between HbA1c levels measured on Day 0 and the 3rd, 7th, 15th, and 30th day after blood collection were 0.0%, 0.2%, 0.3% and 0.5% respectively. Bland-Altman plot analysis showed that the differences between the day '0' and the different time points tend to get larger with time, but these were not clinically significant. CONCLUSIONS: HbA1c levels are relatively stable up to 2weeks, if blood samples are stored at -20 degrees C. PMID- 26508473 TI - Polarized CD163+ tumor-associated macrophages are associated with increased angiogenesis and CXCL12 expression in gastric cancer. AB - PURPOSE: Tumor-associated macrophages (TAMs) play a significant role in tumor progression and angiogenesis. However, the prognostic value of TAMs in different histologic locations of gastric cancer (GC) is still unknown. We evaluated the distribution of TAMs in different histologic locations to investigate its importance in predicting prognosis and the relationship with angiogenesis and CXCL12 expression in GC. METHODS AND MATERIALS: The distribution of TAMs and microvessel density (MVD) in 113 GC samples were evaluated by immunohistochemical staining of CD163 and CD105, respectively. The extent of TAM distribution in the tumor was categorized into three groups: infiltrated TAMs in the tumor nest (TN), tumor stroma (TS) and invasive tumor margin (TM). The expression of CXCL12 in GC were evaluated by immunohistochemical staining of tissues from 88 GC samples. RESULTS: The increased CD163+ TAMs in TS and TM were closely correlated with tumor size, depth of invasion, TNM stage, lymph node metastasis, and lymphovascular invasion. TAMs in TN was not related with any clinicopathologic characteristics except histologic differentiation. The high infiltration of CD163+ TAMs in TS and TM were significantly correlated with poor overall survival. Regardless of location, CD163+ TAMs were significantly correlated with increased MVD. CXCL12 expression was significantly associated with increased CD163+ TAMs in TS and TM. CONCLUSIONS: TAMs in different histologic locations in GC were related to distinct aspects of tumor progression. CD163+ TAMs in TS and TM are associated with tumor progression and CXCL12 expression in GC. TAMs may be involved in tumor progression through the angiogenesis. PMID- 26508474 TI - Biogeographical role of the Kuroshio Current in the amphibious mudskipper Periophthalmus modestus indicated by mitochondrial DNA data. AB - Quaternary climatic cycles have influenced marine organisms' spatial distribution and population dynamics. This study aimed to elucidate the evolutionary influences of contemporary and glacial physical barriers on the population structure, demography and colonization history of the mudskipper (Periophthalmus modestus) based on a mitochondrial gene segment (ND5) from 131 individual fish sampled in the northwestern Pacific Ocean. The current Kuroshio Current and the glacial exposure of the Taiwan Strait appeared to have restricted migration among the South China Sea, coastal East China and Japan. However, genetic homogeneity (Nm>1) also suggested contemporary larval transportation by sea circulation between the East China Sea and the South China Sea or historical dispersal along the glacial exposed shoreline among China, Japan and the Ryukyu Islands. Evolutionary signals of the strengthened East Asian Summer Monsoon in the mid Pleistocene and regional difference in intertidal primary productions were indicated by a late-Pleistocene population expansion of P. modestus with a higher effective population size in the South China Sea than in the East China Sea. Furthermore, a potential colonization origin from the South China Sea was consistently inferred by different clues, including the populations' coalescence times, the ancestral haplotype distribution, the number of private haplotypes and species/genetic diversity. PMID- 26508475 TI - Antigenic sites on the HN domain of botulinum neurotoxin A stimulate protective antibody responses against active toxin. AB - Botulinum neurotoxins (BoNTs) are the most toxic substances known. BoNT intoxicates cells in a highly programmed fashion initiated by binding to the cell surface, internalization and enzymatic cleavage of substrate, thus, inhibiting synaptic exocytosis. Over the past two decades, immunological significance of BoNT/A C-terminal heavy chain (HC) and light chain (LC) domains were investigated extensively leading to important findings. In the current work, we explored the significance of BoNT/A heavy chain N-terminal (HN) region as a vaccine candidate. Mice were immunized with recombinant HN519-845 generating antibodies (Abs) that were found to be protective against lethal dose of BoNT/A. Immuno-dominant regions of HN519-845 were identified and individually investigated for antibody response along with synthetic peptides within those regions, using in vivo protection assays against BoNT/A. Results were confirmed by patch-clamp analysis where anti-HN antibodies were studied for the ability to block toxin-induced channel formation. This data strongly indicated that HN519-593 is an important region in generating protective antibodies and should be valuable in a vaccine design. These results are the first to describe and dissect the protective activity of the BoNT/A HN domain. PMID- 26508476 TI - Morphological distribution for cancer of the central nervous system from Cancer Incidence in Five Continents Vol. X. PMID- 26508477 TI - Progressive Saturation Improves the Encapsulation of Functional Proteins in Nanoscale Polymer Vesicles. AB - PURPOSE: To develop a technique that maximizes the encapsulation of functional proteins within neutrally charged, fully PEGylated and nanoscale polymer vesicles (i.e., polymersomes). METHODS: Three conventional vesicle formation methods were utilized for encapsulation of myoglobin (Mb) in polymersomes of varying size, PEG length, and membrane thickness. Mb concentrations were monitored by UV-Vis spectroscopy, inductively coupled plasma optical emission spectroscopy (ICP-OES) and by the bicinchoninic acid (BCA) assay. Suspensions were subject to protease treatment to differentiate the amounts of surface-associated vs. encapsulated Mb. Polymersome sizes and morphologies were monitored by dynamic light scattering (DLS) and by cryogenic transmission electron microscopy (cryo-TEM), respectively. Binding and release of oxygen were measured using a Hemeox analyzer. RESULTS: Using the established "thin-film rehydration" and "direct hydration" methods, Mb was found to be largely surface-associated with negligible aqueous encapsulation within polymersome suspensions. Through iterative optimization, a novel "progressive saturation" technique was developed that greatly increased the final concentrations of Mb (from < 0.5 to > 2.0 mg/mL in solution), the final weight ratio of Mb-to-polymer that could be reproducibly obtained (from < 1 to > 4 w/w% Mb/polymer), as well as the overall efficiency of Mb encapsulation (from < 5 to > 90%). Stable vesicle morphologies were verified by cryo-TEM; the suspensions also displayed no signs of aggregate formation for > 2 weeks as assessed by DLS. "Progressive saturation" was further utilized for the encapsulation of a variety of other proteins, ranging in size from 17 to 450 kDa. CONCLUSIONS: Compared to established vesicle formation methods, "progressive saturation" increases the quantities of functional proteins that may be encapsulated in nanoscale polymersomes. PMID- 26508478 TI - Sustained Pulmonary Delivery of a Water-Soluble Antibiotic Without Encapsulating Carriers. AB - PURPOSE: Traditional polymeric nanoparticle formulations for prolonged local action during inhalation therapy are highly susceptible to muco-ciliary clearance. In addition, polymeric carriers are typically administered in high doses due to finite drug loading. For toxicological reasons, these carriers and their degradation byproducts are undesirable for inhalation therapy, particularly for chronic use, due to potential lung accumulation. METHODS: We synthesized a novel, insoluble prodrug (MRPD) of a time-dependent beta-lactam, meropenem, and formulated MRPD into mucus-penetrating crystals (MRPD-MPCs). After characterizing their mucus mobility (in vitro) and stability, we evaluated the lung pharmacokinetics of intratracheally-instilled MRPD-MPCs and a meropenem solution in guinea pigs. RESULTS: Meropenem levels rapidly declined in the lungs of guinea pigs receiving meropenem solution compared to those given MRPD-MPCs. At 9 h after dosing, drug levels in the lungs of animals that received meropenem solution dropped to 12 ng/mL, whereas those that received MRPD-MPCs maintained an average drug level of >=1,065 ng/mL over a 12-h period. CONCLUSIONS: This work demonstrated that the combination of prodrug chemistry and mucus-penetrating platform created nanoparticles that produced sustained levels of meropenem in guinea pig lungs. This strategy represents a novel approach for sustained local drug delivery to the lung without using encapsulating matrices. PMID- 26508479 TI - Crystal structure of Staphylococcus aureus peptidyl-tRNA hydrolase at a 2.25 A resolution. AB - Peptidyl-tRNA hydrolase (Pth) catalyzes the release of tRNA to relieve peptidyl tRNA accumulation. Because Pth activity is essential for the viability of bacteria, Pth is regarded as a promising target for the discovery of new antimicrobial agents. Here, the structure of Pth from the Gram-positive bacterium Staphylococcus aureus (SaPth) was solved by X-ray crystallography at a 2.25 A resolution. The SaPth structure exhibits significant structural similarity with other members of the Pth superfamily, with a conserved alpha/beta/alpha sandwich fold. A molecular phylogenetic analysis and a structure database search indicated that SaPth is most similar to its homolog in Streptococcus pyogenes, but it has a different substrate-binding cleft state. PMID- 26508481 TI - Environmental Chemistry in Switzerland. PMID- 26508482 TI - Iron Biogeochemistry in Aquatic Systems: From Source to Bioavailability. AB - Iron (Fe) is an essential trace element for several key metabolic processes in phytoplankton; however Fe is present in low concentration in many aquatic systems including vast oceanic regions and large lakes. In these systems, Fe can limit the growth of phytoplankton and atmospheric carbon dioxide biological fixation. Indeed Fe limitation exerts a global impact on the carbon cycle and the imprint of aquatic systems on our climate. In order to understand how aquatic systems function and increase our ability to predict their response to changing conditions, it is therefore paramount to understand when and how Fe controls operate. This review presents the complex relationship between Fe chemistry and the biology of surface waters to highlight the parameters defining the forms of Fe that are accessible for phytoplankton growth (or bioavailable). Particular attention is given to the identification of Fe sources and Fe organic complexation as these, in conjunction with biological recycling and remineralisation, mostly control Fe residence time, chemistry and bioavailability. PMID- 26508480 TI - Targeting epigenetic regulations in cancer. AB - Epigenetic regulation of gene expression is a dynamic and reversible process with DNA methylation, histone modifications, and chromatin remodeling. Recently, groundbreaking studies have demonstrated the importance of DNA and chromatin regulatory proteins from different aspects, including stem cell, development, and tumor genesis. Abnormal epigenetic regulation is frequently associated with diseases and drugs targeting DNA methylation and histone acetylation have been approved for cancer therapy. Although the network of epigenetic regulation is more complex than people expect, new potential druggable chromatin-associated proteins are being discovered and tested for clinical application. Here we review the key proteins that mediate epigenetic regulations through DNA methylation, the acetylation and methylation of histones, and the reader proteins that bind to modified histones. We also discuss cancer associations and recent progress of pharmacological development of these proteins. PMID- 26508483 TI - Environmental Sensing of Aquatic Systems at the University of Geneva. AB - Aquatic environments are complex living systems where biological and chemical constituents change rapidly with time and space and may exhibit synergistic interactions. To understand these processes, the traditional approach based on a typically monthly collection of samples followed by laboratory analysis is not adequate. It must be replaced by high-resolution autonomous in situ detection approaches. In our group at the University of Geneva, we aim to develop and deploy chemical sensor probes to understand complex aquatic systems. Most research centers around electrochemical sensing approaches, which involves: stripping voltammetry at gel-coated microelectrode arrays for direct measurements of bioavailable essential or toxic trace metals; direct potentiometry for the measurement of nutrients and other species involved in the nitrogen and carbon cycles; online desalination for oceanic measurements; the development of robust measurement principles such as thin layer coulometry, and speciation analysis by tandem electrochemical detection with potentiometry and dynamic electrochemistry. These fundamental developments are combined with instrument design, both in-house and with external partners, and result in field deployments in partnership with environmental researchers in Switzerland and the European Union. PMID- 26508484 TI - The Use of Passive Samplers to Reveal Industrial and Agricultural Pollution Trends in Swiss Rivers. AB - This study shows the efficiency of passive sampling to reveal industrial and agricultural pollution trends. Two practical applications for nonpolar and polar contaminants are presented. Low-density polyethylene (LDPE) samplers were deployed for one year in the Venoge River (VD) to monitor indicator PCBs (iPCBs, IUPAC nos. 28, 52, 101, 138, 153 and 180). The results showed that the impact of PCB emissions into the river is higher in summer than in other seasons due to the low flow rate of the river during this period. Polar organic chemical integrative samplers (POCIS) were deployed for 4 months in the Sion-Riddes canal (VS) to investigate herbicides (terbuthylazine, diuron and linuron). Desisopropylatrazine d5 (DIA-d5) was tested as a performance reference compound (PRC) to estimate aqueous concentration. The results showed an increase of water contamination due to the studied agricultural area. The maximal contamination was observed in April and corresponds to the period of herbicide application on the crops. PMID- 26508485 TI - Manufactured Nanoparticle Behavior and Transformations in Aquatic Systems. Importance of Natural Organic Matter. AB - Major concerns to elucidate the fate of nanomaterials and manufactured nanoparticles in aquatic systems are related to the lack of data on nanoparticle transformations under relevant environmental conditions. The present article discusses some of the important physicochemical processes controlling the behavior of manufactured nanoparticles in aqueous systems by focusing on their interaction with natural organic matter, which is expected to play a crucial role when adsorbing at the nanoparticle surface. The precise knowledge and consequences of such adsorption processes are important not only to predict the nanoparticle stability and dispersion state but also to evaluate their chemical reactivity and ecotoxicology. Most importantly, findings indicate that the presence of natural organic matter, at typical environmental concentrations, can induce significant disagglomeration of large nanoparticle agglomerates into small fragments. Such a result constitutes an important outcome with regard to the risk associated with the possible transformation and redispersion of large assemblies containing manufactured nanoparticles. PMID- 26508486 TI - Isotope Effects as New Proxies for Organic Pollutant Transformation. AB - Assessing the pathways and rates of organic pollutant transformation in the environment is a major challenge due to co-occurring transport and degradation processes. Measuring changes of stable isotope ratios (e.g. (13)C/(12)C, (2)H/(1)H, (15)N/(14)N) in individual organic compounds by compound-specific isotope analysis (CSIA) makes it possible to identify degradation pathways without the explicit need to quantify pollutant concentration dynamics. The so called isotope fractionation observed in an organic pollutant is related to isotope effects of (bio)chemical reactions and enables one to characterize pollutant degradation even if multiple processes take place simultaneously. Here, we illustrate some principles of CSIA using benzotriazole, a frequently observed aquatic micropollutant, as example. We show subsequently how the combined C and N isotope fractionation analysis of nitroaromatic compounds reveals kinetics and mechanisms of reductive and oxidative reactions as well as their (bio)degradation pathways in the environment. PMID- 26508487 TI - Exploring the Behaviour of Emerging Contaminants in the Water Cycle using the Capabilities of High Resolution Mass Spectrometry. AB - To characterize a broad range of organic contaminants and their transformation products (TPs) as well as their loads, input pathways and fate in the water cycle, the Department of Environmental Chemistry (Uchem) at Eawag applies and develops high-performance liquid chromatography (LC) methods combined with high resolution tandem mass spectrometry (HRMS/MS). In this article, the background and state-of-the-art of LC-HRMS/MS for detection of i) known targets, ii) suspected compounds like TPs, and iii) unknown emerging compounds are introduced briefly. Examples for each approach are taken from recent research projects conducted within the department. These include the detection of trace organic contaminants and their TPs in wastewater, pesticides and their TPs in surface water, identification of new TPs in laboratory degradation studies and ozonation experiments and finally the screening for unknown compounds in the catchment of the river Rhine. PMID- 26508488 TI - Towards Mechanistic Understanding of Mercury Availability and Toxicity to Aquatic Primary Producers. AB - The present article reviews current knowledge and recent progress on the bioavailability and toxicity of mercury to aquatic primary producers. Mercury is a ubiquitous toxic trace element of global concern. At the base of the food web, primary producers are central for mercury incorporation into the food web. Here, the emphasis is on key, but still poorly understood, processes governing the interactions between mercury species and phytoplankton, and macrophytes, two representatives of primary producers. Mass transfer to biota surface, adsorption to cell wall, internalization and release from cells, as well as underlying toxicity mechanisms of both inorganic mercury and methylmercury are discussed critically. In addition, the intracellular distribution and transformation processes, their importance for mercury toxicity, species-sensitivity differences and trophic transfer are presented. The mini-review is illustrated with examples of our own research. PMID- 26508489 TI - Chemical Aspects of Nanoparticle Ecotoxicology. AB - Nanoecotoxicology strives to understand the processes and mechanisms by which engineered nanoparticles (ENP) may exert toxic effects on aquatic organisms. Detailed knowledge of the chemical reactions of nanoparticles in the media and of their interactions with organisms is required to understand these effects. The processes of agglomeration of nanoparticles, of dissolution and release of toxic metal ions, and of production of reactive oxygen species (ROS) are considered in this article. Important questions concern the role of uptake of nanoparticles in various organisms, in contrast to uptake of ions released from nanoparticles and to nanoparticle attachment to organism surfaces. These interactions are illustrated for effects of silver nanoparticles (AgNP), cerium oxide (CeO2 NP) and titanium dioxide (TiO2 NP), on aquatic organisms, including algae, biofilms, fish cells and fish embryos. PMID- 26508490 TI - Environmental Photochemistry of Amino Acids, Peptides and Proteins. AB - Amino acids, peptides and proteins are central building blocks of life and of key importance in the biogeochemistry of aquatic ecosystems. In sunlit surface waters, amino acid-based molecules at different levels of structural organization are susceptible to transformation by both direct photochemical reactions and indirect processes caused by photochemically produced reactive oxygen species (e.g. hydroxyl radical or singlet oxygen). Photochemical transformation processes can thereby affect the availability of these crucial nutrient sources in aquatic ecosystems, inhibit the function of microbial extracellular enzymes, or even promote the degradation of amino acid-based pollutant molecules. In this article, the environmental photochemistry of amino acids, peptides and proteins in aquatic systems is reviewed. PMID- 26508492 TI - Leveraging Liquid-Liquid Interfaces to Assemble Responsive Vesicles. PMID- 26508491 TI - A Close Look at the Fate of Compounds we are Exposed to. PMID- 26508495 TI - Focused Transesophageal Echocardiography by Emergency Physicians is Feasible and Clinically Influential: Observational Results from a Novel Ultrasound Program. AB - BACKGROUND: Emergency physicians frequently employ transthoracic echocardiography (TTE) to assist in diagnosis and therapy for patients with circulatory failure or arrest. In critically ill patients, transesophageal echocardiography (TEE) offers several advantages over TTE, including reliable, continuous image acquisition and superior image quality. Despite these advantages, TEE is not widely used by emergency physicians. OBJECTIVE: Report the feasibility, findings, and clinical influence observed from the first described TEE program implemented in an emergency department (ED) point-of-care ultrasound program. METHODS: This was a retrospective review of all ED TEE examinations carried out between February 1, 2013 and January 30, 2015. TEE images and report details (including operator, indication, findings, and clinical recommendation[s]) were exported from the institutional ultrasound archive and analyzed. The electronic chart of each patient was subsequently reviewed for the presence of any complications related to the examination and their clinical course in the hospital. RESULTS: A total of 54 TEE examinations were performed by 12 different emergency physicians. All patients were intubated, and 98% of the examinations were determinate. The most common indications for TEE were intracardiac arrest care in 23 (43%), postarrest management in 14 (26%), and undifferentiated hypotension in 16 (40%). Probe insertion was successful in all cases. TEE imparted a diagnostic influence in 78% of cases and impacted therapeutic decisions in 67% of cases. CONCLUSION: From our analysis of a single-center experience, ED-based TEE showed a high degree of feasibility and clinical utility, with a diagnostic and therapeutic influence seen in the majority of cases. Focused TEE demonstrated strongest uptake among intubated patients with either undifferentiated shock or cardiac arrest. PMID- 26508496 TI - Predictors of disease-specific quality of life after arthroscopic rotator cuff repair. AB - PURPOSE: Disease-specific instruments of quality of life (QOL) are more sensitive to disease-specific changes. The purpose of this study is to identify prognostic factors for disease-specific QOL after all-arthroscopic rotator cuff (RC) repair using the Western Ontario Rotator Cuff Index (WORC). METHODS: A total of 140 patients were evaluated after an RC repair with a mean follow-up of 22 +/- 6.7 months. Evaluations included the WORC, EQ-5D and anchor questions. Preoperative patient demographics and radiologic characteristics were assessed to identify predictors of disease-specific QOL. RESULTS: Most patients (81.4 %) were satisfied with their surgical result. Minor tear retraction (odds ratio [OR] 2.97, p = 0.030), male gender (OR 3.67, p = 0.003), no social benefits (OR 3.67, p = 0.042) and pre-surgical complaints for more than six months (OR 3.03, p = 0.021) were independent predictors for superior postoperative WORC score in multivariable analysis. None of these factors were predictive for a higher EQ-5D score. CONCLUSION: These findings highlight the important impact of retraction on QOL after RC repair and underline the utility of disease-specific instruments. Future studies should focus on how these significant predictors can be used to improve decision making and to develop new treatment approaches. PMID- 26508497 TI - Surgical treatment of hallux valgus associated with flexible flatfoot during growing age. AB - PURPOSE: During growth, hallux valgus could present associated with flatfoot. Considering the current disagreement about correction of hallux valgus during growth and the lack of reports about simultaneous correction of hallux valgus associated with flexible flatfoot, we present simultaneous treatment of both deformities during growth combining subtalar arthroeresis and SERI first metatarsal osteotomy, reporting results at an average five-year follow-up. METHODS: Thirty-two children (64 feet, age range 8-12 years) affected by hallux valgus associated with flexible flatfoot underwent surgical treatment combining SERI first metatarsal osteotomy and subtalar arthroereisis with bioabsorbable endorthotic implant. Clinical evaluation was summarized with AOFAS score, and standard standing radiographs were performed. RESULTS: AOFAS score ranged from 86 +/- 2 to 98 +/- 2 (hindfoot) and from 80 +/- 4 to 98 +/- 2 (forefoot). HVA ranged from 21 degrees +/- 2 to 5 degrees +/- 2, IMA from 14 degrees +/- 2 to 7 degrees +/- 2, DMAA from 18 degrees +/- 2 to 2 degrees +/- 2, and Meary's angle from 162 degrees +/- 11 to 175 degrees +/- 4. Complications included one case of delayed wound healing, inflammatory skin reaction around the outlet of the percutaneous Kirschner wire in two cases, displacement of the endorthotic implant in one case, and a second surgery to replace the implant. CONCLUSIONS: SERI osteotomy and subtalar arthroereisis resulted in an effective, technically simple and easily combined approach, with a high rate of good results and low rate of complications at mid-term follow-up. These techniques performed simultaneously represent a viable option in case of hallux valgus associated with flexible flatfoot during growth. Nevertheless, considering the limitations of this study, we believe that a larger case series and a longer follow-up should be desirable. PMID- 26508498 TI - A critical analysis of radiographic factors in patients who develop dislocation after elective primary total hip arthroplasty. AB - PURPOSE: In order to diminish total hip arthroplasty (THA) dislocation rate, surgeons strive to achieve adequate component orientation, offset and limb length. In addition, dislocation rate can theoretically be reduced by increasing head diameter and by choosing implants with favorable head-to-neck and cup-to head ratios. We assessed nine radiographic and implant-related parameters associated with an increased risk of dislocation in patients who sustained a dislocation and in those with a stable arthroplasty. METHODS: A total of 1,487 consecutive elective primary THAs performed by a single surgeon, using a posterolateral approach were reviewed at an average follow-up of 18 months (range, 1-112). Fixation was hybrid in 85 % of hips and non-cemented in 15 %. Thirty-eight patients (38 hips, 2.5 %) sustained at least one dislocation. Thirty seven patients with good quality, standardized anteroposterior radiographs were selected as a "study group". The study group was matched-paired (1:3) with patients who had a stable arthroplasty based on gender, age, BMI, diagnosis and follow-up. Variables compared between the groups included: head size, cup size, head-to-neck ratio, cup-to-head ratio, leg-length discrepancy, offset, cup inclination, cup version and cup orientation based on the safe zone defined by Lewinnek et al. RESULTS: None of the nine parameters showed a statistically significant difference between the groups. DISCUSSION: In this study, 90 % of patients who developed a dislocation had properly positioned acetabular components. In addition, the vast majority of patients in the study group had adequate restoration of limb length and offset. The results of our study may be useful for the orthopedic surgeons who discuss instability following THA surgery, particularly in patients with radiographically sound reconstructions. PMID- 26508499 TI - Snacks With Nutrition Labels: Tastiness Perception, Healthiness Perception, and Willingness to Pay by Norwegian Adolescents. AB - OBJECTIVE: Consumers tend to have the perception that healthy equals less tasty. This study aimed to identify whether information provided by the Keyhole symbol, a widely used front-of-package symbol in Nordic countries to indicate nutritional content, and percent daily values (%DVs) affect Norwegian adolescents' perception of the healthiness of snacks and their intention to buy them. DESIGN: Two tasks were used to evaluate adolescents' perception of snacks with the Keyhole symbol: with %DVs or with no nutrition label. A third task was used to test their abilities to use %DVs (pairwise selections). A survey obtained personal attributes. PARTICIPANTS: A total of 566 Norwegian adolescents. MAIN OUTCOME MEASURES: Taste perception, health perception, and ability to use %DVs. ANALYSIS: Linear mixed models and logistic models that tested effects of labels and personal attributes on main outcome measures. RESULTS: The Keyhole symbol increased health perception without influencing taste perception of snacks. Norwegian adolescents had limited abilities to use information from the %DVs correctly to identify healthier foods. CONCLUSIONS AND IMPLICATIONS: Norwegian adolescents had a positive perception of the Keyhole symbols. Keyhole symbols as a simple, heuristic front-of-package label have potential as an information strategy that may influence self-efficacy in promoting healthy snack choices among adolescents. PMID- 26508500 TI - Assessing the safety of outpatient ventral hernia repair: a NSQIP analysis of 7666 patients. AB - PURPOSE: Given the paucity of literature on outpatient ventral hernia repair (VHR), and that assessment of the safety of outpatient surgical procedures is becoming an active area of investigation, we have performed a multi-institutional retrospective analysis benchmarking rates of 30-day complications and readmissions and identifying predictive factors for these outcomes. METHODS: National surgical quality improvement project data files from 2011 to 2012 were reviewed to collect data on all patients undergoing outpatient VHR during that period. The incidence of 30-day peri-operative complication and unplanned readmission was surveyed. We created a multivariate regression model to identify predictive factors for overall, surgical, and medical complications and unplanned readmissions with proper risk adjustment. RESULTS: 30-day complication and readmission rates in outpatient VHR were acceptably low. 3% of the queried outpatients experienced an overall complication, 2.1% a surgical complication, and 1.1% a medical complication. 3.3% of all patients were readmitted within 30 days. Upon multivariate analysis, predictors of overall complications included age, BMI, history of Chronic Obstructive Pulmonary Disease (COPD), and total operation time, predictors of surgical complications included age, BMI, total operation time, predictors of medical complications included total operation time, and predictors of unplanned readmissions included history of COPD, bleeding disorder, American Society of Anesthesiologists Class 3, 4, or 5, total operation time, and use of the laparoscopic technique. CONCLUSION: We have demonstrated that the risk of peri-operative morbidity in VHR as granularly defined in our study is low in the outpatient setting. Identification of predictive factors will be important to patient risk stratification. PMID- 26508501 TI - Retrospective single-surgeon study of outcomes after laparoendoscopic single-site cholecystectomy and sigmoidectomy. AB - PURPOSE: Laparoendoscopic single-site (LESS) surgery is performed through a single port but requires a larger incision than conventional laparoscopy, which theoretically increases the risk of laparoscopic port hernia. Our primary objective is to determine the trocar site hernia rate among our patients. METHODS: This retrospective study is based on the analysis of demographic, intraoperative, and postoperative data of 219 patients who underwent cholecystectomy or sigmoidectomy by LESS surgery between December 1st, 2009 and November 30th, 2012. RESULTS: Cholecystectomy and sigmoidectomy LESS surgery were performed on 190 and 29 patients, respectively. Three patients developed a trocar site hernia within a median follow-up time of 34.7 months. Eleven patients were obese, 20 had a history of abdominal surgery, and 20 had a preoperative umbilical hernia but none of them developed a trocar site hernia, neither did the 11 subsequently pregnant women. Significant association was found between preoperative umbilical hernia and early complications including incisional cellulitis and hematoma. CONCLUSIONS: A rate of 1.4% of trocar site hernia was observed in our study population. This rate is similar to the one reported after conventional laparoscopy. Peri-umbilical incision, longer than that with conventional laparoscopy, allowed better preexisting hernia handling, made anatomical closing easier among obese patients, and facilitated specimen extraction thus limiting traumatic operations. PMID- 26508502 TI - Erythema multiforme caused by triple therapy with amoxicillin, clarithromycin and vonoprazan for Helicobacter pylori. PMID- 26508503 TI - Iguratimod in combination with methotrexate in active rheumatoid arthritis : Therapeutic effects. AB - BACKGROUND: Rheumatoid arthritis (RA) is a potentially destructive disease that may have a profound impact on patients' function and quality of life. RA therapy is still a challenge for rheumatologists; however, new antirheumatic drugs may be a treatment option for disease-modifying antirheumatic drug (DMARD)-experienced patients with active RA. OBJECTIVES: The present study is a prospective trial that aims to investigate the effects of therapy with iguratimod plus methotrexate (MTX) in comparison with iguratimod or MTX monotherapy in DMARD-experienced adult patients with active RA. METHODS: A total of 131 patients (24 men, 107 women, mean age 46.63 +/- 10.61 years) with a history of being treated with traditional DMARDs were investigated. In all, 44 patients were treated with iguratimod (25 mg, twice daily, orally) plus MTX (a weekly dose of 10 mg, orally), 38 patients received iguratimod (25 mg, twice daily, orally), or 49 patients received MTX (weekly dose of 10 mg, orally) for 24 weeks. RESULTS: A therapeutic effect with iguratimod was observed between 4 and 10 weeks after treatment initiation and was effective even in patients who had a poor response to previous treatment with DMARDs. The combination of iguratimod with MTX was superior to iguratimod or MTX monotherapy. CONCLUSION: The data imply that iguratimod is a welcome addition to the small-molecule drug therapy for DMARD-experienced patients with active RA. Iguratimod (alone or in combination with MTX) is an emerging option for the treatment of DMARD-experienced adult patients with active RA who have had an inadequate response to or are intolerant of other DMARDs. PMID- 26508504 TI - An observational study investigating the impact of simulated patients in teaching communication skills in preclinical dietetic students. AB - BACKGROUND: Simulated patients (SPs) are often used in dietetics for the teaching and assessment of communication skills. The present study aimed to determine the impact of a SP encounter on communication skills in undergraduate preclinical dietetic students in the context of the resources required for delivering this educational strategy. METHODS: This observational study collected assessment data from four cohorts of third-year dietetic students to examine the effect of participation in SP-embedded Objective Structured Clinical Exams. Students completed two SP interviews, 2 weeks apart, and communication skills were measured on both occasions. A subgroup of students received a video of their SP encounter. Differences between the two SP interview scores were compared to assess the impact of the SP encounter on communication skills. The required staff and resources were described. RESULTS: Data were collected involving 215 students. Out of 30 marks, there was a modest mean (SD) improvement in communication skills from the first to the second SP interview of 2.5 (4.2) (P < 0.01). There was an association between student ability and improvement in communication skills, with failing students demonstrating the greatest improvement between SP encounters. There were no observed benefits for the subset of students who received videos. CONCLUSIONS: Providing repeat SP interview opportunities results in only modest improvement in communication skills for most students. The use of SPs needs to be considered in context of the substantial costs and resources involved and tailored to student ability. PMID- 26508505 TI - Multicenter cross-sectional observational study of antibiotic resistance and the genotypes of Propionibacterium acnes isolated from Chinese patients with acne vulgaris. AB - Antibiotics are widely applied in management of acne vulgaris, which raises the issue of antibiotic resistance. Due to improper application and supervision of antibiotics, antibiotic resistance has become a serious problem in China. So, the efficacy of antimicrobial therapy in acne is unclear without an objective monitor of antibiotic resistance of Propionibacterium acnes. This cross-sectional, multicenter observational study is aimed at understanding the status of antibiotic resistance in P. acnes, investigating the measures of acne management in China and analyzing the genotypes of antibiotic-resistant strains of P. acnes. Altogether, 312 strains of P. acnes were collected from patients in five medical centers across central China after reviewing the corresponding medical history in detail. The samples underwent antibiotic susceptibility assays by agar dilution method with a total of 11 classes of antibiotics being tested. The antibiotic resistant strains were screened and further analyzed by investigation of the genotypes regarding 23S rRNA, 16S rRNA and erm(X). The predominant resistance occurred in macrolides and lincomycin with an overall resistance rate of 47.8%. The resistance to tetracyclines was scarce with only two cases identified. The emergence of minimum inhibitory concentration elevation for tetracyclines is associated with its application history (P < 0.005). The genotypes of the reported macrolide-lincosamide-streptogramin B resistance strains were also spotted in Chinese subjects while other resistance determinants may also exist. The tetracyclines have been proved to be vastly susceptible while macrolides and lincomycin face a serious resistance status in China. PMID- 26508506 TI - No evidence for adjustment of maternal investment under alternative mate availability regimes. AB - Using treatments that mimic high and low availability of reproductive males, it was found that female three-spined sticklebacks Gasterosteus aculeatus, previously shown to adjust their mate choices when male mates were rare, did not alter their reproductive investment strategies. These results suggest that plasticity in investment is perhaps limited by physiological requirements or dependent on relatively extreme mate availability regimes. The probability of becoming reproductive, number of clutches per season (per female), initial clutch size and mass and the timing of reproduction were all independent of the experience a female had with mate availability. This suggests that pre-copulatory plasticity in reproductive strategies may contribute more to variation in the strength and direction of sexual selection than reproductive investment in offspring. PMID- 26508507 TI - Role of the phosphatidylinositol-3-kinase/Akt/target of rapamycin pathway during ambidensovirus infection of insect cells. AB - The phosphatidylinositol-3-kinase (PI3K)/Akt/target of rapamycin (TOR) signalling pathway controls cell growth and survival, and is targeted by a number of viruses at different phases of their infection cycle to control translation. Whether and how insect viruses interact with this pathway remain poorly addressed. Here, we investigated the role of PI3K/Akt/TOR signalling during lethal infection of insect cells with an insect parvovirus. Using Junonia coenia densovirus (JcDV; lepidopteran ambidensovirus 1) and susceptible insect cells as experimental models, we first described JcDV cytopathology, and showed that viral infection affects cell size, cell proliferation and survival. We deciphered the role of PI3K/Akt/TOR signalling in the course of infection and found that non-structural (NS) protein expression correlates with the inhibition of TOR and the shutdown of cellular synthesis, concomitant with the burst of viral protein expression. Together, these results suggest that NS proteins control the cellular translational machinery to favour the translation of viral mRNAs at the expense of cellular mRNAs. As a consequence of TOR inhibition, cell autophagy is activated. These results highlight new functions for NS proteins in the course of multiplication of an insect parvovirus. PMID- 26508508 TI - Dual role of Helicobacter and Campylobacter species in IBD: a systematic review and meta-analysis. AB - OBJECTIVE: To conduct a comprehensive global systematic review and meta-analysis on the association between Helicobacter pylori infection and IBD. As bacterial antigen cross-reactivity has been postulated to be involved in this association, published data on enterohepatic Helicobacter spp (EHS) and Campylobacter spp and IBD was also analysed. DESIGN: Electronic databases were searched up to July 2015 for all case-control studies on H. pylori infection/EHS/Campylobacter spp and IBD. Pooled ORs (P-OR) and 95% CIs were obtained using the random effects model. Heterogeneity, sensitivity and stratified analyses were performed. RESULTS: Analyses comprising patients with Crohn's disease (CD), UC and IBD unclassified (IBDU), showed a consistent negative association between gastric H. pylori infection and IBD (P-OR: 0.43, p value <1e-10). This association appears to be stronger in patients with CD (P-OR: 0.38, p value <1e-10) and IBDU (P-OR: 0.43, p value=0.008) than UC (P-OR: 0.53, p value <1e-10). Stratification by age, ethnicity and medications showed significant results. In contrast to gastric H. pylori, non H. pylori-EHS (P-OR: 2.62, p value=0.001) and Campylobacter spp, in particular C. concisus (P-OR: 3.76, p value=0.006) and C. showae (P-OR: 2.39, p value=0.027), increase IBD risk. CONCLUSIONS: H. pylori infection is negatively associated with IBD regardless of ethnicity, age, H. pylori detection methods and previous use of aminosalicylates and corticosteroids. Antibiotics influenced the magnitude of this association. Closely related bacteria including EHS and Campylobacter spp increase the risk of IBD. These results infer that H. pylori might exert an immunomodulatory effect in IBD. PMID- 26508509 TI - Epidemiologic, Virologic, and Host Genetic Factors of Norovirus Outbreaks in Long term Care Facilities. AB - BACKGROUND: In the Unites States, long-term care facilities (LTCFs) are the most common setting for norovirus outbreaks. These outbreaks provide a unique opportunity to better characterize the viral and host characteristics of norovirus disease. METHODS: We enrolled 43 LTCFs prospectively to study the epidemiology, virology, and genetic host factors of naturally occurring norovirus outbreaks. Acute and convalescent stool, serum, and saliva samples from cases, exposed and nonexposed controls were collected. Norovirus infection was confirmed using quantitative polymerase chain reaction testing of stool samples or 4-fold increase in serum antibody titers. The presence of histo-blood group antigens (secretor, ABO, and Lewis type) was determined in saliva. RESULTS: Sixty-two cases, 34 exposed controls, and 18 nonexposed controls from 10 norovirus outbreaks were enrolled. Forty-six percent of acute, 27% of convalescent case, and 11% of control stool samples tested norovirus positive. Outbreak genotypes were GII.4 (Den Haag, n = 3; New Orleans, n = 4; and Sydney, n = 2) and GI.1 (n = 1). Viral load in GII.4 Sydney outbreaks was significantly higher than in outbreaks caused by other genotypes; cases and controls shed similar amounts of virus. Forty-seven percent of cases shed virus for >= 21 days. Symptomatic infections with GII.4 Den Haag and GII.4 New Orleans were detected among nonsecretor individuals. CONCLUSIONS: Almost half of all symptomatic individuals shed virus for at least 21 days. Viral load was highest in GII.4 viruses that most recently emerged; these viruses also infect the nonsecretor population. These findings will help to guide development of targeted prevention and control measures in the elderly. PMID- 26508510 TI - Host Genetic Susceptibility to Enteric Viruses: A Systematic Review and Metaanalysis. AB - BACKGROUND: Norovirus and rotavirus are prominent enteric viruses responsible for severe acute gastroenteritis disease burden around the world. Both viruses recognize and bind to histo-blood group antigens, which are expressed by the fucosyltransferase 2 (FUT2) gene. Individuals with a functional FUT2 gene are termed "secretors." FUT2 polymorphisms may influence viral binding patterns and, therefore, may influence host susceptibility to infection by these viruses. METHODS: We performed a systematic review of the published literature on this topic. Data were abstracted and compiled for descriptive analyses and metaanalyses. We estimated pooled odds ratios (ORs) for infection using random effects models. RESULTS: We found that secretors were 9.9 times (95% confidence interval [CI], 3.9-24.8) as likely to be infected with genogroup II.4 noroviruses and 2.2 times as likely to be infected with genogroup II non-4 noroviruses (95% CI, 1.2-4.2) compared with nonsecretors. Secretors were also 26.6 times more susceptible to infections from P[8]-type rotaviruses compared with nonsecretors (95% CI, 8.3-85.0). CONCLUSIONS: Our analyses indicate that host genetic susceptibility to norovirus and rotavirus infection may be strain specific. As strain distribution and the proportion of genetic phenotypes vary in different countries, future studies should focus on differences in susceptibility among various ethnicities. Knowledge of innate susceptibility to rotavirus and norovirus can lead to improved understanding of both vaccine performance and individual risk of disease. PMID- 26508511 TI - Reply to Merli et al. PMID- 26508512 TI - Costs per Diagnosis of Acute HIV Infection in Community-based Screening Strategies: A Comparative Analysis of Four Screening Algorithms. AB - BACKGROUND: In nonhealthcare settings, widespread screening for acute human immunodeficiency virus (HIV) infection (AHI) is limited by cost and decision algorithms to better prioritize use of resources. Comparative cost analyses for available strategies are lacking. METHODS: To determine cost-effectiveness of community-based testing strategies, we evaluated annual costs of 3 algorithms that detect AHI based on HIV nucleic acid amplification testing (EarlyTest algorithm) or on HIV p24 antigen (Ag) detection via Architect (Architect algorithm) or Determine (Determine algorithm) as well as 1 algorithm that relies on HIV antibody testing alone (Antibody algorithm). The cost model used data on men who have sex with men (MSM) undergoing community-based AHI screening in San Diego, California. Incremental cost-effectiveness ratios (ICERs) per diagnosis of AHI were calculated for programs with HIV prevalence rates between 0.1% and 2.9%. RESULTS: Among MSM in San Diego, EarlyTest was cost-savings (ie, ICERs per AHI diagnosis less than $13.000) when compared with the 3 other algorithms. Cost analyses relative to regional HIV prevalence showed that EarlyTest was cost effective (ie, ICERs less than $69.547) for similar populations of MSM with an HIV prevalence rate >0.4%; Architect was the second best alternative for HIV prevalence rates >0.6%. CONCLUSIONS: Identification of AHI by the dual EarlyTest screening algorithm is likely to be cost-effective not only among at-risk MSM in San Diego but also among similar populations of MSM with HIV prevalence rates >0.4%. PMID- 26508513 TI - Impact of Sex on the Pharmacokinetics and Pharmacodynamics of 1% Tenofovir Gel. AB - BACKGROUND: Tenofovir (TFV) gel partially protected against human immunodeficiency virus (HIV) in one but not subsequent trials. The disappointing results were attributed largely to poor adherence. However, timing of gel application relative to sex may impact pharmacokinetics and contribute to outcomes. Thus, we conducted a single-dose pharmacokinetic study of TFV gel applied 1 or 24 hours before or 1 hour before and 1 hour after (BAT) sex and compared results with dosing without sex. METHODS: Twenty-four couples were enrolled; cervicovaginal lavage (CVL) and tissue were collected 2 hours after sex with matching timed collections at no sex visits and assayed for drug concentrations and CVL anti-HIV activity. RESULTS: Compared with dosing without sex, median TFV concentrations after sex decreased 72% and 78% (P < .001) in CVL, 75% and 71% (P < .001) in vaginal tissue, and 75% (P = .06) and 55% (P < .001) in cervical tissue with -1 hour and -24 hour dosing, respectively. Median concentration of TFV-diphosphate also decreased significantly in cervical tissue with -1 hour, dosing. BAT dosing resulted in drug levels at least as great as those in the absence of sex. Percent inhibition of HIV infection by post-coital CVL increased significantly from median (interquartile range) of 55% (54%) in the absence of gel to 99% (7%), 77% (57%), and 100% (0.4%) with -1 hour, -24 hour, or BAT dosing, respectively, and correlated significantly with drug concentration. CONCLUSIONS: Timing of TFV gel application relative to sex significantly impacts drug levels. BAT dosing or sustained delivery may be optimal for preexposure prophylaxis. PMID- 26508514 TI - Marked Decrease in Lymphocyte Count in HIV/Hepatitis C Virus (HCV)-Coinfected Patients With Advanced Liver Disease During Anti-HCV Treatment With Direct-Acting Antiviral Regimens Including Ribavirin. PMID- 26508516 TI - Nondestructive detection of lead chrome green in tea by Raman spectroscopy. AB - Raman spectroscopy was first adopted for rapid detecting a hazardous substance of lead chrome green in tea, which was illegally added to tea to disguise as high quality. 160 samples of tea infusion with different concentrations of lead chrome green were prepared for Raman spectra acquirement in the range of 2804 cm(-1)-230 cm(-1) and the spectral intensities were calibrated with relative intensity standards. Then wavelet transformation (WT) was adopted to extract information in different time and frequency domains from Raman spectra, and the low-frequency approximation signal (ca4) was proved as the most important information for establishment of lead chrome green measurement model, and the corresponding partial least squares (PLS) regression model obtained good performance in prediction with Rp and RMSEP of 0.936 and 0.803, respectively. To further explore the important wavenumbers closely related to lead chrome green, successive projections algorithm (SPA) was proposed. Finally, 8 characteristic wavenumbers closely related to lead chrome green were obtained and a more convenient and fast model was also developed. These results proved the feasibility of Raman spectroscopy for nondestructive detection of lead chrome green in tea quality control. PMID- 26508515 TI - Multidrug-Resistant Tuberculosis Treatment Outcomes in Relation to Treatment and Initial Versus Acquired Second-Line Drug Resistance. AB - BACKGROUND: Resistance to second-line drugs develops during treatment of multidrug-resistant (MDR) tuberculosis, but the impact on treatment outcome has not been determined. METHODS: Patients with MDR tuberculosis starting second-line drug treatment were enrolled in a prospective cohort study. Sputum cultures were analyzed at a central reference laboratory. We compared subjects with successful and poor treatment outcomes in terms of (1) initial and acquired resistance to fluoroquinolones and second-line injectable drugs (SLIs) and (2) treatment regimens. RESULTS: Of 1244 patients with MDR tuberculosis, 973 (78.2%) had known outcomes and 232 (18.6%) were lost to follow-up. Among those with known outcomes, treatment succeeded in 85.8% with plain MDR tuberculosis, 69.7% with initial resistance to either a fluoroquinolone or an SLI, 37.5% with acquired resistance to a fluoroquinolone or SLI, 29.3% with initial and 13.0% with acquired extensively drug-resistant tuberculosis (P < .001 for trend). In contrast, among those with known outcomes, treatment success increased stepwise from 41.6% to 92.3% as the number of drugs proven effective increased from <=1 to >=5 (P < .001 for trend), while acquired drug resistance decreased from 12% to 16% range, depending on the drug, down to 0%-2% (P < .001 for trend). In multivariable analysis, the adjusted odds of treatment success decreased 0.62-fold (95% confidence interval, .56-.69) for each increment in drug resistance and increased 2.1-fold (1.40-3.18) for each additional effective drug, controlling for differences between programs and patients. Specific treatment, patient, and program variables were also associated with treatment outcome. CONCLUSIONS: Increasing drug resistance was associated in a logical stepwise manner with poor treatment outcomes. Acquired resistance was worse than initial resistance to the same drugs. Increasing numbers of effective drugs, specific drugs, and specific program characteristics were associated with better outcomes and less acquired resistance. PMID- 26508517 TI - Prevalence and predictors of culprit plaque rupture at OCT in patients with coronary artery disease: a meta-analysis. AB - AIMS: The prevalence of plaque rupture at the culprit lesion identified by optical coherence tomography (OCT) in different clinical subset of patients undergoing coronary angiography and its clinical predictors remain to be defined. METHODS: All studies including patients with OCT evaluation of the culprit coronary plaque were included. The prevalence of culprit plaque rupture (CPR) and thin-cap fibro-atheroma (TCFA) were the primary endpoints. The factors associated with these findings were studied in a subset of patients with different clinical presentations [ST-elevation myocardial (STEMI) vs. nonST-elevation myocardial infarction (NSTEMI) vs. unstable angina (UA) vs. stable angina pectoris (SAP)]. RESULTS: One hundred and fifty citations were initially appraised at the abstract level and 23 full-text studies were assessed. The mean prevalence of CPR and TCFA was 48.1% (40.5-55.8) and 48.7% (37.4-60.1), respectively. The prevalence of CPR and TCFA were higher in STEMI (70.4 and 76.6%) than in NSTEMI (55.6 and 56.3%) and UA (39.1 and 52.9%) or SAP (6.2 and 22.8%). In the overall population at meta regression analysis, TCFA and current smoking were the only predictors of CPR (B 3.6:2.0-5.1, P < 0.001 and 0.06:0.02-0.1, P = 0.002, respectively). The factors associated with CPR were different depending on clinical presentation. Hypertension was the only clinical predictor for STEMI (B 3.3: 1.2.-5.3 P = 0.001), while advanced age (B 0.12: 0.02-0.22, P = 0.021), diabetes mellitus (B 0.04: 0.01-0.08, P = 0.012), and hyperlipidaemia (B 0.07:0.02-0.11, P = 0.005) were the predictors in NSTEMI and UA. No clinical predictor was found in SA. CONCLUSIONS: Our analysis showed high rates of CPR and TCFA detected by OCT in CAD patients, especially in those with ACS, although their prevalence is not negligible in stable patients. TCFA seems to be a strong predictor of CPR in all the ACS scenarios. PMID- 26508518 TI - Liberalising agricultural policy for sugar in Europe risks damaging public health. PMID- 26508519 TI - Anti-rheumatoid arthritic effects of Saussurea involucrata on type II collagen induced arthritis in rats. AB - Saussurea involucrata (SI) has long been used under the herbal name "snow lotus" for treatment of inflammation and pain-related diseases in traditional Chinese medicine. The present study aimed to evaluate the pharmacological effects of SI on collagen II (CII)-induced arthritis in rats. Rats with collagen II (CII) induced arthritis were orally administered SI (420 mg kg(-1)) for 40 consecutive days. Histopathological examination indicated that SI alleviates infiltration of inflammatory cells and synovial hyperplasia and slows joint destruction. SI intervention reduced the serum levels of RF, COMP, CRP and anti-CII IgG. Results also showed that SI is a potential therapeutic agent for alleviating the severity of the disease based on the reduced arthritic index. It was concluded that SI can ameliorate inflammation and joint destruction in CIA rats. PMID- 26508520 TI - PtoMYB92 is a Transcriptional Activator of the Lignin Biosynthetic Pathway During Secondary Cell Wall Formation in Populus tomentosa. AB - Wood is the most abundant biomass in perennial woody plants and is mainly made up of secondary cell wall. R2R3-MYB transcription factors are important regulators of secondary wall biosynthesis in plants. In this study, we describe the identification and characterization of a poplar MYB transcription factor PtoMYB92, a homolog of Arabidopsis MYB42 and MYB85, which is involved in the regulation of secondary cell wall biosynthesis. PtoMYB92 is specifically expressed in xylem tissue in poplar. Subcellular localization and transcriptional activation analysis suggest that PtoMYB92 is a nuclear-localized transcriptional activator. Overexpression of PtoMYB92 in poplar resulted in an increase in secondary cell wall thickness in stems and ectopic deposition of lignin in leaves. Quantitative real-time PCR showed that PtoMYB92 specifically activated the expression of lignin biosynthetic genes. Furthermore, transient expression assays using a beta-glucuronidase (GUS) reporter gene revealed that PtoMYB92 is an activator in the lignin biosynthetic pathway during secondary cell wall formation. Taken together, our results suggest that PtoMYB92 is involved in the regulation of secondary cell wall formation in poplar by controlling the biosynthesis of monolignols. PMID- 26508521 TI - Growth Properties and Biomass Production in the Hybrid C4 Crop Sorghum bicolor. AB - Hybrid vigor (heterosis) has been used as a breeding technique for crop improvement to achieve enhanced biomass production, but the physiological mechanisms underlying heterosis remain poorly understood. In this study, to find a clue to the enhancement of biomass production by heterosis, we systemically evaluated the effect of heterosis on the growth rate and photosynthetic efficiency in sorghum hybrid [Sorghum bicolor (L.) Moench cv. Tentaka] and its parental lines (restorer line and maintainer line). The final biomass of Tentaka was 10-14 times greater than that of the parental lines grown in an experimental field, but the relative growth rate during the vegetative growth stage did not differ. Tentaka exhibited a relatively enlarged leaf area with lower leaf nitrogen content per leaf area (Narea). When the plants were grown hydroponically at different N levels, daily CO2 assimilation per leaf area (A) increased with Narea, and the ratio of A to Narea (N-use efficiency) was higher in the plants grown at low N levels but not different between Tentaka and the parental lines. The relationships between the CO2 assimilation rate, the amounts of photosynthetic enzymes, including ribulose-1,5-bisphosphate carboxylase/oxygenase, phosphoenolpyruvate carboxylase and pyruvate phosphate dikinase, Chl and Narea did not differ between Tentaka and the parental lines. Thus, Tentaka tended to exhibit enlargement of leaf area with lower N content, leading to a higher N-use efficiency for CO2 assimilation, but the photosynthetic properties did not differ. The greater biomass in Tentaka was mainly due to the prolonged vegetative growth period. PMID- 26508522 TI - GmCOL1a and GmCOL1b Function as Flowering Repressors in Soybean Under Long-Day Conditions. AB - CONSTANS (CO) has a central role in the photoperiod response mechanism in Arabidopsis. However, the functions of legume CO genes in controlling flowering remain unknown. Here, we analyze the expression patterns of E1, E2 and GmCOL1a/1b using near-isogenic lines (NILs), and we further analyze flowering-related genes in gmcol1b mutants and GmCOL1a-overexpressing plants. Our data showed that both E3 and E4 up-regulate E1 expression, with the effect of E3 on E1 being greater than the effect of E4 on E1. E2 was up-regulated by E3 and E4 but down-regulated by E1. GmCOL1a/1b were up-regulated by E1, E2, E3 and E4. Although the spatial and temporal patterns of GmCOL1a/1b expression were more similar to those of AtCOL2 than to those of AtCO, gmcol1b mutants flowered earlier than wild-type plants under long-day (LD) conditions, and the overexpression of GmCOL1a caused late flowering under LD or natural conditions. In addition, GmFT2a/5a, E1 and E2 were down-regulated in GmCOL1a-overexpressing plants under LD conditions. Because E1/2 influences the expression of GmCOL1a, and vice versa, we conclude that these genes may function as part of a negative feedback loop, and GmCOL1a/b genes may serve as suppressors in photoperiodic flowering in soybean under LD conditions. PMID- 26508523 TI - A-Raf: A new star of the family of raf kinases. AB - The Ras-Raf-MEK-MAPK (mitogen-activated protein kinase)-signaling pathway plays a key role in the regulation of many cellular functions, including cell proliferation, differentiation and transformation, by transmitting signals from membrane receptors to various cytoplasmic and nuclear targets. One of the key components of this pathway is the serine/threonine protein kinase, Raf. The Raf family kinases (A-Raf, B-Raf and C-Raf) have been intensively studied since being identified in the early 1980s as retroviral oncogenes, especially with respect to the discovery of activating mutations of B-Raf in a large number of tumors which led to intensified efforts to develop drugs targeting Raf kinases. This also resulted in a rapid increase in our knowledge of the biological functions of the B-Raf and C-Raf isoforms, which may in turn be contrasted with the little that is known about A-Raf. The biological functions of A-Raf remain mysterious, although it appears to share some of the basic properties of the other two isoforms. Recently, emerging evidence has begun to reveal the functions of A-Raf, of which some are kinase-independent. These include the inhibition of apoptosis by binding to MST2, acting as safeguard against oncogenic transformation by suppressing extracellular signal-regulated kinases (ERK) activation and playing a role in resistance to Raf inhibitors. In this review, we discuss the regulation of A-Raf protein expression, and the roles of A-Raf in apoptosis and cancer, with a special focus on its role in resistance to Raf inhibitors. We also describe the scaffold functions of A-Raf and summarize the unexpected complexity of Raf signaling. PMID- 26508524 TI - Nanoscale characterization of the thermal interface resistance of a heat-sink composite material by in situ TEM. AB - We developed an original method of in situ nanoscale characterization of thermal resistance utilizing a high-resolution transmission electron microscope (HRTEM). The focused electron beam of the HRTEM was used as a contact-free heat source and a piezo-movable nanothermocouple was developed as a thermal detector. This method has a high flexibility of supplying thermal-flux directions for nano/microscale thermal conductivity analysis, and is a powerful way to probe the thermal properties of complex or composite materials. Using this method we performed reproducible measurements of electron beam-induced temperature changes in pre selected sections of a heat-sink alpha-Al(2)O(3)/epoxy-based resin composite. Observed linear behavior of the temperature change in a filler reveals that Fourier's law holds even at such a mesoscopic scale. In addition, we successfully determined the thermal resistance of the nanoscale interfaces between neighboring alpha-Al(2)O(3) fillers to be 1.16 * 10(-8) m(2)K W(-1), which is 35 times larger than that of the fillers themselves. This method that we have discovered enables evaluation of thermal resistivity of composites on the nanoscale, combined with the ultimate spatial localization and resolution sample analysis capabilities that TEM entails. PMID- 26508525 TI - Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature. AB - PURPOSE: To investigate the effect of prolonged glucocorticoid treatment for patients with acute respiratory distress syndrome (ARDS). METHODS: We conducted two sets of intention-to-treat analyses: (1) a primary analysis of individual patients' data (IPD) of four randomized controlled trials (RCTs) which investigated methylprednisolone treatment (n = 322) and (2) a trial-level meta analysis incorporating four additional RCTs which investigated hydrocortisone treatment in early ARDS (n = 297). We standardized definitions to derive outcomes in all datasets. The primary outcome for the IPD analysis was time to achieving unassisted breathing (UAB) by study day 28. Secondary outcomes included mechanical ventilation (MV) and intensive care unit (ICU)-free days, hospital mortality, and time to hospital mortality by day 28. RESULTS: By study day 28, compared to the placebo group, the methylprednisolone group had fewer patients who died before achieving UAB (12 vs. 29 %; p < 0.001) and more patients who achieved UAB (80 vs. 50 %; p < 0.001). In the methylprednisolone group, time to achieving UAB was shorter [hazard ratio 2.59, 95 % confidence interval (CI) 1.95 3.43; p < 0.001], and hospital mortality was decreased (20 vs. 33 %; p = 0.006), leading to increased MV (13.3 +/- 11.8 vs. 7.6 +/- 5.7; p < 0.001) and ICU-free days (10.8 +/- 0.71 vs. 6.4 +/- 0.85; p < 0.001). In those patients randomized before day 14 of ARDS onset, the trial-level meta-analysis indicated decreased hospital mortality (36 vs. 49 %; risk ratio 0.76, 95 % CI 0.59-0.98, I (2) = 17 %, p = 0.035; moderate certainty). Treatment was not associated with increased risk for infections (risk ratio 0.77, 95 % CI 0.56-1.08, I (2) = 26 %; p = 0.13; moderate certainty). CONCLUSIONS: Prolonged methylprednisolone treatment accelerates the resolution of ARDS, improving a broad spectrum of interrelated clinical outcomes and decreasing hospital mortality and healthcare utilization. PMID- 26508526 TI - Extent of alcohol prohibition in civil policy in Muslim majority countries: the impact of globalization. AB - BACKGROUND AND AIMS: Many policies have been introduced to reduce alcohol harm in different countries. However, Muslim majority countries (MMCs), where the major religion (Islam) prohibits alcohol consumption, have less well-developed civil alcohol policies. Overall, MMCs have low prevalence of alcohol consumption, although recently most MMCs have been undergoing transition, which has sometimes increased pressure for alcohol availability and impacted on social practices, alcohol policies and broader public health. Globalization, the influence of the global alcohol industry, recent governmental transition or political instability and the presence of immigrants from non-Muslim countries can all affect civil alcohol policy. In this context, consumption overall has increased compared with two decades ago. This paper presents an overview of current civil alcohol policy, with regard to the presence or absence of alcohol prohibition, and provides an insight into the legal availability of alcohol in MMCs and the challenges facing policymakers. METHODS: English, Arabic and Persian language sources were examined, using PubMed, government websites for each country and the World Health Organization (WHO). Some of the challenges MMCs may face in developing alcohol policies are explored, including the need to interact with the global economy and the potential influence of the alcohol industry. CONCLUSION: Muslim majority countries have adopted a range of civil alcohol policies in recent decades. There is a pressing need for better data and to support Muslim majority countries in alcohol policy development. Lessons from Muslim majority countries can help to inform other parts of the world. PMID- 26508528 TI - The Importance of Interdisciplinary Research Training and Community Dissemination. AB - Funding agencies and institutions are creating initiatives to encourage interdisciplinary research that can be more easily translated into community initiatives to enhance health. Therefore, the current research environment calls for interdisciplinary education and skills to create sustained partnerships with community institutions. However, formalized opportunities in both of these areas are limited for students embarking on research careers. The purpose of this paper is to underscore the historical and current importance of providing interdisciplinary training and community dissemination for research students. We also suggest an approach to begin to address the existing gap. Specifically, we suggest embedding a 10-week summer rotation into existing research curricula with the goals of: (1) providing students with a hands-on interdisciplinary research experience, (2) facilitating dialogue between research students and community settings to disseminate science to the public, and (3) sparking collaborations among researchers who seek to create a way to sustain summer program rotations with grant funding. PMID- 26508529 TI - The Moderating Role of Attachment on the Relationship Between History of Trauma and Intimate Partner Violence Victimization. AB - Exposure to trauma is a well-established predictor of intimate partner violence (IPV), although this relationship is not causal. The current study hypothesized that attachment-based anxiety moderated the relationship between trauma history and IPV revictimization in a sample of women who had reported IPV victimization 1 year earlier. Results confirmed the following hypotheses: When attachment-based anxiety was high, trauma history was positively associated with IPV victimization and use of violence. When attachment-based anxiety was low, trauma history was no longer positively associated with IPV victimization or use of violence. Secure attachments may protect female victims of IPV from the impact of trauma. PMID- 26508530 TI - Measuring Economic Abuse in the Lives of Survivors: Revising the Scale of Economic Abuse. AB - Recent attention has been given by researchers to understanding how abusers use economic abuse strategies. Unfortunately, limited measures are available to accurately understand the prevalence of economic abuse in the lives of survivors. Recently, researchers created the 28-item Scale of Economic Abuse (SEA) but further validation is needed. This article describes the psychometric evaluation of the SEA through confirmatory and exploratory factor analyses using data collected with 120 survivors of abuse. The findings provide evidence for the reliability and validity of the SEA-12 as a shorter instrument to measure economic abuse as a distinct form of abuse. PMID- 26508531 TI - A new injury prevention programme for children's football--FIFA 11+ Kids--can improve motor performance: a cluster-randomised controlled trial. AB - The present study evaluated the effects of a newly developed injury prevention programme for children's football ("FIFA 11+ Kids") on motor performance in 7-12 year-old children. We stratified 12 football teams (under-9/-11/-13 age categories) into intervention (INT, N = 56 players) and control groups (CON, N = 67). INT conducted the 15-min warm-up programme "FIFA 11+ Kids" twice a week for 10 weeks. CON followed a standard warm-up (sham treatment). Pre- and post-tests were conducted using: single leg stance; Y-balance test; drop and countermovement jump; standing long jump; 20-m sprint; agility run; slalom dribble; and wall volley test. We used magnitude-based inferences and linear mixed-effects models to analyse performance test results. We observed likely beneficial effects favouring INT in Y-balance (right leg; +3.2%; standardised mean difference (SMD) = 0.34; P = 0.58) and agility run (+3.6%; SMD = 0.45; P = 0.008). Possibly beneficial effects were found in Y-balance, drop jump reactive strength index, drop jump height, countermovement jump, standing long jump, slalom dribble and wall volley test. At least possibly beneficial improvements in favour of "FIFA 11+ Kids" were observed in nearly all parameters. Most effects were small, but slight improvements in motor performance may potentially contribute to a reduction of injury risk. PMID- 26508532 TI - Increasing the utility of the Functional Assessment for Burns Score: Not just for major burns. AB - The Functional Assessment for Burns (FAB) score is established as an objective measure of physical function that predicts discharge outcome in adult patients with major burn. However, its validity in patients with minor and moderate burn is unknown. This is a multi-centre evaluation of the predictive validity of the FAB score for discharge outcome in adult inpatients with minor and moderate burns. FAB assessments were undertaken within 48 h of admission to (FAB 1), and within 48 h of discharge (FAB 2) from burn wards in 115 patients. Median age was 45 years and median burn size 4%. There were significant improvements in the patients' FAB scores (p<0.0001), 98 patients were discharged home (no social care) and 17 patients discharged to further inpatient rehabilitation or home with social care. FAB 1 score (<= 14) is strongly associated with discharge to inpatient rehabilitation or home with social care (p=0.0001) and as such can be used to facilitate early discharge planning. FAB 2 (<= 30) independently predicts discharge outcome to inpatient rehabilitation or home with social care (p<0.0001), increasing its utility to patients with minor and moderate burns. PMID- 26508533 TI - Initial Development of a Modified Trail Making Test for Individuals with Impaired Manual Functioning. AB - The Trail Making Test (TMT), a widely used neuropsychological test, is highly effective in detecting brain damage. A shortcoming of the test is that it requires drawing lines and thus is impractical for use with persons suffering manual impairment. The 3 studies described herein were designed to describe and evaluate a nonmanual Trail Making Test (NMTMT) that would be suitable for use with manually impaired individuals. The NMTMT utilizes color to permit oral reporting of the stimuli constituting a series of numbers (Part A) or alternating series of numbers and letters (Part B). The studies, which involved a total of 200 university students, indicate that the standard TMT and the NMTMT are moderately related to each other and have similar patterns of association and nonassociation with other neuropsychological measures. Participants with scores falling near the bottom of the NMTMT distribution have a high probability of scoring at least 1 standard deviation below the mean of the TMT distribution for Part B. The clinically important relationship of Part A to Part B seems to be retained in the NMTMT. It is concluded that the NMTMT shows promise as a substitute for the TMT when the TMT cannot be used. PMID- 26508534 TI - Environment-induced conformational and functional changes of L-2-haloacid dehalogenase. AB - 2-Haloacid dehalogenases have been highly studied due to their potential applications in chemical industries and bioremediation. Although biochemical and structural characterizations of the enzyme have been detailed, no information was available regarding environmental effects on the structure-function relationship. Here, circular dichroism spectroscopy (CD) was used to investigate the correlation between changes on the conformation and the function of l-2-haloacid dehalogenase (HadL AJ1) from the Pseudomonas putida induced by the environmental factors. Decreased alpha-helix and increased beta-sheet contents were observed in the structure of HadL AJ1 along with activity losses caused by pH, temperature and inhibitors. Regardless of which factor above-mentioned existed, more than 65.0% of HadL AJ1 activity could be remained if its alpha-helix content was over 12.0%. The maintenance of alpha-helical structure in HadL AJ1 was indispensable to its catalysis, while beta-sheet increase restricts its activity. This study revealed the variation of enzymatic activity due to environmental conditions resulting in structural changes monitored by CD, which contributed to rational modification and was instructive for predicting changes of the enzymatic activity during application. PMID- 26508536 TI - Nitrate reductase mutation alters potassium nutrition as well as nitric oxide mediated control of guard cell ion channels in Arabidopsis. AB - Maintaining potassium (K(+) ) nutrition and a robust guard cell K(+) inward channel activity is considered critical for plants' adaptation to fluctuating and challenging growth environment. ABA induces stomatal closure through hydrogen peroxide and nitric oxide (NO) along with subsequent ion channel-mediated loss of K(+) and anions. However, the interactions of NO synthesis and signalling with K(+) nutrition and guard cell K(+) channel activities have not been fully explored in Arabidopsis. Physiological and molecular techniques were employed to dissect the interaction of nitrogen and potassium nutrition in regulating stomatal opening, CO2 assimilation and ion channel activity. These data, gene expression and ABA signalling transduction were compared in wild-type Columbia-0 (Col-0) and the nitrate reductase mutant nia1nia2. Growth and K(+) nutrition were impaired along with stomatal behaviour, membrane transport, and expression of genes associated with ABA signalling in the nia1nia2 mutant. ABA-inhibited K(+) in current and ABA-enhanced slow anion current were absent in nia1nia2. Exogenous NO restored regulation of these channels for complete stomatal closure in nia1nia2. While NO is an important signalling component in ABA-induced stomatal closure in Arabidopsis, our findings demonstrate a more complex interaction associating potassium nutrition and nitrogen metabolism in the nia1nia2 mutant that affects stomatal function. PMID- 26508537 TI - Fluorescence from an H-aggregated naphthalenediimide based peptide: photophysical and computational investigation of this rare phenomenon. AB - Fluorescence associated with J-aggregated naphthalenediimides (NDIs) is common. However, in this study an NDI based synthetic peptide molecule is found to form a fluorescent H-aggregate in a chloroform (CHCl3)-methylcyclohexane (MCH) mixture. An attempt has been made to explain the unusual fluorescence property of this H aggregated NDI derivative. Time correlated single photon counting (TCSPC) shows that the average lifetime of the NDI based molecule is on the order of a few nanoseconds. It is revealed from the computational study that the transition from the second exited state (S2) to the ground energy state (S0) is responsible for the fluorescence as S1 is a dark state. Such rare violation of Kasha's rule accounts for the unusual fluorescence properties of this type of NDI molecule in the H-aggregated state. PMID- 26508538 TI - Ways of understanding being a healthcare professional in the role of family member of a patient admitted to hospital. A phenomenographic study. AB - Healthcare professionals' experience of being family member of a patient can contribute to knowledge development and organizational learning in further ways than the experiences of general family members. However, there is little research on healthcare professionals' experience being on 'the other side of the bed'. OBJECTIVE: To describe how healthcare professionals understand the role of being a healthcare professional and a family member of a patient admitted to hospital. DESIGN: Qualitative with a phenomenographic approach. SETTING: Three Swedish hospitals. PARTICIPANTS: All healthcare professionals in three hospitals were invited. Twenty-one volunteered for the study and 18 met the inclusion criteria; to have one year of professional experience and to have visited the family member in hospital daily during hospitalization. Family members in maternity or psychiatric care were excluded. METHODS: Semi-structured interviews were used for data collection. Transcripts were analyzed with a phenomenographic method to describe variation and commonality in the ways of understanding the phenomenon under study. RESULTS: Four dominant ways of understanding the phenomenon were identified; the informed bystander, the supervisor, the advocate and the carer. The four ways of understanding were hierarchically related with "The informed bystander" being least involved in the care of the family member and "The carer" more or less taking over the patient's care because of inappropriate, unsafe or omitted care. Common for all ways of understanding the phenomenon, except "The informed bystander", was the difficult balance between their loyalty toward the family member and their colleagues among the staff. "The informed bystander" and "The supervisor" are ways of understanding the phenomenon under study that, to our knowledge, has not been described before. CONCLUSIONS: This study describes how being a family member of a patient can be understood in four different ways when the family member is a healthcare professional. The findings show similarities to previous studies on general family members as well as nurse family members of patients in critical care. The need for professional communication, support and coordination will be substantially different if the family member understands his/her role as an informed bystander compared to if they perceive themselves as a carer. The role conflict and ambivalence toward building relationships described are aspects that need further exploration, as does the experience of being forced to care for a family member. Our findings contribute with new knowledge developing patient- and family-centered care. PMID- 26508539 TI - Comparison of current ATDs with Chinese adults in anthropometry. AB - OBJECTIVE: Crash test dummies are full-scale anthropomorphic test devices (ATDs) that simulate the dimensions, weight proportions, and articulation of the human body and are used to measure human injury potential in vehicle crashes. The Hybrid III dummy family, which is widely used currently, takes selected percentiles of anthropometry dimensions of U.S. adults as design references. The objective of this study was to assess the difference in anthropometry between Chinese adults and the currently used dummy. METHODS: Based on the Chinese National Physical Fitness Surveillance of the year 2000, 2005, 2010 and National Standard of China GB/T 10000-1988, a series of anthropometric parameters for Chinese adults were obtained, and data analysis was conducted between Chinese adults and ATDs that are currently used. RESULTS: The comparison revealed distinct anthropometric difference between ATDs and Chinese adults. Based on the latest data, median Chinese females were about 2.6% lower in stature and about 8.03% lower in body weight than the ATD design targets. Similarly, median Chinese males were about 3.48% shorter and weighed 11.89% less than the ATD design targets. CONCLUSIONS: Although the anthropometric differences between Chinese adults and the Hybrid III ATD specifications were modest and growing smaller, it is advisable to take the differences in anthropometry between ATDs and Chinese adults into consideration when developing new vehicles in China to provide effective protection specifically for Chinese occupants. PMID- 26508540 TI - Patients' satisfaction with facial prostheses. AB - We assessed the "impact on wellbeing" and "satisfaction" of patients who had a facial prosthesis (of the ear, nose, or orbit) fitted in The Netherlands Cancer Institute. Patients had either an adhesive-retained or an implant-retained facial prosthesis between 1951 and 2011. We did a cross-sectional survey of 104 patients, then gave a questionnaire to the final study group of 71 (68%), a year or more later. All were satisfied with their prostheses (visual analogue scale (VAS): mean (SD) 8.1(1.5). The implant-retained group were the most satisfied (p=0.022), and the adhesive-retained group felt more self-conscious (p=0.013). Three-quarters of all patients said that the prosthesis was not painful and there were no problems with the way it functioned. A well-designed facial prosthesis has obvious benefits, but there were no appreciable differences between the two groups. Each patient must make a careful decision about which type of prosthesis to choose, taking into account the quality of their remaining tissue, the site of the defect, and their general health. PMID- 26508541 TI - Protection of the oral commissure during operations for cleft palate. PMID- 26508542 TI - Dietary Acid Load is Associated With Serum Bicarbonate but not Insulin Sensitivity in Chronic Kidney Disease. AB - OBJECTIVE: In chronic kidney disease (CKD), dietary acid may promote metabolic acidosis and insulin resistance, which in turn may contribute to adverse clinical health outcomes. We examined associations between dietary acid load, serum bicarbonate, and insulin sensitivity in CKD. DESIGN: In a cross-sectional study, we collected 3-day prospective food diaries to quantify dietary acid load as net endogenous acid production (NEAP, the nonvolatile acid load produced by the diet's acid balance) and potential renal acid load (PRAL). We measured urine net acid excretion (NAE) in 24-hour urine samples. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp. SUBJECTS: Forty-two patients with CKD Stages 3 to 5 attending nephrology clinics in the Pacific Northwest and 21 control subjects (estimated glomerular filtration rate [eGFR] >= 60 mL/minute/1.73 m(2)). MAIN OUTCOME MEASURES: Serum bicarbonate and insulin sensitivity (SIclamp). RESULTS: Mean age was 60.8 +/- 13.6 years, and 54% of participants were men. Mean eGFR and serum bicarbonate concentrations were 34.4 +/- 13.1 mL/minute/1.73 m(2) and 24.1 +/- 2.9 mEq/L for participants with CKD and 88.6 +/- 14.5 mL/minute/1.73 m(2) and 26.3 +/- 1.8 mEq/L for control subjects, respectively. Mean NEAP, PRAL, and NAE were 58.2 +/- 24.3, 9.7 +/- 18.4, and 32.1 +/- 19.8 mEq/day, respectively. Considering all participants, dietary acid load was significantly, inversely associated with serum bicarbonate, adjusting for age, gender, race, eGFR, body mass index, and diuretic use: -1.2 mEq/L per standard deviation (SD) NEAP (95% confidence interval [CI] -1.8 to -0.6, P < .0001); -0.9 mEq/L bicarbonate per SD PRAL (95% CI -1.5 to -0.4, P = .0005); -0.7 mEq/L bicarbonate per SD NAE (95% CI -1.2 to -0.1, P = .01). These associations were similar in participants with and without CKD. However, neither NEAP and PRAL nor NAE was significantly associated with SIclamp. Serum bicarbonate was also not significantly associated with SIclamp. CONCLUSIONS: In CKD, dietary acid load is associated with serum bicarbonate, suggesting that acidosis may be improved by dietary changes, but not with insulin sensitivity. PMID- 26508543 TI - Correlation of external ear auricle formation with staging of human embryos. AB - The formation of auricles in human embryos was evaluated between Carnegie stage (CS)19 and CS23, and the findings were correlated across the stages. The auricle was categorized into 11 steps according to Streeter's criteria with modifications. Mesenchyme cell condensation was observed at Step 7, and two layers of cartilage consisting of the auricle were recognized at Step 11. The representative steps at each CS shifted from Step 3 to Step 11 during CS16 and CS23, although several steps overlapped between adjacent CSs. These results indicate that observations of the auricle between CS19 and CS23 may be utilized for determining embryo staging as convincing supportive evidence of external features reflecting the internal histological structure, although other findings should also be taken into account. PMID- 26508544 TI - Dynamic changes of histone H3 marks during Caenorhabditis elegans lifecycle revealed by middle-down proteomics. AB - We applied a middle-down proteomics strategy for large-scale protein analysis during in vivo development of Caenorhabditis elegans. We characterized PTMs on histone H3 N-terminal tails at eight time points during the C. elegans lifecycle, including embryo, larval stages (L1-L4), dauer, and L1/L4 postdauer. Histones were analyzed by our optimized middle-down protein sequencing platform using high mass accuracy MS/MS. This allows quantification of intact histone tails and detailed characterization of distinct histone tails carrying cooccurring PTMs. We measured temporally distinct combinatorial PTM profiles during C. elegans development. We show that the doubly modified form H3K23me3K27me3, which is rare or nonexistent in mammals, is the most abundant PTM in all stages of C. elegans lifecycle. The abundance of H3K23me3 increased during development and it was mutually exclusive of the active marks H3K18ac, R26me1, and R40me1, suggesting a role for H3K23me3 in silent chromatin. We observed distinct PTM profiles for normal L1 larvae and for L1-postdauer larvae, or L4 and L4 postdauer, suggesting that histone PTMs mediate an epigenetic memory that is transmitted during dauer formation. Collectively, our data describe the dynamics of histone H3 combinatorial code during C. elegans lifecycle and demonstrate the feasibility of using middle-down proteomics to study in vivo development of multicellular organisms. All MS data have been deposited in the ProteomeXchange with identifier PXD002525 (http://proteomecentral.proteomexchange.org/dataset/PXD002525). PMID- 26508545 TI - Peptidyl prolyl isomerase Pin1-inhibitory activity of D-glutamic and D-aspartic acid derivatives bearing a cyclic aliphatic amine moiety. AB - Pin1 is a peptidyl prolyl isomerase that specifically catalyzes cis-trans isomerization of phosphorylated Thr/Ser-Pro peptide bonds in substrate proteins and peptides. Pin1 is involved in many important cellular processes, including cancer progression, so it is a potential target of cancer therapy. We designed and synthesized a novel series of Pin1 inhibitors based on a glutamic acid or aspartic acid scaffold bearing an aromatic moiety to provide a hydrophobic surface and a cyclic aliphatic amine moiety with affinity for the proline-binding site of Pin1. Glutamic acid derivatives bearing cycloalkylamino and phenylthiazole groups showed potent Pin1-inhibitory activity comparable with that of known inhibitor VER-1. The results indicate that steric interaction of the cyclic alkyl amine moiety with binding site residues plays a key role in enhancing Pin1-inhibitory activity. PMID- 26508546 TI - Discovery of an orally bioavailable isoxazoline benzoxaborole (AN8030) as a long acting animal ectoparasiticide. AB - A novel series of isoxazoline benzoxaborole small molecules was designed and synthesized for a structure-activity relationship (SAR) investigation to assess the ectoparasiticide activity against ticks and fleas. The study identified an orally bioavailable molecule, (S)-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5 (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (38, AN8030), which was long lasting in dogs (t1/2=22 days). Compound 38 demonstrated 97.6% therapeutic effectiveness within 24 h of treatment, with residual efficacy of 95.3% against American dog ticks (Dermacentor variabilis) on day 30% and 100% against cat fleas (Ctenocephalides felis) on day 32 after a single oral dose at 50 mg/kg in dogs. PMID- 26508547 TI - Small molecules that promote regenerative repair for pancreatic and cardiovascular health. AB - Regenerative medicine for repair of organ injury is an emerging area of research. The use of embryonic stem cells and induced pluripotent cells in combination with endogenously expressed growth factors has provided methods to generate differentiated cells for cell-based therapy and for screening purposes. As cell based therapies continue to be investigated in the clinical setting, small molecules for in situ tissue repair are being reported. In this review, we focus on the reports applicable to the field of cardiovascular and metabolic disease by discussing small molecules that target beta-cells, cardiomyocytes and endothelial cells. PMID- 26508548 TI - Antiproliferative and antiplasmodial compounds from selected Streptomyces species. AB - In continuation of our ongoing search for bioactive compounds from microbial extracts, we performed antiproliferative and/or antimalarial assays on extracts of 806 microbial species isolated from Madagascan marine organisms, on 1317 species isolated from Madagascan soil samples and on a Streptomyces species (S.4) from a marine sponge collected from the Florida Keys. This work identified active extracts from four Streptomyces isolates (S.1, S.2, S.3 and S.4). The extracts of Streptomyces S.1 and S.2 showed antiproliferative activity against the A2780 ovarian cancer cell line, while those of S.3 and S.4 displayed both antiproliferative and antimalarial activity. Bioassay-guided fractionation coupled with dereplication of the active extracts led to the identification and isolation of nonactin (1), monactin (2), dinactin (3), +/--nonactic acid (4), toyocamycin (5), piperafizine A (6) and a new dipeptide named xestostreptin (7). The structures of all isolated compounds 1-7 were elucidated by analyses of their NMR spectroscopic and mass spectrometric data, and were confirmed by comparison with the data reported in the literature. Compound 6 was crystallized and subjected to X-ray diffraction analysis to confirm its structure as piperafizine A (6). Compounds 1-3 displayed strong antiproliferative activity against A2780 ovarian cancer cells (IC50 values of 0.1, 0.13 and 0.2 MUM, respectively), A2058 melanoma cells (IC50 values of 0.2, 0.02 and 0.02 MUM, respectively), and H522-T1 non small-cell cancer lung cells (IC50 values of 0.1, 0.01 and 0.01 MUM, respectively), while compounds 4 and 7 exhibited weak antiplasmodial activity against the Dd2 strain of Plasmodium falciparum, with IC50 values of 6.5 and 50 MUM, respectively. PMID- 26508549 TI - Discovery of alpha-mangostin as a novel competitive inhibitor against mutant isocitrate dehydrogenase-1. AB - Somatic heterozygous mutations of isocitrate dehydrogenase-1 (IDH1) are abundantly found in several types of cancer and strongly implicate altered metabolism in carcinogenesis. In the present study, we have identified alpha mangostin as a novel selective inhibitor of mutant IDH1 (IDH1-R132H). We have observed that alpha-mangostin competitively inhibits the binding of alpha ketoglutarate (alpha-KG) to IDH1-R132H. The structure-relationship study reveals that alpha-mangostin exhibits the strongest core inhibitor structure. Finally, we have observed that alpha-mangostin selectively promotes demethylation of 5 methylcytosine (5mC) and histone H3 trimethylated lysine residues in IDH1 (+/R132H) MCF10A cells, presumably via restoring the activity of cellular alpha KG-dependent DNA hydroxylases and histone H3 lysine demethylases. Collectively, we provide evidence that alpha-mangostin selectively inhibits IDH1-R132H. PMID- 26508550 TI - Synthesis of natural phaeosphaeride A derivatives and an in vitro evaluation of their anti-cancer potential. AB - Derivatives of phaeosphaeride A (PPA) were synthesised and characterised; then anti-cancer studies were carried out on the A549 cancer cell line. It was found that the acetyl derivative (compound 3) displayed comparable in vitro cytotoxicity to that of PPA (EC50=49+/-7 MUM and EC50=46+/-5 MUM, respectively), while chloroacetyl derivative 6 (EC50=33+/-7 MUM) was found to have better efficacy towards the A549 cancer cell line. PMID- 26508551 TI - Finding new elicitors that induce resistance in rice to the white-backed planthopper Sogatella furcifera. AB - Herein we report a new way to identify chemical elicitors that induce resistance in rice to herbivores. Using this method, by quantifying the induction of chemicals for GUS activity in a specific screening system that we established previously, 5 candidate elicitors were selected from the 29 designed and synthesized phenoxyalkanoic acid derivatives. Bioassays confirmed that these candidate elicitors could induce plant defense and then repel feeding of white backed planthopper Sogatella furcifera. PMID- 26508552 TI - Sanguiin H6 suppresses TGF-beta induction of the epithelial-mesenchymal transition and inhibits migration and invasion in A549 lung cancer. AB - In the epithelial-mesenchymal transition (EMT), an important cellular process, epithelial cells become mesenchymal cells. This process is also critically involved in cancer metastasis. Sanguiin H6 is a compound derived from ellagitannin, which is found in berries. Sanguiin H6 shows various pharmacological properties, including anti-angiogenic activity. Because the possible role of sanguiin H6 in the EMT and the underlying molecular mechanisms are unclear, we investigated the effect of sanguiin H6 on the EMT. Transforming growth factor-beta 1 (TGF-beta1) induces the EMT and promotes lung adenocarcinoma migration and invasion through the Smad2/3 signaling pathway. Thus, to understand the inhibitory effects of sanguiin H6 on lung cancer migration and invasion, we investigated the ability of sanguiin H6 to inhibit TGF-beta1-induced EMT in the A549 cell line. We found that sanguiin H6 significantly prevented the activation of Smad2/3 signaling pathway by TGF-beta1. Additionally, sanguiin H6 increased the expression of the epithelial marker E-cadherin and repressed the expression of Snail and the mesenchymal marker N-cadherin during TGF-beta1-induced EMT. Moreover, sanguiin H6 regulated the expression of EMT-dependent genes induced by TGF-beta1. Finally, sanguiin H6 inhibited the migration and invasion of TGF-beta1 stimulated A549 cells. Taken together, our findings provide new evidence that sanguiin H6 suppresses lung cancer migration and invasion in vitro by inhibiting TGF-beta1 induction of the EMT. PMID- 26508553 TI - Providers' assessment of transition readiness among adolescent and young adult kidney transplant recipients. AB - The Readiness for Transition Questionnaire- provider version (RTQ-Provider) was developed to evaluate adolescent patients' transition readiness and healthcare behaviors from the perspective of the healthcare provider. The RTQ-Provider is a parallel version of the RTQ-Teen and RTQ-Parent completed by patients and parents. This study seeks to evaluate the psychometric properties of the RTQ Provider and its utility as a clinical transition planning tool. Participants consisted of 49 kidney transplant recipients between the ages of 15 and 21. The RTQ-Provider was completed by the pediatric nephrologist and psychologist from the multidisciplinary healthcare team and compared to RTQ data from teens and parents. The RTQ-Provider demonstrated good-to-excellent internal consistency and interrater reliability. Construct validity was supported through significant predictive relationships between providers' perceptions of transition readiness and older patient age, increased patient healthcare responsibility, and decreased parent involvement in health care. By providing parallel teen, parent, and provider forms, the RTQ has the potential to foster open communication between patients, families, and healthcare team members regarding transition readiness. The study provides initial support for the RTQ-Provider as a clinical tool to assess providers' perceptions of transition readiness; however, future longitudinal research is needed to evaluate predictive validity following patients' transfer to adult care. PMID- 26508554 TI - Emerging roles of system [Formula: see text] antiporter and its inhibition in CNS disorders. AB - System [Formula: see text] is an antiporter belonging to the hetero(di)meric amino acid transporter family. It is located on astrocytes as well as on blood brain barrier within the CNS. It plays a pivotal role in free radical neutralization as well as neuronal signalling by regulating the glutathione production which occurs via the exchange of intracellular glutamate with extracellular cystine at 1:1 molar ratio. Understandably, it is a vital component responsible for the maintenance of neuronal homeostasis (e.g. redox state). Hence, it could be postulated that any perturbation in system [Formula: see text] function may contribute, directly or indirectly, to the pathophysiology of a variety of CNS disorders like Alzheimer's disease, schizophrenia, drug addiction, depression, multiple sclerosis, hypoglycemic neuronal cell death, glioma, and excitotoxicity, making system [Formula: see text] a promising target for treating CNS disorders. In recent times, recognizing the potential of this target, variety of inhibitors has been synthesized by modifying commercially available potent inhibitors including sulfasalazine, erastin, and sorafenib. Although, they have demonstrated efficacy, the in-depth data is still lacking to warrant their use for the treatment of aforementioned CNS disorders. In this review, we discuss the in-depth role of system [Formula: see text] transporter in maintaining normal physiology as well as in the pathophysiology of CNS diseases. Additionally, we have also listed some of the potent inhibitors of system [Formula: see text]. In conclusion, the critical role of system [Formula: see text] in multiple CNS disorders and advanced research on its inhibitors have promising future prospects for better management of the CNS ailments. PMID- 26508555 TI - A unique SNARE machinery for exocytosis of cytotoxic granules and platelets granules. AB - Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells target infected or transformed cells with perforin-containing cytotoxic granules through immune synapses, while platelets secrete several types of granules which contents are essential for thrombosis and hemostasis. Recent work has culminated in the notion that an exocytic SNARE complex, based on a very similar set of components, is primarily responsible for exocytosis of the diverse granules in these different cell types. Granule exocytosis is, in particular, uniquely dependent on the atypical Q-SNARE syntaxin 11, its interacting partners of the Sec/Munc (SM) family, and is regulated by Rab27a. Mutations in these exocytic components underlie disease manifestations of familial hemophagocytic lymphohistiocytosis (FHL) subtypes, characterized by hyperactivation of the immune system, as well as platelet granule secretion defects. Here we discuss the key discoveries that led to the converging notion of the syntaxin 11-based exocytosis machinery for cytotoxic granules and platelet-derived granules. PMID- 26508556 TI - Differential dynamics of the serotonin1A receptor in membrane bilayers of varying cholesterol content revealed by all atom molecular dynamics simulation. AB - The serotonin1A receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target in neuropsychiatric disorders. The receptor has been shown to require membrane cholesterol for its organization, dynamics and function. Although recent work suggests a close interaction of cholesterol with the receptor, the structural integrity of the serotonin1A receptor in the presence of cholesterol has not been explored. In this work, we have carried out all atom molecular dynamics simulations, totaling to 3 MUs, to analyze the effect of cholesterol on the structure and dynamics of the serotonin1A receptor. Our results show that the presence of physiologically relevant concentration of membrane cholesterol alters conformational dynamics of the serotonin1A receptor and, on an average lowers conformational fluctuations. Our results show that, in general, transmembrane helix VII is most affected by the absence of membrane cholesterol. These results are in overall agreement with experimental data showing enhancement of GPCR stability in the presence of membrane cholesterol. Our results constitute a molecular level understanding of GPCR-cholesterol interaction, and represent an important step in our overall understanding of GPCR function in health and disease. PMID- 26508557 TI - Initial and hourly headloss modelling on a tertiary nitrifying wastewater biofiltration plant. AB - The headloss prediction capability of a wastewater biofiltration model is evaluated on data from a full-scale tertiary nitrifying biofilter unit located in the Paris conurbation (Acheres, France; 6,000,000 population equivalent). The model has been previously calibrated on nutrient conversion and TSS filtration observations. In this paper the mass of extracted biofilm during biofilter backwash and the headloss value at the start of an operation cycle are first calibrated on sludge production estimations and relative pressure measurements over the year 2009. The calibrated model is then used on two one-month periods in 2012 for which hourly headloss measurements were acquired. The observed trends are correctly predicted for 2009 but the model exhibits some heavy daily variation that is not found in measurements. Hourly predictions stay close to observations, although the model error rises slightly when the headloss does not vary much. The global model shows that both nutrient conversion and headloss build-up can be reasonably well predicted at the same time on a full-scale plant. PMID- 26508558 TI - Brain tumors in patients with myotonic dystrophy: a population-based study. AB - BACKGROUND AND PURPOSE: Patients with myotonic dystrophy (DM) are at high risk of brain cancer. This study describes the spectrum of brain neoplasms in DM patients. METHODS: Data from 1119 DM patients identified from the National Swedish Patient Register between 1987 and 2007 were linked to the National Cancer and the Cause of Death Registers. Standardized incidence ratios (SIRs) and cumulative incidence to quantify the relative and absolute risks of brain neoplasms were calculated and the Kaplan-Meier estimator was used for survival analysis. Patient follow-up started at birth or the age at the start of Swedish cancer registration (1 January 1958) and ended at the age of brain neoplasm diagnosis, death or on 31 December 2007. RESULTS: Twenty patients developed brain neoplasm during follow-up {median age 53, range 2-76 years, accounting for a five fold excess risk of brain tumors during the patient lifetime [SIR = 5.4, 95% confidence interval (CI) 3.4-8.1, P = 1 * 10(-5) ]}. Astrocytoma was the most common histological subtype (n = 16, 80%), and almost all cases (n = 19) developed after age 20. No statistically significant differences in gender specific risks (SIR in men 6.3 and in women 3.8, P-heterogeneity 0.46) were observed. After accounting for competing mortality related to DM, the cumulative incidence of brain neoplasms reached 2.9% (95% CI 1.8%-4.7%) by age 70. Five-year survival after brain tumor diagnosis was 52% (95%CI 29%-75%) overall (number at risk 8) and 34% (95% CI 26%-47%) for malignant neoplasms (number at risk 5). CONCLUSION: Despite the high relative risk of DM-related brain tumors, the absolute risk is modest. Nonetheless, careful evaluation of DM patients with new central nervous system symptoms is warranted. PMID- 26508559 TI - What the poets of the Tang Dynasty have to teach us about DNA repair. PMID- 26508560 TI - QTL mapping of cucumber fruit flesh thickness by SLAF-seq. AB - Cucumber is an agriculturally and economically important vegetable crop worldwide. Fruit flesh thickness is an important trait for cucumber and also a central determinant of yield, yet little is known about the underlying mechanism of this trait. In this study, bulked segregant analysis (BSA) combined with specific length amplified fragment sequencing (SLAF-seq) was applied to finely map the gene that underlies fruit flesh thickness in cucumber. A 0.19-Mb-long quantitative trait locus on chromosome 2 controlling fruit flesh thickness (QTL fft2.1) was identified and further confirmed by simple sequence repeat (SSR) marker-based classical QTL mapping in 138 F2 individuals. Gene prediction of this 0.19-Mb region identified 20 genes. Quantitative RT-PCR revealed higher expression levels of Csa2 M058670.1 (SET domain protein-lysine methyltransferase) in D8 (thick fruit flesh parent) compared with that in XUE1 (thin fruit flesh parent) during fruit development. Sequence alignment analysis of Csa2M058670.1 from thick and thin fruit flesh cucumber lines revealed a 4-bp deletion mutation in the promoter region of this candidate gene, which may result in the loss of Csa2M058670.1 activation in thin fruit flesh lines. The data presented herein suggest that Csa2M058670.1 is a possible candidate gene for controlling flesh thickness in cucumber. PMID- 26508561 TI - Ionotropic GABA receptor antagonism-induced adverse outcome pathways for potential neurotoxicity biomarkers. AB - Antagonism of ionotropic GABA receptors (iGABARs) can occur at three distinct types of receptor binding sites causing chemically induced epileptic seizures. Here we review three adverse outcome pathways, each characterized by a specific molecular initiating event where an antagonist competitively binds to active sites, negatively modulates allosteric sites or noncompetitively blocks ion channel on the iGABAR. This leads to decreased chloride conductance, followed by depolarization of affected neurons, epilepsy-related death and ultimately decreased population. Supporting evidence for causal linkages from the molecular to population levels is presented and differential sensitivity to iGABAR antagonists in different GABA receptors and organisms discussed. Adverse outcome pathways are poised to become important tools for linking mechanism-based biomarkers to regulated outcomes in next-generation risk assessment. PMID- 26508562 TI - Children's Moral Emotion Attribution in the Happy Victimizer Task: The Role of Response Format. AB - Previous research in the happy victimizer tradition indicated that preschool and early elementary school children attribute positive emotions to the violator of a moral norm, whereas older children attribute negative (moral) emotions. Cognitive and motivational processes have been suggested to underlie this developmental shift. The current research investigated whether making the happy victimizer task less cognitively demanding by providing children with alternative response formats would increase their attribution of moral emotions and moral motivation. In Study 1, 93 British children aged 4-7 years old responded to the happy victimizer questions either in a normal condition (where they spontaneously pointed with a finger), a wait condition (where they had to wait before giving their answers), or an arrow condition (where they had to point with a paper arrow). In Study 2, 40 Spanish children aged 4 years old responded to the happy victimizer task either in a normal or a wait condition. In both studies, participants' attribution of moral emotions and moral motivation was significantly higher in the conditions with alternative response formats (wait, arrow) than in the normal condition. The role of cognitive abilities for emotion attribution in the happy victimizer task is discussed. PMID- 26508563 TI - Virtual design of electrospun-like gelatin scaffolds: the effect of three dimensional fibre orientation on elasticity behaviour. AB - Remarkable mechanical performance of biological tissues is explained by a hierarchical fibrous structure. Designing materials that have similar properties is challenging because of the need to assess complex deformation mechanisms. In order to shed more light on architectural possibilities of biopolymer fibrous networks, we propose a numerical study that relates the fibre arrangement to the elastic modulus of a gelatin scaffold obtained using electrospinning. The adopted approach is based on the virtual designing of scaffolds using all possible combinations of Euler angles that define fibre orientations including preferable alignment. The generated networks are converted into a finite element model and the predicted elastic behaviour is examined. Predictions show that the fibre alignment achieved experimentally in biopolymer fibrous networks is for most of the fibres exhibiting an orthotropic behaviour. Some particular combinations of Euler angles allow transverse isotropic architectures while only limited cases are isotropic. A large sensitivity of Young's moduli to Euler angles is achieved describing multiple scenarios of independent anisotropic behaviours. An anisotropy ratio of the elastic behaviour is suggested based on a suitable combination of elastic moduli. Such a ratio exhibits a wide variation depending on individual and coupled effects of Euler angles. The finite element model predicts 2D, 3D and 4D maps representing all possible configurations of fibre alignment and their consequences on elastic behaviour. The predicted fibre orientation representing the observed anisotropic behaviour of electrospun gelatin networks demonstrates unbalanced contributions of in-plane and out-of plane fibres for a large range of processing conditions. PMID- 26508564 TI - The MitraClip Asia-Pacific registry: Differences in outcomes between functional and degenerative mitral regurgitation. AB - OBJECTIVES: The objective of this study is to describe and compare the use of the MitraClip therapy in mitral regurgitation (MR) patients with degenerative MR (DMR) and functional MR (FMR). INTRODUCTION: Percutaneous edge-to-edge repair of severe MR using the MitraClip device is approved for use in the USA for high risk DMR while European guidelines include its use in FMR patients as well. METHODS: The MitraClip in the Asia-Pacific Registry (MARS) is a multicenter retrospective registry, involving eight sites in five Asia-Pacific countries. Clinical and echocardiographic characteristics, procedural outcomes and 1-month outcomes [death and major adverse events (MAE)] were compared between FMR and DMR patients treated with the MitraClip. RESULTS: A total of 163 patients were included from 2011 to 2014. The acute procedural success rates for FMR (95.5%, n = 84) and DMR (92%, n = 69) were similar (P = 0.515). 45% of FMR had >=2 clips inserted compared to 60% of those with DMR (P = 0.064).The 30-day mortality rate for FMR and DMR was similar at 4.5% and 6.7% respectively (P = 0.555). The 30-day MAE rate was 9.2% for FMR and 14.7% for DMR (P = 0.281). Both FMR and DMR patients had significant improvements in the severity of MR and NYHA class after 30 days. There was a significantly greater reduction in left ventricular end-diastolic diameter (P = 0.002) and end systolic diameter (P = 0.017) in DMR than in FMR. CONCLUSIONS: The MitraClip therapy is a safe and efficacious treatment option for both FMR and DMR. Although, there is a significantly greater reduction in LV volumes in DMR, patients in both groups report clinical benefit with improvement in functional class. (c) 2015 Wiley Periodicals, Inc. PMID- 26508565 TI - Key concepts, strategies, and challenges in dengue vaccine development: an opportunity for sub-unit candidates? AB - Despite 70 years of research that has intensified in the past decade, a safe and efficacious dengue vaccine has yet to be available. In addition to the expected challenges such as identifying immune correlates of protection, the dengue vaccine field has faced additional hurdles including the necessity to design a tetravalent formulation and the risk of antibody-mediated disease enhancement. Nevertheless, tetravalent live attenuated vaccine candidates have reached efficacy trials and demonstrated some benefit, despite imbalanced immunogenicity and incomplete protection against the four serotypes. Meanwhile, the development of sub-unit dengue vaccines has gained momentum. As the target of most of the neutralizing antibodies so far reported, the virus envelope E protein has been the focus of much effort and represents the leading dengue sub-unit vaccine candidate. However, its notorious poor immunogenicity has prompted the development of innovative approaches to make E-derived constructs part of the second generation dengue vaccines portfolio. PMID- 26508566 TI - Guidelines for diagnostic next-generation sequencing. AB - We present, on behalf of EuroGentest and the European Society of Human Genetics, guidelines for the evaluation and validation of next-generation sequencing (NGS) applications for the diagnosis of genetic disorders. The work was performed by a group of laboratory geneticists and bioinformaticians, and discussed with clinical geneticists, industry and patients' representatives, and other stakeholders in the field of human genetics. The statements that were written during the elaboration of the guidelines are presented here. The background document and full guidelines are available as supplementary material. They include many examples to assist the laboratories in the implementation of NGS and accreditation of this service. The work and ideas presented by others in guidelines that have emerged elsewhere in the course of the past few years were also considered and are acknowledged in the full text. Interestingly, a few new insights that have not been cited before have emerged during the preparation of the guidelines. The most important new feature is the presentation of a 'rating system' for NGS-based diagnostic tests. The guidelines and statements have been applauded by the genetic diagnostic community, and thus seem to be valuable for the harmonization and quality assurance of NGS diagnostics in Europe. PMID- 26508567 TI - Polymorphisms of cystathionine beta-synthase gene are associated with susceptibility to sepsis. AB - Sepsis is the systemic inflammatory host response to infection. Cystathionine beta-synthase (CBS)-dependent homocysteine (Hcy) pathway was demonstrated to affect disease severity and mortality in patients with severe sepsis/septic shock. Independent studies identified a single-nucleotide polymorphism (SNP, rs6586282, hg19 chr21:g.44478497C>T) in intron 14 of the CBS-coding gene (CBS) associated with Hcy plasma levels. We aimed to describe the association of this SNP and variants of a splice donor-affecting variable-number tandem repeat (VNTR, NG_008938.1:g.22763_22793[16_22]) 243 bp downstream of rs6586282 with severe human sepsis. We analyzed the VNTR structure and genotyped variants of rs6586282 and a neighboring SNP (rs34758144, hg19 chr21:g.44478582G>A) in two case-control studies including patients with severe sepsis/septic shock from Germany (n=168) and Greece (n=237). In both studies, we consistently observed an association of CBS VNTR alleles with sepsis susceptibility. Risk linearly increased with number of tandem repeats (per allele odds ratio in the adjusted analysis 1.34; 95% confidence interval (CI)=1.17-1.55; P<0.001). Association had also been shown for rs34758144 whose risk allele is in linkage disequilibrium with one long VNTR allele (19 repeat). In contrast, we observed no evidence for an effect on 28-day survival in patients with severe sepsis/septic shock (per allele hazard ratio in the adjusted analysis for VNTR 1.10; 95% CI=0.95-1.28; P=0.20). In a minigene approach, we demonstrated alternative splicing in distinct VNTR alleles, which, however, was independent of the number of tandem units. In conclusion, there is no ordinary conjunction between human CBS and severe sepsis/septic shock, but CBS genotypes are involved in disease susceptibility. PMID- 26508568 TI - Motivations, concerns and preferences of personal genome sequencing research participants: Baseline findings from the HealthSeq project. PMID- 26508569 TI - New EuroGentest/ESHG guidelines and a new clinical utility gene card format for NGS-based testing. PMID- 26508570 TI - De novo variants in sporadic cases of childhood onset schizophrenia. AB - Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing of 17 COS trios in order to test whether de novo variants could contribute to this disease. We identified 20 de novo variants in 17 COS probands, which is consistent with the de novo mutation rate reported in the adult form of the disease. Interestingly, the missense de novo variants in COS have a high likelihood for pathogenicity and were enriched for genes that are less tolerant to variants. Among the genes found disrupted in our study, SEZ6, RYR2, GPR153, GTF2IRD1, TTBK1 and ITGA6 have been previously linked to neuronal function or to psychiatric disorders, and thus may be considered as COS candidate genes. PMID- 26508571 TI - A general approach for combining diverse rare variant association tests provides improved robustness across a wider range of genetic architectures. AB - The widespread availability of genome sequencing data made possible by way of next-generation technologies has yielded a flood of different gene-based rare variant association tests. Most of these tests have been published because they have superior power for particular genetic architectures. However, for applied researchers it is challenging to know which test to choose in practice when little is known a priori about genetic architecture. Recently, tests have been proposed which combine two particular individual tests (one burden and one variance components) to minimize power loss while improving robustness to a wider range of genetic architectures. In our analysis we propose an expansion of these approaches, yielding a general method that works for combining any number of individual tests. We demonstrate that running multiple different tests on the same data set and using a Bonferroni correction for multiple testing is never better than combining tests using our general method. We also find that using a test statistic that is highly robust to the inclusion of non-causal variants (joint-infinity) together with a previously published combined test (sequence kernel adaptive test-optimal) provides improved robustness to a wide range of genetic architectures and should be considered for use in practice. Software for this approach is supplied. We support the increased use of combined tests in practice - as well as further exploration of novel combined testing approaches using the general framework provided here - to maximize robustness of rare variant testing strategies against a wide range of genetic architectures. PMID- 26508572 TI - Development and validation of a measure of informed choice for women undergoing non-invasive prenatal testing for aneuploidy. AB - Non-invasive prenatal testing (NIPT) using cell-free DNA for aneuploidy is a highly accurate screening test; however, concerns exist around the potential for routinisation of testing. The multidimensional measure of informed choice (MMIC) is a quantitative instrument developed to assess informed choice for Down syndrome screening (DSS). We have validated a modified MMIC for NIPT and measured informed choice among women offered NIPT in a public health service. The measure was distributed to women recruited across eight maternity units in the United Kingdom who had accepted DSS. Construct validity was assessed by simultaneously conducting qualitative interviews. Five hundred and eighty-five questionnaires were completed and 45 interviews conducted after blood-draw (or equivalent for those that declined NIPT). The measure demonstrated good internal consistency and internal validity. Results indicate the vast majority of women (89%) made an informed choice; 95% were judged to have good knowledge, 88% had a positive attitude and 92% had deliberated. Of the 11% judged to have made an uninformed choice, 55% had not deliberated, 41% had insufficient knowledge, and 19% had a negative attitude. Ethnicity (OR=2.78, P=0.003) and accepting NIPT (OR=16.05, P=0.021) were found to be significant predictors of informed choice. The high rate of informed choice is likely to reflect the importance placed on the provision of pre-test counselling in this study. It will be vital to ensure that this is maintained once NIPT is offered in routine clinical practice. PMID- 26508573 TI - Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: a challenge for molecular analysis and genetic counseling. AB - Beckwith-Wiedemann and Silver-Russell syndromes (BWS/SRS) are two imprinting disorders (IDs) associated with disturbances of the 11p15.5 chromosomal region. In BWS, epimutations and genomic alterations within 11p15.5 are observed in >70% of patients, whereas in SRS they are observed in about 60% of the cases. In addition, 10% of the SRS patients carry a maternal uniparental disomy of chromosome 7 11p15.5. There is an increasing demand for prenatal testing of these disorders owing to family history, indicative prenatal ultrasound findings or aberrations involving chromosomes 7 and 11. The complex molecular findings underlying these disorders are a challenge not only for laboratories offering these tests but also for geneticists counseling affected families. The scope of counseling must consider the range of detectable disturbances and their origin, the lack of precise quantitative knowledge concerning the inheritance and recurrence risks for the epigenetic abnormalities, which are hallmarks of these developmental disorders. In this paper, experts in the field of BWS and SRS, including members of the European network of congenital IDs (EUCID.net; www.imprinting-disorders.eu), put together their experience and work in the field of 11p15.5-associated IDs with a focus on prenatal testing. Altogether, prenatal tests of 160 fetuses (122 referred for BWS, 38 for SRS testing) from 5 centers were analyzed and reviewed. We summarize the current knowledge on BWS and SRS with respect to diagnostic testing, the consequences for prenatal genetic testing and counseling and our cumulative experience in dealing with these disorders. PMID- 26508574 TI - Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3. AB - A substantial proportion of patients with posterior polymorphous corneal dystrophy (PPCD) lack a molecular diagnosis. We evaluated 14 unrelated probands who had a clinical diagnosis of PPCD who were previously determined to be negative for mutations in ZEB1 by direct sequencing. A combination of techniques was used including whole-exome sequencing (WES), single-nucleotide polymorphism (SNP) array copy number variation (CNV) analysis, quantitative real-time PCR, and long-range PCR. Segregation of potentially pathogenic changes with disease was confirmed, where possible, in family members. A putative run of homozygosity on chromosome 10 was identified by WES in a three-generation PPCD family, suggestive of a heterozygous deletion. SNP array genotyping followed by long-range PCR and direct sequencing to define the breakpoints confirmed the presence of a large deletion that encompassed multiple genes, including ZEB1. Identification of a heterozygous deletion spanning ZEB1 prompted us to further investigate potential CNVs at this locus in the remaining probands, leading to detection of two additional heterozygous ZEB1 gene deletions. This study demonstrates that ZEB1 mutations account for a larger proportion of PPCD than previously estimated, and supports the hypothesis that haploinsufficiency of ZEB1 is the underlying molecular mechanism of disease for PPCD3. PMID- 26508575 TI - Identification of candidate genes for familial early-onset essential tremor. AB - Essential tremor (ET) is one of the most common causes of tremor in humans. Despite its high heritability and prevalence, few susceptibility genes for ET have been identified. To identify ET genes, whole-exome sequencing was performed in 37 early-onset ET families with an autosomal-dominant inheritance pattern. We identified candidate genes for follow-up functional studies in five ET families. In two independent families, we identified variants predicted to affect function in the nitric oxide (NO) synthase 3 gene (NOS3) that cosegregated with disease. NOS3 is highly expressed in the central nervous system (including cerebellum), neurons and endothelial cells, and is one of three enzymes that converts l arginine to the neurotransmitter NO. In one family, a heterozygous variant, c.46G>A (p.(Gly16Ser)), in NOS3, was identified in three affected ET cases and was absent in an unaffected family member; and in a second family, a heterozygous variant, c.164C>T (p.(Pro55Leu)), was identified in three affected ET cases (dizygotic twins and their mother). Both variants result in amino-acid substitutions of highly conserved amino-acid residues that are predicted to be deleterious and damaging by in silico analysis. In three independent families, variants predicted to affect function were also identified in other genes, including KCNS2 (KV9.2), HAPLN4 (BRAL2) and USP46. These genes are highly expressed in the cerebellum and Purkinje cells, and influence function of the gamma-amino butyric acid (GABA)-ergic system. This is in concordance with recent evidence that the pathophysiological process in ET involves cerebellar dysfunction and possibly cerebellar degeneration with a reduction in Purkinje cells, and a decrease in GABA-ergic tone. PMID- 26508576 TI - A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH. AB - Although 22q11.2 deletion syndrome (22q11.2DS) is the most recurrent human microdeletion syndrome associated with a highly variable phenotype, little is known about the condition's true incidence and the phenotype at diagnosis. We performed a multicenter, retrospective analysis of postnatally diagnosed patients recruited by members of the Association des Cytogeneticiens de Langue Francaise (the French-Speaking Cytogeneticists Association). Clinical and cytogenetic data on 749 cases diagnosed between 1995 and 2013 were collected by 31 French cytogenetics laboratories. The most frequent reasons for referral of postnatally diagnosed cases were a congenital heart defect (CHD, 48.6%), facial dysmorphism (49.7%) and developmental delay (40.7%). Since 2007 (the year in which array comparative genomic hybridization (aCGH) was introduced for the routine screening of patients with intellectual disability), almost all cases have been diagnosed using FISH (96.1%). Only 15 cases (all with an atypical phenotype) were diagnosed with aCGH; the deletion size ranged from 745 to 2904 kb. The deletion was inherited in 15.0% of cases and was of maternal origin in 85.5% of the latter. This is the largest yet documented cohort of patients with 22q11.2DS (the most commonly diagnosed microdeletion) from the same population. French cytogenetics laboratories diagnosed at least 108 affected patients (including fetuses) per year from among a national population of ~66 million. As observed for prenatal diagnoses, CHDs were the most frequently detected malformation in postnatal diagnoses. The most common CHD in postnatal diagnoses was an isolated septal defect. PMID- 26508577 TI - Prediction of male-pattern baldness from genotypes. AB - The global demand for products that effectively prevent the development of male pattern baldness (MPB) has drastically increased. However, there is currently no established genetic model for the estimation of MPB risk. We conducted a prediction analysis using single-nucleotide polymorphisms (SNPs) identified from previous GWASs of MPB in a total of 2725 German and Dutch males. A logistic regression model considering the genotypes of 25 SNPs from 12 genomic loci demonstrates that early-onset MPB risk is predictable at an accuracy level of 0.74 when 14 SNPs were included in the model, and measured using the area under the receiver-operating characteristic curves (AUC). Considering age as an additional predictor, the model can predict normal MPB status in middle-aged and elderly individuals at a slightly lower accuracy (AUC 0.69-0.71) when 6-11 SNPs were used. A variance partitioning analysis suggests that 55.8% of early-onset MPB genetic liability can be explained by common autosomal SNPs and 23.3% by X chromosome SNPs. For normal MPB status in elderly individuals, the proportion of explainable variance is lower (42.4% for autosomal and 9.8% for X-chromosome SNPs). The gap between GWAS findings and the variance partitioning results could be explained by a large body of common DNA variants with small effects that will likely be identified in GWAS of increased sample sizes. Although the accuracy obtained here has not reached a clinically desired level, our model was highly informative for up to 19% of Europeans, thus may assist decision making on early MPB intervention actions and in forensic investigations. PMID- 26508578 TI - Clinical utility gene card for: Hereditary thoracic aortic aneurysm and dissection including next-generation sequencing-based approaches. PMID- 26508579 TI - Thrombotic thrombocytopenic purpura after blunt traumatic liver injury. PMID- 26508580 TI - Assessing patient activation and health literacy in the ED. AB - BACKGROUND: Low health literacy and patient activation are linked to unmet health needs, excess emergency department (ED) use, and hospital admission. However, most studies have assessed these measures in non-ED populations. OBJECTIVE: The objective of the study is to assess health literacy and patient activation in the ED. METHODS: A cross-sectional study in adults older than 18 years presenting to an ED were selected using systematic sampling. Demographic data and reason for ED visit were collected. Health literacy was assessed using Rapid Estimate of Adult Literacy in Medicine (REALM). Patient activation was assessed using Patient Activation Measure. Kruskal-Wallis tests compared groups. Spearman rank correlations compared numeric variables. RESULTS: A total of 140 patients were approached, and 108 enrolled. Average age was 51 years. Most were unemployed (71%), were unmarried (80%), had a primary physician (62%), were male (60%), were African American (63%), and were on public insurance (58%). Most had an activation level of 3 or 4. The mean REALM score was 52. Patients with higher REALM scores had higher activation levels (rs = 0.30; P = .0017), although, when adjusted for age, this association was no longer significant. Sex, education, insurance status, and race were not significantly associated with REALM or activation levels. Activation levels decreased with increasing age (rs = -0.24; P = .01). Low activation levels and limited health literacy were significantly associated with admission (odds ratio, 4.4; 95% confidence interval, 1.5-12.6; P = .0061). CONCLUSIONS: This is the first study to assess Patient Activation Measure in the ED. Low activation levels and limited REALM scores assessed in the ED population were significantly associated with hospital admission. Assessing activation levels of ED patients could lead to better education and tailored discharge planning by ED clinicians potentially reducing ED revisits. PMID- 26508581 TI - Development of a prehospital vital signs chart sharing system. AB - OBJECTIVE: Physiological parameters are crucial for the caring of trauma patients. There is a significant loss of prehospital vital signs data of patients during handover between prehospital and in-hospital teams. Effective strategies for reducing the loss remain a challenging research area. We tested whether the newly developed electronic automated prehospital vital signs chart sharing system would increase the amount of prehospital vital signs data shared with a remote trauma center prior to hospital arrival. METHODS: Fifty trauma patients, transferred to a level I trauma center in Japan, were studied. The primary outcome variable was the number of prehospital vital signs shared with the trauma center prior to hospital arrival. RESULTS: The prehospital vital signs chart sharing system significantly increased the number of prehospital vital signs, including blood pressure, heart rate, and oxygen saturation, shared with the in hospital team at a remote trauma center prior to patient arrival at the hospital (P < .0001). There were significant differences in prehospital vital signs during ambulance transfer between patients who had severe bleeding and non-severe bleeding within 24 hours after injury onset. CONCLUSIONS: Vital signs data collected during ambulance transfer via patient monitors could be automatically converted to easily visible patient charts and effectively shared with the remote trauma center prior to hospital arrival. The prehospital vital signs chart sharing system increased the number of precise vital signs shared prior to patient arrival at the hospital, which can potentially contribute to better trauma care without increasing labor and reduce information loss during clinical handover. PMID- 26508582 TI - Use of capnographs to assess quality of pediatric ventilation with 3 different airway modalities. AB - OBJECTIVES: Prehospital pediatric airway management is difficult and controversial. Options include bag-mask ventilation (BMV), endotracheal tube (ETT), and laryngeal mask airway (LMA). Emergency Medical Services personnel report difficulty assessing adequacy of BMV during transport. Capnography, and capnograph tracings in particular, provide a measure of real-time ventilation currently used in prehospital medicine but have not been well studied in pediatric patients or with BMV. Our objective was to compare pediatric capnographs created with 3 airway modalities. METHODS: This was a prospective study of pediatric patients requiring ETT or LMA ventilation during elective surgical procedures. Data were collected during BMV using 2 bag types (flow inflating and self-inflating). The ETT or LMA was placed and ventilation with each bag type repeated. Ten- to 14-second capnographs were reviewed by 2 blinded anesthesiologists who were asked to assess ventilation and identify the airway and bag type used. Descriptive statistics, kappa, and risk ratios were calculated. RESULTS: Twenty-nine patients were enrolled. Median age was 4.4 years (2 months to 16.8 years). One hundred sixteen capnographs were reviewed. Reviewers were unable to differentiate between airway modalities and agreed on adequacy of ventilation 77% of the time (kappa = 0.6, P < .001). Bag-mask ventilation was rated inadequate more frequently than ETT or LMA ventilation. There were no difference between ETT and LMA ventilation and no difference between the 2 bag types. CONCLUSION: Capnographs are generated during BMV and are virtually identical to those produced with ETT or LMA ventilation. Attention to capnographs could improve outcomes during emergency treatment and transport of critically ill pediatric patients requiring ventilation with any of these airway modalities. PMID- 26508583 TI - Drivers of ED efficiency: a statistical and cluster analysis of volume, staffing, and operations. AB - STUDY OBJECTIVE: The percentage of patients leaving before treatment is completed (LBTC) is an important indicator of emergency department performance. The objective of this study is to identify characteristics of hospital operations that correlate with LBTC rates. METHODS: The Emergency Department Benchmarking Alliance 2012 and 2013 cross-sectional national data sets were analyzed using multiple regression and k-means clustering. Significant operational variables affecting LBTC including annual patient volume, percentage of high-acuity patients, percentage of patients admitted to the hospital, number of beds, academic status, waiting times to see a physician, length of stay (LOS), registered nurse (RN) staffing, and physician staffing were identified. LBTC was regressed onto these variables. Because of the strong correlation between waiting times measured as door to first provider (DTFP), we regressed DTFP onto the remaining predictors. Cluster analysis was applied to the data sets to further analyze the impact of individual predictors on LBTC and DTFP. RESULTS: LOS and the time from DTFP were both strongly associated with LBTC rate (P<.001). Patient volume is not significantly associated with LBTC rate (P=.16). Cluster analysis demonstrates that physician and RN staffing ratios correlate with shorter DTFP and lower LBTC. CONCLUSION: Volume is not the main driver of LBTC. DTFP and LOS are much more strongly associated. We show that operational factors including LOS and physician and RN staffing decisions, factors under the control of hospital and physician executives, correlate with waiting time and, thus, in determining the LBTC rate. PMID- 26508584 TI - A rare complication of scorpion venom: atrial fibrillation. AB - Although the clinical findings of scorpion stings are often mild, they may lead to multiorgan failure and even cardiogenic shock. The toxin has both local and systemic effects. Local effects include edema, bruising(ecchymosis), and burning pain,whereas systemic effects include nausea,vomiting, hypotension or hypertension, cardiovascular toxicity, renal failure,and hemorrhage at different areas. The toxins have been implicated in a number of cardiac arrhythmias, including torsade de pointes, long QT syndrome, and atrial fibrillation. Here, we present a 90-year-old woman with no history of drug use or complaints due to dysrhythmias who developed atrial fibrillation after being stung by a scorpion. PMID- 26508586 TI - Comparative dynamics of the emergence of fluoroquinolone resistance in staphylococci from the nasal microbiota of patients treated with fluoroquinolones according to their environment. AB - Fluoroquinolone-resistant staphylococci (FQRS) are primarily selected in the nasal microbiota during fluoroquinolone (FQ) treatment. To gain insight into the dynamics of the emergence of FQRS, 49 hospitalised patients (HPs) and 62 community patients (CPs) treated with FQs were studied. Nasal swabs were collected before (T0), at the end of (T1) and 1 month after (T2) FQ treatment. FQRS were identified by mass spectrometry. Antibiotic resistance was determined. Pre- and post-exposure staphylococci populations were compared phenotypically and by MLST to determine the origin of FQRS. At T0, 33/49 HPs (67%) and 24/62 CPs (39%) carried FQRS (OR=3.3, 95% CI: 1.4-7.9; P<0.001). Among patients with no FQRS at T0, 15/16 HPs (94%) and 16/38 CPs (42%) had FQRS detected at T1 and/or T2 (OR=19.6, 95% CI: 2.5-902; P<0.001). Among FQRS having emerged, co-resistance to meticillin was detected in 87% and 82% of HPs and CPs, respectively. No selection of resistance emerging from the initial microbiota was evidenced. FQRS showed decreased species diversity in favour of Staphylococcus haemolyticus and Staphylococcus epidermidis. As a consequence of FQ treatment, acquisition of FQRS in the nasal microbiota is frequent in the community and almost inevitable in hospitals. Acquisition from extranasal sites prevails. A restriction in species diversity in favour of more pathogenic and resistant species occurs. This highlights the major impact of FQ treatment on nasal microbiota, the role of the ecological environment in the emergence of FQRS, and the high-risk of dissemination of resistant staphylococci. PMID- 26508587 TI - Ultrafast spin exchange-coupling torque via photo-excited charge-transfer processes. AB - Optical control of spin is of central importance in the research of ultrafast spintronic devices utilizing spin dynamics at short time scales. Recently developed optical approaches such as ultrafast demagnetization, spin-transfer and spin-orbit torques open new pathways to manipulate spin through its interaction with photon, orbit, charge or phonon. However, these processes are limited by either the long thermal recovery time or the low-temperature requirement. Here we experimentally demonstrate ultrafast coherent spin precession via optical charge transfer processes in the exchange-coupled Fe/CoO system at room temperature. The efficiency of spin precession excitation is significantly higher and the recovery time of the exchange-coupling torque is much shorter than for the demagnetization procedure, which is desirable for fast switching. The exchange coupling is a key issue in spin valves and tunnelling junctions, and hence our findings will help promote the development of exchange-coupled device concepts for ultrafast coherent spin manipulation. PMID- 26508585 TI - Carbapenem use in French hospitals: A nationwide survey at the patient level. AB - The objective of this study was to evaluate the characteristics of carbapenem use in French healthcare settings in order to guide future actions. Healthcare facilities voluntarily participated in a nationwide cross-sectional survey in 2011. Medical data and reasons for carbapenem treatment (CPR) and discontinuation were recorded for all patients treated with carbapenems. A total of 2338 patients were recorded by 207 facilities. The median duration of CPR was 8 days, and 31.4% of patients received CPR for >10 days. An antibiotic consultant was involved in the initial choice of CPR in 36.8% of cases. CPR was chosen on an empirical (EP) basis for 1229 patients (52.6%), mainly because of severe sepsis (48.6%) or a perceived risk of bacterial resistance (33.7%). Among EP patients, de-escalation was more frequent in the case of intervention of an antibiotic consultant (35.1%) than without intervention (22.9%) (P<0.01). Among the 1109 patients receiving CPR initially based on bacteriological results, 607 (54.7%) had ESBL-producing Enterobacteriaceae and 397 (35.8%) had Gram-negative bacilli susceptible to at least one beta-lactam other than carbapenems or to fluoroquinolones. Among the latter, de-escalation was performed in 59 cases (14.9%). The intervention of an antibiotic consultant did not favour de-escalation in this group. In conclusion, carbapenems are frequently used for treating suspected or confirmed multidrug resistant bacteria, and overall CPR duration is long. De-escalation is frequently not implemented despite isolates being susceptible to other drugs. More frequent antibiotic consultant intervention may help to decrease carbapenem use in the case of EP treatment. PMID- 26508588 TI - Diet Quality of Items Advertised in Supermarket Sales Circulars Compared to Diets of the US Population, as Assessed by the Healthy Eating Index-2010. AB - BACKGROUND: Supermarkets use sales circulars to highlight specific foods, usually at reduced prices. Resulting purchases help form the set of available foods within households from which individuals and families make choices about what to eat. OBJECTIVE: The purposes of this study were to determine how closely foods featured in weekly supermarket sales circulars conform to dietary guidance and how diet quality compares with that of the US population's intakes. DESIGN: Food and beverage items (n=9,149) in 52 weekly sales circulars from a small Midwestern grocery chain in 2009 were coded to obtain food group and nutrient and energy content. Healthy Eating Index-2010 (HEI-2010) total and component scores were calculated using algorithms developed by the National Cancer Institute. HEI-2010 scores for the US population aged 2+ years were estimated using data from the 2009-2010 National Health and Nutrition Examination Survey. HEI-2010 scores of circulars and population intakes were compared using Student's t tests. RESULTS: Mean total (42.8 of 100) HEI-2010 scores of circulars were lower than that of the US population (55.4; P<0.001). Among individual components, Total Protein Foods was the only one for which 100% of the maximum score was met by both circulars and the population. The scores were also similar between the circulars and population for Whole Grains (22%; P=0.81) and Seafood and Plant Proteins (70% to 74%; P=0.33). Circular scores were lower than those of the population for Total and Whole Fruits, Total Vegetables and Greens and Beans, Dairy, Sodium, and Empty Calories (P<0.001); they were higher only for Fatty Acids (P=0.006) and Refined Grains (P<0.001). CONCLUSIONS: HEI-2010 total scores for these sales circulars were even lower than US population scores, which have been shown repeatedly to reflect low diet quality. Supermarkets could support improvements in consumer diets by weekly featuring foods that are more in concordance with food and nutrient recommendations. PMID- 26508589 TI - Metabolic profiling reveals potential metabolic markers associated with Hypoxia Inducible Factor-mediated signalling in hypoxic cancer cells. AB - Hypoxia inducible factors (HIFs) plays an important role in oxygen compromised environments and therefore in tumour survival. In this research, metabolomics has been applied to study HIFs metabolic function in two cell models: mouse hepatocellular carcinoma and human colon carcinoma, whereby the metabolism has been profiled for a range of oxygen potentials. Wild type cells have been compared to cells deficient in HIF signalling to reveal its effect on cellular metabolism under normal oxygen conditions as well as low oxygen, hypoxic and anoxic environments. Characteristic responses to hypoxia that were conserved across both cell models involved the anti-correlation between 2-hydroxyglutarate, 2-oxoglutarate, fructose, hexadecanoic acid, hypotaurine, pyruvate and octadecenoic acid with 4-hydroxyproline, aspartate, cysteine, glutamine, lysine, malate and pyroglutamate. Further to this, network-based correlation analysis revealed HIF specific pathway responses to each oxygen condition that were also conserved between cell models. From this, 4-hydroxyproline was revealed as a regulating hub in low oxygen survival of WT cells while fructose appeared to be in HIF deficient cells. Pathways surrounding these hubs were built from the direct connections of correlated metabolites that look beyond traditional pathways in order to understand the mechanism of HIF response to low oxygen environments. PMID- 26508590 TI - Association analyses of large-scale glycan microarray data reveal novel host specific substructures in influenza A virus binding glycans. AB - Influenza A viruses can infect a wide variety of animal species and, occasionally, humans. Infection occurs through the binding formed by viral surface glycoprotein hemagglutinin and certain types of glycan receptors on host cell membranes. Studies have shown that the alpha2,3-linked sialic acid motif (SA2,3Gal) in avian, equine, and canine species; the alpha2,6-linked sialic acid motif (SA2,6Gal) in humans; and SA2,3Gal and SA2,6Gal in swine are responsible for the corresponding host tropisms. However, more detailed and refined substructures that determine host tropisms are still not clear. Thus, in this study, we applied association mining on a set of glycan microarray data for 211 influenza viruses from five host groups: humans, swine, canine, migratory waterfowl, and terrestrial birds. The results suggest that besides Neu5Acalpha2 6Galbeta, human-origin viruses could bind glycans with Neu5Acalpha2-8Neu5Acalpha2 8Neu5Ac and Neu5Gcalpha2-6Galbeta1-4GlcNAc substructures; Galbeta and GlcNAcbeta terminal substructures, without sialic acid branches, were associated with the binding of human-, swine-, and avian-origin viruses; sulfated Neu5Acalpha2-3 substructures were associated with the binding of human- and swine-origin viruses. Finally, through three-dimensional structure characterization, we revealed that the role of glycan chain shapes is more important than that of torsion angles or of overall structural similarities in virus host tropisms. PMID- 26508591 TI - A critical assessment on the role of sentinel node mapping in endometrial cancer. AB - Endometrial cancer is the most common gynecologic malignancy in the developed countries. Although the high incidence of this occurrence no consensus, about the role of retroperitoneal staging, still exists. Growing evidence support the safety and efficacy of sentinel lymph node mapping. This technique is emerging as a new standard for endometrial cancer staging procedures. In the present paper, we discuss the role of sentinel lymph node mapping in endometrial cancer, highlighting the most controversies features. PMID- 26508592 TI - Immunolocalization of FGF7 (KGF) in the regenerating tail of lizard suggests it is involved in the differentiation of the epidermis. AB - Previous studies showed that Fibroblast Growth Factors (FGF) 1 and 2 are localized in the tissues of the regenerating tail in lizards. In the present immunofluorescence and immunoblotting study we have specifically analyzed the presence and distribution of FGF7 (keratinocyte growth factor) in the regenerating tissues of the tail. FGF7 immunoreactivity is mainly detected in the regenerating epidermis and in sparse fibroblasts of the underlying dermis of the regenerating scales while it is weaker in the other tissues such as the apical ependymal cells and early regenerating muscles. Immunolabeled mesenchymal fibroblasts are frequently present under the epidermis of the forming outer scale surface, a localization that might be connected to beta-cell differentiation in this region of the scale. FGF7 immunolabeling is also seen in differentiating beta-keratinocytes of the beta-layer in the regenerating scales. The present immunofluorescent observations suggest that FGF7 is specifically utilized as a paracrine factor during the process of differentiation of the epidermal layers in the regenerating scales and in particular for beta-cells differentiation. PMID- 26508593 TI - Wavelength-tunable waveguides based on polycrystalline organic-inorganic perovskite microwires. AB - Hybrid organic-inorganic perovskites have emerged as new photovoltaic materials with impressively high power conversion efficiency due to their high optical absorption coefficient and long charge carrier diffusion length. In addition to high photoluminescence quantum efficiency and chemical tunability, hybrid organic inorganic perovskites also show intriguing potential for diverse photonic applications. In this work, we demonstrate that polycrystalline organic-inorganic perovskite microwires can function as active optical waveguides with small propagation loss. The successful production of high quality perovskite microwires with different halogen elements enables the guiding of light with different colours. Furthermore, it is interesting to find that out-coupled light intensity from the microwire can be effectively modulated by an external electric field, which behaves as an electro-optical modulator. This finding suggests the promising applications of perovskite microwires as effective building blocks in micro/nano scale photonic circuits. PMID- 26508594 TI - Calibration of communication skills items in OSCE checklists according to the MAAS-Global. AB - BACKGROUND: Communication skills (CS) are commonly assessed using 'communication items' in Objective Structured Clinical Examination (OSCE) station checklists. Our aim is to calibrate the communication component of OSCE station checklists according to the MAAS-Global which is a valid and reliable standard to assess CS in undergraduate medical education. METHOD: Three raters independently compared 280 checklists from 4 disciplines contributing to the undergraduate year 4 OSCE against the 17 items of the MAAS-Global standard. G-theory was used to analyze the reliability of this calibration procedure. RESULTS: G-Kappa was 0.8. For two raters G-Kappa is 0.72 and it fell to 0.57 for one rater. 46% of the checklist items corresponded to section three of the MAAS-Global (i.e. medical content of the consultation), whilst 12% corresponded to section two (i.e. general CS), and 8.2% to section one (i.e. CS for each separate phase of the consultation). 34% of the items were not considered to be CS. CONCLUSION: A G-Kappa of 0.8 confirms a reliable and valid procedure for calibrating OSCE CS checklist items using the MAAS-Global. We strongly suggest that such a procedure is more widely employed to arrive at a stable (valid and reliable) judgment of the communication component in existing checklists for medical students' communication behaviours. PRACTICE IMPLICATIONS: It is possible to measure the 'true' caliber of CS in OSCE stations. Students' results are thereby comparable between and across stations, students and institutions. A reliable calibration procedure requires only two raters. PMID- 26508595 TI - Intermediate Neoadjuvant Radiotherapy Combined With Total Mesorectal Excision for Locally Advanced Rectal Cancer: Outcomes After a Median Follow-Up of 5 Years. AB - BACKGROUND: We previously reported the oncologic results for intermediate neoadjuvant radiotherapy (nRT) plus total mesorectal excision (TME) for locally advanced rectal cancer in a retrospective study. The objective of the present study was to further investigate the efficacy and long-term outcomes after this nRT regimen. PATIENTS AND METHODS: From 2002 to 2011, 382 patients with resectable locally advanced rectal cancer were treated at the Peking University Cancer Hospital with 30 Gy of intermediate nRT in 10 fractions (biologic equivalent dose, 36 Gy) plus TME. Surgery, RT, and pathologic examination were standardized. The primary endpoints were local recurrence-free survival (LRFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: The median patient age at the initial treatment was 58 years (range, 22-85 years). The median patient follow-up time was 5.5 years. The estimated 5-year LRFS, CSS, and OS were 93.6%, 79.0%, and 73.6%, respectively. Of the 382 patients, 4 (1%), 4 (1%), 4 (1%), and 11 (2.9%) patients died of postoperative complications, secondary malignancies, cardiovascular and/or neurologic events, or other causes, respectively. Seven patients (1.8%) developed late-onset ileus and died after conservative treatment in peripheral hospitals. CONCLUSION: The 10-fraction intermediate nRT regimen reported in the present study is efficient and safe. The long-term outcome is acceptable. This treatment schedule is useful as an alternative that provides efficiency, patient convenience, and low medical costs. PMID- 26508596 TI - Swiss Life Sciences Start-ups - A 'tour d'horizon'. PMID- 26508597 TI - Venture Capital Investments for Life Sciences Start-ups in Switzerland. AB - Despite its economic and technological importance, the Swiss life sciences sector faces severe challenges in attracting enough venture capital for its own development. Although biotechnology and medical technology have been the most important areas of venture financing from 1999 through 2012 according to our own data, average investment volumes nevertheless remain on a low level of only 0.05 percent of Swiss GDP. After 2008, there was a pronounced shift away from early stage financing. While business angels still play an important role at the early stage, venture capitalists are the most important investor type by volumes having their main focus on expansion financing. The industry faces predominant challenges in securing capital availability for entrepreneurs, in transforming the highly skewed and back-loaded payoff profile of investments into a more stable return stream, and in defining appropriate business and collaboration models. PMID- 26508598 TI - Beyond Borders 2014 - Overview of the Biotechnology Landscape. AB - The global biotechnology industry rebounded strongly in 2013. Public companies achieved double-digit revenue growth and there was a sharp rise in funds. Product successes have boosted revenues, drawn investors and motivated large companies to invest strongly in R&D. However, much of the industry's growth was driven by a relatively small group of commercial stage companies, increasing the urgency for the rest of the industry to achieve greater efficiency in their drug development efforts. PMID- 26508599 TI - Business Angels - A Subspecies of the homo oeconomicus ludens. AB - Business Angels invest in start-up companies in their early stage. This type of investor usually has a good knowledge of the start-up's industry sector, and in addition to the funds he invests, his management experience and his network can be useful for start-ups. Business Angel involvement has shown to improve the success rate and the profitability of start-ups. The article depicts the relationship between entrepreneurs and Business Angels in four case examples. PMID- 26508600 TI - Venture Capital Investment in the Life Sciences in Switzerland. AB - Innovation is one of the main driving factors for continuous and healthy economic growth and welfare. Switzerland as a resource-poor country is particularly dependent on innovation, and the life sciences, which comprise biotechnologies, (bio)pharmaceuticals, medical technologies and diagnostics, are one of the key areas of innovative strength of Switzerland. Venture capital financing and venture capitalists (frequently called 'VCs') and investors in public equities have played and still play a pivotal role in financing the Swiss biotechnology industry. In the following some general features of venture capital investment in life sciences as well as some opportunities and challenges which venture capital investors in Switzerland are facing are highlighted. In addition certain means to counteract these challenges including the 'Zukunftsfonds Schweiz' are discussed. PMID- 26508601 TI - Legal Challenges and Pitfalls for Start-up Companies - 48 Common Questions and Answers. AB - Transforming a business idea into reality requires a legal implementation plan. The following 48 questions and answers address key issues that typically arise in start-up situations. Early planning can help avoid costly mistakes. PMID- 26508602 TI - A Strong Start-up Scene Flourishes in the Life Sciences Capital Basel. AB - Basel is known for its successful global players in Pharma, Agro and Chemicals. The wealth of top-tier companies, universities and academic institutions in such a small region is unparalleled. It creates an optimum climate for world-class research and its translation into successful businesses. This is also reflected in a strong start-up scene. Over the past decades the multinational players have shown that they are able to adapt to the ever-increasing challenges in the market. Basel has seen blue-chip company mergers, accompanied by the transfer of business assets into spin-off companies. This process created a mind-set for change which has positively influenced the local start-up environment. Actelion is one of these former spin-offs that successfully made the transition to become a global player. BioVersys and PIQUR are two of the most promising very early stage Swiss biotech companies. Many other examples can be found in Northwestern Switzerland. The region also offers a solid background of supporting activities. Infrastructure, coaching and all other support are offered and complement national innovation initiatives. PMID- 26508603 TI - The Greater Zurich Area is Well-positioned in the Life Sciences in Switzerland and Europe. AB - The Greater Zurich Area has become a hub for the life sciences industry in recent years, with above-average numbers of medtech companies and brisk spin-off activities from the Zurich universities. The spin-offs have established themselves near their scientific origins, in incubators and parks where they have access to functional and affordable laboratory infrastructures. Numerous cluster initiatives and networks foster exchanges between start-ups, established companies and academia. An international regional comparison conducted within the framework of the EU HealthTIES project gave the region of Zurich a good score in the life sciences area. The detailed comparison shows that Zurich is strong in the academic field and the existing companies are well-positioned. However, weaknesses are evident in the field of clinical research and in the interface between academia and industry. The infrastructure offerings in the Greater Zurich Area for life sciences companies and for exchanges between academia and industry will be further expanded in the coming years. Whether the high growth rate of the industry in the Greater Zurich Area can be maintained or even increased depends on the economy and other factors, but also on the political environment. PMID- 26508604 TI - The Health Valley: Global Entrepreneurial Dynamics. AB - In the space of a decade, the Lake Geneva region has become the Health Valley, a world-class laboratory for discovering and developing healthcare of the future. Through visionary individuals and thanks to exceptional infrastructure this region has become one of the most dynamic in the field of innovation, including leading scientific research and exceptional actors for the commercialization of academic innovation to industrial applications that will improve the lives of patients and their families. Here follows the chronicle of a spectacular expansion into the Health Valley. PMID- 26508605 TI - Life Sciences in the Ticino: Two Scientists - Two Stories. AB - Luca Varani, PhD, a group leader in Structural Biology at the Institute for Research in Biomedicine, Bellinzona, and Marco Brini, founder and CEO of EnvEve SA, in the Tecnopolo in Manno, describe their life sciences background, their careers and why they percieve their ideal situation being a basic scientist who wants to remain in science, or being an entrepreneur respectively. PMID- 26508606 TI - Life Science Start-up Activities at the Universities of Applied Sciences (UAS). AB - The universities of applied sciences (UAS) provide several values for the society and economy of a country. Besides education of high level professionals, transfer of knowledge from research to applications in industry or as new start-up companies is an important task. This is done in different ways in the various disciplines. In Life Sciences, a key industry branch in Switzerland, innovation is a competitive success factor and research findings from UAS/Life Sciences contribute to the valorization of new technologies to products, services and to business performance. In order to foster awareness for the innovation need of industry, UAS install processes and support for transfer of research and technology results to marketable applications. Furthermore they may facilitate contacts of researchers and students with entrepreneurs in order to animate start up founding as a true alternative to being employed. Access to coaching and entrepreneurial training completes the essential basis. PMID- 26508607 TI - Commercializing Academic Research Results and the Role of Spin-off Companies. AB - The commercialization of academic research results is often difficult and requires a flexible approach that depends on the nature of the project. Most technologies are very early-stage and often not mature enough for industry partners or financial investors. Spin-off companies play an important role in this process. Through their activities universities make an important contribution to the innovation capacity of industry. PMID- 26508608 TI - Life Sciences Start-ups in Switzerland: CTI and its Support for Young Entrepreneurs. AB - According to the Global Entrepreneurship Monitor 2013, perceived opportunities to start a business in Switzerland are high and rank above average compared to other innovation-based countries. 2013 was a record year for start-ups in Switzerland. Around 40,000 new businesses were recorded in the commercial register and the trend is set to continue. There are two main criteria that lead to success, particularly for science- or technology- based start-ups: first of all, it is the business or product idea itself, and secondly it is the entrepreneurial team. CTI is supporting innovation in a manner that responds to a need in the market identified by industry. PMID- 26508609 TI - Innovate with the CTI National Thematic Networks. AB - Winning in the global market place with brilliant innovations is the recipe for success for the Swiss economy. Indeed, Switzerland always stands out in the global rankings when it comes to innovation. Yet there is nothing as dangerous as to rest on one's laurels, and this is particularly true for R&D-based businesses. For this reason CTI, the Commission for Technology and Innovation, offers Swiss companies quick and effective access to knowledge available at Swiss public research institutions, and to international R&D programs promoting application oriented research. Knowledge and technology transfer are promoted - via its KTT support - through National Thematic Networks (NTNs), Innovation Mentors and information platforms. The following article highlights the activities of the National Thematic Networks and invites Swiss companies and research institutes to benefit from the multiple offers and services available. PMID- 26508610 TI - Foundations as Promoters of Life Science Start-ups. AB - Because private foundations have only modest financial resources compared to public and private-sector research funding, the only way in which foundations can play a key role is in the initial and risk financing of gap areas. This is generally in what is known as the 'valley of death', but even there an additional focus is needed. One promising field is the very early-stage support for high risk but high-potential business cases in order to increase the number of start ups, not only but very often in the field of life sciences. The pre-seed fund venture kick, an initiative by private foundations, is a good example of success. There is still a gap in the innovation chain in Switzerland from the first research results to becoming a successful life science company. However, for the first time promising solutions are on the way, and here too, foundations can play an important role. PMID- 26508611 TI - >>venture>>: Support for Early Stage Start-ups and Potential Entrepreneurs. AB - >>venture>>, the leading Swiss-wide business plan competition, is an ideal partner for young start-ups and entrepreneurs. For the upcoming tenth anniversary edition the competition will receive an update. Building upon a successful base of the past nine editions and equipped with contemporary networking events and more know-how transferring seminars, >>venture>> will fit even better into the Swiss start-up ecosystem. PMID- 26508612 TI - Seed Capital for Young Entrepreneurs since more than 25 Years. AB - The WA de Vigier Foundation has supported start-up companies with a total of almost CHF 10 million since the late 1980s. And very successfully too: thanks to the seed money from Solothurn, the sponsored start-ups have provided hundreds of jobs. PMID- 26508613 TI - BioVersys Works to Bring Antibiotic Resistance to an End. AB - BioVersys, founded in 2008, is working on bringing a technology for screening and for the development of 'transcriptional regulator inhibiting compounds' (TRICs) to patients in order to overcome antibiotic resistance. The co-founders share their view on what makes successful scientists pursue a career as start-up entrepreneurs rather than a classic academic career. They describe the history and milestones of their company, and how their everyday work differs from that of peers in an academic or industrial research setting. PMID- 26508614 TI - Big Hopes with Small Molecules - PIQUR Therapeutics AG is aiming to Turn Cancer into a Manageable Disease. AB - The origins of PIQUR Therapeutics AG, which was established in 2011, are found in significant research work at the University of Basel. The main focus of the spin off of the University of Basel is the active pharmaceutical ingredient PQR309, which was used for the first time at the beginning of 2014 in Phase I trials in humans at University Hospital Basel. The small molecule, which was developed for targeted cancer therapy, intervenes with two major signaling pathways of cell growth. In just three years PIQUR secured funding of over 37 million Swiss Francs from private investors and Versant Venture, a leading venture capital firm. PMID- 26508615 TI - Crystal-clear - The '2014 Most Superlative Crystal Growth Contest' for School Classes. AB - To celebrate the International Year of Crystallography among the general public, a consortium of chemists, physicists and crystallographers of the University of Geneva organised in Spring 2014 an incentive crystal growth contest for Geneva scholars aged 4 to 19. Starting from a kit containing a salt and user instructions, classes had to prepare a crystal that met specific criteria according to their category of age. The composition of the salt - potassium dihydrogen phosphate (KDP) - was only disclosed to the participants during the final Awards Ceremony. This contest positively exceeded our expectations with almost 100 participating classes (ca. 1800 participants) and 54 specimens received over all categories. PMID- 26508616 TI - A Novel Approach to Shear-sensitive Fluids When Research and Industry Get Creative Together. AB - ZHAW Wadenswil, a pioneer in single-use technology, and Zurich-based LEVITRONIX, the world leader in bearingless motor technology, are developing a novel centrifugal pump with support from the Commission for Technology and Innovation (CTI). By increasing process efficiency, the pump sets new standards in biopharmaceutical production. PMID- 26508617 TI - Advancing Schwarzenbach's Complexometry: Nano-scale Titration Reagents Based on Heterogeneous Reactions. PMID- 26508620 TI - CRTC2 and Nedd4 ligase involvement in FSH and TGFbeta1 upregulation of connexin43 gap junction. AB - The major mission of the ovarian follicle is the timely production of the mature fertilizable oocyte, and this is achieved by gonadotropin-regulated, gap junction mediated cell-cell communication between the oocyte and surrounding nurturing granulosa cells. We have demonstrated that FSH and transforming growth factor beta 1 (TGFbeta1) stimulate Gja1 gene-encoded connexin43 (Cx43) gap junction formation/function in rat ovarian granulosa cells is important for their induction of steroidogenesis; additionally, cAMP-protein kinase A (PKA)- and calcium-calcineurin-sensitive cAMP response element-binding (CREB) coactivator CRTC2 plays a crucial role during steroidogenesis. This study was to explore the potential molecular mechanism whereby FSH and TGFbeta1 regulate Cx43 synthesis and degradation, particularly the involvement of CRTC2 and ubiquitin ligase Nedd4. Primary culture of granulosa cells from ovarian antral follicles of gonadotropin-primed immature rats was used. At 48 h post-treatment, FSH plus TGFbeta1 increased Cx43 level and gap junction function in a PKA- and calcineurin dependent manner, and TGFbeta1 acting through its type I receptor modulated FSH action. Chromatin-immunoprecipitation analysis reveals FSH induced an early-phase (45 min) and FSH+TGFbeta1 further elicited a late-phase (24 h) increase in CRTC2, CREB and CBP binding to the Gja1 promoter. Additionally, FSH+TGFbeta1 increased the half-life of hyper-phosphorylated Cx43 (Cx43-P2). Also, the proteasome inhibitor MG132 prevented the brefeldin A (blocker of protein transport through Golgi)-reduced Cx43-P2 level and membrane Cx43 gap junction plaque. This is associated with FSH+TGFbeta1-attenuated Cx43 interaction with Nedd4 and Cx43 ubiquitination. In all, this study uncovers that FSH and TGFbeta1 upregulation of Cx43 gap junctions in ovarian granulosa cells critically involves enhancing CRTC2/CREB/CBP-mediated Cx43 expression and attenuating ubiquitin ligase Nedd4 mediated proteosomal degradation of Cx43 protein. PMID- 26508621 TI - Charles Bernard Puestow (1902-1973): American surgeon and commander of the 27th Evacuation Hospital during the Second World War. AB - Dr. Charles Bernard Puestow (1902-1973) was an American surgeon who is well known for developing the longitudinal pancreaticojejunostomy, which is known as the "Puestow procedure" in his honor. Puestow served in the American military during the Second World War and commanded the 27th Evacuation Hospital, which provided medical and surgical services to wounded individuals in Europe and North Africa. In 1946, he founded the surgical residency training program at the Hines Veterans Hospital, which was the first such program in the United States based at a veterans hospital. PMID- 26508622 TI - Franklin Delano Roosevelt's (FDR's) (1882-1945) 1921 neurological disease revisited; the most likely diagnosis remains Guillain-Barre syndrome. AB - In 2003, we published evidence that the most likely cause of FDR's 1921 neurological disease was Guillain-Barre syndrome. Afterwards, several historians and neurologists stated in their publications that FDR had paralytic poliomyelitis. However, significant criticism of our article or new support for that diagnosis was not revealed. One critic claimed that FDR's cerebrospinal fluid indicated poliomyelitis, but we did not find evidence that a lumbar puncture was performed. The diagnosis of FDR's neurological disease still depends upon documented clinical abnormalities. His age, prolonged symmetric ascending paralysis, transient numbness, protracted dysaesthesia (pain on slight touch), facial paralysis, bladder and bowel dysfunction, and absence of meningismus are typical of Guillain-Barre syndrome and are inconsistent with paralytic poliomyelitis. FDR's prolonged fever was atypical for both diseases. Finally, permanent paralysis, though commoner in paralytic poliomyelitis, is frequent in Guillain-Barre syndrome. Thus, the clinical findings indicate the most likely diagnosis in FDR's case remains Guillain-Barre syndrome. PMID- 26508623 TI - Edward Gantt (1742-1837): US senate chaplain and first White House physician to Thomas Jefferson. AB - In his long and eventful life, Edward Gantt (1742-1837) made important contributions to the newly independent American Republic, as well as to the development of scientific evidence-based American medicine. Unfortunately, his achievements have gone unrecognized and unreported in mainstream historical publications. Specifically, his service as the first designated White House doctor, and personal physician to President Thomas Jefferson from 1801 to 1809 has not been reported. The purpose of this paper is to document the biographical and scientific details of his extraordinary life and notable contributions. PMID- 26508624 TI - Beethoven's autopsy revisited: A pathologist sounds a final note. AB - This review of the original autopsy report of Beethoven's remains indicates Paget's disease within the skull, which was dense and twice normal thickness, with dilated vessels at the petrous bone. The facial nerves were enlarged and the eighth nerves atrophied despite their sharing a common meatus at the internal auditory canal. Nephrolithiasis and pyelonephritis with cortical and perinephric abscesses were also reported. The hypercalcaemia was probably caused by hyperparathyroidism, which may be associated with Paget's disease, and both may have played a role in his psychiatric symptoms as well as in his abdominal pain and gastrointestinal complaints. Since Paget's disease may also be associated with gout, some of the joint pains could be attributable to this as well. Hypovitaminosis A from chronic pancreatitis is suggested as a cause of painful eyes and either quinine abuse or severe hypercalcaemia as a cause of arrhythmias. Beethoven died of terminal cirrhosis with chronic pancreatitis, most likely related to chronic excessive intake of alcohol. Thus, Paget's disease, complicated by hyperparathyroidism, gout, and attempts to find relief of symptoms through the use of alcohol, quinine, and possibly salicylates can explain virtually all of Beethoven's medical problems, some of which appear to have influenced his musical compositions. PMID- 26508625 TI - Downward shift of montane grasslands exemplifies the dual threat of human disturbances to cloud forest biodiversity. PMID- 26508626 TI - Reply to Feeley and Rehm: Land-use intensification increases risk of species losses from climate change. PMID- 26508627 TI - Reply to Salkeld et al.: Diversity-disease patterns are robust to study design, selection criteria, and publication bias. PMID- 26508628 TI - Patterns, causes, and consequences of marine larval dispersal. AB - Quantifying the probability of larval exchange among marine populations is key to predicting local population dynamics and optimizing networks of marine protected areas. The pattern of connectivity among populations can be described by the measurement of a dispersal kernel. However, a statistically robust, empirical dispersal kernel has been lacking for any marine species. Here, we use genetic parentage analysis to quantify a dispersal kernel for the reef fish Elacatinus lori, demonstrating that dispersal declines exponentially with distance. The spatial scale of dispersal is an order of magnitude less than previous estimates the median dispersal distance is just 1.7 km and no dispersal events exceed 16.4 km despite intensive sampling out to 30 km from source. Overlaid on this strong pattern is subtle spatial variation, but neither pelagic larval duration nor direction is associated with the probability of successful dispersal. Given the strong relationship between distance and dispersal, we show that distance-driven logistic models have strong power to predict dispersal probabilities. Moreover, connectivity matrices generated from these models are congruent with empirical estimates of spatial genetic structure, suggesting that the pattern of dispersal we uncovered reflects long-term patterns of gene flow. These results challenge assumptions regarding the spatial scale and presumed predictors of marine population connectivity. We conclude that if marine reserve networks aim to connect whole communities of fishes and conserve biodiversity broadly, then reserves that are close in space (<10 km) will accommodate those members of the community that are short-distance dispersers. PMID- 26508629 TI - HER2 missense mutations have distinct effects on oncogenic signaling and migration. AB - Recurrent human epidermal growth factor receptor 2 (HER2) missense mutations have been reported in human cancers. These mutations occur primarily in the absence of HER2 gene amplification such that most HER2-mutant tumors are classified as "negative" by FISH or immunohistochemistry assays. It remains unclear whether nonamplified HER2 missense mutations are oncogenic and whether they are targets for HER2-directed therapies that are currently approved for the treatment of HER2 gene-amplified breast cancers. Here we functionally characterize HER2 kinase and extracellular domain mutations through gene editing of the endogenous loci in HER2 nonamplified human breast epithelial cells. In in vitro and in vivo assays, the majority of HER2 missense mutations do not impart detectable oncogenic changes. However, the HER2 V777L mutation increased biochemical pathway activation and, in the context of a PIK3CA mutation, enhanced migratory features in vitro. However, the V777L mutation did not alter in vivo tumorigenicity or sensitivity to HER2-directed therapies in proliferation assays. Our results suggest the oncogenicity and potential targeting of HER2 missense mutations should be considered in the context of cooperating genetic alterations and provide previously unidentified insights into functional analysis of HER2 mutations and strategies to target them. PMID- 26508630 TI - Foxg1 localizes to mitochondria and coordinates cell differentiation and bioenergetics. AB - Forkhead box g1 (Foxg1) is a nuclear-cytosolic transcription factor essential for the forebrain development and involved in neurodevelopmental and cancer pathologies. Despite the importance of this protein, little is known about the modalities by which it exerts such a large number of cellular functions. Here we show that a fraction of Foxg1 is localized within the mitochondria in cell lines, primary neuronal or glial cell cultures, and in the mouse cortex. Import of Foxg1 in isolated mitochondria appears to be membrane potential-dependent. Amino acids (aa) 277-302 were identified as critical for mitochondrial localization. Overexpression of full-length Foxg1 enhanced mitochondrial membrane potential (DeltaPsim) and promoted mitochondrial fission and mitosis. Conversely, overexpression of the C-term Foxg1 (aa 272-481), which is selectively localized in the mitochondrial matrix, enhanced organelle fusion and promoted the early phase of neuronal differentiation. These findings suggest that the different subcellular localizations of Foxg1 control the machinery that brings about cell differentiation, replication, and bioenergetics, possibly linking mitochondrial functions to embryonic development and pathological conditions. PMID- 26508631 TI - Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation. AB - Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) on dendritic cells (DCs) leads to DC maturation, a process involving up regulation of MHC and costimulatory molecules and secretion of proinflammatory cytokines. All TLRs except TLR3 achieve these outcomes by using the signaling adaptor myeloid differentiation factor 88. TLR4 and TLR3 can both use the Toll-IL 1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-dependent signaling pathway leading to IFN regulatory factor 3 (IRF3) activation and induction of IFN beta and -alpha4. The TRIF signaling pathway, downstream of both of these TLRs, also leads to DC maturation, and it has been proposed that the type I IFNs act in cis to induce DC maturation and subsequent effects on adaptive immunity. The present study was designed to understand the molecular mechanisms of TRIF mediated DC maturation. We have discovered that TLR4-TRIF-induced DC maturation was independent of both IRF3 and type I IFNs. In contrast, TLR3-mediated DC maturation was completely dependent on type I IFN feedback. We found that differential activation of mitogen-activated protein kinases by the TLR4- and TLR3-TRIF axes determined the type I IFN dependency for DC maturation. In addition, we found that the adjuvanticity of LPS to induce T-cell activation is completely independent of type I IFNs. The important distinction between the TRIF mediated signaling pathways of TLR4 and TLR3 discovered here could have a major impact in the design of future adjuvants that target this pathway. PMID- 26508632 TI - Heterochromatin remodeling by CDK12 contributes to learning in Drosophila. AB - Dynamic regulation of chromatin structure is required to modulate the transcription of genes in eukaryotes. However, the factors that contribute to the plasticity of heterochromatin structure are elusive. Here, we report that cyclin dependent kinase 12 (CDK12), a transcription elongation-associated RNA polymerase II (RNAPII) kinase, antagonizes heterochromatin enrichment in Drosophila chromosomes. Notably, loss of CDK12 induces the ectopic accumulation of heterochromatin protein 1 (HP1) on euchromatic arms, with a prominent enrichment on the X chromosome. Furthermore, ChIP and sequencing analysis reveals that the heterochromatin enrichment on the X chromosome mainly occurs within long genes involved in neuronal functions. Consequently, heterochromatin enrichment reduces the transcription of neuronal genes in the adult brain and results in a defect in Drosophila courtship learning. Taken together, these results define a previously unidentified role of CDK12 in controlling the epigenetic transition between euchromatin and heterochromatin and suggest a chromatin regulatory mechanism in neuronal behaviors. PMID- 26508633 TI - Public health perspective on patterns of biodiversity and zoonotic disease. PMID- 26508634 TI - Allosteric activation of M4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice. AB - Mutations that lead to Huntington's disease (HD) result in increased transmission at glutamatergic corticostriatal synapses at early presymptomatic stages that have been postulated to set the stage for pathological changes and symptoms that are observed at later ages. Based on this, pharmacological interventions that reverse excessive corticostriatal transmission may provide a novel approach for reducing early physiological changes and motor symptoms observed in HD. We report that activation of the M4 subtype of muscarinic acetylcholine receptor reduces transmission at corticostriatal synapses and that this effect is dramatically enhanced in presymptomatic YAC128 HD and BACHD relative to wild-type mice. Furthermore, chronic administration of a novel highly selective M4 positive allosteric modulator (PAM) beginning at presymptomatic ages improves motor and synaptic deficits in 5-mo-old YAC128 mice. These data raise the exciting possibility that selective M4 PAMs could provide a therapeutic strategy for the treatment of HD. PMID- 26508636 TI - Phase transition-induced band edge engineering of BiVO4 to split pure water under visible light. AB - Through phase transition-induced band edge engineering by dual doping with In and Mo, a new greenish BiVO4 (Bi1-XInXV1-XMoXO4) is developed that has a larger band gap energy than the usual yellow scheelite monoclinic BiVO4 as well as a higher (more negative) conduction band than H(+)/H2 potential [0 VRHE (reversible hydrogen electrode) at pH 7]. Hence, it can extract H2 from pure water by visible light-driven overall water splitting without using any sacrificial reagents. The density functional theory calculation indicates that In(3+)/Mo(6+) dual doping triggers partial phase transformation from pure monoclinic BiVO4 to a mixture of monoclinic BiVO4 and tetragonal BiVO4, which sequentially leads to unit cell volume growth, compressive lattice strain increase, conduction band edge uplift, and band gap widening. PMID- 26508635 TI - The essential gene set of a photosynthetic organism. AB - Synechococcus elongatus PCC 7942 is a model organism used for studying photosynthesis and the circadian clock, and it is being developed for the production of fuel, industrial chemicals, and pharmaceuticals. To identify a comprehensive set of genes and intergenic regions that impacts fitness in S. elongatus, we created a pooled library of ~ 250,000 transposon mutants and used sequencing to identify the insertion locations. By analyzing the distribution and survival of these mutants, we identified 718 of the organism's 2,723 genes as essential for survival under laboratory conditions. The validity of the essential gene set is supported by its tight overlap with well-conserved genes and its enrichment for core biological processes. The differences noted between our dataset and these predictors of essentiality, however, have led to surprising biological insights. One such finding is that genes in a large portion of the TCA cycle are dispensable, suggesting that S. elongatus does not require a cyclic TCA process. Furthermore, the density of the transposon mutant library enabled individual and global statements about the essentiality of noncoding RNAs, regulatory elements, and other intergenic regions. In this way, a group I intron located in tRNA(Leu), which has been used extensively for phylogenetic studies, was shown here to be essential for the survival of S. elongatus. Our survey of essentiality for every locus in the S. elongatus genome serves as a powerful resource for understanding the organism's physiology and defines the essential gene set required for the growth of a photosynthetic organism. PMID- 26508637 TI - Structural rearrangements preceding dioxygen formation by the water oxidation complex of photosystem II. AB - Photosynthetic water oxidation is catalyzed by the Mn4CaO5 cluster of photosystem II. Recent studies implicate an oxo bridge atom, O5, of the Mn4CaO5 cluster, as the "slowly exchanging" substrate water molecule. The D1-V185N mutant is in close vicinity of O5 and known to extend the lag phase and retard the O2 release phase (slow phase) in this critical last [Formula: see text] transition of water oxidation. The pH dependence, hydrogen/deuterium (H/D) isotope effect, and temperature dependence on the O2 release kinetics for this mutant were studied using time-resolved O2 polarography, and comparisons were made with WT and two mutants of the putative proton gate D1-D61. Both kinetic phases in V185N are independent of pH and buffer concentration and have weaker H/D kinetic isotope effects. Each phase is characterized by a parallel or even lower activation enthalpy but a less favorable activation entropy than the WT. The results indicate new rate-determining steps for both phases. It is concluded that the lag does not represent inhibition of proton release but rather, slowing of a previously unrecognized kinetic phase involving a structural rearrangement or tautomerism of the S3 (+) ground state as it approaches a configuration conducive to dioxygen formation. The parallel impacts on both the lag and O2 formation phases suggest a common origin for the defects surmised to be perturbations of the H-bond network and the water cluster adjacent to O5. PMID- 26508638 TI - CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice. AB - Here, we show CRISPR/Cas9-based targeted somatic multiplex-mutagenesis and its application for high-throughput analysis of gene function in mice. Using hepatic single guide RNA (sgRNA) delivery, we targeted large gene sets to induce hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). We observed Darwinian selection of target genes, which suppress tumorigenesis in the respective cellular/tissue context, such as Pten or Cdkn2a, and conversely found low frequency of Brca1/2 alterations, explaining mutational spectra in human ICC/HCC. Our studies show that multiplexed CRISPR/Cas9 can be used for recessive genetic screening or high-throughput cancer gene validation in mice. The analysis of CRISPR/Cas9-induced tumors provided support for a major role of chromatin modifiers in hepatobiliary tumorigenesis, including that of ARID family proteins, which have recently been reported to be mutated in ICC/HCC. We have also comprehensively characterized the frequency and size of chromosomal alterations induced by combinatorial sgRNA delivery and describe related limitations of CRISPR/Cas9 multiplexing, as well as opportunities for chromosome engineering in the context of hepatobiliary tumorigenesis. Our study describes novel approaches to model and study cancer in a high-throughput multiplexed format that will facilitate the functional annotation of cancer genomes. PMID- 26508639 TI - Defining the mRNA recognition signature of a bacterial toxin protein. AB - Bacteria contain multiple type II toxins that selectively degrade mRNAs bound to the ribosome to regulate translation and growth and facilitate survival during the stringent response. Ribosome-dependent toxins recognize a variety of three nucleotide codons within the aminoacyl (A) site, but how these endonucleases achieve substrate specificity remains poorly understood. Here, we identify the critical features for how the host inhibition of growth B (HigB) toxin recognizes each of the three A-site nucleotides for cleavage. X-ray crystal structures of HigB bound to two different codons on the ribosome illustrate how HigB uses a microbial RNase-like nucleotide recognition loop to recognize either cytosine or adenosine at the second A-site position. Strikingly, a single HigB residue and 16S rRNA residue C1054 form an adenosine-specific pocket at the third A-site nucleotide, in contrast to how tRNAs decode mRNA. Our results demonstrate that the most important determinant for mRNA cleavage by ribosome-dependent toxins is interaction with the third A-site nucleotide. PMID- 26508640 TI - Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity. AB - Adipose triglyceride lipase (ATGL) initiates intracellular triglyceride (TG) catabolism. In humans, ATGL deficiency causes neutral lipid storage disease with myopathy (NLSDM) characterized by a systemic TG accumulation. Mice with a genetic deletion of ATGL (AKO) also accumulate TG in many tissues. However, neither NLSDM patients nor AKO mice are exceedingly obese. This phenotype is unexpected considering the importance of the enzyme for TG catabolism in white adipose tissue (WAT). In this study, we identified the counteracting mechanisms that prevent excessive obesity in the absence of ATGL. We used "healthy" AKO mice expressing ATGL exclusively in cardiomyocytes (AKO/cTg) to circumvent the cardiomyopathy and premature lethality observed in AKO mice. AKO/cTg mice were protected from high-fat diet (HFD)-induced obesity despite complete ATGL deficiency in WAT and normal adipocyte differentiation. AKO/cTg mice were highly insulin sensitive under hyperinsulinemic-euglycemic clamp conditions, eliminating insulin insensitivity as a possible protective mechanism. Instead, reduced food intake and altered signaling by peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and sterol regulatory element binding protein-1c in WAT accounted for the phenotype. These adaptations led to reduced lipid synthesis and storage in WAT of HFD-fed AKO/cTg mice. Treatment with the PPAR-gamma agonist rosiglitazone reversed the phenotype. These results argue for the existence of an adaptive interdependence between lipolysis and lipid synthesis. Pharmacological inhibition of ATGL may prove useful to prevent HFD-induced obesity and insulin resistance. PMID- 26508641 TI - Fundamental insights into ontogenetic growth from theory and fish. AB - The fundamental features of growth may be universal, because growth trajectories of most animals are very similar, but a unified mechanistic theory of growth remains elusive. Still needed is a synthetic explanation for how and why growth rates vary as body size changes, both within individuals over their ontogeny and between populations and species over their evolution. Here, we use Bertalanffy growth equations to characterize growth of ray-finned fishes in terms of two parameters, the growth rate coefficient, K, and final body mass, minfinity. We derive two alternative empirically testable hypotheses and test them by analyzing data from FishBase. Across 576 species, which vary in size at maturity by almost nine orders of magnitude, K scaled as [Formula: see text]. This supports our first hypothesis that growth rate scales as [Formula: see text] as predicted by metabolic scaling theory; it implies that species that grow to larger mature sizes grow faster as juveniles. Within fish species, however, K scaled as [Formula: see text]. This supports our second hypothesis, which predicts that growth rate scales as [Formula: see text] when all juveniles grow at the same rate. The unexpected disparity between across- and within-species scaling challenges existing theoretical interpretations. We suggest that the similar ontogenetic programs of closely related populations constrain growth to [Formula: see text] scaling, but as species diverge over evolutionary time they evolve the near-optimal [Formula: see text] scaling predicted by metabolic scaling theory. Our findings have important practical implications because fish supply essential protein in human diets, and sustainable yields from wild harvests and aquaculture depend on growth rates. PMID- 26508642 TI - Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity. AB - Thyroid hormone binds to nuclear receptors and regulates gene transcription. Here we report that in mice, at around the first day of life, there is a transient surge in hepatocyte type 2 deiodinase (D2) that activates the prohormone thyroxine to the active hormone triiodothyronine, modifying the expression of ~165 genes involved in broad aspects of hepatocyte function, including lipid metabolism. Hepatocyte-specific D2 inactivation (ALB-D2KO) is followed by a delay in neonatal expression of key lipid-related genes and a persistent reduction in peroxisome proliferator-activated receptor-gamma expression. Notably, the absence of a neonatal D2 peak significantly modifies the baseline and long-term hepatic transcriptional response to a high-fat diet (HFD). Overall, changes in the expression of approximately 400 genes represent the HFD response in control animals toward the synthesis of fatty acids and triglycerides, whereas in ALB D2KO animals, the response is limited to a very different set of only approximately 200 genes associated with reverse cholesterol transport and lipase activity. A whole genome methylation profile coupled to multiple analytical platforms indicate that 10-20% of these differences can be related to the presence of differentially methylated local regions mapped to sites of active/suppressed chromatin, thus qualifying as epigenetic modifications occurring as a result of neonatal D2 inactivation. The resulting phenotype of the adult ALB-D2KO mouse is dramatic, with greatly reduced susceptibility to diet induced steatosis, hypertriglyceridemia, and obesity. PMID- 26508643 TI - Accelerating scientific publication in biology. AB - Scientific publications enable results and ideas to be transmitted throughout the scientific community. The number and type of journal publications also have become the primary criteria used in evaluating career advancement. Our analysis suggests that publication practices have changed considerably in the life sciences over the past 30 years. More experimental data are now required for publication, and the average time required for graduate students to publish their first paper has increased and is approaching the desirable duration of PhD training. Because publication is generally a requirement for career progression, schemes to reduce the time of graduate student and postdoctoral training may be difficult to implement without also considering new mechanisms for accelerating communication of their work. The increasing time to publication also delays potential catalytic effects that ensue when many scientists have access to new information. The time has come for life scientists, funding agencies, and publishers to discuss how to communicate new findings in a way that best serves the interests of the public and the scientific community. PMID- 26508644 TI - Improved blood culture identification by FilmArray in cultures from regional hospitals compared with teaching hospital cultures. AB - Rapid identification of bacteria isolated from blood cultures by direct matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is now in wide spread use in major centres but is not yet feasible in smaller hospital laboratories. A FilmArray multiplex PCR panel for blood culture isolate identification (BCID) provides an alternative approach to near point-of-care microbial identification in regional hospitals. We assessed the accuracy and time to identification of the BCID FilmArray in a consecutive series of 149 blood cultures from 143 patients in a teaching hospital and smaller regional hospitals, currently identified by direct MALDI-TOF and proprietary molecular methods. The BCID FilmArray contained 18 of 34 species and 20 of 23 species isolated from teaching and regional hospital, respectively. Overall, 85 % of the teaching hospital and 100 % of the regional hospital monomicrobial blood cultures were identified, compared with 60 and 68 %, respectively, for direct MALDI-TOF on the same cultures. There were no incorrect results from blood cultures containing Staphylococcus aureus, streptococci, Pseudomonas aeruginosa or Enterobacteriaceae. The three discrepant results were all in mixed cultures. The mean reduction in time to identification of blood culture isolates was 53 h, which did not include the time required to transport cultures from regional centres to a central laboratory. The overall performance of the BCID FilmArray is stronger in blood cultures from smaller regional hospitals that encounter a narrower range of bacterial species dominated by the commonest species. This approach is more suited to smaller clinical laboratories than the MALDI-TOF direct method. PMID- 26508645 TI - Evaluation of the effects of silicone implants on the breast parenchyma. AB - BACKGROUND: Despite being the cosmetic procedure most performed worldwide, there are still few objective measurements of postoperative volumetric analysis of breast augmentation available in the literature. OBJECTIVE: The aim of this study was to evaluate volumetric changes in the breast parenchyma after the placement of silicone implants in the subglandular plane. METHODS: Thirty-four women were randomly allocated to the intervention group (n = 24), who underwent breast augmentation in the subglandular plane, or to the control group (n = 10), who received no intervention. Volumetric magnetic resonance imaging was performed at inclusion, and after 6 and 12 months in all participants. The non-parametric Friedman's test was used for statistical analysis. RESULTS: There was a significant reduction in glandular volume (mean, 22%) at 12 months postoperatively in patients who underwent breast augmentation. CONCLUSIONS: Breast augmentation caused reduction in the volume of the breast parenchyma. LEVEL OF EVIDENCE: 3 Therapeutic. PMID- 26508646 TI - Commentary on: evaluation of the effects of silicone implants on the breast parenchyma. PMID- 26508647 TI - Safety of vertical augmentation-mastopexy: prospective evaluation of breast perfusion using laser fluorescence imaging. AB - BACKGROUND: Augmentation-mastopexy is often recommended to simultaneously correct breast ptosis and restore upper pole fullness. However, some investigators believe that this procedural combination increases risk and recommend staging the surgery for some patients. OBJECTIVES: This prospective study was undertaken to evaluate the blood supply of the breast and, specifically, the nipples and areolae to determine whether breast implants inserted at the time of a vertical mastopexy compromise blood supply. METHODS: The SPY Elite Intraoperative Perfusion Assessment System was used to provide objective measurements of skin perfusion during surgery. To avoid confounding variables, patients served as their own controls. Twenty-five women (50 breasts) meeting the inclusion criteria (inclusion rate: 96%) were studied. All patients underwent bilateral vertical augmentation-mastopexies using a medial pedicle. No surgery was staged. The mean implant volume was 360 cc (range, 180-575 cc). The breasts were imaged in surgery after completion of bilateral mastopexies with insertion of (unfilled) saline breast implants and a second time after inflation of the implants. RESULTS: Complications included 1 distal deep venous thrombosis, 1 infection, 1 partial areola necrosis, and 1 case of delayed wound healing. There was no significant difference (P < .01) in intraoperative perfusion measurements comparing absolute and relative values before and after breast implant inflation (saline-filled implants) or insertion (silicone gel implants), including 5 patients undergoing secondary mastopexies. CONCLUSIONS: The insertion of breast implants at the time of a vertical mammaplasty with a medial pedicle does not significantly reduce perfusion of nipple/areola complexes. Staging the procedure is unnecessary. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26508648 TI - Commentary on: safety of vertical augmentation-mastopexy: prospective evaluation of breast perfusion using laser fluorescence imaging. PMID- 26508649 TI - Redefining abdominal anatomy: 10 key elements for restoring form in abdominoplasty. AB - While traditional abdominoplasty methods can successfully achieve the objective of restoring a flat appearance, the results can be artificially board-like, lacking the subtle anatomical features of a three-dimensional abdomen, thus creating the potential for patient dissatisfaction. While often difficult to articulate, patient criticism is almost always distilled to the ubiquitous concern that the surgical abdomen lacks the natural features of an authentic, youthful abdomen. In an effort to provide a more anatomically accurate outcome and improve patient satisfaction, I have made a series of technical modifications to the abdominoplasty that I now perform. Ten key technical refinements, including a modified "Anatomy Defining" Progressive Tension Suture technique, were successively incorporated in 177 patients during the first 5 years of 2000 2014. All have been applied consistently in 961 abdominoplasty procedures during the subsequent 10 years, often accompanied by liposuction of adjacent lateral (non-abdominal) areas to ensure harmonious proportion. This series of refinements adds precision and detail by redefining the native anatomical nuances of the abdomen, an aesthetic objective that has been consistently achieved in BMI ranges between 20 and 35. Overall satisfaction with results was high (94%). The 10 elements described are safe, effective, and lasting. PMID- 26508650 TI - A comprehensive examination of topographic thickness of skin in the human face. AB - BACKGROUND: Knowledge of topographic skin thickness is important to plastic surgery of the face as it may guide resection and restoration in oncologic, aesthetic, and reconstructive procedures. OBJECTIVE: The purpose of this study is to report the relative thickness of the face throughout 39 distinct subunits. METHODS: Full-thickness punch biopsy samples were obtained at 39 predetermined anatomic locations of the face from 10 human cadaveric heads. Tissue was fixed in paraffin-embedded slides and analyzed using triplicate measurement of dermis and epidermis using computerized measurements. Data were analyzed using univariate statistical analysis and expressed as mean thickness values and relative thickness (RT) values based on the thinnest portion of the face. RESULTS: The area of the face with the thickest dermis was the lower nasal sidewall (1969.2 um, dRT: 2.59), and the thinnest was the upper medial eyelid (758.9 um, dRT: 1.00). The area with the thickest epidermis was the upper lip (62.6 um, eRT: 2.12), and the thinnest was the posterior auricular skin (29.6 um, eRT: 1.00). Our results confirm that eyelid skin is the thinnest in the face. The thickest portions of the skin appeared to be in the lower nasal sidewall, but the measurements are comparable to those in the ala and posterior auricular skin, which are novel findings. CONCLUSIONS: The greatest epidermal, dermal and total skin thickness are found in the upper lip, right lower nasal sidewall, and left lower nasal sidewall respectively. The least epidermal skin thickness is in the posterior auricular skin. The least dermal skin thickness, and the least total skin thickness, are both in the upper medial eyelid. PMID- 26508651 TI - Corrigendum on: ten-year results from the Natrelle 410 anatomical form-stable silicone breast implant core study. PMID- 26508652 TI - External rhinoplasty by skin excision to correct hypertrophic tip of an elderly patient. PMID- 26508653 TI - Comments on "ten-year results from the Natrelle 410 anatomical form-stable silicone breast implant core study" and its assigned level of evidence. PMID- 26508654 TI - Does lower extremity elevation reduce thromboembolism risk after abdominoplasty? PMID- 26508655 TI - Response to "does lower extremity elevation reduce thromboembolism risk after abdominoplasty?". PMID- 26508656 TI - Submission bias and the rise of open access journals. PMID- 26508658 TI - Multiple dermatofibromas in a patient with Down syndrome. PMID- 26508657 TI - Ubiquitin-Activated Interaction Traps (UBAITs) identify E3 ligase binding partners. AB - We describe a new class of reagents for identifying substrates, adaptors, and regulators of HECT and RING E3s. UBAITs (Ubiquitin-Activated Interaction Traps) are E3-ubiquitin fusion proteins and, in an E1- and E2-dependent manner, the C terminal ubiquitin moiety forms an amide linkage to proteins that interact with the E3, enabling covalent co-purification of the E3 with partner proteins. We designed UBAITs for both HECT (Rsp5, Itch) and RING (Psh1, RNF126, RNF168) E3s. For HECT E3s, trapping of interacting proteins occurred in vitro either through an E3 thioester-linked lariat intermediate or through an E2 thioester intermediate, and both WT and active-site mutant UBAITs trapped known interacting proteins in yeast and human cells. Yeast Psh1 and human RNF126 and RNF168 UBAITs also trapped known interacting proteins when expressed in cells. Human RNF168 is a key mediator of ubiquitin signaling that promotes DNA double-strand break repair. Using the RNF168 UBAIT, we identify H2AZ--a histone protein involved in DNA repair--as a new target of this E3 ligase. These results demonstrate that UBAITs represent powerful tools for profiling a wide range of ubiquitin ligases. PMID- 26508659 TI - Topical adenosine increases the proportion of thick hair in Caucasian men with androgenetic alopecia. AB - Adenosine is an effective treatment for androgenetic alopecia (AGA) in Japanese men and women. Adenosine exerts its effects by significantly increasing the proportion of thick hair. In this study, we assessed the clinical outcome of adenosine treatment for 6 months in 38 Caucasian men. The change in proportion of thick hair (>=60 MUm) compared with baseline in the adenosine group was significantly higher than that in the placebo group (P < 0.0001). The change in vellus hair proportion (<40 MUm) was significantly lower in the adenosine group than that in the placebo group (P = 0.0154). The change in hair density compared with baseline of the adenosine group was also significantly higher compared with that of the placebo group (P = 0.0470). No adverse effects due to treatment were noted during this study by dermatological evaluation. Adenosine is effective in increasing the proportion of thick hair in Caucasian men with AGA as well as in Japanese men and women. PMID- 26508660 TI - Ballistic Beloniformes attacking through Snell's Window. AB - Needlefishes (Beloniformes) were observed employing a range of stalking and attacking behaviours to attack schools of bait fishes ranging from the use of tactics common to predatory fishes to a novel behaviour: the use of leaping, aerial attacks. These aerial attacks are suggested to serve two purposes: to extend the attack range of the needlefishes and to reduce their prey's potential for evasion. Furthermore, a third purpose is hypothesized that the needlefishes are taking advantage of Snell's Window, an optical effect which may mask their approach to their prey. PMID- 26508661 TI - Acupuncture in osteoporosis: more evidence is needed. PMID- 26508662 TI - Anatomical relationship between BL23 and the posterior ramus of the L2 spinal nerve. AB - BACKGROUND: The acupuncture point BL23 is located in the region of the posterior ramus of the second lumbar spinal nerve (L2) and has historically been used to treat conditions such as lower back pain, pollakiuria, erectile dysfunction, dysmenorrhoea, tinnitus, and vertigo. Some of these treatment effects have been hypothesised to be mediated by the sympathetic nervous system. It was recently discovered that the posterior ramus of the spinal nerve (PRSN) at L2 forms not two but three branches. OBJECTIVE: To examine the relationship between the acupuncture point BL23 and the L2 PRSN in order to consider the pathways possibly affected by BL23 acupuncture. METHODS: Acupuncture needles were inserted through the skin at BL23 to a depth of 3 cm a total of 13 times in eight donor cadavers (seven right-sided, six left-sided). Leaving the needle in place, ventral dissection was performed to determine the PRSN anatomy between the L1 and L3 spinal segments. In four cadavers, the relationship between the L2 spinal nerve and sympathetic branches was additionally evaluated. Following dissection, three dimensional (3D) data were acquired using a photo scanner and 3D structural images were created using 3D computer graphics software. One additional (female) cadaver was studied without insertion of an acupuncture needle (due to significant scoliosis). RESULTS: The L2 PRSN was divided into medial, intermediate and lateral branches. The needle inserted at BL23 came to lie in the region of the intermediate or lateral branches in all cases. Rami communicantes were found between the L2 spinal nerve and sympathetic trunk with fibres going on to supply the superior hypogastric plexus. CONCLUSIONS: Our findings suggest that acupuncture needles inserted at BL23 come into close proximity with the intermediate or lateral branch of the L2 PRSN, which could result in stimulation of both the somatic and sympathetic nervous systems. PMID- 26508663 TI - Effects and mechanisms of acupuncture and moxibustion on reproductive endocrine function in male rats with partial androgen deficiency. AB - OBJECTIVES: Partial androgen deficiency of the aging male (PADAM) is characterised by a deficiency in serum androgen levels. Both electroacupuncture (EA) and mild moxibustion (MM) can raise serum testosterone levels in PADAM. We investigated the mechanisms underlying the use of EA and MM in a rodent model of PADAM. METHODS: Fifty rats received cyclophosphamide injection over 5 consecutive days to induce PADAM, which was verified by comparing total testosterone (TT) and free testosterone (FT) levels with 10 non-PADAM healthy control rats (CON). Successful modelling was confirmed in 43 of 50 rats, 40 of which were randomly divided into untreated (PADAM), EA-treated (PADAM+EA), MM-treated (PADAM+MM), and androlin (AD)-treated (PADAM+AD) groups (n=10 each). EA and MM were administered at BL23 and CV4 acupuncture points for 8 weeks, and no treatment was given to rats in the PADAM and CON groups. Serum levels of luteinising hormone (LH) and follicle-stimulating hormone (FSH), mRNA expression of cytochrome P450c17 (P450c17) and 3beta-hydroxysteroid dehydrogenase 1 (3beta-HSD1), and protein levels of cytochrome P450 side chain cleavage (P450scc), 17beta-hydroxysteroid dehydrogenase 3 (17beta-HSD3) and steroidogenic factor 1 (SF-1) were evaluated after 8 weeks. RESULTS: Both EA and mild MM significantly increased serum TT and FT levels with MM displaying superiority. P450scc, 17beta-HSD3 and SF-1 protein expression, and P450c17 and 3beta-HSD1 mRNA expression, were significantly increased and serum LH and FSH levels were significantly decreased in PADAM+EA and PADAM+MM relative to PADAM rats. Moreover, serum LH and FSH levels were significantly lower and 17beta-HSD3 protein expression significantly higher in PADAM+MM relative to PADAM+EA rats. CONCLUSIONS: EA and MM at the BL23 and CV4 acupuncture points appear to be effective treatments for PADAM, and MM displays superior efficacy to EA. PMID- 26508665 TI - Interventions addressing health inequalities in European regions: the AIR project. AB - Disparities in health between social groups have been documented all over Europe. We summarize the methods and results of the Addressing Inequalities in Regions (AIR) project, which identified illustrative interventions and policies developed in European regions to reduce inequalities at the primary health care level. The first phase was a systematic review of the published literature. The second phase was a survey of European regions, collecting information on policies aiming at reducing health inequalities through primary health care and identifying regional, innovative and evaluated interventions. The third phase assessed interventions through methods defined by a formal consensus, and selected illustrative practices considered good practices for several of nine evaluation criteria. The review included 98 evaluations of interventions and 10 reviews; 80% of interventions were from North-America. Three main pathways to reduce health inequalities were identified: providing health promotion, improving financial access to care and modifying care provision. The first survey identified 90 interventions. Most national strategies included health inequalities issues. Education was the most frequently identified targeted determinant. Most interventions were health promotion general or targeted at specific health determinants, conditions or groups. The second survey assessed 46 interventions. Many involved the population in planning, implementation and evaluation. We also identified the multidisciplinary of interventions, and some who had an impact on empowerment of the targeted population. The AIR project documented that policies and actions can be implemented at the regional level through primary care providers. Policies and interventions are seldom evaluated. PMID- 26508666 TI - Sex Differences in Dabigatran Use, Safety, And Effectiveness In a Population Based Cohort of Patients With Atrial Fibrillation. AB - BACKGROUND: Sex differences were observed with regard to warfarin treatment in patients with atrial fibrillation, with women having a higher risk of stroke compared with men. We aimed to compare sex differences in use, safety, and effectiveness of dabigatran. METHODS AND RESULTS: We conducted a population-based cohort study of patients with atrial fibrillation using administrative data in Quebec, Canada, 1999 to 2013. Men and women who filled a prescription for dabigatran (110 and 150 mg bid) were compared with matched warfarin users with respect to their rates of stroke, bleeding, and myocardial infarction events, using propensity score analysis. The cohort comprised 31 786 women (50.4%) and 31 324 men (49.6%). Women had a higher baseline stroke risk and lower baseline bleeding risk compared with men. Women filled more prescriptions for the lower dabigatran dose compared with men (adjusted OR, 1.35; 95% confidence interval, 1.24-1.48). In multivariable analyses adjusted for propensity scores, dabigatran use was associated with a lower risk of bleeding compared with warfarin in men (P for interaction=0.008). Dabigatran was associated with a trend toward lower risk of stroke in women treated with the 150-mg dose (HR, 0.79; 95% confidence interval, 0.56-1.04), but was not associated with a difference in the risk of myocardial infarction compared with warfarin in either sex. CONCLUSIONS: In real life practice, women are more frequently treated with low-dose dabigatran, yet a trend toward lower stroke rates in women taking high-dose dabigatran was observed. Men benefit from lower bleeding rates with dabigatran compared with warfarin. PMID- 26508664 TI - Sites of retroviral DNA integration: From basic research to clinical applications. AB - One of the most crucial steps in the life cycle of a retrovirus is the integration of the viral DNA (vDNA) copy of the RNA genome into the genome of an infected host cell. Integration provides for efficient viral gene expression as well as for the segregation of viral genomes to daughter cells upon cell division. Some integrated viruses are not well expressed, and cells latently infected with human immunodeficiency virus type 1 (HIV-1) can resist the action of potent antiretroviral drugs and remain dormant for decades. Intensive research has been dedicated to understanding the catalytic mechanism of integration, as well as the viral and cellular determinants that influence integration site distribution throughout the host genome. In this review, we summarize the evolution of techniques that have been used to recover and map retroviral integration sites, from the early days that first indicated that integration could occur in multiple cellular DNA locations, to current technologies that map upwards of millions of unique integration sites from single in vitro integration reactions or cell culture infections. We further review important insights gained from the use of such mapping techniques, including the monitoring of cell clonal expansion in patients treated with retrovirus-based gene therapy vectors, or patients with acquired immune deficiency syndrome (AIDS) on suppressive antiretroviral therapy (ART). These insights span from integrase (IN) enzyme sequence preferences within target DNA (tDNA) at the sites of integration, to the roles of host cellular proteins in mediating global integration distribution, to the potential relationship between genomic location of vDNA integration site and retroviral latency. PMID- 26508667 TI - Association of Patient Enrollment in Medicare Part D With Outcomes After Acute Myocardial Infarction. AB - BACKGROUND: Little is known about whether enrollment versus nonenrollment in Medicare's prescription drug plan (Part D) is associated with better outcomes after acute myocardial infarction (AMI). METHODS AND RESULTS: Using Medicare records linked to Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines, we identified 59 149 Medicare beneficiaries (age >=65 years) discharged after AMI between January 2007 and December 2010. We described trends in Medicare Part D enrollment, and compared the following 30-day and 1-year outcomes: all-cause death, all-cause readmissions, and major adverse cardiac events (a composite of all-cause death or readmission for AMI or stroke) between Part D enrollees and nonenrollees, after adjustment for patient and hospital factors. From 2007 to 2010, 29 264 (49.5%) patients with AMI enrolled in Medicare were also participating in Part D by hospital discharge. All-cause 30 day death was more common among enrollees versus nonenrollees (4.0% versus 3.3%), but this difference was not statistically significant after multivariable adjustment (adjusted hazard ratio, 1.06 [95% confidence interval, 0.97-1.17]). Enrollees also had higher unadjusted risks of 30-day all-cause readmissions or major adverse cardiac events, and 1-year mortality, all-cause readmissions, or major adverse cardiac events, but these were attenuated after multivariable adjustment. Adherence to key secondary prevention medications (statins, beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and P2Y12 antagonists) remained low (range, 55%-64%) at 1 year post discharge among Part D enrollees. CONCLUSIONS: Only half of Medicare-insured patients with AMI were enrolled in Part D by hospital discharge, and their 30-day and 1-year adjusted outcomes did not differ substantially from nonenrollees. There remain opportunities for improvement in medication adherence among patients with prescription drug coverage. PMID- 26508668 TI - Disabled and elderly citizens' perceptions and experiences of voluntarism as an alternative to publically financed care in the Netherlands. AB - Many European welfare states are replacing comprehensive welfare schemes with selective and conditional entitlements. Such changes affect the recognition of vulnerable citizens' needs, which are increasingly framed as private responsibilities to be met by the voluntary sector. Repeated interviews with 30 clients affected by cutbacks to publicly financed (day)care in the Netherlands show that although disabled and elderly citizens are often hesitant to open their doors to volunteers, they do experiment with voluntarism to reduce their social isolation, both by receiving voluntary care and by engaging in volunteer work themselves. However, the turn to voluntarism does not always prompt recognition of the needs of vulnerable citizens. This study signals how disappointing and sometimes demeaning experiences with volunteers can increase feeling of misrecognition. We conclude that the virtues of voluntarism may be overstated by policy makers and that the bases of recognition should be reconsidered as welfare states implement reform. PMID- 26508669 TI - Definition of lymph node areas for radiotherapy of prostate cancer: A critical literature review by the French Genito-Urinary Group and the French Association of Urology (GETUG-AFU). AB - PURPOSE: Recommendations for pelvic lymph node (LN) contouring rely on relatively dated studies that defined the Clinical Target Volume (CTV) of interest proposed for radiotherapy. The aim of this article was to review these recommendations with a critical analysis of published data on prostate cancer drainage. METHODS: We performed a review of data on LN drainage in prostate cancer, based on anatomy texts and studies on lymphography, pelvic LN dissections, sentinel LN techniques, magnetic resonance imaging, computed tomography and functional imaging. We also present the GETUG experts' opinion, based on a survey on nodal CTV definition. RESULTS: For lymphatic drainage of prostate cancers, pelvic LN areas classically considered are: distal common iliac, external iliac, internal iliac and obturator regions. Recently published data allow a mapping of sites at risk of pathological LN invasion. In 10-70% of cases, these sites are not included in the pelvic LN CTVs defined in consensuses. In accordance with other cooperative groups, the GETUG experts' survey showed that proximal common iliac, para-aortic, para-rectal and pre-sacral regions could include sites at risk of invasion in extended LN CTV, but were not considered in CTV contouring common practice. New recommendations are needed for nodal CTV in radiotherapy of prostate cancer. CONCLUSIONS: The assessment of the efficacy and safety of LN radiotherapy is still the subject of several randomised studies. Whether or not meaningful results are obtained depends directly on the quality and homogeneity of the data analysed. A new consensus for delineation of LN regions appears necessary. PMID- 26508670 TI - Inhibition of Proteasome Activity by Low-dose Bortezomib Attenuates Angiotensin II-induced Abdominal Aortic Aneurysm in Apo E(-/-) Mice. AB - Abdominal aortic aneurysm (AAA) is a leading cause of sudden death in aged people. Activation of ubiquitin proteasome system (UPS) plays a critical role in the protein quality control and various diseases. However, the functional role of UPS in AAA formation remains unclear. In this study, we found that the proteasome activities and subunit expressions in AAA tissues from human and angiotensin II (Ang II)-infused apolipoprotein E knockout (Apo E(-/-)) mice were significantly increased. To investigate the effect of proteasome activation on the AAA formation, Apo E(-/-) mice were cotreated with bortezomib (BTZ) (a proteasome inhibitor, 50 MUg/kg, 2 times per week) and Ang II (1000 ng/kg/min) up to 28 days. Ang II infusion significantly increased the incidence and severity of AAA in Apo E(-/-) mice, whereas BTZ treatment markedly inhibited proteasome activities and prevented AAA formation. Furthermore, BTZ treatment significantly reduced the inflammation, inhibited the metal matrix metalloprotease activity, and reversed the phenotypic SMC modulation in AAA tissue. In conclusion, these results provide a new evidence that proteasome activation plays a critical role in AAA formation through multiple mechanisms, and suggest that BTZ might be a novel therapeutic target for treatment of AAA formation. PMID- 26508671 TI - Complete genome sequence of the heavy metal resistant bacterium Altererythrobacter atlanticus 26DY36(T), isolated from deep-sea sediment of the North Atlantic Mid-ocean ridge. AB - Altererythrobacter atlanticus 26DY36(T) (CGMCC 1.12411(T)=JCM 18865(T)) was isolated from the North Atlantic Mid-Ocean Ridge. The strain is resistant to heavy metals, such as Mn(2+) (200 mM), Co(2+) (2.0mM), Cu(2+) (1mM), Zn(2+) (1mM), Hg(2+) (0.1mM) and Cd(2+) (0.5mM). Here we describe the genome sequence and annotation, as well as the features of the organism. A. atlanticus 26DY36(T) harbors a chromosome (3,386,291 bp) and a circular plasmid (88,815 bp). The genome contains 3322 protein-coding genes (2483 with predicted functions), 47 tRNA genes and 6 rRNA genes. A. atlanticus 26DY36(T) encodes dozens of genes related to heavy metal resistance and has potential applications in the bioremediation of heavy metal-contaminated environments. PMID- 26508672 TI - Genome sequence of Bacillus sp. CHD6a, isolated from the shallow-sea hydrothermal vent. AB - Bacillus sp. CHD6a, which can produce oval endosperms, isolated from the shallow sea hydrothermal vent systems off northeast Taiwan's coast. Here, we report the draft genome sequence of Bacillus sp. CHD6a. It comprises ~3.97 Mb in 55 contigs with the G+C content of 39.9%, and a total of 3740 protein-coding genes were obtained. PMID- 26508673 TI - Genome sequence of obligate marine polycyclic aromatic hydrocarbons-degrading bacterium Cycloclasticus sp. 78-ME, isolated from petroleum deposits of the sunken tanker Amoco Milford Haven, Mediterranean Sea. AB - Cycloclasticus sp. 78-ME isolated from petroleum deposits of the sunken tanker "Amoco Milford Haven" (Gulf of Genoa, Ligurian Sea, Italy) could effectively degrade polycyclic aromatic hydrocarbons of up to five condensed rings. The genome of 78-ME was sequenced and analysed to gain insights into its remarkable degrading capacities. It comprises two circular replicons, the 2,613,078 bp chromosome and the plasmid of 42,347 bp, with 41.84% and 53.28% of the G + C content respectively. A total of 2585 protein-coding genes were obtained, and three large operons with more than fifteen enzymes belonging to four different classes of ring-cleavage dioxygenases were found. PMID- 26508674 TI - The prevalence of exfoliation syndrome in Turkey. AB - PURPOSE: To investigate the prevalence of the exfoliation syndrome and its relationship with ocular and cardiovascular diseases in the Central Anatolia region of Turkey. METHODS: This cross-sectional and population-based study was conducted at the Sivas Province among the population aged 40 years and over. The diagnosis of XFS was made when exfoliative material was found on the anterior lens capsule or iris on slit-lamp examination. The subjects were divided into an XFS group and a non-XFS group according to the presence of exfoliative material, and the groups were compared for the presence of glaucoma, cataract, age-related macular degeneration, phacodonesis, hypertension, diabetes mellitus, coronary artery disease, smoking and alcohol-use frequency. RESULTS: XFS was present in 63 subjects consisting of 42 males (8.0%) and 21 females (3.6%) for an overall rate of 5.7% (95% CI: 0.054-0.060). Once we adjusted the values for age, we found a statistically significant relationship of increased age and male gender with the presence of XFS (p = 0.001, p = 0.027, respectively). The relationship between XFS and glaucoma, cataract and phacodonesis was found to be statistically significant (p = 0.001). No relationship was found between exfoliation syndrome and hypertension, diabetes mellitus and coronary artery disease. CONCLUSION: The prevalence of exfoliation syndrome was 5.7% in this population-based study. There was a statistically significant relationship between XFS and advancing age and male gender. PMID- 26508675 TI - Sitagliptin, a DPP-4 inhibitor, alters the subsets of circulating CD4+ T cells in patients with type 2 diabetes. AB - OBJECTIVE: CD26/DPP-4 is highly expressed by T cells, especially CD4+ T cells (T helper cells; Th) and may regulate the differentiation, maturation, or proliferation of these cells. We investigated the effects of sitagliptin, a DPP-4 inhibitor, on the absolute number and percentage of various subsets of circulating CD4+ T cells in patients with type 2 diabetes. METHODS: We enrolled 30 consecutive patients (16 women and 14 men) with type 2 diabetes in a prospective, randomized, open-label, blinded endpoint study. Eligible participants were randomly assigned at a 2:1 ratio to either a sitagliptin group (sitagliptin at 50mg/day) or an active control group (glimepiride at 1mg/day). Patients were followed for 12 weeks with monthly review. Peripheral blood mononuclear cells were examined by flow cytometry for intracellular expression of cytokines (IFN-gamma as a marker of Th1cells, IL-4 for Th2 cells, and IL-17 for Th17 cells) and for expression of CD4, CD25, and Foxp3 (regulatory T cells [Treg]). RESULTS: Both groups showed similar improvement of glycemic control. The total number of CD4+ T cells was decreased by treatment with sitagliptin, while it did not change in the control group. The number and percentage of Th17 cells and Treg cells both decreased significantly in the sitagliptin group, but not in the control group. There was a significant positive correlation between changes in the percentage of Th17 cells and Treg cells after treatment with sitagliptin. CONCLUSIONS: Treatment with sitagliptin for 12 weeks reduced the number of circulating CD4+ T cells, especially Th17 and Treg cells, in patients with type 2 diabetes. PMID- 26508676 TI - Glucose intolerance in cystic fibrosis as a determinant of pulmonary function and clinical status. AB - BACKGROUND: Cystic fibrosis related diabetes (CFRD) is associated with a decrease in pulmonary function and nutritional status. We investigated the clinical significance of impaired glucose tolerance (IGT) in cystic fibrosis (CF) patients. METHODS: Fifty-five CF patients (aged 22.8 +/- 9.2 years, 29 males, mean FEV1 67.9 +/- 22% predicted, mean BMI-SDS -0.23 +/- 1.1) underwent a 2-h Oral Glucose Tolerance Test (OGTT) with 30-min interval measurements of glucose and insulin. Additional clinical and laboratory data were obtained from the medical charts. RESULTS: Thirty-eight participants (69%) had normal glucose tolerance (NGT), 13 (23.7%) had IGT, and 4 (7.3%) had newly diagnosed CFRD. Compared to patients with NGT, patients with IGT had significantly lower BMI-SDS (-1.1 +/- 0.8 vs. 0.1 +/- 1.1, p<0.001), mean FEV1 (57 +/- 19 vs. 74 +/- 21% predicted, p<0.01), and albumin (3.9 +/- 0.3 vs. 4.3 +/- 0.2g/dl, p=0.004), and higher fibrinogen (376 +/- 56 vs. 327 +/- 48 g/dl, p=0.02). Patients with IGT had impaired beta-cell function, with reduced first phase insulin secretion, a delayed insulin peak, and significantly lower total insulin secretion, HOMA-%B and insulinogenic index. Seven patients had HbA1c in the "diabetic" range (>=6.5%; 47.5 mmol/mol), however, HbA1c was not a sensitive or specific marker of glucose tolerance status. CONCLUSIONS: IGT in CF patients is associated with increased inflammation and decreased nutritional status and pulmonary function. PMID- 26508677 TI - Hydrophilic interaction liquid chromatography-electrospray ionization-tandem mass spectrometry of a complex mixture of native and oxidized phospholipids. AB - A mixture of native and oxidized phospholipids (PLs), generated by the soybean lipoxygenase type V-catalyzed partial oxidation of a lipid extract obtained from human platelets, was analyzed by Hydrophilic Interaction Liquid Chromatography ElectroSpray Ionization-Tandem Mass Spectrometry (HILIC-ESI-MS/MS). The complexity of the resulting mixture was remarkable, considering that the starting lipid extract, containing (as demonstrated in a previous study) about 130 native PLs, was enriched with enzymatically generated hydroperoxylated derivatives and chemically generated hydroxylated forms of PLs bearing polyunsaturated side chains. Nonetheless, the described analytical approach proved to be very powerful; indeed, focusing on phosphatidylcolines (PCs), the most abundant PL class in human platelets, about fifty different native/oxidized species could be identified in a single HILIC-ESI-MS/MS run. Low-energy collision induced dissociation tandem MS (CID-MS/MS) experiments on chromatographically separated species showed single neutral losses of H2O2 and H2O to be typical fragmentation pathways of hydroperoxylated PCs, whereas a single H2O loss was observed for hydroxylated ones. Moreover, diagnostic losses of n-hexanal or n-pentanol were exploited to recognize PCs hydroperoxylated on the last but five carbon atom of a omega-6 polyunsaturated side chain. Despite the low resolution of the 3D ion trap mass analyzer used, the described HILIC-ESI-MS/MS approach appears very promising for the identification of oxidized lipids in oxidatively stressed complex biological systems. PMID- 26508678 TI - The photosynthetic capacity in 35 ferns and fern allies: mesophyll CO2 diffusion as a key trait. AB - Ferns and fern allies have low photosynthetic rates compared with seed plants. Their photosynthesis is thought to be limited principally by physical CO2 diffusion from the atmosphere to chloroplasts. The aim of this study was to understand the reasons for low photosynthesis in species of ferns and fern allies (Lycopodiopsida and Polypodiopsida). We performed a comprehensive assessment of the foliar gas-exchange and mesophyll structural traits involved in photosynthetic function for 35 species of ferns and fern allies. Additionally, the leaf economics spectrum (the interrelationships between photosynthetic capacity and leaf/frond traits such as leaf dry mass per unit area or nitrogen content) was tested. Low mesophyll conductance to CO2 was the main cause for low photosynthesis in ferns and fern allies, which, in turn, was associated with thick cell walls and reduced chloroplast distribution towards intercellular mesophyll air spaces. Generally, the leaf economics spectrum in ferns follows a trend similar to that in seed plants. Nevertheless, ferns and allies had less nitrogen per unit DW than seed plants (i.e. the same slope but a different intercept) and lower photosynthesis rates per leaf mass area and per unit of nitrogen. PMID- 26508679 TI - Chloride-Anion-Templated Synthesis of a Strapped-Porphyrin-Containing Catenane Host System. AB - The synthesis, structure and anion-recognition properties of a new strapped porphyrin-containing [2]catenane anion host system are described. The assembly of the catenane is directed by discrete chloride anion templation acting in synergy with secondary aromatic donor-acceptor and coordinative pyridine-zinc interactions. The [2]catenane incorporates a three-dimensional, hydrogen-bond donating anion-binding pocket; solid-state structural analysis of the catenane?chloride complex reveals that the chloride anion is encapsulated within the catenane's interlocked binding cavity through six convergent CH????Cl and NH???Cl hydrogen-bonding interactions and solution-phase (1) H NMR titration experiments demonstrate that this complementary hydrogen-bonding arrangement facilitates the selective recognition of chloride over larger halide anions in DMSO solution. PMID- 26508680 TI - Levocarnitine Improves Cardiac Function in Hemodialysis Patients With Left Ventricular Hypertrophy: A Randomized Controlled Trial. AB - BACKGROUND: Levocarnitine deficiency in hemodialysis patients is common. Although the effect of levocarnitine therapy on uremic anemia has been studied in small trials, its effects on cardiac function remain unclear. STUDY DESIGN: Multicenter, prospective, open-label, parallel, randomized, controlled trial. SETTING & PARTICIPANTS: Patients undergoing maintenance hemodialysis with carnitine deficiency (free carnitine plasma concentration < 40MUmol/L) enrolled in 3 hemodialysis centers. INTERVENTION: Random assignment to treatment for 12 months with oral levocarnitine therapy at a dose of 20mg/kg/d or control group (no levocarnitine therapy). OUTCOMES & MEASUREMENTS: Cardiac function was assessed by echocardiography. The primary end point was change in ejection fraction from baseline at the end of the study. Secondary end points included changes in left ventricular mass index and clinical parameters from baseline at the end of the study. RESULTS: 222 patients were randomly assigned, of whom 148 patients (levocarnitine group, n=75; control group, n=73) were analyzed. Ejection fraction increased from baseline to the end of the study in the levocarnitine group by 5.43% (95% CI, 4.53%-6.32%), but not in the control group (change, 0.14%; between-group difference, 5.57% [95% CI, 4.48%-6.66%]; P<0.001). Left ventricular mass index decreased from baseline to the end of the study in the levocarnitine group (change of -8.89 [95% CI, -11.7 to -6.09] g/m(2)), but not in the control group (change of 1.62g/m(2); between-group difference, 10.50 [95% CI, 7.51 to 13.60] g/m(2); P<0.001). Levocarnitine therapy reduced N-terminal pro brain natriuretic peptide (NT-proBNP) levels and improved the erythropoietin responsiveness index, whereas no such effects were observed in the control group. LIMITATIONS: Not a double-blinded study. CONCLUSIONS: Levocarnitine therapy is useful for hemodialysis patients with carnitine deficiency; these patients may benefit from such therapy, with amelioration of cardiac function and reduction of left ventricular mass index. PMID- 26508681 TI - Hyperphosphatemia in Dialysis Patients: Beyond Nonadherence to Diet and Binders. AB - Hyperphosphatemia in dialysis patients is routinely attributed to nonadherence to diet, prescribed phosphate binders, or both. The role of individual patient variability in other determinants of phosphate control is not widely recognized. In a manner that cannot be explained by dialysis parameters or serum phosphate levels, dialytic removal of phosphate may vary by >400mg per treatment. Similarly, enteral phosphate absorption, unexplained by diet or vitamin D intake, may differ by >=250mg/d among patients. Binder efficacy also varies among patients, with 2-fold differences reported. One or more elements of this triple threat-varying dialytic removal, phosphate absorption, and phosphate binding-may account for hyperphosphatemia in dialysis patients rather than nonadherence to therapy. Just as the cause(s) of hyperphosphatemia may vary, so too may an individual patient's response to different therapeutic interventions. PMID- 26508682 TI - Comparative Effectiveness of Iron and Erythropoiesis-Stimulating Agent Dosing on Health-Related Quality of Life in Patients Receiving Hemodialysis. AB - BACKGROUND: The potential effects of iron-dosing strategies and erythropoiesis stimulating agents (ESAs) on health-related quality of life (HRQoL) in the dialysis population are unclear. We examined the independent associations of bolus versus maintenance iron dosing and high versus low ESA dosing on HRQoL. STUDY DESIGN: Retrospective cohort design. SETTING & PARTICIPANTS: Clinical data (2008-2010) from a large dialysis organization merged with data from the US Renal Data System. 13,039 patients receiving center-based hemodialysis were included. PREDICTOR: Iron and ESA dosing were assessed during 1-month (n=14,901) and 2-week (n=15,296) exposure periods. OUTCOMES: HRQoL was measured by the Kidney Disease Quality of Life (KDQOL) instrument (0-100 scale) during a 3-month follow-up period. MEASUREMENTS: Generalized linear mixed models, adjusting for several covariates, were used to estimate associations between iron and ESA dosing and HRQoL overall and for clinically relevant subgroups. RESULTS: For the 1-month exposure period, patients with lower baseline hemoglobin levels who received higher ESA dosing had higher physical health and kidney disease symptom scores (by 2.4 [95% CI, 0.6-4.2] and 5.6 [95% CI, 2.8-8.4] points, respectively) in follow-up than patients who received lower ESA dosing. For the 2-week exposure period, patients with low baseline hemoglobin levels who received bolus dosing had higher mental health scores (by 1.9 [95% CI, 0.0-3.8] points) in follow-up. Within the low-baseline-hemoglobin subgroup, individuals with a catheter or dialysis vintage less than 1 year who received higher ESA dosing had higher HRQoL scores in follow-up (by 5.0-9.9 points) and individuals with low baseline transferrin saturations who received bolus dosing had higher HRQoL scores in follow-up (by 2.6-5.8 points). LIMITATIONS: Observational design; short duration of observation. CONCLUSIONS: For individuals with low baseline hemoglobin levels, higher ESA dosing and bolus iron dosing were associated with slightly higher HRQoL scores in follow-up. These differences became more pronounced and clinically relevant for specific subgroups. PMID- 26508683 TI - Stroke Subtypes and Topographic Locations Associated with Neurological Deterioration in Acute Isolated Pontine Infarction. AB - OBJECTIVE: This study investigated predictors of neurological deterioration (ND) in acute isolated pontine infarction. METHODS: Two hundred fifty-nine patients with acute isolated pontine infarctions identified using diffusion-weighted imaging were retrospectively analyzed. The patients were divided according to the presence/absence of ND, defined as increased (>=2 units) National Institutes of Health Stroke Scale scores 5 days after onset. Pontine infarctions comprised 3 stroke subtypes: vertebrobasilar large-artery disease, basilar artery branch disease (BABD), and small-artery disease (SAD), according to basilar artery atherosclerosis severity and lesion extent of the transverse axial plane. Topographic locations of longitudinal pontine infarctions in the axial plane were divided into upper, middle, lower, and whole. RESULTS: Of the 259 patients (male : female = 136:123, 68.84 +/- 10.24), only 27.4% exhibited ND. The prevalence was significantly increased in females, whereas smoking was significantly decreased in patients with ND. BABD and lower pontine infarctions were significantly more frequent in patients with ND (70.4% and 43.7%, respectively) than in patients without ND (51.6% and 30.3%, respectively). SAD and upper pontine infarctions were significantly less frequent in patients with ND (16.9% and 7.0%, respectively) than in patients without ND (30.3% and 23.4%, respectively). BABD and lower pontine infarctions were positively related to ND. CONCLUSIONS: This is the first study to demonstrate that BABD and lower pons lesions are predictors of ND in acute isolated pontine infarction. These findings indicate the potential importance of early identification of stroke subtypes and topographic locations in the prevention of ND in patients with suspected pontine infarction. PMID- 26508684 TI - Dysphagia Post Subcortical and Supratentorial Stroke. AB - BACKGROUND: Studies have recognized that the damage in the subcortical and supratentorial regions may affect voluntary and involuntary aspects of the swallowing function. The current study attempted to explore the dysphagia characteristics in patients with subcortical and supratentorial stroke. METHODS: Twelve post first or second subcortical and supratentorial stroke patients were included in the study. The location of the stroke was ascertained by computed tomography and magnetic resonance imaging. The characteristics of swallowing disorder were assessed by video fluoroscopic swallowing assessment/fiberoptic endoscopic evaluation of swallowing. The following main parameters were analyzed: oral transit time, pharyngeal delay time, presence of cricopharyngeal muscle achalasia (CMA), distance of laryngeal elevation, the amounts of vallecular residue and pyriform sinus residue (PSR), and the extent of pharyngeal contraction. RESULTS: Eighty-three percent of the 12 patients were found suffering from pharyngeal dysphagia, with 50% having 50%-100% PSRs, 50% having pharyngeal delay, and 41.6% cases demonstrating CMA. Simple regression analysis showed PSRs were most strongly associated with CMA. Pharyngeal delay in the study can be caused by infarcts of basal ganglia/thalamus, infarcts of sensory tract, infarcts of swallowing motor pathways in the centrum semiovale, or a combination of the three. CONCLUSION: Subcortical and supratentorial stroke may result in pharyngeal dysphagia such as PSR and pharyngeal delay. PSR was mainly caused by CMA. PMID- 26508685 TI - Redox proteomics: Methods for the identification and enrichment of redox-modified proteins and their applications. AB - PTMs are defined as covalent additions to functional groups of amino acid residues in proteins like phosphorylation, glycosylation, S-nitrosylation, acetylation, methylation, lipidation, SUMOylation as well as oxidation. Oxidation of proteins has been characterized as a double-edged sword. While oxidative modifications, in particular of cysteine residues, are widely involved in the regulation of cellular homeostasis, oxidative stress resulting in the oxidation of biomolecules along with the disruption of their biological functions can be associated with the development of diseases, such as cancer, diabetes, and neurodegenerative diseases, respectively. This is also the case for advanced glycation end products, which result from chemical reactions of keto compounds such as oxidized sugars with proteins. The role of oxidative modifications under physiological and pathophysiological conditions remains largely unknown. Recently, novel technologies have been established that allow the enrichment, identification, and characterization of specific oxidative PTMs (oxPTMs). This is essential to develop strategies to prevent and treat diseases that are associated with oxidative stress. Therefore this review will focus on (i) the methods and technologies, which are currently applied for the detection, identification, and quantification of oxPTMs including the design of high throughput approaches and (ii) the analyses of oxPTMs related to physiological and pathological conditions. PMID- 26508686 TI - Tribute to Our Reviewers. PMID- 26508688 TI - Pseudomembranous variant of collagenous colitis. PMID- 26508689 TI - CORRIGENDUM. PMID- 26508691 TI - Forcing through Tumor Metastasis: The Interplay between Tissue Rigidity and Epithelial-Mesenchymal Transition. AB - The mechanical properties of the tumor microenvironment have been increasingly recognized as potent modulators of cell behavior and function. In particular, tissue rigidity is functionally important during tumor progression. In this review, we survey recent advances in our understanding of the role of tissue rigidity in tumor progression and metastasis, the mechanisms by which mechanical cues integrate with biochemical signals from the microenvironment, and the underlying mechanotransduction pathways involved in tumor progression. These findings highlight the importance of understanding and defining cellular mechanotransduction pathways and the breadth of signals derived from the tumor microenvironment that influence tumor progression. PMID- 26508692 TI - In silico approach to reveal viral populations in grapevine cultivar Tannat using transcriptome data. AB - Viruses are ubiquitous and present in a wide range of settings, from living organisms to various environments. Although viruses are regarded as important pathogens in higher plants, viral populations in specific host plants have not yet been fully examined. This study revealed viral populations in grape berries obtained from a cultivar from a single vineyard using currently available grapevine transcriptomes. Eight viruses and two viroids were identified using 11 grapevine libraries. Virus-associated sequences in each transcriptome ranged from 0.2% (seed) to 8.8% (skin). The amount of viral RNAs and virus copy numbers was quantified, thus revealing the dominant virus or viroid in each individual library. In addition, five viral genomes were successfully assembled de novo using transcriptome data. Phylogenetic analyses revealed that the viruses and viroids might have originated from Europe, along with the host. Single nucleotide variation studies revealed the quasispecies of RNA viruses. Taken together, this study defines complex viral populations in three different grape tissues from a single vineyard. PMID- 26508693 TI - Regulatory evaluation of antiviral drug resistance in the era of next-generation sequencing. PMID- 26508694 TI - Aging in the Canine Kidney. AB - Given the irreversible nature of nephron loss, aging of the kidney is of special interest to diagnostic and toxicologic pathologists. There are many similarities among histologic lesions in aged human and canine kidneys, including increased frequency of glomerulosclerosis, interstitial fibrosis, and tubular atrophy. Unfortunately, there are few studies in which renal tissue from aged healthy dogs was adequately examined with advanced diagnostics-namely, transmission electron microscopy and immunofluorescence-so age-associated changes in canine podocytes and glomerular basement membranes are poorly characterized. An age-associated decrease in the glomerular filtration rate in humans and dogs (specifically small breed dogs) has been documented. Although lesions in aged rats and mice differ somewhat from those of aged dogs and humans, the knowledge gained from rodent models is still vital to elucidating the pathogenesis of age-associated renal disease. Many novel molecules implicated in renal aging have been identified through genetically modified rodent models and transcriptomic and proteomic analysis of human kidneys. These molecules represent intriguing therapeutic targets and diagnostic biomarkers. Likewise, influencing critical pathways of cellular aging, such as telomere shortening, cellular senescence, and autophagy, could improve renal function in the elderly. PMID- 26508695 TI - Experimental North American West Nile Virus Infection in the Red-legged Partridge (Alectoris rufa). AB - After the introduction of West Nile virus (WNV) into North America, bird mortalities associated with West Nile disease have dramatically increased in this continent and, to a lesser extent, in Europe. The different West Nile disease incidence in birds in these 2 continents demands an explanation, and experimental studies can provide important information. The authors inoculated thirteen 9-week old red-legged partridges (Alectoris rufa) with 10(7)plaque-forming units of a WNV strain isolated in New York in 1999. The objective was to study the pathogenesis of the infection in a native Euro-Mediterranean bird species with a WNV strain known to be highly pathogenic for numerous native American bird species. Additionally, the authors evaluated the dynamics of inflammatory cell activation and recruitment into the brain. WNV was detected in tissues 3 days postinoculation (dpi), and the birds developed macroscopic and microscopic lesions. Two partridges succumbed to the disease. The most affected tissues were the heart, brain, and spinal cord. The main microscopic findings were the presence of mononuclear infiltrates in the heart and brain, gliosis, and degeneration and necrosis of cardiomyocytes and neurons. These lesions were aggravated in the birds that died or were euthanized 7 dpi or later. In the brain, there was an upregulation of microglial cells and astrocytes and an increase in the number of T cells, especially after 7 dpi. These results show that this WNV strain is of moderate virulence for the red-legged partridge and that WNV-infected red-legged partridges develop an immune cell response in the brain similar to that of mammals. PMID- 26508696 TI - Cause-of-Death Analysis in Rodent Aging Studies. AB - In research studies using rats or mice, the cause of death is often not evaluated or reported. An analysis of the causes of death is particularly valuable for aging and carcinogenesis studies. Comparing causes of death among the study groups is often an important adjunct to the biochemical, molecular, clinical, and histopathologic findings. The methods for evaluating causes of death, contributing causes of death, and comorbidities have been suggested in several publications. Surprisingly, in important mouse aging studies, causes of death are often not reported. Cause-of-death assignment in preclinical rodent model aging research suffers from a lack of a standardized approach and an understanding of the value that it can add to longevity and interventional studies. While assigning single cause of death may facilitate data analysis, defining and publishing data on contributing causes (comorbidities) provides more information on associated underlying chronic conditions and health span in mouse models. This article reviews factors that affect determination of cause of death and the methods for evaluating causes of death and comorbidities. The proposed systematic pathology analysis includes assigning cause of death and comorbidities to define total disease burden. The combination of pathology with in vivo data will fully characterize the effect of tested interventions on multiple chronic diseases and health span of aging mice with improved translation to human aging and age associated lesions. PMID- 26508697 TI - Transcatheter occlusion of gigantic persistent ductus arteriosus (PDA) using a custom-made persistent ductus arteriosus occluder. AB - We reported transcatheter closure of gigantic persistent ductus arteriosus (PDA) complicated by severe pulmonary hypertension (PH) using a custom-made PDA occluder. A 19-year-old lady weighing 45 kg visited to our Heart Saving Project in Mongolia with a chief complaint of shortness of breath. Contrast CT scan showed ellipsoidal section of PDA whose long axis being 28 mm, and the short axis of 21 mm. A custom-made PDA occluder, whose retention skirt, the aortic side, and the pulmonic side diameter of the body were 54, 36, 34 mm, respectively, was successfully deployed using 14-Fr sheath. Pulmonary pressure decreased around a half compared to before closure. A custom-made duct occluder could be a reasonable and cost-effective choice for transcatheter closure of gigantic PDA complicated by severe PH. (c) 2015 Wiley Periodicals, Inc. PMID- 26508698 TI - An Altered, Unresponsive Teenager in the Emergency Department. PMID- 26508699 TI - En Caul Delivery. PMID- 26508700 TI - Commentary on Reconstituting Fibrinogen Concentrate to Maintain Blinding in a Double-blind, Randomized Trial in an Emergency Setting. AB - BACKGROUND: The gold standard of trial design is the double-blind, placebo controlled, randomized trial. Intravenous medication, which needs reconstitution by the attending clinician in an emergency situation, can be challenging to incorporate into a suitably blinded study. DISCUSSION: We have developed a method of blindly reconstituting and administering fibrinogen concentrate (presented as a lyophilized powder), where the placebo is normal saline. Fibrinogen concentrate is increasingly being used early in the treatment of major hemorrhage. Our methodology was designed for a multicenter study investigating the role of fibrinogen concentrate in the treatment of the coagulopathy associated with major obstetric hemorrhage. The method has been verified by a stand-alone pharmaceutical manufacturing unit with an investigational medicinal products license, and to date has successfully been applied 45 times in four study centers. There have been no difficulties in reconstitution and no related adverse events reported. CONCLUSION: We feel our method is simple to perform and maintains blinding throughout, making it potentially suitable for use in other trials conducted in psychologically high-pressure environments. Although fibrinogen concentrate was the focus of our study, it is likely that the method is applicable to other lyophilized medication with limited shelf life (e.g., antibiotics). PMID- 26508701 TI - Pharmacogenomics of estrogens on changes in carotid artery intima-medial thickness and coronary arterial calcification: Kronos Early Estrogen Prevention Study. AB - Prior to the initiation of menopausal hormone treatment (MHT), genetic variations in the innate immunity pathway were found to be associated with carotid artery intima-medial thickness (CIMT) and coronary arterial calcification (CAC) in women (n = 606) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Whether MHT might affect these associations is unknown. The association of treatment outcomes with variation in the same 764 candidate genes was evaluated in the same KEEPS participants 4 yr after randomization to either oral conjugated equine estrogens (0.45 mg/day), transdermal 17beta-estradiol (50 MUg/day), each with progesterone (200 mg/day) for 12 days each month, or placebo pills and patch. Twenty SNPs within the innate immunity pathway most related with CIMT after 4 yr were not among those associated with CIMT prior to MHT. In 403 women who completed the study in their assigned treatment group, single nucleotide polymorphisms (SNPs) within the innate immunity pathway were found to alter the treatment effect on 4 yr change in CIMT (i.e., significant interaction between treatment and genetic variation in the innate immunity pathway; P < 0.001). No SNPs by treatment effects were observed with changes of CAC >5 Agatston units after 4 yr. Results of this study suggest that hormonal status may interact with genetic variants to influence cardiovascular phenotypes, specifically, the pharmacogenomic effects within the innate immunity pathway for CIMT. PMID- 26508702 TI - Protein-leucine ingestion activates a regenerative inflammo-myogenic transcriptome in skeletal muscle following intense endurance exercise. AB - Protein-leucine supplement ingestion following strenuous endurance exercise accentuates skeletal-muscle protein synthesis and adaptive molecular responses, but the underlying transcriptome is uncharacterized. In a randomized single-blind triple-crossover design, 12 trained men completed 100 min of high-intensity cycling then ingested 70/15/180/30 g protein-leucine-carbohydrate-fat (15LEU), 23/5/180/30 g (5LEU), or 0/0/274/30 g (CON) beverages during the first 90 min of a 240 min recovery period. Vastus lateralis muscle samples (30 and 240 min postexercise) underwent transcriptome analysis by microarray followed by bioinformatic analysis. Gene expression was regulated by protein-leucine in a dose-dependent manner affecting the inflammatory response and muscle growth and development. At 30 min, 15LEU and 5LEU vs. CON activated transcriptome networks with gene-set functions involving cell-cycle arrest (Z-score 2.0-2.7, P < 0.01), leukocyte maturation (1.7, P = 0.007), cell viability (2.4, P = 0.005), promyogenic networks encompassing myocyte differentiation and myogenin (MYOD1, MYOG), and a proteinaceous extracellular matrix, adhesion, and development program correlated with plasma lysine, arginine, tyrosine, taurine, glutamic acid, and asparagine concentrations. High protein-leucine dose (15LEU-5LEU) activated an IL-1I-centered proinflammatory network and leukocyte migration, differentiation, and survival functions (2.0-2.6, <0.001). By 240 min, the protein-leucine transcriptome was anti-inflammatory and promyogenic (IL-6, NF- beta, SMAD, STAT3 network inhibition), with overrepresented functions including decreased leukocyte migration and connective tissue development (-1.8-2.4, P < 0.01), increased apoptosis of myeloid and muscle cells (2.2-3.0, P < 0.002), and cell metabolism (2.0-2.4, P < 0.01). The analysis suggests protein-leucine ingestion modulates inflammatory-myogenic regenerative processes during skeletal muscle recovery from endurance exercise. Further cellular and translational research is warranted to validate amino acid-mediated myeloid and myocellular mechanisms within skeletal-muscle functional plasticity. PMID- 26508703 TI - Telomere dynamics during aging in polygenic left ventricular hypertrophy. AB - Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk. PMID- 26508705 TI - Pentraxin 3 sputum levels differ in patients with chronic obstructive pulmonary disease vs asthma. AB - BACKGROUND: Immune response has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD) and asthma. Pentraxin 3 (PTX3) is a multifunctional pattern recognition protein and an important component of the innate immune system that can be assessed in blood and induced sputum. OBJECTIVE: To determine whether PTX3 measured in induced sputum could discriminate patients with COPD from patients with asthma. METHODS: A cross-sectional study of 68 participants (27 with COPD, 25 with asthma, and 16 healthy controls) was performed. At study inclusion sputum was collected and total and differential cell numbers and PTX3 levels were determined. RESULTS: Pentraxin 3 was detected in 89% of patients with COPD, 56% of patients with asthma, and 19% of controls (P = .001). It discriminated participants with COPD (24.6 ng/mL, 0-384 ng/mL) from controls (0 ng/mL, 0-36 ng/mL, P < .001) and from participants with asthma (1.2 ng/mL, 0-100 ng/mL, P = .01; area under the receiver operating curve 0.82 [0.71 0.94]). Regression analyses determined that sputum PTX3 and neutrophil counts were independently associated with COPD. In addition, PTX3 levels were independently associated with COPD severity. CONCLUSION: Pentraxin 3 sputum levels are increased in patients with COPD and has good power to discriminate these patients from patients with asthma and healthy individuals. PMID- 26508704 TI - Proteomic profiling of nuclear fractions from native renal inner medullary collecting duct cells. AB - The control of renal water excretion occurs in part by regulation of transcription in response to vasopressin in cells of the collecting duct. A systems biology-based approach to understanding transcriptional control in renal collecting duct cells depends on knowledge of what transcription factors and other regulatory proteins are present in the cells' nuclei. The goal of this article is to report comprehensive proteomic profiling of cellular fractions enriched in nuclear proteins from native inner medullary collecting duct (IMCD) cells of the rat. Multidimensional separation procedures and state-of-the art protein mass spectrometry produced 18 GB of spectral data that allowed the high stringency identification of 5,048 proteins in nuclear pellet (NP) and nuclear extract (NE) fractions of biochemically isolated rat IMCD cells (URL: https://helixweb.nih.gov/ESBL/Database/IMCD_Nucleus/). The analysis identified 369 transcription factor proteins out of the 1,371 transcription factors coded by the rat genome. The analysis added 1,511 proteins to the recognized proteome of rat IMCD cells, now amounting to 8,290 unique proteins. Analysis of samples treated with the vasopressin analog dDAVP (1 nM for 30 min) or its vehicle revealed 99 proteins in the NP fraction and 88 proteins in the NE fraction with significant changes in spectral counts (Fisher exact test, P < 0.005). Among those altered by vasopressin were seven distinct histone proteins, all of which showed decreased abundance in the NP fraction, consistent with a possible effect of vasopressin to induce chromatin remodeling. The results provide a data resource for future studies of vasopressin-mediated transcriptional regulation in the renal collecting duct. PMID- 26508706 TI - 5-HT2 receptors modulate the expression of antipsychotic-induced dopamine supersensitivity. AB - Antipsychotic treatment can produce supersensitivity to dopamine receptor stimulation. This compromises the efficacy of ongoing treatment and increases the risk of relapse to psychosis upon treatment cessation. Serotonin 5-HT2 receptors modulate dopamine function and thereby influence dopamine-dependent responses. Here we evaluated the hypothesis that 5-HT2 receptors modulate the behavioural expression of antipsychotic-induced dopamine supersensitivity. To this end, we first treated rats with the antipsychotic haloperidol using a clinically relevant treatment regimen. We then assessed the effects of a 5-HT2 receptor antagonist (ritanserin; 0.01 and 0.1mg/kg) and of a 5-HT2A receptor antagonist (MDL100,907; 0.025-0.1mg/kg) on amphetamine-induced psychomotor activity. Antipsychotic treated rats showed increased amphetamine-induced locomotion relative to antipsychotic-naive rats, indicating a dopamine supersensitive state. At the highest dose tested (0.1mg/kg for both antagonists), both ritanserin and MDL100,907 suppressed amphetamine-induced locomotion in antipsychotic-treated rats, while having no effect on this behaviour in control rats. In parallel, antipsychotic treatment decreased 5-HT2A receptor density in the prelimbic cortex and nucleus accumbens core and increased 5-HT2A receptor density in the caudate putamen. Thus, activation of either 5-HT2 receptors or of 5-HT2A receptors selectively is required for the full expression of antipsychotic-induced dopamine supersensitivity. In addition, antipsychotic-induced dopamine supersensitivity enhances the ability of 5-HT2/5-HT2A receptors to modulate dopamine-dependent behaviours. These effects are potentially linked to changes in 5-HT2A receptor density in the prefrontal cortex and the striatum. These observations raise the possibility that blockade of 5-HT2A receptors might overcome some of the behavioural manifestations of antipsychotic-induced dopamine supersensitivity. PMID- 26508707 TI - A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice. AB - Gut-brain hormones such as ghrelin have recently been suggested to have a role in reward regulation. Ghrelin was traditionally known to regulate food intake and body weight homoeostasis. In addition, recent work has pin-pointed that this peptide has a novel role in drug-induced reward, including morphine-induced increase in the extracellular levels of accumbal dopamine in rats. Herein the effect of the ghrelin receptor (GHS-R1A) antagonist, JMV2959, on morphine-induced activation of the mesolimbic dopamine system was investigated in mice. In addition, the effects of JMV2959 administration on opioid peptide levels in reward related areas were investigated. In the present series of experiment we showed that peripheral JMV2959 administration, at a dose with no effect per se, attenuates the ability of morphine to cause locomotor stimulation, increase the extracellular levels of accumbal dopamine and to condition a place preference in mice. JMV2959 administration significantly increased tissue levels of Met enkephalin-Arg(6)Phe(7) in the ventral tegmental area, dynorphin B in hippocampus and Leu-enkephalin-Arg(6) in striatum. We therefore hypothesise that JMV2959 prevents morphine-induced reward via stimulation of delta receptor active peptides in striatum and ventral tegmental areas. In addition, hippocampal peptides that activate kappa receptor may be involved in JMV2959's ability to regulate memory formation of reward. Given that development of drug addiction depends, at least in part, of the effects of addictive drugs on the mesolimbic dopamine system the present data suggest that GHS-R1A antagonists deserve to be elucidated as novel treatment strategies of opioid addiction. PMID- 26508708 TI - When Results Also Allow the Opposite Conclusion.... PMID- 26508709 TI - Influence of Cardiovascular and Noncardiovascular Co-morbidities on Outcomes and Treatment Effect of Heart Rate Reduction With Ivabradine in Stable Heart Failure (from the SHIFT Trial). AB - Incidence of chronic heart failure (HF) increases with age and cardiovascular (CV) morbidity. Co-morbidities increase hospitalization and mortality in HF, and non-CV co-morbidities may lead to preventable hospitalizations. We studied the impact of co-morbidities on mortality and morbidity in Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial, and investigated whether the impact of ivabradine was affected by co-morbidities. We analyzed the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trialpopulation, with moderate-to-severe HF and left ventricular dysfunction (in sinus rhythm with heart rate at rest >=70 beats/min), according to co-morbidity: chronic obstructive pulmonary disease, diabetes mellitus, anemia, stroke, impaired renal function, myocardial infarction, hypertension, and peripheral artery disease. Co morbidity load was classed as 0, 1, 2, 3, 4+ or 1 to 2 co-morbidities, or 3+ co morbidities. Co-morbidities were evenly distributed between the placebo and ivabradine groups. Patients with more co-morbidities were likely to be older, women, had more advanced HF, were less likely to be on beta blockers, with an even distribution on ivabradine 2.5, 5, or 7.5 mg bid and placebo at all co morbidity loads. Number of co-morbidities was related to outcomes. Cardiovascular death or HF hospitalization events significantly increased (p <0.0001) with co morbidity load, with the most events in patients with >3 co-morbidities for both, ivabradine and placebo. There was no interaction between co-morbidity load and the treatment effects of ivabradine. Hospitalization rate was lower at all co morbidity loads for ivabradine. In conclusion, cardiac and noncardiac co morbidities significantly affect CV outcomes, particularly if there are >3 co morbidities. The effect of heart rate reduction with ivabradine is maintained at all co-morbidity loads. PMID- 26508710 TI - Association Between Transcatheter Aortic Valve Implantation Volume and Outcomes in the United States. AB - With the rapid advance of transcatheter aortic valve implantation (TAVI), it is important to evaluate the relationship between TAVI volumes and outcomes. The aim of this study was to analyze in-hospital outcomes after TAVI stratified according to hospital volumes. Using the National Inpatient Sample files from 2012, hospitals performing transfemoral (TF)-TAVI and transapical (TA)-TAVI were divided into high-volume and low-volume centers. A total of 7,660 patients underwent TAVI in 256 hospitals in 2012. In the TF-TAVI cohort, multivariate logistic regression analyses demonstrated that low TF-TAVI volume status was an independent predictor of death and bleeding. In the TA-TAVI cohort, low volume status was a predictor of death, myocardial infarction, and need for permanent pacemaker. In addition, hospitals that performed low TA-TAVI volume were associated with significantly higher rate of death after surgical aortic valve replacement in comparison with the hospitals that perform high TA-TAVI volume (3.6% vs 2.3%, p <0.001). In conclusion, centers with lower volume of TAVI had more frequent adverse events compared with higher volume centers. PMID- 26508711 TI - Effects of Statins on First and Recurrent Supraventricular Arrhythmias in Patients With Mild Heart Failure (from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). AB - Previous studies suggested that statin therapy reduces the risk of occurrence and recurrence of atrial fibrillation mainly in patients with coronary artery disease. Data regarding the effect of statins on the risk for the entire range of supraventricular arrhythmias (SVA) in mild heart failure (HF) with different disease causes are lacking. Multivariate Cox proportional hazards regression models were used to assess the effect of statin therapy, evaluated as a time dependent covariate, on the risk of SVA and recurrent SVA (defined as atrial fibrillation, atrial flutter, atrial tachycardia, and supraventricular tachycardia) that were inappropriately treated with implantable cardioverter defibrillator device in 1,790 patients enrolled in the Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy trial. Statin users constituted 68% of the study patients (n = 1209). They were older and more frequently men; they were more likely to have ischemic cardiomyopathy, diabetes, hypertension, and previous atrial arrhythmias. During the 3.7-year median follow up time, 160 patients had an SVA event, and the total number of recurrent events was 335. Time-dependent statin therapy was independently associated with a significant 29% reduction of the first SVA event (p = 0.046) and 33% reduction of recurrent SVA events (p = 0.003), consistent across all prespecified subgroups. In conclusion, in mild HF with either cardiac resynchronization therapy with a defibrillator or an implantable cardioverter-defibrillator device, statin therapy was associated with significant reduction of occurrence and recurrence of inappropriately treated SVA. PMID- 26508712 TI - Could Takotsubo Syndrome Trigger Type I Myocardial Infarction? PMID- 26508713 TI - QTc Interval and Mortality in Takotsubo Syndrome. PMID- 26508714 TI - Implementation of a Brief Treatment Counseling Toolkit in Federally Qualified Healthcare Centers: Patient and Clinician Utilization and Satisfaction. AB - INTRODUCTION: The need to integrate behavioral health care within medical settings is widely recognized, and integrative care approaches are associated with improved outcomes for a range of disorders. As substance use treatment integration efforts expand within primary care settings, training behavioral health providers in evidence-based brief treatment models that are cost-effective and easily fit within the medical flow is essential. METHODS: Guided by principles drawn from Diffusion of Innovations theory (Rogers, 2003) and the Consolidated Framework of Implementation Research (Damschroder et al., 2009), we adapted elements of Motivational Enhancement Therapy, cognitive-behavioral therapy, and 12-step facilitation into a brief counseling toolkit. The toolkit is a menu driven assortment of 35 separate structured clinical interventions that each include client takeaway resources to reinforce brief clinical contacts. We then implemented this toolkit in the context of a randomized clinical trial in three Federally Qualified Healthcare Centers. Behavioral Health Consultants (BHCs) used a pre-screening model wherein 10,935 patients received a brief initial screener, and 2011 received more in-depth substance use screening. Six hundred patients were assigned to either a single session brief intervention or an expanded brief treatment encompassing up to five additional sessions. We conducted structured interviews with patients, medical providers, and BHCs to obtain feedback on toolkit implementation. RESULTS: On average, patients assigned to brief treatment attended 3.29 sessions. Fifty eight percent of patients reported using most or all of the educational materials provided to them. Patients assigned to brief treatment reported that the BHC sessions were somewhat more helpful than did patients assigned to a single session brief intervention (p=.072). BHCs generally reported that the addition of the toolkit was helpful to their work in delivering screening and brief treatment. DISCUSSION: This work is significant because it provides support to clinicians in delivering evidence based brief interventions and has been formatted into presentation styles that can be presented flexibly depending on patient need. PMID- 26508715 TI - Using link analysis to explore the impact of the physical environment on pharmacist tasks. AB - BACKGROUND: National community pharmacy organizations have been redesigning pharmacies to better facilitate direct patient care. However, evidence suggests that changing the physical layout of a pharmacy prior to understanding how the environment impacts pharmacists' work may not achieve the desired benefits. This study describes an objective method to understanding how the physical layout of the pharmacy may affect how pharmacists perform tasks. METHOD: Link analysis is a systems engineering method used to describe the influence of the physical environment on task completion. This study used a secondary data set of field notes collected from 9 h of direct observation in one mass-merchandise community pharmacy in the U.S. State, Wisconsin. A node is an individual location in the environment. A link is the movement between two nodes. Tasks were inventoried and task themes identified. The mean, minimum, and maximum number of links needed to complete each task were then determined and used to construct a link table. A link diagram is a graphical display showing the links in conjunction with the physical layout of the pharmacy. RESULTS: A total of 92 unique tasks were identified resulting in 221 links. Tasks were sorted into five themes: patient care activities, insurance issues, verifying prescriptions, filling prescriptions, and other. Insurance issues required the greatest number of links with a mean of 4.75. Verifying prescriptions and performing patient care were the most commonly performed tasks with 36 and 30 unique task occurrences, respectively. CONCLUSION: Link analysis provides an objective method for identifying how a pharmacist interacts with the physical environment to complete tasks. This method provides designers with useful information to target interventions to improve the effectiveness of pharmacist work. Analysis beyond link analysis should be considered for large scale system redesign. PMID- 26508716 TI - Natural and ion-exchanged illite clays reduce bacterial burden and inflammation in cutaneous meticillin-resistant Staphylococcus aureus infections in mice. AB - Discoveries associated with antibacterial activity of hydrated clays necessitate assessments of in vivo efficacy, practical use and safety. Surface properties of clays can lead to variations in the composition and abundance of bound compounds or ions, thus affecting antibacterial activity. Since exchangeable metal ions released from the clay surface are responsible for in vitro antibacterial activity, we evaluated the in vivo antibacterial efficacy of four natural clays (one illite clay, two montmorillonite clays and one kaolinite clay) and three ion exchanged, antibacterial clays against superficial, cutaneous meticillin resistant Staphylococcus aureus (MRSA) infections in mice. Superficial, cutaneous wounds on the back of SKH1-Elite mice were generated and subsequently infected with MRSA. Following twice daily applications of a hydrated clay poultice to infected wounds for 7 days, we observed significant differences in the in vivo antibacterial efficacy between different types of clays. The natural and ion exchanged illite clays performed best, as measured by bacterial load, inflammatory response and gross wound morphology with significant decreases in bacterial viability and dermatitis. Topical application of kaolinite clay was the least effective, resulting in the lowest decrease in bacterial load and exhibiting severe dermatitis. These data suggest that specific types of clays may offer a complementary and integrative strategy for topically treating MRSA and other cutaneous infections. However, since natural clays exhibit in vitro antibacterial variability and vary vastly in surface chemistries, adsorptive/absorptive characteristics and structural composition, the properties and characteristics of illite clays could aid in the development of standardized and customized aluminosilicates for topical infections. PMID- 26508717 TI - Viral meningitis epidemics and a single, recent, recombinant and anthroponotic origin of swine vesicular disease virus. AB - BACKGROUND AND OBJECTIVES: Swine vesicular disease virus (SVDV) is a close relative of the human Enterovirus B serotype, coxsackievirus B5. As the etiological agent of a significant emergent veterinary disease, several studies have attempted to explain its origin. However, several key questions remain, including the full biological ancestry of the virus, and its geographical and temporal origin. METHODOLOGY: We sequenced near-complete genomes of 27 SVDV and 13 coxsackievirus B5 samples, all originally isolated between 1966 and 2006, and analysed these in conjunction with existing sequences and historical information. RESULTS: While analyses incorporating 24 additional near-complete SVDV genomic sequences indicate clear signs of within-SVDV recombination, all 51 SVDV isolates remain monophyletic. This supports a hypothesis of a single anthroponotic transfer origin. Analysis of individual coding and non-coding regions supports that SVDV has a recombinant origin between coxsackievirus B5 and another Enterovirus B serotype, most likely coxsackievirus A9. Extensive Bayesian sequence-based analysis of the time of the most recent common ancestor of all analysed sequences places this within a few years around 1961. Epidemiological evidence points to China as an origin, but there are no available samples to test this conclusively. CONCLUSIONS AND IMPLICATIONS: Historical investigation and the clinical aspects of the involved Enterovirus B serotypes, makes the current results consistent with a hypothesis stating that SVDV originated through co infection, recombination, and a single anthroponotic event, during large viral meningitis epidemics around 1960/1961 involving the ancestral serotypes. The exact geographical origin of SVDV may remain untestable due to historical aspects. PMID- 26508718 TI - Caffeine consumption and self-assessed stress, anxiety, and depression in secondary school children. AB - Previous research suggests that effects of caffeine on behaviour are positive unless one is investigating sensitive groups or ingestion of large amounts. Children are a potentially sensitive subgroup, and especially so considering the high levels of caffeine currently found in energy drinks. The present study used data from the Cornish Academies Project to investigate associations between caffeine (both its total consumption, and that derived separately from energy drinks, cola, tea, and coffee) and single-item measures of stress, anxiety, and depression, in a large cohort of secondary school children from the South West of England. After adjusting for additional dietary, demographic, and lifestyle covariates, positive associations between total weekly caffeine intake and anxiety and depression remained significant, and the effects differed between males and females. Initially, effects were also observed in relation to caffeine consumed specifically from coffee. However, coffee was found to be the major contributor to high overall caffeine intake, providing explanation as to why effects relating to this source were also apparent. Findings from the current study increase our knowledge regarding associations between caffeine intake and stress, anxiety, and depression in secondary school children, though the cross sectional nature of the research made it impossible to infer causality. PMID- 26508719 TI - Perifollicular haemorrhage with corkscrew hair due to scurvy. PMID- 26508720 TI - Global health training in US obstetrics and gynaecology residency programmes: perspectives of students, residents and programme directors. AB - BACKGROUND: Benefits of exposure to global health training during medical education are well documented and residents' demand for this training is increasing. Despite this, it is offered by few US obstetrics and gynaecology (OBGYN) residency training programmes. OBJECTIVES: To evaluate interest, perceived importance, predictors of global health interest and barriers to offering global health training among prospective OBGYN residents, current OBGYN residents and US OGBYN residency directors. METHODS: We designed two questionnaires using Likert scale questions to assess perceived importance of global health training. The first was distributed to current and prospective OBGYN residents interviewing at a US residency programme during 2012-2013. The second questionnaire distributed to US OBGYN programme directors assessed for existing global health programmes and global health training barriers. A composite Global Health Interest/Importance score was tabulated from the Likert scores. Multivariable linear regression was performed to assess for predictors of Global Health Interest/Importance. RESULTS: A total of 159 trainees (77%; 129 prospective OBGYN residents and 30 residents) and 69 (28%) programme directors completed the questionnaires. Median Global Health Interest/Importance score was 7 (IQR 4-9). Prior volunteer experience was predictive of a 5-point increase in Global Health Interest/Importance score (95% CI -0.19 to 9.85; p=0.02). The most commonly cited barriers were cost and time. CONCLUSION: Interest and perceived importance of global health training in US OBGYN residency programmes is evident among trainees and programme directors; however, significant financial and time barriers prevent many programmes from offering opportunities to their trainees. Prior volunteer experience predicts global health interest. PMID- 26508721 TI - Possible role of granulysin in pathogenesis of osteoarthritis. AB - Increased presence of immune mediator and cytotoxic/apoptotic molecule granulysin was noticed in different tissues during pathological processes with the domination of Th1 over Th2 mediated immunity. Beside granulysin expression in T and NKT cells, activated NK cells are thought to be the major source of chemotactic 15 kDa and cytotoxic 9 kDa granulysin in vivo. As NK cells are the principal joint's tissue-infiltrating lymphocyte subset, we hypothesized that granulysin mediated human cell death (apoptosis) could be responsible for the relatively silent damage of the joint's tissue without clinically notable signs of systemic inflammation in the patients with osteoarthritis (OA). The analyzes of the presence and frequency of granulysin expressing lymphocytes at protein and gene levels in peripheral blood and synovial samples and/or the samples of joint's tissue after the joint replacement therapy in patients with OA could give the initial insight to evaluate our hypothesis. It would be of the particular interest to differentiate the expression of 9 kDa and 15 kDa granulysin forms in the effector cells, since only the shorter form exhibits cytotoxic properties. The measurement of granulysin mediated early apoptosis in human NK sensitive K562 cells could be suitable in vitro model for evaluating granulysin activity. Furthermore, disturbed balance of pro-inflammatory and anti-inflammatory cytokines in OA patients, could influence the level of the granulysin expression. Having in mind that the granulysin and its regulation is still unknown in the pathogenesis of OA, it could be worth to explore this important pro-inflammatory, cytotoxic/apoptotic mediator. PMID- 26508722 TI - Mechanism of failure of the Cabrol procedure: A computational fluid dynamic analysis. AB - Sudden failure of the Cabrol graft is common and frequently fatal. We utilised the technique of computational fluid dynamic (CFD) analysis to evaluate the mechanism of failure and potentially improve on the design of the Cabrol procedure. CFD analysis of the classic Cabrol procedure and a number of its variants was performed. Results from this analysis was utilised to generate further improved geometric options for the Cabrol procedure. These were also subjected to CFD analysis. All current Cabrol and variations of the Cabrol procedure are predicated by CFD analysis to be prone to graft thrombosis, secondary to stasis around the right coronary artery button. The right coronary artery flow characteristics were found to be the dominant reason for Cabrol graft failure. A simple modification of the Cabrol geometry is predicated to virtually eliminate any areas of blood stasis, and graft failure. Modification of the Cabrol graft geometry, due to CFD analysis may help reduce the incidence of graft thrombosis. A C shaped Cabrol graft with the right coronary button anastomosed to its side along its course from the aorta to the left coronary button is predicted to have the least thrombotic tendency. Clinical correlation is needed. PMID- 26508723 TI - Urinary Transforming Growth Factor beta-1 as a Marker of Renal Dysfunction in Sickle Cell Disease. AB - BACKGROUND: Sickle cell disease (SCD) is a genetic disorder that results in deformity of red blood cells. Renal dysfunction affects 5-18% of patients with SCD. To date, few studies have described urinary levels of transforming growth factor beta-1 (TGF-beta1), which is a marker of fibrosis, as a biomarker in identifying patients at risk of developing renal disease in SCD. The aim of this study is to determine prevalence of sickle cell nephropathy in Egyptian SCD patients. We aimed also to evaluate the association of urinary TGF-beta1 with other conventional biomarkers of renal damage in SCD patients to identify a novel renal biomarker for early diagnosis of sickle nephropathy. METHODS: We examined 40 SCD patients, 21 with sickle cell anemia, 16 sickle thalassemia, and three with sickle trait. We compared them to 20 control children with matched age and sex. The study was held in the time period between May 2013 and December 2013 in the Hematology Clinic, New Cairo University Children Hospital, Cairo, Egypt. RESULTS: Urinary excretion of TGF-beta1 was 7.07 +/- 1.91 ng/mL in SCD patients versus 2.23 +/- 0.76 ng/mL in control children (p < 0.001). SCD patients had elevated estimated glomerular filtration rate (177.44 +/- 35.6 mL/min/1.73 m(2)), denoting a state of glomerular hyperfiltration. 47.5% of SCD patients had microalbuminuria. Urinary TGF-beta1 correlated positively with microalbuminuria and estimated glomerular filtration rate (p = 0.001 and p = 0.018, respectively). CONCLUSION: We concluded that urinary TGF-beta1 may serve as a marker of early renal injury in SCD. PMID- 26508724 TI - Alemtuzumab as a novel treatment for refractory giant cell myocarditis after heart transplantation. PMID- 26508725 TI - Left ventricular dimension decrement index early after axial flow assist device implantation: A novel risk marker for late pump thrombosis. AB - BACKGROUND: It is increasingly recognized that pump thrombosis most likely represents the end stage of a complex interaction between the patient-pump interface. We hypothesized that early patient/pump mismatch, as manifested by suboptimal left ventricular (LV) unloading early after left ventricular assist device (LVAD) implantation, may be a harbinger of increased risk for later LVAD thrombosis. METHODS: In 64 patients (59 +/- 11 years old, 78% men, 44% destination therapy) discharged alive without thrombosis or other device malfunction after first HeartMate II LVAD implantation (between January 2011 and June 2014), LV dimensions in end diastole (LVIDd) and end systole (LVIDs) were compared between pre-implant and optimal set speed pre-discharge echocardiography. LV dimension decrement indices (pre-implant dimension - optimal set speed dimension / pre-implant dimension * 100) for LVIDd [LVIDdDI] and LVIDs [LVIDsDI] were calculated. RESULTS: The incidence of pump thrombosis was 0.06 per patient year (n = 18, median time 8 [interquartile range 2, 17] months). Baseline characteristics including pre-operative LVIDd and LVIDs were similar between LVAD thrombosis and no thrombosis groups. After ventricular assist device implantation, set speed and other ramp parameters did not differ between groups. However, LVIDdDI (19 +/- 13% vs 25 +/- 11%, p = 0.04) and LVIDsDI (16 +/- 16% vs 27 +/- 13%, p = 0.008) were significantly lower in patients with later pump thrombosis. A cutoff value of <=15% using receiver operating characteristic curve analysis was 83% sensitive for LVIDdDI and LVIDsDI for predicting pump thrombosis. Patients with LVIDdDI of >15% vs <=15% were significantly more likely to be free of pump thrombosis over a median follow-up period of 15 (interquartile range 9, 26) months (log-rank test, p = 0.045). CONCLUSIONS: LV dimension decrement index at optimized speed setting on pre-discharge echocardiography is associated with LVAD thrombosis. PMID- 26508726 TI - Gender differences in the risk of stroke during support with continuous-flow left ventricular assist device. AB - BACKGROUND: There is increasing recognition that the risk of stroke after left ventricular assist device (LVAD) implantation varies based on gender, with a higher risk in female patients. We reviewed our own data to determine gender differences in the risk of stroke. METHODS: Frequency of stroke, including intracranial hemorrhage and ischemic stroke, was retrospectively evaluated in 110 heart failure patients (mean age 49.6 +/- 13.6 years, 32% women) discharged from the hospital after implantation of a HeartMate II (N = 74) or HeartWare (N = 36) LVAD. Competing outcomes analysis was used to determine which clinical risk factors were associated with the risk of stroke and death, with the primary end point being time to first stroke event. RESULTS: During a median follow-up of 1.3 years, 26 patients had a stroke (23.6%, 0.14 case per person-year). The median time to first stroke was 0.7 (interquartile range 0.3 to 1.4) years. After adjusting for covariates, risk of stroke was higher for women than for men (hazard ratio 3.1, 95% confidence interval 1.4 to 6.9; p = 0.007). There was no difference in overall survival between men and women. CONCLUSION: The risk of stroke after LVAD varies based on gender, with a higher risk in female patients. More research is needed to fully understand these differences, and whether device management strategies should be tailored based on gender. PMID- 26508728 TI - Corrigendum. PMID- 26508727 TI - Bronchial artery revascularization and en bloc lung transplant in children. AB - BACKGROUND: Long-term success in pediatric lung transplantation is limited by infection and bronchiolitis obliterans syndrome (BOS). The bilateral sequential lung transplantation (BSLT) technique may result in airway ischemia leading to bronchial stenosis, dehiscence, or loss of small airways. En bloc lung transplant (EBLT) with bronchial artery revascularization (BAR) minimizes airway ischemia, thus promoting superior airway healing. BAR also allows for safe tracheal anastomosis, circumventing the need for bilateral bronchial anastomoses in small children. METHODS: This was a retrospective review of bilateral transplantations from 2005 to 2014. Both techniques were used in parallel. Redo and multiorgan transplants were excluded. RESULTS: There were 119 recipients comprising 88 BSLTs and 31 EBLTs. Follow-up time was 3 years (interquartile range, 1-5 years). Donor ischemic and cardiopulmonary bypass times were not different between techniques (p = 0.48 and p = 0.18, respectively). Degree of graft dysfunction and cellular rejection scores were not different (p = 0.83 and p = 0.93, respectively). There were 3 hospital deaths after BSLT and 2 after EBLT (p = 0.60). Overall survival was 61% for the BSLT group and 77% for the EBLT group (p = 0.54). Freedom from BOS was 71% in the BSLT group and 94% in the EBLT group (p = 0.08). On routine bronchoscopy, 57% BSLT and 16% EBLT patients had 1 or more airway ischemic findings (p < 0.0001). Multivariate analysis showed BSLT was associated with higher ischemic injury (relative risk, 2.86; 95 confidence interval, 1.3-6.5; p = 0.01) and non-airway complications (relative risk, 4.62; 95% confidence interval, 1.1-20.2; p = 0.04) but not airway reinterventions (p = 0.07). Airway dehiscence occurred in 3 BSLT patients. CONCLUSIONS: Pediatric EBLT with BAR can be safely performed without increasing operative or graft ischemic times. Airway ischemia and non-airway complications were significantly reduced when BAR was combined with tracheal anastomosis, potentially diminishing morbidity caused by anastomotic healing complications. PMID- 26508729 TI - Results-Based Accountability for Cardiovascular Epidemiology Research by the National Heart, Lung, and Blood Institute. PMID- 26508730 TI - Impact of National Heart, Lung, and Blood Institute-Supported Cardiovascular Epidemiology Research, 1998 to 2012. PMID- 26508731 TI - Genetic Ablation of Extra Domain A of Fibronectin in Hypercholesterolemic Mice Improves Stroke Outcome by Reducing Thrombo-Inflammation. AB - BACKGROUND: The fibronectin-splicing variant containing extra domain A (Fn-EDA) is present in negligible amounts in the plasma of healthy humans but markedly elevated in patients with comorbid conditions, including diabetes mellitus and hypercholesterolemia, which are risk factors for stroke. It remains unknown, however, whether Fn-EDA worsens stroke outcomes in such conditions. We determined the role of Fn-EDA in stroke outcome in a model of hypercholesterolemia, the apolipoprotein E-deficient (Apoe(-/-)) mouse. METHODS AND RESULTS: In a transient cerebral ischemia/reperfusion injury model, Apoe(-/-) mice expressing fibronectin deficient in EDA (Fn-EDA(-/-)Apoe(-/-) mice) exhibited smaller infarcts and improved neurological outcomes at days 1 and 8 (P<0.05 versus Apoe(-/-) mice). Concomitantly, intracerebral thrombosis [assessed by fibrin(ogen) deposition] and postischemic inflammation (phospho-nuclear factor-kappaB p65, phospho-IkappaB kinase alpha/beta, interleukin 1beta, and tumor necrosis factor-alpha) within lesions of Fn-EDA(-/-)Apoe(-/-) mice were markedly decreased (P<0.05 versus Apoe( /-) mice). In an FeCl3 injury-induced carotid artery thrombosis model, thrombus growth rate and the time to occlusion were prolonged in Fn-EDA(-/-)Apoe(-/-) mice (P<0.05 versus Apoe(-/-) mice). Genetic ablation of TLR4 improved stroke outcome in Apoe(-/-) mice (P<0.05) but had no effect on stroke outcome in Fn-EDA(-/ )Apoe(-/-) mice. Bone marrow transplantation experiments revealed that nonhematopoietic cell-derived Fn-EDA exacerbates stroke through Toll-like receptor-4 expressed on hematopoietic cells. Infusion of a specific inhibitor of Fn-EDA into Apoe(-/-) mouse 15 minutes after reperfusion significantly improved stroke outcome. CONCLUSIONS: Hypercholesterolemic mice deficient in Fn-EDA exhibit reduced cerebral thrombosis and less inflammatory response after ischemia/reperfusion injury. These findings suggest that targeting Fn-EDA could be an effective therapeutic strategy in stroke associated with hypercholesterolemia. PMID- 26508732 TI - Toward a Biological Therapy to Improve Stroke Outcomes After Thrombolytic Therapy. PMID- 26508733 TI - Maternal hCG concentrations in early IVF pregnancies: associations with number of cells in the Day 2 embryo and oocytes retrieved. AB - STUDY QUESTION: Do number of cells in the transferred cleavage stage embryo and number of oocytes retrieved for IVF influence maternal hCG concentrations in early pregnancies? SUMMARY ANSWER: Compared with transfer of a 2-cell embryo, transfer of a 4-cell embryo results in higher hCG concentrations on Day 12 after transfer, and more than 20 oocytes retrieved were associated with low hCG concentrations. WHAT IS KNOWN ALREADY: Maternal hCG concentration in very early pregnancy varies considerably among women, but is likely to be an indicator of time since implantation of the embryo into the endometrium, in addition to number and function of trophoblast cells. STUDY DESIGN, SIZE, DURATION: We followed 1047 pregnancies after IVF/ICSI from oocyte retrieval until Day 12 after embryo transfer. Women were recruited in Norway during the years 2005-2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: Successful pregnancies after transfer of one single embryo that had been cultured for 2 days were included. Maternal hCG was quantified on Day 12 after embryo transfer by chemiluminescence immunoassay, which measures intact hCG and the free beta-hCG chain. Information on a successful pregnancy, defined as birth after >16 weeks, was obtained by linkage to the Medical Birth Registry of Norway. MAIN RESULTS AND THE ROLE OF CHANCE: Transfer of a 4-cell embryo resulted in higher maternal hCG concentrations compared with transfer of a 2-cell embryo (134.8 versus 87.8 IU/l, P < 0.05). A high number of oocytes retrieved (>20) was associated with low hCG concentrations (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The factors studied explain a limited part of the total variation of hCG concentrations in early pregnancy. Although embryo transfer was performed at the same time after fertilization, we do not know the exact time of implantation. A further limitation to our study is that the number of pregnancies after transfer of a 2 cell embryo was small (27 cases). WIDER IMPLICATIONS OF THE FINDINGS: Number of cells in the transferred embryo and number of oocytes retrieved may influence the conditions and timing for embryo implantation in different ways and thereby influence maternal hCG concentrations. Such knowledge may be important for interpretation of hCG concentrations in early pregnancy. PMID- 26508734 TI - Smac mimetic with TNF-alpha targets Pim-1 isoforms and reactive oxygen species production to abrogate transformation from blebbishields. AB - Cancer cells are capable of sphere formation (transformation) through reactive oxygen species (ROS) and glycolysis shift. Transformation is linked to tumorigenesis and therapy resistance, hence targeting regulators of ROS and glycolysis is important for cancer therapeutic candidates. Here, we demonstrate that Smac mimetic AZ58 in combination with tumour necrosis factor-alpha (TNF alpha) was able to inhibit the production of ROS, inhibit glycolysis through Pim 1 kinase-mediated Ser-112 phosphorylation of BAD, and increase depolarization of mitochondria. We also identified mitochondrial isoforms of Pim-1 kinase that were targeted for degradation by AZ58 in combination with TNF-alpha or AZ58 in combination with Fas ligand (FasL) plus cycloheximide (CHX) through caspase-3 to block transformation. Our study demonstrates that Smac mimetic in combination with TNF-alpha is an ideal candidate to target Pim-1 expression, inhibit ROS production and to block transformation from blebbishields. PMID- 26508735 TI - LL-37-induced host cell cytotoxicity depends on cellular expression of the globular C1q receptor (p33). AB - The human host-defence peptide (HDP) LL-37 not only displays anti-microbial activity but also immune-modulating properties that trigger intracellular signalling events in host cells. Since the cytolytic activity of high LL-37 concentrations affects cell viability, the function of LL-37 requires tight regulation. Eukaryotic cells therefore benefit from protective measures to prevent harmful effects of LL-37. p33, also known as globular C1q receptor (gC1qR), is reported to act as an LL-37 antagonist by binding the peptide, thereby reducing its cytotoxic activity. In the present report, we show that high levels of endogenous p33 correlate with an increased viability in human cells treated with LL-37. Sub-cellular localization analysis showed p33 distribution at the mitochondria, the plasma membrane and in the cytosol. Strikingly, cytosolic overexpression of p33 significantly antagonized detrimental effects of LL-37 on cell fitness, whereas the reverse effect was observed by siRNA-induced down regulation of p33. However, modulation of p33 expression had no effect on LL-37 induced plasma membrane pore forming capacity pointing to an intracellular mechanism. A scavenging function of intracellular p33 is further supported by co immunoprecipitation experiments, showing a direct interaction between intracellular p33 and LL-37. Thus, our findings support an important role of intracellular p33 in maintaining cell viability by counteracting LL-37-induced cytotoxicity. PMID- 26508736 TI - Arterial to end-tidal Pco2 difference during exercise in normoxia and severe acute hypoxia: importance of blood temperature correction. AB - Negative arterial to end-tidal pco2 differences ((a-ET)pco2) have been reported in normoxia. To determine the influence of blood temperature on (a-ET)pco2, 11 volunteers (21 +/- 2 years) performed incremental exercise to exhaustion in normoxia (Nx, Pio2: 143 mmHg) and hypoxia (Hyp, Pio2: 73 mmHg), while arterial blood gases and temperature (ABT) were simultaneously measured together with end tidal pco2 (PE tco2). After accounting for blood temperature, the (a-ET) pco2 was reduced (in absolute values) from -4.2 +/- 1.6 to -1.1 +/- 1.5 mmHg in normoxia and from -1.7 +/- 1.6 to 0.9 +/- 0.9 mmHg in hypoxia (both P < 0.05). The temperature corrected (a-ET)pco2 was linearly related with absolute and relative exercise intensity, VO2, VCO2, and respiratory rate (RR) in normoxia and hypoxia (R(2): 0.52-0.59). Exercise CO2 production and PE tco2 values were lower in hypoxia than normoxia, likely explaining the greater (less negative) (a-ET)pco2 difference in hypoxia than normoxia (P < 0.05). At near-maximal exercise intensity the (a-ET)pco2 lies close to 0 mmHg, that is, the mean Paco2 and the mean PE tco2 are similar. The mean exercise (a-ET)pco2 difference is closely related to the mean A-aDO2 difference (r = 0.90, P < 0.001), as would be expected if similar mechanisms perturb the gas exchange of O2 and CO2 during exercise. In summary, most of the negative (a-ET)pco2 values observed in previous studies are due to lack of correction of Paco2 for blood temperature. The absolute magnitude of the (a-ET)pco2 difference is lower during exercise in hypoxia than normoxia. PMID- 26508737 TI - Rats undernourished in utero have altered Ca2+ signaling and reduced fertility in adulthood. AB - Epidemiological and animal studies have shown that placental undernutrition impairs reproduction in adult offspring, but the underlying molecular mechanisms within the male genital tract remain unknown. Due to its special physiological characteristics in transport and the modulation of the environment to which its luminal content is exposed, we hypothesized that the vas deferens would be a highly sensitive target. The goals were to investigate whether intrauterine malnutrition affects molecular mechanisms related to Ca(2+)- and oxidative stress modulated processes and causes structural alterations in the adult rat vas deferens that could attenuate fecundity and fertility. Male adult rats malnourished in utero had increased vas deferens weight associated with thickening of the muscular coat, a decrease in the total and haploid germ cells, a marked increase in the immature cells, and a decline in the numbers of pregnant females and total offspring per male rat. The ex vivo response of vas deferens from malnourished rats demonstrated an accentuated decrease in the contractile response to phenylephrine. The vas deferens had a marked decrease in Ca(2+) transport due to the uncoupling of Ca(2+)-stimulated ATP hydrolysis and ATP driven Ca(2+) flux, and the downregulation of both sarco-endoplasmic reticulum Ca(2+)-ATPase 2 and the coupling factor 12-kDa FK506-binding protein. An increase in protein carbonylation (a marker of oxidative damage) and an imbalance between protein kinases C and A were observed as a legacy of undernutrition in early life. These results provide the structural and molecular basis to explain at least in part how maternal undernutrition affects fecundity and fertility in adult male rats. PMID- 26508738 TI - TNF-alpha stimulates System A amino acid transport in primary human trophoblast cells mediated by p38 MAPK signaling. AB - Maternal obesity and gestational diabetes mellitus (GDM) increase the risk of delivering infants that are large for gestational age with greater adiposity, who are prone to the development of metabolic disease in childhood and beyond. These maternal conditions are also associated with increased levels of the proinflammatory cytokine TNF-alpha in maternal tissues and the placenta. Recent evidence suggests that changes in placental amino acid transport contribute to altered fetal growth. TNF-alpha was previously shown to stimulate System A amino acid transport in primary human trophoblasts (PHTs), however the molecular mechanisms remain unknown. In this study, we tested the hypothesis that TNF-alpha regulates amino acid uptake in cultured PHTs by a mitogen-activated protein kinase (MAPK)-dependent mechanism. Treatment of PHTs with TNF-alpha significantly increased System A amino acid transport, as well as Erk and p38 MAPK signaling. Pharmacological antagonism of p38, but not Erk MAPK activity, inhibited TNF-alpha stimulated System A activity. Silencing of p38 MAPK using siRNA transfections prevented TNF-alpha stimulated System A transport in PHTs. TNF-alpha significantly increased the protein expression of System A transporters SNAT1 and SNAT2, but did not affect their mRNA expression. The effects of TNF-alpha on SNAT1 and SNAT2 protein expression were reversed by p38 MAPK siRNA silencing. In conclusion, TNF-alpha regulates System A activity through increased SNAT1 and SNAT2 transporter protein expression in PHTs. These findings suggest that p38 MAPK may represent a critical mechanistic link between elevated proinflammatory cytokines and increased placental amino acid transport in obese and GDM pregnancies associated with fetal overgrowth. PMID- 26508739 TI - The response of apoptotic and proteolytic systems to repeated heat stress in atrophied rat skeletal muscle. AB - We examined the effect of repeated heat stress on muscle atrophy, and apoptotic and proteolytic regulation in unloaded rat slow- and fast-type skeletal muscles. Forty male Wistar rats (11 week-old) were divided into control (CT), hindlimb unweighting (HU), intermittent weight-bearing during HU (HU + IWB), and intermittent weight-bearing with heat stress during HU (41-41.5 degrees C for 30 min; HU + IWB + HS) groups. The HU + IWB + HS and HU + IWB groups were released from unloading for 1 h every second day, during which the HU + IWB + HS group underwent the heating. Our results revealed that repeated bouts of heat stress resulted in protection against disuse muscle atrophy in both soleus and plantaris muscles. This heat stress-induced protection against disuse-induced muscular atrophy may be partially due to reduced apoptotic activation in both muscles, and decreased ubiquitination in only the soleus muscle. We concluded that repeated heat stress attenuated skeletal muscle atrophy via suppressing apoptosis but the response to proteolytic systems depend on the muscle phenotype. PMID- 26508740 TI - Distinct Aspects of Left Ventricular Mechanical Function Are Differentially Associated With Cardiovascular Outcomes and All-Cause Mortality in the Community. AB - BACKGROUND: There are few data relating novel measures of left ventricular (LV) mechanical function to cardiovascular disease (CVD) outcomes in the community. Whether distinct components of LV mechanical function provide information regarding risk for different CVD outcomes is unclear. METHODS AND RESULTS: We used speckle tracking echocardiography to quantify distinct components of LV mechanical function (measured as LV strain in multiple planes) in 2831 Framingham Offspring Study participants (mean age, 66 years; 57% women, 97% with LV fractional shortening >0.29). Participants were followed for 6.0+/-1.2 years for onset of 69 coronary heart disease (CHD), 71 heart failure (HF), and 199 mortality events. Adjusting for CVD risk factors, longitudinal LV strain appeared associated with incident CHD (hazards ratio [HR] per SD increment, 1.29; 95% confidence interval [CI], 1.00-1.67; P=0.05), whereas circumferential and radial strain were not (P>0.37 for both); however, the association of longitudinal strain with CHD was nonsignificant after Bonferroni correction. By contrast, circumferential strain was a significant predictor of incident HF (HR per SD increment, 1.79; 95% CI, 1.35-2.37; P<0.0001). Decrements in circumferential, radial, and longitudinal strain measures were related to all-cause mortality (P<0.008 for all). Results remained similar in multivariable models adjusting additionally for the conventional echocardiographic measures of LV mass and fractional shortening. CONCLUSIONS: In our large, community-based sample, distinct components of LV mechanical function were associated with specific CVD outcomes. Additional studies are needed to replicate these findings and investigate the prognostic and therapeutic utility of these novel measures of LV mechanical function. PMID- 26508741 TI - Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology. AB - BACKGROUND: Familial hypercholesterolemia (FH) is a prevalent hereditary disease associated with increased atherosclerosis and calcific aortic valve disease (CAVD). However, in both FH and non-FH individuals, the role of hypercholesterolemia in the development of CAVD is poorly understood. This study used Rapacz FH (RFH) swine, an established model of human FH, to investigate the role of hypercholesterolemia alone in the initiation and progression of CAVD. The valves of RFH swine have not previously been examined. METHODS AND RESULTS: Aortic valve leaflets were isolated from wild-type (0.25- and 1-year-old) and RFH (0.25-, 1-, 2-, and 3-year-old) swine. Adult RFH animals exhibited numerous hallmarks of early CAVD. Significant leaflet thickening was found in adult RFH swine, accompanied by extensive extracellular matrix remodeling, including proteoglycan enrichment, collagen disorganization, and elastin fragmentation. Increased lipid oxidation and infiltration of macrophages were also evident in adult RFH swine. Intracardiac echocardiography revealed mild aortic valve sclerosis in some of the adult RFH animals, but unimpaired valve function. Microarray analysis of valves from adult versus juvenile RFH animals revealed significant upregulation of inflammation-related genes, as well as several commonalities with atherosclerosis and overlap with human CAVD. CONCLUSIONS: Adult RFH swine exhibited several hallmarks of early human CAVD, suggesting potential for these animals to help elucidate CAVD etiology in both FH and non-FH individuals. The development of advanced atherosclerotic lesions, but only early stage CAVD, in RFH swine supports the hypothesis of an initial shared disease process, with additional stimulation necessary for further progression of CAVD. PMID- 26508742 TI - Reducing the Blood Pressure-Related Burden of Cardiovascular Disease: Impact of Achievable Improvements in Blood Pressure Prevention and Control. AB - BACKGROUND: US blood pressure reduction policies are largely restricted to hypertensive populations and associated benefits are often estimated based on unrealistic interventions. METHODS AND RESULTS: We used multivariable linear regression to estimate incidence rate differences contrasting the impact of 2 pragmatic hypothetical interventions to reduce coronary heart disease, stroke, and heart failure (HF) incidence: (1) a population-wide intervention that reduced systolic blood pressure by 1 mm Hg and (2) targeted interventions that reduced the prevalence of unaware, untreated, or uncontrolled blood pressure above goal (per Eighth Joint National Committee treatment thresholds) by 10%. In the Atherosclerosis Risk in Communities Study (n=15 744; 45 to 64 years at baseline, 1987-1989), incident coronary heart disease and stroke were adjudicated by physician panels. Incident HF was defined as the first hospitalization with discharge diagnosis code of "428." A 10% proportional reduction in unaware, untreated, or uncontrolled blood pressure above goal resulted in ~4.61, 3.55, and 11.01 fewer HF events per 100,000 person-years in African Americans, and 3.77, 1.63, and 4.44 fewer HF events per 100 000 person-years, respectively, in whites. In contrast, a 1 mm Hg population-wide systolic blood pressure reduction was associated with 20.3 and 13.3 fewer HF events per 100 000 person-years in African Americans and whites, respectively. Estimated event reductions for coronary heart disease and stroke were smaller than for HF, but followed a similar pattern for both population-wide and targeted interventions. CONCLUSIONS: Modest population wide shifts in systolic blood pressure could have a substantial impact on cardiovascular disease incidence and should be developed in parallel with interventions targeting populations with blood pressure above goal. PMID- 26508743 TI - Effects of Vegetarian Diets on Blood Lipids: A Systematic Review and Meta Analysis of Randomized Controlled Trials. AB - BACKGROUND: Vegetarian diets exclude all animal flesh and are being widely adopted by an increasing number of people; however, effects on blood lipid concentrations remain unclear. This meta-analysis aimed to quantitatively assess the overall effects of vegetarian diets on blood lipids. METHODS AND RESULTS: We searched PubMed, Scopus, Embase, ISI Web of Knowledge, and the Cochrane Library through March 2015. Studies were included if they described the effectiveness of vegetarian diets on blood lipids (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride). Weighted mean effect sizes were calculated for net changes by using a random-effects model. We performed subgroup and univariate meta-regression analyses to explore sources of heterogeneity. Eleven trials were included in the meta-analysis. Vegetarian diets significantly lowered blood concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol, and the pooled estimated changes were 0.36 mmol/L (95% CI -0.55 to -0.17; P<0.001), -0.34 mmol/L (95% CI -0.57 to 0.11; P<0.001), -0.10 mmol/L (95% CI -0.14 to -0.06; P<0.001), and -0.30 mmol/L (95% CI -0.50 to -0.10; P=0.04), respectively. Vegetarian diets did not significantly affect blood triglyceride concentrations, with a pooled estimated mean difference of 0.04 mmol/L (95% CI -0.05 to 0.13; P=0.40). CONCLUSIONS: This systematic review and meta-analysis provides evidence that vegetarian diets effectively lower blood concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and non-high density lipoprotein cholesterol. Such diets could be a useful nonpharmaceutical means of managing dyslipidemia, especially hypercholesterolemia. PMID- 26508744 TI - Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events. PMID- 26508745 TI - Shock Wave Treatment Protects From Neuronal Degeneration via a Toll-Like Receptor 3 Dependent Mechanism: Implications of a First-Ever Causal Treatment for Ischemic Spinal Cord Injury. AB - BACKGROUND: Paraplegia following spinal cord ischemia represents a devastating complication of both aortic surgery and endovascular aortic repair. Shock wave treatment was shown to induce angiogenesis and regeneration in ischemic tissue by modulation of early inflammatory response via Toll-like receptor (TLR) 3 signaling. In preclinical and clinical studies, shock wave treatment had a favorable effect on ischemic myocardium. We hypothesized that shock wave treatment also may have a beneficial effect on spinal cord ischemia. METHODS AND RESULTS: A spinal cord ischemia model in mice and spinal slice cultures ex vivo were performed. Treatment groups received immediate shock wave therapy, which resulted in decreased neuronal degeneration and improved motor function. In spinal slice cultures, the activation of TLR3 could be observed. Shock wave effects were abolished in spinal slice cultures from TLR3(-/-) mice, whereas the effect was still present in TLR4(-/-) mice. TLR4 protein was found to be downregulated parallel to TLR3 signaling. Shock wave-treated animals showed significantly better functional outcome and survival. The protective effect on neurons could be reproduced in human spinal slices. CONCLUSIONS: Shock wave treatment protects from neuronal degeneration via TLR3 signaling and subsequent TLR4 downregulation. Consequently, it represents a promising treatment option for the devastating complication of spinal cord ischemia after aortic repair. PMID- 26508746 TI - "Fleshing Out" the Benefits of Adopting a Vegetarian Diet. PMID- 26508747 TI - Enhanced antigen detection in immunohistochemical staining using a 'digitized' chimeric antibody. AB - The immunohistochemical (IHC) staining of mouse tissue sections using antibodies of mouse origin can result in high nonspecific background due to the staining of endogenous immunoglobulins (Igs) by enzyme-conjugated secondary antibodies. In order to obviate this issue, we developed a chimeric mouse-human anti-p53 monoclonal antibody (MH242) by grafting the variable regions of a known mouse antibody into a human Ig scaffold. This facilitated use of an anti-human secondary antibody, and resulted in near-zero background when compared with its parental mouse monoclonal antibody (PAb242). Furthermore, the chimeric antibody enabled reproducible detection of mutant p53 (homozygous R172H) expression in mouse tissue, an observation hitherto largely equivocal based on the use of existing antibodies. The approach we describe leads to the generation of tractable antibody reagents, whose integrity can be readily verified through DNA sequencing of expressor plasmids. The wide-spread adoption of such 'digitized' antibodies should reduce experimental disparities that can commonly arise through variations in antibody quality. PMID- 26508748 TI - Response to Letter Regarding Article, "Intracranial Carotid Calcification on Cranial Computed Tomography: Visual Scoring Methods, Semiautomated Scores, and Volume Measurements in Patients With Stroke". PMID- 26508749 TI - Improving Adherence to Secondary Stroke Prevention Strategies Through Motivational Interviewing: Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: Stroke recurrence rates are high (20%-25%) and have not declined over past 3 decades. This study tested effectiveness of motivational interviewing (MI) for reducing stroke recurrence, measured by improving adherence to recommended medication and lifestyle changes compared with usual care. METHODS: Single-blind, prospective phase III randomized controlled trial of 386 people with stroke assigned to either MI treatment (4 sessions at 28 days, 3, 6, and 9 months post stroke) or usual care; with outcomes assessed at 28 days, 3, 6, 9, and 12 months post stroke. Primary outcomes were change in systolic blood pressure and low-density lipoprotein cholesterol levels as indicators of adherence at 12 months. Secondary outcomes included self-reported adherence, new stroke, or coronary heart disease events (both fatal and nonfatal); quality of life (Short Form-36); and mood (Hospital Anxiety and Depression Scale). RESULTS: MI did not significantly change measures of blood pressure (mean difference in change, -0.2.35 [95% confidence interval, -6.16 to 1.47]) or cholesterol (mean difference in change, -0.0.12 [95% confidence interval, -0.30 to 0.06]). However, it had positive effects on self-reported medication adherence at 6 months (1.979; 95% confidence interval, 0.98-3.98; P=0.0557) and 9 months (4.295; 95% confidence interval, 1.56-11.84; P=0.0049) post stroke. Improvement across other measures was also observed, but the differences between MI and usual care groups were not statistically significant. CONCLUSIONS: MI improved self-reported medication adherence. All other effects were nonsignificant, though in the direction of a treatment effect. Further study is required to determine whether MI leads to improvement in other important areas of functioning (eg, caregiver burden). CLINICAL TRIAL REGISTRATION: URL: http://www.anzctr.org.au. Unique identifier: ACTRN-12610000715077. PMID- 26508750 TI - Left Atrial Appendage Function and Stroke Risk. PMID- 26508751 TI - Letter by Bos et al Regarding Article, "Intracranial Carotid Calcification on Cranial Computed Tomography: Visual Scoring Methods, Semiautomated Scores, and Volume Measurements in Patients With Stroke". PMID- 26508752 TI - Mechanical Thrombectomy in and Outside the REVASCAT Trial: Insights From a Concurrent Population-Based Stroke Registry. AB - BACKGROUND AND PURPOSE: Recent trials have shown the superiority of endovascular thrombectomy (EVT) over medical therapy alone in certain stroke patients with proximal arterial occlusion. Using data from the Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within 8-Hours of Symptom Onset (REVASCAT) and a parallel reperfusion treatment registry, we sought to assess the utilization of EVT in a defined patient population, comparing the outcomes of patients treated in and outside the REVASCAT trial. METHODS: SONIIA [Sistema Online d'Informacio de l'Ictus Agut], a population-based, government-mandated, prospective registry of reperfusion therapies for stroke encompassing the entire population of Catalonia, was used as data source. The registry documents 5 key inclusion criteria of the REVASCAT trial: age, stroke severity, time to treatment, baseline functional status, and occlusion site. We compared procedural, safety, and functional outcomes in patients treated inside and outside the trial. RESULTS: From November 2012 to December 2014, out of 17596 ischemic stroke patients in Catalonia (population 7.5 million), 2576 patients received reperfusion therapies (17/100000 inhabitants year), mainly intravenous thrombolysis only (2036). From the remaining 540 treated with EVT, 103 patients (out of 206 randomized) were treated within REVASCAT and 437 outside the trial. Of these, 399 did not fulfill some of the study criteria, and 38 were trial candidates (8 treated at REVASCAT centers and 30 at 2 non-REVASCAT centers). The majority of procedural, safety, and functional outcomes were similar in patients treated with EVT within and outside REVASCAT. CONCLUSIONS: REVASCAT enrolled nearly all eligible patients representing one third of all patients treated with EVT. Patients treated with EVT within and outside REVASCAT had similar outcomes, reinforcing the therapeutic value of EVT. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379. PMID- 26508753 TI - Benefits of Stroke Treatment Using a Mobile Stroke Unit Compared With Standard Management: The BEST-MSU Study Run-In Phase. AB - BACKGROUND AND PURPOSE: Faster treatment with intravenous tissue-type plasminogen activator (tPA) is likely to improve outcomes. Optimizing prehospital triage by mobile stroke units (MSUs) may speed treatment times. The Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit (BEST-MSU) study was launched in May 2014 using the first MSU in the United States to compare stroke management using an MSU versus standard management (SM). Herein, we describe the results of the prespecified, nonrandomized run-in phase designed to obtain preliminary data on study logistics. METHODS: The run-in phase consisted of 8 MSU weeks when all patient care occurred on the MSU and 2 SM weeks when the MSU nurse met personnel on scene or at the emergency department to ensure comparability with MSU patients. Telemedicine was independently performed in 9 MSU cases. RESULTS: Of 130 alerts, 24 MSU and 2 SM patients were enrolled. Twelve of 24 MSU patients received tPA on board; 4 were treated within 60 minutes of last seen normal, and 4 went on to endovascular treatment. There were no hemorrhagic complications. Four had primary intracerebral hemorrhage. Agreement on tPA eligibility between the onsite and telemedicine physician was 90%. CONCLUSIONS: The run-in phase provided a tPA treatment rate of 1.5 patients per week, assured us that treatment within 60 minutes of onset is possible, and enabled enrollment of patients on SM weeks. We also recognized the opportunity to assess the effect of the MSU on endovascular treatment and intracerebral hemorrhage. Challenges include the need to control biased patient selection on MSU versus SM weeks and establish inter rater agreement for tPA treatment using telemedicine. PMID- 26508754 TI - Omokage search: shape similarity search service for biomolecular structures in both the PDB and EMDB. AB - Omokage search is a service to search the global shape similarity of biological macromolecules and their assemblies, in both the Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB). The server compares global shapes of assemblies independent of sequence order and number of subunits. As a search query, the user inputs a structure ID (PDB ID or EMDB ID) or uploads an atomic model or 3D density map to the server. The search is performed usually within 1 min, using one-dimensional profiles (incremental distance rank profiles) to characterize the shapes. Using the gmfit (Gaussian mixture model fitting) program, the found structures are fitted onto the query structure and their superimposed structures are displayed on the Web browser. Our service provides new structural perspectives to life science researchers. AVAILABILITY AND IMPLEMENTATION: Omokage search is freely accessible at http://pdbj.org/omokage/. PMID- 26508755 TI - caRpools: an R package for exploratory data analysis and documentation of pooled CRISPR/Cas9 screens. AB - MOTIVATION: Genetic screens by CRISPR/Cas9-mediated genome engineering have become a powerful tool for functional genomics. However, there is currently a lack of end-to-end software pipelines to analyze CRISPR/Cas9 screens based on next generation sequencing. RESULTS: The CRISPR-AnalyzeR for pooled screens (caRpools) is an R package for exploratory data analysis that provides a complete workflow to analyze CRISPR/Cas9 screens. To further support the analysis of large scale screens, caRpools integrates screening documentation and generation of standardized analysis reports. AVAILABILITY AND IMPLEMENTATION: caRpools, manuals and an open virtual appliance are available at http://github.com/boutroslab/caRpools. PMID- 26508756 TI - PPIXpress: construction of condition-specific protein interaction networks based on transcript expression. AB - Protein-protein interaction networks are an important component of modern systems biology. Yet, comparatively few efforts have been made to tailor their topology to the actual cellular condition being studied. Here, we present a network construction method that exploits expression data at the transcript-level and thus reveals alterations in protein connectivity not only caused by differential gene expression but also by alternative splicing. We achieved this by establishing a direct correspondence between individual protein interactions and underlying domain interactions in a complete but condition-unspecific protein interaction network. This knowledge was then used to infer the condition-specific presence of interactions from the dominant protein isoforms. When we compared contextualized interaction networks of matched normal and tumor samples in breast cancer, our transcript-based construction identified more significant alterations that affected proteins associated with cancerogenesis than a method that only uses gene expression data. The approach is provided as the user-friendly tool PPIXpress. AVAILABILITY AND IMPLEMENTATION: PPIXpress is available at https://sourceforge.net/projects/ppixpress/. PMID- 26508757 TI - LOLA: enrichment analysis for genomic region sets and regulatory elements in R and Bioconductor. AB - Genomic datasets are often interpreted in the context of large-scale reference databases. One approach is to identify significantly overlapping gene sets, which works well for gene-centric data. However, many types of high-throughput data are based on genomic regions. Locus Overlap Analysis (LOLA) provides easy and automatable enrichment analysis for genomic region sets, thus facilitating the interpretation of functional genomics and epigenomics data. AVAILABILITY AND IMPLEMENTATION: R package available in Bioconductor and on the following website: http://lola.computational-epigenetics.org. PMID- 26508758 TI - Understanding the fabric of protein crystals: computational classification of biological interfaces and crystal contacts. AB - Modern structural biology still draws the vast majority of information from crystallography, a technique where the objects being investigated are embedded in a crystal lattice. Given the complexity and variety of those objects, it becomes fundamental to computationally assess which of the interfaces in the lattice are biologically relevant and which are simply crystal contacts. Since the mid-1990s, several approaches have been applied to obtain high-accuracy classification of crystal contacts and biological protein-protein interfaces. This review provides an overview of the concepts and main approaches to protein interface classification: thermodynamic estimation of interface stability, evolutionary approaches based on conservation of interface residues, and co-occurrence of the interface across different crystal forms. Among the three categories, evolutionary approaches offer the strongest promise for improvement, thanks to the incessant growth in sequence knowledge. Importantly, protein interface classification algorithms can also be used on multimeric structures obtained using other high-resolution techniques or for protein assembly design or validation purposes. A key issue linked to protein interface classification is the identification of the biological assembly of a crystal structure and the analysis of its symmetry. Here, we highlight the most important concepts and problems to be overcome in assembly prediction. Over the next few years, tools and concepts of interface classification will probably become more frequently used and integrated in several areas of structural biology and structural bioinformatics. Among the main challenges for the future are better addressing of weak interfaces and the application of interface classification concepts to prediction problems like protein-protein docking. PMID- 26508759 TI - Detecting dispersed duplications in high-throughput sequencing data using a database-free approach. AB - MOTIVATION: Dispersed duplications (DDs) such as transposon element insertions and copy number variations are ubiquitous in the human genome. They have attracted the interest of biologists as well as medical researchers due to their role in both evolution and disease. The efforts of discovering DDs in high throughput sequencing data are currently dominated by database-oriented approaches that require pre-existing knowledge of the DD elements to be detected. RESULTS: We present DD_DETECTION, a database-free approach to finding DD events in high-throughput sequencing data. DD_DETECTION is able to detect DDs purely from paired-end read alignments. We show in a comparative study that this method is able to compete with database-oriented approaches in recovering validated transposon insertion events. We also experimentally validate the predictions of DD_DETECTION on a human DNA sample, showing that it can find not only duplicated elements present in common databases but also DDs of novel type. AVAILABILITY AND IMPLEMENTATION: The software presented in this article is open source and available from https://bitbucket.org/mkroon/dd_detection. PMID- 26508760 TI - RVFam: an R package for rare variant association analysis with family data. AB - Family-based designs offer unique advantage for identifying rare risk variants in genetic association studies. There are existing tools for analyzing rare variants in families but lacking components to handle binary traits properly and survival traits. In this report, we introduce an R software package RVFam (Rare Variant association analysis with Family data) designed to analyze continuous, binary and survival traits against rare and common sequencing variants in genome-wide association studies (GWAS) involving family data. Single and multiple variant association tests were implemented while accounting for arbitrary family structures. Extensive simulation studies were performed to evaluate all the approaches implemented in RVFam. AVAILABILITY AND IMPLEMENTATION: http://cran.r project.org/web/packages/RVFam/. PMID- 26508761 TI - openBIS ELN-LIMS: an open-source database for academic laboratories. AB - The open-source platform openBIS (open Biology Information System) offers an Electronic Laboratory Notebook and a Laboratory Information Management System (ELN-LIMS) solution suitable for the academic life science laboratories. openBIS ELN-LIMS allows researchers to efficiently document their work, to describe materials and methods and to collect raw and analyzed data. The system comes with a user-friendly web interface where data can be added, edited, browsed and searched. AVAILABILITY AND IMPLEMENTATION: The openBIS software, a user guide and a demo instance are available at https://openbis-eln-lims.ethz.ch. The demo instance contains some data from our laboratory as an example to demonstrate the possibilities of the ELN-LIMS (Ottoz et al., 2014). For rapid local testing, a VirtualBox image of the ELN-LIMS is also available. PMID- 26508762 TI - ancGWAS: a post genome-wide association study method for interaction, pathway and ancestry analysis in homogeneous and admixed populations. AB - MOTIVATION: Despite numerous successful Genome-wide Association Studies (GWAS), detecting variants that have low disease risk still poses a challenge. GWAS may miss disease genes with weak genetic effects or strong epistatic effects due to the single-marker testing approach commonly used. GWAS may thus generate false negative or inconclusive results, suggesting the need for novel methods to combine effects of single nucleotide polymorphisms within a gene to increase the likelihood of fully characterizing the susceptibility gene. RESULTS: We developed ancGWAS, an algebraic graph-based centrality measure that accounts for linkage disequilibrium in identifying significant disease sub-networks by integrating the association signal from GWAS data sets into the human protein-protein interaction (PPI) network. We validated ancGWAS using an association study result from a breast cancer data set and the simulation of interactive disease loci in the simulation of a complex admixed population, as well as pathway-based GWAS simulation. This new approach holds promise for deconvoluting the interactions between genes underlying the pathogenesis of complex diseases. Results obtained yield a novel central breast cancer sub-network of the human interactome implicated in the proteoglycan syndecan-mediated signaling events pathway which is known to play a major role in mesenchymal tumor cell proliferation, thus providing further insights into breast cancer pathogenesis. AVAILABILITY AND IMPLEMENTATION: The ancGWAS package and documents are available at http://www.cbio.uct.ac.za/~emile/software.html. PMID- 26508763 TI - Light-Harvesting Complex Stress-Related Proteins Catalyze Excess Energy Dissipation in Both Photosystems of Physcomitrella patens. AB - Two LHC-like proteins, Photosystem II Subunit S (PSBS) and Light-Harvesting Complex Stress-Related (LHCSR), are essential for triggering excess energy dissipation in chloroplasts of vascular plants and green algae, respectively. The mechanism of quenching was studied in Physcomitrella patens, an early divergent streptophyta (including green algae and land plants) in which both proteins are active. PSBS was localized in grana together with photosystem II (PSII), but LHCSR was located mainly in stroma-exposed membranes together with photosystem I (PSI), and its distribution did not change upon high-light treatment. The quenched conformation can be preserved by rapidly freezing the high-light-treated tissues in liquid nitrogen. When using green fluorescent protein as an internal standard, 77K fluorescence emission spectra on isolated chloroplasts allowed for independent assessment of PSI and PSII fluorescence yield. Results showed that both photosystems underwent quenching upon high-light treatment in the wild type in contrast to mutants depleted of LHCSR, which lacked PSI quenching. Due to the contribution of LHCII, P. patens had a PSI antenna size twice as large with respect to higher plants. Thus, LHCII, which is highly abundant in stroma membranes, appears to be the target of quenching by LHCSR. PMID- 26508764 TI - Arabidopsis RZFP34/CHYR1, a Ubiquitin E3 Ligase, Regulates Stomatal Movement and Drought Tolerance via SnRK2.6-Mediated Phosphorylation. AB - Abscisic acid (ABA) is a phytohormone that plays a fundamental role in plant development and stress response, especially in the regulation of stomatal closure in response to water deficit stress. The signal transduction that occurs in response to ABA and drought stress is mediated by protein phosphorylation and ubiquitination. This research identified Arabidopsis thaliana RING ZINC-FINGER PROTEIN34 (RZP34; renamed here as CHY ZINC-FINGER AND RING PROTEIN1 [CHYR1]) as an ubiquitin E3 ligase. CHYR1 expression was significantly induced by ABA and drought, and along with its corresponding protein, was expressed mainly in vascular tissues and stomata. Analysis of CHYR1 gain-of-function and loss-of function plants revealed that CHYR1 promotes ABA-induced stomatal closure, reactive oxygen species production, and plant drought tolerance. Furthermore, CHYR1 interacted with SNF1-RELATED PROTEIN KINASE2 (SnRK2) kinases and could be phosphorylated by SnRK2.6 on the Thr-178 residue. Overexpression of CHYR1(T178A), a phosphorylation-deficient mutant, interfered with the proper function of CHYR1, whereas CHYR1(T178D) phenocopied the gain of function of CHYR1. Thus, this study identified a RING-type ubiquitin E3 ligase that functions positively in ABA and drought responses and detailed how its ubiquitin E3 ligase activity is regulated by SnRK2.6-mediated protein phosphorylation. PMID- 26508767 TI - Addressing misuse and diversion of opioid substitution medication: guidance based on systematic evidence review and real-world experience. AB - BACKGROUND: Opioid dependence treatment, comprising opioid substitution treatment (OST) and psychosocial intervention, is accepted to improve outcomes in opioid addiction for both the individual and public health. OST medication such as methadone or buprenorphine may be misused or diverted. This results in failure to recover from addiction, increased crime and the spread of blood-borne viruses. Worldwide, attempts to address misuse and diversion have been proposed and implemented with varying impact. METHODS: A structured, expert-led process recommended the most impact. As an initial step, a broad range of strategies were defined, and a systematic review of published literature identified 37 highly relevant sources of evidence. Experts reviewed this evidence and ranked the list of strategies for effectiveness and ease of implementation, based on their clinical experience. RESULTS/CONCLUSIONS: Three groups of strategies to address misuse or diversion are defined, depending on impact (effectiveness and ease of implementation). Preferred strategies include the promotion of access to treatment and the use of product formulations less likely to be misused. However, additional data and innovative approaches to address this complex problem are needed. PMID- 26508768 TI - Testing for Deperet's Rule (Body Size Increase) in Mammals using Combined Extinct and Extant Data. AB - Whether or not evolutionary lineages in general show a tendency to increase in body size has often been discussed. This tendency has been dubbed "Cope's rule" but because Cope never hypothesized it, we suggest renaming it after Deperet, who formulated it clearly in 1907. Deperet's rule has traditionally been studied using fossil data, but more recently a number of studies have used present-day species. While several paleontological studies of Cenozoic placental mammals have found support for increasing body size, most studies of extant placentals have failed to detect such a trend. Here, we present a method to combine information from present-day species with fossil data in a Bayesian phylogenetic framework. We apply the method to body mass estimates of a large number of extant and extinct mammal species, and find strong support for Deperet's rule. The tendency for size increase appears to be driven not by evolution toward larger size in established species, but by processes related to the emergence of new species. Our analysis shows that complementary data from extant and extinct species can greatly improve inference of macroevolutionary processes. PMID- 26508769 TI - Doubly robust methods for handling confounding by cluster. AB - In clustered designs such as family studies, the exposure-outcome association is usually confounded by both cluster-constant and cluster-varying confounders. The influence of cluster-constant confounders can be eliminated by studying the exposure-outcome association within (conditional on) clusters, but additional regression modeling is usually required to control for observed cluster-varying confounders. A problem is that the working regression model may be misspecified, in which case the estimated within-cluster association may be biased. To reduce sensitivity to model misspecification we propose to augment the standard working model for the outcome with an auxiliary working model for the exposure. We derive a doubly robust conditional generalized estimating equation (DRCGEE) estimator for the within-cluster association. This estimator combines the two models in such a way that it is consistent if either model is correct, not necessarily both. Thus, the DRCGEE estimator gives the researcher two chances instead of only one to make valid inference on the within-cluster association. We have implemented the estimator in an R package and we use it to examine the association between smoking during pregnancy and cognitive abilities in offspring, in a sample of siblings. PMID- 26508770 TI - Association Between High-Flow Nasal Cannula and End-Expiratory Esophageal Pressures in Premature Infants. AB - BACKGROUND: High-flow nasal cannula (HFNC) is commonly being used to provide noninvasive respiratory support in newborn infants. Continuous distending pressure generated by these devices in preterm infants has not been elucidated. The aim of this work was to determine the association between HFNC flow in L/min and end-expiratory esophageal pressure in cm H2O in premature infants. METHODS: In a prospective observational study, end-expiratory esophageal pressure measurements were conducted in clinically stable premature infants who required HFNC. The end-expiratory esophageal pressure generated by the HFNC was measured by a regular feeding tube overlying the lower esophagus and connected to a pressure transducer. Each infant had different end-expiratory esophageal pressure measurements at different high flows ranging from 2 to 8 L/min. RESULTS: Nineteen premature infants were studied. Their birthweight (mean +/- SD) was 904 +/- 574 g, and gestational age was 26.6 +/- 3.1 weeks. Overall, 93 end-expiratory esophageal pressure measurements were conducted. At the time of the end expiratory esophageal pressure measurements, infants were 1,458 +/- 828 g and 7.2 +/- 4.8 weeks old. At HFNC flows ranging from 2 to 8 L/min, the corresponding esophageal pressures ranged from 2 to 15 cm H2O. There was a statistically significant association between esophageal pressures and flows. In a linear regression model with the end-expiratory esophageal pressure as the dependent variable and HFNC flow as the independent variable, there was a significant correlation between the 2 variables: end-expiratory esophageal pressure (cm H2O) = 1.18 * HFNC (L/min) (r(2) = 0.95, P < .001). CONCLUSIONS: HFNC-associated end expiratory esophageal pressure is measurable in premature infants. There is a significant association between flows and generated esophageal pressures. There is also variability in the amount of end-expiratory esophageal pressure generated. These observations should be kept in mind when using high HFNC flows in preterm infants. PMID- 26508771 TI - Neonatal Transcutaneous Carbon Dioxide Monitoring--Effect on Clinical Management and Outcomes. AB - BACKGROUND: This work aimed to compare frequency of blood gas measurements per day of mechanical ventilation, occurrence of extreme blood gas CO2 values, and clinical outcomes among ventilated neonates managed with and without transcutaneous carbon dioxide (PtcCO2) monitors. This work also measures agreement between simultaneous PtcCO2 and blood gas CO2 measurements and ascertains factors that affect agreement. METHODS: This is a cohort study with retrospective analysis comparing 5,726 blood gas measurements and clinical outcomes for 123 neonates intubated for >48 h before and after the introduction of transcutaneous carbon-di-oxide monitoring devices in a single tertiary care unit. RESULTS: Median (interquartile range) blood gas frequency per mechanical ventilation day was 3.9 (2.6-5.3) and 2.9 (2.1-4.0) before and after PtcCO2 monitoring (P = .002) without differences in clinical outcomes at discharge. After adjusting for confounders using Poisson regression, this difference remained significant. The mean +/- 2 SD blood gas-PtcCO2 difference was -5.2 +/- 17.3 mm Hg. 64% of simultaneous blood gas-PtcCO2 measurements per subject were within +/- 7 mm Hg. Greater bias was noted with arterial sample and during the use of high-frequency ventilation. CONCLUSION: Despite only moderate agreement between simultaneous PtcCO2 and blood gas measurements, PtcCO2 monitoring statistically decreased blood gas frequency among ventilated neonates without affecting the duration of mechanical ventilation or clinical outcomes at discharge. The clinical impact of this technology appears to be minimal. PMID- 26508772 TI - Improved Filtering of Pulse Oximeter Monitoring Alarms in the Neonatal ICU: Bedside Significance. AB - BACKGROUND: The OxiMax N-600x containing SatSeconds alarm management software was designed to assist clinicians in discriminating nuisance alarms from those that are clinically relevant. Instead of sounding an alarm the moment the oxygen saturation reading violates the upper or lower limit settings, a magnitude and duration of tolerance can be set. The primary objective was to study the proportion of nuisance alarms relative to the proportion of clinically relevant alarms being filtered under 4 different SatSeconds alarm settings (ie, 10, 25, 50, and 100) in the neonatal intensive care environment. METHODS: This is an observational prospective study of 50 infants cared for in 3 large neonatal ICUs. Infants were monitored for 4 continuous h each by a study observer with the study monitor, in addition to standard multiparameter monitors. The performance of the SatSeconds alarm was compared with nursing intervention. RESULTS: The area under the receiver operating characteristic curve (95% CI) for SatSeconds alarm settings when compared with nursing intervention were as follows: 0.61 (0.57 0.66) when the SatSeconds alarm setting was off, 0.63 (0.59-0.68) for the 10 SatSeconds alarm setting, 0.64 (0.59-0.69) for the 25 SatSeconds alarm setting, 0.64 (0.59-0.69) for the 50 SatSeconds alarm setting, and 0.63 (0.58-0.68) for the 100 SatSeconds alarm setting, respectively. CONCLUSIONS: The SatSeconds feature of the OxiMax N-600x pulse oximeter reduced some nuisance alarms; however, its specificity to nurse-identified desaturation events does not significantly improve with lengthening SatSeconds alarm settings. PMID- 26508773 TI - What happens to the mental health of UK service personnel after they return home from Afghanistan? AB - OBJECTIVE: Fear et al identified a small but significant increase in probable post-traumatic stress disorder (PTSD) in UK military personnel from around 3% in first year post deployment to around 6% by year 5. As yet it is not clear what factors are linked to the increase in probable PTSD, and therefore, serial measurement of poor mental health would be helpful. METHOD: Rates of mental ill health among UK service personnel were compared upon deployment completion and at follow-up and identified factors associated with maladjustment. RESULTS: Poor mental health symptomatology increased from baseline to follow-up, PTSD symptoms and related functional impairment increased significantly. Poor baseline mental health was predictive of transition and family relationship difficulties. CONCLUSIONS: The results are discussed in relation to encouraging recognition and reporting of symptoms among personnel and their social networks. PMID- 26508774 TI - Neural signatures of experimentally induced flow experiences identified in a typical fMRI block design with BOLD imaging. AB - Previously, experimentally induced flow experiences have been demonstrated with perfusion imaging during activation blocks of 3 min length to accommodate with the putatively slowly evolving "mood" characteristics of flow. Here, we used functional magnetic resonance imaging (fMRI) in a sample of 23 healthy, male participants to investigate flow in the context of a typical fMRI block design with block lengths as short as 30 s. To induce flow, demands of arithmetic tasks were automatically and continuously adjusted to the individual skill level. Compared against conditions of boredom and overload, experience of flow was evident from individuals' reported subjective experiences and changes in electrodermal activity. Neural activation was relatively increased during flow, particularly in the anterior insula, inferior frontal gyri, basal ganglia and midbrain. Relative activation decreases during flow were observed in medial prefrontal and posterior cingulate cortex, and in the medial temporal lobe including the amygdala. Present findings suggest that even in the context of comparably short activation blocks flow can be reliably experienced and is associated with changes in neural activation of brain regions previously described. Possible mechanisms of interacting brain regions are outlined, awaiting further investigation which should now be possible given the greater temporal resolution compared with previous perfusion imaging. PMID- 26508775 TI - TaFROG Encodes a Pooideae Orphan Protein That Interacts with SnRK1 and Enhances Resistance to the Mycotoxigenic Fungus Fusarium graminearum. AB - All genomes encode taxonomically restricted orphan genes, and the vast majority are of unknown function. There is growing evidence that such genes play an important role in the environmental adaptation of taxa. We report the functional characterization of an orphan gene (Triticum aestivum Fusarium Resistance Orphan Gene [TaFROG]) as a component of resistance to the globally important wheat (T. aestivum) disease, Fusarium head blight. TaFROG is taxonomically restricted to the grass subfamily Pooideae. Gene expression studies showed that it is a component of the early wheat response to the mycotoxin deoxynivalenol (DON), which is a virulence factor produced by the causal fungal agent of Fusarium head blight, Fusarium graminearum. The temporal induction of TaFROG by F. graminearum in wheat spikelets correlated with the activation of the defense Triticum aestivum Pathogenesis-Related-1 (TaPR1) gene. But unlike TaPR1, TaFROG induction by F. graminearum was toxin dependent, as determined via comparative analysis of the effects of wild-type fungus and a DON minus mutant derivative. Using virus induced gene silencing and overexpressing transgenic wheat lines, we present evidence that TaFROG contributes to host resistance to both DON and F. graminearum. TaFROG is an intrinsically disordered protein, and it localized to the nucleus. A wheat alpha subunit of the Sucrose Non-Fermenting1-Related Kinase1 was identified as a TaFROG-interacting protein based on a yeast two-hybrid study. In planta bimolecular fluorescence complementation assays confirmed the interaction. Thus, we conclude that TaFROG encodes a new Sucrose Non-Fermenting1 Related Kinase1-interacting protein and enhances biotic stress resistance. PMID- 26508776 TI - Nitrate-Dependent Control of Shoot K Homeostasis by the Nitrate Transporter1/Peptide Transporter Family Member NPF7.3/NRT1.5 and the Stelar K+ Outward Rectifier SKOR in Arabidopsis. AB - Root-to-shoot translocation and shoot homeostasis of potassium (K) determine nutrient balance, growth, and stress tolerance of vascular plants. To maintain the cation-anion balance, xylem loading of K(+) in the roots relies on the concomitant loading of counteranions, like nitrate (NO3 (-)). However, the coregulation of these loading steps is unclear. Here, we show that the bidirectional, low-affinity Nitrate Transporter1 (NRT1)/Peptide Transporter (PTR) family member NPF7.3/NRT1.5 is important for the NO3 (-)-dependent K(+) translocation in Arabidopsis (Arabidopsis thaliana). Lack of NPF7.3/NRT1.5 resulted in K deficiency in shoots under low NO3 (-) nutrition, whereas the root elemental composition was unchanged. Gene expression data corroborated K deficiency in the nrt1.5-5 shoot, whereas the root responded with a differential expression of genes involved in cation-anion balance. A grafting experiment confirmed that the presence of NPF7.3/NRT1.5 in the root is a prerequisite for proper root-to-shoot translocation of K(+) under low NO3 (-) supply. Because the depolarization-activated Stelar K(+) Outward Rectifier (SKOR) has previously been described as a major contributor for root-to-shoot translocation of K(+) in Arabidopsis, we addressed the hypothesis that NPF7.3/NRT1.5-mediated NO3 (-) translocation might affect xylem loading and root-to-shoot K(+) translocation through SKOR. Indeed, growth of nrt1.5-5 and skor-2 single and double mutants under different K/NO3 (-) regimes revealed that both proteins contribute to K(+) translocation from root to shoot. SKOR activity dominates under high NO3 (-) and low K(+) supply, whereas NPF7.3/NRT1.5 is required under low NO3 (-) availability. This study unravels nutritional conditions as a critical factor for the joint activity of SKOR and NPF7.3/NRT1.5 for shoot K homeostasis. PMID- 26508777 TI - Cognitive Behavioral Therapy Normalizes Functional Connectivity for Social Threat in Psychosis. AB - Psychosis is often characterized by paranoia and poor social functioning. Neurally, there is evidence of functional dysconnectivity including abnormalities when processing facial affect. We sought to establish whether these abnormalities are resolved by cognitive behavioral therapy for psychosis (CBTp). The study involved 38 outpatients with one or more persistent positive psychotic symptoms, and 20 healthy participants. All participants completed an implicit facial affect processing task during functional magnetic resonance imaging (fMRI). Subsequently, patients either continued to receive standard care only (SCO,n= 16) or received CBTp on top of standard care (+CBTp,n= 22), with fMRI repeated 6-8 months later. To examine the mechanisms underlying CBTp-led changes in threat processing and appraisal, functional connectivity during the social threat (angry faces) condition was assessed separately from left amygdala and right dorsolateral prefrontal cortex (DLPFC) seeds. At baseline, patients, compared with healthy participants, showed greater amygdala connectivity with the insula and visual areas, but less connectivity with somatosensory areas. These differences normalized following CBTp and, compared with the SCO group, the +CBTp group showed greater increases in amygdala connectivity with DLPFC and inferior parietal lobule, with the latter correlating with improvement in positive symptoms. From the DLPFC seed, the +CBTp (compared with SCO) group showed significantly greater increase in DLPFC connectivity with other prefrontal regions including dorsal anterior cingulate and ventromedial prefrontal cortex. These findings indicate that CBTp strengthens connectivity between higher-order cognitive systems and those involved in threat and salience, potentially facilitating reappraisal. PMID- 26508778 TI - Long-term preservation of donor corneas in glycerol for keratoplasty: exploring new protocols. AB - AIM: To evaluate the role of temperature and adjunctive dehydration in better long-term preservation of human corneas when preserved and stored in glycerol. METHODS: Different preservation temperatures and effects of adding silica gel in glycerol-preserved corneal tissues were evaluated. Human corneal tissues not suitable for optical keratoplasty initially preserved in McCarey-Kaufman medium were transferred to glycerol and stored at four different temperatures for 3 months as follows: tissues in anhydrous glycerol with and without silica gel at 80 degrees C, -20 degrees C, 4 degrees C and at room temperature (RT). Parameters evaluated included microbial sterility, thickness (Digimatic micrometer), transparency (slit lamp examination, UV-Vis spectrophotometer), mechanical strength (Instron 5848 Microtester), tissue integrity (H&E staining), antigenicity (immunohistochemistry) and ultrastructure of collagen (transmission electron microscopy, TEM). RESULTS: Microbial test after 3 months of glycerol preservation confirmed sterility of the tissues. The thickness increased in corneas preserved at RT with and without silica gel (p<0.001). RT corneas had the lowest transparency and tensile strength. Tissues in anhydrous glycerol stored with and without silica gel at -80 degrees C were the most transparent (p<0.001) and had the highest tensile strength (p<0.001). Tissue integrity was maintained and expression of Human Leukocyte Antigen D related (HLA-DR) was less in glycerol preserved corneas at -80 degrees C. TEM studies indicated that parallel alignment of stromal collagen was disrupted at RT-preserved corneas. CONCLUSIONS: Corneal tissue preserved at -80 degrees C was the best method for preservation as it maintained the sterility, thickness, optical transparency, mechanical strength and ultrastructural features. PMID- 26508779 TI - Treatment of partial limbal stem cell deficiency with topical interferon alpha-2b and retinoic acid. AB - BACKGROUND: The combination of topical interferon alpha-2b (IFN alpha-2b) and all trans retinoic acid (ATRA) 0.01% has previously been shown to be effective in conjunctival and corneal intraepithelial neoplasia. This combination was incidentally found to be effective in a patient with partial limbal stem cell deficiency (LSCD), a condition which can be challenging to treat if conservative measures fail. This retrospective study evaluates the combination of topical IFN alpha-2b and ATRA 0.01% in the treatment of partial LSCD. METHODS: Five patients from one institution with a clinical and/or histopathological diagnosis of LSCD had failed a period of conservative treatment with cessation of toxic stimuli and use of lubricating eye-drops. These patients were treated with a combination regimen of topical IFN alpha-2b and ATRA 0.01%. RESULTS: All five patients had partial LSCD, but limbal involvement was significantly worse in one patient who later progressed to total LSCD. Complete clinical resolution of signs of LSCD was achieved in the four patients with partial LSCD after a mean of 9 months of treatment. The one patient who progressed to total LSCD did not respond to treatment. Duration of follow-up after clinical resolution in the four patients with partial LSCD was at least 18 months, with no signs of recurrence seen. Aside from the complaint of ocular irritation in one patient, no other side effects were observed. CONCLUSIONS: Combination treatment of topical IFN alpha-2b and ATRA 0.01% can be considered in partial LSCD, where adjacent parts of the limbus remain intact. This treatment is associated with minimal side effects and no recurrence of signs of LSCD at least 18 months after clinical resolution. PMID- 26508780 TI - Graft preparation for hemi-Descemet membrane endothelial keratoplasty (hemi DMEK). AB - BACKGROUND/AIMS: There is a substantial shortage of donor tissue for endothelial keratoplasty worldwide. Using two endothelial grafts of one donor cornea may potentially increase the pool of suitable donor tissue for Descemet membrane endothelial keratoplasty (DMEK). This study evaluates the technical feasibility of obtaining two DMEK grafts with a different (semicircular) shape, but similar surface area as a 'conventional' 8-9 mm circular transplant from a single donor cornea and to evaluate the viability of these grafts stored in organ-culture medium up to 5 weeks after graft preparation. METHODS: Ten human corneas not suitable for transplantation were used for preparation of semicircular-shaped grafts (hemi-DMEK grafts). The viability of these hemi-DMEK grafts was measured by evaluating the endothelial cell density (ECD) with light microscopy before and immediately after preparation and during five additional weeks of organ culture. RESULTS: Hemi-DMEK preparation was successful in all cases. All grafts formed a roll. A small area denuded of cells was observed after preparation along the straight edge of the DM roll. The mean ECD was 2654 (+/-65) cells/mm(2) before and 2651 (+/-94) cells/mm(2) immediately after hemi-DMEK preparation and declined gradually from 2518 (+/-133) cells/mm(2) after 1 week to 1847 (+/-170) cells/mm(2) after 5 weeks of organ-culture storage. DISCUSSION: Preparation of two hemi-DMEK grafts from one single human donor cornea is technically feasible, and the grafts can be stored after preparation in organ-culture similar to standard circular DMEK grafts. Hemi-DMEK may have the potential to double the availability of donor endothelial tissue for DMEK. PMID- 26508781 TI - Changes in corneal endothelial cell density and the cumulative risk of corneal decompensation after Ahmed glaucoma valve implantation. AB - AIMS: To evaluate changes in the corneal endothelial cell density (ECD) and corneal decompensation following Ahmed glaucoma valve (AGV) implantation. METHODS: This study was retrospective and observational case series. Patients with refractory glaucoma who underwent AGV implantation and were followed >5 years were consecutively enrolled. We reviewed the medical records, including the results of central corneal specular microscopy. Of the 127 enrolled patients, the annual change in ECD (%) was determined using linear regression for 72 eyes evaluated at least four times using serial specular microscopic examination and compared with 31 control eyes (fellow glaucomatous eyes under medical treatment). The main outcome measures were cumulative risk of corneal decompensation and differences in the ECD loss rates between subjects and controls. RESULTS: The mean follow-up after AGV implantation was 43.1 months. There were no cases of postoperative tube-corneal touch. The cumulative risk of corneal decompensation was 3.3%, 5 years after AGV implantation. There was a more rapid loss of ECD in the 72 subject eyes compared with the 31 controls (-7.0% and -0.1%/year, respectively; p<0.001). However, the rate of loss decreased over time and statistical significance compared with control eyes disappeared after 2 years postoperatively: -10.7% from baseline to 1 year (p<0.01), -7.0% from 1 year to 2 years (p=0.037), -4.2% from 2 years to 3 years (p=0.230) and -2.7% from 3 years to the final follow-up (p=0.111). CONCLUSIONS: In case of uncomplicated AGV implantation, the cumulative risk of corneal decompensation was 3.3%, 5 years after the operation. The ECD loss was statistically greater in eyes with AGV than in control eyes without AGV, but the difference was significant only up to 2 years post surgery. PMID- 26508782 TI - Integration of innate into adaptive immune responses in ZAP-70-positive chronic lymphocytic leukemia. AB - The crucial dependence of chronic lymphocytic leukemia (CLL) cells on signals derived from the B cell receptor (BCR) has encouraged the development of new inhibitors, which interfere with BCR signaling and demonstrate clinical benefits in nearly all patients. In addition, signaling through Toll-like receptor (TLR) 9 of the innate immune system has been shown to further contribute to the activation of CLL cells. However, responses to TLR9 engagement are not uniform, but diametrically opposed with cell death in some patients and cell proliferation in others. We now provide evidence that heterogeneous responses to TLR agonists are related to differences in the ability of CLL cells to activate the BCR associated kinase Syk. Notably, expression of ZAP-70 appears to be of crucial importance for TLR9-mediated activation of Syk. We show that the activation of Syk provides an antiapoptotic signal, which is independent of Mcl-1, Bcl-2, and Bcl-XL, but related to the degradation of the proapoptotic Bim. Mechanistically, TLR9-mediated antiapoptotic signals in ZAP-70-positive CLL trigger secretion of immunoglobulin M, which then serves as (auto-) antigen for a prosurvival BCR signal. Thus, our data show that single activation of the innate immune receptor TLR9 is sufficient to fully engage BCR signaling in ZAP-70-positive CLL, protecting malignant cells from apoptosis. We conclude that the integration of TLR signaling into an adaptive immune response can further promote survival of CLL cells and may contribute to the unfavorable prognosis of ZAP-70-positive CLL. PMID- 26508783 TI - TALEN-mediated genetic inactivation of the glucocorticoid receptor in cytomegalovirus-specific T cells. AB - Cytomegalovirus (CMV) infection is responsible for substantial morbidity and mortality after allogeneic hematopoietic stem cell transplant. T-cell immunity is critical for control of CMV infection, and correction of the immune deficiency induced by transplant is now clinically achievable by the adoptive transfer of donor-derived CMV-specific T cells. It is notable, however, that most clinical studies of adoptive T- cell therapy exclude patients with graft-versus-host disease (GVHD) from receiving systemic corticosteroid therapy, which impairs cellular immunity. This group of patients remains the highest clinical risk group for recurrent and problematic infections. Here, we address this unmet clinical need by genetic disruption of the glucocorticoid receptor (GR) gene using electroporation of transcription activator-like effector nuclease (TALEN) messenger RNA. We demonstrate efficient inactivation of the GR gene without off target activity in Streptamer-selected CMV-specific CD8(+) T cells (HLA-A02/NLV peptide), conferring resistance to glucocorticoids. TALEN-modified CMV-specific T cells retained specific killing of target cells pulsed with the CMV peptide NLV in the presence of dexamethasone (DEX). Inactivation of the GR gene also conferred resistance to DEX in a xenogeneic GVHD model in sublethally irradiated NOD-scid IL2rgamma(null) mice. This proof of concept provides the rationale for the development of clinical protocols for producing and administering high-purity genetically engineered virus-specific T cells that are resistant to the suppressive effects of corticosteroids. PMID- 26508784 TI - All overweight adults should be screened for abnormal blood sugar, says US task force. PMID- 26508785 TI - Older patients with diabetes are often overtreated, say researchers. PMID- 26508786 TI - The Autism Spectrum Disorders Stem Cell Resource at Children's Hospital of Orange County: Implications for Disease Modeling and Drug Discovery. PMID- 26508787 TI - Glucocorticoid signaling drives epigenetic and transcription factors to induce key regulators of human parturition. AB - Glucocorticoids are thought to play an important role in parturition. Two recent articles by Di Stefano et al. in the Archives and Wang et al. in this issue of Science Signaling reveal novel mechanisms by which glucocorticoid signaling can drive the epigenetic and transcriptional machinery to induce molecules involved in parturition, including the neuropeptide corticotropin-releasing hormone (CRH), the enzyme cyclooxygenase-2 (COX-2), and the autacoid hormone prostaglandin E2. These findings contribute to our understanding of how glucocorticoids may regulate human parturition. PMID- 26508788 TI - Phosphorylation of STAT3 mediates the induction of cyclooxygenase-2 by cortisol in the human amnion at parturition. AB - The induction of cyclooxygenase-2 (COX-2) and subsequent production of prostaglandin E2 (PGE2) by cortisol in the amnion contrast with the effect of cortisol on most other tissues, but this proinflammatory effect of cortisol may be a key event in human parturition (labor). We evaluated the underlying mechanism activated by cortisol in primary human amnion fibroblasts. Exposure of the amnion fibroblasts to cortisol led to the activation of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, which induced the phosphorylation of the kinase SRC and STAT3 (signal transducer and activator of transcription 3). STAT3 interacted with the glucocorticoid receptor (GR) and the transcription factor CREB-1 (cAMP response element-binding protein 1) at the promoter of the gene encoding COX-2, which promoted the production of the secreted prostaglandin PGE2. PGE2 activates the prostaglandin receptors EP2 and EP4, which stimulate cAMP-PKA signaling. Thus, cortisol reinforced the activation of cAMP-PKA signaling through an SRC-STAT3-COX-2-PGE2-mediated feedback loop. Inhibiting STAT3, SRC, or the cAMP-PKA pathway attenuated the cortisol-stimulated induction of COX-2 and PGE2 production in amnion fibroblasts. In human amnion tissue, the amount of phosphorylated STAT3 correlated positively with that of cortisol, COX-2, and PGE2, and all were more abundant in tissue obtained after active labor than in tissue obtained from cesarean surgeries in the absence of labor. These results indicated that the coordinated recruitment of STAT3, CREB-1, and GR to the promoter of the gene encoding COX-2 contributes to the feed-forward induction of COX-2 activity and prostaglandin synthesis in the amnion during parturition. PMID- 26508789 TI - Genome-wide RNAi screening implicates the E3 ubiquitin ligase Sherpa in mediating innate immune signaling by Toll in Drosophila adults. AB - The Drosophila Toll pathway plays important roles in innate immune responses against Gram-positive bacteria and fungi. To identify previously uncharacterized components of this pathway, we performed comparative, ex vivo, genome-wide RNA interference screening. In four screens, we overexpressed the Toll adaptor protein dMyd88, the downstream kinase Pelle, or the nuclear factor kappaB (NF kappaB) homolog Dif, or we knocked down Cactus, the Drosophila homolog of mammalian inhibitor of NF-kappaB. On the basis of these screens, we identified the E3 ubiquitin ligase Sherpa as being necessary for the activation of Toll signaling. A loss-of-function sherpa mutant fly exhibited compromised production of antimicrobial peptides and enhanced susceptibility to infection by Gram positive bacteria. In cultured cells, Sherpa mediated ubiquitylation of dMyd88 and Sherpa itself, and Sherpa and Drosophila SUMO (small ubiquitin-like modifier) were required for the proper membrane localization of an adaptor complex containing dMyd88. These findings highlight a role for Sherpa in Drosophila host defense and suggest the SUMOylation-mediated regulation of dMyd88 functions in Toll innate immune signaling. PMID- 26508790 TI - Ubiquitin-dependent endocytosis of NKG2D-DAP10 receptor complexes activates signaling and functions in human NK cells. AB - Cytotoxic lymphocytes share the presence of the activating receptor NK receptor group 2, member D (NKG2D) and the signaling-competent adaptor DNAX-activating protein 10 (DAP10), which together play an important role in antitumor immune surveillance. Ligand stimulation induces the internalization of NKG2D-DAP10 complexes and their delivery to lysosomes for degradation. In experiments with human NK cells and cell lines, we found that the ligand-induced endocytosis of NKG2D-DAP10 depended on the ubiquitylation of DAP10, which was also required for degradation of the internalized complexes. Moreover, through combined biochemical and microscopic analyses, we showed that ubiquitin-dependent receptor endocytosis was required for the activation of extracellular signal-regulated kinase (ERK) and NK cell functions, such as the secretion of cytotoxic granules and the inflammatory cytokine interferon-gamma. These results suggest that NKG2D-DAP10 endocytosis represents a means to decrease cell surface receptor abundance, as well as to control signaling outcome in cytotoxic lymphocytes. PMID- 26508791 TI - Prostate cancer-specific mortality after radical prostatectomy: value of preoperative MRI. AB - BACKGROUND: Although magnetic resonance imaging (MRI) is currently indispensable in the preoperative setting of biopsy-proven prostate cancer, the value of preoperative MRI for predicting prostate cancer-specific mortality (PCSM) is not well known. PURPOSE: To evaluate the value of MRI for predicting PCSM in patients who underwent radical prostatectomy (RP) for localized prostate cancer. MATERIAL AND METHODS: A total of 318 patients underwent MRI followed by RP. MRI was assessed for the presence of clinically significant cancer using a five-point Likert scale, where >=4 was considered positive. Cox proportional hazards regression analyses was used to determine the relationship of preoperative factors with PCSM. PCSM was calculated using the Kaplan-Meier method and compared between factors using the log-rank test. RESULTS: After a median follow-up of 104 months, 11 (3.5%) patients died of prostate cancer. One hundred and four (32.7%) patients had clinically significant prostate cancer on MRI. Univariate analysis revealed that Gleason grade, greatest percentage of involved core length (GPCL), and clinically significant cancer on MRI were significantly related to PCSM (P = 0.001-0.003). Multivariate analysis showed that GPCL (hazard ratio [HR], 1.028; 95% confidence interval [CI], 1.000-1.057; P = 0.048) and clinically significant cancer on MRI (HR, 10.903; 95% CI, 1.287-92.374; P = 0.028) were independent predictors of PCSM. The 5 - and 10-year PCSM rates were 0.6% and 1.3% in patients with GPCL <50% and 5.1% and 8.6% in those with GPCL >=50% (P = 0.012). Patients without clinically significant cancer on MRI showed 5 - and 10-year PCSM rates of 0% and 0.5%, respectively, whereas those with clinically significant cancer on MRI showed rates of 8% and 14.2%, respectively (P < 0.001). CONCLUSION: Preoperative MRI and GPCL may be used to predict PCSM after RP. PMID- 26508792 TI - Idiopathic granulomatous mastitis: magnetic resonance imaging findings with diffusion MRI. AB - BACKGROUND: Idiopathic granulomatous mastitis (IGM) is a rare benign breast disease with unknown etiology which can mimic breast carcinoma, both clinically and radiologically. Magnetic resonance imaging (MRI) findings of IGM have been previously described; however there is no study evaluating diffusion-weighted MRI findings of IGM. PURPOSE: To analyze conventional, dynamic contrast-enhanced, and diffusion-weighted MRI signal characteristics of IGM by comparing it with the contralateral normal breast parenchyma. MATERIAL AND METHODS: A total of 39 patients were included in the study. On dynamic contrast-enhanced MRI, the distribution and enhancement patterns of the lesions were evaluated. We also detected the frequencies of involving quadrants, retroareolar involvement, accompanying abscess, and skin edema. T2-weighted (T2W) and STIR signal intensities and both mean and minimum apparent diffusion coefficient (ADC) values were compared with the contralateral normal parenchyma. RESULTS: IGM showed significantly lower mean and minimum ADC values when compared with the normal parenchyma. Signal intensities on T2W and STIR sequences of the lesion were significantly higher than the normal parenchyma. On dynamic contrast-enhanced MRI, 7.7% of the patients had mass-like contrast enhancement, 92.3% of the patients had non-mass-like contrast enhancement. Abscess was positive in 33.3% of the patients. CONCLUSION: As a result, IGM showed commonly non-mass-like lesions with restricted diffusion. Although it is a benign pathology, it may show clustered ring-like enhancement like malignant lesions. PMID- 26508793 TI - MRI and CT imaging characteristics of myoepithelioma of the parotid gland. AB - BACKGROUND: Myoepithelioma is a rare tumor of the salivary gland and only few reports have focused on its imaging characteristics. PURPOSE: To characterize the magnetic resonance imaging (MRI) and computed tomography (CT) characteristics of myoepithelioma of the parotid gland. MATERIAL AND METHODS: We retrospectively analyzed the MRI and CT findings of nine patients with myoepithelioma in the parotid gland as demonstrated by pathologic analysis. The MRI and CT findings were analyzed regarding the tumor position, size, marginal morphology, and degree and patterns of enhancement. RESULTS: Unilocular and multilocular tumors were found in seven cases (7/9, 77.8%) and two cases (2/9, 22.2%), respectively. Most of the tumors were located in the superficial lobe (6/9, 66.7%) and abutted the capsule of the parotid gland (7/9, 77.8%). Six of the seven unilocular tumors were round. Most of the tumors displayed smooth contours (6/9, 66.7%) and well defined margins (5/9, 55.6%). Four of five tumors (80%) display the capsule on T2 weighted (T2W) and contrast-enhanced T1-weighted (T1W) imaging. All five examined tumors exhibited homogeneous intermediate signal intensity on T1W imaging and high signal intensity on T2W imaging. On contrast-enhanced T1W imaging, the tumors displayed homogeneous (n = 4) or heterogeneous (n = 1) moderate to marked contrast enhancement. Based on the enhanced CT scans, four tumors exhibited moderate homogeneous (n = 2) or heterogeneous (n = 2) contrast enhancement. CONCLUSION: Myoepitheliomas are characterized as small, unilocular, round tumors with smooth contours that are located in the superficial lobe and abut the capsule of the parotid gland, display the capsule on T2W and contrast-enhanced T1W imaging, and exhibit homogeneous signal intensities or densities based on MRI and CT. PMID- 26508794 TI - Ultrasound of the coracoacromial ligament in asymptomatic volunteers and patients with shoulder impingement. AB - BACKGROUND: The coracoacromial ligament is part of the coracoacromial arch, which is considered to be involved in shoulder impingement. PURPOSE: To compare the coracoacromial ligament on ultrasound in asymptomatic volunteers and in patients with subacromial shoulder impingement. MATERIAL AND METHODS: Twenty-nine asymptomatic volunteers (mean age, 35.5 years) and 29 patients (mean age, 49.9 years) with shoulder impingement, diagnosed by experienced shoulder surgeons, were prospectively included. Two radiologists obtained and analyzed ultrasound images of the coracoacromial ligament in the longitudinal axis. RESULTS: The ligament thickness was 1.4 +/- 0.2 mm at its midportion, 1.8 +/- 0.4 mm at the coracoid, and 2.1 +/- 0.6 mm at the acromion in asymptomatic volunteers compared with 1.3 +/- 0.2 mm, 1.9 +/- 0.5 mm, and 1.9 +/- 0.5 mm in impingement patients for observer 1. The ligament length was 30.6 +/- 2.4 mm in asymptomatic volunteers compared with 30.4 +/- 3.6 mm in impingement patients for observer 1. An anteriorly convex shape of the superficial contour of the coracoacromial ligament was significantly more frequent in impingement patients compared with asymptomatic volunteers for both observers (observer 1: 10% (3/29) versus 45% (13/29), P value <0.01; observer 2: 10% (3/29) versus 38% (11/29), P value <0.03). The comparison of the remaining parameters of the coracoacromial ligament, such as the thickness, length, echogenicity, and fibrillation did not reveal significant differences between volunteers and patients. CONCLUSION: While thickness or length of the coracoacromial ligament were similar in volunteers and patients with shoulder impingement, an anteriorly convex shape of the superficial contour of the coracoacromial ligament was significantly more frequent in impingement patients compared with asymptomatic volunteers. PMID- 26508795 TI - Anger and disaster management. PMID- 26508796 TI - Use of dexmedetomidine in treatment-refractory post-electroconvulsive therapy agitation. PMID- 26508797 TI - Transdiagnostic psychological treatments for anxiety and depression. PMID- 26508798 TI - 'What is to be done?'. PMID- 26508799 TI - When is it lawful to re-impose compulsory psychiatric treatment after discharge by a mental health tribunal? PMID- 26508800 TI - A clinical repetitive transcranial magnetic stimulation service in Australia: 6 years on. AB - OBJECTIVE: There is considerable research evidence for the effectiveness of repetitive transcranial magnetic stimulation in the treatment of depression. However, there is little information about its acceptability and outcomes in clinical settings. METHOD: This naturalistic study reports on a clinical repetitive transcranial magnetic stimulation service that has been running in Adelaide, South Australia (SA), for 6 years. During this time, 214 complete acute courses were provided to patients with treatment-resistant Major Depressive Disorder. Patients received either sequential bilateral or right unilateral repetitive transcranial magnetic stimulation treatment involving either 18 or 20 sessions given over 6 or 4 weeks respectively. Data included patient demographic details, duration of depression, and medication at the beginning of their repetitive transcranial magnetic stimulation course. The Hamilton Depression Rating Scale was used to assess response to repetitive transcranial magnetic stimulation. RESULTS: Of those undergoing a first-time acute treatment course of repetitive transcranial magnetic stimulation (N = 167), 28% achieved remission, while a further 12% met the criteria for a response to treatment. Most patients (N = 123, 77%) had previously been treated with five or more antidepressant medications, and 77 (47%) had previously received electroconvulsive therapy. Referral rates remained high over the 6 years, indicating acceptance of the treatment by referring psychiatrists. There were no significant adverse events, and the treatment was generally well tolerated. In all, 41 patients (25%) had a second course of repetitive transcranial magnetic stimulation and 6 (4%) patients had a third course; 21 patients subsequently received maintenance repetitive transcranial magnetic stimulation. CONCLUSION: This naturalistic study showed that repetitive transcranial magnetic stimulation was well accepted by both psychiatrists and patients, and has good efficacy and safety. Furthermore, repetitive transcranial magnetic stimulation can provide a useful treatment alternative as part of outpatient mental health services for people with depression. PMID- 26508801 TI - 'Mastication rage': a review of misophonia - an under-recognised symptom of psychiatric relevance? AB - OBJECTIVE: To explore the condition of misophonia, its definition, possible neurological correlates, its associated morbidity, its possible psychiatric relevance and potential treatment. METHOD: Provision of an illustrative case vignette and a review of the limited literature. RESULTS: Misophonia is a symptom associated with obsessive-compulsive disorder and anxiety disorders and may be a syndrome in itself associated with significant distress and avoidance. Treatments are not well validated. CONCLUSION: Misophonia may be an under-recognised condition of psychiatric relevance. PMID- 26508802 TI - Measuring Hope Among Children Affected by Armed Conflict: Cross-Cultural Construct Validity of the Children's Hope Scale. AB - We investigated the cross-cultural construct validity of hope, a factor associated with mental health protection and promotion, using the Children's Hope Scale (CHS). The sample ( n = 1,057; 48% girls) included baseline data from three cluster-randomized controlled trials with children affected by armed conflict ( n = 329 Burundi; n = 403 Indonesia; n = 325 Nepal). The confirmatory factor analysis in each country indicated good fit for the hypothesized two-factor model. Analysis by gender indicated that configural invariance was supported and that scalar invariance was demonstrated in Indonesia. However, metric and scalar invariance were not supported in Burundi and Nepal. In country comparisons, configural and metric invariance were met, but scalar invariance was not supported. Evidence from this study supports the use of the CHS within various sociocultural settings and across genders, but direct comparisons of CHS scores across groups should be done with caution. Rigorous evaluations of the measurement properties of mental health protective and promotive factors are necessary to inform both research and practice. PMID- 26508803 TI - Advanced Math Course Taking: Effects on Math Achievement and College Enrollment. AB - Using data from the Educational Longitudinal Study of 2002-2006 (ELS:02/06), this study investigated the effects of advanced math course taking on math achievement and college enrollment and how such effects varied by socioeconomic status (SES) and race/ethnicity. Results from propensity score matching and sensitivity analyses showed that advanced math course taking had positive effects on math achievement and college enrollment. Results also demonstrated that the effect of advanced math course taking on math achievement was greater for low SES students than for high SES students, but smaller for Black students than for White students. No interaction effects were found for college enrollment. Limitations, policy implications, and future research directions are discussed. PMID- 26508804 TI - Stepfather-Adolescent Relationship Quality During the First Year of Transitioning to a Stepfamily. AB - This study contributes to the growing literature on factors associated with the formation of close relationships between stepfathers and stepchildren. The authors extend prior research by using nationally representative data from Add Health (N = 179) to examine how factors existing prior to stepfamily formation are associated with the quality of stepfather-adolescent ties within the first year after married stepfathers join the household. Results from structural equation models revealed that both the quality of the mother-adolescent relationship and adolescent adjustment prior to stepfamily formation were significantly associated with the perceived quality of adolescents' relationships with their stepfathers. PMID- 26508805 TI - Development and Feasibility of a Cell Phone-Based Transitional Intervention for Women Prisoners with Comorbid Substance Use and Depression. AB - This article describes the development and feasibility testing of a cell phone based intervention (Sober Network IPT) among 22 women with comorbid substance use and depressive disorders transitioning from prison to surrounding communities. Feasibility/acceptability measures included phone logs, exit interviews, and pre post measures of substance use and depressive symptoms up to 9 months post release. Results indicated that phone-based transitional treatment is feasible and acceptable. Participants valued the opportunity to maintain contact with familiar prison treatment providers by phone after release, and used the cell phones for help with service linkage, support, and crisis management. We describe relational and practical lessons learned. PMID- 26508806 TI - Rhodium-Catalyzed Intermolecular [5+1] and [5+2] Cycloadditions Using 1,4-Enynes with an Electron-Donating Ester on the 3-Position. AB - Various 3-acyloxy-1,4-enynes could be employed in rhodium-catalyzed intermolecular [5+1] and [5+2] cycloadditions with CO or alkynes, respectively. The rate of these cycloadditions could be accelerated significantly by using 1,4 enynes with an electron-donating ester on the 3-position. The scope of rhodium catalyzed [5+1] and [5+2] cycloadditions were examined by using 1,4-enynes bearing an electron-donating ester. PMID- 26508807 TI - WHO TAKES CARE OF WHOM IN THE U.S.? EVIDENCE FROM MATRICES OF TIME TRANSFERS BY AGE AND SEX. AB - Non-monetary intergenerational transfers of time, such as informal care time transfers, represent a largely unknown, yet pivotal component of the support system in a country. In this article, we offer estimates of time transfers, by age and sex, related to informal childcare and adult care in the United States. We developed methods to extract both intra-household and inter-household time transfers from the American Time Use Survey (2011-2013) and the recently-added Eldercare Roster. We then summarized the results in matrices of time flows by age and sex for the general U.S. population, as well as for the so-called "sandwich generation." We observed that most time transfers flow downwards from parents to young children. Grandmothers spend more time with newborn grandchildren than grandfathers, who, on the other hand, spend more time with slightly older grandchildren. The time produced by the sandwich generation is directed towards a more diverse population spectrum, including substantial intra-generational transfers to spouses. Estimates of time produced and consumed by the population with various demographic characteristics establish a foundation for extrapolating the degree to which the demand for care services will be met in the years to come. Extrapolation based on our findings reveals a steady rise in demand, relative to supply, of informal care lasting decades into the future. This projection indicates that, to maintain current levels of care, our society will have to either rely more heavily on the market or on an increased effort of caregivers. PMID- 26508808 TI - Gender, Emotion Work, and Relationship Quality: A Daily Diary Study. AB - We use the gender relations perspective from feminist theorizing to investigate how gender and daily emotion work predict daily relationship quality in 74 couples (148 individuals in dating, cohabiting, or married relationships) primarily from the southwest U.S. Emotion work is characterized by activities that enhance others' emotional well-being. We examined emotion work two ways: trait (individuals' average levels) and state (individuals' daily fluctuations). We examined actor and partner effects of emotion work and tested for gender differences. As outcome variables, we included six types of daily relationship quality: love, commitment, satisfaction, closeness, ambivalence, and conflict. This approach allowed us to predict three aspects of relationship quality: average levels, daily fluctuations, and volatility (overall daily variability across a week). Three patterns emerged. First, emotion work predicted relationship quality in this diverse set of couples. Second, gender differences were minimal for fixed effects: Trait and state emotion work predicted higher average scores on, and positive daily increases in, individuals' own positive relationship quality and lower average ambivalence. Third, gender differences were more robust for volatility: For partner effects, having a partner who reported higher average emotion work predicted lower volatility in love, satisfaction, and closeness for women versus greater volatility in love and commitment for men. Neither gender nor emotion work predicted average levels, daily fluctuations, or volatility in conflict. We discuss implications and future directions pertaining to the unique role of gender in understanding the associations between daily emotion work and volatility in daily relationship quality for relational partners. PMID- 26508809 TI - Climate as a driver of tropical insular diversity: comparative phylogeography of two ecologically distinctive frogs in Puerto Rico. AB - The effects of late Quaternary climate on distributions and evolutionary dynamics of insular species are poorly understood in most tropical archipelagoes. We used ecological niche models under past and current climate to derive hypotheses regarding how stable climatic conditions shaped genetic diversity in two ecologically distinctive frogs in Puerto Rico. Whereas the Mountain Coqui, Eleutherodactylus portoricensis, is restricted to montane forest in the Cayey and Luquillo Mountains, the Red-eyed Coqui, E. antillensis, is a habitat generalist distributed across the entire Puerto Rican Bank (Puerto Rico and the Virgin Islands, excluding St. Croix). To test our hypotheses, we conducted phylogeographic and population genetic analyses based on mitochondrial and nuclear loci of each species across their range in Puerto Rico. Patterns of population differentiation in E. portoricensis, but not in E. antillensis, supported our hypotheses. For E. portoricensis, these patterns include: individuals isolated by long-term unsuitable climate in the Rio Grande de Loiza Basin in eastern Puerto Rico belong to different genetic clusters; past and current climate strongly predicted genetic differentiation; and Cayey and Luquillo Mountains populations split prior to the last interglacial. For E. antillensis, these patterns include: genetic clusters did not fully correspond to predicted long-term unsuitable climate; and past and current climate weakly predicted patterns of genetic differentiation. Genetic signatures in E. antillensis are consistent with a recent range expansion into western Puerto Rico, possibly resulting from climate change and anthropogenic influences. As predicted, regions with a large area of long-term suitable climate were associated with higher genetic diversity in both species, suggesting larger and more stable populations. Finally, we discussed the implications of our findings for developing evidence-based management decisions for E. portoricensis, a taxon of special concern. Our findings illustrate the role of persistent suitable climatic conditions in promoting the persistence and diversification of tropical island organisms. PMID- 26508810 TI - Closely-spaced double-row microstrip RF arrays for parallel MR imaging at ultrahigh fields. AB - Radiofrequency (RF) coil arrays with high count of elements, e.g., closely-spaced multi-row arrays, exhibit superior parallel imaging performance in MRI. However, it is technically challenging and time-consuming to build multi-row arrays due to complex coupling issues. This paper presents a novel and simple method for closely-spaced multi-row RF array designs. Induced current elimination (ICE) decoupling method has shown the capability of reducing coupling between microstrip elements from different rows. In this study, its capability for decoupling array elements from the same row was investigated and validated by bench tests, with an isolation improvement from -8.9 dB to -20.7 dB. Based on this feature, a closely-spaced double-row microstrip array with 16 elements was built at 7T. S21 between any two elements of the 16-channel closely-spaced was better than -14 dB. In addition, its feasibility and performance was validated by MRI experiments. No significant image reconstruction- related noise amplifications were observed for parallel imaging even when reduced factor (R) achieves 4. The experimental results demonstrated that the proposed design might be a simple and efficient approach in fabricating closely-spaced multi-row RF arrays. PMID- 26508811 TI - Assessment of Hair Aluminum, Lead, and Mercury in a Sample of Autistic Egyptian Children: Environmental Risk Factors of Heavy Metals in Autism. AB - BACKGROUND AND AIMS: The etiological factors involved in the etiology of autism remain elusive and controversial, but both genetic and environmental factors have been implicated. The aim of this study was to assess the levels and possible environmental risk factors and sources of exposure to mercury, lead, and aluminum in children with autism spectrum disorder (ASD) as compared to their matched controls. METHODS: One hundred ASD children were studied in comparison to 100 controls. All participants were subjected to clinical evaluation and measurement of mercury, lead, and aluminum through hair analysis which reflects past exposure. RESULTS: The mean Levels of mercury, lead, and aluminum in hair of the autistic patients were significantly higher than controls. Mercury, lead, and aluminum levels were positively correlated with maternal fish consumptions, living nearby gasoline stations, and the usage of aluminum pans, respectively. CONCLUSION: Levels of mercury, lead, and aluminum in the hair of autistic children are higher than controls. Environmental exposure to these toxic heavy metals, at key times in development, may play a causal role in autism. PMID- 26508812 TI - Music Perception Influences Language Acquisition: Melodic and Rhythmic-Melodic Perception in Children with Specific Language Impairment. AB - Language and music share many properties, with a particularly strong overlap for prosody. Prosodic cues are generally regarded as crucial for language acquisition. Previous research has indicated that children with SLI fail to make use of these cues. As processing of prosodic information involves similar skills to those required in music perception, we compared music perception skills (melodic and rhythmic-melodic perception and melody recognition) in a group of children with SLI (N = 29, five-year-olds) to two groups of controls, either of comparable age (N = 39, five-year-olds) or of age closer to the children with SLI in their language skills and about one year younger (N = 13, four-year-olds). Children with SLI performed in most tasks below their age level, closer matching the performance level of younger controls with similar language skills. These data strengthen the view of a strong relation between language acquisition and music processing. This might open a perspective for the possible use of musical material in early diagnosis of SLI and of music in SLI therapy. PMID- 26508813 TI - The Influence of Music on Prefrontal Cortex during Episodic Encoding and Retrieval of Verbal Information: A Multichannel fNIRS Study. AB - Music can be thought of as a complex stimulus able to enrich the encoding of an event thus boosting its subsequent retrieval. However, several findings suggest that music can also interfere with memory performance. A better understanding of the behavioral and neural processes involved can substantially improve knowledge and shed new light on the most efficient music-based interventions. Based on fNIRS studies on music, episodic encoding, and the dorsolateral prefrontal cortex (PFC), this work aims to extend previous findings by monitoring the entire lateral PFC during both encoding and retrieval of verbal material. Nineteen participants were asked to encode lists of words presented with either background music or silence and subsequently tested during a free recall task. Meanwhile, their PFC was monitored using a 48-channel fNIRS system. Behavioral results showed greater chunking of words under the music condition, suggesting the employment of associative strategies for items encoded with music. fNIRS results showed that music provided a less demanding way of modulating both episodic encoding and retrieval, with a general prefrontal decreased activity under the music versus silence condition. This suggests that music-related memory processes rely on specific neural mechanisms and that music can positively influence both episodic encoding and retrieval of verbal information. PMID- 26508814 TI - Interactions between Myc and Mediators of Inflammation in Chronic Liver Diseases. AB - Most chronic liver diseases (CLDs) are characterized by inflammatory processes with aberrant expressions of various pro- and anti-inflammatory mediators in the liver. These mediators are the driving force of many inflammatory liver disorders, which often result in fibrosis, cirrhosis, and liver tumorigenesis. c Myc is involved in many cellular events such as cell growth, proliferation, and differentiation. c-Myc upregulates IL-8, IL-10, TNF-alpha, and TGF-beta, while IL 1, IL-2, IL-4, TNF-alpha, and TGF-beta promote c-Myc expression. Their interactions play a central role in fibrosis, cirrhosis, and liver cancer. Molecular interference of their interactions offers possible therapeutic potential for CLDs. In this review, current knowledge of the molecular interactions between c-Myc and various well known inflammatory mediators is discussed. PMID- 26508815 TI - N-Acetyl-seryl-aspartyl-lysyl-proline Alleviates Renal Fibrosis Induced by Unilateral Ureteric Obstruction in BALB/C Mice. AB - To expand the armamentarium of treatment for chronic kidney disease (CKD), we explored the utility of boosting endogenously synthesized N-acetyl-seryl-aspartyl lysyl-proline (Ac-SDKP), which is augmented by inhibition of the angiotensin converting enzyme. Male BALB/c mice underwent unilateral ureteral ligation (UUO) or sham operation and received exogenously administered Ac-SDKP delivered via a subcutaneous osmotic minipump or Captopril treatment by oral gavage. Seven days after UUO, there were significant reductions in the expression of both collagen 1 and collagen 3 in kidneys treated with Ac-SDKP or Captopril, and there was a trend towards reductions in collagen IV, alpha-SMA, and MCP-1 versus control. However, no significant attenuation of interstitial injury or macrophage infiltration was observed. These findings are in contrary to observations in other models and underscore the fact that a longer treatment time frame may be required to yield anti-inflammatory effects in BALB/c mice treated with Ac-SDKP compared to untreated mice. Finding an effective treatment regimen for CKD requires fine-tuning of pharmacologic protocols. PMID- 26508816 TI - Proinflammatory Cytokines and Potassium Channels in the Kidney. AB - Proinflammatory cytokines affect several cell functions via receptor-mediated processes. In the kidney, functions of transporters and ion channels along the nephron are also affected by some cytokines. Among these, alteration of activity of potassium ion (K(+)) channels induces changes in transepithelial transport of solutes and water in the kidney, since K(+) channels in tubule cells are indispensable for formation of membrane potential which serves as a driving force for the transepithelial transport. Altered K(+) channel activity may be involved in renal cell dysfunction during inflammation. Although little information was available regarding the effects of proinflammatory cytokines on renal K(+) channels, reports have emerged during the last decade. In human proximal tubule cells, interferon-gamma showed a time-dependent biphasic effect on a 40 pS K(+) channel, that is, delayed suppression and acute stimulation, and interleukin 1beta acutely suppressed the channel activity. Transforming growth factor-beta1 activated KCa3.1 K(+) channel in immortalized human proximal tubule cells, which would be involved in the pathogenesis of renal fibrosis. This review discusses the effects of proinflammatory cytokines on renal K(+) channels and the causal relationship between the cytokine-induced changes in K(+) channel activity and renal dysfunction. PMID- 26508817 TI - Live or Die: Choice Mechanisms in Stressed Cells. PMID- 26508818 TI - Cancer as a Proinflammatory Environment: Metastasis and Cachexia. AB - The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-alpha, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines. PMID- 26508819 TI - Role of Inflammation in Muscle Homeostasis and Myogenesis. AB - Skeletal muscle mass is subject to rapid changes according to growth stimuli inducing both hypertrophy, through increased protein synthesis, and hyperplasia, activating the myogenic program. Muscle wasting, characteristic of several pathological states associated with local or systemic inflammation, has been for long considered to rely on the alteration of myofiber intracellular pathways regulated by both hormones and cytokines, eventually leading to impaired anabolism and increased protein breakdown. However, there are increasing evidences that even alterations of the myogenic/regenerative program play a role in the onset of muscle wasting, even though the precise mechanisms involved are far from being fully elucidated. The comprehension of the links potentially occurring between impaired myogenesis and increased catabolism would allow the definition of effective strategies aimed at counteracting muscle wasting. The first part of this review gives an overview of skeletal muscle intracellular pathways determining fiber size, while the second part considers the cells and the regulatory pathways involved in the myogenic program. In both parts are discussed the evidences supporting the role of inflammation in impairing muscle homeostasis and myogenesis, potentially determining muscle atrophy. PMID- 26508820 TI - Potential Biomarkers of Fat Loss as a Feature of Cancer Cachexia. AB - Fat loss is associated with shorter survival and reduced quality of life in cancer patients. Effective intervention for fat loss in cachexia requires identification of the condition using prognostic biomarkers for early detection and prevention of further depletion. No biomarkers of fat mass alterations have been defined for application to the neoplastic state. Several inflammatory cytokines have been implicated in mediating fat loss associated with cachexia; however, plasma levels may not relate to adipose atrophy. Zinc-alpha2 glycoprotein may be a local catabolic mediator within adipose tissue rather than serving as a plasma biomarker of fat loss. Plasma glycerol and leptin associate with adipose tissue atrophy and mass, respectively; however, no study has evaluated their potential as a prognostic biomarker of cachexia-associated fat loss. This review confirms the need for further studies to identify valid prognostic biomarkers to identify loss of fat based on changes in plasma levels of biomarkers. PMID- 26508821 TI - EPR Spectroscopic Studies of [FeFe]-Hydrogenase Maturation. AB - Proton reduction and H2 oxidation are key elementary reactions for solar fuel production. Hydrogenases interconvert H+ and H2 with remarkable efficiency and have therefore received much attention in this context. For [FeFe]-hydrogenases, catalysis occurs at a unique cofactor called the H-cluster. In this article, we discuss ways in which EPR spectroscopy has elucidated aspects of the bioassembly of the H-cluster, with a focus on four case studies: EPR spectroscopic identification of a radical en route to the CO and CN- ligands of the H-cluster, tracing 57Fe from the maturase HydG into the H-cluster, characterization of the auxiliary Fe-S cluster in HydG, and isotopic labeling of the CN- ligands of HydA for electronic structure studies of its Hox state. Advances in cell-free maturation protocols have enabled several of these mechanistic studies, and understanding H-cluster maturation may in turn provide insights leading to improvements in hydrogenase production for biotechnological applications. PMID- 26508822 TI - Reducing Risks for Problem Behaviors During the High School Transition: Proximal Outcomes in the Common Sense Parenting Trial. AB - This study tests Common Sense Parenting (CSP)(r), a widely used parent-training program, in its standard form and in a modified form known as CSP Plus, with low income 8th graders and their families during the high school transition. The six session CSP program proximally targets parenting and child emotion regulation skills. CSP Plus adds two sessions that include youth, and the eight-session program further targets skills for avoiding negative peers and activities in high school. Over two cohorts, 321 families were enrolled and randomly assigned to either CSP, CSP Plus, or minimal-contact control conditions. To date, pretest and posttest assessments have been completed, with 93% retention over about a 6-month interval. Here, analyses of preliminary outcomes from pretest to posttest focus on data collected from parents, who represent the primary proximal intervention targets. Intent-to-treat structural equation modeling analyses were conducted. CSP and CSP Plus had statistically significant effects on increased parent reported child emotion regulation skills. CSP Plus further showed a statistically significant effect on increased parent perceptions of their adolescent being prepared for high school, but only in a model that excluded the CSP condition. Neither program had a significant proximal effect on parenting practices. Emotion regulation, one indicator of self-control, is a robust protective factor against problem behaviors. Intervention effects on this outcome may translate into reduced problems during high school. Moreover, CSP Plus showed some limited signs of added value for preparing families for the high school transition. PMID- 26508823 TI - Past, Present, and Future of Minimally Invasive Abdominal Surgery. AB - Laparoscopic surgery has generated a revolution in operative medicine during the past few decades. Although strongly criticized during its early years, minimization of surgical trauma and the benefits of minimization to the patient have been brought to our attention through the efforts and vision of a few pioneers in the recent history of medicine. The German gynecologist Kurt Semm (1927-2003) transformed the use of laparoscopy for diagnostic purposes into a modern therapeutic surgical concept, having performed the first laparoscopic appendectomy, inspiring Erich Muhe and many other surgeons around the world to perform a wide spectrum of procedures by minimally invasive means. Laparoscopic cholecystectomy soon became the gold standard, and various laparoscopic procedures are now preferred over open approaches, in the light of emerging evidence that demonstrates less operative stress, reduced pain, and shorter convalescence. Natural orifice transluminal endoscopic surgery (NOTES) and single incision laparoscopic surgery (SILS) may be considered further steps toward minimization of surgical trauma, although these methods have not yet been standardized. Laparoscopic surgery with the use of a robotic platform constitutes a promising field of investigation. New technologies are to be considered under the prism of the history of surgery; they seem to be a step toward further minimization of surgical trauma, but not definite therapeutic modalities. Patient safety and medical ethics must be the cornerstone of future investigation and implementation of new techniques. PMID- 26508824 TI - Laparoscopic Greater Curve Plication as an Outpatient Weight Loss Procedure. AB - BACKGROUND AND OBJECTIVES: Laparoscopic greater curve plication is emerging as a weight loss procedure that avoids many of the complications of other surgeries that require gastrointestinal division, amputation, or use of a foreign body. Cost savings and affordability have also been promoted, as plication does not require the use of stapling devices, adjustable gastric bands, or prolonged hospitalization. The ability to predictably perform plication as an outpatient surgery may further define its role as a therapeutic option for treating morbid obesity. We present the 30-day outcomes and supplementary 12-month data in a series of 141 laparoscopic greater curve plication surgeries performed as outpatient procedures. METHODS: Laparoscopic greater curve plication was performed as outpatient surgery in 141 consecutive patients. Outcomes including perioperative complications, incidental 12-month follow-up for weight loss, and change in diabetic and hypertensive medication are reported. RESULTS: Of the 141 plications performed, 138 patients were discharged from the recovery room and 6 were readmitted. There was no conversion to open surgery and no mortality. CONCLUSIONS: The ability to reliably perform greater curve plication as an outpatient surgery may further define its role as an additional weight loss surgery technique. PMID- 26508825 TI - Paraesophageal Hernia Repair With Partial Longitudinal Gastrectomy in Obese Patients. AB - BACKGROUND AND OBJECTIVES: Treatment of gastroesophageal reflux disease (GERD) with hiatal hernia in obese patients has proven difficult, as studies demonstrate poor symptom control and high failure rates in this patient population. Recent data have shown that incorporating weight loss procedures into the treatment of reflux may improve overall outcomes. METHODS: We retrospectively reviewed 28 obese and morbidly obese patients who presented from December 2007 through July 2013 with large or recurrent type 3 or 4 paraesophageal hernia. All of the patients underwent combined paraesophageal hernia repair and partial longitudinal gastrectomy. Charts were retrospectively reviewed, and the patients were contacted to determine symptomatic relief. RESULTS: Mean preoperative body mass index was 38.1 +/- 4.9 kg/m(2). Anatomic failure of prior fundoplication occurred in 7 patients (25%). The remaining 21 had primary paraesophageal hernia, 3 of which were type 4. Postoperative complications included pulmonary embolism (n = 1), pulmonary decompensation (n = 2), and wound infection (n = 1). Mean hospital stay was 5 +/- 3 days. Upper gastrointestinal esophagogram was performed in 21 patients with no immediate recurrence or staple line dehiscence. Mean excess weight loss was 44 +/- 25%. All of the patients surveyed experienced near to total resolution of their preoperative symptoms within the first month. At 1 year, symptom scores decreased significantly. At 27 months, however, there was a mild increase in the scores. Return of severe symptoms occurred in 2 patients, both of whom underwent conversion to gastric bypass. CONCLUSIONS: Combined laparoscopic paraesophageal hernia repair with longitudinal partial gastrectomy offers a safe, feasible approach to the management of large or recurrent paraesophageal hernia in well-selected obese and morbidly obese patients. Short term results were promising; however, intermediate results showed increasing rates of reflux symptoms that required medical therapy or conversion to gastric bypass. PMID- 26508826 TI - Phylogenetic Trees and Networks Reduce to Phylogenies on Binary States: Does It Furnish an Explanation to the Robustness of Phylogenetic Trees against Lateral Transfers. AB - This article presents an innovative approach to phylogenies based on the reduction of multistate characters to binary-state characters. We show that the reduction to binary characters' approach can be applied to both character- and distance-based phylogenies and provides a unifying framework to explain simply and intuitively the similarities and differences between distance- and character based phylogenies. Building on these results, this article gives a possible explanation on why phylogenetic trees obtained from a distance matrix or a set of characters are often quite reasonable despite lateral transfers of genetic material between taxa. In the presence of lateral transfers, outer planar networks furnish a better description of evolution than phylogenetic trees. We present a polynomial-time reconstruction algorithm for perfect outer planar networks with a fixed number of states, characters, and lateral transfers. PMID- 26508827 TI - Publication Bias in Methodological Computational Research. AB - The problem of publication bias has long been discussed in research fields such as medicine. There is a consensus that publication bias is a reality and that solutions should be found to reduce it. In methodological computational research, including cancer informatics, publication bias may also be at work. The publication of negative research findings is certainly also a relevant issue, but has attracted very little attention to date. The present paper aims at providing a new formal framework to describe the notion of publication bias in the context of methodological computational research, facilitate and stimulate discussions on this topic, and increase awareness in the scientific community. We report an exemplary pilot study that aims at gaining experiences with the collection and analysis of information on unpublished research efforts with respect to publication bias, and we outline the encountered problems. Based on these experiences, we try to formalize the notion of publication bias. PMID- 26508828 TI - Decreased Phosphorylated Protein Kinase B (Akt) in Individuals with Autism Associated with High Epidermal Growth Factor Receptor (EGFR) and Low Gamma Aminobutyric Acid (GABA). AB - Dysregulation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway could contribute to the pathogenesis of autism spectrum disorders. In this study, phosphorylated Akt concentration was measured in 37 autistic children and 12, gender and age similar neurotypical, controls using an enzyme-linked immunosorbent assay. Akt levels were compared to biomarkers known to be associated with epidermal growth factor receptor (EGFR) and c-Met (hepatocyte growth factor (HGF) receptor) pathways and severity levels of 19 autism-related symptoms. We found phosphorylated Akt levels significantly lower in autistic children and low Akt levels correlated with high EGFR and HGF and low gamma aminobutyric acid, but not other biomarkers. Low Akt levels also correlated significantly with increased severity of receptive language, conversational language, hypotonia, rocking and pacing, and stimming, These results suggest a relationship between decreased phosphorylated Akt and selected symptom severity in autistic children and support the suggestion that the AKT pathways may be associated with the etiology of autism. PMID- 26508829 TI - Acanthamoeba encystment: multifactorial effects of buffers, biocides, and demulcents present in contact lens care solutions. AB - PURPOSE: To determine whether agents which are purportedly capable of inducing encystment of Acanthamoeba can recapitulate the signal when tested in differing formulations. METHODS: In accordance with the International Standard ISO 19045, Acanthamoeba castellanii ATCC 50370 trophozoites were cultured in antibiotic-free axenic medium, treated with test solutions, and encystment rates plus viability were measured via bright field and fluorescent microscopy. Test solutions included phosphate-buffered saline (PBS), borate-buffered saline, biguanide- and hydrogen peroxide (H2O2)-based biocides, propylene glycol (PG) and povidone (POV) ophthalmic demulcents, and one-step H2O2-based contact lens disinfection systems. RESULTS: Only PBS solutions with 0.25 ppm polyaminopropyl biguanide (PAPB) and increasing concentrations of PG and POV stimulated A. castellanii encystment in a dose-dependent manner, whereas PBS solutions containing 3% H2O2 and increasing concentrations of PG and POV did not stimulate encystment. Borate-buffered saline and PBS/citrate solutions containing PG also did not stimulate encystment. In addition, no encystment was observed after 24 hours, 7 days, or 14 days of exposures of trophozoites to one-step H2O2 contact lens disinfection products or related solutions. CONCLUSION: The lack of any encystment observed when trophozoites were treated with existing or new one-step H2O2 contact lens care products, as well as when trophozoites were exposed to various related test solutions, confirms that Acanthamoeba encystment is a complex process which depends upon simultaneous contributions of multiple factors including buffers, biocides, and demulcents. PMID- 26508830 TI - Experiences with developing and implementing a virtual clinic for glaucoma care in an NHS setting. AB - BACKGROUND: This article describes the development of a virtual glaucoma clinic, whereby technicians collect information for remote review by a consultant specialist. DESIGN AND METHODS: This was a hospital-based service evaluation study. Patients suitable for the stable monitoring service (SMS) were low-risk patients with "suspect", "early"-to-"moderate" glaucoma who were deemed stable by their consultant care team. Three technicians and one health care assistant ran the service. Patients underwent tests in a streamlined manner in a dedicated clinical facility, with virtual review of data by a consultant specialist through an electronic patient record. MAIN OUTCOME MEASURE: Feasibility of developing a novel service within a UK National Health Service setting and improvement of patient journey time within the service were studied. RESULTS: Challenges to implementation of virtual clinic include staffing issues and use of information technology. Patient journey time within the SMS averaged 51 minutes, compared with 92 minutes in the glaucoma outpatient department. Patient satisfaction with the new service was high. CONCLUSION: Implementing innovation into existing services of the National Health Service is challenging. However, the virtual clinic showed an improved patient journey time compared with that experienced within the general glaucoma outpatient department. There exists a discrepancy between patient management decisions of reviewers, suggesting that some may be more risk averse than others when managing patients seen within this model. Future work will assess the ability to detect progression of disease in this model compared with the general outpatient model of care. PMID- 26508831 TI - Investigation of postoperative intraocular pressure in cases of silicone oil removal using 25-gauge transconjunctival sutureless vitrectomy with oblique incisions. AB - BACKGROUND: The purpose of this study was to investigate postoperative intraocular pressure (IOP) in cases of silicone oil (SO) removal when using 25 gauge transconjunctival sutureless vitrectomy (TSV) with oblique incisions. METHODS: We enrolled ten consecutive eyes with SO removal (SO group) and eleven consecutive eyes with idiopathic epiretinal membrane (ERM) as the initial vitrectomy (ERM group) in cases using 25-gauge TSV with oblique incisions. Postoperative IOPs were compared between the two groups at each of the four examination periods. RESULTS: No significant differences were identified in any of the periods examined. CONCLUSION: The use of 25-gauge TSV with oblique incisions resulted in almost equivalent postoperative IOPs between cases with SO removal and idiopathic ERM as the initial operation. Self-sealing sclerotomy in 25-gauge TSV with oblique incisions may primarily involve the valve architecture, and be complemented by vitreous incarceration. PMID- 26508832 TI - Human adenovirus type identification. PMID- 26508833 TI - Acquired latent tuberculosis infection in psoriasis patients treated with etanercept in the People's Republic of China. AB - BACKGROUND: TNF-alpha plays a key role in host defense against mycobacterial infection, and patients receiving TNF-alpha blocker treatment have increased susceptibility to tuberculosis disease. In the People's Republic of China, an intermediate tuberculosis-burden country, the latent tuberculosis infection (LTBI) risk in patients with psoriasis who are treated with etanercept, the safest kind of TNF-alpha blocker, is unknown. OBJECTIVES: This study reports the LTBI risk in patients with psoriasis after etanercept treatment and aims to answer the question of how often rescreening for LTBI should be done in order to reduce active tuberculosis infection of patients and further reduce the incidence of active tuberculosis disease. PATIENTS AND METHODS: This retrospective review evaluated patients with moderate-to-severe chronic plaque psoriasis between 2009 and 2013. All patients were excluded tuberculosis infection and received etanercept 25 mg twice weekly, then the patients were checked for LTBI 3 months after etanercept treatment to observe the incidence of LTBI and assess the need for rescreening for LTBI every 3 months. RESULTS: We retrospectively analyzed 192 patients with psoriasis with moderate-to-severe chronic plaque whose tuberculin skin test and chest X-rays were negative and who received etanercept 25 mg twice weekly. Eighteen of them were excluded because they received less than 3 months of etanercept therapy. After treatment with etanercept, four patients were found to have LTBI. CONCLUSION: In this study, the incidence of LTBI after 3 months was four in 192 (2.1%), which is higher than the annual incidence of LTBI in the People's Republic of China (0.72%), so LTBI could be expected to occur within 3 months in psoriasis patients on etanercept. Periodic screening for LTBI in the therapy course, as well as before initiating treatment, is necessary in those patients who use a TNF-alpha blocker. We recommend rescreening for LTBI every 3 months. PMID- 26508834 TI - Urinary kallidinogenase for the treatment of cerebral arterial stenosis. AB - AIM: Urinary kallidinogenase (UK) has shown promise in improving cerebral perfusion. This study aimed to examine how UK affects cognitive status and serum levels of amyloid betas (Abetas) 1-40 and 1-42 in patients with cerebral arterial stenosis. METHODS: Ninety patients with cerebral arterial stenosis were enrolled, of whom 45 patients received UK + conventional treatment (UK group), and 45 patients received conventional treatment alone as control group. Cognitive status and Abeta1-40 and Abeta1-42 serum levels were determined before treatment and at 4 weeks and 8 weeks after treatment. RESULTS: At 4 weeks after treatment, cognitive status in patients treated with UK clearly improved accompanied by Abeta1-40 serum levels decreasing while there was no change of Abeta1-42. Cognitive status in patients receiving UK continued to improve, Abeta1-40 serum levels declined further as well as Abeta1-42 serum levels began to decrease dramatically at 8 weeks after treatment. CONCLUSION: UK could improve cognitive status and decrease both Abeta1-40 and Abeta1-42 serum levels to prevent ischemic cerebral injury, which represents a good option for patients with cerebral arterial stenosis. PMID- 26508835 TI - Paeoniflorin inhibits human glioma cells via STAT3 degradation by the ubiquitin proteasome pathway. AB - We investigated the underlying mechanism for the potent proapoptotic effect of paeoniflorin (PF) on human glioma cells in vitro, focusing on signal transducer and activator of transcription 3 (STAT3) signaling. Significant time- and dose dependent apoptosis and inhibition of proliferation were observed in PF-treated U87 and U251 glioma cells. Expression of STAT3, its active form phosphorylated STAT3 (p-STAT3), and several downstream molecules, including HIAP, Bcl-2, cyclin D1, and Survivin, were significantly downregulated upon PF treatment. Overexpression of STAT3 induced resistance to PF, suggesting that STAT3 was a critical target of PF. Interestingly, rapid downregulation of STAT3 was consistent with its accelerated degradation, but not with its dephosphorylation or transcriptional modulation. Using specific inhibitors, we demonstrated that the prodegradation effect of PF on STAT3 was mainly through the ubiquitin proteasome pathway rather than via lysosomal degradation. These findings indicated that PF-induced growth suppression and apoptosis in human glioma cells through the proteasome-dependent degradation of STAT3. PMID- 26508836 TI - Comment on a meta-analysis comparing hepatic resection or transarterial chemoembolization as initial treatment for hepatocellular carcinoma. PMID- 26508837 TI - Development of PPAR-agonist GW0742 as antidiabetic drug: study in animals. AB - BACKGROUND: The development of new drugs for the treatment of diabetes mellitus (DM) is critically important. Insulin resistance (IR) is one of the main problems associated with type-2 DM (T2DM) seen in clinics. GW0742, a selective peroxisome proliferator-activated receptor (PPAR)-delta agonist, has been shown to ameliorate metabolic abnormalities including IR in skeletal muscle in mice fed high-fructose corn syrup. However, the influence of GW0742 on systemic insulin sensitivity has still not been elucidated. Therefore, it is important to investigate the effect of GW0742 on systemic IR in diabetic rats for the development of new drugs. METHODS: The present study used a T2DM animal model to compare the effect of GW0742 on IR using homeostasis model assessment-IR (HOMA IR) and hyperinsulinemic euglycemic clamping. Additionally, the insulinotropic action of GW0742 was investigated in type-1 DM (T1DM) rats. Changes in the protein expression of glucose transporter 4 (GLUT4) and phosphoenolpyruvate carboxykinase (PEPCK) in skeletal muscle and in liver, respectively, were also identified by Western blots. RESULTS: GW0742 attenuated the increased HOMA-IR in diabetic rats fed a fructose-rich diet. This action was blocked by GSK0660 at the dose sufficient to inhibit PPAR-delta. Improvement of IR by GW0742 was also characterized in diabetic rats using hyperinsulinemic euglycemic clamping. Additionally, an increase of insulin sensitivity due to GW0742 was observed in these diabetic rats. Moreover, GW0742 reduced the hyperglycemia in T1DM rats lacking insulin. Western blotting analysis indicated that GW0742 reversed the decrease in GLUT4 and markedly reduced the increased PEPCK in liver. CONCLUSION: The data showed that GW0742 has the ability to improve glucose homeostasis in diabetic rats through activation of PPAR-delta. Therefore, PPAR-delta is a good target for the development of antidiabetic drugs in the future. PMID- 26508838 TI - Pain relief and improved physical function in knee osteoarthritis patients receiving ongoing hylan G-F 20, a high-molecular-weight hyaluronan, versus other treatment options: data from a large real-world longitudinal cohort in Canada. AB - From the Southwestern Ontario database, one of the largest primary-care datasets in Canada, 1,263 patients with osteoarthritis (OA) of one or both knees were identified who received two consecutive series of intra-articular (IA) injections of hylan G-F 20 preparation and no other prescribed OA medications, and were evaluated fully between 2006 and 2012. A cohort of 3,318 demographically matched OA patients who had not been treated with IA injection therapy was identified from the same database for comparison. Responses to therapy were assessed by means of a 10-point visual analog scale (VAS) for pain at rest and after completion of a 6-minute walk test (6 MWT), while physical capacity was measured by performance in the 6 MWT itself. After two cycles of hylan G-F 20 therapy, the average VAS score for pain at rest declined from 7.82 +/- 1.27 at baseline to 4.16 +/- 1.51 (average change 3.66 +/- 1.78, significantly more than the reduction of 3.12 +/- 2.03 seen in the reference group [P < 0.012]) and the average VAS score for pain after the 6 MWT decreased by 5.56 +/- 1.74 points (from 9.58 +/- 0.4 at baseline to 4.02 +/- 1.67 at the final assessment), a significantly larger change than that seen in the reference group (Delta2.99 +/- 1.85; P<0.001 for intergroup comparison). Distance walked in the 6 MWT increased on average by 115 m, significantly more than that seen in the reference group (Delta91 m; P < 0.001 for intergroup comparison). These findings from a primary care database suggest sustained benefits in terms of pain and physical function from repeat cycles of IA injections of hylan G-F 20 and no other prescribed OA medications in adults with OA of the knee. PMID- 26508839 TI - Dacomitinib in lung cancer: a "lost generation" EGFR tyrosine-kinase inhibitor from a bygone era? AB - EGFR tyrosine-kinase inhibitors (TKIs) have now been firmly established as the first-line treatment for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations, based on seven prospective randomized Phase III trials. However, despite significantly improved overall response rate and improved median progression-free survival when compared to platinum-doublet chemotherapy, EGFR-mutant NSCLC patients treated with EGFR TKIs invariably progress due to the emergence of acquired resistances, with the gatekeeper T790M mutation accounting for up to 60% of the resistance mechanisms. Second-generation irreversible EGFR TKIs were developed in part to inhibit the T790M mutation, in addition to the common activating EGFR mutations. Dacomitinib is one such second generation EGFR TKI designed to inhibit both the wild-type (WT) EGFR and EGFR T790M. Afatinib is another second-generation EGR TKI that has been now been approved for the first-line treatment of EGFR-mutant NSCLC patients, while dacomitinib continues to undergo clinical evaluation. We will review the clinical development of dacomitinib from Phase I to Phase III trials, including the two recently published negative large-scale randomized Phase III trials (ARCHER 1009, NCIC-BR-26). Results from another large-scale randomized trial (ARCHER 1050) comparing dacomitinib to gefitinib as first-line treatment of advanced treatment naive EGFR-mutant NSCLC patients will soon be available and will serve as the lynchpin trial for the potential approval of dacomitinib in NSCLC. Meanwhile, third-generation EGFR TKIs (eg, CO-1686 [rociletinib], AZ9291, HM61713, EGF816, and ASP8273) that preferentially and potently inhibit EGFR T790M but not WT EGFR are in full-scale clinical development, and some of these EGFR TKIs have received "breakthrough" designation by the US Food and Drug Administration and will likely be approved in late 2015. Given the rapid development of third-generation EGFR TKIs and the approval of gefitinib, erlotinib, and afatinib as first-line treatment of EGFR-mutant NSCLC patients, the future role of dacomitinib in the treatment of NSCLC seems to be limited. PMID- 26508840 TI - Factors associated with medication information in diabetes care: differences in perceptions between patients and health care professionals. AB - PURPOSE: This qualitative study in patients with type 2 diabetes and health care professionals (HCPs) aimed to investigate which factors they perceive to enhance or impede medication information provision in primary care. Similarities and differences in perspectives were explored. METHODS: Eight semistructured focus groups were conducted, four with type 2 diabetes patients (n=25) and four with both general practitioners (n=13) and health care assistants (n=10). Sessions were audio and video recorded, transcribed verbatim, and subjected to computer aided qualitative content analysis. RESULTS: Diabetes patients and HCPs broadly highlighted similar factors as enablers for satisfactory medication information delivery. Perceptions substantially differed regarding impeding factors. Both patients and HCPs perceived it to be essential to deliver tailored information, to have a trustful and continuous patient-provider relationship, to regularly reconcile medications, and to provide tools for medication management. However, substantial differences in perceptions related to impeding factors included the causes of inadequate information, the detail required for risk-related information, and barriers to medication reconciliation. Medication self management was a prevalent topic among patients, whereas HCPs' focus was on fulfilling therapy and medication management responsibilities. CONCLUSION: The findings suggest a noteworthy gap in perceptions between information provision and patients' needs regarding medication-related communication. Medication safety and adherence may be improved if HCPs collaborate more closely with diabetes patients in managing their medication, in particular by incorporating the patients' perspective. Health care systems need to be structured in a way that supports this process. PMID- 26508841 TI - Patients' and physicians' preferences for type 2 diabetes mellitus treatments in Spain and Portugal: a discrete choice experiment. AB - OBJECTIVE: To assess Spanish and Portuguese patients' and physicians' preferences regarding type 2 diabetes mellitus (T2DM) treatments and the monthly willingness to pay (WTP) to gain benefits or avoid side effects. METHODS: An observational, multicenter, exploratory study focused on routine clinical practice in Spain and Portugal. Physicians were recruited from multiple hospitals and outpatient clinics, while patients were recruited from eleven centers operating in the public health care system in different autonomous communities in Spain and Portugal. Preferences were measured via a discrete choice experiment by rating multiple T2DM medication attributes. Data were analyzed using the conditional logit model. RESULTS: Three-hundred and thirty (n=330) patients (49.7% female; mean age 62.4 [SD: 10.3] years, mean T2DM duration 13.9 [8.2] years, mean body mass index 32.5 [6.8] kg/m(2), 41.8% received oral + injected medication, 40.3% received oral, and 17.6% injected treatments) and 221 physicians from Spain and Portugal (62% female; mean age 41.9 [SD: 10.5] years, 33.5% endocrinologists, 66.5% primary-care doctors) participated. Patients valued avoiding a gain in bodyweight of 3 kg/6 months (WTP: ?68.14 [95% confidence interval: 54.55-85.08]) the most, followed by avoiding one hypoglycemic event/month (WTP: ?54.80 [23.29 82.26]). Physicians valued avoiding one hypoglycemia/week (WTP: ?287.18 [95% confidence interval: 160.31-1,387.21]) the most, followed by avoiding a 3 kg/6 months gain in bodyweight and decreasing cardiovascular risk (WTP: ?166.87 [88.63 843.09] and ?154.30 [98.13-434.19], respectively). Physicians and patients were willing to pay ?125.92 (73.30-622.75) and ?24.28 (18.41-30.31), respectively, to avoid a 1% increase in glycated hemoglobin, and ?143.30 (73.39-543.62) and ?42.74 (23.89-61.77) to avoid nausea. CONCLUSION: Both patients and physicians in Spain and Portugal are willing to pay for the health benefits associated with improved diabetes treatment, the most important being to avoid hypoglycemia and gaining weight. Decreased cardiovascular risk and weight reduction became the third most valued attributes for physicians and patients, respectively. PMID- 26508842 TI - Developing a discrete choice experiment in Malawi: eliciting preferences for breast cancer early detection services. AB - BACKGROUND: In Malawi, routine breast cancer screening is not available and little is known about women's preferences regarding early detection services. Discrete choice experiments are increasingly used to reveal preferences about new health services; however, selecting appropriate attributes that describe a new health service is imperative to ensure validity of the choice experiment. OBJECTIVE: To identify important factors that are relevant to Malawian women's preferences for breast cancer detection services and to select attributes and levels for a discrete choice experiment in a setting where both breast cancer early detection and choice experiments are rare. METHODS: We reviewed the literature to establish an initial list of potential attributes and levels for a discrete choice experiment and conducted qualitative interviews with health workers and community women to explore relevant local factors affecting decisions to use cancer detection services. We tested the design through cognitive interviews and refined the levels, descriptions, and designs. RESULTS: Themes that emerged from interviews provided critical information about breast cancer detection services, specifically, that breast cancer interventions should be integrated into other health services because asymptomatic screening may not be practical as an individual service. Based on participants' responses, the final attributes of the choice experiment included travel time, health encounter, health worker type and sex, and breast cancer early detection strategy. Cognitive testing confirmed the acceptability of the final attributes, comprehension of choice tasks, and women's abilities to make trade-offs. CONCLUSION: Applying a discrete choice experiment for breast cancer early detection was feasible with appropriate tailoring for a low-income, low-literacy African setting. PMID- 26508844 TI - Erratum: The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives [Corrigendum]. PMID- 26508843 TI - The importance of community consultation and social support in adhering to an obesity reduction program: results from the Healthy Weights Initiative. AB - BACKGROUND: Few community-based obesity reduction programs have been evaluated. After 153 community consultations, the City of Moose Jaw, SK, Canada, decided to initiate a free comprehensive program. The initiative included 71 letters of support from the Mayor, every family physician, cardiologist, and internist in the city, and every relevant community group including the Heart and Stroke Foundation, the Canadian Cancer Society, and the Public Health Agency of Canada. OBJECTIVE: To promote strong adherence while positively influencing a wide range of physical and mental health variables measured through objective assessment or validated surveys. METHODS: The only inclusion criterion was that the individuals must be obese adults (body mass index >30 kg/m(2)). Participants were requested to sign up with a "buddy" who was also obese and identify three family members or friends to sign a social support contract. During the initial 12 weeks, each individual received 60 group exercise sessions, 12 group cognitive behavioral therapy sessions, and 12 group dietary sessions with licensed professionals. During the second 12-week period, maintenance therapy included 12 group exercise sessions (24 weeks in total). RESULTS: To date, 243 people have been referred with 229 starting. Among those who started, 183 completed the program (79.9%), while 15 quit for medical reasons and 31 quit for personal reasons. Mean objective reductions included the following: 31.0 lbs of body fat, 3.9% body fat, 2.9 in from the waist, 2.3 in from the hip, blood cholesterol by 0.5 mmol/L, systolic blood pressure by 5.9 mmHg, and diastolic blood pressure by 3.2 mmHg (all P<0.000). There were no changes in blood sugar levels. There was also statistically significant differences in aerobic fitness, self-report health, quality of life measured by Short Form-36, and depressed mood measured by Beck Depression Inventory-II (all P<0.000). Independent risk factors for not completing the program were not having a family member or friend sign a social support contract (odds ratio 2.91, 95% confidence interval 1.01-8.34, P=0.047) and lower education (odds ratio 2.90, 95% confidence interval 1.20-7.03, P=0.018). CONCLUSION: Comprehensive obesity reduction programs can be effective when there is extensive consultation at the community level and social support at the individual level. PMID- 26508845 TI - Bariatric surgery in elderly patients: a systematic review. AB - Controversy exists regarding the effectiveness and safety of bariatric/metabolic surgery in elderly patients. We performed a systematic review on this issue in patients aged 60 years or older. MEDLINE, Cochrane Library, Embase, Scopus, and Google Scholar were searched until August 2015 for studies on outcomes of bariatric surgery in elderly patients. The results were expressed as pooled proportions (%) with 95% confidence intervals. Heterogeneity across the studies was evaluated by the I (2) test, and a random-effects model was used. Twenty-six articles encompassing 8,149 patients were pertinent with this issue and included data on bariatric surgery outcomes in elderly population. Fourteen patients died during the 30-day postoperative period, with a pooled mortality of 0.01%. Pooled overall complication rate was 14.7%. At 1-year follow-up, pooled mean excess weight loss was 53.77%, pooled diabetes resolution was 54.5%, and pooled hypertension resolution was 42.5%, while pooled lipid disorder resolution was 41.2%. Outcomes and complication rates of bariatric surgery in patients older than 60 years are comparable to those in a younger population, independent of the type of procedure performed. Patients should not be denied bariatric surgery because of their age alone. PMID- 26508846 TI - Falls in hospital and new placement in a nursing home among older people hospitalized with acute illness. AB - PURPOSE: To examine the association between falls in hospital and new placement in a nursing home among older people hospitalized with acute illness. MATERIALS AND METHODS: This prospective cohort study of 2,945 consecutive patients discharged alive from an acute geriatric medicine service used multivariate logistic regression to model the association between one or more falls and nursing home placement (primary analysis). Secondary analyses stratified falls by injury and occurrence of multiple falls. Demographic, medical, and frailty measures were considered in adjusted models. RESULTS: The mean age of all patients was 82.8+/-7.6 years and 94% were admitted through the emergency department. During a median length of stay (LOS) of 11 days, 257 (8.7%) patients had a fall. Of these, 66 (25.7%) sustained an injury and 53 (20.6%) had two or more falls. Compared with nonfallers, fallers were more likely to be placed in a nursing home (odds ratio [OR]: 2.03, 95% confidence interval [CI]: 1.37-3.00), after adjustment for age, sex, frailty, and selected medical variables (including dementia and delirium). Patients without injury (OR: 1.83, 95% CI: 1.17-2.85) and those with injury (OR: 2.35, 95% CI: 1.15-4.77) were also more likely to be placed. Patients who fell had a longer LOS (median 19 days vs 10 days; P<0.001). CONCLUSION: This study of older people in acute care shows that falls in the hospital are significantly associated with new placement in a nursing home. Given the predominantly negative experiences and the financial costs associated with placement in a nursing home, fall prevention should be a high priority in older people hospitalized with acute illness. PMID- 26508847 TI - Optimized balance rehabilitation training strategy for the elderly through an evaluation of balance characteristics in response to dynamic motions. AB - Balance is important in daily activities and essential for maintaining an independent lifestyle in the elderly. Recent studies have shown that balance rehabilitation training can improve the balance ability of the elderly, and diverse balance rehabilitation training equipment has been developed. However, there has been little research into optimized strategies for balance rehabilitation training. To provide an optimized strategy, we analyzed the balance characteristics of participants in response to the rotation of a base plate on multiple axes. Seven male adults with no musculoskeletal or nervous system-related diseases (age: 25.5+/-1.7 years; height: 173.9+/-6.4 cm; body mass: 71.3+/-6.5 kg; body mass index: 23.6+/-2.4 kg/m(2)) were selected to investigate the balance rehabilitation training using customized rehabilitation equipment. Rotation of the base plate of the equipment was controlled to induce dynamic rotation of participants in the anterior-posterior, right-diagonal, medial-lateral, and left-diagonal directions. We used a three-dimensional motion capture system employing infrared cameras and the Pedar Flexible Insoles System to characterize the major lower-extremity joint angles, center of body mass, and center of pressure. We found statistically significant differences between the changes in joint angles in the lower extremities in response to dynamic rotation of the participants (P<0.05). The maximum was greater with anterior-posterior and medial-lateral dynamic rotation than with that in other directions (P<0.05). However, there were no statistically significant differences in the frequency of center of body mass deviations from the base of support (P>0.05). These results indicate that optimizing rotation control of the base plate of balance rehabilitation training equipment to induce anterior-posterior and medial-lateral dynamic rotation preferentially can lead to effective balance training. Additional tests with varied speeds and ranges of angles of base plate rotation are expected to be useful as well as an analysis of the balance characteristics considering a balance index that reflects the muscle activity and cooperative characteristics. PMID- 26508848 TI - Effect of tiotropium on lung function decline in early-stage of chronic obstructive pulmonary disease patients: propensity score-matched analysis of real world data. AB - BACKGROUND: Tiotropium failed to slow the annual rate of forced expiratory volume in 1 second (FEV1) decline in chronic obstructive pulmonary disease (COPD) patients with <70% predicted FEV1. However, the rate of FEV1 decline is known to be faster at early stages, which suggests that the effects of tiotropium may be more prominent in early-stage of COPD patients. The aim of this study was to test the hypothesis that tiotropium modifies the rate of FEV1 decline in COPD patients with an FEV1>=70%. METHODS: We retrospectively reviewed the records of COPD patients diagnosed between January 1, 2004, and July 31, 2012, at Seoul National University Hospital, Seoul National University Bundang Hospital, and Seoul Metropolitan Government-Seoul National University Boramae Medical Center. The inclusion criteria were as follows: age >=40 years, postbron-chodilator (BD) FEV1>=70% of predicted and FEV1/FVC (forced vital capacity) <0.70, and spirometry more than two times at certain times of the year. Conversely, the exclusion criteria were as follows: asthma, lung cancer, pulmonary tuberculosis, pulmonary resection, or long-term use of a short-acting muscarinic antagonist. The annual lung function decline in patients using tiotropium was compared with that in patients not using the drug. RESULTS: Of the 587 patients enrolled in the study, 257 took tiotropium. Following propensity score matching, 404 patients were included in the analysis. The mean annual rate of post-BD FEV1 decline was 23.9 (tiotropium) and 22.5 (control) mL/yr (P=0.86); corresponding pre-BD values were 30.4 and 21.9 mL/yr (P=0.31), respectively. Mean annual rate of post-BD FVC decline was 55.1 (tiotropium) and 43.5 (control) mL/yr (P=0.33); corresponding pre-BD values were 37.1 and 33.3 mL/yr (P=0.13). CONCLUSION: Therefore, tiotropium does not reduce the rate of lung function decline in COPD patients with FEV1>=70%. PMID- 26508849 TI - A new approach to assess COPD by identifying lung function break-points. AB - PURPOSE: COPD is a progressive disease, which can take different routes, leading to great heterogeneity. The aim of the post-hoc analysis reported here was to perform continuous analyses of advanced lung function measurements, using linear and nonlinear regressions. PATIENTS AND METHODS: Fifty-one COPD patients with mild to very severe disease (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I-IV) and 41 healthy smokers were investigated post bronchodilation by flow-volume spirometry, body plethysmography, diffusion capacity testing, and impulse oscillometry. The relationship between COPD severity, based on forced expiratory volume in 1 second (FEV1), and different lung function parameters was analyzed by flexible nonparametric method, linear regression, and segmented linear regression with break-points. RESULTS: Most lung function parameters were nonlinear in relation to spirometric severity. Parameters related to volume (residual volume, functional residual capacity, total lung capacity, diffusion capacity [diffusion capacity of the lung for carbon monoxide], diffusion capacity of the lung for carbon monoxide/alveolar volume) and reactance (reactance area and reactance at 5Hz) were segmented with break-points at 60%-70% of FEV1. FEV1/forced vital capacity (FVC) and resonance frequency had break-points around 80% of FEV1, while many resistance parameters had break-points below 40%. The slopes in percent predicted differed; resistance at 5 Hz minus resistance at 20 Hz had a linear slope change of -5.3 per unit FEV1, while residual volume had no slope change above and -3.3 change per unit FEV1 below its break-point of 61%. CONCLUSION: Continuous analyses of different lung function parameters over the spirometric COPD severity range gave valuable information additional to categorical analyses. Parameters related to volume, diffusion capacity, and reactance showed break-points around 65% of FEV1, indicating that air trapping starts to dominate in moderate COPD (FEV1 =50%-80%). This may have an impact on the patient's management plan and selection of patients and/or outcomes in clinical research. PMID- 26508850 TI - A comprehensive assessment using COPD assessment test scoring and modified Medical Research Council dyspnea scoring is necessary for personalized therapy for COPD patients. PMID- 26508851 TI - Chronic obstructive lung disease and posttraumatic stress disorder: current perspectives. AB - BACKGROUND: Several studies have reported on the co-occurrence of chronic obstructive pulmonary disease (COPD) and psychiatric conditions, with the most robust evidence base demonstrating an impact of comorbid anxiety and depression on COPD-related outcomes. In recent years, research has sought to determine if there is a co-occurrence between COPD and posttraumatic stress disorder (PTSD) as well as for associations between PTSD and COPD-related outcomes. To date, there have been no published reviews summarizing this emerging literature. OBJECTIVES: The primary objective of this review was to determine if there is adequate evidence to support a co-occurrence between PTSD and COPD. Secondary objectives were to: 1) determine if there are important clinical considerations regarding the impact of PTSD on COPD management, and 2) identify targeted areas for further research. METHODS: A structured review was performed using a systematic search strategy limited to studies in English, addressing adults, and to articles that examined: 1) the co-occurrence of COPD and PTSD and 2) the impact of PTSD on COPD related outcomes. To be included, articles must have addressed some type of nonreversible obstructive lung pathology. RESULTS: A total of 598 articles were identified for initial review. Upon applying the inclusion and exclusion criteria, n=19 articles or abstracts addressed our stated objectives. Overall, there is inconclusive evidence to support the co-occurrence between PTSD and COPD. Studies finding a significant co-occurrence generally had inferior methods of identifying COPD; in contrast, studies that utilized more robust COPD measures (such as a physician exam) generally failed to find a relationship. Among studies that examined the impact of PTSD on COPD-related outcomes, there was more consistent evidence that PTSD affects the perception of respiratory symptom burden and management. In addition, methods for measuring an important confounder (smoking) were generally lacking. CONCLUSION: There is inconclusive evidence to support the co-occurrence of COPD and PTSD. There was stronger evidence implicating PTSD as an important comorbidity impacting COPD management. Further research is needed to: 1) determine whether or not COPD and PTSD are likely to be comorbid, and 2) further elucidate the mechanisms connecting PTSD and COPD related outcomes. PMID- 26508852 TI - Effect of particle size on oral absorption of carvedilol nanosuspensions: in vitro and in vivo evaluation. AB - The purpose of this work was to explore the particle size reduction effect of carvedilol on dissolution and absorption. Three suspensions containing different sized particles were prepared by antisolvent precipitation method or in combination with an ultrasonication process. The suspensions were characterized for particle size, surface morphology, and crystalline state. The crystalline form of carvedilol was changed into amorphous form after antisolvent precipitation. The dissolution rate of carvedilol was significantly accelerated by a reduction in particle size. The intestinal absorption of carvedilol nanosuspensions was greatly improved in comparison with microsuspensions and solution in the in situ single-pass perfusion experiment. The in vivo evaluation demonstrated that carvedilol nanosuspensions and microsuspensions exhibited markedly increased C(max) (2.09- and 1.48-fold) and AUC(0-t) (2.11- and 1.51 fold), and decreased T(max) (0.34- and 0.48-fold) in contrast with carvedilol coarse suspensions. Moreover, carvedilol nanosuspensions showed good biocompatibility with the rat gastric mucosa in in vivo gastrointestinal irritation test. The entire results implicated that the dissolution rate and the oral absorption of carvedilol were significantly affected by the particle size. Particle size reduction to form nanosized particles was found to be an efficient method for improving the oral bioavailability of carvedilol. PMID- 26508853 TI - Enhancement of encapsulation efficiency of nanoemulsion-containing aripiprazole for the treatment of schizophrenia using mixture experimental design. AB - Aripiprazole is considered as a third-generation antipsychotic drug with excellent therapeutic efficacy in controlling schizophrenia symptoms and was the first atypical anti-psychotic agent to be approved by the US Food and Drug Administration. Formulation of nanoemulsion-containing aripiprazole was carried out using high shear and high pressure homogenizers. Mixture experimental design was selected to optimize the composition of nanoemulsion. A very small droplet size of emulsion can provide an effective encapsulation for delivery system in the body. The effects of palm kernel oil ester (3-6 wt%), lecithin (2-3 wt%), Tween 80 (0.5-1 wt%), glycerol (1.5-3 wt%), and water (87-93 wt%) on the droplet size of aripiprazole nanoemulsions were investigated. The mathematical model showed that the optimum formulation for preparation of aripiprazole nanoemulsion having the desirable criteria was 3.00% of palm kernel oil ester, 2.00% of lecithin, 1.00% of Tween 80, 2.25% of glycerol, and 91.75% of water. Under optimum formulation, the corresponding predicted response value for droplet size was 64.24 nm, which showed an excellent agreement with the actual value (62.23 nm) with residual standard error <3.2%. PMID- 26508854 TI - Development and evaluation of sunscreen creams containing morin-encapsulated nanoparticles for enhanced UV radiation protection and antioxidant activity. AB - The objective of present work was to develop novel sunscreen creams containing polymeric nanoparticles (NPs) of morin. Polymeric NPs containing morin were prepared and optimized. The creams containing morin NPs were also prepared and evaluated. Optimized NPs exhibited particle size of 90.6 nm and zeta potential of -31 mV. The entrapment efficiency of morin, within the polymeric NPs, was found to be low (12.27%). Fourier transformed infrared spectroscopy and differential scanning calorimetry studies revealed no interaction between morin and excipients. Transmission electron microscopy and atomic force microscopy revealed that the NPs were spherical in shape with approximately 100 nm diameter. Optimized NPs showed excellent in vitro free radical scavenging activity. Skin permeation and deposition of morin from its NPs was higher than its plain form. Different sunscreen creams (SC1-SC8) were formulated by incorporating morin NPs along with nano zinc oxide and nano titanium dioxide. SC5 and SC8 creams showed excellent sun protection factor values (~40). In vitro and in vivo skin permeation studies of sunscreen creams containing morin NPs indicated excellent deposition of morin within the skin. Morin NPs and optimized cream formulations (SC5 and SC8) did not exhibit cytotoxicity in Vero and HaCaT cells. Optimized sunscreen creams showed excellent dermal safety. SC5 and SC8 creams demonstrated exceptional in vivo antioxidant effect (estimation of catalase, superoxide dismutase, and glutathione) in UV radiation-exposed rats. The optimized sunscreen creams confirmed outstanding UV radiation protection as well as antioxidant properties. PMID- 26508855 TI - Design and evaluation of an intravesical delivery system for superficial bladder cancer: preparation of gemcitabine HCl-loaded chitosan-thioglycolic acid nanoparticles and comparison of chitosan/poloxamer gels as carriers. AB - This study aimed to develop an intravesical delivery system of gemcitabine HCl for superficial bladder cancer in order to provide a controlled release profile, to prolong the residence time, and to avoid drug elimination via urination. For this aim, bioadhesive nanoparticles were prepared with thiolated chitosan (chitosan-thioglycolic acid conjugate) and were dispersed in bioadhesive chitosan gel or in an in situ gelling poloxamer formulation in order to improve intravesical residence time. In addition, nanoparticle-loaded gels were diluted with artificial urine to mimic in vivo conditions in the bladder and were characterized regarding changes in gel structure. The obtained results showed that chitosanthioglycolic acid nanoparticles with a mean diameter of 174.5+/ 3.762 nm and zeta potential of 32.100+/-0.575 mV were successfully developed via ionotropic gelation and that the encapsulation efficiency of gemcitabine HCl was nearly 20%. In vitro/ex vivo characterization studies demonstrated that both nanoparticles and nanoparticle-loaded chitosan and poloxamer gels might be alternative carriers for intravesical administration of gemcitabine HCl, prolonging its residence time in the bladder and hence improving treatment efficacy. However, when the gel formulations were diluted with artificial urine, poloxamer gels lost their in situ gelling properties at body temperature, which is in conflict with the aimed formulation property. Therefore, 2% chitosan gel formulation was found to be a more promising carrier system for intravesical administration of nanoparticles. PMID- 26508856 TI - A hyperspectral and toxicological analysis of protein corona impact on silver nanoparticle properties, intracellular modifications, and macrophage activation. AB - The inevitable adsorption of biomolecules on nanomaterials results in the formation of a protein corona (PC), which modifies the nanoparticle (NP)-cell interface resulting in modified uptake, activity, clearance, and toxicity. While the physicochemical properties of the NP govern the composition of PC, the formation of PC in turn alters the characteristics of the NP by imparting a new unique "biological" identity. To assess how the PC influences AgNP properties, intracellular modifications, and cellular responses, we utilized a combination of hyperspectral and toxicological analyses. AgNPs were coated with a complex PC (multiple proteins, eg, 10% fetal bovine serum) or a simple PC (single protein, eg, bovine serum albumin [BSA]) and evaluated by hyperspectral and dynamic light scattering for modifications in AgNP properties. Mouse macrophages were exposed to AgNPs with PCs and examined for differences in uptake, cytotoxicity, and cell activation. Hyperspectral imaging revealed intracellular modifications to AgNPs that were found to spectrally match alterations in AgNPs following incubation in lysosomal fluid. Addition of the PC influenced AgNP uptake and cytotoxicity; however, hydrodynamic size and surface charge did not contribute to these responses. Assessments of all endpoints demonstrated differences between complex and BSA PC, suggesting that these responses are not purely driven by the primary protein component of the complex PC (ie, BSA). Alterations in cellular-NP uptake/interactions may be driven through cell surface receptor recognition of protein constituents that make up the PC rather than the physicochemical differences in AgNPs. PMID- 26508857 TI - Design and activity of a cyclic mini-beta-defensin analog: a novel antimicrobial tool. AB - We have designed a cyclic 17-amino acid beta-defensin analog featuring a single disulfide bond. This analog, designated "AMC" (ie, antimicrobial cyclic peptide), combines the internal hydrophobic domain of hBD1 and the C-terminal charged region of hBD3. The novel peptide was synthesized and characterized by nuclear magnetic resonance spectroscopy. The antimicrobial activities against gram positive and gram-negative bacteria as well as against herpes simplex virus type 1 were analyzed. The cytotoxicity and serum stability were assessed. Nuclear magnetic resonance of AMC in aqueous solution suggests that the structure of the hBD1 region, although not identical, is preserved. Like the parent defensins, AMC is not cytotoxic for CaCo-2 cells. Interestingly, AMC retains the antibacterial activity of the parent hBD1 and hBD3 against Pseudomonas aeruginosa, Enterococcus faecalis, and Escherichia coli, and exerts dose-dependent activity against herpes simplex virus type 1. Moreover, while the antibacterial and antiviral activities of the oxidized and reduced forms of the parent defensins are similar, those of AMC are significantly different, and oxidized AMC is also considerably more stable in human serum. Taken together, our data also suggest that this novel peptide may be added to the arsenal of tools available to combat antibiotic resistant infectious diseases, particularly because of its potential for encapsulation in a nanomedicine vector. PMID- 26508858 TI - Increased mean platelet volume in patients with panic disorder. AB - OBJECTIVE: The relationship between platelet activation and psychiatric disorders has been shown in previous work. Mean platelet volume (MPV) is a measure of platelet size and a good indicator of platelet activity, which increases in cardiovascular diseases (CVDs). It is known that anxiety is a considerable factor in the etiology of mortality in CVDs. The aim of the present study was to investigate any probable difference in the MPV of patients with panic disorder (PD). METHODS: Sixty-one drug-free patients, aged 18-65 years and diagnosed with PD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were included in the study, along with 63 healthy age- and sex-matched volunteers. The body mass index (BMI) was calculated and MPV measured for each subject. RESULTS: The MPV was found to be higher in the PD group compared to the control group (P=0.004). There were no significant differences between the two groups in terms of platelet count or BMI. CONCLUSION: Alterations in platelet activity may be a reflection of abnormal 5-hydroxytryptamine (5-HT) 1A receptor function in the central nervous system of subjects with a diagnosis of PD. These findings may elucidate the relationship between CVDs and PD. The findings of the present study suggest that MPV is increased in PD patients. PMID- 26508859 TI - Aripiprazole: from pharmacological profile to clinical use. AB - Clinical experience with aripiprazole has confirmed the effectiveness and the safety of this novel antipsychotic drug in patients with schizophrenia as well as for the treatment of mania in type I bipolar disorder. However the generalization of the results from clinical trials requires further effort in order to address some issues and to overcome incorrect and partial interpretation of the clinical evidence. This article provides some straightforward guidance that may help clinical psychiatrists to translate the mechanism of action of aripiprazole into clinical setting, thus improving the appropriate use of the drug through rational application of its pharmacological profile. Examples of paradigmatic clinical situations are presented and discussed, suggesting possible intervention strategies, which may contribute to achieving the most appropriate use of the pharmacological properties of aripiprazole in real life settings. PMID- 26508860 TI - Ultrastructural mitochondria changes in perihematomal brain and neuroprotective effects of Huperzine A after acute intracerebral hemorrhage. AB - AIM: The purpose of the study was to observe the ultrastructural changes of neuronal mitochondria in perihematomal brain tissue and assess the therapeutic potential of Huperzine A (HA, a mitochondrial protector) following intracerebral hemorrhage (ICH). METHODS: Brain hemorrhage was induced in adult Sprague Dawley rats by injecting autologous blood into the striatum and then removing the brains 3, 6, 12, 24, or 48 hours later to analyze mitochondrial ultrastructure in a blinded manner. Parallel groups of ICH rats were treated with HA or saline immediately after ICH. Perihematomal apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), caspase-3 activation and cytochrome C translocation were tracked by immunoblots, and neurobehavioral test results were compared between the groups. RESULTS: Mitochondria in perihematomal neurons demonstrated dramatic changes including mitochondrial swelling, intracristal dilation, and decreased matrix density. HA treatment decreased mitochondrial injury and apoptosis, inhibited caspase-3 activation and cytochrome C translocation, and improved behavioral recovery. CONCLUSION: These data show that ICH induces dramatic mitochondrial damage, and HA exhibits protective effects possibly through ameliorating mitochondrial injury and apoptosis. Collectively, these findings suggest a new direction for novel therapeutics. PMID- 26508861 TI - Altered regional homogeneity of spontaneous brain activity in idiopathic trigeminal neuralgia. AB - The pathophysiology of idiopathic trigeminal neuralgia (ITN) has conventionally been thought to be induced by neurovascular compression theory. Recent structural brain imaging evidence has suggested an additional central component for ITN pathophysiology. However, far less attention has been given to investigations of the basis of abnormal resting-state brain activity in these patients. The objective of this study was to investigate local brain activity in patients with ITN and its correlation with clinical variables of pain. Resting-state functional magnetic resonance imaging data from 17 patients with ITN and 19 age- and sex matched healthy controls were analyzed using regional homogeneity (ReHo) analysis, which is a data-driven approach used to measure the regional synchronization of spontaneous brain activity. Patients with ITN had decreased ReHo in the left amygdala, right parahippocampal gyrus, and left cerebellum and increased ReHo in the right inferior temporal gyrus, right thalamus, right inferior parietal lobule, and left postcentral gyrus (corrected). Furthermore, the increase in ReHo in the left precentral gyrus was positively correlated with visual analog scale (r=0.54; P=0.002). Our study found abnormal functional homogeneity of intrinsic brain activity in several regions in ITN, suggesting the maladaptivity of the process of daily pain attacks and a central role for the pathophysiology of ITN. PMID- 26508862 TI - Off-label use of transmucosal ketamine as a rapid-acting antidepressant: a retrospective chart review. AB - OBJECTIVE: This study evaluated the effectiveness and safety of subanesthetic doses of ketamine using an off-label, transmucosal administration route in patients with treatment-resistant depression. METHODS: A retrospective chart review was conducted to identify patients who met the inclusion criteria for treatment-resistant major depressive disorder. Seventeen such patients who received subanesthetic doses of ketamine were included. Patient demographics, efficacy (drug refill, clinician notes), side effects, and concurrent medications were assessed. RESULTS: Benefit from low-dose transmucosal ketamine was noted in 76% of subjects (average age 48 years, 88% female), with a dose duration lasting 7-14 days. No notable side effects were noted. The most common classes of concurrent medications to which ketamine was added were serotonin-norepinephrine reuptake inhibitors (59%), stimulants (47%), folate replacement (47%), and benzodiazepines (47%). CONCLUSION: Our results provide preliminary evidence of the effectiveness and safety of low-dose transmucosal ketamine in treatment resistant patients. A controlled, prospective pilot study is warranted to validate these findings. PMID- 26508863 TI - Neurobehavioral burden of multiple sclerosis with nanotheranostics. AB - Multiple sclerosis (MS) is a chronic demyelinating neurological disorder affecting people worldwide; women are affected more than men. MS results in serious neurological deficits along with behavioral compromise, the mechanisms of which still remain unclear. Behavioral disturbances such as depression, anxiety, cognitive impairment, psychosis, euphoria, sleep disturbances, and fatigue affect the quality of life in MS patients. Among these, depression and psychosis are more common than any other neurological disorders. In addition, depression is associated with other comorbidities. Although anxiety is often misdiagnosed in MS patients, it can induce suicidal ideation if it coexists with depression. An interrelation between sleep abnormalities and fatigue is also reported among MS patients. In addition, therapeutics for MS is always a challenge because of the presence of the blood-brain barrier, adding to the lack of detailed understanding of the disease pathology. In this review, we tried to summarize various behavioral pathologies and their association with MS, followed by its conventional treatment and nanotheranostics. PMID- 26508864 TI - Obstructive sleep apnea: management considerations in psychiatric patients. AB - Psychiatric disorders and obstructive sleep apnea (OSA) are often comorbid. However, there is limited information on the impact of psychotropic medications on OSA symptoms, on how to manage psychiatric pharmacotherapy in patients presenting with OSA, or on the effectiveness and challenges of OSA treatments in patients with comorbid mental illness. As such, the objective of this article is to provide an overview of some epidemiological aspects of OSA and treatment considerations in the management of OSA in individuals with comorbid psychiatric disorders. Predefined keywords were used to search for relevant literature in electronic databases. Data show that OSA is particularly prevalent in patients with psychiatric disorders. The medical care that patients with these comorbidities require can be challenging, as some of the psychiatric medications used by these patients may exacerbate OSA symptoms. As such, continuous positive airway pressure continues to be the first-line treatment, even in patients with psychiatric comorbidity. However, more controlled studies are required, particularly to determine continuous positive airway pressure compliance in patients with mental illness, the impact of treating OSA on psychiatric symptoms, and the impact of the use of psychotropic medications on OSA symptoms. PMID- 26508865 TI - Motivation for everyday social participation in cognitively able individuals with autism spectrum disorder. AB - OBJECTIVE: The purpose of the present study was to examine motivation for the contextual nature of motivations for social participation in cognitively able adolescents and adults with autism spectrum disorder, using self-determination theory as a theoretical framework. METHODS: Fourteen Australians and 16 Taiwanese (aged 16-45 years) with Asperger's syndrome and high functioning autism were asked to carry a device which prompted them seven times/day for 7 days, to record what they were doing, with whom, perceived difficulty and social reciprocity, and the reasons for engaging in a situation, which were then coded into degree of self-determination. RESULTS: Multilevel analyses showed that participants were more likely to be self-determined while engaging in "solitary/parallel leisure" and "social activities" than in other types of activities. Interactions with "family members" and "casual/intimate friends" were also positively associated with self-determined motivation. Further, participants were more likely to perceive higher levels of being listened to during interaction with casual/intimate friends than in interaction with other people. Global social anxiety served as a moderator for their perceptions of difficulty and social reciprocity during social engagement. CONCLUSION: The findings highlight the context-dependent motivations for social engagement of cognitively able individuals with autism spectrum disorder. PMID- 26508866 TI - Successful administration of venovenous extracorporeal membrane oxygenation through the modified Blalock-Taussig operation in an infant with graft dysfunction after the Norwood procedure. PMID- 26508867 TI - Hydrogen-rich saline may be an effective and specific novel treatment for osteoradionecrosis of the jaw. AB - Hydrogen, a therapeutic medical gas, can exert antioxidant activity via selectively reducing cytotoxic reactive oxygen species such as hydroxyl radicals. Hydrogen-rich saline is an alternative form of molecular hydrogen that has been widely used in many studies, including metabolic syndrome, cerebral, hepatic, myocardial ischemia/reperfusion, and liver injuries with obstructive jaundice, with beneficial results. Osteoradionecrosis of the jaw is a serious complication following radiotherapy for head and neck cancers. It has long been known that most radiation-induced symptoms are caused by free radicals generated by radiolysis of H2O, and the hydroxyl radical is the most reactive of these. Reducing the hydroxyl radical can distinctly improve the protection of cells from radiation damage. We hypothesized that hydrogen-rich saline might be an effective and specific method of managing and preventing osteoradionecrosis of the jaw. PMID- 26508868 TI - Mandibular bone mineral density in patients with Behcet's disease. AB - OBJECTIVES: Behcet's disease (BD) is a chronic, recurring vasculitis of unknown etiology. Patients with BD may use a lot of medications associated with the clinical symptoms. Drugs that are used in the treatment of BD may cause bone loss. The aims of the current study were to compare the bone mineral density (BMD) values between BD and healthy volunteers and describe the effect of disease duration on mandibular BMD. MATERIALS AND METHODS: The study comprised 30 healthy volunteers (15 males and 15 females, mean age 35.50+/-6.80 years) and 45 patients with BD (24 males and 21 females, mean age 38.93+/-8.93 years). The BD group was subdivided according to disease duration (0-5, 6-10, and >10 years). The BMD value of the mandibular body was determined by the dual energy X-ray absorptiometry technique. RESULTS: The mean mandibular body BMD values were 1.294+/-0.21 g/cm(2) in the control group and 1.216+/-0.22 g/cm(2) in the BD patients, although there was no statistically significant difference. The BMD was observed to decrease with increased disease duration but not to a statistically significant degree. CONCLUSION: The results of this study showed that although the BMD value decreased as the duration of the disease increased, no statistically significant difference was found between the BD patients and the healthy control group. PMID- 26508869 TI - Feasibility of full and rapid neuromuscular blockade recovery with sugammadex in myasthenia gravis patients undergoing surgery - a series of 117 cases. AB - PURPOSE: Myasthenia gravis (MG) is an autoimmune disease interfering with neuromuscular transmission. Patients are at risk of postoperative residual curarization (PORC) if nondepolarizing muscle relaxants are used. Clinically inapparent insufficient muscle strength may result in hypoventilation and postoperative bronchopneumonia. We describe a cohort of 117 cases in which sugammadex was used in MG patients undergoing surgery with muscle relaxation with rocuronium. METHODS AND PATIENTS: We anesthetized 117 patients with MG using rocuronium and sugammadex as neuromuscular blockade reversal agent. One hundred five patients underwent surgical thymectomy and 12 underwent cholecystectomy (five laparotomic and seven laparoscopic). We measured time from sugammadex administration to recovery and to extubation, using the TOF-Watch((r)) (series of four consecutive electrical impulses [the train-of-four] >0.9). We tracked peripheral capillary oxygen saturation (SpO2) <95%, elevation of partial pressure of carbon dioxide (pCO2) >10% above baseline, number of reintubations within the first 48 hours, and number of pneumonias within 120 hours, postoperatively. Results were processed as average, minimum, and maximum values. RESULTS: The period needed to reach train-of-four of 0.9 following sugammadex administration was on average 117 seconds (minimum of 105 seconds/maximum of 127 seconds) and differed within deviation <10%. The time to extubation following sugammadex administration was on average 276 seconds (minimum of 251 seconds/maximum of 305 seconds) and differed minimally among patients as well. We observed no SpO2 <95%, no pCO2 elevation >10% above a baseline, no emergent reintubation within the first 48 hours, and no pneumonia diagnosed on clinical basis within 120 hours, postoperatively in all 117 patients. CONCLUSION: In this cohort of MG patients undergoing surgery using rocuronium and sugammadex, we did not observe any signs of postoperative residual curarization and respiratory depression. The neuromuscular blockade recovery was reliable, predictable, and rapid. PMID- 26508870 TI - Reducing the risk of surgical site infection using a multidisciplinary approach: an integrative review. AB - PURPOSE: To identify and describe the strategies and processes used by multidisciplinary teams of health care professionals to reduce surgical site infections (SSIs). MATERIALS AND METHODS: An integrative review of the research literature was undertaken. Searches were conducted in April 2015. Following review of the included studies, data were abstracted using summary tables and the methodological quality of each study assessed using the Standards for Quality Improvement Reporting Excellence guidelines by two reviewers. Discrepancies were dealt with through consensus. Inductive content analysis was used to identify and describe the strategies/processes used by multidisciplinary health care teams to prevent SSI. RESULTS AND DISCUSSION: In total, 13 studies met the inclusion criteria. Of these, 12 studies used quantitative methods, while a single study used qualitative interviews. The majority of the studies were conducted in North America. All quantitative studies evaluated multifaceted quality-improvement interventions aimed at preventing SSI in patients undergoing surgery. Across the 13 studies reviewed, the following multidisciplinary team-based approaches were enacted: using a bundled approach, sharing responsibility, and, adhering to best practice. The majority of studies described team collaborations that were circumscribed by role. None of the reviewed studies used strategies that included the input of allied health professionals or patient participation in SSI prevention. CONCLUSION: Patient-centered interventions aimed at increasing patient participation in SSI prevention and evaluating the contributions of allied health professionals in team-based SSI prevention requires future research. PMID- 26508871 TI - Applying Side-chain Flexibility in Motifs for Protein Docking. AB - Conventional rigid docking algorithms have been unsatisfactory in their computational results, largely due to the fact that protein structures are flexible in live environments. In response, we propose to introduce the side chain flexibility in protein motif into the docking. First, the Morse theory is applied to curvature labeling and surface region growing, for segmentation of the protein surface into smaller patches. Then, the protein is described by an ensemble of conformations that incorporate the flexibility of interface side chains and are sampled using rotamers. Next, a 3D rotation invariant shape descriptor is proposed to deal with the flexible motifs and surface patches; thus, pairwise complementarity matching is needed only between the convex patches of ligand and the concave patches of receptor. The iterative closest point (ICP) algorithm is implemented for geometric alignment of the two 3D protein surface patches. Compared with the fast Fourier transform-based global geometric matching algorithm and other methods, our FlexDock system generates much less false positive docking results, which benefits identification of the complementary candidates. Our computational experiments show the advantages of the proposed flexible docking algorithm over its counterparts. PMID- 26508872 TI - Evaluation of Patient Satisfaction with Tuberculosis Services in Southern Nigeria. AB - OBJECTIVE: Knowing tuberculosis (TB) patients' satisfaction enables TB program managers to identify gaps in service delivery and institute measures to address them. This study is aimed at evaluating patients' satisfaction with TB services in southern Nigeria. MATERIALS AND METHODS: A total of 378 patients accessing TB care were studied using a validated Patient Satisfaction (PS-38) questionnaire on various aspects of TB services. Factor analysis was used to identify eight factors related to TB patient satisfaction. Test of association was used to study the relation between patient satisfaction scores and patient and health facility characteristics, while multilinear regression analysis was used to identify predictors of patient satisfaction. RESULTS: Highest satisfaction was reported for adherence counseling and access to care. Patient characteristics were associated with overall satisfaction, registration, adherence counseling, access to care, amenities, and staff attitude, while health system factors were associated with staff attitude, amenities, and health education. Predictors of satisfaction with TB services included gender, educational status, if tested for HIV, distance, payment for TB services, and level and type of health-care facility. CONCLUSION: Patient- and health system-related factors were found to influence patient satisfaction and, hence, should be taken into consideration in TB service programing. PMID- 26508873 TI - Enumeration of Organohalide Respirers in Municipal Wastewater Anaerobic Digesters. AB - Organohalide contaminants such as triclosan and triclocarban have been well documented in municipal wastewater treatment plants (WWTPs), but the degradation of these contaminants is not well understood. One possible removal mechanism is organohalide respiration by which bacteria reduce the halogenated compound. The purpose of this study was to determine the abundance of organohalide-respiring bacteria in eight WWTP anaerobic digesters. The obligate organohalide respiring Dehalococcoides mccartyi was the most abundant and averaged 3.3 * 10(7) copies of 16S rRNA genes per gram, while the Dehalobacter was much lower at 2.6 * 10(4) copies of 16S rRNA genes per gram. The genus Sulfurospirillum spp. was also detected at 1.0 * 10(7) copies of 16S rRNA genes per gram. No other known or putatively organohalide-respiring strains in the Dehalococcoidaceae family were found to be present nor were the genera Desulfitobacterium or Desulfomonile. PMID- 26508874 TI - Resistance Exercise Attenuates High-Fructose, High-Fat-Induced Postprandial Lipemia. AB - INTRODUCTION: Meals rich in both fructose and fat are commonly consumed by many Americans, especially young men, which can produce a significant postprandial lipemic response. Increasing evidence suggests that aerobic exercise can attenuate the postprandial increase in plasma triacylglycerols (TAGs) in response to a high-fat or a high-fructose meal. However, it is unknown if resistance exercise can dampen the postprandial lipemic response to a meal rich in both fructose and fat. METHODS: Eight apparently healthy men (Mean +/- SEM; age = 27 +/- 2 years) participated in a crossover study to examine the effects of acute resistance exercise on next-day postprandial lipemia resulting from a high fructose, high-fat meal. Participants completed three separate two-day conditions in a random order: (1) EX-COMP: a full-body weightlifting workout with the provision of additional kilocalories to compensate for the estimated net energy cost of exercise on day 1, followed by the consumption of a high-fructose, high fat liquid test meal the next morning (day 2) (~600 kcal) and the determination of the plasma glucose, lactate, insulin, and TAG responses during a six-hour postprandial period; (2) EX-DEF: same condition as EX-COMP but without exercise energy compensation on day 1; and (3) CON: no exercise control. RESULTS: The six hour postprandial plasma insulin and lactate responses did not differ between conditions. However, the postprandial plasma TAG concentrations were 16.5% and 24.4% lower for EX-COMP (551.0 +/- 80.5 mg/dL * 360 minutes) and EX-DEF (499.4 +/ 73.5 mg/dL * 360 minutes), respectively, compared to CON (660.2 +/- 95.0 mg/dL * 360 minutes) (P < 0.05). CONCLUSIONS: A single resistance exercise bout, performed ~15 hours prior to a high-fructose, high-fat meal, attenuated the postprandial TAG response, as compared to a no-exercise control condition, in healthy, resistance-trained men. PMID- 26508875 TI - The functional role of microRNA in acute lymphoblastic leukemia: relevance for diagnosis, differential diagnosis, prognosis, and therapy. AB - MicroRNAs (miRNAs), a new class of noncoding RNAs, which can hybridize to target messenger RNAs and regulate their expression posttranscriptionally, express differentially in distinct stages of lymphopoiesis and influence the direction of lymphoid precursor maturation. Hence, there is aberrant expression of miRNAs involved in malignant lymphopoiesis, and these aberrations can be used as signatures of acute lymphoblastic leukemia (ALL) with different subtypes. In addition, changes in the expression of several miRNAs may have functional relevance with leukemogenesis or drug resistance. As a result, the reversal of the expression of these miRNAs may alleviate the disease to some extent and improve clinical outcomes. However, among the studies of miRNAs, there are still some problems that need to be solved to understand the function of miRNAs in ALL more thoroughly. PMID- 26508876 TI - EGFR-TKIs in adjuvant treatment of lung cancer: to give or not to give? AB - Epidermal growth factor receptor-tyrosine-kinase inhibitors (EGFR-TKIs) brought a significant revolution in the treatment of non-small-cell lung cancer (NSCLC). In a short period of time, EGFR-TKIs became the standard of treatment for mutation positive, advanced stage non-squamous NSCLC. In recent years, second- and third generation EGFR-TKIs are emerging, further widening the clinical use. However, the question of EGFR-TKIs efficiency in the treatment of early stage NSCLC still remains open. Early clinical trials failed to approve the use of EGFR-TKIs in adjuvant setting. The majority of these early trials were performed in unselected NSCLC populations and without standardized biomarker identification. One should certainly not rely solely on these results and dismiss the use of EGFR-TKIs as adjuvant therapy. Many important questions are still unanswered. Most important issues such as stage heterogeneity (IA-IIIA), timing (after or concomitantly with chemotherapy), and type of administration (monotherapy or combination) need to be answered in near future. Adjuvant TKIs in the treatment of lung cancer might offer significant number of advancements. Having in mind the significant duration of response observed in advance disease setting, there could be place for prolongation of response in adjuvant setting potentially, leading to improvement in survival. TKIs could offer less-toxic adjuvant treatment with better efficiency than chemotherapy. However, there is a chronic lack of randomized controlled trials in this field, leading to inability to draw any scientifically sound conclusion with regard to the adjuvant treatment. For now, the use of EGFR TKIs outside clinical trial setting is not recommended. The purpose of this review is to evaluate current and available data. PMID- 26508877 TI - Deregulation of secreted frizzled-related proteins is associated with aberrant beta-catenin activation in the carcinogenesis of oral submucous fibrosis. AB - Secreted frizzled-related proteins (SFRPs), the first identified Wnt antagonists, have been well recognized as tumor suppressors in multiple human cancers through suppressing the Wnt/beta-catenin pathway. To better elucidate the mechanisms of SFRPs involved in the carcinogenesis of oral submucous fibrosis (OSF), one of the precancerous lesions of oral squamous cell carcinoma (OSCC), we investigated expression and localization of SFRP1, SFRP5, and beta-catenin in normal oral epithelium, OSF, and OSCC tissues. We found that SFRP1 and SFRP5 were readily expressed in normal oral mucous tissues but gradually decreased in OSF early, moderately advanced, and advanced tissues and rarely expressed in OSCC tissues. We found the changes of SFRP1 localization and SFRP5 localization from nucleus to cytoplasm in the carcinogenesis of OSF. There is a significant association among reduced SFRP1, SFRP5, and cytoplasmic/nuclear beta-catenin expression, which is correlated with higher tumor grade and stage of OSCC. We further found that SFRP1 and SFRP5 were frequently methylated in OSCC cases with betel quid chewing habit but not in normal oral mucous and different stages of OSF tissues, suggesting that methylation of SFRP1 and SFRP5 is tumor specific in the carcinogenesis of OSF. Taken together, our data demonstrated that reduced SFRP1 and SFRP5 by promoter methylation could lead to cytoplasmic/nuclear accumulation of beta catenin and tumor progression. The changes of SFRPs and beta-catenin localization, as well as SFRPs' methylation, could be useful predictors or biomarkers of OSF malignant progression and prognosis. PMID- 26508878 TI - A human leucyl-tRNA synthetase as an anticancer target. AB - Several aminoacyl-tRNA synthetases have been reported to be overexpressed for charging essential aminoacyl-tRNAs in many cancer types. In this study, we aimed to explore the potential role of leucyl-tRNA synthetase (LARS) as an anticancer target. MTT assay was performed to screen inhibitors to human LARS (hsLARS) from compounds AN2690 and its derivatives, compounds 1-6, in U2OS and SKOV3 cells. The compound with the strongest inhibitory ability was further investigated for its inhibitory effect in cancer cell lines and in an animal tumor model. Additionally, a LARS-rescue experiment was performed to explore the potential target in U2OS using Western blot and flow cytometry. Luciferase reporter assay was designed to analyze the effect of of hsLARS inhibitor on p21 activation. We identified an hsLARS inhibitor (compound 2) that suppressed the proliferation of U2OS and SKOV3 cells in vitro. A LARS-rescue experiment demonstrated that the proliferation inhibition was induced by targeting intracellular LARS. In addition, the hsLARS inhibition was shown to activate the p21 early transcription and promote cell apoptosis, as well as reduce implanted EMT6 tumor progression in mice. Our results suggest that LARS might serve as a potential anticancer target through the p21 signaling pathway and that the nutritional signaling pathway may provide a valuable anticancer strategy for further investigation. PMID- 26508879 TI - Incidence and clinical characteristics of unexpected uterine sarcoma after hysterectomy and myomectomy for uterine fibroids: a retrospective study of 10,248 cases. AB - BACKGROUND: Uterine fibroids often require a hysterectomy or myomectomy via laparotomy or laparoscopy. Morcellation is often necessary to perform a laparoscopic surgery. The objective of this study is to determine the incidence of unexpected uterine sarcomas (UUSs) after hysterectomy and myomectomy for uterine fibroids and to reduce the occurrence and avoid the morcellation of UUSs by analyzing their characteristics. METHODS: Women who had a hysterectomy or myomectomy for uterine fibroids in Shengjing Hospital of China Medical University between November 2008 and November 2014 were selected for the study, and their clinical characteristics were analyzed. RESULTS: During the period, 48 UUSs were found in 10,248 cases, and the overall incidence was 0.47%. There was no statistical difference (P=0.449) regarding the incidence (0.50% vs 0.33%) between 42 UUSs in 8,456 cases undergoing laparotomy and six UUSs in 1,792 cases undergoing laparoscopy. Most of the UUSs were stage I (89.58%), which occurred more commonly (56.25%) in women aged 40-49. Abnormal uterine bleeding (39.58%) was the main clinical manifestation. Rapidly growing pelvic masses (12.5%), rich blood flow signals (18.75%), and degeneration of uterine fibroids (18.75%) prompted by ultrasonography may suggest the possibility of UUSs. The margins of most UUSs (93.75%) were regular, which may cause UUSs to be misdiagnosed as uterine fibroids. Fifteen cases underwent magnetic resonance imaging examinations. Approximately 73.33% showed heterogeneous and hypointense signal intensity on T1-weighted images, and 80% showed intermediate-to-high signal intensity on T2-weighted images, with necrosis and hemorrhage in 40% of cases. After contrast administration, 80% presented early heterogeneous enhancement. CONCLUSION: The incidence of UUSs after hysterectomy and myomectomy for uterine fibroids was low, and their clinical characteristics are atypical. It is necessary and very critical to make a complete and cautious preoperative evaluation to reduce the occurrence and avoid the morcellation of UUSs. PMID- 26508880 TI - Molecular profiling in the treatment of colorectal cancer: focus on regorafenib. AB - Metastatic colorectal cancer (mCRC) is a highly heterogeneous disease. Its treatment outcome has been significantly improved over the last decade with the incorporation of biological targeted therapies, including anti-EGFR antibodies, cetuximab and panitumumab, and VEGF inhibitors, bevacizumab, ramucirumab, and aflibercept. The identification of predictive biomarkers has further improved the survival by accurately selecting patients who are most likely to benefit from these treatments, such as RAS mutation profiling for EGFR antibodies. Regorafenib is a multikinase inhibitor currently used as late line therapy for mCRC. The molecular and genetic markers associated with regorafenib treatment response are yet to be characterized. Here, we review currently available clinical evidence of mCRC molecular profiling, such as RAS, BRAF, and MMR testing, and its role in targeted therapies with special focus on regorafenib treatment. PMID- 26508881 TI - Cost-effectiveness of three echinocandins and fluconazole in the treatment of candidemia and/or invasive candidiasis in nonneutropenic adult patients. AB - OBJECTIVE: To estimate the cost-effectiveness of three echinocandins (anidulafungin, caspofungin, and micafungin) and generic fluconazole in the treatment of nonneutropenic adult patients with candidemia and/or invasive candidiasis in intensive care units in Spain. MATERIALS AND METHODS: A decision tree model was applied. The success and safety (hepatic and renal adverse effects) of first-line treatments were obtained from meta-analyses and systematic reviews of clinical trials. In the case of failure, a second-line treatment (liposomal amphotericin B after the echinocandins, or one of the echinocandins after fluconazole) was administered. The duration of the treatments (14 days total) was established by a panel of clinical experts using the Delphi method and according to Infectious Diseases Society of America guidelines. The cost of the medications and renal toxicity were considered. Deterministic and probabilistic sensitivity analysis using Monte Carlo simulations were carried out. RESULTS: The total cost of the treatment of candidemia and/or invasive candidiasis with anidulafungin, caspofungin, micafungin, and fluconazole was ?5,483, ?5,968, ?6,231, and ?2,088, respectively. Anidulafungin was the dominant treatment (more effective, less expensive) compared to micafungin and caspofungin. The cost of achieving one more patient successfully treated with anidulafungin, caspofungin, and micafungin compared to fluconazole was ?17,199, ?23,962, and ?27,339, respectively. The result remained stable, despite modification of the duration of the first-line and second-line treatments, as well as most of the dosing regimens. The probabilistic analysis also remained stable. CONCLUSION: In accordance with this economic study, anidulafungin would produce savings and would be the dominant treatment compared with micafungin and caspofungin in nonneutropenic adult patients with candidemia and/or invasive candidiasis in intensive care units in Spain. PMID- 26508882 TI - Weight loss for women with and without polycystic ovary syndrome following a very low-calorie diet in a community-based setting with trained facilitators for 12 weeks. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) affects between 2% and 26% of reproductive-age women in the UK, and accounts for up to 75% of anovulatory infertility. The major symptoms include ovarian disruption, hyperandrogenism, insulin resistance, and polycystic ovaries. Interestingly, at least half of the women with PCOS are obese, with the excess weight playing a pathogenic role in the development and progress of the syndrome. The first-line treatment option for overweight/obese women with PCOS is diet and lifestyle interventions; however, optimal dietary guidelines are missing. Although many different dietary approaches have been investigated, data on the effectiveness of very low-calorie diets on PCOS are very limited. MATERIALS AND METHODS: The aim of this paper was to investigate how overweight/obese women with PCOS responded to LighterLife Total, a commercial very low-calorie diet, in conjunction with group behavioral change sessions when compared to women without PCOS (non-PCOS). RESULTS: PCOS (n=508) and non-PCOS (n=508) participants were matched for age (age +/-1 unit) and body mass index (body mass index +/-1 unit). A 12-week completers analysis showed that the total weight loss did not differ significantly between PCOS (n=137) and non-PCOS participants (n=137) (-18.5+/-6.6 kg vs -19.4+/-5.7 kg, P=0.190). Similarly, the percentage of weight loss achieved by both groups was not significantly different (PCOS 17.1%+/-5.6% vs non-PCOS 18.2%+/-4.4%, P=0.08). CONCLUSION: Overall, LighterLife Total could be an effective weight-loss strategy in overweight/obese women with PCOS. However, further investigations are needed to achieve a thorough way of understanding the physiology of weight loss in PCOS. PMID- 26508883 TI - Prognostic significance of urinary NGAL in chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is a worldwide public health problem. Recently urinary NGAL (uNGAL) has been proven to be a useful (potentially ideal) biomarker for early detection of CKD. The aim of the present study was to examine the correlation of uNGAL with severity of renal impairment in CKD and to evaluate its prognostic value in these subjects. METHODS: This was a prospective study carried out over a period of 24 months in subjects with CKD due to primary chronic glomerulonephritis. New cases of CKD stage II, III, IV aged between 18 and 65 years were enrolled as per KDIGO (Kidney Disease: Improving Global Outcomes) guidelines 2012. A total of 90 subjects completed the study up to the end-point. The primary follow-up end-point was 18 months, or decreased glomerular filtration rate of less than 15 mL/min. Secondary follow-up end-point was the number of subjects who expired during this period. RESULTS: Multiple regression model of estimated glomerular filtration rate showed significant associations with log uNGAL (beta=0.38, P<0.001), Ca*PO4 (beta=0.60, P<0.001), hemoglobin (beta=0.37, P<0.001), urine protein (beta=0.34, P<0.001), serum albumin (beta=0.48, P<0.001), and systolic blood pressure (beta=0.76, P<0.001). Receiver operator curve for uNGAL considering the progression of CKD showed area under the curve for uNGAL was 0.878 (95% confidence interval: 0.68-0.96). Cut-off value for uNGAL was log 3.5 unit with a sensitivity of 93.08% and specificity of 71.43% for predicting the progression of CKD. Kaplan-Meier survival curve showed that patients with log uNGAL levels <3.51 unit had a survival rate of 71.4% while patients with NGAL level >3.51 unit had a renal survival rate of 14.7%. CONCLUSION: Our study result showed that uNGAL has a positive correlation with disease severity which signifies the prognostic importance of uNGAL in CKD. PMID- 26508884 TI - Feet swelling in a multistage ultraendurance triathlete: a case study. AB - Recent studies investigating ultraendurance athletes showed an association between excessive fluid intake and swelling of the lower limbs such as the feet. To date, this association has been investigated in single-stage ultraendurance races, but not in multistage ultraendurance races. In this case study, we investigated a potential association between fluid intake and feet swelling in a multistage ultraendurance race such as a Deca Iron ultratriathlon with ten Ironman triathlons within 10 consecutive days. A 49-year-old well-experienced ultratriathlete competed in autumn 2013 in the Deca Iron ultratriathlon held in Lonata del Garda, Italy, and finished the race as winner within 129:33 hours:minutes. Changes in body mass (including body fat and lean body mass), foot volume, total body water, and laboratory measurements were assessed. Food and fluid intake during rest and competing were recorded, and energy and fluid turnovers were estimated. During the ten stages, the volume of the feet increased, percentage body fat decreased, creatinine and urea levels increased, hematocrit and hemoglobin values decreased, and plasma [Na(+)] remained unchanged. The increase in foot volume was significantly and positively related to fluid intake during the stages. The poststage volume of the foot was related to poststage total body water, poststage creatinine, and poststage urea. This case report shows that the volume of the foot increased during the ten stages, and the increase in volume was significantly and positively related to fluid intake during the stages. Furthermore, the poststage volume of the foot was related to poststage total body water, poststage creatinine, and poststage urea. The continuous feet swelling during the race was most probably due to a combination of a high fluid intake and a progressive decline in renal function (ie, continuous increase in creatinine and urea), leading to body fluid retention (ie, increase in total body water). PMID- 26508885 TI - Single- and multiple-dose pharmacokinetics of biphasic immediate-release/extended release hydrocodone bitartrate/acetaminophen (MNK-155) compared with immediate release hydrocodone bitartrate/ibuprofen and immediate-release tramadol HCl/acetaminophen. AB - OBJECTIVE: To characterize the single-dose and steady-state pharmacokinetics (PK) of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (IR/ER HB/APAP), IR HB/ibuprofen, and IR tramadol HCl/APAP. METHODS: In this single-center, open-label, randomized, four-period crossover study, healthy participants received four treatments under fasted conditions: 1) a single dose of two IR/ER HB/APAP 7.5/325 mg tablets (15/650 mg total dose) on day 1, followed by two tablets every 12 hours (q12h) beginning on day 3; 2) a single dose of IR HB/ibuprofen 15/400 mg (divided as one 7.5/200 mg tablet at hour 0 and 6), followed by one tablet every 6 hours (q6h) beginning on day 3; 3) a single dose of IR tramadol HCl/APAP 75/650 mg (divided as one 37.5/325 mg tablet at hour 0 and 6), followed by one tablet q6h beginning on day 3; and 4) a single dose of three IR/ER HB/APAP 7.5/325 mg tablets (22.5/975 mg total dose) on day 1, a three-tablet initial dose at 48 hours followed by two tablet doses q12h beginning on day 3. Hydrocodone and APAP single-dose and steady state PK were assessed. Adverse events were monitored. RESULTS: The PK analysis was carried out on 29 of 48 enrolled participants who completed all treatment periods. Single-dose hydrocodone exposure was similar for IR/ER HB/APAP 22.5/975 mg and IR HB/ibuprofen 15/400 mg; time to maximum observed plasma concentration was shorter and half-life was longer for IR/ER HB/APAP (22.5/975 mg and 15/650 mg) vs IR HB/ibuprofen. Single-dose APAP exposure was similar for IR/ER HB/APAP 15/650 mg and IR tramadol HCl/APAP 75/650 mg. Steady-state hydrocodone and APAP exposures were similar between treatments. Adverse events were similar for each treatment and typical of low-dose combination opioid analgesics. With dosing q12h, IR/ER HB/APAP had half as many concentration peaks and troughs as the comparators treated q6h. CONCLUSION: With dosing q12h, IR/ER HB/APAP provided similar peak and total steady-state hydrocodone and APAP exposure vs IR comparators. PMID- 26508886 TI - The Toronto General Hospital Transitional Pain Service: development and implementation of a multidisciplinary program to prevent chronic postsurgical pain. AB - Chronic postsurgical pain (CPSP), an often unanticipated result of necessary and even life-saving procedures, develops in 5-10% of patients one-year after major surgery. Substantial advances have been made in identifying patients at elevated risk of developing CPSP based on perioperative pain, opioid use, and negative affect, including depression, anxiety, pain catastrophizing, and posttraumatic stress disorder-like symptoms. The Transitional Pain Service (TPS) at Toronto General Hospital (TGH) is the first to comprehensively address the problem of CPSP at three stages: 1) preoperatively, 2) postoperatively in hospital, and 3) postoperatively in an outpatient setting for up to 6 months after surgery. Patients at high risk for CPSP are identified early and offered coordinated and comprehensive care by the multidisciplinary team consisting of pain physicians, advanced practice nurses, psychologists, and physiotherapists. Access to expert intervention through the Transitional Pain Service bypasses typically long wait times for surgical patients to be referred and seen in chronic pain clinics. This affords the opportunity to impact patients' pain trajectories, preventing the transition from acute to chronic pain, and reducing suffering, disability, and health care costs. In this report, we describe the workings of the Transitional Pain Service at Toronto General Hospital, including the clinical algorithm used to identify patients, and clinical services offered to patients as they transition through the stages of surgical recovery. We describe the role of the psychological treatment, which draws on innovations in Acceptance and Commitment Therapy that allow for brief and effective behavioral interventions to be applied transdiagnostically and preventatively. Finally, we describe our vision for future growth. PMID- 26508887 TI - Correction to "Molecular and Physiological Factors of Neuroprotection in Hypoxia tolerant Models: Pharmacological Clues for the Treatment of Stroke". AB - [This corrects the article on p. 1 in vol. 9, PMID: 25780340.]. PMID- 26508888 TI - Tuberculosis case finding in first-degree relative contacts not living with index tuberculosis cases in Kampala, Uganda. AB - PURPOSE: To assess the prevalence of pulmonary tuberculosis among first-degree relative (FDR) contacts not living with tuberculosis (TB) cases. METHODS: A cross sectional analysis of household contacts living with an index TB case and FDR contacts living outside of households in Kampala, Uganda, is presented. RESULTS: A total of 177 contacts (52 FDRs and 125 index household contacts) of 31 TB cases were examined. Compared with index household contacts, FDR contacts were older, more likely to be TB symptomatic (50% vs 33%), had a higher percentage of abnormal chest X-rays (19% vs 11%), sputum smear positive (15% vs 5%), and many similar epidemiologic risk factors, including HIV infection (13% vs 10%). Contact groups had similar pulmonary tuberculosis prevalence: 9.6% in FDR vs 10.4% in index household contacts and similar Mycobacterium tuberculosis infection: 62% in FDR vs 61% in index households. CONCLUSION: TB is common among FDR contacts. High TB prevalence justifies targeting FDRs during household contact investigations. Combining TB active-case finding among FDR contacts with household contact investigation in low-income setting is feasible. This should be part of national TB control program strategies for increasing TB case-detection rates and reducing community TB transmission and death. PMID- 26508889 TI - Preexposure prophylaxis-related stigma: strategies to improve uptake and adherence - a narrative review. AB - Despite high levels of efficacy, the implementation of preexposure prophylaxis (PrEP) as a strategy to prevent new HIV infection has been slow. Studies show that PrEP works so long as it is taken, making adherence one of the great challenges of effective PrEP implementation alongside issues of access and uptake. Given that effective PrEP use requires ongoing self-administration of pills by people at high risk of HIV acquisition, it is a strategy best understood not as simply biomedical, but as biobehavioral or biopsychosocial, meaning that that social, psychological, cultural, and structural factors all contribute to the success or failure of the intervention. The willingness of people at risk of HIV to take up and adhere to PrEP depends greatly upon social understandings - whether it is seen as effective, as a healthy option, and a socially acceptable strategy for preventing HIV. Stigma - unfavorable associations - can negatively influence the implementation of PrEP. Because it is associated with high-risk sexual activity, PrEP risks multiple stigmas that can differ according to specific cultural conditions. This includes the stigma of being related to HIV (which may also relate to other stigmas, such as homosexuality, sex work, and/or drug use) and the stigma of PrEP being an alternative to condoms (as condom use is associated with responsible sexual activity). PrEP-related stigma has emerged as a significant social harm that can arise from PrEP research participation, reported by trial participants from a range of different trial sites, different trial populations, and spanning different continents. Social marketing needs to redress PrEP-related stigmas through health promotion campaigns aimed at clinicians, HIV-affected communities, and people at high risk of HIV who might benefit from PrEP access. PrEP access needs to be reframed as a positive and responsible option to help people remain HIV-negative. PMID- 26508890 TI - Update on denosumab in the management of postmenopausal osteoporosis: patient preference and adherence. AB - Patient adherence to many osteoporosis treatments, primarily bisphosphonates, is generally poor, thus leading to a significant reduction in antifracture efficacy. Patient perceptions about the necessity of the prescribed medication to treat osteoporosis and the concerns about the potential adverse effects are important and potentially modifiable determinants of adherence, in addition to other factors, such as difficult dosing regimens and high dosing frequency. Denosumab (Dmab) is a fully human monoclonal antibody against the receptor activator of nuclear factor-kappaB ligand (RANKL), which, through the prevention of the RANKL/RANK interaction, inhibits osteoclast-mediated bone resorption and significantly reduces the risk of vertebral, nonvertebral, and hip fractures. It is administered subcutaneously every 6 months for the treatment of postmenopausal osteoporosis. Preference and adherence to Dmab treatment were assessed in various clinical trials. Although with some limitations, available data suggest that Dmab is preferred to bisphosphonates, produces greater satisfaction than bisphosphonates, and would be preferentially chosen for long-term treatment. Moreover, patient perceptions about the necessity of Dmab treatment clearly outweigh the concerns about the injections, and positive beliefs about treatment positively influence medication-taking behavior. According to these data, Dmab may represent a reasonable alternative to bisphosphonates, particularly for osteoporotic women in whom a suboptimal or even poor adherence to oral treatments is expected. PMID- 26508891 TI - Case report of atypical hemolytic uremic syndrome with retinal arterial and venous occlusion treated with eculizumab. AB - Atypical hemolytic uremic syndrome (aHUS) is a rare disease caused by chronic, uncontrolled activation of the alternative complement pathway, leading to thrombotic microangiopathy. Renal impairment and progression to end-stage renal disease are common in untreated patients with aHUS, and extrarenal manifestations are being increasingly characterized in the literature. Ocular involvement remains rare in aHUS. This report describes a patient with aHUS with bilateral central retinal artery and vein occlusion, vitreous hemorrhage, and blindness in addition to renal impairment. The patient's hematologic and renal parameters and ocular manifestation improved following initiation of eculizumab therapy. PMID- 26508892 TI - Urinary retention and acute kidney injury in a tetraplegic patient using condom catheter after partying: a preventable complication. AB - BACKGROUND: Spinal cord injury patients, who manage their bladder using a condom catheter, are at risk of developing urine retention when they consume large volumes of alcoholic drinks within a short period of time. CASE PRESENTATION: A male tetraplegic patient had been managing satisfactorily penile sheath drainage for 8 years. He went out socializing during which he consumed large volumes of alcohol but did not take any recreational drugs. The following morning, he noticed distension of the lower abdomen and passed urine in dribbles. He then developed a temperature and became unwell. He was seen by district nurses and a doctor, who prescribed antibiotics. He continued to feel unwell. After 8 days, he referred himself to a spinal unit at Regional Spinal Injuries Centre, Southport. The blood test results showed the following: blood urea: 19.8 mmol/L; creatinine: 172 MUmol/L; and C-reactive protein: 336.4 mg/L. Urethral catheterization led to immediate drainage of 1,400 mL of urine. A computed tomography scan revealed an enlarged, swollen left kidney, indicating acute bacterial nephritis. He was prescribed intravenous fluids and Meropenem. Creatinine decreased to 46 MUmol/L. CONCLUSION: Spinal cord injury patients using condom catheters should be made aware of the risk of urine retention when they consume large amounts of alcoholic drinks in a short period of time. Patients and caregivers should be informed to consider intermittent catheterizations for 24-48 hours or insert indwelling urethral catheter when planning for an evening out. PMID- 26508893 TI - Management of a thyroid "incidentaloma" in a patient with cancer: a case report. AB - The routine use of (18)F-fluorodeoxyglucose-positron emission tomography (PET)/computed tomography scans for staging and assessment of treatment response for cancer has resulted in a large number of thyroid abnormalities being detected as incidental findings ("incidentalomas"). Since most PET/CT scans are performed in the setting of a known nonthyroid malignancy, the need for "incidentalomas" to be further investigated and managed depends on the stage, prognosis, and current treatment plan for the known malignancy. We present a case describing the management of an incidental F-fluorodeoxyglucose-avid thyroid nodule detected in a patient with known metastatic colorectal cancer. On the basis of this case, we discuss the management of incidental PET-detected thyroid nodules in patients with metastatic cancer. Thyroid "incidentalomas" must be seen in the context of the prognosis and treatment plan for the known malignancy. PMID- 26508894 TI - Psychosocial support and parents' social life determine the self-esteem of orphan children. AB - Parental death affects the life of children in many ways, one of which is self esteem problems. Providing psychosocial support and equipping orphans play a vital role in their lifes. A cross-sectional study was conducted on 7-18-year-old orphans at 17 local districts of Gamo Gofa Zone, Southern Regional State of Ethiopia. From a total of 48,270 orphans in these areas, 4,368 were selected using stratified simple random sampling technique. Data were collected with a designed questionnaire based on the Rosenberg's rating scale to measure their self-esteem levels. Self-esteem with a score less than or equal to an average score was considered to be low self-esteem in the analysis. Binary logistic regression model was used to analyze the data using the SPSS software. The results of the study revealed that the probability of orphans suffering from low self-esteem was 0.59. Several risk factors were found to be significant at the level of 5%. Psychosocial support (good guidance, counseling and treatment, physical protection and amount of love shared, financial and material support, and fellowship with other children), parents living together before death, strong relationship between parents before death, high average monthly income, voluntary support, and consideration from the society are some of the factors that decrease the risk of being low in self-esteem. There are many orphans with low self-esteem in the study areas. The factors negatively affecting the self-esteem of orphans include the lack of psychosocial support, poor social life of parents, and death of parents due to AIDS. Society and parents should be aware of the consequences of these factors which can influence their children's future self-esteem. PMID- 26508895 TI - Osteolysis Affecting the Jaws in Systemic Sclerosis: Clinical and Osseous Changes Based on a Case Presentation. AB - OBJECTIVES: The aim of the current paper is to present a case of systemic sclerosis of the jaws with all the characteristics and some extensive findings. METHODS: Systemic sclerosis is a connective tissue condition characterized by chronic inflammatory changes, presenting with a number of symptoms. The paper aims to present a case of systemic sclerosis that had some of the characteristics of the condition unilaterally. The features were prominent and well demarcated on the panoramic radiograph. RESULTS: The panoramic radiograph of the patient showed extensive condylar head resorption almost to the level of complete flattening. DISCUSSION: The rarity of the condition and the awareness the oral radiologist must have upon presentation of similar images is the main reason for the presentation of the case. The features the case presents are both characteristic and well demarcated. Finally, the authors try to alert the clinician, who should be mindful of the fact that sclerodermatous involvement of organ systems is so pleotropic, that it may include the oral cavity, which is not always thoroughly observed, and is often left unattended by medical practitioners. PMID- 26508896 TI - Case Studies in the Management of Metastatic Breast Cancer with Eribulin. AB - Outcomes for triple-negative or hormone-refractory metastatic breast cancer (MBC) are poor and treatment options are limited. Described herein are cases of two women who developed MBC following adjuvant chemotherapy and endocrine therapy for human epidermal growth factor receptor 2 (HER2)-negative ductal carcinoma. Both underwent treatment with fulvestrant, followed by paclitaxel and letrozole or nab paclitaxel. Following disease progression, both patients started single-agent eribulin mesylate (1.4 mg/m(2) on Days 1 and 8 of a 21-day cycle). The first patient is currently continuing on eribulin at full dose, despite interruption for hip surgery and the presence of grade 1 neuropathy in the hands and feet. The second patient had a partial response with eribulin, which was sustained for 4 months. She was able to tolerate the full dose of eribulin despite slight worsening of the neuropathy that was present at baseline. Eribulin may be a beneficial option for hormone-refractory MBC with extensive treatment experience. PMID- 26508897 TI - Predictive Risk Factors in the Treatment of Gestational Diabetes Mellitus. AB - OBJECTIVE: This study aims to investigate predictive risk factors in the treatment of gestational diabetes mellitus (GDM). PATIENTS AND METHODS: A total of 256 pregnant women who underwent 75 g oral glucose tolerance test (OGTT) during 24-28 weeks of pregnancy were included according to the World Health Organization criteria. Demographic characteristics of the patients, including age, parity, family history of diabetes, body weight before pregnancy, and body weight at the diagnosis of GDM, were recorded. Fasting insulin and hemoglobin A1c (HbA1c) values at the time of diagnosis were evaluated. The patients were divided into two groups: those requiring insulin treatment (insulin group, n = 89) and those receiving diet therapy (diet group, n = 167) during pregnancy according to the American Diabetes Association recommendations. RESULTS: A total of 34.76% of the pregnant women with GDM required insulin treatment. The mean age of these patients was significantly higher compared to the diet group (34.9 +/- 0.6 years vs. 31.9 +/- 0.6 years; P = 0.004). Body mass index before pregnancy was also significantly higher in the insulin group than that in the diet group (32 +/- 0.9 kg/m(2) vs. 29 +/- 0.7 kg/m(2); P = 0.004). Fasting blood glucose (FBG) during OGTT was 105.6 +/- 2.1 mg/dL and 96.7 +/- 1.1 mg/dL in the insulin group and diet group, respectively (P < 0.001). There was no significant difference in fasting plasma glucose during OGTT between the groups (P = 0.069), while plasma glucose at two hours was 161.1 +/- 6.8 mg/dL in the insulin group and 145.1 +/- 3.7 mg/dL in the diet group (P = 0.027). At the time of diagnosis, HbA1c values were significantly higher in the insulin group compared to the diet group (5.3 +/- 0.1 vs. 4.9 +/- 0.1; P = 0.001). There was no significant difference in FBG and homeostasis model assessment-insulin resistance values between the groups (P = 0.908, P = 0.073). CONCLUSION: Our study results suggest that age, family history of diabetes, body weight before pregnancy, FBG, and HbA1c values are predictors for the necessity of insulin treatment. PMID- 26508898 TI - The trend toward digital in medical education - playing devil's advocate. PMID- 26508899 TI - Do "trainee-centered ward rounds" help overcome barriers to learning and improve the learning satisfaction of junior doctors in the workplace? AB - Ward rounds are widely considered an underutilized resource with regard to medical education, and therefore, a project was undertaken to assess if the initiation of "trainee-centered ward rounds" would help improve the confidence, knowledge acquisition, and workplace satisfaction of junior doctors in the clinical environment. Data were collated from junior doctors, registrar grade doctors, and consultants working in the delivery suite at Luton and Dunstable University Hospital in Luton over a 4-week period in March-April 2013. A review of the relevant literature was also undertaken. This pilot study found that despite the reservations around time constraints held by both junior and senior clinicians alike, feedback following the intervention was largely positive. The junior doctors enjoyed having a defined role and responsibility during the ward round and felt they benefited from their senior colleagues' feedback. Both seniors and junior colleagues agreed that discussing learning objectives prior to commencing the round was beneficial and made the round more learner-orientated; this enabled maximal learner-focused outcomes to be addressed and met. The juniors were generally encouraged to participate more during the round and the consultants endeavored to narrate their decision-making, both were measures that led to greater satisfaction of both parties. This was in keeping with the concept of "Legitimate peripheral participation" as described by Lave and Wenger. Overall, trainee-centered ward rounds did appear to be effective in overcoming some of the traditional barriers to teaching in the ward environment, although further work to formalize and quantify these findings, as well as using greater sample sizes from different hospital departments and the inclusion of a control group, is needed. PMID- 26508900 TI - The Foundation Programme application: an alternative to the Situational Judgement Test. PMID- 26508901 TI - Age, Tumor Characteristics, and Treatment Regimen as Event Predictors in Ewing: A Children's Oncology Group Report. AB - Purpose. To associate baseline patient characteristics and relapse across consecutive COG studies. Methods. We analyzed risk factors for LESFT patients in three randomized COG trials. We evaluated age at enrollment, primary site, gender, tumor size, and treatment (as randomized). We estimated event-free survival (EFS, Kaplan-Meier) and compared risk across groups (log-rank test). Characteristics were assessed by proportional hazards regression with the characteristic of interest as the only component. Confidence intervals (CI) for RR were derived. Factors related to outcome at level 0.05 were included in a multivariate regression model. Results. Between 12/1988 and 8/2005, 1444 patients were enrolled and data current to 2001, 2004, or 2008 were used. Patients were with a median age of 12 years (0-45), 55% male and 88% Caucasian. The 5-year EFS was 68.3% +/- 1.3%. In univariate analysis age, treatment, and tumor location were identified for inclusion in the multivariate model, and all remained significant (p < 0.01). Since tumor size was not collected in the last study, the other two were reanalyzed. This model identified age, treatment, tumor location, and tumor size as significant predictors. Conclusion. Age > 18 years, pelvic tumor, size > 8 cms, and chemotherapy without ifosfamide/etoposide significantly predict worse outcome. AEWS0031 is NCT00006734, INT0091 and INT0054 designed before 1993 (unregistered). PMID- 26508902 TI - From Structure-Function Analyses to Protein Engineering for Practical Applications of DNA Ligase. AB - DNA ligases are indispensable in all living cells and ubiquitous in all organs. DNA ligases are broadly utilized in molecular biology research fields, such as genetic engineering and DNA sequencing technologies. Here we review the utilization of DNA ligases in a variety of in vitro gene manipulations, developed over the past several decades. During this period, fewer protein engineering attempts for DNA ligases have been made, as compared to those for DNA polymerases. We summarize the recent progress in the elucidation of the DNA ligation mechanisms obtained from the tertiary structures solved thus far, in each step of the ligation reaction scheme. We also present some examples of engineered DNA ligases, developed from the viewpoint of their three-dimensional structures. PMID- 26508903 TI - Effects of Vocabulary Size on Online Lexical Processing by Preschoolers. AB - This study was designed to investigate the relationship between vocabulary size and the speed and accuracy of lexical processing in preschoolers between the ages of 30-46 months using an automatic eye tracking task based on the looking-while listening paradigm (Fernald, Zangl, Portillo, & Marchman, 2008) and mispronunciation paradigm (White & Morgan, 2008). Children's eye gaze patterns were tracked while they looked at two pictures (one familiar object, one unfamiliar object) on a computer screen and simultaneously heard one of three kinds of auditory stimuli: correct pronunciations of the familiar object's name, one-feature mispronunciations of the familiar object's name, or a nonword. The results showed that children with larger expressive vocabularies, relative to children with smaller expressive vocabularies, were more likely to look to a familiar object upon hearing a correct pronunciation and to an unfamiliar object upon hearing a novel word. Results also showed that children with larger expressive vocabularies were more sensitive to mispronunciations; they were more likely to look toward the unfamiliar object rather than the familiar object upon hearing a one-feature mispronunciation of a familiar object-name. These results suggest that children with smaller vocabularies, relative to their larger vocabulary age peers, are at a disadvantage for learning new words, as well as for processing familiar words. PMID- 26508904 TI - Palatal Rugae Patterns in Edentulous Cases, Are They A Reliable Forensic Marker? AB - One of the main objectives of the forensic sciences is establishing a person's identity which can be a very complex process. The analysis of the teeth, fingerprints and DNA evaluation are probably the most used techniques allowing fast and secure identification processes. Palatal rugae or transverse palatine folds are asymmetrical and irregular elevations of the mucosa located in the anterior third of the palate and are permanent, prominent and unique for individuals and thus can be used as identification for forensic purposes widely in edentulous patients wherein no teeth are present in the oral cavity. In forensic odontology dentists play a prime role in supporting legal and criminal issues. Palatoscopy or palatal rugoscopy is the name given to the study of palatal rugae in order to ascertain a person's identity. Studies have demonstrated that no two individual rugae patterns are alike in their configuration and the characteristic rugae pattern of the palate does not change as a result of growth. Hence this article reviews the significance of palatal rugae patterns in edentulous cases as a reliable forensic marker. PMID- 26508905 TI - A Review on Biomaterials in Dental Implantology. AB - Implants have been gaining popularity amongst the patients and frequently are being considered as a first treatment option. Modern dentistry is beginning to understand, realize, and utilize the benefits of biotechnology in health care. Study of material sciences along with the biomechanical sciences provides optimization of design and material concepts for surgical implants. Biocompatibility is property of implant material to show favorable response in given biological environment. In attempt to replace a missing tooth many biomaterials have been evolved as implants for many years in an effort to create an optimal interaction between the body and the implanted material. With all the advancements and developments in the science and technology, the materials available for dental implants also improved. The choice of material for a particular implant application will generally be a compromise to meet many different required properties. There is, however, one aspect that is always of prime importance that how the tissue at the implant site responds to the biochemical disturbance that a foreign material presents. PMID- 26508906 TI - Lymphocyte Activation Markers in Pediatric Kidney Transplant Recipients. AB - BACKGROUND AND OBJECTIVES: The role of CD4+CD25+ T regulatory cells (Tregs) in immune tolerance in experimental transplantation is very important but the clinical significance of circulating Tregs in the peripheral blood is undetermined. We evaluated the association between the frequency of T cell activation markers CD25 and CD71 and clinical parameters that may affect the level of these T cell markers. METHODS: In 47peditric kidney transplant (KT) recipients and 20 healthy controls, the frequency of T cell activation markers, CD25 and CD71 was measured with flow cytometry after transplantation. Two clinical protocols of induction immunosuppression were used: (1) anti-thymocyte globulin (THYMO) group (n =29) and Basiliximab (BSX) group (n=10). RESULTS: The percentage of circulating CD25 after KT was significantly lower than that in the controls. There is no significant difference between KT and the controls s regard to circulating CD71. The percentage of CD25 was significantly increased in children with acute rejection compared with those without acute rejection. Calcineurin inhibitors (CNIs) decreased the frequency of CD25 but mammalian target rapamycin (mTOR) inhibitor did not. The proportion of CD25 significantly decreased in THYMO group during the first year after transplantation. CONCLUSION: The frequency of circulating T cell activation marker CD25 in pediatric KT recipients is strongly affected by CNIs, and a high frequency of CD25 is associated with acute rejection during the early posttransplant period. The measurement of T cell activation markers, may become a useful immune monitoring tool after kidney transplantation. PMID- 26508907 TI - Peruvian Maca (Lepidium peruvianum): (I) Phytochemical and Genetic Differences in Three Maca Phenotypes. AB - Glucosinolates were previously reported as physiologically-important constituents present in Peruvian Maca (Lepidium peruvianum Chacon) and linked to various therapeutic functions of differently-colored Peruvian Maca hypocotyls. In two separate Trials, three colours of Maca hypocotyls "Black", "Red" and "Yellow" (termed "Maca phenotypes"), were selected from mixed crops of Peruvian Maca for laboratory studies as fresh and after being dried. Individual Maca phenotypes were cultivated in the highlands of the Peruvian Andes at 4,200m a.s.l. (Junin and Ninacaca). Glucosinolate levels, chromatographic HPLC profiles and DNA variability in the investigated Maca phenotypes are presented. Genotypic profiles were determined by the ISSR-PCR and RAPD techniques. Compared to the Black and Red phenotypes, the Yellow phenotype contained much lower Glucosinolate levels measured against Glucotropaeolin and m-methoxy-glucotropaeolin standards, and exhibited different RAPD and ISSR-PCR reactions. The Red Maca phenotype showed the highest concentrations of Glucosinolates as compared to the Black and Yellow Maca. It appears that the traditional system used by natives of the Peruvian Andean highlands in preparing Maca as a vegetable dish (boiling dried Maca after soaking in water), to supplement their daily meals, is as effective as laboratory methods - for extracting Glucosinolates, which are considered to be one of the key bioactive constituents responsible for therapeutic functions of Peruvian Maca phenotypes. It is reasonable to assume that the HPLC and DNA techniques combined, or separately, may assist in determining ID and "Fingerprints" identifying individual Peruvian Maca phenotypes, hence confirming the authenticity of marketable Maca products. The above assumptions warrant further laboratory testing. PMID- 26508908 TI - Pattern of Otorhinolaryngological Admissions via Emergency Unit in a Suburban Tertiary Center. AB - BACKGROUND: Patients with ORL lesions sometimes present to the general emergency room. This study reviews the common ENT admissions via emergency room in a sub urban town in Nigeria. METHODS: A retrospective study spanning five years from January 2009 to December 2013. RESULTS: A total of 211 cases consisting of 131 (62.1%) males with male: female ratio 1.6: 1 and a mean age of 32.8 +/- 22.4 years. About a quarter of the patients were children, the peak age was 21-40 years (in 37%). The common indications for emergency otorhinolaryngological admissions were Epistaxis (16.1%), Nasal/facial trauma (14.7%), pharyngo esophageal foreign bodies (13.3%) and upper airway obstruction (8.1%). Majority 16 (57.1%) of the Pharyngo-esophageal FBs occurred in children. Most of the airway obstructions in children were due to juvenile recurrent respiratory papillomatosis while laryngeal cancer was the major cause among the adult. Sixty percent had surgical procedures, 86.7% had satisfactory outcome and mortalities were recorded in 1.4%. CONCLUSION: Majority of causes for ORL admissions via emergency unit are of pharyngo-esophageal origin. There is apparent reversal of the otological origin trend in ENT admissions via A&E unit. PMID- 26508909 TI - Detection of IgG against Toxocara in Sera of Employees of Meat Industry. AB - Contact with raw meat could represent a risk for Toxocara infection. We assessed the association of Toxocara infection with an occupation of meat worker though a case-control seroprevalence study of 124 meat workers and 248 subjects without this occupation. Sera of participants was analyzed for the presence of anti Toxocara IgG antibodies. One (0.8%) of the 124 meat workers, and 5 (2.0%) of the 248 controls were positive for anti-Toxocara IgG antibodies (OR=0.39; 95% CI: 0.04-3.41; P=0.66). The seropositive meat worker was a male aged 28 years old, without vision impairment. None of the work characteristics i.e. frequency of contact with raw meat, use of safety practices, history of splashes at face with blood or raw meat, and injuries with sharp material at work was associated with Toxocara exposure. Seroprevalence of Toxocara infection was significantly higher (P=0.04) in meat workers with consumption of boar meat (1/6: 16.7%) than in those without this consumption (0/117: 0%). We conclude that meat workers do not have a higher risk for Toxocara infection than subjects without this occupation do. The 2% seroprevalence of Toxocara infection found in control subjects might suggest a low seroprevalence of this infection among people with other occupations in Durango City. However, additional case-control studies with larger sample sizes to confirm our results are needed. PMID- 26508910 TI - The Role of Spirituality in the Lives of Mothers of Breast Cancer Survivors. AB - Breast cancer impacts an entire family system. A cancer diagnosis embeds the patient/survivor and their loved ones in the illness process. The mothers of breast cancer patients are likely impacted in a variety of ways by their daughters' diagnoses. To date, few researchers have investigated the experiences and perspectives of this population. In the present study, authors explored how mothers of breast cancer survivors managed adversities associated with this disease and illness. Using secondary data and narrative analysis, investigators analyzed data gathered from 30 mothers. Findings indicate that participants relied on their spirituality for the management of stress and hardship related to having a loved one with breast cancer. This research has implications for family health and well-being. PMID- 26508911 TI - An Opinion Interactive Model Based on Individual Persuasiveness. AB - In order to study the formation process of group opinion in real life, we put forward a new opinion interactive model based on Deffuant model and its improved models in this paper because current models of opinion dynamics lack considering individual persuasiveness. Our model has following advantages: firstly persuasiveness is added to individual's attributes reflecting the importance of persuasiveness, which means that all the individuals are different from others; secondly probability is introduced in the course of interaction which simulates the uncertainty of interaction. In Monte Carlo simulation experiments, sensitivity analysis including the influence of randomness, initial persuasiveness distribution, and number of individuals is studied at first; what comes next is that the range of common opinion based on the initial persuasiveness distribution can be predicted. Simulation experiment results show that when the initial values of agents are fixed, no matter how many times independently replicated experiments, the common opinion will converge at a certain point; however the number of iterations will not always be the same; the range of common opinion can be predicted when initial distribution of opinion and persuasiveness are given. As a result, this model can reflect and interpret some phenomena of opinion interaction in realistic society. PMID- 26508912 TI - Leprosy Reaction in Thai Population: A 20-Year Retrospective Study. AB - Background. Leprosy is a chronic infectious disease that presents with varying dermatological and neurological symptoms. The leprosy reactions occur over the chronic course of the disease and lead to extensive disability and morbidity. Objective. To analyze and identify the risk factors which contribute to leprosy reactions. Methods. In a retrospective study, we reviewed the medical records of leprosy patients registered at the leprosy clinic, Ramathibodi Hospital, Thailand, between March 1995 and April 2015. One hundred and eight patients were included; descriptive analysis was used for baseline characteristics and a binary logistic regression model was applied for identifying risk factors correlated with leprosy reactions. Results. Of the 108 cases analyzed, 51 were male and 57 were female. The mean age of presentation was 45 years. The borderline tuberculoid type was the most common clinical form. Leprosy reactions were documented in 61 cases (56.5%). The average time to reaction was 8.9 months. From multivariate analysis, risk factors for leprosy reactions were being female, positive bacillary index status, and MB treatment regimen. Conclusions. Leprosy reactions are common complications in leprosy patients. Being female, positive bacillary index status, and multibacillary treatment regimen are significantly associated with the reactions. Early detection in cases with risk factors followed by appropriate treatment could prevent the morbidity of leprosy patients. PMID- 26508913 TI - Recurrent Thrombotic Events after Discontinuation of Vitamin K Antagonist Treatment for Splanchnic Vein Thrombosis: A Multicenter Retrospective Cohort Study. AB - It is generally recommended that patients with splanchnic vein thrombosis (SVT) should receive a minimum of 3 months of anticoagulant treatment. However, little information is available on the long-term risk of recurrent thrombotic events. The aim of this study was to evaluate the risk of venous and arterial thrombosis after discontinuation of vitamin K antagonist (VKA) in SVT patients. Retrospective information from a cohort of SVT patients treated with VKA and followed by 37 Italian Anticoagulation Clinics, up to June 2013, was collected. Only patients who discontinued VKA and did not receive any other anticoagulant drug were enrolled in this study. Thrombotic events during follow-up were centrally adjudicated. Ninety patients were included: 33 unprovoked SVT, 27 SVT secondary to transient risk factors, and 30 with permanent risk factors. During a median follow-up of 1.6 years, 6 venous and 1 arterial thrombosis were documented, for an incidence of 3.3/100 patient-years (pt-y). The recurrence rate was highest in the first year after VKA discontinuation (8.2/100'pt-y) and in patients with permanent risk factors (10.2/100'pt-y). Liver cirrhosis significantly increased the risk of recurrence. In conclusion, the rate of recurrent vascular complications after SVT is not negligible, at least in some patient subgroups. PMID- 26508914 TI - Atypical Presentation of Disseminated Zoster in a Patient with Rheumatoid Arthritis. AB - Patients with rheumatoid arthritis (RA) have 2-fold increased risk of herpes zoster. In literature, limited information exists about disseminated cutaneous zoster in RA patients. An 83-year-old African-American female with RA presented with generalized and widespread vesicular rash covering her entire body. Comorbidities include hypertension, type II diabetes, and dyslipidemia. Patient was on methotrexate 12.5 mg and was not receiving any corticosteroids, anti-TNF therapy, or other biological agents. The patient was afebrile (98 F) with no SIRS criteria. Multiple vesicular lesions were present covering patient's entire body including face. Lesions were in different stages, some umbilicated with diameter of 2-7 cm. Many lesions have a rim of erythema with no discharge. On admission, patient was also pancytopenic with leukocyte count of 1.70 k/mm(3). Biopsies of lesions were performed, which were positive for Varicella antigen. Subsequently, patient was started on Acyclovir. The patient's clinical status improved and rash resolved. Our patient presented with "atypical" clinical picture of disseminated cutaneous zoster with no obvious dermatome involvement. Disseminated zoster is a potentially serious infection that can have an atypical presentation in patients with immunocompromised status. High index of suspicion is needed to make the diagnosis promptly and to initiate therapy to decrease mortality and morbidity. PMID- 26508915 TI - Bacteriological and physical quality of locally packaged drinking water in Kampala, Uganda. AB - OBJECTIVE: To assess the bacteriological and physical quality of locally packaged drinking water sold for public consumption. METHODS: This was cross-sectional study where a total of 60 samples of bottled water from 10 brands and 30 samples of sachet water from 15 brands purchased randomly were analyzed for bacteriological contamination (total coliform and faecal coliform per 100 mL) using membrane filtrate method and reported in terms of cfu/100 mL. RESULTS: Both bottled water and sachet water were not contaminated with faecal coliform. Majority (70%, 21/30) of the sachet water analyzed exceeded acceptable limits of 0 total coliforms per 100 mL set by WHO and the national drinking water standards. The physical quality (turbidity and pH) of all the packaged water brands analyzed was within the acceptable limits. There was statistically significant difference between the median count of total coliform in both sachet water and bottled water brands (U(24) = 37.0, p = 0.027). CONCLUSION: Both bottled water and sachet water were not contaminated with faecal coliforms; majority of sachet water was contaminated with total coliform above acceptable limits. Government and other stakeholders should consider intensifying surveillance activities and enforcing strict hygienic measures in this rapidly expanding industry to improve packaged water quality. PMID- 26508916 TI - Factors Associated with Health-Related Quality of Life in Tuberculosis Patients Referred to the National Research Institute of Tuberculosis and Lung Disease in Tehran. AB - BACKGROUND: In tuberculosis (TB) patients, health-related quality of life (HRQoL) is significant in self-management, which in turn can be effective in therapeutic acceptance and prevention of treatment failure due to multi-drug resistant TB. This study was conducted to evaluate HRQoL and associated factors in TB patients referred to the National Research Institute of Tuberculosis and Lung Disease (NRITLD). METHODS: In this study, patients were selected from TB clinics of the NRITLD in Tehran. In addition to an Iranian version of the Short-Form Health Survey (SF-36), demographic and disease characteristic questionnaires were used for data collection. The data were then analyzed using SPSS software. RESULTS: Two hundred five TB patients, with the average age of 42.33+/-17.64 years, participated in this study. The HRQoL scores in different domains ranged from 14.68+/-11.60 for role limitations due to emotional problems to 46.99+/-13.25 for general health perceptions. The variables of sex, marital status, education, job status, place of residence, and cigarette smoking, influenced the HRQoL scores in different dimensions. CONCLUSION: According to the study findings are the important variables that influenced the HRQoL of TB patients. The consideration of its can improve the HRQoL of TB patients. PMID- 26508917 TI - The Prognostic Value of the Tumor Shrinkage Rate for Progression-Free Survival in Patients with Non-Small Cell Lung Cancer Receiving Gefitinib. AB - BACKGROUND: The efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy can be measured based on the rate of treatment response, based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria or progression-free survival (PFS). However, there are some patients harboring sensitive EGFR mutations who responded poorly to EGFR-TKI therapy. In addition, there is variability in the PFS after EGFR-TKI treatment. METHODS: We performed a retrospective analysis of the medical records of 85 patients with non small cell lung cancer, who had achieved a stable disease or better response at the first evaluation of treatment response, after receiving a 2-month course of gefitinib. We calculated the tumor shrinkage rate (TSR) by measuring the longest and perpendicular diameter of the main mass on computed tomography before, and 2 months after, gefitinib therapy. RESULTS: There was a significant positive correlation between the TSR and PFS (R=0.373, p=0.010). In addition, a simple linear regression analysis showed that the TSR might be an indicator for the PFS (B+/-standard error, 244.54+/-66.79; p=0.001). On univariate analysis, the sex, histologic type, smoking history and the number of prior chemotherapy regimens, were significant prognostic factors. On multivariate regression analysis, both the TSR (beta=0.257, p=0.029) and adenocarcinoma (beta=0.323, p=0.005) were independent prognostic factors for PFS. CONCLUSION: Our results showed that the TSR might be an early prognostic indicator for PFS in patients receiving EGFR-TKI therapy. PMID- 26508918 TI - Effect of a Dose-Escalation Regimen for Improving Adherence to Roflumilast in Patients with Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: The adverse effects of the phosphodiesterase-4 inhibitor roflumilast, appear to be more frequent in clinical practice than what was observed in chronic obstructive pulmonary disease (COPD) clinical trials. Thus, we designed this study to determine whether adverse effects could be reduced by starting roflumilast at half the dose, and then increasing a few weeks later to 500 ug daily. METHODS: We retrospectively investigated 85 patients with COPD who had taken either 500 ug roflumilast, or a starting dose of 250 ug and then increased to 500 ug. We analyzed all adverse events and assessed differences between patients who continued taking the drug after dose escalation and those who had stopped. RESULTS: Adverse events were reported by 22 of the 85 patients (25.9%). The most common adverse event was diarrhea (10.6%). Of the 52 patients who had increased from a starting dose of 250 ug roflumilast to 500 ug, 43 (82.7%) successfully maintained the 500 ug roflumilast dose. No difference in factors likely to affect the risk of adverse effects, was detected between the dose escalated and the discontinued groups. Of the 26 patients who started with the 500 ug roflumilast regimen, seven (26.9%) discontinued because of adverse effects. There was no statistically significant difference in discontinuation rate between the dose-escalated and the control groups (p=0.22). CONCLUSION: Escalating the roflumilast dose may reduce treatment-related adverse effects and improve tolerance to the full dose. This study suggests that the dose-escalated regimen reduced the rate of discontinuation. However, longer-term and larger scale studies are needed to support the full benefit of a dose escalation strategy. PMID- 26508919 TI - The Influence of Asian Dust, Haze, Mist, and Fog on Hospital Visits for Airway Diseases. AB - BACKGROUND: Asian dust is known to have harmful effects on the respiratory system. Respiratory conditions are also influenced by environmental conditions regardless of the presence of pollutants. The same pollutant can have different effects on the airway when the air is dry compared with when it is humid. We investigated hospital visits for chronic obstructive pulmonary disease (COPD) and asthma in relation to the environmental conditions. METHODS: We conducted a retrospective study using the Korean National Health Insurance Service claims database of patients who visited hospitals in Chuncheon between January 2006 and April 2012. Asian dust, haze, mist, and fog days were determined using reports from the Korea Meteorological Administration. Hospital visits for asthma or COPD on the index days were compared with the comparison days. We used two-way case crossover techniques with one to two matching. RESULTS: The mean hospital visits for asthma and COPD were 59.37 +/- 34.01 and 10.04 +/- 6.18 per day, respectively. Hospital visits for asthma significantly increased at lag0 and lag1 for Asian dust (relative risk [RR], 1.10; 95% confidence interval [CI], 1.01 1.19; p<0.05) and haze (RR, 1.13; 95% CI, 1.06-1.22; p<0.05), but were significantly lower on misty (RR, 0.89; 95% CI, 0.80-0.99; p<0.05) and foggy (RR, 0.89; 95% CI, 0.84-0.93; p<0.05) days than on control days. The hospital visits for COPD also significantly increased on days with Asian dust (RR, 1.29; 95% CI, 1.05-1.59; p<0.05), and were significantly lower at lag4 for foggy days, compared with days without fog (RR, 0.85; 95% CI, 0.75-0.97; p<0.05). CONCLUSION: Asian dust showed an association with airway diseases and had effects for several days after the exposure. In contrast to Asian dust, mist and fog, which occur in humid air conditions, showed the opposite effects on airway diseases, after adjusting to the pollutants. It would require more research to investigate the effects of various air conditions on airway diseases. PMID- 26508920 TI - Unplanned Extubation in Patients with Mechanical Ventilation: Experience in the Medical Intensive Care Unit of a Single Tertiary Hospital. AB - BACKGROUND: Potentially harmful unplanned extubation (UE) may occur in patients on mechanical ventilation (MV) in an intensive care unit (ICU) setting. This study aimed to evaluate the clinical characteristics of UE and its impact on clinical outcomes in patients with MV in a medical ICU (MICU). METHODS: We retrospectively evaluated MICU data prospectively collected between December 2011 and May 2014. RESULTS: A total of 468 patients were admitted to the MICU, of whom 450 were on MV. Of the patients on MV, 30 (6.7%) experienced UE; 13 (43.3%) required reintubation after UE, whereas 17 (56.7%) did not require reintubation. Patients who required reintubation had a significantly longer MV duration and ICU stay than did those not requiring reintubation (19.4+/-15.1 days vs. 5.9+/-5.9 days days and 18.1+/-14.2 days vs. 7.1+/-6.5 days, respectively; p<0.05). In addition, mortality rate was significantly higher among patients requiring reintubation than among those not requiring reintubation (54.5% vs. 5.9%; p=0.007). These two groups of patients exhibited no significant differences, within 2 hours after UE, in the fraction of inspired oxygen, blood pressure, heart rate, respiratory rate, and pH. CONCLUSION: Although reintubation may not always be required in patients with UE, it is associated with a poor outcome after UE. PMID- 26508921 TI - Predictors of Recurrence after Curative Resection in Patients with Early-Stage Non-Small Cell Lung Cancer. AB - BACKGROUND: There have been various results from studies concerning the predictors of recurrence in early-stage nonsmall cell lung cancer (NSCLC). Therefore, an accurate assessment is needed to guide effective adjuvant therapy. We investigated the predictors of a recurrence in patients with resected, early stage NSCLC and the risk factors associated with locoregional or distant recurrence. METHODS: This retrospective study was conducted on patients at the Pusan National University Hospital from January 2006 to December 2011. Patients with pathological stages I or II were included in this study, as based on the seventh edition TNM staging system. Multivariate Cox proportional hazard models were used to identify factors associated with recurrence. RESULTS: Two hundred and forty-nine patients were included. Among them, 180 patients were stage I, and 69 were stage II. Overall, by multivariate analysis, the independent factors associated with a 5-year total recurrence were the presence of visceral pleural invasion (VPI) (p=0.018) and maximal standardized uptake values (SUVs) of tumors on positron emission tomography (PET) >4.5 (p=0.037). The VPI was the only independent risk factor associated with both locoregional and distant recurrence, in the analysis of the patterns of tumor recurrence and their risk factors. In the subgroup analysis of stage I patients, three variables (male, VPI and resection margin positive) were significantly associated with a 5-year recurrence. CONCLUSION: The independent factors associated with postoperative recurrence in early-stage NSCLC were as follows: PET SUV >4.5 and the presence of VPI. For patients with those factors adjuvant therapy should be recommended as a more efficacious treatment. PMID- 26508922 TI - The Prevalence Rate of Tuberculin Skin Test Positive by Contacts Group to Predict the Development of Active Tuberculosis After School Outbreaks. AB - BACKGROUND: The tuberculin skin test (TST) is the standard tool to diagnose latent tuberculosis infection (LTBI) in mass screening. The aim of this study is to find an optimal cut-off point of the TST+ rate within tuberculosis (TB) contacts to predict the active TB development among adolescents in school TB outbreaks. METHODS: The Korean National Health Insurance Review and Assessment database was used to identify active TB development in relation to the initial TST (cut-off, 10 mm). The 7,475 contacts in 89 schools were divided into two groups: Incident TB group (43 schools) and no incident TB group (46 schools). LTBI treatment was initiated in 607 of the 1,761 TST+ contacts. The association with active TB progression was examined at different cut-off points of the TST+ rate. RESULTS: The mean duration of follow-up was 3.9+/-0.9 years. Thirty-three contacts developed active TB during the 4,504 person-years among the TST+ contacts without LTBI treatment (n=1,154). The average TST+ rate for the incident TB group (n=43) and no incident TB group (n=46) were 31.0% and 15.5%, respectively. The TST+ rate per group was related with TB progression (odds ratio [OR], 1.025; 95% confidence interval [CI], 1.001-1.050; p=0.037). Based on the TST+ rate per group, active TB was best predicted at TST+ >= 16% (OR, 3.11; 95% CI, 1.29-7.51; area under curve, 0.64). CONCLUSION: Sixteen percent of the TST+ rate per group within the same grade students can be suggested as an optimal cut off to predict active TB development in middle and high schools TB outbreaks. PMID- 26508923 TI - A Case of Pulmonary Mycobacterium kansasii Disease Complicated with Tension Pneumothorax. AB - Pneumothorax is an extremely rare complication of non-tuberculous mycobacterial infection. A 52-year-old man presenting with difficulty breathing and chest pain was admitted to our hospital. A right-sided pneumothorax was observed on chest radiography and chest computed tomography showed multiple cavitating and non cavitating nodules with consolidation in the upper to middle lung zones bilaterally. Serial sputum cultures were positive for Mycobacterium kansasii, and he was diagnosed with pulmonary M. kansasii disease complicated by tension pneumothorax. After initiation of treatment including decortications and pleurodesis, the patient made a full recovery. We herein describe this patient's course in detail and review the current relevant literature. PMID- 26508924 TI - Spontaneous Pneumomediastinum: An Unusual Pulmonary Complication in Anorexia Nervosa. AB - Spontaneous pneumomediastinum (PM) is an uncommon condition in which free air enters the mediastinum. This usually occurs either through esophageal tears after vigorous vomiting, or after alveolar rupture subsequent to a rapid increase in intra-alveolar pressure. Spontaneous PM is a rare entity in anorexia nervosa (AN) and self-induced vomiting is often the cause of PM in patients with AN. We experienced a case of spontaneous PM in an anorexic adolescent, in whom vomiting was not the cause of PM. PMID- 26508925 TI - Spontaneous Pulmonary Hematoma with No Underlying Causes: A Case Report. AB - A 57-year-old male patient was admitted to our center because of a cystic mass on the lower portion of the right major fissure that was found incidentally by chest X-ray. He did not have a history of trauma or anticoagulant use. The lesion was removed by video-assisted thoracoscopic surgery. Pathological examination revealed an organizing pulmonary hematoma without any complications, and a follow up chest X-ray after 1 year showed no recurrence. PMID- 26508926 TI - A Case of Severe Pseudomembranous Tracheobronchitis Complicated by Co-infection of Influenza A (H1N1) and Staphylococcus aureus in an Immunocompetent Patient. AB - Although influenza A (H1N1) virus leads to self-limiting illness, co-infection with bacteria may result in cases of severe respiratory failure due to inflammation and necrosis of intra-airway, as pseudomembranous tracheobronchitis. Pseudomembranous tracheobronchitis is usually developed in immunocompromised patients, but it can also occur in immunocompetent patients on a very rare basis. We report a case of pseudomembranous tracheobronchitis complicated by co infection of inflenaza A and Staphylococcus aureus, causing acute respiratory failure in immunocompetent patients. PMID- 26508927 TI - Pulmonary Pneumatocele in a Pneumonia Patient Infected with Extended-Spectrum beta-Lactamase Producing Proteus mirabilis. AB - Pulmonary pneumatoceles are air-filled thin-walled spaces within the lung and are rare in adult cases of pneumonia. We report the case of a 74-year-old male who was admitted with a cough and sputum production. He had been treated with oral dexamethasone since a brain tumorectomy 6 months prior. Contrast-enhanced computed tomography (CT) of the chest revealed a large pneumatocele in the right middle lobe and peripheral pneumonic consolidation. Bronchoalveolar lavage was performed; cultures identified extended-spectrum beta-lactamase (ESBL) producing Proteus mirabilis. A 4-week course of intravenous ertapenem was administered, and the pneumatocele with pneumonia resolved on follow-up chest CT. To the best of our knowledge, this is the first reported case of pulmonary pneumatocele caused by ESBL-producing P. mirabilis associated with pneumonia. PMID- 26508928 TI - A 45-Year-Old Man With Recurrent Dyspnea and Hemoptysis during Exercise: Exercise Induced Pulmonary Hemorrhage/Edema. AB - A 45-year-old man presented with dyspnea and hemoptysis during exercise. A chest computed tomography (CT) revealed multifocal diffuse patchy ground glass opacity and interlobular septal thickening in both the lungs. Permeability pulmonary edema or pulmonary hemorrhage was suspected. Serologic studies for autoimmune disorders and vasculitis were negative. There was no laboratory evidence of coagulopathy, other hematopoietic disease or infectious disease. Considering correlation with exercise, we diagnosed exercise-induced pulmonary hemorrhage (EIPH) or exercise-induced pulmonary edema (EIPE). The patient was managed with antifibrinolytics, antibiotics, and antitussive agent. After a week, follow-up chest CT revealed completely resolved pulmonary hemorrhage. About 2 months after the first event, he visited again with dyspnea and hemoptysis during running. In the present study, we report a case of recurrent pulmonary hemorrhage after exercise. PMID- 26508929 TI - Aberrant Bronchial Artery to Non-Sequestrated Left Upper Lobe in Massive Hemoptysis. AB - Systemic arterial supply from the descending thoracic aorta to the basal segment of the left lower lobe without a pulmonary arterial supply is a rare congenital anomaly within the spectrum of sequestration lung disease. The most common pattern of anomalous systemic artery to the lung arises from the descending thoracic aorta and feeds the basal segments of the left lower lobe. We report an extremely rare case of a 29-year-old woman who underwent a successful left upper lobectomy for the treatment of recurrent massive hemoptysis from anomalous bronchial arterial supply to the lingular segment of left upper lobe. PMID- 26508930 TI - Single Nodular Pulmonary Amyloidosis: Case Report. AB - Amyloidosis is defined as the presence of extra-cellular deposits of an insoluble fibrillar protein, amyloid. The pulmonary involvement of amyloidosis is usually classified as tracheobronchial, parenchymal nodular, or diffuse alveolar septal. A single nodular lesion can mimic various conditions, including malignancy, pulmonary tuberculosis, and fungal infection. To date, only one case of nodular pulmonary amyloidosis has been reported in Korea, a case involving multiple nodular lesions. Here, we report and discuss the case of a patient having single nodular amyloidosis. PMID- 26508931 TI - Endobronchial ALK-Positive Anaplastic Large Cell Lymphoma Presenting Massive Hemoptysis. AB - Primary anaplastic large cell lymphoma (ALCL) of the lung is highly aggressive and quite rare. We report here a case of anaplastic lymphoma kinase-positive endobronchial ALCL, that was initially thought to be primary lung cancer. A 68 year-old woman presented with hemoptysis, dyspnea, and upper respiratory symptoms persisting since 1 month. The hemoptysis and and bronchial obstruction lead to respiratory failure, prompting emergency radiotherapy and steroid treatment based on the probable diagnosis of lung cancer, although a biopsy did not confirm malignancy. Following treatment, her symptoms resolved completely. Chest computed tomography scan performed 8 months later showed increased and enlarged intra abdominal lymph nodes, suggesting lymphoma. At that time, a lymph node biopsy was recommended, but the patient refused and was lost to follow up. Sixteen months later, the patient revisited the emergency department, complaining of persistent abdominal pain since several months. A laparoscopic intra-abdominal lymph node biopsy confirmed a diagnosis of ALCL. PMID- 26508932 TI - A Case of Extensive IgG4-Related Disease Presenting as Massive Pleural Effusion, Mediastinal Mass, and Mesenteric Lymphadenopathy in a 16-Year-Old Male. AB - IgG4-related disease is an immune-mediated fibro-inflammatory disease, characterized by lymphoplasmacytic infiltration composed of IgG4-positive plasma cells of various organs with elevated circulating levels of IgG4. This disease is now reported with increasing frequency and usually affects middle-aged men. Massive pleural effusion in children is an uncommon feature in IgG4-related disease. Here, we report a case of a 16-year-old male patient with extensive IgG4 related disease presenting with massive pleural effusion, mediastinal mass, and mesenteric lymphadenopathy. PMID- 26508933 TI - Different Responses to Clarithromycin in Patients with Cryptogenic Organizing Pneumonia. AB - Cryptogenic organizing pneumonia (COP) is an idiopathic interstitial pneumonia characterized by a subacute course and favorable prognosis with corticosteroids. However, some patients show resistance to steroids. Macrolides have been used with success in those patients showing resistance to steroids. A few reports showed treatment failure with macrolides in patients with COP who were resistant to steroids. In this report, we described two cases of COP who showed different responses to clarithromycin. One recovered completely, but the other gradually showed lung fibrosis with clarithromycin. PMID- 26508934 TI - Successful Treatment of a Large Pulmonary Arteriovenous Malformation by Repeated Coil Embolization. AB - Pulmonary arteriovenous malformations (AVMs) are caused by abnormal vascular communications between the pulmonary arteries and pulmonary veins, which lead to the blood bypassing the normal pulmonary capillary beds. Pulmonary AVMs result in right-to-left shunts, resulting in hypoxemia, cyanosis, and dyspnea. Clinical signs and symptoms vary depending on the size, number, and flow of the AVMs. Transcatheter embolization is the treatment of choice for pulmonary AVMs. However, this method can fail if the AVM is large or has multiple complex feeding arteries. Surgical resection is necessary in those kind of cases. Here, we report the case of a patient with a 6-cm pulmonary AVM with multiple feeding arteries that was successfully treated by repeated coil embolization without surgery. PMID- 26508935 TI - Isolated Endobronchial Mycobacterium avium Disease Associated with Lobar Atelectasis in an Immunocompetent Young Adult: A Case Report and Literature Review. AB - The prevalence of lung diseases caused by nontuberculous mycobacteria (NTM) is increasing worldwide. Unlike pulmonary tuberculosis, endobronchial NTM diseases are very rare with the majority of cases reported in patients with human immunodeficiency virus infection and acquired immune deficiency syndrome. We reported a rare case of endobronchial Mycobacterium avium disease associated with lobar atelectasis in a young immunocompetent patient and reviewed the relevant iterature. PMID- 26508936 TI - Nontuberculous Mycobacterial Lung Disease Caused by Mycobacterium shinjukuense: The First Reported Case in Korea. AB - Mycobacterium shinjukuense is a novel species of nontuberculous mycobacteria (NTM) that was first reported in Japan in 2011. It is a slow-growing NTM pathogen that can cause chronic pulmonary infections. There are only a few reported cases of M. shinjukuense infections, all of which are from Japan. We reported a case of chronic lung disease caused by M. shinjukuense. The organism was identified by 16S rRNA, rpoB, and hsp65 gene sequencing. To the best of our knowledge, this was the first confirmed case of lung disease caused by M. shinjukuense outside of Japan. PMID- 26508937 TI - The Natural Course of Endobronchial Inflammatory Polyps as a Complication after Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration. AB - We presented a case of unusual endobronchial inflammatory polyps as a complication following endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in a patient with tuberculous lymphadenitis. EBUS-TBNA of the right hilar lymph node was performed in a 29-year-old, previously healthy man. The patient was confirmed with tuberculous lymphadenitis and received antituberculosis medication over the course of 6 months. Chest computed tomography, after 6 months of antituberculosis therapy following the EBUS-TBNA showed nodular bronchial wall thickening of the right main bronchus. Histological and microbiological examinations revealed inflammatory polyps. After 7 months, the inflammatory polyps regressed almost completely without need for removal. PMID- 26508938 TI - A Case of Acute Fulminant Fat Embolism Syndrome after Liposuction Surgery. AB - Fat embolism syndrome (FES) is a clinical manifestation that consists of multiple organ dysfunction due to fat emboli. FES occurs as a complication after trauma or procedures such as surgery. The diagnostic criteria of FES have not yet been established, so clinical criteria are used for its diagnosis. The clinical course of acute fulminant FES can be rapid. Liposuction surgery, in which adipocytes are mechanically disrupted, is one cause of FES. As the number of liposuction surgeries increases, clinicians should be aware of the possibility of FES. This was the first report of a case of acute fulminant FES with severe acute respiratory distress syndrome after liposuction surgery, in Korea. PMID- 26508939 TI - A Rare Case of Bronchial Epithelial-Myoepithelial Carcinoma with Solid Lobular Growth in a 53-Year-Old Woman. AB - Epithelial-myoepithelial carcinoma (EMC) of lung is a minor subset of salivary type carcinoma of lung of known low grade malignancy. Histologically, two-cell components forming duct-like structure with inner epithelial cell layer and outer myoepithelial cell layer are characteristics of EMC. In salivary gland, dedifferentiation of conventional low grade malignancy has been reported and is thought to be related with poor prognosis. However, precise histomorphology and prognostic factors of pulmonary EMC have not been clarified due to its rarity. Herein, we reported a rare case of EMC presented as endobronchial mass in a 53 year old woman, which showed predominant solid lobular growth pattern and lymph node metastases. PMID- 26508940 TI - Nontuberculous Mycobacterial Lung Disease Caused by Mycobacterium simiae: The First Reported Case in South Korea. AB - This is a report of the first South Korean case of a lung disease caused by Mycobacterium simiae. The patient was a previously healthy 52-year-old female. All serial isolates were identified as M. simiae by multi-locus sequencing analysis, based on hsp65, rpoB, 16S-23S rRNA internal transcribed spacer, and 16S rRNA fragments. A chest radiography revealed deterioration, and the follow-up sputum cultures were persistently positive, despite combination antibiotic treatment, including azithromycin, ethambutol, and rifampin. To the best of our knowledge, this is the first confirmed case of a lung disease caused by M. simiae in South Korea. PMID- 26508941 TI - A Case of Ectopic Adrenocorticotropic Hormone Syndrome in Small Cell Lung Cancer. AB - Small cell lung cancer (SCLC), which originated from neuroendocrine tissue, can develop into paraneoplastic endocrine syndromes, such as Cushing syndrome, because of an inappropriate secretion of ectopic adrenocorticotropic hormone (ACTH). This paraneoplastic syndrome is known to be a poor prognostic factor in SCLC. The reason for poor survival may be because of a higher risk of infection associated with hypercortisolemia. Therefore, early detection and appropriate treatment for this syndrome is necessary. But the diagnosis is challenging and the source of ACTH production can be difficult to identify. We report a 69-year old male patient who had severe hypokalemia, metabolic alkalosis, and hypertension as manifestations of an ACTH-secreting small cell carcinoma of the lung. He was treated with ketoconazole and spironolactone to control the ACTH dependent Cushing syndrome. He survived for 15 months after chemotherapy, which is unusual considering the poor outcome of the ectopic ATH syndrome associated with SCLC. PMID- 26508942 TI - A Case of Significant Endobronchial Injury due to Recurrent Iron Pill Aspiration. AB - Gastric mucosal damage by iron pills is often reported. However, iron pill aspiration is uncommon. Oxidation of the impacted iron pill causes bronchial mucosal damage that progresses to chronic bronchial inflammation, necrosis, endobronchial stenosis and rarely, perforation. We reported a case of a 92-year old woman with chronic productive cough and significant left-sided atelectasis. Bronchoscopy revealed substantial luminal narrowing with exudative inflammation of the left main bronchus. Bronchial washing cytology showed necroinflammatory exudate and a small amount of brown material. Mucosal biopsy showed diffuse brown pigments indicative of ferrous pigments, crystal deposition, and marked tissue degeneration. After vigorous coughing, she expectorated dark sediments and her symptoms and radiological abnormalities improved. There are a few such reports worldwide; however, this was the first case reported in Korea. Careful observation of aspiration-prone patients and early detection of iron pill aspiration may prevent iron pill-induced bronchial injury. PMID- 26508943 TI - Pulmonary Foreign Body Granulomatosis in Dental Technician. AB - Occupational lung diseases are caused by several toxic substances including heavy metals; however, the exact pathologic mechanisms remain unknown. In the workplace, dental technicians are often exposed to heavy metals such as cobalt, nickel, or beryllium and occasionally develop occupational lung diseases. We described a case of occupational lung disease in a patient who was employed as a dental technician for over a decade. A 31-year-old, non-smoking woman presented with productive cough and shortness of breath of several weeks duration. Chest computed tomography revealed a large number of scattered, bilateral small pulmonary nodules throughout the lung field, and multiple mediastinal lymph nodes enlargement. Percutaneous needle biopsy showed multifocal small granulomas with foreign body type giant cells suggestive of heavy metals inhalation. The patient's condition improved on simple avoidance strategy for several months. This case highlighted the importance of proper workplace safety. PMID- 26508944 TI - Congenital Tuberculosis as a Result of Disseminated Maternal Disease: Case Report. AB - Although tuberculosis is highly prevalent worldwide, congenital tuberculosis is one of the least common manifestations of the disease. The diagnosis is usually difficult because of the non-specific clinical presentation and the lack of awareness of maternal disease prior to pregnancy and delivery. We present the case of a preterm neonate with congenital tuberculosis, born to a previously healthy mother who had developed severe disseminated tuberculosis during her pregnancy. Once the diagnosis was confirmed in the mother, the congenital infection was confirmed by isolation of Mycobacterium tuberculosis in gastric aspirates, and positive polymerase chain reaction in a cerebrospinal fluid examination. Treatment for tuberculosis with a four-drug regimen resulted in an adequate clinical response in both the mother and infant. PMID- 26508945 TI - Successful High Flow Nasal Oxygen Therapy for Excessive Dynamic Airway Collapse: A Case Report. AB - Excessive dynamic airway collapse (EDAC) is a disease entity of excessive reduction of the central airway diameter during exhalation, without cartilage collapse. An 80-year-old female presented with generalized edema and dyspnea at our hospital. The patient was in a state of acute decompensated heart failure due to pneumonia with respiratory failure. We accordingly managed the patient with renal replacement therapy, mechanical ventilation and antibiotics. Bronchoscopy confirmed the diagnosis of EDAC. We scheduled extubation after the improvement of pneumonia and heart condition. However, extubation failure occurred due to hypercapnic respiratory failure with poor expectoration. Her EDAC was improved in response to high flow nasal oxygen therapy (HFNOT). Subsequently, the patient was stabilized and transferred to the general ward. HFNOT, which generates physiologic positive end expiratory pressure (PEEP) effects, could be an alternative and effective management of EDAC. Further research and clinical trials are needed to demonstrate the therapeutic effect of HFNOT on EDAC. PMID- 26508946 TI - Progressive Pulmonary Fibrocystic Changes of Both Upper Lungs in a Patient with Ankylosing Spondylitis. AB - Ankylosing spondylitis is a chronic inflammatory multisystem disease that primarily affects the axial joints. Pleuropulmonary involvement is an uncommon extra-articular manifestation of ankylosing spondylitis. There is a wide spectrum of pulmonary parenchymal changes in ankylosing spondylitis, beginning in the early stages of the disease and increasing over time. The lesions are usually asymptomatic, and not visible on chest radiographs in early stages. We reported a case of advanced ankylosing spondylitis in a 56-year-old man with progressive pulmonary bullous fibrocystic changes on both upper lobes that were misdiagnosed as tuberculosis in the early stages of the disease. PMID- 26508947 TI - Pulmonary Langerhans Cell Histiocytosis in an Adult Male Presenting with Central Diabetes Insipidus and Diabetes Mellitus: A Case Report. AB - Pulmonary Langerhans cell histiocytosis is an uncommon diffuse cystic lung disease in adults. In rare cases, it can involve extrapulmonary organs and lead to endocrine abnormalities such as central diabetes insipidus. A 42-year-old man presented with polyphagia and polydipsia, as well as a dry cough and dyspnea on exertion. Magnetic resonance imaging of the hypothalamic-pituitary system failed to show the posterior pituitary, which is a typical finding in patients with central diabetes insipidus. This condition was confirmed by a water deprivation test, and the patient was also found to have type 2 diabetes mellitus. Computed tomographic scanning of the lungs revealed multiple, irregularly shaped cystic lesions and small nodules bilaterally, with sparing of the costophrenic angles. Lung biopsy through video-assisted thoracoscopic surgery revealed pulmonary Langerhans cell histiocytosis. On a follow-up visit, only 1 year after the patient had quit smoking, clinical and radiological improvement was significant. Here, we report an uncommon case of pulmonary Langerhans cell histiocytosis that simultaneously presented with diabetes insipidus and diabetes mellitus. PMID- 26508948 TI - A Case of Cryptogenic Organizing Pneumonia after Transarterial Chemoembolization for the Treatment of Hepatocellular Carcinoma. AB - Cryptogenic organizing pneumonia (COP) is an inflammatory lung disease involving the distal bronchioles, respiratory bronchioles, bronchiolar ducts, and alveolae. The etiology is usually unknown; however, there are several known causes and associated systemic diseases. Corticosteroid therapy is the best treatment option and the prognosis of COP is good, with recovery in up to 80% of patients. We described a patient with in-operable hepatocellular carcinoma (HCC) undergoing chemoembolization with doxorubicin in a drug-eluting bead (DEB). COP developed in the patient after chemoembolization but resolved spontaneously in several months. PMID- 26508949 TI - Real-Time Polymerase Chain Reaction Assay for the Diagnosis of Pulmonary Tuberculosis. PMID- 26508950 TI - Erratum: Update of Sepsis: Recent Evidences about Early Goal Directed Therapy. AB - [This corrects the article on p. 156 in vol. 78, PMID: 26175766.]. PMID- 26508951 TI - Relationship between Serotonergic Dysfunction Based on Loudness Dependence of Auditory-Evoked Potentials and Suicide in Patients with Major Depressive Disorder. AB - The relationship between suicidality and the loudness dependence of auditory evoked potentials (LDAEP) remains controversial. This article reviews the literature related to the LDAEP and suicide in patients with major depressive disorder, and suggests future research directions. Serotonergic dysfunction in suicidality seems to be more complicated than was originally thought. Studies of suicide based on the LDAEP have produced controversial results, but it is possible that these are due to differences in study designs and the smallness of samples. For example, some studies have evaluated suicide ideation and the LDAEP, while others have evaluated suicide attempts and the LDAEP. Furthermore, some of the latter studies enrolled acute suicide attempters, while others enrolled those with the history of previous suicide attempts, irrespective of whether these were acute or chronic. Thus, a more robust study design is needed in future studies, for example by evaluating the LDAEP immediately after a suicide attempt rather than in those with a history of suicide attempts and suicide ideation in order to reduce bias. Moreover, genuine suicide attempt, self-injurious behaviors, and faked suicide attempt need to be discriminated in the future. PMID- 26508952 TI - Outpatient Follow-Up Visit after Hospital Discharge Lowers Risk of Rehospitalization in Patients with Schizophrenia: A Nationwide Population-Based Study. AB - OBJECTIVE: Non-adherence to medication is a recognized problem in psychiatric patients and may be one of the most challenging aspects of treatment for patients with schizophrenia. Failure of follow-up care after discharge greatly increases non-adherence to prescribed medications, relapse and rehospitalization. However, it is still unknown whether and how much outpatient follow-up visits can mitigate the risk of rehospitalization. Therefore we sought to investigate the continuity and effectiveness of outpatient care after inpatient discharge and its effect on rehospitalization of patients with schizophrenia. METHODS: Data were extracted from National Health Insurance Claim Database covering the period from 2007 through 2010. We identified 10,246 patients aged 18 years or older who were admitted in psychiatric facilities with the diagnosis of schizophrenia between January 1 and December 31 in 2007. The number of outpatient visits within 60 days after discharge from index admission was defined as the indicator for the continuous care and rehospitalization was inspected during the following 36-month period. Cox's proportional hazard model was used to examine the factors affecting the risk of rehospitalization including the number of outpatient visits, age, sex, comorbidities, antipsychotics, and characteristics of medical institution. RESULTS: We found that 12.7% (n=1,327) of the patients visited psychiatric outpatient department once within 60 days after hospital discharge, 34.8% (n=3,626) twice, and 27.8% (n=2,900) more than three times. Patients taking atypical antipsychotics showed higher proportion in 2 or more outpatient visits, whereas patients taking typical antipsychotics showed higher proportion in one or no outpatient visits. Cox hazard ratios of rehospitalization for the factor of 3 or more outpatient visits referenced to that of no follow-up visit were 0.567 (0.428-0.750, 95% confidence interval) within 90 days, 0.673 (0.574-0.789) within 180 days, 0.800 (0.713-0.898) within a year, 0.906 (0.824-0.997) within 2 years, and 0.993 (0.910-1.084) within 3 years. CONCLUSION: Although continuous outpatient treatment is important for relapse prevention, patients with schizophrenia showed a low rate of outpatient visit as 62.6% of total patients in 2 or more visits within 60 days after discharge. Lack of follow-up treatment might lead to increase psychotic symptoms and raised risk of relapse and rehospitalization. Our data suggest that the number of outpatient visits within 60 days after discharge in patients with schizophrenia is an important indicator of rehospitalization within a year. Therefore, further efforts to examine factors affecting failure of outpatient follow-up after discharge are warranted. PMID- 26508953 TI - Healthy and Unhealthy Dietary Patterns Are Related to Depression: A Case-Control Study. AB - OBJECTIVE: Major depressive disorder is the leading cause of disability around the world. The relationship between depression and dietary patterns has been reported in a few studies but with controversial results. This study aimed to investigate this relationship in an Iranian population. METHODS: In our study, 330 depressed patients (cases) and healthy people (controls) (1:2) were individually matched according to age, sex and area of residence. New cases of depression were recruited from two psychiatric clinics in Tehran. Interviewers went to each patient's residential area, and invited qualified individuals to participate in the study as controls. Food intake over the past year was collected using a validated semi quantitative food frequency questionnaire. Dietary patterns were determined by the principal components method. Binary logistic regression was used to test the effect of dietary patterns on depression. RESULTS: We identified two major dietary patterns by using factor analysis: the healthy and unhealthy dietary patterns. We categorized the scores of these patterns to quartiles. After adjusting for non-depression drug use, job, marital status, children number, and body mass index, the relations of depression and quartiles of two dietary patterns are significant (p=0.04 & p=0.01, respectively). Compared with participants in the lowest quartile, those in the highest quartile had significantly lower odds ratio (OR) for depression in healthy dietary pattern, and higher OR for depression in unhealthy dietary pattern. CONCLUSION: This study indicates that healthy and unhealthy dietary patterns may be associated with the risk of depression. The results can be used for developing interventions that aim to promote healthy eating for the prevention of depression. PMID- 26508954 TI - Associations of Pulmonary Function with Dementia and Depression in an Older Korean Population. AB - OBJECTIVE: Previous studies reported an association between pulmonary function and cognitive function. However, not much has been investigated in this regard concerning dementia in a community population, taking depression into account. We aimed to examine the associations of pulmonary function with dementia and depression in a community-dwelling elderly population. METHODS: A total of 1,038 participants were evaluated for dementia and depression using the Korean version of the Geriatric Mental State Schedule B3 (GMS B3-K), the Community Screening Interview for Dementia-Korean version (CSID-K) and a modified 10-item Word List Learning from the Consortium to Establish a Registry of Alzheimer's Disease (CERAD). Pulmonary function was measured as forced expiratory volume in 1 s (FEV1) from a forced expiratory maneuver. RESULTS: Prevalence rates of dementia and depression were 11.0% and 10.4%, respectively. Individuals who were diagnosed with dementia manifested a lower mean FEV1, as compared to those without dementia after adjusting for potential confounders, including disability and depression [OR=1.34 (1.05-1.72)]. Following gender-stratified analysis, the association was only statistically significant in women [OR=1.40 (1.04-1.89)]. The association between depression and mean FEV1 was less significant compared to dementia [OR=1.32 (1.10-1.58)]. However, the association was no longer significant after adjusting for age and years of education. No association was significant in the gender-stratified analysis. CONCLUSION: Decreased pulmonary function was associated with dementia status only in an older female Korean population. Pulmonary function and depression were not significantly associated in either gender. PMID- 26508955 TI - Educational and Relational Stressors Associated with Burnout in Korean Medical Students. AB - OBJECTIVE: This study aimed to examine whether educational stressors and relational stressors are associated with burnout in medical students and to test social support as a moderator between stressors and burnout. METHODS: A total of 263 medical students attending Gyeongsang National University composed the study sample. A standardized questionnaire was used to investigate educational and relational stressors, three dimensions of burnout, and social support of medical students. RESULTS: The findings showed that overall burnout is very high among Korean medical students, with 9.9% totally burned out. Educational and relational stressors were significantly associated with the risk of burnout in medical students after controlling for socio-demographics and health behaviors. Social support moderated educational and relational stressors on personal accomplishment, but did not moderate stressors on emotional exhaustion and depersonalization. CONCLUSION: Burnout level is substantially high among Korean medical students. Educational and relational stressors are significantly associated with burnout risk in Korean medical students. Social support had moderated educational and relational stressors on personal accomplishment. The results suggest that more social support for medical students is needed to buffer stressors on and burnout. PMID- 26508956 TI - Temperamental Predictive Factors for Success in Korean Professional Baseball Players. AB - OBJECTIVE: In this five-year cohort study, we hypothesize that factors of temperament and character in professional baseball players predict the speed of obtaining success and the quality of success as well as anxiety control. METHODS: Participants included 120 male rookie players from the Korea Baseball Organization (KBO) and 107 male non-players with no history of playing baseball. The personality/characters and state/trait anxieties of participants were assessed with the Temperament and Character Inventory (TCI) and Spielberg's State Trait Anxiety Inventory-Y (STAI-Y). Over the duration of five years, all the players were subsequently classified into either a success group (major leaguers) or a non-success group (non-major leaguers), depending on their status in the professional baseball league in Korea. RESULTS: The players in the group of starters had higher novelty seeking (NS) scores than those of non-starters. The reward dependence (RD) scores of the success group were higher than those of the non-success group. The state anxiety scores in the starter group were negatively correlated with NS scores. The state and trait anxieties in the non-success group were positively correlated with RD scores. CONCLUSION: The results of this study suggest that predictive temperamental factors for success in baseball players include traits of novelty seeking and reward dependence. PMID- 26508957 TI - Substance Use and Sexual Behaviors of Adolescents in Multicultural Families in Korea. AB - OBJECTIVE: To investigate the substance use and sexual behavior of adolescents in multicultural families compared with adolescents in Korean families in South Korea. METHODS: Data from the 2013 Korean Youth Risk Behavior Web-Based Survey collected from 66,591 adolescents aged 12-18 years (mean age 14.89+/-1.76 years) were analyzed. We classified the adolescents into four groups: those whose father and mother were born in South Korea, those whose father was born in South Korea but whose mother was not, those whose mother was born in South Korea but whose father was not, and those whose father and mother were not born in South Korea. Experiences with alcohol, cigarette, and drug use and sexual relations were investigated. RESULTS: Compared with adolescents whose fathers and mothers were born in Korea, adolescents whose fathers were born in Korea but whose mothers were not were less likely to use alcohol and cigarettes. Adolescents whose mothers were born in Korea but whose fathers were not and adolescents whose fathers and mothers were both born outside Korea were more likely to use cigarettes and drugs and to have sexual relations. CONCLUSION: These results indicate that adolescents whose fathers were not born in Korea and whose fathers and mothers were both born outside Korea are at greater risk for cigarette and drug use and risky sexual behaviors. For these high risk groups, health education should include dependency prevention program, safety issue, and health screening as well as programs aimed at preventing substance use and sexual activity. PMID- 26508958 TI - Motor Activity in Adult Patients with Attention Deficit Hyperactivity Disorder. AB - OBJECTIVE: Hyperactivity is a core symptom of attention-deficit hyperactivity disorder (ADHD), but limited information is available on analysis of activity patterns in this disorder. The aim of the study was to analyze motor activity during daily living in adult patients with ADHD. METHODS: Patients (n=76) from the private psychiatric practice of two of the authors were recruited, and were compared to patients with other psychiatric disorders and to normal controls. Actigraphs were used to record motor activity for six days, with one minute intervals, and data were analysed using linear and non-linear mathematical methods. RESULTS: For short recording periods (300 minutes) the activity levels of ADHD patients do not differ from normal controls, but the autocorrelation (lag 1) is lower and Fourier analysis shows higher power in the high frequency range, corresponding to the period from 2-8 min. During recordings for six days there are no significant differences between ADHD patients and the control groups. The combined and inattentive subgroups differ only in the six days recordings. The Fourier analyses show that the combined type has lower power in the high frequency range, corresponding to the period from 4-8 hours, and in the analysis of rhythms the intra-daily variability is lower, compared to the inattentive type. CONCLUSION: Adult ADHD patients do not show evidence of hyperactivity, but have levels of activity similar to normal controls. However, on several measures ADHD patients display altered activity patterns, indicating that the regulation of motor activity in this disorder is different from controls. PMID- 26508959 TI - Reliability and Validity of the Korean Version of the Modified Adult Attachment Scale for the Use of Medically Ill Patients. AB - OBJECTIVE: The Modified Experiences in Close Relationships (ECR-M36) scale was developed for medically ill, older individuals in 2008 (Toronto, Canada, department of psychosocial oncology and palliative care, Princess Margaret Hospital). The scale has displayed satisfactory reliability and validity. This study aimed to test the reliability and validity of the Korean version of Modified Experiences in Close Relationships (K-ECR-M36) questionnaire in female patients with breast cancer. METHODS: A total of 199 post-operative breast cancer patients completed the K-ECR-M36 as well as other psychological measures including the Revised Adult Attachment Scale (RAAS), World Health Organization Quality of Life Scale Abbreviated Version (WHOQOL-BREF), and Hospital Anxiety and Depression Scale (HADS). The reliability and validity of the K-ECR-M36 were evaluated. Explorative factor analysis was conducted to identify the factor structure of the K-ECR-M36. RESULTS: The K-ECR-M36 showed good internal consistency (Cronbach's alpha=0.87) and reasonable test-retest reliability (r=0.752, p<0.001). The total as well as avoidance and anxiety subscales demonstrated construct validity with the RAAS, the HADS, and the WHOQOL-BREF. Factor analysis revealed four-factor structure which was originally proposed by Brennan, Clark, and Shaver (1998). CONCLUSION: These findings support that the K ECR-M36 has satisfactory reliability, validity and factor structure among patients with breast cancer. PMID- 26508961 TI - Psychometric Properties of the 20-Item Toronto Alexithymia Scale in a Group of Italian Younger Adolescents. AB - OBJECTIVE: Alexithymia is a personality construct that inhibits and interferes with normal affect regulating abilities. The purpose of our study was to assess psychometric properties of TAS-20 in younger adolescents. METHODS: Data were collected from 508 younger adolescents (48.8% male and 51.2% female) with a mean age of 12.56 years (DS=0.50, range: 12-13 years). We administered the following scales: 20-Item-Toronto Alexithymia Scale. RESULTS: The confirmatory factor analysis performed on the second random subsample showed reasonable goodness-of fit for the oblique bi-factorial model: [chi](2) (32, n=254)=54.22; p=0.008; chi(2)/df=1.69; NNFI=0.92; CFI=0.95; SRMR=0.05; RMSEA=0.05; 90% confidence interval=0.027-0.078. CONCLUSION: Based on the outcomes of our research we support the idea of evaluating adolescents for alexithymia. PMID- 26508960 TI - Psychometric Properties of the Self-Report Version of the Strengths and Difficulties Questionnaire in Korea. AB - OBJECTIVE: To examine the reliability and validity of the self-report Korean version of Strengths and Difficulties Questionnaire (SDQ-Kr) in the community sample. METHODS: The SDQ-Kr was administered to a large sample of school children and adolescents (n=2814) and youth attendees of a psychiatric clinic (n=385) aged 11-16 years. To examine temporal stability, the same questionnaire was administered to a subsample of 167 school youths five to six weeks after the initial assessment. To examine the reliability, we calculated Cronbach's alpha coefficients for internal consistency and Pearson's correlations for test-retest stability. In order to evaluate the factorial structure of the SDQ-Kr items, we conducted an exploratory factor analysis (EFA) with varimax rotation. Finally, discriminant validity was examined by using receiver operating characteristic (ROC) curves employing the area under the curve (AUC) as an index of discriminant ability. RESULTS: Although the internal consistency of some subscales of the SDQ Kr was somewhat less satisfactory (alpha coefficients; 0.28-0.54) than the English original, coefficients for the total difficulties scores approached sufficient levels (coefficients; 0.69). Other psychometric properties including discriminant validity (AUC for total difficulties and four subscales >0.7) were comparable to those obtained in other language studies. CONCLUSION: The self report SDQ-Kr exhibited a low level of reliability, indicating that some items need to be further evaluated and revised to improve the psychometric properties. We suggest that the total difficulties score could be used with more confidence for screening possible mental health problems in youths. PMID- 26508962 TI - A Validation Study of the Korean-Ruminative Response Scale in Korean Adolescents. AB - OBJECTIVE: We aimed to evaluate the psychometric properties of Korean version of Ruminative Response Scale (K-RRS) for Korean adolescents. METHODS: A community sample of 1220 adolescents was recruited from middle schools and high schools. Exploratory factor analyses and confirmatory factor analyses were conducted, and additional analyses were performed to assess the reliability and validity of the K-RRS. RESULTS: An exploratory factor analysis of a sample of adolescents (n=550) yielded a three factor structure: 'depressive rumination', 'reflective pondering', and 'brooding'. Confirmatory factor analyses of another sample of adolescents (n=530) supported the three-factor model for the K-RRS. The K-RRS was found to have good internal consistency and construct validity. CONCLUSION: Our results suggest that K-RRS is a valid measurement to assess rumination in adolescents, as well as in adults. PMID- 26508963 TI - Impact of White Matter Lesions on Depression in the Patients with Alzheimer's Disease. AB - OBJECTIVE: Comorbid depression is common in patients with Alzheimer's disease (AD). An increase in white matter lesions (WMLs) has been associated with depression in both elderly individuals with normal cognition and patients with Alzheimer's disease. We investigated whether the severity and location of WMLs influence the association between WMLs and comorbid depression in AD. METHODS: We enrolled 93 AD patients from Seoul National University Bundang Hospital. We administered both the Mini International Neuropsychiatric Inventory (MINI) and the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-K) clinical and neuropsychological battery. Subjects also underwent brain magnetic resonance imaging (MRI). We diagnosed AD according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. We diagnosed depressive disorders according to the DSM-IV diagnostic criteria, and evaluated the severity of depressive symptoms using the Korean version of the Geriatric Depression Scale (GDS-K). We quantified the WML volumes from the brain MRI using a fully automated segmentation algorithm. RESULTS: The log of the WML volume in the frontal lobe was significantly associated with depressive disorders (odds ratio=1.905, 95% CI=1.027-3.533, p=0.041), but not with the severity of depressive symptoms as measured by the GDS K. CONCLUSION: The WML volume in the frontal lobe conferred a risk of comorbid depressive disorders in AD, which implies that comorbid depression in AD may be attributed to vascular causes. PMID- 26508964 TI - A Longitudinal Study of BDNF Promoter Methylation and Depression in Breast Cancer. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is investigated in depression related to medical disorders and its secretion is influenced by epigenetic factors. We investigated the association between BDNF promoter methylation and depression following mastectomy for breast cancer. METHODS: In total, 309 patients with breast cancer were evaluated 1 week after mastectomy, and 244 (79%) were followed up 1 year later. Depression was diagnosed (major or minor depressive disorder) according to DSM-IV criteria and depression severity was estimated by Montgomery-Asberg Depression Rating Scale (MADRS). We assessed BDNF promoter methylation using leukocyte DNA. The effects of BDNF methylation on depression diagnosis and severity were investigated using multivariate logistic and linear regression models, respectively. The two-way interaction between BDNF methylation and the val66met polymorphism on depression was also evaluated using multivariate logistic regression models. RESULTS: Higher BDNF methylation was independently associated with depression diagnosis and with more severe symptoms at both 1 week and 1 year after mastectomy. No significant methylation-genotype interactions were found. CONCLUSION: A role for BDNF in depression related to breast cancer was supported. Indeed, the association between depression and BDNF methylation may be useful for identifying patients who are at high risk for depression and for suggesting directions for promising drug research. PMID- 26508965 TI - Increases in iPS Transcription Factor (Oct4, Sox2, c-Myc, and Klf4) Gene Expression after Modified Electroconvulsive Therapy. AB - OBJECTIVE: Electroconvulsive therapy (ECT) is a reasonable option for intractable depression or schizophrenia, but a mechanism of action has not been established. One credible hypothesis is related to neural plasticity. Three genes (Oct4, Sox2, c-Myc) involved in the induction of induced pluripotent stem (iPS) cells are Wnt target genes, which constitute a key gene group involved in neural plasticity through the TCF family. Klf4 is the other gene among Yamanaka's four transcription factors, and increases in its expression are induced by stimulation of the canonical Wnt pathway. METHODS: We compared the peripheral blood gene expression of the four iPS genes (Oct4, Sox2, c-Myc, and Klf4) before and after modified ECT (specifically ECT with general anesthesia) of patients with intractable depression (n=6) or schizophrenia (n=6). Using Thymatron ten times the total bilateral electrical stimulation was evoked. RESULTS: Both assessments of the symptoms demonstrated significant improvement after mECT stimulation. Expression of all four genes was confirmed to increase after initial stimulation. The gene expression levels after treatment were significantly different from the initial gene expression in all twelve cases at the following treatment stages: at the 3rd mECT for Oct4; at the 6th and 10th mECT for Sox2; and at the 3rd, 6th and 10th mECT for c-Myc. CONCLUSION: These significant differences were not present after correction for multiple testing; however, our data have the potential to explain the molecular mechanisms of mECT from a unique perspective. Further studie should be conducted to clarify the pathophysiological involvement of iPS inducing genes in ECT. PMID- 26508966 TI - Neurosteroid Levels in Patients with Obsessive-Compulsive Disorder. AB - OBJECTIVE: Changes in serum neurosteroid levels have been reported in stress related disorders such as anxiety and depression, but not in patients with obsessive-compulsive disorder (OCD). We thus investigated such changes in patients with OCD. METHODS: We compared the serum levels of progesterone, pregnanolone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEA-S), cortisol and testosterone in 30 patients with OCD and 30 healthy controls. RESULTS: When male and female patients were evaluated together, DHEA and cortisol levels were significantly higher in patients with OCD than the control group. When the genders were evaluated separately, DHEA and cortisol levels were higher in female patients than the female controls. The increase in DHEA levels in female patients is likely an effect of the hypothalamic-pituitary adrenal (HPA) axis. In contrast, cortisol levels in male patients were higher than the control group, while testosterone levels were lower. The increased cortisol and decreased testosterone levels in male patients likely involves the hypothalamic-pituitary-gonadal (HPG) axis. CONCLUSION: These findings suggest that neurosteroid levels in patients with OCD should be investigated together with the HPA and HPG axes in future studies. PMID- 26508967 TI - The Effect of Methylphenidate on Neurological Soft Signs in ADHD. AB - OBJECTIVE: Neurological soft signs are very common in children with the attention deficit hyperactivity disorder (ADHD), and the first line medication of this disorder is methylphenidate. The aim of the study was to assess the effect of methylphenidate on the neurological soft signs in children and adolescents suffering from ADHD depending on the dose of methylphenidate. METHODS: Thirty five patients with ADHD were investigated by the ADHD RS-IV parent version questionnaire and the Revised Neurological Examination for Subtle Signs before treatment adjustment and after four weeks of methylphenidate medication. The changes in hyperactivity symptomatology, neurological soft signs during therapy and the influence of the methylphenidate dose were statistically analyzed. RESULTS: A significant decrease in hyperactivity symptomatology was found after one month of methylphenidate medication (p=0.0001) and significant decrease in neurological soft signs was demonstrated in 21 from a total of 26 items (p<0.05). Correlation analysis showed no relationship between the dose of methylphenidate and the improvement of neurological soft signs. Similarly, the improvement of ADHD symptomatology had not correlation with the improvement of neurological soft signs. CONCLUSION: The study demonstrated the positive effect of methylphenidate on neurological soft signs in which improvement occurred independently of the dose, indicating that their progress may be due to methylphenidate treatment of any dose. The unrelated effect of methylphenidate on the attention deficit hyperactivity disorder and neurological soft signs suggest that methylphenidate might be useful in the therapy of clumsy child syndrome and in ADHD treatment of non-responders. PMID- 26508968 TI - Association Study between Norepinephrine Transporter Gene Polymorphism and Schizophrenia in a Korean Population. AB - OBJECTIVE: We aimed to investigate possible associations between three norepinephrine transporter gene (SLC6A2) single nucleotide polymorphisms (T182C, A3081T, and G1287A) and schizophrenia. Also, we investigated the relationships of those polymorphisms with clinical severity and characteristics of schizophrenia. METHODS: Participants were 220 schizophrenia patients in the acute phase and 167 healthy controls. The genotype, allele frequency, and haplotype of each group were analyzed for T182C, A3081T, and G1287A polymorphisms. Of the 220 schizophrenia patients, 163 patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) and the Korean version of the Calgary depression scale for schizophrenia (K-CDSS) at baseline. RESULTS: We found no significant differences between the schizophrenia patient group and the control group in genotype distribution or allele frequency of the three tested polymorphisms. Likewise, we could not find any significant differences in genotype or allele frequency by analyzing according to gender. In the haplotype study, no significant association emerged between specific haplotype combinations and schizophrenia. We also found no association between clinical scales (PANSS and K CDSS) and the studied polymorphisms. CONCLUSION: Our results suggest that the investigated polymorphisms of the NET gene are not associated with susceptibility to schizophrenia or its clinical features in a Korean population. However, this study remains significant because it is the first haplotype study to investigate associations between NET gene (SLC6A2) single nucleotide polymorphisms and schizophrenia in a Korean population. Future research with a larger sample size and more genetic markers is needed to replicate our results. PMID- 26508969 TI - Socioeconomic and Geographic Inequalities of Internet Addiction in Korean Adolescents. AB - The aim of this study was to evaluate the social economic and geographic influences on Internet addiction in Korean youth using the Korean Youth Risk Behavior Web-Based Survey. Middle and high school students (n=73,238) were randomly selected from the respondents to a web-based survey using two-stage stratified complex sampling. A Geographical Information System was used to generate a Korean map of the level of Internet addiction for each province and complex sampling lower case logistic regression was used to investigate the relationship between social economic status (SES) and Internet addiction. Gyeonggi-do and Gyeongsang-namdo provinces have a higher total scores of Internet addiction. There were associations between Internet addiction and low SES (OR=1.504, 95% CI 1.156-1.956, p<0.01). There may need to be at multilevel approach which recognizes the different levels of need in provinces as well as trying to understand why the differences arise at an individual level. PMID- 26508970 TI - Association of the Catechol O-Methyltransferase Val158-Met Polymorphism and Reduced Interference Control in Korean Children with Attention-Deficit Hyperactivity Disorder. AB - OBJECTIVE: We tested for association of the catechol-O-methyltransferase (COMT) Val(158)-Met (rs4680) polymorphism with attention-deficit hyperactivity disorder (ADHD) using family-based test in Korean trios. METHODS: A total of 181 subjects with ADHD along with both of their biological parents were recruited from University Hospitals in Korea. We performed a transmission disequilibrium test (TDT) on 181 trios. RESULTS: In the TDT, we found the over-transmission of the Val allele in children with ADHD (chi(2)=4.21, p=0.040). CONCLUSION: These results suggest that the COMT Val158-Met polymorphism is associated with ADHD among the Korean population. However, this study must be replicated in larger populations. PMID- 26508971 TI - One-Year Follow-Up of Serum Prolactin Level in Schizophrenia Patients Treated with Blonanserin: A Case Series. AB - In our previous study, a prolactin elevation was more frequently in risperidone than in blonanserin; however, it was more often in blonanserin than in olanzapine. Therefore, while a rate of PRL rising is low to moderate, hyperprolactinemia is a considerable adverse effect in the blonanserin treatment. In this study, to examine detailed characteristics of hyperprolactinemia of blonanserin, we analyzed the prolactin data in six schizophrenic patients who were switched to blonanserin from other antipsychotics and followed for one year. As a result, blonanserin dose was clearly associated with serum prolactin level. The average prolactin level was almost normal when the mean blonanserin dosage was 8.0 mg/day. Regardless of the dose decrease of blonanserin, there were no remarkable changes in symptoms and social functions. Based on our findings, we conclude that low dose blonanserin medication may be useful for schizophrenia maintenance treatment without hyperprolactinemia and a high rate of relapse. PMID- 26508972 TI - A Selective Mutism Arising from First Language Attrition, Successfully Treated with Paroxetine-CBT Combination Treatment. AB - After immersion in a foreign language, speakers often have difficulty retrieving native-language words and may experience a decrease in its proficiency, this phenomenon, in the non-pathological form, is known as first language attrition. Self-perception of this low native-language proficiency and apprehension occurring when speaking is expected and, may sometimes lead these people to a state of social anxiety and, in extreme forms, can involve the withholding of speech as a primitive tool for self-protection, linking them to selective mutism. We report an unusual case of selective mutism arising from first language attrition in an Italian girl after attending a two-year "German language school", who successfully responded to a paroxetine-cognitive behavioral treatment (CBT) combination treatment. PMID- 26508973 TI - Comment on "Atypical Epidemiologic Finding in Association between Depression and Alcohol Use or Smoking in Korean Male: Korean Longitudinal Study of Aging". PMID- 26508974 TI - Knowledge, Attitude, and Utilization of Traditional Medicine among the Communities of Merawi Town, Northwest Ethiopia: A Cross-Sectional Study. AB - Background. In Ethiopia, up to 80% of the population use traditional medicine for primary health care. Studies on the current knowledge and practices of communities in the era of modern health care expansion are lacking. Therefore, this study is aimed at assessing the knowledge, attitude, and practice of traditional medicine among communities in Merawi town. Methods. A descriptive cross-sectional study was carried out among 403 residents of Merawi town. A systematic random sampling was used to select households. Data was collected through house to house interview. Results. 392 out of 403 questionnaires were analysed. Among the participants, 220 (56.1%) were female. The mean (+/-s.d.) age of the participants was 32.5 (+/-12.4) years. Nearly two-thirds, 241 (61.5%), of study participants have good knowledge about traditional medicines. Three quarters of participants prefer modern medicine to traditional drugs. 70.9% of participants had the experience of personal use of traditional therapies. Conclusions. The population in Merawi has good knowledge with high acceptability and use of traditional medicine. The main reasons for high acceptability and practice were cultural acceptability, lesser cost, and good outcome of traditional medicine. PMID- 26508975 TI - Collaboration of Japanese Kampo Medicine and Modern Biomedicine 2015. PMID- 26508976 TI - Antitumor Efficacy and Mechanism in Hepatoma H22-Bearing Mice of Brucea javanica Oil. AB - Brucea javanica is a traditional herbal medicine in China, and its antitumor activities are of research interest. Brucea javanica oil, extracted with ether and refined with 10% ethyl alcohol from Brucea javanica seed, was used to treat hepatoma H22-bearing mice in this study. The antitumor effect and probable mechanisms of the extracted Brucea javanica oil were studied in H22-bearing mice by WBC count, GOT, GPT levels, and western blotting. The H22 tumor inhibition ratio of 0.5, 1, and 1.5 g/kg bw Brucea javanica oil were 15.64%, 23.87%, and 38.27%. Brucea javanica oil could inhibit the involution of thymus induced by H22 tumor-bearing, but it could not inhibit the augmentation of spleen and liver. Brucea javanica oil could decrease the levels of WBC count and GOT and GPT in H22 bearing mice. The protein levels of GAPDH, Akt, TGF-beta1, and alpha-SMA in tumor tissues decreased after being treated with Brucea javanica oil. Disturbing energy metabolism and neoplastic hyperplasia controlled by Akt and immunoregulation activity were its probable antitumor mechanisms in hepatoma H22-bearing mice. PMID- 26508977 TI - ACE Reduces Metabolic Abnormalities in a High-Fat Diet Mouse Model. AB - The medicinal plants Artemisia iwayomogi (A. iwayomogi) and Curcuma longa (C. longa) radix have been used to treat metabolic abnormalities in traditional Korean medicine and traditional Chinese medicine (TKM and TCM). In this study we evaluated the effect of the water extract of a mixture of A. iwayomogi and C. longa (ACE) on high-fat diet-induced metabolic syndrome in a mouse model. Four groups of C57BL/6N male mice (except for the naive group) were fed a high-fat diet freely for 10 weeks. Among these, three groups (except the control group) were administered a high-fat diet supplemented with ACE (100 or 200 mg/kg) or curcumin (50 mg/kg). Body weight, accumulation of adipose tissues in abdomen and size of adipocytes, serum lipid profiles, hepatic steatosis, and oxidative stress markers were analyzed. ACE significantly reduced the body and peritoneal adipose tissue weights, serum lipid profiles (total cholesterol and triglycerides), glucose levels, hepatic lipid accumulation, and oxidative stress markers. ACE normalized lipid synthesis-associated gene expressions (peroxisome proliferator activated receptor gamma, PPARgamma; fatty acid synthase, FAS; sterol regulatory element-binding transcription factor-1c, SREBP-1c; and peroxisome proliferator activated receptor alpha, PPARalpha). The results from this study suggest that ACE has the pharmaceutical potential reducing the metabolic abnormalities in an animal model. PMID- 26508978 TI - TCM Formula Xiaoyaosan Decoction Improves Depressive-Like Behaviors in Rats with Type 2 Diabetes. AB - The mechanism of depression with type 2 diabetes remains elusive, requiring further study. Objective. To evaluate the effect of TCM formula Xiaoyaosan on depressive-like behaviors in rats with type 2 diabetes. Methods. Rats were divided into 5 groups and drugs were administered during the model period of 21 days. The model of depressive-like behaviors in rats with type 2 diabetes was induced by a high fat diet, low doses of STZ injection, and chronic restraint stress for 21 days. The body weight, fasting blood glucose, ITT, OGTT, 5-HT, DA, depression behaviors, and morphological changes of formation were measured and observed. Results. After modeling, marked changes were found in model rats; behavioral analyses of rats indicated that this modeling method negatively impacts locomotor function. In the H&E staining, changes were found predominately in the CA1 and DG subregions of the hippocampus. After 21 days of treatment by fluoxetine and Xiaoyaosan, rats' body weights, behaviors and fasting blood glucose, and hippocampal formation were modified. Conclusions. A new model of depressive-like behaviors in rats with type 2 diabetes was successfully created. Xiaoyaosan and fluoxetine in this study independently contribute to exacerbate the disease progression. PMID- 26508979 TI - Adipogenic Activity of Wild Populations of Rhododendron groenlandicum, a Medicinal Shrub from the James Bay Cree Traditional Pharmacopeia. AB - The traditional medicinal plant, Labrador tea (Rhododendron groenlandicum (Oeder) Kron & Judd; Ericaceae), present in the pharmacopoeia of the Cree of Eeyou Istchee, has shown glitazone-like activity in the 3T3-L1 adipogenesis bioassay. This activity has been attributed to phenolic compounds, which have been shown to vary in this plant as a function of insolation parameters. The goal of this study was to determine if these changes in phenolic content were pharmacologically significant. Leaves were harvested in 2006 throughout the James Bay region of Northern Quebec and ethanol extracts were tested in vitro using the 3T3-L1 murine cell line adipogenesis bioassay. This traditional medicinal plant was found active in the assay. However, there was no detectable spatial pattern in the accumulation of intracellular triglycerides, suggesting that such patterns previously observed in the phenolic profile of Labrador tea were not pharmacologically significant. Nonetheless, a reduction in the adipogenic activity was observed and associated with higher concentrations of quercetin for which selected environmental variables did not appropriately explain its variation. PMID- 26508980 TI - Traditional Chinese Medicine Decreases the Stroke Risk of Systemic Corticosteroid Treatment in Dermatitis: A Nationwide Population-Based Study. AB - Epidemiological studies have shown a strong association between dermatitis and stroke. Systemic corticosteroid, the mainstay treatment for dermatitis, could enhance the atherosclerotic process. Traditional Chinese Medicine (TCM) has been used for dermatitis to decrease the side effects of corticosteroid. However, the different stroke risk in dermatitis patients treated with systemic corticosteroid or TCM remains unclear. This study identified 235,220 dermatitis patients and same comorbidity matched subjects between 2000 and 2009 from database of NHRI in Taiwan. The two cohorts were followed until December 31, 2011. The primary outcome of interest was new diagnosis of stroke. The crude hazard ratio (HR) for future stroke among dermatitis patients treated with systemic corticosteroid was 1.40 (95% CI, 1.34-1.45; P < 0.0001) and TCM was 1.09 (95% CI, 1.05-1.13; P < 0.0001). The log-rank test showed a higher cumulative incidence of ischemic stroke in the patient treated with only systemic corticosteroid group than that treated with systemic corticosteroid and TCM, only TCM, and neither systemic corticosteroid nor TCM in the matched cohort during the follow-up period (P < 0.0001). We demonstrated that patients treated with systemic corticosteroid had an increased risk of stroke and that the risk probably decreased by TCM treatment. PMID- 26508981 TI - Postmarketing Safety Surveillance and Reevaluation of Danhong Injection: Clinical Study of 30888 Cases. AB - Traditional Chinese medicine injections (TCMIs) have played an irreplaceable role for treating some clinical emergency, severe illness, and infectious diseases in China. In recent years, the incidence rates of adverse drug reactions (ADRs) of TCMIs have increased year by year. Danhong injection (DHI) is one representative TCMI comprised of Danshen and Honghua for treating cardiovascular and cerebrovascular diseases in clinic. In present study, the postmarketing safety surveillance and reevaluation of DHI were reported. Total 30888 patients in 37 hospitals from 6 provinces participated in the study. The results showed that the ADR incidence rate of DHI was 3.500/00. Seventeen kinds of new adverse reactions of DHI were found. The main type of ADRs of DHI was type A (including sweating, dizziness, headache, flushing, vasodilation, eye hemorrhage, faintness, chest pain, palpitations, breathlessness, anxious, nausea, flatulence, vomiting, hypotension, hypertension, local numbness, dyspnea, joint disease, and tinnitus) accounting for 57.75%. The severities of most ADRs of DHI were mild and moderate reactions accounting for 25.93% and 66.67%, respectively. The main disposition of ADRs of DHI was drug withdrawal and without any treatments. The results can provide basis for amendment and improvement of the instructions of DHI, as well as demonstration and reference for the postmarketing safety surveillance and reevaluation of other TCMIs. And the rationality, scientificity, and safety of clinical applications of TCMIs could be improved. PMID- 26508982 TI - Bai-Hu-Jia-Ren-Shen-Tang Decoction Reduces Fatty Liver by Activating AMP Activated Protein Kinase In Vitro and In Vivo. AB - Obesity and associated conditions, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), are currently a worldwide health problem. In Asian traditional medicine, Bai-Hu-Jia-Ren-Shen-Tang (BHJRST) is widely used in diabetes patients to reduce thirst. However, whether it has a therapeutic effect on T2DM or NAFLD is not known. The aim of this study was to examine whether BHJRST had a lipid-lowering effect using a HuS-E/2 cell model of fatty liver induced by palmitate and in a db/db mouse model of dyslipidemia. Incubation of HuS-E/2 cells with palmitate markedly increased lipid accumulation and expression of adipose triglyceride lipase (ATGL), which is involved in lipolysis. BHJRST significantly decreased lipid accumulation and increased ATGL levels and phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream target, acetyl-CoA carboxylase (ACC), which are involved in fatty acid oxidation. Furthermore, after twice daily oral administration for six weeks, BHJRST significantly reduced hepatic fat accumulation in db/db mice, as demonstrated by increased hepatic AMPK and ACC phosphorylation, reduced serum triglyceride levels, and reduced hepatic total lipid content. The results show that BHJRST has a lipid-lowering effect in the liver that is mediated by activation of the AMPK signaling pathway. PMID- 26508983 TI - Analysis of Individual Variations in Autonomic Responses to Urban and Forest Environments. AB - Autonomic responses to urban and forest environments were studied in 625 young male subjects. The experimental sites were 57 forests and 57 urban areas across Japan. The subjects viewed the landscape (forest or urban environment) for a period of 15 min while sitting on a chair. During this period, heart rate variability (HRV) was monitored continuously. The results were presented as histograms and analyzed with special reference to individual variations. Approximately 80% of the subjects showed an increase in the parasympathetic indicator of HRV (lnHF), whereas the remaining subjects showed a decrease in the parasympathetic activity. Similarly, 64.0% of the subjects exhibited decreases in the sympathetic indicator of HRV (ln[LF/HF]), whereas the remaining subjects showed opposite responses. Analysis of the distribution of HRV indices (lnHF and ln[LF/HF]) demonstrated the effect of forest environments on autonomic activity more specifically than the conventional analysis based on the difference in mean values. PMID- 26508984 TI - Evaluation of the Effects of Cornus mas L. Fruit Extract on Glycemic Control and Insulin Level in Type 2 Diabetic Adult Patients: A Randomized Double-Blind Placebo-Controlled Clinical Trial. AB - Background. The plant Cornus mas L. (cornelian cherry) is traditionally used as an antidiabetic supplement; however, there is no related clinical trial. In this study, we evaluated the effects of the fruit extract of this plant on biomarkers of glycemic control in adult patients with type 2 diabetes. Methods. Sixty patients with type 2 diabetes were randomly assigned to two groups to receive either the extract or placebo capsules (2 capsules twice daily) for 6 weeks. Each drug capsule contained 150 mg of anthocyanins. Fasting plasma levels of glucose, insulin, HgbA1C, and triglyceride as well as 2-hour postprandial glucose level (2Hpp) were measured before and after the intervention and finally the mean values were compared between groups. Results. After 6 weeks of intervention, significant increase in insulin level (1.13 +/- 1.90 versus -0.643 +/- 1.82, P < 0.05) as well as decrease in HgbA1C (-0.24 +/- 0.429 versus 0.023 +/- 0.225, P < 0.05) and TG (-23.66 +/- 55.40 versus 2.83 +/- 15.71, P < 0.05) levels was observed in drug group compared to placebo. Conclusion. Daily consumption of the fruit extract of Cornus mas L. improves glycemic control by increasing insulin level and reduces TG serum level in type 2 diabetic adult patients. PMID- 26508985 TI - Effects of Berberine on Cell Cycle, DNA, Reactive Oxygen Species, and Apoptosis in L929 Murine Fibroblast Cells. AB - Berberine, an isoquinoline alkaloid isolated from several traditional Chinese herbal medicines (TCM), exhibits a strong antimicrobial activity in the treatment of diarrhea. However, it causes human as well as animal toxicity from heavy dosage. The present study was conducted to investigate the cytotoxicity of berberine and its possible trigger mechanisms resulting in cell cycle arrest, DNA damage, ROS (reactive oxygen species) level, mitochondrial membrane potential change, and cell apoptosis in L929 murine fibroblast (L929) cells. The cells were cultured in vitro and treated with different concentrations of berberine for 24 h. The results showed that cell viability was significantly decreased in a subjected dose-dependent state; berberine concentrations were higher than 0.05 mg/mL. Berberine at a concentration above 0.1 mg/mL altered the morphology of L929 cells. Cells at G2/M phase were clear that the level of ROS and cell apoptosis rates increased in 0.1 mg/mL group. Each DNA damage indicator score (DIS) increased in groups where concentration of berberine was above 0.025 mg/mL. The mitochondrial membrane potential counteractive balance mechanics were significantly altered when concentrations of berberine were above 0.005 mg/mL. In all, the present study suggested that berberine at high dosage exhibited cytotoxicity on L929 which was related to resultant: cell cycle arrest; DNA damage; accumulation of intracellular ROS; reduction of mitochondrial membrane potential; and cell apoptosis. PMID- 26508986 TI - Oxidative Stress Type Influences the Properties of Antioxidants Containing Polyphenols in RINm5F Beta Cells. AB - The in vitro methods currently used to screen bioactive compounds focus on the use of a single model of oxidative stress. However, this simplistic view may lead to conflicting results. The aim of this study was to evaluate the antioxidant properties of two natural extracts (a mix of red wine polyphenols (RWPs) and epigallocatechin gallate (EGCG)) with three models of oxidative stress induced with hydrogen peroxide (H2O2), a mixture of hypoxanthine and xanthine oxidase (HX/XO), or streptozotocin (STZ) in RINm5F beta cells. We employed multiple approaches to validate their potential as therapeutic treatment options, including cell viability, reactive oxygen species production, and antioxidant enzymes expression. All three oxidative stresses induced a decrease in cell viability and an increase in apoptosis, whereas the level of ROS production was variable depending on the type of stress. The highest level of ROS was found for the HX/XO-induced stress, an increase that was reflected by higher expression antioxidant enzymes. Further, both antioxidant compounds presented beneficial effects during oxidative stress, but EGCG appeared to be a more efficient antioxidant. These data indicate that the efficiency of natural antioxidants is dependent on both the nature of the compound and the type of oxidative stress generated. PMID- 26508987 TI - Effect of Rhizoma coptidis (Huang Lian) on Treating Diabetes Mellitus. AB - The rapidly increasing diabetes mellitus (DM) is becoming a major public health issue globally; considerable progress has been made in the field of western hypoglycemic drug and insulin, but some shortages still exist. As one of the most important parts in complementary and alternative therapies, traditional Chinese medicine (TCM) performs a good clinical practice and is showing a bright future in the treatment of DM. TCM therapy has certain advantages of less toxicity and/or side effects, and Chinese herbal medicine which usually contains various active ingredients could provide multiple therapeutic effects. Huang Lian (Rhizoma coptidis, RC) is a herb frequently used in many traditional formulas for properties of "clearing damp-heat, quenching fire, and counteracting poison" in Asia for centuries. In this review, we summarize the application of RC in the treatment of DM from two aspects of contents. Firstly, theoretical principles are explained, including the properties and related records about RC in ancient references and modern pharmacological researches and pharmacokinetics on RC and its active components. Secondly, the clinical application of RC is mainly reviewed, such as applicable stage and syndrome, the reasonable dose range, the preparation formulations, and the toxicity and/or side effects and solutions to its adverse actions. This review provides scientific evidence about the effective components, pharmacological researches, and toxicity of RC, as well as introducing traditional Chinese medical theory and clinical experience, in order to guide clinician to use RC more suitably and reasonably in the clinical practice. PMID- 26508988 TI - The Clinical Value of Oxymatrine in Preventing Lamivudine Induced YMDD Mutation: A Meta-Analysis. AB - Oxymatrine (OMTR) is widely used for the treatment of chronic hepatitis B (CHB) in China. Several reports revealed that combination of OMTR and lamivudine reduced the incidence of tyrosine- (Y-) methionine- (M-) aspartic acid- (D-) aspartic acid (D) (YMDD) mutations in CHB patients. The aim of this study was to evaluate the clinical value of oxymatrine in preventing lamivudine induced YMDD mutation using meta-analysis of data from published randomized controlled trials (RCTs) and to provide some useful information for clinical treatment and future research of YMDD mutation. The Cochrane Central Register of Controlled Trials, Medline, Science Citation Index, EMBASE, China National Knowledge Infrastructure, Wanfang Database, and China Biomedical Database were searched to identify RCTs that evaluated the incidence of YMDD-motif mutation to lamivudine therapy and lamivudine plus OMTR therapies in CHB patients. Data analysis was carried out with the use of RevMan 5.3.2. The literature search yielded 324 studies, and 16 RCTs matched the selection criteria. Overall, the incidence of YMDD mutation was significantly lower in patients treated with lamivudine plus OMTR than in patients treated with lamivudine alone (11.14% versus 28.18%; RR: 0.41; 95% CI: 0.33-0.52; p < 0.05). The exact outcome needs to perform rigorously designed, multicenter, and large randomized controlled trials. PMID- 26508989 TI - Buckwheat Honey Attenuates Carbon Tetrachloride-Induced Liver and DNA Damage in Mice. AB - Buckwheat honey, which is widely consumed in China, has a characteristic dark color. The objective of this study was to investigate the protective effects of buckwheat honey on liver and DNA damage induced by carbon tetrachloride in mice. The results revealed that buckwheat honey had high total phenolic content, and rutin, hesperetin, and p-coumaric acid were the main phenolic compounds present. Buckwheat honey possesses super DPPH radical scavenging activity and strong ferric reducing antioxidant power. Administration of buckwheat honey for 10 weeks significantly inhibited serum lipoprotein oxidation and increased serum oxygen radical absorbance capacity. Moreover, buckwheat honey significantly inhibited aspartate aminotransferase and alanine aminotransferase activities, which are enhanced by carbon tetrachloride. Hepatic malondialdehyde decreased and hepatic antioxidant enzymes (superoxide dismutase and glutathione peroxidase) increased in the presence of buckwheat honey. In a comet assay, lymphocyte DNA damage induced by carbon tetrachloride was significantly inhibited by buckwheat honey. Therefore, buckwheat honey has a hepatoprotective effect and inhibits DNA damage, activities that are primarily attributable to its high antioxidant capacity. PMID- 26508990 TI - A Systematic Evaluation of Feature Selection and Classification Algorithms Using Simulated and Real miRNA Sequencing Data. AB - Sequencing is widely used to discover associations between microRNAs (miRNAs) and diseases. However, the negative binomial distribution (NB) and high dimensionality of data obtained using sequencing can lead to low-power results and low reproducibility. Several statistical learning algorithms have been proposed to address sequencing data, and although evaluation of these methods is essential, such studies are relatively rare. The performance of seven feature selection (FS) algorithms, including baySeq, DESeq, edgeR, the rank sum test, lasso, particle swarm optimistic decision tree, and random forest (RF), was compared by simulation under different conditions based on the difference of the mean, the dispersion parameter of the NB, and the signal to noise ratio. Real data were used to evaluate the performance of RF, logistic regression, and support vector machine. Based on the simulation and real data, we discuss the behaviour of the FS and classification algorithms. The Apriori algorithm identified frequent item sets (mir-133a, mir-133b, mir-183, mir-937, and mir-96) from among the deregulated miRNAs of six datasets from The Cancer Genomics Atlas. Taking these findings altogether and considering computational memory requirements, we propose a strategy that combines edgeR and DESeq for large sample sizes. PMID- 26508991 TI - Identification of Chemical Toxicity Using Ontology Information of Chemicals. AB - With the advance of the combinatorial chemistry, a large number of synthetic compounds have surged. However, we have limited knowledge about them. On the other hand, the speed of designing new drugs is very slow. One of the key causes is the unacceptable toxicities of chemicals. If one can correctly identify the toxicity of chemicals, the unsuitable chemicals can be discarded in early stage, thereby accelerating the study of new drugs and reducing the R&D costs. In this study, a new prediction method was built for identification of chemical toxicities, which was based on ontology information of chemicals. By comparing to a previous method, our method is quite effective. We hope that the proposed method may give new insights to study chemical toxicity and other attributes of chemicals. PMID- 26508992 TI - Computational Modeling of the Trauma Injury. PMID- 26508993 TI - Exploring young adult sexual minority women's perspectives on LGBTQ smoking. AB - Smoking rates are higher among lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals than among heterosexuals. These disparities are exacerbated during the transition from youth to young adulthood. The current study uses in depth qualitative interviews to understand perceptions of LGBTQ smoking among LBQ identified women (N=30, ages 18-24). Major themes identified include the belief that smoking was a way of overcoming stressors faced by heterosexual and LGBTQ young adults alike, a mechanism to relieve sexuality-related stressors, and an ingrained part of LGBTQ culture. Results suggest unique stressors influence LGBTQ smokers. Implications for smoking cessation interventions for LGBTQ youth are discussed. PMID- 26508994 TI - Oxidative Stress in Dilated Cardiomyopathy Caused by MYBPC3 Mutation. AB - Cardiomyopathies can result from mutations in genes encoding sarcomere proteins including MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C). However, whether oxidative stress is augmented due to contractile dysfunction and cardiomyocyte damage in MYBPC3-mutated cardiomyopathies has not been elucidated. To determine whether oxidative stress markers were elevated in MYBPC3-mutated cardiomyopathies, a previously characterized 3-month-old mouse model of dilated cardiomyopathy (DCM) expressing a homozygous MYBPC3 mutation (cMyBP-C((t/t))) was used, compared to wild-type (WT) mice. Echocardiography confirmed decreased percentage of fractional shortening in DCM versus WT hearts. Histopathological analysis indicated a significant increase in myocardial disarray and fibrosis while the second harmonic generation imaging revealed disorganized sarcomeric structure and myocyte damage in DCM hearts when compared to WT hearts. Intriguingly, DCM mouse heart homogenates had decreased glutathione (GSH/GSSG) ratio and increased protein carbonyl and lipid malondialdehyde content compared to WT heart homogenates, consistent with elevated oxidative stress. Importantly, a similar result was observed in human cardiomyopathy heart homogenate samples. These results were further supported by reduced signals for mitochondrial semiquinone radicals and Fe-S clusters in DCM mouse hearts measured using electron paramagnetic resonance spectroscopy. In conclusion, we demonstrate elevated oxidative stress in MYPBC3-mutated DCM mice, which may exacerbate the development of heart failure. PMID- 26508995 TI - Enantioselective reductive multicomponent coupling reactions between isatins and aldehydes. AB - A metal-free stereoselective reductive coupling reaction between isatins and aldehydes is reported. The reaction relies on commercial diethyl phosphite (~?70 kg-1) as the stoichiometric reductant. Base-catalyzed Pudovik addition and phosphonate/phosphate rearrangement achieved polarity inversion on the isatin, and the derived carbanions were trapped by aldehydes with subsequent dialkoxyphosphinyl migration. Chiral iminophosphoranes were used as basic catalysts to achieve high diastereo- and enantioselectivities with excellent yields. PMID- 26508996 TI - Spectroscopic and Computational Studies of Nitrile Hydratase: Insights into Geometric and Electronic Structure and the Mechanism of Amide Synthesis. AB - Nitrile hydratases (NHases) are mononuclear nonheme enzymes that catalyze the hydration of nitriles to amides. NHase is unusual in that it utilizes a low-spin (LS) FeIII center and a unique ligand set comprised of two deprotonated backbone amides, cysteine-based sulfenic acid (RSO(H)) and sulfinic acid (RSO2-), and an unmodified cysteine trans to an exogenous ligand site. Electron paramagnetic resonance (EPR), magnetic circular dichroism (MCD) and low-temperature absorption (LT-Abs) spectroscopies are used to determine the geometric and electronic structures of butyrate-bound (NHaseBA) and active (NHaseAq) NHase. These data calibrate DFT models, which are then extended to explore the mechanism of nitrile hydration by NHase. In particular, the nitrile is activated by coordination to the LS FeIII and the sulfenate group is found to be deprotonated and a significantly better nucleophile than water that can attack the coordinated nitrile to form a cyclic species. Attack at the sulfenate S atom of the cyclic species is favorable and leads to a lower kinetic barrier than attack by water on coordinated, uncyclized nitrile, while attack at the C of the cyclic species is unfavorable. The roles of the unique ligand set and low-spin nature of the NHase active site in function are also explored. It is found that the oxidized thiolate ligands are crucial to maintaining the LS state, which is important in the binding and activation of nitrile susbtrates. The dominant role of the backbone amidate ligands appears to be as a chelate in keeping the sulfenate properly oriented for nucleophilic attack on the coordinated substrate. PMID- 26508997 TI - Oxygen diffusion pathways in a cofactor-independent dioxygenase. AB - Molecular oxygen plays an important role in a wide variety of enzymatic reactions. Through recent research efforts combining computational and experimental methods a new view of O2 diffusion is emerging, where specific channels guide O2 to the active site. The focus of this work is DpgC, a cofactor independent oxygenase. Molecular dynamics simulations, together with mutagenesis experiments and xenon-binding data, reveal that O2 reaches the active site of this enzyme using three main pathways and four different access points. These pathways connect a series of dynamic hydrophobic pockets, concentrating O2 at a specific face of the enzyme substrate. Extensive molecular dynamics simulations provide information about which pathways are more frequently used. This data is consistent with the results of kinetic measurements on mutants and is difficult to obtain using computational cavity-location methods. Taken together, our results reveal that although DpgC is rare in its ability of activating O2 in the absence of cofactors or metals, the way O2 reaches the active site is similar to that reported for other O2-using proteins: multiple access channels are available, and the architecture of the pathway network can provide regio- and stereoselectivity. Our results point to the existence of common themes in O2 access that are conserved among very different types of proteins. PMID- 26508998 TI - Reactive Species Involved in the Regioselective Photooxidation of Heptamethine Cyanines. AB - Heptamethine cyanines are important near-IR fluorophores used in many fluorescence applications. Despite this utility, these molecules are susceptible to light-promoted reactions (photobleaching) involving photochemically generated reactive oxygen species (ROS). Here, we have sought to define key chemical aspects of this nearly inescapable process. Near-IR photolysis of a model heptamethine cyanine leads to the regioselective oxidative cleavage of the cyanine polyene. We report the first quantitative analysis of the major reaction pathway following either photolysis or exposure to candidate ROS. These studies clearly indicate that only singlet oxygen (1O2), and not other feasible ROS, recapitulates the direct photolysis pathway. Computational studies were employed to investigate the regioselectivity of the oxidative cleavage process, and the theoretical ratio is comparable to observed experimental values. These results provide a more complete picture of heptamethine cyanine photooxidation, and provide insight for design of improved compounds for future applications. PMID- 26508999 TI - Rh-Catalyzed Desymmetrization of alpha-Quaternary Centers by Isomerization Hydroacylation. AB - We describe a Rh-catalyzed desymmetrization of all-carbon quaternary centers from alpha,alpha-bis(allyl)aldehydes by a cascade featuring isomerization and hydroacylation. This desymmetrization competes with two other novel olefin functionalizations that are triggered by C-H bond activation, including carboacylation and bisacylation. A BIPHEP ligand promotes enantioselective formation of alpha-vinylcyclopentanones. Mechanistic studies support irreversible and enantioselective olefin-isomerization followed by olefin-hydroacylation. PMID- 26509000 TI - Stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach. AB - Macrocyclic compounds occupy an important chemical space between small molecules and biologics and are prevalent in many natural products and pharmaceuticals. The growing interest in macrocycles has been fueled, in part, by the design of novel synthetic methods to these compounds. One appealing strategy is ring-closing metathesis (RCM) that seeks to construct macrocycles from acyclic diene precursors using defined transition-metal alkylidene catalysts. Despite its broad utility, RCM generally gives rise to a mixture of E- and Z-olefin isomers that can hinder efforts for the large-scale production and isolation of such complex molecules. To address this issue, we aimed to develop methods that can selectively enrich macrocycles in E- or Z-olefin isomers using an RCM/ethenolysis strategy. The utility of this methodology was demonstrated in the stereoselective formation of macrocyclic peptides, a class of compounds that have gained prominence as therapeutics in drug discovery. Herein, we report an assessment of various factors that promote catalyst-directed RCM and ethenolysis on a variety of peptide substrates by varying the olefin type, peptide sequence, and placement of the olefin in macrocycle formation. These methods allow for control over olefin geometry in peptides, facilitating their isolation and characterization. The studies outlined in this report seek to expand the scope of stereoselective olefin metathesis in general RCM. PMID- 26509001 TI - A common language to assess allergic rhinitis control: results from a survey conducted during EAACI 2013 Congress. AB - BACKGROUND: The concept of control is gaining importance in the field of allergic rhinitis (AR), with a visual analogue scale (VAS) score being a validated, easy and attractive tool to evaluate AR symptom control. The doctors' perception of a VAS score as a good tool for evaluating AR symptom control is unknown, as is the level of AR control perceived by physicians who treat patients. METHODS: 307 voluntarily selected physicians attending the annual (2013) European Academy of Allergy and Clinical Immunology (EAACI) meeting completed a digital survey. Delegates were asked to (1) estimate how many AR patients/week they saw during the season, (2) estimate the proportion of patients they considered to have well , partly- and un-controlled AR, (3) communicate how they gauged this control and (4) assess how useful they would find a VAS as a method of gauging control. 257 questionnaires were filled out completely and analysed. RESULTS: EAACI delegates reported seeing 46.8 [standard deviation (SD) 68.5] AR patients/week during the season. They estimated that 38.7 % (SD 24.0), 34.2 % (SD 20.2) and 20.0 % (SD 16.34) of their AR patients had well-controlled (no AR symptoms), partly controlled (some AR symptoms), or un-controlled-(moderate/severe AR symptoms) disease despite taking medication [remainder unknown (7.1 %)]. However, AR control was assessed in many ways, including symptom severity (74 %), frequency of day- and night-time symptoms (67 %), activity impairment (57 %), respiratory function monitoring (nasal and/or lung function; 40 %) and incidence of AR exacerbations (50 %). 91 % of delegates felt a simple VAS would be a useful tool to gauge AR symptom control. CONCLUSIONS: A substantial portion of patients with AR are perceived as having uncontrolled or partly controlled disease even when treated. A simple VAS score is considered a useful tool to monitor AR control. PMID- 26509002 TI - Nontraumatic rhabdomyolysis with short-term alcohol intoxication - a case report. AB - Alcohol-induced rhabdomyolysis is a potentially life-threatening condition due to the probability of progression to acute renal injury. Patients admitted to emergency department with acute alcohol intoxication should always undergo blood and urine tests for early recognition and treatment of rhabdomyolysis. PMID- 26509003 TI - Safe tracheostomy: blunt puncture and dilation after minimal surgical exposure of the trachea (BPAD tracheostomy). AB - A number of complications can occur following both surgical tracheostomy (ST) and percutaneous tracheostomy (PT). A flexible new tracheostomy insertion technique with the advantages of both ST and PT is proposed to reduce these complications. Our blunt puncture and dilation technique (BPAD tracheostomy) appears to be technically safe and feasible to perform. PMID- 26509004 TI - Superior vena cava syndrome with retropharyngeal edema as a complication of ventriculoatrial shunt. AB - Thirty-seven-year old female with hydrocephalus managed by a ventriculoatrial (VA) shunt presented with upper body edema, dysphagia, and headache. Imaging demonstrated thrombosis of the superior vena cava (SVC). Direct catheter thrombolysis led to resolution of thrombus burden. Superior vena cava thrombosis is a rare consequence of VA shunting and must be managed emergently. PMID- 26509005 TI - Transient neonatal diabetes due to a missense mutation (E227K) in the gene encoding the ATP-sensitive potassium channel (KCNJ11). AB - Neonatal diabetes is a monogenic form of diabetes. Herein, we report on a newborn presenting diabetic ketoacidosis at 17 days of life. A KCNJ11 mutation was identified. In such cases, insulin can be replaced by sulfonylurea with a successful metabolic control, as an example of how molecular diagnosis may influence the clinical management of the disorder. PMID- 26509006 TI - Are de novo rea(21;21) chromosomes really de novo? AB - We report a rare case of recurrent trisomy 21 caused by an isochromosome 21q and what is very likely to be maternal germ-line cell mosaicism. Over 90% of cases of rob(21;21) reported in the literature are due to an isochromosome 21q, with a risk of recurrence of more than 10%. PMID- 26509007 TI - Anticoagulant therapy with rivaroxaban in a young patient with paroxysmal nocturnal hemoglobinuria. AB - The new direct oral anticoagulants such us rivaroxaban, could play an important role in the anticoagulant treatment of patients with paroxysmal nocturnal hemoglobinuria where anticoagulant treatment is complex to run, since they have shown a reduction in serious bleeding complications compared to antithrombotic therapy with classical vitamin k antagonist. PMID- 26509008 TI - A novel CYP17A1 deletion causes a functional knockout of the steroid enzyme 17 hydroxylase and 17,20-lyase in a Turkish family and illustrates the precise role of the CYP17A1 gene. AB - A novel homozygous long-range deletion of the CYP17A1 gene abolished protein expression and caused the severest form of 17-hydroxylase deficiency in one kindred of a Turkish family. The affected subjects presented with 46,XY sex reversal and 46,XX lack of pubertal development as well as severe hypertension. PMID- 26509009 TI - Flare-up reactions in severe drug hypersensitivity: infection or ongoing T-cell hyperresponsiveness. AB - "Flare-up" reactions are late manifestations of severe T-cell-mediated drug hypersensitivity reactions. Management is anti-inflammatory treatment and avoiding unnecessary medicines. Symptoms like fever, lymph node swelling, and blood count abnormalities may lead to confusion with bacterial infections. For prompt recognition it is important to keep the differential diagnosis in mind. PMID- 26509010 TI - Fulminant isolated adenovirus hepatitis 5 months after haplo-identical HSCT for AML. AB - The principal limitation of allogeneic hematopoietic stem cell transplantation except relapse remains the transplant-related mortality (TRM). In addition to graft-versus-host disease (GvHD), infections contribute to TRM in many patients. We describe herein a case of an adult patient presenting 5 months after haplo identical transplantation an isolated fulminant hepatitis due to adenovirus. PMID- 26509011 TI - Fahr's disease: a rare neurological presentation in a tropical setting. AB - While rare, Fahr's disease should be considered as a differential diagnosis for seizures, movement disorders, or cognitive impairment in tropical settings. Classically, bilateral calcification of the basal ganglia is seen on CT. Endemic infections, metabolic, and toxic causes should be excluded. Treatment using Levodopa is often beneficial. PMID- 26509012 TI - Early-onset hypoparathyroidism and chronic keratitis revealing APECED. AB - Early diagnosis of potentially life-threatening autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy (APECED) is crucial, but is often delayed due to the clinical heterogeneity of the disorder. Even in the absence of the classic disease triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency, a diagnosis of APECED should be considered in children who have hypoparathyroidism and chronic keratitis, with a past medical history showing a mild and transient Candida infection. PMID- 26509013 TI - Diagnosis of intrachromosomal amplification of chromosome 21 (iAMP21) by molecular cytogenetics in pediatric acute lymphoblastic leukemia. AB - Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis that should be investigated in routine practice. Single nucleotide polymorphism (SNP)-array provides a useful method to detect such cases showing a highly characteristic profile. PMID- 26509014 TI - P16 and HPV discordance in metastatic carcinoma of cervical lymph nodes of unknown primary. AB - The prognostic utility of HPV in oropharyngeal squamous cell carcinoma (OPSCC) and non-OPSCC as has been well documented. Currently, a standardized IHC scoring system does not exist and is needed to define HPV positivity. We have recently seen a patient that provides a caution in using p16 status as a diagnostic aid. PMID- 26509015 TI - Idiopathic hyperzincemia with associated copper deficiency anemia: a diagnostic dilemma. AB - Prompt serum copper and zinc in addition to vitamin B12 levels should be measured in patients suffering from refractory anemia with neurological symptoms. A timely copper supplementation can help revert the hematological and possibly the neurological manifestations. PMID- 26509016 TI - Recurrent peritoneal serous carcinoma that was unmanageable with paclitaxel carboplatin therapy responded to autologous formalin-fixed tumor vaccine. AB - Paclitaxel-carboplatin therapy (TC) usually controls primary peritoneal serous carcinoma (PPSC) but not recurrent disease. In this case, PPSC recurred after three courses of TC, responded dramatically to additional autologous formalin fixed tumor vaccine (AFTV), and resulted in prolonged, progression-free survival without visible lesions detected by positron emission tomography-computed tomography. PMID- 26509017 TI - Hypocalcemia and hyperkalemia during magnesium infusion therapy in a pre eclamptic patient. AB - We present a case of prominent hypocalcemia and hyperkalemia attributed to magnesium infusion in a preeclamptic patient. Iatrogenic hypermagnesemia is an underrecognized cause of hypocalcemia and hyperkalemia. Our report illustrates the effects of magnesium therapy on serum calcium and potassium, necessitating close electrolytes monitoring when used. PMID- 26509018 TI - Tongue fasciculations in an infant with spinal muscular atrophy type 1. AB - Muscular hypotonia in infants may be associated with several conditions, such as spinal muscular atrophy (SMA). We report on an infant with tongue fasciculations and a rare mutation of the SMN1 gene. The presence of tongue fasciculations in combination with a thorough history may be suggestive of SMA. PMID- 26509019 TI - A case of adolescent giant parathyroid adenoma presenting multiple osteolytic fractures and postoperative hungry bone syndrome. AB - Primary hyperparathyroidism (PHPT) and postoperative hungry bone syndrome are very rare conditions in adolescents, and may be frequently misdiagnosed as a metastatic bone tumor. However, delay in diagnosis may lead to a fatal preoperative hypercalcemia and postoperative hypocalcemia. PHPT is a differential diagnosis of adolescent hypercalcemia and osteolytic fractures. PMID- 26509020 TI - Aplasia cutis congenita: a conservative approach of a case with large, extensive skin, and underlying skull defect. AB - Aplasia cutis congenita is a disease in which skin, bone, and dura mater can be absent. In majority of the cases it affects the scalp. We report a baby girl born at term with a large scalp and skull defect measuring 9 * 10 cm. Conservative treatment led to complete epithelization. PMID- 26509021 TI - Pseudoaneurysm of pulmonary artery: rare complication of systemic chemotherapy. AB - Pulmonary artery pseudoaneurysm is an uncommon yet fatal clinical entity. Its presentation can mimic a number of common diseases and can be easily missed. As pseudoaneurysm is associated with a number of fatal complications, clinicians should be aware of imaging features which distinguishes pseudoaneurysms from its close differentials. Early recognition and treatment of pseudoaneurysm can prevent fatal outcomes including hemothorax, rupture, or death. PMID- 26509022 TI - Prenatal diagnosis of a 46,XX male following noninvasive prenatal testing. AB - Case report involving a normal female by NIPT with male external genitalia on routine fetal morphology assessment. QF-PCR, CGH microarray, and FISH revealed an unbalanced translocation, involving the short arms of the X and Y chromosomes. This case demonstrates the possible limitations of correctly identifying sex chromosome abnormalities via NIPT. PMID- 26509023 TI - Early definite stent thrombosis with everolimus-eluting stents. AB - Stent thrombosis (ST) is a serious complication of percutaneous coronary intervention. Several factors are associated with ST, and combination of these factors increase the risk, even in everolimus-eluting stents, which have low risk of ST. We experienced a case of ST caused by limited coronary flow and resistance to antiplatelet agent. PMID- 26509024 TI - Primary pleural precursor B-Cell lymphoblastic lymphoma. AB - Intrathoracic lymphoblastic lymphoma (LBL) is classically of T-cell lineage, but these cases of pleural B-cell LBL suggest that this is not always the case. Despite the clinical challenges involved every attempt should be made to secure a biopsy and histological diagnosis, as we move into an era of lineage-directed therapies. PMID- 26509025 TI - Successful treatment of fetal hemolytic disease due to glucose phosphate isomerase deficiency (GPI) using repeated intrauterine transfusions: a case report. AB - Hemolytic anemia due to GPI deficiency can be severe and life threatening during fetal life. When parents decline invasive testing, ultrasound monitoring of fetuses at risk is feasible. Intrauterine transfusion can be effective for the treatment of severe fetal anemia due to GPI deficiency. PMID- 26509026 TI - Congenital isolated Iso-Kikuchi syndrome in a newborn. AB - Classic CO (also called Iso-Kikuchi syndrome) represents a benign, isolated condition associated with normal patient outcome. Nevertheless, clinical follow up and/or further clinically-based tests are needed to exclude other nail diseases associated with multisystem pathology; complete family history is also important to determine sporadic or hereditary transmission of such condition. PMID- 26509027 TI - Nonsurgical management of multiple splenic abscesses in an obese patient that underwent laparoscopic sleeve gastrectomy: case report and review of literature. AB - Sleeve gastrectomy (SG) is a surgical weight-loss procedure. Splenic abscess is a rare complication of SG. Four cases of splenic abscess after SG have been reported, all managed by surgical intervention. We report the first documented case of multiple splenic abscesses following SG managed conservatively by an integrated medical treatment. PMID- 26509028 TI - Rapidly progressive sarcomatoid malignant mesothelioma of the pleura mimicking pulmonary empyema. AB - Refractory empyema occasionally reflects hidden malignant disease. We presented a rare case of rapidly progressive malignant mesothelioma of the pleura (MPM) mimicking empyema. Physicians should be aware of MPM when patients with empyema are refractory to the standard treatment, and PET-CT may be helpful in establishing a precise diagnosis in such cases. PMID- 26509029 TI - Rosai Dorfman disease diagnosed by fine-needle aspiration cytology in a young man with HIV infection. AB - RDD (Rosai Dorfman disease) is a rare and benign histiocytic proliferative disorder of unknown etiology. FNAC (Fine-needle aspiration cytology) is a useful and reliable tool for the diagnosis of RDD, and as such, biopsy is avoidable. PMID- 26509030 TI - The value of in vitro studies in a case of neonatal diabetes with a novel Kir6.2 W68G mutation. AB - In infants, especially with novel previously undescribed mutations of the KATP channel causing neonatal diabetes, in vitro studies can be used to both predict the response to sulphonylurea treatment and support a second trial of glibenclamide at higher than standard doses if the expected response is not observed. PMID- 26509031 TI - Sclerosing angiomatoid nodular transformation of the spleen. AB - Sclerosing angiomatoid nodular transformation (SANT) of spleen is a very rare benign entity with unknown etiology. Here, we report this unusual case in a fit middle-aged gentleman and discuss various diagnostic modalities along with the management of this condition. PMID- 26509032 TI - Multiple mycotic hepatic and splenic artery aneurysms in a patient with pneumococcal pneumonia: a case report with a review of the literature. AB - It is well-known that the major organisms for mycotic aneurysms are Staphylococcus aureus, Salmonella spp but is extremely rare in Streptococcus pneumoniae in postantibiotic era. We demonstrated the first case with multiple mycotic aneurysms simultaneously generated in the splenic and hepatic arteries in a patient with pneumococcal pneumonia. PMID- 26509033 TI - Aberrant right retroesophageal subclavian artery causing esophageal compression. AB - Dysphagia lusoria is present in 0.2-2.5% of the population representing the most common anomaly of the aortic arch (De Araujo et al., 2015, Int. J. Surg. Case Rep., 7, 32). It usually presents in infants, but can present at any age. Symptoms include cough, dysphagia, thoracic pain, and pulmonary infection. Barium contrast studies, CT, and MR angiography are useful studies for evaluating the condition. Dietary modification and PPI therapy are the first-line treatments with surgical intervention reserved for those with ongoing symptoms (Janssen et al., 2000, Am. J. Gastroenterol., 95, 1411). PMID- 26509034 TI - A different type of dominoes in the stomach. AB - Ingestion of foreign bodies is one of the common causes of emergency department visits. History, physical examination, and noninvasive imaging such as plain radiography and computer tomography scan can guide us regarding the type and location of the ingested foreign body. Most of the patients can be managed conservatively but few may need endoscopic evaluation and treatment. PMID- 26509035 TI - Visible light-initiated interfacial thiol-norbornene photopolymerization for forming islet surface conformal coating. AB - A cytocompatible visible light-mediated interfacial thiol-norbornene photopolymerization scheme was developed for creating hydrogel conformal coating on pancreatic islets. The step-growth thiol-norbornene reaction affords high consistency and tunability in gel coating thickness. Furthermore, isolated islets coated with thiol-norbornene gel maintained their viability and function in vitro. PMID- 26509036 TI - Shaping bio-inspired nanotechnologies to target thrombosis for dual optical magnetic resonance imaging. AB - Arterial and venous thrombosis are among the most common causes of death and hospitalization worldwide. Nanotechnology approaches hold great promise for molecular imaging and diagnosis as well as tissue-targeted delivery of therapeutics. In this study, we developed and investigated bioengineered nanoprobes for identifying thrombus formation; the design parameters of nanoparticle shape and surface chemistry, i.e. incorporation of fibrin-binding peptides CREKA and GPRPP, were investigated. Two nanoparticle platforms based on plant viruses were studied - icosahedral cowpea mosaic virus (CPMV) and elongated rod-shaped tobacco mosaic virus (TMV). These particles were loaded to carry contrast agents for dual-modality magnetic resonance (MR) and optical imaging, and both modalities demonstrated specificity of fibrin binding in vitro with the presence of targeting peptides. Preclinical studies in a carotid artery photochemical injury model of thrombosis confirmed thrombus homing of the nanoprobes, with the elongated TMV rods exhibiting significantly greater attachment to thrombi than icosahedral (sphere-like) CPMV. While in vitro studies confirmed fibrin-specificity conferred by the peptide ligands, in vivo studies indicated the nanoparticle shape had the greatest contribution toward thrombus targeting, with no significant contribution from either targeting ligand. These results demonstrate that nanoparticle shape plays a critical role in particle deposition at the site of vascular injury. Shaping nanotechnologies opens the door for the development of novel targeted diagnostic and therapeutic strategies (i.e., theranostics) for arterial and venous thrombosis. PMID- 26509037 TI - Systematic evaluation of natural scaffolds in cutaneous wound healing. AB - Current strategies to improve wound healing are often created from multiple components that may include a scaffold, cells, and bioactive cues. Acellular natural hydrogels are an attractive approach since the material's intrinsic biological activity can be paired with mechanical properties similar to soft tissue to induce a host's response toward healing. In this report, a systematic evaluation was conducted to study the effect of hydrogel scaffold implantation in skin healing using a human-relevant murine wound healing model. Fibrin, micro porous hyaluronic acid, and composite hydrogels were utilized to study the effect of conductive scaffolds on the wound healing process. Composite hydrogels were paired with plasmin-degradable VEGF nanocapsules to investigate its impact as an inductive composite hydrogel on tissue repair. By 7 days, wound healing and vessel maturation within the newly formed tissue was significantly improved by the inclusion of porous scaffold architecture and VEGF nanocapsules. PMID- 26509038 TI - Zwitterionic amphiphile coated magnetofluorescent nanoparticles - synthesis, characterization and tumor cell targeting. AB - Magnetofluorescent nanoparticles (MFNPs) have recently attracted significant research interests due to their potential applications in biological manipulation and imaging. In this work, through a simple and fast self-assembling process, we first report the preparation of zwitterionic MFNPs (ZW-MFNPs) in the form of micelles using our newly synthesized zwitterionic amphiphiles, CuInS2/ZnS quantum dots, and MnFe2O4 magnetic nanoparticles. ZW-MFNPs integrate both MnFe2O4 magnetic nanoparticles and CuInS2/ZnS quantum dots in their hydrophobic cores and zwitterionic groups such as carboxybetaine and sulfobetaine on their hydrophilic shells. ZW-MFNPs possess dual imaging properties, high (Mn + Fe) recovery, excellent stability in aqueous solutions with a wide pH/ionic-strength range and physiological media, minimal cytotoxicity, and specific targeting to brain tumor cells after bioconjugation with chlorotoxin. The unique characteristics of ZW MFNPs may open an avenue for these particles to be employed in broad biomedical applications. PMID- 26509039 TI - Incidences and influences of device-associated healthcare-associated infections in a pediatric intensive care unit in Japan: a retrospective surveillance study. AB - BACKGROUND: Device-associated healthcare-associated infections (DA-HAIs) are a major problem in pediatric intensive care units (PICUs). However, there are no data available regarding the incidences of DA-HAIs in PICUs in Japan and their influences on length of PICU stay and mortality. The objective of this study was to investigate the incidences of three common DA-HAIs in a PICU and their influences on length of PICU stay and mortality in Japan. METHODS: We performed a retrospective surveillance study over 12 months in a single PICU in Japan. First, we investigated the incidences of three common DA-HAIs: central line-associated bloodstream infections (CLABSI), ventilator-associated pneumonia (VAP), and catheter-associated urinary tract infection (CAUTI) by chart review, according to the surveillance definitions of the Centers for Disease Control and Prevention/National Healthcare Safety Network. Second, we compared patient characteristics, morbidity, and mortality between the patients with and without DA-HAIs. RESULTS: Of all 426 patients admitted to the PICU, 73 % had a central venous catheter, 75 % had an endotracheal tube, and 81 % had a urinary catheter during their PICU stay; the device utilization ratios per patient-days for these were 0.78, 0.53, and 0.44, respectively. In total, 28 patients (6.6 %) acquired at least one of the three DA-HAIs investigated, with an overall incidence per 1000 patient-days of 11.2. The incidences of CLABSI, VAP, and CAUTI per 1000 device-days were 4.3, 3.5, and 13.6, respectively. The median length of PICU stay for the patients with DA-HAIs was 22.5 days, compared with 2 days for those without DA-HAIs. Although there was no statistical difference, the mortality of the patients with DA-HAIs was 7.1 %, whereas the mortality of the patients without DA-HAIs was 2.3 %. CONCLUSIONS: This study showed the incidences of three common DA-HAIs in a PICU in Japan, and that they were associated with a longer length of PICU stay. PMID- 26509040 TI - Demographic, health-related, and work-related factors associated with body mass index and body fat percentage among workers at six Connecticut manufacturing companies across different age groups: a cohort study. AB - BACKGROUND: Effective workplace interventions that consider the multifactorial nature of obesity are needed to reduce and prevent obesity among adults. Furthermore, the factors associated with obesity may differ for workers across age groups. Therefore, the objective of this study was to identify demographic, health-related, and work-related factors associated with baseline and changes in body mass index (BMI) and body fat percentage (BFP) and among Connecticut manufacturing workers acrossage groups. METHODS: BMI and BFPof 758 workers from six Connecticut manufacturing companies were objectively measuredat two time points approximately 36 months apart. Demographic, health-related, and work related factors wereassessed via questionnaire. All variables were included in linear regression models to identify factors associated with baseline and changes in BMI and BFP for workers in 3 age groups: <45 years (35 %), 45-55 years (37 %), >55 years (28 %). RESULTS: There were differences in baseline and changes in BMI and BFP among manufacturing workers across age groups. Being interested in changing weight was significantly (p < 0.01) associated with higher baseline BMI and BFP across all age categories. Other factors associated with higher baseline BMI and BFP differed by age group and included: male gender (BMI p = 0.04), female gender (BFP p < 0.01), not having a college education (BMI p = 0.01, BFP p = 0.04), having childcare responsibilities (BMI p = 0.04), and working less overtime (p = 0.02) among workers in the <45 year age category, male gender (BMI p = 0.02), female gender (BFP p < 0.01) and reporting higher stress in general (BMI p = 0.04) among workers in the 45-55 year age category, and female gender (BFP p < 0.01) and job tenure (BFP p = 0.03) among workers in the >55 year age category. Few factors were associated with change in BMI or BFP across any age category. CONCLUSIONS: Among manufacturing workers, we identified associations between individual, health-related, and work-related factors and baseline BMIand BFP that differed by age. Such results support the use of strategies tailored to the challenges faced by workers in specific age groups rather than adopting a one size fits all approach. Effective interventions should consider a full range of individual, health-related, and work-related factors. More work must be done to identify factors or strategies associated with changes in obesity over time. PMID- 26509041 TI - Does BMI generated by self-reported height and weight measure up in older adults from middle-income countries? Results from the study on global AGEing and adult health (SAGE). AB - BACKGROUND: Self-reported (SR) body mass index (BMI) values are often used to determine obesity prevalence. However, individuals frequently overestimate their height and underestimate their weight, resulting in artificially lower obesity prevalence rates. These patterns are especially apparent among older adults and overweight individuals. The present cross-sectional study uses nationally representative datasets from five countries to assess the accuracy of SR BMI values in diverse settings. METHODS: Samples of older adults (>=50 years old) and comparative samples of younger adults (18-49 years old) were drawn from five middle-income countries (China, India, Mexico, Russian Federation, and South Africa) in the World Health Organization's Study on global AGEing and adult health (SAGE). Participant-reported and researcher-obtained height and weight measures were used to calculate SR and measured BMI, respectively. Paired t-tests assessed differences between SR and measured BMI values by country. Linear regressions examined the contribution of measured weight and age to differences between SR and measured BMI. RESULTS: Significant differences between SR and measured BMI values were observed (p < 0.05), but the direction of these discrepancies varied by country, age, and sex. Measured weight significantly contributed to differences between SR and measured BMI in all countries (p < 0.01). Age did not contribute significantly to variation in BMI discrepancy, except in China (p < 0.001). CONCLUSIONS: These results suggest that SR BMI may not accurately reflect measured BMI in middle-income countries, but the direction of this discrepancy varies by country. This has considerable implications for obesity-related disease estimates reliant on SR data. PMID- 26509042 TI - What is the prevalence of MRI-detected inflammation and erosions in small joints in the general population? A collation and analysis of published data. AB - INTRODUCTION: MRI sensitively depicts erosions, bone marrow edema (BME) and synovitis in rheumatoid arthritis (RA). Recently developed European League Against Rheumatism (EULAR) recommendations stated that MRI is valuable to improve the certainty of a considered diagnosis and to detect structural damage at an early time point. However, these recommendations were mainly based on the data of patients with RA; prevalences of MRI features in the general population were not extensively explored. We reviewed the literature on MRI studies including symptom free persons to assess the occurrence of MRI features. METHODS: Medical literature databases up to September 2013 were systematically reviewed for symptom-free persons with MRI data on metacarpophalangeal, wrist and metatarsophalangeal joints. Data were extracted and summarised. When allowed because of comparable scanning and scoring protocols, a mean frequency of features was calculated. RESULTS: Of the 338 articles screened, 31 studies evaluated MRI findings in symptom-free persons (n=516 in total). Both the imaging techniques (<1/>=1 T, with/without contrast enhancement) and the scoring methods (non-validated or RA MRI score (RAMRIS)) varied widely, prohibiting direct comparisons of the results of many studies. 15 studies scored data according to RAMRIS; combining data of similar joint regions showed that erosions (RAMRIS >=1) were present in 33-52% of symptom-free persons. Similarly, synovitis was present in 27% and BME in 0-16% of symptom-free persons. The prevalence of MRI-detected erosions increased with age. CONCLUSIONS: MRI features, erosions in particular, occur frequently in symptom-free persons. Before MRI can be implemented in the diagnostic process, larger studies should be conducted determining the degree and combination of MRI features that are disease specific. PMID- 26509043 TI - Psoriatic arthritis: an evolving matter. PMID- 26509044 TI - A prospective study of the 1-year incidence of fibromyalgia after acute whiplash injury. AB - OBJECTIVE: To measure the 1-year incidence of fibromyalgia in a cohort of acute whiplash-injured participants. METHODS: Consecutive acute patients with whiplash were assessed via the 2010 Modified American College of Rheumatology (ACR) criteria for fibromyalgia at 3 months, 6 months and 1 year postinjury. At each of these follow-up points, participants were also examined for recovery from whiplash injury. RESULTS: Of an initial 268 participants, data on recovery was available for 264 participants during the 1-year follow-up period. At the 3-month follow-up, 62% (167/268) of participants reported recovery from their whiplash injuries. At 6 months, 76% (203/268) reported recovery, and at 1 year 82% (216/264) reported recovery. At 3 and 6 months follow-up none of the participants met the 2010 Modified ACR Criteria for fibromyalgia, but fibromyalgia criteria were met for 2 (of 264) seen at the 1-year follow-up, yielding a 1-year incidence of 0.8% (95% CI 0.1% to 3.0%). CONCLUSIONS: In the primary care setting, a significant proportion of patients with whiplash recover from whiplash injury at 1 year, and the incidence of fibromyalgia after acute whiplash injury is very low. The impression that fibromyalgia is common after whiplash injury may be due to the failure to exclude precollision fibromyalgia cases or due to referral bias of non-recovered patients. PMID- 26509045 TI - For patients with rheumatic disease and hepatitis C infection: the end of interferon. AB - Hepatitis C virus (HCV) is a global pathogen and is the cause of rare but complex rheumatic complications but more commonly exists as a challenging comorbidity for patients with existing rheumatic diseases. Until recently, the standard of care of HCV has been the use of interferon-based regimens, which not only have limited effectiveness in curing the underlying viral illness but are poorly tolerated and in patients with rheumatic diseases especially problematic given their association with a wide variety of autoimmune toxicities. Numerous and other more effective and better tolerated regimens are rapidly emerging incorporating direct acting antiviral agents that do not require the use of interferon, that is, interferon free. The potential of interferon free treatment of HCV makes screening for this comorbidity more important than ever. Rheumatologists need to be knowledgeable about these therapeutic advances and partner with hepatologists to craft the most efficacious and toxicity-free regimes possible. PMID- 26509046 TI - Biosimilars in rheumatology: what the clinician should know. AB - Biosimilars are now a reality in rheumatology. Although analytical and non clinical procedures to establish similarity have evolved significantly, clinical trials demonstrating equivalent efficacy and safety are absolutely required for all biosimilars. The design of such trials, including equivalence and non inferiority statistical approaches, are discussed. Clinical evidence on biosimilars that have been approved recently or are presently being developed for use in rheumatology is also reviewed and contrasted with that available for biomimics (or intended copies), which are non-innovator biologics that are marketed in several countries but have not undergone review according to a regulatory pathway for biosimilars. PMID- 26509047 TI - Belimumab in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is one of the most challenging autoimmune disorders with a complex pathophysiology and diverse clinical presentation. Many drugs have been used to treat SLE with suboptimal results, especially in patients with moderate-to-severe disease. Belimumab is the first biological drug to be approved for the treatment of SLE in more than 50 years. This monoclonal antibody blocks B-cell activating factor, a cytokine important for B-cell differentiation and survival. In this review we focus on the activity of belimumab in patients with SLE and discuss the controversies of its use. PMID- 26509048 TI - Obesity and inflammatory arthritis: impact on occurrence, disease characteristics and therapeutic response. AB - Overweight and obesity are increasing worldwide and now reach about one-third of the world's population. Obesity also involves patients with inflammatory arthritis. Knowing the impact of obesity on rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis) is thus an important issue. This article first reviews the epidemiological and clinical data available on obesity in inflammatory rheumatic diseases, that is, its impact on incident disease, disease characteristics and the therapeutic response. The second part of this review gives an overview of the factors potentially involved in the specifics of inflammatory arthritis in patients with obesity, such as limitations in the clinical assessment, diet, microbiota and adipokines. PMID- 26509049 TI - Glucocorticoid-induced osteoporosis. AB - Corticosteroid-induced osteoporosis is the most common form of secondary osteoporosis and the first cause in young people. Bone loss and increased rate of fractures occur early after the initiation of corticosteroid therapy, and are then related to dosage and treatment duration. The increase in fracture risk is not fully assessed by bone mineral density measurements, as it is also related to alteration of bone quality and increased risk of falls. In patients with rheumatoid arthritis, a treat-to-target strategy focusing on low disease activity including through the use of low dose of prednisone, is a key determinant of bone loss prevention. Bone loss magnitude is variable and there is no clearly identified predictor of the individual risk of fracture. Prevention or treatment of osteoporosis should be considered in all patients who receive prednisone. Bisphosphonates and the anabolic agent parathyroid hormone (1-34) have shown their efficacy in the treatment of corticosteroid-induced osteoporosis. Recent international guidelines are available and should guide management of corticosteroid-induced osteoporosis, which remains under-diagnosed and under treated. Duration of antiosteoporotic treatment should be discussed at the individual level, depending on the subject's characteristics and on the underlying inflammation evolution. PMID- 26509050 TI - Predictors of response to TNF antagonists in patients with ankylosing spondylitis and psoriatic arthritis: systematic review and meta-analysis. AB - OBJECTIVE: To identify predictors of response to tumor necrosis factor (TNF) antagonists in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS: Systematic review and meta-analysis of clinical trials and observational studies based on a systematic search. Meta-analyses of similar observations were performed using random effects computing summary OR. Heterogeneity was tested using I(2), and risks of bias using funnel plots and the Egger test. Meta regression was used to explore causes of heterogeneity. RESULTS: The electronic search captured 1340 references and 217 abstracts. 17 additional articles were identified after searching by hand. A total of 59 articles meet the purpose of the study and were reviewed. 37 articles (33 studies) included 6736 patients with AS and 23 articles (22 studies) included 4034 patients with PsA. 1 article included data on AS and PsA. Age (OR (95% CI) 0.91 (0.84 to 0.99), I(2)=84.1%), gender (1.57 (1.10 to 2.25), I(2)=0.0%), baseline BASDAI (1.31 (1.09 to 1.57), I(2)=0.0%), baseline BASFI (0.86 (0.79 to 0.93), I(2)=24.9%), baseline dichotomous C reactive protein (CRP) (2.14 (1.71 to 2.68), I(2)=22.3%) and human leucocyte antigen B27 (HLA-B27) (1.81 (1.35 to 2.42), I(2)=0.0%) predict BASDAI50 response in AS. No factor was identified as a source of heterogeneity. Only meta analysis of baseline BASFI showed risk of publication bias (Egger test, p=0.004). Similar results were found for ASAS criteria response. No predictors of response were identified in PsA. CONCLUSIONS: Young age, male sex, high baseline BASDAI, low baseline BASFI, high baseline CRP and HLA-B27 predict better response to TNF antagonists in AS but not in PsA. PMID- 26509051 TI - Identifying patients with rheumatoid arthritis with moderate disease activity at risk of significant radiographic progression despite methotrexate treatment. AB - OBJECTIVES: To determine the baseline factors predictive of significant radiographic progression (SRP) in patients with moderately active rheumatoid arthritis (RA) despite receiving methotrexate (MTX). METHODS: Patients from the MTX arm of the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) trial with sustained moderate RA (defined as >=3.2 mean disease activity score in 28 joints <=5.1 during the last 6 months of the first year) were analysed for SRP (mTSS >3.0 overall) after 2 and 3 years. Baseline predictors for SRP were identified by univariate and multivariate analyses. All variables shown to be significantly associated with SRP were categorised based on clinically relevant cut-offs and tertiles and were included in a matrix risk model. RESULTS: 228 patients were assigned MTX treatment, 210 patients were in the radiographic intention-to-treat population, and 96 of these had sustained moderate RA. SRP occurred in 25 (26%) and 33 (34%) patients after 2 and 3 years of MTX treatment, respectively. Univariate and multivariate analyses found that C reactive protein (CRP) and rheumatoid factor (RF) positivity at baseline were predictive of SRP after 2 and 3 years (p<0.05 for all). The matrix risk model showed that RF positivity and CRP levels >40 mg/L at baseline were significantly associated with SRP after 2 (p<0.05 for both; R(2)=0.24) and 3 years (p<0.05 for both; R(2)=0.22). The baseline erosion score was not found to be predictive of SRP. CONCLUSIONS: Patients with sustained moderate RA despite receiving MTX treatment are at risk of SRP, with both RF positivity and high CRP levels shown to be predictive of this. PMID- 26509052 TI - Patient-reported outcomes as end points in clinical trials in rheumatoid arthritis. AB - There is a growing interest in patient-reported outcomes (PROs) in rheumatology, which goes with a global trend for more 'patient-centred care'. This review considers the use of PROs in trials, including their strengths and limitations. In rheumatoid arthritis (RA) trials, the most frequently used PROs to assess treatments include pain, patient global assessment, assessment of functional status, but also health-related quality of life and less commonly fatigue. Other aspects of importance for patients, such as sleep, psychological well-being or ability to cope, are rarely assessed. PROs as outcome measures in RA trials have strengths as well as limitations. PROs have face validity, they are reproducible and sensitive to change and they bring additional information beyond joint counts or acute phase reactants. However, their predictive validity for later outcomes has been little explored, some PROs show redundancy (they bring similar information) and, due to the apparently moderate link between some PROs such as fatigue and the disease process, the use of some PROs to inform treatment choices has been questioned. We suggest the choice of PROs for trials depends on the study objective and on the viewpoint of the stakeholder. There needs to be agreed prioritisation across all stakeholders about what is most important to collect in a trial, which is why a prioritisation and selection process is necessary. Trials in RA will continue to include PROs and their interpretation will become easier as our knowledge progresses. PMID- 26509053 TI - Depression is a stronger predictor of the risk to consider work disability in early arthritis than disease activity or response to therapy. AB - OBJECTIVES: To evaluate the factors that influence patients with early inflammatory arthritis to consider a disability pension. METHODS: A total of 528 patients aged 63 or younger from an early arthritis cohort with a mean symptom duration of 3 months at inclusion were asked at 12 and 24 months whether they were considering applying for, had applied for or were receiving a disability pension because of arthritis. Possible predictors were analysed with univariate and multivariate logistic regression. RESULTS: 69 patients (13%) were considering, had applied for or were receiving a disability pension. Univariate predictors were older age, disease activity, several patient-reported outcomes and depression. In a multivariate analysis, age, days on sick leave, impairment of physical function and depression were predictive for considering a disability pension (OR for severe vs no depression: 3.85, 95% CI 1.43 to 10.4). CONCLUSIONS: In patients with early arthritis, depression appears to be a stronger predictor of the risk to consider applying for work disability pension than the features of disease activity. Patients at risk could be identified with one single depression statement. This finding should prompt physicians to react early to signs and symptoms of depression to help patients to maintain their ability to work. PMID- 26509054 TI - EULAR Sjogren's syndrome disease activity index (ESSDAI): a user guide. AB - The EULAR Sjogren's syndrome (SS) disease activity index (ESSDAI) is a systemic disease activity index that was designed to measure disease activity in patients with primary SS. With the growing use of the ESSDAI, some domains appear to be more challenging to rate than others. The ESSDAI is now in use as a gold standard to measure disease activity in clinical studies, and as an outcome measure, even a primary outcome measure, in current randomised clinical trials. Therefore, ensuring an accurate and reproducible rating of each domain, by providing a more detailed definition of each domain, has emerged as an urgent need. The purpose of the present article is to provide a user guide for the ESSDAI. This guide provides definitions and precisions on the rating of each domain. It also includes some minor improvement of the score to integrate advance in knowledge of disease manifestations. This user guide may help clinicians to use the ESSDAI, and increase the reliability of rating and consequently of the ability to detect true changes over time. This better appraisal of ESSDAI items, along with the recent definition of disease activity levels and minimal clinically important change, will improve the assessment of patients with primary SS and facilitate the demonstration of effectiveness of treatment for patients with primary SS. PMID- 26509055 TI - What makes psoriatic and rheumatoid arthritis so different? AB - In many ways, it may be easier to highlight what rheumatoid arthritis (RA) and psoriatic arthritis (PsA) have in common. They are both common conditions characterised by a spectrum of features or clinical manifestations in different organ systems that have led many to conclude that they are actually 'disease syndromes'. Furthermore, many of the organ systems that are affected in both conditions are the same: skin, joints, eyes, vasculature and even the immune system. Indeed, some clinicians fail to recognise these two common arthritides as distinct. And yet, while the manifestations may have a superficial similarity, there are significant differences at a number of levels including clinical, anatomical, microscopic and molecular levels. However, these differences may explain certain clinical manifestations of the two diseases, and more importantly, they may explain different responses to specific therapies and potentially different disease outcomes and prognoses. This may be especially relevant as new therapeutic targets are examined that may be specific for RA or PsA. PMID- 26509056 TI - Patient-reported improvements in health are maintained 2 years after completing a short course of cognitive behaviour therapy, exercise or both treatments for chronic widespread pain: long-term results from the MUSICIAN randomised controlled trial. AB - OBJECTIVES: The MUSICIAN study has previously shown short-term benefit but only marginal cost-effectiveness for two non-pharmacological interventions for chronic widespread pain (CWP). We wished to determine their long-term effectiveness and cost-effectiveness. METHODS: A 2*2 factorial randomised controlled trial based in primary care in the UK. People were eligible if they were aged >=25 years with CWP for which they had consulted their general practitioner. The interventions were a 6-month telephone cognitive behaviour therapy (tCBT) and/or a tailored exercise programme, in comparison to usual care. The primary outcome was patient reported change in health. RESULTS: 884 persons were eligible, 442 were randomised and 81.7% were followed up 24 months post-treatment. In comparison to usual care (positive outcome 12.8%), tCBT (35.4%; OR 3.7 95% CI (1.8 to 8.0)), exercise (29.3%; OR 2.8 95% CI (1.3 to 6.0)) and both interventions (31.2%; OR 3.1 95% CI (1.3 to 6.0)) were significantly more effective. There was only a small decrease in effectiveness over time for individual and combined treatments. Those with more intense/disabling pain, higher distress and those who exhibited passive coping at baseline were more likely to have a positive outcome with tCBT than persons without these characteristics. tCBT was associated with the greatest increase in quality of life and lowest costs. Cost per quality adjusted life year was L3957-L5917 depending on method of analysis. CONCLUSIONS: A short course of tCBT for people with CWP was effective long-term and was highly cost-effective. Exercise was also effective but delivered positive outcome for fewer patients at greater cost, and there was no advantage for patients receiving both interventions. TRIAL REGISTRATION NUMBER: ISRCTN67013851. PMID- 26509057 TI - Non-surgical management of knee osteoarthritis: where are we now and where do we need to go? AB - After the successful treatment of inflammatory rheumatic diseases with targeted therapies, the greatest challenge in rheumatic diseases remains the treatment of the most common chronic joint disorder, osteoarthritis. Osteoarthritis (OA) commonly affects the knee, with an age-standardised and sex-standardised incidence of 240 per 100.000 person-years. With the aging of the population and rising obesity throughout the world, it is anticipated that the burden of OA will increase and become a major problem for health systems globally. Given this background, proper guidance on the management of OA is needed. This issue has been addressed over recent months in updated guidelines or recommendations detailing three treatment modalities: non-pharmacological, pharmacological and surgical. It should be noted, that OA is not a uniform disease entity. In some patients, progression of the disease seems to be driven by cartilage factors, in others by bone factors or by inflammatory factors. Ongoing research aims to identify potential biomarkers for these different forms of OA. Research is also underway into disease modifying OA drugs (DMOADs) that target different aspects of the disease, treatments for OA pain, and cell-based therapies. PMID- 26509058 TI - Genetics of RA susceptibility, what comes next? AB - Genome-wide association studies (GWASs) have been used to great effect to identify genetic susceptibility loci for complex disease. A series of GWAS and meta-analyses have informed the discovery of over 100 loci for rheumatoid arthritis (RA). In common with findings in other autoimmune diseases the lead signals for the majority of these loci do not map to known gene sequences. In order to realise the benefit of investment in GWAS studies it is vital we determine how disease associated alleles function to influence disease processes. This is leading to rapid development in our knowledge as to the function of non coding regions of the genome. Here we consider possible functional mechanisms for intergenic RA-associated variants which lie within lncRNA sequences. PMID- 26509059 TI - Introducing RMD Open. PMID- 26509060 TI - Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the AutoImmunity and Rituximab registry. AB - OBJECTIVES: To evaluate the prevalence of late-onset neutropenia and its complications in patients treated with rituximab (RTX) for rheumatoid arthritis (RA) and other autoimmune diseases (AIDs) in a prospective registry. METHODS: The AutoImmunity and Rituximab registry is an independent 7-year prospective registry promoted by the French Society of Rheumatology. For each episode of neutropenia, data were validated by the clinician in charge of the patient. RESULTS: Among 2624 patients treated with RTX for refractory AIDs, and at least 1 follow-up visit (a total follow-up of 4179 patient-years in RA and 987 patient-years in AIDs), late-onset neutropenia was observed in 40 patients (25 RA (1.3% of patients with RA, 0.6/100 patient-years), and AIDs in 15 (2.3% of patients with AIDs, 1.5/100 patient-years)). 6 patients (15%) had neutrophils <500/mm(3), 8 (20%) had neutrophils between 500 and 1000/mm(3), and 26 (65%) had neutrophils between 1000 and 1500/mm(3). Neutropenia occurred after a median period of 4.5 (3 6.5) months after the last RTX infusion in patients with RA, and 5 (3-6.5) months in patients with AIDs. 5 patients (12.5%), 4 of them with neutrophils lower than 500/mm(3), developed a non-opportunistic serious infection and required antibiotics and granulocyte colony-stimulating factor injections, with a favourable outcome. After resolution of their RTX-related neutropenia, 19 patients (47.5%) were re-treated, and neutropenia reoccurred in 3 of them. CONCLUSIONS: Late-onset neutropenia might occur after RTX and may result in serious infections. Thus, monitoring of white cell count should be performed after RTX. However, in this large registry of patients with AIDs, the frequency of RTX-induced neutropenia was much lower than that previously reported in patients treated for blood malignancies or AIDs. PMID- 26509061 TI - Biological treatment in systemic juvenile idiopathic arthritis: achievement of inactive disease or clinical remission on a first, second or third biological agent. AB - OBJECTIVES: To analyse the effect of biological agents (BAs) in terms of achieving inactive disease (ID) or clinical remission (CR) in patients with systemic juvenile idiopathic arthritis (SJIA), to describe effects of switching or discontinuing a BA and to assess the proportion of patients able to maintain ID or CR off steroids and after withdrawing BA therapy. METHODS: Retrospective study in a French paediatric rheumatology reference centre using the CEMARA (CEntre des MAladies RAres) register. RESULTS: Seventy-seven patients were included with a cumulative follow-up of 245.5 patient-years (median 1.1, range 0.5-8.0). On a first BA, ID was achieved in 37 patients, including 1 patient out of 12 patients on etanercept, 26 patients out of 51 on anakinra and 7 out of 10 on canakinumab. One patient on abatacept and two patients on tocilizumab also achieved ID. Switching of BA was common. The switch to a second (n=34), third (n=18) or fourth (n=4) BA resulted in ID in a further 13 patients, either on canakinumab (n=6) or tocilizumab (n=7). At last follow-up, 40 patients were in CR (27 patients off steroids, 5 patients having never received steroid treatment), either on (n=29) or off (n=11) BA. CONCLUSIONS: In this series of patients with SJIA, interleukin-1 inhibitors were associated with a higher proportion of ID than tumour necrosis factor inhibitors when used as first BA. Switching allowed some patients to achieve ID when treated with canakinumab or tocilizumab. CR was eventually achieved in more than half of the patients. PMID- 26509062 TI - The impact of patient heterogeneity and socioeconomic factors on abatacept retention in rheumatoid arthritis across nine European countries. AB - BACKGROUND: There are substantial differences in accessibility to biological disease modifying antirheumatic drugs (bDMARDs) across countries. The objective of this study was to analyse the impact of patient demographics, disease characteristics and gross domestic product (GDP) on abatacept (ABA) retention in patients with rheumatoid arthritis (RA) treated in clinical practice. METHODS: Data from nine European observational RA cohorts of patients treated with ABA were pooled. Kaplan-Meier analysis was used to compare drug retention across registries. Specific causes of drug retention were investigated using competing risks multivariate Cox regression. RESULTS: A total of 3961 patients treated with ABA, with 6188 patient-years of follow-up, were included. Patients in the different national registries had similar demographic features, but varied in baseline disease characteristics. ABA drug retention differed between countries, with median drug retention rates ranging from 1.2 to more than 6 years. The differences in drug retention were marginally explained by disparities in disease characteristics, while the national GDP per capita was strongly associated with drug retention (correlation coefficient -0.74; p=0.02). CONCLUSIONS: Patient characteristics at ABA initiation vary across Europe, probably reflecting differences in eligibility criteria and prescription patterns. However, the difference in ABA drug retention between countries was not primarily explained by disparities in patient characteristics. Lower ABA retention was observed in countries with a more liberal access to bDMARDs and higher GDP. National differences need to be accounted for when pooling data on treatment with bDMARDs from various countries. PMID- 26509063 TI - Fatigue in rheumatoid arthritis; a persistent problem: a large longitudinal study. AB - OBJECTIVE: Fatigue is prevalent and disabling in rheumatoid arthritis (RA). Surprisingly, the long-term course of fatigue is studied seldom and it is unclear to what extent it is influenced by inflammation. This study aimed to determine the course of fatigue during 8 years follow-up, its association with the severity of inflammation and the effect of improved treatment strategies. METHODS: 626 patients with RA included in the Leiden Early Arthritis Clinic cohort were studied during 8 years. Fatigue severity, measured on a 0-100 mm scale, and other clinical variables were assessed yearly. Patients included in 1993-1995, 1996 1998 and 1999-2007 were treated with delayed treatment with disease-modifying antirheumatic drugs (DMARDs), early treatment with mild DMARDs and early treatment with methotrexate respectively. After multiple imputation, the serial measurements were analysed using linear quantile mixed models. RESULTS: Median fatigue severity at baseline was 45 mm and remained, despite treatment, rather stable thereafter. Female gender (effect size=4.4 mm), younger age (0.2 mm less fatigue/year), higher swollen and tender joint counts (0.3 mm and 1.0 mm more fatigue/swollen or tender joint) and C reactive protein-levels (0.1 mm more fatigue per mg/L) were independently and significantly (p<0.05) associated with fatigue severity over 8 years. Although improved treatment strategies associated with less severe radiographic progression, there was no effect on fatigue severity (p=0.96). CONCLUSIONS: This largest longitudinal study on fatigue so far demonstrated that the association between inflammation and fatigue is statistically significant but effect sizes are small, suggesting that non inflammatory pathways mediate fatigue as well. Improved treatment strategies did not result in less severe fatigue. Therefore, fatigue in RA remains an 'unmet need'. PMID- 26509064 TI - The incidence of tuberculosis in patients treated with certolizumab pegol across indications: impact of baseline skin test results, more stringent screening criteria and geographic region. AB - OBJECTIVES: We report the incidence of tuberculosis (TB) across certolizumab pegol (CZP) clinical trials in rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), before and after the introduction of stricter TB screening. METHODS: TB incidence rates (IRs) were assessed and stratified according to screening guidelines used at the time of CZP trials. Before 2007 (original trials), purified protein derivative (PPD) tuberculin skin test positivity varied according to local standards (induration >=5 up to >=20 mm). Since 2007, all CZP trial protocols have been amended, including trials spanning (intermediate) and initiated after 2007 (current), mandating that any patient with PPD>=5 mm receives treatment for latent TB infection (LTBI). All cases of suspected TB or PPD>=5 mm, in pooled data from 5402 CZP patients across all CZP trials up to 2012, underwent blinded central review by independent experts. RESULTS: 44 TB cases were confirmed in pooled CZP RA trials (IR 0.47/100PY, patient-years) with no cases in Japanese RA trials (J RAPID, HIKARI). Single TB cases were confirmed in psoriasis and axSpA trials (RAPID-axSpA), and no cases in the PsA trial (RAPID-PsA). IR of TB was 0.51/100PY across original or intermediate RA trials and 0.18/100PY in current trials. The majority of TB cases in RA occurred in Eastern (IR 1.02/100PY) and Central Europe (IR 0.58/100PY). Of 242/370 PPD>=5 mm patients who received 9 months isoniazid (INH) treatment for latent TB infection (LTBI), none developed TB, versus 7.8% of 128 untreated PPD>=5 mm patients. CONCLUSIONS: Implementation of more stringent LTBI screening, plus treatment for LTBI, reduced the IR of TB, even when INH was administered after starting CZP therapy. PMID- 26509065 TI - Inflammation, bone loss and fracture risk in spondyloarthritis. AB - Osteoporosis (ie, low bone mineral density) is common in ankylosing spondylitis, related to both systemic inflammation and decreased mobility. Vertebral fracture risk is increased; acute back pain in these patients is not always a flare-up of the disease, as it can be related to bone complications. Intervertebral disc fractures in the ankylosed spine are associated with severe neurological complications. As expected from pathophysiology, treatments effective against inflammation have a positive effect on bone, and prospective open studies have shown that tumour-necrosis-factor blockers can improve bone mineral density at the spine and the hip. There is so far no evidence of a decreased risk of fractures with such treatment. PMID- 26509066 TI - ACPA-positive primary Sjogren's syndrome: true primary or rheumatoid arthritis associated Sjogren's syndrome? AB - OBJECTIVES: Anticyclic citrullinated protein antibodies (ACPA) are highly specific of rheumatoid arthritis (RA). However, they have also been detected in 5 10% of primary Sjogren's syndrome (pSS). We compared ACPA-positive and negative patients with pSS and assessed the risk of evolution to RA. PATIENTS AND METHODS: ACPA-positive and negative patients with pSS were included in this study. For ACPA-positive patients, clinical and radiological re-evaluation was systematically performed after at least 5 years of follow-up. Diagnosis was reassessed at the end of the follow-up to identify patients that developed RA according to the American College of Rheumatology 1987 classification criteria. RESULTS: At inclusion in the cohort 16 patients with pSS were ACPA positive and 278 were ACPA negative. ACPA-positive patients, had more frequently arthritis (43.7% vs 12.2%; p=0.003) but not arthralgias. They also had more frequent lung involvement (25% vs 8.1%; p=0.05). After median follow-up of 8 (5-10) years, 7/16 (43.8%) patients developed RA including 5 (31.25%) with typical RA erosions. Elevation of acute phase reactants at inclusion was the only parameter associated with progression to erosive RA. CONCLUSIONS: Median term follow-up of ACPA positive patients with pSS showed that almost half of them developed RA, particularly in the presence of elevation of acute phase reactants. These results support the usefulness of a close radiological monitoring of these patients for early detection of erosive change not to delay initiation of effective treatment. Indeed, number of these patients with ACPA-positive pSS may actually have RA and associated SS. PMID- 26509067 TI - The H2 blocker famotidine suppresses progression of ossification of the posterior longitudinal ligament in a mouse model. AB - BACKGROUND: Ossification of the posterior longitudinal ligament (OPLL) of the spine is a common human myelopathy that leads to spinal cord compression. No disease-modifying drug for OPLL has been identified, whereas surgery and conservative management have been established. OBJECTIVES: To evaluate the therapeutic potential of the H2 blocker famotidine for ectopic ossification in the cervical spine in an OPLL mouse model. METHODS: The H2 blocker famotidine was orally administered to Enpp1 (ttw/ttw) mice, a model of OPLL, at either 4 or 15 weeks of age. Radiological and survival rate analyses were performed to assess the effects of famotidine on OPLL-like lesions and mortality in Enpp1 (ttw/ttw) mice. RESULTS: Oral administration of famotidine suppressed the progression of OPLL-like ectopic ossification and reduced mortality in Enpp1 (ttw/ttw) mice when administration began at 4 weeks of age, early in the development of ossification. CONCLUSIONS: This study points to the use of famotidine as a disease-modifying drug for ectopic ossification of spinal soft tissue, including OPLL. PMID- 26509068 TI - Eosinophilia predicts poor clinical outcomes in recent-onset arthritis: results from the ESPOIR cohort. AB - OBJECTIVES: To determine the prevalence of eosinophilia in patients with recent onset arthritis suggestive of rheumatoid arthritis (RA) and to describe their features and outcomes. METHODS: We performed an ancillary study of data from a French prospective multicentre cohort study monitoring clinical, laboratory and radiographic data in patients with inflammatory arthritis of 6 weeks to 6 months duration. We determined the proportion of patients with eosinophilia, defined as a count >500/mm(3), at baseline and after 3 years. Features of patients with and without baseline eosinophilia were compared. RESULTS: Baseline eosinophilia was evidenced in 26 of 804 (3.2%) patients; their mean eosinophil count was 637.7+/ 107/mm(3). Baseline eosinophilia was ascribed to atopic syndrome in 6 of 26 (23.1%) patients. After 3 years, patients with eosinophilia had higher Health Assessment Questionnaire scores (0.9 vs 0.5, p=0.004), higher patient visual analogue scale activity score and morning stiffness intensity (p=0.05), and were more often taking disease-modifying antirheumatic drugs (p=0.02). Baseline eosinophilia was not associated with presence of extra-articular manifestations. CONCLUSIONS: Eosinophilia is rare in recent-onset arthritis suggestive of RA, and is usually directly related to the rheumatic disease. Our data suggest that patients with mild eosinophilia at diagnosis could respond worse to the treatment than those without. PMID- 26509069 TI - Hyaluronan for knee osteoarthritis: an updated meta-analysis of trials with low risk of bias. AB - BACKGROUND: The effectiveness of intra-articular hyaluronic acid (IAHA) injection for knee osteoarthritis (KOA) is debated. OBJECTIVES: To evaluate the effect of IAHA for patients with KOA by analysing data from trials of IAHA versus placebo with low risk of bias, to provide the highest level of evidence. METHODS: A systematic review and meta-analysis was conducted. Randomised controlled trials (RCTs) with a low risk of bias (adequate randomisation and concealment and double blind design) that investigated IAHA versus placebo (saline solution) injection were eligible. The primary efficacy measure was pain intensity and secondary outcome function at 3 months. The treatment effect was summarised with the standardised mean difference (SMD) calculated from differences in means of pain and function measures between treatment and control groups at 3 months. Trials were pooled by a random-effects model with DerSimonian and Laird weights. Statistical heterogeneity was explored by a visual exploration of forest plots and the I(2) statistic. RESULTS: A total of eight RCTs (2 199 randomised patients) met our inclusion criteria. IAHA significantly reduced the pain intensity (SMD=-0.21, 95% CI (95% CI) -0.32 to -0.10) and improved function (SMD= 0.12, 95% CI -0.22 to -0.02). Trials showed no heterogeneity. CONCLUSIONS: This meta-analysis of high-quality trials of IAHA versus placebo shows that IAHA provides a moderate but real benefit for patients with KOA. PMID- 26509070 TI - Tophus resolution with pegloticase: a prospective dual-energy CT study. AB - OBJECTIVE: To investigate the effect of intensive lowering of serum uric acid (SUA) levels by pegloticase on the resolution of tophi in patients with refractory gout. METHODS: Descriptive study in patients with refractory gout receiving pegloticase treatment. SUA levels were measured before and after each infusion. Dual-energy CT (DECT) scans were taken from all patients before the first infusion and after the last infusion. Computerised tophus volumes were calculated for the baseline and follow-up assessments and compared with each other. RESULTS: 10 patients with refractory gout and baseline mean SUA level of 8.1 mg/dL were enrolled. Patients were treated for a mean of 13.3 weeks. Pegloticase effectively reduced tophi in all patients showing a decrease in volume by 71.4%. Responders, showing reduction of SUA level below 6 mg/dL during at least 80% of the treatment time, were virtually cleared from tophi (-94.8%). Dependent on their anatomical localisation, resolution of tophi showed different dynamics, with articular tophi showing fast, and tendon tophi slow, resolution. CONCLUSIONS: Tophi are highly sensitive to pegloticase treatment, particularly when located at articular sites. Debulking of disease and a tophus-free state can be reached within a few months of pegloticase treatment. DECT allows for comprehensively assessing tophus burden and monitoring treatment responses. PMID- 26509071 TI - Use of corticosteroids in patients with rheumatoid arthritis treated with infliximab: treatment implications based on a real-world Canadian population. AB - OBJECTIVE: To describe the rate of concomitant oral corticosteroid use at antitumour necrosis factor (TNF) initiation and at disease remission, and to assess its effect on incidence of infection and sustainability of remission among patients with rheumatoid arthritis (RA) treated with infliximab in Canadian routine care. METHODS: Biological naive patients with RA followed in the Biologic Treatment Registry Across Canada (BioTRAC) were included. The time-dependent association between corticosteroid dose (no use, <=5 mg/day, >5 mg/day) and the incidence of first infection, while considering possible confounders, remission sustainability and the incidence of subsequent infections were assessed with Cox regression. RESULTS: 838 patients were included; mean (SD) baseline age and disease duration were 55.6 (13.5) and 10.5 (9.8) years, respectively. After a mean (SD) of 51.3 (43.6) months, the total incidence of adverse events (AEs) and infections were 110.2 and 19.6 per 100 person-years (PY), respectively. In multivariate analysis, the HR (95% CI) for acquiring an infection was 2.48 (1.24 to 4.98) with >5 mg/day of corticosteroids versus no corticosteroids. Similarly, <=5 mg/day of corticosteroids was associated with increased hazard for infection (2.12 (0.97 to 4.66)). Despite DAS28 (disease activity score 28) or Clinical Disease Activity Index (CDAI) remission, corticosteroids were continued in 16.4% and 16.7% of cases, respectively. Continued corticosteroid treatment was not associated with sustainability of remission (HRDAS28 (95% CI) 1.40 (0.95 to 2.06); HRCDAI 1.19 (0.75 to 1.88)), however, it had a significant impact on development of infection (HRDAS28 (95% CI) 1.78 (1.00 to 3.19); HRCDAI 2.38 (1.14 to 4.99)). CONCLUSIONS: Oral corticosteroid treatment was associated with increased risk of development of infection without impacting sustainability of remission. These results support the notion that corticosteroids should be used concomitantly with anti-TNF for the shortest period possible to achieve remission, and then tapered. TRIAL REGISTRATION NUMBER: NCT00741793. PMID- 26509072 TI - Balancing on the edge: implications of a UK national audit of the use of BSR-BHPR guidelines for the diagnosis and management of polymyalgia rheumatica. AB - INTRODUCTION: The British Society for Rheumatology and British Health Professionals in Rheumatology (BSR-BHPR) guidelines for management of polymyalgia rheumatica (PMR) were published in 2010, aiming to provide guidance for diagnosis, management and disease monitoring. A national study was conducted across multiple rheumatology units throughout the UK in order to study the level of adoption of guidelines in clinical practice. METHODS: This study was a retrospective analysis of patient records with a diagnosis of PMR from multiple centres across the UK. The primary objective was to explore the national compliance of PMR management according to BSR guidelines. RESULTS: We included 81 responses across 10 rheumatology units in the UK. The guideline core inclusion criteria were followed in more than 90% in making the diagnosis of PMR, but limited concordance was observed with respect to excluding PMR-mimics, the initial recommended glucocorticoid dosage (74%), steroid taper (41%), treatment of relapse (76%), bone protection (84%) and patient follow-up (43%). CONCLUSIONS: We observed a wide variation in clinical practice and limited adherence to BSR BHPR guidelines in the UK. This study highlights the need for robust multilayered and multifaceted implementation strategies involving the providers and the consumers for apposite dissemination of guideline-based practice and consistency of care. We believe that the findings of this study have significant relevance for formulation and dissemination of PMR guidelines in the future. PMID- 26509073 TI - Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease. AB - The recent identification of genetic mutations leading to dysfunction of inflammatory and apoptotic pathways, has allowed to characterise a group of diseases, recognised as monogenic autoinflammatory syndromes. Among those, Blau syndrome (BS) and early-onset sarcoidosis (EOS) have been identified as familial and sporadic phenotypes of the same non-caseating granulomatous form. Both the diseases are caused by mutations in the CARD15/NOD2 gene, encoding the cytosolic NOD2 protein, one of the key molecules in the regulation of innate immunity. Clinical onset is typically located in the first years of life and phenotype is characterised by simultaneous or less articular, cutaneous and ocular non caseating granulomatous inflammation, which can be variably associated with a heterogeneous systemic spectrum. The CARD15/NOD2 gene has also been identified as one of the genes linked to susceptibility to Crohn's disease (CD), a common polygenic inflammatory granulomatous bowel disease. The heightened nuclear factor kappaB activity, found in the intestinal tissue of patients affected by CD, has probably a genetic cause related to several CARD15/NOD2 polymorphisms. Other substitutions in the CARD15/NOD2 gene have also been found in a recently described disorder, called NOD2-associated autoinflammatory disease, which shares several clinical characteristics with BS and EOS. This review attempts to describe these diseases on the basis of the most recent evidences. We described genetic and clinical aspects, mainly focusing on BS and EOS, the most representative diseases of autoinflammatory granulomatous diseases, with the ultimate purpose to expand their knowledge. PMID- 26509074 TI - Effect of certolizumab pegol over 96 weeks in patients with psoriatic arthritis with and without prior antitumour necrosis factor exposure. AB - OBJECTIVE: Previous reports of RAPID-PsA (NCT01087788) demonstrated efficacy and safety of certolizumab pegol (CZP) over 24 weeks in patients with psoriatic arthritis (PsA), including patients with prior antitumour necrosis factor (TNF) therapy. We report efficacy and safety data from a 96-week data cut of RAPID-PsA. METHODS: RAPID-PsA was placebo-controlled to week 24, dose-blind to week 48 and open-label to week 216. We present efficacy data including American College of Rheumatology (ACR)/Psoriasis Area and Severity Index (PASI) responses, HAQ-DI, pain, minimal disease activity (MDA), modified total Sharp score (mTSS) and ACR responses in patients with/without prior anti-TNF exposure, in addition to safety data. RESULTS: Of 409 patients randomised, 273 received CZP from week 0. 54 (19.8%) CZP patients had prior anti-TNF exposure. Of patients randomised to CZP, 91% completed week 24, 87% week 48 and 80% week 96. ACR responses were maintained to week 96: 60% of patients achieved ACR20 at week 24, and 64% at week 96. Improvements were observed with both CZP dose regimens. ACR20 responses were similar in patients with (week 24: 59%; week 96: 63%) and without (week 24: 60%; week 96: 64%) prior anti-TNF exposure. Placebo patients switching to CZP displayed rapid clinical improvements, maintained to week 96. In patients with >=3% baseline skin involvement (60.8% week 0 CZP patients), PASI responses were maintained to week 96. No progression of structural damage was observed over the 96-week period. In the Safety Set (n=393), adverse events occurred in 345 patients (87.8%) and serious adverse events in 67 (17.0%), including 6 fatal events. CONCLUSIONS: CZP efficacy was maintained to week 96 with both dose regimens and in patients with/without prior anti-TNF exposure. The safety profile was in line with that previously reported from RAPID-PsA, with no new safety signals observed with increased exposure. TRIAL REGISTRATION NUMBER: NCT01087788. PMID- 26509075 TI - Patient participation as an integral part of patient-reported outcomes development ensures the representation of the patient voice: a case study from the field of rheumatology. AB - INTRODUCTION: Patient-reported outcomes (PROs) are important instruments to evaluate healthcare interventions, both in clinical practice and clinical research. OBJECTIVE: To describe how representation of the perspective of people with psoriatic arthritis was obtained through active participation on different levels in the development of PROs. METHODS: This case study focuses on the methods of involving patients in the elaboration and validation of the Psoriatic Arthritis Impact of Disease (PsAID) score. We used the concept of the participation ladder and the European League Against Rheumatism (EULAR) recommendations for the involvement of patient representatives in scientific projects to analyse the variety of ways patients participated in this process. RESULTS: Two patient experts were part of the steering group. 12 patient research partners, coming from 12 different European countries, participated in identifying domains, formulating items for the questionnaire and determining the number of items, the recall period and the questionnaire format. They also helped with the translation of the items into different European languages. Then, 139 patients took part in ranking and prioritising the domains for importance; 65 patients were involved in cognitive debriefing interviews; 499 new patients were recruited for the validation study. Challenges of patient participation in PRO development, such as the representation of patients, are discussed. CONCLUSIONS: Making patient participation an integral part of the PRO development and validation process is an important requisite for outcome research. The variety of patient contributions at different phases in this case study resulted in an instrument with high face validity. PMID- 26509076 TI - The Ocular Biometry of Adult Cataract Patients on Lifeline Express Hospital Eye Train in Rural China. AB - Aims. To describe and explore the distribution of ocular biometric parameters of adult cataract patients in rural China. Methods. Three Lifeline Express Hospital Eye-Train missions of Peking University People's Hospital in China were chosen. 3828 adult cataract patients aged 29 to 88 years with axial length (AL) less than 27.0 mm were enrolled. The ocular biometry including visual acuity (VA), intraocular pressure, AL, corneal power (K1 and K2), and corneal endothelial counting (CEC) were collected and analysis. Corneal radius (CR) was calculated from the corneal power. Results. The participants in Zhoukou of these three missions had the worse preoperative VA (p < 0.001), the lowest K1 (p < 0.001), K2 (p < 0.001), and K (p < 0.001) and the highest |K1 - K2| (p < 0.001), moreover AL/CR more closely to 3.0. The AL, |K1 - K2|, and AL/CR were normally distributed. But the K1, K2, K, and CEC were not normal distributions. Except K1, all parameters were positively skewed and peaked. Conclusion. Our study provides normative ocular biometry in a large, representative rural Chinese population. The AL is normally distributed with a positive skew and big kurtosis. The corneal powers are not normal distribution. The corneal astigmatism might have a significant effect on the visual acuity. PMID- 26509077 TI - Effect of Glyceraldehyde Cross-Linking on a Rabbit Bullous Keratopathy Model. AB - Background. To evaluate the effects of corneal glyceraldehyde CXL on the rabbit bullous keratopathy models established by descemetorhexis. Methods. Fifteen rabbits were randomly divided into five groups. Group A (n = 3) is the control group. The right eyes of animals in Groups B,C, D, and E (n = 3, resp.) were suffered with descemetorhexis procedures. From the 8th day to the 14th day postoperatively, the right eyes in Groups C and D were instilled with hyperosmolar drops and glyceraldehyde drops, respectively; the right eyes in Group E were instilled with both hyperosmolar drops and glyceraldehyde drops. Central corneal thickness (CCT), corneal transparency score, and histopathological analysis were applied on the eyes in each group. Results. Compared with Group A, statistically significant increase in CCT and corneal transparency score was found in Groups B, C, D, and E at 7 d postoperatively (P < 0.05) and in Groups C, D, and E at 14 d postoperatively (P < 0.05). Conclusion. Chemical CXL technique using glyceraldehyde improved the CCT and corneal transparency of the rabbit bullous keratopathy models. Topical instillation with glyceraldehyde and hyperosmolar solutions seems to be a good choice for the bullous keratopathy treatment. PMID- 26509078 TI - Continuous Curvilinear Capsulorhexis in Cataract Surgery Using a Modified 3-Bend Cystotome. AB - We modified a 2-bend cystotome for continuous curvilinear capsulorhexis (CCC) in manual or phacoemulsification cataract surgery to improve the safety and ease of performance. A 26G needle was converted into a cystotome with 3 bends. In this retrospective study, the performance of modified 3-bend cystotome was compared with conventional 2-bend cystotome. During cataract surgery, in the 3-bend cystotome group, mean completion time of CCC was shorter, mean times of viscoelastic agent supplement were less, and CCC success rate was higher than that in 2-bend group. Complication incidence, such as postoperative transient corneal edema and irreparable V-shaped tear, was also lower in 3-bend group. No posterior capsular rupture or no other complication was observed in either group. A polymethyl methacrylate intraocular lens or a hydrogel intraocular lens was implanted in the capsular bag in all eyes. We conclude that it is safe and efficient to accomplish a CCC using the 3-bend cystotome due to its ability to sustain the anterior chamber depth (ACD) and keep the posterior lip intact. Using the 3-bend cystotome also allowed for an adequate view into the anterior chamber from lack of wound deformation. PMID- 26509079 TI - Epigenetic Regulation of Werner Syndrome Gene in Age-Related Cataract. AB - Purpose. To examine the promoter methylation and histone modification of WRN (Werner syndrome gene), a DNA repair gene, and their relationship with the gene expression in age-related cataract (ARC) lens. Methods. We collected the lenses after cataract surgery from 117ARC patients and 39 age-matched non-ARC. WRN expression, DNA methylation and histone modification around the CpG island were assessed. The methylation status of Human-lens-epithelium cell (HLEB-3) was chemically altered to observe the relationship between methylation and expression of WRN. Results. The WRN expression was significantly decreased in the ARC anterior lens capsules comparing with the control. The CpG island of WRN promoter in the ARC anterior lens capsules displayed hypermethylation comparing with the controls. The WRN promoter was almost fully methylated in the cortex of ARC and control lens. Acetylated H3 was lower while methylated H3-K9 was higher in ARC anterior lens capsules than that of the controls. The expression of WRN in HLEB-3 increased after demethylation of the cells. Conclusions. A hypermethylation in WRN promoter and altered histone modification in anterior lens capsules might contribute to the ARC mechanism. The data suggest an association of altered DNA repair capability in lens with ARC pathogenesis. PMID- 26509080 TI - An Evaluation of Effects of Different Mydriatics on Choroidal Thickness by Examining Anterior Chamber Parameters: The Scheimpflug Imaging and Enhanced Depth Imaging-OCT Study. AB - Aim. To assess the effects of mydriatics commonly used in clinical practice on choroidal thickness and anterior chamber change. Methods. This was a prospective, randomized, controlled, double-blinded study including a single eye of the participants. The subjects were assigned into 4 groups to receive tropicamide 1%, phenylephrine 2.5%, cyclopentolate 1%, and artificial tears. At the baseline, anterior chamber parameters were assessed using a Pentacam Scheimpflug camera system, and choroidal thickness (CT) was measured using a spectral-domain OCT with Enhanced Depth Imaging (EDI) modality. All measurements were repeated again after drug administration. Results. Increases in pupil diameter, volume, and depth of anterior chamber were found to be significant (p = 0.000, p = 0.000, and p = 0.000, resp.), while decreases in the choroidal thickness were found to be significant in subjects receiving mydriatics (p < 0.05). Conclusions. The study has shown that while cyclopentolate, tropicamide, and phenylephrine cause a decrease in choroidal thickness, they also lead to an increase in the volume and depth of anterior chamber. However, no correlation was detected between anterior chamber parameters and choroidal changes after drug administration. These findings suggest that the mydriatics may affect the choroidal thickness regardless of anterior chamber parameters. This study was registered with trial registration number 2014/357. PMID- 26509081 TI - Factors Associated with Medication Nonadherence among Hypertensives in Ghana and Nigeria. AB - Background. Blood pressure (BP) control is poor among hypertensives in many parts of sub-Saharan Africa. A potentially modifiable factor for control of BP is medication nonadherence (MNA); our study therefore aimed to determine factors associated with MNA among hypertensives in Ghana and Nigeria. Methodology. We conducted a multicenter cross-sectional study. Patients were recruited from Korle Bu Hospital (n = 120), Ghana; and University of Port Harcourt Teaching Hospital, (n = 73) Apapa General Hospital Lagos (n = 79) and University College Hospital Ibadan (n = 85), Nigeria. Results. 357 hypertensive patients (42.6% males) participated. MNA was found in 66.7%. Adherence showed correlation with depression (r = -0.208, P < 0.001), concern about medications (r = -0.0347, P = 0.002), and knowledge of hypertension (r = 0.14, P = 0.006). MNA was associated with formal education (P = 0.001) and use of herbal preparation (P = 0.014). MNA was found in 61.7% of uninsured participants versus 73.1% of insured participants (P = 0.032). Poor BP control was observed in 69.7% and there was significant association between MNA and poor BP control (P = 0.006). Conclusion. MNA is high among hypertensives in Ghana and Nigeria and is associated with depression, concern about hypertensive medications, formal education, and use of herbal preparations. The negative association between health insurance and MNA suggests interplay of other factors and needs further investigation. PMID- 26509082 TI - Low-Glycemic-Index Foods Can Decrease Systolic and Diastolic Blood Pressure in the Short Term. AB - Background. We aimed to compare the effects of low- and high-GI foods on 24-hour ambulatory blood pressure. Methods. This longitudinal study was performed on 30 women, aged 18 to 40 years, during 24 hours. In the first leg of study all recruited subjects were assigned to LGI period for 24 hours and, after a 2-week washout period, all subjects were assigned to HGI period. BP was measured every hour during the 24-hour monitoring. Results. After the intervention, there were significant decreases in SBP and DBP in the LGI period (102.26 +/- 14.18 mmHg versus 112.86 +/- 9.33 mmHg for SBP and 66.96 +/- 10.39 mmHg versus 74.46 +/- 7.61 mmHg for DBP) (P = 0.00 and P = 0.002, resp.). However, in the HGI period, there was no significant change in SBP or DBP (110.66 +/- 9.85 versus 111.80 +/- 9.57 for SBP and 71.16 +/- 9.16 versus 74.26 +/- 10.09 for DBP) (P = 0.6 and P = 0.06, resp.). Conclusion. The results suggest that LGI foods may be beneficial in reducing 24-hour BP. PMID- 26509083 TI - Ketamine, Transcranial Magnetic Stimulation, and Depression Specific Yoga and Mindfulness Based Cognitive Therapy in Management of Treatment Resistant Depression: Review and Some Data on Efficacy. AB - Depression affects about 121 million people worldwide and prevalence of major depressive disorder (MDD) in US adults is 6.4%. Treatment resistant depression (TRD) accounts for approximately 12-20% of all depression patients and costs $29 $48 billion annually. Ketamine and repetitive transcranial magnetic stimulation (rTMS) have useful roles in TRD, but their utility in long term is unknown. As per the latest literature, the interventions using Yoga and meditation including the mindfulness based cognitive therapy (MBCT) have been useful in treatment of depression and relapse prevention. We present a review of rTMS, ketamine, and MBCT and also report efficacy of a depression specific, innovative, and translational model of Yoga and mindfulness based cognitive therapy (DepS Y MBCT), developed by the first author. DepS Y-MBCT as an adjunctive treatment successfully ameliorated TRD symptoms in 27/32 patients in an open label pilot trial in TRD patients. Considering the limitations of existing treatment options, including those of ketamine and rTMS when used as the sole modality of treatment, we suggest a "tiered approach for TRD" by combining ketamine and rTMS (alone or along with antidepressants) for rapid remission of acute depression symptoms and to use DepS Y-MBCT for maintaining remission and preventing relapse. PMID- 26509084 TI - Modulatory Effects of Eschscholzia californica Alkaloids on Recombinant GABAA Receptors. AB - The California poppy (Eschscholzia californica Cham.) contains a variety of natural compounds including several alkaloids found exclusively in this plant. Because of the sedative, anxiolytic, and analgesic effects, this herb is currently sold in pharmacies in many countries. However, our understanding of these biological effects at the molecular level is still lacking. Alkaloids detected in E. californica could be hypothesized to act at GABAA receptors, which are widely expressed in the brain mainly at the inhibitory interneurons. Electrophysiological studies on a recombinant alpha 1 beta 2 gamma 2 GABAA receptor showed no effect of N-methyllaurotetanine at concentrations lower than 30 MUM. However, (S)-reticuline behaved as positive allosteric modulator at the alpha 3, alpha 5, and alpha 6 isoforms of GABAA receptors. The depressant properties of aerial parts of E. californica are assigned to chloride-current modulation by (S)-reticuline at the alpha 3 beta 2 gamma 2 and alpha 5 beta 2 gamma 2 GABAA receptors. Interestingly, alpha 1, alpha 3, and alpha 5 were not significantly affected by (R)-reticuline, 1,2-tetrahydroreticuline, codeine, and morphine-suspected (S)-reticuline metabolites in the rodent brain. PMID- 26509086 TI - Right Ventricular Outflow Tract Tachycardia with Structural Abnormalities of the Right Ventricle and Left Ventricular Diverticulum. AB - A 43-year-old woman presented to the emergency room with a sustained ventricular tachycardia (VT). ECG showed a QRS in left bundle branch block morphology with inferior axis. Echocardiography, ventricular angiography, and cardiac magnetic resonance imaging (CMRI) revealed a normal right ventricle and a left ventricular diverticulum. Electrophysiology studies with epicardial voltage mapping identified a large fibrotic area in the inferolateral layer of the right ventricular wall and a small area of fibrotic tissue at the anterior right ventricular outflow tract. VT ablation was successfully performed with combined epicardial and endocardial approaches. PMID- 26509085 TI - The Effects of Exercise on Cognitive Recovery after Acquired Brain Injury in Animal Models: A Systematic Review. AB - The objective of the present paper is to review the current status of exercise as a tool to promote cognitive rehabilitation after acquired brain injury (ABI) in animal model-based research. Searches were conducted on the PubMed, Scopus, and psycINFO databases in February 2014. Search strings used were: exercise (and) animal model (or) rodent (or) rat (and) traumatic brain injury (or) cerebral ischemia (or) brain irradiation. Studies were selected if they were (1) in English, (2) used adult animals subjected to acquired brain injury, (3) used exercise as an intervention tool after inflicted injury, (4) used exercise paradigms demanding movement of all extremities, (5) had exercise intervention effects that could be distinguished from other potential intervention effects, and (6) contained at least one measure of cognitive and/or emotional function. Out of 2308 hits, 22 publications fulfilled the criteria. The studies were examined relative to cognitive effects associated with three themes: exercise type (forced or voluntary), timing of exercise (early or late), and dose-related factors (intensity, duration, etc.). The studies indicate that exercise in many cases can promote cognitive recovery after brain injury. However, the optimal parameters to ensure cognitive rehabilitation efficacy still elude us, due to considerable methodological variations between studies. PMID- 26509087 TI - Reversible Myocarditis and Pericarditis after Black Widow Spider Bite or Kounis Syndrome? AB - Clinical manifestation of black widow spider bite is variable and occasionally leads to death in rural areas. Cases of myocarditis and pericarditis after black widow spider bite are rare and the associated prognostic significance is unknown. Kounis syndrome has been defined as an acute coronary syndrome in the setting of allergic or hypersensitivity and anaphylactic or anaphylactoid insults that manifests as vasospastic angina or acute myocardial infarction or stent thrombosis. Allergic myocarditis is caused by myocardial inflammation triggered by infectious pathogens, toxic, ischemic, or mechanical injuries, such as drug related inflammation and other immune reactions. A 15-year-old child was admitted to the emergency department with pulmonary edema after spider bite. ST segment depression on ECG, elevated cardiac enzymes and global left ventricular hypokinesia (with ejection fraction of 22%), and local pericardial effusion findings confirmed the diagnosis of myopericarditis. After heart failure and pulmonary edema oriented medical therapy, clinical status improved. Patient showed a progressive improvement and LV functions returned to normal on the sixth day. Myopericarditis complicating spider bite is rare and sometimes fatal. The mechanism is not clearly known. Alpha-latrotoxin of the black widow spider is mostly convicted in these cases. But allergy or hypersensitivity may play a role in myocardial damage. PMID- 26509088 TI - Fabrication of Zirconia-Reinforced Lithium Silicate Ceramic Restorations Using a Complete Digital Workflow. AB - This case report describes the fabrication of monolithic all-ceramic restorations using zirconia-reinforced lithium silicate (ZLS) ceramics. The use of powder-free intraoral scanner, generative fabrication technology of the working model, and CAD/CAM of the restorations in the dental laboratory allows a completely digitized workflow. The newly introduced ZLS ceramics offer a unique combination of fracture strength (>420 MPa), excellent optical properties, and optimum polishing characteristics, thus making them an interesting material option for monolithic restorations in the digital workflow. PMID- 26509089 TI - Pseudotumoral and Multiple Retinal Pigment Epithelium Proliferation in Vogt Koyanagi-Harada Disease. AB - We report a case of pseudotumoral retinal pigment epithelium (RPE) proliferation in Vogt-Koyanagi-Harada (VKH) disease, in a 50-year-old female who presented with a juxtapapillary and peripheral subretinal hyperpigmented lesions in the left eye and "sunset glow fundus," hyperpigmented striae, and multiple atrophic chorioretinal spots in the periphery. The darkly pigmented exuberant larger subretinal mass extended to the periphery with associated subretinal fibrosis. This patient demonstrated the entire clinical presentation of VKH disease, which tends to course with a chronic, bilateral, granulomatous panuveitis and exudative retinal detachment associated with poliosis, vitiligo, alopecia, and central nervous system and auditory signs. Our case is unique for the presence of exuberant, pseudotumoral RPE proliferation at the juxtapapillary region and peripheral area. Although this complication has rarely been reported, a high index of suspicion is warranted for early diagnosis and avoids unnecessary treatments of a pseudotumor. PMID- 26509090 TI - Anterior Segment Findings in Vitamin A Deficiency: A Case Series. AB - Vitamin A deficiency is a rare but vision threatening disorder in the developed world, which can lead to blindness for severe keratomalacia with cornea scarring and perforation or night blindness due to impaired dark adaptation. Conversely, the disease is quite common in developing countries, as a consequence of chronic malnutrition. The correct diagnosis and therapy with prompt vitamin A supplementation avoid blindness. We report a series of 3 local cases with different age and causes for vitamin A deficiency. The diagnostic workup, therapy, and prognosis are discussed. PMID- 26509091 TI - Cascading Adjacent Level Vertebral Compression Fractures Necessitating a Series of Eleven Kyphoplasties. AB - Vertebral kyphoplasty is a procedure used for the treatment of compression fractures. While early randomized-controlled trials were equivocal regarding its benefits, more recent RCTs have shown favorable results for kyphoplasty with regard to pain relief, functional recovery, and health-care related quality of life compared to control patients. Risks of kyphoplasty include but are not limited to cement extrusion, infection, hematoma, and vertebral body fracture of adjacent levels. We describe a case of a 66-year-old male attorney who underwent eleven kyphoplasties in an approximately one-year period, the majority of which were for fractures of vertebrae adjacent to those previously treated with kyphoplasty. Information on treatment was gathered from the patient's hospital chart and outpatient office notes. Following the last of the eleven kyphoplasties (two at T8, one each at all vertebrae from T9 to L5), the patient was able to function without pain and return to work. His physiologic thoracic kyphosis of 40 degrees prior to the first procedure was maintained, as were his lung and abdominal volumes. We conclude that kyphoplasty is an appropriate procedure for the treatment of vertebral compression fractures and can be used repeatedly to address fractures of levels adjacent to a previous kyphoplasty. PMID- 26509092 TI - Castleman's Disease Presenting as a Parotid Mass in the Pediatric Population: A Report of 2 Cases. AB - Introduction. Angiofollicular lymph node hyperplasia (Castleman's disease) is a nonmalignant lymphoproliferative disorder that generally involves the lymph nodes of young adults, most commonly in the mediastinum. Rarely, Castleman's disease may present in the parotid gland. The disease can be further classified into unicentric or multicentric forms, with considerable differences in presentation, treatment, and prognosis. Case(s). We present cases of two pediatric patients, aged 7 and 11, who both presented with a slow-growing, painless parotid mass. In each case, the mass was excised via a superficial parotidectomy and the diagnosis made postoperatively upon further pathologic examination. At 6 months of follow up, both had fully intact facial nerve function and no evidence of recurrence. Discussion. Castleman's disease presents a diagnostic challenge in the head and neck region, as radiographic characteristics and fine needle aspiration results are often inconclusive. Definitive diagnosis requires surgical excision for pathologic examination. The unicentric form generally presents as a painless mass and can be successfully treated with complete excision. The multicentric form is associated with constitutional symptoms and its treatment remains controversial. Conclusion. Although rare, clinicians should be aware of both forms of Castleman's disease when creating a differential diagnosis for parotid masses. PMID- 26509093 TI - Synchronous Fibrolamellar Hepatocellular Carcinoma and Auricular Myxoma. AB - Synchronic occurrence of benign and malignant tumors is extremely rare. Fibrolamellar hepatocellular carcinoma represents 1% to 2% of all hepatocarcinomas, while myxomas represent about half of all the cases of primary tumors of the heart. We present the case of a 53-year-old woman with a left atrial myxoma that was surgically removed. Several weeks later, the patient returned to the hospital with abdominal pain. CT scan showed a mass in the left lobe of the liver that was resected and diagnosed as fibrolamellar hepatocellular carcinoma. As of this writing, the patient is healthy. PMID- 26509094 TI - A Case Study of Intractable Vomiting with Final Diagnosis of Neuromyelitis Optica. AB - This case study presents a patient living in a suburban/rural community who received appropriate referral to secondary and tertiary care for nausea and vomiting, accompanied by waxing and waning neurological symptoms, yet proved difficult to diagnose. This patient is presented to draw attention to a rare neurological disorder which should be included in the differential diagnosis of nausea and vomiting with some key neurological complaints, even in the absence of physical findings. PMID- 26509095 TI - Increased Anxiety, Akathisia, and Suicidal Thoughts in Patients with Mood Disorder on Aripiprazole and Lamotrigine. AB - Introduction. Akathisia affects around 18% of patients with bipolar disorder treated with aripiprazole and may worsen when aripiprazole is combined with lamotrigine and antidepressants. Case. This paper reports on two clinical cases involving patients with a diagnosis of mood disorder who developed severe akathisia, anxiety, and suicidal ideation while using a combination of aripiprazole, antidepressants, and lamotrigine. Discussion. We recommend that patients with a mood disorder taking multiple drugs should begin aripiprazole therapy with low doses and be monitored for the development of akathisia, increased anxiety, or suicidal thoughts. The appearance of these limiting side effects requires discontinuation of the drug. PMID- 26509096 TI - Giant Right Intrathoracic Myxoid Fusocellular Lipoma. AB - Intrathoracic lipomas are rare benign tumors; their behavior is not completely clear and their surgical removal may be challenging. We report a case of a giant right intrathoracic myxoid fusocellular lipoma compressing the lung, tracheobronchial tree, and esophagus which was removed through a posterolateral thoracotomy. Complete removal resulted in resolution of the chest pain and improvement of the dyspnea, with no recurrence at 4-year follow-up. PMID- 26509098 TI - Rho/Rock signal transduction pathway is required for MSC tenogenic differentiation. AB - Mesenchymal stem cell (MSC)-based treatments have shown promise for improving tendon healing and repair. MSCs have the potential to differentiate into multiple lineages in response to select chemical and physical stimuli, including into tenocytes. Cell elongation and cytoskeletal tension have been shown to be instrumental to the process of MSC differentiation. Previous studies have shown that inhibition of stress fiber formation leads MSCs to default toward an adipogenic lineage, which suggests that stress fibers are required for MSCs to sense the environmental factors that can induce differentiation into tenocytes. As the Rho/ROCK signal transduction pathway plays a critical role in both stress fiber formation and in cell sensation, we examined whether the activation of this pathway was required when inducing MSC tendon differentiation using rope-like silk scaffolds. To accomplish this, we employed a loss-of-function approach by knocking out ROCK, actin and myosin (two other components of the pathway) using the specific inhibitors Y-27632, Latrunculin A and blebbistatin, respectively. We demonstrated that independently disrupting the cytoskeleton and the Rho/ROCK pathway abolished the expression of tendon differentiation markers and led to a loss of spindle morphology. Together, these studies suggest that the tension that is generated by MSC elongation is essential for MSC teno-differentiation and that the Rho/ROCK pathway is a critical mediator of tendon differentiation on rope like silk scaffolds. PMID- 26509099 TI - An Optical Actuation System and Curvature Sensor for a MR-compatible Active Needle. AB - A side optical actuation method is presented for a slender MR-compatible active needle. The needle includes an active region with a shape memory alloy (SMA) wire actuator, where the wire generates a contraction force when optically heated by a laser delivered though optical fibers, producing needle tip bending. A prototype, with multiple side heating spots, demonstrates twice as fast an initial response compared to fiber tip heating when 0.8 W of optical power is applied. A single ended optical sensor with a gold reflector is also presented to measure the curvature as a function of optical transmission loss. Preliminary tests with the sensor prototype demonstrate approximately linear response and a repeatable signal, independent of the bending history. PMID- 26509097 TI - The Interaction between Obstructive Sleep Apnea and Parkinson's Disease: Possible Mechanisms and Implications for Cognitive Function. AB - Parkinson's disease (PD) is a relentlessly progressive neurodegenerative disorder associated with hallmark motor and nonmotor symptoms (NMS) such as sleep disturbances and cognitive dysfunction. While dopaminergic treatments have improved the motor aspects of PD, progression remains inevitable. Research has recently increasingly focused on strategies to modify disease progression and on nonmotor manifestations of PD, given their impact on patients' quality of life. Obstructive sleep apnea (OSA) is a treatable sleep disorder, common in the general population, associated with excessive daytime sleepiness and neurocognitive deficits. Neuroimaging has demonstrated structural and functional changes in OSA patients; in animal models, OSA causes brain inflammation and oxidative injury, including in key areas involved in PD pathophysiology such as locus coeruleus. The prevalence of OSA in PD has been variable in studies to date, and potential consequences and interrelationship between the two disorders have not been well studied. There is however emerging evidence that OSA is associated with increased NMS in PD, particularly cognitive dysfunction. This review focuses on the possible interrelationship between OSA and PD. Mechanisms promoting OSA in PD will be reviewed, as well as mechanisms whereby OSA can affect the neurodegenerative process in PD. PMID- 26509100 TI - Feasibility Study of an Optically Actuated MR-compatible Active Needle. AB - An active needle is proposed for the development of MRI guided percutaneous procedures. The needle uses internal laser heating, conducted via optical fibers, of a shape memory alloy (SMA) actuator to produce bending in the distal section of the needle. Active bending of the needle as it is inserted allows it to reach small targets while overcoming the effects of interactions with surrounding tissue, which can otherwise deflect the needle away from its ideal path. The active section is designed to bend preferentially in one direction under actuation, and is also made from SMA for its combination of MR and bio compatibility and its superelastic bending properties. A prototype, with a size equivalent to standard 16G biopsy needle, exhibits significant bending with a tip rotation of more than 10 degrees . A numerical analysis and experiments provide information concerning the required amount of heating and guidance for design of efficient optical heating systems. PMID- 26509101 TI - Detection of Membrane Puncture with Haptic Feedback using a Tip-Force Sensing Needle. AB - This paper presents calibration and user test results of a 3-D tip-force sensing needle with haptic feedback. The needle is a modified MRI-compatible biopsy needle with embedded fiber Bragg grating (FBG) sensors for strain detection. After calibration, the needle is interrogated at 2 kHz, and dynamic forces are displayed remotely with a voice coil actuator. The needle is tested in a single axis master/slave system, with the voice coil haptic display at the master, and the needle at the slave end. Tissue phantoms with embedded membranes were used to determine the ability of the tip-force sensors to provide real-time haptic feedback as compared to external sensors at the needle base during needle insertion via the master/slave system. Subjects were able to determine the position of the embedded membranes with significantly better accuracy using FBG tip feedback than with base feedback using a commercial force/torque sensor (p = 0.045) or with no added haptic feedback (p = 0.0024). PMID- 26509102 TI - On nonparametric hazard estimation. AB - The Nelson-Aalen estimator provides the basis for the ubiquitous Kaplan-Meier estimator, and therefore is an essential tool for nonparametric survival analysis. This article reviews martingale theory and its role in demonstrating that the Nelson-Aalen estimator is uniformly consistent for estimating the cumulative hazard function for right-censored continuous time-to-failure data. PMID- 26509103 TI - Development and use of an instrument adapted to assess the clinical skills learning environment in the pre-clinical years. AB - BACKGROUND: The Communication, Curriculum, and Culture (C3) instrument is a well established survey for measuring the professional learning climate or hidden curriculum in the clinical years of medical school. However, few instruments exist for assessing professionalism in the pre-clinical years. We adapted the C3 instrument and assessed its utility during the pre-clinical years at two U.S. medical schools. METHODS: The ten-item Pre-Clinical C3 survey was adapted from the C3 instrument. Surveys were administered at the conclusion of the first and second years of medical school using a repeated cross-sectional design. Factor analysis was performed and Cronbach's alphas were calculated for emerging dimensions. RESULTS: The authors collected 458 and 564 surveys at two medical schools during AY06-07 and AY07-09 years, respectively. Factor analysis of the survey data revealed nine items in three dimensions: "Patients as Objects", "Talking Respectfully of Colleagues", and "Patient-Centered Behaviors". Reliability measures (Cronbach's alpha) for the Pre-Clinical C3 survey data were similar to those of the C3 survey for comparable dimensions for each school. Gender analysis revealed significant differences in all three dimensions. CONCLUSIONS: The Pre-Clinical C3 instrument's performance was similar to the C3 instrument in measuring dimensions of professionalism. As medical education moves toward earlier and more frequent clinical and inter-professional educational experiences, the Pre-Clinical C3 instrument may be especially useful in evaluating the impact of curricular revisions. PMID- 26509104 TI - Neurocognitive Changes after Sustained Ketamine Administration in Children with Chronic Pain. AB - INTRODUCTION: Ketamine has received attention recently as an agent for chronic pain. There are concerns, however, regarding the neurocognitive changes patients might experience after ketamine exposure. METHODS: This prospective, uncontrolled study describes the neurocognitive functioning of 11 children with chronic pain before and after 2 weeks of daily oral ketamine exposure. Neurocognitive assessment was performed at baseline, Week 2, and Week 14. We hypothesized that there would be declines in neurocognitive scores at either Week 2 or Week 14. RESULTS: No decline in neurocognitive function was detected in the children investigated. Mean scores for tests measuring executive function and memory were improved at Weeks 2 and 14 compared to baseline. DISCUSSION: This study did not detect any decline in neurocognitive scores in a small number of children exposed to 2 weeks of oral ketamine therapy. Randomized, controlled studies of the neurocognitive effects of ketamine in children are recommended to further investigate these preliminary findings. PMID- 26509105 TI - Engineering of Human Corneal Endothelial Grafts. AB - Human corneal endothelial cells (HCEC) play a pivotal role in maintaining corneal transparency. Unlike in other species, HCEC are notorious for their limited proliferative capacity in vivo after diseases, injury, aging, and surgery. Persistent HCEC dysfunction leads to sight-threatening bullous keratopathy with either an insufficient cell density or retrocorneal membrane due to endothelial mesenchymal transition (EMT). Presently, the only solution to restore vision in eyes inflicted with bullous keratopathy or retrocorneal membrane relies upon transplantation of a cadaver human donor cornea containing a healthy corneal endothelium. Due to a severe global shortage of donor corneas, in conjunction with an increasing trend toward endothelial keratoplasty, it is opportune to develop a tissue engineering strategy to produce HCEC grafts. Prior attempts of producing these grafts by unlocking the contact inhibition-mediated mitotic block using trypsin-EDTA and culturing of single HCEC in a bFGF-containing medium run the risk of losing the normal phenotype to EMT by activating canonical Wnt signaling and TGF-beta signaling. Herein, we summarize our novel approach in engineering HCEC grafts based on selective activation of p120-Kaiso signaling that is coordinated with activation of Rho-ROCK-canonical BMP signaling to reprogram HCEC into neural crest progenitors. Successful commercialization of this engineering technology will not only fulfill the global unmet need but also encourage the scientific community to re-think how cell-cell junctions can be safely perturbed to uncover novel therapeutic potentials in other model systems. PMID- 26509106 TI - Stress and the Development of Cognitive Vulnerabilities to Depression Explain Sex Differences in Depressive Symptoms during Adolescence. AB - Although cognitive vulnerabilities to depression have received considerable empirical support, little research has evaluated the differential development of cognitive vulnerabilities in adolescent girls and boys. The current study examined the role of stressful life events, as well as sex differences in reactivity and exposure to stress, in the development of negative cognitive style and rumination in a multi-wave study of 382 adolescents. Path analyses indicated that interpersonal dependent stress predicted higher prospective levels of negative cognitive styles and rumination. Additionally, girls' greater exposure to interpersonal dependent stress explained their higher levels of rumination, which accounted for girls' higher levels of depressive symptoms than boys. These findings suggest that interpersonal dependent stress is a significant risk factor for the formation of cognitive vulnerabilities to depression during adolescence, and that the sex difference in depressive symptoms may result from girls' greater exposure to interpersonal dependent stress and ruminative response style than boys. PMID- 26509107 TI - Interaction of Wnt pathway related variants with type 2 diabetes in a Chinese Han population. AB - Aims. Epistasis from gene set based on the function-related genes may confer to the susceptibility of type 2 diabetes (T2D). The Wnt pathway has been reported to play an important role in the pathogenesis of T2D. Here we applied tag SNPs to explore the association between epistasis among genes from Wnt and T2D in the Han Chinese population. Methods. Variants of fourteen genes selected from Wnt pathways were performed to analyze epistasis. Gene-gene interactions in case control samples were identified by generalized multifactor dimensionality reduction (GMDR) method. We performed a case-controlled association analysis on a total of 1,026 individual with T2D and 1,157 controls via tag SNPs in Wnt pathway. Results. In single-locus analysis, SNPs in four genes were significantly associated with T2D adjusted for multiple testing (rs7903146(C) in TCF7L2, p = 3.21*10(-3), OR = 1.39, 95% CI [1.31-1.47], rs12904944(G) in SMAD3, p = 2.51*10( 3), OR = 1.39, 95% CI [1.31-1.47], rs2273368(C) in WNT2B, p = 4.46*10(-3), OR = 1.23, 95% CI [1.11-1.32], rs6902123(C) in PPARD, p = 1.14*10(-2), OR = 1.40, 95% CI [1.32-1.48]). The haplotype TGC constructed by TCF7L2 (rs7903146), DKK1 (rs2241529) and BTRC (rs4436485) showed a significant association with T2D (OR = 0.750, 95% CI [0.579-0.972], P = 0.03). For epistasis analysis, the optimized combination was the two locus model of WNT2B rs2273368 and TCF7L2rs7903146, which had the maximum cross-validation consistency. This was 9 out of 10 for the sign test at 0.0107 level. The best combination increased the risk of T2D by 1.47 times (95% CI [1.13-1.91], p = 0.0039). Conclusions. Epistasis between TCF7L2 and WNT2B is associated with the susceptibility of T2D in a Han Chinese population. Our results were compatible with the idea of the complex nature of T2D that would have been missed using conventional tools. PMID- 26509108 TI - Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE): Review of Evidence and Guidelines for Assessment. AB - The effects of prenatal alcohol use have been well documented. In this review, we discuss the inclusion of Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE) as a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5). We present a review of the evidence for impairment in three domains highlighted in ND-PAE: neurocognitive functioning, self2 regulation, and adaptive functioning. In addition, we provide guidelines for clinical assessment of each domain. When considering ND-PAE, it is essential to obtain as comprehensive an assessment as possible, including multidisciplinary/multimethod assessment of the individual by a qualified team. It is our aim to provide clinicians with a useful reference for assessing ND-PAE and highlight important guidelines to be followed when conducting neuropsychological assessment. PMID- 26509109 TI - Ebola virus entry into host cells: identifying therapeutic strategies. AB - Filoviruses cause severe hemorrhagic fever in humans. The archetypal virus of this group, Ebola virus, is responsible for the current filovirus epidemic in West Africa. Filoviruses infect most mammalian cells, resulting in broad species tropism and likely contributing to rapid spread of virus throughout the body. A thorough understanding of filovirus entry events will facilitate the development of therapeutics against these critical steps in the viral life cycle. This review summarizes the current understanding of filovirus entry and discusses some of the recent advancements in therapeutic strategies that target entry. PMID- 26509110 TI - Transcriptional Control of Stem and Progenitor Potential. AB - Hematopoiesis is characterized by a lifelong balance between hematopoietic stem cell (HSC) self-renewal and differentiation into mature blood populations. Proper instruction of cell fate decisions requires tight homeostatic regulation of transcriptional programs through a combination of epigenetic modifications, management of cis-regulatory elements, and transcription factor activity. Recent work has focused on integrating biochemical, genetic, and evolutionary data sets to gain further insight into these regulatory components. Long noncoding RNA (lncRNA), post-translational modifications of transcription factors, and circadian rhythm add additional layers of complexity. These analyses have provided a wealth of information, much of which has been made available through public databases. Elucidating the regulatory processes that govern hematopoietic transcriptional programs is expected to provide useful insights into hematopoiesis that may be applied broadly across tissue types while enabling the discovery and implementation of therapeutics to treat human disease. PMID- 26509111 TI - Functional neuroimaging of visuospatial working memory tasks enables accurate detection of attention deficit and hyperactivity disorder. AB - Finding neurobiological markers for neurodevelopmental disorders, such as attention deficit and hyperactivity disorder (ADHD), is a major objective of clinicians and neuroscientists. We examined if functional Magnetic Resonance Imaging (fMRI) data from a few distinct visuospatial working memory (VSWM) tasks enables accurately detecting cases with ADHD. We tested 20 boys with ADHD combined type and 20 typically developed (TD) boys in four VSWM tasks that differed in feedback availability (feedback, no-feedback) and reward size (large, small). We used a multimodal analysis based on brain activity in 16 regions of interest, significantly activated or deactivated in the four VSWM tasks (based on the entire participants' sample). Dimensionality of the data was reduced into 10 principal components that were used as the input variables to a logistic regression classifier. fMRI data from the four VSWM tasks enabled a classification accuracy of 92.5%, with high predicted ADHD probability values for most clinical cases, and low predicted ADHD probabilities for most TDs. This accuracy level was higher than those achieved by using the fMRI data of any single task, or the respective behavioral data. This indicates that task-based fMRI data acquired while participants perform a few distinct VSWM tasks enables improved detection of clinical cases. PMID- 26509112 TI - Assessing brain structural associations with working-memory related brain patterns in schizophrenia and healthy controls using linked independent component analysis. AB - Schizophrenia (SZ) is a psychotic disorder with significant cognitive dysfunction. Abnormal brain activation during cognitive processing has been reported, both in task-positive and task-negative networks. Further, structural cortical and subcortical brain abnormalities have been documented, but little is known about how task-related brain activation is associated with brain anatomy in SZ compared to healthy controls (HC). Utilizing linked independent component analysis (LICA), a data-driven multimodal analysis approach, we investigated structure-function associations in a large sample of SZ (n = 96) and HC (n = 142). We tested for associations between task-positive (fronto-parietal) and task negative (default-mode) brain networks derived from fMRI activation during an n back working memory task, and brain structural measures of surface area, cortical thickness, and gray matter volume, and to what extent these associations differed in SZ compared to HC. A significant association (p < .05, corrected for multiple comparisons) was found between a component reflecting the task-positive fronto parietal network and another component reflecting cortical thickness in fronto temporal brain regions in SZ, indicating increased activation with increased thickness. Other structure-function associations across, between and within groups were generally moderate and significant at a nominal p-level only, with more numerous and stronger associations in SZ compared to HC. These results indicate a complex pattern of moderate associations between brain activation during cognitive processing and brain morphometry, and extend previous findings of fronto-temporal brain abnormalities in SZ by suggesting a coupling between cortical thickness of these brain regions and working memory-related brain activation. PMID- 26509113 TI - Resting-state functional magnetic resonance imaging of the subthalamic microlesion and stimulation effects in Parkinson's disease: Indications of a principal role of the brainstem. AB - During implantation of deep-brain stimulation (DBS) electrodes in the target structure, neurosurgeons and neurologists commonly observe a "microlesion effect" (MLE), which occurs well before initiating subthalamic DBS. This phenomenon typically leads to a transitory improvement of motor symptoms of patients suffering from Parkinson's disease (PD). Mechanisms behind MLE remain poorly understood. In this work, we exploited the notion of ranking to assess spontaneous brain activity in PD patients examined by resting-state functional magnetic resonance imaging in response to penetration of DBS electrodes in the subthalamic nucleus. In particular, we employed a hypothesis-free method, eigenvector centrality (EC), to reveal motor-communication-hubs of the highest rank and their reorganization following the surgery; providing a unique opportunity to evaluate the direct impact of disrupting the PD motor circuitry in vivo without prior assumptions. Penetration of electrodes was associated with increased EC of functional connectivity in the brainstem. Changes in connectivity were quantitatively related to motor improvement, which further emphasizes the clinical importance of the functional integrity of the brainstem. Surprisingly, MLE and DBS were associated with anatomically different EC maps despite their similar clinical benefit on motor functions. The DBS solely caused an increase in connectivity of the left premotor region suggesting separate pathophysiological mechanisms of both interventions. While the DBS acts at the cortical level suggesting compensatory activation of less affected motor regions, the MLE affects more fundamental circuitry as the dysfunctional brainstem predominates in the beginning of PD. These findings invigorate the overlooked brainstem perspective in the understanding of PD and support the current trend towards its early diagnosis. PMID- 26509114 TI - EEG resting state analysis of cortical sources in patients with benign epilepsy with centrotemporal spikes. AB - Benign epilepsy with centrotemporal spikes (BECTS) is the most common idiopathic childhood epilepsy, which is often associated with developmental disorders in children. In the present study, we analyzed resting state EEG spectral changes in the sensor and source spaces in eight BECTS patients compared with nine age matched controls. Using high-resolution scalp EEG data, we assessed statistical differences in spatial distributions of EEG power spectra and cortical sources of resting state EEG rhythms in five frequency bands: delta (0.5-3.5 Hz), theta (4-8 Hz), alpha (8.5-13 Hz), beta1 (13.5-20 Hz) and beta2 (20.5-30 Hz) under the eyes closed resting state condition. To further investigate the impact of centrotemporal spikes on EEG spectra, we split the EEG data of the patient group into EEG portions with and without spikes. Source localization demonstrated the homogeneity of our population of BECTS patients with a common epileptic zone over the right centrotemporal region. Significant differences in terms of both spectral power and cortical source densities were observed between controls and patients. Patients were characterized by significantly increased relative power in theta, alpha, beta1 and beta2 bands in the right centrotemporal areas over the spike zone and in the right temporo-parieto-occipital junction. Furthermore, the relative power in all bands significantly decreased in the bilateral frontal and parieto-occipital areas of patients regardless of the presence or absence of spikes in EEG segments. However, the spectral differences between patients and controls were more pronounced in the presence of spikes. This observation emphasized the impact of benign epilepsy on cortical source power, especially in the right centrotemporal regions. Spectral changes in bilateral frontal and parieto-occipital areas may also suggest alterations in the default mode network in BECTS patients. PMID- 26509115 TI - The 5-HTTLPR variant in the serotonin transporter gene modifies degeneration of brain regions important for emotion in behavioral variant frontotemporal dementia. AB - The serotonin transporter length polymorphism (5-HTTLPR) short allele (5-HTTLPR s) has been associated with differential susceptibility for anxiety and depression in multiple psychiatric disorders. 5-HTTLPR-s modifies the serotonergic systems that support emotion and behavioral regulation by reducing gene expression, which slows the reuptake of serotonin, and is associated with distinct morphological and functional effects. Serotonergic systems are also shown to be dysfunctional in behavioral variant frontotemporal dementia (bvFTD), a disease characterized by marked socioemotional dysfunction. However, studies of 5-HTTLPR-s effects in bvFTD have been inconsistent. Our objective was to investigate the patterns of gray matter volume by 5-HTTLPR-s genotype in both healthy older controls and bvFTD patients. We performed voxel-based morphometry of 179 cognitively normal older adults and 24 bvFTD cases to determine brain changes associated with dose (0/1/2) of 5-HTTLPR-s allele. 5-HTTLPR-s frequency did not differ between controls and bvFTD. We found a significant interaction effect whereby carrying more 5-HTTLPR-s alleles in bvFTD was associated with smaller volume in left inferior frontal gyrus (T = 4.86, PFWE = 0.03) and larger volume in right temporal lobe (T = 5.01, PFWE = 0.01). These results suggest that the 5-HTTLPR-s allele differentially influences brain morphology in bvFTD. We propose that patients with bvFTD and 5-HTTLPR-s have altered volumes in regions that support socioemotional behavior, which may be a developmental or disease related compensation for altered serotonergic activity. PMID- 26509116 TI - Clinically feasible NODDI characterization of glioma using multiband EPI at 7 T. AB - Recent technological progress in the multiband echo planer imaging (MB EPI) technique enables accelerated MR diffusion weighted imaging (DWI) and allows whole brain, multi-b-value diffusion imaging to be acquired within a clinically feasible time. However, its applications at 7 T have been limited due to B1 field inhomogeneity and increased susceptibility artifact. It is an ongoing debate whether DWI at 7 T can be performed properly in patients, and a systematic SNR comparison for multiband spin-echo EPI between 3 T and 7 T has not been methodically studied. The goal of this study was to use MB EPI at 7 T in order to obtain 90-directional multi-shell DWI within a clinically feasible acquisition time for patients with glioma. This study included an SNR comparison between 3 T and 7 T, and the application of B1 mapping and distortion correction procedures for reducing the impact of variations in B0 and B1. The optimized multiband sequence was applied in 20 patients with glioma to generate both DTI and NODDI maps for comparison of values in tumor and normal appearing white matter (NAWM). Our SNR analysis showed that MB EPI at 7 T was comparable to that at 3 T, and the data quality acquired in patients was clinically acceptable. NODDI maps provided unique contrast within the T2 lesion that was not seen in anatomical images or DTI maps. Such contrast may reflect the complexity of tissue compositions associated with disease progression and treatment effects. The ability to consistently obtain high quality diffusion data at 7 T will contribute towards the implementation of a comprehensive brain MRI examination at ultra-high field. PMID- 26509117 TI - Effects of rhythmic stimulus presentation on oscillatory brain activity: the physiology of cueing in Parkinson's disease. AB - The basal ganglia play an important role in beat perception and patients with Parkinson's disease (PD) are impaired in perception of beat-based rhythms. Rhythmic cues are nonetheless beneficial in gait rehabilitation, raising the question how rhythm improves movement in PD. We addressed this question with magnetoencephalography recordings during a choice response task with rhythmic and non-rhythmic modes of stimulus presentation. Analyses focused on (i) entrainment of slow oscillations, (ii) the depth of beta power modulation, and (iii) whether a gain in modulation depth of beta power, due to rhythmicity, is of predictive or reactive nature. The results show weaker phase synchronisation of slow oscillations and a relative shift from predictive to reactive movement-related beta suppression in PD. Nonetheless, rhythmic stimulus presentation increased beta modulation depth to the same extent in patients and controls. Critically, this gain selectively increased the predictive and not reactive movement-related beta power suppression. Operation of a predictive mechanism, induced by rhythmic stimulation, was corroborated by a sensory gating effect in the sensorimotor cortex. The predictive mode of cue utilisation points to facilitation of basal ganglia-premotor interactions, contrasting with the popular view that rhythmic stimulation confers a special advantage in PD, based on recruitment of alternative pathways. PMID- 26509118 TI - Neural mechanisms of response inhibition and impulsivity in 22q11.2 deletion carriers and idiopathic attention deficit hyperactivity disorder. AB - *22q11DS offers a compelling model to understand the neural substrates of attentional dysfunction.*First study directly comparing neural function in 22q11DS vs. ADHD patients*22q11DS and ADHD patients show a shared deficit in RI related activation.*ADHD patients showed greater activity in the middle frontal gyrus than 22q11DS during RI.*Neural activity is inversely correlated with self reported Cognitive Impulsivity in 22q11DS. PMID- 26509119 TI - Regional vulnerability of longitudinal cortical association connectivity: Associated with structural network topology alterations in preterm children with cerebral palsy. AB - Preterm born children with spastic diplegia type of cerebral palsy and white matter injury or periventricular leukomalacia (PVL), are known to have motor, visual and cognitive impairments. Most diffusion tensor imaging (DTI) studies performed in this group have demonstrated widespread abnormalities using averaged deterministic tractography and voxel-based DTI measurements. Little is known about structural network correlates of white matter topography and reorganization in preterm cerebral palsy, despite the availability of new therapies and the need for brain imaging biomarkers. Here, we combined novel post-processing methodology of probabilistic tractography data in this preterm cohort to improve spatial and regional delineation of longitudinal cortical association tract abnormalities using an along-tract approach, and compared these data to structural DTI cortical network topology analysis. DTI images were acquired on 16 preterm children with cerebral palsy (mean age 5.6 +/- 4) and 75 healthy controls (mean age 5.7 +/- 3.4). Despite mean tract analysis, Tract-Based Spatial Statistics (TBSS) and voxel-based morphometry (VBM) demonstrating diffusely reduced fractional anisotropy (FA) reduction in all white matter tracts, the along-tract analysis improved the detection of regional tract vulnerability. The along-tract map structural network topology correlates revealed two associations: (1) reduced regional posterior-anterior gradient in FA of the longitudinal visual cortical association tracts (inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, optic radiation, posterior thalamic radiation) correlated with reduced posterior-anterior gradient of intra-regional (nodal efficiency) metrics with relative sparing of frontal and temporal regions; and (2) reduced regional FA within frontal-thalamic-striatal white matter pathways (anterior limb/anterior thalamic radiation, superior longitudinal fasciculus and cortical spinal tract) correlated with alteration in eigenvector centrality, clustering coefficient (inter-regional) and participation co-efficient (inter-modular) alterations of frontal-striatal and fronto-limbic nodes suggesting re-organization of these pathways. Both along tract and structural topology network measurements correlated strongly with motor and visual clinical outcome scores. This study shows the value of combining along-tract analysis and structural network topology in depicting not only selective parietal occipital regional vulnerability but also reorganization of frontal-striatal and frontal-limbic pathways in preterm children with cerebral palsy. These finding also support the concept that widespread, but selective posterior-anterior neural network connectivity alterations in preterm children with cerebral palsy likely contribute to the pathogenesis of neurosensory and cognitive impairment in this group. PMID- 26509120 TI - Pain and spinal cord imaging measures in children with demyelinating disease. AB - Pain is a significant problem in diseases affecting the spinal cord, including demyelinating disease. To date, studies have examined the reliability of clinical measures for assessing and classifying the severity of spinal cord injury (SCI) and also to evaluate SCI-related pain. Most of this research has focused on adult populations and patients with traumatic injuries. Little research exists regarding pediatric spinal cord demyelinating disease. One reason for this is the lack of reliable and useful approaches to measuring spinal cord changes since currently used diagnostic imaging has limited specificity for quantitative measures of demyelination. No single imaging technique demonstrates sufficiently high sensitivity or specificity to myelin, and strong correlation with clinical measures. However, recent advances in diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) measures are considered promising in providing increasingly useful and specific information on spinal cord damage. Findings from these quantitative imaging modalities correlate with the extent of demyelination and remyelination. These techniques may be of potential use for defining the evolution of the disease state, how it may affect specific spinal cord pathways, and contribute to the management of pediatric demyelination syndromes. Since pain is a major presenting symptom in patients with transverse myelitis, the disease is an ideal model to evaluate imaging methods to define these regional changes within the spinal cord. In this review we summarize (1) pediatric demyelinating conditions affecting the spinal cord; (2) their distinguishing features; and (3) current diagnostic and classification methods with particular focus on pain pathways. We also focus on concepts that are essential in developing strategies for the detection, monitoring, treatment and repair of pediatric myelitis. PMID- 26509122 TI - The development of youth-onset severe obesity in urban US girls. AB - OBJECTIVE: To understand the incidence and persistence of severe obesity (>=1.2* 95th BMI percentile-for-age) in girls across the transition to adolescence, and map developmental trajectories of adolescent severe obesity in a high-risk sample. METHODS: We examined ten years of prospectively collected data from a population sample of urban girls (n=2,226; 53% African American, aged 7-10 in 2003-2004). We determined severe obesity prevalence and incidence by age. Logistic regression evaluated for secular trend in the association between age and severe obesity prevalence. Unconditional latent growth curve models (LGCMs) compared BMI development through the adolescence transition between girls with severe obesity versus healthy BMI. RESULTS: Severe obesity prevalence was 8.3% at age 7-10 and 10.1% at age 16-19 (white: 5.9%; African American: 13.2%; p<0.001). Age-specific prevalence increased more rapidly among the latest-born, versus earliest-born, girls (p=0.034). Incidence was 1.3% to 2.4% annually. When we compared 12-15 year-old girls with severe obesity versus healthy BMI, average body weight was already distinct 5 years earlier (16.5 kg versus 25.7 kg; p<0.001) and the BMI difference between groups increased annually. LCGMs between ages 7-10 and 11-14 indicated an increase of 3.32 kg/m2 in the healthy-BMI group and 8.50 kg/m2 in the severe obesity group, a 2.6-fold difference. CONCLUSIONS: Youth-onset severe obesity warrants particular concern in urban girls due to high prevalence and an increasing secular prevalence trend. Late childhood and early adolescence may represent a key developmental window for prevention and treatment, but is too late to prevent youth-onset severe obesity entirely. PMID- 26509121 TI - Factoring the brain signatures of anesthesia concentration and level of arousal across individuals. AB - Combining resting-state functional magnetic resonance imaging (fMRI) connectivity and behavioral analysis during sedation, we factored out general effects of the anesthetic drug propofol and a specific index of conscious report, participants' level of responsiveness. The factorial analysis shows that increasing concentration of propofol in blood specifically decreases the connectivity strength of fronto-parietal cortical loops. In contrast, loss of responsiveness is indexed by a functional disconnection between the thalamus and the frontal cortex, balanced by an increase in connectivity strength of the thalamus to the occipital and temporal regions of the cortex. PMID- 26509123 TI - Open Transthoracic Plication of the Diaphragm for Unilateral Diaphragmatic Eventration in Infants and Children. AB - BACKGROUND: To evaluate our experience of early surgical plication for diaphragmatic eventration (DE) in infancy and childhood. METHODS: This study evaluated infants and children with symptomatic DE who underwent plication through an open transthoracic approach in our childhood development department between January 2005 and December 2012. Surgical plication was performed in several rows using polypropylene U-stitches with Teflon pledgets. RESULTS: The study included 12 infants and children (7 boys and 5 girls) with symptomatic DE (9 congenital and 3 acquired). Reported symptoms included respiratory distress (91.7%), wheezing (75%), cough (66.7%), and recurrent pneumonia (50%). Preoperative mechanical ventilatory support was required in 41.7% of the patients. The mean length of hospital stay was 6.3+/-2.5 days. The mean follow-up period was 24.3+/-14.5 months. Preoperative symptoms were immediately relieved after surgery in 83.3% of patients and persisted in 16.7% of patients one year after surgery. All patients survived to the end of the two-year follow-up and none had recurrence of DE. CONCLUSION: Early diagnosis and surgical plication of the diaphragm for symptomatic congenital or acquired diaphragmatic eventration offers a good clinical outcome with no recurrence. PMID- 26509124 TI - Current Trend of Robotic Thoracic and Cardiovascular Surgeries in Korea: Analysis of Seven-Year National Data. AB - BACKGROUND: Robotic surgery is an alternative to minimally invasive surgery. The aim of this study was to report on current trends in robotic thoracic and cardiovascular surgical techniques in Korea. METHODS: Data from the National Evidence-based Healthcare Collaborating Agency (NECA) between January 2006 and June 2012 were used in this study, including a total of 932 cases of robotic surgeries reported to NECA. The annual trends in the case volume, indications for robotic surgery, and distribution by hospitals and surgeons were analyzed in this study. RESULTS: Of the 932 cases, 591 (63%) were thoracic operations and 340 (37%) were cardiac operations. The case number increased explosively in 2007 and 2008. However, the rate of increase regained a steady state after 2011. The main indications for robotic thoracic surgery were pulmonary disease (n=271, 46%), esophageal disease (n=199, 34%), and mediastinal disease (n=117, 20%). The main indications for robotic cardiac surgery were valvular heart disease (n=228, 67%), atrial septal defect (n=79, 23%), and cardiac myxoma (n=27, 8%). Robotic thoracic and cardiovascular surgeries were performed in 19 hospitals. Three large volume hospitals performed 94% of the case volume of robotic cardiac surgery and 74% of robotic thoracic surgery. Centralization of robotic operation was significantly (p<0.0001) more common in cardiac surgery than in thoracic surgery. A total of 39 surgeons performed robotic surgeries. However, only 27% of cardiac surgeons and 23% of thoracic surgeons performed more than 10 cases of robotic surgery. CONCLUSION: Trend analysis of robotic and cardiovascular operations demonstrated a gradual increase in the surgical volume in Korea. Meanwhile, centralization of surgical cases toward specific surgeons in specific hospitals was observed. PMID- 26509125 TI - Comparison of Extracorporeal Cardiopulmonary Resuscitation with Conventional Cardiopulmonary Resuscitation: Is Extracorporeal Cardiopulmonary Resuscitation Beneficial? AB - BACKGROUND: With improvements in cardiopulmonary resuscitation (CPR) techniques, the quality and the effectiveness of CPR have been established; nevertheless, the survival rate after cardiac arrest still remains poor. Recently, many reports have shown good outcomes in cases where extracorporeal membrane oxygenation (ECMO) was used during prolonged CPR. Accordingly, we attempted to evaluate the impact of extracorporeal cardiopulmonary resuscitation (ECPR) on the survival of patients who experienced a prolonged cardiac arrest and compared it with that of conventional CPR (CCPR). METHODS: Between March 2009 and April 2014, CPR, including both in-hospital and out-of-hospital CPR, was carried out in 955 patients. The ECPR group, counted from the start of the ECPR program in March 2010, included 81 patients in total, and the CCPR group consisted of 874 patients. All data were retrospectively collected from the patients' medical records. RESULTS: The return of spontaneous circulation (ROSC) rate was 2.24 times better in CPR of in-hospital cardiac arrest (IHCA) patients than in CPR of out-of-hospital CA (OHCA) patients (p=0.0012). For every 1-minute increase in the CPR duration, the ROSC rate decreased by 1% (p=0.0228). Further, for every 10 year decrease in the age, the rate of survival discharge increased by 31%. The CPR of IHCA patients showed a 2.49 times higher survival discharge rate than the CPR of OHCA patients (p=0.03). For every 1-minute increase in the CPR duration, the rate of survival discharge was decreased by 4%. ECPR showed superiority in terms of the survival discharge in the univariate analysis, although with no statistical significance in the multivariate analysis. CONCLUSION: The survival discharge rate of the ECPR group was comparable to that of the CCPR group. As the CPR duration increased, the survival discharge and the ROSC rate decreased. Therefore, a continuous effort to reduce the time for the decision of ECMO initiation and ECMO team activation is necessary, particularly during the CPR of relatively young patients and IHCA patients. PMID- 26509126 TI - Postoperative Outcomes of Mitral Valve Repair for Mitral Restenosis after Percutaneous Balloon Mitral Valvotomy. AB - BACKGROUND: There have been a number of studies on mitral valve replacement and repeated percutaneous mitral balloon valvotomy for mitral valve restenosis after percutaneous mitral balloon valvotomy. However, studies on mitral valve repair for these patients are rare. In this study, we analyzed postoperative outcomes of mitral valve repair for mitral valve restenosis after percutaneous mitral balloon valvotomy. METHODS: In this study, we assessed 15 patients (mean age, 47.7+/-9.7 years; 11 female and 4 male) who underwent mitral valve repair between August 2008 and March 2013 for symptomatic mitral valve restenosis after percutaneous mitral balloon valvotomy. The mean interval between the initial percutaneous mitral balloon valvotomy and the mitral valve repair was 13.5+/-7 years. The mean preoperative Wilkins score was 9.4+/-2.6. RESULTS: The mean mitral valve area obtained using planimetry increased from 1.16+/-0.16 cm(2) to 1.62+/-0.34 cm(2) (p=0.0001). The mean pressure half time obtained using Doppler ultrasound decreased from 202.4+/-58.6 ms to 152+/-50.2 ms (p=0.0001). The mean pressure gradient obtained using Doppler ultrasound decreased from 9.4+/-4.0 mmHg to 5.8+/ 1.5 mmHg (p=0.0021). There were no early or late deaths. Thromboembolic events or infective endocarditis did not occur. Reoperations such as mitral valve repair or mitral valve replacement were not performed during the follow-up period (39+/-16 months). The 5-year event-free survival was 56.16% (95% confidence interval, 47.467-64.866). CONCLUSION: On the basis of these results, we could not conclude that mitral valve repair could be an alternative for patients with mitral valve restenosis after percutaneous balloon mitral valvotomy. However, some patients presented with results similar to those of mitral valve replacement. Further studies including more patients with long-term follow-up are necessary to determine the possibility of this application of mitral valve repair. PMID- 26509127 TI - The Significance of Serum Carcinoembryonic Antigen in Lung Adenocarcinoma. AB - BACKGROUND: A raised carcinoembryonic antigen (CEA) may be associated with significant pathology during the postoperative follow-up of lung adenocarcinoma. METHODS: We reviewed the medical records of 305 patients who underwent surgical resections for primary lung adenocarcinoma at a single institution between April 2006 and February 2013. RESULTS: Preoperative CEA levels were significantly associated with age, smoking history, pathologic stage including pT (pathologic tumor stge), pN (pathologic nodal stage) and overall pathological stage, tumor size and differentiation, pathologically positive total lymph node, N1 and N2 lymph node, N2 nodal station (0/1/2=1.83/2.94/7.21 ng/mL, p=0.019), and 5-year disease-free survival (0.591 in group with normal preoperative CEA levels vs. 0.40 in group with high preoperative CEA levels, p=0.001). Preoperative CEA levels were significantly higher than postoperative CEA levels (p<0.001, Wilcoxon signed-rank test). Postoperative CEA level was also significantly associated with disease-free survival (p<0.001). A follow-up serum CEA value of >2.57 ng/mL was found to be the appropriate cutoff value for the prediction of cancer recurrence with sensitivity and specificity of 71.4% and 72.3%, respectively. Twenty percent of patients who had recurrence of disease had a CEA level elevated above this cutoff value prior to radiographic evidence of recurrence. Postoperative CEA, pathologic stage, differentiation, vascular invasion, and neoadjuvant therapy were identified as independent predictors of 5-year disease-free survival in a multivariate analysis. CONCLUSION: The follow-up CEA level can be a useful tool for detecting early recurrence undetected by postoperative imaging studies. The perioperative follow-up CEA levels may be helpful for providing personalized evaluation of lung adenocarcinoma. PMID- 26509128 TI - Comparative Study of Cryostripping and Endovenous Laser Therapy for Varicose Veins: Mid-Term Results. AB - BACKGROUND: Conventional stripping is considered to be the standard procedure for great saphenous vein (GSV) varicosities, but many other alternative treatments such as cryostripping, endovenous laser therapy (EVLT), radio-frequency ablation, and ultrasound-guided foam sclerotherapy have been developed. Among them, both cryostripping and laser therapy have been reported to be less traumatic, with lower rates of complications and recurrences when compared to conventional stripping. To compare the efficacy of these treatments, we have analyzed and compared the mid-term clinical outcomes of cryostripping and EVLT. METHODS: Patients diagnosed with varicose veins of the GSV and treated with cryostripping or laser therapy between September 2008 and April 2013 were enrolled in this study. Duplex ultrasonography was used for the diagnosis and evaluation of varicosity and reflux, and the clinical-etiology-anatomy-pathophysiology classification was used to measure the clinical severity. The symptoms, Venous Clinical Severity Score (VCSS), recurrence rates, and complication rates of the cryostripping and laser therapy groups were analyzed and compared. RESULTS: A total of 68 patients were enrolled in this study. 32 patients were treated with cryostripping, and 36 patients were treated with laser therapy. The median follow up period was 29.6 months. Recurrence was noted in three patients from the cryostripping group and in two patients from the EVLT group. There was no difference in the VCSS score, operative time, duration of hospital stay, and complication rate between the cryostripping group and the EVLT group. CONCLUSION: The mid-term clinical outcomes of cryostripping were not inferior to those of EVLT. Further, considering its cost-effectiveness, cryostripping seems to be a safe and feasible method for the treatment of varicose veins. PMID- 26509129 TI - Pulmonary Root Translocation with the Lecompte Maneuver: For Transposition of the Great Arteries with Ventricular Septal Defect and Pulmonary Stenosis. AB - A five-month-old boy who had undergone previously transcatheter balloon atrioseptostomy at 3 days of age for complete transposition of the great arteries with ventricular septal defect and pulmonary stenosis underwent pulmonary root translocation with the Lecompte maneuver. This operation has the advantages of maintaining pulmonary valve function, preserving the capacity for growth, and avoiding problems inherent to the right ventricular to pulmonary artery conduit. This patient progressed well for 9 months postoperatively and we report this case of pulmonary root translocation with the Lecompte maneuver. PMID- 26509130 TI - Isolated Congenital Left Ventricular Diverticulum in Adults. AB - Isolated congenital left ventricular diverticulum is a rare cardiac malformation. Here, we report the case of a 33-year-old woman who had suffered from recurrent transient ischemic attacks for 6 years. Preoperative cardiac magnetic resonance imaging and computed tomography angiography revealed a diverticulum near the apex. The diverticulum was successfully obliterated by cardiopulmonary bypass. We suggest that isolated congenital left ventricular diverticulum can be easily corrected with a low surgical risk by patch repair and plication techniques. PMID- 26509131 TI - Neo-Leaflet Failure after Comprehensive Aortic Root and Valve Reconstruction. AB - The comprehensive aortic root and valve reconstruction (CARVAR) technique comprises two main procedures, which are aortic root reduction using prosthetic rings and neo-leaflet reconstruction using a pericardial patch. Although concerns about durability of the pericardial neo-leaflet have been raised in the CARVAR technique, complications related to leaflet reconstruction have not been reported to date. The present report describes two cases of complications associated with leaflet reconstruction. After resecting the reconstructed leaflets, aortic valve replacement was performed in the patients. Careful and close follow-up is required for patients who had undergone CARVAR surgery, and aortic valve surgery should be performed in a timely manner if needed. PMID- 26509132 TI - Emergency Quadrido-Bentall Procedure for Aortic Rupture in a Patient with Behcet's Disease. AB - Cardiovascular involvement in cases of Behcet's disease is a rare but life threatening condition, and prosthetic valve detachment is a frequent and serious complication attributable to Behcet's disease following the surgical repair of aortic regurgitation. We report the case of a patient with Behcet's disease presenting with contained aortic rupture around the aortic root. The patient had previously undergone aortic valve surgery three times due to recurrent prosthetic valve detachment. An emergency operation was performed, consisting of aortic root replacement (ARR) using a composite valved conduit and the replacement of the hemiarch. ARR may be an appropriate surgical option for patients with Behcet's disease in order to prevent recurrence of the disease. PMID- 26509133 TI - Trapped Stent in the Left Coronary Sinus in a Myocardial Infarction Patient. AB - Stent entrapment is a very rare complication of percutaneous coronary intervention. The interventional approach could be a treatment strategy. However, if it does not work, surgical treatment should be considered. Here, we report a case of surgical treatment of stent entrapment in the left coronary sinus of a 53 year-old male patient. PMID- 26509134 TI - Crossed Renal Ectopia and Aorto-Occlusive Disease: A Management Strategy. AB - We present a rare case of a patient with aortoiliac occlusive disease on the background of type A crossed renal ectopia, for whom open surgical intervention was required. Aortic exposure in patients with concomitant crossed renal ectopia can present technical challenges to the vascular surgeon. The knowledge of variations in the ectopic renal blood supply is of paramount importance when performing surgery to treat this condition and affects the choice of surgical exposure. We present and discuss the operative details of our patient and outline an approach to this subset of patients. PMID- 26509135 TI - Lung Entrapment between the Pectus Bar and Chest Wall after Pectus Surgery: An Incidental Finding during Video-Assisted Thoracoscopic Surgery. AB - We report a case of an entrapped lung after the pectus bar repair of a pectus deformity. The entrapped lung was found incidentally during video-assisted thoracoscopic surgery (VATS) for pneumothorax. Based on VATS exploration, multiple bullae seemed to be the cause of the pneumothorax, but the entrapped lung was suspected to have been a cause of the air leakage. PMID- 26509136 TI - A Novel Mediastinal Drainage Tube for Mediastinitis. AB - Mediastinitis is a life-threatening disease, and effective drainage is needed to treat mediastinitis with abscess formation. We recommend an alternative drainage method using chest tube binding with a Silastic Penrose drainage tube. The use of a Silastic Penrose drainage tube may help to manage mediastinitis with abscess formation. This method facilitates effective draining and prevents tissue adhesion. PMID- 26509137 TI - Carbon Dioxide Angiography: Scientific Principles and Practice. AB - Carbon dioxide (CO2) is a colorless, odorless gas which occurs naturally in the atmosphere and human body. With the advent of digital subtraction angiography, the gas has been used as a safe and useful alternative contrast agent in both arteriography and venography. Because of its lack of renal toxicity and allergic potential, CO2 is a preferred contrast agent in patients with renal failure or contrast allergy, and particularly in patients who require large volumes of contrast medium for complex endovascular procedures. Understanding of the unique physical properties of CO2 (high solubility, low viscosity, buoyancy, and compressibility) is essential in obtaining a successful CO2 angiogram and in guiding endovascular intervention. Unlike iodinated contrast material, CO2 displaces the blood and produces a negative contrast for digital subtraction imaging. Indications for use of CO2 as a contrast agent include: aortography and runoff, detection of bleeding, renal transplant arteriography, portal vein visualization with wedged hepatic venous injection, venography, arterial and venous interventions, and endovascular aneurysm repair. CO2 should not be used in the thoracic aorta, the coronary artery, and cerebral circulation. Exploitation of CO2 properties, avoidance of air contamination and facile catheterization technique are important to the safe and effective performance of CO2 angiography and CO2-guided endovascular intervention. PMID- 26509138 TI - Open Repair of Ruptured Abdominal Aortic Aneurysm: The Suitability of Endovascular Aneurysm Repair Does Not Influence Operative Mortality. AB - PURPOSE: We analyze the outcomes of open repair (OR) in patients with ruptured abdominal aortic aneurysm (RAAA) according to the anatomic suitability for endovascular aneurysm repair (EVAR). MATERIALS AND METHODS: We reviewed retrospectively all consecutive RAAA patients who underwent OR from January 2005 to March 2014. All suspected patients underwent preoperative computed tomography (CT). Outcomes were major morbidities and mortality. Multivariate analysis was performed by using logistic regression adjusted by controlled variables; gender, Hardman index, maximal aneurysmal diameter, rupture type, perioperative transfusion requirement, and perioperative urinary output. RESULTS: Among 54 consecutive patients with RAAA who underwent OR, 45 patients were included after exclusion of 9 patients (7, suprarenal; 1, infected; 1, inflammatory). Preoperative CT showed 27% (12/45) EVAR-suitable patients. Hostile neck anatomy was found in 88% (29/33) among unsuitable anatomy (UA) (n=33). The maximal aneurysmal diameter was statistically larger (83.1+/-21.0 mm vs. 68.8+/-12.3 mm, P=0.032) in the UA group. The 30-day mortality was 28.9% (13/45; 33% vs. 17% in UA group vs. suitable anatomy [SA] group, P=0.460; adjusted P=0.445). UA group had more patients with cardiac morbidity (55% vs. 25%, P=0.079; adjusted P=0.032; odds ratio, 12.914; 95% confidence interval, 1.238-134.675). There was no statistical difference in survival rate between SA and UA groups (74.1%, 74.1%, and 74.1% vs. 60.6%, 55.6%, and 32.4% at 1-, 3- and 5-year, respectively; P=0.145). CONCLUSION: In this study, relatively unfavorable outcomes were found in the EVAR-unsuitable group after OR in RAAA patients. However, unsuitable anatomy did not influence patient survival after OR by multivariate analysis. PMID- 26509139 TI - Anatomical Features and Early Outcomes of Endovascular Repair of Abdominal Aortic Aneurysm from a Korean Multicenter Registry. AB - PURPOSE: To introduce a nation-based endovascular aneurysm repair (EVAR) registry in South Korea and to analyze the anatomical features and early clinical outcomes of abdominal aortic aneurysms (AAA) in patients who underwent EVAR. MATERIALS AND METHODS: The Korean EVAR registry (KER) was a template-based online registry developed and established in 2009. The KER recruited 389 patients who underwent EVAR from 13 medical centers in South Korea from January 2010 to June 2010. We retrospectively reviewed the anatomic features and 30-day clinical outcomes. RESULTS: Initial deployment without open conversion was achieved in all cases and procedure-related 30-day mortality rate was 1.9%. Anatomic features showed the following variables: proximal aortic neck angle 48.8+/-25.7 degrees (mean+/ standard deviation), vertical neck length 35.0+/-17.2 mm, aneurysmal sac diameter 57.2+/-14.2 mm, common iliac artery (CIA) involvement in 218 (56.3%) patients, and median right CIA length 34.9 mm. Two hundred and nineteen (56.3%) patients showed neck calcification, 98 patients (25.2%) had neck thrombus, and the inferior mesenteric arteries of 91 patients (23.4%) were occluded. CONCLUSION: Anatomical features of AAA in patients from the KER were characterized as having angulated proximal neck, tortuous iliac artery, and a higher rate of CIA involvement. Long-term follow-up and ongoing studies are required. PMID- 26509140 TI - Anatomical Popliteal Artery Entrapment Syndrome Caused by an Aberrant Plantaris Muscle. AB - PURPOSE: We report on cases of anatomical popliteal artery entrapment syndrome (PAES) caused by an aberrant plantaris muscle and highlight the involvement of this muscle in PAES. MATERIALS AND METHODS: Seven symptomatic PAES legs in six patients treated at The Division of Vascular Surgery, Asan Medical Center, Seoul, Korea, between 1995 and 2011 were included in this study. We retrospectively analyzed patient records, magnetic resonance imaging (MRI) and/or computed tomography (CT) scans of the knee joint, Doppler pressure studies, CT angiographies, and conventional femoral arteriographies. RESULTS: Five males and one female patient with a median age of 32 (18-53) years old were enrolled in the study. All patients complained of intermittent claudication of the affected leg. All aberrant plantaris muscles were higher and more medially located than normal plantaris muscles, causing occlusion of the popliteal artery upon forced plantar flexion of the ankle. For arterial lesions, five occlusions of the popliteal artery and two patent popliteal arteries with positive provocation were noted. As for treatment, myotomy of the aberrant plantaris muscle was done for two non occlusive PAES legs. For occlusive PAES legs, one thrombectomy, one saphenous vein graft interposition of the popliteal artery followed by myotomy, and two below-knee femoro-popliteal bypasses were performed. The median follow-up period was 88 (7-148) months. CONCLUSION: An aberrant plantaris muscle can cause anatomical PAES. Classification or diagnosis of PAES should be based on axial studies using CT scans or MRI using various reconstruction methods. Treatment, including myotomy of the plantaris muscle, should be individualized. PMID- 26509141 TI - Popliteal-to-Dorsalis Pedis In-Situ Small Saphenous Vein Bypass under Planning with Mapping Using Computed Tomography Volume Rendering Technique. AB - The small saphenous vein (SSV) is an important graft in limb salvage surgery. It is frequently translocated for bypass surgery. Sometimes, the use of the SSV as an in-situ graft for posterior tibial artery or peroneal artery reconstruction offers the advantages of reduced vein graft injury and improved patency. Recently, saphenous vein mapping through computed tomography (CT) volume rendering technique offers a great quality view to the surgeon. We experienced a patient in whom a CT image with volume rendering technique revealed an aberrant SSV connected with the great saphenous vein at the medial malleolus level. This case indicates that an aberrant SSV may be successfully used as an in-situ conduit for bypass to the dorsalis pedis artery. Here, we present the case of a popliteal-to-dorsalis pedis in-situ vein bypass using a LeMaitre valvulotome (LeMaitre Vascular Inc., USA) under mapping of the aberrant SSV by CT volume rendering technique. PMID- 26509142 TI - Chronic Cerebrospinal Venous Insufficiency. PMID- 26509143 TI - Tourette Syndrome: Bridging the Gap between Genetics and Biology. AB - Tourette syndrome is a childhood neuropsychiatric disorder, which presents with disruptive motor and vocal tics. The disease also has a high comorbidity with obsessive-compulsive disorder and attention deficit hyperactivity disorder, which may further increase the distress experienced by patients. Current treatments act with varying efficacies in alleviating symptoms, as the underlying biology of the disease is not fully understood to provide precise therapeutic targets. Moreover, the genetic complexity of the disorder presents a substantial challenge to the identification of genetic alterations that contribute to the Tourette's phenotype. Nevertheless, genetic studies have suggested involvement of dopaminergic, serotonergic, glutamatergic, and histaminergic pathways in the pathophysiology of at least some cases. In addition, genetic overlaps with other neuropsychiatric disorders may point toward a shared biology. The findings that are emerging from genetic studies will allow researchers to piece together the underlying components of the disease, in the hopes that a deeper understanding of Tourette's can lead to improved treatments for those affected by it. PMID- 26509144 TI - CT Perfusion Characteristics Identify Metastatic Sites in Liver. AB - Tissue perfusion plays a critical role in oncology because growth and migration of cancerous cells require proliferation of new blood vessels through the process of tumor angiogenesis. Computed tomography (CT) perfusion is an emerging functional imaging modality that measures tissue perfusion through dynamic CT scanning following intravenous administration of contrast medium. This noninvasive technique provides a quantitative basis for assessing tumor angiogenesis. CT perfusion has been utilized on a variety of organs including lung, prostate, liver, and brain, with promising results in cancer diagnosis, disease prognostication, prediction, and treatment monitoring. In this paper, we focus on assessing the extent to which CT perfusion characteristics can be used to discriminate liver metastases from neuroendocrine tumors from normal liver tissues. The neuroendocrine liver metastases were analyzed by distributed parameter modeling to yield tissue blood flow (BF), blood volume (BV), mean transit time (MTT), permeability (PS), and hepatic arterial fraction (HAF), for tumor and normal liver. The result reveals the potential of CT perfusion as a tool for constructing biomarkers from features of the hepatic vasculature for guiding cancer detection, prognostication, and treatment selection. PMID- 26509145 TI - Evidential Value That Exercise Improves BMI z-Score in Overweight and Obese Children and Adolescents. AB - Background. Given the cardiovascular disease (CVD) related importance of understanding the true effects of exercise on adiposity in overweight and obese children and adolescents, this study examined whether there is evidential value to rule out excessive and inappropriate reporting of statistically significant results, a major problem in the published literature, with respect to exercise induced improvements in BMI z-score among overweight and obese children and adolescents. Methods. Using data from a previous meta-analysis of 10 published studies that included 835 overweight and obese children and adolescents, a novel, recently developed approach (p-curve) was used to test for evidential value and rule out selective reporting of findings. Chi-squared tests (chi (2)) were used to test for statistical significance with alpha (p) values <0.05 considered statistically significant. Results. Six of 10 findings (60%) were statistically significant. Statistically significant right-skew to rule out selective reporting was found (chi (2) = 38.8, p = 0.0001). Conversely, studies neither lacked evidential value (chi (2) = 6.8, p = 0.87) nor lacked evidential value and were intensely p-hacked (chi (2) = 4.3, p = 0.98). Conclusion. Evidential value results confirm that exercise reduces BMI z-score in overweight and obese children and adolescents, an important therapeutic strategy for treating and preventing CVD. PMID- 26509146 TI - Effects of P-15 Peptide Coated Hydroxyapatite on Tibial Defect Repair In Vivo in Normal and Osteoporotic Rats. AB - This study assessed the efficacy of anorganic bone mineral coated with P-15 peptide (ABM/P-15) on tibia defect repair longitudinally in both normal and osteoporotic rats in vivo. A paired design was used. 24 Norwegian brown rats were divided into normal and osteoporotic groups. 48 cylindrical defects were created in proximal tibias bilaterally. Defects were filled with ABM/P-15 or left empty. Osteoporotic status was assessed by microarchitectural analysis. Microarchitectural properties of proximal tibial defects were evaluated at 4 time points. 21 days after surgery, tibias were harvested for histology and histomorphometry. Significantly increased bone volume fraction, surface density, and connectivity were seen in all groups at days 14 and 21 compared with day 0. Moreover, the structure type of ABM/P-15 group was changed toward typical plate like structure. Microarchitectural properties of ABM/P-15 treated newly formed bones at 21 days were similar in normal and osteoporotic rats. Histologically, significant bone formation was seen in all groups. Interestingly, significantly increased bone formation was seen in osteoporotic rats treated with ABM/P-15 indicating optimized healing potential. Empty defects showed lower healing potential in osteoporotic bone. In conclusion, ABM/P-15 accelerated bone regeneration in osteoporotic rats but did not enhance bone regeneration in normal rats. PMID- 26509147 TI - The Power of Phase I Studies to Detect Clinical Relevant QTc Prolongation: A Resampling Simulation Study. AB - Concentration-effect (CE) models applied to early clinical QT data from healthy subjects are described in the latest E14 Q&A document as promising analysis to characterise QTc prolongation. The challenges faced if one attempts to replace a TQT study by thorough ECG assessments in Phase I based on CE models are the assurance to obtain sufficient power and the establishment of a substitute for the positive control to show assay sensitivity providing protection against false negatives. To demonstrate that CE models in small studies can reliably predict the absence of an effect on QTc, we investigated the role of some key design features in the power of the analysis. Specifically, the form of the CE model, inclusion of subjects on placebo, and sparse sampling on the performance and power of this analysis were investigated. In this study, the simulations conducted by subsampling subjects from 3 different TQT studies showed that CE model with a treatment effect can be used to exclude small QTc effects. The number of placebo subjects was also shown to increase the power to detect an inactive drug preventing false positives while an effect can be underestimated if time points around t max are missed. PMID- 26509148 TI - Comment on "The Role of Overweight and Obesity in In Vitro Fertilization Outcomes of Poor Ovarian Responders". PMID- 26509149 TI - Macrophage-Targeting Gene Delivery Using a Micelle Composed of Mannose-Modified Lipid with Triazole Ring and Dioleoyl Trimethylammonium Propane. AB - Gene carriers with cell specific ligand molecules are needed for the treatment of several diseases. Mannose is known to be recognized and incorporated into the cells through mannose recognition lectins that are exclusively expressed on macrophages. In this study, we synthesized two types of mannose-modified lipids with different stereoisomer (alpha-mannose and beta-mannose). To make a complex with plasmid DNA (pDNA), termed "lipoplex," we prepared a two-component micelle made from cationic lipid; dioleoyltrimethylammoniumpropane (DOTAP); and mannose modified lipid (D/alpha-Man or D/beta-Man). The prepared D/alpha-Man lipoplexes were able to bind to one of the alpha-mannose lectins concanavalin A (ConA) immobilized on gold substrate in the quartz-crystal microbalance sensor cell. D/beta-Man lipoplexes did not show any frequency changes. These results indicate that the mannose residues were exposed on the lipoplexes, leading to not only the binding to ConA but also the prevention of nonspecific interactions with proteins. Both lipoplexes showed high transfection efficiencies to RAW264.7 cells which have several kinds of mannose lectins. This delivery system to macrophages may overcome the problems for gene therapy and may be used for the treatment of immune diseases involved in macrophages. PMID- 26509150 TI - The Demographic and Clinical Characteristics of Ulcerative Colitis in a Northeast Brazilian Population. AB - INTRODUCTION: The purpose of this study was to describe the clinical and demographic characteristics of UC in Bahia, a Brazilian state, and to identify the variables associated with extensive colitis, steroid therapy, immunosuppression, and colectomy. METHODS: In this cross-sectional study UC patients were interviewed, and additional information was collected from the medical records. Descriptive statistics and multivariate Poisson regression analysis were used. RESULTS: This study included 267 individuals, the mean age of whom was 39.4 years at diagnosis. There was a predominance of females and left side colitis. Extensive colitis was positively associated with male gender, diarrhea, weight loss, and a younger age at diagnosis. In contrast, active smoking and a family history of IBD were negatively associated with extensive colitis. Positive associations were observed between steroid therapy and diarrhea, weight loss, urban patients, extraintestinal manifestations (EIMs), and hospitalization. Younger age and weight loss at diagnosis, a family history of IBD, extensive colitis, EIMs, hospitalization, and steroid therapy were all positively associated with immunosuppression. In contrast, Caucasian individuals, smokers, patients with rectal bleeding, and rural patients areas were all observed to have a decreased likelihood of immunosuppression. CONCLUSIONS: Our results corroborate the association between higher prevalence of extensive colitis and younger age at diagnosis. An association between steroid therapy and clinical presentation at diagnosis was observed. The observation that white individuals and rural patients use less immunosuppressive drugs highlights the need to study the influence of environmental and genetic factors on the behavior of UC in this population. PMID- 26509151 TI - Twelve-Month Results of a Single or Multiple Dexamethasone Intravitreal Implant for Macular Edema following Uncomplicated Phacoemulsification. AB - The clinical efficacy of one or two intravitreal injections of a continued deliverance dexamethasone 700 MUg implant in ten patients with persistent macular edema following uncomplicated phacoemulsification was evaluated. Complete ophthalmological examination and spectral domain optical coherence tomography were carried out. Follow-up was at day 7 and months 1, 2, 4, 6, 8, and 12. At baseline mean best corrected visual acuity was 62 Early Treatment Diabetic Retinopathy Study Chart letters, which showed statistically significant improvement at each follow-up, except at month 6, to reach 79 letters at month 12 (P = 0.018). Prior to treatment mean central foveal thickness was 622 MUm, which showed statistically significant improvement at each follow-up to reach a mean value of 282 MUm (P = 0.012) at month 12. Five patients received a second dexamethasone implant at month 7. Two patients were excluded from the study at months 4 and 8. Intraocular pressure remained stable during the study period with the exception of mild increase in two patients requiring topical therapy. In conclusion there was statistically significant improvement of best corrected visual acuity and mean central foveal thickness with one or two intravitreal dexamethasone implants over 12 months. PMID- 26509152 TI - Comparison of Pressure Changes by Head and Neck Position between High-Volume Low Pressure and Taper-Shaped Cuffs: A Randomized Controlled Trial. AB - The present study compared changes in cuff pressure by head and neck position between high-volume low-pressure (HVLP) and taper-shaped (taper) cuffs in a prospective randomized clinical trial. Methods. Forty patients were intubated using tracheal tubes with either HVLP (n = 20; HVLP group) or taper-shaped (n = 20; Taper group) cuffs. Initial cuff pressure was adjusted to 15, 20, or 25 cmH2O in the neutral position. Cuff pressure was evaluated after changing the head and neck positions to flexion, extension, and rotation. Results. Cuff pressure significantly increased with flexion in both HVLP and Taper groups at all initial cuff pressures. It significantly increased with extension in the HVLP group, but not in the Taper group. Cuff pressure did not significantly differ with rotation in either group and was significantly smaller in the Taper group during flexion and extension than in the HVLP group, regardless of initial cuff pressure. Conclusion. Cuff pressure changes with head and neck flexion and extension were smaller in the Taper group than in the HVLP group. Our results highlight the potential for taper cuffs to prevent excessive cuff pressure increases with positional changes in the head and neck. This trial is registered with UMIN000016119. PMID- 26509153 TI - Custom-Made Antibiotic Cement Nails in Orthopaedic Trauma: Review of Outcomes, New Approaches, and Perspectives. AB - Since the first description in 2002 by Paley and Herzenberg, antibiotic bone cement nails (ACNs) have become an effective tool in the orthopaedic trauma surgeons' hands. They simultaneously elute high amounts of antibiotics into medullary canal dead space and provide limited stability to the debrided long bone. In this paper, we perform a systematic review of current evidence on ACNs in orthopaedic trauma and provide an up-to-date review of the indications, operative technique, failure mechanisms, complications, outcomes, and outlooks for the ACNs use in long bone infection. PMID- 26509154 TI - A Current View of Functional Biomaterials for Wound Care, Molecular and Cellular Therapies. AB - The intricate process of wound healing involves activation of biological pathways that work in concert to regenerate a tissue microenvironment consisting of cells and external cellular matrix (ECM) with enzymes, cytokines, and growth factors. Distinct stages characterize the mammalian response to tissue injury: hemostasis, inflammation, new tissue formation, and tissue remodeling. Hemostasis and inflammation start right after the injury, while the formation of new tissue, along with migration and proliferation of cells within the wound site, occurs during the first week to ten days after the injury. In this review paper, we discuss approaches in tissue engineering and regenerative medicine to address each of these processes through the application of biomaterials, either as support to the native microenvironment or as delivery vehicles for functional hemostatic, antibacterial, or anti-inflammatory agents. Molecular therapies are also discussed with particular attention to drug delivery methods and gene therapies. Finally, cellular treatments are reviewed, and an outlook on the future of drug delivery and wound care biomaterials is provided. PMID- 26509155 TI - Angiotensinase C mRNA and Protein Downregulations Are Involved in Ethanol Deteriorated Left Ventricular Systolic Dysfunction in Spontaneously Hypertensive Rats. AB - The influences of angiotensinase C on ethanol-induced left ventricular (LV) systolic function were assessed in spontaneously hypertensive rats (SHRs). SHRs were fed by a liquid diet with or without ethanol for 49 days. The normotensive Wistar Kyoto rats (WKY) were fed by the liquid diet without ethanol and used as control. We evaluated LV systolic function, angiotensinase C mRNA and protein expressions, activation of the renin-angiotensin system (RAS), and the gene expressions of LV collagen (Col) III a1 and matrix metalloproteinases- (MMP-) 9. Compared to the WKY, LV systolic dysfunction (expressed by decreased fractional shortening and ejection fraction) was observed in the SHRs before ethanol treatment and further deteriorated by ethanol treatment. In the ethanol-treated SHRs, the following were observed: downregulations of angiotensinase C mRNA and protein, increased RAS activity with low collagen production as evidenced by angiotensin II and angiotensin type 1 receptor (AT1R) protein upregulation, AT1aR mRNA downregulation, and an MMP-9 mRNA expression upregulation trend with the downregulation of Col III a1 mRNA expression in LV. We conclude that chronic ethanol regimen is sufficient to promote the enhanced RAS activity-induced decrease in the production of cardiac collagen via downregulated angiotensinase C, leading to the further deterioration of LV systolic dysfunction in SHRs. PMID- 26509156 TI - Bone Regeneration from PLGA Micro-Nanoparticles. AB - Poly-lactic-co-glycolic acid (PLGA) is one of the most widely used synthetic polymers for development of delivery systems for drugs and therapeutic biomolecules and as component of tissue engineering applications. Its properties and versatility allow it to be a reference polymer in manufacturing of nano- and microparticles to encapsulate and deliver a wide variety of hydrophobic and hydrophilic molecules. It additionally facilitates and extends its use to encapsulate biomolecules such as proteins or nucleic acids that can be released in a controlled way. This review focuses on the use of nano/microparticles of PLGA as a delivery system of one of the most commonly used growth factors in bone tissue engineering, the bone morphogenetic protein 2 (BMP2). Thus, all the needed requirements to reach a controlled delivery of BMP2 using PLGA particles as a main component have been examined. The problems and solutions for the adequate development of this system with a great potential in cell differentiation and proliferation processes under a bone regenerative point of view are discussed. PMID- 26509157 TI - Perspective for Aquaponic Systems: "Omic" Technologies for Microbial Community Analysis. AB - Aquaponics is the combined production of aquaculture and hydroponics, connected by a water recirculation system. In this productive system, the microbial community is responsible for carrying out the nutrient dynamics between the components. The nutrimental transformations mainly consist in the transformation of chemical species from toxic compounds into available nutrients. In this particular field, the microbial research, the "Omic" technologies will allow a broader scope of studies about a current microbial profile inside aquaponics community, even in those species that currently are unculturable. This approach can also be useful to understand complex interactions of living components in the system. Until now, the analog studies were made to set up the microbial characterization on recirculation aquaculture systems (RAS). However, microbial community composition of aquaponics is still unknown. "Omic" technologies like metagenomic can help to reveal taxonomic diversity. The perspectives are also to begin the first attempts to sketch the functional diversity inside aquaponic systems and its ecological relationships. The knowledge of the emergent properties inside the microbial community, as well as the understanding of the biosynthesis pathways, can derive in future biotechnological applications. Thus, the aim of this review is to show potential applications of current "Omic" tools to characterize the microbial community in aquaponic systems. PMID- 26509159 TI - Biological Niches within Human Calcified Aortic Valves: Towards Understanding of the Pathological Biomineralization Process. AB - Despite recent advances, mineralization site, its microarchitecture, and composition in calcific heart valve remain poorly understood. A multiscale investigation, using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and energy dispersive X-ray spectrometry (EDS), from micrometre up to nanometre, was conducted on human severely calcified aortic and mitral valves, to provide new insights into calcification process. Our aim was to evaluate the spatial relationship existing between bioapatite crystals, their local growing microenvironment, and the presence of a hierarchical architecture. Here we detected the presence of bioapatite crystals in two different mineralization sites that suggest the action of two different growth processes: a pathological crystallization process that occurs in biological niches and is ascribed to a purely physicochemical process and a matrix-mediated mineralized process in which the extracellular matrix acts as the template for a site directed nanocrystals nucleation. Different shapes of bioapatite crystallization were observed at micrometer scale in each microenvironment but at the nanoscale level crystals appear to be made up by the same subunits. PMID- 26509158 TI - Glycosylation-Based Serum Biomarkers for Cancer Diagnostics and Prognostics. AB - Cancer is the second most common cause of death in developed countries with approximately 14 million newly diagnosed individuals and over 6 million cancer related deaths in 2012. Many cancers are discovered at a more advanced stage but better survival rates are correlated with earlier detection. Current clinically approved cancer biomarkers are most effective when applied to patients with widespread cancer. Single biomarkers with satisfactory sensitivity and specificity have not been identified for the most common cancers and some biomarkers are ineffective for the detection of early stage cancers. Thus, novel biomarkers with better diagnostic and prognostic performance are required. Aberrant protein glycosylation is well known hallmark of cancer and represents a promising source of potential biomarkers. Glycoproteins enter circulation from tissues or blood cells through active secretion or leakage and patient serum is an attractive option as a source for biomarkers from a clinical and diagnostic perspective. A plethora of technical approaches have been developed to address the challenges of glycosylation structure detection and determination. This review summarises currently utilised glycoprotein biomarkers and novel glycosylation-based biomarkers from the serum glycoproteome under investigation as cancer diagnostics and for monitoring and prognostics and includes details of recent high throughput and other emerging glycoanalytical techniques. PMID- 26509160 TI - Pathologic Assessment of Rectal Carcinoma after Neoadjuvant Radio(chemo)therapy: Prognostic Implications. AB - Neoadjuvant radio(chemo)therapy is increasingly used in rectal cancer and induces a number of morphologic changes that affect prognostication after curative surgery, thereby creating new challenges for surgical pathologists, particularly in evaluating morphologic changes and tumour response to preoperative treatment. Surgical pathologists play an important role in determining the many facets of rectal carcinoma patient care after neoadjuvant treatment. These range from proper handling of macroscopic specimens to accurate microscopic evaluation of pathological features associated with patients' prognosis. This review presents the well-established pathological prognostic indicators and discusses challenging features in order to provide both surgical pathologists and treating physicians with a checklist that is useful in a neoadjuvant setting. PMID- 26509161 TI - Anti-Inflammatory and Anticancer Activities of Taiwanese Purple-Fleshed Sweet Potatoes (Ipomoea batatas L. Lam) Extracts. AB - Purple-fleshed sweet potato (PFSP) (Ipomoea batatas L. Lam) has been known to possess high amount of anthocyanins which contribute to its antioxidant activity. However, a few reports are available concerning its anti-inflammatory and anticancer properties. In this study, PFSP "Tainung 73," which is locally grown in Taiwan, was steamed and extracted using acidified ethanol pH 3.5 under 80 degrees C. Two kinds of crude anthocyanins extracts were obtained, namely, SP (Steamed, Peeled) and SNP (Steamed, No Peeled). Then, anti-inflammatory and anticancer activities of these extracts were investigated. Cell viability assay (MTT) showed that SP and SNP extracts were not toxic to RAW 264.7 cells. They even exhibited anti-inflammatory activities by suppressing the production of NO and proinflammatory cytokines, such as NF-kappabeta, TNF-alpha, and IL-6, in LPS induced macrophage cells. Anticancer activities of these extracts were displayed through their ability to inhibit the growth of cancer cell lines, such as MCF-7 (breast cancer), SNU-1 (gastric cancer), and WiDr (colon adenocarcinoma), in concentration- and time-dependent manner. Further studies also revealed that SP extracts could induce apoptosis in MCF-7 and SNU-1 cancer cells through extrinsic and intrinsic pathway. In the future, PSFP extracts may have potential to be applied in nutraceutical, pharmaceutical, and food industries. PMID- 26509162 TI - Identification of Human Herpesvirus 8 Sequences in Conjunctiva Intraepithelial Neoplasia and Squamous Cell Carcinoma of Ugandan Patients. AB - The incidence of squamous cell carcinoma of the conjunctiva is particularly high in sub-Saharan Africa with temporal trends similar to those of Kaposi sarcoma (KS). Human herpesvirus type 8 (HHV8), has not yet been investigated in conjunctiva tumors. In this study biopsies and PBMCs of conjunctiva neoplasia patients along with nonneoplastic conjunctiva tissues have been analyzed for HHV8 sequences by PCR targeting ORF26. All amplimers were subjected to nucleotide sequencing followed by phylogenetic analysis. HHV8 DNA has been identified in 12 out of 48 (25%) HIV-positive, and in 2 out of 24 (8.3%) HIV-negative conjunctiva neoplastic tissues and in 4 out of 33 (12.1%) PBMC samples from conjunctiva neoplasia diseased patients as well as in 4 out of 60 (6.7%) nontumor conjunctiva tissues. The viral load ranged from 1 to 400 copies/10(5) cells. Phylogenetic analysis showed that the majority of HHV8 ORF26 amplimers clustered with subtypes R (n = 11) and B2 (n = 6). This variant distribution is in agreement with that of HHV8 variants previously identified in Ugandan KS cases. The presence of HHV8 in conjunctiva tumors from HIV-positive patients warrants further studies to test whether HHV8 products released by infected cells may have paracrine effects on the growth of conjunctiva lesions. PMID- 26509163 TI - Diagnostic Options and Challenges for Dengue and Chikungunya Viruses. AB - Dengue virus (DENV) and Chikungunya virus (CHIKV) are arboviruses that share the same Aedes mosquito vectors and thus overlap in their endemic areas. These two viruses also cause similar clinical presentations, especially in the initial stages of infection, with neither virus possessing any specific distinguishing clinical features. Because the outcomes and management strategies for these two viruses are vastly different, early and accurate diagnosis is imperative. Diagnosis is also important for surveillance, outbreak control, and research related to vaccine and drug development. Available diagnostic tests are aimed at detection of the virus, its antigenic components, or the host immune antibody response. In this review, we describe the recent progress and continued challenges related to the diagnosis of DENV and CHIKV infections. PMID- 26509164 TI - Are Endothelial Progenitor Cells the Real Solution for Cardiovascular Diseases? Focus on Controversies and Perspectives. AB - Advanced knowledge in the field of stem cell biology and their ability to provide a cue for counteracting several diseases are leading numerous researchers to focus their attention on "regenerative medicine" as possible solutions for cardiovascular diseases (CVDs). However, the lack of consistent evidence in this arena has hampered the clinical application. The same condition affects the research on endothelial progenitor cells (EPCs), creating more confusion than comprehension. In this review, this aspect is discussed with particular emphasis. In particular, we describe biology and physiology of EPCs, outline their clinical relevance as both new predictive, diagnostic, and prognostic CVD biomarkers and therapeutic agents, discuss advantages, disadvantages, and conflicting data about their use as possible solutions for vascular impairment and clinical applications, and finally underline a very crucial aspect of EPCs "characterization and definition," which seems to be the real cause of large heterogeneity existing in literature data on this topic. PMID- 26509165 TI - Naturally Occurring Extracellular Matrix Scaffolds for Dermal Regeneration: Do They Really Need Cells? AB - The pronounced effect of extracellular matrix (ECM) scaffolds in supporting tissue regeneration is related mainly to their maintained 3D structure and their bioactive components. These decellularized matrix scaffolds could be revitalized before grafting via adding stem cells, fibroblasts, or keratinocytes to promote wound healing. We reviewed the online published literature in the last five years for the studies that performed ECM revitalization and discussed the results of these studies and the related literature. Eighteen articles met the search criteria. Twelve studies included adding cells to acellular dermal matrix (ADM), 3 studies were on small intestinal mucosa (SIS), one study was on urinary bladder matrix (UBM), one study was on amniotic membrane, and one study included both SIS and ADM loaded constructs. We believe that, in chronic and difficult-to-heal wounds, revitalizing the ECM scaffolds would be beneficial to overcome the defective host tissue interaction. This belief still has to be verified by high quality randomised clinical trials, which are still lacking in literature. PMID- 26509166 TI - Fabrication of an Amperometric Flow-Injection Microfluidic Biosensor Based on Laccase for In Situ Determination of Phenolic Compounds. AB - We aim to develop an in situ microfluidic biosensor based on laccase from Trametes pubescens with flow-injection and amperometry as the transducer method. The enzyme was directly immobilized by potential step chronoamperometry, and the immobilization was studied using cyclic voltammetry and electrochemical impedance spectroscopy. The electrode response by amperometry was probed using ABTS and syringaldazine. A shift of interfacial electron transfer resistance and the electron transfer rate constant from 18.1 kOmega to 3.9 MOmega and 4.6 * 10(-2) cm s(-1) to 2.1 * 10(-4) cm s(-1), respectively, evidenced that laccase was immobilized on the electrode by the proposed method. We established the optimum operating conditions of temperature (55 degrees C), pH (4.5), injection flow rate (200 uL min(-1)), and applied potential (0.4 V). Finally, the microfluidic biosensor showed better lower limit of detection (0.149 uM) and sensitivity (0.2341 nA uM(-1)) for ABTS than previous laccase-based biosensors and the in situ operation capacity. PMID- 26509167 TI - Overexpression of NTRK1 Promotes Differentiation of Neural Stem Cells into Cholinergic Neurons. AB - Neurotrophic tyrosine kinase type 1 (NTRK1) plays critical roles in proliferation, differentiation, and survival of cholinergic neurons; however, it remains unknown whether enhanced expression of NTRK1 in neural stem cells (NSCs) can promote their differentiation into mature neurons. In this study, a plasmid encoding the rat NTRK1 gene was constructed and transfected into C17.2 mouse neural stem cells (NSCs). NTRK1 overexpression in C17.2 cells was confirmed by western blot. The NSCs overexpressing NTRK1 and the C17.2 NSCs transfected by an empty plasmid vector were treated with or without 100 ng/mL nerve growth factor (NGF) for 7 days. Expression of the cholinergic cell marker, choline acetyltransferase (ChAT), was detected by florescent immunocytochemistry (ICC). In the presence of NGF induction, the NSCs overexpressing NTRK1 differentiated into ChAT-immunopositive cells at 3-fold higher than the NSCs transfected by the plasmid vector (26% versus 9%, P < 0.05). The data suggest that elevated NTRK1 expression increases differentiation of NSCs into cholinergic neurons under stimulation of NGF. The approach also represents an efficient strategy for generation of cholinergic neurons. PMID- 26509168 TI - A Review of Computational Methods to Predict the Risk of Rupture of Abdominal Aortic Aneurysms. AB - Computational methods have played an important role in health care in recent years, as determining parameters that affect a certain medical condition is not possible in experimental conditions in many cases. Computational fluid dynamics (CFD) methods have been used to accurately determine the nature of blood flow in the cardiovascular and nervous systems and air flow in the respiratory system, thereby giving the surgeon a diagnostic tool to plan treatment accordingly. Machine learning or data mining (MLD) methods are currently used to develop models that learn from retrospective data to make a prediction regarding factors affecting the progression of a disease. These models have also been successful in incorporating factors such as patient history and occupation. MLD models can be used as a predictive tool to determine rupture potential in patients with abdominal aortic aneurysms (AAA) along with CFD-based prediction of parameters like wall shear stress and pressure distributions. A combination of these computer methods can be pivotal in bridging the gap between translational and outcomes research in medicine. This paper reviews the use of computational methods in the diagnosis and treatment of AAA. PMID- 26509169 TI - Shear Stress Induces Differentiation of Endothelial Lineage Cells to Protect Neonatal Brain from Hypoxic-Ischemic Injury through NRP1 and VEGFR2 Signaling. AB - Neonatal hypoxic-ischemic (HI) brain injuries disrupt the integrity of neurovascular structure and lead to lifelong neurological deficit. The devastating damage can be ameliorated by preserving the endothelial network, but the source for therapeutic cells is limited. We aim to evaluate the beneficial effect of mechanical shear stress in the differentiation of endothelial lineage cells (ELCs) from adipose-derived stem cells (ASCs) and the possible intracellular signals to protect HI injury using cell-based therapy in the neonatal rats. The ASCs expressed early endothelial markers after biochemical stimulation of endothelial growth medium. The ELCs with full endothelial characteristics were accomplished after a subsequential shear stress application for 24 hours. When comparing the therapeutic potential of ASCs and ELCs, the ELCs treatment significantly reduced the infarction area and preserved neurovascular architecture in HI injured brain. The transplanted ELCs can migrate and engraft into the brain tissue, especially in vessels, where they promoted the angiogenesis. The activation of Akt by neuropilin 1 (NRP1) and vascular endothelial growth factor receptor 2 (VEGFR2) was important for ELC migration and following in vivo therapeutic outcomes. Therefore, the current study demonstrated importance of mechanical factor in stem cell differentiation and showed promising protection of brain from HI injury using ELCs treatment. PMID- 26509170 TI - Molecular Characterization of Reactive Oxygen Species in Myocardial Ischemia Reperfusion Injury. AB - Myocardial ischemia-reperfusion (I/R) injury is experienced by individuals suffering from cardiovascular diseases such as coronary heart diseases and subsequently undergoing reperfusion treatments in order to manage the conditions. The occlusion of blood flow to the tissue, termed ischemia, can be especially detrimental to the heart due to its high energy demand. Several cellular alterations have been observed upon the onset of ischemia. The danger created by cardiac ischemia is somewhat paradoxical in that a return of blood to the tissue can result in further damage. Reactive oxygen species (ROS) have been studied intensively to reveal their role in myocardial I/R injury. Under normal conditions, ROS function as a mediator in many cell signaling pathways. However, stressful environments significantly induce the generation of ROS which causes the level to exceed body's antioxidant defense system. Such altered redox homeostasis is implicated in myocardial I/R injury. Despite the detrimental effects from ROS, low levels of ROS have been shown to exert a protective effect in the ischemic preconditioning. In this review, we will summarize the detrimental role of ROS in myocardial I/R injury, the protective mechanism induced by ROS, and potential treatments for ROS-related myocardial injury. PMID- 26509171 TI - Comparison of Different Strategies for Selection/Adaptation of Mixed Microbial Cultures Able to Ferment Crude Glycerol Derived from Second-Generation Biodiesel. AB - Objective of this study was the selection and adaptation of mixed microbial cultures (MMCs), able to ferment crude glycerol generated from animal fat-based biodiesel and produce building-blocks and green chemicals. Various adaptation strategies have been investigated for the enrichment of suitable and stable MMC, trying to overcome inhibition problems and enhance substrate degradation efficiency, as well as generation of soluble fermentation products. Repeated transfers in small batches and fed-batch conditions have been applied, comparing the use of different inoculum, growth media, and Kinetic Control. The adaptation of activated sludge inoculum was performed successfully and continued unhindered for several months. The best results showed a substrate degradation efficiency of almost 100% (about 10 g/L glycerol in 21 h) and different dominant metabolic products were obtained, depending on the selection strategy (mainly 1,3 propanediol, ethanol, or butyrate). On the other hand, anaerobic sludge exhibited inactivation after a few transfers. To circumvent this problem, fed-batch mode was used as an alternative adaptation strategy, which led to effective substrate degradation and high 1,3-propanediol and butyrate production. Changes in microbial composition were monitored by means of Next Generation Sequencing, revealing a dominance of glycerol consuming species, such as Clostridium, Klebsiella, and Escherichia. PMID- 26509172 TI - A Media and Clinic Intervention to Increase Colorectal Cancer Screening in Ohio Appalachia. AB - OBJECTIVE: To test the effectiveness of a colorectal cancer (CRC) screening intervention among adults living in Ohio Appalachia. METHODS: We conducted a group-randomized trial of a county-level intervention among adults living in 12 Ohio Appalachian counties who received a media campaign and clinic intervention focused on either CRC screening or fruits and vegetables. Participants' percentage within CRC screening guidelines was assessed with cross-sectional surveys conducted annually for four years, and validated with medical record review of screening. RESULTS: On average, screening data were obtained on 564 intervention and 559 comparison participants per year. There was no difference in the Wave 4 CRC screening rates of intervention and comparison counties (35.2% versus 31.4%). Multivariate analyses found that high perceived risk of CRC, willingness to have a CRC test if recommended by a doctor, doctor recommendation of a CRC screening test, and patient-physician communication about changes in bowel habits, family history of CRC, and eating fruits and vegetables were significant (p < 0.05) predictors of being within CRC screening guidelines. CONCLUSIONS: The intervention was not effective in increasing CRC rates among Ohio Appalachian adults. Future research should determine how media and clinic based interventions can be modified to improve CRC screening rates among this underserved population. PMID- 26509173 TI - Biologic Agents for Periodontal Regeneration and Implant Site Development. AB - The advancement of molecular mediators or biologic agents has increased tremendously during the last decade in periodontology and dental implantology. Implant site development and reconstruction of the lost periodontium represent main fields in which these molecular mediators have been employed and investigated. Different growth factors trigger different reactions in the tissues of the periodontium at various cellular levels. Proliferation, migration, and differentiation constitute the main target areas of these molecular mediators. It was the purpose of this comprehensive review to describe the origin and rationale, evidence, and the most current understanding of the following biologic agents: Recombinant Human Platelet-Derived Growth Factor-BB (rhPDGF-BB), Enamel Matrix Derivate (EMD), Platelet-Rich Plasma (PRP) and Platelet-Rich Fibrin (PRF), Recombinant Human Fibroblast Growth Factor-2 (rhFGF-2), Bone Morphogenic Proteins (BMPs, BMP-2 and BMP-7), Teriparatide PTH, and Growth Differential Factor-5 (GDF 5). PMID- 26509174 TI - High 15-F2t-Isoprostane Levels in Patients with a Previous History of Nonmelanoma Skin Cancer: The Effects of Supplementary Antioxidant Therapy. AB - BACKGROUND: Phase I of this study was aimed at comparing the profiles of oxidative stress biomarkers in patients with history of nonmelanoma skin cancer (NMSC), previously treated with surgery, to the healthy subjects. Phase II aimed to evaluate the effects of supplementary antioxidant therapy on the levels of biomarkers in the case group. MATERIALS AND METHODS: In Phase I, oxidative stress biomarkers were measured in blood samples obtained from 24 healthy subjects and 60 patients with history of NMSC previously treated with surgery. In Phase II, the 60 patients with history of NMSC were randomized into two subgroups, one receiving placebo (n = 34) and the other (n = 26) receiving vitamin C, vitamin E, and zinc supplementation for 8 weeks, followed by reevaluation of biomarkers. RESULTS: In Phase I, patients with history of NMSC showed increased plasma concentrations of all biomarkers, but only 15-F2t-isoprostane was significantly higher than in the healthy subjects. Risk of NMSC increased by 4% for each additional 1 pg/mL increase in 15-F2t-isoprostane. In Phase II, supplementation did not significantly reduce levels of oxidative stress biomarkers. CONCLUSION: Patients with history of NMSC had significantly high 15-F2t-isoprostane plasma levels; supplementation did not result in significant reduction of oxidative stress biomarkers. This trial was registered with ClinicalTrials.gov (ID NCT02248584). PMID- 26509175 TI - Low Intensity Physical Exercise Attenuates Cardiac Remodeling and Myocardial Oxidative Stress and Dysfunction in Diabetic Rats. AB - We evaluated the effects of a low intensity aerobic exercise protocol on cardiac remodeling and myocardial function in diabetic rats. Wistar rats were assigned into four groups: sedentary control (C-Sed), exercised control (C-Ex), sedentary diabetes (DM-Sed), and exercised diabetes (DM-Ex). Diabetes was induced by intraperitoneal injection of streptozotocin. Rats exercised for 9 weeks in treadmill at 11 m/min, 18 min/day. Myocardial function was evaluated in left ventricular (LV) papillary muscles and oxidative stress in LV tissue. Statistical analysis was given by ANOVA or Kruskal-Wallis. Echocardiogram showed diabetic groups with higher LV diastolic diameter-to-body weight ratio and lower posterior wall shortening velocity than controls. Left atrium diameter was lower in DM-Ex than DM-Sed (C-Sed: 5.73 +/- 0.49; C-Ex: 5.67 +/- 0.53; DM-Sed: 6.41 +/- 0.54; DM Ex: 5.81 +/- 0.50 mm; P < 0.05 DM-Sed vs C-Sed and DM-Ex). Papillary muscle function was depressed in DM-Sed compared to C-Sed. Exercise attenuated this change in DM-Ex. Lipid hydroperoxide concentration was higher in DM-Sed than C Sed and DM-Ex. Catalase and superoxide dismutase activities were lower in diabetics than controls and higher in DM-Ex than DM-Sed. Glutathione peroxidase activity was lower in DM-Sed than C-Sed and DM-Ex. CONCLUSION: Low intensity exercise attenuates left atrium dilation and myocardial oxidative stress and dysfunction in type 1 diabetic rats. PMID- 26509176 TI - Detecting Genetic Associations between ATG5 and Lupus Nephritis by trans-eQTL. AB - Objectives. Numerous loci were identified to perturb gene expression in trans. As elevated ATG5 expression was observed in systemic lupus erythematosus (SLE), the study was conducted to analyze the genome-wide genetic regulatory mechanisms associated with ATG5 expression in a Chinese population with lupus nephritis (LN). Methods. The online expression quantitative trait loci database was searched for trans-expression single nucleotide polymorphisms (trans-eSNPs) of ATG5. Tagging trans-eSNPs were genotyped by a custom-made genotyping chip in 280 patients and 199 controls. For positive findings, clinical information and bioinformation analyses were performed. Results. Four trans-eSNPs were observed to be associated with susceptibility to LN (P < 0.05), including ANKRD50 rs17008504, AGA rs2271100, PAK7 rs6056923, and TET2 rs1391441, while seven other trans-eSNPs showed marginal significant associations (0.05 < P < 0.1). Correlations between the trans-eSNPs and ATG5 expression and different expression levels of ATG5 in SLE patients and controls were validated, and their regulatory effects were annotated. However, no significant associations were observed between different genotypes of trans-eSNPs and severity or outcome of the patients. Conclusion. Using the new systemic genetics approach, we identified 10 loci associated with susceptibility to LN potentially, which may be complementary to future pathway based genetic studies. PMID- 26509177 TI - IFN-gamma Priming Effects on the Maintenance of Effector Memory CD4(+) T Cells and on Phagocyte Function: Evidences from Infectious Diseases. AB - Although it has been established that effector memory CD4(+) T cells play an important role in the protective immunity against chronic infections, little is known about the exact mechanisms responsible for their functioning and maintenance, as well as their effects on innate immune cells. Here we review recent data on the role of IFN-gamma priming as a mechanism affecting both innate immune cells and effector memory CD4(+) T cells. Suboptimal concentrations of IFN gamma are seemingly crucial for the optimization of innate immune cell functions (including phagocytosis and destruction of reminiscent pathogens), as well as for the survival and functioning of effector memory CD4(+) T cells. Thus, IFN-gamma priming can thus be considered an important bridge between innate and adaptive immunity. PMID- 26509178 TI - Uterine Natural Killer Cell and Human Leukocyte Antigen-G1 and Human Leukocyte Antigen-G5 Expression in Vaginal Discharge of Threatened-Abortion Women: A Case Control Study. AB - The immunotolerant human leukocyte antigen-G (HLA-G) molecules have a major role in fetal-maternal tolerance during pregnancy. Interaction between these molecules and uterine natural killer (uNK) cells inhibitory receptors prevents NK cell invasion against fetus trophoblast cells. The aim of this study was to evaluate the percentages of uNK cells and HLA-G1 and HLA-G5 isoforms expression in vaginal discharge of threatened-abortion women in comparison with control. In a case control study, we investigated 30 threatened-abortion women with bleeding or spotting less than 20 weeks of pregnancy as compared to 30 normal pregnant women. uNK cells percentage was assessed by flow cytometry. Furthermore, we evaluated HLA-G1 and HLA-G5 isoforms expression by Real-Time PCR in these groups. The results of this study showed that threatened-abortion women had increased uNK cells and decreased T cells percentage in vaginal discharge in comparison with normal pregnant women (p = 0.01, p = 0.003, resp.). In addition, HLA-G1 isoform had lower expression in threatened-abortion women in comparison with control group (p = 0.0001). The increase of uNK cells level with the decrease of HLA-G expression in vaginal discharge of threatened-abortion pregnant women is an indicator of mother's immune dysregulation. It is concluded that HLA-G expression level with uNK cells percentage can be determined as a diagnostic marker for threatened-abortion women. PMID- 26509180 TI - Reply: Subgroup Differences in Response to 8 Weeks of Ledipasvir/Sofosbuvir for Chronic Hepatitis C. PMID- 26509179 TI - The Potential Role of Th9 Cell Related Cytokine and Transcription Factors in Patients with Hepatic Alveolar Echinococcosis. AB - Human alveolar echinococcosis (AE) is a lethal parasitic infectious disease which may lead to liver failure if left untreated. It is caused by the larval stage of the fox tapeworm Echinococcus multilocularis and usually develops a substantial infiltrative occupation in solid organs. During the infection, T helper subsets are known to play crucial role in crosstalk between the parasite and human host. Th9 cells, a new member of CD4(+) T cell family which is characterized by its specific cytokine IL-9 and transcription factors PU.1 and IRF-4, have been known recently to have a critical role in allergic diseases, and cancers as well as the parasitic infection. To assess the potential role of Th9 cells during the infection, the mRNA levels of IL-9, PU.1, and IRF-4 both in peripheral blood mononuclear cells and in liver tissues were, respectively, detected by using real time PCR. The plasma concentration levels of IL-9 were detected by using enzyme linked immunosorbent assay (ELISA). Th9 related cytokine IL-9 and transcription factors PU.1 and IRF-4 mRNA levels elevated both in PBMCs, and in hepatic lesion and paralesion tissues in AE patients. This may facilitate the infiltrative growth of the parasite and its persistence in human host. PMID- 26509181 TI - Are Staphylococcus intermedius Infections in Humans Cases of Mistaken Identity? A Case Series and Literature Review. AB - Staphylococcus intermedius and Staphylococcus pseudintermedius are difficult to distinguish using conventional microbiological methods. Molecular diagnostic tools change our understanding of the epidemiology of these 2 organisms. In this study, we present (1) a detailed review of the current literature on molecular diagnostics and (2) a case series in which misidentification was proven in 1 case. We conclude that S pseudintermedius is a more common human pathogen than previously recognized. PMID- 26509183 TI - Towards the safer clinical translation of human induced pluripotent stem cell derived cells to regenerative medicine. PMID- 26509182 TI - Association Between Outpatient Antibiotic Prescribing Practices and Community Associated Clostridium difficile Infection. AB - Background. Antibiotic use predisposes patients to Clostridium difficile infections (CDI), and approximately 32% of these infections are community associated (CA) CDI. The population-level impact of antibiotic use on adult CA CDI rates is not well described. Methods. We used 2011 active population- and laboratory-based surveillance data from 9 US geographic locations to identify adult CA-CDI cases, defined as C difficile-positive stool specimens (by toxin or molecular assay) collected from outpatients or from patients <=3 days after hospital admission. All patients were surveillance area residents and aged >=20 years with no positive test <=8 weeks prior and no overnight stay in a healthcare facility <=12 weeks prior. Outpatient oral antibiotic prescriptions dispensed in 2010 were obtained from the IMS Health Xponent database. Regression models examined the association between outpatient antibiotic prescribing and adult CA CDI rates. Methods. Healthcare providers prescribed 5.2 million courses of antibiotics among adults in the surveillance population in 2010, for an average of 0.73 per person. Across surveillance sites, antibiotic prescription rates (0.50-0.88 prescriptions per capita) and unadjusted CA-CDI rates (40.7-139.3 cases per 100 000 persons) varied. In regression modeling, reducing antibiotic prescribing rates by 10% among persons >=20 years old was associated with a 17% (95% confidence interval, 6.0%-26.3%; P = .032) decrease in CA-CDI rates after adjusting for age, gender, race, and type of diagnostic assay. Reductions in prescribing penicillins and amoxicillin/clavulanic acid were associated with the greatest decreases in CA-CDI rates. Conclusions and Relevance. Community associated CDI prevention should include reducing unnecessary outpatient antibiotic use. A modest reduction of 10% in outpatient antibiotic prescribing can have a disproportionate impact on reducing CA-CDI rates. PMID- 26509185 TI - Maize MeJA-responsive proteins identified by high-resolution 2-DE PAGE. AB - Exogenous methyl jasmonate (MeJA) is well-known to induce plant defense mechanisms effective against a wide variety of insect and microbial pests. High resolution 2-DE gel electrophoresis was used to discover changes in the leaf proteome of maize exposed to MeJA. We sequenced 62 MeJA-responsive proteins by tandem mass spectroscopy, and deposited the mass spectra and identities in the EMBL-EBI PRIDE repository under reference number PXD001793. An analysis and discussion of the identified proteins in relation to maize defense against Asian corn borer is published by Zhang et al. (2015) [1]. PMID- 26509184 TI - Design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophy. AB - Globoid cell leukodystrophy (GLD) is a demyelinating lysosomal storage disease due to the deficiency of the galactocerebrosidase (GALC) enzyme. The favorable outcome of hematopoietic stem and progenitor cell (HSPC)-based approaches in GLD and other similar diseases suggests HSPC gene therapy as a promising therapeutic option for patients. The path to clinical development of this strategy was hampered by a selective toxicity of the overexpressed GALC in the HSPC compartment. Here, we presented the optimization of a lentiviral vector (LV) in which miR-126 regulation was coupled to codon optimization of the human GALC cDNA to obtain a selective and enhanced enzymatic activity only upon transduced HSPCs differentiation. The safety of human GALC overexpression driven by this LV was extensively demonstrated in vitro and in vivo on human HSPCs from healthy donors. No perturbation in the content of proapoptotic sphingolipids, gene expression profile, and capability of engraftment and mutlilineage differentiation in chimeric mice was observed. The therapeutic potential of this LV was then assessed in a severe GLD murine model that benefited from transplantation of corrected HSPCs with longer survival and ameliorated phenotype as compared to untreated siblings. This construct has thus been selected as a candidate for clinical translation. PMID- 26509186 TI - Gene expression profiling of brakeless mutant Drosophila embryos. AB - The transcriptional co-regulator Brakeless performs many important functions during Drosophila development, but few target genes have been identified. Here we use Affymetrix microarrays to identify Brakeless-regulated genes in 2-4 h old Drosophila embryos. Robust multi-array analysis (RMA) and statistical tests revealed 240 genes that changed their expression more than 1.5 fold. We find that up- and down-regulated genes fall into distinct gene ontology categories. In our associated study [2] we demonstrate that both up- and down-regulated genes can be direct Brakeless targets. Our results indicate that the co-repressor and co activator activities of Brakeless may result in distinct biological responses. The microarray data complies with MIAME guidelines and is deposited in GEO under accession number GSE60048. PMID- 26509187 TI - Characteristics of soils in selected maize growing sites along altitudinal gradients in East African highlands. AB - Maize is the main staple crop in the East African Mountains. Understanding how the edaphic characteristics change along altitudinal gradients is important for maximizing maize production in East African Highlands, which are the key maize production areas in the region. This study evaluated and compared the levels of some macro and micro-elements (Al, Ca, Fe, K, Mg, Mn, Na and P) and other soil parameters (pH, organic carbon content, soil texture [i.e. % Sand, % Clay and % Silt], cation exchange capacity [CEC], electric conductivity [EC], and water holding capacity [HC]). Soil samples were taken from maize plots along three altitudinal gradients in East African highlands (namely Machakos Hills, Taita Hills and Mount Kilimanjaro) characterized by graded changes in climatic conditions. For all transects, pH, Ca, K and Mg decreased with the increase in altitude. In contrast, % Silt, organic carbon content, Al and water holding capacity (HC) increased with increasing altitude. The research provides information on the status of the physical-chemical characteristics of soils along three altitudinal ranges of East African Highlands and includes data available for further research. PMID- 26509188 TI - Hybrid RGSA and Support Vector Machine Framework for Three-Dimensional Magnetic Resonance Brain Tumor Classification. AB - A novel hybrid approach for the identification of brain regions using magnetic resonance images accountable for brain tumor is presented in this paper. Classification of medical images is substantial in both clinical and research areas. Magnetic resonance imaging (MRI) modality outperforms towards diagnosing brain abnormalities like brain tumor, multiple sclerosis, hemorrhage, and many more. The primary objective of this work is to propose a three-dimensional (3D) novel brain tumor classification model using MRI images with both micro- and macroscale textures designed to differentiate the MRI of brain under two classes of lesion, benign and malignant. The design approach was initially preprocessed using 3D Gaussian filter. Based on VOI (volume of interest) of the image, features were extracted using 3D volumetric Square Centroid Lines Gray Level Distribution Method (SCLGM) along with 3D run length and cooccurrence matrix. The optimal features are selected using the proposed refined gravitational search algorithm (RGSA). Support vector machines, over backpropagation network, and k nearest neighbor are used to evaluate the goodness of classifier approach. The preliminary evaluation of the system is performed using 320 real-time brain MRI images. The system is trained and tested by using a leave-one-case-out method. The performance of the classifier is tested using the receiver operating characteristic curve of 0.986 (+/-002). The experimental results demonstrate the systematic and efficient feature extraction and feature selection algorithm to the performance of state-of-the-art feature classification methods. PMID- 26509189 TI - MR-compatible biopsy needle with enhanced tip force sensing. AB - We describe an instrumented biopsy needle that provides physicians the capability to sense interaction forces directly at the tip of the needle's inner stylet. The sensors consist of optical fiber Bragg gratings (FBGs), and are unaffected by electromagnetic fields; hence the needle is suitable for MR-guided procedures. In comparison to previous instrumented needles that measure bending strains, the new design has additional sensors and a series of micro-machined holes at the tip. The holes increase strain sensitivity, especially to axial forces, without significantly reducing the stiffness or strength. A comparison of the dynamic forces measured with the new needle and those obtained using a force/torque sensor at the needle base shows that the enhanced tip sensitivity is particularly noticeable when there is significant friction along the needle sleeve. PMID- 26509190 TI - An electrochemical-TUNEL method for sensitive detection of apoptotic cells. AB - An electrochemical-TUNEL method was developed for a cell sensor. A 3-D bio interface based on CNT@PDA-FA was employed in the cytosensor, which significantly improved the cell capture. By coupling with a QD-based nanoprobe and electrochemical stripping analysis, the cytosensor exhibited attractive performance for detection of apoptotic cells. PMID- 26509191 TI - Probing DNA-stabilized fluorescent silver nanocluster spectral heterogeneity by time-correlated single photon counting. AB - DNA-stabilized silver nanoclusters (DNA-AgNCs) are promising fluorophores whose photophysical properties and synthesis procedures have received increased attention in the literature. However, depending on the preparation conditions and the DNA sequence, the DNA-AgNC samples can host a range of different emitters, which can influence the reproducibility of the optical response and the evolution over time of the populations of these emitters. We have developed a simple method to characterize the spectral heterogeneity and time evolution of these emissive species at any given point in time after preparation, by plotting the average decay time as a function of emission wavelength. These so-called average decay time spectra were acquired for different excitation wavelengths of AgNCs stabilized by an oligonucleotide containing 24 cytosines (C24-AgNCs). The average decay time spectra allowed the comparison of sample preparation and the judgment of reproducibility. Therefore, we propose the use of the average decay time spectra as a robust and easy tool to characterize and compare different as synthesized DNA-AgNC samples. The average decay time spectra can in general also be used to characterize the spectral heterogeneity of other fluorophores, such as luminescent colloidal nanoparticles, and to assess the reproducibility of a synthetic procedure containing an unknown distribution of emissive species. PMID- 26509192 TI - Improvement of DNA recognition through molecular imprinting: hybrid oligomer imprinted polymeric nanoparticles (oligoMIP NPs). AB - High affinity and specific binding are cardinal properties of nucleic acids in relation to their biological function and their role in biotechnology. To this end, structural preorganization of oligonucleotides can significantly improve their binding performance, and numerous examples of this can be found in Nature as well as in artificial systems. Here we describe the production and characterization of hybrid DNA-polymer nanoparticles (oligoMIP NPs) as a system in which we have preorganized the oligonucleotide binding by molecular imprinting technology. Molecularly imprinted polymers (MIPs) are cost-effective "smart" polymeric materials capable of antibody-like detection, but characterized by superior robustness and the ability to work in extreme environmental conditions. Especially in the nanoparticle format, MIPs are dubbed as one of the most suitable alternatives to biological antibodies due to their selective molecular recognition properties, improved binding kinetics as well as size and dispersibility. Nonetheless, there have been very few attempts at DNA imprinting in the past due to structural complexity associated with these templates. By introducing modified thymine bases into the oligonucleotide sequences, which allow establishing covalent bonds between the DNA and the polymer, we demonstrate that such hybrid oligoMIP NPs specifically recognize their target DNA, and that the unique strategy of incorporating the complementary DNA strands as "preorganized selective monomers" improves the recognition properties without affecting the NPs physical properties such as size, shape or dispersibility. PMID- 26509193 TI - Independent non-medical prescribing for paramedics. AB - Independent non-medical prescribing has made significant advances in nursing and is now being considered and developed by other professions. The role of the paramedic is evolving and there is great emphasis on managing people at home and reducing rates of conveyance to hospital. This article discusses the role of the paramedic and suggests the benefits that independent non-medical prescribing could have for both the paramedic profession and for the patients paramedics treat during their clinical practice. PMID- 26509194 TI - Retraction Notice: Adenocarcinoma of the lung with scattered consolidation: Radiological-pathological correlation and prognosis. PMID- 26509195 TI - [Not Available]. PMID- 26509196 TI - In Reply. PMID- 26509197 TI - Reply: To PMID 25287001. PMID- 26509198 TI - In Reply. PMID- 26509199 TI - William J. Hadlow. PMID- 26509200 TI - In Reply. PMID- 26509201 TI - In Reply. PMID- 26509202 TI - Cancer care coordination: building a platform for the development of care coordinator roles and ongoing evaluation. AB - Continuity of care is integral to the quality and safety of care provided to people with cancer and their carers. Further evidence is required to examine the contribution Nurse Cancer Care Coordinator (NCCC) roles make in improving the continuity. The aim of the present study was to clarify the assumptions underpinning the NCCC roles and provide a basis for ongoing evaluation. The project comprised a literature review and a qualitative study to develop program logic. The participants who were purposively sampled included policy makers, practitioners, patient advocates, and researchers. Both the literature and participant reports found that NCCC roles are diverse and responsive to contextual influences to coordinate care at the individual (patient), organisational, and systems levels. The application of the program logic for the development of NCCC roles was explored. The conceptualisation of NCCC roles was also examined in relation to Boundary Spanning and Relational Coordination theory. Further research is required to examine how NCCCs contribute to improving equity, safety, quality and coordination of care. The project has implications for research, policy and practice, and makes explicit existing assumptions to provide a platform for further development and evaluation of these roles. PMID- 26509203 TI - Help seeking among vision-impaired adults referred to their GP for depressive symptoms: patient characteristics and outcomes associated with referral uptake. AB - Adults with vision impairment commonly experience depression; however, depression often remains undetected and therefore untreated in this group. Using a prospective longitudinal design, the aim of this study was to determine the rate of uptake for a referral to a general practitioner (GP), in vision-impaired adults, who were screened for depression in low vision rehabilitation and eye care settings. Fifty-seven vision-impaired adults (aged >= 18 years) were recruited from low vision rehabilitation centres across Australia and the Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, between June 2010 and May 2012. Participants screened positive for depressive symptoms and were referred to their GP for follow up. Telephone assessments took place at baseline, 3 and 6 months to determine uptake of a GP referral and changes in depressive symptoms over 6 months. Forty-six per cent of participants followed through with the GP referral. A desire for emotional support and stigma towards seeking support from a psychologist were significantly associated with uptake (both P < 0.05). GPs were more likely to recommend anti-depressant medication compared with a psychologist consultation (69% v. 54%) and patients themselves were more likely to take anti-depressant medication (94% v. 14% who saw a psychologist). Depressive symptoms decreased significantly over 6 months for those who followed through with a GP referral (baseline M = 10.04, s.d. = 5.76 v. 6-months M = 6.20, s.d. = 3.38; z = -2.26, P = 0.02) but not for those who did not use the GP referral (z = -1.92, P = 0.55). This method of referral to a GP following depression screening may provide an effective pathway to detect and manage depression in vision-impaired adults. PMID- 26509204 TI - How do primary health-care practitioners identify and manage communication impairments in preschool children? AB - Communication impairments (CIs) in preschool children are common and can have long-term adverse consequences if not detected and treated early. This study investigated the knowledge, training and practice of primary health-care practitioners in the identification and management of CIs in preschool-aged children. A cross-sectional survey of 277 primary health-care practitioners in the Inner West and South West Sydney was undertaken. The majority of practitioners surveyed understood the importance of early identification of CIs. Eight per cent ofpractitioners correctly identified all of the 'red flags' for verbal and non-verbal communication. The majority (80%) correctly described the management of a typical case presentation. Two-thirds of practitioners reported using a tool in their practice for developmental surveillance, but the quality of surveillance tools was variable. One-third felt their training in this area was poor and 90% indicated they would like further training. Barriers to referral included waiting times, availability and cost of services. We concluded that primary health-care practitioners are aware that CIs are significant and they need to be identified early. There are opportunities for further training and promoting high-quality developmental surveillance in primary care. In addition, there are broader health system issues that include promotion of an integrated response to the detection and management of CIs. PMID- 26509205 TI - Longitudinal comparison of a physiotherapist-led, home-based and group-based program for increasing physical activity in community-dwelling middle-aged adults. AB - Few studies have compared the longer-term effects of physical activity interventions. Here we compare a 6-month physiotherapist-led, home-based physical activity program to a community group exercise program over 2 years. Healthy, sedentary community-dwelling 50-65 year olds were recruited to a non-randomised community group exercise program (G, n = 93) or a physiotherapist-led, home-based physical activity program (HB, n = 65). Outcomes included 'sufficient' physical activity (Active Australia Survey), minutes of moderate-vigorous physical activity (ActiGraph GT1M), aerobic capacity (2-min step-test), quality of life (SF-12v2), blood pressure, waist circumference, waist-to-hip ratio and body mass index. Outcome measures were collected at baseline, 6, 12, 18 and 24 months. Using intention-to-treat analysis, both interventions resulted in significant and sustainable increases in the number of participants achieving 'sufficient' physical activity (HB 22 v. 41%, G 22 v. 47%, P <= 0.001) and decreases in waist circumference (HB 90 v. 89 cm, G 93 v. 91 cm, P < 0.001) over 2 years. The home based program was less costly (HB A$47 v. G $84 per participant) but less effective in achieving the benefits at 2 years. The physiotherapist-led, home based physical activity program may be a low-cost alternative to increase physical activity levels for those not interested in, or unable to attend, a group exercise program. PMID- 26509206 TI - Application of spatial analysis technology to the planning of access to oral health care for at-risk populations in Australian capital cities. AB - Australians are one of the healthiest populations in the world but there is strong evidence that health inequalities exist. Australia has 23.1 million people spread very unevenly over -20 million square kilometres. This study aimed to apply spatial analysis tools to measure the spatial distribution of fixed adult public dental clinics in the eight metropolitan capital cities of Australia. All population data for metropolitan areas of the eight capital cities were integrated with socioeconomic data and health-service locations, using Geographic Information Systems, and then analysed. The adult population was divided into three subgroups according to age, consisting of 15-year-olds and over (n = 7.2 million), retirees 65 years and over (n = 1.2 million), and the elderly, who were 85 years and over (n = 0.15 million). It was evident that the States fell into two groups; Tasmania, Northern Territory, Australian Capital Territory and Western Australia in one cluster, and Victoria, New South Wales, Queensland and South Australia in the other. In the first group, the average proportion of the population of low socioeconomic status living in metropolitan areas within 2.5 km of a government dental clinic is 13%, while for the other cluster, it is 42%. The clustering remains true at 5 km from the clinics. The first cluster finds that almost half (46%) of the poorest 30% of the population live within 5km of a government dental clinic. The other cluster of States finds nearly double that proportion (86%). The results from this study indicated that access distances to government dental services differ substantially in metropolitan areas of the major Australian capital cities. PMID- 26509207 TI - Role of public transport in accessibility to emergency dental care in Melbourne, Australia. AB - The aim of this study was to develop a method for the analysis of the influence of public transport supply in a large city (Melbourne) on the access to emergency dental treatment. Geographic Information Systems (GIS) tools were used to associate the geographical distribution of patients (and their socioeconomic status) with accessibility (through public transport supply, i.e. bus, tram and/or train) to emergency dental care. The methodology used allowed analysis of the socioeconomic status of patient residential areas and both spatial location and supply frequency of public transport by using existing data from patient records, census and transport departments. In metropolitan Melbourne, a total of 13 784 patients met the inclusion criteria for the study sample, of which 95% (n = 13 077) were living within a 50 km radius of the Royal Dental Hospital of Melbourne. Low socioeconomic areas had a higher demand for dental emergency care in the Royal Dental Hospital of Melbourne. Public transport supply was similar across the various socioeconomic strata in the population, with 80% of patients having good access to public transport. However, when considering only high frequency bus stops, the percentage of patients living within 400 m from a bus stop dropped to 65%. Despite this, the number of patients (adjusted to the population) coming from areas not supplied by public transport, and from areas with good or poor public transport supply, was similar. The methodology applied in the present study highlights the importance of evaluating not only the spatial distribution but also the frequency of public transport supply when studying access to services. This methodology can be extrapolated to other settings to identity transport/access patterns for a variety of services. PMID- 26509208 TI - Weighing up the costs of seeking health care for dengue symptoms: a grounded theory study of backpackers' decision-making processes. AB - Dengue fever, a mosquito-borne virus, is an ongoing public health issue in North Queensland. Importation of dengue fever by travellers visiting or returning to Australia can lead to epidemics. The mosquito can acquire the virus in the symptomatic viraemic phase, so timely recognition of cases is important to prevent epidemics. There is a gap in the literature about backpackers' knowledge of dengue fever and the decision-making process they use when considering utilising the Australian health-care system. This study uses grounded theory methods to construct a theory that explains the process backpackers use when seeking health care. Fifty semi-structured interviews with backpackers, hostel receptionists, travel agents and pharmacists were analysed, resulting in identification of a core category: 'weighing up the costs of seeking health care'. This core category has three subcategories: 'self-assessment of health status', 'wait-and-see' and 'seek direction'. Findings from this study identified key areas where health promotion material and increased access to health-care professionals could reduce the risk of backpackers spreading dengue fever. PMID- 26509209 TI - What are school leavers' priorities for festival preparation? AB - This paper reports on the findings from a qualitative research study that explored how young people prepared to minimise and/or avoid alcohol-related harm while attending a Schoolies Festival (SF). SFs are mass gatherings at which young people (schoolies) celebrate their graduation from high school. The attendance of schoolies, in various Australian communities, ranges between 10 000 and 30 000 individuals during the event. The literature suggests that schoolies are at higher than normal risk of harm at SF from misuse of alcohol, unsafe sex, aggressive behaviour, and other risk-taking factors. As a result of these concerns, SF organisers developed an infrastructure that treats alcohol-related harm, and provides on-site care (first aid stations) by St John Ambulance staff. This study used focus groups to identify strategies used by schoolies to avoid alcohol-related harm during SFs. Data revealed that schoolies did not actively seek health information before attending the event and did not display an interest in doing so. It is important to note that schoolies planned to use alcohol to celebrate and have a good time. Therefore a harm minimisation approach with a focus on providing the necessary infrastructure at SFs to minimise the dangers associated with excess alcohol use is important. Schoolies indicated that they had no desire for information about the hazards of alcohol ingestion. If any health messages were to be used by health authorities, it would be far more appropriate to promote the message of 'take care of your mate', to contribute to building a supportive environment at the event. This may be of more benefit to minimise harm at SFs than funding other health messages. PMID- 26509210 TI - Smoke-free politics--lessons to learn for Romania. AB - Very recently ASH -Global Action for everyone's health 2014 published two lesson on the progress of smoke free regulations in two countries France and Uruguay with all the explanations and comments referring to the results, limits and benefits of different strategies. I am trying to see in comparison with this two examples what we have done and what is necessary to learn in the future for also having in Romania a strong free regulation for smoke free environment. PMID- 26509211 TI - CO2 Exsolution from CO2 Saturated Water: Core-Scale Experiments and Focus on Impacts of Pressure Variations. AB - For CO2 sequestration and utilization in the shallow reservoirs, reservoir pressure changes are due to the injection rate changing, a leakage event, and brine withdrawal for reservoir pressure balance. The amounts of exsolved CO2 which are influenced by the pressure reduction and the subsequent secondary imbibition process have a significant effect on the stability and capacity of CO2 sequestration and utilization. In this study, exsolution behavior of the CO2 has been studied experimentally using a core flooding system in combination with NMR/MRI equipment. Three series of pressure variation profiles, including depletion followed by imbibitions without or with repressurization and repetitive depletion and repressurization/imbibition cycles, were designed to investigate the exsolution responses for these complex pressure variation profiles. We found that the exsolved CO2 phase preferentially occupies the larger pores and exhibits a uniform spatial distribution. The mobility of CO2 is low during the imbibition process, and the residual trapping ratio is extraordinarily high. During the cyclic pressure variation process, the first cycle has the largest contribution to the amount of exsolved CO2. The low CO2 mobility implies a certain degree of self-sealing during a possible reservoir depletion. PMID- 26509212 TI - Geometry- and QTAIM-Based Comparison of Intramolecular Charge-Inverted Hydrogen Bonds, M...(H-Si) "Agostic Bond", and M...(eta(2)-SiH) sigma Interactions. AB - Using large sets of systems having an intramolecular charge-inverted hydrogen bond (IMCIHB), M...(Ha-Si) "agostic bond" or M...(eta(2)-SiH) sigma interaction, we have compared both geometric and QTAIM-based topological parameters characterizing all these three types of interactions. It is shown that IMCIHBs can be distinguished from the other relevant interactions by the significantly less elongated Si-H bond. The other geometric parameters are not characteristic because they accept wide ranges of values in systems having either an M...(Ha-Si) "agostic bond" or M...(eta(2)-SiH) sigma interaction. If QTAIM-based results are investigated, then it is shown that an IMCIHB can be characterized by the position of the BCPH...M that is closer to the metal atom, whereas, quite the contrary, this BCP has been found to be closer to the agostic hydrogen in complexes having either M...(Ha-Si) or M...(eta(2)-SiH) interactions. Another difference is in the curvature of the M...H bond path. If the M...H bond path tracing the M...(H-E) (E = Si, C) interaction is curved, then this curvature appears near the agostic hydrogen-a property particularly pronounced in M...(Ha C) agostic bonds. Moreover, it has also been shown that an IMCIHB can be characterized by lower curvatures and, in general, lower values of the electron density computed at BCPH...Al than at BCPs of either M...(Ha-Si) or M...(eta(2) SiH) interactions. Importantly, IMCIHBs can be distinguished from the other two types of interactions on the basis of values of delocalization index, which are significantly lower for IMCIHBs. Other QTAIM-based parameters have occurred to be not characteristic for IMCIHBs due to wide ranges of their values obtained for M...(Ha-Si) and M...(eta(2)-SiH) interactions. It has also been shown that the PBE0 functional gives the best molecular structure in comparison with experimental data. PMID- 26509213 TI - Metal-organic frameworks for electrocatalytic reduction of carbon dioxide. AB - A key challenge in the field of electrochemical carbon dioxide reduction is the design of catalytic materials featuring high product selectivity, stability, and a composition of earth-abundant elements. In this work, we introduce thin films of nanosized metal-organic frameworks (MOFs) as atomically defined and nanoscopic materials that function as catalysts for the efficient and selective reduction of carbon dioxide to carbon monoxide in aqueous electrolytes. Detailed examination of a cobalt-porphyrin MOF, Al2(OH)2TCPP-Co (TCPP-H2 = 4,4',4",4'''-(porphyrin 5,10,15,20-tetrayl)tetrabenzoate) revealed a selectivity for CO production in excess of 76% and stability over 7 h with a per-site turnover number (TON) of 1400. In situ spectroelectrochemical measurements provided insights into the cobalt oxidation state during the course of reaction and showed that the majority of catalytic centers in this MOF are redox-accessible where Co(II) is reduced to Co(I) during catalysis. PMID- 26509214 TI - Self-Healing and Thermoresponsive Dual-Cross-Linked Alginate Hydrogels Based on Supramolecular Inclusion Complexes. AB - beta-Cyclodextrin (beta-CD), with a lipophilic inner cavity and hydrophilic outer surface, interacts with a large variety of nonpolar guest molecules to form noncovalent inclusion complexes. Conjugation of beta-CD onto biomacromolecules can form physically cross-linked hydrogel networks upon mixing with a guest molecule. Herein, the development and characterization of self-healing, thermoresponsive hydrogels, based on host-guest inclusion complexes between alginate-graft-beta-CD and Pluronic F108 (poly(ethylene glycol)-b-poly(propylene glycol)-b-poly(ethylene glycol)), are described. The mechanics, flow characteristics, and thermal response were contingent on the polymer concentration and the host-guest molar ratio. Transient and reversible physical cross-linking between host and guest polymers governed self-assembly, allowing flow to occur under shear stress and facilitating complete recovery of the material's properties within a few seconds of unloading. The mechanical properties of the dual-cross-linked, multi-stimuli-responsive hydrogels were tuned as high as 30 kPa at body temperature and are advantageous for biomedical applications such as drug delivery and cell transplantation. PMID- 26509215 TI - Biomimetic Submicroarrayed Cross-Linked Liquid Crystal Polymer Films with Different Wettability via Colloidal Lithography. AB - Photoresponsive cross-linked liquid crystal polymer (CLCP) films with different surface topographies, submicropillar arrays, and submicrocone arrays were fabricated through colloidal lithography technique by modulating different types of etching masks. The prepared submicropillar arrays were uniform with an average pillar diameter of 250 nm and the cone bottom diameter of the submicrocone arrays was about 400 nm, which are much smaller than previously reported CLCP micropillars. More interestingly, these two species of films with the same chemical structure represented completely different wetting behavior of water adhesion and mimicked rose petal and lotus leaf, respectively. Both the submicropillar arrayed film and the submicrocone arrayed film exhibited superhyrophobicity with a water contact angle (CA) value of 144.0 +/- 1.7 degrees and 156.4 +/- 1.2 degrees , respectively. Meanwhile, the former demonstrated a very high sliding angle (SA) greater than 90 degrees , and thus, the water droplet was pinned on the surface as rose petal. On the contrary, the SA of the submicrocone arrayed CLCP film consisting of micro- and nanostructure was only 3.1 +/- 2.0 degrees , which is as low as that of lotus leaf. Furthermore, the change on the wettability of the films was also investigated under alternating irradiation of visible light with two different wavelengths, blue light and green light. PMID- 26509216 TI - Stereoselective Catalysis Achieved through in Situ Desymmetrization of an Achiral Iron Catalyst Precursor. AB - Stereoselective catalysis is described that proceeds with catalyst control but without the need to synthesize preformed chiral catalysts or ligands. Iron-based catalysts were discovered to effect the stereoselective polymerization of lactides starting from a single achiral precursor and the proper choice of an achiral silanol additive. Spectroscopic analysis of the polymer revealed that the stereoselectivity originates from an enantiomorphic site rather than a chain end stereocontrol mechanism. Iron intermediates that are stereogenic at iron are proposed to form in situ as a result of desymmetrization that occurs from a change in the metal coordination number. The proposed mechanism is supported by a combination of spectroscopic measurements, model complexes, kinetic measurements, and DFT calculations. PMID- 26509217 TI - Bevacizumab and other novel therapies for recurrent oligodendroglial tumors. AB - Oligodendroglioma (WHO Grade 2) and anaplastic oligodendroglioma (WHO Grade 3) are glial tumors composed of neoplastic cellular elements that resemble oligodendrocytes. The treatment of recurrent, alkylator refractory oligodendroglial tumors is challenging given the paucity of effective treatment and lack of randomized controlled trials on which to base therapy. Notwithstanding the lack of prospective, randomized data, treatment of oligodendroglial tumors with bevacizumab can be recommended tentatively recognizing that preliminary studies suggest efficacy. Somatic mutations of the isocitrate dehydrogenase enzymes (IDH1 and IDH2) appear to play a critical role in the pathogenesis of most oligodendroglial tumors and agents that target these mutations are a potential therapeutic option. Additionally, reversal of CpG island hypermethylated phenotype status through inhibition of DNA methyltransferase with an inhibitor such as decitabine may provide a target for future studies. PMID- 26509218 TI - Bromopyridone Nucleotide Analogues, Anoxic Selective Radiosensitizing Agents That Are Incorporated in DNA by Polymerases. AB - Ionizing radiation is frequently used to kill tumor cells. However, hypoxic solid tumor cells are more resistant to this treatment, providing the impetus to develop molecules that sensitize cells to ionizing radiation. 5-Bromo-2' deoxyuridine (BrdU) has been investigated as a radiosensitizing agent in the lab and clinic for almost 5 decades. Recent reports that BrdU yields DNA interstrand cross-links (ICLs) in non-base-paired regions motivated us to develop radiosensitizing agents that generate cross-links in duplex DNA selectively under anoxic conditions. 4-Bromo- and 5-bromopyridone analogues of BrdU were synthesized and incorporated into oligonucleotides via solid-phase synthesis. Upon irradiation, these molecules yield DNA interstrand cross-links under anaerobic conditions. The respective nucleotide triphosphates are substrates for some DNA polymerases. ICLs are produced upon irradiation under anoxic conditions when the 4-bromopyridone is present in a PCR product. Because the nucleoside analogue is a poor phosphorylation substrate for human deoxycytidine kinase, a pro-nucleotide form of the 4-bromopyridone was used to incorporate this analogue into cellular DNA. Despite these efforts, the 4-bromopyridone nucleotide was not detected in cellular DNA. Although these molecules are improvements over previously reported nucleotide analogues designed to be hypoxic radiosensitizing agents, additional advances are needed to create molecules that function in cells. PMID- 26509219 TI - Five Easy Pieces. The Total Synthesis of Phosphoiodyn A (and Placotylene A). AB - The convergent total synthesis of the marine natural product phosphoiodyn A, a nanomolar agonist of human peroxisome proliferator-activated receptor delta (hPPARdelta), was achieved in five steps total from commercially available and inexpensive starting materials. The synthesis relies on the unprecedented regioselective hydrozirconation of a terminal acetylene in the presence of a conjugated 1,3-diyne and on ammonolysis of a beta-chlorophosphonic acid monoester. The scheme also provides the newly isolated placotylene A, an inhibitor of bone marrow-derived macrophage (BMM) differentiation. PMID- 26509220 TI - SUBFOVEAL CHOROIDAL THICKNESS IN PAPILLITIS TYPE OF VOGT-KOYANAGI-HARADA DISEASE AND IDIOPATHIC OPTIC NEURITIS. AB - PURPOSE: To evaluate the subfoveal choroidal thickness before and after treatment in papillitis type of Vogt-Koyanagi-Harada (VKH) disease and idiopathic optic neuritis (ON) using enhanced depth imaging spectral domain optical coherence tomography. METHODS: A total of 11 eyes of 7 patients (average age 47.3 years old) with papillitis type of VKH disease and 11 eyes of 8 patients (average 36.4 years old) with idiopathic ON case were included. The subfoveal choroidal thickness before and 1 month after treatment was measured using enhanced depth imaging spectral domain optical coherence tomography technique. Diagnosis was defined using fluorescein and indocyanine green angiography for VKH disease and magnetic resonance imaging for ON. Either case was treated with systemic steroid therapy. RESULTS: The mean subfoveal choroidal thickness before treatment in papillitis type of VKH disease was significantly thicker than in idiopathic ON case (527 +/- 119 MUm vs. 321 +/- 86 MUm, P < 0.01). Choroidal thickness in papillitis type of VKH disease decreased significantly to 313 +/- 91 MUm 1 month after treatment (P < 0.01, as compared with baseline), whereas choroidal thickness in idiopathic ON case remained about the same (319 +/- 89 MUm, P = 0.62, as compared with baseline). CONCLUSION: Although papillitis type of VKH disease is often misdiagnosed as idiopathic ON case, the initial choroidal thickness and its change after treatment may be useful in the differential diagnosis and management. PMID- 26509221 TI - VISION-RELATED QUALITY OF LIFE AND VISUAL FUNCTION AFTER RETINAL DETACHMENT SURGERY. AB - PURPOSE: To investigate and compare the vision-related quality of life after rhegmatogenous retinal detachment (RRD) surgery with that of normal controls and to evaluate the relationship between the vision-related quality of life and visual function after surgery for RRD. METHODS: In this prospective, consecutive, comparative case series, the 25-Item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) was completed by 100 RRD patients at 6 months after surgery. Among the patients with RRD, 86 underwent pars plana vitrectomy and 14 received scleral buckling. Best-corrected visual acuity was obtained using ETDRS charts and converted to the logarithm of the minimum angle of resolution for statistical calculations. The VFQ-25 also was administered to 107 normal controls. RESULTS: The VFQ-25 composite score and the subscales associated with general vision, mental health, social functioning, driving, and color vision were significantly lower in the RRD group than in the normal controls (P < 0.05). The VFQ-25 composite score significantly correlated with logarithm of the minimum angle of resolution best-corrected visual acuity (P < 0.0001) on both the operated and the fellow eye. CONCLUSION: The vision-related quality of life is significantly impaired in patients after surgery for RRD. Higher age and female gender negatively influences the results of the composite score. PMID- 26509222 TI - A NOVEL TECHNIQUE FOR SECURING SCLEROTOMIES IN 20-GAUGE TRANSCONJUNCTIVAL PARS PLANA VITRECTOMY: Surgical Outcomes and Complications in 529 Consecutive Cases. AB - PURPOSE: To describe a novel technique for securing sclerotomies after 20-gauge transconjunctival pars plana vitrectomy and determine the efficacy, and short term safety in various vitreoretinal diseases. METHODS: Retrospective chart review of consecutive cases that underwent 20-gauge transconjunctival pars plana vitrectomy with sclerotomy hydration was conducted. The main outcome measures included intraocular pressure, intraocular gas bubble size in postoperative Day 1, and early postoperative complications. Secondary outcomes included postoperative visual acuity at 1-month postoperative visit. RESULTS: Five hundred and twenty-nine eyes were evaluated. Mean gas/air fill and mean intraocular pressure were 75.1% and 14.8 mmHg on postoperative Day 1. Seven eyes (1.32%) had hypotony (intraocular pressure <6 mmHg) on Day 1, which normalized in all eyes by Day 7 (P = 0.0083). On postoperative Day 7, mean intraocular pressure was 17.1 mmHg. Hypotony was associated with a preoperative diagnosis of retinal detachment (P = 0.022), and silicone oil tamponade (P = 0.017). Mean best corrected visual acuity was 20/320 preoperatively and 20/125 postoperatively at 1-month follow-up visit (P < 0.0001). Twenty-seven cases had intraoperative or postoperative complications (5.1%). Rate of complications was not associated with the type of tamponade (P = 0.076). CONCLUSION: Twenty-gauge transconjunctival sutureless vitrectomy with sclerotomy hydration appears to be safe with a low rate of hypotony and complications, and good final visual outcome. PMID- 26509223 TI - REPRODUCIBILITY AND COMPARISON OF VISUAL ACUITY OBTAINED WITH SIGHTBOOK MOBILE APPLICATION TO NEAR CARD AND SNELLEN CHART. AB - PURPOSE: To investigate test-retest reproducibility of visual acuities obtained with a popular mobile application (app) and to explore the agreement with the standard clinic charts. METHODS: Records of patients who had visual acuity measured during the same routine clinic visit with Snellen chart, Rosenbaum near vision card, and SightBook mobile app were reviewed. Acuities were converted to approximate ETDRS letters for statistical purposes. RESULTS: One hundred and twenty-six patients were identified. SightBook, Snellen, and near card acuities had excellent test-retest reproducibility. SightBook acuities were significantly different from the near card acuities (mean absolute difference of 5.4 and 6.1 letters in the right and left eyes) and the Snellen acuities (mean absolute difference of 7.7 and 7.9 letters in the right and left eyes). The agreement was also poor between the near card and the Snellen acuities (mean absolute difference of 6.4 and 7.6 letters in the right and left eyes). CONCLUSION: The discrepancy between SightBook mobile app and the clinic charts acuities may be large; however, the results are highly reproducible. Obtaining baseline SightBook acuity allows future vision comparisons. SightBook mobile app offers a new portable vision assessment tool for the office and remote patient monitoring. PMID- 26509224 TI - High catalytic activity of oriented 2.0.0 copper(I) oxide grown on graphene film. AB - Metal oxide nanoparticles supported on graphene exhibit high catalytic activity for oxidation, reduction and coupling reactions. Here we show that pyrolysis at 900 degrees C under inert atmosphere of copper(II) nitrate embedded in chitosan films affords 1.1.1 facet-oriented copper nanoplatelets supported on few-layered graphene. Oriented (1.1.1) copper nanoplatelets on graphene undergo spontaneous oxidation to render oriented (2.0.0) copper(I) oxide nanoplatelets on few-layered graphene. These films containing oriented copper(I) oxide exhibit as catalyst turnover numbers that can be three orders of magnitude higher for the Ullmann type coupling, dehydrogenative coupling of dimethylphenylsilane with n-butanol and C-N cross-coupling than those of analogous unoriented graphene-supported copper(I) oxide nanoplatelets. PMID- 26509225 TI - Potassium Ion Batteries with Graphitic Materials. AB - Graphite intercalation compounds (GICs) have attracted tremendous attention due to their exceptional properties that can be finely tuned by controlling the intercalation species and concentrations. Here, we report for the first time that potassium (K) ions can electrochemically intercalate into graphitic materials, such as graphite and reduced graphene oxide (RGO) at ambient temperature and pressure. Our experiments reveal that graphite can deliver a reversible capacity of 207 mAh/g. Combining experiments with ab initio calculations, we propose a three-step staging process during the intercalation of K ions into graphite: C -> KC24 (Stage III) -> KC16 (Stage II) -> KC8 (Stage I). Moreover, we find that K ions can also intercalate into RGO film with even higher reversible capacity (222 mAh/g). We also show that K ions intercalation can effectively increase the optical transparence of the RGO film from 29.0% to 84.3%. First-principles calculations suggest that this trend is attributed to a decreased absorbance produced by K ions intercalation. Our results open opportunities for novel nonaqueous K-ion based electrochemical battery technologies and optical applications. PMID- 26509227 TI - Use of Poly(I:C) Stabilized with Chitosan As a Vaccine-Adjuvant Against Viral Hemorrhagic Septicemia Virus Infection in Zebrafish. AB - There is an urgent need for more efficient viral vaccines in finfish aquaculture worldwide. Here, we report the use of poly(I:C) stabilized with chitosan as an adjuvant for development of better finfish vaccines. The adjuvant was co-injected with inactivated viral hemorrhagic septicemia virus (VHSV) (CSpIC+iV vaccine) in adult zebrafish and its efficiency in protection against VHSV infection was compared to a live, attenuated VHS virus vaccine (aV). Both free and stabilized poly(I:C) were strong inducers of an antiviral state, measured by transcriptional activation of the genes of viral sensors: toll-like receptors, interferons, and interferon-stimulated genes, such as MXa within 48 h after injection. Both the CSpIC+iV and the aV formulations provided a significant protection against VHSV induced mortality. However, when plasma from survivors was tested for neutralizing antibodies in an in vitro protection assay, we could not demonstrate any protective effect. On the contrary, plasma from aV vaccinated fish enhanced cytopathic effects, indicating that antibody-dependent entry may play a role in this system. Our results show that poly(I:C) is a promising candidate as an adjuvant for fish vaccination against viral pathogens, and that the zebrafish is a promising model for aquaculture-relevant vaccination studies. PMID- 26509226 TI - STARD 2015: An Updated List of Essential Items for Reporting Diagnostic Accuracy Studies. AB - Incomplete reporting has been identified as a major source of avoidable waste in biomedical research. Essential information is often not provided in study reports, impeding the identification, critical appraisal, and replication of studies. To improve the quality of reporting of diagnostic accuracy studies, the Standards for Reporting of Diagnostic Accuracy Studies (STARD) statement was developed. Here we present STARD 2015, an updated list of 30 essential items that should be included in every report of a diagnostic accuracy study. This update incorporates recent evidence about sources of bias and variability in diagnostic accuracy and is intended to facilitate the use of STARD. As such, STARD 2015 may help to improve completeness and transparency in reporting of diagnostic accuracy studies. PMID- 26509228 TI - TAS-102 for the treatment of metastatic colorectal cancer. AB - The survival of patients with metastatic colorectal cancer has notably increased in the past 20 years, from 12 months to around 30 months. Nevertheless, the prognosis of patients pretreated with all available agents is poor and there is high unmet need for newer treatments. TAS-102 is an orally administered combination of the nucleoside analogue trifluridine and tipiracil hydrochloride, a thymidine phosphorylase inhibitor. In a randomized trial of 800 patients who had received at least two other treatments previously (most patients had received more than four treatments). TAS-102 demonstrated a significant prolongation of overall survival compared with placebo (median survival 7.1 vs. 5.3 months; hazard ratio 0 . 68, 95%CI: 0 . 58-0 . 81; p < 0 . 001). The toxicity was manageable, grade 3 or higher events occurred in 69% of patients in the TAS-102 group versus 52% in the placebo group, with neutropenia the most common event. PMID- 26509229 TI - Comparison of the Effects of In-office Bleaching Times on Whitening and Tooth Sensitivity: A Single Blind, Randomized Clinical Trial. AB - OBJECTIVES: The objective of the present study was to compare the bleaching efficacy (BE) and tooth sensitivity (TS) of in-office bleaching applied under different time protocols. METHODS AND MATERIALS: Fifty-three patients were randomly distributed into three groups: the bleaching agent was applied in one (1*15), two (2*15), or three (3*15) 15-minute applications. The labial surfaces of the anterior teeth were bleached using a 35% hydrogen peroxide gel. Two bleaching sessions with a one-week interval between were performed. The shade evaluation was performed with a visual shade guide and spectrophotometer before and 30 days after bleaching. Participants recorded TS with a five-point verbal scale. Color change was analyzed by one-way analysis of variance and Tukey tests. The absolute risk of TS and TS intensity were evaluated by the Fisher exact and Friedman/Kruskal-Wallis tests, respectively (alpha= 0.05). RESULTS: Significant whitening was observed in all groups, with statistically lower BE for the 1*15 group (p<0.05). The absolute risk of TS (95% confidence interval) was lower for the 1*15 group than for the other groups (p<0.05). The TS intensity of the 3*15 group was statistically higher than that associated with the other protocols (p<0.05). CONCLUSIONS: A single 15-minute application produced less TS but reduced BE. The protocol with 2*15 produced a degree of BE similar to that of the 3*15 group, but with reduced overall TS intensity. PMID- 26509230 TI - The Effect of Resin-modified Glass-ionomer Cement Base and Bulk-fill Resin Composite on Cuspal Deformation. AB - OBJECTIVES: This study investigated cuspal deformation in teeth restored with different types of adhesive materials with and without a base. METHODS: Mesio occluso-distal slot cavities of moderately large dimension were prepared on extracted maxillary premolars (n=24). Teeth were assigned to one of four groups and restored with either a sonic-activated bulk-fill resin composite (RC) (SonicFill), or a conventional nanohybrid RC (Herculite Ultra). The base materials used were a flowable nanofilled RC (Premise Flowable) and a high viscosity resin-modified glass-ionomer cement (RMGIC) (Riva Light-Cure HV). Cuspal deflection was measured with two direct current differential transformers, each contacting a buccal and palatal cusp. Cuspal movements were recorded during and after restoration placement. Data for the buccal and palatal cusp deflections were combined to give the net cuspal deflection. RESULTS: Data varied widely. All teeth experienced net inward cuspal movement. No statistically significant differences in cuspal deflection were found among the four test groups. CONCLUSIONS: The use of a flowable RC or an RMGIC in closed-laminate restorations produced the same degree of cuspal movement as restorations filled with only a conventional nanohybrid or bulk-fill RC. PMID- 26509231 TI - Digital Smile Design for Computer-assisted Esthetic Rehabilitation: Two-year Follow-up. AB - OBJECTIVE: The esthetics of the smile are related to the color, shape, texture, dental alignment, gingival contour, and the relationship of these with the face. PURPOSE: To present a two-year follow-up for an esthetic rehabilitation clinical case in which the method of digital smile design (DSD) was used to assist and improve diagnosis, communication, and predictability of treatment through an esthetic analysis of the assembly: face, smile, periodontal tissue, and teeth. CLINICAL PROCEDURE: The smile's esthetics were improved through gingival recontouring, dental home bleaching, and a restorative procedure with thin porcelain laminate veneers using lithium disilicate glass-ceramic (e.max Ceram, Ivoclar-Vivadent) laminates on teeth 4 through 13. DISCUSSION: The proposed technique had an acceptable clinical performance at the end of a two-year follow up. SIGNIFICANCE: DSD can be used to increase professional/patient communication and to provide greater predictability for the smile's esthetic rehabilitation. PMID- 26509232 TI - Effect of Adhesive Cementation Strategies on the Bonding of Y-TZP to Human Dentin. AB - This study evaluated the effects of different adhesive strategies on the adhesion of zirconia to dentin using conventional and self-adhesive cements and their corresponding adhesive resins. The occlusal parts of human molars (N=80) were sectioned, exposing the dentin. The teeth and zirconia cylinders (N=80) (diameter=3.4 mm; height=4 mm) were randomly divided into eight groups according to the factors "surface conditioning" and "cement type" (n=10 per group). One conventional cement (CC: RelyX ARC, 3M ESPE) and one self-adhesive cement (SA: RelyX U200, 3M ESPE) and their corresponding adhesive resin (for CC, Adper Single Bond Plus; for SA, Scotchbond Universal Adhesive-SU) were applied on dentin. Zirconia specimens were conditioned either using chairside (CJ: CoJet, 30 MUm, 2.5 bar, four seconds), laboratory silica coating (RC: Rocatec, 110 MUm, 2.5 bar, four seconds), or universal primer (Single Bond Universal-UP). Nonconditioned groups for both cements acted as the control (C). Specimens were stored in water (37 degrees C, 30 days) and subjected to shear bond strength (SBS) testing (1 mm/min). Data (MPa) were analyzed using two-way analysis of variance and a Tukey test (alpha=0.05). While surface conditioning significantly affected the SBS values (p=0.0001) (C 0.05). Results from this study indicate that mcrA gene targeted qPCR can be used as an alternate tool to monitor and compare certain methanogen communities in anaerobic digesters. SIGNIFICANCE AND IMPACT OF THE STUDY: Using quantitative PCR (qPCR), we demonstrate that the abundance of mcrA, a gene specific to methane producing archaea, correlated with specific methanogenic activity (SMA) measurements when H2 and CO2 , or propionate were provided as substrates. However, mcrA abundance did not correlate with SMA with acetate. SMA values are often used as a fitness indicator of anaerobic biomass. Results from qPCR can be obtained within a day while SMA analysis requires days to weeks to complete. Therefore, qPCR for mcrA abundance is a sensitive and fast method to compare and monitor the fitness of certain anaerobic biomass. As a monitoring tool, qPCR of mcrA will help anaerobic digester operators optimize treatment and encourage more widespread use of this valuable technology. PMID- 26509246 TI - Therapeutic innovations in inflammatory bowel diseases. AB - Inflammatory bowel disease (IBD) is a spectrum of complex multifactorial immune disorders characterized by chronic inflammation of the gut. Significant advances have been made in unraveling the pathogenesis of this disease spectrum, which have spurred the discovery of new therapeutic targets and strategies. In this review, we highlight the emerging new classes of IBD therapeutics under clinical evaluation and their method of action, including JAK inhibitors, anti-SMAD7 oligonucleotides, and cell-based therapies. Moreover, we discuss how an approach based on unique molecular insights in a given patient will, in the future, lead to a truly individualized/tailored disease management, starting at diagnosis, aiding in prognosis, and resulting in a personalized therapeutic approach. PMID- 26509247 TI - Formation and stability of gas-phase o-benzoquinone from oxidation of ortho hydroxyphenyl: a combined neutral and distonic radical study. AB - Gas-phase product detection studies of o-hydroxyphenyl radical and O2 are reported at 373, 500, and 600 K, at 4 Torr (533.3 Pa), using VUV time-resolved synchrotron photoionisation mass spectrometry. The dominant products are assigned as o-benzoquinone (C6H4O2, m/z 108) and cyclopentadienone (C5H4O, m/z 80). It is concluded that cyclopentadienone forms as a secondary product from prompt decomposition of o-benzoquinone (and dissociative ionization of o-benzoquinone may contribute to the m/z 80 signal at photon energies ?9.8 eV). Ion-trap reactions of the distonic o-hydroxyphenyl analogue, the 5-ammonium-2 hydroxyphenyl radical cation, with O2 are also reported and concur with the assignment of o-benzoquinone as the dominant product. The ion-trap study also provides support for a mechanism where cyclopentadienone is produced by decarbonylation of o-benzoquinone. Kinetic studies compare oxidation of the ammonium-tagged o-hydroxyphenyl and o-methylphenyl radical cations along with trimethylammonium-tagged analogues. Reaction efficiencies are found to be ca. 5% for both charge-tagged o-hydroxyphenyl and o-methylphenyl radicals irrespective of the charged substituent. G3X-K quantum chemical calculations are deployed to rationalise experimental results for o-hydroxyphenyl + O2 and its charge-tagged counterpart. The prevailing reaction mechanism, after O2 addition, involves a facile 1,5-H shift in the peroxyl radical and subsequent elimination of OH to yield o-benzoquinone that is reminiscent of the Waddington mechanism for beta hydroxyperoxyl radicals. These results suggest o-hydroxyphenyl + O2 and decarbonylation of o-benzoquinone serve as plausible OH and CO sources in combustion. PMID- 26509248 TI - [Challenges for Urologists in the Care of Patients with Lynch Syndrome: Example of A Patient with Muir-Torre Syndrome, A Subtype of Lynch Syndrome]. AB - The Muir-Torre syndrome (MTS) is a subtype of the Lynch syndrome (hereditary nonpolyposis colorectal cancer). In addition to tumours typically related to LS, MTS is associated with tumours of the sebaceous gland or keratoacanthoma. MTS is mostly characterised by a mutation of MSH2. In contrast to LS-associated tumours carrying a mutation of MLH1, MSH6 or PMS2, the frequency of urological neoplasms seems to be higher in Lynch syndrome patients with MSH2 mutation. Urological implications for the care of patients with LS or MTS include the early diagnosis of a possible hereditary background in patients presenting with urothelial cancers at an atypically young age and potentially the surveillance of carriers of mutations with an increased risk for urothelial cancers like males harbouring a MSH2 mutation. We report on a patient with various types of LS-associated cancers and cancers without a known association with LS, who died from multifocal metastasis of urothelial cancer. This case report shows that close interdisciplinary cooperation is mandatory for the treatment of patients with complex diseases. PMID- 26509249 TI - Growth factors for treating diabetic foot ulcers. AB - BACKGROUND: Foot ulcers are a major complication of diabetes mellitus, often leading to amputation. Growth factors derived from blood platelets, endothelium, or macrophages could potentially be an important treatment for these wounds but they may also confer risks. OBJECTIVES: To assess the benefits and harms of growth factors for foot ulcers in patients with type 1 or type 2 diabetes mellitus. SEARCH METHODS: In March 2015 we searched the Cochrane Wounds Group Specialised Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations, Ovid EMBASE and EBSCO CINAHL. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Randomised clinical trials in any setting, recruiting people with type 1 or type 2 diabetes mellitus diagnosed with a foot ulcer. Trials were eligible for inclusion if they compared a growth factor plus standard care (e.g., antibiotic therapy, debridement, wound dressings) versus placebo or no growth factor plus standard care, or compared different growth factors against each other. We considered lower limb amputation (minimum of one toe), complete healing of the foot ulcer, and time to complete healing of the diabetic foot ulcer as the primary outcomes. DATA COLLECTION AND ANALYSIS: Independently, we selected randomised clinical trials, assessed risk of bias, and extracted data in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We subjected our analyses to both fixed-effect and random-effects model analyses. MAIN RESULTS: We identified 28 randomised clinical trials involving 2365 participants. The cause of foot ulcer (neurologic, vascular, or combined) was poorly defined in all trials. The trials were conducted in ten countries. The trials assessed 11 growth factors in 30 comparisons: platelet-derived wound healing formula, autologous growth factor, allogeneic platelet-derived growth factor, transforming growth factor beta2, arginine-glycine-aspartic acid peptide matrix, recombinant human platelet-derived growth factor (becaplermin), recombinant human epidermal growth factor, recombinant human basic fibroblast growth factor, recombinant human vascular endothelial growth factor, recombinant human lactoferrin, and recombinant human acidic fibroblast growth factor. Topical intervention was the most frequent route of administration. All the trials were underpowered and had a high risk of bias. Pharmaceutical industry sponsored 50% of the trials.Any growth factor compared with placebo or no growth factor increased the number of participants with complete wound healing (345/657 (52.51%) versus 167/482 (34.64%); RR 1.51, 95% CI 1.31 to 1.73; I(2) = 51%, 12 trials; low quality evidence). The result is mainly based on platelet-derived wound healing formula (36/56 (64.28%) versus 7/27 (25.92%); RR 2.45, 95% 1.27 to 4.74; I(2) = 0%, two trials), and recombinant human platelet-derived growth factor (becaplermin) (205/428 (47.89%) versus 109/335 (32.53%); RR 1.47, 95% CI 1.23 to 1.76, I(2)= 74%, five trials).In terms of lower limb amputation (minimum of one toe), there was no clear evidence of a difference between any growth factor and placebo or no growth factor (19/150 (12.66%) versus 12/69 (17.39%); RR 0.74, 95% CI 0.39 to 1.39; I(2) = 0%, two trials; very low quality evidence). One trial involving 55 participants showed no clear evidence of a difference between recombinant human vascular endothelial growth factor and placebo in terms of ulcer-free days following treatment for diabetic foot ulcers (RR 0.64, 95% CI 0.14 to 2.94; P value 0.56, low quality of evidence)Although 11 trials reported time to complete healing of the foot ulcers in people with diabetes , meta-analysis was not possible for this outcome due to the unique comparisons within each trial, failure to report data, and high number of withdrawals. Data on quality of life were not reported. Growth factors showed an increasing risk of overall adverse event rate compared with compared with placebo or no growth factor (255/498 (51.20%) versus 169/332 (50.90%); RR 0.83; 95% CI 0.72 to 0.96; I(2) = 48%; eight trials; low quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated. AUTHORS' CONCLUSIONS: This Cochrane systematic review analysed a heterogeneous group of trials that assessed 11 different growth factors for diabetic foot ulcers. We found evidence suggesting that growth factors may increase the likelihood that people will have complete healing of foot ulcers in people with diabetes. However, this conclusion is based on randomised clinical trials with high risk of systematic errors (bias). Assessment of the quality of the available evidence (GRADE) showed that further trials investigating the effect of growth factors are needed before firm conclusions can be drawn. The safety profiles of the growth factors are unclear. Future trials should be conducted according to SPIRIT statement and reported according to the CONSORT statement by independent investigators and using the Foundation of Patient-Centered Outcomes Research recommendations. PMID- 26509250 TI - Intravenous administration of tranexamic acid effectively reduces blood loss in primary total knee arthroplasty in a 610-patient consecutive case series. AB - BACKGROUND: Tranexamic acid (TXA) has been reported to demonstrate efficacy in reducing blood loss during arthroplasty procedures. STUDY DESIGN AND METHODS: This study examines the effectiveness of TXA as a central element of a patient blood management program (PBMP) by evaluating blood loss and transfusion of red blood cells in three consecutive groups of patients undergoing routine total knee arthroplasty (TKA). Approximately 200 patients were in each group as follows: Group 1 was a control without TXA, Group 2 was intraarticular administration, and Group 3 was intravenous (IV) administration. RESULTS: The IV group demonstrated a small but significant lower blood loss compared to the two other groups measured by hemoglobin (Hb) drift and nadir Hb levels. The routine use of TXA along with the other aspects of our PBMP provided significant cost savings due to the reduction in transfusions as well as a decrease in length of stay and has been an important element of our successful implementation of a PBMP. CONCLUSION: This study demonstrates a significant benefit from the routine use of TXA for total knee arthroplasty and is one of the first studies to demonstrate a small but significant benefit for IV administration in comparison to intraarticular administration. The routine use of TXA as a central element of a PBMP provides a cost savings and can help reduce the rate of transfusions for total knee arthroplasty. PMID- 26509252 TI - Rapid Software-Based Design and Optical Transient Liquid Molding of Microparticles. AB - Microparticles with complex 3D shape and composition are produced using a novel fabrication method, optical transient liquid molding, in which a 2D light pattern exposes a photopolymer precursor stream shaped along the flow axis by software aided inertial flow engineering. PMID- 26509251 TI - Generalized whole-body Patlak parametric imaging for enhanced quantification in clinical PET. AB - We recently developed a dynamic multi-bed PET data acquisition framework to translate the quantitative benefits of Patlak voxel-wise analysis to the domain of routine clinical whole-body (WB) imaging. The standard Patlak (sPatlak) linear graphical analysis assumes irreversible PET tracer uptake, ignoring the effect of FDG dephosphorylation, which has been suggested by a number of PET studies. In this work: (i) a non-linear generalized Patlak (gPatlak) model is utilized, including a net efflux rate constant kloss, and (ii) a hybrid (s/g)Patlak (hPatlak) imaging technique is introduced to enhance contrast to noise ratios (CNRs) of uptake rate Ki images. Representative set of kinetic parameter values and the XCAT phantom were employed to generate realistic 4D simulation PET data, and the proposed methods were additionally evaluated on 11 WB dynamic PET patient studies. Quantitative analysis on the simulated Ki images over 2 groups of regions-of-interest (ROIs), with low (ROI A) or high (ROI B) true kloss relative to Ki, suggested superior accuracy for gPatlak. Bias of sPatlak was found to be 16-18% and 20-40% poorer than gPatlak for ROIs A and B, respectively. By contrast, gPatlak exhibited, on average, 10% higher noise than sPatlak. Meanwhile, the bias and noise levels for hPatlak always ranged between the other two methods. In general, hPatlak was seen to outperform all methods in terms of target-to-background ratio (TBR) and CNR for all ROIs. Validation on patient datasets demonstrated clinical feasibility for all Patlak methods, while TBR and CNR evaluations confirmed our simulation findings, and suggested presence of non negligible kloss reversibility in clinical data. As such, we recommend gPatlak for highly quantitative imaging tasks, while, for tasks emphasizing lesion detectability (e.g. TBR, CNR) over quantification, or for high levels of noise, hPatlak is instead preferred. Finally, gPatlak and hPatlak CNR was systematically higher compared to routine SUV values. PMID- 26509253 TI - Numerical modeling of fluid-structure interaction in arteries with anisotropic polyconvex hyperelastic and anisotropic viscoelastic material models at finite strains. AB - The accurate prediction of transmural stresses in arterial walls requires on the one hand robust and efficient numerical schemes for the solution of boundary value problems including fluid-structure interactions and on the other hand the use of a material model for the vessel wall that is able to capture the relevant features of the material behavior. One of the main contributions of this paper is the application of a highly nonlinear, polyconvex anisotropic structural model for the solid in the context of fluid-structure interaction, together with a suitable discretization. Additionally, the influence of viscoelasticity is investigated. The fluid-structure interaction problem is solved using a monolithic approach; that is, the nonlinear system is solved (after time and space discretizations) as a whole without splitting among its components. The linearized block systems are solved iteratively using parallel domain decomposition preconditioners. A simple - but nonsymmetric - curved geometry is proposed that is demonstrated to be suitable as a benchmark testbed for fluid structure interaction simulations in biomechanics where nonlinear structural models are used. Based on the curved benchmark geometry, the influence of different material models, spatial discretizations, and meshes of varying refinement is investigated. It turns out that often-used standard displacement elements with linear shape functions are not sufficient to provide good approximations of the arterial wall stresses, whereas for standard displacement elements or F-bar formulations with quadratic shape functions, suitable results are obtained. For the time discretization, a second-order backward differentiation formula scheme is used. It is shown that the curved geometry enables the analysis of non-rotationally symmetric distributions of the mechanical fields. For instance, the maximal shear stresses in the fluid structure interface are found to be higher in the inner curve that corresponds to clinical observations indicating a high plaque nucleation probability at such locations. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26509254 TI - Novel Roles for CRF-Binding Protein and CRF Receptor 2 in Binge Drinking. PMID- 26509255 TI - Loss of asthma control and activation of coagulation and fibrinolysis. AB - BACKGROUND: Epidemiologic studies have shown that patients with severe asthma have increased risk of pulmonary embolism, in particular patients with frequent asthma exacerbations. Therefore, we hypothesized that asthma exacerbations are associated with increased haemostatic activity. OBJECTIVE: To investigate whether induced loss of asthma control is associated with changes in coagulation and fibrinolytic parameters in peripheral blood. METHODS: We performed a prospective, inhaled steroid withdrawal study in 23 patients with moderate to moderately severe asthma, consisting of a baseline visit and a visit after loss of asthma control. During the visits, we measured asthma control questionnaire (ACQ), atopy, lung function, inflammatory markers (eosinophils and neutrophils), and haemostatic parameters in plasma. RESULTS: Complete cessation of inhaled corticosteroids led to a loss of asthma control in 22 of 23 patients. We found increased asthma symptoms (ACQ 0.9 vs. 2.9, P < 0.01), significantly reduced lung function (forced expiratory volume in 1 s (FEV1) 3.51L vs. 3.13L, P < 0.01) and increased levels of eosinophils in plasma (0.26 * 10(E9)/L vs. 0.16 * 10(E9)/L, P = 0.03) in patients after loss of asthma control. However, we observed no significant changes in the coagulation and fibrinolysis parameters. CONCLUSION: Loss of asthma control after cessation of inhaled corticosteroids does not lead to increased haemostatic activation in patients with moderate to moderately severe asthma. This suggests that more severe inflammation or additional risk factors are required for activation of coagulation or reduction of fibrinolysis in asthma. PMID- 26509256 TI - Modulation of ultrafast photoinduced electron transfer in H-bonding environment: PET from aniline to coumarin 153 in the presence of an inert co-solvent cyclohexane. AB - Despite intensive research, the role of the H-bonding environment on ultrafast PET remains illusive. For example, coumarin 153 (C153) undergoes ultrafast photoinduced electron transfer (PET) in electron-donating solvents, in both aniline (AN) and N,N-dimethylaniline (DMA), despite their very different H bonding abilities. Thus, donor-acceptor (AN-C153) H-bonding may have only a minor role in PET (Yoshihara and co-workers, J. Phys. Chem. A, 1998, 102, 3089). However, donor-acceptor H-bonding may be somehow less effective in the neat H bonding environment but could become dominant in the presence of an inert solvent (Phys. Chem. Chem. Phys., 2014, 16, 6159). We successfully applied and tested the proposal here. The nature of PET modulation of C153 in the presence of a passive component cyclohexane is found to be very different for aniline and DMA. Upon addition of cyclohexane to DMA, the PET process gradually becomes retarded but in the case of AN, the PET rate was indeed found to be accelerated at some intermediate composition (mole fraction of aniline, XAN~ 0.74) compared to that of neat aniline. It is intuitive that cyclohexane may replace some of the donors (AN or DMA) from the vicinity of the acceptor and, thus, should disfavour PET. However, in the hydrogen bonding environment using molecular dynamics simulation, for the first time, we show that the average number of aniline molecules orienting their N-H group in the proximity of the C=O group of C153 is actually higher at the intermediate mole fraction (0.74) of aniline in a mixture rather than in neat aniline. This small but finite excess of C153-AN H-bonding already present in the ground state may possibly account for the anomalous effect. The TD DFT calculations presented here showed that the intermolecular H-bonding between C153 and AN strengthens from 21.1 kJ mol(-1) in the ground state to 33.0 kJ mol( 1) in the excited state and, consequently, H-bonding may assist PET according to the Zhao and Han model. Thus, we not only justified both the theoretical prediction (efficient H-bond assisted PET within the C153-AN pair) and experimental observation (minor H-bond assisted PET in neat solvent) but also established our previous hypothesis that an inert co-solvent can enhance the effect of H-bonding from molecular insights. PMID- 26509257 TI - Biochemical, biophysical, and genetic changes of porcine trophoblast-derived stem like cells during differentiation as evaluated using Raman microspectroscopy, Atomic force microscopy, and quantitative polymerase chain reaction. AB - Porcine trophoblast-derived stem-like cells grown into serum medium start to differentiate and become senescent within 30 days. However, trophoblast-derived cells, cultured in vitro in a defined and non-serum medium, have the regenerative properties, such as indefinite passage and foreign DNA receptivity, similar to stem cells. To evaluate the biochemical, biophysical, and genetic changes of the terminal differentiation of trophoblast derived cells, Raman microspectroscopy, atomic force microscopy, and qPCR were applied. It was found that Raman spectral intensities of characteristic peaks, cell morphology, and Young's modulus can be used to distinguish differentiated and undifferentiated trophoblast cells. In addition, 17 cytoskeleton and extracellular matrix-related genes were significantly impacted by medium type (non-serum versus serum). Our findings suggest that Raman microspectroscopy and atomic force microscopy-both considered as label-free, non-invasive techniques-can be applied to distinguish differentiated trophoblast cells, and cellular biochemical information and biophysical properties can be indicative of cellular differences during cell differentiation. In addition, most of cytoskeleton-related genes exhibit similar pattern to that of Young's modulus during trophoblast cell differentiation, indicating the potential connection between cytoskeleton-related genes and cellular stiffness. PMID- 26509259 TI - The Effect of Hypoxic Preconditioning on Induced Schwann Cells under Hypoxic Conditions. AB - OBJECT: Our objective was to explore the protective effects of hypoxic preconditioning on induced Schwann cells exposed to an environment with low concentrations of oxygen. It has been observed that hypoxic preconditioning of induced Schwann cells can promote axonal regeneration under low oxygen conditions. METHOD: Rat bone marrow mesenchymal stem cells (MSCs) were differentiated into Schwann cells and divided into a normal oxygen control group, a hypoxia-preconditioning group and a hypoxia group. The ultrastructure of each of these groups of cells was observed by electron microscopy. In addition, flow cytometry was used to measure changes in mitochondrial membrane potential. Annexin V-FITC/PI staining was used to detect apoptosis, and Western blots were used to detect the expression of Bcl-2/Bax. Fluorescence microscopic observations of axonal growth in NG-108 cells under hypoxic conditions were also performed. RESULTS: The hypoxia-preconditioning group maintained mitochondrial cell membrane and crista integrity, and these cells exhibited less edema than the hypoxia group. In addition, the cells in the hypoxia-preconditioning group were found to be in early stages of apoptosis, whereas cells from the hypoxia group were in the later stages of apoptosis. The hypoxia-preconditioning group also had higher levels of Bcl-2/Bax expression and longer NG-108 cell axons than were observed in the hypoxia group. CONCLUSION: Hypoxic preconditioning can improve the physiological state of Schwann cells in a severe hypoxia environment and improve the ability to promote neurite outgrowth. PMID- 26509260 TI - Peculiarities and Patterns of Cervical Spine Injuries in Children and Adolescents: A Retrospective Series of 84 Patients from a Single Institute. AB - Cervical spine injuries occur infrequently in children but are associated with significant disability and mortality. A retrospective analysis was performed of 84 consecutive pediatric spine injuries treated at our institute from January 2002 to December 2011. The mean age was 14.7 years. There were 18 patients (21%) in group A (0-12 years) and 66 patients (79%) in group B (13-18 years). Overall, injury was more common in boys (ratio of 6:1). Trivial fall was the predominant cause in group A and fall from height in group B. There were 30 children (36%) with injuries of the upper cervical spine, 53 (63%) with injuries of the lower cervical spine and 1 patient (1%) with a combined injury of upper cervical spine and thoracic spine. Overall, 22% of the group A children and 67% of the group B patients had more severe injuries (Frankel grades A, B and C); 21% (18/84) were treated by surgical fusion. Where follow-up was available, 17 out of 22 children (77%) had good outcome (Frankel grade >C). In conclusion, mechanisms and patterns of injury in children are age related and the majority of the children had good outcome. PMID- 26509261 TI - Therapeutic Potential of Stem Cells from Human Exfoliated Deciduous Teeth in Models of Acute Kidney Injury. AB - BACKGROUND: Acute kidney injury (AKI) is a critical condition associated with high mortality. However, the available treatments for AKI are limited. Stem cells from human exfoliated deciduous teeth (SHED) have recently gained attention as a novel source of stem cells. The purpose of this study was to clarify whether SHED have a therapeutic effect on AKI induced by ischemia-reperfusion injury. METHODS: The left renal artery and vein of the mice were clamped for 20 min to induce ischemia. SHED, bone marrow derived mesenchymal stem cells (BMMSC) or phosphate buffered saline (control) were administered into the subrenal capsule. To confirm the potency of SHED in vitro, H2O2 stimulation assays and scratch assays were performed. RESULTS: The serum creatinine and blood urea nitrogen levels of the SHED group were significantly lower than those of the control group, while BMMSC showed no therapeutic effect. Infiltration of macrophages and neutrophils in the kidney was significantly attenuated in mice treated with SHED. Cytokine levels (MIP-2, IL-1beta, and MCP-1) in mice kidneys were significantly reduced in the SHED group. In in vitro experiments, SHED significantly decreased MCP-1 secretion in tubular epithelial cells (TEC) stimulated with H2O2. In addition, SHED promoted wound healing in the scratch assays, which was blunted by anti-HGF antibodies. DISCUSSION: SHED attenuated the levels of inflammatory cytokines and improved kidney function in AKI induced by IRI. SHED secreted factors reduced MCP 1 and increased HGF expression, which promoted wound healing. These results suggest that SHED might provide a novel stem cell resource, which can be applied for the treatment of ischemic kidney injury. PMID- 26509262 TI - Divergent Androgen Receptor and Beta-Catenin Signaling in Prostate Cancer Cells. AB - Despite decades of effort to develop effective therapy and to identify promising new drugs, prostate cancer is lethal once it progresses to castration-resistant disease. Studies show mis-regulation of multiple pathways in castration-resistant prostate cancer (CRPC), reflecting the heterogeneity of the tumors and also hinting that targeting androgen receptor (AR) pathway alone might not be sufficient to treat CRPC. In this study, we present evidence that the Wnt/beta catenin pathway might be activated in prostate cancer cells after androgen deprivation to promote androgen-independent growth, partly through enhanced interaction of beta-catenin with TCF4. Androgen-independent prostate cancer cells were more prone to activate a Wnt-reporter, and inhibition of the Wnt/beta catenin pathway increased sensitivity of these cells to the second-generation antiandrogen, enzalutamide. Combined treatment of enzalutamide and Wnt/beta catenin inhibitor showed increased growth repression in both androgen-dependent and -independent prostate cancer cells, suggesting therapeutic potential for this approach. PMID- 26509263 TI - Endothelin-1 Overexpression Improves Renal Function in eNOS Knockout Mice. AB - BACKGROUND/AIMS: To investigate the renal phenotype under conditions of an activated renal ET-1 system in the status of nitric oxide deficiency, we compared kidney function and morphology in wild-type, ET-1 transgenic (ET+/+), endothelial nitric oxide synthase knockout (eNOS-/-) and ET+/+eNOS-/- mice. METHODS: We assessed blood pressure, parameters of renal morphology, plasma cystatin C, urinary protein excretion, expression of genes associated with glomerular filtration barrier and tissue remodeling, and plasma metabolites using metabolomics. RESULTS: eNOS-/- and ET+/+eNOS-/- mice developed hypertension. Osteopontin, albumin and protein excretion were increased in eNOS-/- and restored in ET+/+eNOS-/- animals. All genetically modified mice developed renal interstitial fibrosis and glomerulosclerosis. Genes involved in tissue remodeling (serpine1, TIMP1, Col1a1, CCL2) were up-regulated in eNOS-/-, but not in ET+/+eNOS-/- mice. Plasma levels of free carnitine and acylcarnitines, amino acids, diacyl phosphatidylcholines, lysophosphatidylcholines and hexoses were descreased in eNOS-/- and were in the normal range in ET+/+eNOS-/- mice. CONCLUSION: eNOS-/- mice developed renal dysfunction, which was partially rescued by ET-1 overexpression in eNOS-/- mice. The metabolomics results suggest that ET 1 overexpression on top of eNOS knockout is associated with a functional recovery of mitochondria (rescue effect in beta-oxidation of fatty acids) and an increase in antioxidative properties (normalization of monounsaturated fatty acids levels). PMID- 26509264 TI - Bone Morphogenetic Protein for the Healing of Tibial Fracture: A Meta-Analysis of Randomized Controlled Trials. AB - PURPOSE: To review the evidence from RCTs on clinical outcomes and benefit of acute tibial fracture and nonunion treated with and without BMPs. MATERIAL: We searched multiple databases (MEDLINE, EMABSE, BIOSIS and Cochrane central) as well as reference lists of articles and contacted authors. Evaluated outcomes included union rate, revision rate, hardware failure and infection. The weighted and standard mean difference (WMD and SMD) or the relative risk (RR) was calculated for continuous or dichotomous data respectively. The quality of the trial was assessed, and meta-analyses were performed with the Cochrane Collaboration's REVMAN 5.0 software. RESULTS: Eight RCTs involving 1113 patients were included. For acute tibial fracture, BMP group was associated with a higher rate of union (RR, 1.16; 95% CI, 1.04 to 1.30) and a lower rate of revision (RR, 0.68; 95% CI, 0.54 to 0.85) compared with control group. No significant differences were found in rate of hardware failure and infection. The pooled RR for achieving union for tibial fracture nonunion was 0.98 (95% CI, 0.86 to 1.13). There was no significant difference between the two groups in the rate of revision (RR, 0.48; 95% CI, 0.13 to 1.85) and infection (RR, 0.61; 95% CI, 0.37 to 1.02). CONCLUSION: Study on acute tibial fractures suggests that BMP is more effective that controls, for bone union and for decreasing the rate of surgical revision to achieve union. For the treatment of tibial fracture nonunion, BMP leads to similar results to as autogenous bone grafting. Finally, well-designed RCTs of BMP for tibial fracture treatment are also needed. PMID- 26509265 TI - Assessment of Lower Limb Muscle Strength and Power Using Hand-Held and Fixed Dynamometry: A Reliability and Validity Study. AB - INTRODUCTION: Hand-held dynamometry (HHD) has never previously been used to examine isometric muscle power. Rate of force development (RFD) is often used for muscle power assessment, however no consensus currently exists on the most appropriate method of calculation. The aim of this study was to examine the reliability of different algorithms for RFD calculation and to examine the intra rater, inter-rater, and inter-device reliability of HHD as well as the concurrent validity of HHD for the assessment of isometric lower limb muscle strength and power. METHODS: 30 healthy young adults (age: 23+/-5 yrs, male: 15) were assessed on two sessions. Isometric muscle strength and power were measured using peak force and RFD respectively using two HHDs (Lafayette Model-01165 and Hoggan microFET2) and a criterion-reference KinCom dynamometer. Statistical analysis of reliability and validity comprised intraclass correlation coefficients (ICC), Pearson correlations, concordance correlations, standard error of measurement, and minimal detectable change. RESULTS: Comparison of RFD methods revealed that a peak 200 ms moving window algorithm provided optimal reliability results. Intra rater, inter-rater, and inter-device reliability analysis of peak force and RFD revealed mostly good to excellent reliability (coefficients >= 0.70) for all muscle groups. Concurrent validity analysis showed moderate to excellent relationships between HHD and fixed dynamometry for the hip and knee (ICCs >= 0.70) for both peak force and RFD, with mostly poor to good results shown for the ankle muscles (ICCs = 0.31-0.79). CONCLUSIONS: Hand-held dynamometry has good to excellent reliability and validity for most measures of isometric lower limb strength and power in a healthy population, particularly for proximal muscle groups. To aid implementation we have created freely available software to extract these variables from data stored on the Lafayette device. Future research should examine the reliability and validity of these variables in clinical populations. PMID- 26509266 TI - In-Depth Characterization of Live Vaccines Used in Europe for Oral Rabies Vaccination of Wildlife. AB - Although rabies incidence has fallen sharply over the past decades in Europe, the disease is still present in Eastern Europe. Oral rabies immunization of wild animal rabies has been shown to be the most effective method for the control and elimination of rabies. All rabies vaccines used in Europe are modified live virus vaccines based on the Street Alabama Dufferin (SAD) strain isolated from a naturally-infected dog in 1935. Because of the potential safety risk of a live virus which could revert to virulence, the genetic composition of three commercial attenuated live rabies vaccines was investigated in two independent laboratories using next genome sequencing. This study is the first one reporting on the diversity of variants in oral rabies vaccines as well as the presence of a mix of at least two different variants in all tested batches. The results demonstrate the need for vaccine producers to use new robust methodologies in the context of their routine vaccine quality controls prior to market release. PMID- 26509267 TI - Higher Serum Ferritin Levels Correlate with an Increased Risk of Cutaneous Morbidity in Adult Patients with beta-Thalassemia: A Single-Center Retrospective Study. AB - Disturbed iron homeostasis characterizes beta-thalassemia and increases its morbidity. Our aim was to retrospectively associate beta-thalassemia disease characteristics with treatment-requiring skin conditions. The files of adult beta thalassemia (including sickle beta-thalassemia) patients were screened over a 10 year period for treatment-requiring skin disease episodes and their correlation with hematologic diagnoses and epidemiological and serological characteristics. Seventy-eight patients were identified, and 7 (9%) developed at least one relevant episode including cutaneous small-vessel vasculitis (CSVV), urticaria, and leg ulcers. Average ferritin serum level correlated significantly with development of a dermatosis (2,034 +/- 799 MUg/l in cases vs. 920 +/- 907 MUg/l in the overall population; p = 0.001, ANOVA). This difference relied exclusively on the high ferritin levels observed in patients with 'generalized' dermatoses (urticaria and CSVV: 3,860 +/- 1,220 MUg/l) as opposed to values within the normal range in the case of 'localized' ones (leg ulcers: 662 +/- 167 MUg/l). The employed iron chelation treatment influenced ferritin levels (p = 0.002, Kruskal Wallis test) since chelation with a single agent seems to increase the risk of a skin disease (p = 0.013, likelihood ratio method). Conclusively, serum ferritin can be evaluated as risk factor for generalized dermatoses, but not for leg ulcers, in patients with the beta-thalassemia genotype. This risk can be efficiently controlled with adequate chelation. PMID- 26509268 TI - Trends in Determinants of Entry into the Academic Career: The Case of South Korea, 1980-2010. AB - Substantial research documents the determinants of entry into the academic career, yet little is known about how these determinants have evolved over time. Using data from a large sample of Korean scholars who received their doctoral degrees between 1980 and 2010, we estimate discrete-time event history models of transitioning to an academic position in any academic field. Results indicate that universalistic characteristics, such as publication record, strongly affect subsequent career success, but so do particularistic factors, including doctoral institution prestige. Since the 1980s, the influence of doctoral degree prestige increased substantially more than the influence of one's publication record on higher education employment, implying that the rising importance of particularistic factors has outpaced growing consideration of universalistic characteristics in Korean academia. However, the importance of gender on academic employment has declined since the early 2000s, suggesting that the implementation of employment quotas for female professors may have stymied gender discrimination. PMID- 26509269 TI - Novel Trichoderma polysporum Strain for the Biocontrol of Pseudogymnoascus destructans, the Fungal Etiologic Agent of Bat White Nose Syndrome. AB - White-nose syndrome (WNS), an emerging disease of hibernating bats, has rapidly spread across eastern North America killing millions of bats. Pseudogymnoascus destructans (Pd), the sole etiologic agent of WNS, is widespread and persistent in bat hibernacula. Control of Pd in the affected sites is urgently needed to break the transmission cycle while minimizing any adverse impact on the native organisms. We isolated a novel strain of Trichoderma polysporum (Tp) from one of the caves at the epicenter of WNS zoonotic. Detailed experimental studies revealed: (1) Tp WPM 39143 was highly adapted to grow at temperatures simulating the cave environment (6 degrees C-15 degrees C), (2) Tp WPM 39143 restricted Pd colony growth in dual culture challenges, (3) Tp WPM 39143 caused four logs reduction of Pd colony forming units and genome copies in autoclaved soil samples from one of the WNS affected caves, (4) Tp WPM 39143 extract showed specific fungicidal activity against Pd in disk diffusion assay, but not against closely related fungus P. pannorum (Pp), (5) Tp WPM 39143 extract retained inhibitory activity after exposure to high temperatures, light and proteinase K, and (6) Inhibitory metabolites in Tp WPM 39143 extract comprised of water-soluble, high polarity compounds. These results suggest that Tp WPM 39143 is a promising candidate for further evaluation as a biocontrol agent of Pd in WNS affected sites. PMID- 26509270 TI - Large-Scale Range Collapse of Hawaiian Forest Birds under Climate Change and the Need for 21st Century Conservation Options [corrected]. AB - Hawaiian forest birds serve as an ideal group to explore the extent of climate change impacts on at-risk species. Avian malaria constrains many remaining Hawaiian forest bird species to high elevations where temperatures are too cool for malaria's life cycle and its principal mosquito vector. The impact of climate change on Hawaiian forest birds has been a recent focus of Hawaiian conservation biology, and has centered on the links between climate and avian malaria. To elucidate the differential impacts of projected climate shifts on species with known varying niches, disease resistance and tolerance, we use a comprehensive database of species sightings, regional climate projections and ensemble distribution models to project distribution shifts for all Hawaiian forest bird species. We illustrate that, under a likely scenario of continued disease-driven distribution limitation, all 10 species with highly reliable models (mostly narrow-ranged, single-island endemics) are expected to lose >50% of their range by 2100. Of those, three are expected to lose all range and three others are expected to lose >90% of their range. Projected range loss was smaller for several of the more widespread species; however improved data and models are necessary to refine future projections. Like other at-risk species, Hawaiian forest birds have specific habitat requirements that limit the possibility of range expansion for most species, as projected expansion is frequently in areas where forest habitat is presently not available (such as recent lava flows). Given the large projected range losses for all species, protecting high elevation forest alone is not an adequate long-term strategy for many species under climate change. We describe the types of additional conservation actions practitioners will likely need to consider, while providing results to help with such considerations. PMID- 26509271 TI - Disproportionate Contributions of Select Genomic Compartments and Cell Types to Genetic Risk for Coronary Artery Disease. AB - Large genome-wide association studies (GWAS) have identified many genetic loci associated with risk for myocardial infarction (MI) and coronary artery disease (CAD). Concurrently, efforts such as the National Institutes of Health (NIH) Roadmap Epigenomics Project and the Encyclopedia of DNA Elements (ENCODE) Consortium have provided unprecedented data on functional elements of the human genome. In the present study, we systematically investigate the biological link between genetic variants associated with this complex disease and their impacts on gene function. First, we examined the heritability of MI/CAD according to genomic compartments. We observed that single nucleotide polymorphisms (SNPs) residing within nearby regulatory regions show significant polygenicity and contribute between 59-71% of the heritability for MI/CAD. Second, we showed that the polygenicity and heritability explained by these SNPs are enriched in histone modification marks in specific cell types. Third, we found that a statistically higher number of 45 MI/CAD-associated SNPs that have been identified from large scale GWAS studies reside within certain functional elements of the genome, particularly in active enhancer and promoter regions. Finally, we observed significant heterogeneity of this signal across cell types, with strong signals observed within adipose nuclei, as well as brain and spleen cell types. These results suggest that the genetic etiology of MI/CAD is largely explained by tissue-specific regulatory perturbation within the human genome. PMID- 26509272 TI - Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis. AB - Urinary colics from calculosis are frequent and intense forms of pain whose current pharmacological treatment remains unsatisfactory. New and more effective drugs are needed to control symptoms and improve stone expulsion. Recent evidence suggested that the Nitric Oxide (NO) / cyclic guanosine monophosphate (cGMP)/phosphodiesterase type 5 (PDE5) system may contribute to ureteral motility influencing stone expulsion. We investigated if PDE5 inhibitors and sGC stimulators influence ureteral contractility, pain behaviour and stone expulsion in a rat model of ureteral calculosis. We investigated: a) the sex-specific PDE5 distribution in the rat ureter; b) the functional in vitro effects of vardenafil and sildenafil (PDE5 inhibitors) and BAY41-2272 (sGC stimulator) on induced ureteral contractility in rats and c) the in vivo effectiveness of vardenafil and BAY41-2272, alone and combined with ketoprofen, vs hyoscine-N-butylbromide alone or combined with ketoprofen, on behavioural pain indicators and stone expulsion in rats with artificial calculosis in one ureter. PDE5 was abundantly expressed in male and female rats' ureter. In vitro, both vardenafil and BAY41-2272 significantly relaxed pre-contracted ureteral strips. In vivo, all compounds significantly reduced number and global duration of "ureteral crises" and post stone lumbar muscle hyperalgesia in calculosis rats. The highest level of reduction of the pain behaviour was observed with BAY41-2272 among all spasmolytics administered alone, and with the combination of ketoprofen with BAY41-2272. The percentage of stone expulsion was maximal in the ketoprofen+BAY41 2272 group. The NO/cGMP/PDE5 pathway is involved in the regulation of ureteral contractility and pain behaviour in urinary calculosis. PDE5 inhibitors and sGC stimulators could become a potent new option for treatment of urinary colic pain. PMID- 26509273 TI - When Ontogeny Matters: A New Japanese Species of Brittle Star Illustrates the Importance of Considering both Adult and Juvenile Characters in Taxonomic Practice. AB - Current taxonomy offers numerous approaches and methods for species delimitation and description. However, most of them are based on the adult characters and rarely suggest a dynamic representation of developmental transformations of taxonomically important features. Here we show how the underestimation of ontogenetic changes may result in long term lack of recognition of a new species of one of the most common ophiacanthid brittle stars (Echinodermata: Ophiuroidea) from the North Pacific. Based on vast material collected predominantly by various Japanese expeditions in the course of more than 50 years, and thorough study of appropriate type material, we revise the complex of three common species of the ophiuroid genus Ophiacantha which have been persistently confused with each other. The present study thus reveals the previously unrecognized new species Ophiacantha kokusai sp.nov. which is commonly distributed off the Pacific coast of Japan. The new species shows developmental differentiation from the closely related species Ophiacantha rhachophora H. L. Clark, 1911 and retains clearly expressed early juvenile features in the adult morphology. Another species, Ophiacantha clypeata Kyte, 1977, which had been separated from O. rhachophora, is in turn shown to be just a juvenile stage of another North Pacific species, Ophiacantha trachybactra H.L. Clark, 1911. For every species, detailed morphological data from both adult and juvenile specimens based on scanning electron microscopy are presented. A special grinding method showing complex internal features has been utilized for the first time. For all three species in this complex, a clear bathymetric differentiation is revealed: O. rhachophora predominantly inhabits shallow waters, 0-250 m, the new species O. kokusai lives deeper, at 250-600 m, and the third species, O. trachybactra, is found at 500 2,000 m. The present case clearly highlights the importance of considering developmental transformations, not only for a limited number of model organisms, but as part of the taxonomic process. PMID- 26509274 TI - Risk of Injection-Site Abscess among Infants Receiving a Preservative-Free, Two Dose Vial Formulation of Pneumococcal Conjugate Vaccine in Kenya. AB - There is a theoretical risk of adverse events following immunization with a preservative-free, 2-dose vial formulation of 10-valent-pneumococcal conjugate vaccine (PCV10). We set out to measure this risk. Four population-based surveillance sites in Kenya (total annual birth cohort of 11,500 infants) were used to conduct a 2-year post-introduction vaccine safety study of PCV10. Injection-site abscesses occurring within 7 days following vaccine administration were clinically diagnosed in all study sites (passive facility-based surveillance) and, also, detected by caregiver-reported symptoms of swelling plus discharge in two sites (active household-based surveillance). Abscess risk was expressed as the number of abscesses per 100,000 injections and was compared for the second vs first vial dose of PCV10 and for PCV10 vs pentavalent vaccine (comparator). A total of 58,288 PCV10 injections were recorded, including 24,054 and 19,702 identified as first and second vial doses, respectively (14,532 unknown vial dose). The risk ratio for abscess following injection with the second (41 per 100,000) vs first (33 per 100,000) vial dose of PCV10 was 1.22 (95% confidence interval [CI] 0.37-4.06). The comparator vaccine was changed from a 2-dose to 10-dose presentation midway through the study. The matched odds ratios for abscess following PCV10 were 1.00 (95% CI 0.12-8.56) and 0.27 (95% CI 0.14-0.54) when compared to the 2-dose and 10-dose pentavalent vaccine presentations, respectively. In Kenya immunization with PCV10 was not associated with an increased risk of injection site abscess, providing confidence that the vaccine may be safely used in Africa. The relatively higher risk of abscess following the 10-dose presentation of pentavalent vaccine merits further study. PMID- 26509275 TI - A Novel High-Content Immunofluorescence Assay as a Tool to Identify at the Single Cell Level gamma-Globin Inducing Compounds. AB - The identification of drugs capable of reactivating gamma-globin to ameliorate beta-thalassemia and Sickle Cell anemia is still a challenge, as available gamma globin inducers still have limited clinical indications. High-throughput screenings (HTS) aimed to identify new potentially therapeutic drugs require suitable first-step-screening methods combining the possibility to detect variation in the gamma/beta globin ratio with the robustness of a cell line. We took advantage of a K562 cell line variant expressing beta-globin (beta-K562) to set up a new multiplexed high-content immunofluorescence assay for the quantification of gamma- and beta-globin content at single-cell level. The assay was validated by using the known globin inducers hemin, hydroxyurea and butyric acid and further tested in a pilot screening that confirmed HDACs as targets for gamma-globin induction (as proved by siRNA-mediated HDAC3 knockdown and by treatment with HDACs inhibitors entinostat and dacinostat) and identified Heme oxygenases as novel candidate targets for gamma-globin induction. Indeed, Heme oxygenase2 siRNA knockdown as well as its inhibition by Tin protoporphyrin-IX (TinPPIX) greatly increased gamma-globin expression. This result is particularly interesting as several metalloporphyrins have already been developed for clinical uses and could be tested (alone or in combination with other drugs) to improve pharmacological gamma-globin reactivation for the treatment of beta hemoglobinopathies. PMID- 26509277 TI - Methyl-alpha-D-2-selenonyl Pent-2-enofuranoside: A Reactive Selenosugar for the Diversity Oriented Synthesis of Enantiomerically Pure Heterocycles, Carbocycles, and Isonucleosides. AB - The construction of vinyl selenone on a furanoside led to a highly reactive synthetic intermediate methyl-alpha-D-2-selenonyl pent-2-enofuranoside composed of a masked aldehyde, an electron-deficient double bond along with an excellent leaving group. This new Michael acceptor on reactions with different nucleophiles afforded bicyclic azasugars, cyclopropanated carbohydrate, dihydrofuran- and dihydroisoxazole- substituted furanosides, and isonucleosides in moderate to good yields. Hydrolysis of the hemiacetal linkage of some of these modified carbohydrates afforded enantiopure aziridines, nitrocyclopropane, and dihydrofuran. PMID- 26509276 TI - Bioinformatics Knowledge Map for Analysis of Beta-Catenin Function in Cancer. AB - Given the wealth of bioinformatics resources and the growing complexity of biological information, it is valuable to integrate data from disparate sources to gain insight into the role of genes/proteins in health and disease. We have developed a bioinformatics framework that combines literature mining with information from biomedical ontologies and curated databases to create knowledge "maps" of genes/proteins of interest. We applied this approach to the study of beta-catenin, a cell adhesion molecule and transcriptional regulator implicated in cancer. The knowledge map includes post-translational modifications (PTMs), protein-protein interactions, disease-associated mutations, and transcription factors co-activated by beta-catenin and their targets and captures the major processes in which beta-catenin is known to participate. Using the map, we generated testable hypotheses about beta-catenin biology in normal and cancer cells. By focusing on proteins participating in multiple relation types, we identified proteins that may participate in feedback loops regulating beta catenin transcriptional activity. By combining multiple network relations with PTM proteoform-specific functional information, we proposed a mechanism to explain the observation that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator activity. Finally, by overlaying cancer associated mutation data with sequence features, we observed mutation patterns in several beta-catenin PTM sites and PTM enzyme binding sites that varied by tissue type, suggesting multiple mechanisms by which beta-catenin mutations can contribute to cancer. The approach described, which captures rich information for molecular species from genes and proteins to PTM proteoforms, is extensible to other proteins and their involvement in disease. PMID- 26509278 TI - In Pursuit of Novel Porphyrin Isomers. Aromatic Character and Relative Stability of Conjugated Tetrapyrroles with Two Neo-Confused Rings or with Mixed Neo Confused and N-Confused Subunits. AB - The conformations of five doubly neo-confused porphyrin structures and fifty-four neo-confused N-confused porphyrin (neo-C-NCP) tautomers were minimized using DFT B3LYP/6-311++G(d,p). The relative stabilities of the tautomers for each series were computed using M06-2X and B3LYP-D functionals, and the bond lengths and bond angles were calculated. Nucleus-independent chemical shifts and anisotropy of induced current density plots were used to provide further insights into the diatropic properties of each species. The results demonstrate that porphyrinoid structures with two modified rings of this type are far less stable than porphyrins, N-confused porphyrins, or neo-confused porphyrins, but the fully conjugated tautomers retain highly diatropic characteristics. Nevertheless, the lowest-energy neo-C-NCP tautomers have similar relative energies to known doubly N-confused porphyrins, and the results suggest that these types of porphyrin isomers may be synthetically accessible. PMID- 26509279 TI - Visualization of multimerization and self-assembly of DNA-functionalized gold nanoparticles using in-liquid transmission electron microscopy. AB - Base-pairing stability in DNA-gold nanoparticle (DNA-AuNP) multimers along with their dynamics under different electron beam intensities was investigated with in liquid transmission electron microscopy (in-liquid TEM). Multimer formation was triggered by hybridization of DNA oligonucleotides to another DNA strand (Hyb DNA) related to the concept of DNA origami. We analyzed the degree of multimer formation for a number of samples and a series of control samples to determine the specificity of the multimerization during the TEM imaging. DNA-AuNPs with Hyb DNA showed an interactive motion and assembly into 1D structures once the electron beam intensity exceeds a threshold value. This behavior was in contrast with control studies with noncomplementary DNA linkers where statistically significantly reduced multimerization was observed and for suspensions of citrate stabilized AuNPs without DNA, where we did not observe any significant motion or aggregation. These findings indicate that DNA base-pairing interactions are the driving force for multimerization and suggest a high stability of the DNA base pairing even under electron exposure. PMID- 26509280 TI - Glycopolymer Nanobiotechnology. PMID- 26509281 TI - Ordered Polypyrrole Nanowire Arrays Grown on a Carbon Cloth Substrate for a High Performance Pseudocapacitor Electrode. AB - Highly aligned nanoarchitecture arrays directly grown on conducting substrates open up a new direction to accelerate Faradaic reactions for charge storage as well as address "dead volume" limitations for high-performance pseudocapacitor electrodes. Here we reported the electrochemical fabrication of well-ordered polypyrrole (PPy) nanowire arrays (NWAs) on surfaces of carbon fibers in an untreated carbon cloth to construct hierarchical structures constituted by the three-dimensional conductive carbon fiber skeleton and the atop well-ordered electroactive polymer nanowires. The morphologies, wetting behaviors, and charge storage performances of the polymer were investigated by scanning electron microscopy, transmission electron microscopy, contact-angle measurement, cyclic voltammetry, galvanostatic charge-discharge, and electrochemical impedance spectroscopy. The well-ordered PPy NWA electrode exhibited a high specific capacitance of 699 F/g at 1 A/g with excellent rate capability, and 92.4% and 81.5% of its capacitance could be retained at 10 and 20 A/g, respectively. An extremely high energy density of 164.07 Wh/kg could be achieved by the PPy NWAs at a power density of 0.65 kW/kg. It also displayed a quite high energy density of 133.79 Wh/kg at a high power density of 13 kW/kg. The assembled symmetric supercapacitor of PPy NWAs//PPy NWAs also exhibited excellent rate capability, and only 19% of its energy density decreased when the power density increased 20 times from 0.65 to 13 kW/kg. PMID- 26509282 TI - Water Contact Angle Dependence with Hydroxyl Functional Groups on Silica Surfaces under CO2 Sequestration Conditions. AB - Functional groups on silica surfaces under CO2 sequestration conditions are complex due to reactions among supercritical CO2, brine and silica. Molecular dynamics simulations have been performed to investigate the effects of hydroxyl functional groups on wettability. It has been found that wettability shows a strong dependence on functional groups on silica surfaces: silanol number density, space distribution, and deprotonation/protonation degree. For neutral silica surfaces with crystalline structure (Q(3), Q(3)/Q(4), Q(4)), as silanol number density decreases, contact angle increases from 33.5 degrees to 146.7 degrees at 10.5 MPa and 318 K. When Q(3) surface changes to an amorphous structure, water contact angle increases 20 degrees . Water contact angle decreases about 12 degrees when 9% of silanol groups on Q(3) surface are deprotonated. When the deprotonation degree increases to 50%, water contact angle decreases to 0. The dependence of wettability on silica surface functional groups was used to analyze contact angle measurement ambiguity in literature. The composition of silica surfaces is complicated under CO2 sequestration conditions, the results found in this study may help to better understand wettability of CO2/brine/silica system. PMID- 26509283 TI - High-Efficiency Colloidal Quantum Dot Photovoltaics via Robust Self-Assembled Monolayers. AB - The optoelectronic tunability offered by colloidal quantum dots (CQDs) is attractive for photovoltaic applications but demands proper band alignment at electrodes for efficient charge extraction at minimal cost to voltage. With this goal in mind, self-assembled monolayers (SAMs) can be used to modify interface energy levels locally. However, to be effective SAMs must be made robust to treatment using the various solvents and ligands required for to fabricate high quality CQD solids. We report robust self-assembled monolayers (R-SAMs) that enable us to increase the efficiency of CQD photovoltaics. Only by developing a process for secure anchoring of aromatic SAMs, aided by deposition of the SAMs in a water-free deposition environment, were we able to provide an interface modification that was robust against the ensuing chemical treatments needed in the fabrication of CQD solids. The energy alignment at the rectifying interface was tailored by tuning the R-SAM for optimal alignment relative to the CQD quantum-confined electron energy levels. This resulted in a CQD PV record power conversion efficiency (PCE) of 10.7% with enhanced reproducibility relative to controls. PMID- 26509284 TI - The Patient Protection and Affordable Care Act: Suggestions for Improvements. PMID- 26509285 TI - Impact of the Patient Protection and Affordable Care Act: Overview. PMID- 26509286 TI - Integrating Health Care for the Most Vulnerable: Bridging the Differences in Organizational Cultures Between US Hospitals and Community Health Centers. AB - Policymakers have increasingly promoted health services integration to improve quality and efficiency. The US health care safety net, which comprises providers of health care to uninsured, Medicaid, and other vulnerable patients, remains a largely fragmented collection of providers. We interviewed leadership from safety net hospitals and community health centers in 5 US cities (Boston, MA; Denver, CO; Los Angeles, CA; Minneapolis, MN; and San Francisco, CA) throughout 2013 on their experiences with service integration. We identify conflicts in organizational mission, identity, and consumer orientation that have fostered reluctance to enter into collaborative arrangements. We describe how smaller scale initiatives, such as capitated model for targeted populations, health information exchange, and quality improvements led by health plans, can help bridge cultural differences to lay the groundwork for developing integrated care programs. PMID- 26509287 TI - Reversible Bacterial Adhesion on Mixed Poly(dimethylaminoethyl methacrylate)/Poly(acrylamidophenyl boronic acid) Brush Surfaces. AB - A simple and versatile method for the preparation of surfaces to control bacterial adhesion is described. Substrates were first treated with two catechol based polymerization initiators, one for thermal initiation and one for visible light photoinitiation. Graft polymerization in sequence of dimethylaminoethyl methacrylate (DMAEMA) and 3-acrylamidebenzene boronic acid (BA) from the surface bound initiators to form mixed polymer brushes on the substrate was then carried out. The PDMAEMA grafts were thermally initiated and the PBA grafts were visible light-photoinitiated. Gold, poly(vinyl chloride) (PVC), and poly(dimethylsiloxane) (PDMS) were used as model substrates. X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FT-IR), and ellipsometry analysis confirmed the successful grafting of PDMAEMA/PBA mixed brushes. We demonstrated that the resulting surfaces showed charge-reversal properties in response to change of pH. The transition in surface charge at a specific pH allowed the surface to be reversibly switched from bacteria-adhesive to bacteria-resistant. At pH 4.5, below the isoelectric points (IEP, pH 5.3) of the mixed brushes, the surfaces are positively charged and the negatively charged Gram-positive S. aureus adheres at high density (2.6 * 10(6) cells/cm(2)) due to attractive electrostatic interactions. Subsequently, upon increasing the pH to 9.0 to give negatively charged polymer brush surface, ~90% of the adherent bacteria are released from the surface, presumably due to repulsive electrostatic interactions. This approach provides a simple method for the preparation of surfaces on which bacterial adhesion can be controlled and is applicable to a wide variety of substrates. PMID- 26509288 TI - ProBiS-CHARMMing: Web Interface for Prediction and Optimization of Ligands in Protein Binding Sites. AB - Proteins often exist only as apo structures (unligated) in the Protein Data Bank, with their corresponding holo structures (with ligands) unavailable. However, apoproteins may not represent the amino-acid residue arrangement upon ligand binding well, which is especially problematic for molecular docking. We developed the ProBiS-CHARMMing web interface by connecting the ProBiS ( http://probis.cmm.ki.si ) and CHARMMing ( http://www.charmming.org ) web servers into one functional unit that enables prediction of protein-ligand complexes and allows for their geometry optimization and interaction energy calculation. The ProBiS web server predicts ligands (small compounds, proteins, nucleic acids, and single-atom ligands) that may bind to a query protein. This is achieved by comparing its surface structure against a nonredundant database of protein structures and finding those that have binding sites similar to that of the query protein. Existing ligands found in the similar binding sites are then transposed to the query according to predictions from ProBiS. The CHARMMing web server enables, among other things, minimization and potential energy calculation for a wide variety of biomolecular systems, and it is used here to optimize the geometry of the predicted protein-ligand complex structures using the CHARMM force field and to calculate their interaction energies with the corresponding query proteins. We show how ProBiS-CHARMMing can be used to predict ligands and their poses for a particular binding site, and minimize the predicted protein ligand complexes to obtain representations of holoproteins. The ProBiS-CHARMMing web interface is freely available for academic users at http://probis.nih.gov. PMID- 26509289 TI - Construction of Grape-like Silica-Based Hierarchical Porous Interlocked Microcapsules by Colloidal Crystals Templates. AB - We present a facile strategy to prepare grape-like silica-based hierarchical porous interlocked microcapsules (HPIMs) by polystyrene colloidal crystals templates, whose structure is the subtle integration of open mouthed structure, hierarchical porous nanostructure and interlocked architecture. HPIMs are fabricated by replicating colloidal crystals templates that have a hexagonal close-packed structure; thus, theoretically, each microcapsule has 12 open mouths, and these open mouths with mesoporous microcapsule wall construct the hierarchical porous structure. Furthermore, the interlocked architecture of the microcapsules can endow HPIMs with excellent mechanical stability and recyclability. By adjusting sulfonation time, the morphology, shell thickness, and even mesporous size of the HPIMs can be precisely controlled. In addition, HPIMs with various compositions are obtained via this method, such as silica and aminopropyl polysilsesquioxane (APSQ). All these unique features derived from a readily available method will give products with a broader range of applications. PMID- 26509290 TI - Human cytomegalovirus encoded microRNAs: hitting targets. AB - Human cytomegalovirus (HCMV) infection is of particular concern in immunodeficient individuals notably transplant recipients, leading to increased morbidity and mortality. HCMV is predicted to encode multiple microRNAs (miRNAs) and several have been characterized in vitro. Furthermore, these miRNAs have been shown to target human and viral mRNAs. Pathways involved in human cellular targets have key roles in vesicle trafficking, immune evasion and cell cycle control. This demonstration of viral miRNA targets provides novel insights into viral pathogenesis. This review details the evidence for the existence of HCMV encoded miRNA and their targets. HCMV miRNA in blood and other tissues is a potential diagnostic tool and blocking the effects of specific HCMV-encoded miRNA with sequence specific antagomirs is a potential new therapy. PMID- 26509291 TI - Giardia Assemblages A and B in Diarrheic Patients: A Comparative Study in Egyptian Children and Adults. AB - Giardia duodenalis is considered the most common intestinal parasite in humans worldwide. Children are especially affected, with more severe consequences than adults. The present study was designed to determine the distribution of assemblages A and B Giardia infection in children and adults, with the use of light microscopy and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) as diagnostic procedures, and to investigate its associations with clinical and epidemiological data collected from children and adult groups. This cross-sectional study was conducted from October 2012 to October 2013 by collecting fecal samples from 200 children and 200 adults complaining of diarrhea. Samples were subjected to parasitological examination by direct wet smear and formol-ether methods. Genotyping of G. doudenalis samples was conducted by PCR-RFLP analysis. Giardia duodenalis infection caused by assemblages A and B was identified in 60 samples, 34 from children and 26 from adults. Assemblage B was detected in 38 patients (63.34%), and assemblage A was detected in 22 patients (36.66%). Assemblage A was significantly more frequent in children with age range 2-8 yr, and assemblage B was higher in children with age range 6-16 yr old. Diarrhea frequency/day and recurrences per month affected patients infected with assemblage A (P value < 0.001) more frequently. Children infected with assemblage A presented significantly more severe diarrhea and dehydration than those infected with assemblage B (P value < 0.001). Although both Giardia assemblages A and B were identified in children and adults, assemblage A infected younger children more frequently and was more closely related to severe clinical manifestations than assemblage B. PMID- 26509292 TI - Anaplastic gliomas: end-of-life care recommendations. AB - Despite multimodal antitumor treatment, all patients with an anaplastic glioma will be confronted with incurability in due course and enter the end-of-life (EOL) phase; the period when the patients' condition declines and tumor-directed treatment is no longer effective. Although palliative care is important in all stages of the disease, it is of utmost importance in the EOL phase. The main goal of palliative care is to improve or maintain the quality of life of the patients and their relatives through the prevention and relief of suffering. This review focuses on different aspects of the EOL phase (symptoms and signs, EOL decision making, advance care planning, organization of care and caregiver burden) and will provide recommendations to optimize palliative care. PMID- 26509293 TI - Spleen Size Is Significantly Influenced by Body Height and Sex: Establishment of Normal Values for Spleen Size at US with a Cohort of 1200 Healthy Individuals. AB - PURPOSE: To define height- and sex-corrected normal values for spleen length and volume determined with ultrasonography (US). MATERIALS AND METHODS: The authors performed a retrospective data review of stem cell donors who had provided written informed consent for stem cell donation and use of anonymized data and biologic materials for scientific and quality control purposes. Spleen length, spleen volume, and anthrophometric data were correlated in 1230 healthy volunteers to identify variables that affect spleen size. Multiple linear regression analysis was performed to weight effects of various variables on spleen size. Linear regression through the 95th percentile for men and women of different height cohorts generated the formula for the upper limit of normal for spleen length and volume. For validation, the upper limit of normal was calculated for each volunteer and compared with the observed value. Formulae to calculate the additional percentiles were similarly generated and validated. A cohort of 75 volunteers was analyzed twice to assess the stability of spleen length and volume over time. RESULTS: Spleen length and volume were significantly and independently associated with sex (length: P < .001; volume: P = .012), body height (P < .001 for both), and weight (P < .001 for both), with men and taller and heavier individuals having longer and larger spleens. The spleen length of 20 of 324 women (6%) and 234 of 906 men (26%) exceeded the previously reported upper limit of normal of 12 cm. Repeat measurements indicated that spleen length (median difference, 0.10 cm; range, -1.8 to 1.7 cm) and volume (median difference, 3 cm(3); range, -106 to 142 cm(3)) were quite stable. A mobile application that performs these calculations is available for download. CONCLUSION: The authors define height- and sex-corrected normal values for spleen length and volume for women with a body height of 155-179 cm and men with a body height of 165-199 cm and propose validated algorithms to gauge the percentile of an individual's spleen size. PMID- 26509294 TI - The U.S. Radiologist Workforce: An Analysis of Temporal and Geographic Variation by Using Large National Datasets. AB - PURPOSE: To determine recent trends related to temporal as well as national and statewide geographic variation in the U.S. radiologist and radiology resident workforce. MATERIALS AND METHODS: This retrospective HIPAA-compliant study was exempted from the internal review board. Federal Area Health Resources Files and Medicare 5% research identifiable files were used to compute parameters related to the radiologist workforce. Geographic variation and annual temporal trends were analyzed. Pearson and Spearman correlations were assessed. RESULTS: Nationally, the number of radiology trainees increased 84.2% from a nadir in 1997 (3080 trainees) to 2011 (5674 trainees) and showed high state-to-state variation (range, 0-678 trainees in 2011). However, total radiologists nationally increased 39.2% from 1995 (27 906 radiologists) to 2011 (38 875 radiologists), and radiologists per 100 000 population nationally increased by 7.5% from 1995 (10.62%) to 2011 (11.42%), while showing high state-to-state variation (highest to-lowest state ratio of 4.3). Radiologists' share of the overall physician workforce declined nationally by 8.8% from 1995 (4.0%) to 2011 (3.7%), with moderate state-to-state variation (highest-to-lowest state ratio of 1.7). Radiology trainee numbers exhibited weak-to-moderate positive state-by-state correlation with radiologists per 100 000 population (r = 0.292-0.532), but moderate-to-strong inverse correlation with the percentage of radiologists in rural practice (r = -0.464 to -0.635). CONCLUSION: Although the number of radiology trainees dramatically increased, radiologists per 100 000 population increased only slightly, and radiologists' share of the overall physician workforce declined. State-to-state variations in radiologist and radiology resident workforces are high, which suggests a potential role for geographic redistribution rather than changes in the overall workforce size. PMID- 26509295 TI - Fat Attenuation at CT in Anorexia Nervosa. AB - PURPOSE: To investigate the composition, cross-sectional area (CSA), and hormonal correlates of different fat depots in women with anorexia nervosa (AN) and control subjects with normal weights to find out whether patients with AN have lower fat CSA but higher attenuation than did control subjects and whether these changes may be mediated by gonadal steroids, cortisol, and thyroid hormones. MATERIALS AND METHODS: This study was institutional review board approved and HIPAA compliant. Written informed consent was obtained. Forty premenopausal women with AN and 40 normal-weight women of comparable age (mean age +/- standard deviation, 26 years +/- 5) were studied. All individuals underwent computed tomography of the abdomen and thigh with a calibration phantom. Abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), thigh SAT, and thigh intermuscular adipose tissue CSA and attenuation were quantified. Serum estradiol, thyroid hormones, and urinary free cortisol levels were assessed. Variables were compared by using analysis of variance. Associations were examined by using linear regression analysis. RESULTS: Women with AN had higher fat attenuation than did control subjects (-100.1 to -46.7 HU vs -117.6 to -61.8 HU, P < .0001), despite lower fat CSA (2.0-62.8 cm(2) vs 5.5-185.9 cm(2), P < .0001). VAT attenuation but not CSA was inversely associated with lowest prior lifetime body mass index in AN (r = -0.71, P = .006). Serum estradiol levels were inversely associated with fat attenuation (r = -0.34 to -0.61, P = .03 to <.0001) and were positively associated with fat CSA of all compartments (r = 0.42-0.64, P = .007 to <.0001). Thyroxine levels and urinary free cortisol levels were positively associated with thigh SAT attenuation (r = 0.64 [P = .006] and r = 0.68 [P = .0004], respectively) and were inversely associated with abdominal SAT and VAT CSA (r = -0.44 to -0.58, P = .04 to .02). CONCLUSION: Women with AN have differences in fat composition, with higher fat attenuation than that of control subjects, as well as low fat mass. VAT attenuation but not CSA is inversely associated with lowest prior lifetime body mass index, suggesting that fat attenuation may serve as a biomarker of prior and current disease status in AN. PMID- 26509296 TI - [Research in pediatrics]. AB - In the interest of encouraging the promotion of research done by physicians of the Instituto Mexicano del Seguro Social, in this supplement we publish articles written by residents of different specialties related to critical themes on pediatrics. These residents are guided by affiliated physicians from the Hospital de Pediatria del Centro Medico Nacional Siglo XXI. PMID- 26509297 TI - [Insights about uncertainty in genetic counseling]. AB - Genetic counseling is an information process to help people in the understanding and adaptation to the medical, psychological and family implications of the genetic contribution in diseases. This counseling encompasses all sorts of patients. This represents a challenge in the daily work of the medical geneticist, because giving information in a meaningful way to the patient and his family implies an emotional and psychological burden. Generally we can see two outcomes in the medical practice of genetics, which converge after a diagnosis process: 1) we can face the inability to reach a diagnostic conclusion or 2) we can establish or confirm a diagnosis with certainty, which is the main piece in the genetic counseling. However, in all the situations the uncertainty is a fact, since in the case of those individuals who come in for genetic counseling before symptoms appear or those in prenatal cases, the absence of clinical manifestations and the impossibility to change the course of events lead to the appearance of helplessness and despair. In those cases without diagnostic conclusion, this situation represents a reason for uncertainty, and even in those patients with a diagnosis, certain factors can modify the circumstances in which genetic counseling occurs, such as unpredictability or lack of control. Therefore, it is important to consider the management of uncertainty as an inherent part throughout the process of care in medical genetics. The teaching of medical genetics should also consider the inclusion of topics related to this circumstance. PMID- 26509298 TI - [Molecular biology and childhood leukemia: E2A-PBX1 and central nervous system relapse]. AB - Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The inclusion of molecular biology techniques in the diagnosis and prognostic stratification of these patients has allowed major treatment achievements in developed countries. One of the best studied gene rearrangements is E2A-PBX1, which predicts isolated central nervous system relapse in patients with ALL. However, further research on the search for new molecular markers related to prognosis of patients with childhood leukemia is required. Such studies need the integration of different disciplines, including epidemiology. Epidemiological studies are needed not only to accelerate the discovery of new molecular markers and new biological signals as to the etiology and pathophysiology of cancer, but also to evaluate the clinical impact of these findings in well-defined populations. PMID- 26509299 TI - [Pineal region tumors in children: is gross-total resection necessary? A single center experience]. AB - BACKGROUND: Survival of children with pineal region tumors has increased significantly in the last decade; these tumors have an insidious outcome associated with endocrine disorders with high morbidity and mortality, especially after gross resection. The objective was to report the survival, outcome, morbidity and mortality according to type of surgery, histology and treatment in children with pineal region tumors. METHODS: This retrospective study included all patients of 17 years or less with diagnosis of pineal region tumor, who went over a period of 10 years to a children's hospital. A histopathological review was made, and the extent of resection was determined. The survival was also estimated. RESULTS: Forty-six patients were included, out of which 36 had complete medical records and adequate pathologic material. Gross resection was performed in 24 (66.6 %), and biopsy in 12 (33.3 %); 23 (88 %) patients died; hydroelectrolytic imbalance was the cause of 14 deaths (60 %) and the other nine (39.1 %) were secondary to tumor progression. Ten-years survivals among patients treated with gross resection and biopsy were 52 and 75 %, respectively (p = 0.7). Endocrine alterations were observed in 13 patients (36.1 %); in 10 of these (76.9 %) the total resection was performed. CONCLUSIONS: Pineal region tumors in children can be treated with diagnostic biopsy, followed by adjuvant treatment consisting of chemotherapy and radiotherapy. PMID- 26509300 TI - [Infectious complications in children with end-stage renal disease on replacement therapy]. AB - BACKGROUND: Annually, 5000 children younger than 20 years of age and 200 younger than two-years require treatment for chronic kidney disease (CKD). The objective was to estimate the incidence rate of infectious complications in children requiring renal replacement therapy. METHODS: Retrospective cohort. Patients with a minimum of three months of follow-up in programs of peritoneal dialysis and hemodyalisis were included. The incidence rate for infections associated to replacement therapy was calculated. RESULTS: 67 patients were analysed. In 88 %, initial therapy for CKD was peritoneal dialysis. A total of 52 episodes of peritonitis occured, with an incidence rate of 0.63 episodes/patient-year. Thirty children (48 %) never had an episode of peritonits during the folow-up. At six months, 90 % of the children had the same peritoneal dialysis catheter, decreasing to 84, 74 and 50 % at 12, 18 and 24 months, respectively. Forty-five children were on hemodialysis, 82 % preceded by peritoneal dialysis. Dialysis treatment time in 25 % of them was longer than 19 months. Twenty-two episodes of catheter-related bacteremia occurred, with an incidence rate of 1 episode/1000 catheter-days or 2.5/1000 hemodyalisis sesions. Twenty-nine patients received a transplant (43 %); two of them died. Median waiting time to transplant was 15 months. CONCLUSIONS: Incidence rate of infectious complications was similar to the rates reported in the literature by other centers. At 20 months, half of the patients had at least one infectious complication. PMID- 26509301 TI - [Ventilator associated pneumonia in a neonatal intensive care unit]. AB - BACKGROUND: The studies that describe risk factors for the development of ventilator-associated pneumonia (VAP) in newborn infants report dissimilar information, possibly related to the type of intensive care unit and population included. The objective of this study was to identify risk factors for the development of VAP in a neonatal intensive-care unit. METHODS: Case-control study. Patients with the diagnosis of VAP were classified as cases and compared with two controls of the same gestational age, weight, and diagnosis at admission. We analysed the data using descriptive and inferential statistics: chi squared test, Student's t-test, odds-ratio, 95 % confidence interval and logistic regression analysis. RESULTS: A total of 45 cases and 90 controls were analysed. The risk factors statistically significant in the univariate analysis were: previous episode of sepsis, reintubation, airway malformation, exclusive parenteral nutrition, and days of mechanical ventilation. In the logistic regression analysis we obtained these data: reintubation (OR 41.26, CI 95 % 11.9 158.4, p = 0.001), airway malformation (OR 19.5, CI 95 % 1.34-282.3, p = 0.029), and days of mechanical ventilation (OR 8.9, CI 95 % 1.9-40.8, p = 0.005). These were the only risk factors independently associated to VAP. CONCLUSION: Of the significant risk factors, it is possible to intervene in reintubation events, by securing the endotracheal cannula with an adequate fixation, mobilize the patient ensuring safety, and follow a decannulation protocol to reduce ventilation days. PMID- 26509302 TI - [Parenteral nutrition in pediatric patients: indications and complications in third level]. AB - BACKGROUND: Parenteral nutrition (PN) is a mixture that covers the nutritional needs when enteral nutrition is not an option; however, PN is not free of complications. The aim of our study was to determine the indication and frequency of NP complications in pediatric patients treated at a tertiary center. METHODS: Children receiving PN at the Hospital de Pediatria del Centro Medico Nacional Siglo XXI were included. Demographic and anthropometric characteristics were recorded, as well as the reason of indicating PN, the time of administration, and the complications associated to this type of nutrition. RESULTS: Sixty-nine pediatric patients with PN were included: 33 neonates, 18 infants (between one and 11 months of age), nine preschoolers (from 1 to 5 years of age), and nine children over five years of age. Instructions for initiating the PN were given for the treatment of 71 % of the patients with diseases of the digestive tract who were treated surgically. Complications of PN occurred in 87 % of the children and 76.7 % had more than one complication. Metabolic complications occurred in 98 % of the children while mechanical and infectious complications only in 1 %, respectively. CONCLUSIONS: Parenteral nutrition was indicated more frequently in pediatric patients with digestive diseases treated surgically. Metabolic complications were the main concern in pediatric patients with PN. PMID- 26509303 TI - [Prognostic factors related to mortality of children with atresia of bile ducts]. AB - BACKGROUND: The biliary atresia (BA) is the end result of a destructive and idiopathic inflammatory process affecting the intrahepatic and extrahepatic bile ducts, leading to fibrosis and biliary cirrhosis. The objective was to identify factors associated with mortality in children with BA. METHODS: Observational, longitudinal, analytical and retrospective study carried out in patients with biliary atresia treated between 2008 and 2012 in a tertiary care hospital from the Instituto Mexicano del Seguro Social. RESULTS: A total of 66 patients with BA; 49 were girls (74.2 %), 47 underwent hepatic portoenterostomy (or Kasai procedure: KP), the age at delivery was 4.5 months. When comparing the groups with and without KP, the lower age at the time of delivery, the age of diagnosis, a lower score on the PELD score and the Child-Pugh for the group with Kasai were statistically significant. Patients who died had a PELD score statistically higher (median 20) than those who lived (median 13), p = 0.004. The factor directly related with the mortality was the history of KP with an OR of 0.17 (95 % CI 0.04-0.71, p = 0.016). CONCLUSIONS: The prognosis of children with BA remains gloomy because they are diagnosed in late stages. The most important factor associated with mortality in these patients is to perform KP. PMID- 26509304 TI - [Cardiovascular risk factors in children with primary nephrotic syndrome]. AB - BACKGROUND: It has been suggested that patients with nephrotic syndrome (NS) have an increased frequency of cardiovascular risk factors. The aim of this study was to determine the frequency of cardiovascular risk factors in children with primary NS. METHODS: Cross-sectional, descriptive and prospective study. Fifty five patients with primary NS were included. The presence of overweight/obesity, hypertension, dyslipidemias, hyperglycemia, elevated C-reactive protein and carotid intima-media thickness (IMT) was evaluated. The treatment time, the type of treatment and the number of relapses were analyzed. For statistical analysis chi-square and Spearman's rho were used. RESULTS: The most frequent cardiovascular risk factor was increased carotid IMT (98.1 %), followed by hypertriglyceridemia (54.4 %) and total cholesterol (40 %). Patients with corticosensitive NS had fewer risk factors compared with patients with steroid resistant NS. There was also a positive correlation of longer time of evolution and number of relapses with the increase in the number of factors. CONCLUSIONS: Ninety-eight percent of children with primary NS had at least one cardiovascular risk factor. Certain clinical features, such as steroid-resistant NS, and the time of evolution and treatment, seem to be related to the presence of larger number of risk factors. PMID- 26509305 TI - [Glycosylated hemoglobin A1c as a diagnostic test for diabetes mellitus in adolescents with overweight and obesity]. AB - BACKGROUND: In 2009 it was introduced a new diagnostic criteria based on hemoglobin A1c (HbA1c) greater than or equal to 6.5 % in the adult population; some studies suggest that the cutoff may be smaller in pediatric population. The objective was to determine the utility of HbA1c greater than or equal to 6.5 % as a diagnostic test for DM in Mexican adolescents with overweight or obesity. METHODS: Full somatometry was performed. Also, Tanner stage, blood pressure, blood glucose, glucose tolerance curve (GTC) and HbA1c were analyzed. Specificity, sensitivity, positive and negative predictive values and ROC curve were calculated for the diagnosis of DM with HbA1c. RESULTS: 109 adolescents between 10 and 16 years referred for obesity or overweight plus comorbidities were studied; 58 % were females, the age was of 13 +/- 1.74 years, the BMI percentile 95.3, and the HbA1c 5.73 +/- 0.9 %. It was made a diagnosis of DM in 9 cases (8.3 %), prediabetes in 8 (7.3 %) and normal glucose tolerance in 92 (84.4 %). The HbA1c mean was 5.6 +/- 0.04, 5.7 +/- 0.4, and 5.6 +/- 0.73 %, respectively. HbA1c greater than or equal to 6.5 % had a sensitivity of 12.5 %, a specificity of 89.8 %, a PPV of 10.65 and a NPV of 14.28. The best cutoff point for diagnosing DM through ROC curve was 5.45 %, with a sensitivity of 62.5 %, a specificity of 57.1 %, PPV 2.53 and NPV 33.3. CONCLUSIONS: The level of HbA1c greater than or equal to 6.5 % had low sensitivity and specificity for the diagnosis of DM. A lower cutoff point is insufficient to use HbA1c as a diagnostic criterion. These results are consistent with the ones of other journals. PMID- 26509306 TI - [Survival and complication rate of central venous catheters in newborns]. AB - BACKGROUND: In the current medical practice, central venous catheters (CVC) are very useful; however, their use involves certain risks, which increase morbidity and mortality, especially in newborns. The aim of this study was to describe both the frequency of complications and survival of CVC placed in newborns hospitalized in a third level neonatal intensive care unit (NICU). METHODS: A descriptive, observational and prospective study was carried-out in the NICU from the Hospital de Pediatria, Centro Medico Nacional Siglo XXI. Demographic, perinatal and CVC variables were recorded. RESULTS: We included 152 CVCs, which were inserted in 123 newborns. For the CVC insertion, the puncture technique [percutaneous and subclavian] was used in 56.6 % (n = 86). There was at least one complication in 48.7 %.(n = 74). The most frequent complications were colonization 32.4 % (n = 24) and CVC-related bacteremia in 27 % (n = 20). Survival probability for CVC was 93.4 % at 10 days and 91.4 % at 17 days. Kaplan Meier survival analysis demonstrated significantly lower survival probability for non-central catheters. CONCLUSIONS: Most of CVC complications occurred within the first two weeks after these CVC were installed. Infectious complications were the most frequent. PMID- 26509307 TI - [Incidence of adverse events associated to the use of short peripheral venous catheters]. AB - BACKGROUND: Surveillance of adverse events associated to the use of short peripheral venous catheters (SPVC) is an indicator of quality of service. The objective was to report the incidence and risk factors associated to adverse events in SPVC. METHODS: Prospective cohort study. All patients with a SPVC for more than 48 hours were included. The outcome variables were dysfunction, chemical phlebitis and bacterial phlebitis. The data registered were age, sex, underlying diseases, nutritional status, site of placement, skin condition, administered intravenous fluids, and catheter dressing. Regarding statistical analysis, incidence rate for each adverse event was calculated per 100 catheters and per 1000 catheter-days. Univariate and multivariate analysis of risk factors were performed. RESULTS: 410 catheters were analyzed. Median of SPVC use was of three days. There was no evidence of infectious complications: 47 (11.4 %) presented chemical phlebitis and 231 (56.3 %) mechanical malfunction; the incidence rate was 35.6 and 175 per 1000 catheter-days, respectively. In the multivariate analysis, the risk factors associated to chemical phlebitis were skin lesions (p = 0.001, RR 3.479), and additional dressing use (p = 0.007, RR 4.025); for mechanical malfunction the only risk factor was the administration of intravenous chemotherapy (p = 0.026, RR 4.293). CONCLUSIONS: The malfunction incidence rate was high; in consequence, the catheter was removed before 96 hours of use. This could explain the absence of infectious complications. PMID- 26509308 TI - [Risk factors related to nosocomial pneumonia in pediatric patients undergoing heart surgery]. AB - BACKGROUND: Procalcitonin is a diagnostic marker useful to discern infections and non-infectious complications in heart surgeries. The aim is to describe risk factors related to nosocomial pneumonia and the predictive value of serum procalcitonin in pediatric patients undergoing heart surgery. METHODS: During a year a nested case-control study was carried out in a third level hospital. All patients undergoing open-heart surgery were followed and clinical data searching for pneumonia were registered every day. Blood samples for determination of procalcitonin were taken 48 hours after surgery. Those patients who developed pneumonia based on CDC clinical criteria were defined as cases; and controls were those patients who did not developed pneumonia. RESULTS: 188 patients underwent heart surgery (15 % developed pneumonia). Ninety-seven patients were submitted to open-heart surgery: 24 cases and 73 controls. Seventy-eight % of cases developed pneumonia between second and fifth day after surgery. The average time of surgery, extracorporial bypass, aortic cross-clamp, and mechanical ventilation were greater in control patients. The frequency of open sternotomy, reintubation, and surgical wound infections was greater in case patients. CONCLUSIONS: Some of the events related to heart surgery and their subsequent management are associated significantly to the development of hospital-acquired pneumonia. PMID- 26509309 TI - [Prognostic factors associated with postoperative morbidity in children with isolated ventricular septal defect]. AB - BACKGROUND: Isolated ventricular septal defect (VSD) is one of the most common congenital heart diseases worldwide. Prognostic factors associated with postoperative morbidity in patients with isolated VSD in the Hospital de Pediatria del Centro Medico Nacional Siglo XXI have not been identified. METHODS: A retrospective cohort study was conducted from January 1, 2009 to December 31, 2013. Descriptive statistics and comparisons between groups were performed using chi-square test, Mann Whitney U test and linear regression. Relative risks (RR) and 95 % confidence intervals (95% CI) were calculated. RESULTS: A total of 64 patients who underwent isolated VSD closure were included, 12.5 % (n = 8) had a history of pulmonary banding and 22 patients (34.3 %) had Down syndrome. The perimembranous and subaortic lesions occurred in 70 % of cases. Factors associated with an increased morbidity and a prolonged intensive care unit (ICU) stay were: lactate at the end of extracorporeal circulation (ECC) greater than 3 mmol/L (p = 0.02) and Down syndrome (p = 0.02), who had the highest incidence of postoperative complications (p = 0.02). CONCLUSIONS: A statistically significant association was found: the higher the preoperative functional class, the longer the hospital stay, the number of days at ICU and the hours of mechanical ventilation. PMID- 26509310 TI - Growth Assessment and the Risk of Growth Retardation in Congenital Diaphragmatic Hernia: A Long-Term Follow-Up Study from the Japanese Congenital Diaphragmatic Hernia Study Group. AB - INTRODUCTION: Little information exists about the physical growth of patients with congenital diaphragmatic hernia (CDH). This study aimed to assess the growth of patients with CDH during long follow-up periods, and to identify growth retardation (GR) risk factors. PATIENTS AND METHODS: A multicenter retrospective observational study was conducted in 2013. Of the 228 patients with CDH born between 2006 and 2010, 182 (79.8%) survived to discharge, and 174 cases were included in the study. Body weights and heights were measured at 1.5, 3, and 6 years of age. GR was defined as a Z-score relating to the weight or height of < - 2.0. Cases with GR at 1.5, 3, or 6 years of age comprised the GR group. The clinical variables of the GR and non-GR groups were compared using univariate analysis. Multiple logistic regression analyses were conducted successively on the factors that were significant at p < 0.01 in the univariate analysis and had low correlations with other factors (r < 0.7). The numerical data were divided into two groups based on a cutoff value that was calculated from a receiver operating characteristic curve. RESULTS: The GR group comprised 35 cases (22.7%). The rates of GR at 1.5, 3, and 6 years of age were 19.5 (26/133), 14.4 (16/111), and 13.5% (5/37), respectively. The body weight Z-scores improved in cases with GR between the ages of 1.5 and 3 years (p = 0.036). As the patients aged, the wasting type of GR decreased in frequency (31, 0, and 0% at 1.5, 3, and 6 years of age, respectively) and the stunting type of GR increased in frequency (27, 31, and 100% at 1.5, 3, and 6 years of age, respectively). The univariate analysis showed that birth weight and height, liver-up, large defect size of the diaphragm, use of nitric oxide, patch repair, long hospital stay, home oxygen treatment (HOT), and vasodilator administration at discharge were significant risk factors of GR. The multivariate analysis determined that a birth weight of < 2,698 g (odds ratio [OR] = 5.5, 95% confidence interval [CI] = 2.1-16.8, p < 0.001) and HOT (OR = 5.8, 95%CI = 1.6-23.8, p = 0.007) were significant risk factors for GR. CONCLUSION: GR was observed in 22.7% of the CDH survivors. Body weight improved between 1.5 and 3 years of age in the GR cases, but some patients developed chronic malnutrition via acute malnutrition. Low birth weight and the need for HOT were GR risk factors. Aggressive management of acute malnutrition may improve the growth of patients with CDH. PMID- 26509311 TI - Early Detection of Neonatal Cholestasis: Inadequate Assessment of Stool Color by Parents and Primary Healthcare Doctors. AB - INTRODUCTION: Early diagnosis and surgery (< 60 days of age) improve outcomes in children with biliary atresia. Only 56% of patients undergo timely surgery in the Netherlands. Lack of acquaintance with symptoms such as discolored stools might underlie this delay. We analyzed whether Dutch parents, youth healthcare doctors, or general practitioners recognized discolored stools and evaluated the effect of the Infant Stool Color Card (ISCC) on recognizing discolored stools. MATERIAL AND METHODS: We asked 100 parents, 33 youth healthcare doctors, and 50 general practitioners to classify photographs of stools as "normal" or "abnormal." Subsequently, we asked whether parents would seek medical help and doctors would refer the patient for medical investigation. Finally, parents scored stools using the ISCC. RESULTS: Two-third of both parents and youth healthcare doctors recognized all discolored stools. Only half of them would seek medical help for all discolored stools resp. refer patient for medical investigation. Only one third of the general practitioners recognized all discolored stools and would refer for medical investigation for all discolored stools. Using the ISCC, the percentage of parents recognizing all discolored stool increased from 66 to 87% (p < 0.01). CONCLUSION: Neither parents nor youth healthcare doctors nor general practitioners reliably recognize discolored stool. The ISCC is an effective screening method for discolored stool. Our data indicate that the ISCC should be accompanied by unequivocal advices regarding referral for medical investigation upon detection of discolored stools. PMID- 26509312 TI - Factors Predicting Testicular Atrophy after Testicular Salvage following Torsion. AB - INTRODUCTION: Testicular atrophy (TA) is a significant complication in patients who undergo salvage procedures for testicular torsion. Studies on outcome focus on factors predicting testicular viability during scrotal exploration but few assess factors predicting TA in patients who undergo salvage procedures. We assess the incidence of TA after salvage and identify associated factors. MATERIALS AND METHODS: With ethical approval, we reviewed patients who underwent salvage for testicular torsion in our institution from 2001 to 2013. Data was collected on patient demographics, duration of pain, sonographic findings, postoperative complications, and follow-up assessment of TA (defined as difference in testicular volume > 50% compared with the contralateral testis, based on measurement by Prader orchidometer or by ultrasound). We excluded patients with torted undescended testis, those under 1 month, and those with follow-up < 6 months. Chi-square or Mann-Whitney U tests were used as appropriate with significance level < 0.05. RESULTS: Of 85 patients who had scrotal exploration for testicular torsion, 53 had testicular salvage. Overall, 16 patients defaulted or had < 6 months follow-up, leaving 37 patients who were studied, median age 12 years (range, 0.5-16.0 years) at presentation. Median follow-up was 12.5 months (range, 6-88 months). A total of 20 patients (54%) developed TA. Median duration to TA was 12.5 months (range, 2-88 months). All had clinical evidence of atrophy by 14 months, except two who initially defaulted follow-up, but were diagnosed with TA at 35 and 88 months postoperatively when presenting with unrelated complaints. Factors associated with TA were duration of pain > 1 day (p = 0.004) and heterogeneous echogenicity on ultrasound (p = 0.001). Sonographic evidence of reduced vascularity was not predictive. Of 11 that had pain > 1 day, 10 (91%) had TA. No testes survived when pain >= 3 days. CONCLUSION: Half of patients with testicular torsion undergoing salvage surgery will develop testicular atrophy, even when intraoperatively assessed as viable, and should be counseled accordingly. Duration of pain > 1 day and sonographic heterogeneous echogenicity are predictive. Salvage rates are dismal when duration of symptoms exceeds 1 day. PMID- 26509313 TI - Prolidase Enzyme Activity in Conjunctiva and Pterygium Tissues. AB - BACKGROUND: The aim of this study was to determine prolidase activity in conjunctival tissue and its relationship with pterygium. MATERIAL AND METHODS: Prolidase activity was measured in 23 pterygium and 25 healthy conjunctival tissues and the 2 groups were compared. RESULTS: Prolidase enzyme activity could not be measured in either the healthy conjunctival or in pterygium tissues. The mean serum prolidase levels of the control and pterygium groups were 967.46+/ 353.64 and 858.29+/-301.83, respectively. Statistically, there was no significant difference between the groups with regard to serum prolidase levels (p>0.05). CONCLUSIONS: In conclusion, absence of prolidase activity in pterygium tissue indicates that there is no collagen turnover in this tissue. We may explain this finding with the elastin-rich structure of the conjunctiva. PMID- 26509314 TI - Solvent effects on electrosynthesis, morphological and electrochromic properties of a nitrogen analog of PEDOT. AB - A new nitrogen analog of 3,4-ethylenedioxythiophene (EDOT), N-methyl-3,4 dihydrothieno[3,4-b][1,4]oxazine (MDTO), was electropolymerized in different solvents (deionized water, acetonitrile, and propylene carbonate) using LiClO4 as the electrolyte. The structure and performance of as-prepared PMDTO polymers were systematically studied by cyclic voltammetry, UV-vis spectroscopy, FT-IR, SEM, thermogravimetry, spectroelectrochemistry and electrochromic techniques. To our surprise, solvents had a major influence on the electropolymerization of MDTO and properties of the resultant polymers, including morphology, electrochemistry, electronic and optical properties, and electrochromics, etc. In aqueous solution, MDTO revealed the lowest onset oxidation potential (0.19 V) than in acetonitrile (0.48 V) and propylene carbonate (0.49 V). However, PMDTO films showed rather poor cycling stability in water, while outstanding stability in acetonitrile and propylene carbonate. Films prepared in propylene carbonate displayed a rather smooth morphology, lower band gap (1.65 eV), higher transparency (97.3%) and a contrast ratio (44.6%) at lambda = 466 nm. PMDTO films obtained in acetonitrile showed significantly higher coloration efficiency (169.5 cm(2) C(-1)) than in other two solvents (~ 97.6 cm(2) C(-1)) with a moderate contrast ratio (24.5%). PMID- 26509315 TI - Analysis of Serial Radiographs of the Foot to Determine Normative Values for the Growth of the First Metatarsal to Guide Hemiepiphysiodesis for Immature Hallux Valgus. AB - BACKGROUND: Hallux valgus deformity in the immature patient can be difficult to manage, as osteotomy can result in recurrence with additional growth. Lateral hemiepiphysiodesis of the first metatarsal offers a promising alternative, by permitting gradual correction of the intermetatarsal angle with growth. An important limitation of this approach is the lack of normative tables of first metatarsal growth to guide timing of intervention. METHODS: First metatarsal lengths were measured from anteroposterior foot radiographs of children. For females, 95 patients totaling 894 radiographs were used ranging from 6 months to 18 years of age. For males, 122 patients totaling 1018 radiographs were measured ranging from 8 months to 19.5 years of age. All patients with image series including a closed proximal metatarsal physis were sorted into an older group, with multipliers generated by setting last image to a multiplier of 1. Patients with serial imaging not inclusive of a closed physis were classified as a younger group, with multipliers based off of the multiplier at age 7 from the older group. First metatarsal multiplier values were then compared with published multiplier values for the overall foot. RESULTS: For both females and males, the multipliers followed a logarithmic curve versus age, with R values of 0.921 and 0.888, respectively. Comparison of the first metatarsal multiplier values with previously studied multiplier values of the entire foot showed high correlation with ICC=0.955 for females and ICC=0.969 for males. CONCLUSIONS: The pattern of growth of the first metatarsal follows a logarithmic regression curve. These normative tables allow for clinical prediction of first metatarsal remaining growth based on age and sex, and in turn guide timing of hemiepiphysiodesis for the surgical correction of hallux valgus deformity. CLINICAL RELEVANCE: The normative tables generated in this study can be used for the calculation of hemiepiphysiodesis and the timing of intervention. Future clinical correlation studies will be important. PMID- 26509316 TI - Effects of crystallographic facet-specific peptide adsorption along single ZnO nanorods on the characteristic fluorescence intensification on nanorod ends (FINE) phenomenon. AB - The precise effect of crystallographically discriminating biomolecular adsorption on the fluorescence intensification profiles of individual zinc oxide nanorod (ZnO NR) platforms was elucidated in this study by employing peptide binding epitopes biased towards particular ZnO crystal surfaces and isolating the peptides on given crystalline facets of ZnO NRs. Subsequently, the fluorescence emission profiles of the preferentially bound peptide cases on the basal versus prismic planes of ZnO NRs were carefully evaluated both experimentally and via computer simulations. The phenomenon of fluorescence intensification on NR ends (FINE) was persistently observed on the individual ZnO NR platforms, regardless of the location of the bound peptides. In contrast to the consistent occurrence of FINE, the degree and magnitude of FINE were largely influenced by the discriminatory peptide adsorption to different ZnO NR facets. The temporal stability of the fluorescence signal was also greatly affected by the selectively located peptides on the ZnO NR crystal when spatially resolved on different NR facets. Similarities and differences in the spatial and temporal fluorescence signal of the crystalline NR facet-specific versus -nonspecific biomolecular adsorption events were then compared. To further illuminate the basis of our experimental findings, we also performed finite-difference-time-domain (FDTD) calculations and examined the different degrees of FINE by modelling the biased peptide adsorption cases. Our multifaceted efforts, providing combined insight into the spatial and temporal characteristics of the biomolecular fluorescence signal characteristically governed by the biomolecular location on the specific NR facets, will be valuable for novel applications and accurate signal interpretation of ZnO NR-based biosensors in many rapidly growing, highly miniaturized biodetection configurations. PMID- 26509317 TI - Shared Decision Making in ICUs: An American College of Critical Care Medicine and American Thoracic Society Policy Statement. AB - OBJECTIVES: Shared decision making is endorsed by critical care organizations; however, there remains confusion about what shared decision making is, when it should be used, and approaches to promote partnerships in treatment decisions. The purpose of this statement is to define shared decision making, recommend when shared decision making should be used, identify the range of ethically acceptable decision-making models, and present important communication skills. DESIGN: The American College of Critical Care Medicine and American Thoracic Society Ethics Committees reviewed empirical research and normative analyses published in peer reviewed journals to generate recommendations. Recommendations approved by consensus of the full Ethics Committees of American College of Critical Care Medicine and American Thoracic Society were included in the statement. MAIN RESULTS: Six recommendations were endorsed: 1) DEFINITION: Shared decision making is a collaborative process that allows patients, or their surrogates, and clinicians to make healthcare decisions together, taking into account the best scientific evidence available, as well as the patient's values, goals, and preferences. 2) Clinicians should engage in a shared decision making process to define overall goals of care (including decisions regarding limiting or withdrawing life-prolonging interventions) and when making major treatment decisions that may be affected by personal values, goals, and preferences. 3) Clinicians should use as their "default" approach a shared decision making process that includes three main elements: information exchange, deliberation, and making a treatment decision. 4) A wide range of decision-making approaches are ethically supportable, including patient- or surrogate-directed and clinician directed models. Clinicians should tailor the decision-making process based on the preferences of the patient or surrogate. 5) Clinicians should be trained in communication skills. 6) Research is needed to evaluate decision-making strategies. CONCLUSIONS: Patient and surrogate preferences for decision-making roles regarding value-laden choices range from preferring to exercise significant authority to ceding such authority to providers. Clinicians should adapt the decision-making model to the needs and preferences of the patient or surrogate. PMID- 26509318 TI - Spinal Cord Infarct During Concomitant Circulatory Support With Intra-Aortic Balloon Pump and Veno-Arterial Extracorporeal Membrane Oxygenation. AB - OBJECTIVE: To report a series of three patients who received simultaneous circulatory support with both veno-arterial extracorporeal membrane oxygenation and intra-aortic balloon pump and subsequently developed spinal cord infarction, and present a brief review of the relevant literature. DATA SOURCES: Hospital medical records and MEDLINE and PubMed databases. STUDY SELECTION: Any patient who developed lower limb neurologic symptoms during a period of concurrent venoarterial extracorporeal membrane oxygenation and intra-aortic balloon pump support, with subsequent MRI changes involving the spinal cord, from 2006 (the year of institution of venoarterial extracorporeal membrane oxygenation in our ICU) to 2014. DATA EXTRACTION: Patient records were retrospectively reviewed. Medical databases were searched for any literature linking intra-aortic balloon pump and/or venoarterial extracorporeal membrane oxygenation with neurologic injury of the lower limbs. DATA SYNTHESIS: Three female patients presented in cardiogenic shock or arrest requiring circulatory support. Intra-aortic balloon pump was inserted, and peripheral veno-arterial extracorporeal membrane oxygenation was initiated with subsequent loss of native ejection in each case. Neurologic signs were noted clinically, and subsequent imaging demonstrated spinal cord infarction and small aortic size for all three patients. CONCLUSIONS: The timeline of events suggests a causal relation between intra-aortic balloon pump, veno-arterial extracorporeal membrane oxygenation, and significant neurologic deficits. This is likely due to hypoperfusion of the spinal cord, which is multifactorial in origin, including small aortic calibre, low cardiac output states, high vasopressor requirements causing vasospasm of the artery of Adamkiewicz, occlusion of retrograde oxygenated blood flow from peripheral veno arterial extracorporeal membrane oxygenation due to intra-aortic balloon pump being in situ, and possible thromboembolic phenomena. The thoracic spinal cord is intrinsically susceptible to ischemia due to the anatomy of the arterial supply, which is described here. We identify several risk factors and make several recommendations to avoid this rare but catastrophic complication in the future. We also suggest interventions should this challenging complication be identified. PMID- 26509320 TI - Incidence and Mortality of Acute Respiratory Distress Syndrome in Children: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Our understanding of the acute respiratory distress syndrome in children is limited, and literature is dominated by investigations in adult patients. Recent preclinical studies suggest that the susceptibility to and severity of acute respiratory distress syndrome in children could differ from that in adults. We assessed the incidence and mortality of acute respiratory distress syndrome reported in children in studies published in the last two decades. DATA SOURCES: Medline, Embase, and CINAHL databases were searched up to August 2014. STUDY SELECTION: Articles reporting study data on population- or PICU-based incidence and mortality of acute respiratory distress syndrome in children (> 36 wk gestation and < 18 yr old) were selected. DATA EXTRACTION: Two authors independently collected data and assessed methodological quality and risk of bias of selected studies. Pooled estimates of incidence and mortality were calculated using random-effects models. To explore heterogeneity, influence of study characteristics, including median year of conduct, study location, inclusion and exclusion criteria, and study design and quality, was assessed by meta-regression analysis. DATA SYNTHESIS: Twenty-nine studies reported on incidence and 32 on mortality. Pooled weighted estimate of the population-based and PICU-based incidence of pediatric acute respiratory distress syndrome was 3.5 (95% CI, 2.2-5.7) cases per 100,000 person years and 2.3% (95% CI, 1.9-2.9), respectively. Pooled weighted mortality was 33.7% (95% CI, 28.6-39.7). There were no trends over time, but mortality was significantly associated with study location. CONCLUSIONS: This systematic review and meta-analysis shows a low incidence but a high mortality. Its results also indicate that both incidence and mortality of pediatric acute respiratory distress syndrome have not changed over the last two decades and that mortality depends on the geographic location of studies. PMID- 26509319 TI - Kidney and Liver Injuries After Major Burns in Rats Are Prevented by Resolvin D2. AB - OBJECTIVES: Innate immune dysfunction after major burn injuries increases the susceptibility to organ failure. Lipid mediators of inflammation resolution, e.g., resolvin D2, have been shown recently to restore neutrophil functionality and reduce mortality rate in a rat model of major burn injury. However, the physiological mechanisms responsible for the benefic activity of resolvin D2 are not well understood. DESIGN: Prospective randomized animal investigation. SETTING: Academic research setting. SUBJECTS: Wistar male rats. INTERVENTIONS: Animals were subjected to a full-thickness burn of 30% total body surface area. Two hours after burn, 25 ng/kg resolvin D2 was administered IV and repeated every day, for 8 days. At day 10 post burn, 2 mg/kg of lipopolysaccharide was administered IV, and the presence of renal and hepatic injuries was evaluated at day 11 post burn by histology, immunohistochemistry, and relevant blood chemistry. MEASUREMENTS AND MAIN RESULTS: In untreated animals, we found significant tissue damage in the kidneys and liver, consistent with acute tubular necrosis and multifocal necrosis, and changes in blood chemistry, reflecting the deterioration of renal and hepatic functions. We detected less tissue damage and significantly lower values of blood urea nitrogen (26.4 +/- 2.1 vs 36.0 +/- 9.3 mg/dL; p <= 0.001), alanine aminotransferase (266.5 +/- 295.2 vs 861.8 +/- 813.7 U/L; p <= 0.01), and total bilirubin (0.13 +/- 0.05 vs 0.30 +/- 0.14 mg/dL; p <= 0.01) in resolvin D2-treated rats than in untreated animals. The mean blood pressure of all animals was above 65 mm Hg, indicating adequate tissue perfusion throughout the experiments. We measured significantly larger amounts of chromatin in the circulation of untreated than of resolvin D2-treated rats (575.1 +/- 331.0 vs 264.1 +/- 122.4 ng/mL; p <= 0.05) and identified neutrophil extracellular traps in kidney and liver tissues from untreated rats, consistent with the tissue damage. CONCLUSIONS: Pathologic changes in kidney and liver tissues in a rat model of major burn and endotoxin insults are ameliorated by resolvin D2. PMID- 26509321 TI - Trait Anxiety But Not State Anxiety During Critical Illness Was Associated With Anxiety and Depression Over 6 Months After ICU. AB - OBJECTIVE: To determine the association between anxiety during critical illness and symptoms of anxiety and depression over 6 months after ICU discharge in survivors of intensive care treatment. DESIGN: Longitudinal study. SETTING: One closed mixed ICU in an adult tertiary hospital in Brisbane, Australia. PATIENTS: Participants (n = 141) were adults (>= 8 yr), admitted to ICU for at least 24 hours, able to communicate either verbally or nonverbally, understand English, and open their eyes spontaneously or in response to voice. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The outcomes of symptoms of anxiety and depression over 6 months after ICU discharge were assessed using the Hospital Anxiety Depression Scale. The primary variable of interest was anxiety during critical illness. Two components of anxiety (state and trait) were assessed during critical illness using the Faces Anxiety Scale and the trait component of the State-Trait Anxiety Inventory. Perceived social support, cognitive functioning, and posttraumatic stress symptoms were also assessed using standardized instruments. Clinical and demographic data were obtained from patients and medical records. Participants were followed up in hospital wards and at 3 and 6 months after ICU discharge. During ICU treatment, 81 of the 141 participants (57%) reported moderate to severe levels of state anxiety. Of the 92 participants who completed the surveys at the 6-month follow-up, 26 participants (28%) reported symptoms of anxiety and 21 (23%) symptoms of depression. Symptoms of anxiety and depression were strongly correlated in this cohort of survivors. Trait anxiety was significantly associated with both anxiety and depression symptoms over time; however, state anxiety was not associated with either outcome. Participants who reported post-ICU memories of intra-ICU anxiety were significantly more anxious during recovery over 6 months. Cognitive functioning and posttraumatic stress symptoms were both significantly associated with anxiety and depression symptoms over time. CONCLUSION: Symptoms of anxiety and depression are a significant issue for general ICU survivors. Trait anxiety was significantly associated with adverse emotional outcomes over 6 months after ICU discharge. There was also a significant relationship between post-ICU memories of intra-ICU anxiety and anxiety during recovery. Interventions to reduce anxiety during critical illness need to be considered and evaluated for their longer term benefits for survivors of critical illness. PMID- 26509322 TI - Endotoxemia Following Multiple Trauma: Risk Factors and Prognostic Implications. AB - OBJECTIVE: To evaluate the prevalence and time course of systemic endotoxemia following severe multiple trauma, to define its risk factors, and to explore the correlation between post-trauma endotoxemia and organ dysfunction. DESIGN: Prospective single-center cohort study. SETTING: Emergency department and ICU of adult tertiary care level I trauma center. PATIENTS: Forty-eight severely injured (Injury Severity Score >= 16) patients, admitted to ICU within 24 hours of injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Endotoxemia was not evident on initial presentation, but developed subsequently in 75% of patients, even in the absence of Gram-negative infection. Nonsurviving patients had higher endotoxin levels than survivors on day 1 (endotoxemia, 0.48 vs 0.28; p = 0.048). Shock at admission, or surgery within the first 48 hours after trauma, was associated with higher endotoxin levels and predicted subsequent maximal endotoxemia, after adjusting for other significant covariates. Maximal endotoxemia levels were higher in patients who developed organ dysfunction, reflected in a cumulative Multiple Organ Dysfunction Score greater than 25, and patients with an intermediate endotoxemia level (>= 0.4) had more cardiovascular dysfunction. CONCLUSIONS: It is the first study to detect increasing levels of endotoxemia following multiple trauma. Shock and early surgery predict the development of endotoxemia; endotoxemia is particularly associated with cardiovascular dysfunction. However, Gram-negative infections are uncommon in these patients, suggesting that the gastrointestinal tract is the dominant reservoir of endotoxin. Endotoxin may be an appropriate therapeutic target in patients who have sustained severe multiple trauma. PMID- 26509323 TI - Towards a general diastereoselective route to oxabicyclo[3.2.1]octanes via a gold catalysed cascade reaction. AB - The development of an efficient diastereoselective synthesis of the oxabicyclo[3.2.1]octane ring system bearing two oxygenated quaternary chiral centres represents a significant challenge. This motif can be found in a wide range of natural products with significant biological activities. Here we report the synthesis of such kind of scaffold using a cyclohexane-trans-1,4-diol with an alkyne side chain in the presence of Au(I) catalyst. This is a domino process in which two C-H, two C-O and one C-C bond is assembled through a sequence of cyclization/semi-pinacol rearrangements. This strategy has been successfully applied to the asymmetric formal total synthesis of (+)-cortistatins. PMID- 26509324 TI - Current issues in postoperative pain management. AB - Postoperative pain has been poorly managed for decades. Recent surveys from USA and Europe do not show any major improvement. Persistent postoperative pain is common after most surgical procedures, and after thoracotomy and mastectomy, about 50% of patients may experience it. Opioids remain the mainstay of postoperative pain treatment in spite of strong evidence of their drawbacks. Multimodal analgesic techniques are widely used but new evidence is disappointing. Regional anaesthetic techniques are the most effective methods to treat postoperative pain. Current evidence suggests that epidural analgesia can no longer be considered the 'gold standard'. Perineural techniques are good alternatives for major orthopaedic surgery but remain underused. Infiltrative techniques with or without catheters are useful for almost all types of surgery. Simple surgeon-delivered local anaesthetic techniques such as wound infiltration, preperitoneal/intraperitoneal administration, transversus abdominis plane block and local infiltration analgesia can play a significant role in improvement of postoperative care, and the last of these has changed orthopaedic practice in many institutions. Current postoperative pain management guidelines are generally 'one size fits all'. It is well known that pain characteristics such as type, location, intensity and duration vary considerably after different surgical procedures. Procedure-specific postoperative pain management recommendations are evidence based, and also take into consideration the role of anaesthetic and surgical techniques, clinical routines and risk-benefit aspects. The role of acute pain services to improve pain management and outcome is well accepted but implementation seems challenging. The need for upgrading the role of surgical ward nurses and collaboration with surgeons to implement enhanced recovery after surgery protocols with regular audits to improve postoperative outcome cannot be overstated. PMID- 26509325 TI - Fully automatized renal parenchyma volumetry using a support vector machine based recognition system for subject-specific probability map generation in native MR volume data. AB - In epidemiological studies as well as in clinical practice the amount of produced medical image data strongly increased in the last decade. In this context organ segmentation in MR volume data gained increasing attention for medical applications. Especially in large-scale population-based studies organ volumetry is highly relevant requiring exact organ segmentation. Since manual segmentation is time-consuming and prone to reader variability, large-scale studies need automatized methods to perform organ segmentation. Fully automatic organ segmentation in native MR image data has proven to be a very challenging task. Imaging artifacts as well as inter- and intrasubject MR-intensity differences complicate the application of supervised learning strategies. Thus, we propose a modularized framework of a two-stepped probabilistic approach that generates subject-specific probability maps for renal parenchyma tissue, which are refined subsequently by using several, extended segmentation strategies. We present a three class-based support vector machine recognition system that incorporates Fourier descriptors as shape features to recognize and segment characteristic parenchyma parts. Probabilistic methods use the segmented characteristic parenchyma parts to generate high quality subject-specific parenchyma probability maps. Several refinement strategies including a final shape-based 3D level set segmentation technique are used in subsequent processing modules to segment renal parenchyma. Furthermore, our framework recognizes and excludes renal cysts from parenchymal volume, which is important to analyze renal functions. Volume errors and Dice coefficients show that our presented framework outperforms existing approaches. PMID- 26509326 TI - A Painless Mass in the Pancreas: Incidental Finding. PMID- 26509327 TI - Increasing African American Representation in Dermatology. PMID- 26509328 TI - An Urgent Call to Address the Deadly Consequences of Serious Mental Disorders. PMID- 26509329 TI - Ligand-centred fluorescence and electronic relaxation cascade at vibrational time scales in transition-metal complexes. AB - Using femtosecond-resolved photoluminescence up-conversion, we report the observation of the fluorescence of the high-lying ligand-centered (LC) electronic state upon 266 nm excitation of an iridium complex, Ir(ppy)3, with a lifetime of 70 +/- 10 fs. It is accompanied by a simultaneous emission of all lower-lying electronic states, except the lowest triplet metal-to-ligand charge-transfer ((3)MLCT) state that shows a rise on the same time scale. Thus, we observe the departure, the intermediate steps, and the arrival of the relaxation cascade spanning ~1.6 eV from the (1)LC state to the lowest (3)MLCT state, which then yields the long-lived luminescence of the molecule. This represents the first measurement of the total relaxation time over an entire cascade of electronic states in a polyatomic molecule. We find that the relaxation cascade proceeds in <=10 fs, which is faster than some of the highest-frequency modes of the system. We invoke the participation of the latter modes in conical intersections and their overdamping to low-frequency intramolecular modes. On the basis of literature, we also conclude that this behavior is not specific to transition metal complexes but also applies to organic molecules. PMID- 26509330 TI - Environmental Justice Aspects of Exposure to PM2.5 Emissions from Electric Vehicle Use in China. AB - Plug-in electric vehicles (EVs) in China aim to improve sustainability and reduce environmental health impacts of transport emissions. Urban use of EVs rather than conventional vehicles shifts transportation's air pollutant emissions from urban areas (tailpipes) to predominantly rural areas (power plants), changing the geographic distribution of health impacts. We model PM2.5-related health impacts attributable to urban EV use for 34 major cities. Our investigation focuses on environmental justice (EJ) by comparing pollutant inhalation versus income among impacted counties. We find that EVs could increase EJ challenge in China: most (~77%, range: 41-96%) emission inhalation attributable to urban EVs use is distributed to predominately rural communities whose incomes are on average lower than the cities where EVs are used. Results vary dramatically across cities depending on urban income and geography. Discriminant analysis reveals that counties with low income and high inhalation of urban EV emissions have comparatively higher agricultural employment rates, higher mortality rates, more children in the population, and lower education levels. We find that low-emission electricity sources such as renewable energy can help mitigate EJ issues raised here. Findings here are not unique to EVs, but instead are relevant for nearly all electricity-consuming technologies in urban areas. PMID- 26509331 TI - A Systematic Study of Plasma Activation of Silicon Surfaces for Self Assembly. AB - We study the plasma activation systematically in an attempt to simplify and optimize the formation of hydrophilic silicon (Si) surface critical for self assembly of nanostructures that typically uses piranha solution, a high molarity cocktail of sulfuric acid and hydrogen peroxide at elevated temperatures. In the proposed safer and simpler approach, O2 plasma is used under optimized process conditions in a capacitively coupled parallel-plate chamber to induce strong hydrophilic behavior on silicon surfaces associated with the formation of suboxide groups. Surface activation is validated and studied via contact angle measurements as well as XPS spectra and consequently optimized using a novel atomic force spectroscopy approach, which can streamline characterization. It is found that plasma power around 100 W and exposure duration of ~65 s are the most effective parameters to enhance surface activation for the reactive ion etcher system used. Other optimum plasma process conditions for pressure and flow-rate are also reported along with temporal development of activation, which peaks within 1 h and wears off in 24 h scale in air. The applicability of the plasma approach to nanoassembly process was demonstrated using simple drop coating and spinning of polystyrene (d < 500 nm, 2.5-4.5% w/v) and inkjet printing on polydimethylsiloxane. PMID- 26509332 TI - Nanofluidics of Single-Crystal Diamond Nanomechanical Resonators. AB - Single-crystal diamond nanomechanical resonators are being developed for countless applications. A number of these applications require that the resonator be operated in a fluid, that is, a gas or a liquid. Here, we investigate the fluid dynamics of single-crystal diamond nanomechanical resonators in the form of nanocantilevers. First, we measure the pressure-dependent dissipation of diamond nanocantilevers with different linear dimensions and frequencies in three gases, He, N2, and Ar. We observe that a subtle interplay between the length scale and the frequency governs the scaling of the fluidic dissipation. Second, we obtain a comparison of the surface accommodation of different gases on the diamond surface by analyzing the dissipation in the molecular flow regime. Finally, we measure the thermal fluctuations of the nanocantilevers in water and compare the observed dissipation and frequency shifts with theoretical predictions. These findings set the stage for developing diamond nanomechanical resonators operable in fluids. PMID- 26509333 TI - Impact of red blood cell alloimmunization on sickle cell disease mortality: a case series. AB - BACKGROUND: Although red blood cell (RBC) transfusion represents an integral component of sickle cell disease (SCD) care, transfusion support for some patients can result in alloimmunization to RBC antigens. Alloimmunized patients with SCD appear to experience worse survival compared to nonalloimmunized patients. While this difference in mortality may in part be due to underlying immunologic differences related to disease severity, it may also reflect direct clinical consequences of RBC alloimmunization. Alloimmunized patients have an increased risk of serious hemolytic transfusion reactions (HTRs) and may not receive adequate RBC transfusion support due to lack of compatible RBC units. CASE REPORT: This study reports on five RBC alloimmunized patients with SCD who died, to illustrate the concept that RBC alloimmunization itself contributes to premature death. RESULTS: The clinical course for each of the reported patients provides insight into the direct and indirect consequences of RBC alloimmunization, where patients experienced delayed HTRs or did not receive needed RBC transfusions. CONCLUSION: Future work examining the clinical impact of RBC alloimmunization should not only consider HTRs but should also address the potential consequences associated with difficulties in obtaining compatible blood. PMID- 26509334 TI - The contribution of neuroinflammation to amyloid toxicity in Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. Deposition of amyloid-beta (Abeta) remains a hallmark feature of the disease, yet the precise mechanism(s) by which this peptide induces neurotoxicity remain unknown. Neuroinflammation has long been implicated in AD pathology, yet its contribution to disease progression is still not understood. Recent evidence suggests that various Abeta complexes interact with microglial and astrocytic expressed pattern recognition receptors that initiate innate immunity. This process involves secretion of pro-inflammatory cytokines, chemokines and generation of reactive oxygen species that, in excess, drive a dysregulated immune response that contributes to neurodegeneration. The mechanisms by which a neuroinflammatory response can influence Abeta production, aggregation and eventual clearance are now becoming key areas where future therapeutic intervention may slow progression of AD. This review will focus on evidence supporting the combined neuroinflammatory-amyloid hypothesis for pathogenesis of AD, describing the key cell types, pathways and mediators involved. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Deposition of intracellular plaques containing amyloid-beta (Abeta) is a hallmark proteinopathy of the disease yet the precise mechanisms by which this peptide induces neurotoxicity remains unknown. A neuroinflammatory response involving polarized microglial activity, enhanced astrocyte reactivity and elevated pro-inflammatory cytokine and chemokine load has long been implicated in AD and proposed to facilitate neurodegeneration. In this issue we discuss key receptor systems of innate immunity that detect Abeta, drive pro-inflammatory cytokine and chemokine production and influence Abeta aggregation and clearance. Evidence summarized in this review supports the combined neuroinflammatory-amyloid hypothesis for pathogenesis of AD and highlights the potential of immunomodulatory agents as potential future therapies for AD patients. PMID- 26509335 TI - rAAV-CFTRDeltaR Rescues the Cystic Fibrosis Phenotype in Human Intestinal Organoids and Cystic Fibrosis Mice. AB - RATIONALE: Gene therapy holds promise for a curative mutation-independent treatment applicable to all patients with cystic fibrosis (CF). The various viral vector-based clinical trials conducted in the past have demonstrated safety and tolerance of different vectors, but none have led to a clear and persistent clinical benefit. Recent clinical breakthroughs in recombinant adeno-associated viral vector (rAAV)-based gene therapy encouraged us to reexplore an rAAV approach for CF. OBJECTIVES: We evaluated the preclinical potential of rAAV gene therapy for CF to restore chloride and fluid secretion in two complementary models: intestinal organoids derived from subjects with CF and a CF mouse model, an important milestone toward the development of a clinical rAAV candidate for CF gene therapy. METHODS: We engineered an rAAV vector containing a truncated CF transmembrane conductance regulator (CFTRDeltaR) combined with a short promoter (CMV173) to ensure optimal gene expression. A rescue in chloride and fluid secretion after rAAV-CFTRDeltaR treatment was assessed by forskolin-induced swelling in CF transmembrane conductance regulator (CFTR)-deficient organoids and by nasal potential differences in DeltaF508 mice. MEASUREMENTS AND MAIN RESULTS: rAAV-CFTRDeltaR transduction of human CFTR-deficient organoids resulted in forskolin-induced swelling, indicating a restoration of CFTR function. Nasal potential differences demonstrated a clear response to low chloride and forskolin perfusion in most rAAV-CFTRDeltaR-treated CF mice. CONCLUSIONS: Our study provides robust evidence that rAAV-mediated gene transfer of a truncated CFTR functionally rescues the CF phenotype across the nasal mucosa of CF mice and in patient-derived organoids. These results underscore the clinical potential of rAAV-CFTRDeltaR in offering a cure for all patients with CF in the future. PMID- 26509336 TI - Photoswitching and Thermoresponsive Properties of Conjugated Multi-chromophore Nanostructured Materials. AB - Conjugated multi-chromophore organic nanostructured materials have recently emerged as a new class of functional materials for developing efficient light harvesting, photosensitization, photocatalysis, and sensor devices because of their unique photophysical and photochemical properties. Here, we demonstrate the formation of various nanostructures (fibers and flakes) related to the molecular arrangement (H-aggregation) of quaterthiophene (QTH) molecules and their influence on the photophysical properties. XRD studies confirm that the fiber structure consists of >95% crystalline material, whereas the flake structure is almost completely amorphous and the microstrain in flake-shaped QTH is significantly higher than that of QTH in solution. The influence of the aggregation of the QTH molecules on their photoswitching and thermoresponsive photoluminescence properties is revealed. Time-resolved anisotropic studies further unveil the relaxation dynamics and restricted chromophore properties of the self-assembled nano/microstructured morphologies. Further investigations should pave the way for the future development of organic electronics, photovoltaics, and light-harvesting systems based on pi-conjugated multi chromophore organic nanostructured materials. PMID- 26509337 TI - Malaria eradication and economic outcomes in sub-Saharan Africa: Evidence from Uganda. AB - This study evaluates the economic consequences of a 1959-1960 malaria eradication campaign in southwestern Uganda. The effort constitutes a rare, large-scale, and well-documented attempt to eliminate malaria in sub-Saharan Africa and produced an immediate disease reduction. We use this quasi-experimental health shock to identify long-term changes in educational and economic outcomes. Comparing the treatment district to a similar synthetic control, we find malaria eradication raised educational attainment by about a half year for both males and females, increased primary school completion among females and generated an almost 40% rise in the likelihood of male wage employment. PMID- 26509338 TI - Implications of mitogen-activated protein kinase signaling in glioma. AB - Gliomas are the most common primary central nervous system tumors. Gliomas originate from astrocytes, oligodendrocytes, and neural stem cells or their precursors. According to WHO classification, gliomas are classified into four different malignant grades ranging from grade I to grade IV based on histopathological features and related molecular aberrations. The induction and maintenance of these tumors can be attributed largely to aberrant signaling networks. In this regard, the mitogen-activated protein kinase (MAPK) network has been widely studied and is reported to be severely altered in glial tumors. Mutations in MAPK pathways most frequently affect RAS and B-RAF in the ERK, c-Jun N-terminal kinase (JNK), and p38 pathways leading to malignant transformation. Also, it is linked to both inherited and sequential accumulations of mutations that control receptor tyrosine kinase (RTK)-activated signal transduction pathways, cell cycle growth arrest pathways, and nonresponsive cell death pathways. Genetic alterations that modulate RTK signaling can also alter several downstream pathways, including RAS-mediated MAP kinases along with JNK pathways, which ultimately regulate cell proliferation and cell death. The present review focuses on recent literature regarding important deregulations in the RTK activated MAPK pathway during gliomagenesis and progression. PMID- 26509339 TI - Precisely Controlled Ultrastrong Photoinduced Doping at Graphene-Heterostructures Assisted by Trap-State-Mediated Charge Transfer. AB - Ultrastrong and precisely controllable n-type photoinduced doping at a graphene/TiOx heterostructure as a result of trap-state-mediated charge transfer is demonstrated, which is much higher than any other reported photodoping techniques. Based on the strong light-matter interactions at the graphene/TiOx heterostructure, precisely controlled photoinduced bandgap opening of a bilayer graphene device is demonstrated. PMID- 26509340 TI - Biventricular Mural Endocarditis on the Intraventricular Septum. AB - Mural endocarditis is an inflammation and disruption of the nonvalvular endocardial surface of the cardiac chambers. We present a rare case of mural endocarditis on the intraventricular (IV) septum on both the left and right ventricular side with intact valvular annulus. This case highlights the complexity of the operative and postoperative management in an unprecedented case of biventricular mural endocarditis. PMID- 26509341 TI - A Probable Life-Saving Switch from Apixaban to Phenprocoumon. AB - The direct oral anticoagulants (DOAC) dabigatran, rivaroxaban, and apixaban are increasingly prescribed in atrial fibrillation (AF) patients, although dosage in elderly patients, safety in chronic kidney disease, food- and drug-interactions, laboratory tests for monitoring, and antidote are not clarified. In a 78-year-old man with an acute stroke, paroxysmal AF and sick-sinus-syndrome were detected as he received a DDD-pacemaker and 5 mg apixaban/bid. He had a history of hypertension, hypothyroidism, diabetes mellitus, hyperlipidemia, sleep apnea, lumbar discopathy, and nephropathy. Renal function deteriorated after 2 months, and apixaban was changed to phenprocoumon. Three months later, he suffered from abdominal pain and hemorrhagic shock due to rupture of an infrarenal aortic aneurysm. After reversal of the anticoagulation with prothrombin-complex concentrate, a stent-graft with exclusion of the aneurysm was implanted. Switching from apixaban to phenprocoumon was probably life-saving. Vitamin-K antagonists should be preferred to DOAC in patients with AF and vascular disease. PMID- 26509342 TI - Concomitant Persistent Atelectasis following TEVAR Due to a Descending Aortic Aneurysm: Hybrid Endovascular Repair and ECMO Therapy. AB - Many thoracic aortic aneurysms are discovered incidentally, and most develop without symptoms. Symptoms are usually due to sudden expansion of the aneurysm, which can cause a vague pain in the back, or sometimes a sharp pain that may denote the presence of impending rupture. Other symptoms are related to pressure on adjacent structures, such as pressure on the bronchus that can cause respiratory distress, or pressure on the laryngeal nerve causing vocal hoarseness. Pressure on the esophagus can cause difficulty in swallowing. Currently, open surgery and thoracic endovascular aneurysm repair (TEVAR) are the choices of treatment for descending thoracic aneurysms (DTA). The decision to intervene on a DTA depends on its size, location, rate of growth and symptoms, and the overall medical condition of the patient. The indications for TEVAR should not differ from those for open surgery and typically include aneurysms larger than 6 cm in diameter. Saccular and symptomatic aneurysms are often repaired at a smaller size. It is also suggested that aneurysms with a growth rate more than 1 cm per year, or 0.5 cm in 6 months should be considered for early repair.Despite the close proximity of the aorta and left main bronchus, atelectasis caused by thoracic aortic aneurysms is rare. We review the case report of a patient with concomitant persistent left pulmonary atelectasis causing acute respiratory distress due to complete compression of the left main bronchus after TEVAR of a descending thoracic aortic aneurysm. PMID- 26509343 TI - Mediastinal Myxoid Liposarcoma with Intrapericardial Involvement and Large Pericardial Effusion. AB - Liposarcoma is the name given to a group of soft tissue sarcomas (STSs) with adipocytic differentiation. As a group, liposarcomas are the second most common STSs in adults. In 1951 Kozonis et al published that in the English language only four cases of liposarcomas originating in the mediastinum had been described. Primary mediastinal liposarcoma is an uncommon neoplasm of intrathoracic origin. We present the case of a 47-year-old woman diagnosed with a large mediastinal mass with intrapericardial invasion and massive pericardial effusion; biopsies showed a mediastinal liposarcoma. PMID- 26509344 TI - An Epicardial Mesothelial Cyst Attached to the Ascending Aorta. AB - An epicardial mesothelial cyst, which can be defined as a mesothelial cyst attached to the epicardium surrounding the heart and the great vessels inside the pericardial sac, is a rare condition. We herein report a case of epicardial cyst, which was attached to the ascending aorta. The patient was a 76-year-old male who underwent coronary artery bypass surgery, and the cyst was found incidentally. It was approximately 5 cm in diameter, and histological examination confirmed mesothelial cell origin. The ascending aorta has not previously been reported as the origin of an epicardial mesothelial cyst. This case gives new insight into the embryology of these cysts. PMID- 26509345 TI - Blood Cyst of the Anterior Leaflet of the Mitral Valve in an Asymptomatic Adult: Is Surgery an Objective? AB - Blood cysts of the heart are rare benign tumors that usually involve the cardiac valves and are mainly found in fetuses and very early in life. However, no consensus on the surgical management of asymptomatic cases has been postulated. We believe surgical resection should be performed in patients with symptoms, tumor growth, and valvular dysfunction. We report a case of a blood cyst of the anterior leaflet of the mitral valve, which was incidentally discovered in a 55 year-old man. PMID- 26509346 TI - A Case of Successful Treatment of Infective Endocarditis Complicated with Intracranial Hemorrhage, and Literature Review. AB - The risks of neurological deteriorations during open heart surgery under heparinization in patients with infective endocarditis complicated by intracranial hemorrhage remain unknown. The optimal timing for heart surgery is still a point of conflict. We report a case in which a young man who had suffered from infective endocarditis complicated with intracranial hemorrhage successfully received mitral valve replacement on day 9 after the onset of intracranial hemorrhage. PMID- 26509347 TI - Effect of Proximal Anastomotic Diameter on Venous Bypass Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting. AB - BACKGROUND: In this study, the relationship between patency of saphenous vein (SV) graft and different sizes of aorta wall punches was investigated during the follow-up period after coronary artery bypass graft surgery. We also evaluated the other possible factors affecting SV graft patency. METHODS: This study consisted of 266 consecutive and symptomatic patients with postoperative angiography. The primary endpoint was at least one saphenous graft failure observed from coronary computed tomography angiography (cCTA) and/or invasive angiography after surgery. Groups were created as SV occluded and patent group. Survival curves of patients in groups were estimated using Kaplan-Meier method and compared by log-rank test. Multivariate analysis was performed using the Cox proportional hazard model. RESULTS: Cox-regression analysis demonstrated influence of older age (P = .023) and Diabetes Mellitus (DM) (P = .002) on SV graft failure. However, increasing ejection fraction (P = .011) was a protective factor against SV graft failure. There was no significant difference between the two groups in terms of usage rate of the punches with different diameters (P = .296). CONCLUSION: The incidence of SV graft patency does not seem to increase in patients whose 4.8-mm aortic punch was used during proximal anastomosis compared to the reference group in which a punch of 4.0 mm was used. Also, the final proximal anastomosis graft size that was measured using cCTA was similar between patients with 4.8-mm punch and patients with 4-mm punch. Results from this study could help to determine which size for aortosaphenous anastomosis is clinically optimal. PMID- 26509348 TI - False Lumen Catheterization in a Patient Who Has Type A Aortic Dissection That Mimics Acute Inferior Myocardial Infarction: A Case Report. AB - We report a 61-year-old patient who suffered from a type A aortic dissection that mimicked an acute inferior myocardial infarction. During a routine cardiac catheterization procedure, diagnostic catheters can be inserted accidentally into the false lumen. Invasive cardiologists should keep this complication in mind. PMID- 26509349 TI - Is Carotid Artery Stenting an Alternative to Simultaneous Carotid Endarterectomy Performed for Carotid Artery Stenosis in Patients Undergoing Isolated Coronary Bypass Surgery? AB - BACKGROUND: Treatment method in patients with coronary artery disease undergoing coronary bypass surgery with accompanying carotid artery disease is still a hot topic among clinicians. This study is designed to investigate if there is an effect on myocardial infarction, cerebrovascular events and mortality during postoperative period of simultaneous carotid endarterectomy with coronary bypass surgery compared to staged carotid artery stenting before coronary bypass surgery. METHODS: 102 patients (79 male, 23 female) who underwent simultaneous carotid endarterectomy with coronary bypass surgery or staged carotid artery stenting with coronary bypass surgery in the same center with the same surgical team were divided into 2 groups and retrospectively reviewed. Group 1 (n = 71) had coronary artery bypass surgery under general anesthesia with carotid endarterectomy followed by cardiopulmonary bypass with heart team decision. Again with heart team decision, Group 2 (n=31), patients at high-risk for carotid endarterectomy (serious cardiac disease, severe chronic obstructive pulmonary disease, superiorly located lesions), received carotid artery stents in the interventional radiology department and a month later, coronary bypass surgery was performed with cardiopulmonary bypass under elective conditions. RESULTS: Median of patient age was 67.5 (45-83) years. Twenty-two patients (31%) in Group 1 and 19 patients (56.3%) in Group 2 had neurological symptoms, which was statistically significant (P = .004). During the early postoperative term, three patients (4.2%) in Group 1 and two patients (6.5%) in Group 2 died (P = .64). Five patients (7.0%) in Group 1 and two patients (6.5%) in Group 2 developed neurological symptoms during the early postoperative term (P > .05). Likewise, two patients (2.8%) in Group 1 and five patients (16.1%) in Group 2 developed myocardial infarction following carotid intervention (P = .03). CONCLUSIONS: In patients with significant carotid artery stenosis undergoing coronary bypass surgery with cardiopulmonary bypass, in comparison to simultaneous carotid endarterectomy with coronary bypass technique and carotid artery stenting followed with coronary bypass technique showed no difference in combined endpoint (postoperative myocardial infarction, neurological events, and mortality). With proper tools and according to the decisions made by heart teams, both management strategies can be safely performed. PMID- 26509350 TI - Successful Concomitant Revascularization in a Patient with Carotid, Coronary, and Intestinal Artery Occlusive Disease. AB - BACKGROUND: Chronic mesenteric ischemia and carotid stenosis frequently have coexistent coronary artery disease. Myocardial ischemia is the most common cause of morbidity and mortality following revascularization of the peripheral arteries. The optimal treatment of concurrent mesenteric, carotid, and coronary disease is unknown. CASE REPORT: We report a case of a 75-year-old man who required revascularization of the left anterior descending coronary and superior mesenteric arteries and carotid endarterectomy. After concomitant surgical revascularization, the patient remained asymptomatic during the 3-year follow-up. CONCLUSION: A good result in this case encourages us for one-stage combined surgical intervention in patients who require multisystem revascularization. PMID- 26509351 TI - Body fat differences by self-reported race/ethnicity in healthy term newborns. AB - BACKGROUND: Ethnic differences in total body fat (fat mass [FM]) have been reported in adults and children, but the timing of when these differences manifest and whether they are present at birth are unknown. OBJECTIVES: This study aimed to assess whether ethnic differences in body fat are present at birth in healthy infants born at term, where body fat is measured using air displacement plethysmography and fat distribution by skin-fold thickness. METHODS: Data were from a multiracial cross-sectional convenience sample of 332 term infants from four racial or ethnic groups based on maternal self-report (A, Asian; AA, non-Hispanic Black [African-American]; C, non-Hispanic White; and H, Hispanic). The main outcome measure was infant body fat at 1-3 days after birth, with age, birth weight, gestational age and maternal pre-pregnancy weight as covariates. RESULTS: Significant effects for race (P = 0.0011), sex (P = 0.0051) and a race by sex interaction (P = 0.0236) were found. C females had higher FM than C males (P = 0.0001), and AA females had higher FM than AA males (P = 0.0205). C males had less FM than A males (P = 0.0353) and H males (P = 0.0001). CONCLUSION: Race/ethnic and sex differences in FM are present in healthy term newborns. Although the implications of these differences are unclear, studies beginning in utero and birth set the stage for a life course approach to understanding disease later in life. PMID- 26509352 TI - The rise and fall of tuberculosis in Malawi: associations with HIV infection and antiretroviral therapy. AB - OBJECTIVES: Since 1985, Malawi has experienced a dual epidemic of HIV and tuberculosis (TB) which has been moderated recently by the advent of antiretroviral therapy (ART). The aim of this study was to describe the association over several decades between HIV/AIDS, the scale-up of ART and TB case notifications. METHODS: Aggregate data were extracted from annual reports of the National TB Control Programme, the Ministry of Health HIV Department and the National Statistics Office. ART coverage was calculated using the total HIV population as denominator (derived from UNAIDS Spectrum software). RESULTS: In 1970, there were no HIV-infected persons but numbers had increased to a maximum of 1.18 million by 2014. HIV prevalence reached a maximum of 10.8% in 2000, thereafter decreasing to 7.5% by 2014. Numbers alive on ART increased from 2586 in 2003 to 536 527 (coverage 45.3%) by 2014. In 1985, there were 5286 TB cases which reached a maximum of 28 234 in 2003 and then decreased to 17 723 by 2014 (37% decline from 2003). There were increases in all types of new TB between 1998 2003 which then declined by 30% for extrapulmonary TB, by 37% for new smear positive PTB and by 50% for smear-negative PTB. Previously treated TB cases reached a maximum of 3443 in 2003 and then declined by 42% by 2014. CONCLUSION: The rise and fall of TB in Malawi between 1985 and 2014 was strongly associated with HIV infection and ART scale-up; this has implications for ending the TB epidemic in high HIV-TB burden countries. PMID- 26509353 TI - Discovering New Acetylcholinesterase Inhibitors by Mining the Buzhongyiqi Decoction Recipe Data. AB - Myasthenia gravis (MG) is a neuromuscular disease that is conventionally treated with acetylcholinesterase (AChE) inhibitors, which may not fully remove the symptom for many reasons. When AChE inhibitors do not work, Chinese patients turn to Chinese medicine, such as the Buzhongyiqi decoction (BD), to treat MG. By elucidating the relations between the herbs of the Buzhongyiqi decoction recipe and AChE inhibitors with structure-based and ligand-based drug design methods and chemoinformatics approaches, we have found the key active components of BD. Using these key active components as templates, we have discovered five new AChE inhibitors through virtual screening of a commercial compound library. The new AChE inhibitors have been confirmed with Ellman assays. This study demonstrates that lead identification can be inspired by elucidating Chinese medicine. Since BD is a mixture, further studies against other drug targets are needed. PMID- 26509354 TI - Systematic review of randomized trials of the effect of iron supplementation on iron stores and oxygen carrying capacity in pregnancy. AB - INTRODUCTION: Anemia in pregnancy affects 25% of all pregnancies in Europe with iron deficiency affecting even more. Despite supplementation, iron deficiency persists. This review will assess the effect on serum ferritin (iron stores) and hemoglobin (oxygen-carrying capacity) following iron supplementation in pregnant women with anemic and non-anemic iron deficiency. MATERIAL AND METHODS: A systemic search of electronic databases and trial registers was conducted from inception to January 2014. Randomized controlled trials of iron supplementation that measured serum ferritin and hemoglobin levels before and after supplementation were selected. Two independent reviewers selected studies, extracted data and assessed quality. Descriptive analyses were carried out. RESULTS: The review included 23 randomized controlled trials (3525 women). In iron deficiency anemia, more studies described statistically significant increases in serum ferritin levels than in hemoglobin levels following intravenous iron supplementation. In non-anemic iron deficiency there were more statistically significant increases in serum ferritin levels than in hemoglobin levels following oral supplementation. There were no studies reporting maternal quality of life outcomes. CONCLUSIONS: Serum ferritin appears to change more than hemoglobin following iron supplementation. The clinical effects of this need further investigation. PMID- 26509355 TI - Controlling Orientational and Translational Order of Iron Oxide Nanocubes by Assembly in Nanofluidic Containers. AB - We demonstrate that spatial confinement can be used to control the orientational and translational order of cubic nanoparticles. For this purpose we have combined X-ray scattering and scanning electron microscopy to study the ordering of iron oxide nanocubes that have self-assembled from toluene-based dispersions in nanofluidic channels. An analysis of scattering vector components with directions parallel and perpendicular to the slit walls shows that the confining walls induce a preferential parallel alignment of the nanocube (100) faces. Moreover, slit wall separations that are commensurate with an integer multiple of the edge length of the oleic acid-capped nanocubes result in a more pronounced translational order of the self-assembled arrays compared to incommensurate confinement. These results show that the confined assembly of anisotropic nanocrystals is a promising route to nanoscale devices with tunable anisotropic properties. PMID- 26509356 TI - Off-label use of maraviroc in clinical practice. AB - Maraviroc is a first-in-class selective CCR5 antagonist only approved in combination with other antiretrovirals for the treatment of HIV-infection. However, sometimes, off-label prescribing is necessary. In this regard, interesting data have been obtained with maraviroc from studies using murine models. In human daily clinical practice there are many researching areas of interest where CCR5 could play an important role. Nowadays few clinical trials are evaluating maraviroc's role in non-HIV-infected patients but there are many open issues that need to be answered about CCR5 antagonists. In this article we review some of them. PMID- 26509357 TI - Genetic variants in the renin-angiotensin system predict response to bevacizumab in cancer patients. AB - BACKGROUND: Currently, there are no predictive biomarkers for anti-angiogenic strategies in cancer, but response to anti-angiogenic drugs is associated with development of hypertension secondary to treatment. Therefore, this study explored the clinical relevance of genetic polymorphisms in some components of the renin-angiotensin system (RAS). MATERIAL AND METHODS: Genomic DNA was isolated from peripheral blood from 95 metastatic breast or colorectal cancer patients treated with bevacizumab, and AGTR1-A1166C (rs5186), AGT-M235T (rs699) SNPs and ACE I/D (rs4646994) polymorphisms were genotyped using RT-PCR. Circulating vascular endothelial grow factor and angiotensin converting enzyme (ACE) levels were analysed using ELISA kits. The antitumoral activity of bevacizumab was assayed in mice orthotopically xenografted with AGTR1 overexpressing breast cancer cells. RESULTS: The ACE IN/IN genotype was associated with a higher rate of disease progression compared to DEL/IN and DEL/DEL genotypes (36% vs. 11.1% P < 0.05). Similarly, AGTR1-1166A/A genotype was also associated with a higher rate of disease progression compared to AGTR1 1166A/C and AGTR1-1166C/C genotypes (24.4% vs. 2.7% P < 0.01). ACE IN/IN genotype was also found to be associated with shorter time to treatment failure compared to ACE IN/DEL and ACE DEL/DEL genotypes (14 weeks vs. 41.71, P = 0.033), whereas circulating ACE levels were found to be associated with a better response to bevacizumab treatment. Besides, in vivo experiments showed a significantly higher antitumoral activity of bevacizumab in tumours derived from AGTR1-overexpressing breast cancer cells. CONCLUSIONS: A higher activity of ACE-angiotensin-II-AGTR1 axis is associated with a better response to bevacizumab, supporting that the RAS can be an important source of potential predictive markers of response to anti angiogenic drugs. PMID- 26509358 TI - Continuous urethral pressure measurements; measurement techniques; pressure variations; clinical interpretations; and clinical relevance. A Systematic Literature Analysis. AB - AIMS: The clinical relevance of urethral pressure variations (UPV) in the pathophysiology of over active bladder syndrome (OAB) has remained controversial to date. Some studies report an association with OAB and/or detrusor over activity (DO). Recently the International Consultation on Incontinence-Research Society recommended new clinical research to be performed on this subject. We provide a systematic review of the literature to specify this recommendation. METHODS: Literature search was performed in PubMed, Embase, Web of Science, Cochrane, Central, Cinahl, Academic Science Premier, Science Direct, and Wiley Online using a sensitive search string combination. All authors independently reviewed and scored full text papers and consensus about methodological quality was obtained according to Oxford Level of Evidence (LoE). RESULTS: Four hundred eighty seven abstracts were screened, 25 papers met all predefined inclusion selection criteria. Incidence figures of UPV varied between 2% and 95%. Studies are of poor methodological quality with Oxford LoE scores of 3B and 4. Measurement methods and techniques show a large variety. The above mentioned association of DO/OAB with UPV is however frequently reported. CONCLUSION: There exists a phenomenon of UPV, apart from DO, which may be a separate entity within OAB syndrome. Large variation in measurement techniques and patient populations hinders fundamental research as well as clinical progress. Clinical relevance of UPV and consequences for treatment therefore are yet to be established. Future prospective research with well-defined patient population and standardised urodynamic measurement techniques is needed. Results of standardized and objective evaluations should be compared to clinical signs and symptoms by validated questionnaires. Neurourol. Urodynam. 36:51-56, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26509359 TI - Unhealthy Alcohol Use is Associated with Monocyte Activation Prior to Starting Antiretroviral Therapy. AB - BACKGROUND: Alcohol use may accelerate HIV disease progression, but the plausible biological mechanisms have not been clearly elucidated. METHODS: HIV-positive persons who were not on antiretroviral therapy (ART) completed the baseline assessment for a longitudinal study examining the association of alcohol use with HIV disease markers. Oversampling drinkers, baseline samples were tested for markers of monocyte activation (soluble CD14 [sCD14]), inflammation (interleukin 6 [IL-6]-6), and coagulation (d-dimer). We defined "unhealthy alcohol use" as testing positive using the Alcohol Use Disorders Identification Test-Consumption (>=3 for women and >=4 for men) in the past 3 months or testing positive using a biomarker of heavy drinking, phosphatidylethanol (>=50 ng/ml). Multiple linear regression was used to examine the associations of unhealthy alcohol use with sCD14, log10 IL-6, and d-dimer. RESULTS: Compared to those who were abstinent from alcohol, unhealthy drinkers had significantly higher sCD14 levels (mean = 1,676 vs. 1,387 ng/ml; mean difference [95% confidence interval (CI)] = 289 [83, 495], p < 0.01). In analyses adjusted for demographic factors, current cigarette smoking, and HIV disease markers, unhealthy drinkers continued to display significantly higher sCD14 levels compared to those who were abstinent from alcohol (adjusted mean = 1,670 vs. 1,406 ng/ml; adjusted mean difference [95% CI] = 264 [47, 480], p = 0.02). Unhealthy alcohol use was not significantly associated with IL-6 or d-dimer levels. CONCLUSIONS: Unhealthy alcohol use was independently associated with a marker of monocyte activation (i.e., higher sCD14) that predicts mortality in treated HIV infection. Longitudinal research should examine whether unhealthy alcohol use predicts changes in sCD14 prior to and following ART initiation. PMID- 26509360 TI - Continuous Subcutaneous Insulin Infusion in Neonates and Infants Below 1 Year: Analysis of Initial Bolus and Basal Rate Based on the Experiences from the German Working Group for Pediatric Pump Treatment. AB - BACKGROUND: Diabetes mellitus is rare in young infants and neonates. Continuous subcutaneous insulin infusion (CSII) is used most frequently for insulin treatment in this age group. However, the individual doctor's experience is scarce because of the low prevalence of diabetes in this age. For this study patients treated with CSII with an age below 1 year were selected from the German/Austrian DPV (Diabetes-Patienten-Verlaufsdokumentation) database, and basal rate and bolus calculation were described. MATERIALS AND METHODS: For all patients less than 1 year of age, basal rate and mealtime boluses were compared among infants with type 1 diabetes mellitus (T1DM), infants with neonatal diabetes mellitus (NDM), and infants with antibody status unknown diabetes mellitus (AUDM). RESULTS: Fifty-eight patients with T1DM, 67 neonates with NDM, and 43 infants with early diabetes development after 6 months and negative beta cell antibodies (AUDM) could be analyzed. T1DM patients at onset required a median total insulin amount of 0.83 IU/kg of body weight, whereas NDM patients required 0.74 IU/kg of body weight (P = 0.63). Basal insulin requirement however, was different between the two groups (0.56 IU/kg of body weight in NDM vs. 0.43 IU/kg in T1DM) (P = 0.036). The percentage basal profile of NDM and T1DM patients was quite similar to children at the age of 1-5 years. The proportion of prandial insulin at onset was significantly different (32% in NDM vs. 53% in T1DM) (P < 0.00001). AUDM patients showed almost similar data to T1DM patients. The pattern of mealtime bolus insulin was not different among the groups. CONCLUSIONS: The presented data can be used as an initial guide value to start CSII treatment in neonates and infants. To be on the safe side we recommend the lower quartile for the dosage as the starting value in nonketotic patients. PMID- 26509361 TI - Effective Dose Titration of Fentanyl Sublingual Spray in Patients With Breakthrough Cancer Pain. AB - OBJECTIVE: To further describe effective dose titration of fentanyl sublingual spray to treat breakthrough cancer pain (BTCP) during the 26-day open-label titration phase of a phase 3, randomized, double-blind, placebo-controlled study. METHODS: Opioid-tolerant patients with 1 to 4 episodes of BTCP per day were enrolled. For randomization into double-blind treatment, patients must have titrated to a dose (100 to 1,600 mcg) providing effective analgesia for 2 consecutive BTCP episodes. The Treatment Satisfaction Questionnaire for Medication was administered at baseline and at titration end and included a Global Satisfaction domain. RESULTS: Of 130 patients undergoing titration, 98 (75%) achieved pain relief (median dose = 800 mcg). The most common doses that allowed for adequate pain relief were 800 mcg (24.5%) and 1,200 mcg (20.4%). Of 32 (25%) patients who withdrew from the study, only 3 (2.3%) did not achieve an effective dose. In patients attaining an effective dose, mean Global Satisfaction increased from 54.9 +/- 2.1 at baseline to 75.3 +/- 1.7 at the end of the titration phase. Seventy-eight patients (60%) reported >= 1 adverse event (AE). Thirty-three AEs (25.4%) were considered probably related to treatment, with nausea (6.2%) and somnolence (4.6%) most commonly reported. CONCLUSIONS: In patients with BTCP, fentanyl sublingual spray can be rapidly and safely titrated to an effective dose, resulting in greater satisfaction with fentanyl sublingual spray than previous BTCP medications. PMID- 26509362 TI - Comparative assessment of (18) F-Mefway as a serotonin 5-HT1A receptor PET imaging agent across species: Rodents, nonhuman primates, and humans. AB - We have developed (18) F-trans-Mefway ((18) F-Mefway) for positron emission tomography (PET) imaging studies of serotonin 5-HT1A receptors which are implicated in various brain functions. Translation of imaging the 5-HT1A receptor in animal models to humans will facilitate an understanding of the role of the receptor in human brain disorders. We report comparative brain distribution of (18) F-Mefway in normal mice, rats, monkeys, and healthy human volunteers. Mefway was found to be very selective, with subnanomolar affinity for the 5-HT1A receptor. Affinities of >55 nM were found for all other human-cloned receptor subtypes tested. Mefway was found to be a poor substrate (>30 MUM) for the multidrug resistance 1 protein, suggesting low likelihood of brain uptake being affected by P-glycoprotein. Cerebellum was used as a reference region in all imaging studies across all species due to the low levels of (18) F-Mefway binding. Consistent binding of (18) F-Mefway in cortical regions, hippocampus, and raphe was observed across all species. (18) F-Mefway in the human brain regions correlated with the known postmortem distribution of 5-HT1A receptors. Quantitation of raphe was affected by the resolution of the PET scanners in rodents, whereas monkeys and humans showed a raphe to cerebellum ratio of approximately 3. (18) F-Mefway appears to be an effective 5-HT1A receptor imaging agent in all models, including humans. (18) F-Mefway therefore may be used to quantify 5-HT1A receptor distribution in brain regions for the study of various CNS disorders. J. Comp. Neurol. 524:1457-1471, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26509363 TI - Comparable actions of omalizumab on mast cells and basophils. AB - BACKGROUND: Omalizumab (OmAb) has recently been approved for the treatment of diseases other than allergic asthma, including chronic urticaria. The exploration of the use of OmAb in chronic urticaria was based on the presence of IgE autoantibodies against autoantigens such as anti-IgE, anti-FcepsilonRI, and IgE antibodies against thyroid peroxidase in certain patients with chronic urticaria. OmAb recognizes and sequesters free IgE to prevent its interaction with FcepsilonRI. However, OmAb is equally and rapidly effective against autoimmune and non-autoimmune urticaria, suggesting the possible involvement of additional mechanisms of IgE. OBJECTIVES: We sought to investigate the in vitro mechanism of action of OmAb in mast cells and basophils. METHODS: Both LAD2 human mast cell line, previously sensitized with IgE, and ex vivo basophils were incubated with OmAb at different doses, analysing its effect on IgE-dependent events (e.g., degranulation, phosphorylation-mediated signalling, and eicosanoid release). RESULTS: We found that OmAb dissociates pre-bound IgE from mast cells and basophils, resulting in a reduction of proximal phosphorylation-mediated signalling events (Syk, PLCgamma, and LAT) and in a decrease in degranulation and leukotriene synthesis. CONCLUSION: Our data prove the existence of common mechanisms of action of OmAb in mast cells and basophils that would explain its effectiveness and rapid effect in chronic urticaria and provide a basis for its use in other diseases mediated by these cells. PMID- 26509364 TI - The Cortisol Awakening Response and Resilience in Elite Swimmers. AB - The sports environment is stress-eliciting in that it encapsulates perceived uncontrollability, unpredictability and requires ego-involvement. The HPA axis has been shown (indicated by cortisol release) to respond to anticipated sports competition up to a week prior to the event. Research also alludes to the importance of individual differences, such as optimism and trait perfectionism, in moderating the impact of cortisol upon performance. In total, 41 (male n=27) national (n=38) and international (n=3) swimmers were recruited from northeast England and Australia. Swimmers completed a measure of resilience and also provided buccal saliva swabs, from which total cortisol release prior to and during the event was calculated. Findings revealed that resilience significantly predicted performance and the influence of AUC (cortisol release) upon performance was moderated by resilience. These findings suggest that resilience can influence athletic performance either directly or indirectly, through appraisal (i. e., interpretation of the stressor to be facilitative and non threatening). PMID- 26509365 TI - Melatonin is an Ergogenic Aid for Exhaustive Aerobic Exercise only during the Wakefulness Period. AB - This study tested the ergogenic effects of acute administration of melatonin on exhaustive exercise (tlim) at the anaerobic threshold intensity (iAnT) during periods of lower (L) and higher (H) spontaneous physical activity in swimming rats. Additionally, we evaluated the time of day effect on aerobic exercise tolerance. The periods of L and H were determined gravimetrically. All animals were subjected to an incremental test to determine the iAnT. Melatonin was administered (10 mg.kg(-1), intraperitoneal) and after 30 min, the rats were subjected to tlim during the L (LM) or H (HM) period. Control groups were called LC and HC. The criterion of significance was 5%. Melatonin enhanced tlim by 169% during H (HC=72 min; HM=194 min; P<0.01; ES=1.23) and by 90% during L (LC=31 min vs. LM=59 min; P=0.39; ES=1.18), demonstrating a significant effect on tlim (F=10.35; P<0.01) and a strong effect size (ES). Additionally, tlim was higher during H (F=14.24; P<0.01). Melatonin is a reasonable ergogenic aid, particularly during the wakefulness period, and the exercise tolerance is dependent on the time of day for swimming rats. PMID- 26509366 TI - Creatine Supplementation Increases Total Body Water in Soccer Players: a Deuterium Oxide Dilution Study. AB - This study aimed to evaluate changes in total body water (TBW) in soccer athletes using a deuterium oxide dilution method and bioelectrical impedance (BIA) formulas after 7 days of creatine supplementation. In a double-blind controlled manner, 13 healthy (under-20) soccer players were divided randomly in 2 supplementation groups: Placebo (Pla, n=6) and creatine supplementation (CR, n=7). Before and after the supplementation period (0.3 g/kg/d during 7 days), TBW was determined by deuterium oxide dilution and BIA methods. 7 days of creatine supplementation lead to a large increase in TBW (2.3+/-1.0 L) determined by deuterium oxide dilution, and a small but significant increase in total body weight (1.0+/-0.4 kg) in Cr group compared to Pla. The Pla group did not experience any significant changes in TBW or body weight. Although 5 of 6 BIA equations were sensitive to determine TBW changes induced by creatine supplementation, the Kushner et al. 16 method presented the best concordance levels when compared to deuterium dilution method. In conclusion, 7-days of creatine supplementation increased TBW determined by deuterium oxide dilution or BIA formulas. BIA can be useful to determine TBW changes promoted by creatine supplementation in soccer athletes, with special concern for formula choice. PMID- 26509367 TI - Tendon Adaptation to Sport-specific Loading in Adolescent Athletes. AB - Tendon adaptation due to mechanical loading is controversially discussed. However, data concerning the development of tendon thickness in adolescent athletes is sparse. The purpose of this study was to examine possible differences in Achilles (AT) and patellar tendon (PT) thickness in adolescent athletes while considering age, gender and sport-specific loading. In 500 adolescent competitive athletes of 16 different sports and 40 recreational controls both ATs and PTs were sonographically measured. Subjects were divided into 2 age groups (< 13; >= 13 years) and 6 sport type categories (ball, combat, and water sports, combined disciplines, cycling, controls). In addition, 3 risk groups (low, moderate, high) were created according to the athlete's risk of developing tendinopathy. AT and PT thickness did not significantly differ between age groups (AT/PT:<13: 5.4+/ 0.7 mm/3.6+/-0.5 mm;>=13: 5.3+/-0.7 mm/3.6+/-0.5 mm). In both age groups males presented higher tendon thickness than females (p<0.001). AT thickness was highest in ball sports/cyclists and lowest in controls (p<=0.002). PT thickness was greatest in water sports and lowest in controls (p=0.02). High risk athletes presented slightly higher AT thickness compared to the low risk group (p=0.03). Increased AT and PT thickness in certain sport types compared to controls supports the hypothesis of structural tendon adaptation due to sport-specific loading. PMID- 26509368 TI - Eccentric Fatigue Modulates Stretch-shortening Cycle Effectiveness--A Possible Role in Lower Limb Overuse Injuries. AB - The role of fatigue in injury development is an important consideration for clinicians. In particular, the role of eccentric fatigue in stretch-shortening cycle (SSC) activities may be linked to lower limb overuse conditions. The purpose of this study was to explore the influence of ankle plantarflexor eccentric fatigue on SSC effectiveness during a hopping task in healthy volunteers. 11 healthy volunteers (23.2+/-6.7 years) performed a sub-maximal hopping task on a custom-built sledge system. 3D motion capture and surface EMG were utilised to measure lower limb stiffness, temporal kinematic measures and muscle timing measures at baseline and immediately following an eccentric fatigue protocol. A linear mixed model was used to test whether measures differed between conditions. Compared to baseline, eccentric fatigue induced increased stiffness during the hopping task (+ 15.3%; P<0.001). Furthermore, ankle stretch amplitude decreased (- 9.1%; P<0.001), whilst all other ankle kinematic measures remained unchanged. These changes were accompanied by a temporal shift in onset of activity in soleus and tibialis anterior muscles (- 4.6 to - 8.5%; p<0.001). These findings indicate that eccentric fatigue alters SSC effectiveness in healthy volunteers. These findings may be applied to inform pathogenetic models of overuse injury development. PMID- 26509369 TI - The Effect of Platelet-rich Fibrin Matrix on Rotator Cuff Healing in a Rat Model. AB - The purpose of the current study was to determine if the application of platelet rich fibrin matrix could improve regeneration of the tendon-bone insertion site in a rat rotator cuff repair model. 25 Lewis syngeneic rats underwent bilateral tenotomy and repair of the supraspinatus tendon. 10 separate rats were used for PRFM harvest. All left (control) shoulders underwent transosseous rotator cuff repair, while all right (treatment) shoulders were repaired similarly with PRFM augmentation. 9 rats were sacrificed at 2-weeks and ten at 4-weeks for biomechanical testing. 3 separate rats were sacrificed at 2-weeks and 4-weeks each for histologic analysis of the insertion site. At 2 weeks, the experimental group repairs were significantly stronger in ultimate load to failure (P=0.01), stress (P=0.03), and stiffness (P=0.03). Differences in biomechanical testing were not found between the groups at 4 weeks. Histological analysis revealed less collagen organization and cartilage formation at the insertion site in the experimental group. Semiquantitative histologic analysis confirmed our qualitative assessment of the specimens. PRFM does not recapitulate the native enthesis, but rather induces an exuberant and disordered healing response that is characterized by fibrovascular scar tissue. PMID- 26509370 TI - Step Frequency and Step Length of 200-m Sprint in Able-bodied and Amputee Sprinters. AB - The goal of this study was to examine the hypothesis that the difference in the 200-m sprint performance of amputee and able-bodied sprinters is due to a shorter step length rather than a lower step frequency. Men's elite-level 200-m races with a total of 16 able-bodied, 13 unilateral transtibial, 5 bilateral transtibial, and 16 unilateral transfemoral amputee sprinters were analyzed from publicly available internet broadcasts. For each run, the average forward velocity, step frequency, and step length over the entire 200-m distance were analyzed for each sprinter. The average forward velocity of able-bodied sprinters was faster than that of the other 3 groups, but there was no significant difference in average step frequency between able-bodied and transtibial amputee sprinters. However, the average step length of able-bodied sprinters was significantly longer than that of the transtibial amputee sprinters. In contrast, the step frequency and step length of transfemoral amputees were significantly lower and shorter than those of the other 3 groups. These results suggest that the differences in 200-m sprint performance between able-bodied and amputee sprinters are dependent on amputation level. PMID- 26509371 TI - The Effects of a Transition to Minimalist Shoe Running on Intrinsic Foot Muscle Size. AB - A proposed benefit of minimalist shoe running is an increase in intrinsic foot muscle strength. This study examined change in intrinsic foot muscle size in runners transitioning to Vibram FiveFingersTM minimalist shoes compared to a control group running in traditional running shoes. We compare pre-transition size between runners who developed bone marrow edema to those who did not. 37 runners were randomly assigned to the Vibram FiveFingersTM group (n=18) or control group (n=19). Runners' bone marrow edema and intrinsic foot muscle size were measured at baseline and after 10 weeks. Total running volume was maintained by all runners. A significant increase in abductor hallucis cross-sectional area of 10.6% occurred in the Vibram FiveFingersTM group compared to the control group (p=0.01). There was no significant change in any of the other muscles examined (p>0.05). 8 of the Vibram FiveFingersTM runners, and 1 control runner developed bone marrow edema. Those who developed bone marrow edema, primarily women, had significantly smaller size in all assessed muscles (p<=0.05). Size of intrinsic foot muscles appears to be important in safely transitioning to minimalist shoe running. Perhaps intrinsic foot muscle strengthening may benefit runners wanting to transition to minimalist shoes. PMID- 26509372 TI - Road Cycling and Mountain Biking Produces Adaptations on the Spine and Hamstring Extensibility. AB - The purposes of this study were as follows: 1) to analyse the influence of training in road cycling or cross-country mountain biking on sagittal spinal curvatures, pelvic tilt and trunk inclination in cyclists of both cycling modalities; 2) to evaluate the specific spinal posture and pelvic tilt adopted on the road bicycle and cross-country mountain bike; and 3) to compare the spinal sagittal capacity of flexion and pelvic tilt mobility as well as hamstring muscle extensibility among road cyclists, cross-country mountain bikers and non cyclists. Thirty matched road cyclists, 30 mountain bikers and 30 non-cyclists participated in this study. The road cyclists showed significantly greater thoracic kyphosis and trunk inclination than did the mountain bikers and non cyclists in a standing posture. On the bicycle, the road bicycling posture was characterised by greater lumbar flexion and more significant anterior pelvic tilt and trunk inclination compared with the mountain biking posture. The thoracic spine was more flexed in mountain biking than in road cycling. Road cyclists had significantly greater hamstring muscle extensibility in the active knee extension test, and showed greater anterior pelvic tilt and trunk inclination capacity in the sit-and-reach test, compared with mountain bikers and non-cyclists. PMID- 26509373 TI - The Influence of Glove Type on Simulated Wheelchair Racing Propulsion: A Pilot Study. AB - Our purpose was to examine the influence of glove type on kinetic and spatiotemporal parameters at the handrim in elite wheelchair racers. Elite wheelchair racers (n=9) propelled on a dynamometer in their own racing chairs with a force and moment sensing wheel attached. Racers propelled at 3 steady state speeds (5.36, 6.26 & 7.60 m/s) and performed one maximal effort sprint with 2 different glove types (soft & solid). Peak resultant force, peak torque, impulse, contact angle, braking torque, push time, velocity, and stroke frequency were recorded for steady state and sprint conditions. Multiple nonparametric Wilcoxon matched pair's tests were used to detect differences between glove types, while effect sizes were calculated based on Cohen's d. During steady state trials, racers propelled faster, using more strokes and larger contact angle, while applying less impulse with solid gloves compared to soft gloves. During the sprint condition, racers achieved greater top end velocities, applying larger peak force, with less braking torque with solid gloves compared to soft gloves. Use of solid gloves may provide some performance benefits to wheelchair racers during steady state and top end velocity conditions. PMID- 26509374 TI - Interrupting Sitting Time with Regular Walks Attenuates Postprandial Triglycerides. AB - We compared the effects of prolonged sitting with the effects of sitting interrupted by regular walking and the effects of prolonged sitting after continuous walking on postprandial triglyceride in postmenopausal women. 15 participants completed 3 trials in random order: 1) prolonged sitting, 2) regular walking, and 3) prolonged sitting preceded by continuous walking. During the sitting trial, participants rested for 8 h. For the walking trials, participants walked briskly in either twenty 90-sec bouts over 8 h or one 30-min bout in the morning (09:00-09:30). Except for walking, both exercise trials mimicked the sitting trial. In each trial, participants consumed a breakfast (08:00) and lunch (11:00). Blood samples were collected in the fasted state and at 2, 4, 6 and 8 h after breakfast. The serum triglyceride incremental area under the curve was 15 and 14% lower after regular walking compared with prolonged sitting and prolonged sitting after continuous walking (4.73+/-2.50 vs. 5.52+/-2.95 vs. 5.50+/-2.59 mmol/L?8 h respectively, main effect of trial: P=0.023). Regularly interrupting sitting time with brief bouts of physical activity can reduce postprandial triglyceride in postmenopausal women. PMID- 26509375 TI - Changes of Hematological Markers during a Multi-stage Ultra-marathon Competition in the Heat. AB - This study examined the changes in resting hematological variables in ultra endurance runners throughout a multi-stage ultra-marathon competition, and compared athletes that completed all stages with those that failed to complete at least one stage within the cut-off time of competition. 19 ultra-endurance runners competing in a 230 km multi-stage ultra-marathon, conducted over 5 consecutive days in hot ambient conditions (32-40 degrees C T(max)), volunteered to participate in the study. Each day, whole blood samples were collected prior to stage commencement and analyzed for full cell counts by Coulter counter. Linear increases were observed for leukocytes, monocytes and lymphocytes; with increases until Stage 3 and a decrease thereafter. Granulocytes showed a cubic growth exponent, indicating decrements to baseline after the significant increments until Stage 3. Hemoglobin and hematocrit showed linear decrements throughout the multi-stage ultra-marathon. No changes in erythrocytes and platelets were observed throughout the multi-stage ultra-marathon. Granulocytes, erythrocytes, hemoglobin and hematocrit changes along the multi-stage ultra marathon differed in runners that completed all stages compared to those who failed to complete at least one stage within the cut-off time. Multi-stage ultra marathon in the heat has a large impact on hematological responses of ultra endurance runners associated with altered performance. PMID- 26509376 TI - Myths and Facts About the Effects of Ischemic Preconditioning on Performance. AB - Although numerous studies have demonstrated the effect of ischemic preconditioning (IPC) in clinical application, the effectiveness of this procedure on performance and physiological variables is still debatable. Therefore a systematic review was performed, including a meta-analysis and evaluation of the quality of the papers that addressed this scope. The electronic databases of the National Library of Medicine (PubMed), Google Scholar (using [advanced search], [all fields]) and other online journals were searched, for the following descriptors: a) "ischemic preconditioning"; b) "blood flow" and "hyperemia"; c) "blood flow occlusion," combined with "exercise performance", "athletes", "exercise" and "performance". Relevant studies were included, if they conformed to strict pre-formulated criteria, excluding systematic review articles, meta-analyses and studies with only animals or non-healthy subjects. The 20 studies included had high quality scores (87%). The majority of the studies lacked statistical significance (P<0.05) for both performance and physiological variables when comparing IPC, placebo and control groups. Most studies showed that IPC has no significant influence on performance. The few studies with significant differences mainly described an improvement only in performance without altered physiological parameters. Therefore, the influence of IPC on performance is still unclear and physiologically highly debatable. PMID- 26509377 TI - Knee Extension Strength and Hamstrings-to-Quadriceps Imbalances in Elite Soccer Players. AB - This study examined the relationship between hamstrings-to-quadriceps strength ratio (H:Q) and relative strength of the knee extensors in elite soccer players. Peak torque was measured during isokinetic knee extension/flexion at angular velocities of 60 degrees .s(-1), 180 degrees .s(-1) and 300 degrees .s(-1). 18 professional players were divided into 2 groups, depending on their H:Q at 60 degrees .s(-1). Players in the lower H:Q group (n=7) had significantly smaller H:Q ratios compared with the higher H:Q group (n=11) at all angular velocities (60 degrees .s(-1): 49.2%; 95% CI: 61.3-57.8% vs. 59.5%; 95% CI: 52.2-46.2%, p=0.001). Players in the lower H:Q group had greater knee-extension peak torque compared with the higher H:Q group (60 degrees .s(-1): 313; 95% CI: 335-291 vs. 269; 95% CI: 289-250 N.m, p=0.01). No differences were found in hamstrings' strength between the 2 groups (60 degrees .s(-1): 156; 95% CI: 170-143 vs. 160; 95% CI: 173-148 N.m, p=0.96). Negative correlations between knee extension peak torque and H:Q ratio were observed at all angular velocities (r=-0.65 to -0.67, p<0.01). In conclusion, a low H:Q strength ratio measured during isokinetic strength testing in professional soccer players, is observed mainly in those with strong quadriceps muscles, while players with lower quadriceps strength have H:Q ratios around the recommended values. PMID- 26509378 TI - The Utility of a High-intensity Exercise Protocol to Prospectively Assess ACL Injury Risk. AB - This study investigated the utility of a 5-min high-intensity exercise protocol (SAFT(5)) to include in prospective cohort studies investigating ACL injury risk. 15 active females were tested on 2 occasions during which their non-dominant leg was analysed before SAFT(5) (PRE), immediately after (POST0), 15 min after (POST15), and 30 min after (POST30). On the first occasion, testing included 5 maximum isokinetic contractions for eccentric and concentric hamstring and concentric quadriceps and on the second occasion, 3 trials of 2 landing tasks (i. e., single-leg hop and drop vertical jump) were conducted. Results showed a reduced eccentric hamstring peak torque at POST0, POST15 and POST30 (p<0.05) and a reduced functional HQ ratio (Hecc/Qcon) at POST15 and POST30 (p<0.05). Additionally, a more extended knee angle at POST30 (p<0.05) and increased knee internal rotation angle at POST0 and POST15 (p<0.05) were found in a single-leg hop. SAFT(5) altered landing strategies associated with increased ACL injury risk and similar to observations from match simulations. Our findings therefore support the utility of a high-intensity exercise protocol such as SAFT(5) to strengthen injury screening tests and to include in prospective cohort studies where time constraints apply. PMID- 26509379 TI - The Acute Effect of Direct Vibration on Muscular Power Performance in Master Athletes. AB - This study examined the acute effect of direct vibration on biceps brachii muscular power in master athletes. 10 healthy male national representative master field-hockey players were randomly assigned to receive 10 min of pulsing sinusoidal vibration or no vibration (control) to the right and left biceps brachii. Pre- and post-testing included lifting 2 repetitions of standing dumbbell (DB) biceps curl at 50% 1 RM (repetition maximum). Mechanical peak power (PP), mean concentric power (MCP) and normalised electromyography (EMG) was assessed during the concentric phase of the biceps curl. Following vibration PP increased 44.3+/-23.6 W (difference pre-post; p=0.013) compared to control (5.9+/ 9.5 W; p=0.334). Similarly, MCP increased 12.0+/-4.5 W (p=0.002) compared to control (1.5+/-0.8 W; p=0.397). However, there was no significant difference in normalised EMG between vibration and control (p>0.05). The increase in PP and MCP did not coincide with an increase in EMG and suggests that other mechanisms may be contributing to changes in muscle performance. Given its ease of use and portability the vibratory device may be considered as an alternative warm-up modality immediately prior to explosive activities. PMID- 26509380 TI - Aerial and Terrestrial Patterns: A Novel Approach to Analyzing Human Running. AB - Biomechanical parameters are often analyzed independently, although running gait is a dynamic system wherein changes in one parameter are likely to affect another. Accordingly, the Volodalen(r) method provides a model for classifying running patterns into 2 categories, aerial and terrestrial, using a global subjective rating scoring system. We aimed to validate the Volodalen(r) method by verifying whether the aerial and terrestrial patterns, defined subjectively by a running coach, were associated with distinct objectively-measured biomechanical parameters. The running patterns of 91 individuals were assessed subjectively using the Volodalen(r) method by an expert running coach during a 10-min running warm-up. Biomechanical parameters were measured objectively using the OptojumpNext(r) during a 50-m run performed at 3.3, 4.2, and 5 m.s(-1) and were compared between aerial- and terrestrial-classified subjects. Longer contact times and greater leg compression were observed in the terrestrial compared to the aerial runners. The aerial runners exhibited longer flight time, greater center of mass displacement, maximum vertical force and leg stiffness than the terrestrial ones. The subjective categorization of running patterns was associated with distinct objectively-quantified biomechanical parameters. Our results suggest that a subjective holistic assessment of running patterns provides insight into the biomechanics of running gaits of individuals. PMID- 26509381 TI - Atrial Size and Function in Athletes. AB - We wanted to explore whether change in LA (left atrium) size would influence LA function, or increase regurgitation in the atrioventricular valves. 595 male elite football players and 47 non-athletic controls were included. End-systolic LA volume and RA area and end-diastolic LV volume and RV area were measured by 2 dimensional (2D) echocardiography Pulsed and colour Doppler were used to estimate tricuspid and mitral regurgitations. 2D longitudinal strain of the 50 football players with the largest LA volumes were compared with the 50 players with the smallest LA volumes. The LA volumes in some athletes with large atria were more than tripled, compared to athletes with small atria. 2D strain however, could not reveal any impairment of LA function in the players with the largest atria, compared to those with the smallest LA. Tricuspid valve regurgitation was found in 343 (58%) of the athletes, compared to 17 (36%) of the controls (p<0.01), while mitral regurgitation was found in 116 (20%) football players and 7 (15%) controls (NS). Furthermore, the RA area was significantly larger in athletes with tricuspid regurgitation compared to athletes without. The present study demonstrated a huge variation in atrial size between the athletes. This variation, however, had no impact on LA function. Tricuspid regurgitation was significantly more prevalent among the athletes, than among the controls. PMID- 26509382 TI - Acute, Low-dose CO Inhalation does not Alter Energy Expenditure during Submaximal Exercise. AB - Carbon monoxide, a gas known most widely for its toxic effects at high doses, is receiving increased attention for its role as a physiological signaling molecule and potential therapeutic agent when administered in low doses. We sought to quantify any changes to oxygen consumption and energy expenditure during submaximal exercise after low-dose CO inhalation. 9 active individuals completed 4 graded submaximal exercise tests, with each test occurring during a separate visit. For their first exercise test, subjects inhaled CO or room air (1.2 mL.kg( 1) body mass) in a randomized, subject-blind fashion. A second test was repeated 24 h later when the inhaled gas should have cleared the system. Subjects repeated study procedures with the alternate dose after a washout period of at least 2 days. Low-dose CO administration did not affect oxygen consumption or energy expenditure during submaximal exercise immediately or 24 h following its administration. Increases in heart rate, blood [lactate], and perceived exertion were observed following acute CO inhalation but these effects were absent after 24 h. The results of this study suggest that low-dose CO administration does not influence the energetics of submaximal exercise, but it acutely increases the relative intensity associated with absolute workloads below the lactate threshold. PMID- 26509383 TI - Anaerobic Threshold by Mathematical Model in Healthy and Post-Myocardial Infarction Men. AB - The aim of this study was to determine the anaerobic threshold (AT) in a population of healthy and post-myocardial infarction men by applying Hinkley's mathematical method and comparing its performance to the ventilatory visual method. This mathematical model, in lieu of observer-dependent visual determination, can produce more reliable results due to the uniformity of the procedure. 17 middle-aged men (55+/-3 years) were studied in 2 groups: 9 healthy men (54+/-2 years); and 8 men with previous myocardial infarction (57+/-3 years). All subjects underwent an incremental ramp exercise test until physical exhaustion. Breath-by-breath ventilatory variables, heart rate (HR), and vastus lateralis surface electromyography (sEMG) signal were collected throughout the test. Carbon dioxide output (VCO2), HR, and sEMG were studied, and the AT determination methods were compared using correlation coefficients and Bland Altman plots. Parametric statistical tests were applied with significance level set at 5%. No significant differences were found in the HR, sEMG, and ventilatory variables at AT between the different methods, such as the intensity of effort relative to AT. Moreover, important concordance and significant correlations were observed between the methods. We concluded that the mathematical model was suitable for detecting the AT in both healthy and myocardial infarction subjects. PMID- 26509384 TI - Monitoring Perceived Stress and Recovery in Relation to Cycling Performance in Female Athletes. AB - The purpose was to investigate perceived stress and recovery related to cycling performance of female athletes over one full year. 20 female athletes (age, 27+/ 8 years; VO2max, 50.3+/-4.6 mL.kg(-1).min(-1)) were measured 8 times in one year to determine perceived stress and recovery (RESTQ-Sport) in relation to cycling performance (Lamberts and Lambert Submaximal Cycle Test (LSCT)). All 19 RESTQ Sport scales were calculated and scores of the 4 main categories were determined (i. e., general stress, general recovery, sport-specific stress and sport specific recovery). A balance score of total stress and recovery was calculated by recovery-stress. Power at the second stage (P80), third stage (P90) and heart rate recovery (HRR60 s) of the LSCT were determined as performance parameters. 110 RESTQ-Sports and LSCTs were analysed using a multilevel approach (random intercepts model). Higher self-efficacy was related to improvement of all performance parameters. Higher total recovery stress, and lower emotional stress were related to improvement of P90 and HRR60 s. Higher sport-specific recovery was related to P80, higher general stress, fatigue and physical complaints were related to decreased P90 and higher social stress and injury were related to decreased HRR60 s. Improved perceived recovery and stress contributed to an improved performance. Relevant information could be provided by monitoring changes in perceived stress and recovery of female athletes. PMID- 26509385 TI - A Tool to Quickly Detect Short Hamstring Syndrome in Boys who Play Soccer. AB - There is a lack of studies of alternative techniques differing from the straight leg raise test (SLR) and the passive knee extension test (PKE) to diagnose short hamstring syndrome (SHS). We built a predictive model with simple parameters to diagnose SHS and implemented it in a mobile app. This cross-sectional study analyzed 85 Spanish boys aged 10-16 years who played soccer in 2012. OUTCOMES: SHS (SLR<70 degrees and/or PKE>15 degrees ), and grade II SHS (SLR<60 degrees and/or PKE>=35 degrees ). Secondary variables: toe-touch test (TT), body mass index (BMI), age, laterality and number of years registered as part of a federation. A risk table implemented in a mobile app was built to estimate the probability of SHS and grade II SHS according to secondary variables. The area under the ROC curve (AUC) was calculated and we constructed risk groups. Scoring factors for SHS: low TT, younger age and lower BMI. AUC: 0.89 (95% CI: 0.82-0.96, p<0.001). Scoring factors for grade II SHS: younger age, higher BMI, left footed and lower TT. AUC: 0.78 (95% CI: 0.68-0.88, p<0.001). We provide a tool with minimum material but with a high discriminatory power to quickly calculate whether a boy who plays soccer has SHS. The models need validation studies. PMID- 26509386 TI - Intra-abdominal Pressure and Trunk Muscular Activities during Abdominal Bracing and Hollowing. AB - This study examined the difference in intra-abdominal pressure (IAP) between abdominal bracing and hollowing in relation to trunk muscular activities. IAP with a pressure transducer placed in the rectum and surface electromyograms for rectus abdominis, external oblique, internal oblique, and erector spinae during the 2 tasks were obtained in 7 young adult men. The difference between IAP at rest and its peak value (DeltaIAPmax) showed high intra- and inter-day repeatability, and was significantly greater in abdominal bracing (116.4+/-15.0 mmHg) than in abdominal hollowing (9.9+/-4.5 mmHg). The trunk muscular activities at DeltaIAPmax were significantly higher in abdominal bracing than in abdominal hollowing, and in the internal oblique than in the other 3 muscles. In both abdominal bracing and hollowing, the changes in IAP during the tasks were linearly correlated with those in trunk muscular activities, but the slope of the regression line for the relationship differed between the 2 tasks. The current results indicate that 1) abdominal bracing is an effective maneuver to elevate IAP compared with abdominal hollowing, and 2) in the 2 tasks, the changes in IAP are linked with those in trunk muscular activities, but the association is task specific. PMID- 26509387 TI - Skeletal Muscle Response to Endurance Training in IL-6-/- Mice. AB - We examined effects of moderate-intensity endurance training on muscle COX/CS activities and V'O2max in control WT and IL-6(-/-) mice. Animals were exercised for 10 weeks on treadmill for 1 h, 5 days a week at velocity of 6 m.min(-1) which was increased by 0.5 m.min(-1) every 2 weeks up to 8 m.min(-1) . Training triggered an increase of enzyme activities in soleus muscle of WT mice (COX: 480.3+/-8.9 U.g(-1) in sedentary group vs. 773.3+/-62.6 U.g(-1) in trained group, P<0.05 and CS: 374.0+/-6.0 U.g(-1) in sedentary group vs. 534.2+/-20.5 U.g(-1) in trained group, P<0.01, respectively) whereas no changes were observed in soleus of IL6(-/-) mice. Moreover, in mixed gastrocnemius muscle of trained IL-6(-/-) mice enzyme activities tended to be lower (COX: 410.7+/-48.4 U.g(-1) for sedentary vs. 277.0+/-36.5 U.g(-1) for trained group and CS: 343.8+/-24.6 U.g(-1) for sedentary vs. 251.7+/-27.1 U.g(-1) for trained group). No changes in V'O2max were observed in WT and IL-6(-/-) mice after training. Concluding, moderate velocity endurance training-induced increase in COX and CS activities in muscles of WT mice only which suggests that IL-6 regulates training-induced skeletal muscle responses to exercise. PMID- 26509389 TI - Case Report: Relieving the Itch of Cholestasis with Corticosteroids in Palliative Care. PMID- 26509390 TI - Prophylactic Use of Antiemetics for Prevention of Opioid-Induced Nausea and Vomiting: A Questionnaire Survey among Japanese Physicians. AB - BACKGROUND: Antiemetics are being used both for the treatment and prophylaxis of opioid-induced nausea and vomiting (OINV) in clinical practice, despite the lack of evidence for the prophylactic benefit. Data regarding the actual status of prophylactic antiemetic use for OINV remain to be elucidated. OBJECTIVE: The objective of this study was to evaluate the practice among Japanese physicians of the prophylactic use of antiemetics when starting opioids prescription for the prevention of opioid-induced nausea and vomiting. METHODS: This questionnaire survey was targeted among physicians experienced in cancer pain treatment at two institutions of Japan (Nagoya University Hospital and Ichinomiya City Municipal Hospital). The questionnaire assessed the physicians' practice and beliefs regarding the prophylactic antiemetics prescription when they start opioids in patients with cancer pain. RESULTS: Questionnaires were filled in and received from 112 physicians from two institutions. Eighty-two percent of physicians prescribed prophylactic antiemetics at the beginning of opioid prescription, and the most commonly prescribed drug for this purpose was prochlorperazine (88%). CONCLUSION: Despite the lack of evidence, Japanese physicians commonly prescribe prophylactic antiemetics, most commonly prochlorperazine, for OINV. Prospective clinical trials are necessary to evaluate the efficacy of this practice. PMID- 26509392 TI - Editorial. PMID- 26509393 TI - Initial results of the management of aortoiliac aneurysms with GORE(r) Excluder(r) Iliac Branched Endoprosthesis. AB - AIM: We prospectively observed the outcomes of all patients (N.=15) with an aortoiliac and a common iliac artery aneurysm who were electively treated with the GORE(r) Excluder(r) Iliac Branched Endoprosthesis (IBE) with regard to clinical, anatomical and radiological results. METHODS: We evaluated operative mortality, aneurysm rupture rate and aneurysm related mortality as well as conversion to open surgery, incidence of endoleak, rate of aneurysm migration, aneurysm enlargement, graft patency, reintervention rate and the clinical outcome. Postoperative follow-up included a computed tomography angiography (CTA) before discharge, clinical evaluation and Duplex ultrasound or CTA 3 weeks after the intervention and Duplex ultrasound every 3 months afterwards. RESULTS: Mean patient age was 79 years (range 61-83 years); f/m: 1/2; mean follow-up was 9 months; 80% of the patients presented 2 or more major comorbidities and 1/3 were considered to be not eligible for open repair. Mean hospitalization time was 5 days. Technical success rate was 93.3% (intent-to-treat basis). Mortality within 30 days was 0%; there were no ruptures; type II endoleak directly after the procedure occurred in 20%, dropping to 13.3% after 3 months. We defined the initial technical success in absence of type I endoleaks. The initial technical success rate was 100%. No IBE occlusion or type Ia, Ib or III endoleak was observed during the postoperative follow-up (mean follow-up: 9 months). All of the internal iliac side branches remained patent. Reintervention rate, buttock claudication rate and pelvic complication rate were 0%. CONCLUSION: The GORE(r) IBE provides a new and safe alternative for the management of complete endovascular repair of an extensive aortoiliac or common iliac aneurysm while maintaining pelvic blood flow in iliac branched devices. Due to the lower complexity if compared to previous endovascular or hybrid methods, it should be performed in every anatomically suitable case. PMID- 26509394 TI - Five classes Euroscore modification improves accuracy of prediction of postoperative mortality and possibly the length of mechanical ventilation of cardiac surgery patients. AB - AIM: The additive EuroSCORE system for predicting operative mortality of cardiac patients tends to underestimate the mortality risk of high risk patients and concomitantly to overestimate that of low risk patients. We propose a modification of stratification groups aiming at improving its precision. We also tested its ability to predict the length of postoperative mechanical ventilation of our patients. METHODS: The high risk group of the EuroSCORE system (>6 points) was divided into three additional groups (group I: 0-2 points, group II: 3-5 points, group III: 6-8 points, group IV: 9-13 points, group V: >14 points) thus producing a 5 classes system. In a group of 301 cardiac surgery patients operated on in a low volume cardiac center, we calculated the expected mortality rate for each EuroSCORE class, the calibration of the modified scoring system, the ROC and the corresponding AUC values and the relative risk of each predisposing factor used by the original EuroSCORE sytem. RESULTS: The proposed modification increased the discrimination ability of EuroSCORE in predicting mortality (Hosmer Lemeshow P=0.78, ROC size: 0.791) and marginally affected its accuracy in predicting length of postoperative mechanical ventilation (Hosmer-Lemeshow: 0.11, ROC size: 0.711). Combined operations of CABG and valve replacement were shown to exert a statistically significant effect on mortality (odds ratio 3.85, CI: 1.15 12.87, P=0.028). CONCLUSION: The proposed modification of additive EuroSCORE can presumably increase its discrimination ability in predicting mortality of cardiac patients handled in a low volume cardiac center. The need for prolonged mechanical ventilation could be predicted with acceptable accuracy, possibly providing support in resource management. PMID- 26509395 TI - Giving Thanks! PMID- 26509397 TI - Writing Multiple Choice Outcome Questions to Assess Knowledge and Competence. AB - Few articles contemplate the need for good guidance in question item-writing in the continuing education (CE) space. Although many of the core principles of sound item design translate to the CE health education team, the need exists for specific examples for nurse educators that clearly describe how to measure changes in competence and knowledge using multiple choice items. In this article, some keys points and specific examples for nursing CE providers are shared. PMID- 26509398 TI - Development of a Diabetes Learning Needs Assessment Tool to Promote an Individualized Predischarge Patient Education Plan. AB - The purpose of this article is to feature a nursing staff initiative to improve patients' understanding of their diabetes management by empowering them with knowledge for successful glycemic control. This initiative also enhanced patient and family-centered care and patient safety through individualized, targeted instruction. PMID- 26509399 TI - Microaggression and Its Relevance in Health Care. AB - The concept of microaggression is introduced with the intent of encouraging professional development educators to advance the concept when providing leadership training and development. The use of education, rather than adjudication, is promoted. PMID- 26509400 TI - Nurses on Boards. AB - Health care systems are faced with significant changes. Nurses have a depth and breadth of knowledge to help the boards of these systems adapt to the Patient Protection and Affordable Care Act requirements, especially regarding quality and safety issues. To help with these important issues, nurses must be appointed to these boards AND to government boards, commissions, and councils, which are also facing significant questions about health care. PMID- 26509401 TI - Designing Simulation Scenarios to Support Performance Assessment Validity. AB - This article advances and demonstrates a validation process to guide the development of health care simulation scenarios for assessing performance competency. The development and evaluation of each scenario used in a simulation based competency assessment must be based on multiple sources of evidence that support the validity of the assessment for its intended use. Procedures are proposed to optimize the validity of simulation-based assessments by linking the scenario directly to the instrument and using a systematic approach for gathering and processing input from experts in the field. This validation process is then applied to the development of an original scenario for use in an assessment of nursing competency that targets objectives through patient simulation scenarios scored by multiple raters. PMID- 26509402 TI - SQUIRE 2.0 (Standards for QUality Improvement Reporting Excellence): Revised Publication Guidelines From a Detailed Consensus Process. AB - Since the publication of Standards for QUality Improvement Reporting Excellence (SQUIRE 1.0) guidelines in 2008, the science of the field has advanced considerably. In this manuscript, we describe the development of SQUIRE 2.0 and its key components. We undertook the revision between 2012 and 2015 using (1) semi-structured interviews and focus groups to evaluate SQUIRE 1.0 plus feedback from an international steering group, (2) two face-to-face consensus meetings to develop interim drafts, and (3) pilot testing with authors and a public comment period. SQUIRE 2.0 emphasizes the reporting of three key components of systematic efforts to improve the quality, value, and safety of healthcare: the use of formal and informal theory in planning, implementing, and evaluating improvement work; the context in which the work is done; and the study of the intervention(s). SQUIRE 2.0 is intended for reporting the range of methods used to improve healthcare, recognizing that they can be complex and multidimensional. It provides common ground to share these discoveries in the scholarly literature (http://www.squire-statement.org). PMID- 26509403 TI - Revision of Immediate Post-Open Heart Surgery Education for Critical Care RNs. AB - Responding to the complex nature of critical care is imperative, as extensive clinical judgment is required during those vital moments when patients are experiencing complications related to open heart surgery, post-vessel bypass, or valve replacement. Critical care registered nurses must rely on evidence-based foundational knowledge and skills particular to cardiovascular pathophysiology, hemodynamic monitoring, and medications. This article reports on the critical care educator's revision of the immediate post-open heart surgery curriculum. Mixed educational methods within the plan were foundational to develop clinicians for competent care of these complex patients (within the first 8 hours). The revision included experiential learning and learner centeredness to bolster the learner's confidence, reduce the time to competence, and, most important, ensure positive patient outcomes. Kirkpatrick's classic four-level model provided the framework for evaluation. Lessons learned were discussed following the program initiation. PMID- 26509404 TI - Pilot for Nurse-Led, Interprofessional In-Service Training on Trauma-Informed Perinatal Care. AB - BACKGROUND: Perinatal health care providers receive little training on addressing posttraumatic stress in childbearing women. Provision of trauma-informed care requires agency-wide adaptations. The authors developed a brief, agency-level, in service training on trauma-informed perinatal care and evaluated the training using a knowledge, skills, and attitudes framework. METHOD: A single-group, pretest-posttest design was used for this project. Data were collected from attendees who were in mental health, health care, and administrative staff roles. RESULTS: Forty-seven participants were included in the analysis. Statistically significant gains in knowledge, skills, and attitudes following the in-service were noted. Qualitative data provided suggestions for future improvements. CONCLUSION: Most participants found that the training program was useful and relevant to their practice settings, but more advanced programs are needed for some professionals. Educational programs and training for trauma-informed care addressing these needs should be developed and evaluated in the future. PMID- 26509405 TI - Perceptions of New Nurses Concerning Incivility in the Workplace. AB - BACKGROUND: Although an atmosphere of civility in which nurses respect and value each other is crucial to health care, incivility continues to be widespread. METHOD: New graduate nurses completed an online questionnaire in which they described incivility and discussed its impact on new nurses and patients. RESULTS: Findings were categorized according to the impact of incivility on new nurses and patients. Embedded in these categories are rich descriptions of incivility in health care. CONCLUSIONS: The participants witnessed uncivil interactions that negatively impacted them emotionally, professionally, and physically. They also discussed the harmful effects of incivility on patients, whose care may be impeded or their faith in caregivers eroded in hostile, uncivil care environments. Nurses in professional development play a crucial role in promoting a culture of civility through raising awareness, supporting nurses new to the profession, and helping health care workers to better cope with incivility. PMID- 26509406 TI - Dendritic Ni(Cu)-polypyrrole hybrid films for a pseudo-capacitor. AB - Dendritic Ni(Cu)-polypyrrole hybrid films are fabricated for a pseudo-capacitor in a unique morphology using two simple methods: electro-deposition and electrochemical de-alloying. Three-dimensional structures of porous dendrites are prepared by electro-deposition within the hydrogen evolution reaction (HER) at a high cathodic potential; the high-surface-area structure provides sufficient redox reactions between the electrodes and the electrolyte. The dependence of the active-layer thickness on the super-capacitor performance is also investigated, and the 60 MUm-thick Ni(Cu)PPy hybrid electrode presents the highest performance of 659.52 F g(-1) at the scan rate of 5 mV s(-1). In the thicker layers, the specific capacitance became smaller due to the diffusion limitation of the ions in an electrolyte. The polypyrrole-hybridization on the porous dendritic Ni(Cu) electrode provides superior specific capacitance and excellent cycling stability due to the improvement in electric conductivity by the addition of conducting polypyrrole in the matrices of the dendritic nano-porous Ni(Cu) layer and the synergistic effect of composite materials. PMID- 26509407 TI - Incorporation of detailed eye model into polygon-mesh versions of ICRP-110 reference phantoms. AB - The dose coefficients for the eye lens reported in ICRP 2010 Publication 116 were calculated using both a stylized model and the ICRP-110 reference phantoms, according to the type of radiation, energy, and irradiation geometry. To maintain consistency of lens dose assessment, in the present study we incorporated the ICRP-116 detailed eye model into the converted polygon-mesh (PM) version of the ICRP-110 reference phantoms. After the incorporation, the dose coefficients for the eye lens were calculated and compared with those of the ICRP-116 data. The results showed generally a good agreement between the newly calculated lens dose coefficients and the values of ICRP 2010 Publication 116. Significant differences were found for some irradiation cases due mainly to the use of different types of phantoms. Considering that the PM version of the ICRP-110 reference phantoms preserve the original topology of the ICRP-110 reference phantoms, it is believed that the PM version phantoms, along with the detailed eye model, provide more reliable and consistent dose coefficients for the eye lens. PMID- 26509408 TI - Development of a Simulation Scenario and Evaluation Checklist for Patients With Asthma in Emergency Care. AB - Care for patients with asthma requires prompt and effective decision-making abilities. Many nursing students report a lack of preparedness and competence with respect to their ability to perform nursing duties. Simulation-based learning has been developed as a potential solution to this problem. Moreover, the simulation scenario with an evaluation checklist offers a reliable evaluation strategy for the education and training of clinical decision-making skills among nursing students. The simulation scenario and evaluation checklist developed in this study offer a means to improve patient safety during asthma care in the emergency care unit, as well as to improve nursing students' problem-solving competencies and communication with patients with asthma. PMID- 26509409 TI - Impact of Bar-code Medication Administration on Medication Administration Best Practices. AB - Medication errors in hospitals are common and often lead to patient harm, contributing to increased costs and hospital length of stay. Bar-code medication administration can improve patient safety by leveraging technology to improve accuracy throughout the medication administration process. This study was designed to determine whether implementation of a bar-code medication administration process could improve the safety of medication administration. Researchers used a pre-post comparative design to describe the workflow process of nurses during medication administration before and after implementation of a pilot bar-code medication administration process. It was proposed that implementation of bar-code medication administration would increase real-time medication administration documentation, decrease medication administration related errors, increase Workstation on Wheels usage at the bedside for medication administration, and increase use of the electronic medication administration record for medication retrieval. Descriptive statistics were used to summarize data and assess differences in distributions between preimplementation and postimplementation phases. There was a marked increase in use of the Workstation on Wheels at the bedside as well as real-time documentation. Use of the electronic medication administration record to retrieve medications did not increase after implementation. Medication errors showed a slight rate increase after bar-code medication administration was introduced. PMID- 26509410 TI - Asymmetric Reduction of tert-Butanesulfinyl Ketimines by N-Heterocyclic Carbene Boranes. AB - N-heterocyclic carbene borane (NHC-borane) based on a triazole core is demonstrated for the first time to be efficient for reduction of a variety of tert-butanesulfinyl ketimines. Up to 95% yield and up to >99% diastereomeric excess were achieved. NHC-borane exhibited excellent activities that are more efficient than or comparable to commonly used reductive reagents such as NaBH4, NaBH3CN, l-selectride, Ru catalyst, or BH3-THF. PMID- 26509411 TI - Making a Difference in Surgery Residency Programs. PMID- 26509412 TI - Optimized measurements of separations and angles between intra-molecular fluorescent markers. AB - We demonstrate a novel, yet simple tool for the study of structure and function of biomolecules by extending two-colour co-localization microscopy to fluorescent molecules with fixed orientations and in intra-molecular proximity. From each colour-separated microscope image in a time-lapse movie and using only simple means, we simultaneously determine both the relative (x,y)-separation of the fluorophores and their individual orientations in space with accuracy and precision. The positions and orientations of two domains of the same molecule are thus time-resolved. Using short double-stranded DNA molecules internally labelled with two fixed fluorophores, we demonstrate the accuracy and precision of our method using the known structure of double-stranded DNA as a benchmark, resolve 10-base-pair differences in fluorophore separations, and determine the unique 3D orientation of each DNA molecule, thereby establishing short, double-labelled DNA molecules as probes of 3D orientation of anything to which one can attach them firmly. PMID- 26509413 TI - Video-rate in vivo fluorescence imaging with a line-scanned dual-axis confocal microscope. AB - Video-rate optical-sectioning microscopy of living organisms would allow for the investigation of dynamic biological processes and would also reduce motion artifacts, especially for in vivo imaging applications. Previous feasibility studies, with a slow stage-scanned line-scanned dual-axis confocal (LS-DAC) microscope, have demonstrated that LS-DAC microscopy is capable of imaging tissues with subcellular resolution and high contrast at moderate depths of up to several hundred microns. However, the sensitivity and performance of a video-rate LS-DAC imaging system, with low-numerical aperture optics, have yet to be demonstrated. Here, we report on the construction and validation of a video-rate LS-DAC system that possesses sufficient sensitivity to visualize fluorescent contrast agents that are topically applied or systemically delivered in animal and human tissues. We present images of murine oral mucosa that are topically stained with methylene blue, and images of protoporphyrin IX-expressing brain tumor from glioma patients that have been administered 5-aminolevulinic acid prior to surgery. In addition, we demonstrate in vivo fluorescence imaging of red blood cells trafficking within the capillaries of a mouse ear, at frame rates of up to 30 fps. These results can serve as a benchmark for miniature in vivo microscopy devices under development. PMID- 26509414 TI - Monitoring photodynamic therapy with photoacoustic microscopy. AB - Abstract. We present our work on examining the feasibility of monitoring photodynamic therapy (PDT)-induced vasculature change with acoustic-resolution photoacoustic microscopy (PAM). Verteporfin, an FDA-approved photosensitizer for clinical PDT, was utilized. With a 60-MUm-resolution PAM system, we demonstrated the capability of PAM to monitor PDT-induced vasculature variations in a chick chorioallantoic membrane model with topical application and in a rat ear with intravenous injection of the photosensitizer. We also showed oxygen saturation change in target blood vessels due to PDT. Success of the present approach may potentially lead to the application of PAM imaging in evaluating PDT efficacy, guiding treatment, and predicting responders from nonresponders. PMID- 26509415 TI - Optimization of the method for assessment of brain perfusion in humans using contrast-enhanced reflectometry: multidistance time-resolved measurements. AB - The aim of the study was to determine optimal measurement conditions for assessment of brain perfusion with the use of optical contrast agent and time resolved diffuse reflectometry in the near-infrared wavelength range. The source detector separation at which the distribution of time of flights (DTOF) of photons provided useful information on the inflow of the contrast agent to the intracerebral brain tissue compartments was determined. Series of Monte Carlo simulations was performed in which the inflow and washout of the dye in extra- and intracerebral tissue compartments was modeled and the DTOFs were obtained at different source-detector separations. Furthermore, tests on diffuse phantoms were carried out using a time-resolved setup allowing the measurement of DTOFs at 16 source-detector separations. Finally, the setup was applied in experiments carried out on the heads of adult volunteers during intravenous injection of indocyanine green. Analysis of statistical moments of the measured DTOFs showed that the source-detector separation of 6 cm is recommended for monitoring of inflow of optical contrast to the intracerebral brain tissue compartments with the use of continuous wave reflectometry, whereas the separation of 4 cm is enough when the higher-order moments of DTOFs are available. PMID- 26509416 TI - Management of brain-dead donors outside the intensive care unit: a necessary recourse. PMID- 26509417 TI - Knowledge of 'trusted person' and 'advance directive' in end-of-life situations in prehospital emergency medicine 10 years after Leonetti's law publication. PMID- 26509418 TI - Emergency Medicine training and working conditions in Europe: a joint EuSEM young doctors - European Junior Doctors Survey. PMID- 26509419 TI - Correction to Effect of Adduct Formation with Molecular Nitrogen on the Measured Collisional Cross Sections of Transition Metal-1,10- Phenanthroline Complexes in Traveling Wave Ion-Mobility Spectrometry: N2 Is Not Always an "Inert" Buffer Gas. PMID- 26509420 TI - A Novel Bilateral Approach for Suprasellar Arachnoid Cysts: A Case Report. AB - The endoscopic method is used to treat suprasellar arachnoid cysts (SACs) but it is sometimes difficult to make sufficiently sized fenestrations. Creating a larger fenestration on the cyst wall is preferable to prevent closure of the stoma. In this paper, we report a novel endoscopic approach for SAC treatment in which we use bilateral burr holes to achieve a more extensive cyst fenestration. A 7-year-old girl was referred to our hospital because of incidentally detected hydrocephalus by computed tomography scans. Physical examination did not show any signs of intracranial hypertension, but a digital impression of her skull on X ray implied chronic intracranial hypertension. Magnetic resonance imaging (MRI) revealed enlargement of both lateral ventricles and a cystic mass occupying the third ventricle. We performed cyst wall fenestration using a bilateral approach in which we created two burr holes to introduce a flexible endoscope and a rigid endoscope. The cyst wall was held by forceps with the flexible endoscope, and resection of the cyst wall was achieved by using a pair of scissors with the rigid endoscope. There were no postoperative complications, and MRI performed 1 year after treatment showed disappearance of the superior part of the cyst wall. PMID- 26509421 TI - Identification of vibrational excitations and optical transitions of the organic electron donor tetraphenyldibenzoperiflanthene (DBP). AB - Tetraphenyldibenzoperiflanthene (DBP) attracts interest as an organic electron donor for photovoltaic applications. In order to assist in the analysis of vibrational and optical spectra measured during the formation of thin films of DBP, we have studied the vibrational modes and the electronic states of this molecule. Information on the vibrational modes of the electronic ground state has been obtained by IR absorption spectroscopy of DBP grains embedded in polyethylene and CsI pellets and by calculations using density functional theory (DFT). Electronic transitions have been measured by UV/vis absorption spectroscopy applied to DBP molecules isolated in rare-gas matrices. These measurements are compared with the results of ab initio and semi-empirical calculations. Particularly, the vibrational pattern observed in the S1 <- S0 transition is interpreted using a theoretical vibronic spectrum computed with an ab initio model. The results of the previous experiments and calculations are employed to analyze the data obtained by high-resolution electron energy loss spectroscopy (HREELS) applied to DBP molecules deposited on a Au(111) surface. They are also used to examine the measurements performed by differential reflectance spectroscopy (DRS) on DBP molecules deposited on a muscovite mica(0001) surface. It is concluded that the DBP molecules in the first monolayer do not show any obvious degree of chemisorption on mica(0001). Regarding the first monolayer of DBP on Au(111), the HREELS data are consistent with a face-on anchoring and the absence of strong electronic coupling. PMID- 26509423 TI - Chinese Herbal Formulas Si-Wu-Tang and Er-Miao-San Synergistically Ameliorated Hyperuricemia and Renal Impairment in Rats Induced by Adenine and Potassium Oxonate. AB - BACKGROUND/AIMS: Hyperuricemia is an independent risk factor for chronic kidney disease and cardiovascular disease. Here, we examined the combined protective effects of Chinese herbal formula Si-Wu-Tang and Er-Miao-San on hyperuricemia and renal impairment in rats. METHODS: Rats were randomly divided into normal rats, hyperuricemic rats, and hyperuricemic rats orally administrated with benzbromarone (4.5 mg.kg-1.d-1), Si-Wu-Tang (3.78 g.kg-1.d-1) and Si-Wu-Tang plus Er-Miao-San (6.48 g.kg-1.d-1) for 4 weeks. Hyperuricemic rats were orally gavaged with adenine (0.1 g.kg-1.d-1) and potassium oxonate (1.5 g.kg-1.d-1) daily for 4 weeks. Serum uric acid, creatinine, total cholesterol (TCH), triglyceride and blood urea nitrogen (BUN) concentrations, as well as urinary uric acid and microalbuminuria were measured weekly. Serum xanthine oxidase (XOD) activity and renal histopathology were also evaluated. The renal expression of organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) was detected by western blot. RESULTS: Si-Wu-Tang plus Er-Miao-San lowered serum uric acid, creatinine, triglyceride and BUN levels to a greater degree than did Si-Wu-Tang alone. Si-Wu-Tang plus Er-Miao-San ameliorated microalbuminuria and renal histopathology, as well as decreased serum TCH concentration and XOD activity in hyperuricemic rats. Combination of Si-Wu-Tang and Er-Miao-San also led to a greater increase in OAT1 and OAT3 expression than did Siwutang alone. CONCLUSION: Si-Wu-Tang and Er-Miao-San synergistically ameliorated hyperuricemia and renal impairment in rats through upregulation of OAT1 and OAT3. PMID- 26509424 TI - Triarylborane conjugated dicyanovinyl chromophores: intriguing optical properties and colorimetric anion discrimination. AB - Three new triarylborane conjugated dicyanovinyl chromophores (Mes2B-pi-donor DCV); donor: N-methyldiphenylamine () and triphenylamine ( and [with two BMes2 substitutions]) of type A-D-A (acceptor-donor-acceptor) are reported. Compounds exhibit intense charge transfer (CT) absorption bands in the visible region. These absorption peaks are combination CT bands of the amine donor to both the BMes2 and DCV units. This inference was supported by theoretical studies. Compound shows weak fluorescence compared to and . The discrimination of fluoride and cyanide ions is essential in the case of triarylborane (TAB) based anion sensors as a similar response is given towards both the anions. Anion binding studies of , and showed that fluoride ions bind selectively to the boron centre and block the corresponding CT transition (donor to BMes2) leaving the other CT transition to be red shifted. On the other hand, cyanide ions bind with both the receptor sites and stop both the CT transition processes and hence a different colorimetric response was noted. The binding of F(-)/CN(-) induces colour changes in the visible region of the electronic spectra of and , which allows for the naked-eye detection of F(-) and CN(-) ions. The anion binding mechanisms are established using NMR titration experiments. PMID- 26509425 TI - Retracting, Replacing, and Correcting the Literature for Pervasive Error in Which the Results Change but the Underlying Science Is Still Reliable. PMID- 26509426 TI - Refining the Breakpoints of Three New Translocations Identified in Myelodysplastic Syndromes. AB - Recurrent translocations are uncommon in myelodysplastic syndromes (MDS). Three new recurrent translocations, namely der(12)t(3;12)(q13;p13), t(11;13;22)(q13;q14;q12) and der(17)t(13;17)(q21;p13), identified by conventional cytogenetics (CC) in 4 MDS patients, were further characterized using a panel of commercial and homemade fluorescence in situ hybridization (FISH) probes. The goal of this study was to determine the precise breakpoints and to identify genes that could be related with the neoplastic process. Half of the breakpoints (4/8) were precisely identified and in the remaining half they were narrowed to a region ranging from 14 to 926 kb. All the studied breakpoints had interstitial or terminal deletions ranging from 536 kb to 89 Mb, and only those 7 Mb were detected by CC. The genes located in or around the breakpoints described in our study have not been previously related to MDS. The deleted regions include the ETV6 and RB1 genes, among others, and exclude the TP53 gene. FISH studies were useful to refine the breakpoints of the translocations, but further studies are needed to determine the role of the involved genes in the neoplastic process. PMID- 26509427 TI - Metabolomics to Explore Imidacloprid-Induced Toxicity in the Central Nervous System of the Freshwater Snail Lymnaea stagnalis. AB - Modern toxicology is seeking new testing methods to better understand toxicological effects. One of the most concerning chemicals is the neonicotinoid pesticide imidacloprid. Although imidacloprid is designed to target insects, recent studies have shown adverse effects on nontarget species. Metabolomics was applied to investigate imidacloprid-induced sublethal toxicity in the central nervous system of the freshwater snail Lymnaea stagnalis. The snails (n = 10 snails) were exposed for 10 days to increasing imidacloprid concentrations (0.1, 1, 10, and 100 MUg/L). The comparison between control and exposure groups highlighted the involvement and perturbation of many biological pathways. The levels of several metabolites belonging to different metabolite classes were significantly changed by imidacloprid exposure. A change in the amino acids and nucleotide metabolites like tryptophan, proline, phenylalanine, uridine, and guanosine was found. Many fatty acids were down-regulated, and the levels of the polyamines, spermidine and putrescine, were found to be increased which is an indication of neuron cell injury. A turnover increase between choline and acetylcholine led us to hypothesize an increase in cholinergic gene expression to overcome imidacloprid binding to the nicotinic acetylcholine receptors. Metabolomics revealed imidacloprid induced metabolic changes at low and environmentally relevant concentration in a nontarget species and generated a novel mechanistic hypothesis. PMID- 26509428 TI - Photoelectron wave function in photoionization: plane wave or Coulomb wave? AB - The calculation of absolute total cross sections requires accurate wave functions of the photoelectron and of the initial and final states of the system. The essential information contained in the latter two can be condensed into a Dyson orbital. We employ correlated Dyson orbitals and test approximate treatments of the photoelectron wave function, that is, plane and Coulomb waves, by comparing computed and experimental photoionization and photodetachment spectra. We find that in anions, a plane wave treatment of the photoelectron provides a good description of photodetachment spectra. For photoionization of neutral atoms or molecules with one heavy atom, the photoelectron wave function must be treated as a Coulomb wave to account for the interaction of the photoelectron with the +1 charge of the ionized core. For larger molecules, the best agreement with experiment is often achieved by using a Coulomb wave with a partial (effective) charge smaller than unity. This likely derives from the fact that the effective charge at the centroid of the Dyson orbital, which serves as the origin of the spherical wave expansion, is smaller than the total charge of a polyatomic cation. The results suggest that accurate molecular photoionization cross sections can be computed with a modified central potential model that accounts for the nonspherical charge distribution of the core by adjusting the charge in the center of the expansion. PMID- 26509429 TI - Photoresponsive Self-Healing Polymer Composite with Photoabsorbing Hybrid Microcapsules. AB - Microcapsule-based self-healing polymer materials are highly desirable because they can heal large-volume cracks without changing the original chemical structures of polymers. However, they are limited by processing difficulties and inhomogeneous distributions of two components. Herein, we report a one-component photoresponsive self-healing polymer composite with photoabsorbing hybrid microcapsules (PAHM), which gives the microcapsules photoabsorbing properties by introducing nano-TiO2 particles as photoabsorbing and emulsified agents in the poly(urea-formaldehyde)/TiO2 hybrid shells. Upon mechanical damage and then exposure to light, the photoresponsive healing agents in the cracks will be solidified to allow for self-healing, while the healing agents in the unbroken PAHM will be protected and remain unreacted, which endows this photoresponsive microcapsule-based self-healing composite with self-healing properties like those found in the conventional two-component microcapsule-based systems. Given the universality of this hybrid polymerization method, incorporation of the photoabsorbing particles to conventional polymer shells may further broaden the scope of applications of these widely used materials. PMID- 26509430 TI - A High-Valent Iron(IV) Peroxo Core Derived from O2. AB - Dioxygen-tolerant [NiFe] hydrogenases catalyze not only the conversion of H2 into 2 H(+) and 2 e(-) but also the reduction of O2 to H2O. Chemists have sought to mimic such bifunctional catalysts with structurally simpler compounds to facilitate analysis and improvement. Herein, we report a new [NiFe]-based catalyst for O2 reduction via an O2 adduct. Structural investigations reveal the first example of a side-on iron(IV) peroxo complex. PMID- 26509431 TI - Evidence for Defect-Mediated Tunneling in Hexagonal Boron Nitride-Based Junctions. AB - We investigate electron tunneling through atomically thin layers of hexagonal boron nitride (hBN). Metal (Cr/Au) and semimetal (graphite) counter-electrodes are employed. While the direct tunneling resistance increases nearly exponentially with barrier thickness as expected, the thicker junctions also exhibit clear signatures of Coulomb blockade, including strong suppression of the tunnel current around zero bias and step-like features in the current at larger biases. The voltage separation of these steps suggests that single-electron charging of nanometer-scale defects in the hBN barrier layer are responsible for these signatures. We find that annealing the metal-hBN-metal junctions removes these defects and the Coulomb blockade signatures in the tunneling current. PMID- 26509432 TI - A retrospective analysis of false-positive infectious screening results in blood donors. AB - BACKGROUND: False-positive infectious transfusion screening results remain a challenge with continued loss of both donors and blood products. We sought to identify associations between donor demographic characteristics (age, race, sex, education, first-time donor status) and testing false positive for viruses during routine blood donation screening. In addition the study assessed the prevalence of high-risk behaviors in false-positive donors. STUDY DESIGN AND METHODS: Blood Systems, Inc. donors with allogeneic donations between January 1, 2011, and December 31, 2012, were compared in a case-control study. Those with a false positive donation for one of four viruses (human immunodeficiency virus [HIV], human T-lymphotropic virus [HTLV], hepatitis B virus [HBV], and hepatitis C virus [HCV]) were included as cases. Those with negative test results were controls. For a subset of cases, infectious risk factors were evaluated. RESULTS: Black race and Hispanic ethnicity were associated with HCV and HTLV false-positive results. Male sex and lower education were associated with HCV false positivity, and age 25 to 44 was associated with HTLV false positivity. First-time donors were more likely to be HCV false positive although less likely to be HBV and HTLV false positive. No significant associations between donor demographics and HIV false positivity were observed. A questionnaire for false-positive donors showed low levels of high-risk behaviors. CONCLUSION: Demographic associations with HCV and HTLV false-positive results overlap with those of true infection. While true infection is unlikely given current testing algorithms and risk factor evaluation, the findings suggest nonrandom association. Further investigation into biologic mechanisms is warranted. PMID- 26509434 TI - Cation Exchange Synthesis and Unusual Resistive Switching Behaviors of Ag2Se Nanobelts. AB - Ag2Se nanobelts are prepared through employing ZnSe nanobelts as templates via a facile cation exchange approach. The templates are derived from precursor ZnSe.0.5N2 H4 nanobelts, which are synthesized by a simple hydrothermal method. As-synthesized precursor nanobelts are with 200 nm in width and several hundreds of micrometers in length. Annealed in N2 , they are transformed into ZnSe nanobelts with preserving their initial morphology. Following with a complete replacement of Zn(2+) by Ag(+), Ag2Se nanobelts with single crystalline are obtained via a cation-exchange reaction. Combined with the Langmuir-Blodgett assembly technique, regular films of ZnSe nanobelts can be achieved on transparent glass substrates and Si wafers with interdigital Au electrode arrays. Further, the optical and electrical evolutions are investigated from ZnSe nanobelts to Ag2 Se nanobelts. Finally, the resistive switching characteristic are carefully explored for Ag2Se nanobelts regularly arranged on interdigital Au microelectrodes. The results indicate that it is analogous to complementary resistive switching behaviors, which is different from that of traditional two terminal devices about previously reported Ag2Se. In order to clarify this phenomenon, a possible mechanism has been proposed and indirectly demonstrated through in situ SEM (scanning electron microscropy) observation. PMID- 26509433 TI - Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin mediated mitophagy. AB - Impairment of the autophagy-lysosome pathway is implicated with the changes in alpha-synuclein and mitochondrial dysfunction observed in Parkinson's disease (PD). Damaged mitochondria accumulate PINK1, which then recruits parkin, resulting in ubiquitination of mitochondrial proteins. These can then be bound by the autophagic proteins p62/SQSTM1 and LC3, resulting in degradation of mitochondria by mitophagy. Mutations in PINK1 and parkin genes are a cause of familial PD. We found a significant increase in the expression of p62/SQSTM1 mRNA and protein following mitophagy induction in human neuroblastoma SH-SY5Y cells. p62 protein not only accumulated on mitochondria, but was also greatly increased in the cytosol. Increased p62/SQSMT1 expression was prevented in PINK1 knock-down cells, suggesting increased p62 expression was a consequence of mitophagy induction. The transcription factors Nrf2 and TFEB, which play roles in mitochondrial and lysosomal biogenesis, respectively, can regulate p62/SQSMT1. We report that both Nrf2 and TFEB translocate to the nucleus following mitophagy induction and that the increase in p62 mRNA levels was significantly impaired in cells with Nrf2 or TFEB knockdown. TFEB translocation also increased expression of itself and lysosomal proteins such as glucocerebrosidase and cathepsin D following mitophagy induction. We also report that cells with increased TFEB protein have significantly higher PGC-1alpha mRNA levels, a regulator of mitochondrial biogenesis, resulting in increased mitochondrial content. Our data suggests that TFEB is activated following mitophagy to maintain autophagy lysosome pathway and mitochondrial biogenesis. Therefore, strategies to increase TFEB may improve both the clearance of alpha-synuclein and mitochondrial dysfunction in PD. Damaged mitochondria are degraded by the autophagy-lysosome pathway and is termed mitophagy. Following mitophagy induction, the transcription factors Nrf2 and TFEB translocate to the nucleus, inducing the transcription of genes encoding for autophagic proteins such as p62, as well as lysosomal and mitochondrial proteins. We propose that these events maintain autophagic flux, replenish lysosomes and replace mitochondria. PMID- 26509435 TI - Vitamin D Status at Birth and Future Risk of Attention Deficit/Hyperactivity Disorder (ADHD). AB - OBJECTIVE: To investigate whether children with Attention Deficit/Hyperactivity Disorder have lower levels of Vitamin D3 at birth than matched controls. MATERIAL: Umbilical cord blood samples collected at birth from 202 children later diagnosed with Attention Deficit/Hyperactivity Disorder were analysed for vitamin D content and compared with 202 matched controls. 25-OH vitamin D3 was analysed by liquid chromatography tandem mass spectrometry. RESULTS: No differences in cord blood vitamin D concentration were found between children with Attention Deficit/Hyperactivity Disorder (median 13.0 ng/ml) and controls (median 13.5 ng/ml) (p = 0.43). In a logistic regression analysis, Attention Deficit/Hyperactivity Disorder showed a significant association with maternal age (odds ratio: 0.96, 95% confidence interval: 0.92-0.99) but not with vitamin D levels (odds ratio: 0.99, 95% confidence interval: 0.97-1.02). CONCLUSION: We found no difference in intrauterine vitamin D levels between children later developing Attention Deficit/Hyperactivity Disorder and matched control children. However, the statistical power of the study was too weak to detect an eventual small to medium size association between vitamin D levels and Attention Deficit/Hyperactivity Disorder. PMID- 26509436 TI - Mushrooms as Rainmakers: How Spores Act as Nuclei for Raindrops. AB - Millions of tons of fungal spores are dispersed in the atmosphere every year. These living cells, along with plant spores and pollen grains, may act as nuclei for condensation of water in clouds. Basidiospores released by mushrooms form a significant proportion of these aerosols, particularly above tropical forests. Mushroom spores are discharged from gills by the rapid displacement of a droplet of fluid on the cell surface. This droplet is formed by the condensation of water on the spore surface stimulated by the secretion of mannitol and other hygroscopic sugars. This fluid is carried with the spore during discharge, but evaporates once the spore is airborne. Using environmental electron microscopy, we have demonstrated that droplets reform on spores in humid air. The kinetics of this process suggest that basidiospores are especially effective as nuclei for the formation of large water drops in clouds. Through this mechanism, mushroom spores may promote rainfall in ecosystems that support large populations of ectomycorrhizal and saprotrophic basidiomycetes. Our research heightens interest in the global significance of the fungi and raises additional concerns about the sustainability of forests that depend on heavy precipitation. PMID- 26509438 TI - Correction: Laboratory Evaluation of the Shinyei PPD42NS Low-Cost Particulate Matter Sensor. PMID- 26509437 TI - Thrombin Generating Capacity and Phenotypic Association in ABO Blood Groups. AB - Individuals with blood group O have a higher bleeding risk than non-O blood groups. This could be explained by the lower levels of FVIII and von Willebrand Factor (VWF) levels in O individuals. We investigated the relationship between blood groups, thrombin generation (TG), prothrombin activation and thrombin inactivation. Plasma levels of VWF, FVIII, antithrombin, fibrinogen, prothrombin and alpha2Macroglobulin (alpha2M) levels were determined. TG was measured in platelet rich (PRP) and platelet poor plasma (PPP) of 217 healthy donors and prothrombin conversion and thrombin inactivation were calculated. VWF and FVIII levels were lower (75% and 78%) and alpha2M levels were higher (125%) in the O group. TG is 10% lower in the O group in PPP and PRP. Less prothrombin was converted in the O group (86%) and the thrombin decay capacity was lower as well. In the O group, alpha2M plays a significantly larger role in the inhibition of thrombin (126%). In conclusion, TG is lower in the O group due to lower prothrombin conversion, and a larger contribution of alpha2M to thrombin inactivation. The former is unrelated to platelet function because it is similar in PRP and PPP, but can be explained by the lower levels of FVIII. PMID- 26509439 TI - CLL Exosomes Modulate the Transcriptome and Behaviour of Recipient Stromal Cells and Are Selectively Enriched in miR-202-3p. AB - Bi-directional communication with the microenvironment is essential for homing and survival of cancer cells with implications for disease biology and behaviour. In chronic lymphocytic leukemia (CLL), the role of the microenvironment on malignant cell behaviour is well described. However, how CLL cells engage and recruit nurturing cells is poorly characterised. Here we demonstrate that CLL cells secrete exosomes that are nanovesicles originating from the fusion of multivesicular bodies with the plasma membrane, to shuttle proteins, lipids, microRNAs (miR) and mRNAs to recipient cells. We characterise and confirm the size (50-100 nm) and identity of the CLL-derived exosomes by Electron microscopy (EM), Atomic force microscopy (AFM), flow cytometry and western blotting using both exosome- and CLL-specific markers. Incubation of CLL-exosomes, derived either from cell culture supernatants or from patient plasma, with human stromal cells shows that they are readily taken up into endosomes, and induce expression of genes such as c-fos and ATM as well as enhance proliferation of recipient HS-5 cells. Furthermore, we show that CLL exosomes encapsulate abundant small RNAs and are enriched in certain miRs and specifically hsa-miR-202-3p. We suggest that such specific packaging of miR-202-3p into exosomes results in enhanced expression of 'suppressor of fused' (Sufu), a Hedgehog (Hh) signalling intermediate, in the parental CLL cells. Thus, our data show that CLL cells secrete exosomes that alter the transcriptome and behaviour of recipient cells. Such communication with microenvironment is likely to have an important role in CLL disease biology. PMID- 26509440 TI - The First New Zealanders? An Alternative Interpretation of Stable Isotope Data from Wairau Bar, New Zealand. AB - PLOS ONE Volume 8 includes an article "The First New Zealanders: Patterns of Diet and Mobility Revealed through Isotope Analysis". The paper proposes that burial groups within the settlement phase site of Wairau Bar differ in terms of dietary stable isotopes and 87Sr/86Sr. The authors argue this difference is probably due to one group being a founding population while the other burials are later. Here we review the work of Kinaston et al. and present an alternative analysis and interpretation of the isotopic data. Treating the isotope data independently from cultural and biological factors we find that sex best explains dietary variation. Our reassessment of 87Sr/86Sr confirms the authors original finding of high mobility of early New Zealanders but suggests a larger range of individuals should be considered 'non-local' on current evidence. PMID- 26509441 TI - The Virological and Immunological Characteristics of the HIV-1-Infected Population in Brazil: From Initial Diagnosis to Impact of Antiretroviral Use. AB - BACKGROUND: Immunological and virological status of HIV-infected individuals entering the Brazilian public system over time was analyzed. We evaluated the impact of ART on virological, immunological and antiretroviral resistance over time. METHODS: CD4+ T cell counts, viral loads and genotypes from patients over 13 years old from 2001-2011 were analyzed according to demographic data. We compared groups using parametric t-tests and linear regression analysis in the R statistical software language. RESULTS: Mean baseline CD4+ T cell counts varied from 348 (2003) to 389 (2009) and was higher among women (p = 1.1 x 10(-8)), lower in older patients (p< 1 x 10(-8)) and lower in less developed regions (p = 1.864 x 10(-5)). Percentage of treated patients with undetectable viral loads increased linearly from 46% (2001) to 77% (2011), was lower among women (p = 2.851 x 10(-6)), younger ages (p = 1 x 10(-3)), and in less developed regions (p = 1.782 x 10(-4)). NRTI acquired resistance was 86% in 2001-3 and decreased over time. NNRTI resistance increased from 2001-3(50%) to 2006-9 (60%), PI resistance decreased from 2001-3 (60%) to 2009 (40%), and 3-class resistance was stable over time around 25%. Subtype prevalence comprised B (75.3%), B/F recombinants (12.2%), C (5.7%), F (5.3%) and B/C recombinants (1.5%), with regional variations. Three-class resistance was 26.5% among Bs, 22.4% among Fs and 17.2% among Cs. CONCLUSIONS: HIV diagnosis occurs late, especially among elderly Brazilians. Younger individuals need special attention due to poor virological response to treatment. Antiretroviral Resistance profile is subtype related. PMID- 26509442 TI - Trace Levels of Staphylococcal Enterotoxin Bioactivity Are Concealed in a Mucosal Niche during Pulmonary Inflammation. AB - Pathogen and cellular by-products released during infection or trauma are critical for initiating mucosal inflammation. The localization of these factors, their bioactivity and natural countermeasures remain unclear. This concept was studied in mice undergoing pulmonary inflammation after Staphylococcal enterotoxin A (SEA) inhalation. Highly purified bronchoalveolar lavage fluid (BALF) fractions obtained by sequential chromatography were screened for bioactivity and subjected to mass spectrometry. The Inflammatory and inhibitory potentials of the identified proteins were measured using T cells assays. A potent pro-inflammatory factor was detected in BALF, and we hypothesized SEA could be recovered with its biological activity. Highly purified BALF fractions with bioactivity were subjected to mass spectrometry. SEA was the only identified protein with known inflammatory potential, and unexpectedly, it co-purified with immunosuppressive proteins. Among them was lactoferrin, which inhibited SEA and anti-CD3/-CD28 stimulation by promoting T cell death and reducing TNF synthesis. Higher doses of lactoferrin were required to inhibit effector compared to resting T cells. Inhibition relied on the continual presence of lactoferrin rather than a programming event. The data show a fraction of bioactive SEA resided in a mucosal niche within BALF even after the initiation of inflammation. These results may have clinical value in human diagnostic since traces levels of SEA can be detected using a sensitive bioassay, and may help pinpoint potential mediators of lung inflammation when molecular approaches fail. PMID- 26509444 TI - Impact of SNP array karyotyping on the diagnosis and the outcome of chronic myelomonocytic leukemia with low risk cytogenetic features or no metaphases. AB - Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder with heterogeneous clinical, morphological and genetic characteristics. Clonal cytogenetic abnormalities are found in 20-30% of patients with CMML. Patients with low risk cytogenetic features (normal karyotype and isolated loss of Y chromosome) account for ~80% of CMML patients and often fall into the low risk categories of CMML prognostic scores. We hypothesized that single nucleotide polymorphism arrays (SNP-A) karyotyping could detect cryptic chromosomal alterations with prognostic impact in these subgroup of patients. SNP-A were performed at diagnosis in 128 CMML patients with low risk karyotypes or uninformative results for conventional G-banding cytogenetics (CC). Copy number alterations (CNAs) and regions of copy number neutral loss of heterozygosity (CNN LOH) were detected in 67% of patients. Recurrent CNAs included gains in regions 8p12 and 21q22 as well as losses in 10q21.1 and 12p13.2. Interstitial CNN-LOHs were recurrently detected in the following regions: 4q24-4q35, 7q32.1-7q36.3, and 11q13.3-11q25. Statistical analysis showed that some of the alterations detected by SNP-A associated with the patients' outcome. A shortened overall survival (OS) and progression free survival (PFS) was observed in cases where the affected size of the genome (considering CNAs and CNN-LOHs) was >11 Mb. In addition, presence of interstitial CNN-LOH was predictive of poor OS. Presence of CNAs (>=1) associated with poorer OS and PFS in the patients with myeloproliferative CMML. Overall, SNP-A analysis increased the diagnostic yield in patients with low risk cytogenetic features or uninformative CC and added prognostic value to this subset of patients. PMID- 26509443 TI - Targeting Integrin-Dependent Adhesion and Signaling with 3-Arylquinoline and 3 Aryl-2-Quinolone Derivatives: A new Class of Integrin Antagonists. AB - We previously reported the anti-migratory function of 3-aryl-2-quinolone derivatives, chemically close to flavonoids (Joseph et al., 2002). Herein we show that 3-arylquinoline or 3-aryl-2-quinolone derivatives disrupt cell adhesion in a dose dependent and reversible manner yet antagonized by artificial integrin activation such as manganese. Relying on this anti-adhesive activity, a Structure Activity Relationship (SAR) study was established on 20 different compounds to throw the bases of future optimization strategies. Active drugs efficiently inhibit platelet spreading, aggregation, and clot retraction, processes that rely on alphallbbeta3 integrin activation and clustering. In vitro these derivatives interfere with beta3 cytoplasmic tail interaction with kindlin-2 in pulldown assays albeit little effect was observed with pure proteins suggesting that the drugs may block an alternative integrin activation process that may not be directly related to kindlin recruitment. Ex vivo, these drugs blunt integrin signaling assayed using focal adhesion kinase auto-phosphorylation as a read-out. Hence, 3-arylquinoline and 3-aryl-2-quinolone series are a novel class of integrin activation and signaling antagonists. PMID- 26509445 TI - Genetic Structure of Pacific Trout at the Extreme Southern End of Their Native Range. AB - Salmonid fishes are cold water piscivores with a native distribution spanning nearly the entire temperate and subarctic northern hemisphere. Trout in the genus Oncorhynchus are the most widespread salmonid fishes and are among the most important fish species in the world, due to their extensive use in aquaculture and valuable fisheries. Trout that inhabit northwestern Mexico are the southernmost native salmonid populations in the world, and the least studied in North America. They are unfortunately also facing threats to their continued existence. Previous work has described one endemic species, the Mexican golden trout (O. chrysogaster), and one endemic subspecies, Nelson's trout (O. mykiss nelsoni), in Mexico, but previous work indicated that there is vastly more biodiversity in this group than formally described. Here we conducted a comprehensive genetic analysis of this important group of fishes using novel genetic markers and techniques to elucidate the biodiversity of trout inhabiting northwestern Mexico, examine genetic population structure of Mexican trout and their relationships to other species of Pacific trout, and measure introgression from non-native hatchery rainbow trout. We confirmed substantial genetic diversity and extremely strong genetic differentiation present in the Mexican trout complex, not only between basins but also between some locations within basins, with at least four species-level taxa present. We also revealed significant divergence between Mexican trout and other trout species and found that introgression from non-native rainbow trout is present but limited, and that the genetic integrity of native trout is still maintained in most locations. This information will help to guide effective conservation strategies for this important group of fishes. PMID- 26509446 TI - Validation of Reference Genes for Accurate Normalization of Gene Expression in Lilium davidii var. unicolor for Real Time Quantitative PCR. AB - Lilium is an important commercial market flower bulb. qRT-PCR is an extremely important technique to track gene expression levels. The requirement of suitable reference genes for normalization has become increasingly significant and exigent. The expression of internal control genes in living organisms varies considerably under different experimental conditions. For economically important Lilium, only a limited number of reference genes applied in qRT-PCR have been reported to date. In this study, the expression stability of 12 candidate genes including alpha-TUB, beta-TUB, ACT, eIF, GAPDH, UBQ, UBC, 18S, 60S, AP4, FP, and RH2, in a diverse set of 29 samples representing different developmental processes, three stress treatments (cold, heat, and salt) and different organs, has been evaluated. For different organs, the combination of ACT, GAPDH, and UBQ is appropriate whereas ACT together with AP4, or ACT along with GAPDH is suitable for normalization of leaves and scales at different developmental stages, respectively. In leaves, scales and roots under stress treatments, FP, ACT and AP4, respectively showed the most stable expression. This study provides a guide for the selection of a reference gene under different experimental conditions, and will benefit future research on more accurate gene expression studies in a wide variety of Lilium genotypes. PMID- 26509447 TI - Factors Associated with Leaving Hospital against Medical Advice among People Who Use Illicit Drugs in Vancouver, Canada. AB - BACKGROUND: Leaving hospital against medical advice (AMA) is common among people who use illicit drugs (PWUD) and is associated with severe health-related harms and costs. However, little is known about the prevalence of and factors associated with leaving AMA among PWUD. METHODS: Data were collected through two Canadian prospective cohort studies involving PWUD between September 2005 and July 2011 and linked to a hospital admission/discharge database. Bivariable and multivariable generalized estimating equations were used to examine factors associated with leaving hospital AMA among PWUD who were hospitalized. RESULTS: Among 488 participants who experienced at least one hospitalization, 212 (43.4%) left the hospital AMA at least once during the study period. In multivariable analyses, factors positively and significantly associated with leaving hospital AMA included: unstable employment (AOR = 1.92; 95% confidence interval [CI]: 1.22 3.03); recent incarceration (AOR = 1.63; 95%CI: 1.07-2.49); >= daily heroin injection (AOR = 1.49; 95%CI: 1.05-2.11); and younger age per year younger (adjusted odds ratio [AOR] = 1.04; 95%CI: 1.02-1.06). CONCLUSIONS: We found a substantial proportion of PWUD in this setting left hospital AMA and that various markers of risk and vulnerability were associated with this phenomenon. Our findings highlight the need to address substance abuse issues early following hospital admission. These findings further suggest a need to develop novel interventions to minimize PWUD leaving hospital prematurely. PMID- 26509448 TI - EEG-MEG Integration Enhances the Characterization of Functional and Effective Connectivity in the Resting State Network. AB - At the sensor level many aspects, such as spectral power, functional and effective connectivity as well as relative-power-ratio ratio (RPR) and spatial resolution have been comprehensively investigated through both electroencephalography (EEG) and magnetoencephalography (MEG). Despite this, differences between both modalities have not yet been systematically studied by direct comparison. It remains an open question as to whether the integration of EEG and MEG data would improve the information obtained from the above mentioned parameters. Here, EEG (64-channel system) and MEG (275 sensor system) were recorded simultaneously in conditions with eyes open (EO) and eyes closed (EC) in 29 healthy adults. Spectral power, functional and effective connectivity, RPR, and spatial resolution were analyzed at five different frequency bands (delta, theta, alpha, beta and gamma). Networks of functional and effective connectivity were described using a spatial filter approach called the dynamic imaging of coherent sources (DICS) followed by the renormalized partial directed coherence (RPDC). Absolute mean power at the sensor level was significantly higher in EEG than in MEG data in both EO and EC conditions. At the source level, there was a trend towards a better performance of the combined EEG+MEG analysis compared with separate EEG or MEG analyses for the source mean power, functional correlation, effective connectivity for both EO and EC. The network of coherent sources and the spatial resolution were similar for both the EEG and MEG data if they were analyzed separately. Results indicate that the combined approach has several advantages over the separate analyses of both EEG and MEG. Moreover, by a direct comparison of EEG and MEG, EEG was characterized by significantly higher values in all measured parameters in both sensor and source level. All the above conclusions are specific to the resting state task and the specific analysis used in this study to have general conclusion multi-center studies would be helpful. PMID- 26509449 TI - Children Undergoing Radiotherapy: Swedish Parents' Experiences and Suggestions for Improvement. AB - Approximately 300 children, from 0 to 18 years old, are diagnosed with cancer in Sweden every year. Of these children, 80-90 of them undergo radiotherapy treatment for their cancer. Although radiotherapy is an encounter with advanced technology, few studies have investigated the child's and the parent's view of the procedure. As part of an ongoing multicenter study aimed to improve patient preparation and the care environment in pediatric radiotherapy, this article reports the findings from interviews with parents at baseline. The aim of the present study was twofold: to describe parents' experience when their child undergoes radiotherapy treatment, and to report parents' suggestions for improvements during radiotherapy for their children. Sixteen mothers and sixteen fathers of children between 2-16 years old with various cancer diagnoses were interviewed. Data were analyzed using content analysis. The findings showed that cancer and treatment turns people's lives upside down, affecting the entire family. Further, the parents experience the child's suffering and must cope with intense feelings. Radiotherapy treatment includes preparation by skilled and empathetic staff. The parents gradually find that they can deal with the process; and lastly, parents have suggestions for improvements during the radiotherapy treatment. An overarching theme emerged: that despair gradually turns to a sense of security, with a sustained focus on and close interaction with the child. In conclusion, an extreme burden was experienced around the start of radiotherapy, though parents gradually coped with the process. PMID- 26509450 TI - Quantitative CT Imaging of Ventral Hernias: Preliminary Validation of an Anatomical Labeling Protocol. AB - OBJECTIVE: We described and validated a quantitative anatomical labeling protocol for extracting clinically relevant quantitative parameters for ventral hernias (VH) from routine computed tomography (CT) scans. This information was then used to predict the need for mesh bridge closure during ventral hernia repair (VHR). METHODS: A detailed anatomical labeling protocol was proposed to enable quantitative description of VH including shape, location, and surrounding environment (61 scans). Intra- and inter-rater reproducibilities were calculated for labeling on 18 and 10 clinically acquired CT scans, respectively. Preliminary clinical validation was performed by correlating 20 quantitative parameters derived from anatomical labeling with the requirement for mesh bridge closure at surgery (26 scans). Prediction of this clinical endpoint was compared with similar models fit on metrics from the semi-quantitative European Hernia Society Classification for Ventral Hernia (EHSCVH). RESULTS: High labeling reproducibilities were achieved for abdominal walls (+/-2 mm in mean surface distance), key anatomical landmarks (+/-5 mm in point distance), and hernia volumes (0.8 in Cohen's kappa). 9 out of 20 individual quantitative parameters of hernia properties were significantly different between patients who required mesh bridge closure versus those in whom fascial closure was achieved at the time of VHR (p<0.05). Regression models constructed by two to five metrics presented a prediction with 84.6% accuracy for bridge requirement with cross-validation; similar models constructed by EHSCVH variables yielded 76.9% accuracy. SIGNIFICANCE: Reproducibility was acceptable for this first formal presentation of a quantitative image labeling protocol for VH on abdominal CT. Labeling derived metrics presented better prediction of the need for mesh bridge closure than the EHSCVH metrics. This effort is intended as the foundation for future outcomes studies attempting to optimize choice of surgical technique across different anatomical types of VH. PMID- 26509451 TI - Bottom-Up Instructive Quality Control in the Biofabrication of Smart Protein Materials. AB - The impact of cell factory quality control on material properties is a neglected but critical issue in the fabrication of protein biomaterials, which are unique in merging structure and function. The molecular chaperoning of protein conformational status is revealed here as a potent molecular instructor of the macroscopic properties of self-assembling, cell-targeted protein nanoparticles, including biodistribution upon in vivo administration. PMID- 26509452 TI - Morphological and Molecular Characterization of Clinostomum detruncatum (Trematoda: Clinostomidae) Metacercariae Infecting Synbranchus marmoratus. AB - A complete morphological description, supported by molecular data, of Clinostomum detruncatum metacercariae is reported in this study. The metacercariae were found infecting Synbranchus marmoratus from the Parana River, municipality of Guaira, Parana State, Brazil. The taenioidean uterus is the main morphological characteristic of this species. Both neighbor-joining (NJ) and maximum likelihood (ML) trees showed 2 clear separate clusters grouping together the species from the Palearctic region (Clinostomum complanatum, Clinostomum cutaneum, Clinostomum phalacrocoracis, Clinostomum philippinense) and those from the Nearctic/Neotropical regions (Clinostomum marginatum, Clinostomum tataxumui, C. detruncatum, Clinostomum sp. 7). The latter clade is divided into 2 subclades grouping species from North America and Mexico (C. marginatum and C. tataxumui), and those from Brazil (C. detruncatum and Clinostomum sp. 7). PMID- 26509453 TI - [Granulomatosis with polyangiitis - a rare but important differential diagnosis]. AB - Granulomatosis with polyangiitis (GPA) is a rare disease with inflammation in the small vessels. This is a case report of GPA, where lung cancer was initially suspected. A 54-year-old woman eventually developed manifestations from several organ systems, and a diagnosis of GPA was confirmed. Treatment was initiated, but the neurological manifestations proved to be irreversible. This case illustrates that GPA is important to acknowledge, because timely treatment is crucial to reduce mortality and morbidity. PMID- 26509454 TI - [Low dose naltrexone for treatment of pain]. AB - Recent years have seen an increasing interest in the use of low dose naltrexone (LDN) for off-label treatment of pain in diseases as fibromyalgia, multiple sclerosis and morbus Crohn. The evidence is poor, with only few randomized double blind placebo-controlled studies. The studies currently available are reviewed in this paper. LDN could be a potentially useful drug in the future for the treatment of pain in fibromyalgia, but more studies are needed to verify that it is superior to placebo, and currently it cannot be recommended as first-line therapy. PMID- 26509455 TI - [High physical activity is important in chronic obstructive pulmonary disease treatment]. AB - Patients with chronic obstructive pulmonary disease (COPD) have lower activity levels than healthy controls. Loss of skeletal muscle affects COPD negatively, and strengthening of the musculature is probably part of the explanation for the positive effects of physical activity. This review describes the recent literature on restoring and maintaining physical activity in COPD and the importance of maintaining high physical activity levels. Furthermore, the future perspectives for research in COPD, physical activity, and the possible mechanisms for the beneficial effects are discussed. PMID- 26509456 TI - [Severe haemolysis caused by Mycoplasma pneumoniae]. AB - Mycoplasma pneumoniae is naturally resistant to betalactamase antibiotics but is sensitive to macrolides. Occasionally, infections with M. pneumoniae can lead to severe anaemia due to its ability to cause haemolysis when cold agglutination occurs. Increasing bacterial resistance to macrolid antibiotics is a growing concern worldwide. We present two cases where infection with M. pneumoniae caused severe haemolysis, one of which was macrolide-resistant. PMID- 26509457 TI - [Patients with spinal cord injuries experience many sequelae]. AB - Spinal cord injuries (SCI) affect all organs and may cause multiple sequelae. Complications after SCI can be life-threatening and socially disabling. Furthermore, a spinal cord injury is often a chronic condition and the patient may have contact with both the general practitioner and several departments in a hospital. Thus, it is important for all doctors to recognize risks and morbidities related to SCI, in order to prevent and treat the short- and long term complications and disabilities. This article systematically describes the most commonly encountered sequelae after SCI. PMID- 26509458 TI - [Bilateral scleritis and extra-ocular inflammation in a patient with undiagnosed chronic lymphatic leukaemia]. AB - A 55-year-old healthy man presented with redness and pain in both eyes and was diagnosed with bilateral scleritis. A year later impairment of ocular movement and cervical adenopathy appeared. Laboratory tests revealed signs of inflammation: increased erythrocyte sedimentation rate, lymphocytosis, lactate dehydrogenase, S-ACE converting enzyme and interleukin-2-antibody. An orbital MR scan revealed inflammation of the extra-ocular muscles. PET-CT showed vascular changes consistent with vasculitis. Lymph node biopsy confirmed the diagnosis chronic lymphatic leukaemia (CLL). This is a rare case - presentation of bilateral scleritis in a patient with undiagnosed CLL, increased inflammatory markers and vasculitis - a possible ocular manifestation of a paraneoplastic syndrome. PMID- 26509459 TI - Increased prevalence of airway reactivity in children with eosinophilic esophagitis. AB - RATIONALE: Asthma is prevalent in children with eosinophilic esophagitis (EoE) estimated at 24-42% in prior studies versus 9% for the general population. However, pulmonary function and airway hyperresponsiveness (AHR) in children with EoE have not been previously defined. METHODS: A cross-sectional prospective study was conducted of children ages 7-18 years with EoE and healthy controls. Methacholine bronchial challenge and exhaled nitric oxide were assessed. As measures of atopy and immune activation, peripheral blood was analyzed for total IgE, specific IgE to selected aeroallergens, eosinophil count, and serum cytokines including eotaxin. RESULTS: EoE subjects (n = 33) and healthy controls (n = 37) demonstrated similar, normal baseline spirometry. AHR occurred in 33% of children with EoE and 11% of healthy controls (P = 0.04; 95% confidence intervals [19%, 52%] and [4%, 26%], respectively). The majority of EoE subjects with AHR had no prior diagnosis of asthma. Overall, 69.7% of EoE subjects had either asthma or AHR. For EoE subjects, total serum IgE was the only biomarker associated with a greater risk of AHR (OR = 9.643, 95%CI 1.633, 56.925). EoE subjects with and without asthma were similar to healthy controls in mean levels of serum cytokines (IL-5, IL-9, EGF, FGF-2, eotaxin). In exploratory analyses, the subgroup with EoE and asthma without asthma controller therapy had higher mean FGF-2 than EoE subjects without asthma (110 pg/ml vs. 65 pg/ml, P = 0.0426). CONCLUSIONS: Asthma and AHR may be more prevalent than previous estimates in children with EoE. For subjects with EoE, elevation in serum IgE was associated with a greater risk of AHR. PMID- 26509460 TI - The intrinsic cephalosporin resistome of Listeria monocytogenes in the context of stress response, gene regulation, pathogenesis and therapeutics. AB - Intrinsic resistance to antibiotics is a serious therapeutic problem in the case of many bacterial species. The Gram-positive human pathogen Listeria monocytogenes is intrinsically resistant to broad spectrum cephalosporin antibiotics, which are commonly used in therapy of bacterial infections. Besides three penicillin-binding proteins the intrinsic cephalosporin resistome of L. monocytogenes includes multidrug resistance transporter transporters, proteins involved in peptidoglycan biosynthesis and modification, cell envelope proteins with structural or general detoxification function, cytoplasmic proteins with unknown function and regulatory proteins. Analysis of the regulation of the expression of genes involved in the intrinsic resistance of L. monocytogenes to cephalosporins highlights the high complexity of control of the intrinsic resistance phenotype. The regulation of the transcription of the intrinsic resistome determinants involves the activity of eight regulators, namely LisR, CesR, LiaR, VirR, sigma(B) , sigma(H) , sigma(L) and PrfA, of which the most prominent role play LisR, CesR and sigma(B) . Furthermore, the vast majority of the intrinsic resistome determinants contribute to the tolerance of different stress conditions and virulence. A study indicates that O-acetyltransferase OatA is the most promising candidate for co-drug development since an agent targeting OatA should sensitize L. monocytogenes to certain antibiotics, therefore improving the efficacy of listeriosis treatment as well as food preservation measures. PMID- 26509461 TI - Self-Reported Outcomes in Individuals Aged 65 and Older Admitted for Treatment to an Acute Care Surgical Service: A 6-Month Prospective Cohort Study. AB - OBJECTIVES: To examine health-related quality of life (HRQL) and cognitive and functional status before and after emergency surgical care in elderly adults. DESIGN: Six-month prospective cohort study. SETTING: Acute care and emergency surgery service at a single, academic tertiary care center, Edmonton, Alberta, Canada. PARTICIPANTS: Admitted individuals aged 65 and older (mean age 77.8 +/- 7.9, 52% female) or their surrogates. MEASUREMENTS: Abbreviated Mental Test Score 4 (AMTS), Barthel Index, Vulnerable Elders Survey (VES-13), and EuroQol-5 Dimensional Scale (EQ-5D) completed by participants or their surrogates within 24 hours of admission to the hospital and 6 months after discharge. Paired t-tests and McNemar tests were used to assess the difference between baseline and 6 months. RESULTS: One hundred fifty-five consecutive individuals (including 16 surrogates) were enrolled. Sixteen (10%) died within 6 months of discharge, and 116 (75%, including 18 surrogates) completed a follow-up assessment 6 months after discharge. Cognitive status improved substantially over 6 months, with 72 (52%) of participants having AMTS scores showing cognitive impairment at baseline and four (4%) having AMTS scores showing cognitive impairment at 6 months (P < .001). There was no statistically significant change from baseline on the Barthel Index, VES-13, or EQ-5D. CONCLUSION: There was significant cognitive improvement in older adults after surgical hospitalization. HRQL improved back to age-matched population norms. These results suggest that elderly adults admitted for emergency surgery have good cognitive, functional, and HRQL outcomes. PMID- 26509462 TI - HCV Council--critical appraisal of data: recommendations for clinical practice in a rapidly evolving therapeutic landscape. AB - BACKGROUND & AIMS: HCV Council 2014, like its predecessor HCV Council 2011, assembled leading clinicians and researchers in the field of hepatitis C to critically evaluate current data regarding best practices for managing patients with chronic hepatitis C virus (HCV). METHODS: Clinical practice statements were developed that reflect the areas of potential controversy with high clinical impact. Faculty members were responsible for reviewing the literature to support or reject these statements. After a review and comprehensive discussion of the data, the HCV Council faculty voted on the nature of the evidence and the level of support for each statement. RESULTS: The results of the detailed analysis with expert opinion are summarized in this article. CONCLUSION: Numerous questions regarding optimal management of certain populations and clinical scenarios remain unanswered. The discussion in the article provides a summary of evidenced-based expert opinion that may help guide clinicians as additional information is developed. PMID- 26509463 TI - Quantification and regulation of the adipokines resistin and progranulin in human cerebrospinal fluid. AB - BACKGROUND: Adipokines bearing the potential to cross the blood-brain barrier (BBB) are promising candidates for the endocrine regulation of central nervous processes and of a postulated fat-brain axis. Resistin and progranulin concentrations in paired serum and cerebrospinal fluid (CSF) samples of patients undergoing neurological evaluation and spinal puncture were investigated. MATERIALS AND METHODS: Samples of n = 270 consecutive patients with various neurological diseases were collected without prior selection. Adipokine serum and CSF concentrations were measured by enzyme-linked immunosorbent assay and serum and CSF routine parameters by standard procedures. Anthropometric data, medication and patient history were available. RESULTS: Serum levels of resistin and progranulin were positively correlated among each other, with respective CSF levels, low-density lipoprotein cholesterol levels and markers of systemic inflammation. CSF resistin concentrations were generally low. Progranulin CSF concentrations and CSF/serum progranulin ratio were significantly higher in patients with infectious diseases, with disturbed BBB function and with elevated CSF cell count and presence of oligoclonal bands. Both adipokines are able to cross the BBB depending on a differing patency that increases with increasing grade of barrier dysfunction. Whereas resistin represents a systemic marker of inflammation, CSF progranulin levels strongly depend on the underlying disease and dysfunction of blood-CSF barrier. CONCLUSIONS: Resistin and progranulin represent novel and putative regulators of the fat-brain axis by their ability to cross the BBB under physiological and pathophysiological conditions. The presented data provide insight into the characteristics of BBB function regarding progranulin and resistin and the basis for future establishment of normal values for CSF concentrations and CSF/serum ratios. PMID- 26509464 TI - Use of a new model allowing controlled uniaxial loading to evaluate tendon healing in a bone tunnel. AB - The optimal mechanical loading regimen for the healing of a tendon graft in a bone tunnel is unknown. We developed a rat model that directly tensions a healing tendon graft, without the use of confounding joint motion. Fifty cycles of either 0, 3, or 6 N of tension were applied to groups daily for 3 or 6 weeks. At 3 weeks the low load (3 N) group had the highest failure load (p = 0.009), but by 6 weeks there were no differences in failure load among groups. At 3 weeks the high load (6 N) group had greater osteoclast activity compared to the immobilized (0 N) group (p < 0.05), and by 6 weeks there were significantly more osteoclasts in the high load group compared to the low load group (p = 0.01). Bone volume fraction was higher in the immobilized group compared to the 3 N load group at 3 weeks (p = 0.014) and 6 weeks (p = 0.007). At 6 weeks, the immobilized group had greater trabecular number compared to both loading groups (p < 0.05). In conclusion, low magnitude loading had a beneficial early effect but continued loading led to poorer new bone formation over time and no beneficial effect at 6 weeks, perhaps due to delayed maturation from cumulative loads. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:852-859, 2016. PMID- 26509468 TI - Derivation of a clinical prediction score for chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. AB - Essentials Predicting chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism is hard. We studied 772 patients with pulmonary embolism who were followed for CTEPH (incidence 2.8%). Logistic regression analysis revealed 7 easily collectable clinical variables that combined predict CTEPH. Our score identifies patients at low (0.38%) or higher (10%) risk of CTEPH. SUMMARY: Introduction Validated risk factors for the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism (PE) are currently lacking. Methods This is a post hoc patient-level analysis of three large prospective cohorts with a total of 772 consecutive patients with acute PE, without major cardiopulmonary or malignant comorbidities. All underwent echocardiography after a median of 1.5 years. In cases with signs of pulmonary hypertension, additional diagnostic tests to confirm CTEPH were performed. Baseline demographics and clinical characteristics of the acute PE event were included in a multivariable regression analysis. Independent predictors were combined in a clinical prediction score. Results CTEPH was confirmed in 22 patients (2.8%) by right heart catheterization. Unprovoked PE, known hypothyroidism, symptom onset > 2 weeks before PE diagnosis, right ventricular dysfunction on computed tomography or echocardiography, known diabetes mellitus and thrombolytic therapy or embolectomy were independently associated with a CTEPH diagnosis during follow-up. The area under the receiver operating charateristic curve (AUC) of the prediction score including those six variables was 0.89 (95% confidence interval [CI] 0.84-0.94). Sensitivity analysis and bootstrap internal validation confirmed this AUC. Seventy-three per cent of patients were in the low-risk category (CTEPH incidence of 0.38%, 95% CI 0-1.5%) and 27% were in the high-risk category (CTEPH incidence of 10%, 95% CI 6.5-15%). Conclusion The 'CTEPH prediction score' allows for the identification of PE patients with a high risk of CTEPH diagnosis after PE. If externally validated, the score may guide targeting of CTEPH screening to at-risk patients. PMID- 26509469 TI - Matrix metalloproteinases as promising regulators of axonal regrowth in the injured adult zebrafish retinotectal system. AB - Overcoming the failure of axon regeneration in the mammalian central nervous system (CNS) after injury remains a major challenge, which makes the search for proregenerative molecules essential. Matrix metalloproteinases (MMPs) have been implicated in axonal outgrowth during CNS development and show increased expression levels during vertebrate CNS repair. In mammals, MMPs are believed to alter the suppressive extracellular matrix to become more permissive for axon regrowth. We investigated the role of MMPs in axonal regeneration following optic nerve crush (ONC) in adult zebrafish, which fully recover from such injuries due to a high intrinsic axon growth capacity and a less inhibitory environment. Lowering general retinal MMP activity through intravitreal injections of GM6001 after ONC strongly reduced retinal ganglion cell (RGC) axonal regrowth, without influencing RGC survival. Based on a recently performed transcriptome profiling study, the expression pattern of four MMPs after ONC was determined via combined use of western blotting and immunostainings. Mmp-2 and -13a were increasingly present in RGC somata during axonal regrowth. Moreover, Mmp-2 and -9 became upregulated in regrowing RGC axons and inner plexiform layer (IPL) synapses, respectively. In contrast, after an initial rise in IPL neurites and RGC axons during the injury response, Mmp-14 expression decreased during regeneration. Altogether, a phase-dependent expression pattern for each specific MMP was observed, implicating them in axonal regrowth and inner retina remodeling after injury. In conclusion, these data suggest a novel, neuron-intrinsic function for multiple MMPs in axon regrowth that is distinct from breaking down environmental barriers. J. Comp. Neurol. 524:1472-1493, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26509470 TI - Early Effect of Bariatric Surgery on the Circadian Rhythms of Adipokines in Morbidly Obese Women. AB - BACKGROUND: The circadian pattern of adipokines is blunted in obese subjects, and we tested the hypothesis that bariatric surgery could normalize the 24-hr pattern of adipokines. Therefore, this study was designed to examine the early impact of the newly designed sleeve gastrectomy with transit bipartition (SGTB) surgery on the circadian pattern of leptin, adiponectin, and resistin in morbidly obese subjects. METHODS: The study group included six morbidly obese women [body mass index (BMI) 41.3 +/- 1.53 kg/m(2)] who underwent SGTB and four lean women (BMI 18.61 +/- 0.92 kg/m(2)). Blood from all subjects was collected before and 3 months after bariatric surgery every 6 hr throughout the 24-hr period. The circadian pattern of leptin, adiponectin, and resistin was measured by enzyme linked immunosorbent assay or Luminex techniques. RESULTS: Lean women exhibited rise of plasma leptin levels at nighttime, whereas obese women had an increase in the overall plasma leptin levels throughout the 24-hr period, lacking the physiological rise of nocturnal leptin levels compared to controls. Obese women had a decrease in 24-hr adiponectin levels and similar plasma resistin levels compared to controls. Three months after SGTB, obese women lost 16.0% (P < 0.005) of their initial body weight and had a decrease in overall 24-hr leptin levels. However, there was no recovery of the nocturnal rise in leptin levels 3 months after SGTB. The 24-hr adiponectin levels were still decreased after SGTB surgery compared to controls, while resistin levels were decreased only during night time after SGTB. CONCLUSIONS: These results suggested that SGTB is an efficient innovative procedure to rapidly decrease 24-hr leptin levels. However, after 3 months, SGTB was not enough to recover the physiological nocturnal rise of leptin levels present in lean subjects. PMID- 26509471 TI - One-pot one-cluster synthesis of fluorescent and bio-compatible Ag14 nanoclusters for cancer cell imaging. AB - Small-molecule-protected silver nanoclusters have smaller hydrodynamic diameter, and thus may hold greater potential in biomedicine application compared with the same core-sized, macromolecule (i.e. DNA)-protected silver nanoclusters. However, the live cell imaging labeled by small-molecule-protected silver nanoclusters has not been reported until now, and the synthesis and atom-precise characterization of silver nanoclusters have been challenging for a long time. We develop a one pot one-cluster synthesis method to prepare silver nanoclusters capped with GSH which is bio-compatible. The as-prepared silver nanoclusters are identified to be Ag14(SG)11 (abbreviated as Ag14, SG: glutathione) by isotope-resolvable ESI-MS. The structure is probed by 1D NMR spectroscopy together with 2D COSY and HSQC. This cluster species is fluorescent and the fluorescence quantum yield is solvent dependent. Very importantly, Ag14 was successfully applied to label lung cancer cells (A549) for imaging, and this work represents the first attempt to image live cells with small-molecule-protected silver nanoclusters. Furthermore, it is revealed that the Ag14 nanoclusters exhibit lower cytotoxicity compared with some other silver species (including silver salt, silver complex and large silver nanoparticles), and the explanation is also provided. The comparison of silver nanoclusters to state-of-the-art labeling materials in terms of cytotoxicity and photobleaching lifetime is also conducted. PMID- 26509472 TI - [Impact of Microsurgical Exstirpation of Vestibular Schwannomas on the Sense of Taste]. AB - Patients with single sided vestibular schwannoma may report about a taste dysfunction apart from the well known cardinal symptoms. Very few data are published so far on that topic. The aim of this study was to investigate the influence of microsurgery for vestibular schwannomas on taste perception prospectively using a well validated taste test. 25 patients could be included in the study. No ageusia was claimed by the patients. In average a decrease of the taste score postoperatively could be detected on the tumor as well as on the non treated side. The differences were not statistically significant. But a subgroup of 1/4 of the subjects revealed a new onset of side difference in the taste score that was not present before surgery. In all those cases the treated side showed a clinically significant reduced taste score of 6,2 in average. Within this subgroup the temporal access was overpresented in contrast to the whole group. This may indicate an influence of the choosen approach and that for the position of the tumor to the change of the taste score. The observations should be verified on a greater collective. PMID- 26509473 TI - Quantitative Computed Tomography Measurement of Tracheal Cross-Sectional Areas in Relapsing Polychondritis: Correlations with Spirometric Values. AB - BACKGROUND: Although tracheal stenosis occurs in relapsing polychondritis (RP), no studies exist that have clarified correlations between quantitative airway measurement and spirometry in RP patients. OBJECTIVES: The aim of this study was to investigate correlations between the cross-sectional area (CSA) of the trachea and spirometric values in patients with RP. METHODS: The institutional review board approved this retrospective study, and written informed consent was waived. Twenty-six patients with RP underwent spirometry and chest computed tomography (CT) at full inspiration and end-expiration. On inspiratory and expiratory chest CT images, CSA at the intrathoracic trachea was measured for all CT slices, and the mean and minimum tracheal CSA were obtained. Correlations between the tracheal CSA and spirometric values were assessed by Spearman's rank correlation analysis. Results: Tracheal CSA measurements for inspiratory and expiratory scans were significantly correlated with FEV 1 , FEV 25-75% , and peak flow values (rho = 0.51-0.86, p <0.01). During each inspiratory or expiratory phase, the minimum tracheal CSA achieved a higher correlation coefficient with spirometric values than the mean CSA. CONCLUSION: Tracheal dimensions for both inspiratory and expiratory CT are significant predictors of pulmonary function in patients with RP. The narrowest tracheal dimension likely determines the severity of airflow limitation in RP. PMID- 26509474 TI - Skidding at Speed: The Ethics of Head Protection While Skiing. PMID- 26509475 TI - MRI properties of a unique hypo-intense layer in degraded articular cartilage. AB - To investigate the characteristics of a hypo-intense laminar appearance in articular cartilage under external loading, microscopic magnetic resonance imaging (MUMRI) T1, T2 and T1rho experiments of a total of 15 specimens of healthy and trypsin-degraded cartilage were performed at different soaking solutions (saline and 100 mM phosphate buffered saline (PBS)). T2 and T1rho images of the healthy tissue in saline showed no load-induced laminar appearance, while a hypo-intense layer was clearly visible in the deep part of the degraded tissue at the magic angle. A significant difference was found between T2 values at 0 degrees and 55 degrees (from 16.5 +/- 2.8 ms to 20.2 +/- 2.7 ms, p = 0.0005), and at 0 degrees and 90 degrees (16.5 +/- 2.8 ms to 21.3 +/- 2.6 ms, p < 0.0001) in saline solution. In contrast, this hypo-intense laminar appearance largely disappeared when tissue was soaked in PBS. The visualization of this hypo-intensity appearance in different soaking mediums calls for caution in interpreting the data of relaxation times, chemical exchange and collagen fiber deformation. PMID- 26509476 TI - Simple, rapid detection of influenza A (H1N1) viruses using a highly sensitive peptide-based molecular beacon. AB - A peptide-based molecular beacon (PEP-MB) was prepared for the simple, rapid, and specific detection of H1N1 viruses using a fluorescence resonance energy transfer (FRET) system. The PEP-MB exhibited minimal fluorescence in its "closed" hairpin structure. However, in the presence of H1N1 viruses, the specific recognition of the hemagglutinin (HA) protein of H1 strains by the PEP-MB causes the beacon to assume an "open" structure that emits strong fluorescence. The PEP-MB could detect H1N1 viruses within 15 min or even 5 min and can exhibit strong fluorescence even at low viral concentrations, with a detection limit of 4 copies. PMID- 26509477 TI - Does Decreasing Variability Affect Quality? PMID- 26509478 TI - Rh-Catalyzed Synthesis of Coumarin Derivatives from Phenolic Acetates and Acrylates via C-H Bond Activation. AB - An efficient annulation strategy involving the reaction of phenolic acetates with acrylates in the presence of [Rh2(OAc)4] as catalyst and formic acid as reducing agent, leading to the high yield synthesis of coumarin derivatives, has been developed. The addition of NaOAc as a base increased the yield of the products. The reaction is quite successful for both electron-rich as well as electron deficient phenolic acetates, affording coumarins with excellent regioselectivity, and proceeds via C-H bond activation proven by deuterium incorporation studies. PMID- 26509479 TI - Engineering DNA Three-Way Junction with Multifunctional Moieties: Sensing Platform for Bioanalysis. AB - Functionalization of DNA nanostructures is critical to the achievement of the application in biosensors. Herein, we demonstrate a novel DNA three-way junction (TWJ) with three functional moieties, which integrates the electrochemical, fluorescent, and colorimetric properties. Upon addition of external stimuli, including DNA, thrombin, and ATP, the specific interactions between targets and sensing elements could induce strand displacement reaction and conformation transformation, resulting in the integration of G-quadruplex/hemin complex as electrochemical probe, lighting up the fluorescence of DNA/Ag nanoclusters and enhancing the catalytic activity of DNAzyme to catalyze the H2O2-TMB system to generate colorimetric signal. Such a functional DNA nanostructure actually serves as a biosensing platform, showing high sensitivity and selectivity for DNA, thrombin, and ATP detection. Furthermore, We also show that this novel sensing platform can be utilized to detect three different kinds of targets independently and simultaneously. Our integrated concept provides a paradigm for exploring the potential of TWJs in analytical applications. PMID- 26509480 TI - Interplay of experiment and theory: high resolution infrared spectrum and accurate equilibrium structure of BF2OH. AB - The high-resolution Fourier transform infrared (FTIR) spectrum of (11)BF2OH (difluoroboric acid) is analyzed taking into account numerous interactions. The nu1, nu2 and nu3 infrared bands are analyzed for the first time, whereas the parameters of the 6(1), 7(1), 8(1) and 9(1) states and for the 4(1) and 9(2) interacting states are redetermined. These results are used to check the quality of the ab initio force field. It is found that the ab initio rovibrational corrections are more accurate than the experimental ones. An earlier attempt to determine a semiexperimental structure did not allow us to obtain an accurate equilibrium structure. The reasons of this failure are investigated. This failure was mainly due to the lack of useful experimental information. Indeed, there is no isotopic substitution available for the fluorine atoms, and the boron atom is extremely close to the center of mass. Furthermore, the available isotopic substitutions (H -> D and (16)O -> (18)O) induce a large rotation of the principal axis system which amplifies the errors. However, the mixed estimation method has allowed us to determine a complete and reliable equilibrium structure. Thanks to this method, it is possible to determine an accurate structure, even in extremely difficult cases. An extensive analysis of the quality of structure calculations at the CCSD(T) level is also performed using basis sets up to five zeta quality. It was found that, at the convergence limit, the effects of the diffuse functions are practically disappearing, whereas the core-core and core valence electron correlation effects are quite important for the bond lengths. PMID- 26509481 TI - Rationality in Human Movement. AB - It long has been appreciated that humans behave irrationally in economic decisions under risk: they fail to objectively consider uncertainty, costs, and rewards and instead exhibit risk-seeking or risk-averse behavior. We hypothesize that poor estimates of motor variability (influenced by motor task) and distorted probability weighting (influenced by relevant emotional processes) contribute to characteristic irrationality in human movement decisions. PMID- 26509482 TI - Soleus Muscle as a Surrogate for Health Status in Human Heart Failure. AB - We propose the hypothesis that soleus muscle function may provide a surrogate measure of functional capacity in patients with heart failure. We summarize literature pertaining to skeletal muscle as a locus of fatigue and present our recent findings, using in vivo imaging in combination with biomechanical experimentation and modeling, to reveal novel structure-function relationships in chronic heart failure skeletal muscle and gait. PMID- 26509483 TI - Exercise-Mediated Effects on White and Brown Adipose Tissue Plasticity and Metabolism. AB - Exercise training increases the thermogenic capacity of white adipose tissue (WAT), an effect known as "browning" of the WAT. Here, we discuss how this affects whole-body energy homeostasis. We put forth the hypothesis that browning of the subcutaneous WAT allows the organism to adjust its metabolic rate according to energy availability while coping with increased heat production through exercise. PMID- 26509484 TI - The Vascular Endothelium in Chronic Kidney Disease: A Novel Target for Aerobic Exercise. AB - Endothelial dysfunction occurs in chronic kidney disease (CKD) and increases the risk for cardiovascular disease. The mechanisms of endothelial dysfunction seem to evolve throughout kidney disease progression, culminating in reduced L arginine transport and impaired nitric oxide bioavailability in advanced disease. This review examines the hypothesis that aerobic exercise may reverse endothelial dysfunction by improving endothelial cell L-arginine uptake in CKD. PMID- 26509485 TI - Analgesic Drugs Alter Connective Tissue Remodeling and Mechanical Properties. AB - Exercising individuals commonly consume analgesics, but these medications alter tendon and skeletal muscle connective tissue properties, possibly limiting a person from realizing the full benefits of exercise training. I detail the novel hypothesis that analgesic medications alter connective tissue structure and mechanical properties by modifying fibroblast production of growth factors and matrix enzymes, which are responsible for extracellular matrix remodeling. PMID- 26509487 TI - Error in Calculating Main Outcome in Gamma Ventral Capsulotomy for Obsessive Compulsive Disorder Randomized Clinical Trial. PMID- 26509488 TI - Relative Magnitude and Controls of in Situ N2 and N2O Fluxes due to Denitrification in Natural and Seminatural Terrestrial Ecosystems Using (15)N Tracers. AB - Denitrification is the most uncertain component of the nitrogen (N) cycle, hampering our ability to assess its contribution to reactive N (Nr) removal. This uncertainty emanates from the difficulty in measuring in situ soil N2 production and from the high spatiotemporal variability of the process itself. In situ denitrification was measured monthly between April 2013 and October 2014 in natural (organic and forest) and seminatural ecosystems (semi-improved and improved grasslands) in two UK catchments. Using the (15)N-gas flux method with low additions of (15)NO3(-) tracer, a minimum detectable flux rate of 4 MUg N m( 2) h(-1) and 0.2 ng N m(-2) h(-1) for N2 and N2O, respectively, was achieved. Denitrification rates were lower in organic and forest (8 and 10 kg N ha(-1) y( 1), respectively) than in semi-improved and improved grassland soils (13 and 25 kg N ha(-1) y(-1), respectively). The ratio of N2O/N2 + N2O was low and ranged from <1% to 7% across the sites. Variation in denitrification was driven by differences in soil respiration, nitrate, C:N ratio, bulk density, moisture, and pH across the sites. Overall, the contribution of denitrification to Nr removal in natural ecosystems was ~50% of the annual atmospheric Nr deposition, making these ecosystems vulnerable to chronic N saturation. PMID- 26509489 TI - Osteopontin Promotes Invasion, Migration and Epithelial-Mesenchymal Transition of Human Endometrial Carcinoma Cell HEC-1A Through AKT and ERK1/2 Signaling. AB - BACKGROUND/AIMS: Osteopontin (OPN) is an Extracellular Matrix (ECM) molecule and is involved in many physiologic and pathologic processes, including cell adhesion, angiogenesis and tumor metastasis. OPN is a well-known multifunctional factor involved in various aspects of cancer progression, including endometrial cancer. In this study, we examined the significance of OPN in endometrial cancer. METHODS: The proliferation, migration and invasion ability of HEC-1A cells were detected by Cell Counting Kit-8 (CCK-8), Wound scratch assay and transwell. Western blots were employed to detect the expression of Matrix metalloproteinase 2 (MMP-2) and epithelial-mesenchymal transition (EMT)-related factors in HEC-1A cells treated with rhOPN. RESULTS: rhOPN promotes cell proliferation, migration and invasion in HEC-1A cells. rhOPN influenced EMT-related factors and MMP-2 expression in HEC-1A cells. rhOPN promoted HEC-1A cells migration, invasion and EMT through protein kinase B (PKB/AKT) and Extracellular regulated protein kinases (ERK1/2) signaling pathway. CONCLUSIONS: These results may open up a novel therapeutic strategy for endometrial cancer: namely, rhOPN have important roles in controlling growth of endometrial of cancer cells and suggest a novel target pathway for treatment of this cancer. PMID- 26509490 TI - Is Leg Ulceration a Defending Mechanism against Toxic Iron Accumulation. PMID- 26509491 TI - Insight into the Supramolecular Architecture of Intact Diatom Biosilica from DNP Supported Solid-State NMR Spectroscopy. AB - Diatom biosilica is an inorganic/organic hybrid with interesting properties. The molecular architecture of the organic material at the atomic and nanometer scale has so far remained unknown, in particular for intact biosilica. A DNP-supported ssNMR approach assisted by microscopy, MS, and MD simulations was applied to study the structural organization of intact biosilica. For the first time, the secondary structure elements of tightly biosilica-associated native proteins in diatom biosilica were characterized in situ. Our data suggest that these proteins are rich in a limited set of amino acids and adopt a mixture of random-coil and beta-strand conformations. Furthermore, biosilica-associated long-chain polyamines and carbohydrates were characterized, thereby leading to a model for the supramolecular organization of intact biosilica. PMID- 26509492 TI - How Structure-Directing Agents Control Nanocrystal Shape: Polyvinylpyrrolidone Mediated Growth of Ag Nanocubes. AB - The importance of structure-directing agents (SDAs) in the shape-selective synthesis of colloidal nanostructures has been well documented. However, the mechanisms by which SDAs actuate shape control are poorly understood. In the polyvinylpyrrolidone (PVP)-mediated growth of {100}-faceted Ag nanocrystals, this capability has been attributed to preferential binding of PVP to Ag(100). We use molecular dynamics simulations to probe the mechanisms by which Ag atoms add to Ag(100) and Ag(111) in ethylene glycol solution with PVP. We find that PVP induces kinetic Ag nanocrystal shapes by regulating the relative Ag fluxes to these facets. Stronger PVP binding to Ag(100) leads to a larger Ag flux to Ag(111) and cubic nanostructures through two mechanisms: enhanced Ag trapping by more extended PVP films on Ag(111) and a reduced free-energy barrier for Ag to cross lower-density films on Ag(111). These flux-regulating capabilities depend on PVP concentration and chain length, consistent with experiment. PMID- 26509493 TI - Use of a simple, inexpensive device for collection of blood during acute normovolaemic haemodilution in a Jehovah's Witness patient. AB - Postoperative anaemia is a concern for patients who refuse blood products or have rare blood types. Acute normovolaemic haemodilution (ANH) is a potential solution for these challenging populations. However, protocols for ANH provide limited detail on preparation of blood collection systems. This report describes a novel protocol for ANH and an example of a patient who clearly benefited from ANH. PMID- 26509495 TI - Stretchable Si Logic Devices with Graphene Interconnects. AB - Stretchable integrated circuits consisting of ultrathin Si transistors connected by multilayer graphene are demonstrated. Graphene interconnects act as an effective countervailing component to maintain the electrical performance of Si integrated circuits against external strain. Concentration of the applied strain on the graphene interconnect parts can stably protect the Si active devices against applied strains over 10%. PMID- 26509496 TI - Phytotoxicity of umbelliferone and its analogs: Structure-activity relationships and action mechanisms. AB - Two coumarins, umbelliferone and daphnoretin, were isolated from roots of Stellera chamaejasme L; the former had been identified as one of the main allelochemicals in our previous studies. Both of them have the skeleton of 7 hydroxycoumarin, but showed different phytotoxic effects. Umbelliferone and its analogs were then prepared to investigate the structure-activity relationship of hydroxycoumarins and screened for phytotoxicity. The inhibitory effects varied observably in response to the coumarin derivatives, especially umbelliferone (1), 7-hydroxy-4-methylcoumarin (3) and coumarin (10) displayed strong inhibition of lettuce and two field weeds, Setaria viridis and Amaranthus retroflexus, and compounds 11 and 12 also exhibited phytotoxic activity with species specificity. The number and location of hydroxyl groups were importantly responsible for the phytotoxicity. A C7 hydroxyl group was considered to be a potentially active site and methyl substitution at the C4 position contributed significantly to the activity. The phytotoxic mechanism was briefly studied with umbelliferone by evaluating the reactive oxygen species (ROS) and chlorophylls level in lettuce seedlings. The results showed that umbelliferone induced the accumulation of ROS in the root tip and significantly decreased the chlorophyll content in the leaves. Thus, a ROS-mediated regulation pathway and the inhibition of photosynthesis were definitely involved in the phytotoxicity of umbelliferone. PMID- 26509497 TI - Overcoming seed dormancy using gibberellic acid and the performance of young Syagrus coronata plants under severe drought stress and recovery. AB - Syagrus coronata, a native palm tree of the Brazilian semi-arid region, exhibits low germinability due to seed dormancy. This study aimed to increase the germinability, analyze the morphology of seedlings and evaluate the performance of young plants under a water deficit. We used immersion in water and gibberellic acid (GA3) as pyrene (seed with endocarp) pre-germination treatments, and we analyzed the water relations, gas exchange, chlorophyll fluorescence and carbon balance components of young plants under drought and rehydration conditions. The immersion of pyrenes in 0.3 mM GA3 solution for 24 h enhanced the emergence and survival of plants and the emergence rate index. The germination of S. coronata is of the remote tubular type, and seedling growth originates with the protrusion of the cotyledon petiole, followed by the subsequent emergence of the root, leaf sheaths and eophyll. The plants exhibited high tolerance to no irrigation for 37 days, which was attributed to strong stomatal control, a higher proportion of energy dissipation and a higher content of photoprotective pigments. Despite the reduced stomatal conductance (regardless of soil water availability), the photosynthetic rate remained high throughout the day, which indicated a low correlation between these two parameters. After rehydration, we observed that both the leaf water content and photosynthesis recovered, which showed an absence of irreversible damage of the photosynthetic apparatus. The use of 0.3 mM GA3 is recommended as a treatment for overcoming seed dormancy in this species. Young S. coronata plants showed high tolerance during drought and resilience after rehydration by adjusting their leaf metabolism, which could explain the endemism of this species in semi-arid regions and its ability to remain evergreen throughout the year. Furthermore, with high photosynthetic rate in the most favorable time of day, even under drought stress. PMID- 26509498 TI - Lead Toxicity Risks in Gunshot Victims. AB - BACKGROUND: Gunshot wounds require surgeons to decide whether to remove or leave bullet fragments in the body. Surgeons also decide how to follow up with patients who have lead fragments retained in their body. Current literature recommends to remove only intra-articular fragments without the need for a follow-up for patients with the metal retained. Therefore, this study investigates chronic lead toxicity for gunshot wounds. METHODS: The study was performed in the metropolitan area of Rio de Janeiro/Brazil, between 2013 and 2015. It was a case-control study that included 45 victims of gunshot lesions with metallic fragments retained for more than 6 months. The 45 controls were matched for gender, age, and race. We compared the lead blood levels and frequency of symptoms. RESULTS: The control group had average blood lead levels of 2.17 MUg/dL (95% Confidence Interval [CI]; 1.71-2.63) and median 2.1 MUg/dL. The case group had average values of 9.01 MUg/dL (CI; 6.07-11.96) and median values of 6.5 MUg/dL with p-values < = 0.001. The case group reported the following more frequently: irritancy, bad mood, headache, memory losses, daylight drowsiness, myalgia, weakness, abdominal pain, joint pain, trembling, tingling limbs. There was statistical significance for the differences of symptoms frequencies and for odds ratio between groups. CONCLUSIONS: Although the mean lead levels found were lower than the current laboratory references, low levels have been associated with both rising morbidity and mortality. The WHO stated: "There is no known level of lead exposure that is considered safe". In conclusion, this work showed that bullets retained in the body are not innocuous. There are impacts in the blood lead levels and symptoms related to it, even with few fragments, extra-articular located or existing with low blood lead levels. PMID- 26509499 TI - Role of (p)ppGpp in Viability and Biofilm Formation of Actinobacillus pleuropneumoniae S8. AB - Actinobacillus pleuropneumoniae is a Gram-negative bacterium and the cause of porcine pleuropneumonia. When the bacterium encounters nutritional starvation, the relA-dependent (p)ppGpp-mediated stringent response is activated. The modified nucleotides guanosine 5'-diphosphate 3'-diphosphate (ppGpp) and guanosine 5'-triphosphate 3'-diphosphate (pppGpp) are known to be signaling molecules in other prokaryotes. Here, to investigate the role of (p)ppGpp in A. pleuropneumoniae, we created a mutant A. pleuropneumoniae strain, S8DeltarelA, which lacks the (p)ppGpp-synthesizing enzyme RelA, and investigated its phenotype in vitro. S8DeltarelA did not survive after stationary phase (starvation condition) and grew exclusively as non-extended cells. Compared to the wild-type (WT) strain, the S8DeltarelA mutant had an increased ability to form a biofilm. Transcriptional profiles of early stationary phase cultures revealed that a total of 405 bacterial genes were differentially expressed (including 380 up-regulated and 25 down-regulated genes) in S8DeltarelA as compared with the WT strain. Most of the up-regulated genes are involved in ribosomal structure and biogenesis, amino acid transport and metabolism, translation cell wall/membrane/envelope biogenesis. The data indicate that (p)ppGpp coordinates the growth, viability, morphology, biofilm formation and metabolic ability of A. pleuropneumoniae in starvation conditions. Furthermore, S8DeltarelA could not use certain sugars nor produce urease which has been associated with the virulence of A. pleuropneumoniae, suggesting that (p)ppGpp may directly or indirectly affect the pathogenesis of A. pleuropneumoniae during the infection process. In summary, (p)ppGpp signaling represents an essential component of the regulatory network governing stress adaptation and virulence in A. pleuropneumoniae. PMID- 26509501 TI - Correction: Site-Directed Mutagenesis of a Hyperthermophilic Endoglucanase Cel12B from Thermotoga maritima Based on Rational Design. PMID- 26509500 TI - Delineating the Tes Interaction Site in Zyxin and Studying Cellular Effects of Its Disruption. AB - Focal adhesions are integrin-based structures that link the actin cytoskeleton and the extracellular matrix. They play an important role in various cellular functions such as cell signaling, cell motility and cell shape. To ensure and fine tune these different cellular functions, adhesions are regulated by a large number of proteins. The LIM domain protein zyxin localizes to focal adhesions where it participates in the regulation of the actin cytoskeleton. Because of its interactions with a variety of binding partners, zyxin has been proposed to act as a molecular scaffold. Here, we studied the interaction of zyxin with such a partner: Tes. Similar to zyxin, Tes harbors three highly conserved LIM domains of which the LIM1 domain directly interacts with zyxin. Using different zyxin variants in pull-down assays and ectopic recruitment experiments, we identified the Tes binding site in zyxin and showed that four highly conserved amino acids are crucial for its interaction with Tes. Based upon these findings, we used a zyxin mutant defective in Tes-binding to assess the functional consequences of abrogating the zyxin-Tes interaction in focal adhesions. Performing fluorescence recovery after photobleaching, we showed that zyxin recruits Tes to focal adhesions and modulates its turnover in these structures. However, we also provide evidence for zyxin-independent localization of Tes to focal adhesions. Zyxin increases focal adhesion numbers and reduces focal adhesion lifetimes, but does so independent of Tes. Quantitative analysis showed that the loss of interaction between zyxin and Tes affects the process of cell spreading. We conclude that zyxin influences focal adhesion dynamics, that it recruits Tes and that this interaction is functional in regulating cell spreading. PMID- 26509502 TI - The Efficacy and Safety of the Probiotic Bacterium Lactobacillus reuteri DSM 17938 for Infantile Colic: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: To evaluate the efficacy and safety of Lactobacillus reuteri DSM 17938 for treating infantile colic. METHODS: A systematic literature retrieval was carried out to obtain randomized controlled trials of L. reuteri DSM 17938 for infantile colic. Trials were performed before May 2015 and retrieved from the PubMed, EMBASE, Cochrane library, CNKI, WanFang, VIP, and CBM databases. Data extraction and quality evaluation of the trials were performed independently by two investigators. A meta-analysis was performed using STATA version 12.0. RESULTS: Six randomized controlled trials of 423 infants with colic were included. Of these subjects, 213 were in the L. reuteri group, and 210 were in the placebo group. Lactobacillus reuteri increased colic treatment effectiveness at two weeks (RR = 2.84; 95% CI: 1.24-6.50; p = 0.014) and three weeks (relative risk [RR] = 2.33; 95% CI: 1.38-3.93; P = 0.002) but not at four weeks (RR = 1.41; 95% CI: 0.52-3.82; P = 0.498). Lactobacillus reuteri decreased crying time (min/d) at two weeks (weighted mean difference [WMD] = -42.89; 95% CI: -60.50 to 25.29; P = 0.000) and three weeks (WMD = -45.83; 95% CI: -59.45 to -32.21; P = 0.000). In addition, L. reuteri did not influence infants' weight, length or head circumference and was not associated with serious adverse events. CONCLUSIONS: Lactobacillus reuteri possibly increased the effectiveness of treatment for infantile colic and decreased crying time at two to three weeks without causing adverse events. However, these protective roles are usurped by gradual physiological improvements. The study is limited by the heterogeneity of the trials and should be considered with caution. Higher quality, multicenter randomized controlled trials with larger samples are needed. PMID- 26509503 TI - Seeing Inscriptions on the Shroud of Turin: The Role of Psychological Influences in the Perception of Writing. AB - The Shroud of Turin (hereafter the Shroud) is one of the most widely known and widely studied artifacts in existence, with enormous historical and religious significance. For years, the Shroud has inspired worldwide interest in images on its fabric which appear to be of the body and face of a man executed in a manner consistent with crucifixion, and many believe that these images were formed in the Shroud's fibers during the Resurrection of Jesus of Nazareth. But, more recently, other reports have suggested that the Shroud also contains evidence of inscriptions, and these reports have been used to add crucial support to the view that the Shroud is the burial cloth of Jesus. Unfortunately, these reports of inscriptions are based on marks that are barely visible on the Shroud, even when images are enhanced, and the actual existence of writing on the Shroud is still a matter of considerable debate. Here we discuss previous evidence concerning the psychological processes involved generally in the perception of writing, and especially when letters and words are indistinct. We then report two experiments in which the influence of religious context on perception of inscriptions was addressed specifically, using an image of woven fabric (modern linen) containing no writing and with no religious provenance. This image was viewed in two different contexts: in the Religious Context, participants were informed that the image was of a linen artifact that was important to the Christian faith whereas, in the non-religious Neutral Context, participants were informed that the image was of a simple piece of linen. Both groups were told that the image may contain faint words and were asked to report any words they could see. All participants detected words on the image, and indicated that these words were visible and were able to trace on the image the words they detected. In each experiment, more religious words were detected in the Religious Context condition than in the Neutral Context condition whereas the two contexts showed no effect on the number of non-religious words detected, indicating that religious context had a specific effect on the perception of illusory writing. Indeed, in the Neutral Context condition, no religious words at all were reported in either experiment. These findings suggest that images of woven material, like linen, inspire illusory perceptions of writing and that the nature of these perceptions is influenced considerably by the religious expectations of observers. As a consequence, the normal psychological processes underlying perception of writing, and the tendency of these processes to produce illusory perceptions, should be an essential consideration when addressing the existence of religious inscriptions on religious artifacts such as the Shroud of Turin. PMID- 26509504 TI - The Impact of Hepatitis B Vaccination Status on the Risk of Diabetes, Implicating Diabetes Risk Reduction by Successful Vaccination. AB - BACKGROUND: The liver plays a key role in fuel metabolism. It is well established that liver disease is associated with an increased risk for diabetes mellitus. Hepatitis C virus infection has been known to increase the risk of diabetes. However, much less is known about the role of hepatitis B virus (HBV) infection in diabetes. We examined the association of diabetes based on the vaccination status for HBV. METHODS: In this cross-sectional study, we included adult subjects (>=20 y/o) with HBV serology available from the National Health and Nutrition Examination Survey 2005-2010. Diabetes was defined as established diabetes or fasting plasma glucose concentration >=7.0 mmol/L, 2-hour plasma glucose concentration >=11.1 mmol/L, or HbA1c >= 47.5 mmol/mol (6.5%). Vaccination was based on the reported history and immunization was determined by HBV serology. The odds ratio (OR) with 95% confidence intervals (95% CI) were calculated with consideration of the following covariates: age, gender, BMI, ethnic/racial group, current smoker, current alcohol consumption, family history of diabetes, poverty index, and education. RESULTS: This study included 15,316 subjects. Among them, 2,320 subjects was immunized based the HBV serology. Among 4,063 subjects who received HBV vaccination, successful vaccination was only noted in 39% of subjects. The HBV vaccination was not associated with diabetes (OR: 1.08, 95%CI: 0.96-1.23). Serology evidence of HBV immunization was associated with a reduced OR of diabetes (0.75, 95%CI: 0.62-0.90). Successful HBV vaccination was also associated with a reduced OR of diabetes (0.67, 95%CI: 0.52 0.84). CONCLUSIONS: Although our study shows the association of HBV vaccination with the reduced odds of diabetes by 33%, a prospective study is warranted to confirm and examine the impact of HBV vaccination in prevention of diabetes. PMID- 26509505 TI - Impact of obesity in favorable-risk AML patients receiving intensive chemotherapy. AB - We assessed the influence of obesity on the characteristics and prognosis of acute myeloid leukemia (AML). Indeed, safety of intensive chemotherapy and outcome of obese AML patients in a real-life setting are poorly described, and chemotherapy dosing remains challenging. We included 619 consecutive genetically defined cases of AML treated with intensive chemotherapy between 2004 and 2012. In this cohort, 93 patients (15%) were classified in the obese category according to WHO classification; 59% of them received capped doses of chemotherapy because of a body surface area above 2 m(2) . Obese patients were older and presented more often with cardiovascular comorbidities. Although obese patients had more frequently de novo AML, main characteristics of AML including white blood cell count, karyotype and mutations were well-balanced between obese and non-obese patients. After induction chemotherapy, early death and complete remission rates were similar. Overall (OS), event-free (EFS) and disease-free (DFS) survival were not significantly different compared to non-obese patients. However, in the European LeukemiaNet (ELN) favorable subgroup, obese patients had lower median OS, EFS and DFS than non-obese patients (18.4, 16.8 and 17.2 vs. 43.6, 31.8 and 29.7 months, respectively) and obesity showed a significant impact on OS (OR 2.54; P = 0.02) in multivariate models. Although we did not find any significant impact of obesity on outcome in the whole series, this study suggests that special efforts for chemotherapy dose optimization are needed in the ELN favorable subgroup since dose capping may be deleterious. PMID- 26509506 TI - In Situ Persistence and Migration of Biochar Carbon and Its Impact on Native Carbon Emission in Contrasting Soils under Managed Temperate Pastures. AB - Pyrogenic carbon (PyC) is an important component of the global soil carbon (C) pool, but its fate, persistence, and loss dynamics in contrasting soils and environments under planted field conditions are poorly understood. To fill this knowledge gap, a 13C-labelled biochar, as a surrogate material for PyC, produced from Eucalyptus saligna by slow pyrolysis (450 degrees C; delta13C -36.70/00) was surface (0-10 cm) applied in C3 dominated temperate pasture systems across Arenosol, Cambisol and Ferralsol. The results show a low proportion of the applied biochar-C mineralised over 12 months in a relatively clay- and C-poor Arenosol (i.e., 2.0% loss via mineralisation), followed by a clay- and C-rich Cambisol (4.6%), and clay-, C- and earthworm-rich Ferralsol (7.0%). The biochar-C mean residence time (MRT), estimated by different models, varied between 44-1079 (Arenosol), 18-172 (Cambisol), and 11-29 (Ferralsol) years, with the shorter MRT estimated by a one-pool exponential and the longer MRT by an infinite-pool power or a two-pool exponential model. The two-pool model was best fitted to biochar-C mineralisation. The biochar-C recovery in the 12-30 cm soil layer varied from between 1.2% (Arenosol), 2.5-2.7% (Cambisol) and 13.8-15.7% (Ferralsol) of the applied biochar-C after 8-12 months. There was a further migration of biochar-C below the 50-cm depth in the Arenosol, as the combined biochar-C recovery in the mineralised pool and soil profile (up to 30 or 50 cm) was 82%, in contrast to 101% in the Cambisol and 104% in the Ferralsol after 12 months. These results indicate that the downward migration of biochar-C was greatest in the Arenosol (cf. Cambisol and Ferralsol). Cumulative CO2-C emission from native soil-plant sources was lower (p <0.10) in the biochar-amended vs. non-amended Ferralsol. This field-based study shows that the downward migration of biochar-C exceeded its loss via mineralisation in the Arenosol and Ferralsol, but not in the Cambisol. It is thus important to understand biochar-soil interactions to maximise long-term biochar C sequestration potential in planted soil systems. PMID- 26509507 TI - Tar Heel Footprints in Health Care: Sheree Vodicka, MA, RD, LDN. PMID- 26509508 TI - Practice Characteristics and Geographic Distribution of Clinical Pharmacist Practitioners in North Carolina. AB - BACKGROUND: Clinical pharmacist practitioners (CPPs) are specially credentialed pharmacists in North Carolina. CPPs potentially play an important role in meeting the health care needs of populations in rural and underserved areas. METHODS: A cross-sectional study was conducted using an electronic survey sent to all active and inactive CPPs in North Carolina. The survey consisted of 36 multiple-choice and free text questions. Respondents were queried regarding qualifications, experience, practice characteristics, and perceived rewards and challenges of CPP practice. RESULTS: Survey responses were received from 54 active CPPs and 22 inactive CPPs, for an overall response rate of 65.5%. Forty-one active CPPs (75.9%) and 14 inactive CPPs (63.6%) came from ambulatory care backgrounds. Twenty-eight active CPPs (51.9%) and 11 inactive CPPs (50.0%) practiced in an urban setting, while 7 active CPPs (13.0%) and 3 inactive CPPs (13.6%) practiced in a rural setting. The majority of CPPs work in larger practices. Thirty-three active CPPs (61.1%) and 12 inactive CPPs (54.5%) were paid by the institutions for which they were employed. LIMITATIONS: The overall survey response rate was only 65.5%. Additionally, the majority of survey questions were in a multiple choice format, which may have prevented more honest reflection. CONCLUSIONS: Active CPPs most often come from ambulatory care backgrounds. Few CPPs are practicing in rural areas, a circumstance that may be related to financial viability, as most CPP practice in, and are compensated by, larger institutions such as academic health centers. PMID- 26509509 TI - Glaucoma Blindness at a Tertiary Eye Care Center. AB - BACKGROUND: Glaucoma is an important cause of irreversible blindness. This study describes the characteristics of a large, diverse group of glaucoma patients and evaluates associations between demographic and clinical characteristics and blindness. METHODS: Data were gathered via retrospective chart review of patients (N = 1,454) who were seen between July 2007 and July 2010 by glaucoma service providers at Duke Eye Center. Visual acuity and visual field criteria were used to determine whether patients met the criteria for legal blindness. Descriptive and comparative statistical analyses were performed on the glaucoma patients who were not blind (n = 1,258) and those who were blind (n = 196). A subgroup analysis of only those patients with primary open-angle glaucoma was also performed. RESULTS: In this tertiary care population, 13% (n = 196) of glaucoma patients met criteria for legal blindness, nearly one-half of whom (n = 94) were blind from glaucoma, and another one-third of whom (n = 69) had glaucoma-related blindness. The most common glaucoma diagnosis at all levels of vision was primary open-angle glaucoma. A larger proportion of black patients compared with white patients demonstrated vision loss; the odds ratio (OR) for blindness was 2.25 (95% CI, 1.6-3.2) for black patients compared with white patients. The use of systemic antihypertensive medications was higher among patients who were blind compared with patients who were not blind (OR = 2.1; 95% CI, 1.4-3.1). A subgroup analysis including only patients with primary open-angle glaucoma showed similar results for both black race and use of systemic antihypertensive medications. The relationship between use of systemic antihypertensive medications and blindness was not different between black patients and white patients (interaction P = .268). LIMITATIONS: Data were based on chart review, and associations may be confounded by unmeasured factors. CONCLUSIONS: Treated systemic hypertension may be correlated with blindness, and the cause cannot be explained solely by race. In addition, this study demonstrated that there is continued disparity between black patients and white patients with regards to blindness from glaucoma. PMID- 26509510 TI - Readmission Patterns and Effectiveness of Transitional Care Among Medicaid Patients With Schizophrenia and Medical Comorbidity. AB - BACKGROUND: Patients with chronic medical and mental health comorbidities are at increased risk of hospital admission, but little is known about their hospital utilization patterns or whether nurse-directed transitional care interventions have any appreciable impact on future hospitalizations. METHOD: Using paid Medicaid claims and a care management database, we examined patterns of hospital utilization for adults with multiple chronic conditions where one of the conditions was schizophrenia. Patients were enrolled in Community Care of North Carolina's medical home program and were discharged from 100 different hospitals throughout the state from July 1, 2010 through June 30, 2011. We examined readmission rates after psychiatric and nonpsychiatric hospital discharges, and we compared patients who received community-based, nurse-directed, transitional care management services to patients who received usual care. RESULTS: A total of 1,717 patients were included in the final analysis. Patients in this study experienced 980 readmissions over the course of 1 year, with 20% of readmissions for a different reason than the primary hospitalization, and 36% of readmissions occurring at a different hospital. Controlling for demographic, clinical, and hospital characteristics, patients receiving transitional care (n = 1,104) were as much as 30% less likely to experience a readmission during the year following discharge compared to patients receiving usual care (n = 613). LIMITATIONS: This descriptive study reports on a nonrandomized intervention and its impact on service utilization for Medicaid patients with complex illnesses in North Carolina. CONCLUSIONS: Regardless of the reason for hospitalization, patients with chronic medical and psychiatric conditions may benefit from transitional care support that addresses both conditions. This holds true even when the patient is already receiving intensive outpatient psychiatric care. PMID- 26509511 TI - Revealing Evidence-Based Practice. PMID- 26509512 TI - What, How, and Why. AB - Practice guidelines are not new, but they continue to evolve-from ad-hoc practice standards, informed expert opinions, and consensus-based guidelines to best practice and evidence-based guidelines that improve individual and community outcomes. From the extensive national guidelines of the US Preventive Services Task Force to state and local initiatives, this issue of the NCMJ explores the development and implementation of clinical guidelines that are now (along with cost and patient experience) the third of the Triple Aim objectives, the new "north star" of our profession. PMID- 26509513 TI - Translating Clinical Guidelines Into Practice: Challenges and Opportunities in a Dynamic Health Care Environment. AB - Clinical practice guidelines are evidence-based recommendations with the potential to improve population health, yet they remain inconsistently utilized. In this commentary we discuss barriers and drivers to implementing clinical practice guidelines. We also suggest ways to support their translation into practice. PMID- 26509514 TI - Translating Medical Guidelines Into Practice. PMID- 26509515 TI - The Benefits and Concerns Surrounding the Automation of Clinical Guidelines. AB - Automated guidelines often improve outcomes when applied to simple clinical states. They are more effective when human-computer interaction and workflow changes are considered in implementation. "Alert fatigue" might lead to uneven implementation of guidelines. For complex patients with multiple illnesses, more research should be geared toward the structure and effect of guidelines. Evidentiary uncertainty and complicating comorbid conditions continue to require meticulous incorporation of patient values and physician judgment. PMID- 26509516 TI - The US Preventive Services Task Force: What Is It and What Does It Do? AB - The US Preventive Services Task Force (USPSTF) is an independent body comprised of national experts in prevention and evidence-based medicine. The primary audience for the USPSTF's work is primary care clinicians, and many consider the Task Force's recommendations to be definitive standards for preventive services. PMID- 26509517 TI - Decoding Levels of Evidence. PMID- 26509518 TI - Guidelines and Value-Based Decision Making: An Evolving Role for Payers. AB - Payers use evidence-based guidelines to promote effective health diagnoses and treatments for their members and to ensure that members are not subject to harmful or wasteful care. Payer guidelines inform coverage, but the content of these guidelines relies on the same evidentiary base as clinical treatment guidelines. Recent strategies to foster value through benefit design and alternative reimbursement methodologies illustrate emerging applications for evidence-based guidelines. The current focus on cost effectiveness within health technology assessment, comparative effectiveness research in collaboration with payers, and transparency around payer evidence assessment could better align payers' interests in evidence-based care with those of other stakeholders. The move to value in health care will depend upon credible clinical evidence to enable informed decision making. PMID- 26509519 TI - Implementing Evidence-Based Guidelines: The Role of Ambulatory Care Pharmacists. AB - Pharmacists strive to align patients' medication regimens with evidence-based guidelines through medication therapy management and through the utilization of protocols based on best practices for chronic disease management. Ambulatory care pharmacists also assist in implementing guidelines through developing evidence based algorithms and processes, educating providers and staff, and participating in population management. PMID- 26509520 TI - Dissemination and Adoption of Guidelines: The Experience of Community Care of North Carolina. AB - Dissemination and adoption of practice guidelines has the potential to improve the health of a population. However, these processes are complex and take place in the context of a myriad of factors that impact patient and provider behaviors. Therefore, successful strategies-like the ones utilized by Community Care of North Carolina-need to be multifaceted. PMID- 26509521 TI - North Carolina College of Emergency Physicians' Guidance Document on Emergency Medical Services. AB - The North Carolina College of Emergency Physicians (NCCEP) Emergency Medical Services (EMS) Committee uses an evidence-based approach in writing its protocols and procedures. The most recent revision of the NCCEP document, which was started in late 2010, lasted for more than 1 year and utilized committee members from across the state. Four meetings were held at locations across North Carolina. In addition, 2 surveys were sent to get input from EMS providers. Since 2010, the document has been updated on an ongoing basis, aligning it with the latest evidence-based medicine. PMID- 26509522 TI - Review of Clinical Guidelines for Cardiopulmonary Resuscitation. PMID- 26509523 TI - Pregnancy Medical Home Care Pathways Improve Quality of Perinatal Care and Birth Outcomes. AB - The clinical leadership of the Pregnancy Medical Home (PMH) program develops and disseminates clinical pathways to promote evidence-based practice and to improve quality of care and outcomes. PMH pathways represent the first standardized clinical guidance for obstetric providers statewide across all care settings. PMID- 26509524 TI - Implementing Guidelines One Patient at a Time. AB - Clinical practice guidelines are an important component of health care delivery. Although guidelines can be viewed negatively, as "cookbook medicine," many guidelines have improved care delivery. Work is needed to refine guidelines in real-world settings and to assure that they are patient-centered. PMID- 26509525 TI - Spotlight on the Safety Net: Use of Evidence-Based Clinical Practice Guidelines at Matthews Free Medical Clinic. PMID- 26509526 TI - Make Suicide Prevention a National Priority. PMID- 26509527 TI - Let the Kids Play Football! PMID- 26509528 TI - Defect-Rich Ultrathin ZnAl-Layered Double Hydroxide Nanosheets for Efficient Photoreduction of CO2 to CO with Water. AB - Defect-rich ultrathin ZnAl-layered double hydroxide nanosheets are successfully prepared. Under UV-vis irradiation, these nanosheets are superior efficient catalysts for the photoreduction of CO2 to CO with water. The formed oxygen vacancies lead to the formation of coordinatively unsaturated Zn(+) centers within the nanosheets, responsible for the very high photocatalytic activities. PMID- 26509529 TI - Therapeutic Effects of alpha1-Antitrypsin on Psedumonas aeruginosa Infection in ENaC Transgenic Mice. AB - Cystic fibrosis (CF) is a genetic disease with many airway pathological features, including aberrant epithelial sodium channel (ENaC) function, persistent Pseudomonas aeruginosa (PA) infection and neutrophil-dominant inflammation. PA infection in CF airways is difficult to treat due to antibiotic resistance and other factors. Recently, alpha1-antitrypsin (A1AT) have been shown to be effective to reduce CF airway PA infection. However, there is a dearth of studies about the mechanisms underlying A1AT's therapeutic effects. The goal of our study is to provide an animal model of A1AT therapy in CF lungs. ENaC transgenic mice with PA infection were used as a CF-like model. Mice were intratracheally treated with PA or saline (control) in a fibrin plug. Two hours after PA infection, aerosolized A1AT were delivered to mouse lungs once daily. At day 1 and day 3 post PA infection, lung inflammation, PA load as well as host defence protein short palate, lung, and nasal epithelium clone 1 (SPLUNC1) were measured. At day 1 post PA infection when A1AT was delivered once to ENaC transgenic mouse lungs, A1AT did not reduce lung inflammation (e.g., neutrophils) and PA load. However, at day 3 post PA infection when ENaC transgenic mice received three repeated A1AT treatments, a significant decrease in airspace inflammation and PA load was observed. Although A1AT prevented the loss of SPLUNC1 in bronchoalveolar lavage fluid of PA-infected wild-type mice, it did not restore SPLUNC1 levels in ENaC transgenic mice. Our current study has provided a valid and quick A1AT therapeutic model in CF-like lungs that may serve as a platform for future mechanistic studies about how A1AT exerts beneficial effects in human CF patients. PMID- 26509530 TI - In Vitro Insemination of the Microphallid Digenean Gynaecotyla adunca. AB - In vitro cultivation of adult digeneans can benefit research on their biology and contribute to the development of new drugs and vaccines. Successful in vitro growth of excysted metacercariae into adults capable of producing embryonated eggs typically requires that the worms be inseminated. The goal of the study was to develop an in vitro insemination procedure for the progenetic microphallid digenean Gynaecotyla adunca. To do so, we determined the length of time needed for in vitro sperm development in excysted metacercariae and whether the adult worms could self-inseminate in the absence of conspecifics. We also examined the effect of different culture vessels, worm densities, incubation temperatures, length of time incubated with conspecifics, and different pH levels on the percentage of worms inseminated. We found that sperm maturation time for G. adunca was 8-10 hr postexcystment. In the absence of conspecifics, the parasite did not self-inseminate. We observed the highest percentage of inseminated worms when 50 excysted metacercariae were incubated at 37 C for 48 hr in 15-ml conical bottom tubes containing pH 7 Hank's balanced salt solution. Furthermore, freshly excysted worms incubated in these conditions and then transferred to culture in Dulbecco's modified Eagle medium/F-12 medium and horse serum deposited normal shaped, embryonated eggs. Our findings provide the basis for a straightforward, reproducible procedure that permits the in vitro insemination of the parasite G. adunca and should be applicable to other progenetic digeneans. PMID- 26509531 TI - Exploring the Relationship between Skeletal Mass and Total Body Mass in Birds. AB - Total body mass (TBM) is known to be related to a number of different osteological features in vertebrates, including limb element measurements and total skeletal mass. The relationship between skeletal mass and TBM in birds has been suggested as a way of estimating the latter in cases where only the skeleton is known (e.g., fossils). This relationship has thus also been applied to other extinct vertebrates, including the non-avian pterosaurs, while other studies have used additional skeletal correlates found in modern birds to estimate TBM. However, most previous studies have used TBM compiled from the literature rather than from direct measurements, producing values from population averages rather than from individuals. Here, we report a new dataset of 487 extant birds encompassing 79 species that have skeletal mass and TBM recorded at the time of collection or preparation. We combine both historical and new data for analyses with phylogenetic control and find a similar and well-correlated relationship between skeletal mass and TBM. Thus, we confirm that TBM and skeletal mass are accurate proxies for estimating one another. We also look at other factors that may have an effect on avian body mass, including sex, ontogenetic stage, and flight mode. While data are well-correlated in all cases, phylogeny is a major control on TBM in birds strongly suggesting that this relationship is not appropriate for estimating the total mass of taxa outside of crown birds, Neornithes (e.g., non-avian dinosaurs, pterosaurs). Data also reveal large variability in both bird skeletal and TBM within single species; caution should thus be applied when using published mass to test direct correlations with skeletal mass and bone lengths. PMID- 26509532 TI - Home Care Providers to the Rescue: A Novel First-Responder Programme. AB - AIM: To describe the implementation of a novel first-responder programme in which home care providers equipped with automated external defibrillators (AEDs) were dispatched in parallel with existing emergency medical services in the event of a suspected out-of-hospital cardiac arrest (OHCA). METHODS: We evaluated a one-year prospective study that trained home care providers in performing cardiopulmonary resuscitation (CPR) and using an AED in cases of suspected OHCA. Data were collected from cardiac arrest case files, case files from each provider dispatch and a survey among dispatched providers. The study was conducted in a rural district in Denmark. RESULTS: Home care providers were dispatched to 28 of the 60 OHCAs that occurred in the study period. In ten cases the providers arrived before the ambulance service and subsequently performed CPR. AED analysis was executed in three cases and shock was delivered in one case. For 26 of the 28 cases, the cardiac arrest occurred in a private home. Ninety-five per cent of the providers who had been dispatched to a cardiac arrest reported feeling prepared for managing the initial resuscitation, including use of AED. CONCLUSION: Home care providers are suited to act as first-responders in predominantly rural and residential districts. Future follow-up will allow further evaluation of home care provider arrivals and patient survival. PMID- 26509534 TI - [In Process Citation]. PMID- 26509533 TI - Periosteum Metabolism and Nerve Fiber Positioning Depend on Interactions between Osteoblasts and Peripheral Innervation in Rat Mandible. AB - The sympathetic nervous system controls bone remodeling by regulating bone formation and resorption. How nerves and bone cells influence each other remains elusive. Here we modulated the content or activity of the neuropeptide Vasoactive Intestinal Peptide to investigate nerve-bone cell interplays in the mandible periosteum by assessing factors involved in nerve and bone behaviors. Young adult rats were chemically sympathectomized or treated with Vasoactive Intestinal Peptide or Vasoactive Intestinal Peptide10-28, a receptor antagonist. Sympathectomy depleted the osteogenic layer of the periosteum in neurotrophic proNerve Growth Factor and neurorepulsive semaphorin3a; sensory Calcitonin-Gene Related Peptide-positive fibers invaded this layer physiologically devoid of sensory fibers. In the periosteum non-osteogenic layer, sympathectomy activated mast cells to release mature Nerve Growth Factor while Calcitonin-Gene Related Peptide-positive fibers increased. Vasoactive Intestinal Peptide treatment reversed sympathectomy effects. Treating intact animals with Vasoactive Intestinal Peptide increased proNerve Growth Factor expression and stabilized mast cells. Vasoactive Intestinal Peptide10-28 treatment mimicked sympathectomy effects. Our data suggest that sympathetic Vasoactive Intestinal Peptide modulate the interactions between nervous fibers and bone cells by tuning expressions by osteogenic cells of factors responsible for mandible periosteum maintenance while osteogenic cells keep nervous fibers at a distance from the bone surface. PMID- 26509535 TI - [In Process Citation]. PMID- 26509536 TI - [Not Available]. PMID- 26509537 TI - [In Process Citation]. PMID- 26509538 TI - [Pervasive refusal syndrome is a severe child psychiatric disorder]. AB - Pervasive refusal syndrome (PRS) is a severe, pervasive and potentially life threatening disorder, which was first de--scribed in 1991, as a syndrome of child psychiatric disorder. Little has been written about PRS. We report a case story of a ten-year-old boy developing all symptoms of PRS, including inability to eat, move or speak. Psychopharmacological treat-ment was not successful. Full rehabilitation was reported after a period of inpatient treatment and outpatient follow-up. Different aetiological factors for PRS have been proposed. A number of these are presented in the case story. PMID- 26509539 TI - [Gallstones and gallstone-associated complications in patients treated with statin]. AB - Statins are a widely used group of drugs which can lower cholesterol levels. Recently, there has been emerging evidence that statins may decrease the formation of cholesterol gallstones and several studies have reported invert association between symptomatic cholesterol gallstones and statin use. Subsequent evidence for decrease in gallstone-associated complications among statin users have not been clearly described. In this review we summarize current evidence for the association between statin use and the risk of gallstone-associated complications. PMID- 26509540 TI - [Dacryocystitis in a three-week-old girl]. AB - Dacryocystocele is a rare disease, which can be difficult to distinguish from haemangioma, dermoid cyst or encephalocele. Proper diagnosis and treatment is important as the risk of complications is high. A newborn baby with dacryocystitis was referred to a department of plastic surgery with a bluish tumour in the medial corner of the eye. The girl was treated with i.v. antibiotics and the dacryocystocele disappeared in 20 days. Knowledge of the disease is important so patients quickly can be treated medically and possibly surgically in order to avoid fatal complications. PMID- 26509541 TI - [Self-inflicted penetrating stab wound in mentally unstable patient - a clinical approach]. AB - A mentally ill 46-year-old woman was admitted to our hospital because of a self inflicted stab wound to the abdomen. Diagnostic laparoscopy was performed and the peritoneum was found to be intact. She was discharged in good physical health the next day. Local wound exploration could not be performed because of the slim stab wound. Conservative treatment with 12-24 hours of in hospital-observation could be an option, but since the patient presented with abdominal pain, surgery was the treatment of choice in this case. PMID- 26509542 TI - [Treatment of gastric antral vascular ectasia with endoscopic banding]. AB - Gastric antral vascular ectasia (GAVE) is an important cause of gastro-intestinal bleeding. An 81-year-old male twice experienced severe anaemia as a result of GAVE. On the second occasion he was treated with endoscopic banding, and since he kept a stable haemoglobin level. GAVE has previously been treated which several different methods. Recently, endoscopic band ligation has, however, emerged as a new treatment of GAVE. Endoscopic band ligation has proven to be a safe and efficient treatment of GAVE. PMID- 26509543 TI - [Laparoscopy can be used when treating atypical femoral hernias in children]. AB - Direct and femoral hernias in children are a diagnostic challenge. They are often presumed to be recurrent hernias after open exploration for indirect inguinal hernia. We present three children, who underwent laparoscopic inguinal herniotomy. Two patients had a direct hernia, and one patient had a femoral hernia. All three had previously undergone negative open exploration. We argue that negative open exploration should be followed by diagnostic laparoscopy and herniotomy in the same procedure and that inguinal herniotomy in children should be performed in departments with expertise in laparoscopy. PMID- 26509544 TI - [Drug dosage in obese children]. AB - The prevalence of obesity in children is increasing rapidly worldwide. Obese children have a higher use of medicinal products than their normal-weight peers. Several general physiological alterations associated with obesity have been described. However, the impact of these alterations on drug metabolism and its consequences for drug dosing in children remains largely unknown. Pharmacokinetic studies are of utmost importance in order to avoid undertreatment, adverse effects or even toxicity. PMID- 26509545 TI - Interleukin17A Promotes Postoperative Cognitive Dysfunction by Triggering beta Amyloid Accumulation via the Transforming Growth Factor-beta (TGFbeta)/Smad Signaling Pathway. AB - Although postoperative cognitive dysfunction (POCD) is relatively common in elderly patients who have undergone major surgery, the mechanisms underlying this postoperative complication are unclear. Previously, we have investigated the role of cytokine-mediated hippocampal inflammation in the development of POCD in a rat model. Here, we sought to determine in mice the role of cytokine interleukin17A (IL17A) in POCD and to characterize the associated signaling pathways. Old mice underwent hepatectomy surgery in the presence or absence of IL17A monoclonal antibody, and cognitive function, hippocampal neuroinflammation, and pathologic markers of Alzheimer's disease (AD) were assessed. We found that the level of IL17A in the hippocampus was increased in hepatectomy mice and that cognitive impairment after surgery was associated with the appearance of certain pathological hallmarks of AD: activation of astrocytes, beta-amyloid1-42 (Abeta1 42) production, upregulation of transforming growth factor-beta (TGFbeta), and increased phosphorylation of signaling mother against decapentaplegic peptide 3 (Smad3) protein in the hippocampus. Surgery-induced changes in cognitive dysfunction and changes in Abeta1-42 and TGFbeta/Smad signaling were prevented by the administration of IL17A monoclonal antibody. In addition, IL17A-stimulated TGFbeta/Smad activation and Abeta1-42 expression were reversed by IL17A receptor small interfering RNA and a TGFbeta receptor inhibitor in cultured astrocytes. Our findings suggest that surgery can provoke IL17A-related hippocampal damage, as characterized by activation of astrocytes and TGFbeta/Smad pathway dependent Abeta1-42 accumulation in old subjects. These changes likely contribute to the cognitive decline seen in POCD. PMID- 26509546 TI - Detection of autophagy in Hirschsprung's disease: implication for its role in aganglionosis. AB - Hirschsprung's disease (HD) is a common congenital gastrointestinal malformation, characterized by the lack of ganglion cells from the distal rectum to the proximal bowel, but the pathogenesis is not well understood. This paper evaluates the effects of autophagy in HD. Using electron microscopy, the autophagosomes were detected in three segments: narrow segment (NS), transitional segment (TS), and dilated segment (DS). Typical autophagosome structures are found in the Auerbach plexus of both NS and TS. Real-time PCR results showed that Beclin1 (NS vs. TS, P<0.01) and LC3 (NS vs. TS, P<0.05) mRNA were the highest in the NS, but p75 (NS vs. TS, P<0.01) was the highest in the DS. Correlation analysis results showed a positive correlation between Beclin1 and LC3 mRNA levels (R=0.736, P=0.000), whereas inverse correlations were found between p75 and Beclin1/LC3 mRNA levels (p75 vs. Beclin1: R=-0.714, P=0.000; p75 vs. LC3: R=-0.619, P=0.000). Immunohistochemistry analyses indicated a consistent result with mRNA levels, by increased Beclin1-positive and LC3-positive neurons, but reduced p75-positive neurons in the Auerbach plexus of TS compared with DS. These findings indicated that autophagy exists in the bowel of patients with HD. On the basis of the detection of the highest expression of the autophagy genes in NS, autophagy may additionally cause the lack of neurons. PMID- 26509547 TI - Prolonged L2 immersion engenders little change in morphosyntactic processing of bilingual natives. AB - Bilingual and monolingual language processing differ, presumably because of constant parallel activation of both languages in bilinguals. We attempt to isolate the effects of parallel activation in a group of German first-language (L1) attriters, who have grown up as monolingual natives before emigrating to an L2 environment. We hypothesized that prolonged immersion will lead to changes in the processing of morphosyntactic violations. Two types of constructions were presented as stimuli in an event-related potential experiment: (1) verb form combinations (auxiliaries+past participles and modals+infinitives) and (2) determiner-noun combinations marked for grammatical gender. L1 attriters showed the same response to violations of gender agreement as monolingual controls (i.e. a significant P600 effect strongest over posterior electrodes). Incorrect verb form combinations also elicited a significant posterior P600 effect in both groups. In attriters, however, there was an additional posterior N400 effect for this type of violation. Such biphasic patterns have been found before in L1 and L2 speakers of English and might reflect the influence of this language. Generally, we interpret our results as evidence for the stability of the deeply entrenched L1 system, even in the face of L2 interference. PMID- 26509548 TI - Structural asymmetry of cortical visual areas is related to ocular dominance. AB - The grey matter of the human brain is asymmetrically distributed between the cerebral hemispheres. This asymmetry includes visual areas, but its relevance to visual function is not understood. Voxel-based morphometry is a well-established technique for localization and quantification of cerebral grey matter on the basis of MR images. This method has been used previously for interhemispheric comparison, but without examining the functional implications of the identified anatomical asymmetries of the visual system. The aim of the present study was to relate anatomical interhemispheric asymmetries to asymmetries of visual function. We examined grey matter asymmetries of visual areas in a large population (n=56) of ophthalmologically and neurologically healthy individuals. We used state-of the-art 3 T MRI and voxel-based morphometry to relate the visual parameters, (a) ocular dominance, (b) interocular difference in visual acuity and (c) visual attention (i.e. deviation on a line-bisection task), to interhemispheric differences in grey matter volume. As most visual input from one eye is processed in the contralateral hemisphere, ocular features may also depend on cerebral lateralization. Several lateralized visual areas were identified, both right>left and left>right. When correlating the asymmetries to the functional parameters, we found a significant correlation to ocular dominance (P<0.05), whereas visual acuity and visual attention showed no such relationship. The lateral occipital complex was identified to be significantly larger in the left hemisphere for right-eyed participants and vice versa. These results suggest a cerebral basis for ocular dominance. PMID- 26509549 TI - Functional neural correlates of figure copy and recall task performances in cognitively impaired individuals: an 18F-FDG-PET study. AB - Figure copy and recall tasks from the Benton Visual Retention Test (BVRT) and the Consortium to Establish a Registry of Alzheimer's Disease (CERAD) neuropsychological battery are used widely to assess visuospatial function in cognitively impaired (CI) individuals. We aimed to identify functional neural correlates of figure copy and recall task performances as measured by the BVRT and the CERAD constructional praxis (CP) and CP recall (CR) in CI individuals. Both tasks were administered to 64 CI individuals with early or prodromal stage Alzheimer's disease and 36 cognitively normal individuals. Voxel-wise correlations between test scores and regional cerebral glucose metabolism (rCMglc) measured by fluorine-18 fluorodeoxyglucose PET in CI participants were analyzed. BVRT figure copy task performance was associated with rCMglc of the bilateral posterior brain regions including the parieto-temporo-occipital regions, whereas the BVRT figure recall task performance was predominantly correlated with rCMglc of the left parietal and temporo-occipital regions. Meanwhile, CERAD CP performance was associated mainly with rCMglc of the left prefrontal and temporo-occipital areas as well as in the bilateral parietal regions, whereas CERAD CR performance was correlated with rCMglc of the right prefrontal, parietal, and temporal regions. In conclusion, the functional neural correlates of the two tasks were markedly different, suggesting that these tasks might measure different visuospatial functions. Our findings contribute toward understanding the functional neuroanatomical aspects of these tasks, which is useful for both interpreting the task results as well as for more sophisticated utilization of these tasks for probing specific neuroanatomical functions. PMID- 26509550 TI - Effect of Cellular Location of Human Carboxylesterase 2 on CPT-11 Hydrolysis and Anticancer Activity. AB - CPT-11 is an anticancer prodrug that is clinically used for the treatment of metastatic colorectal cancer. Hydrolysis of CPT-11 by human carboxylesterase 2 (CE2) generates SN-38, a topoisomerase I inhibitor that is the active anti-tumor agent. Expression of CE2 in cancer cells is under investigation for the tumor localized activation of CPT-11. CE2 is normally expressed in the endoplasmic reticulum of cells but can be engineered to direct expression of active enzyme on the plasma membrane or as a secreted form. Although previous studies have investigated different locations of CE2 expression in cancer cells, it remains unclear if CE2 cellular location affects CPT-11 anticancer activity. In the present study, we directly compared the influence of CE2 cellular location on substrate hydrolysis and CPT-11 cytotoxicity. We linked expression of CE2 and enhanced green fluorescence protein (eGFP) via a foot-and-mouth disease virus 2A (F2A) peptide to facilitate fluorescence-activated cell sorting to achieve similar expression levels of ER-located, secreted or membrane-anchored CE2. Soluble CE2 was detected in the medium of cells that expressed secreted and membrane-anchored CE2, but not in cells that expressed ER-retained CE2. Cancer cells that expressed all three forms of CE2 were more sensitive to CPT-11 as compared to unmodified cancer cells, but the membrane-anchored and ER-retained forms of CE2 were consistently more effective than secreted CE2. We conclude that expression of CE2 in the ER or on the membrane of cancer cells is suitable for enhancing CPT-11 anticancer activity. PMID- 26509551 TI - Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin 1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases. AB - Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders including vasculitis and cardiovascular and Parkinson's diseases, implying that MPO inhibitors may represent a therapeutic treatment option. Herein, we present the design, synthesis, and preclinical evaluation of N1-substituted-6-arylthiouracils as potent and selective inhibitors of MPO. Inhibition proceeded in a time-dependent manner by a covalent, irreversible mechanism, which was dependent upon MPO catalysis, consistent with mechanism-based inactivation. N1-Substituted-6-arylthiouracils exhibited low partition ratios and high selectivity for MPO over thyroid peroxidase and cytochrome P450 isoforms. N1-Substituted-6-arylthiouracils also demonstrated inhibition of MPO activity in lipopolysaccharide-stimulated human whole blood. Robust inhibition of plasma MPO activity was demonstrated with the lead compound 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H) yl)acetamide (PF-06282999, 8) upon oral administration to lipopolysaccharide treated cynomolgus monkeys. On the basis of its pharmacological and pharmacokinetic profile, PF-06282999 has been advanced to first-in-human pharmacokinetic and safety studies. PMID- 26509552 TI - Analysis and Correction of Dynamic Geometric Misalignment for Nano-Scale Computed Tomography at BSRF. AB - Due to its high spatial resolution, synchrotron radiation x-ray nano-scale computed tomography (nano-CT) is sensitive to misalignments in scanning geometry, which occurs quite frequently because of mechanical errors in manufacturing and assembly or from thermal expansion during the time-consuming scanning. Misalignments degrade the imaging results by imposing artifacts on the nano-CT slices. In this paper, the geometric misalignment of the synchrotron radiation nano-CT has been analyzed by partial derivatives on the CT reconstruction algorithm and a correction method, based on cross correlation and least-square sinusoidal fitting, has been reported. This work comprises a numerical study of the method and its experimental verification using a dataset measured with the full-field transmission x-ray microscope nano-CT at the beamline 4W1A of the Beijing Synchrotron Radiation Facility. The numerical and experimental results have demonstrated the validity of the proposed approach. It can be applied for dynamic geometric misalignment and needs neither phantom nor additional correction scanning. We expect that this method will simplify the experimental operation of synchrotron radiation nano-CT. PMID- 26509553 TI - Catabolite responsive element deficiency of xyl operon resulting in carbon catabolite derepression in Lactobacillus fermentum 1001. AB - AIMS: To explore the molecular mechanism of the carbon catabolite derepression in Lactobacillus fermentum 1001 when this strain consumed xylose and glucose simultaneously. METHODS AND RESULTS: The transcriptional level of ccpAf was measured by real-time qPCR, revealing that ccpAf transcribed mRNA normally in Lact. fermentum 1001. The ccpAf gene could complement the ccpA-deficiency of a Lactococcus lactis mutant. Moreover, when the phosphofructokinase from Lactobacillus delbrueckii subsp. bulgaricus ATCC 11842 was expressed in Lact. fermentum 1001, the recombinant preferred glucose to fructose rather than to xylose. All data suggested that CcpAf was functional in Lact. fermentum 1001. In addition, the promoter (Plx) activity of the xyl operon from Lact. fermentum 1001 was further test in Lactobacillus casei BL23, and it could drive the expression of green fluorescent protein in the presence of glucose. CONCLUSIONS: The ability of Lact. fermentum 1001 to co-utilize xylose and glucose resulted from the deficiency of catabolite responsive element in P1x rather than the null mutation of the ccpAf gene. SIGNIFICANCE AND IMPACT OF THE STUDY: Lactobacillus fermentum 1001 is a potential candidate as a CCR-absent cell factory to transform biomass to high-value-added products. P1x was provided for engineering LAB to enhance fermentation efficiency by avoiding CCR. PMID- 26509554 TI - Different applications of virus-like particles in biology and medicine: Vaccination and delivery systems. AB - Virus-like particles (VLPs) mimic the whole construct of virus particles devoid of viral genome as used in subunit vaccine design. VLPs can elicit efficient protective immunity as direct immunogens compared to soluble antigens co administered with adjuvants in several booster injections. Up to now, several prokaryotic and eukaryotic systems such as insect, yeast, plant, and E. coli were used to express recombinant proteins, especially for VLP production. Recent studies are also generating VLPs in plants using different transient expression vectors for edible vaccines. VLPs and viral particles have been applied for different functions such as gene therapy, vaccination, nanotechnology, and diagnostics. Herein, we describe VLP production in different systems as well as its applications in biology and medicine. PMID- 26509555 TI - Increasing aortic stiffness is predictive of advanced liver fibrosis in patients with type 2 diabetes: the Rio-T2DM cohort study. AB - BACKGROUND & AIMS: Type 2 diabetes mellitus (T2DM) is a risk factor for cardiovascular disease (CVD) and advanced stages of non-alcoholic fatty liver disease (NAFLD). The aim was to evaluate the association between aortic stiffness, a preclinical CVD marker, with advanced liver fibrosis identified by transient elastography (TE) in T2DM outpatients with NAFLD. METHODS: This longitudinal study included 291 T2DM patients with NAFLD detected by ultrasonography, who had two carotid-femoral pulse wave velocity (cf-PWV) measurements and a TE examination (Fibroscan((r)) ) performed over a median follow-up of 7 years. Advanced liver fibrosis (corresponding to >= F3 stage) was considered as median values >7.9 kPa (M probe) or >7.2 kPa (XL probe). Increased aortic stiffness was defined as cf-PWV >10 m/s. RESULTS: Eighty patients (27.5%) had advanced liver fibrosis. Overall, there was an increase in cf-PWV of 0.1 m/s/year (1% per year). Both a high aortic stiffness at the 2nd cf-PWV examination [odds ratios (OR): 3.0; 95% CI: 1.3-7.2; P = 0.011] and a serial increase in aortic stiffness (OR: 2.1; 95% CI: 1.0-4.3; P = 0.046) were associated with increased odds of having advanced liver fibrosis. Patients who presented either an increase in aortic stiffness or persisted with high values had significantly higher mean liver stiffness than those who either decreased aortic stiffness or persisted with normal cf-PWV values (mean difference: 2.1 kPa, 95% CI: 0.5-3.7 kPa, P = 0.012), after adjustments for anthropometric demographic and clinical laboratory covariates. CONCLUSIONS: In T2DM patients with NAFLD, a high or increasing aortic stiffness predicted development of advanced liver fibrosis on TE. PMID- 26509556 TI - Development of a bovine decellularized extracellular matrix-biomaterial for nucleus pulposus regeneration. AB - Painful intervertebral disc (IVD) degeneration is a common cause for spinal surgery. There is a clinical need to develop injectable biomaterials capable of promoting IVD regeneration, yet many available biomaterials do not mimic the native extracellular matrix (ECM) or promote matrix production. This study aimed to develop a decellularized injectable bovine ECM material that maintains structural and compositional features of native tissue and promotes nucleus pulposus (NP) cell (NPC) and mesenchymal stem cell (MSC) adaption. Injectable decellularized ECM constructs were created using 3 NP tissue decellularization methods (con.A: sodium deoxycholate, con.B: sodium deoxycholate & sodium dodecyl sulfate, con.C: sodium deoxycholate, sodium dodecyl sulfate & TritonX-100) and evaluated for protein, microstructure, and for cell adaptation in 21 day human NPC and MSC culture experiments. Con.A was most efficient at DNA depletion, preserved best collagen microstructure and content, and maintained the highest glycosaminoglycan (GAG) content. NPCs in decellularized constructs of con.A&B demonstrated newly synthesized GAG production, which was apparent from "halos" of GAG staining surrounding seeded NPCs. Con.A also promoted MSC adaption with high cell viability and ECM production. The injectable decellularized NP biomaterial that used sodium deoxycholate without additional decellularization steps maintained native NP tissue structure and composition closest to natural ECM and promoted cellular adaptation of NP cells and MSCs. This natural decellularized biomaterial warrants further investigation for its potential as an injectable cell seeded supplement to augment NP replacement biomaterials and deliver NPCs or MSCs. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:876-888, 2016. PMID- 26509557 TI - MARVELD1 modulates cell surface morphology and suppresses epithelial-mesenchymal transition in non-small cell lung cancer. AB - Integrins have been known to play pivotal roles in malignant progression and epithelial-mesenchymal transition (EMT) of non-small cell lung cancer (NSCLC). We previously demonstrated that MARVELD1, a potential tumor suppressor, is epigenetically silenced in multiple cancer cells. In this study, we found MARVELD1 silencing altered cell surface ultrastructure of NSCLC cells and inhibited the formation of punctate integrin beta1/beta4 cluster in microvillus, whereas MARVELD1 overexpression suppressed TGF-beta1-induced EMT. Remarkably, the balance of integrin beta1 and beta4 was modulated by MARVELD1. MARVELD1 silencing led to imbalance of integrin beta1/beta4 and significantly reduced microvillus length, furthermore affected the localization of beta1/beta4 at microvilli tips. TGF-beta1-induced EMT was promoted by MARVELD1 silencing, while rebalance of integrin beta1/beta4 partly rescued the epithelial phenotype of MARVELD1-silenced cells. Mechanistically, we demonstrate that MARVELD1-mediated balance of integrin beta1 and beta4 regulates cell surface ultrastructure and EMT phenotype of NSCLC cells, suggesting MARVELD1 has a potential to be developed as a therapeutic target for NSCLC. (c) 2015 Wiley Periodicals, Inc. PMID- 26509558 TI - A liposome-based size calibration method for measuring microvesicles by flow cytometry. AB - ESSENTIALS: A gold standard to determine the sizes of microvesicles by flow cytometry is needed. We used fluorescently labeled liposomes to estimate the size of microvesicles with flow cytometry. We suggest that liposomes are more accurate size calibrators than the commonly used polystyrene beads. The liposome-based size calibrators improve the size assessment of microvesicle made with flow cytometry. BACKGROUND: During the past years, the need for a gold standard to determine the sizes of extracellular vesicles including microvesicles by flow cytometry has been emphasized. METHODS: This work suggests that artificial vesicles can be used as calibrators to estimate the size of microvesicles from the side scattering (SSC) measured with flow cytometry. We prepared fluorescently labeled liposomes with different maximum sizes defined by the pore size (200, 400, 800, and 1000 nm) of the membrane used for the extrusion. The fluorescence strengths from the largest liposomes pertaining to each pore size enabled us to verify the correlation between the SSC from a liposome and the corresponding size. CONCLUSIONS: This study indicates that artificial vesicles are more accurate size calibrators compared to the commonly used polystyrene calibrator beads illustrated by the SSC from 110 nm polystyrene beads corresponds to the scattering from ~400 nm vesicle-like particles. We also show that this method of size assessment based on SSC has a low resolution that is roughly estimated to be between 60 and 200 nm, dependent on the vesicle size. PMID- 26509559 TI - Cervical vertebrae maturation index estimates on cone beam CT: 3D reconstructions vs sagittal sections. AB - OBJECTIVES: The aim of this study was to evaluate the performance of CBCT three dimensional (3D) reconstructions and sagittal sections for estimates of cervical vertebrae maturation index (CVMI). METHODS: The sample consisted of 72 CBCT examinations from patients aged 8-16 years (45 females and 27 males) selected from the archives of two private clinics. Two calibrated observers (kappa scores: >=0.901) interpreted the CBCT settings twice. Intra- and interobserver agreement for both imaging exhibition modes was analyzed by kappa statistics, which was also used to analyze the agreement between 3D reconstructions and sagittal sections. Correlations between cervical vertebrae maturation estimates and chronological age, as well as between the assessments by 3D reconstructions and sagittal sections, were analyzed using gamma Goodman-Kruskal coefficients (alpha = 0.05). RESULTS: The kappa scores evidenced almost perfect agreement between the first and second assessments of the cervical vertebrae by 3D reconstructions (0.933-0.983) and sagittal sections (0.983-1.000). Similarly, the agreement between 3D reconstructions and sagittal sections was almost perfect (kappa index: 0.983). In most divergent cases, the difference between 3D reconstructions and sagittal sections was one stage of CVMI. Strongly positive correlations (>0.8, p < 0.001) were found not only between chronological age and CVMI but also between the estimates by 3D reconstructions and sagittal sections (p < 0.001). CONCLUSIONS: Although CBCT imaging must not be used exclusively for this purpose, it may be suitable for skeletal maturity assessments. PMID- 26509560 TI - [The middle lobe syndrome]. PMID- 26509561 TI - Informed Consent in Contrast-Enhanced CT: Understanding of Risks and Identification of Possible Prognostic Factors. AB - PURPOSE: Aim of our study was to assess understanding of risks associated with intravascular application of contrast media in patients undergoing CT examination. We wanted to evaluate epidemiologic and socio-economic prognostic factors for a higher understanding of risks. Additionally, we evaluated a possible correlation between an extensive, outcome-oriented oral informed consent and better understanding of risks. MATERIALS AND METHODS: 120 patients distributed in 2 study arms participated in this prospective study. In study arm I, the treating physician was not informed that his patients participated in a study whereas the physician in study arm II knew about the survey. After the informed consent we performed a standardized, semi-structured interview to enquire the 3 most frequent risks of intravascular application of contrast agents (anaphylactoid reactions, nephropathy and thyrotoxic crisis) and epidemiologic data. The understanding of the risks was evaluated using a 6 point scale. RESULTS: Patients scored 3.73 points in study arm I and 4.93 points in arm II on average. The statistical difference between both study arms was highly significant (p <0.001). In a combined logistic regression analysis, only "higher education" (p = 0.001) and participation in study arm II (p =0 .001) showed a significant connection to a better understanding of risks. CONCLUSION: Patients profit from an outcome-oriented and individualized informed consent. Due to the significant correlation between educational level and understanding of risks, informed consent should be adjusted to the educational status of the individual patient, e. g. by using didactic aids or individualized information sheets. PMID- 26509562 TI - [Rheumatoid arthritis of the cricoarytenoid joint: important differential diagnosis in uncertain space-occupying lesion of the larynx]. PMID- 26509563 TI - [Heritage Day 2015 - "there is lots to do, yes?"]. PMID- 26509564 TI - [Membership discount in STATdx and RADPrimer]. PMID- 26509565 TI - [AG heart and vascular diagnosis - position paper on MRI examination of patients with cardiac pacemakers]. PMID- 26509567 TI - [Admissibility of the delegation of management responsibilities to physician executives]. PMID- 26509568 TI - Custom-Made Foot Orthoses Decrease Medial Foot Loading During Drop Jump in Individuals With Patellofemoral Pain. AB - OBJECTIVE: To investigate the effect of foot orthoses on medial-to-lateral plantar forces during drop jump and single leg squat, and second, to explore the self-reported change in symptoms after 12 weeks of wearing the orthoses in individuals with patellofemoral pain (PFP). DESIGN: Cohort study with 12 weeks of follow-up. SETTING: Hospital setting. PARTICIPANTS: 23 adults with PFP. INTERVENTIONS: Custom-made foot orthoses. MAIN OUTCOME MEASURES: Foot loading (plantar pressure) was collected from the most painful side during drop jump and single leg squat using pressure sensitive Pedar insoles. Primary outcome was the medial-to-lateral peak force under the forefoot during drop jump. The PFP syndrome severity score was used to measure self-reported improvement from baseline to follow-up. RESULTS: Orthoses were associated with a significant 2.9% point (95% confidence intervals: 0.7-5.1) reduction in peak medial-to-lateral force during drop jump. Individuals with a self-reported improvement after 12 weeks had a significant 4.2%-point larger reduction in medial-to-lateral foot loading during drop jump. CONCLUSIONS: This preliminary study showed that foot orthoses were associated with a decrease in medially directed foot loading among individuals with PFP. Individuals, who have an immediate decrease in the medial to-lateral peak force after fitting the orthoses, were more likely to report improvements after 12 weeks of use. PMID- 26509570 TI - Behavioural and Glucocorticoid Responses of a Captive Group of Spider Monkeys to Short-Term Variation in Food Presentation. AB - The presentation of food may affect feeding competition and the well-being of captive social species. We hypothesized that feeding competition in a captive group of 5 black-handed spider monkeys (Ateles geoffroyi) should increase in response to certain food presentations in terms of size, distribution and quality of food, and that higher feeding competition should lead to an increase in agonism and physiological stress (measured by faecal glucocorticoid metabolites, FGCM) as well as to a decrease in affiliation, proximity among individuals and feeding activity. We used 5 experimental treatments representing different combinations of size, distribution and quality of food. We observed social interactions for 100 h, collected 6,500 proximity and feeding activity records, and gathered 226 faecal samples. When food was clumped, individuals spent less time feeding, and there was also significant individual variation in feeding activity within treatments. FGCM levels were higher when food was clumped. These results are probably linked to an increase in feeding competition when food is concentrated. At least in small groups of spider monkeys, dispersing food in two feeding stations may be sufficient to decrease differences among individuals in priority of access to food resources, hence reducing physiological stress and interindividual differences in feeding activity. PMID- 26509571 TI - Proper Patient Selection--The Key to Beneficial Mechanical Thrombectomy in Acute Stroke Therapy. PMID- 26509572 TI - Modeling Invasion Dynamics with Spatial Random-Fitness Due to Micro-Environment. AB - Numerous experimental studies have demonstrated that the microenvironment is a key regulator influencing the proliferative and migrative potentials of species. Spatial and temporal disturbances lead to adverse and hazardous microenvironments for cellular systems that is reflected in the phenotypic heterogeneity within the system. In this paper, we study the effect of microenvironment on the invasive capability of species, or mutants, on structured grids (in particular, square lattices) under the influence of site-dependent random proliferation in addition to a migration potential. We discuss both continuous and discrete fitness distributions. Our results suggest that the invasion probability is negatively correlated with the variance of fitness distribution of mutants (for both advantageous and neutral mutants) in the absence of migration of both types of cells. A similar behaviour is observed even in the presence of a random fitness distribution of host cells in the system with neutral fitness rate. In the case of a bimodal distribution, we observe zero invasion probability until the system reaches a (specific) proportion of advantageous phenotypes. Also, we find that the migrative potential amplifies the invasion probability as the variance of fitness of mutants increases in the system, which is the exact opposite in the absence of migration. Our computational framework captures the harsh microenvironmental conditions through quenched random fitness distributions and migration of cells, and our analysis shows that they play an important role in the invasion dynamics of several biological systems such as bacterial micro habitats, epithelial dysplasia, and metastasis. We believe that our results may lead to more experimental studies, which can in turn provide further insights into the role and impact of heterogeneous environments on invasion dynamics. PMID- 26509573 TI - Radial Shock Wave Devices Generate Cavitation. AB - BACKGROUND: Conflicting reports in the literature have raised the question whether radial extracorporeal shock wave therapy (rESWT) devices and vibrating massage devices have similar energy signatures and, hence, cause similar bioeffects in treated tissues. METHODS AND FINDINGS: We used laser fiber optic probe hydrophone (FOPH) measurements, high-speed imaging and x-ray film analysis to compare fundamental elements of the energy signatures of two rESWT devices (Swiss DolorClast; Electro Medical Systems, Nyon, Switzerland; D-Actor 200; Storz Medical, Tagerwillen, Switzerland) and a vibrating massage device (Vibracare; G5/General Physiotherapy, Inc., Earth City, MO, USA). To assert potential bioeffects of these treatment modalities we investigated the influence of rESWT and vibrating massage devices on locomotion ability of Caenorhabditis elegans (C. elegans) worms. RESULTS: FOPH measurements demonstrated that both rESWT devices generated acoustic waves with comparable pressure and energy flux density. Furthermore, both rESWT devices generated cavitation as evidenced by high-speed imaging and caused mechanical damage on the surface of x-ray film. The vibrating massage device did not show any of these characteristics. Moreover, locomotion ability of C. elegans was statistically significantly impaired after exposure to radial extracorporeal shock waves but was unaffected after exposure of worms to the vibrating massage device. CONCLUSIONS: The results of the present study indicate that both energy signature and bioeffects of rESWT devices are fundamentally different from those of vibrating massage devices. CLINICAL RELEVANCE: Prior ESWT studies have shown that tissues treated with sufficient quantities of acoustic sound waves undergo cavitation build-up, mechanotransduction, and ultimately, a biological alteration that "kick-starts" the healing response. Due to their different treatment indications and contra indications rESWT devices cannot be equated to vibrating massage devices and should be used with due caution in clinical practice. PMID- 26509574 TI - Correction: Analyses of Twelve New Whole Genome Sequences of Cassava Brown Streak Viruses and Ugandan Cassava Brown Streak Viruses from East Africa: Diversity, Supercomputing and Evidence for Further Speciation. PMID- 26509575 TI - The Effect of Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) on Erectile Function: A Systematic Review and Meta-Analysis. AB - BACKGROUND: High prevalence of erectile dysfunction (ED) has been observed in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). However, whether or not CP/CPPS is a risk factor of ED remains unknown and controversial. Therefore, we conducted this systematic review and meta-analysis to evaluate the relationship between CP/CPPS and ED. METHODS: PubMed, Embase, Web of Science, and The Cochrane Library were searched up to November 11, 2014 to identify studies reporting the association between CP/CPPS and ED. Case-control, cohort and cross-sectional studies were included. Quality of the included studies was assessed. The odds ratio of ED and the mean difference of five-item International Index of Erectile Function (IIEF-5) score were pooled using a random effects model. Subgroup analysis and sensitivity analyses were performed. RESULTS: Three cross-sectional studies, two case-control studies, and four retrospective studies with 31,956 participants were included to calculate the pooled odds ratio of ED, and two studies with 1499 participants were included to calculate the pooled mean difference of IIEF-5 scores. A strong correlation was found between CP/CPPS and ED (pooled odds ratio: 3.02, 95% CI: 2.18-4.17, P < 0.01), with heterogeneity across studies (I2 = 65%; P < 0.01). A significant decrease in the IIFE-5 score was observed in the CP/CPPS group (pooled mean difference: -4.54, 95% CI: -5.11--3.98; P < 0.01). CONCLUSION: Our study indicates that patients with CP/CPPS have an increased risk of suffering from ED. Assessment of erectile function is necessary for the therapy of patients with CP/CPPS. Further evidence is necessary to confirm the relationship between CP/CPPS and ED. PMID- 26509576 TI - Binge Ethanol and MDMA Combination Exacerbates Toxic Cardiac Effects by Inducing Cellular Stress. AB - Binge drinking is a common pattern of ethanol consumption among young people. Binge drinkers are especially susceptible to brain damage when other substances are co-administered, in particular 3,4 methylendioxymethamphetamine (MDMA). The aim of the present work was to study the mechanisms implicated in the adaptive changes observed after administration of these drugs of abuse. So, we have evaluated the cardiac sympathetic activity and the expression and activation of heat shock protein 27 (HSP27), after voluntary binge ethanol consumption, alone and in combination with MDMA. Both parameters are markers of stressful situations and they could be modified inducing several alterations in different systems. Adolescent mice received MDMA, ethanol or both (ethanol plus MDMA). Drinking in the dark (DID) procedure was used as a model of binge. Noradrenaline (NA) turnover, tyrosine hydroxylase (TH), TH phosphorylated at serine 31 and HSP27 expression and its phosphorylation at serine 82 were evaluated in adolescent mice 48 h, 72 h, and 7 days after treatments in the left ventricle. NA and normetanephrine (NMN) were determined by high-performance liquid chromatography (HPLC); TH and HSP27 expression and phosphorylation were measured by quantitative blot immunollabeling using specific antibodies. Ethanol and MDMA co administration increased NA turnover and TH expression and phosphorylation versus the consumption of each one of these drugs. In parallel with the described modifications in the cardiac sympathetic activity, our results showed that binge ethanol+MDMA exposure is associated with an increase in HSP27 expression and phosphorylation in the left ventricle, supporting the idea that the combination of both drugs exacerbates the cellular stress induced by ethanol or MDMA alone. PMID- 26509577 TI - Impact of Facial Conformation on Canine Health: Brachycephalic Obstructive Airway Syndrome. AB - The domestic dog may be the most morphologically diverse terrestrial mammalian species known to man; pedigree dogs are artificially selected for extreme aesthetics dictated by formal Breed Standards, and breed-related disorders linked to conformation are ubiquitous and diverse. Brachycephaly--foreshortening of the facial skeleton--is a discrete mutation that has been selected for in many popular dog breeds e.g. the Bulldog, Pug, and French Bulldog. A chronic, debilitating respiratory syndrome, whereby soft tissue blocks the airways, predominantly affects dogs with this conformation, and thus is labelled Brachycephalic Obstructive Airway Syndrome (BOAS). Despite the name of the syndrome, scientific evidence quantitatively linking brachycephaly with BOAS is lacking, but it could aid efforts to select for healthier conformations. Here we show, in (1) an exploratory study of 700 dogs of diverse breeds and conformations, and (2) a confirmatory study of 154 brachycephalic dogs, that BOAS risk increases sharply in a non-linear manner as relative muzzle length shortens. BOAS only occurred in dogs whose muzzles comprised less than half their cranial lengths. Thicker neck girths also increased BOAS risk in both populations: a risk factor for human sleep apnoea and not previously realised in dogs; and obesity was found to further increase BOAS risk. This study provides evidence that breeding for brachycephaly leads to an increased risk of BOAS in dogs, with risk increasing as the morphology becomes more exaggerated. As such, dog breeders and buyers should be aware of this risk when selecting dogs, and breeding organisations should actively discourage exaggeration of this high-risk conformation in breed standards and the show ring. PMID- 26509578 TI - Transport Mechanisms and Quality Changes During Frying of Chicken Nuggets--Hybrid Mixture Theory Based Modeling and Experimental Verification. AB - Hybrid mixture theory (HMT) based 2-scale fluid transport relations of Takhar coupled with a multiphase heat transfer equation were solved to model water, oil and gas movement during frying of chicken nuggets. A chicken nugget was treated as a heterogeneous material consisting of meat core with wheat-based coating. The coupled heat and fluid transfer equations were solved using the finite element method. Numerical simulations resulted in data on spatial and temporal profiles for moisture, rate of evaporation, temperature, oil, pore pressure, pressure in various phases, and coefficient of elasticity. Results showed that most of the oil stayed in the outer 1.5 mm of the coating region. Temperature values greater than 100 degrees C were observed in the coating after 30 s of frying. Negative gage-pore pressure (p(w) < p(g)) magnitudes were observed in simulations, which is in agreement with experimental observations of Sandhu and others. It is hypothesized that high water-phase capillary pressure (p(c) > p(g)) in the hydrophilic matrix causes p(w) < p(g), which further results in negative pore pressure. The coefficient of elasticity was the highest at the surface (2.5 * 10(5) Pa) for coating and the interface of coating and core (6 * 10(5) Pa). Kinetics equation for color change obtained from experiments was coupled with the HMT based model to predict the color (L, a, and b) as a function of frying time. PMID- 26509579 TI - Multiplex Identification of Antigen-Specific T Cell Receptors Using a Combination of Immune Assays and Immune Receptor Sequencing. AB - Monitoring antigen-specific T cells is critical for the study of immune responses and development of biomarkers and immunotherapeutics. We developed a novel multiplex assay that combines conventional immune monitoring techniques and immune receptor repertoire sequencing to enable identification of T cells specific to large numbers of antigens simultaneously. We multiplexed 30 different antigens and identified 427 antigen-specific clonotypes from 5 individuals with frequencies as low as 1 per million T cells. The clonotypes identified were validated several ways including repeatability, concordance with published clonotypes, and high correlation with ELISPOT. Applying this technology we have shown that the vast majority of shared antigen-specific clonotypes identified in different individuals display the same specificity. We also showed that shared antigen-specific clonotypes are simpler sequences and are present at higher frequencies compared to non-shared clonotypes specific to the same antigen. In conclusion this technology enables sensitive and quantitative monitoring of T cells specific for hundreds or thousands of antigens simultaneously allowing the study of T cell responses with an unprecedented resolution and scale. PMID- 26509581 TI - Validation of Spectra and Phase in Sub-1 cm(-1) Resolution Sum-Frequency Generation Vibrational Spectroscopy through Internal Heterodyne Phase-Resolved Measurement. AB - Reliable determination of the spectral features and their phases in sum-frequency generation vibrational spectroscopy (SFG-VS) for surfaces with closely overlapping peaks has been a standing issue. Here we present two approaches toward resolving such issue. The first utilizes the high-resolution and accurate line shape from the recently developed subwavenumber high-resolution broadband SFG-VS (HR-BB-SFG-VS), from which the detail spectral parameters, including relative spectral phases, of overlapping peaks can be determined through reliable spectral fitting. These results are further validated by using the second method that utilizes the azimuthal angle phase dependence of the z-cut alpha-quartz crystal, a common phase standard, through the spectral interference between the SFG fields of the quartz surface, as the internal phase reference, and the adsorbed molecular layer. Even though this approach is limited to molecular layers that can be transferred or deposited onto the quartz surface, it is simple and straightforward, as it requires only an internal phase standard with a single measurement that is free of phase drifts. More importantly, it provides unambiguous SFG spectral phase information on such surfaces. Using this method, the absolute phase of the molecular susceptibility tensors of the CH3, CH2, and chiral C-H groups in different Langmuir-Blodgett (LB) molecular monolayers and drop-cast peptide films are determined. These two approaches are fully consistent with and complement to each other, making both easily applicable tools in SFG-VS studies. More importantly, because the HR-BB-SFG-VS technique can be easily applied to various surfaces and interfaces, such validation of the spectral and phase information from HR-BB-SFG-VS measurement demonstrates it as one of the most promising tools for interrogating the detailed structure and interactions of complex molecular interfaces. PMID- 26509580 TI - Early Holocenic and Historic mtDNA African Signatures in the Iberian Peninsula: The Andalusian Region as a Paradigm. AB - Determining the timing, identity and direction of migrations in the Mediterranean Basin, the role of "migratory routes" in and among regions of Africa, Europe and Asia, and the effects of sex-specific behaviors of population movements have important implications for our understanding of the present human genetic diversity. A crucial component of the Mediterranean world is its westernmost region. Clear features of transcontinental ancient contacts between North African and Iberian populations surrounding the maritime region of Gibraltar Strait have been identified from archeological data. The attempt to discern origin and dates of migration between close geographically related regions has been a challenge in the field of uniparental-based population genetics. Mitochondrial DNA (mtDNA) studies have been focused on surveying the H1, H3 and V lineages when trying to ascertain north-south migrations, and U6 and L in the opposite direction, assuming that those lineages are good proxies for the ancestry of each side of the Mediterranean. To this end, in the present work we have screened entire mtDNA sequences belonging to U6, M1 and L haplogroups in Andalusians--from Huelva and Granada provinces--and Moroccan Berbers. We present here pioneer data and interpretations on the role of NW Africa and the Iberian Peninsula regarding the time of origin, number of founders and expansion directions of these specific markers. The estimated entrance of the North African U6 lineages into Iberia at 10 ky correlates well with other L African clades, indicating that U6 and some L lineages moved together from Africa to Iberia in the Early Holocene. Still, founder analysis highlights that the high sharing of lineages between North Africa and Iberia results from a complex process continued through time, impairing simplistic interpretations. In particular, our work supports the existence of an ancient, frequently denied, bridge connecting the Maghreb and Andalusia. PMID- 26509582 TI - Imaging of Proteins in Tissue Samples Using Nanospray Desorption Electrospray Ionization Mass Spectrometry. AB - Chemical maps of tissue samples provide important information on biological processes therein. Recently, advances in tissue imaging have been achieved using ambient ionization techniques, such as desorption electrospray ionization mass spectrometry (DESI-MS), but such techniques have been almost exclusively confined to the mapping of lipids and metabolites. We report here the use of nanospray desorption electrospray ionization (nanoDESI) that allows us to image proteins in tissue samples in a label-free manner at atmospheric pressure with only minimum sample preparation. Multiply charged proteins with masses up to 15 kDa were successfully detected by nanoDESI using an LTQ Orbitrap mass spectrometer. In an adult mice brain section, expression of proteins including ubiquitin, beta thymosin, myelin basic protein, and hemoglobin were spatially mapped and characterized. We also determined the location of methylation on myelin basic protein. This imaging modality was further implemented to MYC-induced lymphomas. We observed an array of truncated proteins in the region where normal thymus cells were infiltrated by tumor cells, in contrast to healthy tissue. PMID- 26509583 TI - Metal/Oxide Interface Nanostructures Generated by Surface Segregation for Electrocatalysis. AB - Strong metal/oxide interactions have been acknowledged to play prominent roles in chemical catalysis in the gas phase, but remain as an unexplored area in electrocatalysis in the liquid phase. Utilization of metal/oxide interface structures could generate high performance electrocatalysts for clean energy storage and conversion. However, building highly dispersed nanoscale metal/oxide interfaces on conductive scaffolds remains a significant challenge. Here, we report a novel strategy to create metal/oxide interface nanostructures by growing mixed metal oxide nanoparticles on carbon nanotubes (CNTs) and then selectively promoting migration of one of the metal ions to the surface of the oxide nanoparticles and simultaneous reduction to metal. Employing this strategy, we have synthesized Ni/CeO2 nanointerfaces coupled with CNTs. The Ni/CeO2 interface promotes hydrogen evolution catalysis by facilitating water dissociation and modifying the hydrogen binding energy. The Ni/CeO2-CNT hybrid material exhibits superior activity for hydrogen evolution as a result of synergistic effects including strong metal/oxide interactions, inorganic/carbon coupling, and particle size control. PMID- 26509584 TI - Aerobic interval exercise improves parameters of nonalcoholic fatty liver disease (NAFLD) and other alterations of metabolic syndrome in obese Zucker rats. AB - Metabolic syndrome (MS) is a group of metabolic alterations that increase the susceptibility to cardiovascular disease and type 2 diabetes. Nonalcoholic fatty liver disease has been described as the liver manifestation of MS. We aimed to test the beneficial effects of an aerobic interval training (AIT) protocol on different biochemical, microscopic, and functional liver alterations related to the MS in the experimental model of obese Zucker rat. Two groups of lean and obese animals (6 weeks old) followed a protocol of AIT (4 min at 65%-80% of maximal oxygen uptake, followed by 3 min at 50%-65% of maximal oxygen uptake for 45-60 min, 5 days/week, 8 weeks of experimental period), whereas 2 control groups remained sedentary. Obese rats had higher food intake and body weight (P < 0.0001) and suffered significant alterations in plasma lipid profile, area under the curve after oral glucose overload (P < 0.0001), liver histology and functionality, and antioxidant status. The AIT protocol reduced the severity of alterations related to glucose and lipid metabolism and increased the liver protein expression of PPARgamma, as well as the gene expression of glutathione peroxidase 4 (P < 0.001). The training protocol also showed significant effects on the activity of hepatic antioxidant enzymes, although this action was greatly influenced by rat phenotype. The present data suggest that AIT protocol is a feasible strategy to improve some of the plasma and liver alterations featured by the MS. PMID- 26509586 TI - Histone deacetylase-mediated silencing of AMWAP expression contributes to cisplatin nephrotoxicity. AB - Cisplatin-induced acute kidney injury is a serious problem in cancer patients during treatment of solid tumors. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. Since histone deacetylase (HDAC) inhibition augments cisplatin anti-tumor activity, we tested whether HDAC inhibitors can prevent cisplatin-induced nephrotoxicity and determined the underlying mechanism. Cisplatin upregulated the expression of several HDACs in the kidney. Inhibition of HDAC with clinically used trichostatin A suppressed cisplatin-induced kidney injury, inflammation, and epithelial cell apoptosis. Moreover, trichostatin A upregulated the novel anti-inflammatory protein, activated microglia/macrophage WAP domain protein (AMWAP), in epithelial cells which was enhanced with cisplatin treatment. Interestingly, HDAC1 and -2 specific inhibitors are sufficient to potently upregulate AMWAP in epithelial cells. Administration of recombinant AMWAP or its epithelial cell-specific overexpression reduced cisplatin-induced kidney dysfunction. Moreover, AMWAP treatment suppressed epithelial cell apoptosis, and siRNA-based knockdown of AMWAP expression abolished trichostatin A-mediated suppression of epithelial cell apoptosis in vitro. Thus, HDAC-mediated silencing of AMWAP may contribute to cisplatin nephrotoxicity. Hence, HDAC1 and -2 specific inhibitors or AMWAP could be useful therapeutic agents for the prevention of cisplatin nephrotoxicity. PMID- 26509587 TI - Assessing the risk of incident hypertension and chronic kidney disease after exposure to shock wave lithotripsy and ureteroscopy. AB - In this study we sought to determine if among individuals with urolithiasis, extracorporeal shock wave lithotripsy (SWL) and ureteroscopy are associated with a higher risk of incident arterial hypertension (HTN) and/or chronic kidney disease (CKD). This was measured in a population-based retrospective study of 11,570 participants with incident urolithiasis and 127,464 without urolithiasis in The Health Improvement Network. Patients with pre-existing HTN and CKD were excluded. The study included 1319 and 919 urolithiasis patients with at least one SWL or URS procedure, respectively. Multivariable Cox regression was used to estimate the hazard ratio for incident CKD stage 3-5 and HTN in separate analyses. Over a median of 3.7 and 4.1 years, 1423 and 595 of urolithiasis participants developed HTN and CKD, respectively. Urolithiasis was associated with a significant hazard ratio each for HTN of 1.42 (95% CI: 1.35, 1.51) and for CKD of 1.82 (1.67, 1.98). SWL was associated with a significant increased risk of HTN 1.34 (1.15, 1.57), while ureteroscopy was not. When further stratified as SWL to the kidney or ureter, only SWL to the kidney was significantly and independently associated with HTN 1.40 (1.19, 1.66). Neither SWL nor ureteroscopy was associated with incident CKD. Since urolithiasis itself was associated with a hazard ratio of 1.42 for HTN, an individual who undergoes SWL to the kidney can be expected to have a significantly increased hazard ratio for HTN of 1.96 (1.67, 2.29) compared with an individual without urolithiasis. PMID- 26509589 TI - AT1 receptor antagonism before ischemia prevents the transition of acute kidney injury to chronic kidney disease. AB - Despite clinical recovery of patients from an episode of acute kidney injury (AKI), progression to chronic kidney disease (CKD) is possible on long-term follow-up. However, mechanisms of this are poorly understood. Here, we determine whether activation of angiotensin-II type 1 receptors during AKI triggers maladaptive mechanisms that lead to CKD. Nine months after AKI, male Wistar rats develop CKD characterized by renal dysfunction, proteinuria, renal hypertrophy, glomerulosclerosis, tubular atrophy, and tubulointerstitial fibrosis. Renal injury was associated with increased oxidative stress, inflammation, alpha-smooth muscle actin expression, and activation of transforming growth factor beta; the latter mainly found in epithelial cells. Although administration of losartan prior to the initial ischemic insult did not prevent or reduce AKI severity, it effectively prevented eventual CKD. Three days after AKI, renal dysfunction, tubular structural injury, and elevation of urinary biomarkers were present. While the losartan group had similar early renal injury, renal perfusion was completely restored as early as day 3 postischemia. Further, there was increased vascular endothelial growth factor expression and an early activation of hypoxia inducible factor 1 alpha, a transcription factor that regulates expression of many genes that help reduce renal injury. Thus, AT1 receptor antagonism prior to ischemia prevented AKI to CKD transition by improving early renal blood flow recovery, lesser inflammation, and increased hypoxia-inducible factor 1 alpha activity. PMID- 26509588 TI - Increased plasma kidney injury molecule-1 suggests early progressive renal decline in non-proteinuric patients with type 1 diabetes. AB - Progressively decreasing glomerular filtration rate (GFR), or renal decline, is seen in patients with type 1 diabetes (T1D) and normoalbuminuria or microalbuminuria. Here we examined the associations of kidney injury molecule-1 (KIM-1) in plasma and urine with the risk of renal decline and determine whether those associations are independent of markers of glomerular damage. The study group comprised patients with T1D from the 2nd Joslin Kidney Study of which 259 had normoalbuminuria and 203 had microalbuminuria. Serial measurements over 4 to 10 years of follow-up (median 8 years) of serum creatinine and cystatin C were used jointly to estimate eGFRcr-cys slopes and time of onset of CKD stage 3 or higher. Baseline urinary excretion of IgG2 and albumin were used as markers of glomerular damage, and urinary excretion of KIM-1 and its plasma concentration were used as markers of proximal tubular damage. All patients had normal renal function at baseline. During follow-up, renal decline (eGFRcr-cys loss 3.3% or more per year) developed in 96 patients and 62 progressed to CKD stage 3. For both outcomes, the risk rose with increasing baseline levels of plasma KIM-1. In multivariable models, elevated baseline plasma KIM-1 was strongly associated with risk of early progressive renal decline, regardless of baseline clinical characteristics, serum TNFR1 or markers of glomerular damage. Thus, damage to proximal tubules may play an independent role in the development of early progressive renal decline in non-proteinuric patients with T1D. PMID- 26509590 TI - Long wavelength multiphoton excitation is advantageous for intravital kidney imaging. AB - Intravital multiphoton microscopy is a powerful tool to study kidney physiology in living animals. However, certain technical issues have curbed its usage to date, including limited depth of tissue penetration and high background emission of endogenous signals. Most previous studies have used the excitation range 700 1000 nm. Since newer longer wavelength excitation lasers may provide solutions to these problems we constructed a microscope coupled to a laser tunable up to 1300 nm and optimized for kidney imaging. This set-up offers substantial advantages for intravital studies, especially when coupled with newly available far-red probes. First, the background at longer wavelengths is markedly reduced, thus increasing the signal to background ratio. Second, the depth of tissue penetration is significantly increased, enabling detailed imaging of previously inaccessible structures, such as deeper glomeruli. Third, using a combination of two- and three-photon excitation, multiple different fluorescent probes can be imaged simultaneously in the same animal, with clear spectral separation. Application of these techniques helped visualize pathological aspects of tubular cell function in a well-established model of acute kidney injury (maleate toxicity). Thus, utilizing long wavelength excitation offers substantial advantages for intravital kidney imaging, which together enhance the capabilities of this powerful and increasingly used research technique. PMID- 26509591 TI - Using experimental evolution to probe molecular mechanisms of protein function. AB - Directed evolution is a powerful tool for engineering protein function. The process of directed evolution involves iterative rounds of sequence diversification followed by assaying activity of variants and selection. The range of sequence variants and linked activities generated in the course of an evolution are a rich information source for investigating relationships between sequence and function. Key residue positions determining protein function, combinatorial contributors to activity and even potential functional mechanisms have been revealed in directed evolutions. The recent application of high throughput sequencing substantially increases the information that can be retrieved from directed evolution experiments. Combined with computational analysis this additional sequence information has allowed high-resolution analysis of individual residue contributions to activity. These developments promise to significantly enhance the depth of insight that experimental evolution provides into mechanisms of protein function. PMID- 26509592 TI - Corrigendum: Collective Motion of Swarming Agents Evolving on a Sphere Manifold: A Fundamental Framework and Characterization. PMID- 26509593 TI - Synthesis and antibiotic activity of oxazolidinone-catechol conjugates against Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a Gram-negative pathogenic bacterium responsible for severe infections in which resistance to most of the approved families of antibiotics is increasing. Oxazolidinone antibiotics are active against many Gram positive bacteria, but are only weakly active against Gram-negative pathogens. We describe the synthesis of conjugates between a catechol moiety and oxazolidinone antibiotics. These conjugates were significantly more active against P. aeruginosa (218-1024 MUM) than linezolid (MIC > 1024 MUM), the reference molecule from the oxazolidinone family. Antibiotic activity was slightly higher in medium depleted of iron, suggesting the involvement of a bacterial iron uptake system in this biological activity. The bacterial iron uptake pathway involved in the transport is still to be addressed, but the present data excluded a contribution of the enterobactin transporter PfeA. PMID- 26509594 TI - Marital Status and Postoperative Functional Recovery. PMID- 26509595 TI - Severity of Mitral Valve Degeneration Is Associated with Chromosome 15 Loci in Whippet Dogs. AB - Mitral valve degeneration (MVD) is the most common form of heart disease in dogs, frequently leading to left-sided congestive heart failure and cardiac mortality. Although breed-specific disease characteristics and overrepresentation point towards a genetic origin for MVD, a causative mutation and complete molecular pathogenesis are unknown. Whippet dogs are overrepresented in incidence of MVD, suggesting an inherited component in this breed. Expressivity of this condition is variable with some dogs showing evidence of more severe disease at earlier ages than other dogs. This phenomenon makes a traditional case versus control genetic study prone to phenotyping error. This study sought to avoid these common pitfalls by identifying genetic loci associated with severity of MVD in Whippets through a genome-wide association study (GWAS). 138 Whippet dogs were characterized for MVD by echocardiographic examination and a novel disease severity score was developed and adjusted for age in each subject. Single nucleotide polymorphism (SNP) genotype data (170k Illumina CanineHD SnpChip) was obtained for DNA isolated from blood of each study subject. Continuous variable genome wide association was performed after correction for population stratification by efficient mixed model association expedited (EMMAX) in 130 dogs. A genome wide significant association was identified on chromosome 15 (peak locus 57,770,326; Padj = 0.049) and secondary loci of suggestive association were identified on chromosome 2 (peak locus 37,628,875; Padj = 0.079). Positional candidate genes were identified within the primary and secondary loci including follistatin-related protein 5 precursor (FSTL5) and Rho GTPase-activating protein 26 (ARHGAP26). These results support the hypothesis that severity of MVD in whippets has a genetic basis and warrants further study by either candidate gene sequencing or next-generation techniques. PMID- 26509596 TI - Resolution limits of ultrafast ultrasound localization microscopy. AB - As in other imaging methods based on waves, the resolution of ultrasound imaging is limited by the wavelength. However, the diffraction-limit can be overcome by super-localizing single events from isolated sources. In recent years, we developed plane-wave ultrasound allowing frame rates up to 20,000 fps. Ultrafast processes such as rapid movement or disruption of ultrasound contrast agents (UCA) can thus be monitored, providing us with distinct punctual sources that could be localized beyond the diffraction limit. We previously showed experimentally that resolutions beyond lambda/10 can be reached in ultrafast ultrasound localization microscopy (uULM) using a 128 transducer matrix in reception. Higher resolutions are theoretically achievable and the aim of this study is to predict the maximum resolution in uULM with respect to acquisition parameters (frequency, transducer geometry, sampling electronics). The accuracy of uULM is the error on the localization of a bubble, considered a point-source in a homogeneous medium. The proposed model consists in two steps: determining the timing accuracy of the microbubble echo in radiofrequency data, then transferring this time accuracy into spatial accuracy. The simplified model predicts a maximum resolution of 40 MUm for a 1.75 MHz transducer matrix composed of two rows of 64 elements. Experimental confirmation of the model was performed by flowing microbubbles within a 60 MUm microfluidic channel and localizing their blinking under ultrafast imaging (500 Hz frame rate). The experimental resolution, determined as the standard deviation in the positioning of the microbubbles, was predicted within 6 MUm (13%) of the theoretical values and followed the analytical relationship with respect to the number of elements and depth. Understanding the underlying physical principles determining the resolution of superlocalization will allow the optimization of the imaging setup for each organ. Ultimately, accuracies better than the size of capillaries are achievable at several centimeter depths. PMID- 26509597 TI - Berberine as a novel light-up i-motif fluorescence ligand and its application in designing molecular logic systems. AB - Berberine, a new light-up fluorescence ligand, for i-motif structures has been reported. This interaction enabled the development of label-free DNA-based logic gates in response to input signals. PMID- 26509598 TI - Unbiased Selection of Peptide-Peptoid Hybrids Specific for Lung Cancer Compared to Normal Lung Epithelial Cells. AB - To develop widely applicable diagnostic and potentially therapeutic approaches overcoming protein heterogeneity in human cancer, we have developed a technology to unbiasedly select high specificity compound(s) that bind any biomolecule (e.g., proteins, lipids, carbohydrates) presented on the cancer cell surface but not on normal cells. We utilized a peptidomimetic based on-bead two-color (OBTC) combinatorial cell screen that can detect differences between two cell surfaces at high accuracy by looking for beads (where each bead in the library had one peptide-peptoid hybrid on the surface) that only bound cancer but not normal cells. We screened a library of 393 216 compounds targeting HCC4017 lung adenocarcinoma cells (labeled in red) in the presence of HBEC30KT normal bronchial epithelial cells (labeled in green) derived from the same tissue of the same patient. This screen identified a peptide-peptoid hybrid called PPS1 which displayed high specific binding for HCC4017 cancer cells over HBEC30KT cells. Specificity was validated through on-bead, ELISA-like and magnetic bead pulldown studies, while a scrambled version of PPS1 did not show any binding. Of interest, the simple dimeric version (PPS1D1) displayed cytotoxic activity on HCC4017 cells, but not on normal HBEC30KT cells. PPS1D1 also strongly accumulated in HCC4017 lung cancer xenografts in mice over control constructs. We conclude that such combinatorial screens using tumor and normal cells from the same patient have significant potential to develop new reagents for cancer biology, diagnosis, and potentially therapy. PMID- 26509600 TI - Understanding Career Success and Its Contributing Factors for Clinical and Translational Investigators. AB - PURPOSE: To understand the factors that facilitate career success for career development awardees in clinical and translational science and reconceptualize understand ing of career success for this population. METHOD: In 2013-2014, the authors conducted semistructured interviews with former NIH KL2 or K12 scholars from nine Clinical and Translational Science Award-funded institutions. Participants either had or had not secured independent funding at least two years after the end of their last K award. Questions covered the factors that facilitate or hinder junior investigators' transition to independent funding. Interviews were recorded and transcribed, and the transcripts were analyzed thematically. RESULTS: Forty individuals participated, with equal representation by men and women and by independently and not independently funded investigators. Personal factors that facilitated success included networks, persistence and resilience, initiative, autonomy, and personal and professional balance. Organizational factors included appropriate mentorship, protected research time, and institutional resources and support.Even independently funded participants described challenges regarding career direction. Five participants without independent funding modeled a broad spectrum of successful career paths, having assumed leadership positions not reliant on grant funding. Alternative definitions of career success included improving public health, enjoying work, seeing mentees succeed, and receiving external acknowledgment of successes. CONCLUSIONS: Awareness of the factors that facilitate or hinder career success can help junior faculty, mentors, and institutional leaders support career development in clinical and translational science. New definitions of career success are needed, as are career paths for faculty who want to engage in research in roles other than principal investigator. PMID- 26509599 TI - Vaccination Method Affects Immune Response and Bacterial Growth but Not Protection in the Salmonella Typhimurium Animal Model of Typhoid. AB - Understanding immune responses elicited by vaccines, together with immune responses required for protection, is fundamental to designing effective vaccines and immunisation programs. This study examines the effects of the route of administration of a live attenuated vaccine on its interactions with, and stimulation of, the murine immune system as well as its ability to increase survival and provide protection from colonisation by a virulent challenge strain. We assess the effect of administration method using the murine model for typhoid, where animals are infected with S. Typhimurium. Mice were vaccinated either intravenously or orally with the same live attenuated S. Typhimurium strain and data were collected on vaccine strain growth, shedding and stimulation of antibodies and cytokines. Following vaccination, mice were challenged with a virulent strain of S. Typhimurium and the protection conferred by the different vaccination routes was measured in terms of challenge suppression and animal survival. The main difference in immune stimulation found in this study was the development of a secretory IgA response in orally-vaccinated mice, which was absent in IV vaccinated mice. While both strains showed similar protection in terms of challenge suppression in systemic organs (spleen and liver) as well as survival, they differed in terms of challenge suppression of virulent pathogens in gut-associated organs. This difference in gut colonisation presents important questions around the ability of vaccines to prevent shedding and transmission. These findings demonstrate that while protection conferred by two vaccines can appear to be the same, the mechanisms controlling the protection can differ and have important implications for infection dynamics within a population. PMID- 26509601 TI - Driving Care Quality: Aligning Trainee Assessment and Supervision Through Practical Application of Entrustable Professional Activities, Competencies, and Milestones. AB - To address the long-standing challenge of meaningful trainee assessment, the authors reviewed and expanded on the Accountable Assessment for Quality Care and Supervision (AAQCS) equation. The equation proposes that care quality is the product of the interaction between trainee performance (measured by workplace assessment) and supervision (required level of intervention to ensure care quality) in the context of the environment where the care occurs: Trainee performance * Appropriate supervision = Safe, effective patient-centered care. Assessing trainee performance and matching that performance to "appropriate" supervision, however, is fraught with challenges. The authors suggest a unifying framework that integrates entrustable professional activities (EPAs), competencies, and milestones to inform trainee assessment and supervision, thereby enabling the practical application of the AAQCS equation in the workplace. Because the unit of measure for an EPA is the outcome of whether the trainee can safely and effectively perform the professional activity without supervision, the proposed unifying framework directly aligns with the dependent variable in the AAQCS equation: care quality.The value of applying a unifying framework that integrates EPAs, competencies, and milestones to the AAQCS equation in the clinical learning environment lies in its ability to provide supervisors with a shared mental model of performance expectations for trainees, reducing unwanted variability and improving assessment accuracy; guidance for aligning performance milestones of trainees with the needed level of supervisor intervention to ensure care quality; and substrate for specific feedback to improve the trainee's professional development as a way to ensure future care quality. PMID- 26509602 TI - Notice of Retraction and Replacement. Lopes et al. Gamma ventral capsulotomy for obsessive-compulsive disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71(9):1066-1076. PMID- 26509603 TI - Dynamic Enhancer Methylation--A Previously Unrecognized Switch for Tissue-Type Plasminogen Activator Expression. AB - Tissue-type plasminogen activator (t-PA), which is synthesized in the endothelial cells lining the blood vessel walls, is a key player in the fibrinolytic system protecting the circulation against occluding thrombus formation. Although classical gene regulation has been quite extensively studied in order to understand the mechanisms behind t-PA regulation, epigenetics, including DNA methylation, still is a largely unexplored field. The aim of this study was to establish the methylation pattern in the t-PA promoter and enhancer in non cultured compared to cultured human umbilical vein endothelial cells (HUVECs), and to simultaneously examine the level of t-PA gene expression. Bisulphite sequencing was used to evaluate the methylation status, and real-time RT-PCR to determine the gene expression level. While the t-PA promoter was stably unmethylated, we surprisingly observed a rapid reduction in the amount of methylation in the enhancer during cell culturing. This demethylation was in strong negative correlation with a pronounced (by a factor of approximately 25) increase in t-PA gene expression levels. In this study, we show that the methylation level in the t-PA enhancer appears to act as a previously unrecognized switch controlling t-PA expression. Our findings, which suggest that DNA methylation is quite dynamic, have implications also for the interpretation of cell culture experiments in general, as well as in a wider biological context. PMID- 26509604 TI - Cucurbit[8]uril-Regulated Nanopatterning of Binary Polymer Brushes via Colloidal Templating. AB - Sub-micrometer/nanoscale patterned polymer brushes are prepared by employing cucurbit[8]uril (CB[8]) as a supramolecular recognition motif to assemble functional silica colloids onto Au surfaces as a sacrificial nanopatterning template. By employing CB[8]-mediated host-guest interactions at the interface, it is possible to readily generate nanopatterned materials in aqueous media under ambient conditions. PMID- 26509622 TI - Second Tumor Induction Risk in IMRT for Prostate Cancer: An Unbalanced Comparison Between Surgery and Radiotherapy? AB - The aim of this study was to evaluate the risk of second tumor induction for prostate patients treated with volumetric modulated arc therapy in age classes 50 70. Based on both age-dependent models and doses to critical organs, the risk of second tumor induction was evaluated simulating the small field (prostate and seminal vesicles) and large field (whole pelvis) for Helical Tomotherapy and Rapid Arc. The doses to the organs closest to the treatment volume were derived from treatment planning system data. Whereas, due to the lack of calculation algorithms where leakage and internal radiation scattering are unreliable at a large distance from target, the doses to the organs outside the treatment volume were measured in an anthropomorphic phantom. Doses from Image Guided Radiotherapy (IGRT) were also assessed on phantom measurements. The Lifetime Attributable Risk (LAR) for second tumor induction increases from 2.2 to 13.7% as irradiated volume increases and age decreases. IGRT could add a non-negligible factor to the risk when daily set-up verification with high-resolution modality is included. As prostate cancer is detected earlier, the probability of an increase in early stage patients rises, and life expectancy thus increases. Radiotherapy has improved its capability in the tailoring of the dose around the target at the cost of a greater dose to surrounding organs, thus increasing the risk of second tumor induction, especially for those patients expected to survive 15 y or more. PMID- 26509605 TI - 24 versus 48 Weeks of Peginterferon Plus Ribavirin in Hepatitis C Virus Genotype 6 Chronically Infected Patients with a Rapid Virological Response: A Non Inferiority Randomized Controlled Trial. AB - OBJECTIVES: The optimal treatment of hepatitis C virus (HCV) genotype 6 is unclear owing to its limited geographic distribution. Because of a high predictive value of rapid virological response (RVR) for sustained virological response (SVR), we conducted an open-label randomized controlled trial to compare 24- and 48-week peginterferon/ribavirin combination therapy for patients with HCV genotype 6 in Southern China who achieved an RVR. METHODS AND FINDINGS: Treatment naive, non-cirrhotic patients with chronic hepatitis C genotype 6 were treated with pegylated interferon alpha-2a (180 MUg/week) and ribavirin (800-1,200 mg, according to weight) for 4 weeks. Patients who achieved an RVR, which was defined as HCV RNA negativity at week 4 (<50 IU), were randomized to receive either an additional 20 or 44 weeks of treatment (24- and 48-week treatment groups, respectively). The primary outcome measure was SVR. From January 2011 to June 2014, 152(152/210, 72.4%) patients with HCV genotype 6a and RVR were randomized 1:1 to the 24- or 48-week treatment group. The SVR rates in the 24- and 48-week groups in the intention-to-treat analysis were 90.8% (69/76) and 88.2% (67/76), respectively; those in the per-protocol analysis were 95.7% (67/70) and 97.0% (64/66), respectively. More patients in the 48-week group had anemia (46.1% vs. 28.9%, P = 0.03), but other adverse events were comparable between the groups. The limitation of the present study was that only patients from Southern China were enrolled which may inhibit the extensive application of the findings. CONCLUSION: Twenty-four weeks of peginterferon/ribavirin combination therapy was non-inferior to 48 weeks in patients with HCV genotype 6a in Southern China who achieved an RVR. TRIAL REGISTRATION: ClinicalTrials.gov NCT01263860. PMID- 26509623 TI - Dosimetric Uncertainties: Magnetic Field Coupling to Peripheral Nerve. AB - The International Commission on Non-ionizing Radiation Protection (ICNIRP) and the Institute for Electrical and Electronic Engineers (IEEE) have established magnetic field exposure limits for the general public between 400 Hz (ICNIRP)/759 Hz (IEEE) and 100 kHz to protect against adverse effects associated with peripheral nerve stimulation (PNS). Despite apparent common purpose and similarly stated principles, the two sets of limits diverge between 3.35-100 kHz by a factor of about 7.7 with respect to PNS. To address the basis for this difference and the more general issue of dosimetric uncertainty, this paper combines experimental data of PNS thresholds derived from human subjects exposed to magnetic fields together with published estimates of induced in situ electric field PNS thresholds to evaluate dosimetric relationships of external magnetic fields to induced fields at the threshold of PNS and the uncertainties inherent to such relationships. The analyses indicate that the logarithmic range of magnetic field thresholds constrains the bounds of uncertainty of in situ electric field PNS thresholds and coupling coefficients related to the peripheral nerve (the coupling coefficients define the dosimetric relationship of external field to induced electric field). The general public magnetic field exposure limit adopted by ICNIRP uses a coupling coefficient that falls above the bounds of dosimetric uncertainty, while IEEE's is within the bounds of uncertainty toward the lower end of the distribution. The analyses illustrate that dosimetric estimates can be derived without reliance on computational dosimetry and the associated values of tissue conductivity. With the limits now in place, investigative efforts would be required if a field measurement were to exceed ICNIRP's magnetic field limit (the reference level), even when there is a virtual certainty that the dose limit (the basic restriction) has not been exceeded. The constraints on the range of coupling coefficients described in this paper could facilitate a re-evaluation of ICNIRP and IEEE dose and exposure limits and possibly lead toward harmonization. PMID- 26509624 TI - A Dosimetry Study of Deuterium-Deuterium Neutron Generator-based In Vivo Neutron Activation Analysis. AB - A neutron irradiation cavity for in vivo neutron activation analysis (IVNAA) to detect manganese, aluminum, and other potentially toxic elements in human hand bone has been designed and its dosimetric specifications measured. The neutron source is a customized deuterium-deuterium neutron generator that produces neutrons at 2.45 MeV by the fusion reaction 2H(d, n)3He at a calculated flux of 7 * 10(8) +/- 30% s(-1). A moderator/reflector/shielding [5 cm high density polyethylene (HDPE), 5.3 cm graphite and 5.7 cm borated (HDPE)] assembly has been designed and built to maximize the thermal neutron flux inside the hand irradiation cavity and to reduce the extremity dose and effective dose to the human subject. Lead sheets are used to attenuate bremsstrahlung x rays and activation gammas. A Monte Carlo simulation (MCNP6) was used to model the system and calculate extremity dose. The extremity dose was measured with neutron and photon sensitive film badges and Fuji electronic pocket dosimeters (EPD). The neutron ambient dose outside the shielding was measured by Fuji NSN3, and the photon dose was measured by a Bicron MicroREM scintillator. Neutron extremity dose was calculated to be 32.3 mSv using MCNP6 simulations given a 10-min IVNAA measurement of manganese. Measurements by EPD and film badge indicate hand dose to be 31.7 +/- 0.8 mSv for neutrons and 4.2 +/- 0.2 mSv for photons for 10 min; whole body effective dose was calculated conservatively to be 0.052 mSv. Experimental values closely match values obtained from MCNP6 simulations. These are acceptable doses to apply the technology for a manganese toxicity study in a human population. PMID- 26509625 TI - A Study of Thyroid 131I Activity of Five Human Subjects Exposed to a Radioactive Plume at Tamura City in Fukushima. AB - Thyroid 131I activities were determined for five human subjects from a disaster medical assistance team of Fukui Prefectural Hospital. The team was dispatched to the Tamura City Sports Park, 40 km from the Fukushima Daiichi nuclear power plant. They were exposed to a radioactive plume on 15 March 2011. In vivo measurements at Fukui Prefectural Hospital were conducted around 17 h after the team left the park. A thyroid counter equipped with a 51-mm-diameter * 51-mm thick NaI(Tl) detector with a 20-mm-thick lead collimator was used. Mock iodine (133Ba and 137Cs) with a thyroid uptake neck phantom was used for calibration. On 16 March 2011, at 11:30, thyroid activity of a member of the team age 53 y, who was never administered stable iodine, was 268 +/- 38 Bq. The remaining four men, aged 49, 35, 34, and 27 y, ingested two stable iodine pills (a total of 100 mg of potassium iodide) approximately 36 h before being exposed to the plume. Their thyroid activity values were 249 +/- 86 Bq, 676 +/- 107 Bq, 569 +/- 96 Bq, and 1,082 +/- 119 Bq, respectively. An inverse relationship between age and thyroid activity was observed among those who ingested potassium iodide before exposure, indicating that stable iodine administration may have a protective effect. Thyroid 131I activity was reduced by approximately 70% in the oldest person. This can be explained by the iodine metabolism in the thyroid of younger individuals being significantly faster than that of older individuals. PMID- 26509626 TI - Workshop Report on Atomic Bomb Dosimetry--Review of Dose Related Factors for the Evaluation of Exposures to Residual Radiation at Hiroshima and Nagasaki. AB - Groups of Japanese and American scientists, supported by international collaborators, have worked for many years to ensure the accuracy of the radiation dosimetry used in studies of health effects in the Japanese atomic bomb survivors. Reliable dosimetric models and systems are especially critical to epidemiologic studies of this population because of their importance in the development of worldwide radiation protection standards. While dosimetry systems, such as Dosimetry System 1986 (DS86) and Dosimetry System 2002 (DS02), have improved, the research groups that developed them were unable to propose or confirm an additional contribution by residual radiation to the survivor's total body dose. In recognition of the need for an up-to-date review of residual radiation exposures in Hiroshima and Nagasaki, a half-day technical session was held for reports on newer studies at the 59 th Annual HPS Meeting in 2014 in Baltimore, MD. A day-and-a-half workshop was also held to provide time for detailed discussion of the newer studies and to evaluate their potential use in clarifying the residual radiation exposure to atomic bomb survivors at Hiroshima and Nagasaki. The process also involved a re-examination of very early surveys of radioisotope emissions from ground surfaces at Hiroshima and Nagasaki and early reports of health effects. New insights were reported on the potential contribution to residual radiation from neutron-activated radionuclides in the airburst's dust stem and pedestal and in unlofted soil, as well as from fission products and weapon debris from the nuclear cloud. However, disparate views remain concerning the actual residual radiation doses received by the atomic bomb survivors at different distances from the hypocenter. The workshop discussion indicated that measurements made using thermal luminescence and optically stimulated luminescence, like earlier measurements, especially in very thin layers of the samples, could be expanded to detect possible radiation exposures to beta particles and to determine their significance plus the extent of the various residual radiation areas at Hiroshima and Nagasaki. Other suggestions for future residual radiation studies are included in this workshop report. PMID- 26509627 TI - Novel Equipment for In Situ Alpha Spectrometry with Good Energy Resolution. AB - An approach for in situ alpha spectrometry that allows one to measure the spectra with good energy resolution at ambient air pressure has been developed recently. Here, novel equipment is introduced for in situ measurements. Neither vacuum pumps nor radiochemical sample processing are necessary. Flat and smooth surfaces are ideal sources provided that the radionuclide contamination represents a thin layer on the surface. Other sources, such as air filters or evaporation residues, are also possible. Alpha particle collimation is used to obtain good energy resolution, but the equipment can also be used without collimation. An estimation of the detection efficiency with and without collimation is given using an extended area source containing 241Am. PMID- 26509628 TI - A Simpler Alternative to the Probability Ratio Model for Simultaneous Source Detection and Count Rate Analysis. PMID- 26509629 TI - Response to Lemay. PMID- 26509634 TI - Specific Effects of Dietary Methylmercury and Inorganic Mercury in Zebrafish (Danio rerio) Determined by Genetic, Histological, and Metallothionein Responses. AB - A multidisciplinary approach is proposed here to compare toxicity mechanisms of methylmercury (MeHg) and inorganic mercury (iHg) in muscle, liver, and brain from zebrafish (Danio rerio). Animals were dietary exposed to (1) 50 ng Hg g(-1), 80% as MeHg; (2) diet enriched in MeHg 10000 ng Hg g(-1), 95% as MeHg; (3) diet enriched in iHg 10000 ng Hg g(-1), 99% as iHg, for two months. Hg species specific bioaccumulation pathways were highlighted, with a preferential bioaccumulation of MeHg in brain and iHg in liver. In the same way, differences in genetic pattern were observed for both Hg species, (an early genetic response (7 days) for both species in the three organs and a late genetic response (62 days) for iHg) and revealed a dissimilar metabolization of both Hg species. Among the 18 studied genes involved in key metabolic pathways of the cell, major genetic responses were observed in muscle. Electron microscopy revealed damage mainly because of MeHg in muscle and also in liver tissue. In brain, high MeHg and iHg concentrations induced metallothionein production. Finally, the importance of the fish origin in ecotoxicological studies, here the seventh descent of a zebrafish line, is discussed. PMID- 26509633 TI - Tumor-Associated Endothelial Cells Promote Tumor Metastasis by Chaperoning Circulating Tumor Cells and Protecting Them from Anoikis. AB - Tumor metastasis is a highly inefficient biological process as millions of tumor cells are released in circulation each day and only a few of them are able to successfully form distal metastatic nodules. This could be due to the fact that most of the epithelial origin cancer cells are anchorage-dependent and undergo rapid anoikis in harsh circulating conditions. A number of studies have shown that in addition to tumor cells, activated endothelial cells are also released into the blood circulation from the primary tumors. However, the precise role of these activated circulating endothelial cells (CECs) in tumor metastasis process is not known. Therefore, we performed a series of experiments to examine if CECs promoted tumor metastasis by chaperoning the tumor cells to distal sites. Our results demonstrate that blood samples from head and neck cancer patients contain significantly higher Bcl-2-positive CECs as compared to healthy volunteers. Technically, it is challenging to know the origin of CECs in patient blood samples, therefore we used an orthotopic SCID mouse model and co-implanted GFP labeled endothelial cells along with tumor cells. Our results suggest that activated CECs (Bcl-2-positive) were released from primary tumors and they co migrated with tumor cells to distal sites. Bcl-2 overexpression in endothelial cells (EC-Bcl-2) significantly enhanced adhesion molecule expression and tumor cell binding that was predominantly mediated by E-selectin. In addition, tumor cells bound to EC-Bcl-2 showed a significantly higher anoikis resistance via the activation of Src-FAK pathway. In our in vivo experiments, we observed significantly higher lung metastasis when tumor cells were co-injected with EC Bcl-2 as compared to EC-VC. E-selectin knockdown in EC-Bcl-2 cells or FAK/FUT3 knockdown in tumor cells significantly reversed EC-Bcl-2-mediated tumor metastasis. Taken together, our results suggest a novel role for CECs in protecting the tumor cells in circulation and chaperoning them to distal sites. PMID- 26509635 TI - Morphological Brain Changes after Climbing to Extreme Altitudes--A Prospective Cohort Study. AB - BACKGROUND: Findings of cerebral cortical atrophy, white matter lesions and microhemorrhages have been reported in high-altitude climbers. The aim of this study was to evaluate structural cerebral changes in a large cohort of climbers after an ascent to extreme altitudes and to correlate these findings with the severity of hypoxia and neurological signs during the climb. METHODS: Magnetic resonance imaging (MRI) studies were performed in 38 mountaineers before and after participating in a high altitude (7126 m) climbing expedition. The imaging studies were assessed for occurrence of new WM hyperintensities and microhemorrhages. Changes of partial volume estimates of cerebrospinal fluid, grey matter, and white matter were evaluated by voxel-based morphometry. Arterial oxygen saturation and acute mountain sickness scores were recorded daily during the climb. RESULTS: On post-expedition imaging no new white matter hyperintensities were observed. Compared to baseline testing, we observed a significant cerebrospinal fluid fraction increase (0.34% [95% CI 0.10-0.58], p = 0.006) and a white matter fraction reduction (-0.18% [95% CI -0.32--0.04], p = 0.012), whereas the grey matter fraction remained stable (0.16% [95% CI -0.46 0.13], p = 0.278). Post-expedition imaging revealed new microhemorrhages in 3 of 15 climbers reaching an altitude of over 7000 m. Affected climbers had significantly lower oxygen saturation values but not higher acute mountain sickness scores than climbers without microhemorrhages. CONCLUSIONS: A single sojourn to extreme altitudes is not associated with development of focal white matter hyperintensities and grey matter atrophy but leads to a decrease in brain white matter fraction. Microhemorrhages indicative of substantial blood-brain barrier disruption occur in a significant number of climbers attaining extreme altitudes. PMID- 26509636 TI - Preference for shelter and additional heat in horses exposed to Nordic winter conditions. AB - REASONS FOR PERFORMING STUDY: Horses may adapt to a wide range of temperatures and weather conditions. Owners often interfere with this natural thermoregulation ability by clipping and use of blankets. OBJECTIVES: To investigate the effects of different winter weather conditions on shelter seeking behaviour of horses and their preference for additional heat. STUDY DESIGN: Observational study in various environments. METHODS: Mature horses (n = 22) were given a free choice test between staying outdoors, going into a heated shelter compartment or into a nonheated shelter compartment. Horse location and behaviour was scored using instantaneous sampling every minute for 1 h. Each horse was tested once per day and weather factors were continuously recorded by a local weather station. RESULTS: The weather conditions influenced time spent outdoors, ranging from 52% (of all observations) on days with mild temperatures, wind and rain to 88% on days with <0 degrees C and dry weather. Shivering was only observed during mild temperatures and rain/sleet. Small Warmblood horses were observed to select outdoors less (34% of all observations) than small Coldblood horses (80%). We found significant correlations between hair coat sample weight and number of observations outdoors (rho = 0.23; P = 0.004). CONCLUSIONS: Horses selected shelters the most on days with precipitation and horses changed from a nonheated compartment to a heated compartment as weather changed from calm and dry to wet and windy. Horse breed category affected the use of shelter and body condition score and hair coat weight were associated with voluntary shelter selection. PMID- 26509638 TI - Development of an Orthogonal Protection Strategy for the Synthesis of Mycobacterial Arabinomannan Fragments. AB - Mycobacterium tuberculosis, the organism that causes tuberculosis (TB), has a carbohydrate-rich cell wall structure that possesses a number of immunogenic antigens. Circulating antibodies that recognize these glycans are present in patients infected by mycobacteria; detection of these antibodies could be the basis for new TB diagnostics. We describe here the synthesis of a panel of mycobacterial arabinomannan fragments for use in investigations directed at testing the feasibility of such a diagnostic method. In this study, we focused on structural motifs present in the core of the key immunogenic polysaccharide lipoarabinomannan (LAM). To access these compounds, we developed an efficient orthogonal protection strategy that allowed access to seven arabinomannan fragments of LAM (1-7). The targets included one tetrasaccharide, one pentasaccharide, three octasaccharides, and two nonasaccharides. Starting from a differentially protected trimannopyranoside derivative (8 or 9), the targets were obtained using an approach that involved selective removal of the protecting group present at the O-2 position of a single mannopyranoside residue, followed by glycosylation with a pentaarabinofuranose thioglycoside and/or a mannopyranose trichloroacetimidate. PMID- 26509637 TI - Anti-Transcription Factor RNA Aptamers as Potential Therapeutics. AB - Transcription factors (TFs) are DNA-binding proteins that play critical roles in regulating gene expression. These proteins control all major cellular processes, including growth, development, and homeostasis. Because of their pivotal role, cells depend on proper TF function. It is, therefore, not surprising that TF deregulation is linked to disease. The therapeutic drug targeting of TFs has been proposed as a frontier in medicine. RNA aptamers make interesting candidates for TF modulation because of their unique characteristics. The products of in vitro selection, aptamers are short nucleic acids (DNA or RNA) that bind their targets with high affinity and specificity. Aptamers can be expressed on demand from transgenes and are intrinsically amenable to recognition by nucleic acid-binding proteins such as TFs. In this study, we review several natural prokaryotic and eukaryotic examples of RNAs that modulate the activity of TFs. These examples include 5S RNA, 6S RNA, 7SK, hepatitis delta virus-RNA (HDV-RNA), neuron restrictive silencer element (NRSE)-RNA, growth arrest-specific 5 (Gas5), steroid receptor RNA activator (SRA), trophoblast STAT utron (TSU), the 3' untranslated region of caudal mRNA, and heat shock RNA-1 (HSR1). We then review examples of unnatural RNA aptamers selected to inhibit TFs nuclear factor-kappaB (NF-kappaB), TATA-binding protein (TBP), heat shock factor 1 (HSF1), and runt-related transcription factor 1 (RUNX1). The field of RNA aptamers for DNA-binding proteins continues to show promise. PMID- 26509639 TI - Product comparison model in otolaryngology: Equivalency analysis of absorbable hemostatic agents after endoscopic sinus surgery. AB - OBJECTIVES/HYPOTHESIS: Evidence-based medicine in otolaryngology literature continues to be lacking, especially with regard to new products brought to market. The marketing of products often includes statements of benefit that have limited objective support in research or literature. To address this, and to adequately determine product equivalency/superiority, careful evaluation must be made. In order to establish standards for this process in rhinology products, we directly compare three different absorbable hemostatic agents in patients with chronic rhinosinusitis (CRS) after undergoing endoscopic sinus surgery (ESS), using both objective and subjective outcomes. STUDY DESIGN: Double-blinded prospective (level 1) comparison and equivalency analysis of three plant-based absorbable hemostatic agents (carboxymethylcellulose [CMC] gel, mucopolysaccharide hemospheres (MPH), and potato starch wafer) in patients undergoing bilateral ESS. METHODS: Patients with medically refractory CRS who underwent bilateral ESS were recruited and prospectively followed. At the conclusion of ESS, one of three different hemostatic agents was applied to each nasal passage. Subjective patient data was obtained using rated symptoms compared between the two sides (nasal obstruction, bleeding, pain, and nasal discharge) at baseline and on postoperative days 1, 7, and 14. Objective data was obtained by blinded endoscopic scoring to rate mucosal edema, inflammation, granulation, crusting, infection, and synechiae formation on postoperative weeks 1, 3, and 6. RESULTS: Forty-eight patients who underwent ESS for CRS were included. There is no statistical difference in subjective scores for any of the variables measured, although (MPH) nearly reached statistical significance at postoperative day 7 for increased pain (P = 0.06) and obstruction (P = 0.22). Objective measures showed equivalency between all products, except the CMC gel approached significance at week 3 for increased crusting (P = 0.10), granulation (P = 0.24), and debridement (P = 0.07). At 6 weeks, increased debridement (P = 0.14) also approached significance. CONCLUSION: Careful and deliberate consideration should be taken when choosing products to assist our surgical endeavors. Subjectively, patients treated with MPH showed near-significant increases in pain and obstruction. In objective measures, CMC gel nearly reaches significance for more postoperative debridement, with increased crusting and inflammation. Product choice could consider these factors, although it remains at the discretion of the surgeon. This model of comparison allows careful product comparison and should be applied to other hemostatics, as well as other materials in use in otolaryngology. LEVEL OF EVIDENCE: 1b. Laryngoscope, 126:S5-S13, 2016. PMID- 26509640 TI - Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P5) Agonist for the Potential Treatment of Neurodegenerative Disorders. AB - S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris, 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam , , AAIC 2014). Herein we describe the development of a series of selective S1P5 agonists that led to the identification of compound 29, which is highly selective for S1P5 and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P5 biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P1 and S1P3 function in rats. In addition, we found that 29 improves blood-brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P5 agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood brain barrier such as Alzheimer's disease or multiple sclerosis. PMID- 26509641 TI - Strategies to reduce wastage of red blood cell units. AB - BACKGROUND AND OBJECTIVES: Wastage of red blood cell units (RBCs) due to their inappropriate storage at the clinical ward has become both a financial and ethical challenge in the daily hospital practice. This study was aimed at identifying the extent of RBC wastage and evaluating the effects of various interventions in reducing this wastage. MATERIALS AND METHODS: From January 2011 to March 2011, baseline wastage level was evaluated using temperature-sensitive labels. Following this initial analysis, various interventions were implemented, including modifying the transfusion practice, intensifying training of and communication with the medical staff and improving the transport conditions. The impact of these interventions on wastage was measured during two periods, and results were compared with baseline wastage level. RESULTS: Based on the extent of label colouring, 7.5% of the units dispensed by the transfusion laboratory were determined as non-reusable at baseline. After implementation of the various interventions, wastage decreased to 1% of the units dispensed, potentially leading to an annual saving for our hospital of approximately ?208.000/$230.600 on the total number of RBCs dispensed. CONCLUSION: Relative straightforward interventions, such as raising awareness among medical staff and particularly improving transport conditions, had a clear impact on the level of RBC wastage, accommodating the financial issue not to waste public money as well as the ethical issue that RBC wastage should be as low as possible. PMID- 26509642 TI - A New Phaeodarian Species Discovered from the Japan Sea Proper Water, Auloscena pleuroclada sp. nov. (Aulosphaeridae, Phaeosphaerida, Phaeodaria). AB - A new phaeodarian species, characterized by the presence of long developed side branches recurved proximally and distally on the surface of its radial tube, was described as Auloscena pleuroclada. This new species was only collected from the layers below the 250 m depth in the Sea of Japan. They have never been found in the shallower layers (above 250 m) of this sea or in other investigated areas. The distribution of the present new species is presumably restricted within the deep water of this area, and this species could be a specific phaeodarian adapted to the deep-sea environment. PMID- 26509643 TI - Perioperative Cost Analysis of Minimally Invasive vs Open Resection of Intradural Extramedullary Spinal Cord Tumors. AB - BACKGROUND: Minimally invasive spinal surgery (MIS) has emerged as a clinically effective tool but its cost-effectiveness remains unclear. No studies have compared MIS vs open surgical techniques for the treatment of intradural extramedullary (IDEM) tumors. OBJECTIVE: To analyze and compare open and MIS techniques for resection of IDEM tumors, with focus on perioperative costs. METHODS: Retrospective analysis of a prospectively collected database including 35 IDEM patients (18 open, 17 MIS). Perioperative data, hospital costs, and hospital and physician charges for in-hospital services associated with the index surgical procedure and readmissions within 90 days were compared. RESULTS: Mean estimated blood loss, operative time, preoperative hospital charges, and physician fees were similar between open and MIS techniques. Patient and tumor characteristics were similar between groups. MIS cases were associated with shorter intensive care unit and floor stay. There were 3 complications in the open group, requiring 2 readmissions and 1 reoperation. Hospital costs ($21 307.80 open, $15 015.20 MIS, P < .01), and postoperative ($75 383.48 open, $56 006.88 MIS, P < .01) and total charges ($100 779.38 open, $76 100.92 MIS, P < .01) were significantly lower in the MIS group. There were no tumor recurrences in either group. All patients except for one in the open group maintained or improved their Nurick score. CONCLUSION: Both MIS and open techniques were able to adequately treat IDEM tumors. Reductions in complication rate and intensive care unit and hospital stay led to a decrease in hospital costs of almost 30% in the MIS group. MIS resection of IDEM tumors is not only an effective and safe option, but allows faster hospital discharge and significant cost savings. PMID- 26509645 TI - Donor Selection in Flow Replacement Bypass Surgery for Cerebral Aneurysms: Quantitative Analysis of Long-term Native Donor Flow Sufficiency. AB - BACKGROUND: Graft selection in extracranial-intracranial bypass surgery for cerebral aneurysms has traditionally been based on clinical impression and operator preference. However, decision making can be optimized with a donor selection algorithm based on intraoperative flow data. OBJECTIVE: To present long term follow-up and quantitative assessment of flow sufficiency for native donors selected in this manner. METHODS: Patients with bypass for anterior circulation intracranial aneurysms using only a native donor (superficial temporal artery) selected on the basis of an intraoperative flow algorithm over a 10-year period were retrospectively studied. Intracranial hemispheric and bypass flows were assessed preoperatively and postoperatively when available with quantitative magnetic resonance angiography. RESULTS: Twenty-two patients with flow data were included (median aneurysm size, 22 mm). The intraoperative flow offer (cut flow) of the superficial temporal artery was sufficient in these cases relative to the flow demand in the sacrificed vessel (59 vs 28 mL/min) to warrant its use. Bypass flow averaged 81 mL/min postoperatively (n = 19). Bypass flows were highest in the immediate postoperative period but remained stable between the intermediate and final follow-up (40 vs 52 mL/min; P = .39; n = 8). Mean ipsilateral hemisphere flows were maintained after bypass (299 vs 335 mL/min; P = .42; n = 7), and remained stable over intermediate and long-term follow-up. Ipsilateral hemispheric flows remained similar to contralateral flows at all time points. CONCLUSION: Despite a relative reduction in bypass flow over time, hemispheric flows were maintained, indicating that simple native donors can carry sufficient flow for territory demand long term when an intraoperative flow-based algorithm is used for donor selection. PMID- 26509647 TI - Outcomes of Multimodality Therapy in Pediatric Patients With Ruptured and Unruptured Brain Arteriovenous Malformations. AB - BACKGROUND: Brain arteriovenous malformations (BAVMs) are a frequent cause of pediatric hemorrhagic stroke, which frequently results in significant morbidity and mortality. OBJECTIVE: To analyze the results of multimodality treatment for a consecutive series of pediatric patients with ruptured and unruptured BAVMs at a single institution. METHODS: Forty patients <18 years of age were retrospectively reviewed. Results were divided by hemorrhage status, ie, ruptured or unruptured, and the intended curative treatment modality, ie, surgical resection or stereotactic radiosurgery. RESULTS: Twenty-seven patients (68%) presented with hemorrhage, and 13 patients (32%) presented without hemorrhage. Among ruptured patients, 19 (70%) underwent surgery and 8 (30%) underwent stereotactic radiosurgery. In surviving patients who presented with hemorrhage, 23 of 26 (88%) had a modified Rankin Scale (mRS) score of 0 to 2 at the last follow-up, and 24 of 26 (92%) obtained radiographic cure. For unruptured BAVMs, all 6 patients with grade I to III BAVM obtained radiographic cure and had an mRS score of 0 to 1 at the last follow-up, whereas 1 of 5 patients (20%) with grade IV and V BAVM had BAVM obliteration and a mean mRS score of 1.8 at the last follow-up. In a total of 93.6 years of follow-up from date of presentation to last clinical follow-up, there was 1 hemorrhage (1.1%/y). Of 30 patients with radiographic obliteration, 2 patients had radiographic recurrence (7% incidence). CONCLUSION: The majority of ruptured patients had an mRS score of 0 to 2 at the last follow-up and obtained radiographic cure. Unruptured patients with grade I to III BAVMs had superior outcomes compared with those with grade IV and V AVMs. Treatment of grade I to III BAVMs appears safe, and additional study is needed to determine optimal strategies for the management of unruptured grade IV and V BAVMs. PMID- 26509649 TI - Intermolecular [2+2+1] Carbonylative Cycloaddition of Aldehydes with Alkynes, and Subsequent Oxidation to gamma-Hydroxybutenolides by a Supported Ruthenium Catalyst. AB - Intermolecular [2+2+1] carbonylative cycloaddition of aldehydes with alkynes and subsequent oxidation to gamma-hydroxybutenolides is achieved using a supported ruthenium catalyst. A ceria-supported ruthenium catalyst promotes the reaction efficiently, even with an ambient pressure of CO or without external CO, thus giving the corresponding gamma-hydroxybutenolide derivatives in good to high yields. Moreover this catalyst can be reused with no loss of activity. PMID- 26509650 TI - Soluble TL1A is sufficient for activation of death receptor 3. AB - Death receptor 3 (DR3) is a typical member of the tumor necrosis factor receptor family, and was initially identified as a T-cell co-stimulatory molecule. However, further studies revealed a more complex and partly dichotomous role for DR3 and its ligand TL1A under (patho)physiological conditions. TL1A and DR3 are not only a driving force in the development of autoimmune and inflammatory diseases, but also play an important role in counteracting these processes through an increase in the number of regulatory T cells. Ligands of the tumor necrosis factor family typically occur in two forms, membrane-bound and soluble, that can differ strikingly with respect to their efficacy in activating their corresponding receptor(s). Ligand-based approaches to activate the TL1A-DR3 pathway therefore require understanding of the molecular prerequisites of TL1A based DR3 activation. To date, this has not been addressed. Here, we show that recombinant soluble trimeric TL1A is fully sufficient to strongly activate DR3 associated pro- and anti-apoptotic signaling pathways. In contrast to the TRAIL death receptors, which are much better activated by soluble TRAIL upon secondary ligand oligomerization, but similarly to the death receptor tumor necrosis factor receptor 1, DR3 is efficiently activated by soluble TL1A trimers. Additionally, we have measured the affinity of TL1A-DR3 interaction in a cell-based system, and demonstrated TL1A-induced DR3 internalization. Identification of DR3 as a tumor necrosis factor receptor that responds to soluble ligand trimers without further oligomerization provides a basis for therapeutic exploitation of the TL1A-DR3 pathway. PMID- 26509648 TI - Prospective nationwide outcome audit of surgery for suspected acute appendicitis. AB - BACKGROUND: Studies comparing laparoscopic and open appendicectomy are difficult to interpret owing to several types of bias, and the results often seem of limited clinical importance. National audits can be valuable to provide insight into outcomes following appendicectomy at a population level. METHODS: A prospective, observational, resident-led, nationwide audit was carried out over a period of 2 months, including all consecutive adult patients who had surgery for suspected acute appendicitis. Complications after laparoscopic and open appendicectomy were compared by means of logistic regression analysis; subgroup analyses were performed for patients with complicated appendicitis. RESULTS: A total of 1975 patients were included from 62 participating Dutch hospitals. A normal appendix was seen in 3.3 per cent of patients. Appendicectomy was performed for acute appendicitis in 1378 patients, who were analysed. All but three patients underwent preoperative imaging. Laparoscopy was used in 79.5 per cent of patients; the conversion rate was 3.4 per cent. A histologically normal appendix was found in 2.2 per cent. Superficial surgical-site infection was less common in the laparoscopic group (odds ratio 0.25, 95 per cent c.i. 0.14 to 0.44; P < 0.001). The rate of intra-abdominal abscess formation was not significantly different following laparoscopic or open surgery (odds ratio 1.71, 0.80 to 3.63; P = 0.166). Similar findings were observed in patients with complicated appendicitis. CONCLUSION: Management of acute appendicitis in the Netherlands is preferably performed laparoscopically, characterized by a low conversion rate. Fewer superficial surgical-site infections occurred with laparoscopy, although the rate of abscess formation was no different from that following open surgery. A low normal appendix rate is the presumed effect of a mandatory preoperative imaging strategy. PMID- 26509651 TI - Culture-Independent Detection and Genotyping of Mycoplasma pneumoniae in Clinical Specimens from Beijing, China. AB - A duplex real-time PCR assay was designed for simultaneous detection and genotyping of Mycoplasma pneumoniae (M. pneumoniae). The detection/typing performance of this duplex PCR method, targeting specific genes for M. pneumoniae type 1 (mpn 459) and type 2 (mpna 5864), was compared to that of the previously published MpP1 real-time PCR assay and the genotyping method for the adhesin P1 gene (mpn 141). A total of 1,344 throat swab specimens collected from patients in Beijing, China were tested for M. pneumoniae by bacterial culture, MpP1 real-time PCR assay, and our duplex PCR assay, and positive detection rates of 26.9%, 34.4%, and 33.7%, respectively, were obtained. The duplex PCR method demonstrated high sensitivity and accuracy for detecting and genotyping M. pneumoniae, and significant differences in genotyping ability were observed when compared to the conventional P1 gene-based method. M. pneumoniae type 1 was the predominate genotype from 2008 to 2012 in Beijing, and a shift from type 1 to type 2 began to occur in 2013. To our knowledge, this is the first reported incidence of a type shift phenomenon of M. pneumoniae clinical isolates in China. These genotyping results provide important information for understanding recent changes in epidemiological characteristics of M. pneumoniae in Beijing. PMID- 26509652 TI - Bloch-Siegert B1+-mapping for human cardiac (31) P-MRS at 7 Tesla. AB - PURPOSE: Phosphorus MR spectroscopy ((31) P-MRS) is a powerful tool for investigating tissue energetics in vivo. Cardiac (31) P-MRS is typically performed using surface coils that create an inhomogeneous excitation field across the myocardium. Accurate measurements of B1+ (and hence flip angle) are necessary for quantitative analysis of (31) P-MR spectra. We demonstrate a Bloch Siegert B1+-mapping method for this purpose. THEORY AND METHODS: We compare acquisition strategies for Bloch-Siegert B1+-mapping when there are several spectral peaks. We optimize a Bloch-Siegert sensitizing (Fermi) pulse for cardiac (31) P-MRS at 7 Tesla (T) and apply it in a three-dimensional (3D) chemical shift imaging sequence. We validate this in phantoms and skeletal muscle (against a dual-TR method) and present the first cardiac (31) P B1+-maps at 7T. RESULTS: The Bloch-Siegert method correlates strongly (Pearson's r = 0.90 and 0.84) and has bias <25 Hz compared with a multi-TR method in phantoms and dual-TR method in muscle. Cardiac 3D B1+-maps were measured in five normal volunteers. B1+ maps based on phosphocreatine and alpha-adenosine-triphosphate correlated strongly (r = 0.62), confirming that the method is T1 insensitive. CONCLUSION: The 3D (31) P Bloch-Siegert B1+-mapping is consistent with reference methods in phantoms and skeletal muscle. It is the first method appropriate for (31) P B1+-mapping in the human heart at 7T. Magn Reson Med 76:1047-1058, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 26509653 TI - Clinical analysis of patients suffering from chronic hepatitis B superinfected with other hepadnaviruses. AB - To compare the clinical manifestations, laboratory examinations, and prognoses of patients with chronic hepatitis B (CHB) who were superinfected with hepatitis A virus (HAV), hepatitis C virus (HCV), hepatitis D virus (HDV), or hepatitis E virus (HEV). Two hundred and eleven patients with confirmed CHB in our hospital, a tertiary teaching hospital in China, between 2005 and 2014 were analyzed retrospectively. Among 211 patients with CHB, 35 were superinfected with HAV, 31 were superinfected with HCV, 22 were superinfected with HDV, and 53 were superinfected with HEV. We analyzed and compared the clinical features of the five groups. The tested biochemical indices and markers of liver function included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), prothrombin activity (PTA), serum albumin (Alb), and the serum levels of HBV DNA. The peak values of ALT, AST, and TBil were significantly higher in all of the superinfected groups. Lower peak Alb concentration and PTA were also observed in the superinfected patients, with the exception of patients in the CHB + HAV group. The CHB + HCV, and CHB + HEV groups had higher death rates than the CHB monoinfected group, and the difference was statistically significant. Further analysis of the liver failure groups showed that the level of HBV DNA was not correlated with prognosis. The comparison of clinical outcomes revealed that CHB patients superinfected with HCV, HDV, and HEV compared with CHB monoinfection had statistically greater incidences of exacerbation of the condition and poor prognosis, whereas the patients superinfected with HAV generally had better outcomes. PMID- 26509654 TI - ROR1 contributes to melanoma cell growth and migration by regulating N-cadherin expression via the PI3K/Akt pathway. AB - The Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is primarily expressed by neural crest cells during embryogenesis. Following a complete downregulation after birth, ROR1 was shown to re-express in various types of cancers. Little is known about ROR1 expression and function in melanoma. Here we show that ROR1 is aberrantly expressed in both melanoma cell lines and tumors and that its expression associates with poor Post-Recurrence Survival of melanoma. Using gain- and loss-of-function approaches we found that ROR1 enhances both anchorage dependent and -independent growth of melanoma cells. In addition, ROR1 decreases cell adhesion and increases cell motility and migration. Mechanistically, ROR1 was found to induce upregulation of Akt and the mesenquimal markers N-cadherin and vimentin. The regulation of N-cadherin by ROR1 relies on both Akt dependent and independent mechanisms. ROR1 does not affect Wnt canonical pathway but was found to be engaged in a positive feedback loop with Wnt5a. In summary, we show that ROR1 contributes to melanoma progression and is a candidate biomarker of poor prognosis. Although further studies are needed to confirm this possibility, the present work indicates that ROR1 is a good prospective target for melanoma cancer therapy. (c) 2015 Wiley Periodicals, Inc. PMID- 26509655 TI - Cost-effectiveness of active-passive prophylaxis and antiviral prophylaxis during pregnancy to prevent perinatal hepatitis B virus infection. AB - In an era of antiviral treatment, reexamination of the cost-effectiveness of strategies to prevent perinatal hepatitis B virus (HBV) transmission in the United States is needed. We used a decision tree and Markov model to estimate the cost-effectiveness of the current U.S. strategy and two alternatives: (1) Universal hepatitis B vaccination (HepB) strategy: No pregnant women are screened for hepatitis B surface antigen (HBsAg). All infants receive HepB before hospital discharge; no infants receive hepatitis B immunoglobulin (HBIG). (2) Current strategy: All pregnant women are screened for HBsAg. Infants of HBsAg-positive women receive HepB and HBIG <=12 hours of birth. All other infants receive HepB before hospital discharge. (3) Antiviral prophylaxis strategy: All pregnant women are screened for HBsAg. HBsAg-positive women have HBV-DNA load measured. Antiviral prophylaxis is offered for 4 months starting in the third trimester to women with DNA load >=10(6) copies/mL. HepB and HBIG are administered at birth to infants of HBsAg-positive women, and HepB is administered before hospital discharge to infants of HBsAg-negative women. Effects were measured in quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICER). Compared to the universal HepB strategy, the current strategy prevented 1,006 chronic HBV infections and saved 13,600 QALYs (ICER: $6,957/QALY saved). Antiviral prophylaxis dominated the current strategy, preventing an additional 489 chronic infections, and saving 800 QALYs and $2.8 million. The results remained robust over a wide range of assumptions. CONCLUSION: The current U.S. strategy for preventing perinatal HBV remains cost-effective compared to the universal HepB strategy. An antiviral prophylaxis strategy was cost saving compared to the current strategy and should be considered to continue to decrease the burden of perinatal hepatitis B in the United States. PMID- 26509656 TI - Psychiatric disorders in Danish children aged 5-7 years: A general population study of prevalence and risk factors from the Copenhagen Child Cohort (CCC 2000). AB - BACKGROUND: Knowledge about the presentation of psychopathology in preschool age and associated risk factors is fundamental to preventive intervention before schooling. AIMS: To investigate the full spectrum of psychiatric diagnoses in general population children at the period of transition from preschool to school. METHODS: A sample of 1585 children from the Copenhagen Child Cohort, CCC2000 aged 5-7 years was assessed using the Development and Well-Being Assessment (DAWBA) with diagnostic classification by experienced clinicians. Perinatal, sociodemographic and socio-economic data was obtained from Danish national registries. RESULTS: The prevalence of any ICD-10 psychiatric disorder was 5.7% (95%CI: 4.4-7.1). Pervasive developmental disorders (PDD) were found in 1.3% (95%CI: 0.8-1.8) and behavioural and hyperkinetic disorders were found in 1.5% (95%CI: 0.9-2.1) and 1.0% (95%CI: 0.4-1.6), respectively. Emotional disorders were found in 2.9% (95%CI: 1.9-40). More boys were diagnosed with PDD, behavioural disorders and tics. No gender differences were found in hyperactivity disorders (HD) and emotional disorders. Co-morbidity was frequent, in particular between HD and PDD, but also between HD and emotional disorder and behavioural disorder. Teenage mothers, single parents and low household income the first two years after the child's birth were associated with a three-to fourfold increased risk of psychiatric disorder in the child at age 5-7 years. CONCLUSION: The study results point to two "windows of opportunity" for prevention. In the earliest postnatal years, prevention should target families at socio-economic risk; and in the years before schooling, intervention should focus on children with symptoms of PDD, HD, and behavioural disorders. PMID- 26509657 TI - A six-site method for the evaluation of periodontal bone loss in cone-beam CT images. AB - OBJECTIVES: In contrast to two-dimensional planar images, a measuring point is hardly repeatedly determined in a CBCT image when alveolar bone loss is assessed. Thus, the aim of the present study was to propose a six-site measuring method, which is closely related to anatomical structure, for the evaluation of alveolar bone loss in CBCT images. METHODS: 150 measuring points in 11 molars and 14 premolars from 6 patients (2 males and 4 females) were included. CBCT images of the teeth were acquired prior to periodontal surgery. Four observers measured the distances between cemento-enamel junctions and the apical bases of the periodontal bone defect at the mesio-buccal, mid-buccal, disto-buccal, mesio lingual/palatal, mid-lingual/palatal and disto-lingual/palatal sites in CBCT images. Direct measurements of the six sites were correspondingly obtained in the subsequent periodontal surgeries. Differences between the distances measured in the CBCT images and during the surgery were analysed. Interobserver and intraobserver variances were tested. RESULTS: No statistically significant difference was found between the surgical and CBCT measurements (p = 0.84). Diagnostic coincidence rates of four observers were 86.7%, 87.3%, 88.7% and 88.0%, respectively. The interobserver (p = 0.95) and intraobserver (p = 0.30) variances were not significant. CONCLUSIONS: The six-site measuring method validated in the present study may be a useful three-dimensional measuring method for the evaluation of periodontal disease. PMID- 26509658 TI - Band alignment and charge transfer in rutile-TiO2/CH3NH3PbI3-xClx interfaces. AB - Rutile-TiO2/hybrid halide perovskite CH3NH3PbI3-xClx interfaces are investigated by ab initio density functional theory calculations. The role of chlorine in achieving enhanced solar cell power conversion efficiencies is in the focus of recent studies, which point to increased carrier mobilities, reduced recombination rates, a driven morphology evolution of the perovskite layer and improved carrier transport across the interface. As it was recently established that chlorine is preferentially localized in the vicinity of the interface and not in the bulk of the perovskite layer, we analyze the changes introduced in the electronic properties by varying the chlorine concentration near the interface. In particular, we discuss the effects introduced in the electronic band structure and show the role of chlorine in the enhanced electron injection into the rutile TiO2 layer. Taking into account these implications, we discuss the conditions for optimizing the solar cell efficiency in terms of interfacial chlorine concentration. PMID- 26509659 TI - Tibial Tuberosity-Posterior Cruciate Ligament Distance. AB - When trochlear dysplasia is present, it is difficult to measure the tibial tuberosity to trochlear groove (TT-TG) distance. A new measurement to assess tuberosity position was recently described by Seitlinger et al, which avoids the difficulty of identifying the TG as it references the posterior cruciate ligament (PCL). To evaluate the reproducibility of the Seitlinger et al findings, 42 knees in 41 patients with a documented history of recurrent patellar instability and 84 knees in patients with no history of patellar instability or patellofemoral symptoms were evaluated with magnetic resonance imaging. The TT-PCL distance was increased in the instability group (mean, 21.6 mm) compared with the control group (mean, 19.0 mm). The TT-PCL distance is an independent risk factor for patients with recurrent patellar instability. Its role in surgical planning remains to be determined. PMID- 26509660 TI - Outcome of Posterior Tibial Plateau Fixation. AB - Isolated posterior tibial plateau fractures are rare injuries that encompass a wide variety of fracture patterns. Based on the variation in fracture pattern, the surgical approach varies, with both anterior and posterior approaches described for surgical fixation. Postoperative protocol also varies among studies. The aim of this article is to summarize the outcomes related to posterior column tibial plateau fractures. The papers reviewed, primarily small retrospective case series, showed functional knee range of motion is preserved, a low incidence of wound complications, and patient outcome scores comparable to other reported lower extremity injury outcome scores. PMID- 26509662 TI - Innate and adaptive dendritic cell responses to immunotherapy. AB - PURPOSE OF REVIEW: In allergic disease, dendritic cells play a critical role in orchestrating immune responses to innate stimuli and promoting the formation of T helper 2 (TH2) effector versus T-regulatory cells. Here, we review recent advances in our understanding of how current forms of immunotherapy modulate dendritic cell responses. (Figure is included in full-text article.) RECENT FINDINGS: Sublingual immunotherapy (SLIT) and oral immunotherapy (OIT) for peanut allergy alter the expression of costimulatory molecules on dendritic cells, which leads to reduced expression of TH2 effector cytokines in an antigen-nonspecific manner. SLIT and OIT also modulate dendritic cell innate immune responses to Toll like receptor agonists, including enhanced production of interferon alpha and reduced expression of proinflammatory cytokines that may serve to promote the development of tolerance. Dendritic cells isolated from patients post-OIT promoted hypomethylation of the FOXP3 locus in effector T cells. Reduced methylation of the FOXP3 locus has been associated with more persistent clinical desensitization following OIT. Recent studies have additionally highlighted a role for B cells in inducing tolerogenic dendritic cell populations and T regulatory cells during immunotherapy. Epicutaneous immunotherapy may also elicit immunosuppressive populations of cutaneous dendritic cells, although in some cases, antigen exposure through the skin can lead to sensitization. Finally, efforts have focused on identifying pharmacologic and/or antigen-independent strategies of altering dendritic cell function to enhance the immunosuppressive effects of immunotherapy. SUMMARY: Dendritic cells are a critical target of immunotherapy. Alterations in both adaptive and innate immunity likely underlie the immunosuppressive effects of this treatment. PMID- 26509663 TI - Effect of allergen-specific immunotherapy on CD4+ T cells. AB - PURPOSE OF REVIEW: The aims of this review are to discuss the impact of chronic high-dose allergen exposure on allergen-specific CD4(+) T-cell subset during allergen-specific immunotherapy (AIT) and discuss recent advances supporting novel mechanisms for desensitization and tolerance induction during AIT. (Figure is included in full-text article.) RECENT FINDINGS: New technologies for direct molecular and cellular analysis have now provided an unprecedented opportunity to compare the functions and phenotypes of allergen-specific T cells at a single cell level, both in the context of disease and clinical intervention. Recent studies have demonstrated that AIT may restore tolerance by transiently inducing interleukin (IL)-10 producing T cells followed by selective deletion of allergen specific TH2 cell subset. SUMMARY: With antigen-specific TH2 cells at the core of the allergic process in atopic individuals, the duration and dose of antigen exposure can be the driving force behind current AIT protocol. Mechanisms modulating allergen-specific CD4(+) T-cell responses may include autocrine IL-10 production to limit excessive TH2 cell effector responses, T-cell exhaustion, and preferential proallergic TH2 cell deletion allowing concurrent downregulating T cell responses to emerge. Administration of AIT in the context of immune modulating strategies able to induce counter-regulatory immune response may lead to improved AIT with durable clinical benefit. PMID- 26509666 TI - Retrospective Consent to Hemicraniectomy after Malignant Stroke among the Elderly, Despite Impaired Functional Outcome. AB - BACKGROUND: Decompressive hemicraniectomy (DHC) after space-occupying strokes among patients older than 60 years has been shown to reduce mortality rates but at the cost of severe disability. There is an ongoing debate about what could be considered an acceptable outcome for these patients. Data about retrospective consent to the procedure after lengthy time periods are lacking. METHODS: This study included 79 consecutive patients who underwent DHC during a 7.75-year period. Surviving patients were assessed for functional and psychological outcome, quality of life (QoL) and retrospective consent for the procedure. Patients younger than 60 years were compared with older patients. RESULTS: Of our 79 patients, 44 were younger than 60 years (median 50 years, interquartile range (IQR) 19-59 years) and 35 were older (median 68 years, interquartile range 60-87 years). The 30-day mortality rate was higher for the older group, but the difference was not statistically significant. Functional outcome was significantly better in the younger group: 31% of the patients in this group vs. 10% in the older group had a modified Rankin Scale score of 0-3 (p = 0.046). The mean National Institutes of Health Stroke Scale score was 17 +/- 14 for the younger group and 29 +/- 15 for the older group (p = 0.002). On the 36-Item Short Form Health Survey, with the exception of the item 'General health', the older group reported higher values for all items, with statistically significant differences between the 2 groups on the items 'Role limitation emotional' (p = 0.0007) and 'Vitality' (p = 0.02). In the younger group, 29% of patients retrospectively declined consent for DHC opposed to 0% of patients in the older group (p = 0.07). CONCLUSIONS: Despite impaired functional outcome after DHC, indicators of QoL and retrospective consent are higher for patients older than 60 years over the long term. This finding should be taken into account by those who counsel patients and caregivers with regard to this serious procedure. PMID- 26509667 TI - Effects of Fermentation Temperature on Key Aroma Compounds and Sensory Properties of Apple Wine. AB - Fermentation temperature strongly affects yeast metabolism during apple wine making and thus aromatic and quality profiles. In this study, the temperature effect during apple wine making on both the key aroma compounds and sensory properties of apple wine were investigated. The concentration of nine key aroma compounds (ethyl acetate, isobutyl acetate, isopentylacetate, ethyl caprylate, ethyl 4-hydroxybutanoate, isobutylalcohol, isopentylalcohol, 3-methylthio-1 propanol, and benzeneethanol) in apple wine significantly increased with the increase of fermentation temperature from 17 to 20 degrees C, and then eight out of the nine key aroma compounds with an exception of ethyl 4-hydroxybutanoate, decreased when the temperature goes up 20 to 26 degrees C. Sensory analysis showed that the apple wine fermented at 20 degrees C had the highest acceptance for consumers. Fermentation at the temperature of 20 degrees C was therefore considered to be the most suitable condition using the selected yeast strain (Saccharomyces cerevisiae AP05) for apple wine making. Changes in the fermentation temperature can considerably affect the production of key aroma compounds and sensory profiles of apple wine. These results could help apple wine producers make better quality production for consumers at the optimal fermentation temperature. PMID- 26509668 TI - Genetic Variants on Chromosome 1p13.3 Are Associated with Non-ST Elevation Myocardial Infarction and the Expression of DRAM2 in the Finnish Population. AB - Myocardial infarction (MI) is divided into either ST elevation MI (STEMI) or non ST elevation MI (NSTEMI), differing in a number of clinical characteristics. We sought to identify genetic variants conferring risk to NSTEMI or STEMI by conducting a genome-wide association study (GWAS) of MI stratified into NSTEMI and STEMI in a consecutive sample of 1,579 acute MI cases with 1,576 controls. Subsequently, we followed the results in an independent population-based sample of 562 cases and 566 controls, a partially independent prospective cohort (N = 16,627 with 163 incident NSTEMI cases), and examined the effect of disease associated variants on gene expression in 513 healthy participants. Genetic variants on chromosome 1p13.3 near the damage-regulated autophagy modulator 2 gene DRAM2 associated with NSTEMI (rs656843; odds ratio 1.57, P = 3.11 * 10(-10)) in the case-control analysis with a consistent but not statistically significant effect in the prospective cohort (rs656843; hazard ratio 1.13, P = 0.43). These variants were not associated with STEMI (rs656843; odds ratio, 1.11, P = 0.20; hazard ratio 0.97, P = 0.87), appearing to have a pronounced effect on NSTEMI risk. A majority of the variants at 1p13.3 associated with NSTEMI were also associated with the expression level of DRAM2 in blood leukocytes of healthy controls (top-ranked variant rs325927, P = 1.50 * 10(-12)). The results suggest that genetic factors may in part influence whether coronary artery disease results in NSTEMI rather than STEMI. PMID- 26509670 TI - Keeper-Animal Interactions: Differences between the Behaviour of Zoo Animals Affect Stockmanship. AB - Stockmanship is a term used to describe the management of animals with a good stockperson someone who does this in a in a safe, effective, and low-stress manner for both the stock-keeper and animals involved. Although impacts of unfamiliar zoo visitors on animal behaviour have been extensively studied, the impact of stockmanship i.e familiar zoo keepers is a new area of research; which could reveal significant ramifications for zoo animal behaviour and welfare. It is likely that different relationships are formed dependant on the unique keeper animal dyad (human-animal interaction, HAI). The aims of this study were to (1) investigate if unique keeper-animal dyads were formed in zoos, (2) determine whether keepers differed in their interactions towards animals regarding their attitude, animal knowledge and experience and (3) explore what factors affect keeper-animal dyads and ultimately influence animal behaviour and welfare. Eight black rhinoceros (Diceros bicornis), eleven Chapman's zebra (Equus burchellii), and twelve Sulawesi crested black macaques (Macaca nigra) were studied in 6 zoos across the UK and USA. Subtle cues and commands directed by keepers towards animals were identified. The animals latency to respond and the respective behavioural response (cue-response) was recorded per keeper-animal dyad (n = 93). A questionnaire was constructed following a five-point Likert Scale design to record keeper demographic information and assess the job satisfaction of keepers, their attitude towards the animals and their perceived relationship with them. There was a significant difference in the animals' latency to appropriately respond after cues and commands from different keepers, indicating unique keeper animal dyads were formed. Stockmanship style was also different between keepers; two main components contributed equally towards this: "attitude towards the animals" and "knowledge and experience of the animals". In this novel study, data demonstrated unique dyads were formed between keepers and zoo animals, which influenced animal behaviour. PMID- 26509669 TI - Toward Atomistic Resolution Structure of Phosphatidylcholine Headgroup and Glycerol Backbone at Different Ambient Conditions. AB - Phospholipids are essential building blocks of biological membranes. Despite a vast amount of very accurate experimental data, the atomistic resolution structures sampled by the glycerol backbone and choline headgroup in phoshatidylcholine bilayers are not known. Atomistic resolution molecular dynamics simulations have the potential to resolve the structures, and to give an arrestingly intuitive interpretation of the experimental data, but only if the simulations reproduce the data within experimental accuracy. In the present work, we simulated phosphatidylcholine (PC) lipid bilayers with 13 different atomistic models, and compared simulations with NMR experiments in terms of the highly structurally sensitive C-H bond vector order parameters. Focusing on the glycerol backbone and choline headgroups, we showed that the order parameter comparison can be used to judge the atomistic resolution structural accuracy of the models. Accurate models, in turn, allow molecular dynamics simulations to be used as an interpretation tool that translates these NMR data into a dynamic three dimensional representation of biomolecules in biologically relevant conditions. In addition to lipid bilayers in fully hydrated conditions, we reviewed previous experimental data for dehydrated bilayers and cholesterol-containing bilayers, and interpreted them with simulations. Although none of the existing models reached experimental accuracy, by critically comparing them we were able to distill relevant chemical information: (1) increase of choline order parameters indicates the P-N vector tilting more parallel to the membrane, and (2) cholesterol induces only minor changes to the PC (glycerol backbone) structure. This work has been done as a fully open collaboration, using nmrlipids.blogspot.fi as a communication platform; all the scientific contributions were made publicly on this blog. During the open research process, the repository holding our simulation trajectories and files ( https://zenodo.org/collection/user-nmrlipids ) has become the most extensive publicly available collection of molecular dynamics simulation trajectories of lipid bilayers. PMID- 26509671 TI - Correction: A Next-Generation Sequencing Method for Genotyping-by-Sequencing of Highly Heterozygous Autotetraploid Potato. PMID- 26509672 TI - Circulating microRNAs, miR-939, miR-595, miR-519d and miR-494, Identify Cirrhotic Patients with HCC. AB - The performance of circulating biomarkers for the diagnosis of hepatocellular carcinoma (HCC) is sub-optimal. In this study we tested circulating microRNAs as biomarkers for HCC in cirrhotic patients by performing a two stage study: a discovery phase conducted by microarray and a validation phase performed by qRT PCR in an independent series of 118 patients. Beside miRNAs emerged from the discovery phase, miR-21, miR-221, miR-519d were also tested in the validation setting on the basis of literary and tissue findings. Deregulated microRNAs were assayed in HCC-derived cells in the intracellular compartment, cell culture supernatant and exosomal fraction. Serum and tissue microRNA levels were compared in 14 patients surgically treated for HCC. From the discovery study, it emerged that seven circulating microRNAs were differentially expressed in cirrhotic patients with and without HCC. In the validation set, miR-939, miR-595 and miR 519d were shown to differentiate cirrhotic patients with and without HCC. MiR-939 and miR-595 are independent factors for HCC. ROC curves of miR-939, miR-595 and miR-519d displayed that AUC was higher than AFP. An exosomal secretion of miR 519d, miR-21, miR-221 and miR-1228 and a correlation between circulating and tissue levels of miR-519d, miR-494 and miR-21 were found in HCC patients. Therefore, we show that circulating microRNAs deserve attention as non-invasive biomarkers in the diagnostic setting of HCC and that exosomal secretion contributes to discharging a subset of microRNAs into the extracellular compartment. PMID- 26509673 TI - Ticagrelor Does Not Inhibit Adenosine Transport at Relevant Concentrations: A Randomized Cross-Over Study in Healthy Subjects In Vivo. AB - BACKGROUND AND PURPOSE: In patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We now investigated the effects of ticagrelor on the adenosine system in humans in vivo. EXPERIMENTAL APPROACH: In a double-blinded, placebo-controlled cross-over trial in 14 healthy subjects, we have tested whether ticagrelor (180 mg) affects adenosine- and dipyridamole-induced forearm vasodilation, as surrogates of nucleoside uptake inhibition and adenosine formation, respectively. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was measured. Primary endpoint was adenosine-induced vasodilation. KEY RESULTS: Ticagrelor did not affect adenosine- or dipyridamole induced forearm vasodilation. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was not affected by ticagrelor. In vitro, ticagrelor dose-dependently inhibited nucleoside uptake, but only at supra-physiological concentrations. CONCLUSION AND IMPLICATIONS: In conclusion, at relevant plasma concentration, ticagrelor does not affect adenosine transport, nor adenosine formation in healthy subjects. Therefore, it is unlikely that this mechanism is a relevant pleiotropic effect of ticagrelor. TRIAL REGISTRATION: ClinicalTrials.gov NCT01996735. PMID- 26509674 TI - Modeling the Sensitivity of Field Surveys for Detection of Environmental DNA (eDNA). AB - The environmental DNA (eDNA) method is the practice of collecting environmental samples and analyzing them for the presence of a genetic marker specific to a target species. Little is known about the sensitivity of the eDNA method. Sensitivity is the probability that the target marker will be detected if it is present in the water body. Methods and tools are needed to assess the sensitivity of sampling protocols, design eDNA surveys, and interpret survey results. In this study, the sensitivity of the eDNA method is modeled as a function of ambient target marker concentration. The model accounts for five steps of sample collection and analysis, including: 1) collection of a filtered water sample from the source; 2) extraction of DNA from the filter and isolation in a purified elution; 3) removal of aliquots from the elution for use in the polymerase chain reaction (PCR) assay; 4) PCR; and 5) genetic sequencing. The model is applicable to any target species. For demonstration purposes, the model is parameterized for bighead carp (Hypophthalmichthys nobilis) and silver carp (H. molitrix) assuming sampling protocols used in the Chicago Area Waterway System (CAWS). Simulation results show that eDNA surveys have a high false negative rate at low concentrations of the genetic marker. This is attributed to processing of water samples and division of the extraction elution in preparation for the PCR assay. Increases in field survey sensitivity can be achieved by increasing sample volume, sample number, and PCR replicates. Increasing sample volume yields the greatest increase in sensitivity. It is recommended that investigators estimate and communicate the sensitivity of eDNA surveys to help facilitate interpretation of eDNA survey results. In the absence of such information, it is difficult to evaluate the results of surveys in which no water samples test positive for the target marker. It is also recommended that invasive species managers articulate concentration-based sensitivity objectives for eDNA surveys. In the absence of such information, it is difficult to design appropriate sampling protocols. The model provides insights into how sampling protocols can be designed or modified to achieve these sensitivity objectives. PMID- 26509675 TI - Effects of High Temperature and Water Stress on Seed Germination of the Invasive Species Mexican Sunflower. AB - Mexican sunflower is native to Mexico and Central America and was introduced into China early last century. Now it has widely naturalized and is exhibiting increasing invasiveness in South China. As this species often dominates bare ground, a habitat characterized by extreme fluctuation in temperature and water, it is reasonable to hypothesize that it has special adaptations to high temperature and water stress. Using laboratory experiments to simulate these stresses, this study investigated the response of Mexican sunflower seed germination to temperature and water stress, and compared these responses with those previously reported for another invasive, bamboo piper, which is confined to relatively cool and moist habitats in Xishuangbanna. As expected, Mexican sunflower seeds exhibited higher tolerance to these stresses than bamboo piper. Germination of Mexican sunflower seeds was highest at 15-30 degrees C, but significant numbers of seeds germinated and formed seedlings at 10 degrees C and 35 degrees C, at which no bamboo piper seeds formed seedlings, indicating a wider temperature range for germination than the latter. Roughly half the seeds survived 240 h continuous heat treatment and up to 15 h daily periodical heat treatment at 40 degrees C, while bamboo piper seeds were mostly killed by these treatments. About 20% of Mexican sunflower but no bamboo piper seeds germinated after heat treatment for 30 min at 80 degrees C. Germination was completely inhibited in bamboo piper seeds at -0.6 mPa, while 20-60% of Mexican sunflower seeds germinated depending on PEG or NaCl as osmoticum. This higher tolerance in Mexican sunflower seeds accords with its stronger invasiveness in this area. This comparison between two plant invaders demonstrates that invasiveness is not an all-or-nothing situation, and that adaptation to local habitats is a critical determinant of successful invasiveness for an alien plant. PMID- 26509676 TI - Environmental Radiofrequency Electromagnetic Fields Exposure at Home, Mobile and Cordless Phone Use, and Sleep Problems in 7-Year-Old Children. AB - BACKGROUND: We evaluated if exposure to RF-EMF was associated with reported quality of sleep in 2,361 children, aged 7 years. METHODS: This study was embedded in the Amsterdam Born Children and their Development (ABCD) birth cohort study. When children were about five years old, school and residential exposure to RF-EMF from base stations was assessed with a geospatial model (NISMap) and from indoor sources (cordless phone/WiFi) using parental self-reports. Parents also reported their children's use of mobile or cordless phones. When children were seven years old, we evaluated sleep quality as measured with the Child Sleep Habits Questionnaire (CSHQ) filled in by parents. Of eight CSHQ subscales, we evaluated sleep onset delay, sleep duration, night wakenings, parasomnias and daytime sleepiness with logistic or negative binomial regression models, adjusting for child's age and sex and indicators of socio-economic position of the parents. We evaluated the remaining three subscales (bedtime resistance, sleep anxiety, sleep disordered breathing) as unrelated outcomes (negative control) because these were a priori hypothesised not to be associated with RF EMF. RESULTS: Sleep onset delay, night wakenings, parasomnias and daytime sleepiness were not associated with residential exposure to RF-EMF from base stations. Sleep duration scores were associated with RF-EMF levels from base stations. Higher use mobile phones was associated with less favourable sleep duration, night wakenings and parasomnias, and also with bedtime resistance. Cordless phone use was not related to any of the sleeping scores. CONCLUSION: Given the different results across the evaluated RF-EMF exposure sources and the observed association between mobile phone use and the negative control sleep scale, our study does not support the hypothesis that it is the exposure to RF EMF that is detrimental to sleep quality in 7-year old children, but potentially other factors that are related to mobile phone usage. PMID- 26509677 TI - Screening for DNA Alkylation Mono and Cross-Linked Adducts with a Comprehensive LC-MS(3) Adductomic Approach. AB - A high-resolution/accurate-mass DNA adductomic approach was developed to investigate anticipated and unknown DNA adducts induced by DNA alkylating agents in biological samples. Two new features were added to a previously developed approach to significantly broaden its scope, versatility, and selectivity. First, the neutral loss of a base (guanine, adenine, thymine, or cytosine) was added to the original methodology's neutral loss of the 2'-deoxyribose moiety to allow for the detection of all DNA base adducts. Second, targeted detection of anticipated DNA adducts based on the reactivity of the DNA alkylating agent was demonstrated by inclusion of an ion mass list for data dependent triggering of MS(2) fragmentation events and subsequent MS(3) fragmentation. Additionally, untargeted screening of the samples, based on triggering of an MS(2) fragmentation event for the most intense ions of the full scan, was included for detecting unknown DNA adducts. The approach was tested by screening for DNA mono and cross-linked adducts in purified DNA and in DNA extracted from cells treated with PR104A, an experimental DNA alkylating nitrogen mustard prodrug currently under investigation for the treatment of leukemia. The results revealed the ability of this new DNA adductomic approach to detect anticipated and unknown PR104A-induced mono and cross-linked DNA adducts in biological samples. This methodology is expected to be a powerful tool for screening for DNA adducts induced by endogenous or exogenous exposures. PMID- 26509678 TI - Copper-Promoted Cycloaddition of alpha-Methylenyl Isocyanides with Benzothiazoles: Tunable Access to Benzo[d]imidazothiazoles. AB - A tunable route to both isomers of benzo[d]imidazothiazole has been developed through copper-promoted cycloaddition of alpha-methylenyl isocyanides with benzothiazoles. When the C2 position of benzothiazole is linked to a C-H or C-C bond, benzo[d]imidazo[2,1-b]thiazoles are obtained through a novel rearrangement via C-S bond cleavage and formation of a new C-S bond. When 2-chloro- or 2 bromobenzothiazoles are used under the same reaction conditions, the isomeric benzo[d]imidazo[5,1-b]thiazoles are formed selectively. These reactions proceed smoothly in moderate to excellent yields at room temperature, and a wide range of functional groups are tolerated. PMID- 26509679 TI - Effectiveness of Front-Of-Pack Nutrition Labels in French Adults: Results from the NutriNet-Sante Cohort Study. AB - BACKGROUND: To date, no consensus has emerged on the most appropriate front-of pack (FOP) nutrition label to help consumers in making informed choices. We aimed to compare the effectiveness of the label formats currently in use: nutrient specific, graded and simple summary systems, in a large sample of adults. METHODS: The FOP label effectiveness was assessed by measuring the label acceptability and understanding among 13,578 participants of the NutriNet-Sante cohort study, representative of the French adult population. Participants were exposed to five conditions, including four FOP labels: Guideline Daily Amounts (GDA), Multiple Traffic Lights (MTL), 5-Color Nutrition Label (5-CNL), Green Tick (Tick), and a "no label" condition. Acceptability was evaluated by several indicators: attractiveness, liking and perceived cognitive workload. Objective understanding was assessed by the percentage of correct answers when ranking three products according to their nutritional quality. Five different product categories were tested: prepared fish dishes, pizzas, dairy products, breakfast cereals, and appetizers. Differences among the label effectiveness were compared with chi-square tests. RESULTS: The 5-CNL was viewed as the easiest label to identify and as the one requiring the lowest amount of effort and time to understand. GDA was considered as the least easy to identify and to understand, despite being the most attractive and liked label. All FOP labels were found to be effective in ranking products according to their nutritional quality compared with the "no label" situation, although they showed differing levels of effectiveness (p<0.0001). Globally, the 5-CNL performed best, followed by MTL, GDA and Tick labels. CONCLUSIONS: The graded 5-CNL label was considered as easy to identify, simple and rapid to understand; it performed well when comparing the products' nutritional quality. Therefore, it is likely to present advantages in real shopping situations where choices are usually made quickly. PMID- 26509680 TI - Effect of Emamectin Benzoate on Root-Knot Nematodes and Tomato Yield. AB - Southern root-knot nematode (Meloidogyne incognita) is an obligate, sedentary endoparasite of more than 3000 plant species, that causes heavy economic losses and limit the development of protected agriculture of China. As a biological pesticide, emamectin benzoate has effectively prevented lepidopteran pests; however, its efficacy to control M. incognita remains unknown. The purpose of the present study was to test soil application of emamectin benzoate for management of M. incognita in laboratory, greenhouse and field trials. Laboratory results showed that emamectin benzoate exhibited high toxicity to M. incognita, with LC50 and LC90 values 3.59 and 18.20 mg L(-1), respectively. In greenhouse tests, emamectin benzoate soil application offered good efficacy against M. incognita while maintaining excellent plant growth. In field trials, emamectin benzoate provided control efficacy against M. incognita and resulted in increased tomato yields. Compared with the untreated control, there was a 36.5% to 81.3% yield increase obtained from all treatments and the highest yield was received from the highest rate of emamectin benzoate. The results confirmed that emamectin benzoate has enormous potential for the control of M. incognita in tomato production in China. PMID- 26509681 TI - Wireless Versus Wired Iontophoresis for Treating Patellar Tendinopathy: A Randomized Clinical Trial. AB - CONTEXT: The efficacy of the relatively new wireless iontophoresis patch compared with the traditional wired dose controller is unknown. OBJECTIVE: To determine the differences among 2 iontophoresis drug-delivery systems (wireless patch versus wired dose controller) and a sham treatment in treating patellar tendinopathy. DESIGN: Randomized controlled clinical trial. SETTING: Physical therapy clinic. PATIENTS OR OTHER PARTICIPANTS: Thirty-one participants diagnosed with patellar tendinopathy (men = 22, women = 9, age = 24.5 +/- 5.9 years). INTERVENTION(S): Participants were randomly assigned into 1 of 3 treatment groups: wireless patch, wired dose controller, or sham treatment. Participants in the active treatment groups received six 80 mA/min iontophoresis treatments using 2 mL of 4% dexamethasone sodium phosphate. During each visit, clinical outcome measures were assessed and then the assigned treatment was applied. MAIN OUTCOME MEASURE(S): Clinical outcome measures were Kujala Anterior Knee Pain Scale, pressure sensitivity, knee-extension force, and sit-to-stand pain assessment using a numeric rating scale. For each clinical outcome measure, we used a repeated-measures analysis of covariance to determine differences among the treatment groups over the treatment period. RESULTS: Participants reported a clinically important improvement on the Kujala Anterior Knee Pain Scale across all treatment groups, with no differences among groups (P = .571). A placebo effect was observed with pressure sensitivity (P = .0152); however, the active treatment decreased participants' pain during the sit-to-stand test (P = .042). CONCLUSIONS: A placebo effect occurred with the sham treatment group. Generally, improvement was noted in all groups regardless of treatment type, but greater pain reduction during a functional task was evident within the active treatment groups during the sit-to-stand test. The wireless patch and wired dose controller treatments were equivalent across all variables. PMID- 26509682 TI - Forward Shoulder Posture in Collegiate Swimmers: A Comparative Analysis of Muscle Energy Techniques. AB - CONTEXT: Empirical data for treating forward shoulder posture supports stretching the anterior shoulder musculature. Although muscle-energy techniques (METs) have been hypothesized to lengthen muscle, no data have described the usefulness of this technique among swimmers. OBJECTIVE: To determine if an MET provides improvements in resting pectoralis minor length (PML), forward scapular position, and scapular upward rotation in female collegiate swimmers. DESIGN: Controlled laboratory study. SETTING: Athletic training room. PATIENTS OR OTHER PARTICIPANTS: Thirty-nine asymptomatic National Collegiate Athletic Association Division I women's swimmers (19 experimental, 20 control). INTERVENTION(S): The experimental group received 2 treatment sessions per week for 6 weeks. The control group received no intervention during this 6-week period. MAIN OUTCOME MEASURE(S): We administered pretest and posttest measurements for PML, forward scapular position, and scapular upward rotation in positions of rest and 60 degrees , 90 degrees , and 120 degrees of humeral elevation. The MET consisted of a 3-second stretch in the direction of the pectoralis minor fibers, followed by a 5-second isometric horizontal adduction contraction at 25% of maximum force. Immediately after this contraction, the entire sequence was repeated with the muscle being stretched to the new endpoint. A total of 4 cycles of MET were continuously applied per treatment session twice per week for 6 weeks. We conducted 1-way analyses of covariance to determine any between-groups postintervention test differences. RESULTS: The MET group had a greater increase in PML postintervention (P = .001, effect size = 1.6) and a greater decrease in forward scapular position postintervention (P = .001, effect size = 1.07) compared with the control group. No differences were found for scapular upward rotation (P > .10). CONCLUSIONS: Our results indicate that 6 weeks of MET treatments applied to the pectoralis minor of asymptomatic female swimmers provided improvements in PML and forward scapular position compared with a control group. PMID- 26509683 TI - Intramuscular Heating Characteristics of Multihour Low-Intensity Therapeutic Ultrasound. AB - CONTEXT: The heating characteristics of a stationary device delivering sustained acoustic medicine with low-intensity therapeutic ultrasound (LITUS) are unknown. OBJECTIVE: To measure intramuscular (IM) heating produced by a LITUS device developed for long-duration treatment of musculoskeletal injuries. DESIGN: Controlled laboratory study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 26 healthy volunteers (16 men, 10 women; age = 23.0 +/- 2.1 years, height = 1.74 +/- 0.09 m, mass = 73.48 +/- 14.65 kg). INTERVENTION(S): Participants were assigned randomly to receive active (n = 20) or placebo (n = 6) LITUS at a frequency of 3 MHz and an energy intensity of 0.132 W/cm(2) continuously for 3 hours with a single transducer or dual transducers on the triceps surae muscle. We measured IM temperature using thermocouples inserted at 1.5- and 3-cm depths into muscle. Temperatures were recorded throughout treatment and 30 minutes posttreatment. MAIN OUTCOME MEASURE(S): We used 2-sample t tests to determine the heating curve of the LITUS treatment and differences in final temperatures between depth and number of transducers. RESULTS: A mild IM temperature increase of 1 degrees C was reached 10 +/- 5 minutes into the treatment, and a more vigorous temperature increase of 4 degrees C was reached 80 +/- 10 minutes into the treatment. The maximal steady-state IM temperatures produced during the final 60 minutes of treatment at the 1.5-cm depth were 4.42 degrees C +/- 0.08 degrees C and 3.92 degrees C +/- 0.06 degrees C using 1 and 2 transducers, respectively. At the 3.0-cm depth, the maximal steady-state IM temperatures during the final 60 minutes of treatment were 3.05 degrees C +/- 0.09 degrees C and 3.17 degrees C +/- 0.05 degrees C using 1 and 2 transducers, respectively. We observed a difference between the temperatures measured at each depth (t78 = -2.45, P = .02), but the number of transducers used to generate heating was not different (t78 = 1.79, P = .08). CONCLUSIONS: The LITUS device elicited tissue heating equivalent to traditional ultrasound but could be sustained for multiple hours. It is a safe and effective alternative tool for delivering therapeutic ultrasound and exploring dosimetry for desired physiologic responses. PMID- 26509684 TI - Qualitative Examination of Adolescent Health-Related Quality of Life at 1 Year Postconcussion. AB - CONTEXT: Moderate to severe traumatic brain injuries can negatively influence health-related quality of life (HRQOL) in adolescent patients. The effect of sport-related concussion on adolescent HRQOL remains unclear. OBJECTIVE: To investigate the perceptions of adolescent student-athletes and their parents regarding the adolescents' HRQOL 1 year after sport-related concussion. DESIGN: Qualitative study. SETTING: Secondary school. PATIENTS OR OTHER PARTICIPANTS: Seven adolescent student-athletes (age range, 12-16 years) who sustained a sport related concussion at least 1 year (15.3 +/- 2.8 months) before the study participated along with their primary care-giving parents (n = 7). DATA COLLECTION AND ANALYSIS: Fourteen semistructured face-to-face interviews (7 adolescents, 7 parents) were completed. Interviews were transcribed and inductively analyzed by a team of 3 athletic trainers with 32 combined years of professional experience. Themes were negotiated through a consensual review process. Participant checks were completed to ensure trustworthiness of the results. RESULTS: Four major themes emerged from the interviews: (1) significant effect of symptoms, (2) feelings of frustration, (3) influence on school attendance and activities, and (4) nature of interpersonal and team relationships. Participants indicated that the physical symptoms of the concussion substantially affected their emotional and academic function. The influence of the concussion on social interactions seemed to depend on the nature of interpersonal relationships. CONCLUSIONS: Sport-related concussion can negatively influence physical and emotional function, academics, and interpersonal interactions as perceived by adolescent student-athletes and their parents. Education of parents and their children, school professionals, coaches, and teammates remains critical to effectively recognize and manage sport-related concussion. Secondary school districts also play a critical role in the concussion-management process by establishing and implementing accommodation policies that alleviate student concerns about falling behind while ensuring a healthy return to normal school routines. Furthermore, adolescent support systems must be considered throughout the recovery process. PMID- 26509685 TI - Unc93b Induces Apoptotic Cell Death and Is Cleaved by Host and Enteroviral Proteases. AB - Unc93b is an endoplasmic reticulum (ER)-resident transmembrane protein that serves to bind and traffic toll-like receptors (TLRs) from the ER to their appropriate subcellular locations for ligand sensing. Because of its role in TLR trafficking, Unc93b is necessary for an effective innate immune response to coxsackievirus B3 (CVB), a positive-sense single stranded RNA virus belonging to the enterovirus family. Here, we show that Unc93b is cleaved by a CVB-encoded cysteine protease (3Cpro) during viral replication. Further, we define a role for Unc93b in the induction of apoptotic cell death and show that expression of wild type Unc93b, but not a mutant incapable of binding TLRs or exiting the ER (H412R), induces apoptosis. Furthermore, we show that cellular caspases activated during apoptosis directly cleave Unc93b. Interestingly, we show that the 3Cpro- and caspase-mediated cleavage of Unc93b both occur within ten amino acids in the distal N-terminus of Unc93b. Mechanistically, neither caspase-mediated nor 3Cpro mediated cleavage of Unc93b altered its trafficking function, inhibited its role in facilitating TLR3 or TLR8 signaling, or altered its apoptosis-inducing effects. Taken together, our studies show that Unc93b is targeted by both viral- and host cell-specific proteases and identify a function of Unc93b in the induction of apoptotic cell death. PMID- 26509686 TI - A South American Prehistoric Mitogenome: Context, Continuity, and the Origin of Haplogroup C1d. AB - Based on mitochondrial DNA (mtDNA), it has been estimated that at least 15 founder haplogroups peopled the Americas. Subhaplogroup C1d3 was defined based on the mitogenome of a living individual from Uruguay that carried a lineage previously identified in hypervariable region I sequences from ancient and modern Uruguayan individuals. When complete mitogenomes were studied, additional substitutions were found in the coding region of the mitochondrial genome. Using a complete ancient mitogenome and three modern mitogenomes, we aim to clarify the ancestral state of subhaplogroup C1d3 and to better understand the peopling of the region of the Rio de la Plata basin, as well as of the builders of the mounds from which the ancient individuals were recovered. The ancient mitogenome, belonging to a female dated to 1,610+/-46 years before present, was identical to the mitogenome of one of the modern individuals. All individuals share the mutations defining subhaplogroup C1d3. We estimated an age of 8,974 (5,748 12,261) years for the most recent common ancestor of C1d3, in agreement with the initial peopling of the geographic region. No individuals belonging to the defined lineage were found outside of Uruguay, which raises questions regarding the mobility of the prehistoric inhabitants of the country. Moreover, the present study shows the continuity of Native lineages over at least 6,000 years. PMID- 26509687 TI - Clinical Characteristics of Anti-3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Antibodies in Chinese Patients with Idiopathic Inflammatory Myopathies. AB - OBJECTIVE: The objective of this study was to detect the prevalence of anti-3 hydroxyl-3- methylglutaryl coenzyme A reductase (anti-HMGCR) antibodies in Chinese patients with idiopathic inflammatory myopathies (IIMs), and to analyze the clinical features of the antibody-positive IIM patients. METHODS: The presence of anti-HMGCR antibodies was detected in 405 patients with IIMs, 90 healthy controls, and 221 patients with other rheumatic diseases by using an ELISA kit. Clinical data from anti-HMGCR antibody-positive and -negative patients were compared. Long-term follow-up of the anti-HMGCR antibody-positive patients was conducted to evaluate the role of anti-HMGCR antibody in IIM disease prognosis. RESULTS: Of the 405 IIM patients, 22 (5.4%) were found to carry the anti-HMGCR antibody. These IIM patients were predominantly female (73%), and only 3 anti-HMGCR antibody-positive patients with IIM were exposure to statins. Most patients experienced progressive onset, and presented with muscular weakness. Dysphagia was observed in half of the patients (p < 0.01), and 15% of these patients experienced the complication of interstitial lung disease (ILD) (p > 0.05). Mean creatine kinase (CK) levels were higher in antibody-positive patients than in antibody-negative patients (p < 0.05). Muscle biopsies were available from 12 anti-HMGCR antibody-positive patients, eight who experienced myofiber necrosis and showed very little or no evidence of inflammatory cell infiltrates in their muscle biopsies. Of these eleven patients who were followed-up 2.5- to 29-month, 73% experienced improvement after treatment. A cross-sectional study showed that anti-HMGCR antibody levels were significantly associated with CK levels (r = 0.486, p = 0.026) as well as with Myositis Disease Activity Assessment (MYOACT) scores (r = -0.67, p = 0.003) during the initial visit. However, changes in serum anti-HMGCR antibody levels did not correlate with changes in CK levels, Manual Muscle Testing 8 (MMT-8) scores or MYOACT scores in long-term follow-up. CONCLUSION: The major clinical features of anti-HMGCR antibody-positive Chinese IIM patients were muscle weakness and dysphagia, which were seen in patients with and without statin exposure. This subtype of patients were responsive to immunosuppressive treatment and received good prognoses after treatment, but serum levels of the anti-HMGCR antibody do not correlate with disease activity. PMID- 26509688 TI - A selective summary of visual averaging research and issues up to 2000. AB - Ariely's (2001) "Seeing Sets: Representation by Statistical Properties" (Psychological Science, 12, 157-162) rekindled interest in summary-value estimation for visual ensembles (groups of similar items). Revisiting and reinvigorating research on the "intuitive statistician" has prompted a new set of insights and debates concerning how and why the visual system might benefit from a compact representation of the optic array and how this might relate to crowding, sparse representation, efficiency coding, and processing limits. New research tools and imaging techniques coupled with solid psychophysical work have added substantially to the large base of work done in the 20th century. The present brief review acts as a summary of the ensemble of work prior to Ariely's (2001) landmark paper to encourage a comprehensive continuity of knowledge and reintroduce some of the contemporaneous concerns to help inform ongoing research and modeling. PMID- 26509689 TI - Unstable mean context causes sensitivity loss and biased estimation of variability. AB - A recent study has suggested that statistical representations of ensemble objects may provide contextual stability to facilitate perception. The present study investigated whether facilitating such perception occurs in the extraction of variability information and how the stability of context mean values influences variability perception. We designed two tasks in which participants directly judged the variability of stimuli. In Experiment 1, we manipulated both the stability of the mean values and the exposure time to observe the time course of stability facilitation. In Experiment 2, we decomposed the stability of the context mean values into between-trials and within-trial levels to further investigate the mechanism of such facilitation. The results revealed that stable mean contexts do facilitate variability perception. In particular, unstable long term mean context causes loss of sensitivity to variability whereas response bias is determined by the interaction between long-term and transient mean stability. PMID- 26509690 TI - Hypothesis Testing of Inclusion of the Tolerance Interval for the Assessment of Food Safety. AB - In the testing of food quality and safety, we contrast the contents of the newly proposed food (genetically modified food) against those of conventional foods. Because the contents vary largely between crop varieties and production environments, we propose a two-sample test of substantial equivalence that examines the inclusion of the tolerance intervals of the two populations, the population of the contents of the proposed food, which we call the target population, and the population of the contents of the conventional food, which we call the reference population. Rejection of the test hypothesis guarantees that the contents of the proposed foods essentially do not include outliers in the population of the contents of the conventional food. The existing tolerance interval (TI0) is constructed to have at least a pre-specified level of the coverage probability. Here, we newly introduce the complementary tolerance interval (TI1) that is guaranteed to have at most a pre-specified level of the coverage probability. By applying TI0 and TI1 to the samples from the target population and the reference population respectively, we construct a test statistic for testing inclusion of the two tolerance intervals. To examine the performance of the testing procedure, we conducted a simulation that reflects the effects of gene and environment, and residual from a crop experiment. As a case study, we applied the hypothesis testing to test if the distribution of the protein content of rice in Kyushu area is included in the distribution of the protein content in the other areas in Japan. PMID- 26509691 TI - The genomics of wild yeast populations sheds light on the domestication of man's best (micro) friend. AB - The domestication of plants, animals and microbes by humans are the longest artificial evolution experiments ever performed. The study of these long-term experiments can teach us about the genomics of adaptation through the identification of the genetic bases underlying the traits favoured by humans. In laboratory evolution, the characterization of the molecular changes that evolved specifically in some lineages is straightforward because the ancestors are readily available, for instance in the freezer. However, in the case of domesticated species, the ancestor is often missing, which leads to the necessity of going back to nature in order to infer the most likely ancestral state. Significant and relatively recent examples of this approach include wolves as the closest wild relative to domestic dogs (Axelsson et al. 2013) and teosinte as the closest relative to maize (reviewed in Hake & Ross-Ibarra 2015). In both cases, the joint analysis of domesticated lineages and their wild cousins has been key in reconstructing the molecular history of their domestication. While the identification of closest wild relatives has been done for many plants and animals, these comparisons represent challenges for micro-organisms. This has been the case for the budding yeast Saccharomyces cerevisiae, whose natural ecological niche is particularly challenging to define. For centuries, this unicellular fungus has been the cellular factory for wine, beer and bread crafting, and currently for bioethanol and drug production. While the recent development of genomics has lead to the identification of many genetic elements associated with important wine characteristics, the historical origin of some of the domesticated wine strains has remained elusive due to the lack of knowledge of their close wild relatives. In this issue of Molecular Ecology, Almeida et al. (2015) identified what is to date the closest known wild population of the wine yeast. This population is found associated with oak trees in Europe, presumably its natural host. Using population genomics analyses, Almeida and colleagues discovered that the initial divergence between natural and domesticated wine yeasts in the Mediterranean region took place around the early days of wine production. Surprisingly, genomic regions that are key to wine production today appeared not to be derived from these natural populations but from genes gained from other yeast species. PMID- 26509692 TI - Ring species as demonstrations of the continuum of species formation. AB - In the mid-20th century, Ernst Mayr (1942) and Theodosius Dobzhansky (1958) championed the significance of 'circular overlaps' or 'ring species' as the perfect demonstration of the gradual nature of species formation. As an ancestral species expands its range, wrapping around a geographic barrier, derived taxa within the ring display interactions typical of populations, such as genetic and morphological intergradation, while overlapping taxa at the terminus of the ring behave largely as sympatric, reproductively isolated species. Are ring species extremely rare or are they just difficult to detect? What conditions favour their formation? Modelling studies have attempted to address these knowledge gaps by estimating the biological parameters that result in stable ring species (Martins et al. 2013), and determining the necessary topographic parameters of the barriers encircled (Monahan et al. 2012). However, any generalization is undermined by a major limitation: only a handful of ring species are known to exist in nature. In addition, many of them have been broken into multiple species presumed to be evolving independently, usually obscuring the evolutionary dynamics that generate diversity. A paper in this issue of Molecular Ecology by Fuchs et al. (2015), focused on the entire genealogy of a bulbul (Alophoixus) species complex, offers key insights into the evolutionary processes underlying diversification of this Indo-Malayan bird. Their findings fulfil most of the criteria that can be expected for ring species (Fig. ): an ancestor has colonized the mainland from Sundaland, expanded along the forested habitat wrapping around Thailand's lowlands, adjacent taxa intergrade around the ring distribution, and terminal taxa overlap at the ring closure. Although it remains unclear whether ring divergence has resulted in restrictive gene flow relative to that observed around the ring, their results suggest that circular overlaps might be more common in nature than currently recognized in the literature. Most importantly, this work shows that the continuum of species formation that Mayr and Dobzhansky praised in circular overlaps is found in biological systems currently described as 'rings of species', in addition to the idealized 'ring species'. PMID- 26509694 TI - Premature Mortality Among Adults With Schizophrenia in the United States. AB - IMPORTANCE: Although adults with schizophrenia have a significantly increased risk of premature mortality, sample size limitations of previous research have hindered the identification of the underlying causes. OBJECTIVE: To describe overall and cause-specific mortality rates and standardized mortality ratios (SMRs) for adults with schizophrenia compared with the US general population. DESIGN, SETTING, AND PARTICIPANTS: We identified a national retrospective longitudinal cohort of patients with schizophrenia 20 to 64 years old in the Medicaid program (January 1, 2001, to December 31, 2007). The cohort included 1,138,853 individuals, 4,807,121 years of follow-up, and 74,003 deaths, of which 65,553 had a known cause. MAIN OUTCOMES AND MEASURES: Mortality ratios for the schizophrenia cohort standardized to the general population with respect to age, sex, race/ethnicity, and geographic region were estimated for all-cause and cause specific mortality. Mortality rates per 100,000 person-years and the mean years of potential life lost per death were also determined. Death record information was obtained from the National Death Index. RESULTS: Adults with schizophrenia were more than 3.5 times (all-cause SMR, 3.7; 95% CI, 3.7-3.7) as likely to die in the follow-up period as were adults in the general population. Cardiovascular disease had the highest mortality rate (403.2 per 100,000 person-years) and an SMR of 3.6 (95% CI, 3.5-3.6). Among 6 selected cancers, lung cancer had the highest mortality rate (74.8 per 100,000 person-years) and an SMR of 2.4 (95% CI, 2.4-2.5). Particularly elevated SMRs were observed for chronic obstructive pulmonary disease (9.9; 95% CI, 9.6-10.2) and influenza and pneumonia (7.0; 95% CI, 6.7-7.4). Accidental deaths (119.7 per 100,000 person-years) accounted for more than twice as many deaths as suicide (52.0 per 100,000 person-years). Nonsuicidal substance-induced death, mostly from alcohol or other drugs, was also a leading cause of death (95.2 per 100,000 person-years). CONCLUSIONS AND RELEVANCE: In a US national cohort of adults with schizophrenia, excess deaths from cardiovascular and respiratory diseases implicate modifiable cardiovascular risk factors, including especially tobacco use. Excess deaths directly attributable to alcohol or other drugs highlight threats posed by substance abuse. More aggressive identification and management of cardiovascular risk factors, as well as reducing tobacco use and substance abuse, should be leading priorities in the medical care of adults with schizophrenia. PMID- 26509695 TI - Corrigendum: Direct Correlation Between Ligand-Induced alpha-Synuclein Oligomers and Amyloid-like Fibril Growth. PMID- 26509698 TI - Predicting the Presence of Nonmelanoma Skin Cancers After Biopsy: A Method to Reduce Unnecessary Surgical Procedures. PMID- 26509697 TI - Mucosal Immunogenicity of Genetically Modified Lactobacillus acidophilus Expressing an HIV-1 Epitope within the Surface Layer Protein. AB - Surface layer proteins of probiotic lactobacilli are theoretically efficient epitope-displaying scaffolds for oral vaccine delivery due to their high expression levels and surface localization. In this study, we constructed genetically modified Lactobacillus acidophilus strains expressing the membrane proximal external region (MPER) from human immunodeficiency virus type 1 (HIV-1) within the context of the major S-layer protein, SlpA. Intragastric immunization of mice with the recombinants induced MPER-specific and S-layer protein-specific antibodies in serum and mucosal secretions. Moreover, analysis of systemic SlpA specific cytokines revealed that the responses appeared to be Th1 and Th17 dominant. These findings demonstrated the potential use of the Lactobacillus S layer protein for development of oral vaccines targeting specific peptides. PMID- 26509699 TI - Relationship Between Pneumocystis carinii Burden and the Degree of Host Immunosuppression in an Airborne Transmission Experimental Model. AB - To quantitatively assess the risk of contamination by Pneumocystis depending on the degree of immunosuppression (ID) of the exposed rat hosts, we developed an animal model, where rats went through different doses of dexamethasone. Then, natural and aerial transmission of Pneumocystis carinii occurred during cohousing of the rats undergoing gradual ID levels (receivers) with nude rats developing pneumocystosis (seeders). Following contact between receiver and seeder rats, the P. carinii burden of receiver rats was determined by toluidine blue ortho staining and by qPCR targeting the dhfr monocopy gene of this fungus. In this rat model, the level of circulating CD4(+) and CD8(+) T lymphocytes remained significantly stable and different for each dose of dexamethasone tested, thus reaching the goal of a new stable and gradual ID rat model. In addition, an inverse relationship between the P. carinii burden and the level of circulating CD4(+) or CD8(+) T lymphocytes was evidenced. This rat model may be used to study other opportunistic pathogens or even co-infections in a context of gradual ID. PMID- 26509700 TI - Fast Color Change with Photochromic Fused Naphthopyrans. AB - Photochromic molecules can reversibly develop color upon irradiation with UV light. These smart molecules, mainly in the naphthopyran family, have been applied with success to ophthalmic lenses that darken quickly under sunlight and revert to the uncolored state after several minutes in the dark. This slow adaptation to the absence of light is one of the limitations and is due to the formation of an unwanted photoisomer. We have designed a new naphthopyran with a bridged structure which prohibits the formation of the undesirable, persistent photoisomer and thus shows a very fast switching between the uncolored and colored states. UV irradiation of a hybrid siloxane matrix doped with the new fused naphthopyran leads to the formation of a pink coloration bleaching in a few milliseconds, in the absence of light, at room temperature. This new fused naphthopyran is easily prepared in three steps from readily accessible precursors and is amenable to structural modifications to tailor color and lifetime of the colored photoisomer. PMID- 26509701 TI - Oncogenic activin C interacts with decorin in colorectal cancer in vivo and in vitro. AB - Activin C is a member of the transforming growth factor-beta (TGF-beta) superfamily with various biological activities. Decorin is a member of the small leucine-rich proteoglycan family, which can bind to TGF-beta and modulate TGF beta-mediated signaling. In the decorin-deficient mouse model, we found that the expression of activin C was remarkably increased in the intestine of Dcn-/- mice compared to the expression of activin C in the intestine of Dcn+/+ mice. Addition of activin C protein to colorectal cancer cells or over-expression of activin C in these cells stimulated cell growth, migration, and invasion in vitro. Enhanced AP-1 expression in colorectal cancer cells was found to be associated with the oncoprotein-like effects of activin C through the JNK/AP-1 pathway, and not the Smad signaling pathway. However, these effects were abolished when decorin expression was restored by transfecting the cells with a decorin-expressing plasmid or by reducing the expression of activin C via interfering RNA. Further analysis demonstrated that decorin could directly bind to and accelerate the degradation of activin C. In conclusion, our data provided the first evidence demonstrating the oncogenic role of activin C in intestinal tumorigenesis of decorin-deficient mice and colorectal cancer cells. (c) 2015 Wiley Periodicals, Inc. PMID- 26509702 TI - First-Principles Design of a Deep-Ultraviolet Nonlinear-Optical Crystal from KBe2BO3F2 to NH4Be2BO3F2. AB - KBe2BO3F2 (KBBF) is so far the sole nonlinear-optical (NLO) material that can be practically applied in the deep-ultraviolet (DUV) region. For the purpose of overcoming its layering tendency in crystal growth, herein a computer-assisted material design system is employed to design a new KBBF analogue, ammonia beryllium fluoroborate (NH4Be2BO3F2, ABBF). The first-principles calculations demonstrate that ABBF possesses NLO properties very close to those of KBBF, thus exhibiting good DUV NLO capability. Moreover, owing to the relatively strong chemical binding between layers, ABBF would have a better growth habit compared with KBBF. Upon synthesis, ABBF would be a very promising DUV NLO material. PMID- 26509703 TI - Periplasmic nitrate reductase and formate dehydrogenase: similar molecular architectures with very different enzymatic activities. AB - It is remarkable how nature has been able to construct enzymes that, despite sharing many similarities, have simple but key differences that tune them for completely different functions in living cells. Periplasmic nitrate reductase (Nap) and formate dehydrogenase (Fdh) from the DMSOr family are representative examples of this. Both enzymes share almost identical three-dimensional protein foldings and active sites, in terms of coordination number, geometry and nature of the ligands. The substrates of both enzymes (nitrate and formate) are polyatomic anions that also share similar charge and stereochemistry. In terms of the catalytic mechanism, both enzymes have a common activation mechanism (the sulfur-shift mechanism) that ensures a constant coordination number around the metal ion during the catalytic cycle. In spite of these similarities, they catalyze very different reactions: Nap abstracts an oxygen atom from nitrate releasing nitrite, whereas FdH catalyzes a hydrogen atom transfer from formate and releases carbon dioxide. In this Account, a critical analysis of structure, function, and catalytic mechanism of the molybdenum enzymes periplasmic nitrate reductase (Nap) and formate dehydrogenase (Fdh) is presented. We conclude that the main structural driving force that dictates the type of reaction, catalyzed by each enzyme, is a key difference on one active site residue that is located in the top region of the active sites of both enzymes. In both enzymes, the active site is centered on the metal ion of the cofactor (Mo in Nap and Mo or W in Fdh) that is coordinated by four sulfur atoms from two pyranopterin guanosine dinucleotide (PGD) molecules and by a sulfido. However, while in Nap there is a Cys directly coordinated to the Mo ion, in FdH there is a SeCys instead. In Fdh there is also an important His that interacts very closely with the SeCys, whereas in Nap the same position is occupied by a Met. The role of Cys in Nap and SeCys in FdH is similar in both enzymes; however, Met and His have different roles. His participates directly on catalysis, and it is therefore detrimental for the catalytic cycle of FdH. Met only participates in substrate binding. We concluded that this small but key difference dictates the type of reaction that is catalyzed by each enzyme. In addition, it allows explaining why formate can bind in the Nap active site in the same way as the natural substrate (nitrate), but the reaction becomes stalled afterward. PMID- 26509704 TI - Social Function and Frontopolar Activation during a Cognitive Task in Patients with Bipolar Disorder. AB - BACKGROUND: It is important to understand the neural basis of functional impairments in patients with bipolar disorder (BD) in order to be able to address the recovery. Recently, neurocognitive impairment emerged as a predictor of psychosocial function. A number of functional brain imaging studies have shown that social function is associated with activation of the prefrontal cortex during a cognitive task in healthy adults, and in patients with major depressive disorder and schizophrenia. However, few studies have been conducted in patients with BD. METHODS: We performed multichannel near-infrared spectroscopy (NIRS) imaging to investigate the activation of the prefrontal cortex during a verbal fluency task (VFT). We also used the Social Adaptation Self-Evaluation Scale (SASS) to assess social functioning in patients with BD. Thirty-three depressed patients with BD and 65 age-, gender- and task performance-matched healthy controls (HCs) participated in this study. RESULTS: Depressed patients with BD showed reduced activation in the broader bilateral prefrontal cortex during the VFT compared to HCs. Moreover, a significant positive correlation was observed between the total SASS scores and right prefrontal activation in patients with BD. In the SASS subscores, the interest and motivation factor was also positively correlated with frontopolar activation. CONCLUSIONS: These results suggest an association between social function and prefrontal activation in depressed patients with BD. The present study provides evidence that NIRS imaging could be helpful in understanding the neural basis of social function. PMID- 26509705 TI - Awaken, You Arteries and Limbs! PMID- 26509706 TI - Trends and Determinants of Oral Anti-Diabetic Initiation in Youth with Suspected Type 2 Diabetes. AB - OBJECTIVE: To evaluate trends and identify predictors of treatment initiation of oral anti-diabetic drugs (OAD) in youth. PATIENTS AND METHODS: We identified a select population of children, ages 8-18 years, with at least 13 months of continuous health plan coverage within the years 2001-2012 in a large US commercial insurance claims database. New use of an OAD was defined as the first claim for an outpatient dispensing following a 12-month wash out period. Treatment incidence was estimated monthly over the study period, and stratified by age, gender, geographic region, and provider specialty. RESULTS: The median size of the source population during the study period was 2.2 million children. A total of 13,824 initiators (mean monthly incidence of 4.6 (95% CI = 3.6, 5.5) per 100,000 youths) were identified. Initiators were more likely to be females, age 15-18, from the southern region, and have visited a family practitioner (versus a general pediatrician) prior to initiation. Time trends demonstrate a 43% increase in initiation from 2002-2012, with a gradual decrease starting from early 2008. CONCLUSION: Incidence of filled OAD medications in youth increased over time, especially for patients treated by family practitioners. Additional research is needed into factors influencing prescribing by family practitioners and pediatricians. PMID- 26509707 TI - Correction: A Fast Incremental Gaussian Mixture Model. PMID- 26509708 TI - Emergence of Cryptosporidium hominis Monkey Genotype II and Novel Subtype Family Ik in the Squirrel Monkey (Saimiri sciureus) in China. AB - A single Cryptosporidium isolate from a squirrel monkey with no clinical symptoms was obtained from a zoo in Ya'an city, China, and was genotyped by PCR amplification and DNA sequencing of the small-subunit ribosomal RNA (SSU rRNA), 70-kDa heat shock protein (HSP70), Cryptosporidium oocyst wall protein, and actin genes. This multilocus genetic characterization determined that the isolate was Cryptosporidium hominis, but carried 2, 10, and 6 nucleotide differences in the SSU rRNA, HSP70, and actin loci, respectively, which is comparable to the variations at these loci between C. hominis and the previously reported monkey genotype (2, 3, and 3 nucleotide differences). Phylogenetic studies, based on neighbor-joining and maximum likelihood methods, showed that the isolate identified in the current study had a distinctly discordant taxonomic status, distinct from known C. hominis and also from the monkey genotype, with respect to the three loci. Restriction fragment length polymorphisms of the SSU rRNA gene obtained from this study were similar to those of known C. hominis but clearly differentiated from the monkey genotype. Further subtyping was performed by sequence analysis of the gene encoding the 60-kDa glycoprotein (gp60). Maximum homology of only 88.3% to C. hominis subtype IdA10G4 was observed for the current isolate, and phylogenetic analysis demonstrated that this particular isolate belonged to a novel C. hominis subtype family, IkA7G4. This study is the first to report C. hominis infection in the squirrel monkey and, based on the observed genetic characteristics, confirms a new C. hominis genotype, monkey genotype II. Thus, these results provide novel insights into genotypic variation in C. hominis. PMID- 26509709 TI - Critical Review of Brown and Thomas "The First New Zealanders? An Alternative Interpretation of the Stable Isotope Data from Wairau Bar". PMID- 26509710 TI - Lipid-Laden Multilocular Cells in the Aging Thymus Are Phenotypically Heterogeneous. AB - Intrathymic lipid-laden multilocular cells (LLMC) are known to express pro inflammatory factors that might regulate functional activity of the thymus. However, the phenotype of age-associated intrathymic LLMC is still controversial. In this study, we evaluated LLMC density in the aging thymus and better characterized their distribution, ultrastructure and phenotype. Our results show an increased density of LLMC in the thymus from 03 to 24 months of age. Morphologically, intrathymic LLMC exhibit fibroblastoid fusiform, globular or stellate shapes and can be found in the subcapsular region as well as deeper in the parenchyma, including the perivascular area. Some parenchymal LLMC were like telocytes accumulating lipids. We identified lipid droplets with different electrondensities, lipofuscin granules and autolipophagosome-like structures, indicating heterogeneous lipid content in these cells. Autophagosome formation in intrathymic LLMC was confirmed by positive staining for beclin-1 and perilipin (PLIN), marker for lipid droplet-associated proteins. We also found LLMC in close apposition to thymic stromal cells, endothelial cells, mast cells and lymphocytes. Phenotypically, we identified intrathymic LLMC as preadipocytes (PLIN+PPARgamma2+), brown adipocytes (PLIN+UCP1+), macrophages (PLIN+Iba-1+) or pericytes (PLIN+NG2+) but not epithelial cells (PLIN- panCK+). These data indicate that intrathymic LLMC are already present in the young thymus and their density significantly increases with age. We also suggest that LLMC, which are morphologically distinct, establish direct contact with lymphocytes and interact with stromal cells. Finally, we evidence that intrathymic LLMC correspond to not only one but to distinct cell types accumulating lipids. PMID- 26509711 TI - IRBIT Interacts with the Catalytic Core of Phosphatidylinositol Phosphate Kinase Type Ialpha and IIalpha through Conserved Catalytic Aspartate Residues. AB - Phosphatidylinositol phosphate kinases (PIPKs) are lipid kinases that generate phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), a critical lipid signaling molecule that regulates diverse cellular functions, including the activities of membrane channels and transporters. IRBIT (IP3R-binding protein released with inositol 1,4,5-trisphosphate) is a multifunctional protein that regulates diverse target proteins. Here, we report that IRBIT forms signaling complexes with members of the PIPK family. IRBIT bound to all PIPK isoforms in heterologous expression systems and specifically interacted with PIPK type Ialpha (PIPKIalpha) and type IIalpha (PIPKIIalpha) in mouse cerebellum. Site-directed mutagenesis revealed that two conserved catalytic aspartate residues of PIPKIalpha and PIPKIIalpha are involved in the interaction with IRBIT. Furthermore, phosphatidylinositol 4-phosphate, Mg2+, and/or ATP interfered with the interaction, suggesting that IRBIT interacts with catalytic cores of PIPKs. Mutations of phosphorylation sites in the serine-rich region of IRBIT affected the selectivity of its interaction with PIPKIalpha and PIPKIIalpha. The structural flexibility of the serine-rich region, located in the intrinsically disordered protein region, is assumed to underlie the mechanism of this interaction. Furthermore, in vitro binding experiments and immunocytochemistry suggest that IRBIT and PIPKIalpha interact with the Na+/HCO3- cotransporter NBCe1 B. These results suggest that IRBIT forms signaling complexes with PIPKIalpha and NBCe1-B, whose activity is regulated by PI(4,5)P2. PMID- 26509712 TI - Stable Bioactive Enzyme-Containing Multilayer Films Based on Covalent Cross Linking from Mussel-Inspired Adhesives. AB - The use of immobilized enzymes is mandatory for the easy separation of the enzyme, the unreacted substrates, and the obtained products to allow repeated enzymatic assays without cumbersome purification steps. The immobilization procedure is however critical to obtain a high fraction of active enzyme. In this article, we present an enzyme immobilization strategy based on a catechol functionalized alginate. We demonstrate that alkaline phosphatase (ALP) remains active in multilayered films made with alginate modified with catechol moieties (AlgCat) for long duration, that is, up to 7 weeks, provided the multilayered architecture is cross-linked with sodium periodate. This cross-linking reaction allows to create covalent bonds between the amino groups of ALP and the quinone group carried by the modified alginate. In the absence of cross-linking, the enzymatic activity is rapidly lost and this reduction is mainly due to enzyme desorption. We also show that NaIO4 cross-linked (AlgCat-Alp)n films can be freeze-dried and reused at least 3 weeks later without lost in enzymatic activity. PMID- 26509713 TI - RNA 3D Modules in Genome-Wide Predictions of RNA 2D Structure. AB - Recent experimental and computational progress has revealed a large potential for RNA structure in the genome. This has been driven by computational strategies that exploit multiple genomes of related organisms to identify common sequences and secondary structures. However, these computational approaches have two main challenges: they are computationally expensive and they have a relatively high false discovery rate (FDR). Simultaneously, RNA 3D structure analysis has revealed modules composed of non-canonical base pairs which occur in non homologous positions, apparently by independent evolution. These modules can, for example, occur inside structural elements which in RNA 2D predictions appear as internal loops. Hence one question is if the use of such RNA 3D information can improve the prediction accuracy of RNA secondary structure at a genome-wide level. Here, we use RNAz in combination with 3D module prediction tools and apply them on a 13-way vertebrate sequence-based alignment. We find that RNA 3D modules predicted by metaRNAmodules and JAR3D are significantly enriched in the screened windows compared to their shuffled counterparts. The initially estimated FDR of 47.0% is lowered to below 25% when certain 3D module predictions are present in the window of the 2D prediction. We discuss the implications and prospects for further development of computational strategies for detection of RNA 2D structure in genomic sequence. PMID- 26509714 TI - Quantitative Description of Crystal Nucleation and Growth from in Situ Liquid Scanning Transmission Electron Microscopy. AB - Recent advances in liquid cell (scanning) transmission electron microscopy (S)TEM has enabled in situ nanoscale investigations of controlled nanocrystal growth mechanisms. Here, we experimentally and quantitatively investigated the nucleation and growth mechanisms of Pt nanostructures from an aqueous solution of K2PtCl6. Averaged statistical, network, and local approaches have been used for the data analysis and the description of both collective particles dynamics and local growth features. In particular, interaction between neighboring particles has been revealed and attributed to reduction of the platinum concentration in the vicinity of the particle boundary. The local approach for solving the inverse problem showed that particles dynamics can be simulated by a stationary diffusional model. The obtained results are important for understanding nanocrystal formation and growth processes and for optimization of synthesis conditions. PMID- 26509716 TI - News and Views - December 2015. PMID- 26509715 TI - Evaluation of the preventive effect of dexpanthenol in radiation injury by lung perfusion scintigraphy: a preclinical experimental model of radiation injury. AB - AIM: The aim of this study was to show the preventative effects of dexpanthenol in radiation injuries caused by radiotherapy (RT) through the use of lung perfusion scintigraphy in the pre-RT and post-RT periods. MATERIALS AND METHODS: Six male New Zealand rabbits (5-6 months of age and ~2.5-3 kg in weight) were the used in this study. The animals were subjected to Tc-macroaggregated albumin lung perfusion scintigraphy in the pre-RT and post-RT (i.e. 2 weeks after treatment) periods. The scintigraphies were performed with the same dose by the same staff and the methodology used the same acquisition parameters. The rabbits were divided into two groups: group I (administered RT only) and group II (also administered intramuscular 500 mg dexpanthenol injections for 14 consecutive days after RT). Quantification was performed to compare the groups and the quantification variables were compared using a paired samples t-test, with P value less than 0.05 considered to be statistically significant. Histopathological analysis was also carried out. RESULTS: The post-RT scintigraphies indicated a decrease in the counts in both lungs, suggesting early post-RT injury. The difference between the counts obtained from both lungs in groups I and II was significantly different and favoured group II. Histopathological results confirmed the scintigraphy results. CONCLUSION: It is possible to estimate post-RT changes in the early period (in contrast to previous data) by lung perfusion scintigraphy. Dexpanthenol may also reduce the effects of RT to a degree. Although this is the first study to report the preventive effects of dexpanthenol on RT injuries, further studies are warranted in this area. PMID- 26509717 TI - Adaptive soft molecular self-assemblies. AB - Adaptive molecular self-assemblies provide possibility of constructing smart and functional materials in a non-covalent bottom-up manner. Exploiting the intrinsic properties of responsiveness of non-covalent interactions, a great number of fancy self-assemblies have been achieved. In this review, we try to highlight the recent advances in this field. The following contents are focused: (1) environmental adaptiveness, including smart self-assemblies adaptive to pH, temperature, pressure, and moisture; (2) special chemical adaptiveness, including nanostructures adaptive to important chemicals, such as enzymes, CO2, metal ions, redox agents, explosives, biomolecules; (3) field adaptiveness, including self assembled materials that are capable of adapting to external fields such as magnetic field, electric field, light irradiation, and shear forces. PMID- 26509718 TI - SIRT1 Polymorphisms Associate with Seasonal Weight Variation, Depressive Disorders, and Diastolic Blood Pressure in the General Population. AB - SIRT1 polymorphisms have previously been associated with depressive and anxiety disorders. We aimed at confirming these earlier findings and extending the analyses to seasonal variations in mood and behavior. Three tag single-nucleotide polymorphisms (SNPs) were selected to capture the common variation in the SIRT1 gene. 5910 individuals (with blood sample, diagnostic interview, self-report of on seasonal changes in mood and behavior) were selected from a representative Finnish nationwide population-based sample. Logistic and linear regression models were used to analyze the associations between the SNPs and depressive and anxiety disorders, metabolic syndrome (EGIR criteria) and its components, and health examination measurements, Homeostasis Model Assessments, and diagnoses of type 2 and type 1 diabetes. SIRT1 rs2273773 showed evidence of association with seasonal variation in weight (C-allele, OR = 0.85, 95% CI = 0.76-0.95, p = 0.005). In addition, our study gave further support for the association of SIRT1 gene with depressive disorders (rs3758391) and diastolic blood pressure (rs2273773). PMID- 26509719 TI - Califf for the FDA. PMID- 26509720 TI - Family Nurse Practitioner or Acute Care Nurse Practitioner in the Emergency Department? PMID- 26509721 TI - Are Pediatric Pain Self-Report Scores Accurate? AB - Review of recent evidence with translation to practice for the advanced practice nurse (APN) role is presented using a case study module for "Clinically Significant Differences in Acute Pain Measured on Self-Report Pain Scales in Children." The study results showed that there were 314 pediatric patients with acute pain evaluated for minimum (MCSD) and ideal clinically significant differences (ICSD) using the Faces Pain Scale-Revised (FPS-R) and the Color Analog Scale (CAS). These data reveal stable MCSD estimates for the FPS-R and the CAS with generalizability for acute pediatric pain. The ICSD estimates did not prove to be stable for different groupings of acute pain. The implications and clinical relevance of these findings for APNs are discussed, highlighting best evidence. PMID- 26509722 TI - Finger Proximal Interphalangeal Joint Dislocation. AB - Finger dislocations are common injuries that are often managed by emergency nurse practitioners. A systematic physical examination following these injuries is imperative to avoid complications. Radiographic views, including the anteroposterior, lateral, and oblique views, are imperative to evaluate these finger dislocations. A dorsal dislocation of the proximal interphalangeal (PIP) joint is the most common finger dislocation type often easily reduced. A volar PIP dislocation can often be difficult to reduce and may result in finger deformity. Finger dislocations should be reduced promptly. Referral to an orthopedic hand specialist is required if the dislocation is unable to be reduced or if the finger joint is unstable following reduction attempts. PMID- 26509723 TI - Alteplase for the Treatment of Pulmonary Embolism: A Review. AB - Pulmonary embolism can present with a wide range of symptoms, from asymptomatic to cardiac arrest, making diagnosis challenging. Alteplase is a fibrinolytic that is indicated for the treatment of pulmonary embolism in intermediate- and high risk patients. Controversy exists as to the patient population that will benefit most from fibrinolytic therapy, as well as the proper dose and administration technique. The patient's risk of bleeding should be weighed against the potential benefits of treatment in light of the clinical presentation because of the high mortality rate associated with pulmonary embolism. Nurses at the bedside must monitor for signs of bleeding when alteplase is administered. Fibrinolytic therapy will frequently be started in the emergency department, and the nurse must ensure that alteplase is administered in a safe and effective manner. This review discusses the clinical evidence for alteplase in pulmonary embolism and its specific role in treatment. PMID- 26509724 TI - A Case of Pertussis: What Emergency Health Care Providers Need to Know. AB - Pertussis is a highly contagious acute respiratory illness. Prior to the availability of the whole-cell pertussis vaccine in the late 1940s, pertussis was one of the most common infectious diseases of childhood in the United States and a major cause of infant morbidity and mortality. Although pertussis vaccination has resulted in a substantial reduction in the disease, the incidence has been steadily increasing since the 1990s. The clinical presentation of pertussis may be variable depending on the age and immunization status of the patient. The classic presentation includes a triad of symptoms: paroxysms of coughing; an inspiratory whoop following cough; and posttussive vomiting. Those most vulnerable are the ones not yet immunized and the ones most likely to transmit the illness who may not exhibit "classic" pertussis symptoms, delaying or preventing identification and treatment. Because pertussis carries known morbidity and mortality risks, prevention and early identification are paramount. PMID- 26509725 TI - Modified Early Warning System as a Predictor for Hospital Admissions and Previous Visits in Emergency Departments. AB - This study addresses the development of a modified early warning system (MEWS) to predict hospital admissions from emergency departments (EDs) using the 2010 National Hospital Ambulatory Medical Care Survey (NHAMCS). A MEWS score was created for each patient in the NHAMCS data set using the vital signs recorded at admission. Multiple logistic regression analyses indicated that for every 1 unit increase in the MEWS score, patients were 33% more likely to be admitted to the hospital for further care even after controlling for demographics. Females were 19% less likely to be admitted and older persons were more likely to be admitted. A MEWS score of 13 resulted in almost 90% chance of admission to the hospital. Results indicate that an early warning system may be used to identify signs of physiological decline in many health care settings. Use of MEWS in EDs could be a helpful predictor of the need for hospitalization and could serve as a focus for early decision making and as a point of comparison for efficacy of interventions both in the emergency department and if the patient is admitted to the hospital. PMID- 26509726 TI - The Value of Continuous ST-Segment Monitoring in the Emergency Department. AB - Practice standards for electrocardiographic monitoring recommend continuous ST segment monitoring (C-STM) in patients presenting to the emergency department (ED) with signs and/or symptoms of acute coronary syndrome (ACS), but few studies have evaluated its use in the ED. We compared time to diagnosis and 30-day adverse events before and after implementation of C-STM. We also evaluated the diagnostic accuracy of C-STM in detecting ischemia and infarction. We prospectively studied 163 adults (preintervention: n = 78; intervention: n = 85) in a single ED and stratified them into low (n = 51), intermediate (n = 100), or high (n = 12) risk using History, ECG, Age, Risk factors, and Troponin (HEART) scores. The principal investigator monitored participants, activating C-STM on bedside monitors in the intervention phase. We used likelihood ratios (LRs) as the measure of diagnostic accuracy. Overall, 9% of participants were diagnosed with ACS. Median time to diagnosis did not differ before and after implementation of C-STM (5.55 vs. 5.98 hr; p = 0.43). In risk-stratified analyses, no significant pre-/postdifference in time to diagnosis was found in low-, intermediate-, or high-risk participants. There was no difference in the rate of 30-day adverse events before versus after C-STM implementation (11.5% vs. 10.6%; p = 0.85). The +LR and -LR of C-STM for ischemia were 24.0 (95% confidence interval [CI]: 1.4, 412.0) and 0.3 (95% CI: 0.02, 2.9), respectively, and for infarction were 13.7 (95% CI: 1.7, 112.3) and 0.7 (95% CI: 0.3, 1.5), respectively. Use of C-STM did not provide added diagnostic benefit for patients with signs and/or symptoms of myocardial ischemia in the ED. PMID- 26509727 TI - Characteristics of Children Who Undergo Intraosseous Needle Placement. AB - Intraosseous (IO) access is a standard of care for pediatric emergencies in the absence of conventional intravenous access. Intraosseous needles provide access for resuscitation fluids and medications and are often placed in the emergency department. However, there are no studies to date that describe the characteristics of pediatric IO needle recipients or their dispositions and outcomes. This study examined the characteristics and disposition of children following IO needle placement by prehospital and emergency room teams before being transported to a children's hospital. We conducted a retrospective descriptive analysis of pediatric patients who had an IO needle placed as a part of their transport care. Data was extracted from a Level 1 trauma tertiary care children's hospital transport database from 1993 to 2009. We measured diagnosis, insertion reason, insertion time (day vs. night shift), complications, and disposition of patients after IO needle placement. There were 143 eligible patients in the study; 65% were males. Mean patient's age was 1.2 years (range: 0.01-13 years). Intraosseous needles were placed most often for patients with cardiopulmonary compromise. Of the 143 patients transported, 53% (n = 76) were placed for no intravenous access and 34% (n = 49) were placed for nonperfusing rhythm. The majority of the IO needles were placed during the daytime (0700-1900 hr), and most patients experienced no complications (n = 67; 47%). However, of those who experienced a complication, 27% were due to infiltration of the IO needle. Of those admitted to hospital, 58% (n = 83) were ultimately discharged home. Intraosseous access provides a safe and reliable method for rapidly achieving a route for administration of medications, fluids and blood products. It is a lifesaving measure with most IO needles successfully placed by referring facilities prior to transport, with few reported complications. PMID- 26509728 TI - Making the Case for Nurse Practitioners in the Emergency Department: A Clinical Case Study. AB - Emergency departments (EDs) across the country are inundated with patients and they struggle to provide the expected standard of care while meeting set benchmarks. A shortage of emergency medicine physicians further complicates the situation, and many facilities are utilizing nurse practitioners to bridge the gap. A clinical case study was conducted at Touro Infirmary, a large urban hospital in New Orleans, LA, to provide an in-depth look at the implementation and positive outcomes of nurse practitioners in one ED. The model used at this facility included a nurse practitioner in the "fast track" area of the ED as well as a nurse practitioner in triage. Overall, the door-to-provider time decreased from 59.25 min in 2012 to 32.08 min in 2013. The bed-to-provider time decreased by an average of 9.17 min, with a 22.92-min average seen in 2012 and a 13.75-min average seen in 2013. An average decrease of 18.3 min was seen in the overall length of stay from 2012 to 2013. The percentage of left without treatment dropped by 3.77%, from 5.07% in 2012 to 1.3% in 2013. In addition to the improved statistics, an increase in the number of patients was also seen. The number of daily visits increased by an average of 2.25 patients per day or 51.4 patients per month. The acuity of the patients did not change, with an average admission rate of 21% noted in both 2012 and 2013. Patient satisfaction remained high at more than 90% during both years. The percentage of significant returns also remained constant at less than 1% in both 2012 and 2013. Assessment of the CMS (Centers for Medicare & Medicaid Services) Quality Measures and PRQS (Physician Quality Reporting System) Indicators do not reveal any change of statistical significance. The average of all providers was shown to be at or above the benchmark set for each measurement/indicator. PMID- 26509730 TI - Traditional Glue, Adhesive and Poison Used for Composite Weapons by Ju/'hoan San in Nyae Nyae, Namibia. Implications for the Evolution of Hunting Equipment in Prehistory. AB - Ju/'hoan hunters from Nyae Nyae, near Tsumkwe in Namibia, demonstrate the manufacture of three fixative pastes made from plant extracts, and poison made from grubs and plant extracts. Ammocharis coranica and Terminalia sericea produce simple glue. Ozoroa schinzii latex mixed with carbonized Aristeda adscensionis grass is a compound adhesive. Composite poison is made from Chrysomelid grub viscera mixed with salivary extracts of Acacia mellifera inner bark and the tuber sap of Asparagus exuvialis. In order to document potential variability in the chaine operatoire, and to eliminate inherent biases associated with unique observations, we studied manufacturing processes in three separate Nyae Nyae villages. Although there are methodological similarities in the Nyae Nyae area, we observed a few differences in contemporary traditions of poison manufacture. For example, some hunters make powder from Asparagus exuvialis tuber sap by boiling, reducing, hardening and grinding it, while others simply use heated sap. The Ju/'hoan hunting kit provides insights for archaeologists, but we must exercise caution when looking for continuity between prehistoric and historical technical systems. Some traditions have been lost to modern hunters, while others are new. We should also expect variability in the Stone Age because of geographically restricted resources. Simple glue, compound adhesive, and poison recipes identified in the Stone Age have no modern equivalents. By about 60,000 years ago at Diepkloof, simple glue was used for hafting tools, but at similarly aged Sibudu there are recipes that combine red ochre powder with plant and/or animal ingredients. At Border Cave, novel poisons and compound adhesives were used in the Early Later Stone Age. It is possible that the complexity that we record in the manufacture of fixative pastes and poison used by Ju/'hoan hunters represents a hafting system both similar to and different from that observed at the Stone Age sites of Diepkloof, Sibudu, and Border Cave. PMID- 26509731 TI - Gnidimacrin, a Potent Anti-HIV Diterpene, Can Eliminate Latent HIV-1 Ex Vivo by Activation of Protein Kinase C beta. AB - HIV-1-latency-reversing agents, such as histone deacetylase inhibitors (HDACIs), were ineffective in reducing latent HIV-1 reservoirs ex vivo using CD4 cells from patients as a model. This deficiency poses a challenge to current pharmacological approaches for HIV-1 eradication. The results of this study indicated that gnidimacrin (GM) was able to markedly reduce the latent HIV-1 DNA level and the frequency of latently infected cells in an ex vivo model using patients peripheral blood mononuclear cells. GM induced approximately 10-fold more HIV-1 production than the HDACI SAHA or romidepsin, which may be responsible for the effectiveness of GM in reducing latent HIV-1 levels. GM achieved these effects at low picomolar concentrations by selective activation of protein kinase C betaI and betaII. Notably, GM was able to reduce the frequency of HIV-1 latently infected cells at concentrations without global T cell activation or stimulating inflammatory cytokine production. GM merits further development as a clinical trial candidate for latent HIV-1 eradication. PMID- 26509732 TI - Toxicological effects of pyrethroids on non-target aquatic insects. AB - The toxicological effects of pyrethroids on non-target aquatic insects are mediated by several modes of entry of pyrethroids into aquatic ecosystems, as well as the toxicological characteristics of particular pyrethroids under field conditions. Toxicokinetics, movement across the integument of aquatic insects, and the toxicodynamics of pyrethroids are discussed, and their physiological, symptomatic and ecological effects evaluated. The relationship between pyrethroid toxicity and insecticide uptake is not fully defined. Based on laboratory and field data, it is likely that the susceptibility of aquatic insects (vector and non-vector) is related to biochemical and physiological constraints associated with life in aquatic ecosystems. Understanding factors that influence aquatic insects susceptibility to pyrethroids is critical for the effective and safe use of these compounds in areas adjacent to aquatic environments. PMID- 26509733 TI - The effect of lipopolysaccharide-induced obesity and its chronic inflammation on influenza virus-related pathology. AB - Obese individuals show increased susceptibility to infection, low vaccine efficacy, and worse pathophysiology. However, it is unclear how obesity affects these events. The aim of this study was to investigate the effect of obesity triggered chronic inflammation on immune cells after influenza virus infection. Control and lipopolysaccharide mice, in which an osmotic pump continually released Tween saline or lipopolysaccharide, were prepared and 3 weeks later were infected with pandemic H1N1 2009 influenza A virus. In lipopolysaccharide mice, we found a reduction in macrophage activation markers in the steady state, and reduced production of pro-inflammatory cytokines including tumor necrosis factor alpha, interleukin-1beta, and interleukin-6, in restimulated peritoneal macrophages. Interestingly, lipopolysaccharide-triggered chronic inflammation exacerbated the severity of pathological symptoms in the lungs after challenge with influenza virus. Taken together, the increased severity of virus-induced symptoms in obese individuals with chronic inflammation may be, at least partially, caused by macrophage dysfunction. PMID- 26509734 TI - Equine disease events resulting from international horse movements: Systematic review and lessons learned. AB - REASONS FOR PERFORMING STUDY: An analysis of the factors leading to equine disease events was used to support the development of international recommendations for mitigating the risk of disease dissemination through sport horse movements (high health, high performance - 'HHP' horses). OBJECTIVES: A review was undertaken to identify the factors resulting in equine disease events following international movement of horses to draw lessons in support of the development of international recommendations for the safe movements of a specific subpopulation of horses: the HHP sport horses. STUDY DESIGN: Systematic review carried out in accordance with the PRISMA statement. METHODS: The review covered disease events that occurred from 1995 to 2014, identified from the databases of the World Organisation for Animal Health (OIE) and international surveillance reports. RESULTS: Overall, 54 disease events were identified, of which 7 were contained in post arrival quarantine and the others resulted in the introduction of pathogens into importing countries. For 81% of the introductions, the OIE recommendations applicable to the diseases involved had not been complied with. Subclinical infections are a challenge for international trade: 88% of the regulated movements that resulted in introductions involved infected horses that showed no clinical signs at the time of import. Biosecurity and management practices in resident equine populations were identified as important mitigating factors in preventing disease spread to the local horse population. CONCLUSIONS: The global increase in international horse movements, if not appropriately regulated and supervised by competent veterinary authorities and respective equine industry partners, could potentially lead to increased global spread of infectious equine diseases. Appropriate mitigation measures and compliance with OIE import recommendations for specific diseases can significantly reduce this risk. The recommendations proposed under the HHP approach take into account the mitigation measures identified by this review as important factors in preventing pathogen introduction and spread. PMID- 26509735 TI - Chronic up-regulation of sonic hedgehog has little effect on postnatal craniofacial morphology of euploid and trisomic mice. AB - BACKGROUND: In Ts65Dn, a mouse model of Down syndrome (DS), brain and craniofacial abnormalities that parallel those in people with DS are linked to an attenuated cellular response to sonic hedgehog (SHH) signaling. If a similarly reduced response to SHH occurs in all trisomic cells, then chronic up-regulation of the pathway might have a positive effect on development in trisomic mice, resulting in amelioration of the craniofacial anomalies. RESULTS: We crossed Ts65Dn with Ptch1(tm1Mps/+) mice and quantified the craniofacial morphology of Ts65Dn;Ptch(+/-) offspring to assess whether a chronic up-regulation of the SHH pathway rescued DS-related anomalies. Ts65Dn;Ptch1(+/-) mice experience a chronic increase in SHH in SHH-receptive cells due to haploinsufficiency of the pathway suppressor, Ptch1. Chronic up-regulation had minimal effect on craniofacial shape and did not correct facial abnormalities in Ts65Dn;Ptch(+/-) mice. We further compared effects of this chronic up-regulation of SHH with acute pathway stimulation in mice treated on the day of birth with a SHH pathway agonist, SAG. We found that SHH affects facial morphology differently based on chronic vs. acute postnatal pathway up-regulation. CONCLUSIONS: Our findings have implications for understanding the function of SHH in craniofacial development and for the potential use of SHH-based agonists to treat DS-related abnormalities. PMID- 26509737 TI - Hybrid functional study of the NASICON-type Na3V2(PO4)3: crystal and electronic structures, and polaron-Na vacancy complex diffusion. AB - The crystal and electronic structures, electrochemical properties and diffusion mechanism of NASICON-type Na3V2(PO4)3 have been investigated based on the hybrid density functional Heyd-Scuseria-Ernzerhof (HSE06). A polaron-Na vacancy complex model for revealing the diffusion mechanism is proposed for the first time in the field of Na-ion batteries. The bound polaron is found to favorably form at the first nearest V site to the Na vacancy. Consequently, the movement of the Na vacancy will be accompanied by the polaron. Three preferable diffusion pathways are revealed; these are two intra-layer diffusion pathways and one inter-layer pathway. The activation barriers for the intra-layer and inter-layer pathways are 353 meV and 513 meV, respectively. For further comparison, the generalized gradient approximation with an onsite Coulomb Hubbard U (GGA+U) is also employed. PMID- 26509736 TI - Effects of Methylation Status of CpG Sites within the HPV16 Long Control Region on HPV16-Positive Head and Neck Cancer Cells. AB - OBJECTIVE: To map comprehensively the methylation status of the CpG sites within the HPV16 long control region (LCR) in HPV-positive cancer cells, and to explore further the effects of methylation status of HPV16 LCR on cell bioactivity and E6 and E7 expression. In addition, to analyze the methylation status of the LCR in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) patients. METHODS AND MATERIALS: Methylation patterns of HPV16 LCR in UM-SCC47, CaSki, and SiHa cells and HPV16-positiive OPSCC specimens were detected by bisulfite-sequencing PCR and TA cloning. For cells treated with 5-aza-2'-deoxycytidine and E6 and E7 knockdown, MTS and trypan blue staining, annexin-V and 7-AAD staining, and prodidium iodide were used to evaluate cell growth and cell proliferation, cell apoptosis, and cell cycle arrest, respectively. E6 and E7 mRNA and protein expression were analyzed by quantitative real-time PCR and immunocytochemistry, respectively. RESULTS: Hypermethylation status of the LCR in UM-SCC47 (79.8%) and CaSki cells (90.0%) and unmethylation status of the LCR in SiHa cells (0%) were observed. Upon demethylation, the cells with different methylation levels responded differently during growth, apoptosis, and cell cycle arrest, as well as in terms of their E6 and E7 expression. In HPV16-positive OPSCC patients, the methylation rates were 9.5% in the entire LCR region, 13.9% in the 5'-LCR, 6.0% in the E6 enhancer, and 9.5% in the p97 promoter, and hypermethylation of p97 promoter was found in a subset of cases (20.0%, 2/10). CONCLUSIONS: Our study revealed two different methylation levels of the LCR in HPV16-positive cancer cells and OPSCC patients, which may represent different carcinogenesis mechanisms of HPV-positive cancers cells. Demethylating the meCpGs in HPV16 LCR might be a potential target for a subgroup of HPV16-positive patients with head and neck squamous cell carcinoma. PMID- 26509738 TI - Vivax malaria in a blood donor in Spain, relapse or a new infection in a malaria non-endemic country? AB - Malaria is a vectorborne disease caused by protozoan of the genus Plasmodium, which can also be transmitted by the transfusion of infected red blood cells. One year after return from a travel to Honduras, a Spanish traveller developed vivax malaria. Prior to the onset of symptoms, the donor made a donation that tested non-reactive using an immunological test for malaria. Samples from the donor taken before donation and tested by serological and molecular methods were negative but positive at the time of hospital admission. The possible sources of the donors' infection, imported versus locally acquired, are discussed. PMID- 26509739 TI - Innervation of the cricothyroid muscle by extralaryngeal branches of the recurrent laryngeal nerve. AB - OBJECTIVES/HYPOTHESIS: A major concern in thyroid surgery is possible changes in the patient's voice due to dysfunction of the laryngeal muscles. The classical understanding of the anatomy is that the cricothyroid muscle (CTM) is innervated solely by the external branch of the superior laryngeal nerve (EBSLN), and the endolaryngeal muscles are covered only by the recurrent laryngeal nerve (RLN). Meticulous anatomical studies found communication between these nerves. Recent neurophysiological studies revealed cross-innervations among these nerve-muscle sets. Here, we report innervation of the CTM by extralaryngeal branches of the RLN. STUDY DESIGN: Clinical observation during thyroid surgery at a hospital center for thyroid diseases. METHODS: During thyroid cancer surgeries, we encountered four adult Japanese patients who had an extralaryngeal branch of the RLN, the electrical stimulation of which showed contraction of the CTM. The EBSLN and RLN were electrically stimulated. Responses were evaluated by visual observation of contraction of the CTM and palpable laryngeal twitch of the endolaryngeal muscles. Electromyographic studies were also performed in two patients. RESULTS: Five of the seven RLNs examined showed contraction of the CTM on stimulation. Four of these five RLNs had an extralaryngeal branch that showed contraction of the CTM on stimulation. Stimulation of the RLN proximal to the branch yielded contraction of the CTM and laryngeal twitch, whereas stimulation of the RLN distal to the branch yielded only laryngeal twitch. CONCLUSIONS: Extralaryngeal branches of the RLN innervated the CTM in four patients. This phenomenon might influence voice changes following thyroid surgery. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1157-1162, 2016. PMID- 26509740 TI - Stereotactic Localization of the Monro Foramen and the Safest Stereotactic Interforniceal Approach to the Third Ventricle: A Neuroanatomical Study. AB - BACKGROUND AND OBJECTIVE: To localize the human foramen of Monro stereotactically, to define the anatomical parameters of the safest stereotactic transcallosal transseptal interforniceal approach to the third ventricle, and to show how neurosurgeons could use them in preoperative planning. MATERIAL AND METHODS: Our material consisted of 44 formalin-fixated human cerebral hemispheres. We found the location of the anterior (AC) and posterior commissure at the internal hemispheric surface. The posterosuperior border of the AC (point A) was our stereotactic reference point with coordinates (X, Y, Z) = (0, 0, 0). We found the Monro foramen location and measured the stereotactic coordinates of its anterior inferior border (point B). The safest trajectory to the third ventricle has to pass as far as possible from points A and B so as not to traumatize the choroid plexus of the Monro foramina or the AC. The midpoint of the AB distance (point M) is the stereotactic point that provides this safest trajectory. We also measured AB length and point M stereotactic coordinates. RESULTS: Mean stereotactic coordinates of the (midline projection of the) point B were (X, Y, Z) = (0, -0.6, 2.4). Point B was located averagely 3.2 mm far from point A. Mean stereotactic coordinates of the point M, a necessary component of the trajectory of the safest stereotactic interforniceal approach to the third ventricle, were (X, Y, Z) = (0, -0.3, 1.2). Point M was located 1.6 mm far from point A. CONCLUSIONS: The present study shows how neurosurgeons can localize and use crucial anatomical landmarks, namely the AC and foramen of Monro, to approach the third ventricle safely via a stereotactic interforniceal technique. This can be achieved during preoperative planning with simple identification of stereotactic points A, B, and M on preoperative median sagittal magnetic resonance images. PMID- 26509741 TI - Structure-Directing Behaviors of Tetraethylammonium Cations toward Zeolite Beta Revealed by the Evolution of Aluminosilicate Species Formed during the Crystallization Process. AB - Organic structure-directing agents (OSDAs) have been widely used for the synthesis of zeolites. In most cases, OSDAs are occluded in zeolites as an isolated cation or molecule geometrically fitted within the zeolite cavities. This is not the case for zeolite beta synthesized by using tetraethylammonium (TEA(+)) cation as an OSDA, in which a cluster/aggregate of ca. six TEA(+) cations is occluded intact in the cavity (i.e., the channel intersection) of zeolite beta. The structure direction of TEA(+) in such a nontypical, clustered mode has remained elusive. Here, zeolite beta was hydrothermally synthesized using TEA(+) in the absence of other alkali metal cations in order to focus on the structure-directing behaviors of TEA(+) alone. The solid products formed throughout the hydrothermal synthesis were analyzed by an array of characterization techniques including argon adsorption-desorption, high-energy X ray total scattering, Raman and solid-state NMR spectroscopy, and high-resolution transmission electron microscopy. It was revealed that the formation of amorphous TEA(+)-aluminosilicate composites and their structural, chemical, and textural evolution toward the amorphous zeolite beta-like structure during the induction period is vital for the formation of zeolite beta. A comprehensive scheme of the formation of zeolite beta is proposed paying attention to the clustered behavior of TEA(+) as follows: (i) the formation of the TEA(+)-aluminosilicate composites after heating, (ii) the reorganization of aluminosilicates together with the conformational rearrangement of TEA(+), yielding the formation of the amorphous TEA(+)-aluminosilicate composites with the zeolite beta-like structure, (iii) the formation of zeolite beta nuclei by solid-state reorganization of such zeolite beta-like, TEA(+)-aluminosilicate composites, and (iv) the subsequent crystal growth. It is anticipated that these findings can provide a basis for broadening the utilization of OSDAs in the clustered mode of structure direction in more effective ways. PMID- 26509742 TI - The Dimensionality of Language Ability in Young Children. AB - The purpose of this study was to empirically examine the dimensionality of language ability for young children (4-8 years) from prekindergarten to third grade (n = 915), theorizing that measures of vocabulary and grammar ability will represent a unitary trait across these ages, and to determine whether discourse skills represent an additional source of variance in language ability. Results demonstrated emergent dimensionality of language across development with distinct factors of vocabulary, grammar, and discourse skills by third grade, confirming that discourse skills are an important source of variance in children's language ability and represent an important additional dimension to be accounted for in studying growth in language skills over the course of childhood. PMID- 26509743 TI - Minimizing metastatic risk in radiotherapy fractionation schedules. AB - Metastasis is the process by which cells from a primary tumor disperse and form new tumors at distant anatomical locations. The treatment and prevention of metastatic cancer remains an extremely challenging problem. This work introduces a novel biologically motivated objective function to the radiation optimization community that takes into account metastatic risk instead of the status of the primary tumor. In this work, we consider the problem of developing fractionated irradiation schedules that minimize production of metastatic cancer cells while keeping normal tissue damage below an acceptable level. A dynamic programming framework is utilized to determine the optimal fractionation scheme. We evaluated our approach on a breast cancer case using the heart and the lung as organs-at risk (OAR). For small tumor [Formula: see text] values, hypo-fractionated schedules were optimal, which is consistent with standard models. However, for relatively larger [Formula: see text] values, we found the type of schedule depended on various parameters such as the time when metastatic risk was evaluated, the [Formula: see text] values of the OARs, and the normal tissue sparing factors. Interestingly, in contrast to standard models, hypo-fractionated and semi-hypo-fractionated schedules (large initial doses with doses tapering off with time) were suggested even with large tumor alpha/beta values. Numerical results indicate the potential for significant reduction in metastatic risk. PMID- 26509744 TI - Visible-Light-Induced Direct Photocatalytic Carboxylation of Indoles with CBr4 /MeOH. AB - Photocatalysis enables the cascade reactions of indoles and CBr4 in MeOH through a C(sp(2) )?H functionalization/methanolysis sequence. The title reaction provides an efficient access to indole 2- and 3-carboxylates in a single operation (no preinstallation of protecting as well as directing groups was required) with good yields under mild reaction conditions. PMID- 26509746 TI - MR fingerprinting with simultaneous B1 estimation. AB - PURPOSE: MR fingerprinting (MRF) can be used for quantitative estimation of physical parameters in MRI. Here, we extend the method to incorporate B1 estimation. METHODS: The acquisition is based on steady state free precession MR fingerprinting with a Cartesian trajectory. To increase the sensitivity to the B1 profile, abrupt changes in flip angle were introduced in the sequence. Slice profile and B1 effects were included in the dictionary and the results from two- and three-dimensional (3D) acquisitions were compared. Acceleration was demonstrated using retrospective undersampling in the phase encode directions of 3D data exploiting redundancy between MRF frames at the edges of k-space. RESULTS: Without B1 estimation, T2 and B1 were inaccurate by more than 20%. Abrupt changes in flip angle improved B1 maps. T1 and T2 values obtained with the new MRF methods agree with classical spin echo measurements and are independent of the B1 field profile. When using view sharing reconstruction, results remained accurate (error <10%) when sampling under 10% of k-space from the 3D data. CONCLUSION: The methods demonstrated here can successfully measure T1, T2, and B1. Errors due to slice profile can be substantially reduced by including its effect in the dictionary or acquiring data in 3D. Magn Reson Med 76:1127-1135, 2016. (c) 2015 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non commercial and no modifications or adaptations are made. PMID- 26509747 TI - Revealing G-protein-coupled receptor oligomerization at the single-molecule level through a nanoscopic lens: methods, dynamics and biological function. AB - The introduction of super-resolution fluorescence microscopy has allowed the visualization of single proteins in their biological environment. Recently, these techniques have been applied to determine the organization of class A G-protein coupled receptors (GPCRs), and to determine whether they exist as monomers, dimers and/or higher-order oligomers. On this subject, this review highlights recent evidence from photoactivated localization microscopy (PALM), which allows the visualization of single molecules in dense samples, and single-molecule tracking (SMT), which determines how GPCRs move and interact in living cells in the presence of different ligands. PALM has demonstrated that GPCR oligomerization depends on the receptor subtype, the cell type, the actin cytoskeleton, and other proteins. Conversely, SMT has revealed the transient dynamics of dimer formation, whereby receptors show a monomer-dimer equilibrium characterized by rapid association and dissociation. At steady state, depending on the subtype, approximately 30-50% of receptors are part of dimeric complexes. Notably, the existence of many GPCR dimers/oligomers is also supported by well known techniques, such as resonance energy transfer methodologies, and by approaches that exploit fluorescence fluctuations, such as fluorescence correlation spectroscopy (FCS). Future research using single-molecule methods will deepen our knowledge related to the function and druggability of homo oligomers and hetero-oligomers. PMID- 26509748 TI - History and medicine--The case of silicosis. PMID- 26509749 TI - Truncating a disease. The reduction of silica hazards to silicosis at the 1930 international labor office conference on silicosis in Johannesburg. AB - The current nosology and etiology of silicosis were officially adopted by the 1930 International Labor Office (ILO) Conference on silicosis in Johannesburg. Convened by the International Labor Office and by the Transvaal Chamber of Mines, it paved the way to the adoption of a 1934 ILO convention which recognized silicosis as an occupational disease. Even though it constituted a social and sanitary turning point, the Johannesburg conference, strongly influenced by South African physicians working for the gold mining industry, reduced silica hazards to silicosis, an equation which is questioned nowadays. While the definition of silicosis adopted in 1930 was a major step in the recognition of occupational pneumoconioses, it also led to the under-identification of some pathogenic effects of silica. Going back to history opens new avenues for contemporary medical research. PMID- 26509750 TI - Conspicuous disease: The surveillance of silicosis in South Africa, 1910-1970. AB - Scholarly understanding of the nature of the science around silicosis has been strongly influenced, in recent years, by the idea that the mine doctors were responsible for hiding an epidemic, on the mines and in the countryside. In this paper, I try to show that the opposite was in fact the case, and that the science and government institutions for the regulation of silicosis and tuberculosis in white and black male workers were distinctively elaborated, and very largely successful in tracking and controlling the disease. This singular visibility, funded by the mines, stands in marked contrast with disease in general in South Africa, and forms a major part of the explanation for the very strong association of silicosis with mine work. PMID- 26509751 TI - Miners, silica and disability: The bi-national interplay between South Africa and the United Kingdom, c1900-1930s. AB - This paper investigates silicosis as a disabling disease in underground mining in the United Kingdom (UK) before Second World War, exploring the important connections between South Africa and the UK and examining some of the issues raised at the 1930 International Labour Office Conference on silicosis in Johannesburg in a British context. The evidence suggests there were significant paradoxes and much contestation in medical knowledge creation, advocacy, and policy-making relating to this occupational disease. It is argued here that whilst there was an international exchange of scientific knowledge on silicosis in the early decades of the twentieth century, it was insufficient to challenge the traditional defense adopted by the British government of proven beyond all scientific doubt before effective intervention in coal mining. This circumspect approach reflected dominant business interests and despite relatively robust trade union campaigning and eventual reform, the outcome was an accumulative legacy of respiratory disease and disability that blighted coalfield communities. PMID- 26509752 TI - From the definition of silicosis at the 1930 Johannesburg conference to the blurred boundaries between pneumoconioses, sarcoidosis, and pulmonary alveolar proteinosis (PAP). AB - The 1930 International Labour Office Conference on silicosis in Johannesburg identified silicosis by setting a medicolegal framework to its nosology: as with other occupational illnesses, its medical content was fixed under economic pressure. This article follows a reading of all the proceedings of this conference (debates and reports of experts) to examine their potential impact on the etiology and nosology of other diseases, specifically sarcoidosis and pulmonary alveolar proteinosis (PAP), "idiopathic" diseases in which inorganic particles may be involved. We propose renewed study of the role of inorganic particles in these diseases. To do this, we propose to mobilize detection means such as mineralogical analysis and electron microscopy and in depth interviewing that are currently seldom used in France, in order to establish diagnosis and the potential occupational and environmental origin of these diseases. PMID- 26509753 TI - The pathologist's view of silicosis in 1930 and in 2015. The Johannesburg Conference legacy. AB - The 1930 International Labour Office Conference on silicosis in Johannesburg was a turning point in the history of silicosis and in the recognition of the associated pathologic patterns. Since 1930, pneumoconioses such as silicosis have become much rarer in developed countries and can now be diagnosed at an early stage based on clinical and radiologic criteria. However, in spite of these advances, pathologists must remember to look for silica in tissues, particularly when clinical and radiologic findings are more uncertain. Furthermore, nowadays pathologists essentially observe silicotic lesions as incidental findings adjacent to lung cancers. In addition to identifying the characteristic lesions, pathologists must also try to identify their causative agent, in the case of crystalline silica firstly by using polarized light examination, followed as appropriate by more sophisticated devices. Finally, pathologists and clinicians must always keep in mind the various implications of exposure to silica compounds in a wide range of diseases. PMID- 26509754 TI - From the 1930 International Johannesburg conference on silicosis, to "tables" of occupational diseases, France, 2000 onward: A comparative reading. AB - Through the concept of "thought collectives" in particular, Ludwik Fleck was a pioneer in demonstrating how much scientific knowledge is inherently made up of social and historical material. In this article, I propose to follow a Fleckian path by comparing the proceedings of the 1930 International Labour Office Conference on silicosis in Johannesburg on the one hand, and on the other the content of the debates that took place in France in the 2000s to revise the "tables" of occupational diseases which define the compensation rules for salaried workers in the French general (as well as the farm) health insurance scheme. The text offers an analysis of the striking similarities between these two distant sources, pointing out particularly the repetitiveness of ignorance and knowledge, and the nature of what can be admitted as a body of "evidence" in medico-legal issues such as the definition and compensation of occupational diseases. PMID- 26509755 TI - Historical and emerging workplaces affected by silica exposure since the 1930 Johannesburg conference on Silicosis, with special reference to construction. AB - INTRODUCTION: At the time of the 1930 International Labour Office Conference on silicosis in Johannesburg, mining was the main sector affected by silicosis; however, other industries would later emerge as areas of concern. METHODS: A search of the occupational hygiene and epidemiological literature was conducted to retrieve historical and current documents pertaining to silica exposure and associated hazards. RESULTS: The potential risk of silicosis in construction became evident starting in the 1960s, and the body of literature including case reports, sampling surveys, and medical surveillance continues to grow to this day. Among non-construction activities, hydraulic fracturing and engineered countertop manufacturing have recently appeared as industries with a potential for overexposure, while mining remains the industrial sector with the highest prevalence of exposure. CONCLUSIONS: The risk of developing this "ancient disease" remains a current issue in many workplaces, and requires ongoing surveillance and prevention efforts. PMID- 26509756 TI - Aberrant Motility in Unaffected Small Bowel is Linked to Inflammatory Burden and Patient Symptoms in Crohn's Disease. AB - BACKGROUND: Inflammation-related enteric dysmotility has been postulated as a cause for abdominal symptoms in Crohn's disease (CD). We investigated the relationship between magnetic resonance imaging-quantified small bowel (SB) motility, inflammatory activity, and patient symptom burden. METHODS: The Harvey Bradshaw index (HBI) and fecal calprotectin were prospectively measured in 53 patients with CD (median age, 35; range, 18-78 years) the day before magnetic resonance enterography, which included a dynamic (cine), breath-hold motility sequence, repeated to encompass the whole SB volume. A validated registration based motility quantitation technique produced motility maps, and regions of interest were drawn to include all morphologically normal SB (i.e., excluding diseased bowel). Global SB motility was correlated with calprotectin, HBI, and symptom components (well-being, pain, and diarrhea). Adjustment for age, sex, smoking, and surgical history was made using multivariate linear regression. RESULTS: Median calprotectin was 336 (range, 0-1280). Median HBI, motility mean, and motility variance were 3 (range, 0-16), 0.33 (0.18-0.51), and 0.01 (0.0014 0.034), respectively. Motility variance was significantly negatively correlated with calprotectin (rho = -0.33, P = 0.015), total HBI (rho = -0.45, P < 0.001), well-being (rho = -0.4, P = 0.003), pain (rho = -0.27, P = 0.05), and diarrhea (rho = -0.4, P = 0.0025). The associations remained highly significant after adjusting for covariates. There was no association between mean motility and calprotectin or HBI (P > 0.05). CONCLUSIONS: Reduced motility variance in morphologically normal SB is associated with patient symptoms and fecal calprotectin levels, supporting the hypothesis that inflammation-related enteric dysmotility may explain refractory abdominal symptoms in CD. PMID- 26509757 TI - Regio- and Stereospecific 1,3-Allyl Group Transfer Triggered by a Copper Catalyzed Borylation/ortho-Cyanation Cascade. AB - A copper-catalyzed borylation/ortho-cyanation/allyl group transfer cascade was developed. Initiated by an unconventional copper-catalyzed electrophilic dearomatization, this process features regio- and stereospecific 1,3 transposition of the allyl fragment enabled by an aromatization-driven Cope rearrangement. This method provides an effective means for the construction of adjacent tertiary and quaternary stereocenters with excellent diastereocontrol. PMID- 26509758 TI - Split-hand phenomenon in amyotrophic lateral sclerosis: A motor unit number index study. AB - INTRODUCTION: The split-hand phenomenon refers to preferential wasting of the thenar muscles with relative sparing of the hypothenar muscles in amyotrophic lateral sclerosis (ALS). METHODS: We compared the split-hand index (SI) calculated from the compound muscle action potential (CMAP; SICMAP ) with that calculated from the motor unit number index (MUNIX; SIMUNIX ). We performed MUNIX on the abductor policis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) muscles of 39 ALS patients and 40 age-matched, healthy controls. SI is derived by multiplying the CMAP (or MUNIX) recorded over the APB and FDI and dividing by the CMAP (or MUNIX) recorded over the ADM. RESULTS: Receiver-operating characteristic curve analysis revealed good diagnostic accuracy for both indices, but better performance of SIMUNIX than SICMAP . CONCLUSION: SIMUNIX and SICMAP were useful in differentiating ALS patients from healthy controls. SIMUNIX appears to be a better electrophysiological marker than SICMAP for the split-hand sign of ALS. Muscle Nerve 53: 885-888, 2016. PMID- 26509759 TI - Femtosecond Laser-Assisted Lamellar Keratectomy for Corneal Opacities Secondary to Anterior Corneal Dystrophies: An Interventional Case Series. AB - PURPOSE: To report results of femtosecond laser-assisted lamellar keratectomy (FLK) for corneal opacities secondary to anterior corneal dystrophies. METHODS: Patients with a clinical diagnosis of Reis-Bucklers corneal dystrophy, granular corneal dystrophy, lattice corneal dystrophy, and macular corneal dystrophy were treated. FLK was performed to remove a central corneal free cap of 9.5 mm in diameter at a depth of 110 to 140 MUm on which histological analysis was undertaken. Preoperative and postoperative refraction, best spectacle-corrected visual acuity, corneal topography results, and color photographs were recorded. Postoperative in vivo confocal microscopy of the cornea was performed. Changes in uncorrected visual acuity and best spectacle-corrected visual acuity, keratometry, refractive error, corneal irregularity, residual or recurrent central corneal opacities, and corneal haze were used to assess the outcome. RESULTS: Eight eyes of 6 patients were treated. The clinical diagnosis was confirmed histologically in all cases. Visual acuity improved significantly from 0.49 +/- 0.2 logMAR to 0.14 +/- 0.13 logMAR after a mean follow-up of 29 +/- 14 (range 8-54) months. Residual central stromal opacities were noted in 5 of 8 eyes immediately postoperatively. Clinically significant recurrence of disease was noted in 1 eye. Keratometry and refraction remained stable, and no further surgical intervention was needed. Patients with stromal corneal dystrophies had worse outcome than those with Reis-Bucklers corneal dystrophy. CONCLUSIONS: In this case series, FLK provided both therapeutic and diagnostic intervention, delaying more invasive surgery. In vivo confocal microscopy showed signs of postoperative corneal stromal neuropathy. PMID- 26509760 TI - Novel Technique for Descemet Membrane Remnant Stripping in Hazy Cornea During DSAEK. AB - PURPOSE: To describe a novel technique for removal of Descemet membrane (DM) tags or remnants in hazy corneas during Descemet stripping automated endothelial keratoplasty. METHODS: The DM tags or remnants may be difficult to visualize in the presence of hazy corneas. To identify and remove the residual DM remnants and tags, a crescent knife is introduced into the anterior chamber through the 3.2 mm temporal corneoscleral tunnel and is placed intracamerally, parallel to the iris plane underneath scored DM (which had been previously stained with the trypan blue solution). Under direct illumination from the operating microscope, the crescent blade acts as a light reflector so that the blue DM remnants and tags are highlighted against the silver background of the crescent knife. These tags or remnants may then be identified and then peeled off using intravitreal forceps. The donor lenticule is inserted and air tamponade is used for apposition of the donor lenticule to the recipient host. RESULTS: This technique was used successfully in 10 eyes. No DM tags were present in any of the eyes postoperatively and all the grafts were well apposed. CONCLUSIONS: The crescent blade as a reflector is a simple and useful tool to identify trypan blue stained DM remnants or tags in the presence of hazy corneas during endothelial keratoplasty. PMID- 26509761 TI - Irregular Astigmatism After Corneal Transplantation--Efficacy and Safety of Topography-Guided Treatment. AB - PURPOSE: To analyze the efficacy and safety of topography-guided photorefractive keratectomy (TG-PRK) to treat irregular astigmatism after corneal transplantation. METHODS: This was a retrospective observational case series. Eyes with irregular astigmatism after penetrating keratoplasty treated with TG PRK (Allegretto Wave Eye-Q) with the topography-guided customized ablation treatment protocol were included. All treatments had been planned to correct the topographic irregularities, as well as to reduce the refractive error after neutralizing the induced refractive change. Clinical records, treatment plan, and the examinations performed were reviewed and the following data were collected: corrected and uncorrected distance visual acuities; manifest refraction; topographic parameters, and corneal endothelial cell count. RESULTS: We included 31 eyes [30 patients; mean age 45.0 +/- 13.4 (SD) years]. At the last postoperative follow-up (mean 9.2 +/- 8.2 months), we observed a significant improvement in corrected (P = 0.001) and uncorrected distance visual acuities (P < 0.001). There was a gain of >=1 uncorrected distance visual acuity line in 96.8% (n = 30) of the eyes. Similarly, the refractive parameters also improved (cylinder P < 0.001; spherical equivalent P = 0.002). At the last visit, 54.8% (n = 17) of the patients presented a spherical equivalent of +/-1 D. The 3-mm topographic irregularity also decreased significantly (P < 0.001). There was no significant variation of the corneal endothelial cell count. CONCLUSIONS: This is the largest case series of TG-PRK to treat irregular astigmatism in postcorneal transplantation eyes. Our results confirm that TG-PRK is an efficient treatment, associated with significant improvements of both visual acuity and refractive parameters. PMID- 26509762 TI - Glued Intrascleral Fixation of Intraocular Lens With Pupilloplasty and Pre Descemet Endothelial Keratoplasty: A Triple Procedure. AB - PURPOSE: To describe a surgical approach of glue-assisted intrascleral fixation of an intraocular lens (IOL) with pupilloplasty and pre-Descemet endothelial keratoplasty as a single-stage procedure. METHODS: Glue-assisted intrascleral fixation of an IOL is performed initially because it helps to secure the IOL fixation, followed by pupilloplasty that imparts stability to the anterior chamber and prevents air diversion into the vitreous cavity, thereby facilitating the pre-Descemet endothelial keratoplasty procedure that is performed to complete the surgical repair. RESULTS: The procedure was performed in 5 eyes of 5 patients, and the donor age ranged from 9 months to 65 years. There was a significant change in the uncorrected (P = 0.034) and corrected (P = 0.043) distance visual acuities in the postoperative period. The mean graft size was 7.6 +/- 0.4 mm (range, 7-8 mm). The mean preoperative and postoperative specular endothelial counts were 2788 +/- 204 cells per square millimeter and 1898 +/- 90 cells per square millimeter, respectively. No incidence of primary graft failure or graft rejection during the entire follow-up period was reported in any of the eyes. CONCLUSIONS: The combined procedure serves as an effective method in select cases of endothelial decompensation that require a secondary IOL implantation or an IOL exchange with good postoperative results. PMID- 26509763 TI - Gatifloxacin 0.3% Versus Fortified Tobramycin-Cefazolin in Treating Nonperforated Bacterial Corneal Ulcers: Randomized, Controlled Trial. AB - PURPOSE: To compare the equivalence of gatifloxacin 0.3% with a combination of fortified cefazolin sodium 5% and tobramycin sulfate 1.3% eye drops in the treatment of nonperforated bacterial corneal ulcers. METHODS: In randomized, controlled, equivalence clinical trials, microbiologically proven cases of nonperforated bacterial corneal ulcers were enrolled and were allocated randomly to one of the 2 treatment groups. Group A was given combination therapy (fortified cefazolin sodium 5% and tobramycin sulfate 1.3%) and group B was given monotherapy (gatifloxacin 0.3%). The primary outcome measure was the percentage of corneal ulcers that healed at 3 months of follow-up. RESULTS: Out of 204 patients enrolled, 103 patients were randomized to group A, whereas 101 patients were randomized to group B. The mean +/- SD of ulcer size in groups A and B were 4.35 +/- 1.36 and 4.18 +/- 1.31 mm, respectively (P = 0.376). The most common bacterial isolate was coagulase-negative Staphylococcus (51.5% in group A and 45.5% in group B). Worsening of the ulcer was seen in 27.2% (28/103) of the cases in group A and in 21.8% (22/101) of the cases in group B. The percentage healing difference was calculated to be 5.4% (90% confidence interval, -4.5 to 15.3). No serious events attributable to therapy were reported in any group. CONCLUSIONS: Using the prespecified definition of equivalence of +/-20%, this trial found evidence that gatifloxacin monotherapy was equivalent to combination therapy with cefazolin and tobramycin for the treatment of nonperforated bacterial corneal ulcers. PMID- 26509764 TI - Assessment of a Novel Corneal-Shaping Device With Simultaneous Corneal Collagen Cross-Linking Using a Porcine Eye Model. AB - PURPOSE: Corneal collagen cross-linking (CXL) alone cannot substantially improve refractive errors. We designed a novel corneal-shaping device, showing that a prototype applied during CXL can alter corneal curvature to a greater extent than CXL alone in a porcine eye model. METHODS: The device prototype was made with flat, UV-transmissible material. Enucleated porcine eyes were deepithelialized and perfused. Preexperimental and postexperimental corneal curvature (K) measurements and Anterior Segment Optical Coherence Tomography imaging were performed. A conventional CXL protocol was followed. Six experiments of 6 treatment groups in duplicate were performed (n = 12/group): (A) no CXL + no device, (B) no CXL + 30 minutes device, (C) 10 minutes, CXL + no device, (D) 10 minutes, CXL + device, (E) 30 minutes, CXL + no device, and (F) 30 minutes, CXL + device. RESULTS: There was a significant decrease (P < 0.001) in corneal curvature after 30 minutes. CXL between group F (-1.54 +/- 0.90 D) and groups E (+0.34 +/- 0.53 D), B (+0.69 +/- 1.02 D), or A (+0.22 +/- 1.24 D). The demarcation line depth was greater in group F (34% +/- 4%) than group D (30% +/- 4%, P < 0.05). Groups D (-2.3% +/- 21%) and F (0.24% +/- 15%) had less change in corneal thickness than in control groups A (15% +/- 12%, P < 0.05) and E (12% +/- 11%, P < 0.05). CONCLUSIONS: Application of our corneal-shaping device during CXL significantly decreased corneal curvature compared with controls. Anterior Segment Optical Coherence Tomography imaging showed comparable extent of cross linking in eyes treated +/- device. This demonstrates that our novel device used during CXL may further promote corneal strengthening and refractive correction in patients. PMID- 26509765 TI - Comparison of a Supraglottic Gel Device and an Endotracheal Tube in Keratoplasty Performed Under General Anesthesia: A Randomized Clinical Trial. AB - PURPOSE: To assess the safety of a laryngeal mask (i-gel) in keratoplasty performed under general anesthesia. METHODS: Patients with indications for keratoplasty (n = 110) were enrolled in a prospective study and randomly assigned to the i-gel (n = 55; 30 lamellar keratoplasty and 25 penetrating keratoplasty) or tracheal tube group (n = 55; 29 lamellar keratoplasty and 26 penetrating keratoplasty). Perioperative complications and the recovery time were compared between the 2 groups using the t test or chi(2) test. Contraindications to elective use of the laryngeal mask airway (esophageal reflux, extreme obesity, oropharyngeal pathology, or expected difficult intubation) and expected difficult intubation were excluded. RESULTS: No surgical perioperative complications were reported in either group. There was a significantly greater incidence of coughing at extubation and/or after extubation in the tracheal group (40/55; 73%) than in the laryngeal mask group (3/55; 5%) (P < 0.001). The recovery time was shorter in the i-gel group (80 minutes; 95% confidence interval, 75-86) compared with that in the tracheal tube group (88 minutes; 95% confidence interval, 82-95) (P = 0.03). There were no significant differences in the incidence of sore throat and hoarseness between both devices. CONCLUSIONS: The use of i-gel for keratoplasty under general anesthesia appears to be safe, reduces the risk of potential ocular hypertension during recovery, and saves recovery time. PMID- 26509766 TI - Real-Time Microscope-Integrated OCT to Improve Visualization in DSAEK for Advanced Bullous Keratopathy. AB - PURPOSE: To report the intraoperative use of microscope-integrated optical coherence tomography (MIOCT) to enable visualization for Descemet's stripping automated endothelial keratoplasty (DSAEK) in 2 patients with advanced bullous keratopathy. METHODS: Patient 1 was an 83-year-old female and patient 2 was a 28 year-old male both with limited vision and significant pain from bullous keratopathy who underwent palliative DSAEK. Because of the severity and chronicity of the corneal decompensation in both patients, the view past the anterior cornea was negligible using standard microscope illumination techniques. We used spectral-domain (Patient 1) and swept-source (Patient 2) MIOCT, both of which rely on infrared illumination, to visualize key parts of the DSAEK procedure. RESULTS: Graft insertion, unfolding, tamponade, and attachment could be dynamically visualized intraoperatively despite the nearly opaque nature of the host corneas. Postoperatively, the grafts remained attached with significant corneal clearing, and there was improvement in visual acuity, and pain relief for both patients. CONCLUSIONS: MIOCT is a valuable tool for the corneal surgeon, allowing for DSAEK to be successfully performed even when the surgical microscope view is limited from severe corneal edema, as is often the case in patients with advanced bullous keratopathy. By using MIOCT, these patients can benefit from the advantages of DSAEK despite a clinically opaque cornea, which would otherwise be treated with a penetrating keratoplasty. PMID- 26509767 TI - Association Between Keratoconus and Familial Mediterranean Fever in Turkey. AB - PURPOSE: To evaluate the association between familial Mediterranean fever (FMF) and keratoconus (KC). METHODS: This retrospective case-control study was performed to compare the prevalence of KC in patients with FMF with the corresponding prevalence in control patients without FMF referred to Genetic Diagnostic Center at Diskapi Yildirim Beyazit Training and Research Hospital from June 2012 to June 2015. We included all 100 patients with FMF. Each FMF-affected patient was matched to 3 controls. RESULTS: None of the patients in the control group (0%, 0/300) had KC, whereas 4 of 100 patients with FMF (4%) had KC (P < 0.004). Three of 33 patients with a homozygous mutation (9.1%) (M694V/M694V in 2 cases and M680I/M680I in 1 case) and 1 of the 46 patients with a compound heterozygous mutation (2.2%) (M694V/M680I) had KC, whereas none of the 21 patients with a heterozygous mutation (0%) had KC. All patients with KC were women, and mean age was 40.8 years (range, 30-51). Although 1 of the 4 patients with KC had hypertension and type 2 diabetes mellitus, the other 3 patients did not have any systemic illness except FMF. When we compared the prevalence of KC in patients with FMF (4%) with the highest prevalence of KC reported in the literature (0.2%), FMF was a predisposing factor to develop KC [odds ratio: 18.1 (95% CI: 11.9-27.5)] especially in patients with a homozygous mutation [odds ratio: 43.4 (95% CI: 28.6-65.7)]. CONCLUSIONS: Mediterranean fever (MEFV) gene mutations, particularly in homozygous mutations of the MEFV gene, may be a predisposing factor in the development of KC. PMID- 26509768 TI - Corneal Collagen Cross-Linking for Infectious Keratitis: A Systematic Review and Meta-Analysis. AB - PURPOSE: To assess the efficacy of corneal collagen cross-linking (CXL) in the management of infectious keratitis. METHODS: Comprehensive literature search was performed in MEDLINE/PubMed and Cochrane Central Register of Controlled Trials using combinations of the following search terms: "corneal collagen cross linking" or "photoactivated riboflavin" or "UVA light and riboflavin" and "infectious keratitis" or "corneal ulcer." Last search was on March 19, 2015. Extracted data from individual studies were summarized and summary proportions of eyes healed and complications for different subgroups were estimated. RESULTS: Twenty-five studies were included (2 randomized controlled trials, 13 case series, and 10 case reports) with a total of 210 eyes of 209 patients, of which 175 eyes underwent CXL. Causative microorganisms were bacteria, fungi, acanthamoeba, and Herpes simplex virus in 96, 32, 11, and 2 cases, respectively. Coinfections were present in 13 and cause was inconclusive in 21 cases. Sixteen of 175 eyes received no additional antibiotics, whereas 159 underwent CXL as an adjunct to antimicrobial treatment. Proportion of eyes healed with CXL was 87.2% (95% confidence interval (CI), 81.9%, 91.8%). For bacterial keratitis, the proportion of eyes healed was 85.7% (95% CI, 78.5%, 91.7%), whereas 10/11 and 25/32 eyes with acanthamoeba and fungal keratitis, respectively, were healed (available data not sufficient to provide a valid proportion analysis). Treatment resulted in corneal melting and tectonic keratoplasty in both Herpes simplex virus cases. CONCLUSIONS: CXL seems promising in the management of infectious keratitis, excluding viral infections. However, more randomized controlled trials are required to assess its efficacy. PMID- 26509769 TI - Efficacy and Safety of Carbomer-Based Lipid-Containing Artificial Tear Formulations in Patients With Dry Eye Syndrome. AB - PURPOSE: To evaluate the efficacy and safety profile of carbomer-based lipid containing artificial tear formulations (CBLAT) in patients with dry eye syndrome. METHODS: A multicenter parallel-group study was conducted in 412 patients with dry eye syndrome. Of these patients, 221 switched from using artificial tears to CBLAT (switching group) and 191 added CBLAT to their current treatment (add-on group). Ocular symptom scores, ocular staining grades, tear film breakup time (tBUT), Schirmer I test value, and Korean dry eye level (as defined by the Korean Corneal Disease Study Group guidelines) were evaluated at baseline and after 4 weeks of treatment. RESULTS: After 4 weeks of treatment, ocular surface staining grade, tBUT, Schirmer I value, ocular irritation symptom scores, and the positive rate of visual symptom improved significantly in both groups. Mean reductions in ocular surface staining grades (-0.8 +/- 0.9) and ocular irritation symptom scores (-0.8 +/- 0.8) in the add-on group were significantly higher than those (-0.5 +/- 0.8 and -0.6 +/- 0.8) in the switching group (P < 0.01 and P < 0.05). The positive rate of visual symptoms (44.2%) in the add-on group was significantly higher than that (26.4%) in the switching group (P < 0.01). The decrease of Korean dry eye level was 30.1% in the switching group and 51.6% in the add-on group. More patients in the add-on group had decreased dry eye levels than those in the switching group (P < 0.0001). CONCLUSIONS: CBLAT improves ocular surface staining grades, tBUT, Schirmer I values, and ocular symptoms in patients with dry eye syndrome. PMID- 26509770 TI - Comparison of Descemet-On Versus Descemet-Off Deep Anterior Lamellar Keratoplasty in Keratoconus Patients: A Randomized Trial. PMID- 26509771 TI - Atypical Fibroxanthoma of the Bulbar Conjunctiva. AB - PURPOSE: To report a rare case of atypical fibroxanthoma (AFX) of the bulbar conjunctiva, and to compare it with previously published cases of conjunctival AFX. METHODS: A 37-year-old woman developed a growth on the bulbar conjunctiva of her left eye that increased in size and redness over 4 months and was associated with blurry vision in the left eye, occasional diplopia, irritation of the eye, and increasing tearing. The mass was surgically excised. RESULTS: Slit-lamp examination disclosed a highly vascularized conjunctival lesion with intact lustrous epithelium and a raised nodular edge encroaching on the nasal corneal limbus of the left eye. Pathological examination and immunohistochemistry were diagnostic of AFX. CONCLUSIONS: AFX of the conjunctiva is rare, with this being only the fifth example of this neoplasm reported at this site. Complete surgical excision is the most appropriate treatment option. PMID- 26509772 TI - Bruising and Hemorrhagic Vesicles on the Tongue. PMID- 26509775 TI - Brain Activation for Knee Movement Measured Days Before Second Anterior Cruciate Ligament Injury: Neuroimaging in Musculoskeletal Medicine. AB - BACKGROUND: Anterior cruciate ligament (ACL) injury has multifactorial causes encompassing mechanical, hormonal, exposure, and anatomical factors. Alterations in the central nervous system also play a role, but their influence after injury, recovery, and recurrent injury remain unknown. Modern neuroimaging techniques can be used to elucidate the underlying functional and structural alterations of the brain that predicate the neuromuscular control adaptations associated with ACL injury. This knowledge will further our understanding of the neural adaptations after ACL injury and rehabilitation and in relation to injury risk. In this paper, we describe the measurement of brain activation during knee extension flexion after ACL injury and reconstruction and 26 days before a contralateral ACL injury. METHODS: Brain functional magnetic resonance imaging data for an ACL injured participant and a matched control participant were collected and contrasted. RESULTS: Relative to the matched control participant, the ACL-injured participant exhibited increased activation of motor-planning, sensory-processing, and visual-motor control areas. A similar activation pattern was present for the contralateral knee that sustained a subsequent injury. CONCLUSIONS: Bilateral neuroplasticity after ACL injury may contribute to the risk of second injury, or aspects of neurophysiology may be predisposing factors to primary injury. CLINICAL IMPLICATIONS: Sensory-visual-motor function and motor-learning adaptations may provide targets for rehabilitation. PMID- 26509776 TI - Athletic Directors' Barriers to Hiring Athletic Trainers in High Schools. AB - CONTEXT: In its best-practices recommendation, the Inter-Association Task Force for Preventing Sudden Death in Secondary School Athletics Programs urged all high schools to have a certified athletic trainer (AT) on staff. Despite the recommendation, many high schools lack the medical services of an AT. OBJECTIVE: To examine the barriers that athletic directors (ADs) face in hiring ATs in public high schools and in providing medical coverage for their student-athletes. DESIGN: Qualitative study. SETTING: Semistructured telephone interviews. PATIENTS OR OTHER PARTICIPANTS: Twenty full-time public high school ADs (17 men, 3 women) from various geographical regions of the United States (6 North, 4 South, 4 Midwest, 6 West) participated. Data saturation guided the total number of participants. DATA COLLECTION AND ANALYSIS: We completed telephone interviews guided by a semistructured questionnaire with all participants. Interviews were recorded and transcribed verbatim. Multiple-analyst triangulation and peer review were included as steps to establish data credibility. We analyzed the data using the principles of the general inductive approach. RESULTS: We identified 3 themes. Lack of power represented the inability of an AD to hire an AT, which was perceived to be a responsibility of the superintendent and school board. Budget concerns pertained to the funding allocated to specific resources within a school, which often did not include an AT. Nonbudget concerns represented rural locations without clinics or hospitals nearby; misconceptions about the role of an AT, which led to the belief that first-aid-trained coaches are appropriate medical providers; and community support from local clinics, hospitals, and volunteers. CONCLUSIONS: Many ADs would prefer to employ ATs in their schools; however, they perceive that they are bound by the hiring and budgeting decisions of superintendents and school boards. Public school systems are experiencing the consequences of national budget cuts and often do not have the freedom to hire ATs when other school staff are being laid off. PMID- 26509777 TI - Incidence and Predictors of Second Anterior Cruciate Ligament Injury After Primary Reconstruction and Return to Sport. PMID- 26509778 TI - Revisiting the Aqueous Solutions of Dimethyl Sulfoxide by Spectroscopy in the Mid and Near-Infrared: Experiments and Car-Parrinello Simulations. AB - The infrared and near-infrared spectra of the aqueous solutions of dimethyl sulfoxide are revisited. Experimental and computational vibrational spectra are analyzed and compared. The latter are determined as the Fourier transformation of the velocity autocorrelation function of data obtained from Car-Parrinello molecular dynamics simulations. The experimental absorption spectra are deconvolved, and the excess spectra are determined. The two-dimensional excess contour plot provides a means of visualizing and identifying spectral regions and concentration ranges exhibiting nonideal behavior. In the binary mixtures, the analysis of the SO stretching band provides a semiquantitative picture of the formation and dissociation of hydrogen-bonded DMSO-water complexes. A maximum concentration of these clusters is found in the equimolar mixture. At high DMSO concentration, the formation of rather stable 3DMSO:1water complexes is suggested. The formation of 1DMSO:2water clusters, in which the water oxygen atoms interact with the sulfoxide methyl groups, is proposed as a possible reason for the marked depression of the freezing temperature at the eutectic point. PMID- 26509779 TI - Laboratory testing requirements for diagnosis and follow-up of multiple myeloma and related plasma cell dyscrasias. AB - Monoclonal immunoglobulins are markers of plasma cell proliferative diseases and have been described as the first (and perhaps best) serological tumor marker. The unique structure of each monoclonal protein makes them highly specific for each plasma cell clone. The difficulties of using monoclonal proteins for diagnosing and monitoring multiple myeloma, however, stem from the diverse disease presentations and broad range of serum protein concentrations and molecular weights. Because of these challenges, no single test can confidently diagnose or monitor all patients. Panels of tests have been recommended for sensitivity and efficiency. In this review we discuss the various disease presentations and the use of various tests such as protein electrophoresis and immunofixation electrophoresis as well as immunoglobulin quantitation, free light chain quantitation, and heavy-light chain quantitation by immuno-nephelometry. The choice of tests for inclusion in diagnostic and monitoring panels may need to be tailored to each patient, and examples are provided. The panel currently recommended for diagnostic screening is serum protein electrophoresis, immunofixation electrophoresis, and free light chain quantitation. PMID- 26509780 TI - Eryptosis is induced by hyperthermia in hereditary spherocytosis red blood cells. PMID- 26509781 TI - Heparinate but not serum tubes are susceptible to hemolysis by pneumatic tube transportation. AB - BACKGROUND: Pneumatic tube transportation (PTT) may induce hemolysis (H) in blood samples. We aimed to compare the H degree before and after PTT implementation in our hospital. METHODS: Hemolysis indices (HI) for all lithium-heparin plasma samples (P) drawn by the Emergency Department in 2-month periods were retrospectively collected and pre- (n=3579) and post-PTT (n=3469) results compared. The impact of PTT introduction was investigated on LDH [HI threshold (HIt), 25], conjugated bilirubin (cBIL) (HIt, 30), K (HIt, 100) and ALT (HIt, 125). In addition, HI retrieved for P and paired serum samples collected in silica clot activator tubes (S) from the same venipuncture were compared in pre- (n=501) and post-PTT (n=509) periods. RESULTS: Median (5-95th percentile) HI in P was significantly higher in post-PTT period [7 (0-112) vs. 6 (0-82), p<0.001]. Results reported as 'Hemolysis' in P increased from 6.6% in pre-PTT to 9.4% in post-PTT (p<0.001). Investigated tests gave the following rejection rates (pre PTT vs. post-PTT): LDH, 13.4% vs. 18.8%, p<0.001; cBIL, 9.4% vs. 27.0%, p<0.05; K, 3.7% vs. 5.6%, p<0.001; ALT, 2.9% vs. 4.4%, p<0.01. The slightly higher susceptibility to H of S compared to paired P found in the pre-PTT [9 (1-64) vs. 6 (0-85)] was not confirmed in the post-PTT period [7 (0-90) vs. 8 (1-72)], in which median HI in S was significantly lower (p<0.001) than in pre-PTT. CONCLUSIONS: In our setting PTT promotes H in P, increasing the rate of rejected tests. The use of S appears to protect against the hemolysing effect of PTT. PMID- 26509782 TI - Crystalluria. AB - Crystalluria is a marker of urine supersaturation with substances deriving from metabolic disorders, inherited diseases or drugs. The investigation of crystalluria must be done according to a protocol which includes the delivery to the laboratory of a proper urine sample, the use of a microscope equipped with polarized light, the accurate knowledge of urine pH, and a comprehensive examination of the crystals, which is based on their identification, quantification and size measurement. For unusual crystals, infrared spectroscopy may also be needed. The main urinary crystalline categories include: calcium oxalates, calcium phosphates, uric acids and urates, struvite, aminoacids (cystine), purines (2,8-dihydroxyadenine and xanthine) and drugs (e.g. sulfamethoxazole, amoxycillin, ceftriaxone, atazanavir). The investigation of crystalluria is a cheap and valuable tool for the detection and the monitoring of inherited and acquired diseases associated with urinary stone formation or renal function impairment - either acute or chronic - due to intrarenal crystal precipitation. PMID- 26509783 TI - Screening of presumptive urinary tract infections by the automated urine sediment analyser sediMAX. AB - BACKGROUND: Urinary tract infections (UTI) are among the most common bacterial infections and urine samples represent a large proportion of the specimens processed in clinical microbiology laboratories, up to 80% of which, however, yield negative results. Automated microscopy is widely used for urine sediment analysis and has recently been evaluated in a few studies for bacteriological screening of urine samples, achieving high levels of performance. METHODS: We present a study in which urine samples from both inpatients and outpatients, with either clean-catch or indwelling catheter urine samples, were screened for UTI by urine culture, as the reference method, and the automated urine analyser sediMAX, for the detection of bacteria, leukocytes and yeasts. RESULTS: In total, 3443 urine samples were evaluated. When a single algorithm was adopted for sediMAX to screen the total patient population, 96.4% sensitivity, 75.4% specificity, 57.8% positive predictive value, and 98.4% negative predictive value were found. However, for male outpatients and all patients with indwelling catheter other algorithms were necessary to improve performances. Altogether, with sediMAX false negative rate was 2.4% and false positive rate was 27.6%. In addition, 54% of the investigated samples could have avoided urine culture. CONCLUSIONS: After the identification of specific algorithms for different patient subgroups, the automated urine analyser sediMAX can be reliably employed in the screening of UTI. PMID- 26509784 TI - The roles of leptin and adiponectin at the fetal-maternal interface in humans. AB - Infertility now affects one in seven couples, and the prevalence of this condition continues to increase. Ovulatory defects and unknown causes account for more than half of the cases of infertility. It has been postulated that a significant proportion of these cases are directly or indirectly related to obesity, since the presence of excess adipose tissue has a variety of effects on reproductive function. Here, we review on the effects of the two major adipokines (leptin and adiponectin) on fertility, with a focus on the first steps in embryo implantation and the key components of fetal-maternal interface (the placenta and the endometrium). These adipokines are reportedly involved in the regulation of cell proliferation and differentiation, and as such affect local angiogenesis, immune tolerance and inflammatory processes in placental and endometrial tissues. In placental cells, leptin and adiponectin also modulate trophoblast invasiveness and the nutrient supply. These observations strongly suggest by interfering with the placenta and endometrium, adipokines can create a favorable environment for embryo implantation and have a key role in fetal-maternal metabolism, fetal maternal communication, and gestation. Given that reproductive functions are tightly coupled to the energy balance, metabolic abnormalities may lead to the development of complications of pregnancy and changes in fetal growth. In this context, we suggest that the leptin/adiponectin ratio may be a clinically valuable marker for detecting a number of pathologies in pregnancy. PMID- 26509785 TI - Serum steroids remain within the same normal postmenopausal values during 12 month intravaginal 0.50% DHEA. AB - OBJECTIVE: Analyze the serum levels of DHEA (prasterone) and its metabolites after daily intravaginal 0.50% (6.5 mg) DHEA in postmenopausal women with vulvovaginal atrophy (VVA). METHODS: Serum samples were obtained at baseline and after 12, 26 and 52 weeks of treatment. The serum levels of DHEA, DHEA-sulfate (DHEA-S), androstene-3beta, 17beta-diol (5-diol), androstenedione (4-dione), testosterone, dihydrotestosterone (DHT), estrone (E1), estradiol (E2), E1-sulfate (E1-S), androsterone glucuronide (ADT-G) and androstane-3alpha,17beta-diol 17 glucuronide (3alpha-diol-17G) were measured by validated liquid chromatography tandem mass spectrometry. RESULTS: A total of 435 women were exposed for 52 weeks. All serum steroids remained within normal values with no significant differences between lengths of treatment. For the most relevant estrogen-related compounds, namely E1, E2, and E1-S, a reliable marker of total estrogen exposure, the values in the DHEA-treated group at 52 weeks were -3.4%, -9.1% and +1.8%, respectively, compared to the normal postmenopausal values, thus clearly confirming the absence of significant systemic estrogen exposure. CONCLUSION: While confirming that all serum sex steroids originating exclusively from DHEA after menopause are maintained within the normal postmenopausal values, the present data show that the dose of intravaginal DHEA used is free from systemic exposure with no detectable change in metabolism up to 52 weeks of treatment. PMID- 26509786 TI - A parametric approach to kinship hypothesis testing using identity-by-descent parameters. AB - There is a large number of applications where family relationships need to be determined from DNA data. In forensic science, competing ideas are in general verbally formulated as the two hypotheses of a test. For the most common paternity case, the null hypothesis states that the alleged father is the true father against the alternative hypothesis that the father is an unrelated man. A likelihood ratio is calculated to summarize the evidence. We propose an alternative framework whereby a model and the hypotheses are formulated in terms of parameters representing identity-by-descent probabilities. There are several advantages to this approach. Firstly, the alternative hypothesis can be completely general. Specifically, the alternative does not need to specify an unrelated man. Secondly, the parametric formulation corresponds to the approach used in most other applications of statistical hypothesis testing and so there is a large theory of classical statistics that can be applied. Theoretical properties of the test statistic under the null hypothesis are studied. An extension to trios of individuals has been carried out. The methods are exemplified using simulations and a real dataset of 27 Spanish Romani individuals. PMID- 26509787 TI - Amino Acid, Organic Acid, and Sugar Profiles of 3 Dry Bean (Phaseolus vulgaris L.) Varieties. AB - In this study, we compared the amino acid, organic acid and sugar profiles of 3 different varieties of dry beans (black bean [BB], dark red bean [DRB], and cranberry bean [CB]). The efficiency of the 2 commonly used extraction solvents (water and methanol:chloroform:water [2.5:1:1, v/v/v/]) for cultivar differentiation based on their metabolic profile was also investigated. The results showed that the BB contained the highest concentration of amino acids followed by DRB and CB samples. Phenylalanine, a precursor for the biosynthesis of phenolic secondary metabolites was detected at low concentration in CB samples and correlated with the reduced anthocyanins content in CB extract as documented in the published literature. Comparing the extractability of 2 extraction solvents, methanol:chloroform:water (2.5:1:1, v/v/v/) showed higher recoveries of amino acids from 3 beans, whereas, sugars were extracted in higher concentration with water. Analytically, gas chromatography detected sugars (9), amino acids (11), and organic acids (3) in a single run after derivatization of the extracts. In comparison, ion chromatography detected only sugars in a single run without any derivatization step with the tested procedure. Bean samples are better differentiated by the sugar content extracted with water as compared to the aqueous organic solvent extracts using partial least-square discriminant analysis. PMID- 26509788 TI - Infective Juveniles of the Entomopathogenic Nematode, Steinernema feltiae Produce Cryoprotectants in Response to Freezing and Cold Acclimation. AB - Steinernema feltiae is a moderately freeze-tolerant entomopathogenic nematode which survives intracellular freezing. We have detected by gas chromatography that infective juveniles of S. feltiae produce cryoprotectants in response to cold acclimation and to freezing. Since the survival of this nematode varies with temperature, we analyzed their cryoprotectant profiles under different acclimation and freezing regimes. The principal cryoprotectants detected were trehalose and glycerol with glucose being the minor component. The amount of cryoprotectants varied with the temperature and duration of exposure. Trehalose was accumulated in higher concentrations when nematodes were acclimated at 5 degrees C for two weeks whereas glycerol level decreased from that of the non acclimated controls. Nematodes were seeded with a small ice crystal and held at 1 degrees C, a regime that does not produce freezing of the nematodes but their bodies lose water to the surrounding ice (cryoprotective dehydration). This increased the levels of both trehalose and glycerol, with glycerol reaching a higher concentration than trehalose. Nematodes frozen at -3 degrees C, a regime that produces freezing of the nematodes and results in intracellular ice formation, had elevated glycerol levels while trehalose levels did not change. Steinernema feltiae thus has two strategies of cryoprotectant accumulation: one is an acclimation response to low temperature when the body fluids are in a cooled or supercooled state and the infective juveniles produce trehalose before freezing. During this process a portion of the glycerol is converted to trehalose. The second strategy is a rapid response to freezing which induces the production of glycerol but trehalose levels do not change. These low molecular weight compounds are surmised to act as cryoprotectants for this species and to play an important role in its freezing tolerance. PMID- 26509789 TI - The toxicity of crude 4-methylcyclohexanemethanol (MCHM): review of experimental data and results of predictive models for its constituents and a putative metabolite. AB - Crude 4-methylcyclohexanemethanol (MCHM) is an industrial solvent used to clean coal. Approximately 10 000 gallons of a liquid mixture containing crude MCHM were accidently released into the Elk River in West Virginia in January 2014. Because of the proximity to a water treatment facility, the contaminated water was distributed to approximately 300 000 residents. In this review, experimental data and computational predictions for the toxicity for crude MCHM, distilled MCHM, its other components and its putative metabolites are presented. Crude MCHM, its other constituents and its metabolites have low to moderate acute and subchronic oral toxicity. Crude MCHM has been shown not to be a skin sensitizer below certain doses, indicating that at plausible human exposures it does not cause an allergic response. Crude MCHM and its constituents cause slight to moderate skin and eye irritation in rodents at high concentrations. These chemicals are not mutagenic and are not predicted to be carcinogenic. Several of the constituents were predicted through modeling to be possible developmental toxicants; however, 1,4-cyclohexanedimethanol, 1,4-cyclohexanedicarboxylic acid and dimethyl 1,4 cyclohexanedicarboxylate did not demonstrate developmental toxicity in rat studies. Following the spill, the Centers for Disease Control and Prevention recommended a short-term health advisory level of 1 ppm for drinking water that it determined was unlikely to be associated with adverse health effects. Crude MCHM has an odor threshold lower than 10 ppb, indicating that it could be detected at concentrations at least 100-fold less than this risk criterion. Collectively, the findings and predictions indicate that crude MCHM poses no apparent toxicological risk to humans at 1 ppm in household water. PMID- 26509791 TI - Azopeptides: Synthesis and Pericyclic Chemistry. AB - Azopeptides possess an imino urea as an amino amide surrogate in the sequence. Azopeptides were synthesized by oxidation of aza-glycine residues and employed in pericyclic chemistry. Diels-Alder cyclizations and Alder-ene reactions on azopeptides enabled construction of constrained aza-pipecolyl and reactive aza allylglycyl residues. X-ray crystallographic analyses of azopeptide 16a and azapeptides 30a and 35a provided insight into imino urea configuration and conformational affects of cycloalkane side chains at the semicarbazide alpha- and beta-nitrogen, respectively. PMID- 26509790 TI - Drift, not selection, shapes toll-like receptor variation among oceanic island populations. AB - Understanding the relative role of different evolutionary forces in shaping the level and distribution of functional genetic diversity among natural populations is a key issue in evolutionary and conservation biology. To do so accurately genetic data must be analysed in conjunction with an unambiguous understanding of the historical processes that have acted upon the populations. Here, we focused on diversity at toll-like receptor (TLR) loci, which play a key role in the vertebrate innate immune system and, therefore, are expected to be under pathogen mediated selection. We assessed TLR variation within and among 13 island populations (grouped into three archipelagos) of Berthelot's pipit, Anthus berthelotii, for which detailed population history has previously been ascertained. We also compared the variation observed with that found in its widespread sister species, the tawny pipit, Anthus campestris. We found strong evidence for positive selection at specific codons in TLR1LA, TLR3 and TLR4. Despite this, we found that at the allele frequency level, demographic history has played the major role in shaping patterns of TLR variation in Berthelot's pipit. Levels of diversity and differentiation within and across archipelagos at all TLR loci corresponded very closely with neutral microsatellite variation and with the severity of the bottlenecks that occurred during colonization. Our study shows that despite the importance of TLRs in combating pathogens, demography can be the main driver of immune gene variation within and across populations, resulting in patterns of functional variation that can persist over evolutionary timescales. PMID- 26509792 TI - Genomic Dissection of Leaf Angle in Maize (Zea mays L.) Using a Four-Way Cross Mapping Population. AB - Increasing grain yield by the selection for optimal plant architecture has been the key focus in modern maize breeding. As a result, leaf angle, an important determinant of plant architecture, has been significantly improved to adapt to the ever-increasing plant density in maize production over the past several decades. To extend our understanding on the genetic mechanisms of leaf angle in maize, we developed the first four-way cross mapping population, consisting of 277 lines derived from four maize inbred lines with varied leaf angles. The four way cross mapping population together with the four parental lines were evaluated for leaf angle in two environments. In this study, we reported linkage maps built in the population and quantitative trait loci (QTL) on leaf angle detected by inclusive composite interval mapping (ICIM). ICIM applies a two-step strategy to effectively separate the cofactor selection from the interval mapping, which controls the background additive and dominant effects at the same time. A total of 14 leaf angle QTL were identified, four of which were further validated in near-isogenic lines (NILs). Seven of the 14 leaf angle QTL were found to overlap with the published leaf angle QTL or genes, and the remaining QTL were unique to the four-way population. This study represents the first example of QTL mapping using a four-way cross population in maize, and demonstrates that the use of specially designed four-way cross is effective in uncovering the basis of complex and polygenetic trait like leaf angle in maize. PMID- 26509793 TI - Lactobacillus casei Shirota Supplementation Does Not Restore Gut Microbiota Composition and Gut Barrier in Metabolic Syndrome: A Randomized Pilot Study. AB - Metabolic syndrome is associated with disturbances in gut microbiota composition. We aimed to investigate the effect of Lactobacillus casei Shirota (LcS) on gut microbiota composition, gut barrier integrity, intestinal inflammation and serum bile acid profile in metabolic syndrome. In a single-centre, prospective, randomised controlled pilot study, 28 subjects with metabolic syndrome received either LcS for 12 weeks (n = 13) or no LcS (n = 15). Data were compared to healthy controls (n = 16). Gut microbiota composition was characterised from stool using 454 pyrosequencing of 16S rRNA genes. Serum bile acids were quantified by tandem mass spectrometry. Zonulin and calprotectin were measured in serum and stool by ELISA. Bacteroidetes/Firmicutes ratio was significantly higher in healthy controls compared to metabolic syndrome but was not influenced by LcS. LcS supplementation led to enrichment of Parabacteroides. Zonulin and calprotectin were increased in metabolic syndrome stool samples but not influenced by LcS supplementation. Serum bile acids were similar to controls and not influenced by LcS supplementation. Metabolic syndrome is associated with a higher Bacteroidetes/Firmicutes ratio and gut barrier dysfunction but LcS was not able to change this. LcS administration was associated with subtle microbiota changes at genus level. TRIAL REGISTRATION: ClinicalTrials.gov NCT01182844. PMID- 26509795 TI - Audiovisual Delay as a Novel Cue to Visual Distance. AB - For audiovisual sensory events, sound arrives with a delay relative to light that increases with event distance. It is unknown, however, whether humans can use these ubiquitous sound delays as an information source for distance computation. Here, we tested the hypothesis that audiovisual delays can both bias and improve human perceptual distance discrimination, such that visual stimuli paired with auditory delays are perceived as more distant and are thereby an ordinal distance cue. In two experiments, participants judged the relative distance of two repetitively displayed three-dimensional dot clusters, both presented with sounds of varying delays. In the first experiment, dot clusters presented with a sound delay were judged to be more distant than dot clusters paired with equivalent sound leads. In the second experiment, we confirmed that the presence of a sound delay was sufficient to cause stimuli to appear as more distant. Additionally, we found that ecologically congruent pairing of more distant events with a sound delay resulted in an increase in the precision of distance judgments. A control experiment determined that the sound delay duration influencing these distance judgments was not detectable, thereby eliminating decision-level influence. In sum, we present evidence that audiovisual delays can be an ordinal cue to visual distance. PMID- 26509796 TI - Trichostatin A, an Inhibitor of Histone Deacetylase, Inhibits the Viability and Invasiveness of Hypoxic Rheumatoid Arthritis Fibroblast-Like Synoviocytes via PI3K/Akt Signaling. AB - This study was undertaken to explore the effects of trichostatin A (TSA), an inhibitor of histone deacetylase, on the viability, apoptosis, and invasiveness of hypoxic rheumatoid arthritis fibroblast-like synoviocytes (RA FLSs). RA FLSs were exposed to hypoxia for 24 h in the presence or absence of 2 MUM TSA and tested for cell viability, apoptosis, invasion, and gene expression. The involvement of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway was checked. TSA significantly inhibited the viability and induced apoptosis of hypoxic RA FLSs, compared to vehicle control. TSA blocked hypoxia-induced invasion of RA FLSs during Matrigel invasion assays and reduced the expression of matrix metalloproteinases (MMP-2 and MMP-9) and PI3K and phosphorylation of Akt. Overexpression of constitutively active Akt reversed TSA-mediated suppression of invasiveness and downregulation of MMP-2 and MMP-9. Our results indicate the antisurvival and antiinvasive activities of TSA in hypoxic RA FLSs, which is associated with inactivation of PI3K/Akt signaling. PMID- 26509797 TI - Neurosurgeons' Critical Role in Managing Traumatic Brain Injury. PMID- 26509798 TI - Silencing of X-Linked MicroRNAs by Meiotic Sex Chromosome Inactivation. AB - During the pachytene stage of meiosis in male mammals, the X and Y chromosomes are transcriptionally silenced by Meiotic Sex Chromosome Inactivation (MSCI). MSCI is conserved in therian mammals and is essential for normal male fertility. Transcriptomics approaches have demonstrated that in mice, most or all protein coding genes on the X chromosome are subject to MSCI. However, it is unclear whether X-linked non-coding RNAs behave in a similar manner. The X chromosome is enriched in microRNA (miRNA) genes, with many exhibiting testis-biased expression. Importantly, high expression levels of X-linked miRNAs (X-miRNAs) have been reported in pachytene spermatocytes, indicating that these genes may escape MSCI, and perhaps play a role in the XY-silencing process. Here we use RNA FISH to examine X-miRNA expression in the male germ line. We find that, like protein-coding X-genes, X-miRNAs are expressed prior to prophase I and are thereafter silenced during pachynema. X-miRNA silencing does not occur in mouse models with defective MSCI. Furthermore, X-miRNAs are expressed at pachynema when present as autosomally integrated transgenes. Thus, we conclude that silencing of X-miRNAs during pachynema in wild type males is MSCI-dependent. Importantly, misexpression of X-miRNAs during pachynema causes spermatogenic defects. We propose that MSCI represents a chromosomal mechanism by which X-miRNAs, and other potential X-encoded repressors, can be silenced, thereby regulating genes with critical late spermatogenic functions. PMID- 26509799 TI - Fungal compositions and diversities on indoor surfaces with visible mold growths in residential buildings in the Seoul Capital Area of South Korea. AB - Indoor visible mold growths are known to be associated with allergies and respiratory illnesses. However, a question remains of their compositions and diversities. Using swab sampling and high-throughput DNA sequencing, this study analyzed taxonomic compositions and diversities of fungi on indoor surfaces laden with visible mold growths in residential apartments in South Korea. The sequencing results showed low species diversities with Shannon indices ranging from 0.14 to 2.29 (mean = 1.11). Several allergy-related genera were detected on the same surface, where the most abundant Cladosporium with a mean relative abundance of 41% co-occurred with less abundant Aspergillus (0.094%), Rhodotorula (6.3%), Cryptococcus (3.7%), Alternaria (4.1%), and Crivellia (17%). beta diversity analyses showed significant differences in the fungal communities between enclosed balconies and other indoor areas (P < 0.05, ANOSIM), emphasizing a need to sample at multiple indoor locations when assessments are made for indoor visible mold growths. High-throughput sequencing is powerful in characterizing compositions and diversities of fungal communities. Future studies should examine the relationships between taxonomic compositions and diversities of indoor visible molds and health outcomes of allergies and respiratory illnesses in residential buildings. PMID- 26509800 TI - Ambient-Pressure Polymerization of Carbon Anions in the High-Pressure Phase Mg2C. AB - Experimental and theoretical methods were employed to investigate the ambient pressure, metastable phase transition pathways for Mg2C, which was recovered after high-pressure synthesis. We demonstrate that at temperatures above 600 K isolated C(4-) anions within the Mg2C structure polymerize into longer-chain carbon polyanions, resulting in the formation of the alpha-Mg2C3 (Pnnm) structure, which is another local energy minimum for the carbon-magnesium system. Access to the thermodynamic ground state (decomposition into graphite) was achieved at temperatures above ~1000 K. These results indicate that recoverable high-pressure materials can serve as useful high-energy precursors for ambient pressure materials synthesis, and they show a novel mechanism for the formation of carbon chains from methanide structures. PMID- 26509801 TI - Human Papillomavirus (HPV) Prevalence in Nasal and Antrochoanal Polyps and Association with Clinical Data. AB - OBJECTIVES: The pathogenesis of sinonasal polyposis remains unclear, in spite of several investigative approaches. Antrochoanal polyps, a subgroup of sinonasal polyposis along with allergic- and chronic-inflammatory nasal polyps, mostly originate from the maxillary sinus and develop as a unilateral, pedunculated mass towards the nasopharynx. The human papillomavirus (HPV) is discussed as a possible causative and influencing factor in development and progression of sinonasal polyposis. This study aims to elucidate HPV frequency in nasal polyps and antrochoanal polyps. MATERIALS AND METHODS: Genomic DNA from 257 tissue specimens (166 nasal polyps, 39 antrochoanal polyps and 52 nasal turbinates) was subjected to three different established HPV- polymerase chain reaction assays, testing for 37 low- and high-risk HPV. In addition, immunohistochemical analyses for HPV16 were carried out, as well as immunohistochemistry and western blots of p16, a biomarker for HPV induced cancer. RESULTS: HPV-DNA was detected in 53.8% of antrochoanal polyps, 15.1% of nasal polyps, and 5.8% of nasal turbinates. HPV16 was the predominant type with a detection rate of 76% in nasal polyps and 62% in antrochoanal polyps. Immunohistochemically, HPV positive tissues stained positive for HPV16 antigens and p16 in epithelial cell layers. No significant p16 overexpression was traceable in antrochoanal polyps, nasal polyps and nasal turbinates by western blot. There was no correlation of HPV-status with sex, age, smoking, alcohol consumption or allergic background. CONCLUSION: The present study shows a significant frequency of high-risk type HPV16 in antrochoanal polyps. Absence of oncogenic transformation or correlation of the HPV-status with clinical data suggests a latent superinfection, possibly because of anatomical proximity to the oropharynx. PMID- 26509802 TI - Association Analysis for Bacterial Spot Resistance in a Directionally Selected Complex Breeding Population of Tomato. AB - Bacterial spot of tomato is caused by at least four species of Xanthomonas with multiple physiological races. We developed a complex breeding population for simultaneous discovery of marker-trait linkage, validation of existing quantitative trait loci (QTL), and pyramiding of resistance. Six advanced accessions with resistance from distinct sources were crossed in all combinations and their F1 hybrids were intercrossed. Over 1,100 segregating progeny were evaluated in the field following inoculation with X. euvesicatoria race T1 strains. We selected 5% of the most resistant and 5% of the most susceptible progeny for evaluation as plots in two subsequent replicated field trials inoculated with T1 and T3 (X. perforans) strains. The estimated heritability of T1 resistance was 0.32. In order to detect previously reported resistance genes, as well as novel QTL, we explored methods to correct for population structure and analysis based on single markers or haplotypes. Both single-point and haplotype analyses identified strong associations in the genomic regions known to carry Rx 3 (chromosome 5) and Rx-4/Xv3 (chromosome 11). Accounting for kinship and structure generally improved the fit of statistical models. Detection of known loci was improved by adding kinship or a combination of kinship and structure using a Q matrix from model-based clustering. Additional QTL were detected on chromosomes 1, 4, 6, and 7 for T1 resistance and chromosomes 2, 4, and 6 for T3 resistance (P < 0.01). Haplotype analysis improved our ability to trace the origin of positive alleles. These results demonstrate that both known and novel associations can be identified using complex breeding populations that have experienced directional selection. PMID- 26509803 TI - Brain Arousal Regulation in Carriers of Bipolar Disorder Risk Alleles. AB - OBJECTIVES: Recent genome-wide association studies identified a number of chromosomal risk loci for bipolar disorder (BD, 'manic-depressive illness'). According to the vigilance regulation model, the regulation of brain arousal (referred to as 'vigilance') when assessed via EEG is an emerging biomarker linked to the pathogenesis of manic and depressive episodes. On this basis, the present study aimed to assess whether carriers of BD risk alleles differ in brain arousal regulation. METHODS: Healthy participants of the population-based Leipzig Health Care Study (LIFE) underwent a 20-min eyes-closed resting EEG paradigm. Brain arousal was assessed applying the computer-based Vigilance Algorithm Leipzig (VIGALL). The primary sample (n = 540) was genotyped for ten of the most reliable BD risk variants, of which two qualified for replication (n = 509). RESULTS: Primary sample analyses revealed Bonferroni-adjusted significance for rs1006737 in CACNA1C (encoding a calcium channel subunit), with risk allele carriers exhibiting relatively steep brain arousal declines. Further, carriers of two risk alleles of rs472913 at 1p32.1 showed generally lower brain arousal levels for the duration of the resting paradigm. However, both associations failed replication. CONCLUSION: Although our initial findings are in line with the vigilance regulation model and convincing in view of the previously reported notable role of ion channelopathies in BD, our results do not provide consistent evidence for a link between BD risk variants and brain arousal regulation. Several between-sample differences may account for this inconsistency. The molecular genetics of brain arousal regulation remain to be clarified. PMID- 26509804 TI - Electron Transport at the TiO2 Surfaces of Rutile, Anatase, and Strontium Titanate: The Influence of Orbital Corrugation. AB - The two-dimensional electron gas in SrTiO3 created by an overlayer of amorphous LaAlO3 is compared with those at the TiO2-terminated surfaces of rutile and anatase. Differences in conductivity are explained in terms of the limiting Ti-O Ti bond angles (orbital corrugation), band dispersion, and polaron formation. At 300 K, the sheet conductivity and mobility of anatase exceed those for SrTiO3 or rutile by one or two orders of magnitude, respectively. The electrons in rutile become localized below 25 K. PMID- 26509805 TI - New Era for Stroke Therapy: Is This a Global Perspective? PMID- 26509806 TI - Bayesian Modeling of Prion Disease Dynamics in Mule Deer Using Population Monitoring and Capture-Recapture Data. AB - Epidemics of chronic wasting disease (CWD) of North American Cervidae have potential to harm ecosystems and economies. We studied a migratory population of mule deer (Odocoileus hemionus) affected by CWD for at least three decades using a Bayesian framework to integrate matrix population and disease models with long term monitoring data and detailed process-level studies. We hypothesized CWD prevalence would be stable or increase between two observation periods during the late 1990s and after 2010, with higher CWD prevalence making deer population decline more likely. The weight of evidence suggested a reduction in the CWD outbreak over time, perhaps in response to intervening harvest-mediated population reductions. Disease effects on deer population growth under current conditions were subtle with a 72% chance that CWD depressed population growth. With CWD, we forecasted a growth rate near one and largely stable deer population. Disease effects appear to be moderated by timing of infection, prolonged disease course, and locally variable infection. Long-term outcomes will depend heavily on whether current conditions hold and high prevalence remains a localized phenomenon. PMID- 26509808 TI - Correction: Applying Linear and Non-Linear Methods for Parallel Prediction of Volume of Distribution and Fraction of Unbound Drug. PMID- 26509807 TI - Congestive Heart Failure Leads to Prolongation of the PR Interval and Atrioventricular Junction Enlargement and Ion Channel Remodelling in the Rabbit. AB - Heart failure is a major killer worldwide. Atrioventricular conduction block is common in heart failure; it is associated with worse outcomes and can lead to syncope and bradycardic death. We examine the effect of heart failure on anatomical and ion channel remodelling in the rabbit atrioventricular junction (AVJ). Heart failure was induced in New Zealand rabbits by disruption of the aortic valve and banding of the abdominal aorta resulting in volume and pressure overload. Laser micro-dissection and real-time polymerase chain reaction (RT-PCR) were employed to investigate the effects of heart failure on ion channel remodelling in four regions of the rabbit AVJ and in septal tissues. Investigation of the AVJ anatomy was performed using micro-computed tomography (micro-CT). Heart failure animals developed first degree heart block. Heart failure caused ventricular myocardial volume increase with a 35% elongation of the AVJ. There was downregulation of HCN1 and Cx43 mRNA transcripts across all regions and downregulation of Cav1.3 in the transitional tissue. Cx40 mRNA was significantly downregulated in the atrial septum and AVJ tissues but not in the ventricular septum. mRNA abundance for ANP, CLCN2 and Navbeta1 was increased with heart failure; Nav1.1 was increased in the inferior nodal extension/compact node area. Heart failure in the rabbit leads to prolongation of the PR interval and this is accompanied by downregulation of HCN1, Cav1.3, Cx40 and Cx43 mRNAs and anatomical enlargement of the entire heart and AVJ. PMID- 26509809 TI - Relation of Childhood Home Environment to Cortical Thickness in Late Adolescence: Specificity of Experience and Timing. AB - What are the long-term effects of childhood experience on brain development? Research with animals shows that the quality of environmental stimulation and parental nurturance both play important roles in shaping lifelong brain structure and function. Human research has so far been limited to the effects of abnormal experience and pathological development. Using a unique longitudinal dataset of in-home measures of childhood experience at ages 4 and 8 and MRI acquired in late adolescence, we were able to relate normal variation in childhood experience to later life cortical thickness. Environmental stimulation at age 4 predicted cortical thickness in a set of automatically derived regions in temporal and prefrontal cortex. In contrast, age 8 experience was not predictive. Parental nurturance was not predictive at either age. This work reveals an association between childhood experience and later brain structure that is specific relative to aspects of experience, regions of brain, and timing. PMID- 26509810 TI - Correction: DNA Damage Response Checkpoint Activation Drives KP1019 Dependent Pre Anaphase Cell Cycle Delay in S. cerevisiae. PMID- 26509811 TI - Shape-Directed Patterning and Surface Reaction of Tetra-diacetylene Monolayers: Formation of Linear and Two-Dimensional Grid Polydiacetylene Alternating Copolymers. AB - Side chains containing two diacetylene units spaced by an odd number of methylene units exhibit pronounced "bumps" composed of 0.3 nm steps, in opposite directions, at odd and even side-chain positions. In densely packed self assembled monolayers, the bis-diacetylene bumps stack into each other, similar to the stacking of paper cups. Bis-diacetylene side chain structure and associated packing constraints can be tailored by altering the bump width, direction, side chain location, and overall side-chain length as a means to direct the identities and alignments of adjacent molecules within monolayers. Scanning tunneling microscopy (STM) at the solution-HOPG interface confirms the high selectivity and fidelity with which bis-diacetylene bump stacking directs the packing of shape complementary side chains within one-component monolayers and within two component, 1-D self-patterned monolayers. Drop cast or moderately annealed monolayers of anthracenes bearing two bis-diacetylene side chains assemble single domains as large as 10(5) nm2. Light-induced cross-linking of two-component, 1-D patterned monolayers generates linear polydiacetylene alternating copolymers (A-B )x and 2-D grid polydiacetylene alternating copolymers (A(-B-)(-B-)A(-B-)(-B-))x that covalently lock in monolayer structure and patterns. PMID- 26509812 TI - Repeated Aerosolized-Boosting with Gamma-Irradiated Mycobacterium bovis BCG Confers Improved Pulmonary Protection against the Hypervirulent Mycobacterium tuberculosis Strain HN878 in Mice. AB - Mycobacterium bovis bacillus Calmette-Guerin (BCG), the only licensed vaccine, shows limited protection efficacy against pulmonary tuberculosis (TB), particularly hypervirulent Mycobacterium tuberculosis (Mtb) strains, suggesting that a logistical and practical vaccination strategy is urgently required. Boosting the BCG-induced immunity may offer a potentially advantageous strategy for advancing TB vaccine development, instead of replacing BCG completely. Despite the improved protection of the airway immunization by using live BCG, the use of live BCG as an airway boosting agent may evoke safety concerns. Here, we analyzed the protective efficacy of gamma-irradiated BCG as a BCG-prime boosting agent for airway immunization against a hypervirulent clinical strain challenge with Mycobacterium tuberculosis HN878 in a mouse TB model. After the aerosol challenge with the HN878 strain, the mice vaccinated with BCG via the parenteral route exhibited only mild and transient protection, whereas BCG vaccination followed by multiple aerosolized boosting with gamma-irradiated BCG efficiently maintained long-lasting control of Mtb in terms of bacterial reduction and pathological findings. Further immunological investigation revealed that this approach resulted in a significant increase in the cellular responses in terms of a robust expansion of antigen (PPD and Ag85A)-specific CD4+ T cells concomitantly producing IFN-gamma, TNF-alpha, and IL-2, as well as a high level of IFN-gamma producing recall response via both the local and systemic immune systems upon further boosting. Collectively, aerosolized boosting of gamma-irradiated BCG is able to elicit strong Th1-biased immune responses and confer enhanced protection against a hypervirulent Mycobacterium tuberculosis HN878 infection in a boosting number-dependent manner. PMID- 26509813 TI - Chronic Hypoxemia in Children With Congenital Heart Defect Impairs Airway Epithelial Sodium Transport. AB - OBJECTIVE: Ambient hypoxia impairs the airway epithelial Na transport, which is crucial in lung edema reabsorption. Whether chronic systemic hypoxemia affects airway Na transport has remained largely unknown. We have therefore investigated whether chronic systemic hypoxemia in children with congenital heart defect affects airway epithelial Na transport, Na transporter-gene expression, and short term lung edema accumulation. DESIGN: Prospective, observational study. SETTING: Tertiary care medical center responsible for nationwide pediatric cardiac surgery. PATIENTS: Ninety-nine children with congenital heart defect or acquired heart disease (age range, 6 d to 14.8 yr) were divided into three groups based on their level of preoperative systemic hypoxemia: 1) normoxemic patients (SpO2% >= 95%; n = 44), 2) patients with cyanotic congenital heart defect and moderate hypoxemia (SpO2 86-94%; n = 16), and 3) patients with cyanotic congenital heart defect and profound systemic hypoxemia (SpO2 <= 85%; n = 39). MEASUREMENTS AND MAIN RESULTS: Nasal transepithelial potential difference served as a surrogate measure for epithelial Na transport of the respiratory tract. Profoundly hypoxemic patients had 29% lower basal nasal transepithelial potential difference (p = 0.02) and 55% lower amiloride-sensitive nasal transepithelial potential difference (p = 0.0003) than normoxemic patients. In profoundly hypoxemic patients, nasal epithelial messenger RNA expressions of two airway Na transporters (amiloride-sensitive epithelial Na channel and beta1- Na-K-ATPase) were not attenuated, but instead alpha1-Na-K-ATPase messenger RNA levels were higher (p = 0.03) than in the normoxemic patients, indicating that posttranscriptional factors may impair airway Na transport. The chest radiograph lung edema score increased after congenital cardiac surgery in profoundly hypoxemic patients (p = 0.0004) but not in patients with normoxemia or moderate hypoxemia. CONCLUSIONS: The impaired airway epithelial amiloride-sensitive Na transport activity in profoundly hypoxemic children with cyanotic congenital heart defect may hinder defense against lung edema after cardiac surgery. PMID- 26509814 TI - A Cross-Sectional Survey of Near-Infrared Spectroscopy Use in Pediatric Cardiac ICUs in the United Kingdom, Ireland, Italy, and Germany. AB - OBJECTIVES: Despite the increasing use of near-infrared spectroscopy across pediatric cardiac ICUs, there is significant variability and equipoise with no universally accepted management algorithms. We aimed to explore the use of near infrared spectroscopy in pediatric cardiac ICUs in the United Kingdom, Ireland, Italy, and Germany. DESIGN: A cross-sectional multicenter, multinational electronic survey of one consultant in each pediatric cardiac ICU. SETTING: Pediatric cardiac ICUs in the United Kingdom and Ireland (n = 13), Italy (n = 12), and Germany (n = 33). INTERVENTIONS: Questionnaire targeted to establish use, targets, protocols/thresholds for intervention, and perceived usefulness of near-infrared spectroscopy monitoring. RESULTS: Overall, 42 of 58 pediatric cardiac ICUs (72%) responded: United Kingdom and Ireland, 11 of 13 (84.6%); Italy, 12 of 12 (100%); and Germany, 19 of 33 (57%, included all major centers). Near-infrared spectroscopy usage varied with 35% (15/42) reporting that near infrared spectroscopy was not used at all (7/42) or occasionally (8/42); near infrared spectroscopy use was much less common in the United Kingdom (46%) when compared with 78% in Germany and all (100%) in Italy. Only four units had a near infrared spectroscopy protocol, and 18 specifically used near-infrared spectroscopy in high-risk patients; 37 respondents believed that near-infrared spectroscopy added value to standard monitoring and 23 believed that it gave an earlier indication of deterioration, but only 19 would respond based on near infrared spectroscopy data alone. Targets for absolute values and critical thresholds for intervention varied widely between units. The reasons cited for not or occasionally using near-infrared spectroscopy were expense (n = 6), limited evidence and uncertainty on how it guides management (n = 4), difficulty in interpretation, and unreliability of data (n = 3). Amongst the regular or occasional near-infrared spectroscopy users (n = 35), 28 (66%) agreed that a multicenter study is warranted to ascertain its use. CONCLUSIONS: Although most responding units used near-infrared spectroscopy for high-risk patients, the majority (31/35 [88%]) did not have any protocols or guidelines for intervention. Target thresholds and intervention algorithms are needed to support the use of near-infrared spectroscopy in pediatric cardiac ICUs; an international multicenter study is warranted. PMID- 26509815 TI - Worldwide Survey of Nutritional Practices in PICUs. AB - OBJECTIVE: To assess current nutritional practices in critically ill children worldwide. DESIGN: A two-part online, international survey. The first part, "the survey", was composed of 59 questions regarding nutritional strategies and protocols (July-November 2013). The second part surveyed the "point prevalence" of nutritional data of patients present in a subgroup of the responding PICUs (May-September 2014). SETTING: Members of the World Federation of Pediatric Intensive and Critical Care Societies were asked to complete the survey. SUBJECTS: Pediatric critical care providers. INTERVENTIONS: Survey. MEASUREMENTS AND MAIN RESULTS: We analyzed 189 responses from 156 PICUs in 52 countries (survey). We received nutritional data on 295 patients from 41 of these 156 responding PICUs in 27 countries (point prevalence). According to the "survey", nutritional protocols and support teams were available in 52% and 57% of the PICUs, respectively. Various equations were in use to estimate energy requirements; only in 14% of PICUs, indirect calorimetry was used. Nutritional targets for macronutrients, corrected for age/weight, varied widely. Enteral nutrition would be started early (within 24 hr of admission) in 60% of PICUs, preferably by the gastric route (88%). In patients intolerant to enteral nutrition, parenteral nutrition would be started within 48 hours in 55% of PICUs. Overall, in 72% of PICUs supplemental parenteral nutrition would be used if enteral nutrition failed to meet at least 50% of energy delivery goal. Several differences between the intended (survey) and the actual (point prevalence) nutritional practices were found in the responding PICUs, predominantly overestimating the ability to adequately feed patients. CONCLUSION: Nutritional practices vary widely between PICUs worldwide. There are significant differences in macronutrient goals, estimating energy requirements, timing of nutrient delivery, and threshold for supplemental parenteral nutrition. Uniform consensus based nutrition practices, preferably guided by evidence, are desirable in the PICU. PMID- 26509816 TI - Patterns of Sedation Weaning in Critically Ill Children Recovering From Acute Respiratory Failure. AB - OBJECTIVE: To characterize sedation weaning patterns in typical practice settings among children recovering from critical illness. DESIGN: A descriptive secondary analysis of data that were prospectively collected during the prerandomization phase (January to July 2009) of a clinical trial of sedation management. SETTING: Twenty-two PICUs across the United States. PATIENTS: The sample included 145 patients, aged 2 weeks to 17 years, mechanically ventilated for acute respiratory failure who received at least five consecutive days of opioid exposure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Group comparisons were made between patients with an intermittent weaning pattern, defined as a 20% or greater increase in daily opioid dose after the start of weaning, and the remaining patients defined as having a steady weaning pattern. Demographic and clinical characteristics, tolerance to sedatives, and iatrogenic withdrawal symptoms were evaluated. Sixty-six patients (46%) were intermittently weaned; 79 patients were steadily weaned. Prior to weaning, intermittently weaned patients received higher peak and cumulative doses and longer exposures to opioids and benzodiazepines, demonstrated more sedative tolerance (58% vs 41%), and received more chloral hydrate and barbiturates compared with steadily weaned patients. During weaning, intermittently weaned patients assessed for withdrawal had a higher incidence of Withdrawal Assessment Tool-version 1 scores of greater than or equal to 3 (85% vs 46%) and received more sedative classes compared with steadily weaned patients. CONCLUSIONS: This study characterizes sedative administration practices for pediatric patients prior to and during weaning from sedation after critical illness. It provides a novel methodology for describing weaning in an at-risk pediatric population that may be helpful in future research on weaning strategies to prevent iatrogenic withdrawal syndrome. PMID- 26509817 TI - The Effect of Methylprednisolone on Plasma Concentrations of Neutrophil Gelatinase-Associated Lipocalin in Pediatric Heart Surgery. AB - OBJECTIVES: Plasma neutrophil gelatinase-associated lipocalin is a kidney injury marker used in pediatric heart surgery. Neutrophil gelatinase-associated lipocalin is also a constituent of specific granules of neutrophils. Corticosteroids are widely used in pediatric heart surgery. Methylprednisolone inhibits degranulation of neutrophil-specific granules. Use of corticosteroids has not been taken into account in studies of neutrophil gelatinase-associated lipocalin in pediatric heart surgery. We studied the influence of systemically administered methylprednisolone on plasma neutrophil gelatinase-associated lipocalin concentrations in pediatric heart surgery. DESIGN: Two separate double blinded randomized trials. SETTING: PICU at a university-affiliated hospital. PATIENTS: Forty neonates undergoing open-heart surgery and 45 children undergoing ventricular and atrioventricular septal defect correction. INTERVENTIONS: First trial (neonate trial), 40 neonates undergoing open-heart surgery received either 30 mg/kg IV methylprednisolone (n = 20) or placebo (n = 20). Second trial (ventricular septal defect trial), 45 children undergoing ventricular or atrioventricular septal defect correction received one of the following: 30 mg/kg of methylprednisolone IV after anesthesia induction (n = 15), 30 mg/kg methylprednisolone in the cardiopulmonary bypass prime solution (n = 15), or placebo (n = 15). MEASUREMENTS AND MAIN RESULTS: Plasma neutrophil gelatinase associated lipocalin and creatinine were measured in both series. Lactoferrin levels were measured as a marker of neutrophil-specific granules in the ventricular septal defect trial only. No differences in creatinine levels occurred between the groups of either trial. Preoperative, neutrophil gelatinase associated lipocalin did not differ between the study groups of either trial. Preoperatively administered methylprednisolone in the neonate trial reduced neutrophil gelatinase-associated lipocalin by 41% at 6 hours postoperatively (p = 0.002). Preoperatively administered methylprednisolone in the ventricular septal defect trial reduced neutrophil gelatinase-associated lipocalin by 47% (p = 0.010) and lactoferrin by 52% (p = 0.013) 6 hours postoperatively. Lactoferrin levels in the ventricular septal defect trial correlated with neutrophil gelatinase-associated lipocalin (R = 0.492; p = 0.001) preoperatively and after weaning from cardiopulmonary bypass (R = 0.471; p = 0.001). CONCLUSIONS: Preoperatively administered methylprednisolone profoundly decreases plasma neutrophil gelatinase-associated lipocalin levels. Neutrophil gelatinase associated lipocalin seems to originate to a significant extent from activated neutrophils. Preoperative methylprednisolone is a confounding factor when interpreting plasma neutrophil gelatinase-associated lipocalin levels as a kidney injury marker in pediatric heart surgery. PMID- 26509818 TI - Exploration of the Canyon-Incised Continental Margin of the Northeastern United States Reveals Dynamic Habitats and Diverse Communities. AB - The continental margin off the northeastern United States (NEUS) contains numerous, topographically complex features that increase habitat heterogeneity across the region. However, the majority of these rugged features have never been surveyed, particularly using direct observations. During summer 2013, 31 Remotely Operated Vehicle (ROV) dives were conducted from 494 to 3271 m depth across a variety of seafloor features to document communities and to infer geological processes that produced such features. The ROV surveyed six broad-scale habitat features, consisting of shelf-breaching canyons, slope-sourced canyons, inter canyon areas, open-slope/landslide-scar areas, hydrocarbon seeps, and Mytilus Seamount. Four previously unknown chemosynthetic communities dominated by Bathymodiolus mussels were documented. Seafloor methane hydrate was observed at two seep sites. Multivariate analyses indicated that depth and broad-scale habitat significantly influenced megafaunal coral (58 taxa), demersal fish (69 taxa), and decapod crustacean (34 taxa) assemblages. Species richness of fishes and crustaceans significantly declined with depth, while there was no relationship between coral richness and depth. Turnover in assemblage structure occurred on the middle to lower slope at the approximate boundaries of water masses found previously in the region. Coral species richness was also an important variable explaining variation in fish and crustacean assemblages. Coral diversity may serve as an indicator of habitat suitability and variation in available niche diversity for these taxonomic groups. Our surveys added 24 putative coral species and three fishes to the known regional fauna, including the black coral Telopathes magna, the octocoral Metallogorgia melanotrichos and the fishes Gaidropsarus argentatus, Guttigadus latifrons, and Lepidion guentheri. Marine litter was observed on 81% of the dives, with at least 12 coral colonies entangled in debris. While initial exploration revealed the NEUS region to be both geologically dynamic and biologically diverse, further research into the abiotic conditions and the biotic interactions that influence species abundance and distribution is needed. PMID- 26509820 TI - Fabrication of interconnected porous calcite by bridging calcite granules with dicalcium phosphate dihydrate and their histological evaluation. AB - Interconnected porous calcite has attracted attention as an artificial bone replacement material and as a precursor for the fabrication of carbonate apatite, which is also an artificial bone replacement material. In this study, calcite granules were exposed to acidic calcium phosphate solution, and the feasibility of fabricating interconnected porous calcite using this process was evaluated. No setting reaction was observed under the nonloading condition. In contrast, under loading conditions, calcite granules were bridged with dicalcium phosphate dihydrate crystals, and the calcite granules set into interconnected porous calcite foam. When applied 0.4 MPa of loading pressure during sample preparation, compressive strength of the obtained interconnected porous calcite was ~1.5 MPa. The exposure of the calcite granules to acidic calcium phosphate solution under loading conditions was the key for the setting reaction to occur. This is because calcite granules cannot contact one another under the nonloading condition because of bubble formation on the surfaces of the calcite granules. The interconnected porous calcite revealed excellent tissue response, and new bone was able to penetrate into the porous calcite 2 weeks after implantation. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A 104A: 652-658, 2016. PMID- 26509821 TI - The anti-CD20 monoclonal antibody rituximab to treat acquired haemophilia A. AB - BACKGROUND: Acquired haemophilia A (AHA) is a rare bleeding disorder caused by the development of specific autoantibodies against naturally occurring factor VIII (FVIII). Although about half of cases are idiopathic, AHA may be associated with several non-neoplastic conditions, autoimmune disorders, as well as haematological malignancies, such as chronic lymphocytic leukaemia and lymphoma. The long-term suppression of inhibitors is one of the mainstays of the treatment of AHA. Apart from standard immunosuppressive treatments, rituximab has been proven to be effective in AHA. MATERIALS AND METHODS: The aim of this review is to provide a systematic description of data available in the literature on this topic. To do so, we performed a search using the indexed online database Medline/PubMed, without temporal limits, matching the words "rituximab" and "acquired h(a)emophilia". Furthermore, additional published studies were identified in the reference list of the publications found in PubMed. RESULTS: The review of the literature confirms that rituximab may be a safe and useful treatment for AHA. DISCUSSION: Although rituximab is not a standard therapy for AHA, it may be useful in resistant cases. However, the definitive place of this monoclonal antibody in the therapeutic strategy for AHA (first or second-line, alone or in combination with other drugs) remains to be determined more precisely and warrants further investigation. PMID- 26509822 TI - Multicentre standardisation of a clinical grade procedure for the preparation of allogeneic platelet concentrates from umbilical cord blood. AB - BACKGROUND: In addition to a largely prevalent use for bleeding prophylaxis, platelet concentrates from adult blood have also been used for many years to prepare platelet gels for the repair of topical skin ulcers. Platelet gel can be obtained by activation of fresh, cryopreserved, autologous or allogeneic platelet concentrates with calcium gluconate, thrombin and/or batroxobin. The high content of tissue regenerative factors in cord blood platelets and the widespread availability of allogeneic cord blood units generously donated for haematopoietic transplant but unsuitable for this use solely because of low haematopoietic stem cell content prompted us to develop a national programme to standardise the production of allogeneic cryopreserved cord blood platelet concentrates (CBPC) suitable for later preparation of clinical-grade cord blood platelet gel. MATERIALS AND METHODS: Cord blood units collected at public banks with total nucleated cell counts <1.5*10(9), platelet count >150*10(9)/L and volume >50 mL, underwent soft centrifugation within 48 hours of collection. Platelet-rich plasma was centrifuged at high speed to obtain a CBPC with target platelet concentration of 800-1,200*10(9)/L, which was cryopreserved, without cryoprotectant, below -40 degrees C. RESULTS: During 14 months, 13 banks produced 1,080 CBPC with mean (+/- standard deviation) volume of 11.4+/-4.4 mL and platelet concentration of 1,003+/ 229*10(9)/L. Total platelet count per CBPC was 11.3+/-4.9*10(9). Platelet recovery from cord blood was 47.7+/-17.8%. About one-third of cord blood units donated for haematopoietic transplant could meet the requirements for preparation of CBPC. The cost of preparation was ? 160.92/CBPC. About 2 hours were needed for one technician to prepare four CBPC. DISCUSSION: This study yielded valuable scientific and operational information regarding the development of clinical trials using allogeneic CBPC. PMID- 26509823 TI - A model for integrating molecular-based testing in transfusion services. AB - BACKGROUND: Molecular-based laboratory tests can predict blood group antigens and supplement serological methods, adding a unique technology to assist in resolving discrepant or incomplete blood group typing or antibody identification. Hospital transfusion services have options for integrating molecular-based methods in their routine operations. We describe here the model of a hospital-reference laboratory partnership. MATERIALS AND METHODS: Blood samples for compatibility testing were obtained from patients in a 609-bed hospital serving an urban multiethnic and multiracial population. When results of blood group phenotyping by serological methods were inconclusive, samples were referred for molecular based testing. The reference laboratory used several methods for genotyping, including polymerase chain reaction followed by restriction enzyme-linked polymorphism analysis, sequence-specific primer polymerase chain reaction and array-based approaches. Human erythrocyte antigen, RHCE and RHD single nucleotide polymorphism arrays were integrated into the laboratory as they became commercially available. RESULTS: The hospital-reference laboratory model made it possible to integrate blood group genotyping promptly by current technology without the expense of new laboratory equipment or adding personnel with technical expertise. We describe ten cases that illustrate the categories of serological problems that were resolved by molecular methods. DISCUSSION: In hospital molecular testing for transfusion services has logistical advantages, but is financially impractical for most hospitals. Our model demonstrates the advantages of a hospital-reference laboratory partnership. In conclusion, hospital transfusion services can integrate molecular-based testing in their routine services without delay by establishing a partnership with a molecular blood group reference laboratory. The hospital reference-laboratory model promotes genomic medicine without the expense of new equipment and skilled personnel, while supporting the economy of centralised large-scale laboratory operations. PMID- 26509824 TI - Blood donor selection in European Union directives: room for improvement. AB - BACKGROUND: Transfusion-transmissible infections have made both blood bankers and health authorities overly cautious. The general public expects and hence reinforces this policy. To obtain a high level of blood product safety, blood and plasma donors have to meet increasingly stringent eligibility criteria; however, it is not known whether this policy translates into improved outcomes for patients. There is a risk that the management of donors does not match the ambition of greater safety for patients. European directives related to the collection process and donor selection will probably be reconsidered in the next few years. MATERIAL AND METHODS: The development of European directives on donor selection and their basis in the literature were reviewed with an emphasis on the background and considerations for eligibility criteria to be included in the directives. RESULTS: The precautionary principle appears to be the predominant reason behind the set of eligibility criteria. However, the formal eligibility criteria, put into force in 2004, do not balance with the developments of the past decade in laboratory tests and measures that have substantially reduced actual infection risks. In no cases were the effects of eligibility criteria on the donor pool and donor well-being quantified. Regional differences in the epidemiology of transfusion-transmissible infections were not taken into consideration either. DISCUSSION: First, the Authors promote the collection of epidemiological data on the incidence and prevalence of conditions in the general population and in blood and plasma donors which could pose a risk for transfused patients, in order to use these data as a basis for decision-making in donor selection policies. Second, the Authors suggest including allowance for differential deferral criteria throughout Europe, based on factual risk levels. There should be an accepted balance between donor and patient welfare, and also between risk to transfusion safety and risk of compromising the blood supply. PMID- 26509825 TI - Homosexuals and blood donation: a delicate issue for the European Union Court of Justice. PMID- 26509826 TI - Evaluation of group A1B erythrocytes converted to type as group O: studies of markers of function and compatibility. AB - BACKGROUND: Enzymatic conversion of blood group A1B red blood cells (RBC) to group O RBC (ECO) was achieved by combined treatment with alpha-galactosidase and alpha-N-acetylgalactosaminidase. The aim of this study was to evaluate the function and safety of these A1B-ECO RBC in vitro. MATERIALS AND METHODS: A 20% packed volume of A1B RBC was treated with enzymes in 250 mM glycine buffer, pH 6.8. The efficiency of the conversion of A and B antigen was evaluated by traditional typing in test tubes, gel column agglutination technology and fluorescence-activated cell sorting (FACS) analysis. The physiological and metabolic parameters of native and ECO RBC were compared, including osmotic fragility, erythrocyte deformation index, levels of 2,3-diphosphoglycerate, ATP, methaemoglobin, free Na(+), and free K(+). The morphology of native and ECO RBC was observed by scanning electron microscopy. Residual alpha-galactosidase or alpha-N-acetylgalactosaminidase in A1B-ECO RBC was detected by double-antibody sandwich ELISA method. Manual cross-matching was applied to ensure blood compatibility. RESULTS: The RBC agglutination tests and FACS results showed that A1B RBC were efficiently converted to O RBC. Functional analysis suggested that the conversion process had little impact on the physiological and metabolic parameters of the RBC. The residual amounts of either alpha-galactosidase or alpha-N-acetylgalactosaminidase in the A1B-ECO RBC were less than 10 ng/mL of packed RBC. About 18% of group B and 55% of group O sera reacted with the A1B-ECO RBC in a sensitive gel column cross-matching test. DISCUSSION: The conversion process does not appear to affect the morphological, physiological or metabolic parameters of A1B-ECO RBC. However, the A1B-ECO RBC still reacted with some antigens. More research on group O and B sera, which may partly reflect the complexity of group A1 the safety of A1B-ECO RBC is necessary before the application of these RBC in clinical transfusion. PMID- 26509827 TI - Efficacy of autologous platelet-rich plasma for the treatment of muscle rupture with haematoma: a multicentre, randomised, double-blind, placebo-controlled clinical trial. AB - BACKGROUND: The goals of the treatment of muscle injuries are to shorten the time of healing and to avoid relapses. The aim of this study was to assess the efficacy of autologous platelet-rich plasma (PRP) in the healing of muscle injuries. MATERIALS AND METHODS: A multicentre, randomised, double-blind, parallel, controlled clinical trial was conducted in 71 patients (81.8% males) aged 45.6 (SD=10.0) years with muscle tears in the legs and haematoma. The haematoma was evacuated in all patients. Thirty-three patients were randomised to a single dose of autologous PRP and 38 patients to simulation of PRP administration. The primary end-point was time to complete recovery of muscle injury. Secondary end-points were pain, relapses, ultrasound parameters, and adverse events. The total follow-up per patient was 12 months. RESULTS: Time to complete recovery after the treatment was 31.63 days (SD=15.38) in the PRP group, and 38.43 days (SD=18.58) in the control group (p=0.261). Pain decreased over time in both groups without statistical differences between them. Eight patients relapsed (seven in the control group, and one in the PRP group). There were no adverse effects related to the interventions. DISCUSSION: Autologous PRP did not significantly improve the time to healing compared to that in the control group. PMID- 26509828 TI - Molecular screening of the Cw antigen for typing donors compatible with patients with anti-MAR-like antibodies. PMID- 26509829 TI - Health Care Reform's Unfinished Work--Remaining Barriers to Coverage and Access. PMID- 26509830 TI - HIV/AIDS in South Africa: how many people died from the disease between 1997 and 2010? AB - OBJECTIVES: Empirical estimates of the number of HIV/AIDS deaths are important for planning, budgeting, and calibrating models. However, there is an extensive misattribution of HIV/AIDS as an underlying cause-of-death. This study estimates the true numbers of AIDS deaths from South African vital statistics between 1997 and 2010. METHODS: Individual-level cause-of-death data were grouped according to a local burden of disease list and source causes (i.e. causes under which AIDS deaths are misclassified) that recorded a rapid increase. After adjusting for completeness of registration, the mortality rate of the source causes, by age and sex, was regressed on the lagged HIV prevalence to estimate the rate of increase correlated with HIV. Background trends in the source-cause mortality rates were estimated from the trend experienced among 75-84 year olds. RESULTS: Of 214 causes considered, 19 were identified as potential sources for cause misattribution. High proportions of deaths from tuberculosis, lower respiratory infections (mostly pneumonia), diarrhoeal diseases, and ill-defined natural causes were estimated to be HIV-related, with only 7% of the estimated AIDS deaths being recorded as HIV. Estimated HIV/AIDS deaths increased rapidly, then reversed after 2006, totalling 2.8 million deaths over the whole period. The number was lower than model estimates from Joint United Nations Programme on HIV/AIDS (UNAIDS) and the Global Burden of Disease Study. CONCLUSION: Empirically based estimates confirm the considerable loss of life from HIV/AIDS and should be used for calibrating models of the AIDS epidemic which generally appear too low for infants but too high for other ages. Doctors are urged to specify HIV on death notifications to provide reliable cause-of-death statistics. PMID- 26509831 TI - Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends. AB - The early effectiveness of combinatorial antiretroviral therapy (cART) in the treatment of HIV infection has been compromised to some extent by rapid development of multidrug-resistant HIV strains, poor bioavailability, and cumulative toxicities, and so there is a need for alternative strategies of antiretroviral drug discovery and additional therapeutic agents with novel action modes or targets. From this perspective, we first review current strategies of antiretroviral drug discovery and optimization, with the aid of selected examples from the recent literature. We highlight the development of phosphate ester-based prodrugs as a means to improve the aqueous solubility of HIV inhibitors, and the introduction of the substrate envelope hypothesis as a new approach for overcoming HIV drug resistance. Finally, we discuss future directions for research, including opportunities for exploitation of novel antiretroviral targets, and the strategy of activation of latent HIV reservoirs as a means to eradicate the virus. PMID- 26509832 TI - Gene Structures, Evolution, Classification and Expression Profiles of the Aquaporin Gene Family in Castor Bean (Ricinus communis L.). AB - Aquaporins (AQPs) are a class of integral membrane proteins that facilitate the passive transport of water and other small solutes across biological membranes. Castor bean (Ricinus communis L., Euphobiaceae), an important non-edible oilseed crop, is widely cultivated for industrial, medicinal and cosmetic purposes. Its recently available genome provides an opportunity to analyze specific gene families. In this study, a total of 37 full-length AQP genes were identified from the castor bean genome, which were assigned to five subfamilies, including 10 plasma membrane intrinsic proteins (PIPs), 9 tonoplast intrinsic proteins (TIPs), 8 NOD26-like intrinsic proteins (NIPs), 6 X intrinsic proteins (XIPs) and 4 small basic intrinsic proteins (SIPs) on the basis of sequence similarities. Functional prediction based on the analysis of the aromatic/arginine (ar/R) selectivity filter, Froger's positions and specificity-determining positions (SDPs) showed a remarkable difference in substrate specificity among subfamilies. Homology analysis supported the expression of all 37 RcAQP genes in at least one of examined tissues, e.g., root, leaf, flower, seed and endosperm. Furthermore, global expression profiles with deep transcriptome sequencing data revealed diverse expression patterns among various tissues. The current study presents the first genome-wide analysis of the AQP gene family in castor bean. Results obtained from this study provide valuable information for future functional analysis and utilization. PMID- 26509833 TI - Predictive factors for invasive cancer in surgical specimens following an initial diagnosis of ductal carcinoma in situ after stereotactic vacuum-assisted breast biopsy in microcalcification-only lesions. AB - PURPOSE: The aim of this study was to determine the incidence of invasive breast carcinoma in patients with preoperative diagnosis of ductal carcinoma in situ (DCIS) by stereotactic vacuum-assisted biopsy (SVAB) performed for microcalcification-only lesions, and to identify the predictive factors of invasion. METHODS: From 2000 to 2010, the records of 353 DCIS patients presenting with microcalcification-only lesions who underwent SVAB were retrospectively reviewed. The mammographic size of microcalcification cluster, presence of microinvasion within the cores, the total number of calcium specks, and the number of calcium specks within the retrieved core biopsy specimen were recorded. Patients were grouped as those with or without invasion in the final pathologic report, and variables were compared between the two groups. RESULTS: The median age was 58 years (range, 34-88 years). At histopathologic examination of the surgical specimen, 63 of 353 patients (17.8%) were found to have an invasive component, although SVAB cores had only shown DCIS preoperatively. The rate of underestimation was significantly higher in patients with microcalcification covering an area of 40 mm or more, in the presence of microinvasion at biopsy, and in cases where less than 40% of the calcium specks were removed from the lesion. CONCLUSION: Invasion might be underestimated in DCIS cases diagnosed with SVAB performed for microcalcification-only lesions, especially when the mammographic size of calcification is equal to or more than 40 mm or if microinvasion is found within the biopsy specimen and less than 40% of the calcifications are removed. At least 40% of microcalcification specks should be removed from the lesion to decrease the rate of underestimation with SVAB. PMID- 26509834 TI - The longitudinal effect of a multi-strain probiotic on the intestinal bacterial microbiota of neonatal foals. AB - REASONS FOR PERFORMING THE STUDY: The microbiota plays a key role in health and disease. Probiotics are a potential way to therapeutically modify the intestinal microbiota and prevent disease. OBJECTIVES: The aim of this study was to investigate the effects of probiotics on the bacterial microbiota of foals during and after administration. STUDY DESIGN: Randomised placebo controlled field trial. METHODS: Thirty-eight healthy neonatal foals enrolled in a previous study were selected. The foals had received a multi-strain probiotic (four Lactobacillus spp. 3-4 * 103 colony-forming units (cfu)/g each, Bifidobacterium animalis spp. lactis, 1 * 103-4 cfu/g) or placebo once daily for 3 weeks. A total of 3 faecal samples were collected from each foal at 2-week intervals and assessed via metagenomic sequencing. The Wilcoxon test was used to compare data between treatment groups. RESULTS: There were no changes on the phylum, order or class level between treatment groups at any age (all P>0.05) but some significant changes in relative abundance of families. Probiotic administration did not result in an increased relative abundance of lactobacilli or bifidobacteria at any age (Lactobacillus: P = 0.9, P = 0.1 and P = 0.2, Bifidobacterium: P = 0.3, P = 0.6 and P = 0.1 for Weeks 2, 4 and 6, respectively). Lactobacillus was enriched in the probiotic group at Week 6 on LEfSe analysis (linear discriminant analysis score 0.34, P = 0 .02). There was no effect on alpha diversity (all P>0.2) or community structure when parsimony and unifrac analysis were applied (all P>0.6). CONCLUSIONS: There were limited effects of probiotic treatment on the bacterial microbiota of foals. The studied probiotic based on lactobacilli and bifidobacteria has a limited potential for therapeutic modification of the gastrointestinal microbiota. PMID- 26509836 TI - From actomyosin oscillations to tissue-level deformations. AB - Pulsatile actomyosin contractility driving cell shape oscillations is a common feature of actomyosin networks present in a variety of tissues undergoing morphogenetic processes. The origin of this oscillatory dynamics, how it is stabilized over time to give rise to net cell shape changes and how it is spatially coordinated across a tissue, are questions that have being extensively investigated in recent years. In this work, I review how genetics, cell biology, and quantitative and theoretical approaches have started to give a comprehensive understanding of these problems revealing that both biochemical and mechanical regulation play an important role in the emergence, coordination and stabilization of this activity. PMID- 26509835 TI - Does Dietary Mitigation of Enteric Methane Production Affect Rumen Function and Animal Productivity in Dairy Cows? AB - It has been suggested that the rumen microbiome and rumen function might be disrupted if methane production in the rumen is decreased. Furthermore concerns have been voiced that geography and management might influence the underlying microbial population and hence the response of the rumen to mitigation strategies. Here we report the effect of the dietary additives: linseed oil and nitrate on methane emissions, rumen fermentation, and the rumen microbiome in two experiments from New Zealand (Dairy 1) and the UK (Dairy 2). Dairy 1 was a randomized block design with 18 multiparous lactating cows. Dairy 2 was a complete replicated 3 x 3 Latin Square using 6 rumen cannulated, lactating dairy cows. Treatments consisted of a control total mixed ration (TMR), supplementation with linseed oil (4% of feed DM) and supplementation with nitrate (2% of feed DM) in both experiments. Methane emissions were measured in open circuit respiration chambers and rumen samples were analyzed for rumen fermentation parameters and microbial population structure using qPCR and next generation sequencing (NGS). Supplementation with nitrate, but not linseed oil, decreased methane yield (g/kg DMI; P<0.02) and increased hydrogen (P<0.03) emissions in both experiments. Furthermore, the effect of nitrate on gaseous emissions was accompanied by an increased rumen acetate to propionate ratio and consistent changes in the rumen microbial populations including a decreased abundance of the main genus Prevotella and a decrease in archaeal mcrA (log10 copies/g rumen DM content). These results demonstrate that methane emissions can be significantly decreased with nitrate supplementation with only minor, but consistent, effects on the rumen microbial population and its function, with no evidence that the response to dietary additives differed due to geography and different underlying microbial populations. PMID- 26509837 TI - Visible-Light-Induced Decarboxylative Functionalization of Carboxylic Acids and Their Derivatives. AB - Visible-light-induced radical decarboxylative functionalization of carboxylic acids and their derivatives has recently received considerable attention as a novel and efficient method to create C?C and C?X bonds. Generally, this visible light-promoted decarboxylation process can smoothly occur under mild reaction conditions with a broad range of substrates and an excellent functional-group tolerance. The radical species formed from the decarboxylation step can participate in not only single photocatalytic transformations, but also dual catalytic cross-coupling reactions by combining photoredox catalysis with other catalytic processes. Recent advances in this research area are discussed herein. PMID- 26509838 TI - Potential national savings from prescribing guideline-recommended antibiotics for acute rhinosinusitis. PMID- 26509839 TI - Four-factor prothrombin complex concentrates in paediatric patients - a retrospective case series. AB - BACKGROUND: Four-factor prothrombin complex concentrates (PCCs) are human plasma derived products containing coagulation factors II, VII, IX and X as well as proteins C and S. They are licensed in many countries for treatment of bleeding or urgent periprocedural prophylaxis in patients with acquired deficiency of prothrombin complex coagulation factors, typically in the setting of vitamin K antagonist (VKA) usage. Efficacy and safety have been established in the adult population, but there is little information in the literature regarding their use for these indications in the paediatric population. We report on our institution's experience with these products in paediatric patients over a five year period. METHOD: A retrospective case series study was performed, whereby any patient aged 0-16 years who had received PCCs between 2009 and 2013 was identified. Details regarding patient demographics, indications, dose, relevant bloodwork, additional blood products used, adverse effects and general outcomes were obtained through chart and blood bank reviews. RESULTS: A total of sixteen patients were included in our study, fourteen of whom received PCCs in a perioperative setting. Eleven received product for VKA reversal. Significant improvements in PT INRs were observed in those patients who had timely bloodwork drawn. Five others received product for reasons not related to VKA use. One thrombotic event was detected a day following PCC infusion, but causation is uncertain. CONCLUSION: Within study limitations, when used for rapid reversal of VKAs, efficacy and safety of these products in a paediatric population appear to be similar to those reported in adults. PMID- 26509841 TI - Stacking Interactions Drive Selective Self-Assembly and Self-Sorting of Pyrene Based M(II)4L6 Architectures. AB - Subcomponent self-assembly of two isomeric bis(3-aminophenyl)pyrenes, 2 formylpyridine and the metal ions Fe(II), Co(II), and Zn(II) led to the formation of two previously unidentified structure types: a C2-symmetric M(II)4L6 assembly with meridionally coordinated metal centers, and a C3-symmetric self-included M(II)4L6 assembly with facially coordinated metal centers. In both structures the meta linkages within the ligands facilitate pi-stacking between the pyrene panels of the ligands. A C2h-symmetric M(II)2L2 box was also obtained, which was observed to selectively bind electron-deficient aromatic guests between two parallel pyrene subunits. Similar donor-acceptor interactions drove the selective self-assembly of a singular M(II)4L4L'2 architecture incorporating both a pyrene containing diamine and an electron-deficient NDI-based diamine. This heteroleptic architecture was shown to be thermodynamically favored over the corresponding homoleptic M(II)4L6 and M(II)4L'6 complexes, which were nonetheless stable in each others' absence. By contrast, an isomeric pyrene-based diamine was observed to undergo narcissistic self-sorting in the presence of the NDI-based diamine. PMID- 26509840 TI - Long Withdrawal of Methylphenidate Induces a Differential Response of the Dopaminergic System and Increases Sensitivity to Cocaine in the Prefrontal Cortex of Spontaneously Hypertensive Rats. AB - Methylphenidate (MPD) is one of the most prescribed drugs for alleviating the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). However, changes in the molecular mechanisms related to MPD withdrawal and susceptibility to consumption of other psychostimulants in normal individuals or individuals with ADHD phenotype are not completely understood. The aims of the present study were: (i) to characterize the molecular differences in the prefrontal dopaminergic system of SHR and Wistar strains, (ii) to establish the neurochemical consequences of short- (24 hours) and long-term (10 days) MPD withdrawal after a subchronic treatment (30 days) with Ritalin(r) (Methylphenidate Hydrochloride; 2.5 mg/kg orally), (iii) to investigate the dopaminergic synaptic functionality after a cocaine challenge in adult MPD-withdrawn SHR and Wistar rats. Our results indicate that SHR rats present reduced [3H]-Dopamine uptake and cAMP accumulation in the prefrontal cortex (PFC) and are not responsive to dopaminergic stimuli in when compared to Wistar rats. After a 24-hour withdrawal of MPD, SHR did not present any alterations in [3H]-Dopamine Uptake, [3H]-SCH 23390 binding and cAMP production; nonetheless, after a 10-day MPD withdrawal, the results showed a significant increase of [3H]-Dopamine uptake, of the quantity of [3H]-SCH 23390 binding sites and of cAMP levels in these animals. Finally, SHR that underwent a 10-day MPD withdrawal and were challenged with cocaine (10 mg/kg i.p.) presented reduced [3H]-Dopamine uptake and increased cAMP production. Wistar rats were affected by the 10-day withdrawal of MPD in [3H]-dopamine uptake but not in cAMP accumulation; in addition, cocaine was unable to induce significant modifications in [3H]-dopamine uptake and in cAMP levels after the 10-day withdrawal of MPD. These results indicate a mechanism that could explain the high comorbidity between ADHD adolescent patients under methylphenidate treatment and substance abuse in adult life. PMID- 26509842 TI - Analysis of Behavioral and Emotional Problems in Children Highlights the Role of Genotype * Environment Interaction. AB - This study tested for Genotype * Environment (G * E) interaction on behavioral and emotional problems in children using new methods that do not require identification of candidate genes or environments, can distinguish between interaction with shared and unique environment, and are insensitive to scale effects. Parental ratings of problem behavior from 14,755 twin pairs (5.3 years, SD = 0.22) indicated G * E interaction on emotional liability, social isolation, aggression, attention problems, dependency, anxiety, and physical coordination. Environmental influences increased in children who were genetically more predisposed to problem behavior, with ~20% of the variance due to G * E interaction (8% for anxiety to 37% for attention problems). Ignoring G * E interaction does not greatly bias heritability estimates, but it does offer a comprehensive model of the etiology for childhood problems. PMID- 26509843 TI - The past, present, and future of basal insulins. AB - Insulin production by the pancreas follows a basic pattern where basal levels of insulin are secreted during fasting periods, with prandial increases in insulin associated with food ingestion. The aim of insulin therapy in patients with diabetes is to match the endogenous pattern of insulin secretion as closely as possible without causing hypoglycaemia. There are several optimal pharmacokinetic and pharmacodynamic properties of long-acting basal insulins that can help to achieve this aim, namely, as follows: activity that is flat and as free of peaks as possible, a duration of action of >=24-h, and as little day-to-day variation as possible. The long-acting basal insulins are a fundamental therapy for patients with type 1 and type 2 diabetes, and those that are currently available have many benefits; however, the development of even longer-acting insulins and improved insulin delivery techniques may lead to better glycemic control for patients in the future. Established long-acting basal insulins available in the United States and Europe include insulin glargine 100 units/mL and insulin detemir, both of which exhibit similar glycemic control to that of the intermediate-acting neutral protamine Hagedorn insulin, but with a reduction in hypoglycaemia. Newer insulin products available include new insulin glargine 300 units/mL (United States and Europe) and the ultra-long-acting insulin degludec (Europe) with basal insulin peglispro currently in development. These new insulins demonstrate different pharmacokinetic/pharmacodynamic profiles and longer durations of action (>24 h) compared with insulin glargine 100 units/mL, which may lead to potential benefits. The introduction of biosimilar insulins may also broaden access to insulins by reducing treatment costs. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26509847 TI - An investigation of new infrared nonlinear optical material: BaCdSnSe4, and three new related centrosymmetric compounds: Ba2SnSe4, Mg2GeSe4, and Ba2Ge2S6. AB - A series of new metal chalcongenides, BaCdSnSe4 (1), Ba2SnSe4 (2), Mg2GeSe4 (3), and Ba2Ge2S6 (4), were successfully synthesized for the first time. Among them, compounds 2 and 4 were prepared by a molten flux method with Zn as the flux. In their structures, all of them have MQ4 (M = Sn, Ge; Q = S, Se) units. For compound 1, the CdSe4 and SnSe4 groups are connected to form CdSnSe6 layers and these layers are linked together by the Ba atoms. Compounds 2 and 3 are composed of isolated MSe4 (M = Sn, Ge) units and charge-balanced by the Ba or Mg atoms, respectively, while compound 4 has infinite infinity(GeS3)n chains, which is different from the structures of the other three compounds that only have isolated MSe4 (M = Sn, Ge) units. The measured IR and Raman data of the title compounds show wide infrared transmission ranges. The experimental band gaps of compounds 1, 2, 3 and were determined to be 1.79, 1.90, and 2.02 eV, respectively. Band structures were also calculated and indicate that their tetrahedral units, such as [SnSe4], [GeS4] and [GeSe4], determine the energy band gaps of the title compounds, respectively. As for compound 1, based on fundamental light at 2.09 MUm, the experimental second harmonic generation (SHG) response is about 1.6 times that of the benchmark AgGaS2, which is also consistent with the calculated value. Based on the above results, compound 1 has promising applications in the IR field as a NLO material. PMID- 26509846 TI - Free-breathing variable flip angle balanced SSFP cardiac cine imaging with reduced SAR at 3T. AB - PURPOSE: To develop a free-breathing variable flip angle (VFA) balanced steady state free precession (bSSFP) cardiac cine imaging technique with reduced specific absorption rate (SAR) at 3 Tesla. METHODS: Free-breathing VFA (FB-VFA) images in the short-axis and four-chamber views were acquired using an optimal VFA scheme, then compared with conventional breath-hold constant flip angle (BH CFA) acquisitions. Two cardiac MRI experts used a 5-point scale to score images from healthy subjects (N = 10). The left ventricular ejection fraction, end diastolic volume (LVEDV), end systolic volume, stroke volume (LVSV), and end diastolic myocardial mass (LVEDM) were determined by manual contour analysis for BH-CFA and FB-VFA. A pilot evaluation of FB-VFA was performed in one patient with Duchenne muscular dystrophy. RESULTS: FB-VFA SAR was 25% lower than BH-CFA with similar blood-myocardium contrast. The qualitative FB-VFA score was lower than the BH-CFA for the short-axis (3.1 +/- 0.5 versus 4.3 +/- 0.8; P < 0.05) and the four-chamber view (3.4 +/- 0.4 versus 4.6 +/- 0.6; P < 0.05). The LVEDV and the LVSV were 5% and 12% larger (P < 0.05) for FB-VFA compared with BH-CFA. There was no difference in LVEDM. CONCLUSION: FB-VFA bSSFP cardiac cine imaging decreased the SAR at 3T with image quality sufficient to perform cardiac functional analysis. Magn Reson Med 76:1210-1216, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26509844 TI - Radiotherapy planning using MRI. AB - The use of magnetic resonance imaging (MRI) in radiotherapy (RT) planning is rapidly expanding. We review the wide range of image contrast mechanisms available to MRI and the way they are exploited for RT planning. However a number of challenges are also considered: the requirements that MR images are acquired in the RT treatment position, that they are geometrically accurate, that effects of patient motion during the scan are minimized, that tissue markers are clearly demonstrated, that an estimate of electron density can be obtained. These issues are discussed in detail, prior to the consideration of a number of specific clinical applications. This is followed by a brief discussion on the development of real-time MRI-guided RT. PMID- 26509848 TI - Glucose-Responsive Hybrid Nanoassemblies in Aqueous Solutions: Ordered Phenylboronic Acid within Intermixed Poly(4-hydroxystyrene)-block-poly(ethylene oxide) Block Copolymer. AB - Coassembly behavior of the double hydrophilic block copolymer poly(4 hydroxystyrene)-block-poly(ethylene oxide) (PHOS-PEO) with three amphiphilic phenylboronic acids (PBA) differing in hydrophobicity, 4-dodecyloxyphenylboronic acid (C12), 4-octyloxyphenylboronic acid (C8), and 4-isobutoxyphenylboronic acid (i-Bu) was studied in alkaline aqueous solutions and in mixtures of NaOHaq/THF by spin-echo (1)H NMR spectroscopy, dynamic and electrophoretic light scattering, and SAXS. The study reveals that only the coassembly of C12 with PHOS-PEO provides spherical nanoparticles with intermixed PHOS and PEO blocks, containing densely packed C12 micelles. NMR measurements have shown that spatial proximity of PHOS-PEO and C12 leads to the formation of ester bonds between -OH of PHOS block and hydroxyl groups of -B(OH)2. Due to the presence of PBA moieties, the release of compounds with 1,2- or 1,3-dihydroxy groups loaded in the coassembled PHOS-PEO/PBA nanoparticles by covalent binding to PBA can be triggered by addition of a surplus of glucose that bind to PBA competitively. The latter feature has been confirmed by fluorescence measurements using Alizarin Red as a model compound. Nanoparticles were proved to exhibit swelling in response to glucose as detected by light scattering. PMID- 26509849 TI - Staging Lymphadenectomy in Patients With Clear Cell Carcinoma of the Ovary. AB - OBJECTIVE: The purpose of this study was to assess the rate of lymph node (LN) metastasis in comprehensively staged ovarian clear cell carcinoma (OCCC) clinically confined to the ovary and determine factors associated with LN metastasis. METHODS: We identified all cases of OCCC treated at 4 institutions from January 1994 through December 2011. We included cases with disease grossly confined to the ovary that had surgical staging performed, including at least 10 LNs sampled. Clinical and pathologic data were abstracted from electronic medical records, and a deidentified data set was compiled and processed at a single institution. Factors potentially associated with LN metastasis were tested. Appropriate statistical tests were performed. RESULTS: We identified 145 eligible cases that met the criteria for this analysis. Median age was 52.9 years (range, 30-81 years), and median total LN count was 19 (range, 10-74). Seven (4.8%) of 145 comprehensively staged cases had LN metastasis; 6 of these cases (4.1%) were isolated metastasis. Cytologic washings, peritoneal, omental, and fallopian tube involvement were not associated with nodal metastasis. Cases with ovarian surface involvement and positive cytology had a 37.5% incidence of LN positivity, which was statistically meaningful when compared with all other cases (P = 0.003). CONCLUSIONS: Women who underwent comprehensive staging for clinical stage I OCCC had an LN metastasis rate of 4.8%. The subgroup of cases with both ovarian surface involvement and positive cytology had the highest incidence of LN metastasis. This may influence clinical decision making on whether to perform lymphadenectomy in patients with incidental OCCC found after salpingo oophorectomy. PMID- 26509850 TI - The Impact of Adjuvant Therapy on Survival and Recurrence Patterns in Women With Early-Stage Uterine Carcinosarcoma: A Multi-institutional Study. AB - OBJECTIVE: The aim of the study was to characterize the impact of adjuvant therapy on survival in women with stage I/II uterine carcinosarcoma after primary surgery. METHODS: We reviewed records of 118 consecutively treated women with 2009 International Federation of Gynecology and Obstetrics stage I/II uterine carcinosarcoma who underwent hysterectomy between 1990 and 2014 at 4 academic institutions. Patients were categorized by adjuvant treatment group into observation, chemotherapy only, radiation only, and combined chemotherapy and radiation. Survival analyses were conducted using Kaplan-Meier and Cox proportional hazards models. RESULTS: Median follow-up was 28 months (range, 1 244 months). Lymphadenectomy was performed in 94 patients (80%). Postoperative management included observation (n = 37 [31%]), chemotherapy alone (n = 19 [16%]), radiation therapy (RT) alone (n = 24 [20%]), and combined RT and chemotherapy (n = 38 [32%]). Radiation therapy modality included vaginal brachytherapy in 22 patients, pelvic external beam RT in 21 patients, and combination in 19 patients. In 58% of women, chemotherapy consisted of carboplatin/paclitaxel. Median overall survival for all women was 97 months. On univariate analysis, adjuvant treatment group was associated with improved overall survival (hazard ratio [HR], 0.74; confidence interval [CI], 0.58-0.96; p = 0.02), freedom from vaginal recurrence (HR, 0.55; CI, 0.37-0.82]; p = 0.004), and freedom from any recurrence (HR, 0.70; CI, 0.54-0.92; p = 0.01). Pairwise comparisons demonstrated a significant benefit to chemoradiation over other adjuvant treatments. Adjuvant treatment group remained a significant covariate for all 3 end points on multivariate analysis as well. In addition, lymphadenectomy improved overall survival on multivariate analysis (HR, 0.24; CI, 0.09-0.61; p = 0.003). Of patients under observation only who had a recurrence, 8 (44%) of 18 had a recurrence in the vagina as the sole site of recurrence. By contrast, of women who received vaginal brachytherapy, significantly fewer had a recurrence in the vagina (1/42 [2.3%]; p < 0.003, log-rank test). CONCLUSIONS: In women with early-stage uterine carcinosarcoma, our data suggest superior survival end points with combined RT and chemotherapy. The frequency of vaginal recurrence suggests a role for incorporating vaginal brachytherapy in the adjuvant management of this disease. PMID- 26509851 TI - Impact of Hematopoietic Growth Factors on Blood Transfusion Needs, Incidence of Neutropenia, and Overall Survival Among Elderly Advanced Ovarian Cancer Patients Treated With Chemotherapy. AB - OBJECTIVE: To determine the effectiveness of erythropoietin-stimulating agent (ESA) and granulocyte colony-stimulating factor (CSF) in reducing blood transfusion needs and neutropenia incidence in community-dwelling elderly ovarian cancer patients. METHODS: The SEER (Surveillance Epidemiology and End Results) Medicare database was used to identify 5572 women with stage III/IV ovarian cancer who received chemotherapy. To assess clinical effectiveness, we categorized patients based on the number of administrations of ESA (ie, epoetin alfa and darbepoetin-alfa) and CSF (ie, filgrastim and pegfilgrastim). To evaluate effect on survival, patients were categorized as receiving ESA only, CSF only, ESA + CSF, and no ESA/CSF. RESULTS: Two thirds of patients received growth factor support (24% ESA only, 13% CSF only, 30% ESA + CSF). Depending on the number of epoetin-alfa administrations, ESA was associated with 48% to 56% lower need for blood transfusion compared with no ESA (hazard ratio for 1-3 claims, 0.47; 4-6 claims, 0.52; 7-10 claims, 0.48; >=11 claims, 0.44). Patients who received at least 3 prophylactic filgrastim administrations had 71% to 98% lower risk of developing neutropenia (hazard ratio for 3-4 claims, 0.29; >=5 claims, 0.02) compared with those without CSF. Effectiveness was comparable for darbepoetin-alfa and pegfilgrastim use. Overall survival was longer in those who received CSF only; however, the risk of mortality after 24 months was higher in those who received ESA (P = 0.0005). All models were adjusted for relevant covariates. CONCLUSIONS: Erythropoietin-stimulating agents were effective in reducing blood transfusion need. Granulocyte colony-stimulating factors were effective in lowering neutropenia incidence and also were associated with improved survival in elderly ovarian cancer patients. Findings are consistent with clinical trials and clinical guidelines. PMID- 26509852 TI - Factors Affecting Short-term Mortality in Women With Ovarian, Tubal, or Primary Peritoneal Cancer: Population-Based Cohort Analysis of English National Cancer Registration Data. AB - OBJECTIVE: International studies show lower survival rates in the United Kingdom than other countries with comparable health care systems. We report on factors associated with excess mortality in the first year after diagnosis of primary invasive epithelial ovarian, tubal, and primary peritoneal cancer. METHODS: Routinely collected national data were used for patients diagnosed in England in 2008 to 2010. A multivariate Poisson model was used to model excess mortality in 3 periods covering the first year after diagnosis, adjusting for various factors including age at diagnosis, route to diagnosis, tumor stage, tumor morphology, and treatment received. RESULTS: Of 14,827 women diagnosed as having ovarian cancer, 5296 (36%) died in the first year, with 1673 deaths in the first month after diagnosis. Age older than 70 years, diagnosis after an emergency presentation or by an unknown route, and unspecified or unclassified epithelial morphologies were strongly and independently associated with excess mortality in the first year after diagnosis. Of the 2100 (14%) women who fulfilled all 3 criteria, 1553 (74%) did not receive any treatment and 1774 (85%) died in the first year after diagnosis. In contrast, only 193 (4%) of the 4414 women without any of these characteristics did not receive any treatment, and only 427 (9%) died in the first year after diagnosis. CONCLUSIONS: Although our results are based on data from England, they are likely to have implications for cancer care pathways worldwide because most of the identified factors are not specific to the UK health care system. Our results suggest the need to increase symptom awareness, promote timely general practitioner referral, and optimize diagnostic and early treatment pathways within secondary care to increase access to treatment for women with advanced-stage invasive epithelial ovarian, tubal, and primary peritoneal cancer. This process should be pursued alongside continued efforts to develop primary prevention and screening strategies. PMID- 26509853 TI - An Electrically Driven and Readable Molecular Monolayer Switch Based on a Solid Electrolyte. AB - The potential application of molecular switches as active elements in information storage has been demonstrated through numerous works. Importantly, such switching capabilities have also been reported for self-assembled monolayers (SAMs). SAMs of electroactive molecules have recently been exploited as electrochemical switches. Typically, the state of these switches could be read out through their optical and/or magnetic response. These output reading processes are difficult to integrate into devices, and furthermore, there is a need to use liquid environments for switching the redox-active molecular systems. In this work, both of these challenges were overcome by using an ionic gel as the electrolyte medium, which led to an unprecedented solid-state device based on a single molecular layer. Moreover, electrochemical impedance has been successfully exploited as the output of the system. PMID- 26509854 TI - Effects of Anxiety and Depression on Arterial Elasticity of Subjects With Suboptimal Physical Health. AB - BACKGROUND: The authors investigated the effects of suboptimal health status (SHS; high-normal blood pressure, blood glucose, and blood lipids) on arterial elasticity in subjects with or without anxiety or depression. HYPOTHESIS: Suboptimal physical health status and anxiety or depression increase the risk of cardiovascular diseases. METHODS: This was a cross-sectional, observational, multicenter study. Among 1520 subjects who underwent physical examination between May 2009 and December 2012 in Beijing and Chongqing, China, 955 were included. All subjects completed anxiety and depression questionnaires. Systemic vascular compliance (SVC), systemic vascular resistance, and brachial artery distensibility (BAD) were measured during arterial elasticity evaluation. RESULTS: Of 955 participants, 633 were classified as having SHS and 322 were classified as healthy. Systemic vascular compliance and BAD were worse in SHS subjects than in healthy subjects (SVC: 1.23 +/- 0.22 vs 1.29 +/- 0.25 mL/mm Hg; BAD: 6.26 +/- 1.32 vs 6.61 +/- 1.24%/mm Hg, respectively; both P < 0.05). Of 955 subjects, 37.7% and 43.9% had anxiety and depression, respectively. Systemic vascular compliance and BAD in SHS subjects with concomitant anxiety or depression were significantly lower than in SHS subjects without anxiety or depression (SVC: 1.22 +/- 0.23 vs 1.23 +/- 0.20 mL/mm Hg; BAD: 6.10 +/- 1.36 vs 6.33 +/- 1.20 %/mm Hg, respectively; both P < 0.05) and even lower than in healthy subjects. CONCLUSIONS: Though anxiety and depression had less impact on arterial elasticity in a healthy population, they may be involved in pathogenesis of vascular damage in the population with SHS. PMID- 26509855 TI - AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME--PART 1. AB - Polycystic Ovary Syndrome (PCOS) is recognized as the most common endocrine disorder of reproductive-aged women around the world. This document, produced by the collaboration of the American Association of Clinical Endocrinologists (AACE) and the Androgen Excess and PCOS Society (AES) aims to highlight the most important clinical issues confronting physicians and their patients with PCOS. It is a summary of current best practices in 2015. PCOS has been defined using various criteria, including menstrual irregularity, hyperandrogenism, and polycystic ovary morphology (PCOM). General agreement exists among specialty society guidelines that the diagnosis of PCOS must be based on the presence of at least two of the following three criteria: chronic anovulation, hyperandrogenism (clinical or biological) and polycystic ovaries. There is need for careful clinical assessment of women's history, physical examination, and laboratory evaluation, emphasizing the accuracy and validity of the methodology used for both biochemical measurements and ovarian imaging. Free testosterone (T) levels are more sensitive than the measurement of total T for establishing the existence of androgen excess and should be ideally determined through equilibrium dialysis techniques. Value of measuring levels of androgens other than T in patients with PCOS is relatively low. New ultrasound machines allow diagnosis of PCOM in patients having at least 25 small follicles (2 to 9 mm) in the whole ovary. Ovarian size at 10 mL remains the threshold between normal and increased ovary size. Serum 17-hydroxyprogesterone and anti-Mullerian hormone are useful for determining a diagnosis of PCOS. Correct diagnosis of PCOS impacts on the likelihood of associated metabolic and cardiovascular risks and leads to appropriate intervention, depending upon the woman's age, reproductive status, and her own concerns. The management of women with PCOS should include reproductive function, as well as the care of hirsutism, alopecia, and acne. Cycle length >35 days suggests chronic anovulation, but cycle length slightly longer than normal (32 to 35 days) or slightly irregular (32 to 35-36 days) needs assessment for ovulatory dysfunction. Ovulatory dysfunction is associated with increased prevalence of endometrial hyperplasia and endometrial cancer, in addition to infertility. In PCOS, hirsutism develops gradually and intensifies with weight gain. In the neoplastic virilizing states, hirsutism is of rapid onset, usually associated with clitoromegaly and oligomenorrhea. Girls with severe acne or acne resistant to oral and topical agents, including isotretinoin (Accutane), may have a 40% likelihood of developing PCOS. Hair loss patterns are variable in women with hyperandrogenemia, typically the vertex, crown or diffuse pattern, whereas women with more severe hyperandrogenemia may see bitemporal hair loss and loss of the frontal hairline. Oral contraceptives (OCPs) can effectively lower androgens and block the effect of androgens via suppression of ovarian androgen production and by increasing sex hormone-binding globulin. Physiologic doses of dexamethasone or prednisone can directly lower adrenal androgen output. Anti-androgens can be used to block the effects of androgen in the pilosebaceous unit or in the hair follicle. Anti-androgen therapy works through competitive antagonism of the androgen receptor (spironolactone, cyproterone acetate, flutamide) or inhibition of 5alpha-reductase (finasteride) to prevent the conversion of T to its more potent form, 5alpha-dihydrotestosterone. The choice of antiandrogen therapy is guided by symptoms. The diagnosis of PCOS in adolescents is particularly challenging given significant age and developmental issues in this group. Management of infertility in women with PCOS requires an understanding of the pathophysiology of anovulation as well as currently available treatments. Many features of PCOS, including acne, menstrual irregularities, and hyperinsulinemia, are common in normal puberty. Menstrual irregularities with anovulatory cycles and varied cycle length are common due to the immaturity of the hypothalamic-pituitary-ovarian axis in the 2- to 3-year time period post-menarche. Persistent oligomenorrhea 2 to 3 years beyond menarche predicts ongoing menstrual irregularities and greater likelihood of underlying ovarian or adrenal dysfunction. In adolescent girls, large, multicystic ovaries are a common finding, so ultrasound is not a first-line investigation in women <17 years of age. Ovarian dysfunction in adolescents should be based on oligomenorrhea and/or biochemical evidence of oligo/anovulation, but there are major limitations to the sensitivity of T assays in ranges applicable to young girls. Metformin is commonly used in young girls and adolescents with PCOS as first-line monotherapy or in combination with OCPs and anti-androgen medications. In lean adolescent girls, a dose as low as 850 mg daily may be effective at reducing PCOS symptoms; in overweight and obese adolescents, dose escalation to 1.5 to 2.5 g daily is likely required. Anti-androgen therapy in adolescents could affect bone mass, although available short-term data suggest no effect on bone loss. PMID- 26509856 TI - COMBINING CREATININE-BASED eGFR WITH CYSTATIN C-BASED EGFR TO BETTER ASSESS RENAL FUNCTION IN PATIENTS WITH DIABETES AND CHRONIC KIDNEY DISEASE 3A: IMPLICATIONS FOR DRUG SELECTION AND DOSAGE IN TYPE 2 DIABETES. PMID- 26509857 TI - The therapeutic potential of exercise to treat cachexia. AB - PURPOSE OF REVIEW: To discuss the role of physical exercise in the attenuation of cancer cachexia-associated symptoms, and upon the outcome of chemotherapy, with special focus on the anti-inflammatory role of chronic exercise. RECENT FINDINGS: The review addresses the recent findings regarding the positive effects of endurance and strength exercise training upon metabolic dysfunction, systemic inflammation and body composition alterations in the syndrome of cachexia. The employment of different exercise protocol strategies, in respect to intensity, duration, work load and in concomitance with pharmacological treatment is considered. SUMMARY: Cachexia is a multifactorial wasting syndrome afflicting patients with cancer, chronic obstructive pulmonary disease, chronic heart failure, trauma, among other diseases. This condition markedly compromises the quality of life, treatment outcome and survival. Recent literature indicates an unequivocal role of chronic exercise in modulating cachexia and other cancer associated dysfunctions. Exercise is proposed as a complementary treatment in cancer, and represents a function-preserving, anti-inflammatory and metabolism modulating strategy with low cost, and high versatility and availability. Furthermore, exercise decreases cancer recurrence and presents a positive impact on public health management, reducing hospitalization and medication costs. PMID- 26509858 TI - Patient-reported outcomes in cancer cachexia clinical trials. AB - PURPOSE OF REVIEW: Patient-reported outcome (PRO) measures should be used when measuring concepts best known to the patient. To maximize the translation of findings into clinical practice, PRO measures that are most relevant for the patient group, should be used and careful reporting of the PRO results is required. The study reviews the use of PRO assessments in cancer cachexia randomized controlled trials. RECENT FINDINGS: Most, but not all, recent cancer cachexia randomized controlled trials include PRO measures, and significant informative results have been found. PRO measures are rarely the primary endpoint. Most frequently, health -related quality of life and/or symptoms are assessed. However, instruments which are not cancer cachexia-specific are often used. Reporting of PRO data is generally poor. SUMMARY: Patient-centred care cannot be delivered without patient-centred outcome information and the assessment of the efficacy of interventions is partly determined by whether there is a measurable perceived patient benefit. To improve the chance of finding significant and useful results, investigators should use cancer cachexia-specific instruments and report their studies carefully. PMID- 26509859 TI - Multimodal management as requirement for the clinical use of anticachexia drugs - a regulatory and a clinical perspective. AB - PURPOSE OF REVIEW: Multimodal management has been proposed as key to any effective drug intervention in cachexia. This article attempts to reflect on clinical and regulatory considerations of multimodal management treatment as a regulatory requirement in anticachexia drug therapy. To date, no European Union (EU) regulatory guidelines have been published and therefore this review could attempt to present and discuss some central issues to consider when developing an anticachexia drug. RECENT FINDINGS: The following themes are considered: EU regulatory pathways for drug approval (conditional and exceptional circumstances as well as adaptive licensing); selection criteria for randomized clinical trials allowing the identification and characterization of the population of interest that is an at-risk population with undisputable clinical need; issues related to primary and secondary outcome measures that are adequate to determine the efficacy of the intervention and the approach for the development of clinical biomarkers for cachexia. SUMMARY: Conversely, the incorporation of multimodal treatment in anticachexia drug therapy is expected to increase the effectiveness of intervention. This aspect is the aspect that appeals to pharmaceutical companies; however, at the same time, this raises regulatory and clinical issues that need to be kept in mind when designing randomised clinical trials. PMID- 26509861 TI - Evaluation tools for spiritual support in end of life care: increasing evidence for their clinical application. AB - PURPOSE OF REVIEW: To summarize current evidence on evaluation tools for spiritual care, paying special attention to recent validations and new instruments, systematic reviews, recent consensus on spiritual care and its measurement, plus other emergent topics. RECENT FINDINGS: The systematic review resulted in 45 identified studies, 14 of which were considered: five works addressed the need for development and validation of spiritual tools; three studies reviewed tools for spirituality assessment, interventions, or related concepts; three more covered the efforts to define guidelines and priorities for spiritual care and its measurement. Other topics such as pediatric spiritual care, the use of new technologies, or nationwide surveys, also arose. SUMMARY: Recent contributions outline usability traits such as to shorten scales and measurement protocols for maximum respect of patients' quality of life. Other works addressed complicated grief or satisfaction with attention to spiritual care, transcending the patients, family and professionals' focus in on a sort of combined perspective. Further attention to culturally based specific models supporting questionnaires, a deeper understanding of quality of the spiritual care, both for patients and families, or further research on the relation between spiritual care and life span should be welcomed. PMID- 26509860 TI - The last days of life: symptom burden and impact on nutrition and hydration in cancer patients. AB - PURPOSE OF REVIEW: To examine the symptom burden in cancer patients during the last days of life, its impact on nutrition and hydration, and the role of artificial nutrition and hydration in the final days. RECENT FINDINGS: During the last days of life, cancer patients often experience progressive functional decline and worsening symptom burden. Many symptoms such as anorexia-cachexia, dysphagia, and delirium could impair oral intake. These, coupled with refractory cachexia, contribute to persistent weight loss and decreased quality of life. Furthermore, the inability to eat/drink and body image changes can result in emotional distress for patients and caregivers. Clinicians caring for these individuals need to ensure longitudinal communication about goals of care, education about the natural process of dying, optimization of symptom management, and provide appropriate emotional support for patients and caregivers. There is a lack of evidence to support that artificial nutrition and hydration can improve outcomes during the last days of life. Artificial nutrition is not recommended because of its invasive nature, whereas artificial hydration may be considered on a case-by-case basis. SUMMARY: This review highlights the need to conduct further research on symptom burden, nutrition, and hydration during the last days of life. PMID- 26509862 TI - Unexpected death in palliative care: what to expect when you are not expecting. AB - PURPOSE OF REVIEW: Death is a certainty in life. Yet, the timing of death is often uncertain. When death occurs suddenly and earlier than anticipated, it is considered as an unexpected death. In this article, we shall discuss when is death expected and unexpected, and review the frequency, impact, causes, and approach to unexpected death in the palliative care setting. RECENT FINDINGS: Even in the palliative care setting in which death is relatively common, up to 5% of deaths in hospice and 10% of deaths in palliative care units were considered to be unexpected. Unexpected death has significant impact on care, including unrealized dreams and unfinished business among patients, a sense of uneasiness and complicated bereavement among caregivers, and uncertainty in decision making among healthcare providers. Clinicians may minimize the impact of unexpected events by improving their accuracy of prognostication, communicating the uncertainty with patients and families, and helping them to expect the unexpected by actively planning ahead. Furthermore, because of the emotional impact of unexpected death on bereaved caregivers, clinicians should provide close monitoring and offer prompt treatment for complicated grief. SUMMARY: Further research is needed to understand how we can better predict and address unexpected events. PMID- 26509864 TI - Cutaneous Vasculopathy as an Adverse Effect of the Anti-Vascular Endothelial Growth Factor Agent Axitinib. PMID- 26509867 TI - Ion pairing in ionic liquids. AB - In the present article we briefly review the extensive discussion in literature about the presence or absence of ion pair-like aggregates in ionic liquids. While some experimental studies point towards the presence of neutral subunits in ionic liquids, many other experiments cannot confirm or even contradict their existence. Ion pairs can be detected directly in the gas phase, but no direct method is available to observe such association behavior in the liquid, and the corresponding indirect experimental proofs are based on such assumptions as unity charges at the ions. However, we have shown by calculating ionic liquid clusters of different sizes that assuming unity charges for ILs is erroneous, because a substantial charge transfer is taking place between the ionic liquid ions that reduce their total charge. Considering these effects might establish a bridge between the contradicting experimental results on this matter. Beside these results, according to molecular dynamics simulations the lifetimes of ion-ion contacts and their joint motions are far too short to verify the existence of neutral units in these materials. PMID- 26509865 TI - Do TFSA Anions Slither? Pressure Exposes the Role of TFSA Conformational Exchange in Self-Diffusion. AB - Multinuclear ((1)H, (2)H, and (19)F) magnetic resonance spectroscopy techniques as functions of temperature and pressure were applied to the study of selectively deuterated 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide (EMIM TFSA) ionic liquid isotopologues and related ionic liquids. For EMIM TFSA, temperature-dependent (2)H T1 data indicate stronger electric field gradients in the alkyl chain region compared to the imidazolium ring. Most significantly, the pressure dependences of the EMIM and TFSA self-diffusion coefficients revealed that the displacements of the cations and anions are independent, with diffusion of the TFSA anions being slowed much more by increasing pressure than for the EMIM cations, as shown by their respective activation volumes (28.8 +/- 2.5 cm(3)/mol for TFSA vs 14.6 +/- 1.3 cm(3)/mol for EMIM). Increasing pressure may lower the mobility of the TFSA anion by hindering its interconversion between trans and cis conformers, a process that is coupled to diffusion according to published molecular dynamics simulations. Measured activation volumes (DeltaV(?)) for ion self-diffusion in EMIM bis(fluoromethylsulfonyl)amide and EMIM tetrafluoroborate support this hypothesis. In addition, (2)H T1 data suggest increased ordering with increasing pressure, with two T1 regimes observed for the MD3 and D2 isotopologues between 0.1-100 and 100-250 MPa, respectively. The activation volumes for T1 were 21 and 25 cm(3)/mol (0-100 MPa) and 11 and 12 cm(3)/mol (100-250 MPa) for the MD3 and D2 isotopologues, respectively. PMID- 26509868 TI - Microbiological Quality of Raw Dried Pasta from the German Market, with Special Emphasis on Cronobacter Species. AB - The microbiological quality of 132 dried pasta products available on the German market, originating from 11 different countries, was studied. Sample materials included soft or durum wheat products, some of which produced with other ingredients such as eggs, spices, or vegetables. Parameters included hygiene indicators (aerobic plate count, mold count, the presence of Enterobacteriaceae) and pathogenic/toxinogenic bacterial species (Salmonella spp., Staphylococcus aureus, presumptive Bacillus cereus, and Cronobacter spp.). The overall results of hygiene parameters indicated a satisfactory quality. Salmonella was not found in any sample. Three samples were positive for S. aureus (10(2) to 10(4) colony forming unit (CFU)/g). Presumptive B. cereus at levels of 10(3) to 10(4) CFU/g were detected in 3 samples. Cronobacter spp. were isolated from 14 (10.6%) products. Of these, 9 isolates were identified as C. sakazakii, 2 each as C. turicensis and C. malonaticus, and 1 as C. muytjensii. The isolates were assigned to 9 multilocus sequence typing (MLST) sequence types and to 14 different PFGE profiles. Although pasta products are typically cooked before consumption, some consumers, and children in particular, may also eat raw pasta as nibbles. Raw pasta seems to be a relevant source of exposure to dietary Cronobacter spp., although health risks are probably restricted to vulnerable consumers. High numbers of presumptive B. cereus as found in some samples may be a risk after improper storage of cooked pasta products because toxinogenic strains are frequently found within this species. PMID- 26509869 TI - Factors Associated With Change in 25-Hydroxyvitamin D Levels Over Longitudinal Follow-Up in the ARIC Study. AB - CONTEXT: A single measurement of 25-hydroxyvitamin D (25 [OH] D) may not accurately reflect long-term vitamin D status. Little is known about change in 25(OH)D levels over time, particularly among blacks. OBJECTIVE: The objective of the study was to determine the longitudinal changes in 25(OH)D levels among Atherosclerosis Risk in Communities (ARIC) study participants. DESIGN: This was a longitudinal study. SETTING: The study was conducted in the general community. PARTICIPANTS: A total of 9890 white and 3222 black participants at visit 2 (1990 1992), 888 whites and 876 blacks at visit 3 (1993-1994), and 472 blacks at the brain visit (2004-2006) participated in the study. MAIN OUTCOME MEASURE: The 25(OH)D levels were measured, and regression models were used to assess the associations between clinical factors and longitudinal changes in 25(OH)D. RESULTS: Vitamin D deficiency (<50 nmol/L [<20 ng/mL]) was seen in 23% and 25% of whites at visits 2 and 3, and in 61%, 70%, and 47% of blacks at visits 2, 3, and the brain visit, respectively. The 25(OH)D levels were correlated between visits 2 and 3 (3 y interval) among whites (r = 0.73) and blacks (r = 0.66). Among blacks, the correlation between visit 2 and the brain visit (14 y interval) was 0.33. Overall, increases in 25(OH)D levels over time was associated with male gender, use of vitamin D supplements, greater physical activity, and higher high density lipoprotein-cholesterol (P < .001). Decreases in 25(OH)D levels over time were associated with current smoking, higher body mass index, higher education, diabetes, and hypertension (all P < .05). CONCLUSIONS: Among US blacks and whites, 25(OH)D levels remained relatively stable over time. Certain modifiable lifestyle factors were associated with change in 25(OH)D levels over time. PMID- 26509870 TI - Sex Hormones and Ischemic Stroke: A Prospective Cohort Study and Meta-Analyses. AB - CONTEXT AND OBJECTIVE: Whether endogenous sex hormones are associated with ischemic stroke (IS) is unclear. We tested the hypothesis that extreme concentrations of endogenous sex hormones are associated with risk of IS in the general population. DESIGN, SETTING, AND PARTICIPANTS: Adult men (n = 4615) and women (n = 4724) with measurements of endogenous sex hormones during the 1981 1983 examination of the Copenhagen City Heart Study, Denmark, were followed for up to 29 years for incident IS, with no loss to follow-up. Mediation analyses assessed whether risk of IS was mediated through potential mediators. Present and previous findings were summarized in meta-analyses. MAIN OUTCOME MEASURES: Plasma total testosterone and total estradiol were measured by competitive immunoassays. Diagnosis of IS was ascertained from the national Danish Patient Registry and the national Danish Causes of Death Registry and verified by experienced neurologists. RESULTS: During follow-up, 524 men and 563 women developed IS. Men with testosterone concentrations <=10th percentile compared to the 11th-90th percentiles had a hazard ratio for IS of 1.34 (95% confidence interval, 1.05 1.72); 21% of this risk was mediated by body mass index (P = .002) and 14% by hypertension (P = .02). In accordance with this, the corresponding hazard ratio was 1.46 (1.09-1.95) in overweight/obese and hypertensive men. The corresponding hazard ratio in the meta-analysis was 1.43 (1.21-1.70). Other extreme concentrations of testosterone or estradiol were not associated with risk of IS in men or women. CONCLUSIONS: Extremely low endogenous testosterone concentrations were associated with high risk of IS in men, a risk mediated in part by body mass index and hypertension. Whether or not low testosterone is a causal factor for IS or merely a biomarker of poor metabolic health is still not known. PMID- 26509871 TI - Is Exposure to Famine in Childhood and Economic Development in Adulthood Associated With Diabetes? AB - CONTEXT: The Chinese were afflicted by great famine between 1959 and 1962. These people then experienced rapid economic development during which the gross domestic product per capita increased from $28 in 1978 to $6807 in 2013. We hypothesize that these two events are associated with the booming rate of diabetes in China. OBJECTIVE: We aimed to explore whether exposure to famine in early life and high economic status in adulthood was associated with diabetes in later life. DESIGN AND SETTING: Our data of 6897 adults were from a cross sectional Survey on Prevalence in East China for Metabolic Diseases and Risk Factors study in 2014. Among them, 3844 adults experienced famine during different life stages and then lived in areas with different economic statuses in adulthood. MAIN OUTCOME MEASURE: Diabetes was considered as fasting plasma glucose of 7.0 mmol/L or greater, hemoglobin A1c of 6.5% or greater, and/or a previous diagnosis by health care professionals. RESULTS: Compared with nonexposed subjects, famine exposure during the fetal period (odds ratio [OR]1.53, 95% confidence interval [CI]1.09-2.14) and childhood (OR 1.82, 95% CI 1.21-2.73) was associated with diabetes after adjusting for age and gender. Further adjustments for adiposity, height, the lipid profile, and blood pressure did not significantly attenuate this association. Subjects living in areas with high economic status had a greater diabetes risk in adulthood (OR 1.46, 95% CI 1.20-1.78). In gender-specific analyses, fetal-exposed men (OR 1.64, 95% CI, 1.04 2.59) and childhood-exposed women (OR 2.81, 95% CI, 1.59-4.97) had significantly greater risk of diabetes. CONCLUSIONS: The rapid increase in the prevalence of diabetes in middle-aged and elderly people in China is associated with the combination of exposure to famine during the fetal stage and childhood and high economic status in adulthood. Our findings may partly explain the booming diabetes phenomenon in China. PMID- 26509872 TI - New GABAergic Neurogenesis in the Hippocampal CA1 Region of a Gerbil Model of Long-Term Survival after Transient Cerebral Ischemic Injury. AB - We investigated the probability of newly generated neurons that could survive and mature in the ischemic hippocampal CA1 region (CA1) of a gerbil model of transient cerebral ischemia. Neuronal death was shown in the stratum pyramidale (SP) from 4 days post-ischemia, and a significant increase in NeuN-positive ((+) ) neurons was found in the SP at 180 days post-ischemia. 5-Bromo-2-deoxyuridine (BrdU)(+) cells were co-stained with NeuN and glutamic decarboxylase 67 (GAD67). Brain-derived neurotrophic factor (BDNF) immunoreactivity and protein level was shown in nonpyramidal cells from 4 days post-ischemia, and the immunoreactivity was strong at 30 days post-ischemia and not significantly changed until 180 days post-ischemia. Furthermore, TrkB immunoreactivity was co-stained with GAD67 when we examined at 180 days post-ischemia. Myelin basic protein (MBP)(+) nerve fibers were reduced at 4 days post-ischemia and maintained until 60 days post-ischemia, and MBP immunoreactivity and levels were significantly increased at 180 days post ischemia. In the passive avoidance test, cognitive dysfunction was improved at 180 days post-ischemia. These results suggest that the differentiation of neural progenitor cells into new GABAergic neurons may be promoted via BDNF in the ischemic CA1 and that the neurogenesis may partially mediate the recovery of cognitive impairments via increasing myelinated nerve fibers. PMID- 26509873 TI - Protecting-Group-Free Total Synthesis of (-)-Jiadifenolide: Development of a [4 + 1] Annulation toward Multisubstituted Tetrahydrofurans. AB - A concise, protecting-group-free total synthesis of (-)-jiadifenolide, a synthetically challenging seco-prezizaane sesquiterpene with potent neurotrophic activity, is reported. The convergent route features a SmI2/H2O-mediated stereoselective reductive cyclization, an unprecedented formal [4 + 1] annulative tetrahydrofuran-forming reaction and programmed redox manipulations. The newly developed annulation of beta-hydroxy aldehydes or ketones with lithium trimethylsilyldiazomethane provides access to a diverse array of multisubstituted tetrahydrofurans. The synthetic jiadifenolide exhibited weak cytotoxicity against five human cancer cell lines. PMID- 26509874 TI - A Higher Frequency of CD14+ CD169+ Monocytes/Macrophages in Patients with Colorectal Cancer. AB - OBJECTIVE: Monocytes and macrophages can infiltrate into tumor microenvironment and regulate the progression of tumors. This study aimed at determining the frequency of different subsets of circulating monocytes and tumor infiltrating macrophages (TIMs) in patients with colorectal cancer (CRC). METHODS: The frequency of different subsets of circulating monocytes was characterized in 46 CRC patients and 22 healthy controls (HC) by flow cytometry. The frequency of different subsets of macrophages was analyzed in TIMs from 30 tumor tissues and in lamina propria mononuclear cells (LPMCs) from 12 non-tumor tissues. The concentrations of plasma cytokines and carcinoembryonic antigen (CEA) were determined. The potential association of these measures with the values of clinical parameters was analyzed. RESULTS: In comparison with that in the HC, the percentages of circulating CD14+ CD169+, CD14+ CD169+ CD163+ and CD14+ CD169+ CD206+ monocytes and TIMs CD14+ CD169+ as well as IL-10+ CD14+ CD169+, but not IL 12+ CD14+ CD169+ macrophages were significantly increased, accompanied by higher levels of plasma IL-10 in the CRC patients. The percentages of CD14+ CD169+ circulating monocytes and TIM macrophages were associated with the stage of disease and correlated positively with the levels of plasma IL-10 and CEA in CRC patients. CONCLUSION: Our data suggest that an increase in the frequency of CD14+ CD169+ cells may be associated with the development and progression of CRC and is concomitant rise of both, pro-tumor (M2-like, IL-10 producing) and anti-tumor (M1 like, IL-12 producing) monocytes and infiltrating macrophages. The frequency of CD14+ CD169+ circulating monocytes and infiltrating macrophages may serve as a biomarker for evaluating the pathogenic degrees of CRC. PMID- 26509875 TI - Salivary IgA from the sublingual compartment as a novel noninvasive proxy for intestinal immune induction. AB - Whole-saliva IgA appears like an attractive noninvasive readout for intestinal immune induction after enteric infection or vaccination, but has failed to show consistent correlation with established invasive markers and IgA in feces or intestinal lavage. For reference, we measured antibodies in samples from 30 healthy volunteers who were orally infected with wild-type enterotoxigenic Escherichia coli. The response against these bacteria in serum, lavage, and lymphocyte supernatants (antibody-in-lymphocyte-supernatant, ALS) was compared with that in targeted parotid and sublingual/submandibular secretions. Strong correlation occurred between IgA antibody levels against the challenge bacteria in sublingual/submandibular secretions and in lavage (r=0.69, P<0.0001) and ALS (r=0.70, P<0.0001). In sublingual/submandibular secretions, 93% responded with more than a twofold increase in IgA antibodies against the challenge strain, whereas the corresponding response in parotid secretions was only 67% (P=0.039). With >twofold ALS as a reference, the sensitivity of a >twofold response for IgA in sublingual/submandibular secretion was 96%, whereas it was only 67% in the parotid fluid. To exclude that flow rate variations influenced the results, we used albumin as a marker. Our data suggested that IgA in sublingual/submandibular secretions, rather than whole saliva with its variable content of parotid fluid, is a preferential noninvasive proxy for intestinal immune induction. PMID- 26509876 TI - Mucosal production of uric acid by airway epithelial cells contributes to particulate matter-induced allergic sensitization. AB - Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contributes to allergic sensitization, although the mechanisms governing this process remain unclear. Lung mucosal uric acid has also been linked to allergic sensitization. The links among PM exposure, uric acid, and allergic sensitization remain unexplored. We therefore investigated the mechanisms behind PM-induced allergic sensitization in the context of lung mucosal uric acid. PM10 and house dust mite exposure selectively induced lung mucosal uric acid production and secretion in vivo, which did not occur with other challenges (lipopolysaccharide, virus, bacteria, or inflammatory/fibrotic stimuli). PM10-induced uric acid mediates allergic sensitization and augments antigen-specific T-cell proliferation, which is inhibited by uricase. We then demonstrate that human airway epithelial cells secrete uric acid basally and after stimulation through a previously unidentified mucosal secretion system. Our work discovers a previously unknown mechanism of air pollution-induced, uric acid mediated, allergic sensitization that may be important in the pathogenesis of asthma. PMID- 26509879 TI - Thermal Isomerizations of Diethynyl Cyclobutadienes and Implications for Fullerene Formation. AB - The mechanism by which carbon condenses to form PAHs or fullerenes is a problem that has garnered considerable theoretical and experimental attention. The ring coalescence and annealing model for the formation of C(60) involves a [2 + 2] cycloaddition reaction of a cyclopolyyne to form a tetraalkynyl cyclobuta-1,3 diene intermediate, followed by a Bergman cycloaromatization reaction of the enediyne moiety. Intramolecular trapping of the incipient p-benzyne diradical across a diyne moiety of the macrocyclic ring affords an aromatic ring that must undergo further intramolecular reactions via polyradical intermediates to produce a condensed graphitic structure or fullerene. Computational studies of a model system for the intriguing tetraalkynylcyclobuta-1,3-diene intermediate, however, reveal that the corresponding p-benzyne diradical lies in a shallow minimum with a very low barrier to ring opening to cyclooctadienediyne. This pathway has not been previously considered in the mechanism for carbon condensation. PMID- 26509877 TI - In men at risk of HIV infection, IgM, IgG1, IgG3, and IgA reach the human foreskin epidermis. AB - We profiled the humoral response in the penis, an area that has been minimally explored but may be relevant for protecting insertive men against HIV and other sexually acquired infections. Comparing paired tissue samples from 20 men at risk of HIV infection, foreskin contains less immunoglobulin A (IgA) and more IgG2 than colon. Using foreskin dermal and epidermal explants and paired plasma from 17 men, we examined Ig accumulation by normalizing Ig to human serum albumin (HSA) transudation. Dermal IgM, IgG2, IgA, and IgE ratios were greater than that in plasma, suggesting there is local antibody secretion at the dermis. Local Ig transcription was concentrated at the inner rather than the outer foreskin, and inner foreskin Ig ratios did not correlate with blood, indicating that localized production can contribute to the foreskin response. IgM, IgG1, IgG3, and IgA have preferential access to the foreskin epidermis, whereas IgG2, IgG4, and IgE are restricted to the dermis. Lastly, Ad5-specific IgA was selectively present in the colon, whereas foreskin Ad5 IgG was mainly derived from blood, and reached the inner epidermis at higher ratios than the outer (P<0.002). In summary, the foreskin antibody response combines local and systemic sources, and there is selective isotype accumulation in the epidermis. PMID- 26509880 TI - Clinical Prognosis in Neonatal Bacterial Meningitis: The Role of Cerebrospinal Fluid Protein. AB - Neonates are at high risk of meningitis and of resulting neurologic complications. Early recognition of neonates at risk of poor prognosis would be helpful in providing timely management. From January 2008 to June 2014, we enrolled 232 term neonates with bacterial meningitis admitted to 3 neonatology departments in Shanghai, China. The clinical status on the day of discharge from these hospitals or at a postnatal age of 2.5 to 3 months was evaluated using the Glasgow Outcome Scale (GOS). Patients were classified into two outcome groups: good (167 cases, 72.0%, GOS = 5) or poor (65 cases, 28.0%, GOS = 1-4). Neonates with good outcome had less frequent apnea, drowsiness, poor feeding, bulging fontanelle, irritability and more severe jaundice compared to neonates with poor outcome. The good outcome group also had less pneumonia than the poor outcome group. Besides, there were statistically significant differences in hemoglobin, mean platelet volume, platelet distribution width, C-reaction protein, procalcitonin, cerebrospinal fluid (CSF) glucose and CSF protein. Multivariate logistic regression analyses suggested that poor feeding, pneumonia and CSF protein were the predictors of poor outcome. CSF protein content was significantly higher in patients with poor outcome. The best cut-offs for predicting poor outcome were 1,880 mg/L in CSF protein concentration (sensitivity 70.8%, specificity 86.2%). After 2 weeks of treatment, CSF protein remained higher in the poor outcome group. High CSF protein concentration may prognosticate poor outcome in neonates with bacterial meningitis. PMID- 26509881 TI - Point Me in the Right Direction: Same and Cross Category Visual Aftereffects to Directional Cues. AB - Of the many hand gestures that we use in communication pointing is one of the most common and powerful in its role as a visual referent that directs joint attention. While numerous studies have examined the developmental trajectory of pointing production and comprehension, very little consideration has been given to adult visual perception of hand pointing gestures. Across two studies, we use a visual adaptation paradigm to explore the mechanisms underlying the perception of proto-declarative hand pointing. Twenty eight participants judged whether 3D modeled hands pointed, in depth, at or to the left or right of a target (test angles of 0 degrees , 0.75 degrees and 1.5 degrees left and right) before and after adapting to either hands or arrows which pointed 10 degrees to the right or left of the target. After adaptation, the perception of the pointing direction of the test hands shifted with respect to the adapted direction, revealing separate mechanisms for coding right and leftward pointing directions. While there were subtle yet significant differences in the strength of adaptation to hands and arrows, both cues gave rise to a similar pattern of aftereffects. The considerable cross category adaptation found when arrows were used as adapting stimuli and the asymmetry in aftereffects to left and right hands suggests that the adaptation aftereffects are likely driven by simple orientation cues, inherent in the morphological structure of the hand, and not dependent on the biological status of the hand pointing cue. This finding provides evidence in support of a common neural mechanism that processes these directional social cues, a mechanism that may be blind to the biological status of the stimulus category. PMID- 26509882 TI - Neurosurgeons' Critical Role in Managing Traumatic Brain Injury--Reply. PMID- 26509883 TI - Radiolabeled liposome imaging determines an indication for liposomal anticancer agent in ovarian cancer mouse xenograft models. AB - Liposomal anticancer agents can effectively deliver drugs to tumor lesions, but their therapeutic effects are enhanced in only limited number of patients. Appropriate biomarkers to identify responder patients to these liposomal agents will improve their treatment efficacies. We carried out pharmacological and histopathological analyses of mouse xenograft models bearing human ovarian cancers (Caov-3, SK-OV-3, KURAMOCHI, and TOV-112D) to correlate the therapeutic effects of doxorubicin-encapsulated liposome (Doxil((r)) ) and histological characteristics linked to the enhanced permeability and retention effect. We next generated (111) In-encapsulated liposomes to examine their capacities to determine indications for Doxil((r)) treatment by single-photon emission computed tomography (SPECT)/CT imaging. Antitumor activities of Doxil((r)) were drastically enhanced in Caov-3, moderately in SK-OV-3, and minimally in KURAMOCHI and TOV-112D when compared to doxorubicin. Microvessel density and vascular perfusion were high in Caov-3 and SK-OV-3, indicating a close relation with the enhanced antitumor effects. Next, (111) In-encapsulated liposomes were given i.v. to the animals. Their tumor accumulation and area under the curve values over 72 h were high in Caov-3, relatively high in SK-OV-3, and low in two other tumors. Importantly, as both Doxil((r)) effects and liposomal accumulation varied in the SK-OV-3 group, we individually obtained SPECT/CT images of SK-OV-3-bearing mouse (n = 11) before Doxil((r)) treatment. Clear correlation between liposomal tumor accumulation and effects of Doxil((r)) was confirmed (R(2) = 0.73). Taken together, our experiments definitely verified that enhanced therapeutic effects through liposomal formulations of anticancer agents depend on tumor accumulation of liposomes. Tumor accumulation of the radiolabeled liposomes evaluated by SPECT/CT imaging is applicable to appropriately determine indications for liposomal antitumor agents. PMID- 26509884 TI - The Role of the Amino Protecting Group during Parahydrogenation of Protected Dehydroamino Acids. AB - A series of dehydroamino acids endowed with different protective groups at the amino and carboxylate moieties and with different substituents at the double bond have been reacted with parahydrogen. The observed ParaHydrogen Induced Polarization (PHIP) effects in the (1)H NMR spectra are strongly dependent on the amino protecting group. DFT calculations allowed us to establish a relationship between the structures of the reaction intermediates (whose energies depend on the amido substitution) and the observed PHIP patterns. PMID- 26509885 TI - Pre-implantation analysis of kidney biopsies from expanded criteria donors: testing the accuracy of frozen section technique and the adequacy of their assessment by on-call pathologists. AB - Pre-implantation renal biopsies of expanded criteria donors are one of the criteria used for allocation decisions, but there are concerns about the impact of the interobserver variability and the technique to be used. The aim was (i) to compare the original report performed by on-call pathologists using frozen sections (FS) to a retrospective analysis carried out by a trained pathologist using the same frozen section, and (ii) to compare the same FS to subsequently obtained paraffin sections (PS) by the same pathologist. A total of 92 biopsies, 78 from transplanted and 14 from nontransplanted cases, were analyzed. Agreement between observers using the same FS was weaker than the correlation between FS and PS in all the examined parameters (Kendall's Tau b for the Remuzzi score 0.104 vs. 0.306). According to the Remuzzi score, the revised FS analysis would have resulted in a higher rate of organ discard (n = 19) than PS (n = 14) and the original report (n = 6). However, kidneys that would have been discarded according to the retrospective analysis showed adequate outcomes in terms of graft survival and function. Accordingly, the impact of interobserver and technique-related variability can be minimized by the use of a relatively low threshold (RS <= 4) for organ acceptance. PMID- 26509886 TI - Probing Electronic Communications in Heterotrinuclear Fe-Ru-Fe Molecular Wires Formed by Ruthenium(II) Tetraphenylporphyrin and Isocyanoferrocene or 1,1' Diisocyanoferrocene Ligands. AB - Two new heterotrinuclear Fe-Ru-Fe complexes of ruthenium(II) tetraphenylporphyrin axially coordinated with a pair of isocyanoferrocene ((FcNC)2RuTPP, 1) or 1,1' diisocyanoferrocene (([C5H4NC]2Fe)2RuTPP, 2) ligands [Fc = ferrocenyl, TPP = 5,10,15,20-tetraphenylporphyrinato(2-) anion] were synthesized and characterized by UV-vis, magnetic circular dichroism, NMR, and FTIR spectroscopies as well as by electrospray ionization mass spectrometry and single-crystal X-ray diffraction. Isolation of insoluble polymeric {([C5H4NC]2Fe)RuTPP}n molecular wires (3) was also achieved for the first time. The redox properties of the new trinuclear complexes 1 and 2 were probed using electrochemical (cyclic voltammetry and differential pulse voltammetry), spectroelectrochemical, and chemical oxidation methods and correlated to those of the bis(tert butylisocyano)ruthenium(II) tetraphenylporphyrin reference compound, (t BuNC)2RuTPP (4). In all cases, the first oxidation process was attributed to the reversible oxidation of the Ru(II) center. The second and third reversible oxidation processes in 1 are separated by ~100 mV and were assigned to two single electron Fe(II)/Fe(III) couples, suggesting a weak long-range iron-iron coupling in this complex. Electrochemical data acquired for 2 are complicated by the interaction between the axial eta(1)-1,1'-diisocyanoferrocene ligand and the electrode surface as well as by axial ligand dissociation in solution. Spectroelectrochemical and chemical oxidation methods were used to elucidate the spectroscopic signatures of the [1](n+), [2](n+), and [4](n+) species in solution. DFT and time-dependent DFT calculations aided in correlating the spectroscopic and redox properties of complexes 1, 2, and 4 with their electronic structures. PMID- 26509887 TI - Linagliptin Limits High Glucose Induced Conversion of Latent to Active TGFbeta through Interaction with CIM6PR and Limits Renal Tubulointerstitial Fibronectin. AB - BACKGROUND: In addition to lowering blood glucose in patients with type 2 diabetes mellitus, dipeptidyl peptidase 4 (DPP4) inhibitors have been shown to be antifibrotic. We have previously shown that cation independent mannose-6 phosphate receptor (CIM6PR) facilitates the conversion of latent to active transforming growth factor beta1 (GFbeta1) in renal proximal tubular cells (PTCs) and linagliptin (a DPP4 inhibitor) reduced this conversion with downstream reduction in fibronectin transcription. OBJECTIVE: We wanted to demonstrate that linagliptin reduces high glucose induced interaction between membrane bound DPP4 and CIM6PR in vitro and demonstrate reduction in active TGFbeta mediated downstream effects in a rodent model of type 1 diabetic nephropathy independent of high glycaemic levels. MATERIALS AND METHODS: We used human kidney 2 (HK2) cells and endothelial nitric oxide synthase knock out mice to explore the mechanism and antifibrotic potential of linagliptin independent of glucose lowering. Using a proximity ligation assay, we show that CIM6PR and DPP4 interaction was increased by high glucose and reduced by linagliptin and excess mannose-6-phosphate (M6P) confirming that linagliptin is operating through an M6P dependent mechanism. In vivo studies confirmed these TGFbeta1 pathway related changes and showed reduced fibronectin, phosphorylated smad2 and phosphorylated smad2/3 (pSmad2/3) with an associated trend towards reduction in tubular atrophy, which was independent of glucose lowering. No reduction in albuminuria, glomerulosclerotic index or cortical collagen deposition was observed. CONCLUSION: Linagliptin inhibits activation of TGFbeta1 through a M6P dependent mechanism. However this in isolation is not sufficient to reverse the multifactorial nature of diabetic nephropathy. PMID- 26509889 TI - Technological memory aid use by people with acquired brain injury. AB - Evans, Wilson, Needham, and Brentnall ( 2003 ) investigated memory aid use by people with acquired brain injury (ABI) and found little use of technological memory aids. The present study aims to investigate use of technological and other memory aids and strategies 10 years on, and investigate what predicts use. People with ABI and self-reported memory impairments (n = 81) completed a survey containing a memory aid checklist, demographic questions and memory questionnaires. Chi-square analysis showed that 10 of 18 memory aids and strategies were used by significantly more people in the current sample than in Evans et al. ( 2003 ). The most commonly used strategies were leaving things in noticeable places (86%) and mental retracing of steps (77%). The most commonly used memory aids were asking someone to remind you (78%), diaries (77%), lists (78%), and calendars (79%) and the most common technologies used were mobile phone reminders (38%) and alarms/timers (38%). Younger people who used more technology prior to their injury and who use more non-technological memory aids currently were more likely to use technology. Younger people who used more memory aids and strategies prior to their injury and who rated their memory as poorer were more likely to use all types of memory aids and strategies. PMID- 26509888 TI - Histone H2AFX Links Meiotic Chromosome Asynapsis to Prophase I Oocyte Loss in Mammals. AB - Chromosome abnormalities are common in the human population, causing germ cell loss at meiotic prophase I and infertility. The mechanisms driving this loss are unknown, but persistent meiotic DNA damage and asynapsis may be triggers. Here we investigate the contribution of these lesions to oocyte elimination in mice with chromosome abnormalities, e.g. Turner syndrome (XO) and translocations. We show that asynapsed chromosomes trigger oocyte elimination at diplonema, which is linked to the presence of phosphorylated H2AFX (gammaH2AFX). We find that DNA double-strand break (DSB) foci disappear on asynapsed chromosomes during pachynema, excluding persistent DNA damage as a likely cause, and demonstrating the existence in mammalian oocytes of a repair pathway for asynapsis-associated DNA DSBs. Importantly, deletion or point mutation of H2afx restores oocyte numbers in XO females to wild type (XX) levels. Unexpectedly, we find that asynapsed supernumerary chromosomes do not elicit prophase I loss, despite being enriched for gammaH2AFX and other checkpoint proteins. These results suggest that oocyte loss cannot be explained simply by asynapsis checkpoint models, but is related to the gene content of asynapsed chromosomes. A similar mechanistic basis for oocyte loss may operate in humans with chromosome abnormalities. PMID- 26509890 TI - Impact of Childhood Maltreatment on the Recognition of Facial Expressions of Emotions. AB - The development of the explicit recognition of facial expressions of emotions can be affected by childhood maltreatment experiences. A previous study demonstrated the existence of an explicit recognition bias for angry facial expressions among a population of adolescent Sierra Leonean street-boys exposed to high levels of maltreatment. In the present study, the recognition bias for angry facial expressions was investigated in a younger population of street-children and age matched controls. Participants performed a forced-choice facial expressions recognition task. Recognition bias was measured as participants' tendency to over attribute anger label to other negative facial expressions. Participants' heart rate was assessed and related to their behavioral performance, as index of their stress-related physiological responses. Results demonstrated the presence of a recognition bias for angry facial expressions among street-children, also pinpointing a similar, although significantly less pronounced, tendency among controls. Participants' performance was controlled for age, cognitive and educational levels and for naming skills. None of these variables influenced the recognition bias for angry facial expressions. Differently, a significant effect of heart rate on participants' tendency to use anger label was evidenced. Taken together, these results suggest that childhood exposure to maltreatment experiences amplifies children's "pre-existing bias" for anger labeling in forced choice emotion recognition task. Moreover, they strengthen the thesis according to which the recognition bias for angry facial expressions is a manifestation of a functional adaptive mechanism that tunes victim's perceptive and attentive focus on salient environmental social stimuli. PMID- 26509891 TI - Plasma Oxytocin Levels in Untreated Adult Obsessive-Compulsive Disorder Patients. AB - BACKGROUND AND AIM: Given the paucity of information on the possible role of oxytocin (OT) in the pathophysiology of obsessive-compulsive disorder (OCD), our study aimed at evaluating plasma OT levels in a group of 44 OCD outpatients, as compared with a similar group of healthy control subjects. At the same time, the relationships between OT and clinical features and romantic attachment characteristics were examined as well. METHODS: Diagnosis was assessed according to DSM-IV-TR criteria, while the OCD severity was measured by means of the Y-BOCS rating scale. All patients were drug free and not depressed. The romantic attachment was assessed by means of the Italian version of the 'Experiences in Close Relationships' questionnaire. Plasma OT levels were evaluated by means of a standard RIA kit. RESULTS: The main findings of our study showed that OT levels were increased in OCD patients, as compared with healthy subjects, and negatively related to symptom severity. Positive relationships were detected between OT levels and the fearful-avoidant and dismissing styles of romantic attachments, but only in male OCD patients. CONCLUSION: Taken together, these findings suggest that OT may play a role in OCD pathophysiology and also in the romantic attachment of patients with gender specificity. PMID- 26509892 TI - Breaking an Ice: New Era in Stroke Therapy. PMID- 26509893 TI - Fetal Alcohol Exposure Reduces Dopamine Receptor D2 and Increases Pituitary Weight and Prolactin Production via Epigenetic Mechanisms. AB - Recent evidence indicated that alcohol exposure during the fetal period increases the susceptibility to tumor development in mammary and prostate tissues. Whether fetal alcohol exposure increases the susceptibility to prolactin-producing tumor (prolactinoma) development in the pituitary was studied by employing the animal model of estradiol-induced prolactinomas in Fischer 344 female rats. We employed an animal model of fetal alcohol exposure that simulates binge alcohol drinking during the first two trimesters of human pregnancy and involves feeding pregnant rats with a liquid diet containing 6.7% alcohol during gestational day 7 to day 21. Control rats were pair-fed with isocaloric liquid diet or fed ad libitum with rat chow diet. Adult alcohol exposed and control female offspring rats were used in this study on the day of estrus or after estrogen treatment. Results show that fetal alcohol-exposed rats had increased levels of pituitary weight, pituitary prolactin (PRL) protein and mRNA, and plasma PRL. However, these rats show decreased pituitary levels of dopamine D2 receptor (D2R) mRNA and protein and increased pituitary levels of D2R promoter methylation. Also, they show elevated pituitary mRNA levels of DNA methylating genes (DNMT1, DNMT3b, MeCP2) and histone modifying genes (HDAC2, HDAC4, G9a). When fetal alcohol exposed rats were treated neonatally with a DNA methylation inhibitor 5-Aza deoxycytidine and/or a HDAC inhibitor trichostatin-A their pituitary D2R mRNA, pituitary weights and plasma PRL levels were normalized. These data suggest that fetal alcohol exposure programs the pituitary to increase the susceptibility to the development of prolactinomas possibly by enhancing the methylation of the D2R gene promoter and repressing the synthesis and control of D2R on PRL-producing cells. PMID- 26509894 TI - A Survey on Use of Rapid Tests and Tuberculosis Diagnostic Practices by Primary Health Care Providers in South Africa: Implications for the Development of New Point-of-Care Tests. AB - BACKGROUND: Effective infectious disease control requires early diagnosis and treatment initiation. Point-of-care testing offers rapid turn-around-times, facilitating same day clinical management decisions. To maximize the benefits of such POC testing programs, we need to understand how rapid tests are used in everyday clinical practice. METHODS: In this cross-sectional survey study, 400 primary healthcare providers in two cities in South Africa were interviewed on their use of rapid tests in general, and tuberculosis diagnostic practices, between September 2012 and June 2013. Public healthcare facilities were selected using probability-sampling techniques and private healthcare providers were randomly selected from the Health Professional Council of South Africa list. To ascertain differences between the two healthcare sectors 2-sample z-tests were used to compare sample proportions. RESULTS: The numbers of providers interviewed were equally distributed between the public (n = 200) and private sector (n = 200). The most frequently reported tests in the private sector include blood pressure (99.5%), glucose finger prick (89.5%) and urine dipstick (38.5%); and in the public sector were pregnancy (100%), urine dipstick (100%), blood pressure (100%), glucose finger prick (99%) and HIV rapid test (98%). The majority of TB testing occurs in the public sector, where significantly more providers prefer Xpert MTB/RIF assay, the designated clinical TB diagnostic tool by the national TB program, as compared to the private sector (87% versus 71%, p-value >0.0001). Challenges with regard to TB diagnosis included the long laboratory turn-around time, difficulty in obtaining sputum samples and lost results. All providers indicated that a new POC test for TB should be rapid and cheap, have good sensitivity and specificity, ease of sample acquisition, detect drug-resistance and work in HIV-infected persons. CONCLUSION/SIGNIFICANCE: The existing centralized laboratory services, poor quality assurance, and lack of staff capacity deter the use of more rapid tests at POC. Further research into the practices and choices of these providers is necessary to aid the development of new POC tests. PMID- 26509895 TI - Beyond Self-Report: Tools to Compare Estimated and Real-World Smartphone Use. AB - Psychologists typically rely on self-report data when quantifying mobile phone usage, despite little evidence of its validity. In this paper we explore the accuracy of using self-reported estimates when compared with actual smartphone use. We also include source code to process and visualise these data. We compared 23 participants' actual smartphone use over a two-week period with self-reported estimates and the Mobile Phone Problem Use Scale. Our results indicate that estimated time spent using a smartphone may be an adequate measure of use, unless a greater resolution of data are required. Estimates concerning the number of times an individual used their phone across a typical day did not correlate with actual smartphone use. Neither estimated duration nor number of uses correlated with the Mobile Phone Problem Use Scale. We conclude that estimated smartphone use should be interpreted with caution in psychological research. PMID- 26509896 TI - Correction: Accuracy of Pulse Oximeters in Detecting Hypoxemia in Patients with Chronic Thromboembolic Pulmonary Hypertension. PMID- 26509897 TI - Cerebral Cortex Expression of Gli3 Is Required for Normal Development of the Lateral Olfactory Tract. AB - Formation of the lateral olfactory tract (LOT) and innervation of the piriform cortex represent fundamental steps to allow the transmission of olfactory information to the cerebral cortex. Several transcription factors, including the zinc finger transcription factor Gli3, influence LOT formation by controlling the development of mitral cells from which LOT axons emanate and/or by specifying the environment through which these axons navigate. Gli3 null and hypomorphic mutants display severe defects throughout the territory covered by the developing lateral olfactory tract, making it difficult to identify specific roles for Gli3 in its development. Here, we used Emx1Cre;Gli3fl/fl conditional mutants to investigate LOT formation and colonization of the olfactory cortex in embryos in which loss of Gli3 function is restricted to the dorsal telencephalon. These mutants form an olfactory bulb like structure which does not protrude from the telencephalic surface. Nevertheless, mitral cells are formed and their axons enter the piriform cortex though the LOT is shifted medially. Mitral axons also innervate a larger target area consistent with an enlargement of the piriform cortex and form aberrant projections into the deeper layers of the piriform cortex. No obvious differences were found in the expression patterns of key guidance cues. However, we found that an expansion of the piriform cortex temporally coincides with the arrival of LOT axons, suggesting that Gli3 affects LOT positioning and target area innervation through controlling the development of the piriform cortex. PMID- 26509898 TI - Formation of Tethers from Spreading Cellular Aggregates. AB - Membrane tubes are commonly extruded from cells and vesicles when a point-like force is applied on the membrane. We report here the unexpected formation of membrane tubes from lymph node cancer prostate (LNCaP) cell aggregates in the absence of external applied forces. The spreading of LNCaP aggregates deposited on adhesive glass substrates coated with fibronectin is very limited because cell cell adhesion is stronger than cell-substrate adhesion. Some cells on the aggregate periphery are very motile and try to escape from the aggregate, leading to the formation of membrane tubes. Tethered networks and exchange of cargos between cells were observed as well. Growth of the tubes is followed by either tube retraction or tube rupture. Hence, even very cohesive cells are successful in escaping aggregates, which may lead to epithelial mesenchymal transition and tumor metastasis. We interpret the dynamics of formation and retraction of tubes in the framework of membrane mechanics. PMID- 26509899 TI - Suicides in Visually Impaired Persons: A Nation-Wide Register-Linked Study from Finland Based on Thirty Years of Data. AB - Focusing on seasonality, gender, age, and suicide methods a Finnish nation-wide cohort-based study was carried out to compare suicide data between sighted, visually-impaired (WHO impairment level I-II, i.e., visual acuity >0.05, but <0.3) and blind (WHO impairment level III-V, i.e., visual acuity <0.05) victims. Standardized mortality ratios (SMR) of age- and gender-matched populations from official 1982-2011 national registers were used. Group differences in categorical variables were assessed with Pearson's Chi-square or Fisher's Exact test and in continuous variables with Mann-Whitney U-test. Seasonality was assessed by Chi square for multinomials; ratio of observed to expected number of suicides was calculated with 95% confidence level. Hanging, poisoning, drowning, but rarely shooting or jumping from high places, were preferred suicide methods of the blind. Mortality was significantly increased in the visually impaired (SMR = 1.3; 95% CI 1.07-1.61), but in gender-stratified analyses the increase only affected males (1.34; 95% CI = 1.06-1.70) and not females (1.24; 95% CI 0.82-1.88). Age stratified analyses identified blind males of working age rather than older men (as in the general population) as a high risk group that requires particular attention. The statistically significant spring suicide peak in blind subjects mirrors that of sighted victims and its possible cause in the blind is discussed. PMID- 26509900 TI - Sequential Subterranean Transport of Excavated Sand and Foraged Seeds in Nests of the Harvester Ant, Pogonomyrmex badius. AB - During their approximately annual nest relocations, Florida harvester ants (Pogonomyrmex badius) excavate large and architecturally-distinct subterranean nests. Aspects of this process were studied by planting a harvester ant colony in the field in a soil column composed of layers of 12 different colors of sand. Quantifying the colors of excavated sand dumped on the surface by the ants revealed the progress of nest deepening to 2 m and enlargement to 8 L in volume. Most of the excavation was completed within about 2 weeks, but the nest was doubled in volume after a winter lull. After 7 months, we excavated the nest and mapped its structure, revealing colored sand deposited in non-host colored layers, especially in the upper 30 to 40 cm of the nest. In all, about 2.5% of the excavated sediment was deposited below ground, a fact of importance to sediment dating by optically-stimulated luminescence (OSL). Upward transport of excavated sand is carried out in stages, probably by different groups of ants, through deposition, re-transport, incorporation into the nest walls and floors and remobilization from these. This results in considerable mixing of sand from different depths, as indicated in the multiple sand colors even within single sand pellets brought to the surface. Just as sand is transported upward by stages, incoming seeds are transported downward to seed chambers. Foragers collect seeds and deposit them only in the topmost nest chambers from which a separate group of workers rapidly transports them downward in increments detectable as a "wave" of seeds that eventually ends in the seed chambers, 20 to 80 cm below the surface. The upward and downward transport is an example of task partitioning in a series-parallel organization of work carried out by a highly redundant work force in which each worker usually completes only part of a multi step process. PMID- 26509902 TI - Ibuprofen loaded PLA nanofibrous scaffolds increase proliferation of human skin cells in vitro and promote healing of full thickness incision wounds in vivo. AB - This article presents successful incorporation of ibuprofen in polylactic acid (PLA) nanofibers to create scaffolds for the treatment of both acute and chronic wounds. Nanofibrous PLA scaffolds containing 10, 20, or 30 wt % ibuprofen were created and ibuprofen release profiles quantified. In vitro cytotoxicity to human epidermal keratinocytes (HEK) and human dermal fibroblasts (HDF) of the three scaffolds with varying ibuprofen concentrations were evaluated and compared to pure PLA nanofibrous scaffolds. Thereafter, scaffolds loaded with ibuprofen at the concentration that promoted human skin cell viability and proliferation (20 wt %) were evaluated in vivo in nude mice using a full thickness skin incision model to determine the ability of these scaffolds to promote skin regeneration and/or assist with scarless healing. Both acellular and HEK and HDF cell-seeded 20 wt % ibuprofen loaded nanofibrous bandages reduced wound contraction compared with wounds treated with TegadermTM and sterile gauze. Newly regenerated skin on wounds treated with cell-seeded 20 wt % ibuprofen bandages exhibited significantly greater blood vessel formation relative to acellular ibuprofen bandages. We have found that degradable anti-inflammatory scaffolds containing 20 wt % ibuprofen promote human skin cell viability and proliferation in vitro, reduce wound contraction in vivo, and when seeded with skin cells, also enhance new blood vessel formation. The approaches and results reported here hold promise for multiple skin tissue engineering and wound healing applications. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 327-339, 2017. PMID- 26509903 TI - Bringing the Common Rule into the 21st Century. PMID- 26509904 TI - Reprofiling Metastatic Samples for Chromosome 9p and 14q Aberrations as a Strategy to Overcome Tumor Heterogeneity in Clear-cell Renal Cell Carcinoma. AB - Losses of chromosomes 9p and 14q are associated with worse outcomes in patients affected by clear-cell renal cell carcinoma (RCC) and are helpful for prognostic risk stratification. Both chromosomal loci harbor several hot-spot molecular pathways suitable for targeted therapeutic interventions. Intratumor heterogeneity may foster tumor adaptation and therapeutic failure. We sought to investigate the presence of losses of the hot spots of chromosomal loci 9p and 14q in primary clear-cell RCC and matched metastatic tissues. CD10 and CD13 were performed on 7 cases of clear-cell RCC with hematogenous tissue metastases. Cytogenetic fluorescence in situ hybridization analysis was performed on primary and matched metastatic tissues using specific probes mapping the 9p and the 14q loci. The loss of chromosome 9p was observed in 85% of both primary clear-cell RCCs and in matched metastases; 14% showed discordance between primary and matched metastases showing gains. The loss of chromosome 14q was observed in 58% of both primary and matched metastases. Only 3/7 (42%) did show an equal status of loss of chromosome 14q. Heterogeneity of the cytogenetic status between metastatic and primary clear-cell RCCs is observed for the loss of chromosome 14q rather than chromosome 9p. The impact of chromosome 14q cytogenetic status, harboring the HIF1 gene, a major driver for the angiogenenic switch, may drive the efficacy of targeted inhibitors, whereas the loss of chromosome 9p, harboring other hot-spot genes, seems to be related to the metastatic behavior per se, without cytogenetic modulation. Reprofiling the metastatic tissue, as compared with the primary tumor, in patients affected by metastatic RCC could be a novel approach to overcome resistance to VEGF(Rs)-targeting agents. PMID- 26509905 TI - Mixed Epithelial and Stromal Tumor of the Kidney: Mutation Analysis of the DICER 1 Gene in 29 Cases. AB - Cystic nephroma (CN) and mixed epithelial stromal tumor (MEST) of the kidney have been considered as synonymous terms describing a single nosologic entity in adult patients. Cystic nephroma in pediatric patients (PCN) is, apparently, a completely different nosologic entity. Although the presence of DICER 1 mutations is well established in PCN, nothing is currently known about the DICER 1 gene status in adult MEST/CN. About 33 cases of MEST/CN were selected from the Plzen Tumor Registry; 4 cases were later excluded from the study due to low DNA quality. About 28 of the studied tumors displayed a benign morphology, whereas 1 was diagnosed as a malignant MEST/CN with sarcomatoid differentiation of the stromal component. All 29 samples analyzed using polymerase chain reaction and direct sequencing, including the case with the malignant morphology, were negative for mutation in DICER 1 hot-spot codons 1705, 1709, 1809, 1810, 1813, and 1814. Our results show that MEST/CN has no relation to PCN on a molecular genetic level. On the basis of our findings and the established morphologic differences between PCN and MEST/CN, we conclude that the term CN should be used for pediatric cases only and should be avoided in adult cases of MEST. PMID- 26509906 TI - Is Aquaporin-3 a Determinant Factor of Intrinsic and Extrinsic Aging? An Immunohistochemical and Morphometric Study. AB - Aquaporin-3 (AQP3) is an aquaglyceroporin that plays a role in skin hydration, cell proliferation, and migration. The aim of this work was to investigate the expression of AQP3 in sun-exposed and sun-protected human skin from different age groups to understand the relationship between AQP3 and skin aging. Using standard immunohistochemical techniques, sun-exposed and sun-protected skin biopsies were taken from 60 normal individuals. AQP3 was expressed in the basal and the suprabasal layers, sparing the stratum corneum, in all specimens. Dermal expression was detected in fibroblasts, endothelial cells, and adnexa. Sun protected skin showed a significantly higher epidermal H-score and percentage of expression (P=0.002 and <0.001, respectively) compared with sun-exposed skin. The AQP3 expression intensity showed a gradual decrease from the 20 to 35-year-old group to the 35 to 50-year-old group, with the least immunoreactivity in the above 50-year-old group. A significant difference was detected in the H-score in favor of the 20 to 35-year-old group in sun-exposed and sun-protected skin (P<0.001 for both). A significant negative correlation was noted between the AQP3 expression percentage and the age in sun-exposed (r=-0.64, P<0.001) and sun protected skin (r=-0.53, P<0.001). In conclusion, the skin dryness observed in intrinsic and extrinsic aged skin may be explained, at least in part, by AQP3 downregulation. This may open new avenues sufficient to control skin texture and beauty. Its interaction in skin protein organization and gene polymorphism can also be tackled in future research. In addition, clinical trials using AQP3 topical applications should be carried out to evaluate its effectiveness in the reversal of age-related skin changes. PMID- 26509907 TI - Optimized Protocol of Methanol Treatment for Immunofluorescent Staining in Fixed Brain Slices. AB - We optimized methanol treatment in paraformaldehyde-fixed slices for immunofluorescent staining of ependymal basal bodies in brain ventricles. As 100% methanol induced severe deformations to the slices (including rolling and folding over), we tried to decrease methanol concentration. We found that 33.3% to 75% methanol could result in ideal immunostaining of basal bodies without inducing obvious deformations. Instead of treating slices at -20 degrees C (without proper cryoprotection measurements) as suggested in previous studies, we carried out methanol treatment at room temperature. Our modified protocol can not only raise immunostaining efficiency in tissue slices, it may also prevent potential freezing damages to the samples. PMID- 26509908 TI - Anti-Treponema Antibody Also Stains Helicobacter heilmannii. PMID- 26509909 TI - The Performance of Ki-67 Labeling Index in Different Specimen Categories of Invasive Ductal Carcinoma of the Breast Using 2 Scoring Methods. AB - In breast carcinoma proliferative rate is not only prognostic, but also predictive factor. Ki-67 labeling index (Ki-67 LI) is a superior and more reproducible way to assess proliferation than counting mitoses. There are different Ki-67 LI cut-off values proposed for stratification. The best method of scoring Ki-67 LI is still controversial. Our aim was to test the consensus of Ki 67 LI read in the 2 most common specimens, diagnostic core biopsies (CNB) and surgical excision (SE), first using the hot spot (HS) for counting, and then the average (Av) Ki-67 LI. Cases diagnosed as having invasive duct breast carcinoma on CNB followed by SE over 6 years were recruited (n=96). Ki-67 LI was counted in both specimen types using HS and Av scoring methods. For both methods, agreement between the 2 specimen categories was tested using different cut-off values. Intraobserver reproducibility was also measured for both scoring methods. Ki-67 LI was significantly lower in CNBs compared with SEs (mean difference: -13.3 and 6.3, P<0.001, using HS and Av methods, respectively). The agreement between Ki-67 LI in CNBs and SEs using 10, 14, and 20 as cut-off value was superior when we used Av method (for kappa=0.793, 0.814, and 0.745; vs. for HS: kappa=0.542, 0.525, and 0.672, respectively). Intraobserver reproducibility ranged from very good to perfect for both methods. Our results suggested that specimen-specific cut-off value should be applied for both scoring methods. PMID- 26509910 TI - Association of Stromal Factors With the Histologic Risk Assessment Model in Oral Squamous Cell Carcinoma. AB - The aim of the present study was to evaluate angiogenesis, lymphangiogenesis, and mast cell density in association with the histologic risk assessment (HRA) model in oral squamous cell carcinoma. One hundred oral squamous cell carcinomas were graded according to the HRA system and immunostained with antibodies against D2 40, CD34, and CD105 to determine lymphvessel density (LVD) and microvessel density (MVD). Mast cells were detected by toluidine blue and counted in all samples. Assessments were made between the evaluated factors and the histologic variables of HRA. Kruskal-Wallis and Mann-Whitney U test were used for statistical analysis and P<0.05 was considered significant. There were 32, 26, and 42 cases of low, intermediate, and high-grade neoplasms, respectively. Only LVD (P=0.05) and CD34MVD (P=0.03) showed significant associations with lymphocytic infiltration and were both higher in score 0 cases compared with score 3 tumors (P=0.05 and <0.001, respectively). None of the other variables showed significant relationships with the HRA risk scores or subcategories (P>0.05). According to our findings, it appears that the role of lymphangiogenesis and angiogenesis is limited in the HRA system. The significant relationship of lymphocytic infiltration with LVD and CD34MVD, but not CD105MVD, might indicate that "inflammatory lymphangiogenesis/angiogenesis" may differ from that induced by noninflamed neoplastic tissues. It also seems that the vasculature in inflamed tumor tissues is not entirely newly formed. PMID- 26509911 TI - p16 Immunohistochemistry is Less Useful Than MDM2 and CDK4 to Distinguish Dedifferentiated Liposarcomas From Other Retroperitoneal Mimics. AB - Dedifferentiated liposarcoma (DDL) frequently involves the retroperitoneum. In the absence of a lipogenic component histologically, the differential diagnosis of a retroperitoneal DDL includes other sarcomas and, if the tumor has visceral involvement, sarcomatoid carcinoma. DDL demonstrates amplification of chromosome subregion 12q13-q15. Detection of the amplification itself, or the resulting overexpression of the MDM2 and CDK4 genes by genetic and immunohistochemical methods, is a useful ancillary test in the diagnosis of DDL. More recently, immunohistochemistry for p16, the product of the CDKN2A gene, was shown to be a useful adjunct in differentiating well-differentiated liposarcoma from benign adipocytic tumors. In the present study, we examined the utility of p16 immunohistochemistry to distinguish DDL (n=44) from other high-grade and low grade retroperitoneal mimics (n=73). p16 positivity was observed in 43/44 (98%) DDLs, with the majority of these showing strong, diffuse, staining. The rate of p16 positivity in other retroperitoneal tumors was lower (37/73, 51%) and staining was not as consistently diffuse or intense. Furthermore, p16 positivity varied between the control sarcomas based on tumor type as follows: 11/11 leiomyosarcomas, 8/11 pleomorphic undifferentiated sarcomas, 9/39 sarcomatoid carcinomas, 7/7 desmoid tumors, 1/3 endometrial stromal sarcomas, and 1/2 malignant gastrointestinal stromal tumors. On the basis of these findings, we conclude that p16 is highly sensitive for retroperitoneal DDL. However, the lack of specificity limits the diagnostic utility compared with the more established markers MDM2 and CDK4. PMID- 26509912 TI - Oncogenic Activation of the Wnt/beta-Catenin Signaling Pathway in Signet Ring Stromal Cell Tumor of the Ovary. AB - Signet ring stromal cell tumor (SRSCT) of the ovary is a very rare benign ovarian neoplasm. To date, no underlying genetic mechanism has been identified. In this study, 50 oncogenes and tumor suppressor genes were evaluated for mutations in a typical SRSCT using the next-generation DNA sequencing approach. An in-frame deletion of 30 nucleotides in the glycogen serine kinase-3 beta phosphorylation region of the beta-catenin gene (CTNNB1) was identified, and the finding was confirmed by Sanger sequencing. This deletion (c.68_97del) at the protein level would lead to a p.Ser23_Ser33delinsThr oncogenic-type mutation. Subsequent immunohistochemistry showed prominent nuclear accumulation of beta-catenin and cyclin D1 in tumor cells. Thus, mutational activation of the Wnt/beta-catenin pathway could be a crucial event in the molecular pathogenesis of SRSCT of the ovary. These findings may also assist in the diagnosis of this rare tumor. PMID- 26509913 TI - Semiquantitation of Axonal Injury in Traumatically Damaged Brains Using Color Deconvolution. AB - INTRODUCTION: In traumatic brain injury biomechanics, macroscale biomechanical events need to be correlated with microscale neuropathologic changes and improved quantitation of microscopic axonal injury is an essential component of lesion evaluation. OBJECTIVES: To develop a novel technique for automatically identifying injured amyloid precursor protein immunopositive axons and aggregating these observations over a macroscopic brain dissection. METHODS: A color deconvolution method was adapted into Matlab to identify clusters of pixels with colors typical of amyloid precursor protein positive tissue from large-scale brain dissection. RESULTS: The methodology is demonstrated in the brain of a sheep subjected to a controlled cortical indentation. CONCLUSIONS: The technique will be of interest to pathologists and bioengineers seeking to quantitate brain injury over macroscales. PMID- 26509914 TI - Synthesis, Structural Characterization, and Bioactivity of the Stable Peptide RCB 1 from Ricinus communis. AB - The Ricinus communis biomarker peptides RCB-1 to -3 comprise homologous sequences of 19 (RCB-1) or 18 (RCB-2 and -3) amino acid residues. They all include four cysteine moieties, which form two disulfide bonds. However, neither the 3D structure nor the biological activity of any of these peptides is known. The synthesis of RCB-1, using microwave-assisted, Fmoc-based solid-phase peptide synthesis, and a method for its oxidative folding are reported. The tertiary structure of RCB-1, subsequently established using solution-state NMR, reveals a twisted loop fold with antiparallel beta-sheets reinforced by the two disulfide bonds. Moreover, RCB-1 was tested for antibacterial, antifungal, and cytotoxic activity, as well as in a serum stability assay, in which it proved to be remarkably stable. PMID- 26509915 TI - AngioVac extraction of intra-atrial hepatoma masquerading as PICC-associated thrombus. AB - Thrombus associated with peripherally inserted central catheterization is not uncommon. Treatment is typically conservative; however, more aggressive therapies can be considered in patients with tenuous medical condition. The authors present a patient with metastatic hepatocellular carcinoma masquerading as peripherally inserted central catheter-associated intra-atrial thrombus, subsequently removed via vacuum-assisted mechanical thrombectomy. PMID- 26509916 TI - Intravenous administration of a polyionic solution containing 84 mEq/l of lactate resolves experimentally induced hyperchloraemic acidosis in horses. AB - REASONS FOR PERFORMING STUDY: Treatment of metabolic acidosis using sodium bicarbonate solutions is safe when blood gas analysis is available. The evidence that solutions containing metabolisable buffers can be used as an alternative for treatment of metabolic acidosis in horses is of practical interest. OBJECTIVES: To investigate the safety and efficacy of a polyionic solution containing 84 mEq/l of lactate (L84) for the correction of induced hyperchloraemic metabolic acidosis. STUDY DESIGN: Non-randomised crossover design. METHODS: Five healthy, adult, crossbred horses were used. A solution containing 100 mmol/l of HCl was infused intravenously (100 ml/kg bwt) for 5 h to induce metabolic acidosis. Metabolic acidosis was induced in each horse twice, with a minimum 15-day interval after recovery from the first induction: the first time no treatment was administered (control group) and the second time horses were treated with an intravenous infusion of L84 solution, 100 ml/kg bwt for 5 h, beginning 3 h after the end of HCl infusion. Venous blood samples were taken at 0, 2.5, 5, 8, 10.5, 13, 24 and 48 h; and urine at 0, 5, 8 and 13 h. Laboratory data included pH (blood and urine), PCO2 , HCO3- , base excess, total plasma protein concentration, l-lactate, Na+ , K+ , Cl- , strong ion difference (SID4 ), anion gap, change in plasma volume and fractional excretions of Na+ , K+ and Cl- . Effects of time and treatment were tested by 2-way repeated measures ANOVA. RESULTS: Severe hyperchloraemic metabolic acidosis was induced. In the untreated horses, correction of the imbalance occurred gradually, and mild acidosis was still present at 48 h. In horses treated with the L84 solution, acidosis was corrected by the end of the infusion. There were no adverse effects with the administration of the L84 solution. CONCLUSIONS: A polyionic solution containing 84 mEq/l of lactate effectively corrected induced metabolic acidosis in horses within 5 h. PMID- 26509917 TI - Three-dimensional imaging of palatal muscles in the human embryo and fetus: Development of levator veli palatini and clinical importance of the lesser palatine nerve. AB - BACKGROUND: After palatoplasty, incomplete velopharyngeal closure in speech articulation sometimes persists, despite restoration of deglutition function. The levator veli palatini (LVP) is believed to be significantly involved with velopharyngeal function in articulation; however, the development and innervation of LVP remain obscure. The development of LVP in human embryos and fetuses has not been systematically analyzed using the Carnegie stage (CS) to standardize documentation of development. RESULTS: The anlage of LVP starts to develop at CS 21 beneath the aperture of the auditory tube (AT) to the pharynx. At CS 23, LVP runs along AT over its full length, as evidenced by three-dimensional image reconstruction. In the fetal stage, the lesser palatine nerve (LPN) is in contact with LVP. CONCLUSIONS: The positional relationship between LVP and AT three dimensionally, suggesting that LVP might be derived from the second branchial arch. Based on histological evidence, we hypothesize that motor components from the facial nerve may run along LPN, believed to be purely sensory. The multiple innervation of LVP by LPN and pharyngeal plexus may explain the postpalatoplasty discrepancy between the partial impairment in articulation vs. the functional restoration of deglutition. That is, the contribution of LPN is greater in articulation than in deglutition. PMID- 26509918 TI - A Standardised Vocabulary for Identifying Benthic Biota and Substrata from Underwater Imagery: The CATAMI Classification Scheme. AB - Imagery collected by still and video cameras is an increasingly important tool for minimal impact, repeatable observations in the marine environment. Data generated from imagery includes identification, annotation and quantification of biological subjects and environmental features within an image. To be long-lived and useful beyond their project-specific initial purpose, and to maximize their utility across studies and disciplines, marine imagery data should use a standardised vocabulary of defined terms. This would enable the compilation of regional, national and/or global data sets from multiple sources, contributing to broad-scale management studies and development of automated annotation algorithms. The classification scheme developed under the Collaborative and Automated Tools for Analysis of Marine Imagery (CATAMI) project provides such a vocabulary. The CATAMI classification scheme introduces Australian-wide acknowledged, standardised terminology for annotating benthic substrates and biota in marine imagery. It combines coarse-level taxonomy and morphology, and is a flexible, hierarchical classification that bridges the gap between habitat/biotope characterisation and taxonomy, acknowledging limitations when describing biological taxa through imagery. It is fully described, documented, and maintained through curated online databases, and can be applied across benthic image collection methods, annotation platforms and scoring methods. Following release in 2013, the CATAMI classification scheme was taken up by a wide variety of users, including government, academia and industry. This rapid acceptance highlights the scheme's utility and the potential to facilitate broad scale multidisciplinary studies of marine ecosystems when applied globally. Here we present the CATAMI classification scheme, describe its conception and features, and discuss its utility and the opportunities as well as challenges arising from its use. PMID- 26509919 TI - Creating Reactivity with Unstable Endmembers using Pressure and Temperature: Synthesis of Bulk Cubic Mg0.4 Fe0.6 N. AB - Alloy and nitride solid solutions are prominent for structural, energy and information processing applications. There are frequently however barriers to making them. We remove barriers to reactivity here using pressure with a new synthetic approach. We target pressures where the reasons for cubic endmember nitride instability can become the driving force for cubic nitride solid solution stability. Using this approach we form a novel rocksalt Mg0.4 Fe0.6 N solid solution at between 15 and 23 GPa and up to 2500 K. This is a system where, neither an alloy nor a nitride solid solution form at ambient conditions and bulk MgN and FeN endmembers do not form, either at ambient or at high pressure. The new nitride is formed, by removing endmember lattice mismatch with pressure, allowing a stabilizing redistribution of valence electrons upon heating. This approach can be employed for a range of normally unreactive systems. Mg, Fe and enhanced nitrogen presence, may also indicate a richer reaction chemistry in our planets interior. PMID- 26509920 TI - A flexible, single-arm robotic surgical system for transoral resection of the tonsil and lateral pharyngeal wall: Next-generation robotic head and neck surgery. AB - OBJECTIVES/HYPOTHESIS: To describe the application of a novel flexible robotic surgical system to transoral endoscopic head and neck surgery of the tonsillar fossa and lateral oropharyngeal wall. STUDY DESIGN: Preclinical anatomic study using three human cadavers. METHODS: Transoral resection of the lateral oropharyngeal wall with mucosal and muscular resection of the tonsillar fossa. RESULTS: This single-port flexible robotic system could be used to successfully perform transoral resection of this region. The optimal angle to dock the patient side cart was at a 90-degree angle to the operating room table. The placement of the remote center of the robotic instrument arm was evaluated in three positions. When the cannula tip was placed at 10 to 15 cm, all instruments could be deployed past the first and second joggle joint settings, without collision or restriction of arm movement. Using this position and docking location, all four arms were deployed inside the oral cavity without collision or restriction of movement in all three cadavers. The Da Vinci SP (Intuitive Surgical, Inc., Sunnyvale, CA) provided sufficient access, reach, and visualization in order to complete a transoral lateral oropharyngectomy. CONCLUSION: The first preclinical feasibility study of a novel, flexible, single-arm robotic surgical system is presented for its use in transoral endoscopic head and neck surgery. LEVEL OF EVIDENCE: N/A. PMID- 26509921 TI - Effect of Hyperoxia on Retinoid Metabolism and Retinoid Receptor Expression in the Lungs of Newborn Mice. AB - BACKGROUND: Preterm newborns that receive oxygen therapy often develop bronchopulmonary dysplasia (BPD), which is abnormal lung development characterized by impaired alveologenesis. Oxygen-mediated injury is thought to disrupt normal lung growth and development. However, the mechanism of hyperoxia induced BPD has not been extensively investigated. We established a neonatal mouse model to investigate the effects of normobaric hyperoxia on retinoid metabolism and retinoid receptor expression. METHODS: Newborn mice were exposed to hyperoxic or normoxic conditions for 15 days. The concentration of retinol and retinyl palmitate in the lung was measured by HPLC to gauge retinoid metabolism. Retinoid receptor mRNA levels were assessed by real-time PCR. Proliferation and retinoid receptor expression in A549 cells were assessed in the presence and absence of exogenous vitamin A. RESULTS: Hyperoxia significantly reduced the body and lung weight of neonatal mice. Hyperoxia also downregulated expression of RARalpha, RARgamma, and RXRgamma in the lungs of neonatal mice. In vitro, hyperoxia inhibited proliferation and expression of retinoid receptors in A549 cells. CONCLUSION: Hyperoxia disrupted retinoid receptor expression in neonatal mice. PMID- 26509922 TI - Bioactive natural products from novel microbial sources. AB - Despite the importance of microbial natural products for human health, only a few bacterial genera have been mined for the new natural products needed to overcome the urgent threat of antibiotic resistance. This is surprising, given that genome sequencing projects have revealed that the capability to produce natural products is not a rare feature among bacteria. Even the bacteria occurring in the human microbiome produce potent antibiotics, and thus potentially are an untapped resource for novel compounds, potentially with new activities. This review highlights examples of bacteria that should be considered new sources of natural products, including anaerobes, pathogens, and symbionts of humans, insects, and nematodes. Exploitation of these producer strains, combined with advances in modern natural product research methodology, has the potential to open the way for a new golden age of microbial therapeutics. PMID- 26509923 TI - Lithium for schizophrenia. AB - BACKGROUND: Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary anti-psychotic drug treatment. In these cases, various add-on medications are used, among them lithium. OBJECTIVES: To assess whether:1. Lithium alone is an effective treatment for schizophrenia, schizophrenia-like psychoses and schizoaffective psychoses; and2. Lithium augmentation of antipsychotic medication is an effective treatment for the same illnesses. SEARCH METHODS: In July 2012, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. This search was updated on January 20, 2015. For the first version of the review, we also contacted pharmaceutical companies and authors of relevant studies to identify further trials and obtain original participant data. SELECTION CRITERIA: Randomised controlled trials (RCTs) of lithium compared with antipsychotics or placebo (or no intervention), whether as sole treatment or as an adjunct to antipsychotic medication, in the treatment of schizophrenia or schizophrenia-like psychoses or both. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data, we calculated random-effects meta analyses, risk ratios (RRs), and 95% confidence intervals (CI) on an intention-to treat basis. For continuous data, we calculated mean differences (MD) and 95% confidence intervals. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to create 'Summary of findings' tables and assessed risk of bias for included studies. MAIN RESULTS: The update search in 2012 detected two further studies that met our inclusion criteria. We did not find any further studies that met our inclusion criteria in the 2015 search. This review now includes 22 studies, with a total of 763 participants (median mean age: 35 years, range: 26 to 72 years). Most studies were small, of short duration, and incompletely reported. As we detected a high risk of bias in many studies, the overall methodological quality of the included sample was rather low.Three small studies comparing lithium with placebo as the sole treatment showed no difference in any of the outcomes we analysed.In eight studies comparing lithium with antipsychotic drugs as the sole treatment, more participants in the lithium group left the studies early (eight RCTs; n = 270, RR 1.77, 95% CI 1.01 to 3.11, low quality evidence).Thirteen studies examined whether the augmentation of antipsychotic drugs with lithium salts is more effective than antipsychotic drugs alone. More participants who received lithium augmentation had a clinically significant response (10 RCTs; n = 396, RR 1.81, 95% CI 1.10 to 2.97, low quality evidence). However, this effect became non-significant when we excluded participants with schizoaffective disorders in a sensitivity analysis (seven RCTs; n = 272, RR 1.64, 95% CI 0.95 to 2.81), when we excluded non-double-blind studies (seven RCTs; n = 224, RR 1.82, 95% CI 0.84 to 3.96), or when we excluded studies with high attrition (nine RCTs; n = 355, RR 1.67, CI 0.93 to 3.00). The overall acceptability of treatment (measured by the number of participants leaving the studies early) was not significantly different between groups (11 RCTs; n = 320, RR 1.89, CI 0.93 to 3.84, very low quality evidence). Few studies reported on side effects. There were no significant differences, but the database is too limited to make any judgement in this regard. For example, there were no data on thyroid dysfunction and kidney problems - two major and well-known side effects of lithium. AUTHORS' CONCLUSIONS: The evidence base for the use of lithium in schizophrenia is limited to 22 studies of overall low methodological quality. There is no randomised trial-based evidence that lithium on its own is an effective treatment for people with schizophrenia. There is some GRADE low quality evidence that augmentation of antipsychotics with lithium is effective, but the effects are not significant when more prone-to-bias open RCTs are excluded. Nevertheless, further large and well-designed trials are justified. These should concentrate on two target groups: (1) people with no affective symptoms, so that trialists can determine whether lithium has an effect on the core symptoms of schizophrenia, and (2) people with schizoaffective disorders for whom lithium is widely used in clinical practice, although there is no evidence to support this use. PMID- 26509924 TI - Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo. AB - Water molecules play integral roles in the formation of many protein-ligand complexes, and recent computational efforts have been focused on predicting the thermodynamic properties of individual waters and how they may be exploited in rational drug design. However, when water molecules form highly coupled hydrogen bonding networks, there is, as yet, no method that can rigorously calculate the free energy to bind the entire network or assess the degree of cooperativity between waters. In this work, we report theoretical and methodological developments to the grand canonical Monte Carlo simulation technique. Central to our results is a rigorous equation that can be used to calculate efficiently the binding free energies of water networks of arbitrary size and complexity. Using a single set of simulations, our methods can locate waters, estimate their binding affinities, capture the cooperativity of the water network, and evaluate the hydration free energy of entire protein binding sites. Our techniques have been applied to multiple test systems and compare favorably to thermodynamic integration simulations and experimental data. The implications of these methods in drug design are discussed. PMID- 26509925 TI - Iraqi, Syrian, and Palestinian Refugee Adolescents' Beliefs About Parental Authority Legitimacy and Its Correlates. AB - This study examined intra- and interindividual variations in parental legitimacy beliefs in a sample of 883 Arab refugee adolescents (M(age) = 15.01 years, SD = 1.60), 277 Iraqis, 275 Syrians, and 331 Palestinians in Amman, Jordan. Confirmatory factor analyses showed distinct latent factors for moral conventional, prudential, and personal legitimacy items. Older adolescents rated legitimacy lower for personal issues, but higher for prudential issues. Beliefs were associated with socioeconomic status (fathers' education, family size), particularly for personal issues, but were more pervasively associated with displacement-related experiences. Greater war trauma was associated with less prudential legitimacy for all youth and more authority legitimacy over moral conventional issues for Syrian youth. Greater hopefulness was associated with more authority legitimacy over all but personal issues. PMID- 26509926 TI - Epigenetic role of CCAAT box-binding transcription factor NF-Y on ID gene family in human embryonic carcinoma cells. AB - Nuclear factor Y (NF-Y) is a histone substitute protein that specifically binds to the CCAAT box of the target genes and thereby promotes their regulation. NF-Y transcription factor, with defined CCAAT element-binding activities, target a gene family that encodes a group of basic helix-loop-helix ID factors (ID1-ID4), with or without CCAAT box at their promoter region. In this study, the expressions of NF-Y in mRNA and protein level were evaluated in a human embryonic carcinoma cell line, named NTera2, before and after 7 days induction of differentiation. We also looked into expression levels of ID genes in NTera2 cells during differentiation because of their critical role in development. By using chromatin immunoprecipitation coupled with real-time polymerase chain reaction, NF-Y incorporation and acetylation/dimethylation of histone H3 at lysine 9 (H3K9ac/me2) was quantitatively evaluated on the regulatory regions of considered genes to monitor the changes in epigenetic markers at ID gene promoters throughout differentiation. The results demonstrated a marked down regulation of ID1, ID2, and ID3 genes, parallel to a loss of NF-Y binding to the promoters of these genes. The data show that although the genes encoding NF-Y complex remained expressed at mRNA level, NF-YC is lost at the protein level onset of differentiation. Additionally, the epigenetic marks of H3K9ac and H3K9me2 at the target gene promoters decreased and increased, respectively, after 1 day of differentiation. It is suggested that, in the absence of NF-Y binding, the corresponding regions adopt a heterochromatic nature, whereas when NF-Y comes back after 7 days of differentiation, the ID1-3 promoters become again converted into active chromatin. The ID4 gene, lacking a CCAAT box, behaves differently and does not show any incorporation. This experiment implies for the first time that the presence of NF-Y transcription factor plays a pivotal role in transcriptional regulation of ID genes in development. PMID- 26509927 TI - "Taller and Shorter": Human 3-D Spatial Memory Distorts Familiar Multilevel Buildings. AB - Animal experiments report contradictory findings on the presence of a behavioural and neuronal anisotropy exhibited in vertical and horizontal capabilities of spatial orientation and navigation. We performed a pointing experiment in humans on the imagined 3-D direction of the location of various invisible goals that were distributed horizontally and vertically in a familiar multilevel hospital building. The 21 participants were employees who had worked for years in this building. The hypothesis was that comparison of the experimentally determined directions and the true directions would reveal systematic inaccuracy or dimensional anisotropy of the localizations. The study provides first evidence that the internal representation of a familiar multilevel building was distorted compared to the dimensions of the true building: vertically 215% taller and horizontally 51% shorter. This was not only demonstrated in the mathematical reconstruction of the mental model based on the analysis of the pointing experiments but also by the participants' drawings of the front view and the ground plan of the building. Thus, in the mental model both planes were altered in different directions: compressed for the horizontal floor plane and stretched for the vertical column plane. This could be related to human anisotropic behavioural performance of horizontal and vertical navigation in such buildings. PMID- 26509929 TI - Correction: Significant differences of monooxotungsten(IV) and dioxotungsten(VI) benzenedithiolates containing two intramolecular NH...S hydrogen bonds from molybdenum analogues. AB - Correction for 'Significant differences of monooxotungsten(IV) and dioxotungsten(VI) benzenedithiolates containing two intramolecular NH...S hydrogen bonds from molybdenum analogues' by Taka-aki Okamura et al., Dalton Trans., 2015, 44, 18090-18100. PMID- 26509928 TI - High-resolution (1) H-MRSI of the brain using SPICE: Data acquisition and image reconstruction. AB - PURPOSE: To develop data acquisition and image reconstruction methods to enable high-resolution (1) H MR spectroscopic imaging (MRSI) of the brain, using the recently proposed subspace-based spectroscopic imaging framework called SPICE (SPectroscopic Imaging by exploiting spatiospectral CorrElation). THEORY AND METHODS: SPICE is characterized by the use of a subspace model for both data acquisition and image reconstruction. For data acquisition, we propose a novel spatiospectral encoding scheme that provides hybrid data sets for determining the subspace structure and for image reconstruction using the subspace model. More specifically, we use a hybrid chemical shift imaging /echo-planar spectroscopic imaging sequence for two-dimensional (2D) MRSI and a dual-density, dual-speed echo-planar spectroscopic imaging sequence for three-dimensional (3D) MRSI. For image reconstruction, we propose a method that can determine the subspace structure and the high-resolution spatiospectral reconstruction from the hybrid data sets generated by the proposed sequences, incorporating field inhomogeneity correction and edge-preserving regularization. RESULTS: Phantom and in vivo brain experiments were performed to evaluate the performance of the proposed method. For 2D MRSI experiments, SPICE is able to produce high-SNR spatiospectral distributions with an approximately 3 mm nominal in-plane resolution from a 10 min acquisition. For 3D MRSI experiments, SPICE is able to achieve an approximately 3 mm in-plane and 4 mm through-plane resolution in about 25 min. CONCLUSION: Special data acquisition and reconstruction methods have been developed for high-resolution (1) H-MRSI of the brain using SPICE. Using these methods, SPICE is able to produce spatiospectral distributions of (1) H metabolites in the brain with high spatial resolution, while maintaining a good SNR. These capabilities should prove useful for practical applications of SPICE. Magn Reson Med 76:1059-1070, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26509930 TI - Disulfide-Based Diblock Copolymer Worm Gels: A Wholly-Synthetic Thermoreversible 3D Matrix for Sheet-Based Cultures. AB - It is well-known that 3D in vitro cell cultures provide a much better model than 2D cell cultures for understanding the in vivo microenvironment of cells. However, significant technical challenges in handling and analyzing 3D cell cultures remain, which currently limits their widespread application. Herein, we demonstrate the application of wholly synthetic thermoresponsive block copolymer worms in sheet-based 3D cell culture. These worms form a soft, free-standing gel reversibly at 20-37 degrees C, which can be rapidly converted into a free flowing dispersion of spheres on cooling to 5 degrees C. Functionalization of the worms with disulfide groups was found to be essential for ensuring sufficient mechanical stability of these hydrogels to enable long-term cell culture. These disulfide groups are conveniently introduced via statistical copolymerization of a disulfide-based dimethacrylate under conditions that favor intramolecular cyclization and subsequent thiol/disulfide exchange leads to the formation of reversible covalent bonds between adjacent worms within the gel. This new approach enables cells to be embedded within micrometer-thick slabs of gel with good viability, permits cell culture for at least 12 days, and facilitates recovery of viable cells from the gel simply by incubating the culture in buffer at 4 degrees C (thus, avoiding the enzymatic degradation required for cell harvesting when using commercial protein-based gels, such as Matrigel). PMID- 26509931 TI - CD3(+)CD56(+) Natural Killer-Like T Cells Display Anti-HCV Activity but Are Functionally Impaired in HIV(+) Patients With Acute Hepatitis C. AB - OBJECTIVE: To analyze the role of CD3(+)CD56(+) natural killer (NK)-like T cells in HIV(+) patients with acute hepatitis C. DESIGN: Frequency, phenotype, and anti hepatitis C virus (HCV) activity of CD3(+)CD56(+) NK-like T cells were studied in 36 HIV(+) patients with acute hepatitis C. As controls, 12 patients with chronic HCV/HIV coinfection, 8 HIV monoinfected patients, and 12 healthy donors were enrolled in this study. METHODS: CD3(+)CD56(+) NK-like T-cell-mediated inhibition of HCV replication was analyzed using the HuH7A2HCVreplicon model. The CD3(+)CD56(+) NK-like T-cell phenotype and interferon (IFN)-gamma secretion were studied by flow cytometry. RESULTS: Interleukin 12/interleukin 15 stimulated CD3(+)CD56(+) NK-like T cells from healthy donors effectively block HCV replication in vitro in an IFN-gamma dependent manner. Accordingly, we found that blocking of IFN-gamma with a specific antibody significantly reduced the antiviral activity of CD3(+)CD56(+) NK-like T cells. However, when CD3(+)CD56(+) NK-like T cells from HIV(+) patients were studied, we found HIV infection to be associated with a significantly impaired IFN-gamma production, irrespective of HCV coinfection. Accordingly, CD3(+)CD56(+) NK-like T cells from HIV(+) patients were significantly less effective in blocking HCV replication in vitro than cells from healthy individuals. CONCLUSIONS: Taken together, our data indicate that HIV infection is associated with an impaired anti-HCV activity of CD3(+)CD56(+) NK like T cells, which might represent a novel mechanism of dysregulated immune response in HIV/HCV-coinfected patients. PMID- 26509932 TI - Expression and Function of NKG2D Is Impaired in CD8+ T Cells of Chronically HIV-1 Infected Patients Without ART. AB - OBJECTIVES: Increasing line of evidence indicates that the NKG2D-activating receptor plays a relevant role in the effector functions of cytotoxic lymphocytes. In this study, we investigated the expression and function of NKG2D in CD8+ T cells from chronically HIV-1-infected patients with or without antiretroviral therapy (ART). METHODS: We measured by flow cytometry the expression of NKG2D on CD8+ T-cell subsets of ART-naive and ART patients as well as seronegative healthy subjects (HIV-neg). An intrapatient analysis before and after ART initiation was also performed. Results were correlated with viral load, CD4+ T-cell counts, markers of immune activation (CD38, sCD14), and soluble NKG2D ligands (sMICA and sULBP2). The function of NKG2D on CD8+ T cell cytotoxicity was tested by ex vivo degranulation assays. RESULTS: We showed that NKG2D was downregulated on all CD8+ T-cell subsets of ART-naive patients. The expression of NKG2D on CD8+ T cells inversely correlated with viral load and CD38 expression but not with plasma levels of sMICA and sULBP2. Importantly, we found that NKG2D mediated costimulation of CD8+ T-cell lytic activity was strongly reduced in ART naive patients if compared with HIV-neg and ART subjects. Finally, intrapatient analysis demonstrated that effective anti-HIV-1 therapy restores NKG2D expression and NKG2D-induced cytotoxicity by CD8+ T cells. CONCLUSIONS: These data underscore that NKG2D downregulation contributes to impaired CD8+ T-cell responses in untreated HIV-1 infection and have implications for monitoring immune functions and response to treatments, and for the development of novel anti-HIV-1 strategies combining ART with drugs that stimulate NKG2D expression and function. PMID- 26509933 TI - Neuropsychological Impairment in Acute HIV and the Effect of Immediate Antiretroviral Therapy. AB - OBJECTIVE: To investigate neuropsychological performance (NP) during acute HIV infection (AHI) before and after combination antiretroviral therapy (cART). DESIGN: Prospective study of Thai AHI participants examined at 3 and 6 months after initiation of cART. METHODS: Thirty-six AHI participants were evaluated pre cART at median 19 days since HIV exposure and 3 and 6 months after cART with the Grooved Pegboard test, Color Trails 1 & 2 (CT1, CT2), and Trail Making Test A. Raw scores were standardized to 251 age- and education-matched HIV-uninfected Thais. To account for learning effects, change in NP performance was compared with that of controls at 6 months. Analyses included multivariable regression, nonparametric repeated measures analysis of variance, and Mann-Whitney U test. RESULTS: Baseline NP scores for the AHI group were within normal range (z-scores range: -0.26 to -0.13). NP performance improved on CT1, CT2, and Trail Making Test A in the initial 3 months (P < 0.01) with no significant change during the last 3 months. Only improvement in CT1 was greater than that seen in controls at 6 months (P = 0.018). Participants who performed >1 SD below normative means on >=2 tests (n = 8) exhibited higher baseline cerebrospinal fluid HIV RNA (P = 0.047) and had no improvement after cART. CONCLUSIONS: Most AHI individuals had normal NP performance, and early cART slightly improved their psychomotor function. However, approximately 25% had impaired NP performance, which correlated with higher cerebrospinal fluid HIV RNA, and these abnormalities were not reversed by early cART possibly indicating limited reversibility of cognitive impairment in a subset of AHI individuals. PMID- 26509934 TI - Graft-versus-host disease-like erythroderma: a manifestation of thymoma associated multiorgan autoimmunity. PMID- 26509935 TI - Supercalifragilisticexpialidocious! PMID- 26509936 TI - Corrigendum. PMID- 26509937 TI - Tailoring of Electronic Structure and Thermoelectric Properties of a Topological Crystalline Insulator by Chemical Doping. AB - Topological crystalline insulators (TCIs) are a new quantum state of matter in which linearly dispersed metallic surface states are protected by crystal mirror symmetry. Owing to its vanishingly small bulk band gap, a TCI like Pb0.6 Sn0.4 Te has poor thermoelectric properties. Breaking of crystal symmetry can widen the band gap of TCI. While breaking of mirror symmetry in a TCI has been mostly explored by various physical perturbation techniques, chemical doping, which may also alter the electronic structure of TCI by perturbing the local mirror symmetry, has not yet been explored. Herein, we demonstrate that Na doping in Pb0.6 Sn0.4 Te locally breaks the crystal symmetry and opens up a bulk electronic band gap, which is confirmed by direct electronic absorption spectroscopy and electronic structure calculations. Na doping in Pb0.6 Sn0.4 Te increases p-type carrier concentration and suppresses the bipolar conduction (by widening the band gap), which collectively gives rise to a promising zT of 1 at 856 K for Pb0.58 Sn0.40 Na0.02 Te. Breaking of crystal symmetry by chemical doping widens the bulk band gap in TCI, which uncovers a route to improve TCI for thermoelectric applications. PMID- 26509938 TI - Evaluation of Pharyngeal Function in Dogs with Laryngeal Paralysis Before and After Unilateral Arytenoid Lateralization. AB - OBJECTIVE: To evaluate pharyngeal and laryngeal function using esophagography, topical pharyngeal/laryngeal sensitivity testing, and electromyography (EMG) in normal and dogs with idiopathic laryngeal paralysis (ILP) before and after unilateral arytenoid lateralization. STUDY: Prospective controlled cohort study. ANIMALS: Dogs with laryngeal paralysis (ILP; n = 8) and age/breed-matched (AB, n = 8) and young breed-matched dogs (B, n = 8) were recruited. METHODS: Evaluation consisted of esophagography, topical pharyngeal/laryngeal sensitivity testing, and electrodiagnostic testing. Esophagography was performed with liquid and canned phases. Pharyngeal and laryngeal sensitivity was tested by applying a cotton-tipped applicator to the mucosa of pharynx/larynx at anesthetic induction. In all dogs, electrophysiological testing included EMG, direct evoked muscle potentials, motor nerve conduction velocities, and F wave testing. These were performed in the thoracic/pelvic limbs, extrinsic laryngeal muscles, epaxial, and masticatory muscles. RESULTS: Topical pharyngeal and laryngeal sensitivity testing was decreased in LP dogs compared with age-matched healthy control dogs. Esophagram showed dysmotility in the cranial and caudal esophagus. Gastroesophageal reflux was significantly higher in ILP dogs compared with the other 2 groups (P < .03). In all affected dogs, EMG abnormalities were limited to the interosseous muscles of both pelvic and thoracic limbs bilaterally. CONCLUSION: Dogs with ILP not only have recurrent laryngeal nerve (RLN) and pararecurrent laryngeal nerve (pRLN) dysfunction, but may also have concurrent cranial laryngeal nerve dysfunction. PMID- 26509939 TI - Fun and Games. PMID- 26509940 TI - Energy Expenditure During Xbox Kinect Play in Early Adolescents: The Relationship with Player Mode and Game Enjoyment. AB - OBJECTIVE: There has been growing interest in the use of active videogames to influence levels of physical activity. Most studies have investigated energy expenditure in general, without taking into account moderating factors such as player mode and game enjoyment. This study therefore examines whether children's energy expenditure and game enjoyment are higher when games are played in a two player mode than in a single-player mode. MATERIALS AND METHODS: Forty-three children from the 7th grade who exhibited an inactive lifestyle engaged in six sports exergames on an Xbox((r)) Kinect((r)) (Microsoft, Redmond, WA) console. The player mode (single-player or two-player mode) was manipulated (within subjects design). The primary parameters were "energy expenditure," which was measured with a SenseWear((r)) device (Bodymedia Inc., Pittsburgh, PA), and "game enjoyment," which was assessed through self-report. RESULTS: On average, Kinect play elicits moderate physical activity (approximately 4 metabolic equivalents of task). Games that are played in a two-player mode elicit more energy than games that are played in a single-player mode. However, this was only the case for simultaneous play (boxing, dancing, and tennis), not for turn-based play (bowling, baseball, and golf). Furthermore, participants generally liked exergaming, regardless of their sex or the player mode. Finally, no significant correlation was found between energy expenditure and game enjoyment. CONCLUSIONS: This study has shown that Kinect play elicits physical activity of moderate intensity. Furthermore, Kinect play is generally enjoyed by both boys and girls. Simultaneous play may be the best suited to increase levels of physical activity in early adolescents who exhibit an inactive lifestyle. PMID- 26509941 TI - Examining Enjoyment of Casual Videogames. AB - OBJECTIVE: This study investigated the processes leading to enjoyment of casual videogames on both mobile devices and console systems. Building upon a foundation in mental models theory and the psychology of play, the study focuses on how performance and experience-based variables impact enjoyment of casual videogames played on mobile devices and console devices. The grounding assumption of this research is that playing videogames produces enjoyment that contributes to mental health in the form of a brief distraction from the stress of daily life, social connections with family and friends through casual gameplay, and, in some cases, a compelling reason to engage in physical activity. MATERIALS AND METHODS: A student sample of players (n=363) played a variety of casual games on mobile (iPad((r)) or iPod((r)) Touch((r)) [Apple, Cupertino, CA]) or console (WiiTM [Nintendo, Japan], Xbox((r)) 360 Kinect((r)) [Microsoft, Redmond, WA], or PS3TM Move [Sony, Tokyo, Japan]) platforms. They then answered a questionnaire assessing their evaluations of the game's interactivity level, their sense of spatial presence in the game, their perception of the game's realism, and, most importantly, their enjoyment. Path analysis demonstrated the interrelationships among these variables. RESULTS: The results show that spatial presence is a powerful predictor of videogame enjoyment for both console- and mobile-based casual games. Patterns of prediction for games on each platform, as demonstrated using path analysis, were similar and aligned with predictions based on mental models and the psychology of play. CONCLUSIONS: The psychological theory of play and the mental models perspective offer firm theoretical grounds for understanding how enjoyment is wrought in the process of playing casual games. The relationships among interactivity, spatial presence, perceived reality, and enjoyment hold for games played on handheld or console devices. Furthermore, this study is one of the first to demonstrate these relationships and test them simultaneously, breaking new ground in research on game enjoyment. PMID- 26509942 TI - The Demographics and Rates of Tattoo Complications, Regret, and Unsafe Tattooing Practices: A Cross-Sectional Study. AB - BACKGROUND: Tattoos have become increasingly common in the United States; however, there are limited data on the rates of tattoo complications and tattoo regret. OBJECTIVE: To determine the rates of infectious and allergic complications after tattooing, rates of tattoo regret, the perception of dermatologists among people with tattoos, and the demographics of people with tattoos. MATERIALS AND METHODS: An 18-question cross-sectional survey was fielded in New Orleans in January 2015. Participants had to be at least 18 years old, have at least 1 tattoo, and reside within the United States. RESULTS: In total, 501 participants from 38 American states were enrolled. Of all participants, 3.2% had a history of an infected tattoo, 3.8% had a history of a painful tattoo, and 21.2% had a history of a pruritic tattoo; 16.2% of participants regret a current tattoo and 21.2% are interested in having 1 or more tattoos removed; 21.2% received a tattoo while intoxicated and 17.6% had a tattoo placed somewhere other than at a tattoo parlor; and 78.9% believe dermatologists are knowledgeable about the infectious and allergic complications of tattoos. CONCLUSION: Given the rates of pruritic tattoos and tattoo regret, there is an opportunity, and trust among people with tattoos, for dermatologists to manage these complications. PMID- 26509943 TI - A Randomized, Double-Blind Trial to Investigate the Equivalence of IncobotulinumtoxinA and OnabotulinumtoxinA for Glabellar Frown Lines. AB - BACKGROUND: IncobotulinumtoxinA and onabotulinumtoxinA are indicated for the temporary improvement in the appearance of glabellar frown lines (GFL). This is the first randomized direct comparator study to date, at the Food and Drug Administration-recommended dose of 20 units (U), for the treatment of GFL. OBJECTIVE: To investigate the dose equivalence of incobotulinumtoxinA (20 U) and onabotulinumtoxinA (20 U) for the treatment of moderate-to-severe GFL. MATERIALS AND METHODS: Prospective, randomized (1:1), double-blinded, parallel-group study in 250 females (18-50 years), employing a single treatment with incobotulinumtoxinA or onabotulinumtoxinA, followed by a 4-month observational period. RESULTS: At the primary efficacy endpoint (1 month after treatment), incobotulinumtoxinA was equivalent to onabotulinumtoxinA in the treatment of GFL at the 20 U dose within the prespecified +/- 15% margin of equivalence. Efficacy remained similar between treatment groups through 4 months after treatment as assessed by the independent masked panel and the masked treating physicians. Patient satisfaction ratings were similar between groups and favorable (>90%) throughout. Both treatments were well tolerated. CONCLUSION: Equivalence was demonstrated at the primary endpoint between incobotulinumtoxinA and onabotulinumtoxinA in the treatment of GFL at the 20 U dose at 1 month. Similar efficacy and tolerability profiles were observed through 4 months after treatment. PMID- 26509944 TI - Commentary on: Randomized Split-Face Study to Assess the Efficacy and Safety of AbobotulinumtoxinA Versus OnabotulinumtoxinA in the Treatment of Melomental Folds (Depressor Anguli Oris). PMID- 26509945 TI - Intermittent Vismodegib Therapy in Basal Cell Nevus Syndrome. PMID- 26509946 TI - Is it possible to increase the n-3 fatty acid content of eggs without affecting their technological and/or sensorial quality and the laying performance of hens? AB - The aim of this study was to increase the n-3 fatty acid (n-3 FA) content of eggs without affecting their sensorial and/or technological properties or the laying performance of hens. Laying hens from line 477 were divided into 5 groups corresponding to 5 different diets over the laying period: control diet (C) and diets containing extruded linseed with a high level of fibre (ELHF), extruded linseed with a low level of fibre (ELLF), microalgae, or a combination of 75% ELLF and 25% MA (ELLF+MA). Dietary enrichment with n-3 FA had no effect on the laying performance, hen body weight or egg white viscosity. The egg yolks produced by hens fed the diet containing microalgae were redder than egg yolks from the other groups, suggesting the presence of red pigments in the microalgae preparation. However, the colour difference was low and not perceptible to the human eye. Moreover, colour measurement of egg yolks by sensorial analysis panellists using the Roche colour fan did not reveal a diet effect on this parameter. Egg yolk lipid content was not affected by diet. The egg yolk of hens fed on diets containing linseed and/or microalgae had greater n-3 FA content (*2.5 to 2.9 compared to group C). Linseed mainly increased the linolenic acid content (*3.0 to 3.4 compared to group C) and the microalgae increased the LC n-3 FA content (*4.1 compared to group C). Dietary enrichment with n-3 FA had no effect on the sensorial quality of shell cooked eggs except for the "unusual flavour" criterion for which the score was higher for the MA group compared to the other groups and corresponded to a fishy flavour. PMID- 26509947 TI - Recycling: Lazarus batteries. PMID- 26509948 TI - Energy storage: Power revolution. PMID- 26509949 TI - Batteries: 4 big questions. PMID- 26509950 TI - Batteries. PMID- 26509951 TI - From gadgets to the smart grid. PMID- 26509952 TI - Perspective: The energy-storage revolution. PMID- 26509953 TI - Lithium batteries: To the limits of lithium. PMID- 26509954 TI - Technology: A solid future. PMID- 26509955 TI - Electrochemistry: Liquid assets. PMID- 26509956 TI - Symmetry-dependent spin-charge transport and thermopower through a ZSiNR-based FM/normal/FM junction. AB - We investigate the spin-dependent transport and spin thermopower for a zigzag silicene nanoribbon (ZSiNR) with two ends covered by ferromagnets (FMs) under the modulation of a perpendicular electric field, where we take the 6- and 7-ZSiNR to exemplify the effect of the even- and odd-N ZSiNRs, respectively. By using the nonequilibrium Green's function approach, it is demonstrated that a ZSiNR-based FM/normal/FM junction still shows an interesting symmetry-dependent property although the sigma mirror plane is absent for any ZSiNR due to the buckled structure of silicene. The junction with even- or odd-N ZSiNR has very different transport and thermopower behavior, which is attributed to the different parity of pi and [Formula: see text] band wavefunctions under the c 2 symmetry operation with respect to the centre axis between two edges, and is linked to the unique symmetry of the band structure for the ribbon. As a result, the magnetoresistance (MR) for the 6-ZSiNR junction with a 100% plateau around zero electron energy is observed, but the plateau is absent for the 7-ZSiNR one. In addition, the spin thermopower also displays the even-odd behaviour. The 6-ZSiNR junction is found to possess superior thermospin performance compared with the 7-ZSiNR one, and its spin thermopower can be improved by one order of magnitude in the absence of an electric field. As the strength of the field increases, the spin thermopower for the 6-ZSiNR junction dramatically decreases, while it notably enhances for the 7 ZSiNR one. Interestingly, the spin thermopower for both junctions is strongly dependent on the strength of magnetisation in FM, and it can be very pronounced with a maximum absolute value of 200 MUV K(-1)by the optimisation of the parameters. However, with the increase in temperature, the spin thermopower for the 6-ZSiNR junction decreases, but the situation for the 7-ZSiNR one is opposite. Finally, the spin figure of merit for the 6-ZSiNR junction is found to be four orders of magnitude larger than that for the 7-ZSiNR one. This even-odd effect is common for N-SiNR, and the result can be regarded as an advance in the understanding of the characteristics of silicene and may be valuable for experimentally designing spin valve and heat spintronic devices based on silicene. PMID- 26509957 TI - Synthesis of a Precursor to Sacubitril Using Enabling Technologies. AB - An efficient preparation of a precursor to the neprilysin inhibitor sacubitril is described. The convergent synthesis features a diastereoselective Reformatsky type carbethoxyallylation and a rhodium-catalyzed stereoselective hydrogenation for installation of the two key stereocenters. Moreover, by integrating machine assisted methods with batch processes, this procedure allows a safe and rapid production of the key intermediates which are promptly transformed to the target molecule (3.HCl) over 7 steps in 54% overall yield. PMID- 26509958 TI - Electrophoresis of pH-regulated nanoparticles: impact of the Stern layer. AB - A multi-ion model taking into account the Stern layer effect and the surface chemistry reactions is developed for the first time to investigate the surface charge properties and electrophoresis of pH-regulated silica nanoparticles (NPs). The applicability of the model is validated by comparing its prediction to the experimental data of the electrophoretic mobility of silica NPs available from the literature. Results show that if the particle size is fixed, the Stern layer effect on the surface charge properties of the NP is notable at high pH and background salt concentration; however, that effect on the particle mobility is significant when pH is around neutrality and the salt concentration is medium high (ca. 0.07 M) because of the double-layer polarization effect. Moreover, if pH and the background salt concentration are fixed, the Stern layer effect on the zeta potential and electrophoretic mobility of the NP becomes more significant for smaller particle size. Neglecting the Stern layer effect could result in the overestimation of the zeta potential, surface charge density, and electrophoretic mobility of a NP on the order of several times. PMID- 26509959 TI - Coacervation of Elastin-Like Recombinamer Microgels. AB - The investigation of the coacervation (self-aggregation) behavior of biomicrogels which can potentially be used as drug carriers is an important topic, because self-aggregation can not only cause loss of activity, but also toxicity and immunogenicity. To study this effect microgels from elastin-like recombinamer are synthesized using miniemulsion technique. The existence of coacervation for such microgels, at different concentrations and temperatures, is studied and proved by cryo-field emission scanning clectron microscopy (cryo-FESEM), cryo-transmission electron microscopy (cryo-TEM), and by a novel (1) H high-resolution magic angle sample spinning (HRMAS), nuclear magnetic resonance (NMR) spectroscopy, and relaxometry methods. The findings by (1) H HRMAS NMR spectroscopy and relaxometry show simultaneous processes of volume phase temperature transition and coacervation with different sensitivity for hydrophobic and hydrophilic amino acid side-chains in the microgel. The coacervation process is more evidential by the behavior of glycine alpha-CH2 , (1) H NMR peak as compared to the proline beta-CH2 . PMID- 26509960 TI - Factors Associated With Interhospital Variability in Inpatient Costs of Liver and Pancreatic Resections. AB - IMPORTANCE: In an era of accountable care, understanding variation in health care costs is critical to reducing health care spending. OBJECTIVE: To identify factors associated with increased hospital costs and quantify variations in costs among individual hospitals in patients undergoing liver and pancreatic surgery in the United States. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of total costs among 42 480 patients undergoing hepatopancreaticobiliary surgery from January 1, 2002, through December 31, 2011, using a nationally representative data set (Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project). Analysis was conducted in May 2015. MAIN OUTCOMES AND MEASURES: Total inpatient costs and proportional variation in inpatient costs among individual hospitals. RESULTS: Among the 42 480 patients who underwent liver or pancreatic resection, the median age was 62 years, 52.4% were female, and 72.9% had a Charlson Comorbidity Index of 2 or higher. The median cost for the entire cohort was $21,535 (interquartile range, $15,373-$31,104), varying from $3320 to $279,102 among individual hospitals. On multivariable analysis, increasing patient comorbidity (coefficient, 2000.30; 95% CI, 1363.33-2637.27; P < .001) and operative characteristics (total pancreatectomy: coefficient, 12 742.31; 95% CI, 10 063.66-15 420.94; P < .001; lobectomy: coefficient, 6336.42; 95% CI, 3934.61-8737.24; P < .001) were associated with higher hospital costs. The development of postoperative complications, such as sepsis (coefficient, 30 571.25; 95% CI, 29 308.96-31 833.54; P < .001) or stroke (coefficient, 8925.34; 95% CI, 2801.38-15 049.30; P = .004), and a longer length of stay were most strongly predictive of higher inpatient cost (length of stay >14 days: coefficient, 44 162.24; 95% CI, 43 125.56-45 198.92; P < .001). After adjusting for patient and hospital characteristics, the overall cost of hepatopancreaticobiliary surgery varied by $9000 among individual hospitals. CONCLUSIONS AND RELEVANCE: Significant variability was noted in hospital costs among patients undergoing pancreatic and liver surgery. Future policies should focus on reducing variations in costs by promoting payment paradigms that support a better quality of care and lower costs. PMID- 26509961 TI - Photoelectron Imaging Spectroscopy of AuC3H(-) Anions: Four Isomers. AB - Laser ablation generated AuC3H(-) anions were skimmed into a time-of-flight mass spectrometer (TOF-MS) and selected with a mass gate. Photoelectron spectra of AuC3H(-) were recorded using the velocity map imaging technique at several photon energies. The experimental spectra, quantum chemistry calculations, and Franck Condon simulations suggest that the AuC3H(-) cluster has four structure isomers, including one unexpected structure of [C?C?C-Au-H](-). When AuC3H(-) is compared with C3H2(-), introduction of gold into the hydrocarbon system results in the much lower isomerization barriers. PMID- 26509962 TI - Pattern of Variation of Fruit Traits and Phenol Content in Olive Fruits from Six Different Cultivars. AB - In the present study, olive fruits from six cultivars grown under similar agronomical and environmental conditions were collected at four different times during fruit ripening. Some agronomical traits were determined, and general increases in the size of the fruit and oil contents were recorded for all cultivars. The phenolic fraction in fruits was also identified and quantified during the same period using high-performance liquid chromatography-diode array detection-time-of-flight-mass spectrometry. Thus, a total of 57 phenolic compounds were determined, and qualitative and quantitative differences among cultivars and also among sampling times were observed. In contrast to the agronomical traits, a general decrease of total phenolic compounds was observed, characterized by a domination of secoiridoids at the beginning of ripening and by a domination of simple phenols and flavonoids in the end. This is the first time that four of the six cultivars have been studied regarding phenolic compounds evolution during ripening. PMID- 26509963 TI - Tumor-suppressive microRNA-223 inhibits cancer cell migration and invasion by targeting ITGA3/ITGB1 signaling in prostate cancer. AB - Analysis of microRNA (miRNA) expression signatures in prostate cancer (PCa) and castration-resistant PCa has revealed that miRNA-223 is significantly downregulated in cancer tissues, suggesting that miR-223 acts as a tumor suppressive miRNA by targeting oncogenes. The aim of this study was to investigate the functional roles of miR-223 and identify downstream oncogenic targets regulated by miR-223 in PCa cells. Functional studies of miR-223 were carried out to investigate cell proliferation, migration, and invasion using PC3 and PC3M PCa cell lines. Restoration of miR-223 significantly inhibited cancer cell migration and invasion in PCa cells. In silico database and genome-wide gene expression analyses revealed that ITGA3 and ITGB1 were direct targets of miR-223 regulation. Knockdown of ITGA3 and ITGB1 significantly inhibited cancer cell migration and invasion in PCa cells by regulating downstream signaling. Moreover, overexpression of ITGA3 and ITGB1 was observed in PCa clinical specimens. Thus, our data indicated that downregulation of miR-223 enhanced ITGA3/ITGB1 signaling and contributed to cancer cell migration and invasion in PCa cells. Elucidation of the molecular pathways modulated by tumor-suppressive miRNAs provides insights into the mechanisms of PCa progression and metastasis. PMID- 26509964 TI - Compartmentalization Approaches in Soft Matter Science: From Nanoreactor Development to Organelle Mimics. AB - Compartmentalization is an essential feature found in living cells to ensure that biological processes occur without being affected by undesired external influences. Over the years many scientists have designed self-assembled soft matter structures that mimic these natural catalytic compartments. The rationale behind this research is threefold. First of all, compartmentalization leads to the creation of a secluded environment for the catalytic species, which solves compatibility issues and which can improve catalyst efficiency and selectivity. Secondly, nano- and micro-compartments are constructed with the aim to obtain microenvironments that more closely mimic the cellular architecture. These biomimetic platforms are used to attain a better understanding of how cellular processes are executed. Thirdly, natural design rules are applied to create biomolecular assemblies with unusual functionality, which for example are used as artificial organelles. Here, recent developments will be discussed regarding these compartmentalized catalytic systems, with a selected number of illustrative examples to demonstrate which strategies have been followed, and to show to what extent the ambitious goals of this field of science have been reached. The focus here is on the field of soft matter science, covering the wide spectrum from polymeric assemblies to protein nanocages. PMID- 26509965 TI - Correction to "dynamics of energy transfer in a conjugated dendrimer driven by ultrafast localization of excitations". PMID- 26509966 TI - Effect of Physicians' Attitudes and Knowledge on the Quality of Antibiotic Prescription: A Cohort Study. AB - Resistance increases with the use and abuse of antibiotics. Since physicians are primarily responsible for the decision to use antibiotics, ascertaining the attitudes and knowledge that underlie their prescribing habits is thus a prerequisite for improving prescription. Three-year follow-up cohort study (2008 2010) targeting primary-care physicians (n = 2100) in Galicia, a region in NW Spain. We used data obtained from a postal survey to assess knowledge and attitudes. A physician was deemed to have demonstrated Appropriate Quality Prescription of Antibiotics (dependent variable) in any case where half or more of the indicators proposed by the European Surveillance of Antimicrobial Consumption had values that were better than the reference values for Spain. The mail-questionnaire response rate was 68.0% (1428/2100). The adjusted increase in the interquartile OR of displaying good prescribing of antibiotics for each attitude was: 205% for fear ("When in doubt, it is better to ensure that a patient is cured of an infection by using a broad-spectrum antibiotic"; 95%CI: 125% to 321%); 119% for better knowledge ("Amoxicillin is useful for resolving most respiratory infections in primary care"; 95%CI: 67% to 193%); and 21% for complacency with patients' demands ("Antibiotics are often prescribed due to patients' demands"; 95%CI: 0% to 45%). Due to the fact that physicians' knowledge and attitudes are potentially modifiable, the implementation of purpose-designed educational interventions based on the attitudes identified may well serve to improve antibiotic prescription. PMID- 26509967 TI - Clinicopathologic Features and Molecular Characteristics of Glucose Metabolism Contributing to 18F-fluorodeoxyglucose Uptake in Gastrointestinal Stromal Tumors. AB - Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) is useful in the preoperative diagnosis of gastrointestinal stromal tumors (GISTs); however, the molecular characteristics of glucose metabolism of GIST are unknown. We evaluated 18F-FDG uptake on preoperative PET/CT of 40 patients and analyzed the expression of glycolytic enzymes in resected GIST tissues by qRT-PCR, western blotting, and immunohistochemistry. Results of receiver operating characteristic curve analysis showed that the maximum standardized uptake value (SUVmax) cut-off value of 4.99 had a sensitivity of 89.5%, specificity was 76.2%, and accuracy of 82.5% for identifying tumors with a high risk of malignancy. We found that 18F-FDG uptake correlated positively with tumor size, risk grade, and expression levels of glucose transporter 1 (GLUT1), hexokinase 1 (HK1), and lactate dehydrogenase A (LDHA). Elevated HK and LDH activity was found in high-risk tumors. Among the isoforms of GLUT and HK, GLUT1 and HK1 expression increased with higher tumor risk grade. In addition, overexpression of glycolytic enzymes M2 isoform of pyruvate kinase (PKM2) and LDHA was observed in GISTs, especially in high-risk tumors. These results suggest that upregulation of GLUT1, HK1, PKM2, and LDHA may play an important role in GIST tumorigenesis and may be useful in the preoperative prediction of malignant potential. PMID- 26509968 TI - The Influence of Naringin or Hesperidin Dietary Supplementation on Broiler Meat Quality and Oxidative Stability. AB - An experiment was conducted to examine the effects of supplementing broiler feed with hesperidin or naringin, on growth performance, carcass characteristics, breast meat quality and the oxidative stability of breast and thigh meat. Two hundred and forty 1-day-old Ross 308 broiler chickens were randomly assigned to 6 groups. One of the groups served as a control (C) and was given commercial basal diets, whereas the other five groups were given the same diets further supplemented with naringin at 0.75 g/kg (N1), naringin at 1.5 g/kg (N2), hesperidin at 0.75 g/kg (E1), hesperidin at 1.5 g/kg (E2) and a-tocopheryl acetate at 0.2 g/kg (E). At 42 days of age, 10 chickens per treatment group were slaughtered for meat quality and oxidative stability assessment. No significant differences were observed among groups in final body weight, carcass weight and internal organs weights (P>0.05) apart from liver that decreased linearly with increased levels of naringin (P-linear<0.05). Regarding the breast meat quality parameters, only redness (a*) value was higher in E1 and N1 group compared to VE group (P<0.05), while all the others i.e. shear values (N/mm2), pH24, cooking loss (%) and L* and b* color parameters were not significantly different among groups (P>0.05). Measurement of lipid oxidation values showed that after hesperidin and naringin dietary supplementation, malondialdehyde values decreased in tissue samples in a dose depended manner (P-linear<0.05). In conclusion, hesperidin and naringin, positively influence meat antioxidative properties without negative implications on growth performance and meat quality characteristics in poultry, thus appearing as important additives for both the consumer and the industry. PMID- 26509970 TI - [Attachment Quality of Young Children with Mentally Ill Parents on the Example of the Munchausen by Proxy Syndrome]. AB - One of the most discussed questions in clinical literature concerns the impact of child abuse by mentally ill parents (cf. Mattejat, 1998). It's obvious that most children cannot understand such a parental behaviour and that this lack of understanding along with the lack of knowledge about their parents' emotional disorder results in childrens' fear, disorientation and uncertainty. The consequences are massive interferences in the relationship between parents and children, who could develop an anxious-resistant insecure or even a disorganized/disoriented attachment. But how does a child react, if the behaviour of its parents is ambivalent itself and alternates from abuse to care? Such a parental behaviour is described as the "Munchausen by Proxy Syndrome". This article regards the effects of a "Munchausen by Proxy Syndrome" on the childrens' attachment development. After discussing the basic assumptions about the "Munchhauen by Proxy Syndrome" and the attachment theory we draw conclusions about the syndrome's effect on childrens' attachment behaviour. PMID- 26509971 TI - [Relationship Between Child Behavior and Emotional Problems and School Based Effort Avoidance]. AB - The present study has examined the relationship between school based effort avoidance tendencies and problem behavior in children aged 9 to 16 years. Effort avoidance tendencies were assessed in 367 children with and without child care. Teachers and social workers rated children on behavioral and emotional problems with the Strengths and Difficulties Questionnaire (SDQ). Results confirmed significant but low correlations between teacher ratings of behavior and emotional problems in children and selected subscales of self-reported effort avoidance in school, especially for children in child care institutions. For them "conduct problems" were significantly correlated with three of the four subscales and the total sum score of effort avoidance whereas "hyperactivity" was the only scale which was significantly associated with the fourth subscale. In the school sample only "hyperactivity" and "peer problems" were significantly correlated with one subscale of school-based effort avoidance. The findings suggest that more problem behavior is in relation to more school based effort avoidance tendencies. PMID- 26509972 TI - [The Play-PAB and its Validation in a Preschool Psychiatric Population]. AB - With community samples, parent behavior can be assessed in standardized mother child interaction situations with the observational instrument Lab-PAB by Wilson und Durbin (2012) with respect to five dimensions (Involvement, Positive Emotionality, Hostility, Intrusiveness and Discipline). We examined an adaptation of Lab-PAB for non-standardized free-play interaction situations (Play-PAB version) with a preschool psychiatric sample. We examined the internal consistency, interrater reliability and dimensional structure of the Play-PAB and its associations to the clinical relationship assessment scale PIR-GAS from DC:0 3R. Interaction sequences of 47 parent-child dyads who were treated in our Family Day Clinic were evaluated at admission with the Play-PAB, in addition to the PIR GAS-rating. Each instrument was rated by two independent raters. We report means, standard deviations, internal consistencies and the interrater-reliability for each of the five Play-PAB scales. Furthermore we examine if the scale intercorrelations are reasonable in comparison to the original version. Finally, the associations to PIR-GAS are presented. The Play-PAB scales reflect sufficient variation of parenting, good internal consistencies and satisfactory interrater reliability. The adaptation shows psychometric properties that are comparable to the original version. The scale intercorrelations as well as the associations to PIR-GAS are reasonable. The Play-PAB is a promising instrument for assessing different aspects of parent behavior in a preschool psychiatric sample, with meaningful associations to parent-child-relationship quality. PMID- 26509976 TI - Modeling the Impact of Alternative Immunization Strategies: Using Matrices as Memory Lanes. AB - Existing modeling approaches are divided between a focus on the constitutive (micro) elements of systems or on higher (macro) organization levels. Micro-level models enable consideration of individual histories and interactions, but can be unstable and subject to cumulative errors. Macro-level models focus on average population properties, but may hide relevant heterogeneity at the micro-scale. We present a framework that integrates both approaches through the use of temporally structured matrices that can take large numbers of variables into account. Matrices are composed of several bidimensional (time*age) grids, each representing a state (e.g. physiological, immunological, socio-demographic). Time and age are primary indices linking grids. These matrices preserve the entire history of all population strata and enable the use of historical events, parameters and states dynamically in the modeling process. This framework is applicable across fields, but particularly suitable to simulate the impact of alternative immunization policies. We demonstrate the framework by examining alternative strategies to accelerate measles elimination in 15 developing countries. The model recaptured long-endorsed policies in measles control, showing that where a single routine measles-containing vaccine is employed with low coverage, any improvement in coverage is more effective than a second dose. It also identified an opportunity to save thousands of lives in India at attractively low costs through the implementation of supplementary immunization campaigns. The flexibility of the approach presented enables estimating the effectiveness of different immunization policies in highly complex contexts involving multiple and historical influences from different hierarchical levels. PMID- 26509977 TI - The GTP- and Phospholipid-Binding Protein TTD14 Regulates Trafficking of the TRPL Ion Channel in Drosophila Photoreceptor Cells. AB - Recycling of signaling proteins is a common phenomenon in diverse signaling pathways. In photoreceptors of Drosophila, light absorption by rhodopsin triggers a phospholipase Cbeta-mediated opening of the ion channels transient receptor potential (TRP) and TRP-like (TRPL) and generates the visual response. The signaling proteins are located in a plasma membrane compartment called rhabdomere. The major rhodopsin (Rh1) and TRP are predominantly localized in the rhabdomere in light and darkness. In contrast, TRPL translocates between the rhabdomeral plasma membrane in the dark and a storage compartment in the cell body in the light, from where it can be recycled to the plasma membrane upon subsequent dark adaptation. Here, we identified the gene mutated in trpl translocation defective 14 (ttd14), which is required for both TRPL internalization from the rhabdomere in the light and recycling of TRPL back to the rhabdomere in the dark. TTD14 is highly conserved in invertebrates and binds GTP in vitro. The ttd14 mutation alters a conserved proline residue (P75L) in the GTP-binding domain and abolishes binding to GTP. This indicates that GTP binding is essential for TTD14 function. TTD14 is a cytosolic protein and binds to PtdIns(3)P, a lipid enriched in early endosome membranes, and to phosphatidic acid. In contrast to TRPL, rhabdomeral localization of the membrane proteins Rh1 and TRP is not affected in the ttd14P75L mutant. The ttd14P75L mutation results in Rh1-independent photoreceptor degeneration and larval lethality suggesting that other processes are also affected by the ttd14P75L mutation. In conclusion, TTD14 is a novel regulator of TRPL trafficking, involved in internalization and subsequent sorting of TRPL into the recycling pathway that enables this ion channel to return to the plasma membrane. PMID- 26509979 TI - The Association of Guided Bone Regeneration and Enamel Matrix Derivative for Suprabony Reconstruction in the Esthetic Area: A Case Report. AB - This case report presents the correction of severe alveolar ridge atrophy due to congenital and iatrogenic factors. Implants that compromised the natural adjacent teeth and overall esthetics for this young patient were removed and replaced after significant vertical bone and soft tissue regenerative procedures. A treatment combination of bone graft particles, a nonresorbable membrane, and enamel matrix derivatives was used. Significant and stable improvement in esthetics was achieved 12 months after final prosthetic restoration, demonstrating the ability of such a combined treatment to correct the esthetic deformity, improve the health of the adjacent natural teeth, and allow for successful implant treatment. PMID- 26509978 TI - Functional Analysis of Mutations in Exon 9 of NF1 Reveals the Presence of Several Elements Regulating Splicing. AB - Neurofibromatosis type 1 (NF1) is one of the most common human hereditary disorders, predisposing individuals to the development of benign and malignant tumors in the nervous system, as well as other clinical manifestations. NF1 is caused by heterozygous mutations in the NF1 gene and around 25% of the pathogenic changes affect pre-mRNA splicing. Since the molecular mechanisms affected by these mutations are poorly understood, we have analyzed the splicing mutations identified in exon 9 of NF1, which is particularly prone to such changes, to better define the possible splicing regulatory elements. Using a minigene approach, we studied the effect of five splicing mutations in this exon described in patients. These highlighted three regulatory motifs within the exon. An in vivo splicing analysis of an extensive collection of changes generated in the minigene demonstrated that the CG motif at c.910-911 is critical for the recognition of exon 9. We also found that the GC motif at c.945-946 is involved in exon recognition through SRSF2 and that this motif is part of a Composite Exon Splicing Regulatory Element made up of physically overlapping enhancer and silencer elements. Finally, through an in vivo splicing analysis and in vitro binding assays, we demonstrated that the c.1007G>A mutation creates an Exonic Splicing Silencer element that binds the hnRNPA1 protein. The complexity of the splicing regulatory elements present in exon 9 is most likely responsible for the fact that mutations in this region represent 25% of all exonic changes that affect splicing in the NF1 gene. PMID- 26509980 TI - Occlusion: A Contemporary Overview and Recommendations. AB - Dental occlusal concepts have developed over time, essentially by trial and error. Most have stood the test of observation, and more recently science has verified some of the viewed occlusal successes. The purpose of this article is to examine and distill, in an evidence-based manner, the commonalities that allow practitioners of one occlusal philosophy or another to achieve consistent success. Medline and the Cochrane Collaboration were used to procure relevant articles. PMID- 26509981 TI - Wound Healing of the Laterally Positioned Flap: A Histomorphometric Assessment. AB - The aim of this study was to histomorphometrically assess the soft tissue anatomy in single gingival recessions (GR) treated with a laterally positioned flap (LPF). Five patients presenting maxillary first molars with GR to the apex of the buccal surface of the mesial-buccal root were invited to take part. The LPF treated roots were removed en bloc (the root and the soft tissue covering the treated GR) 3 to 4 months postoperatively. Photomicrographs of Mallory trichrome stain sections were taken to allow reassessment of the specimens regarding the longitudinal dimensions of the crevicular/sulcular and junctional epithelia. The use of LPF resulted in new attachment with formation of crevicular epithelium, long junctional epithelium, and some connective tissue, re-establishing the normal anatomical characteristics of the soft tissues covering the previously exposed root. PMID- 26509982 TI - A Novel Approach for the Coronal Advancement of the Buccal Flap. AB - An adequate flap release is necessary to perform a tension-free suture over an augmented area. This is a fundamental requisite to attain and maintain a reliable biological seal, protecting the graft from bacterial contamination during the healing period. In the posterior mandible, in particular, the use of conventional periosteal incisions is not always sufficient for a proper buccal flap passivation, as they are often limited by anatomical factors. This article reports a series of 76 consecutive cases of vertical guided bone regeneration in the posterior mandible introducing a novel surgical technique to enhance the coronal advancement of the buccal flap in a safe and predictable way. PMID- 26509983 TI - Flapless Postextraction Socket Implant Placement, Part 2: The Effects of Bone Grafting and Provisional Restoration on Peri-implant Soft Tissue Height and Thickness- A Retrospective Study. AB - This article presents the results of evaluating the changes in peri-implant soft tissue dimensions associated with immediate implant placement into anterior postextraction sockets for four treatment groups: no BGPR (no bone graft, no provisional restoration), PR (no bone graft, provisional restoration), BG (bone graft, no provisional restoration), and BGPR (bone graft, provisional restoration). The vertical distance of the peri-implant soft tissue was greater for grafted sites than for nongrafted ones (2.72 mm vs 2.29 mm, P < .06). The facial soft tissue thickness at the gingival third also was greater for grafted than for nongrafted sites (2.90 mm vs 2.28 mm, P < .008) and for sites with provisional restorations compared to sites without them (2.81 mm vs 2.37 mm, P < .06), respectively. The net gain in soft tissue height and thickness was about 1 mm. The increases in vertical and horizontal dimensions for grafted sites were between 0.5 and 1.0 mm, as compared to sites with no bone graft and no provisional restoration. PMID- 26509984 TI - Comparison of Freeze-Dried and Solvent-Dehydrated Acellular Dermal Matrix for Root Coverage: A Randomized Controlled Trial. AB - The prevalence of gingival recession has been estimated at around 22.5% in people aged older than 29 years. Classic treatment approaches include the use of connective tissue grafts in combination with coronally advanced flaps (CAFs). To reduce morbidity and the need for a secondary surgical site, allograft materials are currently being used. Nevertheless, long-term randomized studies testing the efficacy of these materials are lacking. Hence, the aim of the present randomized controlled clinical trial was to compare two acellular dermal matrix (ADM) materials produced by different processing techniques, freeze-dried (FDADM) and solvent-dehydrated ADM (SDADM). At 12 months, both groups showed significant improvement in attachment level, recession depth, and recession width. A mean improvement in attachment level of 2.0 +/- 1.08 mm for FDADM and 2.0 +/- 0.70 mm for both SDADM was achieved (P = .002). Root coverage after 12 months was 80.66 +/- 22.90% for FDADM and 80.97 +/- 18.08% for SDADM. Hence, it was concluded that both FDADM and SDADM grafting materials can successfully achieve root coverage in Miller Class I and II recession defects for up to 12 months when used in combination with CAFs. PMID- 26509985 TI - Comparative Clinical and Histologic Assessments of Dental Implants Delivered with a Manual Torque Limiting Wrench Versus with an Electronically Controlled Torque Limiting Device. AB - The goal of this preclinical investigation was to evaluate the healing of tapered roughened surfaced dental implants that were delivered by either a manual torque limiting wrench or an electronically controlled torque limiting device. Three canines underwent bilateral extraction of third and fourth premolars and first molar. The extraction sites were allowed to heal for 2 months before two dental implants were placed bilaterally. All animals underwent a normal healing process. One animal was sacrificed at 1 month and the remaining two animals were sacrificed at 2 months to perform histologic evaluations including bone-to implant contact (BIC) and soft tissue healing. The clinical stability and histologic osseointegration were similar when the results obtained with the manual torque limiting wrench were compared to those delivered by the electronically controlled torque limiting device. However, BIC and maintenance of the crestal bone level achieved appeared to be higher in the electronically controlled torque limiting device groups. PMID- 26509986 TI - Platelet-Derived Growth Factor-Mediated Guided Bone Regeneration in Immediate Implant Placement in Molar Sites with Buccal Bone Defects. AB - This study compared the clinical outcomes of recombinant human platelet-derived growth factor BB and beta-tricalcium phosphate (rhPDGF-BB/betaTCP) with guided bone regeneration (GBR) in immediate implant placement in molar extraction sockets with buccal bone defects versus conventional implant placement. Twenty eight implants were placed in fourteen patients. Clinical and radiographic evaluations assessed peri-implant soft and hard tissue parameters after 12 months. No implants were lost during the 1-year observation period, yielding a survival rate of 100%. Similar clinical and radiographic parameters were observed for both treatment groups. Use of rhPDGF-BB/betaTCP and GBR in immediate implants in molars was as successful as conventional implant placement in fully healed extraction sites. PMID- 26509987 TI - A Step-by-Step Description of PDL-Mediated Ridge Preservation for Immediate Implant Rehabilitation in the Esthetic Region. AB - The aim of this study was to present in detail the clinical steps of the root membrane technique. This technique combines the benefits of conventional root submergence via intentional maintenance of a root fragment for ridge preservation with those of immediate implant placement for functional rehabilitation of the treated site. A case study of a tooth diagnosed with a horizontal root fracture is used to illustrate this technique step by step. The clinical application of the root-membrane technique not only allowed for immediate placement in a site with compromised buccal plate but also facilitated excellent clinical stability of soft tissue contours during the 3 years of follow-up. PMID- 26509988 TI - Failure Probability of Three Designs of Zirconia Crowns. AB - This study used a two-parameter Weibull analysis for evaluation of the lifespan of fully or partially porcelain-/glaze-veneered zirconia crowns after fatigue test. A sample of 60 first molars were selected and prepared for full-coverage crowns with three different designs (n = 20): traditional (crowns with zirconia framework covered with feldspathic porcelain), modified (crowns partially covered with veneering porcelain), and monolithic (full-contour zirconia crowns). All specimens were treated with a glaze layer. Specimens were subjected to mechanical cycling (100 N, 3 Hz) with a piston with a hemispherical tip (O = 6 mm) until the specimens failed or up to 2 * 106 cycles. Every 500,000 cycles, the fatigue tests were interrupted and stereomicroscopy (10*) was used to inspect the specimens for damage. The authors performed Weibull analysis of interval data to calculate the number of failures in each interval. The types and numbers of failures according to the groups were: cracking (13 traditional, 6 modified) and chipping (4 traditional) of the feldspathic porcelain, followed by delamination (1 traditional) at the veneer/core interface and debonding (2 monolithic) at the cementation interface. Weibull parameters (beta, scale; eta, shape), with a two sided confidence interval of 95%, were: traditional-1.25 and 0.9 * 106 cycles; modified-0.58 and 11.7 * 106 cycles; and monolithic-1.05 and 16.5 * 106 cycles. Traditional crowns showed greater susceptibility to fatigue, the modified group presented higher propensity to early failures, and the monolithic group showed no susceptibility to fatigue. The modified and monolithic groups presented the highest number of crowns with no failures after the fatigue test. The three crown designs presented significantly different behaviors under fatigue. The modified and monolithic groups presented less probability of failure after 2 * 106 cycles. PMID- 26509989 TI - Fractal Measure and Microscopic Modeling of Osseointegration. AB - In this study, the process of osseointegration on titanium implant surfaces with different physicochemical treatments subjected to a simulated corporal fluid submersion was evaluated using the concept of fractal dimension. It was found that different treatments led to rather different calcium phosphate crystal growth patterns, with fractal dimension ranging from 1.68 to 1.93. The observed crystal patterns may be explained by a general deposition, diffusion, and aggregation growth mechanism, where diffusing particle sticking probability plays a fundamental role. PMID- 26509990 TI - A Regenerative Approach to the Successful Treatment of Peri-implantitis: A Consecutive Series of 170 Implants in 100 Patients with 2- to 10-Year Follow-up. AB - This article presents the results of a consecutive case series of 170 treated peri-implantitis-affected implants in 100 patients with follow-up measurements from 2 to 10 years. A total of 51 implants in 38 patients previously reported on were followed for an additional 2.5 years, and 119 additional implants in 62 additional patients were treated with the same protocol and monitored for at least 2 years posttreatment. The treatment consisted of flap reflection, surface decontamination, use of enamel matrix derivative (EMD) or platelet-derived growth factor (PDGF), and guided bone regeneration with mineralized freezedried bone and/or anorganic bovine bone combined with PDGF or EMD and covered with an absorbable membrane and/or subepithelial connective tissue graft. Maintenance and monitoring followed every 2 to 3 months. Two implants were lost 6 months posttreatment, for a 98.8% survival rate. Bleeding on probing was eliminated in 91% of the treated implants. Probing depth reduction averaged 5.10 mm, bone level gain averaged 1.77 mm, and soft tissue marginal gain averaged 0.52 mm. These outcomes were obtained with one surgical procedure on 140 implants, with two procedures on 18 implants, and with three procedures on 10 implants. The results to date with this layered/combined regenerative approach for the treatment of peri-implantitis appear to be encouraging. PMID- 26509991 TI - Influence of a Laser-Lok Surface on Immediate Functional Loading of Implants in Single-Tooth Replacement: Three-Year Results of a Prospective Randomized Clinical Study on Soft Tissue Response and Esthetics. AB - The purpose of the present prospective randomized study was to evaluate the influence of Laser-Lok microtextured surface on soft tissue peri-implant parameters and esthetics around immediate, functionally loaded implants for single-tooth replacement in the esthetic zone. This study included 77 patients divided into two groups based on different implants used: the control group had BioHorizons tapered internal non-Laser-Lok-type implants (NLL; n = 39) and the test group had BioHorizons tapered internal Laser-Lok-type implants (LL; n = 39). Outcome measures were survival, radiographic marginal bone-level changes, soft tissue parameters, and esthetics. One implant was lost in the test group and one in the control group, for a total survival rate of 96.1% after 3 years. Radiographically, mean crestal bone loss +/- standard deviation was 0.59 +/- 0.27 mm in the LL group compared with 1.17 +/- 0.31 mm in the NLL group. A mean gain in papilla level of 0.41 +/- 0.34 mm and 0.17 +/- 0.36 mm was observed in the LL and the NLL groups, respectively, while the level of the midfacial peri-implant mucosa remained stable in both groups with no statistically significant differences (0.08 +/- 0.42 mm for the LL group vs 0.06 +/- 0.36 mm for the NLL group). The mean probing depth values in the LL and NLL groups were 0.58 +/- 0.2 mm and 1.89 +/- 0.3 mm, respectively. Within the limitations of this study, it was demonstrated that the clinical and esthetic outcome of immediate functional loading was more favorable for LL implants than for NLL implants. PMID- 26509992 TI - Postextraction Socket Seal Surgery with an Epithelized Connective Tissue Graft Using a Subpapillar Tunneling Procedure. AB - Ridge preservation in the esthetic area is still a challenging procedure. The aim of the present case series was to introduce a technique for postextraction socket seal surgery using an epithelized connective tissue graft and socket filling with a xenogeneic biomaterial. Using a tunneling approach, the buccal gingiva and interdental papillae are undermined and augmented with the soft tissue graft. This method was applied and evaluated in 16 sites in 13 patients with need for extraction of at least one maxillary anterior tooth. Five months postoperative, the mean reduction of the horizontal width of the alveolar ridge was 0.5 mm, while the height of the mesial and distal papillae were reduced by 0.2 mm and 0.4 mm, respectively. The buccogingival margin of the alveolar ridge showed a vertical gain of 0.5 mm. Therefore, the presented technique seems appropriate for preservation of the alveolar ridge in esthetically relevant areas. PMID- 26509993 TI - Reducing Distortion of Implant- or Abutment-Level Impressions for Implant Supported Prosthetic Rehabilitation: A Technique Report. AB - Passive fit between prosthesis and implants or abutments is a significant factor in preventing mechanical and biologic failures of implant-supported prostheses. Therefore, impression techniques must transfer the 3D implant position as accurately as possible for a correct superstructure fabrication. A novel impression protocol that uses an individualized open tray design is proposed. It allows the clinician to splint the transfers between the copings, outside the impression area, and to the tray itself to create a rigid monoblock. Thus, distortions produced by the tear of impression material or by transfer abutments' micromovements during tray retrieval are limited and superstructure misfits are minimized. This technique is specifically recommended for long spanning or completely edentulous patients. PMID- 26509994 TI - Management of Fenestration Defects During Flapless Immediate Implant Placement in the Esthetic Zone. AB - The success of flapless immediate implant placement is dependent on the bony architecture on the buccal aspect of the socket. The presence of a fenestration defect in the buccal cortical plate may jeopardize the esthetic outcome, especially if the clinician does not undertake adequate soft and hard tissue augmentation procedures. This article describes the use of an esthetic buccal flap design to deal with fenestration defects created during anterior implant placement immediately after extraction. This technique has been proven effective in maintaining the soft tissue architecture and allows hard tissue grafting of the fenestration defect around the implant in a postextraction socket. PMID- 26509995 TI - Ultra-Thin Veneers Without Tooth Preparation in Extensive Oligodontia. AB - Dental agenesis is the most commonly encountered dental anomaly in humans. Oligodontia, however, is a rare condition that involves the congenital absence of six or more teeth, excluding the third molars. Treatment of oligodontia requires an interdisciplinary approach. The prosthetic treatment plan should carefully consider esthetic and functional rehabilitation but should take a conservative approach. Adhesive techniques, combined with the new ceramic materials, permit functional and esthetic prosthetic restorations that are more conservative in comparison to those used in the past. Ultrathin occlusal veneers without tooth preparations may represent a good esthetic and conservative approach for oral rehabilitation of patients affected by severe hypodontia. PMID- 26509996 TI - Association of Brain-Derived Neurotrophic Factor G196A and Attempted Suicide: A Case-Control Study in Rural China. AB - BACKGROUND: Suicide is an important public problem, the mechanism of which has not been clarified. Many studies have focused on the molecular, biological and genetic mechanisms of suicide. Brain-derived neurotrophic factor (BDNF) G196A is one of the most leading loci in recent studies, but the results are inconsistent. METHODS: We conducted a 1:1 age- and sex-matched case-control study in rural areas of Shandong Province, China. A total of 365 pairs of cases and controls were finally recruited into our study. The adjusted odds ratios (AORs) of BDNF 196G/G and their 95% confidence intervals (CIs) were calculated by multivariate conditional logistic regression models. RESULTS: No association between BDNF polymorphisms and attempted suicide was found in the overall population. However, the BDNF 196G/G genotype was significantly related to attempted suicide in the elderly population (AOR = 7.85, 95% CI: 1.12-54.90, p = 0.038), while the associations were not significant in young and middle-aged groups. CONCLUSION: Our study suggests that the BDNF 196G/G genotype increases the risk of attempted suicide in elderly people. PMID- 26509997 TI - Hsa-miR-21 and Hsa-miR-29 in Tissue as Potential Diagnostic and Prognostic Biomarkers for Gastric Cancer. AB - BACKGROUND/AIMS: Gastric cancer (GC) is the fourth most common cancer and the second most common cause of cancer deaths worldwide. Endoscopic examination is the most used method to detect the GC nowadays, whereas this method is expensive and invasive. MicroRNAs (miRNAs) are a group of recently discovered small non protein-coding RNAs. They regulate the expression of hundreds of target genes; thereby control a wide range of tumorigenic processes. In this study, we selected two miRNAs, hsa-miR-21 and hsa-miR-29, as the targets to assess their diagnostic and prognostic value for GC. METHODS: A total of 50 GC patients including 24 females and 26 males were recruited. Tumor and adjacent non-tumor tissue samples were collected from all these participants during the endoscopic examination. RNAs were extracted from these samples, then quantified via qRT-PCR and normalized with RNU43 as the internal control. Statistical analyses were conducted using the GraphPad Prism 5.0. RESULTS: We discovered a higher expression of hsa-miR-21 and a relatively lower expression of hsa-miR-29hsa-miR 29 in the tumor tissue than in the adjacent non-tumor tissue. Moreover, both the two miRNAs showed moderate diagnostic performance (hsa-miR-21: AUC = 0.75, sensitivity = 0.70, specificity = 0.78; hsa-miR-29hsa-miR-29: AUC = 0.73, sensitivity = 0.70, specificity = 0.68). In the follow-up research, we found that higher tissue hsa-miR-21 level was related to a lower overall survival rate, whereas higher tissue hsa-miR-29hsa-miR-29 level was associated with the higher overall survival rate. These results indicated that both hsa-miR-21 and hsa-miR 29 had the potential to be the biomarkers for GC prognosis. CONCLUSION: In summary, we verified the diagnostic and prognostic value of tissue hsa-miR-21hsa miR-21 and hsa-miR-29 in GC. Both of them can be potentially applied as novel and non-invasive biomarkers for GC. PMID- 26509998 TI - Contact Mechanics of Nanoparticles: Pulling Rigid Nanoparticles from Soft, Polymeric Surfaces. AB - Detachment of rigid nanoparticles from soft, gel-like polymeric surfaces is studied by using a combination of the molecular dynamics simulations and theoretical calculations. Simulations show that detachment of nanoparticles from soft surfaces proceeds through a neck formation. Analysis of the simulation results demonstrates that the magnitude of the detachment force f* depends on the nanoparticle radius R(p), shear modulus of substrate G(s), surface tension of substrate gamma(s), and work of adhesion W. It is controlled by the balance of the elastic energy, surface energy of the neck, and nanoparticle adhesion energy to a substrate and depends on the dimensionless parameter delta ? gamma(s)(G(s)R(p))(-1/3)W(-2/3). In the case of small values of the parameter delta ? 1, the critical detachment force approaches a critical detachment force calculated by Johnson, Kendall, and Roberts for adhesive contact, f* = 1.5piWR(p). However, in the opposite limit, corresponding to soft substrates, for which delta ? 1, the critical detachment force f* ? gamma(s)(3/2)R(p)(1/2)G(s)( 1/2). All simulation data can be described by a scaling function f* ? gamma(s)(3/2)R(p)(1/2)G(s)(-1/2)delta(-1.89). PMID- 26509999 TI - POLYPOIDAL CHOROIDAL VASCULOPATHY SECONDARY TO A STABLE CHOROIDAL NEVUS. AB - PURPOSE: Choroidal nevus is the most common ocular fundus tumor in adults. Previous studies have widely discussed the features of choroidal neovascularization secondary to nevus and its treatment options. Polypoidal choroidal vasculopathy (PCV) is an exudative chorioretinopathy that is often underdiagnosed. Clinical features, natural history, and treatment response of PCV are distinct from occult choroidal neovascularization. Polypoidal choroidal vasculopathy secondary to choroidal nevus has not been previously documented. We report a patient with a history of stable choroidal nevus who developed a polypoidal lesion at the edge of the nevus lesion. METHODS: A white woman who presented with a choroidal nevus and clinical features of PCV was examined using fundoscopy, optical coherence tomography, fluorescein angiography, and indocyanine green angiography. RESULTS: A polypoidal lesion with an associated branching vascular network adjacent to the nevus was demonstrated by optical coherence tomography, fluorescein angiography, and indocyanine green angiography. The patient was asymptomatic and was managed conservatively. CONCLUSION: Our case showed that PCV developing in association with a stable choroidal nevus. Pathogenic mechanisms of this condition may include chronic degenerative or inflammatory changes at the level of the retinal pigment epithelium resulting in vascular changes. Unlike treatment of occult choroidal neovascularization secondary to nevus, optimal management of PCV secondary to nevus may vary. Indocyanine green angiography is the gold standard for the diagnosis of PCV and is a useful investigation in atypical choroidal neovascularization. PMID- 26510000 TI - BATTEN DISEASE CAUSED BY A NOVEL MUTATION IN THE PPT1 GENE. AB - PURPOSE: To report a case of Batten disease due to a previously unreported mutation in PPT1. METHODS: A 9-year-old girl presented with classic clinical findings of Batten Disease. RESULTS: Genetic testing for the mutations in the most common Batten disease gene, CLN3, was negative. Evaluation of a panel of genes known to be implicated in neuronal ceroid lipofuscinoses revealed disease causing mutations in PPT1, one of which was novel. CONCLUSION: Mutations in PPT1 typically cause the infantile form of neuronal ceroid lipofuscinosis. Clinical diagnosis of the juvenile form of neuronal ceroid lipofuscinosis, Batten disease, should still be considered in cases with negative CLN3 genetic testing. Batten disease can occur due to genetic heterogeneity. Testing of other members of the neuronal ceroid lipofuscinosis gene family can lead to confirmation of the correct diagnosis. PMID- 26510001 TI - RECURRENT CENTRAL SEROUS CHORIORETINOPATHY ASSOCIATED WITH RETINITIS PIGMENTOSA TREATED WITH CARBONIC ANHYDRASE INHIBITORS. AB - PURPOSE: To describe a rare case of recurring central serous chorioretinopathy associated with retinitis pigmentosa successfully treated with oral acetazolamide. METHODS: A 17-year-old male with retinitis pigmentosa who developed four separate episodes of central serous chorioretinopathy over a 12 month period. RESULTS: After the patient's fourth recurrence, he was treated with daily oral acetazolamide, which resulted in resolution of submacular fluid. He has had no subsequent recurrences while being maintained on alternating and then biweekly doses of oral acetazolamide. CONCLUSION: Recurrent central serous chorioretinopathy associated with retinitis pigmentosa is a rare occurrence. The presented case demonstrates that oral acetazolamide successfully treated and may have delayed recurrent episodes of central serous chorioretinopathy in the patient with retinitis pigmentosa. PMID- 26510002 TI - SINGLE ACQUISITION OF THE VITREOUS, RETINA AND CHOROID WITH SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY IN ACUTE TOXOPLASMOSIS. AB - BACKGROUND/PURPOSE: To report the swept-source optical coherence tomography (SS OCT) findings in a case of acute toxoplasmosis chorioretinitis. METHODS: A 35 year-old male presented with acute blurry vision and floaters in his left eye. Ophthalmic examination, color photographs, spectral-domain OCT (SD-OCT), enhanced depth imaging OCT (EDI-OCT), SS-OCT and wide-field fluorescein angiography images were obtained to diagnose and follow the subsequent changes of toxoplasmosis chorioretinitis over a 2-month period. RESULTS: Initial imaging with different modalities of SD- and EDI-OCT including radial vitreous scans and horizontal high speed B-scan raster lines demonstrated thickening of the posterior hyaloid and acute vitreous cells emanating from the retinal blood vessels, thickening and disorganization of the retinal layers within the chorioretinal lesion, and increased sub-lesional choroidal thickness, respectively. SS-OCT demonstrated all of these same findings in a single 12-mm B-scan. Topical steroids were initiated and imaging over the next 2 months showed separation of the posterior hyaloid, decrease in vitreous cell, and atrophy of the chorioretinal lesion. CONCLUSION: We report the first SS-OCT images of an acute case of toxoplasmosis chorioretinitis. SS-OCT can visualize the choroidal, retinal, and vitreous changes in a single scan, compared with the different imaging algorithms required with SD-OCT. PMID- 26510003 TI - THE ROLE OF EARLY VITRECTOMY IN THE TREATMENT OF FUNGAL ENDOGENOUS ENDOPHTHALMITIS. AB - PURPOSE: To review the therapeutic role of vitrectomy in fungal endogenous endophthalmitis. METHODS: Six cases were identified as fungal endogenous endophthalmitis through positive cultures or clinical presentation. RESULTS: All six cases had fungal endogenous endophthalmitis risk factors; average diagnostic delay was 7.5 days; all cases were managed with vitrectomy, intravitreal antifungals, and systemic antifungals within 24 hours of fungal endogenous endophthalmitis diagnosis. Visual acuity of 20/200 or better was achieved by 5 of 6 eyes, with 4 of those eyes achieving 20/40 or better. CONCLUSION: An early vitrectomy in high-risk patients may improve visual outcomes and aid in diagnosis. PMID- 26510004 TI - SYMPTOMATIC DYNAMIC VITREOMACULAR TRACTION INDUCED BY NEAR-VISION. AB - PURPOSE: To report a case of dynamic vitreomacular traction secondary to near response vision demonstrated by optical coherence tomography imaging of macular anatomical changes both pre and post induced near-vision. METHODS: Case report and literature review. RESULTS: Dynamic vitreomacular traction led to significant foveal anatomical changes on optical coherence tomography after approximately 15 minutes of induced near-vision, which was associated with bilateral central metamorphopsia that self-resolved after approximately 15-30 minutes. The patient eventually experienced improvement of symptoms in one eye after spontaneous vitreomacular detachment, while the other eye still remained symptomatic. DISCUSSION: The near-vision complex affects movement of the posterior vitreous humor, which may actively contribute to dynamic vitreomacular traction. Therefore, cases of transient central blurring after a self-induced near-response mechanism should be investigated for potential dynamic vitreomacular traction syndrome. PMID- 26510005 TI - Characterization of Traveling Wave Ion Mobility Separations in Structures for Lossless Ion Manipulations. AB - We report on the development and characterization of a traveling wave (TW)-based Structures for Lossless Ion Manipulations (TW-SLIM) module for ion mobility separations (IMS). The TW-SLIM module uses parallel arrays of rf electrodes on two closely spaced surfaces for ion confinement, where the rf electrodes are separated by arrays of short electrodes, and using these TWs can be created to drive ion motion. In this initial work, TWs are created by the dynamic application of dc potentials. The capabilities of the TW-SLIM module for efficient ion confinement, lossless ion transport, and ion mobility separations at different rf and TW parameters are reported. The TW-SLIM module is shown to transmit a wide mass range of ions (m/z 200-2500) utilizing a confining rf waveform (~1 MHz and ~300 Vp-p) and low TW amplitudes (<20 V). Additionally, the short TW-SLIM module achieved resolutions comparable to existing commercially available low pressure IMS platforms and an ion mobility peak capacity of ~32 for TW speeds of <210 m/s. TW-SLIM performance was characterized over a wide range of rf and TW parameters and demonstrated robust performance. The combined attributes of the flexible design and low voltage requirements for the TW-SLIM module provide a basis for devices capable of much higher resolution and more complex ion manipulations. PMID- 26510006 TI - Displaying Lipase B from Candida antarctica in Pichia pastoris Using the Yeast Surface Display Approach: Prospection of a New Anchor and Characterization of the Whole Cell Biocatalyst. AB - Yeast Surface Display (YSD) is a strategy to anchor proteins on the yeast cell wall which has been employed to increase enzyme stability thus decreasing production costs. Lipase B from Candida antarctica (LipB) is one of the most studied enzymes in the context of industrial biotechnology. This study aimed to assess the biochemical features of this important biocatalyst when immobilized on the cell surface of the methylotrophic yeast Pichia pastoris using the YSD approach. For that purpose, two anchors were tested. The first (Flo9) was identified after a prospection of the P. pastoris genome being related to the family of flocculins similar to Flo1 but significantly smaller. The second is the Protein with Internal Repeats (Pir1) from P. pastoris. An immunolocalization assay showed that both anchor proteins were able to display the reporter protein EGFP in the yeast outer cell wall. LipB was expressed in P. pastoris fused either to Flo9 (FLOLIPB) or Pir1 (PIRLIPB). Both constructions showed hydrolytic activity towards tributyrin (>100 U/mgdcw and >80 U/mgdcw, respectively), optimal hydrolytic activity around 45 degrees C and pH 7.0, higher thermostability at 45 degrees C and stability in organic solvents when compared to a free lipase. PMID- 26510007 TI - Global and Regional Estimates of Prevalent and Incident Herpes Simplex Virus Type 1 Infections in 2012. AB - BACKGROUND: Herpes simplex virus type 1 (HSV-1) commonly causes orolabial ulcers, while HSV-2 commonly causes genital ulcers. However, HSV-1 is an increasing cause of genital infection. Previously, the World Health Organization estimated the global burden of HSV-2 for 2003 and for 2012. The global burden of HSV-1 has not been estimated. METHODS: We fitted a constant-incidence model to pooled HSV-1 prevalence data from literature searches for 6 World Health Organization regions and used 2012 population data to derive global numbers of 0-49-year-olds with prevalent and incident HSV-1 infection. To estimate genital HSV-1, we applied values for the proportion of incident infections that are genital. FINDINGS: We estimated that 3709 million people (range: 3440-3878 million) aged 0-49 years had prevalent HSV-1 infection in 2012 (67%), with highest prevalence in Africa, South East Asia and Western Pacific. Assuming 50% of incident infections among 15-49 year-olds are genital, an estimated 140 million (range: 67-212 million) people had prevalent genital HSV-1 infection, most of which occurred in the Americas, Europe and Western Pacific. CONCLUSIONS: The global burden of HSV-1 infection is huge. Genital HSV-1 burden can be substantial but varies widely by region. Future control efforts, including development of HSV vaccines, should consider the epidemiology of HSV-1 in addition to HSV-2, and especially the relative contribution of HSV-1 to genital infection. PMID- 26510008 TI - Risk Factors and Early Predictors for Heterotopic Pregnancy after In Vitro Fertilization. AB - This study investigated the risk factors and early predictors for heterotopic pregnancy (HP) after in vitro fertilization and embryo transfer (IVF-ET). From January 2008 to January 2013, 41 cases of HP and 72 cases of intrauterine twin pregnancy after IVF-ET were recruited and retrospectively analyzed. Compared with intrauterine twin pregnancy group, the HP group had a lower basal luteinizing hormone (LH) level (P = 0.005) and more cases had a history of hydrosalpinx (P = 0.008). After 14 days of IVF-ET, the serum beta-HCG (beta-human chorionic gonadotropin), E2 (Estradiol) and P (Progesterone) levels were lower in HP group (P<0.001, respectively). Moreover, vaginal bleeding and abdominal pain were the significant features of HP before diagnosis (P<0.001, respectively). Further by logistic regression, serum beta-hCG, P levels on the 14th day after ET, and vaginal bleeding were identified as the independent factors of HP. These results indicate that when two or more embryos transferred in IVF procedure, beta-hCG, P levels on the 14th day after ET, and vaginal bleeding could be taken as predictors for HP. PMID- 26510009 TI - Preliminary Evidence for the Amplification of Global Warming in Shallow, Intertidal Estuarine Waters. AB - Over the past 50 years, mean annual water temperature in northeastern U.S. estuaries has increased by approximately 1.2 degrees C, with most of the warming recorded in the winter and early spring. A recent survey and synthesis of data from four locations in Southern Rhode Island has led us to hypothesize that this warming may be amplified in the shallow (<1 m), nearshore portions of these estuaries. While intertidal areas are not typically selected as locations for long-term monitoring, we compiled data from published literature, theses, and reports that suggest that enhanced warming may be occurring, perhaps at rates three times higher than deeper estuarine waters. Warmer spring waters may be one of the factors influencing biota residing in intertidal regions both in general as well as at our specific sites. We observed greater abundance of fish, and size of Menidia sp., in recent (2010-2012) seine surveys compared to similar collections in 1962. While any linkages are speculative and data are preliminary, taken together they suggest that shallow intertidal portions of estuaries may be important places to look for the effects of climate change. PMID- 26510011 TI - Potential of Hazardous Waste Encapsulation in Concrete Compound Combination with Coal Ash and Quarry Fine Additives. AB - Coal power plants are producing huge amounts of coal ash that may be applied to a variety of secondary uses. Class F fly ash may act as an excellent scrubber and fixation reagent for highly acidic wastes, which might also contain several toxic trace elements. This paper evaluates the potential of using Class F fly ashes (<20% CaO), in combination with excessive fines from the limestone quarry industry as a fixation reagent. The analysis included leaching experiments (EN12457-2) and several analytical techniques (ICP, SEM, XRD, etc.), which were used in order to investigate the fixation procedure. The fine sludge is used as a partial substitute in concrete that can be used in civil engineering projects, as it an environmentally safe product. PMID- 26510012 TI - A focused investigation of expedited, stack of three shocks versus chest compressions first followed by single shocks for monitored ventricular fibrillation/ventricular tachycardia cardiopulmonary arrest in an in-hospital setting. AB - BACKGROUND: In cases of in-hospital-witnessed ventricular fibrillation/ventricular tachycardia (VF/VT) arrest, it is unclear whether cardiopulmonary resuscitation prior to defibrillation attempt or expedited stacked defibrillation attempt is superior. METHODS: Retrospective, observational study of all admitted patients with continuous cardiac monitoring who suffered VF/VT arrest between July 2005 and June 2013. In the stacked shock period (2005 2008), institutional protocols advocated early defibrillation with administration of 3 stacked shocks with brief pauses between each single defibrillation attempt to confirm sustained VF/VT. During the initial chest compression period (2008 2011), the protocol was modified to perform a 2-minute period of chest compressions prior to each defibrillation, including the initial. In the modified stack shock period (2011-2013), for a monitored arrest, defibrillation attempts were expedited with up to 3 successive shocks administered for persistent VF/VT. In unmonitored arrest, chest compressions and ventilations were initiated prior to defibrillation. The primary outcome measure was survival to hospital discharge. RESULTS: Six hundred sixty-one cardiopulmonary arrests were recorded during the study period, with 106 patients (16%) representing primary VF/VT. The incidence of VF/VT arrest did not vary significantly between the study periods (P= 0.16) Survival to hospital discharge for all primary VF/VT arrest victims decreased, then increased significantly from the stacked shock period to initial chest compression period to modified stacked shock period (58%, 18%, 71%, respectively, P < 0.01). Specific group differences were significant between the initial chest compression versus the stacked and modified stacked shock groups (all P < 0.01). CONCLUSION: Data suggest that monitored VF/VT should undergo expeditious defibrillation with use of stacked shocks. PMID- 26510013 TI - Effect on Physical Activity of a Randomized Afterschool Intervention for Inner City Children in 3rd to 5th Grade. AB - BACKGROUND: Less than 45% of U.S. children meet the 60 min.d(-1) physical activity (PA) guideline. Structured after-school PA programing is one approach to help increase activity levels. This study aimed to evaluate the feasibility and short-term impact of a supervised after-school PA and nutrition education program on activity levels. METHODS: Forty-two 3rd-5th graders from an inner-city school in Boston, MA were randomly assigned to a 10-wk after-school program of either: 1) weekly nutrition education, or 2) weekly nutrition education plus supervised PA 3 d.wk(-1) at a community-based center. At baseline and follow-up, PA was measured using accelerometry and fitness (VO2max) was estimated using the PACER 15-m shuttle run. Additional measures obtained were non-fasting finger stick total cholesterol (TC) and glucose levels, waist circumference (WC), body mass index (BMI), percent body fat (%BF), and blood pressure (BP). Values are presented as mean+/-SE, unless noted otherwise. RESULTS: Thirty-six participants completed the study (mean+/-SD; age 9.7+/-0.9 years). Participants attended >80% of the sessions. After adjusting for accelerometer wear time and other design factors, light and moderate-to-vigorous PA (MVPA) increased in the nutrition+PA group (+21.5+/-14.5 and +8.6+/-8.0 min.d(-1), respectively) and decreased in the nutrition only group (-35.2+/-16.3 and -16.0+/-9.0 min.d(-1), respectively); mean difference between groups of 56.8+/-21.7 min.d(-1) (light PA, p = 0.01) and 24.5+/-12.0 min.d(-1) (MVPA, p = 0.04). Time spent in sedentary behaviors declined in the nutrition+PA group (-14.8+/-20.7 min.d(-1)) and increased in the nutrition only group (+55.4+/-23.2 min.d(-1)); mean difference between groups of 70.2+/-30.9 min.d(-1) (p = 0.02). Neither group showed changes in TC, BP, WC, %BF, BMI percentile, or fitness (p>0.05). CONCLUSIONS: The supervised afterschool community-based nutrition and PA program was well accepted and had high attendance. The changes in light PA and MVPA has potential to promote weight maintenance in inner-city elementary school children, however longer term studies with larger samples are needed. TRIAL REGISTRATION: ClinicalTrials.gov NCT01104038. PMID- 26510014 TI - Genetic and epigenetic variation in the lineage specification of regulatory T cells. AB - Regulatory T (Treg) cells, which suppress autoimmunity and other inflammatory states, are characterized by a distinct set of genetic elements controlling their gene expression. However, the extent of genetic and associated epigenetic variation in the Treg cell lineage and its possible relation to disease states in humans remain unknown. We explored evolutionary conservation of regulatory elements and natural human inter-individual epigenetic variation in Treg cells to identify the core transcriptional control program of lineage specification. Analysis of single nucleotide polymorphisms in core lineage-specific enhancers revealed disease associations, which were further corroborated by high-resolution genotyping to fine map causal polymorphisms in lineage-specific enhancers. Our findings suggest that a small set of regulatory elements specify the Treg lineage and that genetic variation in Treg cell-specific enhancers may alter Treg cell function contributing to polygenic disease. PMID- 26510015 TI - Experiments Testing the Causes of Namibian Fairy Circles. AB - The grasslands on the sandy soils of the eastern edge of the Namib Desert of Namibia are strikingly punctuated by millions of mostly regularly-spaced circular bare spots 2 to 10 m or more in diameter, generally with a margin of taller grasses. The causes of these so called fairy circles are unknown, but several hypotheses have been advanced. In October 2009, we set up experiments that specifically tested four hypothesized causes, and monitored these 5 times between 2009 and 2015. Grass exclusion in circles due to seepage of subterranean vapors or gases was tested by burying an impermeable barrier beneath fairy circles, but seedling density and growth did not differ from barrier-less controls. Plant germination and growth inhibition by allelochemicals or nutrient deficiencies in fairy circle soils were tested by transferring fairy circle soil to artificially cleared circles in the grassy matrix, and matrix soil to fairy circles (along with circle to circle and matrix to matrix controls). None of the transfers changed the seedling density and growth from the control reference conditions. Limitation of plant growth due to micronutrient depletion within fairy circles was tested by supplementing circles with a micronutrient mixture, but did not result in differences in plant seedling density and growth. Short-range vegetation competitive feedbacks were tested by creating artificially-cleared circles of 2 or 4 m diameter located 2 or 6 m from a natural fairy circle. The natural circles remained bare and the artificial circles revegetated. These four experiments provided evidence that fairy circles were not caused by subterranean vapors, that fairy circle soil per se did not inhibit plant growth, and that the circles were not caused by micronutrient deficiency. There was also no evidence that vegetative feedbacks affected fairy circles on a 2 to 10 m scale. Landscape scale vegetative self-organization is discussed as a more likely cause of fairy circles. PMID- 26510016 TI - Plasmonic color analysis of Ag-coated black-Si SERS substrate. AB - Red-Green-Blue (RGB) dark-field imaging can direct the choice of laser excitation for Raman enhancements on nanostructured plasmonic surfaces. Here we demonstrate that black silicon (b-Si) is a structured surface that has been shown to effectively absorb broad wavelengths of light, but also enables surface enhanced Raman scattering (SERS) when coated with silver (Ag). Coating b-Si with increasing amounts of Ag results in increased dark-field scattering at discrete frequencies associated with localized plasmon resonances. The dark-field scattering was monitored by collecting a far-field image with an inexpensive complementary metal oxide semiconductor (CMOS) camera, similar to what is available on most mobile phones. Color analysis of the RGB pixel intensities correlates with the observed SERS intensity obtained with either green (532 nm) or red (633 nm) laser excitation in SERS experiments. Of particular note, the SERS response at 633 nm showed low spectral variation and a lack of background scattering compared to SERS at 532 nm. The difference in background suggests sub radiant (dark or Fano resonances) may be associated with the SERS response at 633 nm and a non-resonant character of SERS. These results indicate that b-Si serves a template where Ag nucleates during physical vapor deposition. Increased deposition causes the deposits to coalesce, and at larger Ag thicknesses, bulk scattering is observed. Comparison with a high enhancement Ag SERS substrate further illustrates that a high density of plasmonic junctions, or hotspots, is important for maximizing the SERS response. The randomness of the b-Si substrate and the corresponding Ag nano-features contributes to a broadband spectral response and enhancement in SERS. Metal-coated b-Si is a promising SERS substrate due to its performance and facile fabrication. PMID- 26510017 TI - Trends in Metastatic Breast and Prostate Cancer--Lessons in Cancer Dynamics. PMID- 26510018 TI - Hospital Charity Care--Effects of New Community-Benefit Requirements. PMID- 26510019 TI - Medical-Imaging Stewardship in the Accountable Care Era. PMID- 26510021 TI - Excess Mortality among Persons with Type 2 Diabetes. AB - BACKGROUND: The excess risks of death from any cause and death from cardiovascular causes among persons with type 2 diabetes and various levels of glycemic control and renal complications are unknown. In this registry-based study, we assessed these risks according to glycemic control and renal complications among persons with type 2 diabetes. METHODS: We included patients with type 2 diabetes who were registered in the Swedish National Diabetes Register on or after January 1, 1998. For each patient, five controls were randomly selected from the general population and matched according to age, sex, and county. All the participants were followed until December 31, 2011, in the Swedish Registry for Cause-Specific Mortality. RESULTS: The mean follow-up was 4.6 years in the diabetes group and 4.8 years in the control group. Overall, 77,117 of 435,369 patients with diabetes (17.7%) died, as compared with 306,097 of 2,117,483 controls (14.5%) (adjusted hazard ratio, 1.15; 95% confidence interval [CI], 1.14 to 1.16). The rate of cardiovascular death was 7.9% among patients versus 6.1% among controls (adjusted hazard ratio, 1.14; 95% CI, 1.13 to 1.15). The excess risks of death from any cause and cardiovascular death increased with younger age, worse glycemic control, and greater severity of renal complications. As compared with controls, the hazard ratio for death from any cause among patients younger than 55 years of age who had a glycated hemoglobin level of 6.9% or less (<=52 mmol per mole of nonglycated hemoglobin) was 1.92 (95% CI, 1.75 to 2.11); the corresponding hazard ratio among patients older than 75 years of age or older was 0.95 (95% CI, 0.94 to 0.96). Among patients with normoalbuminuria, the hazard ratio for death among those younger than 55 years of age with a glycated hemoglobin level of 6.9% or less, as compared with controls, was 1.60 (95% CI, 1.40 to 1.82); the corresponding hazard ratio among patients older than 75 years of age or older was 0.76 (95% CI, 0.75 to 0.78), and patients 65 to 75 years of age also had a significantly lower risk of death (hazard ratio, 0.87; 95% CI, 0.84 to 0.91). CONCLUSIONS: Mortality among persons with type 2 diabetes, as compared with that in the general population, varied greatly, from substantial excess risks in large patient groups to lower risks of death depending on age, glycemic control, and renal complications. (Funded by the Swedish government and others.). PMID- 26510020 TI - DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. AB - BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib. METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies. RESULTS: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib. CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.). PMID- 26510022 TI - SHATTUCK LECTURE: The Future of Public Health. PMID- 26510023 TI - CLINICAL PRACTICE. Cryopreservation of Oocytes. PMID- 26510024 TI - IMAGES IN CLINICAL MEDICINE. Sporotrichoid Mycobacterial Infection. PMID- 26510025 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 34-2015. A 36-Year-Old Woman with a Lung Mass, Pleural Effusion, and Hip Pain. PMID- 26510026 TI - Fifteen Years. PMID- 26510027 TI - Fibrinolysis as a Target to Enhance Fracture Healing. PMID- 26510028 TI - Liraglutide in Weight Management. PMID- 26510029 TI - Liraglutide in Weight Management. PMID- 26510030 TI - Liraglutide in Weight Management. PMID- 26510031 TI - Liraglutide in Weight Management. PMID- 26510032 TI - Liraglutide in Weight Management. PMID- 26510033 TI - Liraglutide in Weight Management. PMID- 26510034 TI - Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. PMID- 26510035 TI - Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. PMID- 26510036 TI - A Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. PMID- 26510037 TI - A Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. PMID- 26510038 TI - A Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. PMID- 26510039 TI - An Integrated View of Potassium Homeostasis. PMID- 26510040 TI - An Integrated View of Potassium Homeostasis. PMID- 26510041 TI - An Integrated View of Potassium Homeostasis. PMID- 26510042 TI - An Integrated View of Potassium Homeostasis. PMID- 26510043 TI - Nitroglycerin and Nitric Oxide--A Rondo of Themes in Cardiovascular Therapeutics. PMID- 26510044 TI - Nitroglycerin and Nitric Oxide--A Rondo of Themes in Cardiovascular Therapeutics. PMID- 26510045 TI - Shifting Patterns of Prescription Opioid and Heroin Abuse in the United States. PMID- 26510046 TI - IMAGES IN CLINICAL MEDICINE. Erucism Due to Lepidoptera Caterpillar Envenomation. PMID- 26510047 TI - Identification of Elaiophylin Skeletal Variants from the Indonesian Streptomyces sp. ICBB 9297. AB - Four new elaiophylin macrolides (1-4), together with five known elaiophylins (5 9), have been isolated from cultures of the Indonesian soil bacterium Streptomyces sp. ICBB 9297. The new compounds have macrocyclic skeletons distinct from those of the known dimeric elaiophylins in that one or both of the polyketide chains contain(s) an additional pendant methyl group. Further investigations revealed that 1 and 2 were derived from 3 and 4, respectively, during isolation processes. Compounds 1-3 showed comparable antibacterial activity to elaiophylin against Staphylococcus aureus. However, interestingly, only compounds 1 and 3, which contain a pendant methyl group at C-2, showed activity against Mycobacterium smegmatis, whereas compound 2, which has two pendant methyl groups at C-2 and C-2', and the known elaiophylin analogues (5-7), which lack pendant methyl groups at C-2 and/or C-2', showed no activity. The production of 3 and 4 in strain ICBB 9297 indicates that one of the acyltransferase (AT) domains in the elaiophylin polyketide synthases (PKSs) can recruit both malonyl-CoA and methylmalonyl-CoA as substrates. Bioinformatic analysis of the AT domains of the elaiophylin PKSs revealed that the ela_AT7 domain contains atypical active site amino acid residues, distinct from those conserved in malonyl-CoA- or methylmalonyl-CoA-specific ATs. PMID- 26510048 TI - Why Worry About The View's Views? PMID- 26510049 TI - Nurses and the Elder Justice Act. PMID- 26510050 TI - Perinatal Loss. PMID- 26510051 TI - Honoring Patients' Pain. PMID- 26510052 TI - Refusing Vaccines. PMID- 26510055 TI - A UK Review Corroborates the Negative Consequences of 12-Hour Workdays. PMID- 26510056 TI - E-Cigarettes May Steer Teens to Smoking. PMID- 26510058 TI - Rethinking Chemotherapy at the End of Life. PMID- 26510060 TI - Many Hospital Isolation Gowns Fail Performance Tests. PMID- 26510064 TI - The World of Apps in Health Care. PMID- 26510069 TI - Teaching at the University of Jordan. PMID- 26510070 TI - Prescription Opioid Analgesics: Promoting Patient Safety with Better Patient Education. AB - Patients expect and deserve adequate postoperative pain relief. Opioid analgesics are widely used and effective in controlling postoperative pain, but their use poses risks that many patients don't understand and that all too often result in adverse outcomes. Inappropriate and often dangerous use of prescription medication has increased sharply in the past two decades in the United States. Patients and caregivers must have an adequate understanding of safe use, storage, and disposal of opioids to prevent adverse drug events in patients and others. Nurses play a key role in providing this patient education. This article provides a case study that highlights the risks and important aspects of opioid medication use in the postoperative patient. PMID- 26510072 TI - Preventing Newborn Falls While Supporting Family Bonding. PMID- 26510077 TI - Lessons Learned from Litigation: Skin Care and the Expert Witness. PMID- 26510078 TI - Nurses Cared Intensely. PMID- 26510079 TI - Final Connection. PMID- 26510080 TI - Is there any relationship between unrecognized Celiac disease and unexplained infertile couples? AB - BACKGROUND/AIMS: Celiac Disease (CD) is a chronic autoimmune disease characterized by small intestinal malabsorbtion and diarrhea, triggered by the ingestion of food products containing gluten. There are studies reporting that some nutritional deficiencies and some factors related to immunity may cause a decrease in fertility as well as some problems in sperm parameters. The prevalence of CD in unexplained infertility (UEI) couples is not as high as that mentioned in some reports. There is no accurate knowledge about the prevalence of CD in a UEI couple. MATERIALS AND METHODS: A total of 68 couples with UEI who were admitted at Turk Diyanet Vakfi 29 Mayis Hospital Center of in vitro fertilization (IVF) between January and June 2014 were included in this prospective pilot study. The diagnosis of UEI was made with basic infertility tests. A history of CD was questioned in the initial evaluation. Anti-gliadin, anti-endomysial, and tissue transglutaminase antibodies as well as total IgA were tested. Gastroscopy was performed in patients with positive serologic tests. Histopathological CD diagnosis was made according to Marsh criteria. RESULTS: The mean age of the study population was 33.40+/-4.59 years. Out of the 65 couples who were included into the study group, one of the five couples was positive for the autoantibodies (7.69%). Out of these 65 couples, none of them had autoantibody positivity at the same time in both partners. Anti-gliadin antibodies were found to be positive for two females out of five couples and in three male partners of the same group. Out of these five couples, only one male partner had all the antibodies as positive (1.5%). In the histopathological examination of patients with positive autoantibodies, only the patient in whom all autoantibodies were positive had findings compatible with Marsh IIIa gluten enteropathy. Only one couple had a diagnosis of CD (1.5%). CONCLUSION: In many studies, CD was shown to affect the reproductive system of women. CD may also cause a decrease in fertility in men by affecting sperm motility and androgen levels. Our study is based on a limited sample size. Our data should be confirmed in a larger cohort of subjects. These results suggest that investigation of both couples with a diagnosis of UEI may be more beneficial in clarifying the etiology. PMID- 26510081 TI - Multidisciplinary decision making in the management of hepatocellular carcinoma: A hospital-based study. AB - BACKGROUND/AIMS: To evaluate the short-term outcome of the decision taken by the Hepatoma Board for the treatment of Hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This was a prospective descriptive study involving 74 patients with HCC diagnosed by the known criteria. The decisions taken by the Hepatoma Board for the 74 patients were as follows: 1- surgical resection (7 patients), 2- local ablative therapy (LAT) (22 patients), 3- conventional transarterial chemoembolization (TACE) (24 patients), and 4- palliative supportive care (21 patients). RESULTS: The short-term mortality rate was 25.7% of the total patients. The success rate was nearly equal in LAT (68.2%) and surgery (71.4%), whereas the success rate was approximately 33.3% in TACE. There was no difference in the mean total bilirubin level before and after LAT, surgery, or TACE (p>0.05 for each). There was a significant decrease in the mean serum albumin level after TACE (p=0.000). There was a decrease in the mean alpha fetoprotein level after surgery and LAT (p=0.033) for surgery and (p=0.048) for LAT. CONCLUSION: The management of HCC is better performed through a multidisciplinary team decision. Surgery has comparable outcome to LAT but is more invasive. According to our local experience, conventional TACE has a success rate of 33.3%. PMID- 26510082 TI - Influence of vitamin C and E supplementation on the eradication rates of triple and quadruple eradication regimens for Helicobacter pylori infection. AB - BACKGROUND/AIMS: In our study, we aimed to assess the effect of vitamin E and C supplementation to triple and quadruple Helicobacter pylori eradication regimens. MATERIALS AND METHODS: Four hundred patients with H. pylori infection were classified into four groups. Patients in group A (n=100) received amoxicillin, clarithromycin, and lansoprazole for 2 weeks. In group B, patients (n=100) received vitamins C and E for a month, in addition to amoxicillin, clarithromycin, and lansoprazole for 2 weeks. Patients in group C (n=100) received amoxicillin, clarithromycin, lansoprazole, and bismuth subcitrate for 2 weeks, whereas those in group D (n=100) received vitamins C and E for a month, in addition to amoxicillin, clarithromycin, lansoprazole, and bismuth subcitrate for 2 weeks. H. pylori eradication was assessed with the C14 urea breath test 2 months after the end of the therapy. The eradication rate was assessed using per protocol (PP) and intention-to-treat (ITT) analyses. RESULTS: Three hundred forty eight patients finished the study. The eradication of H. pylori was achieved in 63 of 84 patients (75%) by PP and 63 of 100 (63%) by ITT analysis in group A, 60 of 84 (71.4%) by PP and 60 of 100 (60%) by ITT analysis in group B, 72 of 89 (80.9 %) by PP and 72 of 100 (72%) by ITT analysis in group C, and 76 of 91 (83.5%) by PP and 76 of 100 (76%) by ITT analysis in group D. There was no remarkable change between groups A and B (p>0.05). Similar results were also found between groups D and C (p>0.05). CONCLUSION: This study revealed that supplementing vitamins C and E to either the triple or quadruple therapies did not provide an additional advantage for achieving significantly higher eradication rates for H. pylori. PMID- 26510083 TI - Rare disorders can be an underlying cause of cyclic vomiting: Familial Mediterranean fever, Helicobacter pylori gastritis, and cavernous transformation of the portal vein. AB - BACKGROUND/AIMS: Considering the etiology of cyclic vomiting syndrome (CVS) in childhood, a variety of underlying organic causes has been clearly identified in the literature. The aim of this study was to emphasize that endoscopic evaluation in the first step may help diagnosis and treatment in patients with CVS, unlike the CVS-related "North American Society for Pediatric Gastroenterology, Hepatology and Nutrition" (NASPGHAN) consensus statement in 2008. MATERIALS AND METHODS: The medical files of patients with vomiting complaints admitted to our tertiary center between the years 2007 and 2012 were analyzed retrospectively. Patients were identified according to the International Classification of Diseases (ICD) codes at their initial presentation, including vomiting. RESULTS: A total of 815 patients with vomiting complaints were evaluated. Of the 379 patients who presented with vomiting only, 336 patients were already being followed for chronic vomiting. Cyclic vomiting was detected in 31 out of 336 patients. CONCLUSION: In our series, familial Mediterranean fever (FMF), cavernous transformation of the portal vein, and Helicobacter pylori (HP) gastritis presented with CVS for the first time in the pediatric age group. We emphasize that endoscopic evaluation in patients with CVS should be performed as the first step for appropriate diagnosis and treatment. PMID- 26510084 TI - Cystic fluid chromogranin A levels in different pancreatic cystic lesions. AB - BACKGROUND/AIMS: Pancreatic cystic lesions have a broad spectrum of differential diagnosis. There is an ongoing demand to identify specific and sensitive cystic fluid markers for the differential diagnosis of pancreatic cysts. We aimed to evaluate the diagnostic value of cystic fluid chromogranin A (CgA) in the differential diagnosis of pancreatic cysts. MATERIALS AND METHODS: Patients who underwent endoscopic ultrasound (EUS)-guided aspiration for pancreatic cysts were included in the study. Cytopathological analysis and biochemical analysis, including cystic fluid carcinoembryonic antigen (CEA), amylase, Ca 19-9, and CgA, were performed. RESULTS: Fifty-three patients were included in the study. The final diagnosis of patients was 14 pancreatic pseudocysts, 10 intraductal papillary mucinous neoplasms (IPMNs), 8 mucinous cystic neoplasms (MCN), 8 serous cystadenomas (SCAs), 2 cystic pancreatic neuroendocrine tumors (PNETs), and 11 others. The mean CgA levels were 50.51+/-130.04 ng/mL in pseudocysts, 12.38+/ 8.59 in MCN, and 13.76+/-10.90 in cystic PNET. There was only one patient with a very high cystic fluid CgA (515.49 ng/mL) and was diagnosed as pseudocyst developed in chronic pancreatitis patient. Two patients with cystic PNET had normal levels of cystic fluid CgA. CONCLUSION: Cystic fluid CgA is not a useful marker for the differential diagnosis of cystic PNETs. It also has no value in the differential diagnosis of other pancreatic cysts. PMID- 26510085 TI - Show Me ECHO-Hepatitis C: A telemedicine mentoring program for patients with hepatitis C in underserved and rural areas in Missouri as a model in developing countries. AB - Project (Extension for Community Healthcare Outcomes) (ECHO) is a telemedicine case-based training model for primary care providers to treat complex diseases by mentoring academicians of universities. It was first developed by the University of New Mexico for rural and underserved areas in New Mexico. The project Show Me ECHO- Hepatitis C (HCV) is an adaptation of Project ECHO to improve healthcare and hepatitis C therapy in the entire state of Missouri, including rural and underserved areas. Show Me ECHO- HCV uses telemedicine as videoconferencing technology for the case-based learning. The medical specialists of the University of Missouri-Columbia provide training and mentoring to primary care providers working in rural and urban underserved areas to deliver the best evidence-based care for patients with hepatitis C. This type of a model is promising in the management of patients with hepatitis C in developing countries with the availability of basic internet connections and potential voluntary participants. PMID- 26510086 TI - Evaluation of fluvastatin in combination with the standard of care therapy (PEG IFN/Ribavirin) in Egyptian patients with hepatitis C virus. AB - BACKGROUND/AIMS: Cholesterol biosynthesis suppresses the replication of HCV-1b replicons, thus influencing hepatitis C virus (HCV) natural history. This study aimed at comparing the efficacy and safety of fluvastatin (FLV) as an adjuvant therapy to the standard of care (SOC) therapy, i.e., pegylated interferon (PEG IFN) and ribavirin, for the treatment of HCV patients. MATERIALS AND METHODS: Sixty HCV patients were enrolled and allocated to either group I, who received the triple therapy (fluvastatin + SOC), or group II, who received SOC; the duration for both treatments was 48 weeks. All patients were subjected to pretreatment liver biopsy and monthly biochemical tests (liver profile, CBC), and quantitative HCV-RNA test was performed at weeks 0, 4, 12, 48, and 72. RESULTS: All virological responses were higher in group I than in group II, with no statistical difference. Group I showed no manifestations of hepatotoxicity. CONCLUSION: Fluvastatin yielded a borderline, significantly higher complete early virological response than SOC; therefore, it is a safe adjuvant to the SOC therapy. PMID- 26510087 TI - Relationship between Helicobacter pylori infection and metabolic syndrome. AB - BACKGROUND/AIMS: To investigate the prevalence of metabolic syndrome (MS) and its components in patients with Helicobacter pylori that was detected using histopathological diagnostic methods. MATERIALS AND METHODS: The study included 200 patients who presented with dyspeptic complaints and had indication for endoscopy. H. pylori-positive [HP (+)] and H. pylori-negative [HP (-)] patients were compared in terms of MS and its components. RESULTS: The prevalence of H. pylori in general patient population is 49.5%. When patients were examined using a diagnostic criteria of MS, MS was present in 78 patients (78.8%) in the HP (+) (n=99) group and in 22 patients (21.8%) in the HP (-) (n=101) group (p<0.01). Logistic regression analysis revealed that H. pylori infection enhances the risk of developing MS by approximately 3.6 times (Relative Risk - (RR)=3.617, 95% CI: 2.465-5.307, p<0.001). With regard to the MS criteria, mean systolic-diastolic blood pressures and body mass index were significantly higher in HP (+) individuals than in HP (-) individuals. Furthermore, fasting plasma glucose, insulin and homeostatic model assessment-insulin resistance, very low-density lipoproteins, and triglyceride levels were also higher in the HP (+) group, whereas high-density lipoproteins levels were lower. CONCLUSION: H. pylori infection is a risk factor for MS. H. pylori leads to insulin resistance by developing chronic inflammation and accordingly facilitates the development of MS. PMID- 26510088 TI - Serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression in patients with familial Mediterranean fever. AB - BACKGROUND/AIMS: Serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) are well-known inflammatory biomarkers, with a diagnostic potential for various diseases. The aim of the present study was to determine the potential diagnostic applications of serum MMP-9 and TIMP-1 concentrations in patients with familial Mediterranean fever (FMF). MATERIALS AND METHODS: A total of 66 male FMF patients and 40 age-matched healthy subjects were included in this research. TIMP-1 and MMP-9 levels with conventional inflammation markers were determined. Pearson correlation analysis was used to determine the correlation between the characteristics of patients and the laboratory data. RESULTS: In patients with FMF, serum MMP-9 levels and MMP-9/TIMP-1 ratios were found to be significantly elevated in both acute episode and asymptomatic periods (p=0.0001 and p=0.0001, respectively). There was no significant difference between TIMP-1 levels. A significant negative correlation between patients' current age and TIMP-1 level in patients with acute episodes was detected (p=0.0008, r=-0.52). Moreover, a moderate negative correlation was noticed between erythrocyte sedimentation rate and TIMP-1 level in patients with acute episodes (p=0.01, r=-0.39). Additionally, a moderate negative correlation was found between the duration of colchicine use and MMP-9 and TIMP-1 levels during the attack period (p=0.04, r=-0.36 and p=0.02, r=-0.39, respectively). CONCLUSION: Our findings demonstrate that a significant MMP-9/TIMP-1 imbalance exists in patients with FMF, which reflects an ongoing inflammation in both FMF periods. Thus, the increased MMP-9 levels observed in FMF patients could rationalize therapeutic targeting to MMPs. PMID- 26510089 TI - Plasma Chromogranin A levels: Consider the associated disease entities. PMID- 26510090 TI - Using biofilms for monitoring metal contamination in lotic ecosystems: The protective effects of hardness and pH on metal bioaccumulation. AB - Biofilms can make good bioindicators and biomarkers, offering a convenient tool to monitor metal contamination in streams that results from mine tailing sites. Biofilm metal content (Cu, Zn, Cd, Pb) as well as diatom diversity and the presence of teratologies (diatom abnormalities) were determined for biofilms from rivers with a variety of physicochemical properties across a metal contamination gradient. The results of metal accumulation were highly consistent from year to year, with significant relationships between calculated free metal ion concentrations and biofilm metal contents for samples from different rivers. This indicates the "universal nature" of the metal accumulation process in biofilms. The authors observed that protons and major cations protected against metal accumulation. A very low number of diatom taxa were found at the most contaminated sites, and the highest proportions of deformities were observed at these sites. However, it was difficult to distinguish the effect of metal contamination from the effect of other parameters, especially pH. The results suggest that the development of biofilm-based proxies for metal bioavailability is useful and that incorporation of the effects of hardness and pH in this metal contamination monitoring tool is important. Environ Toxicol Chem 2016;35:1489 1501. (c) 2015 SETAC. PMID- 26510091 TI - Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway. AB - To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high-methylation CRC. The methylation levels of six Group-1 and 14 Group-2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development. SSA/P showed high methylation levels of both Group-1 and Group-2 markers, frequent BRAF mutation and occurrence in proximal colon, which were features of high-methylation CRC. But TSA showed low-methylation levels of Group 1 markers, less frequent BRAF mutation and occurrence at distal colon. SSA/P, but not TSA, is thus considered to be precursor of high-methylation CRC. High methylation CRC had even higher methylation levels of some genes, e.g., MLH1, than SSA/P, and significant frequency of somatic mutations in nonsynonymous mutations (p < 0.0001) and insertion/deletions (p = 0.002). MLH1-methylated SSA/P showed lower methylation level of MLH1 compared with high-methylation CRC, and rarely accompanied silencing of MLH1 expression. The mutation frequencies were not different between MLH1-methylated and MLH1-unmethylated SSA/P, suggesting that MLH1 methylation might be insufficient in SSA/P to acquire a hypermutation phenotype. Mutations of mismatch repair genes, e.g., MSH3 and MSH6, and genes in PI3K, WNT, TGF-beta and BMP signaling (but not in TP53 signaling) were significantly involved in high-methylation CRC compared with adenoma, suggesting importance of abrogation of these genes in serrated pathway. PMID- 26510092 TI - Identification and Functional Characterization of CLCN1 Mutations Found in Nondystrophic Myotonia Patients. AB - Mutations in the gene coding for the skeletal muscle Cl(-) channel (CLCN1) lead to dominant or recessive myotonia. Here, we identified and characterized CLCN1 mutations in Costa Rican patients, who had been clinically diagnosed with myotonic dystrophy type 1 but who were negative for DM1 mutations. CLCN1 mutations c.501C>G, p.F167L and c.1235A>C, p.Q412P appeared to have recessive inheritance but patients had atypical clinical phenotypes; c.313C>T, p.R105C was found in combination with c.501C>G, p.F167L in an apparently recessive family and the c.461A>G, p.Q154R variant was associated with a less clear clinical picture. In Xenopus oocytes, none of the mutations exhibited alterations of fast or slow gating parameters or single channel conductance, and mutations p.R105C, p.Q154R, and p.F167L were indistinguishable from wild-type (WT). p.Q412P displayed a dramatically reduced current density, surface expression and exerted no dominant negative effect in the context of the homodimeric channel. Fluorescently tagged constructs revealed that p.Q412P is expressed inefficiently. Our study confirms p.F167L and p.R105C as myotonia mutations in the Costa Rican population, whereas p.Q154R may be a benign variant. p.Q412P most likely induces a severe folding defect, explaining the lack of dominance in patients and expression systems, but has WT properties once expressed in the plasma membrane. PMID- 26510093 TI - Phosphorus cycling in deciduous forest soil differs between stands dominated by ecto- and arbuscular mycorrhizal trees. AB - Although much is known about how trees and their associated microbes influence nitrogen cycling in temperate forest soils, less is known about biotic controls over phosphorus (P) cycling. Given that mycorrhizal fungi are instrumental for P acquisition and that the two dominant associations - arbuscular mycorrhizal (AM) and ectomycorrhizal (ECM) fungi - possess different strategies for acquiring P, we hypothesized that P cycling would differ in stands dominated by trees associated with AM vs ECM fungi. We quantified soil solution P, microbial biomass P, and sequentially extracted inorganic and organic P pools from May to November in plots dominated by trees forming either AM or ECM associations in south central Indiana, USA. Overall, fungal communities in AM and ECM plots were functionally different and soils exhibited fundamental differences in P cycling. Organic forms of P were more available in ECM plots than in AM plots. Yet inorganic P decreased and organic P accumulated over the growing season in both ECM and AM plots, resulting in increasingly P-limited microbial biomass. Collectively, our results suggest that P cycling in hardwood forests is strongly influenced by biotic processes in soil and that these are driven by plant associated fungal communities. PMID- 26510094 TI - Sulthiame add-on therapy for epilepsy. AB - BACKGROUND: Epilepsy is a common neurological condition characterised by recurrent seizures. Most patients respond to conventional antiepileptic drugs, however, around 30% will continue to experience seizures despite multiple antiepileptic drugs. Sulthiame, also known as sultiame, is a widely used antiepileptic drug in Europe and Israel. We present a summary of the evidence for the use of sulthiame as add-on therapy in epilepsy. OBJECTIVES: To compare the efficacy and side-effect profile of sulthiame as add-on therapy compared with placebo or another antiepileptic drug. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, ClinicalTrials.gov and the WHO ICTRP Search Portal on 11 August 2015. No language restrictions were imposed. We contacted the manufacturers of sulthiame and researchers in the field to seek any ongoing or unpublished studies. SELECTION CRITERIA: Randomised controlled add-on trials of sulthiame in people of any age with epilepsy of any aetiology. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted relevant data. The following outcomes were assessed: 1) reduction in seizure frequency of 50% or greater between baseline and end of follow-up; 2) complete cessation of seizures during follow-up; 3) mean seizure frequency; 4) time to treatment withdrawal; 5) adverse drug effects; and 6) quality of life scoring. Primary analyses were intention-to-treat. We present a narrative analysis. MAIN RESULTS: We included one trial with 37 participants with a new diagnosis of West syndrome. Sulthiame was given as an add-on therapy to pyridoxine. No data were reported for outcomes 1), 3) or 6). Overall risk ratio with 95% confidence intervals (CI) for complete cessation of seizures during a nine-day follow-up period versus placebo was 0.71 (95% CI 0.53 to 0.96). Meaningful analysis of time to treatment withdrawal and adverse drug effects was not possible due to incomplete data. AUTHORS' CONCLUSIONS: Sulthiame may lead to a cessation of seizures when used as an add-on therapy to pyridoxine in patients with West syndrome. The included study was small and had a significant risk of bias which limits the impact of the evidence. No conclusions can be drawn about the occurrence of adverse drug effects, change in quality of life or mean reduction in seizure frequency. No evidence exists for the use of sulthiame as an add-on therapy in patients with epilepsy outside West syndrome. Large, multi centre randomized controlled trials are necessary to inform clinical practice if sulthiame is to be used as an add-on therapy for epilepsy. PMID- 26510095 TI - Comparison of Dexmedetomidine and Clonidine as Adjuvants to Local Anesthetics for Intrathecal Anesthesia: A Meta-Analysis of Randomized Controlled Trials. AB - The authors performed a meta-analysis to compare the characteristics of clonidine and dexmedetomidine as adjuvants to local anesthetic in intravertebral anesthesia. Four investigators independently searched electronic databases for randomized trials comparing the characteristics of clonidine vs dexmedetomidine as adjuvants to local anesthetic on adults. The endpoints were onset of analgesia, sensory and motor block, and duration of analgesia. A random-effects model was used to perform quantitative analysis. Seven studies comprising 354 subjects were included in this meta-analysis. The onset of sensory block was significantly 40 seconds shorter when dexmedetomidine was added as an adjuvant in the intrathecal injection. The duration of stable sensory block, duration of overall sensory block, and the time before the need for analgesic requirements were significantly extended, 10.8 minutes, 22.3 minutes, and 38.6 minutes, respectively, when dexmedetomidine was used as an adjuvant to local anesthetics (bupivacaine or ropivacaine). No significant differences were detected in the motor block characteristics and the time to achieve peak sensory level between dexmedetomidine and clonidine as adjuvants to local anesthetics. Compared to clonidine, the addition of dexmedetomidine as an adjuvant to local anesthetics is associated with earlier, prolonged sensory block characteristics and later need for analgesic requirements. PMID- 26510096 TI - Direct Observation of Short-Range Structural Coherence During a Charge Transfer Induced Spin Transition in a CoFe Prussian Blue Analogue by Transmission Electron Microscopy. AB - The local structure within the Co-Fe atomic array of the photoswitchable coordination polymer magnet, K0.3Co[Fe(CN)6]0.77.nH2O, is directly observed during charge transfer induced spin transition (CTIST), a solid-solid phase change, using high-resolution transmission electron microscopy (HRTEM). Along with the low-spin (LS) or thermally quenched high-spin (HS) states normally observed in CTIST solids at low temperature, slow cooling of K0.3Co[Fe(CN)6]0.77.nH2O results in an intermediate phase containing both HS and LS domains with short coherence length. By mapping individual metal-metal distances, the nanometer-scale HS domains are directly visualized within the LS array. Temperature-dependent analyses allow monitoring of HS domain coarsening along the warming branch of the CTIST, providing direct visualization of the elastic process and insight into the mechanism of phase propagation. Normally sensitive to electron beam damage, the low-temperature TEM measurements of the porous coordination polymer are enabled by using appropriate ionic liquids instead of usual conductive thin-film coatings, an approach that should find general utility in related classes of materials. PMID- 26510098 TI - Growth Conditions Control the Elastic and Electrical Properties of ZnO Nanowires. AB - Great efforts have been made to synthesize ZnO nanowires (NWs) as building blocks for a broad range of applications because of their unique mechanical and mechanoelectrical properties. However, little attention has been paid to the correlation between the NWs synthesis condition and these properties. Here we demonstrate that by slightly adjusting the NW growth conditions, the cross sectional shape of the NWs can be tuned from hexagonal to circular. Room temperature photoluminescence spectra suggested that NWs with cylindrical geometry have a higher density of point defects. In situ transmission electron microscopy (TEM) uniaxial tensile-electrical coupling tests revealed that for similar diameter, the Young's modulus and electrical resistivity of hexagonal NWs is always larger than that of cylindrical NWs, whereas the piezoresistive coefficient of cylindrical NWs is generally higher. With decreasing diameter, the Young's modulus and the resistivity of NWs increase, whereas their piezoresistive coefficient decreases, regardless of the sample geometry. Our findings shed new light on understanding and advancing the performance of ZnO-NW-based devices through optimizing the synthesis conditions of the NWs. PMID- 26510097 TI - Effects of the Staphylococcus aureus and Staphylococcus epidermidis Secretomes Isolated from the Skin Microbiota of Atopic Children on CD4+ T Cell Activation. AB - Interactions between the immune system and skin bacteria are of major importance in the pathophysiology of atopic dermatitis (AD), yet our understanding of them is limited. From a cohort of very young AD children (1 to 3 years old), sensitized to Dermatophagoides pteronyssinus allergens (Der p), we conducted culturomic analysis of skin microbiota, cutaneous transcript profiling and quantification of anti-Der p CD4+ T cells. This showed that the presence of S. aureus in inflamed skin of AD patients was associated with a high IgE response, increased expression of inflammatory and Th2/Th22 transcripts and the prevalence of a peripheral Th2 anti-Der p response. Monocyte-derived dendritic cells (moDC) exposed to the S. aureus and S. epidermidis secretomes were found to release pro inflammatory IFN-gamma and anti-inflammatory IL-10, respectively. Allogeneic moDC exposed to the S. aureus secretome also induced the proliferation of CD4+ T cells and this effect was counteracted by concurrent exposure to the S. epidermidis secretome. In addition, whereas the S. epidermidis secretome promoted the activity of regulatory T cells (Treg) in suppressing the proliferation of conventional CD4+ T cells, the Treg lost this ability in the presence of the S. aureus secretome. We therefore conclude that S. aureus may cause and promote inflammation in the skin of AD children through concomitant Th2 activation and the silencing of resident Treg cells. Commensals such as S. epidermidis may counteract these effects by inducing the release of IL-10 by skin dendritic cells. PMID- 26510099 TI - Impacts of a Comprehensive School Readiness Curriculum for Preschool Children at Risk for Educational Difficulties. AB - This article reports findings from a cluster-randomized study of an integrated literacy- and math-focused preschool curriculum, comparing versions with and without an explicit socioemotional lesson component to a business-as-usual condition. Participants included 110 classroom teachers from randomized classrooms and approximately eight students from each classroom (N = 760) who averaged 4.48 (SD = 0.44) years of age at the start of the school year. There were positive impacts of the two versions of the curriculum on language, phonological awareness, math, and socioemotional outcomes, but there were no added benefits to academic or socioemotional outcomes for the children receiving explicit socioemotional instruction. Results are discussed with relevance to early childhood theory, policy, and goals of closing the school readiness gap. PMID- 26510100 TI - DStat: A Versatile, Open-Source Potentiostat for Electroanalysis and Integration. AB - Most electroanalytical techniques require the precise control of the potentials in an electrochemical cell using a potentiostat. Commercial potentiostats function as "black boxes," giving limited information about their circuitry and behaviour which can make development of new measurement techniques and integration with other instruments challenging. Recently, a number of lab-built potentiostats have emerged with various design goals including low manufacturing cost and field-portability, but notably lacking is an accessible potentiostat designed for general lab use, focusing on measurement quality combined with ease of use and versatility. To fill this gap, we introduce DStat (http://microfluidics.utoronto.ca/dstat), an open-source, general-purpose potentiostat for use alone or integrated with other instruments. DStat offers picoampere current measurement capabilities, a compact USB-powered design, and user-friendly cross-platform software. DStat is easy and inexpensive to build, may be modified freely, and achieves good performance at low current levels not accessible to other lab-built instruments. In head-to-head tests, DStat's voltammetric measurements are much more sensitive than those of "CheapStat" (a popular open-source potentiostat described previously), and are comparable to those of a compact commercial "black box" potentiostat. Likewise, in head-to-head tests, DStat's potentiometric precision is similar to that of a commercial pH meter. Most importantly, the versatility of DStat was demonstrated through integration with the open-source DropBot digital microfluidics platform. In sum, we propose that DStat is a valuable contribution to the "open source" movement in analytical science, which is allowing users to adapt their tools to their experiments rather than alter their experiments to be compatible with their tools. PMID- 26510101 TI - [Not Available]. PMID- 26510103 TI - [Case Report - Really a diving accident?]. AB - A 17 y old male SCUBA diver presents himself for hospital admission after a suspected diving accident. All clinical signs are favouring the initial diagnosis: loss of leg motor function, paresthesia, disturbed vision and headache. What are your further diagnostic and therapeutic steps? Can you proof the initial diagnosis? What differential diagnoses are relevant or even mimicked? PMID- 26510104 TI - [Case report: Snake bite - an odd case]. AB - Emergency medical service is called by a 54-year-old man bitten by his rattlesnake. Upon initial survey we find the patient in a cardiopulmonary stable condition. He has bite marks and pain on his rapidly swelling middle finger of his right hand. Our initial treatment is immobilization of the patient. The snake raiser has already called the poison control center in Munich. By the help of this institution we bring him to a hospital having the right antivenom on hand. PMID- 26510105 TI - [Long-term administration of opioids for non-tumor pain - LONTS guideline provides an orientation]. AB - The long-term usage of opioid analgesics (> 3 months) for chronic, non-cancer related pain is critically discussed nationally and internationally. There are indications of under- and oversupply as well as misuse of opioids in Germany, but an "opioid epidemic" such as is evident in the USA cannot be detected at present.The S3-guideline LONTS (long-term usage of opioid analgesics for non cancer related pain)serves as an orientation to improve provision of opioids and contains statements about the available evidence, indications and contraindications of use, as well as practical recommendations for managing a long-term opioid therapy. PMID- 26510106 TI - [Not Available]. PMID- 26510107 TI - [Not Available]. PMID- 26510108 TI - [Hyperbaric therapy and diving medicine - hyperbaric therapy part 2: adjuvant therapy]. AB - Hyperbaric oxygen therapy (HBOT), i. e. breathing pure oxygen at elevated ambient pressure, remains the gold standard of care in treating air or gas embolism and decompression illness. Guidelines are less clear on the value of HBOT in acute management of carbon monoxide (CO) poisoning or clostridial necrosis. To evaluate the evidence of clinical efficacy of HBOT we performed a systematic literature review. Part 1 assesses acute indications such as air or gas embolism, decompression sickness, CO-poisoning, clostridialmyonecrosis, necrotizing problem wounds, acute traumatic wounds and arterial retinal occlusion. Part 2 discusses further uses of HBOT as adjuvant treatment and highlights problems in assessing the value of HBOT using evidence-based medicine criteria. PMID- 26510109 TI - [Hyperbaric therapy and diving medicine - diving medicine - present state and prospects]. AB - The diving accident (decompression incident, DCI) occurs in the decompression phase of dives. The DCI can either be caused by an arterial gas embolism (AGE) subsequent to a pulmonary barotrauma or by the formation of inert gas bubbles subsequent to a reduction of ambient pressure during the ascent from depth. In contrast to the traditional assumption that decompression incidents only occur if decompression rules are neglected, recent data indicate that a vast amount of diving accidents occur even though divers adhered to the rules. Hence, there is a large inter- and intraindividual variability in the predisposition for diving accidents. Within the past few years, the molecular understanding of the pathophysiology of diving accidents has improved considerably. It is now well accepted that pro-inflammatory and pro-coagulatory mechanisms play a central role. Moreover, microparticles are increasingly discussed in the pathogenesis of diving accidents. These new molecular findings have not yet resulted in new therapeutic approaches. However, new approaches of preconditioning before the dive have been developed which are intended to reduce the risk of diving accidents. The symptoms of a diving accident show a large variability and range. They reach from pruritus over tension in the female breast, marbled skin and pain in the joints to severe neurological disability like paraplegia or hemiplegia. Furthermore, pulmonary symptoms can be a result of a pulmonary gas embolism and/or a tension pneumothorax. Extreme cases can also manifest as generalized, difficult-to-treat seizures, loss of consciousness or even death. The evidence based therapy of diving accidents consists of an immediate application of 100% inspiratory O2. This can be performed via a demand valve, face mask with reservoir bag or ventilation bag connected to a reservoir bag. Fluid substitution is performed by i. v. infusion of 500-1000ml/h of cristalloids. If consciousness is not impaired, the diver is positioned in a supine position, in case of impaired or absent consciousness in a lateral recovery position. Especially in severe cases of DCI a fast transfer to a qualified hyperbaric center and the earliest possible hyperbaric O2-therapy is essential. PMID- 26510110 TI - [Hyperbaric therapy and diving medicine - hyperbaric chambers in use]. AB - Hyperbaric oxygen therapy (HBOT) is a scientifically justified and internationally established therapy, which is however not well-known thus rarely used in Germany. During a HBOT, the ambient pressure is raised while the patient breathes 100% O2, causing tissue partial oxygen pressure (ptO2) to increase distinctly. Through that, various pressure- and O2-associated processes are initiated. Herein 3 case studies are described that illustrate the mechanism of action and the range of applications of HBOT. PMID- 26510114 TI - Influence of Matrix metalloproteinase 1 and 3 genetic variations on susceptibility and severity of juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease affecting children aged less than 16 years, characterized by chronic synovitis, cartilage damage, and bony erosions mediated by matrix metalloproteinases (MMPs), mainly MMP-1 and MMP-3. The purpose of this study was to investigate MMP-1 and MMP-3 gene polymorphisms in patients with JIA, the role of genes in susceptibility to JIA, and their associations with JIA activity and prognosis. Case-control study included 100 patients diagnosed with JIA, according to the criteria of the International League of Associations for Rheumatology (ILAR), and 100 healthy children, age and sex matched, as controls. The MMP-1 (-1607 1G/2G) and MMP-3 ( 1171 5A/6A) polymorphisms were screened by polymerase chain reaction-restriction fragment length polymorphism. The serum levels of MMP-1 and MMP 3 were measured by enzyme-linked immunosorbent assay. There were significant differences between patients with JIA and control groups regarding the genotype and allele frequencies distributions of both MMP-1 1G/2G and MMP-3 5A/6A polymorphisms. The haplotype 2G-6A, which carries the abnormal alleles, showed higher frequencies in patients with JIA than in controls (OD = 2.8, P = 0.002). The prevalence of MMP-1 2G and 6A allele for MMP-3 polymorphism was found to be significantly associated with persistent oligoarticular, rheumatoid factor (RF)-positive polyarthritis, and systemic JIA groups. There were significantly increased serum levels of MMP-1 and MMP-3 associated with 2G/6A haplotype in the patient group, especially with the polyarticular RF (+ve) group than in other groups and the control group. MMP 1 and MMP-3 haplotypes could be useful genetic markers for JIA susceptibility and severity in the juvenile Egyptian population. Moreover, our data further support the use of serum MMP-3 and MMP-1 as specific markers of disease activity in JIA. PMID- 26510115 TI - A review of progress in the physics of open quantum systems: theory and experiment. AB - This report on progress explores recent advances in our theoretical and experimental understanding of the physics of open quantum systems (OQSs). The study of such systems represents a core problem in modern physics that has evolved to assume an unprecedented interdisciplinary character. OQSs consist of some localized, microscopic, region that is coupled to an external environment by means of an appropriate interaction. Examples of such systems may be found in numerous areas of physics, including atomic and nuclear physics, photonics, biophysics, and mesoscopic physics. It is the latter area that provides the main focus of this review, an emphasis that is driven by the capacity that exists to subject mesoscopic devices to unprecedented control. We thus provide a detailed discussion of the behavior of mesoscopic devices (and other OQSs) in terms of the projection-operator formalism, according to which the system under study is considered to be comprised of a localized region (Q), embedded into a well defined environment (P) of scattering wavefunctions (with Q + P = 1). The Q subspace must be treated using the concepts of non-Hermitian physics, and of particular interest here is: the capacity of the environment to mediate a coupling between the different states of Q; the role played by the presence of exceptional points (EPs) in the spectra of OQSs; the influence of EPs on the rigidity of the wavefunction phases, and; the ability of EPs to initiate a dynamical phase transition (DPT). EPs are singular points in the continuum, at which two resonance states coalesce, that is where they exhibit a non-avoided crossing. DPTs occur when the quantum dynamics of the open system causes transitions between non-analytically connected states, as a function of some external control parameter. Much like conventional phase transitions, the behavior of the system on one side of the DPT does not serve as a reliable indicator of that on the other. In addition to discussing experiments on mesoscopic quantum point contacts that provide evidence of the environmentally mediated coupling of quantum states, we also review manifestations of DPTs in mesoscopic devices and other systems. These experiments include observations of resonance-trapping behavior in microwave cavities and open quantum dots, phase lapses in tunneling through single-electron transistors, and spin swapping in atomic ensembles. Other possible manifestations of this phenomenon are presented, including various superradiant phenomena in low-dimensional semiconductors. From these discussions a generic picture of OQSs emerges in which the environmentally mediated coupling between different quantum states plays a critical role in governing the system behavior. The ability to control or manipulate this interaction may even lead to new applications in photonics and electronics. PMID- 26510116 TI - Reproductive Stage and Modulation of Stress-Induced Tau Phosphorylation in Female Rats. AB - Chronic stress is implicated as a risk factor for Alzheimer's disease (AD) and other neurodegenerative disorders. Although the specific mechanisms linking stress exposure and AD vulnerability have yet to be fully determined, our laboratory and others have shown that acute and repeated restraint stress in rodents leads to an increase in hippocampal tau phosphorylation (tau-P) and tau insolubility, a critical component of tau pathology in AD. Although tau phosphorylation induced by acute psychological stress is dependent on intact signaling through the type 1 corticotropin-releasing factor receptor, how sex steroids or other modulators contribute to this effect is unknown. A naturally occurring attenuation of the stress response is observed in female rats at the end of pregnancy and throughout lactation. To test the hypothesis that decreased sensitivity to stress during lactation modulates stress-induced tau-P, cohorts of virgin, lactating and weaned female rats were subjected to 30 min of restraint stress or no stress (control) and were killed 20 min or 24 h after the episode. Exposure to restraint stress induced a significant decrease in tau-P in the hippocampus of lactating rats killed 20 min after stress compared to lactating controls and virgins subjected to stress treatment. Lactating rats killed 24 hr after restraint stress exposure showed significant elevation in tau-P compared to lactating cohorts killed 20 min after stress. Levels of tau-P in these latter cohorts did not differ signficantly from control animals. Furthermore, glycogen synthase kinase (GSK)3-alpha levels were significantly decreased in stressed lactating animals at both timepoints. This suggests a steep, yet transient stress induced dephosphorylation of tau, influenced by GSK3, in the hippocampus of lactating rats. PMID- 26510117 TI - Array-compressed parallel transmit pulse design. AB - PURPOSE: To design array-compressed parallel transmit radiofrequency (RF) pulses and compare them to pulses designed with existing transmit array compression strategies. THEORY AND METHODS: Array-compressed parallel RF pulse design is proposed as the joint optimization of a matrix of complex-valued compression weights that relate a full-channel physical array to a reduced-channel virtual array, along with a set of RF pulses for the virtual array. In this way, the physics of the RF pulse application determine the coil combination weights. Array compressed pulse design algorithms are described for four parallel transmit applications: accelerated two-dimensional spiral excitation, multislice RF shimming, small-tip-angle kT -points excitation, and slice-selective spokes refocusing. Array-compressed designs are compared in simulations and an experiment to pulses designed using four existing array compression strategies. RESULTS: In all cases, array-compressed pulses achieved the lowest root-mean square excitation error among the array compression approaches. Low errors were generally achieved without increasing root-mean-square RF amplitudes or maximum local 10-gram specific absorption rate. Leave-one-out multisubject shimming simulations demonstrated that array-compressed RF shimming can identify useful fixed coil combination weights that perform well across a population. CONCLUSION: Array-compressed pulse design jointly identifies the transmit coil array compression weights and RF pulses that perform best for a specific parallel excitation application. Magn Reson Med 76:1158-1169, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26510118 TI - Quercitrin offers protection against brain injury in mice by inhibiting oxidative stress and inflammation. AB - Quercitrin is one of the primary flavonoid compounds present in vegetables and fruits. The aim of the present study was to evaluate the effects of quercitrin against carbon tetrachloride (CCl4) induced brain injury and further to elucidate its probable mechanisms. ICR mice received CCl4 intraperitoneally with or without quercitrin co-administration for 4 weeks. Our data showed that quercitrin significantly suppressed the elevation of reactive oxygen species (ROS) production and malondialdehyde (MDA) content, reduced tissue plasminogen activator (t-PA) activity, enhanced the antioxidant enzyme activities and abrogated cytochrome P450 2E1 (CYP2E1) induction in mouse brains. Quercitrin also prevented CCl4 induced cerebral function disorders associated with its ability to inhibit the activities of monoamine oxidase (MAO), acetylcholine esterase (AChE) and the N-methyl-d-aspartate receptor 2B subunit (NR2B). In addition, western blot analysis showed that quercitrin suppressed the release of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL 6). Taken together, our findings suggested that quercitrin may be a potential candidate to be developed as a neuroprotective agent. PMID- 26510119 TI - Three-step open and hybrid surgical treatment for contained rupture of De Bakey Type 3 thoracoabdominal aortic dissection: case report. PMID- 26510120 TI - Multi-Variate EEG Analysis as a Novel Tool to Examine Brain Responses to Naturalistic Music Stimuli. AB - Note onsets in music are acoustic landmarks providing auditory cues that underlie the perception of more complex phenomena such as beat, rhythm, and meter. For naturalistic ongoing sounds a detailed view on the neural representation of onset structure is hard to obtain, since, typically, stimulus-related EEG signatures are derived by averaging a high number of identical stimulus presentations. Here, we propose a novel multivariate regression-based method extracting onset-related brain responses from the ongoing EEG. We analyse EEG recordings of nine subjects who passively listened to stimuli from various sound categories encompassing simple tone sequences, full-length romantic piano pieces and natural (non-music) soundscapes. The regression approach reduces the 61-channel EEG to one time course optimally reflecting note onsets. The neural signatures derived by this procedure indeed resemble canonical onset-related ERPs, such as the N1-P2 complex. This EEG projection was then utilized to determine the Cortico-Acoustic Correlation (CACor), a measure of synchronization between EEG signal and stimulus. We demonstrate that a significant CACor (i) can be detected in an individual listener's EEG of a single presentation of a full-length complex naturalistic music stimulus, and (ii) it co-varies with the stimuli's average magnitudes of sharpness, spectral centroid, and rhythmic complexity. In particular, the subset of stimuli eliciting a strong CACor also produces strongly coordinated tension ratings obtained from an independent listener group in a separate behavioral experiment. Thus musical features that lead to a marked physiological reflection of tone onsets also contribute to perceived tension in music. PMID- 26510121 TI - Thromboelastography predicts risks of obstetric complication occurrence in (hypo)dysfibrinogenemia patients under non-pregnant state. AB - Congenital (hypo)dysfibrinogenemia patients may have obstetric complications during their pregnancies. This study aimed to evaluate thromboelastography (TEG) as a potential tool for assessing the tendency for obstetric complications in those patients in a non-pregnant state. A total of 22 female subjects with congenital (hypo)dysfibrinogenemia were recruited. Nine subjects had histories of obstetric complications and the other 13 subjects had at least one uneventful pregnancy without obstetric complications as yet. Detailed clinical investigation and phenotype/genotype detection were carried out, and both kaolin-activated TEG and functional fibrinogen TEG (FF-TEG) were applied in all subjects. Significant differences were identified in all TEG parameters except for R and angle between these two groups (P < 0.05) by covariance analysis. Receiver operating characteristic (ROC) analysis of discrimination between these two groups of patients was performed for TEG parameters. Significantly high odds ratio (OR) of obstetric complications occurrence were demonstrated in K >= 3.8 min, maximum amplitude (MA) <= 54.2 mm, comprehensive index (CI) <= -3 (11.67, 95% CI 1.527 89.121, P < 0.05 in all), and MA-CFF <= 12.1 mm (20.00, 95% confidence interval (95% CI) 1.967-203.322, P = 0.002). Moreover, MA-CFF had better prognostic performance, with a corresponding area under the receiver operating curve of 0.923 (range 0.815-1.031, P = 0.001). This study suggests that (hypo)dysfibrinogenemia patients with values outside of the cut-off values of TEG assays under non-pregnant state may have a higher risk of obstetric complications occurring when they are pregnant. No parameters under non-pregnant state in clinical laboratory have ever been reported to be risk factors for obstetric complication occurrence in (hypo)dysfibrinogenemia patients. This study explored such parameters in TEG assays and found that parameters of TEG assays under non pregnant status might predict the occurrence of obstetric complications, which could provide physicians with important information about whether fibrinogen replacement therapy is required, so as to prevent the occurrence of obstetric complications, especially for patients who are asymptomatic in daily life. PMID- 26510122 TI - Inline radiofrequency pre-coagulation simplifies single-incision laparoscopic minor liver resection. AB - BACKGROUND: Single-incision laparoscopy (SIL) has been developed to reduce surgical trauma, whereas technical difficulties in bleeding control limit the broad acceptance for hepatectomy. A novel minimized invasive strategy combining inline radiofrequency pre-coagulation and transumbilical SIL is presented herein. METHODS: A cohort of 21 selected patients underwent transumbilical SIL hepatectomies (segmentectomies II-VI) utilizing inline radiofrequency pre coagulation for hepatic transection (Habib 4X). Bleeding control, postoperative complications and positive resection margins in malignant diseases served as primary and secondary outcome parameters, respectively. RESULTS: Single-incision laparoscopy was successfully completed in all patients. A total of 33 segments were retrieved: mean resection time was 66 +/- 35 min, including 11 anatomical (52.38%) and 10 non-anatomical (47.62%) resections. Sixteen patients (76.19%) underwent concomitant abdominal surgery. No substantial blood loss occurred. Neither additional staplers nor clips were necessary to control any bleeding or bile leakage. One pleural effusion counted for the only postoperative complication. Free margins could be achieved in all but one resection (12/13 patients with malignancies; 92.31%). Ninety-day mortality was zero. CONCLUSIONS: The combination of SIL and inline radiofrequency pre-coagulation proved to be a simple, efficacious and safe technique in minor hepatectomy. PMID- 26510123 TI - Isolation of Elusive HAsAsH in a Crystalline Diuranium(IV) Complex. AB - The HAsAsH molecule has hitherto only been proposed tentatively as a short-lived species generated in electrochemical or microwave-plasma experiments. After two centuries of inconclusive or disproven claims of HAsAsH formation in the condensed phase, we report the isolation and structural authentication of HAsAsH in the diuranium(IV) complex [{U(Tren(TIPS) )}2 (MU-eta(2) :eta(2) -As2 H2 )] (3, Tren(TIPS) =N(CH2 CH2 NSiPr(i) 3 )3 ; Pr(i) =CH(CH3 )2 ). Complex 3 was prepared by deprotonation and oxidative homocoupling of an arsenide precursor. Characterization and computational data are consistent with back-bonding-type interactions from uranium to the HAsAsH pi*-orbital. This experimentally confirms the theoretically predicted excellent pi-acceptor character of HAsAsH, and is tantamount to full reduction to the diarsane-1,2-diide form. PMID- 26510124 TI - Genetic Variants in Six-Transmembrane Epithelial Antigen of Prostate 4 Increase Risk of Developing Metabolic Syndrome in a Han Chinese Population. AB - BACKGROUND: Altered expression of six-transmembrane epithelial antigen of prostate 4 (STEAP4) is linked to obesity, insulin insensitivity, metabolic homeostasis, and inflammation. This study assessed STEAP4 single nucleotide polymorphisms (SNPs) for association with a risk in developing metabolic syndrome in a Han Chinese population. METHODS: A total of 3375 Han Chinese subjects were included in this case-control study with 1583 metabolic syndrome (MetS) patients and 1792 healthy controls. Four SNPs (rs1981529, rs2040657, rs10263111, rs12386756) were genotyped using polymerase chain reaction and MALDI-TOF-MS. The associations between the STAMP4 SNPs and MetS were then analyzed statistically. RESULTS: There was no statistical difference in allele frequency of these four SNPs between the case and control populations. The genotype of rs12386756 was shown to be significantly associated with MetS (p = 0.035). Compared with the AA/GG genotypes, the GA genotype of rs12386756 significantly decreased the risk of developing MetS (OR = 0.77; 95% CI, 0.63-0.94; p = 0.0098). There was also no haplotype that could be associated with the risk of developing MetS. Furthermore, the SNP rs1981529 of STEAP4 was associated with body-mass index, waist circumference, and systolic blood pressure, while SNP rs10263111 was associated with waist circumference and fasting glucose levels. SNP rs12386756 was associated with waist and hip circumferences. CONCLUSION: Some SNPs of the STEAP4 gene altered the risk of developing a metabolic syndrome in the Han Chinese population. Further studies must be conducted to understand the role of the STEAP4 gene in the pathogenesis of metabolic syndrome. PMID- 26510125 TI - The Audiometric and Mechanical Effects of Partial Ossicular Discontinuity. AB - OBJECTIVES: Ossicular discontinuity may be complete, with no contact between the disconnected ends, or partial, where normal contact at an ossicular joint or along a continuous bony segment of an ossicle is replaced by soft tissue or simply by contact of opposing bones. Complete ossicular discontinuity typically results in an audiometric pattern of a large, flat conductive hearing loss. In contrast, in cases where otomicroscopy reveals a normal external ear canal and tympanic membrane, high-frequency conductive hearing loss has been proposed as an indicator of partial ossicular discontinuity. Nevertheless, the diagnostic utility of high-frequency conductive hearing loss has been limited due to gaps in previous research on the subject, and clinicians often assume that an audiogram showing high-frequency conductive hearing loss is flawed. This study aims to improve the diagnostic utility of high-frequency conductive hearing loss in cases of partial ossicular discontinuity by (1) making use of a control population against which to compare the audiometry of partial ossicular discontinuity patients and (2) examining the correlation between high-frequency conductive hearing loss and partial ossicular discontinuity under controlled experimental conditions on fresh cadaveric temporal bones. Furthermore, ear-canal measurements of umbo velocity and wideband acoustic immittance measurements were investigated to determine the usefulness regarding diagnosis of ossicular discontinuity. DESIGN: The authors analyzed audiograms from 66 patients with either form of surgically confirmed ossicular discontinuity and no confounding pathologies. The authors also analyzed umbo velocity (n = 29) and power reflectance (n = 12) measurements from a subset of these patients. Finally, the authors performed experiments on six fresh temporal bone specimens to study the differing mechanical effects of complete and partial discontinuity. The mechanical effects of these lesions were assessed via laser Doppler measurements of stapes velocity. In a subset of the specimen (n = 4), wideband acoustic immittance measurements were also collected. RESULTS: (1) Calculations comparing the air-bone gap (ABG) at high and low frequencies show that when high-frequency ABGs are larger than low-frequency ABGs, the surgeon usually reported soft-tissue bands at the point of discontinuity. However, in cases with larger low-frequency ABGs and flat ABGs across frequencies, some partial discontinuities as well as complete discontinuities were reported. (2) Analysis of umbo velocity and power reflectance (calculated from wideband acoustic immittance) in patients reveal no significant difference across frequencies between the two types of ossicular discontinuities. (3) Temporal bone experiments reveal that partial discontinuity results in a greater loss in stapes velocity at high frequencies when compared with low frequencies, whereas with complete discontinuity, large losses in stapes velocity occur at all frequencies. CONCLUSION: The clinical and experimental findings suggest that when encountering larger ABGs at high frequencies when compared with low frequencies, partial ossicular discontinuity should be considered in the differential diagnosis. PMID- 26510126 TI - Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer. AB - IMPORTANCE: Immune dysfunction underlies the pathogenesis of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Immunosuppressive therapy is the standard of care for these diseases. Both immune dysfunction and therapy-related immunosuppression can inhibit cancer-related immune surveillance in this population. Drug-induced immunosuppression is a risk factor for nonmelanoma skin cancer (NMSC), particularly squamous cell tumors. For patients with a history of NMSC, data are limited on the effect of these drugs on the risk of additional NMSCs. OBJECTIVE: To determine the relative hazard of a second NMSC in patients with RA or IBD who use methotrexate, anti-tumor necrosis factor (anti-TNF) therapy, or thiopurines after an initial NMSC. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, we studied 9460 individuals with RA or IBD enrolled in Medicare from January 1, 2006, through December 31, 2012. EXPOSURES: Exposure to methotrexate, thiopurines, anti-TNFs, sulfasalazine, hydroxychloroquine, abatacept, or rituximab after the incident NMSC surgery. MAIN OUTCOMES AND MEASURES: A second NMSC occurring 1 year or more after the incident NMSC using Cox proportional hazards regression models. RESULTS: Among 9460 individuals (6841 with RA and 2788 with IBD), the incidence rate of a second NMSC per 1000 person-years was 58.2 (95% CI, 54.5-62.1) and 58.9 (95% CI, 53.2-65.2) in patients with RA and IBD, respectively. Among patients with RA, methotrexate used in conjunction with other medications was associated with an increased risk of a second NMSC (hazard ratio [HR], 1.60; 95% CI, 1.08-2.37). Adjusted for other medications, the risk of NMSC increased with 1 year or more of methotrexate use (HR, 1.24; 95% CI, 1.04-1.48). Compared with methotrexate alone, the addition of anti-TNF drugs was significantly associated with risk of NMSC (HR, 1.49; 95% CI, 1.03-2.16). Abatacept and rituximab were not associated with increased NMSC risk. The nonsignificant HRs for 1 year or more of thiopurine and anti-TNF use for IBD were 1.49 (95% CI, 0.98-2.27) and 1.36 (95% CI, 0.76-2.44), respectively. CONCLUSIONS AND RELEVANCE: Methotrexate use is associated with an increased risk of a second NMSC. Anti-TNF use may increase the risk of a second NMSC when used with methotrexate for RA. Further long-term studies are required before one can conclude that thiopurine and/or anti-TNF do not increase the risk of a second NMSC in patients with IBD. PMID- 26510128 TI - Properties of some Hamiltonians describing topologically non-trivial fermionic systems. AB - We introduce a Hamiltonian for fermions on a lattice and prove a theorem regarding its topological properties. We identify the topological criterion as a [Formula: see text]-topological invariant [Formula: see text] (the Pfaffian polynomial). The topological invariant is not only the first Chern number, but also the sign of the Pfaffian polynomial coming from a notion of duality. Such Hamiltonian can describe non-trivial Chern insulators, single band superconductors or multiorbital superconductors. The topological features of these families are completely determined as a consequence of our theorem. Some specific model examples are explicitly worked out, with the computation of different possible topological invariants. PMID- 26510127 TI - Structural basis for phosphatidylinositol-phosphate biosynthesis. AB - Phosphatidylinositol is critical for intracellular signalling and anchoring of carbohydrates and proteins to outer cellular membranes. The defining step in phosphatidylinositol biosynthesis is catalysed by CDP-alcohol phosphotransferases, transmembrane enzymes that use CDP-diacylglycerol as donor substrate for this reaction, and either inositol in eukaryotes or inositol phosphate in prokaryotes as the acceptor alcohol. Here we report the structures of a related enzyme, the phosphatidylinositol-phosphate synthase from Renibacterium salmoninarum, with and without bound CDP-diacylglycerol to 3.6 and 2.5 A resolution, respectively. These structures reveal the location of the acceptor site, and the molecular determinants of substrate specificity and catalysis. Functional characterization of the 40%-identical ortholog from Mycobacterium tuberculosis, a potential target for the development of novel anti tuberculosis drugs, supports the proposed mechanism of substrate binding and catalysis. This work therefore provides a structural and functional framework to understand the mechanism of phosphatidylinositol-phosphate biosynthesis. PMID- 26510129 TI - A magnetooptical study of (4-(2-dibutylaminoethanolato-N,O,O,O) chlorido copper(II)): a cubane complex with dominant ferromagnetic interactions. AB - This paper reports the experimental and theoretical study of a tetranuclear (CuClOCH2CH2N(C4H9)2)4 complex. Analysis of the magnetic circular dichroism spectrum was performed based on the Hamiltonian that includes the crystal field of the nearest ligands and the spin-orbit interaction. The crystal field parameters were evaluated in the framework of the exchange charge model that accounts for the exchange and covalence effects. The values of the crystal field parameters obtained during the analysis of the magnetic circular dichroism spectrum were used for the calculation of the principal values and the directions of the principal axes of the local g-tensors and for the simulation of both temperature dependence of the magnetic susceptibility and field dependence of the magnetization. The value of the exchange parameter (Jex = 30 cm(-1)) was obtained. It was demonstrated that the description of the low temperature magnetic properties requires taking into account the intercluster interaction. PMID- 26510130 TI - Alternating Intramolecular and Intermolecular Catalyst-Transfer Suzuki-Miyaura Condensation Polymerization: Synthesis of Boronate-Terminated pi-Conjugated Polymers Using Excess Dibromo Monomers. AB - The Suzuki-Miyaura coupling polymerization of dibromoarene 1 and arylenediboronic acid (ester) 2 with a Pd catalyst having a high propensity for intramolecular catalyst transfer is reported. The polymerization of excess 1 with 2 affords high molecular-weight pi-conjugated polymer having boronic acid (ester) moieties at both ends, contrary to Flory's principle. This unstoichiometric polycondensation behavior is accounted for by intramolecular transfer of the Pd catalyst on 1. In the polymerization of 1 and 2 having different aryl residues, high-molecular weight polymer is obtained when the stronger donor aromatic is used as the dibromo monomer and the weaker donor or acceptor aromatic is used as diboronic acid (ester) monomer. The pinacol boronate moieties at both ends of the obtained poly(p-phenylene) (PPP) can be converted to benzoic acid ester, hydroxyl group, and bromine. Furthermore, the reaction of the pinacol boronate-terminated PPP with poly(3-hexylthiophene) (P3HT) having bromine at one end yields a triblock copolymer of P3HT-b-PPP-b-P3HT. PMID- 26510131 TI - Using Patient Outcomes to Evaluate General Surgery Residency Program Performance. AB - IMPORTANCE: To evaluate and financially reward general surgery residency programs based on performance, performance must first be defined and measureable. OBJECTIVE: To assess general surgery residency program performance using the objective clinical outcomes of patients operated on by program graduates. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted of discharge records from 349 New York and Florida hospitals between January 1, 2008, and December 31, 2011. The records comprised 230,769 patients undergoing 1 of 24 general surgical procedures performed by 454 surgeons from 73 general surgery residency programs. Analysis was conducted from June 4, 2014, to June 16, 2015. MAIN OUTCOMES AND MEASURES: In-hospital death; development of 1 or more postoperative complications before discharge; prolonged length of stay, defined as length of stay greater than the 75th percentile when compared with patients undergoing the same procedure type at the same hospital; and failure to rescue, defined as in-hospital death after the development of 1 or more postoperative complications. RESULTS: Patients operated on by surgeons trained in residency programs that were ranked in the top tertile were significantly less likely to experience an adverse event than were patients operated on by surgeons trained in residency programs that were ranked in the bottom tertile. Adjusted adverse event rates for patients operated on by surgeons trained in programs that were ranked in the top tertile and those who were operated on by surgeons trained in programs that were ranked in the bottom tertile were, respectively, 0.483% vs 0.476% for death, 9.68% vs 10.79% for complications, 16.76% vs 17.60% for prolonged length of stay, and 2.68% vs 2.98% for failure to rescue (all P < .001). The differences remained significant in procedure-specific subset analyses. The rankings were significantly correlated among some but not all outcome measures. The magnitude of the effect of the residency program on the outcomes achieved by the graduates decreased with increasing years of practice. Within the analyses of surgeons within 20, 10, and 5 years of practice, the relative difference in adjusted adverse event rates across the individual models between the top and bottom tertiles ranged from 1.5% to 12.3% (20 years), 9.1% to 33.8% (10 years), and 8.0% to 44.4% (5 years). CONCLUSIONS AND RELEVANCE: Objective data were successfully used to rank the clinical outcomes achieved by graduates of general surgery residency programs. Program rankings differed by the outcome measured. The magnitude of differences across programs was small. Careful consideration must be used when identifying potential targets for payment-for-performance initiatives in graduate medical education. PMID- 26510132 TI - Piezo-Phototronic Enhanced UV Sensing Based on a Nanowire Photodetector Array. AB - A large array of Schottky UV photodetectors (PDs) based on vertical aligned ZnO nanowires is achieved. By introducing the piezo-phototronic effect, the performance of the PD array is enhanced up to seven times in photoreponsivity, six times in sensitivity, and 2.8 times in detection limit. The UV PD array may have applications in optoelectronic systems, adaptive optical computing, and communication. PMID- 26510134 TI - Understanding the adsorption behavior of surface active molecules on ZnO nanostructures by experimental and first-principles calculations. AB - Zinc oxide (ZnO) nanostructures with different morphologies are prepared in the presence of surface active molecules such as sodium dodecyl sulphate (SDS), Tween 80 and Triton X-100 by a chemical method. The experimental and first principles methods are employed to understand the microscopic origin of the asymmetric growth mechanism of ZnO in the presence of various surface active molecules. Effect of increase in the amount of surface active molecules and temperature is studied on the growth morphology of ZnO. An innovative method is developed to synthesize ZnO nanowires (NWs) in the presence of SDS. Spherical nanoparticles (NPs) to spherical clusters are obtained in the presence of Triton X-100 and Tween 80. These results are then supported by first principles calculations. The adsorption of the -OH functional group on both polar and nonpolar surfaces of ZnO is modelled by using density functional theory (DFT). The calculated binding energy (BE) is almost equivalent on both the surfaces with no preference on any particular surface. The calculated value of BE shows that the -OH group is physio adsorbed on both the surfaces. This results in the spherical morphology of nanoparticles prepared in the presence of Tween 80. Bader charge analysis shows that the charge transfer mainly takes place on top two layers of the ZnO(101[combining macron]0) surface. The absence of high values of electron localization function (ELF) reflects the lack of covalent bonding between the -OH group and the ZnO(101[combining macron]0) surface. PMID- 26510133 TI - Transcriptomic Changes Due to Cytoplasmic TDP-43 Expression Reveal Dysregulation of Histone Transcripts and Nuclear Chromatin. AB - TAR DNA-binding protein 43 (TDP-43) is normally a nuclear RNA-binding protein that exhibits a range of functions including regulation of alternative splicing, RNA trafficking, and RNA stability. However, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved, and is mislocalized to the cytoplasm where it forms distinctive aggregates. We previously developed a mouse model expressing human TDP-43 with a mutation in its nuclear localization signal (DeltaNLS-hTDP-43) so that the protein preferentially localizes to the cytoplasm. These mice did not exhibit a significant number of cytoplasmic aggregates, but did display dramatic changes in gene expression as measured by microarray, suggesting that cytoplasmic TDP-43 may be associated with a toxic gain-of-function. Here, we analyze new RNA-sequencing data from the DeltaNLS-hTDP-43 mouse model, together with published RNA-sequencing data obtained previously from TDP-43 antisense oligonucleotide (ASO) knockdown mice to investigate further the dysregulation of gene expression in the DeltaNLS model. This analysis reveals that the transcriptomic effects of the overexpression of the DeltaNLS-hTDP-43 transgene are likely due to a gain of cytoplasmic function. Moreover, cytoplasmic TDP-43 expression alters transcripts that regulate chromatin assembly, the nucleolus, lysosomal function, and histone 3' untranslated region (UTR) processing. These transcriptomic alterations correlate with observed histologic abnormalities in heterochromatin structure and nuclear size in transgenic mouse and human brains. PMID- 26510135 TI - Effectiveness of a Randomized Controlled Lifestyle Intervention to Prevent Obesity among Chinese Primary School Students: CLICK-Obesity Study. AB - BACKGROUND: Childhood obesity has been increasing rapidly worldwide. There is limited evidence for effective lifestyle interventions to prevent childhood obesity worldwide, especially in developing countries like China. The objective of this study was to assess the effectiveness of a school-based multi-component lifestyle childhood obesity prevention program (the CLICK-Obesity study) in Mainland China. METHODS: A cluster randomized controlled trial was developed among grade 4 students from 8 urban primary schools (638 students in intervention, 544 as control) in Nanjing City, China. Students were randomly allocated to the control or intervention group at school-level. A one-year multi component intervention program (classroom curriculum, school environment support, family involvement and fun programs/events) together with routine health education was provided to the intervention group, while the control group received routine health education only. The main outcome variables assessed were changes in body mass index, obesity occurrence, obesity-related lifestyle behaviors and knowledge. RESULTS: Overall, 1108 (93.7%) of the 1182 enrolled students completed the intervention study. The intervention group had a larger marginal reduction than did the control group in overall mean BMI value (-0.32+/ 1.36 vs. -0.29+/-1.40, p = 0.09), although this was not significant. Compared with the control group, the intervention group was more likely to decrease their BMI (OR = 1.44, 95%CI = 1.10, 1.87) by 0.5 kg/m2 or above, increase the frequency of jogging/running (OR = 1.55, 95%CI = 1.18, 2.02), decrease the frequency of TV/computer use (OR = 1.41, 95%CI = 1.09, 1.84) and of red meat consumption (OR = 1.50, 95%CI = 1.15, 1.95), change commuting mode to/from school from sedentary to active mode (OR = 2.24, 95%CI = 1.47, 3.40), and be aware of the harm of selected obesity risk factors. CONCLUSIONS: The school-based lifestyle intervention program was practical and effective in improving health behaviors and obesity related knowledge for children in China. This study provides important policy implications on school-based intervention programs for modifications of obesity related lifestyles. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR ERC-11001819. PMID- 26510136 TI - Culicoides Species Communities Associated with Wild Ruminant Ecosystems in Spain: Tracking the Way to Determine Potential Bridge Vectors for Arboviruses. AB - The genus Culicoides Latreille 1809 is a well-known vector for protozoa, filarial worms and, above all, numerous viruses. The Bluetongue virus (BTV) and the recently emerged Schmallenberg virus (SBV) are responsible for important infectious, non-contagious, insect-borne viral diseases found in domestic ruminants and transmitted by Culicoides spp. Both of these diseases have been detected in wild ruminants, but their role as reservoirs during the vector-free season still remains relatively unknown. In fact, we tend to ignore the possibility of wild ruminants acting as a source of disease (BTV, SBV) and permitting its reintroduction to domestic ruminants during the following vector season. In this context, a knowledge of the composition of the Culicoides species communities that inhabit areas where there are wild ruminants is of major importance as the presence of a vector species is a prerequisite for disease transmission. In this study, samplings were conducted in areas inhabited by different wild ruminant species; samples were taken in both 2009 and 2010, on a monthly basis, during the peak season for midge activity (in summer and autumn). A total of 102,693 specimens of 40 different species of the genus Culicoides were trapped; these included major BTV and SBV vector species. The most abundant vector species were C. imicola and species of the Obsoletus group, which represented 15% and 11% of total numbers of specimens, respectively. At the local scale, the presence of major BTV and SBV vector species in areas with wild ruminants coincided with that of the nearest sentinel farms included in the Spanish Bluetongue Entomological Surveillance Programme, although their relative abundance varied. The data suggest that such species do not exhibit strong host specificity towards either domestic or wild ruminants and that they could consequently play a prominent role as bridge vectors for different pathogens between both types of ruminants. This finding would support the hypothesis that wild ruminants could act as reservoirs for such pathogens, and subsequently be involved in the reintroduction of disease to livestock on neighbouring farms. PMID- 26510137 TI - Blunting of Colon Contractions in Diabetics with Gastroparesis Quantified by Wireless Motility Capsule Methods. AB - Generalized gut transit abnormalities are observed in some diabetics with gastroparesis. Relations of gastric emptying abnormalities to colon contractile dysfunction are poorly characterized. We measured colon transit and contractility using wireless motility capsules (WMC) in 41 healthy subjects, 12 diabetics with gastroparesis (defined by gastric retention >5 hours), and 8 diabetics with normal gastric emptying (<=5 hours). Overall numbers of colon contractions >25 mmHg were calculated in all subjects and were correlated with gastric emptying times for diabetics with gastroparesis. Colon transit periods were divided into quartiles by time and contraction numbers were calculated for each quartile to estimate regional colon contractility. Colon transit in diabetics with gastroparesis was prolonged vs. healthy subjects (P<0.0001). Overall numbers of colon contractions in gastroparetics were lower than controls (P = 0.02). Diabetics with normal emptying showed transit and contraction numbers similar to controls. Gastric emptying inversely correlated with overall contraction numbers in gastroparetics (r = -0.49). Numbers of contractions increased from the 1st to 4th colon transit quartile in controls and diabetics with normal emptying (P<=0.04), but not gastroparetics. Numbers of contractions in the 3rd and 4th quartiles were reduced in gastroparetics vs. healthy controls (P<=0.05) and in the 4th quartile vs. diabetics with normal emptying (P = 0.02). Numbers of contractions were greatest in the final 15 minutes of transit, but were reduced in gastroparetics vs. healthy controls and diabetics with normal emptying (P<=0.005). On multivariate analyses, differences in numbers of contractions were not explained by demographic or clinical variables. In conclusion, diabetics with gastroparesis exhibit delayed colon transit associated with reductions in contractions that are prominently blunted in latter transit phases and which correlate with delayed gastric emptying, while diabetics with normal emptying show no significant colonic impairments. These findings emphasize diabetic gastroparesis may be part of a generalized dysmotility syndrome. PMID- 26510138 TI - Ordering chest X-rays in Australian general practice. AB - Data from the BEACH program between 2012-14 were used to examine general practice encounters where chest X-rays were ordered. This included the most common problems associated with chest X-ray ordering and patient characteristics. Changes in ordering between 2004-05 and 2013-14 were also investigated. The rate of chest X-ray ordering between 2004-05 and 2013-14 decreased significantly. In 2012-14, chest X-rays were most often ordered in the management of acute bronchitis/bronchiolitis, cough and pneumonia. Pleurisy/pleural effusion had the highest likelihood of resulting in a chest X-ray order, followed by shortness of breath/dyspnoea and pneumonia. PMID- 26510139 TI - Musculoskeletal chest wall pain. AB - BACKGROUND: Chest pain is a common general practice presentation that requires careful diagnostic assessment because of its diverse and potentially serious causes. OBJECTIVE: This article describes the causes, assessment and differential diagnosis of musculoskeletal chest wall pain, and the management of its most common causes. DISCUSSION: It is critical to rule out non-musculoskeletal causes of chest pain, particularly those requiring urgent intervention such as ischaemic heart disease. However, once this has been done, most musculoskeletal diagnoses can be made from a thorough history and examination. Further investigations are often unnecessary and should only be used when the provisional diagnosis suggests they are needed, for example, when systemic or rheumatological causes are suspected. The evidence underpinning the treatment of specific localised causes of musculoskeletal chest wall pain is very limited. PMID- 26510140 TI - Interstitial lung disease in 2015: where are we now? AB - BACKGROUND: Interstitial lung disease (ILD) includes a diverse group of respiratory conditions characterised by inflammation and fibrosis of the interstitium. Worsening hypoxia and respiratory failure may develop with disease progression. Disease behaviour and treatment responsiveness vary widely depending on the underlying aetiology. One of the most common types of ILD is idiopathic pulmonary fibrosis (IPF), which is associated with poor prognosis. OBJECTIVE: This article discusses recent advances in the field of ILD, including updated classification, diagnostic approach and break-through therapies. DISCUSSION: Establishing an accurate diagnosis in patients with ILD, ideally within a multidisciplinary team discussion, is critical for ensuring optimal outcomes. Recently, novel antifibrotic therapies have been shown to be effective in slowing disease progression in IPF, offering new hope for patients with the disease. PMID- 26510141 TI - Adult-onset asthma. AB - BACKGROUND: Asthma is commonly overlooked or misdiagnosed in adults. Adult-onset asthma differs from asthma that first occurs in childhood as it is less well controlled, more likely to be non-atopic and associated with a faster decline in lung function. Risk factors include exposure to sensitising or irritant substances, obesity, pharmaceutical agents, rhinitis, environmental pollutants, respiratory tract infections and psychological stress. OBJECTIVE: The aim of this article is to provide an overview of adult-onset asthma. DISCUSSION: The clinical presentation of adult-onset asthma is similar to that in any age group. Care needs to be taken to differentiate it from chronic obstructive pulmonary disease and other conditions with similar symptoms. Measurement of reversible airflow obstruction, as demonstrated by an increase in forced expiratory volume in 1 second (FEV1) following inhalation of a short-acting beta-2 agonist (eg salbutamol) of more than 200 ml or 12%, or a positive provocation test is needed to confirm the diagnosis. Management of asthma in adults is based on confirming the diagnosis, assessing the symptoms and their control, asthma education and establishing treatment goals. PMID- 26510142 TI - Guide to thoracic imaging. AB - BACKGROUND: Thoracic imaging is commonly ordered in general practice. Guidelines exist for ordering thoracic imaging but few are specific for general practice. OBJECTIVE: This article summarises current indications for imaging the thorax with chest X-ray and computed tomography. A simple frame-work for interpretation of the chest X-ray, suitable for trainees and practitioners providing primary care imaging in rural and remote locations, is presented. DISCUSSION: Interpretation of thoracic imaging is best done using a systematic approach. Radiological investigation is not warranted in un-complicated upper respiratory tract infections or asthma, minor trauma or acute-on-chronic chest pain. PMID- 26510143 TI - Your questions about complementary medicines answered: gingko biloba. AB - This is the fourth article in a series providing evidence-based answers to common questions about complementary medicines from consumers and healthcare professionals. PMID- 26510144 TI - Management of the disappearing skin cancer. PMID- 26510145 TI - An itchy, scaly plaque on the scalp. PMID- 26510146 TI - Disclosure for same-sex attracted women enhancing the quality of the patient doctor relationship in general practice. AB - BACKGROUND: Same-sex-attracted women describe lower satisfaction with their general practice care, compared with heterosexual women. Yet, they have greater health inequalities, which requires effective care. A lack of disclosure of sexual orientation to general practitioners (GPs) may be one factor influencing these issues. METHODS: This study on the disclosure of sexual orientation by same sex attracted women to their usual GP explored the impact of disclosure on the quality of the patient-doctor relationship. In-depth interviews with 33 same-sex attracted women and 27 GPs in Australia were conducted during 2005-06. These interviews were analysed to understand the perspectives of the women and their GPs. RESULTS: Disclosure in the context of provider sensitivity and normalisation enhanced the perceived quality of the patient-doctor relation-ship. Conversely, silencing of disclosure and pathologising of sexual orientation diminished the relationship. DISCUSSION: Facilitating disclosure should be a shared responsibility between same-sex attracted women and their usual GP. This must be accompanied by improved GP knowledge and affirming attitudes regarding specific health needs of same-sex attracted women. PMID- 26510147 TI - Multicentre audit of ACE-inhibitor associated angioedema (MAAAA). AB - BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are a commonly used class of medications that are generally well tolerated. However, angioedema, a rare but potentially life-threatening adverse effect, may occur. METHODS: A retrospective audit was performed on patients who presented with angioedema to two emergency departments in Adelaide, Australia. Case notes of patients presenting with angioedema who were using an ACE inhibitor were reviewed. This study examined the clinical features of presentation, treatment and outcomes of the patients. RESULTS: A total of 164 patients were identified as having angioedema across the two emergency departments. Fifty-one (31%; 95% CI = 24-39) were found to be on an ACE inhibitor. The two main presenting symptoms were soft tissue swelling in the head and neck (98%), and respiratory distress (33%), both of which usually developed after several hours. Patients were commonly treated with steroids (70%), antihistamines (65%) and adrenaline (35%). Two patients developed airway obstruction. DISCUSSION: A substantial proportion of emergency department encounters with angioedema in South Australia are from patients who also use an ACE inhibitor. It is important that general practitioners are aware of this problem, to enable rapid recognition and appropriate patient education when prescribing these medications. PMID- 26510148 TI - Age-related variation in primary care-type presentations to emergency departments. AB - BACKGROUND: A significant amount of attention has been paid to the increase in emergency department (ED) presentations in Australia. Questions have arisen regarding whether all of those presenting to the ED are actually in need of true emergency services. Under-standing the characteristics of those patients who may be cared for in non-emergency settings is important for future health system strategies. The aim of this study was to identify age-related variation in primary care type emergency department (ED) presentations over time. METHODS: A secondary analysis of data from the Victorian emergency minimum dataset (VEMD) between 2002-13 was conducted. The main outcomes were patterns of primary care type ED presentations for different ages groups over time, age-specific patterns of specific primary care type exclusion criteria and primary care type ED presentations by residents from aged care facilities. RESULTS: The proportion of triage category 4 or 5 ED presentations that met the criteria for a primary care type visit was greatest in the 0-4-year age group and tended to decrease as the age of the patient increased. Triage category 4 or 5 presentation by ambulance was uncommon in the younger age groups, surpassed 10% in the 50-54-year age group, and was >70% for those aged >90 years. The greater proportion of residential aged care facility patients who arrived by ambulance resulted in a much smaller proportion of primary care type visits. DISCUSSION: There are marked differences by age in the proportion of triage category 4 or 5 ED presentations that met the criteria for primary care type visits. These results indicate it was primarily younger patients who presented to the ED with non-urgent conditions. Most might be able to safely receive care in a primary care setting. PMID- 26510149 TI - Therapeutic venesection at the Australian Red Cross Blood Service: impact of the High Ferritin Application on management of hereditary haemochromatosis. AB - BACKGROUND: Therapeutic venesection is an established treatment for hereditary haemochromatosis. The C282Y homozygotes and C282Y/H63D compound heterozygotes are the most likely human haemochromatosis protein (HFE) variants to cause iron over load. The principal indications for treatment include iron overload, which is detected through measurement of hepatic iron concentration or a liver biopsy, or suspected iron-overload on the basis of elevated serum ferritin levels. Venesection is not indicated for other HFE genetic variants or in patients with isolated hyperferritinaemia in the absence of the main HFE gene mutations. The Australian Red Cross Blood Service provides a therapeutic venesection program. Since January 2013, referral has been conducted electronically using the novel, web-based High Ferritin Application. OBJECTIVE: The aim of this article is to provide information regarding implementation of the High Ferritin Application and document its im-pact on referral patterns. DISCUSSION: This referral process is based on nationally endorsed, evidence-based algorithms, which have markedly reduced the number of unnecessary therapeutic venesections. An estimated 4000 unnecessary venesections are averted each year and this equates to a saving of $1.4 million. PMID- 26510150 TI - General practice ethics: text messages and boundaries in the GP-patient relationship. AB - Virtual forms of communication (eg texting) can support patients and may contribute to better care. However, these informal communication methods may intrude on the doctor's leisure time and undermine standards of care if they replace face-to-face consultations.Texting may cross boundaries in potentially unprofessional ways, especially when particular patients are favoured with this privilege. It may disadvantage patients who are not favoured or who are not comfortable using mobile technology. We also note that GPs cannot control the distribution of their number or recall it without the inconvenience of changing the number once it has been disclosed.Virtual communication is an integral part of the way we live, despite the potential pitfalls. Each form (social media, electronic messaging systems, video consultations, mobile phones, etc) has its advantages and disadvantages. This makes it important for practices to develop policies supporting the responsible use of virtual communication. Such policies should:clarify (for patients and GPs) when its use is appropriate accommodate doctors' individual preferences regarding technology provide guidance regarding GPs' duties, especially for interactions that do not allow full evaluation of patients.GPs may wish to have specific criteria for providing patients with this degree of access, set very clear indications and contraindications to its use, explain the potential pitfalls, and ensure that text messages augment good care rather than replace it. PMID- 26510151 TI - Multiparametric MRI in the diagnosis of prostate cancer - a generational change. AB - BACKGROUND: Whether a general practitioner (GP) should order prostate-specific antigen (PSA) testing for a patient is a question that has been unresolved for 25 years. The authors suggest that the image-based diagnostic pathway, rather than the biopsy-driven diagnostic pathway, will answer this question. OBJECTIVE: This article describes, in non-technical terms, the methodology of prostate imaging with multiparametric magnetic resonance imaging (mpMRI), and targeted biopsies of lesions within the prostate. The benefits and risks of the new technology are discussed. DISCUSSION: Accurate anatomical and functional imaging of the prostate gland, and diagnosis of significant (intermediate- and high-risk) prostate cancer, is now becoming available in Australia. However, there is still a learning curve in the implementation of this technology. PMID- 26510152 TI - Sentinel node biopsy should be the standard of care for patients with intermediate and thick melanomas. PMID- 26510153 TI - Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection. AB - Macrophages display flexible activation states that range between pro inflammatory (classical activation) and anti-inflammatory (alternative activation). These macrophage polarization states contribute to a variety of organismal phenotypes such as tissue remodeling and susceptibility to infectious and inflammatory diseases. Several macrophage- or immune-related genes have been shown to modulate infectious and inflammatory disease pathogenesis. However, the potential role that differences in macrophage activation phenotypes play in modulating differences in susceptibility to infectious and inflammatory disease is just emerging. We integrated transcriptional profiling and linkage analyses to determine the genetic basis for the differential murine macrophage response to inflammatory stimuli and to infection with the obligate intracellular parasite Toxoplasma gondii. We show that specific transcriptional programs, defined by distinct genomic loci, modulate macrophage activation phenotypes. In addition, we show that the difference between AJ and C57BL/6J macrophages in controlling Toxoplasma growth after stimulation with interferon gamma and tumor necrosis factor alpha mapped to chromosome 3, proximal to the Guanylate binding protein (Gbp) locus that is known to modulate the murine macrophage response to Toxoplasma. Using an shRNA-knockdown strategy, we show that the transcript levels of an RNA helicase, Ddx1, regulates strain differences in the amount of nitric oxide produced by macrophage after stimulation with interferon gamma and tumor necrosis factor. Our results provide a template for discovering candidate genes that modulate macrophage-mediated complex traits. PMID- 26510154 TI - Bidirectional Association between Self-Reported Hypertension and Gout: The Singapore Chinese Health Study. AB - It has been hypothesized that the association between hypertension and gout is bidirectional, however, few studies have examined this in a prospective cohort. We analyzed data from the Singapore Chinese Health Study (SCHS) follow-up I (1999 2004) and II (2006-2010) interviews, when both physician-diagnosed hypertension and gout were self-reported. We included participants with data for both follow up interviews and who were free of heart disease, stroke and cancer at follow-up I. The analysis of hypertension and risk of gout included 31,137 participants when prevalent gout cases were excluded, while the analysis of gout and risk of hypertension included 20,369 participants when prevalent hypertension cases were excluded. Cox proportional hazards models were used to estimate multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The mean age at follow-up I was 60.1 (SD 7.3) years, and the average follow-up was 6.8 (SD 1.4) years. In the analysis of hypertension and risk of gout, 682 incident cases were identified. Compared to normotensive participants, hypertensive patients had an 88% increased risk of developing gout (HR 1.88; 95% CI 1.61-2.21). In the parallel analysis, 5,450 participants reported to have newly diagnosed hypertension during follow-up. Compared to participants without gout, those with gout had an 18% increased risk of developing hypertension (HR 1.18; 95% CI 1.02 1.37). The bidirectional association was stronger in normal weight adults compared to overweight/obese individuals (Pinteraction = 0.06 and 0.04, respectively). The hypertension to gout association was stronger in women compared to men (Pinteraction = 0.04), while the gout to hypertension association was evident in women but not in men (Pinteraction = 0.02). In conclusion, our results suggest that the hypertension-gout association is bidirectional in this cohort of Singapore Chinese adults. The potential interactions of the bidirectional association with obesity and sex deserve further investigations. PMID- 26510155 TI - Leptomeningeal Angiomatosis in a Case of Neurofibromatosis Type 2: An Unusual Finding. AB - Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterised by multiple neoplasms of the central and peripheral nervous system associated with ocular abnormalities. Leptomeningeal angiomatosis has not been described with this tumour predisposition syndrome. This report documents an unusual association of leptomeningeal angiomatosis in a case of NF2. PMID- 26510156 TI - Valproic Acid Improves Porcine Parthenogenetic Embryo Development Through Transient Remodeling of Histone Modifiers. AB - BACKGROUND/AIMS: Parthenogenetic embryos are useful in many applications, such as being an alternative source of embryonic stem cells that would avoid ethical problems. Aberrance in epigenetic reprogramming is considered the major reason for the developmental failure of parthenogenetic embryos. Many histone deacetylase inhibitors have been shown to improve the reprogramming of stem cells and embryos. Here, the relationship between histone modification and parthenogenetic embryonic development was explored. METHODS: Valproic acid (VPA) treatment was applied during the culture of parthenogenetic embryos. The abundance of histone modifiers was examined by immunofluorescence and quantified by Image-pro software. RESULTS: The acH3K9 level in in vitro fertilized embryos was significantly higher than parthenogenetic embryos. VPA treatment improved both the blastocyst formation rate and the acH3K9 level in parthenogenetic embryos. The signal intensities of acH4K5 and H3K4me2 were also enhanced in VPA treated embryos. The H3K27me2 level was decreased in the VPA treated embryos at the 2-cell stage. However, the enhancement in the acH3K9, acH4K5 and H3K4me2 level, or the decrease in the H3K27me2 level disappeared shortly after VPA withdrawal. CONCLUSION: Optimizing histone modifications for a short time following activation was sufficient to enhance the in vitro development of parthenogenetic embryos. PMID- 26510157 TI - Competition between a Lawn-Forming Cynodon dactylon and a Tufted Grass Species Hyparrhenia hirta on a South-African Dystrophic Savanna. AB - South African savanna grasslands are often characterised by indigestible tufted grass species whereas lawn grasses are far more desirable in terms of herbivore sustenance. We aimed to investigate the role of nutrients and/or the disturbance (grazing, trampling) by herbivores on the formation of grazing lawns. We conducted a series of common garden experiments to test the effect of nutrients on interspecific competition between a typical lawn-forming grass species (Cynodon dactylon) and a species that is frequently found outside grazing lawns (Hyparrhenia hirta), and tested for the effect of herbivore disturbance in the form of trampling and clipping. We also performed a vegetation and herbivore survey to apply experimentally derived insights to field observations. Our results showed that interspecific competition was not affected by soil nutrient concentrations. C. dactylon did show much more resilience to disturbance than H. hirta, presumably due to the regenerative capacity of its rhizomes. Results from the field survey were in line with these findings, describing a correlation between herbivore pressure and C. dactylon abundance. We conclude that herbivore disturbance, and not soil nutrients, provide C. dactylon with a competitive advantage over H. hirta, due to vegetative regeneration from its rhizomes. This provides evidence for the importance of concentrated, high herbivore densities for the creation and maintenance of grazing lawns. PMID- 26510158 TI - Total Nitrogen Sources of the Three Gorges Reservoir--A Spatio-Temporal Approach. AB - Understanding the spatial and temporal variation of nutrient concentrations, loads, and their distribution from upstream tributaries is important for the management of large lakes and reservoirs. The Three Gorges Dam was built on the Yangtze River in China, the world's third longest river, and impounded the famous Three Gorges Reservoir (TGR). In this study, we analyzed total nitrogen (TN) concentrations and inflow data from 2003 till 2010 for the main upstream tributaries of the TGR that contribute about 82% of the TGR's total inflow. We used time series analysis for seasonal decomposition of TN concentrations and used non-parametric statistical tests (Kruskal-Walli H, Mann-Whitney U) as well as base flow segmentation to analyze significant spatial and temporal patterns of TN pollution input into the TGR. Our results show that TN concentrations had significant spatial heterogeneity across the study area (Tuo River> Yangtze River> Wu River> Min River> Jialing River>Jinsha River). Furthermore, we derived apparent seasonal changes in three out of five upstream tributaries of the TGR rivers (Kruskal-Walli H rho = 0.009, 0.030 and 0.029 for Tuo River, Jinsha River and Min River in sequence). TN pollution from non-point sources in the upstream tributaries accounted for 68.9% of the total TN input into the TGR. Non-point source pollution of TN revealed increasing trends for 4 out of five upstream tributaries of the TGR. Land use/cover and soil type were identified as the dominant driving factors for the spatial distribution of TN. Intensifying agriculture and increasing urbanization in the upstream catchments of the TGR were the main driving factors for non-point source pollution of TN increase from 2003 till 2010. Land use and land cover management as well as chemical fertilizer use restriction were needed to overcome the threats of increasing TN pollution. PMID- 26510159 TI - Transcriptomic Changes in Coral Holobionts Provide Insights into Physiological Challenges of Future Climate and Ocean Change. AB - Tropical reef-building coral stress levels will intensify with the predicted rising atmospheric CO2 resulting in ocean temperature and acidification increase. Most studies to date have focused on the destabilization of coral-dinoflagellate symbioses due to warming oceans, or declining calcification due to ocean acidification. In our study, pH and temperature conditions consistent with the end-of-century scenarios of the Intergovernmental Panel on Climate Change (IPCC) caused major changes in photosynthesis and respiration, in addition to decreased calcification rates in the coral Acropora millepora. Population density of symbiotic dinoflagellates (Symbiodinium) under high levels of ocean acidification and temperature (Representative Concentration Pathway, RCP8.5) decreased to half of that found under present day conditions, with photosynthetic and respiratory rates also being reduced by 40%. These physiological changes were accompanied by evidence for gene regulation of calcium and bicarbonate transporters along with components of the organic matrix. Metatranscriptomic RNA-Seq data analyses showed an overall down regulation of metabolic transcripts, and an increased abundance of transcripts involved in circadian clock control, controlling the damage of oxidative stress, calcium signaling/homeostasis, cytoskeletal interactions, transcription regulation, DNA repair, Wnt signaling and apoptosis/immunity/ toxins. We suggest that increased maintenance costs under ocean acidification and warming, and diversion of cellular ATP to pH homeostasis, oxidative stress response, UPR and DNA repair, along with metabolic suppression, may underpin why Acroporid species tend not to thrive under future environmental stress. Our study highlights the potential increased energy demand when the coral holobiont is exposed to high levels of ocean warming and acidification. PMID- 26510160 TI - A Positive Twist to the Centromeric Nucleosome. AB - Centromeric nucleosomes are critical for chromosome attachment to the mitotic spindle. In this issue of Cell Reports, Diaz-Ingelmo et al. (2015) propose that the yeast centromeric nucleosome is stabilized by a positively supercoiled loop formed by the sequence-specific CBF3 complex. PMID- 26510161 TI - The Many Facets of Genetic Literacy: Assessing the Scalability of Multiple Measures for Broad Use in Survey Research. AB - OBJECTIVES: To determine how three dimensions of genetic literacy (familiarity, skills, and factual knowledge) fit the hierarchy of knowledge outlined in E.M. Rogers' Diffusion of Innovations to better conceptualize lay understandings of genomics. METHODS: A consumer panel representing the US adult population (N = 1016) completed an electronic survey in November 2013. Adjusting for education, we used correlations, principle components analysis, Mokken Scale tests, and linear regressions to assess how scores on the three genetic literacy sub dimensions fit an ordered scale. RESULTS: The three scores significantly loaded onto one factor, even when adjusting for education. Analyses revealed moderate strength in scaling (0.416, p<0.001) and a difficulty ordering that matched Rogers' hierarchy (knowledge more difficult than skills, followed by familiarity). Skills scores partially mediated the association between familiarity and knowledge with a significant indirect effect (0.241, p<0.001). CONCLUSION: We established an ordering in genetic literacy sub-dimensions such that familiarity with terminology precedes skills using information, which in turn precedes factual knowledge. This ordering is important to contextualizing previous findings, guiding measurement in future research, and identifying gaps in the understanding of genomics relevant to the demands of differing applications. PMID- 26510162 TI - The differentiation of progressive supranuclear palsy. PMID- 26510163 TI - Strand-Specific RNA-Seq Analyses of Fruiting Body Development in Coprinopsis cinerea. AB - The basidiomycete fungus Coprinopsis cinerea is an important model system for multicellular development. Fruiting bodies of C. cinerea are typical mushrooms, which can be produced synchronously on defined media in the laboratory. To investigate the transcriptome in detail during fruiting body development, high throughput sequencing (RNA-seq) was performed using cDNA libraries strand specifically constructed from 13 points (stages/tissues) with two biological replicates. The reads were aligned to 14,245 predicted transcripts, and counted for forward and reverse transcripts. Differentially expressed genes (DEGs) between two adjacent points and between vegetative mycelium and each point were detected by Tag Count Comparison (TCC). To validate RNA-seq data, expression levels of selected genes were compared using RPKM values in RNA-seq data and qRT PCR data, and DEGs detected in microarray data were examined in MA plots of RNA seq data by TCC. We discuss events deduced from GO analysis of DEGs. In addition, we uncovered both transcription factor candidates and antisense transcripts that are likely to be involved in developmental regulation for fruiting. PMID- 26510164 TI - Effects of Increased Flight on the Energetics and Life History of the Butterfly Speyeria mormonia. AB - Movement uses resources that may otherwise be allocated to somatic maintenance or reproduction. How does increased energy expenditure affect resource allocation? Using the butterfly Speyeria mormonia, we tested whether experimentally increased flight affects fecundity, lifespan or flight capacity. We measured body mass (storage), resting metabolic rate and lifespan (repair and maintenance), flight metabolic rate (flight capacity), egg number and composition (reproduction), and food intake across the adult lifespan. The flight treatment did not affect body mass or lifespan. Food intake increased sufficiently to offset the increased energy expenditure. Total egg number did not change, but flown females had higher early-life fecundity and higher egg dry mass than control females. Egg dry mass decreased with age in both treatments. Egg protein, triglyceride or glycogen content did not change with flight or age, but some components tracked egg dry mass. Flight elevated resting metabolic rate, indicating increased maintenance costs. Flight metabolism decreased with age, with a steeper slope for flown females. This may reflect accelerated metabolic senescence from detrimental effects of flight. These effects of a drawdown of nutrients via flight contrast with studies restricting adult nutrient input. There, fecundity was reduced, but flight capacity and lifespan were unchanged. The current study showed that when food resources were abundant, wing-monomorphic butterflies living in a continuous meadow landscape resisted flight-induced stress, exhibiting no evidence of a flight-fecundity or flight-longevity trade-off. Instead, flight changed the dynamics of energy use and reproduction as butterflies adopted a faster lifestyle in early life. High investment in early reproduction may have positive fitness effects in the wild, as long as food is available. Our results help to predict the effect of stressful conditions on the life history of insects living in a changing world. PMID- 26510165 TI - Impacts of 2,4-dichlorophenoxyacetic acid aquatic herbicide formulations on reproduction and development of the fathead minnow (Pimephales promelas). AB - The authors studied the effects of 2 formulations of 2,4-dichlorophenoxyacetic acid, dimethylamine salt (2,4-D) herbicide on fathead minnow reproduction, embryonic development, and larval survival. Groups of reproductively mature fathead minnows were exposed for 28 d to 0.00 ppm, 0.05 ppm, 0.50 ppm, and 2.00 ppm 2,4-D (target) in a flow-through system. Weedestroy(r) AM40 significantly (p <= 0.05) depressed male tubercle presence and significantly increased female gonadosomatic index, and there were statistical trends (0.05 <= p <= 0.10) for effects on fecundity and hepatic vitellogenin mRNA expression in females and males. The herbicide DMA(r) 4 IVM also significantly depressed male tubercle presence. Gonads of females exposed to DMA 4 IVM exhibited significantly depressed stage of oocyte maturation, significantly increased severity of oocyte atresia, and a significant presence of an unidentified tissue type. Also, DMA 4 IVM significantly decreased larval survival. It had no impact on hepatic vitellogenin mRNA expression or gonadosomatic index. No significant effects on fertilization, hatchability, or embryonic development were observed in either trial. The formulations tested exhibited different toxicological profiles from pure 2,4-D. These data suggest that the formulations have the potential for endocrine disruption and can exert some degree of chronic toxicity. The present use of 2,4-D formulations in lake management practices and their permitting based on the toxicological profile of 2,4-D pure compound should be reconsidered. Environ Toxicol Chem 2016;35:1478-1488. (c) 2015 SETAC. PMID- 26510166 TI - Microvessel density and endothelial cell proliferation levels in colorectal liver metastases from patients given neo-adjuvant cytotoxic chemotherapy and bevacizumab. AB - The treatment of patients with colorectal liver metastasis has improved significantly and first line therapy is often combined chemotherapy and bevacizumab, although it is unknown who responds to this regimen. Colorectal liver metastases grow in different histological growth patterns showing differences in angiogenesis. To identify possible response markers, histological markers of angiogenesis were assessed. Patients who underwent resection of colorectal liver metastasis at Rigshospitalet, Copenhagen, Denmark from 2007 to 2011 were included (n = 254) including untreated and patients treated with chemotherapy or chemotherapy plus bevacizumab. The resected liver metastases were characterised with respect to growth pattern, endothelial and tumour cell proliferation as well as microvessel density and tumour regression. Tumour regression grade of liver metastases differed significantly between untreated/chemotherapy treated patients in comparison to chemotherapy plus bevacizumab treated patients (both p < 0.0001). Microvessel density was decreased in liver metastases from patients treated with bevacizumab in comparison to those from untreated/chemotherapy-treated patients (p = 0.006/p = 0.002). Tumour cell proliferation assessed by Ki67 expression correlated to a shorter recurrence free survival in the total patient cohort. In conclusion, liver metastases from patients treated with neo-adjuvant chemotherapy and bevacizumab had significantly lower microvessel densities and tumour regression grades when compared to liver metastases from untreated or chemotherapy treated patients. This may indicate that bevacizumab treatment results in altered vascular biology and tumour viability, with possible tumour reducing effect. PMID- 26510167 TI - Associations between polygenic risk for schizophrenia and brain function during probabilistic learning in healthy individuals. AB - A substantial proportion of schizophrenia liability can be explained by additive genetic factors. Risk profile scores (RPS) directly index risk using a summated total of common risk variants weighted by their effect. Previous studies suggest that schizophrenia RPS predict alterations to neural networks that support working memory and verbal fluency. In this study, we apply schizophrenia RPS to fMRI data to elucidate the effects of polygenic risk on functional brain networks during a probabilistic-learning neuroimaging paradigm. The neural networks recruited during this paradigm have previously been shown to be altered to unmedicated schizophrenia patients and relatives of schizophrenia patients, which may reflect genetic susceptibility. We created schizophrenia RPS using summary data from the Psychiatric Genetic Consortium (Schizophrenia Working Group) for 83 healthy individuals and explore associations between schizophrenia RPS and blood oxygen level dependency (BOLD) during periods of choice behavior (switch-stay) and reflection upon choice outcome (reward-punishment). We show that schizophrenia RPS is associated with alterations in the frontal pole (PWHOLE BRAIN-CORRECTED = 0.048) and the ventral striatum (PROI-CORRECTED = 0.036), during choice behavior, but not choice outcome. We suggest that the common risk variants that increase susceptibility to schizophrenia can be associated with alterations in the neural circuitry that support the processing of changing reward contingencies. Hum Brain Mapp 37:491-500, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26510168 TI - Individual Differences in Statistical Learning Predict Children's Comprehension of Syntax. AB - Variability in children's language acquisition is likely due to a number of cognitive and social variables. The current study investigated whether individual differences in statistical learning (SL), which has been implicated in language acquisition, independently predicted 6- to 8-year-old's comprehension of syntax. Sixty-eight (N = 68) English-speaking children completed a test of comprehension of four syntactic structures, a test of SL utilizing nonlinguistic visual stimuli, and several additional control measures. The results revealed that SL independently predicted comprehension of two syntactic structures that show considerable variability in this age range: passives and object relative clauses. These data suggest that individual differences in children's capacity for SL are associated with the acquisition of the syntax of natural languages. PMID- 26510169 TI - How Imaging Glutamate, gamma-Aminobutyric Acid, and Dopamine Can Inform the Clinical Treatment of Alcohol Dependence and Withdrawal. AB - Neuroimaging studies have dramatically advanced our understanding of the neurochemical basis of alcohol dependence, a major public health issue. In this paper, we review the research generated from neurochemical specific imaging modalities including magnetic resonance spectroscopy, positron emission tomography, and single-photon emission computed tomography in studies of alcohol dependence and withdrawal. We focus on studies interrogating gamma-aminobutyric acid (GABA), glutamate, and dopamine, as these are prominent neurotransmitter systems implicated in alcohol dependence. Highlighted findings include diminished dopaminergic functioning and modulation of the GABA system by tobacco smoking during alcohol withdrawal. Then, we consider how these findings impact the clinical treatment of alcohol dependence and discuss directions for future experiments to address existing gaps in the literature, for example, sex differences and smoking comorbidity. These and other considerations provide opportunities to build upon the current neurochemistry imaging literature of alcohol dependence and withdrawal, which may usher in improved therapeutic and relapse prevention strategies. PMID- 26510170 TI - Addition of a Synthetically Fabricated Osteoinductive Biphasic Calcium Phosphate Bone Graft to BMP2 Improves New Bone Formation. AB - BACKGROUND: Bone morphogenetic protein-2 (BMP2) has been successfully utilized in dentistry to promote new bone formation because of its osteoinductive ability to recruit mesenchymal progenitor cells and induce their differentiation to bone forming osteoblasts. Recently, novel biphasic calcium phosphate scaffolds have been developed with similar osteoinductive properties capable of forming ectopic bone formation. PURPOSE: The aim of the present study was to assess whether the combination of BMP2 with this novel Biphasic Calcium Phosphate (BCP) scaffold may additionally promote new bone regeneration. MATERIALS AND METHODS: Cylindrical bone defects measuring 2.5 mm were created bilaterally in the femurs of 18 Wistar rats. After 4 weeks, the following six groups were assessed for new bone formation by micro-computed tomography (CT) as well as histological assessment: 1) collagen scaffolds + 20 MUg of BMP2; 2) collagen scaffolds + 50 MUg of BMP2; 3) collagen scaffolds + 100 MUg of BMP2; 4) BCP scaffolds + 20 MUg of BMP2; 5) BCP scaffolds + 50 MUg of BMP2; and 6) BCP scaffolds + 100 MUg of BMP2. Furthermore, tartrate-resistant acid phosphatase (TRAP) staining was utilized to assess osteoclast activity and osteoclast number. The release kinetics of BMP2 from both BCP and collagen scaffolds was investigated over a 14-day period. RESULTS: The results from present study demonstrate that BMP2 is able to promote new bone formation in a concentration dependant manner when loaded with either a collagen scaffolds or BCP scaffolds. Micro-CT analysis demonstrated significantly higher levels of new bone formation in groups containing BCP + BMP2 when compared with collagen scaffolds + BMP2. BMP2 had little effect on osteoclast activity; however, less TRAP staining and osteoclast number was observed in the defects receiving collagen scaffolds when compared with BCP scaffolds. The release of BMP2 over time was rapidly released after 1 day on BCP scaffolds whereas a gradually release over time was observed for collagen scaffolds up to 14 days. CONCLUSION: The osteoinductive properties of BMP2 may further be enhanced by its combination with a novel synthetically fabricated osteoinductive BCP scaffold. Future clinical testing is required to further assess these preliminary findings. PMID- 26510172 TI - Reducing slab boundary artifacts in three-dimensional multislab diffusion MRI using nonlinear inversion for slab profile encoding (NPEN). AB - PURPOSE: To propose a method to reduce the slab boundary artifacts in three dimensional multislab diffusion MRI. METHODS: Bloch simulation is used to investigate the effects of multiple factors on slab boundary artifacts, including characterization of residual errors on diffusion quantification. A nonlinear inversion method is proposed to simultaneously estimate the slab profile and the underlying (corrected) image. RESULTS: Correction results of numerical phantom and in vivo data demonstrate that the method can effectively remove slab boundary artifacts for diffusion data. Notably, the nonlinear inversion is also successful at short TR, a regimen where previously proposed methods (slab profile encoding and weighted average) retain residual artifacts in both diffusion-weighted images and diffusion metrics (mean diffusion coefficient and fractional anisotropy). CONCLUSION: The nonlinear inversion for removing slab boundary artifacts provides improvements over existing methods, particularly at the short TRs required to maximize SNR efficiency. Magn Reson Med 76:1183-1195, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 26510171 TI - A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS). AB - Chronic rhinosinusitis (CRS) has been known as a disease with strong infectious and inflammatory components for decades. The recent advancement in methods identifying microbes has helped implicate the airway microbiome in inflammatory respiratory diseases such as asthma and COPD. Such studies support a role of resident microbes in both health and disease of host tissue, especially in the case of inflammatory mucosal diseases. Identifying interactive events between microbes and elements of the immune system can help us to uncover the pathogenic mechanisms underlying CRS. Here we provide a review of the findings on the complex upper respiratory microbiome in CRS in comparison with healthy controls. Furthermore, we have reviewed the defects and alterations of the host immune system that interact with microbes and could be associated with dysbiosis in CRS. PMID- 26510173 TI - From the Editor-in-Chief. PMID- 26510175 TI - Social Cognition in Individuals at Ultra-High Risk for Psychosis: A Meta Analysis. AB - OBJECTIVE: Treatment in the ultra-high risk stage for a psychotic episode is critical to the course of symptoms. Markers for the development of psychosis have been studied, to optimize the detection of people at risk of psychosis. One possible marker for the transition to psychosis is social cognition. To estimate effect sizes for social cognition based on a quantitative integration of the published evidence, we conducted a meta-analysis of social cognitive performance in people at ultra high risk (UHR). METHODS: A literature search (1970-July 2015) was performed in PubMed, PsychINFO, Medline, Embase, and ISI Web of Science, using the search terms 'social cognition', 'theory of mind', 'emotion recognition', 'attributional style', 'social knowledge', 'social perception', 'empathy', 'at risk mental state', 'clinical high risk', 'psychosis prodrome', and 'ultra high risk'. The pooled effect size (Cohen's D) and the effect sizes for each domain of social cognition were calculated. A random effects model with 95% confidence intervals was used. RESULTS: Seventeen studies were included in the analysis. The overall significant effect was of medium magnitude (d = 0.52, 95% Cl = 0.38-0.65). No moderator effects were found for age, gender and sample size. Sub-analyses demonstrated that individuals in the UHR phase show significant moderate deficits in affect recognition and affect discrimination in faces as well as in voices and in verbal Theory of Mind (TOM). Due to an insufficient amount of studies, we did not calculate an effect size for attributional bias and social perception/ knowledge. A majority of studies did not find a correlation between social cognition deficits and transition to psychosis, which may suggest that social cognition in general is not a useful marker for the development of psychosis. However some studies suggest the possible predictive value of verbal TOM and the recognition of specific emotions in faces for the transition into psychosis. More research is needed on these subjects. CONCLUSION: The published literature indicates consistent general impairments in social cognition in people in the UHR phase, but only very specific impairments seem to predict transition to psychosis. PMID- 26510176 TI - Evidence Accumulation and Choice Maintenance Are Dissociated in Human Perceptual Decision Making. AB - Perceptual decision making in monkeys relies on decision neurons, which accumulate evidence and maintain choices until a response is given. In humans, several brain regions have been proposed to accumulate evidence, but it is unknown if these regions also maintain choices. To test if accumulator regions in humans also maintain decisions we compared delayed and self-paced responses during a face/house discrimination decision making task. Computational modeling and fMRI results revealed dissociated processes of evidence accumulation and decision maintenance, with potential accumulator activations found in the dorsomedial prefrontal cortex, right inferior frontal gyrus and bilateral insula. Potential maintenance activation spanned the frontal pole, temporal gyri, precuneus and the lateral occipital and frontal orbital cortices. Results of a quantitative reverse inference meta-analysis performed to differentiate the functions associated with the identified regions did not narrow down potential accumulation regions, but suggested that response-maintenance might rely on a verbalization of the response. PMID- 26510177 TI - Epigenetics and Preeclampsia: Defining Functional Epimutations in the Preeclamptic Placenta Related to the TGF-beta Pathway. AB - Preeclampsia is a potentially fatal pregnancy disorder affecting millions of women around the globe. Dysregulation in gene and protein expression within key biological pathways controlling angiogenesis has been implicated in the development of preeclampsia. Altered CpG methylation, a type of epimutation, may underlie this pathway dysregulation. In the present study, placental tissue from preeclamptic cases and normotensive controls was analyzed for genome-wide differential CpG methylation and concomitant changes in gene expression. A set of 123 genes, representing 19.9% of all genes with altered CpG methylation, was associated with functional changes in transcript levels. Underscoring the complex relationships between CpG methylation and gene expression, here hypermethylation was never associated with gene silencing, nor was hypomethylation always associated with gene activation. Moreover, the genomic region of the CpG mark was important in predicting the relationship between CpG methylation and gene expression. The 123 genes were enriched for their involvement in the transforming growth factor beta (TGF-beta) signaling pathway, a known regulator of placental trophoblast invasion and migration. This is the first study to identify CpG hypomethylation as an activator of TGF-beta-associated gene expression in the preeclamptic placenta. The results suggest functional epimutations are associated with preeclampsia disease status and the identified genes may represent novel biomarkers of disease. PMID- 26510178 TI - Acid-sensing ion channels in trigeminal ganglion neurons innervating the orofacial region contribute to orofacial inflammatory pain. AB - Orofacial pain is a common clinical symptom that is accompanied by tooth pain, migraine and gingivitis. Accumulating evidence suggests that acid-sensing ion channels (ASICs), especially ASIC3, can profoundly affect the physiological properties of nociception in peripheral sensory neurons. The aim of this study is to examine the contribution of ASICs in trigeminal ganglion (TG) neurons to orofacial inflammatory pain. A Western blot (WB), immunofluorescence assay of labelled trigeminal ganglion neurons, orofacial formalin test, cell preparation and electrophysiological experiments are performed. This study demonstrated that ASIC1, ASIC2a and ASIC3 are highly expressed in TG neurons innervating the orofacial region of rats. The amplitude of ASIC currents in these neurons increased 119.72% (for ASIC1-like current) and 230.59% (for ASIC3-like current) in the formalin-induced orofacial inflammatory pain model. In addition, WB and immunofluorescence assay demonstrated a significantly augmented expression of ASICs in orofacial TG neurons during orofacial inflammation compared with the control group. The relative protein density of ASIC1, ASIC2a and ASIC3 also increased 58.82 +/- 8.92%, 45.30 +/- 11.42% and 55.32 +/- 14.71%, respectively, compared with the control group. Furthermore, pharmacological blockade of ASICs and genetic deletion of ASIC1 attenuated the inflammation response. These findings indicate that peripheral inflammation can induce the upregulation of ASICs in TG neurons, causing orofacial inflammatory pain. Additionally, the specific inhibitor of ASICs may have a significant analgesic effect on orofacial inflammatory pain. PMID- 26510179 TI - Synthesis of Atomically Thin Boron Films on Copper Foils. AB - Two-dimensional boron materials have recently attracted extensive theoretical interest because of their exceptional structural complexity and remarkable physical and chemical properties. However, such 2D boron monolayers have still not been synthesized. In this report, the synthesis of atomically thin 2D gamma boron films on copper foils is achieved by chemical vapor deposition using a mixture of pure boron and boron oxide powders as the boron source and hydrogen gas as the carrier gas. Strikingly, the optical band gap of the boron film was measured to be around 2.25 eV, which is close to the value (2.07 eV) determined by first-principles calculations, suggesting that the gamma-B28 monolayer is a fascinating direct band gap semiconductor. Furthermore, a strong photoluminescence emission band was observed at approximately 626 nm, which is again due to the direct band gap. This study could pave the way for applications of two-dimensional boron materials in electronic and photonic devices. PMID- 26510180 TI - Single-stage endoscopic treatment for mild to moderate acute cholangitis associated with choledocholithiasis: a multicenter, non-randomized, open-label and exploratory clinical trial. AB - BACKGROUND: Two-stage treatment involving stone removal after drainage is recommended for mild to moderate acute cholangitis associated with choledocholithiasis. However, single-stage treatment has some advantages. We aimed to assess the efficacy and safety of single-stage endoscopic treatment for mild to moderate acute cholangitis associated with choledocholithiasis. METHODS: A multicenter, non-randomized, open-label, exploratory clinical trial was performed in 12 institutions. A total of 50 patients with a naive papilla and a body temperature >=37 degrees C who were diagnosed with mild to moderate cholangitis associated with choledocholithiasis were enrolled between August 2012 and February 2014. RESULTS: Of the 50 patients, 15 had mild cholangitis and 35 had moderate cholangitis. The median number of common bile duct stones was 2 (range, 1-8), and the median diameter of the common bile duct stones was 7.5 mm (range, 1-18). The cure rate of acute cholangitis within 4 days after single stage treatment was 90% (45/50) based on a body temperature <37 degrees C for >=24 h. The incidence of complications was 10% (5/50). CONCLUSION: Single-stage endoscopic treatment may be effective and safe for mild to moderate acute cholangitis associated with choledocholithiasis (clinical trial registration number: UMIN000008494). PMID- 26510181 TI - High temperature alcoholic fermentation of orange peel by the newly isolated thermotolerant Pichia kudriavzevii KVMP10. AB - This work explores the potential for the development of orange peel based ethanol bioprocesses through isolation of the thermotolerant Pichia kudriavzevii KVMP10. A model solution of hydrolysed Valencia orange peel was employed to determine the ethanologenic potential of the yeast, which was maximized at 42 degrees C producing 54 g l(-1) of ethanol. The effect of orange peel oil on bioethanol formation was investigated at 30 and 42 degrees C confirming that the minimum inhibitory peel oil content was 0.01% (v/v). Pichia kudriavzevii KVMP10 demonstrated significant technological advantages for the production of sustainable bioenergy, such as utilization of both hexoses (glucose, sucrose, fructose and galactose) and pentoses (xylose) at high temperatures, exemplifying its great potential for application in orange peel based biorefineries for ethanol production. SIGNIFICANCE AND IMPACT OF THE STUDY: Citrus peel waste is one of the most underutilized and geographically diverse residues in the planet. In attempt to develop a citrus peel based biorefinery we report here the isolation of a yeast which exhibited favourable technological characteristics for the production of ethanol through utilization of the specific food waste. Pichia kudriavzevii KVMP10 was highly thermotolerant and utilized both hexoses and pentoses for ethanol production, which was achieved at elevated rates, highlighting its great potential for application in ethanol production processes from citrus peel. PMID- 26510183 TI - Effects of Patient-Controlled Epidural Analgesia and Patient-Controlled Intravenous Analgesia on Analgesia in Patients Undergoing Spinal Fusion Surgery. AB - We compared the outcomes of patient-controlled epidural analgesia (PCEA) and patient-controlled intravenous analgesia (PCIA) in analgesia after spinal fusion surgery. A total of 120 patients who underwent spinal fusion surgeries between April 2013 and April 2015 at Shaanxi Provincial People's Hospital were selected for this study based on defined inclusion criteria. All patients were randomly divided into 2 groups before surgery: PCEA group (n = 65) and PCIA group (n = 55). Visual analog scales (VAS) were used to evaluate the degree of pain. Besides, the active and passive activities of patients during 1- to 3-day recovery period after surgery were recorded. Verbal rating scales were used to measure pain levels after surgery and after surgery. Adverse effects of PCEA and PCIA were monitored, which included nausea, vomiting, pruritus, drowsiness, respiratory depression, and headache. Our results showed no statistically significant differences between PCEA and PCIA in sex ratio, age, height, weight, American Society of Anesthesiologists level, surgery time, number of fusion section, surgery methods, and duration of anesthesia (all P > 0.05). The PCEA group was associated with significantly lower VAS scores, compared with the PCIA group, at 3, 6, 12, 24, and 48-hour postsurgery (all P < 0.05) when surgery associated pain is expected to be intense. Also, compared with the PCIA group, the PCEA group showed higher frequency of recovery activities on first and second day postsurgery (all P < 0.05). The overall patient satisfaction level of analgesia in the PCEA group was significantly higher than in the PCIA group (P < 0.05). Moreover, the incidence of hypopiesia and skin itching in the PCIA group was higher than in the PCEA group (all P < 0.05). Finally, drowsiness and headache were markedly lower in the PCIA group after surgery, compared with the PCEA group, and this difference was statistically significant (all P < 0.05). Our results provide strong evidence that PCEA exhibits significantly greater efficacy than PCIA for pain management after spinal fusion surgery, with lower VAS scores, higher frequency of recovery activities, and overall higher satisfaction level. PMID- 26510184 TI - Phonons of Fe-based superconductor Ca10Pt4As8(Fe1-x Pt x As)10. AB - We report the results of inelastic neutron scattering measurements on particular phonons of a superconducting (SC) Ca10Pt4As8(Fe1-x Pt x As)10 with the onset transition temperature T c ~ 33 K to investigate mainly what roles orbital fluctuation plays in Cooper pairing, where we observed a slight softening of the in-plane transverse acoustic mode corresponding to the elastic constant C 66. This softening starts at temperature T well above the SC T c, as T decreases. An anomalously strong change of the scattering intensity of in-plane optical modes was observed at the M point of the pseudo tetragonal reciprocal space in the range of 35 < omega < 40 meV with decreasing T from far above T c. Because this omega region mainly corresponds to the motion of Fe and As atoms in the FeAs planes, the finding presents information on the coupling between the orbital fluctuation of Fe 3d electrons and the lattice system, useful for studying the possible roles of orbital fluctuation in the pairing mechanism and/or the appearance of the so-called nematic phase. PMID- 26510185 TI - The Influence of Age and Gender on Skin-Associated Microbial Communities in Urban and Rural Human Populations. AB - Differences in the bacterial community structure associated with 7 skin sites in 71 healthy people over five days showed significant correlations with age, gender, physical skin parameters, and whether participants lived in urban or rural locations in the same city. While body site explained the majority of the variance in bacterial community structure, the composition of the skin-associated bacterial communities were predominantly influenced by whether the participants were living in an urban or rural environment, with a significantly greater relative abundance of Trabulsiella in urban populations. Adults maintained greater overall microbial diversity than adolescents or the elderly, while the intragroup variation among the elderly and rural populations was significantly greater. Skin-associated bacterial community structure and composition could predict whether a sample came from an urban or a rural resident ~5x greater than random. PMID- 26510186 TI - The Effect of Neutral Peritoneal Dialysis Solution with Low Glucose-Degradation Product on the Fluid Status and Body Composition--A Randomized Control Trial. AB - BACKGROUND: Previous studies report conflicting results on the benefit of peritoneal dialysis (PD) patients treated with low glucose degradation product (GDP) solution. The effects of low GDP solution on body fluid status and arterial pulse wave velocity (PWV) have not been studied. METHODS: We randomly assigned 68 incident PD patients to low GDP (Intervention Group) or conventional solutions (Control Group); 4 dropped off before they received the assigned treatment. Patients were followed for 52 weeks for changes in ultrafiltration, residual renal function, body fluid status and arterial PWV. RESULT: After 52 weeks, Intervention Group had higher overhydration (3.1 +/- 2.6 vs 1.9 +/- 2.2 L, p = 0.045) and extracellular water volume (17.7 +/- 3.9 vs 15.8 +/- 3.1 L, p = 0.034) than Control Group. There was no significant difference in PWV between groups. There was no significant difference in residual renal function between the Groups. Intervention Group had lower ultrafiltration volume than Control Group at 4 weeks (0.45 +/- .0.61 vs 0.90 +/- 0.79 L/day, p = 0.013), but the difference became insignificant at later time points. Intervention Group had lower serum CRP levels than Control Group (4.17 +/- 0.77 vs 4.91 +/- 0.95 mg/dL, p < 0.0001). CONCLUSION: Incident PD patients treated with low GDP solution have less severe systemic inflammation but trends of less ultrafiltration, and more fluid accumulation. However, the effects on ultrafiltration and fluid accumulation disappear with time. The long term effect of low GDP solution requires further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00966615. PMID- 26510187 TI - Treatment Effects of Removable Functional Appliances in Pre-Pubertal and Pubertal Class II Patients: A Systematic Review and Meta-Analysis of Controlled Studies. AB - BACKGROUND: Treatment effects of removable functional appliances in Class II malocclusion patients according to the pre-pubertal or pubertal growth phase has yet to be clarified. OBJECTIVES: To assess and compare skeletal and dentoalveolar effects of removable functional appliances in Class II malocclusion treatment between pre-pubertal and pubertal patients. SEARCH METHODS: Literature survey using the Medline, SCOPUS, LILACS and SciELO databases, the Cochrane Library from inception to May 31, 2015. A manual search was also performed. SELECTION CRITERIA: Randomised (RCTs) or controlled clinical trials with a matched untreated control group. No restrictions were set regarding the type of removable appliance whenever used alone. DATA COLLECTION AND ANALYSIS: For the meta analysis, cephalometric parameters on the supplementary mandibular growth were the main outcomes, with other cephalometric parameters considered as secondary outcomes. Risk of bias in individual and across studies were evaluated along with sensitivity analysis for low quality studies. Mean differences and 95% confidence intervals for annualised changes were computed according to a random model. Differences between pre-pubertal and pubertal patients were assessed by subgroup analyses. GRADE assessment was performed for the main outcomes. RESULTS: Twelve articles (but only 3 RCTs) were included accounting for 8 pre-pubertal and 7 pubertal groups. Overall supplementary total mandibular length and mandibular ramus height were 0.95 mm (0.38, 1.51) and 0.00 mm (-0.52, 0.53) for pre-pubertal patients and 2.91 mm (2.04, 3.79) and 2.18 mm (1.51, 2.86) for pubertal patients, respectively. The subgroup difference was significant for both parameters (p<0.001). No maxillary growth restrain or increase in facial divergence was seen in either subgroup. The GRADE assessment was low for the pre-pubertal patients, and generally moderate for the pubertal patients. CONCLUSIONS: Taking into account the limited quality and heterogeneity of the included studies, functional treatment by removable appliances may be effective in treating Class II malocclusion with clinically relevant skeletal effects if performed during the pubertal growth phase. PMID- 26510188 TI - Impact of Diverse Immune Evasion Mechanisms of Cancer Cells on T Cells Engaged by EpCAM/CD3-Bispecific Antibody Construct AMG 110. AB - BACKGROUND: Bispecific T cell engager (BiTE(r)) are single-chain bispecific antibody constructs with dual specificity for CD3 on T cells and a surface antigen on target cells. They can elicit a polyclonal cytotoxic T cell response that is not restricted by T cell receptor (TCR) specificity, and surface expression of MHC class I/peptide antigen complexes. Using human EpCAM/CD3 bispecific BiTE(r) antibody construct AMG 110, we here assessed to what extent surface expression of PD-L1, cytoplasmic expression of indoleamine-2,3 deoxygenase type 1, Bcl-2 and serpin PI-9, and the presence of transforming growth factor beta (TGF-beta), interleukin-10 (IL-10) and adenosine in culture medium can impact redirected lysis by AMG 110-engaged T cells. METHODS: The seven factors, which are all involved in inhibiting T cell functions by cancer cells, were tested with human EpCAM-expressing Chinese hamster ovary (CHO) target cells at levels that in most cases exceeded those observed in a number of human cancer cell lines. Co-culture experiments were used to determine the impact of the evasion mechanisms on EC50 values and amplitude of redirected lysis by AMG 110, and on BiTE(r)-induced proliferation of previously resting human peripheral T cells. FINDINGS: An inhibitory effect on redirected lysis by AMG 110-engaged T cells was seen upon overexpression of serpin PI-9, Bcl-2, TGF-beta and PD-L1. An inhibitory effect on induction of T cell proliferation was only seen with CHO cells overexpressing IDO. In no case, a single evasion mechanism rendered target cells completely resistant to BiTE(r)-induced lysis, and even various combinations could not. CONCLUSIONS: Our data suggest that diverse mechanisms employed by cancer cells to fend off T cells cannot inactivate AMG 110-engaged T cells, and that inhibitory effects observed in vitro may be overcome by increased concentrations of the BiTE(r) antibody construct. PMID- 26510190 TI - Religiousness, spirituality, and coping with stress among late adolescents: A meaning-making perspective. AB - The purpose of this study was to examine the associations between religiousness, spirituality (R/S), and coping among late adolescents within a meaning-making perspective. Specifically, global meaning and situational meaning were examined as potential mediators. Two hundred and twenty one Polish participants (115 women and 106 men) completed the Religious Meaning System Questionnaire, the Self description Questionnaire of Spirituality, the Meaning in Life Questionnaire, and the Situational Meaning Scale. Results of SEM analysis showed that R/S had both direct and indirect effects on coping, suggesting that global meaning and situational meaning served as partial mediators among late adolescents. The mediating role of global meaning and situational meaning may be more fully understood within the framework of the meaning-making model. Consistent with the model, individuals with higher levels of R/S had a propensity to experience stronger global meaning in life and situational meaning, which in turn contributed to more frequent using coping styles. PMID- 26510189 TI - Enzymatic Characterization of Recombinant Food Vacuole Plasmepsin 4 from the Rodent Malaria Parasite Plasmodium berghei. AB - The rodent malaria parasite Plasmodium berghei is a practical model organism for experimental studies of human malaria. Plasmepsins are a class of aspartic proteinase isoforms that exert multiple pathological effects in malaria parasites. Plasmepsins residing in the food vacuole (FV) of the parasite hydrolyze hemoglobin in red blood cells. In this study, we cloned PbPM4, the FV plasmepsin gene of P. berghei that encoded an N-terminally truncated pro-segment and the mature enzyme from genomic DNA. We over-expressed this PbPM4 zymogen as inclusion bodies (IB) in Escherichia coli, and purified the protein following in vitro IB refolding. Auto-maturation of the PbPM4 zymogen to mature enzyme was carried out at pH 4.5, 5.0, and 5.5. Interestingly, we found that the PbPM4 zymogen exhibited catalytic activity regardless of the presence of the pro segment. We determined the optimal catalytic conditions for PbPM4 and studied enzyme kinetics on substrates and inhibitors of aspartic proteinases. Using combinatorial chemistry-based peptide libraries, we studied the active site preferences of PbPM4 at subsites S1, S2, S3, S1', S2' and S3'. Based on these results, we designed and synthesized a selective peptidomimetic compound and tested its inhibition of PbPM4, seven FV plasmepsins from human malaria parasites, and human cathepsin D (hcatD). We showed that this compound exhibited a >10-fold selectivity to PbPM4 and human malaria parasite plasmepsin 4 orthologs versus hcatD. Data from this study furthesr our understanding of enzymatic characteristics of the plasmepsin family and provides leads for anti-malarial drug design. PMID- 26510192 TI - Brown's Household Panacea: Stealing Away Pain. PMID- 26510191 TI - Differential genetic and environmental influences on developmental trajectories of antisocial behavior from adolescence to young adulthood. AB - Little research has investigated differential genetic and environmental influences on different developmental trajectories of antisocial behavior. This study examined genetic and environmental influences on liabilities of being in life-course-persistent (LCP) and adolescent-limited (AL) type delinquent groups from adolescence to young adulthood while considering nonviolent and violent delinquency subtypes and gender differences. A genetically informative sample (n = 356, 15-16 years) from the first three waves of In-Home Interview of the National Longitudinal Study of Adolescent to Adult Health was used, with 94 monozygotic and 84 dizygotic pairs of same-sex twins (50% male). Biometric liability threshold models were fit and found that the male-specific LCP type class, chronic, showed more genetic influences, while the AL type classes, decliner and desister, showed more environmental influences. Genetic liability and shared environment both influence the persistence of antisocial behavior. The development of female antisocial behavior appears to be influenced more by shared environment. PMID- 26510193 TI - "Between Long and Morton"? C. W. Mayo Opines. PMID- 26510194 TI - Laughing Gas for the "Pulpit Clown"? PMID- 26510195 TI - Telling Him. PMID- 26510196 TI - Postoperative Outcomes in Obstructive Sleep Apnea: Matched Cohort Study. PMID- 26510197 TI - In Reply. PMID- 26510198 TI - Neostigmine: You Can't Have It Both Ways. PMID- 26510199 TI - In Reply. PMID- 26510200 TI - Confounders versus Mediators: An Important Distinction. PMID- 26510201 TI - High-molecular Hydroxyethyl Starch: Is More Data Still Needed? PMID- 26510202 TI - In Reply. PMID- 26510203 TI - Tracheal Tube Obstruction Assessed by Computed Tomography. PMID- 26510204 TI - Can the Continuous Hemofiltration Control Ebola-induced Systemic Inflammatory Response Syndrome? PMID- 26510211 TI - Structural and electronic control of the metal to insulator transition and local orderings in the theta-(BEDT-TTF)2X organic conductors. AB - A first-principles density functional theory (DFT) study of [Formula: see text] (BEDT-TTF)2X molecular conductors with X = I3, CsCo(SCN)4 (ambient pressure, 7.5 kbar and 10 kbar), CsZn(SCN)4, TlCo(SCN)4, RbCo(SCN)4 and RbZn(SCN)4 (220 K and 90 K) is reported. It is shown that these salts exhibit three different types of band structure each of them associated with a different physical behavior. In contrast with previous proposals it is found that the key electronic parameter behind the differences in the band structures is the intrastack transfer integral, t c . A new mechanism for the metal to insulator transition in the [Formula: see text]-(BEDT-TTF)2MM'(SCN)4 ([Formula: see text], Tl; [Formula: see text], Co) salts is proposed, where an order-disorder structural transition of the ethylenedithio groups doubling the periodicity along the stack direction drives the system into an electronically pseudo-1D system along the interstack direction that is subject to a 4k F charge localization of holes. The structural rearrangement is such that the holes are not distributed equally between the two donors; the larger hole density is associated with the B donors which establish the strongest hydrogen bonds with the anion layers. A detailed microscopic description of how disorder of the ethylenedithio groups, the theta dihedral angle and the electronic structure intermingle and lead to the unusual phase diagram of these salts is presented. In this framework the role of pressure and uniaxial strain in controlling the physical behavior of these salts is discussed. PMID- 26510212 TI - How to Optimize the Interface between Photosensitizers and TiO2 Nanocrystals with Molecular Engineering to Enhance Performances of Dye-Sensitized Solar Cells? AB - In this work, the interfacial properties of a series of metal-free organic naphthodithienothiophene (NDTT)-based photosensitizers adsorbed on TiO2 surfaces were investigated by a combination of ab initio calculations and experimental measurements. The calculations and experiments reveal that because of the efficient charge transfer from the adsorbed dyes to TiO2 nanocrystal surface there is an upward shift for the energy levels of dyes and a downward shift for the conduction band of surface TiO2 and that the band gaps for both of them are also reduced. Such electronic level alignments at the interface would lead to increased light absorption range by adsorbed dyes and increased driving force for charge injection but reduced open-circuit potential (V(oc)). More interestingly, we found that molecule engineering of the donor group and introducing additional electron-withdrawing unit have little effect on the electronic level alignments at the interface (because band gaps of the dyes adsorbed on TiO2 surfaces become approximately identical when compared with those of the dyes measured in solution) but that they can affect the steric effect and the charge separation at the interface to tune V(oc) and the short-circuit current density (J(sc)) effectively. All these findings suggest that optimizing the interfacial properties of dyes adsorbed on TiO2 surfaces by synchronously modifying steric effects of dye molecules anchored on TiO2 and charge-transfer and separation properties at the interfaces is important to construct efficient dye-sensitized solar cells. PMID- 26510213 TI - Nanostructuring graphene by dense electronic excitation. AB - The ability to manufacture tailored graphene nanostructures is a key factor to fully exploit its enormous technological potential. We have investigated nanostructures created in graphene by swift heavy ion induced folding. For our experiments, single layers of graphene exfoliated on various substrates and freestanding graphene have been irradiated and analyzed by atomic force and high resolution transmission electron microscopy as well as Raman spectroscopy. We show that the dense electronic excitation in the wake of the traversing ion yields characteristic nanostructures each of which may be fabricated by choosing the proper irradiation conditions. These nanostructures include unique morphologies such as closed bilayer edges with a given chirality or nanopores within supported as well as freestanding graphene. The length and orientation of the nanopore, and thus of the associated closed bilayer edge, may be simply controlled by the direction of the incoming ion beam. In freestanding graphene, swift heavy ion irradiation induces extremely small openings, offering the possibility to perforate graphene membranes in a controlled way. PMID- 26510214 TI - High spatial resolution dosimetric response maps for radiotherapy ionization chambers measured using kilovoltage synchrotron radiation. AB - Small circular beams of synchrotron radiation (0.1 mm and 0.4 mm in diameter) were used to irradiate ionization chambers of the types commonly used in radiotherapy. By scanning the chamber through the beam and measuring the ionization current, a spatial map of the dosimetric response of the chamber was recorded. The technique is able to distinguish contributions to the large-field ionization current from the chamber walls, central electrode and chamber stem. Scans were recorded for the NE 2571 Farmer chamber, the PTW 30013, IBA FC65-G Farmer-type chambers, the NE 2611A and IBA CC13 thimble chambers, the PTW 31006 and 31014 pinpoint chambers, the PTW Roos and Advanced Markus plane-parallel chambers, and the PTW 23342 thin-window soft x-ray chamber. In all cases, large contributions to the response arise from areas where the incident beam grazes the cavity surfaces. Quantitative as well as qualitative information about the relative chamber response was extracted from the maps, including the relative contribution of the central electrode. Line scans using monochromatic beams show the effect of the photon energy on the chamber response. For Farmer-type chambers, a simple Monte Carlo model was in good agreement with the measured response. PMID- 26510215 TI - Oral Health in North Carolina: Relationship With General Health and Behavioral Risk Factors. AB - BACKGROUND: Oral health is an integral part of general health, and loss of teeth may affect both physical and mental health. We examined how an individual's perception of his or her general health is related to oral care and loss of teeth, as well as how socioeconomic and behavioral factors are related to loss of teeth and oral care. METHODS: Logistic regression was used to analyze data from the North Carolina Behavioral Risk Factor Surveillance System (BRFSS) survey to investigate how oral health relates to general health. We examined the effects of loss of teeth and recency of dental clinic visits on perceived general health; we also examined the effects of demographic characteristics and health-related behavioral risk factors on oral health. RESULTS: Adults who had lost 6 or more teeth were more likely to report poor or fair general health, especially among those who were younger than 65 years (adjusted odds ratio = 3.59) compared to those who were 65 years or older (adjusted odds ratio = 1.87). Those who had not visited a dentist within the past year, those who had less education, those with lower incomes, and smokers were more likely to have lost 6 or more teeth. LIMITATIONS: BRFSS is a large-scale survey that collects self-reported data using random telephone methods; during the years included in this analysis, the sample included only households with landline phones that answered the survey. The measure of general health is subjective. As the BRFSS survey is a cross-sectional survey, causal relationships cannot be established. CONCLUSIONS: Loss of teeth and poor oral care are significant predictors of poor general health, indicating that oral health and oral care are integral parts of general health. Loss of teeth and oral care are affected by demographic factors such as educational attainment, income, and health-related risk factors. PMID- 26510217 TI - A Truly Therapeutic Visit. PMID- 26510218 TI - The Patient Engagement Prescription. AB - Written by a volunteer patient advisor, this issue brief provides at 50-foot view of patient engagement as seen through the eyes of various stakeholders including payers, providers, and patients. The benefits and barriers are noted, and the undeniable need for engaged patients is discussed. Many techniques and programs are reviewed including those offered from insurers, clinicians, caretakers, and community members. The overall message builds a case for why authentic patient engagement is the missing ingredient in health care if we truly want better outcomes, better health, and lower costs. PMID- 26510216 TI - Mental Health and Substance Use Among Patients in a North Carolina HIV Clinic. AB - BACKGROUND: The HIV/AIDS epidemic is a significant public health concern in North Carolina, and previous research has pointed to elevated mental health distress and substance use among HIV-infected populations, which may impact patients' adherence to medications. The aims of this study were to describe the prevalence of mental health and substance use issues among patients of a North Carolina HIV clinic, to examine differences by demographic characteristics, and to examine factors associated with suboptimal adherence to HIV medications. METHODS: This study was a secondary analysis of clinical data routinely collected through a health behavior questionnaire at a large HIV clinic in North Carolina. We analyzed data collected from February 2011 to August 2012. RESULTS: The sample included 1,398 patients. Overall, 12.2% of patients endorsed current symptomology indicative of moderate or severe levels of depression, and 38.6% reported receiving a psychiatric diagnosis at some point in their life. Additionally, 19.1% had indications of current problematic drinking, and 8.2% reported problematic drug use. Nearly one-quarter (22.1%) reported suboptimal adherence to HIV medications. Factors associated with poor adherence included racial/ethnic minority, age less than 35 years, and indications of moderate or severe depression. LIMITATIONS: The questionnaire was not completed systematically in the clinic, which may limit generalizability, and self-reported measures may have introduced social desirability bias. CONCLUSION: Patients were willing to disclose mental health distress, substance use, and suboptimal medication adherence to providers, which highlights the importance of routinely assessing these behaviors during clinic visits. Our findings suggest that treating depression may be an effective strategy to improve adherence to HIV medications. PMID- 26510219 TI - Creating Change in Health Care: Developing a Shared Understanding and Roadmap for Action. AB - The Patient and Family Engagement Framework and the Roadmap for Patient and Family Engagement in Healthcare Practice and Research are tools designed to create a shared understanding of what patient and family engagement is and how it can be translated into concrete action. PMID- 26510220 TI - Giving a Voice to Patients and Caregivers. AB - A key part of patient and family engagement involves listening to patients and keeping their perspective in mind. This article provides a chance for patients and family caregivers to tell their stories. PMID- 26510221 TI - Culture Change to Promote Patient Engagement: It Isn't How... It's Who. AB - Patient and family engagement is no longer a "why," "when," or even "how" conversation. So why are many health care organizations still struggling to embrace the patient as a partner? Now is the time to shift the conversation to a personal level. PMID- 26510222 TI - The Transforming Power of Patient Advisors. AB - Vidant Health, a private, not-for-profit health system in Eastern North Carolina, began a system-wide quality transformation in 2006. A key strategy in the transformation was increasing the engagement of patients and families, including the establishment of Patient Family Advisory Councils. Meaningful partnerships with patients and families accelerated improvement efforts and sustained performance excellence over time. PMID- 26510223 TI - Returning to the Bedside: Notes From a Clinical Educator. AB - Over the past 3 decades, teaching rounds have drifted away from the bedside in favor of management discussions in a conference room or hallway. As a result, patients and families--2 of the most valuable resources in health care--are being left out of the loop. This trend is now being reversed by bedside presentations of newly admitted patients and structured interdisciplinary bedside rounds. PMID- 26510224 TI - Motivational Interviewing: Patient Engagement as the Key to Healthy Practices, Patients, and Practitioners. PMID- 26510225 TI - Can Incentives Improve Medicaid Patient Engagement and Prevent Chronic Diseases? AB - Under the Medicaid Incentives for the Prevention of Chronic Diseases model, 10 states are testing whether incentives can encourage Medicaid beneficiaries to lose weight, stop smoking, work to prevent diabetes, or control risk factors for other chronic diseases. This commentary describes these incentive programs and how they will be evaluated. PMID- 26510226 TI - Health Insurance Incentives to Enhance Patient Engagement. PMID- 26510227 TI - Healing With CAARE: An Oasis of Care in the Changing Landscape of Translational Science. AB - There is increasing interest in understanding the impact of clinical and behavioral interventions in real-world settings. In this commentary, we draw on our experiences as partners in community engagement research to illustrate its effectiveness and practicality to reach and serve marginalized individuals across a spectrum of needs. PMID- 26510228 TI - Youth Empowerment to Achieve Patient Engagement. PMID- 26510229 TI - Bringing Patients Into the Patient-Centered Medical Home: Lessons Learned in a Large Primary Care Practice. AB - There is consensus that patients need to be engaged with their care, but how to do this in a primary care setting remains unclear. This case study demonstrates Patient Advisory Council engagement with the operations of a patient-centered medical home. PMID- 26510230 TI - Spotlight on the Safety Net: Charlotte Community Health Clinic. PMID- 26510231 TI - Let's Drop High School Football. PMID- 26510232 TI - Issue Brief: Patient and Family Engagement: A Partnership for Culture Change: A Report of the NCIOM Task Force on Patient and Family Engagement. PMID- 26510233 TI - Partnership for educating new graduates working in aged care. PMID- 26510234 TI - Editorial. PMID- 26510235 TI - Clinical Economics. Cough, cold & flu. PMID- 26510236 TI - Dealing with Mr. Smith. PMID- 26510237 TI - ICD-10 DEFEAT THE DEADLINE. PMID- 26510238 TI - PCMH Accreditation: Is it worth it? PMID- 26510239 TI - Off the rounds: Making care transitions work as an outpatient-only physician. PMID- 26510241 TI - Physicians and telehealth: Is it time to embrace virtual visits? PMID- 26510240 TI - Coding: Optimize for success. PMID- 26510242 TI - DESPITE MOC CRITICISM, ABIM CONTINUES SUPPORT FOR CEO BARON. PMID- 26510243 TI - Ready or not, hospitals face mandatory bundling for joint replacement. PMID- 26510244 TI - AHIP's move signals ACA acceptance. PMID- 26510245 TI - New Hampshire website reduces sticker shock for patients. PMID- 26510246 TI - Doc pay resumes upward march after prior year's slowdown. PMID- 26510247 TI - Coverage parity draws investors to behavioral health. PMID- 26510248 TI - When it comes to care, there's no place like home. PMID- 26510249 TI - New strategy, technology emerging in ongoing fight against healthcare fraud. PMID- 26510250 TI - Helping staff who are traumatized by errors. PMID- 26510251 TI - A risk that 'nobody will have access to pediatric specialty care'. PMID- 26510252 TI - Largest healthcare merger-and-acquisition deals through June 2015. Ranked by announced purchase price ($ in millions). PMID- 26510253 TI - Stepping into the light. PMID- 26510254 TI - Impact of Long-Term Care on Retirement Wellness. AB - Retirement wellness is the result of retiring at an appropriate age, saving enough and managing risks appropriately. One of the major risks that often is not addressed effectively is the long-term care (LTC) risk, i.e., the risk of needing help due to physical or cognitive limitations. In 2014, the Society of Actuaries issued a call for papers on the link between LTC and retirement security. This article will discuss the topic of LTC and retirement security broadly, drawing from several of the papers. Some of the topics include the impact of LTC on the individual, family members and caregivers; modeling results showing the impact of LTC on assets needed for a secure retirement; alternative methods of financing LTC; the link between housing decisions and LTC; and some ideas for the future. PMID- 26510255 TI - Accidental Death and Dismemberment Benefits. Green v Life Ins. Co. of North America, 754 F.3d 324 (5th Cir. 2014). PMID- 26510256 TI - Fund Reimbursement Under Subrogation Provisions. Central States Health and Welfare Fund v. Lewis, 745 F.3d 283 (7th Cir. 2014). PMID- 26510257 TI - ERISA Preemption. Central States, Southeast & Southwest Areas Health & Welfare Fund v. Gerber Life Ins. Co., 771 F.3d 150, 151 (2d Cir. 2014). PMID- 26510258 TI - Master challenges by maximizing efficiency. PMID- 26510259 TI - NEW MODIFIERS PHYSICIANS NEED TO KNOW FOR 2015. PMID- 26510260 TI - 6 WAYS TO EVALUATE A PHYSICIAN EMPLOYMENT OFFER. PMID- 26510261 TI - Will Medicaid parity be extended? PMID- 26510262 TI - PRIMARY CARE GETS $20 MILLION MAKEOVER WITH 'HEALTH IS PRIMARY'. PMID- 26510263 TI - Effects of propofol and isoflurane on haemodynamics and the inflammatory response in cardiopulmonary bypass surgery. AB - Cardiopulmonary bypass (CPB) causes reperfusion injury that when most severe is clinically manifested as a systemic inflammatory response syndrome. The anaesthetic propofol may have anti-inflammatory properties that may reduce such a response. We hypothesised differing effects of propofol and isoflurane on inflammatory markers in patients having CBR Forty patients undergoing elective CPB were randomised to receive either propofol or isoflurane for maintenance of anaesthesia. CRP, IL-6, IL-8, HIF-1alpha (ELISA), CD11 and CD18 expression (flow cytometry), and haemoxygenase (HO-1) promoter polymorphisms (PCR/electrophoresis) were measured before anaesthetic induction, 4 hours post-CPB, and 24 hours later. There were no differences in the 4 hours changes in CRP, IL-6, IL-8 or CD18 between the two groups, but those in the propofol group had higher HIF-1alpha (P = 0.016) and lower CD11 expression (P = 0.026). After 24 hours, compared to the isoflurane group, the propofol group had significantly lower levels of CRP (P < 0.001), IL-6 (P < 0.001) and IL-8 (P < 0.001), with higher levels CD11 (P = 0.009) and CD18 (P = 0.002) expression. After 24 hours, patients on propofol had increased expression of shorter HO-1 GT(n) repeats than patients on isoflurane (P = 0.001). Use of propofol in CPB is associated with a less adverse inflammatory profile than is isofluorane, and an increased up-regulation of HO-1. This supports the hypothesis that propofol has anti-inflammatory activity. PMID- 26510264 TI - Elevated fibrinogen and lowered homocysteine-vitamin determinants and their association with left atrial thrombus in patients with rheumatic mitral stenosis. AB - Mitral stenosis (MS) causes stagnation of blood flow, leading to thrombus formation in the left atrium (LA), which may lead to systemic thrombo-embolic complications and stroke. We compared the alterations in echocardiographic and procoagulant parameters in patients with severe rheumatic MS with and without LA thrombus. The study was a cross-sectional study of patients with rheumatic MS, being evaluated for percutaneous mitral commisurotomy. Group 1 patients comprised of patients with rheumatic MS with LA thrombus (n=35) and Group 2 patients had rheumatic MS without LA thrombus (n = 45). Platelet aggregability, fibrinogen, homocysteine, vitamin B12 and folate; mitral valve area (MVA), mean mitral gradient and pulmonary artery pressure (PAP) were assessed in all study subjects. Significant increase in fibrinogen, homocysteine and platelet aggregation and fall in homocysteine-associated determinants were seen in Group 1, as compared with Group 2. Raised fibrinogen, lowered homocysteine-vitamin determinants and lowered mitral valve area were associated independently, with presence of LA thrombus in rheumatic MS. In this study, fibrinogen, vitamin B12 and folate were independently associated with the occurrence of thrombus in patients with rheumatic MS. Hence, our results suggest that increase in procoagulant mechanisms contribute to increased risk of thrombosis in the left atrium in patients with rheumatic MS. PMID- 26510265 TI - Snail transcript levels in diagnosis of pancreatic carcinoma with fine-needle aspirate. AB - Expression of the transcription factor Snail that mediates epithelial-mesenchymal transition is correlated with poor prognosis in many tumour types. The aim of this study is to determine, as a proof of principle, whether Snail messenger RNA (mRNA) could be detected in fine-needle aspirate (FNA) biopsies of pancreatic ductal adenocarcinoma (PDAC) and could accurately differentiate malignant from benign pancreatic tissues. We also investigate the expression of Snail mRNA and its clinical significance in PDAC. FNA (22- or 25-gauge needle) samples were obtained from patients from June 1999 to June 2010. FNA samples that were either benign or chronic pancreatitis or confirmed as PDAC were included in this study. Snail mRNA was detected by quantitative real-time polymerase chain reaction (qRT PCR). The associations of Snail mRNA expression with various clinicopathological parameters was analysed in addition to the relation between its expression and patient survival. Levels of Snail mRNA were increased in tumour samples in comparison to benign and chronic pancreatitis. Transcript copy numbers for Snail were 0.7 +/- 0.21 for tumour, 0.16 +/- 0.09 for benign (P = 0.002) and 0.23 +/- 0.12 for chronic pancreatitis (P = 0.024). Snail expression was found to be associated significantly with lymph node metastasis (P = 0.001), perineural invasion (P = 0.038) and elevated preoperative serum carcinoembryonic antigen (CEA) level (P = 0.043). Snail mRNA was increased in patients with poor outcome compared with those who remained alive and well. Snail mRNA levels can aid in the pathological evaluation of suspicious cases and may become a valuable asset in obtaining a definitive diagnosis of PDAC. The strong association between Snail expression and lymph node metastasis suggests that Snail mRNA can be used as an adjunct to lymph node positivity to predict survival in pancreatic cancer. PMID- 26510266 TI - Platelet transfusion in chemotherapy patients: comparison of the effect of intravenous infusion pumps versus gravity transfusion. AB - Platelet concentrates are given to patients suffering with severe thrombocytopenia usually by a gravity transfusion procedure. Increasing patient numbers that are in need of this treatment increase the pressure on hospital staff and space. In order to combat time issues, the use of medical devices such as intravenous infusion pumps are thought to be beneficial for time and simultaneously for safety in transfusion practices. By using infusion pumps, platelet concentrates can be transfused in less time and provide accurate volume measurements. Manufacturers of infusion pumps claim that these devices are safe to be used for blood products including platelet concentrates. However, published studies were performed on older models and newer devices are on the market now. The purpose of this study is to evaluate infusion pumps, which are claimed to be suitable for blood products and to investigate the impact the pumps had on platelets. Furthermore, the study revealed if the intravenous infusion pumps are safe to be used for platelet transfusion as claimed by manufacturers. A simulated transfusion was performed using the Carefusion Alaris GP Plus volumetric pump and Fresenius Kabi Volumat Agilia infusion pump. Samples were taken from expired platelet concentrates before and after passage through the pump. All samples were investigated for full blood count that included platelet count, mean platelet volume (MPV), platelet distribution width (PDW) and a plateletcrit (PCT). The samples were then centrifuged to achieve platelet-poor plasma and then tested for lactate dehydrogenase (LDH). A power calculation performed on the statistical power analysis program G*power indicated a requirement of 82 samples for a power of 80%. Statistical analysis was performed with the IBM SPSS statistic software. A paired sample t-test was used to calculate mean, standard deviation and P values for the infusion pumps used. The Wilcoxon Signed Rank Test was used to evaluate results that had a non-normal distribution. No statistically significant changes were found for LDH, PDW and platelet count with the Carefusion infusion pump. PCT and MPV were found to have a statistically significant change with P values of 0.005 and 0.001, respectively, and showed a decrease in their values. The Fresenius Kabi infusion pump has shown no statistically difference in LDH, platelet count, PCT or PDW, with P values of 0.075, 0.425, 0.151 and 0.397, respectively. The MPV showed a statistically significant decrease in its value with a P value < 0.043. Although only two pumps were tested, the results achieved by testing the devices revealed that there was no influence on the platelet enzyme LDH or the platelet count as the main parameters. However, the findings showed that there was statistically significant differences in MPV of the expired platelet concentrates. PMID- 26510267 TI - Pseudomonas aeruginosa displays an altered phenotype in vitro when grown in the presence of mannitol. AB - D-mannitol has been approved in dry powder formulation as an effective antimucolytic agent in patients with cystic fibrosis. What is not known is the effect of adding a metabolisable sugar on the biology of chronic bacterial pathogens in the CF lung. Therefore, a series of simple in vitro experiments were performed to examine the effect of adding D-mannitol on the phenotype of the CF respiratory pathogens Pseudomonas aeruginosa and Burkholderia cenocepacia. Clinical isolates (n = 86) consisting of P. aeruginosa (n = 51), B. cenocepacia (n = 26), P. putida (n = 4), Stenotrophomonas maltophila (n = 3) and Pseudomonas spp. (n = 2) were examined by supplementing basal nutrient agar with varying concentrations of D-mannitol (0-20% [w/v]) and subsequently examining for any change in microbial phenotype. The effect of supplementation with mannitol was four-fold, namely i) To increase the proliferation and increase in cell density of all CF organisms examined, with an optimal concentration of 2-4% (w/v) D mannitol. No such increase in cell proliferation was observed when mannitol was substituted with sodium chloride. ii) Enhanced pigment production was observed in 2/51 (3.9%) of the P. aeruginosa isolates examined, in one of the P. putida isolates, and in 3/26 (11.5%) of the B. cenocepacia isolates examined. iii). When examined at 4.0% (w/v) supplementation with mannitol, 11/51 (21.6%) P. aeruginosa isolates and 3/26 (11.5%) B. cenocepacia isolates were seen to exhibit the altered adhesion phenotype. iv). With respect to the altered mucoid phenotype, 5/51 (9.8%) P. aeruginosa produced this phenotype when grown at 4% mannitol. Mucoid production was greatest at 4%, was poor at 10% and absent at 20% (w/v) mannitol. The altered mucoid phenotype was not observed in the B. cenocepacia isolates or any of the other clinical taxa examined. Due consideration therefore needs to be given, where there is altered physiology within the small airways, leading to a potentially altered biological state of the colonising microorganisms in novel inhaled pharmaceutical interventions in CF, particularly those, which are not designated as antimicrobial agents. PMID- 26510268 TI - Evaluation of rep-PCR/DiversiLab versus PFGE and spa typing in genotyping methicillin-resistant Staphylococcus aureus (MRSA). AB - Pulsed-field gel electrophoresis (PFGE) is the 'gold standard' for genotyping of methicillin-resistant Staphylococcus aureus (MRSA); however, the DiversiLab (DL) system, based on rep-PCR, is faster, simpler and could be better adapted to daily routine hospital work. We genotyped 100 MRSA isolates using PFGE, DL, and spa typing, and evaluated the discriminatory power of each technique and the correlation between them by Simpson's index(SI) and adjusted Rand coefficient (ARI), respectively. The isolates were from clinical samples from eight hospitals in Extremadura (Spain) during 2010. DL separated the 100 MRSA into 18 patterns, with 69% of the isolates grouped into four predominant patterns. spa typing reported 17 spa types, classifying 69% of MRSA into two major types (t067 and t002). PFGE revealed the existence of 27 patterns, gathering 54% of MRSA into three pulse types (E8a, E7a and E7b). SI values were 0.819, 0.726, 0.887 and 0.460 for DL, spa typing, PFGE and CC-BURP, respectively. ARI values of DL over PFGE, spa typing and CC-BURP were 0.151, 0.321 and 0.071, respectively. DL has less discriminatory power than PFGE but more than spa typing. The concordance of DL with PFGE is low, primarily because DL does not discriminate between the three predominant MRSA pulse types in our environment. PMID- 26510269 TI - Application of RT-Bst to enhance detection of pathogenic viruses of the respiratory tract. AB - Inefficiency of RT-PCR can be associated with the suboptimal process of reverse transcription as only 40-80% of RNA is converted to cDNA. We employed a novel method, RT-Bst, to enrich the concentration of cDNA for subsequent multiplex PCR detection of selected RNA viruses. The RT-Bst method amplifies cDNA through reverse transcription of viral RNA using reverse transcriptase and amplification of cDNA using Bst DNA polymerase. Viral RNA was extracted from 25 nasopharyngeal samples for detection of influenza A, B and C; parainfluenza 1-4; human coronaviruses 229E and OC43; respiratory syncytial virus (RSV) and rhinovirus. Both multiplex one-step RT-PCR and RT-Bst PCR were used to compare their performances for detection of virus sequences. These findings were compared with routine laboratory detection. When using RT-Bst PCR, 28% of samples yielded a viral pathogen compared to 20% with RT-PCR and 12% using routine diagnostic tests. RT-Bst PCR was shown to have particular utility in the detection of RSV RNA as this was present in 20% of the samples studied compared to 8% when using RT-PCR. For one patient, RT-Bst PCR was able to detect RSV five days earlier than conventional hospital diagnostic testing. RT-Bst and RT-Bst PCR can be used as alternative approaches to reverse transcription and one-step RT-PCR, respectively, for sequence-independent amplification of RNA virus sequences and a larger scale analysis of this new diagnostic approach is warranted. PMID- 26510270 TI - Asymptomatic group B streptococcal bacteriuria among pregnant women in Saudi Arabia. AB - This study aims to determine the asymptomatic bacteriuria in pregnancy due to GBS and its antimicrobial sensitivity pattern for planning strategy for the management of these cases and also to determine the relationship between asymptomatic bacteriuria and pyuria. A total of 3863 consecutive urine specimens were collected from 3863 pregnant women with asymptomatic bacteriuria attending the obstetrics and gynaecology department of our hospital over a period of two years. Specimens were processed using standard microbiological procedures. All the subjects were evaluated for bacteriuria. The prevalence of asymptomatic bacteriuria due to group B streptococci (GBS) was 82/3863 (2.1%) among pregnant women in Saudi Arabia. Among these, 69/82 patients (84.2%) had clinical and microbiological features consistent with cystitis, versus 13/82 (15.8%) for pyelonephritis. About 51.2% (42/82) of the patients who had urine analysis performed had positive results based on positive urinary leucocyte esterase and pyuria. Disc-diffusion analysis of all 82 GBS isolates showed that they were highly susceptible to Augmentin and linezolid. Screening for bacteriuria in pregnancy and proper treatment must be considered as an essential part of antenatal care in this community. To prevent asymptomatic bacteriuria complications, all pregnant women should be screened at the first antenatal visit. A negative test for pyuria is not a reliable indicator of the absence of asymptomatic bacteriuria in pregnant women. Further, ongoing surveillance and evaluation of outcomes in pregnancies complicated by GBS bacteriuria is required to optimise maternal and newborn care. PMID- 26510271 TI - Development of new and accurate measurement devices (TruSlice and TruSlice Digital) for use in histological dissection: an attempt to improve specimen dissection precision. AB - Histological dissection of human tissue has relied on conventional procedures, which have largely remained unchanged for decades. Practices to determine measurement parameters employed in these procedures have largely relied on the use of rulers and weighing scales. It is well documented in the scientific literature that both fixation and processing of tissue can significantly affect the viability of the of tissue sections both for tinctorial and immunocytochemical investigations. Both of these factors can be compounded in their negative effects by inappropriate sampling of tissue at histological cut up. There are five key factors to ensure good surgical grossing technique, flat uniformly perpendicular specimen cutting face, appropriate immobilisation of the tissue specimen during grossing, good visualisation of the cutting tissue face, sharp cutting knives and the grossing knife action. Meeting these factors implies the devices are fit for purpose. Here we describe an innovative approach to designing cut up devices to improve accuracy and precision, which take these five key requirements into consideration. The devices showed accuracy and precision, enabling tissue slices to be produced in a uniformly perpendicular fashion to within 2 mm in thickness and to enable consistency and reproducibility of performance across a series of tissue types. The application of a digital rule on one of these devices ensures accuracy and also enables quality control issues to be clearly assessed. As cellular pathology laboratories conform to ever increasing standards of compliance and performance in practice, the advent of assured precision and accuracy at cut up is awaited. Recommendations from accreditation bodies such as the United Kingdom Accreditation Service (UKAS) continue to push for improvements in this area of histological investigation. These newly designed devices may give the answers to these requirements and provide the impetus for a new generation of innovative equipment for histological dissection. PMID- 26510272 TI - Comparison of the in vitro susceptibility of veterinary antibiotics with human antibiotics within aminoglycosides, beta-lactam and fluoroquinolone antibiotic classes to highly resistant Gram-negative pathogens from human medicine. PMID- 26510273 TI - Anthem-Cigna merger poses promise, perils for providers and consumers. PMID- 26510274 TI - CMS to test concurrent coverage of hospice and curative care. PMID- 26510275 TI - Pressure mounts for measures to control drug prices. PMID- 26510276 TI - Hospitals return to building mode as economy picks up steam. PMID- 26510277 TI - States may tap hospitals to help pay for Medicaid expansion in 2017. PMID- 26510278 TI - Delayed scrutiny: Reported problems with birth control device expose gaps in FDA post-market surveillance. PMID- 26510279 TI - ANTI-FRAUD FERVOR: STATES STEP UP FALSE CLAIMS ACTIONS TO RECOVER MEDICAID DOLLARS. PMID- 26510280 TI - Think big on healthcare finance reform. PMID- 26510281 TI - Expansion of Medicaid offers benefits far beyond improving access to care. PMID- 26510282 TI - Linking personality, treatment compliance. PMID- 26510283 TI - Texas medical center keeps its focus on process improvement. PMID- 26510284 TI - Largest allopathic medical schools. Ranked by total active enrollment for the 2014-15 school year. PMID- 26510285 TI - Medical school enrollment grows while residency slots remain tight. PMID- 26510286 TI - A new algorithm for essential proteins identification based on the integration of protein complex co-expression information and edge clustering coefficient. AB - Essential proteins provide valuable information for the development of biology and medical research from the system level. The accuracy of topological centrality only based methods is deeply affected by noise in the network. Therefore, exploring efficient methods for identifying essential proteins would be of great value. Using biological features to identify essential proteins is efficient in reducing the noise in PPI network. In this paper, based on the consideration that essential proteins evolve slowly and play a central role within a network, a new algorithm, named CED, is proposed. CED mainly employs gene expression level, protein complex information and edge clustering coefficient to predict essential proteins. The performance of CED is validated based on the yeast Protein-Protein Interaction (PPI) network obtained from DIP database and BioGRID database. The prediction accuracy of CED outperforms other seven algorithms when applied to the two databases. PMID- 26510287 TI - Fuzzy watershed segmentation algorithm: an enhanced algorithm for 2D gel electrophoresis image segmentation. AB - Detection and quantification of protein spots is an important issue in the analysis of two-dimensional electrophoresis images. However, there is a main challenge in the segmentation of 2DGE images which is to separate overlapping protein spots correctly and to find the weak protein spots. In this paper, we describe a new robust technique to segment and model the different spots present in the gels. The watershed segmentation algorithm is modified to handle the problem of over-segmentation by initially partitioning the image to mosaic regions using the composition of fuzzy relations. The experimental results showed the effectiveness of the proposed algorithm to overcome the over segmentation problem associated with the available algorithm. We also use a wavelet denoising function to enhance the quality of the segmented image. The results of using a denoising function before the proposed fuzzy watershed segmentation algorithm is promising as they are better than those without denoising. PMID- 26510288 TI - Regularised extreme learning machine with misclassification cost and rejection cost for gene expression data classification. AB - The main purpose of traditional classification algorithms on bioinformatics application is to acquire better classification accuracy. However, these algorithms cannot meet the requirement that minimises the average misclassification cost. In this paper, a new algorithm of cost-sensitive regularised extreme learning machine (CS-RELM) was proposed by using probability estimation and misclassification cost to reconstruct the classification results. By improving the classification accuracy of a group of small sample which higher misclassification cost, the new CS-RELM can minimise the classification cost. The 'rejection cost' was integrated into CS-RELM algorithm to further reduce the average misclassification cost. By using Colon Tumour dataset and SRBCT (Small Round Blue Cells Tumour) dataset, CS-RELM was compared with other cost-sensitive algorithms such as extreme learning machine (ELM), cost-sensitive extreme learning machine, regularised extreme learning machine, cost-sensitive support vector machine (SVM). The results of experiments show that CS-RELM with embedded rejection cost could reduce the average cost of misclassification and made more credible classification decision than others. PMID- 26510289 TI - Design and implementation of a hybrid MPI-CUDA model for the Smith-Waterman algorithm. AB - This paper provides a novel hybrid model for solving the multiple pair-wise sequence alignment problem combining message passing interface and CUDA, the parallel computing platform and programming model invented by NVIDIA. The proposed model targets homogeneous cluster nodes equipped with similar Graphical Processing Unit (GPU) cards. The model consists of the Master Node Dispatcher (MND) and the Worker GPU Nodes (WGN). The MND distributes the workload among the cluster working nodes and then aggregates the results. The WGN performs the multiple pair-wise sequence alignments using the Smith-Waterman algorithm. We also propose a modified implementation to the Smith-Waterman algorithm based on computing the alignment matrices row-wise. The experimental results demonstrate a considerable reduction in the running time by increasing the number of the working GPU nodes. The proposed model achieved a performance of about 12 Giga cell updates per second when we tested against the SWISS-PROT protein knowledge base running on four nodes. PMID- 26510290 TI - An ensemble method for reconstructing gene regulatory network with jackknife resampling and arithmetic mean fusion. AB - During the past decades, numerous computational approaches have been introduced for inferring the GRNs. PCA-CMI approach achieves the highest precision on the benchmark GRN datasets; however, it does not recover the meaningful edges that may have been deleted in an earlier iterative process. To recover this disadvantage and enhance the precision and robustness of GRNs inferred, we present an ensemble method, named as JRAMF, to infer GRNs from gene expression data by adopting two strategies of resampling and arithmetic mean fusion in this work. The jackknife resampling procedure were first employed to form a series of sub-datasets of gene expression data, then the PCA-CMI was used to generate the corresponding sub-networks from the sub-datasets, and the final GRN was inferred by integrating these sub-networks with an arithmetic mean fusion strategy. Compared with PCA-CMI algorithm, the results show that JRAMF outperforms significantly PCA-CMI method, which has a high and robust performance. PMID- 26510291 TI - Employing social network analysis for disease biomarker detection. AB - Detection of disease biomarkers in general and cancer biomarkers in particular is an important task which has received considerable attention in the area of in silico genomic experiments. We describe a new approach for detecting cancer biomarkers based on genomic microarray data; it is characterised by employing Social Network Analysis (SNA) techniques. Through social interaction perspective, we can have genes as actors in a social network, where similarities between genes can be described as connections between these actors. The correct determination of biomarkers out of huge genomic data dramatically decreases the number of features. It is also possible to achieve the same or better classification performance compared to using the whole data. The minimum number of biomarkers can be researched further biologically to reduce the numerous time-consuming in vitro experiments. Results of the conducted experiments with selected biomarkers are promising and efficient. PMID- 26510292 TI - A novel filter feature selection method for paired microarray expression data analysis. AB - In recent years, a large amount of microarray data sets are produced with tens of thousands of genes. Feature selection has become a very sharp tool to select the informative genes. However, few feature selection methods consider the effect of paired samples, which are much more considered in the experiments of these years. Here, we propose a new feature selection method for paired microarray data sets analysis. It uses the fold change instead of the subtraction in the original approach, measures the statistical significant using the q-value of False Discovery Rate (FDR) and also decreases the influence of redundant genes. We compare the proposed method with another six existing methods in predict performance, stability of gene lists, functional stability and functional enrichment analysis using six kinds of paired cancer data sets. Comparison results show that our proposed method achieves better effectiveness, stability and consistency when it is applied to paired data sets. PMID- 26510293 TI - A method for extracting task-oriented information from biological text sources. AB - A method for information extraction which processes the unstructured data from document collection has been introduced. A dynamic programming technique adopted to find relevant genes from sequences which are longest and accurate is used for finding matching sequences and identifying effects of various factors. The proposed method could handle complex information sequences which give different meanings in different situations, eliminating irrelevant information. The text contents were pre-processed using a general-purpose method and were applied with entity tagging component. The bottom-up scanning of key-value pairs improves content finding to generate relevant sequences to the testing task. This paper highlights context-based extraction method for extracting food safety information, which is identified from articles, guideline documents and laboratory results. The graphical disease model verifies weak component through utilisation of development data set. This improves the accuracy of information retrieval in biological text analysis and reporting applications. PMID- 26510294 TI - Automatic extraction of reference gene from literature in plants based on texting mining. AB - Real-Time Quantitative Polymerase Chain Reaction (qRT-PCR) is widely used in biological research. It is a key to the availability of qRT-PCR experiment to select a stable reference gene. However, selecting an appropriate reference gene usually requires strict biological experiment for verification with high cost in the process of selection. Scientific literatures have accumulated a lot of achievements on the selection of reference gene. Therefore, mining reference genes under specific experiment environments from literatures can provide quite reliable reference genes for similar qRT-PCR experiments with the advantages of reliability, economic and efficiency. An auxiliary reference gene discovery method from literature is proposed in this paper which integrated machine learning, natural language processing and text mining approaches. The validity tests showed that this new method has a better precision and recall on the extraction of reference genes and their environments. PMID- 26510295 TI - LMDS-based approach for efficient top-k local ligand-binding site search. AB - In this work, we propose a LMDS-based binding-site search for improving the search speed of the Patch-Surfer method. Patch-Surfer is efficient in recognition of protein-ligand binding partners, further speedup is necessary to address multiple-user access. Futher speedup is realised by exploiting Landmark Multi Dimensional Scaling (LMDS). It computes embedding coordinates for data points based on their distances from landmark points. When selecting the landmark points, we adopt two approaches--random and greedy selection. Our method approximately retrieves top-k results and the accuracy increases as we exploit more landmark points. Although two landmark selection approaches show comparable results, the greedy selection shows the best performance when the number of landmark points is large. Using our method, the searching time is reduced up to 99% and it retrieves almost 80% of exact top-k results. Additionally, LMDS-based binding-site search+ improves the retrieval accuracy from 80% to 95% while sacrificing the speedup ratio from 99% to 90% compared to Patch-Surfer. PMID- 26510296 TI - Minimum Bayesian error probability-based gene subset selection. AB - Sifting functional genes is crucial to the new strategies for drug discovery and prospective patient-tailored therapy. Generally, simply generating gene subset by selecting the top k individually superior genes may obtain an inferior gene combination, for some selected genes may be redundant with respect to some others. In this paper, we propose to select gene subset based on the criterion of minimum Bayesian error probability. The method dynamically evaluates all available genes and sifts only one gene at a time. A gene is selected if its combination with the other selected genes can gain better classification information. Within the generated gene subset, each individual gene is the most discriminative one in comparison with those that classify cancers in the same way as this gene does and different genes are more discriminative in combination than in individual. The genes selected in this way are likely to be functional ones from the system biology perspective, for genes tend to co-regulate rather than regulate individually. Experimental results show that the classifiers induced based on this method are capable of classifying cancers with high accuracy, while only a small number of genes are involved. PMID- 26510297 TI - Granular support vector machine to identify unknown structural classes of protein. AB - To date, classification of structural class using local protein structure rather than the whole structure has been gaining widespread attention. It is noted that the structural class lies in local composition or arrangement of secondary structure, while the threshold-based classification method has restricted rules in determining these structural classes. As a consequence, some of the structures are unknown. In order to determine these unknown structural classes, we propose a fusion algorithm, abbreviated as GSVM-SigLpsSCPred (Granular Support Vector Machine--with Significant Local protein structure for Structural Class Prediction), which consists of two major components, which are: optimal local protein structure to represent the feature vector and granular support vector machine to predict the unknown structural classes. The results highlight the performance of GSVM-SigLpsSCPred as an alternative computational method for low identity sequences. PMID- 26510298 TI - A new approach for detecting fungal and oomycete plant pathogens in next generation sequencing metagenome data utilising electronic probes. AB - Early stage infections caused by fungal/oomycete spores may not be detected until signs or symptoms develop. Serological and molecular techniques are currently used for detecting these pathogens. Next-generation sequencing (NGS) has potential as a diagnostic tool, due to the capacity to target multiple unique signature loci of pathogens in an infected plant metagenome. NGS has significant potential for diagnosis of important eukaryotic plant pathogens. However, the assembly and analysis of huge amounts of sequence is laborious, time consuming, and not necessary for diagnostic purposes. Previous work demonstrated that a bioinformatic tool termed Electronic probe Diagnostic Nucleic acid Analysis (EDNA) had potential for greatly simplifying detecting fungal and oomycete plant pathogens in simulated metagenomes. The initial study demonstrated limitations for detection accuracy related to the analysis of matches between queries and metagenome reads. This study is a modification of EDNA demonstrating a better accuracy for detecting fungal and oomycete plant pathogens. PMID- 26510299 TI - Discovery of phenotypic networks from genotypic association studies with application to obesity. AB - Genome-wide Association Studies (GWAS) have resulted in many discovered risk variants for several obesity-related traits. However, before clinical relevance of these discoveries can be achieved, molecular or physiological mechanisms of these risk variants needs to be discovered. One strategy is to perform data mining of phenotypically-rich data sources such as those present in dbGAP (database of Genotypes and Phenotypes) for hypothesis generation. Here we propose a technique that combines the power of existing Bayesian Network (BN) learning algorithms with the statistical rigour of Structural Equation Modelling (SEM) to produce an overall phenotypic network discovery system with optimal properties. We illustrate our method using the analysis of a candidate SNP data set from the AMERICO sample, a multi-ethnic cross-sectional cohort of roughly 300 children with detailed obesity-related phenotypes. We demonstrate our approach by showing genetic mechanisms for three obesity-related SNPs. PMID- 26510300 TI - Improving protein-protein interaction article classification using biological domain knowledge. AB - Interaction Article Classification (IAC) is a specific text classification application in biological domain that tries to find out which articles describe Protein-Protein Interactions (PPIs) to help extract PPIs from biological literature more efficiently. However, the existing text representation and feature weighting schemes commonly used for text classification are not well suited for IAC. We capture and utilise biological domain knowledge, i.e. gene mentions also known as protein or gene names in the articles, to address the problem. We put forward a new gene mention order-based approach that highlights the important role of gene mentions to represent the texts. Furthermore, we also incorporate the information concerning gene mentions into a novel feature weighting scheme called Gene Mention-based Term Frequency (GMTF). By conducting experiments, we show that using the proposed representation and weighting schemes, our Interaction Article Classifier (IACer) performs better than other leading systems for the moment. PMID- 26510301 TI - Ensemble of sparse classifiers for high-dimensional biological data. AB - Biological data are often high in dimension while the number of samples is small. In such cases, the performance of classification can be improved by reducing the dimension of data, which is referred to as feature selection. Recently, a novel feature selection method has been proposed utilising the sparsity of high dimensional biological data where a small subset of features accounts for most variance of the dataset. In this study we propose a new classification method for high-dimensional biological data, which performs both feature selection and classification within a single framework. Our proposed method utilises a sparse linear solution technique and the bootstrap aggregating algorithm. We tested its performance on four public mass spectrometry cancer datasets along with two other conventional classification techniques such as Support Vector Machines and Adaptive Boosting. The results demonstrate that our proposed method performs more accurate classification across various cancer datasets than those conventional classification techniques. PMID- 26510302 TI - Predicting gene functions from multiple biological sources using novel ensemble methods. AB - The functional classification of genes plays a vital role in molecular biology. Detecting previously unknown role of genes and their products in physiological and pathological processes is an important and challenging problem. In this work, information from several biological sources such as comparative genome sequences, gene expression and protein interactions are combined to obtain robust results on predicting gene functions. The information in such heterogeneous sources is often incomplete and hence making the maximum use of all the available information is a challenging problem. We propose an algorithm that improves the performance of prediction of different models built on individual sources. We also develop a heterogeneous boosting framework that uses all the available information even if some sources do not provide any information about some of the genes. We demonstrate the superior performance of the proposed methods in terms of accuracy and F-measure compared to several imputation and integration schemes. PMID- 26510303 TI - Two stages weighted sampling strategy for detecting the relation between gene expression and disease. AB - For microarray data analysis, most of them focus on selecting relevant genes and calculating the classification accuracy by the selected relevant genes. This paper wants to detect the relation between the gene expression levels and the classes of a cancer (or a disease) to assist researchers for initial diagnosis. The proposed method is called a Two Stages Weighted Sampling strategy (TSWS strategy). According to the results, the performance of TSWS strategy is better than other existing methods in terms of the classification accuracy and the number of selected relevant genes. Furthermore, TSWS strategy also can use to understand and detect the relation between the gene expression levels and the classes of a cancer (or a disease). PMID- 26510304 TI - Mining literatures to discover novel multiple biological associations in a disease context. AB - The text mining methods proposed to discover associations between pairs of biological entities by mining a scientific literature often extract associations already existing in the literature, whereas their extensions supervise too much the discovery process with heuristics and ontologies that limit the research space. On the other hand, the methods that search novel associations applying the text mining methods to two literatures do not avoid the risk of discovering syllogisms based on faulty premises. For this reason, the paper proposes a method that helps the users to discover associations among biological entities by mining the literature using an unsupervised clustering approach. The discovered multiple associations are derived from binary associations to limit the computational load without compromising the methodology accuracy. A case study demonstrates how the tool derived from the methodology works in practice. A comparison between this tool and other tools available in the literature points out the methodology effectiveness. PMID- 26510305 TI - Micro/Nanostructured Films and Adhesives for Biomedical Applications. AB - The advanced technologies available for micro/nanofabrication have opened new avenues for interdisciplinary approaches to solve the unmet medical needs of regenerative medicine and biomedical devices. This review highlights the recent developments in micro/nanostructured adhesives and films for biomedical applications, including waterproof seals for wounds or surgery sites, drug delivery, sensing human body signals, and optical imaging of human tissues. We describe in detail the fabrication processes required to prepare the adhesives and films, such as tape-based adhesives, nanofilms, and flexible and stretchable film-based electronic devices. We also discuss their biomedical functions, performance in vitro and in vivo, and the future research needed to improve the current systems. PMID- 26510306 TI - Gene Interference with Morpholinos in a Gold Nanoparticle-Based Delivery Platform in Rat PC12 Cells. AB - For the first time the efficiency of gene knockdown of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor 1 (PAC1R) is demonstrated by employing gold nanocomplexes. This gene knockdown subsequently affects the action of PACAP on neurite outgrowth in PC12 cells. These nanocomplexes comprise cholera toxin B (CTB)-gold nanoparticle conjugates loaded with double-stranded morpholinos (MOs) (photo MO and antisense MO). Nanocomplexes are introduced into cells via lipid raft-dependent endocytosis. After UV light exposure, the photolinker in the photo MO is cleaved, bisecting the photo MO and releasing the antisense MO from the conjugate. The antisense MO then binds the PAC1R mRNA and decreases gene expression. The maximal efficiency of gene knockdown is observed after 24 hours, resulting in a 65% +/- 12 reduction of the protein level. This reduction in PAC1R impairs the responsiveness of cells to PACAP exposure. Following PAC1R gene knockdown, only 10% +/- 8 and 11%+/- 9 of cells exhibit neurite outgrowth after 4-day exposure to PACAP-38 and PACAP-27, respectively. These results demonstrate an efficient PAC1R gene knockdown and noticeable difference in response to PACAP action on neural cell differentiation, adding an extra dimension to determine the involvement of PACAP and its PAC1R in the neurotropic effect to PC12 cells. PMID- 26510307 TI - Multifunctional PLGA Nanobubbles as Theranostic Agents: Combining Doxorubicin and P-gp siRNA Co-Delivery Into Human Breast Cancer Cells and Ultrasound Cellular Imaging. AB - Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. One of the effective approaches to overcome MDR is to use nanoparticle-mediated the gene silence of chemotherapeutic export proteins by RNA interference to increase drug accumulation in drug resistant cancer cells. In this work, a new co-delivery system, DOX-PLGA/PEI/P-gp shRNA nanobubbles (NBs) around 327 nm, to overcome doxorubicin (DOX) resistance in MCF-7 human breast cancer was designed and developed. Positively charged polyethylenimine (PEI) were modified onto the surface of DOX-PLGA NBs through DCC/NHS crosslinking, and could efficiently condense P-gp shRNA into DOX-PLGA/PEI NBs at vector/shRNA weight ratios of 70:1 and above. An in vitro release profile demonstrated an efficient DOX release (more than 80%) from DOX-PLGA/PEI NBs at pH 4.4, suggesting a pH responsive drug release for the multifunctionalized NBs. Cellular experimental results further showed that DOX-PLGA/PEI/P-gp shRNA NBs could facilitate cellular uptake of DOX into cells and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells (a DOX-resistant and P-glycoprotein (P-gp) over expression cancer cell line). The IC50 of DOX-PLGA NBs against MCF-7/ADR cells was 2-fold lower than that of free DOX. The increased cellular uptake and nuclear accumulation of DOX delivered by DOX-PLGA/PEI/P-gp shRNA NBs in MCF-7/ADR cells was confirmed by fluorescence microscopy and fluorescence spectrophotometry, and might be owning to the down-regulation of P-gp and reduced the efflux of DOX. The cellular uptake mechanism of DOX-PLGA/PEI/P-gp shRNA NBs indicated that the macropinocytosis was one of the pathways for the uptake of NBs by MCF-7/ADR cells, which was also an energy-dependent process. Furthermore, the in vitro cellular ultrasound imaging suggested that the employment of the DOX-PLGA/PEI/P gp shRNA NBs could efficiently enhance ultrasound imaging of cancer cells. These results demonstrated that the developed DOX-PLGA/PEI/P-gp shRNA NBs is a potential, safe and efficient theranotic agent for cancer therapy and diagnostics. PMID- 26510308 TI - Preparation,-Characterization and Anti-Glioma Effects of Docetaxel-Incorporated Albumin-Lipid Nanoparticles. AB - Poor aqueous solubility is a serious problem for most chemotherapeutics. Docetaxel (DTX), an inhibitor of microtubule depolymerization, is frequently used to treat many malignancies. However, the surfactant used in its commercial preparation (Taxotere) has proven problematic in clinical use because it has been associated with several side effects. By utilizing the high DTX-loading property of albumin, a new formulation, DTX-incorporated albumin-lipid nanoparticles (DNPs), was prepared and evaluated. DTX was bound to albumin in vitro and dispersed by egg yolk lecithin. The DNP particle size was 110.1 nm, while the average DNP zeta potential was -2.95 mV. The median lethal dose of DNPs was 180.6 mg/kg, which was 75.3% higher than that of Taxotere. DNPs could effectively inhibit the proliferation of several cell lines and induce cell apoptosis. In vivo imaging suggested that DNPs localize to and accumulate at the glioma site, which is likely due to the enhanced permeation and retention effects of DNPs. These pharmacological experiments further confirmed that DNPs can inhibit tumor growth, prolong the median survival time of mice with gliomas and induce higher levels of apoptosis. In conclusion, this novel formulation of DTX (DNPs) displayed lower toxicity and a superior anti-glioma effect relative to standard DTX preparations. PMID- 26510309 TI - Noninvasive In Vivo Diagnosis of Brain Glioma Using RGD-Decorated Fluorescent Carbonaceous Nanospheres. AB - Fluorescent carbonaceous nanospheres (CDs) have gained significant attention because of their promising applications, especially in biology and medicine, due to their unique properties. However, the application of CDs in the noninvasive imaging of diseased tissues has been restricted by the poor targeting efficiency of CDs. In this study, CDs were prepared from sucrose and glutamic acid with a particle size of 122.5 nm. Due to quantum confinement in the nanoparticles, CDs exhibited emission from 450 to 600 nm upon excitation at approximately 400 nm. This feature made it possible to use the CDs for low-background bioimaging of deep diseased tissues. RGD, a ligand that can target alpha(v)beta3, which is highly expressed on most tumor and neovascular cells, was decorated onto the CDs after PEGylation. The product, RGD-PEG-CDs, possessed low cytotoxicity, as determined by MTT assay. In vitro, RGD-PEG-CDs targeted U87 (a human brain glioma cell line) cells with a higher cellular uptake intensity than CDs and PEGylated CDs (PEG-CDs), and endosomes were involved in the uptake procedure. The internalization of RGD-PEG-CDs, PEG-CDs and CDs all were primarily mediated by macropinocytosis and a clathrin-mediated pathway, which were energy-dependent. Additionally, the uptake of RGD-PEG-CDs could be significantly inhibited by free RGD, indicating that the uptake was mediated by the receptor of RGD. In vivo, RGD PEG-CDs accumulated in U87 glioma at high intensity, at values that were 1.67- and 1.64-fold higher than those of PEG-CDs and CDs. Furthermore, RGD-PEG-CDs exhibited good colocalization with neovasculature. In conclusion, RGD-PEG-CDs could be successfully used for noninvasive U87 glioma imaging. PMID- 26510310 TI - Enhanced Anti-Metastatic Activity of Etoposide Using Layered Double Hydroxide Nano Particles. AB - Cell migration and invasion are integral to lung cancer metastasis. In this study, we investigated the combination of traditional chemotherapy and a layered double hydroxide (LDH) carrier as a new strategy for the inhibition of migration and invasion. To investigate the characteristics and possible mechanisms of VP16 LDH [the Mg-Al/LDH containing etoposide (VP16)], we used several experimental techniques, such as transmission electron microscopy (TEM) and fluorescent microscopy. The TEM, X-ray diffraction (XRD) and zeta potential results indicated that VP16 binds well with LDH, with an average size of 70 nm, and the drug delivery system was confirmed to have the desired quality of slow release by the in vitro release test results. Fluorescent images showed that the cellular uptake of VP16-LDH was a caveolae-mediated and energy-dependent process. Moreover, A549 cells treated with VP16-LDH (5 MUg/ml, 10 MUg/ml) demonstrated significant inhibition of cell migration and invasion compared with the cells treated with free VP16 at the same concentration. The inhibition of AKT, mTOR and STAT3 phosphorylation and p-beta-catenin up-regulation in VP16-LDH-treated cells revealed a possible molecular mechanism via the mTOR/AKT and STAT pathways, through which VP16-LDH had a stronger inhibitory effect on migration than the drug alone. PMID- 26510311 TI - Improved Anti-Tumoral Therapeutic Efficacy of 4-Hydroxynonenal Incorporated in Novel Lipid Nanocapsules in 2D and 3D Models. AB - 4-hydroxynonenal (HNE), a lipid peroxidation product, is a promising anti neoplastic drug due to its remarkable anti-cancer activities. However, this possibility has not been explored, because the delivery of HNE is very challenging as a result of its low solubility and its poor stability. This study intentionally designed a new type of lipid nanocapsules specifically for HNE delivery. They consist of a medium chain triglyceride liquid oil core surrounded by a polymer shell. A beta-cyclodextrin-poly(4-acryloylmorpholine) conjugate was selected as the shell component. HNE-loaded nanocapsules were about 350 nm in size with a negative surface charge. They were stable for two years when stored in suspensions at 4 degrees C. In vitro experiments showed that HNE was released from the nanocapsules at a considerable rate. Nanocapsule uptake into cells was evaluated using a fluorescent formulation that revealed rapid internalisation. Cytotoxicity studies demonstrated the safety of the formulation. Enhanced anti tumoral activity against various cell lines, depending on increased HNE stability, was obtained by using HNE-loaded nanocapsules. In particular, we have demonstrated an increase in anti-proliferative, pro-apoptotic and differentiative activity in several tumour cell lines from different tissues. Moreover, we evaluated the effects of these new nanocapsules on a three-dimensional human reconstructed model of skin melanoma. Interestingly, the encouraging results obtained with topical administration on the epidermal surface could open new perspectives in melanoma treatments. PMID- 26510312 TI - Inhibition of Bacterial Attachment on Surfaces by Immobilization of Tobramycin Loaded Liposomes. AB - Stainless steel surfaces were processed by gold deposition in order to immobilize tobramycin-loaded liposomes which were functionalized on their surface with thiol groups (through maleimide (MAL) derivatization with thiols). After optimizing the tobramycin loading in liposomes (LIPs), and the immobilization of THIOL-MAL functionalized LIPs on gold-sputtered surfaces, the coated surfaces were challenged with two reference Staphylococcus epidermidis strains: ATCC 35984 (slime-positive) and ATCC 12228 (slime-negative), in order to measure the degree of surface protection from biofilm formation. Moreover, the effect of the reference and two well characterized clinical S. epidermidis strains on the integrity of LIPs (composed of PC or DSPC) was evaluated, in order to investigate whether specific interactions between LIPs and bacteria occur, and if they are affected by LIP membrane composition and/or bacterial strain type. Bacteria growth on surfaces is substantially inhibited by TOBR-loaded-LIP immobilization, especially in the case of the non-biofilm forming bacterial strain. Gold sputtered surfaces were moderately (albeit significantly) protected, from both reference strains tested (compared to bare surfaces). Interestingly, LIP integrity is significantly decreased in the presence of bacteria (at specific lipid/bacteria ratios); the biofilm-forming bacteria being most potent for LIP disruption, whereas, less rigid liposomal membranes (PC) are affected more compared to rigid (DSPC) ones. The clinical strains are also reactive against LIP. This interaction indicates a potential for triggered release of LIP encapsulated drugs in presence of biofilm-forming bacteria, therefore LIP encapsulation/immobilization may be envisioned as a potential platform technology for triggered antimicrobial therapy. PMID- 26510313 TI - Negatively Charged Carbon Nanohorn Supported Cationic Liposome Nanoparticles: A Novel Delivery Vehicle for Anti-Nicotine Vaccine. AB - Tobacco addiction is the second-leading cause of death in the world. Due to the nature of nicotine (a small molecule), finding ways to combat nicotine's deleterious effects has been a constant challenge to the society and the medical field. In the present work, a novel anti-nicotine vaccine based on nanohorn supported liposome nanoparticles (NsL NPs) was developed. The nano-vaccine was constructed by using negatively charged carbon nanohorns as a scaffold for the assembly of cationic liposomes, which allow the conjugation of hapten conjugated carrier proteins. The assembled bio-nanoparticles are stable. Mice were immunized subcutaneously with the nano-vaccine, which induced high titer and high affinity of nicotine specific antibodies in mice. Furthermore, no evidence of clinical signs or systemic toxicity followed multiple administrations of NsL-based anti nicotine vaccine. These results suggest that NsL-based anti-nicotine vaccine is a promising candidate in treating nicotine dependence and could have potential to significantly contribute to smoking cessation. PMID- 26510314 TI - Mechanism of Nanotization-Mediated Improvement in the Efficacy of Caffeine Against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism. AB - The study aimed to measure the neuroprotective efficacy of caffeine-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles over bulk and to delineate the mechanism of improvement in efficacy both in vitro and in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinsonism. Caffeine encapsulated PLGA nanoparticles exhibited more pronounced increase in the endurance of dopaminergic neurons, fibre outgrowth and expression of tyrosine hydroxylase (TH) and growth-associated protein-43 (GAP-43) against 1-methyl-4 phenylpyridinium (MPP+)-induced alterations in vitro. Caffeine-encapsulated PLGA nanoparticles also inhibited MPP(+)-mediated nuclear translocation of nuclear factor-kappa B (NF-kappaB) and augmented protein kinase B phosphorylation more potentially than bulk counterpart. Conversely, MPTP reduced the striatal dopamine and its metabolites and nigral TH immunoreactivity whereas augmented the nigral microglial activation and nigrostriatal lipid peroxidation and nitrite content, which were shifted towards normalcy by caffeine. The modulations were more evident in caffeine-encapsulated PLGA nanoparticles treated animals as compared with bulk. Moreover, the striatal caffeine and its metabolites were found to be significantly higher in caffeine-encapsulated PLGA nanoparticles-treated mice as compared with bulk. The results thus suggest that nanotization improves the protective efficacy of caffeine against MPTP-induced Parkinsonism owing to enhanced bioavailability, inhibition of the nuclear translocation of NF-kappaB and activation of protein kinase B phosphorylation. PMID- 26510315 TI - Rapid and Sensitive Determination of HIV-1 Virus Based on Surface Enhanced Raman Spectroscopy. AB - In this study, rapid and sensitive detection of human immunodeficiency virus (HIV)-1 was performed based on immunoreactions with an Au nanodot fabricated indium tin oxide (ITO) substrate using surface-enhanced Raman spectroscopy (SERS). Highly ordered Au nanodots (ca. 20 nm) were electrochemically fabricated over a large surface area (20 mm x 10 mm) of an ITO substrate using a simple deposition method with Triton X-100. On the Au nanodot surface, monoclonal antibody fragments against gp120 were selectively bound by gold-sulfur interactions. Various concentrations (35 fg/mL to 350 pg/mL) of HIV-1 virus-like particles (HIV-1 VLPs) were used for the measurements. The presence of HIV-1 VLPs was rapidly (within 5 s) and successfully determined by SERS due to specific immunoreactions on the Au nanodots without the use of labeling probes. The results showed the possibility of using SERS-related methods as a new immunoassay for the study of biomolecular interactions and detection of low viral loads. Moreover, based on its high sensitivity and chemical specificity, SERS could be used as a promising clinical tool for detecting infectious small biological components. PMID- 26510316 TI - Poly-alpha,beta-Polyasparthydrazide-Based Nanogels for Potential Oral Delivery of Paclitaxel: In Vitro and In Vivo Properties. AB - A family of nanogel drug carriers has been designed to enhance the oral absorption of paclitaxel (PTX). The PAHy-based nanogels were prepared by the interpenetration of poly-alpha,beta-polyasparthydrazide (PAHy) chains and dicarboxyl-poly (ethylene glycol) (CPEG), forming a smart chain network. The PAHy based nanogels were characterized by Fourier Transform Infrared Spectroscopy (FT IR), dynamic light scattering (DLS), X-ray diffraction (XRD) and high performance liquid chromatography (HPLC). The adhesion and retention properties of fluorescein isothiocyanate (FITC)-nanogels in vivo were investigated using an in vivo imaging system and confocal laser scanning microscopy (CLSM). The smart nanogels had a particle size of -200 nm, increased the degree and rate of release, and spent over 12 h in the gastrointestinal tract. They also produced excellent adhesion, permeability and retention (APR) effects and increased oral absorption, confirming their use as potential sustained-release carriers for the oral delivery of the hydrophobic anticancer agent PTX. PMID- 26510317 TI - Enhancing Methotrexate Tolerance with Folate Tagged Liposomes in Arthritic Mice. AB - Methotrexate is the first line of treatment of rheumatoid arthritis. Since many patients become unresponsive to methotrexate treatment, only very expensive biological therapies are effective and increased methotrexate tolerance strategies need to be identified. Here we propose the encapsulation of methotrexate in a new liposomal formulation using a hydrophobic fragment of surfactant protein conjugated to a linker and folate to enhance their tolerance and efficacy. In this study we aim to evaluate the efficiency of this system to treat rheumatoid arthritis, by targeting folate receptor beta present at the surface of activated macrophages, key effector cells in this pathology. The specificity of our liposomal formulation to target folate receptor beta was investigated both in vitro as in vivo using a mouse model of arthritis (collagen induced arthritis in DBA/1J mice strain). In both systems, the liposomal constructs were shown to be highly specific and efficient in targeting folate receptor beta. These liposomal formulations also significantly increase the clinical benefit of the encapsulated methotrexate in vivo in arthritic mice, together with reduced expression of CD39 and CD73 ectonucleotidases by joint infiltrating macrophages. Thus, our formulation might be a promising cost effective way to treat rheumatoid arthritis and delay or reduce methotrexate intolerance. PMID- 26510318 TI - Antibacterial Nanostructured Polyhydroxybutyrate Membranes for Guided Bone Regeneration. AB - The principle of guided bone regeneration (GBR) in orthopedic, cranio maxillofacial and dental tissue engineering applications is to create a secluded space for the treatment of large bone defects while excluding fibrous connective tissue formation at the defect area. In dental surgeries, a GBR membrane is placed near the dental implant in post-extraction sockets to grow new bone at the implant site, along with inhibiting infection due to the microbial nature of the mouth flora. Poly[(R)-3-hydroxybutyric acid] (PHB) is a natural polyester synthesized by a wide variety of microorganisms which has been proposed for various biomedical applications. In this study, to improve the performance of PHB as a GBR, a NaOH based alkaline treatment was designed to create nanofeatured PHB membranes. The newly fabricated nanofeatured PHB membranes were investigated for GBR applications. The results showed that a quick, simple, and inexpensive sodium hydroxide treatment modified the nanostructured surface morphology and chemistry of the PHB membranes by inducing hydrolysis of the ester bonds in the PHB backbone creating carboxylic surface functional groups, which increased the hydrophilicity of the PHB surfaces. Cytocompatibility studies showed increased proliferation of human osteoblasts (bone forming cells) on the NaOH treated PHB membranes compared to the untreated ones. Importantly, in vitro bacterial studies with Staphylococcus aureus (S. aureus) indicated that the NaOH-treated PHB surfaces inhibited S. aureus growth more than 60% after 48 hours of culture compared to the untreated PHB membrane. Thus, this study, for the first time, showed that nanofeatured PHB membranes modified with a NaOH treatment may be a useful anti-bacterial, osteoconductive GBR membrane for numerous orthopedic, cranio-maxillofacial and dental tissue engineering applications. PMID- 26510319 TI - Development of an Anti-Vascular Cell Adhesion Protein-1 Aptamer for Molecular Imaging and Inflammation Detection in Transgenic Mouse Model of Alzheimer's Disease. AB - Cerebrovascular inflammation is often involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). Non-invasive and sensitive molecular imaging of cerebrovascular inflammation biomarkers therefore represents a potential AD diagnostic and therapeutic monitoring method. Here, we describe the development of a novel aptamer-based near infrared fluorescence imaging probe targeting Vascular Cell Adhesion Molecule-1 (VCAM-1), an adhesion molecule overexpressed by the activated cerebrovasculature during inflammation. A SELEX-type screening of a random ssDNA library against human VCAM-1 identified a high-affinity ssDNA aptamer with a dissociation constant of 49 nM. We demonstrated that the Cy5.5-labeled aptamer binds to activated endothelial cells, with no affinity to non-activated cells. A scrambled aptamer labeled with Cy5.5 did not image activated and non-activated endothelial cells, confirming the sequence specificity of the targeting. In vivo, the aptameric imaging agent targeting VCAM-1 successfully identified inflammation associated with amyloid beta plaques deposition in the vessels of the cerebellum of transgenic AD mice. It exhibited excellent retention by remaining bound to vessels 4 hours post injection, indicating its effectiveness in in vivo imaging and its potential in early detection of cerebrovascular inflammation. PMID- 26510320 TI - Nanoporous Aluminum Oxide Membranes Coated with Atomic Layer Deposition-Grown Titanium Dioxide for Biomedical Applications: An In Vitro Evaluation. AB - The surface topographies of nanoporous anodic aluminum oxide (AAO) and titanium dioxide (TiO2) membranes have been shown to modulate cell response in orthopedic and skin wound repair applications. In this study, we: (1) demonstrate an improved atomic layer deposition (ALD) method for coating the porous structures of 20, 100, and 200 nm pore diameter AAO with nanometer-thick layers of TiO2 and (2) evaluate the effects of uncoated AAO and TiO2-coated AAO on cellular responses. The TiO2 coatings were deposited on the AAO membranes without compromising the openings of the nanoscale pores. The 20 nm TiO2-coated membranes showed the highest amount of initial protein adsorption via the micro bicinchoninic acid (micro-BCA) assay; all of the TiO2-coated membranes showed slightly higher protein adsorption than the uncoated control materials. Cell viability, proliferation, and inflammatory responses on the TiO2-coated AAO membranes showed no adverse outcomes. For all of the tested surfaces, normal increases in proliferation (DNA content) of L929 fibroblasts were observed over from 4 hours to 72 hours. No increases in TNF-alpha production were seen in RAW 264.7 macrophages grown on TiO2-coated AAO membranes compared to uncoated AAO membranes and tissue culture polystyrene (TCPS) surfaces. Both uncoated AAO membranes and TiO2-coated AAO membranes showed no significant effects on cell growth and inflammatory responses. The results suggest that TiO2-coated AAO may serve as a reasonable prototype material for the development of nanostructured wound repair devices and orthopedic implants. PMID- 26510322 TI - MARKET FOCUS HEALTH CARE. PMID- 26510321 TI - Targeting Mast Cells and Basophils with Anti-FcepsilonRIalpha Fab-Conjugated Celastrol-Loaded Micelles Suppresses Allergic Inflammation. AB - Mast cells and basophils are effector cells in the pathophysiology of allergic diseases. Targeted elimination of these cells may be a promising strategy for the treatment of allergic disorders. Our present study aims at targeted delivery of anti-FcepsilonRIalpha Fab-conjugated celastrol-loaded micelles toward FcepsilonRIalpha receptors expressed on mast cells and basophils to have enhanced anti-allergic effect. To achieve this aim, we prepared celastrol-loaded (PEO block-PPO-block-PEO, Pluronic) polymeric nanomicelles using thin-film hydration method. The anti-FcepsilonRIalpha Fab Fragment was then conjugated to carboxyl groups on drug-loaded micelles via EDC amidation reaction. The anti FcepsilonRIalpha Fab-conjugated celastrol-loaded micelles revealed uniform particle size (93.43 +/- 12.93 nm) with high loading percentage (21.2 +/- 1.5% w/w). The image of micelles showed oval and rod like. The anti-FcepsilonRIalpha Fab-conjugated micelles demonstrated enhanced cellular uptake and cytotoxity toward target KU812 cells than non-conjugated micelles in vitro. Furthermore, diffusion of the drug into the cells allowed an efficient induction of cell apoptosis. In mouse model of allergic asthma, treatment with anti FcepsilonRIalpha Fab-conjugated micelles increased lung accumulation of micelles, and significantly reduced OVA-sIgE, histamine and Th2 cytokines (IL-4, IL-5, TNF alpha) levels, eosinophils infiltration and mucus production. In addition, in mouse model of passive cutaneous anaphylaxis, anti-FcepsilonRIalpha Fab conjugated celastrol-loaded micelles treatment significantly decreased extravasated evan's in the ear. These results indicate that anti-FcepsilonRIalpha Fab-conjugated celastrol-loaded micelles can target and selectively kill mast cells and basophils which express FcepsilonRIalpha, and may be efficient reagents for the treatment of allergic disorders and mast cell related diseases. PMID- 26510323 TI - THE WATER CURE. PMID- 26510324 TI - Health Care. PMID- 26510325 TI - Raising the Bar. PMID- 26510326 TI - Natural Remedy. PMID- 26510327 TI - On the Mend. PMID- 26510328 TI - Tree of Hope. PMID- 26510329 TI - Life?SUPPORT. PMID- 26510330 TI - Fetal tissue is critical to scientific progress. PMID- 26510331 TI - Inhaled Foreign Bodies In Pediatric Patients: Proven Management Techniques In The Emergency Department. AB - Foreign body inhalation affects thousands of children every year, and it remains a significant cause of morbidity and mortality in children. Inhaled organic or inorganic foreign bodies can become lodged in the posterior nasopharynx, larynx, trachea, or bronchi. Presentation of foreign body inhalation can range from nonspecific respiratory symptoms to respiratory failure associated with a choking episode. In this issue, an in-depth review of the etiology, pathophysiology, diagnosis, and treatment of inhaled foreign bodies is presented. Risk factors for foreign body inhalation and clinical clues to diagnosis, as well as emergent management of inhaled foreign bodies are reviewed. A systematic approach, as described in this issue, will aid in timely and accurate diagnosis and treatment of inhaled foreign bodies, thereby limiting future complications and morbidity. PMID- 26510332 TI - IMPACT OF LIQUID NITROGEN EXPOSURE ON SELECTED BIOCHEMICAL AND STRUCTURAL PARAMETERS OF HYDRATED Phaseolus vulgaris L. SEEDS. AB - BACKGROUND: It is well known that cryopreserving seeds with high water content is detrimental to survival, but biochemical and structural parameters of cryostored hydrated common bean seeds have not been published. OBJECTIVE: The objective of this work was to study the effect of liquid nitrogen exposure on selected biochemical and structural parameters of hydrated Phaseolus vulgaris seeds. MATERIALS AND METHODS: We cryopreserved seeds at various moisture contents and evaluated: germination; electrolyte leakage; fresh seed weight; levels of chlorophyll pigments, malondialdehyde, other aldehydes, phenolics and proteins; thickness of cotyledon epidermis, parenchyma, and starch storage parenchyma; and radicle and plumule lengths. RESULTS: Germination was totally inhibited when seeds were immersed in water for 50 min (moisture content of 38%, FW basis) before cryopreservation. The combined effects of seed water imbibition and cryostorage decreased phenolics (free, cell wall-linked, total), chlorophyll a and protein content. By contrast, electrolyte leakage and levels of chlorophyll b and other aldehydes increased as a result of the combination of these two experimental factors. These were the most significant effects observed during exposure of humid seed to liquid nitrogen. CONCLUSION: Further studies are still required to clarify the molecular events taking place in plant cells during cryostorage. PMID- 26510333 TI - TOXICITY OF CRYOPROTECTIVE AGENTS AND SIGNALING OF INSULIN-LIKE GROWTH FACTOR IN HEN CLAM (MACTRA CHINENSIS) EMBRYOS. AB - BACKGROUND: Signaling of Insulin-like growth factor-I (IGF-I) is involved in development, growth, reproduction and aging of organisms. OBJECTIVE: The work investigated the toxicity of glycerol, dimethyl sulfoxide (DMSO), and ethylene glycol (EG) to hen clam (Mactra chinensis) embryos, as well as the possible role of the insulin-like growth factor-I (IGF-I) during the development and growth of embryos after freeze. MATERIALS AND METHODS: Effects of glycerol, DMSO and EG at different concentrations were tested. The relationship between larval viability and signaling of IGF-I receptor after cryoprotective treatment and/or freezing was examined using immuno-blot analysis. RESULTS: Glycerol had the highest toxicity, followed by DMSO or EG. No embryo survived freeze and thaw without CPAs. After freeze, the activation of the IGF-I signaling pathway, including the IGF-I receptor (IGF-IR) beta-subunit, could be detected in freeze-thawed embryos. The level of IGF-IR expression was very weak in freeze-thawed embryos. CONCLUSION: The survival and developmental rate of embryos was closely related to CPA concentration. IGF-IR was activated and regulated the downstream IGF-I signaling in embryos. The reduced activation of IGF-IR could be related to the death of hen clam embryos. PMID- 26510334 TI - VITRIFICATION OF THAI NATIVE CATTLE OOCYTES: EFFECTS OF ETHYLENE GLYCOL CONCENTRATIONS AND EXPOSURE TIME, LINOLEIC ACID ALBUMIN AND CHOLESTEROL-LOADED METHYL-B-CYCLODEXTRIN. AB - The present study aimed to improve the oocyte vitrification procedure for preservation of Thai native cattle genetic resources. In Experiment I, oocytes were exposed to various doses (2%, 4% and 6%) of ethylene glycol (EG) in vitrification solution I (VS-I) for different equilibration times (10 or 20 min) before being exposed to VS-II and then subjected to vitrification. Experiment II was divided into two parts: (a) oocytes were matured in medium supplemented with linoleic acid albumin (LAA) (1% or 2%) and then vitrified; (b) matured oocytes were preincubated with cholesterol-loaded methyl-beta-cyclodextrin (CLC) (1% or 2%) and then vitrified. Equilibration of oocytes by exposure to 6% EG in VS-I for 10 min (Experiment I), and in vitro maturation of immature oocytes in medium supplementation with 2% LAA (Experiment II) were the most effective methods; vitrified/thawed oocytes showed higher rates of survival and subsequent embryonic development compared with the other experimental groups. PMID- 26510335 TI - EXTENDING THE VIABILITY OF SPERMATOZOA AND EGGS OF THE SEA URCHIN LYTECHINUS VARIEGATUS. AB - BACKGROUND: The storage of spermatozoa and eggs of the sea urchin Lytecninus variegatus can meet the demand of different human activities. OBJECTIVE: To develop a protocol easy to reproduce for spermatozoa cryopreservation and cooling of the eggs of the sea urchin. MATERIALS AND METHODS: Different formulations of artificial sea water were tested for their effectiveness in the freezing of sea urchin spermatozoa and storage of the eggs. RESULTS: Protocol for freezing of spermatozoa in liquid nitrogen presented the positive results when the cryoprotectant solution was diluted in artificial seawater free of calcium and magnesium. For the conservation of the eggs by cooling, the calcium-free artificial sea water, the calcium- and magnesium-free sea water, and the low sodium water proved more efficient in preserving the integrity of the eggs. CONCLUSION: The results showed success in the freezing protocol of spermatozoa and cooling of the eggs mainly in artificial calcium- and magnesium-free sea water. PMID- 26510336 TI - EFFECTS OF VARIOUS SEMEN EXTENDERS ON SEMEN PARAMETERS FOR THE PURPOSE OF HUMAN MALE FERTILITY PRESERVATION. AB - BACKGROUND: Cryopreservation enables semen to be preserved at subzero temperatures, usually at -196 degrees C. There is a need in preparing good extender for the semen to be cryopreserved until use, especially in the field of assisted reproduction. OBJECTIVE: To elucidate the apt extender for preserving both infertile and fertile samples for a minimum period and to check the post thaw results for various extenders used. MATERIALS AND METHODS: A total of 103 samples were collected for this research, and after semen analysis the semen samples were categorized into oligospermia (n = 20), oligoasthenospermia (n = 22), asthenospermia (n = 24), normospermia (n = 28), and control (n = 9). RESULTS: The extender supplemented with various antioxidants yields better results when compared to all the other extenders in case of fertile and infertile samples. CONCLUSION: Supplementing semen extender with antioxidants and various ingredients is the concern in designing an apt semen extender recipe. This research prescribes antioxidant extender (E4) to preserve the infertile and fertile semen samples for the purpose of research and also for doing assisted reproduction. PMID- 26510337 TI - EVALUATION OF DMSO TRANSPORT IN HUMAN ARTICULAR CARTILAGE: VEHICLE SOLUTIONS AND EFFECTS ON CELL FUNCTION. AB - Osteochondral allografting techniques are limited by the availability of suitable donor tissue; there is an urgent need for effective cryopreservation. A fundamental requirement is the need to establish initial conditions of exposure to cryoprotectant that the chondrocytes will tolerate and that load the tissue with an adequate concentration of cryoprotectant. Three vehicle solutions to transport DMSO into the tissue were studied. Knee joints were obtained from deceased donors with appropriate consent. Whole condyles were treated with 20% w/w DMSO in each of three vehicle solutions and chondrocyte function and tissue CPA content measured. The results showed that exposure to 20% DMSO in each vehicle solution for 2 hours at 0 degrees C was tolerated without loss of GAG synthetic activity. It was observed that penetration of DMSO increased little after 1 hour of CPA exposure at 0 degrees C but the final tissue concentration of CPA was markedly lower than that in the medium. PMID- 26510338 TI - CRYOPRESERVATION OF IN VITRO-GROWN SHOOT TIPS OF CHINESE MEDICINAL PLANT Atractylodes macrocephala KOIDZ. USING A DROPLET-VITRIFICATION METHOD. AB - BACKGROUND: Atractylodes macrocephala Koidz. is an important medicinal species from China that has been used for thousands of years for its special pharmacological antioxidant, hepatoprotective, anti-inflammatory, anti-allergic, antithrombotic, antiviral, and anticarcinogenic activities. OBJECTIVE: The aim of this research was to develop an efficient droplet-vitrification protocol for A. macrocephala shoot tips which could be used as a strategy for long-term conservation within gene banks. MATERIALS AND METHODS: The duration of preculture, loading, and PVS2 steps, as well as the recovery medium formulation, were optimized to achieve high levels of survival and regrowth for A. macrocephala shoot tips after liquid nitrogen exposure. RESULTS: Survival and regrowth levels after cryopreservation in the cultivar 'Baizhu' were as high as 76% and 62%, respectively. Thermal analysis using differential scanning calorimetry suggested that the PVS2 treatment plays a critical role for successful cryopreservation. CONCLUSION: The droplet-vitrification method established in this study could be used to cryopreserve A. macrocephala. PMID- 26510339 TI - SEASONAL CHANGES OF FATTY ACID COMPOSITION IN Thitarodes pui Larvae, A HOST OF Ophiocordyceps sinensis. AB - BACKGROUND: Thitarodes larvae are the host of Ophiocordyceps sinensis and exist in the permafrost region of the Tibetan Plateau. OBJECTIVE: To understand the adaptation mechanism of Thitarodes larvae to seasonal fluctuations of ambient temperatures in the Tibetan Plateau by studying seasonal changes of the fatty acids composition in the larvae of T. pui. MATERIALS AND METHODS: The profile of fatty acids in the 6th instar T. pui larvae collected at the mid-month in a whole year were examined by GC-MS. RESULTS: There was a negative correlation between the total lipid and ambient (soil) temperature. Further study indicated that oleic, palmitic, linoliec, palmitoleic, stearic were the major fatty acids. The ratio of unsaturated fatty acids to saturated fatty acids (U/S) and the unsaturated index (UI) in triacylglycerols remain stable during the whole year, while the U/S and UI in phospholipids vary dramatically in response to soil temperature. CONCLUSION: The fluctuations in phospholipids were attributed to seasonal changes of oleic and linoleic. The changes of the fatty acid composition may result from their adaptation to the variation of temperature in different seasons. PMID- 26510340 TI - NUMERICAL SIMULATION ON MICROWAVE REWARMING OF CRYOPRESERVED RABBIT KIDNEY WITH EMBEDDED SUPERPARAMAGNETIC NANOPARTICLES. AB - BACKGROUND: Rewarming cryopreserved organs without detrimental damages is a task full of challenging, since devitrification-associated thermal stresses can cause uncontrollable injuries. The ideal rewarming method should obtain a uniform thermal field with a rapid warming rate enough to avoid devitrification. Microwave rewarming is considered to be the most promising method to rewarm cryopreserved organs safely. However, it is difficult to accurately predict the rewarming rates and temperature gradients in cryopreserved organs since the coupling of electromagnetic field and temperature field is changing during microwave rewarming process. OBJECTIVE: This study is to evaluate the feasibility of microwave rewarming of cryopreserved rabbit kidney embedded with superparamagnetic nanoparticles in a single-mode resonant cavity (434MHz, TE101 mode). MATERIALS AND METHODS: The Finite Element Method (FEM) was used to calculate the coupling of the electromagnetic field and temperature field in a microwave system composed of a rectangular resonant cavity, an antenna source, and a frozen rabbit kidney with temperature-dependent properties. Heat generated by water molecules and nanoparticles in the electromagnetic field of microwave cavity was calculated. RESULTS: The simulation results showed that, during the rewarming process of the sample phantom without nanoparticles, the rewarming rate was 29.45 degrees C/min and the maximum temperature gradient in the sample was 2.23 degrees C/mm. With nanoparticles embedded in the sample at the same power input to the microwave cavity, the rewarming rate was increased to be 41.38 degrees C/min and the maximum temperature gradient in the sample was 1.93 degrees C/mm. CONCLUSION: The study indicates that the use of nanoparticles increases the rewarming rate and temperature uniformity. PMID- 26510341 TI - DEVELOPMENT OF A MODEL TO INVESTIGATE RED BLOOD CELL SURFACE CHARACTERISTICS AFTER CRYOPRESERVATION. AB - BACKGROUND: Maintaining cell surface properties after freezing and thawing, characterized in particular by the surface potential and associated with it cell ability to intercellular adhesion, could be used as a characteristic of successful cryopreservation. OBJECTIVE: This study was conducted to research applying different erythrocytes freezing modes and analyses the regimes cryopreservation effect on the cell surface charge and adhesion to microorganisms. MATERIALS AND METHODS: Human erythrocytes frozen by three modes. In order to determine adhesion index was used dried bacterial cells of S. thermophilus. The surface charge of erythrocytes was evaluated using Alcian blue cationic dye. RESULTS: The results showed the significant decrease in the lactobacillus adhesion to erythrocytes frozen glycerol and 1,2-propanediol. After erythrocytes were freezen with glycerol and 1,2-propanediol, the cationic dye binding to erythrocytes significantly reduced. AB binding to erythrocytes frozen with PEG-1500 does not differ from control data. CONCLUSION: Erythrocytes frozen with PEG-1500 mantained surface properties after thawing better, compared to erythrocytes cryopreserved by other methods. PMID- 26510342 TI - [Innovate, invent, discover ... research]. PMID- 26510343 TI - [Understanding nursing care in hospitals]. AB - In a context in which sanitary institutions have transparency obligations toward authorities and patients, quality management and best practices--defined according to scientific standards--have become major concerns with respect to in house management. While protocols and prescriptions are necessary for orienting work, they don't apply by themselves. Given that these various documents provide standardized and stabilized work descriptions, they contribute to hide what workers effectively do in unstable and variable situations in which numerous, sometimes contradictory, elements need to be simultaneously considered. In the present work, we follow this claim held by the French ergonomics stream and we consider the serious and irreducible gap between "prescribed work" and "real effective work". Such an understanding based on research evidence appears more adapted to professional realities and provides (valued) resources in nursing education. Based on information collected in three work analysis studies conducted by our team in hospital settings, we deepen these notions and their implication for practice and education. PMID- 26510344 TI - [Ethnography for nursing research, a sensible way to understand human behaviors in their context]. AB - Understanding human behaviours is at the heart of the nursing discipline. Knowledge development about behaviours is essential to guide nursing practice in the clinical field, for nursing education or in nursing management. In this context, ethnography is often overlooked as a research method to understand better behaviours in their sociocultural environment This article aims to present the principles guiding this qualitative method and its application to nursing research. First, the ethnographic method and some of its variants will be described. The conduct of an ethnographic study will then be exposed. Finally, examples of ethnographic studies in nursing will be presented. This article provides a foundation for the development of research protocols using ethnography for the advancement of nursing knowledge, as well as better use of ethnographic findings to improve care practices. PMID- 26510345 TI - [The journal club as a teaching strategy to develop evidence-based practice for undergraduate students in nursing]. AB - INTRODUCTION: Contemporary nursing practice requires constant updating of knowledge, especially in regards to research results found in academic or scientific papers. CONTEXT: As part of the university curriculum in nursing, students must develop their skills in relation to the understanding and evaluation of research evidence. OBJECTIVES: The objective of this study was to explore the appreciation and effects of a new teaching approach, the use of a journal club within a nursing research course, with undergraduate students in nursing sciences. METHOD: As part of a qualitative exploratory descriptive design, a questionnaire with open-ended questions about their appreciation and perception of the effects of the journal club was administered to the participating students (n = 41) at the end of the course. RESULTS: Participation in the journal club appears to have provided an introduction to the scientific area of nursing, to have improved several skills related to the evaluation of scientific articles and has increased motivation to adopt evidence-based practice. CONCLUSION: The use of a journal club within an undergraduate research course in nursing was a relevant teaching method that aroused great interest in the undergraduate students in nursing. PMID- 26510346 TI - [Identification and management of violence in psychiatry: Nurse and patient perceptions of safety and dangerousness]. AB - This paper reports the results of a study on the identification and management of violence on a psychiatric ward and in the psychiatric emergency of a Quebec hospital. The purpose of this exploratory and descriptive study was to examine patients' and nurses' perceptions and strategies for identifying and managing patient aggression and violence. Results show that the type of setting influences the way aggressive behaviour issues are perceived and managed. The types of behaviours deemed aggressive or risky also vary between the two units. Moreover, patients and nurses are similarly described by all participants as susceptible to being violent and to being a victim of violence. Prevention of aggression and violence remains a significant challenge in psychiatric nursing, where administrative and environmental constraints, the growing complexity of clinical profiles, divergent interprofessional approaches to care, and collective feelings of apprehension and vulnerability interact. PMID- 26510347 TI - [Determinants of collaborative practices in schools in promoting healthy eating and physical activity and role of the nurse in these practices]. AB - CONTEXT: Overweight and obesity rates have more than doubled among 12 to 17 year olds over the past 25 years. To date, few studies have documented collaborative practices in activities aimed at promoting healthy eating and physical activity in schools, although collaboration is a key element in health promotion. OBJECTIVES: To identify the determinants that influence collaborative practices in secondary schools. To define the role of the school nurse in these practices. METHOD: A descriptive multiple case study was conducted in three Quebec secondary schools. The methods used were: focus group; interviews (21); observation (5); and document review (3). Qualitative analysis was conducted by more than one researcher. RESULTS: Determinants of collaborative practices relate to the individual, team and organization. The time needed to adapt to a role is a determinant that influences the contribution a newly appointed school nurse can make to collaborative practices in a school setting. CONCLUSION: Understanding the determinants that influence collaborative practices paves the way to establishing the conditions conducive to various stakeholders becoming involved in promoting the health of young people. PMID- 26510348 TI - [Looking for help on the Internet by adolescents with suicidal thoughts: a concept analysis]. AB - The help-seeking concept is largely used in the healthcare system and seems relatively well understood by healthcare professionals even though no consensus on this concept has yet been reached. More specifically, the Internet help seeking concept by adolescents with suicidal thoughts has yet to be explored. To clarify this concept and eventually develop tools for future research in nursing, a concept analysis using the Walker and Avant method was conducted. Three main help-seeking attributes were identified as a result of the analysis: problem oriented, intentional action and use of an external mean. The antecedents that precede the concept are: problem recognition and perception influenced by beliefs, desired relief, help-source selection and decision to act. The consequents that follow help-seeking are relef, maintenance or exacerbation of the problem. Many empirical referents are identified but none seem to evaluate or conceptually define the attributes of the concept. Finally, a deeper meaning of Internet help-seeking by adolescents with suicidal thoughts is reached by this concept analysis and further research and practice recommendations are given. PMID- 26510349 TI - [The meaning of caregiving experience lived by Lebanese family caregivers of stroke survivors at home]. AB - Introduction six million of deaths are due today to stroke, while stroke survivors will depend on their caregivers at home. BACKGROUND: As the literature noted in, these caregivers meet challenges and satisfactions, encouraging them to resort to adaptation strategies in order to cope with their care situation. OBJECTIVE: The purpose of this article is to describe and understand the experience of Lebanese family caregivers who take care at home of a relative stroke survivor. METHOD: Using the phenomenological approach of Giorgi (1997), twelve interviews were conducted with six family caregivers who have been recruited through a rehabilitation center in Beirut. RESULTS: Eight themes have emerged from the phenomenological analysis: the family caregiver burden, the missing social support, the learning through his experience of a family caregiver, the contribution to caregiving survivor, the selflessness in the caregiving, the gratitude in the caregiving, the familiarization with new routines and reconciliation with new lifestyle. The proposed essence from this phenomenological analysis is: the satisfaction in taking care of the stoke survivor by facing challenges and bringing order into the chaos caused by the stroke. CONCLUSION: The knowledge gained from this study would allow nurses to identify family caregivers at risk in order to help them to adapt to their new role as caregivers, and to develop health promotion strategies, taking into consideration their experience. PMID- 26510350 TI - [Integration and demonstration of key techniques in surveillance and forecast of schistosomiasis in Jiangsu Province I Layout and effect of the demonstration sites for schistosomiasis surveillance and forecast]. AB - OBJECTIVE: To explore and integrate the key techniques used in the surveillance and forecast of schistosomiasis in the water regions along the Yangtze River, so as to provide technical support for identifying rapidly the risk of schistosomiasis transmission and implementing control measures targeting the risk. METHODS: According to the distribution of water systems and water regions along the Yangtze River in Jiangsu Province, the demonstration sites for surveillance and forecast of schistosomiasis were set across the province, where the integration and demonstration of the techniques regarding monitoring of Schistosoma japonicum infection in sentinel mice, human and animal activities, release of forecast information, and emergency treatment of water regions at risk of infection were performed. The pattern of human and animal activities was compared with the S. japonicum infection in sentinel mice in the demonstration sites, and the operability of the release of information and emergency treatment of the risk of S. japonicum infection was evaluated. RESULTS: A total of 50 demonstration sites for surveillance and forecast of schistosomiasis were set in fixed anchor points, opening of the navigation lock to the Yangtze River, freight terminal, agritainment places, ferry, large construction places, and places for guaranteeing the Youth Olympic Games in 23 counties (districts) of 5 cities, Jiangsu Province. During the period between May. and September, 2014, the infectivity of water body was monitored by using 5 batches of sentinel mice, with a 99.06% (4,954/5,001) gross recovery rate of mice. S. japonicum infection was detected in a demonstration site, and an infected mouse was found, with a 0.02% (1/4,933) gross positive rate of sentinel mice. The field survey showed 2 088 person-times contacting water, including 91.95% (1,920/2,088) contacting water due to the production such as capturing fish, harvesting and cultivating crops, and repairing and building boats, and 8.05% (168/2 088) contacting water due to the life activity, such as fishing, washing vegetables and playing with water. The people contacted water predominantly in August and September (49.57%). A total of 859 boats containing 1,877 boatmen were observed, 68.22% (586/859) of which were fishing boats containing 1,306 fishermen (69.58%). There were 32 sheep found in 4 demonstration sites, and 3 sheep were seen in the demonstration site with infected sentinel mouse. Four blue forecasts (emergence of water contact) and one orange forecast (S. japonicum-infected sentinel mouse detected) were released across the province, with one forecast map released which showed 5 sites with fishing and one site with sheep grazing, one emergency response system initiated, mollusciciding implemented in 10 hm2 high-risk regions, 120 sheep grazed in fence, and 35 fishermen given health-education materials, schistosomiasis examination and preventive therapy. In addition, no acute schistosomiasis occurred in the demonstration site with S. japonicum-infected sentinel mice. CONCLUSIONS: The integration and demonstration of the techniques regarding monitoring of S. japonicum infection in sentinel mice, human and animal activities, release of forecast information, and emergency treatment of water regions at risk of infection provides an effective approach for the large-scale surveillance and forecast of schistosomiasis. PMID- 26510351 TI - [Analysis of endemic changes of schistosomiasis in China from 2002 to 2010]. AB - OBJECTIVE: To provide the reference for schistosomiasis control through analyzing the changes of endemic status of schistosomiasis in China in recent years. METHODS: The annual data of schistosomiasis prevention and control from 2002 to 2012 were collected, and the descriptive analysis was conducted to describe the changes of schistosomiasis endemic status. RESULTS: Sichuan, Yunan and Jiangxi provinces reached the criteria of transmission controlled from 2002 to 2010 while Hubei, Hunan, Jiangxi and Anhui provinces reached the criteria of infection controlled in 2008. The number of counties where the transmission of schistosomiasis was controlled decreased from 110 in 2002 to 80 in 2010. The numbers of estimated schistosomiasis cases and reported acute cases fell from 810.4 thousands and 913 in 2002 to 325.8 thousands and 43 in 2010, respectively, and they were reduced by 59.79% and 95.40% respectively. The number of infected bovine went down from 23,199 in 2002 to 7,173 in 2010, with a fall of 69.03%. However, the Oncomelania hupensis snails breeding areas kept in 3.7 to 3.8 billion m2 and among which, 125 million m2 areas were newly discovered in non endemic areas during the nine years. In 2010, 90% of schistosomiasis cases, acute cases, infected bovine, and snail breeding areas were concentrated in 5 provinces, especially in the Dongting Lake and Poyang Lake areas and the regions along the Yangtze River. CONCLUSIONS: The epidemic of schistosomiasis decreased significantly from 2002 to 2010. The lake regions are the key and tough areas for schistosomiasis prevention and control. To consolidate the achievements, the surveillance and case management need to be strengthened as the extension of snail breeding areas and acute cases reported from other places becomes common. PMID- 26510352 TI - [Trend analysis of schistosomiasis endemic situation in Anhui Province from 2004 to 2014]. AB - OBJECTIVE: To analyze the changes of schistosomiasis endemic situation in Anui Province from 2004 to 2014, so as to provide the evidence for formulating "The thirteenth five year" schistosomiasis control plan. METHODS: The information for schistosomiasis control and the data of the endemic surveillance of schistosomiasis were collected and analyzed for the changes of schistosomiasis endemic situation in Anhui Province from 2004 to 2014. RESULTS: The Oncomelania hupensis snail areas presented on a rising trend, and reached to the largest area with about 3.1 billon m2in 2011. However, the snail areas decreased from 2012, and reduced by 10.55% in 2012 compared with the areas in 2011, and reduced to the lowest level in 2014 in recent 10 years. The density of living snails presented a fluctuation situation from 2004 to 2008, and on a decreasing trend from 2008, and the density of living snails was below 1 snail/0.l i2 after 2011. The infection rate of snails remained stagnant state from 2004 to 2011, and decreased rapidly in 2012, and no schistosome infected snails were found in 2013 and 2014. The schistosome infection rate of residents decreased gradually, and the number of acute schistosomiasis was under 50 cases with scattered distribution after 2006, and no acute cases occurred in 2013 and 2014. The infection rate of livestock was above 1% from 2004 to 2011, and reduced to 0.55% in 2012, and it was the first time that the infection rate of livestock was lower than that of residents in the same year in 2014. The progress for achieving the goal of schistosomiasis transmission control accelerated after 2011, and the number of counties that reached the standard of schistosomiasis transmission controlled from 2012 to 2014 was 4, 9 and 14 and the number of townships was 33, 76 and 32, respectively. CONCLUSION: Schistosomiasis control has achieved remarkable effectiveness in Anhui Province, but there still exists hard work to consolidate the achievement and reach schistosomiasis transmission interrupted. PMID- 26510353 TI - [Effect of ditching for drain on control of Oncomelania hupensis snail in beaches of Dongting Lake]. AB - OBJECTIVE: To evaluate the effect of ditching for drain on the control of the breed of Oncomelania hupensis snails in beaches of Dongting Lake. METHODS: From November, 2009 to November, 2012, an 0. hupensis snail infested beach of the Yueyang jail and an O. hupensis snail infested beach of Junshan District were selected as research fields in the eastern Dongting Lake area, and the former, as the intervention field, was performed with the ditching for drain by excavators and the latter, as the control field, was not. RESULTS: Before the project implemented, the average soil moisture contents on the beaches in dry seasons of the two fields were both about 35.56%. After the project implemented, in the intervention field, the average soil moisture content was 26.53% which was significantly lower than that (35.56%) in the control field (F = 6.53, P < 0.05). The underground water levels in different heights in the intervention field were lower than those in the control field (chi2 = 33.33, P < 0.05). Before the project implemented, the natural death rates of the snails were 0.98% and 0.89% in the two research fields respectively (P > 0.05), and after the project implemented (in 2012), no adult and young snails were found in the interventional field, but in the control field, the average densities of living snails and young snails were 29.37 snails/0.1 m2 and 213 +/- 108.45 snails/0.1 m2 respectively. CONCLUSION: The intervention of ditching for drain can decrease the soil moisture contents quickly and change the ecological condition, therefore, can control the breed of O. hupensis snails in the beaches of Dongting Lake. PMID- 26510354 TI - [Investigation of theoretical knowledge on schistosomiasis prevention and control among professionals in county level in Hunan and Hubei provinces]. AB - OBJECTIVE: To understand the knowledge level on schistosomiasis prevention and treatment among professionals of schistosomiasis endemic counties in Hunan and Hubei provinces, so as to provide the basis for the ability construction of schistosomiasis control institution. METHODS: The theoretical test was applied to investigate the mastering situation on schistosomiasis prevention and control among professionals of 12 selected schistosomiasis endemic counties in Hunan and Hubei provinces, and the results were analyzed statistically. RESULTS: Ninety-six professionals were surveyed. The average score was 66.94 +/- 11.53, in the range of 34-91, and the pass rate was 75.00%. The scoring rates of the knowledge points of the test and treatment of schistosomiasis, snail survey and killing as well as basic knowledge and laws and regulations about schistosome were 68.69%, 70.54% and 73.19%, respectively. On the knowledge points of the test and treatment of schistosomiasis and basic knowledge and laws and regulations about schistosome, the differences among different education backgrounds were significant (F = 3.337, 4.793, both P < 0.05), and the scores were higher in professionals with higher diploma. In the scores, there were no statistical differences between or among different genders, age groups, professional titles or specialties (all P > 0.05). CONCLUSION: The overall knowledge level on schistosomiasis prevention and treatment of the professionals from 12 schistosomiasis endemic counties in Hunan and Hubei provinces is low. Therefore, the learning of relative knowledge should be strengthened. PMID- 26510355 TI - [Analysis of epidemic situation of malaria in Jiangsu Province from 2005 to 2014]. AB - OBJECTIVE: To understand the epidemic situation and epidemiological characteristics of malaria in Jiangsu Province from 2005 to 2014, so as to provide the evidence for formulating and adjusting the strategies and measures on malaria elimination in this province. METHOD: The epidemiological data of malaria in Jiangsu province from 2005 to 2014 were collected, and the prevalence situation, infection sources as well as the temporal, regional and population distribution of the cases were analyzed. RESULT: A total of 5,069 malaria cases were reported in Jiangsu Province form 2005 to 2014, there were 3,422 cases (67.51%) of vivax malaria, 1,497 cases (29.53%) of falciparum malaria, and 150 cases (2.96%) that were unclassified. Among all the reported cases, 2,139 (42.20%) were local cases, 1,131 were (22.31%) imported cases from other places in China, and 1,799 (35.49%)were imported cases from abroad. There were 3,809 male cases and 1,260 female cases, with a sex ratio of 3.02:1. The patients were mainly aged from 25 to < 60 years (accounting for 67.15%), and were mainly young adult farmers (40.26%) and migrant workers (23.63%), who mainly distributed (accounting for 60.58%) in Xuzhou, Suqian, Huai'an, Suzhou and Nantong cities. The predominant malaria type from 2005 to 2009 were vivax malaria, while after 2010, it changed to falciparum malaria. CONCLUSIONS: The malaria epidemic situation has been effectively controlled in Jiangsu Province, which reflects the initiative achievements of malaria elimination. However, there are still many imported malaria cases from abroad, and the species of the Plasmodium are diverse. Therefore, the imported malaria from abroad still remains the key of malaria control in Jiangsu Province. PMID- 26510356 TI - [Establishment and application of monitoring and evaluation indicator framework for malaria elimination at province and county levels in China]. AB - OBJECTIVE: To establish a monitoring and evaluation indicator framework in the context of malaria elimination in pilot areas in China, so as to further assess the malaria elimination work in the future. METHODS: Based on the consultancy, and according to the government documents such as Action Plan for Malaria Elimination in China (2010-2020), Technical Guidance for Malaria Elimination, Programme Evaluation on Malaria Elimination, the indicators were set up at both provincial and county levels and their application was conducted in Yunnan and Anhui provinces to assess the accountability, accessibility and applicability. RESULTS: An indicator framework was built up including four key components, which were input, process, output and impact indicators, in which 95 were provincial indicators and 98 were county indicators. The completion rate of the indicators of Yunnan and Anhui provinces were 94.7% (90/95) and 95.8% (91/95) respectively; and the completion rate of indicators of Tengchong and Feidong counties were 93.9% (92/98) and 92.9% (91/98) respectively. CONCLUSION: The established indicator framework is reliable and applicable, which could effectively help to track the malaria elimination progress and identify gaps. PMID- 26510357 TI - [Investigation on human Cryptosporidium infection in local area of Anhui Province]. AB - OBJECTIVE: To investigate the status of Cryptosporidium infection in the population in the local area of Anhui Province, and discuss the risk factors of the infection, so as to provide the evidence for the prevention and treatment of cryptosporidiosis. METHODS: Qianshan County and Lingbi County of Anhui Province were selected as investigation spots, and the oocysts of Cryptosporidium in the feces of the investigation objects and the specific IgG antibody against Cryptosporidium in the serum were checked by using the pathogenic modified acid fast staining method and ELISA, respectively, so as to determine the status of Cryptosporidium infection in these investigation objects. At the same time, the questionnaire surveys were conducted in the investigation objects so as to know about the risk factors of Cryptosporidium infection. RESULTS: A total of 668 people were investigated in the two counties, 635 people received etiological examinations, and 15 people were positive with the positive rate of 2.36%; 642 people received serological examinations, and 140 people were positive with the positive rate of 21.81%; 628 people received pathogenic and serological examinations at the same time, and the examination results of the both methods showed that 12 people were positive (there were 4 people in Qianshan County and 8 people in Lingbi County) , and the positive rate was 1.94%. The rates of Cryptosporidium infection in the population of Qianshan County and Lingbi County were 1.24% (4/322) and 2.71% (8/295) respectively, and the difference had no statistical significance (P > 0.05). The single factor analysis found that the rate of Cryptosporidium infection was higher in the children and diarrhea patients; the multivariate logistics regression analysis indicated that the rate of Cryptosporidium infection was higher in the people who bred poultry and the diarrhea patients. CONCLUSIONS: The positive rate of serum antibody of Cryptosporidium in the population of the local area of Anhui Province is higher, which indicates that the previous infection is serious, and the rate of Cryptosporidium infection in human is relative to the age, diarrhea and whether there are poultries to be bred in the family, which is worthy of attention in the future prevention and treatment. PMID- 26510358 TI - [Species identification of freshwater snail Planorbella trivolvis and analysis of its potential distribution]. AB - OBJECTIVE: To identify the species classification of an ornamental Planorbidae from a flower market in Shanghai and analyze its potential distribution in China. METHODS: In August 2013, six freshwater snail specimens were collected from the Wanshang flower market. The species was identified by morphology and molecular biology. An ecological niche model was constructed based on the native geographic presence occurrence data, and projected onto the whole of China to predict the potential distribution. RESULTS: Their shell external morphology suggested that the specimens belonged to Planorbella trivolvis (Say 1817) of Planorbidae, which is native in North America. The sequence data of a fragment of the mitochondrial cytochrome c oxidase subunit I (COI) confirmed its identification. A total of 2 294 georeferenced occurrence points in North America were carried out from the Global Biodiversity Information Facility databases and 614 records with coordinates were used to produce a North American native niche model by a maximum entropy method (Maxent). The projection on China results suggested high probabilities of occurrence mostly in Henan Province and its borderland with nearby provinces. CONCLUSIONS: P. trivolvis is similarly with Biomphalaria species from shell morphology. It is the first records of the species in China, and the field dispersal is not clear. PMID- 26510359 TI - [Molecular characteristics and RNA interference efficiency of Schistosoma japonicum Sj79 gene]. AB - OBJECTIVE: To study the structural features and characteristics of a novel gene Schistosoma japonicum 79 (Sj79), and observe its effect of RNA interference (RNAi) , so as to provide the experimental basis for its further function study and mechanism study of anti reproductive development of schistosome. METHODS: The gene structure and characteristics of Sj79 were analyzed by bioinformatics methods. Then the expressions of Sj79 messenger RNA (mRNA) during the different developmental stages of schistosome were analyzed and the effects of RNAi silencing were observed by the soaking method. The transcriptional levels of Sj79 after RNAi were detected by real time PCR. RESULTS: The open reading frame of Sj79 contained 696 base pairs with an exon structure. The gene had obvious stage specificity, and its transcriptional level in mature female worms was the highest. After soaking for 3 d, the Sj79 mRNA level [ (41.0 +/- 12.3)%] in the siRNA-1 group with low dosage (20 nmol/L) was lower than that in the siRNA-NC group [(103.2 +/- 14.4)%], the difference was statistically significant (t = 3.28,P < 0.05). When with high dosage (200 nmol/L), both the Sj79 mRNA levels in the siRNA-1 group [(15.8 +/- 10.9)%] and siRNA-2 group [(11.1 +/- 8.8)%] were significantly lower than that in the siRNA-NC group [(100.1 +/- 6.3)%] (t = 13.44, 27.84, both P < 0.01). After soaking for 7 d, only the Sj79 mRNA levels in the siRNA-1 group [(43.4 +/- 4.5)%] and siRNA-2 group [(62.5 +/- 5.4)%] with low dosage were lower than that in the siRNA-NC group [(100.4 +/- 5.2)%], and the differences had statistical significance (t = 8.33, 5.07, both P < 0.01). CONCLUSION: Through this study, we have improved the mRNA sequence and genomic information of Sj79 gene, and understood its structural features, as well as selected out two effect fragments siRNA-1 and siRNA-2, which will provide the basic evidences for the further study on egg laying interference of the female adult worm of schistosome in vitro. PMID- 26510360 TI - [Recombinant expression of Schistosoma japonicum fructose-1, 6-bisphos- phate aldolase and its expression in different developmental stages of S. japonicum]. AB - OBJECTIVE: To clone, express and purify Schistosoma japonicum fructose-1, 6 bisphosphate aldolase (SjFBPA) in E. coli and observe its expression in different developmental stages of S. japonicum. METHODS: FBPA gene was amplified from S. japonicum adult worm cDNA by using PCR. The amplified product was recombined into pET28a plasmid, and inducibly expressed with IPTG in E. coli BL21. SDS-PAGE and Western blotting were employed to analyze and identify the recombinant protein SjFBPA (rSjFBPA). Then, rSjFBPA was purified by chromatographic purification and its purity was analyzed by SDS- PAGE. The protein concentration of rSjFBPA purified was measured by the BCA method. Furthermore, SjFBPA mRNA was ana- lyzed in different developmental stages of S. japonicum by RT-PCR. RESULTS: SjFBPA was successfully amplified by using PCR and identified by restriction enzyme digestion and sequencing. The Western blotting analysis confirmed that the recombinant pro- tein could specifically reactive to the anti-His-tag monoclonal antibody. The concentration of the purified recombinant protein was about 4 mg/ml. The result of RT-PCR showed that SjFBPA mRNA was expressed in cercaria, schistosomulum, adult worm and egg of S. japonicum. CONCLUSION: SjFBPA is successfully recombined and expressed in a prokaryotic system, and SjFBPA mRNA is expressed in cercaria, schistosomulum, adult worm and egg of S. japonicum. PMID- 26510361 TI - [Isolation and identification of macrophages from liver of Microtus fortis]. AB - OBJECTIVE: To separate and purify intrahepatic macrophages from Microtus fortis (Mf) and identify its phagocytosis. METHODS: The intrahepatic macrophages from Mf were separated and purified by perfusion, collagenase digestion and density gradient centrifugation. The function of the cells was identified by FACS analysis and ink phagocytosis activity. RESULTS: The macrophage cells from the liver of Mf were obtained. These cells were bright and circular, and grew adhering to the wall. The proportion of the living cells was 95%. The binding rate of these cells from Mf with anti-mouse CD14 antibody (Clone, Sa2-8) was about 50% of the rate of macrophage from C57BL/6 mice with this monoclonal antibody. The result of ink-phagocytosis experiment of macrophage cells from the liver of Mf was positive. CONCLUSION: The method above mentioned is useful to separate and purify macrophage from the liver of Mf. The study builds the foundation for further research on macrophages of Mf against Schistosomajaponicum. PMID- 26510362 TI - [Cloning, prokaryotic expression and immunological identification of Toxoplasma surface antigen IMP1]. AB - OBJECTIVE: To subelone, express and identify the immune mapped protein 1 (IMP1) which encodes a surface antigen of Toxoplasma gondii. METHODS: The cDNA of T. gondii RH strain was synthesized by reverse transcription PCR, the IMP1 open reading frame (ORF) was amplified by PCR using the T. gondii RH strain cDNA as template, the PCR products were identified by TA-cloning and sequencing, then the IMPI ORF was subcloned into the Nde I and Xho I sites of the vector pET28b, and the positive recombinant pET28b-IMP1 was identified by double-digesting and sequencing. The protein of 6 x His tagged IMP1 was inducibly expressed in E. coli strain BL21 (DE3) with isopropyl beta-D-1-thiogalactopyranoside (IPTG), and the induction time, concentration of IPTG and temperature gradients to optimize protein expression conditions were determined. After the cells carried IMP1 were induced by the optimized conditions and harvested, the resulting bacteria were suspended in resuspension buffer and lysed by sonication, and the supernatants were loaded onto the Ni2+ Chelating Sepharose Fast Flow column for affinity chromatography of the N-terminal 6 x His tagged IMP1 protein. Finally, the fusion IMP1 proteins were identified by Western blotting. RESULTS: The ORF sequence of IMP1 was successfully subcloned from the cDNA of Toxoplasma Gondii RH strain, and the amplified product was sequenced and identified, based on which the IMP1 ORF gene was inserted into the prokaryotic expression vector pET28b, and the recombinant pET28b-IMP1 was constructed successfully. The double-digesting and sequencing results indicated the validity of the recombinant vector. And the optimized conditions for the expression of IMP1 was determined, namely 0.3 mmol/L IPTG induction for 9 h at 20 degrees C. Furthermore, IMP1 protein was expressed solubly and chelated on Ni2 sepharose beads with high affinity, thus this protein could be purified efficiently by affinity chromatography. The pure fusion protein was confirmed with fine immunocompetence by SDS-PAGE and Western blotting. CONCLUSIONS: IMP1 protein can be high efficiently expressed by the E. coli prokaryotic expression systems, the protein of IMP1 is soluble and has stable characters. The study may lay a useful foundation for the following works including in vivo expression of IMP1, crystal structure study of IMP1 and anti toxoplasmosis subunit vaccine development. PMID- 26510363 TI - [Biological toxicity of heavy metals to Caenorhabditis elegans]. AB - OBJECTIVE: To evaluate the biological toxicity of heavy metals by using Caenorhabditis elegans. METHODS: The C. elegans at L4 stage were exposed to CdCl, CrCl3, As2O3, PbCh2, HgCl2 with low concentrations and M9 buffer (the control group) for 72 h, respectively, and the effects of heavy metals with different concentrations on the survival time and reproduction of C. elegans were evaluated. RESULTS: After exposure to 2.5, 10 umol/L HgCl2 and PbCl2, 10 umol/L CdCl2, and 50 umol/L CrCl3 for 72 h, respectively, the life spans and survival curves of the C. elegans were different from those in the control group, the differences were statistically significant (all P < 0.05). After exposure to CdCl2, CrCl3, As2O3, PbCl2 and HgCl2 with the con- centrations of 2.5, 50, 100 umol/L for 72 h, respectively, the generational time and brood size of C. elegans were all different from those in the control group (all P < 0.01). Among the 5 heavy metals at low concentrations, the reproduction toxicity of Hg was bigger than Pb, Cd, Cr, and the toxicity of As was the weakest. CONCLUSION: Heavy metal exposure can affect the life span and reproductive toxicity of C. elegans. PMID- 26510364 TI - [Composition and diversity of Acaroid mites' communities in indoor environments of kindergartens in Wuhu City]. AB - OBJECTIVE: To understand the breeding situation of Acaroid mites in indoor environments of kindergartens in Wuhu City, so as to provide the evidence for its prevention and control. METHODS: From March to June and September to December in 2014, dust samples were collected from 15 kindergartens of 3 ranks every month. Acaroid mites in the samples were isolated, identified and counted. RESULTS: Totally 360 samples were selected, and 169 samples (46.94%) had mite infestation. Pyroglyphidae accounted for the most in the population, with the breeding rate of 45.00%. Totally 18 504 mites were found, and Dermatophagoides farina and Dermatophagoides pteronyssinus were the dominant species, with the composition ratios of 30.21% (5 590 mites) and 17.83% (3 300 mites), respectively. The third ranked kindergartens were in the most serious situation concerning with 81.67% (98/120) of the breeding rate of Acaroid mites. The differences were statistically significant among the kindergartens with different ranks (F = 6.048, chi2 = 73.523, both P < 0.05). There were no significant differences about the Acaroid mite population among different grades in kindergartens (F = 0.132, chi2 = 2.377, both P > 0.05). CONCLUSION: Acaroid mites in the kindergartens in Wuhu City were in serious condition, and the population and species composition of Acaroid mite community is influenced by the human behavior and indoors environments. PMID- 26510365 TI - [Metorchis orientalis founded in basin of Wuhu City, Anhui Province]. AB - OBJECTIVE: To investigate the epidemic situation of Metorchis orientalis in Wuhu City, Anhui Province. METHODS: Three lakes (Fengming, Longwo and Kui lakes) were selected in Wuhu City, and the poultries around the lakes and freshwater fishes in the lakes were captured to test the infection of M. orientalis, and the infection rates were calculated. RESULTS: The adult worms of M. orientalis were found in gall bladder and hepatic duct of domestic ducks with infection rate of 16.7%. The metacercariae of M. orientalis were discovered in the muscle of Pseudorasbora parva and Pseudogobio rivularis with infection rates of 7.13% and 3.38% respectively. CONCLUSION: M. orientalis is endemic in Wuhu City, which should be paid enough attention to the animal husbandry, aquaculture and medicine. PMID- 26510366 TI - [Analysis of relationship between natural death of Oncomelania hupensis snails and water level in Eastern Dongting Lake district]. AB - OBJECTIVE: To study the reasons of natural death of Oncomelania hupensis snails by comparing the differences of the indicator days covered with water (DCW) in snail marshland and non-snail marshland around the build of Three Gorges Dam in Eastern Dongting Lake areas. METHODS: Two marshlands were selected, one was a non snail marshland (Qianliang Lake) and another was a snail marshland (Junshan Park). The measuring points were set through the mechanical sampling. The snails and elevation of the points were surveyed, and the data of the water levels from the hydrological station were collected, and then DCWs were calculated. RESULTS: From 1995 to 2013, DCWs of the marshland of natural death of snails were all more than that of the snail marshland (P < 0.01). In Qianliang Lake marshland, the difference between DCW before natural death and DCW from natural death until the dam was not significant (P = 0.23), while DCWs of the two stages both were more than that after the dam (P1 = 0.045, P2 = 0.002). Before the build of the dam, DCW of the Qianliang Lake marshland of natural death of snails was more than that after the build of the dam (P = 0.013), and there was the same situation in Junshan Park marshland (P = 0.005). The relationship between snail density and DCW was not significant in Junshan Park marshland (r(s) = 0.008, P = 0.914), and the reference range of DCW of all the measuring points was 76-251 days. CONCLUSION: In the eastern Dongting Lake district, the build of Three Gorges Dam and DCW may be not the direct factors affecting the natural death of snails and the latter may change the distribution of snails. PMID- 26510367 TI - [Research of water contact and labor practice of residents in plateau mountain schistosomiasis endemic areas in Yunnan Province]. AB - OBJECTIVE: To understand the status of water contact and labor practice of residents in plateau mountain schisto- somiasis endemic areas in Yunnan Province, so as to provide the evidence for formulating the strategy of prevention and control of schistosomiasis in the next step of work. METHODS: A total of 412 residents aged 6-65 years old in 2 villages were randomly sampled and investigated with questionnaires for their water contacts and labor practices in plateau valley schistosomiasis endem- ic areas. Then the schistosome infection status of the residents was surveyed with the indirect hemagglutination assay (IHA). RE- SULTS: Among the 412 residents investigated, the rate of water contact was 88.35%, and the main causes of water contact were watering, and swimming and playing. The percentages of residents who had schistosomiasis history were 1.16%, 0.00%, 30.80%, 3.85%, and 0 in them who had swimming and playing water-contacts, bathing, watering, washing hands, and others, respectively (chi2 = 38.96, P < 0.01). The positives of IHA in the above-mentioned residents were 18.60%, 0.00%, 37.60%, 23.08%, and 0, respectively (chi2 = 12.61, P < 0.05). CONCLUSIONS: The productive infested water contact is the main way of schistosome infection. Therefore, the changes of labor practices and water contact of the residents are very important for the ef- fective prevention and control of schistosomiasis transmission. PMID- 26510368 TI - [Observation on comprehensive control strategy for schistosomiasis with emphasis on infectious source control in Poyang Lake areas from 2009 to 2014]. AB - OBJECTIVE: To evaluate the long-term effect of the comprehensive control strategy for schistosomiasis with emphasis on infectious source control in marshland-type endemic areas of Poyang Lake. METHODS: Three heavy endemic villages with schistosomiasis in the lake areas were selected as pilots for the comprehensive control strategy which included replacing bovine with tractors and forbidding grazing on marshlands. The data of schistosome infections of residents and Oncomelania hupensis snails were collected and analyzed statistically from 2009 to 2014. RESULTS: There were no patients with schistosomiasis through feces examinations in the 3 pilot villages. The average density of live snails in Niuzhou marshland showed a decline trend and the density was stable in Liulingwei marshland. There were no infected snails in the 2 marshlands, and no schistosome adult worms were found in the sentinel rats. CONCLUSION: The implantation of the comprehensive control strategy for schistosomiasis with emphasis on infectious source control can control the prevalence of schistosomiasis during a long period. PMID- 26510369 TI - [Evaluation of implementing effects of Global Fund Malaria Program Round 1 in Junlian County, Sichuan Province]. AB - OBJECTIVE: To evaluate the implementing effects of the first round malaria control project supported by the Global Fund on malaria control in Sichuan Province, so as to provide the evidence for intensifying the control strategy of malaria. METHODS: Based on the requirements of the malaria project of Globe Fund, the comprehensive malaria control measures including case identification, health education and training for doctors were carried out. RESULTS: In 2007, the malaria incidence was 0.12/10 000, while it was 1.66/10 000 in 2002, with a reduction rate of 92.77%. The number of malaria endemic towns reduced from 13 to 2. The awareness rate of knowledge about malaria of the local residents rose from 26.86% to 79.83% (chi2 = 403.00, P < 0.01), with an increase rate of 197.21%. The awareness rate of knowledge about malaria of the students rose from 36.87% to 99.22% (chi2 = 359.62, P < 0.01), with an increase rate of 169.11%. CONCLUSIONS: With the support of Globe Fund, the transmission of malaria has been effectively controlled. The capacity of malaria control and the malaria control knowledge of the inhabitants have been enhanced. The implementation of the project has significant effects on malaria control in Sichuan Province. PMID- 26510370 TI - [A bite of parasite, experiences of application of documentaries into parasitology class teaching]. AB - Medical parasitology education has been facing some difficulties, because it is a course of wide range, lacking clinical cases and concerned specimens of parasites currently. In addition, its relationship with life is not closely enough. All these reasons may impact the effect of class education negatively. Therefore, it is important to increase the vitality of parasitology education and diversify the instructional mode by using the resources from Internet. In recent years, the Discovery Channel has uploaded a documentary Monsters Inside Me online. This documentary is high professional and closely linked with parasitology. It maintains numbers of clinical cases about parasitic diseases. Each episode is about 3 minutes and shortly enough to be introduced into class teaching. However, this resource has not been fully used in domestic temporally. We found that direct introduction of the documentary into class teaching can enrich teaching forms to attract learning interest of students, and finally improve the teaching effect of class. Above that, another popular documentary A Bite of China involves many related knowledge points of parasitology. The appropriate usage of the knowledge can build up close linkage between book and life, which is extremely helpful to give students a deep impression of parasitology. In brief, it is our strong recommendation to introduce the documentary Monsters Inside Me into class. PMID- 26510371 TI - [Effect of clinical pathway on advanced schistosomiasis patients with acites: a report of 220 cases]. AB - OBJECTIVE: To evaluate the effect of the clinical pathway on advanced schistosomiasis patients with acites. METHODS: According to the Handbook of Schistosomiasis Control, and the Clinical Pathway on Advanced Schistosomiasis in Hubei Province, the therapeutic effects, disease awareness, and the satisfaction of patients of 220 advanced schistosomiasis patients (ascitic type) who were treated by the traditional pathway in 2013 and 220 patients who treated by the clinical pathway in 2014, respectively, were evaluated and compared with the statistical method. RESULTS: As the outcomes of the patients had no significant difference between the traditional pathway therapy and the clinical pathway therapy, the average hospitalization days and medical expense were reduced when the patients were treated by the clinical pathway. The average hospitalization days were reduced to 12 days from 14 days. The average medical expense was reduced to RMB 5,800 form RMB 6,400. The average rate of awareness about the disease and the satisfaction rate of the patients were raised to 95% in the patients treated by the clinical pathway. The results of t test for the three indicators above mentioned showed significant differences between the two therapies (all P < 0.05). CONCLUSION: The clinical pathway can standardize the medical behavior and avoid the waste of medical resources, so as to improve the treatment of advanced schistosomiasis. PMID- 26510372 TI - [Measures and effect of malaria prevention and control in Libo County]. AB - OBJECTIVE: To understand the implementation status and effect of prevention and control of malaria in Libo County, so as to provide the evidence for improving the malaria elimination working. METHODS: The data about malaria from the county CDC and county hospital were collected and 16 villages from 8 townships were randomly sampled and 10 villagers of each village were investigated. Other information about the prevention and control of malaria was also investigated. RESULTS: The incidence of malaria was decreasing annually, from 5.75 per 10,000 in 2008 to zero in 2012. The malaria monitoring could be well conducted in the county and township levels. The infection source could be controlled in time. The utilization rate of anti-mosquito facilities in the residents was 93.25% and the awareness rate of knowledge about malaria prevention and control was 40.13%. CONCLUSIONS: The implementation and effect of prevention and control of malaria are satisfactory in Libo County, but the medium control is limited and the active protection consciousness of the residents is not strong. Therefore, the task of malaria elimination is still very arduous. PMID- 26510373 TI - [Progress in researches on molecular markers of Plasmodium falciparum drug resistance]. AB - Effective chemotherapy is the mainstay of malaria control. However, it is undergoing the serious threat by resis- tance of falciparum malaria to antimalarial drugs. In recent years, with the development of molecular biology technology, molec- ular markers have been widely used to monitor antimalarial drug resistance. This paper reviews the researches on the common molecular markers related to Plasmodiumfalciparum drug resistance. PMID- 26510374 TI - [Comparative analysis of epidemiological situation and trategies to control schistosomiasis between China and African countries]. AB - Schistosomiasis is a neglected tropical disease which is socioeconomically devastating and a significant cause of morbidity in endemic countries or regions. Some countries and regions have brought down the prevalence of schistosomiasis through positive prevention and control programs. However, in the past few years, with the social and economic development and globalization, re-emergence and spread of schistosomiasis led to a growing concern that new endemic areas may occur. This article analyzes the epidemiological situation and the strategies to control schistosomiasis in China and African countries. PMID- 26510375 TI - [One case of overseas imported quartan malaria]. AB - A case of overseas imported quartan malaria was reported in Weihai City. The patient worked in Africa for many years, had no blood transfusion history, and had not been to malaria endemic regions of China. In approximately half a month after returning from Africa, the patient appeared suspected malaria symptoms, such as irregular fever, sweating, and headache. The patient was diagnosed as quartan malaria by a blood test in basic hospital, reviewed with a microscope by Weihai Centre for Disease Control and Prevention, and checked through the microscopic examination of malaria diagnosis and reference laboratory and PCR amplification by Shandong Institute of Parasitic Diseases. The patient was cured after the treatment with chloroquine/ primaquine for 8 days, and did not recur in the 3-month following up. PMID- 26510376 TI - Efficient purification of ethene by an ethane-trapping metal-organic framework. AB - Separating ethene (C2H4) from ethane (C2H6) is of paramount importance and difficulty. Here we show that C2H4 can be efficiently purified by trapping the inert C2H6 in a judiciously designed metal-organic framework. Under ambient conditions, passing a typical cracked gas mixture (15:1 C2H4/C2H6) through 1 litre of this C2H6 selective adsorbent directly produces 56 litres of C2H4 with 99.95%+ purity (required by the C2H4 polymerization reactor) at the outlet, with a single breakthrough operation, while other C2H6 selective materials can only produce ca. ? litre, and conventional C2H4 selective adsorbents require at least four adsorption-desorption cycles to achieve the same C2H4 purity. Single-crystal X-ray diffraction and computational simulation studies showed that the exceptional C2H6 selectivity arises from the proper positioning of multiple electronegative and electropositive functional groups on the ultramicroporous pore surface, which form multiple C-H...N hydrogen bonds with C2H6 instead of the more polar competitor C2H4. PMID- 26510377 TI - The anterior process of the malleus in Cetartiodactyla. AB - The anterior fixation of the anterior process of the malleus has been studied in a number of Cetartiodactyla. This anterior process, also known as processus gracilis, is provided by the prearticular (gonial), a dermal bone, whereas the cartilage of Meckel becomes resorbed in perinatal ontogenetic stages. Posteriorly, the prearticular fuses with the cartilaginous caput of the malleus; rostrally, the prearticular (= processus gracilis) is always fixed to the anterior crus of the ectotympanic by an extremely thin splint (thickness < 50 MUm). From the rostral part of the processus gracilis all studied cetartiodactyls develop a processus internus of considerable size. This process was known as 'ossiculum accessorium mallei' in former times, and its homology has been disputed; from our microscopic-anatomical study we can definitely state that it is always a 'processus internus praearticularis'. This process contacts the fascia of the tensor tympani muscle. In non-ruminants, it articulates dorsally with the tegmen tympani and dorsolaterally with the ectotympanic; whereas the processus gracilis becomes more and more slender, the processus internus may grow to considerable size and normally is fused to the adjacent bones already in juveniles. However, in ruminants, the tegmen tympani tends to disappear and the processus internus praearticularis appears as relatively small bony knob at the floor of the medial cranial cavity, and it seems not to be fused to the surrounding bones; in later age stages, it may become secondarily overgrown by the petrosal. This dorsally exposed processus internus praearticularis seems to be a synapomorphy of the Ruminantia. The functional meaning of this internal process of the prearticular, which is also developed to a minor degree in Carnivora, remains unclear at the moment - but we present some speculations about this. PMID- 26510378 TI - Editorial overview: Autoimmunity. PMID- 26510379 TI - Electrical stimulation with periodic alternating intervals stimulates neuronal cells to produce neurotrophins and cytokines through activation of mitogen activated protein kinase pathways. AB - Peripheral neuropathy is a representative complication of dental surgery. Electrical therapy, based on electrical stimulation with periodic alternating intervals (ES-PAI), may promote nerve regeneration after peripheral nerve injury in a non-invasive manner, potentially providing an effective therapy for neuropathy. This study aimed to analyze the molecular mechanisms underlying the nerve recovery stimulated by ES-PAI. In brief, ES-PAI was applied to a neuronal cell line, Neuro2A, at various intensities using the pulse generator apparatus, FREUDE. Cell viability, neurotrophin mRNA expression, and cytokine production were examined using a tetrazolium-based assay, real-time RT-PCR, and ELISA, respectively. Mitogen-activated protein kinase (MAPK) signaling was assessed using flow cytometry. It was found that ES-PAI increased the viability of cells and elevated expression of nerve growth factor (NGF) and neurotrophin-3 (NT-3); ESPAI also augmented vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) expression, which was restored by addition of p38 inhibitors. Phosphorylation of p38 and extracellular signal-regulated kinase 1/2 (ERK-1/2) was augmented by ES-PAI. Hence, ES-PAI may ameliorate peripheral neuropathy by promoting neuronal cell proliferation and production of neurogenic factors by activating p38 and ERK-1/2 pathways. PMID- 26510381 TI - Fragment based G-QSAR and molecular dynamics based mechanistic simulations into hydroxamic-based HDAC inhibitors against spinocerebellar ataxia. AB - Expansion of polyglutamine (CAG) triplets within the coding gene ataxin 2 results in transcriptional repression, forming the molecular basis of the neurodegenerative disorder named spinocerebellar ataxia type-2 (SCA2). HDAC inhibitors (HDACi) have been elements of great interest in polyglutamine disorders such as Huntington's and Ataxia's. In this study, we have selected hydroxamic acid derivatives as HDACi and performed fragment-based G-QSAR, molecular docking studies and molecular dynamics simulations for elucidating the dynamic mode of action of HDACi with His-Asp catalytic dyad of HDAC4. The model was statistically validated to establish its predictive robustness. The model was statistically significant with r(2) value of .6297, cross-validated co-relation coefficient q(2) value of .5905 and pred_r(2) (predicted square co-relation coefficient) value of .85. An F-test value of 56.11 confirms absolute robustness of the model. Two combinatorial libraries comprising of 3180 compounds were created with hydroxamate moiety as the template and their pIC50 activities were predicted based on the G-QSAR model. The combinatorial library created was screened on the basis of predicted activity (pIC50), with two resultant top scoring compounds, HIC and DHC. The interaction of the compounds with His-Asp dyad in terms of H-bond interactions with His802, Asp840, Pro942, and Gly975 residues of HDAC4 was evaluated by docking and 20 ns long molecular dynamics simulations. This study provides valuable leads for structural substitutions required for hydroxamate moiety to exhibit enhanced inhibitory activity against HDAC4. The reported compounds demonstrated good binding and thus can be considered as potent therapeutic leads against ataxia. PMID- 26510380 TI - Chemosensory signalling pathways involved in sensing of amino acids by the ghrelin cell. AB - Taste receptors on enteroendocrine cells sense nutrients and transmit signals that control gut hormone release. This study aimed to investigate the amino acid (AA) sensing mechanisms of the ghrelin cell in a gastric ghrelinoma cell line, tissue segments and mice. Peptone and specific classes of amino acids stimulate ghrelin secretion in the ghrelinoma cell line. Sensing of L-Phe occurs via the CaSR, monosodium glutamate via the TAS1R1-TAS1R3 while L-Ala and peptone act via 2 different amino acid taste receptors: CaSR &TAS1R1-TAS1R3 and CaSR &GPRC6A, respectively. The stimulatory effect of peptone on ghrelin release was mimicked ex vivo in gastric but not in jejunal tissue segments, where peptone inhibited ghrelin release. The latter effect could not be blocked by receptor antagonists for CCK, GLP-1 or somatostatin. In vivo, plasma ghrelin levels were reduced both upon intragastric (peptone or L-Phe) or intravenous (L-Phe) administration, indicating that AA- sensing is not polarized and is due to inhibition of ghrelin release from the stomach or duodenum respectively. In conclusion, functional AA taste receptors regulate AA-induced ghrelin release in vitro. The effects differ between stomach and jejunum but these local nutrient sensing mechanisms are overruled in vivo by indirect mechanisms inhibiting ghrelin release. PMID- 26510382 TI - Predictors of prolonged stay in patients with community-acquired pneumonia and complicated parapneumonic effusion. AB - BACKGROUND AND OBJECTIVE: Development of CPE in CAP is associated with prolonged hospital stay and it may increase the morbidity and mortality. We aimed to identify microbiological and clinical factors that predicate a prolonged hospital admission in patients treated with a tube thoracostomy to control CPE. METHODS: This retrospective cohort included patients with CPE requiring chest tube drainage in a tertiary referral Korean hospital from 1 January 2004 to 30 July 2012. After dichotomous grouping according to the mean duration of hospital stay, clinical, laboratory and microbiological parameters were compared. RESULTS: The final analysis included 158 patients with CPE. The majority were male (130, 85.0%), and the mean age was 62.8 years. The mean duration of hospital stay was 17.7 (+/-10.2) days. The mean duration of chest tube drainage was 9.6 (+/-6.7) days. Streptococcus viridans (48.4%) was the most common pathogen. Intrapleural fibrinolysis was performed in 85 (53.8%); additional tube insertion was needed in 40 (25.3%) patients. In the multivariate analysis after adjusting for covariates, a prolonged hospital stay was associated with fever (aOR: 3.42, P = 0.02), lower PaO2 (aOR: 4.89, P = 0.007) and haemoglobin (aOR: 4.90, P = 0.003) levels, and an increased blood neutrophil fraction (aOR: 3.83, P = 0.01) on admission as well as the identification of microbes in CPE (aOR: 4.14, P = 0.03), and ineffective pleural drainage (aOR: 3.28, P = 0.03). CONCLUSIONS: This study suggests that physicians should note the clinical symptoms and laboratory findings of severe infection and effectiveness of pleural drainage to predicate which patients with a CAP needing thoracostomy for CPE will have a prolonged hospital stay. PMID- 26510383 TI - National Survey of Thai Infectious Disease Physicians on Treatment of Carbapenem Resistant Acinetobacter baumannii Ventilator-Associated Pneumonia: The Role of Infection Control Awareness. AB - OBJECTIVE To evaluate the expected and treatment outcomes of Thai infectious disease physicians (IDPs) regarding carbapenem-resistant Acinetobacter baumannii (CRAB) ventilator-associated pneumonia (VAP) METHODS From June 1, 2014, to March 1, 2015, survey data regarding the expected and clinical success rates of CRAB VAP treatment were collected from all Thai IDPs. The expected success rate was defined as the expectation of clinical response after CRAB VAP treatment for the given case scenario. Clinical success rate was defined as the overall reported success rate of CRAB VAP treatment based on the clinical practice of each IDP. The expected and clinical success rates were divided into low (80%) categories and were then compared with standard clinical response rates archived in the existing literature. RESULTS Of 183 total Thai IDPs, 111 (60%) were enrolled in this study. The median expected and clinical success rates were 68% and 58%, respectively. Using multivariate analysis, we determined that working in a hospital that implemented the standard intervention combined with an intensified infection control (IC) intervention for CRAB (adjusted odds ratio [aOR], 3.01; 95% confidence interval [CI], 1.17-7.73; P=.02) was associated with standard and high expected rates (>60%). Being a board-certified IDP (aOR, 5.76; 95% CI, 2.16 15.37; P60%). We identified a significant correlation between expected and clinical success rates (r=0.58; P<.001). CONCLUSIONS Awareness of IC among IDPs can improve physicians' expected and clinical success rates for CRAB VAP treatment, and treatment experience impacts overall treatment success. Infect. Control Hosp. Epidemiol. 2015;37(1):61-69. PMID- 26510384 TI - Distribution of single wall carbon nanotubes in the Xenopus laevis embryo after microinjection. AB - Single wall carbon nanotubes (SWCNTs) are advanced materials with the potential for a myriad of diverse applications, including biological technologies and large scale usage with the potential for environmental impacts. SWCNTs have been exposed to developing organisms to determine their effects on embryogenesis, and results have been inconsistent arising, in part, from differing material quality, dispersion status, material size, impurity from catalysts and stability. For this study, we utilized highly purified SWCNT samples with short, uniform lengths (145 +/- 17 nm) well dispersed in solution. To test high exposure doses, we microinjected > 500 ug ml(-1) SWCNT concentrations into the well-established embryogenesis model, Xenopus laevis, and determined embryo compatibility and subcellular localization during development. SWCNTs localized within cellular progeny of the microinjected cells, but were heterogeneously distributed throughout the target-injected tissue. Co-registering unique Raman spectral intensity of SWCNTs with images of fluorescently labeled subcellular compartments demonstrated that even at regions of highest SWCNT concentration, there were no gross alterations to subcellular microstructures, including filamentous actin, endoplasmic reticulum and vesicles. Furthermore, SWCNTs did not aggregate and localized to the perinuclear subcellular region. Combined, these results suggest that purified and dispersed SWCNTs are not toxic to X. laevis animal cap ectoderm and may be suitable candidate materials for biological applications. PMID- 26510385 TI - Connecting Tyrosine and Tryptophan Units of Diazonamide A and Azonazine by a Diastereodivergent Arylative Dearomatization. AB - We report the Friedel-Crafts coupling of a tyrosine unit with tryptophan-derived pyrrolindolenium ions which are configurationally stable. The reaction allowed the stereoselective and divergent access to the required quaternary stereocenters found in diazonamide A and azonazine at the junction of the tyrosine and tryptophan units. PMID- 26510386 TI - NMR characterization of HIV-1 reverse transcriptase binding to various non nucleoside reverse transcriptase inhibitors with different activities. AB - Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is an important target for antiviral therapy against acquired immunodeficiency syndrome. However, the efficiency of available drugs is impaired most typically by drug-resistance mutations in this enzyme. In this study, we applied a nuclear magnetic resonance (NMR) spectroscopic technique to the characterization of the binding of HIV-1 RT to various non-nucleoside reverse transcriptase inhibitors (NNRTIs) with different activities, i.e., nevirapine, delavirdine, efavirenz, dapivirine, etravirine, and rilpivirine. (1)H-(13)C heteronuclear single-quantum coherence (HSQC) spectral data of HIV-1 RT, in which the methionine methyl groups of the p66 subunit were selectively labeled with (13)C, were collected in the presence and absence of these NNRTIs. We found that the methyl (13)C chemical shifts of the M230 resonance of HIV-1 RT bound to these drugs exhibited a high correlation with their anti-HIV-1 RT activities. This methionine residue is located in proximity to the NNRTI-binding pocket but not directly involved in drug interactions and serves as a conformational probe, indicating that the open conformation of HIV-1 RT was more populated with NNRTIs with higher inhibitory activities. Thus, the NMR approach offers a useful tool to screen for novel NNRTIs in developing anti-HIV drugs. PMID- 26510387 TI - Identification of Acetaminophen Adducts of Rat Liver Microsomal Proteins using 2D LC-MS/MS. AB - Xenobiotic metabolism in the liver can give rise to reactive metabolites that covalently bind to proteins, and determining which proteins are targeted is important in drug discovery and molecular toxicology. However, there are difficulties in the analysis of these modified proteins in complex biological matrices due to their low abundance. In this study, an analytical approach was developed to systematically identify target proteins of acetaminophen (APAP) in rat liver microsomes (RLM) using two-dimensional chromatography and high resolution tandem mass spectrometry. In vitro microsomal incubations, with and without APAP, were digested and subjected to strong cation exchange (SCX) fractionation prior to reverse-phase UHPLC-MS/MS. Four data processing strategies were combined into an efficient label-free workflow meant to eliminate potential false positives, using peptide spectral matching, statistical differential analysis, product ion screening, and a custom-built delta-mass filtering tool to pinpoint potential modified peptides. This study revealed four proteins, involved in important cellular processes, to be covalently modified by APAP. Data are available via ProteomeXchange with identifier PXD002590. PMID- 26510388 TI - Stagewise pseudo-value regression for time-varying effects on the cumulative incidence. AB - In a competing risks setting, the cumulative incidence of an event of interest describes the absolute risk for this event as a function of time. For regression analysis, one can either choose to model all competing events by separate cause specific hazard models or directly model the association between covariates and the cumulative incidence of one of the events. With a suitable link function, direct regression models allow for a straightforward interpretation of covariate effects on the cumulative incidence. In practice, where data can be right censored, these regression models are implemented using a pseudo-value approach. For a grid of time points, the possibly unobserved binary event status is replaced by a jackknife pseudo-value based on the Aalen-Johansen method. We combine a stagewise regression technique with the pseudo-value approach to provide variable selection while allowing for time-varying effects. This is implemented by coupling variable selection between the grid times, but determining estimates separately. The effect estimates are regularized to also allow for model fitting with a low to moderate number of observations. This technique is illustrated in an application using clinical cancer registry data from hepatocellular carcinoma patients. The results are contrasted with traditional hazard-based modeling. In addition to a more straightforward interpretation, when using the proposed technique, the identification of time varying effect patterns on the cumulative incidence is seen to be feasible with a moderate number of observations. PMID- 26510389 TI - Long-term health economic benefits of sensor-augmented pump therapy vs continuous subcutaneous insulin infusion alone in type 1 diabetes: a U.K. perspective. AB - AIMS/HYPOTHESIS: Continuous subcutaneous insulin infusion (CSII) is an important treatment option for type 1 diabetes patients unable to achieve adequate glycemic control with multiple daily injections (MDI). Combining CSII with continuous glucose monitoring (CGM) in sensor-augmented pump therapy (SAP) with a low glucose-suspend (LGS) feature may further improve glycemic control and reduce the frequency of hypoglycemia. A cost-effectiveness analysis of SAP + LGS vs. CSII plus self-monitoring of blood glucose (SMBG) was performed to determine the health economic benefits of SAP + LGS in type 1 diabetes patients using CSII in the U.K. METHODS: Cost-effectiveness analysis was performed using the CORE diabetes model. Treatment effects were sourced from the literature, where SAP + LGS was associated with a projected HbA1c reduction of -1.49% vs. -0.62% for CSII, and a reduced frequency of severe hypoglycemia. The time horizon was that of patient lifetimes; future costs and clinical outcomes were discounted at 3.5% and 1.5% per annum, respectively. RESULTS: Projected outcomes showed that SAP + LGS was associated with higher mean quality-adjusted life expectancy (17.9 vs. 14.9 quality-adjusted life years [QALYs], SAP + LGS vs. CSII), and higher life expectancy (23.8 vs. 21.9 years), but higher mean lifetime direct costs (GBP 125,559 vs. GBP 88,991), leading to an incremental cost-effectiveness ratio (ICER) of GBP 12,233 per QALY gained for SAP + LGS vs. CSII. Findings of the base case analysis remained robust in sensitivity analyses. CONCLUSIONS/INTERPRETATION: For UK-based type 1 diabetes patients with poor glycemic control, the use of SAP + LGS is likely to be cost-effective compared with CSII plus SMBG. PMID- 26510390 TI - Electrochemical/mechanical coupling in ion-conducting soft matter. AB - Mechanical and electrochemical phenomena exhibit many interesting multidirectional couplings in ion-exchange soft matter due to their intrinsic material physiochemical states and responses to environmental stressors. In this Perspective, such coupling is explored in terms of recent studies with a focus on the degradation of polymer-electrolyte fuel-cell membranes. In addition, (electro)chemical-mechanical coupling of ion-conducting polymers in other applications is also introduced, as there is a research need to explore the interactions between these often wrongly assumed disparate fields in order to optimize, exploit, and discover new technologies and applications. PMID- 26510391 TI - Protein-protein interactions as drug targets. AB - Modulation of protein-protein interactions (PPIs) is becoming increasingly important in drug discovery and chemical biology. While a few years ago this 'target class' was deemed to be largely undruggable an impressing number of publications and success stories now show that targeting PPIs with small, drug like molecules indeed is a feasible approach. Here, we summarize the current state of small-molecule inhibition and stabilization of PPIs and review the active molecules from a structural and medicinal chemistry angle, especially focusing on the key examples of iNOS, LFA-1 and 14-3-3. PMID- 26510392 TI - Renormalization group invariance and optimal QCD renormalization scale-setting: a key issues review. AB - A valid prediction for a physical observable from quantum field theory should be independent of the choice of renormalization scheme--this is the primary requirement of renormalization group invariance (RGI). Satisfying scheme invariance is a challenging problem for perturbative QCD (pQCD), since a truncated perturbation series does not automatically satisfy the requirements of the renormalization group. In a previous review, we provided a general introduction to the various scale setting approaches suggested in the literature. As a step forward, in the present review, we present a discussion in depth of two well-established scale-setting methods based on RGI. One is the 'principle of maximum conformality' (PMC) in which the terms associated with the beta-function are absorbed into the scale of the running coupling at each perturbative order; its predictions are scheme and scale independent at every finite order. The other approach is the 'principle of minimum sensitivity' (PMS), which is based on local RGI; the PMS approach determines the optimal renormalization scale by requiring the slope of the approximant of an observable to vanish. In this paper, we present a detailed comparison of the PMC and PMS procedures by analyzing two physical observables R(e+e-) and [Formula: see text] up to four-loop order in pQCD. At the four-loop level, the PMC and PMS predictions for both observables agree within small errors with those of conventional scale setting assuming a physically-motivated scale, and each prediction shows small scale dependences. However, the convergence of the pQCD series at high orders, behaves quite differently: the PMC displays the best pQCD convergence since it eliminates divergent renormalon terms; in contrast, the convergence of the PMS prediction is questionable, often even worse than the conventional prediction based on an arbitrary guess for the renormalization scale. PMC predictions also have the property that any residual dependence on the choice of initial scale is highly suppressed even for low-order predictions. Thus the PMC, based on the standard RGI, has a rigorous foundation; it eliminates an unnecessary systematic error for high precision pQCD predictions and can be widely applied to virtually all high energy hadronic processes, including multi-scale problems. PMID- 26510394 TI - Efficient Excited-State Symmetry Breaking in a Cationic Quadrupolar System Bearing Diphenylamino Donors. AB - We report a joint experimental and theoretical investigation of a quadrupolar D pi-A(+) -pi-D system, the electron donors being diphenylamino groups and the electron acceptor being a methylpyridinium, in comparison with the dipolar D-pi A(+) system. The emission spectra of the two compounds overlap in all the investigated solvents. This finding could be rationalized by TD-DFT calculations: the LUMO-HOMO molecular orbitals involved in the emission transition are localized on the same branch of the quadrupolar structure that becomes the fluorescent portion, corresponding to that of the single-arm compound. Excited state symmetry breaking has been rarely observed for quadrupolar systems showing negative solvatochromism and is here surprisingly revealed, even in low polarity solvents. Femtosecond transient absorption measurements revealed that an efficient photoinduced intramolecular charge transfer takes place in the quadrupolar chromophore, more efficient than in its dipolar analogue. This result is promising in view of the application of these compounds as novel two-photon absorbing materials. PMID- 26510393 TI - Gut microbe-derived extracellular vesicles induce insulin resistance, thereby impairing glucose metabolism in skeletal muscle. AB - Gut microbes might influence host metabolic homeostasis and contribute to the pathogenesis of type 2 diabetes (T2D), which is characterized by insulin resistance. Bacteria-derived extracellular vesicles (EVs) have been suggested to be important in the pathogenesis of diseases once believed to be non-infectious. Here, we hypothesize that gut microbe-derived EVs are important in the pathogenesis of T2D. In vivo administration of stool EVs from high fat diet (HFD) fed mice induced insulin resistance and glucose intolerance compared to regular diet (RD)-fed mice. Metagenomic profiling of stool EVs by 16S ribosomal DNA sequencing revealed an increased amount of EVs derived from Pseudomonas panacis (phylum Proteobacteria) in HFD mice compared to RD mice. Interestingly, P. panacis EVs blocked the insulin signaling pathway in both skeletal muscle and adipose tissue. Moreover, isolated P. panacis EVs induced typical diabetic phenotypes, such as glucose intolerance after glucose administration or systemic insulin injection. Thus, gut microbe-derived EVs might be key players in the development of insulin resistance and impairment of glucose metabolism promoted by HFD. PMID- 26510395 TI - The Relationship of Longitudinal Levels of Complement Bb During Pregnancy with Preeclampsia. AB - PROBLEM: To determine the understudied relationship between complement Bb during pregnancy in subjects with preeclampsia compared with normotensive controls. METHOD OF STUDY: Nested case-control study. RESULTS: Average Bb levels significantly decreased over time in pregnancy [weekly slope (S.E.): -0.0094 (0.0005), P < 0.01]. Cross-sectionally, at less than 10 weeks, Bb levels decreased with increasing gestational age in women who remained normotensive [weekly slope (S.E.): -0.007 (0.02) and for women who developed preeclampsia (weekly slope (S.E.): -0.059 (0.03) P = 0.12]. Among women who developed preeclampsia, Bb levels were greatest when samples were drawn in the gestational window of 15-20 weeks [(weekly slope (S.E.): 0.06 (0.02)], while levels among normotensive women were inversely related with gestational age [weekly slope (S.E.): -0.02 (0.01)]. The differences in slopes between cases and controls between 10 and 21 weeks' gestation were statistically significant (P = 0.003). CONCLUSIONS: We suggest dysregulation of Bb activation between 10 and 20 weeks' gestation in women who develop preeclampsia. PMID- 26510396 TI - Inactivation of TGFbeta receptor II signalling in pancreatic epithelial cells promotes acinar cell proliferation, acinar-to-ductal metaplasia and fibrosis during pancreatitis. AB - Determining signalling pathways that regulate pancreatic regeneration following pancreatitis is critical for implementing therapeutic interventions. In this study we elucidated the molecular mechanisms underlying the effects of transforming growth factor-beta (TGFbeta) in pancreatic epithelial cells during tissue regeneration. To this end, we conditionally inactivated TGFbeta receptor II (TGFbeta-RII) using a Cre-LoxP system under the control of pancreas transcription factor 1a (PTF1a) promoter, specific for the pancreatic epithelium, and evaluated the molecular and cellular changes in a mouse model of cerulein induced pancreatitis. We show that TGFbeta-RII signalling does not mediate the initial acinar cell damage observed at the onset of pancreatitis. However, TGFbeta-RII signalling not only restricts acinar cell replication during the regenerative phase of the disease but also limits ADM formation in vivo and in vitro in a cell-autonomous manner. Analyses of molecular mechanisms underlying the observed phenotype revealed that TGFbeta-RII signalling stimulates the expression of cyclin-dependent kinase inhibitors and intersects with the EGFR signalling axis. Finally, TGFbeta-RII ablation in epithelial cells resulted in increased infiltration of inflammatory cells in the early phases of pancreatitis and increased activation of pancreatic stellate cells in the later stages of pancreatitis, thus highlighting a TGFbeta-based crosstalk between epithelial and stromal cells regulating the development of pancreatic inflammation and fibrosis. Collectively, our data not only contribute to clarifying the cellular processes governing pancreatic tissue regeneration, but also emphasize the conserved role of TGFbeta as a tumour suppressor, both in the regenerative process following pancreatitis and in the initial phases of pancreatic cancer. PMID- 26510397 TI - A high-throughput RNA-seq approach to profile transcriptional responses. AB - In recent years RNA-seq protocols have been developed to investigate a variety of biological problems by measuring the abundance of different RNAs. Many study designs involve performing expensive preliminary studies to screen or optimize experimental conditions. Testing a large number of conditions in parallel may be more cost effective. For example, analyzing tissue/environment-specific gene expression generally implies screening a large number of cellular conditions and samples, without prior knowledge of which conditions are most informative (e.g., some cell types may not respond to certain treatments). To circumvent these challenges, we have established a new two-step high-throughput RNA-seq approach: the first step consists of gene expression screening of a large number of conditions, while the second step focuses on deep sequencing of the most relevant conditions (e.g., largest number of differentially expressed genes). This study design allows for a fast and economical screen in step one, with a more efficient allocation of resources for the deep sequencing of the most biologically relevant libraries in step two. We have applied this approach to study the response to 23 treatments in three lymphoblastoid cell lines demonstrating that it should also be useful for other high-throughput transcriptome profiling applications requiring iterative refinement or screening. PMID- 26510398 TI - Melatonergic system-based two-gene index is prognostic in human gliomas. AB - Gliomas, the most common primary brain tumors in adults, are classified into four malignancy grades according to morphological features. Recent studies have shown that melatonin treatment induces cytotoxicity in glioma-initiating cells and reduces the invasion and migration of glioma cell lines, inhibiting the nuclear factor kappaB (NFkappaB) oncopathway. Given that C6 rat glioma cells produce melatonin, we investigated the correlation between the capacity of gliomas to synthesize/metabolize melatonin and their overall malignancy. We first characterized the melatonergic system of human gliomas cell lines with different grades of aggressiveness (HOG, T98G, and U87MG) and demonstrated that glioma synthesized melatonin exerts an autocrine antiproliferative effect. Accordingly, the sensitivity to exogenous melatonin was higher for the most aggressive cell line, U87MG, which synthesized/accumulated less melatonin. Using The Cancer Genome Atlas RNAseq data of 351 glioma patients, we designed a predictive model of the content of melatonin in the tumor microenvironment, the ASMT:CYP1B1 index, combining the gene expression levels of melatonin synthesis and metabolism enzymes. The ASMT:CYP1B1 index negatively correlated with tumor grade, as well as with the expression of pro-proliferation and anti-apoptotic NFkappaB target genes. More importantly, the index was a grade- and histological type-independent prognostic factor. Even when considering only high-grade glioma patients, a low ASMT:CYP1B1 value, which suggests decreased melatonin and enhanced aggressiveness, was strongly associated with poor survival. Overall, our data reveal the prognostic value of the melatonergic system of gliomas and provide insights into the therapeutic role of melatonin. PMID- 26510399 TI - Endomyocardial biopsy safety and clinical yield in pediatric myocarditis: An Italian perspective. AB - OBJECTIVES: The objective of this investigation is to evaluate the safety, the impact of endomyocardial biopsy (EMB) results in myocarditis management and the incidence of different etiologies of myocarditis in a pediatric population. BACKGROUND: Although EMB is an established diagnostic tool to evaluate suspected myocarditis, there is lack of clear diagnostic and management guidelines for myocarditis in pediatric patients, particularly in infants. METHODS: We performed a retrospective database review and subsequent outcomes analysis from five Italian pediatric cardiology centers to identify patients aged 0-18 years who underwent EMB for suspected myocarditis or inflammatory cardiomyopathy (ICMP) between 2009 and 2011. RESULTS: EMB was performed in 41 children, of which 16 were male. The population ranged between 16 days of age to 17 years (mean age at EMB = 5.2 +/- 4.9 years). The overall incidence of EMB-related complications was 15.5% (31.2% in infants, and 6.8% in children > 1 year of age; P = 0.079) while the incidence of EMB-driven treatment changes was 29.2%. Histological examination together with PCR on heart biopsy specimens allowed an etiological diagnosis in 26/41 patients (63%). Among the 15 patients (36.5%) with diagnosis of dilated cardiomyopathy (DCM) 11 had idiopathic DCM. Finally, we found an overall incidence of death/cardiac transplantation of 24%. CONCLUSIONS: In a pediatric population with suspected myocarditis/ICMP, EMB was useful in confirming the diagnosis only in 41% of cases but showed an overall diagnostic power of 63%. As complications of EBM are not negligible, particularly in infants, the risk/benefit ratio should be taken into account in each patient. PMID- 26510400 TI - Reduction of MDHAR activity in cherry tomato suppresses growth and yield and MDHAR activity is correlated with sugar levels under high light. AB - Ascorbate is oxidized into the radical monodehydroascorbate (MDHA) through ascorbate oxidase or peroxidase activity or non-enzymatically by reactive oxygen species. Regeneration of ascorbate from MDHA is ensured by the enzyme MDHA reductase (MDHAR). Previous work has shown that growth processes and yield can be altered by modifying the activity of enzymes that recycle ascorbate; therefore, we have studied similar processes in cherry tomato (Solanum lycopersium L.) under or overexpressing MDHAR. Physiological and metabolic characterization of these lines was carried out under different light conditions or by manipulating the source-sink ratio. Independently of the light regime, slower early growth of all organs was observed in MDHAR silenced lines, decreasing final fruit yield. Photosynthesis was altered as was the accumulation of hexoses and sucrose in a light-dependent manner in plantlets. Sucrose accumulation was also repressed in young fruits and final yield of MDHAR silenced lines showed a stronger decrease under carbon limitation, and the phenotype was partially restored by reducing fruit load. Ascorbate and MDHA appear to be involved in control of growth and sugar metabolism in cherry tomato and the associated enzymes could be potential targets for yield improvement. PMID- 26510401 TI - Separation of cancer cells from white blood cells by pinched flow fractionation. AB - In this paper, the microfluidic size-separation technique pinched flow fractionation (PFF) is used to separate cancer cells from white blood cells (WBCs). The cells are separated at efficiencies above 90% for both cell types. Circulating tumor cells (CTCs) are found in the blood of cancer patients and can form new tumors. CTCs are rare cells in blood, but they are important for the understanding of metastasis. There is therefore a high interest in developing a method for the enrichment of CTCs from blood samples, which also enables further analysis of the separated cells. The separation is challenged by the size overlap between cancer cells and the 10(6) times more abundant WBCs. The size overlap prevents high efficiency separation, however we demonstrate that cell deformability can be exploited in PFF devices to gain higher efficiencies than expected from the size distribution of the cells. PMID- 26510402 TI - Commentary to 'Changes in Cajal cell density in ureteropelvic junction obstruction in children'. PMID- 26510403 TI - Precise determination of N-acetylcysteine in pharmaceuticals by microchip electrophoresis. AB - A novel microchip electrophoresis method for the rapid and high-precision determination of N-acetylcysteine, a pharmaceutically active ingredient, in mucolytics has been developed. Isotachophoresis separations were carried out at pH 6.0 on a microchip with conductivity detection. The methods of external calibration and internal standard were used to evaluate the results. The internal standard method effectively eliminated variations in various working parameters, mainly run-to-run fluctuations of an injected volume. The repeatability and accuracy of N-acetylcysteine determination in all mucolytic preparations tested (Solmucol 90 and 200, and ACC Long 600) were more than satisfactory with the relative standard deviation and relative error values <0.7 and <1.9%, respectively. A recovery range of 99-101% of N-acetylcysteine in the analyzed pharmaceuticals predetermines the proposed method for accurate analysis as well. This work, in general, indicates analytical possibilities of microchip isotachophoresis for the quantitative analysis of simplified samples such as pharmaceuticals that contain the analyte(s) at relatively high concentrations. PMID- 26510404 TI - Increased Numbers of 6-sulfo LacNAc (slan) Dendritic Cells in Hand Transplant Recipients. AB - BACKGROUND: Vascularized composite allotransplantation (VCA) is a modern option for the treatment of functionally significant limb and tissue defects. In our study we aimed to characterize the morphological and histological features of the hand transplant recipient skin rejection. MATERIAL AND METHODS: We clinically evaluated the skin and mucous membranes and microscopically assessed biopsies taken from the patient's own skin and from the allogenic grafted limb (n=5). We also performed immunohistochemistry for presence of T lymphocytes (CD3, CD4, and CD8), B lymphocytes (CD20), macrophages (CD68), Langerhans cells (CD1a+), plasmacytoid dendritic cells (pDCs) (CD123+) and 6-sulfo LacNAc+ dendritic cells (slanDCs) (DD2+). RESULTS: Only scattered pDCs were present in both own and skin grafts. The number of LC in the epidermis was higher in graft skin in all cases and CD1a+ cells were also present in the dermis in transplanted skin in patients with grade 1 rejection. Most interestingly, we identified far increased numbers of dermal slanDCs in the grafted skin. SlanDCs have a high capacity to produce proinflammatory cytokines and have been described as inflammatory dermal dendritic cells in psoriasis and lupus erythematosus. CONCLUSIONS: It may be hypothesized that slanDCs identified in the skin after limb transplantation may support the local inflammatory skin reaction. PMID- 26510406 TI - A concentration dependent auto-relay-recognition by the same analyte: a dual fluorescence switch-on by hydrogen sulfide via Michael addition followed by reduction and staining for bio-activity. AB - H2S is shown, for the first time, to play an extraordinary dual role due to its nucleophilicity and reducing property with our single chemosensor, PND [4 (piperidin-1-yl) naphthalene-1,2-dione]. The initial nucleophilic attack via Michael addition (a lower concentration of H2S, blue fluorescence) is followed by the reduction of the 1,2-diketo functionality (a higher concentration of H2S, green fluorescence). This chemosensor, which also shows biological response, is remarkably effective in sensing the same analyte (H2S) at its different concentrations in a relay pathway via a fluorescence "off-on-on" mechanism, and this is also supported by DFT calculation and Cyclic voltammograms. PMID- 26510408 TI - Indirect signs of blunt duodenal injury on computed tomography: Is non-operative management safe? AB - INTRODUCTION: Clear signs of duodenal injury (DI) such as pneumoperitoneum and/or oral contrast extravasation mandate laparotomy. Management when computed tomography (CT) reveals indirect evidence of DI namely duodenal hematoma or periduodenal fluid is unclear. We evaluated the utility of indirect signs to identify DI and the success of expected management, hypothesizing patients with indirect evidence of DI on CT can be safely managed non-operatively. METHODS: We retrospectively reviewed patients with a computed tomography (CT) scan with periduodenal hematoma or periduodenal fluid treated between January 2003 and January 2013 at a level 1 Trauma Center. Demographics, injury characteristics, laboratory values, injury severity scores (ISS), and outcome measures were recorded. Patients having immediate laparotomy were compared to those initially managed nonoperatively. RESULTS: We identified 74 patients with indirect signs of DI, with 35 patients (47%) undergoing immediate operative exploration and 39 (53%) initially managed non-operatively. Lactate (4.5 mg/dL, standard deviation (SD) 2.1 vs 3.1 mg/dL, SD 1.4, p<0.001), ISS (median (IQR) 34 (27-44) vs. 24 (17 34), p=0.002) and abdominal AIS (3 (3-4) vs 2 (2-3), p<0.001) were higher in those with immediate operation. The incidence of DI requiring operative repair was 11% (8 of 74). Six of 35 (17%) explored urgently had a DI requiring repair while 29 of 35 (83%) had no DI or minor injury not requiring surgical therapy. Of those managed non-operatively, 7 of 39 (18%) failed observation but only two (5%) required duodenal repair. There was no significant difference in intensive care unit (ICU) (10.2 days, standard error [SE] 2.1 vs 9.7 days, SE 4.8, p=0.93) or hospital (22.5 days, SE 3.8 vs 23.6 days, SE 8.5, p=0.91) length of stay between those operated on immediately and those that failed non-operative management when adjusted for age, sex, and ISS. There was no mortality in the non-operative group related to an intra-abdominal injury. CONCLUSION: Observation of patients with indirect sign of DI fails in about 20% of patients, but failure rate due to DI is low at 5%. Conservative management in appropriately selected patients is reasonable with close observation. PMID- 26510409 TI - Direct transport versus inter hospital transfer of severely injured trauma patients. AB - INTRODUCTION: Several studies have suggested that severely injured patients should be transported directly to a trauma centre bypassing the nearest hospital. However, the evidence remains inconclusive. The purpose of this study was to examine the benefits in terms of mortality of direct transport to a trauma centre versus primary treatment in a level II or III centre followed by inter hospital transfer to a trauma centre for severely injured patients without Traumatic Brain Injury (TBI). PATIENTS AND METHODS: We used the regional trauma registry and included all patients with an Injury Severity Score (ISS) >15 and an Abbreviated Injury Score <4 for head injury. We adjusted for survival bias by including "potential transfers": patients who died at the nearest hospitals before transportation to a trauma centre. RESULTS: A total of 439 patients was included. The majority of patients (349/439, 79%) was transported directly to the level I trauma centre (direct group). The transferred group was formed by the remaining 90 patients, of whom 81 were transferred to the level I trauma centre after initial stabilisation elsewhere and 9 patients died in the emergency room before transfer to a level 1 trauma centre could occur. There were no significant differences in baseline and injury characteristics between the groups. Overall, 60 patients died in-hospital including 41 of the 349 patients (12%) in the direct group and 19 of the 90 patients (21%) in the transferred group. Nine of the 19 deaths in the transferred group were ascribed to potential transfers. After adjusting for prehospital Revised Trauma Score (RTS) and ISS, the odds ratio of death was 2.40 (95%CI: 1.07-5.40) for patients in the transfer group. When potential transfer patients were excluded from the analysis, the adjusted odds ratio of death was 1.14 (95%CI: 0.43-3.01). CONCLUSIONS: After adjusting for survivor bias by including potential transfers, the results of this study suggest a lower risk of death for patients who are directly transported to a level I trauma centre than for patients who receive primary treatment in a level II or III centre and are transferred to a trauma centre. However, this finding was only significant when adjusting for survival bias and therefore we conclude that it is still uncertain if there is a lower risk of death for patients who are transported directly to a level I trauma centre. PMID- 26510410 TI - Triacylglycerol composition, physico-chemical characteristics and oxidative stability of interesterified canola oil and fully hydrogenated cottonseed oil blends. AB - BACKGROUND: Partial hydrogenation process is used worldwide to produce shortening, baking, and pastry margarines for food applications. However, demand for such products is decreased during last decade due to their possible links to consumer health and disease. This has raised the need to replace hydrogenation with alternative acceptable interesterification process which has advantage in context of modifying the physico-chemical properties of edible fat-based products. Therefore, the main mandate of research was the development of functional fat through chemical interesterification of canola oil (CaO) and fully hydrogenated cottonseed oil (FHCSO) mixtures. METHODS: Blends were prepared in the proportions of 75:25 (T1), 50:50 (T2) and 25:75 (T3) of CaO:FHCSO (w/w). Interesterification was performed using sodium methoxide (0.2 %) as catalyst at 120 degrees C, under reduced pressure and constant agitation for 60 minutes. The non-interesterified and interesterified CaO:FHCSO blends were evaluated for triacylglycerol (TAG) composition, physico-chemical characteristics, oxidative stability and consumer acceptability at 0, 30 and 60 days of storage interval. RESULTS: The oleic acid (58.3 +/- 0.6 %) was predominantly present in CaO while the contents of stearic acid (72 +/- 0.8 %) were significantly higher in FHCSO. Maximum trisaturated (S3) contents (63.9 +/- 0.5 %) were found in T3 while monounsaturated (S2U), diunsaturated (U2S) and triunsaturated (U3) contents were quite low in T2 and T3 before interesterification. A marked reduction in S3 and U3 contents with concomitant increase in S2U and U2S contents was observed for all CaO:FHCSO blends on interesterification. During storage, the changes in S3, S2U and U2S contents were not found significant (p >= 0.05). However, maximum decrease 13 %, 7.5 and 5.6 % in U3 contents for T1, T2 and T3 was noted after 60 days of interesterification, respectively. The Lovibond color R, melting point, refractive index, specific gravity, peroxide and free fatty acids values of CaO:FHCSO blends decreased after interesterification and increased within the permissible limits during storage (p >= 0.05). The CaO:FHCSO blends maintained their sensory acceptability before and after interesterification which decreased significantly as storage length increased from days 30 to 60-days. Most important was the 50 % CaO:50 % FHCSO blend (T2) which possessed the desirable TAG profile, physico-chemical and sensory characteristics coming from T1 and T3. CONCLUSIONS: The present study concludes that functional lipids with desirable characteristics can be developed through interesterification of 50 % CaO:50 % FHCSO blend and should be explored as ingredient for the production of various healthier products for discerning consumers. PMID- 26510411 TI - Erratum to: Polymorphisms in GCKR, SLC17A1 and SLC22A12 were associated with phenotype gout in Han Chinese males: a case-control study. PMID- 26510413 TI - Cost-effectiveness of endovenous laser ablation of the great saphenous vein in patients with uncomplicated primary varicosis. AB - BACKGROUND: Although widely applied, the cost-effectiveness of endovenous laser ablation (EVLT) for varicose veins has not been established. METHODS: Cost effectiveness analysis was performed on the evaluation of EVLT for the treatment of uncomplicated varicose veins by using published data from randomizd clinical trials regarding the costs and the quality of life. Incremental cost per quality adjusted life year (QALY) gained at 6 months following treatment was calculated. Sensitivity analysis was carried out to investigate the uncertainty associated with the results of our analysis. RESULTS: Over the time horizon of 1-6 months, it was found that the incremental cost of EVLT compared with conventional surgery was ?466.66 and the incremental effect was -0.007 QALY at 1 month, -0.0075 QALY at 3 months and 0.0 QALY at 6 months. This shows that the strategy "EVLT" was dominated by the strategy "HL/S" at any time point for the base cases analyses. The results of various alternative economic evaluations indicated that EVLT may be a potentially cost effective (i.e. incremental cost effectiveness ratio of between ?12158.67 and ?514721.67 per QALY, respectively) treatment option compared to conventional surgical treatment for varicose veins with a certainty between 54.9 and 98.8 %. CONCLUSION: For patients with uncomplicated varicose veins and evidence of saphenofemoral reflux, surgical treatment for varicose veins offers a robust health benefit for relatively less costs compared to EVLT. PMID- 26510412 TI - Analysis of cervical resistance during continuous controllable balloon dilatation: controlled clinical and experimental study. AB - BACKGROUND: Hydraulic dilatation is a novel method of cervical dilatation that is based on continuous controllable dilatation (CCBD) by the pumping of fluid into the balloon extension of the system. The main advantage of this procedure is that it allows control of and insight into the process of cervical dilatation. METHODS: For the purposes of our research, we created a new and upgraded system for CCBD which consists of a programmed hydrostatic pump connected to a balloon extension. With regard to our aim to precisely measure and determine the location of the cervical resistance, we placed two pressure-measuring films, one on the top and one on the bottom of the balloon extension. This study included 42 patients in whom cervical resistance was measured before suction curettage. RESULTS: Cervical dilatation and measurement of cervical resistance were successful in all patients. The analysis of the pressure-measuring films showed that the points of highest resistance were located in the zone of the internal cervical os and that these values were much higher than those in the zone of the external cervical os (0.402 versus 0.264 MPa at the upper pressure-sensitive film; 0.387 versus 0.243 MPa at the lower pressure-sensitive film). This study also showed that an increase in cervical resistance in the zone of the internal cervical os was followed by an increase in cervical resistance in the zone of the external cervical os. CONCLUSIONS: During CCBD, the internal cervical os is the centre of cervical resistance, and the values do not decline with the number of miscarriages or the number of previous births. TRIAL REGISTRATION NUMBER: ISRCTN Registry identifier: ISRCTN30949871 . Date of registration: 13 May 2015. PMID- 26510407 TI - Animal models of gene-environment interaction in schizophrenia: A dimensional perspective. AB - Schizophrenia has long been considered as a disorder with multifactorial origins. Recent discoveries have advanced our understanding of the genetic architecture of the disease. However, even with the increase of identified risk variants, heritability estimates suggest an important contribution of non-genetic factors. Various environmental risk factors have been proposed to play a role in the etiopathogenesis of schizophrenia. These include season of birth, maternal infections, obstetric complications, adverse events at early childhood, and drug abuse. Despite the progress in identification of genetic and environmental risk factors, we still have a limited understanding of the mechanisms whereby gene environment interactions (G * E) operate in schizophrenia and psychoses at large. In this review we provide a critical analysis of current animal models of G * E relevant to psychotic disorders and propose that dimensional perspective will advance our understanding of the complex mechanisms of these disorders. PMID- 26510415 TI - Perceptions and acceptability of pictorial health warning labels vs text only--a cross-sectional study in Lao PDR. AB - BACKGROUND: In Lao PDR, health warnings were first introduced with printed warning messages on the side of the cigarette package in 1993 and again in 2004. Lao PDR same year ratified the Framework Convention on Tobacco Control (WHO FCTC) but has not yet implemented pictorial health warnings. This paper aims to examine the perception and opinion of policymakers on "text-only" and "pictorial" health warnings and to understand lay people's perceptions on current health warnings and their opinions on the recommended types of health warnings. METHODS: A combination of quantitative and qualitative methods were used in this cross sectional study conducted in 2008. A purposive sample of 15 policymakers, and a representative sample of 1360 smokers and non-smokers were recruited. A range of different areas were covered including consumer attitudes towards current and proposed cigarette package design, views on health warning messages on the flip/slide and inserts, and views on the relative importance of the size, content and pictures of health warning messages. Descriptive statistics and content analysis were used. RESULTS: Policy makers and survey respondents said that the current health warning messages were inappropriate, ineffective, and too small in size. All respondents perceived pictorial health warnings as a potentially powerful element that could be added to the messages that can communicate quickly, and dramatically. The majority of policymakers and survey respondents strongly supported the implementation of pictorial health warnings. The non smokers agreed that the graphic pictorial health warnings were generally more likely than written health warnings to stimulate thinking about the health risks of smoking, by conveying potential health effects, increasing and reinforcing awareness of the negative health effect of smoking, aiding memorability of the health effects and arousing fear of smoking among smokers. CONCLUSIONS: The study suggested that current warnings are too small and that content is inadequate and designed to be hidden on the side pack. These findings are in line with FCTC's requirements and provide strong support for introducing pictorial warning labels also in Lao PDR. Furthermore, the awareness of Members of Parliament about tobacco control measures holds promise at the highest political level. PMID- 26510414 TI - The prevalence of malaria at first antenatal visit in Blantyre, Malawi declined following a universal bed net campaign. AB - BACKGROUND: Preventing malaria during pregnancy is important for the health of mothers and newborns. Interventions, which include distribution of bed nets and administration of intermittent preventive treatment (IPT), typically occur at the first antenatal visit, usually in the second or third trimester of pregnancy. In 2012, during the course of ongoing clinical studies of malaria among pregnant women in Malawi, a universal bed net campaign was implemented by the Government. This study tested the hypothesis that a universal bed net campaign would decrease the prevalence of malaria among pregnant women at their first antenatal visit. METHODS: Some 1661 women were recruited for two studies from 2009 to 2014. Quantitative PCR (qPCR) was conducted from dried blood spots collected at the first antenatal care visit (prior to administration of IPT or any study interventions) from women who were in their first or second pregnancy and less than 28 weeks gestation by clinical assessment. RESULTS: Overall, 320 of 1629 (19.6 %) women tested for malaria at their first antenatal visit were infected. Malaria infection rates declined from 28.4 % before the universal bed net campaign, to 18.5 % in 2012, to 15.0 % in the years following the universal bed net campaign. The odds of malaria infection at the time of first antenatal visit in 2012 and the years following the bed net campaign were significantly lower than in the years prior to the intervention (OR 0.6, 95 % CI 0.4-0.8; and OR 0.4, 95 % CI 0.3-0.6, respectively). A similar pattern was observed for the prevalence of clinical malaria. The inverse trend was observed for reported bed net use. However bed net use and malaria infection were not significantly associated on the individual level. CONCLUSIONS: Malaria infection in pregnant women is common even after a bed net campaign in Malawi, though prevalence rates declined. These early infections may cause maternal anaemia and placental malaria resulting in adverse maternal and fetal outcomes. Infection early in pregnancy may also contribute to malaria transmission as pregnant women represent a significant untreated reservoir of parasites. Universal bed net distribution appears to have moderate success in preventing malaria early in pregnancy and these findings support continued efforts to target women early in pregnancy and all women of childbearing age. PMID- 26510416 TI - Employment and income among first-time cases diagnosed with non-affective psychosis in Stockholm, Sweden: a follow-up study 2004/2005-2010. AB - PURPOSE: Non-affective psychoses (F20-F29) are serious conditions causing a high degree of disability. Loss of income and increasing costs for personal care and treatment are severe consequences following the disorders, but less is known about employment and income in different social strata. The aim was to study these conditions among persons with non-affective psychosis compared to the general population, and possible social differentials. METHODS: A population based follow-up study with 530,350 persons (aged 18-44), including 756 first-time cases diagnosed with non-affective psychosis registered in in- or outpatient psychiatric care in 2005 or 2006. Age-standardised rates of non-employment, disability pension, social assistance and poverty were calculated at baseline and at follow-up in 2010. Odds ratios of poverty were estimated using logistic regression, adjusting for employment status, age, education and country of birth. RESULTS: Before diagnosis, rates of non-employment, disability pension and social assistance were higher among persons with non-affective psychosis compared to the general population. At the follow-up, rates of disability pension had doubled, most pronounced among women with only compulsory education. Rates of social assistance were twice as high for foreign-born women. Among persons with non affective psychosis, non-employment, lower education (among men) and being foreign born (among women) were associated with an increased risk of poverty at follow-up. CONCLUSIONS: Poor employment and income conditions were found among persons with non-affective psychosis, but the social insurance system seemed to alleviate the poor income conditions. Early and preventative support to encourage employment and income security is needed, which could support recovery. PMID- 26510417 TI - Perceptions of public attitudes towards persons with mental illness in Beijing, China: results from a representative survey. AB - OBJECTIVES: Many studies have examined the general public's attitudes towards people with mental illness, but such studies are scarce in China. This study examined the perceptions of the Beijing population regarding their society's prevalent attitudes towards people with mental illness. METHODS: A total of 5000 individuals aged 18 or above living in Beijing were selected using a multistage, stratified, cluster and random sampling method. This was followed by a face-to face interview which used a standardized questionnaire asking about societal attitudes towards individuals with mental illness. RESULTS: 4602 out of 5000 eligible individuals met the inclusion criteria and participated in the interview. 4596 questionnaires were deemed valid and included in the analyses. A large proportion of respondents believed that most individuals within their society held negative attitudes and had a strong desire to distance themselves from people with mental illness. Respondents aged 60 or older, who lived farther to downtown Beijing, or with higher education tended to believe that most individuals have relatively positive and tolerant attitudes towards people with mental illness. CONCLUSIONS: Many people in Beijing perceive that most members of their society have negative beliefs towards people with mental illness. Further efforts are needed to determine if these perceptions are accurate and to reduce the stigma that is reinforced by these perceptions. PMID- 26510418 TI - The vaginal microbiome is stable in prepubertal and sexually mature Ellegaard Gottingen Minipigs throughout an estrous cycle. AB - Although the pig has been introduced as an advanced animal model of genital tract infections in women, almost no knowledge exists on the porcine vaginal microbiota, especially in barrier-raised Gottingen Minipigs. In women, the vaginal microbiota plays a crucial role for a healthy vaginal environment and the fate of sexually transmitted infections such as Chlamydia trachomatis infections. Therefore, knowledge on the vaginal microbiota is urgently needed for the minipig model. The aim of this study was to characterize the microbiota of the anterior vagina by 16 s rRNA gene sequencing in prepubertal and sexually mature Gottingen Minipigs during an estrous cycle. The dominating phyla in the vaginal microbiota consisted of Firmicutes, Proteobacteria, Actinobacteria, Bacteriodetes and Tenericutes. The most abundant bacterial families were Enterobacteriaceae, unclassified families from Gammaproteobacteria, Clostridiales Family XI Incertae Sedis, Paenibacillaceae, Lactobacillaceae, Ruminococcaceae and Syntrophaceae. We found a higher abundance of Lactobacillaceae in the prepubertal Gottingen Minipigs compared to sexually mature non-pregnant Gottingen Minipigs. However, correlation tests and diversity parameters revealed a very stable vaginal microbiota in the Gottingen Minipigs, both before and after sexual maturity and on different days throughout an estrous cycle. The vaginal microbiota in Gottingen Minipigs was not dominated by lactobacilli, as it is in women and according to our results the minipig vaginal microbiota is very stable, in opposite to women. These differences should be considered when using the minipig as a model of the genital tract in women. PMID- 26510420 TI - HDSS Profile: The Kersa Health and Demographic Surveillance System. AB - Kersa HDSS was established in 12 sub-districts of Kersa district, Eastern Hararge, Oromia Region, Ethiopia. The site is principally rural with two small towns (Kersa and Weter). The baseline census was conducted in 2007 and since then has been updated every 6 months, with registration of demographic and health events. Data are entered into the HRS-2 relational database. At baseline a total of 10,085 houses, 10,522 households and 50,830 people were registered. The sex ratio and number of persons per household were 1.0 and 5.1, respectively. At the end of 2013, the population was 60,694. Up to the end of 2013, 12,571 births and 3143 deaths were registered, respectively. Over 85% of births and deaths occurred at home. The annual net population growth ranges from 0.06 to 1.6. The majority of the population in Kersa are not working age group; hence the dependency ratio in most of the years is below 1. The total fertility rate ranges from 4.0 to 5.3. A reduction in neonatal, infant and under-five mortalities was observed. For all deaths, verbal autopsies were done. Tuberculosis is the leading cause of death among adults and malnutrition is the leading cause of death among children aged under 5 years. Kersa HDSS is ready to collaborate with interested researchers on health and demographic issues. For further details please visit: [http://www.haramaya.edu.et/research/projects/kds-hrc/]. PMID- 26510421 TI - The effect of cost-sharing in private health insurance on the utilization of health care services between private insurance purchasers and non-purchasers: a study of the Korean health panel survey (2008-2012). AB - BACKGROUND: Private health insurance in South Korea mainly functions as supplementary and complementary health insurance that compensates for insufficient coverage by National Health Insurance. However, full private coverage of public sector cost-sharing led to the problem of encouraging moral hazard-induced utilization, resulting in a policy change that occurred in October 2009. At that time, the Korean government introduced a minimum cost-sharing policy for indemnity health insurance. The purpose of this study was to analyze the effect of cost-sharing in private health insurance on health care utilization. METHODS: We analyzed data collected from the Korean Health Panel Survey from October 2008 to December 2011. We restricted the two groups to 803 purchasers with indemnity health insurance and 7023 non-purchasers who did not obtain any private health insurance. A difference-in-difference analysis was used to evaluate the effect of the 2009 policy. RESULTS: After the policy change, the utilization of outpatient visits by purchasers gradually decreased more than non purchasers (0.015 in 2009 [p = 0.758], -0.117 in 2010 [p < 0.016], and -0.140 in 2011 [p = 0.004]). However, utilization of inpatient services was not statistically significant. Notably, the magnitude of the cost-sharing effect in indemnity health insurance was stronger for those receiving medical aid. Among this group, utilization of outpatient services (after the policy change in 2009) decreased more so than non-purchasers. Patients with three or more chronic diseases have not changed their health care utilization. CONCLUSIONS: Our results implied meaningful lessons for decision-makers and future health insurance policies in Korea and other countries in terms of cost-sharing in medical care. When policy makers intend to implement the cost-sharing, a different copayment scheme is needed according to the socioeconomic status or disease severity. PMID- 26510419 TI - Occluding junctions of invertebrate epithelia. AB - Invertebrate diversity and architecture is immense. This is achieved by the organization and function of four tissue types found in most metazoan phyla epithelial, connective, muscle and nervous tissue. Epithelial tissue is found in all extant animals (parazoan and metazoan alike). Epithelial cells form cellular sheets that cover internal or external surfaces and regulate the passage of material between separated compartments. The transepithelial movement of biological material between compartments can occur across the transcellular pathway (i.e. across cells) or the paracellular pathway (i.e. between cells) and the latter is regulated by occluding junctions that typically link cells in a subapical domain. In this review, information on occluding junctions of invertebrate epithelia is consolidated and discussed in the context of morphology, ultrastructure and physiology. In addition, an overview of what is currently known about invertebrate occluding junction proteins and their role in maintaining the integrity of invertebrate epithelia and regulating the barrier properties of these tissues is presented. PMID- 26510422 TI - Integration of Ixodes ricinus genome sequencing with transcriptome and proteome annotation of the naive midgut. AB - BACKGROUND: In Europe, Ixodes ricinus ticks are the most important vectors of diseases threatening humans, livestock, wildlife and companion animals. Nevertheless, genomic sequence information is missing and functional annotation of transcripts and proteins is limited. This lack of information is restricting studies of the vector and its interactions with pathogens and hosts. Here we present and integrate the first analysis of the I. ricinus genome with the transcriptome and proteome of the unfed I. ricinus midgut. METHODS: Whole genome sequencing was performed on I. ricinus ticks and the sequences were de novo assembled. In parallel, I. ricinus ticks were dissected and the midgut transcriptome sequenced. Both datasets were integrated by transcript discovery analysis to identify putative genes and genome contigs were screened for homology. An alignment-based and a motif-search-based approach were combined for the annotation of the midgut transcriptome. Additionally, midgut proteins were identified and annotated by mass spectrometry with public databases and the in house built transcriptome database as references and results were cross validated. RESULTS: The de novo assembly of 1 billion DNA sequences to a reference genome of 393 Mb length provides an unprecedented insight into the I. ricinus genome. A homology search revealed sequences in the assembled genome contigs homologous to 89% of the I. scapularis genome scaffolds indicating coverage of most genome regions. We identified moreover 6,415 putative genes. More than 10,000 transcripts from naive midgut were annotated with respect of predicted function and/or cellular localization. By combining an alignment-based with a motif-search-based annotation approach, we doubled the number of annotations throughout all functional categories. In addition, 574 gel spots were significantly identified by mass spectrometry (p<0.05) and 285 distinct proteins expressed in the naive midgut were annotated functionally and/or for cellular localization. Our systems approach reveals a midgut metabolism of the unfed tick that is prepared to sense and process an anticipated blood meal. CONCLUSIONS: This multiple-omics study vastly extends the publicly available DNA and RNA databases for I. ricinus, paving the way for further in-depth analysis of the most important European disease vector and its interactions with pathogens and hosts. PMID- 26510423 TI - 'Munchausen syndrome': a forgotten diagnosis in the spine. AB - PURPOSE: To present the case of a patient with Munchausen's syndrome who underwent multiple surgeries in the spine before the diagnosis was made and, therefore, to highlight the importance of this obscure condition that can result in unnecessary surgical treatment. METHODS: A 44-year-old businesswoman presented with multiple episodes of low back pain and weakness in both lower limbs over past 11 years. Past history consisted of multiple hospitalizations, and three surgeries on her lumbar spine at different hospitals, with dramatic improvement in symptoms being reported each time after surgery. Clinical examination showed inconsistent and nonspecific neurological findings. Imaging studies like X-rays, magnetic resonance imaging, and all neurophysiological studies were within normal limits. RESULTS: Multi-disciplinary evaluation by a team of orthopedicians, neurologist and psychiatrist and rehabilitation specialists diagnosed it as 'Munchausen syndrome'. Only one report of this fictitious disease in spine was found in review of literature (Association AP, Diagnostic and statistical manual of mental disorders: DSM-IV-TR((r)), 2003). CONCLUSIONS: A history of multiple surgical interventions at multiple hospitals, often followed by dramatic improvement and then relapse, should trigger a suspicion of Munchausen syndrome, particularly in the scenario of normal imaging studies. Diagnosing this rare condition in spine is key to avoid unnecessary surgery. PMID- 26510424 TI - Answer to the Letter to the Editor of J. M. Duart-Clemente et al. concerning "Systematic review of the effect of dynamic fixation systems compared with rigid fixation in the anterior cervical spine" by Campos RR, Botelho RV; Eur Spine J (2014); 23(2):298-304. PMID- 26510425 TI - A rare case of coexistence of metastasis from head and neck squamous cell carcinoma and tuberculosis within a neck lymph node. AB - Coexistence of metastasis from squamous cell carcinoma and tuberculosis within lymph nodes is rare. We report a case of 86 years old woman with a mass in the left laterocervical region. The patient had undergone excision of a poorly differentiated squamous cell carcinoma from the mucosa of the left cheek, a few months before. Histological examination of a mass of few fused lymph nodes, isolated from left laterocervical lymphadenectomy, showed metastatic squamous cell carcinoma with concomitant granulomatous inflammation. A diagnosis of tuberculosis associated with malignancy was posed. The suspect was confirmed by a positive anamnestic finding of a previous tuberculosis infection. The granulomatous reaction may be associated with many types of tumor, and can be found in the draining lymph nodes. The possibility that this reaction is also due to a tuberculosis infection should be kept in mind for elderly oncology patient. PMID- 26510426 TI - Effect of pentoxifylline in proteinuric chronic kidney disease: a systematic review and meta-analysis. AB - AIM: The aim of this study was to assess the effect of pentoxifylline on proteinuria and renal function in chronic kidney disease (CKD) treatment. METHODS: We systematically searched PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov for randomized and non-randomized controlled trials comparing pentoxifylline to placebo, no treatment or renin-angiotensin system blockade in proteinuric CKD patients. The outcomes concerning proteinuria, renal function, blood pressure and adverse events were extracted. RESULTS: Twelve trials with 613 participants were identified. Pentoxifylline significantly decreased proteinuria [weighted mean difference (WMD) -0.60 g/day (95 % CI -0.84 to -0.36); p < 0.001] compared to placebo or no-treatment groups, but the decrease was not significant [WMD: 0.10 g/day (-0.34 to 0.54); p = 0.66] compared to captopril treatment. The decrease of glomerular filtration rate was significantly less [WMD: 3.67 ml/min (2.71-4.62); p < 0.001] in the pentoxifylline group than in the controls. There was no significant difference in serum creatinine [WMD: -0.03 mg/dl (-0.10 to 0.03); p = 0.28], diastolic blood pressure [WMD: 0.94 mmHg (-0.74 to 2.61); p = 0.27] and adverse events [RR: 0.89 (0.60 to 1.32); p = 0.56]. CONCLUSIONS: Pentoxifylline may decrease proteinuria and protect renal function in patients with CKD. Further studies are needed to confirm this result. PMID- 26510427 TI - The Association Between Men's Sexist Attitudes and Facial Hair. AB - Facial hair, like many masculine secondary sexual traits, plays a significant role in perceptions of an array of sociosexual traits in men. While there is consensus that beards enhance perceptions of masculinity, age, social dominance, and aggressiveness, the perceived attractiveness of facial hair varies greatly across women. Given the ease with which facial hair can be groomed and removed entirely, why should some men retain beards and others choose to remove them? We hypothesized that men with relatively sexist attitudes would be more likely to allow their facial hair to grow than men with less sexist attitudes. Men from the USA (n = 223) and India (n = 309) completed an online survey measuring demographic variables, ambivalent sexism, and facial hair status. After controlling for demographic variables, men with facial hair were significantly higher in hostile sexism than clean-shaven men; hostile sexism was a significant predictor of facial hair status over and above demographic variables; and facial hair was more frequent among ambivalent and hostile sexists than among benevolent and non-sexists. It is suggested that sexist men choose to grow facial hair because it maximizes sexual dimorphism and augments perceived masculinity and dominance. PMID- 26510428 TI - MicroRNA-129-1 acts as tumour suppressor and induces cell cycle arrest of GBM cancer cells through targeting IGF2BP3 and MAPK1. AB - BACKGROUND: MicroRNA-129-1 (miR-129-1) seems to behave as a tumour suppressor since its decreased expression is associated with different tumours such as glioblastoma multiforme (GBM). GBM is the most common form of brain tumours originating from glial cells. The impact of miR-129-1 downregulation on GBM pathogenesis has yet to be elucidated. METHODS: MiR-129-1 was overexpressed in GBM cells, and its effect on proliferation was investigated by cell cycle assay. MiR-129-1 predicted targets (CDK6, IGF1, HDAC2, IGF2BP3 and MAPK1) were also evaluated by western blot and luciferase assay. RESULTS: Restoration of miR-129-1 reduced cell proliferation and induced G1 accumulation, significantly. Several functional assays confirmed IGF2BP3, MAPK1 and CDK6 as targets of miR-129-1. Despite the fact that IGF1 expression can be suppressed by miR-129-1, through 3' untranslated region complementary sequence, we could not find any association between IGF1 expression and GBM. MiR-129-1 expression inversely correlates with CDK6, IGF2BP3 and MAPK1 in primary clinical samples. CONCLUSION: This is the first study to propose miR129-1 as a negative regulator of IGF2BP3 and MAPK1 and also a cell cycle arrest inducer in GBM cells. Our data suggests miR-129-1 as a potential tumour suppressor and presents a rationale for the use of miR-129-1 as a novel strategy to improve treatment response in GBM. PMID- 26510430 TI - The Assessment of the Magnitude of Frontal Plane Postural Changes in Breast Cancer Patients After Breast-Conserving Therapy or Mastectomy - Follow-up Results 1 Year After the Surgical Procedure. AB - Breast cancer is the most common malignancy in Polish women. Management of breast cancer includes surgical treatment as well as adjuvant chemotherapy, radiotherapy, hormonal therapy, and combination regimens. One of the adverse consequences of oncological management of breast cancer may involve changes in frontal plane body posture. The objective of the study was to assess the frontal plane body posture changes in women treated for breast cancer. A prospective study including 101 of female breast cancer patients subjected to surgical treatment in the period from October 2011 to October 2012 (mastectomy was performed in 51 cases while breast conserving therapy was administered in the remaining 50 cases). The body posture in the frontal plane was assessed using the computer-assisted postural assessment system with Moire fringe analysis. No statistically significant differences were observed in pre-operational postural parameters of interest. Exam II revealed highly significant differences in SLA values; results suggesting more pronounced dysfunction were observed in the MAS group. Exam III revealed highly significant differences in PIA, SH, SD and SLA values; results suggesting more pronounced dysfunction were observed in the MAS group. Undesirable postural changes occur both in women who were treated with radical mastectomy and in those who underwent breast-conserving surgery; breast conserving surgery is associated with decreased severity in postural abnormalities. PMID- 26510429 TI - Eligibility for clinical trials in primary Sjogren's syndrome: lessons from the UK Primary Sjogren's Syndrome Registry. AB - OBJECTIVE: To identify numbers of participants in the UK Primary Sjogren's Syndrome Registry (UKPSSR) who would fulfil eligibility criteria for previous/current or potential clinical trials in primary SS (pSS) in order to optimize recruitment. METHODS: We did a retrospective analysis of UKPSSR cohort data of 688 participants who had pSS with evaluable data. RESULTS: In relation to previous/current trials, 75.2% fulfilled eligibility for the Belimumab in Subjects with Primary Sjogren's Syndrome study (Belimumab), 41.4% fulfilled eligibility for the Trial of Remicade in primary Sjogren's syndrome study (Infliximab), 35.4% for the Efficacy of Tocilizumab in Primary Sjogren's Syndrome study (Tocilizumab), 31.6% for the Tolerance and Efficacy of Rituximab in Sjogren's Disease study (Rituximab), 26.9% for the Trial of anti-B-cell therapy in pSS study (Rituximab) and 26.6% for the Efficacy and Safety of Abatacept in Patients With Primary Sjogren's Syndrome study (Abatacept). If recent measures of outcome, such as the EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) score ?5 (measure of patient symptoms) and the EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) score ?5 (measure of systemic disease activity) are incorporated into a study design, with requirements for an unstimulated salivary flow >0 and anti-Ro positivity, then the pool of eligible participants is reduced to 14.3%. CONCLUSION: The UKPSSR identified a number of options for trial design, including selection on ESSDAI ?5, ESSPRI ?5 and serological and other parameters. PMID- 26510431 TI - Nutritional and therapeutic approaches to modulate NADPH oxidase-derived ROS signaling in platelets. AB - Experimental and clinical studies provided evidence that formation of intra platelet reactive oxidant species (ROS) is implicated in the process of thrombosis. Animal models demonstrated that enhanced ROS formation was associated with serious thrombotic complications and death. In recent years, nutritional and therapeutic approaches were tested to modulate ROS mediated thrombus formation. The use of a nutritional approach stems from the observation that foods rich in antioxidant elements, such as polyphenols, were able to modulate ROS formation. Similarly, some drugs used for different diseases (i.e. statins) showed the ability to modulate oxidative stress. Aim of this review is to summarize current evidences supporting the role of nutrients rich in polyphenols, such as olive oil and cocoa, and of some drugs, such as statins as antiplatelet agents interfering with the Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase signaling. Indeed, for nutrients and statins, the antiplatelet activity seems to be dependent, at least in part, upon the inhibition of platelet NADPH oxidase derived ROS formation, resulting in down-regulation of isoprostanes, which are pro-aggregating molecules, and up-regulation of nitric oxide, which is a platelet inhibitor. PMID- 26510433 TI - Protein disulfide isomerase and Nox: new partners in redox signaling. AB - Reactive oxygen species (ROS) contribute to the pathogenesis of cardiovascular disease, including hypertension, atherosclerosis, cardiac hypertrophy, heart failure and restenosis. Thiol proteins and thiol oxidoreductases are key players in cell signaling, and their altered expression and/or activity has been associated with a disrupture in cardiac and vascular homeostasis. Protein disulfide isomerase (PDI) is a thiol oxidoreductase member of the thioredoxin family that has multiple roles in cellular function. Originally discovered in the endoplasmic reticulum (ER), PDI is essential for protein folding. However, it can also be found in the cytosol and closely associated with the surface of platelets, smooth muscle cells, neutrophils and endothelial cells. On the cell surface, PDI is imperative for platelet aggregation and transnitrosation, which are related to thrombosis and control of vascular tone by nitric oxide, respectively. Furthermore, PDI signaling contributes to redox-dependent events such as smooth muscle cell migration induced by PDGF and TNFalpha-dependent angiogenesis. Studies from our group have shown that intracellular PDI regulates the expression and activity of the NADPH oxidase family of proteins (Nox), which are enzymes dedicated to ROS generation. PDI acts as a new organizer of leukocyte Nox2 by redox dependently associating with p47phox and controlling its recruitment to the plasma membrane, an essential step for assembly of the active enzyme. Such multiple effects of PDI suggest that specific targeting of this oxidoreductase could represent a new approach in the treatment of vascular disease. In this review, we present a novel role for PDI as an adaptor protein involved in redox processes and Nox signaling and propose PDI as a potential therapeutic target in the treatment of atherosclerosis, thrombosis and hypertension. PMID- 26510434 TI - NOX3-TARGETED THERAPIES FOR INNER EAR PATHOLOGIES. AB - Inner ear pathologies are associated with major morbidity and loss of life quality in affected patients. In many of these conditions, production of reactive oxygen-species (ROS) is thought to be a key pathological mechanism. While the sources of ROS are complex (including for example mitochondria), there is increasing evidence that activation of NOX enzymes, in particular NOX3, plays a key role. NOX3 is a multi-subunit NADPH oxidase, functionally and structurally closely related to NOX1 and NOX2. In both the vestibular and the cochlear compartments of the inner ear, high levels of NOX3 mRNA are expressed. In NOX3 mutant mice, the vestibular function is perturbed due to a lack of otoconia, while only minor alterations of hearing have been documented. However, there is increasing evidence that activation of NOX3 through drugs, noise and probably also aging, leads to hearing loss. Thus, NOX3 is an interesting target to treat and prevent inner ear pathologies and a few first animal models based on drug - or molecular therapy have been reported. So far however, there are no specific NOX3 inhibitors with a documented penetration into the inner ear. Nevertheless, certain antioxidants and non-specific NOX inhibitors diminish hearing loss in animal models. Development of small molecules inhibitors or molecular strategies against NOX3 could improve specificity and efficiency of redox-targeted treatments. In this review, we will discuss arguments for the involvement of NOX3 in inner ear pathologies and therapeutic approaches to target NOX3 activity. PMID- 26510432 TI - The role of Nox-mediated oxidation in the regulation of cytoskeletal dynamics. AB - Nox generated ROS, particularly those derived from Nox1, Nox2 and Nox4, have emerged as important regulators of the actin cytoskeleton and cytoskeleton supported cell functions, such as migration and adhesion. The effects of Nox derived ROS on cytoskeletal remodeling may be largely attributed to the ability of ROS to directly modify proteins that constitute or are associated with the cytoskeleton. Additionally, Nox-derived ROS may participate in signaling pathways governing cytoskeletal remodeling. In addition to these more extensively studied signaling pathways involving Nox-derived ROS, there also exist redox sensitive pathways for which the source of ROS is unclear. ROS from as of yet undetermined sources play a role in modifying, and thus regulating, the activity of several proteins critical for remodeling of the actin cytoskeleton. In this review we discuss ROS sensitive targets that are likely to affect cytoskeletal dynamics, as well as the potential involvement of Nox proteins. PMID- 26510435 TI - The role of NADPH oxidase in vascular disease--hypertension, atherosclerosis & stroke. AB - The family of NADPH oxidase (Nox) proteins plays an integral role in the homeostatic functions of the cell, including gene expression, cell migration, proliferation, senescence and inflammation. There are currently 4 isoforms (Nox1, 2, 4 and 5) that are expressed across all cell types of the vascular system and play an important role in many physiological processes such as endothelial function, vascular tone and angiogenesis. The balance between Nox derived reactive oxygen species production and their elimination by dismutase enzymes is a critical finely tuned process. It is when this balance is shifted in disease states, either leading to an over- or under-production of reactive oxygen species that vascular injury develops. To date, Nox isoforms have been linked to the development of many vascular diseases including hypertension, atherosclerosis and stroke. The contribution of each isoform to the pathophysiology of vascular disease appears to be a matter of debate with most studies suggesting that Nox1 oxidase and Nox2 oxidase play deleterious roles, whereas Nox4 oxidase potentially plays a protective role in the vasculature. This review will discuss the current knowledge on the role of Nox derived oxidative stress in the pathophysiology of various vascular diseases including hypertension and atherosclerosis. PMID- 26510436 TI - Cross-Talk Between TGF-beta and NADPH Oxidases During Liver Fibrosis and Hepatocarcinogenesis. AB - Liver fibrosis is a pathological consequence of chronic liver diseases and results from the progressive accumulation of altered extracellular matrix, highly enriched in type I and III fibrillar collagens. In advanced stages, fibrosis leads to cirrhosis, defined by abnormal liver architecture and altered vascularization. Clinical consequences of cirrhosis are failure in the synthetic function of the liver, portal hypertension, high susceptibility to infection and high risk to develop hepatocellular carcinoma (HCC). The TGF-beta family of cytokines plays essential roles in many cellular processes, including growth inhibition, cell migration and invasion, extracellular matrix remodelling and immune suppression, being involved in the maintenance of tissue homeostasis. However, TGF-betas are often continuously overexpressed in disease states, such as fibrosis, inflammation and cancer, and they play pivotal roles in the sequence of events leading to end-stage of chronic liver diseases. Reactive oxygen species (ROS) are critical intermediates in liver physiology and pathology. When the equilibrium between ROS generation and the antioxidant defence of the cell is disrupted, it results in an oxidative stress process. The NADPH oxidase (NOX) family has emerged in the last years as important source of ROS in liver pathologies. Interestingly, NOXes mediate TGF-beta actions in liver cells, such as regulation of hepatocyte growth and death, as well as activation of hepatic stellate cells to myofibroblasts, key executers of the fibrotic process. In this review we will update the relevant and differential roles of NOX isoforms during liver fibrosis and hepatocarcinogenesis, their cross-talk with the TGF-beta pathway and their potential as therapeutic targets for these diseases. PMID- 26510437 TI - Nox Inhibitors & Therapies: Rational Design of Peptidic and Small Molecule Inhibitors. AB - Oxidative stress-related diseases underlie many if not all of the major leading causes of death in United States and the Western World. Thus, enormous interest from both academia and pharmaceutical industry has been placed on the development of agents which attenuate oxidative stress. With that in mind, great efforts have been placed in the development of inhibitors of NADPH oxidase (Nox), the major enzymatic source of reactive oxygen species and oxidative stress in many cells and tissue. The regulation of a catalytically active Nox enzyme involves numerous protein-protein interactions which, in turn, afford numerous targets for inhibition of its activity. In this review, we will provide an updated overview of the available Nox inhibitors, both peptidic and small molecules, and discuss the body of data related to their possible mechanisms of action and specificity towards each of the various isoforms of Nox. Indeed, there have been some very notable successes. However, despite great commitment by many in the field, the need for efficacious and well-characterized, isoform-specific Nox inhibitors, essential for the treatment of major diseases as well as for delineating the contribution of a given Nox in physiological redox signalling, continues to grow. PMID- 26510438 TI - Enzymatic regulation and functional relevance of NOX5. AB - The NADPH oxidases (NOX) represent a family of 7 related transmembrane enzymes that share a basic structural paradigm and the common ability to utilize NADPH to synthesize superoxide and other reactive oxygen species (ROS). NOX isoforms are distinguished from each other by their amino acid sequences, expression levels in different cell types, the mechanisms of enzyme activation and the type of ROS that are generated. NOX5 was the last NOX family member to be identified and in the past decade and a half we have gained significant insights into how NOX5 produces ROS, the cell types where it is expressed and the functional significance of NOX5 in health and disease. The objective of this review is to highlight accumulated and recent knowledge of the genetic and enzymatic regulation of NOX5 and the importance of NOX5 in human physiology and pathophysiology. PMID- 26510439 TI - Redox mechanisms in pathological angiogenesis in the retina: roles for NADPH oxidase. AB - Pathological angiogenesis in the retina is a leading cause of serious vision loss in potentially blinding eye diseases, including proliferative diabetic retinopathy, retinopathy of prematurity and the wet form of age-related macular degeneration. Hypoxia is thought to be the driver of pathological angiogenesis, and transcription factors such as hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF) are key mediators in these processes. Current treatments employ either laser photocoagulation or intravitreal injection of therapeutic antibodies for VEGF, in order to arrest the growth of leaky blood vessels in the avascular vitreous cavity and to restore visual acuity. However, all such therapeutic approaches are limited by low or variable efficacy, and the inconvenience, risk and financial burden of such treatments, which need to be given frequently. The lack of noninvasive and efficacious therapy has therefore driven the search for alternative strategies. We have been interested in the roles of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, which when produced intracellularly at low concentration can act as second messengers to regulate physiological and pathological angiogenesis. Accumulating evidence suggests NADPH oxidase-dependent ROS are involved in regulation of the angiogenic signalling pathways of HIF and VEGF. Suppressing pathological neovascularisation in the retina by manipulating such redox mechanisms appears to be an attractive and clinically translatable therapeutic strategy to treat proliferative neovascular eye diseases. Here we provide a brief overview of the roles of NADPH oxidase in the sensing and regulation processes involving HIF and VEGF that contribute to the development of pathological angiogenesis in the retina. PMID- 26510440 TI - Evaluation of public involvement in research: time for a major re-think? AB - The way that public involvement in research has been evaluated as a complex intervention has derailed the development of an evidence base. Two alternative approaches are available for constructing and evaluating patient involvement, each of which requires us to revisit the purposes and values that underpin it in each stage of the research process. PMID- 26510441 TI - Navicular bone position determined by positional MRI: a reproducibility study. AB - OBJECTIVE: To examine intraobserver, interobserver and between-day reproducibility of positional MRI for evaluation of navicular bone height (NVH) and medial navicular position (MNP). MATERIALS AND METHODS: Positional MRI (pMRI) of the foot was performed on ten healthy participants (0.25 T G-scanner). Scanning was performed in supine and standing position, respectively. Two radiologists evaluated the images in a blinded manner. Reliability and agreement were assessed by calculation of intraclass correlation coefficient (ICC) and 95 % limits of agreement as a percentage of the mean (LOA%). RESULTS: Intraobserver and interobserver reliability was "substantial" in both supine and standing position (ICC 0.86-0.98) and showed good agreement (LOA% 4.9-14.7 %). Between-day reliability of navicular height and medial navicular position in standing position remained substantial (ICC 0.85-0.92) with adequate agreement (LOA% 8.3 19.8 %). In supine position between-day reliability was "moderate" for NVH (ICC 0.72) and "slight" for MNP (ICC 0.39). Agreement remained adequate between-days for MNP in supine position (LOA% 17.7 %), but it was less than adequate for NVH in supine position (LOA% 24.2 %). CONCLUSION: Navicular height and medial navicular position can be measured by pMRI in a very reproducible manner within and between observers. Increased measurement variation is observed between-days in supine position, which may be due to small positional differences or other unknown biomechanical factors. PMID- 26510442 TI - Diabetic ketoacidosis in adults. PMID- 26510443 TI - Image-based modelling of organogenesis. AB - One of the major challenges in biology concerns the integration of data across length and time scales into a consistent framework: how do macroscopic properties and functionalities arise from the molecular regulatory networks-and how can they change as a result of mutations? Morphogenesis provides an excellent model system to study how simple molecular networks robustly control complex processes on the macroscopic scale despite molecular noise, and how important functional variants can emerge from small genetic changes. Recent advancements in three-dimensional imaging technologies, computer algorithms and computer power now allow us to develop and analyse increasingly realistic models of biological control. Here, we present our pipeline for image-based modelling that includes the segmentation of images, the determination of displacement fields and the solution of systems of partial differential equations on the growing, embryonic domains. The development of suitable mathematical models, the data-based inference of parameter sets and the evaluation of competing models are still challenging, and current approaches are discussed. PMID- 26510444 TI - Benefitting from Dopant Loss and Ostwald Ripening in Mn Doping of II-VI Semiconductor Nanocrystals. AB - Annealing or growth at high temperatures for an extended period of time is considered detrimental for most synthetic strategies for high-quality Mn-doped II VI semiconductor nanocrystals. It can lead to the broadening of size distribution and, more importantly, to the loss of dopants. Here, we examine how ripening can be beneficial to doping in a simple "heat-up" approach, where high dopant concentrations can be achieved. We discuss the interplay of the loss of dopants, Ostwald ripening, and the clustering of Mn near the surface during nanocrystal growth. Smaller nanocrystals in a reaction batch, on average, exhibit higher undesirable band-edge photoluminescence (PL) and lower desirable dopant PL. The optimization of dopant loss and the removal of such smaller undesirable nanocrystals through Ostwald ripening along with surface exchange/passivation to remove Mn clustering lead to high Mn PL quantum yields (45 to 55 %) for ZnSxSe1 x, ZnS, CdS, and CdSxSe1-x host nanocrystals. These results provide an improved understanding of the doping process in a simple and potentially scalable synthetic strategy for achieving "pure" and bright dopant emission. PMID- 26510445 TI - Facile Synthesis of Porous Silicon Nanofibers by Magnesium Reduction for Application in Lithium Ion Batteries. AB - We report a facile fabrication of porous silicon nanofibers by a simple three stage procedure. Polymer/silicon precursor composite nanofibers are first fabricated by electrospinning, a water-based spinning dope, which undergoes subsequent heat treatment and then reduction using magnesium to be converted into porous silicon nanofibers. The porous silicon nanofibers are coated with a graphene by using a plasma-enhanced chemical vapor deposition for use as an anode material of lithium ion batteries. The porous silicon nanofibers can be mass produced by a simple and solvent-free method, which uses an environmental friendly polymer solution. The graphene-coated silicon nanofibers show an improved cycling performance of a capacity retention than the pure silicon nanofibers due to the suppression of the volume change and the increase of electric conductivity by the graphene. PMID- 26510446 TI - Maintaining compassion and preventing compassion fatigue: a practical guide. AB - Compassion is innate in us as human beings. Compassion can be defined as a deep awareness of the suffering of another individual, coupled with the wish to relieve it. It has been increasingly topical, recently, in situations where an apparent breathtaking absence of compassion has allowed great harm to come to patients. So, how do we sustain compassion and prevent this loss? Central to our ability to maintain compassion is how we look after ourselves and those in our teams. PMID- 26510447 TI - Where are we with RSV prophylaxis? AB - Respiratory syncytial virus (RSV) is a predictable, seasonal disease with significant morbidity and mortality in children below 24 months. Prophylaxis, which decreases hospitalisation in those most vulnerable to the disease, has been available since 1998. Pharmacological prophylaxis is however, expensive and requires good infrastructure to deliver. It is out of reach for many patients in low-income and middle-income countries where mortality is highest. This article looks at the pathophysiology and risk factors for RSV. It also outlines what agents are currently available for prophylaxis and prevention. PMID- 26510448 TI - Metformin for treatment of antipsychotic-induced weight gain in a South Asian population with schizophrenia or schizoaffective disorder: A double blind, randomized, placebo controlled study. AB - BACKGROUND: Antipsychotic-induced weight gain causes serious health problems. We investigated the efficacy and safety of metformin in treating antipsychotic induced weight gain in South Asian patients. METHODS: Sixty six adult patients with schizophrenia or schizoaffective disorder treated, with atypical antipsychotics, and who had increased by more than 10% their pre treatment body weight, were randomly assigned to receive metformin or placebo in a double-blind study. Patients received usual treatment and metformin 500 mg or placebo twice daily for 24 weeks. The primary outcome measure was change in body weight from baseline to week 24. Linear mixed models were used in the analysis. RESULTS: Mean change in body weight in the metformin group was -1.56 kg (95% CI=-3.06 to -0.05) and 1.0 kg (95% CI=0.03-1.97) in the placebo group. Between-group difference was 2.56 kg. At 24 weeks the between-group difference showed significant time-by treatment interaction (F=3.23, p=0.004). Between-group difference in BMI showed significant time-by-treatment interaction (F=3.41 p=0.03). There was no significant difference in waist-hip ratio or fasting blood sugar. CONCLUSIONS: Metformin is effective in reducing weight in South Asian patients with schizophrenia or schizoaffective disorder who had increased their body by more than 10% after treatment with atypical antipsychotics. PMID- 26510450 TI - Antipsychotic efficacy in psychosis with co-morbid cannabis misuse: A systematic review. AB - The prevalence of cannabis use in patients with psychotic mental illness is known to be high and is suspected to exacerbate symptoms and worsen prognosis. We aimed to evaluate evidence of antipsychotic efficacy in reducing the burden of psychotic symptoms and cannabis use in individuals with psychotic mental illness and co-morbid cannabis use. A systematic review was conducted of antipsychotic treatment in those with psychotic mental illness and co-morbid cannabis use. Quality of evidence for each study and outcomes were rated using the 'GRADE' approach. Twenty-two studies were identified: 13 experimental and 9 observational, including a total sample of 1543 patients, 761 of whom had a diagnosed cannabis use disorder. The most frequent antipsychotics compared were risperidone, olanzapine and clozapine with olanzapine, risperidone and haloperidol. No clear differences between antipsychotics were demonstrated. Future studies are needed to confirm whether clozapine is superior to other antipsychotics in reducing cannabis use. PMID- 26510449 TI - THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia. AB - Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. PMID- 26510451 TI - High-energy cosmic neutrino puzzle: a review. AB - We appraise the status of high-energy neutrino astronomy and summarize the observations that define the 'IceCube puzzle.' The observations are closing in on the source candidates that may contribute to the observation. We highlight the potential of multi-messenger analysis to assist in the identification of the sources. We also give a brief overview of future search strategies that include the realistic possibility of constructing a next-generation detector larger by one order of magnitude in volume. PMID- 26510452 TI - Endoscopic resection of gastric and esophageal cancer. AB - Endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) techniques have reduced the need for surgery in early esophageal and gastric cancers and thus has lessened morbidity and mortality in these diseases. ESD is a relatively new technique in western countries and requires rigorous training to reproduce the proficiency of Asian countries, such as Korea and Japan, which have very high complete (en bloc) resection rates and low complication rates. EMR plays a valuable role in early esophageal cancers. ESD has shown better en bloc resection rates but it is easier to master and maintain proficiency in EMR; it also requires less procedural time. For early esophageal adenocarcinoma arising from Barrett's, ESD and EMR techniques are usually combined with other ablative modalities, the most common being radiofrequency ablation because it has the largest dataset to prove its success. The EMR techniques have been used with some success in early gastric cancers but ESD is currently preferred for most of these lesions. ESD has the added advantage of resecting into the submucosa and thus allowing for endoscopic resection of more aggressive (deeper) early gastric cancer. PMID- 26510453 TI - Targeted therapy in gastroesophageal cancers: past, present and future. AB - Gastroesophageal cancer is a significant global problem that frequently presents at an incurable stage and has very poor survival with standard chemotherapy approaches. This review will examine the epidemiology and molecular biology of gastroesophageal cancer and will focus on the key deregulated signaling pathways that have been targeted in the clinic. A comprehensive overview of clinical data highlighting successes and failures with targeted agents will be presented. Most notably, HER2-targeted therapy with the monoclonal antibody trastuzumab has proven beneficial in first-line therapy and has been incorporated into standard practice. Targeting the VEGF pathway has also proven beneficial, and the VEGFR targeted monoclonal antibody ramucirumab is now approved for second-line therapy. In contrast to these positive results, agents targeting the EGFR and MET pathways have been evaluated extensively in gastroesophageal cancer but have repeatedly failed to show benefit. An increased understanding of the molecular predictors of response to targeted therapies is sorely needed. In the future, improved molecular pathology approaches should subdivide this heterogeneous disease entity to allow individualization of cancer therapy based on integrated and global identification of deregulated signaling pathways. Better patient selection, rational combinations of targeted therapies and incorporation of emerging immunotherapeutic approaches should further improve the treatment of this deadly disease. PMID- 26510454 TI - Mycobacterium avium subspecies hominissuis in Crohn's disease: a case report. AB - We have cultured Mycobacteria avium subspecies hominissuis (MAH) from the blood of a patient with Crohn's disease. The patient is a 21 year-old-female with a diagnosis of Crohn's disease for two years. She had been treated with corticosteroids and Humira for six months. A blood specimen was cultured in a specialized medium, and there was visible bacterial growth present in the liquid culture medium after eight weeks. PCR analysis of the bacterial growth and subsequent direct sequencing of the PCR amplicon confirmed the presence of MAH. The significance of this finding is discussed. PMID- 26510455 TI - Immune checkpoints and immunotherapy for colorectal cancer. AB - Colorectal cancer (CRC) remains one of the major causes of death worldwide, despite steady improvement in early detection and overall survival over the past decade. Current treatment paradigms, with chemotherapy and biologics, appear to have reached their maximum benefit. Immunotherapy, especially with checkpoint inhibitors, has shown considerable clinical benefit in various cancers, including mismatch-repair-deficient CRC. This has led to the planning and initiation of several clinical trials evaluating novel immunotherapy agents-as single agents, combinations and in conjunction with chemotherapy-in patients with CRC. This article reviews biological and preclinical data for checkpoint inhibitors and discusses various immunotherapy trials in CRC, as well as current efforts in CRC immunotherapy. PMID- 26510456 TI - POH1 deubiquitylates and stabilizes E2F1 to promote tumour formation. AB - Hyperactivation of the transcriptional factor E2F1 occurs frequently in human cancers and contributes to malignant progression. E2F1 activity is regulated by proteolysis mediated by the ubiquitin-proteasome system. However, the deubiquitylase that controls E2F1 ubiquitylation and stability remains undefined. Here we demonstrate that the deubiquitylase POH1 stabilizes E2F1 protein through binding to and deubiquitylating E2F1. Conditional knockout of Poh1 alleles results in reduced E2F1 expression in primary mouse liver cells. The POH1 mediated regulation of E2F1 expression strengthens E2F1-downstream prosurvival signals, including upregulation of Survivin and FOXM1 protein levels, and efficiently facilitates tumour growth of liver cancer cells in nude mice. Importantly, human hepatocellular carcinomas (HCCs) recapitulate POH1 regulation of E2F1 expression, as nuclear abundance of POH1 is increased in HCCs and correlates with E2F1 overexpression and tumour growth. Thus, our study suggests that the hyperactivated POH1-E2F1 regulation may contribute to the development of liver cancer. PMID- 26510457 TI - Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project. AB - BACKGROUND: Spinal muscular atrophy (SMA) is the most common pan-ethnic cause of early childhood death due to mutations in a single gene, SMN1. Most chromosome 5 homologs have a functional gene and dysfunctional copy, SMN2, with a single synonymous base substitution that results in faulty RNA splicing. However, the copy number of SMN1 and SMN2 is highly variable, and one in 60 adults worldwide are SMA carriers. Although population-wide screening is recommended, current SMA carrier tests have not been incorporated into targeted gene panels. METHODS: Here we describe a novel computational protocol for determining SMA carrier status based solely on individual exome data. Our method utilizes a Bayesian hierarchical model to quantify an individual's carrier probability given only his or her SMN1 and SMN2 reads at six loci of interest. RESULTS: We find complete concordance with results obtained with the current qPCR-based testing standard in known SMA carriers and affecteds. We applied our protocol to the phase 3 cohort of the 1,000 Genomes Project and found carrier frequencies in multiple populations consistent with the present literature. CONCLUSION: Our process is a convenient, robust alternative to qPCR, which can easily be integrated into the analysis of large multi-gene NGS carrier screens. PMID- 26510458 TI - Correlation between small dense low-density lipoprotein cholesterol and carotid artery intima-media thickness in a healthy Chinese population. AB - BACKGROUND: Small dense low-density lipoprotein cholesterol (sdLDL-C) concentration was useful in the assessment of the presence of cardiovascular diseases (CVD) and its severity. We examined whether SdLDL-C is more closely associated with carotid artery intima-media thickness (CA-IMT), a surrogate measure of atherosclerosis, than LDL-C and traditional CVD risk factors in Chinese healthy subjects. METHODS: We measured CA-IMT, blood pressure (BP), sdLDL C, glucose metabolism and lipid in 183 native Chinese healthy subjects. CA-IMT was assessed by ultrasonography, and sdLDL-C concentrations were measured by a homogenous assay. Pearson's correlation coefficient analyses and Multiple regression analyses were used to examine the relationships between CA-IMT values and other clinical variables. RESULTS: The sdLDL-C level was significantly higher in males than in females (p <0.05) and there was an age effect on sdLDL-C (p <0.05). When the effects of age, gender and other traditional CVD risk factors were adjusted using multiple regression analysis. CA-IMT remained significantly associated with sdLDL-C(beta = 0.437, p <0.001). CONCLUSIONS: There are gender and age differences in sdLDL-C levels among a healthy Chinese population. Moreover, we found adjusted traditional CVD risk factors such as higher age, male sex, and other traditional CVD risk factors, the association between CA-IMT and SdLDL-C remained significant. sdLDL-C is may be a useful predictor in the assessment of CA-IMT in Chinese population. PMID- 26510459 TI - Dietary fiber prevents obesity-related liver lipotoxicity by modulating sterol regulatory element binding protein pathway in C57BL/6J mice fed a high fat/cholesterol diet. AB - Adequate intake of dietary fibers has proven metabolic and cardiovascular benefits, molecular mechanisms remain still limited. This study was aimed to investigate the effects of cereal dietary fiber on obesity-related liver lipotoxicity in C57BL/6J mice fed a high-fat/cholesterol (HFC) diet and underlying mechanism. Forty-eight adult male C57BL/6J mice were randomly given a reference chow diet, or a high fat/cholesterol (HFC) diet supplemented with or without oat fiber or wheat bran fiber for 24 weeks. Our results showed mice fed oat or wheat bran fiber exhibited lower weight gain, lipid profiles and insulin resistance, compared with HFC diet. The two cereal dietary fibers potently decreased protein expressions of sterol regulatory element binding protein-1 and key factors involved in lipogenesis, including fatty acid synthase and acetyl-CoA carboxylase in target tissues. At molecular level, the two cereal dietary fibers augmented protein expressions of peroxisome proliferator-activated receptor alpha and gamma, liver X receptor alpha, and ATP-binding cassette transporter A1 in target tissues. Our findings indicated that cereal dietary fiber supplementation abrogated obesity-related liver lipotoxicity and dyslipidemia in C57BL/6J mice fed a HFC diet. In addition, the efficacy of oat fiber is greater than wheat bran fiber in normalizing these metabolic disorders and pathological profiles. PMID- 26510460 TI - Field and experimental symptomless infections support wandering donkeys as healthy carriers of Trypanosoma vivax in the Brazilian Semiarid, a region of outbreaks of high mortality in cattle and sheep. AB - BACKGROUND: The Brazilian Semiarid is the home of the largest herd of donkeys in South America and of outbreaks of Trypanosoma vivax infection of high mortality in dairy cattle and sheep. For a comprehensive understanding of the underlying mechanisms of these outbreaks and epidemiological role of donkeys, we surveyed for T. vivax in wandering donkeys and follow the experimental infection of donkeys and sheep with a highly virulent isolate from the Semiarid. METHODS: Blood samples from 180 randomly selected wandering donkeys from the Brazilian Semiarid region were employed for PCV and parasitemia assessments and tested using the T. vivax-specific TviCATL-PCR assay. PCR-amplifed Cathepsin L (CATL) sequences were employed for genotyping and phylogenetic analysis. Four wandering donkeys were experimentally infected with a T. vivax isolate obtained during an outbreak of high mortality in the Semiarid; the control group consisted of two non-inoculated donkeys. RESULTS: We detected T. vivax in 30 of 180 wandering donkeys (16.6 %) using TviCATL-PCR. The prevalence was higher during the dry (15.5 %) than the wet season (1.1 %) and more females (23.1 %) than males (8.9 %) were infected. All the PCR-positive donkeys lacked patent parasitemia and showed normal values of body condition score (BCS) and packed cell volume (PCV). To evaluate the probable tolerance of donkeys to T. vivax, we inoculated five donkeys with a highly virulent isolate (TviBrRp) from the Semiarid. All inoculated donkeys became PCR-positive, but their parasitemia was always subpatent. A control goat inoculated with TviBrRp showed increasing parasitemia concurrently with fever, declining PCV, tachycardia, mucous membrane pallor, enlarged lymph nodes and anorexia. None of these signs were observed in donkeys. However, T. vivax from wandering donkeys shared identical or highly similar genotypes (identified by Cathepsin L sequences) with isolates from cattle and sheep outbreaks of acute disease in the Semiarid. CONCLUSIONS: This is the first report of T. vivax in donkeys in Brazil and, to our knowledge, the first experimental infection of donkeys with T. vivax. The symptomless field and experimental infections corroborated that donkeys are more tolerant to T. vivax than other livestock species as shown in African countries. Therefore, farmers, veterinaries and control programmes should be aware of healthy carrier donkeys as a possible source of T. vivax for susceptible livestock species in the Brazilian Semiarid. PMID- 26510461 TI - Bipolar radiofrequency catheter ablation for refractory perimitral flutter: a case report. AB - BACKGROUND: Mitral isthmus is often targeted as a part of stepwise approach during radiofrequency ablation for persistent atrial ablation. Acute success rate in achieving the mitral isthmus block is only modest, late reconduction rate is relatively high and, consequently, incomplete lesion may be proarrhythmic. We describe the first-in-man experience with successful MI ablation by bipolar RF energy delivery. CASE PRESENTATION: A 64-year-old caucasian man after two previous ablation procedures for drug resistant atrial fibrillation in recent four years, which included pulmonary vein isolation and linear left atrial lesions, was referred for the treatment of recurrent perimitral flutter. Despite the third attempt to create bidirectional block at the mitral isthmus region, we were not even able to stop the arrhythmia by aggressive unipolar radiofrequency ablation both from the left atrium and coronary sinus, because of deeply embedded slow conducting channel probably around the vein of Marshall. Arrhythmia was finally terminated and the block was achieved by bipolar radiofrequency ablation between two irrigated-tip catheters positioned at the left atrial endocardium and contralaterally inside the coronary sinus. CONCLUSION: Bipolar radiofrequency energy delivery can be an option for ablation of perimitral flutter resistant to standard unipolar radiofrequency ablation. This may improve clinical outcome of patients undergoing non-pharmacological treatment for persistent atrial fibrillation. The safety and efficacy of this technique has to be confirmed in future studies. PMID- 26510463 TI - Structural evidence for the role of polar core residue Arg175 in arrestin activation. AB - Binding mechanism of arrestin requires photoactivation and phosphorylation of the receptor protein rhodopsin, where the receptor bound phosphate groups cause displacement of the long C-tail 'activating' arrestin. Mutation of arginine 175 to glutamic acid (R175E), a central residue in the polar core and previously predicted as the 'phosphosensor' leads to a pre-active arrestin that is able to terminate phototransduction by binding to non-phosphorylated, light-activated rhodopsin. Here, we report the first crystal structure of a R175E mutant arrestin at 2.7 A resolution that reveals significant differences compared to the basal state reported in full-length arrestin structures. These differences comprise disruption of hydrogen bond network in the polar core, and three-element interaction including disordering of several residues in the receptor-binding finger loop and the C-terminus (residues 361-404). Additionally, R175E structure shows a 7.5 degrees rotation of the amino and carboxy-terminal domains relative to each other. Consistent to the biochemical data, our structure suggests an important role of R29 in the initial activation step of C-tail release. Comparison of the crystal structures of basal arrestin and R175E mutant provide insights into the mechanism of arrestin activation, where binding of the receptor likely induces structural changes mimicked as in R175E. PMID- 26510464 TI - Inhaled nitric oxide as adjunctive therapy for severe malaria: a randomized controlled trial. AB - BACKGROUND: Severe malaria remains a major cause of childhood mortality globally. Decreased endothelial nitric oxide is associated with severe and fatal malaria. The hypothesis was that adjunctive inhaled nitric oxide (iNO) would improve outcomes in African children with severe malaria. METHODS: A randomized, blinded, placebo-controlled trial of iNO at 80 ppm by non-rebreather mask versus room air placebo as adjunctive treatment to artesunate in children with severe malaria was conducted. The primary outcome was the longitudinal course of angiopoietin-2 (Ang 2), an endothelial biomarker of malaria severity and clinical outcome. RESULTS: One hundred and eighty children were enrolled; 88 were assigned to iNO and 92 to placebo (all received IV artesunate). Ang-2 levels measured over the first 72 h of hospitalization were not significantly different between groups. The mortality at 48 h was similar between groups [6/87 (6.9 %) in the iNO group vs 8/92 (8.7 %) in the placebo group; OR 0.78, 95 % CI 0.26-2.3; p = 0.65]. Clinical recovery times and parasite clearance kinetics were similar (p > 0.05). Methaemoglobinaemia >7 % occurred in 25 % of patients receiving iNO and resolved without sequelae. The incidence of neurologic deficits (<14 days), acute kidney injury, hypoglycaemia, anaemia, and haemoglobinuria was similar between groups (p > 0.05). CONCLUSIONS: iNO at 80 ppm administered by non-rebreather mask was safe but did not affect circulating levels of Ang-2. Alternative methods of enhancing endothelial NO bioavailability may be necessary to achieve a biological effect and improve clinical outcome. TRIAL REGISTRATION: ClinicalTrials.gov NCT01255215. PMID- 26510465 TI - Genetic analysis of Indian tasar silkmoth (Antheraea mylitta) populations. AB - Indian tasar silkmoth, Antheraea mylitta is an economically important wild silkmoth species distributed across India. A number of morphologically and ethologically well-defined ecotypes are known for this species that differ in their primary food plant specificity. Most of these ecotypes do not interbreed in nature, but are able to produce offspring under captive conditions. Microsatellite markers were developed for A. mylitta, and out of these, ten well behaved microsatellite loci were used to analyze the population structure of different ecoraces. A total of 154 individual moths belonging to eight different ecoraces, were screened at each locus. Hierarchical analysis of population structure using Analysis of MOlecular VAriance (AMOVA) revealed significant structuring (FST = 0.154) and considerable inbreeding (FIS = 0.505). A significant isolation by distance was also observed. The number of possible population clusters was investigated using distance method, Bayesian algorithm and self organization maps (SOM). The first two methods revealed two distinct clusters, whereas the SOM showed the different ecoraces not to be clearly differentiated. These results suggest that although there is a large degree of phenotypic variation among the different ecoraces of A. mylitta, genetically they are not very different, and the phenotypic differences may largely be a result of their respective ecology. PMID- 26510466 TI - Pseudoachalasia: Still a Tough Clinical Challenge. AB - BACKGROUND: Treatment of achalasia is focused on decreasing the resting lower esophageal sphincter by either pneumatic dilation or surgical myotomy. When patients symptomatically relapse after one or more pneumatic dilations, then one explanation is to consider the possibility of pseudoachalasia as the diagnosis. CASE REPORT: We present a rare case of an elderly patient with a presentation of chronic dysphagia and severe weight loss, who had diagnostic findings consistent with achalasia, and who also responded very well to a series of pneumatic dilations, but for only brief intervals. Further investigations finally uncovered esophageal adenocarcinoma, thus making our patient an example of the entity "pseudoachalasia". CONCLUSIONS: Pseudoachalasia secondary to an esophageal malignancy should be suspected when dysphagia progresses despite technically well performed pneumatic dilations, and is particularly suspicious in the setting of an elderly patient with marked weight loss. Endoscopic ultrasound is a new diagnostic tool for detecting and staging malignancy by obtaining diagnostic tissue and allowing appropriate therapy to be planned. PMID- 26510467 TI - The Cedar Project: resilience in the face of HIV vulnerability within a cohort study involving young Indigenous people who use drugs in three Canadian cities. AB - BACKGROUND: Indigenous scholars have long argued that it is critical for researchers to identify factors related to cultural connectedness that may protect against HIV and hepatitis C infection and buffer the effects of historical and lifetime trauma among young Indigenous peoples. To our knowledge, no previous epidemiological studies have explored the effect of historical and lifetime traumas, cultural connectedness, and risk factors on resilience among young, urban Indigenous people who use drugs. METHODS: This study explored risk and protective factors associated with resilience among participants of the Cedar Project, a cohort study involving young Indigenous peoples who use illicit drugs in three cities in British Columbia, Canada. We utilized the Connor-Davidson Resilience Scale to measure resilience, the Childhood Trauma Questionnaire to measure childhood maltreatment, and the Symptom-Checklist 90-Revised to measure psychological distress among study participants. Multivariate linear mixed effects models (LME) estimated the effect of study variables on mean change in resilience scores between 2011-2012. RESULTS: Among 191 participants, 92 % had experienced any form of childhood maltreatment, 48 % had a parent who attended residential school, and 71 % had been in foster care. The overall mean resilience score was 62.04, with no differences between the young men and women (p = 0.871). Adjusted factors associated with higher mean resilience scores included having grown up in a family that often/always lived by traditional culture (B = 7.70, p = 0.004) and had often/always spoken their traditional language at home (B = 10.52, p < 0.001). Currently knowing how to speak a traditional language (B = 13.06, p = 0.001), currently often or always living by traditional culture (B = 6.50, p = 0.025), and having recently sought drug/alcohol treatment (B = 4.84, p = 0.036) were also significantly associated with higher mean resilience scores. Adjusted factors associated with diminished mean resilience scores included severe childhood emotional neglect (B = -13.34, p = 0.001), smoking crack daily (B = -5.42, p = 0.044), having been sexual assaulted (B = 14.42, p = 0.041), and blackout drinking (B = -6.19, p = 0.027). CONCLUSIONS: Young people in this study have faced multiple complex challenges to their strength. However, cultural foundations continue to function as buffers that protect young Indigenous people from severe health outcomes, including vulnerability to HIV and HCV infection. PMID- 26510468 TI - A genetic biosensor for identification of transcriptional repressors of target promoters. AB - Transcriptional repressors provide widespread biological significance in the regulation of gene expression. However, in prokaryotes, it is particularly difficult to find transcriptional repressors that recognize specific target promoters on genome-scale. To address this need, a genetic biosensor for identifying repressors of target promoters was developed in Escherichia coli from a de novo designed genetic circuit. This circuit can convert the negative input of repressors into positive output of reporters, thereby facilitating the selection and identification of repressors. After evaluating the sensitivity and bias, the biosensor was used to identify the repressors of scbA and aco promoters (PscbA and Paco), which control the transcription of signalling molecule synthase genes in Streptomyces coelicolor and Streptomyces avermitilis, respectively. Two previously unknown repressors of PscbA were identified from a library of TetR family regulators in S. coelicolor, and three novel repressors of Paco were identified from a genomic library of S. avermitilis. Further in vivo and in vitro experiments confirmed that these newly identified repressors attenuated the transcription of their target promoters by direct binding. Overall, the genetic biosensor developed here presents an innovative and powerful strategy that could be applied for identifying genome-wide unknown repressors of promoters in bacteria. PMID- 26510469 TI - Enantioselective synthesis of (-)-chloramphenicol via silver-catalysed asymmetric isocyanoacetate aldol reaction. AB - The highly enantio- and diastereoselective aldol reaction of isocyanoacetates catalysed by Ag2O and cinchona-derived amino phosphines applied to the synthesis of (-)- and (+)-chloramphenicol is described. The concise synthesis showcases the utility of this catalytic asymmetric methodology for the preparation of bioactive compounds possessing alpha-amino-beta-hydroxy motifs. PMID- 26510470 TI - Erratum to: Improved OTU-picking using long-read 16S rRNA gene amplicon sequencing and generic hierarchical clustering. PMID- 26510471 TI - Investigation of a Case of Genotype 5a Hepatitis C Virus Transmission in a French Hemodialysis Unit Using Epidemiologic Data and Deep Sequencing. AB - BACKGROUND Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide. A patient was recently found to be HCV seropositive during hemodialysis follow-up. OBJECTIVE To determine whether nosocomial transmission had occurred and which viral populations were transmitted. DESIGN HCV transmission case. SETTING A dialysis unit in a French hospital. METHODS Molecular and epidemiologic investigations were conducted to determine whether 2 cases were related. Risk analysis and auditing procedures were performed to determine the transmission pathway(s). RESULTS Sequence analyses of the NS5b region revealed a 5a genotype in the newly infected patient. Epidemiologic investigations suggested that a highly viremic genotype 5a HCV-infected patient who underwent dialysis in the same unit was the source of the infection. Phylogenetic analysis of NS5b and hypervariable region-1 sequences revealed a genetically related virus (>99.9% nucleotide identity). Deep sequencing of hypervariable region-1 indicated that HCV quasispecies were found in the source whereas a single hypervariable region-1 HCV variant was found in the newly infected patient, and that this was identical to the major variant identified in the source patient. Risk analysis and auditing procedures were performed to determine the transmission pathway(s). Nosocomial patient-to-patient transmission via healthcare workers' hands was the most likely explanation. In our dialysis unit, this unique incident led to the adjustment of infection control policy. CONCLUSIONS The data support transmission of a unique variant from a source with a high viral load and genetic diversity. This investigation also underlines the need to periodically evaluate prevention and control practices. PMID- 26510472 TI - Structure-based approach for the study of thyroid hormone receptor binding affinity and subtype selectivity. AB - Thyroid hormone (TH) possesses the ability to lower cholesterol and improve cardiac performance, which have prompted the efforts to design analogs that can utilize the cholesterol-lowering property without adversely affecting heart function. In order to gain insights into the interaction mechanism for agonists at the active site of thyroid hormone receptor beta (TRbeta), quantitative structure-activity relationship (QSAR) models have been developed on TRbeta agonists, significant statistical coefficients were obtained (CoMFA, R(2)cv, .732), (CoMSIA, R(2)cv, .853), indicating the internal consistency of the models, the obtained models were further validated using the test set, the acquired R(2)pred values .7054 and .7129 were in good agreement with the experimental results. The key amino acids affecting ligand binding were identified by molecular docking, and the detailed binding modes of the compounds with different activities were also determined. Furthermore, molecular dynamics (MD) simulations were conducted to assess the reliability of the derived models and the docking results. Moreover, TH exerts significant physiological effects through modulation of the two human thyroid hormone receptor subtypes. Because TRbeta and TRalpha locate in different target cells, selective TR ligands would target specific tissues regulated by one receptor without affecting the other. Thus, the 3D information was analyzed to reveal the most relevant structural features involved in selectivity. The findings serve as the basis for further investigation into selective TRbeta/TRalpha agonists. PMID- 26510474 TI - Toward peptide-based inhibitors as therapies for Parkinson's disease. PMID- 26510473 TI - Long-term mental health of war-refugees: a systematic literature review. AB - BACKGROUND: There are several million war-refugees worldwide, majority of whom stay in the recipient countries for years. However, little is known about their long-term mental health. This review aimed to assess prevalence of mental disorders and to identify their correlates among long-settled war-refugees. METHODS: We conducted a systematic review of studies that assessed current prevalence and/or factors associated with depression and anxiety disorders in adult war-refugees 5 years or longer after displacement. We searched Medline, Embase, CINAHL, PsycINFO, and PILOTS from their inception to October 2014, searched reference lists, and contacted experts. Because of a high heterogeneity between studies, overall estimates of mental disorders were not discussed. Instead, prevalence rates were reviewed narratively and possible sources of heterogeneity between studies were investigated both by subgroup analysis and narratively. A descriptive analysis examined pre-migration and post-migration factors associated with mental disorders in this population. RESULTS: The review identified 29 studies on long-term mental health with a total of 16,010 war affected refugees. There was significant between-study heterogeneity in prevalence rates of depression (range 2.3-80%), PTSD (4.4-86%), and unspecified anxiety disorder (20.3-88%), although prevalence estimates were typically in the range of 20% and above. Both clinical and methodological factors contributed substantially to the observed heterogeneity. Studies of higher methodological quality generally reported lower prevalence rates. Prevalence rates were also related to both which country the refugees came from and in which country they resettled. Refugees from former Yugoslavia and Cambodia tended to report the highest rates of mental disorders, as well as refugees residing in the USA. Descriptive synthesis suggested that greater exposure to pre-migration traumatic experiences and post-migration stress were the most consistent factors associated with all three disorders, whilst a poor post-migration socio-economic status was particularly associated with depression. CONCLUSIONS: There is a need for more methodologically consistent and rigorous research on the mental health of long settled war refugees. Existing evidence suggests that mental disorders tend to be highly prevalent in war refugees many years after resettlement. This increased risk may not only be a consequence of exposure to wartime trauma but may also be influenced by post-migration socio-economic factors. PMID- 26510475 TI - Quantitative Analysis of Rat Dorsal Root Ganglion Neurons Cultured on Microelectrode Arrays Based on Fluorescence Microscopy Image Processing. AB - Microelectrode Arrays (MEA) are devices for long term electrophysiological recording of extracellular spontaneous or evocated activities on in vitro neuron culture. This work proposes and develops a framework for quantitative and morphological analysis of neuron cultures on MEAs, by processing their corresponding images, acquired by fluorescence microscopy. The neurons are segmented from the fluorescence channel images using a combination of segmentation by thresholding, watershed transform, and object classification. The positioning of microelectrodes is obtained from the transmitted light channel images using the circular Hough transform. The proposed method was applied to images of dissociated culture of rat dorsal root ganglion (DRG) neuronal cells. The morphological and topological quantitative analysis carried out produced information regarding the state of culture, such as population count, neuron-to neuron and neuron-to-microelectrode distances, soma morphologies, neuron sizes, neuron and microelectrode spatial distributions. Most of the analysis of microscopy images taken from neuronal cultures on MEA only consider simple qualitative analysis. Also, the proposed framework aims to standardize the image processing and to compute quantitative useful measures for integrated image signal studies and further computational simulations. As results show, the implemented microelectrode identification method is robust and so are the implemented neuron segmentation and classification one (with a correct segmentation rate up to 84%). The quantitative information retrieved by the method is highly relevant to assist the integrated signal-image study of recorded electrophysiological signals as well as the physical aspects of the neuron culture on MEA. Although the experiments deal with DRG cell images, cortical and hippocampal cell images could also be processed with small adjustments in the image processing parameter estimation. PMID- 26510476 TI - A Preclinical Study of Laryngeal Motor-Evoked Potentials as a Marker Vagus Nerve Activation. AB - Vagus nerve stimulation (VNS) is a treatment for refractory epilepsy and depression. Previous studies using invasive recording electrodes showed that VNS induces laryngeal motor-evoked potentials (LMEPs) through the co-activation of the recurrent laryngeal nerve and subsequent contractions of the laryngeal muscles. The present study investigates the feasibility of recording LMEPs in chronically VNS-implanted rats, using a minimally-invasive technique, to assess effective current delivery to the nerve and to determine optimal VNS output currents for vagal fiber activation. Three weeks after VNS electrode implantation, signals were recorded using an electromyography (EMG) electrode in the proximity of the laryngeal muscles and a reference electrode on the skull. The VNS output current was gradually ramped up from 0.1 to 1.0 mA in 0.1 mA steps. In 13/27 rats, typical LMEPs were recorded at low VNS output currents (median 0.3 mA, IQR 0.2-0.3 mA). In 11/27 rats, significantly higher output currents were required to evoke electrophysiological responses (median 0.7 mA, IQR 0.5-0.7 mA, p < 0.001). The latencies of these responses deviated significantly from LMEPs (p < 0.05). In 3/27 rats, no electrophysiological responses to simulation were recorded. Minimally invasive LMEP recordings are feasible to assess effective current delivery to the vagus nerve. Furthermore, our results suggest that low output currents are sufficient to activate vagal fibers. PMID- 26510477 TI - Electrode-electrolyte interface in Li-ion batteries: current understanding and new insights. AB - Understanding reactions at the electrode/electrolyte interface (EEI) is essential to developing strategies to enhance cycle life and safety of lithium batteries. Despite research in the past four decades, there is still limited understanding by what means different components are formed at the EEI and how they influence EEI layer properties. We review findings used to establish the well-known mosaic structure model for the EEI (often referred to as solid electrolyte interphase or SEI) on negative electrodes including lithium, graphite, tin, and silicon. Much less understanding exists for EEI layers for positive electrodes. High-capacity Li-rich layered oxides yLi2-xMnO3.(1-y)Li1-xMO2, which can generate highly reactive species toward the electrolyte via oxygen anion redox, highlight the critical need to understand reactions with the electrolyte and EEI layers for advanced positive electrodes. Recent advances in in situ characterization of well defined electrode surfaces can provide mechanistic insights and strategies to tailor EEI layer composition and properties. PMID- 26510478 TI - Biomimetic Preparation and Dual-Color Bioimaging of Fluorescent Silicon Nanoparticles. AB - Fluorescent silicon nanoparticles (SiNPs), as the most important zero-dimensional silicon nanostructures, hold high promise for long-awaited silicon-based optic applications. There currently remain major challenges for the green, inexpensive, and mass production of fluorescent SiNPs, resulting in difficulties in sufficiently exploiting the properties of these remarkable materials. Here, we show that fluorescent small-sized (~3.8 nm) SiNPs can be produced through biomimetic synthesis in rapid (10 min), low-cost, and environmentally benign manners. The as-prepared SiNPs simultaneously feature bright fluorescence (quantum yield (QY), ~15-20%), narrow emission spectral width (full width at half maximum (fwhm), ~30 nm), and nontoxicity, making them as high-quality fluorescent probes for biological imaging in vitro and in vivo. PMID- 26510479 TI - Prospecting major genes in dairy buffaloes. AB - BACKGROUND: Asian buffaloes (Bubalus bubalis) have an important socio-economic role. The majority of the population is situated in developing countries. Due to the scarce resources in these countries, very few species-specific biotechnology tools exist and a lot of cattle-derived technologies are applied to buffaloes. However, the application of cattle genomic tools to buffaloes is not straightforward and, as results suggested, despite genome sequences similarity the genetic polymorphisms are different. RESULTS: The first SNP chip genotyping platform designed specifically for buffaloes has recently become available. Herein, a genome-wide association study (GWAS) and gene network analysis carried out in buffaloes is presented. Target phenotypes were six milk production and four reproductive traits. GWAS identified SNP with significant associations and suggested candidate genes that were specific to each trait and also genes with pleiotropic effect, associated to multiple traits. CONCLUSIONS: Network predictions of interactions between these candidate genes may guide further molecular analyses in search of disruptive mutations, help select genes for functional experiments and evidence metabolism differences in comparison to cattle. The cattle SNP chip does not offer an optimal coverage of buffalo genome, thereafter the development of new buffalo-specific genetic technologies is warranted. An annotated reference genome would greatly facilitate genetic research, with potential impact to buffalo-based dairy production. PMID- 26510480 TI - Application of local gene induction by infrared laser-mediated microscope and temperature stimulator to amphibian regeneration study. AB - Urodele amphibians (newts and salamanders) and anuran amphibians (frogs) are excellent research models to reveal mechanisms of three-dimensional organ regeneration since they have exceptionally high regenerative capacity among tetrapods. However, the difficulty in manipulating gene expression in cells in a spatially restricted manner has so far hindered elucidation of the molecular mechanisms of organ regeneration in amphibians. Recently, local heat shock by laser irradiation has enabled local gene induction even at the single-cell level in teleost fishes, nematodes, fruit flies and plants. In this study, local heat shock was made with infrared laser irradiation (IR-LEGO) by using a gene expression inducible system in transgenic animals containing a heat shock promoter, and gene expression was successfully induced only in the target region of two amphibian species, Xenopus laevis and Pleurodeles waltl (a newt), at postembryonic stages. Furthermore, we induced spatially restricted but wider gene expression in Xenopus laevis tadpoles and froglets by applying local heat shock by a temperature-controlled metal probe (temperature stimulator). The local gene manipulation systems, the IR-LEGO and the temperature stimulator, enable us to do a rigorous cell lineage trace with the combination of the Cre-LoxP system as well as to analyze gene function in a target region or cells with less off-target effects in the study of amphibian regeneration. PMID- 26510481 TI - Inhomogeneity of collagen organization within the fibrotic scar after myocardial infarction: results in a swine model and in human samples. AB - We aimed to characterize the organization of collagen within a fibrotic scar in swine and human samples from patients with chronic infarctions. Swine were subjected to occlusion of the left anterior descending artery followed by reperfusion 1 week (acute myocardial infarction group) or 1 month (chronic myocardial infarction group) after infarction. The organization of the collagen fibers (Fast Fourier Transform of samples after picrosirius staining; higher values indicate more disorganization) was studied in 100 swine and 95 human samples. No differences in collagen organization were found between the acute and chronic groups in the core area of the scar in the experimental model. In the chronic group, the endocardium [0.90 (0.84-0.94); median (interquartile range)], epicardium [0.84 (0.79-0.91)] and peripheral area [0.73 (0.63-0.83)] displayed a much more disorganized pattern than the core area of the fibrotic scar [0.56 (0.45-0.64)]. Similarly, in human samples, the collagen fibers were more disorganized in all of the outer areas than in the core of the fibrotic scar (P < 0.0001). Both in a highly controlled experimental model and in patient samples, collagen fibers exhibited an organized pattern in the core of the infarction, whereas the outer areas displayed a high level of inhomogeneity. This finding contributes pathophysiological information regarding the healing process and may lead to a clearer understanding of the genesis and invasive treatment of arrhythmias after acute myocardial infarction. PMID- 26510482 TI - Tamoxifen as a new therapeutic tool for neutrophilic lung inflammation. AB - BACKGROUND AND OBJECTIVE: Neutrophilic asthma is an important disease subgroup, including patients with severe phenotypes and erratic responses to standard treatments. Tamoxifen (TX), a selective estrogen receptor modulator (SERM) used as treatment of human breast cancer, has been shown to induce early apoptosis of equine blood and bronchoalveolar lavage fluid (BALF) neutrophils in vitro. Equine recurrent airway obstruction (RAO) is a naturally occurring neutrophilic condition, closely related with human asthma. Our purpose was to investigate the therapeutic potential of tamoxifen in horses with neutrophilic lung inflammation. METHODS: Twelve horses underwent acute lung inflammation through exposure to allergens known to cause RAO, after which they received treatment with either tamoxifen or dexamethasone. Outcome measures included evaluation of clinical signs, BALF cytology, and early apoptosis of blood and BALF neutrophils. RESULTS: Tamoxifen treatment decreased BALF neutrophil counts (65.3 +/- 19.38% before treatment; 7.6 +/- 4.5% 2 days post-treatment,; and 13.6 +/- 9.3% 5 days post treatment). A similar decrease was observed with dexamethasone treatment (48.6 +/ 5.88% before treatment; 11.5 +/- 8.1% 2 days post-treatment; 14.6 +/- 10.3% 5 days post-treatment). Clinical and endoscopic scores improved in both treatment groups. Tamoxifen treatment significantly increased early apoptosis of peripheral blood neutrophils at 5 days post-treatment (27.04 +/- 15.2%), and in BALF neutrophils at 2 and 5 days post-treatment (42.11 +/- 11.67% and 48.98 +/- 2.6%, respectively). CONCLUSION: Tamoxifen treatment in horses with induced acute pulmonary inflammation promoted early apoptosis of blood and BALF neutrophils, reduction in BALF neutrophils and improvement in the animals' clinical status. PMID- 26510483 TI - Development of a new classification for in vivo diagnosis of duodenal epithelial tumors with confocal laser endomicroscopy: A pilot study. AB - BACKGROUND AND AIM: Confocal laser endomicroscopy (CLE) has been established for in vivo diagnosis of various gastrointestinal diseases. However, validated criteria for confocal diagnosis of duodenal tumors do not exist. Therefore, the aim of the present pilot study was to develop a novel classification for in vivo optical diagnosis of duodenal tumors using CLE. METHODS: Consecutive patients with duodenal tumorous lesions were included. First, an initial classification system was developed which was then validated. Histopathology was used as a reference standard. RESULTS: A simple classification system for in vivo diagnosis of duodenal epithelial tumors using CLE was developed. Sensitivity, specificity, and accuracy were 90%, 100%, and 97%, respectively. Positive and negative predictive values were calculated as 100% and 96%. The kappa coefficient representing consistency was 1 between observers and within each observer. CONCLUSION: A new classification for in vivo diagnosis of duodenal epithelial tumors using confocal imaging has been developed. The new classification system allows adequate prediction of histology and could therefore be used to guide subsequent therapy of duodenal lesions. PMID- 26510484 TI - Mitochondrial oxidative stress and dysfunction in arsenic neurotoxicity: A review. AB - Arsenic is a toxic metalloid present ubiquitously on earth. Since the last decade, it has gained considerable attention due to its severe neurotoxic effects. Arsenic can cross the blood-brain barrier and accumulate in different regions of the brain suggesting its role in neurological diseases. Arsenic exposure has been associated with reactive oxygen species generation, which is supposed to be one of the mechanisms of arsenic-induced oxidative stress. Mitochondria, being the major source of reactive oxygen species generation may present an important target of arsenic toxicity. It is speculated that the proper functioning of the brain depends largely on efficient mitochondrial functions. Multiple studies have reported evidence of brain mitochondrial impairment after arsenic exposure. In this review, we have evaluated the proposed mechanisms of arsenic-induced mitochondrial oxidative stress and dysfunction. The understanding of molecular mechanism of mitochondrial dysfunction may be helpful to develop therapeutic strategies against arsenic-induced neurotoxicity. The ameliorative measures undertaken in arsenic-induced mitochondrial dysfunction have also been highlighted. PMID- 26510485 TI - The Origin of Life--Out of the Blue. AB - Either to sustain autotrophy, or as a prelude to heterotrophy, organic synthesis from an environmentally available C1 feedstock molecule is crucial to the origin of life. Recent findings augment key literature results and suggest that hydrogen cyanide--"Blausaure"--was that feedstock. PMID- 26510486 TI - Synthesis of Hydroxypyrrolone Carboxamides Employing Selectfluor. AB - Reaction of pyrrole-2-carboxamides with Selectfluor in MeCN/water (4:1) affords 2 hydroxy-5-oxopyrrole-2-carboxamides in yields of up to 80 %. A variety of sensitive functional groups is tolerated, among them aldehydes and alkynes. The new method also works in the presence of allyl groups and appears to be superior to the use of singlet oxygen. Reaction of the monobrominated dihydropyrrolo[1,2 a]pyrazinone mukanadin C and its nonbrominated analogue afforded bicyclic hydroxypyrrolones. These compounds are interesting as they constitute a partial structure of the marine natural product oxocyclostylidol. PMID- 26510487 TI - A short history of portal hypertension and of its management. AB - The aim of our study was to review the changing trends in the treatment of complications from portal hypertension. A short history of portal hypertension and of the treatment of its complications is reported, underlying the most important achievements and changes. PMID- 26510488 TI - Intravenous Immunoglobulin G Improves Pregnancy Outcome in Women with Recurrent Pregnancy Losses with Cellular Immune Abnormalities. AB - PROBLEM: We investigated the therapeutic effect of intravenous immunoglobulin (IVIG) in women with recurrent pregnancy loss (RPL). METHOD OF STUDY: This was a retrospective observational study. Total 189 RPL women who experienced >=2 miscarriages were enrolled and investigated conventional etiologies, thrombophilia, and cellular immunity. Patients were divided into four groups; known etiology with (Gr1) and without cellular immune abnormality (Gr2), unknown etiology with (Gr3) and without cellular immune abnormality (Gr4). IVIG was administrated from early pregnancy to 30 weeks of gestation to women with cellular immune abnormality (Gr1 + Gr3). RESULTS: Cellular immune abnormalities (increased level or cytotoxicity of NK cells and Th1/Th2 ratio) were present in 111 of 189 RPL women (58.7%). Live birth rates of women with and without cellular immune abnormality were not different (Gr1 + Gr3, 84.8% versus Gr2 + Gr4, 89.7%). Furthermore, IVIG success rates were the same between Gr1 and Gr3, those who had cellular immune abnormality. Nevertheless lack of an appropriate control in this study, our IVIG outcome demonstrated better live birth rate compared with those of other investigators. CONCLUSION: Treatment modalities stratified by underlying etiologies of RPL may improve pregnancy outcome. Administration of IVIG is likely to have clinical efficacy in RPL women with cellular immune abnormality. PMID- 26510489 TI - Spectrofluorimetric determination of the antineoplastic agent lomustine based on the sensitizing effect of beta-cyclodextrin. AB - The effects of solvent dipolarity/polarizability and solvent-solute hydrogen bonding on the photophysical properties of the antineoplastic drug lomustine were analysed by means of the linear solvation energy relationship (LSER) concept proposed by Kamlet and Taft. The LSER method enabled the overall solvent effects to be quantitatively estimated and separated into specific and non-specific contributions. The molecular encapsulation of lomustine by beta-cyclodextrin (beta-CD) has been studied using fluorescence spectroscopy. The results are discussed in terms of the binding parameter and the effect of the solvent used. It was concluded that beta-CD forms a 1:1 inclusional complex with lomustine in acetonitrile solution and its association constant was calculated to be 500 M( 1). In addition, and for the first time, a simple, rapid and high sensitive fluorimetric method for the determination of lomustine was developed based upon the enhancement effect produced through complex formation with beta-CD. The new approach for the quantification of lomustine in the presence of beta-CD was described in aqueous and organic solutions. Better limits of detection (0.31 ug ml(-1)) and quantification (1.05 ug ml(-1)) were obtained in aqueous solution with respect to those obtained in organic solvent. PMID- 26510490 TI - Patients With Spina Bifida and Their Caregivers' Feelings About Intermittent Bladder Catheterization in Brazil and Germany: A Correlational Study. AB - : A major complication for individuals with spina bifida (SB) is managing their neurogenic bladder. For many, this process evokes negative feelings associated with guilt, dependence, and lack of self-worth. PURPOSE: The aim of the study was to compare feelings that hinder the performing of intermittent bladder catheterization reported by individuals with SB and their families in two countries of different sociocultural characteristics: Brazil and Germany. DESIGN AND METHODS: Quantitative and comparative study with convenience sampling. The sample comprised 200 SB patients and their caregivers, 100 from Brazil and 100 from Germany. FINDINGS: When asked about the existence of negative feelings or ideas that may hinder the performance of key person responsible for IC, 155 (77.5%) participants did not report such feelings. On the other hand, 45 (22.5%) reported emotional difficulties; among these participants, 31 (69%) were Brazilians and 14 (31%) were Germans. CONCLUSIONS AND CLINICAL RELEVANCE: Although emotional factors are important to the adjustment of using IC methods for bladder management, the majority of people with SB and their caregivers seem to report no major emotional difficulties with this process. Yet a considerable group of participants did report such emotional difficulties associated with fear and shame. Knowing more about the factors associated with such negative feelings can facilitate interactions, provide mutual aid, and assist with resolution of practical concerns related to intermittent bladder catheterization. PMID- 26510491 TI - In Situ Raman Monitoring of Silver(I)-Aided Laser-Driven Cleavage Reaction of Cyclobutane. AB - The cyclobutane cleavage reaction is an important process and has received continuous interest. Herein, we demonstrate the visible laser-driven cleavage reaction of cyclobutane in crystal form by using in situ Raman spectroscopy. Silver(I) coordination-induced strain and thermal effects from the laser irradiation are the two main driving forces for the cleavage of cyclobutane crystals. This work may open up a new avenue for studying cyclobutane cleavage reactions, as compared to the conventional routes using ex situ techniques. PMID- 26510492 TI - Formate: an Energy Storage and Transport Bridge between Carbon Dioxide and a Formate Fuel Cell in a Single Device. AB - We demonstrate the first device to our knowledge that uses a solar panel to power the electrochemical reduction of dissolved carbon dioxide (carbonate) into formate that is then used in the same device to operate a direct formate fuel cell (DFFC). The electrochemical reduction of carbonate is carried out on a Sn electrode in a reservoir that maintains a constant carbon balance between carbonate and formate. The electron-rich formate species is converted by the DFFC into electrical energy through electron release. The product of DFFC operation is the electron-deficient carbonate species that diffuses back to the reservoir bulk. It is possible to continuously charge the device using alternative energy (e.g., solar) to convert carbonate to formate for on-demand use in the DFFC; the intermittent nature of alternative energy makes this an attractive design. In this work, we demonstrate a proof-of-concept device that performs reduction of carbonate, storage of formate, and operation of a DFFC. PMID- 26510493 TI - Implementing health promotion programmes in schools: a realist systematic review of research and experience in the United Kingdom. AB - BACKGROUND: Schools have long been viewed as a good setting in which to encourage healthy lifestyles amongst children, and schools in many countries aspire to more comprehensive, integrated approaches to health promotion. Recent reviews have identified evidence of the effects of school health promotion on children's and young people's health. However, understanding of how such programmes can be implemented in schools is more limited. METHODS: We conducted a realist review to identify the conditions and actions which lead to the successful implementation of health promotion programmes in schools. We used the international literature to develop programme theories which were then tested using evaluations of school health promotion programmes conducted in the United Kingdom (UK). Iterative searching and screening was conducted to identify sources and clear criteria applied for appraisal of included sources. A review advisory group comprising educational and public health practitioners, commissioners, and academics was established at the outset. RESULTS: In consultation with the review advisory group, we developed four programme theories (preparing for implementation, initial implementation, embedding into routine practice, adaptation and evolution); these were then refined using the UK evaluations in the review. This enabled us to identify transferable mechanisms and enabling and constraining contexts and investigate how the operation of mechanisms differed in different contexts. We also identified steps that should be taken at a senior level in relation to preparing for implementation (which revolved around negotiation about programme delivery) and initial implementation (which centred on facilitation, support, and reciprocity-the latter for both programme deliverers and pupils). However, the depth and rigour of evidence concerning embedding into routine practice and adaptation and evolution was limited. CONCLUSIONS: Our findings provide guidance for the design, implementation, and evaluation of health promotion in schools and identify the areas where further research is needed. PMID- 26510494 TI - Lipid signalling in plant responses to abiotic stress. AB - Lipids are one of the major components of biological membranes including the plasma membrane, which is the interface between the cell and the environment. It has become clear that membrane lipids also serve as substrates for the generation of numerous signalling lipids such as phosphatidic acid, phosphoinositides, sphingolipids, lysophospholipids, oxylipins, N-acylethanolamines, free fatty acids and others. The enzymatic production and metabolism of these signalling molecules are tightly regulated and can rapidly be activated upon abiotic stress signals. Abiotic stress like water deficit and temperature stress triggers lipid dependent signalling cascades, which control the expression of gene clusters and activate plant adaptation processes. Signalling lipids are able to recruit protein targets transiently to the membrane and thus affect conformation and activity of intracellular proteins and metabolites. In plants, knowledge is still scarce of lipid signalling targets and their physiological consequences. This review focuses on the generation of signalling lipids and their involvement in response to abiotic stress. We describe lipid-binding proteins in the context of changing environmental conditions and compare different approaches to determine lipid-protein interactions, crucial for deciphering the signalling cascades. PMID- 26510495 TI - Diverse routes to liver regeneration. AB - The liver's ability to regenerate is indisputable; for example, after a two thirds partial hepatectomy in rats all residual hepatocytes can divide, questioning the need for a specific stem cell population. On the other hand, there is a potential stem cell compartment in the canals of Hering, giving rise to ductular reactions composed of hepatic progenitor cells (HPCs) when the liver's ability to regenerate is hindered by replicative senescence, but the functional relevance of this response has been questioned. Several papers have now clarified regenerative mechanisms operative in the mouse liver, suggesting that the liver is possibly unrivalled in its versatility to replace lost tissue. Under homeostatic conditions a perivenous population of clonogenic hepatocytes operates, whereas during chronic damage a minor population of periportal clonogenic hepatocytes come to the fore, while the ability of HPCs to completely replace the liver parenchyma has now been shown. PMID- 26510496 TI - Multiclassifier combinatorial proteomics of organelle shadows at the example of mitochondria in chromatin data. AB - Subcellular localization is an important aspect of protein function, but the protein composition of many intracellular compartments is poorly characterized. For example, many nuclear bodies are challenging to isolate biochemically and thus remain inaccessible to proteomics. Here, we explore covariation in proteomics data as an alternative route to subcellular proteomes. Rather than targeting a structure of interest biochemically, we target it by machine learning. This becomes possible by taking data obtained for one organelle and searching it for traces of another organelle. As an extreme example and proof-of concept we predict mitochondrial proteins based on their covariation in published interphase chromatin data. We detect about 1/3 of the known mitochondrial proteins in our chromatin data, presumably most as contaminants. However, these proteins are not present at random. We show covariation of mitochondrial proteins in chromatin proteomics data. We then exploit this covariation by multiclassifier combinatorial proteomics to define a list of mitochondrial proteins. This list agrees well with different databases on mitochondrial composition. This benchmark test raises the possibility that, in principle, covariation proteomics may also be applicable to structures for which no biochemical isolation procedures are available. PMID- 26510497 TI - The complex genetic and molecular basis of a model quantitative trait. AB - Quantitative traits are often influenced by many loci with small effects. Identifying most of these loci and resolving them to specific genes or genetic variants is challenging. Yet, achieving such a detailed understanding of quantitative traits is important, as it can improve our knowledge of the genetic and molecular basis of heritable phenotypic variation. In this study, we use a genetic mapping strategy that involves recurrent backcrossing with phenotypic selection to obtain new insights into an ecologically, industrially, and medically relevant quantitative trait-tolerance of oxidative stress, as measured based on resistance to hydrogen peroxide. We examine the genetic basis of hydrogen peroxide resistance in three related yeast crosses and detect 64 distinct genomic loci that likely influence the trait. By precisely resolving or cloning a number of these loci, we demonstrate that a broad spectrum of cellular processes contribute to hydrogen peroxide resistance, including DNA repair, scavenging of reactive oxygen species, stress-induced MAPK signaling, translation, and water transport. Consistent with the complex genetic and molecular basis of hydrogen peroxide resistance, we show two examples where multiple distinct causal genetic variants underlie what appears to be a single locus. Our results improve understanding of the genetic and molecular basis of a highly complex, model quantitative trait. PMID- 26510498 TI - A LAPF/phafin1-like protein regulates TORC1 and lysosomal membrane permeabilization in response to endoplasmic reticulum membrane stress. AB - Lysosomal membrane permeabilization (LMP) is a poorly understood regulator of programmed cell death that involves leakage of luminal lysosomal or vacuolar hydrolases into the cytoplasm. In Saccharomyces cerevisiae, LMP can be induced by antifungals and endoplasmic reticulum stressors when calcineurin also has been inactivated. A genome-wide screen revealed Pib2, a relative of LAPF/phafin1 that regulates LMP in mammals, as a pro-LMP protein in yeast. Pib2 associated with vacuolar and endosomal limiting membranes in unstressed cells in a manner that depended on its FYVE domain and on phosphatidylinositol 3-phosphate (PI(3)P) biosynthesis. Genetic experiments suggest that Pib2 stimulates the activity of TORC1, a vacuole-associated protein kinase that is sensitive to rapamycin, in a pathway parallel to the Ragulator/EGO complex containing the GTPases Gtr1 and Gtr2. A hyperactivating mutation in the catalytic subunit of TORC1 restored LMP to the gtr1? and pib2? mutants and also prevented the synthetic lethality of the double mutants. These findings show novel roles of PI(3)P and Pib2 in the regulation of TORC1, which in turn promoted LMP and nonapoptotic death of stressed cells. Rapamycin prevented the death of the pathogenic yeast Candida albicans during exposure to fluconazole plus a calcineurin inhibitor, suggesting that TORC1 broadly promotes sensitivity to fungistats in yeasts. PMID- 26510499 TI - OCRL1 engages with the F-BAR protein pacsin 2 to promote biogenesis of membrane trafficking intermediates. AB - Mutation of the inositol 5-phosphatase OCRL1 causes Lowe syndrome and Dent-2 disease. Loss of OCRL1 function perturbs several cellular processes, including membrane traffic, but the underlying mechanisms remain poorly defined. Here we show that OCRL1 is part of the membrane-trafficking machinery operating at the trans-Golgi network (TGN)/endosome interface. OCRL1 interacts via IPIP27A with the F-BAR protein pacsin 2. OCRL1 and IPIP27A localize to mannose 6-phosphate receptor (MPR)-containing trafficking intermediates, and loss of either protein leads to defective MPR carrier biogenesis at the TGN and endosomes. OCRL1 5 phosphatase activity, which is membrane curvature sensitive, is stimulated by IPIP27A-mediated engagement of OCRL1 with pacsin 2 and promotes scission of MPR containing carriers. Our data indicate a role for OCRL1, via IPIP27A, in regulating the formation of pacsin 2-dependent trafficking intermediates and reveal a mechanism for coupling PtdIns(4,5)P2 hydrolysis with carrier biogenesis on endomembranes. PMID- 26510500 TI - Tousled-like kinase regulates cytokine-mediated communication between cooperating cell types during collective border cell migration. AB - Collective cell migration is emerging as a major contributor to normal development and disease. Collective movement of border cells in the Drosophila ovary requires cooperation between two distinct cell types: four to six migratory cells surrounding two immotile cells called polar cells. Polar cells secrete a cytokine, Unpaired (Upd), which activates JAK/STAT signaling in neighboring cells, stimulating their motility. Without Upd, migration fails, causing sterility. Ectopic Upd expression is sufficient to stimulate motility in otherwise immobile cells. Thus regulation of Upd is key. Here we report a limited RNAi screen for nuclear proteins required for border cell migration, which revealed that the gene encoding Tousled-like kinase (Tlk) is required in polar cells for Upd expression without affecting polar cell fate. In the absence of Tlk, fewer border cells are recruited and motility is impaired, similar to inhibition of JAK/STAT signaling. We further show that Tlk in polar cells is required for JAK/STAT activation in border cells. Genetic interactions further confirmed Tlk as a new regulator of Upd/JAK/STAT signaling. These findings shed light on the molecular mechanisms regulating the cooperation of motile and nonmotile cells during collective invasion, a phenomenon that may also drive metastatic cancer. PMID- 26510502 TI - The endocytic recycling compartment maintains cargo segregation acquired upon exit from the sorting endosome. AB - The endocytic recycling compartment (ERC) is a series of perinuclear tubular and vesicular membranes that regulates recycling to the plasma membrane. Despite evidence that cargo is sorted at the early/sorting endosome (SE), whether cargo mixes downstream at the ERC or remains segregated is an unanswered question. Here we use three-dimensional (3D) structured illumination microscopy and dual-channel and 3D direct stochastic optical reconstruction microscopy (dSTORM) to obtain new information about ERC morphology and cargo segregation. We show that cargo internalized either via clathrin-mediated endocytosis (CME) or independently of clathrin (CIE) remains segregated in the ERC, likely on distinct carriers. This suggests that no further sorting occurs upon cargo exit from SE. Moreover, 3D dSTORM data support a model in which some but not all ERC vesicles are tethered by contiguous "membrane bridges." Furthermore, tubular recycling endosomes preferentially traffic CIE cargo and may originate from SE membranes. These findings support a significantly altered model for endocytic recycling in mammalian cells in which sorting occurs in peripheral endosomes and segregation is maintained at the ERC. PMID- 26510501 TI - Lamin B1 protein is required for dendrite development in primary mouse cortical neurons. AB - Lamin B1, a key component of the nuclear lamina, plays an important role in brain development and function. A duplication of the human lamin B1 (LMNB1) gene has been linked to adult-onset autosomal dominant leukodystrophy, and mouse and human loss-of-function mutations in lamin B1 are susceptibility factors for neural tube defects. In the mouse, experimental ablation of endogenous lamin B1 (Lmnb1) severely impairs embryonic corticogenesis. Here we report that in primary mouse cortical neurons, LMNB1 overexpression reduces axonal outgrowth, whereas deficiency of endogenous Lmnb1 results in aberrant dendritic development. In the absence of Lmnb1, both the length and complexity of dendrites are reduced, and their growth is unresponsive to KCl stimulation. This defective dendritic outgrowth stems from impaired ERK signaling. In Lmnb1-null neurons, ERK is correctly phosphorylated, but phospho-ERK fails to translocate to the nucleus, possibly due to delocalization of nuclear pore complexes (NPCs) at the nuclear envelope. Taken together, these data highlight a previously unrecognized role of lamin B1 in dendrite development of mouse cortical neurons through regulation of nuclear shuttling of specific signaling molecules and NPC distribution. PMID- 26510503 TI - Angiotensin II down-regulates nephrin-Akt signaling and induces podocyte injury: roleof c-Abl. AB - Recent studies have shown that nephrin plays a vital role in angiotensin II (Ang II)-induced podocyte injury and thus contributes to the onset of proteinuria and the progression of renal diseases, but its specific mechanism remains unclear. c Abl is an SH2/SH3 domain-containing nonreceptor tyrosine kinase that is involved in cell survival and regulation of the cytoskeleton. Phosphorylated nephrin is able to interact with molecules containing SH2/SH3 domains, suggesting that c-Abl may be a downstream molecule of nephrin signaling. Here we report that Ang II infused rats developed proteinuria and podocyte damage accompanied by nephrin dephosphorylation and minimal interaction between nephrin and c-Abl. In vitro, Ang II induced podocyte injury and nephrin and Akt dephosphorylation, which occurred in tandem with minimal interaction between nephrin and c-Abl. Moreover, Ang II promoted c-Abl phosphorylation and interaction between c-Abl and SH2 domain-containing 5'-inositol phosphatase 2 (SHIP2). c-Abl small interfering RNA (siRNA) and STI571 (c-Abl inhibitor) provided protection against Ang II-induced podocyte injury, suppressed the Ang II-induced c-Abl-SHIP2 interaction and SHIP2 phosphorylation, and maintained a stable level of nephrin phosphorylation. These results indicate that c-Abl is a molecular chaperone of nephrin signaling and the SHIP2-Akt pathway and that the released c-Abl contributes to Ang II-induced podocyte injury. PMID- 26510504 TI - Outcome of assisted reproductive technology in men with treated and untreated varicocele: systematic review and meta-analysis. AB - Varicocele affects approximately 35%-40% of men presenting for an infertility evaluation. There is fair evidence indicating that surgical repair of clinical varicocele improves semen parameters, decreases seminal oxidative stress and sperm DNA fragmentation, and increases the chances of natural conception. However, it is unclear whether performing varicocelectomy in men with clinical varicocele prior to assisted reproductive technology (ART) improve treatment outcomes. The objective of this study was to evaluate the role of varicocelectomy on ART pregnancy outcomes in nonazoospermic infertile men with clinical varicocele. An electronic search was performed to collect all evidence that fitted our eligibility criteria using the MEDLINE and EMBASE databases until April 2015. Four retrospective studies were included, all of which involved intracytoplasmic sperm injection (ICSI), and accounted for 870 cycles (438 subjected to ICSI with prior varicocelectomy, and 432 without prior varicocelectomy). There was a significant increase in the clinical pregnancy rates (OR = 1.59, 95% CI: 1.19-2.12, I 2 = 25%) and live birth rates (OR = 2.17, 95% CI: 1.55-3.06, I 2 = 0%) in the varicocelectomy group compared to the group subjected to ICSI without previous varicocelectomy. Our results indicate that performing varicocelectomy in patients with clinical varicocele prior to ICSI is associated with improved pregnancy outcomes. PMID- 26510505 TI - Use of early chemotherapy for hormone-sensitive prostate cancer: time for CHAARTED. PMID- 26510506 TI - Proteomic analysis of mature and immature ejaculated spermatozoa from fertile men. AB - Dysfunctional spermatozoa maturation is the main reason for the decrease in sperm motility and morphology in infertile men. Ejaculated spermatozoa from healthy fertile men were separated into four fractions using three-layer density gradient. Proteins were extracted and bands were digested on a LTQ-Orbitrap Elite hybrid mass spectrometer system. Functional annotations of proteins were obtained using bioinformatics tools and pathway databases. Western blotting was performed to verify the expression levels of the proteins of interest. 1469 proteins were identified in four fractions of spermatozoa. The number of detected proteins decreased according to the maturation level of spermatozoa. During spermatozoa maturation, proteins involved in gamete generation, cell motility, energy metabolism and oxidative phosphorylation processes showed increasing expression levels and those involved in protein biosynthesis, protein transport, protein ubiquitination, and response to oxidative stress processes showed decreasing expression levels. We validated four proteins (HSP 70 1A, clusterin, tektin 2 and tektin 3) by Western blotting. The study shows protein markers that may provide insight into the ejaculated spermatozoa proteins in different stages of sperm maturation that may be altered or modified in infertile men. PMID- 26510507 TI - Can radical prostatectomy shortly after prostate biopsy affect intra-operative and postoperative outcomes? PMID- 26510508 TI - Unravelling structural ambiguities in lithium- and manganese-rich transition metal oxides. AB - Although Li- and Mn-rich transition metal oxides have been extensively studied as high-capacity cathode materials for Li-ion batteries, the crystal structure of these materials in their pristine state is not yet fully understood. Here we apply complementary electron microscopy and spectroscopy techniques at multi length scale on well-formed Li1.2(Ni0.13Mn0.54Co0.13)O2 crystals with two different morphologies as well as two commercially available materials with similar compositions, and unambiguously describe the structural make-up of these samples. Systematically observing the entire primary particles along multiple zone axes reveals that they are consistently made up of a single phase, save for rare localized defects and a thin surface layer on certain crystallographic facets. More specifically, we show the bulk of the oxides can be described as an aperiodic crystal consisting of randomly stacked domains that correspond to three variants of monoclinic structure, while the surface is composed of a Co- and/or Ni-rich spinel with antisite defects. PMID- 26510509 TI - Coherent ultrafast spin-dynamics probed in three dimensional topological insulators. AB - Topological insulators are candidates to open up a novel route in spin based electronics. Different to traditional ferromagnetic materials, where the carrier spin-polarization and magnetization are based on the exchange interaction, the spin properties in topological insulators are based on the coupling of spin- and orbit interaction connected to its momentum. Specific ways to control the spin polarization with light have been demonstrated: the energy momentum landscape of the Dirac cone provides spin-momentum locking of the charge current and its spin. We investigate a spin-related signal present only during the laser excitation studying real and imaginary part of the complex Kerr angle by disentangling spin and lattice contributions. This coherent signal is only present at the time of the pump-pulses' light field and can be described in terms of a Raman coherence time. The Raman transition involves states at the bottom edge of the conduction band. We demonstrate a coherent femtosecond control of spin-polarization for electronic states at around the Dirac cone. PMID- 26510510 TI - Renal disease and accidental falls: a review of published evidence. AB - BACKGROUND: The pathogenesis of falling is complex, and identification of risk factors may be essential for prevention. The relationship between renal disease and falls is unclear, and the goal of this study was to collect the available evidence and investigate the relationship between accidental falls and renal dysfunction. METHODS: Electronic searches were performed in the MEDLINE, Scopus, Ovid SP and Web of Science databases to identify the appropriate literature. The themes used were: falls (combined in the title/abstract fall or falls or falling or faller* or fallen or slip* or trip* or (MeSH) accidental falls) and renal insufficiency (chronic or renal insufficiency or kidney diseases combined in title/abstract renal disease* or kidney disease* or renal insufficiency or kidney insufficiency or kidney failure or renal failure or MeSH renal insufficiency, chronic or renal insufficiency or kidney diseases). The incidence, risk factors, complications, and characteristics of the falls were analyzed. RESULTS: Eight prospective cohorts including five cross-sectional studies, and one case-control study were identified. No randomized controlled studies were found. The incidence of falls in chronic kidney disease patients ranged between 1.18 and 1.60 fall/patient year. These were frequent in frail older adults on hemodialysis treatment. Falling relapses in the same group of patients caused serious consequences. Data on pre-end stage renal disease (ESRD) were scarce. CONCLUSIONS: The risk of falling appears to be common in patients with renal dysfunction especially in older adults undergoing hemodialysis. On the other hand, we could not find any conclusive data on pre-ESRD patients. PMID- 26510511 TI - Hybrid nanoprobes of bismuth sulfide nanoparticles and CdSe/ZnS quantum dots for mouse computed tomography/fluorescence dual mode imaging. AB - BACKGROUND: X-ray computed tomography (CT) imaging can be used to reveal the three-dimensional structure of deep tissue with high spatial resolution. However, it cannot reveal molecular or cellular changes, and has great limitations in terms of specificity and sensitivity. Fluorescence imaging technology is one of the main methods used for the study of molecular events in vivo and has important applications in life science research. Therefore, the combination of CT and fluorescence imaging is an ideal dual-modal molecular imaging method, which can provide data on both molecular function and tissue structure, and has important research value. In a previous study, Bi2S3 nanoparticles were wrapped with quantum dots in SiO2 to generate CT and fluorescence imaging. However, this type of probe led to low survival and caused innegligible in vivo toxicity in mice. Therefore, it is necessary to develop new multifunctional probes that demonstrate biocompatibility and safety in vivo. METHODS: A polyethylene glycol-phospholipid bilayer structure was used to synthesize hybrid clusters containing hydrophobic Bi2S3 nanoparticles and quantum dots for combined CT/fluorescence imaging. Mean particle size, polydispersity index, and zeta potential were used to study the stability over an 8-week test period. In vivo CT and fluorescence imaging experiments were performed, and the in vivo safety of the probe was evaluated, using histopathological, biochemical, and blood analyses. RESULTS: The probe distinctly enhanced the CT contrast and had fluorescence imaging capability. In addition, the nanocomposite hybrid clusters showed a longer circulation time (>4 h) than iobitridol. The results also showed that the Bi2S3-QD@DSPE probe had good biocompatibility and safety, and did not affect normal organ functioning. CONCLUSIONS: Bi2S3-QD@DSPE hybrid clusters exhibited remarkable performance in CT angiography and fluorescence imaging in vivo. PMID- 26510512 TI - Occupational and non-occupational strains should be concomitantly considered in research on burnout, organizational commitment, and turnover intention. PMID- 26510514 TI - Subject-Specific Fully-Coupled and One-Way Fluid-Structure Interaction Models for Modeling of Carotid Atherosclerotic Plaques in Humans. AB - BACKGROUND: Hemodynamics play an important role in the development and progression of carotid atherosclerosis, and may be important in the assessment of plaque vulnerability. The aim of this study was to develop a system to assess the hemodynamics of carotid atherosclerotic plaques using subject-specific fluid structure interaction (FSI) models based on magnetic resonance imaging (MRI). MATERIAL AND METHODS: Models of carotid bifurcations (n=86 with plaques from 52 patients, n=14 normal carotids from 12 participants) were obtained at the Department of Radiology, Beijing Tian Tan Hospital between 2010 and 2013. The maximum von Mises stress, minimum pressure, and flow velocity values were assessed at the most stenotic site in patients, or at the carotid bifurcations in healthy volunteers. Results of one-way FSI were compared with fully-coupled FSI for the plaques of 19 randomly selected models. RESULTS: The maximum von Mises stress and the minimum pressure and velocity were significantly increased in the stenosis group compared with controls based on one-way FSI (all P<0.05). The maximum von Mises stress and the minimum pressure were significantly higher and the velocity was significantly lower based on fully coupled FSI compared with on way FSI (all P<0.05). Although there were differences in numerical values, both methods were equivalent. The maximum von Mises stress of vulnerable plaques was significantly higher than stable plaques (P<0.001). The maximum von Mises stress of the group with fibrous cap defect was significantly higher than the group without fibrous cap defect (P=0.001). CONCLUSIONS: The hemodynamics of atherosclerotic plaques can be assessed noninvasively using subject-specific models of FSI based on MRI. PMID- 26510515 TI - Production of reproductively sterile fish by a non-transgenic gene silencing technology. AB - We developed a novel bath-immersion technology to produce large numbers of infertile fish. As seafood consumption shifts from fishery harvests towards artificially propagated species, optimization of aquaculture practices will be necessary to maximize food production and minimize ecological impact. Farming infertile fish is the most effective genetic-containment strategy to support the development of environmentally-responsible aquaculture. We discovered that a molecular transporter, Vivo, can effectively carry the Morpholino oligomer (MO) across the chorion, enter the embryo and reach target cells. Vivo-conjugated MO against zebrafish deadend (dnd-MO-Vivo) effectively caused primordial germ cell mis-migration and differentiation into somatic cells, which resulted in generation of infertile fish. Optimal conditions were achieved when embryos, immediately after fertilization, were immersed with dnd-MO-Vivo at the initial concentration of either 60 or 40 MUM followed by a lower serially diluted concentration. Under these conditions, 100% induced sterility was achieved even when the total immersion time was reduced from 24 to 5 hours. In 8 independent experiments, 736 adults developed from these conditions were all found to be infertile fish that possessed minimally-developed gonads that lacked any gametes. The results demonstrate that dnd-MO-Vivo bath immersion is an effective strategy to produce infertile fish without introducing transgenic modifications. PMID- 26510516 TI - Occult Klebsiella pneumoniae bacteremia at emergency department: A single center experience. AB - BACKGROUND/PURPOSE: Patients with undetected bacteremia when discharged from a hospital are considered to have occult bacteremia. Klebsiella pneumoniae bacteremia (KPB) is endemic to Taiwan. Our purpose was to study the impact of occult KPB. METHODS: We retrospectively reviewed the records of patients who were discharged from our emergency department (ED) and subsequently diagnosed with KPB (occult bacteremia), from January 2008 to March 2014. All patients are followed for at least 3 months after the index ED visit. The study group was compared to KPB patients who were directly hospitalized (DH) from ED in 2008. Thirty-day mortality was the primary endpoint. RESULTS: A total of 913 patients were admitted to our ED with KPB, and 88 of these patients (9.6%) had occult KPB. Among them, 43 had second ED visit and 41 were admitted. The overall 30-day mortality was 2.3%. Relative to patients with occult KPB, DH patients had more respiratory tract infections (p < 0.001) but fewer other intra-abdominal infections (p = 0.015). Liver abscess was the major diagnosis for the second ED visit (37.2%). DH patients had significantly greater 30-day mortality than that of overall patients with KPB (19.2% vs.2.3%, p < 0.001). CONCLUSION: Most patients with occult KPB had favorable outcomes, but about half of them required a second ED visit. Clinicians should aggressively follow patients with occult KPB and should seek to identify the focus of infection in this endemic area. PMID- 26510517 TI - Cryofibrinogenemia and risk of cancer in cryoglobulinemic patients without vasculitis criteria. PMID- 26510518 TI - Parsimonious description for predicting high-dimensional dynamics. AB - When we observe a system, we often cannot observe all its variables and may have some of its limited measurements. Under such a circumstance, delay coordinates, vectors made of successive measurements, are useful to reconstruct the states of the whole system. Although the method of delay coordinates is theoretically supported for high-dimensional dynamical systems, practically there is a limitation because the calculation for higher-dimensional delay coordinates becomes more expensive. Here, we propose a parsimonious description of virtually infinite-dimensional delay coordinates by evaluating their distances with exponentially decaying weights. This description enables us to predict the future values of the measurements faster because we can reuse the calculated distances, and more accurately because the description naturally reduces the bias of the classical delay coordinates toward the stable directions. We demonstrate the proposed method with toy models of the atmosphere and real datasets related to renewable energy. PMID- 26510519 TI - Oxidative DNA damage in mouse sperm chromosomes: Size matters. AB - Normal embryo and foetal development as well as the health of the progeny are mostly dependent on gamete nuclear integrity. In the present study, in order to characterize more precisely oxidative DNA damage in mouse sperm we used two mouse models that display high levels of sperm oxidative DNA damage, a common alteration encountered both in in vivo and in vitro reproduction. Immunoprecipitation of oxidized sperm DNA coupled to deep sequencing showed that mouse chromosomes may be largely affected by oxidative alterations. We show that the vulnerability of chromosomes to oxidative attack inversely correlated with their size and was not linked to their GC richness. It was neither correlated with the chromosome content in persisting nucleosomes nor associated with methylated sequences. A strong correlation was found between oxidized sequences and sequences rich in short interspersed repeat elements (SINEs). Chromosome position in the sperm nucleus as revealed by fluorescent in situ hybridization appears to be a confounder. These data map for the first time fragile mouse sperm chromosomal regions when facing oxidative damage that may challenge the repair mechanisms of the oocyte post-fertilization. PMID- 26510520 TI - Direct Conversion of CH3NH3PbI3 from Electrodeposited PbO for Highly Efficient Planar Perovskite Solar Cells. AB - Organic-inorganic hybrid perovskite materials have recently been identified as a promising light absorber for solar cells. In the efficient solar cells, the perovskite active layer has generally been fabricated by either vapor deposition or two-step sequential deposition process. Herein, electrochemically deposited PbO film is in situ converted into CH3NH3PbI3 through solid-state reaction with adjacent CH3NH3I layer, exhibiting a large-scale flat and uniform thin film with fully substrate coverage. The resultant planar heterojunction photovoltaic device yields a best power conversion efficiency of 14.59% and an average power conversion efficiency of 13.12 +/- 1.08% under standard AM 1.5 conditions. This technique affords a facile and environment-friendly method for the fabrication of the perovskite based solar cells with high reproducibility, paving the way for the practical application. PMID- 26510521 TI - Discretized knot motion on a tensioned fiber induced by transverse waves. AB - Topological entanglement is a ubiquitous feature of many biological as well as artificial polymers and fibers. While the equilibrium properties of entangled chains have been the subject of several studies, little is known about their out of-equilibrium behavior. Here, we address the problem of a stretched knotted fiber driven by a periodic force applied to one of its termini. We show that the onset of standing waves kinetically traps the knot in spatially localized states where the amplitude of the oscillations is maximal, while the knot normal diffusive dynamics is replaced by a discrete jump dynamics. PMID- 26510522 TI - Synthesis and mode of action of oligomeric sesquiterpene lactones. AB - Covering: up to 2015In this highlight we describe two case studies from our laboratory, involving the biomimetic syntheses and the biological mechanism elucidation of the bioactive oligomeric sesquiterpenoids, (+)-ainsliadimer A () and (-)-ainsliatrimer A (). Ainsliadimer A possesses potent anti-inflammatory activity by inhibition of the NF-kappaB signalling pathway via binding at a previously untargeted allosteric site. (-)-Ainsliatrimer A induces apoptosis in cancer cells by activation of PPARgamma. Furthermore, we highlight a new bioorthogonal ligation (TQ-ligation) developed in our laboratory which facilitates the target identification of complex natural products via pre-target fluorescence imaging and affinity chromatography. Generally, this paper will discuss the complete process from total synthesis to biological studies of complex natural products, and from the establishment of new bio-orthogonal chemistry to successful target identification. Our approach provides a systematic and efficient methodology for addressing the challenge of natural product target identification. PMID- 26510524 TI - Healthcare resource utilization and cost in dementia: are there differences between patients screened positive for dementia with and those without a formal diagnosis of dementia in primary care in Germany? - ERRATUM. AB - In the above mentioned article by Michalowsky et al., Johannes Hertel was mistakenly omitted from the authorship list. This error has been corrected in the print, PDF and HTML versions of the original article. PMID- 26510523 TI - Field evaluation of the establishment potential of wMelPop Wolbachia in Australia and Vietnam for dengue control. AB - BACKGROUND: Introduced Wolbachia bacteria can influence the susceptibility of Aedes aegypti mosquitoes to arboviral infections as well as having detrimental effects on host fitness. Previous field trials demonstrated that the wMel strain of Wolbachia effectively and durably invades Ae. aegypti populations. Here we report on trials of a second strain, wMelPop-PGYP Wolbachia, in field sites in northern Australia (Machans Beach and Babinda) and central Vietnam (Tri Nguyen, Hon Mieu Island), each with contrasting natural Ae. aegypti densities. METHODS: Mosquitoes were released at the adult or pupal stages for different lengths of time at the sites depending on changes in Wolbachia frequency as assessed through PCR assays of material collected through Biogents-Sentinel (BG-S) traps and ovitraps. Adult numbers were also monitored through BG-S traps. Changes in Wolbachia frequency were compared across hamlets or house blocks. RESULTS: Releases of adult wMelPop-Ae. aegypti resulted in the transient invasion of wMelPop in all three field sites. Invasion at the Australian sites was heterogeneous, reflecting a slower rate of invasion in locations where background mosquito numbers were high. In contrast, invasion across Tri Nguyen was relatively uniform. After cessation of releases, the frequency of wMelPop declined in all sites, most rapidly in Babinda and Tri Nguyen. Within Machans Beach the rate of decrease varied among areas, and wMelPop was detected for several months in an area with a relatively low mosquito density. CONCLUSIONS: These findings highlight challenges associated with releasing Wolbachia-Ae. aegypti combinations with low fitness, albeit strong virus interference properties, as a means of sustainable control of dengue virus transmission. PMID- 26510525 TI - Development and validation of a self-administered questionnaire to estimate the distance and mode of children's travel to school in urban India. AB - BACKGROUND: Although some 300 million Indian children travel to school every day, little is known about how they get there. This information is important for transport planners and public health authorities. This paper presents the development of a self-administered questionnaire and examines its reliability and validity in estimating distance and mode of travel to school in a low resource urban setting. METHODS: We developed a questionnaire on children's travel to school. We assessed test re-test reliability by repeating the questionnaire one week later (n = 61). The questionnaire was improved and re-tested (n = 68). We examined the convergent validity of distance estimates by comparing estimates based on the nearest landmark to children's homes with a 'gold standard' based on one-to-one interviews with children using detailed maps (n = 50). RESULTS: Most questions showed fair to almost perfect agreement. Questions on usual mode of travel (kappa 0.73- 0.84) and road injury (kappa 0.61- 0.72) were found to be more reliable than those on parental permissions (kappa 0.18- 0.30), perception of safety (kappa 0.00- 0.54), and physical activity (kappa -0.01- 0.07). The distance estimated by the nearest landmark method was not significantly different than the in-depth method for walking , 52 m [95 % CI -32 m to 135 m], 10 % of the mean difference, and for walking and cycling combined, 65 m [95 % CI -30 m to 159 m], 11 % of the mean difference. For children who used motorized transport (excluding private school bus), the nearest landmark method under-estimated distance by an average of 325 metres [95 % CI -664 m to 1314 m], 15 % of the mean difference. CONCLUSIONS: A self-administered questionnaire was found to provide reliable information on the usual mode of travel to school, and road injury, in a small sample of children in Hyderabad, India. The 'nearest landmark' method can be applied in similar low-resource settings, for a reasonably accurate estimate of the distance from a child's home to school. PMID- 26510526 TI - The effect of Astym(r) Therapy on muscle strength: a blinded, randomized, clinically controlled trial. AB - BACKGROUND: Astym((r)) therapy is a manual therapy intervention used to stimulate tissue healing, decrease pain, improve mobility, and improve muscle performance associated with musculoskeletal pathology. The purpose of this study was to determine if Astym therapy administered to the lower extremity would result in an immediate change of maximal force output during a unilateral isometric squat test among individuals with a lower extremity injury. METHODS: Forty-five subjects (14 males; 31 females) between 18 and 65 years of age were randomized into 3 treatment groups: 1) Control group - received no treatment 2) Placebo group - received a sham Astym treatment 3) Astym therapy group- received Astym therapy to the lower extremity. A baseline measure of maximal force output (pre-test) during a unilateral isometric squat was performed. The subjects then received the designated treatment intervention. Immediately following the treatment intervention, maximal force output (post-test) was retested using identical testing procedures by an investigator who was blinded to the treatment intervention received by the subjects. The percent change of maximal force output from pre-test to post-test measures was compared using a one-way analysis of variance. A Tukey's post-hoc analysis determined the statistical differences between the groups. RESULTS: The treatment intervention had a significant effect on the percent change of maximal force output [F(2,42) = 7.91, p = 0.001]. Tukey's post hoc analysis demonstrated that the percent change of maximal force output was significantly greater in the Astym group (15 +/- 18 % change of Newtons) compared to the placebo (-6 +/- 11 % change of Newtons; p = 0.0001) and control (-1 +/- 17 % change of Newtons; p = 0.0014) groups. No significant difference (p = 0.68) was noted between the control and placebo groups. CONCLUSIONS: Astym therapy to the involved lower extremity increased maximum force output during an isometric squat test immediately following treatment. The results of this study suggest that Astym therapy can immediately improve muscle performance (maximal force output) for patients presenting with muscular weakness caused by a lower extremity musculoskeletal injury. TRIAL REGISTRATION: Clinicaltrials.gov NCT02349230. Registered 23 January 2015. PMID- 26510527 TI - Model-assisted formate dehydrogenase-O (fdoH) gene knockout for enhanced succinate production in Escherichia coli from glucose and glycerol carbon sources. AB - Succinic acid is an important platform chemical that has broad applications and is been listed as one of the top twelve bio-based chemicals produced from biomass by the US Department of Energy. The metabolic role of Escherichia coli formate dehydrogenase-O (fdoH) under anaerobic conditions in relation to succinic acid production remained largely unspecified. Herein we report, what are to our knowledge, the first metabolic fdoH gene knockout that have enhanced succinate production using glucose and glycerol substrates in E. coli. Using the most recent E. coli reconstruction iJO1366, we engineered its host metabolism to enhance the anaerobic succinate production by deleting the fdoH gene, which blocked H(+) conduction across the mutant cell membrane for the enhanced succinate production. The engineered mutant strain BMS4 showed succinate production of 2.05 g l(-1) (41.2-fold in 7 days) from glycerol and .39 g l(-1) (6.2-fold in 1 day) from glucose. This work revealed that a single deletion of the fdoH gene is sufficient to increase succinate production in E. coli from both glucose and glycerol substrates. PMID- 26510528 TI - Enhanced artemisinin yield by expression of rol genes in Artemisia annua. AB - BACKGROUND: Despite of many advances in the treatment of malaria, it is still the fifth most prevalent disease worldwide and is one of the major causes of death in the developing countries which accounted for 584,000 deaths in 2013, as estimated by World Health Organization. Artemisinin from Artemisia annua is still one of the most effective treatments for malaria. Increasing the artemisinin content of A. annua plants by genetic engineering would improve the availability of this much-needed drug. METHODS: In this regard, a high artemisinin-yielding hybrid of A. annua produced by the centre for novel agricultural products of the University of York, UK, was selected (artemisinin maximally 1.4 %). As rol genes are potential candidates of biochemical engineering, genetic transformation of A. annua with Agrobacterium tumefaciens GV3101 harbouring vectors with rol B and rol C genes was carried out with the objective of enhancement of artemisinin content. Transgenic lines produced were analysed by the LC-MS for quantitative analysis of artemisinin and analogues. These high artemisinin yielding transgenics were also analysed by real time quantitative PCR to find the molecular dynamics of artemisinin enhancement. Genes of artemisinin biosynthetic pathway were studied including amorphadiene synthase (ADS), cytochrome P450, (CYP71AV1) and aldehyde dehydrogenase 1 (ALDH1). Trichome-specific fatty acyl-CoA reductase 1(TAFR1) is an enzyme involved in both trichome development and sesquiterpenoid biosynthesis and both processes are important for artemisinin biosynthesis. Thus, real time qPCR analysis of the TAFR1 gene was carried out, and trichome density was determined. RESULTS: Transgenics of rol B gene showed two- to ninefold (the decimal adds nothing in the abstract, please simplify to two- to ninefold) increase in artemisinin, 4-12-fold increase in artesunate and 1.2-3-fold increase in dihydroartemisinin. Whereas in the case of rol C gene transformants, a fourfold increase in artemisinin, four to ninefold increase in artesunate and one to twofold increase in dihydroartemisinin concentration was observed. Transformants with the rol B gene had higher expression of these genes than rol C transformants. TAFR1 was also found to be more expressed in rol gene transgenics than wild type A. annua, which was also in accordance with the trichome density of the respective plant. CONCLUSION: Thus it was proved that rol B and rol C genes are effective in the enhancement of artemisinin content of A. annua, rol B gene being more active to play part in this enhancement than rol C gene. PMID- 26510529 TI - Successful strategies in the discovery of small-molecule epigenetic modulators with anticancer potential. AB - As a class, epigenetic enzymes have been identified as clear targets for cancer therapeutics based on their broad hyperactivity in solid and hematological malignancies. The search for effective inhibitors of histone writers and of histone erasers has been a focus of drug discovery efforts both in academic and pharmaceutical laboratories and has led to the identification of some promising leads. This review focuses on the discovery strategies and preclinical evaluation studies of a subset of the more advanced compounds that target histone writers or histone erasers. The specificity and anticancer potential of these small molecules is discussed within the context of their development pipeline. PMID- 26510530 TI - A Method for Comprehensive Glycosite-Mapping and Direct Quantitation of Serum Glycoproteins. AB - A comprehensive glycan map was constructed for the top eight abundant glycoproteins in plasma using both specific and nonspecific enzyme digestions followed by nano liquid chromatography (LC)-chip/quadrupole time-of-flight mass spectrometry (MS) analysis. Glycopeptides were identified using an in-house software tool, GPFinder. A sensitive and reproducible multiple reaction monitoring (MRM) technique on a triple quadrupole MS was developed and applied to quantify immunoglobulins G, A, M, and their site-specific glycans simultaneously and directly from human serum/plasma without protein enrichments. A total of 64 glycopeptides and 15 peptides were monitored for IgG, IgA, and IgM in a 20 min ultra high performance (UP)LC gradient. The absolute protein contents were quantified using peptide calibration curves. The glycopeptide ion abundances were normalized to the respective protein abundances to separate protein glycosylation from protein expression. This technique yields higher method reproducibility and less sample loss when compared with the quantitation method that involves protein enrichments. The absolute protein quantitation has a wide linear range (3-4 orders of magnitude) and low limit of quantitation (femtomole level). This rapid and robust quantitation technique, which provides quantitative information for both proteins and glycosylation, will further facilitate disease biomarker discoveries. PMID- 26510531 TI - A survey of computational tools for downstream analysis of proteomic and other omic datasets. AB - Proteomics is an expanding area of research into biological systems with significance for biomedical and therapeutic applications ranging from understanding the molecular basis of diseases to testing new treatments, studying the toxicity of drugs, or biotechnological improvements in agriculture. Progress in proteomic technologies and growing interest has resulted in rapid accumulation of proteomic data, and consequently, a great number of tools have become available. In this paper, we review the well-known and ready-to-use tools for classification, clustering and validation, interpretation, and generation of biological information from experimental data. We suggest some rules of thumb for the reader on choosing the best suitable learning method for a particular dataset and conclude with pathway and functional analysis and then provide information about submitting final results to a repository. PMID- 26510532 TI - From conceptual pluralism to practical agreement on policy: global responsibility for global health. AB - BACKGROUND: As the human cost of the global economic crisis becomes apparent the ongoing discussions surrounding the post-2015 global development framework continue at a frenzied pace. Given the scale and scope of increased globalization moving forward in a post-Millennium Development Goals era, to protect and realize health equity for all people, has never been more challenging or more important. The unprecedented nature of global interdependence underscores the importance of proposing policy solutions that advance realizing global responsibility for global health. DISCUSSION: This article argues for advancing global responsibility for global health through the creation of a Global Fund for Health. It suggests harnessing the power of the exceptional response to the combined epidemics of AIDS, TB and Malaria, embodied in the Global Fund to Fight AIDS, Tuberculosis and Malaria, to realize an expanded, reconceptualized Global Fund for Health. However this proposal creates both an analytical quandary embedded in conceptual pluralism and a practical dilemma for the scope and raison d'etre of a new Global Fund for Health. To address these issues we offer a logical framework for moving from conceptual pluralism in the theories supporting global responsibility for health to practical agreement on policy to realize this end. We examine how the innovations flowing from this exceptional response can be coupled with recent ideas and concepts, for example a global social protection floor, a Global Health Constitution or a Framework Convention for Global Health, that share the global responsibility logic that underpins a Global Fund for Health. CONCLUSIONS: The 2014 Lancet Commission on Global Governance for Health Report asks whether a single global health protection fund would be better for global health than the current patchwork of global and national social transfers. We concur with this suggestion and argue that there is much room for practical agreement on a Global Fund for Health that moves from the conceptual level into policies and practice that advance global health. The issues of shared responsibility and mutual accountability feature widely in the post-2015 discussions and need to be addressed in a coherent manner. Our article argues why and how a Global Fund for Health effectuates this, thus advancing global responsibility for global health. PMID- 26510533 TI - Expansion of the neck reconstituted the shoulder-diaphragm in amniote evolution. AB - The neck acquired flexibility through modifications of the head-trunk interface in vertebrate evolution. Although developmental programs for the neck musculoskeletal system have attracted the attention of evolutionary developmental biologists, how the heart, shoulder and surrounding tissues are modified during development has remained unclear. Here we show, through observation of the lateral plate mesoderm at cranial somite levels in chicken-quail chimeras, that the deep part of the lateral body wall is moved concomitant with the caudal transposition of the heart, resulting in the infolding of the expanded cervical lateral body wall into the thorax. Judging from the brachial plexus pattern, an equivalent infolding also appears to take place in mammalian and turtle embryos. In mammals, this infolding process is particularly important because it separates the diaphragm from the shoulder muscle mass. In turtles, the expansion of the cervical lateral body wall affects morphogenesis of the shoulder. Our findings highlight the cellular expansion in developing amniote necks that incidentally brought about the novel adaptive traits. PMID- 26510534 TI - Changes in correlation between promoter methylation and gene expression in cancer. AB - BACKGROUND: Methylation of high-density CpG regions known as CpG Islands (CGIs) has been widely described as a mechanism associated with gene expression regulation. Aberrant promoter methylation is considered a hallmark of cancer involved in silencing of tumor suppressor genes and activation of oncogenes. However, recent studies have also challenged the simple model of gene expression control by promoter methylation in cancer, and the precise mechanism of and role played by changes in DNA methylation in carcinogenesis remains elusive. RESULTS: Using a large dataset of 672 matched cancerous and healthy methylomes, gene expression, and copy number profiles accross 3 types of tissues from The Cancer Genome Atlas (TCGA), we perform a detailed meta-analysis to clarify the interplay between promoter methylation and gene expression in normal and cancer samples. On the one hand, we recover the existence of a CpG island methylator phenotype (CIMP) with prognostic value in a subset of breast, colon and lung cancer samples, where a common subset of promoter CGIs hypomethylated in normal samples become hypermethylated. However, this hypermethylation is not accompanied by a decrease in expression of the corresponding genes, which are already lowly expressed in the normal genes. On the other hand, we identify tissue-specific sets of genes, different between normal and cancer samples, whose inter individual variation in expression is significantly correlated with the variation in methylation of the 3' flanking regions of the promoter CGIs. These subsets of genes are not the same in the different tissues, nor between normal and cancerous samples, but transcription factors are over-represented in all subsets. CONCLUSION: Our results suggest that epigenetic reprogramming in cancer does not contribute to cancer development via direct inhibition of gene expression through promoter hypermethylation. It may instead modify how the expression of a few specific genes, particularly transcription factors, are associated with DNA methylation variations in a tissue-dependent manner. PMID- 26510535 TI - The ear region of earliest known elephant relatives: new light on the ancestral morphotype of proboscideans and afrotherians. AB - One of the last major clades of placental mammals recognized was the Afrotheria, which comprises all main endemic African mammals. This group includes the ungulate-like paenungulates, and among them the elephant order Proboscidea. Among afrotherians, the petrosal anatomy remains especially poorly known in Proboscidea. We provide here the first comparative CT scan study of the ear region of the two earliest known proboscideans (and paenungulates), Eritherium and Phosphatherium, from the mid Palaeocene and early Eocene of Morocco. It is helpful to characterize the ancestral morphotype of Proboscidea to understand petrosal evolution within proboscideans and afrotherians. The petrosal structure of these two taxa shows several differences. Eritherium is more primitive than Phosphatherium and closer to the basal paenungulate Ocepeia in several traits (inflated tegmen tympani, very deep fossa subarcuata and ossified canal for ramus superior of stapedial artery). Phosphatherium, however, retains plesiomorphies such as a true crus commune secundaria. A cladistic analysis of petrosal traits of Eritherium and Phosphatherium among Proboscidea results in a single tree with a low level of homoplasy in which Eritherium, Phosphatherium and Numidotherium are basal. This contrasts with previous phylogenetic studies showing homoplasy in petrosal evolution among Tethytheria. It suggests that evolutionary modalities of petrosal characters differ with the taxonomic level among Afrotheria: noticeable convergences occurred among the paenungulate orders, whereas little homoplasy seems to have occurred at intra-ordinal level in orders such as Proboscidea. Most petrosal features of both Eritherium and Phosphatherium are primitive. The ancestral petrosal morphotype of Proboscidea was not specialized but was close to the generalized condition of paenungulates, afrotherians, and even eutherians. This is consistent with cranial and dental characters of Eritherium, suggesting that the ancestral morphotypes of the different paenungulate orders were close to each other. Specializations occurred rapidly after the ordinal radiation of Paenungulata. PMID- 26510536 TI - Undiagnosed airflow limitation is common in patients with coronary artery disease and associated with cardiac stress. AB - BACKGROUND AND OBJECTIVE: Smoking is a common risk factor for coronary artery disease (CAD) and chronic obstructive pulmonary disease (COPD). We evaluated the prevalence of undiagnosed COPD in patients with CAD and assessed the relationship between airflow obstruction and markers of cardiac stress. METHODS: We recruited prospectively consecutive patients aged >40 years without known history of chronic lung disease (e.g. asthma, COPD, bronchiectasis) who had undergone percutaneous coronary intervention (PCI) for obstructive CAD between August 2009 and October 2010. Spirometry was performed and serum ST2, a novel biomarker of cardiomyocyte stress and fibrosis, was measured by enzyme-linked immunosorbent assay. RESULTS: Among 475 subjects (mean age 64 +/- 9.7, range 42-85 years, 87.2% males, 58.5% current or ex-smokers) who underwent spirometry, 51 (10.7%) had undiagnosed airflow obstruction with FEV1 /FVC ratio <70%. Of these 51 subjects, 14 (2.9%), 23 (4.8%) and 14 (2.9%) had FEV1 >=80, 50-80 and 30-50% predicted normal, respectively. ST2 level was measured in all the subjects with undiagnosed airflow obstruction and in 290 subjects with normal lung function. There was no significant difference in left ventricular ejection fraction on echocardiogram between subjects with and without airflow obstruction. Patients with severe airflow obstruction had a higher level of cardiac stress marker ST2 than those with mild and moderate airflow obstruction (rho = -0.214, P <= 0.001). CONCLUSION: Undiagnosed airflow obstruction is common among patients with CAD who have undergone PCI. Severity of airflow limitation is associated with increasing cardiac stress. PMID- 26510537 TI - Simultaneous calcium fluorescence imaging and MR of ex vivo organotypic cortical cultures: a new test bed for functional MRI. AB - Recently, several new functional (f)MRI contrast mechanisms including diffusion, phase imaging, proton density, etc. have been proposed to measure neuronal activity more directly and accurately than blood-oxygen-level dependent (BOLD) fMRI. However, these approaches have proved difficult to reproduce, mainly because of the dearth of reliable and robust test systems to vet and validate them. Here we describe the development and testing of such a test bed for non BOLD fMRI. Organotypic cortical cultures were used as a stable and reproducible biological model of neuronal activity that shows spontaneous activity similar to that of in vivo brain cortex without any hemodynamic confounds. An open-access, single-sided magnetic resonance (MR) "profiler" consisting of four permanent magnets with magnetic field of 0.32 T was used in this study to perform MR acquisition. A fluorescence microscope with long working distance objective was mounted on the top of a custom-designed chamber that keeps the organotypic culture vital, and the MR system was mounted on the bottom of the chamber to achieve real-time simultaneous calcium fluorescence optical imaging and MR acquisition on the same specimen. In this study, the reliability and performance of the proposed test bed were demonstrated by a conventional CPMG MR sequence acquired simultaneously with calcium imaging, which is a well-characterized measurement of neuronal activity. This experimental design will make it possible to correlate directly the other candidate functional MR signals to the optical indicia of neuronal activity in the future. PMID- 26510538 TI - EDUCATION AND IMAGING. Gastrointestinal: Needle tract implantation after endoscopic ultrasound-guided fine-needle aspiration of a pancreatic adenocarcinoma. PMID- 26510539 TI - Inhibition of UV-induced matrix metabolism by a myristoyl tetrapeptide. AB - Regulation of extracellular matrix (ECM) composition is important in tissue homeostasis and function. We screened small peptides for their ability to inhibit ultraviolet (UV)-induced cell metabolism in epidermal fibroblasts. We found that UV irradiation increased matrix metalloproteinase (MMP) expression and inflammatory gene expression in human Hs68 fibroblast cells. We also demonstrated that a myristoyl tetrapeptide with the amino acid sequence Gly-Leu-Phe-Trp (mGLFW) suppressed the UV-induced expression of MMPs and inflammatory genes. Moreover, mGLFW stimulated the expression of ECM proteins in Hs68 fibroblasts. In order to provide the mechanism of action for mGLFW, we investigated UV-induced signaling changes in the presence of mGLFW using a cDNA microarray. UV exposure increased the expression of MMP genes, such as MMP1, MMP3, and MMP14, and inflammation-related genes, including interleukin 1 receptor and peroxisome proliferator-activated receptor gamma (PPARgamma). Treatment with mGLFW abrogated the UV-induced expression of MMP-related genes and inflammatory genes. In addition, mGLFW increased the expression of collagen genes, including COL1A1, COL1A2, and COL5A1. We examined whether the activation of AP-1, a UV-activated transcription factor, is suppressed by mGLFW. The results demonstrated that AP-1 expression increased upon UV exposure and that this expression was inhibited by mGLFW. In conclusion, our results demonstrate that mGLFW reversed the effects of UV exposure by enhancing the expression of collagen proteins and suppressing the expression of MMPs, which degrade the ECM. PMID- 26510540 TI - Obesity is independently associated with infection in hospitalised patients with end-stage liver disease. AB - BACKGROUND: Infection is the most common cause of mortality in end-stage liver disease (ESLD). The impact of obesity on infection risk in ESLD is not established. AIM: To characterise the impact of obesity on infection risk in ESLD. METHODS: We evaluated the association between infection and obesity in patients with ESLD. Patients grouped as non-obese, obesity class I-II and obesity class III were studied using the Nationwide Inpatient Sample. Validated diagnostic code based algorithms were utilised to determine weight category and infections, including bacteraemia, skin/soft tissue infection, urinary tract infection (UTI), pneumonia/respiratory infection, Clostridium difficile infection (CDI) and spontaneous bacterial peritonitis (SBP). Risk factors for infection and mortality were assessed using multivariable logistic regression analysis. RESULTS: Of 115 465 patients identified, 100 957 (87.5%) were non-obese and 14 508 (12.5%) were obese, with 9489 (8.2%) as obesity class I-II and 5019 (4.3%) as obesity class III. 37 117 patients (32.1%) had an infection diagnosis. Infection was most prevalent among obesity class III (44.0%), followed by obesity class I II (38.9%) and then non-obese (31.9%). In multivariable modelling, class III obesity (OR = 1.41; 95% CI 1.32-1.51; P < 0.001), and class I-II obesity (OR = 1.08; 95% CI 1.01-1.15; P = 0.026) were associated with infection. Compared to non-obese patients, obese individuals had greater prevalence of bacteraemia, UTI, and skin/soft tissue infection as compared to non-obese patients. CONCLUSIONS: Obesity is newly identified to be independently associated with infection in end stage liver disease. The distribution of infection sites varies based on weight category. PMID- 26510541 TI - Editorial: untangling symptoms from mucosal healing in UC--a note of caution for patient-reported outcomes. PMID- 26510542 TI - Letter: avoid FODMAPs or follow simple tips? PMID- 26510543 TI - Letter: avoid FODMAPs or follow simple tips--authors' reply. PMID- 26510544 TI - Letter: association between moderate alcohol consumption and non-alcoholic fatty liver disease. PMID- 26510545 TI - Letter: association between moderate alcohol consumption and non-alcoholic fatty liver disease--authors' reply. PMID- 26510546 TI - Letter: limb, muscle, and bone in coeliac disease. PMID- 26510547 TI - Corrigendum. AB - In the paper, 'Systematic analysis of factors associated with progression and regression of ulcerative colitis in 918 patients', published in Volume 42 Issue 5 (September 2015). In Figure 3 the header and y-axis should read 'Cumulative probability of UC regression' and 'Kaplan-Meier curve for UC regression', respectively. The correct figure 3 is shown below. The authors apologise for this error. PMID- 26510548 TI - Hypoxic-ischemic gene expression profile in the isolated variant of biliary atresia. AB - BACKGROUND: Biliary atresia (BA) includes a sclerosing cholangiopathy whose nature is not fully deciphered. Aiming to evaluate the role of an arteriopathy as an etiologic factor in BA, we investigated hypoxia and the correlated angiogenic response in livers from affected patients. METHODS: Gene expression of the molecular axis: hypoxia-inducible factor (HIF)1a, HIF2a and vascular endothelial growth factor A (VEGFA)/VEGFR1, VEGFR2. Liver biopsy specimens collected at exploratory laparotomy of age-matched patients with isolated, cytomegalovirus IgM negative BA (n = 32) and intrahepatic cholestasis (IHC, n = 9) were evaluated. RESULTS: We observed higher HIF1a and HIF2a expression in BA than in IHC. Paradoxically, VEGFR2, the main target of VEGFA-induced angiogenesis, was underexpressed in BA, and VEGFA was decreased in most BA patients. Patients with the highest expression of HIFs and the lowest VEGFA and VEGFR2 were essentially the same, indicating hypoxia without the necessary angiogenesis. This group included most BA patients and, except for HIF2a, they were older and presented increased bilirubin serum levels. In the highest HIF2a/lowest VEGFR2 subsets, gene expression of the cytokeratin 19, marker of cholangiocyte phenotype, was decreased. CONCLUSION: This study suggests that hypoxia-ischemia is present in the livers of patients with BA, progresses over time and leads to a decreased cholangiocyte mass. PMID- 26510549 TI - Bright, "Clickable" Porphyrins for the Visualization of Oxygenation under Ambient Light. AB - A new group of "clickable" and brightly emissive metalloporphyrins has been developed for the visualization of oxygenation under ambient light with the naked eye. These alkynyl-terminated compounds permit the rapid and facile synthesis of oxygen-sensing dendrimers through azide-alkyne click chemistry. With absorption maxima overlapping with the wavelengths of common commercial laser sources, they are readily applicable to biomedical imaging of tissue oxygenation. An efficient synthetic methodology, featuring the stable trimethylacetyl (pivaloyl) protecting group, is described for their preparation. A paint-on liquid bandage containing a new, click-synthesized porphyrin dendrimer has been used to map oxygenation across an ex vivo porcine skin burn model. PMID- 26510550 TI - Safety Standards: Implementing Fall Prevention Interventions and Sustaining Lower Fall Rates by Promoting the Culture of Safety on an Inpatient Rehabilitation Unit. AB - PURPOSE: The purpose of this article is to review a quality improvement project aimed to examine how nurse leaders in an inpatient rehabilitation (IPR) unit can reduce the number of patient falls by implementing multiple fall prevention interventions and sustain their results by promoting a strong culture of safety on the unit. DESIGN AND METHODS: A retrospective review of IPR fall rates was performed. Quarterly fall rates were then compared with implementation dates of fall prevention interventions (safety huddles, signage, and hourly rounding). Culture of safety scores were also examined to assess the effect of an enhanced culture of safety on the sustainability of lowered fall rates. FINDINGS: The largest decrease in fall rate was noted after initial revitalization efforts of the IPR unit's culture of safety concurrently with hourly rounding. CONCLUSIONS: Fall rates rise and fall despite multiple fall prevention interventions and encouraging a positive shift in the culture of safety. CLINICAL RELEVANCE: Physical injuries following a fall can reduce mobility and increase morbidity. Costs associated with falls negatively impact costs and reimbursement. Employing evidence-based fall prevention strategies are then of critical importance to nurse leaders as falls remain an ongoing serious adverse event. PMID- 26510551 TI - 'They rush you and push you too much ... and you can't really get any good response off them': A qualitative examination of family involvement in care of people with dementia in acute care. AB - AIM: To explore the role and needs of the family carer across different acute care contexts and their level of involvement in the care of their relative with dementia in this setting. METHODS: A pragmatic, exploratory-descriptive qualitative approach. A convenience sample of 30 family carers across three sites completed semi-structured interviews. RESULTS: Family carers wanted to be involved in the acute care of their family member with dementia. They acknowledged the importance of a central source of information, educated staff, guidelines on roles and processes, and positive communication, as well as respect from staff for the carer's knowledge of the older person and their needs. They also highlighted the need for medical staff to discuss with them the family member's treatment and care. CONCLUSION: There is a need for family-focused interventions to improve communication and involvement of family in the care of family members with dementia in the acute setting. PMID- 26510552 TI - Resolving the 'nitrogen paradox' of arbuscular mycorrhizas: fertilization with organic matter brings considerable benefits for plant nutrition and growth. AB - Arbuscular mycorrhizal fungi (AMF) can transfer nitrogen (N) to host plants, but the ecological relevance is debated, as total plant N and biomass do not generally increase. The extent to which the symbiosis is mutually beneficial is thought to rely on the stoichiometry of N, phosphorus (P) and carbon (C) availability. While inorganic N fertilization has been shown to elicit strong mutualism, characterized by improved plant and fungal growth and mineral nutrition, similar responses following organic N addition are lacking. Using a compartmented microcosm experiment, we determined the significance to a mycorrhizal plant of placing a (15) N-labelled, nitrogen-rich patch of organic matter in a compartment to which only AMF hyphae had access. Control microcosms denied AMF hyphal access to the patch compartment. When permitted access to the patch compartment, the fungus proliferated extensively in the patch and transferred substantial quantities of N to the plant. Moreover, our data demonstrate that allowing hyphal access to an organic matter patch enhanced total plant N and P contents, with a simultaneous and substantial increase in plant biomass. Furthermore, we demonstrate that organic matter fertilization of arbuscular mycorrhizal plants can foster a mutually beneficial symbiosis based on nitrogen transfer, a phenomenon previously thought irrelevant. PMID- 26510553 TI - Right coronary cusp as a new window of ablation for pilsicainide-induced ventricular premature contractions in a patient with Brugada syndrome. AB - A previous study demonstrated that ventricular premature contractions (VPCs) and ventricular fibrillation (VF) are provoked during sodium channel blocker challenge tests in Brugada syndrome (BrS) patients (Morita et al., J Am Coll Cardiol 42:1624-1631, 2003). The right ventricular outflow tract (RVOT) is a major arrhythmogenic focus and isolated VPCs originating from that area have been shown to initiate VF (Kakishita et al., J Am Coll Cardiol 36:1646-1653, 2000). Here, we describe a case report of a BrS patient with VPCs arising from the posterior aspect of the RVOT epicardium which was provoked by a low-dose of pilsicainide, a pure sodium channel blocker, and was successfully ablated from the right coronary cusp. PMID- 26510554 TI - An epithelial to mesenchymal transition programme does not usually drive the phenotype of invasive lobular carcinomas. AB - Epithelial to mesenchymal transition (EMT) is a cellular phenotype switching phenomenon which occurs during normal development and is proposed to promote tumour cell invasive capabilities during tumour progression. Invasive lobular carcinoma (ILC) is a histological special type of breast cancer with a peculiar aetiology - the tumour cells display an invasive growth pattern, with detached, single cells or single files of cells, and a canonical feature is the loss of E cadherin expression. These characteristics are indicative of an EMT or at the very least that they represent some plasticity between phenotypes. While some gene expression profiling data support this view, the tumour cells remain epithelial and limited immunohistochemistry data suggest that EMT markers may not feature prominently in ILC. We assessed the expression of a panel of EMT markers (fibronectin, vimentin, N-cadherin, smooth muscle actin, osteonectin, Snail, Twist) in 148 ILCs and performed a meta-analysis of publically available molecular data from 154 ILCs. Three out of 148 (2%) ILCs demonstrated an early and coordinated alteration of multiple EMT markers (down-regulation of E cadherin, nuclear TWIST, and up-regulation of vimentin, osteonectin, and smooth muscle actin). However, the data overall do not support a role for EMT in defining the phenotypic peculiarities of the majority of ILCs. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 26510556 TI - Application of multispectral imaging detects areas with neuronal myelin loss, without tissue labelling. AB - The application of multispectral imaging to discriminate myelinated and demyelinated areas of neural tissue is herein presented. The method is applied through a custom-made, multispectral imaging monochromator, coupled to a commercially available microscope. In the present work, a series of spinal cord sections were analysed derived from mice with experimental autoimmune encephalomyelitis (EAE), an experimental model widely used to study multiple sclerosis (MS). The multispectral microscope allows imaging of local areas with loss of myelin without the need of tissue labelling. Imaging with the aforementioned method and system is compared in a parallel way with conventional methods (wide-field and confocal fluorescence microscopies). The diagnostic sensitivity of our method is 90.4% relative to the 'gold standard' method of immunofluorescence microscopy. The presented method offers a new platform for the possible future development of an in vivo, real-time, non-invasive, rapid imaging diagnostic tool of spinal cord myelin loss-derived pathologies. PMID- 26510555 TI - Skeletal stem cells and their contribution to skeletal fragility: senescence and rejuvenation. AB - Age-related osteoporotic fractures are major health care problem worldwide and are the result of impaired bone formation, decreased bone mass and bone fragility. Bone formation is accomplished by skeletal stem cells (SSC) that are recruited to bone surfaces from bone marrow microenvironment. This review discusses targeting SSC to enhance bone formation and to abolish age-related bone fragility in the context of using stem cells for treatment of age-related disorders. Recent studies are presented that have demonstrated that SSC exhibit impaired functions during aging due to intrinsic senescence-related changes as well as the presence of senescent microenvironment. Also, a number of approaches aiming at increasing bone formation through targeting SSC and that include systemic SSC transplantation, systemic SSC targeting using aptamers or antibodies, use of therapeutic screteome and tissue engineering approaches will be presented and discussed. PMID- 26510557 TI - The Transdural Course of Radicular Spinal Cord Veins--A Microangiographical and Microscopical Study. AB - PURPOSE: This study focuses on the following questions: What are the morphological features at the transdural course of radiculomedullary veins? How are these short transdural segments that may harbour pathological arteriovenous shunts connected to the internal vertebral venous plexus? Is the conception of a reflux-impeding mechanism at the transdural segment indispensable and convincing? METHODS: A total of 102 radiculospinal veins were studied microscopically at various levels of the spinal canal using serial paraffin and semi-thin sections. In addition, 26 vessels were investigated microangiographically following orthograde (12) or attempted retrograde (14) opacification of the intradural venous segment with barium sulphate. After paraplast-embedding, contact microradiographs were taken using high-resolution spectroscopic plates. RESULTS: At their transdural course, the veins showed narrowing of their lumen accompanied by changes in the vessel wall composition and a tortuous course. Two structurally distinct arrangements of the transdural segment could be identified: A slit type was seen in 60% of the veins studied and a bulge- or nodular type was seen in 35% of the veins. In total, 5% of cases could not be assigned to either one of these types. Reflux to radicular veins from the outside of the dura mater could be produced in 2 out of 14 specimens. The extradural venous plexus, which primarily receives the radicular vein, was composed more frequently of lacunar spaces rather than plexiform blood vessel convolutions. Rare observations were fibrotic, blind ending radiculomedullary veins and continuation of a distinct venous blood vessel after crossing the dura. CONCLUSIONS: Reflux from the epidural plexus to radicular veins is not reliably stopped at the dural level and possibly physiological. Different arrangements of the transdural course of the veins appear to be at least appropriate to modulate flow. The purpose for two different types of radicular vein exit is unclear. The clinical impact of disturbed reflux control is uncertain, which is in stark contrast to the severe consequences resulting from dural arteriovenous shunts. The functional role of the probably predominant epidural venous plexus for the spinal cord blood circulation remains poorly understood. PMID- 26510558 TI - Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis. AB - Myasthenia gravis (MG) is an autoimmune disease associated with the production of autoantibodies against 1) the skeletal muscle acetylcholine receptor; 2) muscle specific kinase, a receptor tyrosine kinase critical for the maintenance of neuromuscular synapses; 3) low-density lipoprotein receptor-related protein 4, an important molecular binding partner for muscle-specific kinase; and 4) other muscle endplate proteins. In addition to the profile of autoantibodies, MG may be classified according the location of the affected muscles (ocular vs generalized), the age of symptom onset, and the nature of thymic pathology. Immunopathologic events leading to the production of autoantibodies differ in the various disease subtypes. Advances in our knowledge of the immunopathogenesis of the subtypes of MG will allow for directed utilization of the ever-growing repertoire of therapeutic agents that target distinct nodes in the immune pathway relevant to the initiation and maintenance of autoimmune disease. In this review, we examine the pathogenesis of MG subtypes, current treatment options, and emerging new treatments and therapeutic targets. PMID- 26510560 TI - Coronary artery fistulae. PMID- 26510561 TI - Chemical Composition and Yield of Six Genotypes of Common Purslane (Portulaca oleracea L.): An Alternative Source of Omega-3 Fatty Acids. AB - Common purslane (Portulaca oleracea L.) is an annual weed rich in omega-3 fatty acids which is consumed for its edible leaves and stems. In the present study six different genotypes of common purslane (A-F) were evaluated for their nutritional value and chemical composition. Nutritional value and chemical composition depended on genotype. Oxalic acid content was the lowest for genotype D, whereas genotypes E and F are more promising for commercial cultivation, since they have low oxalic acid content. Genotype E had a very good antioxidant profile and a balanced composition of omega-3 and omega-6 fatty acids. Regarding yield, genotype A had the highest yield comparing to the other genotypes, whereas commercial varieties (E and F) did not differ from genotypes B and C. This study provides new information regarding common purslane bioactive compounds as affected by genotype and could be further implemented in food industry for products of high quality and increased added value. PMID- 26510563 TI - Does Lymphadenectomy Improve Survival in Patients with Adrenocortical Carcinoma? A Population-Based Study. AB - BACKGROUND: A recent study suggested a survival benefit in patients with adrenocortical carcinoma (ACC) who had undergone lymphadenectomy. The objective of this study was to study the effect of lymphadenectomy on the survival rates of patients with ACC. METHODS: Data from adult patients with histology-proven ACC from the National Cancer Institute's Surveillance, Epidemiology, and End Results 18 Registries (1973-2011) were analyzed to assess the impact of lymphadenectomy (>=4 lymph nodes removed) on disease-specific survival (DSS). RESULTS: Of 1525 patients with ACC, 45% were male. 36, 20, and 44% of patients presented with localized, regional, and distant metastatic diseases, respectively. 8% of patients (n = 67/802) underwent lymphadenectomy. We observed a higher rate of lymphadenectomy performed in patients with regional disease [locally advanced tumors (stage T3 and T4) and/or lymph node metastasis] and distant metastasis than in those with localized tumors (12.4% and 12.0 vs. 5.1, respectively, p < 0.01) and in patients with primary tumor sizes >10 cm (12.4 vs. 4.2 %, p < 0.01). Lymph node metastasis was present in 12.8% (19.2% in locally advanced ACC). A lymphadenectomy was not associated with improved DSS on univariate analysis (p = 0.30), regardless of tumor size or staging. Independent prognostic factors included: ages >=60 years (p < 0.01, HR 1.70), lymph node metastasis (p < 0.01, HR 1.7), distant metastasis (p < 0.01, HR 5.6), complete resection of tumor (p < 0.01, HR 0.47), and debulking surgery (p < 0.01, HR 0.49). CONCLUSION: A lymphadenectomy is not commonly performed in patients with ACC in the U.S. Although we found no survival benefit in this cohort with a low rate of lymphadenectomy, a lymphadenectomy may be considered in patients with locally advanced tumors (T3 and T4) due to a higher rate of lymph node metastasis. PMID- 26510559 TI - Immunotherapies for Neurological Manifestations in the Context of Systemic Autoimmunity. AB - Neurological involvement is relatively common in the majority of systemic autoimmune diseases and may lead to severe morbidity and mortality, if not promptly treated. Treatment options vary greatly, depending on the underlying systemic pathophysiology and the associated neurological symptoms. Selecting the appropriate therapeutic scheme is further complicated by the lack of definite therapeutic guidelines, the necessity to differentiate primary neurological syndromes from those related to the underlying systemic disease, and to sort out adverse neurological manifestations caused by immunosuppressants or the biological agents used to treat the primary disease. Immunotherapy is a sine qua non for treating most, if not all, neurological conditions presenting in the context of systemic autoimmunity. Specific agents include classical immune modulators such as corticosteroids, cyclophosphamide, intravenous immunoglobulin, and plasma exchange, as well as numerous biological therapies, for example anti tumor necrosis factor agents and monoclonal antibodies that target various immune pathways such as B cells, cytokines, and co-stimulatory molecules. However, experience regarding the use of these agents in neurological complications of systemic diseases is mainly empirical or based on small uncontrolled studies and case series. The aim of this review is to present the state-of-the-art therapies applied in various neurological manifestations encountered in the context of systemic autoimmune diseases; evaluate all treatment options on the basis of existing guidelines; and compliment these data with our personal experience derived from a large number of patients. PMID- 26510566 TI - Genome-scale approaches for studying human and non-human primate evolution. PMID- 26510564 TI - Dilp8 requires the neuronal relaxin receptor Lgr3 to couple growth to developmental timing. AB - How different organs in the body sense growth perturbations in distant tissues to coordinate their size during development is poorly understood. Here we mutate an invertebrate orphan relaxin receptor gene, the Drosophila Leucine-rich repeat containing G protein-coupled receptor 3 (Lgr3), and find body asymmetries similar to those found in insulin-like peptide 8 (dilp8) mutants, which fail to coordinate growth with developmental timing. Indeed, mutation or RNA intereference (RNAi) against Lgr3 suppresses the delay in pupariation induced by imaginal disc growth perturbation or ectopic Dilp8 expression. By tagging endogenous Lgr3 and performing cell type-specific RNAi, we map this Lgr3 activity to a new subset of CNS neurons, four of which are a pair of bilateral pars intercerebralis Lgr3-positive (PIL) neurons that respond specifically to ectopic Dilp8 by increasing cAMP-dependent signalling. Our work sheds new light on the function and evolution of relaxin receptors and reveals a novel neuroendocrine circuit responsive to growth aberrations. PMID- 26510567 TI - Tempo and mode of genomic mutations unveil human evolutionary history. AB - Mutations that have occurred in human genomes provide insight into various aspects of evolutionary history such as speciation events and degrees of natural selection. Comparing genome sequences between human and great apes or among humans is a feasible approach for inferring human evolutionary history. Recent advances in high-throughput or so-called 'next-generation' DNA sequencing technologies have enabled the sequencing of thousands of individual human genomes, as well as a variety of reference genomes of hominids, many of which are publicly available. These sequence data can help to unveil the detailed demographic history of the lineage leading to humans as well as the explosion of modern human population size in the last several thousand years. In addition, high-throughput sequencing illustrates the tempo and mode of de novo mutations, which are producing human genetic variation at this moment. Pedigree-based human genome sequencing has shown that mutation rates vary significantly across the human genome. These studies have also provided an improved timescale of human evolution, because the mutation rate estimated from pedigree analysis is half that estimated from traditional analyses based on molecular phylogeny. Because of the dramatic reduction in sequencing cost, sequencing on-demand samples designed for specific studies is now also becoming popular. To produce data of sufficient quality to meet the requirements of the study, it is necessary to set an explicit sequencing plan that includes the choice of sample collection methods, sequencing platforms, and number of sequence reads. PMID- 26510568 TI - Genetic diversity in humans and non-human primates and its evolutionary consequences. AB - Genetic diversity is a key parameter in population genetics and is important for understanding the process of evolution and for the development of appropriate conservation strategies. Recent advances in sequencing technology have enabled the measurement of genetic diversity of various organisms at the nucleotide level and on a genome-wide scale, yielding more precise estimates than were previously achievable. In this review, I have compiled and summarized the estimates of genetic diversity in humans and non-human primates based on recent genome-wide studies. Although studies on population genetics demonstrated fluctuations in population sizes over time, general patterns have emerged. As shown previously, genetic diversity in humans is one of the lowest among primates; however, certain other primate species exhibit genetic diversity that is comparable to or even lower than that in humans. There exists greater than 10-fold variation in genetic diversity among primate species, and I found weak correlation with species fecundity but not with body or propagule size. I further discuss the potential evolutionary consequences of population size decline on the evolution of primate species. The level of genetic diversity negatively correlates with the ratio of non-synonymous to synonymous polymorphisms in a population, suggesting that proportionally greater numbers of slightly deleterious mutations segregate in small rather than large populations. Although population size decline is likely to promote the fixation of slightly deleterious mutations, there are molecular mechanisms, such as compensatory mutations at various molecular levels, which may prevent fitness decline at the population level. The effects of slightly deleterious mutations from theoretical and empirical studies and their relevance to conservation biology are also discussed in this review. PMID- 26510569 TI - Human genetic diversity in the Japanese Archipelago: dual structure and beyond. AB - The Japanese Archipelago stretches approximately 3,000 kilometers from Hokkaido in the north to the Ryukyu Islands in the south, and has seen human activity since at least 30 thousand years ago (KYA). The Jomon period from 16 to 3 KYA is associated with cord-marked pottery and the people at that time, who were hunter gatherers, occupied a range of locations across the Japanese Archipelago. The Yayoi period from 3 to 1.7 KYA saw the introduction of migrants from the Asian Continent who brought rice agriculture to the archipelago. The dual-structure model, which is based on craniofacial measurements, proposes that admixture between the Jomon and Yayoi people resulted in current-day Japanese. Subsequent genetic studies using uniparental and autosomal markers in current-day and ancient human samples are widely in support of the dual-structure model. These genetic data have also unveiled the uniqueness of the indigenous Ainu and Ryukyuan people while further demonstrating the genetic substructure within the Mainland Japanese. PMID- 26510570 TI - On the use of kernel approximate Bayesian computation to infer population history. AB - Genetic variation is a product of mutation, recombination and natural selection along with a complex history involving population subdivision, gene flow and changes in population size. Elucidating the evolutionary forces that shape genetic differences among populations is a major objective of evolutionary genetics. Recent advances in high-throughput technology enable genomic data to be obtained from samples at a population-based scale. Further, the growth in computational power has facilitated extensive efforts to develop intensive simulation-based approaches with the aim of analyzing such large-scale data and making inferences about population history. Approximate Bayesian computation (ABC) provides a quantitative way to assess the goodness-of-fit of complex models that are based on previous knowledge and to estimate the parameters of interest that produce the observed data. The practical advantage of ABC is the application of Bayesian inference to any model without the need to derive a likelihood function. ABC has rapidly become popular in ecology and evolutionary studies due to the contribution it has made to improving computational efficiency over the past decade. This review provides a brief overview of the background of ABC, including potential biases in estimation due to the assumptions and approximation involved, followed by an in-depth review of one of the recently developed ABCs, "kernel ABC," with an explanation of how to overcome these biases. Finally, the application of kernel ABC to the inference of demographic history is summarized. PMID- 26510571 TI - Role of the ACL2 locus in flower stalk elongation in Arabidopsis thaliana. AB - The acaulis2 (acl2) mutant of Arabidopsis thaliana shows a defect in flower stalk elongation. We identified the mutation point of acl2 by map-based cloning. The ACL2 locus is located within an approximately 320-kb region at around 100 map units on chromosome 1. One nucleotide substitution was detected in this region in the acl2 mutant, but no significant open reading frames were found around this mutation point. When wild-type DNA fragments containing the mutation point were introduced into acl2 mutant plants, some transgenic plants partially or almost completely recovered from the defect in flower stalk elongation. 3'-RACE experiments showed that bidirectional transcripts containing the acl2 mutation point were expressed, and the Plant MPSS database revealed that several small RNAs were produced from this region. Microarray analysis showed that transcription of many genes is activated in flower stalks of acl2 mutant plants. Overexpression of some of these genes caused a dwarf phenotype in wild-type plants. These results suggest the following novel mechanism for control of the elongation of flower stalks. Bidirectional non-coding RNAs are transcribed from the ACL2 locus, and small RNAs are generated from them in flower stalks. These small RNAs repress the transcription of a set of genes whose expression represses flower stalk elongation, and flower stalks are therefore fully elongated. PMID- 26510572 TI - Selection of reliable reference genes for quantitative real-time RT-PCR in alfalfa. AB - Real-time quantitative RT-PCR (qRT-PCR) is the most commonly used method for accurately detecting gene expression patterns. As part of qRT-PCR analysis, normalization of the data requires internal control gene(s) that display uniform expression under different biological conditions. However, no invariable internal control gene exists, and therefore more than one reference gene is needed to normalize RT-PCR results. In this study, we assessed the expression of eight candidate internal control genes, namely 18S ribosomal RNA (18S rRNA), elongation factor-1alpha, beta-Actin, E2 ubiquitin-conjugating enzyme, beta-Tubulin (TUB), ACTIN2, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and Msc27 of unknown function, in a diverse set of 16 alfalfa (Medicago sativa) samples representing different tissues and abiotic stress challenges, using geNorm and BestKeeper software. The results revealed that the eight candidate genes are inconsistently expressed under different experimental conditions. Msc27 and 18S rRNA are suitable reference genes for comparing different tissue types. Under different abscisic acid and NaCl conditions, three reference genes are necessary. Finally, GAPDH, TUB and beta-Actin are unsuitable for normalization of qRT-PCR data under these given conditions in alfalfa. The relative expression level of MsWRKY33 was analyzed using selected reference genes. These results provide an experimental guideline for future research on gene expression in alfalfa using qRT-PCR. PMID- 26510573 TI - Analysis of a rice fickle spikelet1 mutant that displays an increase in flower and spikelet organ number with inconstant expressivity. AB - In rice (Oryza sativa), floral organs develop in the spikelet, an inflorescence unit unique to grass species. The floral organs, such as carpels, stamens and lodicules, are enclosed by two spikelet organs, the palea and lemma. The number of floral organs is genetically regulated. Mutations in the FLORAL ORGAN NUMBER (FON) genes cause an increase in the number of carpels and stamens due to an enlargement of the floral meristem. The spikelet organs, such as lemma and palea, are less affected in the fon mutants. We found a mutant, fickle spikelet1 (fsp1), that displayed an increased number not only of floral organs but also of spikelet organs. Because the fsp1 spikelets showed a pleiotropic phenotype, we classified them into four types. The expressivity of the fsp1 phenotype varied from plant to plant, and also from panicle to panicle within a single plant. In addition, the frequency of each fsp1 spikelet type also varied considerably among plants and among panicles within a plant. When the fsp1 mutants were grown in a growth chamber, an extra abnormality, namely a defect in pollen development, was observed. Furthermore, the expressivity of the mutant phenotype increased dramatically in mutant plants grown in a growth chamber. Thus, the expressivity of the fsp1 phenotype seems to be strongly influenced by environmental conditions. PMID- 26510574 TI - Immediate results of photodynamic therapy for the treatment of halitosis in adolescents: a randomized, controlled, clinical trial. AB - Light with or without chemical agents has been used to induce therapeutic and antimicrobial effects. With photodynamic therapy, the antimicrobial effect is confined to areas covered by a photosensitive dye and irradiated with light. The aim of the present study was to evaluate the effect of photodynamic therapy for the treatment of halitosis in adolescents through the analysis of volatile sulfur compounds, especially sulfide. A controlled, clinical trial was conducted with 45 adolescents randomly allocated to three groups: group 1, photodynamic therapy administered to the dorsum of the tongue; group 2, treatment with a tongue scraper; and group 3, treatment with a tongue scraper combined with photodynamic therapy. The diagnosis of halitosis was performed using gas chromatography before and after treatment. Comparisons were made using the Kruskal-Wallis test followed by the Student-Newman-Keuls test, with the level of significance set at 5 % (p < 0.05). After treatment, a statistically significant reduction in halitosis was found in all groups (p < 0.001). The greatest reduction in total sulfides (median = 0) occurred with the combination of tongue scraper and photodynamic therapy. The present study describes a novel option for the treatment of halitosis in adolescents with an immediate effect that does not involve the mechanical aggression of the lingual papillae that occurs with conventional treatment. TRIAL REGISTRATION: Photodynamic Therapy in Adolescents Halitosis ( https://clinicaltrials.gov/ct2/show/NCT02007993?term=NCT02007993&rank=1 )Number: NCT02007993FUNDING:FAPESPNumber: 2013/13032-8. PMID- 26510575 TI - Influence of Nd:YAG laser on intrapulpal temperature and bond strength of human dentin under simulated pulpal pressure. AB - The aim of this study was to evaluate the effects of simulated pulpal pressure (SPP) on the variation of intrapulpal temperature (DeltaT) and microtensile bond strength (MUTBS) to dentin submitted to an adhesive technique using laser irradiation. One hundred sound human molars were randomly divided into two groups (n = 50), according to the presence or absence of SPP (15 cm H2O). Each group was divided into five subgroups (n = 10) according to Nd:YAG laser energy (60, 80, 100, 120, 140 mJ/pulse). The samples were sequentially treated with the following: 37 % phosphoric acid, adhesive (Scotchbond Universal), irradiation with Nd:YAG laser (60 s), and light curing (10 s). DeltaT was evaluated during laser irradiation using a type K thermocouple. Next, a composite resin block was build up onto the irradiated area. After 48 h, samples were submitted to microtensile test (10 kgf load cell, 0.5 mm/min). Data were analyzed by two-way ANOVA and Tukey tests (p = 0.05). ANOVA revealed significant differences for DeltaT and TBS in the presence of SPP. For DeltaT, the highest mean (14.3 +/- 3.23 degrees C)(A) was observed in 140 mJ and without SPP. For MUTBS, the highest mean (33.4 +/- 4.15 MPa)(A) was observed in 140 mJ and without SPP. SPP significantly reduced both DeltaT and MUTBS during adhesive procedures, lower laser energy parameters resulted in smaller DeltaT, and the laser parameters did not influence the MUTBS values. PMID- 26510576 TI - Abeta42-oligomer Interacting Peptide (AIP) neutralizes toxic amyloid-beta42 species and protects synaptic structure and function. AB - The amyloid-beta42 (Abeta42) peptide is believed to be the main culprit in the pathogenesis of Alzheimer disease (AD), impairing synaptic function and initiating neuronal degeneration. Soluble Abeta42 oligomers are highly toxic and contribute to progressive neuronal dysfunction, loss of synaptic spine density, and affect long-term potentiation (LTP). We have characterized a short, L-amino acid Abeta-oligomer Interacting Peptide (AIP) that targets a relatively well defined population of low-n Abeta42 oligomers, rather than simply inhibiting the aggregation of Abeta monomers into oligomers. Our data show that AIP diminishes the loss of Abeta42-induced synaptic spine density and rescues LTP in organotypic hippocampal slice cultures. Notably, the AIP enantiomer (comprised of D-amino acids) attenuated the rough-eye phenotype in a transgenic Abeta42 fly model and significantly improved the function of photoreceptors of these flies in electroretinography tests. Overall, our results indicate that specifically "trapping" low-n oligomers provides a novel strategy for toxic Abeta42-oligomer recognition and removal. PMID- 26510577 TI - A real-world stepped wedge cluster randomized trial of practice facilitation to improve cardiovascular care. AB - BACKGROUND: Practice facilitation has been associated with meaningful improvements in disease prevention and quality of patient care. Using practice facilitation, the Improved Delivery of Cardiovascular Care (IDOCC) project aimed to improve the delivery of evidence-based cardiovascular care in primary care practices across a large health region. Our goal was to evaluate IDOCC's impact on adherence to processes of care delivery. METHODS: A pragmatic stepped wedge cluster randomized trial recruiting primary care providers in practices located in Eastern Ontario, Canada (ClinicalTrials.gov: NCT00574808). Participants were randomly assigned by region to one of three steps. Practice facilitators were intended to visit practices every 3-4 (year 1-intensive) or 6-12 weeks (year 2 sustainability) to support changes in practice behavior. The primary outcome was mean adherence to indicators of evidence-based care measured at the patient level. Adherence was assessed by chart review of a randomly selected cohort of 66 patients per practice in each pre-intervention year, as well as in year 1 and year 2 post-intervention. RESULTS: Eighty-four practices (182 physicians) participated. On average, facilitators had 6.6 (min: 2, max: 11) face-to-face visits with practices in year 1 and 2.5 (min: 0 max: 10) visits in year 2. We collected chart data from 5292 patients. After adjustment for patient and provider characteristics, there was a 1.9 % (95 % confidence interval (CI): -2.9 to -0.9 %) and 4.2 % (95 % CI: -5.7 to -2.6 %) absolute decrease in mean adherence from baseline to intensive and sustainability years, respectively. CONCLUSIONS: IDOCC did not improve adherence to best-practice guidelines. Our results showed a small statistically significant decrease in mean adherence of questionable clinical significance. Potential reasons for this result include implementation challenges, competing priorities in practices, a broad focus on multiple chronic disease indicators, and use of an overall index of adherence. These results contrast with findings from previously reported facilitation trials and highlight the complexities and challenges of translating research findings into clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT00574808. PMID- 26510579 TI - The role of East Asian monsoon system in shaping population divergence and dynamics of a constructive desert shrub Reaumuria soongarica. AB - Both of the uplift of Qinghai-Tibet Plateau (QTP) and the development of East Asian monsoon system (EAMS) could have comprehensively impacted the formation and evolution of Arid Central Asia (ACA). To understand how desert plants endemic to ACA responded to these two factors, we profiled the historical population dynamics and distribution range shift of a constructive desert shrub Reaumuria soongarica (Tamaricaceae) based on species wide investigation of sequence variation of chloroplast DNA and nuclear ribosomal ITS. Phylogenetic analysis uncovered a deep divergence occurring at ca. 2.96 Mya between the western and eastern lineages of R. soongarica, and ecological niche modeling analysis strongly supported that the monsoonal climate could have fragmented its habitats in both glacial and interglacial periods and impelled its intraspecific divergence. Additionally, the population from the east monsoonal zone expanded rapidly, suggesting that the local monsoonal climate significantly impacted its population dynamics. The isolation by distance tests supported strong maternal gene flow along the direction of the East Asian winter monsoon, whose intensification induced the genetic admixture along the latitudinal populations of R. soongarica. Our results presented a new case that the development of EAMS had prominently impacted the intraspecific divergence and population dynamics of this desert plant. PMID- 26510580 TI - In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury. AB - The pathophysiological mechanism involved in side effects of radiation therapy, and especially the role of the endothelium remains unclear. Previous results showed that plasminogen activator inhibitor-type 1 (PAI-1) contributes to radiation-induced intestinal injury and suggested that this role could be driven by an endothelium-dependent mechanism. We investigated whether endothelial specific PAI-1 deletion could affect radiation-induced intestinal injury. We created a mouse model with a specific deletion of PAI-1 in the endothelium (PAI 1KO(endo)) by a Cre-LoxP system. In a model of radiation enteropathy, survival and intestinal radiation injury were followed as well as intestinal gene transcriptional profile and inflammatory cells intestinal infiltration. Irradiated PAI-1KO(endo) mice exhibited increased survival, reduced acute enteritis severity and attenuated late fibrosis compared with irradiated PAI 1(flx/flx) mice. Double E-cadherin/TUNEL labeling confirmed a reduced epithelial cell apoptosis in irradiated PAI-1KO(endo). High-throughput gene expression combined with bioinformatic analyses revealed a putative involvement of macrophages. We observed a decrease in CD68(+)cells in irradiated intestinal tissues from PAI-1KO(endo) mice as well as modifications associated with M1/M2 polarization. This work shows that PAI-1 plays a role in radiation-induced intestinal injury by an endothelium-dependent mechanism and demonstrates in vivo that the endothelium is directly involved in the progression of radiation-induced enteritis. PMID- 26510581 TI - Modulation of oxidized-LDL receptor-1 (LOX1) contributes to the antiatherosclerosis effect of oleanolic acid. AB - Oleanolic acid (OA) is a bioactive pentacyclic triterpenoid. The current work studied the effects and possible mechanisms of OA in atherosclerosis. Quails (Coturnix coturnix) were treated with high fat diet with or without OA. Atherosclerosis was assessed by examining lipid profile, antioxidant status and histology in serum and aorta. Human umbilical vein endothelial cells (HUVECs) were exposed to 200MUg/mL ox-LDL for 24h, then cell viability was assessed with MTT assay; reactive oxygen species (ROS) was assessed with DCFDA staining. Expression levels of LOX-1, NADPH oxidase subunits, nrf2 and ho-1 were measured with real time PCR and western blotting. Furthermore, LOX-1 was silenced with lentivirus and the expression levels assessment was repeated. OA treatment improved the lipid profile and antioxidant status in quails fed with high fat diet. Histology showed decreased atherosclerosis in OA treated animals. Ox-LDL exposure decreased viability and induced ROS generation in HUVECs, and this progression was alleviated by OA pretreatment. Moreover, elevated expression of LOX-1, NADPH oxidase subunits, nrf2 and ho-1 were observed in ox-LDL exposed HUVECs. OA pretreatment prevented ox-LDL induced increase of LOX-1 and NADPH oxidase subunits expression, while further increased nrf2 and ho-1 expression. Silencing of LOX-1 abolished ox-LDL induced effects in cell viability, ROS generation and gene expression. OA could alleviate high fat diet induced atherosclerosis in quail and ox-LDL induced cytotoxicity in HUVECs; the potential mechanism involves modulation of LOX-1 activity, including inhibition of expression of NADPH oxidase subunits and increase of the expression of nrf2 and ho-1. PMID- 26510582 TI - Cross-talk between TLR4 and PPARgamma pathways in the arachidonic acid-induced inflammatory response in pancreatic acini. AB - Arachidonic acid (AA) is generally associated with inflammation in different settings. We assess the molecular mechanisms involved in the inflammatory response exerted by AA on pancreatic acini as an approach to acute pancreatitis (AP). Celecoxib (COX-2 inhibitor), TAK-242 (TLR4 inhibitor) and 15d-PGJ2 (PPARgamma agonist) were used to ascertain the signaling pathways. In addition, we examine the effects of TAK-242 and 15d-PGJ2 on AP induced in rats by bile pancreatic duct obstruction (BPDO). To carry out in vitro studies, acini were isolated from pancreas of control rats. Generation of PGE2 and TXB2, activation of pro-inflammatory pathways (MAPKs, NF-kappaB, and JAK/STAT3) and overexpression of CCL2 and P-selectin was found in AA-treated acini. In addition, AA up regulated TLR4 and down-regulated PPARgamma expression. Celecoxib prevented the up-regulation of CCL2 and P-selectin but did not show any effect on the AA mediated changes in TLR4 and PPARgamma expression. TAK-242, reduced the generation of AA metabolites and repressed both the cascade of pro-inflammatory events which led to CCL2 and P-selectin overexpression as well as the AA-induced PPARgamma down-regulation. Thus, TLR4 acts as upstream activating pro inflammatory and inhibiting anti-inflammatory pathways. 15d-PGJ2 down-regulated TLR4 expression and hence prevented the synthesis of AA metabolites and the inflammatory response mediated by them. Reciprocal negative cross-talk between TLR4 and PPARgamma pathways is evidenced. In vivo experiments showed that TAK-242 and 15d-PGJ2 treatments reduced the inflammatory response in BPDO-induced AP. We conclude that through TLR4-dependent mechanisms, AA up-regulated CCL2 and P selectin in pancreatic acini, partly mediated by the generation of PGE2 and TXB2, which activated pro-inflammatory pathways, but also directly by down-regulating PPARgamma expression with anti-inflammatory activity. In vitro and in vivo studies support the role of TLR4 in AP and the use of TLR4 inhibitors and PPARgamma agonists in AP treatment. PMID- 26510583 TI - A Gaze Independent Brain-Computer Interface Based on Visual Stimulation through Closed Eyelids. AB - A classical brain-computer interface (BCI) based on visual event-related potentials (ERPs) is of limited application value for paralyzed patients with severe oculomotor impairments. In this study, we introduce a novel gaze independent BCI paradigm that can be potentially used for such end-users because visual stimuli are administered on closed eyelids. The paradigm involved verbally presented questions with 3 possible answers. Online BCI experiments were conducted with twelve healthy subjects, where they selected one option by attending to one of three different visual stimuli. It was confirmed that typical cognitive ERPs can be evidently modulated by the attention of a target stimulus in eyes-closed and gaze independent condition, and further classified with high accuracy during online operation (74.58% +/- 17.85 s.d.; chance level 33.33%), demonstrating the effectiveness of the proposed novel visual ERP paradigm. Also, stimulus-specific eye movements observed during stimulation were verified as reflex responses to light stimuli, and they did not contribute to classification. To the best of our knowledge, this study is the first to show the possibility of using a gaze independent visual ERP paradigm in an eyes-closed condition, thereby providing another communication option for severely locked-in patients suffering from complex ocular dysfunctions. PMID- 26510584 TI - Rehabilitation following surgical repair of the rotator cuff: a systematic review. AB - BACKGROUND: Surgery to repair rotator cuff (RC) tears is a commonly performed orthopaedic procedure with the aim of reducing pain and improving function. Surgery is followed by rehabilitation and recommendations for postoperative rehabilitation include; exercise therapy, continuous passive motion machines and aquatic therapy. Currently, there is uncertainty in the literature as to what constitutes best postsurgical rehabilitation. OBJECTIVE: To systematically review postsurgical research investigations to provide clinical guidance regarding postsurgical management. DATA SOURCES: A keyword search of Medline, Cinahl, Amed, Embase and Cochrane databases from September 1993 to September 2013. STUDY SELECTION: Reviewer assessment using inclusion and exclusion criteria of randomised controlled trials. DATA EXTRACTION: Data pertaining to research design, intervention and subjects was extracted from included papers by one author. The data was grouped by reference to the objectives of the study and collated in themes. DATA SYNTHESIS: Narrative synthesis of the data was used to describe the effects of the intervention. The methodological quality and risk of bias of the included studies was assessed using the standardised Physiotherapy Evidence Database scale. Eleven studies met the inclusion criteria. All the studies were of fair to good methodological quality. No one rehabilitation protocol was found to be superior to another. The findings of this review suggested that following RC repair, patients should expect improvement in pain, ROM and function. CONCLUSION: This review concludes that no single rehabilitation protocol is superior to another following RC repair. Studies with larger study populations and longer term follow up are required to investigate this further. PMID- 26510585 TI - Biomarkers in the Management of Chronic Lung Disease. PMID- 26510586 TI - Perspectives in Medicinal Chemistry: The Evolution of Medicinal Chemistry. PMID- 26510587 TI - Dynamics of cinacalcet use and biochemical control in hemodialysis patients: a retrospective New-user cohort design. AB - BACKGROUND: Cinacalcet is used to treat secondary hyperparathyroidism among hemodialysis patients. Large-scale epidemiologic studies describing patterns of cinacalcet use, effects on parathyroid hormone (PTH), calcium, and phosphorous levels, and predictors of discontinuation have not been previously reported. METHODS: This retrospective cohort study used a clinical database of a large U.S. dialysis provider (2007-2010) merged with administrative data from the United States Renal Data System. Among new users of cinacalcet with Medicare coverage, trends in PTH, calcium, and phosphorus were measured in 30-day intervals following cinacalcet initiation. RESULTS: Seventeen thousand seven hundred sixty three eligible initiators contributed 111,047 30-day follow-up intervals. Of these, 56 % discontinued cinacalcet by month 4. Of those discontinuing, 76.3 % reinitiated. Mean values of PTH, calcium, and phosphorus decreased to recommended levels within 4 months following initiation. Proximal PTH levels < 150 pg/mL were associated with discontinuation: HR = 1.23 (95 % CI: 1.12, 1.36), whereas low calcium (< 7.5 mg/dL) was suggestive of an association, HR = 1.09 (95 % CI 0.91, 1.32). Being in the Part D gap period increased discontinuation risk: HR = 1.09 (95 % CI: 1.03, 1.16). Low-income subsidy status decreased discontinuation risk: HR = 0.77 (95 % CI 0.69, 0.86). Predictors of reinitiation included low-income subsidy, HR = 1.32 (95 % CI 1.22, 1.43); higher albumin level, HR = 1.23 (95 % CI 1.10, 1.36) and higher calcium level, HR = 1.26 (95 % CI 1.19, 1.33). CONCLUSIONS: Substantial and expected declines in laboratory values occurred following cinacalcet initiation. Early discontinuation and reinitiation of cinacalcet were common and may have occurred for clinical and economic reasons. PMID- 26510588 TI - Human mesenchymal stem cells labelled with dye-loaded amorphous silica nanoparticles: long-term biosafety, stemness preservation and traceability in the beating heart. AB - BACKGROUND: Treatment of myocardial infarction with mesenchymal stem cells (MSCs) has proven beneficial effects in both animal and clinical studies. Engineered silica nanoparticles (SiO2-NPs) have been extensively used as contrast agents in regenerative medicine, due to their resistance to degradation and ease of functionalization. However, there are still controversies on their effective biosafety on cellular systems. In this perspective, the aims of the present study are: 1) to deeply investigate the impact of amorphous 50 nm SiO2-NPs on viability and function of human bone marrow-derived MSCs (hMSCs); 2) to optimize a protocol of harmless hMSCs labelling and test its feasibility in a beating heart model. RESULTS: Optimal cell labelling is obtained after 16 h exposure of hMSCs to fluorescent 50 nm SiO2-NPs (50 ug mL(-1)); interestingly, lysosomal activation consequent to NPs storage is not associated to oxidative stress. During prolonged culture hMSCs do not undergo cyto- or genotoxicity, preserve their proliferative potential and their stemness/differentiation properties. Finally, the bright fluorescence emitted by internalized SiO2-NPs allows both clear visualization of hMSCs in normal and infarcted rat hearts and ultrastructural analysis of cell engraftment inside myocardial tissue. CONCLUSIONS: Overall, 50 nm SiO2-NPs display elevated compatibility with hMSCs in terms of lack of cyto- and genotoxicity and maintenance of important features of these cells. The demonstrated biosafety, combined with proper cell labelling and visualization in histological sections, make these SiO2-NPs optimal candidates for the purpose of stem cell tracking inside heart tissue. PMID- 26510589 TI - [Kisspeptin and leptin in the regulation of fertility]. AB - Kisspeptin (KISS1) and its receptor (KISS1R) are important regulators of the reproductive function, along with gonadoliberin (GnRH), gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)), and sex steroid hormones. Mutations of their genes alter sexual maturation. The p.P74S, p.H90D, and p.P110T missense mutations of KISS1 are associated with central precocious puberty (CPP); and the p.G35S, p.C53R, and p.F117L mutations, with delayed puberty and isolated hypogonadotropic hypogonadism (IHH). The p.P196H and p.R386P mutations of KISS1R are also associated with CPP. However, a greater number of KISS1R mutations are associated with IHH, as is the case with p.L102P, p.L148S, p.E232Q, p.R297L, p.Y313H, pX399R, and more complex mutations, such as the 155-bp deletion that removes the acceptor splice site of intron 4 and part of exon 5, a deletion of the GCA triplet in position-2 ...-4 of intron 2, and an ACCGGCT insertion in the same site. The heterozygous compound mutations p.C223R/p.R297L and p.R331X/X399R and the 1-bp insertion 1001_1002insC of KISS1R are similarly associated with IHH. Leptin-dependent activation of KISS1 in hypothalamic neurons was observed in mice and sheep, being especially evident after puberty. Leptin exerts a permissive effect in regulating fertility and facilitate the induction of puberty by hypothalamic KISS1 and GnRH and pituitary LH and FSH, which support the reproductive function during further life. PMID- 26510590 TI - [Molecular genetic mechanisms of drug resistance in prostate cancer]. AB - The major problem in prostate cancer treatment is the development of drug resistance and especially important, cross-resistance. The mechanisms of drug resistance, which are divided into ligand-dependent (requiring the presence of androgens in the cell) and independent (not requiring the presence of androgens) are reviewed. The mechanisms are mainly represented with mutations of the androgen receptor and expression of aberrant constitutively active splice variants, as well as up-regulation of genes involved in androgens synthesis. PMID- 26510591 TI - [Molecular basis and tissue specificity of the progestins action]. AB - The review considers the effect of progestins on the function, proliferation, and apoptosis of cells of various organs in health and noncancerous disorders. Data are summarized to describe the mechanism of progestin action through various progesterone receptors and sensors and the regulation of their levels. The effects of progestins depend on the cell phenotype, including the composition and proportion of different receptors, activity of signaling pathways, and expression of transcription factor coregulators and steroid metabolism enzymes. The role paracrine regulation plays in the progestin effect is described. Particular attention is paid to the progestin effect on the tissues where progestins are thought or known to affect carcinogenesis or to stimulate or suppress the tumor growth, that is, to modulate cell proliferation, apoptosis, and the epithelial mesenchymal transition. PMID- 26510592 TI - [Identification of new conserved and variable regions in the 16S rRNA gene of acetic acid bacteria and acetobacteraceae family]. AB - The Acetobacteraceae family of the class Alpha Proteobacteria is comprised of high sugar and acid tolerant bacteria. The Acetic Acid Bacteria are the economically most significant group of this family because of its association with food products like vinegar, wine etc. Acetobacteraceae are often hard to culture in laboratory conditions and they also maintain very low abundances in their natural habitats. Thus identification of the organisms in such environments is greatly dependent on modern tools of molecular biology which require a thorough knowledge of specific conserved gene sequences that may act as primers and or probes. Moreover unconserved domains in genes also become markers for differentiating closely related genera. In bacteria, the 16S rRNA gene is an ideal candidate for such conserved and variable domains. In order to study the conserved and variable domains of the 16S rRNA gene of Acetic Acid Bacteria and the Acetobacteraceae family, sequences from publicly available databases were aligned and compared. Near complete sequences of the gene were also obtained from Kombucha tea biofilm, a known Acetobacteraceae family habitat, in order to corroborate the domains obtained from the alignment studies. The study indicated that the degree of conservation in the gene is significantly higher among the Acetic Acid Bacteria than the whole Acetobacteraceae family. Moreover it was also observed that the previously described hypervariable regions V1, V3, V5, V6 and V7 were more or less conserved in the family and the spans of the variable regions are quite distinct as well. PMID- 26510593 TI - [Infrared fluorescent markers for microarray DNA analysis on biological microchip]. AB - To expand the informational capabilities of molecular genetic research, on the biological microchips, new indotricarbocyanine dyes that fluoresce in the near infrared (IR) spectral region have been synthesized. The developed IR dyes were studied using a biochip-based test system for detection of mutations in the BRCA1/BRCA2 and CHECK2 genes associated with breast cancer. The fluorescent label was introduced to the analyzed DNA during PCR using primers labeled with the synthesized IR dyes. An analyzer that allows recording and processing of images of fluorescent microarrays in the IR spectral region was designed and manufactured. It has been shown that the use of the synthesized dyes enables to conduct analysis in the IR region and improve the reliability of medical diagnostic tests due to low fluorescence intensity of sample components as well as of a biochip substrate and the reagents used for analysis. PMID- 26510594 TI - [Fish growth-hormone genes: functionality evidence of paralogous genes in Levanidov's charr]. AB - In the genome of most vertebrates growth-hormone gene is presented in a single copy, while in salmonids after one of the duplication events many genes were multiplied, including growth hormone gene. In salmonids, the growth-hormone gene exists as two independently inherited functional paralogues, gh1 and gh2. In this study, we performed a comparative analysis of gh1 and gh2 growth-hormone genes and their adjacent sequences in Levanidov's charr Salvelinus levanidovi to determine their functionality and define the potential differences. We found that both genes have the same gene structure and are composed of six exons (I-VI) and five introns (A, B, C, D, E). However, the respective gene sequences differ in length. A comparison of exons showed that the size of each exon is identical in both paralogues. The overall length of genes differs due to the varying lengths of introns. Coding sequence of both genes contains an open reading frame for 210 amino acids. We identified regulatory elements in the promoter region of both genes: TATA box, A/T-rich regions that contain binding sites for pituitary specific transcriptional activator Pit-1, and regions responsible for interaction with other transcriptional activators and initiators, in particular hormone receptors. The obtained data indicate that both genes are functional. PMID- 26510595 TI - [Antitumor effect of mIFN-lambda3 in C57BL/6 mice model for papilloma tumors]. AB - Although several years have passed since the determination of the human papilloma virus (HPV) as the causative agent for cervical cancer, a definitive treatment has not yet been found. Interferon-alpha (IFN-alpha) immunotherapy is one of the promising methods for tumor treatment, although numerous side effects were observed in clinical trials. Recently, a new type of interferon, lambda interferon (IFN-lambda), has been discovered with fewer side effects than IFN alpha since its receptor repertoire is limited. IFN-lambda has a series of activities including antiviral, anti-proliferative and anti-tumor actions. In the present study, the effects of IFN-alpha and IFN-lambda on the TC1 papilloma tumor model in C57BL/6 mice were evaluated. TC1 cells were injected into the mice subcutaneously. Upon tumor formation, murine IFN, mIFN-alpha and mIFN-lambda, expression plasmids were injected intratumorally in combination or alone. The survival time and tumor size as well as apoptosis in tumors and NK cytoxicity were measured after three injections. As compared with the control group, the remarkable results especially in the group which received mIFN-alpha and mIFN lambda together were obtained for all of the measured parameters. Although IFN lambda is a new member of the interferon family and its properties should be studied in detail, the data obtained suggests that the use of IFN-lambda especially in combination with IFN-alpha could be considered as an effective strategy for papilloma cervical cancer immunotherapy. PMID- 26510596 TI - [cDNA cloning, expression and determination of substrate specificity of mice selenocysteine-containing protein SelV (Selenoprotein V)]. AB - To date various bioinformatics tools allowed to identify 25 selenocysteine containing mammalian proteins. The name of these proteins assumes that they contain the amino acid selenocysteine (Sec). Functionally characterized selenocysteine-containing proteins are oxidoreductases with various functions, including glutathione peroxidases, thioredoxin reductases, deiodinases etc. However, the functions of more than half of identified proteins are still unclear, and mammalian selenoprotein SeIV is among them. We studied the selV in all stages of postnatal development with the maximum level of mRNA expression during puberty, whereas in adult mice (8-18 months) we observed a gradual decrease of expression. In order to get closer to the functional role of Selenoprotein V, we have carried out experiments on the substrate specificity and enzymatic activity measurement of this selenocysteine-containing protein. It was shown that SelV posseses glutathionperoxidase and thioredoxinreductase activities. PMID- 26510597 TI - [Preparation of recombinant serpins B3 and B4 and investigation of their specific interactions with antibodies using hydrogel-based microarrays]. AB - The objective of this work was to obtain preparations of recombinant squamous cell carcinoma antigens (serpins B3 and B4) and to investigate their interactions with different monoclonal antibodies using hydrogel-based microarrays (biochips). Two genetic constructs encoding full-length serpin B3 and serpin B4 molecules were created to produce recombinant SPB3 and SPB4 proteins carrying a N-terminal His6-tag. Monoclonal antibodies against serpin B3 (H3, C5, H5, H81, and G9) were also obtained. An experimental gel-based biological microchip was designed to contain gel elements that carry immobilized antibodies against SPB3, immobilized commercial monoclonal SCC107 and SCC140 antibodies against squamous-cell carcinoma antigen (SCCA), and gel elements with immobilized SPB3 or SPB4. Judging by the specificity of recombinant SPB3 and SPB4, which bind to monoclonal antibodies against SCCA and, according to the manufacturer's data, can recognize conformational epitopes of both SPB3 and SPB4, it was concluded that the obtained recombinant serpins had the correct tertiary structure. A biochip-based direct immunoassay showed that SPB4 could bind effectively only to SCC107 and SCC140 antibodies, while SPB3 interacted specifically not only with these antibodies, but also with H3 and C5 monoclonal antibodies. Using biochip-based sandwich immunoassay, a pair of monoclonal antibodies SCC107/C5 that interacted specifically with serpin B3 but did not interact with serpin B4 was identified. Thus, it has been demonstrated that serpin B3 can be selectively determined in the presence of highly homologous serpin B4 using a biochip-based assay. PMID- 26510598 TI - [Epstein-Barr Virus LMP1 oncogene variants in cell lines of different origin]. AB - It is well known that the Epstein-Barr virus (EBV) is a widespread infection in the human population. Typically, infection occurs in early childhood without serious consequences for infected people. At the same time, a secondary infection with an additional EBV strain occurs quite often. During the in vitro cultivation of peripheral blood lymphocytes from persons infected with multiple strains of the virus, only one of these strains with higher transforming potential becomes dominant, while the others are eliminated. Under certain conditions, such a highly transforming EBV strain apparently is able to be the etiologic agent of EBVassociated diseases. To find out the range of highly transforming EBV strains prevalent among Russians, cell lines from patients with EBV-associated and non associated tumors, as well as healthy individuals, were established. The structural analysis of the latent membrane protein 1 gene (LMP1), a key oncogene of the virus, isolated from established cell lines and peripheral blood lymphocytes of blood donors was carried out, and data obtained were compared with the respective data for LMP1 isolates, amplified from cell lines established from African and Japanese patients with Burkitt's lymphoma. The data obtained show a genetic relationship between Russian LMP1 isolates regardless the fact whether they come from patients with tumors or healthy individuals and differ significantly from LMP1 isolates from Burkitt's lymphoma patients. Thus, the results of the study suggest that in nonendemic region for EBV-associated pathology, Russia, any strain of EBV with any structure of LMP1 with concomitant effect of additional factors may become an etiologic agent for EBV-associated neoplasia. PMID- 26510599 TI - [Production and stabilization of an integrin-binding moiety of complement component 3]. AB - The third component of complement, C3, plays a central role in human innate immunity. The subsequent proteolysis product of native C3, iC3b, is the primary ligand of complement receptors (CRs) CR3 and CR4. CR3 and CR4 are beta2-family integrins, and their binding to iC3b contributes to phagocytosis. How iC3b binds to its receptors and transmits signals into the cells is not clear. To perform structural and functional studies on the interaction between iC3b and its receptors CR3/CR4, we isolated the integrin-binding fragment of iC3b, MG3-4. Low temperature is required for its soluble expression in Escherichia coli. Purified MG3-4 existed as a dimer in solution and was easy to aggregate. We tried different agents and found glycerol could efficiently stabilize the MG3-4 fragment to avoid aggregation. Using surface plasmon resonance (SPR) analysis, we confirmed MG3-4 could bind I domain, the iC3b-binding domain of CR3. Here, we report the successful production of a soluble, stable, and biologically active integrin-binding moiety of human iC3b for further studies. PMID- 26510600 TI - [Probabilistic calculations of biomolecule charge states that generate mass spectra of multiply charged ions]. AB - In this work, information relating to charge states of biomolecule ions in solution obtained using the electrospray ionization mass spectrometry of different biopolymers is analyzed. The data analyses have mainly been carried out by solving an inverse problem of calculating the probabilities of retention of protons and other charge carriers by ionogenic groups of biomolecules with known primary structures. The approach is a new one and has no known to us analogues. A program titled "Decomposition" was developed and used to analyze the charge distribution of ions of native and denatured cytochrome c mass spectra. The possibility of splitting of the charge-state distribution of albumin into normal components, which likely corresponds to various conformational states of the biomolecule, has been demonstrated. The applicability criterion for using previously described method of decomposition of multidimensional charge-state distributions with two charge carriers, e.g., a proton and a sodium ion, to characterize the spatial structure of biopolymers in solution has been formulated. In contrast to known mass-spectrometric approaches, this method does not require the use of enzymatic hydrolysis or collision-induced dissociation of the biopolymers. PMID- 26510601 TI - [Influence of M680I and M694V mutations on pyrin's domain B30.2 tertiary structure and it's complex formation ability with caspase-1]. AB - The M680I and M694V mutations located in the B30.2 pyrin domain are responsible for the manifestation of the most common forms of Familial Mediterranean fever. It is well known that a malfunction of the pyrin-caspase-1 complex is the main cause of inflammation in FMF. The purpose of this study was to identify possible changes in the tertiary structure of mutated B30.2 domain and to determine their potential consequences in the formation of the pyrin-caspase-1 complex. Using computer modeling, it was found that the above mutations change the tertiary structure of B30.2 domain, causing shifts of binding sites and altering the energy of interaction between B30.2 and caspase-1. PMID- 26510602 TI - [Computational analysis of a cys-loop ligand gated ion channel from the green alga Chlamydomonas reinhardtii]. AB - Plants possess several neurotransmitters with well-known physiological roles. Currently only receptors for glutamate were reported to be found in plants, while receptors for acetylcholine, serotonin and GABA have not yet been reported. In animals, these neurotransmitters act via one class of ligand binding ion channels called Cys-loop receptors which play a major role in fast synaptic transmission. They show the presence of two domains namely Neurotransmitter-gated ion-channel ligand-binding domain (Pfam: PF02931) and Neurotransmitter-gated transmembrane domain (Pfam: PF02932). Cys-loop receptors are also known in prokaryotes. No cys loop receptor has been characterized from plants yet. In this study, the Ensembl plants database was searched for proteins with these two domains in the sequenced plant genomes, what resulted in only one protein (LIC1) from the alga Chlamydomonas reinhardtii. BLAST and profile HMM searches against the pdb structure database showed that this protein is related to animal and prokaryotic cys-loop receptors, although the cysteine residues characteristic of the cys-loop are absent. Physico-chemical and sequence analysis indicate that LIC1 is an anionic receptor. A model of this protein was generated using homology modeling based on a nicotinic acetylcholine receptor of Torpedo marmorata. The characteristic extracellular domain (ECD) and transmembrane domain (TMD) are well structured but the intercellular region is poorly formed. This is the first report on a detailed characterization of a cys-loop receptor from the plant kingdom. PMID- 26510603 TI - [Web server for prediction of miRNAs and their precursors and binding sites]. AB - A microRNA (miRNA) is a small noncoding RNA molecule about 22 nucleotides in length. The paper describes a web server for predicting miRNAs and their precursors and binding sites. The predictions are based on either sequence similarity to known miRNAs of 223 organisms or context-structural hidden Markov models. It has been shown that the proposed methods of prediction of human miRNAs and pre-miRNAs outperform the existing ones in accuracy. The average deviation of predicted 5'-ends of human miRNAs from actual positions is 3.13 nt in the case of predicting one pair of complementary miRNAs (miRNA-miRNA* duplex). A useful option for our application is the prediction of an additional miRNA pair. In this mode, the pairs closest to actual miRNA deviate by 1.61 nt on average. The proposed method also shows good performance in predicting mouse miRNAs. Binding sites for miRNAs are predicted by two known approaches based on complementarity and thermodynamic stability of the miRNA-mRNA duplex and on a new approach, which takes into account miRNAs competition for the site. The role of the secondary structure in miRNA processing is considered. The web server is available at http://wwwmgs.bionet.nsc.ru/mgs/programs/rnaanalys/. PMID- 26510605 TI - Recognition of the role of Natural Products as drugs to treat neglected tropical diseases by the 2015 Nobel prize in physiology or medicine. AB - The 2015 Nobel Prize in Physiology or Medicine recognised the advances made in treating neglected tropical diseases, using drugs whose origins lie in natural products. PMID- 26510606 TI - Common pulmonary vein atresia: report of three cases and review of the literature. AB - Common pulmonary vein atresia is a rare and usually fatal congenital anomaly, in which the pulmonary veins come together to form a confluence that does not connect to the left atrium. We report our experience with three cases of common pulmonary vein atresia and review the literature on this anomaly. The diagnosis of common pulmonary vein atresia must be entertained in any newborn that presents with cyanosis, refractory acidosis, and decreased systemic perfusion within the first 48 hours of life. Echocardiography is a useful screening tool, but cardiac catheterisation is the preferred diagnostic tool. Common pulmonary vein atresia can be fatal without surgical intervention, but survival after surgery continues to be poor. PMID- 26510607 TI - Identification of a Pheromone Component and a Critical Synergist for the Invasive Beetle Callidiellum rufipenne (Coleoptera: Cerambycidae). AB - The invasive Asian cerambycid beetle Callidiellum rufipenne (Motschulsky), informally known as the Japanese cedar longhorned beetle, was first detected in North America in North Carolina in 1997. The beetle has since been detected in neighboring states and is expected to further expand its range. However, delineating the current distribution of C. rufipenne has been hindered by the lack of efficient sampling methods. Here, we present the results of research on the chemistry of volatile pheromones of C. rufipenne. Analyses of headspace odors revealed that males produce (R)-3-hydroxyhexan-2-one, with lesser amounts of (S) 3-hydroxyhexan-2-one, and (R)- and (S)-2-hydroxyhexan-3-one. In field bioassays conducted over several years in Connecticut, where populations of the beetle were well established, no reconstructed blend of these compounds was significantly attractive to beetles of either sex. However, during field trials in Japan that targeted another species, we discovered that adult male and female C. rufipenne were attracted to a blend of racemic 3-hydroxyhexan-2-one and a novel natural product, 1-(1H-pyrrol-2-yl)-1,2-propanedione. Attraction to (R)-3-hydroxyhexan-2 one and the pyrrole subsequently was confirmed in field trials in Connecticut. Although it is unclear why the pyrrole acts as a synergist for a species that apparently does not produce it, the serendipitous discovery that adult C. rufipenne are attracted by the blend of ketone and pyrrole provides a badly needed method for monitoring its ongoing range expansion within North America, and for detecting new introductions in other parts of the world. PMID- 26510608 TI - Inheritance and World Variation in Thermal Requirements for Egg Hatch in Lymantria dispar (Lepidoptera: Erebidae). AB - Mode of inheritance of hatch traits in Lymantria dispar L. was determined by crossing populations nearly fixed for the phenotypic extremes. The nondiapausing phenotype was inherited via a single recessive gene and the phenotype with reduced low temperature exposure requirements before hatch was inherited via a single dominant gene. There was no evidence for sex-linkage or cytoplasmic effects with either gene. Eggs from 43 geographic populations were evaluated for hatch characteristics after being held for 60 d at 5 degrees C followed by incubation at 25 degrees C. There was considerable variation both within and among the populations in the proportion able to hatch, time to first hatch, and average time to hatch. Egg masses with reduced requirement for low temperatures before the eggs were ready to hatch were present in all subspecies of L. dispar and the phenotype was not fixed in most populations. The populations clustered into three distinct groups, and climatic variables were found to be rough predictors of those groups. Variation in hatch phenotypes between populations is likely an adaptation to local climate and within a population provides a bet hedging strategy to ensure that at least some hatch synchronizes with host leaf out. Continued vigilance to prevent movement of populations both within and between countries is warranted, because some of the alleles that confer nondiapause or reduced low temperature requirements before egg hatch are not present in all populations and their introduction would increase variation in egg hatch within a population. PMID- 26510609 TI - Special Issue on International Conference on Solid Waste 2013. PMID- 26510610 TI - Assessing the performance of gas collection systems in select Chinese landfills according to the LandGEM model: drawbacks and potential direction. AB - In China, municipal solid waste (MSW) is primarily treated by landfilling. Landfill gas (LFG) collection effectively reduces methane emission from MSW landfills. An accurate system of LFG collection is important in landfill planning, design, and operation. However, China has not developed such systems. In this study, the efficiency of methane collection is calculated in three Chinese landfills with different collection systems (A: vertical wells for MSW before 2010; combined horizontal trenches and under-membrane pipes for MSW from 2011 onwards; B: combined horizontal trenches and vertical wells; C: vertical wells only). This efficiency was computed by dividing the quantity of methane obtained from landfill operation records by the quantity estimated based on the LandGEM model. Results show that the collection efficiencies of landfills with vertical wells and/or horizontal pipes ranged from 8.3% to 27.9%, whereas those of a system equipped with geomembrane reached 65.3%. The poor performance of the landfills was attributed to the open burning of early-stage LFG, LFG release from cracks in high-density polyethylene covers, and high levels of leachate within a landfill site. Therefore, this study proposes an integrated LFG collection system that can remove leachate and collect gas from landfills that accept waste with high moisture content. PMID- 26510611 TI - Removal of ammonium from municipal landfill leachate using natural zeolites. AB - Ammonium ion-exchange performance of the natural zeolite was investigated in both batch and column studies. The effects of zeolite dosage, contact time, stirring speed and pH on ammonium removal were investigated in batch experiments. The result showed that ammonium removal efficiency increased with an increase in zeolite dosage from 25 to 150 g/L, and an increase in stirring speed from 200 to 250 r/min. But further increase in zeolite dosage and stirring speed would result in an unpronounced increase of ammonium removal. The optimal pH for the removal of ammonium was found as 7.1. In the column studies, the effect of flow rate was investigated, and the total ammonium removal percentage during 180 min operation time decreased with the flow rate though the ion-exchange capacity varied to a very small extent with the flow rate ranging from 4 to 9 mL/min. The spent zeolite was regenerated by sodium chloride solution and the ammonia removal capacity of zeolite changed little or even increased after three regeneration cycles. PMID- 26510612 TI - Heavy metal pollution in soils from abandoned Taizhou Chemical Industry Zone in Zhejiang province. AB - Heavy metal (HM) pollution in soils from an abandoned Taizhou Chemical Industry Zone (TCIZ) was investigated. By analysing soils, including sediments, collected from the study zone, the main pollutants were quantitatively identified and their spatial distribution patterns were clearly displayed. Eleven types of HM pollutants were obtained and the results indicated a significant correlation in most of the elements of the soil and sediment. A pollution index Pi was employed to classify the degree of contamination and characterize the main pollutant, which was controlled with the evaluation standard value instead of background one. As was characterized to be one of the main pollutants with the mean concentrations at the pollution source, in the surrounding area, and in the sediment of 603, 20.4, and 22.5 mg/kg, respectively. Our study suggested that the contaminated area of TCIZ may necessitate remediation before it can be considered for reuse. Pollution index method could be a useful tool for assessing soils quality to provide comparable criteria. PMID- 26510613 TI - Micro-observations of different types of nano-Al2O3on the hydration of cement paste with sludge ash replacement. AB - In recent years, sewer systems and wastewater treatment plants have become important in developing countries. Consequently, the amount of sewage sludge produced by these countries has been gradually increasing, and determining how to properly recycle this sludge is becoming an important topic for researchers. In this study, to expand the recyclability of sewage sludge ash (SSA) in engineering applications, two types of nano-aluminium oxides (Al2O3), MC2A and MC2R, were added to SSA/cement paste and mortar specimens. The MC2R type (gamma phase) had a smaller particle size and larger specific surface area than the MC2A type (alpha phase). The results indicate that the addition of nano-Al2O3to SSA/cement paste can effectively improve the hydration products of the paste. Moreover, the amount of hydration products increased as the amount of nano-Al2O3added to the SSA/cement paste increased. The test results indicate that MC2A nano-Al2O3can more uniformly distribute in the paste body and improve the hydration of cement than MC2R nano-Al2O3. Thus, more calcium-silicate-hydrate (C-S-H) gel and calcium aluminate hydrate (C-A-H) salts were produced, and the strength of the specimens was improved. This study suggests that MC2A nano-Al2O3is preferable to MC2R nano- Al2O3for SSA/cement specimen applications. PMID- 26510614 TI - Application of co-anaerobic digester's effluent for sustainable agriculture and aquaculture in the Mekong Delta, Vietnam. AB - This investigation studied the application of digester effluent from co-digestion of pig manure and spent mushroom substrate as a fertilizer for leaf mustard planting and as feed for Tilapia fish growing. The fish raising experiment was set up in 1 * 1 * 1 m hapa conditions (triplicate for each treatment) with the density of 10 individiual per hapa; the fish weight and length were measured every 10 days for 50 continuous days. The leaf mustard was planted in real conditions at farmer's garden with normal cultivation style, and the weight and length of the plant were measured four times during the growing period. The study result shows that the harvest yield of leaf mustard fertilized by the digester effluent was 5.4 times higher than that by an inorganic fertilizer (IF). In addition to its contribution to a higher yield, the digester effluent accelerated the flower formation and shortened cultivation duration. For Tilapia fish culture, the growing rate of fish in the treatments supplied with 50% digester effluent + 50% commercial food (CF) was not significantly different in comparison to the fish cultivation with 100% CF. The result strongly confirms that the digester effluent from a co-digestion biogas plant of pig dung and spent mushroom compost is possible to be used as an organic fertilizer well for not only vegetable planting but also fish culture. PMID- 26510615 TI - Effect of biomass containing zinc metal at different operating parameters on gasification efficiency. AB - This paper describes the effect of Zn on the gas production of a fluidized-bed gasifier to determine the relationship between Zn and the gasification process. Different concentrations of Zn were used in the preparation of artificial waste to elucidate the effect on gas product composition, gas product heat value, gas production rate, and H2 yield in the gasification process. Zn served to increase H2 generation during the gasification process. The molar percentage of H2 with more than 0.1 wt% additional Zn increased by 33.02% and the H2 yield was increased by 11.34% compared to that without Zn. However, the gas heat value decreased, and no significant change in the gas production rate was noted. PMID- 26510616 TI - Paving the way to targeting HECT ubiquitin ligases. PMID- 26510617 TI - HIF-2alpha-induced chemokines stimulate motility of fibroblast-like synoviocytes and chondrocytes into the cartilage-pannus interface in experimental rheumatoid arthritis mouse models. AB - INTRODUCTION: Pannus formation and resulting cartilage destruction during rheumatoid arthritis (RA) depends on the migration of synoviocytes to cartilage tissue. Here, we focused on the role of hypoxia-inducible factor (HIF)-2alpha induced chemokines by chondrocytes in the regulation of fibroblast-like synoviocyte (FLS) migration into the cartilage-pannus interface and cartilage erosion. METHODS: Collagen-induced arthritis (CIA), K/BxN serum transfer, and tumor necrosis factor-alpha transgenic mice were used as experimental RA models. Expression patterns of HIF-2alpha and chemokines were determined via immunostaining, Western blotting and RT-PCR. FLS motility was evaluated using transwell migration and invasion assays. The specific role of HIF-2alpha was determined via local deletion of HIF-2alpha in joint tissues or using conditional knockout (KO) mice. Cartilage destruction, synovitis and pannus formation were assessed via histological analysis. RESULTS: HIF-2alpha and various chemokines were markedly upregulated in degenerating cartilage and pannus of RA joints. HIF 2alpha induced chemokine expression by chondrocytes in both primary culture and cartilage tissue. HIF-2alpha -induced chemokines by chondrocytes regulated the migration and invasion of FLS. Local deletion of HIF-2alpha in joint tissues inhibited pannus formation adjacent to cartilage tissue and cartilage destruction caused by K/BxN serum transfer. Furthermore, conditional knockout of HIF-2alpha in cartilage blocked pannus formation in adjacent cartilage but not bone tissue, along with inhibition of cartilage erosion caused by K/BxN serum transfer. CONCLUSION: Our findings suggest that chemokines induced by IL-1beta or HIF 2alpha in chondrocytes regulate pannus expansion by stimulating FLS migration and invasion, leading to cartilage erosion during RA pathogenesis. PMID- 26510618 TI - The complete sequence of mitochondrial genome of Sinibotia pulchra (Cypriniformes: Cobitidae). AB - Sinibotia pulchra (Cypriniformes: Cobitidae) is a small cyprinid fish. In this study, the complete mitochondrial genome sequence of S. pulchra is sequenced. The S. pulchra complete mitochondrial genome (GenBank accession no. KT362179) was a circular molecule of 16 568 bp in length, with 13 protein-coding genes (PCGs), 2 ribosome RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, an L-strand replication origin (OL) and a control region (D-loop). The nucleotide acid composition of the entire mitogenome was 31.69% for A, 25.63% for T, 26.94% for C and 15.74% for G, with an AT content of 57.32%. The AT content of 12S rRNA, 16S rRNA and D-loop was 50.21%, 56.86% and 66.74%, respectively. PMID- 26510619 TI - Tannerella forsythia Outer Membrane Vesicles Are Enriched with Substrates of the Type IX Secretion System and TonB-Dependent Receptors. AB - Tannerella forsythia, a Gram-negative oral bacterium closely associated with chronic periodontitis, naturally produces outer membrane vesicles (OMVs). In this study, OMVs were purified by gradient centrifugation, and the proteome was investigated together with cellular fractions using LC-MS/MS analyses of SDS-PAGE fractions, resulting in the identification of 872 proteins including 297 OMV proteins. Comparison of the OMV proteome with the subcellular proteomes led to the localization of 173 proteins to the vesicle membrane and 61 proteins to the vesicle lumen, while 27 substrates of the type IX secretion system were assigned to the vesicle surface. These substrates were generally enriched in OMVs; however, the stoichiometry of the S-layer proteins, TfsA and TfsB, was significantly altered, potentially to accommodate the higher curvature required of the S-layer around OMVs. A vast number of TonB-dependent receptors related to SusC, together with their associated SusD-like lipoproteins, were identified, and these were also relatively enriched in OMVs. In contrast, other lipoproteins were significantly depleted from the OMVs. This study identified the highest number of membrane-associated OMV proteins to date in any bacterium and conclusively demonstrates cargo sorting of particular classes of proteins, which may have significant impact on the virulence of OMVs. PMID- 26510620 TI - Contacts with out-of-hours primary care for nonurgent problems: patients' beliefs or deficiencies in healthcare? AB - BACKGROUND: In the Netherlands, about half of the patient contacts with a general practitioner (GP) cooperative are nonurgent from a medical perspective. A part of these problems can wait until office hours or can be managed by the patient himself without further professional care. However, from the patient's perspective, there may be a need to contact a physician immediately. Our objective was to determine whether contacts with out-of-hours primary care made by patients with nonurgent problems are the result of patients' beliefs or of deficiencies in the healthcare system. METHODS: We performed a survey among 2000 patients with nonurgent health problems in four GP cooperatives in the Netherlands. Two GPs independently judged the medical necessity of the contacts of all patients in this study. We examined characteristics, views and motives of patients with medically necessary contacts and those without medically necessary contacts. Descriptive statistics were used to describe the characteristics, views and reasons of the patients with medically unnecessary contacts and medically necessary contacts. Differences between these groups were tested with chi-square tests. RESULTS: The response rate was 32.3 % (N = 646). Of the nonurgent contacts 30.4 % were judged as medically necessary (95 % CI 27.0-34.2). Compared to patients with nonurgent but medically necessary contacts, patients with medically unnecessary contacts were younger and were more often frequent attenders. They had longer-existing problems, lower self-assessed urgency, and more often believed GP cooperatives are intended for all help requests. Worry was the most frequently mentioned motive for contacting a GP cooperative for patients with a medically unnecessary contact (45.3 %) and a perceived need to see a GP for patients with a medically necessary contact (44.2 %). Perceived availability (5.8 %) and accessibility (8.3 %) of a patient's own GP played a role for some patients. CONCLUSION: Motives for contacting a GP cooperative are mostly patient related, but also deficiencies in access to general practice may partly explain medically unnecessary use. Efforts to change the use of GP cooperatives should focus on education of subgroups with an increased likelihood of contact for medically unnecessary problems. Improvement of access to daytime primary care may also decrease use of the GP cooperative. PMID- 26510621 TI - Tourniquet induced ischemia and changes in metabolism during TKA: a randomized study using microdialysis. AB - BACKGROUND: Tourniquet use in total knee arthroplasty (TKA) surgery is applied to minimize blood loss thereby creating better overview of the surgical field. This induces ischemia in the skeletal muscle resulting in reperfusion injury. Our aim was to investigate the in vivo metabolic changes in the skeletal muscle during TKA surgery using microdialysis (MD). METHODS: Seventy patients were randomly allocated to tourniquet group (n = 35) or non-tourniquet group (n = 35). Prior to surgery, catheters were inserted in the operated leg and non-operated leg. Interstitial dialysate was collected before and after surgery and at 20 min intervals during a 5 h reperfusion period. Main variables were ischemic metabolites: glucose, pyruvate, lactate and glycerol and L/P ratio. RESULTS: Significant difference in all metabolites was detected between the two groups, caused by tourniquet application. Tourniquet induced ischemia resulted in decreased levels of glucose and pyruvate to 54 and 60 % respectively, compared to baseline. Simultaneously, accumulation of lactate to 116 % and glycerol to 190 % was observed. L/P ratio was elevated indicating ischemia. In the non-tourniquet group the metabolite changes were less profound and normalized within 60 min. CONCLUSIONS: Microdialysis revealed that performing TKA with tourniquet is associated with increased ischemia. This affects all metabolites but the changes are normalized after 5 h. PMID- 26510622 TI - Pharmacological Targeting of AMP-Activated Protein Kinase and Opportunities for Computer-Aided Drug Design. AB - As a central regulator of metabolism, the AMP-activated protein kinase (AMPK) is an established therapeutic target for metabolic diseases. Beyond the metabolic area, the number of medical fields that involve AMPK grows continuously, expanding the potential applications for AMPK modulators. Even though indirect AMPK activators are used in the clinics for their beneficial metabolic outcome, the few described direct agonists all failed to reach the market to date, which leaves options open for novel targeting methods. As AMPK is not actually a single molecule and has different roles depending on its isoform composition, the opportunity for isoform-specific targeting has notably come forward, but the currently available modulators fall short of expectations. In this review, we argue that with the amount of available structural and ligand data, computer based drug design offers a number of opportunities to undertake novel and isoform specific targeting of AMPK. PMID- 26510623 TI - The efficacy of neuromuscular electrical stimulation with alternating currents in the kilohertz frequency to stimulate gait rhythm in rats following spinal cord injury. AB - BACKGROUND: Rehabilitation facilitates the reorganization of residual/regenerated neural pathways and is key in improving motor function following spinal cord injury. Neuromuscular electrical stimulation (NMES) has been reported as being clinically effective. Although it can be used after the acute phase post-injury, the optimal stimulation conditions to improve motor function remain unclear. In this paper, we examined the effectiveness of NMES with alternating currents in the kilohertz (kHz) frequency in gait rhythm stimulation therapy. METHODS: Tests were performed using 20 mature female Fischer rats. Incomplete spinal cord injuries (T9 level) were made with an IH impactor using a force of 150 kdyn, and NMES was administered for 3 days from the 7th day post-injury. The needle electrodes were inserted percutaneously near the motor point of each muscle in conscious rats, and each muscle on the left and right leg was stimulated for 15 min at two frequencies, 75 Hz and 8 kHz, to induce a gait rhythm. Motor function was evaluated using Basso, Beattie, Bresnahan (BBB) scores and three-dimensional (3D) gait analysis. Rats were divided into four groups (5 rats/group), including the NMES treatment 75-Hz group (iSCI-NMES 75 Hz), 8-kHz group (iSCI-NMES 8 kHz), injury control group (iSCI-NT), and normal group (Normal-CT), and were compared. RESULTS: There was no significant difference in BBB scores among the three groups. In 3D gait analysis, compared with the injury control group, the 8-kHz group showed a significant improvement in synergistic movement of both hindlimbs. CONCLUSION: We suggest that kHz stimulation is effective in gait rhythm stimulation using NMES. PMID- 26510624 TI - Natural History of Adolescent Idiopathic Scoliosis in Skeletally Mature Patients: A Critical Review. AB - The surgical treatment of adolescent idiopathic scoliosis is dependent on several factors, including curve type and magnitude, degree of curve progression, skeletal maturity, and other considerations, such as pain and cosmesis. The most common indication for surgery is curve progression. Most authors agree that surgical treatment should be considered in skeletally mature patients with curves > 50 degrees because of the risk of progression into adulthood. Furthermore, most authors would agree that curves measuring < 40 degrees to 45 degrees in skeletally mature patients should be observed. When a skeletally mature patient with a curve measuring between 45 degrees to 55 degrees is presenting to an orthopaedic surgeon, it is not uncommon that the patient has no pain, no progression, and no imbalance. The generally accepted belief has been that curves that reach 50 degrees are likely to progress into adulthood, progressing at a rate of 1 degrees per year, based largely on the Iowa studies. However, the level of evidence for this is relatively weak, and the existing literature is equivocal in supporting the practice of performing surgery on these patients. PMID- 26510625 TI - Treating the Aging Spine. AB - Demographic trends make it incumbent on orthopaedic spine surgeons to recognize the special challenges involved in caring for older patients with spine pathology. Unique pathologies, such as osteoporosis and degenerative deformities, must be recognized and dealt with. Recent treatment options and recommendations for the medical optimization of bone health include vitamin D and calcium supplementation, diphosphonates, and teriparatide. Optimizing spinal fixation in elderly patients with osteoporosis is critical; cement augmentation of pedicle screws is promising. In the management of geriatric odontoid fractures, nonsurgical support with a collar may be considered for the low-demand patient, whereas surgical fixation is favored for high-demand patients. Management of degenerative deformity must address sagittal plane balance, including consideration of pelvic incidence. Various osteotomies may prove helpful in this setting. PMID- 26510626 TI - Tendinopathies of the Hand and Wrist. AB - Tendinopathies involving the hand and wrist are common. Many are diagnosed easily, and in many cases, the management is straightforward, provided the pathology and principles are understood. Common conditions involving the tendons of the hand and wrist include trigger finger, tenosynovitis of the first through sixth dorsal extensor compartments, and flexor carpi radialis tendonitis. Management strategies include nonsurgical treatments, such as splinting, injection, or therapy, and surgical techniques such as tendon release. PMID- 26510627 TI - Parent-reported pain in non-verbal children and adolescents with cerebral palsy. AB - AIM: This cross-sectional study aimed to determine the prevalence, frequency, and intensity of parent-reported pain among non-verbal children with cerebral palsy (CP) and explore associations with medical, demographic, and parental psychosocial factors. METHOD: Participants were parents of non-verbal outpatients (aged 2-20y) with CP at University of Malaya Medical Centre, Kuala Lumpur and two community centres. Parents answered the Caregiver Priorities and Child Health Index of Life with Disabilities Questionnaire and a pro forma regarding parent reported frequency and intensity of pain during the preceding 4 weeks. Parental psychosocial well-being was assessed via the Depression, Anxiety and Stress Scale and Multidimensional Scale of Perceived Social Support. RESULTS: The response rate was 94%; 104 children (54 males, 50 females) were studied. The majority (51%) were in Gross Motor Function Classification System level V and 65% had spastic quadriplegia. Parents reported pain in 65%, intense pain in 17%, and daily pain in 28%. Intense and frequent pain was reported during physiotherapy. More intense pain was reported in older children (p=0.016) and those with spastic quadriplegia (p=0.020). INTERPRETATION: Caregivers of non-verbal children with CP report a high frequency of pain. Pain intensity is associated with patient factors but not parental psychosocial factors. PMID- 26510628 TI - Violent Fantasies in Young Men With Autism Spectrum Disorders: Dangerous or Miserable Misfits? Duty to Protect Whom? AB - Predictability of dangerousness in association with mental disorders remains elusive, outside of a few relatively well-established risk factors for the prognostication of violence, such as male sex, the presence of a psychotic disorder, and comorbid substance abuse. In clinical practice, inquiry into the presence of aggressive or violent ideation, in the form of ideas of homicide or suicide, is part of a standard mental status examination. Nonetheless, fantasy life, when it concerns harm toward others, may not be as reliable an indicator of imminent danger as it may be in the case of self-harm. Five cases of young Italian men with Asperger syndrome and recurrent and extremely violent femicide fantasies are presented. While there is no direct correlation between autism spectrum conditions and violence, as other humans, persons with an autistic condition are capable of committing crimes, including homicide. All five had in common a number of characteristics and behaviors felt to be pathoplastic: All had been bullied, all had been romantically rejected, all were long-standing First Person Shooter (FPS) game players, and all were avid violent pornography consumers. The potential for an actual neurocognitive impact of violent video games, well documented in the literature, and its combination with personal life history and chronic habituation following long-standing violent pornography use is discussed in the context of social and emotional vulnerabilities. While aggressive fantasies cannot and should not be underestimated, in countries where duty to protect legislation does not exist, a clinical approach is imperative, as, incidentally, should be anywhere. PMID- 26510629 TI - "I Am a Different Man Now"-Sex Offenders in Circles of Support and Accountability: A Prospective Study. AB - In Circles of Support and Accountability (CoSA), a group of trained and supervised volunteers support a sex offender (core member in a circle), with the aim of supporting the core member's transitions toward full desistance. A prospective, multi-method design was used to explore psychological and social transitions in core members. Data were collected at the start of their circle, after 6 months, and after 12 months. Qualitative data were collected in semi structured interviews with 17 core members and a total of 29 professionals, and analyzed with Kwalitan, a computer-assisted program for qualitative data analysis. Quantitative data were assessed with self-report questionnaires for sex offenders. Mean differences between t0, t1, and t2 were tested with repeated measures ANOVAs. Qualitative results indicated improvements in reflective skills, openness, and problem-solving skills, as well as social skills, agency, and self regulation. Quantitative results documented improvements in emotion regulation and internal locus of control, and positive trends in self-esteem and coping skills. Due to the small sample size, our results must be interpreted with caution. Core members as well as professionals reported a unique contribution of circles to their process, but this claim needs further confirmation. PMID- 26510630 TI - Early Puberty, School Context, and Delinquency Among South Korean Girls. AB - Compared with chronological age, criminologists have paid less attention to the biological sense of age typically expressed by pubertal development. Studies that have examined pubertal timing's effects on delinquency have almost exclusively been conducted in Western countries using mostly White samples. To our knowledge, no study has ever examined this issue in the Asian context. The current study is the first attempt to bridge this research gap by examining the association among menarcheal timing, the sex composition of schools, and delinquency in a representative sample of 1,108 ninth-grade girls in South Korea. The results show that significant association between early menarche and delinquency exists only in mixed-sex schools but not in all-girls schools. In addition, the significant linkage between early menarche and delinquency in mixed-sex schools is mediated by delinquent peer associations. PMID- 26510631 TI - Histopathological analysis of the olfactory epithelium of zebrafish (Danio rerio) exposed to sublethal doses of urea. AB - Chronic renal disease is known to alter olfactory function, but the specific changes induced in olfactory organs during this process remain unclear. Of the uraemic toxins generated during renal disease, high levels of urea are known to induce hyposmic conditions. In this study, the effects of environmental exposure to elevated concentrations of urea (7, 13.5 and 20 g L(-1)) on the sensory mucosa of zebrafish in acute toxicity and chronic toxicity tests were described. It was observed that lamellae maintained structural integrity and epithelial thickness was slightly reduced, but only following exposure to the highest concentrations of urea. Pan-neuronal labelling with anti-Hu revealed a negative correlation with levels of urea, leading to investigation of whether distinct neuronal subtypes were equally sensitive. Using densitometric analysis of immunolabelled tissues, numbers of Galpha olf-, TRPC2- and TrkA-expressing cells were compared, representing ciliated, microvillous and crypt neurons, respectively. The three neuronal subpopulations responded differently to increasing levels of urea. In particular, crypt cells were more severely affected than the other cell types, and Galpha olf-immunoreactivity was found to increase when fish were exposed to low doses of urea. It can be concluded that exposure to moderate levels of urea leads to sensory toxicity directly affecting olfactory organs, in accordance with the functional olfactometric measurements previously reported in the literature. PMID- 26510632 TI - Therapeutic effects of dog visits in nursing homes for the elderly. AB - BACKGROUND: Previous studies have suggested that visiting dogs can have positive effects on elderly people in nursing homes. We wanted to study the effects of biweekly dog visits on sleep patterns and the psychiatric well-being of elderly people. METHODS: A total of 100 residents (median age: 85.5 years; [79; 90]) from four nursing homes were randomly assigned to receive biweekly visits for 6 weeks from a person accompanied by either a dog, a robot seal (PARO), or a soft toy cat. Sleep patterns were measured using actigraphy technology before, during (the third and sixth week), and after the series of visits. The participants were weighed and scored on the Geriatric Depression Scale, the Gottfries-Brane-Steen Scale, and the Mini-Mental State Examination before and after the visit period. RESULTS: We found that sleep duration (min) increased in the third week when visitors were accompanied by a dog rather than the robot seal or soft toy cat (dog: 610 +/- 127 min; seal: 498 +/- 146 min; cat: 540 +/- 163 min; F2,37 = 4.99; P = 0.01). No effects were found in the sixth week or after the visit period had ended. We found that visit type had no effect on weight (F2,88 = 0.13; P > 0.05), body mass index (F2,86 = 0.33; P > 0.05), Geriatric Depression Scale (F2,82 = 0.85; P > 0.05), Gottfries-Brane-Steen Scale (F2,90 = 0.41; P > 0.05), or Mini Mental State Examination (F2,91 = 0.35; P > 0.05). Furthermore, we found a decrease in the Geriatric Depression Scale during the experimental period (S = 420; P < 0.05), whereas cognitive impairment worsened as shown by a decrease in Mini-Mental State Examination score (S = -483; P < 0.05) and an increase in the Gottfries-Brane-Steen Scale (t = 2.06; P < 0.05). CONCLUSION: Visit type did not affect the long-term mental state of the participants. The causal relationship between sleep duration and dog-accompanied visits remains to be explored. PMID- 26510633 TI - Indirect costs associated with deaths from the Ebola virus disease in West Africa. AB - BACKGROUND: By 28 June 2015, there were a total of 11,234 deaths from the Ebola virus disease (EVD) in five West African countries (Guinea, Liberia, Mali, Nigeria and Sierra Leone). The objective of this study was to estimate the future productivity losses associated with EVD deaths in these West African countries, in order to encourage increased investments in national health systems. METHODS: A cost-of-illness method was employed to calculate future non-health (NH) gross domestic product (GDP) (NHGDP) losses associated with EVD deaths. The future non health GDP loss (NHGDPLoss) was discounted at 3 %. Separate analyses were done for three different age groups (< =14 years, 15-44 years and = >45 years) for the five countries (Guinea, Liberia, Mali, Nigeria, and Sierra Leone) affected by EVD. We also conducted a one-way sensitivity analysis at 5 and 10 % discount rates to gauge their impacts on expected NHGDPLoss. RESULTS: The discounted value of future NHGDPLoss due to the 11,234 deaths associated with EVD was estimated to be Int$ (international dollars) 155,663,244. About 27.86 % of the loss would be borne by Guinea, 34.84 % by Liberia, 0.10 % by Mali, 0.24 % by Nigeria and 36.96 % by Sierra Leone. About 27.27 % of the loss is attributed to those aged under 14 years, 66.27 % to those aged 15-44 years and 6.46 % to those aged over 45 years. The average NHGDPLoss per EVD death was estimated to be Int$ 17,473 for Guinea, Int$ 11,283 for Liberia, Int$ 25,126 for Mali, Int$ 47,364 for Nigeria and Int$ 14,633 for Sierra Leone. CONCLUSION: In spite of alluded limitations, the estimates of human and economic losses reported in this paper, in addition to those projected by the World Bank, show that EVD imposes a significant economic burden on the affected West African countries. That heavy burden, coupled with human rights and global security concerns, underscores the urgent need for increased domestic and external investments to enable Guinea, Liberia and Sierra Leone (and other vulnerable African countries) to develop resilient health systems, including core capacities to detect, assess, notify, verify and report events, and to respond to public health risks and emergencies. PMID- 26510634 TI - Reducing signal loss of the parahippocampal gyrus improves imaging of the default mode network in 3.0-T MRI: the effect of susceptibility-induced field gradients. AB - Previous investigations have indicated that the default-mode network (DMN) is highly involved in memory processing in the parahippocampal gyrus (PHC). However, because of susceptibility-related signal loss, parahippocampal activation in the DMN is difficult to detect in resting-state functional MRI experiments that are conducted using a 3.0-T MRI scanner. This study investigated the magnetic field gradients of various brain regions and attempted to compensate for signal loss in the PHC using an optimized slice orientation. The field gradients, signal intensities and DMN functional connectivity (FC) of the PHC were investigated using datasets acquired from 18 healthy volunteers. The results show that the field gradient component parallel to the main magnetic field dominates the PHC. The results indicate that the signal intensities and FC of the DMN are significantly low in the PHC when the slice orientation of the imaging plane is transversal. Whether the voxel dimension is isotropic or anisotropic exerts a minimal effect in altering the slice orientation dependence. In conclusion, the results of this study support the selection of the coronal or sagittal planes for imaging of the DMN. PMID- 26510635 TI - Replicating research in ecology and evolution: feasibility, incentives, and the cost-benefit conundrum. AB - We believe that replicating studies in ecology and evolution is extremely valuable, but replication within species and systems is troublingly rare, and even 'quasi-replications' in different systems are often insufficient. We make a case for supporting multiple types of replications and point out that the current incentive structure needs to change if ecologists and evolutionary biologist are to value scientific replication sufficiently. PMID- 26510636 TI - Thiopurine metabolite testing in inflammatory bowel disease. AB - BACKGROUND: Thiopurine use in inflammatory bowel disease (IBD) is limited by drug toxicity and lack of therapeutic efficacy. We assessed the utility of thiopurine metabolite testing and the relationship between disease activity, dose, and metabolite levels in a real world setting. METHODS: Patients identified from pathology databases (2007-2012) at two tertiary IBD centers were included if they had thiopurines for at least four weeks. Demographics, dose, test indication, clinical status, action taken, and outcome were obtained by retrospective medical record review. RESULTS: A total of 169 patients were included. 6-Thioguanine (TGN) levels were sub-therapeutic in 52%, therapeutic in 34%, and supratherapeutic in 14%. Test indication was active disease (79%), adverse effect (11%), or adherence assessment (7%). TGN trended lower in the active disease group compared to those with adverse effects (273 (+/- 23.2) versus 447 (+/- 117.7) pmol/8 * 10(8) RBC, P = 0.05). Weight-based dosing did not improve rates of therapeutic TGN levels (under-dosed 31.5% vs standard dose 35.4%), but was significantly associated with shunting toward 6-MMP (23.1% vs 6.8%, P = 0.008, OR = 4.1). Testing resulted in a change in patient treatment in 86% of patients with active disease and subtherapeutic levels and in 68% of tested patients overall. CONCLUSIONS: Metabolite testing resulted in a change in management in most patients not responding to thiopurines or experiencing adverse events. Weight based dosing did not increase rates of therapeutic levels but was associated with increased 6MMP shunting. PMID- 26510637 TI - Seeing biological actions in 3D: An fMRI study. AB - Precise kinematics or body configuration cannot be recovered from visual input without disparity information. Yet, no imaging study has investigated the role of disparity on action observation. Here, we investigated the interaction between disparity and the main cues of biological motion, kinematics and configuration, in two fMRI experiments. Stimuli were presented as point-light figures, depicting complex action sequences lasting 21 s. We hypothesized that interactions could occur at any of the three levels of the action observation network, comprising occipitotemporal, parietal and premotor cortex, with premotor cortex being the most likely location. The main effects of kinematics and configuration confirmed that the biological motion sequences activated all three levels of the action observation network, validating our approach. The interaction between configuration and disparity activated only premotor cortex, whereas interactions between kinematics and disparity occurred at all levels of the action observation network but were strongest at the premotor level. Control experiments demonstrated that these interactions could not be accounted for by low level motion in depth, task effects, spatial attention, or eye movements, including vergence. These results underscore the role of premotor cortex in action observation, and in imitating others or responding to their actions. PMID- 26510638 TI - Entecavir safety and effectiveness in a national cohort of treatment-naive chronic hepatitis B patients in the US - the ENUMERATE study. AB - BACKGROUND: Entecavir (ETV) has been shown to be safe and efficacious in randomised controlled trials in highly selected patients with hepatitis B virus (HBV) infection. AIM: To determine the safety and effectiveness of ETV in 'real world' HBV patients in the United States (US). METHODS: Treatment-naive HBV patients >=18 years old who received ETV for >=12 months between 2005 and 2013 were included in a retrospective, cohort study. Rates of ALT normalisation, undetectable HBV DNA, HBeAg and HBsAg loss/seroconversion, adverse events (AE) and clinical outcomes were evaluated. RESULTS: Of 841 patients, 658 [65% male, 83% Asian; median age 47 years] met the inclusion criteria. 36% were HBeAg+ and 9.3% cirrhotic. 89% had abnormal ALT. Baseline median HBV DNA was 5.8 log 10 IU/mL. Median duration of ETV treatment was 4 years. Rates of ALT normalisation at 1, 3 and 5 years were 37.2%, 48.7% and 56.2% in HBeAg+ and 39.6%, 46.8% and 55.6% in HBeAg- patients. HBV DNA was undetectable at 1, 3 and 5 years in 34.6%, 64.7% and 84.6% in HBeAg+ patients, and 81.9%, 90.3% and 96.2% in HBeAg patients. Five-year cumulative probability of HBeAg loss and seroconversion was 46% and 33.7% and HBsAg loss was 4.6%. ETV was discontinued due to adverse events in 1.2% of patients. Hepatic decompensation occurred in 0.8%, liver cancer in 2.7% and death in 0.6%. CONCLUSION: Entecavir treatment was safe in a large cohort of US patients, but ALT normalisation and hepatitis B virus DNA suppression rates were lower than previously reported in clinical trials. PMID- 26510639 TI - Prior infection with Type A Francisella tularensis antagonizes the pulmonary transcriptional response to an aerosolized Toll-like receptor 4 agonist. AB - BACKGROUND: Francisella infection attenuates immune cell infiltration and expression of selected pro-inflammatory cytokines in response to endogenous LPS, suggesting the bacteria is actively antagonizing at least some part of the response to Toll-like receptor 4 (TLR4) engagement. The ability of different Francisella strains to inhibit the ability of E. coli LPS to induce a pulmonary inflammatory response, as measured by gene expression profiling, was examined to define the scope of modulation and identify of inflammatory genes/pathways that are specifically antagonized by a virulent F. tularensis infection. RESULTS: Prior aerosol exposure to F. tularensis subsp. tularensis, but not the live attenuated strain (LVS) of F. tularensis subsp. holarctica or F. novicida, significantly antagonized the transcriptional response in the lungs of infected mice exposed to aerosolized E. coli LPS. The response to E. coli LPS was not completely inhibited, suggesting that the bacteria is targeting further downstream of the TLR4 molecule. Analysis of the promotors of LPS-responsive genes that were perturbed by Type A Francisella infection identified candidate transcription factors that were potentially modulated by the bacteria, including multiple members of the forkhead transcription factor family (FoxA1, Foxa2, FoxD1, Foxd3, Foxf2, FoxI1, Fox03, Foxq1), IRF1, CEBPA, and Mef2. The annotated functional roles of the affected genes suggested that virulent Francisella infection suppressed cellular processes including mRNA processing, antiviral responses, intracellular trafficking, and regulation of the actin cytoskeleton. Surprisingly, despite the broad overall suppression of LPS-induced genes by virulent Francisella, and contrary to what was anticipated from prior studies, Type A Francisella did not inhibit the expression of the majority of LPS-induced cytokines, nor the expression of many classic annotated inflammatory genes. CONCLUSIONS: Collectively, this analysis demonstrates clear differences in the ability of different Francisella strains to modulate TLR4 signaling and identifies genes/pathways that are specifically targeted by virulent Type A Francisella. PMID- 26510640 TI - Posterior talar process as a suitable cell source for treatment of cartilage and osteochondral defects of the talus. AB - Osteochondral defects of the ankle are common lesions affecting the talar cartilage and subchondral bone. Current treatments include cell-based therapies but are frequently associated with donor-site morbidity. Our objective is to characterize the posterior process of the talus (SP) and the os trigonum (OT) tissues and investigate their potential as a new source of viable cells for application in tissue engineering and regenerative medicine. SP and OT tissues obtained from six patients were characterized by micro-computed tomography and histological, histomorphometric and immunohistochemical analyses. Proliferation and viability of isolated cells were evaluated by MTS assay, DNA quantification and live/dead staining. The TUNEL assay was performed to evaluate cell death by apoptosis. Moreover, the production of extracellular matrix was evaluated by toluidine blue staining, whereas cells phenotype was investigated by flow cytometry. Characterization of ankle explants showed the presence of a cartilage tissue layer in both SP and OT tissues, which represented at least 20%, on average, of the explant. The presence of type II collagen was detected in the extracellular matrix. Isolated cells presented a round morphology typical of chondrocytes. In in vitro studies, cells were viable and proliferating for up to 21 days of culture. No signs of apoptosis were detected. Flow-cytometry analysis revealed that isolated cells maintained the expression of several chondrocytic markers during culture. The results indicated that the SP and OT tissues were a reliable source of viable chondrocytes, which could find promising applications in ACI/MACI strategies with minimal concerns regarding donor zone complications. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26510641 TI - Synthesis of [n]Cyclo-5,15-porphyrinylene-4,4'-biphenylenes Displaying Size Dependent Excitation-Energy Hopping. AB - A set of 5,15-biphenylene-bridged porphyrin wheels, namely, [n]cyclo-5,15 porphyrinylene-4,4'-biphenylenes [n]CPB, have been synthesized through the platination of 5,15-bis(4-(pinacolboranyl)phenyl) nickel(II) porphyrin and subsequent reductive elimination of Pt(II) (cod)-bridged cyclic porphyrin intermediates. The calculated strain energies for [3]CPB, [4]CPB, [5]CPB, and [6]CPB are 49.3, 32.9, 23.5, and 16.0 kcal mol(-1) , respectively. UV/Vis absorption spectra and cyclic voltammetry indicated characteristic ring-size dependent absorption-peak shifts and redox-potential shifts, which presumably reflect the degree of strain in the pi-systems. Excitation-energy hopping (EEH) times were determined to be 5.1, 8.0, 8.0, and 9.6 ps for [3]CPB, [4]CPB, [5]CPB, and [6]CPB, respectively, in a pump-power-dependent TA experiment. PMID- 26510642 TI - Development and Evaluation of an Information Booklet for Grandparents of Children With Cancer. AB - The needs of grandparents of children with cancer are often overlooked. This study evaluated a new educational resource (booklet) targeted toward grandparents of children with cancer. A multidisciplinary committee developed a printed booklet targeting grandparents' information needs identified in a previous study. Seventy-nine grandparents of children with cancer (63% grandmothers, Mage = 66.04, SD = 7.0 years) read and evaluated the booklet. Quantitative responses were analyzed with SPSS, and qualitative responses were thematically coded using QSR NVivo 10. Grandparents' responses to the resource were positive, with 92% finding the booklet "informative" (n = 73), "useful" (84%, n = 66), and "very relevant" (50%, n = 39). Qualitative responses reflected an appreciation for the booklet's readability, informative content, and quotes from grandparent experiences. The developed booklet was highly acceptable to grandparents of children with cancer and addressed their need for reassurance and guidance on obtaining further support. This study demonstrates the feasibility of developing and evaluating a targeted resource to meet grandparent's identified information needs. PMID- 26510643 TI - Effect of Intravenous (IV) Assistive Device (VeinViewer) on IV Access Attempts, Procedural Time, and Patient and Nurse Satisfaction. AB - This study evaluated the effectiveness of VeinViewer for peripheral vascular accessing a pediatric hematology oncology clinic. After obtaining consent, 53 patients were randomly assigned to either the VeinViewer group (n = 27) or standard methods group (n = 26). Data on number of attempts, procedural time, access complications, and patient and nurse satisfaction were collected. Patients randomized to the VeinViewer group required significantly less time to access a vein as compared with the standard methods group (P <= .05). Additionally, these patients rated nurses as having significantly more skill than nurses who did not use VeinViewer (P <= .05) and assigned significantly higher scores for "overall experience"(P <= .05). Responses by nurses using VeinViewer overall saw the device in a positive light. PMID- 26510644 TI - Telehealth Videoconferencing for Children With Hemophilia and Their Families: A Clinical Project. AB - Telehealth is the use of electronic information and telecommunications technologies to support long-distance health care. It supports quality health care that is accessible, and time- and cost-effective. Telehealth videoconferencing may enhance the care for hemophilia patients who are experiencing a bleed by supporting real-time detailed assessment including appearance, range of motion, and ambulation in addition to the traditional phone methods of verbal description of appearance, pain, and function. The aim of this clinical project was to evaluate the feasibility of using telehealth videoconferencing in children with severe hemophilia in the home setting. Twelve patients with severe hemophilia ages 2to 18 years, who had more than 2 breakthrough bleeds in the past year, and had Internet access with a computer camera were included. The incidence of bleeding was low; however, videoconferencing was effective for 3 patients who completed 4 video appointments. Patients and staff reported that videoconferencing improved communication and satisfaction. Telehealth videoconferencing is a feasible tool for managing bleeding disorders in the home setting. PMID- 26510645 TI - From Chemo to College: The College Experience of Childhood Cancer Survivors. AB - The purpose of this qualitative study was to explore how childhood cancer survivors experience college life. Five undergraduate students who are childhood cancer survivors, aged 19 to 22 years, participated in a 75-minute focus group interview. The survivors attended the same university located in the mid-Atlantic region of the United States. A transcript-based content analysis was used to analyze the data. Four themes and 2 subthemes were generated from the data analysis. Survivors described that the emotional growth they experienced from their cancer experience has provided them some psychological protection in managing the day-to-day challenges of college life and in making informed choices about engaging in high-risk behaviors. As a result of their cancer experience, the findings suggest that these childhood cancer survivors have a strong foundation of self-awareness and self-worth, which has assisted them in making a successful transition into college life and in enjoying positive collegiate experiences. PMID- 26510646 TI - Evolving the practitioner-teacher role to enhance practice-academic partnerships: a literature review. AB - AIMS AND OBJECTIVES: The purpose of this article was to review the development of the practitioner-teacher model and its use in advancing clinical nursing. BACKGROUND: The practitioner-teacher role, or the unification model, incorporates clinical practice, teaching, consultation and research responsibilities for nurses serving in advanced clinical roles or as nursing faculty as part of professional nursing practice. The practitioner-teacher role facilitates a practice-academic partnership that can serve as a beneficial way to advance clinical nursing care. DESIGN: An exploratory literature review was conducted combined with review of practitioner-teacher and practice-academic exemplars. METHODS: A descriptive review of the practitioner-teacher model of nursing practice reveals that activities of the role include clinical nursing care, serving as a preceptor for nursing students in a focused area of expertise, consulting on patient care issues, presenting in-services and course lectures, and serving as a member of faculty and nursing division committees. RESULTS: The practitioner-teacher role lends itself to promoting practice-academic partnerships that combine clinical nursing care with professional nursing activities. CONCLUSIONS: The model of practice, education, consultation and research of the practitioner-teacher position advances practice-academic partnerships. RELEVANCE TO CLINICAL PRACTICE: The practitioner-teacher model serves to optimise the way nursing practice and academic work together to integrate knowledge, scholarship, service and learning and to advance the profession and the discipline of nursing. This article discusses aspects of the unique practice-academic partnership using the practitioner-teacher model, how the role evolved, and how it can improve clinical nursing care globally. PMID- 26510647 TI - Pneumatosis cystoides intestinalis: a benign differential diagnosis for computed tomographic evidence of pneumoperitoneum in a stable patient. PMID- 26510648 TI - Tolvaptan treatment for patients with decompensated cirrhosis and advanced hepatocellular carcinoma. PMID- 26510649 TI - Cirrhosis-related hyponatremia and the role of tolvaptan. PMID- 26510650 TI - Stomatal dynamics are limited by leaf hydraulics in ferns and conifers: results from simultaneous measurements of liquid and vapour fluxes in leaves. AB - Stomatal responsiveness to vapour pressure deficit (VPD) results in continuous regulation of daytime gas-exchange directly influencing leaf water status and carbon gain. Current models can reasonably predict steady-state stomatal conductance (gs ) to changes in VPD but the gs dynamics between steady-states are poorly known. Here, we used a diverse sample of conifers and ferns to show that leaf hydraulic architecture, in particular leaf capacitance, has a major role in determining the gs response time to perturbations in VPD. By using simultaneous measurements of liquid and vapour fluxes into and out of leaves, the in situ fluctuations in leaf water balance were calculated and appeared to be closely tracked by changes in gs thus supporting a passive model of stomatal control. Indeed, good agreement was found between observed and predicted gs when using a hydropassive model based on hydraulic traits. We contend that a simple passive hydraulic control of stomata in response to changes in leaf water status provides for efficient stomatal responses to VPD in ferns and conifers, leading to closure rates as fast or faster than those seen in most angiosperms. PMID- 26510651 TI - Dorsal midline skin covered anomalies. A hamartoma or rachipagus? PMID- 26510652 TI - X-linked hypophosphatemic rickets and sagittal craniosynostosis: three patients requiring operative cranial expansion: case series and literature review. AB - PURPOSE: A defect in a phosphate-regulating gene leads to the most common form of rickets: X-linked hypophosphatemic rickets (XLH) or vitamin D-resistant rickets (VDDR). XLH has been associated with craniosynostosis, the sagittal suture being the most commonly involved. METHODS: We present three patients with rickets and symptomatic sagittal suture craniosynostosis all of whom presented late (>2 years of age). Two had a severe phenotype and papilledema, while the third presented with an osseous bulging near the anterior fontanel and experienced chronic headaches. RESULTS: All underwent successful cranial vault expansion. CONCLUSIONS: Rachitic patients with scaphocephaly should be screened for craniosynostosis. PMID- 26510653 TI - Blepharospasm in children and adolescents. AB - PURPOSE: Benign essential blepharospasm (BEB) generally is considered a disorder of adults; however, it rarely can present in childhood or adolescence. The main purpose of this study was to determine the prevalence of BEB in children and adolescents. Our research question was whether blepharospasm is seen in children or adolescents as well as in the adult population. METHODS: We conducted a retrospective chart review at the University of Utah and Johns Hopkins University. We reviewed our databases for diagnoses of blepharospasm and tic disorder over the past 10 years in patients of all ages. Charts then were reviewed to confirm the diagnosis, and a questionnaire was sent to subjects whose blepharospasm had apparently begun before age 20 years. RESULTS: We identified 26 patients diagnosed with eyelid spasms that had begun while under the age of 20. We confirmed BEB in four of these cases. Of these individuals, all had developed symptoms in adolescence or before and all were still symptomatic but had noted improvement in the severity and frequency of their symptoms. CONCLUSIONS: Although rare, BEB can develop in the first decade of life, producing symptoms and signs that are similar to adults, with persistence into adulthood. PMID- 26510654 TI - ERRATUM TO: Methods to Study the Role of the Glycocalyx in the Uptake of Cell Penetrating Peptides. PMID- 26510655 TI - Erratum to: Sarcocystis oreamni, n. sp. (Apicomplexa: Sarcocystidae) from the mountain goat (Oreamnos americanus). PMID- 26510656 TI - Structural and Biochemical Studies on the Reaction Mechanism of Uridine-Cytidine Kinase. AB - Uridine-cytidine kinase catalyzes phosphorylation of the pyrimidine nucleosides uridine and cytidine and plays an important role in nucleotide metabolism. However, the detailed molecular mechanism of these reactions remains to be elucidated. Here, we determined the structure of the ternary complex of Uridine cytidine kinase from Thermus thermophilus HB8 with both cytidine and beta,gamma methyleneadenosine 5'-triphosphate, a non-hydrolysable ATP analogue. Substrate binding is accompanied by substantial domain movement that allows the substrate binding cleft to close. The terminal phosphodiester bond of the ATP analogue is in an ideal location for an inline attack of the 5'-hydroxyl group of cytidine. Asp40 is located near the 5'-hydroxyl group of cytidine. Mutation of this conserved residue to Asn or Ala resulted in a complete loss of enzyme activity, which is consistent with the notion that Asp40 acts as a general base that activates the 5'-hydroxyl group of cytidine. The pH profile of the activity showed an apparent pK a value of 7.4. Based on this structure, a likely mechanism of the catalytic step is discussed. PMID- 26510657 TI - Identification of Microorganisms by High Resolution Tandem Mass Spectrometry with Accurate Statistical Significance. AB - Correct and rapid identification of microorganisms is the key to the success of many important applications in health and safety, including, but not limited to, infection treatment, food safety, and biodefense. With the advance of mass spectrometry (MS) technology, the speed of identification can be greatly improved. However, the increasing number of microbes sequenced is challenging correct microbial identification because of the large number of choices present. To properly disentangle candidate microbes, one needs to go beyond apparent morphology or simple 'fingerprinting'; to correctly prioritize the candidate microbes, one needs to have accurate statistical significance in microbial identification. We meet these challenges by using peptidome profiles of microbes to better separate them and by designing an analysis method that yields accurate statistical significance. Here, we present an analysis pipeline that uses tandem MS (MS/MS) spectra for microbial identification or classification. We have demonstrated, using MS/MS data of 81 samples, each composed of a single known microorganism, that the proposed pipeline can correctly identify microorganisms at least at the genus and species levels. We have also shown that the proposed pipeline computes accurate statistical significances, i.e., E-values for identified peptides and unified E-values for identified microorganisms. The proposed analysis pipeline has been implemented in MiCId, a freely available software for Microorganism Classification and Identification. MiCId is available for download at http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/downloads.html . Graphical Abstract ?. PMID- 26510658 TI - Magnetotactic molecular architectures from self-assembly of beta-peptide foldamers. AB - The design of stimuli-responsive self-assembled molecular systems capable of undergoing mechanical work is one of the most important challenges in synthetic chemistry and materials science. Here we report that foldectures, that is, self assembled molecular architectures of beta-peptide foldamers, uniformly align with respect to an applied static magnetic field, and also show instantaneous orientational motion in a dynamic magnetic field. This response is explained by the amplified anisotropy of the diamagnetic susceptibilities as a result of the well-ordered molecular packing of the foldectures. In addition, the motions of foldectures at the microscale can be translated into magnetotactic behaviour at the macroscopic scale in a way reminiscent to that of magnetosomes in magnetotactic bacteria. This study will provide significant inspiration for designing the next generation of biocompatible peptide-based molecular machines with applications in biological systems. PMID- 26510660 TI - Percutaneous Transhepatic Embolization of a Bronchobiliary Fistula Developing Secondary to a Biloma After Conventional Transarterial Chemoembolization in a Patient with Hepatocellular Carcinoma. PMID- 26510661 TI - Fluoroscopy-Guided Percutaneous Vertebral Body Biopsy Using a Novel Drill-Powered Device: Technical Case Series. AB - BACKGROUND: A novel coaxial biopsy system powered by a handheld drill has recently been introduced for percutaneous bone biopsy. This technical note describes our initial experience performing fluoroscopy-guided vertebral body biopsies with this system, compares the yield of drill-assisted biopsy specimens with those obtained using a manual technique, and assesses the histologic adequacy of specimens obtained with drill assistance. METHODS: Medical records of all single-level, fluoroscopy-guided vertebral body biopsies were reviewed. Procedural complications were documented according to the Society of Interventional Radiology classification. The total length of bone core obtained from drill-assisted biopsies was compared with that of matched manual biopsies. Pathology reports were reviewed to determine the histologic adequacy of specimens obtained with drill assistance. RESULTS: Twenty eight drill-assisted percutaneous vertebral body biopsies met study inclusion criteria. No acute complications were reported. Of the 86 % (24/28) of patients with clinical follow-up, no delayed complications were reported (median follow-up, 28 weeks; range 5-115 weeks). The median total length of bone core obtained from drill-assisted biopsies was 28 mm (range 8-120 mm). This was longer than that obtained from manual biopsies (median, 20 mm; range 5-45 mm; P = 0.03). Crush artifact was present in 11 % (3/28) of drill-assisted biopsy specimens, which in one case (3.6 %; 1/28) precluded definitive diagnosis. CONCLUSIONS: A drill-assisted, coaxial biopsy system can be used to safely obtain vertebral body core specimens under fluoroscopic guidance. The higher bone core yield obtained with drill assistance may be offset by the presence of crush artifact. PMID- 26510662 TI - Time-dependent changes in insulin requirement for maternal glycemic control during antenatal corticosteroid therapy in women with gestational diabetes: a retrospective study. AB - Though recommended for pregnant women at risk of preterm birth to improve perinatal outcomes, antenatal corticosteroid (ACS) treatment can cause maternal hyperglycemia, especially in cases of glucose intolerance. A standardized protocol for preventing hyperglycemia during ACS treatment remains to be established. We herein retrospectively investigated the time-dependent changes in insulin dose required for maternal glycemic control during ACS treatment in gestational diabetes (GDM). Twelve singleton pregnant women with GDM who received 12 mg of betamethasone intramuscularly twice 24 hours apart were included in this analysis. Of those, eight also received ritodrine hydrochloride for preterm labor. The blood glucose levels were maintained at 70-120 mg/dL with continuous intravenous infusion of insulin and nothing by mouth for 48 hours after the first betamethasone administration. After the first dose of betamethasone, the insulin dosage needed for glycemic control gradually increased and reached a maximum (6.6 +/- 5.8 units/hr) at 10 hours, then, decreased to 4.1 +/- 1.5 units/hr at 24 hours. Similar changes in the insulin requirement were found after the second betamethasone dose (the maximum insulin dosage: 5.5 +/- 1.6 units/hr at 9 hours following the second administration). Women treated with ritodrine hydrochloride needed more insulin, than those without ritodrine hydrochloride treatment (130.8 +/- 15.0 vs. 76.8 +/- 15.2 units/day, respectively, p < 0.05). Our data indicated that the requirement for insulin is highest 9-10 hours after each dose of betamethasone. When GDM is treated with ACS, levels of blood glucose should be carefully monitored, especially in patients treated with ritodrine hydrochloride. PMID- 26510664 TI - The effect of Clostridium butyricum MIYAIRI on the prevention of pouchitis and alteration of the microbiota profile in patients with ulcerative colitis. AB - PURPOSE: Ulcerative colitis (UC) is a chronic, relapsing, and refractory disorder of the intestine. Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is the preferred and standard surgical procedure for patients' refractory to medical therapy. Pouchitis is one of the most common long-term complications after IPAA. In the present study, the safety and efficacy of Clostridium butyricum MIYAIRI (CBM) as a probiotic were examined. METHODS: A randomized and placebo-controlled study was performed. Seventeen patients were recruited from 2007 to 2013. Nine tablets of MIYA-BM((r)) or placebo were orally administered once daily. The cumulative pouchitis-free survival, pouch condition (using the modified pouch disease activity index), and blood parameters were evaluated. A fecal sample analysis was also performed. RESULTS: Subjects were randomly allocated to receive MIYA-BM or placebo (9 and 8 subjects, respectively). One subject in the MIYA-BM group and four subjects in the placebo group developed pouchitis. No side effects occurred in either group. Characteristic intestinal flora was observed in each group. CONCLUSIONS: Our results suggest that probiotic therapy with CBM achieved favorable results with minimal side effects and might be a useful complementary therapy for the prevention of pouchitis in patients with UC who have undergone IPAA. PMID- 26510663 TI - Subgroup analyses of the safety and efficacy of ramucirumab in Japanese and Western patients in RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer. AB - BACKGROUND: We evaluated the safety and efficacy of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients previously treated for advanced gastric or gastroesophageal junction adenocarcinoma in Japanese and Western subgroups from the RAINBOW trial. METHODS: Patients received ramucirumab at 8 mg/kg or placebo (days 1 and 15) plus paclitaxel at 80 mg/m(2) (days 1, 8, and 15 of a 28-day cycle). End points were compared between treatment arms within Japanese (N = 140) and Western (N = 398) populations. RESULTS: The incidence of adverse events of grade 3 or higher was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 83.8 % vs 52.1 %; Western population, 79.1 % vs 61.9 %). Neutropenia was the commonest adverse event of grade 3 or higher, with a higher incidence for ramucirumab plus paclitaxel (Japanese population, 66.2 % vs 25.4 %; Western population, 32.1 % vs 14.7 %). The incidence of febrile neutropenia was low and was similar between treatment arms in both populations. The overall survival hazard ratio was 0.88 (95 % confidence interval, 0.60-1.28) in the Japanese population and 0.73 (95 % confidence interval, 0.58-0.91) in the Western population. The progression-free survival hazard ratio was 0.50 (95 % confidence interval, 0.35-0.73) in the Japanese population and 0.63 (95 % confidence interval, 0.51-0.79) in the Western population. The objective response rate was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 41.2 % vs 19.4 %; Western population, 26.8 % vs 13.0 %), as was the 6 month survival rate (Japanese population, 94.1 % vs 71.4 %; Western population, 66.0 % vs 49.0 %). CONCLUSIONS: Safety profiles of the ramucirumab plus paclitaxel arm were similar between populations, though there was a higher incidence of neutropenia in Japanese patients. Progression-free survival and objective response rate improvements were observed for ramucirumab plus paclitaxel in both populations. CLINICALTRIALS. GOV IDENTIFIER: NCT01170663. PMID- 26510665 TI - Local Control Rates of Metastatic Renal Cell Carcinoma (RCC) to Thoracic, Abdominal, and Soft Tissue Lesions Using Stereotactic Body Radiotherapy (SBRT). AB - BACKGROUND AND PURPOSE: We report the radiographic response rate of SBRT compared to conventional fractionated radiotherapy (CF-EBRT) for thoracic, abdominal, skin and soft tissue RCC lesions treated at our institution. MATERIAL AND METHODS: Fifty three lesions where included in the study (36 SBRT, 17 CF-EBRT), treated from 2004 to 2014 at our institution. We included patients that had thoracic, skin & soft tissue (SST), and abdominal metastases of histologically confirmed RCC. The most common SBRT fractionation was 50 Gy in 5 fractions. RESULTS: The median time of follow-up was 16 months (range 3-97 months). Median BED was 216.67 (range 66.67-460.0) for SBRT, and 60 (range 46.67-100.83) for CF-EBRT. Median radiographic local control rates at 12, 24, and 36 months were 100, 93.41, and 93.41 % for lesions treated with SBRT versus 62.02, 35.27 and 35.27 % for those treated with CF-EBRT (p < 0.001). Predictive factors for radiographic local control under univariate analysis included BED >= 100 Gy (HR, 0.048; 95 % CI, 0.006-0.382; p = 0.005), dose per fraction >= 9 Gy (HR, 0.631; 95 % CI, 0.429 0.931; p = 0.021), and gender (HR, 0.254; 95 % CI, 0.066-0.978; p = 0.048). Under multivariate analysis, there were no significant predictors for local control. Toxicity rates were low and equivalent in both groups, with no grade 4 or 5 side effects reported. CONCLUSIONS: SBRT is safe and effective for the treatment of RCC metastases to thoracic, abdominal and integumentary soft tissues. Radiographic response rates were greater and more durable using SBRT compared to CF-EBRT. Further prospective trials are needed to evaluate efficacy and safety of SBRT for RCC metastases. PMID- 26510667 TI - Microbial mediation of complex subterranean mineral structures. AB - Helictites--an enigmatic type of mineral structure occurring in some caves- differ from classical speleothems as they develop with orientations that defy gravity. While theories for helictite formation have been forwarded, their genesis remains equivocal. Here, we show that a remarkable suite of helictites occurring in Asperge Cave (France) are formed by biologically-mediated processes, rather than abiotic processes as had hitherto been proposed. Morphological and petro-physical properties are inconsistent with mineral precipitation under purely physico-chemical control. Instead, microanalysis and molecular-biological investigation reveals the presence of a prokaryotic biofilm intimately associated with the mineral structures. We propose that microbially-influenced mineralization proceeds within a gliding biofilm which serves as a nucleation site for CaCO3, and where chemotaxis influences the trajectory of mineral growth, determining the macroscopic morphology of the speleothems. The influence of biofilms may explain the occurrence of similar speleothems in other caves worldwide, and sheds light on novel biomineralization processes. PMID- 26510668 TI - Gradual edge enhancement in spiral phase contrast imaging with fractional vortex filters. AB - In the spiral phase contrast imaging, the integer spiral phase plate (SPP) are generally employed to perform the radial Hilbert transform on the object. Here we introduce fractional SPP filters, instead of the integer ones, to investigate the gradual formation of edge enhancement for pure phase objects. Two spatial light modulators are used in our experimental configuration. One is addressed to display the pure phase object of a five-pointed star, while the other serves as a dynamic filter of fractional topological charge Q. Of interest is the observation of the complete reversal of the edge and background brightness by gradually changing the fractional vortices from Q = 0 to 1. The experimental results were well interpreted based on the OAM spectra of fractional SPP, which indicates that the filtered output image can be considered as a coherent superposition of all possible images that are individually resulted from the integer OAM filtering. Besides, we show that the spiral phase contrast effect can still be observed in real time for a rotating three-leaf clover. Our results may find potential applications in the optical microscopic imaging. PMID- 26510669 TI - Clinical study to evaluate the role of preoperative dexmedetomidine in attenuation of hemodynamic response to direct laryngoscopy and tracheal intubation. AB - OBJECTIVES: Dexmedetomidine, an alpha2 agonist, has been evaluated for its hypnotic, analgesic, and anxiolytic properties in the intraoperative period and critical care setting. However, data on the effect of dexmedetomidine on attenuation of pressor response to direct laryngoscopy and tracheal intubation are limited. We studied the effect of a single preinduction intravenous dose of dexmedetomidine of 0.5 MUg/kg on hemodynamic responses to tracheal intubation, and dose requirements of anesthetics for induction and their adverse effects. METHODS: Eighty adult patients scheduled for elective surgery under general anesthesia requiring tracheal intubation were included. Patients were randomized into two groups: dexmedetomidine and placebo (n = 40 each). The study drug was administered intravenously over a period of 10 minutes prior to induction. Direct laryngoscopy and endotracheal intubation were performed. Hemodynamic parameters, the total dose of propofol, and adverse effects were recorded during induction and postintubation periods for 15 minutes. RESULTS: The maximum percentage increase in the heart rate after intubation was 19.6% less in the dexmedetomidine group than that in the placebo group (12.96% vs. 32.57%). The maximum percentage increases in systolic blood pressure, diastolic blood pressure, and mean blood pressure after intubation were significantly lower in the dexmedetomidine group than in the placebo group (12.38% vs. 45.63%, 19.36% vs. 60.36%, and 15.34% vs. 50.33%, respectively). There was a significant reduction of the mean total dose of propofol required for induction, 1.04 mg/kg in the dexmedetomidine group versus 2.01 mg/kg in the placebo group (p < 0.001). No serious side effects or adverse reactions were observed in either group. CONCLUSION: Administration of a single preinduction intravenous dose of dexmedetomidine of 0.5 MUg/kg resulted in significant attenuation of the rise in the heart rate, systolic blood pressure, diastolic blood pressure, and mean blood pressure, until 5 minutes postintubation. It significantly reduced the dose requirements of propofol for induction and caused minimal side effects. PMID- 26510670 TI - Ethynylphenyl carbonates and carbamates as dual-action acetylcholinesterase inhibitors and anti-inflammatory agents. AB - Novel ethynylphenyl carbonates and carbamates containing carbon- and silicon based choline mimics were synthesized from their respective phenol and aniline precursors and screened for anticholinesterase and anti-inflammatory activities. All molecules were micromolar inhibitors of acetylcholinesterase (AChE), with IC50s of 28-86 MUM; the carbamates were two-fold more potent than the carbonates. Two of the most potent AChE inhibitors suppressed 12-O-tetradecanoylphorbol-13 acetate (TPA)-induced inflammation by 40%. Furthermore, these molecules have physicochemical properties in the range of other CNS drugs. These molecules have the potential to treat inflammation; they could also dually target Alzheimer's disease through restoration of cholinergic balance and inflammation suppression. PMID- 26510671 TI - CH-pi Interaction Driven Macroscopic Property Transition on Smart Polymer Surface. AB - Life systems have evolved to utilize weak noncovalent interactions, particularly CH-pi interaction, to achieve various biofunctions, for example cellular communication, immune response, and protein folding. However, for artificial materials, it remains a great challenge to recognize such weak interaction, further transform it into tunable macroscopic properties and realize special functions. Here we integrate monosaccharide-based CH-pi receptor capable of recognizing aromatic peptides into a smart polymer with three-component "Recognition-Mediating-Function" design, and report the CH-pi interaction driven surface property switching on smart polymer film, including wettability, adhesion, viscoelasticity and stiffness. Detailed studies indicate that, the CH pi interaction induces the complexation between saccharide unit and aromatic peptide, which breaks the initial amphiphilic balance of the polymer network, resulting in contraction-swelling conformational transition for polymer chains and subsequent dramatic switching in surface properties. This work not only presents a new approach to control the surface property of materials, but also points to a broader research prospect on CH-pi interaction at a macroscopic level. PMID- 26510672 TI - Mitogenomic analysis of a 50-generation chicken pedigree reveals a rapid rate of mitochondrial evolution and evidence for paternal mtDNA inheritance. AB - Mitochondrial genomes represent a valuable source of data for evolutionary research, but studies of their short-term evolution have typically been limited to invertebrates, humans and laboratory organisms. Here we present a detailed study of 12 mitochondrial genomes that span a total of 385 transmissions in a well-documented 50-generation pedigree in which two lineages of chickens were selected for low and high juvenile body weight. These data allowed us to test the hypothesis of time-dependent evolutionary rates and the assumption of strict maternal mitochondrial transmission, and to investigate the role of mitochondrial mutations in determining phenotype. The identification of a non-synonymous mutation in ND4L and a synonymous mutation in CYTB, both novel mutations in Gallus, allowed us to estimate a molecular rate of 3.13 * 10(-7) mutations/site/year (95% confidence interval 3.75 * 10(-8)-1.12 * 10(-6)). This is substantially higher than avian rate estimates based upon fossil calibrations. Ascertaining which of the two novel mutations was present in an additional 49 individuals also revealed an instance of paternal inheritance of mtDNA. Lastly, an association analysis demonstrated that neither of the point mutations was strongly associated with the phenotypic differences between the two selection lines. Together, these observations reveal the highly dynamic nature of mitochondrial evolution over short time periods. PMID- 26510673 TI - Elevated glucocorticoid concentrations during gestation predict reduced reproductive success in subordinate female banded mongooses. AB - Dominant females in social species have been hypothesized to reduce the reproductive success of their subordinates by inducing elevated circulating glucocorticoid (GC) concentrations. However, this 'stress-related suppression' hypothesis has received little support in cooperatively breeding species, despite evident reproductive skews among females. We tested this hypothesis in the banded mongoose (Mungos mungo), a cooperative mammal in which multiple females conceive and carry to term in each communal breeding attempt. As predicted, lower ranked females had lower reproductive success, even among females that carried to term. While there were no rank-related differences in faecal glucocorticoid (fGC) concentrations prior to gestation or in the first trimester, lower ranked females had significantly higher fGC concentrations than higher ranked females in the second and third trimesters. Finally, females with higher fGC concentrations during the third trimester lost a greater proportion of their gestated young prior to their emergence from the burrow. Together, our results are consistent with a role for rank-related maternal stress in generating reproductive skew among females in this cooperative breeder. While studies of reproductive skew frequently consider the possibility that rank-related stress reduces the conception rates of subordinates, our findings highlight the possibility of detrimental effects on reproductive outcomes even after pregnancies have become established. PMID- 26510674 TI - Breeding phenology and winter activity predict subsequent breeding success in a trans-global migratory seabird. AB - Inter-seasonal events are believed to connect and affect reproductive performance (RP) in animals. However, much remains unknown about such carry-over effects (COEs), in particular how behaviour patterns during highly mobile life-history stages, such as migration, affect RP. To address this question, we measured at sea behaviour in a long-lived migratory seabird, the Manx shearwater (Puffinus puffinus) and obtained data for individual migration cycles over 5 years, by tracking with geolocator/immersion loggers, along with 6 years of RP data. We found that individual breeding and non-breeding phenology correlated with subsequent RP, with birds hyperactive during winter more likely to fail to reproduce. Furthermore, parental investment during one year influenced breeding success during the next, a COE reflecting the trade-off between current and future RP. Our results suggest that different life-history stages interact to influence RP in the next breeding season, so that behaviour patterns during winter may be important determinants of variation in subsequent fitness among individuals. PMID- 26510675 TI - Grooming-at-a-distance by exchanging calls in non-human primates. AB - The 'social bonding hypothesis' predicts that, in large social groups, functions of gestural grooming should be partially transferred to vocal interactions. Hence, vocal exchanges would have evolved in primates to play the role of grooming-at-a-distance in order to facilitate the maintenance of social cohesion. However, there are few empirical studies testing this hypothesis. To address this point, we compared the rate of contact call exchanges between females in two captive groups of Japanese macaques as a function of female age, dominance rank, genetic relatedness and social affinity measured by spatial proximity and grooming interactions. We found a significant positive relationship between the time spent on grooming by two females and the frequency with which they exchanged calls. Our results conform to the predictions of the social bonding hypothesis, i.e. vocal exchanges can be interpreted as grooming-at-a-distance. PMID- 26510676 TI - Synchrony and exertion during dance independently raise pain threshold and encourage social bonding. AB - Group dancing is a ubiquitous human activity that involves exertive synchronized movement to music. It is hypothesized to play a role in social bonding, potentially via the release of endorphins, which are analgesic and reward inducing, and have been implicated in primate social bonding. We used a 2 * 2 experimental design to examine effects of exertion and synchrony on bonding. Both demonstrated significant independent positive effects on pain threshold (a proxy for endorphin activation) and in-group bonding. This suggests that dance which involves both exertive and synchronized movement may be an effective group bonding activity. PMID- 26510677 TI - Early post-metamorphic, Carboniferous blastoid reveals the evolution and development of the digestive system in echinoderms. AB - Inferring the development of the earliest echinoderms is critical to uncovering the evolutionary assembly of the phylum-level body plan but has long proven problematic because early ontogenetic stages are rarely preserved as fossils. Here, we use synchrotron tomography to describe a new early post-metamorphic blastoid echinoderm from the Carboniferous (approx. 323 Ma) of China. The resulting three-dimensional reconstruction reveals a U-shaped tubular structure in the fossil interior, which is interpreted as the digestive tract. Comparisons with the developing gut of modern crinoids demonstrate that crinoids are an imperfect analogue for many extinct groups. Furthermore, consideration of our findings in a phylogenetic context allows us to reconstruct the evolution and development of the digestive system in echinoderms more broadly; there was a transition from a straight to a simple curved gut early in the phylum's evolution, but additional loops and coils of the digestive tract (as seen in crinoids) were not acquired until much later. PMID- 26510678 TI - Expression of concern: Predation selectively culls medium-sized species from island mammal faunas. PMID- 26510679 TI - Resurrecting embryos of the tuatara, Sphenodon punctatus, to resolve vertebrate phallus evolution. AB - The breadth of anatomical and functional diversity among amniote external genitalia has led to uncertainty about the evolutionary origins of the phallus. In several lineages, including the tuatara, Sphenodon punctatus, adults lack an intromittent phallus, raising the possibility that the amniote ancestor lacked external genitalia and reproduced using cloacal apposition. Accordingly, a phallus may have evolved multiple times in amniotes. However, similarities in development across amniote external genitalia suggest that the phallus may have a single evolutionary origin. To resolve the evolutionary history of amniote genitalia, we performed three-dimensional reconstruction of Victorian era tuatara embryos to look for embryological evidence of external genital initiation. Despite the absence of an intromittent phallus in adult tuataras, our observations show that tuatara embryos develop genital anlagen. This illustrates that there is a conserved developmental stage of external genital development among all amniotes and suggests a single evolutionary origin of amniote external genitalia. PMID- 26510680 TI - Modulation of DNA methylation machineries in Japanese rice fish (Oryzias latipes) embryogenesis by ethanol and 5-azacytidine. AB - As a sequel of our investigations on the impact of epigenome in inducing fetal alcohol spectrum disorder (FASD) phenotypes in Japanese rice fish, we have investigated on several DNA methylation machinery genes including DNA methyl transferase 3ba (dnmt3ba) and methyl binding proteins (MBPs), namely, mbd1b, mbd3a, mbd3b, and mecp2 at the transcription level. Studies were made during normal development, from 0day post fertilization (dpf) to hatching, and also exposing the fertilized eggs to ethanol or a DNMT inhibitor, 5-azacytidine (5 azaC). We observed that during development, all these genes followed distinct expression patterns, generally high mRNA copies in early phases (0-1dpf) and significantly low mRNA copies prior to or after hatching. Ethanol (100-500mM, 0 2dpf) was unable to alter any of these mRNAs in 2dpf; additional four day (2 6dpf) maintenance of these embryos in ethanol-free environment, on 6dpf, was also unable to establish any significant difference in these mRNA levels in comparison with the corresponding controls. However, continuous exposure of fertilized eggs in 300mM ethanol, 0-6dpf, showed significantly high mRNA copies only in MBPs (mbd1b, mbd3a, mbd3b, mecp2). 5-azaC (2mM) on 2dpf was able to enhance only mbd3b mRNA. Removal of 5-azaC and maintenance of these embryos in clean medium, 2-6dpf, showed significantly enhanced mbd3b and mecp2 mRNAs compared to corresponding controls on 6dpf. Our studies showed that in Japanese rice fish embryogenesis both ethanol and 5-azaC have the potential to specifically modulate the developmental rhythm of DNA methylation machineries. PMID- 26510681 TI - Mechanisms of zinc toxicity in the galaxiid fish, Galaxias maculatus. AB - Zinc (Zn) is an essential metal, which is ubiquitous in aquatic environments occurring both naturally, and through anthropogenic inputs. This study investigated impacts of sub-lethal Zn exposure in the galaxiid fish Galaxias maculatus. Known as inanga, this amphidromous fish is widespread throughout the Southern hemisphere, but to date almost nothing is known regarding its sensitivity to elevated environmental metals. Fish were exposed to environmentally-relevant concentrations of Zn (control, 8, 270 and 1000MUgL(-1)) over 96h. End-points measured included those relating to ionoregulatory disturbance (whole body calcium and sodium influx), oxygen consumption (respirometry), oxidative stress (catalase activity and lipid peroxidation) and whole body accumulation of Zn. Zn exposure caused increases in catalase activity and lipid peroxidation, but only at the highest exposure level tested. Zn also significantly inhibited calcium influx, but stimulated sodium influx, at 1000MUgL(-1). The sub-lethal changes induced by Zn exposure in inanga appear to be conserved relative to other, better-studied species. These data are the first to explore the sensitivity of juvenile galaxiid fish to Zn, information that will be critical to ensuring adequate environmental protection of this important species. PMID- 26510682 TI - Differential temporal changes of primary and secondary bacterial symbionts and whitefly host fitness following antibiotic treatments. AB - Where multiple symbionts coexist in the same host, the selective elimination of a specific symbiont may enable the roles of a given symbiont to be investigated. We treated the Mediterranean species of the whitefly Bemisia tabaci complex by oral delivery of the antibiotic rifampicin, and then examined the temporal changes of its primary symbiont "Candidatus Portiera aleyrodidarum" and secondary symbiont "Ca. Hamiltonella defensa" as well as host fitness for three generations. In adults treated with rifampicin (F0), the secondary symbiont was rapidly reduced, approaching complete disappearance as adults aged. In contrast, the primary symbiont was little affected until later in the adult life. In the offspring of these adults (F1), both symbionts were significantly reduced and barely detectable when the hosts reached the adult stage. The F1 adults laid few eggs (F2), all of which failed to hatch. Mating experiments illustrated that the negative effects of rifampicin on host fitness were exerted via female hosts but not males. This study provides the first evidence of differential temporal reductions of primary and secondary symbionts in whiteflies following an antibiotic treatment. Studies that disrupt functions of bacterial symbionts must consider their temporal changes. PMID- 26510683 TI - Cyclin D1 in pediatric neuroblastic tumors: A microarray analysis. AB - Neuroblastoma is the most common extracranial solid childhood tumor, which is believed to originate from primitive neuroblasts giving rise to the sympathetic nervous system. It was previously shown that cyclin D1 (CCDN1) in pediatric neuroblastic tumors (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) recapitulates its expression during the development of peripheral sympathetic nervous system (PSNS). In the present study, we performed a microarray analysis in order to evaluate the expression of cyclin D1 in neuroblastoma as compared to ganglioneuroma and ganglioneuroblastoma. We first confirmed that comparable levels of cyclin D1 are present in neuroblastoma and fetal neuroblasts. In addition, we observed that neuroblastoma is associated to significantly higher levels of cyclin D1 as compared to both ganglioneuroma and ganglioneuroblastoma. No differences are instead observable between ganglioneuroblastoma and ganglioneuroma. Finally, bioinformatic analysis of cyclin D1-functionally related genes, identified cyclin D2 as an additional marker/etiopathogenic factor in the development of neuroblastoma. PMID- 26510684 TI - Perspectives in Medicinal Chemistry: Metalloprotein Inhibitors: What Have We Made and What is the Next Step? PMID- 26510685 TI - Identification of subjects with polycystic ovary syndrome using electronic health records. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder because of the variable criteria used for diagnosis. Therefore, International Classification of Diseases 9 (ICD-9) codes may not accurately capture the diagnostic criteria necessary for large scale PCOS identification. We hypothesized that use of electronic medical records text and data would more specifically capture PCOS subjects. METHODS: Subjects with PCOS were identified in the Partners Healthcare Research Patients Data Registry by searching for the term "polycystic ovary syndrome" using natural language processing (n = 24,930). A training subset of 199 identified charts was reviewed and categorized based on likelihood of a true Rotterdam PCOS diagnosis, i.e. two out of three of the following: irregular menstrual cycles, hyperandrogenism and/or polycystic ovary morphology. Data from the history, physical exam, laboratory and radiology results were codified and extracted from notes of definite PCOS subjects. Thirty two terms were used to build an algorithm for identifying definite PCOS cases and applied to the rest of the dataset. The positive predictive value cutoff was set at 76.8 % to maximize the number of subjects available for study. A true positive predictive value for the algorithm was calculated after review of 100 charts from subjects identified as definite PCOS cases with at least two documented Rotterdam criteria. The positive predictive value was compared to that calculated using 200 charts identified using the ICD-9 code for PCOS (256.4; n = 13,670). In addition, a cohort of previously recruited PCOS subjects was submitted for algorithm validation. RESULTS: Chart review demonstrated that 64 % were confirmed as definitely PCOS using the algorithm, with a 9 % false positive rate. 66 % of subjects identified by ICD-9 code for PCOS could be confirmed as definitely PCOS, with an 8.5 % false positive rate. There was no significant difference in the positive predictive values using the two methods (p = 0.2). However, the number of charts that had insufficient confirmatory data was lower using the algorithm (5 % vs 11 %; p < 0.04). Of 477 subjects with PCOS recruited and examined individually and present in the database as patients, 451 were found within the algorithm dataset. CONCLUSIONS: Extraction of text parameters along with codified data improves the confidence in PCOS patient cohorts identified using the electronic medical record. However, the positive predictive value was not significantly different when using ICD-9 codes or the specific algorithm. Further studies are needed to determine the positive predictive value of the two methods in additional electronic medical record datasets. PMID- 26510687 TI - Gating of single molecule junction conductance by charge transfer complex formation. AB - The solid-state structures of organic charge transfer (CT) salts are critical in determining their mode of charge transport, and hence their unusual electrical properties, which range from semiconducting through metallic to superconducting. In contrast, using both theory and experiment, we show here that the conductance of metal |single molecule| metal junctions involving aromatic donor moieties (dialkylterthiophene, dialkylbenzene) increase by over an order of magnitude upon formation of charge transfer (CT) complexes with tetracyanoethylene (TCNE). This enhancement occurs because CT complex formation creates a new resonance in the transmission function, close to the metal contact Fermi energy, that is a signal of room-temperature quantum interference. PMID- 26510686 TI - Exploring DNA methylation changes in promoter, intragenic, and intergenic regions as early and late events in breast cancer formation. AB - BACKGROUND: Breast cancer formation is associated with frequent changes in DNA methylation but the extent of very early alterations in DNA methylation and the biological significance of cancer-associated epigenetic changes need further elucidation. METHODS: Pyrosequencing was done on bisulfite-treated DNA from formalin-fixed, paraffin-embedded sections containing invasive tumor and paired samples of histologically normal tissue adjacent to the cancers as well as control reduction mammoplasty samples from unaffected women. The DNA regions studied were promoters (BRCA1, CD44, ESR1, GSTM2, GSTP1, MAGEA1, MSI1, NFE2L3, RASSF1A, RUNX3, SIX3 and TFF1), far-upstream regions (EN1, PAX3, PITX2, and SGK1), introns (APC, EGFR, LHX2, RFX1 and SOX9) and the LINE-1 and satellite 2 DNA repeats. These choices were based upon previous literature or publicly available DNA methylome profiles. The percent methylation was averaged across neighboring CpG sites. RESULTS: Most of the assayed gene regions displayed hypermethylation in cancer vs. adjacent tissue but the TFF1 and MAGEA1 regions were significantly hypomethylated (p <=0.001). Importantly, six of the 16 regions examined in a large collection of patients (105 - 129) and in 15-18 reduction mammoplasty samples were already aberrantly methylated in adjacent, histologically normal tissue vs. non-cancerous mammoplasty samples (p <=0.01). In addition, examination of transcriptome and DNA methylation databases indicated that methylation at three non-promoter regions (far-upstream EN1 and PITX2 and intronic LHX2) was associated with higher gene expression, unlike the inverse associations between cancer DNA hypermethylation and cancer-altered gene expression usually reported. These three non-promoter regions also exhibited normal tissue-specific hypermethylation positively associated with differentiation-related gene expression (in muscle progenitor cells vs. many other types of normal cells). The importance of considering the exact DNA region analyzed and the gene structure was further illustrated by bioinformatic analysis of an alternative promoter/intron gene region for APC. CONCLUSIONS: We confirmed the frequent DNA methylation changes in invasive breast cancer at a variety of genome locations and found evidence for an extensive field effect in breast cancer. In addition, we illustrate the power of combining publicly available whole-genome databases with a candidate gene approach to study cancer epigenetics. PMID- 26510688 TI - Slow AAV2 clearance from the brain of nonhuman primates and anti-capsid immune response. AB - Adeno-associated virus serotype 2 (AAV2) has previously been reported to be a slowly uncoating virus in peripheral tissues, but persistence of intact vector in primate brain has not been explored. Because some neurological gene therapies may require re-administration of the same vector to patients, it seems important to understand the optimal timeframe in which to consider such repeat intervention. Surprisingly, convection-enhanced delivery of AAV2 into the thalamus of nonhuman primates (NHPs) resulted in robust staining of neurons with A20 antibody that detected intact AAV2 particles at ~1.5 months after infusion. However, by 2.5 months, no A20 staining was visible. These data confirmed earlier findings of persistence of intact AAV2 particles in ocular and hepatic tissues. In order to probe the potential consequences of this persistence, we infused AAV2-human aromatic L-amino acid decarboxylase into left and right thalamus of three NHPs, with a 3-month delay between infusions. During that interval, we immunized each animal subcutaneously with AAV2 virus-like particles (empty vector) in order to induce strong anti-capsid humoral immunity. Various high neutralizing antibody titers were achieved. The lowest titer animal showed infiltration of B lymphocytes and CD8(+) T cells into both the secondary and primary infusion sites. In the other two animals, extremely high titers resulted in no transduction of the second site and, therefore, no lymphocytic infiltration. However, such infiltration was prominent at the primary infusion site in each animal and was associated with overt neuronal loss and inflammation. PMID- 26510689 TI - Insights revealed by rodent models of sugar binge eating. AB - Binge eating is seen across the spectrum of eating disorder diagnoses as well as among individuals who do not meet diagnostic criteria. Analyses of the specific types of foods that are frequently binged upon reveal that sugar-rich items feature prominently in binge-type meals, making the effects of binge consumption of sugar an important focus of study. One avenue to do this involves the use of animal models. Foundational and recent studies of animal models of sugar bingeing, both outlined here, lend insight into the various neurotransmitters and neuropeptides that may participate in or be altered by this behavior. Further, several preclinical studies incorporating sugar bingeing paradigms have explored the utility of pharmacological agents that target such neural systems for reducing sugar bingeing in an effort to enhance clinical treatment. Indeed, the translational implications of findings generated using animal models of sugar bingeing are considered here, along with potential avenues for further study. PMID- 26510690 TI - Critical nucleation mesh-size of coarsening transient colloidal networks. AB - Isotropic magnetic field modulations cause the formation and coarsening of transient two dimensional paramagnetic colloidal networks. We show that the virgin transient network consists of sub- and supercritical meshes. In the initial coarsening process subcritical meshes shrink while supercritical meshes grow. While the coarsening is a truly non-equilibrium process, the critical nucleation size is independent of transport coefficients and can be theoretically described by the competition of first order long range collective dipolar interactions and short range second order dipolar pair correlations. PMID- 26510691 TI - Rational, computer-enabled peptide drug design: principles, methods, applications and future directions. AB - Peptides provide promising templates for developing drugs to occupy a middle space between small molecules and antibodies and for targeting 'undruggable' intracellular protein-protein interactions. Importantly, rational or in cerebro design, especially when coupled with validated in silico tools, can be used to efficiently explore chemical space and identify islands of 'drug-like' peptides to satisfy diverse drug discovery program objectives. Here, we consider the underlying principles of and recent advances in rational, computer-enabled peptide drug design. In particular, we consider the impact of basic physicochemical properties, potency and ADME/Tox opportunities and challenges, and recently developed computational tools for enabling rational peptide drug design. Key principles and practices are spotlighted by recent case studies. We close with a hypothetical future case study. PMID- 26510692 TI - Implication of thymoquinone as a remedy for polycystic ovary in rat. AB - CONTEXT: Thymoquinone (TQ), an active component of Nigella sativa L. (Ranunculaceae), possesses anti-inflammatory and anti-oxidative properties. Polycystic ovary syndrome exhibits chronic inflammatory behavior, thus might involve nuclear factor kappa B (NF-kappaB) signaling and related molecular factors. OBJECTIVE: The objective of the present study is to investigate and validate the effect of TQ in polycystic ovary (PCO) rat. MATERIALS AND METHODS: To validate the effect of TQ (1 uM/ml), NF-kappaB activation, COX2 (cyclooxygenase-2) expression and reactive oxygen species (ROS) induction were studied in the KK1 cell line. To evaluate the effect of TQ (2 mg/200 ul olive oil/rat; sc) with an in vivo system, ovulation rate, levels of key ovulation mediators, and ovarian gelatinases activity were compared in superovulated, PCO, and RU486 + TQ-treated Wistar rats. RESULTS: In vitro studies showed that NF kappaB nuclear translocation, COX2, and ROS expression were repressed via TQ supplementation in RU486-treated KK1 cells. Pretreatment of TQ in the PCO rat model induced significant restoration of normal physio-molecular behavior of ovary, such as reduced cysts formation, increased ovulation rate, and normalization of key ovarian factors [like TNF-alpha-stimulated gene/protein 6, hyaluronan, hyaluronan-binding protein 1, COX2, matrix metalloproteinases (membrane type 1-matrix metalloproteinase, MMP9 and MMP2)], tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2), and gelatinases (like MMP9 and -2) activity during follicular maturation. DISCUSSION AND CONCLUSION: Overall, most of the above molecular changes are regulated via NF-kappaB pathway, thus TQ, due to its modulatory effect on the NF-kappaB signaling, could elevate normal ovarian phenotype and physiological function in the PCO model, indicating its remarkable potential as a remedy for rat PCO. PMID- 26510693 TI - Pladipus Enables Universal Distributed Computing in Proteomics Bioinformatics. AB - The use of proteomics bioinformatics substantially contributes to an improved understanding of proteomes, but this novel and in-depth knowledge comes at the cost of increased computational complexity. Parallelization across multiple computers, a strategy termed distributed computing, can be used to handle this increased complexity; however, setting up and maintaining a distributed computing infrastructure requires resources and skills that are not readily available to most research groups. Here we propose a free and open-source framework named Pladipus that greatly facilitates the establishment of distributed computing networks for proteomics bioinformatics tools. Pladipus is straightforward to install and operate thanks to its user-friendly graphical interface, allowing complex bioinformatics tasks to be run easily on a network instead of a single computer. As a result, any researcher can benefit from the increased computational efficiency provided by distributed computing, hence empowering them to tackle more complex bioinformatics challenges. Notably, it enables any research group to perform large-scale reprocessing of publicly available proteomics data, thus supporting the scientific community in mining these data for novel discoveries. PMID- 26510694 TI - The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. PMID- 26510695 TI - Whither Anticoagulation in Pulmonary Arterial Hypertension? Conflicting Evidence REVEALed. PMID- 26510696 TI - Effect of Warfarin Treatment on Survival of Patients With Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). AB - BACKGROUND: Long-term anticoagulation is recommended in idiopathic pulmonary arterial hypertension (IPAH). In contrast, limited data support anticoagulation in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc PAH). We assessed the effect of warfarin anticoagulation on survival in IPAH and SSc-PAH patients enrolled in Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a longitudinal registry of group I PAH. METHODS AND RESULTS: Patients who initiated warfarin on study (n=187) were matched 1:1 with patients never on warfarin, by enrollment site, etiology, and diagnosis status. Descriptive analyses were conducted to compare warfarin users and nonusers by etiology. Survival analyses with and without risk adjustment were performed from the time of warfarin initiation or a corresponding quarterly update in matched pairs to avoid immortal time bias. Time-varying covariate models were used as sensitivity analyses. Mean warfarin treatment was 1 year; mean international normalized ratios were 1.9 (IPAH) and 2.0 (SSc-PAH). Two-thirds of patients initiating warfarin discontinued treatment before the last study assessment. There was no survival difference with warfarin in IPAH patients (adjusted hazard ratio, 1.37; P=0.21) or in SSc-PAH patients (adjusted hazard ratio, 1.60; P=0.15) in comparison with matched controls. However, SSc-PAH patients receiving warfarin within the previous year (hazard ratio, 1.57; P=0.031) or any time postbaseline (hazard ratio, 1.49; P=0.046) had increased mortality in comparison with warfarin naive patients. CONCLUSIONS: No significant survival advantage was observed in IPAH patients who started warfarin. In SSc-PAH patients, long-term warfarin was associated with poorer survival than in patients not receiving warfarin, even after adjusting for confounders. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214. PMID- 26510697 TI - To Pulse or Not to Pulse, Is That the Question? PMID- 26510698 TI - Restoration of Pulsatile Flow Reduces Sympathetic Nerve Activity Among Individuals With Continuous-Flow Left Ventricular Assist Devices. AB - BACKGROUND: Current-generation left ventricular assist devices provide circulatory support that is minimally or entirely nonpulsatile and are associated with marked increases in muscle sympathetic nerve activity (MSNA), likely through a baroreceptor-mediated pathway. We sought to determine whether the restoration of pulsatile flow through modulations in pump speed would reduce MSNA through the arterial baroreceptor reflex. METHODS AND RESULTS: Ten men and 3 women (54 +/- 14 years) with Heartmate II continuous-flow left ventricular assist devices underwent hemodynamic and sympathetic neural assessment. Beat-to-beat blood pressure, carotid ultrasonography at the level of the arterial baroreceptors, and MSNA via microneurography were continuously recorded to determine steady-state responses to step changes (200-400 revolutions per minute) in continuous-flow left ventricular assist device pump speed from a maximum of 10,480 +/- 315 revolutions per minute to a minimum of 8500 +/- 380 revolutions per minute. Reductions in pump speed led to increases in pulse pressure (high versus low speed: 17 +/- 7 versus 26 +/- 12 mm Hg; P<0.01), distension of the carotid artery, and carotid arterial wall tension (P<0.05 for all measures). In addition, MSNA was reduced (high versus low speed: 41 +/- 15 versus 33 +/- 16 bursts per minute; P<0.01) despite a reduction in mean arterial pressure and was inversely related to pulse pressure (P=0.037). CONCLUSIONS: Among subjects with continuous flow left ventricular assist devices, the restoration of pulsatile flow through modulations in pump speed leads to increased distortion of the arterial baroreceptors with a subsequent decline in MSNA. Additional study is needed to determine whether reduction of MSNA in this setting leads to improved outcomes. PMID- 26510699 TI - Reliable Potential Energy Surfaces for the Reactions of H2O with ThO2, PaO2(+), UO2(2+), and UO2(.). AB - The potential energy surfaces for the reactions of H2O with ThO2, PaO2(+), UO2(2+), and UO2(+) have been calculated at the coupled cluster CCSD(T) level extrapolated to the complete basis set limit with additional corrections including scalar relativistic and spin-orbit. The reactions proceed by the formation of an initial Lewis acid-base adduct (H2O)AnO2(0/+/2+) followed by a proton transfer to generate the dihydroxide AnO(OH)2(0/+/2+). The results are in excellent agreement with mass spectrometry experiments and prior calculations of hydrolysis reactions of the group 4 transition metal dioxides MO2. The differences in the energies of the stationary points on the potential energy surface are explained in terms of the charges on the system and the populations on the metal center. The use of an improved starting point for the coupled cluster CCSD(T) calculations based on density functional theory with the PW91 exchange-correlation functional or Brueckner orbitals is described. The importance of including second-order spin-orbit corrections for closed-shell molecules is also described. These improvements in the calculations are correlated with the 5f populations on the actinide. PMID- 26510700 TI - Animal Bites and Rabies Prophylaxis in Rural Children: Indian Perspective. AB - A prospective observational study was conducted in a tertiary care hospital to study clinicoepidemiological profile of potentially rabid animal bite cases from rural India. Total of 308 children (median age 6 years) admitted to hospital, were recruited over 1 year and followed up till completion of antirabies vaccine course. Dog was the commonest (77.27%) offending animal. Of the exposures, 66.88% were scratches, 88.96% were unprovoked and 27.27% were categorized as Class III. The median times to wound toileting and reporting to health facility were 1 and 6 h, respectively. Majority received prompt PEP in hospital, and RIG was administered in 34.55% of Class II and 90.48% of Class III exposures. Compared with their older counterparts, children aged <5 years suffered more bites on face and trunk and more Class III exposures. The rabies prophylaxis scenario is encouraging, when compared with earlier studies, but there are gaps to be addressed. PMID- 26510701 TI - Mortality in patients with acute aortic dissection type A: analysis of pre- and intraoperative risk factors from the German Registry for Acute Aortic Dissection Type A (GERAADA). AB - OBJECTIVES: Acute aortic dissection type A (AADA) is an emergency with excessive mortality if surgery is delayed. Knowledge about independent predictors of mortality on surgically treated AADA patients is scarce. Therefore, this study was conducted to identify pre- and intraoperative risk factors for death. METHODS: Between July 2006 and June 2010, 2137 surgically treated patients with AADA were enrolled in a multicentre, prospective German Registry for Acute Aortic Dissection type A (GERAADA), presenting perioperative status, operative strategies, postoperative outcomes and AADA-related risk factors for death. Multiple logistic regression analysis was performed to identify the influence of different parameters on 30-day mortality. RESULTS: Overall 30-day mortality (16.9%) increased with age [adjusted odds ratio (OR) = 1.121] and among patients who were comatose (adjusted OR = 3.501) or those who underwent cardiopulmonary resuscitation (adjusted OR = 3.751; all P < 0.0001). The higher the number of organs that were malperfused, the risk for death was (adjusted OR for one organ = 1.651, two organs = 2.440, three organs or more = 3.393, P < 0.0001). Mortality increased with longer operating times (total, cardiopulmonary bypass, cardiac ischaemia and circulatory arrest; all P < 0.02). Arterial cannulation site for extracorporeal circulation, operative techniques and arch interventions had no significant impact on 30-day mortality (all P > 0.1). No significant risk factors, but relevant increases in mortality, were determined in patients suffering from hemiparesis pre- and postoperatively (each P < 0.01), and in patients experiencing paraparesis after surgery (P < 0.02). CONCLUSIONS: GERAADA could detect significant disease- and surgery-related risk factors for death in AADA, influencing the outcome of surgically treated AADA patients. Comatose and resuscitated patients have the poorest outcome. Cannulation sites and operative techniques did not seem to affect mortality. Short operative times are associated with better outcomes. PMID- 26510702 TI - A new look at arthritis management: nociceptive reflex excitability as a pain biomarker. AB - Research studies have begun to identify altered neurophysiological mechanisms that develop as a consequence of chronic painful knee arthritis. Neuroplastic changes may occur in nociceptive pathways, thereby contributing to heightened chronic pain and spread of symptoms, as well as diminished quality of life. One biomarker for examining central sensitization of nociceptive pathways is the measurement of flexion reflex excitability, also called the nociceptive reflex. In a recent article in Arthritis Research & Therapy, Rice and colleagues utilize this biomarker to analyze the clinical and neurophysiological effects of a very common and typical medical intervention, joint aspiration and intra-articular corticosteroid injection. PMID- 26510703 TI - Attitudes of Dutch general practitioners towards vaccinating the elderly: less is more? AB - BACKGROUND: In many European countries, vaccinations are offered to the elderly. Expanding the programme to include routine vaccination against pneumococcal disease, herpes zoster, and pertussis, for example, could reduce disease burden amongst the growing population of persons aged 50 years and older. Since most countries involve general practitioners (GPs) in the programmes, the potential success of such new vaccinations depends on the attitude of GPs towards these vaccinations. This qualitative study explores Dutch GPs' attitudes regarding vaccination in general, and their attitudes regarding the incorporation of additional vaccines in the current Dutch influenza vaccination programme. METHODS: Interviews were held with ten Dutch GPs (five men and five women) that worked either in an academic hospital, in a practice based in a health center, or in individual practice. All interviews were recorded with a digital voice recorder and transcribed verbatim. Transcripts were analysed according to thematic analysis. RESULTS: GPs perceived prevention as part as their job and believed vaccination to be effective for preventing infectious diseases. However, influenza vaccination was not always perceived as effective. Doubts regarding the usefulness of additional vaccinations were identified. If additional vaccines would be offered, this should be based on scientific evidence and the severity of the infectious disease. Selection of patients for vaccination should not be based solely on age, but more on risk factors. The GP should be the central point of contact for new vaccination campaigns; however, high workload was seen as a concern. Several GPs questioned their ability to refuse to distribute the vaccinations. CONCLUSIONS: A positive attitude towards implementing additional vaccinations is not apparent. Achieving the most health benefits seems to be the most important consideration of Dutch GPs regarding vaccinating older adults. Questions regarding the usefulness of vaccinating older adults should be taken into consideration. More research is necessary to confirm the results among a wider range of Dutch GPs. PMID- 26510704 TI - Clustering and percolation in protein loop structures. AB - BACKGROUND: High precision protein loop modelling remains a challenge, both in template based and template independent approaches to protein structure prediction. METHOD: We introduce the concepts of protein loop clustering and percolation, to develop a quantitative approach to systematically classify the modular building blocks of loops in crystallographic folded proteins. These fragments are all different parameterisations of a unique kink solution to a generalised discrete nonlinear Schrodinger (DNLS) equation. Accordingly, the fragments are also local energy minima of the ensuing energy function. RESULTS: We show how the loop fragments cover practically all ultrahigh resolution crystallographic protein structures in Protein Data Bank (PDB), with a 0.2 Angstrom root-mean-square (RMS) precision. We find that no more than 12 different loop fragments are needed, to describe around 38 % of ultrahigh resolution loops in PDB. But there is also a large number of loop fragments that are either unique, or very rare, and examples of unique fragments are found even in the structure of a myoglobin. CONCLUSIONS: Protein loops are built in a modular fashion. The loops are composed of fragments that can be modelled by the kink of the DNLS equation. The majority of loop fragments are also common, which are shared by many proteins. These common fragments are probably important for supporting the overall protein conformation. But there are also several fragments that are either unique to a given protein, or very rare. Such fragments are probably related to the function of the protein. Furthermore, we have found that the amino acid sequence does not determine the structure in a unique fashion. There are many examples of loop fragments with an identical amino acid sequence, but with a very different structure. PMID- 26510705 TI - Parent-reported multi-national study of the impact of congenital and childhood onset myotonic dystrophy. AB - AIM: The frequency and impact of symptoms experienced by patients with congenital, childhood, and juvenile-onset myotonic dystrophy (CDM/ChDM/JDM) is not documented. This report identifies symptomatic areas with the greatest disease burden in an international population of patients with early-onset myotonic dystrophy type-1 (DM1). METHOD: We distributed surveys to parents of patients with CDM/ChDM/JDM. Patients with CDM/ChDM/JDM were members of the US National Registry of DM1 Patients and Family Members, the Canadian Neuromuscular Disease Registry, or the Swedish Health System. Surveys inquired about 325 symptoms and 20 themes associated with CDM/ChDM/JDM. Parents identified the importance of each symptom and theme to their affected child. The prevalence of each symptom and theme were compared across subgroups of patients. The statistical analysis was performed using Fisher's exact and Kruskal-Wallis tests. RESULTS: One hundred and fifty parents returned surveys. The most frequently reported symptomatic themes in children were issues involving communication (81.7%) and problems with hands or fingers (79.6%). Problems with communication and fatigue were the issues that were reported to have the greatest impact on childrens' lives, while 24.1% of children reported cardiac disorders and 15.8% had problems with anesthesia. INTERPRETATION: A range of symptoms contribute to the burden of disease faced by children with DM1. Many of these symptoms are under-recognized. PMID- 26510706 TI - Quantitative imaging of tissue sections using infrared scanning technology. AB - Quantification of immunohistochemically (IHC) labelled tissue sections typically yields semi-quantitative results. Visualising infrared (IR) 'tags', with an appropriate scanner, provides an alternative system where the linear nature of the IR fluorophore emittance enables realistic quantitative fluorescence IHC (QFIHC). Importantly, this new technology enables entire tissue sections to be scanned, allowing accurate area and protein abundance measurements to be calculated from rapidly acquired images. Here, some of the potential benefits of using IR-based tissue imaging are examined, and the following are demonstrated. Firstly, image capture and analysis using IR-based scanning technology yields comparable area-based quantification to those obtained from a modern high resolution digital slide scanner. Secondly, IR-based dual target visualisation and expression-based quantification is rapid and simple. Thirdly, IR-based relative protein abundance QIHC measurements are an accurate reflection of tissue sample protein abundance, as demonstrated by comparison with quantitative fluorescent Western blotting data. In summary, it is proposed that IR-based QFIHC provides an alternative method of rapid whole-tissue section low-resolution imaging for the production of reliable and accurate quantitative data. PMID- 26510707 TI - An automatic method to detect and track the glottal gap from high speed videoendoscopic images. AB - BACKGROUND: The image-based analysis of the vocal folds vibration plays an important role in the diagnosis of voice disorders. The analysis is based not only on the direct observation of the video sequences, but also in an objective characterization of the phonation process by means of features extracted from the recorded images. However, such analysis is based on a previous accurate identification of the glottal gap, which is the most challenging step for a further automatic assessment of the vocal folds vibration. METHODS: In this work, a complete framework to automatically segment and track the glottal area (or glottal gap) is proposed. The algorithm identifies a region of interest that is adapted along time, and combine active contours and watershed transform for the final delineation of the glottis and also an automatic procedure for synthesize different videokymograms is proposed. RESULTS: Thanks to the ROI implementation, our technique is robust to the camera shifting and also the objective test proved the effectiveness and performance of the approach in the most challenging scenarios that it is when exist an inappropriate closure of the vocal folds. CONCLUSIONS: The novelties of the proposed algorithm relies on the used of temporal information for identify an adaptive ROI and the use of watershed merging combined with active contours for the glottis delimitation. Additionally, an automatic procedure for synthesize multiline VKG by the identification of the glottal main axis is developed. PMID- 26510708 TI - Influence of pneumonia complications on the prognosis of patients with autopsy confirmed Alzheimer's disease, dementia with Lewy bodies, and vascular dementia. AB - BACKGROUND: Pneumonia is a major, complicated disease in patients with dementia. However, the influence of pneumonia on the prognosis of patients with varying types of dementia has not been fully evaluated. METHODS: We retrospectively analyzed the data from medical and autopsy reports. All study patients had been hospitalized and underwent brain autopsy in a hospital in Toyohashi, Japan, between 2005 and 2014. The patients with subtypes of dementia, specifically Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or vascular dementia (VaD), were neuropathologically diagnosed and examined. Pneumonia incidence, cause of death, and the clinical time-course of dementia were compared among the dementia subtypes. The time to death from dementia onset (survival time) was compared by the Kaplan-Meier method among subtypes of dementia with or without pneumonia. Risk factors for survival time on all study patients were analyzed with the Cox proportional hazard model. RESULTS: Of the 157 eligible patients, 63 (40.1%) had AD, 42 (26.8%) had DLB, and 52 (33.1%) had VaD. Pneumonia complication was observed with high incidence in each subtype of dementia, especially in DLB (90.5%). The median total duration from dementia onset to death was 8 years in AD and DLB, and 5 years in VaD. The VaD subtype had more male patients than AD or DLB (P = 0.010), and age of death in this group was the youngest among the three groups (P = 0.018). A significant difference was observed in the survival time by the Kaplan-Meier method among the three groups (P < 0.001) and among the groups with pneumonia (P = 0.002). The factors associated with shorter survival time were male gender, pneumonia complications, diabetes mellitus, age of dementia onset >= 75 years, and VaD. CONCLUSIONS: Pneumonia complications shortened the survival time of patients with AD, DLB, and VaD. PMID- 26510709 TI - Food acceptance and neophobia in children with phenylketonuria: a prospective controlled study. AB - BACKGROUND: In phenylketonuria (PKU), little is known about the effect of bitter tasting phenylalanine-free l-amino acid exposure on taste preference development. The present prospective study aimed to determine the flavour preferences of children with PKU versus healthy control children. METHODS: Thirty-five children with PKU and 35 age/gender-matched controls, aged 4-13 years, tasted 10 blinded puree foods in random order. They were rated using a seven-point pictorial hedonic scale (super yummy to super yucky) and ranked in preferential order. Caregivers completed a neophobia and food frequency questionnaire on behalf of their children. RESULTS: Both PKU and control groups rated sweet foods higher than savoury, bitter and sour foods. However, control children ranked fruits as a group higher than PKU children (mean 3.7 versus 4.6; P = 0.03), whereas PKU children ranked vegetables as a group higher than controls (mean 5.6 versus 6.3; P = 0.05). Children with PKU had more neophobia and were untrusting/fearful of new foods. CONCLUSIONS: Although there was some evidence to suggest that children with PKU aged >=4 years prefer savoury foods (vegetables) more than control children, they did not prefer bitter-tasting foods, and so early and persistent administration of bitter-tasting l-amino acids was not associated with apparent taste imprinting. Neophobia appears to play significant part in food refusal in PKU, perhaps more so than taste preferences. PMID- 26510710 TI - Recurrence of conversion disorder symptoms in a successfully treated 16-year-old female. AB - We present a case of a 16-year-old Caucasian female with a history of major depressive disorder and post-traumatic stress disorder who was admitted to an inpatient adolescent psychiatric unit with symptoms of conversion disorder, including non-epileptic seizures, an inability to speak or walk, and not eating on her own. She has a history of multiple previous medical and psychiatric hospitalizations without any significant resolution of symptoms, and extensive medical workups have all been negative. Treatment ultimately involved reassuring the patient and family that there was no underlying medical condition and emphasizing the conversion disorder diagnosis. The patient participated daily in physical therapy to improve mobility, deconditioning, and functioning. Hospital staff was instructed on the nature of the non-epileptic seizures, which continued to occur during the hospitalization. After one month, the patient was discharged home fully functional: walking, speaking, and eating on her own. One week after discharge, the patient presented with the same symptoms and was readmitted to the psychiatric facility. She subsequently never regained her previous level of functioning, and she was ultimately transferred to a residential treatment facility. We will discuss factors that led to the initial improvement and the factors that led to recurrence and persistence of symptoms. PMID- 26510711 TI - Are free anti-tuberculosis drugs enough? An empirical study from three cities in China. AB - BACKGROUND: Tuberculosis (TB) patients in China still face a number of barriers in seeking diagnosis and treatment. There is evidence that the economic burden on TB patients and their households discourages treatment compliance. METHODS: A cross-sectional study was conducted in three cities of China. Patients were selected using probability proportional to size (PPS) cluster sampling of rural townships or urban streets, followed by list sampling from a patient register. Data were collected using a questionnaire survey, key informant interviews and focus group discussions with TB patients to gain an understanding of the economic burden of TB and implications of this burden for treatment compliance. RESULTS: A total of 797 TB patients were surveyed, of which 60 were interviewed in-depth following the survey. More than half had catastrophic health expenditure. TB patients with higher household incomes were less likely to report non-compliance (OR 0.355, 95 % CI 0.140-0.830) and patients who felt that the economic burden relating to TB treatment was high more likely to report non-compliance (OR 3.650, 95 % CI 1.278-12.346). Those who had high costs for transportation, lodging and food were also more likely to report non-compliance (OR 4.150, 95 % CI 1.804 21.999). The findings from the qualitative studies supported those from the survey. CONCLUSION: The economic burden associated with seeking diagnosis and treatment remains a barrier for TB patients in China. Reducing the cost of treatment and giving patients subsidies for transportation, lodging and food is likely to improve treatment compliance. Improving doctors' salary system to cut off the revenue-oriented incentive, and expanding current insurance's coverage can be helpful to reduce patients' actual burden or anticipated burden. Future research on this issue is needed. PMID- 26510712 TI - Education and Imaging. Gastrointestinal: Magnifying endoscopy for pseudomelanosis duodeni. PMID- 26510713 TI - Cromolyn-mediated improvement of intestinal barrier function is associated with enhanced piglet performance after weaning. AB - BACKGROUND: Previous work showed that weaning stress causes gut barrier dysfunction partly by triggering the release of corticotropin releasing factor (CRF) and thereby inducing the degranulation of intestinal mast cell (MC). This study investigated the hypothesis that attenuating the weaning-induced activation of the CRF-MC axis via administration of a MC stabilizing agent (cromolyn) may improve gut permeability and piglet performance after weaning. RESULTS: To test the hypothesis twenty piglets were weaned (20 +/- 1.0 d of age; 6.4 +/- 0.4 kg of BW) and injected intraperitoneally with saline (control, n = 10) or 20 mg/kg BW of sodium cromolyn (cromolyn, n = 10) at - 0.5, 8 and 16 h relative to weaning. Piglets were housed individually and fed ad libitum a pre-starter diet from one to 15 d post-weaning followed by a starter diet until the end of the study on d 36. Cromolyn improved intestinal permeability as indicated by the reduced recovery of cobalt and mannitol in plasma samples. Cromolyn treated pigs consumed more feed (369 vs. 313 g/d; P < 0.009), gained more BW (283 vs. 238 g/d; P < 0.006), and grew more efficiently (0.60 vs. 0.40; P < 0.042) than their control counterparts. As a result, cromolyn treated pigs were 1.4 kg heavier than those in the control group by d 36 after weaning (16.5 vs. 17.9 kg; P < 0.002). CONCLUSIONS: In agreement with our hypothesis, present data indicate that the cromolyn-mediated improvement of intestinal permeability is associated with enhanced pig performance after weaning. PMID- 26510714 TI - Pressure-activated microsyringe (PAM) fabrication of bioactive glass-poly(lactic co-glycolic acid) composite scaffolds for bone tissue regeneration. AB - The aim of this work was the fabrication and characterization of bioactive glass poly(lactic-co-glycolic acid) (PLGA) composite scaffolds mimicking the topological features of cancellous bone. Porous multilayer PLGA-CEL2 composite scaffolds were innovatively produced by a pressure-activated microsyringe (PAM) method, a CAD/CAM processing technique originally developed at the University of Pisa. In order to select the optimal formulations to be extruded by PAM, CEL2 PLGA composite films (CEL2 is an experimental bioactive SiO2 -P2 O5 -CaO-MgO-Na2 O-K2 O glass developed at Politecnico di Torino) were produced and mechanically tested. The elastic modulus of the films increased from 30 to > 400 MPa, increasing the CEL2 amount (10-50 wt%) in the composite. The mixture containing 20 wt% CEL2 was used to fabricate 2D and 3D bone-like scaffolds composed by layers with different topologies (square, hexagonal and octagonal pores). It was observed that the increase of complexity of 2D topological structures led to an increment of the elastic modulus from 3 to 9 MPa in the composite porous monolayer. The elastic modulus of 3D multilayer scaffolds was intermediate (about 6.5 MPa) between the values of the monolayers with square and octagonal pores (corresponding to the lowest and highest complexity, respectively). MG63 osteoblast-like cells and periosteal-derived precursor cells (PDPCs) were used to assess the biocompatibility of the 3D bone-like scaffolds. A significant increase in cell proliferation between 48 h and 7 days of culture was observed for both cell phenotypes. Moreover, qRT-PCR analysis evidenced an induction of early genes of osteogenesis in PDPCs. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26510715 TI - High-contrast Noninvasive Imaging of Kidney Clearance Kinetics Enabled by Renal Clearable Nanofluorophores. AB - Noninvasive imaging of kidney clearance kinetics (KCK) of renal clearable probes is key to studying unilateral kidney function diseases, but such imaging is highly challenging to achieve with in vivo fluorescence. While this long-standing challenge is often attributed to the limited light penetration depth, we found that rapid and persistent accumulation of conventional dyes in the skin "shadowed" real fluorescence signals from the kidneys and prevented noninvasive imaging of KCK, which, however, can be addressed with renal clearable nanofluorophores. By integrating near infrared emission with efficient renal clearance and ultralow background interference, the nanofluorophores can increase kidney-contrast enhancement and imaging-time window by approximately 50- and 1000 fold over conventional dyes, and significantly minimize deviation between noninvasive and invasive KCK, laying down a foundation for translating in vivo fluorescence imaging in preclinical noninvasive kidney function assessments. PMID- 26510716 TI - Improved skin flap survival in venous ischemia-reperfusion injury with the use of adipose-derived stem cells. AB - INTRODUCTION: The purpose of this study was to investigate the efficacy of stem cell therapy as an adjuvant treatment for congested skin flap. METHOD: Sprague Dawley rats (n = 21) were randomized into three groups. In group I, the flap was sutured without venous ischemia. In group II, the vein was selectively clamped for 4 hours, and complete medium was administered upon clamp removal. In group III, ADSCs were administered upon removing the clamp. On postoperative day 7, the survival areas and the histopathologic findings were assessed. In addition, the expression of heme oxygenase (HO)-1 and nuclear factor (NF)-kappaB was assessed using immunofluorescent staining and western blot analyses. RESULTS: Compared with group II, group III showed significantly increased flap survival (31.2% +/- 11.9% vs. 51.6% +/- 13.6%, P < 0.05). The degree of histological abnormalities was significantly lower in group III than in group II (9.38% +/- 1.39 vs. 6.46% +/- 2.57, P < 0.05). In addition, in group III, the expression of NF-kappaB was significantly lower (0.51 +/- 0.21 vs. 0.34 +/- 0.21, P < 0.05), whereas that of HO-1 was significantly higher (0.25 +/- 0.11 vs. 0.43 +/- 0.18, P < 0.01). Immunofluorescent staining also showed more HO-1-positive cells in group III than in group II (10.9% +/- 1.6% vs. 16.0% +/- 1.7%, P < 0.01). CONCLUSION: Our study demonstrated that treatment with ADSCs significantly increased flap survival in venous ischemia-reperfusion conditions. Further investigation of these protective effects and optimization of the treatment protocol could make cell therapy a viable treatment. PMID- 26510717 TI - Resistance gene naming and numbering: is it a new gene or not? AB - In the genomic era, studying the epidemiology of individual antibiotic resistance genes and resistance gene discovery are open to all. However, the identification and naming of resistance genes is not currently understandable by all owing to a plethora of competing nomenclature systems, many of which do not comply with the basic rules of bacterial gene nomenclature. Change is needed urgently. Here, we make a case for the resistance research community to begin this process by agreeing on an answer to the question of when a new gene number should be assigned. This cut-off is of necessity arbitrary and we suggest a threshold value of >=2% difference in the sequences of the DNA, predicted protein or both as a realistic boundary for assigning a new gene number. This proposal can be a starting point for agreement or debate followed by renumbering of the affected gene families. PMID- 26510718 TI - Vascular access complications during outpatient parenteral antimicrobial therapy at home: a retrospective cohort study. AB - OBJECTIVES: The need for indwelling vascular access for outpatient parenteral antimicrobial therapy (OPAT) places patients at risk of vascular access complications. The purpose of this study was to describe vascular access complications during OPAT at home, and identify factors associated with their occurrence. METHODS: All OPAT courses carried out at home for patients at Cleveland Clinic in 2013 were identified from the institution's OPAT registry. The first OPAT course per patient was included. Vascular access complications that occurred during the treatment course were abstracted from the electronic medical record. Only complications that triggered a clinical intervention were included. RESULTS: The 1461 included OPAT courses encompassed 33,579 OPAT days of treatment. One-hundred-and-forty-four vascular access complications occurred in 131 OPAT courses (9% of OPAT courses, 4.29 complications per 1000 OPAT days). The most common complication was occlusion (53% of all complications). Hickman catheters [incidence rate ratio (IRR) 0.20, 95% CI 0.03-0.63] and indwelling ports (IRR 0.25, 95% CI 0.04-0.78) were associated with lower complication rates than peripherally inserted central catheters, as was increasing age (IRR 0.99, 95% CI 0.98-1.00). Log OPAT duration (IRR 1.60, 95% CI 1.28-2.03), female sex (IRR 1.62, 95% CI 1.16-2.28) and injection drug use (IRR 3.32, 1.16-7.46) were associated with increased risk of vascular access complications. CONCLUSIONS: Nine percent of OPAT courses at home have at least one vascular access complication requiring clinical intervention. Longer OPAT duration, younger age, female sex and injection drug use are associated with increased risk of vascular access complications. PMID- 26510719 TI - Designing quality of care--contributions from parents: Parents' experiences of care processes in paediatric care and their contribution to improvements of the care process in collaboration with healthcare professionals. AB - AIMS AND OBJECTIVES: The aim of this article was to explore whether current quality dimensions for health care services are sufficient to capture how parents perceive and contribute to quality of health care. BACKGROUND: New quality improvement initiatives that actively involve patients must be examined with a critical view on established quality dimensions to ensure that these measures support patient involvement. DESIGN: This paper used a qualitative and descriptive design. METHODS: This paper is based on interviews with parents participating in two experience-based co-design projects in a Swedish hospital that included qualitative content analysis of data from 12 parent interviews in paediatric care. RESULTS: Health care professionals often overemphasize their own significance for value creation in care processes and underappreciate parents' ability to influence and contribute to better quality. However, quality is not based solely on how professionals accomplish their task, but is co-created by health care professionals and parents. Consequently, assessment of quality outcomes also must include parents' ability and context. CONCLUSIONS: This paper questions current models of quality dimensions in health care, and suggests additional sub-dimensions, such as family quality and involvement quality. RELEVANCE TO CLINICAL PRACTICE: This paper underscores the importance of involving parents in health care improvements with health care professionals to capture as many dimensions of quality as possible. PMID- 26510720 TI - Long-term venous access insertion: 'the learning curve'. AB - BACKGROUND: The central venous access port device (CVAPD) provides reliable vascular access and is used for delivery of fluids and for obtaining blood samples. However, it can carry some intra- and post-operative complications such as thrombosis, pneumothorax, catheter fracture and port malposition. This article describes one surgeon's experience over a 16-year period and strategies to avoid complications. METHODS: The data were prospectively collected from 1996 to 2012 (16-year period). Collected data included age and gender of the patient, pathology, type of port used, anaesthetic type, side and site of insertion, and complications. RESULTS: A total of 958 devices were implanted. The average age of the patient was 57.8 years. Sixty-eight complications were recorded with an average complication rate of 7.1%. This rate decreased from 23% between 1996 and 1997 to 3.6% from 2010 to 2013. Venous thrombosis was the main source of complications with an incidence of 2.5%. This complication occurred in seven of the first 86 patients (8.1%, 1996-1998) and decreased to 1.9% between 2000 and 2013. Twenty infections (2%), five pneumothoraces secondary to insertion (0.5%), one port malposition (0.1%) and three fractures of the catheter (0.3%) occurred over the 16 years. CONCLUSION: The surgeon's complications of CVAPD insertion requiring removal or revision of the port were considerably reduced as the surgeon's experience increases. It is suggested that all surgeons whose practice includes CVAPD insertion will have an initial learning curve, and strategies described in this paper may help decrease the number of complications. PMID- 26510721 TI - Correction. PMID- 26510722 TI - Correction. PMID- 26510723 TI - An observational study to evaluate three pilot programmes of retesting chlamydia positive individuals within 6 months in the South West of England. AB - OBJECTIVES: To evaluate 3 pilot chlamydia retesting programmes in South West England which were initiated prior to the release of new National Chlamydia Screening Programme (NCSP) guidelines recommending retesting in 2014. METHODS: Individuals testing positive between August 2012 and July 2013 in Bristol (n=346), Cornwall (n=252) and Dorset (n=180) programmes were eligible for inclusion in the retesting pilots. The primary outcomes were retest within 6 months (yes/no) and repeat diagnosis at retest (yes/no), adjusted for area, age and gender. RESULTS: Overall 303/778 (39.0%) of participants were retested within 6 months and 31/299 (10.4%) were positive at retest. Females were more likely to retest than males and Dorset had higher retesting rates than the other areas. CONCLUSIONS: More than a third of those eligible were retested within the time frame of the study. Chlamydia retesting programmes appear feasible within the context of current programmes to identify individuals at continued risk of infection with relatively low resource and time input. PMID- 26510724 TI - Determinants of childhood morbidity in Bangladesh: evidence from the Demographic and Health Survey 2011. AB - OBJECTIVES: The present study aims to estimate the incidence of preventable infectious diseases or associated symptoms among young children in Bangladesh and also determine the factors affecting these conditions. The study hypothesised that various background characteristics of children as well as their parents influence the incidence of morbidity of children aged below 5 years. SETTING: The study used data from the most recent nationally representative cross-sectional Bangladesh Demographic and Health Survey (BDHS) conducted in 2011. PARTICIPANTS: A total of 7550 children aged below 5 years during the survey from mothers aged between 12 and 49 years are the participants of the study. RESULTS: In general, younger children were more likely to suffer from multiple health conditions than their older counterparts. Children belonging to households classified as poor (OR=1.425, 95% CI (1.130 to 1.796)) or middle (OR=1.349, 95% CI (1.113 to 1.636)) faced greater risk of illness than those from well-off households. A combination of source and treatment practices of drinking water showed a significant impact on incidence of childhood morbidity. Children from households using untreated non piped water were 85.8% (OR=1.860, 95% CI (1.269 to 2.728)) more likely to suffer from comorbidity than those who treat their piped drinking water. However, we observed that water treatment alone has no impact unless the water itself was sourced from a pipe. CONCLUSIONS: Accelerated programmes promoting access to safe drinking water along with water treatment practices, and better household environment may prove effective in reducing the incidence of childhood morbidity in Bangladesh. PMID- 26510725 TI - Double blind, randomised, placebo-controlled trial to evaluate the efficacy of esomeprazole to treat early onset pre-eclampsia (PIE Trial): a study protocol. AB - INTRODUCTION: Pre-eclampsia is a major complication of pregnancy, globally responsible for 60 000 maternal deaths per year, and far greater numbers of fetal losses. There is no definitive treatment other than delivery. A drug that can quench the disease process could be useful to treat early onset pre-eclampsia, as it could allow pregnancies to safely continue to a gestation where fetal outcomes are significantly improved. We have generated preclinical data to show esomeprazole, a proton pump inhibitor used for gastric reflux, has potent biological effects that makes it a worthwhile therapeutic candidate. Esomeprazole potently decreases soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin secretion from placenta and endothelial cells, and has biological actions to mitigate endothelial dysfunction and oxidative stress. METHODS AND ANALYSIS: We propose undertaking a phase II, double blind, randomised controlled clinical trial to examine whether administering 40 mg esomeprazole daily may prolong gestation in women with early onset pre-eclampsia. We will recruit 120 women (gestational age of 26+0 to 31+6 weeks) who will be randomised to receive either esomeprazole or an identical placebo. The primary outcome will be the number of days from randomisation to delivery. Secondary outcomes include maternal, fetal and neonatal composite and individual outcomes. Maternal outcomes include maternal death, eclampsia, pulmonary oedema, severe renal impairment, cerebral vascular events and liver haematoma or rupture. Neonatal outcomes include neonatal death within 6 weeks after the due date, intraventricular haemorrhage, necrotising enterocolitis and bronchopulmonary dysplasia. We will examine whether esomeprazole can decrease serum sFlt-1 and soluble endoglin levels and we will record the safety of esomeprazole in these pregnancies. ETHICS AND DISSEMINATION: This study has ethical approval (Protocol V.2.4, M14/09/038, Federal Wide assurance Number 00001372, IRB0005239), and is registered with NHREC (ID 3649) and the Pan African Clinical Trial Registry (PACTR201504000771349). Data will be presented at international conferences and published in peer reviewed journals. PMID- 26510726 TI - Identifying low-value clinical practices in critical care medicine: protocol for a scoping review. AB - INTRODUCTION: Reducing unnecessary, low-value clinical practice (ie, de-adoption) is key to improving value for money in healthcare, especially among patients admitted to intensive care units (ICUs) where resource consumption exceeds other medical and surgical populations. Research suggests that low-value clinical practices are common in medicine, however systematically and objectively identifying them is a widely cited barrier to de-adoption. We will conduct a scoping review to identify low-value clinical practices in adult critical care medicine that are candidates for de-adoption. METHODS AND ANALYSIS: We will systematically search the literature to identify all randomised controlled trials or systematic reviews that focus on diagnostic or therapeutic interventions in adult patients admitted to medical, surgical or specialty ICUs, and are published in 3 general medical journals with the highest impact factor (New England Journal of Medicine, The Lancet, Journal of the American Medical Association). 2 investigators will independently screen abstracts and full-text articles against inclusion criteria, and extract data from included citations. Included citations will be classified according to whether or not they represent a repeat examination of the given research question (ie, replication research), and whether the results are similar or contradictory to the original study. Studies with contradictory results will determine clinical practices that are candidates for de-adoption. ETHICS AND DISSEMINATION: Our scoping review will use robust methodology to systematically identify a list of clinical practices in adult critical care medicine with evidence supporting their de-adoption. In addition to adding to advancing the study of de-adoption, this review may also serve as the launching point for clinicians and researchers in critical care to begin reducing the number of low-value clinical practices. Dissemination of these results to relevant stakeholders will include tailored presentations at local, national and international meetings, and publication of a manuscript. Ethical approval is not required for this study. PMID- 26510727 TI - Safety and immunogenicity of novel respiratory syncytial virus (RSV) vaccines based on the RSV viral proteins F, N and M2-1 encoded by simian adenovirus (PanAd3-RSV) and MVA (MVA-RSV); protocol for an open-label, dose-escalation, single-centre, phase 1 clinical trial in healthy adults. AB - INTRODUCTION: Respiratory syncytial virus (RSV) infection causes respiratory disease throughout life, with infants and the elderly at risk of severe disease and death. RSV001 is a phase 1 (first-in-man), open-label, dose-escalation, clinical trial of novel genetic viral-vectored vaccine candidates PanAd3-RSV and modified vaccinia virus Ankara (MVA)-RSV. The objective of RSV001 is to characterise the (primary objective) safety and (secondary objective) immunogenicity of these vaccines in healthy younger and older adults. METHODS AND ANALYSIS: Heterologous and homologous 'prime'/boost combinations of PanAd3-RSV and single-dose MVA-RSV are evaluated in healthy adults. 40 healthy adults aged 18-50 years test one of four combinations of intramuscular (IM) or intranasal (IN) PanAd3-RSV prime and IM PanAd3 or IM MVA-RSV boost vaccination, starting at a low dose for safety. The following year an additional 30 healthy adults aged 60 75 years test either a single dose of IM MVA-RSV, one of three combinations of IN or IM PanAd3-RSV prime and PanAd3-RSV or MVA-RSV boost vaccination used in younger volunteers, and a non-vaccinated control group. Study participants are self-selected volunteers who satisfy the eligibility criteria and are assigned to study groups by sequential allocation. Safety assessment includes the daily recording of solicited and unsolicited adverse events for 1 week after vaccination, as well as visit (nursing) observations and safety bloods obtained at all scheduled attendances. Laboratory measures of RSV-specific humoral and cellular immune responses after vaccination will address the secondary end points. All study procedures are performed at the Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), Oxford, UK. ETHICS AND DISSEMINATION: RSV001 has clinical trial authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA) and ethics approval from NRES Berkshire (reference 13/SC/0023). All study procedures adhere to International Conference on Harmonisation (ICH) Good Clinical Practice guidelines. The results of the trial are to be published in peer-reviewed journals, conferences and academic forums. TRIAL REGISTRATION NUMBER: NCT01805921. PMID- 26510728 TI - Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts. AB - OBJECTIVE: To investigate differences between young children, adolescents and adults with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). STUDY DESIGN: Comparison of clinical cohorts from 8 paediatric and 27 adult CFS/ME services in the UK and a paediatric randomised controlled trial from the Netherlands. Outcome measures include: fatigue (the UK-Chalder Fatigue Scale); Disability (the UK-SF-36 physical function subscale; the Netherlands-CHQ-CF87); school attendance, pain, anxiety and depression (the UK-Hospital Anxiety & Depression Scale, Spence Children's Anxiety Scale; the Netherlands-Spielberger State-Trait Anxiety Inventory for Children, Children's Depression Inventory); symptoms; time-to-assessment; and body mass index. We used multinomial regression to compare younger (aged <12 years) and older (aged 12-18 years) children with adults, and logistic regression to compare UK and Dutch adolescents. RESULTS: Younger children had a more equal gender balance compared to adolescents and adults. Adults had more disability and fatigue, and had been ill for longer. Younger children were less likely to have cognitive symptoms (OR 0.18 (95% CI 0.13 to 0.25)) and more likely to present with a sore throat (OR 1.42 (1.07 to 1.90). Adolescents were more likely to have headaches (81.1%, OR 1.56 (1.36% to 1.80%)) and less likely to have tender lymph nodes, palpitations, dizziness, general malaise and pain, compared to adults. Adolescents were more likely to have comorbid depression (OR 1.51 (1.33 to 1.72)) and less likely to have anxiety (OR 0.46 (0.41 to 0.53)) compared to adults. CONCLUSIONS: Paediatricians need to recognise that children with CFS/ME present differently from adults. Whether these differences reflect an underlying aetiopathology requires further investigation. TRIAL REGISTRATION NUMBERS: FITNET trial registration numbers are ISRCTN59878666 and NCT00893438. This paper includes secondary (post-results) analysis of data from this trial, but are unrelated to trial outcomes. PMID- 26510729 TI - Prognosis of patients with dementia: results from a prospective nationwide registry linkage study in the Netherlands. AB - OBJECTIVE: To report mortality risks of dementia based on national hospital registry data, and to put these risks into perspective by comparing them with those in the general population and following cardiovascular diseases. DESIGN: Prospective cohort study from 1 January 2000 through 31 December 2010. SETTING: Hospital-based cohort. PARTICIPANTS: A nationwide hospital-based cohort of 59,201 patients with clinical diagnosis of dementia (admitted to a hospital or visiting a day clinic) was constructed (38.7% men, 81.4 years (SD 7.0)). MAIN OUTCOMES AND MEASURES: 1-year and 5-year age-specific and sex-specific mortality risks were reported for patients with dementia visiting a day clinic compared with the general population; for patients hospitalised with dementia compared with patients hospitalised for acute myocardial infarction (AMI), heart failure or stroke, these were presented as absolute and relative risks (RRs). RESULTS: 1 year mortality was 38.3% in men and 30.5% in women. 5-year risk was 65.4% and 58.5%, respectively. Mortality risks were significantly higher in patients with dementia admitted to the hospital than in those visiting a day clinic (1-year RR 3.29, 95% CI 3.16 to 3.42; and 5-year RR 1.79, 95% CI 1.76 to 1.83). Compared with the general population, mortality risks were significantly higher among patients visiting a day clinic (1-year RR for women 2.99, 95% CI 2.84 to 3.14; and for men 3.94, 95% CI 3.74 to 4.16). 5-year RRs were somewhat lower, but still significant. Results were more pronounced at younger ages. Mortality risks among admitted patients were comparable or even exceeded those of cardiovascular diseases (1-year RR for women with dementia vs AMI 1.24, 95% CI 1.19 to 1.29; vs heart failure 1.05, 95% CI 1.02 to 1.08; vs stroke 1.07, 95% CI 1.04 to 1.10). 5 year RRs were comparable. For men, RRs were slightly higher. CONCLUSIONS: Dementia has a poor prognosis as compared with other diseases and the general population. The risks among admitted patients even exceeded those following cardiovascular diseases. PMID- 26510730 TI - Multimorbidity in primary care: protocol of a national cross-sectional study in Switzerland. AB - INTRODUCTION: With the ageing of the population and the general improvement of care, an increasing number of people are living with multiple chronic health conditions or 'multimorbidity'. Multimorbidity often implies multiple medical treatments. As a consequence, the risk of adverse events and the time spent by patients for their treatments increase exponentially. In many cases, treatment guidelines traditionally defined for single conditions are not easily applicable. Primary care for individuals with multimorbidity requires complex patient-centred care and good communication between the patient and the general practitioner (GP). This often includes prioritising among the different chronic conditions. METHODS AND ANALYSIS: The main objectives of this study are to describe the burden related to multimorbidity (disease-related burden and burden of treatment) in primary care and to identify the factors influencing it. Other objectives include evaluating patients' perception of treatment burden and quality of life, assessing factors influencing that perception, and investigating prioritisation in the management of multimorbidity from the perspectives of GPs and patients. For this cross-sectional study, patient enrolment will take place in GP's private practices across Switzerland. A convenient sample of 100 GPs will participate; overall, 1000 patients with at least three chronic health conditions will be enrolled. Data will be collected as paper-based questionnaires for GPs and delayed telephone interview questionnaires for patients. GPs will provide demographic and practice-related data. In addition, each GP will complete a paper based questionnaire for each patient that they enrol. Each patient will complete a telephone interview questionnaire. ETHICS AND DISSEMINATION: This study has been approved by the research ethics committee of Canton Vaud, Switzerland (Protocol 315/14). The results of the study will be reported in international peer-reviewed journals. PMID- 26510731 TI - Validation of the multivariable In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) prediction rule within an all-payer inpatient administrative claims database. AB - OBJECTIVE: To validate the In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) prediction rule, in a database consisting only of inpatient claims. DESIGN: Retrospective claims database analysis. SETTING: The 2012 Healthcare Cost and Utilization Project National Inpatient Sample. PARTICIPANTS: Pulmonary embolism (PE) admissions were identified by an International Classification of Diseases, ninth edition (ICD-9) code either in the primary position or secondary position when accompanied by a primary code for a PE complication. The multivariable IMPACT rule, which includes age and 11 comorbidities, was used to estimate patients' probability of in-hospital mortality and classify them as low or higher risk (<=1.5% deemed low risk). PRIMARY AND SECONDARY OUTCOME MEASURES: The rule's sensitivity, specificity, positive and negative predictive values (PPV and NPV) and area under the receiver operating characteristic curve statistic for predicting in-hospital mortality with accompanying 95% CIs. RESULTS: A total of 34,108 admissions for PE were included, with a 3.4% in-hospital case-fatality rate. IMPACT classified 11, 025 (32.3%) patients as low risk, and low risk patients had lower in-hospital mortality (OR, 0.17, 95% CI 0.13 to 0.21), shorter length of stay (-1.2 days, p<0.001) and lower total treatment costs (-$3074, p<0.001) than patients classified as higher risk. IMPACT had a sensitivity of 92.4%, 95% CI 90.7 to 93.8 and specificity of 33.2%, 95% CI 32.7 to 33.7 for classifying mortality risk. It had a high NPV (>99%), low PPV (4.6%) and an AUC of 0.74, 95% CI 0.73 to 0.76. CONCLUSIONS: The IMPACT rule appeared valid when used in this all payer, inpatient only administrative claims database. Its high sensitivity and NPV suggest the probability of in-hospital death in those classified as low risk by IMPACT was minimal. PMID- 26510732 TI - Mental health in women 20-23 years after IVF treatment: a Swedish cross-sectional study. AB - OBJECTIVE: To assess self-perceived mental health in women treated with in vitro fertilisation (IVF) 20-23 years previously, while comparing them to a reference group, and to determine any differences in mental health between those who had given birth, those who had adopted a child, those who had given birth and adopted a child and those who remained childless. DESIGN: A cross-sectional study. SETTING: A Center of Reproductive Medicine (RMC) at a Swedish University hospital. PARTICIPANTS: 520 women who had undergone at least one IVF cycle at the University Hospital in Linkoping between 1986 and 1989. 504 of 520 women (97%) were eligible for follow-up. While 34 women declined, 93 per cent (n=470) of the women agreed to participate. The reference group consisted of 150 women of the Swedish population included in a study that was used to validate the Symptom CheckList (SCL)-90. INTERVENTIONS: Follow-up was conducted in 2008-2009. The SCL 90 was used to measure the women's self-perceived mental health and a questionnaire specific for this study was used to retain demographic information. OUTCOME MEASURES: The SCL-90 assesses 9 primary dimensions; somatisation, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation and psychoticism. There is also a global index of distress. RESULTS: Women who had previously undergone IVF treatment were at increased risk of symptoms of depression (p=0.017), obsessive-compulsion (p=0.02) and somatisation (p<=0.001) when compared to a reference group. In addition, the women who have remained childless are at increased risk of symptoms of depression (p=0.009) and phobic anxiety (p=0.017). CONCLUSIONS: The majority of the women who have been treated with IVF 20-23 years previously appear to be in good mental health. However, women who remain childless and/or without partner after unsuccessful infertility treatment constitute a vulnerable group even later on in life. PMID- 26510733 TI - Changes in government spending on healthcare and population mortality in the European union, 1995-2010: a cross-sectional ecological study. AB - OBJECTIVE: Economic measures such as unemployment and gross domestic product are correlated with changes in health outcomes. We aimed to examine the effects of changes in government healthcare spending, an increasingly important measure given constrained government budgets in several European Union countries. DESIGN: Multivariate regression analysis was used to assess the effect of changes in healthcare spending as a proportion of total government expenditure, government healthcare spending as a proportion of gross domestic product and government healthcare spending measured in purchasing power parity per capita, on five mortality indicators. Additional variables were controlled for to ensure robustness of data. One to five year lag analyses were conducted. SETTING AND PARTICIPANTS: European Union countries 1995-2010. MAIN OUTCOME MEASURES: Neonatal mortality, postneonatal mortality, one to five years of age mortality, under five years of age mortality, adult male mortality, adult female mortality. RESULTS: A 1% decrease in government healthcare spending was associated with significant increase in all mortality metrics: neonatal mortality (coefficient -0.1217, p = 0.0001), postneonatal mortality (coefficient -0.0499, p = 0.0018), one to five years of age mortality (coefficient -0.0185, p = 0.0002), under five years of age mortality (coefficient -0.1897, p = 0.0003), adult male mortality (coefficient 2.5398, p = 0.0000) and adult female mortality (coefficient -1.4492, p = 0.0000). One per cent decrease in healthcare spending, measured as a proportion of gross domestic product and in purchasing power parity, was both associated with significant increases (p < 0.05) in all metrics. Five years after the 1% decrease in healthcare spending, significant increases (p < 0.05) continued to be observed in all mortality metrics. CONCLUSIONS: Decreased government healthcare spending is associated with increased population mortality in the short and long term. Policy interventions implemented in response to the financial crisis may be associated with worsening population health. PMID- 26510734 TI - Proteomics in the genome engineering era. AB - Genome engineering experiments used to be lengthy, inefficient, and often expensive, preventing a widespread adoption of such experiments for the full assessment of endogenous protein functions. With the revolutionary clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 technology, genome engineering became accessible to the broad life sciences community and is now implemented in several research areas. One particular field that can benefit significantly from this evolution is proteomics where a substantial impact on experimental design and general proteome biology can be expected. In this review, we describe the main applications of genome engineering in proteomics, including the use of engineered disease models and endogenous epitope tagging. In addition, we provide an overview on current literature and highlight important considerations when launching genome engineering technologies in proteomics workflows. PMID- 26510735 TI - Surfactant protein-D attenuates the lipopolysaccharide-induced inflammation in human intestinal cells overexpressing toll-like receptor 4. AB - PURPOSE: Necrotizing enterocolitis (NEC) is a devastating inflammatory disease of preterm infants that may depend on overexpression of toll-like receptor-4 (TLR4) in the immature intestine. Surfactant protein (SP)-D is a member of the collectin family and plays an important role in innate immunity, particularly in the airways. Although SP-D also exists in the intestines, little is known about its function. This study investigated whether SP-D can attenuate the inflammatory response of TLR4-overexpressing embryonal intestinal cells. METHODS: All experimental procedures were performed using the human intestinal cell line INT407 originally derived from human embryonal intestines. Platelet-activating factor (PAF), reported to be elevated in NEC patients, was used to induce TLR4 overexpression in the human embryonal intestinal cell line INT407. TLR4 expression was measured using quantitative real-time PCR. Inflammatory responses to PAF (5 uM), the TLR4 agonist lipopolysaccharide (LPS, 100 ng/ml), PAF + LPS, and PAF + LPS following SP-D pretreatment (20 ug/ml) were assessed by enzyme linked immunosorbent assay (ELISA) of interleukin-8 (IL-8) release (in pg/ml). RESULTS: Expression of TLR4 mRNA (mean +/- SD) was upregulated by PAF (369 % +/- 28 %, p < 0.001). Stimulation with PAF + LPS resulted in higher IL-8 release (1959.3 +/- 52.3) than control (141.2 +/- 12.4), LPS (167.3 +/- 65.8), or PAF (1527.2 +/- 129.4) treatment (p < 0.05). Release in response to PAF + LPS (1590.1 +/- 319.3) was attenuated by SP-D pretreatment (1161.6 +/- 131.6; p < 0.05). CONCLUSION: SP-D attenuates LPS-induced IL-8 production in TLR4-overexpressing intestinal cells, suggesting that SP-D may have a protective effect in the development of NEC in preterm infants. PMID- 26510736 TI - Use of anoctamin 1 (ANO1) to evaluate interstitial cells of Cajal in Hirschsprung's disease. AB - PURPOSE: Interstitial cells of Cajal (ICCs) are pacemaker cells involved in facilitating neurotransmission and the generation of slow electrical waves necessary for colonic peristalsis. Their distribution has been found to be abnormal in the aganglionic and ganglionic colon in Hirschsprung's disease (HSCR) using c-kit-labelling. Anoctamin-1 (ANO1) is a Ca(2+)-activated Cl(-) channel thought to be specifically expressed on ICCs. Unlike c-kit, it plays a key role in ICC pacemaker activity. We aimed to investigate the utility of ANO1 in evaluating the colonic ICC network in HSCR. MATERIALS AND METHODS: We collected full-length pull-through specimens from children with HSCR (n = 10). Control colon specimens were collected at colostomy closure in children with anorectal malformation (n = 6). The distribution of ANO1 and c-kit expression was evaluated using immunofluorescence and confocal microscopy. ANO1 expression was quantified using Western blot analysis. RESULTS: ANO1 was not expressed on 23 % of c-kit immuno-positive cells in the circular muscle; however, 100 % of ANO1-positive ICCs were c-kit positive. The distribution of ANO1-positive ICCs was sparse in aganglionic colon, with a modest reduction in ICCs seen in the ganglionic colon in HSCR compared to controls (p = 0.044). ANO1 protein expression was reduced in aganglionic colon but similar in ganglionic colon relative to controls. CONCLUSIONS: ANO1 is preferential to c-kit in evaluating the ICC network in HSCR due to its specificity and functional importance. Abnormal distribution of ANO1 positive ICCs in the ganglionic colon in HSCR may contribute to persistent bowel symptoms in some patients after pull-through surgery. PMID- 26510737 TI - Influence of hypoxia-dependent factors on the progression of neuroblastoma. AB - PURPOSE: Several oxygen-dependent factors, e.g., CAIX (carbonic anhydrase IX) or phosphoglycerate kinase 1 (PGK1) interacting with the CXCR4/SDF1 axis (chemokine receptor 4/stromal cell derived factor 1) have been shown to be involved in processes of tumour pathology including tumourigenicity, tumour cell dissemination and poor survival in several solid tumour entities. The aim of the current study was to evaluate the influence of the hypoxia-inducible factors CAIX and PGK1 on progression of neuroblastoma and to evaluate the clinical relevance of possible therapeutic approaches. METHODS: Expression of hypoxia-dependent factors PGK1 and CAIX was examined in neuroblastoma specimen, was correlated with clinical parameters, and was studied in neuroblastoma cells. The impact of these hypoxic factors was evaluated by proliferation assays under targeted therapy. RESULTS: Expression of hypoxia-dependent factors was found in 50 % of neuroblastoma specimen. In neuroblastoma cells, CAIX and PGK1 expression is up regulated under hypoxia and correlates with response to targeted anti proliferative treatment. The negative impact on survival, although significant for both CAIX and PGk1, appears to be stronger for CAIX. CONCLUSIONS: Our results show that the hypoxic factors in the tumour's microenvironment further the progression of tumour disease. This strengthens the perspectives for additive novel therapeutic approaches targeting hypoxia-dependent factors in this childhood disease. PMID- 26510738 TI - Bioaugmentation with isolated strains for the removal of toxic and refractory organics from coking wastewater in a membrane bioreactor. AB - The bioaugmentation strains for phenol, pyridine, quinoline, carbazole, and naphthalene degradation were employed to treat coking wastewater in a membrane bioreactor (MBR). The results showed that the bioaugmented MBR was much better in pollutant removal than that of the control MBR with conventional activated sludge. Compared to the control MBR, the bioaugmented MBR displayed an additional 3.2 mg/L of phenol, pyridine, quinoline, naphthalene and carbazole in total by the addition of the degrading strains. Also, about 10 % of the chemical oxygen demand in the effluent was further removed by the bioaugmentation. The pyrosequencing analysis of the sludge in the MBRs revealed that the microbial community shifted in response to the addition of the degrading strains. The diversity of the microbial community increased during the bioaugmentation, and some bacterial taxa favorable to the removal of toxic and refractory pollutants appeared in the bioaugmented MBR. The results indicated that the use of high efficiency bacteria was a feasible method for industrial coking wastewater treatment. PMID- 26510739 TI - Perinatal Influences of Valproate on Brain and Behaviour: An Animal Model for Autism. AB - Valproic acid or valproate (VPA) is an anti-convulsant and mood stabiliser effective in treating epilepsy and bipolar disorders. Although in adults VPA is well tolerated and safe, there is convincing evidence that it has teratogenic properties, ranging from mild neurodevelopmental changes to severe congenital malformations. In particular, studies involving humans and other animals have shown that prenatal exposure to VPA can induce developmental abnormalities reminiscent of autism spectrum disorder (ASD). In this chapter, we discuss the connection between VPA and ASD, evaluate the VPA animal model of ASD, and describe the possible molecular mechanisms underlying VPA's teratogenic properties. PMID- 26510740 TI - Postnatal Phencyclidine (PCP) as a Neurodevelopmental Animal Model of Schizophrenia Pathophysiology and Symptomatology: A Review. AB - Cognitive dysfunction and negative symptoms of schizophrenia remain an unmet clinical need. Therefore, it is essential that new treatments and approaches are developed to recover the cognitive and social impairments that are seen in patients with schizophrenia. These may only be discovered through the use of carefully validated, aetiologically relevant and translational animal models. With recent renewed interest in the neurodevelopmental hypothesis of schizophrenia, postnatal administration of N-methyl-D-aspartate receptor (NMDAR) antagonists such as phencyclidine (PCP) has been proposed as a model that can mimic aspects of schizophrenia pathophysiology. The purpose of the current review is to examine the validity of this model and compare it with the adult subchronic PCP model. We review the ability of postnatal PCP administration to produce behaviours (specifically cognitive deficits) and neuropathology of relevance to schizophrenia and their subsequent reversal by pharmacological treatments. We review studies investigating effects of postnatal PCP on cognitive domains in schizophrenia in rats. Morris water maze and delayed spontaneous alternation tasks have been used for working memory, attentional set-shifting for executive function, social novelty discrimination for selective attention and prepulse inhibition of acoustic startle for sensorimotor gating. In addition, we review studies on locomotor activity and neuropathology. We also include two studies using dual hit models incorporating postnatal PCP and two studies on social behaviour deficits following postnatal PCP. Overall, the evidence we provide supports the use of postnatal PCP to model cognitive and neuropathological disturbances of relevance to schizophrenia. To date, there is a lack of evidence to support a significant advantage of postnatal PCP over the adult subchronic PCP model and full advantage has not been taken of its neurodevelopmental component. When thoroughly characterised, it is likely that it will provide a useful neurodevelopmental model to complement other models such as maternal immune activation, particularly when combined with other manipulations to produce dual or triple hit models. However, the developmental trajectory of behavioural and neuropathological changes induced by postnatal PCP and their relevance to schizophrenia must be carefully mapped out. Overall, we support further development of dual (or triple) hit models incorporating genetic, neurodevelopmental and appropriate environmental elements in the search for more aetiologically valid animal models of schizophrenia and neurodevelopmental disorders (NDDs). PMID- 26510741 TI - Altered Blood Gene Expression of Tumor-Related Genes (PRKCB, BECN1, and CDKN2A) in Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common of the neurodegenerative diseases. Recent diagnostic criteria have defined a preclinical disease phase during which neuropathological substrates are thought to be present in the brain. There is an urgent need to find measurable alterations in this phase as well as a good peripheral biomarker in the blood. We selected a cohort of 100 subjects (controls = 47; preclinical AD = 11; patients with AD = 42) and analyzed whole blood expression of 20 genes by quantitative polymerase chain reaction. The selected genes belonged to calcium signaling, senescence and autophagy, and mitochondria/oxidative stress pathways. Additionally, two genes associated with an increased risk of developing AD (clusterin (CLU) and bridging integrator 1 (BIN1)) were also analyzed. We detected significantly different gene expressions of BECN1 and PRKCB between the control and the AD groups and of CDKN2A between the control and the preclinical AD groups. Notably, these three genes are also considered tumor suppressor (CDKN2A and BECN1) or tumor promoter (PRKCB) genes. Gene-gene expression Pearson correlations were computed separately for controls and patients with AD. The significant correlations (p < 0.001) were represented in a network analysis with Cytoscape tool, which suggested an uncoupling of mitochondria-related genes in AD group. Whole blood is emerging as a valuable tissue in the study of the physiopathology of AD. PMID- 26510743 TI - Experimental Neonatal Sepsis Causes Long-Term Cognitive Impairment. AB - Neonatal sepsis is a major cause of morbidity and mortality in neonatal intensive care units. Treatment with antibiotics reduces mortality and morbidity, but neonatal sepsis remains a serious life-threatening condition. The objective of this study was to evaluate cognitive impairment in adult mice submitted to sepsis in the neonatal period. To this aim, 2-day-old male C57BL/6 mice were submitted to sepsis by injection of 25 MUg of LPS. Sixty days after, the learning and memory were evaluated. It was observed that the mice submitted to neonatal sepsis presented impairment of habituation, aversive, and object recognition memories, and had an increase of immobility time in forced swimming test in adulthood. In conclusion, this study shows that the neonatal sepsis causes long-term brain alterations. These alterations can persist to adulthood in an animal model due to a vulnerability of the developing brain. PMID- 26510742 TI - Astrocytic CCAAT/Enhancer-Binding Protein Delta Contributes to Glial Scar Formation and Impairs Functional Recovery After Spinal Cord Injury. AB - After spinal cord injury, inflammatory reaction induces the aggregation of astrocytes to form a glial scar that eventually blocks axonal regeneration. Transcription factor CCAAT/enhancer-binding protein delta (C/EBPdelta) is a regulatory protein of genes responsive to inflammatory factors, but its role in glial scar formation after spinal cord injury remains unknown. By using a model of moderate spinal cord contusion injury at the mid-thoracic level, we found that C/EBPdelta was expressed mostly in the reactive astrocytes bordering the lesion in wild-type mice from 7 days after the injury. C/EBPdelta-deficient mice showed reduced glial scar formation, more residual white matter, and better motor function recovery compared with wild-type mice 28 days after the injury. Upon interleukin (IL)-1beta stimulation in vitro, the increased expression of C/EBPdelta in reactive astrocytes inhibited RhoA expression and, subsequently, the ability of astrocyte migration. However, these reactive astrocytes also produced an increased amount of matrix metalloproteinase-3, which promoted the migration of non-IL-1beta-treated, inactive astrocytes. Although the involvement of other non-astroglial C/EBPdelta cannot be entirely excluded, our studies suggest that astrocytic C/EBPdelta is integral to the inflammatory cascades leading to glial scar formation after spinal cord injury. PMID- 26510744 TI - Genome-wide identification and characterization of the apple (Malus domestica) HECT ubiquitin-protein ligase family and expression analysis of their responsiveness to abiotic stresses. AB - The ubiquitin-protein ligases (E3s) directly participate in ubiquitin (Ub) transferring to the target proteins in the ubiquitination pathway. The HECT ubiquitin-protein ligase (UPL), one type of E3s, is characterized as containing a conserved HECT domain of approximately 350 amino acids in the C terminus. Some UPLs were found to be involved in trichome development and leaf senescence in Arabidopsis. However, studies on plant UPLs, such as characteristics of the protein structure, predicted functional motifs of the HECT domain, and the regulatory expression of UPLs have all been limited. Here, we present genome-wide identification of the genes encoding UPLs (HECT gene) in apple. The 13 genes (named as MdUPL1-MdUPL13) from ten different chromosomes were divided into four groups by phylogenetic analysis. Among these groups, the encoding genes in the intron-exon structure and the included additional functional domains were quite different. Notably, the F-box domain was first found in MdUPL7 in plant UPLs. The HECT domain in different MdUPL groups also presented different spatial features and three types of conservative motifs were identified. The promoters of each MdUPL member carried multiple stress-response related elements by cis-acting element analysis. Experimental results demonstrated that the expressions of several MdUPLs were quite sensitive to cold-, drought-, and salt-stresses by qRT PCR assay. The results of this study helped to elucidate the functions of HECT proteins, especially in Rosaceae plants. PMID- 26510745 TI - Rapid HIV Screening in an Urban Jail: How Testing at Exit With Linkage to Community Care Can Address Perceived Barriers. AB - Despite recommendations from the CDC, only 36 % of jails offer routine HIV screening to inmates. Our purpose was to explore the feasibility of rapid HIV testing at release from an urban jail, and to identify potential barriers to this process. This project was incorporated into an established partnership between the jail, local academic medical center, and local public health department. We offered rapid HIV testing at the time of release to 507 jail inmates over a 7 week period of 2013. Three hundred and two (60 %) inmates elected testing. All participating inmates received individual test counseling, HIV prevention education, and linkage to care in the community prior to release. All tested inmates received results before release; one inmate screened positive for HIV and was linked to care. Previous HIV testing was the most frequently cited reason given (60 %) among the 205 inmates who declined at the time of the study. Utilizing the partnership between the jail, public health, and an academic medical center, we found that rapid HIV testing at exit was feasible and acceptable in this urban jail setting and could provide immediate linkage to care for those in need. PMID- 26510746 TI - Process and Outcomes From a Youth-Led Campaign to Address Healthy Eating in an Urban High School. AB - This article describes a pilot youth advocacy initiative for obesity prevention informed by social cognitive theory, social network theory, and theories of community mobilization. With assistance from school and health leaders, adolescent-aged youth led a cafeteria food labeling and social marketing campaign. We implemented an anonymous survey 2 weeks prior to and again at the conclusion of the campaign, and used cafeteria records to track servings of fruits and vegetables. The campaign resulted in a significant increase in youths' confidence to identify healthy foods (OR 1.97, 95 % CI 1.01, 3.84, p = .048), and a significant increase in per person per day servings of fruits (0.02, p = .03) and vegetables (0.01, p = .02). The results of our pilot were promising, and the integration of concepts from multiple theories benefited the implementation process. Obesity prevention initiatives should include strategies that encourage youth to create health promotion community networks and lead changes to their social and physical environments. PMID- 26510747 TI - [Patellofemoral instability]. PMID- 26510750 TI - Opposite correlations between cation disordering and amorphization resistance in spinels versus pyrochlores. AB - Understanding and predicting radiation damage evolution in complex materials is crucial for developing next-generation nuclear energy sources. Here, using a combination of ion beam irradiation, transmission electron microscopy and X-ray diffraction, we show that, contrary to the behaviour observed in pyrochlores, the amorphization resistance of spinel compounds correlates directly with the energy to disorder the structure. Using a combination of atomistic simulation techniques, we ascribe this behaviour to structural defects on the cation sublattice that are present in spinel but not in pyrochlore. Specifically, because of these structural defects, there are kinetic pathways for the relaxation of disorder in spinel that are absent in pyrochlore. This leads to a direct correlation between amorphization resistance and disordering energetics in spinel, the opposite of that observed in pyrochlores. These results provide new insight into the origins of amorphization resistance in complex oxides beyond fluorite derivatives. PMID- 26510752 TI - Radiology Quality Measure Compliance Reporting: an Automated Approach. AB - As part of its ongoing effort to improve healthcare quality, the Center of Medicare and Medicaid Services (CMS) has transitioned from monetary rewards to reimbursement penalties for noncompliance or nonparticipation with its quality measurement initiatives. More specifically, eligible providers who bill for CMS patient care, such as radiologists, will face a 2 % negative payment adjustment, if they fail to report adequate participation and compliance with sufficient CMS quality measures in 2015. Although several methods exist to report participation and compliance, each method requires the gathering of relevant studies and assessing the reports for compliance. To aid in this data gathering and to prevent reduced reimbursements, radiology groups should consider implementing automated processes to monitor compliance with these quality measure standards. This article describes one method of creating an automated report scanner, utilizing an open source interface engine called Mirth Connect, that may facilitate the data gathering and monitoring related to reporting compliance with CMS standard #195 Stenosis measurement in Ultrasound Carotid Imaging Reports. The process described in this article is currently utilized by a large multi institutional radiology group to assess for report compliance and offers the user near real time surveillance of compliance with the quality measure. PMID- 26510751 TI - Circulating levels of plasminogen and oxidized phospholipids bound to plasminogen distinguish between atherothrombotic and non-atherothrombotic myocardial infarction. AB - Oxidized phospholipids (OxPL) are abundant in atherosclerotic plaques. They are also bound to circulating plasminogen after myocardial infarction (MI), and their binding to plasminogen may accentuate fibrinolysis. We sought to assess whether circulating levels of plasminogen and OxPL bound to plasminogen (OxPL-PLG) increase following acute MI and whether this increase differs between atherothrombotic (Type 1) and non-atherothrombotic (Type 2) MI. We measured circulating levels of plasminogen and OxPL-PLG at 0, 6, 24, 48 h, and >3 months (stable state) following acute MI and following an angiogram for stable coronary artery disease (CAD). Forty-nine subjects met the criteria for acute MI, of whom 34 had clearly defined atherothrombotic (n = 22) or non-atherothrombotic (n = 12) MI; 15 patients met the criteria for stable CAD. Mean baseline levels of plasminogen and OxPL-PLG were lower in the acute MI group than in the stable CAD group (9.75 vs 20.2, p < 0.0001 for plasminogen and 165.5 vs 275.1, p = 0.0002 for OxPL-PLG) and did not change over time or between time points, including the 3-month follow-up. Mean baseline levels of plasminogen and OxPL-PLG were also lower in atherothrombotic (Type 1) than in non-atherothrombotic (Type 2) MI subjects (8.65 vs 12.1, p < 0.03 for plasminogen and 164.5 vs 245.7, p = 0.02 for OxPL-PLG), and this relationship did not change over time or between time points. Plasminogen and OxPL-PLG were lower in patients presenting with an acute MI than in those with stable CAD and also in those with atherothrombotic MI (Type 1) vs. those with non-atherothrombotic MI (Type 2). These findings persisted at a median follow-up of 3 months post-MI. The association of plasminogen and OxPL-PLG with acute MI, particularly atherothrombotic MI (Type 1), could reflect a reduced fibrinolytic capacity, associated with an increased risk of atherothrombotic events differentiating stable CAD from unstable CAD and atherothrombotic MI (Type 1) from non-atherothrombotic MI (Type 2). Additional study with a larger sample size is warranted. PMID- 26510753 TI - Online Error Reporting for Managing Quality Control Within Radiology. AB - Information technology systems within health care, such as picture archiving and communication system (PACS) in radiology, can have a positive impact on production but can also risk compromising quality. The widespread use of PACS has removed the previous feedback loop between radiologists and technologists. Instead of direct communication of quality discrepancies found for an examination, the radiologist submitted a paper-based quality-control report. A web-based issue-reporting tool can help restore some of the feedback loop and also provide possibilities for more detailed analysis of submitted errors. The purpose of this study was to evaluate the hypothesis that data from use of an online error reporting software for quality control can focus our efforts within our department. For the 372,258 radiologic examinations conducted during the 6 month period study, 930 errors (390 exam protocol, 390 exam validation, and 150 exam technique) were submitted, corresponding to an error rate of 0.25 %. Within the category exam protocol, technologist documentation had the highest number of submitted errors in ultrasonography (77 errors [44 %]), while imaging protocol errors were the highest subtype error for computed tomography modality (35 errors [18 %]). Positioning and incorrect accession had the highest errors in the exam technique and exam validation error category, respectively, for nearly all of the modalities. An error rate less than 1 % could signify a system with a very high quality; however, a more likely explanation is that not all errors were detected or reported. Furthermore, staff reception of the error reporting system could also affect the reporting rate. PMID- 26510754 TI - Roux-en-Y Esophagojejunostomy Ameliorates Renal Function Through Reduction of Renal Inflammatory and Fibrotic Markers in Diabetic Nephropathy. AB - BACKGROUND: Roux-en-Y bariatric surgery has been shown to have a remarkable and sustainable improvement in type 2 diabetes. Recent clinical studies have shown that bariatric surgery can improve or halt the development of diabetic microvascular complications such as nephropathy. However, the exact underlying mechanisms of surgical procedures are unknown. Here, we have investigated the effects of Roux-en-Y esophagojejunostomy (RYEJ) on renal function and inflammation and fibrosis biomarkers for renal injury in type 2 diabetic rats. METHODS: Sprague-Dawley rats with high fat diet and streptozotocin (STZ)-induced diabetes were randomly assigned into four groups: diabetic nephropathy (DN), DN treated with food restriction (DN-FR), DN treated with RYEJ surgery (DN-RYEJ), and DN-RYEJ sham (n = 6/group). Age-matched normal rats were assigned as control group. RYEJ and sham surgeries were performed. Hyperinsulinemic-euglycemic clamps with tracer infusion were completed to assess insulin sensitivity. Twenty-four hour urine albumin excretion rate (UAER) and glomerular filtration rate (GFR) were measured. The renal pathological injury was assessed by hematoxylin and eosin (HE) staining. Kidney messenger RNA (mRNA) and/or protein content/distribution of phospho-c-Jun NH2-terminal kinase (JNK), monocyte chemoattractant protein (MCP)-1, transforming growth factor (TGF)-beta1, and mitogen-activated protein kinase phosphatase 5 (MKP5) were evaluated by real-time PCR and/or Western blotting/immunohistochemistry. RESULTS: Roux-en-Y esophagojejunostomy improved insulin sensitivity. RYEJ ameliorated renal function by improving UAER and GFR and attenuated glomerular hypertrophy after surgery. RYEJ also significantly downregulated the levels of JNK-mediated inflammatory response and upregulated the level of the anti-inflammatory mediator MKP5. CONCLUSION: Roux-en-Y esophagojejunostomy alleviates insulin resistance. RYEJ surgery ameliorated renal function and attenuated glomerular hypertrophy in a DN rat model. The considerable nephroprotective function may be mainly attributed to the reduced inflammatory and fibrotic biomarkers after RYEJ. The improvements in renal function and inflammation are not wholly dependent on the magnitude of weight loss. PMID- 26510755 TI - Effect of Statin Therapy in 4-Year-Old Dichorionic Diamniotic Twins with Familial Hypercholesterolemia Showing Multiple Xanthomas. AB - Familial hypercholesterolemia (FH) is characterized by a high level of low density lipoprotein cholesterol (LDL-C) and is inherited as an autosomal dominant trait. We report 4-year-old dichorionic diamniotic twins (boy and girl) with FH who presented with multiple xanthomas on the face, both knees, both feet, and buttocks. Family history revealed vertical transmission of hypercholesterolemia from father to patients, thereby suggesting dominant inheritance. Lipid data of their mother did not match the criteria of FH. However, lipid data of maternal grandmother and maternal sister matched the criteria of FH. LDL receptor gene analysis of the family revealed that their father was heterozygous for a missense mutation, L547V, their mother was heterozygous for a nonsense mutation, C675X, and patients were compound heterozygous for L547V and C675X. After 10 months of treatment with pitavastatin (2 mg/day) and ezetimibe (10 mg/day), LDL-C decreased from 595 mg/dL to 267 mg/dL in the boy and from 530 mg/dL to 182 mg/dL in the girl. These findings suggest that lipid-lowering therapy with statin may be considered in pediatric patients with compound heterozygous FH (hetero FH) before inducing LDL apheresis, and gene analysis for true diagnosis in pediatric patients with multiple xanthomas should be considered, though they appear to be hetero FH from the family history and lipid data of parents. PMID- 26510757 TI - Development of internal models and predictive abilities for visual tracking during childhood. AB - The prediction of the consequences of our own actions through internal models is an essential component of motor control. Previous studies showed improvement of anticipatory behaviors with age for grasping, drawing, and postural control. Since these actions require visual and proprioceptive feedback, these improvements might reflect both the development of internal models and the feedback control. In contrast, visual tracking of a temporarily invisible target gives specific markers of prediction and internal models for eye movements. Therefore, we recorded eye movements in 50 children (aged 5-19 yr) and in 10 adults, who were asked to pursue a visual target that is temporarily blanked. Results show that the youngest children (5-7 yr) have a general oculomotor behavior in this task, qualitatively similar to the one observed in adults. However, the overall performance of older subjects in terms of accuracy at target reappearance and variability in their behavior was much better than the youngest children. This late maturation of predictive mechanisms with age was reflected into the development of the accuracy of the internal models governing the synergy between the saccadic and pursuit systems with age. Altogether, we hypothesize that the maturation of the interaction between smooth pursuit and saccades that relies on internal models of the eye and target displacement is related to the continuous maturation of the cerebellum. PMID- 26510756 TI - Mechanisms of deep brain stimulation. AB - Deep brain stimulation (DBS) is widely used for the treatment of movement disorders including Parkinson's disease, essential tremor, and dystonia and, to a lesser extent, certain treatment-resistant neuropsychiatric disorders including obsessive-compulsive disorder. Rather than a single unifying mechanism, DBS likely acts via several, nonexclusive mechanisms including local and network-wide electrical and neurochemical effects of stimulation, modulation of oscillatory activity, synaptic plasticity, and, potentially, neuroprotection and neurogenesis. These different mechanisms vary in importance depending on the condition being treated and the target being stimulated. Here we review each of these in turn and illustrate how an understanding of these mechanisms is inspiring next-generation approaches to DBS. PMID- 26510758 TI - Calcium-induced calcium release supports recruitment of synaptic vesicles in auditory hair cells. AB - Hair cells from auditory and vestibular systems transmit continuous sound and balance information to the central nervous system through the release of synaptic vesicles at ribbon synapses. The high activity experienced by hair cells requires a unique mechanism to sustain recruitment and replenishment of synaptic vesicles for continuous release. Using pre- and postsynaptic electrophysiological recordings, we explored the potential contribution of calcium-induced calcium release (CICR) in modulating the recruitment of vesicles to auditory hair cell ribbon synapses. Pharmacological manipulation of CICR with agents targeting endoplasmic reticulum calcium stores reduced both spontaneous postsynaptic multiunit activity and the frequency of excitatory postsynaptic currents (EPSCs). Pharmacological treatments had no effect on hair cell resting potential or activation curves for calcium and potassium channels. However, these drugs exerted a reduction in vesicle release measured by dual-sine capacitance methods. In addition, calcium substitution by barium reduced release efficacy by delaying release onset and diminishing vesicle recruitment. Together these results demonstrate a role for calcium stores in hair cell ribbon synaptic transmission and suggest a novel contribution of CICR in hair cell vesicle recruitment. We hypothesize that calcium entry via calcium channels is tightly regulated to control timing of vesicle fusion at the synapse, whereas CICR is used to maintain a tonic calcium signal to modulate vesicle trafficking. PMID- 26510759 TI - Computational modeling of neurons: intensity-duration relationship of extracellular electrical stimulation for changes in intracellular calcium. AB - In many instances of extensive nerve damage, the injured nerve never adequately heals, leaving lack of nerve function. Electrical stimulation (ES) has been shown to increase the rate and orient the direction of neurite growth, and is a promising therapy. However, the mechanism in which ES affects neuronal growth is not understood, making it difficult to compare existing ES protocols or to design and optimize new protocols. We hypothesize that ES acts by elevating intracellular calcium concentration ([Ca(2+)]i) via opening voltage-dependent Ca(2+) channels (VDCCs). In this work, we have created a computer model to estimate the ES Ca(2+) relationship. Using COMSOL Multiphysics, we modeled a small dorsal root ganglion (DRG) neuron that includes one Na(+) channel, two K(+) channels, and three VDCCs to estimate [Ca(2+)]i in the soma and growth cone. As expected, the results show that an ES that generates action potentials (APs) can efficiently raise the [Ca(2+)]i of neurons. More interestingly, our simulation results show that sub-AP ES can efficiently raise neuronal [Ca(2+)]i and that specific high-voltage ES can preferentially raise [Ca(2+)]i in the growth cone. The intensities and durations of ES on modeled growth cone calcium rise are consistent with directionality and orientation of growth cones experimentally shown by others. Finally, this model provides a basis to design experimental ES pulse parameters, including duration, intensity, pulse-train frequency, and pulse train duration to efficiently raise [Ca(2+)]i in neuronal somas or growth cones. PMID- 26510760 TI - Vision is superior to touch in shape perception even with equivalent peripheral input. AB - Results from previous studies suggest that two-dimensional spatial patterns are processed similarly in vision and touch when the patterns are equated for effective size or when visual stimuli are blurred to mimic the spatial filtering of the skin. In the present study, we measured subjects' ability to perceive the shape of familiar and unfamiliar visual and tactile patterns to compare form processing in the two modalities. As had been previously done, the two dimensional tactile and visual patterns were adjusted in size to stimulate an equivalent number of receptors in the two modalities. We also distorted the visual patterns, using a filter that accurately mimics the spatial filtering effected by the skin to further equate the peripheral images in the two modalities. We found that vision consistently outperformed touch regardless of the precise perceptual task and of how familiar the patterns were. Based on an examination of both the earlier and present data, we conclude that visual processing of both familiar and unfamiliar two-dimensional patterns is superior to its tactile counterpart except under very restricted conditions. PMID- 26510761 TI - Presynaptic GluN2D receptors detect glutamate spillover and regulate cerebellar GABA release. AB - Glutamate directly activates N-methyl-d-aspartate (NMDA) receptors on presynaptic inhibitory interneurons and enhances GABA release, altering the excitatory inhibitory balance within a neuronal circuit. However, which class of NMDA receptors is involved in the detection of glutamate spillover is not known. GluN2D subunit-containing NMDA receptors are ideal candidates as they exhibit a high affinity for glutamate. We now show that cerebellar stellate cells express both GluN2B and GluN2D NMDA receptor subunits. Genetic deletion of GluN2D subunits prevented a physiologically relevant, stimulation-induced, lasting increase in GABA release from stellate cells [long-term potentiation of inhibitory transmission (I-LTP)]. NMDA receptors are tetramers composed of two GluN1 subunits associated to either two identical subunits (di-heteromeric receptors) or to two different subunits (tri-heteromeric receptors). To determine whether tri-heteromeric GluN2B/2D NMDA receptors mediate I-LTP, we tested the prediction that deletion of GluN2D converts tri-heteromeric GluN2B/2D to di heteromeric GluN2B NMDA receptors. We find that prolonged stimulation rescued I LTP in GluN2D knockout mice, and this was abolished by GluN2B receptor blockers that failed to prevent I-LTP in wild-type mice. Therefore, NMDA receptors that contain both GluN2D and GluN2B mediate the induction of I-LTP. Because these receptors are not present in the soma and dendrites, presynaptic tri-heteromeric GluN2B/2D NMDA receptors in inhibitory interneurons are likely to mediate the cross talk between excitatory and inhibitory transmission. PMID- 26510762 TI - A geometric model of defensive peripersonal space. AB - Potentially harmful stimuli occurring within the defensive peripersonal space (DPPS), a protective area surrounding the body, elicit stronger defensive reactions. The spatial features of the DPPS are poorly defined and limited to descriptive estimates of its extent along a single dimension. Here we postulated a family of geometric models of the DPPS, to address two important questions with respect to its spatial features: What is its fine-grained topography? How does the nervous system represent the body area to be defended? As a measure of the DPPS, we used the strength of the defensive blink reflex elicited by electrical stimulation of the hand (hand-blink reflex, HBR), which is reliably modulated by the position of the stimulated hand in egocentric coordinates. We tested the goodness of fit of the postulated models to HBR data from six experiments in which we systematically explored the HBR modulation by hand position in both head centered and body-centered coordinates. The best-fitting model indicated that 1) the nervous system's representation of the body area defended by the HBR can be approximated by a half-ellipsoid centered on the face and 2) the DPPS extending from this area has the shape of a bubble elongated along the vertical axis. Finally, the empirical observation that the HBR is modulated by hand position in head-centered coordinates indicates that the DPPS is anchored to the face. The modeling approach described in this article can be generalized to describe the spatial modulation of any defensive response. PMID- 26510763 TI - When brain damage "improves" perception: neglect patients can localize motion shifted probes better than controls. AB - When we look at bars flashed against a moving background, we see them displaced in the direction of the upcoming motion (flash-grab illusion). It is still debated whether these motion-induced position shifts are low-level, reflexive consequences of stimulus motion or high-level compensation engaged only when the stimulus is tracked with attention. To investigate whether attention is a causal factor for this striking illusory position shift, we evaluated the flash-grab illusion in six patients with damaged attentional networks in the right hemisphere and signs of left visual neglect and six age-matched controls. With stimuli in the top, right, and bottom visual fields, neglect patients experienced the same amount of illusion as controls. However, patients showed no significant shift when the test was presented in their left hemifield, despite having equally precise judgments. Thus, paradoxically, neglect patients perceived the position of the flash more veridically in their neglected hemifield. These results suggest that impaired attentional processes can reduce the interaction between a moving background and a superimposed stationary flash, and indicate that attention is a critical factor in generating the illusory motion-induced shifts of location. PMID- 26510764 TI - Kinase-KCC2 coupling: Cl- rheostasis, disease susceptibility, therapeutic target. AB - The intracellular concentration of Cl(-) ([Cl(-)]i) in neurons is a highly regulated variable that is established and modulated by the finely tuned activity of the KCC2 cotransporter. Despite the importance of KCC2 for neurophysiology and its role in multiple neuropsychiatric diseases, our knowledge of the transporter's regulatory mechanisms is incomplete. Recent studies suggest that the phosphorylation state of KCC2 at specific residues in its cytoplasmic COOH terminus, such as Ser940 and Thr906/Thr1007, encodes discrete levels of transporter activity that elicit graded changes in neuronal Cl(-) extrusion to modulate the strength of synaptic inhibition via Cl(-)-permeable GABAA receptors. In this review, we propose that the functional and physical coupling of KCC2 to Cl(-)-sensitive kinase(s), such as the WNK1-SPAK kinase complex, constitutes a molecular "rheostat" that regulates [Cl(-)]i and thereby influences the functional plasticity of GABA. The rapid reversibility of (de)phosphorylation facilitates regulatory precision, and multisite phosphorylation allows for the control of KCC2 activity by different inputs via distinct or partially overlapping upstream signaling cascades that may become more or less important depending on the physiological context. While this adaptation mechanism is highly suited to maintaining homeostasis, its adjustable set points may render it vulnerable to perturbation and dysregulation. Finally, we suggest that pharmacological modulation of this kinase-KCC2 rheostat might be a particularly efficacious strategy to enhance Cl(-) extrusion and therapeutically restore GABA inhibition. PMID- 26510765 TI - The temporal dynamics of heading perception in the presence of moving objects. AB - Many forms of locomotion rely on the ability to accurately perceive one's direction of locomotion (i.e., heading) based on optic flow. Although accurate in rigid environments, heading judgments may be biased when independently moving objects are present. The aim of this study was to systematically investigate the conditions in which moving objects influence heading perception, with a focus on the temporal dynamics and the mechanisms underlying this bias. Subjects viewed stimuli simulating linear self-motion in the presence of a moving object and judged their direction of heading. Experiments 1 and 2 revealed that heading perception is biased when the object crosses or almost crosses the observer's future path toward the end of the trial, but not when the object crosses earlier in the trial. Nonetheless, heading perception is not based entirely on the instantaneous optic flow toward the end of the trial. This was demonstrated in Experiment 3 by varying the portion of the earlier part of the trial leading up to the last frame that was presented to subjects. When the stimulus duration was long enough to include the part of the trial before the moving object crossed the observer's path, heading judgments were less biased. The findings suggest that heading perception is affected by the temporal evolution of optic flow. The time course of dorsal medial superior temporal area (MSTd) neuron responses may play a crucial role in perceiving heading in the presence of moving objects, a property not captured by many existing models. PMID- 26510767 TI - Heme Oxygenase-1 Suppresses Bovine Viral Diarrhoea Virus Replication in vitro. AB - Viral cycle progression depends upon host-cell processes in infected cells, and this is true for bovine viral diarrhoea virus (BVDV), the causative agent of BVD that is a worldwide threat to the bovine industry. Heme oxygenase-1 (HO-1) is a ubiquitously expressed inducible isoform of the first and rate-limiting enzyme for heme degradation. Recent studies have demonstrated that HO-1 has significant antiviral properties, inhibiting the replication of viruses such as ebola virus, human immunodeficiency virus, hepatitis C virus, and porcine reproductive and respiratory syndrome virus. However, the function of HO-1 in BVDV infection is unclear. In the present study, the relationship between HO-1 and BVDV was investigated. In vitro analysis of HO-1 expression in BVDV-infected MDBK cells demonstrated that a decrease in HO-1 as BVDV replication increased. Increasing HO 1 expression through adenoviral-mediated overexpression or induction with cobalt protoporphyrin (CoPP, a potent HO-1 inducer), pre- and postinfection, effectively inhibited BVDV replication. In contrast, HO-1 siRNA knockdown in BVDV-infected cells increased BVDV replication. Therefore, the data were consistent with HO-1 acting as an anti-viral factor and these findings suggested that induction of HO 1 may be a useful prevention and treatment strategy against BVDV infection. PMID- 26510769 TI - An analytic model for accurate spring constant calibration of rectangular atomic force microscope cantilevers. AB - Spring constant calibration of the atomic force microscope (AFM) cantilever is of fundamental importance for quantifying the force between the AFM cantilever tip and the sample. The calibration within the framework of thin plate theory undoubtedly has a higher accuracy and broader scope than that within the well established beam theory. However, thin plate theory-based accurate analytic determination of the constant has been perceived as an extremely difficult issue. In this paper, we implement the thin plate theory-based analytic modeling for the static behavior of rectangular AFM cantilevers, which reveals that the three dimensional effect and Poisson effect play important roles in accurate determination of the spring constants. A quantitative scaling law is found that the normalized spring constant depends only on the Poisson's ratio, normalized dimension and normalized load coordinate. Both the literature and our refined finite element model validate the present results. The developed model is expected to serve as the benchmark for accurate calibration of rectangular AFM cantilevers. PMID- 26510768 TI - A comparison of the leaf gel extracts of Aloe ferox and Aloe vera in the topical treatment of atopic dermatitis in Balb/c mice. AB - Aloe vera gel is widely used in the treatment of an array of disturbances, especially skin disorders. The wound-healing effects have been attributed to its moisturizing and anti-inflammatory effects as well as its beneficial effect on the maturation of collagen. The aim of the present study is to compare the effects of topically applied extracts of Aloe ferox with that of Aloe vera on the symptoms as well as IgE levels of a mouse model of atopic dermatitis (AD). Mice were sensitized and challenged with 2,4-dinitrochlorobenzene and treated afterwards for 10 consecutive days with the gels of either A. ferox or A. vera applied topically to the affected areas. A placebo gel was used for the control mice. Blood was collected at the beginning and end of the treatment period to measure serum IgE levels. Although the gels of both the Aloe species inhibited the cutaneous inflammatory response as well as serum IgE levels in the rats, the extracts of A. ferox were superior to that of A. vera in reducing IgE levels. The gels of A. ferox and A. vera, applied topically, may be a safe and useful alternative to antihistamines and topical corticosteroids, for the treatment of patients suffering from recurring chronic AD. PMID- 26510770 TI - Childhood Atopic Dermatitis in Taiwan. AB - The prevalence of atopic dermatitis (AD) appears to have increased dramatically over the past decades. It is generally believed that such rapid increase in prevalence cannot be explained fully by genetic factors. Environmental factors might play a role in such an increment. Children with AD are most likely to suffer considerable school absences, family stress, and health care expenditures. Because the onset of AD occurs relatively early in life, identification of early life risk factors and early management for AD to prevent the development of atopic march are of critical importance. However, there is still no consensus on coordinated prevention and management for AD in Taiwan. In this review, we discuss the specific risk factors of AD and important results of recent articles on AD from Taiwan. The management and prevention strategies of AD for Asian skin are also discussed. PMID- 26510771 TI - Difference in nasolabial features between awake and asleep infants with unilateral cleft lip: Anthropometric measurements using three-dimensional stereophotogrammetry. AB - PURPOSE: Cleft lip repair is performed in the supine position, tilting the head back under general anesthesia. However, postoperative results are evaluated in the upright position while patients are awake. The purpose of this study was to anthropometrically assess whether nasolabial features of infants with unilateral cleft lip are influenced by posture and anesthesia. MATERIAL AND METHODS: Three dimensional facial images in a preoperative upright position and operating supine position under general anesthesia were captured from 51 consecutive infants with unilateral cleft lip. Twenty-four indirect anthropometric measurements (11 for the nose and 13 for the lip elements) were considered on each infant. RESULTS: In the supine position under general anesthesia, alar surface distance was significantly shorter (p < 0.001). Regarding lip measurements, medial lip height of the cleft side and philtrum height were significantly smaller (p < 0.05 and p < 0.05, respectively), whereas vermilion height was greater (p < 0.01). In addition, the cleft width and lip width were significantly broader (p < 0.001 and p < 0.001, respectively) after general anesthesia. CONCLUSIONS: Several nasolabial alteration patterns are found after general anesthesia that are presumably attributable to cessation of nasal breathing and the action of muscle relaxation. Surgeons should take these nasolabial changes into account during preoperative planning and postoperative assessment. PMID- 26510772 TI - Synergistic antidepressant-like effect of the joint administration of caffeine and NMDA receptor ligands in the forced swim test in mice. AB - The optimal treatment of depressed patients remains one of the most important challenges concerning depression. The identification of the best treatment strategies and development of new, safer, and more effective agents are crucial. The glutamatergic system seems to be a promising drug target, and consequently the use of the NMDA receptor ligands, particularly in co-administration with other substances exerting the antidepressant activity, has emerged among the new ideas. The objective of this study was to examine the effect of caffeine on the performance of mice treated with various NMDA modulators in the forced swim test. We demonstrated a significant interaction between caffeine (5 mg/kg) and the following NMDA receptor ligands: MK-801 (an antagonist binding in the ion channel, 0.05 mg/kg), CGP 37849 (an antagonist of the glutamate site, 0.312 mg/kg), L-701,324 (an antagonist of the glycine site, 1 mg/kg), and D-cycloserine (a high-efficacy partial agonist of the glycine site, 2.5 mg/kg), while the interaction between caffeine and the inorganic modulators, i.e., Zn(2+) (2.5 mg/kg) and Mg(2+) (10 mg/kg), was not considered as significant. Based on the obtained results, the simultaneous blockage of the adenosine and NMDA receptors may be a promising target in the development of new antidepressants. PMID- 26510773 TI - Comparison of clinical outcomes between total knee arthroplasty and unicompartmental knee arthroplasty for osteoarthritis of the knee: a retrospective analysis of preoperative and postoperative results. AB - BACKGROUND: Excellent results have recently been reported for both total knee arthroplasty (TKA) and unicompartmental knee arthroplasty (UKA), but there have been few reports about which has a better long-term outcome. The preoperative and postoperative results of TKA and UKA for osteoarthritis of the knee were thus compared. METHODS: The results of 48 patients who underwent TKA and 25 patients who underwent UKA were evaluated based on clinical scores and survivorship in the middle long-term period. Preoperative, latest postoperative, and changes in the femoro-tibial angle (FTA), range of motion (ROM), Japanese Orthopedic Association score (JOA score), and Japanese Knee Osteoarthritis Measure (JKOM) were compared. The patients' mean age was 73 years. The mean follow-up period was 9 years (TKA: mean, 10.5 years; range, 7-12 years; UKA: mean, 9 years; range, 6-11 years). RESULTS: Preoperative FTA and ROM were significantly higher in the UKA group than in the TKA group. Total changes in all scores were similar among the two groups, as were changes in scores for all JOA and JKOM domains. The cumulative revision rate was higher for UKA than for TKA (7 versus 4%). Kaplan-Meier survivorship at 10 years was 84% for UKA and 92% for TKA. CONCLUSIONS: This clinical study found no significant differences between TKA and UKA, except in long-term survivorship. PMID- 26510774 TI - Dual-Modality Photoacoustic and Ultrasound Imaging System for Noninvasive Sentinel Lymph Node Detection in Patients with Breast Cancer. AB - The detection of regional lymph node metastases is important in cancer staging as it guides the prognosis of the patient and the strategy for treatment. Sentinel lymph node biopsy (SLNB) is an accurate, less invasive alternative to axillary lymph node dissection. The sentinel lymph node hypothesis states that the pathological status of the axilla can be accurately predicted by determining the status of the first lymph nodes that drain from the primary tumor. Physicians use radio-labeled sulfur colloid and/or methylene blue dye to identify the SLN, which is most likely to contain metastatic cancer cells. However, the surgical procedure causes morbidity and associated expenses. To overcome these limitations, we developed a dual-modality photoacoustic and ultrasonic imaging system to noninvasively detect SLNs based on the accumulation of methylene blue dye. Ultimately, we aim to guide percutaneous needle biopsies and provide a minimally invasive method for axillary staging of breast cancer. PMID- 26510775 TI - Using Videogame Apps to Assess Gains in Adolescents' Substance Use Knowledge: New Opportunities for Evaluating Intervention Exposure and Content Mastery. AB - BACKGROUND: Videogame interventions are becoming increasingly popular as a means to engage people in behavioral interventions; however, strategies for examining data from such interventions have not been developed. OBJECTIVE: The objective of this study was to describe how a technology-based intervention can yield meaningful, objective evidence of intervention exposure within a behavioral intervention. This study demonstrates the analysis of automatic log files, created by software from a videogame intervention, that catalog game play and, as proof of concept, the association of these data with changes in substance use knowledge as documented with standardized assessments. METHODS: We analyzed 3- and 6-month follow-up data from 166 participants enrolled in a randomized controlled trial evaluating a videogame intervention, PlayForward: Elm City Stories (PlayForward). PlayForward is a videogame developed as a risk reduction and prevention program targeting HIV risk behaviors (substance use and sex) in young minority adolescents. Log files were analyzed to extract the total amount of time spent playing the videogame intervention and the total number of game levels completed and beaten by each player. RESULTS: Completing and beating more of the game levels, and not total game play time, was related to higher substance use knowledge scores at the 3- (P=.001) and 6-month (P=.001) follow-ups. CONCLUSIONS: Our findings highlight the potential contributions a videogame intervention can make to the study of health behavior change. Specifically, the use of objective data collected during game play can address challenges in traditional human-delivered behavioral interventions. TRIAL REGISTRATION: Clinicaltrials.gov NCT01666496; https://clinicaltrials.gov/ct2/show/NCT01666496 (Archived by WebCite at http://www.webcitation.org/6cV9fxsOg). PMID- 26510776 TI - The effects of a novel aliphatic-chain hydroxamate derivative WMJ-S-001 in HCT116 colorectal cancer cell death. AB - Hydroxamate derivatives have attracted considerable attention due to their broad pharmacological properties and have been extensively investigated. We recently demonstrated that WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory and anti-angiogenic activities. In this study, we explored the underlying mechanisms by which WMJ-S-001 induces HCT116 colorectal cancer cell death. WMJ-S-001 inhibited cell proliferation and induced cell apoptosis in HCT116 cells. These actions were associated with AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK) activation, p53 phosphorylation and acetylation, as well as the modulation of p21(cip/Waf1), cyclin D1, survivin and Bax. AMPK-p38MAPK signaling blockade reduced WMJ-S-001 induced p53 phosphorylation. Transfection with AMPK dominant negative mutant (DN) reduced WMJ-S-001's effects on p53 and Sp1 binding to the survivn promoter region. Transfection with HDAC3-Flag or HDAC4-Flag also abrogated WMJ-S-001's enhancing effect on p53 acetylation. WMJ-S-001's actions on p21(cip/Waf1), cyclin D1, survivin, Bax were reduced in p53-null HCT116 cells. Furthermore, WMJ-S-001 was shown to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. In summary, the death of HCT116 colorectal cancer cells exposed to WMJ-S 001 may involve AMPK-p38MAPK-p53-survivin cascade. These results support the role of WMJ-S-001 as a potential drug candidate and warrant the clinical development in the treatment of cancer. PMID- 26510777 TI - Trends in cause-specific mortality in Chinese provinces. PMID- 26510778 TI - Cause-specific mortality for 240 causes in China during 1990-2013: a systematic subnational analysis for the Global Burden of Disease Study 2013. AB - BACKGROUND: China has experienced a remarkable epidemiological and demographic transition during the past three decades. Far less is known about this transition at the subnational level. Timely and accurate assessment of the provincial burden of disease is needed for evidence-based priority setting at the local level in China. METHODS: Following the methods of the Global Burden of Disease Study 2013 (GBD 2013), we have systematically analysed all available demographic and epidemiological data sources for China at the provincial level. We developed methods to aggregate county-level surveillance data to inform provincial-level analysis, and we used local data to develop specific garbage code redistribution procedures for China. We assessed levels of and trends in all-cause mortality, causes of death, and years of life lost (YLL) in all 33 province-level administrative units in mainland China, all of which we refer to as provinces, for the years between 1990 and 2013. FINDINGS: All provinces in mainland China have made substantial strides to improve life expectancy at birth between 1990 and 2013. Increases ranged from 4.0 years in Hebei province to 14.2 years in Tibet. Improvements in female life expectancy exceeded those in male life expectancy in all provinces except Shanghai, Macao, and Hong Kong. We saw significant heterogeneity among provinces in life expectancy at birth and probability of death at ages 0-14, 15-49, and 50-74 years. Such heterogeneity is also present in cause of death structures between sexes and provinces. From 1990 to 2013, leading causes of YLLs changed substantially. In 1990, 16 of 33 provinces had lower respiratory infections or preterm birth complications as the leading causes of YLLs. 15 provinces had cerebrovascular disease and two (Hong Kong and Macao) had ischaemic heart disease. By 2013, 27 provinces had cerebrovascular disease as the leading cause, five had ischaemic heart disease, and one had lung cancer (Hong Kong). Road injuries have become a top ten cause of death in all provinces in mainland China. The most common non-communicable diseases, including ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and cancers (liver, stomach, and lung), contributed much more to YLLs in 2013 compared with 1990. INTERPRETATION: Rapid transitions are occurring across China, but the leading health problems and the challenges imposed on the health system by epidemiological and demographic change differ between groups of Chinese provinces. Localised health policies need to be implemented to tackle the diverse challenges faced by local health-care systems. FUNDING: China National Science & Technology Pillar Program 2013 (2013BAI04B02) and Bill & Melinda Gates Foundation. PMID- 26510779 TI - Reducing child mortality in China: successes and challenges. PMID- 26510781 TI - Egibacter rhizosphaerae gen. nov., sp. nov., an obligately halophilic, facultatively alkaliphilic actinobacterium and proposal of Egibaceraceae fam. nov. and Egibacterales ord. nov. AB - A novel obligately halophilic, facultatively alkaliphilic actinobacterium, designated EGI 80759T, was isolated from the rhizosphere of Tamarix hispida Willd, Karamay, Xinjiang province, north-west China. Cells of strain EGI 80759T were Gram-stain-positive, non-motile and non-endospore-forming rods. Strain EGI 80759T showed obligately halophilic growth with a tolerance to 8-25 % (w/v) NaCl (optimum growth at 10-12 %, w/v) and facultatively alkaliphilic growth within the pH range 7.0-11.0 (optimum growth at pH 9.0-10.0). Cell-wall hydrolysates of the isolate contained meso-diaminopimelic acid (peptidoglycan type A1gamma), with glucose, glucosamine, ribose and mannose as the major sugars. The major fatty acids identified were 10-methyl-C17 : 0, C17 : 1omega8c and C17 : 0. The predominant menaquinone was MK-9(H4). The G+C content of the genomic DNA was 72.1 mol%. Phylogenetic analysis, based on 16S rRNA gene sequences, revealed that strain EGI 80759T clustered with members of the class Nitriliruptoria and showed highest 16S rRNA gene sequence similarities with Euzebya tangerina F10T (90.3 %) and Nitriliruptor alkaliphilus ANL-iso2T (88.1 %). On the basis of the data obtained from phenotypic and chemotaxonomic studies and the phylogenetic analysis, the isolate is proposed to be a representative of a novel genus and a novel species, Egibacter rhizosphaerae gen. nov., sp. nov., of a proposed novel family, Egibacteraceae fam. nov., and order, Egibacterales ord. nov., within the class Nitriliruptoria. The type strain of the type species, Egibacter rhizosphaerae, is EGI 80759T ( = CGMCC 1.14997T = KCTC 39588T). PMID- 26510780 TI - Under-5 mortality in 2851 Chinese counties, 1996-2012: a subnational assessment of achieving MDG 4 goals in China. AB - BACKGROUND: In the past two decades, the under-5 mortality rate in China has fallen substantially, but progress with regards to the Millennium Development Goal (MDG) 4 at the subnational level has not been quantified. We aimed to estimate under-5 mortality rates in mainland China for the years 1970 to 2012. METHODS: We estimated the under-5 mortality rate for 31 provinces in mainland China between 1970 and 2013 with data from censuses, surveys, surveillance sites, and disease surveillance points. We estimated under-5 mortality rates for 2851 counties in China from 1996 to 2012 with the reported child mortality numbers from the Annual Report System on Maternal and Child Health. We used a small area mortality estimation model, spatiotemporal smoothing, and Gaussian process regression to synthesise data and generate consistent provincial and county-level estimates. We compared progress at the county level with what was expected on the basis of income and educational attainment using an econometric model. We computed Gini coefficients to study the inequality of under-5 mortality rates across counties. FINDINGS: In 2012, the lowest provincial level under-5 mortality rate in China was about five per 1000 livebirths, lower than in Canada, New Zealand, and the USA. The highest provincial level under-5 mortality rate in China was higher than that of Bangladesh. 29 provinces achieved a decrease in under-5 mortality rates twice as fast as the MDG 4 target rate; only two provinces will not achieve MDG 4 by 2015. Although some counties in China have under-5 mortality rates similar to those in the most developed nations in 2012, some have similar rates to those recorded in Burkina Faso and Cameroon. Despite wide differences, the inter-county Gini coefficient has been decreasing. Improvement in maternal education and the economic boom have contributed to the fall in child mortality; more than 60% of the counties in China had rates of decline in under-5 mortality rates significantly faster than expected. Fast reduction in under-5 mortality rates have been recorded not only in the Han population, the dominant ethnic majority in China, but also in the minority populations. All top ten minority groups in terms of population sizes have experienced annual reductions in under-5 mortality rates faster than the MDG 4 target at 4.4%. INTERPRETATION: The reduction of under-5 mortality rates in China at the country, provincial, and county level is an extraordinary success story. Reductions of under-5 mortality rates faster than 8.8% (twice MDG 4 pace) are possible. Extremely rapid declines seem to be related to public policy in addition to socioeconomic progress. Lessons from successful counties should prove valuable for China to intensify efforts for those with unacceptably high under-5 mortality rates. FUNDING: National "Twelfth Five-Year" Plan for Science and Technology Support, National Health and Family Planning Commission of The People's Republic of China, Program for Changjiang Scholars and Innovative Research Team in University, the National Institute on Aging, and the Bill & Melinda Gates Foundation. PMID- 26510782 TI - Multiscale morphology design of hybrid halide perovskites through a polymeric template. AB - Hybrid halide perovskites have emerged as promising active constituents of next generation solution processable optoelectronic devices. During their assembling process, perovskite components undergo very complex dynamic equilibria starting in solution and progressing throughout film formation. Finding a methodology to control and affect these equilibria, responsible for the unique morphological diversity observed in perovskite films, constitutes a fundamental step towards a reproducible material processability. Here we propose the exploitation of polymer matrices as cooperative assembling components of novel perovskite CH3NH3PbI3 : polymer composites, in which the control of the chemical interactions in solution allows a predictable tuning of the final film morphology. We reveal that the nature of the interactions between perovskite precursors and polymer functional groups, probed by Nuclear Magnetic Resonance (NMR) spectroscopy and Dynamic Light Scattering (DLS) techniques, allows the control of aggregates in solution whose characteristics are strictly maintained in the solid film, and permits the formation of nanostructures that are inaccessible to conventional perovskite depositions. These results demonstrate how the fundamental chemistry of perovskite precursors in solution has a paramount influence on controlling and monitoring the final morphology of CH3NH3PbI3 (MAPbI3) thin films, foreseeing the possibility of designing perovskite : polymer composites targeting diverse optoelectronic applications. PMID- 26510784 TI - Sex differences in the blood antioxidant defense system in juvenile rats with various genetic predispositions to hypertension. AB - This study investigated the contribution of blood oxidative stress (OS) to the development of hypertension, as well as sex differences in the antioxidant defense system (ADS) in genetic models of hypertension. Nine-week-old normotensive Wistar-Kyoto (WKY) rats, borderline hypertensive rats (BHR) and spontaneously hypertensive rats (SHR) of both sexes were used. Systolic blood pressure (SBP) was determined by tail-cuff plethysmography, the trolox equivalent antioxidant capacity (TEAC) and the concentration of lipid peroxides (LP) were determined in plasma. The activity of the antioxidant enzymes Cu/Zn-superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) was determined in erythrocytes. SBP was significantly elevated in BHR and SHR in both sexes. BHR and SHR males had a higher SBP than the respective females. Sex-dependent differences in the ADS were found only in SHR, in which TEAC, SOD and CAT were significantly higher in males than in females. No differences in TEAC, SOD, CAT and GPx were observed between BHR (males and females) and WKY controls. LP levels were similar in all the groups investigated. Significant positive correlations were observed between SBP and both SOD and CAT. TEAC correlated positively with SOD and LP. As no signs of oxidative damage to lipids were found in young BHR and SHR of either sex, OS in the blood does not seem to be causatively related to the development of hypertension in these rats. However, despite activated antioxidant defenses, the positive correlation between plasma TEAC and LP suggests that oxidative damage is progressing slowly and therefore it seems to be a consequence rather than the cause of hypertension. PMID- 26510783 TI - Maternal clinic and home blood pressure measurements during pregnancy and infant birth weight: the BOSHI study. AB - This prospective cohort study compared measurements of maternal home blood pressure (HBP) with clinic blood pressure (CBP) before 20 weeks' gestation to determine associations with the risk of delivering a lower birth weight infant. A total of 605 Japanese women were included. Exposures were initial CBP, made between 10 weeks 0 days and 19 weeks 0 days, and HBP for comparison made within 1 week of CBP. Outcome was infant's birth weight, categorized and ranked as follows: ?3500 g, 3000-3499 g, 2500-2999 g and <2500 g. The proportional odds model with possible confounding factors was applied to compare the associations between CBP and HBP on infant birth weight. When both CBP and HBP were included simultaneously, the adjusted odds ratios (ORs) per 1 standard deviation (1s.d.) increase in clinic and home diastolic BP (DBP) were 1.06 (95% confidence interval (CI): 0.87-1.30) and 1.28 (95% CI: 1.04-1.58), respectively. The adjusted ORs per 1s.d. increase in clinic and home mean arterial pressure (MAP) were 1.02 (95% CI: 0.83-1.24) and 1.29 (95% CI: 1.04-1.59), respectively. Systolic BP measurement was not associated with infant birth weight. In conclusion, high maternal home DBP and MAP before 20 weeks' gestation was associated with a higher risk of lower infant birth weight than clinic DBP and MAP. Therefore, in addition to CBP, it may be worth having pregnant women measure HBP to determine the risk of lower infant birth weight. PMID- 26510785 TI - Home blood pressure level and decline in renal function among treated hypertensive patients: the J-HOME-Morning Study. AB - We examined the association between home and office blood pressure (BP) levels and further decline in renal function among treated hypertensive patients with and without renal dysfunction. We calculated annual decline in estimated glomerular filtration rate (DeltaeGFR) in 1535 treated hypertensive patients with home and office BP measurements. We defined DeltaeGFR <0 as decline in renal function, and DeltaeGFR ?0 as non-decline in renal function based on 1.5 years of follow-up. For 520 patients with low eGFR at baseline, morning home, evening home and office systolic BP (SBP) levels and morning home diastolic BP (DBP) levels were positively associated with the risk of decline in renal function (trend P=0.003, 0.002, 0.003 and 0.004). Compared to patients with home SBP <125 mm Hg, the risk of decline in renal function was higher in those with home SBPs ?135 mm Hg and between 130-135 mm Hg, while the risk was similar in those with home SBP of 125-130 mm Hg. For 1015 patients with normal eGFR at baseline, only morning home SBP level was positively associated with the risk of decline in renal function (trend P=0.004). Morning home BP might be useful for risk evaluation of decline in renal function even among treated hypertensive patients with normal renal function. Target levels of home BP control among treated hypertensive patients need to be further investigated. PMID- 26510786 TI - The potential therapeutic value for bereaved relatives participating in research: An exploratory study. AB - OBJECTIVE: Conducting research with the bereaved presents an immediate ethical challenge, as they are undoubtedly a vulnerable group, associated with high levels of distress and susceptible to both physical and mental health issues. A comprehensive understanding of the potential therapeutic benefits for bereaved relatives participating in palliative care research is limited, and therefore the ethics of engaging this group remain questionable. METHOD: This paper describes a secondary analysis of qualitative data collected in the Care of the Dying Evaluation (CODE) project, examining the experiences of patients who died at home. It explores the motivations and potential benefits for bereaved relatives participating in research with reference to the recently developed concepts in bereavement theory. Cognitive interviews were conducted with 15 bereaved relatives and secondary analysis using a content analysis framework was employed to classify the data. RESULTS: The results center around six recurring concepts identified as adaptive in current bereavement theory: an opportunity to share the narrative accounts of the final hours of their relative's life; a search for sense and meaning in loss; an ongoing bond/attachment with the deceased; altruistic motivations; oscillation between loss and restorative orientations; and a sense of resilience. Overall, the participants found that taking part in the research was valuable and that it could be described as offering therapeutic benefits. SIGNIFICANCE OF RESULTS: The need for bereaved relatives to take part in research studies should be encouraged, as they provide an accurate proxy for the patient's experience of end-of-life care while also providing a valuable account of their own perspective as family member and carer. In addition, we highlight the need for ethics committees to be aware of the potential benefits for bereaved relatives participating in research of this kind. PMID- 26510787 TI - Cell Differentiation and Spatial Organization in Yeast Colonies: Role of Cell Wall Integrity Pathway. AB - Many microbial communities contain organized patterns of cell types, yet relatively little is known about the mechanism or function of this organization. In colonies of the budding yeast Saccharomyces cerevisiae, sporulation occurs in a highly organized pattern, with a top layer of sporulating cells sharply separated from an underlying layer of nonsporulating cells. A mutant screen identified the Mpk1 and Bck1 kinases of the cell-wall integrity (CWI) pathway as specifically required for sporulation in colonies. The CWI pathway was induced as colonies matured, and a target of this pathway, the Rlm1 transcription factor, was activated specifically in the nonsporulating cell layer, here termed feeder cells. Rlm1 stimulates permeabilization of feeder cells and promotes sporulation in an overlying cell layer through a cell-nonautonomous mechanism. The relative fraction of the colony apportioned to feeder cells depends on nutrient environment, potentially buffering sexual reproduction against suboptimal environments. PMID- 26510788 TI - Escape from Mitotic Arrest: An Unexpected Connection Between Microtubule Dynamics and Epigenetic Regulation of Centromeric Chromatin in Schizosaccharomyces pombe. AB - Accurate chromosome segregation is necessary to ensure genomic integrity. Segregation depends on the proper functioning of the centromere, kinetochore, and mitotic spindle microtubules and is monitored by the spindle assembly checkpoint (SAC). In the fission yeast Schizosaccharomyces pombe, defects in Dis1, a microtubule-associated protein that influences microtubule dynamics, lead to mitotic arrest as a result of an active SAC and consequent failure to grow at low temperature. In a mutant dis1 background (dis1-288), loss of function of Msc1, a fission yeast homolog of the KDM5 family of proteins, suppresses the growth defect and promotes normal mitosis. Genetic analysis implicates a histone deacetylase (HDAC)-linked pathway in suppression because HDAC mutants clr6-1, clr3?, and sir2?, though not hos2?, also promote normal mitosis in the dis1-288 mutant. Suppression of the dis phenotype through loss of msc1 function requires the spindle checkpoint protein Mad2 and is limited by the presence of the heterochromatin-associated HP1 protein homolog Swi6. We speculate that alterations in histone acetylation promote a centromeric chromatin environment that compensates for compromised dis1 function by allowing for successful kinetochore-microtubule interactions that can satisfy the SAC. In cells arrested in mitosis by mutation of dis1, loss of function of epigenetic determinants such as Msc1 or specific HDACs can promote cell survival. Because the KDM5 family of proteins has been implicated in human cancers, an appreciation of the potential role of this family of proteins in chromosome segregation is warranted. PMID- 26510789 TI - Evidence for a Nonendosomal Function of the Saccharomyces cerevisiae ESCRT-III Like Protein Chm7. AB - Endosomal sorting complex required for transport (ESCRT) proteins are involved in a number of cellular processes, such as endosomal protein sorting, HIV budding, cytokinesis, plasma membrane repair, and resealing of the nuclear envelope during mitosis. Here we explored the function of a noncanonical member of the ESCRT-III protein family, the Saccharomyces cerevisiae ortholog of human CHMP7. Very little is known about this protein. In silico analysis predicted that Chm7 (yeast ORF YJL049w) is a fusion of an ESCRT-II and ESCRT-III-like domain, which would suggest a role in endosomal protein sorting. However, our data argue against a role of Chm7 in endosomal protein sorting. The turnover of the endocytic cargo protein Ste6 and the vacuolar protein sorting of carboxypeptidase S (CPS) were not affected by CHM7 deletion, and Chm7 also responded very differently to a loss in Vps4 function compared to a canonical ESCRT-III protein. Our data indicate that the Chm7 function could be connected to the endoplasmic reticulum (ER). In line with a function at the ER, we observed a strong negative genetic interaction between the deletion of a gene function (APQ12) implicated in nuclear pore complex assembly and messenger RNA (mRNA) export and the CHM7 deletion. The patterns of genetic interactions between the APQ12 deletion and deletions of ESCRT-III genes, two-hybrid interactions, and the specific localization of mCherry fusion proteins are consistent with the notion that Chm7 performs a novel function at the ER as part of an alternative ESCRT-III complex. PMID- 26510790 TI - A Gene Regulatory Program in Human Breast Cancer. AB - Molecular heterogeneity in human breast cancer has challenged diagnosis, prognosis, and clinical treatment. It is well known that molecular subtypes of breast tumors are associated with significant differences in prognosis and survival. Assuming that the differences are attributed to subtype-specific pathways, we then suspect that there might be gene regulatory mechanisms that modulate the behavior of the pathways and their interactions. In this study, we proposed an integrated methodology, including machine learning and information theory, to explore the mechanisms. Using existing data from three large cohorts of human breast cancer populations, we have identified an ensemble of 16 master regulator genes (or MR16) that can discriminate breast tumor samples into four major subtypes. Evidence from gene expression across the three cohorts has consistently indicated that the MR16 can be divided into two groups that demonstrate subtype-specific gene expression patterns. For example, group 1 MRs, including ESR1, FOXA1, and GATA3, are overexpressed in luminal A and luminal B subtypes, but lowly expressed in HER2-enriched and basal-like subtypes. In contrast, group 2 MRs, including FOXM1, EZH2, MYBL2, and ZNF695, display an opposite pattern. Furthermore, evidence from mutual information modeling has congruently indicated that the two groups of MRs either up- or down-regulate cancer driver-related genes in opposite directions. Furthermore, integration of somatic mutations with pathway changes leads to identification of canonical genomic alternations in a subtype-specific fashion. Taken together, these studies have implicated a gene regulatory program for breast tumor progression. PMID- 26510791 TI - Sec66-Dependent Regulation of Yeast Spindle-Pole Body Duplication Through Pom152. AB - In closed mitotic systems such as Saccharomyces cerevisiae, the nuclear envelope (NE) does not break down during mitosis, so microtubule-organizing centers such as the spindle-pole body (SPB) must be inserted into the NE to facilitate bipolar spindle formation and chromosome segregation. The mechanism of SPB insertion has been linked to NE insertion of nuclear pore complexes (NPCs) through a series of genetic and physical interactions between NPCs and SPB components. To identify new genes involved in SPB duplication and NE insertion, we carried out genome wide screens for suppressors of deletion alleles of SPB components, including Mps3 and Mps2. In addition to the nucleoporins POM152 and POM34, we found that elimination of SEC66/SEC71/KAR7 suppressed lethality of cells lacking MPS2 or MPS3. Sec66 is a nonessential subunit of the Sec63 complex that functions together with the Sec61 complex in import of proteins into the endoplasmic reticulum (ER). Cells lacking Sec66 have reduced levels of Pom152 protein but not Pom34 or Ndc1, a shared component of the NPC and SPB. The fact that Sec66 but not other subunits of the ER translocon bypass deletion mutants in SPB genes suggests a specific role for Sec66 in the control of Pom152 levels. Based on the observation that sec66? does not affect the distribution of Ndc1 on the NE or Ndc1 binding to the SPB, we propose that Sec66-mediated regulation of Pom152 plays an NPC-independent role in the control of SPB duplication. PMID- 26510792 TI - Coordination of Recombination with Meiotic Progression in the Caenorhabditis elegans Germline by KIN-18, a TAO Kinase That Regulates the Timing of MPK-1 Signaling. AB - Meiosis is a tightly regulated process requiring coordination of diverse events. A conserved ERK/MAPK-signaling cascade plays an essential role in the regulation of meiotic progression. The Thousand And One kinase (TAO) kinase is a MAPK kinase kinase, the meiotic role of which is unknown. We have analyzed the meiotic functions of KIN-18, the homolog of mammalian TAO kinases, in Caenorhabditis elegans. We found that KIN-18 is essential for normal meiotic progression; mutants exhibit accelerated meiotic recombination as detected both by analysis of recombination intermediates and by crossover outcome. In addition, ectopic germ cell differentiation and enhanced levels of apoptosis were observed in kin-18 mutants. These defects correlate with ectopic activation of MPK-1 that includes premature, missing, and reoccurring MPK-1 activation. Late progression defects in kin-18 mutants are suppressed by inhibiting an upstream activator of MPK-1 signaling, KSR-2. However, the acceleration of recombination events observed in kin-18 mutants is largely MPK-1-independent. Our data suggest that KIN-18 coordinates meiotic progression by modulating the timing of MPK-1 activation and the progression of recombination events. The regulation of the timing of MPK-1 activation ensures the proper timing of apoptosis and is required for the formation of functional oocytes. Meiosis is a conserved process; thus, revealing that KIN-18 is a novel regulator of meiotic progression in C. elegans would help to elucidate TAO kinase's role in germline development in higher eukaryotes. PMID- 26510794 TI - Job satisfaction and motivation among public sector health workers: evidence from Ethiopia. AB - BACKGROUND: Although human resources for health have received increased attention by health systems decision-makers and researchers in recent years, insufficient attention has been paid to understanding the factors that influence the performance of health workers. This empirical study investigates the factors that are associated with health worker motivation over time among public sector primary health care workers in Ethiopia. METHODS: The study is based on data from public sector health worker surveys collected through a convenience sample of 43 primary health care facilities in four regions (Addis Ababa, Oromia, Amhara, and Somali) at three points in time: 2003/04, 2006, and 2009. Using a Likert scale, respondents were asked to respond to statements regarding job satisfaction, pride in work, satisfaction with financial rewards, self-efficacy, satisfaction with facility resources, and self-perceived conscientiousness. Inter-reliability of each construct was assessed using Cronbach's alpha, and indices of motivational determinants and outcomes were calculated for each survey round. To explore the associations between motivational determinants and outcomes, bivariate and multivariate regression analyses were carried out based on a pooled dataset. RESULTS: Among the sample public sector health workers, several dimensions of health worker motivation significantly increased over the study period, including two indicators of motivational outcomes-overall job satisfaction and self perceived conscientiousness-and two indicators of motivational determinants-pride and self-efficacy. However, two other dimensions of motivation-satisfaction with financial rewards and satisfaction with facility resources-significantly decreased. The multivariate analyses found that the constructs of pride, self efficacy, satisfaction with financial rewards, and satisfaction with facility resources were significantly associated with the motivational outcomes, after controlling for other factors. CONCLUSIONS: Overall, the findings support the premise that both financial and non-financial factors are important determinants of health worker motivation in the Ethiopian context. Although the findings do not point to specific interventions that should be introduced, they do suggest possible areas that interventions should target to help improve health worker motivation. PMID- 26510793 TI - Genome-Wide Structural Variation Detection by Genome Mapping on Nanochannel Arrays. AB - Comprehensive whole-genome structural variation detection is challenging with current approaches. With diploid cells as DNA source and the presence of numerous repetitive elements, short-read DNA sequencing cannot be used to detect structural variation efficiently. In this report, we show that genome mapping with long, fluorescently labeled DNA molecules imaged on nanochannel arrays can be used for whole-genome structural variation detection without sequencing. While whole-genome haplotyping is not achieved, local phasing (across >150-kb regions) is routine, as molecules from the parental chromosomes are examined separately. In one experiment, we generated genome maps from a trio from the 1000 Genomes Project, compared the maps against that derived from the reference human genome, and identified structural variations that are >5 kb in size. We find that these individuals have many more structural variants than those published, including some with the potential of disrupting gene function or regulation. PMID- 26510795 TI - A versatile model for soft patchy particles with various patch arrangements. AB - We propose a simple and general mesoscale soft patchy particle model, which can felicitously describe the deformable and surface-anisotropic characteristics of soft patchy particles. This model can be used in dynamics simulations to investigate the aggregation behavior and mechanism of various types of soft patchy particles with tunable number, size, direction, and geometrical arrangement of the patches. To improve the computational efficiency of this mesoscale model in dynamics simulations, we give the simulation algorithm that fits the compute unified device architecture (CUDA) framework of NVIDIA graphics processing units (GPUs). The validation of the model and the performance of the simulations using GPUs are demonstrated by simulating several benchmark systems of soft patchy particles with 1 to 4 patches in a regular geometrical arrangement. Because of its simplicity and computational efficiency, the soft patchy particle model will provide a powerful tool to investigate the aggregation behavior of soft patchy particles, such as patchy micelles, patchy microgels, and patchy dendrimers, over larger spatial and temporal scales. PMID- 26510797 TI - Abortion law in Australia: it's time for national consistency and decriminalisation. PMID- 26510796 TI - Adjudin--A Male Contraceptive with Other Biological Activities. AB - BACKGROUND: Adjudin has been explored as a male contraceptive for the last 15 years since its initial synthesis in the late 1990s. More than 50 papers have been published and listed in PubMed in which its mechanism that induces exfoliation of germ cells from the seminiferous epithelium, such as its effects on actin microfilaments at the apical ES (ectoplasmic specialization, a testis specific actin-rich anchoring junction) has been delineated. OBJECTIVE: Recent studies have demonstrated that, besides its activity to induce germ cell exfoliation from the seminiferous epithelium to cause reversible infertility in male rodents, adjudin possesses other biological activities, which include anti cancer, anti-inflammation in the brain, and anti-ototoxicity induced by gentamicin in rodents. Results of these findings likely spark the interest of investigators to explore other medical use of this and other indazole-based compounds, possibly mediated by the signaling pathway(s) in the mitochondria of mammalian cells following treatment with adjudin. In this review, we carefully evaluate these recent findings. METHODS: Papers published and listed at www.pubmed.org and patents pertinent to adjudin and its related compounds were searched. Findings were reviewed and critically evaluated, and summarized herein. RESULTS: Adjudin is a novel compound that possesses anti-spermatogenetic activity. Furthermore, it possesses anti-cancer, anti-inflammation, anti neurodegeneration, and anti-ototoxicity activities based on studies using different in vitro and in vivo models. CONCLUSION: Studies on adjudin should be expanded to better understand its biological activities so that it can become a useful drug for treatment of other ailments besides serving as a male contraceptive. PMID- 26510798 TI - Antibiotic resistance changing management of urinary tract infections in aged care. PMID- 26510800 TI - Testing times! Choosing Wisely when it comes to monitoring type 2 diabetes. PMID- 26510801 TI - Breastmilk banking and the Mercy Health experience. AB - Breastmilk banking provides an alternative to infant formula, not a substitute for mother's own milk. PMID- 26510802 TI - Are some more equal than others? Challenging the basis for prisoners' exclusion from Medicare. AB - A mixed funding approach can help meet the urgent requirement for a level of health care in prison commensurate with need and equivalent to community standards. PMID- 26510803 TI - Reducing the impact of coaching on selection into medicine. PMID- 26510804 TI - Post-artesunate delayed haemolysis in severe imported Plasmodium falciparum malaria. PMID- 26510805 TI - Orbital myositis secondary to statin therapy. PMID- 26510806 TI - Presentations with alcohol-related serious injury to a major Sydney trauma hospital after 2014 changes to liquor laws. AB - OBJECTIVE: To determine any impact associated with changes to liquor licensing regulations on emergency department attendances for alcohol-related serious injuries in an inner-city entertainment precinct. DESIGN, SETTING AND PARTICIPANTS: A blinded retrospective analysis of data from the Emergency Department Information System (EDIS) of the major trauma and teaching hospital (St Vincent's Hospital, Darlinghurst) in the Sydney CBD Entertainment Precinct. Data for trauma cases classified as Australasian triage categories 1 (immediately life-threatening) and 2 (imminently life-threatening, important time-critical treatment, very severe pain) in the 12 months before (24 February 2013 - 23 February 2014; period 1) and the 12 months after (24 February 2014 - 23 February 2015; period 2) the 2014 changes to liquor licensing regulations applied to the precinct. MAIN OUTCOME MEASURES: Critically or seriously injured emergency presentations that were identified as related to alcohol use. RESULTS: In the 2 year study period, there were 13 110 triage category 1 and 2 presentations to the St Vincent's Hospital emergency department: 6467 during period 1 and 6643 during period 2. Of these, 1564 (4.3%) were patients who presented with alcohol-related serious injuries: 318 (4.9%) during period 1 and 246 (3.7%) during period 2 (P < 0.05). The proportion of alcohol-related serious injury presentations (triage categories 1 and 2) was much higher (9.1% of presentations) during the high alcohol time (HAT; 6 pm Friday to 6 am Sunday) than during the rest of the week (3.1%). After the introduction of the regulatory changes, there was a significant decrease in the number of seriously injured patients during HAT, from 140 presentations (10.4% of presentations) before the change to 106 (7.8%) after their introduction, a relative reduction of 24.8% (P < 0.05). There was a small increase in the number of patients presenting with alcohol-related injuries between 9 pm and midnight. CONCLUSIONS: There was a significant reduction in the number of alcohol-related serious injury and trauma presentations to the emergency department in the 12 months after the introduction of the new liquor regulations. This change was seen throughout the week, but was especially marked at weekends. PMID- 26510807 TI - The extra resource burden of in-hospital falls: a cost of falls study. AB - OBJECTIVE: To quantify the additional hospital length of stay (LOS) and costs associated with in-hospital falls and fall injuries in acute hospitals in Australia. DESIGN, SETTING AND PARTICIPANTS: A multisite prospective cohort study conducted during 2011-2013 in the control wards of a falls prevention trial (6 PACK). The trial included all admissions to 12 acute medical and surgical wards of six Australian hospitals. In-hospital falls data were collected from medical record reviews, daily verbal reports by ward nurse unit managers, and hospital incident reporting and administrative databases. Clinical costing data were linked for three of the six participating hospitals to calculate patient-level costs. OUTCOME MEASURES: Hospital LOS and costs associated with in-hospital falls and fall injuries for each patient admission. RESULTS: We found that 966 of a total of 27 026 hospital admissions (3.6%) involved at least one fall, and 313 (1.2%) at least one fall injury, a total of 1330 falls and 418 fall injuries. After adjustment for age, sex, cognitive impairment, admission type, comorbidity and clustering by hospital, patients who had an in-hospital fall had a mean increase in LOS of 8 days (95% CI, 5.8-10.4; P < 0.001) compared with non fallers, and incurred mean additional hospital costs of $6669 (95% CI, $3888 $9450; P < 0.001). Patients with a fall-related injury had a mean increase in LOS of 4 days (95% CI, 1.8-6.6; P = 0.001) compared with those who fell without injury, and there was also a tendency to additional hospital costs (mean, $4727; 95% CI, -$568 to $10 022; P = 0.080). CONCLUSION: Patients who experience an in hospital fall have significantly longer hospital stays and higher costs. Programs need to target the prevention of all falls, not just the reduction of fall related injuries. PMID- 26510808 TI - Survival after an acute coronary syndrome: 18-month outcomes from the Australian and New Zealand SNAPSHOT ACS study. AB - OBJECTIVES: To assess the impact of the availability of a catheterisation laboratory and evidence-based care on the 18-month mortality rate in patients with suspected acute coronary syndromes (ACS). DESIGN, SETTING AND PARTICIPANTS: Management and outcomes are described for patients enrolled in the 2012 Australian and New Zealand SNAPSHOT ACS audit. Patients were stratified according to their presentation to hospitals with or without cardiac catheterisation facilities. Data linkage ascertained patient vital status 18 months after admission. Descriptive and Cox proportional hazards analyses determined predictors of outcomes, and were used to estimate the numbers of deaths that could be averted by improved application of evidence-based care. MAIN OUTCOME MEASURES: Mortality for ACS patients from admission to 18 months after admission. RESULTS: Definite ACS patients presenting to catheterisation-capable (CC) hospitals (n = 1326) were more likely to undergo coronary angiography than those presenting to non-CC hospitals (n = 1031) (61.5% v 50.8%; P = 0.0001), receive timely reperfusion (for ST elevation myocardial infarction (STEMI) patients: 45.2% v 19.2%; P < 0.001), and be referred for cardiac rehabilitation (57% v 53%; P = 0.05). All-cause mortality over 18 months was highest for STEMI (16.2%) and non-STEMI (16.3%) patients, and lowest for those presenting with unstable angina (6.8%) and non-cardiac chest pain (4.8%; P < 0.0001 for trend). After adjustment for patient propensity to present to a CC hospital and patient risk, presentation to a CC hospital was associated with 21% (95% CI, 2%-37%) lower mortality than presentation to a non-CC hospital. This mortality difference was attenuated after adjusting for delivery of evidence-based care. CONCLUSION: In Australia and New Zealand, the availability of a catheterisation laboratory appears to have a significant impact on long-term mortality in ACS patients, which is still substantial. This mortality may be reduced by improvements in evidence-based care in both CC and non-CC hospitals. PMID- 26510809 TI - Continuous quality improvement and metabolic screening during pregnancy at primary health centres attended by Aboriginal and Torres Strait Islander women. AB - OBJECTIVE: To investigate associations between the provision of routine metabolic screening and follow-up in pregnancy and participation by primary health care centres in a large-scale continuous quality improvement (CQI) initiative. DESIGN: Longitudinal analysis of 2592 audited maternal health records. SETTING AND PARTICIPANTS: Seventy-six community-controlled or government-operated primary health care centres serving predominantly Aboriginal and Torres Strait Islander communities, in urban, regional or remote locations in five Australian states and territories. INTERVENTION: Up to four CQI cycles supported by the Audit and Best Practice for Chronic Disease Research Partnership. MAIN OUTCOMES MEASURES: Screening and follow-up for body mass index (BMI), blood pressure and diabetes in pregnancy. RESULTS: Overall, 87.9% of women attending the participating health centres were Aboriginal or Torres Strait Islander. Women attending a health centre after it had conducted one or more CQI cycles were more likely to receive BMI, blood pressure and diabetes screening. For example, the proportion of women receiving diabetes screening at baseline (before the first CQI cycle) was 56.1%; after cycle 1 it was 63.7% (odds ratio [OR], 1.3; 95% CI, 1.0-1.6), after cycle 2, 61.6% (OR, 1.2; 95% CI, 0.9-1.7), after cycle 3, 63.7% (OR, 1.7; 95% CI, 1.1 2.6), and after cycle 4, 75.5% (OR, 3.4; 95% CI, 1.9-5.9). Diabetes screening was associated with higher self-ratings of overall organisational systems (P = 0.03), self-management support (P = 0.04) and organisational influence and integration (P = 0.01). CONCLUSION: These findings support the value of CQI approaches that focus on systems-level issues in primary care to improve the provision of recommended pregnancy care at primary health care centres in predominantly Aboriginal and Torres Strait Islander communities. PMID- 26510810 TI - The dangers of diagnosing cystic neck masses as benign in the era of HPV associated oropharyngeal cancer. PMID- 26510811 TI - Travels with Charlie. AB - Playing woodwind instruments has long been shown to assist those with asthma; now playing the didgeridoo is also found to help. PMID- 26510812 TI - My journey from suit to skin. PMID- 26510813 TI - Philosophy for ageing. PMID- 26510815 TI - Oligonucleotide therapeutics: chemistry, delivery and clinical progress. AB - Oligonucleotide therapeutics have the potential to become a third pillar of drug development after small molecules and protein therapeutics. However, the three approved oligonucleotide drugs over the past 17 years have not proven to be highly successful in a commercial sense. These trailblazer drugs have nonetheless laid the foundations for entire classes of drug candidates to follow. This review will examine further advances in chemistry that are earlier in the pipeline of oligonucleotide drug candidates. Finally, we consider the possible effect of delivery systems that may provide extra footholds to improve the potency and specificity of oligonucleotide drugs. Our overview focuses on strategies to imbue antisense oligonucleotides with more drug-like properties and their applicability to other nucleic acid therapeutics. PMID- 26510816 TI - Suppression of Homologous Recombination by insulin-like growth factor-1 inhibition sensitizes cancer cells to PARP inhibitors. AB - BACKGROUND: Impairment of homologous recombination (HR) is found in close to 50 % of ovarian and breast cancer. Tumors with BRCA1 mutations show increased expression of the Insulin-like growth factor type 1 receptor (IGF-1R). We previously have shown that inhibition of IGF-1R results in growth inhibition and apoptosis of ovarian tumor cells. In the current study, we aimed to investigate the correlation between HR and sensitivity to IGF-1R inhibition. Further, we hypothesized that IGF-1R inhibition might sensitize HR proficient cancers to Poly ADP ribose polymerase (PARP) inhibitors. METHODS: Using ovarian and breast cancer cellular models with known BRCA1 status, we evaluated their HR functionality by RAD51 foci formation assay. The 50 % lethal concentration (LC50) of Insulin-like growth factor type 1 receptor kinase inhibitor (IGF-1Rki) in these cells was assessed, and western immunoblotting was performed to determine the expression of proteins involved in the IGF-1R pathway. Moreover, IGF-1R inhibitors were added on HR proficient cell lines to assess mRNA and protein expression of RAD51 by qPCR and western blot. Also, we explored the interaction between RAD51 and Insulin receptor substance 1 (IRS-1) by immunoprecipitation. Next, combination effect of IGF-1R and PARP inhibitors was evaluated by clonogenic assay. RESULTS: Cells with mutated/methylated BRCA1 showed an impaired HR function, and had an overactivation of the IGF-1R pathway. These cells were more sensitive to IGF-1R inhibition compared to HR proficient cells. In addition, the IGF-IR inhibitor reduced RAD51 expression at mRNA and protein levels in HR proficient cells, and sensitized these cells to PARP inhibitor. CONCLUSION: Targeting IGF-1R might lead to improved personalized therapeutic approaches in cancer patients with HR deficiency. Targeting both PARP and IGF-1R might increase the clinical efficacy in HR deficient patients and increase the population of patients who may benefit from PARP inhibitors. PMID- 26510817 TI - Effect of black mulberry (Morus nigra) extract treatment on cognitive impairment and oxidative stress status of D-galactose-induced aging mice. AB - CONTEXT: Morus nigra L. (Moraceae) has various uses in traditional medicine. However, the effect of M. nigra on cognitive impairment has not been investigated yet. OBJECTIVE: The objective of this study is to determine the phenolic acid content and DNA damage protection potential of M. nigra leaf extract and to investigate the extract effect on cognitive impairment and oxidative stress in aging mice. MATERIALS AND METHODS: Phenolic acid content was determined by quantitative chromatographic analysis. DNA damage protection potential was evaluated on pBR322 plasmid DNA. Thirty-two Balb-C mice were randomly divided into four groups (control, d-galactose, d-galactose + M. nigra 50, and d galactose + M. nigra 100). Mice were administered d-galactose (100 mg/kg, subcutaneous) and M. nigra (50 or 100 mg/kg, orally) daily for 8 weeks. Behavioral responses were evaluated with Morris water maze. Activities of antioxidant enzymes and levels of malondialdehyde (MDA) were assayed in serum, brain, and liver. RESULTS: In extract, vanillic (632.093 MUg/g) and chlorogenic acids (555.0 MUg/g) were determined. The extract between 0.02 and 0.05 mg/mL effectively protected all DNA bands against the hazardous effect of UV and H2O2. Morus nigra significantly improved learning dysfunctions (p < 0.01), increased memory retention (p < 0.01), reduced MDA levels (p < 0.05), and elevated SOD, GPx, and CAT activities (p < 0.05) compared with the d-galactose group. DISCUSSION AND CONCLUSION: These results show that M. nigra has the potential in improving cognitive deficits in mice and that M. nigra may be useful to suppress aging, partially due to its scavenging activity of free radicals and high antioxidant capacity. PMID- 26510818 TI - Theoretical Study on the Catalytic Reduction Mechanism of NO by CO on Tetrahedral Rh4 Subnanocluster. AB - The catalytic mechanism of 2NO + 2CO -> N2 + 2CO2 on Rh4 cluster has been systematically investigated on the ground and first excited states at the B3LYP/6 311+G(2d),SDD level. For the overall reaction of 2NO + 2CO -> N2 + 2CO2, the main reaction pathways take place on the facet site rather than the edge site of the Rh4 cluster. The turnover frequency (TOF) determining transition states are characteristic of the second N-O bond cleavage with rate constant k4 = 1.403 * 10(11) exp (-181 203/RT) and the N-N bond formation for the intermediate N2O formation with rate constant k2 = 3.762 * 10(12) exp (-207 817/RT). The TOF determining intermediates of (3)N(b)Rh4NO and (3)N(b)Rh4O(b)(NO) are associated with the nitrogen-atom molecular complex, which is in agreement with the experimental observation of surface nitrogen. On the facet site of Rh4 cluster, the formation of CO2 stems solely from the recombination of CO and O atom, while N2 originates partly from the recombination of two N atoms and partly from the decomposition of N2O. For the N-O bond cleavage or the synchronous N-O bond cleavage and C-O bond formation, the neutral Rh4 cluster exhibits better catalytic performance than the cationic Rh4(+) cluster. Alternatively, for N-N bond formation, the cationic Rh4(+) cluster possesses better catalytic performance than the neutral Rh4 cluster. PMID- 26510819 TI - The luminescence properties of the heteroleptic [Re(CO)3(N?N)Cl] and [Re(CO)3(N?N)(CH3CN)](+) complexes in view of the combined Marcus-Jortner and Mulliken-Hush formalism. AB - The luminescence properties of the heteroleptic fac-Re(CO)3(+) complexes with alpha-diimine N?N ligands, neutral [Re(CO)3(N?N)Cl] and cationic [Re(CO)3(N?N)(CH3CN)](+) species, have been studied in acetonitrile solutions at room temperature. The investigated complexes exhibit the metal to ligand charge transfer (MLCT) phosphorescence with the emission characteristics strongly affected by the nature of coordinated alpha-diimine N?N ligands. The observed trends can be quantitatively described by invoking the electronic interactions between (3)*LC and (3)*MLCT states as well as the spin-orbit interactions between (3)*MLCT and (1)*MLCT states, respectively. All quantities necessary for the description can be straightforwardly accounted from analysis of the radiative (1)*MLCT <- S0 and (3)*MLCT -> S0 charge transfer processes. It is also demonstrated that the radiative kr and non-radiative knr decay rate constants of the excited (3)*MLCT states can be interpreted within the same set of parameters. As expected from the Mulliken-Hush formalism the both processes are strictly related that allows prediction of the non-radiative knr rate constants using the parameters available from analysis of the radiative (1)*MLCT <- S0 and (3)*MLCT > S0 charge transfer processes. PMID- 26510820 TI - Muscle growth is reduced in 15-month-old children with cerebral palsy. AB - AIM: Lack of muscle growth relative to bone growth may be responsible for development of contractures in children with cerebral palsy (CP). Here, we used ultrasonography to compare growth of the medial gastrocnemius muscle in children with and without CP. METHOD: Twenty-six children with spastic CP (15 males, 11 females; mean age 35mo, range 8-65mo) and 101 typically developing children (47 males, 54 females; mean age 29mo, range 1-69mo) were included. Functional abilities of children with CP equalled levels I to III in the Gross Motor Function Classification System. Medial gastrocnemius muscle volume was constructed from serial, transverse, two-dimensional ultrasonography images. RESULTS: In typically developing children, medial gastrocnemius volume increased linearly with age. Among children with CP, medial gastrocnemius volume increased less with age and deviated significantly from typically developing children at 15 months of age (p<0.05). Bone length increased with age without significant difference (p=0.49). INTERPRETATION: Muscle growth in children with CP initially follows that of typically developing children, but decreases at 15 months of age. This may be related to reduced physical activity and neural activation of the muscle. Interventions stimulating muscle growth in young children with CP may be important to prevent contractures. PMID- 26510821 TI - Uncovered secret of a Vasseur-Tramond wax model. AB - The technique of anatomical wax modelling reached its heyday in Italy during the 18th century, through a fruitful collaboration between sculptors and anatomists. It soon spread to other countries, and prestigious schools were created in England, France, Spain and Austria. Paris subsequently replaced Italy as the major centre of manufacture, and anatomical waxes were created there from the mid 19th century in workshops such as that of Vasseur-Tramond. This workshop began to sell waxes to European Faculties of Medicine and Schools of Surgery around 1880. Little is known of the technique employed in the creation of such artefacts as this was deemed a professional secret. To gain some insight into the methods of construction, we have studied a Vasseur-Tramond wax model in the Valladolid University Anatomy Museum, Spain, by means of multi-slice computerised tomography and X-ray analysis by means of environmental scanning electron microscopy. Scanning electron microscopy was used to examine the hair. These results have revealed some of the methods used to make these anatomical models and the materials employed. PMID- 26510822 TI - A critical review of scoring options for clinical measurement tools. AB - BACKGROUND: The aim of this paper is twofold: (1) to describe the fundamental differences between formative and reflective measurement models, and (2) to review the options proposed in the literature to obtain overall instrument summary scores, with a particular focus on formative models. METHODS: An extensive literature search was conducted using the following databases: MEDLINE, EMBASE, PsycINFO, CINAHL and ABI/INFORM, using "formative" and "reflective" as text words; relevant articles' reference lists were hand searched. RESULTS: Reflective models are most frequently scored by means of simple summation, which is consistent with the theory underlying these models. However, our review suggests that formative models might be better summarized using weighted combinations of indicators, since each indicator captures unique features of the underlying construct. For this purpose, indicator weights have been obtained using choice-based, statistical, researcher-based, and combined approaches. CONCLUSION: Whereas simple summation is a theoretically justified scoring system for reflective measurement models, formative measures likely benefit from the use of weighted scores that preserve the contribution of each of the aspects of the construct. PMID- 26510823 TI - Discriminant ability of the Eating Assessment Tool-10 to detect aspiration in individuals with amyotrophic lateral sclerosis. AB - BACKGROUND: Oropharyngeal dysphagia is prevalent in individuals with amyotrophic lateral sclerosis (ALS) leading to malnutrition, aspiration pneumonia, and death. These factors necessitate early detection of at-risk patients to prolong maintenance of safe oral intake and pulmonary function. This study aimed to evaluate the discriminant ability of the Eating Assessment Tool (EAT-10) to identify ALS patients with unsafe airway protection during swallowing. METHODS: Seventy ALS patients completed the EAT-10 survey and underwent a standardized videofluoroscopic evaluation of swallowing. Two blinded raters determined airway safety using the Penetration Aspiration Scale (PAS). A between groups anova (safe vs penetrators vs aspirators) was conducted and sensitivity, specificity, area under the curve (AUC), and likelihood ratios calculated. KEY RESULTS: Mean EAT-10 scores for safe swallowers, penetrators, and aspirators (SEM) were: 4.28 (0.79) vs 7.10 (1.79) vs 20.50 (3.19), respectively, with significant differences noted for aspirators vs safe swallowers and aspirators vs penetrators (p < 0.001). The EAT-10 demonstrated good discriminant ability to accurately identify ALS penetrator/aspirators (PAS >=3) with a cut off score of 3 (AUC: 0.77, sensitivity: 88%, specificity: 57%). The EAT-10 demonstrated excellent accuracy at identifying aspirators (PAS >=6) utilizing a cut off score of 8 (AUC: 0.88, sensitivity: 86%, specificity: 72%, likelihood ratio: 3.1, negative predictive value: 95.5%). CONCLUSIONS & INFERENCES: The EAT-10 differentiated safe vs unsafe swallowing in ALS patients. This patient self-report scale could represent a quick and meaningful aide to dysphagia screening in busy ALS clinics for the identification and referral of dysphagic patients for further instrumental evaluation. PMID- 26510824 TI - Osseous associated cervical spondylomyelopathy at the C2-C3 articular facet joint in 11 dogs. AB - In dogs, vertebral canal stenosis at C2-C3 due to articular facet joint degeneration is only sporadically identified. The authors' aims were to review the clinical presentation, MRI characteristics, treatment and outcome of dogs presenting with this condition. Eleven cases were eligible for inclusion. Neurological examination revealed tetraparesis and proprioceptive ataxia in all 4 limbs in 3/11, proprioceptive tetra-ataxia only in 4/11, pelvic limb proprioceptive ataxia in 2/11 and no gait abnormalities in 2/11 dogs. Cervical hyperaesthesia was present in 7/11 dogs. MRI revealed bilateral articular facet joint degeneration in 10/11 cases and unilateral degeneration in one. Surgery was performed in six cases and medical management elected in five. Long-term follow up information was available for 11 animals. Four of the surgical cases are alive and have no neurological deficits, one was euthanased for an unrelated condition and one lost to follow-up. Of the cases managed medically, three are alive showing no neurological deficits, one is alive still displaying neurological deficits and one euthanased for an unrelated condition whilst still ataxic. This study shows that both medical and surgical management can result in good outcomes in dogs with vertebral canal stenosis resulting from articular facet joint degeneration at the level of C2-C3. PMID- 26510825 TI - Wire-guided cannulation over a pancreatic stent versus double guidewire technique in patients with difficult biliary cannulation. AB - BACKGROUND: In cases of difficult bile duct cannulation, the use of wire-guided cannulation over a pancreatic stent (WGC-PS) or the double guidewire technique (DGT) may facilitate biliary cannulation. The aim of this study was to compare the outcomes of WGC-PS and DGT in patients with difficult biliary cannulation. METHODS: We conducted a retrospective cohort study of all endoscopic retrograde cholangiopancreatographies (ERCPs) performed between July 2009 and November 2014 at a single tertiary referral center. WGC-PS or DGT was performed in patients for whom biliary cannulation was difficult and guidewire insertion into the pancreatic duct (PD) was inadvertently achieved while attempting the standard WGC technique. In those cases, we used the WGC-PS technique from July 2009 to January 2012 (WGC-PS group), and the DGT technique from February 2012 to November 2014 (DGT group). In the DGT group, WGC-PS was sequentially performed if successful biliary cannulation was not achieved during the DGT attempt. Consecutive patients who underwent DGT and/or WGC-PS with the aim of selective biliary cannulation were enrolled. The primary outcome parameter was the rate of initial successful biliary cannulation. RESULTS: During the study period 3270 ERCPs were performed and a total of 177 patients were enrolled. The rate of initial successful cannulation was 66.7 % (60/90) in the WGC-PS group and 70.1 % (61/87) in the DGT group (P = 0.632). In 26 cases of failed DGT, WGC-PS was sequentially performed in the DGT group, and cannulation was successful in 14 of these patients. The rate of successful cannulation without the needle-knife precut technique was significantly higher in the DGT group compared with the WGC-PS group (75/87, 86.2 % vs. 60/90, 66.7 %, P = 0.003). The incidence of post-ERCP pancreatitis was 3.3 % (3/90) in the WGC-PS group and 10.3 % (9/87) in the DGT group (P = 0.077). CONCLUSIONS: In patients for whom biliary cannulation was difficult and PD access was inadvertently achieved while attempting the standard WGC technique, both WGC PS and DGT were equally effective. Furthermore, the stepwise approach using DGT followed by WGC-PS as needed facilitated successful biliary cannulation and reduced the need for the needle-knife precut technique. PMID- 26510826 TI - Clinical course of IgG4-related hypophysitis presenting with focal seizure and relapsing lymphocytic hypophysitis. AB - BACKGROUND: This is the first case report of focal seizure as a manifestation of Immunoglobulin G4 (IgG4)-related hypophysitis. IgG4-related hypophysitis is a novel category of hypophysitis. The clinical presentations, imaging studies and initial pathology studies can mimic lymphocytic hypophysitis. Here we report additional clinical clues in differentiating these two conditions. CASE PRESENTATION: A 43-year-old Thai male presented with focal seizure, headache, and anterior pituitary hypofunction. His MRI study showed typical hypophysitis lesion with abnormal cerebral parenchymal signal intensity at right frontal lobe. The pituitary biopsied was obtained and the patient was initially diagnosed with lymphocytic hypophysitis. Following initial low-dose steroid therapy, his seizure and headache resolved but his anterior pituitary hormones remained deficient. However, during steroid tapering, he developed new onset acute visual loss. Upon rigorous pathologic review, his diagnosis of IgG4-related hypophysitis with suspected CNS involvement was established. He was subsequently treated with high dose steroid and rapidly regained his sight. CONCLUSION: This case report highlights the important distinguishing features of IgG4-related hypophysitis from lymphocytic hypophysitis. These include the relapsing clinical course of hypophysitis after steroid decrement and concomitant pachymeningitis particularly in middle-aged to elderly Asian male who presented with hypophysitis. With appropriate dosage of steroids, medical treatment is usually sufficient to control the disease and surgical interventions are usually not required. PMID- 26510827 TI - Cancer therapeutic potential of combinatorial immuno- and vasomodulatory interventions. AB - Currently, most of the basic mechanisms governing tumour-immune system interactions, in combination with modulations of tumour-associated vasculature, are far from being completely understood. Here, we propose a mathematical model of vascularized tumour growth, where the main novelty is the modelling of the interplay between functional tumour vasculature and effector cell recruitment dynamics. Parameters are calibrated on the basis of different in vivo immunocompromised Rag1(-/-) and wild-type (WT) BALB/c murine tumour growth experiments. The model analysis supports that tumour vasculature normalization can be a plausible and effective strategy to treat cancer when combined with appropriate immunostimulations. We find that improved levels of functional tumour vasculature, potentially mediated by normalization or stress alleviation strategies, can provide beneficial outcomes in terms of tumour burden reduction and growth control. Normalization of tumour blood vessels opens a therapeutic window of opportunity to augment the antitumour immune responses, as well as to reduce intratumoral immunosuppression and induced hypoxia due to vascular abnormalities. The potential success of normalizing tumour-associated vasculature closely depends on the effector cell recruitment dynamics and tumour sizes. Furthermore, an arbitrary increase in the initial effector cell concentration does not necessarily imply better tumour control. We evidence the existence of an optimal concentration range of effector cells for tumour shrinkage. Based on these findings, we suggest a theory-driven therapeutic proposal that optimally combines immuno- and vasomodulatory interventions. PMID- 26510828 TI - Thermodynamics of firms' growth. AB - The distribution of firms' growth and firms' sizes is a topic under intense scrutiny. In this paper, we show that a thermodynamic model based on the maximum entropy principle, with dynamical prior information, can be constructed that adequately describes the dynamics and distribution of firms' growth. Our theoretical framework is tested against a comprehensive database of Spanish firms, which covers, to a very large extent, Spain's economic activity, with a total of 1,155,142 firms evolving along a full decade. We show that the empirical exponent of Pareto's law, a rule often observed in the rank distribution of large size firms, is explained by the capacity of economic system for creating/destroying firms, and that can be used to measure the health of a capitalist-based economy. Indeed, our model predicts that when the exponent is larger than 1, creation of firms is favoured; when it is smaller than 1, destruction of firms is favoured instead; and when it equals 1 (matching Zipf's law), the system is in a full macroeconomic equilibrium, entailing 'free' creation and/or destruction of firms. For medium and smaller firm sizes, the dynamical regime changes, the whole distribution can no longer be fitted to a single simple analytical form and numerical prediction is required. Our model constitutes the basis for a full predictive framework regarding the economic evolution of an ensemble of firms. Such a structure can be potentially used to develop simulations and test hypothetical scenarios, such as economic crisis or the response to specific policy measures. PMID- 26510829 TI - Dynamics of deceptive interactions in social networks. AB - In this paper, we examine the role of lies in human social relations by implementing some salient characteristics of deceptive interactions into an opinion formation model, so as to describe the dynamical behaviour of a social network more realistically. In this model, we take into account such basic properties of social networks as the dynamics of the intensity of interactions, the influence of public opinion and the fact that in every human interaction it might be convenient to deceive or withhold information depending on the instantaneous situation of each individual in the network. We find that lies shape the topology of social networks, especially the formation of tightly linked, small communities with loose connections between them. We also find that agents with a larger proportion of deceptive interactions are the ones that connect communities of different opinion, and, in this sense, they have substantial centrality in the network. We then discuss the consequences of these results for the social behaviour of humans and predict the changes that could arise due to a varying tolerance for lies in society. PMID- 26510830 TI - A perceptual map for gait symmetry quantification and pathology detection. AB - BACKGROUND: The gait movement is an essential process of the human activity and the result of collaborative interactions between the neurological, articular and musculoskeletal systems, working efficiently together. This explains why gait analysis is important and increasingly used nowadays for the diagnosis of many different types (neurological, muscular, orthopedic, etc.) of diseases. This paper introduces a novel method to quickly visualize the different parts of the body related to an asymmetric movement in the human gait of a patient for daily clinical usage. The proposed gait analysis algorithm relies on the fact that the healthy walk has (temporally shift-invariant) symmetry properties in the coronal plane. The goal is to provide an inexpensive and easy-to-use method, exploiting an affordable consumer depth sensor, the Kinect, to measure the gait asymmetry and display results in a perceptual way. METHOD: We propose a multi-dimensional scaling mapping using a temporally shift invariant distance, allowing us to efficiently visualize (in terms of perceptual color difference) the asymmetric body parts of the gait cycle of a subject. We also propose an index computed from this map and which quantifies locally and globally the degree of asymmetry. RESULTS: The proposed index is proved to be statistically significant and this new, inexpensive, marker-less, non-invasive, easy to set up, gait analysis system offers a readable and flexible tool for clinicians to analyze gait characteristics and to provide a fast diagnostic. CONCLUSION: This system, which estimates a perceptual color map providing a quick overview of asymmetry existing in the gait cycle of a subject, can be easily exploited for disease progression, recovery cues from post-operative surgery (e.g., to check the healing process or the effect of a treatment or a prosthesis) or might be used for other pathologies where gait asymmetry might be a symptom. PMID- 26510831 TI - Interactive endothelial phenotype maintenance and osteogenic differentiation of adipose tissue stromal vascular fraction SSEA-4+ -derived cells. AB - Bone formation relies on complex processes that require well-orchestrated interactions between several cell types, such as bone-forming cells (osteoblasts, OBs) and endothelial cells (ECs). Their co-culture has been proved relevant to mimicking specific features of the bone niche. Here we propose the co-culture of microvascular-like ECs and pre-OBs, both derived from the SSEA-4+ cell subpopulation from the stromal vascular fraction of human adipose tissue (SSEA-4+ hASCs), to define the conditions in which cells synergistically communicate to support the full differentiation of pre-OBs and maintenance of the EC phenotype. Co-cultures of different ratios of the two cell types were established and maintained for up to 21 days in standard endothelial maintenance (ENDO) and osteogenic differentiation (OST) media, as well as in a mixture of these (MIX). The osteogenic maturation of pre-OBs (ALP activity, OPN and OCN expression, calcium deposition), the evolution of EC numbers (CD31+ cells) and maintenance of the endothelial phenotype (CD31 and vWF expression, LDL uptake) were assessed throughout the culture time as a function of cell ratio and culture media. The results obtained demonstrate that EC number has a significant effect on the osteogenic differentiation of pre-OBs, depending on the medium used. While in ENDO medium the osteogenic differentiation was not observed, in the OST and MIX media it was attained at similar levels, except for the co-culture with a higher number of ECs in MIX medium. These findings demonstrate that the use of SSEA-4+ hASCs as a single-cell source is promising to attain 3D bone-like models with the potential to promote vascularized bone tissue regeneration. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26510832 TI - Systematic review with meta-analysis: the incidence and prevalence of eosinophilic oesophagitis in children and adults in population-based studies. AB - BACKGROUND: The recognition of eosinophilic oesophagitis (EoE) has risen sharply, but its current epidemiology is still under debate. AIM: To estimate accurately the prevalence and incidence rates of EoE, by a systematic review and meta analysis. METHODS: MEDLINE, EMBASE and SCOPUS databases were searched for population-based studies on the epidemiology of EoE. Pooled incidence and prevalence rates, male:female and children:adult ratios, and geographical and temporal variations were calculated with random-effects models. RESULTS: The search yielded 1334 references; the final quantitative summary included 13 population-based studies from North America, Europe and Australia, with the results showing high heterogeneity. The pooled EoE incidence rate was 3.7/100 000 persons/year [95% confidence interval (CI): 1.7-6.5] and was higher for adults (7; 95% CI: 1-18.3) than for children (5.1; 95% CI: 1.5-10.9). The pooled prevalence of EoE was 22.7 cases/100 000 inhabitants (95% CI: 12.4-36), rising to 28.1 (95% CI: 13-49) when studies with a lower risk of bias were considered; prevalence was higher in adults than in children (43.4; 95% CI: 22.5-71.2 vs. 29.5; 95% CI: 17.5-44.7, respectively), and in American compared to European studies. A steady rise in EoE incidence and prevalence rates was observed upon comparison of studies conducted before and after 2008. No significant publication bias was found. CONCLUSIONS: Eosinophilic oesophagitis is an increasingly common diagnosis in North America and Europe. The population-based incidence and prevalence of eosinophilic oesophagitis vary widely across individual studies, probably due to variations in diagnosis and risk of bias of research. More prospective, large-scale, multicenter studies are needed to evaluate reported data. PMID- 26510833 TI - Rhodium-Catalyzed Regioselective C7-Functionalization of N-Pivaloylindoles. AB - An efficient rhodium-catalyzed method for direct C-H functionalization at the C7 position of a wide range of indoles has been developed. Good to excellent yields of alkenylation products were observed with acrylates, styrenes, and vinyl phenyl sulfones, whereas the saturated alkylation products were obtained in good yield with alpha,beta-unsaturated ketones. Both the N-pivaloyl directing group and the rhodium catalyst proved to be crucial for high regioselectivity and conversion. PMID- 26510834 TI - Surgeon-performed ultrasound guided fine-needle aspirate biopsy with report of learning curve; a consecutive case-series study. AB - BACKGROUND: Fine-needle aspiration biopsy has become the standard of care for the evaluation of thyroid nodules. More recently, the use of ultrasound guided fine needle aspiration biopsy (UG-FNAB) has improved adequacy of sampling. Now there has been improved access to UG-FNAB as ultrasound technology has become more accessible. Here we review the adequacy rate and learning curve of a single surgeon starting at the adoption of UG-FNAB into surgical practice. METHODS: UG FNABs performed at Sunnybrook Health Sciences Centre from 2010 to 2015 were reviewed retrospectively. Nodule characteristics were recorded along with cytopathology and final pathology reports. Chi-square analysis, followed by the reporting of odds ratios with confidence intervals, were used to assess the statistical significance and frequencies, respectively, of nodule characteristics amongst both diagnostic and non-diagnostic samples. A multiple regression analysis was conducted to determine if any nodule characteristic were predictive of adequacy of UG-FNABs. The learning curve was assessed by calculating the eventual adequacy rates across each year, and its statistical significance was measured using Fischer's Exact Test. RESULTS: In total 423 biopsies were reviewed in 289 patients. The average nodule size was 23.05 mm. When examining if each patient eventually received a diagnostic UG-FNAB, regardless of the number attempts, adequacy was seen to increase from 70.8% in 2010 to, 81.0% in 2011, 90.3% in 2012, 85.7% in 2013, 89.7% in 2014, and 94.3% in 2015 (Fischer's Exact Test, p = 0.049). Cystic (chi(2) = 19.70, p <0.001) nodules were found to yield higher rates of non-diagnostic samples, and their absence are predictive of obtaining an adequate biopsy as seen in a multiple regression analysis (p < 0.001) Adequacy of repeat biopsies following an initial non-diagnostic sample was 75.0%. CONCLUSIONS: Surgeons are capable of performing UG-FNAB with a learning curve noted to achieve standard adequacy rates. Cystic nodules are shown to yield more non-diagnostic samples in the surgeon's office. PMID- 26510835 TI - Impact of active thermoregulation on the microcirculation of free flaps. AB - BACKGROUND: While it is a known fact that warming increases blood flow in healthy tissue, little is known about the impact of active thermoregulation on the altered microcirculation of free flaps. The objective of the study was to identify the impact of postoperative active thermoregulation on free flap microcirculation. METHODS: Tissue temperature was assessed in 25 free perforator flaps using an implanted probe. Active thermoregulation was achieved using a water circulation based system. Changes in microcirculation were evaluated at the day of surgery and throughout the first three postoperative days after passive cooling (room temperature), passive warming (wound dressing), active warming (38 degrees C) and active cooling (15 degrees C) using laser Doppler flowmetry and remission spectroscopy. RESULTS: Active warming increased flap temperature by 7.7% to 36.4 degrees C +/- 0.5 degrees C in comparison to the initial values of flaps without dressing (P < 0.001). As a result, the blood flow increased by 77.7% of the base value (P < 0.001). A significant correlation between all microcirculation parameters and tissue temperature was observed with a 5.52 AU blood flow increase per degree temperature increase (r = 0.7; P < 0.001). All microcirculation parameters showed a statistically significant increase after both passive and active warming, whereby active warming showed significantly higher values than passive warming. CONCLUSIONS: Active thermoregulation using water-based circulation is an effective and safe procedure to improve microcirculation in free flaps and is superior to conventional passive warming strategies. PMID- 26510836 TI - Nurses' attitude and intention of medication administration error reporting. AB - AIMS AND OBJECTIVES: The Aims of this study were to explore the effects of nurses' attitudes and intentions regarding medication administration error reporting on actual reporting behaviours. BACKGROUND: Underreporting of medication errors is still a common occurrence. Whether attitude and intention towards medication administration error reporting connect to actual reporting behaviours remain unclear. DESIGN: This study used a cross-sectional design with self-administered questionnaires, and the theory of planned behaviour was used as the framework for this study. METHODS: A total of 596 staff nurses who worked in general wards and intensive care units in a hospital were invited to participate in this study. The researchers used the instruments measuring nurses' attitude, nurse managers' and co-workers' attitude, report control, and nurses' intention to predict nurses' actual reporting behaviours. Data were collected from September-November 2013. Path analyses were used to examine the hypothesized model. RESULTS: Of the 596 nurses invited to participate, 548 (92%) completed and returned a valid questionnaire. The findings indicated that nurse managers' and co-workers' attitudes are predictors for nurses' attitudes towards medication administration error reporting. Nurses' attitudes also influenced their intention to report medication administration errors; however, no connection was found between intention and actual reporting behaviour. CONCLUSIONS: The findings reflected links among colleague perspectives, nurses' attitudes, and intention to report medication administration errors. The researchers suggest that hospitals should increase nurses' awareness and recognition of error occurrence. RELEVANCE TO CLINICAL PRACTICE: Regardless of nurse managers' and co-workers' attitudes towards medication administration error reporting, nurses are likely to report medication administration errors if they detect them. Management of medication administration errors should focus on increasing nurses' awareness and recognition of error occurrence. PMID- 26510837 TI - Prevalence of bullying, discrimination and sexual harassment in surgery in Australasia. AB - BACKGROUND: The topic of discrimination, bullying and sexual harassment in surgery was raised in the Australian media earlier in 2015. This led the Royal Australasian College of Surgeons (RACS) to commission an Expert Advisory Group to investigate and advise the College on their prevalence in surgery in Australia and New Zealand. This paper reports the findings with respect to prevalence of these inappropriate behaviours. METHODS: The data in this paper were drawn from the published results of two quantitative surveys. One was an online survey sent to all RACS members. The other was an invited survey of hospitals, medical institutions and other related professional organizations including surgical societies. RESULTS: The prevalence survey achieved a 47.8% response rate, representing 3516 individuals. Almost half of the respondents 1516 (49.2%) indicated that they had experienced one or more of the behaviours. This proportion was consistent across every specialty. Male surgical consultants were identified as the most likely perpetrators. More than 70% of the hospitals reported that they had instances in their organization of discrimination, bullying or sexual harassment by a surgeon within the last 5 years. Surgical directors or surgical consultants were by far the most frequently reported perpetrators (in 50% of hospitals). CONCLUSIONS: Discrimination, bullying and sexual harassment are common in surgical practice and training in Australia and New Zealand. RACS needs to urgently address these behaviours in surgery. This will involve a change in culture, more education for fellows and trainees, and better processes around complaints including support for those who have suffered. PMID- 26510838 TI - Flux-sum analysis identifies metabolite targets for strain improvement. AB - BACKGROUND: Rational design of microbial strains for enhanced cellular physiology through in silico analysis has been reported in many metabolic engineering studies. Such in silico techniques typically involve the analysis of a metabolic model describing the metabolic and physiological states under various perturbed conditions, thereby identifying genetic targets to be manipulated for strain improvement. More often than not, the activation/inhibition of multiple reactions is necessary to produce a predicted change for improvement of cellular properties or states. However, as it is more computationally cumbersome to simulate all possible combinations of reaction perturbations, it is desirable to consider alternative techniques for identifying such metabolic engineering targets. RESULTS: In this study, we present the modified version of previously developed metabolite-centric approach, also known as flux-sum analysis (FSA), for identifying metabolic engineering targets. Utility of FSA was demonstrated by applying it to Escherichia coli, as case studies, for enhancing ethanol and succinate production, and reducing acetate formation. Interestingly, most of the identified metabolites correspond to gene targets that have been experimentally validated in previous works on E. coli strain improvement. A notable example is that pyruvate, the metabolite target for enhancing succinate production, was found to be associated with multiple reaction targets that were only identifiable through more computationally expensive means. In addition, detailed analysis of the flux-sum perturbed conditions also provided valuable insights into how previous metabolic engineering strategies have been successful in enhancing cellular physiology. CONCLUSIONS: The application of FSA under the flux balance framework can identify novel metabolic engineering targets from the metabolite centric perspective. Therefore, the current approach opens up a new research avenue for rational design and engineering of industrial microbes in the field of systems metabolic engineering. PMID- 26510839 TI - Comparison of universal screening with targeted high-risk case finding for diagnosis of thyroid disorders. AB - OBJECTIVE: Debate about the need for universal screening of thyroid dysfunction in pregnancy is ongoing. The present study aimed to compare universal screening with targeted high-risk case findings for early diagnosis of thyroid disorders in Iranian pregnant women. STUDY DESIGN: This cross-sectional prospective study was carried out on 1600 pregnant women in their first trimester. A checklist, including all related risk factors recommended by The American Thyroid Association, was completed for all participants. Serum concentrations of thyroxine (T4), T-uptake, TSH and thyroid peroxidase antibody (TPOAb) were measured and thyroid status was documented, based on hormonal measurements and clinical examinations. RESULTS: There were 656 women (44.3%) that had at least one risk factor for thyroid diseases and were eligible for the targeted high-risk case finding (high-risk group) approach, while 55.7% had no risk factors (low risk group). Using the universal screening approach, there were 974 women (65.8%) with normal thyroid status and 506 participants (34.2%) with thyroid disturbances, including overt hyperthyroidism (0.7%), overt hypothyroidism (1.1%), subclinical hypothyroidism (30.1%; positive TPOAb (5.5%) and negative TPOAb (24.6%); and euthyroid and positive TPOAb (2.3%). Of women with thyroid dysfunction, 64.4% were in the high-risk group and 35.6% were in the low-risk group (P<0.0001). CONCLUSIONS: The targeted high-risk case finding approach overlooks about one-third of pregnant women with thyroid dysfunction. If ongoing prospective trials provide evidence on the efficacy of treating subclinical hypothyroidism in pregnancy, in populations with a low prevalence of presumed risk factors, the targeted high-risk case finding approach will be proven inefficient. PMID- 26510840 TI - ENDOCRINE TUMOURS: Genetic predictors of thyroid cancer outcome. AB - Genetic predictors of outcome are reviewed in the context of a disease--cancer- that can be (too) simplistically described as a 'successful, invasive clone of our own tissues'. Context has many faces that determine a thyroid cancer patient's outcome beyond the influence of genetic markers. There is also plenty of evidence on the prognostic meaning of the interplay between genetics and context/microenvironment factors (encapsulation, degree of invasion, staging, etc.). This review addresses only genetic alterations detected by molecular methods in surgically resected specimens, thus ruling out immunohistochemistry and (F)ISH, despite their crucial relevance as topographically oriented methods. For the sake of the discussion, well-differentiated carcinomas were divided into two main morphologic types: papillary carcinoma (classic and most variants) displaying BRAFV600E mutations and RET/papillary thyroid carcinoma rearrangements and the group of follicular patterned carcinomas that encompasses follicular carcinoma and the encapsulated form of follicular variant of papillary carcinoma, displaying RAS mutations and PAX8/PPARgamma rearrangement. TERT promoter mutations have been recently described (and associated with distant metastases and reduced survival) in papillary and follicular carcinomas, as well as in poorly differentiated and undifferentiated carcinoma. TP53 mutations, previously thought to be restricted to less differentiated carcinomas, were also detected in papillary and follicular carcinoma and found to carry a guarded prognosis. Besides their putative importance for targeted therapies, the prognostic meaning of such mutations is discussed per se and in the setting of concurrent BRAF mutation. PMID- 26510841 TI - VariantMetaCaller: automated fusion of variant calling pipelines for quantitative, precision-based filtering. AB - BACKGROUND: The low concordance between different variant calling methods still poses a challenge for the wide-spread application of next-generation sequencing in research and clinical practice. A wide range of variant annotations can be used for filtering call sets in order to improve the precision of the variant calls, but the choice of the appropriate filtering thresholds is not straightforward. Variant quality score recalibration provides an alternative solution to hard filtering, but it requires large-scale, genomic data. RESULTS: We evaluated germline variant calling pipelines based on BWA and Bowtie 2 aligners in combination with GATK UnifiedGenotyper, GATK HaplotypeCaller, FreeBayes and SAMtools variant callers, using simulated and real benchmark sequencing data (NA12878 with Illumina Platinum Genomes). We argue that these pipelines are not merely discordant, but they extract complementary useful information. We introduce VariantMetaCaller to test the hypothesis that the automated fusion of measurement related information allows better performance than the recommended hard-filtering settings or recalibration and the fusion of the individual call sets without using annotations. VariantMetaCaller uses Support Vector Machines to combine multiple information sources generated by variant calling pipelines and estimates probabilities of variants. This novel method had significantly higher sensitivity and precision than the individual variant callers in all target region sizes, ranging from a few hundred kilobases to whole exomes. We also demonstrated that VariantMetaCaller supports a quantitative, precision based filtering of variants under wider conditions. Specifically, the computed probabilities of the variants can be used to order the variants, and for a given threshold, probabilities can be used to estimate precision. Precision then can be directly translated to the number of true called variants, or equivalently, to the number of false calls, which allows finding problem-specific balance between sensitivity and precision. CONCLUSIONS: VariantMetaCaller can be applied to small target regions and whole exomes as well, and it can be used in cases of organisms for which highly accurate variant call sets are not yet available, therefore it can be a viable alternative to hard filtering in cases where variant quality score recalibration cannot be used. VariantMetaCaller is freely available at http://bioinformatics.mit.bme.hu/VariantMetaCaller . PMID- 26510842 TI - Adult cannibalism in an oligophagous herbivore, the Colorado potato beetle. AB - Cannibalism, or intraspecific predation, can play a major role in changing individual fitness and population processes. In insects, cannibalism frequently occurs across life stages, with cannibals consuming a smaller or more vulnerable stage. Predation of adult insects on one another is considered to be uncommon. We investigated adult cannibalism in the Colorado potato beetle, Leptinotarsa decemlineata (Say), which is an oligophagous herbivore specializing on plants in family Solanaceae, and an important agricultural pest. Under laboratory conditions, starvation and crowding encouraged teneral adults to feed upon each other, which reduced their weight loss during the period of starvation. However, pupae were attacked and consumed before adults. Injured beetles had a higher probability of being cannibalized than intact beetles. Males were more frequently attacked than females, but that appeared to be a function of their smaller size rather than other gender-specific traits. Cannibalizing eggs at a larval stage did not affect beetle propensity to cannibalize adults at an adult stage. When given a choice between conspecific adults and mealworms, the beetles preferred to eat conspecifics. Cannibalistic behavior, including adult cannibalism, could be important for population persistence in this species. PMID- 26510843 TI - Another care bundle to improve care of the dying? PMID- 26510844 TI - Polymorphisms of the WNT16 gene are associated with the heel ultrasound parameter in young adults. AB - SUMMARY: Bone mineral content is influenced by genetic factors. We investigated the role of WNT16 in bone properties determined using quantitative ultrasound (QUS) on young adults. Three WNT16 genetic markers (rs2908007, rs2908004, and rs2707466) were found to have a significant association with the broadband ultrasound attenuation (BUA) measurement, suggesting that WNT16 influences bone mass in young adults. INTRODUCTION: The aim of this study was to investigate whether genetic markers on the WNT16 gene are associated with bone mass, as assessed using QUS in a population of healthy young Spanish adults. METHODS: A cross-sectional study was conducted on 575 individuals (mean age 20.41 +/- 2.69). Bone quality was assessed using BUA measurements (dB/MHz) on the right calcaneus. Six single nucleotide polymorphisms (SNPs) (rs2908007, rs2908004, rs3801387, rs3801385, rs2707466, and rs2536184) covering the WNT16 gene were selected as genetic markers and genotyped to test their association with BUA variations. RESULTS: The rs2908007, rs2908004, and rs2707466 SNPs were found to have a significant association with BUA (p = 0.004, p = 0.001, and p = 0.004, respectively). CONCLUSION: We demonstrate for the first time that WNT16 genetic polymorphisms influence QUS traits in a population of young adults. This finding suggests that WNT16 might be an important genetic factor in determining peak bone mass acquisition. PMID- 26510845 TI - Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports. AB - Osteoporosis treatments are usually given for a limited period of time in order to balance benefits and risks. We report three cases of postmenopausal women without any previous fragility fracture who presented severe spontaneous vertebral fractures after denosumab discontinuation. We think that the occurrence of these fractures could be explained by the severe rebound effect observed after denosumab discontinuation and that a consensus regarding the end of treatment with denosumab has to be defined. PMID- 26510846 TI - Hip fractures, preceding distal radius fractures and screening for osteoporosis: should we be screening earlier? A minimum 10-year retrospective cohort study at a single centre. AB - Both men and women who sustain a fracture of the distal forearm run an increased risk of sustaining a subsequent hip fracture. Our study implies that these patients may not necessarily constitute a group in which osteoporosis screening is warranted. INTRODUCTION: People who sustain a distal radius fracture run an increased risk of sustaining a subsequent hip fracture. However, many institutions only screen for osteoporosis at the time of a hip fracture. We aimed to determine the true incidence of preceding distal radius fractures in an Asian population of patients with a hip fracture aged 60 years or older and whether screening for osteoporosis earlier would be beneficial. METHODS: We reviewed 22 parameters of 572 patients aged 60 years or older admitted after sustaining a hip fracture over a 3-year period. This included the occurrence or absence of a distal radius fracture in the 10 years preceding their hip fracture. RESULTS: Twenty-nine patients (5 %) had a fracture of the distal radius in the preceding decade. Univariate analyses suggested that hip fracture patients who had preceding distal radius fractures were older, female, have lower mean haemoglobin levels, and right-sided hip fractures. Of these factors, only age was found to have significant predictive value in a multivariate analysis. CONCLUSIONS: A number of institutions have started to screen for osteoporosis when a patient presents with a fracture of the distal radius because these patients may have an increased risk of a subsequent hip fracture. Our study implies that this may not be warranted. Implementing such a screening service from both cost and resource utilization point of view must be studied prospectively and in greater detail considering earlier screening may only be beneficial to a very small percentage of patients. PMID- 26510847 TI - Calcium plus vitamin D supplementation and risk of fractures: an updated meta analysis from the National Osteoporosis Foundation. AB - The aim was to meta-analyze randomized controlled trials of calcium plus vitamin D supplementation and fracture prevention. Meta-analysis showed a significant 15 % reduced risk of total fractures (summary relative risk estimate [SRRE], 0.85; 95 % confidence interval [CI], 0.73-0.98) and a 30 % reduced risk of hip fractures (SRRE, 0.70; 95 % CI, 0.56-0.87). INTRODUCTION: Calcium plus vitamin D supplementation has been widely recommended to prevent osteoporosis and subsequent fractures; however, considerable controversy exists regarding the association of such supplementation and fracture risk. The aim was to conduct a meta-analysis of randomized controlled trials [RCTs] of calcium plus vitamin D supplementation and fracture prevention in adults. METHODS: A PubMed literature search was conducted for the period from July 1, 2011 through July 31, 2015. RCTs reporting the effect of calcium plus vitamin D supplementation on fracture incidence were selected from English-language studies. Qualitative and quantitative information was extracted; random-effects meta-analyses were conducted to generate summary relative risk estimates (SRREs) for total and hip fractures. Statistical heterogeneity was assessed using Cochran's Q test and the I (2) statistic, and potential for publication bias was assessed. RESULTS: Of the citations retrieved, eight studies including 30,970 participants met criteria for inclusion in the primary analysis, reporting 195 hip fractures and 2231 total fractures. Meta-analysis of all studies showed that calcium plus vitamin D supplementation produced a statistically significant 15 % reduced risk of total fractures (SRRE, 0.85; 95 % confidence interval [CI], 0.73-0.98) and a 30 % reduced risk of hip fractures (SRRE, 0.70; 95 % CI, 0.56-0.87). Numerous sensitivity and subgroup analyses produced similar summary associations. A limitation is that this study utilized data from subgroup analysis of the Women's Health Initiative. CONCLUSIONS: This meta-analysis of RCTs supports the use of calcium plus vitamin D supplements as an intervention for fracture risk reduction in both community-dwelling and institutionalized middle-aged to older adults. PMID- 26510848 TI - Serum total estradiol, but not testosterone is associated with reduced bone mineral density (BMD) in HIV-infected men: a cross-sectional, observational study. AB - SUMMARY: By investigating the relationship between serum testosterone, estradiol, and bone mineral density (BMD) in a large cohort of HIV-infected men, estradiol was associated with BMD, relative estrogen deficiency being involved in bone loss in men with hypogonadism, in addition to all HIV-related factors. Increased aromatization in adipose tissue does not counteract HIV-related bone loss. INTRODUCTION: The purpose of this study is to evaluate the relationship between serum testosterone, estradiol, and BMD in a large cohort of HIV-infected men. METHODS: We investigated biochemical, hormonal parameters, and BMD in 1204 HIV infected men (age 45.64 +/- 7.33 years) participating in a cross-sectional, observational study. Among other parameters, the main outcome measures were serum total testosterone and estradiol, gonadotropins, 25-hydroxyvitamin D [25(OH)D], parathormone (PTH), calcium, phosphorous, femoral, and lumbar BMD. RESULTS: In men with HIV, the prevalence of osteoporosis and osteopenia is 15.1 and 63.2% with 25(OH)D insufficiency being very common (60.1%). After age adjustment, BMD is positively associated with estradiol, but not testosterone, at linear (p < 0.001) and stepwise (p < 0.05) multiple regression. Lumbar BMD significantly increases across the estradiol quartiles but not among testosterone quartiles. Femoral and lumbar BMD are significantly higher in men with estradiol >= 27 pg/mL than in those with estradiol <27 pg/mL. Apart from estradiol, only age, calcium, and BMI predict BMD at stepwise linear multiple regression, but the strength of this association is weak. CONCLUSIONS: Estradiol, but not testosterone, is associated with BMD in HIV-infected men and exerts a protective role on bone especially when it is above 27 pg/mL. Relative estrogen deficiency is a potential mechanism involved in bone loss in hypogonadal HIV-infected men, in addition to all HIV-related factors. Increased aromatization in adipose tissue does not counteract HIV-related bone loss. Finally, reduced BMD in young-to-middle-aged HIV-infected men might be considered a peculiar hallmark of HIV infection due to its relevant prevalence, representing one of the several pieces composing the complicated puzzle of premature aging related to HIV infection. PMID- 26510849 TI - Linguistic and Cognitive Profiles of 8- to 15-Year-Old Children With Specific Reading Comprehension Difficulties. AB - This article presents two studies investigating the role of executive functioning in written text comprehension in children and adolescents. In a first study, the involvement of executive functions in reading comprehension performance was examined in normally developing children in fifth grade. Two aspects of text comprehension were differentiated: literal and inferential processes. The results demonstrated that while three aspects of executive functioning (working memory, planning, and inhibition processes) were significantly predictive of the performance on the inferential questions of the comprehension test, these factors did not predict the scores on the literal tasks of the test. In a second experiment, the linguistic and cognitive profiles of children in third/fifth and seventh/ninth grades with a specific reading comprehension deficit were examined. This analysis revealed that the deficits experienced by the less skilled comprehenders in both the linguistic and the executive domains could evolve over time. As a result, linguistic factors do not make it possible to distinguish between good and poor comprehenders among the group of older children, whereas the difficulties relating to executive processing remain stable over development. These findings are discussed in the context of the need to take account of the executive difficulties that characterize less skilled comprehenders of any age, especially for remediation purposes. PMID- 26510850 TI - The frequency of early colorectal cancer derived from sessile serrated adenoma/polyps among 1858 serrated polyps from a single institution. AB - BACKGROUND AND AIM: Sessile serrated adenoma/polyps (SSAPs) are suspected to have a high malignant potential, although few reports have evaluated the incidence of carcinomas derived from SSAPs using the new classification for serrated polyps (SPs). The aim of study was to compare the frequency of cancer coexisting with the various SP subtypes including mixed polyps (MIXs) and conventional adenomas (CADs). METHODS: A total of 18,667 CADs were identified between April 2005 and December 2011, and 1858 SPs (re-classified as SSAP, hyperplastic polyp (HP), traditional serrated adenoma (TSA), or MIX) were removed via snare polypectomy, endoscopic mucosal resection, or endoscopic sub-mucosal dissection. RESULTS: Among 1160 HP lesions, 1 (0.1%) coexisting sub-mucosal invasive carcinoma (T1) was detected. Among 430 SSAP lesions, 3 (0.7%) high-grade dysplasia (HGD/Tis) and 1 (0.2%) T1 were detected. All of the lesions were detected in the proximal colon, with a mean tumor diameter of 18 mm (SD 9 mm). Among 212 TSA lesions, 3 (1%) HGD/Tis were detected but no T1 cancer. Among 56 MIX lesions, 9 (16%) HGD/Tis and 1 (2%) T1 cancers were detected, and among 18,677 CAD lesions, 964 (5%) HGD/Tis and 166 (1%) T1 cancers were identified. CONCLUSIONS: Among the resected lesions that were detected during endoscopic examination, a smaller proportion (1%) of SSAPs harbored HGD or coexisting cancer, compared to CAD or MIX lesions. Therefore, more attention should be paid to accurately identifying lesions endoscopically for intentional resection and the surveillance of each SP subtype. PMID- 26510852 TI - The 8th international symposium on the breast: Using next-generation science to understand the normal breast and the development of breast cancer- conference report. AB - Dr. Susan Love Research Foundation is committed to performing and advancing research that will lead to the discovery of what causes cancer to develop in the human breast. As part of this effort, the Foundation hosted the 8th International Symposium on the Breast in Santa Monica, Calif., Feb. 19 to Feb. 21, 2015. More than 120 forward-thinking clinical researchers, epidemiologists, pathologists, basic scientists, translational investigators, and breast cancer advocates from six countries attended this year's conference, "Using Next Generation Science to Understand the Normal Breast and the Development of Cancer." The highlights from this year's symposium are summarized in this report. PMID- 26510851 TI - Dose-response effects of aerobic exercise on estrogen among women at high risk for breast cancer: a randomized controlled trial. AB - Medical and surgical interventions for elevated breast cancer risk (e.g., BRCA1/2 mutation, family history) focus on reducing estrogen exposure. Women at elevated risk may be interested in less aggressive approaches to risk reduction. For example, exercise might reduce estrogen, yet has fewer serious side effects and less negative impact than surgery or hormonal medications. Randomized controlled trial. Increased risk defined by risk prediction models or BRCA mutation status. Eligibility: Age 18-50, eumenorrheic, non-smokers, and body mass index (BMI) between 21 and 50 kg/m(2). 139 were randomized. Treadmill exercise: 150 or 300 min/week, five menstrual cycles. Control group maintained exercise <75 min/week. PRIMARY OUTCOME: Area under curve (AUC) for urinary estrogen. Secondary measures: urinary progesterone, quantitative digitized breast dynamic contrast-enhanced magnetic resonance imaging background parenchymal enhancement. Mean age 34 years, mean BMI 26.8 kg/m(2). A linear dose-response relationship was observed such that every 100 min of exercise is associated with 3.6 % lower follicular phase estrogen AUC (linear trend test, p = 0.03). No changes in luteal phase estrogen or progesterone levels. There was also a dose-response effect noted: for every 100 min of exercise, there was a 9.7 % decrease in background parenchymal enhancement as measured by imaging (linear trend test, p = 0.009). Linear dose response effect observed to reduce follicular phase estrogen exposure measured via urine and hormone sensitive breast tissue as measured by imaging. Future research should explore maintenance of effects and extent to which findings are repeatable in lower risk women. Given the high benefit to risk ratio, clinicians can inform young women at increased risk that exercise may blunt estrogen exposure while considering whether to try other preventive therapies. PMID- 26510853 TI - The Nutritional Intake of Patients with Organic Acidaemias on Enteral Tube Feeding: Can We Do Better? AB - BACKGROUND: Detailed nutritional intake data on children with organic acidaemias (OA) (propionic acidaemia (PA), vitamin B12 nonresponsive methylmalonic acidaemia (MMA) and isovaleric acidaemia (IVA)) remains unreported. Aim and subjects: A review of the longitudinal nutritional intake of 14 children with organic acidaemias (PA n = 8; MMA n = 5; IVA n = 1) dependent on enteral tube feeding (>=90% of energy requirements) from a single treatment centre. METHODS: Nutritional intake (energy, protein, precursor-free L-amino acids, vitamins and minerals), anthropometry and nutritional biochemistry data were collated from diagnosis to current age. RESULTS: The median energy intake was only 72% (63-137) of the estimated average DH (1991) requirement (EAR), decreasing significantly by 40% between 6 months and 5 years (p < 0.05). Total protein intake met WHO/FAO/UNU (2007) safe intake levels with median (range) precursor-free L-amino acids providing 21% (14-28) of total protein intake. Median mineral intake for sodium was 57% (20-97%), potassium 64% (27-125%) and magnesium 72% (22-116%) and was consistently < RNI for all age points. Fibre median intake was 4 g/day (0-11 g), and fluid intake provided 80% (60-100%) of the requirements for age. Linear growth was poor, and children were overweight for their height (1-10 years: z score median weight +0.6, height -1.2). Nutritional markers consistently indicated that plasma valine concentrations were < target reference ranges in PA and MMA. Iron deficiency anaemia was common in MMA/PA, and in PA, 50% of plasma zinc concentrations were < reference range. CONCLUSION: In MMA/PA, energy intake decreases over time, weight gain accelerates, but linear height is poor. There are many nutrient deficiencies which may affect short- and long-term outcome of patients with organic acidaemias. The quality of long-term diet in these conditions deserves more attention. PMID- 26510854 TI - Inhibiting the PI3K signaling pathway: buparlisib as a new targeted option in breast carcinoma. AB - Aberrations in the PI3K signaling pathway are frequently observed in patients with breast cancer. Because of that, PI3K inhibitors are attractive options for the treatment of breast cancer because PI3K is the most proximal component of the pathway other than receptor tyrosine kinases. Buparlisib is a potent and highly specific oral pan-class I PI3K inhibitor, which is currently under investigation in patients with breast cancer. In this article, we describe the PI3K signaling pathway, the prognostic value of PI3K pathway mutations, as well as the mechanism of action of buparlisib. Lastly, we discuss preliminary results of preclinical and clinical studies showing the efficacy and safety profile of this agent in breast cancer patients. PMID- 26510855 TI - Religious Beliefs Against Smoking Among Black and White Urban Youth. AB - This study explores the relation of religiosity to cigarette smoking in a sample of 4776 Black versus White adolescents. Findings show that Black adolescents have significantly stronger religious beliefs against smoking than do White students. Further, teens with strong or very strong religious beliefs are less likely to have smoked. The protective effect of religious beliefs against smoking was stronger for Whites than for Blacks. These findings suggest that efforts in the Black religious community to prevent cigarette smoking have been somewhat successful. Similar efforts in the White community might help stem the tide of tobacco use among White teens. PMID- 26510856 TI - Fc Gamma Receptor 3A and 2A Polymorphisms Do Not Predict Response to Rituximab in Follicular Lymphoma. AB - PURPOSE: Preclinical studies suggest that SNPs in the Fc gamma receptor (FCGR) genes influence response to rituximab, but the clinical relevance of this is uncertain. EXPERIMENTAL DESIGN: We prospectively obtained specimens for genotyping in the rituximab extended schedule or re-treatment trial (RESORT) study, in which 408 previously untreated, low tumor burden follicular lymphoma (FL) patients were treated with single agent rituximab. Patients received rituximab in 4 weekly doses and responders were randomized to rituximab re treatment (RR) upon progression versus maintenance rituximab (MR). SNP genotyping was performed in 321 consenting patients. RESULTS: Response rates to initial therapy and response duration were correlated with the FCGR3A SNP at position 158 (rs396991) and the FCGR2A SNP at position 131 (rs1801274). The response rate to initial rituximab was 71%. No FCGR genotypes or grouping of genotypes were predictive of initial response. A total of 289 patients were randomized to RR (n = 143) or to MR (n = 146). With a median follow-up of 5.5 years, the 3-year response duration in the RR arm and the MR arm was 50% and 78%, respectively. Genotyping was available in 235 of 289 randomized patients. In patients receiving RR (n = 115) or MR (n = 120), response duration was not associated with any FCGR genotypes or genotype combinations. CONCLUSIONS: Based on this analysis of treatment-naive, low tumor burden FL, we conclude that the FCGR3A and FCGR2A SNPs do not confer differential responsiveness to rituximab. PMID- 26510857 TI - Right-Sizing Adjuvant and Neoadjuvant Clinical Trials in Breast Cancer. AB - I describe a simple and intuitive method for finding sample size for clinical trials in primary breast cancer based on neoadjuvant trial results and using the FDA's patient-level meta-analysis. Then I explain a problem with this method and how the problem can be remedied. PMID- 26510858 TI - Patients with a High Polygenic Risk of Breast Cancer do not have An Increased Risk of Radiotherapy Toxicity. AB - PURPOSE: It has been hypothesized that increased predisposition to breast cancer may correlate with radiosensitivity, and thus increased risk of toxicity following breast irradiation. This study investigated the relationship between common breast cancer risk variants and radiotherapy toxicity. EXPERIMENTAL DESIGN: SNP genotypes were determined in female breast cancer patients from the RAPPER (Radiogenomics: Assessment of polymorphisms for predicting the effects of radiotherapy) study using the Illumina CytoSNP12 genome-wide array. A further 15,582,449 genotypes were imputed using the 1000 Genomes Project reference panel. Patient (n = 1,160) polygenic risk scores were generated by summing risk-allele dosages, both unweighted and weighted by published effect sizes for breast cancer risk. Regression models were used to test associations of individual variants and polygenic risk scores with acute and late toxicity phenotypes (telangiectasia, breast edema, photographically assessed shrinkage, induration, pigmentation, breast pain, breast sensitivity, and overall toxicity). RESULTS: Genotypes of 90 confirmed breast cancer risk variants were accurately determined and polygenic risk scores were approximately normally distributed. Variant rs6964587 was associated with increased breast edema 5 years following radiotherapy (Beta, 0.22; 95% confidence interval, 0.09-0.34; P = 7 * 10(-4)). No other associations were found between individual variants or the unweighted (P > 0.17) or weighted (P > 0.13) polygenic risk score and radiotherapy toxicity. This study had >87% power to detect an association between the polygenic risk score (relative risk > 1.1) and toxicity. CONCLUSIONS: Cancer patients with a high polygenic predisposition to breast cancer do not have an increased risk of radiotherapy toxicity up to 5 years following radiotherapy but individual variants may increase risk. PMID- 26510859 TI - Incidence of Clear Cell Papillary Renal Cell Carcinoma in Low-Grade Renal Cell Carcinoma Cases: A 12-Year Retrospective Clinicopathologic Study From a Single Cancer Center. AB - Clear cell papillary renal cell carcinoma (CCPRCC) is a recently recognized subtype of renal cell carcinoma entity after 2004 World Health Organization classification of renal tumors. CCPRCC has unique histomorphological and immunohistochemical characteristics. The distinction of CCPRCC from renal cell carcinoma (RCC) with clear cell morphology is crucial because the former is considered to have a favorable clinical outcome. CCPRCC may be interpreted in the past as other renal cell carcinomas, particularly low-grade clear cell RCC. In this study, the frequency of CCPRCC in previously diagnosed low-grade RCC and its clinicopathologic features were examined. A total of 126 cases of stage T1a with low nuclear grade RCC were identified from 625 consecutive RCCs removed by radical/partial nephrectomy over 12-year period (2000-2011). Archival tissue sections were retrospectively reviewed along with patient medical charts. Eight cases (1.3% of all RCC, 6.3% of pT1a low grade RCC) with characteristic histologic features of CCPRCC were confirmed by immunohistochemical studies. Seven cases were previously diagnosed as clear cell RCC and one as multilocular cystic RCC. Radiographically, CCPRCC favored a mid-pole location in the kidneys. At a median follow-up period of 52 months (range 20-114.5 months), there were no cases of local or distant recurrence. In conclusion, CCPRCC is not uncommon among small low-grade RCC tumors. CCPRCC can be correctly recognized by its unique histomorphological features and confirmed by immunohistochemistry studies, which is important due to the excellent clinical outcome following resection. PMID- 26510860 TI - Mesonephric Adenocarcinoma of the Uterine Corpus: A Case Report and Diagnostic Pitfall. AB - Mesonephric adenocarcinoma is a rare tumor type that is usually found in areas where the Wolffian duct was present during the fetal period. We report a case of mesonephric adenocarcinoma of the uterine corpus in a 66-year-old woman who presented with vaginal bleeding. Pelvic magnetic resonance imaging revealed a 2.7 cm-sized irregular thickening and enhancement of the uterine body. The diagnosis following endometrial curettage biopsy was endometrioid adenocarcinoma, and the patient underwent a total hysterectomy with bilateral salpingo-oophorectomy. The tumor was composed of small tubular and ductal components, and a retiform appearance was also observed in the deeper areas. The tumor cells were immunopositive for cytokeratin, vimentin, CD10 with a luminal staining pattern, PAX2, and PAX8, and immunonegative for estrogen receptor and progesterone receptor, which was consistent with tumor of mesonephric origin. Mesonephric neoplasms reveal relatively low-grade nuclear feature, characteristic immunoprofiles (immunonegative for ER and PR, and immunopositive for CD10, PAX2, PAX8, and GATA3), and unique tumor location (myometrium), whereas Mullerian neoplasms such as endometrial adenocarcinoma show various morphology, immunopositivity for ER and PR, and primarily endometrial location. As described above, an integration of the clinical features, morphologic characteristics, and immunohistochemical profiles is needed to make a diagnosis. PMID- 26510861 TI - Primary Intracranial Myoepithelial Neoplasm: A Potential Mimic of Meningioma. AB - Myoepithelial neoplasms were originally described in the salivary glands but their spectrum has been expanding with reports in other locations, including soft tissue. Intracranial cases are exceptionally rare outside the sellar region where they are assumed to be arising from Rathke pouch rests. Two cases of pediatric intracranial myoepithelial neoplasm in the interhemispheric fissure and the right cerebral hemisphere are reported here. Imaging studies suggest that the second case was associated with cerebrospinal fluid dissemination. Both cases showed typical variation in morphology and immunophenotype between more epithelioid and more mesenchymal features. The differential diagnosis at this particular anatomic location includes meningioma, which can show some overlap in immunophenotype since both tumors express EMA as well as GLUT1. One case was positive for EWSR1 rearrangement by fluorescence in situ hybridization. One patient is disease free at last follow-up while the other succumbed to the disease within days illustrating the clinical spectrum of these tumors. PMID- 26510862 TI - General synthesis of inorganic single-walled nanotubes. AB - The single-walled nanotube (SWNT) is an interesting nanostructure for fundamental research and potential applications. However, very few inorganic SWNTs are available to date due to the lack of efficient fabrication methods. Here we synthesize four types of SWNT: sulfide; hydroxide; phosphate; and polyoxometalate. Each type of SWNT possesses essentially uniform diameters. Detailed studies illustrate that the formation of SWNTs is initiated by the self coiling of the corresponding ultrathin nanostructure embryo/building blocks on the base of weak interactions between them, which is not limited to specific compounds or crystal structures. The interactions between building blocks can be modulated by varying the solvents used, thus multi-walled tubes can also be obtained. Our results reveal that the generalized synthesis of inorganic SWNTs can be achieved by the self-coiling of ultrathin building blocks under the proper weak interactions. PMID- 26510863 TI - Signal Inhibition Reveals JAK/STAT3 Pathway as Critical for Bovine Inner Cell Mass Development. AB - The inner cell mass (ICM) of mammalian blastocysts consists of pluripotent epiblast and hypoblast lineages, which develop into embryonic and extraembryonic tissues, respectively. We conducted a chemical screen for regulators of epiblast identity in bovine Day 8 blastocysts. From the morula stage onward, in vitro fertilized embryos were cultured in the presence of cell-permeable small molecules targeting nine principal signaling pathway components, including TGFbeta1, BMP, EGF, VEGF, PDGF, FGF, cAMP, PI3K, and JAK signals. Using 1) blastocyst quality (by morphological grading), 2) cell numbers (by differential stain), and 3) epiblast (FGF4, NANOG) and hypoblast (PDGFRa, SOX17) marker gene expression (by quantitative PCR), we identified positive and negative regulators of ICM development and pluripotency. TGFbeta1, BMP, and cAMP and combined VEGF/PDGF/FGF signals did not affect blastocyst development while PI3K was important for ICM growth but did not alter lineage-specific gene expression. Stimulating cAMP specifically increased NANOG expression, while combined VEGF/PDGF/FGF inhibition up-regulated epiblast and hypoblast markers. The strongest effects were observed by suppressing JAK1/2 signaling with AZD1480. This treatment interfered with ICM formation, but trophectoderm cell numbers and markers (CDX2, KTR8) were not altered. JAK inhibition repressed both epiblast and hypoblast transcripts as well as naive pluripotency-related genes (KLF4, TFCP2L1) and the JAK substrate STAT3. We found that tyrosine (Y) 705-phosphorylated STAT3 (pSTAT3(Y705)) was restricted to ICM nuclei, where it colocalized with SOX2 and NANOG. JAK inhibition abolished this ICM-exclusive pSTAT3(Y705) signal and strongly reduced the number of SOX2-positive nuclei. In conclusion, JAK/STAT3 activation is required for bovine ICM formation and acquisition of naive pluripotency markers. PMID- 26510865 TI - Effects of High-Butterfat Diet on Embryo Implantation in Female Rats Exposed to Bisphenol A. AB - Bisphenol A (BPA) is an endocrine disruptor associated with poor pregnancy outcomes in human and rodents. The effects of butterfat diets on embryo implantation and whether it modifies BPA's actions are currently unknown. We aimed to determine the effects of butterfat diet on embryo implantation success in female rats exposed to an environmentally relevant dose of BPA. Female Sprague Dawley rats were exposed to dietary butterfat (10% or 39% kcal/kg body weight [BW]) in the presence or absence of BPA (250 MUg/kg BW) or ethinylestradiol (0.1 MUg/kg BW) shortly before and during pregnancy to assess embryo implantation potentials by preimplantation development and transport, in vitro blastulation, outgrowth, and implantation. On gestational day (GD) 4.5, rats treated with BPA alone had higher serum total BPA level (2.3-3.7 ng/ml). They had more late-stage preimplantation embryos, whereas those receiving high butterfat (HBF) diet had the most advanced-stage embryos; dams cotreated with HBF and BPA had the most number of advanced embryos. BPA markedly delayed embryo transport to the uterus, but neither amount of butterfat had modifying effects. An in vitro implantation assay showed HBF doubled the outgrowth area, with BPA having no effect. In vivo, BPA reduced the number of implanted embryos on GD8, and cotreatment with HBF eliminated this adverse effect. HBF diet overall resulted in more and larger GD8 embryos. This study reveals the implantation disruptive effects of maternal exposure to an environmentally relevant dose of BPA and identifies HBF diet as a modifier of BPA in promoting early embryonic health. PMID- 26510864 TI - Pregnancy Increases Relaxation in Human Omental Arteries to the CGRP Family of Peptides. AB - Calcitonin gene-related peptide (CALCB) and its family members adrenomedullin (ADM) and intermedin (ADM2) play important roles in maintaining vascular adaptations during pregnancy in animal models. The present study was designed to evaluate the responses of omental arteries to CALCB, ADM, and ADM2 in pregnant and nonpregnant women, and to determine the mechanisms involved. By using resistance omental arteries collected from nonpregnant women (n = 15) during laparotomy and from term pregnant women (n = 15) at cesarean delivery, this study shows that the receptor components--calcitonin receptor-like receptor (CALCRL) and receptor activity-modifying proteins (RAMPs) 1, 2 and 3--are localized to endothelial and smooth muscle cells in omental arteries, with increased expressions of both mRNA and protein in pregnant compared with nonpregnant women. The myography study demonstrated that CALCB, ADM, and ADM2 (0.1-100 nM) dose dependently relax U46619 (1 muM) precontracted omental artery segments, and the maximum possible effects to CALCB and ADM2, but not to ADM, are significantly enhanced in pregnant compared with nonpregnant women. Further, the vasodilatory responses to CALCB, ADM, and ADM2 are reduced by inhibitors of nitric oxide (NO) synthase (L-NAME), adenylyl cyclase (SQ22536), voltage-activated potassium channels (4-aminopyrodin and tetrabutylammonium), Ca(2+)-activated potassium channel (charybdotoxin), and cyclooxygenase (indomethacin). In conclusion, the CALCB family of peptides, CALCB and ADM2, increase human omental artery relaxation during pregnancy through diverse mechanisms, including NO, endothelium derived hyperpolarizing factors (EDHFs) and prostaglandins, and thus could contribute to the vascular adaptations during pregnancy in the human. PMID- 26510866 TI - GATA4 and GATA6 Knockdown During Luteinization Inhibits Progesterone Production and Gonadotropin Responsiveness in the Corpus Luteum of Female Mice. AB - The surge of luteinizing hormone triggers the genomic reprogramming, cell differentiation, and tissue remodeling of the ovulated follicle, leading to the formation of the corpus luteum. During this process, called luteinization, follicular granulosa cells begin expressing a new set of genes that allow the resulting luteal cells to survive in a vastly different hormonal environment and to produce the extremely high amounts of progesterone (P4) needed to sustain pregnancy. To better understand the molecular mechanisms involved in the regulation of luteal P4 production in vivo, the transcription factors GATA4 and GATA6 were knocked down in the corpus luteum by crossing mice carrying Gata4 and Gata6 floxed genes with mice carrying Cre recombinase fused to the progesterone receptor. This receptor is expressed exclusively in granulosa cells after the luteinizing hormone surge, leading to recombination of floxed genes during follicle luteinization. The findings demonstrated that GATA4 and GATA6 are essential for female fertility, whereas targeting either factor alone causes subfertility. When compared to control mice, serum P4 levels and luteal expression of key steroidogenic genes were significantly lower in conditional knockdown mice. The results also showed that GATA4 and GATA6 are required for the expression of the receptors for prolactin and luteinizing hormone, the main luteotropic hormones in mice. The findings demonstrate that GATA4 and GATA6 are crucial regulators of luteal steroidogenesis and are required for the normal response of luteal cells to luteotropins. PMID- 26510867 TI - Anti-Mullerian Hormone Is Required for Chicken Embryonic Urogenital System Growth but Not Sexual Differentiation. AB - In mammals, the primary role of anti-Mullerian hormone (AMH) during development is the regression of Mullerian ducts in males. These structures otherwise develop into fallopian tubes, oviducts, and upper vagina, as in females. This highly conserved function is retained in birds and is supported by the high levels of AMH expression in developing testes. In mammals, AMH expression is controlled partly by the transcription factor, SOX9. However, in the chicken, AMH mRNA expression precedes that of SOX9 , leading to the view that AMH may lie upstream of SOX9 and play a more central role in avian testicular development. To help define the role of AMH in chicken gonad development, we suppressed AMH expression in chicken embryos using RNA interference. In males, AMH knockdown did not affect the expression of key testis pathway genes, and testis cords developed normally. However, a reduction in the size of the mesonephros and gonads was observed, a phenotype that was evident in both sexes. This growth defect occurred as a result of the reduced proliferative capacity of the cells of these tissues, and male gonads also had a significant reduction in germ cell numbers. These data suggest that although AMH does not directly contribute to testicular or ovarian differentiation, it is required in a sex-independent manner for proper cell proliferation and urogenital system growth. PMID- 26510868 TI - DICER Regulates the Formation and Maintenance of Cell-Cell Junctions in the Mouse Seminiferous Epithelium. AB - The endonuclease DICER that processes micro-RNAs and small interfering RNAs is essential for normal spermatogenesis and male fertility. We previously showed that the deletion of Dicer1 gene in postnatal spermatogonia in mice using Ngn3 promoter-driven Cre expression caused severe defects in the morphogenesis of haploid spermatid to mature spermatozoon, including problems in cell polarization and nuclear elongation. In this study, we further analyzed the same mouse model and revealed that absence of functional DICER in differentiating male germ cells induces disorganization of the cell-cell junctions in the seminiferous epithelium. We detected discontinuous and irregular apical ectoplasmic specializations between elongating spermatids and Sertoli cells. The defective anchoring of spermatids to Sertoli cells caused a premature release of spermatids into the lumen. Our findings may help also explain the abnormal elongation process of remaining spermatids because these junctions and the correct positioning of germ cells in the epithelium are critically important for the progression of spermiogenesis. Interestingly, cell adhesion-related genes were generally upregulated in Dicer1 knockout germ cells. Claudin 5 ( Cldn5 ) was among the most upregulated genes and we show that the polarized localization of CLAUDIN5 in the apical ectoplasmic specializations was lost in Dicer1 knockout spermatids. Our results suggest that DICER-dependent pathways control the formation and organization of cell-cell junctions in the seminiferous epithelium via the regulation of cell adhesion-related genes. PMID- 26510869 TI - Adrenomedullin 2 (ADM2) Regulates Mucin 1 at the Maternal-Fetal Interface in Human Pregnancy. AB - Association of an altered expression of placental mucin 1 (MUC1) with first trimester spontaneous abortion and its regulation in placenta by an invasion promoting peptide, adrenomedullin 2 (ADM2), is not known. The objective of this study was to assess 1) the association of MUC1 mRNA expression in the placental villi and decidua with first-trimester spontaneous abortion, 2) the effects of ADM2 on the expression of MUC1 in trophoblast cells in the presence or absence of hypoxia, 3) the effects of ADM2 on expression of MUC1 in decidual stromal cells (DSCs), and 4) if ADM2 regulates the expression of MUC1 and MMP2 protein in trophoblastic spheroids. Data demonstrate that 1) expression of MUC1 mRNA in villous tissue is higher in spontaneous abortion compared to age-matched electively terminated pregnancies (P > 0.05), 2) ADM2 decreases the expression of MUC1 mRNA and protein in trophoblast cells and spheroids with concomitant increases in MMP2 immunoreactivity in the spheroids, 3) ADM2 decreases hypoxia induced increases in MUC1 immunoreactivity in trophoblast cells, 4) decidual MUC1 mRNA expression is lower in spontaneous compared to elective abortions (P < 0.05), and 5) DSCs express MUC1 mRNA and protein and ADM2 decreases the expression of MUC1 mRNA and protein in DSCs. Taken together, this study demonstrates that first-trimester spontaneous abortion is associated with increases in MUC1 expression in villi and decreases in the decidual tissues, and suggests that ADM2 may contribute to the physiology of embryo implantation and placental growth via increasing MMP2 and decreasing MUC1 expression to facilitate trophoblast invasion. PMID- 26510871 TI - Diagnostic Efficacy of a Single Progesterone Determination to Assess Full-Term Pregnancy in the Bitch. AB - In clinical settings, when the reproductive history of a near-term bitch is limited to mating dates, the possibility to accurately assess whether pregnancy is at term could be very useful in order to be able to plan a correct management of parturition or to safely perform an elective Caesarean section. The aim of this study was to assess the diagnostic efficacy of a single progesterone determination, measured by chemiluminescent immunoassay (CLIA), in predicting the occurrence of parturition on the following day. At least one blood sample was collected from 51 pre-partum bitches during the 3 days before parturition and on day of parturition. The efficacy of progesterone as a marker of the end of pregnancy was tested using a receiver operating characteristic (ROC) analysis. Youden's index was calculated to select the optimal cut-off value (with 95% confidence interval), aiming at maximizing the correct identification of negative events, so not to risk to diagnose as full term a bitch which is not. Progesterone concentration lower than 3.4 ng/ml correctly identified the bitches whelping the following day; however, because of the obliged prudential approach, sensitivity was low (46.88%), and 17 of 32 full-term bitches were missed. Due to a very large individual variation, a single progesterone determination has low diagnostic efficacy, although it can represent a useful first screening. PMID- 26510870 TI - Environmentally Induced Epigenetic Transgenerational Inheritance of Reproductive Disease. AB - Reproductive disease and fertility issues have dramatically increased in the human population over the last several decades, suggesting environmental impacts. Epigenetics provides a mechanistic link by which an organism can respond to environmental factors. Interestingly, environmentally induced epigenetic alterations in the germ line can promote aberrant gene expression and disease generationally. Environmentally induced epigenetic transgenerational inheritance is defined as germ-line transmission of altered epigenetic information between generations in the absence of continued environmental exposures. This form of nongenetic inheritance has been shown to directly influence fertility and reproductive disease. This review describes the studies in a variety of species that impact reproductive disease and abnormalities. Observations suggest serious attention be paid to the possibility that ancestral exposures to environmental insults promotes transgenerational inheritance of reproductive disease susceptibility. Environmentally induced epigenetic transgenerational inheritance appears to be an important contributing factor to reproductive disease in many organisms, including humans. PMID- 26510872 TI - Toscana virus infects dendritic and endothelial cells opening the way for the central nervous system. AB - Toscana virus (TOSV) is a Phlebovirus responsible for human neurological infections in endemic Mediterranean areas. The main viral target is the central nervous system, with viremia as a way of dissemination throughout the host. This study was aimed at understanding the spread of TOSV in the host by identifying the cell population infected by the virus and the vehicle to the organs. In vivo studies provided evidence that endothelial cells are infected by TOSV, indicating their potential role in the diffusion of the virus following viremic spread. These results were further confirmed in vitro. Human peripheral mononuclear blood cells were infected with TOSV; only monocyte-derived dendritic cells were identified as susceptible to TOSV infection. Productive viral replication was then observed in human monocyte-derived dendritic cells (moDCs) and in human endothelial cells by recovery of the virus from a cell supernatant. Interleukin-6 was produced by both cell types upon TOSV infection, mostly by endothelial cells, while moDCs particularly expressed TNF-alpha, which is known to induce a long lasting decrease in endothelial cell barrier function. These cells could therefore be implicated in the spread of the virus in the host and in the infection of tissues that are affected by the disease, such as the central nervous system. The identification of in vitro and in vivo TOSV cell targets is an important tool for understanding the pathogenesis of the infection, providing new insight into virus-cell interaction for improved knowledge and control of this viral disease. PMID- 26510873 TI - Evaluation of Obesity in School-Age Children. AB - To prevent obesity in middle age, early precautions and interventions are required during childhood. Therefore, it is very important to accurately evaluate the degree of overweight in children. Body mass index (BMI) is widely used worldwide in adults, but not in children. Because standard BMI, which is calculated using the average height and weight for age, changes widely during growth, a constant cut-off point cannot be set for children. An international unified method defining childhood obesity has not been established. In many countries, BMI-for-age percentile (BMI%) value or Z (standard deviation) score is used, whereas in Japan, the percentage of overweight (POW), which is the modified weight-for-height method, is used. We compared BMI% values with POW values obtained using the anthropometric data of elementary and junior high school students based on the Japanese school survey conducted in 2000 and found that the values for the degree of overweight were significantly different between the two methods. It became clear that tall students were easily defined as being overweight, whereas short students tended to be evaluated as being underweight when using BMI%. POW method seemed to be more appropriate than BMI% for school age children. Abdominal obesity, excess visceral adipose tissue (VAT), is highly associated with obesity-related complications. Waist circumference (WC) is now accepted as an appropriate guide to VAT accumulation. The cut-off value of WC defining excess VAT is 80 cm at the umbilical level in Japanese school-age children. It is not easy to decide the obesity criteria and optimum WC in school age children. Childhood obesity should be discussed more internationally. PMID- 26510874 TI - Transgenic Wuzhishan minipigs designed to express a dominant-negative porcine growth hormone receptor display small stature and a perturbed insulin/IGF-1 pathway. AB - Growth hormone (GH) is an anabolic mitogen with widespread influence on cellular growth and differentiation as well as on glucose and lipid metabolism. GH binding to the growth hormone receptor (GHR) on hepatocytes prompts expression of insulin growth factor I (IGF-1) involved in nutritionally induced compensatory hyperplasia of pancreatic beta-cell islets and insulin release. A prolonged hyperactivity of the IGF-1/insulin axis in the face of insulinotropic nutrition, on the other hand, can lead to collapse of the pancreatic islets and glucose intolerance. Individuals with Laron syndrome carry mutations in the GHR gene resulting in severe congenital IGF-1 deficiency and elevated GH serum levels leading to short stature as well as perturbed lipid and glucose metabolism. However, these individuals enjoy a reduced prevalence of acne, cancer and possibly diabetes. Minipigs have become important biomedical models for human conditions due to similarities in organ anatomy, physiology, and metabolism relative to humans. The purpose of this study was to generate transgenic Wuzhishan minipigs by handmade cloning with impaired systemic GHR activity and assess their growth profile and glucose metabolism. Transgenic minipigs featuring overexpression of a dominant-negative porcine GHR (GHR(dm)) presented postnatal growth retardation and proportionate dwarfism. Molecular changes included elevated GH serum levels and mild hyperglycemia. We believe that this model may prove valuable in the study of GH functions in relation to cancer, diabetes and longevity. PMID- 26510875 TI - The Role of Ideal Angles, Ratios, and Divine Proportions in Aesthetic Evaluation of Adolescents. AB - OBJECTIVES: The aim of our study was to investigate whether the parameters of ideal angles, ratios, and divine proportions that have been previously mentioned in the literature influence the aesthetic evaluation of Turkish adolescents. MATERIALS AND METHODS: A total of sixty patients (30 males and 30 females) were enrolled in this study. Ages of the subjects ranged from 9 to 17. Pre-treatment extra-oral photographs were taken to evaluate facial aesthetics. Two distinct panels consisting of 50 orthodontists and 50 laypersons were created for scoring the photographs of the patients. Scoring was performed using the VAS scale. Twenty-seven ratios and 19 divine proportions were measured in frontal photographs, and 26 angles were measured in profile photographs. RESULTS: Pearson correlation was used to determine the relationship between the photograph analysis measurements and VAS scores, and then regression analyses were performed to disclose to what extent significant values may warrant the term beauty. CONCLUSION: As a result of our investigations, none of the golden proportions was associated with facial aesthetics according to both orthodontists and laypersons. According to other angles and ratios that were measured, it was determined that orthodontists noticed the sagittal position of the lower jaw, the distance between the eyes and length of the face, whereas laypersons noticed only the distance between the eyes and length of the face. LEVEL OF EVIDENCE V: This journal requires that the authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26510876 TI - Prevalent cardiac, renal and cardiorenal damage in patients with advanced abdominal aortic aneurysms. AB - Chronic kidney disease (CKD), cardiac damage (CD) and the combination of the two are associated with increased morbidity and death in patients admitted to vascular surgery units. We assessed the prevalence of cardiac and renal damage and cardiorenal syndrome (CRS) in 563 patients with abdominal aortic aneurysms (AAA) who underwent cardiac screening before either an endovascular procedure (EVAR) or open surgery (OS) for aneurysm repair. CD was defined by >=stage B as per the ACC/AHA classification of congestive heart failure (CHF), while CKD was defined by estimated GFR <60 mL/min/1.73 m(2) (CKD-EPI). Anemia [World Health Organization (WHO) guidelines] and iron deficiency (ID) (criteria for CHF patients) were also calculated. AAA patients were stratified into the following groups: CD, CKD, CRS or none of these conditions [no risk factors (NoRF)]. The prevalence of isolated cardiac and renal structural damage, of combined cardiorenal damage and of ID was 24.1, 15.0, 20.6 and 23.4 %, respectively. The frequency of anemia (mostly unrecognized) among the groups increased from NoRF (12.8 %)/CKD (19 %)/CD (25 %) up to CRS (38.8 %). This large-scale observational study provides clues for the increased CD/CKD risk profiles of unselected AAA patients, and underlines the need for better identification of ID/anemia and for appropriate treatment of CKD and CD before these patients undergo EVAR/OS. PMID- 26510877 TI - Evaluating the potential impact of a mobile telemedicine system on coordination of specialty care for patients with complicated oral lesions in Botswana. AB - Mobile telemedicine involves the use of mobile device (e.g., cell phones, tablets) technology to exchange information to assist in the provision of patient care. Throughout the world, mobile telemedicine initiatives are increasing in number and in scale, but literature on their impact on patient outcomes in low resource areas is limited. This study explores the potential impact of a mobile oral telemedicine system on the oral health specialty referral system in Botswana. Analysis of 26 eligible cases from June 2012 to July 2013 reveals high diagnosis concordance between dental officers and oral health specialists at 91.3% (21/23) but significant management plan discordance at 64.0% (16/25), over two-thirds of which involved the specialists disagreeing with the referring clinicians about the need for a visit to a specialist. These findings suggest mobile telemedicine can optimize the use of insights and skills of specialists remotely in regions where they are scarce. PMID- 26510878 TI - Identifying unmet informational needs in the inpatient setting to increase patient and caregiver engagement in the context of pediatric hematopoietic stem cell transplantation. AB - BACKGROUND: Patient-centered care has been shown to improve patient outcomes, satisfaction, and engagement. However, there is a paucity of research on patient centered care in the inpatient setting, including an understanding of unmet informational needs that may be limiting patient engagement. Pediatric hematopoietic stem cell transplantation (HSCT) represents an ideal patient population for elucidating unmet informational needs, due to the procedure's complexity and its requirement for caregiver involvement. METHODS: We conducted field observations and semi-structured interviews of pediatric HSCT caregivers and patients to identify informational challenges in the inpatient hospital setting. Data were analyzed using a thematic grounded theory approach. RESULTS: Three stages of the caregiving experience that could potentially be supported by a health information technology system, with the goal of enhancing patient/caregiver engagement, were identified: (1) navigating the health system and learning to communicate effectively with the healthcare team, (2) managing daily challenges of caregiving, and (3) transitioning from inpatient care to long term outpatient management. DISCUSSION: We provide four practical recommendations to meet the informational needs of pediatric HSCT patients and caregivers: (1) provide patients/caregivers with real-time access to electronic health record data, (2) provide information about the clinical trials in which the patient is enrolled, (3) provide information about the patient's care team, and (4) properly prepare patients and caregivers for hospital discharge. CONCLUSION: Pediatric HSCT caregivers and patients have multiple informational needs that could be met with a health information technology system that integrates data from several sources, including electronic health records. Meeting these needs could reduce patients' and caregivers' anxiety surrounding the care process; reduce information asymmetry between caregivers/patients and providers; empower patients/caregivers to participate in the care process; and, ultimately, increase patient/caregiver engagement in the care process. PMID- 26510879 TI - Evaluating the implementation of RxNorm in ambulatory electronic prescriptions. AB - OBJECTIVE: RxNorm is a standardized drug nomenclature maintained by the National Library of Medicine that has been recommended as an alternative to the National Drug Code (NDC) terminology for use in electronic prescribing. The objective of this study was to evaluate the implementation of RxNorm in ambulatory care electronic prescriptions (e-prescriptions). METHODS: We analyzed a random sample of 49 997 e-prescriptions that were received by 7391 locations of a national retail pharmacy chain during a single day in April 2014. The e-prescriptions in the sample were generated by 37 801 ambulatory care prescribers using 519 different e-prescribing software applications. RESULTS: We found that 97.9% of e prescriptions in the study sample could be accurately represented by an RxNorm identifier. However, RxNorm identifiers were actually used as drug identifiers in only 16 433 (33.0%) e-prescriptions. Another 431 (2.5%) e-prescriptions that used RxNorm identifiers had a discrepancy in the corresponding Drug Database Code qualifier field or did not have a qualifier (Term Type) at all. In 10 e prescriptions (0.06%), the free-text drug description and the RxNorm concept unique identifier pointed to completely different drug concepts, and in 7 e prescriptions (0.04%), the NDC and RxNorm drug identifiers pointed to completely different drug concepts. DISCUSSION: The National Library of Medicine continues to enhance the RxNorm terminology and expand its scope. This study illustrates the need for technology vendors to improve their implementation of RxNorm; doing so will accelerate the adoption of RxNorm as the preferred alternative to using the NDC terminology in e-prescribing. PMID- 26510880 TI - Ancient Chinese Formula Qiong-Yu-Gao Protects Against Cisplatin-Induced Nephrotoxicity Without Reducing Anti-tumor Activity. AB - Cisplatin is a highly effective anti-cancer chemotherapeutic agent; however, its clinical use is severely limited by serious side effects, of which nephrotoxicity is the most important. In this study, we investigated whether Qiong-Yu-Gao (QYG), a popular traditional Chinese medicinal formula described 840 years ago, exhibits protective effects against cisplatin-induced renal toxicity. Using a mouse model of cisplatin-induced renal dysfunction, we observed that pretreatment with QYG attenuated cisplatin-induced elevations in blood urea nitrogen and creatinine levels, ameliorated renal tubular lesions, reduced apoptosis, and accelerated tubular cell regeneration. Cisplatin-mediated elevations in tumor necrosis factor alpha (TNF-alpha) mRNA, interleukin-1 beta (IL-1beta) mRNA, and cyclooxygenase-2 (COX-2) protein in the kidney were also significantly suppressed by QYG treatment. Furthermore, QYG reduced platinum accumulation in the kidney by decreasing the expression of copper transporter 1 and organic cation transporter 2. An in vivo study using implanted Lewis lung cancer cells revealed that concurrent administration of QYG and cisplatin did not alter the anti-tumor activity of cisplatin. Our findings suggest that the traditional Chinese medicinal formula QYG inhibits cisplatin toxicity by several mechanisms that act simultaneously, without compromising its therapeutic efficacy. Therefore, QYG may be useful in the clinic as a protective agent to prevent cisplatin-induced nephrotoxicity. PMID- 26510881 TI - Contrast-dependent orientation discrimination in the mouse. AB - As an important animal model to study the relationship between behaviour and neural activity, the mouse is able to perform a variety of visual tasks, such as orientation discrimination and contrast detection. However, it is not clear how stimulus contrast influences the performance of orientation discrimination in mice. In this study, we used two task designs, two-alternative forced choice (2AFC) and go/no-go, to examine the performance of mice to discriminate two orthogonal orientations at different contrasts. We found that the performance tended to increase with contrast, and the performance at high contrast was better when the stimulus set contained a single contrast than multiple contrasts. Physiological experiments in V1 showed that neural discriminability of two orthogonal orientations increased with contrast. Furthermore, orientation discriminability of V1 neurons at high contrast was higher in the single than in the multiple contrast condition, largely due to smaller response variance in the single contrast condition. Thus, the performance of mice to discriminate orientations at high contrast is adapted to the contrast range in the stimuli, partly attributed to the contrast-range dependent capacity of V1 neurons to discriminate orientations. PMID- 26510882 TI - What treatment wins in the battle against sleepiness? PMID- 26510883 TI - rbCLCA1 is a putative metalloprotease family member: localization and catalytic domain identification. AB - Here, we identify the rat brain (rb) CLCA1 metalloprotease motif and its role in rbCLCA1 processing. GFP tagging or c-myc tagging adjacent to the rbCLCA1 signal sequence was used to detect rbCLCA1 expression and localization patterns if they matched those of other CLCA family members. Immunoblot analysis revealed that massive deletion of the metalloprotease motif affects the protein cleavage process by restricting two cleavage products to only one product. rbCLCA1 as well as the mutant proteins H155A, E156Q, H159A, D166A, E167A, E170A, and D171A overexpressed in HEK293T cells showed plasma membrane localization; and intracellular localizations of H159A and E167A were observed in permeabilized and non-permeabilized conditions. C-terminally GFP-tagged rbCLCA1 showed either ER localization or overall signal within the cells rather than on the cell surface. Cell surface biotinylation analysis was used to show that rbCLCA1, H155A, E156Q, D166A, E170A, and D171A reach the cell surface while little H159A and E167A reach the cell surface. Taken together, our findings indicate that the amino acids H159 and E167 in the rbCLCA1 metalloprotease motif are important in rbCLCA1 processing for localization to the cell surface. Our data demonstrate that rbCLCA1 localization is dependent on the H159 and E167, suggesting either the metalloprotease motif including H159 and E167 may be the key site for rbCLCA1 cellular processing or that a novel rbCLCA1 regulation mechanism exists with a metalloprotease activity. PMID- 26510884 TI - Renal Hemodynamics in AKI: In Search of New Treatment Targets. AB - Novel therapeutic interventions are required to prevent or treat AKI. To expedite progress in this regard, a consensus conference held by the Acute Dialysis Quality Initiative was convened in April of 2014 to develop recommendations for research priorities and future directions. Here, we highlight the concepts related to renal hemodynamics in AKI that are likely to reveal new treatment targets on investigation. Overall, we must better understand the interactions between systemic, total renal, and glomerular hemodynamics, including the role of tubuloglomerular feedback. Furthermore, the net consequences of therapeutic maneuvers aimed at restoring glomerular filtration need to be examined in relation to the nature, magnitude, and duration of the insult. Additionally, microvascular blood flow heterogeneity in AKI is now recognized as a common occurrence; timely interventions to preserve the renal microcirculatory flow may interrupt the downward spiral of injury toward progressive kidney failure and should, therefore, be investigated. Finally, development of techniques that permit an integrative physiologic approach, including direct visualization of renal microvasculature and measurement of oxygen kinetics and mitochondrial function in intact tissue in all nephron segments, may provide new insights into how the kidney responds to various injurious stimuli and allow evaluation of new therapeutic strategies. PMID- 26510885 TI - Potassium and Its Discontents: New Insight, New Treatments. AB - Hyperkalemia is common in patients with impaired kidney function or who take drugs that inhibit the renin-angiotensin-aldosterone axis. During the past decade, substantial advances in understanding how the body controls potassium excretion have been made, which may lead to improved standard of care for these patients. Renal potassium disposition is primarily handled by a short segment of the nephron, comprising part of the distal convoluted tubule and the connecting tubule, and regulation results from the interplay between aldosterone and plasma potassium. When dietary potassium intake and plasma potassium are low, the electroneutral sodium chloride cotransporter is activated, leading to salt retention. This effect limits sodium delivery to potassium secretory segments, limiting potassium losses. In contrast, when dietary potassium intake is high, aldosterone is stimulated. Simultaneously, potassium inhibits the sodium chloride cotransporter. Because more sodium is then delivered to potassium secretory segments, primed by aldosterone, kaliuresis results. When these processes are disrupted, hyperkalemia results. Recently, new agents capable of removing potassium from the body and treating hyperkalemia have been tested in clinical trials. This development suggests that more effective and safer approaches to the prevention and treatment of hyperkalemia may be on the horizon. PMID- 26510886 TI - Views of Women and Health Professionals on mHealth Lifestyle Interventions in Pregnancy: A Qualitative Investigation. AB - BACKGROUND: Evidence suggests that women are failing to meet guidelines for nutrition, physical activity, and weight gain during pregnancy. Interventions to promote a healthy lifestyle in pregnancy demonstrate mixed results and many are time and resource intensive. mHealth-delivered interventions offer an opportunity to provide trusted source information in a timely and cost-effective manner. Studies regarding women's and health professionals' views of mHealth in antenatal care are limited. OBJECTIVE: This study aimed to explore women's and health professionals' views regarding mHealth information sources and interventions to assist women to eat well, be physically active, and gain healthy amounts of weight in pregnancy. METHODS: A descriptive qualitative research approach employed focus groups and in-depth interviews with 15 pregnant or postpartum women and 12 in-depth interviews with health professionals including two from each category: obstetricians, general practitioners, midwives, dietitians, physiotherapists, and community pharmacists. All interviews were transcribed verbatim and thematically analyzed. RESULTS: Women uniformly embraced the concept of mHealth information sources and interventions in antenatal care and saw them as central to information acquisition and ideally incorporated into future antenatal care processes. Health professionals exhibited varied views perceiving mHealth as an inevitable, often parallel, service rather than one integrated into the care model. Four key themes emerged: engagement, risk perception, responsibility, and functionality. Women saw their ability to access mHealth elements as a way to self-manage or control information acquisition that was unavailable in traditional care models and information sources. The emergence of technology was perceived by some health professionals to have shifted control of information from trusted sources, such as health professionals and health organizations, to nontrusted sources. Some health professionals were concerned about the medicolegal risks of mHealth (incorrect or harmful information and privacy concerns), while others acknowledged that mHealth was feasible if inherent risks were addressed. Across both groups, there was uncertainty as to who should be responsible for ensuring high-quality mHealth. The absence of a key pregnancy or women's advocacy group, lack of health funds for technologies, and the perceived inability of maternity hospitals to embrace technology were seen to be key barriers to provision. Women consistently identified the functionality of mHealth as adding value to antenatal care models. For some health professionals, lack of familiarity with and fear of mHealth limited their engagement with and comprehension of the capacity of new technologies to support antenatal care. CONCLUSIONS: Women exhibited positive views regarding mHealth for the promotion of a healthy lifestyle in antenatal care. Conversely, health professionals expressed a much wider variation in attitudes and were more able to identify potential risks and barriers to development and implementation. This study contributes to the understanding of the opportunities and challenges in developing mHealth lifestyle interventions in antenatal care. PMID- 26510887 TI - High efficacy vasopermeability drug candidates identified by screening in an ex ovo chorioallantoic membrane model. AB - The use of rodent models to evaluate efficacy during testing is accompanied by significant economic and regulatory hurdles which compound the costs of screening for promising drug candidates. Vasopermeation Enhancement Agents (VEAs) are a new class of biologics that are designed to increase the uptake of cancer therapeutics at the tumor site by modifying vascular permeability in the tumor to increase the therapeutic index of co-administered drugs. To evaluate the efficacy of a panel of VEA clinical candidates, we compared the rodent Miles assay to an equivalent assay in the ex ovo chicken embryo model. Both model systems identified the same candidate (PVL 10) as the most active promoter of vasopermeation in non-tumor tissues. An ex ovo chicken embryo system was utilized to test each candidate VEA in two human tumor models at a range of concentrations. Vasopermeation activity due to VEA was dependent on tumor type, with HEp3 tumors displaying higher levels of vasopermeation than MDA-MB-435. One candidate (PVL 10) proved optimal for HEp3 tumors and another (PVL 2) for MDA-MB 435. The use of the ex ovo chicken embryo model provides a rapid and less costly alternative to the use of rodent models for preclinical screening of drug candidates. PMID- 26510888 TI - Streptomyces actinomycinicus sp. nov., isolated from soil of a peat swamp forest. AB - A novel actinomycete, strain RCU-197T, was isolated from soil of a peat swamp forest in Rayong Province, Thailand. Using a polyphasic approach, the strain was classified in the genus Streptomyces. It contained ll-diaminopimelic acid in the cell-wall peptidoglycan. No diagnostic sugars were detected in whole-cell hydrolysates and there was a lack of mycolic acids. The major menaquinones were MK-9(H6) and MK-9(H8). The predominant cellular fatty acids were iso-C14 : 0, iso C15 : 0, anteiso-C15 : 0 and iso-C16 : 0. The polar lipids profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol and phosphatidylinositol mannoside, an unknown aminolipid and two unknown phospholipids. Phylogenetic analysis of 16S rRNA gene sequences showed the strain formed distinct clade within the genus Streptomyces and was closely related to Streptomyces echinatus NBRC 12763T (98.78 % 16S rRNA gene sequence similarity). According to the polyphasic approach as well as DNA-DNA relatedness, the strain could be clearly differentiated from closely related species and represents a novel species of the genus Streptomyces, for which the name Streptomyces actinomycinicus sp. nov. is proposed. The type strain is RCU 197T ( = JCM 30864T = TISTR 2208T = PCU 342T). PMID- 26510889 TI - Electrical stimulation of non-classical photon emission from diamond color centers by means of sub-superficial graphitic electrodes. AB - Focused MeV ion beams with micrometric resolution are suitable tools for the direct writing of conductive graphitic channels buried in an insulating diamond bulk, as already demonstrated for different device applications. In this work we apply this fabrication method to the electrical excitation of color centers in diamond, demonstrating the potential of electrical stimulation in diamond-based single-photon sources. Differently from optically-stimulated light emission from color centers in diamond, electroluminescence (EL) requires a high current flowing in the diamond subgap states between the electrodes. With this purpose, buried graphitic electrode pairs, 10 MUm spaced, were fabricated in the bulk of a single-crystal diamond sample using a 6 MeV C microbeam. The electrical characterization of the structure showed a significant current injection above an effective voltage threshold of 150 V, which enabled the stimulation of a stable EL emission. The EL imaging allowed to identify the electroluminescent regions and the residual vacancy distribution associated with the fabrication technique. Measurements evidenced isolated electroluminescent spots where non-classical light emission in the 560-700 nm spectral range was observed. The spectral and auto-correlation features of the EL emission were investigated to qualify the non classical properties of the color centers. PMID- 26510890 TI - Vertically self-ordered orientation of nanocrystalline hexagonal boron nitride thin films for enhanced thermal characteristics. AB - Vertically self-ordered hexagonal boron nitride (ordered h-BN) is a highly ordered turbostratic BN (t-BN) material similar to hexagonal BN, with its planar structure perpendicularly oriented to the substrate. The ordered h-BN thin films were grown using a High Power Impulse Magnetron Sputtering (HiPIMS) system with a lanthanum hexaboride (LaB6) target reactively sputtered in nitrogen gas. The best vertical alignment was obtained at room temperature, with a grounded bias and a HiPIMS peak power density of 60 W cm(-2). Even though the film contains up to 7.5 at% lanthanum, it retains its highly insulative properties and it was observed that an increase in compressive stress is correlated to an increase in film ordering quality. Importantly, the thermal conductivity of vertically ordered h BN is considerably high at 5.1 W m(-1) K(-1). The favourable thermal conductivity coupled with the dielectric properties of this novel material and the low temperature growth could outperform SiO2 in high power density electronic applications. PMID- 26510891 TI - Spirituality as an ethical challenge in Indian palliative care: A systematic review. AB - OBJECTIVE: Spiritual care is recognized as an essential component of palliative care (PC). However, patients' experience of spirituality is heavily context dependent. In addition, Western definitions and findings regarding spirituality may not be applicable to patients of non-Western origin, such as Indian PC patients. Given the particular sociocultural, religious, and economic conditions in which PC programs in India operate, we decided to undertake a systematic review of the literature on spirituality among Indian PC patients. We intended to assess how spirituality has been interpreted and operationalized in studies of this population, to determine which dimensions of spirituality are important for patients, and to analyze its ethical implications. METHOD: In January of 2015, we searched five databases (ATLA, CINAHL, EMBASE, PsycINFO, and PubMed) using a combination of controlled and noncontrolled vocabulary. A content analysis of all selected reports was undertaken to assess the interpretation and dimensions of spirituality. Data extraction from empirical studies was done using a data extraction sheet. RESULTS: A total of 39 empirical studies (12 qualitative, 21 quantitative, and 6 mixed-methods) and 18 others (10 reviews, 4 opinion articles, and 4 case studies) were retrieved. To date, no systematic review on spirituality in Indian PC has been published. Spirituality was the main focus of only six empirical studies. The content analysis revealed three dimensions of spirituality: (1) the relational dimension, (2) the existential dimension, and (3) the values dimension. Religion is prominent in all these dimensions. Patients' experiences of spirituality are determined by the specifically Indian context, which leads to particular ethical issues. SIGNIFICANCE OF RESULTS: Since spiritual well-being greatly impacts quality of life, and because of the substantial presence of people of Indian origin living outside the subcontinent, the findings of our review have international relevance. Moreover, our review illustrates that spirituality can be an ethical challenge and that more ethical reflection on provision of spiritual care is needed. PMID- 26510892 TI - Immunomodulation of endothelial differentiated mesenchymal stromal cells: impact on T and NK cells. AB - Wharton's jelly mesenchymal stromal cells (WJ-MSCs) are promising candidates for tissue engineering, as their immunomodulatory activity allows them to escape immune recognition and to suppress several immune cell functions. To date, however, few studies have investigated the effect of differentiation of the MSCs on this immunomodulation. To address this question, we sought to determine the impact of differentiation toward endothelial cells on immunoregulation by WJ MSCs. Following differentiation, the endothelial-like cells (ELCs) were positive for CD31, vascular endothelial cadherin and vascular endothelial growth factor receptor 2, and able to take up acetylated low-density lipoproteins. The expression of HLA-DR and CD86, which contribute to MSCs immunoprivilege, was still weak after differentiation. We then co-cultured un- and differentiated MSCs with immune cells, under conditions of both direct and indirect contact. The proliferation and phenotype of the immune cells were analyzed and the mediators secreted by both ELCs and WJ-MSCs quantified. Interleukin (IL)-6, IL-1beta, prostaglandin E2 and in particular indoleamine-2,3-dioxygenase expression were upregulated in ELCs on stimulation by T and NK cells, suggesting the possible involvement of these factors in allosuppression. ELCs co-cultured with T cells were able to generate CD25(+) T cells, which were shown to be of the CD4(+)CD25(+)FoxP3(+) regulatory subset. Direct contact between NK cells and ELCs or WJ-MSCs decreased the level of NK-activating receptor natural-killer group 2, member D. Moreover, direct co-culturing with ELCs stimulates CD73 acquisition on NK cells, a mechanism which may induce adenosine secretion by the cells and lead to an immunosuppressive function. Taken together, our results show that ELCs obtained following differentiation of WJ-MSCs remain largely immunosuppressive. PMID- 26510893 TI - A timeline demarcating two waves of clonal deletion and Foxp3 upregulation during thymocyte development. AB - Thymocytes that bind strongly to self-antigens are prevented from becoming naive T cells by several mechanisms. They undergo clonal deletion at two stages of development; wave 1 in immature thymocytes lacking the medulla-homing chemokine receptor, CCR7, or wave 2 in more mature CCR7(+) thymocytes. Alternatively, self reactive thymocytes upregulate Foxp3 to become T-regulatory cells. Here, we describe the differential timing of the two waves of deletion and Foxp3 upregulation relative to the immature proliferating stage. Proliferating thymocytes were pulse-labeled in normal C57BL/6 mice with 5-ethynyl-2' deoxyuridine (EdU). Thymocytes progressed into wave 1 (CCR7(-)) and wave 2 (CCR7(+)) of clonal deletion ~2 and 5 days after proliferation, respectively. Foxp3 upregulation occurred between 4 and 8 days after proliferation, predominantly in thymocytes with a Helios(+) CCR7(+) phenotype. These findings establish a timeline that suggests that wave 1 of clonal deletion occurs in the thymic cortex, whereas wave 2 and Foxp3 upregulation both occur in the thymic medulla. PMID- 26510894 TI - Matrix metalloproteinase-2 enhances platelet deposition on collagen under flow conditions. AB - Platelets contain and release matrix metalloproteinase-2 (MMP-2) that in turn potentiates platelet aggregation. Platelet deposition on a damaged vascular wall is the first, crucial, step leading to thrombosis. Little is known about the effects of MMP-2 on platelet activation and adhesion under flow conditions. We studied the effect of MMP-2 on shear-dependent platelet activation using the O'Brien filtration system, and on platelet deposition using a parallel-plate perfusion chamber. Preincubation of human whole blood with active MMP-2 (50 ng/ml, i.e. 0.78 nM) shortened filter closure time (from 51.8 +/- 3.6 sec to 40 +/- 2.7 sec, p<0.05) and increased retained platelets (from 72.3 +/- 2.3% to 81.1 +/- 1.8%, p<0.05) in the O'Brien system, an effect prevented by a specific MMP-2 inhibitor. High shear stress induced the release of MMP-2 from platelets, while TIMP-2 levels were not significantly reduced, therefore, the MMP-2/TIMP-2 ratio increased significantly showing enhanced MMP-2 activity. Preincubation of whole blood with active MMP-2 (0.5 to 50 ng/ml, i.e 0.0078 to 0.78 nM) increased dose dependently human platelet deposition on collagen under high shear-rate flow conditions (3000 sec-1) (maximum +47.0 +/- 11.9%, p<0.05, with 50 ng/ml), while pre-incubation with a MMP-2 inhibitor reduced platelet deposition. In real-time microscopy studies, increased deposition of platelets on collagen induced by MMP 2 started 85 sec from the beginning of perfusion, and was abolished by a GPIIb/IIIa antagonist, while MMP-2 had no effect on platelet deposition on fibrinogen or VWF. Confocal microscopy showed that MMP-2 enhances thrombus volume (+20.0 +/- 3.0% vs control) rather than adhesion. In conclusion, we show that MMP 2 potentiates shear-induced platelet activation by enhancing thrombus formation. PMID- 26510895 TI - Harnessing dynamic combinatorial chemistry in the search for new ligands for protein targets. PMID- 26510896 TI - The application of anethole, menthone, and eugenol in transdermal penetration of valsartan: Enhancement and mechanistic investigation. AB - CONTEXT: The main barrier for transdermal delivery is the obstacle property of the stratum corneum. Many types of chemical penetration enhancers have been used to breach the skin barrier; among the penetration enhancers, terpenes are found as the most highly advanced, safe, and proven category. OBJECTIVE: In the present investigation, the terpenes anethole, menthone, and eugenol were used to enhance the permeation of valsartan through rat skin in vitro and their enhancement mechanism was investigated. MATERIALS AND METHODS: Skin permeation studies of valsartan across rat skin in the absence and the presence of terpenes at 1% w/v, 3% w/v, and 5% w/v in vehicle were carried out using the transdermal diffusion cell sampling system across rat skin and samples were withdrawn from the receptor compartment at 1, 2, 3, 4, 6, 8, 10, 12, and 24 h and analysed for drug content by the HPLC method. The mechanism of skin permeation enhancement of valsartan by terpenes treatment was evaluated by Fourier transform infrared spectroscopy (FTIR) analysis and differential scanning calorimetry (DSC). RESULTS: All the investigated terpenes provided a significant (p < 0.01) enhancement in the valsartan flux at a concentration of 1%, and less so at 3% and 5%. The effectiveness of terpenes at 1% concentration was in the following order: anethole > menthone > eugenol with 4.4-, 4.0-, and 3.0-fold enhancement ratio over control, respectively. DSC study showed that the treatment of stratum corneum with anethole shifted endotherm down to lower melting point while FTIR studies revealed that anethole produced maximum decrease in peak height and area than other two terpenes. CONCLUSION: The investigated terpenes can be successfully used as potential enhancers for the enhancement of skin permeation of lipophilic drug. PMID- 26510897 TI - Future directions of imaging MS in pharmaceutical R&D. AB - MS imaging has rapidly evolved over the last decade, finding roles in all aspects of pharmaceutical research and development. This article discusses possible methodological and technological future advancements and describes research areas where the technology can expand and continue to prove to be worthwhile tool for drug discovery and development. PMID- 26510898 TI - Genomic research in Zambia: confronting the ethics, policy and regulatory frontiers in the 21st Century. AB - Genomic research has the potential to increase knowledge in health sciences, but the process has to ensure the safety, integrity and well-being of research participants. A legal framework for the conduct of health research in Zambia is available. However, the ethical, policy and regulatory framework to operationalise genomic research requires a paradigm shift. This paper outlines the current legal and policy framework as well as the ethics environment, and suggests recommendations for Zambia to fully benefit from the opportunity that genomic research presents. This will entail creating national research interest, improving knowledge levels, and building community trust among researchers, policymakers, donors, regulators and, most importantly, patients and research participants. A real balancing act of the risk and benefits will need to be objectively undertaken. PMID- 26510899 TI - Incarvine C suppresses proliferation and vasculogenic mimicry of hepatocellular carcinoma cells via targeting ROCK inhibition. AB - BACKGROUND: Studies have described vasculogenic mimicry (VM) as an alternative circulatory system to blood vessels in multiple malignant tumor types, including hepatocellular carcinoma (HCC). In the current study, we aimed to seek novel and more efficient treatment strategies by targeting VM and explore the underlying mechanisms in HCC cells. METHODS: Cell counting kit-8 (CCK-8) assay and colony survival assay were performed to explore the inhibitory effect of incarvine C (IVC) on human cancer cell proliferation. Flow cytometry was performed to analyze the cell cycle distribution after DNA staining and cell apoptosis by the Annexin V-PE and 7-AAD assay. The effect of IVC on Rho-associated, coiled-coil-containing protein kinase (ROCK) was determined by western blotting and stress fiber formation assay. The inhibitory role of IVC on MHCC97H cell VM formation was determined by formation of tubular network structures on Matrigel in vitro, real time-qPCR, confocal microscopy and western blotting techniques. RESULTS: We explored an anti-metastatic HCC agent, IVC, derived from traditional Chinese medicinal herbs, and found that IVC dose-dependently inhibited the growth of MHCC97H cells. IVC induced MHCC97H cell cycle arrest at G1 transition, which was associated with cyclin-dependent kinase 2 (CDK-2)/cyclin-E1 degradation and p21/p53 up-regulation. In addition, IVC induced apoptotic death of MHCC97H cells. Furthermore, IVC strongly suppressed the phosphorylation of the ROCK substrate myosin phosphatase target subunit-1 (MYPT-1) and ROCK-mediated actin fiber formation. Finally, IVC inhibited cell-dominant tube formation in vitro, which was accompanied with the down-regulation of VM-key factors as detected by real time-qPCR and immunofluorescence. CONCLUSIONS: Taken together, the effective inhibitory effect of IVC on MHCC97H cell proliferation and neovascularization was associated with ROCK inhibition, suggesting that IVC may be a new potential drug candidate for the treatment of HCC. PMID- 26510900 TI - Effect of Pistacia atlantica Fruit and Leaf Extracts on Hydatid Cyst Protoscolices. AB - BACKGROUND: Treatment of human hydatidosis is mainly surgical, with chemical treatment being reserved as a coadjuvant treatment. Use of effective protoscolicidal agents during surgery of hydatid disease is essential to reduce the recurrence rate. OBJECTIVE: The aim of this study was to investigate the scolicidal effects of Pistacia atlantica leaf and fruit hydroalcoholic extracts on protoscolices of hydatid cyst. METHOD: Echinococcus granulosus protoscolices were obtained from 50 sheep infected with hydatid cysts. Various concentrations of plant hydroalcoholic extracts were used in different exposure times for viability assay of protoscolices. RESULTS: The scolicidal effects of the hydroalcoholic extracts of the leaf, fresh and dried fruits were significant compared to the control groups (P < 0.05). Among the Pistacia atlantica extracts tested, 0.1% (mg/ml) concentrations of fresh fruit extract (99.09 +/- 1.27) and leaf extract (89.25 +/- 18.42) had strong scolicidal effects in 360 min, of exposure times and the mortality rate decreased with the lower concentration. CONCLUSION: Information from the current study has the strong scolicidal effect of fresh fruit hydroalcoholic extract of Pistacia atlantica on protoscoleces, which may be used as a scolicidal agent during the surgery techniques. PMID- 26510901 TI - Biological Potential of Halfsandwich Ruthenium(II) and Iridium (III) Complexes. AB - In vitro studies with the ruthenium(II) and analogous iridium(III) complexes [Ru(eta6- p-cymene)Cl2{Ph2PCH2CH2CH2S(O)xPh-kappaP}], [Ru(eta6-p cymene)Cl{Ph2PCH2CH2CH2S(O)xPh- kappaP,kappaS}][PF6] (1-4), [Ir(eta5 C5Me5)Cl2{Ph2PCH2CH2CH2S(O)xPh-kappaP}] and [Ir(eta5-C5Me5)Cl{Ph2 PCH2CH2CH2S(O)xPh-kappaP,kappaS}][PF6] (5-8; x = 0, 1) revealed the high selectivity toward the 8505C, A253, MCF-7, SW480 and 518A2 cancer cell lines. Thus, the cationic ruthenium complex 4 proved to be the most selective one. In case of the neutral and cationic ruthenium complexes 1-4 the caspase-dependent apoptotic cell death was proven as the main cause of the drug's tumoricidal action on 8505C cell line. PMID- 26510902 TI - Single-ion 4f element magnetism: an ab-initio look at Ln(COT)2(-). AB - The electron densities associated with the Ln 4f shell, and spin and orbital magnetizations ('magnetic moment densities'), are investigated for the Ln(COT)2( ) series. The densities are obtained from ab-initio calculations including spin orbit coupling. For Ln = Ce, Pr the magnetizations are also derived from crystal field models and shown to agree with the ab-initio results. Analysis of magnetizations from ab-initio calculations may be useful in assisting research on single molecule magnets. PMID- 26510903 TI - Innervation of the rabbit cardiac ventricles. AB - The rabbit is widely used in experimental cardiac physiology, but the neuroanatomy of the rabbit heart remains insufficiently examined. This study aimed to ascertain the architecture of the intrinsic nerve plexus in the walls and septum of rabbit cardiac ventricles. In 51 rabbit hearts, a combined approach involving: (i) histochemical acetylcholinesterase staining of intrinsic neural structures in total cardiac ventricles; (ii) immunofluorescent labelling of intrinsic nerves, nerve fibres (NFs) and neuronal somata (NS); and (iii) transmission electron microscopy of intrinsic ventricular nerves and NFs was used. Mediastinal nerves access the ventral and lateral surfaces of both ventricles at a restricted site between the root of the ascending aorta and the pulmonary trunk. The dorsal surface of both ventricles is supplied by several epicardial nerves extending from the left dorsal ganglionated nerve subplexus on the dorsal left atrium. Ventral accessing nerves are thicker and more numerous than dorsal nerves. Intrinsic ventricular NS are rare on the conus arteriosus and the root of the pulmonary trunk. The number of ventricular NS ranged from 11 to 220 per heart. Four chemical phenotypes of NS within ventricular ganglia were identified, i.e. ganglionic cells positive for choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), and biphenotypic, i.e. positive for both ChAT/nNOS and for ChAT/tyrosine hydroxylase. Clusters of small intensely fluorescent cells are distributed within or close to ganglia on the root of the pulmonary trunk, but not on the conus arteriosus. The largest and most numerous intrinsic nerves proceed within the epicardium. Scarce nerves were found near myocardial blood vessels, but the myocardium contained only a scarce meshwork of NFs. In the endocardium, large numbers of thin nerves and NFs proceed along the bundle of His and both its branches up to the apex of the ventricles. The endocardial meshwork of fine NFs was approximately eight times denser than the myocardial meshwork. Adrenergic NFs predominate considerably in all layers of the ventricular walls and septum, whereas NFs of other neurochemical phenotypes were in the minority and their amount differed between the epicardium, myocardium and endocardium. The densities of NFs positive for nNOS and ChAT were similar in the epicardium and endocardium, but NFs positive for nNOS in the myocardium were eight times more abundant than NFs positive for ChAT. Potentially sensory NFs positive for both calcitonin gene-related peptide and substance P were sparse in the myocardial layer, but numerous in epicardial nerves and particularly abundant within the endocardium. Electron microscopic observations demonstrate that intrinsic ventricular nerves have a distinctive morphology, which may be attributed to remodelling of the peripheral nerves after their access into the ventricular wall. In conclusion, the rabbit ventricles display complex structural organization of intrinsic ventricular nerves, NFs and ganglionic cells. The results provide a basic anatomical background for further functional analysis of the intrinsic nervous system in the cardiac ventricles. PMID- 26510904 TI - The effect of opioid agonists and antagonists on gastrointestinal motility in mice selected for high and low swim stress-induced analgesia. AB - BACKGROUND: The opioid system in the gastrointestinal (GI) tract plays an important physiological role, but is also responsible for the side effect of opioid drugs, including troublesome constipation in chronic pain treatment. The aim of this study was to characterize and validate a new mouse model to study the effects of opioid agonists and antagonists in the GI tract. METHODS: Six-week-old male Swiss-Webster mice, divergently bred for high (HA) and low (LA) swim stress induced analgesia (SSIA), were used in the study. To assess the influence of opioid agonists (morphine and loperamide) and antagonists (naloxone hydrochloride, NLX and naloxone methiodide, NLXM) on GI motility, whole GI transit (whole GIT) and upper GIT assays were conducted. To evaluate the expression of opioid receptors in the ileum and colon of HA and LA mice, immune staining was performed. KEY RESULTS: The effect of morphine was more pronounced in HA line, whereas loperamide exerted a stronger effect in LA mice. Furthermore, NLX and NLXM differentially abolished the inhibitory action of the central and peripheral opioid system on whole and upper GIT in HA and LA mice. The differences in GI motility between HA and LA mice coexisted with parallel changes in the expression of opioid receptors in the ileum and colon. CONCLUSIONS & INFERENCES: Differences in the activity of the endogenous opioid system are responsible for the vulnerability to changes in GI motility during treatment with opioids. Our findings validate the HA/LA model for further studies on opioids in the GI tract. PMID- 26510905 TI - Identifying the optimal criteria of radiotherapeutic parameters for patients with unresectable locally advanced hepatocellular carcinoma. AB - The purpose of this study is to identify the optimal criteria of the radiotherapeutic parameters in patients with unresectable locally advanced hepatocellular carcinoma (HCC). 103 patients were enrolled in this study. All patients received RT delivered using the TomoTherapy Hi-Art system between March 2006 and February 2012. We evaluated the planning target volume (PTV), total dose (Gy10), and NTNL-V(BED20) (non-target normal liver volume receiving more than a biologically effective dose of 20 Gy8) as significant radiotherapeutic parameters associated with hepatic function deterioration and local progression-free survival (PFS). A PTV of 279 cm3 or 304 cm3, a total dose of 60 Gy10, and a NTNL V(BED20) of 40.8% were identified as the optimal cut-off values of radiotherapeutic parameters to prevent hepatic function deterioration and prolong local PFS. Based on these findings, patients were divided in a favorable and an unfavorable prognosis group. The differences in median local PFS, overall survival, and incidence of deteriorated hepatic function between the two groups were 11.2 months, 11.1 months, and 71.7%, respectively (p < 0.001 in each case). In conclusion, we suggest that the optimal criteria of the radiotherapeutic parameters for patients with unresectable locally advanced HCC are: PTV <= 279 cm3, total dose > 60 Gy10, and NTNL-V(BED20) <= 40.8%. PMID- 26510906 TI - Knockdown of linc-POU3F3 suppresses the proliferation, apoptosis, and migration resistance of colorectal cancer. AB - Long intergenic noncoding RNAs (lincRNAs) play important roles in regulating the biological functions and underlying molecular mechanisms of colorectal cancer (CRC). Here, we investigated the association of linc-POU3F3 and prognosis in CRC. We demonstrated that linc-POU3F3 was overexpressed in CRC tissues and positively correlated with tumor grade and N stage. Inhibition of linc-POU3F3 resulted in inhibition of cell proliferation and G1 cell cycle arrest, which was mediated by cyclin D1, CDK4, p18, Rb, and phosphorylated Rb. Inhibition of linc-POU3F3 induced apoptosis, and suppressed migration and invasion in LOVO and SW480 cell lines. This inhibition also increased the expressions of epithelial markers and decreased the expressions of mesenchymal markers, thus inhibiting the cancer epithelial-mesenchymal transition. The decreased migration and invasion following linc-POU3F3 knockdown were mediated by an increased BMP signal. Furthermore, autophagy was enhanced by linc-POU3F3 knockdown, suggesting the involvement of autophagy in the induced apoptosis. Collectively, linc-POU3F3 might be crucial in pro-proliferation, anti-apoptosis, and metastasis in LOVO and SW480 cells by regulating the cell cycle, intrinsic apoptosis, BMP signaling and autophagy. Thus, linc-POU3F3 is a potential therapeutic target and novel molecular biomarker for CRC. PMID- 26510907 TI - Conditional survival among patients with adrenal cortical carcinoma determined using a national population-based surveillance, epidemiology, and end results registry. AB - Surgical excision is essential for management of the rare and aggressive neoplasm adrenal cortical carcinoma (ACC). Five-year overall survival (OS) after surgery for ACC is dependent on disease stage, but for all stages the risk of death declines with time after surgery. We calculated the effect of post-surgical duration on conditional survival (CS) among ACC patients. A total of 641 patients with M0 ACC were selected from the Surveillance, Epidemiology, and End Results (SEER) registry (1988-2012). OS for the entire cohort at 1, 2, 3, 4, 5 and 6 years was 81.4%, 66.8%, 56.3%, 50.3%, 47.2% and 44.3%, respectively. CS for an additional year given prior survival for 0, 1, 2, 3, 4 or 5 years was 81.4%, 81.1%, 83.0%, 87.5%, 93.4% and 93.4%, respectively. Age, tumor stage, tumor grade and marital status affected OS and CS. Increases in 1-year CS over time were more pronounced in patients with poorer prognostic factors. With longer follow-up, tumor stage- and grade-dependent differences in CS decreased or even disappeared. CS may provide more meaningful life expectancy predictions for survivors of ACC than conventional survival analysis. PMID- 26510908 TI - Epigenetic silencing of HIC1 promotes epithelial-mesenchymal transition and drives progression in esophageal squamous cell carcinoma. AB - Downregulation of the novel tumor suppressor gene HIC1 (hypermethylated in cancer 1) occurs frequently in various tumors where it causes tumor progression and metastasis. In this study, we investigated a role of HIC1 in esophageal squamous cell carcinoma (ESCC) and the underlying mechanisms. Downregulation of HIC1 occurred in approximately 70% of primary ESCCs at both mRNA and protein level where it was associated significantly with vascular invasion, advanced clinical stage, lymph node metastasis, and poor disease free survival (DFS). The promoter methylation analyses suggested that loss of HIC1 expression was mediated by epigenetic mechanisms. Functional studies established that ectopic re-expression of HIC1 in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, tumor formation and epithelial-mesenchymal transition (EMT). Our results decipher the mechanism through which HIC1 deficiency induce ESCC cells to undergo EMT and promote tumor progression and metastasis through activation of EphA2 signaling pathway. Together, loss of the regulation of EphA2 pathway through HIC1 epigenetic silencing could be an important mechanism in the ESCC progression. We identify a novel pathway that linking HIC1 downregulation to EphA2-inducing EMT in ESCC cells and may shed light on the development of novel anti-tumor therapeutics. PMID- 26510909 TI - Puquitinib mesylate, an inhibitor of phosphatidylinositol 3-kinase p110delta, for treating relapsed or refractory non-Hodgkin's lymphoma. AB - OBJECTIVES: To determine the safety of Puquitinib Mesylate (XC-302), an oral inhibitor of phosphatidylinositol 3-kinase, in treating relapsed or refractory non-Hodgkin's lymphoma (NHL). METHODS: Between October 2013 and July 2015, 21 patients from Sun Yat-sen University Cancer Center were treated twice daily on each day of a 28-day cycle (median number of cycles, 2; maximum, 20) with XC-302 at a post prandial dose of 25 mg, 37.5 mg, or 50 mg. Adverse events (AEs), AUClast and Cmax, response rates, and overall survival were assessed. RESULTS: Patients had received a median (range) of 1 (1 to 3) previous cancer treatments. At the latest follow-up, two patients were still benefitting from the study. The most common drug-related AEs were elevations in alanine transaminase (ALT, 14 of 21 patients) and aspartate transaminase (AST, 7 of 21 patients). Four patients, both in the-50-mg group, had dose-limiting toxicities, and therapy was discontinued in a fifth because of persistent abnormal liver function. The overall response rate was 2 of19. Serum concentrations of XC-302 increased in a dose-dependent pattern. Median progression-free survival in all patients was 1.9 (95% CI, 1.7 to 2.0) months. CONCLUSION: XC-302 has an acceptable safety profile and offers potential therapeutic value to patients with relapsed or refractory non-Hodgkin lymphoma. PMID- 26510910 TI - Predictive value of pretreatment lymphocyte count in stage II colorectal cancer and in high-risk patients treated with adjuvant chemotherapy. AB - Pretreatment lymphocyte count (LC) has been associated with prognosis and chemotherapy response in several cancers. The predictive value of LC for stage II colorectal cancer (CRC) and for high-risk patients treated with adjuvant chemotherapy (AC) has not been determined. A retrospective review of prospectively collected data from 1332 consecutive stage II CRC patients who underwent curative tumor resection was conducted. A pretreatment LC value <1.3 Giga/L(28.1%, 373/1332) was defined as low LC. A total of 738 patients (55.4%) were considered high-risk, 459 (62.2%) of whom received AC. Patients with low LCs had significantly worse 5-year OS (74.6% vs. 90.2%, p < 0.001) and DFS (61.3% vs. 84.6%, p < 0.001). High-risk patients with low LCs had the poorest DFS (p < 0.001). Multivariate analysis indicated that low LC value or combined with high risk status were both independent prognostic factors(p <0.001). High-risk, AC treated patients with high LCs had significantly longer DFS than untreated patients (HR, 0.594; 95% CI, 0.364-0.970; p = 0.035). There was no difference or trend for DFS or OS in patients with low LCs, regardless of the use of AC (DFS, p = 0.692; OS, p = 0.522). Low LC was also independently associated with poorer DFS in high-risk, AC-treated patients (HR, 1.885; 95% CI, 1.112-3.196; p = 0.019). CONCLUSIONS: Pretreatment LC is an independent prognostic factor for survival in stage II CRC. Furthermore, pretreatment LC reliably predicts chemotherapeutic efficacy in high-risk patients with stage II CRC. PMID- 26510911 TI - Arsenic trioxide disrupts glioma stem cells via promoting PML degradation to inhibit tumor growth. AB - Glioblastoma multiforme (GBM) is the most lethal brain tumor. Tumor relapse in GBM is inevitable despite maximal therapeutic interventions. Glioma stem cells (GSCs) have been found to be critical players in therapeutic resistance and tumor recurrence. Therapeutic drugs targeting GSCs may significantly improve GBM treatment. In this study, we demonstrated that arsenic trioxide (As2O3) effectively disrupted GSCs and inhibited tumor growth in the GSC-derived orthotopic xenografts by targeting the promyelocytic leukaemia (PML). As2O3 treatment induced rapid degradation of PML protein along with severe apoptosis in GSCs. Disruption of the endogenous PML recapitulated the inhibitory effects of As2O3 treatment on GSCs both in vitro and in orthotopic tumors. Importantly, As2O3 treatment dramatically reduced GSC population in the intracranial GBM xenografts and increased the survival of mice bearing the tumors. In addition, As2O3 treatment preferentially inhibited cell growth of GSCs but not matched non stem tumor cells (NSTCs). Furthermore, As2O3 treatment or PML disruption potently diminished c-Myc protein levels through increased poly-ubiquitination and proteasome degradation of c-Myc. Our study indicated a potential implication of As2O3 in GBM treatment and highlighted the important role of PML/c-Myc axis in the maintenance of GSCs. PMID- 26510912 TI - Personalized comprehensive molecular profiling of high risk osteosarcoma: Implications and limitations for precision medicine. AB - BACKGROUND: Despite advances in molecular medicine over recent decades, there has been little advancement in the treatment of osteosarcoma. We performed comprehensive molecular profiling in two cases of metastatic and chemotherapy refractory osteosarcoma to guide molecularly targeted therapy. PATIENTS AND METHODS: Hybridization capture of >300 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from tumor samples from two patients with recurrent, metastatic osteosarcoma. The DNA from each sample was sequenced to high, uniform coverage. Immunohistochemical probes and morphoproteomics analysis were performed, in addition to fluorescence in situ hybridization. All analyses were performed in CLIA-certified laboratories. Molecularly targeted therapy based on the resulting profiles was offered to the patients. Biomedical analytics were performed using QIAGEN's Ingenuity(r) Pathway Analysis. RESULTS: In Patient #1, comprehensive next-generation exome sequencing showed MET amplification, PIK3CA mutation, CCNE1 amplification, and PTPRD mutation. Immunohistochemistry-based morphoproteomic analysis revealed c-Met expression [(p)-c-Met (Tyr1234/1235)] and activation of mTOR/AKT pathway [IGF-1R (Tyr1165/1166), p-mTOR [Ser2448], p-Akt (Ser473)] and expression of SPARC and COX2. Targeted therapy was administered to match the P1K3CA, c-MET, and SPARC and COX2 aberrations with sirolimus+ crizotinib and abraxane+ celecoxib. In Patient #2, aberrations included NF2 loss in exons 2-16, PDGFRalpha amplification, and TP53 mutation. This patient was enrolled on a clinical trial combining targeted agents temsirolimus, sorafenib and bevacizumab, to match NF2, PDGFRalpha and TP53 aberrations. Both the patients did not benefit from matched therapy. CONCLUSIONS: Relapsed osteosarcoma is characterized by complex signaling and drug resistance pathways. Comprehensive molecular profiling holds great promise for tailoring personalized therapies for cancer. Methods for such profiling are evolving and need to be refined to better assist clinicians in making treatment decisions based on the large amount of data that results from this type of testing. Further research in this area is warranted. PMID- 26510913 TI - Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth. AB - Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models. PMID- 26510914 TI - Suppression of death receptor 5 enhances cancer cell invasion and metastasis through activation of caspase-8/TRAF2-mediated signaling. AB - The role of death receptor 5 (DR5), a well-known cell surface pro-apoptotic protein, in the negative regulation of invasion and metastasis of human cancer cells and the underlying mechanisms are largely unknown and were hence the focus of this study. In this report, we have demonstrated that DR5 functions to suppress invasion and metastasis of human cancer cells, as evidenced by enhanced cancer cell invasion and metastasis upon genetic suppression of DR5 either by gene knockdown or knockout. When DR5 is suppressed, FADD and caspase-8 may recruit and stabilize TRAF2 to form a metastasis and invasion signaling complex, resulting in activation of ERK and JNK/AP-1 signaling that mediate the elevation and activation of matrix metalloproteinase-1 (MMP1) and eventual promotion of cancer invasion and metastasis. Our findings thus highlight a novel non-apoptotic function of DR5 as a suppressor of human cancer cell invasion and metastasis and suggest a basic working model elucidating the underlying biology. PMID- 26510915 TI - CAGE profiling of ncRNAs in hepatocellular carcinoma reveals widespread activation of retroviral LTR promoters in virus-induced tumors. AB - An increasing number of noncoding RNAs (ncRNAs) have been implicated in various human diseases including cancer; however, the ncRNA transcriptome of hepatocellular carcinoma (HCC) is largely unexplored. We used CAGE to map transcription start sites across various types of human and mouse HCCs with emphasis on ncRNAs distant from protein-coding genes. Here, we report that retroviral LTR promoters, expressed in healthy tissues such as testis and placenta but not liver, are widely activated in liver tumors. Despite HCC heterogeneity, a subset of LTR-derived ncRNAs were more than 10-fold up-regulated in the vast majority of samples. HCCs with a high LTR activity mostly had a viral etiology, were less differentiated, and showed higher risk of recurrence. ChIP seq data show that MYC and MAX are associated with ncRNA deregulation. Globally, CAGE enabled us to build a mammalian promoter map for HCC, which uncovers a new layer of complexity in HCC genomics. PMID- 26510916 TI - Functional demonstrations of starch binding domains present in Ostreococcus tauri starch synthases isoforms. AB - BACKGROUND: Starch-binding domains are key modules present in several enzymes involved in polysaccharide metabolism. These non-catalytic modules have already been described as essential for starch-binding and the catalytic activity of starch synthase III from the higher plant Arabidopsis thaliana. In Ostreococcus tauri, a unicellular green alga of the Prasinophyceae family, there are three SSIII isoforms, known as Ostta SSIII-A, SSIII-B and SSIII-C. RESULTS: In this work, using in silico and in vitro characterization techniques, we have demonstrated that Ostta SSIII-A, SSIII-B and SSIII-C contain two, three and no starch-binding domains, respectively. Additionally, our phylogenetic analysis has indicated that OsttaSSIII-B, presenting three N-terminal SBDs, is the isoform more closely related to higher plant SSIII. Furthermore, the sequence alignment and homology modeling data gathered showed that both the main 3-D structures of all the modeled domains obtained and the main amino acid residues implicated in starch binding are well conserved in O. tauri SSIII starch-binding domains. In addition, adsorption assays showed that OsttaSSIII-A D2 and SSIII-B D2 domains are the two that make the greatest contribution to amylose and amylopectin binding, while OsttaSSIII-B D1 is also important for starch binding. CONCLUSIONS: The results presented here suggest that differences between OsttaSSIII-A and SSIII-B SBDs in the number of and binding of amino acid residues may produce differential affinities for each isoform to polysaccharides. Increasing the knowledge about SBDs may lead to their employment in biomedical and industrial applications. PMID- 26510917 TI - Nipple-sparing Mastectomy and Sub-areolar Biopsy: To Freeze or not to Freeze? Evaluating the Role of Sub-areolar Intraoperative Frozen Section. AB - Use of nipple-sparing mastectomy (NSM) for risk-reduction and therapeutic breast cancer resection is growing. The role for intraoperative frozen section of the nipple-areolar complex remains controversial. Records of patients undergoing NSM at our institution from 2006 to 2013 were reviewed. Records from 501 nipple sparing mastectomies were reviewed (216 therapeutic, 285 prophylactic). Of the 480 breasts with sub-areolar biopsies, 307 had intraoperative frozen sections and 173 were evaluated with permanent paraffin section only. Among the 307 intraoperative frozen sections, 12 biopsies were positive on permanent paraffin section (3.9% or 12/307). Of the 12 positive permanent biopsies, five were false negative and the remaining seven concordant intraoperatively. Sensitivity and specificity of sub-areolar frozen section were 0.58 and 1, respectively. Positive sub-areolar biopsies consisted primarily of ductal carcinoma in situ (62% or 13/21). The nipples or nipple-areolar complex were resected in a separate procedure following mastectomy (10/21), intraoperatively following frozen section results (7/21) or during second-stage breast reconstruction (3/21; 1 additional scheduled). Only 30% (6/20) of resected specimens had abnormal residual pathology. Intraoperative frozen section is highly specific and moderately sensitive for the detection of positive sub-areolar biopsies in NSM. Its use can help guide intraoperative reconstructive planning. The presence of positive sub areolar biopsies in both contralateral and high-risk prophylactic mastectomy specimens emphasizes the need to perform sub-areolar biopsies in all nipple sparing mastectomies. PMID- 26510918 TI - Comparing the osteogenic potential of bone marrow and tendon-derived stromal cells to repair a critical-sized defect in the rat femur. AB - Despite significant advancements in bone tissue-engineering applications, the clinical impact of bone marrow stromal cells (BMSCs) for the treatment of large osseous defects remains limited. Therefore, other cell sources are under investigation for their osteogenic potential to repair bone. In this study, tendon-derived stromal cells (TDSCs) were evaluated in comparison to BMSCs to support the functional repair of a 5 mm critical-sized, segmental defect in the rat femur. Analysis of the trilineage differentiation capacity of TDSCs and BMSCs cultured on collagen sponges revealed impaired osteogenic differentiation and mineral deposition of TDSCs in vitro, whereas chondrogenic and adipogenic differentiation was evident for both cell types. Radiographic assessment demonstrated that neither cell type significantly improved the healing rate of a challenging 5 mm segmental femoral defect. Transplanted TDSCs and BMSCs both led to the formation of only small amounts of bone in the defect area, and histological evaluation revealed non-mineralized, collagen-rich scar tissue to be present within the defect area. Newly formed lamellar bone was restricted to the defect margins, resulting in closure of the medullary cavity. Interestingly, in comparison to BMSCs, significantly more TDSC-derived cells were present at the osteotomy gap up to 8 weeks after transplantation and were also found to be located within newly formed lamellar bone, suggesting their capacity to directly contribute to de novo bone formation. To our knowledge, this is the first study investigating the in vivo capacity of TDSCs to regenerate a critical-sized defect in the rat femur. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26510919 TI - The effect of early surgery after hip fracture on 1-year mortality. AB - BACKGROUND: Hip fracture injuries are identified as one of the most serious healthcare problems affecting older people. Many studies have explored the associations among patient characteristics, treatment processes, time to surgery and various outcomes in patients hospitalized for hip fracture. The objective of the present study is to evaluate the difference in 1-year mortality after hip fracture between patients undergoing early surgery (within 2 days) and patients undergoing delayed surgery in Italy. METHODS: Observational, retrospective study based on the Hospital Information System (HIS). This cohort study included patients aged 65 years and older who were residing in Italy and were admitted to an acute care hospital for a hip fracture between 1 January 2007 and 31 December 2012. A multivariate Cox regression analysis was used to assess the effect of early surgery on the likelihood of 1-year mortality after hip fracture, adjusting for risk factors that could affect the outcome under study. The absolute number of deaths prevented by exposure to early surgery was calculated. RESULTS: We studied a total of 405,037 admissions for hip fracture. Patients who underwent surgery within 2 days had lower 1-year mortality compared to those who waited for surgery more than 2 days (Hazard Ratios -HR-: 0.83; 95 % CI: 0.82-0.85). The number of deaths prevented by the exposure to early surgery was 5691. CONCLUSIONS: This study is the first to evaluate the association between time to surgery and 1-year mortality for all Italian elderly patients hospitalized for hip fracture. The study confirmed the previous reports on the association between delayed surgery and increased mortality and complication rates in elderly patients admitted for hip fracture. Our data support the notion that deviating from surgical guidelines in hip fracture is costly, in terms of both human life and excess hospital stay. PMID- 26510920 TI - Thyroid dysfunction and dyslipidemia in chronic kidney disease patients. AB - BACKGROUND: Chronic kidney disease (CKD) is becoming a serious health problem; the number of people with impaired renal function is rapidly rising. Progression of CKD is associated with having a number of complications, including thyroid dysfunction, dyslipidemia and cardiovascular diseases. This study was conducted to investigate thyroid function and lipid profile in CKD patients. METHODS: A cross-sectional study was conducted among 360 chronic kidney disease patients at B P Koirala Institute of Health Sciences, Dharan, Nepal. Demographic features (age and sex) and medical history of diabetes mellitus, hypertension and cardiovascular diseases of each patient were noted, and blood samples (5 ml) were analyzed for serum urea, creatinine, glucose, free triiodothyronine (T3), free thyroxine (T4), thyroid stimulating hormone (TSH), total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol and triglyceride. RESULTS: Thyroid dysfunction was found in 38.6 % CKD patients, the most common being subclinical hypothyroidism (27.2 %), followed by overt hypothyroidism (8.1 %) and subclinical hyperthyroidism (3.3 %). Hypercholesterolemia, low HDL cholesterol, undesirable LDL cholesterol and hypertriglyceridemia were observed in 34.4, 34.1, 35 and 36.6 % patients respectively. Stage 4 and 5 CKD patients had significantly higher risk of having thyroid dysfunction as compared to stage 3 patients. Significant risk factors for cardiovascular disease in CKD patients included presence of diabetes mellitus, hypercholesterolemia, undesirable LDL cholesterol and being in stage 4 and 5 (as compared to stage 3). CONCLUSIONS: Thyroid dysfunction, hypercholesterolemia, low HDL cholesterol, undesirable LDL cholesterol and hypertriglyceridemia are common in CKD patients. Progression of CKD is accompanied by rise in hypothyroidism and cardiovascular disease. PMID- 26510921 TI - Asymmetric Synthesis of Spiroketals with Aminothiourea Catalysts. AB - Chiral spiroketal skeletons are found as core structures in a range of bioactive compounds. These natural compounds and their analogues have attracted much attention in the field of drug discovery. However, methods for their enantioselective construction are limited, and easily available optically active spiroketals are rare. We demonstrate a novel catalytic asymmetric synthesis of spiroketal compounds that proceeds through an intramolecular hemiacetalization/oxy-Michael addition cascade mediated by a bifunctional aminothiourea catalyst. This results in spiroketal structures through the relay formation of contiguous oxacycles, in which multipoint recognition by the catalyst through hydrogen bonding imparts high enantioselectivity. This method offers facile access to spiroketal frameworks bearing an alkyl group at the 2 position, which are prevalent in insect pheromones. Optically active (2S,5S) chalcogran, a pheromone of the six-spined spruce bark beetle, and an azide derivative could be readily synthesized from the bicyclic reaction product. PMID- 26510922 TI - Is utilization of health services for HIV patients equal by socioeconomic status? Evidence from the Basque country. AB - INTRODUCTION: Access to ART and health services is guaranteed under universal coverage to improve life expectancy and quality of life for HIV patients. However, it remains unknown whether patients of different socioeconomic background equally use different types of health services. METHODS: We use one year (2010-2011) data on individual healthcare utilization and expenditures for the total population (N = 2262698) of the Basque Country. We observe the prevalence of HIV and use OLS regressions to estimate the impact on health utilization of demographic, socioeconomic characteristics, and health status in such patients. RESULTS: HIV prevalence per 1000 individuals is greater the lower the socioeconomic status (0.784 for highest; 2.135 for lowest), for males (1.616) versus females (0.729), and for middle-age groups (26-45 and 46-65). Health expenditures are 11826? greater for HIV patients than for others, but with differences by socioeconomic group derived from a different mix of services utilization (total cost of 13058? for poorest, 14960? for richest). Controlling for health status and demographic variables, poor HIV patients consume more on pharmaceuticals; rich in specialists and hospital care. Therefore, there is inequity in health services utilization by socioeconomic groups. CONCLUSIONS: Equity in health provision for HIV patients represents a challenge even if access to treatment is guaranteed. Lack of information in poorer individuals might lead to under-provision while richer individuals might demand over-provision. We recommend establishing accurate clinical guidelines with the appropriate mix of health provision by validated need for all socioeconomic groups; promoting educational programs so that patients demand the appropriate mix of services, and stimulating integrated care for HIV patients with multiple chronic conditions. PMID- 26510923 TI - Supermicrosurgical free sensate superficial circumflex iliac artery perforator flap for reconstruction of a soft tissue defect of the ankle in a 1-year-old child. AB - Although a superficial circumflex iliac artery perforator (SCIP) flap has recently been widely used owing to its various advantages, reports on its use in the pediatric population are limited. A case of a supermicrosurgical reconstruction of a soft tissue defect of the ankle associated with the congenital deficiency of the tibia using a free sensate SCIP flap in a 1-year-old child has been presented. The correction of the valgus deformity of the ankle resulted in a soft tissue defect, which required flap coverage. The lateral cutaneous branch of the intercostal nerve of the flap was coapted with the deep peroneal nerve for sensory recovery. Postoperative course was uneventful and the flap completely survived. The patient was able to ambulate independently at 7 months after surgery. To the best of our knowledge, this is the youngest case of a SCIP flap transfer in literature. This case showed that young age is not a contraindication for SCIP flap transfer. It is believed that the SCIP flap procedure may be a useful option for free flap reconstruction in children. PMID- 26510924 TI - Comparison of the pharmacokinetics and pharmacodynamics of dapagliflozin in patients with type 1 versus type 2 diabetes mellitus. AB - AIMS: To compare the pharmacokinetics and pharmacodynamics of dapagliflozin in patients with type 1 diabetes mellitus (T1DM) versus type 2 diabetes mellitus (T2DM) in order to explore the potential of dapagliflozin as add-on therapy to insulin in patients with T1DM. METHODS: Steady-state pharmacokinetics and pharmacodynamics of dapagliflozin (1-100 mg) were evaluated in a meta-analysis of patients with T1DM or T2DM. A model was constructed of the relationship between dapagliflozin systemic exposure and urinary glucose excretion (UGE) in patients with T1DM versus those with T2DM. RESULTS: Data were analysed from 160 patients (T1DM, n = 70; T2DM, n = 90). Dapagliflozin systemic exposure (maximum concentration and area under the curve) increased similarly in a dose-related manner in both patient populations. Dose-dependent increases in 24-h UGE were observed with dapagliflozin in both populations. Unadjusted results showed that with regard to UGE response, dapagliflozin was more potent in patients with T1DM {mean half-maximum effective concentration [EC50 ] = 2.72 ng/ml [95% confidence interval (CI) 1.14, 5.08]} than in patients with T2DM [EC50 = 12.2 ng/ml (95% CI 4.91, 21.1)]. After normalization for baseline fasting plasma glucose, estimated glomerular filtration rate and UGE, however, the UGE potency of dapagliflozin was similar between the two populations [T1DM: mean EC50 , 8.12 ng/ml (95% CI 2.95, 14.6); T2DM: mean EC50 , 7.75 ng/ml (95% CI 1.35, 18.1)]. CONCLUSIONS: Dapagliflozin pharmacokinetics and the predicted UGE dose exposure response to dapagliflozin were similar in patients with T1DM and those with T2DM and suggest that the dapagliflozin dosages currently used for the treatment of T2DM may provide benefit as add-on therapy to insulin in patients with T1DM. PMID- 26510925 TI - Lack of robust satellite cell activation and muscle regeneration during the progression of Pompe disease. AB - INTRODUCTION: Muscle stem cells termed satellite cells are essential for muscle regeneration. A central question in many neuromuscular disorders is why satellite cells are unable to prevent progressive muscle wasting. We have analyzed muscle fiber pathology and the satellite cell response in Pompe disease, a metabolic myopathy caused by acid alpha-glucosidase deficiency and lysosomal glycogen accumulation. Pathology included muscle fiber vacuolization, loss of cross striation, and immune cell infiltration. RESULTS: The total number of Pax7 positive satellite cells in muscle biopsies from infantile, childhood onset and adult patients (with different ages and disease severities) were indistinguishable from controls, indicating that the satellite cell pool is not exhausted in Pompe disease. Pax7/Ki67 double stainings showed low levels of satellite cell proliferation similar to controls, while MyoD and Myogenin stainings showed undetectable satellite cell differentiation. Muscle regenerative activity monitored with expression of embryonic Myosin Heavy Chain was weak in the rapidly progressing classic infantile form and undetectable in the more slowly progressive childhood and adult onset disease including in severely affected patients. CONCLUSIONS: These results imply that ongoing muscle wasting in Pompe disease may be explained by insufficient satellite cell activation and muscle regeneration. The preservation of the satellite cell pool may offer a venue for the development of novel treatment strategies directed towards the activation of endogenous satellite cells. PMID- 26510926 TI - Development of an In Vitro Model to Characterize the Effects of Transcatheter Aortic Valve on Coronary Artery Flow. AB - Impairment of coronary artery flow, in either acute or chronic conditions, is a severe complication of transcatheter aortic valve (TAV) implantation, which can arise due to improper TAV positioning. However, little work has been done to quantify the effects of the TAV positioning on the coronary flow. In this study, a realistic in vitro model of coronary artery flow was developed and used to investigate the impact of TAV deployed orientations on coronary flow. The coronary hemodynamics was first replicated mathematically using a lumped parameter model with time-varying myocardial resistance. Based on the analytical model, two stepper motor controlled stopcock valves were integrated in a left heart simulator to represent the variable myocardial resistance in the experimental setup. The coronary flow and pressure waveforms obtained from the in vitro system were consistent with published data. With a TAV deployed in different orientations, the measured results demonstrated that TAV orientation does not have a significant impact on the coronary flow. The developed in vitro model can be further utilized to simulate coronary flow under various pathological conditions. PMID- 26510927 TI - The HAND Database: a gateway to understanding the role of HIV in HIV-associated neurocognitive disorders. AB - BACKGROUND: Despite an augmented research effort and scale-up of highly active antiretroviral therapy, a high prevalence of HIV-1-associated neurocognitive disorders (HAND) persists in the HIV-infected population. Nearly 50 % of all HIV 1-infected individuals suffer from a neurocognitive disorder due to neural and synaptodendritic damage. Challenges in HAND research, including limited availability of brain tissue from HIV patients, variation in HAND study protocols, and virus genotyping inconsistency and errors, however, have resulted in studies with insufficient power to delineate molecular mechanisms underlying HAND pathogenesis. There exists, therefore, a great need for a reliable and centralized resource specific to HAND research, particularly for epidemiological study and surveillance in resource-limited countries where severe forms of HAND persist. DESCRIPTION: To address the aforementioned imperative need, here we present the HAND Database, a resource containing well-curated and up-to-date HAND virus information and associated clinical and epidemiological data. This database provides information on 5,783 non-redundant HIV-1 sequences from global HAND research published to date, representing a total of 163 unique individuals that have been assessed for HAND. A user-friendly interface allows for flexible searching, filtering, browsing, and downloading of data. The most comprehensive database of its kind, the HAND Database not only bolsters current HAND research by increasing sampling power and reducing study biases caused by protocol variation and genotyping inconsistency, it allows for comparison between HAND studies across different dimensions. Development of the HAND Database has also revealed significant knowledge gaps in HIV-driven neuropathology. These gaps include inadequate sequencing of viral genes beyond env, lack of HAND viral data from HIV epidemiologically important regions including Asian and Sub-Saharan African countries, and biased sampling toward the male gender, all factors that impede efforts toward providing an improved quality of life to HIV-infected individuals, and toward elimination of viruses in the brain. CONCLUSION: Our aim with the HAND database is to provide researchers in both the HIV and neuroscience fields a comprehensive and rigorous data source toward better understanding virus compartmentalization and to help in design of improved strategies against HAND viruses. We also expect this resource, which will be updated on a regular basis, to be useful as a reliable reference for further HAND epidemiology studies. The HAND Database is freely available and accessible online at http://www.handdatabase.org . PMID- 26510928 TI - An investigation of the ability to produce a defined 'target pressure' using the PressCise compression bandage. AB - Compression therapy is the cornerstone in the prevention and treatment of leg ulcers related to chronic venous insufficiency. The application of optimal high pressure is essential for a successful outcome, but the literature has reported difficulty applying the intended pressure, even among highly skilled nurses. The PressCise bandage has a novel design, with both longitudinal and horizontal reference points for correct application. In the current experimental study, the results for the general linear model, where the data set is treated optimally, showed that all 95% confidence intervals of the expected values for pressure were, at most, 5 mmHg from the target value of 50 mmHg, independent of the position on the leg and the state of activity. Moreover, even nurses with limited experience were consistently able to reach the targeted pressure goal. Future studies are needed to determine how well the bandage works on legs of different shapes, the optimal way of using the bandage (day only or both day and night) and whether the bandage should be combined with an outer bandage layer. In addition, special attention should be paid to subjective patient experiences in relation to the treatment as pain, discomfort and bulk are factors that can compromise patients' willingness to adhere to the treatment protocol and thereby prolong the healing process. PMID- 26510929 TI - Cardiac FDG-PET: a straight forward tool with high potential. PMID- 26510930 TI - Blood transcriptomics of drug-naive sporadic Parkinson's disease patients. AB - BACKGROUND: Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder that is clinically defined in terms of motor symptoms. These are preceded by prodromal non-motor manifestations that prove the systemic nature of the disease. Identifying genes and pathways altered in living patients provide new information on the diagnosis and pathogenesis of sporadic PD. METHODS: Changes in gene expression in the blood of 40 sporadic PD patients and 20 healthy controls ("Discovery set") were analyzed by taking advantage of the Affymetrix platform. Patients were at the onset of motor symptoms and before initiating any pharmacological treatment. Data analysis was performed by applying Ranking Principal Component Analysis, PUMA and Significance Analysis of Microarrays. Functional annotations were assigned using GO, DAVID, GSEA to unveil significant enriched biological processes in the differentially expressed genes. The expressions of selected genes were validated using RT-qPCR and samples from an independent cohort of 12 patients and controls ("Validation set"). RESULTS: Gene expression profiling of blood samples discriminates PD patients from healthy controls and identifies differentially expressed genes in blood. The majority of these are also present in dopaminergic neurons of the Substantia Nigra, the key site of neurodegeneration. Together with neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, already found in previous analysis of PD blood and post-mortem brains, we unveiled transcriptome changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation. Candidate transcripts as CBX5, TCF3, MAN1C1 and DOCK10 were validated by RT-qPCR. CONCLUSIONS: Our data support the use of blood transcriptomics to study neurodegenerative diseases. It identifies changes in crucial components of chromatin remodeling and methylation machineries as early events in sporadic PD suggesting epigenetics as target for therapeutic intervention. PMID- 26510931 TI - Autoinducer-2 signaling is involved in regulation of stress-related genes of Deinococcus radiodurans. AB - Autoinducer-2 (AI-2) serves as a quorum-sensing signaling molecule that mediates both intraspecies and interspecies communication among bacteria, and plays critical roles in regulating various bacterial behaviors. In the present study, we investigated the functions of AI-2 signaling in the extremophilic bacterium Deinococcus radiodurans R1 by construction of the LuxS gene disruption mutant, survival phenotype assay and gene transcription assay. The gene mutant (DRDeltaLuxS), which was unable to produce AI-2, was significantly more sensitive to both gamma radiation and H2O2 compared with the wild-type strain. Addition of the wild-type-derived spent medium into the cell culture of DRDeltaLuxS fully restored the radioresistance of D. radiodurans. A higher level of reactive oxygen species accumulated in the mutant compared with the wild type under normal or oxidative stress. Quantitative real-time PCR assays showed that transcriptional levels of stress-related proteins, including catalase, extracellular nuclease, Dps-1 and ABC transporters, were decreased in DRDeltaLuxS, indicating that AI-2 is involved in regulation of stress-related genes of D. radiodurans. Hence, AI-2 signaling may contribute to the extreme resistance of D. radiodurans to radiation and oxidative stresses. PMID- 26510932 TI - The Problem of the Pannus: Physician Preference Survey and a Review of the Literature on Cesarean Skin Incision in Morbidly Obese Women. AB - OBJECTIVE: This study aims to determine preferences of a nationally representative sample of obstetrician/gynecologists (OB/GYNs) regarding cesarean delivery (CD) incision practices for women with morbid obesity (body mass index >= 40 kg/m(2)). STUDY DESIGN: We conducted an online survey using the American College of Obstetricians and Gynecologists database. We compared physician demographics, practice characteristics, and CD incision type preference. RESULTS: After exclusion of ineligible participants, 247 OB/GYNs completed the survey (42% response rate). In nonemergency CD of morbidly obese women, 84% of physicians preferred a Pfannenstiel skin incision (67% preferring taping the pannus; 17% without taping the pannus). In emergency CD, 66% preferred a Pfannenstiel incision (46% without taping the pannus; 20% with taping the pannus) and 20% a vertical incision. For both emergency and nonemergency CD, there was no difference in incision type preferences by provider years in practice, practice scope, or number of CD performed each year. CONCLUSION: Given the preference of a Pfannenstiel incision with taping the pannus during CD of morbidly obese women, further investigation is needed to assess the risks and benefits of this incision and the practice of elevating the pannus. PMID- 26510933 TI - Colorectal polyp prevention by daily aspirin use is abrogated among active smokers. AB - PURPOSE: Based on suggestive findings from a recent study of high-risk Japanese patients, we sought to determine whether the risk of colorectal polyps associated with smoking may be modified by daily use of aspirin in an analysis of a large US screening population. METHODS: This is a cross-sectional study of 2,918 consecutive colonoscopy patients at a university hospital over a 30-month period. Data were abstracted from electronic medical records. Multivariate models of polyp counts were used to examine the competing risks of smoking and aspirin use. Models were further stratified by polyp location (proximal vs. distal) and pathologic subtype (dysplastic vs. serrated). RESULTS: Incidental rate of polyps was higher among active smokers [incidence rate ratio (IRR) 1.72; 95 % confidence interval (CI) 1.46-2.02] and lower among daily aspirin users (IRR 0.73; 95 % CI 0.61-0.86) compared to those who used neither. Smoking interacts significantly with aspirin use resulting in loss of aspirin protection (IRR 1.69; 95 % CI 1.28 2.24). Stratified analyses demonstrate that aspirin specifically reduces the risk of traditional dysplastic adenomas (IRR 0.72; 95 % CI 0.61-0.86) not serrated/hyperplastic polyps (IRR 0.92; 95 % CI 0.72-1.17) and that the modification of aspirin protection by smoking is primarily observed within the distal colorectum (p < 0.03). CONCLUSIONS: We report for the first time, in a typical risk US clinical population, a lack of protective association of aspirin for polyps among active smokers. Future prospective studies are recommended to confirm this mitigating effect in order to improve the precision of the growing evidence base about the chemopreventive benefit of aspirin in colorectal cancer. PMID- 26510934 TI - Compensatory Versus Noncompensatory Shoulder Movements Used for Reaching in Stroke. AB - Background The extent to which the upper-limb flexor synergy constrains or compensates for arm motor impairment during reaching is controversial. This synergy can be quantified with a minimal marker set describing movements of the arm-plane. Objectives To determine whether and how (a) upper-limb flexor synergy in patients with chronic stroke contributes to reaching movements to different arm workspace locations and (b) reaching deficits can be characterized by arm plane motion. Methods Sixteen post-stroke and 8 healthy control subjects made unrestrained reaching movements to targets located in ipsilateral, central, and contralateral arm workspaces. Arm-plane, arm, and trunk motion, and their temporal and spatial linkages were analyzed. Results Individuals with moderate/severe stroke used greater arm-plane movement and compensatory trunk movement compared to those with mild stroke and control subjects. Arm-plane and trunk movements were more temporally coupled in stroke compared with controls. Reaching accuracy was related to different segment and joint combinations for each target and group: arm-plane movement in controls and mild stroke subjects, and trunk and elbow movements in moderate/severe stroke subjects. Arm-plane movement increased with time since stroke and when combined with trunk rotation, discriminated between different subject groups for reaching the central and contralateral targets. Trunk movement and arm-plane angle during target reaches predicted the subject group. Conclusions The upper-limb flexor synergy was used adaptively for reaching accuracy by patients with mild, but not moderate/severe stroke. The flexor synergy, as parameterized by the amount of arm-plane motion, can be used by clinicians to identify levels of motor recovery in patients with stroke. PMID- 26510935 TI - Corrigendum: BMP signalling differentially regulates distinct haematopoietic stem cell types. PMID- 26510936 TI - Multiple estimates of effective population size for monitoring a long-lived vertebrate: an application to Yellowstone grizzly bears. AB - Effective population size (N(e)) is a key parameter for monitoring the genetic health of threatened populations because it reflects a population's evolutionary potential and risk of extinction due to genetic stochasticity. However, its application to wildlife monitoring has been limited because it is difficult to measure in natural populations. The isolated and well-studied population of grizzly bears (Ursus arctos) in the Greater Yellowstone Ecosystem provides a rare opportunity to examine the usefulness of different N(e) estimators for monitoring. We genotyped 729 Yellowstone grizzly bears using 20 microsatellites and applied three single-sample estimators to examine contemporary trends in generation interval (GI), effective number of breeders (N(b)) and N(e) during 1982-2007. We also used multisample methods to estimate variance (N(eV)) and inbreeding N(e) (N(eI)). Single-sample estimates revealed positive trajectories, with over a fourfold increase in N(e) (~100 to 450) and near doubling of the GI (~8 to 14) from the 1980s to 2000s. N(eV) (240-319) and N(eI) (256) were comparable with the harmonic mean single-sample N(e) (213) over the time period. Reanalysing historical data, we found N(eV) increased from ~80 in the 1910s-1960s to ~280 in the contemporary population. The estimated ratio of effective to total census size (N(e) /N(c)) was stable and high (0.42-0.66) compared to previous brown bear studies. These results support independent demographic evidence for Yellowstone grizzly bear population growth since the 1980s. They further demonstrate how genetic monitoring of N(e) can complement demographic-based monitoring of N(c) and vital rates, providing a valuable tool for wildlife managers. PMID- 26510937 TI - Statistical Guidelines for Publishing in the Journal of Youth and Adolescence. PMID- 26510939 TI - The Amniotic Membrane: Development and Potential Applications - A Review. AB - Foetal membranes are essential tissues for embryonic development, playing important roles related to protection, breathing, nutrition and excretion. The amnion is the innermost extraembryonic membrane, which surrounds the foetus, forming an amniotic sac that contains the amniotic fluid (AF). In recent years, the amniotic membrane has emerged as a potential tool for clinical applications and has been primarily used in medicine in order to stimulate the healing of skin and corneal diseases. It has also been used in vaginal reconstructive surgery, repair of abdominal hernia, prevention of surgical adhesions and pericardium closure. More recently, it has been used in regenerative medicine because the amniotic-derived stem cells as well as AF-derived cells exhibit cellular plasticity, angiogenic, cytoprotective, immunosuppressive properties, antitumoural potential and the ability to generate induced pluripotent stem cells. These features make them a promising source of stem cells for cell therapy and tissue engineering. In this review, we discussed the development of the amnion, AF and amniotic cavity in different species, as well as the applicability of stem cells from the amnion and AF in cellular therapy. PMID- 26510938 TI - The BDNF Val66Met Polymorphism Interacts with Maternal Parenting Influencing Adolescent Depressive Symptoms: Evidence of Differential Susceptibility Model. AB - Although depressive symptoms are common during adolescence, little research has examined gene-environment interaction on youth depression. This study chose the brain-derived neurotrophic factor (BDNF) gene, tested the interaction between a functional polymorphism resulting amino acid substitution of valine (Val) to methionine (Met) in the proBDNF protein at codon 66 (Val66Met), and maternal parenting on youth depressive symptoms in a sample of 780 community adolescents of Chinese Han ethnicity (aged 11-17, M = 13.6, 51.3 % females). Participants reported their depressive symptoms and perceived maternal parenting. Results indicated the BDNF Val66Met polymorphism significantly moderated the influence of maternal warmth-reasoning, but not harshness-hostility, on youth depressive symptoms. Confirmatory model evaluation indicated that the interaction effect involving warmth-reasoning conformed to the differential-susceptibility rather than diathesis-stress model of person-X-environment interaction. Thus, Val carriers experienced less depressive symptoms than Met homozygotes when mothering was more positive but more symptoms when mothering was less positive. The findings provided evidence in support of the differential susceptibility hypothesis of youth depressive symptoms and shed light on the importance of examining the gene-environment interaction from a developmental perspective. PMID- 26510940 TI - The protective effect of resveratrol against dentin bonding agents-induced cytotoxicity. AB - This study was designed to evaluate the cytotoxicity of four dentin bonding agents and the effects of an antioxidant addition. Group A: G-aenial Bond, Group B: Optibond All in One, Group C: Gluma Self Etch and Group D: Clearfil S(3) Bond were added to the medium using extract method. The cells were cultured with or without resveratrol (RES) addition. MTT, reactive oxygen species (ROS), DCF, Comet and 8-OHdG measurements were performed. The agents had a dose-dependent (1:1>1:10>1:20) cytotoxic effect. Considering 1:10 concentration; Group D at 1 h (p<0.01) and Group B and D at 24 h had the weakest cytotoxic effect (p<0.05). After RES addition, the highest cell viability was determined in Groups B+RES and D+RES at 1 h and in Groups A+RES and B+RES at 24 h (p<0.01). The dentin bonding agents induced ROS production and DNA damage regarding to their composition. However, RES addition decreased the indicated parameters. PMID- 26510941 TI - The relationship between processes and outcomes for injured older adults: a study of a statewide trauma system. AB - PURPOSE: Age is a risk factor for death, adverse outcomes, and health care use following trauma. The American College of Surgeons' Trauma Quality Improvement Program (TQIP) has published "best practices" of geriatric trauma care; adoption of these guidelines is unknown. We sought to determine which evidence-based geriatric protocols, including TQIP guidelines, were correlated with decreased mortality in Pennsylvania's trauma centers. METHODS: PA's level I and II trauma centers self-reported adoption of geriatric protocols. Survey data were merged with risk-adjusted mortality data for patients >=65 from a statewide database, the Pennsylvania Trauma Systems Foundation (PTSF), to compare mortality outlier status and processes of care. Exposures of interest were center-specific processes of care; outcome of interest was PTSF mortality outlier status. RESULTS: 26 of 27 eligible trauma centers participated. There was wide variation in care processes. Four trauma centers were low outliers; three centers were high outliers for risk-adjusted mortality rates in adults >=65. Results remained consistent when accounting for center volume. The only process associated with mortality outlier status was age-specific solid organ injury protocols (p = 0.04). There was no cumulative effect of multiple evidence-based processes on mortality rate (p = 0.50). CONCLUSIONS: We did not see a link between adoption of geriatric best-practices trauma guidelines and reduced mortality at PA trauma centers. The increased susceptibility of elderly to adverse consequences of injury, combined with the rapid growth rate of this demographic, emphasizes the importance of identifying interventions tailored to this population. LEVEL OF EVIDENCE: III. STUDY TYPE: Descriptive. PMID- 26510942 TI - Subtalar joint instability. AB - PURPOSE: Subtalar joint instability may frequently be overlooked and erroneously be integrated under the diagnosis of ankle joint instability. It was the scope of this review to characterize the present state-of-art with regard to the adequate diagnosis and treatment. METHODS: While the clinical picture is mostly inconclusive for subtalar joint instability, a high degree of suspicion for this diagnosis is needed to employ weight-bearing x-rays, standardized stress radiography, CT scanning and MRI to further elucidate the etiopathology RESULTS: Geometrical reasons as hindfoot deformities, isolated or combined injuries or instabilities in conjunction with the ankle ligament complex do exist which should be differentiated in detail and classified to indicate the adequate treatment. Treatment of acute lesions is simple and effective. A certain percentage of the patients with chronic subtalar instability is incorrectly labeled with the diagnosis of a sinus tarsi syndrome. CONCLUSION: Subtalar joint arthroscopy for reconfirmation of the correct diagnosis conjoined with restoration of physiological hindfoot alignment and a preferably anatomical ligamentous reconstruction provide the basis for a good functional recovery. PMID- 26510943 TI - Cerebral foreign body reaction after carotid aneurysm stenting. AB - Flow diverter stents are new important tools in the treatment of large, giant, or wide-necked aneurysms. Their delivery and positioning may be difficult due to vessel tortuosity. Common adverse events include intracranial hemorrhage and ischemic stroke, which usually occurs within the same day, or the next few days after the procedure. We present a case where we encountered an unusual intracerebral complication several months after endovascular treatment of a large left internal carotid artery aneurysm, and where brain biopsy revealed foreign body reaction to hydrophilic polymer fragments distally to the stent site. Although previously described, embolization of polymer material from intravascular equipment is rare. We could not identify any other biopsy verified case in the literature, with this particular presentation of intracerebral polymer embolization--a multifocal inflammation spread out through the white matter of one hemisphere without hemorrhage or ischemic changes. PMID- 26510944 TI - Cariprazine: First Global Approval. AB - Cariprazine (Vraylar) is an oral atypical antipsychotic originated by Gedeon Richter. It is a potent dopamine D3 and D2 receptor partial agonist, which preferentially binds to the D3 receptor. Cariprazine also has partial agonist activity at serotonin 5-HT1A receptors. In September 2015, cariprazine received its first global approval in the USA for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. It is also in development in a variety of countries for the treatment of schizophrenia with predominant negative symptoms (phase III), as adjunctive therapy for major depressive disorder (phase II/III) and for the treatment of bipolar depression (phase II). This article summarizes the milestones in the development of cariprazine leading to this first approval for schizophrenia and manic or mixed episodes associated with bipolar I disorder. PMID- 26510945 TI - IL6-induced metastasis modulators p-STAT3, MMP-2 and MMP-9 are targets of 3,3' diindolylmethane in ovarian cancer cells. AB - PURPOSE: Ovarian cancer is a highly lethal gynecological malignancy for which the overall prognosis has remained poor over the past few decades. Interleukin (IL6) has been found to be a major contributor to the initiation and progression of ovarian cancer. This cytokine exerts its activity through activation of several signaling pathways, in particular the signal transducer and activator of transcription (STAT3) pathway. Here, we aimed at investigating the capacity of a natural dietary compound found in cruciferous vegetables, i.e., 3,3' diindolylmethane (DIM), to target the metastatic phenotype of ovarian cancer cells through functional p-STAT3. METHODS: The human ovarian carcinoma-derived cell lines SKOV3 and A2780 were treated with IL6 and/or DIM and subjected to in vitro proliferation, adhesion, migration and invasion assays to assess the anti metastatic and anti-IL6 effects of DIM, as well as to assess gene expression alterations before and after shRNA-mediated STAT3 silencing. RESULTS: We found that DIM inhibits IL6-mediated increases in ovarian cancer cell adhesion, migration and invasion. These results were corroborated by shRNA-mediated STAT3 silencing. Through Western blot and ELISA analyses direct evidence was provided for the capacity of DIM to inhibit ovarian cancer cell adhesion, migration and invasion, which was found to be associated with down-regulation of the matrix metalloproteinases MMP-2 and MMP-9. CONCLUSIONS: From our data we conclude that DIM exhibits an anti-IL6-like activity by inhibiting p-STAT3 enhanced ovarian cancer cell proliferation and in vitro metastasis-associated events, i.e., adhesion, migration and invasion. Most significantly, MMP-2 and MMP-9, which are known to promote and enhance metastasis, were found to act as targets of DIM. This anti-IL6-like property of DIM may pave the way for the development of novel ovarian cancer preventive and/or therapeutic strategies. PMID- 26510946 TI - Artificial suckling in Martina Franca donkey foals: effect on in vivo performances and carcass composition. AB - In recent years, there has been an increasing interest on donkey milk production, on its characteristics, and also on breeding techniques. Donkey milk is characterized by high economic value, although the productive level of jennies is poor. During the milking process, foals are usually separated from their dams, allowing the milk collection in the mammary gland of jennies before milking session. This takes 8 h per day of fastening period for lactating donkey foals. During this period, it could be possible to apply a partial artificial suckling system (artificial suckling during daytime and natural suckling during the night). The aim of the work is the evaluation of the effect of this innovative technique on in vivo performances and on meat production traits of Martina Franca donkey foals. Forty Martina Franca jennies with their foals were used for the trial. After colostrum assumption, 20 foals were partially artificially suckled (AS) during each day, and 20 foals were naturally suckled (NS). From 8.00 to 20.00, both groups were separated from their mothers in order to allow the milking procedures of the jennies. The AS group was in a stall equipped with an automatic calf-suckling machine. For each group, 10 foals were slaughtered at 12 months and 10 foals at 18 months. Artificial suckling system positively affected the growth rate of donkey foals, particularly in the first 6 months from birth, with higher weekly weight gain (P < 0.01), higher final live weight (P < 0.001), and carcass weight (P < 0.01), but no effects were observed on carcass dressing percentage (P > 0.05). Artificial suckling system permitted to extend the time of foal separation from their mothers increasing milk collection time per day, awarding fastening periods in foals. PMID- 26510947 TI - The Soybean Peptide Vglycin Preserves the Diabetic beta-cells through Improvement of Proliferation and Inhibition of Apoptosis. AB - Replenishment of insulin-producing pancreatic beta-cells would be beneficial in diabetes. The number of beta-cells is maintained primarily by self-neogenesis to compensate for beta-cell failure, loss or dedifferentiation. We present here a polypeptide vglycin, which was isolated and purified from germinating pea seeds. Vglycin exhibited positive effects in our diabetic models by promoting the proliferation and suppressing the apoptosis and dedifferentiation of beta-cells. Vglycin promoted the restoration of beta-cells in both young streptozotocin (STZ) induced type 1 diabetic SD rats and in aged high-fat diet with (or without) STZ induced type 2 diabetic C57BL/6 mice. We demonstrated that vglycin triggers this positive signaling by activating the insulin receptor and corresponding transcription factors. Impaired insulin sensitivity and glucose tolerance in aged T2DM mice were dramatically improved after long-term vglycin treatment, consistent with the altered level of inflammatory factor IL-1beta/6. In addition, energy expenditure and body weights were significantly decreased in the mouse models after vglycin therapy. These results provide insight into the protective effects of vglycin on ameliorating beta-cell function in standing glucolipotoxicity. Thus, vglycin may represent a new therapeutic agent for preventing and treating diabetes by replenishing endogenous insulin-positive cells. PMID- 26510948 TI - Hepatic FDG uptake is associated with future cardiovascular events in asymptomatic individuals with non-alcoholic fatty liver disease. AB - BACKGROUND: Hepatic F-18 fluoro-2-deoxyglucose (FDG) uptake is associated with non-alcoholic fatty liver disease (NAFLD) which is an independent risk factor for cardiovascular disease. However, the value of hepatic FDG uptake for predicting future cardiovascular events has not been explored. METHODS AND RESULTS: Study participants were 815 consecutive asymptomatic participants who underwent a health screening program that included FDG positron emission tomography/computed tomography (PET/CT), abdominal ultrasonography, and carotid intima-media thickness (CIMT) measurements (age 51.8 +/- 6.0 year; males 93.9%). We measured hepatic FDG uptake and assessed the prognostic significance of this parameter with other cardiovascular risk factors including Framingham risk score and CIMT. Multivariate Cox proportional hazards analyses including all study participants revealed that NAFLD with high-hepatic FDG uptake was the only independent predictor for future cardiovascular events [hazard ratio (HR) 4.23; 95% CI 1.05 17.04; P = .043). Subgroup analysis conducted in the NAFLD group showed that high hepatic FDG uptake was a significant independent predictor of cardiovascular events (HR 9.29; 95% CI 1.05-81.04; P = .045). CONCLUSIONS: This exploratory study suggests that high-hepatic FDG uptake may be a useful prognostic factor for cardiovascular events in individuals with NAFLD. PMID- 26510949 TI - Tunable Multi-switching in Plasmonic Waveguide with Kerr Nonlinear Resonator. AB - We propose a nanoplasmonic waveguide side-coupled with bright-dark-dark resonators in our paper. A multi-oscillator theory derived from the typical two oscillator model, is established to describe spectral features as well as slow light effects in bright-dark-dark structures, and confirmed by the finite difference time domain (FDTD). That a typical plasmon induced transparency (PIT) turns to double PIT spectra is observed in this waveguide structure. At the same time, multi-switching effects with obvious double slow-light bands based on double PIT are also discovered in our proposed structure. What's more, dynamically tuning the multi-switching is achieved by means of filling Fabry Perot resonators with the Kerr nonlinear material Ag-BaO. These results may have applications in all-optical devices, moreover, the multi-oscillator theory may play a guiding role in designing plasmonic devices. PMID- 26510950 TI - Host-directed therapy targeting the Mycobacterium tuberculosis granuloma: a review. AB - Infection by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb) is a major cause of morbidity and mortality worldwide. Slow progress has been made in lessening the impact of tuberculosis (TB) on human health, especially in parts of the world where Mtb is endemic. Due to the complexity of TB disease, there is still an urgent need to improve diagnosis, prevention, and treatment strategies to control global spread of disease. Active research targeting avenues to prevent infection or transmission through vaccination, to diagnose asymptomatic carriers of Mtb, and to improve antimicrobial drug treatment responses is ongoing. However, this research is hampered by a relatively poor understanding of the pathogenesis of early infection and the factors that contribute to host susceptibility, protection, and the development of active disease. There is increasing interest in the development of adjunctive therapy that will aid the host in responding to Mtb infection appropriately thereby improving the effectiveness of current and future drug treatments. In this review, we summarize what is known about the host response to Mtb infection in humans and animal models and highlight potential therapeutic targets involved in TB granuloma formation and resolution. Strategies designed to shift the balance of TB granuloma formation toward protective rather than destructive processes are discussed based on our current knowledge. These therapeutic strategies are based on the assumption that granuloma formation, although thought to prevent the spread of the tubercle bacillus within and between individuals contributes to manifestations of active TB disease in human patients when left unchecked. This effect of granuloma formation favors the spread of infection and impairs antimicrobial drug treatment. By gaining a better understanding of the mechanisms by which Mtb infection contributes to irreversible tissue damage, down regulates protective immune responses, and delays tissue healing, new treatment strategies can be rationally designed. Granuloma-targeted therapy is advantageous because it allows for the repurpose of existing drugs used to treat other communicable and non-communicable diseases as adjunctive therapies combined with existing and future anti-TB drugs. Thus, the development of adjunctive, granuloma targeted therapy, like other host-directed therapies, may benefit from the availability of approved drugs to aid in treatment and prevention of TB. In this review, we have attempted to summarize the results of published studies in the context of new innovative approaches to host-directed therapy that need to be more thoroughly explored in pre-clinical animal studies and in human clinical trials. PMID- 26510951 TI - LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population. AB - Mitochondrial Complex IV [cytochrome c oxidase (COX)] deficiency is one of the most common respiratory chain defects in humans. The clinical phenotypes associated with COX deficiency include liver disease, cardiomyopathy and Leigh syndrome, a neurodegenerative disorder characterized by bilateral high signal lesions in the brainstem and basal ganglia. COX deficiency can result from mutations affecting many different mitochondrial proteins. The French-Canadian variant of COX-deficient Leigh syndrome is unique to the Saguenay-Lac-Saint-Jean region of Quebec and is caused by a founder mutation in the LRPPRC gene. This encodes the leucine-rich pentatricopeptide repeat domain protein (LRPPRC), which is involved in post-transcriptional regulation of mitochondrial gene expression. Here, we present the clinical and molecular characterization of novel, recessive LRPPRC gene mutations, identified using whole exome and candidate gene sequencing. The 10 patients come from seven unrelated families of UK-Caucasian, UK-Pakistani, UK-Indian, Turkish and Iraqi origin. They resemble the French Canadian Leigh syndrome patients in having intermittent severe lactic acidosis and early-onset neurodevelopmental problems with episodes of deterioration. In addition, many of our patients have had neonatal cardiomyopathy or congenital malformations, most commonly affecting the heart and the brain. All patients who were tested had isolated COX deficiency in skeletal muscle. Functional characterization of patients' fibroblasts and skeletal muscle homogenates showed decreased levels of mutant LRPPRC protein and impaired Complex IV enzyme activity, associated with abnormal COX assembly and reduced steady-state levels of numerous oxidative phosphorylation subunits. We also identified a Complex I assembly defect in skeletal muscle, indicating different roles for LRPPRC in post transcriptional regulation of mitochondrial mRNAs between tissues. Patient fibroblasts showed decreased steady-state levels of mitochondrial mRNAs, although the length of poly(A) tails of mitochondrial transcripts were unaffected. Our study identifies LRPPRC as an important disease-causing gene in an early-onset, multisystem and neurological mitochondrial disease, which should be considered as a cause of COX deficiency even in patients originating outside of the French Canadian population. PMID- 26510952 TI - Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer's disease. AB - Amyloid deposition, tangle formation, neuroinflammation and neuronal dysfunction are pathological processes involved in Alzheimer's disease. However, the relative role of these processes in driving disease progression is still unclear. The aim of this positron emission tomography study was to: (i) investigate longitudinal changes of microglial activation, amyloid and glucose metabolism; and (ii) assess the temporospatial relationship between these three processes in Alzheimer's disease. A group of eight patients with a diagnosis of Alzheimer's disease (66 +/ 4.8 years) and 14 healthy controls (65 +/- 5.5 years) underwent T1 and T2 magnetic resonance imaging, along with (11)C-(R)-PK11195, (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography scans for microglial activation, amyloid deposition and glucose metabolism. All patients were followed-up with repeated magnetic resonance imaging and three positron emission tomography scans after 16 months. Parametric maps were interrogated using region of interest analysis, Statistical Parametric Mapping, and between group correlation analysis at voxel-level using Biological Parametric Mapping. At baseline, patients with Alzheimer's disease showed significantly increased microglial activation compared to the control subjects. During follow-up, for the first time, we found that while there is a progressive reduction of glucose metabolism, there was a longitudinal increase of microglial activation in the majority of the patients with Alzheimer's disease. Voxel-wise correlation analysis revealed that microglial activation in patients with Alzheimer's disease was positively correlated with amyloid deposition and inversely correlated with regional cerebral metabolic rate at voxel level over time. Even though one of the limitations of this study is the lack of longitudinal follow-up of healthy control subjects, this study demonstrates that there is persistent neuroinflammation throughout the Alzheimer's disease process with associated synaptic dysfunction and reduced glucose metabolism. Voxel-wise correlation analysis suggests that neuroinflammation is associated with localized amyloid deposition and glucose metabolism over time, however, the level of inflammation could also occur independently of amyloid pathology, especially in the later stages of Alzheimer's disease. PMID- 26510954 TI - Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency. AB - A long-standing mystery surrounding ataxia-telangiectasia is why it is mainly cerebellar neurons, Purkinje cells in particular, that appear vulnerable to ATM deficiency. Here we present data showing that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human ataxia-telangiectasia and Atm(-/-) mouse cerebellar Purkinje cells. We further show that TET1, an enzyme that converts 5 methylcytosine (5mC) to 5hmC, responds to DNA damage and manipulation of TET1 activity directly affects the DNA damage signalling and ATM-deficient neuronal cell cycle re-entry and death. Quantitative genome-wide analysis of 5hmC containing sequences shows that in ATM deficiency there is a cerebellum- and Purkinje cell-specific shift in 5hmC enrichment in both regulatory elements and repeated sequences. Finally, we verify that TET1-mediated 5hmC production is linked to the degenerative process of Purkinje cells and behavioural deficits in Atm(-/-) mice. Taken together, the selective loss of 5hmC plays a critical role in driving Purkinje cell vulnerability in ATM deficiency. PMID- 26510953 TI - Opposing effects of Apoe/Apoa1 double deletion on amyloid-beta pathology and cognitive performance in APP mice. AB - ATP binding cassette transporter A1 (encoded by ABCA1) regulates cholesterol efflux from cells to apolipoproteins A-I and E (ApoA-I and APOE; encoded by APOA1 and APOE, respectively) and the generation of high density lipoproteins. In Abca1 knockout mice (Abca1(ko)), high density lipoproteins and ApoA-I are virtually lacking, and total APOE and APOE-containing lipoproteins in brain substantially decreased. As the epsilon4 allele of APOE is the major genetic risk factor for late-onset Alzheimer's disease, ABCA1 role as a modifier of APOE lipidation is of significance for this disease. Reportedly, Abca1 deficiency in mice expressing human APP accelerates amyloid deposition and behaviour deficits. We used APP/PS1dE9 mice crossed to Apoe and Apoa1 knockout mice to generate Apoe/Apoa1 double-knockout mice. We hypothesized that Apoe/Apoa1 double-knockout mice would mimic the phenotype of APP/Abca1(ko) mice in regards to amyloid plaques and cognitive deficits. Amyloid pathology, peripheral lipoprotein metabolism, cognitive deficits and dendritic morphology of Apoe/Apoa1 double-knockout mice were compared to APP/Abca1(ko), APP/PS1dE9, and single Apoa1 and Apoe knockouts. Contrary to our prediction, the results demonstrate that double deletion of Apoe and Apoa1 ameliorated the amyloid pathology, including amyloid plaques and soluble amyloid. In double knockout mice we show that (125)I-amyloid-beta microinjected into the central nervous system cleared at a rate twice faster compared to Abca1 knockout mice. We tested the effect of Apoe, Apoa1 or Abca1 deficiency on spreading of exogenous amyloid-beta seeds injected into the brain of young pre-depositing APP mice. The results show that lack of Abca1 augments dissemination of exogenous amyloid significantly more than the lack of Apoe. In the periphery, Apoe/Apoa1 double-knockout mice exhibited substantial atherosclerosis and very high levels of low density lipoproteins compared to APP/PS1dE9 and APP/Abca1(ko). Plasma level of amyloid-beta42 measured at several time points for each mouse was significantly higher in Apoe/Apoa1 double-knockout then in APP/Abca1(ko) mice. This result demonstrates that mice with the lowest level of plasma lipoproteins, APP/Abca1(ko), have the lowest level of peripheral amyloid-beta. Unexpectedly, and independent of amyloid pathology, the deletion of both apolipoproteins worsened behaviour deficits of double knockout mice and their performance was undistinguishable from those of Abca1 knockout mice. Finally we observed that the dendritic complexity in the CA1 region of hippocampus but not in CA2 is significantly impaired by Apoe/Apoa1 double deletion as well as by lack of ABCA1. IN CONCLUSION: (i) plasma lipoproteins may affect amyloid-beta clearance from the brain by the 'peripheral sink' mechanism; and (ii) deficiency of brain APOE-containing lipoproteins is of significance for dendritic complexity and cognition. PMID- 26510955 TI - An INDEPTH look at global data collection. PMID- 26510956 TI - Simple intrapleural hyperthermia at thoracoscopic exploration to treat malignant pleural effusion. AB - BACKGROUND: Malignant pleural effusion (MPE) occurs at a terminal stage of cancer, and related symptoms may considerably reduce a patient's respiratory function and quality of life. We assessed the benefit of simple intrapleural hyperthermia (SIH) during thoracoscopic exploration for MPE. METHODS: We conducted a retrospective review of 34 patients underwent thoracoscopic exploration and SIH procedures for MPE between April, 2009 and July, 2014 at our institution. One month after removal of the tube, therapeutic efficacy was evaluated, calculating response rates and recurrence rate. RESULTS: In this cohort (male, 11; female, 23; average age, 54.2 +/- 12.7 years), the most frequent primary cancers were breast (n = 11, 32.4 %), lung (n = 10, 29.4 %), and ovarian (n = 6, 17.6 %). Therapeutic response (ie, presence of pleural effusion) was assessed 1 month after chest tube removal, with 19 (55.9 %) showing complete response (CR), 9 (26.5 %) showing partial response (PR), and non-response (NR) seen in 6 (17.6 %). The combined (CR + PR) response rate was 82.4 %. During follow-up, there were seven instances of recurrence, requiring repeat drainage. Three- and 7-month recurrence-free rates were 86.9 and 73.9 %, respectively. No postoperative respiratory complications or fever developed. Early death within 3 months from progression of primary cancer was identified as a risk factor in patients of NR status (HR = 18.36, p = 0.043). CONCLUSIONS: If thoracoscopic exploration is indicated for MPE, SIH is a safe and effective management alternative in patients whose primary malignancy is not rapidly progressing. PMID- 26510958 TI - Effect of Vitamin D or Activated Vitamin D on Circulating 1,25-Dihydroxyvitamin D Concentrations: A Systematic Review and Metaanalysis of Randomized Controlled Trials. AB - BACKGROUND: Evidence is accumulating that circulating 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations are inversely related to overall mortality. METHODS: We searched PubMed, Embase and ISI Web of Science for randomized controlled trials with a control group receiving a placebo instead of vitamin D/activated vitamin D and performed a metaanalysis to evaluate the effect of oral vitamin D/activated vitamin D on circulating 1,25(OH)2D concentrations using a random effects model. RESULTS: We included 52 vitamin D intervention groups (4796 individuals) and 14 intervention groups with activated vitamin D (668 individuals). Vitamin D supplements increased circulating 1,25(OH)2D by 12.2 pmol/L (95% CI, 7.8-16.5 pmol/L) and 18.8 pmol/L (95% CI, 9.2-28.4 pmol/L) if only studies with a low risk of bias in study design and reporting were considered (n = 18). There was significant heterogeneity among studies (Cohran's Q P < 0.001, I(2) = 91%). The incremental effect was larger in studies using vitamin D alone compared with coadministration of calcium supplements (18.6 pmol/L; 95% CI, 12.7-24.4 pmol/L vs 4.9 pmol/L; 95% CI, -0.4 to 10.2 pmol/L; P = 0.001), and if quantification was performed with RIA vs other methods (17.1 pmol/L; 95% CI, 11.1-23.1 pmol/L vs 6.9 pmol/L; 95% CI, 1.0-12.8 pmol/L; P = 0.02). Activated vitamin D increased the mean circulating 1,25(OH)2D by 20.5 pmol/L (95% CI, 8.3-32.7 pmol/L; P = 0.04). Again, there was evidence for significant heterogeneity among studies (Cochran Q = 85.4; P < 0.001; I(2) = 87%), but subgroup analysis did not identify parameters significantly influencing the increment in 1,25(OH)2D concentrations. CONCLUSIONS: Both vitamin D and activated vitamin D significantly increase circulating 1,25(OH)2D concentrations, but in vitamin D users this increase is suppressed by calcium coadministration. PMID- 26510957 TI - STARD 2015: An Updated List of Essential Items for Reporting Diagnostic Accuracy Studies. AB - Incomplete reporting has been identified as a major source of avoidable waste in biomedical research. Essential information is often not provided in study reports, impeding the identification, critical appraisal, and replication of studies. To improve the quality of reporting of diagnostic accuracy studies, the Standards for Reporting of Diagnostic Accuracy Studies (STARD) statement was developed. Here we present STARD 2015, an updated list of 30 essential items that should be included in every report of a diagnostic accuracy study. This update incorporates recent evidence about sources of bias and variability in diagnostic accuracy and is intended to facilitate the use of STARD. As such, STARD 2015 may help to improve completeness and transparency in reporting of diagnostic accuracy studies. PMID- 26510959 TI - Serum Total Testosterone Concentrations in the US Household Population from the NHANES 2011-2012 Study Population. AB - BACKGROUND: Limited information is available about testosterone concentrations representative of the general US population, especially children, women, and non Hispanic Asians. METHODS: We obtained nationally representative data for total testosterone (totalT), measured with standardized LC-MS/MS, for the US population age 6 years and older from the 2011-2012 National Health and Nutrition Examination Survey (NHANES). We analyzed 6746 serum samples and calculated the geometric means, distribution percentiles, and covariate-adjusted geometric means by age, sex, and race/ethnicity. RESULTS: The 10th-90th percentiles of totalT values in adults (>=20 years) was 150-698 ng/dL (5.20-24.2 nmol/L) in men, 7.1 49.8 ng/dL (0.25-1.73 nmol/L) in women, and 1.0-9.5 ng/dL (0.04-0.33 nmol/L) in children (6-10 years old). Differences among race/ethnic groups existed in children and men: covariate-adjusted totalT values in non-Hispanic Asians were highest among children (58% compared to non-Hispanic black children) and lowest among men (12% compared to Mexican-American men). Covariate-adjusted totalT values in men were higher at age 55-60 years compared to ages 35 and 80 years, a pattern different from that observed in previous NHANES cycles. CONCLUSIONS: TotalT patterns were different among age groups in men compared with previous NHANES cycles. Covariate-adjusted totalT values peaked at age 55-60 years in men, which appeared to be consistent with the increased use of exogenous testosterone. Differences among race/ethnic groups existed and appeared more pronounced in children than adults. PMID- 26510960 TI - A "Community Fit" Community-Based Participatory Research Program for Family Health, Happiness, and Harmony: Design and Implementation. AB - BACKGROUND: A principal factor in maintaining positive family functioning and well-being, family communication time is decreasing in modern societies such as Hong Kong, where long working hours and indulgent use of information technology are typical. OBJECTIVE: The objective of this paper is to describe an innovative study protocol, "Happy Family Kitchen," under the project, "FAMILY: A Jockey Club Initiative for a Harmonious Society," aimed at improving family health, happiness, and harmony (3Hs) through enhancement of family communication. METHODS: This study employed the community-based participatory research (CBPR) approach, and adopted 5 principles of positive psychology and the traditional Chinese concepts of cooking and dining, as a means to connect family members to promote family health, happiness, and harmony (3Hs). RESULTS: In-depth collaboration took place between an academic institution and a large nongovernmental community organization association (NGO association) with 400 social service agency members. Both groups were deeply involved in the project design, implementation, and evaluation of 23 community-based interventions. From 612 families with 1419 individuals' findings, significant increases in mean communication time per week (from 153.44 to 170.31 minutes, P=.002) at 6 weeks after the intervention and mean communication scores (from 67.18 to 69.56 out of 100, P<.001) at 12 weeks after the intervention were shown. Significant enhancements were also found for mean happiness scores 12 weeks after the intervention (from 7.80 to 7.82 out of 10, P<.001), and mean health scores (from 7.70 to 7.73 out of 10, P<.001) and mean harmony scores (from 7.70 to 8.07 out of 10, P<.001) 6 weeks after the intervention. CONCLUSIONS: This was the first CBPR study in a Hong Kong Chinese community. The results should be useful in informing collaborative intervention programs and engaging public health researchers and community social service providers, major stakeholders, and community participants in the promotion of family well-being. Furthermore, this study has generated an effective practice model for the improvement of family communication and well-being. Challenges in maintaining research rigor during data collection and program implementation were observed, and should be considered during future program planning. PMID- 26510962 TI - Exploring the effects of nanocrystal facet orientations in g-C3N4/BiOCl heterostructures on photocatalytic performance. AB - Effective separation and migration of photogenerated electron-hole pairs are two key factors to determine the performance of photocatalysts. It has been widely accepted that photocatalysts with heterojunctions usually exhibit excellent charge separation. However, the migration process of separated charges in the heterojunction structures has not been fully investigated. Herein, photocatalysts with heterojunctions are constructed by loading g-C3N4 nanoparticles onto BiOCl nanosheets with different exposed facets (BOC-001 and BOC-010). The g-C3N4 nanoparticles with decreasing size and increasing zeta potential could induce stronger coupling and scattering in the heterojunction. The relationship between the crystal facet orientation in the BiOCl nanosheets and charge separation/effective migration behaviours of the materials is investigated. The visible light photocatalytic activity of the composites is evaluated by methyl orange (MO) and phenol degradation experiments, and the results show that ng CN/BOC-010 composites exhibit higher photocatalytic performance than that of ng CN/BOC-001 composites. Both photoelectrochemical and fluorescence emission measurements indicate that the different exposed facets in ng-CN/BiOCl composites could induce the migration of the photogenerated electrons in different ways, but do not significantly alter the separation efficiencies. The separated electrons in ng-CN/BOC-010 undergo a shorter transport distance than that of ng-CN/BOC-001 to reach the surface reactive sites. The study may suggest that the crystal facet orientation in polar semiconductors is a critical factor for designing highly efficient heterojunction photocatalysts. PMID- 26510961 TI - 5-Azacytidine modulates interferon regulatory factor 1 in macrophages to exert a cardioprotective effect. AB - Macrophages are actively involved in inflammatory responses during the progression of cardiac injury, including myocardial infarction (MI). A previous study showed that 5-azacytidine (5AZ), a DNA methylation inhibitor, can ameliorate cardiac injury by shifting macrophages toward an anti-inflammatory phenotype via iNOS inhibition. Here, we show that the beneficial effect of 5AZ is associated with sumoylation of interferon regulatory factor-1 (IRF1) in macrophages. IRF1 is a critical transcription factor for iNOS induction and is antagonized by IRF2. In the stimulated macrophages, IRF1 accumulated in the nucleus without degradation by 5AZ treatment. In animal study, 5AZ administration resulted in significant improvements in cardiac function and fibrosis. IRF1 expressing macrophages were more abundant in the 5AZ-treated MI group than in the PBS-treated MI group. Because sumoylated IRF1 is known to mimic IRF2, we examined the IRF1 sumoylation. Sumoylated IRF1 was resistant to degradation and significantly increased in the 5AZ-treated MI group. Collectively, 5AZ had a protective effect after MI by potentiation of IRF1 sumoylation and is suggested as a novel therapeutic intervention for cardiac repair. PMID- 26510963 TI - Doxycycline hinders phenylalanine fibril assemblies revealing a potential novel therapeutic approach in phenylketonuria. AB - A new paradigm for the aetiopathology of phenylketonuria suggests the presence of amyloid-like assemblies in the brains of transgenic mouse models and patients with phenylketonuria, possibly shedding light on the selective cognitive deficit associated with this disease. Paralleling the amyloidogenic route that identifies different stages of peptide aggregation, corresponding to different levels of toxicity, we experimentally address for the first time, the physico-chemical properties of phenylalanine aggregates via Small Angle, Wide Angle X-ray Scattering and Atomic Force Microscopy. Results are consistent with the presence of well-structured, aligned fibres generated by milliMolar concentrations of phenylalanine. Moreover, the amyloid-modulating doxycycline agent affects the local structure of phenylalanine aggregates, preventing the formation of well ordered crystalline structures. Phenylalanine assemblies prove toxic in vitro to immortalized cell lines and primary neuronal cells. Furthermore, these assemblies also cause dendritic sprouting alterations and synaptic protein impairment in neurons. Doxycycline counteracts these toxic effects, suggesting an approach for the development of future innovative non-dietary preventive therapies. PMID- 26510964 TI - Effect of bovine ABCG2 polymorphism Y581S SNP on secretion into milk of enterolactone, riboflavin and uric acid. AB - The ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP) is an efflux protein involved in the bioavailability and milk secretion of endogenous and exogenous compounds, actively affecting milk composition. A limited number of physiological substrates have been identified. However, no studies have reported the specific effect of this polymorphism on the secretion into milk of compounds implicated in milk quality such as vitamins or endogenous compounds. The bovine ABCG2 Y581S polymorphism is described as a gain of-function polymorphism that increases milk secretion and decreases plasma levels of its substrates. This work aims to study the impact of Y581S polymorphism on plasma disposition and milk secretion of compounds such as riboflavin (vitamin B2), enterolactone, a microbiota-derived metabolite from the dietary lignan secoisolariciresinol and uric acid. In vitro transport of these compounds was assessed in MDCK-II cells overexpressing the bovine ABCG2 (WT bABCG2) and its Y581S variant (Y581S-bABCG2). Plasma and milk levels were obtained from Y/Y homozygous and Y/S heterozygous cows. The results show that riboflavin was more efficiently transported in vitro by the Y581S variant, although no differences were noted in vivo. Both uric acid and enterolactone were substrates in vitro of the bovine ABCG2 variants and were actively secreted into milk with a two-fold increase in the milk/plasma ratio for Y/S with respect to Y/Y cows. The in vitro ABCG2-mediated transport of the drug mitoxantrone, as a model substrate, was inhibited by enterolactone in both variants, suggesting the possible in vivo use of this enterolignan to reduce ABCG2-mediated milk drug transfer in cows. The Y581S variant was inhibited to a lesser extent probably due to its higher transport capacity. All these findings point to a significant role of the ABCG2 Y581S polymorphism in the milk disposition of enterolactone and the endogenous molecules riboflavin and uric acid, which could affect both milk quality and functionality. PMID- 26510965 TI - Rufibacter glacialis sp. nov., a psychrotolerant bacterium isolated from glacier soil. AB - A Gram-stain-negative, rod-shaped, red-pigmented bacterium (MDT1-10-3T) was isolated from Midui glacier in Tibet, China. Cells were aerobic and psychrotolerant (growth occurred at 4-25 degrees C). Phylogenetic analysis based on 16S rRNA gene sequences indicated that it was a member of the genus Rufibacter, with Rufibacter immobilis MCC P1T (96.7 % similarity) as its closest phylogenetic relative. MK-7 was the predominant respiratory menaquinone. The major cellular fatty acids were summed feature 4 (iso-C17 : 1 I and/or anteiso C17 : 1 B), summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c), C17 : 1omega6c, iso-C16 : 0, iso-C15 : 0 and C16 : 1omega5c. The predominant polar lipids were phosphatidylethanolamine, two unidentified aminophospholipids, one glycolipid and four unidentified lipids. The G+C content of the genomic DNA was 49 mol%. On the basis of the phenotypic characteristics and phylogenetic analysis, strain MDT1-10-3T represents a novel species of the genus Rufibacter, for which the name Rufibacter glacialis sp. nov. is proposed. The type strain is MDT1-10-3T ( = CGMCC 1.9789T = NBRC 109705T). PMID- 26510966 TI - Factors predicting outcomes of penile rehabilitation with udenafil 50 mg following radical prostatectomy. AB - Udenafil is a selective phosphodiesterase type 5 inhibitor made available in recent years for the treatment of erectile dysfunction. Herein, we evaluated independent predictors of potency recovery in radical prostatectomy (RP) patients who underwent penile rehabilitation with udenafil 50 mg. One hundred and forty three men who underwent RP were enrolled in a penile rehabilitation program using udenafil 50 mg every other day. The rate of regained potency in the study group was significantly higher compared with the recovery rate seen in patients who were not part of the penile rehabilitation program (41.3% vs 13.0%; P<0.001). On the multivariate Cox analyses, preoperative International Index of Erectile Function-5 scores (hazard ratio (HR), 1.049; P=0.040), alcohol consumption (HR, 2.043; P=0.020) and Gleason biopsy score (HR, 0.368; P=0.024) were independent preoperative predictors for potency recovery. Among post-RP variables, the use of robotic procedures (HR, 2.287; P=0.030) and pathologic stage (HR, 0.506; P=0.038) were significantly associated with potency recovery. This study identified predictive factors for the recovery of potency in patients undergoing penile rehabilitation with udenafil following RP. Our results could provide physicians with useful information for counseling RP patients and selecting optimal candidates for penile rehabilitation. PMID- 26510968 TI - Artificial signal transduction therapy: a futuristic approach to disease treatment. PMID- 26510967 TI - Relaxant effect of a metal-based drug in human corpora cavernosa and its mechanism of action. AB - We studied the mechanisms involved in the human corpora cavernosa (HCC) relaxation induced by a new metal-based nitric oxide (NO) donor, the ruthenium complex cis-[Ru(bpy)2Imn(NO)](+3) (FOR0811). FOR0811 produced relaxation in phenylephrine (PE)-precontracted HCC with a maximal response that achieved 112.9 +/- 10.6%. There was no difference between the maximal relaxation induced by FOR0811 when compared with sodium nitroprusside (SNP) (106.8 +/- 7.3%), BAY41 2272 (107.6 +/- 4.1%) or vardenafil (103.4 +/- 3.8%), however, FOR0811 was less potent than SNP and vardenafil. L-N(G)-nitroarginine methyl ester (L-NAME), a NO synthase inhibitor, had no effect in the concentration-response curve elicited by FOR0811. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a heme-site inhibitor of soluble guanylyl cyclase (sGC) was able to either block or reverse the relaxation induced by FOR0811. On the other hand, the relaxation induced by FOR0811 was not affected by glibenclamide, a blocker of ATP-sensitive potassium channels. FOR0811 (10 MUM) was able to increase cyclic guanosine monophosphate (cGMP) levels in corpora cavernosa strips. FOR0811 completely relaxes HCC by a sGC-cGMP-dependent mechanism and can be a lead compound in the development of new stable NO donors. PMID- 26510969 TI - Edoxaban: Impact on routine and specific coagulation assays. A practical laboratory guide. AB - Assessment of plasma concentration/effect of edoxaban may be useful in some situations. Also, clinicians need to know how routine coagulation assays are influenced. It was our aim to determine coagulation tests useful for the assessment of edoxaban's pharmacodynamics and provide recommendations for the interpretation of haemostasis diagnostic tests. Edoxaban was spiked at concentrations ranging from 0 to 1,000 ng/ml in platelet-poor plasma which covers the on-therapy range (from +/- 25 ng/ml at Ctrough to +/- 170 ng/ml at Cmax). aPTT, PT, dRVVT, chromogenic anti-Xa assays, TGA and a large panel of haemostasis diagnostic tests were performed using several reagents. A concentration-dependent prolongation of aPTT, PT and dRVVT was observed. The effect was dependent on the reagents. FXa chromogenic assays showed high sensitivity and a linear correlation depending on the methodology. TGA may be useful to assess the pharmacodynamics of edoxaban but its turnaround time and the lack of standardisation are limitations. Edoxaban impairs the assessment of lupus anticoagulant, protein S (clotting method), APC-R, antithrombin (FXa-based assay) and measurement of clotting factor activity. Immunological assays and assays acting below the FXa are not influenced by edoxaban. In conclusion, some PT reagents could be used to estimate edoxaban activity. Chromogenic anti-Xa assays are required to assess the plasma concentration. TGA may be useful but requires standardisation. In case of thrombophilia or in the exploration of a haemorrhagic event, immunological assays should be recommended, when applicable. Standardisation of the time between the last intake and the sampling is mandatory to provide a proper assessment of the result. PMID- 26510970 TI - Antimicrobial effect of the extracts from Hypericum perforatum against oral bacteria and biofilm formation. AB - CONTEXT: One traditional medicines, Hypericum perforatum L. (Hypericaceae), possesses several beneficial effects against depression, ulcers, dyspepsia, abdominal pains, burns, bacterial infections, migraine headaches, and sciatica. OBJECTIVE: The present study investigates the antimicrobial activity of the ethanol extract (HP-EtOH) of H. perforatum and its sub-extracts, namely n-hexane (HP-hexane), chloroform (HP-CHCl3), ethyl acetate (HP-EtOAc), n-butanol (HP-n BuOH), and water (HP-H2O) extracts, against Streptococcus mutans, S. sobrinus, Lactobacillus plantarum, and Enterococcus faecalis. MATERIALS AND METHODS: For the evaluation of the antimicrobial activity, flowering aerial parts of H. perforatum were extracted with EtOH and then this extract was fractionated to obtain five sub-extracts in different polarities. Antimicrobial activities of HP EtOH and its sub-extracts against Streptococcus mutans, S. sobrinus, L. plantarum, and E. faecalis were assessed by using colorimetric micro-well dilution at concentration ranges of 64-0.5 MUg/ml as well as resazurin microplate and modified microtiter-plate assays between the ranges of 100 and 0.78125 MUg/ml. RESULTS: According to the results of the present study, HP-H2O sub extract displayed strong antibacterial activity (MIC values 8 MUg/mL) against S. sobrinus and L. plantarum, and exerted moderate activity against S. mutans and E. faecalis at 32 and 16 MUg/mL concentrations, respectively. Other sub-extracts also demonstrated antimicrobial activity against S. sobrinus at a concentration of 16 MUg/mL. HP-EtOAc and HP-n-BuOH showed antimicrobial activity against L. plantarum and HP-EtOAc and HP-H2O were also active against E. faecalis at the same concentrations (16 MUg/mL). CONCLUSION: According to the results, we suggest that H. perforatum could be employed as a natural antibacterial agent in oral care products. PMID- 26510971 TI - 3D imaging of biological specimen using MS. AB - Imaging MS can provide unique information about the distribution of native and non-native compounds in biological specimen. MALDI MS and secondary ion MS are the two most commonly applied imaging MS techniques and can provide complementary information about a sample. MALDI offers access to high mass species such as proteins while secondary ion MS can operate at higher spatial resolution and provide information about lower mass species including elemental signals. Imaging MS is not limited to two dimensions and different approaches have been developed that allow 3D molecular images to be generated of chemicals in whole organs down to single cells. Resolution in the z-dimension is often higher than in x and y, so such analysis offers the potential for probing the distribution of drug molecules and studying drug action by MS with a much higher precision - possibly even organelle level. PMID- 26510972 TI - Slight synthetic changes eliciting different topologies: synthesis, structure and magnetic properties of novel dinuclear and nonanuclear dysprosium complexes. AB - Using the Schiff-base ligand 1,5-bis(2-hydroxy-3 methoxybenzylidene)carbonohydrazide (H2hmc), dinuclear and nonanuclear compounds, [Dy2(Hhmc)2(NO3)4].THF.MeCN (1) and [Dy9(MU3-O)4(MU OH)6(hmc)4(NO3)4(DMF)4](OH).H2O.THF.DMF (2) are generated through the addition of different bases, respectively. Single-crystal X-ray diffraction analysis revealed a unique Dy9 core structure of complex 2, and the magnetic properties of both compounds are fully studied. PMID- 26510974 TI - The Integration of Family and Group Therapy as an Alternative to Juvenile Incarceration: A Quasi-Experimental Evaluation Using Parenting with Love and Limits. AB - The current study employed a quasi-experimental design using both intent-to-treat and protocol adherence analysis of 155 moderate- to high-risk juvenile offenders to evaluate the effectiveness of Parenting with Love and Limits(r) (PLL), an integrative group and family therapy approach. Youth completing PLL had significantly lower rates of recidivism than the comparison group. Parents also reported statistically significant improvements in youth behavior. Lengths of service were also significantly shorter for the treatment sample than the matched comparison group by an average of 4 months. This study contributes to the literature by suggesting that intensive community-based combined family and group treatment is effective in curbing recidivism among high-risk juveniles. PMID- 26510973 TI - Cancer anti-angiogenesis vaccines: Is the tumor vasculature antigenically unique? AB - Angiogenesis is essential for the growth and metastasis of solid tumors. The tumor endothelium exists in a state of chronic activation and proliferation, fueled by the tumor milieu where angiogenic mediators are aberrantly over expressed. Uncontrolled tumor growth, immune evasion, and therapeutic resistance are all driven by the dysregulated and constitutive angiogenesis occurring in the vasculature. Accordingly, great efforts have been dedicated toward identifying molecular signatures of this pathological angiogenesis in order to devise selective tumor endothelium targeting therapies while minimizing potential autoimmunity against physiologically normal endothelium. Vaccination with angiogenic antigens to generate cellular and/or humoral immunity against the tumor endothelium has proven to be a promising strategy for inhibiting or normalizing tumor angiogenesis and reducing cancer growth. Here we review tumor endothelium vaccines developed to date including active immunization strategies using specific tumor endothelium-associated antigens and whole endothelial cell based vaccines designed to elicit immune responses against diverse target antigens. Among the novel therapeutic options, we describe a placenta-derived endothelial cell vaccine, ValloVaxTM, a polyvalent vaccine that is antigenically similar to proliferating tumor endothelium and is supported by pre-clinical studies to be safe and efficacious against several tumor types. PMID- 26510975 TI - The importance of extranodal extension in penile cancer: a meta-analysis. AB - BACKGROUND: The role of extranodal extension (ENE) in penile cancer is controversial and has not been well studied. The aim of this study was to investigate the importance of ENE in predicting prognosis and presence of pelvic lymph node metastasis (PLNM) in penile cancer patients. METHODS: We searched related studies in Medline, Embase, Cochrane Library, and Scopus database. Hazard ratio (HR) and odds ratio (OR) were directly extracted or indirectly estimated from the included studies. RESULTS: A total of ten studies with 1,142 patients were included in this meta-analysis. Patients with ENE showed a worse cancer specific survival (CSS) (HR = 1.90, 95 % confidence interval [CI] = 1.35-2.67, P = 0.0002) and overall survival (HR = 4.04, 95 % CI = 1.02-16.1, P = 0.05) than those without ENE. Further subgroup analysis revealed that the predictive value of ENE for CSS in penile cancer patients was significant regardless of the study's country of origin, but not in the subgroup with shorter follow-up time (<36 months, P = 0.38). Patients with ENE also showed a higher incidence of presenting with PLNM (OR = 4.95, 95 % CI = 2.58-9.49, P < 0.001). A stratified analysis demonstrated that the predictive role of ENE for PLNM was only detected in studies with a larger sample size (> 100 cases). No significant publication bias was observed, as suggested by Begg's and Egger's tests. CONCLUSIONS: ENE is associated with worse prognosis and high risk of PLNM in penile cancer patients. Due to the limited number of studies included in this meta-analysis, a large scale, well-designed study will be required to verify our results. PMID- 26510976 TI - Extended notions of sign consistency to relate experimental data to signaling and regulatory network topologies. AB - BACKGROUND: A rapidly growing amount of knowledge about signaling and gene regulatory networks is available in databases such as KEGG, Reactome, or RegulonDB. There is an increasing need to relate this knowledge to high throughput data in order to (in)validate network topologies or to decide which interactions are present or inactive in a given cell type under a particular environmental condition. Interaction graphs provide a suitable representation of cellular networks with information flows and methods based on sign consistency approaches have been shown to be valuable tools to (i) predict qualitative responses, (ii) to test the consistency of network topologies and experimental data, and (iii) to apply repair operations to the network model suggesting missing or wrong interactions. RESULTS: We present a framework to unify different notions of sign consistency and propose a refined method for data discretization that considers uncertainties in experimental profiles. We furthermore introduce a new constraint to filter undesired model behaviors induced by positive feedback loops. Finally, we generalize the way predictions can be made by the sign consistency approach. In particular, we distinguish strong predictions (e.g. increase of a node level) and weak predictions (e.g., node level increases or remains unchanged) enlarging the overall predictive power of the approach. We then demonstrate the applicability of our framework by confronting a large-scale gene regulatory network model of Escherichia coli with high-throughput transcriptomic measurements. CONCLUSION: Overall, our work enhances the flexibility and power of the sign consistency approach for the prediction of the behavior of signaling and gene regulatory networks and, more generally, for the validation and inference of these networks. PMID- 26510977 TI - MicroRNA-211 causes ganglion cell dysplasia in congenital intestinal atresia via down-regulation of glial-derived neurotrophic factor. AB - BACKGROUND: MicroRNAs (miRNAs) are known to be involved in normal brain functions and nervous system diseases. Some evidence have pointed to the dysregulation of miRNAs in congenital intestinal atresia. In this study, we investigated the differential expression of miRNAs and the posttranscriptional regulation of glial derived neurotrophic factor (GDNF) by endogenous miRNA in congenital intestinal atresia. METHODS: Quantitative real-time PCR and a Western blot were performed to determine the regulation of miRNA and GDNF in patients with congenital intestinal atresia. The results were verified in rat model of intestinal atresia and bone marrow derived stem cell BMSCs-derived into intestinal ganglion cells. The effects of miRNA and GDNF on the cell proliferation and apoptosis of isolated intestinal ganglion cells were detected with an 3-(4,5-dimethylthiazol)-2,5 diphenyl tetrazolium (MTT) assay and a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, respectively. KEY RESULTS: Only miR-211 was greatly up-regulated in the patients with congenital intestinal atresia. The other miRNAs examined showed no change. Overexpression of miR-211 suppressed the differentiation of BMSCs into intestinal ganglion cells. In retinal ganglion cells (RGC-5 cells), miR-211 regulated the expression of GDNF. The MTT and TUNEL assays revealed that miR-211 overexpression suppressed the cell proliferation of isolated intestinal ganglion cells and that GDNF overexpression reversed the effect of pre-miR-211 on cell proliferation and apoptosis. CONCLUSIONS & INFERENCES: Our results indicate that overexpression of miR-211 suppresses the differentiation of BMSCs into intestinal ganglion cells by directly down regulating the expression of GDNF. The findings elucidate the role of miRNA in congenital intestinal atresia. PMID- 26510978 TI - An evaluation of choice on instructional efficacy and individual preferences among children with autism. AB - The current study compared the differential effects of choice and no-choice reinforcement conditions on skill acquisition. In addition, we assessed preference for choice-making opportunities with 3 children with autism, using a modified concurrent-chains procedure. We replicated the experiment with 2 participants. The results indicated that choice-making opportunities increased treatment efficacy for 2 of the 3 participants, and all 3 participants demonstrated a preference for choice-making opportunities. PMID- 26510979 TI - Identification of Small Molecule Inhibitors of Tau Aggregation by Targeting Monomeric Tau As a Potential Therapeutic Approach for Tauopathies. AB - A potential strategy to alleviate the aggregation of intrinsically disordered proteins (IDPs) is to maintain the native functional state of the protein by small molecule binding. However, the targeting of the native state of IDPs by small molecules has been challenging due to their heterogeneous conformational ensembles. To tackle this challenge, we applied a high-throughput chemical microarray surface plasmon resonance imaging screen to detect the binding between small molecules and monomeric full-length Tau, a protein linked with the onset of a range of Tauopathies. The screen identified a novel set of drug-like fragment and lead-like compounds that bound to Tau. We verified that the majority of these hit compounds reduced the aggregation of different Tau constructs in vitro and in N2a cells. These results demonstrate that Tau is a viable receptor of drug-like small molecules. The drug discovery approach that we present can be applied to other IDPs linked to other misfolding diseases such as Alzheimer's and Parkinson's diseases. PMID- 26510980 TI - Oral Administration of Thioflavin T Prevents Beta Amyloid Plaque Formation in Double Transgenic AD Mice. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the fourth leading cause of death in the United States and most common cause of adult onset dementia. The major hallmarks of AD are the formation of senile amyloid plaques made of beta amyloid and neurofibrillary tangles (NFT) which are primarily composed of phosphorylated tau protein. Although numerous agents have been considered as providing protection against AD, identification of potential agents with neuroprotective ability is limited. Thioflavin T has been used in the past to stain amyloid beta plaques in brain. In this study, Thioflavin T (ThT) and vehicle (infant formula) were administered orally by gavage to transgenic (B6C3 APP PS1; AD-Tg) mice beginning at 4 months age and continuing until sacrifice at 9 months of age at 40 mg/kg dose. The number of amyloid plaques was reduced dramatically by ThT treatment in both male and female transgenic mice compared to those in control mice. Additionally, GFAP and Amylo-Glo labeling suggest that astrocytic hypertrophy is minimized in ThT-treated animals. Similarly, CD68 labeling, which detects activated microglia, along with Amylo-Glo labeling, suggests that microglial activation is significantly less in ThT treated mice. Both Abeta-40 and Abeta-42 concentrations in blood rose significantly in the ThT-treated animals suggesting that ThT may inhibit the deposition, degradation, and/or clearance of Abeta plaques in brain. PMID- 26510981 TI - The ATP-Binding Cassette Transporter-2 (ABCA2) Overexpression Modulates Sphingosine Levels and Transcription of the Amyloid Precursor Protein (APP) Gene. AB - The ATP-binding cassette transporter-2 (ABCA2) is a member of a family of multipass transmembrane proteins that use the energy of ATP hydrolysis to transport substrates across membrane bilayers. ABCA2 has also been genetically linked with Alzheimer's disease but the molecular mechanisms are unknown. In this report, we hypothesized that ABCA2 modulation of sphingolipid metabolism activates a signaling pathway that regulates amyloid precursor protein transcription. We found that ABCA2 overexpression in N2a cells was associated with increased mass of the sphingolipid sphingosine, derived from the catabolism of ceramide. ABCA2 overexpression increased in vitro alkaline and acid ceramidase activity. Sphingosine is a physiological inhibitor of protein kinase C (PKC) activity. Pharmacological inhibition of ceramidase activity or activation PKC activity with 12-myristate 13-acetate (PMA) or diacylglycerol (DAG) decreased endogenous APP mRNA levels in ABCA2 overexpressing cells. Treatment with PMA also decreased the expression of a transfected human APP promoter reporter construct, while treatment with a general PKC inhibitor, GF109203x, increased APP promoter activity. In N2a cells, chromatin immunoprecipitation experiments revealed that a repressive complex forms at the AP-1 site in the human APP promoter, consisting of c-jun, c-jun dimerization protein 2 (JDP2) and HDAC3 and this complex was reduced in ABCA2 overexpressing cells. Activation of the human APP promoter in A2 cells was directed by the upstream stimulatory factors USF-1 and USF-2 that bound to an E-box element in vivo. These findings indicate that ABCA2 overexpression modulates sphingosine levels and regulates transcription of the endogenous APP gene. PMID- 26510982 TI - Neuroprotection of (+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Against Hydrogen Peroxide and Lipopolysaccharide Induced Injury via Modulating Arachidonic Acid Network and p38-MAPK Signaling. AB - Oxidative stress and neuroinflammation are highly relevant to the pathological processes of various neurodegenerative diseases including Alzheimer's disease (AD). (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), a novel 5 lipoxygenase inhibitor, was isolated from the whole plant of Incarvillea mairei var granditlora (Wehrhahn) Grierson. In this study, we investigated the protective effect of HOEC on hydrogen peroxide (H2O2) and lipopolysaccharide (LPS) -induced cytotoxicity and neuroinflammation in vitro and in vivo. MTT assay, LDH release assay, morphological observation and Hoechst 33342/PI dual staining followed by EIA, immunofluorescence staining and Western Blotting analysis were performed to elucidate the neuroprotective effect of HOEC. Treatment with HOEC at various concentrations prior to H2O2 exposure significantly enhanced cell viability, decreased LDH release, prevented cell morphologic changes and apoptosis. Instead of PGE2 reduction, HOEC markedly inhibited the production of LTB4 and suppressed the macrophage-mediated neurotoxicity. Western blotting and immunofluorescence staining showed that HOEC inhibited H2O2-induced p38 phosphorylation and NF-kappaB activation. Neuroprotective effect of HOEC was abolished by a p38 inhibitor. Further in vivo studies of LPS-induced neuroinflammation confirmed the anti-inflammatory effects of HOEC. These findings that HOEC protects SH-SY5Y cells from H2O2 and LPS induced injury via arachidonic acid network modulation followed by p38 MAPK and NF-kappaB signaling, might make HOEC be considered as a therapeutic candidate for prevention and treatment of neurodegenerative diseases involving oxidative stress or/and inflammation. PMID- 26510983 TI - Socio-economic Aspects of Alzheimer's Disease. AB - Social development, better living conditions and medical advances lead to the fact that more people have the opportunity to live longer than in the past. The aging population is a characteristic feature of demographic trends in developed countries. This trend is closely linked with the issue of increasing number of diseases in old age and increasing government expenditure on health and social care. The most frequently mentioned diseases in old age include dementia. The cause may lie in all kinds of diseases, the most common are Alzheimer's disease and cerebrovascular disease. Now the care of current 35 million patients with dementia costs over $ 600 billion per year, it is approximately one percent of global Gross Domestic Product. This review discusses the recent issues and questions in the area of social and economic aspects of Alzheimer's disease. It focuses in detail on the national strategies in the approach to Alzheimer's disease, the anticipated problems concerning the insufficient number of social workers and necessary expenses of state budgets in the future. The situation in the area of health insurance companies' expenditures is illustrated in the context of the analysis of long-term care systems, in the chosen countries within the European Union. PMID- 26510984 TI - Topological Alterations of the Intrinsic Brain Network in Patients with Functional Dyspepsia. AB - BACKGROUND/AIMS: Previous studies reported that integrated information in the brain ultimately determines the subjective experience of patients with chronic pain, but how the information is integrated in the brain connectome of functional dyspepsia (FD) patients remains largely unclear. The study aimed to quantify the topological changes of the brain network in FD patients. METHODS: Small-world properties, network efficiency and nodal centrality were utilized to measure the changes in topological architecture in 25 FD patients and 25 healthy controls based on functional magnetic resonance imaging. Pearson's correlation assessed the relationship of each topological property with clinical symptoms. RESULTS: FD patients showed an increase of clustering coefficients and local efficiency relative to controls from the perspective of a whole network as well as elevated nodal centrality in the right orbital part of the inferior frontal gyrus, left anterior cingulate gyrus and left hippocampus, and decreased nodal centrality in the right posterior cingulate gyrus, left cuneus, right putamen, left middle occipital gyrus and right inferior occipital gyrus. Moreover, the centrality in the anterior cingulate gyrus was significantly associated with symptom severity and duration in FD patients. Nevertheless, the inclusion of anxiety and depression scores as covariates erased the group differences in nodal centralities in the orbital part of the inferior frontal gyrus and hippocampus. CONCLUSIONS: The results suggest topological disruption of the functional brain networks in FD patients, presumably in response to disturbances of sensory information integrated with emotion, memory, pain modulation, and selective attention in patients. PMID- 26510985 TI - Modified HPLC-ESI-MS Method for Glycated Hemoglobin Quantification Based on the IFCC Reference Measurement Procedure and Its Application for Quantitative Analyses in Clinical Laboratories of China. AB - BACKGROUND: The level of glycated hemoglobin (HbA1c ) has been recognized as an important indicator of long-term glycemic control. However, the HbA1c measurement is not currently included as a diagnostic determinant in China. Current study aims to assess a candidate modified International Federation of Clinical Chemistry reference method for the forthcoming standardization of HbA1c measurements in China. METHODS: The HbA1c concentration was measured using a modified high-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS) method. The modified method replaces the propylcyanide column with a C18 reversed-phase column, which has a lower cost and is more commonly used in China, and uses 0.1% (26.5 mmol/l) formic acid instead of trifluoroacetic acid. Moreover, in order to minimize matrix interference and reduce the running time, a solid-phase extraction was employed. The discrepancies between HbA1c measurements using conventional methods and the HPLC-ESI-MS method were clarified in clinical samples from healthy people and diabetic patients. Corresponding samples were distributed to 89 hospitals in Beijing for external quality assessment. RESULTS: The linearity, reliability, and accuracy of the modified HPLC-ESI-MS method with a shortened running time of 6 min were successfully validated. Out of 89 hospitals evaluated, the relative biases of HbA1c concentrations were < 8% for 74 hospitals and < 5% for 60 hospitals. Compared with other conventional methods, HbA1c concentrations determined by HPLC methods were similar to the values obtained from the current HPLC-ESI-MS method. CONCLUSION: The HPLC-ESI-MS method represents an improvement over existing methods and provides a simple, stable, and rapid HbA1c measurement with strong signal intensities and reduced ion suppression. PMID- 26510986 TI - CYP2D6 Genetic Polymorphisms and Phenotypes in Different Ethnicities of Malaysian Breast Cancer Patients. AB - The cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) is an enzyme that is predominantly involved in the metabolism of tamoxifen. Genetic polymorphisms of the CYP2D6 gene may contribute to inter-individual variability in tamoxifen metabolism, which leads to the differences in clinical response to tamoxifen among breast cancer patients. In Malaysia, the knowledge on CYP2D6 genetic polymorphisms as well as metabolizer status in Malaysian breast cancer patients remains unknown. Hence, this study aimed to comprehensively identify CYP2D6 genetic polymorphisms among 80 Malaysian breast cancer patients. The genetic polymorphisms of all the 9 exons of CYP2D6 gene were identified using high-resolution melting analysis and confirmed by DNA sequencing. Seven CYP2D6 alleles consisting of CYP2D6*1, CYP2D6*2, CYP2D6*4, CYP2D6*10, CYP2D6*39, CYP2D6*49, and CYP2D6*75 were identified in this study. Among these alleles, CYP2D6*10 is the most common allele in both Malaysian Malay (54.8%) and Chinese (71.4%) breast cancer patients, whereas CYP2D6*4 in Malaysian Indian (28.6%) breast cancer patients. In relation to CYP2D6 genotype, CYP2D6*10/*10 is more frequently observed in both Malaysian Malay (28.9%) and Chinese (57.1%) breast cancer patients, whereas CYP2D6*4/*10 is more frequently observed in Malaysian Indian (42.8%) breast cancer patients. In terms of CYP2D6 phenotype, 61.5% of Malaysian Malay breast cancer patients are predicted as extensive metabolizers in which they are most likely to respond well to tamoxifen therapy. However, 57.1% of Chinese as well as Indian breast cancer patients are predicted as intermediate metabolizers and they are less likely to gain optimal benefit from the tamoxifen therapy. This is the first report of CYP2D6 genetic polymorphisms and phenotypes in Malaysian breast cancer patients for different ethnicities. These data may aid clinicians in selecting an optimal drug therapy for Malaysian breast cancer patients, hence improve the clinical outcome of the patients. PMID- 26510987 TI - Negative studies are helpful to compute the specificity of diagnostic tests: measuring Trypanosoma cruzi seroprevalence in Guanajuato, Mexico. AB - BACKGROUND: Publishing negative seroprevalence studies not only helps to have more accurate seroprevalence estimates but also allows calculating the specificity of the diagnostic tests used. We performed a population-based Trypanosoma cruzi seroprevalence survey in a community in central Mexico. RESULTS: We surveyed 204 women and children and collected blood by finger prick. We performed rapid tests (Stat-Pak, Chembio, Inc., Medford, New York) and recombinant Chagas ELISA tests v3.0 (Wiener, Rosario, Argentina). All rapid tests and all ELISA tests were negative. CONCLUSION: The rapid test had 100 % of specificity compared to the ELISA. PMID- 26510988 TI - KA-bridged transplantation of mesencephalic tissue and olfactory ensheathing cells in a Parkinsonian rat model. AB - The pathology of Parkinson's disease (PD) results mainly from nigrostriatal pathway damage. Unfortunately, commonly used PD therapies do not repair the disconnected circuitry. It has been reported that using kainic acid (KA, an excitatory amino acid) in bridging transplantation may be useful to generate an artificial tract and reconstruct the nigrostriatal pathway in 6-hydroxydopamine (6-OHDA) lesioned rats. In this study, we used KA bridging and a co-graft of rat olfactory ensheathing cells (OECs) and rat E14 embryonic ventral mesencephalic (VM) tissue to restore the nigrostriatal pathway of the PD model rats. The methamphetamine-induced rotational behaviour, 4-[18 F]-ADAM (a selectively serotonin transporter radioligand)/micro-PET imaging, and immunohistochemistry were used to assess the effects of the transplantation. At 9 weeks post-grafting in PD model rats, the results showed that the PD rats undergoing VM tissue and OECs co-grafts (VM-OECs) exhibited better motor recovery compared to the rats receiving VM tissue transplantation only. The striatal uptake of 4-[18 F]-ADAM and tyrosine hydroxylase immunoreactivity (TH-ir) of the grafted area in the VM OECs group were also more improved than those of the VM alone group. These results suggested that OECs may enhance the survival of the grafted VM tissue and facilitate the recovery of motor function after VM transplantation. Moreover, OECs possibly promote the elongation of dopaminergic and serotonergic axon in the bridging graft. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26510989 TI - (19)F Paramagnetic Relaxation Enhancement: A Valuable Tool for Distance Measurements in Proteins. AB - Fluorine NMR paramagnetic relaxation enhancement was evaluated as a versatile approach for extracting distance information in selectively F-labeled proteins. Proof of concept and initial applications are presented for the HIV-inactivating lectin cyanovirin-N. Single F atoms were introduced at the 4-, 5-, 6- or 7 positions of Trp49 and the 4-position of Phe4, Phe54, and Phe80. The paramagnetic nitroxide spin label was attached to Cys residues that were placed into the protein at positions 50 or 52. (19)F-T2 NMR spectra with different relaxation delays were recorded and the transverse (19)F-PRE rate, (19)F-Gamma2 , was used to determine the average distance between the F nucleus and the paramagnetic center. Our data show that experimental (19)F PRE-based distances correspond to 0.93 of the (1)HN-PRE distances, in perfect agreement with the gyromagnetic gamma(19)F/gamma(1)H ratio, thereby demonstrating that (19)F PREs are excellent alternative parameters for quantitative distance measurements in selectively F labeled proteins. PMID- 26510991 TI - Osteogenic differentiation of dental pulp stem cells under the influence of three different materials. AB - BACKGROUND: Regeneration of periodontal tissues is a major goal of periodontal therapy. Dental pulp stem cells (DPSCs) show mesenchymal cell properties with the potential for dental tissue engineering. Enamel matrix derivative (EMD) and platelet-derived growth factor (PDGF) are examples of materials that act as signaling molecules to enhance periodontal regeneration. Mineral trioxide aggregate (MTA) has been proven to be biocompatible and appears to have some osteoconductive properties. The objective of this study was to evaluate the effects of EMD, MTA, and PDGF on DPSC osteogenic differentiation. METHODS: Human DPSCs were cultured in medium containing EMD, MTA, or PDGF. Control groups were also established. Evaluation of the achieved osteogenesis was carried out by computer analysis of alkaline phosphatase (ALP)-stained chambers, and spectrophotometric analysis of alizarin red S-stained mineralized nodules. RESULTS: EMD significantly increased the amounts of ALP expression and mineralization compared with all other groups (P < 0.05). Meanwhile, MTA gave variable results with slight increases in certain differentiation parameters, and PDGF showed no significant increase in the achieved differentiation. CONCLUSIONS: EMD showed a very strong osteogenic ability compared with PDGF and MTA, and the present results provide support for its use in periodontal regeneration. PMID- 26510990 TI - Longitudinal immune profiles in type 1 leprosy reactions in Bangladesh, Brazil, Ethiopia and Nepal. AB - BACKGROUND: Acute inflammatory reactions are a frequently occurring, tissue destructing phenomenon in infectious- as well as autoimmune diseases, providing clinical challenges for early diagnosis. In leprosy, an infectious disease initiated by Mycobacterium leprae (M. leprae), these reactions represent the major cause of permanent neuropathy. However, laboratory tests for early diagnosis of reactional episodes which would significantly contribute to prevention of tissue damage are not yet available. Although classical diagnostics involve a variety of tests, current research utilizes limited approaches for biomarker identification. In this study, we therefore studied leprosy as a model to identify biomarkers specific for inflammatory reactional episodes. METHODS: To identify host biomarker profiles associated with early onset of type 1 leprosy reactions, prospective cohorts including leprosy patients with and without reactions were recruited in Bangladesh, Brazil, Ethiopia and Nepal. The presence of multiple cyto-/chemokines induced by M. leprae antigen stimulation of peripheral blood mononuclear cells as well as the levels of antibodies directed against M. leprae-specific antigens in sera, were measured longitudinally in patients. RESULTS: At all sites, longitudinal analyses showed that IFN-gamma-, IP 10-, IL-17- and VEGF-production by M. leprae (antigen)-stimulated PBMC peaked at diagnosis of type 1 reactions, compared to when reactions were absent. In contrast, IL-10 production decreased during type 1 reaction while increasing after treatment. Thus, ratios of these pro-inflammatory cytokines versus IL-10 provide useful tools for early diagnosing type 1 reactions and evaluating treatment. Of further importance for rapid diagnosis, circulating IP-10 in sera were significantly increased during type 1 reactions. On the other hand, humoral immunity, characterized by M. leprae-specific antibody detection, did not identify onset of type 1 reactions, but allowed treatment monitoring instead. CONCLUSIONS: This study identifies immune-profiles as promising host biomarkers for detecting intra-individual changes during acute inflammation in leprosy, also providing an approach for other chronic (infectious) diseases to help early diagnose these episodes and contribute to timely treatment and prevention of tissue damage. PMID- 26510994 TI - Cardiovascular and non-cardiovascular safety of dipeptidyl peptidase-4 inhibition: a meta-analysis of randomized controlled cardiovascular outcome trials. AB - The full licensing of dipeptidyl peptidase-4 (DPP-4) inhibitors in the USA and Europe requires demonstration of cardiovascular (CV) safety with an upper boundary of harm of <30%. We report a total of 3334 CV events during 86,716 person-years of follow-up in 36,543 patients, when combining data from three trials with formal and prospectively assessed endpoints. Fixed-effect meta analysis showed that, compared with placebo, DPP-4 inhibition did not increase the upper boundary of risk for the composite endpoint, nor for any individual component by >30%. Relative risks (RRs) were: 0.99 [confidence interval (CI) 0.93 1.06] for composite CV-specific death, non-fatal myocardial infarction (MI) and non-fatal stroke; 1.01 (CI 0.91-1.12) for CV-specific death; 0.98 (CI 0.89-1.09) for non-fatal MI; and 1.00 (CI 0.86-1.16) for non-fatal stroke. The risk of acute pancreatitis was increased (RR 1.79; CI 1.13-2.81), equating to 5.5 extra cases/10,000 patients/year (weighted mean) and a number needed to harm of 1940/year. These data provide reassurance about the safety of DPP-4 inhibitors with regard to individual atherothrombotic events and a safety signal for pancreatitis. PMID- 26510995 TI - Proceedings of the 14th Annual UT-KBRIN Bioinformatics Summit 2015. PMID- 26510996 TI - Inflammation-associated upregulation of the sulfated steroid transporter Slc10a6 in mouse liver and macrophage cell lines. AB - AIM: Slc10a6, an incompletely characterized member of the SLC10A bile acid transporter family, was one of the most highly induced RNA transcripts identified in a screen for inflammation-responsive genes in mouse liver. This study aimed to elucidate a role for Slc10a6 in hepatic inflammation. METHODS: Mice were treated with lipopolysaccharide (LPS; 2 mg/kg) or interleukin (IL)-1beta (5 mg/kg) for various time points. Cells were treated with LPS (1 MUg/mL) at various time points, with cell signaling inhibitors, nuclear receptor ligands and Slc10a6 substrates. All mRNA levels were determined by quantitative polymerase chain reaction. RESULTS: Slc10a6 mRNA levels were upregulated in mouse liver at 2 h (7 fold), 4 h (100-fold) and 16 h (50-fold) after LPS treatment, and 35-fold by the cytokine IL-1beta (4 h). Both absence of the nuclear receptor Fxr and pretreating mice with the synthetic retinoid X receptor-alpha ligand LG268 attenuated the LPS upregulation of Slc10a6 mRNA by 60-75%. In vitro, Slc10a6 mRNA was induced 30 fold by LPS in mouse RAW264.7 macrophages in a time-dependent manner (maximum at 8 h). The Slc10a6 substrate dehydroepiandrosterone sulfate (DHEAS) enhanced LPS induction of CCL5 mRNA, a pro-inflammatory chemokine, by 50% in RAW264.7 cells. This effect was abrogated in the presence of anti-inflammatory nuclear receptor ligands 9-cis-retinoic acid and dexamethasone. CONCLUSION: Dramatic upregulation of Slc10a6 mRNA by LPS combined with enhanced LPS stimulation of CCL5 expression by the Slc10a6 substrate DHEAS in macrophages suggests that Slc10a6 function contributes to the hepatic inflammatory response. PMID- 26510997 TI - Accumulation of Multipotent Progenitor Cells on Polymethylpentene Membranes During Extracorporeal Membrane Oxygenation. AB - Multipotent progenitor cells were mobilized during pediatric extracorporeal membrane oxygenation (ECMO). We hypothesize that these cells also adhered onto polymethylpentene (PMP) fibers within the membrane oxygenator (MO) during adult ECMO support. Mononuclear cells were removed from the surface of explanted PMP MOs (n = 16). Endothelial-like outgrowth and mesenchymal-like cells were characterized by flow cytometric analysis using different surface markers. Spindle-shaped attaching cells were identified early, but without proliferative activity. After long-term cultivation palisading type or cobblestone-type outgrowth cells with high proliferative activity appeared and were characterized as (i) leukocytoid CD45+/CD31+ (CD133+/VEGFR-II+/CD90+/CD14+/CD146dim/CD105dim); (ii) endothelial-like CD45-/CD31+ (VEGF-RII+/CD146+/CD105+/CD133-/CD14-/CD90-); and (iii) mesenchymal-like cells CD45-/CD31- (CD105+/CD90+/CD133dim/VEGFR-II /CD146-/CD14-). The distribution of the cell populations depended on the MO and cultivation time. Endothelial-like cells formed capillary-like structures and did uptake Dil-acetylated low-density lipoprotein. Endothelial- and mesenchymal-like cells adhered on the surface of PMP-MOs. Further research is needed to identify the clinical relevance of these cells. PMID- 26510998 TI - Ensuring equity of access to primary health care in rural and remote Australia - what core services should be locally available? AB - INTRODUCTION: Australians in rural and remote areas experience poorer health status compared with many metropolitan residents, due partly to inequitable access to primary health care (PHC) services. Building on recent research that identified PHC services which all Australians should be able to access regardless of where they live, this paper aims to define the population thresholds governing which PHC services would be best provided by a resident health worker, and to outline attendant implementation issues. METHODS: A Delphi method comprising panellists with expertise in rural, remote and/or Indigenous PHC was used. Five population thresholds reflecting Australia's diverse rural and remote geography were devised. Panellists participated in two electronic surveys. Using a Likert scale, they were asked at what population threshold each PHC service should be provided by a resident health worker. A follow-up focus group identified important underlying principles which guided the consensus process. RESULTS: Response rates were high. The population thresholds for core PHC services provided by a resident worker were less in remote communities compared with rural communities. For example, the population threshold for 'care of the sick and injured,' was <=100 for remote compared with 101-500 for rural communities. For 'mental health', 'maternal/child health', 'sexual health' and 'public health' services in remote communities the population threshold was 101-500, compared to 501-1000 for rural communities. Principles underpinning implementation included the fundamental importance of equity; consideration of social determinants of health; flexibility, effective expenditure of resources, tailoring services to ensure consumer acceptability, prioritising services according to need, and providing services as close to home as possible. CONCLUSION: This research can assist policy makers and service planners to determine the population thresholds at which PHC services should be delivered by a resident health worker, to allocate resources and provide services more equitably, and inform consumers about PHC services they can reasonably expect to access in their community. This framework assists in developing a systematic approach to strategies seeking to address existing rural-urban health workforce maldistribution, including the training of generalists as opposed to specialists, and providing necessary infrastructure in communities most in need. PMID- 26511000 TI - Compositional MRI assessment of cartilage: what is it and what is its potential for sports medicine? PMID- 26510999 TI - Hydrogen peroxide modulates synaptic transmission in ventral horn neurons of the rat spinal cord. AB - KEY POINTS: Excessive production of reactive oxygen species (ROS) is implicated in many central nervous system disorders; however, the physiological role of ROS in spinal ventral horn (VH) neurons remains poorly understood. We investigated how pathological levels of H2O2, an abundant ROS, regulate synaptic transmission in VH neurons of rats using a whole-cell patch clamp approach. H2O2 increased the release of glutamate and GABA from presynaptic terminals. The increase in glutamate release involved N-type voltage-gated calcium channels (VGCCs), ryanodine receptors (RyRs), and inositol trisphosphate receptors (IP3 Rs); the increase in GABA release, which inhibited glutamatergic transmission, involved IP3 R. Inhibiting N-type VGCCs and RyRs attenuates excitotoxicity resulting from increased glutamatergic activity while preserving the neuroprotective effects of GABA, and may represent a novel strategy for treating H2O2-induced motor neuron disorders resulting from trauma or ischaemia-reperfusion injury. Excessive production of reactive oxygen species (ROS) is a critical component of the cellular and molecular pathophysiology of many central nervous system (CNS) disorders, including trauma, ischaemia-reperfusion injury, and neurodegenerative diseases. Hydrogen peroxide (H2O2), an abundant ROS, modulates synaptic transmission and contributes to neuronal damage in the CNS; however, the pathophysiological role of H2O2 in spinal cord ventral horn (VH) neurons remains poorly understood, despite reports that these neurons are highly vulnerable to oxidative stress and ischaemia. This was investigated in the present study using a whole-cell patch clamp approach in rats. We found that exogenous application of H2O2 increased the release of glutamate from excitatory presynaptic terminals and gamma-aminobutyric acid (GABA) from inhibitory presynaptic terminals. The increase of glutamate release was induced in part by an increase in Ca(2+) influx through N-type voltage-gated calcium channels (VGCCs) as well as by ryanodine receptor (RyR)- and inositol trisphosphate receptor-mediated Ca(2+) release from the endoplasmic reticulum (ER). In inhibitory presynaptic neurons, increased IP3 R-mediated Ca(2+) release from the ER increased GABAergic transmission, which served to rescue VH neurons from excessive release of glutamate from presynaptic terminals. These findings indicate that inhibiting N-type VGCCs or RyRs may attenuate excitotoxicity resulting from increased glutamatergic activity while preserving the neuroprotective effects of GABA, and may therefore represent a novel and targeted strategy for preventing and treating H2O2-induced motor neuron disorders. PMID- 26511001 TI - The ineffectiveness of paracetamol for spinal pain provides opportunities to better manage low back pain. PMID- 26511002 TI - Dentofacial trauma and players' attitude towards mouthguard use in field hockey: a systematic review and meta-analysis. AB - BACKGROUND: Dentofacial injuries are a risk while playing field hockey. Wearing mouthguards is recommended. OBJECTIVE: To synthesise findings on the prevalence and characteristics of dentofacial injuries sustained by field hockey players. We also investigated the prevalence of regular mouthguard use and players' attitude towards use of mouthguard. MATERIAL AND METHODS: A literature search was performed using PubMed, EMBASE, OvidSP, Web of Science, Cochrane and Cinahl databases. Eligible studies were identified based on the title, abstract and full text of articles. If applicable, a random effects model was used to calculate the overall effect size; otherwise, pooled prevalence was reported. RESULTS: 11 studies were eligible for the analysis. The average proportion of field hockey players who had sustained at least one dentofacial injury varied from 12.7% (95% CI 8.5% to 17.0%) among junior and senior players to 45.2% (95% CI 39.3% to 51.0%) among elite players. We did not observe any significant differences with respect to gender. In the 2000s, a significantly higher proportion of players regularly wore a mouthguard, 84.5% (95% CI 69.3% to 99.7%) as compared with players 20 years ago, 31.4% (95% CI 22.7% to 40.1%). The most common complaints about the mouthguard were that it was unnecessary and uncomfortable. CONCLUSION: Dentofacial injuries pose a serious problem in field hockey and a substantial number of players do not regularly wear a mouthguard. Greater use of mouthguards would be expected to reduce dentofacial injuries in field hockey. PMID- 26511003 TI - The medial tibial stress syndrome score: a new patient-reported outcome measure. AB - BACKGROUND: At present, there is no validated patient-reported outcome measure (PROM) for patients with medial tibial stress syndrome (MTSS). AIM: Our aim was to select and validate previously generated items and create a valid, reliable and responsive PROM for patients with MTSS: the MTSS score. METHODS: A prospective cohort study was performed in multiple sports medicine, physiotherapy and military facilities in the Netherlands. Participants with MTSS filled out the previously generated items for the MTSS score on 3 occasions. From previously generated items, we selected the best items. We assessed the MTSS score for its validity, reliability and responsiveness. RESULTS: The MTSS score was filled out by 133 participants with MTSS. Factor analysis showed the MTSS score to exhibit a single-factor structure with acceptable internal consistency (alpha=0.58) and good test-retest reliability (intraclass correlation coefficient=0.81). The MTSS score ranges from 0 to 10 points. The smallest detectable change in our sample was 0.69 at the group level and 4.80 at the individual level. Construct validity analysis showed significant moderate-to-large correlations (r=0.34-0.52, p<0.01). Responsiveness of the MTSS score was confirmed by a significant relation with the global perceived effect scale (beta=-0.288, R(2)=0.21, p<0.001). CONCLUSIONS: The MTSS score is a valid, reliable and responsive PROM to measure the severity of MTSS. It is designed to evaluate treatment outcomes in clinical studies. PMID- 26511004 TI - Does physiotherapy diagnosis of shoulder pathology compare to arthroscopic findings? AB - AIMS: To explore the ability of a physiotherapist, using a standardised musculoskeletal physiotherapy assessment protocol, to accurately identify the structures potentially responsible for shoulder symptoms against a standardised arthroscopic shoulder diagnostic assessment, and to determine the physiotherapists' ability to influence post-test diagnostic accuracy. STUDY DESIGN: Consecutive case-based cohort study. SUBJECT SELECTION: All participants were selected by two orthopaedic surgeons for arthroscopic investigation during a 6-month period. SETTING: Private orthopaedic clinic. METHOD: All consenting participants selected for arthroscopic investigation were examined by the physiotherapist prior to arthroscopy. Presence and priority of impairments/diagnoses were recorded on a standardised form. Inter and intra-rater reliability and diagnostic accuracy were tabulated. STATISTICAL ANALYSIS: Proportional agreement on diagnostic incidence (broad) and priority (strict) using 2*2 contingency tables for sensitivity, specificity, positive and negative predictive value and positive and negative likelihood ratios were calculated. Post-test probabilities were analysed to determine the influence of a positive or a negative finding. RESULTS: 211 participants, aged 14-79 years were included. Overall prevalence of subacromial pathology was (77%) and, disorders of the passive restraints (29%). For both negative and positive findings, post-test probabilities were not notably altered; although positive findings yielded greater value in the decision-making modelling. The physiotherapist's ability to identify individual pathology (eg, tendon rupture vs tendinopathy, capsular vs labral) was lower than recognition of pathology within the broader diagnostic category. CONCLUSIONS: The physiotherapist's ability to diagnose individual pathologies was inconsistent. Indirectly, this raises the issue of whether signs and symptoms identified under arthroscopic surgery are reflective of a lesion/pathology reflective of a specific tissue. PMID- 26511005 TI - Critique of 'The physical activity myth' paper: discussion of flawed logic and inappropriate use of evidence. PMID- 26511006 TI - The acute:chronic workload ratio predicts injury: high chronic workload may decrease injury risk in elite rugby league players. AB - AIM: Investigate whether acute workload (1 week total distance) and chronic workload (4-week average acute workload) predict injury in elite rugby league players. METHODS: Data were collected from 53 elite players over two rugby league seasons. The 'acute:chronic workload ratio' was calculated by dividing acute workload by chronic workload. A value of greater than 1 represented an acute workload greater than chronic workload. All workload data were classified into discrete ranges by z-scores. RESULTS: Compared with all other ratios, a very-high acute:chronic workload ratio (>=2.11) demonstrated the greatest risk of injury in the current week (16.7% injury risk) and subsequent week (11.8% injury risk). High chronic workload (>16 095 m) combined with a very-high 2-week average acute:chronic workload ratio (>=1.54) was associated with the greatest risk of injury (28.6% injury risk). High chronic workload combined with a moderate workload ratio (1.02-1.18) had a smaller risk of injury than low chronic workload combined with several workload ratios (relative risk range from 0.3 to 0.7*//1.4 to 4.4; likelihood range=88-94%, likely). Considering acute and chronic workloads in isolation (ie, not as ratios) did not consistently predict injury risk. CONCLUSIONS: Higher workloads can have either positive or negative influences on injury risk in elite rugby league players. Specifically, compared with players who have a low chronic workload, players with a high chronic workload are more resistant to injury with moderate-low through moderate-high (0.85-1.35) acute:chronic workload ratios and less resistant to injury when subjected to 'spikes' in acute workload, that is, very-high acute:chronic workload ratios ~1.5. PMID- 26511007 TI - The role of procalcitonin as a marker of diabetic foot ulcer infection. AB - Foot ulcers are frequent in diabetic patients and are responsible for 85% of amputations, especially in the presence of infection. The diagnosis of diabetic foot ulcer infection is essentially based on clinical evaluation, but laboratory parameters such as erythrocyte sedimentation rate (ESR), white blood count (WBC), C-reactive protein (CRP) and, more recently, procalcitonin (PCT) could aid the diagnosis, especially when clinical signs are misleading. Fifteen diabetic patients with infected foot ulcers were admitted to our department and were compared with an additional group of patients with non-infected diabetic foot ulcers (NIDFUs). Blood samples were collected from all patients in order to evaluate laboratory markers. In the current study, the diagnostic accuracy of PCT serum levels was evaluated in comparison with other inflammatory markers such as CRP, ESR and WBC as an indicator to make the distinction between infected diabetic foot ulcers (IDFUs) and NIDFUs. CRP, WBC, ESR and especially PCT measurements represent effective biomarkers in the diagnosis of foot infections in diabetic patients particularly when clinical signs are misleading. PMID- 26511008 TI - Spontaneous reaction between an uncharged lithium iron silicate cathode and a LiPF6-based electrolyte. AB - The reaction between an uncharged Li2FeSiO4 (LFS) cathode and a LiPF6-EC/DMC electrolyte is revealed by in situ XANES in coin cells. This study shows clear evidence of delithiation and iron oxidation in LFS prior to cycling. Subsequent cycling appears to partially restore the original lithiation level, an observation that needs to be taken into consideration in future LFS development work. PMID- 26511009 TI - Role of Nrf2 in bone metabolism. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor expressed in many cell types, including osteoblasts, osteocytes, and osteoclasts. Nrf2 has been considered a master regulator of cytoprotective genes against oxidative and chemical insults. The lack of Nrf2 can induce pathologies in multiple organs. Nrf2 deficiency promotes osteoclast differentiation and osteoclast activity, which leads to an increase in bone resorption. The role of Nrf2 in osteoblast differentiation and osteoblast activity is more complex. Nrf2 mediates anabolic effects within an ideal range. Nrf2 deletion suppresses load induced bone formation and delays fracture healing. Overall, Nrf2 plays an important role in the regulation of bone homeostasis in bone cells. PMID- 26511010 TI - De novo transcriptome sequencing in Bixa orellana to identify genes involved in methylerythritol phosphate, carotenoid and bixin biosynthesis. AB - BACKGROUND: Bixin or annatto is a commercially important natural orange-red pigment derived from lycopene that is produced and stored in seeds of Bixa orellana L. An enzymatic pathway for bixin biosynthesis was inferred from homology of putative proteins encoded by differentially expressed seed cDNAs. Some activities were later validated in a heterologous system. Nevertheless, much of the pathway remains to be clarified. For example, it is essential to identify the methylerythritol phosphate (MEP) and carotenoid pathways genes. RESULTS: In order to investigate the MEP, carotenoid, and bixin pathways genes, total RNA from young leaves and two different developmental stages of seeds from B. orellana were used for the construction of indexed mRNA libraries, sequenced on the Illumina HiSeq 2500 platform and assembled de novo using Velvet, CLC Genomics Workbench and CAP3 software. A total of 52,549 contigs were obtained with average length of 1,924 bp. Two phylogenetic analyses of inferred proteins, in one case encoded by thirteen general, single-copy cDNAs, in the other from carotenoid and MEP cDNAs, indicated that B. orellana is closely related to sister Malvales species cacao and cotton. Using homology, we identified 7 and 14 core gene products from the MEP and carotenoid pathways, respectively. Surprisingly, previously defined bixin pathway cDNAs were not present in our transcriptome. Here we propose a new set of gene products involved in bixin pathway. CONCLUSION: The identification and qRT-PCR quantification of cDNAs involved in annatto production suggest a hypothetical model for bixin biosynthesis that involve coordinated activation of some MEP, carotenoid and bixin pathway genes. These findings provide a better understanding of the mechanisms regulating these pathways and will facilitate the genetic improvement of B. orellana. PMID- 26511011 TI - Cognitive Aging Trajectories and Burdens of Disability, Hospitalization and Nursing Home Admission Among Community-living Older Persons. AB - BACKGROUND: The course of cognitive aging has demonstrated substantial heterogeneity. This study attempted to identify distinctive cognitive trajectories and examine their relationship with burdens of disability, hospitalization, and nursing home admission. METHODS: Seven hundred and fifty four community-living persons aged 70 years or older in the Yale Precipitating Events Project were assessed with the Mini-Mental State Examination every 18 months for up to 108 months. A group-based trajectory model was used to determine cognitive aging trajectories while adjusting for age, sex, and education. Cumulative burden of disabilities, hospitalizations, and nursing home admissions over 141 months associated with the cognitive trajectories were evaluated using a generalized estimating equation Poisson model. RESULTS: Five distinct cognitive trajectories were identified, with about a third of participants starting with high baseline cognitive function and demonstrating No decline during the follow up period. The remaining participants diverged with Minimal (prevalence 41%), Moderate (16%), Progressive (8%), and Rapid (3%) cognitive decline. Participants with No decline incurred the lowest incidence rates (per 1,000 person-months) of disability in activities of daily living (ADL; 75, 95% confidence intervals: 60 95) and instrumental ADL (492, 453-535), hospitalization (29, 26-33) and nursing home admission (18, 12-27), whereas participants on the Rapid trajectory experienced the greatest burden of ADL disability (612, 595-758) and those on the Progressive trajectory had the highest nursing home admission (363, 292-451). CONCLUSIONS: Community-living older persons follow distinct cognitive aging trajectories and experience increasing burdens of disability, hospitalization, and nursing home placement as they age, with greater burdens for those on a declining cognitive trajectory. PMID- 26511012 TI - Endothelial Progenitor Cell Levels Predict Future Physical Function: An Exploratory Analysis From the VA Enhanced Fitness Study. AB - BACKGROUND: Levels of circulating progenitor cells (CPCs) are depleted with aging and chronic injury and are associated with level of physical functioning; however, little is known about the correlation of CPCs with longer-term measures of physical capabilities. We sought to determine the association of CPCs with future levels of physical function and with changes in physical function over time. METHODS: CPCs were measured in 117 participants with impaired glucose tolerance in the Enhanced Fitness clinical trial based on the cell surface markers CD34 and CD133 and aldehyde dehydrogenase (ALDH) activity at baseline, 3 months, and 12 months. Physical function was assessed using usual and rapid gait speed, 6-minute walk distance, chair stand time, and SF-36 physical functioning score and reassessed at 3 and 12 months after clinical intervention. RESULTS: Higher baseline levels of CD133(+), CD34(+), CD133(+)CD34(+), and ALDH(br) were each highly predictive of faster gait speed and longer distance walked in 6 minutes at both 3 and 12 months. These associations remained robust after adjustment for age, body mass index, baseline covariates, and inflammation and were independent of interventions to improve physical fitness. Further, higher CPC levels predicted greater improvements in usual and rapid gait speed over 1 year. CONCLUSIONS: Baseline CPC levels are associated not only with baseline mobility but also with future physical function, including changes in gait speed. These findings suggest that CPC measurement may be useful as a marker of both current and future physiologic aging and functional decline. PMID- 26511013 TI - Left Atrial Volume and Pulmonary Artery Diameter Are Noninvasive Measures of Age Related Diastolic Dysfunction in Mice. AB - Impaired cardiac diastolic function occurs with aging in many species and may be difficult to measure noninvasively. In humans, left atrial (LA) volume is a robust measure of chronic diastolic function as the LA is exposed to increased left ventricular filling pressures. We hypothesized that LA volume would be a useful indicator of diastolic function in aging mice. Further, we asked whether pressures were propagated backwards affecting pulmonary arteries (PAs) and right ventricle (RV). We measured LA, PA, and RV infundibulum dimensions with echocardiography and used mouse-specific Doppler systems and pressure catheters for noninvasive and invasive measures. As C57BL/6 mice aged from 3 to 29-31 months, LA volume almost tripled. LA volume increases correlated with traditional diastolic function measures. Within groups of 14- and 31-month-old mice, LA volume correlated with diastolic function measured invasively. In serial studies, mice evaluated at 20 and 24 months showed monotonic increases in LA volume; other parameters changed less predictably. PA diameters, larger in 30-month-old mice than 6-month-old mice, correlated with LA volumes. Noninvasive LA volume and PA diameter assessments are useful and state independent measures of diastolic function in mice, correlating with other measures of diastolic dysfunction in aging. Furthermore, serial measurements over 4 months demonstrated consistent increases in LA volume suitable for longitudinal cardiac aging studies. PMID- 26511014 TI - [Gift of life - gift of time: Possibilities for accompanying old people]. PMID- 26511015 TI - Corrigendum: The reverse evolution from multicellularity to unicellularity during carcinogenesis. PMID- 26511016 TI - Sleep loss: effects on brain and body in the very young and very old. PMID- 26511017 TI - The diagnostic method has a strong influence on classification of obstructive sleep apnea. AB - Polygraphy (PG) and polysomnography (PSG) are used in clinical settings in Europe for diagnosing obstructive sleep apnea (OSA), but their equivalence in unselected clinical cohorts is unknown. We hypothesized that the method would affect both diagnostic outcomes and disease severity stratification. Data from 11 049 patients in the multi-centre European Sleep Apnea Cohort (ESADA) with suspected OSA (male and female, aged 18-80 years) were used in two groups of patients to compare PG (n = 5745) and PSG (n = 5304). Respiratory events were scored using the 2007 American Association of Sleep Medicine (AASM) criteria. In subjects who underwent PSG, mean apnea-hypopnea index (AHI) using sleep time (AHIPSG 31.0 +/- 26.1 h(-1) ) and total analysed time (TAT) (AHITAT 24.7 +/- 22.0 h(-1) ) were higher than in subjects who underwent PG (AHIPG 22.0 +/- 23.5 h(-1) ) (P < 0.0001). The oxygen desaturation index (ODI) was lower in subjects investigated with PG (ODIPG 18.4 +/- 21.7 h(-1) ) compared to subjects investigated with PSG (ODIPSG 23.0 +/- 25.3 h(-1) ) but not different when the PSG was indexed by TAT (ODITAT 18.6 +/- 21.4 h(-1) , P < 0.65). The proportion of patients with an AHI >= 15 was 64% in the subjects who underwent PSG and 47% in the subjects who underwent PG (P < 0.001). Overall, patients investigated using PG are likely to have a 30% lower AHI on average, compared to patients investigated by PSG. This study suggests that PG interpreted using standard guidelines results in underdiagnosis and misclassification of OSA. We advocate the development of PG specific guidelines for the management of OSA patients. PMID- 26511018 TI - Effect of radioactive iodine therapy on carotid intima media thickness in patients with hyperthyroidism. AB - OBJECTIVE: The aim of this study was to evaluate the carotid intima media thickness (IMT) in patients with thyrotoxicosis who received radioactive iodine (RAI) treatment. METHODS: This study was planned to be conducted with two different groups of people. There were 87 patients in the patient group and 98 controls. Participants were evaluated for atherosclerosis risk factors. Mean carotid IMT was measured from three consecutive traces at the common carotid artery bifurcation. RESULTS: The mean carotid IMT was 0.81 +/- 0.20 in patient group and this was higher than the controls (0.68 +/- 0.19) (p < 0.01). IM thickening was positively correlated with the applied RAI dose levels in the treatment group (p = 0.029). In patients with only HT, the data of the two groups showed a significant difference, with the average IMT being higher in the patient group than that of the control group (p: 0.011). CONCLUSION: RAI used in the treatment of thyrotoxicosis increases the IMT of carotid artery independent of age and sex. This treatment yields better results with higher doses, and this effect is more marked in patients with HT. Hence, we believe that it is necessary to calculate the dose properly for hyperthyroid cases in which treatment with RAI is planned. In particular, the patients with HT need to be treated with the minimum possible dose. Further, carotid arteries should be evaluated with US following RAI treatment. PMID- 26511019 TI - Correlation of 4'-[methyl-(11)C]-thiothymidine uptake with Ki-67 immunohistochemistry and tumor grade in patients with newly diagnosed gliomas in comparison with (11)C-methionine uptake. AB - OBJECTIVE: A novel radiopharmaceutical, 4'-[methyl-(11)C]thiothymidine ((11)C 4DST), has been developed as an in vivo cell proliferation marker based on the DNA incorporation method. The purpose of this study was to evaluate (11)C-4DST uptake in patients with newly diagnosed glioma and to correlate the results with proliferative activity and tumor grade, in comparison with L-[methyl-(11)C] methionine ((11)C-MET). METHODS: Investigations of (11)C-4DST and (11)C-MET PET/CT were performed retrospectively in 23 patients with newly diagnosed glioma. The maximum standardized uptake value (SUVmax) for tumor (T) and the mean SUV for normal contralateral hemisphere (N) were calculated, and the tumor-to-normal (T/N) ratio was determined. Metabolic tumor volume (MTV) was defined as the volume with a threshold of 40% of the SUVmax. Proliferative activity as indicated by the Ki-67 index was estimated in tissue specimens. RESULTS: Of 23 gliomas examined, (11)C-4DST PET/CT and (11)C-MET PET/CT detected 20 and 22, respectively. Linear regression analysis between (11)C-4DST and (11)C-MET indicated a weak correlation for SUVmax (r = 0.54, P < 0.008), for T/N ratio (r = 0.56, P < 0.006), and for MTV (r = 0.60, P < 0.003). Linear regression analysis indicated a weak correlation between (11)C-4DST and Ki-67 index for SUVmax (r = 0.46, P < 0.03), for T/N ratio (r = 0.43, P < 0.05), and for MTV (r = 0.68, P < 0.001) and between (11)C-MET MTV and Ki-67 index (r = 0.43, P < 0.04). Using (11)C-4DST, there was a significant difference in SUVmax between grades II and IV (P < 0.03) and in MTV between grades II and IV (P < 0.009) and grades III and IV (P < 0.02). Using (11)C-MET, there was a significant difference in SUVmax (P < 0.009) and T/N ratio (P < 0.02) between grades II and IV and in MTV between grades II and IV (P < 0.03) and grades III and IV (P < 0.02). CONCLUSION: (11)C 4DST PET/CT is feasible for imaging of brain gliomas, as well as (11)C-MET PET/CT. Especially, it showed the highest correlation coefficient between (11)C 4DST MTV and Ki-67 index in newly diagnosed gliomas. PMID- 26511020 TI - Structural basis of membrane budding by the nuclear egress complex of herpesviruses. AB - During nuclear egress, herpesvirus capsids bud at the inner nuclear membrane forming perinuclear viral particles that subsequently fuse with the outer nuclear membrane, releasing capsids into the cytoplasm. This unusual budding process is mediated by the nuclear egress complex (NEC) composed of two conserved viral proteins, UL31 and UL34. Earlier, we discovered that the herpesvirus nuclear egress complex (NEC) could bud synthetic membranes in vitro without the help of other proteins by forming a coat-like hexagonal scaffold inside the budding membrane. To understand the structural basis of NEC-mediated membrane budding, we determined the crystal structures of the NEC from two herpesviruses. The hexagonal lattice observed in the NEC crystals recapitulates the honeycomb coats within the budded vesicles. Perturbation of the oligomeric interfaces through mutagenesis blocks budding in vitro confirming that NEC oligomerization into a honeycomb lattice drives budding. The structure represents the first atomic-level view of an oligomeric array formed by a membrane-deforming protein, making possible the dissection of its unique budding mechanism and the design of inhibitors to block it. PMID- 26511021 TI - Unexpected features and mechanism of heterodimer formation of a herpesvirus nuclear egress complex. AB - Herpesvirus nucleocapsids escape from the nucleus in a process orchestrated by a highly conserved, viral nuclear egress complex. In human cytomegalovirus, the complex consists of two proteins, UL50 and UL53. We solved structures of versions of UL53 and the complex by X-ray crystallography. The UL53 structures, determined at 1.93 and 3.0 A resolution, contained unexpected features including a Bergerat fold resembling that found in certain nucleotide-binding proteins, and a Cys3His zinc finger. Substitutions of zinc-coordinating residues decreased UL50-UL53 co localization in transfected cells, and, when incorporated into the HCMV genome, ablated viral replication. The structure of the complex, determined at 2.47 A resolution, revealed a mechanism of heterodimerization in which UL50 clamps onto helices of UL53 like a vise. Substitutions of particular residues on the interaction interface disrupted UL50-UL53 co-localization in transfected cells and abolished virus production. The structures and the identification of contacts can be harnessed toward the rational design of novel and highly specific antiviral drugs and will aid in the detailed understanding of nuclear egress. PMID- 26511022 TI - [Mononeuritis multiplex due to thrombotic ischemia of primary antiphospholipid antibody syndrome without vasculitis: an autopsy case report]. AB - The patient was a 78-year-old man. Three years before admission, he developed transient peripheral neuropathy and purpura, and at admission, he presented with livedo reticularis of both his lower extremities and with mononeuritis multiplex. Vasculitis was not observed, and antiphospholipid antibodies were detected. The nerve and skin biopsies revealed no inflammation; axonal degeneration accompanied by thrombi was found in his arterioles and venules. Based on these findings, he was diagnosed with ischemic peripheral neuropathy due to primary antiphospholipid syndrome. Administration of anticoagulant therapy resulted in an improvement in symptoms; however, two months later, a relapse occurred, and the patient contracted an infection while undergoing immunosuppressive therapy. The infection became fulminant, and the patient succumbed to multiple organ failure. The autopsy revealed a systemic arterial and venous embolism; however, no vasculitis was observed. Antiphospholipid syndrome, which is responsive to antithrombotic treatment, should be considered as a differential diagnosis of mononeuritis multiplex. PMID- 26511023 TI - [Case of posterior reversible encephalopathy syndrome due to azathioprine]. AB - This report describes a 15-year-old woman presenting posterior reversible encephalopathy syndrome (PRES) due to azathioprine. She was under treatment for ulcerative colitis. She was prescribed azathioprine seven days before admission. Four days after, she complained of headache. Then, she disturbed consciousness and showed generalized convulsive seizure on the day of admission. Magnetic resonance imaging (MRI) revealed vasogenic edema in both hemispheres. She was discontinued azathioprine and treated by anticonvulsant. Her symptoms were recovered and the MRI findings were disappeared. We diagnosed as PRES due to azathioprine because of clinical course and MRI findings. Only one case of PRES due to azathioprine is reported previously. Our case is the first report that showed the changes and improvement of MRI findings along the clinical course. PMID- 26511024 TI - [Ischemic changes and blood coagulation abnormalities as complications of pneumococcal meningitis]. AB - One explanation for cerebral infarctions that occur as a complication of pneumococcal meningitis is blood coagulation abnormalities. We investigated the clinical features, laboratory test results, magnetic resonance imaging (MRI) findings, and pathological features of 10 patients with pneumococcal meningitis between 2006 and 2013 to examine the abnormal findings that may be associated with prognosis. Five patients (50%) that had Glasgow Outcome Scale scores between 1 and 4 were classified as the poor outcome group. In this group, the MRI revealed a high signal intensity on the diffusion-weighted image (DWI), and there was an abnormal signal along the cerebral cortex and Virchow-Robin spaces, which were characterized pathologically by ischemic changes. The plasma thrombin antithrombin complex (TAT) levels showed greater differences between the poor and good prognosis groups than platlet and D-dimer levels; this suggested that high plasma TAT levels indicate a poor prognosis. PMID- 26511025 TI - [Aseptic meningitis in a patient with cerebrospinal fluid anti-agalactosyl IgG antibody-positive preclinical rheumatoid arthritis: a case report]. AB - A 69-year-old woman presented with non-fluent aphasia, ideomotor apraxia, right hemiparesis and convulsion. Her medical history was unremarkable, and she had not suffered from arthritis. DWI and FLAIR image of brain MRI showed hyperintensities in the subarachnoid space along the left frontal and both parietal lobes, and these lesions were associated with gadolinium enhancement. The levels of serum anti-cyclic citrullinated peptide antibody, anti-agalactosyl IgG antibody and matrix metalloproteinase-3 were elevated. The results of blood cultures were negative. Cerebrospinal fluid (CSF) analysis revealed monocytic pleocytosis and negative findings for infection or malignancy. The level of anti-agalactosyl IgG antibody in CSF was elevated. The antibody index (AI) of anti-agalactosyl IgG antibody (the ratio between the CSF/serum quotient for IgG antibodies, and the CSF/serum quotient for total IgG; normal value of AI < 1.3) showed considerably high value of 8.4, indicating the intrathecal-specific antibody synthesis. As a result, the pathogenesis of her disease was consistent with rheumatoid meningitis despite lack of arthritis. After intravenous administration of methylprednisolone, her symptoms, the level of anti-agalactosyl IgG antibody in CSF, and the MRI findings were ameliorated. Anti-agalactosyl IgG antibody in the CSF was a helpful biomarker in diagnosis and assessment of the severity of rheumatoid meningitis. PMID- 26511026 TI - [A case of new-onset refractory status epilepticus (NORSE) with an autoimmune etiology]. AB - A 23-year-old man presented tonic-clonic seizure a week after an episode of antecedent infection. Although several anticonvulsants were used, convulsive attacks were not resolved and intravenous anesthetics were used to stop status epileptics. After combination of immunotherapies (high-dose intravenous methylprednisolone, immune absorbance and intravenous immunoglobulin (IVIg) therapies), frequency of convulsive attacks decreased, however, disturbance of consciousness was not recovered. All anti-neuronal antibodies tested were negative. Indirect immunofluorescence using the serum and rat brain section revealed positive signals in cytoplasm and nucleus in hippocampal neurons, strongly suggesting that this case has an autoimmune pathogenesis. The clinical features and course of this patient are well consistent with those in new-onset refractory status epilepticus (NORSE). The result of immunohistochemical analysis supports the hypothesis that NORSE has an autoimmune pathomechanism. PMID- 26511027 TI - [Case of Takayasu arteritis accompanying hypertrophic pachymeningitis]. AB - A 71-year-old woman was referred to our department for evaluation of a right temporal headache. She had been diagnosed with Takayasu arteritis in her twenties but did not receive steroid therapy. A brain MRI scan detected thickened dura mater with abnormal enhancement on the right cerebral hemisphere. She was diagnosed with hypertrophic pachymeningitis, but she refused to be treated with steroids. Three months later, she noticed periorbital pain and blurred vision in her left eye, although the right temporal headache was reduced. A brain MRI scan detected thickened dura mater with abnormal enhancement on the left cerebral hemisphere adjacent to the left orbit and a swelled left superior rectus muscle with abnormal enhancement. However, the MRI results also showed that the thickening of the dura mater on the right cerebral hemisphere had improved. The new symptoms and the abnormalities revealed with imaging were resolved following steroid therapy. Takayasu arteritis mainly affects the large vessels, but can involve small and systemic vessels. This case presents a rare but possible link between hypertrophic pachymeningitis and Takayasu arteritis. PMID- 26511028 TI - [A patient with familial amyotrophic lateral sclerosis associated with a new valosin-containing protein (VCP) gene mutation]. AB - In this communication, we report a patient with familial amyotrophic lateral sclerosis (ALS) associated with a familial dyslipidemia. Genetic analysis revealed a novel heterozygous valosin-containing protein (VCP) mutation (c.466G>T (p.G156C)). The other gene analysis also disclosed a known homozygous LCAT mutation (c.101C>T (p.P10L)). VCP gene mutation shown should be responsible for familial ALS because of following reasons. The patient's father also was also affected by ALS. The VCP gene mutation (p.G156C) in the patient was located in the vicinity of a site frequently associated with pathogenic VCP variants. The same amino acid transformation as that of this patient has been reported to be involved in the pathogenesis of inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia. This is the first case report of rare association of ALS with VCP mutation and dyslipidemia with LCAT mutation. PMID- 26511029 TI - [Anti-Hu antibody-positive paraneoplastic limbic encephalitis with acute motor sensory neuropathy resembling Guillain-Barre syndrome: a case study]. AB - A 69-year-old man experienced general malaise, weight loss, amnesia, gait disturbance, and restlessness a month prior to admission. Brain MRI showed high intensity areas in the bilateral medial temporal lobes and insular cortices on FLAIR images, and therefore, he was diagnosed with limbic encephalitis. After admission, quadriplegia and respiratory failure progressed rapidly, and he needed ventilatory management. A nerve conduction study revealed low compound muscle action potential amplitude with loss of sensory nerve action potential, which indicated axonal sensorimotor neuropathy. We administered intravenous immunoglobulin and methylprednisolone pulse therapy, but he did not recover. Although no tumor was found on CT, his serum was positive for anti-Hu antibody; therefore, we diagnosed him with paraneoplastic neurological syndrome. An FDG-PET study showed accumulation at lesions on two hilar lymph nodes. Small cell lung carcinoma was detected by endobronchial ultrasound-guided transbronchial needle aspiration. Although paraneoplastic acute sensorimotor neuropathy with respiratory failure resembling Guillain-Barre syndrome is rare, identification of antibodies and servey of tumors aids accurate diagnosis. PMID- 26511030 TI - [A case of rheumatoid meningitis presented with generalized seizure in whom MRI images were helpful for the diagnosis]. AB - We report a 65-years-old woman with rheumatoid meningitis presented with a generalized seizure. She has a 18-year history of rheumatoid arthritis, which has been successfully treated. She developed a generalized seizure. She was diagnosed as having subarachnoid hemorrhage, because the brain magnetic resonance imaging (MRI) showed increased fluid attenuated inversion recovery (FLAIR) signals in her left frontoparietal subarachnoid space. After one month of clinical stabilization, she developed numbness and weakness in her right lower extremity that spread to her right upper extremity and face. Brain MRI showed progression of subarachnoid lesion on FLAIR image and leptomeningeal enhancement on gadolinium-enhanced T1 weighted image. She was diagnosed as having rheumatoid meningitis, and methylprednisolone pulse therapy was started. Then, her symptoms and MRI findings were rapidly improved. Though rheumatoid meningitis is rare and presents a difficulty in the diagnosis, MRI features may support the diagnosis. PMID- 26511031 TI - [Successful treatment with acyclovir and a corticosteroid for lower cranial polyneuropathy in zoster sine herpete: a case report]. AB - A 62-year-old woman developed meningitis as well as acute paralysis of glossopharyngeal, vagus, and accessory nerves on the right side and also had dysfunction of the left hypoglossal nerve. Although there was no evidence of a typical cutaneous or mucosal herpetic lesion, PCR detection of varicella zoster virus (VZV)-DNA in cerebrospinal fluid confirmed the clinical diagnosis of polyneuritis cranialis due to VZV infection and zoster sine herpete. After starting intravenous acyclovir and methylprednisolone, her hypoglossal nerve palsy disappeared within a day and all other symptoms and signs dramatically improved. A rapid improvement observed in our patient suggests that the right cranial polyneuropathy could be caused by inflammation associated with epineurial edema (where the ninth, tenth, and eleventh cranial nerves pass through the right jugular foramen), whereas the exact mechanism of the twelfth cranial nerve involvement on the contralateral side is unknown. Our clinical findings indicate that acute lower cranial polyneuropathy in patients with zoster sine herpete should be treated immediately with combined administration of acyclovir and an anti-inflammatory corticosteroid. PMID- 26511032 TI - Lanthanoid/Alkali Metal beta-Triketonate Assemblies: A Robust Platform for Efficient NIR Emitters. AB - The reaction of hydrated lanthanoid chlorides with tribenzoylmethane and an alkali metal hydroxide consistently resulted in the crystallization of neutral tetranuclear assemblies with the general formula [Ln(Ae?HOEt)(L)4 ]2 (Ln=Eu(3+) , Er(3+) , Yb(3+) ; Ae=Na(+) , K(+) , Rb(+) ). Analysis of the crystal structures of these species revealed a coordination geometry that varied from a slightly distorted square antiprism to a slightly distorted triangular dodecahedron, with the specific geometrical shape being dependent on the degree of lattice solvation and identity of the alkali metal. The near-infrared (NIR)-emitting assemblies of Yb(3+) and Er(3+) showed remarkably efficient emission, characterized by significantly longer excited-state lifetimes (tauobs ~37-47 MUs for Yb(3+) and tauobs ~4-6 MUs for Er(3+) ) when compared with the broader family of lanthanoid beta-diketonate species, even in the case of perfluorination of the ligands. The Eu(3+) assemblies show bright red emission and a luminescence performance (tauobs ~0.5 ms, ${{?Phi}{{{?rm L}?hfill ?atop {?rm Ln}?hfill}}}$~35-37 %, etasens ~68-70 %) more akin to the beta-diketonate species. The results highlight that the beta triketonate ligand offers a tunable and facile system for the preparation of efficient NIR emitters without the need for more complicated perfluorination or deuteration synthetic strategies. PMID- 26511033 TI - Mark-specific hazard ratio model with missing multivariate marks. AB - An objective of randomized placebo-controlled preventive HIV vaccine efficacy (VE) trials is to assess the relationship between vaccine effects to prevent HIV acquisition and continuous genetic distances of the exposing HIVs to multiple HIV strains represented in the vaccine. The set of genetic distances, only observed in failures, is collectively termed the 'mark.' The objective has motivated a recent study of a multivariate mark-specific hazard ratio model in the competing risks failure time analysis framework. Marks of interest, however, are commonly subject to substantial missingness, largely due to rapid post-acquisition viral evolution. In this article, we investigate the mark-specific hazard ratio model with missing multivariate marks and develop two inferential procedures based on (i) inverse probability weighting (IPW) of the complete cases, and (ii) augmentation of the IPW estimating functions by leveraging auxiliary data predictive of the mark. Asymptotic properties and finite-sample performance of the inferential procedures are presented. This research also provides general inferential methods for semiparametric density ratio/biased sampling models with missing data. We apply the developed procedures to data from the HVTN 502 'Step' HIV VE trial. PMID- 26511034 TI - [Central venous pressure - a safety parameter]. PMID- 26511035 TI - Generation of a miniature pig disease model for human Laron syndrome. AB - Laron syndrome is a rare disease caused by mutations of the growth hormone receptor (GHR), inheriting in an autosomal manner. To better understand the pathogenesis and to develop therapeutics, we generated a miniature pig model for this disease by employing ZFNs to knock out GHR gene. Three types of F0 heterozygous pigs (GHR(+/4bp), GHR(+/2bp), GHR(+/3bp)) were obtained and in which no significant phenotypes of Laron syndrome were observed. Prior to breed heterozygous pigs to homozygosity (GHR(4bp/4bp)), pig GHR transcript with the 4 bp insert was evaluated in vitro and was found to localize to the cytoplasm rather than the membrane. Moreover, this mutated transcript lost most of its signal transduction capability, although it could bind bGH. GHR(4bp/4bp) pigs showed a small body size and reduced body weight. Biochemically, these pigs exhibited significantly elevated levels of GH and decreased levels of IGF-I. These results resemble the phenotype observed in Laron patients, suggesting that these pigs could serve as an ideal model for Laron syndrome to bridge the gaps between mouse model and human. PMID- 26511036 TI - Binding global and local object features in visual working memory. AB - When briefly presented with global and local visual information, individuals report global information more quickly and more accurately than local information, a phenomenon known as the global precedence effect (GPE; Navon, 1977). We investigated whether a bias toward global information persists in visual working memory (VWM) and whether the VWM representations for global and local features include information bound to their hierarchical levels and to each other. Navon figures, in which a larger (global) letter is composed of smaller (local) letters, were presented, and participants performed a change detection task that required participants to remember features only (either a global or local letter changed to a new identity); features bound to their hierarchical levels (the global and local letters within an object swapped levels); or features bound to each other within an object (2 letters from the same level swapped between objects). Performance suggested that there was a GPE in VWM (new global letters were more accurately detected than new local letters) and that although global and local features were not necessarily bound together in VWM, they were bound to their corresponding hierarchical levels. These results indicate that level binding in VWM occurs more readily than binding specific object features together. These findings further our understanding of how hierarchical objects are represented in VWM. PMID- 26511037 TI - CCAAT/enhancer-binding protein alpha is required for hepatic outgrowth via the p53 pathway in zebrafish. AB - CCAAT/enhancer-binding protein alpha (C/ebpalpha) is a transcription factor that plays important roles in the regulation of hepatogenesis, adipogenesis and hematopoiesis. Disruption of the C/EBPalpha gene in mice leads to disturbed liver architecture and neonatal death due to hypoglycemia. However, the precise stages of liver development affected by C/ebpalpha loss are poorly studied. Using the zebrafish embryo as a model organism, we show that inactivation of the cebpa gene by TALENs results in a small liver phenotype. Further studies reveal that C/ebpalpha is distinctively required for hepatic outgrowth but not for hepatoblast specification. Lack of C/ebpalpha leads to enhanced hepatic cell proliferation and subsequent increased cell apoptosis. Additional loss of p53 can largely rescue the hepatic defect in cebpa mutants, suggesting that C/ebpalpha plays a role in liver growth regulation via the p53 pathway. Thus, our findings for the first time demonstrate a stage-specific role for C/ebpalpha during liver organogenesis. PMID- 26511038 TI - [Pediatric home ventilation--practical approach]. AB - Out-of-hospital ventilation represents only a marginal area of paediatric therapeutic concepts. In Austria, the proportion of children to be supplied with invasive and non-invasive ventilation increases significantly, together with the challenges of caring for their long-term demands. Neuromuscular diseases accounted for almost the sole indication group. Premature and newborn infants with persistent respiratory failures are an increasing group, needing more extensive care due to additional comorbidities. Children with congenital disorder have often been tracheotomised in order to secure their airway, and non-invasive ventilation as a bridge- or long-term therapy gains in importance more and more. Usually, infants with primary or secondary CNS disorders suffer from respiratory complications and eventually from chronic respiratory insufficiencies during adolescence or young adulthood. Here, invasive or non-invasive ventilation can contribute both to a significant stabilisation of health status and also quality of life. Spirit of research, experience, appropriate support structures, and appropriate networking constitute the most relevant quality- and success criteria for home care. PMID- 26511040 TI - Neural Mechanisms and Children's Intellectual Development: Multiple Impacts of Environmental Factors. AB - Human psychometric intelligence can predict a number of important social and academic outcomes. Substantial parts of the variances of human intelligence and the brain volume supporting those abilities are explained by environmental factors, and during childhood, human brains have higher plasticity and also 60% of variance of intelligence that is explained by environmental factors. Here, we review the representative environmental factors known to affect human intellectual development during each developmental stage. We describe what is (and what is not) being investigated to determine how these factors affect human brain development through analyses of volumetrical and cortical structures. In conclusion, environmental factors that affect children's intellectual development lead to three patterns of brain structural change. The first is global change in the brain structure, observed more often in the earlier phase of development. The second is structural changes concentrated in the medial prefrontal and adjacent areas and medial temporal areas, which are likely to be induced by stress in many cases. The third is sporadic region-specific change, likely to be primarily caused by use-dependent plasticity of the areas that is often observed in the later phase of development. These changes may underlie the alterations in children's intellectual development that is induced by environmental factors. PMID- 26511039 TI - CHESS: an innovative concept for a new generation of population surveillance. PMID- 26511041 TI - Roles of Calcium Stores and Store-Operated Channels in Plasticity of Dendritic Spines. AB - Calcium stores in the endoplasmic reticulum play important roles in a variety of mammalian cellular functions. However, the multitude of calcium-handling machineries in neurons, including voltage- and ligand-gated channels, calcium binding proteins, pumps, and transporters, as well as the rapid mobility of calcium ions among different cellular compartments hampered the singling out of calcium stores as a pivotal player in synaptic plasticity. Despite these methodological obstacles, novel molecular and imaging tools afforded a rapid progress in deciphering the role of specific calcium stores in neuronal functions. In the present review, we will address several key issues related to the involvement of ryanodine receptors and the calcium entry channel Orai1 in dendritic spine development and plasticity as well as their derailing in neurodegenerative diseases. PMID- 26511042 TI - A restatement of recent advances in the natural science evidence base concerning neonicotinoid insecticides and insect pollinators. AB - A summary is provided of recent advances in the natural science evidence base concerning the effects of neonicotinoid insecticides on insect pollinators in a format (a 'restatement') intended to be accessible to informed but not expert policymakers and stakeholders. Important new studies have been published since our recent review of this field (Godfray et al. 2014 Proc. R. Soc. B 281, 20140558. (doi:10.1098/rspb.2014.0558)) and the subject continues to be an area of very active research and high policy relevance. PMID- 26511043 TI - Damsel in distress: captured damselfish prey emit chemical cues that attract secondary predators and improve escape chances. AB - In aquatic environments, many prey animals possess damage-released chemical alarm cues that elicit antipredator behaviours in responsive con- and heterospecifics. Despite considerable study, the selective advantage of alarm cues remains unclear. In an attempt to investigate one of the more promising hypotheses concerning the evolution of alarm cues, we examined whether the cue functions in a fashion analogous to the distress vocalizations emitted by many terrestrial animals. Our results suggest that chemical alarm cues in damselfish (Pomacentridae) may have evolved to benefit the cue sender by attracting secondary predators who disrupt the predation event, allowing the prey a greater chance to escape. The coral reef piscivore, the dusky dottyback (Pseudochromis fuscus), chemically eavesdrops on predation events and uses chemical alarm cues from fish prey (lemon damselfish; Pomacentrus moluccensis) in an attempt to find and steal prey from primary predators. Field studies showed that Ps. fuscus aggregate at sites where prey alarm cue has been experimentally released. Furthermore, secondary predators attempted to steal captured prey of primary predators in laboratory trials and enhanced prey escape chances by 35-40%. These results are the first, to the best of our knowledge, to demonstrate a mechanism by which marine fish may benefit from the production and release of alarm cues, and highlight the complex and important role that semiochemicals play in marine predator-prey interactions. PMID- 26511044 TI - Predicting the effects of human developments on individual dolphins to understand potential long-term population consequences. AB - Human activities that impact wildlife do not necessarily remove individuals from populations. They may also change individual behaviour in ways that have sublethal effects. This has driven interest in developing analytical tools that predict the population consequences of short-term behavioural responses. In this study, we incorporate empirical information on the ecology of a population of bottlenose dolphins into an individual-based model that predicts how individuals' behavioural dynamics arise from their underlying motivational states, as well as their interaction with boat traffic and dredging activities. We simulate the potential effects of proposed coastal developments on this population and predict that the operational phase may affect animals' motivational states. For such results to be relevant for management, the effects on individuals' vital rates also need to be quantified. We investigate whether the relationship between an individual's exposure and the survival of its calves can be directly estimated using a Bayesian multi-stage model for calf survival. The results suggest that any effect on calf survival is probably small and that a significant relationship could only be detected in large, closely studied populations. Our work can be used to guide management decisions, accelerate the consenting process for coastal and offshore developments and design targeted monitoring. PMID- 26511045 TI - Persistent natural acidification drives major distribution shifts in marine benthic ecosystems. AB - Ocean acidification is receiving increasing attention because of its potential to affect marine ecosystems. Rare CO2 vents offer a unique opportunity to investigate the response of benthic ecosystems to acidification. However, the benthic habitats investigated so far are mainly found at very shallow water (less than or equal to 5 m depth) and therefore are not representative of the broad range of continental shelf habitats. Here, we show that a decrease from pH 8.1 to 7.9 observed in a CO2 vent system at 40 m depth leads to a dramatic shift in highly diverse and structurally complex habitats. Forests of the kelp Laminaria rodriguezii usually found at larger depths (greater than 65 m) replace the otherwise dominant habitats (i.e. coralligenous outcrops and rhodolith beds), which are mainly characterized by calcifying organisms. Only the aragonite calcifying algae are able to survive in acidified waters, while high-magnesium calcite organisms are almost completely absent. Although a long-term survey of the venting area would be necessary to fully understand the effects of the variability of pH and other carbonate parameters over the structure and functioning of the investigated mesophotic habitats, our results suggest that in addition of significant changes at species level, moderate ocean acidification may entail major shifts in the distribution and dominance of key benthic ecosystems at regional scale, which could have broad ecological and socio economic implications. PMID- 26511046 TI - Measured voluntary avoidance behaviour during the 2009 A/H1N1 epidemic. AB - Managing infectious disease is among the foremost challenges for public health policy. Interpersonal contacts play a critical role in infectious disease transmission, and recent advances in epidemiological theory suggest a central role for adaptive human behaviour with respect to changing contact patterns. However, theoretical studies cannot answer the following question: are individual responses to disease of sufficient magnitude to shape epidemiological dynamics and infectious disease risk? We provide empirical evidence that Americans voluntarily reduced their time spent in public places during the 2009 A/H1N1 swine flu, and that these behavioural shifts were of a magnitude capable of reducing the total number of cases. We simulate 10 years of epidemics (2003-2012) based on mixing patterns derived from individual time-use data to show that the mixing patterns in 2009 yield the lowest number of total infections relative to if the epidemic had occurred in any of the other nine years. The World Health Organization and other public health bodies have emphasized an important role for 'distancing' or non-pharmaceutical interventions. Our empirical results suggest that neglect for voluntary avoidance behaviour in epidemic models may overestimate the public health benefits of public social distancing policies. PMID- 26511047 TI - The corpus callosum in primates: processing speed of axons and the evolution of hemispheric asymmetry. AB - Interhemispheric communication may be constrained as brain size increases because of transmission delays in action potentials over the length of axons. Although one might expect larger brains to have progressively thicker axons to compensate, spatial packing is a limiting factor. Axon size distributions within the primate corpus callosum (CC) may provide insights into how these demands affect conduction velocity. We used electron microscopy to explore phylogenetic variation in myelinated axon density and diameter of the CC from 14 different anthropoid primate species, including humans. The majority of axons were less than 1 um in diameter across all species, indicating that conduction velocity for most interhemispheric communication is relatively constant regardless of brain size. The largest axons within the upper 95th percentile scaled with a progressively higher exponent than the median axons towards the posterior region of the CC. While brain mass among the primates in our analysis varied by 97-fold, estimates of the fastest cross-brain conduction times, as conveyed by axons at the 95th percentile, varied within a relatively narrow range between 3 and 9 ms across species, whereas cross-brain conduction times for the median axon diameters differed more substantially between 11 and 38 ms. Nonetheless, for both size classes of axons, an increase in diameter does not entirely compensate for the delay in interhemispheric transmission time that accompanies larger brain size. Such biophysical constraints on the processing speed of axons conveyed by the CC may play an important role in the evolution of hemispheric asymmetry. PMID- 26511048 TI - Polyspermy in birds: sperm numbers and embryo survival. AB - Polyspermy is a major puzzle in reproductive biology. In some taxa, multiple sperm enter the ovum as part of the normal fertilization process, whereas in others, penetration of the ovum by more than one sperm is lethal. In birds, several sperm typically enter the germinal disc, yet only one fuses with the female pronucleus. It is unclear whether supernumerary sperm play an essential role in the avian fertilization process and, if they do, how females regulate the progression of sperm through the oviduct to ensure an appropriate number reach the ovum. Here, we show that when very few sperm penetrate the avian ovum, embryos are unlikely to survive beyond the earliest stages of development. We also show that when the number of inseminated sperm is limited, a greater proportion than expected reach and penetrate the ovum, indicating that females compensate for low sperm numbers in the oviduct. Our results suggest a functional role for supernumerary sperm in the processes of fertilization and early embryogenesis, providing an exciting expansion of our understanding of sperm function in birds. PMID- 26511049 TI - Cambrian cinctan echinoderms shed light on feeding in the ancestral deuterostome. AB - Reconstructing the feeding mode of the latest common ancestor of deuterostomes is key to elucidating the early evolution of feeding in chordates and allied phyla; however, it is debated whether the ancestral deuterostome was a tentaculate feeder or a pharyngeal filter feeder. To address this, we evaluated the hydrodynamics of feeding in a group of fossil stem-group echinoderms (cinctans) using computational fluid dynamics. We simulated water flow past three dimensional digital models of a Cambrian fossil cinctan in a range of possible life positions, adopting both passive tentacular feeding and active pharyngeal filter feeding. The results demonstrate that an orientation with the mouth facing downstream of the current was optimal for drag and lift reduction. Moreover, they show that there was almost no flow to the mouth and associated marginal groove under simulations of passive feeding, whereas considerable flow towards the animal was observed for active feeding, which would have enhanced the transport of suspended particles to the mouth. This strongly suggests that cinctans were active pharyngeal filter feeders, like modern enteropneust hemichordates and urochordates, indicating that the ancestral deuterostome employed a similar feeding strategy. PMID- 26511050 TI - Inter-allelic interactions play a major role in microsatellite evolution. AB - Microsatellite mutations identified in pedigrees confirm that most changes involve the gain or loss of single repeats. However, an unexpected pattern is revealed when the resulting data are plotted on standardized scales that range from the shortest to longest allele at a locus. Both mutation rate and mutation bias reveal a strong dependency on allele length relative to other alleles at the same locus. We show that models in which alleles mutate independently cannot explain these patterns. Instead, both mutation probability and direction appear to involve interactions between homologues in heterozygous individuals. Simple models in which the longer homologue in heterozygotes is more likely to mutate and/or biased towards contraction readily capture the observed trends. The exact model remains unclear in all its details but inter-allelic interactions are a vital component, implying a link between demographic history and the mode and tempo of microsatellite evolution. PMID- 26511051 TI - Multi-trait mimicry and the relative salience of individual traits. AB - Mimicry occurs when one species gains protection from predators by resembling an unprofitable model species. The degree of mimic-model similarity is variable in nature and is closely related to the number of traits that the mimic shares with its model. Here, we experimentally test the hypothesis that the relative salience of traits, as perceived by a predator, is an important determinant of the degree of mimic-model similarity required for successful mimicry. We manipulated the relative salience of the traits of a two-trait artificial model prey, and subsequently tested the survival of mimics of the different traits. The unrewarded model prey had two colour traits, black and blue, and the rewarded prey had two combinations of green, brown and grey shades. Blue tits were used as predators. We found that the birds perceived the black and blue traits to be similarly salient in one treatment, and mimic-model similarity in both traits was then required for high mimic success. In a second treatment, the blue trait was the most salient trait, and mimic-model similarity in this trait alone achieved high success. Our results thus support the idea that similar salience of model traits can explain the occurrence of multi-trait mimicry. PMID- 26511052 TI - Functional significance of dinitrogen fixation in sustaining coral productivity under oligotrophic conditions. AB - Functional traits define species by their ecological role in the ecosystem. Animals themselves are host-microbe ecosystems (holobionts), and the application of ecophysiological approaches can help to understand their functioning. In hard coral holobionts, communities of dinitrogen (N2)-fixing prokaryotes (diazotrophs) may contribute a functional trait by providing bioavailable nitrogen (N) that could sustain coral productivity under oligotrophic conditions. This study quantified N2 fixation by diazotrophs associated with four genera of hermatypic corals on a northern Red Sea fringing reef exposed to high seasonality. We found N2 fixation activity to be 5- to 10-fold higher in summer, when inorganic nutrient concentrations were lowest and water temperature and light availability highest. Concurrently, coral gross primary productivity remained stable despite lower Symbiodinium densities and tissue chlorophyll a contents. In contrast, chlorophyll a content per Symbiodinium cell increased from spring to summer, suggesting that algal cells overcame limitation of N, an essential element for chlorophyll synthesis. In fact, N2 fixation was positively correlated with coral productivity in summer, when its contribution was estimated to meet 11% of the Symbiodinium N requirements. These results provide evidence of an important functional role of diazotrophs in sustaining coral productivity when alternative external N sources are scarce. PMID- 26511053 TI - The survival-reproduction association becomes stronger when conditions are good. AB - Positive covariations between survival and reproductive performance (S-R covariation) are generally interpreted in the context of fixed or dynamic demographic heterogeneity (i.e. persistent differences between individuals, or dynamic variation in resource acquisition), but the processes underlying covariations are still unknown. We used multi-event modelling to investigate how environmental and individual features influence S-R covariation patterns in a long-lived seabird, the Monteiro's storm petrel (Oceanodroma monteiroi). Our analysis reveals that a strong positive association between individual breeding success and subsequent survival occurs only when conditions are favourable to reproduction (in favourable years, in high-quality nests and in nest-faithful breeders). This finding reflects differences in the main causes of breeding failure and mortality under favourable and unfavourable conditions, which in turn lead to distinct patterns of S-R covariation. We suggest, in particular, that resource-related sources of demographic heterogeneity do not generate a strong S R covariation, in contrast with hidden and unpredictable sources of variation. PMID- 26511054 TI - Geographical variation in species' population responses to changes in temperature and precipitation. AB - Despite increasing concerns about the vulnerability of species' populations to climate change, there has been little overall synthesis of how individual population responses to variation in climate differ between taxa, with trophic level or geographically. To address this, we extracted data from 132 long-term (greater than or equal to 20 years) studies of population responses to temperature and precipitation covering 236 animal and plant species across terrestrial and freshwater habitats. Our results identify likely geographical differences in the effects of climate change on populations and communities in line with macroecological theory. Temperature tended to have a greater overall impact on populations than precipitation, although the effects of increased precipitation varied strongly with latitude, being most positive at low latitudes. Population responses to increased temperature were generally positive, but did not vary significantly with latitude. Studies reporting significant climatic trends through time tended to show more negative effects of temperature and more positive effects of precipitation upon populations than other studies, indicating climate change has already impacted many populations. Most studies of climate change impacts on biodiversity have focused on temperature and are from middle to high northern latitudes. Our results suggest their findings may be less applicable to low latitudes. PMID- 26511055 TI - The nature and dynamics of world religions: a life-history approach. AB - In contrast with tribal and archaic religions, world religions are characterized by a unique emphasis on extended prosociality, restricted sociosexuality, delayed gratification and the belief that these specific behaviours are sanctioned by some kind of supernatural justice. Here, we draw on recent advances in life history theory to explain this pattern of seemingly unrelated features. Life history theory examines how organisms adaptively allocate resources in the face of trade-offs between different life-goals (e.g. growth versus reproduction, exploitation versus exploration). In particular, recent studies have shown that individuals, including humans, adjust their life strategy to the environment through phenotypic plasticity: in a harsh environment, organisms tend to adopt a 'fast' strategy, pursuing smaller but more certain benefits, while in more affluent environments, organisms tend to develop a 'slow' strategy, aiming for larger but less certain benefits. Reviewing a range of recent research, we show that world religions are associated with a form of 'slow' strategy. This framework explains both the promotion of 'slow' behaviours such as altruism, self regulation and monogamy in modern world religions, and the condemnation of 'fast' behaviours such as selfishness, conspicuous sexuality and materialism. This ecological approach also explains the diffusion pattern of world religions: why they emerged late in human history (500-300 BCE), why they are currently in decline in the most affluent societies and why they persist in some places despite this overall decline. PMID- 26511056 TI - Quality of Life After Treatment with Autologous Bone Marrow Derived Cells in No Option Severe Limb Ischemia. AB - OBJECTIVE: Quality of life (QoL) is an important outcome in evaluating treatment effect in severe limb ischemia. The randomized, double blind, placebo controlled JUVENTAS trial, investigating the effect of bone marrow derived mononuclear cell (BMMNC) administration in no option severe limb ischemia, showed an improved QoL at 6 months compared with baseline in both the treatment and placebo groups. The aim of the present study was to evaluate whether the improved QoL persisted beyond 6 months' follow up, whether this differed in both trial arms, and if major amputation influenced QoL. METHODS: Short form 36 (SF-36) and EuroQol 5D (EQ5D), including the EQ Visual Analogue Scale (EQ-VAS), questionnaires were sent to JUVENTAS trial participants. In the JUVENTAS trial, a norm based scoring method was applied to report the results of the SF-36. The results of the long term follow up were compared with baseline and 6 month follow up and the results of both trial arms were compared, as were the results of patients with and without amputation. RESULTS: One hundred and nine patients (86.5% of surviving patients) responded to the questionnaires. Median follow up after inclusion was 33 months (interquartile range [IQR] 21.2-50.6) for the BMMNC and 36 months (IQR 21.4-50.9) for the placebo group. The improvement in QoL at 6 months persisted in both arms at a median follow up of 35 months. The long-term QoL did not differ between the BMMNC and placebo group in any of the SF-36 or EQ5D domains. Patients with and without a major amputation had similar QoL scores. CONCLUSIONS: The increased QoL in patients with no option severe limb ischemia persisted until 3 years after inclusion, but did not differ between the BMMNC and placebo arms or between patients with and without a major amputation. PMID- 26511057 TI - Innate immunity of surfactant proteins A and D in urinary tract infection with uropathogenic Escherichia coli. AB - To investigate the effects of surfactant proteins A and D (SP-A and SP-D, respectively) in urinary tract infection (UTI), SP-A and SP-D double knockout (SP A/D KO) and wild type (WT) C57BL/6 female mice were infected with uropathogenic Escherichia coli by intravesical inoculation. Compared with WT mice SP-A/D KO mice showed increased susceptibility to UTI, as evidenced by higher bacterial CFU, more infiltrating neutrophils and severe pathological changes. Keratinocyte derived chemokine increased in the kidney of WT mice but not in SP-A/D KO mice 24 h post-infection. Compared with control, the level of IL-17 was elevated in the kidney of infected WT and SP-A/D KO mice and the level of IL-17 was higher in the infected SP-A/D KO mice than in infected WT mice 24 and 48 h post-infection. The basal level of p38 MAPK phosphorylation in SP-A/D KO mice was higher than in WT mice. The phosphorylated p38 level was elevated in the kidney of WT mice post infection but not in SP-A/D KO mice. Furthermore, in vitro growth of uropathogenic E. coli was inhibited by SP-A and SP-D. We conclude that SP-A and SP-D function as mediators of innate immunity by inhibiting bacterial growth and modulating renal inflammation in part by regulating p38 MAPK-related pathway in murine UTI. PMID- 26511059 TI - Satisfaction and responsiveness with health-care services in Qatar--evidence from a survey. AB - BACKGROUND: Satisfaction and responsiveness with health care are some of the main outcome variables of a health system. Although health outcomes have been studied in countries with different levels of economic development, there is limited information on the health provision/satisfaction/responsiveness nexus in countries where rapid transitions from middle to high-income status have occurred. METHODS: Using a 2012 survey conducted in Qatar (amongst both Qatari and non-Qatari respondents), we analysed satisfaction and responsiveness of health care. The sample consisted of 4083 respondents. We use logit analysis [as well as robustness checks involving ordered logit, ordered probit, ordinary least squares (OLS) and probit analysis] in order to estimate the determinants of satisfaction and responsiveness. RESULTS: Both, satisfaction and responsiveness rates were high. Gender, nationality and, to some extent, income and age were significant sociodemographic determinants of satisfaction, with non-Qataris and females, having higher levels of satisfaction. Cost, previous experience with the same health provider and provision of medical insurance for a particular health provider were the attributes significantly correlated with general satisfaction. The results are consistent when the analysis is applied to the correlates of responsiveness. CONCLUSIONS: Sociodemographic factors explain the satisfaction with quality of health care in the state of Qatar (both from the general population point of view and from the patient point of view). PMID- 26511058 TI - Modulation of host defense peptide-mediated human mast cell activation by LPS. AB - Human beta-defensin3 (hBD3) and the cathelicidin LL-37 are host defense peptides (HDPs) that directly kill microbes and display immunomodulatory/wound-healing properties via the activation of chemokine, formylpeptide and epidermal growth factor receptors on leukocytes and epithelial cells. A C-terminal 14 amino acid hBD3 peptide with all Cys residues replaced with Ser (CHRG01) and an LL-37 peptide consisting of residues 17-29 (FK-13) display antimicrobial activity but lack immunomodulatory property. Surprisingly, we found that CHRG01 and FK-13 caused Ca(2+) mobilization and degranulation in human mast cells via a novel G protein-coupled receptor known as Mas-related gene-X2 (MrgX2). At local sites of bacterial infection, the negatively charged LPS likely interacts with cationic HDPs to inhibit their activity and thus providing a mechanism for pathogens to escape host defense mechanisms. We found that LPS caused almost complete inhibition of hBD3 and LL-37-induced Ca(2+) mobilization and mast cell degranulation. In contrast, it had no effect on CHRG01 and FK-13-induced mast cell responses. These findings suggest that HDP derivatives that kill microbes, harness mast cell's host defense and wound-healing properties via the activation of MrgX2 but are resistant to inhibition by LPS could be utilized for the treatment of antibiotic-resistant microbial infections. PMID- 26511060 TI - Obstetric Anaesthetists' Association/Difficult Airway Society difficult and failed tracheal intubation guidelines--the way forward for the obstetric airway. PMID- 26511061 TI - Review and comparison of clinical evidence submitted to support European Medicines Agency market authorization of orphan-designated oncological treatments. AB - BACKGROUND: Clinical trials for treatments indicated for orphan diseases may be limited due to the low prevalence of such diseases; this can result in implications for both regulatory and health economic perspectives. This study assessed the pivotal clinical evidence packages submitted to support applications for European Medicines Agency (EMA) marketing authorizations for treatments for orphan conditions, in relation to the size of the eligible patient population. METHODS: Approved treatments for EMA-designated orphan conditions (defined as life-threatening or chronically debilitating conditions that affect <=5/10,000 people) were identified from the EMA web site. All treatments reviewed were included in anatomical therapeutic chemical (ATC) category L (antineoplastic and immunomodulating drugs): this category was selected because it is the largest ATC category, containing almost 50% of all approved orphan-designated products. Treatments were reviewed if they had been approved within the past 7 years and had been evaluated in a controlled trial using at least one survival-based clinical endpoint. Treatments were compared in terms of patient-years (accumulated duration of follow-up), the number of patients in the pivotal trials and disease prevalence. RESULTS: As of 1 February 2014, 68 treatments had been approved for orphan-designated conditions, of which 30 belonged to ATC category L and 14 met all inclusion criteria. The number of patients in the pivotal trials ranged from 162 to 846 (median 485). In terms of patient-years, the longest duration of follow-up was seen in the pivotal trial of mifamurtide in osteosarcoma, which had 4068 patient-years; excluding this trial, follow-up ranged from 308 to 2906 patient-years (median 1796 years). Osteosarcoma had the second smallest eligible patient population (0.5/10,000 persons) of the reviewed treatments. CONCLUSIONS: Clinical trials of orphan treatments are often limited by low patient numbers and inadequate follow-up. Pooling of expertise in single centres and the establishment of rare disease reference networks and patient registries may facilitate appropriate trial design for orphan-designated treatments. This analysis found that the pivotal clinical trial for mifamurtide in osteosarcoma had the largest number of patient-years of follow-up, despite a small eligible patient population, showing that it is possible to conduct studies with an adequate patient population size and duration of follow-up in patient years, and a comparative design with clinical, survival-based, endpoints. PMID- 26511062 TI - A study on the wake-up effect of ferroelectric Hf0.5Zr0.5O2 films by pulse switching measurement. AB - The appearance of ferroelectric (FE) and anti-ferroelectric (AFE) properties in HfO2-based thin films is highly intriguing in terms of both the scientific context and practical application in various electronic and energy-related devices. Interestingly, these materials showed a "wake-up effect", which refers to the increase in remanent polarization with increasing electric field cycling number before the occurrence of the fatigue effect. In this work, the wake-up effect from Hf0.5Zr0.5O2 was carefully examined by the pulse-switching experiment. In the pristine state, the Hf0.5Zr0.5O2 film mostly showed FE-like behavior with a small contribution from AFE-like distortion, which could be ascribed to the involvement of the AFE phase. The field cycling of only 100 cycles almost completely transformed the AFE phase into the FE phase by depinning the pinned domains. The influence of field cycling on the interfacial layer was also examined through the pulse-switching experiments. PMID- 26511063 TI - LFP-guided targeting of a cortical barrel column for in vivo two-photon calcium imaging. AB - Two-photon microscopy of bulk-loaded functional dyes is an outstanding physiological technique that enables simultaneous functional mapping of hundreds of brain cells in vivo at single-cell resolution. However, precise targeting of a specific cortical location is not easy due to its fine dimensionality. To enable precise targeting, intrinsic-signal optical imaging is often additionally performed. However, the intrinsic-signal optical imaging is not only time consuming but also ineffective in ensuring precision. Here, we propose an alternative method for precise targeting based on local field potential (LFP) recording, a conventional electrophysiological method. The heart of this method lies in use of the same glass pipette to record LFPs and to eject calcium dye. After confirming the target area by LFP using a glass pipette, the calcium dye is ejected from the same pipette without a time delay or spatial adjustment. As a result, the calcium dye is loaded into the same ensemble of brain cells from which the LFP was obtained. As a validation of the proposed LFP-based method, we targeted and successfully loaded calcium dye into layer 2/3 of a mouse barrel column. PMID- 26511064 TI - Superadiabatic Controlled Evolutions and Universal Quantum Computation. AB - Adiabatic state engineering is a powerful technique in quantum information and quantum control. However, its performance is limited by the adiabatic theorem of quantum mechanics. In this scenario, shortcuts to adiabaticity, such as provided by the superadiabatic theory, constitute a valuable tool to speed up the adiabatic quantum behavior. Here, we propose a superadiabatic route to implement universal quantum computation. Our method is based on the realization of piecewise controlled superadiabatic evolutions. Remarkably, they can be obtained by simple time-independent counter-diabatic Hamiltonians. In particular, we discuss the implementation of fast rotation gates and arbitrary n-qubit controlled gates, which can be used to design different sets of universal quantum gates. Concerning the energy cost of the superadiabatic implementation, we show that it is dictated by the quantum speed limit, providing an upper bound for the corresponding adiabatic counterparts. PMID- 26511065 TI - Ancient mitochondrial genome reveals trace of prehistoric migration in the east Pamir by pastoralists. AB - The complete mitochondrial genome of one 700-year-old individual found in Tashkurgan, Xinjiang was target enriched and sequenced in order to shed light on the population history of Tashkurgan and determine the phylogenetic relationship of haplogroup U5a. The ancient sample was assigned to a subclade of haplogroup U5a2a1, which is defined by two rare and stable transversions at 16114A and 13928C. Phylogenetic analysis shows a distribution pattern for U5a2a that is indicative of an origin in the Volga-Ural region and exhibits a clear eastward geographical expansion that correlates with the pastoral culture also entering the Eurasian steppe. The haplogroup U5a2a present in the ancient Tashkurgan individual reveals prehistoric migration in the East Pamir by pastoralists. This study shows that studying an ancient mitochondrial genome is a useful approach for studying the evolutionary process and population history of Eastern Pamir. PMID- 26511066 TI - The paternal ancestry of Uttarakhand does not imitate the classical caste system of India. AB - Although, there have been rigorous research on the Indian caste system by several disciplines, it is still one of the most controversial socioscientific topic. Previous genetic studies on the subcontinent have supported a classical hierarchal sharing of genetic component by various castes of India. In the present study, we have used high-resolution mtDNA and Y chromosomal markers to characterize the genetic structuring of the Uttarakhand populations in the context of neighboring regions. Furthermore, we have tested whether the genetic structuring of caste populations at different social levels of this region, follow the classical chaturvarna system. Interestingly, we found that this region showed a high level of variation for East Eurasian ancestry in both maternal and paternal lines of descent. Moreover, the intrapopulation comparison showed a high level of heterogeneity, likely because of different caste hierarchy, interpolated on asymmetric admixture of populations inhabiting on both sides of the Himalayas. PMID- 26511067 TI - Interaction of vitamin A supplementation level with ADH1C genotype on intramuscular fat in beef steers. AB - Previously, the single nucleotide polymorphism in alcohol dehydrogenase (ADH1C c. 64T>C) was shown to have an association with intramuscular fat (IMF) in the longissimus thoracis (LT) muscle when vitamin A was limited in finishing rations of beef steers. The purpose of this study was to determine the optimum vitamin A supplementation level, in combination with ADH1C genotype, to increase IMF of the LT muscle. In total, 45 TT genotype, 45 CT and 27 CC Black Angus crossbred steers were backgrounded on a commercial ration containing 3360 IU vitamin A/kg dry matter (DM). During finishing, the steers were randomly assigned to one of three vitamin A treatments at 25%, 50% and 75% of the National Research Council recommendation of 2200 IU/kg DM. Treatments were administered via an oral bolus. Carcass quality was evaluated and a sample from the LT muscle was collected for analysis of IMF. A treatment*genotype interaction (P=0.04) was observed for IMF; TT steers on the 75% treatment had higher IMF relative to CT and CC steers on the same treatment. Western blot analysis showed that TT steers had higher (P=0.02) ADH1C protein expression in hepatic tissue. Previously, TT steers exhibited increased IMF when fed limited vitamin A. In the current study, the lack of variation in IMF between treatments and genotypes at the lower vitamin A treatment levels was likely due to the majority of the steers grading Canada AAA (USDA Choice). However, the western blot data supports that TT steers are expected to have higher IMF deposition, due to an increased production of ADH1C. The interaction between ADH1C genotype and vitamin A supplementation level has the potential for use in marker-assisted management programs to target niche markets based on increased marbling. PMID- 26511068 TI - Risk of major bleeding in patients with venous thromboembolism treated with rivaroxaban or with heparin and vitamin K antagonists. AB - The study aim was to identify predictive factors for major bleeding in patients receiving the novel oral factor Xa inhibitor rivaroxaban or enoxaparin-vitamin K antagonists (VKAs) for the treatment of acute symptomatic venous thromboembolism. We analysed data from patients included in the phase III EINSTEIN DVT and EINSTEIN PE studies. Factors associated with major bleeding events were assessed with best subset variable selection using Cox proportional hazards regression model. Three time windows were considered, i.e. the initial three weeks, after the third week onwards, and the entire duration of the anticoagulant treatment. Model discrimination was estimated using the C-statistic and validated internally by bootstrap techniques. Major bleeding occurred in 40 (1.0%) of 4130 patients receiving rivaroxaban and in 72 (1.7%) of 4116 receiving enoxaparin/VKAs, with 44% of the major bleeding events occurring in the first three weeks of treatment. Significant risk factors for major bleeding were older age, black race, low haemoglobin concentrations, active cancer, and antiplatelet or non-steroidal anti inflammatory drug therapy. The discrimination of the model for major bleeding was high for the first three weeks (C-statistic 0.73), from the fourth week onwards (C-statistic 0.68), and the entire period of anticoagulant treatment (C-statistic 0.74). This analysis identified risk factors for major bleeding in patients receiving the novel oral anticoagulant rivaroxaban or enoxaparin/VKAs for the treatment of acute venous thromboembolism. The prognostic model based on the combination of identified risk factors may be informative to estimate the risk of major bleeding both during the initial and later phases of anticoagulation. PMID- 26511069 TI - Rational approach to an antiprion compound with a multiple mechanism of action. AB - BACKGROUND: The main pathogenic event of prion disorders has been identified in the deposition of the disease-associated prion protein (PrP(Sc)), which is accompanied by metal dyshomeostasis. RESULTS: The multitarget-directed ligand 1, designed by combining a heteroaromatic prion recognition motif to an 8 hydroxyquinoline metal chelator, has been developed as a potential antiprion disease-modifying agent. Importantly, 1 was found to effectively clear PrP(Sc) from scrapie-infected cells, and, at the same time, inhibit metal-induced prion aggregation and reactive oxygen species generation. 1 was also characterized in terms of pharmacokinetic properties in a preliminary in vitro investigation. CONCLUSION: Compound 1 has emerged as a suitable lead candidate against prion diseases and as a good starting point for a further optimization process. PMID- 26511070 TI - Hydroalcoholic extract of red propolis promotes functional recovery and axon repair after sciatic nerve injury in rats. AB - CONTEXT: Peripheral axon injury and degeneration are often mediated by oxidative stress and inflammation. The hydroalcoholic extract of the red propolis (HERP) has attracted great attention because of its antioxidant and anti-inflammatory activities. OBJECTIVE: The objective of this work is to study the effect of HERP on nerve repair and functional recovery after sciatic nerve injury (SNI) in rats. MATERIALS AND METHODS: The chemical markers in HERP were identified using high resolution mass spectroscopy. After axonotmesis of sciatic nerve, ibuprofen (IBP) and HERP treatments were orally administered for 28 d. Behavioural tests were performed weekly after SNI. The myelinated axon number was counted using morphometric analysis. RESULTS: The compounds found in HERP were pinocembrin, formononetin, vestitol, and biochanin A. The animals that underwent SNI showed a significant decrease in motor function based on the Basso, Beattie and Bresnahan scale and sciatic functional index compared with sham animals until 7 d after the surgery (p < 0.05). After 14 and 21 d, the SNI groups treated with either HERP or IBP showed significant improvement (p < 0.01), and the SNI group treated with HERP 10 mg/kg showed accelerated motor recovery compared with the other groups (p < 0.01). SNI caused also a reduction in the myelinated axon counts, and treatment with HERP 10 mg/kg induced a significant increase in the number of myelinated fibres compared with all other groups. CONCLUSION: HERP promoted regenerative responses and accelerated functional recovery after sciatic nerve crush. Thus, it can be considered to be a new strategy or complementary therapy for treating nerve injuries. PMID- 26511071 TI - An introduction to MS imaging in drug discovery and development. AB - A vital process in drug discovery and development is to assess the absorption, distribution, metabolism, excretion and toxicology of potentially therapeutic compounds in the body. The potential utility of MS imaging has been demonstrated in many studies focusing on molecules including peptides, proteins and lipids. However, MS imaging also permits the direct analysis of drugs and drug metabolites in tissue samples without requiring the use of target-specific labels or reagents. Here, a brief technical description of the technique is presented along with examples of its usefulness at different stages of the drug discovery and development process including absorption, distribution, metabolism, excretion and toxicology, and blood-brain barrier drug penetration investigations. PMID- 26511072 TI - Group G streptococci mediate fibrinogen-dependent platelet aggregation leading to transient entrapment in platelet aggregates. AB - Platelets have been reported to become activated in response to bacteria and this is proposed to contribute to the acute response to bacterial infection. In the present study, we investigated platelet aggregation in response to group G streptococci (GGS) in vitro in healthy human donors and in vivo in a mouse model of streptococcal sepsis. Platelet aggregation by GGS was dependent on the bacterial surface protein FOG and engagement of the platelet fibrinogen receptor; however, it was independent of IgG and the platelet Fc receptor. Platelets exerted no antibacterial effects on the bacteria, and aggregates formed were markedly unstable, allowing bacteria to rapidly return to the plasma and grow post-aggregation. Thrombocytopenia and platelet activation occurred during invasive infection with GGS, and platelets were demonstrated to contribute to bacterial dissemination during infection. These findings reveal an important role for bacteria-platelet interactions during the pathogenesis of streptococcal infection. PMID- 26511073 TI - Dynamics of Ice/Water Confined in Nanoporous Alumina. AB - Dielectric (DS), IR spectroscopy, and (1)H MAS NMR are employed in the study of ice/water confined in nanoporous alumina with pore diameters ranging from 400 nm down to 25 nm. Within nanoporous alumina there is a transformation from heterogeneous nucleation of hexagonal ice in the larger pores to homogeneous nucleation of cubic ice in the smaller pores. DS and IR show excellent agreement in the temperature interval and pore size dependence of the transformation. DS further revealed two dynamic processes under confinement. The "fast" and "slow" processes with an Arrhenius temperature dependence are attributed to ice and supercooled water relaxation, respectively. The main relaxation process of ice under confinement ("slow" process) has an activation energy of 44 +/- 2 kJ/mol. The latter is in agreement with the reported relaxation times and activation energy of cubic ice prepared following a completely different route (by pressure). (1)H MAS NMR provided new insight in the state of ice structures as well as of supercooled water. Under confinement, a layer of liquid-like water coexists with ice structures. In addition, both ice structures under confinement appear to be more ordered than bulk hexagonal ice. Supercooled water in the smaller pores is different from bulk water. It shows a shift of the signal toward higher chemical shift values which may suggest stronger hydrogen bonding between the water molecules or increasing interactions with the AAO walls. PMID- 26511075 TI - Efficient Electron Injection by Size- and Shape-Controlled Zinc Oxide Nanoparticles in Organic Light-Emitting Devices. AB - Three different sized zinc oxide (ZnO) nanoparticles were synthesized as spherical ZnO (S-ZnO), rodlike ZnO (R-ZnO), and intermediate shape and size ZnO (I-ZnO) by controlling the reaction time. The average sizes of the ZnO nanoparticles were 4.2 nm * 3.4 nm for S-ZnO, 9.8 nm * 4.5 nm for I-ZnO, and 20.6 nm * 6.2 nm for R-ZnO. Organic light-emitting devices (OLEDs) with these ZnO nanoparticles as the electron injection layer (EIL) were fabricated. The device with I-ZnO showed lower driving voltage and higher power efficiency than those with S-ZnO and R-ZnO. The superiority of I-ZnO makes it very effective as an EIL for various types of OLEDs regardless of the deposition order or method of fabricating the organic layer, the ZnO layer, and the electrode. PMID- 26511074 TI - Coagulation activation in sickle cell trait: an exploratory study. AB - Recent epidemiologic data suggest that sickle cell trait (HbAS; AS) is a risk factor for venous thromboembolism. We conducted an exploratory study of healthy subjects with AS under baseline conditions to determine whether a chronic basal hyperactivation of coagulation exists, and if so, what mechanism(s) contribute to this state. Eighteen healthy AS individuals were compared to 22 African-American controls with a normal haemoglobin profile (HbAA; AA) and 17 patients with sickle cell disease (HbSS; SS). Plasma thrombin-antithrombin complexes and D-dimer levels were elevated in AS relative to AA patients (P = 0.0385 and P = 0.017, respectively), and as expected, were much higher in SSversusAA (P < 0.0001 for both). Thrombin generation in platelet poor plasma was indistinguishable between AA and AS subjects, whereas a paradoxical decrease in endogenous thrombin potential was observed in SS (P <= 0.0001). Whole blood tissue factor was elevated in SS compared to AA (P = 0.005), but did not differ between AA and AS. Plasma microparticle tissue factor activity was non-significantly elevated in AS (P = 0.051), but was clearly elevated in SS patients (P = 0.004) when compared to AA controls. Further studies in larger cohorts of subjects with sickle cell trait are needed to confirm the results of this preliminary investigation. PMID- 26511076 TI - Group 1 and group 2 metal complexes supported by a bidentate bulky iminopyrrolyl ligand: synthesis, structural diversity, and epsilon-caprolactone polymerization study. AB - We report here a series of alkali and alkaline earth metal complexes, each with a bulky iminopyrrolyl ligand [2-(Ph3CN=CH)C4H3NH] (1-H) moiety in their coordination sphere, synthesized using either alkane elimination or silylamine elimination methods or the salt metathesis route. The lithium salt of molecular composition [Li(2-(Ph3CN=CH)C4H3N)(THF)2] (2) was prepared using the alkane elimination method, and the silylamine elimination method was used to synthesize the dimeric sodium and tetra-nuclear potassium salts of composition [(2 (Ph3CN=CH)C4H3N)Na(THF)]2 (3) and [(2-(Ph3CN=CH)C4H3N)K(THF)0.5]4 (4) respectively. The magnesium complex of composition [(THF)2Mg(CH2Ph){2 (Ph3CN=CH)C4H3N}] (5) was synthesized through the alkane elimination method, in which [Mg(CH2Ph)2(OEt2)2] was treated with the bulky iminopyrrole ligand 1-H in 1 : 1 molar ratio, whereas the bis(iminopyrrolyl)magnesium complex [(THF)2Mg{2 (Ph3CN=CH)C4H3N}2] (6) was isolated using the salt metathesis route. The heavier alkaline earth metal complexes of the general formula {(THF)nM(2 (Ph3CN=CH)C4H3N)2} [M = Ca (7), Sr (8), and n = 2; M = Ba (9), n = 3] were prepared in pure form using two synthetic methods: in the first method, the bulky iminopyrrole ligand 1-H was directly treated with the alkaline earth metal precursor [M{N(SiMe3)2}2(THF)n] (where M = Ca, Sr and Ba) in 2 : 1 molar ratio in THF solvent at ambient temperature. The complexes 7-9 were also obtained using the salt metathesis reaction, which involves the treatment of the potassium salt (4) with the corresponding metal diiodides MI2 (M = Ca, Sr and Ba) in 2 : 1 molar ratio in THF solvent. The molecular structures of all the metal complexes (1-H, 2 9) in the solid state were established through single-crystal X-ray diffraction analysis. The complexes 5-9 were tested as catalysts for the ring-opening polymerization of epsilon-caprolactone. High activity was observed in the heavier alkaline earth metal complexes 7-9, with a very narrow polydispersity index in comparison to that of magnesium complexes 5 and 6. PMID- 26511077 TI - Psychological distress in Rome III functional dyspepsia patients presenting for testing of gastric emptying. AB - BACKGROUND: There have been conflicting results from studies that have evaluated psychological disturbances in functional dyspepsia (FD). We conducted a comprehensive survey of psychological measures in patients undergoing gastric emptying testing (GET) in order to determine the relationship among psychological distress, gastric emptying, and dyspeptic symptoms. METHODS: Consecutive patients referred for GET were prospectively enrolled. Details regarding patient characteristics, health care utilization, dyspeptic symptoms, quality of life, and psychological dysfunction were obtained. Depression, anxiety, somatization, stress, positive and negative affect, and alexithymia were queried using validated questionnaires. We compared those dyspeptic patients who met Rome III criteria for FD to those who did not meet these criteria. KEY RESULTS: Two hundred and nine patients (160 female; mean age 46.6 years +/- 17.3 years) participated. Around 151 patients (72%) met Rome III criteria for FD. In the entire group, a high level of depression, anxiety, somatization, and perceived stress was present compared to population norms. Health care seeking behavior and symptom severity were greater in those with FD and quality of life was lower compared to non-FD. Gastric emptying did not differentiate the two groups and similar degrees of psychological distress were present whether emptying was delayed or normal. CONCLUSIONS & INFERENCES: In patients referred for GET, substantial psychological distress is present. The degree of distress was similar regardless of whether the patient met Rome III FD criteria or not. Further evaluation of psychological dysfunction in FD patients may lead to improved diagnosis and determination of the most appropriate treatment. PMID- 26511078 TI - Order of stimulus presentation influences children's acquisition in receptive identification tasks. AB - Receptive identification is usually taught in matching-to-sample format, which entails the presentation of an auditory sample stimulus and several visual comparison stimuli in each trial. Conflicting recommendations exist regarding the order of stimulus presentation in matching-to-sample trials. The purpose of this study was to compare acquisition in receptive identification tasks under 2 conditions: when the sample was presented before the comparisons (sample first) and when the comparisons were presented before the sample (comparison first). Participants included 4 typically developing kindergarten-age boys. Stimuli, which included birds and flags, were presented on a computer screen. Acquisition in the 2 conditions was compared in an adapted alternating-treatments design combined with a multiple baseline design across stimulus sets. All participants took fewer trials to meet the mastery criterion in the sample-first condition than in the comparison-first condition. PMID- 26511079 TI - Higher heat shock factor 1 expression in tumor stroma predicts poor prognosis in esophageal squamous cell carcinoma patients. AB - BACKGROUND: Heat shock factor 1 (HSF1) is a powerful, multifaceted modifier of carcinogenesis. However, the clinical significance and biologic function of HSF1 in esophageal squamous cell carcinoma (ESCC) remain unknown. METHODS: HSF1 was detected in ESCC cell lines, fibroblast cell lines and ESCC xenograft tumors and human ESCC tissues by real-time RT-PCR and western blotting. HSF1 protein expression was analyzed by immunochemistry in 134 ESCC patients followed by correlation with clinicopathological parameters. RESULTS: HSF1 expression is weak in fibroblast cell 3T3 and moderate in ESCC cell Eca109, but increasing expression of HSF1 was observed in both of 3T3 and Eca109 cells when they interplayed with each other. In Eca109 xenograft tumors, both tumor cells and stromal fibroblasts showed stronger expression of HSF1. In ESCC patients, the HSF1 expression in tumor or in stromal cells was significantly associated with tumor stage, lymph node metastasis and clinical stage. Multivariate analysis demonstrated a significant negative correlation between disease-free survival (DFS), overall survival (OS) and the HSF1 expression in stromal cells (P < 0.05) but not in tumor cells. Additionally, the expression of HSF1 in tumor cells or stromal cells was an independent factor for DFS (P = 0.032 or P = 0.012) and OS (P = 0.017 or P = 0.013) in metastatic ESCC patients but not for locoregional ESCC. ESCC patients with low HSF1 in both tumor cells and stromal cells had the longest survivals (P < 0.001). CONCLUSIONS: The interaction of tumor cells and stromal fibroblasts increases the expression of HSF1 reciprocally in tumor microenvironment. The HSF1 expression in stromal cells was significantly associated with poor prognosis of ESCC. PMID- 26511080 TI - Ocriplasmin use in a selected case with preserved visual acuity. AB - BACKGROUND: Previous studies described cases of Ocriplasmin injections in patients with vitreo-macular traction and reduced central visual acuity. We describe the first case of a patient with 20/20 visual acuity and vitreo-macular traction treated with Ocriplasmin, and, for the first time in literature, we evaluated the functional changes of the macula in response to pharmacological treatment through multifocal-electroretinogram. CASE PRESENTATION: We report the case of a female Caucasian patient aged 67 years with vitreo-macular traction in the right eye, treated with Ocriplasmin, at the Eye Clinic of the Second University of Naples. Visual acuity was 20/20 before treatment, associated with metamorphopsia. Two weeks after injection, optical coherence tomography showed the release of vitreo-macular traction and multifocal electroretinogram responses showed a significant increase of retinal density responses in all six rings (p < 0.03). Visual acuity remained constant with resolution of symptoms and the appearance of vitreous floaters. CONCLUSION: Intravitreal injection of Ocriplasmin resulted to be a safe and effective treatment in the case here reported. Our data show that the anatomical recovery with release of vitreo macular traction was associated with a full functional recovery. In fact, the electrical retinal density response of the macular area improved two weeks after Ocriplasmin injection. Further studies with broader inclusion criteria for Ocriplasmin treatment (e.g. also with visual acuity higher than 20/25) on a larger study sample are needed to confirm our results. PMID- 26511081 TI - Falsely Elevated Glucose Concentrations in Peritoneal Dialysis Patients Using Icodextrin. AB - BACKGROUND: Peritoneal dialysis (PD) is used as an alternative to hemodialysis in end-stage renal disease (ESRD). Icodextrin has been used as a hyperosmotic agent in PD. The aim of the study was to assess two different point-of-care testing (POCT) glucose strips, affected and not affected by icodextrin, with serum glucose concentrations of the patients using and not using icodextrin. METHODS: Fifty-two chronic ambulatory peritoneal dialysis (CAPD) patients using icodextrin (Extraneal(r)) and 20 CAPD patients using another hyperosmotic fluid (Dianeal(r)) were included in the study. Duplicate capillary and serum glucose concentrations were measured with two different POCT glucose strips and central laboratory hexokinase method. Assay principles of glucose strips were based on glucose dehydrogenase-pyrroloquinoline quinone (GDH-PQQ) and a mutant variant of GDH (Mut Q-GDH). The results of both strips were compared with those of hexokinase method. RESULTS: Regression equations between POCT and hexokinase methods in icodextrin group were y = 2.55x + 1.12 mmol/l and y = 1.057x + 0.16 mmol/l for the GDH-PQQ and Mut Q-GDH methods, respectively. The mean difference between the results of hexokinase and those of GDH-PQQ and Mut Q-GDH in icodextrin group was 3.41 +/- 1.56 and 0.72 +/- 0.64 mmol/l, respectively. However, the mean differences were found much lower in the control group; 0.64 mmol/l for GDH-PQQ and 0.52 mmol/l for Mut Q-GDH. CONCLUSION: Compared to GDH-PQQ, glucose strips of Mut Q-GDH correlated better with hexokinase method in PD patients using icodextrin. PMID- 26511082 TI - Diagnostic Performance of MR-guided Vacuum-Assisted Breast Biopsy: 8 Years of Experience. AB - Breast magnetic resonance imaging (MRI) has demonstrated increased sensitivity over conventional imaging in identifying and characterizing in situ and invasive, multifocal, and multicentric disease. A histologic diagnosis is required for any enhancing lesion displaying suspicious features, especially in the presence of lower and often variable reported specificity values. Breast MRI findings occult on mammography and ultrasound should undergo an MR-guided biopsy. We retrospectively evaluate our 8 years' experience with this procedure. Our study included 259 lesions in 255 consecutive patients referred for MR-guided breast biopsy. MRI screening of women at a high risk for developing breast cancer accounted for 84 lesions, 54 lesions were detected on MRI staging for multifocal and multicentric disease, and 115 were incidental findings or lesions that presented diagnosis related issues on conventional imaging. Six procedures were cancelled due to lack of visualization. MR-guided breast biopsy was performed for 100 mass and 153 nonmass enhancements. Pathology results were classified into benign (113 lesions), high risk (47 lesions), and malignant (40 ductal carcinoma in situ, 38 invasive ductal carcinoma, 15 invasive lobular carcinoma). Subsequent surgery for high risk and malignant findings revealed an underestimation rate of 34% (16/47) for high risk lesions and of 7.5% for ductal carcinoma in situ (3/40). The overall positive predictive value (PPV) was calculated at 43.1% (33.3% for high-risk women, 70.3% for cancer staging, and 37.4% for incidental/undetermined lesions). The PPV was higher for mass (57%) versus nonmass enhancements (34%). MR-guided breast biopsy proved to be a reliable procedure for the diagnosis and management of occult breast MRI findings, or lesions that preclude biopsy under conventional guidance. The PPV displayed significant variation between patient subgroups, correlating higher values with a higher associated breast cancer prevalence. PMID- 26511083 TI - GOTA: GO term annotation of biomedical literature. AB - BACKGROUND: Functional annotation of genes and gene products is a major challenge in the post-genomic era. Nowadays, gene function curation is largely based on manual assignment of Gene Ontology (GO) annotations to genes by using published literature. The annotation task is extremely time-consuming, therefore there is an increasing interest in automated tools that can assist human experts. RESULTS: Here we introduce GOTA, a GO term annotator for biomedical literature. The proposed approach makes use only of information that is readily available from public repositories and it is easily expandable to handle novel sources of information. We assess the classification capabilities of GOTA on a large benchmark set of publications. The overall performances are encouraging in comparison to the state of the art in multi-label classification over large taxonomies. Furthermore, the experimental tests provide some interesting insights into the potential improvement of automated annotation tools. CONCLUSIONS: GOTA implements a flexible and expandable model for GO annotation of biomedical literature. The current version of the GOTA tool is freely available at http://gota.apice.unibo.it. PMID- 26511086 TI - Three-dimensional co-culture of human hepatocytes and mesenchymal stem cells: improved functionality in long-term bioreactor cultures. AB - The development of human cell models that can efficiently restore hepatic functionality and cope with the reproducibility and scalability required for preclinical development poses a significant effort in tissue engineering and biotechnology. Primary cultures of human hepatocytes (HHs), the preferred model for in vitro toxicity testing, dedifferentiate and have short-term viability in two-dimensional (2D) cultures. In this study, hepatocytes isolated from human liver tissue were co-cultured with human bone marrow mesenchymal stem cells (BM MSCs) as spheroids in automated, computer-controlled, stirred-tank bioreactors with perfusion operation mode. A dual-step inoculation strategy was used, resulting in an inner core of parenchymal liver tissue with an outer layer of stromal cells. Hepatocyte polarization and morphology as well as the mesenchymal phenotype of BM-MSCs were maintained throughout the culture period and the crosstalk between the two cell types was depicted. The viability, compact morphology and phenotypic stability of hepatocytes were enhanced in co-cultures in comparison to monocultures. Gene expression of phase I and II enzymes was higher and CYP3A4 and CYP1A2 activity was inducible until week 2 of culture, being applicable for repeated-dose toxicity testing. Moreover, the excretory activity was maintained in co-cultures and the biosynthetic hepatocellular functions (albumin and urea secretion) were not affected by the presence of BM MSCs. This strategy might be extended to other hepatic cell sources and the characterization performed brings knowledge on the interplay between the two cell types, which may be relevant for therapeutic applications. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26511087 TI - Is Boric Acid Toxic to Reproduction in Humans? Assessment of the Animal Reproductive Toxicity Data and Epidemiological Study Results. AB - Boric acid and sodium borates are classified as toxic to reproduction in the CLP Regulation under "Category 1B" with the hazard statement of "H360FD". This classification is based on the reprotoxic effects of boric acid and sodium borates in animal experiments at high doses. However, boron mediated reprotoxic effects have not been proven in epidemiological studies so far. The epidemiological study performed in Bandirma boric acid production plant is the most comprehensive published study in this field with 204 voluntarily participated male workers. Sperm quality parameters (sperm morphology, concentration and motility parameters), FSH, LH and testosterone levels were determined in all participated employees as the reproductive toxicity biomarkers of males. However, boron mediated unfavorable effects on reproduction in male workers have not been determined even in the workers under very high daily boron exposure (0.21 mg B/kg-bw/day) conditions. The NOAEL for rat reproductive toxicity is equivalent to a blood boron level of 2020 ng/g. This level is higher than the mean blood boron concentration (223.89 +/- 69.49 ng/g) of the high exposure group workers in Bandirma boric acid production plant (Turkey) by a factor of 9. Accordingly, classifying boric acid and sodium borates under "Category 1B" as "presumed reproductive human toxicant in the CLP regulation seems scientifically not reasonable. The results of the epidemiological studies (including the study performed in China) support for a down-classification of boric acid from the category 1B, H360FD to category 2, H361d, (suspected of damaging the unborn child). PMID- 26511088 TI - Micro-flow Immunosensor Based on Thin-film Interdigitated Gold Array Microelectrodes for Cancer Biomarker Detection. AB - In this paper, we reported the development of a micro-flow label-free impedimetric biosensor based on the use of thin-film interdigitated gold array microelectrodes (IDA) for the detection of carbohydrate antigen 125 (CA125). The immunosensor is developed through the electropolymerization of anthranilic acid (AA) on the surface of IDA electrodes followed by the covalent attachment of anti CA125 monoclonal antibody. CA125 protein affinity reaction was then evaluated by means of electrochemical impedance spectroscopy (EIS). The sensor was characterized by electrochemical techniques and scanning electron microscopy (SEM). Using the optimized experimental conditions, the developed immunosensor showed a good analytical performance for CA125 detection from 0 to 100 U/mL with estimated limit of detection (LOD = 3Sblank/Slope) of 7 U/mL. PMID- 26511089 TI - Cyclic Peptide Containing Hydrophobic and Positively Charged Residues as a Drug Delivery System for Curcumin. AB - Due to the low water solubility and hydrophobic nature of curcumin, an efficient cellular uptake is critical for its biological activity. We have previously developed a number of homochiral L-cyclic peptides containing arginine and tryptophan as cell-penetrating peptides. Among the synthesized peptides, [WR]5 containing five arginine and five tryptophan residues was found to be the most efficient one. Here, we have compared the application of [WR]5 to improve the intracellular uptake of curcumin by using both peptide-curcumin conjugate and physical mixture (peptide + curcumin) strategies. Flow cytometry results showed that the intracellular uptake of curcumin (50 MUM) was enhanced through the physical mixing with [WR]5 by 5.7 folds compared to that of curcumin alone in human leukemia (CCRFCEM) cells after 3 h. When [WR]5 was conjugated with curcumin, the intracellular uptake was enhanced by 4 fold. These data suggest that the physical mixture can work more efficiently in enhancing the cellular delivery of curcumin. Furthermore, the antiproliferative activity of curcumin was enhanced by 20% and ~13% through the physical mixture and the conjugate, respectively, in CCRF-CEM cells after 72 h. PMID- 26511090 TI - Consensus Guideline Based Therapeutic Drug Monitoring (TDM) in Psychiatry and Neurology. AB - Therapeutic drug monitoring (TDM) is a valuable tool for tailoring the dosage of the prescribed medication(s) to the individual pharmacokinetic characteristics of a patient. In psychiatry and neurology, however, proven evidence that TDM should be used for treatment with the multiple neuropsychiatric medications is restricted to few compounds. Well-designed clinical trials on medical and economic benefits of TDM are rare. The use of TDM is limited in most countries to few antiepileptics, especially carbamazepine, phenobarbital and phenytoin, some mood stabilizers, especially lithium and valproic acid, some antidepressants, especially tricyclic antidepressants and some antipsychotics, primarily clozapine because these drugs have a narrow therapeutic index. On the other hand, specific indications and distinct problems can make TDM most useful for individualized pharmacotherapy with almost any neuropsychiatric drug. Potential benefits of TDM can, however, only be reaped if the method is adequately integrated into the clinical treatment process. The TDM expert group of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued consensus guidelines for the best practice of TDM in psychiatry and neurology. A first version was published in 2004. These guidelines were extended in 2011 and are actually updated (see: www.agnp.de). Exemplified by single cases it is shown here how to use TDM consensus guidelines for problem solving in psychiatry and neurology. Studies on depressed patients give evidence for tricyclic antidepressants, venlafaxine and citalopram that TDM could become a standard of care in psychiatry and neurology. There is potential to accelerate improvement. Reducing phases of suffering will not only have medical benefits for the patients but also an impact on costs for the health system which needs to be clarified by controlled studies. PMID- 26511091 TI - KDM4B promotes epithelial-mesenchymal transition through up-regulation of ZEB1 in pancreatic cancer. AB - Lysine (K)-specific demethylase 4B (KDM4B) is a histone H3K9 demethylase and is reported to activate gene transcription through regulation of chromatin structures. Previous research has revealed that KDM4B plays special regulatory roles in colorectal, prostate and gastric cancers. However, its physiological role in pancreatic cancer remains largely unknown. In the present study, it is demonstrated KDM4B plays a crucial in epithelial-mesenchymal transition (EMT) in pancreatic cancer. siRNA mediated silencing of KDM4B inhibits cell migration, invasion and EMT. Moreover, KDM4B was demonstrated to epigenetically regulate the expression of ZEB1 in the TGF-beta-induced EMT process. In tumor tissues of pancreatic cancer patient, the protein level of KDM4B was positively correlated with ZEB1. In conclusion, our results suggested that KDM4B is a key mediator in EMT process, and may serve as an important prognostic marker and therapeutic target for the metastatic progression of human pancreatic cancer. PMID- 26511092 TI - Inflammatory biomarkers: impact for diabetes and diabetic vascular disease. PMID- 26511093 TI - A novel 4/6-type alpha-conotoxin ViIA selectively inhibits nAchR alpha3beta2 subtype. AB - Conotoxins (CTxs) are typically small peptides composed of 12-50 amino acid residues with 2-5 disulfide bridges. Most of them potently and selectively target a wide variety of ion channels and membrane receptors. They are highly valued as neuropharmacological probes and in pharmaceutical development. In this work, a novel alpha4/6-CTx named ViIA (RDCCSNPPCAHNNPDC-NH2) was identified from a cDNA library of the venom ducts of Conus virgo (C. virgo). ViIA was then synthesized chemically and its disulfide connectivity was identified as 'C(1)-C(3), C(2) C(4)'. Its molecular targets were further assessed using two-electrode voltage clamping. The results indicated that ViIA selectively inhibited nicotinic acetylcholine receptor (nAChR) alpha3beta2 subtype with an IC50 of 845.5 nM, but did not target dorsal root ganglion sodium (Na(+))-, potassium (K(+))- or calcium (Ca(2+))-ion channels. Further structure-activity relationship analysis demonstrated that Arg(1) and His(11) but not Asp(2) were the functional residues. To the best of our knowledge, ViIA is the first 4/6 alpha-CTx that selectively inhibits nAChR alpha3beta2 subtype. This finding expands the knowledge of targets of alpha4/6-family CTxs. PMID- 26511094 TI - Ultrasound plays a key role in imaging and management of genital angiomyofibroblastoma: a case report. AB - INTRODUCTION: Angiomyofibroblastoma is a benign, rare mesenchymal tumor arising from the genital tract of both men and women and was first described by Fletcher and colleagues in 1992. The tumor needs to be distinguished from other, similar lesions, such as deep and superficial aggressive angiomyxoma and cellular angiofibroma, because aggressive angiomyxoma demands much more extensive treatment. The vast majority of angiomyofibroblastomas arise from the vulva and appear as solid cystic masses on ultrasound images. CASE PRESENTATION: We report a case of a 35-year-old Caucasian woman with an angiomyofibroblastoma arising from the vagina. She presented with a painless mass of about 5cm in diameter that had a rather homogeneous, hypoechoic appearance on ultrasound images. The patient underwent surgical resection of the mass, which was subsequently diagnosed as angiomyofibroblastoma. We present sonographic and magnetic resonance imaging findings, intraoperative and histologic images, and a thorough review of the literature. CONCLUSIONS: In our opinion, ultrasonography is the most valuable tool to establish a preoperative diagnosis of this tumor entity, differentiate it from other lesions of the female genital tract, and plan surgery accordingly. Even though it is a rare tumor, gynecologists should be able to recognize it and to differentiate it from other tumor entities that demand more aggressive treatment. We describe a different sonographic appearance of this tumor than previously reported. PMID- 26511096 TI - The activation of pyrin domain-containing-3 inflammasome depends on lipopolysaccharide from Porphyromonas gingivalis and extracellular adenosine triphosphate in cultured oral epithelial cells. AB - BACKGROUND: Gingival epithelial cells are the major population of the gingival tissue, acting as the front-line defense against microbial intrusion and regulating the homeostasis of the periodontal tissue in health and disease via NLR family pyrin domain-containing-3 (NLRP3) inflammasome, which recognizes pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). The aim of this study was to determine whether the activation of NLRP3 inflammasome depends on infection with the periodontal pathogen Porphyromonas gingivalis (P. gingivalis), or stimulation with P. gingivalis lipopolysaccharide (LPS), and/or extracellular adenosine triphosphate (ATP). METHODS: An oral epithelial cell line was treated with P. gingivalis, P. gingivalis LPS and ATP. The gene and protein expression of NLRP3 inflammasome components were quantified by real time RT-PCR and immunoblots. Production of IL-1beta and IL-18 was measured by ELISA. RESULTS: There was no increase in NLRP3 inflammasome gene expression after P. gingivalis infection unless pre-stimulated by ATP. Obvious increases of NLRP3 inflammasome gene expression was observed after P. gingivalis LPS stimulation, even pre stimulated by ATP at 2 h. CONCLUSIONS: The findings indicate that the activation of NLRP3 inflammasome does not rely on P. gingivalis infection, unless stimulated by P. gingivalis LPS and/or extracellular ATP, suggesting diverse signaling pathways are involved in the host immune response. PMID- 26511095 TI - Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance. AB - Cancer stem cells (CSCs) have been identified in several solid malignancies and are now emerging as a plausible target for drug discovery. Beside the questionable existence of CSCs specific markers, the expression of CD133 was reported to be responsible for conferring CSC aggressiveness. Here, we identified two G-rich sequences localized within the introns 3 and 7 of the CD133 gene able to form G-quadruplex (G4) structures, bound and stabilized by small molecules. We further showed that treatment of patient-derived colon CSCs with G4-interacting agents triggers alternative splicing that dramatically impairs the expression of CD133. Interestingly, this is strongly associated with a loss of CSC properties, including self-renewing, motility, tumor initiation and metastases dissemination. Notably, the effects of G4 stabilization on some of these CSC properties are uncoupled from DNA damage response and are fully recapitulated by the selective interference of the CD133 expression.In conclusion, we provided the first proof of the existence of G4 structures within the CD133 gene that can be pharmacologically targeted to impair CSC aggressiveness. This discloses a class of potential antitumoral agents capable of targeting the CSC subpopulation within the tumoral bulk. PMID- 26511097 TI - Oatmeal porridge: impact on microflora-associated characteristics in healthy subjects. AB - Oatmeal porridge has been consumed for centuries and has several health benefits. We aimed to investigate the effect of oatmeal porridge on gut microflora functions. A total of ten healthy subjects ingested 60 g oatmeal porridge daily for 1 week. The following microflora-associated characteristics were assessed before and after the intervention: intestinal gas production following lactulose ingestion, faecal excretion of SCFA and faecal levels of urease and beta galactosidase. In addition, rectal levels of PGE2 were measured. Microbial fermentation as evaluated by intestinal gas production and excretion of SCFA did not change significantly following the dietary intervention. However, faecal levels of beta-galactosidase and urease decreased after eating oatmeal porridge (P=0.049 and 0.031, respectively). Host inflammatory state, as measured by rectal levels of PGE2, also decreased, but the change was not significant (P=0.168). The results suggest that oatmeal porridge has an effect on gut microbial functions and may possess potential prebiotic properties that deserve to be investigated further. PMID- 26511098 TI - Acute Hepatitis E Virus infection with coincident reactivation of Epstein-Barr virus infection in an immunosuppressed patient with rheumatoid arthritis: a case report. AB - BACKGROUND: Hepatitis E virus (HEV) is the most recently discovered of the hepatotropic viruses, and is considered an emerging pathogen in developed countries with the possibility of fulminant hepatitis in immunocompromised patients. Especially in the latter elevated transaminases should be taken as a clue to consider HEV infection, as it can be treated by discontinuation of immunosuppression and/or ribavirin therapy. To our best knowledge, this is a unique case of autochthonous HEV infection with coincident reactivation of Epstein-Barr virus (EBV) infection in an immunosuppressed patient with rheumatoid arthritis (RA). CASE PRESENTATION: A 68-year-old Swiss woman with RA developed hepatitis initially diagnosed as methotrexate-induced liver injury, but later diagnosed as autochthonous HEV infection accompanied by reactivation of her latent EBV infection. She showed confounding serological results pointing to three hepatotropic viruses (HEV, Hepatitis B virus (HBV) and EBV) that could be resolved by detection of HEV and EBV viraemia. The patient recovered by temporary discontinuation of immunosuppressive therapy. CONCLUSIONS: In immunosuppressed patients with RA and signs of liver injury, HEV infection should be considered, as infection can be treated by discontinuation of immunosuppression. Although anti-HEV-IgM antibody assays can be used as first line virological tools, nucleic acid amplification tests (NAAT) for detection of HEV RNA are recommended--as in our case--if confounding serological results from other hepatotropic viruses are obtained. After discontinuation of immunosuppressive therapy, our patient recovered from both HEV infection and reactivation of latent EBV infection without sequelae. PMID- 26511099 TI - Biomolecular Fishing for Calixarene Partners by a Chemoproteomic Approach. AB - MS-based chemical-proteomics technology is introduced herein as a third general strategy to study the biomolecular recognition properties of given calixarene derivatives. In particular, we demonstrate that a simply designed calix[4]arene derivative 1 a bearing acetamido groups at the exo rim (pAC), when linked to a solid support, is able to fish out a specific protein (PDI protein) from a crude extract of HeLa cells. Western blot and surface plasmon resonance studies confirmed the direct interaction between PDI and the linker-free pAC derivative 1 b with considerable affinity, and in vitro tests showed its inhibition of PDI chaperone activity. In accordance with the role of PDI in a variety of human cancers, biological tests showed that pAC 1 b was cytotoxic and cytostatic toward CAL-27 and PC-3 cancer cell lines in vitro. Docking studies showed that H bonds and hydrophobic interactions contribute to the stabilization of the PDI/pAC complex. PMID- 26511100 TI - Beyond the VAD: Human Factors Engineering for Mechanically Assisted Circulation in the 21st Century. AB - Thousands of ventricular assist devices (VADs) currently provide circulatory support to patients worldwide, and dozens of heart pump designs for adults and pediatric patients are under various stages of development in preparation for translation to clinical use. The successful bench-to-bedside development of a VAD involves a structured evaluation of possible system states, including human interaction with the device and auxiliary component usage in the hospital or home environment. In this study, we review the literature and present the current landscape of preclinical design and assessment, decision support tools and procedures, and patient-centered therapy. Gaps of knowledge are identified. The study findings support the need for more attention to user-centered design approaches for medical devices, such as mechanical circulatory assist systems, that specifically involve detailed qualitative and quantitative assessments of human-device interaction to mitigate risk and failure. PMID- 26511101 TI - High spatial resolution compressed sensing (HSPARSE) functional MRI. AB - PURPOSE: To propose a novel compressed sensing (CS) high spatial resolution functional MRI (fMRI) method and demonstrate the advantages and limitations of using CS for high spatial resolution fMRI. METHODS: A randomly undersampled variable density spiral trajectory enabling an acceleration factor of 5.3 was designed with a balanced steady state free precession sequence to achieve high spatial resolution data acquisition. A modified k-t SPARSE method was then implemented and applied with a strategy to optimize regularization parameters for consistent, high quality CS reconstruction. RESULTS: The proposed method improves spatial resolution by six-fold with 12 to 47% contrast-to-noise ratio (CNR), 33 to 117% F-value improvement and maintains the same temporal resolution. It also achieves high sensitivity of 69 to 99% compared the original ground-truth, small false positive rate of less than 0.05 and low hemodynamic response function distortion across a wide range of CNRs. The proposed method is robust to physiological noise and enables detection of layer-specific activities in vivo, which cannot be resolved using the highest spatial resolution Nyquist acquisition. CONCLUSION: The proposed method enables high spatial resolution fMRI that can resolve layer-specific brain activity and demonstrates the significant improvement that CS can bring to high spatial resolution fMRI. Magn Reson Med 76:440-455, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. PMID- 26511103 TI - Calling time on survival times? PMID- 26511102 TI - Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. AB - Currently, six glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for treating type 2 diabetes. These fall into two classes based on their receptor activation: short-acting exenatide twice daily and lixisenatide once daily; and longer-acting liraglutide once daily, exenatide once weekly, albiglutide once weekly and dulaglutide once weekly. The phase III trial of a seventh GLP-1RA, taspoglutide once weekly, was stopped because of unacceptable adverse events (AEs). Nine phase III head-to-head trials and one large phase II study have compared the efficacy and safety of these seven GLP-1RAs. All trials were associated with notable reductions in glycated haemoglobin (HbA1c) levels, although liraglutide led to greater decreases than exenatide formulations and albiglutide, and HbA1c reductions did not differ between liraglutide and dulaglutide. As the short-acting GLP-1RAs delay gastric emptying, they have greater effects on postprandial glucose levels than the longer-acting agents, whereas the longer-acting compounds reduced plasma glucose throughout the 24-h period studied. Liraglutide was associated with weight reductions similar to those with exenatide twice daily but greater than those with exenatide once weekly, albiglutide and dulaglutide. The most frequently observed AEs with GLP 1RAs were gastrointestinal disorders, particularly nausea, vomiting and diarrhoea. Nauseaoccurred less frequently, however, with exenatide once weekly and albiglutide than exenatide twice daily and liraglutide. Both exenatide formulations and albiglutide may be associated with higher incidences of injection-site reactions than liraglutide and dulaglutide. GLP-1RA use in clinical practice should be customized for individual patients, based on clinical profile and patient preference. Ongoing assessments of novel GLP-1RAs and delivery methods may further expand future treatment options. PMID- 26511104 TI - Contamination of multidose butorphanol vials in small animal general practices. AB - OBJECTIVES: To assess and quantify medetomidine contamination of butorphanol multidose vials in small animal general practices and determine if practice policies and procedures regarding drug handling, as determined by questionnaire, impact upon contamination level. METHODS: Samples of butorphanol were withdrawn from in-use vials in participating practices in June and July 2013. Samples were analysed using high-performance liquid chromatography and mass spectrometry. RESULTS: Forty-one samples were obtained from 31 practices. Contamination was detected in 29 samples from 10 mL vials. The mean (alphasd) contamination was 0 . 275 (alpha0 . 393) ug/mL; maximum contamination in any vial was 2 . 034 ug/mL. There was no correlation between volume of the vial used and the level of contamination. None of the survey factors predicted contamination levels of the vials. CLINICAL SIGNIFICANCE: Contamination of butorphanol multidose vials with medetomidine was common but the level of contamination was insufficient to cause detrimental effects in dogs if butorphanol were to be administered alone. The potential for sporadic higher levels of contamination must be taken into account, especially when using 50 mL vials when sedating critically ill cases, because there is a risk of clinical side effects. PMID- 26511105 TI - Perceived affordability of health insurance and medical financial burdens five years in to Massachusetts health reform. AB - INTRODUCTION: Under the Massachusetts health reform, low income residents (those with incomes below 150 % of the Federal Poverty Level [FPL]) were eligible for Medicaid and health insurance exchange-based plans with minimal cost-sharing and no premiums. Those with slightly higher incomes (150 %-300 % FPL) were eligible for exchange-based plans that required cost-sharing and premium payments. METHODS: We conducted face to face surveys in four languages with a convenience sample of 976 patients seeking care at three hospital emergency departments five years after Massachusetts reform. We compared perceived affordability of insurance, financial burden, and satisfaction among low cost sharing plan recipients (recipients of Medicaid and insurance exchange-based plans with minimal cost-sharing and no premiums), high cost sharing plan recipients (recipients of exchange-based plans that required cost-sharing and premium payments) and the commercially insured. RESULTS: We found that despite having higher incomes, higher cost-sharing plan recipients were less satisfied with their insurance plans and perceived more difficulty affording their insurance than those with low cost-sharing plans. Higher cost-sharing plan recipients also reported more difficulty affording medical and non-medical health care as well as insurance premiums than those with commercial insurance. In contrast, patients with low cost-sharing public plans reported higher plan satisfaction and less financial concern than the commercially insured. CONCLUSIONS: Policy makers with responsibility for the benefit design of public insurance available under health care reforms in the U.S. should calibrate cost-sharing to income level so as to minimize difficulty affording care and financial burdens. PMID- 26511106 TI - Clinical and Demographic Correlates of Ejaculatory Dysfunctions Other Than Premature Ejaculation: A Prospective, Observational Study. AB - INTRODUCTION: Ejaculatory dysfunctions other than premature ejaculation are commonly encountered in specialized clinics; however, their characterization in community-dwelling men is lacking. AIM: The aim of this study was to evaluate the prevalence, severity, and associated distress of four ejaculatory dysfunctions: delayed ejaculation (DE), anejaculation (AE), perceived ejaculate volume reduction (PEVR) and/or decreased force of ejaculation (DFE) as a function of demographic and clinical characteristics in men. METHODS: Observational analysis of 988 subjects presenting with one or more types of ejaculatory dysfunctions other than premature ejaculation who screened for a randomized clinical trial assessing the efficacy of testosterone replacement on ejaculatory dysfunction. Demographic and clinical characteristics were assessed as potential risk factors using regression analysis. MAIN OUTCOME MEASURES: The main outcome measures used were ejaculatory dysfunction prevalence and scores (3-item Men's Sexual Health Questionnaire Ejaculatory Dysfunction-Short Form [MSHQ-EjD-SF]), and bother (MSHQ EjD-SF Bother item) and sexual satisfaction/enjoyment (International Index of Erectile Function Questionnaire Q7, Q8) as a function of subject's age, race, body mass index (BMI) and serum testosterone levels (measured by liquid chromatography tandem mass spectrometry). RESULTS: Mean (standard deviation [SD]) age of the participants was 52 years (11). Eighty-eight percent of the men experienced more than one type of ejaculatory dysfunction and 68% considered their symptoms to be bothersome. Prevalence of the ejaculatory dysfunctions was substantial across a range of age, race, BMI, and serum testosterone categories. Prevalence of PEVR and DFE were positively associated with age (<40 years vs. 60 70 years: PEVR: odds ratio [OR], 3.05; 95% confidence interval [CI], 1.32-7.06; DFE: OR, 2.78; 95% CI, 1.46-5.28) while DFE was associated with BMI (>=30 kg/m(2) vs. < 25 kg/m(2) : OR, 1.80; 95% CI, 1.062-3.05). All ejaculatory dysfunctions were more prevalent in black men. CONCLUSION: The majority of the participants experienced multiple ejaculatory dysfunctions and found them to be highly bothersome. Ejaculatory dysfunctions were prevalent across a wide range of demographic and clinical characteristics. PMID- 26511107 TI - LncRNA-GAS5 induces PTEN expression through inhibiting miR-103 in endometrial cancer cells. AB - BACKGROUND: Growth arrest-specific 5 (GAS5) was reported to be implicated and aberrantly express in multiple cancers. However, the expression and mechanism of action of GAS5 were largely poor understood in endometrial carcinoma. RESULTS: According to the result of real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and flow cytometry analysis, we identified that GAS5 was down regulated in endometrial cancer cells and stimulated the apoptosis of endometrial cancer cells. To investigate the expression of GAS5, PTEN and miR-103, RT-PCR was performed. And we found that the expression of PTEN was up-regulated when endometrial cancer cells overexpressed GAS5. The prediction of bioinformatics online revealed that GAS5 could bind to miR-103, which was further found to be regulated by GAS5. Finally, we found that miR-103 mimic could decrease the mRNA and protein levels of PTEN through luciferase reporter assay and western blotting, and GAS5 plasmid may reverse this regulation effect in endometrial cancer cells. CONCLUSION: In summary, we demonstrate that GAS5 acts as an tumor suppressor lncRNA in endometrial cancer. Through inhibiting the expression of miR 103, GAS5 significantly enhanced the expression of PTEN to promote cancer cell apoptosis, and, thus, could be an important mediator in the pathogenesis of endometrial cancer. PMID- 26511109 TI - Erratum: Structural diversity of supercoiled DNA. PMID- 26511108 TI - Identification of miRNAs with potential roles in regulation of anther development and male-sterility in 7B-1 male-sterile tomato mutant. AB - BACKGROUND: The 7B-1 tomato line (Solanum lycopersicum cv. Rutgers) is a photoperiod-sensitive male-sterile mutant, with potential application in hybrid seed production. Small RNAs (sRNAs) in tomato have been mainly characterized in fruit development and ripening, but none have been studied with respect to flower development and regulation of male-sterility. Using sRNA sequencing, we identified miRNAs that are potentially involved in anther development and regulation of male-sterility in 7B-1 mutant. RESULTS: Two sRNA libraries from 7B 1 and wild type (WT) anthers were sequenced and thirty two families of known miRNAs and 23 new miRNAs were identified in both libraries. MiR390, miR166, miR159 were up-regulated and miR530, miR167, miR164, miR396, miR168, miR393, miR8006 and two new miRNAs, miR#W and miR#M were down-regulated in 7B-1 anthers. Ta-siRNAs were not differentially expressed and likely not associated with 7B-1 male-sterility. miRNA targets with potential roles in anther development were validated using 5'-RACE. QPCR analysis showed differential expression of miRNA/target pairs of interest in anthers and stem of 7B-1, suggesting that they may regulate different biological processes in these tissues. Expression level of most miRNA/target pairs showed negative correlation, except for few. In situ hybridization showed predominant expression of miR159, GAMYBL1, PMEI and cystatin in tapetum, tetrads and microspores. CONCLUSION: Overall, we identified miRNAs with potential roles in anther development and regulation of male-sterility in 7B 1. A number of new miRNAs were also identified from tomato for the first time. Our data could be used as a benchmark for future studies of the molecular mechanisms of male-sterility in other crops. PMID- 26511110 TI - Symptoms, functioning and quality of life after treatment in a residential sub acute mental health service in Australia. AB - The aim of this study was to assess clients' and service providers' perspectives on changes in mental health after an admission to a residential recovery-focused, sub-acute service, in Australia. Clients were either step-up clients, entering the service directly from the community, or step-down clients who were transitioning from an inpatient unit to home. During the 30-month period of data collection (August 2011 to January 2014) all clients (N = 102) were invited to participate in the longitudinal study and 41 clients consented to be involved (38% response rate). At admission and exit, participants completed the Behaviour and Symptom Identification Scale (Basis-32) and service providers completed the Life Skills Profile-16 and Health of the Nations Outcome Scales. Follow-up data 3 months after exit were available for 12 clients, including the Basis-32 and a self-report measure of quality of life (Assessment of Quality of Life 8 dimension). Both client groups reported positive improvements between admission and exit in the areas of relation to self and others, psychosis, daily living and presence of depression or anxiety symptoms. Service providers reported gains for clients in the areas of self-care, level of symptoms and presence of social problems. At 3 months, clients generally reported positive quality of life, although there was no significant change in symptoms and functioning. This study demonstrates that after an admission to a sub-acute service, step-up clients experience an improvement in their symptoms and functioning, have avoided a hospital admission and are well enough to return home. Step-down clients also experience further improvements in their symptoms and functioning, indicating that the service has assisted them in their transition to independent living after a hospital admission. Sub-acute residential units provide a continuation of care for inpatients preparing to return home, and people with a mental health problem living in the community who experience an escalation in symptoms and prefer an alternative to hospital. PMID- 26511111 TI - Age Stereotypes and Self-Views Revisited: Patterns of Internalization and Projection Processes Across the Life Span. AB - Objectives: We investigated processes of age stereotype internalization into the self and projection of self-views onto age stereotypes from a life-span perspective, taking age-related differences in the relevance of life domains into account. Method: Age stereotypes and self-views in eight life domains were assessed in a sample of N = 593 persons aged 30-80 years (T1) at two time points that were separated by a 4-year time interval. We estimated cross-lagged projection and internalization effects in multigroup structural equation models. Results: Internalization and projection effects were contingent on age group and life domain: Internalization effects were strongest in the young and middle-aged groups and emerged in the domains family, personality, work, and leisure. Projection effects in different domains were most pronounced for older participants. Discussion: Our findings suggest that the internalization of age stereotypes is triggered by domain-specific expectations of impending age-related changes and transitions during certain phases of the life span. Projection processes, however, seem to occur in response to changes that have already been experienced by the individual. Our study demonstrates the dynamic interrelation of age stereotypes and self-views across the life course and highlights the importance of a differentiated, life-span perspective for the understanding of these mechanisms. PMID- 26511112 TI - Hybrid Assistive Limb (HAL) Rehabilitation in Patients with Acute Hemorrhagic Stroke. AB - The efficacy of hybrid assistive limb (HAL) rehabilitation in the acute phase of stroke remains unclear. The purpose of this study was to evaluate the outcomes of patients with acute intracranial hemorrhage (ICH) who were treated with or without HAL rehabilitation. Among 270 patients with acute ICH from 2009 to 2014, 91 patients with supratentorial ICH were included in this retrospective study. Of these, 14 patients (HAL group) received HAL rehabilitation at approximately 1 week after ICH occurrence, while the remaining 77 patients received usual rehabilitation without HAL (N-HAL group). We obtained various patient data from the hospitals where the patients were moved to for further rehabilitation. Statistical comparisons were performed for the characteristics of the ICH patients, and outcomes between the HAL and N-HAL groups. There were no differences in outcomes between the HAL and N-HAL groups. However, patients with right ICH in the HAL group exhibited a significant association with a functional independence measure (FIM) score of >= 110 compared with patients in the N-HAL group (HAL group: 81.8%, N-HAL group: 43.9%, P = 0.04). In patients with right ICH, HAL rehabilitation was associated with improved outcomes as evaluated by the FIM score. Thus, HAL rehabilitation may improve outcomes of acute ICH in appropriately selected patients. PMID- 26511113 TI - Installation of a Neuromate Robot for Stereotactic Surgery: Efforts to Conform to Japanese Specifications and an Approach for Clinical Use-Technical Notes. AB - The neuromate is a commercially available, image-guided robotic system for use in stereotactic surgery and is employed in Europe and North America. In June 2015, this device was approved in accordance with the Pharmaceutical Affairs Law in Japan. The neuromate can be specified to a wide range of stereotactic procedures in Japan. The stereotactic X-ray system, developed by a Japanese manufacturer, is normally attached to the operating table that provides lateral and anteroposterior images to verify the positions of the recording electrodes. The neuromate is designed to be used with the patient in the supine position on a flat operating table. In Japan, deep brain stimulation surgery is widely performed with the patient's head positioned upward so as to minimize cerebrospinal fluid leakage. The robot base where the patient's head is fixed has an adaptation for a tilted head position (by 25 degrees) to accommodate the operating table at proper angle to hold the patient's upper body. After these modifications, the accuracy of neuromate localization was examined on a computed tomography phantom preparation, showing that the root mean square error was 0.12 +/- 0.10 mm. In our hospital, robotic surgeries, such as those using the Da Vinci system or neuromate, require operative guidelines directed by the Medical Risk Management Office and Biomedical Research and Innovation Office. These guidelines include directions for use, procedural manuals, and training courses. PMID- 26511114 TI - Cyanoacetic Acid as a Masked Electrophile: Transition-Metal-Free Cyanomethylation of Amines and Carboxylic Acids. AB - Using cyanoacetic acid as a masked electrophile, a new cyanomethylation reaction of amines and carboxylic acids was developed, producing a variety of alpha aminonitriles and cyanomethyl esters with good yields and excellent functionality tolerance. This protocol features simple manipulation, inexpensive reagents, and a wide substrate scope. Iodoacetonitrile was generated in situ from the iodination-decarboxylation of cyanoacetic acid in this transformation. PMID- 26511115 TI - Electrothermal bipolar vessel ligation improves operative time during laparoscopic total proctocolectomy: a large single-center experience. AB - BACKGROUND: Laparoscopic total proctocolectomy (TPC) with or without ileoanal pouch is a major operation for which the traditional benefits of laparoscopy were not immediately apparent, in part due to the longer operating times. The use of energy devices has been shown to improve operative outcomes for patients who undergo laparoscopic segmental colectomies, but there are limited data for laparoscopic TPC (LTPC). METHODS: All patients who underwent LTPC between January 2002 and July 2011 were identified from a prospectively maintained institutional review-board-approved database. Univariate and multiple linear regression analyses were performed to assess the impact of electrothermal bipolar vessel sealers (EBVS) for vessel ligation on operative time. Secondary outcomes included vessel ligation failures, estimated blood loss, and other intra- and postoperative outcomes. RESULTS: One hundred and forty-five patients underwent LTPC, including 126 restorative ileoanal pouch and diverting ileostomy operations and 19 TPC and end ileostomy procedures. Fifteen percent of LTPCs were totally laparoscopic, 45 % were laparoscopic-assisted, 32 % were hand-assisted, and 8 % were laparoscopic-converted cases. Laparoscopic vessel ligation was performed using EBVS (76 %), endoscopic staplers (12 %), or hybrid techniques (12 %). Vessel ligation groups were similar in demographics, body mass index, surgical indication, immunosuppression, and prior surgery. EBVS were associated with shorter median operative times (247 vs. 290 vs. 300 min, p = 0.018) and fewer vessel ligation failures (1 vs. 11 vs. 12 %, p = 0.027) compared with endoscopic staplers and hybrid techniques, respectively. There were no differences in estimated blood loss and intra-operative complications among the three groups. Length of stay, 30-day morbidity, and 30-day re-operation rates were also similar. On multiple linear regression analysis, EBVS were a significant predictor of operative time (p = 0.019). CONCLUSIONS: Routine use of electrothermal bipolar vessel ligation for LTPC is associated with shorter operative time and fewer vessel ligation failures without higher risk of complications than other vessel control methods. PMID- 26511116 TI - Near-infrared cholecysto-cholangiography with indocyanine green may secure cholecystectomy in difficult clinical situations: proof of the concept in a porcine model. AB - BACKGROUND: Biliary injuries remain a major concern in laparoscopic cholecystectomy. New intraoperative guidance modalities, including near-infrared fluorescence cholangiography, are under evaluation. Initial results showed limitations in visualizing the biliary tree in specific clinical situations. The aim of this study was to examine the feasibility and potentiality of fluorescence cholecysto-cholangiography performed with a direct injection of indocyanine green (ICG) in the gallbladder and to compare it to systemic injection in such situations. MATERIALS AND METHODS: Seven pigs were included in this non-survival study. In two pigs, the gallbladder was punctured by a percutaneous needle, and 1 mL of ICG in different concentrations (0.001, 0.01, 0.1, and 1 mg/mL) was sequentially injected. Visibility and pattern of the fluorescent signal around Calot's triangle were examined and compared with those of two control pigs receiving 2.5 mg of intravenous ICG, 30 min prior to the operation. Different scenarios of cholecystitis were modeled using an injection of a mixture of blood and agarose gel around Calot's triangle area in the remaining three pigs, and the applicability of direct intragallbladder injection methods was evaluated. RESULTS: The fluorescent signal was identified immediately after intragallbladder injection, and the cystic duct became visible by 0.1 and 1 mg/mL of ICG. The whole cystic duct and the infundibulum of the gallbladder were clearly enhanced by intragallbladder ICG injection, but not by systemic injection. In the cholecystitis models, the cystic duct could be identified only after partial dissection, and fluorescence visualization of the gallbladder infundibulum provided crucial information to find the correct starting point of dissection. CONCLUSIONS: Fluorescence cholecysto-cholangiography through direct intragallbladder ICG injection could rapidly provide an adequate visualization of gallbladder neck and cystic duct and might be a valid option to increase the safety of cholecystectomy in case of cholecystitis. PMID- 26511117 TI - Are gynecologists sufficiently trained and educated on electro surgery and basic laparoscopic setting? AB - BACKGROUND: Basic knowledge of electrosurgery and patient's safety during laparoscopic setup are fundamental, as laparoscopic surgical skills do. The aim of this prospective case-control study was to assess the improvement of such knowledge and skills among gynecologists. METHODS: Gynecologists attending a training course on laparoscopy at the Centre International de Chirurgie Endoscopique (CICE), Clermont Ferrand (France) (December 2013-March 2014) were asked to answer a questionnaire about their own clinical activity and basic surgical knowledge and skills at the beginning and end of the course. The questionnaire included multiple choice questions about technical (four questions) and safety (five questions) aspects of laparoscopic set up and electrosurgery (five questions). RESULTS: Sixty-two residents and 68 graduated gynecologists completed pre- and post-course questionnaires (PrQ and PoQ, respectively). Considering 9 as an arbitrary cut-off score indicating an adequate theoretical knowledge, a total of 70 (51.8 %) and 128 (94.8 %) participants had a sufficient score at the PrQ and PoQ, respectively. Only 9.6 % of participants were able to complete PoQ without making any mistakes, with a mean PrQ score of 9.5. At the beginning, the most difficult steps in laparoscopy in participants' opinion were intra-corporeal suture and insufflation of pneumoperitoneum (both 36.1 %). After the course and the practical training, only 20 % of participants still indicated intra-corporeal suture as the most difficult. CONCLUSION: Education on electro surgery and basic laparoscopic setting and laparoscopic practical training are necessary to improve and maintain laparoscopic surgical skills. The assessment of that knowledge is mandatory to define surgical competence. PMID- 26511118 TI - A multi-degree-of-freedom needle driver with a short tip and small shaft for pediatric laparoscopic surgery: in vivo assessment of multi-directional suturing on the vertical plane of the liver in rabbits. AB - BACKGROUND: Laparoscopic Kasai portoenterostomy has been performed in infants with biliary atresia at several institutions, but laparoscopic anastomosis requiring multi-directional suturing on a vertical plane of the liver remains a challenge. To assist multi-directional suturing, we developed a multi-degree-of freedom (DOF) needle driver whose tip length was 15 mm and shaft diameter was 3.5 mm. The tip of the multi-DOF needle driver has three DOFs for grasp, flection and rotation. The aim of this study was to evaluate the performance of the multi-DOF needle driver in two kinds of in vivo experiments. METHODS: Surgeons were asked to perform four-directional laparoscopic suturing on a vertical plane of the liver in six rabbits using the multi-DOF needle driver or a conventional needle driver. The needle grasping time, the needle handling time, the number of needle insertions, the number of liver lacerations, the suturing width and depth, and the area of necrotic tissues were analyzed and compared. Additionally, one surgeon was asked to perform laparoscopic hepato-jejunostomy in four rabbits to assess the feasibility of Kasai portoenterostomy using the multi-DOF needle driver. RESULTS: The suturing depth using the multi-DOF needle driver was significantly larger than that using the conventional needle driver in both the right and downward suturing directions. No statistically significant differences were found in other metrics. Liver lacerations were observed only when suturing was performed using the conventional needle driver. The experimental laparoscopic hepato-jejunostomy using the multi-DOF needle driver was successful. CONCLUSIONS: Using the multi-DOF needle driver, uniform multi-directional suturing on a vertical plane of the liver could be performed. The short distal tip of the multi DOF needle driver demonstrated its advantages in multi-directional suturing in a small body cavity. The multi-DOF needle driver may be able to be used to perform complex tasks in laparoscopic Kasai portoenterostomy. PMID- 26511119 TI - Late phase II study of robot-assisted gastrectomy with nodal dissection for clinical stage I gastric cancer. AB - BACKGROUND: The feasibility of robot-assisted gastrectomy (RG) in terms of safety is unclear due to a lack of prospective studies. We showed feasible surgical outcomes in our previous study. In this phase II study, we assessed feasibility of the procedure by recruiting a larger number of patients. METHOD: This single center, prospective phase II study included patients with clinical stage I gastric cancer undergoing RG. The primary end point was the incidence of postoperative intra-abdominal infectious complications, including anastomotic leakage, pancreas-related infection, and intra-abdominal abscess. The secondary end points were overall survival, relapse-free survival, RG completion rate, and incidence of all surgical morbidities. RESULTS: A total of 120 patients were recruited between December 2012 and April 2015. The incidence of intra-abdominal infectious complications was 3.3 % (95 % CI 0.9-8.3 %), and all complications were successfully treated conservatively without re-operation. The incidence of overall adverse events was 14.2 % (95 % CI 8.5-21.7 %). Three patients required conversion to open gastrectomy according to the protocol due to advancement of disease. CONCLUSION: Our data show that RG is safe in terms of the incidence and severity of postoperative complications. PMID- 26511120 TI - Comparison of conventional thyroidectomy and endoscopic thyroidectomy via axillo bilateral breast approach in papillary thyroid carcinoma patients. AB - BACKGROUND: Endoscopic thyroidectomy has been applied to solve the cosmetic problems that resulted from conventional thyroidectomy. The aim of this study was to evaluate and compare the surgical outcomes of conventional and endoscopic thyroidectomies via axillo-bilateral-breast approach (ABBA) in patients with papillary thyroid carcinoma (PTC). METHODS: Between May 2007 and February 2011, 1003 patients with PTC underwent thyroidectomies. The eight hundred and thirty patients underwent conventional thyroidectomy and 173 patients underwent endoscopic thyroidectomy via ABBA. Clinicopathologic characteristics, complications, and surgical completeness were analyzed. RESULTS: The mean age was 49.53 years who received a conventional thyroidectomy and 38.90 years in endoscopic thyroidectomy (P < 0.0001). The conventional thyroidectomy group underwent more extensive surgery than the endoscopic thyroidectomy group but the operation time was longer in the endoscopic thyroidectomy group (P < 0.0001). The mean hospitalization length was 6.98 days following open thyroidectomy and 6.40 days after endoscopic thyroidectomy (P = 0.003). The tumor size was larger in the conventional thyroidectomy group than the endoscopic thyroidectomy group and a lesser number of lymph nodes were retrieved in the endoscopic thyroidectomy group compared to the conventional thyroidectomy group (P < 0.0001). The postoperative complications and thyroglobulin levels in both groups were not significantly different. CONCLUSION: These results suggest that conventional and endoscopic thyroidectomy via ABBA has similar surgical outcomes in PTC patients. Therefore, endoscopic thyroidectomy via ABBA may be an appropriate surgical alternative to conventional thyroidectomy for treating PTC in selected patients. PMID- 26511121 TI - Traction with dental floss and endoscopic clip improves trainee success in performing gastric endoscopic submucosal dissection (ESD): a live porcine study (with video). AB - BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is a prolonged procedure with serious adverse events. The clip with line traction method was reported to improve ESD. However, there was no comparison with conventional ESD especially for trainees. We report here on the feasibility and efficacy of traction using dental floss with endoscopic clip to facilitate ESD versus conventional method for ESD trainees. METHODS: Twenty simulated gastric lesions, paired with location and size, were created in porcine stomachs using a standard template. After a circular incision was made, submucosal dissection (control, n = 10) was performed with standard ESD, while the study (clip, n = 10) was performed with traction using dental floss and endoclip. Primary outcome was speed of submucosal dissection. Secondary outcome included frequency of submucosal injection and adverse event. RESULTS: Compared with controls, median procedure time was significantly shorter in the clip group (5.6 +/- 1.1 vs. 13.6 +/- 2.5 min, P = 0.003), with a significantly faster submucosal dissection time (1.8 +/- 0.3 vs. 0.6 +/- 0.1 cm(2)/min, P = 0.001) and less frequent submucosal injection (5.7 +/- 0.6 vs. 8.5 +/- 1.0 times, P = 0.024). There were no perforations in either group, but less adverse events (bleeding and injury to muscularis propria) in the clip group (1 vs. 7, P = 0.068, alpha = 0.1). CONCLUSIONS: Traction provided by dental floss and endoclip improves visualization of the submucosal layer during ESD. It allows a faster and safer gastric ESD especially among trainees in the early learning phase. PMID- 26511122 TI - Elimination of waste: creation of a successful Lean colonoscopy program at an academic medical center. AB - OBJECTIVE: Lean processes involve streamlining methods and maximizing efficiency. Well established in the manufacturing industry, they are increasingly being applied to health care. The objective of this study was to determine feasibility and effectiveness of applying Lean principles to an academic medical center colonoscopy unit. METHODS: Lean process improvement involved training endoscopy personnel, observing patients, mapping the value stream, analyzing patient flow, designing and implementing new processes, and finally re-observing the process. Our primary endpoint was total colonoscopy time (minutes from check-in to discharge) with secondary endpoints of individual segment times and unit colonoscopy capacity. RESULTS: A total of 217 patients were included (November 2013-May 2014), with 107 pre-Lean and 110 post-Lean intervention. Pre-Lean total colonoscopy time was 134 min. After implementation of the Lean process, mean colonoscopy time decreased by 10 % to 121 min (p = 0.01). The three steps of the process affected by the Lean intervention (time to achieve adequate sedation, time to recovery, and time to discharge) decreased from 3.7 to 2.4 min (p < 0.01), 4.0 to 3.4 min (p = 0.09), and 41.2 to 35.4 min (p = 0.05), respectively. Overall, unit capacity of colonoscopies increased from 39.6 per day to 43.6. Post Lean patient satisfaction surveys demonstrated an average score of 4.5/5.0 (n = 73) regarding waiting time, 4.9/5.0 (n = 60) regarding how favorably this experienced compared to prior colonoscopy experiences, and 4.9/5.0 (n = 74) regarding professionalism of staff. One hundred percentage of respondents (n = 69) stated they would recommend our institution to a friend for colonoscopy. DISCUSSION: With no additional utilization of resources, a single Lean process improvement cycle increased productivity and capacity of our colonoscopy unit. We expect this to result in increased patient access and revenue while maintaining patient satisfaction. We believe these results are widely generalizable to other colonoscopy units as well as other process-based interventions in health care. PMID- 26511123 TI - Acquisition and retention of laparoscopic skills is different comparing conventional laparoscopic and single-incision laparoscopic surgery: a single centre, prospective randomized study. AB - BACKGROUND: Training in laparoscopic surgery is important not only to acquire and improve skills but also avoid the loss of acquired abilities. The aim of this single-centre, prospective randomized study was to assess skill acquisition of different laparoscopic techniques and identify the point in time when acquired skills deteriorate and training is needed to maintain these skills. METHODS: Sixty surgical novices underwent laparoscopic surgery (LS) and single-incision laparoscopic surgery (SILS) baseline training (BT) performing two validated tasks (peg transfer, precision cutting). The novices were randomized into three groups and skills retention testing (RT) followed after 8 (group A), 10 (group B) or 12 (group C) weeks accordingly. Task performance was measured in time with time penalties for insufficient task completion. RESULTS: 92 % of the participants completed the BT and managed to complete the task in the required time frame of proficiency. Univariate and multivariate analyses revealed that SILS (P < 0.0001) and precision cutting (P < 0.0001) were significantly more difficult. Males performed significantly better than females (P < 0.005). For LS, a deterioration of skills (comparison of BT vs RT) was not identified; however, for SILS a significant deterioration of skills (adjustment of BT and RT values) was demonstrated for all groups (A-C) (P < 0.05). DISCUSSION: Our data reveal that complex laparoscopic tasks (cutting) and techniques (SILS) are more difficult to learn and acquired skills more difficult to maintain. Acquired LS skills were maintained for the whole observation period of 12 weeks but SILS skills had begun to deteriorate at 8 weeks. These data show that maintenance of LS and SILS skills is divergent and training curricula need to take these specifics into account. PMID- 26511124 TI - Potential benefits of laparoscopy-assisted proximal gastrectomy with esophagogastrostomy for cT1 upper-third gastric cancer. AB - BACKGROUND: Few reports have compared laparoscopy-assisted proximal gastrectomy (LAPG) with laparoscopy-assisted total gastrectomy (LATG) in patients with cT1N0 gastric cancer. This study assessed the safety and feasibility of LAPG with esophagogastrostomy in these patients and compared postgastrectomy disturbances and nutritional status following LAPG and LATG. METHODS: This study compared 40 patients who underwent LAPG with esophagogastrostomy and 59 who underwent LATG with esophagojejunostomy, both with OrVilTM. Surgical outcomes, postoperative complications, nutritional status at 1 and 2 years, and relapse-free survival were compared in these two groups. RESULTS: Operation time was significantly shorter in the LAPG group than in the LATG group (280 min vs. 365 min, P < 0.001). Although the rate of surgical complications was similar in the two groups, the rate of anastomotic stricture was significantly higher in the LAPG group than in the LATG group (28 vs. 8.4 %; P = 0.012). Rates of reflux esophagitis graded A or higher in the Los Angeles classification were 10 and 5.1 %, respectively. Hemoglobin levels 2 years after surgery, relative to baseline levels, were significantly higher in the LAPG group than in the LATG group (98.6 vs. 92.9 %, P = 0.020). Body weight, albumin and total protein concentrations, and total lymphocyte count 1 and 2 years after surgery were slightly, but not significantly, higher in the LAPG group. Relapse-free survival rates were similar, as were 5-year overall survival rates (86 vs. 79 %, P = 0.42). CONCLUSIONS: LAPG with esophagogastrostomy using OrVilTM was safe and feasible for patients with cT1N0 gastric cancer. LAPG may have nutritional advantages over LATG, but the rate of anastomotic stricture was significantly higher for LAPG than for LATG. PMID- 26511125 TI - The incremental value of stress testing in patients with acute chest pain beyond serial cardiac troponin testing. AB - OBJECTIVE: In patients with acute chest pain and normal range cardiac troponin (cTn), accurate risk stratification for acute coronary syndrome is challenging. This study assesses the incremental value of stress testing to identify patients for angiography with a view to revascularisation. METHODS: A single-centre observational study recruited patients with acute chest pain in whom serial cTn tests were negative and stress testing (exercise tolerance testing/dobutamine stress echocardiography) was performed. Stress tests were reported as negative, non-diagnostic or positive. The primary outcomes were revascularisation on index admission, or cardiac death and myocardial infarction over 1 year follow-up. RESULTS: Of 749 patients recruited, 709 underwent exercise tolerance testing and 40 dobutamine stress echo of which 548 (73.2%) were negative, 169 (22.6%) were non-diagnostic and 32 (4.3%) were positive. Patients with positive tests (n=19 (59.4%)) were more likely to undergo index admission revascularisation than patients with non-diagnostic (n=15 (8.9%)) (p<0.001) tests who in turn were more likely undergo index admission revascularisation than those with negative tests (n=2 (0.4%)) (p<0.001). The risks of adverse events including cardiovascular death/acute myocardial infarction were low and were similar across stress test outcomes. CONCLUSIONS: The incremental value of stress testing was the identification of an additional 34 (4.5% (95% CI 3.0% to 6.0%)) patients who underwent index admission revascularisation with a view to preventing future adverse events. Uncertainty in whether revascularisation prevents adverse events in patients with negative cTn means the choice to undertake stress testing depends on whether clinicians perceive value in identifying 4.5% of these patients for revascularisation. CLINICAL TRIAL REGISTRATIONS: ACTRN1260900028327, ACTRN12611001069943. PMID- 26511126 TI - [Violence against elderly people. Recognize--Sensitize--Act!]. AB - Elder abuse is--especially in view of the demographic development--a topic that is still neglected socially and in health policy, but also in terms of scientific research. There are different definitions of violence and these can be difficult to formulate, depending on the field. In gerontology, a rather broad frame is usually used to describe the phenomenon of violence. Its shapes are multilayered and diverse (e.g., physical, psychological, restriction of freedom, neglect, financial exploitation, and structural and cultural). In principle, any act of violence is also a breach of the law. Violence can occur in public places and in family and institutional settings (e.g., hospital and outpatient and inpatient care for the elderly). The statistical occurence in family settings is around 25% and in institutional settings between 11 and 24%. Acts of violence are usually an expression of helplessness, shame, overwork, poor support and lack of knowledge of alternatives. Often there is a pathological relationship, in which the roles of "perpetrators" and "victims" can change. Acts of violence have massive consequences for those affected. Preventative measures to reduce violence have various points of departure (e.g., company, region, institution, professional). So far, there are hardly any points of contact and professional assistance for elderly victims. PMID- 26511127 TI - [Violence at school and the health of students]. AB - The article gives an overview of violence at school combined with the health of students. Based on the assumption that violence and health are two sides of the same coin, the article considers the question of the development of violence and bullying phenomena at German schools and its relation to student health. Long term studies by the authors, such as the international Health Behavior in School aged Children (HBSC) study, constitute the empirical basis. Prevalence and structures of student violence, as well as the relation between violence and health, are clarified and consequences for the prevention of violence and health are shown on the basis of our own empirical studies. Contrary to dramatic estimates in the media, a continuous reduction of bullying problems at German schools has been registered in recent years. In reference to the relation between violence and health, a significant correlation between dissocial behavior and health parameters was found. Victims and bully-victims show the most health problems and innocent bystanders the least health problems. In contrast to previous findings, bullies show a more positive prevailing mood. Due to the found associations between violence and health, it appears reasonable to combine violence prevention and health promotion measures to achieve sustainable prevention effects. PMID- 26511128 TI - Validation of a Food Frequency Questionnaire for Estimating Micronutrient Intakes in an Urban US Sample of Multi-Ethnic Pregnant Women. AB - OBJECTIVE(S): To validate the Block98 food frequency questionnaire (FFQ) for estimating antioxidant, methyl-nutrient and polyunsaturated fatty acids (PUFA) intakes in a pregnant sample of ethnic/racial minority women in the United States (US). METHODS: Participants (n = 42) were from the Programming of Intergenerational Stress Mechanisms study. Total micronutrient intakes from food and supplements was ascertained using the modified Block98 FFQ and two 24-h dietary recalls collected at random on nonconsecutive days subsequent to completion of the FFQ in mid-pregnancy. Correlation coefficients (r) corrected for attenuation from within-person variation in the recalls were calculated for antioxidants (n = 7), methyl-nutrients (n = 8), and PUFAs (n = 2). RESULT(S): The sample was largely ethnic minorities (38 % Black, 33 % Hispanic) with 21 % being foreign born and 41 % having less than or equal to a high school degree. Significant and adequate deattenuated correlations (r >= 0.40) for total dietary intakes of antioxidants were observed for vitamin C, vitamin E, magnesium, and zinc. Reasonable deattenuated correlations were also observed for methyl-nutrient intakes of vitamin B6, betaine, iron, and n:6 PUFAs; however, they did not reach significance. Most women were classified into the same or adjacent quartiles (>=70 %) for total (dietary + supplements) estimates of antioxidants (5 out of 7) and methyl-nutrients (4 out of 5). CONCLUSIONS: The Block98 FFQ is an appropriate dietary method for evaluating antioxidants in pregnant ethnic/minorities in the US; it may be less efficient in measuring methyl-nutrient and PUFA intakes. PMID- 26511129 TI - Differences in Human Papillomavirus Vaccination Among Adolescent Girls in Metropolitan Versus Non-metropolitan Areas: Considering the Moderating Roles of Maternal Socioeconomic Status and Health Care Access. AB - OBJECTIVES: This study is among the first to examine metropolitan status differences in human papillomavirus (HPV) vaccine initiation and completion among United States adolescent girls and is unique in its focus on how maternal socioeconomic status and health care access moderate metropolitan status differences in HPV vaccination. METHODS: Using cross-sectional data from 3573 girls aged 12-17 in the U.S. from the 2008-2010 Behavioral Risk Factor Surveillance System, we estimate main and interaction effects from binary logistic regression models to identify subgroups of girls for which there are metropolitan versus non-metropolitan differences in HPV vaccination. RESULTS: Overall 34 % of girls initiated vaccination, and 19 % completed all three shots. On average, there were no metropolitan status differences in vaccination odds. However, there were important subgroup differences. Among low-income girls and girls whose mothers did not complete high school, those in non-metropolitan areas had significantly higher probability of vaccine initiation than those in metropolitan areas. Among high-income girls and girls whose mothers completed college, those in metropolitan areas had significantly higher odds of vaccine initiation than those in non-metropolitan areas. Moreover, among girls whose mothers experienced a medical cost barrier, non-metropolitan girls were less likely to initiate vaccination compared to metropolitan girls. CONCLUSIONS: Mothers remain essential targets for public health efforts to increase HPV vaccination and combat cervical cancer. Public health experts who study barriers to HPV vaccination and physicians who come into contact with mothers should be aware of group-specific barriers to vaccination and employ more tailored efforts to increase vaccination. PMID- 26511130 TI - Assessing the Continuum of Care Pathway for Maternal Health in South Asia and Sub Saharan Africa. AB - OBJECTIVE: We assess how countries in regions of the world where maternal mortality is highest-South Asia and Sub-Saharan Africa-are performing with regards to providing women with vital elements of the continuum of care. METHODS: Using recent Demographic and Health Survey data from nine countries including 18,036 women, descriptive and multilevel regression analyses were conducted on four key elements of the continuum of care-at least one antenatal care visit, four or more antenatal care visits, delivery with a skilled birth attendant and postnatal checks for the mother within the first 24 h since birth. Family planning counseling within a year of birth was also included in the descriptive analyses. RESULTS: Results indicated that a major drop-out (>50 %) occurs early on in the continuum of care between the first antenatal care visit and four or more antenatal care visits. Few women (<5 %) who do not receive any antenatal care go on to have a skilled delivery or receive postnatal care. Women who receive some or all the elements of the continuum of care have greater autonomy and are richer and more educated than women who receive none of the elements. CONCLUSION: Understanding where drop-out occurs and who drops out can enable countries to better target interventions. Four or more ANC visits plays a pivotal role within the continuum of care and warrants more programmatic attention. Strategies to ensure that vital services are available to all women are essential in efforts to improve maternal health. PMID- 26511131 TI - The Influence of Women's Empowerment on Child Immunization Coverage in Low, Lower Middle, and Upper-Middle Income Countries: A Systematic Review of the Literature. AB - OBJECTIVES: An estimated 1.5 million children under five die annually from vaccine preventable diseases, and 17% of these deaths can be averted with vaccination. Predictors of immunization coverage, such as maternal schooling, are well documented; yet, preventable under-five mortality persists. To understand these patterns, researchers are exploring the mother-child relationship through an empowerment framework. This systematic review assesses evidence of the relationship between women's agency as a component of empowerment and vaccine completion among children <5 years in lower-income countries. METHODS: We searched in Socindex, Pubmed, Web of Science and Women's Studies International for peer-reviewed articles focused on two measures of women's agency-decision making and freedom of movement-and child vaccination. Our initial search identified 406 articles and abstracts for screening; 12 studies met the inclusion and exclusion criteria. RESULTS: A majority (83%) of studies revealed at least one positive association of measures for women's agency with immunization coverage. These relationships varied by geographic location, and most studies focused on women's decision making rather than freedom of movement. No included study came from Latin America or the Middle East. CONCLUSIONS: Overall, women's agency, typically measured by decision-making, was positively associated with the odds of complete childhood immunizations. Yet, the concept of agency was inconsistently defined and operationalized. Future research should address these inconsistencies and focus on under-represented geographic regions including Latin America and the Middle East. PMID- 26511132 TI - Sex differences after environmental enrichment and physical exercise in rats when solving a navigation task. AB - The effects of early environmental enrichment (EE) and voluntary wheel running on the preference for using a landmark or pool geometry when solving a simple spatial task in adult male and female rats were assessed. After weaning, rats were housed in same-sex pairs in enriched or standard cages (EE and control groups) for two and a half months. Then the rats were trained in a triangular shaped pool to find a hidden platform whose location was defined in terms of these two sources of information, a landmark outside the pool and a particular corner of the pool. As expected, enriched rats reached the platform faster than control animals, and males and females did not differ. Enriched rats also performed better on subsequent test trials without the platform with the cues individually presented (either pool geometry or landmark). However, on a preference test without the platform, a clear sex difference was found: Females spent more time in an area of the pool that corresponded to the landmark, whereas males spent more time in the distinctive corner of the pool. The present EE protocol did not alter females' preference for the landmark cue. The results agree with the claim that environmental enrichment is a consequence of a reduced anxiety response (measured by thigmotaxis) during cognitive testing. A possible implication of ancestral selection pressures is discussed. PMID- 26511133 TI - A novel role for von Willebrand factor in the pathogenesis of experimental cerebral malaria. AB - Plasmodium falciparum malaria infection is associated with an early marked increase in plasma von Willebrand factor (VWF) levels, together with a pathological accumulation of hyperreactive ultra-large VWF (UL-VWF) multimers. Given the established critical role of platelets in malaria pathogenesis, these increases in plasma VWF raise the intriguing possibility that VWF may play a direct role in modulating malaria pathogenesis. To address this hypothesis, we used an established murine model of experimental cerebral malaria (ECM), in which wild-type (WT) C57BL/6J mice were infected with Plasmodium berghei ANKA. In keeping with findings in children with P falciparum malaria, acute endothelial cell activation was an early and consistent feature in the murine model of cerebral malaria (CM), resulting in significantly increased plasma VWF levels. Despite the fact that murine plasma ADAMTS13 levels were not significantly reduced, pathological UL-VWF multimers were also observed in murine plasma following P berghei infection. To determine whether VWF plays a role in modulating the pathogenesis of CM in vivo, we further investigated P berghei infection in VWF(-/-) C57BL/6J mice. Clinical ECM progression was delayed, and overall survival was significantly prolonged in VWF(-/-) mice compared with WT controls. Despite this protection against ECM, no significant differences in platelet counts or blood parasitemia levels were observed between VWF(-/-) and WT mice. Interestingly, however, the degree of ECM-associated enhanced blood-brain barrier permeability was significantly attenuated in VWF(-/-) mice compared with WT controls. Given the significant morbidity and mortality associated with CM, these novel data may have direct translational significance. PMID- 26511134 TI - Low ADAMTS13 activity is associated with an increased risk of ischemic stroke. AB - ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin motif repeats 13) has antithrombotic properties because it cleaves von Willebrand factor (VWF) in smaller, less active multimers. The aim of our study was to investigate prospectively the association between ADAMTS13 activity and ischemic stroke. We included 5941 individuals >=55 years without a history of stroke or transient ischemic attack (TIA) of the Rotterdam Study, a population-based cohort study. ADAMTS13 activity was measured at inclusion with the FRETS-VWF73 assay and VWF antigen (VWF:Ag) levels by enzyme-linked immunosorbent assay. We assessed the association among ADAMTS13 activity, VWF:Ag levels, and ischemic stroke by Cox proportional hazard analysis. The added value of ADAMTS13 activity above the traditional risk factors for ischemic stroke risk prediction was examined by the C-statistic and the net reclassification improvement index (NRI). All individuals were followed for incident stroke or TIA. Over a median follow-up time of 10.7 years (56,403 total person-years), 461 participants had a stroke, 306 of which were ischemic. After adjustment for cardiovascular risk factors, individuals with ADAMTS13 activity in the lowest quartile had a higher risk of ischemic stroke (absolute risk, 7.3%) than did those in the reference highest quartile (absolute risk, 3.8%; hazard ratio, 1.65; 95% confidence interval [CI], 1.16-2.32). Adding ADAMTS13 to the model in prediction of ischemic stroke, increased the C-statistic by 0.013 (P = .003) and provided 0.058 (95% CI, -0.002 to 0.119) NRI. Low ADAMTS13 activity is associated with the risk of ischemic stroke and improves the accuracy of risk predictions for ischemic stroke beyond traditional risk factors. PMID- 26511136 TI - Erratum to: Eur J Ophthalmol, 2014; 24: 44-52 and Eur J Ophthalmol. 2012; 22: 175 87. AB - Erratum to: Eur J Ophthalmol. 2014 Jan-Feb;24(1):44-52. doi: 10.5301/ejo.5000335. Comparison of far and near contrast sensitivity in patients symmetrically implanted with multifocal and monofocal IOLs. Gil MA, Varon C, Cardona G, Vega F, Buil JA. PMID: 23813113 [PubMed - indexed for MEDLINE] Eur J Ophthalmol. 2012 Mar Apr;22(2):175-87. doi: 10.5301/EJO.2011.8371. Visual acuity, contrast sensitivity, subjective quality of vision, and quality of life with 4 different multifocal IOLs. Gil MA, Varon C, Rosello N, Cardona G, Buil JA. PMID: 21623590 [PubMed - indexed for MEDLINE] We inform our readers that the articles above are ascribed to the PhD program of the Universitat Autonoma de Barcelona. PMID- 26511135 TI - Pediatric chronic myeloid leukemia is a unique disease that requires a different approach. AB - Chronic myelogenous leukemia (CML) in children is relatively rare. Because of a lack of robust clinical study evidence, management of CML in children is not standardized and often follows guidelines developed for adults. Children and young adults tend to have a more aggressive clinical presentation than older adults, and prognostic scores for adult CML do not apply to children. CML in children has been considered to have the same biology as in adults, but recent data indicate that some genetic differences exist in pediatric and adult CML. Because children with CML may receive tyrosine kinase inhibitor (TKI) therapy for many decades, and are exposed to TKIs during a period of active growth, morbidities in children with CML may be distinct from those in adults and require careful monitoring. Aggressive strategies, such as eradication of CML stem cells with limited duration and intensive regimens of chemotherapy and TKIs, may be more advantageous in children as a way to avoid lifelong exposure to TKIs and their associated adverse effects. Blood and marrow transplantation in pediatric CML is currently indicated only for recurrent progressive disease, and the acute and long-term toxicities of this option should be carefully evaluated against the complications associated with lifelong use of TKIs. PMID- 26511137 TI - Staying Young at Heart: Cardiovascular Disease Prevention in Adolescents and Young Adults. AB - OPINION STATEMENT: Approaches to the prevention and management of cardiovascular disease (CVD) are often too narrow in scope and initiated too late. While the majority of adolescents are free of CVD, far fewer are free of CVD risk factors, especially lifestyle factors such as poor exercise and dietary habits. Most clinicians are familiar with behavioral and pharmacologic strategies for modifying these and other traditional CVD risk factors such as hypertension, hypercholesterolemia, and diabetes. In this review, we highlight those strategies most applicable to teens and also propose fundamental reframing that recognizes the importance of early choices and life experiences to achieving cardiovascular health. Population- and individual-level approaches that support the establishment of positive health behaviors early in life are the foundation of preserving ideal cardiovascular health and promoting positive cardiovascular outcomes. The Positive Youth Development movement supports a frame shift away from seeing young people as merely the sum of their risk factors and instead as developmentally dynamic youth capable of making healthy choices. Informed by the Positive Youth Development framework, our approach to cardiovascular prevention among adolescents is both broad based and proactive, paying heed as early as possible to social, familial, and developmental factors that underlie health behaviors and employing evidence-based behavioral, pharmacologic, and surgical treatments when needed. PMID- 26511138 TI - Cytocompatibility of the selected calcium phosphate based bone cements: comparative study in human cell culture. AB - Calcium phosphate cements (CPC) are valuable bone fillers. Recently they have been also considered as the basis for drug-, growth factors- or cells-delivery systems. Broad possibilities to manipulate CPC composition provide a unique opportunity to obtain materials with a wide range of physicochemical properties. In this study we show that CPC composition significantly influences cell response. Human bone derived cells were exposed to the several well-characterized different cements based on calcium phosphates, magnesium phosphates and calcium sulfate hemihydrate (CSH). Cell viability assays, live/dead staining and real time observation of cells in contact with the materials (time-laps) were performed. Although all the investigated materials have successfully passed a standard cytocompatibility assay, cell behavior in a direct contact with the materials varied depending on the material and the experimental system. The most recommended were the alpha-TCP-based materials which proved suitable as a support for cells in a direct contact. The materials which caused a decrease of calcium ions concentration in culture induced the negative cell response, however this effect might be expected efficiently compensated in vivo. All the materials consisting of CSH had negative impact on the cells. The obtained results strongly support running series of cytocompatibility studies for preclinical evaluation of bone cements. PMID- 26511139 TI - Correlation between mutations and mRNA expression of APC and MUTYH genes: new insight into hereditary colorectal polyposis predisposition. AB - BACKGROUND: Transcript dosage imbalance may influence the transcriptome. To gain insight into the role of altered gene expression in hereditary colorectal polyposis predisposition, in the present study we analyzed absolute and allele specific expression (ASE) of adenomatous polyposis coli (APC) and mutY Homolog (MUTYH) genes. METHODS: We analyzed DNA and RNA extracted from peripheral blood mononuclear cells (PBMC) of 49 familial polyposis patients and 42 healthy blood donors selected according similar gender and age. Patients were studied for germline alterations in both genes using dHPLC, MLPA and automated sequencing. APC and MUTYH mRNA expression levels were investigated by quantitative Real-Time PCR (qRT-PCR) analysis using TaqMan assay and by ASE assays using dHPLC-based primer extension. RESULTS: Twenty out of 49 patients showed germline mutations: 14 in APC gene and six in MUTYH gene. Twenty-nine patients did not show mutations in both genes. Results from qRT-PCR indicated that gene expression of both APC and MUTYH was reduced in patients analyzed. In particular, a significant reduction in APC expression was observed in patients without APC germline mutation vs control group (P < 0.05) while APC expression in the mutation carrier patients, although lower compared to control individuals, did not show statistical significance. On the other hand a significant reduced MUTYH expression was detected in patients with MUTYH mutations vs control group (P < 0.05). Altered ASE of APC was detected in four out of eight APC mutation carriers. In particular one case showed a complete loss of one allele. Among APC mutation negative cases, 4 out of 13 showed a moderate ASE. ASE of MUTYH did not show any altered expression in the cases analyzed. Spearman's Rho Test analysis showed a positive and significant correlation between APC and MUTYH genes both in cases and in controls (P = 0.020 and P < 0.001). CONCLUSIONS: APC and MUTYH showed a reduced germline expression, not always corresponding to gene mutation. Expression of APC is decreased in mutation negative cases and this appears to be a promising indicator of FAP predisposition, while for MUTYH gene, mutation is associated to reduced mRNA expression. This study could improve the predictive genetic diagnosis of at-risk individuals belonging to families with reduced mRNA expression regardless of presence of mutation. PMID- 26511140 TI - Mechanisms of an increased level of serum iron in gamma-irradiated mice. AB - The potential mechanisms underlying the increase in serum iron concentration in gamma-irradiated mice were studied. The gamma irradiation dose used was 4 Gy, and cobalt-60 ((60)Co) source was used for the irradiation. The dose rate was 0.25 Gy/min. In the serum of irradiated mice, the concentration of ferrous ions decreased, whereas the serum iron concentration increased. The concentration of ferrous ions in irradiated mice returned to normal at 21 day post-exposure. The concentration of reactive oxygen species in irradiated mice increased immediately following irradiation but returned to normal at 7 day post-exposure. Serum iron concentration in gamma-irradiated mice that were pretreated with reduced glutathione was significant lower (p < 0.01) than that in mice exposed to gamma radiation only. However, the serum iron concentration was still higher than that in normal mice (p < 0.01). This change was biphasic, characterized by a maximal decrease phase occurring immediately after gamma irradiation (relative to the irradiated mice) and a recovery plateau observed during the 7th and 21st day post irradiation, but serum iron recovery was still less than that in the gamma irradiated mice (4 Gy). In gamma-irradiated mice, ceruloplasmin activity increased and serum copper concentration decreased immediately after irradiation, and both of them were constant during the 7th and 21st day post-irradiation. It was concluded that ferrous ions in irradiated mice were oxidized to ferric ions by ionizing radiation. Free radicals induced by gamma radiation and ceruloplasmin mutually participated in this oxidation process. The ferroxidase effect of ceruloplasmin was achieved by transfer of electrons from ferrous ions to cupric ions. PMID- 26511141 TI - More Benefits for Checkpoint Inhibitors in NSCLC. AB - At the European Cancer Congress held in September 2015 in Vienna, Austria, three research teams presented evidence showing that the checkpoint inhibitors nivolumab and atezolizumab are effective as second-line therapies in certain patients with non-small cell lung cancer. PMID- 26511142 TI - Nobel Recognizes Seminal Work in DNA Repair. AB - Three scientists will share this year's Nobel Prize in Chemistry for pioneering research that established the inherent instability of DNA and the cellular mechanisms underlying its repair. Their discoveries of how living cells function have aided in developing new cancer therapies. PMID- 26511144 TI - Anaemia (and iron deficiency?) in aortic stenosis--a bystander or a potential therapeutic target? PMID- 26511145 TI - Catheter ablation of atrial fibrillation in patients with heart failure: can we break the vicious circle? PMID- 26511146 TI - The Aliskiren Trial to Minimize OutcomeS in Patients with HEart failure trial (ATMOSPHERE): revised statistical analysis plan and baseline characteristics. AB - AIMS AND METHODS: To: (i) describe the baseline characteristics of patients in ATMOSPHERE and the changes in the planned analysis of ATMOSPHERE resulting from the mandated discontinuation of study treatment in patients with diabetes; (ii) compare the baseline characteristics of patients in ATMOSPHERE with those in the Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF); and (iii) compare the characteristics of patients with and without diabetes at baseline in ATMOSPHERE. RESULTS: A total of 7063 patients were randomized into ATMOSPHERE April 2009 April 2014 at 755 sites in 43 countries. Their average age was 63 years and 78% were men. ATMOSPHERE patients were generally similar to those in PARADIGM-HF although fewer had diabetes, renal dysfunction, and were treated with a mineralocorticoid receptor antagonist. In ATMOSPHERE, patients with diabetes differed in numerous ways from those without. Patients with diabetes were older and had worse heart failure status but a similar left ventricular ejection fraction (mean 28%); they had a higher body mass index and more co-morbidity, especially hypertension and coronary heart disease. Mean estimated glomerular filtration rate was slightly lower in those with diabetes compared with those without. CONCLUSION: ATMOSPHERE will determine whether patients with HF and reduced ejection fraction (particularly those without diabetes) benefit from the addition of a direct renin inhibitor to standard background therapy, including an angiotensin-converting enzyme inhibitor, beta-blocker, and a mineralocorticoid receptor antagonist. ATMOSPHERE will also determine whether aliskiren alone is superior to, or at least non-inferior to, enalapril. PMID- 26511147 TI - X-ray Scatter Imaging of Hepatocellular Carcinoma in a Mouse Model Using Nanoparticle Contrast Agents. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form an image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. The enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging. PMID- 26511148 TI - Ionization sources and mass analyzers in MS imaging. AB - Drug absorption, distribution, metabolism, excretion and toxicology study is one important step in drug discovery and development. MS imaging has become one of the popular methods in this field. Here, selected ionization methods such as matrix-assisted laser desorption/ionization, secondary ion MS and desorption electrospray ionization have been briefly discussed. To differentiate drug and drug metabolites from endogenous compounds present in the biological system, exact mass and/or tandem MS is necessary. As a result, mass analyzers such as time-of-flight, Fourier transform ion cyclotron resonance or Orbitrap are often the method of choice and are briefly introduced. PMID- 26511149 TI - Nanoscale volume confinement and fluorescence enhancement with double nanohole aperture. AB - Diffraction ultimately limits the fluorescence collected from a single molecule, and sets an upper limit to the maximum concentration to isolate a single molecule in the detection volume. To overcome these limitations, we introduce here the use of a double nanohole structure with 25 nm gap, and report enhanced detection of single fluorescent molecules in concentrated solutions exceeding 20 micromolar. The nanometer gap concentrates the light into an apex volume down to 70 zeptoliter (10(-21) L), 7000-fold below the diffraction-limited confocal volume. Using fluorescence correlation spectroscopy and time-correlated photon counting, we measure fluorescence enhancement up to 100-fold, together with local density of optical states (LDOS) enhancement of 30-fold. The distinctive features of double nanoholes combining high local field enhancement, efficient background screening and relative nanofabrication simplicity offer new strategies for real time investigation of biochemical events with single molecule resolution at high concentrations. PMID- 26511150 TI - Initial clinical experience with Epid-based in-vivo dosimetry for VMAT treatments of head-and-neck tumors. AB - We evaluated an EPID-based in-vivo dosimetry algorithm (IVD) for complex VMAT treatments in clinical routine. 19 consecutive patients with head-and-neck tumors and treated with Elekta VMAT technique using Simultaneous Integrated Boost strategy were enrolled. In-vivo tests were evaluated by means of (i) ratio R between daily in-vivo isocenter dose and planned dose and (ii) gamma-analysis between EPID integral portal images in terms of percentage of points with gamma value smaller than one (gamma%) and mean gamma-values (gammamean), using a global 3%-3 mm criteria. Alert criteria of +/-5% for R ratio, gamma% < 90% and gammamean > 0.67 were chosen. A total of 350 transit EPID images were acquired during the treatment fractions. The overall mean R ratio was equal to 1.002 +/- 0.019 (1 SD), with 95.9% of tests within +/-5%. The 2D portal images of gamma-analysis showed an overall gammamean of 0.42 +/- 0.16 with 93.3% of tests within alert criteria, and a mean gamma% equal to 92.9 +/- 5.1% with 85.9% of tests within alert criteria. Relevant discrepancies were observed in three patients: a set-up error was detected for one patient and two patients showed major anatomical variations (weight loss/tumor shrinkage) in the second half of treatment. The results are supplied in quasi real-time, with IVD tests displayed after only 1 minute from the end of arc delivery. This procedure was able to detect when delivery was inconsistent with the original plans, allowing physics and medical staff to promptly act in case of major deviations between measured and planned dose. PMID- 26511151 TI - Memory of tolerance and induction of regulatory T cells by erythrocyte-targeted antigens. AB - New approaches based on induction of antigen-specific immunological tolerance are being explored for treatment of autoimmunity and prevention of immunity to protein drugs. Antigens associated with apoptotic debris are known to be processed tolerogenically in vivo. Our group is exploring an approach toward antigen-specific tolerization using erythrocyte-binding antigens, based on the premise that as the erythrocytes circulate, age and are cleared, the erythrocyte surface-bound antigen payload will be cleared tolerogenically along with the eryptotic debris. Here, we characterized the phenotypic signatures of CD8+ T cells undergoing tolerance in response to soluble and erythrocyte-targeted antigen. Signaling through programmed death-1/programmed death ligand-1 (PD-1/PD L1), but not through cytotoxic T lymphocyte antigen 4 (CTLA4), was shown to be required for antigen-specific T cell deletion, anergy and expression of regulatory markers. Generation of CD25+FOXP3+ regulatory T cells in response to erythrocyte-targeted antigens but not soluble antigen at an equimolar dose was observed, and these cells were required for long-term maintenance of immune tolerance in both the CD4+ and CD8+ T cell compartments. Evidence of infectious tolerance was observed, in that tolerance to a one antigenic epitope was able to regulate responses to other epitopes in the same protein antigen. PMID- 26511152 TI - Complications of appendicular fracture repair in cats and small dogs using locking compression plates. AB - OBJECTIVE: Our objectives were: 1) to review the complications associated with stabilization of appendicular fractures in cats and small dogs using locking compression plates (LCP), and 2) to identify factors that could influence fixation construct stability. STUDY DESIGN: Retrospective clinical study. MATERIALS AND METHODS: Medical and radiographic records of cats and small dogs with appendicular fractures treated with LCP were reviewed. Only cases with adequate follow-up to document clinical union and cases for which complications appeared before the clinical union were included. Complications were classified as implant-related complications or other complications. Cases with implant related complications were compared to cases with non-implant-related complications for differences in signalment (species, age, body weight, multiple fractures), fracture location and type (fractured bone, fracture localization, closed or open fracture), reduction method (open reduction and internal fixation [ORIF] or minimally invasive plate osteosynthesis [MIPO]) and fixation evaluations (implant size, plate-bridging ratio, plate span ratio, working length, plate screw density, number of screws and cortices engaged per plate and per main fragment, ratio between screw and bone diameter at the narrowest aspect of the bone, and presence of ancillary fixation). RESULTS: Seventy-five fractures from 63 cats (64 fractures) and 10 dogs (11 fractures) met the inclusion criteria. Eight humeral, 13 radio-ulnar, 26 femoral, and 28 tibio-fibular fractures were treated. Primary repair of the fracture was performed using 2.0 mm and 2.4 mm LCP in 22 and 53 fractures, respectively. Overall and implant-related complications were encountered in 13 and seven of 75 fractures, respectively. Fixation failure was not significantly associated with any aforementioned factor considered in this study, and in particular, there was no significant difference in the occurrence of fixation failure between fractures stabilized with two, or more than two, bicortical locking screws per main fragment. CLINICAL SIGNIFICANCE: 2.0 mm and 2.4 mm LCP were used to manage appendicular fractures in cats and small dogs. The overall complication and fixation failure rate were comparable to those reported in previous studies in which various locking plate systems were used. PMID- 26511153 TI - Reply, Letter to the Editor - Should significant weight loss mandated to be "unintentional" for resulting in and regarded as malnutrition? PMID- 26511154 TI - Reply, Letter to Editor - BMI, FFMI do not seem universally applicable in nutritional assessment & the place of SGA & functional evaluation shouldn't be overlooked. PMID- 26511155 TI - Design and synthesis of purely inorganic 3D frameworks composed of reduced vanadium clusters and manganese linkers. AB - Two purely inorganic three-dimensional (3D) frameworks [Mn4(H2O)11V(IV)(18)O42(PO4)](7-) (1) and [Mn2(H2O)7V(IV)(18)O42(PO4)](11-) (2) were synthesized under hydrothermal conditions and fully characterized by single crystal X-ray structural analysis, IR spectroscopy, thermogravimetric analysis and PXRD. Structural analysis revealed that these two compounds contained a similar all reduced polyoxoanion [V(IV)(18)O42(PO4)](15-) linked by different amounts of manganese centers to form 3D framework materials. The V centers in these two compounds were all reduced to the +IV oxidation state, resulting in an all reduced polyoxoanion, which was firstly used as the building block for constructing 3D framework materials. The all reduced typical polyoxoanion [V(IV)(18)O42(PO4)](15-) with 15 negative charges supplied enough charge amount to accept TM cations. In these two structures, the anions were surrounded by 12 and 5 Mn(2+) ions, respectively, adjusted by varying the feeding amount of MnCl2.4H2O. An electrocatalytic study revealed that compound 1 exhibits electrocatalytic activity for reduction of H2O2. PMID- 26511156 TI - Selective mono-facial modification of graphene oxide nanosheets in suspension. AB - Graphene oxide (GO) is selectively functionalized on one face to prepare Janus platelets which are characterized by various spectroscopic and microscopic techniques. With this methodology, Janus GO platelets can be prepared without the use of a solid substrate and the two platelet faces can be orthogonally modified in a one-pot reaction. PMID- 26511157 TI - Genome-wide analysis correlates Ayurveda Prakriti. AB - The practice of Ayurveda, the traditional medicine of India, is based on the concept of three major constitutional types (Vata, Pitta and Kapha) defined as "Prakriti". To the best of our knowledge, no study has convincingly correlated genomic variations with the classification of Prakriti. In the present study, we performed genome-wide SNP (single nucleotide polymorphism) analysis (Affymetrix, 6.0) of 262 well-classified male individuals (after screening 3416 subjects) belonging to three Prakritis. We found 52 SNPs (p <= 1 * 10(-5)) were significantly different between Prakritis, without any confounding effect of stratification, after 10(6) permutations. Principal component analysis (PCA) of these SNPs classified 262 individuals into their respective groups (Vata, Pitta and Kapha) irrespective of their ancestry, which represent its power in categorization. We further validated our finding with 297 Indian population samples with known ancestry. Subsequently, we found that PGM1 correlates with phenotype of Pitta as described in the ancient text of Caraka Samhita, suggesting that the phenotypic classification of India's traditional medicine has a genetic basis; and its Prakriti-based practice in vogue for many centuries resonates with personalized medicine. PMID- 26511158 TI - Adult male mice conceived by in vitro fertilization exhibit increased glucocorticoid receptor expression in fat tissue. AB - Prenatal development is highly plastic and readily influenced by the environment. Adverse conditions have been shown to alter organ development and predispose offspring to chronic diseases, including diabetes and hypertension. Notably, it appears that the changes in glucocorticoid hormones or glucocorticoid receptor (GR) levels in peripheral tissues could play a role in the development of chronic diseases. We have previously demonstrated that in vitro fertilization (IVF) and preimplantation embryo culture is associated with growth alterations and glucose intolerance in mice. However, it is unknown if GR signaling is affected in adult IVF offspring. Here we show that GR expression is increased in inbred (C57Bl6/J) and outbred (CF-1* B6D2F1/J) blastocysts following in vitro culture and elevated levels are also present in the adipose tissue of adult male mice. Importantly, genes involved in lipolysis and triglyceride synthesis and responsive to GR were also increased in adipose tissue, indicating that increased GR activates downstream gene pathways. The promoter region of GR, previously reported to be epigenetically modified by perinatal manipulation, showed no changes in DNA methylation status. Our findings demonstrate that IVF results in a long-term change in GR gene expression in a sex- and tissue-specific manner. These changes in adipose tissues may well contribute to the metabolic phenotype in mice conceived by IVF. PMID- 26511159 TI - Aligned Carbon Nanotube Thin Films from Liquid Crystal Polyelectrolyte Inks. AB - Single walled carbon nanotube thin films are fabricated by solution shearing from high concentration sodium nanotubide polyelectrolyte inks. The solutions are produced by simple stirring of the nanotubes with elemental sodium in dimethylacetamide, and the nanotubes are thus not subject to any sonication induced damage. At such elevated concentrations (~4 mg mL(-1)), the solutions exist in the liquid crystal phase and during deposition this order is transferred to the films, which are well aligned in the direction of shear with a 2D nematic order parameter of ~0.7 determined by polarized absorption measurements. Compared to similarly formed films made from superacids, the polyelectrolyte films contain smaller bundles and a much narrower distribution of bundle diameters. After p doping with an organic oxidizer, the films exhibit a very high DC electrical to optical conductivity ratio of sigma(DC)/sigma(OP) ~ 35, corresponding to a calculated DC conductivity of over 7000 S cm(-1). When very thin (T550 ~ 96%), smooth (RMS roughness, R(q) ~ 2.2 nm), and highly aligned films made via this new route are used as the front electrodes of carbon nanotube-silicon solar cells, the power conversion efficiency is almost an order of magnitude greater than that obtained when using the much rougher (R(q) ~ 20-30 nm) and less conductive (peak sigma(DC)/sigma(OP) ~ 2.5) films formed by common vacuum filtration of the same starting material, and having the same transmittance. PMID- 26511160 TI - Polymer gel electrolytes for application in aluminum deposition and rechargeable aluminum ion batteries. AB - A polymer gel electrolyte using AlCl3 complexed acrylamide as a functional monomer and acidic ionic liquid based on a mixture of 1-ethyl-3-methylimidazolium chloride (EMImCl) and AlCl3 (EMImCl-AlCl3, 1-1.5, in molar ratio) as a plasticizer has been successfully prepared for the first time via free radical polymerization. Aluminum deposition is successfully achieved using a polymer gel electrolyte containing 80 wt% ionic liquid. The polymer gel electrolytes are also good candidates for rechargeable aluminum ion batteries. PMID- 26511162 TI - Autobiography of Wolfgang Lubitz: A Professional History. PMID- 26511161 TI - Tribute to Wolfgang Lubitz. PMID- 26511166 TI - A new triterpenoid saponin from Clinopodium chinense (Benth.) O. Kuntze. AB - A new triterpene saponin, 3beta,16beta,23alpha,28beta,30beta-pentahydroxyl-olean 11,13(18)-dien-3beta-yl-[beta-D-glucopyranosyl-(1->2)]-[beta-D-glucopyranosyl-(1 >3)]-beta-D-fucopyranoside, was named Clinoposaponin D (1), together with six known triterpene saponins, buddlejasaponin IVb (2), buddlejasaponin IVa (3), buddlejasaponin IV (4), clinopodisides D (5), 11alpha,16beta,23,28 Tetrahydroxyolean-12-en-3beta-yl-[beta-D-glucopyranosyl-(1->2)]-[beta-D glucopyranosyl-(1->3)]-beta-D-fucopyranoside (6) and prosaikogenin A (7), and two known triterpenes, saikogenin A (8) and saikogenin F (9) were isolated from Clinopodium chinense (Benth.) O. Kuntze. Their structures were elucidated on the basis of 1D, 2D NMR and MS analysis. Meanwhile, the effects of all compounds on rabbit platelet aggregation and thrombin time (TT) were investigated in vitro. Compounds 4 and 7 had significant promoting effects on platelet aggregation with EC50 value at 53.4 and 12.2 MUM, respectively. In addition, the highest concentration (200 MUM) of compounds 2 and 9 shortened TT by 20.6 and 25.1%, respectively. PMID- 26511167 TI - Electronic transport in NbSe2 two-dimensional nanostructures: semiconducting characteristics and photoconductivity. AB - The electronic transport properties of two-dimensional (2D) niobium diselenide (NbSe2) layer materials with two-hexagonal single-crystalline structures grown by chemical vapor transport were investigated. Those NbSe2 nanostructures isolated simply using mechanical exfoliation were found to exhibit lower conductivity and semiconducting properties, compared with their bulk metallic counterparts. Benefiting from lower dark conductivity, NbSe2 nanoflakes exhibit a remarkable photoresponse under different wavelengths and intensity excitations. The photocurrent responsivity and photoconductive gain can reach 3.8 A W(-1) and 300, respectively; these values are higher than those of graphene and MoS2 monolayers and are comparable with those of GaS and GaSe nanosheets. The presence of electron trap states at the surface was proposed as an explanation for the reduced dark conductivity and enhanced photoconductivity in the 2D NbSe2 nanostructures. This work identifies another possibility for the application of a metallic layer material as an optoelectronic component in addition to an ultrathin transparent conducting material. PMID- 26511168 TI - Diabetes mellitus exacerbates the clinical and electrophysiological features of Guillain-Barre syndrome. AB - BACKGROUND AND PURPOSE: It is known that underlying diabetes mellitus (DM) can affect the clinical and electrophysiological pattern of coexisting peripheral neuropathies of other etiologies. The aim of this study was to identify the effect of underlying DM on the clinical and electrophysiological features of Guillain-Barre syndrome (GBS) and on the prognosis of GBS with regard to functional outcome. METHODS: This study prospectively included 27 GBS patients with DM (GBS-DM+) and 58 GBS patients without DM (GBS-DM-) from two university based hospitals. The clinical and electrophysiological findings were compared between the two groups. The functional outcomes were quantified by measuring the Hughes grade, whose values were compared between the groups at 3 months after symptom onset. RESULTS: All three sudden deaths that occurred during the acute stage of GBS were GBS-DM+ patients. GBS-DM+ patients had a tendency toward more frequent sensory involvement, and specific electrophysiological patterns and calculated indices disclosed a distal accentuation of conduction abnormalities in these patients. In addition, multivariate analysis identified history of mechanical ventilation (odds ratio 10.057, 95% confidence interval 2.057-49.164, P = 0.04) and DM (odds ratio 9.049, 95% confidence interval 2.152-38.044, P = 0.003) as independent factors for poor functional outcome at 3 months. CONCLUSIONS: The findings of this study suggest that DM exacerbates the clinical and electrophysiological features of GBS and influences long-term disability. Both chronic inflammation and nerve ischaemia in DM may intervene in the disease course of GBS, which is a prototype of acute inflammatory neuropathy. PMID- 26511169 TI - Maternal serum uric acid concentration is associated with the expression of tumour necrosis factor-alpha and intercellular adhesion molecule-1 in patients with preeclampsia. AB - We aimed to investigate whether there is a correlation between elevated serum uric acid (SUA) concentration and endothelial inflammatory response in women with preeclampsia (PE). On the basis of clinical and laboratory findings, patients were assigned to three groups: normal blood pressure (Control (Con)), gestational hypertension (GH) and PE (n=50 in each group). SUA concentration was measured by spectrophotometry, and serum tumour necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) levels were measured by enzyme-linked immunosorbent assay. Western blotting and immunohistochemical staining were also used to detect the changes in TNF-alpha and ICAM-1 expression in subcutaneous fat tissue. PE patients showed significantly higher systolic and diastolic blood pressures compared with Con and GH pregnant women (P=0.02 and P=0.02, respectively). The changes of body mass index (DeltaBMI) before and after pregnancy and 24-h urine protein were significantly different among the three groups (P<0.001). Maternal SUA, TNF-alpha and soluble ICAM-1 (sICAM-1) levels were significantly increased in the patients with PE (P<0.05) compared with the other two groups. Scatterplot analysis revealed that elevated SUA concentration positively correlated with TNF-alpha and sICAM-1 in pregnant women. Moreover, vessels in subcutaneous fat tissues of preeclamptic patients showed intense TNF alpha and ICAM-1 staining compared with Con and GH patients. The results support that, to a certain extent, elevated SUA concentration is significantly associated with inflammation of maternal systemic vasculature as indicated by increased TNF alpha and ICAM-1 expression in women with PE. PMID- 26511170 TI - EFFECT OF SOMATOSTATIN ON DENTAL PULP STEM CELLS. AB - Dental pulp stem cells (DPSCs) are multipotent stem cells with the potential to differentiate into various cell types. For this reason, they have been proposed as an alternative source for mesenchymal stem cells. Somatostatin is a peptide hormone with an inhibitory effect on several endogenous hormones. The aim of our study is to investigate whether somatostatin can promote or inhibit differentiation of DPSCs in osteoblasts and bone tissue. DPSCs were extracted from third molars of healthy subjects, and were treated with somatostatin at the concentration of 100 ng/ml for 24 and 48 h. Gene expression in treated DPSCs was compared with untreated cells (control) in order to check the effect of somatostatin on stem cell differentiation. After 24 h of treatment many genes investigated were down-regulated in treated DPSCs vs untreated DPSCs. Significantly up-regulated gene (Fold change > 2) was the Bone Morphogenetic Protein BMP4. On the contrary somatostatin induced the over-expression of bone related genes after 48 h of treatment (i.e. BMPR1B and BMPR2). TGFB family genes and their receptors were also significantly up-regulated after 48 h of treatment. Somatostatin demonstrated to promote the self-renewal of DPSCs: in our experiments somatostatin mainly acted on TGFB family genes. Further studies are needed to explore this new way of creating bone tissue. PMID- 26511171 TI - SHORT VERSUS STANDARD LENGTH IMPLANTS: A CASE SERIES ANALYSIS. AB - The use of short implants (SIs) has had a great success, particularly in posterior jaws, because SIs avoid the need of alveolar crest reconstruction or sinus lifting. The aim of this study is to perform a retrospective study on 808 SIs to evaluate their survival rate. In the period between January 2008 and December 2013, 877 patients (498 females and 379 males) were operated at the BDD private Practice Clinic (Milan, Italy). The mean post-surgical follow-up was 30+/ 17 months (max ? min, 84 ? 1). Eight hundred and eight implants (EDIERRE Implant System SpA, Genoa, Italy) were included in the present study, 119 (14.7%) 9.0 mm (i.e. short) and 689 (85.3%) 11.0 mm long. All patients underwent the same surgical protocol and agreed to participate in a post-operative check-up program. SPSS program was used for statistical analysis. Survival rate (SVR) was 97.4% since only 21 fixtures were lost from a total of 808 implants. Cross-tabulation between failures and immediate loading had a statistical significant value (p= 0.006) in respect to delayed loading. There were 10 failures out of 161 immediate loaded implants compared to 11 failures out of 626 delayed loaded fixtures. SIs are reliable devices for oral rehabilitation. PMID- 26511172 TI - PILOT EVALUATION OF A SIMPLE ADJUNCTIVE METHOD FOR IMPROVED REMOVAL OF ORAL BIOFILM DURING CONVENTIONAL SCALING AND ROOT PLANING THERAPY. AB - Various studies have evaluated the adjunctive use of chemical and antimicrobial treatments to assist in the mechanical removal of oral microbial biofilm from tissue surfaces during scaling and root planning therapy (SRP). The current study demonstrates the elimination of two classes of surrogate molecular markers from periodontal disease sites. This suggests the current agent may be a more effective adjunctive cleansing agent for complete biofilm removal. A patient with advanced chronic periodontitis was subjected to standard SRP therapy, supplemented by irrigation with HYBENX(r) (HBX). Samples of gingival crevicular fluid were collected with triplicate absorbent paper points from each of three quadrants at three time points: 1) at baseline prior to treatment; 2) after irrigation with the topical agent for 20 seconds and rinsing; and 3) after SRP followed by a second irrigation/rinsing treatment with the agent. Paper points were extracted to assess the presence of 13 bacterial species known to be primarily associated with periodontal disease using DNA pyrosequencing. In addition, the presence of Matrix Metalloproteinase-8 (MMP8), as well as IL-1beta, IL-6, and TNF-alpha were also assessed by immunoassay of the paper point sample extracts. The combined adjunctive treatment indicated a complete absence of detectable bacterial DNA and the four inflammatory mediators from samples taken from the gingival sulci treated with HBX. The advantage of the current adjunctive topical treatment technique is that it is simple and easy to administer in conjunction with standard SRP techniques. It appears to provide a level of cleanliness not currently achieved with other SRP adjunctive procedures. PMID- 26511173 TI - COMPARISON BETWEEN LONG AND STANDARD LENGTH IMPLANTS10. AB - Long implants (LI, i.e. longer than 13 mm) are thought to give longer survival than standard length fixtures. The aim of this study is to evaluate the survival rate of 780 LI. In the period between January 2008 and December 2013, 877 patients (498 females and 379 males) were operated at the BDD private Practice Clinic (Milan, Italy). The mean post-surgical follow-up was 30+/-17 months (max ? min, 84 ? 1). One thousand seven hundred and fifty-three fixtures (EDIERRE Implant System SpA, Genoa, Italy) were evaluated in the present study, 780 15 mm long (LI) and 972 13 mm long (i.e. standard length implants). All patients underwent the same surgical protocol and agreed to participate in a post operative check-up program. SPSS program was used for statistical analysis. Survival rate (SVR) was 97.8% since only 38 fixtures were lost from a total of 1,752 implants. Cross-tabulation between failures and jaws had a statistical significant value (p= 0.027) with worse results fox maxilla (23 failures out of 768 implants). Also tooth position has an impact (p= 0.027) since incisors plus canines had 18 failures out of 550 implants whereas premolars and molars had 20 lost fixtures out of 1,202. LIs give a small but significative advantage in oral rehabilitation. PMID- 26511174 TI - IMMEDIATE VERSUS DELAYED LOADING IMPLANTS: RATIONALE AND CONTROVERSIES. AB - Loading implants immediately after their position in alveolar bone crest is a procedure that has become popular in the last decade. The aim of this study is to evaluate the survival rate of 811 immediate loaded implants (ILIs). In the period between January 2008 and December 2013, 877 patients (498 females and 379 males) were operated at the BDD private Practice Clinic (Milan, Italy). The mean post surgical follow-up was 30+/-17 months (max ? min, 84 ? 1). One thousasnd three hundred and eighty-six fixtures (EDIERRE Implant System SpA, Genoa, Italy) were evaluated in the present study, 811 immediately loaded and 575 loaded after 3 months. All patients underwent the same surgical protocol and agreed to participate in a post-operative check-up program. SPSS program was used for statistical analysis. Survival rate (SVR) was 97.3% since only 38 fixtures were lost from a total of 1,348 implants. Cross-tabulation between failures demonstrated slight but significant worse results for ILIs (p= 0.037). There were 28 failures out of 811 ILIs whereas only 10 fixtures were lost out of 565 implants loaded after 3 months. Immediate loading performed in selected cases is a reliable tool for oral rehabilitation. PMID- 26511175 TI - IMPLANTS INSERTED IN POST EXTRACTIVE SOCKETS HAVE SURVIVAL RATES SIMILAR TO FIXTURES INSERTED IN HEALED BONE: A CASE SERIES STUDY. AB - Post-extractive implants (i.e. PEIs) are widely used to reduce surgical steps and improve patient compliance. The aim of this study is to perform a retrospective study on 2,273 PEIs to evaluate their survival rate. In the period between January 2008 and December 2013, 877 patients (498 females and 379 males) were operated at the BDD private Practice Clinic (Milan, Italy). The mean post surgical follow-up was 30+/-17 months (max ? min, 84 ? 1). Two thousand two hundred and seventy-three PEIs (EDIERRE Implant System SpA, Genoa, Italy) were evaluated in the present study. All patients underwent the same surgical protocol and agreed to participate in a post-operative check-up program. SPSS program was used for statistical analysis. Survival rate (SVR) was 97.7% since only 53 fixtures were lost from a total of 2,273 implants. Cross-tabulation between failures and timing of loading demonstrated a statistically significant higher risk of failures in case of immediate loading (p= 0.013). There were 26 failures out of 761 immediate loaded implants against 27 lost fixtures out of 1,485 delayed loaded implants. PEIs is a reliable procedure, however surgeons should carefully select those cases which can be immediately loaded. PMID- 26511176 TI - CLINICAL OUTCOME OF 2,560 IMPLANTS AFTER A MEAN OF 30-MONTH FOLLOW-UP. AB - The advantage of implantology is to replace dental loss with a fixed prosthesis even in cases of partial or total edentulism without damaging the natural teeth. In the period between January 2008 and December 2013, 877 patients (498 females and 379 males) were operated at the BDD private Practice Clinic (Milan, Italy). The mean post-surgical follow-up was 30+/-17 months (max ? min, 84 ? 1). Two thousand five hundred and sixty out of 2,657 implants had a complete record and were evaluated in the present study. The implants were of different diameters and length, inserted both in mandible (1,327) and in maxilla (1,233) with immediate or delayed loading, and with graft, split crest, post-extraction, osteo condensation, small and big sinus lift techniques, respectively. Fifty-nine out of 2,560 implants were lost (i.e. SVR = 97.7%). Cross-tabulation between failures and timing of loading (p= 0.008) had a statistically significant value, with a worse result for immediate loading (28 failures out of 783). In other comparisons between lost implants and diameter (p= 0.074), length (p=0.293), jaws (i.e. maxilla vs mandible, p=0.208), replaced teeth (incisors plus cuspids vs premolars plus molars, p=0.074), insertion torque (p=0.528), surgeons (p=0.452) and additional surgical procedures (i.e. split crest, post-extraction, graft, osteo condensation, transposition, small and big sinus lift techniques, p= 0.713) no statistically significant difference was detected. EDIERRE Implant System SpA (Genova, Italy) implants have a high SVR (97.7%) allowing more simple surgical procedures for oral rehabilitation of partially or totally edentulous jaws. PMID- 26511177 TI - SURVIVAL RATES OF NARROW VERSUS STANDARD DIAMETER IMPLANTS IN DIFFERENT TREATMENT OPTIONS: A RETROSPECTIVE STUDY. AB - Implant dentistry has had a great success in the last decades for replacing missing teeth; however, implant surgery needs bone availability. The use of narrow diameter implants (NDIs) may be an alternative approach in patients with atrophic maxilla or mandible. The aim of this study is to perform a study on NDIs to evaluate their survival rate. In the period between January 2008 and December 2013, 877 patients (498 females and 379 males) were operated at the BDD private Practice Clinic (Milan, Italy). The mean post-surgical follow-up was 30+/-17 months (max ? min, 84 ? 1). One thousand three hundred and forty-six implants (EDIERRE Implant System SpA, Genoa, Italy) were included in the present study, 112 (8.3%) 3.3 mm (i.e. narrow) and 1,234 (91.7%) 3.75 mm wide. All patients underwent the same surgical protocol and agreed to participate in a post operative check-up program. SPSS program was used for statistical analysis. Survival rate (SVR) was 97.25% since only 37 fixtures were lost from a total of 1,346 implants. Cross-tabulation between failure diameter did not demonstrate any statistical differences between narrow and standard diameter implants. NDIs are reliable devices for oral rehabilitation. PMID- 26511178 TI - ARE WIDE DIAMETER IMPLANTS RELIABLE FOR JAW?S REHABILITATION? A RETROSPECTIVE STUDY ON 450 IMPLANTS. AB - The use of wide diameter implants (WDI) have had a great success, particularly in posterior jaws, because WDI can ensure an increased bone-implant contact, better withstanding occlusal forces and creating a wider platform for prosthesis. The aim of this study is to perform a study on 450 WDI to evaluate their survival rate. In the period between January 2008 and December 2013, 877 patients (498 females and 379 males) were operated at the BDD private Practice Clinic (Milan, Italy). The mean post-surgical follow-up was 30+/-17 months (max ? min, 84 ? 1). Four hundred and fifty WDI (EDIERRE Implant System SpA, Genoa, Italy) were included in the present study, 326 (72.4%) 4.5 mm and 124 (27.6%) 5 mm. All patients underwent the same surgical protocol and agreed to participate in a post operative check-up program. SPSS program was used for statistical analysis. Survival rate (SVR) was 97.3% since only 12 fixtures were lost from a total of 450 implants. Cross-tabulation between failures and immediate loading had a statistically significant value (p= 0.009) in respect to delayed loading. There were 8 failures out of 128 immediate loaded implants in respect to 4 failures out of 315 delayed loaded fixtures. WDI are reliable devices for oral rehabilitation with high SVR. PMID- 26511179 TI - IN VIVO CHARACTERIZATION OF ORAL PEMPHIGUS VULGARIS BY OPTICAL COHERENCE TOMOGRAPHY. AB - Pemphigus vulgaris (PV) is an autoimmune disease that manifests as intraepithelial blisters in skin and mucous membranes. We report the case of a 62 year-old female patient with clinical picture of desquamative gingivitis and a histological and serological diagnosis of pemphigus vulgaris. The aim of this study is to analyse bollous oral diseases in order to evaluate the feasibility to image epithelial architecture of oral mucosae using in vivo optical coherence tomography. Optical coherence tomography seems to be a valid non-invasive auxiliary diagnostic device able to show in vivo the epithelial layers and basal membrane. PMID- 26511180 TI - RECONSTRUCTION OF THE ZYGOMATIC BONE WITH SMARTBONE(r): CASE REPORT. AB - The repair of complex craniofacial bone defects is challenging and a successful result depends on the defect size, the quality of the soft tissue covering the defect and the choice of reconstructive method. Autologous bone grafts are the gold standard for bone replacement. Tissue engineered constructs are temporary substitutes developed to treat damaged or lost tissue. Recent advances in materials science have provided an abundance of innovations, underlining the increasing importance of polymer in this field. The Galeazzi Orthopedical institute of Milan received a Serbian soldier who reported a deep wound, due to the explosion of a grenade, during former-Yugoslavia?s war. His left cheekbone was completely lost, together with the floor of the left eye. SmartBone(r) technology allowed the realization of custom-made grafts which perfectly fitted the bone defect thanks to mechanical strength, also at small thicknesses, and the ability to be shaped without powder formation or unpredicted fractures. Tissue engineering approaches to regeneration utilize 3-dimensional (3D) biomaterial matrices that interact favorably with cells. The potential benefits of using a tissue engineering approach include reduced donor site morbidity, shortened operative time, decreased technical difficulty of the repair, ability to closely mimic the in vivo microenvironment in an attempt to recapitulate normal craniofacial development: this 36-month case study allowed to prove that SmartBone(r) custom-made bone grafts are an effective solution, gathering such benefits and being available now for daily routine. PMID- 26511181 TI - INSULIN ACTIVITY ON DENTAL PULP STEM CELL DIFFERENTIATION: AN IN VITRO STUDY. AB - Insulin is a powerful and important hormone involved in the proliferation and differentiation of osteoblasts. Dental pulp stem cells (DPSCs) have the ability to self-expand and differentiate in pre-osteoblast, producing in vitro autologous bone tissue. The aim of our study is to investigate whether insulin can influence differentiation of DPSCs in osteoblast and bone tissue. Dental germ pulp was extracted from third molars of healthy subjects, following informed consent. DPSCs were treated with insulin at the concentration of 100 ng/MUl for 24 and 48 h. Gene expression in treated DPSCs was compared with untreated cells (control) in order to check the effect of insulin on stem cell differentiation. After 24 h, significant up-regulated genes (Fold change > 2) in DPSCs were the Bone Morphogenetic Proteins BMP3, BMP4 and their receptor BMPR1A. BMP1 results over expressed after 48 h of treatment. Significantly down-regulated genes were BMP4, BMP7 and TGFBR2 after 24 h of treatment and BMP5 and BMP7 after 48 h. Insulin was demonstrated to influence proliferation of DPSC, differentiation and expansion in osteoblasts. Further studies are needed to explore this new way of creating bone tissue. PMID- 26511182 TI - SINGLE APPLICATION OF A DESSICATING AGENT IN THE TREATMENT OF RECURRENT APHTHOUS STOMATITIS. AB - Recurrent aphtous stomatitis (aphthae, canker sores) is ones of the most common and painful oral mucosal inflammatory ulcerative conditions; etiopathogenesis is uncertain and only symptomatic therapy is available. We used a dessicating agent based on a concentrated mixture of sulfates. The rationale for use of this product on canker sores is that it cauterises the epithelial tissue affected by the immune response. The aim of this study was to evaluate the topical application of this dessicating agent on aphtous ulcers, and verify its efficacy in reducing pain. Fifty-seven patients, with oral minor aphtous lesions and a history of recurrent aphtous stomatitis were enrolled into this study and were assigned into two groups: 30 patients were treated with a single topical application of a dessicating agent and 27 without any treatment. A subjective evaluation of symptoms was completed by each patient using a visual analog scale (VAS) of 0-10. Patients? oral lesions were clinically observed at days 0 (before entering the study) and at day 6. We found that from day three the mean differences in pain score between the two groups was about 16.33% with a decrease of symptoms of 49.57% compared with pretreatment VAS score at baseline (P 0.001). Unfortunately, if we compare the mean differences from baseline in the range of 6 days of pretreatment until day 6 in the group treated with the dessicating agent and in the one receiving no treatment, performing an unpaired t-test, no significant differences appeared (P>0.05). These data suggest that a single application of this medicament could become a valid support in the management of recurrent aphtous stomatitis. PMID- 26511183 TI - CRESTAL SINUS LIFT USING A FLUIDO-DYNAMIC COMPUTER GUIDED PRECISE AND ATRAUMATIC TECHNIQUE. AB - One of the most frequent reasons for failure during the maxillary sinus floor lift operation is connected to the possibility of a rupture of the Schneiderian membrane which, if lacerated, cannot perform the function of graft containment. In order to reduce the incidence of complications it is necessary to cut the hard tissue with extreme accuracy and as little trauma as possible, while saving the soft tissue. The precision of pre-operation measures obtained through endoral x rays, dental-scans and cone-beam CT allows us to approach and cut with delicacy the sinus cortical floor. The recent development of computer guided surgery gives the possibility of planning the operation, which reduces the risk of failure. The cortical of the maxillary sinus is reduced through the use of calibrated burs and a profiler to obtain a hole that enables both access to the maxillary sinus and, subsequently, the lifting of the Schneiderian membrane. Each stage of the operation is monitored and all the devices used pass through a custom-made template, which acts as a surgical guide. The sinus was filled using fluid biomaterial distributed through a dispenser, which had been created specifically for this technique. Due to the reduction in trauma and the fact that the process is much less invasive, this technique could be a valid alternative to the techniques known and carried out to date. Work time is reduced to less than 3 minutes in the cortical thinning operation and percussive trauma is avoided. PMID- 26511184 TI - STRAIN ANALYSIS OF MASSETER MUSCLE BY ULTRASOUND. AB - The masseter muscle represents an area of important functional interest. The present study aims to verify the feasibility of ultrasound imaging for quantifying the muscular deformation pattern in the masseter. Fifteen consecutive subjects were enrolled and underwent masseter ultrasound according to a repeatable protocol. Ultrasound was carried out during teeth clenching in natural conditions and after the insertion of a medical device that alters the distance between the dental arches, and was repeated on 3 different days. Results showed that masseter deformation is not uniform within the muscle. The same strain patterns were repeated in the different ultrasounds of the same patient and were modified after the introduction of a medical device. This was supported by quantitative comparisons in the deep portion of the muscle (standard deviation on the three measures: 3% normal conditions, 2% with medical device) showing a systematic reduction with the prosthesis (30% on average). This study demonstrated that masseter strain analysis is a repeatable and sensitive tool for the study of functional analysis of the masticatory organ. This opens new technical perspectives for the diagnosis and therapy of dysfunctional pathologies of the masticatory organ. PMID- 26511185 TI - IN VITRO ANALYSIS OF MARGINAL ADAPTATION AND RESISTANCE OF DIFFERENT DENTAL COMPOSITES: STEREO AND SCANNING ELECTRON MICROSCOPIC EVALUATION. AB - To compare the performance, by scanning electron microscopic analysis, of the interface between tooth and four commercial restorative composite resins in Class I cavities following exposure to acidified artificial solution, pH 4.5, with a background electrolyte composition similar to saliva, 600 teeth were divided into 4 groups. The first group was treated with microfilled light-cured Heliomolar; the second group with Durafill; the third group with the microfilled self-cured Isomolar; and the fourth group was treated using the hybrid self-cured Miradapt. All teeth of each group were randomly divided into two sub-groups: A) a control group that was immersed in artificial saliva (pH 7); B) a study group that was immersed in artificial saliva acidified with phosphoric acid (pH 4.5) in order to obtain artificial caries. The samples were examined by scanning electron microscopy. Data were analyzed using Pearson?s Chi-squared test (chi2) with R statistical software. The statistical analyses demonstrated significant differences in the two sub-groups A and B when considered for the light-cured composites whereas no difference was monitored for self-cured composites. Statistical analysis (p minore di 0.001) also demonstrated that the type of composite strongly influenced the infiltration grade. Our results demonstrate that incremental layering techniques might improve the marginal adaptation for light-cured composites, while self-cured show a marked polymerization contraction which can cause marginal breakdown. PMID- 26511186 TI - CDH1 POLYMORPHISMS AND LOW EXPRESSION OF E-CADHERIN AND beta-CATENIN IN COLORECTAL CANCER PATIENTS. AB - Epithelial-mesenchymal transition (EMT) process has a central role in tumor progression and metastases. Loss of cell-to-cell adhesiveness is a key step in EMT. In particular, E-cadherin and beta-catenin, components of the adherens junctions, play a strategic role. Accumulation of beta-catenin at cytoplasmic level following adherens junctions disruption, induces its translocation into the nucleus, where it binds to members of the TCF/LEF family of transcription factors. In particular, Lymphoid Enhancer-Binding factor 1 (LEF1) product can target genes involved in EMT. The aim of the present study was to evaluate the influence of CDH1 and CTNNB1 genes, coding for E-cadherin and beta-catenin respectively and LEF1 in a sample study of 140 Italian patients affected by colorectal cancer. An association study between four single nucleotide polymorphisms (rs11865026, rs11642413, rs13689, and rs10431923) of CDH1 and the disease did not provide statistically significant results. The gene expression analysis carried out for CDH1, CTNNB1 and LEF1 in 54 paired specimens from 27 patients provided evidence of a reduced expression of the first two in cancer tissues. We believe there may be a sort of cross regulation between the products of these two genes which closely interact in EMT activation and that such hypothesis should be further investigated in a greater number of cases. PMID- 26511187 TI - REGENERATION OF ATROPHIC CRESTAL RIDGES WITH RESORBABLE LAMINA: TECHNICAL NOTE. AB - Several techniques have been proposed to increase the mandibular bone base, both horizontally and vertically, for implant purposes in atrophic distal ridges. Block graft and titanium grids are frequently used for this purpose. The former need to be fixed, in the case of an autologous bone block require a donor site graft, and if not kept sufficiently vascularized could result in necrosis. The latter are manageable with difficulties in the event of exposure and are removed with difficulty. In this work a technique is proposed which makes use of resorbable cortical lamina in order to create recipient sites which can be filled with prehydrated and collagenated granules covered by mesenchymal resorbable membranes. We demonstrated with this technique the good vascularization of the graft combined with the integration of the lamina, which do not need to be removed. Our results allow us to propose this technique as a potential alternative to those used to date. PMID- 26511188 TI - QUANTITATIVE ANALYSIS OF PERIODONTAL PATHOGENS IN PERIODONTITIS AND GINGIVITIS. AB - Periodontal tissues surround the teeth and provide their attachment. Periodontal diseases include a mild and reversible form named gingivitis and periodontitis that is the main cause of tooth loss in adults. Gingivitis, that affects gums and coronal junctional epithelium, as well as periodontitis, that is characterized by loss of connective tissue attachment, are caused by a persistent inflammatory response promoted by alteration of periodontal biofilm. The aim of the study was to test whether the prevalence or relative amount of each species was associated with a particular clinical condition. Periodontal evaluation of 539 unrelated patients was performed by the Periodontal Screening and Recording (PSR) system. Subgingival samples were obtained from the site with the worst PSR score. A selection of eleven bacterial species was evaluated by quantitative real time PCR. Some bacterial species were found to be associated with all phases of periodontal disease, such as Tannerella forsythia, Treponema denticola, and Treponema lecithinolyticum, while other species were more specifically associated with periodontitis, such as Porphyromonas endodontalis and Porphyromonas gingivalis, or with gingivitis, such as Capnocytophaga ochracea and Campylobacter rectus. Quantitative and qualitative analyses helps to better understand the microbial changes associated with different stages of periodontal disease. PMID- 26511189 TI - INTERLEUKIN-6 GENE POLYMORPHISM MODULATES THE RISK OF PERIODONTAL DISEASES. AB - Gingivitis and periodontitis are the two main periodontal diseases. Both are characterized by inflammation of the tissues surrounding the teeth but while tissue damages observed in gingivitis are mild and reversible, destruction caused by periodontitis is deeper and irreversible. Periodontal diseases and levels of degeneration of tissues surrounding teeth depend on several interacting endogenous and exogenous factors. Polymorphisms of genes encoding molecules that modulate the immune response and tissue homeostasis are the main causes of individual susceptibility to periodontal diseases. The aim of this study was to investigate IL6, IL10 and VDR gene polymorphisms in a large number of subjects affected by either gingivitis or chronic periodontitis. The sample included 750 Italian patients. We found that the rs1800795 SNP located in the IL6 gene promoter was strongly associated with the occurrence of both gingivitis and periodontitis. Indeed, homozygous individuals with variant allele appeared less susceptible to both gingivitis OR=0.47 (95% C.I. 0.27-0.82) and periodontitis OR=0.36 (95% C.I. 0.21-0.64). No evidence of association between periodontal diseases and IL10 or VDR polymorphisms was obtained. This data confirmed the role of IL6 in susceptibility to periodontitis among the Italian population. The evidence that IL6 polymorphisms are also involved in gingivitis has implications in periodontal disease pathogenesis and reduces the appeal of IL6 as a periodontitis biomarker. PMID- 26511190 TI - E-CADHERIN CODING GENE (CDH1) AND NONSYNDROMIC CLEFT LIP WITH OR WITHOUT CLEFT PALATE: IS THERE ANY ASSOCIATION? AB - Epithelial to Mesenchymal Transition (EMT) is an important process involved in cancer, embryogenesis and organ development. Its role in nonsyndromic cleft lip with or without cleft palate (NSCL/P) has been extensively investigated and successfully linked to the disease. In this study, we focused on a gene, CDH1, encoding for E-cadherin, a key protein in EMT. We carried out an association study on an Italian sample group, genotyping four single nucleotide variations within the CDH1 gene, in order to verify the potential role of this gene in NSCL/P etiology. Neither the haplotype nor the family-based association test revealed any association between the genotyped SNPs and the pathology. Our results demonstrate that, in our Italian sample study, the analyzed single nucleotide polymorphisms are not associated to NSCL/P. PMID- 26511191 TI - PERIODONTAL POCKETS AS A RESERVOIR OF HELICOBACTER PYLORI CAUSING RELAPSE OF GASTRIC ULCER: A REVIEW OF THE LITERATURE. AB - Helicobacter pylori (HP) is one of the most common gastric infections in the world, affecting about half the world?s population and is the principal cause of adenocarcinoma of the distal stomach. It seems that HP infects the subject early in life and is transmitted from person to person. The HP reaches the stomach through oral ingestion, and because of its non-invasive nature, the stomach is the ultimate site of colonization. Recently, it has been debated whether the oral cavity is a reservoir of HP bacteria participating in infection transmission, or representing a nidus of re-infection after eradication of the bacterium. HP and recurrent aphthous stomatitis (RAS) show similar clinical and histological findings, and the discovery of HP in RAS ulcers support the idea of a correlation between the two diseases. Another important relationship between RAS and HP is the high incidence of anemia in patients with RAS that may be caused by HP positive stomach disease. In fact, antibiotic therapy and treatment of anemia can reduce the frequency of RAS ulcer recurrence. HP is considered a carcinogenic agent type 1 of the stomach by the International Agency for Research on Cancer. In conclusion, the oral cavity is an extra-gastric reservoir of HP and periodontal therapy associated with systemic therapy can better eradicate HP from the mucosa of all gastro-enteric tract, reducing relapse of HP infection. Prospective cohort studies are needed to demonstrate the bacterial action in the oral cavity. PMID- 26511192 TI - EVALUATION OF THE EFFICACY OF TITANIUM DIOXIDE WITH MONOVALENT SILVER IONS COVALENTLY LINKED (TIAB) AS AN ADJUNCT TO SCALING AND ROOT PLANING IN THE MANAGEMENT OF CHRONIC PERIODONTITIS USING PCR ANALYSIS: A MICROBIOLOGICAL STUDY. AB - The use of chemical devices for non-surgical periodontal therapy has led to new treatment strategies aimed primarily at controlling infection. Over the last few years, titanium dioxide (TiO2) with monovalent silver ions (A) covalently linked and added to benzalkonium (B) (named TIAB) has been subjected to medical studies, especially in dermatology. The purpose of the present study was to assess the effect of TIAB on the red complex bacteria using Polymerase Chain Reaction (PCR) for microbiological analysis. A split mouth study was conducted, and 10 subjects were enrolled. TIAB as topical medication was placed at study sites after scaling and root planing. Sub-gingival plaque samples were collected after 2 weeks, and red complex micro-organisms were studied using PCR. SPSS program was used for statistical purposes and a paired sample correlation was performed at the end of the observation period between treated and untreated sites. The results showed statistically significant reduction of red complex organisms in the study compared to the control group. TIAB can be used as an effective local drug along with supportive periodontal therapy in treatment of chronic periodontitis. PMID- 26511193 TI - POLYMERASE CHAIN REACTION TO EVALUATE THE EFFICACY OF SILICA DIOXIDE COLLOIDAL SOLUTIONS IN THE TREATMENT OF CHRONIC PERIODONTITIS: A CASE CONTROL STUDY. AB - The objective of this study was to compare the efficacy of supportive periodontal therapy [i.e. scaling and rooth planing (SRP)] alone versus a chemical silica dioxide (SiO2) colloidal solution (SDCS) device used in association with SRP in the treatment of chronic periodontitis in adult patients. A total of 20 patients with a diagnosis of chronic periodontitis (40 localized chronic periodontitis sites) in the age group of 35 to 55 were selected. None of these patients had previously received any surgical or non-surgical periodontal therapy and had radiographic evidence of moderate bone loss. Two non-adjacent sites in separate quadrants were selected in each patient to monitorize treatment efficacy (split mouth design). Clinical pocket depth (PD) and microbial analysis (MA) were analyzed at baseline and on 15th day. SPSS program and paired simple statistic t test were used to detect significant differences. Total bacteria loading, Tannerella forsitia and Treponema denticola loading were statistically reduced when SiO2 was locally delivered. SDCS gel is an adjuvant therapy which should be added to SRP in the management of moderate-to-severe chronic periodontitis. PMID- 26511194 TI - COMPOSITE POLYMER-COATED MINERAL SCAFFOLDS FOR BONE REGENERATION: FROM MATERIAL CHARACTERIZATION TO HUMAN STUDIES. AB - Bovine bone xenografts, made of hydroxyapatite (HA), were coated with poly(L lactide-co-epsilon- caprolactone) (PLCL) and RGD-containing collagen fragments in order to increase mechanical properties, hydrophilicity, cell adhesion and osteogenicity. In vitro the scaffold microstructure was investigated with Environmental Scanning Electronic Microscopy (ESEM) analysis and micro tomography, while mechanical properties were investigated by means compression tests. In addition, cell attachment and growth within the three-dimensional scaffold inner structure were validated using human osteosarcoma cell lines (SAOS 2 and MG-63). Standard ISO in vivo biocompatibility studies were carried out on model animals, while bone regenerations in humans were performed to assess the efficacy of the product. All results from in vitro to in vivo investigations are here reported, underlining that this scaffold promotes bone regeneration and has good clinical outcome. PMID- 26511195 TI - HYALURONIC ACID IN DERMAL REJUVENATION: AN IN VITRO STUDY. AB - The purpose of this paper is to evaluate the role of hyaluronic acid in bio revitalization by testing several extracellular matrix biological parameters in cultured dermal fibroblasts. To this aim, fibroblastic expressed genes after exposition to three hyaluronic acid medical devices were evaluated. Cells were seeded on a layer of three different medical devices containing 6.2, 10 and 20 mg/ml of hyaluronic acid for 24 h. Real Time Polymerase Chain Reaction was performed to investigate gene expressions. Genes encoding hyaluronic acid synthesis and degradation, Metalloproteinases 2 and 3 and Desmoplakin production as well as GDF6, and IGF1 were activated by hyaluronic acid products. The in vitro study showed similar effects on tested genes despite a different concentration of hyaluronic acid contained in the medical devices and the simultaneous presence of other additives. Based on the reported data, gene activations are an aspect of metabolic modulation of signalling pathways rather than the proportional production of a specific connective tissue molecule. Indeed different hyaluronic acid concentration and the presence of other additives did not change the overall effect on the studied genes. We believe that the optimization of extracellular matrix micro-environment, obtained by enhanced structural support with hyaluronic acid, leads to functional and metabolic improvement. PMID- 26511196 TI - THE THEORIES OF AGING: REACTIVE OXYGEN SPECIES AND WHAT ELSE? AB - This manuscript is a short review on the theories of aging, focusing mainly on the balance between the nutrient and the oxygen intake necessary for energy metabolism and the processes for neutralizing the negative consequences of energy production. The first section entitled ?Why? provides brief historical details regarding the main group of aging theories, firstly the evolutionary theories and secondly the theories of aging related to humans, cells and biomolecules are discussed. The second section entitled ?Where? includes brief summaries of the many cellular levels at which aging damage can occur: replicative senescence with its genetic and epigenetic implications, cytoplasmic accumulation, mitochondrial respiratory chain dysfunction, peroxisome and membrane activity. In the third section entitled ?How? the linking mechanisms between the caloric restriction and the antioxidant intake on lifespan and aging in experimental models are discussed. The role of ROS is evaluated in relation to the mitochondria, the AMPK activated sirtuins, the hormesis, the target of rapamicin and the balance autophagy/apoptosis. PMID- 26511197 TI - NONSURGICAL PERIODONTAL MANAGEMENT OF IATROGENIC PERI-IMPLANTITIS: A CLINICAL REPORT. AB - Dental implants have emerged as a first line of treatment to replace missing teeth for both the edentulous and partially dentate patients. The anticipated high degree of success is somewhat challenged by the onset of peri-implantitis. Peri-implant diseases are a cluster of ?contemporary? oral infections in humans; they are characterized by the inflammatory destruction of the implant-supporting tissues, as a result of biofilm formation on the implant surface. It is still not clear how the roles of its etiologic agents work. A history of periodontitis, poor oral hygiene, and smoking are considered as risk factors for peri-implant diseases. Occasionally failing implants are associated with iatrogenic factors, that, only recently, have been acknowledged as direct cause of peri-implant complications, i.e.: non-parallel adjacent implants or the presence of a gap, between fixture and prosthetic components. The use both of traditional protocols of nonsurgical periodontal therapy and the diode laser seems to be an effective alternative treatment modality for peri-implantitis. By the application of laser assisted non-surgical peri-implant therapy the periodontal pocket depth was reduced. Intraoral periapical radiographs, taken at 6 months and 1 year post nonsurgical treatment, seemed to provide evidence of some improvement of the bone level. The present article illustrates the nonsurgical management of one case, where failure to remove residual cement, from an implant-supported dental prosthesis, seemed to cause peri-implant inflammation. PMID- 26511198 TI - Tailoring graphene-based electrodes from semiconducting to metallic to increase the energy density in supercapacitors. AB - The semiconducting character of graphene and some carbon-based electrodes can lead to noticeably lower total capacitances and stored energy densities in electric double layer (EDL)capacitors. This paper discusses the chemical and electronic structure modifications that enhance the available energy bands, density of states and quantum capacitance of graphene substrates near the Fermi level, therefore restoring the conducting character of these materials. The doping of graphene with p or n dopants, such as boron and nitrogen atoms, or the introduction of vacancy defects that introduce zigzag edges, can significantly increase the quantum capacitance within the potential range of interest for the energy storage applications by either shifting the Dirac point away from the Fermi level or by eliminating the Dirac point. We show that a combination of doping and vacancies at realistic concentrations is sufficient to increase the capacitance of a graphene-based electrode to within 1 MUF cm(-2) from that of a metallic surface.Using a combination of ab initio calculations and classical molecular dynamics simulations we estimate how the changes in the quantum capacitance of these electrode materials affect the total capacitance stored by the open structure EDL capacitors containing room temperature ionic liquid electrolytes. PMID- 26511199 TI - A Rare Case of Acquired Fanconi's Syndrome With Monoclonal Gammopathy in an Infant. AB - BACKGROUND: Monoclonal gammopathies associated with acquired Fanconi's syndrome (AFS) have been reported in the adult population. AFS is characterized by renal dysfunction resulting in proteinuria, aminoaciduria, hypophosphatemia, glucosuria, and hyperchloremic metabolic acidosis. In this case report, we document the clinical and laboratory findings of a preterm infant with features of both AFS and monoclonal gammopathy in the urine. METHODS: Clinical suspicion of AFS prompted the following laboratory studies to be performed: urine protein electrophoresis (UPEP), urine immunofixation, and urine amino acid analysis with high performance liquid chromatography (HPLC). RESULTS: Urine amino acid analysis revealed aminoaciduria. On UPEP, nonselective glomerular proteinuria was seen with a faint band in the gamma region. Urine immunofixation confirmed the presence of a monoclonal IgG lambda component with free monoclonal lambda light chains. CONCLUSION: To the best of our knowledge, this is the first case of pediatric AFS reported with a monoclonal gammopathy and monoclonal free light chains. PMID- 26511200 TI - Effects of methanol extracts from roots, leaves, and fruits of the Lebanese strawberry tree (Arbutus andrachne) on cardiac function together with their antioxidant activity. AB - CONTEXT: Several plant-derived natural products have been used in clinical phase for applications in neurological, cardiovascular, and inflammatory diseases. Arbutus andrachne L. (Ericacea) is an evergreen shrub native to the Mediterranean region. Traditionally, the fruits and leaves of Arbutus tree are well known and used as antiseptics, diuretics, blood tonic, and laxatives. OBJECTIVE: Data regarding the biological effects of compounds derived from the Lebanese Arbutus andrachne are not available. In the present work, we studied the antioxidant activity of methanol extracts of leaves, fruits, and roots of the plant against electrolysis; together with their effects on the cardiodynamics of isolated perfused rabbit hearts. MATERIALS AND METHODS: In vitro electrolysis of the different root, leaves, and fruits methanol extracts was evaluated by the amount of free radicals that has been reduced by increasing the concentration of root extracts ranging from 0.5 to 2 mg after 1, 2, 3, and 4 min. Left ventricular pressure (LVP), heart rate (HR), and coronary flow (CR) were investigated in isolated rabbit heart after administration of 0.5, 1, 2, and 2 mg of each methanol extracts plotted against time (0, 0.5, 1.5, 5, and 10 min), according to the Langendorff method. Lipid peroxidation study was performed by the colorimetric method on myocard tissue after incubation with 500 MUl of the different methanol extracts. The amount of MDA was determined at 500 nm absorbance after 5 min incubation. RESULTS: Among the different methanol extracts, the roots showed the highest in vitro antioxidant activity, particularly observed at concentration of 2 mg which completely inhibits free radical generation after 4 min. LVP decreases by 32% at the dose of 2 mg of root extracts after 5 min. No significant effect was observed by the three tested extracts on the heart rate. The three methanol extracts did not show any significant effect on the coronary flow. Moreover, the roots show an increase in the coronary flow at a concentration of 1 and 2 mg/ml during 1 min. Electrolysis on heart tissue treated with the roots extracts shows a decrease in the MDA level from 70.51 +/- 6.71 to 48.58 +/- 4.15 nmole/g of tissue. DISCUSSION AND CONCLUSION: Methanol extracts of the roots possess antihypertensive effect that may result from its ability to decrease the LVP together with its protective role by inhibiting free radical generation and significantly decreasing the MDA level of heart tissue. PMID- 26511201 TI - Positive parenting and children's prosocial behavior in eight countries. AB - BACKGROUND: Research supports the beneficial role of prosocial behaviors on children's adjustment and successful youth development. Empirical studies point to reciprocal relations between negative parenting and children's maladjustment, but reciprocal relations between positive parenting and children's prosocial behavior are understudied. In this study reciprocal relations between two different dimensions of positive parenting (quality of the mother-child relationship and the use of balanced positive discipline) and children's prosocial behavior were examined in Colombia, Italy, Jordan, Kenya, the Philippines, Sweden, Thailand, and the United States. METHODS: Mother-child dyads (N = 1105) provided data over 2 years in two waves (Mage of child in wave 1 = 9.31 years, SD = 0.73; 50% female). RESULTS: A model of reciprocal relations between parenting dimensions, but not among parenting and children's prosocial behavior, emerged. In particular, children with higher levels of prosocial behavior at age 9 elicited higher levels of mother-child relationship quality in the following year. CONCLUSIONS: Findings yielded similar relations across countries, evidencing that being prosocial in late childhood contributes to some degree to the enhancement of a nurturing and involved mother-child relationship in countries that vary widely on sociodemographic profiles and psychological characteristics. Policy and intervention implications of this study are discussed. PMID- 26511202 TI - Disc haemorrhage associated with an enlarged peripapillary intrachoroidal cavitation in a non-glaucomatous myopic eye: a case report. AB - BACKGROUND: Disc haemorrhage (DH) is considered a characteristic sign of glaucoma, but its causative mechanism remains to be determined. We present a case of DH that occurred in association with an enlarged peripapillary intrachoroidal cavitation in a non-glaucomatous eye. CASE PRESENTATION: A 35-year-old woman was evaluated for a DH that had been detected during a preoperative examination for myopic refractive surgery. Enhanced depth imaging spectral-domain optical coherence tomography imaging of the optic nerve revealed a peripapillary intrachoroidal cavitation adjacent to the DH. The DH was also present at the 1 year follow-up, but had been completely absorbed at the 2-year follow-up, respectively with an enlargement and shrinkage of the intrachoroidal cavitation and prelaminar tissue schisis. Glaucomatous optic nerve change was not observed during the entire follow-up. CONCLUSION: DH can be caused by mechanical damage to capillaries from microscopic changes in peripapillary tissues such as enlargement of the intrachoroidal cavitation, regardless of the presence of glaucoma. PMID- 26511203 TI - B cell epitopes on infliximab identified by oligopeptide microarray with unprocessed patient sera. AB - BACKGROUND: Autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease are treated with TNF-alpha-blocking antibodies such as infliximab and adalimumab. A common side effect of therapeutic antibodies is the induction of anti-drug antibodies, which may reduce therapeutic efficacy. METHODS: In order to reveal immunogenic epitopes on infliximab which are responsible for the adverse effects, sera from patients treated with infliximab were screened by ELISA for anti-infliximab antibodies. Sera containing high levels of anti-drug-antibodies (>1.25 ug/ml) were analyzed in an oligopeptide microarray system containing immobilized 15-meric oligopeptides from the infliximab amino acid sequence. Immunogenic infliximab IgG-epitopes were identified by infrared fluorescence scanning and comparison of infliximab-treated patients versus untreated controls. RESULTS: Six relevant epitopes on infliximab were recognized by the majority of all patient sera: 4 in the variable and 2 in the constant region. Three of the epitopes in the variable region are located in the TNF-alpha binding region of infliximab. The fourth epitope of the variable part of infliximab is located close to the TNF-alpha binding region and contains an N-glycosylation sequon. The sera positive for anti-infliximab antibodies do not contain antibodies against adalimumab as determined by ELISA. Thus, there is no infliximab-adalimumab cross reactivity as determined by these systems. CONCLUSIONS: Our data shall contribute to a knowledge-based recommendation for a potentially necessary therapy switch from infliximab to another type of TNF-alpha-blocker. The characterization of immunogenic epitopes on therapeutic monoclonal antibodies using unprocessed patient sera shall lead to direct translational aspects for the development of less immunogenic therapeutic antibodies. Patients benefit from less adverse events and longer lasting drug effects. PMID- 26511204 TI - Factors Associated with Preoperative Magnetic Resonance Imaging Use among Medicare Beneficiaries with Nonmetastatic Breast Cancer. AB - Preoperative breast magnetic resonance imaging (MRI) use among Medicare beneficiaries with breast cancer has substantially increased from 2005 to 2009. We sought to identify factors associated with preoperative breast MRI use among women diagnosed with ductal carcinoma in situ (DCIS) or stage I-III invasive breast cancer (IBC). Using Surveillance, Epidemiology, and End Results and Medicare data from 2005 to 2009 we identified women ages 66 and older with DCIS or stage I-III IBC who underwent breast-conserving surgery or mastectomy. We compared preoperative breast MRI use by patient, tumor and hospital characteristics stratified by DCIS and IBC using multivariable logistic regression. From 2005 to 2009, preoperative breast MRI use increased from 5.9% to 22.4% of women diagnosed with DCIS and 7.0% to 24.3% of women diagnosed with IBC. Preoperative breast MRI use was more common among women who were younger, married, lived in higher median income zip codes and had no comorbidities. Among women with IBC, those with lobular disease, smaller tumors (<1 cm) and those with estrogen receptor negative tumors were more likely to receive preoperative breast MRI. Women with DCIS were more likely to receive preoperative MRI if tumors were larger (>2 cm). The likelihood of receiving preoperative breast MRI is similar for women diagnosed with DCIS and IBC. Use of MRI is more common in women with IBC for tumors that are lobular and smaller while for DCIS MRI is used for evaluation of larger lesions. PMID- 26511205 TI - Comparing the normalization methods for the differential analysis of Illumina high-throughput RNA-Seq data. AB - BACKGROUND: Recently, rapid improvements in technology and decrease in sequencing costs have made RNA-Seq a widely used technique to quantify gene expression levels. Various normalization approaches have been proposed, owing to the importance of normalization in the analysis of RNA-Seq data. A comparison of recently proposed normalization methods is required to generate suitable guidelines for the selection of the most appropriate approach for future experiments. RESULTS: In this paper, we compared eight non-abundance (RC, UQ, Med, TMM, DESeq, Q, RPKM, and ERPKM) and two abundance estimation normalization methods (RSEM and Sailfish). The experiments were based on real Illumina high throughput RNA-Seq of 35- and 76-nucleotide sequences produced in the MAQC project and simulation reads. Reads were mapped with human genome obtained from UCSC Genome Browser Database. For precise evaluation, we investigated Spearman correlation between the normalization results from RNA-Seq and MAQC qRT-PCR values for 996 genes. Based on this work, we showed that out of the eight non abundance estimation normalization methods, RC, UQ, Med, TMM, DESeq, and Q gave similar normalization results for all data sets. For RNA-Seq of a 35-nucleotide sequence, RPKM showed the highest correlation results, but for RNA-Seq of a 76 nucleotide sequence, least correlation was observed than the other methods. ERPKM did not improve results than RPKM. Between two abundance estimation normalization methods, for RNA-Seq of a 35-nucleotide sequence, higher correlation was obtained with Sailfish than that with RSEM, which was better than without using abundance estimation methods. However, for RNA-Seq of a 76-nucleotide sequence, the results achieved by RSEM were similar to without applying abundance estimation methods, and were much better than with Sailfish. Furthermore, we found that adding a poly A tail increased alignment numbers, but did not improve normalization results. CONCLUSION: Spearman correlation analysis revealed that RC, UQ, Med, TMM, DESeq, and Q did not noticeably improve gene expression normalization, regardless of read length. Other normalization methods were more efficient when alignment accuracy was low; Sailfish with RPKM gave the best normalization results. When alignment accuracy was high, RC was sufficient for gene expression calculation. And we suggest ignoring poly-A tail during differential gene expression analysis. PMID- 26511206 TI - Partially oxidized polyvinyl alcohol as a promising material for tissue engineering. AB - The desired clinical outcome after implantation of engineered tissue substitutes depends strictly on the development of biodegradable scaffolds. In this study we fabricated 1% and 2% oxidized polyvinyl alcohol (PVA) hydrogels, which were considered for the first time for tissue-engineering applications. The final aim was to promote the protein release capacity and biodegradation rate of the resulting scaffolds in comparison with neat PVA. After physical crosslinking, characterization of specific properties of 1% and 2% oxidized PVA was performed. We demonstrated that mechanical properties, hydrodynamic radius of molecules, thermal characteristics and degree of crystallinity were inversely proportional to the PVA oxidation rate. On the other hand, swelling behaviour and protein release were enhanced, confirming the potential of oxidized PVA as a protein delivery system, besides being highly biodegradable. Twelve weeks after in vivo implantation in mice, the modified hydrogels did not elicit severe inflammatory reactions, showing them to be biocompatible and to degrade faster as the degree of oxidation increased. According to our results, oxidized PVA stands out as a novel biomaterial for tissue engineering that can be used to realize scaffolds with customizable mechanical behaviour, protein-loading ability and biodegradability. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26511207 TI - Estimation of dietary flavonoid intake and major food sources of Korean adults- CORRIGENDUM. PMID- 26511208 TI - A rare association--amelogenesis imperfecta, platispondyly and bicytopenia: a case report. AB - INTRODUCTION: Amelogenesis imperfecta is an inherited disease characterized by generalized structural abnormalities of the enamel on all teeth, including both primary and permanent dentition. To the best of our knowledge, this is the first case report of a rare association of amelogenesis imperfecta, platyspondyly, and bicytopenia. CASE PRESENTATION: A 5-year-old Moroccan boy was examined in the Centre for Dental Consultation and Treatment, Faculty of Dentistry, Rabat. He was a child of consanguineous parents (first degree). The child failed to thrive (-4 standard deviation score) and displayed delayed overall development. A dental examination revealed a hypoplastic amelogenesis imperfecta with a bacterial biofilm deposit on tooth surfaces. A complete blood count revealed bicytopenia (normocytic-normochromic anemia with thrombocytopenia). A radiographic examination of the spinal column showed a deviation of the spine in the frontal plane in the form of thoracolumbar scoliosis. The interpedicular distance was not expanded; but a mild platyspondyly exists, especially pronounced in T11 and T12. CONCLUSIONS: No other family members presented amelogenesis imperfecta, bicytopenia, or platyspondyly. The consanguineous marriage suggested an autosomal recessive mode of inheritance. Further studies are necessary to clarify the genetic defect producing this syndrome, and the symptomatic associations of amelogenesis imperfecta, platyspondyly and bicytopenia. PMID- 26511209 TI - Clinical supervision and nursing students' professional competence: support seeking behaviour and the attachment styles of students and mentors. AB - AIMS: To examine whether the interdependent attachment style of students is positively related to their support-seeking behaviour during supervision and whether their over-dependent and counter-dependent attachment styles are negatively related to it. Second, to determine whether the mentors' attachment styles moderate the relationship between the students' support-seeking behaviours and their professional competence, such that this relationship is stronger when supervisors are characterized by higher independent attachment style. BACKGROUND: The mentor-student encounter during nursing clinical supervision is expected to create a supportive environment aimed at promoting support-seeking behaviours and subsequent positive supervision outcomes. Bowlby's attachment theory suggests that the three attachment styles - independent, counter-dependent and over dependent - may have implications for clinical supervision. DESIGN: A correlative prospective study. METHOD: One hundred and seventy-eight students and 66 clinical mentors completed questionnaires at the beginning and end of a clinical supervision session during 2012-2013. RESULTS: Results demonstrated that high compared with low independent nursing students tended to seek less support. Second, students who seek less support evaluated their professional competence as higher than students who seek more support. Third, mentor's counter-dependent attachment style moderated the relationship between students' support-seeking behaviour and their professional competencies. CONCLUSIONS: The results allude to the detrimental meaning of support-seeking in the eyes of nursing students. Results can guide administrators in promoting supervision processes that are compatible with the students' independent learning style, while also preventing the negative implications of autonomic learning. Furthermore, as mentors' counter dependent attachment style can hinder students' support-seeking, attachment styles should be considered in the selection of mentors. PMID- 26511210 TI - A Set of Activity-Based Probes to Visualize Human (Immuno)proteasome Activities. AB - Proteasomes are therapeutic targets for various cancers and autoimmune diseases. Constitutively expressed proteasomes have three active sites, beta1c, beta2c, and beta5c. Lymphoid tissues also express the immunoproteasome subunits beta1i, beta2i, and beta5i. Rapid and simultaneous measurement of the activity of these catalytic subunits would assist in the discovery of new inhibitors, improve analysis of proteasome inhibitors in clinical trials, and simplify analysis of subunit expression. In this work, we present a cocktail of activity-based probes that enables simultaneous gel-based detection of all six catalytic human proteasome subunits. We used this cocktail to develop specific inhibitors for beta1c, beta2c, beta5c, and beta2i, to compare the active-site specificity of clinical proteasome inhibitors, and to demonstrate that many hematologic malignancies predominantly express immunoproteasomes. Furthermore, we show that selective and complete inhibition of beta5i and beta1i is cytotoxic to primary cells from acute lymphocytic leukemia (ALL) patients. PMID- 26511211 TI - In-Series Versus In-Parallel Mechanical Circulatory Support for the Right Heart: A Simulation Study. AB - Right heart failure (RHF) is a serious health issue with increasing incidence and high mortality. Right ventricular assist devices (RVADs) have been used to support the end-stage failing right ventricle (RV). Current RVADs operate in parallel with native RV, which alter blood flow pattern and increase RV afterload, associated with high tension in cardiac muscles and long-term valve complications. We are developing an in-series RVAD for better RV unloading. This article presents a mathematical model to compare the effects of RV unloading and hemodynamic restoration on an overloaded or failing RV. The model was used to simulate both in-series (sRVAD) and in-parallel (pRVAD) (right atrium-pulmonary artery cannulation) support for severe RHF. The results demonstrated that sRVAD more effectively unloads the RV and restores the balance between RV oxygen supply and demand in RHF patients. In comparison to simulated pRVAD and published clinical and in silico studies, the sRVAD was able to provide comparable restoration of key hemodynamic parameters and demonstrated superior afterload and volume reduction. This study concluded that in-series support was able to produce effective afterload reduction and preserve the valve functionality and native blood flow pattern, eliminating complications associated with in-parallel support. PMID- 26511212 TI - Association of Hypothyroidism with Body Mass Index, Systolic Blood Pressure and Proteinuria in Diabetic Patients: Does treated Hypothyroidism with Thyroxine Replacement Therapy Prevent Nephropathy/Chronic Renal Disease? AB - Untreated or sub-clinical hypothyroidism is associated with insulin resistance, obesity, adverse effects on cardiovascular system, hypertension and in turn risk of nephropathy. However, these changes are reversible with thyroxine replacement therapy (TRT). Current research studied 4235 diabetic patients, divided into two groups, those with clinical hypothyroidism /on TRT, compared to those without thyroid disease or undiagnosed. BMI, blood pressure, creatinine, urine microalbumin and spot urine protein levels were compared between these two groups. Study finding demonstrated that for hypothyroid cases, BMI was higher (32.2 +/- 7.44 versus 29.4 +/- 5.7; p < 0.0001), serum creatinine was on lower levels (0.75 +/- 0.27 versus 1.0 +/- 0.74; p = 0.001), systolic BP was on lower side (123.7 +/- 15.9 versus 128.13 +/- 16.8; p= 0.015); spot urine microalbumin was on lower side (52.58 +/- 71.65; versus 87.77 +/- 140.86; p=0.010) and spot urine protein had lower levels (25.3 +/- 38.3 versus 44.28 +/- 123.58; p < 0.0001). Current research also demonstrated that Pearson's x2 and odds/protective odds for hypothyroidism (on TRT) was strongly associated with obesity (p <0.0001; odds ratio 2.28, 95% CI 1.47 to 3.56). However, they were protected from HTN (p= 0.272; protective odds ratio 1.28, 95%CI 0.824 to 1.98), nephropathy (p=0.386; protective odds 1.36, 95% CI 0.861 to 2.14) and chronic renal disease (p= 0.112; protective odds 3.42, 95% CI 0.83 to 14.13). In conclusion, TRT itself has protective effects on cardiovascular and renal system. Hence, thyroid screening is essential among diabetics to detect sub clinical or clinical hypothyroidism. PMID- 26511213 TI - Mixed-effects modelling to quantify the effect of empagliflozin on renal glucose reabsorption in patients with type 2 diabetes. AB - AIMS: To quantify the effect of the sodium-glucose co-transporter 2 inhibitor, empagliflozin, on renal glucose reabsorption in patients with type 2 diabetes, and to evaluate covariate effects, using a mechanistic population pharmacokinetic pharmacodynamic (PK-PD) model. METHODS: Four phase I/II trials were used for model development. Empagliflozin's PK characteristics were characterized by a two compartmental model with sequential zero- and first-order absorption. Urinary glucose excretion (UGE) was described as dependent on renal glucose filtration and reabsorption; splay of the glucose reabsorption/excretion curves was considered. The modelling assumed that empagliflozin lowers the maximum renal glucose reabsorption capacity and, thereby, the renal threshold for glucose (RTg). Covariate effects were investigated using a full covariate modelling approach, emphasizing parameter estimation. RESULTS: The PK-PD model provided a reasonable description of the PK characteristics of empagliflozin and its effects on UGE across a range of renal function levels. Its parameters are consistent with reported values for renal physiology. Using this model, the effect of empagliflozin on renal glucose reabsorption was quantified. Steady-state empagliflozin doses (1, 5, 10 and 25 mg) reduced RTg from 12.5 mmol/L [95% confidence interval (CI) 12.0, 13.1] to 5.66 (95% CI 4.62, 6.72), 3.01 (95% CI 2.33, 3.69), 2.53 (95% CI 1.83, 3.14) and 2.21 (95% CI 1.47, 2.84) mg/dl, respectively. Covariate analysis showed the effect of empagliflozin on UGE was not influenced, to a clinically relevant extent, by sex, age or race. CONCLUSIONS: A method for characterizing renal glucose reabsorption was developed that does not require complex glucose clamp experiments. These analyses indicate that empagliflozin provided concentration-dependent RTg reductions, with 10 and 25 mg providing near-maximum RTg-lowering. PMID- 26511214 TI - CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. PMID- 26511215 TI - Orientation dependence of microcirculation-induced diffusion signal in anisotropic tissues. AB - PURPOSE: To seek a better understanding of the effect of organized capillary flow on the MR diffusion-weighted signal. METHODS: A theoretical framework was proposed to describe the diffusion-weighted MR signal, which was then validated both numerically using a realistic model of capillary network and experimentally in an animal model of isolated perfused heart preparation with myocardial blood flow verified by means of direct arterial spin labeling measurements. RESULTS: Microcirculation in organized tissues gave rise to an MR signal that could be described as a combination of the bi-exponential behavior of conventional intravoxel incoherent motion (IVIM) theory and diffusion tensor imaging (DTI) like anisotropy of the vascular signal, with the flow-related pseudo diffusivity represented as the linear algebraic product between the encoding directional unit vector and an appropriate tensor entity. Very good agreement between theoretical predictions and both numerical and experimental observations were found. CONCLUSION: These findings suggest that the DTI formalism of anisotropic spin motion can be incorporated into the classical IVIM theory to describe the MR signal arising from diffusion and microcirculation in organized tissues. Magn Reson Med 76:1252-1262, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26511216 TI - Previous radiation for prostate neoplasm alters surgical and oncologic outcomes after rectal cancer surgery. AB - BACKGROUND: Previous radiation for prostate cancer (PC) contra-indicates neoadjuvant chemoradiotherapy for rectal cancer (RC) because of risk of cumulative radiation dose toxicity. Postoperative outcomes after proctectomy have not been well studied in these patients who did not receive optimal treatment. METHODS: Eighty-four consecutive male patients underwent surgery for stage II-III mid or low RC between 2002 and 2011. Patients who previously received radiation for PC (n = 8) and patients who had not previously undergone radiation for PC but who received neoadjuvant chemoradiotherapy for RC (n = 64) were retrospectively compared. RESULTS: Previous radiation for PC was an independent factor that significantly increased intraoperative (25% vs. 1.6%, P = 0.002) and postoperative morbidities (62.5% vs. 28.1%, P = 0.028), anastomotic leakage (62.5% vs. 12.5%, P < 0.001) and definitive stoma rates (25% vs. 17.4%, P = 0.022). It significantly altered median overall survival (32.0 vs. 130.6 months, P = 0.05) and local recurrence-free survival rates (14.0 months vs. "median not reached," P = 0.016). CONCLUSIONS: This is the first report of altered survival rates after proctectomy in patients who had previously received radiation for PC. Postoperative morbidity and definitive defunctioning stoma rates were significantly increased in these patients with poor prognoses. Therapeutic strategies should thus be individualized. Large, multicenter cohort studies are needed. PMID- 26511217 TI - Impact of naturally occurring amino acid variations on the detection of HIV-1 p24 in diagnostic antigen tests. AB - BACKGROUND: The detection of HIV-1 p24 antigen in diagnostic tests relies on antibodies binding to conserved areas of the protein to cover the full range of HIV-1 subtypes. Using a panel of 43 different virus-like particles (VLPs) expressing Gag from clinical HIV-1 isolates, we previously found that some highly sensitive tests completely failed to detect p24 of certain VLPs, seemingly unrelated to their subtype. Here we aimed to investigate the reason for this failure, hypothesising that it might be due to single amino acid variations in conserved epitopes. METHODS: Using amino acid alignment, we identified single amino acid variations at position 16 or 170 of p24, unique to those VLPs that failed to be detected in certain diagnostic tests. Through DNA-mutagenesis, these amino acids were changed to ones more commonly found at these positions. The impact of these changes on p24 detection was tested in commercial diagnostic tests as well as by Western Blot and ELISA, using epitope-specific antibodies. RESULTS AND CONCLUSIONS: Changing positions 16 or 170 to consensus amino acids restored the detection of p24 by the investigated diagnostic tests as well as by epitope-specific antibodies in Western Blot and ELISA. Hence, single amino acid changes in conserved epitopes can lead to the failure of p24 detection and thus to false-negative results. To optimise HIV diagnostic tests, they should also be evaluated using isolates which harbour less-frequent epitope variants. PMID- 26511218 TI - Bone healing after low-level laser application in extraction sockets grafted with allograft material and covered with a resorbable collagen dressing: a pilot histological evaluation. AB - BACKGROUND: Our aim was to determine whether low level laser therapy (LLLT) can decrease the time between extraction/socket graft and implant placement, by evaluating histological changes in sockets grafted with a particulate allograft material and treated with LLLT. METHODS: Thirty patients had a socket grafted with a particulate allograft material (MinerOss) covered with a resorbable collagen wound dressing. The patients were then randomly divided into two equal groups (n = 15): test group receiving postoperative LLLT treatment, and control group without postoperative laser treatment. The assessment of bone formation was carried out in both groups at well-determined time intervals after surgery by histostomorphometric analysis. RESULTS: The histological results of the site treated with LLLT for 21 days, harvested at 60 days after grafting showed abundant new bone formation without any sign of inflammation. The same results were obtained in the control group not before 120 days post-surgery. CONCLUSIONS: It can be concluded that LLLT photobiomodulation can reduce the healing time after grafting the extraction socket. Histological evidence suggests that new bone formation in the sockets appeared within 60 days after LLLT treatment compared to a minimum of 120 days in the control group. PMID- 26511219 TI - NIR absorbing D-pi-A-pi-D structured diketopyrrolopyrrole-dithiafulvalene based small molecule for solution processed organic solar cells. AB - A new low band gap small molecule with a D-pi-A-pi-D molecular structure composed of a dithiafulvalene (DTF) donor and a diketopyrrolopyrrole (DPP) acceptor was synthesized and tested for organic solar cells. Using the small molecule as an electron donor, and PC71BM as an acceptor a high power conversion efficiency (PCE) of 4.3% was achieved. PMID- 26511220 TI - Ten-year longitudinal study of factors influencing nocturnal asthma symptoms among Asian patients in primary care. AB - BACKGROUND: Nocturnal asthma symptoms result in poor quality of life and morbidity. AIMS: This study primarily examines key factors predicting and mitigating nocturnal symptom risks among asthma patients, who were enrolled into a Singapore publicly funded asthma care programme. It also studies the association between nocturnal symptoms and medication changes as the secondary outcome. METHODS: A longitudinal study was conducted on 939 multi-racial Asian patients with persistent asthma. Patient clinical and therapeutic data were retrieved retrospectively from the programme's database established in 2004. Association between nocturnal symptoms (defined as night-time cough, wheeze and breathlessness at least twice monthly) and each categorical predictor was tested. The generalised linear mixed-effects model (GLIMM) was used to model the primary and secondary outcomes. RESULTS: Having nocturnal asthma symptoms was significantly associated with the number of days with breathlessness, off usual activities and off work, and asthma severity at baseline (all P values <0.05). The asthma action plan (AAP) status is significantly associated with nocturnal symptoms after adjusting for race, age and smoking status at baseline (odds ratio (OR)=0.49 (updated asthma action plan versus none), OR=0.37 (been-on plan versus none)). The risks of nocturnal asthma symptoms increased over time for those with allergic rhinitis (OR=1.52) and reduced with subsequent visits (OR=0.91). Nocturnal symptoms increased the odds (OR=2.87) of switching from inhaled corticosteroid (ICS) to combination medications (ICS-LABA (long-acting beta2 agonist)). CONCLUSIONS: The risks of having nocturnal symptoms were primarily associated with those with allergic rhinitis. An increase in patients' nocturnal symptoms was also predictive of the switching from ICS medications to combination formulations by their physicians. PMID- 26511221 TI - Targeted Anticoagulation for Atrial Fibrillation Guided by Continuous Rhythm Assessment With an Insertable Cardiac Monitor: The Rhythm Evaluation for Anticoagulation With Continuous Monitoring (REACT.COM) Pilot Study. AB - INTRODUCTION: Chronic anticoagulation is recommended for patients with AF and additional stroke risk factors, even during long periods of sinus rhythm. Continuous rhythm assessment with an insertable cardiac monitor (ICM) and use of rapid onset novel oral anticoagulants (NOACs) allow for targeted anticoagulation only around an AF episode, potentially reducing bleeding complications without compromising stroke risk. METHODS: This multicenter, single-arm study enrolled patients on NOAC with nonpermanent AF and CHADS2 score 1 or 2. After a 60-day run in with no AF episodes >= 1 hour, NOACs were discontinued but reinitiated for 30 days following any AF episode >= 1 hour diagnosed through daily ICM transmissions. Major endpoints included time on NOAC, stroke, and bleeding. RESULTS: Among 59 enrollees, 75% were male, age 67 +/- 8 years, 76% paroxysmal AF, 69% had prior AF ablation, and mean CHADS2 score 1.3 +/- 0.5. Over 466 +/- 131 mean days of follow-up there were 24,004 ICM transmissions with a compliance rate of 98.7%. A total of 35 AF episodes >= 1 hour occurred in 18 (31%) patients, resulting in a total time on NOAC of 1,472 days. This represents a 94% reduction in the time on NOAC compared to chronic anticoagulation. There were three traumatic bleeds (all on aspirin), three potential transient ischemic attacks (all on aspirin with CHADS2 score of 1), and no strokes or deaths. CONCLUSIONS: A targeted strategy of ICM-guided intermittent NOAC administration is feasible. A large-scale trial is necessary to evaluate the safety of this approach. PMID- 26511222 TI - Affordability of health care under publicly subsidized insurance after Massachusetts health care reform: a qualitative study of safety net patients. AB - INTRODUCTION: The Affordable Care Act (ACA) and the 2006 Massachusetts (MA) health reform law, on which the ACA was based, aimed to improve the affordability of care largely by expanding publicly sponsored insurances. Both laws also aimed to promote consumer understanding of how to acquire, maintain and use these public plans. A prior study found an association between the level of cost sharing required in these plans and the affordability of care. Preparatory to a quantitative study we conducted this qualitative study that aimed to examine (1) whether cost sharing levels built into the public insurance types that formed the backbone of the MA health reform led to unaffordability of care and if so, (2) how insurances with higher cost sharing levels led to unaffordability of care in this context. METHODS: We interviewed 12 consumers obtaining the most commonly obtained insurances under MA health reform (Medicaid and Commonwealth Care) at a safety net hospital emergency department. We purposefully interviewed a stratified sample of higher and low cost sharing recipients. We used a combination of inductive and deductive codes to analyze the data according to degree of cost-sharing required by different insurance types. RESULTS: We found that higher cost sharing plans led to unaffordability of care, as evidenced by unmet medical needs, difficulty affording basic non-medical needs due to expenditures on medical care, and reliance on non-insurance resources to pay for care. Participants described two principal mechanisms by which higher cost sharing led to unaffordability of care: (1) cost sharing above what their incomes allowed and (2) poor understanding of how to effectively acquire, maintain and utilize insurance new public plans. CONCLUSIONS: Further efforts to investigate the relationship between perceived affordability of care and understanding of insurance for the insurance types obtained under MA health reform may be warranted. A potential focus for further work may be quantitative investigation of how the level of calibration of cost-sharing to income and understanding of insurances under the MA reform was associated with perceived affordability of care. PMID- 26511223 TI - First complete mitochondrial genome of the South American annual fish Austrolebias charrua (Cyprinodontiformes: Rivulidae): peculiar features among cyprinodontiforms mitogenomes. AB - BACKGROUND: Among teleosts, the South American genus Austrolebias (Cyprinodontiformes: Rivulidae) includes 42 taxa of annual fishes divided into five different species groups. It is a monophyletic genus, but morphological and molecular data do not resolve the relationship among intrageneric clades and high rates of substitution have been previously described in some mitochondrial genes. In this work, the complete mitogenome of a species of the genus was determined for the first time. We determined its structure, gene order and evolutionary peculiar features, which will allow us to evaluate the performance of mitochondrial genes in the phylogenetic resolution at different taxonomic levels. RESULTS: Regarding gene content and order, the circular mitogenome of A. charrua (17,271 pb) presents the typical pattern of vertebrate mitogenomes. It contains the full complement of 13 proteins-coding genes, 22 tRNA, 2 rRNA and one non coding control region. Notably, the tRNA-Cys was only 57 bp in length and lacks the D-loop arm. In three full sibling individuals, heteroplasmatic condition was detected due to a total of 12 variable sites in seven protein-coding genes. Among cyprinodontiforms, the mitogenome of A. charrua exhibits the lowest G+C content (37 %) and GCskew, as well as the highest strand asymmetry with a net difference of T over A at 1st and 3rd codon positions. Considering the 12 coding-genes of the H strand, correspondence analyses of nucleotide composition and codon usage show that A and T at 1st and 3rd codon positions have the highest weight in the first axis, and segregate annual species from the other cyprinodontiforms analyzed. Given the annual life-style, their mitogenomes could be under different selective pressures. All 13 protein-coding genes are under strong purifying selection and we did not find any significant evidence of nucleotide sites showing episodic selection (dN >dS) at annual lineages. When fast evolving third codon positions were removed from alignments, the "supergene" tree recovers our reference species phylogeny as well as the Cytb, ND4L and ND6 genes. Therefore, third codon positions seem to be saturated in the aforementioned coding regions at intergeneric Cyprinodontiformes comparisons. CONCLUSIONS: The complete mitogenome obtained in present work, offers relevant data for further comparative studies on molecular phylogeny and systematics of this taxonomic controversial endemic genus of annual fishes. PMID- 26511224 TI - Associations between human milk oligosaccharides and infant body composition in the first 6 mo of life. AB - BACKGROUND: Evidence linking breastfeeding to reduced risk of developing childhood obesity is inconclusive, yet previous studies have not considered variation in specific components of breast milk that may affect early development. OBJECTIVE: We examined whether differences in the composition of human milk oligosaccharides (HMOs) correlate with infant growth and body composition at 1 and 6 mo of age. DESIGN: Twenty-five mother-infant dyads were recruited from the University Hospital at the University of Oklahoma Health Sciences Center. Infants were breastfed for 6 mo. Breast-milk and infant measures were obtained at 1 and 6 mo of infant age. HMO composition was analyzed by high pressure liquid chromatography, and infant growth (length and weight) and body composition (percentage fat, total fat, lean mass) were measured by dual-energy X ray absorptiometry. Relations between HMOs and infant growth and body composition were examined by using multiple linear regression. A priori covariates included maternal prepregnancy body mass index, pregnancy weight gain, and infant age and sex. RESULTS: Higher HMO diversity and evenness at 1 mo were associated with lower total and percentage fat mass at 1 mo. At 1 mo, each 1-MUg/mL increase in lacto-N-fucopentaose (LNFP) I was associated with a 0.40-kg lower infant weight (P = 0.03). At 6 mo, each 1-MUg/mL increase in LNFPI was associated with a 1.11 kg lower weight (P = 0.03) and a 0.85-g lower lean mass (P = 0.01). At 6 mo, each 1-MUg/mL increase in LNFPI was associated with a 0.79-g lower fat mass (P = 0.02), whereas disialyl-lacto-N-tetraose and LNFPII were associated with a 1.92-g (P = 0.02) and 0.42-g (P = 0.02) greater fat mass, respectively. At 6 mo, each 1 MUg/mL increase in fucosyl-disialyl-lacto-N-hexaose and lacto-N-neotetraose was associated with 0.04% higher (P = 0.03) and 0.03% lower (P < 0.01) body fat, respectively. CONCLUSION: These findings support the hypothesis that differences in HMO composition in mother's milk are associated with infant growth and body composition. This trial was registered at clinicaltrials.gov as NCT02535637. PMID- 26511226 TI - Quantitative profiling of oxylipins in plasma and atherosclerotic plaques of hypercholesterolemic rabbits. AB - Oxylipins are oxidation products of polyunsaturated fatty acids (PUFAs) that affect a broad range of physiological processes, including cell proliferation, inflammation, inflammation resolution, and vascular function. Moreover, oxylipins are readily detectable in plasma, and certain subsets of oxylipins have been detected in human atherosclerotic lesions. Taken together, we set out to produce a detailed quantitative assessment of plasma and plaque oxylipins in a widely used model of atherosclerosis, to identify potential biomarkers of disease progression. We administered regular chow or regular chow supplemented with 0.5% cholesterol (HC) to male New Zealand white rabbits for 12 weeks to induce hypercholesterolemia and atherosclerosis. Our targeted lipidomic analyses of oxylipins on plaques isolated from rabbits fed the HC diet detected 34 oxylipins, 28 of which were in compliance with our previously established quality control acceptance criteria. The arachidonic acid (AA) metabolite derived from the COX pathway, 6-keto-PGF1alpha was the most abundant plaque oxylipin, followed by the linoleic acid (LA) metabolites 9-HODE, 13-HODE and 9,12,13-TriHOME and the arachidonic acid (AA)-derivatives 11-HETE and 12-HETE. We additionally found that the most abundant oxylipins in plasma were three of the five most abundant oxylipins in plaque, namely 11-HETE, 13-HODE, and 9-HODE. The studies reported here make the first step towards a comprehensive characterization of oxylipins as potentially translatable biomarkers of atherosclerosis. PMID- 26511227 TI - 2015 Year in Review. PMID- 26511225 TI - Metabolic profiles of male meat eaters, fish eaters, vegetarians, and vegans from the EPIC-Oxford cohort. AB - BACKGROUND: Human metabolism is influenced by dietary factors and lifestyle, environmental, and genetic factors; thus, men who exclude some or all animal products from their diet might have different metabolic profiles than meat eaters. OBJECTIVE: We aimed to investigate differences in concentrations of 118 circulating metabolites, including acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexose, and sphingolipids related to lipid, protein, and carbohydrate metabolism between male meat eaters, fish eaters, vegetarians, and vegans from the Oxford arm of the European Prospective Investigation into Cancer and Nutrition. DESIGN: In this cross-sectional study, concentrations of metabolites were measured by mass spectrometry in plasma from 379 men categorized according to their diet group. Differences in mean metabolite concentrations across diet groups were tested by using ANOVA, and a false discovery rate controlling procedure was used to account for multiple testing. Principal component analysis was used to investigate patterns in metabolic profiles. RESULTS: Concentrations of 79% of metabolites differed significantly by diet group. In the vast majority of these cases, vegans had the lowest concentration, whereas meat eaters most often had the highest concentrations of the acylcarnitines, glycerophospholipids, and sphingolipids, and fish eaters or vegetarians most often had the highest concentrations of the amino acids and a biogenic amine. A clear separation between patterns in the metabolic profiles of the 4 diet groups was seen, with vegans being noticeably different from the other groups because of lower concentrations of some glycerophospholipids and sphingolipids. CONCLUSIONS: Metabolic profiles in plasma could effectively differentiate between men from different habitual diet groups, especially vegan men compared with men who consume animal products. The difference in metabolic profiles was mainly explained by the lower concentrations of glycerophospholipids and sphingolipids in vegans. PMID- 26511228 TI - Cardiac Arrest Triggered by Subepicardial Aneurysm Without Cardiac Rupture. PMID- 26511229 TI - Mode of Death After Acute Heart Failure Hospitalization - A Clue to Possible Mechanisms. AB - Heart failure continues to be a leading cause of hospitalization worldwide, and acute heart failure (AHF) carries significant risk for short-term morbidity and mortality. Despite many trials of potential new therapies for AHF, there have been very few advances over the recent decades. In this review, we will examine mortality during and after AHF hospitalization, with an emphasis on available data on mode of death (MOD). We will also review data on the timing of different MOD after AHF and the effect of specific therapies, as well as what is known about the contribution of specific pathophysiological mechanisms. Finally, we discuss the potential utility of further study of MOD data for AHF and its application to drug development, risk stratification, and therapeutic tailoring to improve short- and long-term outcomes in AHF. PMID- 26511230 TI - Preprocedural Dual Antiplatelet Therapy for Percutaneous Coronary Intervention in Japanese Current Practice. PMID- 26511231 TI - Role of Metabolic Imaging in Detecting Cardiac Involvement in Sarcoidosis. PMID- 26511232 TI - Pyrrolo[3,2-b]pyrroles-From Unprecedented Solvatofluorochromism to Two-Photon Absorption. AB - A combined experimental and theoretical study of the two-photon absorption (2PA) properties of a series of quadrupolar molecules possessing a highly electron-rich heterocyclic core, pyrrolo[3,2-b]pyrrole, is presented. In agreement with quantum chemical calculations, large 2PA cross-section values, sigma2PA ~10(2) -10(3) GM (1 GM=10(50) cm(4) s photon(-1) ), are observed at wavelengths of 650-700 nm, which correspond to the two-photon allowed but one-photon forbidden transitions. The calculations also predict that increased planarity of this molecule through removal of two N-substituents leads to further increase in the sigma2PA values. Surprisingly, the most quadrupolar pyrrolo[3,2-b]pyrrole derivative, containing two 4-nitrophenyl substituents at positions 2 and 5, demonstrates a very strong solvatofluorochromic effect, with a fluorescence quantum yield as high as 0.96 in cyclohexane, whereas the fluorescence vanishes in DMSO. PMID- 26511233 TI - Dexamethasone promotes hypertrophy of H9C2 cardiomyocytes through calcineurin B pathway, independent of NFAT activation. AB - Metabolic syndrome-induced cardiac hypertrophy is a global concern leading to an increase in the morbidity and mortality of patients, with the signalling mechanism associated with them still unclear. The present study attempts to understand the metabolic syndrome-associated cardiac hypertrophy through an in vitro model using external stimuli well known for inducing metabolic disorders, i.e. dexamethasone (DEX), a synthetic glucocorticoid. DEX (0.1 and 1 MUM) promoted cardiac hypertrophy in H9C2 cells at 4 days of treatment as evidenced through increased cell size and protein content. A significant induction in foetal gene reprogramming was observed, confirming the establishment of hypertrophy. Moreover, the hypertrophic response at 4 days was perceived to be physiological at 0.1 MUM and pathological at 1 MUM based on alpha-MHC and IGF1R expression, but complete inhibition in the PKB/AKT expression confirmed it to be pathological hypertrophy at both the concentrations (0.1 and 1 MUM). The present study reports for the first time the mechanistic insights into DEX-mediated hypertrophy. It is hypothesized to be orchestrated through the activation of AT1R that is involved in the alteration of the cardiac isoform of SERCA2 expression perturbing the calcium homeostasis. This leads to the activation of calcineurin B, independent of NFAT involvement, which in coordination with ROS induces the activation of JNK of the MAPK signalling. PMID- 26511234 TI - Multisensory Integration Reveals Temporal Coding across a Human Sensorimotor Network. PMID- 26511235 TI - Consolidation of Complex Events via Reinstatement in Posterior Cingulate Cortex. AB - It is well-established that active rehearsal increases the efficacy of memory consolidation. It is also known that complex events are interpreted with reference to prior knowledge. However, comparatively little attention has been given to the neural underpinnings of these effects. In healthy adults humans, we investigated the impact of effortful, active rehearsal on memory for events by showing people several short video clips and then asking them to recall these clips, either aloud (Experiment 1) or silently while in an MRI scanner (Experiment 2). In both experiments, actively rehearsed clips were remembered in far greater detail than unrehearsed clips when tested a week later. In Experiment 1, highly similar descriptions of events were produced across retrieval trials, suggesting a degree of semanticization of the memories had taken place. In Experiment 2, spatial patterns of BOLD signal in medial temporal and posterior midline regions were correlated when encoding and rehearsing the same video. Moreover, the strength of this correlation in the posterior cingulate predicted the amount of information subsequently recalled. This is likely to reflect a strengthening of the representation of the video's content. We argue that these representations combine both new episodic information and stored semantic knowledge (or "schemas"). We therefore suggest that posterior midline structures aid consolidation by reinstating and strengthening the associations between episodic details and more generic schematic information. This leads to the creation of coherent memory representations of lifelike, complex events that are resistant to forgetting, but somewhat inflexible and semantic-like in nature. PMID- 26511236 TI - Attention Modulates TMS-Locked Alpha Oscillations in the Visual Cortex. AB - Cortical oscillations, such as 8-12 Hz alpha-band activity, are thought to subserve gating of information processing in the human brain. While most of the supporting evidence is correlational, causal evidence comes from attempts to externally drive ("entrain") these oscillations by transcranial magnetic stimulation (TMS). Indeed, the frequency profile of TMS-evoked potentials (TEPs) closely resembles that of oscillations spontaneously emerging in the same brain region. However, it is unclear whether TMS-locked and spontaneous oscillations are produced by the same neuronal mechanisms. If so, they should react in a similar manner to top-down modulation by endogenous attention. To test this prediction, we assessed the alpha-like EEG response to TMS of the visual cortex during periods of high and low visual attention while participants attended to either the visual or auditory modality in a cross-modal attention task. We observed a TMS-locked local oscillatory alpha response lasting several cycles after TMS (but not after sham stimulation). Importantly, TMS-locked alpha power was suppressed during deployment of visual relative to auditory attention, mirroring spontaneous alpha amplitudes. In addition, the early N40 TEP component, located at the stimulation site, was amplified by visual attention. The extent of attentional modulation for both TMS-locked alpha power and N40 amplitude did depend, with opposite sign, on the individual ability to modulate spontaneous alpha power at the stimulation site. We therefore argue that TMS-locked and spontaneous oscillations are of common neurophysiological origin, whereas the N40 TEP component may serve as an index of current cortical excitability at the time of stimulation. PMID- 26511237 TI - Adaptation of Saccades and Perceived Size after Trans-Saccadic Changes of Object Size. AB - When saccadic eye movements consistently fail to land on the intended target, saccade accuracy is maintained by gradually adapting the amplitude of successive saccades to the same target. Such saccadic adaptation is usually induced by systematically displacing a small visual target during the execution of the saccade. However, saccades are normally performed to extended objects. Here we report changes in saccade amplitude when the size of a target object is systematically changed during a saccade. Moreover, we find that this manipulation also affected the visual perception of the size of that object. Human subjects were tested in shortening and lengthening adaptation where they had to make saccades to targets of different sizes, which were each shortened or lengthened during saccade execution, respectively. In both experiments, a preadaptation and postadaptation phase required manually indicating the horizontal size of each target by grip aperture and, in a further experiment, a verbal size report. We evaluated the effect of change in visual perception on saccade and on the two modalities of judgment. We observed that (1) saccadic adaptation can be induced by modifying target object size and (2) this gradual change in saccade amplitude in the direction of the object size change evokes a concomitant change in perceived object size. These findings suggest that size is a relevant signal for saccadic system and its trans-saccadic manipulation entails considerable changes at multiple levels of sensorimotor performance. PMID- 26511238 TI - Voltage-Mediated Control of Spontaneous Bundle Oscillations in Saccular Hair Cells. AB - Hair cells of the vertebrate vestibular and auditory systems convert mechanical inputs into electrical signals that are relayed to the brain. This transduction involves mechanically gated ion channels that open following the deflection of mechanoreceptive hair bundles that reside on top of these cells. The mechano electrical transduction includes one or more active feedback mechanisms to keep the mechanically gated ion channels in their most sensitive operating range. Coupling between the gating of the mechanosensitive ion channels and this adaptation mechanism leads to the occurrence of spontaneous limit-cycle oscillations, which indeed have been observed in vitro in hair cells from the frog sacculus and the turtle basilar papilla. We obtained simultaneous optical and electrophysiological recordings from bullfrog saccular hair cells with such spontaneously oscillating hair bundles. The spontaneous bundle oscillations allowed us to characterize several properties of mechano-electrical transduction without artificial loading the hair bundle with a mechanical stimulus probe. We show that the membrane potential of the hair cell can modulate or fully suppress innate oscillations, thus controlling the dynamic state of the bundle. We further demonstrate that this control is exerted by affecting the internal calcium concentration, which sets the resting open probability of the mechanosensitive channels. The auditory and vestibular systems could use the membrane potential of hair cells, possibly controlled via efferent innervation, to tune the dynamic states of the cells. PMID- 26511239 TI - Retinoic Acid Receptor beta Controls Development of Striatonigral Projection Neurons through FGF-Dependent and Meis1-Dependent Mechanisms. AB - The mammalian striatum controls sensorimotor and psychoaffective functions through coordinated activities of its two striatonigral and striatopallidal output pathways. Here we show that retinoic acid receptor beta (RARbeta) controls development of a subpopulation of GABAergic, Gad65-positive striatonigral projection neurons. In Rarb(-/-) knock-out mice, concomitant reduction of Gad65, dopamine receptor D1 (Drd1), and substance P expression at different phases of prenatal development was associated with reduced number of Drd1-positive cells at birth, in contrast to normal numbers of striatopallidal projection neurons expressing dopamine receptor D2. Fate mapping using BrdU pulse-chase experiments revealed that such deficits may originate from compromised proliferation of late born striosomal neurons and lead to decreased number of Drd1-positive cells retaining BrdU in postnatal day (P) 0 Rarb(-/-) striatum. Reduced expression of Fgf3 in the subventricular zone of the lateral ganglionic eminence (LGE) at embryonic day 13.5 may underlie such deficits by inducing premature differentiation of neuronal progenitors, as illustrated by reduced expression of the proneural gene Ascl1 (Mash1) and increased expression of Meis1, a marker of postmitotic LGE neurons. In agreement with a critical role of FGF3 in this control, reduced number of Ascl1-expressing neural progenitors, and a concomitant increase of Meis1-expressing cells, were observed in primary cell cultures of Rarb(-/-) LGE. This defect was normalized by addition of fibroblast growth factor (FGF). Such data point to role of Meis1 in striatal development, also supported by reduced neuronal differentiation in the LGE of Meis1(-/-) embryos. Our data unveil a novel mechanism of development of striatonigral projection neurons involving retinoic acid and FGF, two signals required for positioning the boundaries of Meis1-expressing cells. PMID- 26511240 TI - Similar Motor Cortical Control Mechanisms for Precise Limb Control during Reaching and Locomotion. AB - Throughout the course of evolution there has been a parallel development of the complexity and flexibility of the nervous system and the skeletomuscular system that it controls. This development is particularly evident for the cerebral cortical areas and the transformation of the use of the upper limbs from a purely locomotor function to one including, or restricted to, reaching and grasping. This study addresses the issue of whether the control of reaching has involved the development of new cortical circuits or whether the same neurons are used to control both locomotion and reaching. We recorded the activity of pyramidal tract neurons in the motor cortex of the cat both during voluntary gait modifications and during reaching. All cells showed generally similar patterns of activity in both tasks. More specifically, we showed that, in many cases, cells maintained a constant temporal relationship to the activity of synergistic muscle groups in each task. In addition, in some cells the relationship between the intensity of the cell discharge activity and the magnitude of the EMG activity was equally constant during gait modifications and reaching. As such, the results are compatible with the hypothesis that the corticospinal circuits used to control reaching evolved from those used to precisely modify gait. PMID- 26511241 TI - Hemispheric Asymmetries in Striatal Reward Responses Relate to Approach-Avoidance Learning and Encoding of Positive-Negative Prediction Errors in Dopaminergic Midbrain Regions. AB - Some individuals are better at learning about rewarding situations, whereas others are inclined to avoid punishments (i.e., enhanced approach or avoidance learning, respectively). In reinforcement learning, action values are increased when outcomes are better than predicted (positive prediction errors [PEs]) and decreased for worse than predicted outcomes (negative PEs). Because actions with high and low values are approached and avoided, respectively, individual differences in the neural encoding of PEs may influence the balance between approach-avoidance learning. Recent correlational approaches also indicate that biases in approach-avoidance learning involve hemispheric asymmetries in dopamine function. However, the computational and neural mechanisms underpinning such learning biases remain unknown. Here we assessed hemispheric reward asymmetry in striatal activity in 34 human participants who performed a task involving rewards and punishments. We show that the relative difference in reward response between hemispheres relates to individual biases in approach-avoidance learning. Moreover, using a computational modeling approach, we demonstrate that better encoding of positive (vs negative) PEs in dopaminergic midbrain regions is associated with better approach (vs avoidance) learning, specifically in participants with larger reward responses in the left (vs right) ventral striatum. Thus, individual dispositions or traits may be determined by neural processes acting to constrain learning about specific aspects of the world. PMID- 26511242 TI - N-Acetylaspartate Synthase Deficiency Corrects the Myelin Phenotype in a Canavan Disease Mouse Model But Does Not Affect Survival Time. AB - Canavan disease (CD) is a severe, lethal leukodystrophy caused by deficiency in aspartoacylase (ASPA), which hydrolyzes N-acetylaspartate (NAA). In the brains of CD patients, NAA accumulates to high millimolar concentrations. The pathology of the disease is characterized by loss of oligodendrocytes and spongy myelin degeneration in the CNS. Whether accumulating NAA, absence of NAA-derived acetate, or absence of any unknown functions of the ASPA enzyme is responsible for the pathology of the disease is not fully understood. We generated ASPA deficient (Aspa(nur7/nur7)) mice that are also deficient for NAA synthase Nat8L (Nat8L(-/-)/Aspa(nur7/nur7)). These mice have no detectable NAA. Nevertheless, they exhibited normal myelin content, myelin sphingolipid composition, and full reversal of spongy myelin and axonal degeneration. Surprisingly, although pathology was fully reversed, the survival time of the mice was not prolonged. In contrast, Aspa(nur7/nur7) mice with only one intact Nat8L allele accumulated less NAA, developed a less severe pathology, phenotypic improvements, and, importantly, an almost normal survival time. Therefore, inhibition of NAA synthase is a promising therapeutic option for CD. The reduced survival rate of Nat8L(-/-)/Aspa(nur7/nur7) mice, however, indicates that complete inhibition of NAA synthase may bear unforeseeable risks for the patient. Furthermore, we demonstrate that acetate derived from NAA is not essential for myelin lipid synthesis and that loss of NAA-derived acetate does not cause the myelin phenotype of Aspa(nur7/nur7) mice. Our data clearly support the hypothesis that NAA accumulation is the major factor in the development of CD. PMID- 26511244 TI - Expression of ESR1 in Glutamatergic and GABAergic Neurons Is Essential for Normal Puberty Onset, Estrogen Feedback, and Fertility in Female Mice. AB - Circulating estradiol exerts a profound influence on the activity of the gonadotropin-releasing hormone (GnRH) neuronal network controlling fertility. Using genetic strategies enabling neuron-specific deletion of estrogen receptor alpha (Esr1), we examine here whether estradiol-modulated GABA and glutamate transmission are critical for the functioning of the GnRH neuron network in the female mouse. Using Vgat- and Vglut2-ires-Cre knock-in mice and ESR1 immunohistochemistry, we demonstrate that subpopulations of GABA and glutamate neurons throughout the limbic forebrain express ESR1, with ESR1-GABAergic neurons being more widespread and numerous than ESR1-glutamatergic neurons. We crossed Vgat- and Vglut2-ires-Cre mice with an Esr1(lox/lox) line to generate animals with GABA-neuron-specific or glutamate-neuron-specific deletion of Esr1. Vgat ires-Cre;Esr1(lox/lox) mice were infertile, with abnormal estrous cycles, and exhibited a complete failure of the estrogen positive feedback mechanism responsible for the preovulatory GnRH surge. However, puberty onset and estrogen negative feedback were normal. Vglut2-ires-Cre;Esr1(lox/lox) mice were also infertile but displayed a wider range of deficits, including advanced puberty onset, abnormal negative feedback, and abolished positive feedback. Whereas <25% of preoptic kisspeptin neurons expressed Cre in Vgat- and Vglut2-ires-Cre lines, ~70% of arcuate kisspeptin neurons were targeted in Vglut2-ires-Cre;Esr1(lox/lox) mice, possibly contributing to their advanced puberty phenotype. These observations show that, unexpectedly, ESR1-GABA neurons are only essential for the positive feedback mechanism. In contrast, we reveal the key importance of ESR1 in glutamatergic neurons for multiple estrogen feedback loops within the GnRH neuronal network required for fertility in the female mouse. PMID- 26511243 TI - Radial Glial Cell-Neuron Interaction Directs Axon Formation at the Opposite Side of the Neuron from the Contact Site. AB - How extracellular cues direct axon-dendrite polarization in mouse developing neurons is not fully understood. Here, we report that the radial glial cell (RGC) cortical neuron interaction directs axon formation at the opposite side of the neuron from the contact site. N-cadherin accumulates at the contact site between the RGC and cortical neuron. Inhibition of the N-cadherin-mediated adhesion decreases this oriented axon formation in vitro, and disrupts the axon-dendrite polarization in vivo. Furthermore, the RGC-neuron interaction induces the polarized distribution of active RhoA at the contacting neurite and active Rac1 at the opposite neurite. Inhibition of Rho-Rho-kinase signaling in a neuron impairs the oriented axon formation in vitro, and prevents axon-dendrite polarization in vivo. Collectively, these results suggest that the N-cadherin mediated radial glia-neuron interaction determines the contacting neurite as the leading process for radial glia-guided neuronal migration and directs axon formation to the opposite side acting through the Rho family GTPases. PMID- 26511245 TI - Transcranial Stimulation over Frontopolar Cortex Elucidates the Choice Attributes and Neural Mechanisms Used to Resolve Exploration-Exploitation Trade-Offs. AB - Optimal behavior requires striking a balance between exploiting tried-and-true options or exploring new possibilities. Neuroimaging studies have identified different brain regions in humans where neural activity is correlated with exploratory or exploitative behavior, but it is unclear whether this activity directly implements these choices or simply reflects a byproduct of the behavior. Moreover, it remains unknown whether arbitrating between exploration and exploitation can be influenced with exogenous methods, such as brain stimulation. In our study, we addressed these questions by selectively upregulating and downregulating neuronal excitability with anodal or cathodal transcranial direct current stimulation over right frontopolar cortex during a reward-learning task. This caused participants to make slower, more exploratory or faster, more exploitative decisions, respectively. Bayesian computational modeling revealed that stimulation affected how much participants took both expected and obtained rewards into account when choosing to exploit or explore: Cathodal stimulation resulted in an increased focus on the option expected to yield the highest payout, whereas anodal stimulation led to choices that were less influenced by anticipated payoff magnitudes and were more driven by recent negative reward prediction errors. These findings suggest that exploration is triggered by a neural mechanism that is sensitive to prior less-than-expected choice outcomes and thus pushes people to seek out alternative courses of action. Together, our findings establish a parsimonious neurobiological mechanism that causes exploration and exploitation, and they provide new insights into the choice features used by this mechanism to direct decision-making. PMID- 26511246 TI - The Unfolded Protein Response and Cholesterol Biosynthesis Link Luman/CREB3 to Regenerative Axon Growth in Sensory Neurons. AB - We recently revealed that the axon endoplasmic reticulum resident transcription factor Luman/CREB3 (herein called Luman) serves as a unique retrograde injury signal in regulation of the intrinsic elongating form of sensory axon regeneration. Here, evidence supports that Luman contributes to axonal regeneration through regulation of the unfolded protein response (UPR) and cholesterol biosynthesis in adult rat sensory neurons. One day sciatic nerve crush injury triggered a robust increase in UPR-associated mRNA and protein expression in both neuronal cell bodies and the injured axons. Knockdown of Luman expression in 1 d injury-conditioned neurons by siRNA attenuated axonal outgrowth to 48% of control injured neurons and was concomitant with reduced UPR- and cholesterol biosynthesis-associated gene expression. UPR PCR-array analysis coupled with qRT-PCR identified and confirmed that four transcripts involved in cholesterol regulation were downregulated >2-fold by the Luman siRNA treatment of the injury-conditioned neurons. Further, the Luman siRNA-attenuated outgrowth could be significantly rescued by either cholesterol supplementation or 2 ng/ml of the UPR inducer tunicamycin, an amount determined to elevate the depressed UPR gene expression to a level equivalent of that observed with crush injury. Using these approaches, outgrowth increased significantly to 74% or 69% that of injury conditioned controls, respectively. The identification of Luman as a regulator of the injury-induced UPR and cholesterol at levels that benefit the intrinsic ability of axotomized adult rat sensory neurons to undergo axonal regeneration reveals new therapeutic targets to bolster nerve repair. PMID- 26511248 TI - A Lognormal Recurrent Network Model for Burst Generation during Hippocampal Sharp Waves. AB - The strength of cortical synapses distributes lognormally, with a long tail of strong synapses. Various properties of neuronal activity, such as the average firing rates of neurons, the rate and magnitude of spike bursts, the magnitude of population synchrony, and the correlations between presynaptic and postsynaptic spikes, also obey lognormal-like distributions reported in the rodent hippocampal CA1 and CA3 areas. Theoretical models have demonstrated how such a firing rate distribution emerges from neural network dynamics. However, how the other properties also display lognormal patterns remain unknown. Because these features are likely to originate from neural dynamics in CA3, we model a recurrent neural network with the weights of recurrent excitatory connections distributed lognormally to explore the underlying mechanisms and their functional implications. Using multi-timescale adaptive threshold neurons, we construct a low-frequency spontaneous firing state of bursty neurons. This state well replicates the observed statistical properties of population synchrony in hippocampal pyramidal cells. Our results show that the lognormal distribution of synaptic weights consistently accounts for the observed long-tailed features of hippocampal activity. Furthermore, our model demonstrates that bursts spread over the lognormal network much more effectively than single spikes, implying an advantage of spike bursts in information transfer. This efficiency in burst propagation is not found in neural network models with Gaussian-weighted recurrent excitatory synapses. Our model proposes a potential network mechanism to generate sharp waves in CA3 and associated ripples in CA1 because bursts occur in CA3 pyramidal neurons most frequently during sharp waves. PMID- 26511247 TI - Distinct Mechanisms Underlie Quiescence during Two Caenorhabditis elegans Sleep Like States. AB - Electrophysiological recordings have enabled identification of physiologically distinct yet behaviorally similar states of mammalian sleep. In contrast, sleep in nonmammals has generally been identified behaviorally and therefore regarded as a physiologically uniform state characterized by quiescence of feeding and locomotion, reduced responsiveness, and rapid reversibility. The nematode Caenorhabditis elegans displays sleep-like quiescent behavior under two conditions: developmentally timed quiescence (DTQ) occurs during larval transitions, and stress-induced quiescence (SIQ) occurs in response to exposure to cellular stressors. Behaviorally, DTQ and SIQ appear identical. Here, we use optogenetic manipulations of neuronal and muscular activity, pharmacology, and genetic perturbations to uncover circuit and molecular mechanisms of DTQ and SIQ. We find that locomotion quiescence induced by DTQ- and SIQ-associated neuropeptides occurs via their action on the nervous system, although their neuronal target(s) and/or molecular mechanisms likely differ. Feeding quiescence during DTQ results from a loss of pharyngeal muscle excitability, whereas feeding quiescence during SIQ results from a loss of excitability in the nervous system. Together these results indicate that, as in mammals, quiescence is subserved by different mechanisms during distinct sleep-like states in C. elegans. PMID- 26511249 TI - Asymmetric Interhemispheric Transfer in the Auditory Network: Evidence from TMS, Resting-State fMRI, and Diffusion Imaging. AB - Hemispheric asymmetries in human auditory cortical function and structure are still highly debated. Brain stimulation approaches can complement correlational techniques by uncovering causal influences. Previous studies have shown asymmetrical effects of transcranial magnetic stimulation (TMS) on task performance, but it is unclear whether these effects are task-specific or reflect intrinsic network properties. To test how modulation of auditory cortex (AC) influences functional networks and whether this influence is asymmetrical, the present study measured resting-state fMRI connectivity networks in 17 healthy volunteers before and immediately after TMS (continuous theta burst stimulation) to the left or right AC, and the vertex as a control. We also examined the relationship between TMS-induced interhemispheric signal propagation and anatomical properties of callosal auditory fibers as measured with diffusion weighted MRI. We found that TMS to the right AC, but not the left, resulted in widespread connectivity decreases in auditory- and motor-related networks in the resting state. Individual differences in the degree of change in functional connectivity between auditory cortices after TMS applied over the right AC were negatively related to the volume of callosal auditory fibers. The findings show that TMS-induced network modulation occurs, even in the absence of an explicit task, and that the magnitude of the effect differs across individuals as a function of callosal structure, supporting a role for the corpus callosum in mediating functional asymmetry. The findings support theoretical models emphasizing hemispheric differences in network organization and are of practical significance in showing that brain stimulation studies need to take network-level effects into account. PMID- 26511250 TI - Increasing Spontaneous Retinal Activity before Eye Opening Accelerates the Development of Geniculate Receptive Fields. AB - Visually evoked activity is necessary for the normal development of the visual system. However, little is known about the capacity for patterned spontaneous activity to drive the maturation of receptive fields before visual experience. Retinal waves provide instructive retinotopic information for the anatomical organization of the visual thalamus. To determine whether retinal waves also drive the maturation of functional responses, we increased the frequency of retinal waves pharmacologically in the ferret (Mustela putorius furo) during a period of retinogeniculate development before eye opening. The development of geniculate receptive fields after receiving these increased neural activities was measured using single-unit electrophysiology. We found that increased retinal waves accelerate the developmental reduction of geniculate receptive field sizes. This reduction is due to a decrease in receptive field center size rather than an increase in inhibitory surround strength. This work reveals an instructive role for patterned spontaneous activity in guiding the functional development of neural circuits. PMID- 26511251 TI - Typical and Atypical Development of Functional Connectivity in the Face Network. AB - Extensive studies have demonstrated that face recognition performance does not reach adult levels until adolescence. However, there is no consensus on whether such prolonged improvement stems from development of general cognitive factors or face-specific mechanisms. Here, we used behavioral experiments and functional magnetic resonance imaging (fMRI) to evaluate these two hypotheses. With a large cohort of children (n = 379), we found that the ability of face-specific recognition in humans increased with age throughout childhood and into late adolescence in both face memory and face perception. Neurally, to circumvent the potential problem of age differences in task performance, attention, or cognitive strategies in task-state fMRI studies, we measured the resting-state functional connectivity (RSFC) between the occipital face area (OFA) and fusiform face area (FFA) in human brain and found that the OFA-FFA RSFC increased until 11-13 years of age. Moreover, the OFA-FFA RSFC was selectively impaired in adults with developmental prosopagnosia (DP). In contrast, no age-related changes or differences between DP and normal adults were observed for RSFCs in the object system. Finally, the OFA-FFA RSFC matured earlier than face selectivity in either the OFA or FFA. These results suggest the critical role of the OFA-FFA RSFC in the development of face recognition. Together, our findings support the hypothesis that prolonged development of face recognition is face specific, not domain general. PMID- 26511252 TI - Alternative Splicing in Ca(V)2.2 Regulates Neuronal Trafficking via Adaptor Protein Complex-1 Adaptor Protein Motifs. AB - N-type voltage-gated calcium (Ca(V)2.2) channels are expressed in neurons and targeted to the plasma membrane of presynaptic terminals, facilitating neurotransmitter release. Here, we find that the adaptor protein complex-1 (AP-1) mediates trafficking of Ca(V)2.2 from the trans-Golgi network to the cell surface. Examination of splice variants of Ca(V)2.2, containing either exon 37a (selectively expressed in nociceptors) or 37b in the proximal C terminus, reveal that canonical AP-1 binding motifs, YxxPhi and [DE]xxxL[LI], present only in exon 37a, enhance intracellular trafficking of exon 37a-containing Ca(V)2.2 to the axons and plasma membrane of rat DRG neurons. Finally, we identify differential effects of dopamine-2 receptor (D2R) and its agonist-induced activation on trafficking of Ca(V)2.2 isoforms. D2R slowed the endocytosis of Ca(V)2.2 containing exon 37b, but not exon 37a, and activation by the agonist quinpirole reversed the effect of the D2R. Our work thus reveals key mechanisms involved in the trafficking of N-type calcium channels. PMID- 26511253 TI - Distinctive Representation of Mispredicted and Unpredicted Prediction Errors in Human Electroencephalography. AB - The predictive coding model of perception proposes that neuronal responses are modulated by the amount of sensory input that the internal prediction cannot account for (i.e., prediction error). However, there is little consensus on what constitutes nonpredicted stimuli. Conceptually, whereas mispredicted stimuli may induce both prediction error generated by prediction that is not perceived and prediction error generated by sensory input that is not anticipated, unpredicted stimuli involves no top-down, only bottom-up, propagation of information in the system. Here, we examined the possibility that the processing of mispredicted and unpredicted stimuli are dissociable at the neurophysiological level using human electroencephalography. We presented participants with sets of five tones in which the frequency of the fifth tones was predicted, mispredicted, or unpredicted. Participants were required to press a key when they detected a softer fifth tone to maintain their attention. We found that mispredicted and unpredicted stimuli are associated with different amount of cortical activity, probably reflecting differences in prediction error. Moreover, relative to predicted stimuli, the mispredicted prediction error manifested as neuronal enhancement and the unpredicted prediction error manifested as neuronal attenuation on the N1 event-related potential component. These results highlight the importance of differentiating between the two nonpredicted stimuli in theoretical work on predictive coding. PMID- 26511254 TI - Spatial Correlations in Natural Scenes Modulate Response Reliability in Mouse Visual Cortex. AB - Intrinsic neuronal variability significantly limits information encoding in the primary visual cortex (V1). Certain stimuli can suppress this intertrial variability to increase the reliability of neuronal responses. In particular, responses to natural scenes, which have broadband spatiotemporal statistics, are more reliable than responses to stimuli such as gratings. However, very little is known about which stimulus statistics modulate reliable coding and how this occurs at the neural ensemble level. Here, we sought to elucidate the role that spatial correlations in natural scenes play in reliable coding. We developed a novel noise-masking method to systematically alter spatial correlations in natural movies, without altering their edge structure. Using high-speed two photon calcium imaging in vivo, we found that responses in mouse V1 were much less reliable at both the single neuron and population level when spatial correlations were removed from the image. This change in reliability was due to a reorganization of between-neuron correlations. Strongly correlated neurons formed ensembles that reliably and accurately encoded visual stimuli, whereas reducing spatial correlations reduced the activation of these ensembles, leading to an unreliable code. Together with an ensemble-specific normalization model, these results suggest that the coordinated activation of specific subsets of neurons underlies the reliable coding of natural scenes. PMID- 26511255 TI - Selective Dysregulation of Hippocampal Inhibition in the Mouse Lacking Autism Candidate Gene CNTNAP2. AB - Mutations in the human gene encoding contactin-associated protein-like 2 (CNTNAP2) have been strongly associated with autism spectrum disorders (ASDs). Cntnap2(-/-) mice recapitulate major features of ASD, including social impairment, reduced vocalizations, and repetitive behavior. In addition, Cntnap2( /-) mice show reduced cortical neuronal synchrony and develop spontaneous seizures throughout adulthood. As suggested for other forms of ASDs, this phenotype could reflect some form of synaptic dysregulation. However, the impact of lifelong deletion of CNTNAP2 on synaptic function in the brain remains unknown. To address this issue, we have assessed excitatory and inhibitory synaptic transmission in acute hippocampal slices of Cntnap2(-/-) mice. We found that although excitatory transmission was mostly normal, inhibition onto CA1 pyramidal cells was altered in Cntnap2(-/-) mice. Specifically, putative perisomatic, but not dendritic, evoked IPSCs were significantly reduced in these mice. Whereas both inhibitory short-term plasticity and miniature IPSC frequency and amplitude were normal in Cntnap2(-/-) mice, we found an unexpected increase in the frequency of spontaneous, action potential-driven IPSCs. Altered hippocampal inhibition could account for the behavioral phenotype Cntnap2(-/-) mice present later in life. Overall, our findings that Cntnap2 deletion selectively impairs perisomatic hippocampal inhibition while sparing excitation provide additional support for synaptic dysfunction as a common mechanism underlying ASDs. PMID- 26511256 TI - Prevalence and antimicrobial susceptibility of Vibrio parahaemolyticus isolated from oysters in Korea. AB - Vibrio parahaemolyticus is the most prevalent gastroenteritis-causing pathogen in Korea and in some other Asian countries. It is frequently found in oysters and other seafood. This study monitored changes in the prevalence of V. parahaemolyticus and environmental parameters in oyster aquaculture environments in Korea. From June to October 2014, we tested oysters (Crassostrea gigas) from shellfish-harvesting areas off the west coast of Korea. These 71 isolates were the sum of 16 (22.5%), 19 (26.8%), 23 (32.4%), and 13 (18.3%) isolates collected in July, August, September, and October, respectively. These 71 isolates had the following profiles of resistance against 16 antibiotics: all isolates were resistant to ampicillin and vancomycin, and 52.2, 50.7, and 50.7% of isolates exhibited resistance to cephalothin, rifampin, and streptomycin, respectively. PCR analysis for the presence of the species-specific toxR gene confirmed that 38 (53.5%) of the total 71 isolated strains were positive for V. parahaemolyticus. In PCR analysis for virulence of V. parahaemolyticus, of the 71 isolates tested in the present study, only 38 (53.5%) were positive for the trh virulence gene and 71 (100%) was negative for the tdh virulence gene. PMID- 26511257 TI - Microbenthic community structure and trophic status of sediments in the Mar Piccolo of Taranto (Mediterranean, Ionian Sea). AB - This study aimed to assess the benthic ecosystem trophic status in a heavily polluted marine area and the response of the microbenthic community to multiple and diffuse anthropogenic impacts, integrating information coming from the active and resting (plankton's cysts) components of microbenthos. Two sampling campaigns were carried out in the period 2013-2014 and four sampling sites at different levels of industrial contamination were chosen within the first and second inlet of the Mar Piccolo of Taranto. The chemical contamination affected to a higher extent the active microbenthos than the resting one. In the central part of the first inlet, characterised by more marine features, thrives a very rich and biodiverse microbenthic community. In contrast, at the polluted site near the military navy arsenal, extremely low densities (9576 +/- 1732 cells cm(-3)) were observed for active microbenthos, but not for the resting community. Here, the high level of contamination selected for tychopelagic diatom species, i.e., thriving just above the surface sediments, while the other life forms died or moved away. Following the adoption of a 10 MUm mesh, for the first time, resting spores produced by small diatoms of the genus Chaetoceros were found. Our results further indicate that although the Mar Piccolo is very shallow, the benthic system is scarcely productive, likely as a consequence of the accumulated contaminants in the surface sediments that probably interfere with the proper functioning of the benthic ecosystem. PMID- 26511258 TI - Arsenic speciation in rice and risk assessment of inorganic arsenic in Taiwan population. AB - This study assessed the total arsenic content and arsenic speciation in rice to determine the health risks associated with rice consumption in various age-gender subgroups in Taiwan. The average total arsenic levels in white rice and brown rice were 116.6 +/- 39.2 and 215.5 +/- 63.5 ng/g weight (n = 51 and 13), respectively. The cumulative cancer risk among males was 10.4/100,000. The highest fraction of inorganic/total arsenic content in white rice ranged from 76.9 to 88.2 % and from 81.0 to 96.5 % in brown rice. The current study found different arsenic speciation of rice in southern Taiwan, where the famous blackfoot disease has been reported compared with arsenic speciation from other Taiwan areas. Therefore, rice and other grains should be further monitored in southern Taiwan to evaluate whether arsenic contamination is well controlled in this area. PMID- 26511259 TI - Shape effect on the antibacterial activity of silver nanoparticles synthesized via a microwave-assisted method. AB - Silver nanoparticles (AgNPs) are used as sustained-release bactericidal agents for water treatment. Among the physicochemical characteristics of AgNPs, shape is an important parameter relevant to the antibacterial activity. Three typically shaped AgNPs, nanocubes, nanospheres, and nanowires, were prepared via a microwave-assisted method and characterized by TEM, UV-vis, and XRD. The antibacterial activity of AgNPs was determined by OD growth curves tests, MIC tests, and cell viability assay against Escherichia coli. The interaction between AgNPs and bacterial cells was observed by TEM. The results showed that the three differently shaped AgNPs were nanoscale, 55 +/- 10 nm in edge length for nanocubes, 60 +/- 15 nm in diameter for nanospheres, 60 +/- 10 nm in diameter and 2-4 MUm in length for nanowires. At the bacterial concentration of 10(4) CFU/mL, the MIC of nanocubes, nanospheres, and nanowires were 37.5, 75, and 100 MUg/mL, respectively. Due to the worst contact with bacteria, silver nanowires exhibited the weakest antibacterial activity compared with silver nanocubes and silver nanospheres. Besides, silver nanocubes mainly covered by {100} facets showed stronger antibacterial activity than silver nanospheres covered by {111} facets. It suggests that the shape effect on the antibacterial activity of AgNPs is attributed to the specific surface areas and facets reactivity; AgNPs with larger effective contact areas and higher reactive facets exhibit stronger antibacterial activity. PMID- 26511260 TI - Identification and apportionment of hazardous elements in the sediments in the Yangtze River estuary. AB - In this study, positive matrix factorization (PMF) and principal components analysis (PCA) were combined to identify and apportion pollution-based sources of hazardous elements in the surface sediments in the Yangtze River estuary (YRE). Source identification analysis indicated that PC1, including Al, Fe, Mn, Cr, Ni, As, Cu, and Zn, can be defined as a sewage component; PC2, including Pb and Sb, can be considered as an atmospheric deposition component; and PC3, containing Cd and Hg, can be considered as an agricultural nonpoint component. To better identify the sources and quantitatively apportion the concentrations to their sources, eight sources were identified with PMF: agricultural/industrial sewage mixed (18.6 %), mining wastewater (15.9 %), agricultural fertilizer (14.5 %), atmospheric deposition (12.8 %), agricultural nonpoint (10.6 %), industrial wastewater (9.8 %), marine activity (9.0 %), and nickel plating industry (8.8 %). Overall, the hazardous element content seems to be more connected to anthropogenic activity instead of natural sources. The PCA results laid the foundation for the PMF analysis by providing a general classification of sources. PMF resolves more factors with a higher explained variance than PCA; PMF provided both the internal analysis and the quantitative analysis. The combination of the two methods can provide more reasonable and reliable results. PMID- 26511261 TI - Positive Impact of Epidural Analgesia on Oncologic Outcomes in Patients Undergoing Resection of Colorectal Liver Metastases. AB - INTRODUCTION: Previous studies have suggested that the use of regional anesthesia can reduce recurrence risk after oncologic surgery. The purpose of this study was to assess the effect of epidural anesthesia on recurrence-free (RFS) and overall survival (OS) after hepatic resection for colorectal liver metastases (CLM). METHODS: After approval of the institutional review board, the records of all adult patients who underwent elective hepatic resection between January 2006 and October 2011 were retrospectively reviewed. Patients were categorized according to use of perioperative epidural analgesia versus intravenous analgesia. Univariate and multivariate analyses were performed to identify factors influencing RFS and OS. RESULTS: Of 510 total patients, 390 received epidural analgesia (EA group) and 120 patients received intravenous analgesia (IVA group). Compared with the IVA group, more patients in the EA group underwent associated surgical procedures with consequently longer operative times (p < 0.001). In addition, the EA group received more intraoperative fluids and had higher urine output volumes (p <= 0.001). Five-year RFS was longer in the EA group (34.7%) compared with the IVA group (21.1%). On multivariate analysis, the receipt of epidural analgesia was an independent predictor of improved RFS (p = 0.036, hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.56-0.95), but not OS (p = 0.102, HR 0.72; 95% CI 0.49-1.07). CONCLUSIONS: This study suggests an association between epidural analgesia and improved RFS, but not OS, after CLM resection. These results warrant further prospective, randomized studies on the benefits of regional anesthesia on oncologic outcomes after hepatic resection for CLM. PMID- 26511262 TI - A Novel Light-Emitting Wire Enhances the Marking and Visualization of Pathologic Mammary Ducts During Selective Microdochectomy. AB - BACKGROUND: Methylene blue injection of lesions often is inaccurate, and ductoscopic wire marking does not facilitate easy identification of lesions during microdochectomy in patients with pathologic nipple discharge. The authors designed a light-emitting wire that can be inserted into pathologic mammary ducts to facilitate intraoperative duct identification and evaluated the efficacy of this device in patients undergoing selective microdochectomy. METHODS: In this study, 69 patients being evaluated for pathologic discharge were randomized to undergo selective microdochectomy with either methylene blue pathologic duct marking or light-emitting wire pathologic duct marking. The patient clinical characteristics and surgical outcomes were compared and evaluated. RESULTS: Of the 69 study patients, 36 underwent selective microdochectomy guided by methylene blue injection, and 33 underwent light-emitting wire marking. No differences existed between the clinical and histologic characteristics or the diagnostic accuracies of the groups. In 11 (30.56%) of the 36 patients who underwent methylene blue marking, the ducts ruptured after the methylene blue was injected, and normal tissue around the duct was stained. Light-emitting wire marking was associated with a shorter surgical time and smaller surgical specimens. CONCLUSIONS: The use of light-emitting wire marking enabled selective microdochectomy of pathologic ducts under visual guidance. Resection volume was reduced, and blinded extended resection was avoided. PMID- 26511263 TI - Locoregional Control According to Breast Cancer Subtype and Response to Neoadjuvant Chemotherapy in Breast Cancer Patients Undergoing Breast-conserving Therapy. AB - BACKGROUND: Our group previously published data showing that patients could be stratified by constructed molecular subtype with respect to locoregional recurrence (LRR)-free survival after neoadjuvant chemotherapy and breast conserving therapy (BCT). That study predated use of trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive patients. The current study was undertaken to determine the impact of subtype and response to therapy in a contemporary cohort. METHODS: Clinicopathologic data from 751 breast cancer patients who received neoadjuvant chemotherapy (with trastuzumab if HER2(+)) and BCT from 2005 to 2012 were identified. Hormone receptor (HR) and HER2 status were used to construct molecular subtypes: HR(+)/HER2(-) (n = 369), HR(+)/HER2(+) (n = 105), HR(-)/HER2(+) (n = 58), and HR(-)/HER2(-) (n = 219). Actuarial rates of LRR were determined by the Kaplan-Meier method and compared by the log-rank test. Multivariate analysis was performed to determine factors associated with LRR. RESULTS: The pathologic complete response (pCR) rates by subtype were as follows: 16.5% (HR(+)/HER2(-)), 45.7% (HR(+)/HER2(+)), 72.4% (HR(-)/HER2(+)), and 42.0% (HR(-)/HER2(-)) (P < 0.001). Median follow-up was 4.6 years. The 5-year LRR-free survival rate for all patients was 95.4%. Five-year LRR-free survival rates by subtype were 97.2 % (HR(+)/HER2(-)), 96.1% (HR(+)/HER2(+)), 94.4% (HR( )/HER2(+)), and 93.4% (HR(-)/HER2(-)) (P = 0.44). For patients with HR(-)/HER2(+) disease, the LRR-free survival rates were 97.4 and 86.7% for those who did and those who did not experience pCR, respectively. For patients with HR(-)/HER2(-) disease, the LRR-free survival rates were 98.6% (pCR) versus 89.9% (no pCR). On multivariate analysis, the HR(-)/HER2(-) subtype, clinical stage III disease, and failure to experience a pCR were associated with LRR. CONCLUSIONS: Patients undergoing BCT after neoadjuvant chemotherapy have excellent rates of 5-year LRR free survival that are affected by molecular subtype and by response to neoadjuvant chemotherapy. PMID- 26511264 TI - Confocal Imaging and Tissue-Specific Fluorescent Probes for Real-Time In Vivo Immunohistochemistry. Proof of the Concept in a Gastric Lymph Node Metastasis Model. AB - BACKGROUND: Tumor-specific fluorescent antibodies, which can be recognized at a cellular or tissue level using optical imaging such as confocal laser endomicroscopy (CLE), could provide a means for rapid and accurate tumor diagnosis and staging. The aim of this study was to evaluate the ability of CLE to detect the presence of tagged cells within lymph nodes in an original simulated metastatic model. MATERIALS AND METHODS: A solution of indocyanine green containing a suspension of porcine hepatocytes, marked with carboxy fluorescein-succinimidyl-ester (CFSE), was injected endoscopically in the gastric submucosa of 10 pigs. Fluorescence lymphography using a near-infrared laparoscope was used to identify sentinel and secondary drainage nodes. Additionally, a nonfluorescent gastric and a mesenteric node were identified. Every 5-10 min, those nodes were scanned using probe-based or needle-based CLE (pCLE or nCLE). Immunohistochemistry (IHC) using anti-cytokeratin 18 antibodies was subsequently performed to confirm the presence of hepatocytes in the lymph nodes. RESULTS: A total of 36 lymph nodes were analyzed with both CLE probes. Hepatocyte penetration in lymph nodes, as assessed by repeated CLE scanning, took 10-40 min after submucosal injection. Concordance between CLE and IHC was 84 and 72 % for pCLE and nCLE, respectively. False negatives were partly due to incomplete CFSE labeling of hepatocytes, which could not be recognized by CLE, but were detected with IHC. CONCLUSIONS: Real-time CLE analysis effectively recognized the presence in perigastric nodes of marked hepatic cells that had been injected endoscopically in the stomach. Validation studies on tumor-bearing animals using tumor-specific antibodies should be performed. PMID- 26511265 TI - The Effects of Surgery Type and Chemotherapy on Early-Stage Breast Cancer Patients' Quality of Life Over 2-Year Follow-up. AB - BACKGROUND: We examined the effects of surgery type and adjuvant chemotherapy on change in early-stage breast cancer patients' quality of life (QOL) over time. METHODS: A cohort of 549 patients (33.5% ductal carcinoma in situ, 66.5% stages I/IIA) were interviewed a mean 6.1 weeks (Time1), and 6.2 (Time2), 12.3 (Time3), and 24.4 (Time4) months following definitive breast-conserving surgery (BCS) or mastectomy. QOL was measured using the total Functional Assessment of Cancer Therapy-Breast (FACT-B). Adjusting for demographic, psychosocial, and clinical variables, multiple linear regression models estimated the associations between QOL and each of surgery type, chemotherapy, and their 2-way interaction at each interview. Adjusted generalized estimating equation (GEE) models tested Time1 Time4 change in QOL. RESULTS: At Time2, chemotherapy (P < .001) and BCS (P < .001) were independently associated with worse QOL in adjusted linear regression, and the adverse effect of chemotherapy was prominent among patients who received BCS compared with those who received mastectomy (P interaction = .031). In the GEE model, QOL significantly improved over time among patients who received BCS (P trend = .047), mastectomy (P trend = .024), and chemotherapy (P trend < .001), but not among patients who did not receive chemotherapy (P trend = .720). All patients completed adjuvant chemotherapy and radiation by Time3. Regardless of surgery type, patients receiving chemotherapy reported lower QOL following surgery, and QOL improved after completion of adjuvant treatment. CONCLUSIONS: Chemotherapy had a short-term negative impact on QOL after definitive surgical treatment regardless of surgery type. QOL rebounded after completion of adjuvant treatment. PMID- 26511266 TI - Predictive Value of Neutrophil/Lymphocyte Ratio for Efficacy of Preoperative Chemotherapy in Triple-Negative Breast Cancer. AB - BACKGROUND: The neutrophil/lymphocyte ratio (NLR) has been reportedly associated with prognosis in cancer patients by influencing both cancer progression and chemosensitivity. However, the correlation between NLR and the outcome of neoadjuvant chemotherapy (NAC) in breast cancer patients remains unclear. METHODS: NLR was evaluated in 177 patients with breast cancer treated with NAC with 5-fluorouracil, epirubicin, and cyclophosphamide, followed by weekly paclitaxel and subsequent curative surgery. The correlation between NLR and prognosis, including the efficacy of NAC, was evaluated retrospectively. RESULTS: NLR ranged from 0.5 to 10.6. Fifty-eight patients with low NLR (<3.0) had a higher pathological complete response (pCR) rate (p < 0.001) and were more frequently diagnosed with ER-negative/progesterone receptor (PR)-negative/HER2 negative (triple-negative) breast cancer (TNBC; p < 0.001) compared with patients with high NLR (>=3.0). Among TNBC patients who achieved pCR, disease-free survival (p = 0.006) and overall survival (p < 0.001) were significantly longer in patients with low NLR than in those with high NLR. Low NLR was associated with a significantly favorable prognosis in TNBC patients who achieved pCR, according to univariate analysis (p = 0.044, hazard ratio = 0.06). CONCLUSIONS: Low NLR may indicate high efficacy and favorable outcome after NAC in patients with TNBC. PMID- 26511268 TI - Measuring cervical length improves accuracy of estimating due date in late pregnancy, study shows. PMID- 26511267 TI - Is It Time to Centralize Ovarian Cancer Care in the United States? AB - PURPOSE: The purpose of this article was to broadly review the most up-to-date information pertaining to the centralization of ovarian cancer care in the United States (US) and worldwide. METHODS: Much of the present literature pertaining to disparities in, and centralization of, ovarian cancer care in the US and internationally was reviewed, and specifically included original research and review articles. RESULTS: Data show improved optimal debulking rates, National Comprehensive Cancer Network (NCCN) guideline adherence, and overall survival rates in higher-volume, more specialized hospitals, and amongst higher-volume providers. CONCLUSIONS: Patients with invasive epithelial ovarian cancer, especially those with higher stages (III and IV), are better served by centralized care in high-volume hospitals and by high-volume physicians, who adhere to NCCN guidelines wherever possible. More research is needed to determine the policy changes that can increase NCCN guideline adherence in low-volume hospitals and low-provider caseload scenarios. Policy and future research should be aimed at increasing patient access, either directly or indirectly, to high volume hospital and high-volume providers, especially amongst Medicare, lower socioeconomic status, and minority patients. PMID- 26511269 TI - The influence of metallic shell deformation on the contact mechanics of a ceramic on-ceramic total hip arthroplasty. AB - Total hip arthroplasty of ceramic-on-ceramic bearing combinations is increasingly used clinically. The majority of these implants are used with cementless fixation that a metal-backing shell is press-fitted into the pelvic bone. This usually results in the deformation of the metallic shell, which may also influence the ceramic liner deformation and consequently the contact mechanics between the liner and the femoral head under loading. The explicit dynamic finite element method was applied to model the implantation of a cementless ceramic-on-ceramic with a titanium shell and subsequently to investigate the effect of the metallic shell deformation on the contact mechanics. A total of three impacts were found to be necessary to seat the titanium alloy shell into the pelvic bone cavity with a 1 mm diameter interference and a 1.3 kg impactor at 4500 mm s(-1) velocity. The maximum deformation of the metallic shell was found to be 160 um in the antero superior and postero-inferior direction and 97 um in the antero-inferior and postero-superior direction after the press-fit. The corresponding values were slightly reduced to 67 and 45 um after the ceramic liner was inserted and then modified to 74 and 43 um under loading, respectively. The maximum deformation and the maximum principal stress of the ceramic liner were 31 um and 144 MPa (tensile stress), respectively, after it was inserted into the shell and further increased to 52 um and 245 MPa under loading. This research highlights the importance of the press-fit of the metallic shell on the contact mechanics of the ceramic liner for ceramic-on-ceramic total hip arthroplasties and potential clinical performances. PMID- 26511270 TI - Effect of regulating airway pressure on intrathoracic pressure and vital organ perfusion pressure during cardiopulmonary resuscitation: a non-randomized interventional cross-over study. AB - BACKGROUND: The objective of this investigation was to evaluate changes in intrathoracic pressure (Ppl), airway pressure (Paw) and vital organ perfusion pressures during standard and intrathoracic pressure regulation (IPR)-assisted cardiopulmonary resuscitation (CPR). METHODS: Multiple CPR interventions were assessed, including newer ones based upon IPR, a therapy that enhances negative intrathoracic pressure after each positive pressure breath. Eight anesthetized pigs underwent 4 min of untreated ventricular fibrillation followed by 2 min each of sequential interventions: (1) conventional standard CPR (STD), (2) automated active compression decompression (ACD) CPR, (3) ACD+ an impedance threshold device (ITD) CPR or (4) ACD+ an intrathoracic pressure regulator (ITPR) CPR, the latter two representing IPR-based CPR therapies. Intrapleural (Ppl), airway (Paw), right atrial, intracranial, and aortic pressures, along with carotid blood flow and end tidal CO2, were measured and compared during each CPR intervention. RESULTS: The lowest mean and decompression phase Ppl were observed with IPR-based therapies [Ppl mean (mean +/- SE): STD (0.8 +/- 1.1 mmHg); ACD (-1.6 +/- 1.6); ACD-ITD (-3.7 +/- 1.5, p < 0.05 vs. both STD and ACD); ACD-ITPR (-7.0 +/- 1.9, p < 0.05 vs. both STD and ACD)] [Ppl decompression (mean +/- SE): STD (-6.3 +/- 2.2); ACD (-13.0 +/- 3.8); ACD-ITD -16.9 +/- 3.6, p < 0.05 vs. both STD and ACD); ACD-ITPR -18.7 +/- 3.5, p < 0.05 vs. both STD and ACD)]. Interventions with the lower mean or decompression phase Ppl also demonstrated lower Paw and were associated with higher vital organ perfusion pressures. CONCLUSIONS: IPR-based CPR methods, specifically ACD-ITPR, yielded the most pronounced reduction in both Ppl and Paw and resulted in the most favorable augmentation of hemodynamics during CPR. PMID- 26511271 TI - Sleep Health and Appropriate Use of OTC Sleep Aids in Older Adults Recommendations of a Gerontological Society of America Workgroup. AB - Getting a good night's sleep can be challenging for older adults with chronic medical conditions, which often interfere with sleep. As a result, many older adults turn to over-the-counter (OTC) sleep aids, that is, products with diphenhydramine or doxylamine. However, these products are indicated only for occasional difficulty with sleep, not for chronic use; and their safety and efficacy has not been well established in general and in older adults specifically. To engage national stakeholders in a discussion of OTC sleep aids in older adults, the Gerontological Society of America (GSA) convened a multidisciplinary workgroup. The Workgroup examined differences between younger and older adults in sleep health and use of OTC sleep aids using data from the National Health and Wellness Survey; assessed the pharmacologic properties and medication effects of OTC sleep aids; and worked with stakeholders to promote strategies for safe and effective use. Older adults are more likely to take diphenhydramine or doxylamine products 15 or more days in a month, an indicator of inappropriate use. The Workgroup recommends research to investigate the ways older people use OTC sleep aids. The goal should be reduction in inappropriate use and associated risks, such as daytime sedation, compromised cognitive function, and falls. In addition, the Workgroup recommends a greater role for community pharmacists in counseling older adults on appropriate use of OTC sleep aids. PMID- 26511272 TI - Aging in Precarious Circumstances: Do Positive Views on Aging Make a Difference? AB - Purpose of the study: Precariousness, defined as low income combined with lack of security for retirement, can influence the way people grow old and result in health inequalities in old age. Design and methods: A sequential mixed methods approach was used to identify differences in behavioral (physical activity), social (social network), and psychological resources (positive views on aging) that middle-aged individuals from both precarious and financially secure backgrounds use in preparation for positive aging and keep high levels of health and well-being. It was investigated whether positive views on aging can compensate the detrimental association of a lack of resources with health and well-being in midlife. Data from the German Aging Survey (N = 1,992 in the secure group, N = 240 in the precarious group) were analyzed to understand the relationship between resources on the one hand and health and well-being on the other, as well as to compare the strategies of individuals with precarious and financially secure backgrounds. Semistructured interviews with middle-aged individuals (N = 20) from these two categories were analyzed in order to further explain the quantitative findings. Results: Precarious individuals are indeed disadvantaged in terms of behavioral, social, and psychological resources as well as in health and well-being. However, having a positive view on aging can compensate for insufficient resources. Qualitative findings showed differences in strategies for resource management and perceptions of positive aging. Implications: Secondary analysis of quantitative and qualitative data reflects the importance of positive views on aging as a resource for a healthy old age despite aging in precarious circumstances. PMID- 26511273 TI - An Examination of Resilience and Coping in the Oldest Old Using Life Narrative Method. AB - We aimed to identify aspects of late-life resilience and sense of self-identity and locate them within a life narrative to provide insights into methods of coping with the challenges of aging. To do this, in-depth interviews were conducted with 20 oldest-old adults (aged 88-98 years) recruited from the Australian Longitudinal Study of Ageing. Design, analysis, and interpretation of the study were informed by McAdams' life narrative theory, using concepts of redemption and contamination. Participants discussed their autobiographies and recounted significant life events. Interviews drew on McAdams' approach to elicit positive, negative, vivid, and turning point experiences. Analysis involved coding transcripts of the emergent personal narratives specifically to understand a "resilience story." This included data immersion and review of interview transcripts. Emergent codes were identified and discussed among the researchers. Although no contamination events were narrated, we identified the following themes: Adapting to aging-related physical challenges; Changing social networks; Continuity in sense of identity to maintain unity and life's purpose; and Redemptive capacity to cope positively with life challenges. This study fills a gap in knowledge on resilience from a personal perspective by the oldest old. Older people may benefit from interventions that harness positive coping strategies and foster social connections and meaningful activities, especially at times of loss or grief. PMID- 26511274 TI - Plasma kidney injury molecule-1 in heart failure: renal mechanisms and clinical outcome. AB - AIMS: Urinary kidney injury molecule-1 (KIM-1) is a marker of tubular damage and associated with worse outcome in heart failure (HF). Plasma KIM-1 has not been described in HF. METHODS AND RESULTS: In a renal mechanistic cohort of 120 chronic HF patients, we established the association between plasma KIM-1, renal invasive haemodynamic parameters {renal blood flow ([(131) I]hippuran clearance) and measured glomerular filtration rate (GFR; [(125) I]iothalamate)} and urinary tubular damage markers. The association between plasma KIM-1, plasma creatinine, and clinical outcome was further explored in a cohort of 2033 acute HF patients. Median plasma KIM-1 was 171.5 pg/mL (122.8-325.7) in chronic (n = 99) and 295.1 pg/mL (182.2-484.2) in acute HF (n = 1588). In chronic HF, plasma KIM-1 was associated with GFR (P < 0.001), creatinine, and cystatin C. Plasma KIM-1 was associated with urinary N-acetyl-beta-d-glucosaminidase (NAG), but not with other urinary tubular damage markers. Log plasma KIM-1 predicted adverse clinical outcome after adjustment for age, gender, and GFR [hazard ratio (HR) 1.94, 95% confidence interval (CI) 1.07-3.53, P = 0.030]. Statistical significance was lost after correction for NT-proBNP (HR 1.61, 95% CI 0.81-3.20, P = 0.175). In acute HF, higher plasma KIM-1 levels were associated with higher creatinine, lower albumin, and presence of diabetes. Log plasma KIM-1 predicted 60-day HF rehospitalization (HR 1.27, 95% CI 1.03-1.55, P = 0.024), but not 180-day mortality or 60-day death or renal or cardiovascular rehospitalization. CONCLUSIONS: Plasma KIM-1 is associated with glomerular filtration and urinary NAG, but not with other urinary tubular damage markers. Plasma KIM-1 does not predict outcome in chronic HF after correction for NT-proBNP. In acute HF, plasma KIM-1 predicts HF rehospitalization in multivariable analysis. PMID- 26511275 TI - Sall1 in renal stromal progenitors non-cell autonomously restricts the excessive expansion of nephron progenitors. AB - The mammalian kidney develops from reciprocal interactions between the metanephric mesenchyme and ureteric bud, the former of which contains nephron progenitors. The third lineage, the stroma, fills up the interstitial space and is derived from distinct progenitors that express the transcription factor Foxd1. We showed previously that deletion of the nuclear factor Sall1 in nephron progenitors leads to their depletion in mice. However, Sall1 is expressed not only in nephron progenitors but also in stromal progenitors. Here we report that specific Sall1 deletion in stromal progenitors leads to aberrant expansion of nephron progenitors, which is in sharp contrast with a nephron progenitor specific deletion. The mutant mice also exhibited cystic kidneys after birth and died before adulthood. We found that Decorin, which inhibits Bmp-mediated nephron differentiation, was upregulated in the mutant stroma. In contrast, the expression of Fat4, which restricts nephron progenitor expansion, was reduced mildly. Furthermore, the Sall1 protein binds to many stroma-related gene loci, including Decorin and Fat4. Thus, the expression of Sall1 in stromal progenitors restricts the excessive expansion of nephron progenitors in a non-cell autonomous manner, and Sall1-mediated regulation of Decorin and Fat4 might at least partially underlie the pathogenesis. PMID- 26511276 TI - The role of complexity metrics in a multi-institutional dosimetry audit of VMAT. AB - OBJECTIVE: To demonstrate the benefit of complexity metrics such as the modulation complexity score (MCS) and monitor units (MUs) in multi-institutional audits of volumetric-modulated arc therapy (VMAT) delivery. METHODS: 39 VMAT treatment plans were analysed using MCS and MU. A virtual phantom planning exercise was planned and independently measured using the PTW Octavius((r)) phantom and seven29((r)) 2D array (PTW-Freiburg GmbH, Freiburg, Germany). MCS and MU were compared with the median gamma index pass rates (2%/2 and 3%/3 mm) and plan quality. The treatment planning systems (TPS) were grouped by VMAT modelling being specifically designed for the linear accelerator manufacturer's own treatment delivery system (Type 1) or independent of vendor for VMAT delivery (Type 2). Differences in plan complexity (MCS and MU) between TPS types were compared. RESULTS: For Varian((r)) linear accelerators (Varian((r)) Medical Systems, Inc., Palo Alto, CA), MCS and MU were significantly correlated with gamma pass rates. Type 2 TPS created poorer quality, more complex plans with significantly higher MUs and MCS than Type 1 TPS. Plan quality was significantly correlated with MU for Type 2 plans. A statistically significant correlation was observed between MU and MCS for all plans (R = -0.84, p < 0.01). CONCLUSION: MU and MCS have a role in assessing plan complexity in audits along with plan quality metrics. Plan complexity metrics give some indication of plan deliverability but should be analysed with plan quality. ADVANCES IN KNOWLEDGE: Complexity metrics were investigated for a national rotational audit involving 34 institutions and they showed value. The metrics found that more complex plans were created for planning systems which were independent of vendor for VMAT delivery. PMID- 26511277 TI - Utility of fat-suppressed sequences in differentiation of aggressive vs typical asymptomatic haemangioma of the spine. AB - OBJECTIVE: While haemangiomas are common benign vascular lesions involving the spine, some behave in an aggressive fashion. We investigated the utility of fat suppressed sequences to differentiate between benign and aggressive vertebral haemangiomas. METHODS: Patients with the diagnosis of aggressive vertebral haemangioma and available short tau inversion-recovery or T2 fat saturation sequence were included in the study. 11 patients with typical asymptomatic vertebral body haemangiomas were selected as the control group. Region of interest signal intensity (SI) analysis of the entire haemangioma as well as the portion of each haemangioma with highest signal on fat-saturation sequences was performed and normalized to a reference normal vertebral body. RESULTS: A total of 8 patients with aggressive vertebral haemangioma and 11 patients with asymptomatic typical vertebral haemangioma were included. There was a significant difference between total normalized mean SI ratio (3.14 vs 1.48, p = 0.0002), total normalized maximum SI ratio (5.72 vs 2.55, p = 0.0003), brightest normalized mean SI ratio (4.28 vs 1.72, p < 0.0001) and brightest normalized maximum SI ratio (5.25 vs 2.45, p = 0.0003). Multiple measures were able to discriminate between groups with high sensitivity (>88%) and specificity (>82%). CONCLUSION: In addition to the conventional imaging features such as vertebral expansion and presence of extravertebral component, quantitative evaluation of fat-suppression sequences is also another imaging feature that can differentiate aggressive haemangioma and typical asymptomatic haemangioma. ADVANCES IN KNOWLEDGE: The use of quantitative fat-suppressed MRI in vertebral haemangiomas is demonstrated. Quantitative fat-suppressed MRI can have a role in confirming the diagnosis of aggressive haemangiomas. In addition, this application can be further investigated in future studies to predict aggressiveness of vertebral haemangiomas in early stages. PMID- 26511278 TI - Back to the roots: segregation of univalent sex chromosomes in meiosis. AB - In males of many taxa, univalent sex chromosomes normally segregate during the first meiotic division, and analysis of sex chromosome segregation was foundational for the chromosome theory of inheritance. Correct segregation of single or multiple univalent sex chromosomes occurs in a cellular environment where every other chromosome is a bivalent that is being partitioned into homologous chromosomes at anaphase I. The mechanics of univalent chromosome segregation vary among animal taxa. In some, univalents establish syntelic attachment of sister kinetochores to the spindle. In others, amphitelic attachment is established. Here, we review how this problem of segregation of unpaired chromosomes is solved in different animal systems. In addition, we give a short outlook of how mechanistic insights into this process could be gained by explicitly studying model organisms, such as Caenorhabditis elegans. PMID- 26511279 TI - Meiotic cohesin-based chromosome structure is essential for homologous chromosome pairing in Schizosaccharomyces pombe. AB - Chromosome structure is dramatically altered upon entering meiosis to establish chromosomal architectures necessary for the successful progression of meiosis specific events. An early meiotic event involves the replacement of the non-SMC mitotic cohesins with their meiotic equivalents in most part of the chromosome, forming an axis on meiotic chromosomes. We previously demonstrated that the meiotic cohesin complex is required for chromosome compaction during meiotic prophase in the fission yeast Schizosaccharomyces pombe. These studies revealed that chromosomes are elongated in the absence of the meiotic cohesin subunit Rec8 and shortened in the absence of the cohesin-associated protein Pds5. In this study, using super-resolution structured illumination microscopy, we found that Rec8 forms a linear axis on chromosomes, which is required for the organized axial structure of chromatin during meiotic prophase. In the absence of Pds5, the Rec8 axis is shortened whereas chromosomes are widened. In rec8 or pds5 mutants, the frequency of homologous chromosome pairing is reduced. Thus, Rec8 and Pds5 play an essential role in building a platform to support the chromosome architecture necessary for the spatial alignment of homologous chromosomes. PMID- 26511280 TI - Linking replication stress with heterochromatin formation. AB - The eukaryotic genome can be roughly divided into euchromatin and heterochromatin domains that are structurally and functionally distinct. Heterochromatin is characterized by its high compaction that impedes DNA transactions such as gene transcription, replication, or recombination. Beyond its role in regulating DNA accessibility, heterochromatin plays essential roles in nuclear architecture, chromosome segregation, and genome stability. The formation of heterochromatin involves special histone modifications and the recruitment and spreading of silencing complexes that impact the higher-order structures of chromatin; however, its molecular nature varies between different chromosomal regions and between species. Although heterochromatin has been extensively characterized, its formation and maintenance throughout the cell cycle are not yet fully understood. The biggest challenge for the faithful transmission of chromatin domains is the destabilization of chromatin structures followed by their reassembly on a novel DNA template during genomic replication. This destabilizing event also provides a window of opportunity for the de novo establishment of heterochromatin. In recent years, it has become clear that different types of obstacles such as tight protein-DNA complexes, highly transcribed genes, and secondary DNA structures could impede the normal progression of the replisome and thus have the potential to endanger the integrity of the genome. Multiple studies carried out in different model organisms have demonstrated the capacity of such replisome impediments to favor the formation of heterochromatin. Our review summarizes these reports and discusses the potential role of replication stress in the formation and maintenance of heterochromatin and the role that silencing proteins could play at sites where the integrity of the genome is compromised. PMID- 26511281 TI - Dynamical Buildup of Lasing in Mesoscale Devices. AB - The classical description of laser field buildup, based on time-averaged photon statistics of Class A lasers, rests on a statistical mixture of coherent and incoherent photons. Here, applying multiple analysis techniques to temporal streams of data acquired in the threshold region of a Class B mesoscale laser, we conclusively show that new physics is involved in the transition: the lasing buildup is controlled by large dynamical spikes, whose number increases as the pump is raised, evolving into an average coherent field, modulated by population dynamics, and eventually relaxing to a steady state for sufficiently large photon numbers. These results explain inconsistencies observed in small scale devices. Implications for nanolaser coherence properties, threshold identification and regimes of operation, including new potential applications, are discussed. PMID- 26511283 TI - In reply: Ultrasound-guided internal jugular vein cannulation: a novel technique for confirming that the guidewire is directed towards the right atrium. PMID- 26511282 TI - Comparison of the Superagonist Complex, ALT-803, to IL15 as Cancer Immunotherapeutics in Animal Models. AB - IL15, a potent stimulant of CD8(+) T cells and natural killer (NK) cells, is a promising cancer immunotherapeutic. ALT-803 is a complex of an IL15 superagonist mutant and a dimeric IL15 receptor alphaSu/Fc fusion protein that was found to exhibit enhanced biologic activity in vivo, with a substantially longer serum half-life than recombinant IL15. A single intravenous dose of ALT-803, but not IL15, eliminated well-established tumors and prolonged survival of mice bearing multiple myeloma. In this study, we extended these findings to demonstrate the superior antitumor activity of ALT-803 over IL15 in mice bearing subcutaneous B16F10 melanoma tumors and CT26 colon carcinoma metastases. Tissue biodistribution studies in mice also showed much greater retention of ALT-803 in the lymphoid organs compared with IL15, consistent with its highly potent immunostimulatory and antitumor activities in vivo. Weekly dosing with 1 mg/kg ALT-803 in C57BL/6 mice was well tolerated, yet capable of increasing peripheral blood lymphocyte, neutrophil, and monocyte counts by >8-fold. ALT-803 dose dependent stimulation of immune cell infiltration into the lymphoid organs was also observed. Similarly, cynomolgus monkeys treated weekly with ALT-803 showed dose-dependent increases of peripheral blood lymphocyte counts, including NK, CD4(+), and CD8(+) memory T-cell subsets. In vitro studies demonstrated ALT-803 mediated stimulation of mouse and human immune cell proliferation and IFNgamma production without inducing a broad-based release of other proinflammatory cytokines (i.e., cytokine storm). Based on these results, a weekly dosing regimen of ALT-803 has been implemented in multiple clinical studies to evaluate the dose required for effective immune cell stimulation in humans. PMID- 26511284 TI - Printing Highly Controlled Suspended Carbon Nanotube Network on Micro-patterned Superhydrophobic Flexible Surface. AB - Suspended single-walled carbon nanotubes (SWCNTs) offer unique functionalities for electronic and electromechanical systems. Due to their outstanding flexible nature, suspended SWCNT architectures have great potential for integration into flexible electronic systems. However, current techniques for integrating SWCNT architectures with flexible substrates are largely absent, especially in a manner that is both scalable and well controlled. Here, we present a new nanostructured transfer paradigm to print scalable and well-defined suspended nano/microscale SWCNT networks on 3D patterned flexible substrates with micro- to nanoscale precision. The underlying printing/transfer mechanism, as well as the mechanical, electromechanical, and mechanical resonance properties of the suspended SWCNTs are characterized, including identifying metrics relevant for reliable and sensitive device structures. Our approach represents a fast, scalable and general method for building suspended nano/micro SWCNT architectures suitable for flexible sensing and actuation systems. PMID- 26511285 TI - Incidence of complications associated with tibial tuberosity advancement in Boxer dogs. AB - OBJECTIVE: To retrospectively review and describe the incidence of complications associated with tibial tuberosity advancement (TTA) surgical procedures in a group of Boxer dogs (n = 36 stifles) and compare the data with a non-Boxer control population (n = 271 stifles). METHODS: Retrospective analysis of medical records to identify all dogs that underwent TTA surgery due to cranial cruciate ligament disease. These records were categorized into two groups: Boxer dogs and non-Boxer dogs (controls - all other breeds). RESULTS: Of the 307 stifles included, 69 complications were reported in 58 joints. The complication rate differed significantly for Boxer dogs (16/36 stifles) and non-Boxer dogs (42/271 stifles), corresponding to an odds ratio of 5.8 (confidence interval: 1.96-17.02; p-value <0.001). Boxer dogs were more likely to undergo revision surgery and to develop multiple complications. The incidence of tibial tuberosity fractures requiring surgical repair (2/36 versus 1/271) and incisional infections requiring antibiotic treatment (three in each group) was significantly higher in the Boxer group. CLINICAL SIGNIFICANCE: Boxer dogs had more major and multiple complications after TTA surgery than the control non-Boxer group; these complications included higher rates of revision surgery, tibial tuberosity fractures requiring stabilization, and infection related complications. The pertinence and value of breed-specific recommendations for cranial cruciate ligament disease appears to be a subject worthy of further investigation. PMID- 26511286 TI - High pressure synthesis of polar and non-polar cation-ordered polymorphs of Mn2ScSbO6. AB - Two new cation-ordered polymorphs of Mn2ScSbO6 have been synthesised at high pressure. At 5.5 GPa and 1523 K Mn2ScSbO6 crystallizes in the Ni3TeO6-type structure with the polar R3 space group and cell parameters a = 5.3419 (5) A and c = 14.0603 (2) A. Below TC = 42.0 K it exhibits ferrimagnetic order with a net magnetization of 0.6MUB arising from unusual site-selective Mn/Sc disorder and is thus a potential multiferroic material. A double perovskite phase obtained at 12 GPa and 1473 K crystallizes in the non-polar P21/n monoclinic space group with cell parameters a = 5.2909 (3) A, b = 5.4698 (3) A, c = 7.7349 (5) A and beta = 90.165 (6) degrees . Magnetization and neutron diffraction experiments reveal antiferromagnetic order below TN = 22.3 K with the spins lying in the ac plane. PMID- 26511287 TI - MICROBIOME. A unified initiative to harness Earth's microbiomes. PMID- 26511288 TI - 'They will not control us': Ingroup positivity and belief in intergroup conspiracies. AB - This research examined the role of different forms of positive regard for the ingroup in predicting beliefs in intergroup conspiracies. Collective narcissism reflects a belief in ingroup greatness contingent on others' recognition. We hypothesized that collective narcissism should be especially likely to foster outgroup conspiracy beliefs. Non-narcissistic ingroup positivity, on the other hand, should predict a weaker tendency to believe in conspiracy theories. In Study 1, the endorsement of conspiratorial explanations of outgroup actions was positively predicted by collective narcissism but negatively by non-narcissistic ingroup positivity. Study 2 showed that the opposite effects of collective narcissism and non-narcissistic ingroup positivity on conspiracy beliefs were mediated via differential perceptions of threat. Study 3 manipulated whether conspiracy theories implicated ingroup or outgroup members. Collective narcissism predicted belief in outgroup conspiracies but not in ingroup conspiracies, while non-narcissistic ingroup positivity predicted lower conspiracy beliefs, regardless of them being ascribed to the ingroup or the outgroup. PMID- 26511289 TI - William Douglas, artist: I am dying. So are you. PMID- 26511290 TI - Toward industrial scale synthesis of ultrapure singlet nanoparticles with controllable sizes in a continuous gas-phase process. AB - Continuous gas-phase synthesis of nanoparticles is associated with rapid agglomeration, which can be a limiting factor for numerous applications. In this report, we challenge this paradigm by providing experimental evidence to support that gas-phase methods can be used to produce ultrapure non-agglomerated "singlet" nanoparticles having tunable sizes at room temperature. By controlling the temperature in the particle growth zone to guarantee complete coalescence of colliding entities, the size of singlets in principle can be regulated from that of single atoms to any desired value. We assess our results in the context of a simple analytical model to explore the dependence of singlet size on the operating conditions. Agreement of the model with experimental measurements shows that these methods can be effectively used for producing singlets that can be processed further by many alternative approaches. Combined with the capabilities of up-scaling and unlimited mixing that spark ablation enables, this study provides an easy-to-use concept for producing the key building blocks for low cost industrial-scale nanofabrication of advanced materials. PMID- 26511291 TI - Flavonoid derivative exerts an antidiabetic effect via AMPK activation in diet induced obesity mice. AB - In our previous study, a derivative of tiliroside, 3-O-[(E)-4-(4-ethoxyphenyl)-2 oxobut-3-en-1-yl]kaempferol (Fla-OEt) significantly enhanced glucose consumption in insulin resistant HepG2 cells. This article deals with the antihyperglycemic and antihyperlipidemic effects of Fla-OEt in diet-induced obesity (DIO) mice. Daily administration of Fla-OEt significantly decreased oral glucose tolerance test, intraperitoneal insulin tolerance test and serum lipids. Hyperinsulinemic euglycemic clamp and the ratio of high-density-lipoprotein/low-density lipoprotein with Fla-OEt treatment were increased comparing with high-fat diet (HFD) group, so lipid metabolism was improved. Histopathology examination showed that the Fla-OEt restored the damage of adipose tissues and liver in DIO mice. Moreover, compared with HFD group, Fla-OEt treatment significantly increased the phosphorylation of AMPK and ACC in adiposity tissues, liver, and muscles. The mechanism of its action might be the activation of AMPK pathway. It appears that Fla-OEt is worth further study for development as a lead compound for a potential antidiabetic agent. PMID- 26511292 TI - Interface Schottky barrier engineering via strain in metal-semiconductor composites. AB - The interfacial carrier transfer property, which is dominated by the interface Schottky barrier height (SBH), plays a crucial role in determining the performance of metal-semiconductor heterostructures in a variety of applications. Therefore, artificially controlling the interface SBH is of great importance for their industrial applications. As a model system, the Au/TiO2 (001) heterostructure is studied using first-principles calculations and the tight binding method in the present study. Our investigation demonstrates that strain can be an effective way to decrease the interface SBH and that the n-type SBH can be more effectively decreased than the p-type SBH. Astonishingly, strain affects the interface SBH mainly by changing the intrinsic properties of Au and TiO2, whereas the interfacial potential alignment is almost independent of strain due to two opposite effects, which are induced by strain at the interfacial region. These observed trends can be understood on the basis of the general free-electron gas model of typical metals, the tight-binding theory and the crystal-field theory, which suggest that similar trends may be generalized for many other metal semiconductor heterostructures. Given the commonness and tunability of strain in typical heterostructures, we anticipate that the tunability of the interface SBH with strain described here can provide an alternative effective way for realizing more efficient applications of relevant heterostructures. PMID- 26511294 TI - The food industry and conflicts of interest in nutrition research: A Latin American perspective. AB - Conflicts of interest arise when corporations marketing harmful products establish financial relationships with research institutions, researchers, or public health organizations. As obesity becomes a worldwide epidemic, such relationships threaten to jeopardize the integrity of scientific research. Latin America, a region undergoing rapid development, is particularly vulnerable to such conflicts. Here, we provide examples of how food and beverage companies are funding nutrition-focused research and institutions in Latin America, putting their credibility at risk. Public health organizations and institutions should take measures to identify, manage, and limit (or eliminate) conflicts of interest caused by partnerships with food companies making and marketing unhealthful products.Journal of Public Health Policy advance online publication, 29 October 2015; doi:10.1057/jphp.2015.37. PMID- 26511293 TI - Reduced healthcare utilization following successful hepatitis C virus treatment in HIV-co-infected patients with mild liver disease. AB - New direct-acting antivirals (DAA) for hepatitis C virus (HCV) infection have achieved high cure rates in many patient groups previously considered difficult to-treat, including those HIV/HCV co-infected. The high price of these medications is likely to limit access to treatment, at least in the short term. Early treatment priority is likely to be given to those with advanced disease, but a more detailed understanding of the potential benefits in treating those with mild disease is needed. We hypothesized that successful HCV treatment within a co-infected population with mild liver disease would lead to a reduction in the use and costs of healthcare services in the 5 years following treatment completion. We performed a retrospective cohort study of HIV/HCV-co-infected patients without evidence of fibrosis/cirrhosis who received a course of HCV therapy between 2004 and 2013. Detailed analysis of healthcare utilization up to 5 years following treatment for each patient using clinical and electronic records was used to estimate healthcare costs. Sixty-three patients were investigated, of whom 48 of 63 (76.2%) achieved sustained virological response 12 weeks following completion of therapy (SVR12). Individuals achieving SVR12 incurred lower health utilization costs (L5,000 per-patient) compared to (L10 775 per-patient) non-SVR patients in the 5 years after treatment. Healthcare utilization rates and costs in the immediate 5 years following treatment were significantly higher in co-infected patients with mild disease that failed to achieve SVR12. These data suggest additional value to achieving cure beyond the prevention of complications of disease. PMID- 26511295 TI - Traffic medical research status. PMID- 26511296 TI - Biomechanical behavior of brain injury caused by sticks using finite element model and Hybrid-III testing. AB - OBJECTIVE: To study the biomechanical mechanism of head injuries beaten with sticks, which is common in the battery or assaultive cases. METHODS: In this study, the Hybrid-III anthropomorphic test device and finite element model (FEM) of the total human model for safety (THUMS) head were used to determine the biomechanical response of head while being beaten with different sticks. Total eight Hybrid-III tests and four finite element simulations were conducted. The contact force, resultant acceleration of head center of gravity, intracranial pressure and von Mises stress were calculated to determine the different biomechanical behavior of head with beaten by different sticks. RESULTS: In Hybrid-III tests, the stick in each group demonstrated the similar kinematic behavior under the same loading condition. The peak values of the resultant acceleration for thick iron stick group, thin iron stick group, thick wooden stick group and thin wooden stick group were 203.4 g, 221.1 g, 170.5 g and 122.2 g respectively. In finite element simulations, positive intracranial pressure was initially observed in the frontal comparing with negative intracranial pressure in the contra-coup site. Subsequently the intracranial pressure in the coup site was decreasing toward negative value while the contra-coup intracranial pressure increasing toward positive values. CONCLUSIONS: The results illustrated that the stiffer and larger the stick was, the higher the von Mises stress, contact force and intracranial pressure were. We believed that the results in the Hybrid-III tests and THUMS head simulations for brain injury beaten with sticks could be reliable and useful for better understanding the injury mechanism. PMID- 26511297 TI - Study on pedestrian thorax injury in vehicle-to-pedestrian collisions using finite element analysis. AB - OBJECTIVE: To explore the relationship between the collision parameters of vehicle and the pedestrian thorax injury by establishing the chest simulation models in car-pedestrian collision at different velocities and angles. METHODS: 87 cases of vehicle-to-pedestrian accidents, with detailed injury information and determined vehicle impact parameters, were included. The severity of injury was scaled in line with the Abbreviated Injury Scale (AIS). The chest biomechanical response parameters and change characteristics were obtained by using Hyperworks and LS-DYNA computing. Simulation analysis was applied to compare the characteristics of injuries. RESULTS: When impact velocities at 25, 40 and 55 km/h, respectively, 1) the maximum values of thorax velocity criterion (VC) were for 0.29, 0.83 and 2.58 m/s; and at the same collision velocity, the thorax VC from the impact on pedestrian's front was successively greater than on his back and on his side; 2) the maximum values of peak stress on ribs were 154, 177 and 209 MPa; and at the same velocity, peak stress values on ribs from the impact on pedestrian's side were greater than on his front and his back. CONCLUSION: There is a positive correlation between the severity and risk of thorax injury and the collision velocity and angle of car-thorax crashes. At the same velocity, it is of greater damage risk when the soft tissue of thorax under a front impact; and there is also a greater risk of ribs fracture under a side impact of the thorax. This result is of vital significance for diagnosis and protection of thorax collision injuries. PMID- 26511298 TI - Analysis on the risk factors of intracranial infection secondary to traumatic brain injury. AB - OBJECTIVE: To discuss the characteristics and risk factors for intracranial infection post traumatic brain injury to prevent and better the clinical care. METHODS: Retrospective study of 520 patients with traumatic brain injury were included, 308 male and 212 female. The risky factors of intracranial infection were identified. RESULTS: Thirty two cases (6.54%, 32/520) of intracranial infection were diagnosed. Intracranial infection most likely happened 4-10 days after injury. Cerebrospinal fluid leakage, drainage, multiple craniotomies were significant related to intracranial infection. Logistic regression predicted cerebrospinal fluid leakage and drainage as independent factors. CONCLUSION: Intracranial infection is a serious complication after traumatic brain injury. Patients with drainage or cerebrospinal fluid leakage are more risky for intracranial infection. Aggressive precaution should be taken to better outcome. PMID- 26511299 TI - Epidemiological study of community- and hospital-acquired intraabdominal infections. AB - PURPOSE: To investigate and analyze the clinical and etiological characteristics of community-acquired intraabdominal infections (CIAIs) and hospital-acquired or nosocomial intraabdominal infections (NIAIs) in a comprehensive hospital, to understand the characteristics, pathogen composition, and drug resistance of CIAIs as well as NIAIs, and to provide a reference for clinical treatment. METHODS: We collected the clinical data of patients with intraabdominal infections admitted to our hospital from June 2013 to June 2014. In vitro drug sensitivity tests were conducted to separate pathogens, and the data were analyzed using the WHONET 5.4 software and SPSS 13.0 software. RESULTS: A total of 221 patients were enrolled in the study, including 144 with CIAIs (55 mild moderate and 89 severe) and 77 with NIAIs. We isolated 322 pathogenic strains, including 234 strains of gram-negative bacteria, 82 strains of gram-positive bacteria, and 6 strains of fungi. Based on clinical features, NIAIs and severe CIAIs presented significantly higher values in age, length of hospital stay, mortality, and the incidence of severe intra-abdominal infection than mild moderate CIAIs (p < 0.05). There was no significant difference in the prognosis between NIAIs and severe CIAIs. Primary diseases leading to CIAIs and NIAIs mostly were hepatobiliary diseases and gastrointestinal diseases respectively. Bacteria isolated from various types of IAIs mainly were Enterobacteriaceae; mild moderate CIAIs mostly were mono-infection of gram-negative bacteria; NIAIs mostly were mixed infections of gram-negative and gram-positive bacteria; and severe CIAIs were from either type of infection. The rate of Extended Spectrum b Lactamase-producing Escherichia coli and Klebsiella pneumoniae was much higher in NIAIs than in CIAIs (p < 0.05). The antimicrobial drug sensitivity of gram negative bacteria isolated from NIAIs was significantly lower than that of CIAIs. CONCLUSION: CIAIs and NIAIs have their own unique clinical features and epidemiological features of pathogens which should be considered during the initial empiric therapy for the rational use of antimicrobial drugs. Regional IAIs pathogenic bacteria have their own features in drug resistance, slightly different from some recommendations of 2010 Infectious Diseases Society of America guidelines. PMID- 26511300 TI - Changes in cerebral hemodynamics in patients with posttraumatic diffuse brain swelling after external intraventricular drainage. AB - PURPOSE: To investigate the changes of cerebral hemodynamics pre- and post ventricular drainage in patients with posttraumatic acute diffuse brain swelling. METHODS: Twenty-four cases of traumatic diffuse brain swelling were analyzed retrospectively. Patients in nonsurgical group were treated by medicine therapy. Patients in surgical group were treated by external ventricular drainage plus medicine therapy. The first CT perfusion scan was completed within 4-5 h after trauma and scanned again after 7 days. The changes of perfusion parameters in area-of-interest in two groups were analyzed and compared before and after treatment. RESULTS: Compared with the nonsurgical group, the value of cerebral blood volume, cerebral blood flow and mean transit time in bilateral frontal temporoparietal grey matter, basal ganglia, cerebellum, and brain stem at pre- and post-therapy were increased significantly (p < 0.05) in surgical group, and consequently the prognosis of patients undergoing surgery was also better than that of nonsurgical group. CONCLUSION: External ventricular drainage can improve cerebral perfusion and increase survival quality for the patients with posttraumatic acute diffuse brain swelling. PMID- 26511301 TI - Research progress of acute coagulopathy of trauma-shock. AB - Acute coagulopathy of trauma-shock (ACoTS) occurs in 25% of patients with severe trauma in the early phase, and the mortality of those patients is four-fold higher than patients without coagulopathy. The pathophysiology of this complicated phenomenon has been focused on in recent years. Tissue injury and hypoperfusion, activated protein C and Complements play important roles in the early phase after trauma. While the use of blood products, hypothermia, acidosis and inflammation are the main mechanism in late phase. Supplementing coagulation factors and platelets to improve ACoTS are inefficient. Only positive resuscitation from shock and improving tissue hypoperfusion have expected benefits. PMID- 26511302 TI - Transarterial detachable coil embolization combined with ipsilateral intermittent carotid oppression for traumatic carotid-cavernous fistula with small fistula. AB - One case of traumatic carotid-cavernous fistula (TCCF) with small fistula treated by transarterial detachable coil embolization was reported. The intermittent ipsilateral carotid compression was used to identify the final blocking of the residual fistula. The follow-up digital subtraction angiography showed that the TCCF was cured finally. From this case, we conclude that this method may be an effective way to treat TCCF with small fistula. PMID- 26511303 TI - Lateral epicondylar osteotomy for severe varus deformity during total knee arthroplasty. AB - In most cases of arthritic varus knees, stepwise osteophytes removal and medial soft tissue release could achieve satisfactory soft tissue balance during total knee arthroplasty. However, in some severe cases, conventional balancing techniques are not enough, necessitating other procedures like epicondylar osteotomy. To the best of our knowledge, no published article has reported the application of lateral epicondylar osteotomy in a severe varus knee. Here we reported a case of successful correction of a severe varus knee following lateral epicondylar osteotomy, and described its underlying rationale. PMID- 26511304 TI - Comminuted fractures of ipsilateral radial head and distal radius: A rare injury pattern. AB - A new injury pattern of comminuted fractures of ipsilateral radial head and distal radius of forearm in an adult was described. To the best of our knowledge, this type of injury pattern had not been previously reported in the English literature. The possible mechanisms of injury were that the rebound forces were volar to the distal radius as the fracture was dorsally angulated, with a continuation of the radial head fracture due to the longitudinal impaction of the radius against the capitellum. Open reduction and internal fixation can obtain excellent results within 7-12 days after injury. We hope that our experience will increase the awareness of the occurrence of a double injury of the forearm. PMID- 26511305 TI - Perioperative treatment of femoral neck fracture with deep venous thrombosis: A case report. AB - Deep venous thrombosis (DVT) is an important cause of disability and mortality after major orthopedic surgery. The roles of perioperative treatment and prevention of DVT in patients with femoral neck fractures who require major surgery have not yet been well explored in Chinese clinical practice. Here we report a case of calf muscular venous thrombosis in a 55-year-old woman with femoral neck fracture before surgery. Preventive and treatment measures including the administration of heparin sodium, application of venous foot pump and placement of inferior vena cava filter were taken. The condition of the patient was stable during the perioperative period and the surgery was successful. Besides, postoperative examination showed that the femur healed well and the functional recovery was satisfactory. Our results suggest that femoral neck fracture patients combined with DVT can receive surgery after accurate preoperative assessment and proper preoperative treatment. PMID- 26511306 TI - Elbow dislocation with ipsilateral diaphyseal forearm bone fracture: A rare injury report with literature review. AB - Dislocation of the elbow along with shaft fractures of both bones of the ipsilateral forearm is a rare injury though elbow dislocation or fracture of the forearm bones may occur separately. Such injuries need a concentric reduction of the dislocation and an anatomical fixation of forearm bones for optimal functional outcomes. We report a case of elbow dislocation with fracture of the lateral condyle of the humerus along with fractures of shafts of the radius and ulna in a 44-year-old female. Closed reduction of the elbow and operative stabilization of all fractures were done with good clinical, radiological and functional outcomes in 2 years follow-up period. A significant degree of force is needed to produce a combined dislocation of a joint and fracture of bones around that joint and these complex injuries may be missed if the clinician is not aware of the possibility of such injuries. The fact that the previously reported cases had a posterolateral dislocation while our case had a posteromedial dislocation and a fracture of the lateral humeral condyle as well makes it unique in its presentation and worth reporting. We have also included an up to date literature review on this topic. PMID- 26511307 TI - Lateral cortex blowout during PFNA blade insertion in a subtrochanteric fracture- -Should bone quality determine the type of nail used? AB - Subtrochanteric fractures pose a therapeutic challenge to the surgeons. With the advent of proximal femoral nails, most of the cases are treated with nailing. Newer nails like proximal femoral nail antirotation (PFNA) require the blade to be directly hammered into the bone compared to older nails where the screws are drilled and tapped before insertion. We report one such case in a middle aged female that had intraoperative lateral cortex blowout during PFNA blade insertion in a sclerotic bone. This occurrence to the best of our knowledge is unreported in literature. It is therefore imperative to consider the quality of bone before a decision is made on the implant chosen. PMID- 26511308 TI - Pathogenesis, diagnosis and treatment of cerebral fat embolism. AB - In this study, we analyzed two cases of pure cerebral fat embolism and reviewed related literatures to explore the pathogenesis, clinical manifestations, diagnosis and treatment of cerebral fat embolism, improve the treatment efficiency and reduce the misdiagnosis rate. In our cases, patients fully returned to consciousness at the different times with good prognosis, normal vital signs and without obvious sequelae. For patients with the limb fractures, who developed coma without chest distress, dyspnea or other pulmonary symptoms 12 or 24 h post injury, cerebral fat embolism should be highly suspected, except for those with intracranial lesions, such as delayed traumatic intracerebral hemorrhage, etc. The early diagnosis and comprehensive treatment can improve prognosis. PMID- 26511309 TI - Distinction between parkour and freerunning. PMID- 26511310 TI - The influence of sequential ligand exchange and elimination on the performance of P3HT: CdSe quantum dot hybrid solar cells. AB - We report on a sequential ligand exchange and elimination process for the fast and easy surface modification of CdSe quantum dots (QDs) in order to improve the electronic interaction between poly(3-hexylthiophene) (P3HT) and CdSe QDs in P3HT:CdSe hybrid solar cells. We systematically investigated the influence of surface treatment on the insulating ligand shell of CdSe QDs using (1)H-NMR analysis, and correlated their influence on the photovoltaic properties of P3HT:CdSe hybrid solar cells. A decrease in the average thickness of the ligand shells directly improved carrier transport properties. Moreover, the presence of remnant 1-hexylamine ligands provided efficient surface trap passivation. As a result, overall solar cell performance (especially fill factor and power conversion efficiency) was enhanced and the recombination mechanism was dominated by monomolecular recombination due to enhanced carrier collection length (l(C0)). PMID- 26511311 TI - Development and Validation of an Enzymatic Method for Total Cholesterol Analysis Using Whole Blood Spot. AB - BACKGROUND: High serum cholesterol represents a risk factor for cardiovascular disease. This study aims to quantify total cholesterol in dried blood spot (DBS) by direct enzymatic method. METHODS: Three hundred seventeen blood samples with serum cholesterol level ranging from 81 to 337 mg/dl were collected. DBS were manually prepared, cholesterol was extracted using methanol and analyzed by a manual enzymatic method. DBS cholesterol method was validated for imprecision and extraction efficacy. DBS cholesterol values were correlated (training test) with serum values measured by automated enzymatic method (reference method). The obtained correlation was used for predicting serum cholesterol from DBS analysis of a new sample group (validation test, n = 58). RESULTS: Within-day and between day coefficient of variation (CV%) were lower than 7.69 and 6.32, respectively. Residual cholesterol in DBS after extraction was 16%. DBS cholesterol and serum cholesterol showed a linear correlation (slope = 0.5217; r = 0.9139) and a bias of -28%. Furthermore, DBS cholesterol values of validation test (n = 58), converted using the training test correlation, were not statistically different compared to the corresponding plasma values (P = 0.9487), and the comparison by Passing and Bablok showed a linear regression with a slope of 1.068 (r = 0.611) and a bias of -0.22%. CONCLUSIONS: The results show that this enzymatic method is suitable to analyze cholesterol in DBS and it could be automated and used for population screening of total blood cholesterol. PMID- 26511312 TI - Effects of ginsenoside compound K combined with cisplatin on the proliferation, apoptosis and epithelial mesenchymal transition in MCF-7 cells of human breast cancer. AB - CONTEXT: Breast cancer seriously harms the health of women and there are currently few therapeutic options for patients with breast cancer. OBJECTIVE: Effects of ginsenoside compound K (CK) in combination with cisplatin (DDP) on the proliferation, apoptosis, and epithelial mesenchymal transition (EMT) of MCF-7 cells were studied. MATERIALS AND METHODS: MCF-7 cells were divided into CK (50 MUmol/L) group, DDP (10 mg/L) group, CK (50 MUmol/L) +DDP (10 mg/L) group, and control (CON) group. The cells in the CON group were not treated with any drugs. Proliferation, apoptosis, expression of E-cadherin, N-cadherin, vimentin, protein kinase B (Akt), phosphorylated Akt (p-Akt), and level of fibronectin (FN) in MCF 7 cells were detected by methyl thiazolyl tetrazolium (MTT), flow cytometry, western blotting, and enzyme-linked immuno sorbent assay (ELISA), respectively. RESULTS: The proliferation inhibition rates in CK, DDP, and CK + DDP groups at 48 h were 19.18 +/- 2.25, 21.34 +/- 2.84, and 43.37 +/- 5.62, respectively. The apoptosis rates were 2.85 +/- 0.56, 13.37 +/- 2.28, 20.04 +/- 2.92, and 30.78 +/- 4.64 at 24 h and 3.14 +/- 0.72, 20.36 +/- 3.28, 27.58 +/- 4.09, and 41.62 +/- 5.83 at 48 h in CON, CK, DDP, and CK + DDP groups, respectively. CK or DDP alone and their combination all could reduce the levels of N-cadherin, vimentin, p Akt/Akt, and FN and elevate level of E-cadherin. DISCUSSION AND CONCLUSION: Both CK and DDP can inhibit the proliferation, EMT, and induce the apoptosis in MCF-7 cells, which may be related to the PI3K/Akt pathway. In addition, the combination of CK with DDP can produce a better effect. PMID- 26511313 TI - The risk of attention deficit hyperactivity disorder in children exposed to maternal smoking during pregnancy - a re-examination using a sibling design. AB - BACKGROUND: Conventional cohort studies have consistently shown that exposure to maternal smoking in pregnancy is associated with about twice the risk of attention deficit hyperactivity disorder (ADHD) in the offspring. However, recent studies using alternative designs to disentangle the effect of social and genetic confounders have suggested that confounding may account for the association. In this study we aimed to estimate the association by a sibling design. METHODS: We used a design with half and full siblings in a Danish national register-based cohort on all singletons born between January 1991 and December 2006 and followed until January 2011. Data were available for 90% (N = 968,665) of the singleton live births in the period. We used the combination of the International Classification of Diseases (10th version) diagnosis of hyperkinetic disorder (HKD) and ADHD medication to identify children. We used sibling-matched (conditional) Cox regression to control social and genetic confounding. RESULTS: Using conventional cohort analyses, we found the expected association between pregnancy smoking and offspring ADHD (adjusted HR 2.01, 95% CI 1.94-2.07). In the sibling analysis, however, we did not detect such a strong association (adjusted HR 1.07, 95% CI 0.94-1.22). There was no difference between results for half- and full sibling analyses. The link between pregnancy smoking and low birth weight remained robust in the sibling design (adjusted OR 1.68, 95% CI 1.33-2.12). CONCLUSIONS: We found no support for prenatal smoking as a strong causal factor in ADHD. Our findings suggest that the strong association found in most previous epidemiological studies is likely to be due to a strong link between maternal smoking and maternal ADHD genetics or shared family environment. Pregnant women should still be encouraged to stop smoking because of other risks, but we have no reason to believe that this would reduce the risk of ADHD in the offspring. PMID- 26511314 TI - In Vivo Studies in Rhodospirillum rubrum Indicate That Ribulose-1,5-bisphosphate Carboxylase/Oxygenase (Rubisco) Catalyzes Two Obligatorily Required and Physiologically Significant Reactions for Distinct Carbon and Sulfur Metabolic Pathways. AB - All organisms possess fundamental metabolic pathways to ensure that needed carbon and sulfur compounds are provided to the cell in the proper chemical form and oxidation state. For most organisms capable of using CO2 as sole source of carbon, ribulose-1,5-bisphosphate (RuBP) carboxylase/oxygenase (Rubisco) catalyzes primary carbon dioxide assimilation. In addition, sulfur salvage pathways are necessary to ensure that key sulfur-containing compounds are both available and, where necessary, detoxified in the cell. Using knock-out mutations and metabolomics in the bacterium Rhodospirillum rubrum, we show here that Rubisco concurrently catalyzes key and essential reactions for seemingly unrelated but physiologically essential central carbon and sulfur salvage metabolic pathways of the cell. In this study, complementation and mutagenesis studies indicated that representatives of all known extant functional Rubisco forms found in nature are capable of simultaneously catalyzing reactions required for both CO2-dependent growth as well as growth using 5-methylthioadenosine as sole sulfur source under anaerobic photosynthetic conditions. Moreover, specific inactivation of the CO2 fixation reaction did not affect the ability of Rubisco to support anaerobic 5-methylthioadenosine metabolism, suggesting that the active site of Rubisco has evolved to ensure that this enzyme maintains both key functions. Thus, despite the coevolution of both functions, the active site of this protein may be differentially modified to affect only one of its key functions. PMID- 26511315 TI - Hsp90.Cdc37 Complexes with Protein Kinases Form Cooperatively with Multiple Distinct Interaction Sites. AB - Protein kinases are the most prominent group of heat shock protein 90 (Hsp90) clients and are recruited to the molecular chaperone by the kinase-specific cochaperone cell division cycle 37 (Cdc37). The interaction between Hsp90 and nematode Cdc37 is mediated by binding of the Hsp90 middle domain to an N-terminal region of Caenorhabditis elegans Cdc37 (CeCdc37). Here we map the binding site by NMR spectroscopy and define amino acids relevant for the interaction between CeCdc37 and the middle domain of Hsp90. Apart from these distinct Cdc37/Hsp90 interfaces, binding of the B-Raf protein kinase to the cochaperone is conserved between mammals and nematodes. In both cases, the C-terminal part of Cdc37 is relevant for kinase binding, whereas the N-terminal domain displaces the nucleotide from the kinase. This interaction leads to a cooperative formation of the ternary complex of Cdc37 and kinase with Hsp90. For the mitogen-activated protein kinase extracellular signal-regulated kinase 2 (Erk2), we observe that certain features of the interaction with Cdc37.Hsp90 are conserved, but the contribution of Cdc37 domains varies slightly, implying that different kinases may utilize distinct variations of this binding mode to interact with the Hsp90 chaperone machinery. PMID- 26511316 TI - Substrate Oxidation by Indoleamine 2,3-Dioxygenase: EVIDENCE FOR A COMMON REACTION MECHANISM. AB - The kynurenine pathway is the major route of L-tryptophan (L-Trp) catabolism in biology, leading ultimately to the formation of NAD(+). The initial and rate limiting step of the kynurenine pathway involves oxidation of L-Trp to N formylkynurenine. This is an O2-dependent process and catalyzed by indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase. More than 60 years after these dioxygenase enzymes were first isolated (Kotake, Y., and Masayama, I. (1936) Z. Physiol. Chem. 243, 237-244), the mechanism of the reaction is not established. We examined the mechanism of substrate oxidation for a series of substituted tryptophan analogues by indoleamine 2,3-dioxygenase. We observed formation of a transient intermediate, assigned as a Compound II (ferryl) species, during oxidation of L-Trp, 1-methyl-L-Trp, and a number of other substrate analogues. The data are consistent with a common reaction mechanism for indoleamine 2,3 dioxygenase-catalyzed oxidation of tryptophan and other tryptophan analogues. PMID- 26511317 TI - Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation. AB - Diabetes is characterized by increased lipogenesis as well as increased endoplasmic reticulum (ER) stress and inflammation. The nuclear hormone receptor liver X receptor (LXR) is induced by insulin and is a key regulator of lipid metabolism. It promotes lipogenesis and cholesterol efflux, but suppresses endoplasmic reticulum stress and inflammation. The goal of these studies was to dissect the effects of insulin on LXR action. We used antisense oligonucleotides to knock down Lxralpha in mice with hepatocyte-specific deletion of the insulin receptor and their controls. We found, surprisingly, that knock-out of the insulin receptor and knockdown of Lxralpha produced equivalent, non-additive effects on the lipogenic genes. Thus, insulin was unable to induce the lipogenic genes in the absence of Lxralpha, and LXRalpha was unable to induce the lipogenic genes in the absence of insulin. However, insulin was not required for LXRalpha to modulate the phospholipid profile, or to suppress genes in the ER stress or inflammation pathways. These data show that insulin is required specifically for the lipogenic effects of LXRalpha and that manipulation of the insulin signaling pathway could dissociate the beneficial effects of LXR on cholesterol efflux, inflammation, and ER stress from the negative effects on lipogenesis. PMID- 26511318 TI - Hyperosmotic Shock Engages Two Positive Feedback Loops through Caspase-3 dependent Proteolysis of JNK1-2 and Bid. AB - Hyperosmotic shock induces early calpain activation, Smac/DIABLO release from the mitochondria, and p38/JNK activation in Xenopus oocytes. These pathways regulate late cytochrome c release and caspase-3 activation. Here, we show that JNK1-1 and JNK1-2 are activated early by osmostress, and sustained activation of both isoforms accelerates the apoptotic program. When caspase-3 is activated, JNK1-2 is proteolyzed at Asp-385 increasing the release of cytochrome c and caspase-3 activity, thereby creating a positive feedback loop. Expression of Bcl-xL markedly reduces hyperosmotic shock-induced apoptosis. In contrast, expression of Bid induces rapid caspase-3 activation, even in the absence of osmostress, which is blocked by Bcl-xL co-expression. In these conditions a significant amount of Bid in the cytosol is mono- and bi-ubiquitinated. Caspase-3 activation by hyperosmotic shock induces proteolysis of Bid and mono-ubiquitinated Bid at Asp 52 increasing the release of cytochrome c and caspase-3 activation, and thus creating a second positive feedback loop. Revealing the JNK isoforms and the loops activated by osmostress could help to design better treatments for human diseases caused by perturbations in fluid osmolarity. PMID- 26511319 TI - Asn-150 of Murine Erythroid 5-Aminolevulinate Synthase Modulates the Catalytic Balance between the Rates of the Reversible Reaction. AB - 5-Aminolevulinate synthase (ALAS) catalyzes the first step in mammalian heme biosynthesis, the pyridoxal 5'-phosphate (PLP)-dependent and reversible reaction between glycine and succinyl-CoA to generate CoA, CO2, and 5-aminolevulinate (ALA). Apart from coordinating the positioning of succinyl-CoA, Rhodobacter capsulatus ALAS Asn-85 has a proposed role in regulating the opening of an active site channel. Here, we constructed a library of murine erythroid ALAS variants with substitutions at the position occupied by the analogous bacterial asparagine, screened for ALAS function, and characterized the catalytic properties of the N150H and N150F variants. Quinonoid intermediate formation occurred with a significantly reduced rate for either the N150H- or N150F catalyzed condensation of glycine with succinyl-CoA during a single turnover. The introduced mutations caused modifications in the ALAS active site such that the resulting variants tipped the balance between the forward- and reverse-catalyzed reactions. Although wild-type ALAS catalyzes the conversion of ALA into the quinonoid intermediate at a rate 6.3-fold slower than the formation of the same quinonoid intermediate from glycine and succinyl-CoA, the N150F variant catalyzes the forward reaction at a mere 1.2-fold faster rate than that of the reverse reaction, and the N150H variant reverses the rate values with a 1.7-fold faster rate for the reverse reaction than that for the forward reaction. We conclude that the evolutionary selection of Asn-150 was significant for optimizing the forward enzymatic reaction at the expense of the reverse, thus ensuring that ALA is predominantly available for heme biosynthesis. PMID- 26511320 TI - Plasticity in Repressor-DNA Interactions Neutralizes Loss of Symmetry in Bipartite Operators. AB - Transcription factor-DNA interactions are central to gene regulation. Many transcription factors regulate multiple target genes and can bind sequences that do not conform strictly to the consensus. To understand the structural mechanism utilized by the transcription regulators to bind diverse target sequences, we have employed the repressor AraR from Bacillus subtilis as a model system. AraR is known to bind to eight different operator sites in the bacterial genome. Although there are differences in the sequences of four of these operators, ORE1, ORX1, ORA1, and ORR3, the AraR-DNA binding domain (AraR-DBD) as well as full length AraR unexpectedly binds to each of these sequences with similar affinities as measured by fluorescence anisotropy experiments. We have determined crystal structures of AraR-DBD in complex with two different natural operators ORE1 and ORX1 up to 2.07 and 1.97 A resolution, respectively. These structures were compared with the previously reported structures of AraR-DBD bound to two other natural operators (ORA1 and ORR3). Interactions of two molecules of AraR-DBD with the symmetric operator, ORE1, are identical, but their interaction with the non symmetric operator ORX1 results in breakdown of the symmetry in protein-DNA interactions. The novel interactions observed are accompanied by local conformational change in the DNA. ChIP-sequencing (ChIP-Seq) data on other transcription factors has shown that they can bind to diverse targets, and hence the plasticity exhibited by AraR may be a general phenomenon. The ability of transcription factors to form alternate interactions may be important for employment in new functions and evolution of novel regulatory circuits. PMID- 26511321 TI - The Disulfide Bond, but Not Zinc or Dimerization, Controls Initiation and Seeded Growth in Amyotrophic Lateral Sclerosis-linked Cu,Zn Superoxide Dismutase (SOD1) Fibrillation. AB - Aggregation of copper-zinc superoxide dismutase (SOD1) is a defining feature of familial ALS caused by inherited mutations in the sod1 gene, and misfolded and aggregated forms of wild-type SOD1 are found in both sporadic and familial ALS cases. Mature SOD1 owes its exceptional stability to a number of post translational modifications as follows: formation of the intramolecular disulfide bond, binding of copper and zinc, and dimerization. Loss of stability due to the failure to acquire one or more of these modifications is proposed to lead to aggregation in vivo. Previously, we showed that the presence of apo-, disulfide reduced SOD1, the most immature form of SOD1, results in initiation of fibrillation of more mature forms that have an intact Cys-57-Cys-146 disulfide bond and are partially metallated. In this study, we examine the ability of each of the above post-translational modifications to modulate fibril initiation and seeded growth. Cobalt or zinc binding, despite conferring great structural stability, neither inhibits the initiation propensity of disulfide-reduced SOD1 nor consistently protects disulfide-oxidized SOD1 from being recruited into growing fibrils across wild-type and a number of ALS mutants. In contrast, reduction of the disulfide bond, known to be necessary for fibril initiation, also allows for faster recruitment during seeded amyloid growth. These results identify separate factors that differently influence seeded growth and initiation and indicate a lack of correlation between the overall thermodynamic stability of partially mature SOD1 states and their ability to initiate fibrillation or be recruited by a growing fibril. PMID- 26511322 TI - Private Payer's Status Improves Male Breast Cancer Survival. AB - Survival from male breast cancer is influenced by many factors. This study assessed payer's status effect on survival of male breast cancer patients. This study included 8,828 male breast cancer patients diagnosed between 1998-2006 and followed to 2011 in the National Cancer Data Base. Cox regression was used to investigate the effect of payer's status and other factors on overall survival. Patients had 36.2%, 42.7%, 14.7%, and 6.5% of stage I to IV cancer, respectively. Payer status was private 47.7%, Medicare 42.6%, Medicaid 3.24%, unknown 3.59%, and uninsured 2.95%. Median overall survival (MOS) for all patients was 10.6 years. In multivariate analysis, Direct adjusted MOS was 12.46, 11.89, 9.99, 9.02, and 8.29 years for private, "unknown," Medicare, uninsured, and Medicaid payer's status, respectively. Patients with private and "unknown" payer's status showed a significant difference in survival compared to uninsured patients, while Medicaid and Medicare patients did not. Age, race, stage, grade, income, comorbidity, distance travelled, and diagnosing/treating facility were also significant predictors of survival. Treatment delay and cancer program did not have a significant influence on survival. PMID- 26511323 TI - Decellularized biological matrices: an interesting approach for cardiovascular tissue repair and regeneration. AB - The repair and replacement of blood vessels is one of the most challenging topics for biomedical research. Autologous vessels are preferred as graft materials, but they still have many issues to overcome: for instance, they need multiple surgical procedures and often patients may not have healthy and surgically valuable arteries useful as an autograft. A tissue-engineering approach is widely desirable to generate biological vascular prostheses. Recently, decellularization of native tissue has gained significant attention in the biomedical research field. This method is used to obtain biological scaffolds that are expected to maintain the complex three-dimensional structure of the extracellular matrix, preserving the biomechanical properties of the native tissues. The decellularizing methods and the biomechanical characteristics of these products are presented in this review. Decellularization of biological matrices induces the loss of major histocompatibility complex (MHC), which is expected to promote an immunological response by the host. All the studies showed that decellularized biomaterials possess adequate properties for xenografting. Concerning their mechanical properties, several studies have demonstrated that, although chemical decellularization methods do not affect the scaffolds' mechanical properties, these materials can be modified through different treatments in order to provide the desired mechanical characteristics, depending on the specific application. A short overview of legislative issues concerning the use of decellularized substitutes and future perspectives in surgical applications is also presented. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26511324 TI - Synthesis and biocompatibility assessment of sugarcane bagasse-derived biogenic silica nanoparticles for biomedical applications. AB - Sugarcane bagasse is a fibrous material and an excellent bioresource for biogenic silica. Moreover, sugarcane bagasse has low production costs and is a sustainable precursor for the synthesis of biogenic silica nanoparticles (BSNPs). In this study, we synthesized BSNPs using sugarcane bagasse. The acid pretreatment of sugarcane was carried out in an autoclave, which eliminates metal ions and promotes the hydrolysis of organic substances. Residues of the acid pretreatment were incinerated at different temperatures to determine the role of temperature on the formation of BSNPs. The crystalline nature and morphology of the prepared BSNPs were analyzed using X-ray diffraction analysis and transmission electron microscopy. The X-ray diffraction analysis result indicates that the prepared BSNPs have an amorphous nature. Transmission electron microscopy images confirmed that the BSNPs have an irregular shape with a porous morphology. The biocompatibility of BSNPs was studied by assessing their effect on human lung fibroblast cell viability, morphology, mitochondrial function, reactive oxygen species, and gene expression. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assays and microscopy studies suggested that BSNPs do not affect cell viability or morphology. BSNPs slightly affect the mitochondrial membrane potential at high doses. In addition, BSNPs decreased the percentage of human lung fibroblast cell in G1 and G2/M phases and increased the S population. These studies revealed that the BSNPs were biocompatible, indicating that they may be applicable for biomedical applications. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 340-349, 2017. PMID- 26511325 TI - Secondary angle closure glaucoma by lupus choroidopathy as an initial presentation of systemic lupus erythematosus: a case report. AB - BACKGROUND: We present a rare case of secondary angle closure glaucoma due to systemic lupus erythematosus choroidopathy as initial presentation of systemic lupus erythematosus, accompanied by central nervous system vasculitis and uncontrolled nephropathy. CASE PRESENTATION: A 31-year-old woman presented with decreased visual acuity, nausea, vomiting, fever, and bilateral angioedema-like eyelid swelling. She had persistent dry cough while taking medication for 3 months, and had usual posterior neck pain, which was treated with analgesic medication and Asian medicines. Intraocular pressure was 32 and 34 mmHg in her right and left eyes, respectively. Peripheral anterior chambers were shallow (grade I) using the van Herick method. Gonioscopy revealed 360 degrees closed angle in both eyes. In both eyes, serous retinal detachment was found using optical coherence tomography and B scan ultrasonography, as well as choroidal thickening with effusion. Secondary acute angle closure glaucoma was drug induced, or caused by uveitis of unknown etiology when she was first treated with intraocular pressure-lowering medication. During evaluation of the drug-induced angioedema in the internal medicine department, systemic lupus erythematosus was diagnosed, based on malar rash, photosensitivity, proteinuria, and positive anti Smith and anti-DNA antibodies, followed by initiation of steroid pulse therapy. Using fluorescein angiography, multifocal subretinal pinpoint foci were detected at the middle phase. We then diagnosed bilateral angle closure glaucoma by choroidal effusions, with lupus choroidopathy. At 2 months after steroid pulse therapy, subretinal fluid was not found, and visual acuity improved to normal. During the subsequent 2 years, lupus choroidopathy was not aggravated but lupus nephritis was not controlled. CONCLUSION: Patients with systemic lupus erythematosus choroidopathy can develop ciliochoroidal effusion, which can lead to acute angle closure glaucoma. Systemic lupus erythematosus choroidopathy is an early sign of severe complications. Angle closure glaucoma by systemic lupus erythematosus choroidopathy can be effectively treated using antiglaucoma drugs and immunosuppressive therapy. PMID- 26511326 TI - Histopathological evaluation of parotid gland neoplasms in Queensland, Australia. AB - BACKGROUND: Parotid gland tumours are complex neoplasms with a broad histological range. The parotid gland is also a common site of face and scalp skin cancer metastases. METHOD: Parotidectomies performed by ENT department in the Gold Coast health district from 2006 to 2013. RESULTS: A total of 158 specimens were examined. Of these, 53.80 per cent were benign and 46.20 per cent were malignant. Pleomorphic adenoma was the most common tumour (29.11 per cent), followed by cutaneous squamous cell carcinoma (23.42 per cent) and Warthin's tumour (12.03 per cent). CONCLUSION: Metastatic squamous cell carcinoma accounted for a large proportion of parotid masses in our case series, reflecting the high prevalence of non-melanoma skin cancer in Australia. Primary parotid neoplasms had similar incidence rates to other studies. PMID- 26511327 TI - MOG-induced experimental autoimmune encephalomyelitis in the rat species triggers anti-neurofascin antibody response that is genetically regulated. AB - BACKGROUND: Iotan multiple sclerosis (MS), axonal damage leads to permanent neurological disabilities and the spreading of the autoimmune response to axonal antigens is implicated in disease progression. Experimental autoimmune encephalomyelitis (EAE) provides an animal model that mimics MS. Using different EAE models, we investigated the pathophysiological basis of epitope spreading to neurofascin, a protein localized at the node of Ranvier and its regulation by non MHC genes. METHODS: We used two different EAE models in DA rat; one which is induced with myelin oligodendrocyte glycoprotein (MOG) which leads to disease characterized by profound demyelination, and the second which is induced with myelin basic protein (MBP) peptide 63-88 which results in severe central nervous system (CNS) inflammation but little or no demyelination. We determined anti neurofascin antibody levels during the course of disease. Furthermore, the anti neurofascin IgG response was correlated with clinical parameters in 333 (DAxPVG.1AV1) x DA rats on which we performed linkage analysis to determine if epitope spreading to neurofascin was affected by non-MHC genes. RESULTS: Spreading of the antibody response to neurofascin occurred in demyelinating MOG induced EAE but not in EAE induced with MBP peptide 63-88. Anti-neurofascin IgG levels correlated with disease severity in (DAxPVG.1AV1) x DA rats, and a genomic region on chromosome 3 was found to influence this response. CONCLUSIONS: Inter molecular epitope spreading to neurofascin correlates with disease severity in MOG-EAE is dependent on extensive demyelination and is influenced by non-MHC genes. The findings presented here may shed light on factors involved in the severity of MS and its genetics. PMID- 26511328 TI - Dysfunctional or hyperfunctional? The amygdala in posttraumatic stress disorder is the bull in the evolutionary China shop. AB - Our motivation in writing this Review arose not only from the great value in contributing to this special issue of the Journal of Neuroscience Research but also from the desire to express our opinion that the description of the amygdala as "dysfunctional" in posttraumatic stress disorder (PTSD) might not be appropriate. We acknowledge that excessive activation of the amygdala contributes to the cluster of PTSD symptoms, including hypervigilance, intrusive memories, and impaired sleep, that underlies the devastating mental and physical outcomes in trauma victims. The issue that we address is whether the symptoms of PTSD represent an impaired (dysfunctional) or sensitized (hyperfunctional) amygdala status. We propose that the amygdala in PTSD is hyperfunctional rather than dysfunctional in recognition of the fact that the individual has already survived one life-threatening attack and that another may be forthcoming. We therefore consider PTSD to be a state in which the amygdala is functioning optimally if the goal is to ensure a person's survival. The misery caused by a hyperfunctional amygdala in PTSD is the cost of inheriting an evolutionarily primitive mechanism that considers survival more important than the quality of one's life. PMID- 26511330 TI - The Chemical Record Lectureship: D. W. C. MacMillan / Heinrich Emanuel Merck Award: P. S. Dittrich / EurJOC Young Researcher Award: N. Maulide. PMID- 26511329 TI - Novel gene sets improve set-level classification of prokaryotic gene expression data. AB - BACKGROUND: Set-level classification of gene expression data has received significant attention recently. In this setting, high-dimensional vectors of features corresponding to genes are converted into lower-dimensional vectors of features corresponding to biologically interpretable gene sets. The dimensionality reduction brings the promise of a decreased risk of overfitting, potentially resulting in improved accuracy of the learned classifiers. However, recent empirical research has not confirmed this expectation. Here we hypothesize that the reported unfavorable classification results in the set-level framework were due to the adoption of unsuitable gene sets defined typically on the basis of the Gene ontology and the KEGG database of metabolic networks. We explore an alternative approach to defining gene sets, based on regulatory interactions, which we expect to collect genes with more correlated expression. We hypothesize that such more correlated gene sets will enable to learn more accurate classifiers. METHODS: We define two families of gene sets using information on regulatory interactions, and evaluate them on phenotype-classification tasks using public prokaryotic gene expression data sets. From each of the two gene-set families, we first select the best-performing subtype. The two selected subtypes are then evaluated on independent (testing) data sets against state-of-the-art gene sets and against the conventional gene-level approach. RESULTS: The novel gene sets are indeed more correlated than the conventional ones, and lead to significantly more accurate classifiers. The novel gene sets are indeed more correlated than the conventional ones, and lead to significantly more accurate classifiers. CONCLUSION: Novel gene sets defined on the basis of regulatory interactions improve set-level classification of gene expression data. The experimental scripts and other material needed to reproduce the experiments are available at http://ida.felk.cvut.cz/novelgenesets.tar.gz. PMID- 26511331 TI - The Association of Transfer Rate From Hospitals Without Revascularization Capabilities and Mortality Risk for Older Non-ST-Segment Elevation Myocardial Infarction Patients. AB - BACKGROUND: Interhospital transfer invasive management patterns and implications for older non-ST-segment elevation myocardial infarction (NSTEMI) patients initially presenting to non-revascularization-capable hospitals have not been explored. HYPOTHESIS: Patients admitted to hospitals with a higher transfer proportion have lower risk of long-term mortality. METHODS: We linked CRUSADE Registry data on 5678 patients age >=65 years from 65 United States non revascularization-capable hospitals (2003-2006) with inpatient Medicare longitudinal claims. Hospitals were categorized according to hospital-level patient transfer-out rates, low (<=40%) vs high (>40%). The associations between transfer-out rates and 30-day, 6-month, and 3-year mortality risk were evaluated using Cox proportional hazard models. RESULTS: Hospital-level transfer-out rates varied widely (median, 43%; interquartile range, 31%-54%). Compared with patients from low-transfer-out hospitals (n = 2715), patients from high-transfer-out hospitals (n = 2963) were more likely to be male, less likely to have renal insufficiency and prior heart failure, and had lower long-term CRUSADE mortality risk scores. These patients also more commonly received evidence-based acute medications before transfer and underwent subsequent revascularization after transfer. The adjusted risks of mortality at various time intervals were similar for those from high- vs low-transfer-out hospitals: 30 days (hazard ratio: 0.95, 95% confidence interval: 0.79-1.14), 6 months (0.97, 0.84-1.12), and 3 years (1.01, 0.91-1.11). CONCLUSIONS: Transfer rates for older NSTEMI patients vary widely among non-revascularization-capable hospitals. Despite lower predicted mortality risk and higher rates of post-transfer revascularization, patients from high-transfer-out hospitals had a similar risk for short- and long-term mortality compared with those from low-transfer-out hospitals. PMID- 26511332 TI - Relationship of glycaemic control and hypoglycaemic episodes to 4-year cardiovascular outcomes in people with type 2 diabetes starting insulin. AB - AIMS: To examine the relationships between glycated haemoglobin (HbA1c) and cardiovascular (CV) events in people beginning insulin in routine clinical practice in Europe, North America and Asia in a non-interventional study, the Cardiovascular Risk Evaluation in people with Type 2 Diabetes on Insulin Therapy (CREDIT) study. METHODS: Data on 2999 people were collected prospectively over 4 years from physician reports. The primary outcome was the composite of stroke or myocardial infarction (MI) or CV-specific death. Events were blindly adjudicated. The relative hazards of CV events were described from Cox proportional hazards models incorporating patient risk factors, with updated average HbA1c as a time dependent covariate. The relationship of severe and symptomatic hypoglycaemia (collected during the 6 months before yearly ascertainment) with CV and all-cause mortality was examined. RESULTS: A total of 147 primary events were accrued during up to 54 months of follow-up. In all, 60 CV-specific deaths, 44 non-fatal MIs and 57 non-fatal strokes occurred, totalling 161 events. There was a significant positive relationship between updated mean HbA1c and primary outcome: hazard ratio (HR) 1.25 [95% confidence interval (CI) 1.12-1.40; p < 0.0001]. CV death [HR 1.31 (95% CI 1.10-1.57); p = 0.0027] and stroke [HR 1.36 (95% CI 1.17 1.59); p < 0.0001] were both strongly associated with HbA1c, while MI was not [HR 1.05 (95% CI 0.83-1.32)]. One or more severe hypoglycaemic episodes affected 175 participants, while 1508 participants experienced one or more symptomatic hypoglycaemic events. We found no relationship between severe/symptomatic hypoglycaemic events and CV-specific/all-cause death. CONCLUSIONS: Ongoing poorer glucose control was associated with CV events; hypoglycaemia was not associated with CV-specific/all-cause death. PMID- 26511333 TI - Evaluation of Pulmonary Artery Stiffness in Patients with Obstructive Sleep Apnea Syndrome. AB - OBJECTIVE: To investigate whether obstructive sleep apnea syndrome (OSAS) has any effect on pulmonary artery stiffness (PAS) derived from echocardiographic calculation. METHODS: Fifty-two patients with newly diagnosed OSAS and forty-two subjects without OSAS matched by age and sex were enrolled in the study. OSAS was categorized according to apnea hypopnea index (AHI, event/h) as follows: normal (AHI<5), mild OSAS (AHI 5-15), moderate and severe OSAS (AHI>15). All participants were evaluated by echocardiography to determine PAS and right ventricle functions. PAS was calculated throughout pulmonary artery flow by the formula; PAS (kHz/sec) = maximal frequency shift/acceleration time. RESULTS: Demographic and clinical parameters were similar in both groups. PAS significantly increased in OSAS compared with the control group (26.9 +/- 6.1 vs. 18.0 +/- 3.5, P < 0.001). Additionally, PAS in severe and moderate OSAS was considerably high compared with that in mild OSAS and control group (P < 0.001). Right ventricular myocardial performance index (MPI) and mean pulmonary artery pressures (mPAP) were considerably higher in OSAS group than control group (P < 0.001). Tricuspid E/A, right ventricle tissue Doppler E'/A', and right ventricular ejection time (RVET) decreased in OSAS group compared with control group (P < 0.001). There was a significantly positive correlation between PAS and AHI, mPAP, and MPI (P < 0.001), and a significantly negative correlation between PAS and tricuspid E/A, E'/A', and RVET (P < 0.001). Linear regression analyses showed that PAS was an independent factor for mPAP (beta = 0.595, P = 0.034). CONCLUSION: Elastic properties of pulmonary artery deteriorate with severity of OSAS and may be responsible for right ventricular dysfunctions in OSAS. PMID- 26511334 TI - Prostatic biopsy-related rectal bleeding refractory to medical and endoscopic therapy definitively managed by catheter-directed embolotherapy: a case report. AB - INTRODUCTION: Ultrasound-guided transrectal prostatic biopsy is generally a well tolerated radiological technique with low overall complication ratio. If post biopsy rectal bleeding occurs, conservative management is effective in the majority of cases. Endoscopic or interventional treatment is rarely required. CASE PRESENTATION: We report the case of an 82-year-old white man presenting with massive rectal bleeding after ultrasound-guided prostatic biopsy. Medical and endoscopic management were not effective. Angiographic evaluation revealed a prostatic arteriovenous fistula, and definitive treatment was provided in the form of catheter-directed superselective embolotherapy. CONCLUSION: Transrectal prostatic biopsy may be associated with massive rectal bleeding. Transcatheter embolotherapy can be effective in definitively stopping the bleeding. PMID- 26511335 TI - Gastric remnant cancer: A distinct entity or simply another proximal gastric cancer? AB - BACKGROUND: The purpose of this study was to compare outcomes following resection of gastric remnant (GRC) and conventional gastric cancer. METHODS: Patients who underwent resection for gastric cancer in 8 academic institutions from 2000-2012 were evaluated to compare morbidity, mortality, and survival based on history of prior gastrectomy. RESULTS: Of the 979 patients who underwent gastrectomy with curative-intent during the 12-year study period, 55 patients (5.8%) presented with GRC and 924 patients (94.4%) presented with conventional gastric cancer. Patients with GRC were slightly older (median 69 vs. 66 years). GRC was associated with higher rates of complication (56% vs. 41%, P = 0.028), longer operative times (301 vs. 237 min, P < 0.001), higher intraoperative blood loss (300 vs. 200 ml, P = 0.012), and greater need for blood transfusion (43% vs. 23%, P = 0.001). There were no significant differences in 30-day (3.6% vs. 4%) or 90 day mortality (9% vs. 8%) between the two groups. Overall survival rates were similar between GRC and conventional gastric cancer (5-year 20.3% vs. 38.6%, P = 0.446). Multivariate analysis revealed that history of gastrectomy was not predictive of survival while established predictors (older age, advanced T-stage, nodal involvement, blood transfusion, multivisceral resection, and any complication) were associated with poor survival. CONCLUSIONS: Despite higher morbidity, prognosis after resection of gastric remnant cancer is similar to conventional gastric cancer. PMID- 26511336 TI - Carbene-induced synthesis of the first borironium cations using the [(eta(5) C5Me5)Fe(CO)2](-) anion as an unlikely leaving group. AB - Reaction of N-heterocyclic carbenes with ferroborirene complex [{(eta(5) C5Me5)Fe(CO)2}{BC2(SiMe3)2}] results in heterolytic Fe-B bond cleavage, yielding borironium ions, a new class of boron-containing heterocycles. The reaction rests on the surprising ability of the reactive [(eta(5)-C5Me5)Fe(CO)2](-) anion to act as a leaving group. The properties of these species were investigated by multinuclear NMR spectroscopy, as well as single-crystal X-ray diffraction. PMID- 26511337 TI - Patients' experiences with HMEs and attachments after total laryngectomy. AB - OBJECTIVES: The short-term and long-term beneficial effects of HME use by laryngectomees are well described in literature. In this study, we document how laryngectomised patients, who previously did not use an HME, get accustomed to the use of HME and attachments. PARTICIPANTS: Thirty patients, who were at least 3 months post-laryngectomy and previously did not use an HME, were followed for 12 weeks and were asked to complete questionnaires about their experiences with the HME and attachments. RESULTS: Results show that when patients start using an HME, they report some difficulties with breathing resistance during the first 2 weeks of use. However, after 6 weeks, they have become accustomed to the breathing resistance and after 12 weeks over 96% reports that breathing was equal or less strenuous compared with breathing though an open stoma. Only a small proportion of patients experienced problems with increased coughing when starting HME use. CONCLUSIONS: This study provides insight in the way laryngectomised patients are experiencing the use of HMEs in the first weeks. These outcomes can contribute to a better knowledge of HME use by healthcare providers and help them to manage patient expectations and improving support to patients in achieving compliant HME use. PMID- 26511339 TI - Statistical monitoring-based alarming systems in modeling the AIDS epidemic in the United States, 1985-2011. AB - BACKGROUND: Better decisions for the control of HIV/AIDS and other infectious diseases require better information. The large amount of available public health data makes it possible to extract such information to monitor and predict significant disease events in disease epidemic. The detection of unusual events often involves a combination of a forecasting and a decision mechanism assessing the extent to which an observed event differs significantly from a forecast event. A number of methods and models have been proposed to monitor the trend of infectious disease and to detect unusual events. Although these existing methods and models are useful, many new issues remain to be addressed, including the complicated data structure and the infectious disease dynamics. To overcome these issues, we introduced the statistical tool using statistical process control, and proposed a new method under that framework. METHODS: In this paper, we first reviewed the most commonly used methods and models, including the historical limit method, the time series analysis, the hidden Markov models, and the process control charts. Then, we further discussed issues with the current available methods. We proposed a new method using statistical process control. A major feature of the new method is that it prospectively monitors the disease incidence using sequentially collected data over time. It also takes into account a wide variety of longitudinal patterns and possible autocorrelation in the data. RESULTS: We test this novel method with the recorded data of the number of AIDS cases in different states of US from 1985 to 2011. The results show that our new method is effective in detecting and predicting the time trends of AIDS epidemic for individual states and for US as a whole. Although AIDS data are used in our demonstration, this method can be used for monitoring other infectious diseases. PMID- 26511338 TI - Changes in BQCA Allosteric Modulation of [(3)H]NMS Binding to Human Cortex within Schizophrenia and by Divalent Cations. AB - Stimulation of the cortical muscarinic M1 receptor (CHRM1) is proposed as a treatment for schizophrenia, a hypothesis testable using CHRM1 allosteric modulators. Allosteric modulators have been shown to change the activity of CHRMs using cloned human CHRMs and CHRM knockout mice but not human CNS, a prerequisite for them working in humans. Here we show in vitro that BQCA, a positive allosteric CHRM1 modulator, brings about the expected change in affinity of the CHRM1 orthosteric site for acetylcholine in human cortex. Moreover, this effect of BQCA is reduced in the cortex of a subset of subjects with schizophrenia, separated into a discrete population because of a profound loss of cortical [(3)H]pirenzepine binding. Surprisingly, there was no change in [(3)H]NMS binding to the cortex from this subset or those with schizophrenia but without a marked loss of cortical CHRM1. Hence, we explored the nature of [(3)H]pirenzepine and [(3)H]NMS binding to human cortex and showed total [(3)H]pirenzepine and [(3)H]NMS binding was reduced by Zn(2+), acetylcholine displacement of [(3)H]NMS binding was enhanced by Mg(2+) and Zn(2+), acetylcholine displacement of [(3)H]pirenzepine was reduced by Mg(2+) and enhanced by Zn(2+), whereas BQCA effects on [(3)H]NMS, but not [(3)H]pirenzepine, binding was enhanced by Mg(2+) and Zn(2+). These data suggest the orthosteric and allosteric sites on CHRMs respond differently to divalent cations and the effects of allosteric modulation of the cortical CHRM1 is reduced in a subset of people with schizophrenia, a finding that may have ramifications for the use of CHRM1 allosteric modulators in the treatment of schizophrenia. PMID- 26511340 TI - Applying Triple-Matrix Masking for Privacy Preserving Data Collection and Sharing in HIV Studies. AB - BACKGROUND: Many HIV research projects are plagued by the high missing rate of selfreported information during data collection. Also, due to the sensitive nature of the HIV research data, privacy protection is always a concern for data sharing in HIV studies. METHODS: This paper applies a data masking approach, called triple-matrix masking [1], to the context of HIV research for ensuring privacy protection during the process of data collection and data sharing. RESULTS: Using a set of generated HIV patient data, we show step by step how the data are randomly transformed (masked) before leaving the patients' individual data collection device (which ensures that nobody sees the actual data) and how the masked data are further transformed by a masking service provider and a data collector. We demonstrate that the masked data retain statistical utility of the original data, yielding the exactly same inference results in the planned logistic regression on the effect of age on the adherence to antiretroviral therapy and in the Cox proportional hazard model for the age effect on time to viral load suppression. CONCLUSION: Privacy-preserving data collection method may help resolve the privacy protection issue in HIV research. The individual sensitive data can be completely hidden while the same inference results can still be obtained from the masked data, with the use of common statistical analysis methods. PMID- 26511341 TI - Phylogenetics and Phyloanatomy of HIV/SIV Intra-Host Compartments and Reservoirs: The Key Role of the Central Nervous System. AB - BACKGROUND: The ability of the human immunodeficiency virus type 1 (HIV-1) to persist in anatomic compartments and cellular reservoirs is a major obstacle for eradication of replicationcompetent virus in the infected host. APPROACH: We extensively review recent advancements in phylogenetic and phylogeographic techniques that provide a unique opportunity for studies of intra-host HIV-1 compartmentalization and the detection of potential reservoirs. CONCLUSION: We show that infected macrophages in the central nervous system (CNS) harbor viral subpopulations that play a key role in the emergence of escape variants and viral rebound following discontinuation of antiretroviral therapy. An HIV cure, therefore, cannot be achieved without the effective targeting of the virus in the CNS, for which in depth knowledge of viral population dynamics contributing to the development and maintenance of latent reservoirs is critical. PMID- 26511342 TI - Computer-Aided Optimization of Combined Anti-Retroviral Therapy for HIV: New Drugs, New Drug Targets and Drug Resistance. AB - BACKGROUND: Resistance to antiretroviral drugs is a complex and evolving area with relevant implications in the treatment of human immunodeficiency virus (HIV) infection. Several rules, algorithms and full-fledged computer programs have been developed to assist the HIV specialist in the choice of the best patient-tailored therapy. METHODS: Experts' rules and statistical/machine learning algorithms for interpreting HIV drug resistance, along with their program implementations, were retrieved from PubMed and other on-line resources to be critically reviewed in terms of technical approach, performance, usability, update, and evolution (i.e. inclusion of novel drugs or expansion to other viral agents). RESULTS: Several drug resistance prediction algorithms for the nucleotide/nucleoside/non nucleoside reverse transcriptase, protease and integrase inhibitors as well as coreceptor antagonists are currently available, routinely used, and have been validated thoroughly in independent studies. Computer tools that combine single drug genotypic/phenotypic resistance interpretation and optimize combination antiretroviral therapy have been also developed and implemented as web applications. Most of the systems have been updated timely to incorporate new drugs and few have recently been expanded to meet a similar need in the Hepatitis C area. Prototype systems aiming at predicting virological response from both virus and patient indicators have been recently developed but they are not yet being routinely used. CONCLUSION: Computing HIV genotype to predict drug susceptibility in vitro or response to combination antiretroviral therapy in vivo is a continuous and productive research field, translating into successful treatment decision support tools, an essential component of the management of HIV patients. PMID- 26511343 TI - Non-cirrhotic Portal Hypertension Associated with Didanosine and Streptococcus agalactiae Infection: A Case Report. AB - BACKGROUND: Non-Cirrhotic Portal Hypertension (NCPH) is a rare but potentially fatal liver disorder described in patients treated with anti-retroviral therapy for Human Immunodeficiency Virus (HIV). In particular, the most important predisposing factor to its development has been identified as prolonged exposure to Didanosine (ddI). The clinical entity of NCPH is characterized by an increase in portal pressure due to pre- or intra-hepatic causes, in absence of liver cirrhosis. However, the exact pathogenesis remains poorly understood, and due to its rarity, the diagnosis is often delayed. OBJECTIVE: We herein report a case in which ddI administration, with concomitant spontaneous bacterial peritonitis by Streptococcus agalactiae, has induced NCPH in a HIV male patient. CONCLUSION: NPCH should be suspected when HIV patient with an history of ddI treatment presents liver decompensation. PMID- 26511344 TI - Modeling Drinking Behavior Progression in Youth with Cross-sectional Data: Solving an Under-identified Probabilistic Discrete Event System. AB - BACKGROUND: The probabilistic discrete event systems (PDES) method provides a promising approach to study dynamics of underage drinking using cross-sectional data. However, the utility of this approach is often limited because the constructed PDES model is often non-identifiable. The purpose of the current study is to attempt a new method to solve the model. METHODS: A PDES-based model of alcohol use behavior was developed with four progression stages (never drinkers [ND], light/moderate-drinker [LMD], heavy-drinker [HD], and ex-drinker [XD]) linked with 13 possible transition paths. We tested the proposed model with data for participants aged 12-21 from the 2012 National Survey on Drug Use and Health (NSDUH). The Moore-Penrose (M-P) generalized inverse matrix method was applied to solve the proposed model. RESULTS: Annual transitional probabilities by age groups for the 13 drinking progression pathways were successfully estimated with the M-P generalized inverse matrix approach. Result from our analysis indicates an inverse "J" shape curve characterizing pattern of experimental use of alcohol from adolescence to young adulthood. We also observed a dramatic increase for the initiation of LMD and HD after age 18 and a sharp decline in quitting light and heavy drinking. CONCLUSION: Our findings are consistent with the developmental perspective regarding the dynamics of underage drinking, demonstrating the utility of the M-P method in obtaining a unique solution for the partially-observed PDES drinking behavior model. The M-P approach we tested in this study will facilitate the use of the PDES approach to examine many health behaviors with the widely available cross-sectional data. PMID- 26511345 TI - Analytic strategies to evaluate the association of time-varying exposures to HIV related outcomes: Alcohol consumption as an example. AB - BACKGROUND: As persons with HIV are living longer, there is a growing need to investigate factors associated with chronic disease, rate of disease progression and survivorship. Many risk factors for this high-risk population change over time, such as participation in treatment, alcohol consumption and drug abuse. Longitudinal datasets are increasingly available, particularly clinical data that contain multiple observations of health exposures and outcomes over time. Several analytic options are available for assessment of longitudinal data; however, it can be challenging to choose the appropriate analytic method for specific combinations of research questions and types of data. The purpose of this review is to help researchers choose the appropriate methods to analyze longitudinal data, using alcohol consumption as an example of a time-varying exposure variable. When selecting the optimal analytic method, one must consider aspects of exposure (e.g. timing, pattern, and amount) and outcome (fixed or time varying), while also addressing minimizing bias. In this article, we will describe several analytic approaches for longitudinal data, including developmental trajectory analysis, generalized estimating equations, and mixed effect models. For each analytic strategy, we describe appropriate situations to use the method and provide an example that demonstrates the use of the method. Clinical data related to alcohol consumption and HIV are used to illustrate these methods. PMID- 26511346 TI - Manifest Left Atrial Appendage Delay on a 12-Lead EKG After AF Ablation. PMID- 26511347 TI - Determining intestinal parasitic infections (IPIs) in inmates from Kajang Prison, Selangor, Malaysia for improved prison management. AB - BACKGROUND: The prison management in Malaysia is proactively seeking to improve the health status of the prison inmates. Intestinal parasitic infections (IPIs) are widely distributed throughout the world and are still gaining great concern due to their significant morbidity and mortality among infected humans. In Malaysia, there is a paucity of information on IPIs among prison inmates. In order to further enhance the current health strategies employed, the present study aims to establish firm data on the prevalence and diversity of IPIs among HIV-infected and non-HIV-infected individuals in a prison, an area in which informed knowledge is still very limited. METHODS: Samples were subjected to microscopy examination and serological test (only for Strongyloides). Speciation for parasites on microscopy-positive samples and seropositive samples for Strongyloides were further determined via polymerase chain reaction. SPSS was used for statistical analysis. RESULTS: A total of 294 stool and blood samples each were successfully collected, involving 131 HIV positive and 163 HIV negative adult male inmates whose age ranged from 21 to 69-years-old. Overall prevalence showed 26.5% was positive for various IPIs. The IPIs detected included Blastocystis sp., Strongyloides stercoralis, Entamoeba spp., Cryptosporidium spp., Giardia spp., and Trichuris trichiura. Comparatively, the rate of IPIs was slightly higher among the HIV positive inmates (27.5%) than HIV negative inmates (25.8%). Interestingly, seropositivity for S. stercoralis was more predominant in HIV negative inmates (10.4%) compared to HIV-infected inmates (6.9%), however these findings were not statistically significant. Polymerase chain reaction (PCR) confirmed the presence of Blastocystis, Strongyloides, Entamoeba histolytica and E. dispar. CONCLUSIONS: These data will enable the health care providers and prison management staff to understand the trend and epidemiological situations in HIV/parasitic co-infections in a prison. This information will further assist in providing evidence-based guidance to improve prevention, control and management strategies of IPIs co-infections among both HIV positive and HIV negative inmates in a prison environment. PMID- 26511348 TI - Correlates of intimate partner violence against women during a time of rapid social transition in Rwanda: analysis of the 2005 and 2010 demographic and health surveys. AB - BACKGROUND: In Rwanda, women who self-reported in household surveys ever experiencing intimate partner violence (IPV) increased from 34 % in 2005 to 56 % in 2010. This coincided with a new constitution and majority-female elected parliament in 2003, and 2008 legislation protecting against gender-based violence. The increase in self-reported IPV may reflect improved social power for women, and/or disruptions to traditional gender roles that increased actual IPV. METHODS: This is a cross-sectional study of IPV in 4338 couples interviewed in the 2005 and 2010 Rwanda Demographic and Health Surveys (RDHSs). Factors associated with physical or sexual IPV in the last 12 months were modeled using manual backward stepwise logistic regression. Analyses were conducted in Stata v13 adjusting for complex survey design. RESULTS: Risk factors for IPV in 2005 (p < 0.05) were: experiencing emotional IPV (OR = 18.1), beating husband/partner unprovoked (OR = 12.3), witnessing IPV against mother (OR = 1.82), husband/partner consumes alcohol often (OR = 3.13), and polygynous marriage (OR = 1.51), whereas having a husband/partner with secondary education (OR = 0.43) was protective. Factors associated with increased IPV in 2010 (p < 0.05) were husband/partner (OR = 1.30) or woman (OR = 1.36) believes IPV is justified, husband/partner has sex with non-marital partners (OR = 2.52), bottom wealth quintile (OR = 1.25), polygynous marriage (OR = 2.29), having a son (OR = 2.05) or only daughters (OR = 2.58) versus no children, and having a husband/partner employed with in-kind versus cash compensation (OR = 1.58). In 2010, woman being involved with her own health (OR = 0.79) or earnings (OR = 0.57) decision-making was protective against IPV. Several variables were not available in the 2010 RDHS. CONCLUSIONS: Our results may provide evidence of both increased self reporting of IPV and social power disruption. Rwanda's Isange One Stop Center project, with medical, legal, and psychosocial services for domestic violence victims, is currently scaling to all 44 district hospitals, and police station gender desks reduce barriers to legal reporting of IPV. Additional support to Abunzi mediators to hear IPV cases in communities, and involvement of men in grassroots efforts to redefine masculinity in Rwanda are suggested. Additional research is needed to understand why self-reported IPV has increased in Rwanda, and to evaluate effectiveness of IPV interventions. PMID- 26511349 TI - A Patient with Persistent Lactation and Recurrent Hypercalcemia. PMID- 26511350 TI - Commentary. PMID- 26511352 TI - Correction. PMID- 26511351 TI - Commentary. PMID- 26511353 TI - Persistence of Infliximab in Circulation for 7 Years? PMID- 26511354 TI - Extreme Hypernatremia with Markedly Increased Anion Gap. PMID- 26511356 TI - Craftsmanship in Arts and Science. PMID- 26511357 TI - Glycemic Variability on Continuous Glucose Monitoring System Correlates With Non Culprit Vessel Coronary Plaque Vulnerability in Patients With First-Episode Acute Coronary Syndrome - Optical Coherence Tomography Study. AB - BACKGROUND: Glycemic variability (GV) is associated with coronary plaque rupture at the culprit lesion in acute myocardial infarction (AMI). The present study determined the relationship between GV and coronary plaque vulnerability in the non-culprit vessel. METHODS AND RESULTS: The present prospective study involved 46 patients with first-episode acute coronary syndrome (ACS) who underwent optical coherence tomography in the non-culprit vessel. The relationship between GV, assessed with continuous glucose monitoring system, and the presence of thin cap fibroatheroma (TCFA) at the non-culprit plaque with mild-to-moderate stenosis in the non-culprit vessel, was assessed. GV was quantified using mean amplitude of glycemic excursion (MAGE). Patients were divided into tertiles according to MAGE. TCFA was observed in 13 (28%) of the 46 patients. Fibrous cap thickness was thinner (MAGE tertiles: high, 80+/-40 um; intermediate, 152+/-122 um; low, 155+/ 102 um; P=0.01), and TCFA was more common (MAGE tertiles: high, 50%; intermediate, 27%; low, 7%; P=0.03) in patients with high MAGE. On multivariate logistic analysis high MAGE was the only significant determinant of TCFA, independent of coronary risk factors (OR, 5.000; P=0.021), homeostasis model assessment of insulin resistance, and hemoglobin A1c(OR, 5.674; P=0.018). CONCLUSIONS: High MAGE measured early after the onset of first-episode ACS correlated with thinner fibrous cap thickness and higher prevalence of TCFA at the non-culprit plaque in the non-culprit vessel. PMID- 26511358 TI - Temporal Trends in Clinical Outcome After Percutaneous Coronary Intervention 1984 2010 - Report From the Juntendo PCI Registry. AB - BACKGROUND: Since the introduction of PCI in 1977, it has evolved along with advances in the technology, improvement in operator technique and establishment of medical therapy. However, little is known of the improvement in clinical outcome following PCI. METHODS AND RESULTS: Data from the Juntendo PCI Registry during 1984-2010 were analyzed. The patients were divided into 3 groups according to date of index PCI: POBA era, January 1984-December 1997; BMS era, January 1998 July 2004; and DES era, August 2004-February 2010. The primary endpoint was a composite of MACE including all-cause mortality, non-fatal MI, non-fatal stroke and revascularization. A total of 3,831 patients were examined (POBA era, n=1,147; BMS era, n=1,180; DES era, n=1,504). Mean age was highest in the DES era. The prevalence of diabetes and hypertension was higher in the DES and BMS eras than in the POBA era. Unadjusted cumulative event-free survival rate for 2 year MACE was significantly different across the 3 eras. Adjusted relative risk reduction for 2-year MACE was 56% in the DES era and 34% in the BMS era, both compared with the POBA era. Age, ACS, and LVEF were associated with the incidence of MACE. CONCLUSIONS: Clinical outcome of PCI improved across the 26-year study period, despite the higher patient risk profile in the recent era. PMID- 26511359 TI - Coronary Stenosis as an Innocent Bystander in Acute Coronary Syndrome. PMID- 26511362 TI - Deciphering the association between gene function and spatial gene-gene interactions in 3D human genome conformation. AB - BACKGROUND: A number of factors have been investigated in the context of gene function prediction and analysis, such as sequence identity, gene expressions, and gene co-evolution. However, three-dimensional (3D) conformation of the genome has not been tapped to analyse gene function, probably largely due to lack of genome conformation data until recently. METHODS: We construct the genome-wide spatial gene-gene interaction networks for three different human B-cells or cell lines from their chromosomal contact data generated by the Hi-C chromosome conformation capturing technique. The G-SESAME and Fast-SemSim are used to calculate function similarity between interacted / non-interacted genes. The Gene Ontology statistics computed from the gene-gene interaction networks is used for gene function prediction. RESULTS: We compare the function similarity of gene pairs that do not spatially interact and that have interactions. We find that genes that have strong spatial interactions tend to have highly similar function in terms of biological process, molecular function and cellular component of the Gene Ontology. And even though the level of gene-gene interactions generally have no or weak correlation with either sequential genomic distance or sequence identity between genes, the interacted genes with high function similarity tend to have stronger interactions, somewhat shorter genomic distance and significantly higher sequence identity. And combining genomic distance or sequence identity with spatial gene-gene interaction information informs gene gene function similarity much better than using either one of them alone, suggesting gene-gene interaction information is largely complementary with genomic distance and sequence identity in the context of gene function analysis. We develop and evaluate a new gene function prediction method based on gene-gene interacting networks, which can predict gene function well for a large number of human genes. CONCLUSIONS: In this work, we demonstrate that the spatial conformation of the human genome is relevant to gene function similarity and is useful for gene function prediction. PMID- 26511360 TI - Colon cancer care and survival: income and insurance are more predictive in the USA, community primary care physician supply more so in Canada. AB - BACKGROUND: Our research group advanced a health insurance theory to explain Canada's cancer care advantages over America. The late Barbara Starfield theorized that Canada's greater primary care-orientation also plays a critically protective role. We tested the resultant Starfield-Gorey theory by examining the effects of poverty, health insurance and physician supplies, primary care and specialists, on colon cancer care in Ontario and California. METHODS: We analyzed registry data for people with non-metastasized colon cancer from Ontario (n = 2,060) and California (n = 4,574) diagnosed between 1996 and 2000 and followed to 2010. We obtained census tract-based socioeconomic data from population censuses and data on county-level physician supplies from national repositories: primary care physicians, gastroenterologists and other specialists. High poverty neighborhoods were oversampled and the criterion was 10 year survival. Hypotheses were explored with standardized rate ratios (RR) and tested with logistic regression models. RESULTS: Significant inverse associations of poverty (RR = 0.79) and inadequate health insurance (RR = 0.80) with survival were observed in the California, while they were non-significant or non-existent in Ontario. The direct associations of primary care physician (RRs of 1.32 versus 1.11) and gastroenterologist (RRs of 1.56 versus 1.15) supplies with survival were both stronger in Ontario than California. The supply of primary care physicians took precedence. Probably mediated through the initial course of treatment, it largely explained the Canadian advantage. CONCLUSIONS: Poverty and health insurance were more predictive in the USA, community physician supplies more so in Canada. Canada's primary care protections were greatest among the most socioeconomically vulnerable. The protective effects of Canadian health care prior to enactment of the Affordable Care Act (ACA) clearly suggested the following. Notwithstanding the importance of insuring all, strengthening America's system of primary care will probably be the best way to ensure that the ACA's full benefits are realized. Finally, Canada's strong primary care system ought to be maintained. PMID- 26511361 TI - Pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs. AB - BACKGROUND: Mitotic synchrony is the synchronous progression of a population of cells through the cell cycle and is characteristic of non-diseased airway epithelial cells. However, we previously showed that asthmatic airway epithelial cells are characterized by mitotic asynchrony and are pro-inflammatory as a result. Glucocorticoids can induce mitotic synchrony that in turn suppresses the pro-inflammatory state of diseased cells, suggesting a novel anti-inflammatory mechanism of action. Herein, we benchmarked traditional glucocorticoids against the ability of a new clinical-stage dissociative steroidal drug, VBP15, for mitotic resynchronization and associated anti-inflammatory activity in asthmatic airway epithelial cells. METHODS: Primary airway epithelial cells differentiated at air-liquid interface were exposed to VBP15, dexamethasone or vehicle following in vitro mechanical injury. Basolateral cytokine secretions (TGF-beta1, IL-6, IL 10, IL-13, and IL-1beta) were analyzed at different time points using cytometric bead assays and mitosis was examined by flow cytometry. RESULTS: VBP15 improved mitotic synchrony of proliferating asthmatic cells in air-liquid interface cultures compared to vehicle-exposed cultures. VBP15 also significantly reduced the basolateral secretion of pro-inflammatory (i.e. IL-1beta) and pro-fibrogenic cytokines (i.e. TGF-beta1) in air-liquid interface-differentiated asthmatic epithelial cultures following mechanical injury. CONCLUSION: VBP15 improves mitotic asynchrony and injury-induced pro-inflammatory and fibrogenic responses in asthmatic airway epithelial cultures with efficacy comparable to traditional glucocorticoids. As it is predicted to show superior side effect profiles compared to traditional glucocorticoids, VBP15 holds potential for treatment of asthma and other respiratory conditions. PMID- 26511363 TI - Molecular Materials That Can Both Emit Light and Conduct Charges: Strategies and Perspectives. AB - Molecular materials with concomitant light-emissive and semiconducting properties have received increasing attention in recent years. Such dual functional materials ensure the development of multifunctional devices (e.g., organic light emitting transistors) and the emergence of new technologies. However, owing to the fact that intermolecular interactions and dense packing have opposite effects on photoluminescence and charge-carrier mobility, it is still rather challenging to rationally design high-performance molecular materials that exhibit both semiconducting and light-emissive properties. In fact, only a limited number of such dual functional materials are available, and most of their performances need to be further improved. In this concept article we discuss the design strategies and perspectives of this challenging area with the introduction of representative examples of such dual functional materials reported in recent years. PMID- 26511364 TI - A combination of biomolecules enhances expression of E-cadherin and peroxisome proliferator-activated receptor gene leading to increased cell proliferation in primary human meniscal cells: an in vitro study. AB - The present study investigates the impact of biomolecules (biotin, glucose, chondroitin sulphate, proline) as supplement, (individual and in combination) on primary human meniscus cell proliferation. Primary human meniscus cells isolated from patients undergoing meniscectomy were maintained in Dulbecco's Modified Eagle's Medium (DMEM). The isolated cells were treated with above mentioned biomolecules as individual (0-100 ug/ml) and in combinations, as a supplement to DMEM. Based on the individual biomolecule study, a unique combination of biomolecules (UCM) was finalized using one way ANOVA analysis. With the addition of UCM as supplement to DMEM, meniscal cells reached 100 % confluency within 4 days in 60 mm culture plate; whereas the cells in medium devoid of UCM, required 36 days for reaching confluency. The impact of UCM on cell viability, doubling time, histology, gene expression, biomarkers expression, extra cellular matrix synthesis, meniscus cell proliferation with respect to passages and donor's age were investigated. The gene expression studies for E-cadherin and peroxisome proliferator-activated receptor (PPAR?) using RT-qPCR and immunohistochemical analysis for Ki67, CD34 and Vimentin confirmed that UCM has significant impact on cell proliferation. The extracellular collagen and glycosaminoglycan secretion in cells supplemented with UCM were found to increase by 31 and 37 fold respectively, when compared to control on the 4th day. The cell doubling time was reduced significantly when supplemented with UCM. The addition of UCM showed positive influence on different passages and age groups. Hence, this optimized UCM can be used as an effective supplement for meniscal tissue engineering. PMID- 26511365 TI - Reduced passive force in skeletal muscles lacking protein arginylation. AB - Arginylation is a posttranslational modification that plays a global role in mammals. Mice lacking the enzyme arginyltransferase in skeletal muscles exhibit reduced contractile forces that have been linked to a reduction in myosin cross bridge formation. The role of arginylation in passive skeletal myofibril forces has never been investigated. In this study, we used single sarcomere and myofibril measurements and observed that lack of arginylation leads to a pronounced reduction in passive forces in skeletal muscles. Mass spectrometry indicated that skeletal muscle titin, the protein primarily linked to passive force generation, is arginylated on five sites located within the A band, an important area for protein-protein interactions. We propose a mechanism for passive force regulation by arginylation through modulation of protein-protein binding between the titin molecule and the thick filament. Key points are as follows: 1) active and passive forces were decreased in myofibrils and single sarcomeres isolated from muscles lacking arginyl-tRNA-protein transferase (ATE1). 2) Mass spectrometry revealed five sites for arginylation within titin molecules. All sites are located within the A-band portion of titin, an important region for protein-protein interactions. 3) Our data suggest that arginylation of titin is required for proper passive force development in skeletal muscles. PMID- 26511366 TI - [Intra-articular injection of cortisone]. AB - Intra-articular injections with glucocorticoids are standard procedures according to therapy guidelines in many rheumatic conditions. There is increasing evidence from clinical trials on the treatment of rheumatoid arthritis that more patients will attain the target of remission using a combination of systemic medication and intra-articular injections with glucocorticoids compared to systemic medication alone. Intra-articular injections with glucocorticoids play an important role in the therapeutic management of pediatric rheumatic diseases. In many countries competency in performing intra-articular injections is among the important skills necessary for certification as a specialist in rheumatology. PMID- 26511367 TI - A facile, regioselective synthesis of novel 3-(N-phenylcarboxamide)pyrazolo[1,5 a]pyrimidine analogs in the presence of KHSO4 in aqueous media assisted by ultrasound and their antibacterial activities. AB - An environmentally benign, simple, efficient, and convenient route is described for the synthesis of novel pyrazolo[1,5-a]pyrimidine derivatives under ultrasound irradiation. Condensation of aminopyrazole 5 with formylated active proton compounds (6, 8, E-G, 12, and 15) furnished pyrazolopyrimidine (7, 9, 10, 13, and 16) in high-to-excellent yields. In comparison with conventional methods, ultrasound irradiation offers several advantages, such as shorter reaction time, higher yields, milder conditions, and environmental friendliness. The reaction is clean with excellent yields and reduces the use of solvents. X-ray crystallographic study of compound 7c confirmed the regioselectivity of the reaction. The antibacterial profile of the newly synthesized compounds was evaluated by cup and saucer method. PMID- 26511368 TI - Peroxisome proliferator-activated receptor gamma agonists for preventing recurrent stroke and other vascular events in patients with stroke or transient ischaemic attack. AB - BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists are insulin-sensitising drugs used for the treatment of insulin resistance. In addition to lowering glucose in diabetes, these drugs may also protect against hyperlipidaemia and arteriosclerosis, which are risk factors for stroke. OBJECTIVES: To assess the efficacy and safety of PPAR-gamma agonists in the secondary prevention of stroke and related vascular events for people with stroke or transient ischaemic attack (TIA). SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (July 2015), the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 6), MEDLINE (1949 to July 2015), EMBASE (1980 to July 2015), CINAHL (1982 to July 2015), AMED (1985 to July 2015) and 11 Chinese databases (July 2015). In an effort to identify further published, unpublished and ongoing trials we searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted authors and pharmaceutical companies. We did not impose any language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating PPAR-gamma agonists versus placebo for the secondary prevention of stroke and related vascular events in people with stroke or TIA, with the outcomes of recurrent stroke, vascular events and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy, and assessed methodological quality and risk of bias. MAIN RESULTS: We identified four eligible studies with 1163 participants; only one study had a low risk of bias for all domains. Three studies evaluated the drug pioglitazone and one study evaluated rosiglitazone. The participants in different studies were heterogeneous. The number of participants with recurrent stroke was evaluated in two studies, where PPAR-gamma agonists reduced the recurrence of stroke compared with placebo (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.34 to 0.80). PPAR-gamma agonists given over a mean duration of 34.5 months in a single trial were found to reduce a composite outcome of total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (RR 0.73, 95% CI 0.54 to 0.99). Data on additional composite outcomes reflecting serious adverse events (all-cause death and other major vascular events; all cause mortality, non-fatal myocardial infarction or non-fatal stroke) were similar although the confidence intervals were wider and the effects were not statistically significant. In addition, two studies respectively measured insulin sensitivity and the ubiquitin-proteasome activity in carotid plaques. These results were significantly improved by PPAR-gamma agonists in comparison with placebo. None of the studies reported the number of participants with disability due to vascular events or improvement in quality of life. Three RCTs reported information about adverse events. Frequent adverse events included oedema, cardiac failure and anaemia. Evidence that adverse events occurred more frequently in participants treated with PPAR-gamma agonists when compared with placebo was imprecise and inconsistent (risk difference (RD) 10%, 95% CI -8% to 28%, I2 = 86%). AUTHORS' CONCLUSIONS: PPAR-gamma agonists appear to reduce recurrent stroke and total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, and improve insulin sensitivity and the stabilisation of carotid plaques. There is evidence of limited quality that they are well tolerated. However, the conclusions should be interpreted with caution considering the small number and the quality of the included studies. In future, well-designed, double-blind RCTs with large samples are required to assess the efficacy and safety of PPAR-gamma agonists in the secondary prevention of stroke and related vascular events in people with stroke or TIA. PMID- 26511369 TI - ANSLAB: Integrated multichannel peripheral biosignal processing in psychophysiological science. AB - Psychophysiological science employs a large variety of signals from the human body that index the activity of the peripheral nervous system. This allows for studying interactions of psychological and physiological processes that are relevant for understanding cognition, emotion, and psychopathology. The multidimensional nature of the data and the interactions between different physiological signals represent a methodological and computational challenge. Analysis software in this domain is often limited in its coverage of the signals from different physiological systems, and therefore only partially addresses these challenges. ANSLAB (short for Autonomic Nervous System Laboratory) is an integrated software suite that supports data visualization, artifact detection, data reduction, automated processing, and statistical analysis for a large range of autonomic, respiratory, and muscular measures. Analysis modules for cardiovascular (e.g., electrocardiogram, heart rate variability, blood pressure wave, pulse wave, and impedance cardiography), electrodermal (skin conductance level and responses), respiratory (respiratory pattern, timing, and volume variables, as well as capnography), and muscular (eye-blink startle, facial and bodily electromyography) systems are complemented by specialized modules (e.g., body temperature and accelerometry, cross-spectral analysis of respiratory and cardiac measures, signal averaging, and statistical analysis) and productivity enhancing features (batched processing, fully automatized analyses, and data management). ANSLAB also facilitates the analysis of long-term recordings from ambulatory assessment studies. The present article reviews several analysis modules included in ANSLAB and describes how these address some of the current needs and methodological challenges of psychophysiological science. PMID- 26511370 TI - The effectiveness of argumentation in tutorial dialogues with an Intelligent Tutoring System for genetic risk of breast cancer. AB - BRCA Gist is an Intelligent Tutoring System that helps women understand issues related to genetic testing and breast cancer risk. In two laboratory experiments and a field experiment with community and web-based samples, an avatar asked 120 participants to produce arguments for and against genetic testing for breast cancer risk. Two raters assessed the number of argumentation elements (claim, reason, backing, etc.) found in response to prompts soliciting arguments for and against genetic testing for breast cancer risk (IRR=.85). When asked to argue for genetic testing, 53.3 % failed to meet the minimum operational definition of making an argument, a claim supported by one or more reasons. When asked to argue against genetic testing, 59.3 % failed to do so. Of those who failed to generate arguments most simply listed disconnected reasons. However, participants who provided arguments against testing (40.7 %) performed significantly higher on a posttest of declarative knowledge. In each study we found positive correlations between the quality of arguments against genetic testing (i.e., number of argumentation elements) and genetic risk categorization scores. Although most interactions did not contain two or more argument elements, when more elements of arguments were included in the argument against genetic testing interaction, participants had greater learning outcomes. Apparently, many participants lack skills in making coherent arguments. These results suggest an association between argumentation ability (knowing how to make complex arguments) and subsequent learning. Better education in developing arguments may be necessary for people to learn from generating arguments within Intelligent Tutoring Systems and other settings. PMID- 26511371 TI - Thematic relatedness production norms for 100 object concepts. AB - Knowledge of thematic relations is an area of increased interest in semantic memory research because it is crucial to many cognitive processes. One methodological issue that researchers face is how to identify pairs of thematically related concepts that are well-established in semantic memory for most people. In this article, we review existing methods of assessing thematic relatedness and provide thematic relatedness production norming data for 100 object concepts. In addition, 1,174 related concept pairs obtained from the production norms were classified as reflecting one of the five subtypes of relations: attributive, argument, coordinate, locative, and temporal. The database and methodology will be useful for researchers interested in the effects of thematic knowledge on language processing, analogical reasoning, similarity judgments, and memory. These data will also benefit researchers interested in investigating potential processing differences among the five types of semantic relations. PMID- 26511372 TI - Estimating affective word covariates using word association data. AB - Word ratings on affective dimensions are an important tool in psycholinguistic research. Traditionally, they are obtained by asking participants to rate words on each dimension, a time-consuming procedure. As such, there has been some interest in computationally generating norms, by extrapolating words' affective ratings using their semantic similarity to words for which these values are already known. So far, most attempts have derived similarity from word co occurrence in text corpora. In the current paper, we obtain similarity from word association data. We use these similarity ratings to predict the valence, arousal, and dominance of 14,000 Dutch words with the help of two extrapolation methods: Orientation towards Paradigm Words and k-Nearest Neighbors. The resulting estimates show very high correlations with human ratings when using Orientation towards Paradigm Words, and even higher correlations when using k Nearest Neighbors. We discuss possible theoretical accounts of our results and compare our findings with previous attempts at computationally generating affective norms. PMID- 26511373 TI - New methods, measures, and models for analyzing memory impairment using triadic comparisons. AB - We study the effect of memory impairment on triadic comparisons of animal names in a large clinical data set. We define eight groups of subjects in terms of their delayed free recall performance, and present standard analyses of the triadic comparison and free recall data that provide little insight into the effect of memory impairment on semantic structure. We then develop and apply two new methods for analyzing the data, based on cognitive models and using Bayesian statistical inference. The first new method focuses on modeling changes in semantic representation, by inferring multidimensional scaling (MDS) representations for each group based on their triadic comparisons. These representations reveal a successive decrease in semantic cluster structure and increase in uncertainty with increasing impairment. We propose a measure of spatial organization as a means of quantifying the visually evident changes in semantic organization, and demonstrate its usefulness. The second new method focuses on modeling changes in memory access with impairment, inferring the extent to which each individual makes triadic comparisons consistent with a common semantic representation. Although these inferences are based on just 12 comparisons per subject, we show that they vary systematically with memory impairment group. We conclude by discussing the potential for clinical application of our new models, measures, and methods. PMID- 26511374 TI - Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy. AB - This study tested for the benefits of early administration of carvedilol as protection against doxorubicin (DOX)-induced cardiomyopathy. Thirty male, adult B6 mice were categorized into group 1 (untreated control), group 2 [DOX treatment (15 mg/every other day for 2 weeks, i.p.], and group 3 [carvedilol (15 mg/kg/d, from day 7 after DOX treatment for 28 days)], and euthanized by day 35 after DOX treatment. By day 35, the left ventricular ejection fraction (LVEF) was significantly lower in group 2 than in groups 1 and 3, and significantly lower in group 3 than in group 1, whereas the left ventricular (LV) end-diastolic and LV end-systolic dimensions showed an opposite pattern to the LVEF among the three groups. The protein expressions of fibrotic (Smad3, TGF-beta), apoptotic (BAX, cleaved caspase 3, PARP), DNA damage (gamma-H2AX), oxidative stress (oxidized protein), mitochondrial damage (cytosolic cytochrome-C), heart failure (brain natriuretic peptide), and hypertrophic (beta-MHC) biomarkers of the LV myocardium showed an opposite pattern to the LVEF among the three groups. The protein expressions of antifibrotic (BMP-2, Smad1/5), alpha-MHC, and phosphorylated-Akt showed an identical pattern to the LVEF among the three groups. The microscopic findings of fibrotic and collagen-deposition areas and the numbers of gamma H2AX(+) and 53BP1(+) cells in the LV myocardium exhibited an opposite pattern, whereas the numbers of endothelial cell (CD31(+), vWF(+)) markers showed an identical pattern to the LVEF among the three groups. Cardiac stem cell markers (C-kit(+) and Sca-1(+) cells) were significantly and progressively increased from group 1 to group 3. Additionally, the in vitro study showed carvedilol treatment significantly inhibited DOX-induced cardiomyoblast DNA (CD90/XRCC1(+), CD90/53BP1(+), and r-H2AX(+) cells) damage. Early carvedilol therapy protected against DOX-induced DNA damage and cardiomyopathy. PMID- 26511375 TI - Identification of ligands for bacterial sensor proteins. AB - Bacteria have evolved a variety of different signal transduction mechanisms. However, the cognate signal molecule for the very large amount of corresponding sensor proteins is unknown and their functional annotation represents a major bottleneck in the field of signal transduction. The knowledge of the signal molecule is an essential prerequisite to understand the signalling mechanisms. Recently, the identification of signal molecules by the high-throughput protein screening of commercially available ligand collections using differential scanning fluorimetry has shown promise to resolve this bottleneck. Based on the analysis of a significant number of different ligand binding domains (LBDs) in our laboratory, we identified two issues that need to be taken into account in the experimental design. Since a number of LBDs require the dimeric state for ligand recognition, it has to be assured that the protein analysed is indeed in the dimeric form. A number of other examples demonstrate that purified LBDs can contain bound ligand which prevents further binding. In such cases, the apo-form can be generated by denaturation and subsequent refolding. We are convinced that this approach will accelerate the functional annotation of sensor proteins which will help to understand regulatory circuits in bacteria. PMID- 26511377 TI - E-cigarettes could addict a new generation of youth to nicotine, doctors are told. PMID- 26511376 TI - Treatment of Neuropathic Pain. AB - OPINION STATEMENT: Neuropathic pain is notoriously variable in its severity and impact on patients, as well as in its response to treatment. Certain therapies for neuropathic pain have better evidence for their use; however, it is apparent that although some therapies provide relief for only a minority of patients, the relief may be significant. Without a trial of therapy, there is no way to know if that relief is achievable. Our treatment experiences have shown that occasionally unexpected benefit is obtained through a thorough investigation of all options, even in the setting of failure of those with the most compelling evidence or indication. Chronic neuropathic pain is generally best treated with regularly dosed medications, balancing efficacy and tolerability. Evidence supports first line trials of anticonvulsants, tricyclic antidepressants, and serotonin norepinephrine reuptake inhibitors, alone or in certain combinations. While opioid medications, particularly methadone, can be effective in treating neuropathic pain, they are best used only in refractory cases and by experienced clinicians, due to concerns for both short- and long-term safety. Some therapies have a long history of successful use for certain syndromes (e.g., carbamazepine for trigeminal neuralgia pain), but these should not be considered to the exclusion of other more recent, less-supported therapies (e.g., botulinum toxin A for the same), particularly in refractory cases. We find the principles of palliative care highly applicable in the treatment of chronic neuropathic pain, including managing expectations, mutually agreed-upon meaningful outcomes, and a carefully cultivated therapeutic relationship. PMID- 26511378 TI - Antidepressants for neuroprotection in Huntington's disease: A review. AB - Huntington Disease (HD), which is characterized by abnormal dance-like movements, is a neurodegenerative disorder caused by a genetic mutation that results in an expanded polyglutamine stretch in the NH2 terminus of huntingtin protein (HTT). The principal neuropathological hallmarks of disease include loss of striatal and cortical projection neurons. HTT is ubiquitously expressed and is implicated in several cellular functions including neurogenesis, cell trafficking and brain derived neurotrophic factor (BDNF) production. Major depression is the most common symptom among pre-symptomatic HD carriers and numerous pieces of preclinical evidence have suggested the use of antidepressants in HD not only elevates mood but also slows down the disease progression by activating different neuroprotective mechanism like BDNF/TrkB pathway, MAPK/ERK signalling, neurogenesis and Wnt signalling. HTT plays major role in neurogenesis, a physiological phenomenon that is implicated in some of the behavioral effects of antidepressants. Currently, there is no clinically available treatment that can halt or slow down the progression of HD except tetrabenazine (the only FDA approved drug); however, this drug also induces depression and sedation in patients. In this review, a brief discussion has been made about the mutant HTT that induced various cellular and molecular mechanisms underlying behavioral disorders in HD. Further, an attempt has been made to understand the various cellular mechanisms involved in mediating the neuroprotective effects of antidepressants in HD. PMID- 26511379 TI - NCX 4040, a nitric oxide-donating aspirin derivative, inhibits Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages. AB - In this study, the effects and underlying mechanisms of NCX 4040, a nitric oxide (NO)-donating aspirin derivative, on the production of proinflammatory mediators were examined using murine macrophages exposed to lipopolysaccharide (LPS) from Prevotella intermedia, a pathogen implicated in the etiology of periodontal disease. NCX 4040 significantly reduced P. intermedia LPS-induced production of inducible NO synthase (iNOS)-derived NO, IL-1beta and IL-6 as well as their mRNA expression in RAW264.7 cells. Notably, NCX 4040 was much more effective than the parental compound aspirin in reducing LPS-induced production of inflammatory mediators. NCX 4040 induced the expression of heme oxygenase-1 (HO-1) in cells treated with P. intermedia LPS, and the suppressive effect of NCX 4040 on LPS induced NO production was significantly reversed by SnPP, a competitive HO-1 inhibitor. NCX 4040 did not influence LPS-induced phosphorylation of JNK and p38. IkappaB-alpha degradation as well as nuclear translocation and DNA-binding activities of NF-kappaB p65 and p50 subunits induced by P. intermedia LPS were significantly reduced by NCX 4040. Besides, LPS-induced phosphorylation of STAT1 and STAT3 was significantly down-regulated by NCX 4040. Further, NCX 4040 elevated the SOCS1 mRNA in cells stimulated with LPS. This study indicates that NCX 4040 inhibits P. intermedia LPS-induced production of NO, IL-1beta and IL-6 in murine macrophages through anti-inflammatory HO-1 induction and suppression of NF-kappaB, STAT1 and STAT3 activation, which is associated with the activation of SOCS1 signaling. NCX 4040 could potentially be a promising tool in the treatment of periodontal disease, although further studies are required to verify this. PMID- 26511380 TI - The immediate effect of patellar tendon strap on weight-bearing asymmetry during squatting in patients with unilateral knee osteoarthritis: A pilot study. AB - BACKGROUND: Knee osteoarthritis has commonly been associated with a symptom of pain resulting in an inter-limb weight-bearing asymmetry during functional tasks. Patellar tendon strap is one of the non-pharmacologic interventions to alleviate knee pain. OBJECTIVES: To investigate the immediate effect of a patellar tendon strap on weight-bearing asymmetry during squatting in people with unilateral knee osteoarthritis. STUDY DESIGN: Cross-sectional study. METHODS: Ten patients with unilateral knee osteoarthritis and 10 healthy subjects were included in the study. Weight-bearing asymmetry of patients was assessed using a weight-bearing squat test during squatting at 30 degrees and 60 degrees both with and without patellar tendon strap. Pain intensity was assessed during squatting in unstrapped and strapped conditions with Visual Analog Scale. RESULTS: The decrease in weight bearing asymmetry values immediately after wearing patellar tendon strap during 30 degrees (p = 0.006) and 60 degrees (p = 0.011) of squatting tests was significantly higher in knee osteoarthritis patients than in healthy subjects. Reported pain intensity was similar in unstrapped and strapped conditions (p = 0.066). CONCLUSION: The results of this study showed improved inter-limb weight bearing symmetry during squatting. Further research with larger sample sizes investigating the effect of patellar tendon strap on weight-bearing asymmetry during functional activities in people with knee osteoarthritis is warranted. CLINICAL RELEVANCE: Patellar tendon straps (easily fit and cheap unlike knee braces) had more improvements in inter-limb weight-bearing symmetry during squatting in people with knee osteoarthritis compared to healthy subjects. This study is a new insight for future studies to investigate clinical benefits of wearing patellar tendon straps in this population. PMID- 26511381 TI - The Redin SCORE: useful, but not for all: reply. PMID- 26511382 TI - TGF-beta2 induces Grb2 to recruit PI3-K to TGF-RII that activates JNK/AP-1 signaling and augments invasiveness of Theileria-transformed macrophages. AB - Theileria-infected macrophages display many features of cancer cells such as heightened invasive capacity; however, the tumor-like phenotype is reversible by killing the parasite. Moreover, virulent macrophages can be attenuated by multiple in vitro passages and so provide a powerful model to elucidate mechanisms related to transformed macrophage virulence. Here, we demonstrate that in two independent Theileria-transformed macrophage cell lines Grb2 expression is down-regulated concomitant with loss of tumor virulence. Using peptidimer-c to ablate SH2 and SH3 interactions of Grb2 we identify TGF-receptor II and the p85 subunit of PI3-K, as Grb2 partners in virulent macrophages. Ablation of Grb2 interactions reduces PI3-K recruitment to TGF-RII and decreases PIP3 production, and dampens JNK phosphorylation and AP-1-driven transcriptional activity down to levels characteristic of attenuated macrophages. Loss of TGF-R>PI3-K>JNK>AP-1 signaling negatively impacts on virulence traits such as reduced JAM-L/ITG4A and Fos-B/MMP9 expression that contribute to virulent macrophage adhesion and invasiveness. PMID- 26511383 TI - Hemodialysis with end-stage renal disease did not raise the risk of intracranial hemorrhage after a head injury. AB - BACKGROUND: Hemodialysis (HD) treatment for end-stage renal disease (ESRD) (HD(+ESRD)) may increase the risk of intracranial hemorrhage (ICH) after a head injury (HI) for which heparin is used. However, the results of noncontrast head computed tomography (CT) in such patients are not always clear. We aimed to evaluate the effect of HD on the risk of ICH in ESRD patients and in controls without ESRD with HD (HD(-ESRD)), and to determine whether to lower the threshold of head CT in HD(+ESRD) patients after HI. METHODS: In this nationwide population based study using Taiwan's National Health Insurance Research Database, we enrolled 6938 HD(+ESRD) HI patients for the case group and 13,876 randomly selected HD(-ESRD) HI patients for the control group. Measures of the post-HI association between HD(+ESRD) and ICH determined using conditional logistic regression. RESULTS: Five hundred sixty-eight (2.74 %) patients had post-HI ICH: 185 in the HD(+ESRD) group (2.67 % of cases) and 383 were from the HD(-ESRD) group (2.76 % of controls). Conditional logistic regression analysis revealed that after adjusting for age, gender, diabetes, hypertension, congestive heart failure, stroke, cancer, and liver disease, HD(+ESRD) patients had no higher odds of ICH (adjusted odds ratio [AOR]: 0.91; 95 % confidence interval [CI]: 0.75 1.11) than did HD(-ESRD) patients. In the subgroup analysis of immediate ICH, HD(+ESRD) patients had lower odds than did HD(-ESRD) patients (AOR: 0.73; 95 % CI: 0.56-0.94). CONCLUSIONS: HD(+ESRD) did not increase the post-HI risk of ICH. Therefore, it may not be necessary to lower the threshold of head CT in HD(+ESRD) patients. PMID- 26511384 TI - Use of Pulmonary Hypertension Medications in Patients with Tetralogy of Fallot with Pulmonary Atresia and Multiple Aortopulmonary Collaterals. AB - Tetralogy of Fallot (TOF) with pulmonary atresia (PA) and multiple aortopulmonary collaterals (MAPCAs) is a rare and severe form of congenital heart disease with poor prognosis. Aortopulmonary collaterals expose pulmonary arterioles to systemic pressure resulting in pulmonary hypertension (PH). To date, reports regarding the role of PH medications in this population are sparse. The objective of this study was to assess the effect of PH medications in patients with TOF, PA and MAPCAs or similar anatomy, with emphasis on symptoms, echocardiography and invasive hemodynamics. A retrospective review was performed for patients at a single tertiary care pediatric center. Twelve of 66 patients were treated with PH medications (18 %), and eight of these patients had adequate follow-up for further analysis. Median age at last follow-up was 6 years (range 1.4-21 years). Median length of therapy with PH medication was 4 years (range 0.3-17 years). PH medications included sildenafil, bosentan, ambrisentan, inhaled treprostinil and prostacyclin infusion. PH therapy was associated with improvement in symptoms in all patients and improvement in PH by hemodynamic measures in the majority of patients. All patients underwent at least one cardiac intervention by catheterization or surgery while taking PH medication. Two patients died from non PH-related causes. The remaining six patients are alive and remain on PH medication. This review indicates that PH medications are well tolerated by this patient group and provide symptomatic improvement. Further studies are required to determine whether PH medications provide long-term survival benefit for patients with complex congenital heart disease. PMID- 26511385 TI - Adolescent Obesity and Inflammation in Relation to Colorectal Cancer Risk: Recent Findings and Future Implications. PMID- 26511386 TI - Maternal Feeding Goals and Restaurant Menu Choices for Young Children. AB - BACKGROUND: Childhood obesity remains a major public health issue. One recent effort to improve the obesogenic environment is mandating that restaurants provide calorie and other nutritional content on menus. Little is known about whether maternal feeding for young children is influenced by calorie disclosure on menus. This study examined (1) whether maternal feeding goals associate with mothers' food selections for their young children and (2) whether mothers change entree and side selections for their children when calories/fat grams are listed on menus. METHODS: One-hundred seventy mothers of children ages of 3-6 years participated in an online survey. Most participants identified as white (76.5%), with a mean BMI of 25.68 (standard deviation=5.94). Mothers were presented two menus (one with and one without calorie/fat information). RESULTS: The goal of feeding for the child's familiarity with the food was significantly associated with mothers' selection of original side dish and entrees, with greater endorsement of this goal associated with choosing high-calorie/-fat sides and entrees. Feeding for natural content was associated with mothers' selection of original entree, with greater endorsement of this goal associated with choosing low-calorie/-fat entrees. Significantly fewer mothers chose a higher-calorie entree when there was menu labeling. CONCLUSIONS: Maternal feeding goals are associated with mothers' selection of entree and side dishes on restaurant menus. Results from this study suggest that menu labeling of calories and fat grams may influence entree choices by mothers. Targeting mothers' feeding goals and labeling restaurant menus may improve the diets of young children. PMID- 26511388 TI - Episodic akinesia of jaw movements akin to freezing in multiple system atrophy. PMID- 26511387 TI - The Chemokine MIP-1alpha/CCL3 impairs mouse hippocampal synaptic transmission, plasticity and memory. AB - Chemokines are signaling molecules playing an important role in immune regulations. They are also thought to regulate brain development, neurogenesis and neuroendocrine functions. While chemokine upsurge has been associated with conditions characterized with cognitive impairments, their ability to modulate synaptic plasticity remains ill-defined. In the present study, we specifically evaluated the effects of MIP1-alpha/CCL3 towards hippocampal synaptic transmission, plasticity and spatial memory. We found that CCL3 (50 ng/ml) significantly reduced basal synaptic transmission at the Schaffer collateral-CA1 synapse without affecting NMDAR-mediated field potentials. This effect was ascribed to post-synaptic regulations, as CCL3 did not impact paired-pulse facilitation. While CCL3 did not modulate long-term depression (LTD), it significantly impaired long-term potentiation (LTP), an effect abolished by Maraviroc, a CCR5 specific antagonist. In addition, sub-chronic intracerebroventricular (icv) injections of CCL3 also impair LTP. In accordance with these electrophysiological findings, we demonstrated that the icv injection of CCL3 in mouse significantly impaired spatial memory abilities and long-term memory measured using the two-step Y-maze and passive avoidance tasks. These effects of CCL3 on memory were inhibited by Maraviroc. Altogether, these data suggest that the chemokine CCL3 is an hippocampal neuromodulator able to regulate synaptic plasticity mechanisms involved in learning and memory functions. PMID- 26511389 TI - A comparative study of the dorsolateral and ventrolateral approaches for repair of canine sacroiliac luxation. AB - OBJECTIVES: Retrospective comparison of dorsolateral (DLA) and ventrolateral (VLA) surgical approaches for treatment of canine sacroiliac luxation using three different radiographic analyses. METHODS: Surgical cases with immediate and >=4 week postoperative radiographs were reviewed (Jan. 2000 to Jan. 2015). Exactness of reduction, screw position, and sacral body screw purchase were assessed with three separate methods: single plane assessment and orthogonal assessment with or without rotational limits. RESULTS: The reduction index (RI) for DLA and VLA was not significantly different with single plane assessment (p = 0.0789), but it was significantly greater for DLA than VLA with orthogonal assessment, with or without rotational limits (p = 0.0039, p = 0.0146). No differences were observed with screw placement into the intended location (single plane, and orthogonal assessment with or without rotational limits; p = 0.2941, p = 0.4151, p = 0.3550, respectively). No differences were observed between mean screw purchase index (SPI) and the 60% goal for the DLA (p = 0.1303, p = 0.9594, p = 0.7120) or 50% goal for the VLA (p = 0.2224, p = 0.1401, p = 0.2224; single plane, and orthogonal assessment with or without rotational limits). Implant loosening was present in four DLA cases and one VLA case. No differences were observed in the number of cases or number of screws that loosened (p = 0.3483 and p = 0.6873, respectively). CLINICAL SIGNIFICANCE: The key factor demonstrated in maintaining screw and fixation stability was correct screw placement within the sacral body, regardless of the surgical approach. PMID- 26511390 TI - The pharmacology and toxicology of kratom: from traditional herb to drug of abuse. AB - Mitragyna speciosa (Rubiaceae), commonly known as kratom, is a tropical tree with a long history of traditional use in parts of Africa and Southeast Asia. In recent years, kratom has gained popularity for use as a recreational drug across the globe. Relatively new to the illicit market and used in a manner different from its traditional applications, preparations of kratom are touted by many as a safe and legal psychoactive product that improves mood, relieves pain, and may provide benefits in opiate addiction. Available literature was reviewed for M. speciosa via PubMed, Google Scholar, CINAHL, and EBSCO to summarize its traditional uses, phytochemical composition, pharmacology and toxicology of proposed active constituents, and potential for misuse and abuse. Research has demonstrated that both stimulant and sedative dose-dependent effects do exist, but a growing concern for the drug's effects and safety of use has resulted in national and international attention primarily due to an increase in hospital visits and deaths in several countries that are said to have been caused by extracts of the plant. The main active alkaloid substances in kratom, mitragynine and 7-hydroxymitragynine, present with a range of CNS stimulant and depressant effects mediated primarily through monoaminergic and opioid receptors. Recently, Palm Beach County, located in the southeastern corridor of Florida, has considered regulating kratom due to public safety concerns following the death of a young adult. At the local, state, and even federal levels, governments are now being confronted with the task of determining the safety and the possible regulation of kratom extracts. There are currently no standard analytical screening techniques for mitragynine and its metabolites following ingestion limiting its detection to more sophisticated techniques like liquid chromatography-mass spectrometry to determine kratom use. The growing concern of the abuse potential of kratom requires careful evaluation of its benefits and potential toxicities. PMID- 26511391 TI - Solvothermal synthesis of enneanuclear [Cu7(II)Ln2(III)] clusters. AB - Employment of H3L (= 2-(beta-naphthalideneamino)-2-hydroxymethyl-1-propanol) in mixed-metal copper-lanthanide cluster chemistry has led to the isolation of four new enneanuclear heteronuclear isostructural [Cu7(II)Ln2(III)] complexes. More specifically, the solvothermal reaction of Cu2(OAc)4.2H2O with H3L and the corresponding lanthanide nitrate salt in MeCN in the presence of a base, NEt3, yielded three complexes with the general formula [Cu7(II)Ln2(III)(L)4(HL)2(OAc)4].2MeCN (Ln: Gd, 1.2MeCN; Tb, 2.2MeCN; Dy, 3.2MeCN), while in addition the Y(III) analogue, [Cu7(II)Y2(III)(L)4(HL)2(OAc)4].2MeCN (4.2MeCN), was also synthesized in the same manner. The structure of the cluster describes two corner-sharing [Cu3Ln] cubane metallic units, each one further connected to one Cu(II) ion. Dc magnetic susceptibility studies in the 5-300 K range for complexes 1-4 reveal the presence of both ferromagnetic and antiferromagnetic exchange interactions within the metallic clusters. PMID- 26511393 TI - A guideline for whom? PMID- 26511392 TI - Epidemiology and classification of gastroenteropancreatic neuroendocrine neoplasms using current coding criteria. AB - BACKGROUND: The lack of uniform criteria for coding of gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) has hampered previous epidemiological studies. The epidemiology of GEP-NEN was investigated in this study using currently available criteria. METHODS: All patients diagnosed with GEP-NEN between January 2003 and December 2013 in a well defined Norwegian population of approximately 350 000 people were included. Age- and sex-adjusted incidence rates were calculated. The current 2010 World Health Organization criteria, European Neuroendocrine Tumour Society classification and International Union Against Cancer (UICC) classification were used. RESULTS: A total of 204 patients (114 male, 55.9 per cent) were identified. The median age at diagnosis was 61 (range 10-94) years. The annual overall crude incidence was 5.83 per 100,000 inhabitants, with an increasing trend (P = 0.033). The most frequent location was small intestine (60 patients, 29.4 per cent) followed by appendix (48 patients, 23.5 per cent) and pancreas (33 patients, 16.2 per cent). Grade 1 tumours were more common in gastrointestinal (100 patients, 58.5 per cent) than in pancreatic (9 patients, 27 per cent) NEN. According to the UICC classification, 77 patients (37.7 per cent) had stage I, 17 patients (8.3 per cent) stage II, 37 patients (18.1 per cent) stage III and 70 patients (34.3 per cent) had stage IV disease. No patient with stage I disease had grade 3 tumours; advanced tumour grade increased with stage. CONCLUSION: A high crude incidence of GEP-NEN, at 5.83 per 100,000 inhabitants, was noted together with a significant increasing trend over time. PMID- 26511394 TI - Carbon Stable Isotope Analysis of Methylmercury Toxin in Biological Materials by Gas Chromatography Isotope Ratio Mass Spectrometry. AB - A critical component of the biogeochemical cycle of mercury (Hg) is the transformation of inorganic Hg to neurotoxic monomethylmercury (CH3Hg). Humans are exposed to CH3Hg by consuming marine fish, yet the origin of CH3Hg in fish is a topic of debate. The carbon stable isotopic composition (delta(13)C) embedded in the methyl group of CH3Hg remains unexplored. This new isotopic information at the molecular level is thought to represent a new proxy to trace the carbon source at the origin of CH3Hg. Here, we present a compound-specific stable isotope analysis (CSIA) technique for the determination of the delta(13)C value of CH3Hg in biological samples by gas chromatography combustion isotope ratio mass spectrometry analysis (GC-C-IRMS). The method consists first of calibrating a CH3Hg standard solution for delta(13)C CSIA. This was achieved by comparing three independent approaches consisting of the derivatization and halogenation of the CH3Hg standard solution. The determination of delta(13)C(CH3Hg) values on natural biological samples was performed by combining a CH3Hg selective extraction, purification, and halogenation followed by GC-C-IRMS analysis. Reference delta(13)C values were established for a tuna fish certified material (ERM-CE464) originating from the Adriatic Sea (delta(13)C(CH3Hg) = -22.1 +/- 1.50/00, +/- 2 SD). This value is similar to the delta(13)C value of marine algal derived particulate organic carbon (delta(13)CPOC = -210/00). PMID- 26511395 TI - Gap state analysis in electric-field-induced band gap for bilayer graphene. AB - The origin of the low current on/off ratio at room temperature in dual-gated bilayer graphene field-effect transistors is considered to be the variable range hopping in gap states. However, the quantitative estimation of gap states has not been conducted. Here, we report the systematic estimation of the energy gap by both quantum capacitance and transport measurements and the density of states for gap states by the conductance method. An energy gap of ~ 250 meV is obtained at the maximum displacement field of ~ 3.1 V/nm, where the current on/off ratio of ~ 3 * 10(3) is demonstrated at 20 K. The density of states for the gap states are in the range from the latter half of 10(12) to 10(13) eV(-1) cm(-2). Although the large amount of gap states at the interface of high-k oxide/bilayer graphene limits the current on/off ratio at present, our results suggest that the reduction of gap states below ~ 10(11) eV(-1) cm(-2) by continual improvement of the gate stack makes bilayer graphene a promising candidate for future nanoelectronic device applications. PMID- 26511396 TI - Transbaffle catheter ablation of atrial re-entrant tachycardia within the pulmonary venous atrium in adult patients with congenital heart disease. AB - AIMS: Catheter ablation of atrial re-entrant tachycardia in patients after atrial switch procedure for transposition of the great arteries or with a Fontan circulation is technically challenging if the critical part of the re-entry circuit is located within the pulmonary venous atrium (PVA). We report our experience in transbaffle access (TBA) to the PVA for ablation of atrial re entrant tachycardia focusing on technical details. METHODS AND RESULTS: In eight patients, six after Mustard procedure and two with a Fontan circulation, endocardial mapping of atrial re-entrant tachycardia revealed the critical part of the re-entry circuit within the PVA. A total of 10 ablation procedures were performed. Detailed angiographic assessment of the anatomy of the systemic and pulmonary venous atria was performed prior to baffle puncture. Transbaffle access was successfully established with a standard transseptal needle in 9 of 10 procedures. No major complications occurred. At the end of the procedure and the removal of the transseptal sheath, there was no residual shunt in any patient. CONCLUSION: Transbaffle access to the PVA for ablation of atrial re-entrant tachycardia is feasible, less invasive than alternative approaches and can be safely applied in patients after Mustard procedure or with a Fontan circulation. However, the rigidity of prosthetic material may preclude baffle puncture at least in a subset of those patients. PMID- 26511397 TI - Focal impulse and rotor modulation using the novel 64-electrode basket catheter: electrogram characteristics of human rotors. AB - AIMS: Ablation of fractionated electrograms (EGMs) has been performed to eliminate areas of slow conduction in atrial fibrillation (AF). The rotor hypothesis suggests that rapidly activating spiral waves perpetuate and maintain AF. This study describes the EGM characteristics of AF rotors, using the novel 64 electrode basket catheter. METHODS AND RESULTS: Twenty-five patients (male n = 16) with AF (paroxysmal n = 10) underwent focal impulse and rotor modulation. A 3.5 mm irrigated-tip ablation catheter was placed at the identified rotor core and EGMs were analysed for amplitude, characteristics (single-EGM, fractionated EGM, and continuous-EGM), and cycle length over 10 s. A total of 72 rotors were identified [right atrium (RA) = 13, left atrium (LA) = 59]. Seven rotors were excluded from EGM analysis due to location in the pulmonary veins. Single-EGMs were more frequent in the RA compared with the LA (8 (61.5) vs. 12 (23.1); P < 0.01) and EGM amplitudes were smaller in LA rotors when compared with RA rotors (0.14 (0.08-0.17) mV vs. 0.19 (0.15-0.29) mV; P = 0.029). In patients with persistent AF, single-EGMs were observed more often in the right-sided rotors compared with left-sided rotors (4 (57.1) vs. 5 (14.3); P = 0.012), and EGM amplitudes were smaller in patients with persistent AF compared with paroxysmal atrial fibrillation (PAF) patients (0.15 (0.09-0.19) mV vs. 0.22 (0.17-0.47) mV; P = 0.03). Furthermore, the prevalence of fractionated- EGMs was higher in patients with persistent AF compared with PAF patients (31/42 (73.8) vs. 9/23 (39.1); P = 0.03). CONCLUSION: There are no characteristic rotor-EGM potentials. Rotor-EGM characteristics are different between the RA and LA. Although rotors are not associated with abnormal EGMs, rotor-EGMs in persistent AF were more fractionated with lower amplitudes compared with that in PAF. PMID- 26511398 TI - Successful transvenous lead extraction after a failed open surgical attempt. PMID- 26511399 TI - Brugada syndrome: clinical presentation and genotype-correlation with magnetic resonance imaging parameters. AB - AIMS: The purpose of the this study was to evaluate a possible genotype-phenotype correlation in BrS patients and to analyze possible associations with clinical events in affected patients. SCN5A gene encodes the alpha-subunit of the voltage gated sodium channel NaV1.5. Its mutations are associated with a broad spectrum of hereditary arrhythmias such as long-QT syndrome, cardiac conduction diseases, and Brugada syndrome (BrS). Experimental studies have shown an interaction between SCN5A and cellular cytoskeleton, explaining its functional role in cellular integrity of heart cells. METHODS AND RESULTS: Cardiovascular magnetic resonance was performed on 81 consecutive genetically screened BrS patients and 30 healthy controls. Left ventricular (LV) and right ventricular (RV) volumes and dimensions were assessed and compared with respect to the genotype. Brugada syndrome patients with an SCN5A mutation (16 patients; 20%) revealed significantly larger RV volumes, along with lower RV ejection fraction, than patients without a mutation or controls, indicating a more severe phenotype in patients with a mutation. Furthermore, patients with an SCN5A mutation showed significantly more often a spontaneous type 1 BrS-electrocardiogram (ECG). In multivariate analysis, the presence of a spontaneous type 1 BrS-ECG showed the strongest association with cardiac events. Receiver-operating characteristic curve analysis indicated good predictive performance of RV end-diastolic volume, RV end-systolic, and LV cardiac output (area under the curve = 0.81, 0.81, and 0.2), with respect to the presence of an SCN5A mutation. CONCLUSION: Brugada syndrome patients with an SCN5A mutation reveal distinct changes in RV volumes and function when compared with those without an SCN5A mutation. Furthermore, mutation-positive patients have a higher likelihood of a spontaneous type 1 BrS ECG, which is associated with a higher incidence of clinical events. Cardiovascular magnetic resonance may provide additional insight to distinguish between SCN5A mutation-positive and -negative BrS patients. PMID- 26511400 TI - Pollutant capturing SERS substrate: porous boron nitride microfibers with uniform silver nanoparticle decoration. AB - How to concentrate target molecules on the surface of a SERS substrate is a key problem in the practical application of SERS. Herein, we designed for the first time a pollutant capturing surface enhanced Raman spectroscopy (SERS) substrate, namely porous BN microfibers uniformly decorated with Ag nanoparticles, in which the BN microfibers adsorb pollutants, while the Ag nanoparticles provide SERS activity. This SERS substrate captures pollutants from an aqueous solution completely and accumulates them all on its surface without introducing noise signals. The pores of BN protect the silver particles from aggregation which makes BN/Ag a stable and recyclable SERS substrate. What's more, while the dyes are thoroughly concentrated from a diluted solution, the SERS detection limit is easily enhanced, from 10(-6) M to 10(-9) M. PMID- 26511401 TI - Land use change emission scenarios: anticipating a forest transition process in the Brazilian Amazon. AB - Following an intense occupation process that was initiated in the 1960s, deforestation rates in the Brazilian Amazon have decreased significantly since 2004, stabilizing around 6000 km(2) yr(-1) in the last 5 years. A convergence of conditions contributed to this, including the creation of protected areas, the use of effective monitoring systems, and credit restriction mechanisms. Nevertheless, other threats remain, including the rapidly expanding global markets for agricultural commodities, large-scale transportation and energy infrastructure projects, and weak institutions. We propose three updated qualitative and quantitative land-use scenarios for the Brazilian Amazon, including a normative 'Sustainability' scenario in which we envision major socio economic, institutional, and environmental achievements in the region. We developed an innovative spatially explicit modelling approach capable of representing alternative pathways of the clear-cut deforestation, secondary vegetation dynamics, and the old-growth forest degradation. We use the computational models to estimate net deforestation-driven carbon emissions for the different scenarios. The region would become a sink of carbon after 2020 in a scenario of residual deforestation (~1000 km(2) yr(-1)) and a change in the current dynamics of the secondary vegetation - in a forest transition scenario. However, our results also show that the continuation of the current situation of relatively low deforestation rates and short life cycle of the secondary vegetation would maintain the region as a source of CO2 - even if a large portion of the deforested area is covered by secondary vegetation. In relation to the old growth forest degradation process, we estimated average gross emission corresponding to 47% of the clear-cut deforestation from 2007 to 2013 (using the DEGRAD system data), although the aggregate effects of the postdisturbance regeneration can partially offset these emissions. Both processes (secondary vegetation and forest degradation) need to be better understood as they potentially will play a decisive role in the future regional carbon balance. PMID- 26511403 TI - Inside the black box of food safety: a qualitative study of 'non-compliance' among food businesses. AB - Issue addressed This paper examines the meaning of food safety among food businesses deemed non-compliant and considers the need for an insider perspective to inform a more nuanced health promotion practice. Methods In-depth interviews were conducted with 29 food business operators who had recently been deemed 'non compliant' through Council inspection. Results Paradoxically, these 'non compliers' revealed a strong belief in the importance of food safety as well as a desire to comply with the regulations as communicated to them by Environmental Health Officers. Conclusions The evidence base of food safety is largely informed by the science of food hazards, yet there is a very important need to consider the practical daily application of food safety practices. This requires a more socially nuanced appreciation of food businesses beyond the simple dichotomy of compliant/ non-compliant. So what? Armed with a deeper understanding of the social context surrounding food safety practice, it is anticipated that a more balanced, collaborative mode of food safety health promotion could develop, which could add to the current model of regulation. PMID- 26511402 TI - Novel TKI-resistant BCR-ABL1 gatekeeper residue mutations retain in vitro sensitivity to axitinib. PMID- 26511404 TI - Fabrication and characterization of PbSe nanostructures on van der Waals surfaces of GaSe layered semiconductor crystals. AB - The growth morphology, composition and structure of PbSe nanostructures grown on the atomically smooth, clean, nanoporous and oxidized van der Waals (0001) surfaces of GaSe layered crystals were studied by means of atomic force microscopy, x-ray diffractometry,photoelectron spectroscopy and Raman spectroscopy. Semiconductor heterostructures were grown by the hot-wall technique in vacuum. Nanoporous GaSe substrates were fabricated by the thermal annealing of layered crystals in a molecular hydrogen atmosphere. The irradiation of the GaSe(0001) surface by UV radiation was used to fabricate thin Ga(2)O(3) layers with thickness < 2 nm. It was found that the narrow gap semiconductor PbSe shows a tendency to form clusters with a square or rectangular symmetry on the clean?low-energy (0001) GaSe surface, and (001)-oriented growth of PbSe thin films takes place on this surface. Using this growth technique it is possible to grow PbSe nanostructures with different morphologies:continuous epitaxial layers with thickness < 10 nm on the uncontaminated p-GaSe(0001)surfaces, homogeneous arrays of quantum dots with a high lateral density (more than 1011 cm(-2))on the oxidized van der Waals (0001) surfaces and faceted square pillar-like nanostructures with a low lateral density (~10(8) cm(-2)) on the nanoporous GaSe substrates. We exploit the 'vapor-liquid-solid' growth with low-melting metal (Ga) catalyst of PbSe crystalline branched nanostructures via a surface-defect assisted mechanism. PMID- 26511405 TI - Community motivations to engage in conservation behavior to conserve the Sumatran orangutan. AB - Community-based conservation programs in developing countries are often based on the assumption that heteronomous motivation (e.g., extrinsic incentives such as economic rewards and pressure or coercion to act) will incite local communities to adopt conservation behaviors. However, this may not be as effective or sustainable as autonomous motivations (e.g., an intrinsic desire to act due to inherent enjoyment or self-identification with a behavior and through freedom of choice). We analyzed the comparative effectiveness of heteronomous versus autonomous approaches to community-based conservation programs through a case study of Sumatran orangutan (Pongo abelii) conservation in 3 villages in Indonesia. Each village had a different conservation program design. We surveyed people (n = 240) to determine their motivations for and behavior changes relative to orangutan and orangutan habitat (forest) protection. Heteronomous motivations (e.g., income from tourism) led to greater self-reporting of behavior change toward orangutan protection. However, they did not change self-reported behavior toward forest (i.e., orangutan habitat) protection. The most effective approach to creating self-reported behavior change throughout the community was a combination of autonomous and heteronomous motivations. Individuals who were heteronomously motivated to protect the orangutan were more likely to have changed attitudes than to have changed their self-reported behavior. These findings demonstrate that the current paradigm of motivating communities in developing countries to adopt conservation behaviors primarily through monetary incentives and rewards should consider integrating autonomous motivational techniques that promote the intrinsic values of conservation. Such a combination has a greater potential to achieve sustainable and cost-effective conservation outcomes. Our results highlight the importance of using in-depth sociopsychological analyses to inform the design and implementation of community based conservation programs. PMID- 26511406 TI - Put older people on the agenda. AB - England's chief nurse Jane Cummings is developing a new nursing strategy ( page 8 ). The existing strategy, Compassion in Practice, had little to say about how nursing would respond to the needs of the growing older population. Despite this, nurses are taking the initiative, developing roles in comprehensive old age assessment and care management for frail older people. PMID- 26511407 TI - RCN online resource provides advice on end of life care. AB - A new online resource for end of life care has been published by the RCN in response to calls by thousands of nurses for more advice on caring for terminally ill patients. PMID- 26511408 TI - Nursing homes need their funding to be 'doubled' to survive. AB - The government needs to 'double' the amount that it pays private nursing homes for NHS-funded nursing care if home closures are to be avoided. PMID- 26511411 TI - Europe unites to boost active ageing and prevent falls. AB - The British Geriatrics Society (BGS) has issued a joint commitment, along with 16 other European organisations, to promote active ageing through falls prevention. PMID- 26511413 TI - Looking forward: the chief nurse's strategy. AB - Over the next few weeks, chief nursing officer (CNO) for England Jane Cummings and her team will draw up the first draft of a new nursing and midwifery strategy. PMID- 26511414 TI - London is a divided city for provision of end of life care. AB - The first map of specialist palliative care (SPC) provision and access in London reveals huge variations in service quality. PMID- 26511415 TI - Tackling problems on the home front. AB - The NHS in England has been urged to do more to support home care services for older people in guidance published by the National Institute for Health and Care Excellence (NICE). PMID- 26511421 TI - Practice question. AB - Physiotherapists work with patients to restore, improve or maintain their function and enhance their quality of life. They work autonomously but in conjunction with patients and, if necessary, the rest of each multidisciplinary team to assess, diagnose and create treatment plans. Some physiotherapists have extended their scope of practice to order and interpret investigations, such as X rays and blood tests, and to perform joint injections and prescribe medications ( Chartered Society of Physiotherapy (CSP) 2015 ). PMID- 26511422 TI - Improving the hospital environment for people with dementia. AB - This article is the third in a series presenting examples of the positive work achieved by trusts who participated in the Royal College of Nursing's development programme to improve dementia care in acute hospitals. The hospital environment is often disorientating for people with dementia and can be particularly distressing when a patient is admitted in an emergency. Subsequent ward moves can also be disruptive and confusing, especially if they take place out of hours. Two NHS trusts aimed to improve the experience for patients with dementia by addressing the physical environment along with practical aspects of care provision at different stages in the hospital journey. The Queen Elizabeth Hospital King's Lynn NHS Foundation Trust in Norfolk enhanced its emergency department environment by redesigning four bays and an observation area to be dementia-friendly. The hospital has supported these changes by providing dementia awareness training for all staff in these areas. Walsall Healthcare NHS Trust focused on minimising ward moves by implementing procedures to identify patients who should not be moved. Since introducing the new process, adherence has been good and there have been fewer ward moves. PMID- 26511423 TI - Nurse-led management of chronic disease in a residential care setting. AB - Introduction of the advanced nurse practitioner (ANP) role has enabled nurses to develop their clinical knowledge and skills, providing greater service provision and improved access to healthcare services. It can also help with the challenges of providing care to an ageing population in primary care. This article reports on the evaluation of an ANP-led clinic in two residential care homes that provides annual reviews for chronic disease management (CDM). A mixed method approach was used to evaluate the service using clinical data obtained from the electronic patient record system and software and patient satisfaction questionnaires. The number of patients receiving CDM reviews in the homes increased as a result of the clinic. Completed satisfaction questionnaires further demonstrated patients' satisfaction and willingness to engage with the service. The service highlights the ANP's effectiveness in managing residential care home patients with chronic diseases and improving their access to healthcare services. PMID- 26511424 TI - Identifying and managing patients with delirium in acute care settings. AB - Delirium is an acute medical emergency affecting about one in eight acute hospital inpatients. It is associated with poor outcomes, is more prevalent in older people and it is estimated that half of all patients receiving intensive care or surgery for a hip fracture will be affected. Despite its prevalence and impact, delirium is not reliably identified or well managed. Improving the identification and management of patients with delirium has been a focus for the national improving older people's acute care work programme in NHS Scotland. A delirium toolkit has been developed, which includes the 4AT rapid assessment test, information for patients and carers and a care bundle for managing delirium based on existing guidance. This toolkit has been tested and implemented by teams from a range of acute care settings to support improvements in the identification and immediate management of delirium. PMID- 26511425 TI - Dementia Friends sessions for nursing students. AB - All health and social care students must learn about dementia in the curriculum. This article explains how Dementia Friends sessions, which aim to raise awareness about dementia, were delivered in the students' induction at one university. The objective was for all new students to understand some important facts about dementia, thus addressing any misconceptions at an early stage and establishing a foundation for further learning. The sessions were evaluated through an analysis of written comments, which indicated that nursing students enjoyed the sessions and had learnt the five facts about dementia. Students intended to apply their learning through: changes in attitudes and interactions, raising awareness, volunteering, supporting people with dementia in the community, seeking further knowledge and personal support to their families. After this positive response, Dementia Friends sessions will continue to be delivered during induction for undergraduate health and social care students. PMID- 26511426 TI - The caring touch. AB - If Catherine Malia had not become a nurse, she would like to have been a florist. As nurse consultant at St Gemma's Hospice in Leeds, her flower arranging skills have come in handy on more than one occasion. PMID- 26511427 TI - To Madagascar and back: long-distance, return migration across open ocean by a pregnant female bull shark Carcharhinus leucas. AB - A large, pregnant, female bull shark Carcharhinus leucas was tracked migrating from Seychelles across open ocean to south-east Madagascar, c. 2000 km away, and back again. In Madagascar, the shark spent a prolonged period shallower than 5 m, consistent with entering estuarine habitat to pup, and upon return to Seychelles the shark was slender and no longer gravid. This represents an unprecedented return migration across the open ocean for a C. leucas and highlights the need for international collaboration to manage the regional C. leucas population sustainably. PMID- 26511428 TI - Vitamin A dietary supplementation reduces the mortality of velogenic Newcastle disease significantly in cockerels. AB - This project was undertaken to find ways of reducing mortalities and economic losses due to velogenic Newcastle disease (VND) in areas where the disease is enzootic. Four groups of cockerels of 44 birds each were used for this experiment. The birds in groups 1 and 2 received no dietary vitamin A supplementation, whereas groups 3 and 4 received 300 iu and 600 iu of vitamin A per kilogram of commercial feed, respectively, from 1 week of age till the end of the experiment. At 6 weeks of age, the birds in groups 2, 3 and 4 were inoculated intraocularly with a VND virus (duck/Nigeria/Plateau/Kuru/113/1991). The birds in Group 1 were given phosphate-buffered saline intraocularly. Clinical signs appeared in Group 2 birds on day 3 PI and in groups 3 and 4 on day 5 PI. The clinical signs included a drop in feed and water consumption, depression, diarrhoea, torticollis and paralysis in all the infected groups. The average body weights of all groups were significantly different from one another on day 14 PI with Group 2 birds having the lowest body weight. Mortalities were highest in Group 2 birds (0%, 93.18%, 72.73% and 56.82% in groups 1, 2, 3 and 4 respectively). The antibody response in all the groups was significantly different from one another on days 14 and 21 PI. Group 2 birds had the lowest titres on those 2 days and showed more severe atrophy of the bursa, spleen, thymus and fibrin deposition in the spleen and thymus than the birds in groups 3 and 4. The above observations show that vitamin A dietary supplementation delayed the onset of clinical signs and significantly reduced body weight loss, atrophy of the bursa, spleen and thymus, and mortalities by 36%. It also significantly potentiated haemagglutination inhibition antibody response. PMID- 26511429 TI - False-positive Extra-Mammary Findings in Breast MRI: Another Cause for Concern. AB - Breast magnetic resonance imaging (MRI) has been repeatedly shown to have a high false-positive rate for additional findings in the breast resulting in additional breast imaging and biopsies. We hypothesize that breast MRI is also associated with a high rate of false-positive findings outside of the breast requiring additional evaluation, interventions, and delays in treatment. We performed a retrospective review of all breast MRIs performed on breast cancer patients in 2010 at a single institution. MRI reports were analyzed for extra-mammary findings. The timing and yield of the additional procedures was also analyzed. Three hundred and twenty-seven breast cancer patients (average age = 53.53 +/- 11.08 years) had a breast MRI. Incidental, extra-mammary findings were reported in 35/327 patients (10.7%) with a total of 38 incidental findings. The extra mammary findings were located in the liver (n = 21, 60.0%), thoracic cavity (n = 12, 34.3%), kidneys (n = 1, 2.9%), musculoskeletal system (n = 3, 8.6%), and neck (n = 1, 2.9%). Eighteen of the 35 patients (51.4%) received additional radiographic imaging, 3 (8.6%) received additional laboratory testing, 2 (5.7%) received additional physician referrals and 2 (5.7%) received a biopsy of the finding. The average time to additional procedures in these patients was 14.5 days. None of the incidental, extra-mammary findings were associated with breast cancer or other malignancy. Breast MRI was associated with a high rate (10.7%) of extra-mammary findings, which led to costly additional imaging studies, referrals, and tests. These findings were not associated with breast cancer or other malignancies. Extra-mammary findings highlight an unrecognized adverse consequence of breast MRI. PMID- 26511430 TI - Biodegradable nasal stents (MgF2 -coated Mg-2 wt %Nd alloy)-A long-term in vivo study. AB - Despite innovative surgical techniques and use of current frontal sinus stents from different materials, the problem of treatment failure with consecutive reoperation remains present. The aim of our study is to investigate biocompatibility, degradation kinetics, and functionality of a newly developed fluoride-coated magnesium-based nasal stent. A minipig anatomy of frontal sinus adapted design and an external surgical approach were developed and established. The functionality of the stents was evaluated endoscopically. The stent-tissue blocks were analysed after 90 and 180 days using microcomputed tomography (u-CT), histology, scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDS). Functional evaluation revealed an unobstructed stent lumen in all cases. Histological analysis showed moderate mucosal hyperplasia with a mild, nonspecific inflammatory response, and nonosteoconductive effect. Rejection reactions or necrosis did not occur. The volumetric analysis of the stents showed 51% volume loss after 180 days. The EDS analysis did not detect any neodymium (Nd) in the mucosa or bone. The Mg-2 wt % Nd stents are a promising option when treating the narrow passages following paranasal sinus surgery. In particular, its good biocompatibility and good functionality facilitate the re-epithelization of these constricted passages. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 350-365, 2017. PMID- 26511431 TI - Developmental programming of energy balance regulation: is physical activity more 'programmable' than food intake? AB - Extensive human and animal model data show that environmental influences during critical periods of prenatal and early postnatal development can cause persistent alterations in energy balance regulation. Although a potentially important factor in the worldwide obesity epidemic, the fundamental mechanisms underlying such developmental programming of energy balance are poorly understood, limiting our ability to intervene. Most studies of developmental programming of energy balance have focused on persistent alterations in the regulation of energy intake; energy expenditure has been relatively underemphasised. In particular, very few studies have evaluated developmental programming of physical activity. The aim of this review is to summarise recent evidence that early environment may have a profound impact on establishment of individual propensity for physical activity. Recently, we characterised two different mouse models of developmental programming of obesity; one models fetal growth restriction followed by catch-up growth, and the other models early postnatal overnutrition. In both studies, we observed alterations in body-weight regulation that persisted to adulthood, but no group differences in food intake. Rather, in both cases, programming of energy balance appeared to be due to persistent alterations in energy expenditure and spontaneous physical activity (SPA). These effects were stronger in female offspring. We are currently exploring the hypothesis that developmental programming of SPA occurs via induced sex-specific alterations in epigenetic regulation in the hypothalamus and other regions of the central nervous system. We will summarise the current progress towards testing this hypothesis. Early environmental influences on establishment of physical activity are likely an important factor in developmental programming of energy balance. Understanding the fundamental underlying mechanisms in appropriate animal models will help determine whether early life interventions may be a practical approach to promote physical activity in man. PMID- 26511432 TI - Psychiatric Prescribers' Experiences With Doctor Shoppers. AB - Doctor shopping is a primary method of prescription medication diversion. After opioids, benzodiazepines and stimulants are the next most common prescription medications used nonmedically. Studies have shown that patients who engage in doctor shopping find it fun, exciting, and easy to do. There is a lack of research on the prescriber's perspective on the phenomenon of doctor shopping. This study investigates the experiences of prescribers in psychiatry with patients who engage in doctor shopping. Fifteen prescribers including psychiatrists and psychiatric nurse practitioners working in outpatient psychiatry were interviewed to elicit detailed information about their experiences with patients who engage in doctor shopping. Themes found throughout the interview were that psychiatric prescribers' experience with patients who engage in doctor shopping includes (a) detecting red flags, (b) negative emotional responding, (c) addressing the patient and the problem, and (d) inconsistently implementing precautions. When red flags were detected when prescribing controlled drugs, prescribers in psychiatry experienced both their own negative emotional responses such as disappointment and resentment as well as the negative emotions of the patients such as anger and other extreme emotional responses. Psychiatric prescribers responded to patient's doctor shopping in a variety of ways such as changing their practice, discharging the patients or taking steps to not accept certain patients identified as being at risk for doctor shopping, as well as by talking to the patient and trying to offer them help. Despite experiencing doctor shopping, the prescribers inconsistently implemented precautionary measures such as checking prescription drug monitoring programs. PMID- 26511433 TI - "Yoga Was My Saving Grace": The Experience of Women Who Practice Prenatal Yoga. AB - BACKGROUND: Approximately 20% of women in the United States practice prenatal yoga, but there is a paucity of information about the experience of these women. OBJECTIVE: This study examines women's experiences participating in community based prenatal yoga. METHOD: A qualitative descriptive exploratory design used focus groups with a convenience sample of pregnant and postpartum women (n = 14) who engaged in prenatal yoga within the previous 6 months. Content analysis was employed to identify key themes and subthemes. RESULTS: Three themes arose: (a) stress and depressive symptoms commonly instigate women's interest in prenatal yoga, (b) prenatal yoga is perceived to be psychologically and physically beneficial, and (c) prenatal yoga is perceived as more beneficial than other group classes. CONCLUSIONS: Pregnant women with stress and depressive symptoms may be drawn to prenatal yoga for the psychological and physical benefits. It is imperative that health care providers and researchers focus on these needs, particularly when designing prevention and intervention strategies with this population. PMID- 26511434 TI - Evidence for the Implementation of the Early Start Denver Model for Young Children With Autism Spectrum Disorder. AB - BACKGROUND: The Early Start Denver Model (ESDM) is a manualized comprehensive therapy for toddlers with autism spectrum disorder. It emphasizes interpersonal engagement through synchrony, rhythms, and reciprocity to decrease symptom severity and accelerate cognitive, social-emotional, and language development. OBJECTIVE: To systematically review evidence regarding the use of the ESDM as an intervention for young children with autism spectrum disorder. DESIGN: PubMed, Scopus, Web of Science, Embase, and CINAHL were searched from 2010-2015 using predetermined inclusion criteria. Study methodology, participant characteristics, and outcomes were evaluated and quality of evidence was assigned. RESULTS: Eight articles met inclusion criteria and consisted of two randomized controlled trials, four controlled trials, and two observational cohort studies. Evidence quality ranged from low to high. CONCLUSIONS: The ESDM is an effective intervention that improves cognition, language, and adaptive behavior. ESDM strategies delivered in community group settings and in the home by parents have potential to be efficacious and feasible. PMID- 26511435 TI - A Clinical Translation of the Article Titled "Evidence for the Implementation of the Early Start Denver Model for Young Children With Autism Spectrum Disorder". AB - The purpose of this article is to offer a clinical translation of a literature review titled "Evidence for the Implementation of the Early Start Denver Model for Young Children With Autism Spectrum Disorder" by Ryberg (2015). The literature review was conducted to determine the strength of the research evidence regarding the effectiveness of the Early Start Denver Model in improving cognitive, language, and behavioral functioning of children with autism spectrum disorder. In an effort to narrow the gap between evidence and practice, this clinical translation will discuss the components of the literature review in terms of its rationale for and objectives, methods, results, and implications for evidence-based nursing practice. PMID- 26511436 TI - The IOM Report on Psychosocial Interventions for Mental and Substance Use Disorders: Opportunities for Psychiatric-Mental Health Nurses. PMID- 26511437 TI - Unlocking Electronic Health Record Data Helps Drive Behavioral Health Population Management. PMID- 26511438 TI - Neuroprotective activity of stiripentol with a possible involvement of voltage dependent calcium and sodium channels. AB - A growing body of data has shown that recurrent epileptic seizures may be caused by an excessive release of the excitatory neurotransmitter glutamate in the brain. Glutamatergic overstimulation results in massive neuronal influxes of calcium and sodium through N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid, and kainic acid glutamate subtype receptors and also through voltage-gated calcium and sodium channels. These persistent and abnormal sodium and calcium entry points have deleterious consequences (neurotoxicity) for neuronal function. The therapeutic value of an antiepileptic drug would include not only control of seizure activity but also protection of neuronal tissue. The present study examines the in vitro neuroprotective effects of stiripentol, an antiepileptic compound with gamma-aminobutyric acidergic properties, on neuronal-astroglial cultures from rat cerebral cortex exposed to oxygen-glucose deprivation (OGD) or to glutamate (40 uM for 20 min), two in vitro models of brain injury. In addition, the affinity of stiripentol for the different glutamate receptor subtypes and the interaction with the cell influx of Na(+) and of Ca(2+) enhanced by veratridine and NMDA, respectively, are assessed. Stiripentol (10-100 uM) included in the culture medium during OGD or with glutamate significantly increased the number of surviving neurons relative to controls. Stiripentol displayed no binding affinity for different subtypes of glutamate receptors (IC50 >100 uM) but significantly blocked the entry of Na(+) and Ca(2+) activated by veratridine and NMDA, respectively. These results suggest that Na(+) and Ca(2+) channels could contribute to the neuroprotective properties of sitiripentol. PMID- 26511439 TI - Rui Wang. PMID- 26511440 TI - Catenanes: A molecular mechanics analysis of the (C13H26)2 Structure 13-13 D2. AB - Molecular mechanics (MM4) studies have been carried out on the catenane (C13H26)2, specifically 13-13D2. The structure obtained is in general agreement with second-order perturbation theory. More importantly, the MM4 structure allows a breakdown of the energy of the molecule into its component classical parts. This allows an understanding of why the structure is so distorted, in terms of C C bonding and nonbonding interactions, van der Waals repulsion, C-C-C and C-C-H angle bending, torsional energies, stretch-bend, torsion-stretch, and bend torsion-bend interactions. Clearly, the hole in 113-membered ring is too small for the other ring to fit through comfortably. There are too many atoms trying to fit into the limited space at the same time, leading to large van der Waals repulsions. The rings distort in such a way as to enlarge this available space, and lower the total energy of the molecule. While the distortions are spread around the rings, one of the nominally tetrahedral C-C-C bond angles in each ring is opened to 147.9 degrees by MM4 (146.8 degrees by MP2). The stability of the compound is discussed in terms of the strain energy. PMID- 26511441 TI - Vascular expression of annexin A2 in lupus nephritis. AB - AIMS: To evaluate vascular expression of annexin A2 (ANXA2) and its subunit S100A10 in lupus nephritis (LN). METHODS: The present histological study included 14 patients with LN and 11 controls (patients with non-lupus kidney diseases). Kidney biopsies from patients with lupus were scored for lupus glomerulonephritis (according to the International Society of Nephrology/Renal Pathology Society 2003 classification) and vascular lesions (such as microthrombi and antiphospholipid syndrome nephropathy (APSN)). ANXA2 and S100A10 expression in glomerular and peritubular capillaries was evaluated by immunohistochemistry on tissue sections. The staining intensity score ranged from 0 (no expression) to 4 (intense expression). RESULTS: In patients with LN, the median age (range) at first kidney biopsy was 36 (18-49). Vascular lesions were observed in six patients (including two with APSN). We observed intense expression of ANXA2 in glomerular and peritubular capillaries while expression of S100A10 was weaker. However, one of the patients with APSN showed strong S100A10 expression. Patients with LN and controls differed significantly in terms of S100A10 expression in peritubular capillaries. We also observed a statistical difference between patients who had LN with renal vascular lesions and those without renal vascular lesions in terms of ANXA2 expression in peritubular capillaries. CONCLUSIONS: The presence of vascular lesions in LN appears to be associated with significant differences in the vascular expression of ANXA2. Vascular expression of ANXA2 was somewhat higher in LN. Vascular expression of S100A10 was somewhat lower in LN (except one of the two patients with APSN). Further studies of ANXA2's putative value as a biomarker of active LN or of vascular lesions in LN are required. PMID- 26511442 TI - Testing the accelerator hypothesis: a new approach to type 1 diabetes prevention (adAPT 1). PMID- 26511443 TI - Relationship between symptoms of dry eye syndrome and occupational characteristics: the Korean National Health and Nutrition Examination Survey 2010 2012. AB - BACKGROUND: Dry Eye Syndrome (DES) is a broad spectrum of uncomfortable ocular conditions that are caused by reduced production of tears or an increased tear evaporation rate. This study evaluated the relationship between symptoms of DES and occupational characteristics to identify the occupation-dependent differences in the prevalence of symptoms of DES using the Korean National Health and Nutrition Examination Survey V (2010-2012) data. METHODS: A total of 6023 participants were included (3203 men and 2820 women). Questionnaires and physical examinations were used to record clinical characteristics, occupational characteristics and medical history. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for symptoms of DES were calculated according to the occupational characteristics. RESULTS: Among the participants, 963 persons (16.0 %) had symptoms of DES. An increased risk (relative to the green-collar group) was observed for the ordinary white-collar (OR, 1.73; 95 % CI, 1.73-1.41), executive white-collar (OR, 1.40; 95 % CI, 1.02-1.92) and skilled blue-collar (OR, 1.44; 95 % CI, 1.04-2.00) groups. Furthermore, paid workers had a significantly higher risk of dry eye symptoms (OR, 1.21; 95 % CI, 1.02-1.45), compared to self-employed workers. CONCLUSION: Our study is the first research to reveal that white-collar workers have a higher risk of symptoms of DES than blue collar workers, that skilled blue-collar workers have a higher risk than unskilled blue-collar workers, and that paid workers have a higher risk than self employed workers. PMID- 26511444 TI - Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms. AB - BACKGROUND: There are no specific treatments for the neurological alterations of cirrhotic patients with minimal hepatic encephalopathy (MHE). Rats with MHE due to portacaval shunt (PCS) show impaired spatial learning. The underlying mechanisms remain unknown. The aims of this work were to assess: (a) whether PCS rats show neuroinflammation in hippocampus, (b) whether treatment with sildenafil reduces neuroinflammation and restores spatial learning in PCS rats, and (c) analyze the underlying mechanisms. METHODS: Neuroinflammation was assessed by determining inflammatory markers by Western blot. Phosphorylation of MAP-kinase p38 was assessed by immunohistochemistry. Membrane expression of GABA and glutamate receptors was analyzed using BS3 cross-linker. Spatial learning was analyzed using the radial and Morris water mazes. To assess if sildenafil reverses the alterations, rats were treated with sildenafil in the drinking water. RESULTS: PCS rats show increased IL-1beta and TNF-alpha levels and phosphorylation (activity) of p38 in hippocampus. Membrane expression of subunits alpha1 of GABAA receptor and GluR2 of AMPA receptor are increased in PCS rats, while subunits GluR1 of AMPA receptors and NR1 and NR2a of NMDA receptors are reduced. PCS rats show reduced spatial learning in the radial and Morris water mazes. Sildenafil treatment normalizes IL-1beta and TNF-alpha levels, p38 phosphorylation, and membrane expression of GABAA, AMPA, and NMDA receptors and restores spatial learning. CONCLUSIONS: Increased IL-1beta alters GABAergic and glutamatergic neurotransmission in hippocampus and impairs spatial learning in rats with MHE. Sildenafil reduces neuroinflammation and restores learning. Phosphodiesterase-5 inhibitors may be useful to improve cognitive function in patients with MHE. PMID- 26511445 TI - Adenoidal follicular T helper cells provide stronger B-cell help than those from tonsils. AB - OBJECTIVES/HYPOTHESIS: The tonsils and adenoids are secondary lymphoid organs, where antigen processing and immune cell development occur to control bacterial colonization and infection in the upper respiratory tract. Both organs are abundant in follicular T helper cells (TFH), a subset of T cells specialized for promoting B-cell development. There are no prior studies on differences between the immune cells of the tonsils and adenoids and whether the cells function differently. STUDY DESIGN: In vitro assays to assess cell phenotype of tonsils and adenoids from young children (median age = 40 months). METHODS: Mononuclear cells from tonsils and adenoids were cultured with or without 1 ug/mL Staphylococcus enterotoxin B (SEB) for 4 days. Cell phenotype and function were assessed by flow cytometry and multiplex enzyme-linked immunosorbent assay. RESULTS: We found that in resting adenoids, TFH expressed higher CXCR5 and inducible costimulator but lower PD-1 than those from the tonsils, and that adenoidal B cells expressed higher CD27. Upon polyclonal stimulation with SEB, both TFH and B cells from the adenoids proliferated to a greater extent, and culture supernatants contained higher levels of interleukin 21. CONCLUSIONS: We conclude that the cells of the adenoid are disposed toward the provision of more robust B-cell help than the tonsils. LEVEL OF EVIDENCE: NA. PMID- 26511447 TI - Better meta-analytic methods, but best initial treatment for status epilepticus remains obscure. PMID- 26511446 TI - Peak shape clustering reveals biological insights. AB - BACKGROUND: ChIP-seq experiments are widely used to detect and study DNA-protein interactions, such as transcription factor binding and chromatin modifications. However, downstream analysis of ChIP-seq data is currently restricted to the evaluation of signal intensity and the detection of enriched regions (peaks) in the genome. Other features of peak shape are almost always neglected, despite the remarkable differences shown by ChIP-seq for different proteins, as well as by distinct regions in a single experiment. RESULTS: We hypothesize that statistically significant differences in peak shape might have a functional role and a biological meaning. Thus, we design five indices able to summarize peak shapes and we employ multivariate clustering techniques to divide peaks into groups according to both their complexity and the intensity of their coverage function. In addition, our novel analysis pipeline employs a range of statistical and bioinformatics techniques to relate the obtained peak shapes to several independent genomic datasets, including other genome-wide protein-DNA maps and gene expression experiments. To clarify the meaning of peak shape, we apply our methodology to the study of the erythroid transcription factor GATA-1 in K562 cell line and in megakaryocytes. CONCLUSIONS: Our study demonstrates that ChIP seq profiles include information regarding the binding of other proteins beside the one used for precipitation. In particular, peak shape provides new insights into cooperative transcriptional regulation and is correlated to gene expression. PMID- 26511448 TI - Efficacy of nonvenous medications for acute convulsive seizures: A network meta analysis. AB - OBJECTIVE: This is a network meta-analysis of nonvenous drugs used in randomized controlled trials (RCTs) for treatment of acute convulsive seizures and convulsive status epilepticus. METHODS: Literature was searched according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for RCTs examining treatment of acute convulsive seizures or status epilepticus with at least one of the study arms being a nonvenous medication. After demographic and outcome data extraction, a Bayesian network meta-analysis was performed and efficacy results were summarized using treatment effects and their credible intervals (CrI). We also calculated the probability of each route-drug combination being the most clinically effective for a given outcome, and provided their Bayesian hierarchical ranking. RESULTS: This meta-analysis of 16 studies found that intramuscular midazolam (IM-MDZ) is superior to other nonvenous medications regarding time to seizure termination after administration (2.145 minutes, 95% CrI 1.308-3.489), time to seizure cessation after arrival in the hospital (3.841 minutes, 95% CrI 2.697-5.416), and time to initiate treatment (0.779 minutes, 95% CrI 0.495-1.221). Additionally, intranasal midazolam (IN-MDZ) was adjudged most efficacious for seizure cessation within 10 minutes of administration (90.4% of participants, 95% CrI 79.4%-96.9%), and persistent seizure cessation for >=1 hour (78.5% of participants, 95% CrI 59.5%-92.1%). Paucity of RCTs produced evidence gaps resulting in small networks, routes/drugs included in some networks but not others, and some trials not being connected to any network. CONCLUSIONS: Despite the evidence gaps, IM-MDZ and IN-MDZ exhibit the best efficacy data for the nonvenous treatment of acute convulsive seizures or status epilepticus. PMID- 26511449 TI - Angiogenesis: A new paradigm for Parkinson disease with practical and pathogenic implications. PMID- 26511451 TI - Increased CSF biomarkers of angiogenesis in Parkinson disease. AB - OBJECTIVE: To study biomarkers of angiogenesis in Parkinson disease (PD), and how these are associated with clinical characteristics, blood-brain barrier (BBB) permeability, and cerebrovascular disease. METHODS: In this cross-sectional analysis, 38 elderly controls and 100 patients with PD (82 without dementia and 18 with dementia) were included from the prospective Swedish BioFinder study. CSF samples were analyzed for the angiogenesis biomarkers vascular endothelial growth factor (VEGF); its receptors, VEGFR-1 and VEGFR-2; placental growth factor (PlGF); angiopoietin 2 (Ang2); and interleukin-8. BBB permeability, white matter lesions (WMLs), and cerebral microbleeds (CMB) were assessed. CSF angiogenesis biomarkers were also measured in 2 validation cohorts: (1) 64 controls and 87 patients with PD with dementia; and (2) 35 controls and 93 patients with neuropathologically confirmed diagnosis of PD with and without dementia. RESULTS: Patients with PD without dementia displayed higher CSF levels of VEGF, PlGF, and sVEGFR-2, and lower levels of Ang2, compared to controls. Similar alterations in VEGF, PlGF, and Ang2 levels were observed in patients with PD with dementia. Angiogenesis markers were associated with gait difficulties and orthostatic hypotension as well as with more pronounced BBB permeability, WMLs, and CMB. Moreover, higher levels of VEGF and PlGF levels were associated with increased CSF levels of neurofilament light (a marker of neurodegeneration) and monocyte chemotactic protein-1 (a marker of glial activation). The main results were validated in the 2 additional cohorts. CONCLUSIONS: CSF biomarkers of angiogenesis are increased in PD, and they are associated with gait difficulties, BBB dysfunction, WMLs, and CMB. Abnormal angiogenesis may be important in PD pathogenesis and contribute to dopa-resistant symptoms. PMID- 26511452 TI - Memory complaints and risk of cognitive impairment after nearly 2 decades among older women. AB - OBJECTIVES: To investigate the association between subjective memory complaints (SMCs) and long-term risk of cognitive impairment in aging because most previous studies have followed individuals for only a few years. METHODS: Participants were 1,107 cognitively normal, community-dwelling older women (aged 65 years and older at baseline) in a prospective study of aging. SMCs were assessed shortly after baseline and repeatedly over time with the yes/no question, "Do you feel you have more problems with memory than most?" Cognitive status 18 years later (normal or impaired with mild cognitive impairment or dementia) was determined by an expert panel. Using logistic regression, we investigated the association between SMCs over time and risk of cognitive impairment, adjusting for demographics, baseline cognition, and characteristics that differed between those with and without SMCs. RESULTS: At baseline, 8.0% of participants (n = 89) endorsed SMCs. Baseline SMCs were associated with increased risk of cognitive impairment 18 years later (adjusted odds ratio [OR] = 1.7, 95% confidence interval 1.1-2.8). Results were unchanged after excluding participants with depression. The association between SMCs and cognitive impairment was greatest at the last SMC assessment time point (18 years before diagnosis: adjusted OR = 1.7 [1.1-2.9]; 14 years before diagnosis: adjusted OR = 1.6 [0.9-2.7]; 10 years before diagnosis: adjusted OR = 1.9 [1.1-3.1]; 4 years before diagnosis: adjusted OR = 3.0 [1.8-5.0]). CONCLUSIONS: SMCs are associated with cognitive impairment nearly 2 decades later among older women. SMCs may be a very early symptom of an insidious neurodegenerative disease process, such as Alzheimer disease. PMID- 26511450 TI - Risk of rupture of unruptured cerebral aneurysms in elderly patients. AB - OBJECTIVES: The aim of this study was to identify risk factors for rupture of unruptured cerebral aneurysms (UCAs) in elderly Japanese patients aged 70 years or older. METHODS: The participants included all patients 70 years of age or older in 3 prospective studies in Japan (the Unruptured Cerebral Aneurysm Study of Japan [UCAS Japan], UCAS II, and the prospective study at the Jikei University School of Medicine). A total of 1,896 patients aged 70 years or older with 2,227 UCAs were investigated. The median and mean follow-up periods were 990 and 802.7 days, respectively. RESULTS: The mean aneurysm size was 6.2 +/- 3.9 mm. Sixty eight patients (3.6%) experienced subarachnoid hemorrhage during the follow-up period. Multivariable analysis per patient revealed that in patients aged 80 years or older (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.16-3.49, p = 0.012), aneurysms 7 mm or larger (HR, 3.08; 95% CI, 1.35-7.03, p = 0.007 for 7-9 mm; HR, 7.82; 95% CI, 3.60-16.98, p < 0.001 for 10-24 mm; and HR, 43.31; 95% CI, 12.55-149.42, p < 0.001 for >=25 mm) and internal carotid-posterior communicating artery aneurysms (HR, 2.45; 95% CI, 1.23-4.88, p = 0.011) were independent predictors for UCA rupture in elderly patients. CONCLUSIONS: In our pooled analysis of prospective cohorts in Japan, patient age and aneurysm size and location were significant risk factors for UCA rupture in elderly patients. PMID- 26511454 TI - Comment: Diagnosing stroke in acute dizziness-Do the "eyes" still have it? PMID- 26511453 TI - Stroke risk stratification in acute dizziness presentations: A prospective imaging-based study. AB - OBJECTIVE: To estimate the ability of bedside information to risk stratify stroke in acute dizziness presentations. METHODS: Surveillance methods were used to identify patients with acute dizziness and nystagmus or imbalance, excluding those with benign paroxysmal positional vertigo, medical causes, or moderate to severe neurologic deficits. Stroke was defined as acute infarction or intracerebral hemorrhage on a clinical or research MRI performed within 14 days of dizziness onset. Bedside information comprised history of stroke, the ABCD(2) score (age, blood pressure, clinical features, duration, and diabetes), an ocular motor (OM)-based assessment (head impulse test, nystagmus pattern [central vs other], test of skew), and a general neurologic examination for other CNS features. Multivariable logistic regression was used to determine the association of the bedside information with stroke. Model calibration was assessed using low (<5%), intermediate (5% to <10%), and high (>=10%) predicted probability risk categories. RESULTS: Acute stroke was identified in 29 of 272 patients (10.7%). Associations with stroke were as follows: ABCD(2) score (continuous) (odds ratio [OR] 1.74; 95% confidence interval [CI] 1.20-2.51), any other CNS features (OR 2.54; 95% CI 1.06-6.08), OM assessment (OR 2.82; 95% CI 0.96-8.30), and prior stroke (OR 0.48; 95% CI 0.05-4.57). No stroke cases were in the model's low-risk probability category (0/86, 0%), whereas 9 were in the moderate-risk category (9/94, 9.6%) and 20 were in the high-risk category (20/92, 21.7%). CONCLUSION: In acute dizziness presentations, the combination of ABCD(2) score, general neurologic examination, and a specialized OM examination has the capacity to risk stratify acute stroke on MRI. PMID- 26511455 TI - Structural transition and superconductivity in hydrothermally synthesized FeX (X = S, Se). AB - Iron selenide obtained by mild hydrothermal reaction is not superconducting and exhibits a triclinic crystal structure below 60 K unlike superconducting FeSe from conventional solid state synthesis which is orthorhombic. In contrast, tetragonal iron sulphide FeS from hydrothermal synthesis is superconducting but undergoes no structural change on cooling. PMID- 26511456 TI - Faculty of Radiation Oncology 2014 workforce census. AB - INTRODUCTION: This paper reports the key findings of the Faculty of Radiation Oncology 2014 workforce census and compares the results with earlier surveys. METHODS: The census was conducted in mid-2014 with distribution to all radiation oncologists, educational affiliates and trainees listed on the college database. There were six email reminders and responses were anonymous. The overall response rate was 76.1%. RESULTS: The age range of fellows was 32-96 (mean = 49 years, median = 47 years). The majority of the radiation oncologists were male (n = 263, 63%). The minority of radiation oncologists were of Asian descent (n = 43, 13.4%). Radiation oncologists graduated from medical school on average 23 years ago (median = 22 years). A minority of fellows (n = 66, 20%) held another postgraduate qualification. Most radiation oncologists worked, on average, at two practices (median = 2, range 1-7). Practising radiation oncologists worked predominantly in the public sector (n = 131, 49%), but many worked in both the public and private sectors (n = 94, 37%), and a minority worked in the private sector only (n = 38, 14%). The largest proportion of the workforce was from New South Wales accounting for 29% of radiation oncologists. Radiation oncologists worked an average of 43 h/week (median = 43 h, range 6-80). Radiation oncologists who worked in the private sector worked less hours than their public sector or public/private sector colleagues. (38.3 vs. 42.9 vs. 44.3 h, P = 0.042). Victorians worked the fewest average hours per week at 38 h and West Australians the most at 46 h/week. Radiation oncologists averaged 48 min for each new case, 17 min per follow up and 11 min for a treatment review. Radiation oncologists averaged 246 new patients per year (median = 250, range = 20-600) with men (average = 268), Western Australians (average = 354) and those in private practice seeing more (average = 275). Most radiation oncologists considered themselves as specialists (n = 151, 60%), but nearly all those from South Australia were generalists (n = 15, 94%) as were three-quarters of those from private practice. A minority of radiation oncologist respondents (10%) intended to retire within 5 years with a further 16% within 10 years.There was a stabilisation of trainee numbers in Australia and New Zealand with no increase compared with 2010 (142 in 2014 vs. 143 in 2010). The most common age bracket for trainees remained 31-35 years. One-third of trainees were of Asian descent and nearly half held other degrees. The majority of trainees were satisfied with their career, but 30% were not entirely satisfied. Nearly half of trainee respondents would have reconsidered their choice of specialty had they known about the possible oversupply in the workforce with 12.4% undecided about continuing their career in radiation oncology. There were still 16% of trainees with no protected time during the working week, and a further 21% with only 1 h. Only one trainee respondent preferred to work in private practice, and job availability remained a concern for 89% of respondents. CONCLUSIONS: The radiation oncologist workforce numbers have increased at a much slower rate, and unemployment remained low. Many parameters remained similar to the 2010 survey. However, there has been a decrease in the average number of new patients seen per year, working hours and also a slight decrease in the time spent per new patient. The trainee numbers have stabilised, but job availability remained a concern. A significant proportion of trainees were not satisfied with their career. PMID- 26511457 TI - Cancer genomics: The relevance of extensive editing in tumour transcriptomes. PMID- 26511458 TI - Micronutrient treatment for children with emotional and behavioral dysregulation: a case series. AB - INTRODUCTION: In clinical studies of adults and children, broad-spectrum micronutrients (minerals and vitamins) have proven beneficial for improving mood regulation and attention. We report here pilot work whose primary objective was to evaluate the feasibility of studying micronutrient treatment in school-aged children with emotional and behavioral problems. Issues examined included feasibility of participant recruitment from a culturally diverse population, probability of sample retention for a 12-week trial, acceptability of the outcome measures, supplement adherence, as well as trends in treatment benefit. CASE PRESENTATION: The families of two boys (ages 5 and 6) and one girl (age 14) were invited to participate in a 12-week pilot trial of micronutrients carried out during the summer months. All children were enrolled in the private school at which future research was being considered. During the previous school year, all three had been extremely difficult to educate due to their inability to pay attention and learn, as well as their behavior problems. Although the two younger children had not been formally diagnosed, parents and teachers provided reports of hyperactivity and inability to focus on education in the classroom. The oldest child was often aggressive, and had been diagnosed with bipolar disorder, attention deficit hyperactivity disorder, and oppositional defiant disorder. All three children were Hispanic and spoke both Spanish and English. For 12 weeks, after signing consent forms, the children's parents provided weekly ratings on the parent-report Child Mania Rating Scale; the children consumed the micronutrient formula daily and provided a daily rating of how they felt. The parent ratings revealed significantly improved behavior, p = .002. Children's ratings approached the ideal level of 7, indicating "happy" self-reports. Parent interviews confirmed the weekly scores. Several feasibility questions were answered: all three children completed the 12-week trial, all scores were completed by parents and children, adherence to the protocol was excellent, and no adverse reactions emerged. CONCLUSIONS: Family physicians and pediatricians are often confronted with the challenge of improving the lives of families whose children experience school crises due to emotional and behavioral dysregulation. Three children, who participated in pilot work to determine the feasibility of further investigations, experienced impressive changes that clearly warrant both research and clinical exploration. PMID- 26511459 TI - Sudden Cardiac Death Despite a Functional Cardioverter-Defibrillator: The Case for Early and Aggressive Therapy for Ventricular Tachycardia in Selected Patients. AB - We present three cases within 11 months at a single institution of sustained VT that fell below the programmed detection rate of the patients' implantable cardioverter-defibrillators (ICDs), two of which continued until converting to an agonal VF that did not meet criteria for detection, and a third case that could not be successfully defibrillated after a prolonged period of VT. These episodes may be under-recognized due to the dependence of device diagnostic storage on programming and the post-mortem effort that is often required to review these events. Some patients, likely those with the most advanced heart failure, may not tolerate sustained ventricular tachycardia (VT) and may even die from ventricular arrhythmias without ever having a rhythm that meets detection criteria in a ventricular fibrillation (VF) zone. PMID- 26511460 TI - Pulmonary Annular Motion Velocity Assessed Using Doppler Tissue Imaging - Novel Echocardiographic Evaluation of Right Ventricular Outflow Tract Function. AB - BACKGROUND: We assessed whether measuring pulmonary annular motion velocity could serve as a novel method of evaluating right ventricular outflow tract (RVOT) performance in pediatric patients with heart disease. METHODS AND RESULTS: Tissue Doppler-derived pulmonary annular motion velocity was determined from the parasternal long-axis view of the RVOT. Pulmonary annular velocity was measured in children (age, 5-10 years) with an atrial septal defect (ASD), pulmonary arterial hypertension (PAH), surgically repaired tetralogy of Fallot (TOF) and healthy children (control). Pulmonary annular velocity waveforms comprised systolic bimodal (s1' and s2') and diastolic e' and a' waves in all groups. The peak velocity of s1' and s2' was significantly higher in the ASD group than in the controls (15.0+/-2.4 vs. 11.2+/-2.1 and 6.0+/-0.9 vs. 4.4+/-1.2 cm/s; P<0.01 and P<0.001, respectively). The s1' and s2' peak velocities were significantly lower in the PAH group (8.5+/-1.2 and 3.2+/-0.4 cm/s; P<0.05 for both), and in the group with TOF (5.3+/-2.2 and 3.4+/-1.4 cm/s; P<0.001 and P<0.05, respectively). The peak velocity of e' was significantly decreased in the PAH and TOF, compared with the control group (6.8+/-1.6 and 8.2+/-2.9 vs. 11.9+/-1.9 cm/s; P<0.001 for both). CONCLUSIONS: Pulmonary annular motion velocity determined using tissue Doppler imaging is a promising method of assessing RVOT function. PMID- 26511461 TI - Paramalleolar Arterial Bollinger Score in the Era of Diabetes and End-Stage Renal Disease - Usefulness for Predicting Operative Outcome of Critical Limb Ischemia. AB - BACKGROUND: The aim of this study was to evaluate the usefulness of paramalleolar arterial Bollinger score (PBS) for predicting postoperative outcome of infra popliteal bypass surgery for critical limb ischemia (CLI). METHODS AND RESULTS: A total of 104 consecutive patients (118 limbs) who underwent infra-popliteal (tibial or paramalleolar) arterial bypass surgery with an autologous vein conduit for the treatment of CLI (Rutherford 4-6) between January 2002 and December 2012 were classified according to PBS <=45 or >45. Postoperative outcome was compared between these groups. Primary outcomes were major adverse limb events plus perioperative death, and amputation-free survival (AFS). The secondary outcomes were overall survival, limb salvage and secondary graft patency. More than 80% of patients had either diabetes mellitus (DM) or end-stage renal disease (ESRD) and 30 patients with 36 limbs had PBS >45. Compared with the PBS <=45 group, the PBS >45 group had higher CVD and carotid stenosis rate, poor nutrition status and lower malignancy rate. On overall analysis, the PBS >45 group had worse outcome for AFS and survival but this was not statistically significant (P=0.12, NS). In DM or ESRD patients, the PBS >45 group had significantly worse outcome for both AFS (P=0.04, 0.02) and overall survival rate (P=0.04, 0.03). CONCLUSIONS: PBS successfully classified CLI patients with DM or ESRD who had worse outcome after infra-popliteal bypass surgery. PMID- 26511462 TI - Greater Severity of Neurological Defects in Women Admitted With Atrial Fibrillation-Related Stroke. AB - BACKGROUND: The magnitude of the CHA2DS2-VASc score is associated with not only stroke incidence but also long-term outcomes. The association between sex and initial stroke severity in AF-related cardioembolic stroke patients has not been clarified. The present study aimed to elucidate the risk factors for initial stroke severity among patients with cardioembolic stroke enrolled in a multicenter registry. METHODS AND RESULTS: We selected 12,701 patients (age, 77+/ 10 years; 5,653 women) with AF-related cardioembolic stroke from the Japan Standard Stroke Registry Study between January 2000 and July 2013. Indicators of National Institutes of Health Stroke Scale (NIHSS) scores at admission were identified using a multiple linear regression. Increased NIHSS scores positively correlated with CHA2DS2-VASc score (rho=0.197; P<0.001). The initial neurological deficits were more severe in women than in men (NIHSS scores, median [interquartile range] 14 [5-22] vs. 8 [3-18]; P<0.001). Multiple regression analysis revealed that higher age (standardized partial regression coefficient [beta] 0.162; P<0.001), female sex (beta 0.120; P<0.001), diabetes mellitus (beta 0.020; P=0.019), dyslipidemia (beta -0.076; P<0.001), congestive heart failure (beta 0.039; P<0.001), vascular disease (beta 0.030; P=0.001), prior stroke/TIA (beta 0.085; P<0.001) and prior anticoagulant use (beta -0.020; P=0.028) were associated with the NIHSS score at admission. CONCLUSIONS: Female sex was independently associated with the initial neurological severity among AF-related cardioembolic stroke patients. PMID- 26511463 TI - How to Avoid Adverse Events During Apixaban Therapy in Patients With Atrial Fibrillation. PMID- 26511464 TI - Usefulness and Limitation of Protein Mass Analysis. PMID- 26511465 TI - A systematic review of syphilis serological treatment outcomes in HIV-infected and HIV-uninfected persons: rethinking the significance of serological non responsiveness and the serofast state after therapy. AB - BACKGROUND: Syphilis remains a global public health threat and can lead to severe complications. In addition to resolution of clinical manifestations, a reduction in nontreponemal antibody titers after treatment is regarded as "proof of cure." However, some patients manifest < 4-fold decline ("serological non-response") or persistently positive nontreponemal titers despite an appropriate decline ("serofast") that may represent treatment failure, reinfection, or a benign immune response. To delineate these treatment phenomena, we conducted a systematic review of the literature regarding serological outcomes and associated factors among HIV-infected and -uninfected subjects. METHODS: Six databases (PubMed, Embase, CINAHL, Web of Science, Scopus, and BIOSIS) were searched with no date restrictions. Relevant articles that evaluated serological treatment responses and correlates of serological cure (>= four-fold decline in nontreponemal titers) were included. RESULTS: We identified 1693 reports in the literature, of which 20 studies met selection criteria. The median proportion of patients who had serological non-response was 12.1% overall (interquartile range, 4.9-25.6), but varied depending on the time points after therapy. The serofast proportion could only be estimated from 2 studies, which ranged from 35.2-44.4%. Serological cure was primarily associated with younger age, higher baseline nontreponemal titers, and earlier syphilis stage. The relationship between serological cure and HIV status was inconsistent; among HIV-infected patients, CD4 count and HIV viral load was not associated with serological cure. CONCLUSIONS: Serological non-response and the serofast state are common syphilis treatment outcomes, highlighting the importance of determining the immunological and clinical significance of persistent nontreponemal antibody titers after therapy. PMID- 26511466 TI - Evaluation of in vitro anti-inflammatory effects of crude ginger and rosemary extracts obtained through supercritical CO2 extraction on macrophage and tumor cell line: the influence of vehicle type. AB - BACKGROUND: Numerous plants from have been investigated due to their anti inflammatory activity and, among then, extracts or components of ginger (Zingiber officinale Roscoe) and rosemary (Rosmarinus officinalis L.), sources of polyphenolic compounds. 6-gingerol from ginger rhizome and carnosic acid and carnosol from rosemary leaves present anti-tumor, anti-inflammatory and antioxidant activities. However, the evaluation of the mechanisms of action of these and other plant extracts is limited due to their high hydrophobicity. Dimethylsulfoxide (DMSO) is commonly used as a vehicle of liposoluble materials to mammalian cells in vitro, presenting enhanced cell penetration. Liposomes are also able to efficiently deliver agents to mammalian cells, being capable to incorporate in their structure not only hydrophobic molecules, but also hydrophilic and amphiphilic compounds. Another strategy is based on the use of Pluronic F-68, a biocompatible low-foaming, non-ionic surfactant, to disperse hydrophobic components. Here, these three delivery approaches were compared to analyze their influence on the in vitro anti-inflammatory effects of ginger and rosemary extracts, at different concentrations, on primary mammalian cells and on a tumor cell line. METHODS: Ginger and rosemary extracts free of organic solvents were obtained by supercritical fluid extraction and dispersed in DMSO, Pluronic F 68 or liposomes, in variable concentrations. Cell viability, production of inflammatory mediators and nitric oxide (NO) release were measured in vitro on J774 cell line and murine macrophages primary culture stimulated with bacterial lipopolysaccharide and interferon-gamma after being exposed or not to these extracts. RESULTS: Ginger and rosemary extracts obtained by supercritical CO2 extraction inhibited the production of pro-inflammatory cytokines and the release of NO by peritoneal macrophages and J774 cells. The delivery vehicles influenced the anti-inflammatory effects. Comparatively, the ginger extract showed the highest anti-inflammatory activity on the tumor cell line. Controversially, rosemary extract dispersed on DMSO induced a more significant IL-1 and TNF-alpha reduction than ginger extract in primary macrophages. CONCLUSIONS: Amongst the tested delivery vehicles, DMSO was the most suitable, presenting reduced cytotoxicity, followed by Pluronic F-68 and liposomes, provably due to differences in their form of absorption, distribution and cellular metabolism. Co administration of liposomes and plant extracts may cause death of macrophages cells and induction of NO production. It can be concluded that some of the beneficial effects attributed to extracts of ginger and rosemary may be associated with the inhibition of inflammatory mediators due to their high antioxidant activity. However, these effects were influenced by the type of delivery vehicle. PMID- 26511467 TI - Nanomedicinal Approach of Getting Across the Brood-Brain Barrier with Nanomedicinal Nanoparticles. AB - Passage into the brain has always been a major challenge for medicine in order to treat malfunctions of the central nervous system (CNS). The blood-brain-barrier (BBB) is a physical obstacle that controls the entrance of substances -including pharmaceuticals- into the brain. The application of nanotechnology in medicine, namely nanomedicine, is rapidly evolving and opens new prospects for brain imaging and drug delivery into the brain. Nanomedicine when combined with nuclear medicine can offer new, promising and innovative means towards this direction through radiolabeled nanoparticles. Nanoparticles radiolabeled with beta(-), gamma- or beta(+)-emitters can cross the BBB and play major role in CNS imaging and/or drug delivery. PMID- 26511468 TI - Update on SAR Studies Toward New COX-1 Selective Inhibitors. AB - Few selective cyclooxygenase-1 (COX-1) inhibitors have been described up to now, although recent studies underlined the involvement of COX-1 in the carcinogenesis, pathogenesis of neuroinflammation, cardiovascular diseases and pain. Among the known COX-1 inhibitors none proved to be a good drug candidate, with the exception of mofezolac, that is clinically used as an analgesic drug. New selective inhibitors were very often discovered as a minor achievement during SAR investigations to discover selective COX-2 inhibitors (COXIBs). After a recognition of the new COX-1 inhibitors synthesized in the last five years, it was attempted to draw, for each chemical class, a structure which might highlight the determinant molecular features able to switch the selectivity towards the COX 1 isoform. Overall, this review could constitute a tool to a better design of novel selective COX-1 inhibitors, to be used in a disease theranostic approach targeting COX-1. PMID- 26511469 TI - Curcumin: A Natural Lead for Potential New Drug Candidates. AB - Curcumin (1) is a secondary metabolite of turmeric, derived from Curcuma longa L. and was shown to have many biological activities. One of the most interesting properties of curcumin (1) is the antitumour activity allied with the ability to act as a multidrug resistance (MDR) modulator. Several curcumin derivatives have been synthesized with the purpose of discovering more information about the mechanisms of action, to establish structure-activity relationships (SAR), and to overcome pharmacokinetic problems. Over the past few decades, more potent and more stable curcumin derivatives have emerged with potential as drug candidates. Some important SAR studies pointed out that the unstable alpha,beta-unsaturated diketone linker present in curcumin (1) may not be necessary for the antitumour activity; generally, shorter linkers result in more potent compounds than curcumin (1); the type of substituents and their substitution pattern are crucial regarding the biological activities of interest. Overall, the structure of curcumin (1) may represent an important basis for the development of more effective therapeutic agents, particularly in chemotherapy, as reflected by ongoing clinical trials. This article aims to review the synthesis and biological activities of curcumin (1) and derivatives, highlighting the MDR modulation properties of curcumin (1), since these effects makes this natural product a promising lead compound for the development of new anticancer drugs. PMID- 26511470 TI - Ion Channel Modulation as a Therapeutic Approach in Multiple Sclerosis. AB - Ion channel dysfunction has been identified as a contributor to symptom development and neurodegeneration in multiple sclerosis (MS). The molecular insights have been translated into new lines of research, with ion channel modulation now representing a therapeutic approach in MS. Studies of Na+ channel function have demonstrated pathological blockade of Na(+) channels during an acute inflammatory attack. Relapses are typically associated with subsequent alterations in Na+ channel expression and structure. However, these compensatory changes may also be deleterious. Specifically, increased Na(+) channel expression may contribute to neuronal energy insufficiency and a cascade of events that may ultimately lead to neurodegeneration and apoptosis. Pharmacological blockade of Na(+) channels in animal models of MS demonstrated encouraging results, although mixed results were obtained in subsequent clinical trials in MS patient cohorts. The process involved in demyelination, a characteristic event in MS pathology, may also induce complex structural changes mediated by K(+) channels that may in turn hinder neural transmission. From a therapeutic perspective, the potent K(+) channel blocker, 4-aminopyridine (4-AP), has demonstrated neurophysiological and functional improvements in animal models of demyelination. Clinical translation of these results was recently achieved with the advent of Fampridine PR, a modified release form of 4-AP, with phase III clinical trials that demonstrated improvement in neurological symptoms including fatigue, walking speed and strength in MS patients. PMID- 26511471 TI - Superoxide Anion Radical: Generation and Detection in Cellular and Non-Cellular Systems. AB - The production of superoxide anion radical (O2*(-)) is essential for the life of aerobic organisms. This free radical acts as a signaling molecule, regulating numerous biological processes including apoptosis, aging, and senescence. Nevertheless, when overproduction of O2*(-) occurs and/or antioxidant defences are deficient, oxidative stress may develop, damaging important biomolecules and altering their physiological function. These effects have been associated to the development of several diseases. Scavenging of O2*(-) has been used as a hallmark to test the antioxidant capacity of several types of compounds in cellular and non-cellular systems. However, despite the pathophysiological importance of O2*( ), the information about its endogenous and/or chemical generation and detection is dispersed and there are no reports that concisely cover the information in an integrated form. This gap can explain the limitations attributed to the currently used systems, namely in what concerns the selectivity, specificity and validation. This review attempts to provide a critical assessment of the available O2*(-) generating and detection, both in endogenous and chemical systems, scrutinizing its advantages and limitations in order to facilitate the choice and implementation of the O2*(-) generator and/or detection method that better fits the researchers' objectives. PMID- 26511472 TI - Choline-Containing Phospholipids: Structure-Activity Relationships Versus Therapeutic Applications. AB - Choline is a quaternary ammonium salt, and being an essential component of different membrane phospholipids (PLs) contributes to the structural integrity of cell membranes. Choline-containing phospholipids (CCPLs) include phosphatidylcholine (PC), sphingomyelin (SM), and choline alphoscerate (GPC). PC is the major phospholipid in most eukaryotic cells. It is involved in SM synthesis, choline/choline metabolite re-generation, and fatty acid/GPC formation. This paper has reviewed chemical, biological and therapeutic features of CCPLs by analyzing: a) effects of exogenous CCPLs, b) influence of GPC treatment on brain cholinergic neurotransmission, and c) neuroprotective effects of GPC alone or in association with acetylcholinesterase inhibitors in animal models of brain vascular injury, d) synthesis of the choline analogs, containing a short alkyl chain instead of a methyl group. Cytidine-diphosphocholine and GPC, protect cell membranes and could be helpful in the sequelae of cerebrovascular accident treatment. Moreover, cellular membrane breakdown is suggested as a feature of neurodegeneration both in acute (stroke) and in chronic (Alzheimer and vascular dementia) brain disorders. Published data were focused to a larger extent on the biosynthesis, relevant role in cell life, and crucial involvement of CCPLs in cholinergic neurotransmission. The possibility of their use in the treatment of cerebrovascular and neurodegenerative disorders is suggested by published clinical studies. In line with these potential practical applications in pharmacotherapy, the need of further research in the field of the synthesis of new choline derivatives with possible activity in nervous system diseases characterized by cholinergic impairment is discussed. PMID- 26511473 TI - Facile Aluminum Reduction Synthesis of Blue TiO2 with Oxygen Deficiency for Lithium-Ion Batteries. AB - An ultrafacile aluminum reduction method is reported herein for the preparation of blue TiO2 nanoparticles (donated as Al-TiO2 , anatase phase) with abundant oxygen deficiency for lithium-ion batteries. Under aluminum reduction, the morphology of the TiO2 nanosheets changes from well-defined rectangular into uniform round or oval nanoparticles and the particle size also decreases from 60 to 31 nm, which can aggressively accelerate the lithium-ion diffusion. Electron paramagnetic resonance (EPR) and positron annihilation lifetime spectroscopy (PALS) results reveal that plentiful oxygen deficiencies relative to the Ti(3+) species were generated in blue Al-TiO2 ; this effectively enhances the electron conductivity of the TiO2 . X-ray photoelectron spectrometry (XPS) analysis indicates that a small peak is observed for the Al-O bond, which probably plays a very important role in the stabilization of the oxygen deficiencies/Ti(3+) species. As a result, the blue Al-TiO2 possesses significantly higher capacity, better rate performance, and a longer cycle life than the white pure TiO2 . Such improvements can be attributed to the decreased particle size, as well as the existence of the oxygen deficiencies/Ti(3+) species. PMID- 26511474 TI - Effects of individual immigrant attitudes and host culture attitudes on doctor immigrant patient relationships and communication in Canada. AB - INTRODUCTION: In many countries doctors are seeing an increasing amount of immigrant patients. The communication and relationship between such groups often needs to be improved, with the crucial factor potentially being the basic attitudes (acculturation orientations) of the doctors and patients. This study therefore explores how acculturation orientations of Canadian doctors and immigrant patients impact the doctor-patient relationship. METHODS: N = 10 participants (five doctors, five patients) participated in acculturation orientation surveys, video recordings of a regular clinic visit, and semi structured interviews with each person. Acculturation orientations were calculated using the Euclidean distance method, video recordings were analyzed according to the Verona Coding System, and thematic analysis was used to analyze the interviews. Interviews were used to explain and interpret the behaviours observed in the video recordings. RESULTS: The combined acculturation orientations of each the doctor and immigrant patient played a role in the doctor patient relationship, although different combinations than expected produced working relationships. Video recordings and interviews revealed that these particular immigrant patients were open to adapting to their new society, and that the doctors were generally accepting of the immigrants' previous culture. This produced a common level of understanding from which the relationship could work effectively. CONCLUSION: A good relationship and level of communication between doctors and immigrant patients may have its foundation in acculturation orientations, which may affect the quality of care, health behaviours and quality of life of the immigrant. The implications of these findings are more significant when considering effective interventions to improve the quality of doctor-patient relationships, which should have a solid foundational framework. Our research suggests that interventions based on understanding the influence of acculturation orientations could help create a basic level of understanding, and therefore improved interaction between doctors and immigrant patients. PMID- 26511475 TI - Small airway epithelial-C/EBPbeta is increased in patients with advanced COPD. AB - The expression of CCAAT/enhancer-binding protein (C/EBP)beta in the small airway epithelium of COPD is unknown. C/EBPbeta was assessed in peripheral lung tissue of non-smoking/smoking controls and patients with GOLD I-IV COPD by quantitative immunohistochemistry. The expression of C/EBPbeta was decreased in smokers compared to never smokers. Furthermore, C/EBPbeta was significantly elevated in advanced COPD vs. asymptomatic smokers, and the expression correlated to lung function decline. As C/EBPbeta exerts pro-inflammatory effects in the context of cigarette smoke, the elevated C/EBPbeta in advanced COPD may be an indication of a breakdown of regulatory mechanisms and excessive inflammation. PMID- 26511476 TI - The Preventive Effect of Calcium Supplementation on Weak Bones Caused by the Interaction of Exercise and Food Restriction in Young Female Rats During the Period from Acquiring Bone Mass to Maintaining Bone Mass. AB - Increasing calcium (Ca) intake is important for female athletes with a risk of weak bone caused by inadequate food intake. The aim of the present study was to examine the preventive effect of Ca supplementation on low bone strength in young female athletes with inadequate food intake, using the rats as an experimental model. Seven-week-old female Sprague-Dawley rats were divided into four groups: the sedentary and ad libitum feeding group (SED), voluntary running exercise and ad libitum feeding group (EX), voluntary running exercise and 30% food restriction group (EX-FR), and a voluntary running exercise, 30% food-restricted and high-Ca diet group (EX-FR+Ca). To Ca supplementation, we used 1.2% Ca diet as "high-Ca diet" that contains two-fold Ca of normal Ca diet. The experiment lasted for 12 weeks. As a result, the energy availability, internal organ weight, bone strength, bone mineral density, and Ca absorption in the EX-FR group were significantly lower than those in the EX group. The bone strength and Ca absorption in the EX-FR+Ca group were significantly higher than those in the EX FR group. However, the bone strength in the EX-FR+Ca group did not reach that in the EX group. These results suggested that Ca supplementation had a positive effect on bone strength, but the effect was not sufficient to prevent lower bone strength caused by food restriction in young female athletes. PMID- 26511477 TI - Insights from the genome of Ophiocordyceps polyrhachis-furcata to pathogenicity and host specificity in insect fungi. AB - BACKGROUND: Ophiocordyceps unilateralis is an outstanding insect fungus for its biology to manipulate host ants' behavior and for its extreme host-specificity. Through the sequencing and annotation of Ophiocordyceps polyrhachis-furcata, a species in the O. unilateralis species complex specific to the ant Polyrhachis furcata, comparative analyses on genes involved in pathogenicity and virulence between this fungus and other fungi were undertaken in order to gain insights into its biology and the emergence of host specificity. RESULTS: O. polyrhachis furcata possesses various genes implicated in pathogenicity and virulence common with other fungi. Overall, this fungus possesses protein-coding genes similar to those found on other insect fungi with available genomic resources (Beauveria bassiana, Metarhizium robertsii (formerly classified as M. anisopliae s.l.), Metarhizium acridum, Cordyceps militaris, Ophiocordyceps sinensis). Comparative analyses in regard of the host ranges of insect fungi showed a tendency toward contractions of various gene families for narrow host-range species, including cuticle-degrading genes (proteases, carbohydrate esterases) and some families of pathogen-host interaction (PHI) genes. For many families of genes, O. polyrhachis furcata had the least number of genes found; some genes commonly found in other insect fungi are even absent (e.g. Class 1 hydrophobin). However, there are expansions of genes involved in 1) the production of bacterial-like toxins in O. polyrhachis-furcata, compared with other entomopathogenic fungi, and 2) retrotransposable elements. CONCLUSIONS: The gain and loss of gene families helps us understand how fungal pathogenicity in insect hosts evolved. The loss of various genes involved throughout the pathogenesis for O. unilateralis would result in a reduced capacity to exploit larger ranges of hosts and therefore in the different level of host specificity, while the expansions of other gene families suggest an adaptation to particular environments with unexpected strategies like oral toxicity, through the production of bacterial-like toxins, or sophisticated mechanisms underlying pathogenicity through retrotransposons. PMID- 26511478 TI - Predictors of Thiopurine Treatment Failure in Biologic-Naive Ulcerative Colitis Patients. AB - INTRODUCTION: Thiopurines (azathioprine and 6-mercaptopurine) have been used in the management of UC patients for over three decades. Nearly half of patients with UC treated with thiopurines fail to achieve remission or lose remission during treatment. Factors associated with thiopurine failure are poorly understood. The primary aim of our study was to investigate patient-related factors which are associated with thiopurine failure. METHODS: TNF-alpha antagonist-naive patients with histological diagnosis of UC, receiving thiopurine therapy, with follow-up data from 1 to 3 years were included in the study. Data regarding demographics, laboratory results, and disease characteristics were collected. The primary endpoint was failure of thiopurine therapy, defined as treatment with steroids, therapeutic escalation to TNF-alpha antagonist therapy, or need for surgery. RESULTS: Of the 563 patients identified using ICD-9 codes, 78 TNF-alpha antagonist-naive patients with a histological diagnosis of UC, receiving thiopurine treatment, were identified. Over the three-year follow-up period, 38 patients failed thiopurine treatment. On adjusted Cox regression, BMI < 25 kg/m(2) (HR 3, 95 % CI 1.55-5.83; p value = 0.001) was significantly associated with thiopurine failure. Furthermore, although not statistically significant, there was a strong trend toward thiopurine failure among patients with serum albumin level < 4 g/dL (HR 1.98, 95 % CI 0.97-4; p value = 0.06), non smoking status (HR 2.2, 95 % CI 0.96-5.06; p value = 0.06), and higher degree of colon inflammation (HR 1.49, 95 % CI 0.96-2.32; p value = 0.08). DISCUSSION: Our results show that low body mass index is associated with increased risk of failure of thiopurine treatment. Furthermore, there was a strong trend toward thiopurine failure among patients with low serum albumin level (<4gm/dL). These factors should be considered as markers of non-response to thiopurine monotherapy for patients with moderately severe ulcerative colitis. PMID- 26511479 TI - Guest Editorial: Retrospective cohort studies using the registry database of hematopoietic stem cell transplantation in Japan. How can we produce reliable Japanese evidences? PMID- 26511480 TI - Multicenter, prospective study to evaluate the efficacy of biweekly romiplostim administration in patients with immune thrombocytopenia. AB - Multicenter, prospective study was conducted to evaluate the efficacy of biweekly romiplostim in maintaining platelet >= 30 * 10(9)/L for at least 4 weeks. Treatment was started with a weekly injection (1 mcg/kg), and the dose was escalated until a titrated dose was achieved that maintained a platelet 50-200 * 10(9)/L for four consecutive weeks. Patients were scheduled to a biweekly schedule, and returned to a weekly schedule if platelets fell to <30 * 10(9)/L. Eighteen patients were enrolled (median platelet, 14 * 10(9)/L). After the first weekly schedule, ten of eighteen (55.6 %) attained a median titrated dose of 3 mcg/kg and proceeded to the first biweekly schedule. However, all failed to maintain a platelet >= 30 * 10(9)/L for at least 4 weeks, and returned to a second weekly schedule, where eight of the ten achieved a titrated dose (median, 5 mcg/kg) and moved to a second schedule of biweekly romiplostim. Three of the eight (37.5 %) showed platelet >= 30 * 10(9)/L for 4, 8, and 10 weeks, but all eight patients eventually experienced a drop in platelets. Lengthening the dose interval of romiplostim to greater than a week is not feasible to maintain stable platelet count. PMID- 26511481 TI - The contribution of the anaesthetist to risk-adjusted mortality after cardiac surgery. AB - It is widely accepted that the performance of the operating surgeon affects outcomes, and this has led to the publication of surgical results in the public domain. However, the effect of other members of the multidisciplinary team is unknown. We studied the effect of the anaesthetist on mortality after cardiac surgery by analysing data collected prospectively over ten years of consecutive cardiac surgical cases from ten UK centres. Casemix-adjusted outcomes were analysed in models that included random-effects for centre, surgeon and anaesthetist. All cardiac surgical operations for which the EuroSCORE model is appropriate were included, and the primary outcome was in-hospital death up to three months postoperatively. A total of 110 769 cardiac surgical procedures conducted between April 2002 and March 2012 were studied, which included 127 consultant surgeons and 190 consultant anaesthetists. The overwhelming factor associated with outcome was patient risk, accounting for 95.75% of the variation for in-hospital mortality. The impact of the surgeon was moderate (intra-class correlation coefficient 4.00% for mortality), and the impact of the anaesthetist was negligible (0.25%). There was no significant effect of anaesthetist volume above ten cases per year. We conclude that mortality after cardiac surgery is primarily determined by the patient, with small but significant differences between surgeons. Anaesthetists did not appear to affect mortality. These findings do not support public disclosure of cardiac anaesthetists' results, but substantially validate current UK cardiac anaesthetic training and practice. Further research is required to establish the potential effects of very low anaesthetic caseloads and the effect of cardiac anaesthetists on patient morbidity. PMID- 26511482 TI - [Hugo von Ziemssen poster award 2015]. AB - Prize winner: Herr Dr. Stefano Bordignon, for the poster presentation "The SCAR AF study: electroanatomial scar distribution and left atrial conduction delay in patients undergoing pulmonary vein isolation". PMID- 26511483 TI - Spatial heterogeneity of temperature across alpine boulder fields in New South Wales, Australia: multilevel modelling of drivers of microhabitat climate. AB - Understanding the spatial heterogeneity of temperatures across a region is significant for identification and protection of potential microhabitats for species conservation. However, this task is proving difficult because multiple factors drive the temperatures of microhabitats and their effect differs at different scales. In the Australian alpine region, boulder field habitats have been identified as important refugia for a range of small mammals. Vegetation cover and elevation have been found to drive thermal buffering at the level of single sampling sites within boulder fields, whereas the aspect and inclination of slopes have been found to affect thermal buffering at the level of clusters of boulder fields. But how the rock structure (number of rock layers, rock size and cavity of boulders) influences microclimate of boulder fields remains an open question. We used a multilevel modelling approach to detect the factors driving microhabitat temperatures in different seasons at different spatial scales in an Australian alpine region. We found that significant temperature differences existed within and between clusters of boulder fields in different seasons. Besides elevation and vegetation cover, the number of rock layers and rock cavity size also exerts important influences on extreme temperatures at the site (i.e. single boulder field) scale. Topographical variables such as slope gradient and elevation influenced minimum temperatures at the boulder field cluster scale. Variations in boulder field temperatures were significant at fine scales, with variations in minimum temperatures exceeding those of maximum temperatures. We suggest that variations in slope gradient and elevation, interacting with vegetation cover, the number of rock layers and rock cavity size can lead to fine grained thermal variability, which potentially provides refugia for species at microsites, even when regional climatic conditions become less suitable for their survival. PMID- 26511484 TI - Intestinal Carriage of Carbapenemase-Producing Organisms: Current Status of Surveillance Methods. AB - Carbapenemases have become a significant mechanism for broad-spectrum beta-lactam resistance in Enterobacteriaceae and other Gram-negative bacteria such as Pseudomonas and Acinetobacter spp. Intestinal carriage of carbapenemase-producing organisms (CPOs) is an important source of transmission. Isolation of carriers is one strategy that can be used to limit the spread of these bacteria. In this review, we critically examine the clinical performance, advantages, and disadvantages of methods available for the detection of intestinal carriage of CPOs. Culture-based methods (Centers for Disease Control and Prevention [CDC] protocols, chromogenic media, specialized agars, and double-disk synergy tests) for detecting carriage of CPOs are convenient due to their ready availability and low cost, but their limited sensitivity and long turnaround time may not always be optimal for infection control practices. Contemporary nucleic acid amplification techniques (NAATs) such as real-time PCR, hybridization assays, loop-mediated isothermal amplification (LAMP), or a combined culture and NAAT approach may provide fast results and/or added sensitivity and specificity compared with culture-based methods. Infection control practitioners and clinical microbiologists should be aware of the strengths and limitations of available methods to determine the most suitable approach for their medical facility to fit their infection control needs. PMID- 26511486 TI - Methylseleninic Acid Superactivates p53-Senescence Cancer Progression Barrier in Prostate Lesions of Pten-Knockout Mouse. AB - Monomethylated selenium (MM-Se) forms that are precursors of methylselenol, such as methylseleninic acid (MSeA), differ in metabolism and anticancer activities in preclinical cell and animal models from seleno-methionine that had failed to exert preventive efficacy against prostate cancer in North American men. Given that human prostate cancer arises from precancerous lesions such as high-grade prostatic intraepithelial neoplasia (HG-PIN), which frequently have lost phosphatase and tensin homolog (PTEN) tumor suppressor permitting phosphatidylinositol-3-OH kinase (PI3K)-protein kinase B (AKT) oncogenic signaling, we tested the efficacy of MSeA to inhibit HG-PIN progression in Pten prostate-specific knockout (KO) mice and assessed the mechanistic involvement of p53-mediated cellular senescence and of the androgen receptor (AR). We observed that short-term (4 weeks) oral MSeA treatment significantly increased expression of P53 and P21Cip1 proteins and senescence-associated-beta-galactosidase staining, and reduced Ki67 cell proliferation index in Pten KO prostate epithelium. Long-term (25 weeks) MSeA administration significantly suppressed HG PIN phenotype, tumor weight, and prevented emergence of invasive carcinoma in Pten KO mice. Mechanistically, the long-term MSeA treatment not only sustained P53-mediated senescence, but also markedly reduced AKT phosphorylation and AR abundance in the Pten KO prostate. Importantly, these cellular and molecular changes were not observed in the prostate of wild-type littermates which were similarly treated with MSeA. Because p53 signaling is likely to be intact in HG PIN compared with advanced prostate cancer, the selective superactivation of p53 mediated senescence by MSeA suggests a new paradigm of cancer chemoprevention by strengthening a cancer progression barrier through induction of irreversible senescence with additional suppression of AR and AKT oncogenic signaling. PMID- 26511485 TI - A Structure-Based Classification of Class A beta-Lactamases, a Broadly Diverse Family of Enzymes. AB - For medical biologists, sequencing has become a commonplace technique to support diagnosis. Rapid changes in this field have led to the generation of large amounts of data, which are not always correctly listed in databases. This is particularly true for data concerning class A beta-lactamases, a group of key antibiotic resistance enzymes produced by bacteria. Many genomes have been reported to contain putative beta-lactamase genes, which can be compared with representative types. We analyzed several hundred amino acid sequences of class A beta-lactamase enzymes for phylogenic relationships, the presence of specific residues, and cluster patterns. A clear distinction was first made between dd peptidases and class A enzymes based on a small number of residues (S70, K73, P107, 130SDN132, G144, E166, 234K/R, 235T/S, and 236G [Ambler numbering]). Other residues clearly separated two main branches, which we named subclasses A1 and A2. Various clusters were identified on the major branch (subclass A1) on the basis of signature residues associated with catalytic properties (e.g., limited spectrum beta-lactamases, extended-spectrum beta-lactamases, and carbapenemases). For subclass A2 enzymes (e.g., CfxA, CIA-1, CME-1, PER-1, and VEB-1), 43 conserved residues were characterized, and several significant insertions were detected. This diversity in the amino acid sequences of beta-lactamases must be taken into account to ensure that new enzymes are accurately identified. However, with the exception of PER types, this diversity is poorly represented in existing X-ray crystallographic data. PMID- 26511487 TI - Plasma Inflammatory Markers and Risk of Advanced Colorectal Adenoma in Women. AB - Evidence remains inconclusive about the association of systemic inflammatory markers with colorectal neoplasia. We investigated whether circulating inflammatory markers were associated with risk of advanced colorectal adenoma. We measured plasma macrophage inhibitory cytokine-1 (MIC-1), C-reactive protein (CRP), interleukin-6 (IL6), and soluble TNF receptor 2 (sTNFR-2) in blood samples drawn from 32,826 women in 1989 to 1990 in the Nurses' Health Study. Through 2008, we documented 757 cases of advanced colorectal adenomas (>=1 cm or any size with advanced histology); each case was matched by age and time of blood draw with one control randomly selected from participants who underwent lower endoscopy and did not have neoplasia. Plasma MIC-1 was associated with higher risk of advanced adenoma (Ptrend = 0.04), with an OR of 1.55 (95% confidence interval, 1.03-2.32) comparing extreme quintiles of MIC-1 after adjusting for colorectal cancer-risk factors and other inflammatory markers. Among cases, MIC-1 level was positively associated with the number of adenomas (P < 0.001) and gradually increased from adenomas located in the rectum, distal colon, and up to the proximal colon. There was a strong positive association between MIC-1 and risk of adenomas with multiplicity, >=1 cm size and location in the proximal colon (all Ptrend < 0.05). CRP, IL6, or sTNFR-2 was not associated with adenoma risk. In conclusion, plasma MIC-1 was associated with higher risk of colorectal adenoma, especially multiple, large, and proximal adenomas. Our results provide further support for a role for MIC-1 in carcinogenesis and the potential for MIC 1 as an adjunctive biomarker for detection of advanced colorectal adenoma. PMID- 26511488 TI - Anticancer and Cancer Prevention Effects of Piperine-Free Piper nigrum Extract on N-nitrosomethylurea-Induced Mammary Tumorigenesis in Rats. AB - Piper nigrum (P. nigrum) is commonly used in traditional medicine. This current study aimed to investigate the anticancer and cancer preventive activity of a piperine-free P. nigrum extract (PFPE) against breast cancer cells and N nitrosomethylurea (NMU)-induced mammary tumorigenesis in rats. The cytotoxic effects and the mechanism of action were investigated in breast cancer cells using the MTT assay and Western blot analysis, respectively. An acute toxicity study was conducted according to the Organization for Economic Co-operation and Development guideline. Female Sprague-Dawley rats with NMU-induced mammary tumors were used in preventive and anticancer studies. The results showed that PFPE inhibited the growth of luminal-like breast cancer cells more so than the basal like ones by induction of apoptosis. In addition, PFPE exhibited greater selectivity against breast cancer cells than colorectal cancer, lung cancer, and neuroblastoma cells. In an acute toxicity study, a single oral administration of PFPE at a dose of 5,000 mg/kg body weight resulted in no mortality and morbidity during a 14-day observation period. For the cancer preventive study, the incidence of tumor-bearing rats was 10% to 20% in rats treated with PFPE. For the anticancer activity study, the growth rate of tumors in the presence of PFPE treated groups was much slower when compared with the control and vehicle groups. The extract itself caused no changes to the biochemical and hematologic parameters when compared with the control and vehicle groups. In conclusion, PFPE had a low toxicity and a potent antitumor effect on mammary tumorigenesis in rats. PMID- 26511489 TI - Sulforaphane Bioavailability and Chemopreventive Activity in Women Scheduled for Breast Biopsy. AB - Epidemiologic studies suggest a protective effect of cruciferous vegetables on breast cancer. Sulforaphane (SFN), an active food component derived from crucifers, has been shown to be effective in breast cancer chemoprevention. This study evaluated the chemopreventive effect of SFN on selective biomarkers from blood and breast tissues. In a 2- to 8-week double-blinded, randomized controlled trial, 54 women with abnormal mammograms and scheduled for breast biopsy were randomized to consume a placebo or a glucoraphanin (GFN) supplement providing SFN (n = 27). Plasma and urinary SFN metabolites, peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity, and tissue biomarkers (H3K18ac, H3K9ac, HDAC3, HDAC6, Ki-67, p21) were measured before and after the intervention in benign, ductal carcinoma in situ, or invasive ductal carcinoma breast tissues. Within the supplement group, Ki-67 (P = 0.003) and HDAC3 (P = 0.044) levels significantly decreased in benign tissue. Pre-to-postintervention changes in these biomarkers were not significantly different between treatment groups after multiple comparison adjustment. GFN supplementation was associated with a significant decrease in PBMC HDAC activity (P = 0.04). No significant associations were observed between SFN and examined tissue biomarkers when comparing treatment groups. This study provides evidence that GFN supplementation for a few weeks is safe but may not be sufficient for producing changes in breast tissue tumor biomarkers. Future studies employing larger sample sizes should evaluate alternative dosing and duration regimens to inform dietary SFN strategies in breast cancer chemoprevention. PMID- 26511490 TI - Cancer-Specific Production of N-Acetylaspartate via NAT8L Overexpression in Non Small Cell Lung Cancer and Its Potential as a Circulating Biomarker. AB - In order to identify new cancer-associated metabolites that may be useful for early detection of lung cancer, we performed a global metabolite profiling of a non-small cell lung cancer (NSCLC) line and immortalized normal lung epithelial cells from the same patient. Among several metabolites with significant cancer/normal differences, we identified a unique metabolic compound, N acetylaspartate (NAA), in cancer cells-undetectable in normal lung epithelium. NAA's cancer-specific detection was validated in additional cancer and control lung cells as well as selected NSCLC patient tumors and control tissues. NAA's cancer specificity was further supported in our analysis of NAA synthetase (gene symbol: NAT8L) gene expression levels in The Cancer Genome Atlas: elevated NAT8L expression in approximately 40% of adenocarcinoma and squamous cell carcinoma cases (N = 577), with minimal expression in all nonmalignant lung tissues (N = 74). We then showed that NAT8L is functionally involved in NAA production of NSCLC cells through siRNA-mediated suppression of NAT8L, which caused selective reduction of intracellular and secreted NAA. Our cell culture experiments also indicated that NAA biosynthesis in NSCLC cells depends on glutamine availability. For preliminary evaluation of NAA's clinical potential as a circulating biomarker, we developed a sensitive NAA blood assay and found that NAA blood levels were elevated in 46% of NSCLC patients (N = 13) in comparison with age matched healthy controls (N = 21) among individuals aged 55 years or younger. Taken together, these results indicate that NAA is produced specifically in NSCLC tumors through NAT8L overexpression, and its extracellular secretion can be detected in blood. Cancer Prev Res; 9(1); 43-52. (c)2015 AACR. PMID- 26511491 TI - Preclinical In Vitro, In Vivo, and Pharmacokinetic Evaluations of FLLL12 for the Prevention and Treatment of Head and Neck Cancers. AB - Despite its high promise for cancer prevention and therapy, the potential utility of curcumin in cancer is compromised by its low bioavailability and weak potency. The purpose of the current study was to assess the in vitro and in vivo efficacy and pharmacokinetic parameters of the potent curcumin analogue FLLL12 in SCCHN and identify the mechanisms of its antitumor effect. IC50 values against a panel of one premalignant and eight malignant head and neck cancer cell lines as well as apoptosis assay results suggested that FLLL12 is 10- to 24-fold more potent than natural curcumin depending on the cell line and induces mitochondria mediated apoptosis. In vivo efficacy (xenograft) and pharmacokinetic studies also suggested that FLLL12 is significantly more potent and has more favorable pharmacokinetic properties than curcumin. FLLL12 strongly inhibited the expression of p-EGFR, EGFR, p-AKT, AKT, Bcl-2, and Bid and increased the expression of Bim. Overexpression of constitutively active AKT or Bcl-2 or ablation of Bim or Bid significantly inhibited FLLL12-induced apoptosis. Further mechanistic studies revealed that FLLL12 regulated EGFR and AKT at transcriptional levels, whereas Bcl-2 was regulated at the translational level. Finally, FLLL12 strongly inhibited the AKT downstream targets mTOR and FOXO1a and 3a. Taken together, our results strongly suggest that FLLL12 is a potent curcumin analogue with more favorable pharmacokinetic properties that induces apoptosis of head and neck cancer cell lines by inhibition of survival proteins including EGFR, AKT, and Bcl-2 and increasing of the proapoptotic protein Bim. PMID- 26511492 TI - Tumor location, but not H3.3K27M, significantly influences the blood-brain barrier permeability in a genetic mouse model of pediatric high-grade glioma. AB - Pediatric high-grade gliomas (pHGGs) occur with strikingly different frequencies in infratentorial and supratentorial regions. Although histologically these malignancies appear similar, they represent distinct diseases. Recent genomic studies have identified histone K27M H3.3/H3.1 mutations in the majority of brainstem pHGGs; these mutations are rarely encountered in pHGGs that arise in the cerebral cortex. Previous research in brainstem pHGGs suggests a restricted permeability of the blood-brain-barrier (BBB). In this work, we use dynamic contrast-enhanced (DCE) MRI to evaluate BBB permeability in a genetic mouse model of pHGG as a function of location (cortex vs. brainstem, n = 8 mice/group) and histone mutation (mutant H3.3K27M vs. wild-type H3.3, n = 8 mice/group). The pHGG models are induced either in the brainstem or the cerebral cortex and are driven by PDGF signaling and p53 loss with either H3.3K27M or wild-type H3.3. T2 weighted MRI was used to determine tumor location/extent followed by 4D DCE-MRI for estimating the rate constant (K (trans) ) for tracer exchange across the barrier. BBB permeability was 67 % higher in cortical pHGGs relative to brainstem pHGGs (t test, p = 0.012) but was not significantly affected by the expression of mutant H3.3K27M versus wild-type H3.3 (t-test, p = 0.78). Although mice became symptomatic at approximately the same time, the mean volume of cortical tumors was 3.6 times higher than the mean volume of brainstem tumors. The difference between the mean volume of gliomas with wild-type and mutant H3.3 was insignificant. Mean K (trans) was significantly correlated to glioma volume. These results present a possible explanation for the poor response of brainstem pHGGs to systemic therapy. Our findings illustrate a potential role played by the microenvironment in shaping tumor growth and BBB permeability. PMID- 26511493 TI - Association between RAD 51 rs1801320 and susceptibility to glioblastoma. AB - Glioblastoma is the most common and aggressive malignant primary brain tumor. Despite decades of research and the advent of new therapies, patients with glioblastoma continue to have a very poor prognosis. Radiation therapy has a major role as adjuvant treatment for glioblastoma following surgical resection. Many studies have shown that polymorphisms of genes involved in pathways of DNA repair may affect the sensitivity of the cells to treatment. Although the role of these polymorphisms has been investigated in relation to response to radiotherapy, their role as predisposing factors to glioblastoma has not been clarified yet. In the present study, we evaluated the association between polymorphisms in DNA repair genes, namely: XRCC1 rs25487, XRCC3 rs861539 and RAD51 rs1801320, with the susceptibility to develop glioblastoma. Eighty-five glioblastoma patients and 70 matched controls were recruited for this study. Data from the 1000 Genomes Project (98 Tuscans) were also downloaded and used for the association analysis. Subjects carrying RAD51 rs1801320 GC genotype showed an increased risk of glioblastoma (GC vs GG, chi(2) = 10.75; OR 3.0087; p = 0.0010). The C allele was also significantly associated to glioblastoma (chi(2) = 8.66; OR 2.5674; p = 0.0032). Moreover, RAD51 rs1801320 C allele increased the risk to develop glioblastoma also when combined to XRCC1 rs25487 G allele and XRCC3 rs861539 C allele (chi(2) = 6.558; p = 0.0053). PMID- 26511494 TI - CogState computerized memory tests in patients with brain metastases: secondary endpoint results of NRG Oncology RTOG 0933. AB - Whole brain radiotherapy (WBRT) is associated with memory dysfunction. As part of NRG Oncology RTOG 0933, a phase II study of WBRT for brain metastases that conformally avoided the hippocampal stem cell compartment (HA-WBRT), memory was assessed pre- and post-HA-WBRT using both traditional and computerized memory tests. We examined whether the computerized tests yielded similar findings and might serve as possible alternatives for assessment of memory in multi institution clinical trials. Adult patients with brain metastases received HA WBRT to 30 Gy in ten fractions and completed Hopkins Verbal Learning Test-Revised (HVLT-R), CogState International Shopping List Test (ISLT) and One Card Learning Test (OCLT), at baseline, 2 and 4 months. Tests' completion rates were 52-53 % at 2 months and 34-42 % at 4 months. All baseline correlations between HVLT-R and CogState tests were significant (p <= 0.003). At baseline, both CogState tests and one component of HVLT-R differentiated those who were alive at 6 months and those who had died (p <= 0.01). At 4 months, mean relative decline was 7.0 % for HVLT-R Delayed Recall and 18.0 % for ISLT Delayed Recall. OCLT showed an 8.0 % increase. A reliable change index found no significant changes from baseline to 2 and 4 months for ISLT Delayed Recall (z = -0.40, p = 0.34; z = -0.68, p = 0.25) or OCLT (z = 0.15, p = 0.56; z = 0.41, p = 0.66). Study findings support the possibility that hippocampal avoidance may be associated with preservation of memory test performance, and that these computerized tests also may be useful and valid memory assessments in multi-institution adult brain tumor trials. PMID- 26511495 TI - Development of brain metastases in patients with metastatic melanoma while receiving ipilimumab. AB - Ipilimumab is a monoclonal antibody blocking the inhibitory molecule CTLA4 expressed by activated T lympocytes, used for the treatment of metastatic melanoma. Recent studies have shown its potential efficacy on brain metastases. OBJECTIVES: To assess the development of brain metastases under ipilimumab and identify clinical, histological or evolving criteria related to the appearance of these metastases. A retrospective study was conducted in 52 patients treated with 4 cycles of ipilimumab 3 mg/kg every 3 weeks for unresectable stage III or stage IV melanoma between January 2011 and July 2013 in a Department of Dermato Oncology. As no data has been find in the literature, the results were compared to our other cohort of patients treated with vemurafenib during the same period. Ten patients (21.7 %) developed brain metastases under ipilimumab in a median time of 6.58 months after treatment initiation. The multivariate analysis showed a lower rate of brain metastases in patients with acral lentiginous melanoma and melanoma of unknown primary site. The median survival after diagnosis of brain metastases was of 2.5 months. There was no significant difference with vemurafenib-treated patients in terms of incidence rate of brain metastasis, time of development and survival after diagnosis of cerebral metastases. This was the first study focused on the development of brain metastases under treatment with ipilimumab 3 mg/kg. Although ipilimumab is used for the treatment of brain metastases, it paradoxically did not seem to reduce the risk of developing brain metastases. PMID- 26511496 TI - Generation of a Maize B Centromere Minimal Map Containing the Central Core Domain. AB - The maize B centromere has been used as a model for centromere epigenetics and as the basis for building artificial chromosomes. However, there are no sequence resources for this important centromere. Here we used transposon display for the centromere-specific retroelement CRM2 to identify a collection of 40 sequence tags that flank CRM2 insertion points on the B chromosome. These were confirmed to lie within the centromere by assaying deletion breakpoints from centromere misdivision derivatives (intracentromere breakages caused by centromere fission). Markers were grouped together on the basis of their association with other markers in the misdivision series and assembled into a pseudocontig containing 10.1 kb of sequence. To identify sequences that interact directly with centromere proteins, we carried out chromatin immunoprecipitation using antibodies to centromeric histone H3 (CENH3), a defining feature of functional centromeric sequences. The CENH3 chromatin immunoprecipitation map was interpreted relative to the known transmission rates of centromere misdivision derivatives to identify a centromere core domain spanning 33 markers. A subset of seven markers was mapped in additional B centromere misdivision derivatives with the use of unique primer pairs. A derivative previously shown to have no canonical centromere sequences (Telo3-3) lacks these core markers. Our results provide a molecular map of the B chromosome centromere and identify key sequences within the map that interact directly with centromeric histone H3. PMID- 26511497 TI - Genetic Architecture of the Variation in Male-Specific Ossified Processes on the Anal Fins of Japanese Medaka. AB - Traits involved in reproduction evolve rapidly and show great diversity among closely related species. However, the genetic mechanisms that underlie the diversification of courtship traits are mostly unknown. Japanese medaka fishes (Oryzias latipes) use anal fins to attract females and to grasp females during courtship; the males have longer anal fins with male-specific ossified papillary processes on the fin rays. However, anal fin morphology varies between populations: the southern populations tend to have longer anal fins and more processes than the northern populations. In the present study, we conducted quantitative trait locus (QTL) mapping to investigate the genetic architecture underlying the variation in the number of papillary processes of Japanese medaka fish and compared the QTL with previously identified QTL controlling anal fin length. First, we found that only a few QTL were shared between anal fin length and papillary process number. Second, we found that the numbers of papillary processes on different fin rays often were controlled by different QTL. Finally, we produced another independent cross and found that some QTL were repeatable between the two crosses, whereas others were specific to only one cross. These results suggest that variation in the number of papillary processes is polygenic and controlled by QTL that are distinct from those controlling anal fin length. Thus, different courtship traits in Japanese medaka share a small number of QTL and have the potential for independent evolution. PMID- 26511498 TI - Sxl-Dependent, tra/tra2-Independent Alternative Splicing of the Drosophila melanogaster X-Linked Gene found in neurons. AB - Somatic sexual determination and behavior in Drosophila melanogaster are under the control of a genetic cascade initiated by Sex lethal (Sxl). In the female soma, SXL RNA-binding protein regulates the splicing of transformer (tra) transcripts into a female-specific form. The RNA-binding protein TRA and its cofactor TRA2 function in concert in females, whereas SXL, TRA, and TRA2 are thought to not function in males. To better understand sex-specific regulation of gene expression, we analyzed male and female head transcriptome datasets for expression levels and splicing, quantifying sex-biased gene expression via RNA Seq and qPCR. Our data uncouple the effects of Sxl and tra/tra2 in females in the sex-biased alternative splicing of head transcripts from the X-linked locus found in neurons (fne), encoding a pan-neuronal RNA-binding protein of the ELAV family. We show that FNE protein levels are downregulated by Sxl in female heads, also independently of tra/tra2. We argue that this regulation may have important sexually dimorphic consequences for the regulation of nervous system development or function. PMID- 26511499 TI - A Major Locus Controls a Genital Shape Difference Involved in Reproductive Isolation Between Drosophila yakuba and Drosophila santomea. AB - Rapid evolution of genitalia shape, a widespread phenomenon in animals with internal fertilization, offers the opportunity to dissect the genetic architecture of morphological evolution linked to sexual selection and speciation. Most quantitative trait loci (QTL) mapping studies of genitalia divergence have focused on Drosophila melanogaster and its three most closely related species, D. simulans, D. mauritiana, and D. sechellia, and have suggested that the genetic basis of genitalia evolution involves many loci. We report the first genetic study of male genitalia evolution between D. yakuba and D. santomea, two species of the D. melanogaster species subgroup. We focus on male ventral branches, which harm females during interspecific copulation. Using landmark-based geometric morphometrics, we characterized shape variation in parental species, F1 hybrids, and backcross progeny and show that the main axis of shape variation within the backcross population matches the interspecific variation between parental species. For genotyping, we developed a new molecular method to perform multiplexed shotgun genotyping (MSG), which allowed us to prepare genomic DNA libraries from 365 backcross individuals in a few days using little DNA. We detected only three QTL, one of which spans 2.7 Mb and exhibits a highly significant effect on shape variation that can be linked to the harmfulness of the ventral branches. We conclude that the genetic architecture of genitalia morphology divergence may not always be as complex as suggested by previous studies. PMID- 26511500 TI - Oviposition but Not Sex Allocation Is Associated with Transcriptomic Changes in Females of the Parasitoid Wasp Nasonia vitripennis. AB - Linking the evolution of the phenotype to the underlying genotype is a key aim of evolutionary genetics and is crucial to our understanding of how natural selection shapes a trait. Here, we consider the genetic basis of sex allocation behavior in the parasitoid wasp Nasonia vitripennis using a transcriptomics approach. Females allocate offspring sex in line with the local mate competition (LMC) theory. Female-biased sex ratios are produced when one or a few females lay eggs on a patch. As the number of females contributing offspring to a patch increases, less female-biased sex ratios are favored. We contrasted the transcriptomic responses of females as they oviposit under conditions known to influence sex allocation: foundress number (a social cue) and the state of the host (parasitized or not). We found that when females encounter other females on a patch or assess host quality with their ovipositors, the resulting changes in sex allocation is not associated with significant changes in whole-body gene expression. We also found that the gene expression changes produced by females as they facultatively allocate sex in response to a host cue and a social cue are very closely correlated. We expanded the list of candidate genes associated with oviposition behavior in Nasonia, some of which may be involved in fundamental processes underlying the ability to facultatively allocate sex, including sperm storage and utilization. PMID- 26511501 TI - Experiential acceptance, motivation for recovery, and treatment outcome in eating disorders. AB - PURPOSE: This study sought to test whether the relationship between experiential acceptance (EA) and treatment outcome among eating disorder (ED) patients was mediated by motivation. METHODS: Upon admission to a residential ED treatment facility, female patients completed measures of EA, motivation, and baseline ED symptom severity (covariate); symptom severity was reassessed at discharge. RESULTS: Higher levels of baseline EA predicted significantly greater symptom reduction during treatment. Moreover, results from bootstrapped mediation analyses indicated that the relationship between EA and treatment outcome was partially mediated by motivation: increased EA was associated with greater motivation to give up ED behaviors at the beginning of treatment, and this led to greater symptom reduction from admission to discharge. CONCLUSIONS: Motivation appears to be one mechanism by which EA facilitates improved treatment outcomes in EDs. Further development of interventions that promote EA as a means for improving motivation and subsequent ED treatment response may be warranted. PMID- 26511502 TI - Patriarchy, Power, and Pay: The Transformation of American Families, 1800-2015. AB - This article proposes explanations for the transformation of American families over the past two centuries. I describe the impact on families of the rise of male wage labor beginning in the nineteenth century and the rise of female wage labor in the twentieth century. I then examine the effects of decline in wage labor opportunities for young men and women during the past four decades. I present new estimates of a precipitous decline in the relative income of young men and assess its implications for the decline for marriage. Finally, I discuss explanations for the deterioration of economic opportunity and speculate on the impact of technological change on the future of work and families. PMID- 26511503 TI - High levels of WNT-5A in human glioma correlate with increased presence of tumor associated microglia/monocytes. AB - Malignant gliomas are among the most severe types of cancer, and the most common primary brain tumors. Treatment options are limited and the prognosis is poor. WNT-5A, a member of the WNT family of lipoglycoproteins, plays a role in oncogenesis and tumor progression in various cancers, whereas the role of WNT-5A in glioma remains obscure. Based on the role of WNT-5A as an oncogene, its potential to regulate microglia cells and the glioma-promoting capacities of microglia cells, we hypothesize that WNT-5A has a role in regulation of immune functions in glioma. We investigated WNT-5A expression by in silico analysis of the cancer genome atlas (TCGA) transcript profiling of human glioblastoma samples and immunohistochemistry experiments of human glioma tissue microarrays (TMA). Our results reveal higher WNT-5A protein levels and mRNA expression in a subgroup of gliomas (WNT-5A(high)) compared to non-malignant control brain tissue. Furthermore, we show a significant correlation between WNT-5A in the tumor and presence of major histocompatibility complex Class II-positive microglia/monocytes. Our data pinpoint a positive correlation between WNT-5A and a proinflammatory signature in glioma. We identify increased presence of microglia/monocytes as an important aspect in the inflammatory transformation suggesting a novel role for WNT-5A in human glioma. PMID- 26511504 TI - Adrenomedullin attenuates interleukin-1beta-induced inflammation and apoptosis in rat Leydig cells via inhibition of NF-kappaB signaling pathway. AB - The aim of this paper is to investigate the protective effects of adrenomedullin (ADM) on interleukin-1beta (IL-1beta)-induced inflammation and apoptosis in rat Leydig cells and its underlying molecular mechanisms. Leydig cells were isolated from adult Sprague-Dawley rats. The cell culture was established by adding ADM 2h prior to 24h treatment with IL-1beta-induced cytotoxicity. We detected cell viability and concentrations of testosterone, reactive oxygen species (ROS), malondialdehyde (MDA), and reduced glutathione (GSH). Gene expression levels were measured for inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX 2). Concentrations were detected for nitric oxide (NO) and prostaglandin E2 (PGE2). Apoptosis was assessed using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Levels of gene expression and protein were detected for Bcl-2, Bax, caspase-3, and poly adenosine diphosphate-ribose polymerase (PARP). Protein levels were measured for nuclear factor kappa B (NF-kappaB) p65 and IkappaBalpha. ADM reduced IL-1beta-induced cytotoxicity. ADM pretreatment significantly increased testosterone concentrations and decreased ROS, MDA, and GSH concentrations. ADM pretreatment inhibited IL-1beta-induced inflammation in Leydig cells by decreasing the gene expression levels of iNOS and COX-2, as well as the concentrations of NO and PGE2. ADM pretreatment further decreased the number of TUNEL-positive stained Leydig cells, as confirmed by the increase in gene expression and protein levels of Bcl-2 and the decrease of Bax, caspase-3, and PARP levels. Moreover, ADM pretreatment inhibited NF-kappaB p65 phosphorylation and IkappaBalpha phosphorylation and degradation. ADM has potential anti-inflammatory and anti-apoptotic properties in IL-1beta-induced rat Leydig cells, which might be related to NF-kappaB signaling pathway. PMID- 26511505 TI - Electron transport chain inhibitors induce microglia activation through enhancing mitochondrial reactive oxygen species production. AB - Reactive oxygen species (ROS) are believed to be mediators of excessive microglial activation, yet the resources and mechanism are not fully understood. Here we stimulated murine microglial BV-2 cells and primary microglial cells with different inhibitors of electron transport chain (ETC), rotenone, thenoyltrifluoroacetone (TTFA), antimycin A, and NaN3 to induce mitochondrial ROS production and we observed the role of mitochondrial ROS in microglial activation. Our results showed that ETC inhibitors resulted in significant changes in cell viability, microglial morphology, cell cycle arrest and mitochondrial ROS production in a dose-dependent manner in both primary cultural microglia and BV-2 cell lines. Moreover, ETC inhibitors, especially rotenone and antimycin A stimulated secretion of interleukin 1beta (IL-1beta), interleukin 6 (IL-6), interleukin 12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) by microglia with marked activation of mitogen-activated proteinkinases (MAPKs) and nuclear factor kappaB (NF-kappaB), which could be blocked by specific inhibitors of MAPK and NF-kappaB and mitochondrial antioxidants, Mito-TEMPO. Taken together, our results demonstrated that inhibition of mitochondrial respiratory chain in microglia led to production of mitochondrial ROS and therefore may activate MAPK/NF-kB dependent inflammatory cytokines release in microglia, which indicated that mitochondrial-derived ROS were contributed to microglial activation. PMID- 26511506 TI - Preventing friendly fire in the war on microbes. AB - Lung injury induced by Pseudomonas aeruginosa infection might be subverted by targeting a chromatin-remodeling protein (Zou et al., this issue). PMID- 26511507 TI - IL-2Ralpha mediates temporal regulation of IL-2 signaling and enhances immunotherapy. AB - Interleukin-2 (IL-2) is a lymphocyte growth factor that is an important component of many immune-based cancer therapies. The efficacy of IL-2 is thought to be limited by the expansion of T regulatory cells, which express the high-affinity IL-2 receptor subunit IL-2Ralpha. IL-15 is under investigation as an alternative to IL-2. Although both cytokines signal through IL-2Rbetagamma, IL-15 does not bind IL-2Ralpha and therefore induces less T regulatory cell expansion. However, we found that transferred effector CD8(+) T cells induced curative responses in lymphoreplete mice only with IL-2-based therapy. Although conventional in vitro assays showed similar effector T cell responsiveness to IL-2 and IL-15, upon removal of free cytokine, IL-2 mediated sustained signaling dependent on IL 2Ralpha. Mechanistically, IL-2Ralpha sustained signaling by promoting a cell surface IL-2 reservoir and recycling of IL-2 back to the cell surface. Our results demonstrate that IL-2Ralpha endows T cells with the ability to compete temporally for limited IL-2 via mechanisms beyond ligand affinity. These results suggest that strategies to enhance IL-2Ralpha expression on tumor-reactive lymphocytes may facilitate the development of more effective IL-2-based therapies. PMID- 26511508 TI - Mortality factor 4 like 1 protein mediates epithelial cell death in a mouse model of pneumonia. AB - Unchecked epithelial cell death is fundamental to the pathogenesis of pneumonia. The recognition of unique signaling pathways that preserve epithelial cell viability may present new opportunities for interventional strategies. We describe that mortality factor 4 like 1 (Morf4l1), a protein involved in chromatin remodeling, is constitutively expressed at low levels in the lung because of its continuous degradation mediated by an orphan ubiquitin E3 ligase subunit, Fbxl18. Expression of Morf4l1 increases in humans with pneumonia and is up-regulated in lung epithelia after exposure to Pseudomonas aeruginosa or lipopolysaccharide. In a mouse model of pneumonia induced by P. aeruginosa, Morf4l1 is stabilized by acetylation that protects it from Fbxl18-mediated degradation. After P. aeruginosa infection of mice, overexpression of Morf4l1 resulted in lung epithelial cell death, whereas its depletion restored cell viability. Using in silico modeling and drug-target interaction studies, we identified that the U.S. Food and Drug Administration-approved thrombin inhibitor argatroban is a Morf4l1 antagonist. Argatroban inhibited Morf4l1-dependent histone acetylation, reduced its cytotoxicity, and improved survival of mice with experimental lung injury at doses that had no anticoagulant activity. These studies uncover a previously unrecognized biological mechanism whereby pathogens subvert cell viability by extending the life span of a cytotoxic host protein. Morf4l1 may be a potential molecular target for non-antibiotic pharmacotherapy during severe pulmonary infection. PMID- 26511509 TI - Cell-selective arrhythmia ablation for photomodulation of heart rhythm. AB - Heart disease, a leading cause of death in the developed world, is overwhelmingly correlated with arrhythmias, where heart muscle cells, myocytes, beat abnormally. Cardiac arrhythmias are usually managed by electric shock intervention, antiarrhythmic drugs, surgery, and/or catheter ablation. Despite recent improvements in techniques, ablation procedures are still limited by the risk of complications from unwanted cellular damage, caused by the nonspecific delivery of ablative energy to all heart cell types. We describe an engineered nanoparticle containing a cardiac-targeting peptide (CTP) and a photosensitizer, chlorin e6 (Ce6), for specific delivery to myocytes. Specificity was confirmed in vitro using adult rat heart cell and human stem cell-derived cardiomyocyte and fibroblast cocultures. In vivo, the CTP-Ce6 nanoparticles were injected intravenously into rats and, upon laser illumination of the heart, induced localized, myocyte-specific ablation with 85% efficiency, restoring sinus rhythm without collateral damage to other cell types in the heart, such as fibroblasts. In both sheep and rat hearts ex vivo, upon perfusion of CTP-Ce6 particles, laser illumination led to the formation of a complete electrical block at the ablated region and restored the physiological rhythm of the heart. This nano-based, cell targeted approach could improve ablative technologies for patients with arrhythmias by reducing currently encountered complications. PMID- 26511510 TI - Inflammation activation and resolution in human tendon disease. AB - Improved understanding of the role of inflammation in tendon disease is required to facilitate therapeutic target discovery. We studied supraspinatus tendons from patients experiencing pain before and after surgical subacromial decompression treatment. Tendons were classified as having early, intermediate, or advanced disease, and inflammation was characterized through activation of pathways mediated by interferon (IFN), nuclear factor kappaB (NF-kappaB), glucocorticoid receptor, and signal transducer and activator of transcription 6 (STAT-6). Inflammation signatures revealed expression of genes and proteins induced by IFN and NF-kappaB in early-stage disease and genes and proteins induced by STAT-6 and glucocorticoid receptor activation in advanced-stage disease. The proresolving proteins FPR2/ALX and ChemR23 were increased in early-stage disease compared to intermediate- to advanced-stage disease. Patients who were pain-free after treatment had tendons with increased expression of CD206 and ALOX15 mRNA compared to tendons from patients who continued to experience pain after treatment, suggesting that these genes and their pathways may moderate tendon pain. Stromal cells from diseased tendons cultured in vitro showed increased expression of NF kappaB and IFN target genes after treatment with lipopolysaccharide or IFNgamma compared to stromal cells derived from healthy tendons. We identified 15-epi lipoxin A4, a stable lipoxin isoform derived from aspirin treatment, as potentially beneficial in the resolution of tendon inflammation. PMID- 26511511 TI - Identification of type 2 diabetes subgroups through topological analysis of patient similarity. AB - Type 2 diabetes (T2D) is a heterogeneous complex disease affecting more than 29 million Americans alone with a rising prevalence trending toward steady increases in the coming decades. Thus, there is a pressing clinical need to improve early prevention and clinical management of T2D and its complications. Clinicians have understood that patients who carry the T2D diagnosis have a variety of phenotypes and susceptibilities to diabetes-related complications. We used a precision medicine approach to characterize the complexity of T2D patient populations based on high-dimensional electronic medical records (EMRs) and genotype data from 11,210 individuals. We successfully identified three distinct subgroups of T2D from topology-based patient-patient networks. Subtype 1 was characterized by T2D complications diabetic nephropathy and diabetic retinopathy; subtype 2 was enriched for cancer malignancy and cardiovascular diseases; and subtype 3 was associated most strongly with cardiovascular diseases, neurological diseases, allergies, and HIV infections. We performed a genetic association analysis of the emergent T2D subtypes to identify subtype-specific genetic markers and identified 1279, 1227, and 1338 single-nucleotide polymorphisms (SNPs) that mapped to 425, 322, and 437 unique genes specific to subtypes 1, 2, and 3, respectively. By assessing the human disease-SNP association for each subtype, the enriched phenotypes and biological functions at the gene level for each subtype matched with the disease comorbidities and clinical differences that we identified through EMRs. Our approach demonstrates the utility of applying the precision medicine paradigm in T2D and the promise of extending the approach to the study of other complex, multifactorial diseases. PMID- 26511512 TI - Allogeneic hematopoietic stem cell transplantation for Chediak-Higashi syndrome. AB - The clinical outcome of allogeneic HSCT was retrospectively analyzed in eight patients with CHS. In total, six of these eight patients are alive. Four of five patients transplanted with MAC achieved prompt engraftment, and three of the four patients, including two patients with AP before transplant, are alive without disease. In contrast, three patients transplanted with RIC without active AP disease achieved prompt engraftment and survive long term. RIC-HSCT might be an alternative treatment for CHS similar to other types of HLH, at least for patients without active AP disease. PMID- 26511513 TI - Heartbeat of the Sun from Principal Component Analysis and prediction of solar activity on a millenium timescale. AB - We derive two principal components (PCs) of temporal magnetic field variations over the solar cycles 21-24 from full disk magnetograms covering about 39% of data variance, with sigma = 0.67. These PCs are attributed to two main magnetic waves travelling from the opposite hemispheres with close frequencies and increasing phase shift. Using symbolic regression analysis we also derive mathematical formulae for these waves and calculate their summary curve which we show is linked to solar activity index. Extrapolation of the PCs backward for 800 years reveals the two 350-year grand cycles superimposed on 22 year-cycles with the features showing a remarkable resemblance to sunspot activity reported in the past including the Maunder and Dalton minimum. The summary curve calculated for the next millennium predicts further three grand cycles with the closest grand minimum occurring in the forthcoming cycles 26-27 with the two magnetic field waves separating into the opposite hemispheres leading to strongly reduced solar activity. These grand cycle variations are probed by alpha - Omega dynamo model with meridional circulation. Dynamo waves are found generated with close frequencies whose interaction leads to beating effects responsible for the grand cycles (350-400 years) superimposed on a standard 22 year cycle. This approach opens a new era in investigation and confident prediction of solar activity on a millenium timescale. PMID- 26511514 TI - New players in ABA signaling: identification of PUB12/13 involved in degradation of ABA co-receptor ABI1. PMID- 26511515 TI - Twists and turns--How we stepped into and had fun in the "boring" lipid field. AB - Compared to proteins and RNAs, functional specificities associated with structural variations in fatty acids and lipids have been greatly underexplored. This review describes how our lab naively started to work on lipids 14 years ago, and how we have gradually overcome obstacles to address some interesting biological questions by combining genetics with biochemical methods on the nematode Caenorhabditis elegans. Our studies have revealed lipid variants and their metabolic pathways, in specific tissues, impact development and behaviors by regulating specific signaling events. The review also discusses the general research approach, style of lab management, and funding mechanisms that have facilitated the frequent research direction changes in the lab, including the journey into the lipid field. PMID- 26511516 TI - Regulation of sister chromatid cohesion during the mitotic cell cycle. AB - Orderly execution of two critical events during the cell cycle--DNA replication and chromosome segregation--ensures the stable transmission of genetic materials. The cohesin complex physically connects sister chromatids during DNA replication in a process termed sister chromatid cohesion. Timely establishment and dissolution of sister chromatid cohesion is a prerequisite for accurate chromosome segregation, and is tight regulated by the cell cycle machinery and cohesin-associated proteins. In this review, we discuss recent progress in the molecular understanding of sister chromatid cohesion during the mitotic cell cycle. PMID- 26511517 TI - Supramolecular organizing centers (SMOCs) as signaling machines in innate immune activation. AB - Innate immunity offers the first line of defense against infections and other types of danger such as tumorigenesis. Its discovery provides tremendous therapeutic opportunities for numerous human diseases. Delving into the structural basis of signal transduction by innate immune receptors, our lab has recently helped to establish the new paradigm in which innate immune receptors transduce ligand-binding signals through formation of higher-order assemblies containing intracellular adapters, signaling enzymes and their substrates. These large signalosome assemblies may be visible under light microscopy as punctate structures in the um scale, connecting to the underlying molecular structures in the nm scale. They drive proximity-induced enzyme activation, and provide a mechanism for signaling amplification by nucleated polymerization. These supramolecular signaling complexes also open new questions on their cellular organization and mode of regulation, pose challenges to our methodology, and afford valuable implications in drug discovery against these medically important pathways. PMID- 26511518 TI - Cell permeable affinity- and activity-based probes. AB - Chemical biology has a significant role to play in the discovery and validation of new therapeutic targets. Activity- and affinity-based probes have demonstrated considerable promise in the drug discovery setting as they provide a chemoproteomic means to confirm and quantify target engagement and selectivity of small molecule drug candidates. Many of these technologies have been developed using cell lysate (through the use of resin-immobilized enzyme inhibitors for example), but this does not represent the biology of an intact cell. This review highlights recent advances made in the design and application of cell-permeable probes that report on target activity and drug-target occupancy in living cells, thus providing a means to decipher molecular pharmacology and pathology in a more physiologically relevant manner. PMID- 26511520 TI - Electrospun Fibrous Membranes with Super-large-strain Electric Superhydrophobicity. AB - Large-strain elastic superhydrophobicity is highly desirable for its enhanced use performance and functional reliability in mechanically dynamic environments, but remains challenging to develop. Here we have, for the first time, proven that an elastic fibrous membrane after surface hydrophobization can maintain superhydrophobicity during one-directional (uniaxial) stretching to a strain as high as 1500% and two-direction (biaxial) stretching to a strain up to 700%. The fibrous membrane can withstand at least 1,000 cycles of repeated stretching without losing the superhydrophobicity. Stretching slightly increases the membrane air permeability and reduces water breakthrough pressure. It is highly stable in acid and base environments. Such a permeable, highly-elastic superhydrophobic membrane may open up novel applications in membrane separation, healthcare, functional textile and energy fields. PMID- 26511519 TI - STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies. PMID- 26511521 TI - Increases in skeletal muscle ATGL and its inhibitor G0S2 following 8 weeks of endurance training in metabolically different rat skeletal muscles. AB - Adipose triglyceride lipase (ATGL) catalyzes the rate-limiting removal of the first fatty acid from a triglyceride. ATGL is activated by comparative gene identification-58 and inhibited by G(0)/G(1) switch gene-2 protein (G0S2). Research in other tissues and cell culture indicates that inhibition is dependent on relative G0S2-to-ATGL protein content. G0S2 may also have several roles within mitochondria; however, this has yet to be observed in skeletal muscle. The purpose of this study was to determine if muscle G0S2 relative to ATGL content would decrease to facilitate intramuscular lipolysis following endurance training. Male Sprague-Dawley rats (n = 10; age 51-53 days old) were progressively treadmill trained at a 10% incline for 8 wk ending with 25 m/min for 1 h compared with control. Sciatic nerve stimulation for hind-limb muscle contraction (and lipolysis) was administered for 30 min to one leg, leaving the opposing leg as a resting control. Soleus (SOL), red gastrocnemius (RG), and white gastrocnemius were excised from both legs following stimulation or control. ATGL protein increased in all trained muscles. Unexpectedly, G0S2 protein was greater in the trained SOL and RG. In RG-isolated mitochondria, G0S2 also increased with training, yet mitochondrial G0S2 content was unaltered with acute contraction; therefore, any role of G0S2 in the mitochondria does not appear to be acutely mediated by content alone. In summary, G0S2 increased with training in oxidative muscles and mitochondria but not following acute contraction, suggesting that inhibition is not through relative G0S2-to-ATGL content but through more complicated intracellular mechanisms. PMID- 26511522 TI - Orexin signaling is necessary for hypoglycemia-induced prevention of conditioned place preference. AB - While the neural control of glucoregulatory responses to insulin-induced hypoglycemia is beginning to be elucidated, brain sites responsible for behavioral responses to hypoglycemia are relatively poorly understood. To help elucidate central control mechanisms associated with hypoglycemia unawareness, we first evaluated the effect of recurrent hypoglycemia on a simple behavioral measure, the robust feeding response to hypoglycemia, in rats. First, food intake was significantly, and similarly, increased above baseline saline-induced intake (1.1 +/- 0.2 g; n = 8) in rats experiencing a first (4.4 +/- 0.3; n = 8) or third daily episode of recurrent insulin-induced hypoglycemia (IIH, 3.7 +/- 0.3 g; n = 9; P < 0.05). Because food intake was not impaired as a result of prior IIH, we next developed an alternative animal model of hypoglycemia-induced behavioral arousal using a conditioned place preference (CPP) model. We found that hypoglycemia severely blunted previously acquired CPP in rats and that recurrent hypoglycemia prevented this blunting. Pretreatment with a brain penetrant, selective orexin receptor-1 antagonist, SB-334867A, blocked hypoglycemia-induced blunting of CPP. Recurrently hypoglycemic rats also showed decreased preproorexin expression in the perifornical hypothalamus (50%) but not in the adjacent lateral hypothalamus. Pretreatment with sertraline, previously shown to prevent hypoglycemia-associated glucoregulatory failure, did not prevent blunting of hypoglycemia-induced CPP prevention by recurrent hypoglycemia. This work describes the first behavioral model of hypoglycemia unawareness and suggests a role for orexin neurons in mediating behavioral responses to hypoglycemia. PMID- 26511523 TI - Endothelin-1 and antiangiogenesis. AB - Antiangiogenesis, targeting vascular endothelial growth factor (VEGF), has become a well-established treatment for patients with cancer. This treatment is associated with nitric oxide (NO) suppression and a dose-dependent activation of the endothelin system, resulting in preeclampsia-like features, particularly hypertension and renal injury. Studies in endothelium NO synthase (eNOS) deficient mice and pharmacological treatment with endothelin receptor blockers and sildenafil indicate that an activated endothelin system, rather than NO suppression, mediates the side effects of angiogenesis inhibitors. Activation of the endothelin system is also observed in preeclamptic women, where it is related to the increased placental production of sFlt-1, the soluble form of the VEGF receptor-1. This receptor binds VEGF, thereby having the same consequences as antiangiogenic treatment with VEGF inhibitors. The side effects of antiangiogenic treatment in patients with cancer may be dose limiting, thereby impairing its therapeutic potential. In addition, because endothelin exerts proangiogenic effects, investigation of the effects of endothelin receptor blockade in patients with cancer treated with angiogenesis inhibitors is warranted. PMID- 26511524 TI - A qualitative exploration of people's experiences of pain neurophysiological education for chronic pain: The importance of relevance for the individual. AB - Pain neurophysiology education (PNE) is a distinct form of patient education in pain management. The aims of this study were to explore the experience of PNE for people with chronic pain and to gain insight into their understanding of their pain after PNE. This was a qualitative study, based on Interpretive Phenomenology Analysis, using individual semi-structured interviews to collect data. We recruited a purposive sample of 10 adults with chronic musculoskeletal pain (men and women; mean age 48 years; with a mean pain duration of 9 years) who had recently completed PNE delivered as a single 2-h group session. The interview transcripts were analysed for emerging themes. We identified three themes: perceived relevance for the individual participant; perceived benefits for the individual participant; and evidence of reconceptualisation. An interlinking narrative was the importance of relevance. Eight participants viewed the session as relevant and reported benefits ranging from a better understanding of pain, improved ability to cope with the pain, and some suggested improved levels of physical activity. Four of these participants showed evidence of reconceptualisation, which we describe as partial and patchy. Two participants reported no benefit and did not perceive the material delivered within PNE to be relevant to themselves. Relevance to the individual needs of a person with chronic pain may be a key factor in the success of PNE, and this is a particular challenge when it is delivered in a group situation. PMID- 26511525 TI - Correlations between maternal and neonatal serum selenium levels in full term neonates with hypoxic ischemic encephalopathy. AB - Perinatal hypoxic-ischemic encephalopathy (HIE) is an important cause of brain injury in the newborn and can result devastating consequences. The principle mechanisms underlying neurological damage in HIE resulting from hypoxemia and/or ischemia is deprivation of glucose and oxygen supply which energy failure. A consequent reperfusion injury often deteriorates the brain metabolism by increasing the oxidative stress damage. Selenium is a constituent of the antioxidant enzyme Glutathione peroxidase and is vital to antioxidant defense. This study aimed to measure the serum selenium levels in full term neonates with HIE and their mothers and to correlate between them and the severity of HIE. METHODS: The study included 60 full term neonates with HIE admitted to NICU of Minia university hospital during the period from January 2014 to February 2015. Twenty apparently healthy full term neonates selected as a control group. After history taking and careful clinical examination; all neonates were subjected to: Complete blood count, renal and liver function tests and serum electrolytes. Serum selenium was measured for all neonates and their mothers within 48 h of life using atomic flame spectrophotometer method. RESULTS: Neonates with HIE had significant lower serum selenium levels than normal healthy neonates (p = 0.001**) with the lowest levels in neonates with severe HIE but there were no significant differences between patients and controls as regards the maternal serum selenium levels. Significant negative correlations between serum selenium levels and the severity of HIE and base excess were present, while positive significant correlations were present with Apgar score and pH. There were no correlations between serum selenium levels and maternal serum selenium levels urea or creatinine levels. CONCLUSIONS: Neonates with HIE had lower serum selenium level than normal healthy neonates which is not dependent on the maternal serum selenium levels and was negatively correlated with the severity of HIE. PMID- 26511526 TI - Lameness caused by an extradural lumbosacral foraminal synovial cyst in three German Shepherd Dogs. AB - Three German Shepherd Dogs that were presented for investigation of chronic unilateral hindlimb lameness and pain in the lumbosacral region were diagnosed with an intraspinal, extradural synovial cyst and reactive fibrosis protruding into the foramen of the lumbosacral articulation using magnetic resonance imaging and histology. This extradural mass compressed the nerve root in the foramen and the cauda equina. During a dorsal laminectomy and unilateral partial foraminotomy, the cyst and the fibrotic tissue were removed with the aid of a 2.4 mm 30 degrees arthroscope for visualization of the foramen. The fibrotic tissue surrounding the cysts was in all cases confluent with the annulus of the intervertebral disc. The histological examination confirmed the diagnosis of a synovial cyst in all three cases by finding inflamed synovial membrane in the samples from the wall of the cyst as well as reactive fibrosis and cartilaginous metaplasia in the surrounding tissue. The three patients improved after the surgery and were pain free during the follow-up evaluations. PMID- 26511528 TI - Isolation and structural characterization of a mainly ligand-based dimetallic radical. AB - A radical cation of ruthenium was isolated and structurally characterized. The EPR spectrum and theoretical calculations indicate that the spin density mainly resides on ligands. The X-ray structure shows that the change in metal-metal bond lengths is negligible upon one-electron oxidation. sp(3) C-H bond activation was observed during the reaction of the parent molecule with the trityl cation, which possibly occurs via an oxidative EC mechanism: a thermodynamically favorable electron-transfer to give the radical cation intermediate, followed by the hydrogen atom abstraction to afford a cationic tetramethylfulvene complex with formation of a metal-carbon bond. PMID- 26511529 TI - Detection of Growth-Related Quantitative Trait Loci and High-Resolution Genetic Linkage Maps Using Simple Sequence Repeat Markers in the Kelp Grouper (Epinephelus bruneus). AB - To initiate breeding programs for kelp grouper (Epinephelus bruneus), the establishment of genetic linkage maps becomes essential accompanied by the search for quantitative trait loci that may be utilized in selection programs. We constructed a high-resolution genetic linkage map using 1055 simple sequence repeat (SSR) markers in an F1 family. Genome-wide and chromosome-wide significances of growth-related quantitative trait loci (QTLs) (body weight (BW) and total length (TL)) were detected using non-parametric mapping, Kruskal-Wallis (K-W) analysis, simple interval mapping (IM) and a permutation test (PT). Two stages and two families of fish were used to confirm the QTL regions. Ultimately, 714 SSR markers were matched that evenly covered the 24 linkage groups. In total, 509 and 512 markers were localized to the female and male maps, respectively. The genome lengths were approximately 1475.95 and 1370.39 cM and covered 84.68 and 83.21% of the genome, with an average interval of 4.1 and 4.0 cM, in females and males, respectively. One major QTL affecting BW and TL was found on linkage group EBR 17F that identified for 1% of the genome-wide significance and accounted for 14.6-18.9 and 14.7-18.5% of the phenotypic variance, and several putative QTL with 5% chromosome-wide significance were detected on eight linkage groups. Furthermore, the confirmed results of the regions harboring the major and putative QTLs showed consistent significant experiment-wide values of 1 and 5% as well as a chromosome-wide value of 5%. We identified growth-related QTLs that could be applied to find candidate genes for growth traits in further studies, and potentially useful in MAS breeding. PMID- 26511530 TI - Combined intravitreal melphalan and intravenous/intra-arterial chemotherapy for retinoblastoma with vitreous seeds. AB - PURPOSE: We aimed to evaluate the therapeutic effect and complications of combined intravitreal melphalan and intravenous/intra-arterial chemotherapy as a primary approach for retinoblastoma with vitreous seeds. METHODS: In this retrospective case series, eight eyes from eight retinoblastoma patients with vitreous seeds were included. All eyes received 20-30 MUg of intravitreal melphalan accompanied by intravenous and intra-arterial chemotherapy. Triple freeze-thaw cryotherapy was performed when withdrawing the needle from the eye to prevent tumor dissemination. RESULTS: Tumors and vitreous seeds regressed in all eyes. The mean number of intravitreal melphalan injections was 3.25 (median 3.50, range 2-4). Globe salvage was attained in seven of eight eyes (87.5 %). Enucleation was performed in one case, in which the pathologic section showed no residual tumor and tumor-free resection margins. Serous retinal detachment was observed in four eyes (50 %), and vitreous hemorrhage developed in two (25 %). Retinal pigment epithelium atrophy or mottling was found in three eyes (37.5 %). There were no cases of extraocular tumor extension or remote metastasis. CONCLUSIONS: Combined intravitreal melphalan and intravenous/intra-arterial chemotherapy was effective for tumor and vitreous seeding control, but vision threatening complications such as vitreous hemorrhage or serous retinal detachment occurred in half the cases. PMID- 26511531 TI - Outcomes for patients with papillary thyroid cancer who do not undergo prophylactic central neck dissection. AB - BACKGROUND: The role of prophylactic central neck dissection (CND) in the management of papillary thyroid cancer (PTC) is controversial. This report describes outcomes of an observational approach in patients without clinical evidence of nodal disease in PTC. METHODS: All patients who had surgery between 1986 and 2010 without CND for PTC were identified. All patients had careful clinical assessment of the central neck during preoperative and perioperative evaluation, with any suspicious nodal tissue excised for analysis. The cohort included patients in whom lymph nodes had been removed, but no patient had undergone a formal neck dissection. Recurrence-free survival (RFS), central neck RFS and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. RESULTS: Of 1798 patients, 397 (22.1 per cent) were men, 1088 (60.5 per cent) were aged 45 years or more, and 539 (30.0 per cent) had pT3 or pT4 disease. Some 742 patients (41.3 per cent) received adjuvant treatment with radioactive iodine. At a median follow-up of 46 months the 5-year DSS rate was 100 per cent. Five-year RFS and central neck RFS rates were 96.6 and 99.1 per cent respectively. CONCLUSION: Observation of the central neck is safe and should be recommended for all patients with PTC considered before and during surgery to be free of central neck metastasis. PMID- 26511532 TI - Metabolic Engineering toward Sustainable Production of Nylon-6. AB - Nylon-6 is a bulk polymer used for many applications. It consists of the non natural building block 6-aminocaproic acid, the linear form of caprolactam. Via a retro-synthetic approach, two synthetic pathways were identified for the fermentative production of 6-aminocaproic acid. Both pathways require yet unreported novel biocatalytic steps. We demonstrated proof of these bioconversions by in vitro enzyme assays with a set of selected candidate proteins expressed in Escherichia coli. One of the biosynthetic pathways starts with 2-oxoglutarate and contains bioconversions of the ketoacid elongation pathway known from methanogenic archaea. This pathway was selected for implementation in E. coli and yielded 6-aminocaproic acid at levels up to 160 mg/L in lab-scale batch fermentations. The total amount of 6-aminocaproic acid and related intermediates generated by this pathway exceeded 2 g/L in lab-scale fed-batch fermentations, indicating its potential for further optimization toward large-scale sustainable production of nylon-6. PMID- 26511533 TI - Plasma non-esterified docosahexaenoic acid is the major pool supplying the brain. AB - Despite being critical for normal brain function, the pools that supply docosahexaenoic acid (DHA) to the brain are not agreed upon. Using multiple kinetic models in free-living adult rats, we first demonstrate that DHA uptake from the plasma non-esterified fatty acid (NEFA) pool predicts brain uptake of DHA upon oral administration, which enters the plasma NEFA pool as well as multiple plasma esterified pools. The rate of DHA loss by the brain is similar to the uptake from the plasma NEFA pool. Furthermore, upon acute iv administration, although more radiolabeled lysophosphatidylcholine (LPC)-DHA enters the brain than NEFA-DHA, this is due to the longer plasma half-life and exposure to the brain. Direct comparison of the uptake rate of LPC-DHA and NEFA-DHA demonstrates that uptake of NEFA-DHA into the brain is 10-fold greater than LPC-DHA. In conclusion, plasma NEFA-DHA is the major plasma pool supplying the brain. PMID- 26511534 TI - Electrically conducting palladium selenide (Pd4Se, Pd17Se15, Pd7Se4) phases: synthesis and activity towards hydrogen evolution reaction. AB - Electrically conducting, continuous films of different phases of palladium selenides are synthesized by the thermolysis of single source molecular precursors. The films are found to be adherent on flat substrates such as glass, indium tin oxide and glassy carbon and are stable under electrochemical conditions. They are electrocatalytically active and in particular, for hydrogen evolution reaction. Catalytic activities with low Tafel slopes of 50-60 mV per decade are observed. PMID- 26511535 TI - No evidence for a J-shaped curve in treated hypertensive patients with increased cardiovascular risk: The VALUE trial. AB - Previous studies have debated the notion that low blood pressure (BP) during treatment, particularly diastolic (DBP), is associated with increased risk of cardiovascular disease. We evaluated the impact of low BP on cardiovascular outcomes in a high-risk population of 15,244 hypertensive patients, almost half of whom had a history of coronary artery disease (CAD). In the prospective Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, patients were randomized to valsartan or amlodipine regimens and followed for 4.2 years (mean) with no difference in the primary cardiovascular endpoint. A Cox proportional hazards model was used to evaluate the relationship between average on-treatment BP and clinical outcomes. The relationship between BP and cardiovascular events was adjusted for age, gender and body mass index, and baseline qualifying risk factors and diseases (smoking, high total cholesterol, diabetes mellitus, proteinuria, CAD, previous stroke and left ventricular hypertrophy). DBP >= 90 mmHg, compared with < 90 mmHg, was associated with increased incidence of the primary cardiovascular endpoint (all cardiac events); however, DBP < 70 mmHg, compared with >= 70 mmHg, was not associated with increased incidence after covariate adjustment (no J-shaped curve). Similar results were observed for death, myocardial infarction (MI), heart failure and stroke, considered separately. Nadir for MI was at DBP of 76 mmHg and for stroke 60 mmHg. The ratio of MI to stroke increased with lower DBP. In CAD patients the MI to stroke ratio was more pronounced than in patients without CAD but there was no significant J curve in either group. Systolic BP >= 150 but not < 130 mmHg, compared with 130 149 mmHg, similarly was associated with increased risk for primary outcome. In conclusion, patients in BP strata >= 150/90 mmHg, but not patients in BP strata < 130/70 mmHg, were at increased risk for adverse outcomes in this hypertensive, high-risk population. Although benefit in preventing MI in relation to preventing stroke levels off for the lowest BPs, these data provide no support for a J-curve in the treatment of high-risk hypertensive patients . The increase in the ratio of MI to stroke with lower DBP indicates target organ heterogeneity in that the optimal on-treatment DBP for cerebroprotection is below that for cardioprotection. PMID- 26511536 TI - Internet Usage Trends in Thoracic Surgery Patients and Their Caregivers. AB - With trends toward increasing patient involvement in medical decision-making, decreasing clinic times, and the availability of the Internet, patients and their caregivers are increasingly researching cancer diagnoses online. It is essential for physicians to understand patient Internet usage as it relates to their own health education. Internet usage trends have been studied in various areas, but not in thoracic diseases. This prospective cohort study surveyed 337 thoracic surgery patients and their caregivers with both cancer and non-cancer diagnoses to examine their Internet usage trends. Cancer subjects were more likely to research their condition online if they were younger, had a higher income, had a higher education level, and were currently employed. Only age and income level were predictive for non-cancer subjects. Separately, cancer subjects were more likely to trust information found on the Internet if they had a higher education. Subjects were most likely to conduct research on a hospital website than other websites. These data will be helpful to thoracic surgeons who want to appropriately educate patients and their caregivers and direct them to reliable Internet sources. These data also illustrate the importance of developing trustworthy hospital websites with disease-specific information. PMID- 26511537 TI - A dual-functional asymmetric squaraine-based low band gap hole transporting material for efficient perovskite solar cells. AB - We demonstrate for the first time an asymmetric squaraine-based low band-gap hole transporting material, which acted as both light harvesting and hole transporting layers in methylammonium lead triiodide perovskite solar cells. Opto electrochemical characterization revealed extremely high molar extinction coefficients of the absorption bands in the low energy region and prominent space charge delocalization due to its electronically asymmetric nature. A suitable band alignment of the squaraine HOMO level with the valence band edge of the perovskite, and the conduction band of the TiO2 with LUMO of the perovskite allowed a cascade of hole extraction and electron injection, respectively. Red shifted absorption was observed for both HTMs in thin films coated on the perovskite, and the optimized devices exhibited an impressive PCE of 14.7% under full sunlight illumination (100 mW cm(-2), AM1.5 G). The efficiency value is comparable to that of the devices using a state-of-the-art spiro-OMeTAD hole transport layer under similar conditions. Ambient stability after 300 h revealed that 88% of the initial efficiency remained for , and almost no change for , indicating that the devices had good long-term stability thus suggesting that the asymmetric squaraines have great potential as a dual-functional HTM for high performance perovskite solar cells. PMID- 26511539 TI - Power struggle. PMID- 26511538 TI - Nitrogen enrichment weakens ecosystem stability through decreased species asynchrony and population stability in a temperate grassland. AB - Biodiversity generally promotes ecosystem stability. To assess whether the diversity-stability relationship observed under ambient nitrogen (N) conditions still holds under N enriched conditions, we designed a 6-year field experiment to test whether the magnitude and frequency of N enrichment affects ecosystem stability and its relationship with species diversity in a temperate grassland. Results of this experiment showed that the frequency of N addition had no effect on either the temporal stability of ecosystem and population or the relationship between diversity and stability. Nitrogen addition decreased ecosystem stability significantly through decreases in species asynchrony and population stability. Species richness was positively associated with ecosystem stability, but no significant relationship between diversity and the residuals of ecosystem stability was detected after controlling for the effects of the magnitude of N addition, suggesting collinearity between the effects of N addition and species richness on ecosystem stability, with the former prevailing over the latter. Both population stability and the residuals of population stability after controlling for the effects of the magnitude of N addition were positively associated with ecosystem stability, indicating that the stabilizing effects of component populations were still present after N enrichment. Our study supports the theory predicting that the effects of environmental factors on ecosystem functioning are stronger than those of biodiversity. Understanding such mechanisms is important and urgent to protect biodiversity in mediating ecosystem functioning and services in the face of global changes. PMID- 26511540 TI - Burst bubbles. PMID- 26511541 TI - Ghost story. PMID- 26511542 TI - Forensic DNA evidence is not infallible. PMID- 26511554 TI - Malaria vaccine cautiously recommended for use in Africa. PMID- 26511555 TI - Super-fast Antarctic drills ready to hunt for oldest ice. PMID- 26511557 TI - US astronomers stuck in grant-rejection cycle. PMID- 26511556 TI - Massive UK baby study cancelled. PMID- 26511558 TI - Incoming space junk a scientific opportunity. PMID- 26511559 TI - Cancer-fighting viruses win approval. PMID- 26511560 TI - Before we drown we may die of thirst. PMID- 26511561 TI - How to make the most of carbon dioxide. PMID- 26511562 TI - Microbiology: Create a global microbiome effort. PMID- 26511563 TI - Institutions: Revive universities of the Muslim world. PMID- 26511567 TI - China: Engage the public to stop bear trafficking. PMID- 26511568 TI - Emissions estimates: Make raw emissions data public in China. PMID- 26511569 TI - Bovine tuberculosis: Badger-cull targets unlikely to reduce TB. PMID- 26511570 TI - Genetic gain of function: EU report advises on contentious research. PMID- 26511571 TI - 2015 awards: China Nobel stirs up attack on academies. PMID- 26511573 TI - Photonics: Random sudoku light. PMID- 26511574 TI - Plant biology: Pigments on the move. PMID- 26511575 TI - Chemical biology: Protein modification in a trice. PMID- 26511576 TI - Ecology: Foraging further. PMID- 26511578 TI - Abundant molecular oxygen in the coma of comet 67P/Churyumov-Gerasimenko. AB - The composition of the neutral gas comas of most comets is dominated by H2O, CO and CO2, typically comprising as much as 95 per cent of the total gas density. In addition, cometary comas have been found to contain a rich array of other molecules, including sulfuric compounds and complex hydrocarbons. Molecular oxygen (O2), however, despite its detection on other icy bodies such as the moons of Jupiter and Saturn, has remained undetected in cometary comas. Here we report in situ measurement of O2 in the coma of comet 67P/Churyumov-Gerasimenko, with local abundances ranging from one per cent to ten per cent relative to H2O and with a mean value of 3.80 +/- 0.85 per cent. Our observations indicate that the O2/H2O ratio is isotropic in the coma and does not change systematically with heliocentric distance. This suggests that primordial O2 was incorporated into the nucleus during the comet's formation, which is unexpected given the low upper limits from remote sensing observations. Current Solar System formation models do not predict conditions that would allow this to occur. PMID- 26511580 TI - Decadal slowdown of a land-terminating sector of the Greenland Ice Sheet despite warming. AB - Ice flow along land-terminating margins of the Greenland Ice Sheet (GIS) varies considerably in response to fluctuating inputs of surface meltwater to the bed of the ice sheet. Such inputs lubricate the ice-bed interface, transiently speeding up the flow of ice. Greater melting results in faster ice motion during summer, but slower motion over the subsequent winter, owing to the evolution of an efficient drainage system that enables water to drain from regions of the ice sheet bed that have a high basal water pressure. However, the impact of hydrodynamic coupling on ice motion over decadal timescales remains poorly constrained. Here we show that annual ice motion across an 8,000-km(2) land terminating region of the west GIS margin, extending to 1,100 m above sea level, was 12% slower in 2007-14 compared with 1985-94, despite a 50% increase in surface meltwater production. Our findings suggest that, over these three decades, hydrodynamic coupling in this section of the ablation zone resulted in a net slowdown of ice motion (not a speed-up, as previously postulated). Increases in meltwater production from projected climate warming may therefore further reduce the motion of land-terminating margins of the GIS. Our findings suggest that these sectors of the ice sheet are more resilient to the dynamic impacts of enhanced meltwater production than previously thought. PMID- 26511579 TI - Organometallic palladium reagents for cysteine bioconjugation. AB - Reactions based on transition metals have found wide use in organic synthesis, in particular for the functionalization of small molecules. However, there are very few reports of using transition-metal-based reactions to modify complex biomolecules, which is due to the need for stringent reaction conditions (for example, aqueous media, low temperature and mild pH) and the existence of multiple reactive functional groups found in biomolecules. Here we report that palladium(II) complexes can be used for efficient and highly selective cysteine conjugation (bioconjugation) reactions that are rapid and robust under a range of bio-compatible reaction conditions. The straightforward synthesis of the palladium reagents from diverse and easily accessible aryl halide and trifluoromethanesulfonate precursors makes the method highly practical, providing access to a large structural space for protein modification. The resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody drug conjugates. These palladium complexes show potential as benchtop reagents for diverse bioconjugation applications. PMID- 26511582 TI - El Nino and intense tropical cyclones. PMID- 26511583 TI - Jin et al. reply. PMID- 26511584 TI - To know you is to love you: Effects of intergroup contact and knowledge on intergroup anxiety and prejudice among indigenous Chileans. AB - Two surveys were conducted in Chile with indigenous Mapuche participants (N study 1: 573; N study 2: 198). In line with previous theorising, it was predicted that intergroup contact with the non-indigenous majority reduces prejudice. It was expected that this effect would be because of contact leading to more knowledge about the outgroup, which would then lead to less intergroup anxiety. The two studies yielded converging support for these predictions. PMID- 26511585 TI - Magnetic coupling of vortices in a two dimensional lattice. AB - We investigated the magnetization reversal of magnetic vortex structures in a two dimensional lattice. The structures were formed by permalloy (Py) film deposition onto large arrays of self assembled spherical SiO(2)-particles with a diameter of 330 nm. We present the dependence of the nucleation and annihilation field of the vortex structures as a function of the Py layer thickness(aspect ratio) and temperature. By increasing the Py thickness up to 90 nm or alternatively by lowering the temperature the vortex structure becomes more stable as expected. However, the increase of the Py thickness results in the onset of strong exchange coupling between neighboring Py caps due to the emergence of Py bridges connecting them. In particular, we studied the influence of magnetic coupling locally by in-field scanning magne to-resistive microscopy and full-field magnetic soft x-ray microscopy, revealing a domain-like nucleation process of vortex states, which arises via domain wall propagation due to exchange coupling of the closely packed structures. By analyzing the rotation sense of the reversed areas, large connected domains are present with the same circulation sense. Furthermore, the lateral core displacements when an in-plane field is applied were investigated, revealing spatially enlarged vortex cores and a broader distribution with increasing Py layer thickness. In addition, the presence of some mixed states, vortices and c-states, is indicated for the array with the thickest Py layer. PMID- 26511586 TI - Follicular fluid and serum metabolites in Holstein cows are predictive of genetic merit for fertility. AB - The aims of the present study were to: (1) characterise the metabolome of follicular fluid and serum in dairy cows with similar genetic merit for milk production but with extremes of good (Fert+) or poor (Fert-) genetic merit for fertility; and (2) identify potential biomarkers of dairy cow fertility. Follicular fluid from the first wave dominant follicle and serum were collected on Day 7 of the oestrous cycle. The most pronounced effect of genotype was noted in the serum, where the abundance of total polyunsaturated fatty acids and n-6 polyunsaturated fatty acids was greater in Fert+ cows, and the abundance of total saturated fatty acids was greater in Fert- cows. The abundance of nine fatty acids (arachidic acid, heneicosanoic acid, myristic acid, behenic acid, myristoleic acid, heptadecenoic acid, cis-11-eicosanoic acid, nervonic acid and gamma-linolenic acid) in follicular fluid was affected by genotype. Concentrations of cysteine, leucine, ornithine, proline and tyrosine in follicular fluid, and asparagine, creatinine, cysteine, methionine, proline and valine in serum, were also affected by genotype. Receiver operating characteristic curve analysis indicated that the follicular fluid and serum fatty acids and follicular fluid amino acids that were significantly affected by genotype were highly predictive of fertility genotype. PMID- 26511587 TI - Evidence for a role of adaptive immune response in the disease pathogenesis of the MPTP mouse model of Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post-mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). In wild-type mice MHC II levels in the ventral midbrain were upregulated 1-2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP-induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon gamma or tumour necrosis factor-alpha in the brain after MPTP treatment, as was found in wild-type mice. However, interleukin-1beta was significantly increased in both wild-type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II-mediated T cell activation is required for the full expression of pathology in this model of PD. PMID- 26511588 TI - Habitat preferences of Ukrainian brook lamprey Eudontomyzon mariae ammocoetes in the lowland rivers of Central Europe. AB - The pattern of microhabitat preferences of Ukrainian brook lamprey Eudontomyzon mariae ammocoetes was examined in two rivers of central Poland: the Pilica River (the Vistula River basin) and the Grabia River (the Odra River basin). A comparison of abiotic factors of the rivers revealed differences in water speed and principal components: PC1 (determining gradient from decreasing medium sand to the increasing share of three fractions of gravel), PC2 (a gradient from the declining share of very coarse and coarse sand fractions to the growing content of fine sand) and PC3 (correlated with an increasing proportion of silt). The sites did not differ significantly in terms of water depth. Relative abundance and frequency of ammocoete occurrence in the Grabia River were higher than in the Pilica River. Only speed, PC1 and PC2 made a significant contribution to the prediction of larval occurrence. Eudontomyzon mariae larvae preferred substrata with a reduced amount of medium sand and increased content of gravel (PC1) as well as with a lower content of coarse sand and higher proportion of fine-grained sand (PC2). The ammocoetes also preferred areas with a water speed of 0.2 m s(-1) but avoided speeds >= 0.6 m s(-1). The abundance of E. mariae was affected by water speed, as well as by all PCs. The mean +/- s.e. optimal current speed was 0.265 +/- 0.007 m s(-1), while abundance decreased with increasing amounts of gravel (PC1) and increased with increasing amounts of fine sand and silt in the bottom substratum (PC2 and PC3). Comparison of ammocoete microhabitat use in the Pilica and Grabia Rivers showed the lack of differences in distribution in the preferred values of current speed, PC1 and PC2. PMID- 26511589 TI - Comparing parent and teacher assessments of mental health in elementary school children. AB - BACKGROUND: Screening instruments are often used for detecting mental health problems in children and adolescents. The Strengths and Difficulties Questionnaire (SDQ) is one instrument for screening children's mental health. The SDQ can be used for assessment by different informants, i.e. parents, teachers and by 11-16 year olds for self-reporting. AIMS: The aim was to compare the precision and validity of parental and teacher SDQ assessments in elementary school children, and to analyze whether assessments were affected by the child's sex and by socio-demographic factors. METHODS: A total of 512 primary school students were included in a cross-sectional study. Exploratory factor analysis, sensitivity/specificity analysis, Cronbach's alphas, and logistic regression were applied. RESULTS: Parents rated 10.9% and teachers 8.8% of the children as high risk individuals, but the overlap was low (32.1%). Cronbach's alphas were 0.73 and 0.71 for parents and teachers, respectively. However, factor analysis showed that the five-factor solution could be confirmed only for teacher ratings. Moreover, only the parents' ratings were affected by maternal educational level and parental country of birth when rating the same children as the teachers. CONCLUSIONS: Construct validity was only confirmed for teacher assessments. However, parental assessments might capture a dimension of a child's mental health that seems to be sensitive to socioeconomic factors, which could be important when addressing equity issues, and for the dialogue between parents and school. PMID- 26511590 TI - A social way to experience a scientific event: Twitter use at the 7th European Public Health Conference. AB - AIMS: Many studies have analysed Twitter's use by attendees of scientific meetings and the characteristics of conference-related messages and most active attendees. Despite these previous reports, to date no studies have described the use of Twitter during Public Health conferences. For this reason, we decided to perform an analysis of Twitter's use during the 7th European Public Health (EPH) Conference (Glasgow, November 2014). METHODS: All the tweets published from 21 July to 2 December 2014 and including the hashtag #ephglasgow were retrieved and much information (author, date, retweets, favourites, mentions, presence of pictures and/or external links, content type and topics) was analysed. RESULTS: A total of 1066 tweets with the hashtag #ephglasgow were retrieved; 86.3% of these were tweeted during the conference. A total of 209 single accounts tweeted, pictures were present in 29.7% tweets while external links were published in 13.8%. Conference speakers were mentioned in around 30% of tweets. Almost 60% of the tweets had a session-related content. Considering only the session-related tweets, one-third had as the main topic 'Health inequalities and migrant and ethnic minority health', while 20% were 'Health policy and health economics' oriented. CONCLUSIONS: The results of this study have demonstrated a massive use of Twitter by conference attendees during the 7th EPH conference, and that conference attendees are willing to share quotes and impressions particularly about conference-related topics. It is mandatory for conference organisers to promote online discussion and knowledge dissemination during conferences, especially in the public health field. PMID- 26511591 TI - The Movember campaign: Impact on referral patterns and diagnosis of prostate cancer. AB - AIMS: The aims of the present study were to investigate referral patterns and the diagnosis of prostate cancer (PCa) before and after the Movember campaign was initiated in Denmark. METHODS: All men (n=2817) referred to the Department of Urology at Frederiksberg Hospital with suspicion of having PCa in the period 1 January 2007-31 January 2014 were identified. Based on the referral date, patients were categorised as pre-Movember (1 January 2007-31 January 2011) and Movember (1 February 2011-31 January 2014), respectively. Annual referral rates/100.000 inhabitants were calculated and compared with rate-ratio (RR) tests. RESULTS: The median prostate-specific antigen (PSA) at referral dropped significantly from 9.8 ng/mL in 2007-2011 to 7.9 ng/mL in 2011-2014,p< 0.001. The incidence rate of men referred with suspicion of PCa increased from 134/100.000 in the pre-Movember period to 168/100.000 in the Movember period (RR 1.25 [95% CI 1.16-1.35]). In contrast to what we anticipated, there was no increase in referral in the months following the campaign. The incidence rates of men diagnosed with PCa and low-risk PCa were similar in the Movember period and the pre-Movember period (PCa: RR 1.08 [0.97-1.21]; low-risk PCa: RR 1.29 [0.98 1.73]). CONCLUSIONS: After the initiation of the Movember campaign a significant decline in the PSA level at referral and an increase in the number of patients referred under suspicion of PCa was observed; however, only minor differences in referral patterns and PCa diagnosis were detected. The results indicate that the Movember campaign had a limited immediate effect on referral, however, it may have contributed to an increased awareness of PCa. PMID- 26511592 TI - Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia. AB - OBJECTIVES: To study placental patterns in pregnancies complicated by pre eclampsia (PE) and to verify whether the findings are related to gestational age (GA) at PE onset and second-trimester uterine artery (UtA) Doppler. METHODS: For all pre-eclamptic women who delivered between January 2010 and December 2013, we collected retrospectively data related to placental findings and UtA Doppler velocimetry performed at PE onset. The study cohort was divided into groups according to early-onset (EO) or late-onset (LO) PE. Regression analysis was performed to test the ability of UtA Doppler velocimetry to predict subsequent development of placental lesions, after correcting for possible confounders. RESULTS: Placental abnormalities occurred with a significantly lower incidence in the LO-PE group (n = 72) than in the EO-PE group (n = 105) (P = 0.02). Irrespective of GA at PE onset, UtA pulsatility index (PI) was able to predict macroscopic infarctions (P = 0.001), distal villous hypoplasia (P = 0.03), decidual arteriolopathy (P = 0.03), villous infarcts (P < 0.001), syncytiotrophoblast 'knots' (P = 0.02), microcalcifications (P = 0.02), perivillous fibrin deposition (P = 0.02) and placental hemorrhage (P = 0.01). CONCLUSIONS: Similar placental abnormalities were present in both EO-PE and LO-PE groups, although with quantitative differences according to GA and UtA Doppler velocimetry at PE onset. Histological patterns were predicted by UtA-PI, independently of GA, supporting the use of UtA Doppler velocimetry as the key criterion in PE classification. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26511593 TI - Bladder cancer and occupational exposure to diesel and gasoline engine emissions among Canadian men. AB - The International Agency for Research on Cancer has classified diesel exhaust as a carcinogen based on lung cancer evidence; however, few studies have investigated the effect of engine emissions on bladder cancer. The purpose of this study was to investigate the association between occupational exposure to diesel and gasoline emissions and bladder cancer in men using data from the Canadian National Enhanced Cancer Surveillance System; a population-based case control study. This analysis included 658 bladder cancer cases and 1360 controls with information on lifetime occupational histories and a large number of possible cancer risk factors. A job-exposure matrix for engine emissions was supplemented by expert review to assign values for each job across three dimensions of exposure: concentration, frequency, and reliability. Odds ratios (OR) and their corresponding 95% confidence intervals were estimated using logistic regression. Relative to unexposed, men ever exposed to high concentrations of diesel emissions were at an increased risk of bladder cancer (OR = 1.64, 0.87-3.08), but this result was not significant, and those with >10 years of exposure to diesel emissions at high concentrations had a greater than twofold increase in risk (OR = 2.45, 1.04-5.74). Increased risk of bladder cancer was also observed with >30% of work time exposed to gasoline engine emissions (OR = 1.59, 1.04-2.43) relative to the unexposed, but only among men that had never been exposed to diesel emissions. Taken together, our findings support the hypothesis that exposure to high concentrations of diesel engine emissions may increase the risk of bladder cancer. PMID- 26511594 TI - Uncovering Professional Attitudes Toward Treatment of Rare Carcinomas of the Breast: An International Practice e-Survey Involving 32 Countries. AB - World Health Organization classification has identified a dozen rare subtypes accounting for less than 10% of all breast cancers (BC), generally not taken into account in treatment guidelines. We evaluated professionals' attitudes toward decision-making regarding rare BC and consensus guidelines needs. In this international e-survey, 236 BC experts from all specialties were contacted through email to fill an online questionnaire about their practices. Eighty-six experts from 32 countries participated (36%); 50% medical oncologists, 21% surgeons, 17% pathologists, and 12% radiation oncologists. General BC care decisions were based on consensus guidelines in 77% of expert, whereas routine individual treatment decisions for BC were made by multi-disciplinary boards in 76%. Only 10% strongly considered rare BC should be treated following existing standard guidelines. Interestingly, 50-80% described individualizing treatment for rare BC according to pathologic subtype. More than 90% of experts would welcome international recommendations for rare BC. This large scale international multi-disciplinary survey revealed overarching concerns centered on several key themes: the lack of resources and data to address these less common BC; the heterogeneous management of rare BC depending on geographical location and specialist training; the demand for international consensus guidelines regarding their diagnosis and treatment. PMID- 26511595 TI - The epidemiology of traumatic event exposure worldwide: results from the World Mental Health Survey Consortium. AB - BACKGROUND: Considerable research has documented that exposure to traumatic events has negative effects on physical and mental health. Much less research has examined the predictors of traumatic event exposure. Increased understanding of risk factors for exposure to traumatic events could be of considerable value in targeting preventive interventions and anticipating service needs. METHOD: General population surveys in 24 countries with a combined sample of 68 894 adult respondents across six continents assessed exposure to 29 traumatic event types. Differences in prevalence were examined with cross-tabulations. Exploratory factor analysis was conducted to determine whether traumatic event types clustered into interpretable factors. Survival analysis was carried out to examine associations of sociodemographic characteristics and prior traumatic events with subsequent exposure. RESULTS: Over 70% of respondents reported a traumatic event; 30.5% were exposed to four or more. Five types - witnessing death or serious injury, the unexpected death of a loved one, being mugged, being in a life-threatening automobile accident, and experiencing a life-threatening illness or injury - accounted for over half of all exposures. Exposure varied by country, sociodemographics and history of prior traumatic events. Being married was the most consistent protective factor. Exposure to interpersonal violence had the strongest associations with subsequent traumatic events. CONCLUSIONS: Given the near ubiquity of exposure, limited resources may best be dedicated to those that are more likely to be further exposed such as victims of interpersonal violence. Identifying mechanisms that account for the associations of prior interpersonal violence with subsequent trauma is critical to develop interventions to prevent revictimization. PMID- 26511596 TI - Cranial morphological variation in Peromyscus maniculatus over nearly a century of environmental change in three areas of California. AB - Determining how species respond to prolonged environmental change is critical to understanding both their evolutionary biology and their conservation needs. In general, organisms can respond to changing environmental conditions by moving, by adapting in situ, or by going locally or globally extinct. Morphological changes, whether plastic or adaptive, are one way that species may respond in situ to local environmental change. Because cranial morphology is influenced by selective pressures arising from an organism's abiotic and biotic environments, including aspects of thermal physiology, diet, and sensory ecology, studies of cranial morphology may generate important insights into how species are responding to environmental change. To assess potential response of deer mice (Peromyscus maniculatus) to changing conditions in the Sierra Nevada Mountains of California, we quantified cranial variation in museum specimens of this species collected approximately 100 years apart. Specifically, we examined how cranial morphology varies in three populations of this geographically widespread, ecological generalist over elevation and time. Our analyses indicate that cranial morphology does not differ with elevation within either modern or historical samples but does vary between time periods, suggesting that in situ responses to environmental change have occurred. Contrary to predictions based on Bergmann's rule, we found no consistent relationship between body size and either elevation or time, suggesting that morphological differences detected between historic and modern specimens are specific to factors influencing cranial structure. Collectively, these analyses demonstrate the potential importance of in situ changes in morphology as a response to changing environmental conditions. PMID- 26511597 TI - Nontotally symmetric trifurcation of an SN 2 reaction pathway. AB - A new type of reaction pathway which involves a nontotally symmetric trifurcation was found and investigated for a typical SN 2-type reaction, NC(-) + CH3 X -> NC CH3 + X(-) (X = F, Cl). A nontotally symmetric valley-ridge inflection (VRI) point was located along the C3 v reaction path. For X = F, the minimum energy path (MEP) starting from the transition state (TS) leads to a second-order saddle point with C3v symmetry, which connects three product minima of Cs symmetry. For X = Cl, four product minima have been observed, of which three belong to Cs symmetry and one to C3v symmetry. The branching path from the VRI point to the lower symmetry minima was determined by a linear interpolation technique. The branching mechanism is discussed based on the reaction path curvature and net atomic charges, and the possibility of a nonotally symmetric n-furcation is discussed. PMID- 26511599 TI - Is a reduction in albuminuria associated with renal and cardiovascular protection? A post hoc analysis of the ALTITUDE trial. AB - AIMS: To investigate whether the degree of albuminuria reduction observed in the ALTITUDE trial is associated with renal and cardiovascular protection, and secondly, whether the reduction in albuminuria was too small to afford clinical benefit. METHODS: In a post hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of albuminuria changes at 6 months on renal and cardiovascular outcomes using Cox proportional hazard regression. RESULTS: The median change in albuminuria in the first 6 months in the aliskiren arm of the trial was -12% (25th to 75th percentile: -48.7_to_ +41.9%) and 0.0% (25th to 75th percentile: -40.2_to_55%) in the placebo arm. Changes in albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: a >30% reduction in albuminuria in the first 6 months was associated with a 62% reduction in renal risk and a 25% reduction in cardiovascular risk compared with an increase in albuminuria. The association between changes at 6 months in albuminuria and renal or cardiovascular endpoints was similar in the two treatment groups (p for interaction >0.1 for both endpoints). CONCLUSIONS: The addition of aliskiren to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy resulted in albuminuria changes that were associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection because the overall reduction in albuminuria in the aliskiren arm was too small and nearly similar to that in the placebo arm. PMID- 26511600 TI - Characteristics and health of homeless families: the ENFAMS survey in the Paris region, France 2013. AB - BACKGROUND: The objectives were to estimate the size of homeless family population in Paris region, to describe their living conditions and health and to analyse the impact of homelessness on children's growth and development, which was never investigated in France. METHODS: A cross-sectional survey was conducted on a random sample of homeless sheltered families in 2013. Families were interviewed in 17 languages and a nurse took anthropometric measures, blood samples and collected health data from child health reports. RESULTS: The population size was estimated at 10 280 families. Half were single-parent female families and 94% were born outside France. Most families had experienced housing instability and 94% were living below the poverty line (828 euros/month). Malnutrition was a major problem: the prevalence of food insecurity was high (77% of parents and 69% of children), as well as anaemia (50% of mothers and 38% of children), overweight (38% of mothers and 22% of children) and obesity (32% of mothers and 4% of children). High rates of depressive disorders were found in 30% of homeless mothers and 20% of children had signs of possible mental health disorders. DISCUSSION: These first results highlight the important number of families among the homeless population in Paris region. Families differed from other homeless people regarding social characteristics such as birthplace, single parent status and residential instability that are likely to influence schooling, social ties, health and access to care. These results demonstrate the need for urgent actions targeting homeless families, in terms of reducing housing instability and providing adequate care, especially for children. PMID- 26511601 TI - Relationship of secondhand smoke exposure with sociodemographic factors and smoke free legislation in the European Union. AB - BACKGROUND: To explore whether exposure to secondhand smoke (SHS) among non smokers in the European Union (EU) showed any association with sociodemographic factors and/or the extent of national tobacco control policies. METHODS: A secondary analysis was performed on data from 26 751 individuals >=15 years old from 27 EU member states (EU MS), collected during the 2012 Special Eurobarometer survey (wave 77.1). Respondents were asked whether they had been exposed to SHS in eating or drinking establishments during the past 6 months, and/or in their workplace. Data on smoke-free policies were extracted from the European Tobacco Control Status Report and the European Tobacco Control Scale (TCS) in 2013. RESULTS: In total, 29.0% of non-smoking participants reported being exposed to SHS in indoor areas. Males (vs. females) as well as individuals with difficulties to pay bills (vs. those with no difficulties), had significantly greater odds of being exposed to SHS in bars, restaurants and workplaces. For every unit increase of a country's score on the Smoke-free Component of the TCS (indicating greater adherence to smoke-free legislations) the odds ratio of reporting exposure to SHS was 0.82 in bars, 0.85 in restaurants and 0.94 in workplaces. CONCLUSIONS: Differences in exposure to SHS clearly exist between and within EU MS, despite the fact that they all have signed the Framework Convention on Tobacco Control, with the burden found to disproportionally affect younger people and individuals with financial difficulties. Moreover, enforcement of smoke-free legislation was inversely associated with SHS exposure, highlighting the importance of enforcing comprehensive smoking bans. PMID- 26511602 TI - Evaluation of embouchure dysfunction: Experience of 139 patients at a single center. AB - OBJECTIVES/HYPOTHESIS: Our aims are to 1) illustrate the complexity and phenomenological richness of the embouchure; 2) delineate the main clinical features of non-dystonic embouchure problems (NED) versus embouchure dystonia (ED); and 3) provide a practical framework for physicians who may encounter a patient with embouchure dysfunction. STUDY DESIGN: We performed retrospective chart and video review and report 139 instrumentalists with embouchure dysfunction evaluated over a 15-year period. RESULTS: Included in this group are 109 ED patients (20 newly reported and 89 previously published) and 30 NED patients. Non-dystonic embouchure problems included the overuse syndrome, infraorbital neuropathy, and orbicularis oris tears, among others. CONCLUSIONS: Based on this experience, the largest series presented to date, we propose a practical guide to help evaluate patients with embouchure dysfunction in the office. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1327-1333, 2016. PMID- 26511603 TI - Effect of Multiple Clock Gene Ablations on the Circadian Period Length and Temperature Compensation in Mammalian Cells. AB - Most organisms have cell-autonomous circadian clocks to coordinate their activity and physiology according to 24-h environmental changes. Despite recent progress in circadian studies, it is not fully understood how the period length and the robustness of mammalian circadian rhythms are determined. In this study, we established a series of mouse embryonic stem cell (ESC) lines with single or multiplex clock gene ablations using the CRISPR/Cas9-based genome editing method. ESC-based in vitro circadian clock formation assay shows that the CRISPR-mediated clock gene disruption not only reproduces the intrinsic circadian molecular rhythms of previously reported mice tissues and cells lacking clock genes but also reveals that complexed mutations, such as CKIdelta(m/m):CKIepsilon(+/m):Cry2(m/m) mutants, exhibit an additively lengthened circadian period. By using these mutant cells, we also investigated the relation between period length alteration and temperature compensation. Although CKIdelta deficient cells slightly affected the temperature insensitivity of period length, we demonstrated that the temperature compensation property is largely maintained in all mutants. These results show that the ESC-based assay system could offer a more systematic and comprehensive approach to the genotype-chronotype analysis of the intracellular circadian clockwork in mammals. PMID- 26511604 TI - TADDOL-based phosphorus(III)-ligands in enantioselective Pd(0)-catalysed C-H functionalisations. AB - Monodentate TADDOL-derived phosphoramidites and phosphonites are versatile chiral ligands for enantioselective Pd(0)-catalysed C-H functionalisations. They enable highly selective cyclisations to access a wide range of chiral carbo- and heterocycles. The high attractiveness of this ligand class consists in their modular structure, allowing for a quick assembly of a library with variable steric properties. Asymmetric C-H functionalisation methods utilising catalytic systems based on Pd(0) complexes and TADDOL-type ligands are presented and aspects of selectivity are discussed. PMID- 26511605 TI - The Early Psychosis Intervention Center (EPICENTER): development and six-month outcomes of an American first-episode psychosis clinical service. AB - BACKGROUND: There is growing evidence that specialized clinical services targeted toward individuals early in the course of a psychotic illness may be effective in reducing both the clinical and economic burden associated with these illnesses. Unfortunately, the United States has lagged behind other countries in the delivery of specialized, multi-component care to individuals early in the course of a psychotic illness. A key factor contributing to this lag is the limited available data demonstrating the clinical benefits and cost-effectiveness of early intervention for psychosis among individuals served by the American mental health system. Thus, the goal of this study is to present clinical and cost outcome data with regard to a first-episode psychosis treatment center within the American mental health system: the Early Psychosis Intervention Center (EPICENTER). METHODS: Sixty-eight consecutively enrolled individuals with first episode psychosis completed assessments of symptomatology, social functioning, educational/vocational functioning, cognitive functioning, substance use, and service utilization upon enrollment in EPICENTER and after 6 months of EPICENTER care. All participants were provided with access to a multi-component treatment package comprised of cognitive behavioral therapy, family psychoeducation, and metacognitive remediation. RESULTS: Over the first 6 months of EPICENTER care, participants experienced improvements in symptomatology, social functioning, educational/vocational functioning, cognitive functioning, and substance abuse. The average cost of care during the first 6 months of EPICENTER participation was lower than the average cost during the 6-months prior to joining EPICENTER. These savings occurred despite the additional costs associated with the receipt of EPICENTER care and were driven primarily by reductions in the utilization of inpatient psychiatric services and contacts with the legal system. CONCLUSIONS: The results of our study suggest that multi-component interventions for first episode psychosis provided in the US mental health system may be both clinically beneficial and cost-effective. Although additional research is needed, these findings provide preliminary support for the growing delivery of specialized multi-component interventions for first-episode psychosis within the United States. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01570972; Date of Trial Registration: November 7, 2011. PMID- 26511606 TI - Fluorescent protein-tagged Vpr dissociates from HIV-1 core after viral fusion and rapidly enters the cell nucleus. AB - BACKGROUND: HIV-1 Vpr is recruited into virions during assembly and appears to remain associated with the viral core after the reverse transcription and uncoating steps of entry. This feature has prompted the use of fluorescently labeled Vpr to visualize viral particles and to follow trafficking of post-fusion HIV-1 cores in the cytoplasm. RESULTS: Here, we tracked single pseudovirus entry and fusion and observed that fluorescently tagged Vpr gradually dissociates from post-fusion viral cores over the course of several minutes and accumulates in the nucleus. Kinetics measurements showed that fluorescent Vpr released from the cores very rapidly entered the cell nucleus. More than 10,000 Vpr molecules can be delivered into the cell nucleus within 45 min of infection by HIV-1 particles pseudotyped with the avian sarcoma and leukosis virus envelope glycoprotein. The fraction of Vpr from cell-bound viruses that accumulated in the nucleus was proportional to the extent of virus-cell fusion and was fully blocked by viral fusion inhibitors. Entry of virus-derived Vpr into the nucleus occurred independently of envelope glycoproteins or target cells. Fluorescence correlation spectroscopy revealed two forms of nuclear Vpr-monomers and very large complexes, likely involving host factors. The kinetics of viral Vpr entering the nucleus after fusion was not affected by point mutations in the capsid protein that alter the stability of the viral core. CONCLUSIONS: The independence of Vpr shedding of capsid stability and its relatively rapid dissociation from post-fusion cores suggest that this process may precede capsid uncoating, which appears to occur on a slower time scale. Our results thus demonstrate that a bulk of fluorescently labeled Vpr incorporated into HIV-1 particles is released shortly after fusion. Future studies will address the question whether the quick and efficient nuclear delivery of Vpr derived from incoming viruses can regulate subsequent steps of HIV-1 infection. PMID- 26511607 TI - Use of hypofractionated post-mastectomy radiotherapy reduces health costs by over $2000 per patient: An Australian perspective. AB - INTRODUCTION: The most recent clinical practice guidelines released by Cancer Australia draw attention to unanswered questions concerning the health economic considerations associated with hypofractionated radiotherapy. This study aimed to quantify and compare the healthcare costs at a regional Australian radiotherapy institute with respect to conventionally fractionated post-mastectomy radiotherapy (Cf-PMRT) versus hypofractionated post-mastectomy radiotherapy (Hf PMRT) administration. METHODS: Medical records of 196 patients treated with post mastectomy radiotherapy at the NSW North Coast Cancer Institute from February 2008 to June 2014 were retrospectively reviewed. Australian Medicare item numbers billed for patients receiving either Cf-PMRT of 50 Gy in 25 daily fractions or Hf PMRT of 40.05 Gy in 15 daily fractions were calculated. Decision tree analysis was used to model costs. Independent-samples t-tests and Mann-Whitney U-tests were used to compare crude average costs for Cf-PMRT and Hf-PMRT and determine which treatment components accounted for any differences. RESULTS: Hf-PMRT, with or without irradiation to the regional lymph nodes, was associated with significantly reduced Medicare costs ($5613 AUD per patient for Hf-PMRT vs $8272 AUD per patient for Cf-PMRT; P < 0.001). Savings associated with Hf-PMRT ranged from $1353 (22.1%) for patients receiving no regional irradiation to $2898 (32.0%) for patients receiving both axillary and supraclavicular therapy. CONCLUSIONS: Hf-PMRT results in a significant reduction in the financial costs associated with treating breast cancer patients in a regional Australian setting when compared with Cf-PMRT. PMID- 26511608 TI - Analysis of the ways and methods of signaling pathways in regulating cell cycle of NIH3T3 at transcriptional level. AB - BACKGROUND: To analyze the ways and methods of signaling pathways in regulating cell cycle progression of NIH3T3 at transcriptional level, we modeled cell cycle of NIH3T3 and found that G1 phase of NIH3T3 cell cycle was at 5-15 h after synchronization, S phase at 15-21 h, G2 phase at 21-22 h, M phase at 22-25 h. RESULTS: Mouse Genome 430 2.0 microarray was used to detect the gene expression profiles of the model, and results showed remarkable changes in the expressions of 64 cell cycle genes and 960 genes associated with other physiological activity during the cell cycle of NIH3T3. For the next step, IPA software was used to analyze the physiological activities, cell cycle genes-associated signal transduction activities and their regulatory roles of these genes in cell cycle progression, and our results indicated that the reported genes were involved in 17 signaling pathways in the regulation of cell cycle progression. Newfound genes such as PKC, RAS, PP2A, NGR and PI3K etc. belong to the functional category of molecular mechanism of cancer, cyclins and cell cycle regulation HER-2 signaling in breast cancer signaling pathways. These newfound genes could promote DNA damage repairment and DNA replication progress, regulate the metabolism of protein, and maintain the cell cycle progression of NIH3T3 modulating the reported genes CCND1 and C-FOS. CONCLUSION: All of the aforementioned signaling pathways interacted with the cell cycle network, indicating that NIH3T3 cell cycle was regulated by a number of signaling pathways. PMID- 26511609 TI - [Malnutrition and social isolation among elderly residents of city public housing]. AB - OBJECTIVES: The aim of this study was to examine relations between malnutrition and social isolation among elderly residents of a city public housing facility. METHODS: The present participants were 442 residents aged 65 and older of a public housing facility in Nagoya city. An anonymous self-administered questionnaire survey was conducted regarding demographics, nutritional status, and social isolation. Nutritional status was evaluated using the Mini Nutritional Assessment((r))-Short Form (MNA((r))). Combining "at risk for malnutrition" and "malnutrition," the status was classified into two groups: "normal nutrition" and "at risk for malnutrition." Social isolation was examined using the Japanese version of the abbreviated Lubben Social Network Scale (LSNS-6), which was divided into isolation (less than 12 points) and non-isolation (more than 12 points). Multivariate logistic regression analyses were conducted to assess association between malnutrition and isolation by adjusting for the following possible confounders: age, sex, living alone, self-rated economic conditions, housebound, loneliness, eligible for Long-Term Care Insurance, and the Tokyo Metropolitan Institute of Gerontology (TMIG) Index of Competence. RESULTS: Among 343 respondents (77.6%), the number of valid responses was 288 (65.2%)-121 men and 167 women. The average age was 74.7+/-6.1 years old (mean+/-standard deviation), ranging from 65 to 98. Based on the LSNS-6, social isolation was encountered in 44.1%. According to the MNA((r)) classification, 171 (59.4%) were classified as "normal nutritional status," 108 (37.5%) as "at risk for malnutrition," and 9 (3.1%) as "malnutrition." "At risk for malnutrition" and "malnutrition" were found in 40.6% in this study. Multivariate logistic analyses showed that risk factors for malnutrition were social isolation (OR=2.52, 95% CI; 1.44-4.41) and poor economic conditions (OR=1.98, 95% CI; 1.15-3.41). Significant interaction between age and living alone suggested that elderly individuals over 75 years of age who live alone were also at risk for malnutrition. CONCLUSION: This study revealed that malnutrition of elderly individuals was associated with social isolation and poor economic conditions as well as age over 75 and living alone. Malnutrition and social isolation can be prevalent in elderly residents of city public housing facilities. Measures of social isolation as well as nutritional support are necessary for health promotion and preventive care of the elderly. PMID- 26511610 TI - [Fall risk factors and sex differences among community-dwelling elderly individuals in Japan. A Kameoka study]. AB - OBJECTIVES: Although factors associated with falls might differ between men and women, no large-scale studies were conducted to examine the sex difference of risk factors for falls in Japanese elderly. The purpose of this study was to examine fall risk factors and sex differences among community-dwelling elderly individuals using a complete survey of the geriatric population in Kameoka city. METHODS: A self-administered questionnaire survey was conducted with 18,231 community-dwelling elderly individuals aged 65 years or over in Kameoka city, Kyoto Prefecture, between July and August 2011, excluding people who were publicly certified with a long-term care need of grade 3 or higher. The questionnaire was individually distributed and collected via mail. Out of 12,159 responders (recovery rate of 72.2%), we analyzed the data of 12,054 elderly individuals who were not certified as having long-term care needs. The questionnaire was composed of basic attributes, a simple screening test for fall risk, the Kihon Check List with 25 items, and the Tokyo Metropolitan Institute of Gerontology (TMIG) index of competence with 13 items. These items were grouped into nine factors: motor function, malnutrition, oral function, houseboundness, forgetfulness, depression, Instrumental Activity of Daily Living (IADL), intellectual activities, and social role. RESULTS: Of all the respondents, 20.8% experienced falls within the last year, and 26.6% were classified as having high fall risk. Fall risk increased with age in both sexes, and risk in all age groups was higher for women than for men. All factors were significantly associated with fall risk in both sexes. After controlling for these factors, a significant relationship was found between fall risk and motor function, malnutrition, oral function, forgetfulness, depression, and IADL in men and motor function, oral function, forgetfulness, depression, and IADL in women. The deterioration of motor function was associated with three-times-higher risk than non-deterioration of motor function. In addition, significant interaction was found in sex*malnutrition, oral function, IADL, and intellectual activities; malnutrition and low oral function were stronger factors in men than in women; and IADL and intellectual activities were stronger factors in women than in men. CONCLUSION: One in five community-dwelling independent elderly individuals experienced falls in the last year, and one in four had high fall risk. We found a significant relationship between fall risk and the nine factors, particularly deterioration of motor function in both sexes. Sex difference was observed for fall risk factors; therefore, a sex-specific support policy for fall prevention is necessary. PMID- 26511611 TI - [Effect of the national lifestyle modification project conducted in Japan on the parameters of metabolic syndrome]. AB - OBJECTIVES: Although the national lifestyle modification project targeting metabolic syndrome in the general population conducted by the Japanese government started in 2008, the project's long-term effects have not yet been evaluated. Associations of taking the project's lifestyle modification guidance with improvement of parameters related to metabolic syndrome after 1, 2, 3, and 4 years were assessed in participants who met the metabolic syndrome criteria for the guidance. METHODS: While improvement was defined when the parameters had met the criteria for metabolic syndrome at the initial checkup but did not at the time of evaluation without medication, deterioration was defined when they had not met the criteria at the initial checkup but, at the time of evaluation, they did or the subjects received the medication. Logistic regression analyses were used to evaluate improvement by the guidance adjusted for age, sex, systolic blood pressure, HDL cholesterol level, and hemoglobin (Hb)A1c level at baseline. RESULTS: From 2008 to 2011, 3742 participants (mean age 61+/-10 years, men 62%) met the criteria for the lifestyle modification guidance. Numbers of participants eligible for evaluation were 2690, 1894, 1330, and 779 at 1, 2, 3, and 4 years after the initial checkup, respectively. Based on the multivariate logistic regression analyses, receiving the guidance was significantly associated with improvement of body mass index (BMI) (odds ratio (OR)=1.66, 95% confidence interval (CI)=1.17-2.37), waist (OR=1.77, 95%CI=1.35-2.31), and HbA1c (OR=1.82, 95%CI=1.05-3.13) at the 1-year evaluation; improvement of BMI (OR=1.51, 95%CI=1.01-2.26) and waist (OR=1.61, 95%CI=1.18-2.20) at the 2-year evaluation; and improvement of waist (OR=1.67, 95%CI=1.12-2.48) at the 3-year evaluation. However, BMI, waist, and HbA1c at other evaluations including the 4-year evaluation and the remaining parameters at any evaluations were not significantly improved by the guidance. In addition, receiving the guidance was significantly associated with deterioration of HbA1c at the 4-year evaluation (OR=2.49, 95%CI=1.18-5.24). CONCLUSION: Although HbA1c at the 1-year evaluation and parameters related to overweight were improved at the 1-, 2-, and 3-year evaluations, no parameters of metabolic syndrome were significantly improved by the guidance at the 4-year evaluation. PMID- 26511612 TI - [Analysis of elderly individuals who move from a depopulated area and require nursing care and support]. AB - OBJECTIVES: To verify if elderly individuals care can live in familiar places, the authors study cases elderly individuals needing nursing care and moving away from their areas. METHODS: A depopulated area where low birthrate and aging is preceding was selected for the study. Participants were elderly individuals who received "certification of need" and moved away from their areas in the five years since April, 2008. We collected the participants' characteristics, degrees of needing care, utilization of care service, and where they moved to. Further, we performed a hearing survey for a home care support center to determine the status of caregivers and care before moving, where they moved to, and how and why they moved, and we analyzed the reasons. Further, we discovered where they lived and their care service as of the end of August, 2013, and analyzed how they lived after moving. RESULTS: The number of elderly individuals in need of care with "certification of need" who moved out of the town was 74. The percentage of later stage elderly individuals was 89.2%, and 70.3% of them were women. One-person households were the most common with 47.3%, and small families with less than two family members made up over 70%. Main caregivers before moving out were family members or relatives living with them (35.1%), those not living with them (10.8%), and helpers or care staff members (33.8%). The percentage of elderly individuals who utilized ambulatory and attendant care services before moving out was 79.7%. The service use was high for ambulatory and attendant care. Those who moved to live in facilities out of town made up 73.0%. The result revealed that 58.1% of elderly individuals who moved lived in special elderly nursing homes out of town as of the end of August, 2013. CONCLUSION: Over 70% of the elderly individuals who moved are from small families having less than two family members. Therefore, the fact that they have care limitations serves as the background for their moving; 79.7% of the elderly individuals who moved utilized ambulatory and attendant care. Further, we found that 75.7% of them moved to nursing facilities, and those who lived in nursing facilities moved to special elderly nursing homes out of town and were away from Town A. PMID- 26511613 TI - Impact of Catheter Contact Force on Superior Vena Cava Mapping and Localization of the Right Phrenic Nerve by High Output Pacing. AB - BACKGROUND: Right phrenic nerve injury (PNI) is a major concern during superior vena cava (SVC) isolation. Phrenic nerve (PN) localization by high-output pacing is a standard technique for anticipating PNI. This study evaluated the impact of catheter contact force (CF) on SVC mapping and PN localization. METHODS: Twenty one atrial fibrillation patients undergoing cardiac enhanced computed tomography (CT) were prospectively enrolled. SVC geometries were created at the SVC-right atrium junction level with low (<10 * g) and high (>10 * g) CFs. The PN was localized by high-output pacing (10 V, 2 milliseconds) at the SVC and anterior right superior pulmonary vein (RSPV) with different CFs. RESULTS: The SVC cross sectional area was significantly greater when created with high (22.1 +/- 4.9 * g) compared with low CFs (4.2 +/- 1.3 * g) (5.3 +/- 1.4 cm2 vs. 2.3 +/- 0.7 cm2 , P < 0.0001). High CFs distorted the SVC and anterior RSPV by a mean of 4.8 +/- 2.5 and 4.4 +/- 1.7 mm, with minimal distortion at the anteroseptal SVC. The PN was more frequently captured with a high compared with low CF at the SVC (95.2% vs. 71.4%, P = 0.038) and RSPV (66.7% vs. 14.3%, P = 0.0005). The PN capture area was also wider with a high compared with low CF at the SVC (9.0 +/- 4.1 mm vs. 4.5 +/- 2.8 mm, P = 0.001). The PN location was at the anterolateral, lateral, and posterolateral SVC in 3 (14.3%), 13 (61.9%), and 5 (23.8%) patients, respectively, which was identical to that identified on CT. No PNs located >1.98 mm from the RSPV were captured by RSPV pacing. CONCLUSIONS: CF impacted the SVC mapping and PN localization. Cardiac CT identified the PN location, and the distance from the pacing site influenced PN capture. PMID- 26511614 TI - Total and Full-Fat, but Not Low-Fat, Dairy Product Intakes are Inversely Associated with Metabolic Syndrome in Adults. AB - BACKGROUND: Growing evidence suggests that dairy products may have beneficial cardiometabolic effects. The current guidelines, however, limit the intake of full-fat dairy products. OBJECTIVE: We investigated the association of dairy consumption, types of dairy products, and dairy fat content with metabolic syndrome (MetSyn). METHODS: We analyzed baseline data of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), a multicenter cohort study of 15,105 adults aged 35-74 y. We excluded participants with known diabetes, cardiovascular diseases, or other chronic diseases, and those who had extreme values of energy intake, leaving 9835 for analysis. Dairy consumption was assessed by a food-frequency questionnaire. We computed servings per day for total and subgroups of dairy intake. We computed a metabolic risk score (MetScore) as the mean z score of waist circumference, systolic blood pressure, HDL cholesterol (negative z score), fasting triglycerides, and fasting glucose. We performed multivariable linear regression to test the association of servings per day of dairy products with MetScore. RESULTS: In analyses that adjusted for demographics, menopausal status, family history of diabetes, dietary intake, nondietary lifestyle factors, and body mass index, we observed a graded inverse association for MetScore with total dairy (-0.044 +/- 0.01, P = 0.009 for each additional dairy servings per day) and full-fat dairy (-0.126 +/- 0.03, P < 0.001) but not with low-fat dairy intake. Associations were no longer present after additional adjustments for dairy-derived saturated fatty acids. CONCLUSIONS: Total and especially full-fat dairy food intakes are inversely and independently associated with metabolic syndrome in middle-aged and older adults, associations that seem to be mediated by dairy saturated fatty acids. Dietary recommendations to avoid full-fat dairy intake are not supported by our findings. PMID- 26511615 TI - Epidemiology and control of bovine ephemeral fever. AB - Bovine ephemeral fever (or 3-day sickness) is an acute febrile illness of cattle and water buffaloes. Caused by an arthropod-borne rhabdovirus, bovine ephemeral fever virus (BEFV), the disease occurs seasonally over a vast expanse of the globe encompassing much of Africa, the Middle East, Asia and Australia. Although mortality rates are typically low, infection prevalence and morbidity rates during outbreaks are often very high, causing serious economic impacts through loss of milk production, poor cattle condition at sale and loss of traction power at harvest. There are also significant impacts on trade to regions in which the disease does not occur, including the Americas and most of Europe. In recent years, unusually severe outbreaks of bovine ephemeral fever have been reported from several regions in Asia and the Middle East, with mortality rates through disease or culling in excess of 10-20%. There are also concerns that, like other vector-borne diseases of livestock, the geographic distribution of bovine ephemeral fever could expand into regions that have historically been free of the disease. Here, we review current knowledge of the virus, including its molecular and antigenic structure, and the epidemiology of the disease across its entire geographic range. We also discuss the effectiveness of vaccination and other strategies to prevent or control infection. PMID- 26511616 TI - Treatment outcomes in multidrug resistant tuberculosis-human immunodeficiency virus Co-infected patients on anti-retroviral therapy at Sizwe Tropical Disease Hospital Johannesburg, South Africa. AB - BACKGROUND: Multidrug resistant-tuberculosis (MDR-TB) is a threat to global tuberculosis control which is worsened by human immune-deficiency virus (HIV) co infection. There is however paucity of data on the effects of antiretroviral treatment (ART) before or after starting MDR-TB treatment. This study determined predictors of mortality and treatment failure among HIV co-infected MDR-TB patients on ART. METHODS: A retrospective medical record review of 1200 HIV co infected MDR-TB patients admitted at Sizwe Tropical Disease Hospital, Johannesburg from 2007 to 2010 was performed. Chi-square test was used to determine treatment outcomes in HIV co-infected MDR-TB patients on ART. Multivariable logistic regression and Poisson models were used to determine predictors of mortality and treatment failure respectively. RESULTS: Mortality was higher (21.8% vs. 15.4%) among patients who started ART before initiating MDR TB treatment compared with patients initiated on ART after commencing MDR-TB treatment (p = 0.013). Factors significantly associated with mortality included: the use of ART before starting MDR-TB treatment (OR 1.65, 95% CI 1.02-2.73), severely-underweight (OR 3.71, 95% CI 1.89-7.29) and underweight (OR 2.35, 95% CI 1.30-4.26), cavities on chest x-rays at baseline (OR 1.76, 95% CI 1.08-2.94), presence of other opportunistic infections (OR 1.80, 95% CI 1.10-2.94) and presence of other co-morbidities (OR 2.26, 95% CI 1.20-4.21). Factors predicting failure were severe anaemia (IRR (OR 4.72, 95% CI 1.47-15), other co-morbidities (OR 2.39, 95% CI 1.05-5.43) and modified individualised regimen at baseline (OR 2.15, 95% CI 0.98-4.71). CONCLUSIONS: High mortality among patients already on ART before initiating MDR-TB treatment is a worrisome development. Management of adverse-events, opportunistic infections and co-morbidities in these patients is important if the protective benefits of being on ART are to be maximized. There is the need to intensify intervention programmes targeted at early identification of MDR-TB, treatment initiation, drug monitoring and increasing adherence among HIV co-infected MDR-TB patients. PMID- 26511617 TI - Ulcer healing and mechanism(s) of action involved in the gastroprotective activity of fractions obtained from Syngonanthus arthrotrichus and Syngonanthus bisulcatus. AB - BACKGROUND: Syngonanthus arthrotrichus and Syngonanthus bisulcatus, currently known for Comanthera aciphylla (Bong.) L.R.Parra & Giul. and Comanthera bisulcata (Koern.) L.R. Parra & Giul, popularly known in Brazil as "sempre-vivas," are plants from the family Eriocaulaceae. They are found in the states of Minas Gerais and Bahia. The species are known to be rich in flavonoids to which their gastroprotective activity has been attributed. In this research, experimental protocols were performed to elucidate the associated mechanisms of action. METHODS: The activity was evaluated using induced gastric ulcer models (acetic acid and ethanol-induced gastric lesions in NEM or L-NAME pre-treated mice, and by ischemia/reperfusion). Antioxidant enzymes, serum somatostatin, and gastrin were also evaluated. RESULTS: In chronic gastric ulcers, a single daily oral dose of Sa-FRF or Sb-FRF (100 mg/kg body wt.) for 14 consecutive days accelerated ulcer healing to an extent similar to that seen with an equal dose of cimetidine. The pre-treatment of mice with NEM (N-ethylmaleimide) or L-NAME (N-nitro-L arginine) abolished the protective activity of Sa-FRF, Sa-FDF, Sb-FDF and Sb-FRF or Sa-FRF and Sb-FRF, respectively, which indicates that antioxidant compounds and nitric oxide synthase activity are involved in the gastroprotective. Sa-FRF and Sb-FRF (100 mg/kg p.o) protected the gastric mucosa against ulceration that was induced by ischemia/reperfusion (72 and 76 %, respectively). It also decreased lipid peroxidation and restored total thiols in the gastric wall of mice that had been treated with ethanol. When administered to rats submitted to ethanol-induced gastric lesions, Sa-FRF and Sb-FRF (100 mg/kg, p.o.) increased the somatostatin serum levels, while the gastrin serum levels were proportionally decreased. CONCLUSIONS: The results indicate significant healing effects and gastroprotective activity for the Sa-FRF and Sb-FRF, which probably involves the participation of SH groups, nitric oxide (NO), the antioxidant system, somatostatin, and gastrin. All are integral parts of the gastrointestinal mucosa's cytoprotective mechanisms against aggressive factors. PMID- 26511618 TI - Editor's Note. PMID- 26511619 TI - Asked and answered: is the mortality associated with cardiac surgery related to the anaesthetist and should it be used to measure anaesthetic performance? PMID- 26511620 TI - A spatial equity analysis of a public health intervention: a case study of an outdoor walking group provider within local authorities in England. AB - INTRODUCTION: If an intervention is not well spatially targeted, appropriate levels of uptake, efficacy, long-term compliance and improved health outcomes are unlikely to be attained. Effective health interventions should seek to achieve not only absolute improvements in health but also to reduce inequity. There is often a disparity whereby preventative interventions are more likely to be successful amongst the more affluent, a process which has been coined the 'inverse prevention law'. Physical inactivity is known to be socially patterned and disproportionately prevalent in disadvantaged communities yet there is a lack of clear evidence on which interventions have the potential to influence inequity. Walking groups have been found to have multiple health benefits and increase physical activity. In England the major facilitator is a not for profit organisation which has 70,000 regular walkers and is lay led with 10,000 volunteers. The aim of this study was to evaluate the extent to which walking groups operated in those places with the greatest health need and whether consequently the scheme has the potential to influence health inequity. METHOD: The work used a spatial approach whereby geographical variations in walking group provision within the 326 local authorities in England (mean population 163,410) were linked to health and socio-economic measures of population need. RESULTS: Generally, greater need was not associated with higher provision of the walking group intervention. Although the magnitude of differences was small, provision of the intervention tended to be poorest in those local authorities with the greatest health need, as measured by our indicators. CONCLUSIONS: Without targeting those areas with greater health and socio-economic need, there is a concern that walking groups may not be set up in areas that need them most. There is therefore a potential that this intervention could, albeit in a small way, widen inequity between local authorities. However small-scale and well intentioned, interventions need to be evaluated for their potential impact on inequity. PMID- 26511621 TI - Combined influence of nonalcoholic fatty liver and body size phenotypes on diabetes risk. AB - BACKGROUND: We aimed to determine the association between nonalcoholic fatty liver disease (NAFLD) and diabetes risk among body size phenotypes which was based on cross-classification of body mass index (BMI) categories (normal or overweight/obesity) and metabolic status (metabolically health or metabolically at-risk). METHODS: We conducted a cross-sectional analysis using a cohort of 10,761 apparently healthy Chinese adults who underwent comprehensive health checkups including abdominal ultrasonography. Subjects were classified as metabolically at-risk by having any two of the following, consistent with the Adult Treatment Panel-III metabolic syndrome definition: (1) systolic/diastolic blood pressure >=130/85 mmHg, (2) triglycerides >=1.7 mmol/L, (3) fasting blood glucose >=5.6 mmol/L, (4) HDL-cholesterol >=1.0/1.3 mmol/L for men/women. RESULTS: Among participants without metabolically at-risk, multivariate-adjusted odds ratios (ORs) for diabetes from NAFLD compared with those without NAFLD in the normal-weight (BMI <23 kg/m(2)) and overweight/obese (BMI >=23 kg/m(2)) group were 2.10 (1.85-3.93) and 1.85 (1.35-2.53), respectively. Among participants with metabolically at-risk, the significant association between NAFLD and diabetes was lost, regardless of obesity status. There were only 27.1% subjects with the presence of the three factors (overweight/obesity, NAFLD, and metabolically at risk) occurring together, while the three factors occurring together was common (56.16%) in diabetic individuals. The multivariate-adjusted ORs for diabetes were 1.1 (0.61-1.98) for overweight/obesity, 2.23 (1.05-5.14) for NAFLD, and 8.04 (5.0 12.09) for metabolically at-risk. The OR for the presence of all the three factors occurring together was 23.22 (13.96-38.63). CONCLUSIONS: NAFLD was associated with diabetes risk among participants without metabolically at-risk. The clustering of overweight/obesity, NAFLD, and metabolically at-risk is common in diabetic subjects and strikingly and markedly increases the diabetes risk. PMID- 26511622 TI - Exploiting the aerobic endospore-forming bacterial diversity in saline and hypersaline environments for biosurfactant production. AB - BACKGROUND: Biosurfactants are surface-active biomolecules with great applicability in the food, pharmaceutical and oil industries. Endospore-forming bacteria, which survive for long periods in harsh environments, are described as biosurfactant producers. Although the ubiquity of endospore-forming bacteria in saline and hypersaline environments is well known, studies on the diversity of the endospore-forming and biosurfactant-producing bacterial genera/species in these habitats are underrepresented. METHODS: In this study, the structure of endospore-forming bacterial communities in sediment/mud samples from Vermelha Lagoon, Massambaba, Dois Rios and Abraao Beaches (saline environments), as well as the Praia Seca salterns (hypersaline environments) was determined via denaturing gradient gel electrophoresis. Bacterial strains were isolated from these environmental samples and further identified using 16S rRNA gene sequencing. Strains presenting emulsification values higher than 30 % were grouped via BOX-PCR, and the culture supernatants of representative strains were subjected to high temperatures and to the presence of up to 20 % NaCl to test their emulsifying activities in these extreme conditions. Mass spectrometry analysis was used to demonstrate the presence of surfactin. RESULTS: A diverse endospore-forming bacterial community was observed in all environments. The 110 bacterial strains isolated from these environmental samples were molecularly identified as belonging to the genera Bacillus, Thalassobacillus, Halobacillus, Paenibacillus, Fictibacillus and Paenisporosarcina. Fifty-two strains showed emulsification values of at least 30%, and they were grouped into 18 BOX groups. The stability of the emulsification values varied when the culture supernatants of representative strains were subjected to high temperatures and to the presence of up to 20% NaCl. The presence of surfactin was demonstrated in one of the most promising strains. CONCLUSION: The environments studied can harbor endospore forming bacteria capable of producing biosurfactants with biotechnological applications. Various endospore-forming bacterial genera/species are presented for the first time as biosurfactant producers. PMID- 26511624 TI - TMS to object cortex affects both object and scene remote networks while TMS to scene cortex only affects scene networks. AB - Viewing the world involves many computations across a great number of regions of the brain, all the while appearing seamless and effortless. We sought to determine the connectivity of object and scene processing regions of cortex through the influence of transient focal neural noise in discrete nodes within these networks. We consecutively paired repetitive transcranial magnetic stimulation (rTMS) with functional magnetic resonance-adaptation (fMR-A) to measure the effect of rTMS on functional response properties at the stimulation site and in remote regions. In separate sessions, rTMS was applied to the object preferential lateral occipital region (LO) and scene preferential transverse occipital sulcus (TOS). Pre- and post-stimulation responses were compared using fMR-A. In addition to modulating BOLD signal at the stimulation site, TMS affected remote regions revealing inter and intrahemispheric connections between LO, TOS, and the posterior parahippocampal place area (PPA). Moreover, we show remote effects from object preferential LO to outside the ventral perception network, in parietal and frontal areas, indicating an interaction of dorsal and ventral streams and possibly a shared common framework of perception and action. PMID- 26511623 TI - Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants. AB - B cells are implicated in the etiology of multiple sclerosis (MS). Intrathecal IgG synthesis, cerebrospinal fluid (CSF) oligoclonal bands and lesional IgG deposition suggest a role for antibody-mediated pathology. We examined the binding of IgG1 monoclonal recombinant antibodies (rAbs) derived from MS patient CSF expanded B cell clones to central nervous system (CNS) tissue. MS rAbs displaying CNS binding to mouse and human CNS tissue were further tested for their ability to induce complement-mediated tissue injury in ex vivo spinal cord explant cultures. The staining of CNS tissue, primary human astrocytes and human neurons revealed a measurable bias in MS rAb binding to antigens preferentially expressed on astrocytes and neurons. MS rAbs that recognize myelin-enriched antigens were rarely detected. Both myelin-specific and some astrocyte/neuronal specific MS rAbs caused significant myelin loss and astrocyte activation when applied to spinal cord explant cultures in the presence of complement. Overall, the intrathecal B cell response in multiple sclerosis binds to both glial and neuronal targets and produces demyelination in spinal cord explant cultures implicating intrathecal IgG in MS pathogenesis. PMID- 26511625 TI - Effects of vestibular rehabilitation in the elderly: a systematic review. AB - BACKGROUND: Aging is characterized by gradual physiological changes in body systems. Changes in the vestibular system can occur and cause dizziness, vertigo and imbalance, symptoms that are common in the elderly. Vestibular rehabilitation is a therapeutic resource that has been widely used to improve this condition. AIMS: To complete a systematic review of the effects of vestibular rehabilitation on the elderly. METHODS: A search for relevant publications was conducted in SCIELO, PUBMED, MEDLINE, COCHRANE and LILACS databases. Clinical trials and cohort studies that were written in the English language and published over the course of the last 10 years were selected. The methodological quality of the studies was assessed using the PEDro scale. A critical analysis of the studies was composed. RESULTS: Eight studies that involved subjects who were over the age of 60 were selected for inclusion in the systematic review. The most common vestibular dysfunction identified was complaints about dizziness and imbalance. The Dizziness Handicap Inventory was the most frequently used assessment instrument, and the treatment protocol that prevailed was that suggested by Cawthorne and Cooksey. DISCUSSION: The PEDro scale showed that only one article was of an acceptable methodological quality and presented satisfactory outcome measures. This was due, in part, to a lack of a hidden randomization, masking of the subject, evaluators and therapists, and lack of outcome measures, which can reduce the quality of the evidence presented in this study. CONCLUSION: Clinical trials indicate that vestibular rehabilitation represents an effective means of treating elderly patients with vestibular disorders; however, evidence of its effectiveness remains lacking. PMID- 26511626 TI - Fluidic Active Transducer for Electricity Generation. AB - Flows in small size channels have been studied for a long time over multidisciplinary field such as chemistry, biology and medical through the various topics. Recently, the attempts of electricity generation from the small flows as a new area for energy harvesting in microfluidics have been reported. Here, we propose for the first time a new fluidic electricity generator (FEG) by modulating the electric double layer (EDL) with two phase flows of water and air without external power sources. We find that an electric current flowed by the forming/deforming of the EDL with a simple separated phase flow of water and air at the surface of the FEG. Electric signals between two electrodes of the FEG are checked from various water/air passing conditions. Moreover, we verify the possibility of a self-powered air slug sensor by applying the FEG in the detection of an air slug. PMID- 26511628 TI - Control of Cell Survival in Adult Mammalian Neurogenesis. AB - The fact that continuous proliferation of stem cells and progenitors, as well as the production of new neurons, occurs in the adult mammalian central nervous system (CNS) raises several basic questions concerning the number of neurons required in a particular system. Can we observe continued growth of brain regions that sustain neurogenesis? Or does an elimination mechanism exist to maintain a constant number of cells? If so, are old neurons replaced, or are the new neurons competing for limited network access among each other? What signals support their survival and integration and what factors are responsible for their elimination? This review will address these and other questions regarding regulatory mechanisms that control cell-death and cell-survival mechanisms during neurogenesis in the intact adult mammalian brain. PMID- 26511630 TI - Breast MR biopsy: Pathological and radiological correlation. AB - PURPOSE: To identify pathological features for sample analysis of magnetic resonance imaging-guided vaccum-assisted breast biopsy (MRIgVaBB) to optimize radio pathological correlation and identify discordant benign result. MATERIAL AND METHODS: Databases of two centres were queried to identify MRIgVaBB performed between January 2009 and February 2013. A cohort of 197 women (mean age: 54.5 years (24-77)) with 208 lesions was identified. We retrospectively analyzed all prebiopsy MRI examinations according to the new BI-RADS lexicon, and all biopsy samples to describe the lesion of interest, its interface with the surrounding breast tissue and other associated features. RESULTS: The malignancy rate was 26.0 % (54/208) with an underestimation rate of 15.67 % (5/32). A visible interface at pathology between a biopsied lesion and the surrounding breast tissue was more frequently identified in mass enhancement compared to NME or focus (p = 0.0003). Regional NME was correlated with a high degree of fibrosis (p = 0.001) and the presence of PASH (p = 0.0007). Linear or segmental NME was correlated with the presence of periductal mastitis (p = 0.0003). CONCLUSION: The description of a visible interface between the target lesion and the surrounding tissue is crucial to confirm the correct targeting of an MR mass or a NME. KEY POINTS: * Pathological interface correlated with magnetic resonance mass and focal non-mass enhancement (NME). * Linear or segmental NME correlated with mastitis or ductal carcinoma in situ. * Fibrosis and pseudoangiomatous stromal hyperplasia (PASH) are correlated with regional NME. PMID- 26511631 TI - A simple scoring system for breast MRI interpretation: does it compensate for reader experience? AB - PURPOSE: To investigate the impact of a scoring system (Tree) on inter-reader agreement and diagnostic performance in breast MRI reading. MATERIALS AND METHODS: This IRB-approved, single-centre study included 100 patients with 121 consecutive histopathologically verified lesions (52 malignant, 68 benign). Four breast radiologists with different levels of MRI experience and blinded to histopathology retrospectively evaluated all examinations. Readers independently applied two methods to classify breast lesions: BI-RADS and Tree. BI-RADS provides a reporting lexicon that is empirically translated into likelihoods of malignancy; Tree is a scoring system that results in a diagnostic category. Readings were compared by ROC analysis and kappa statistics. RESULTS: Inter reader agreement was substantial to almost perfect (kappa: 0.643-0.896) for Tree and moderate (kappa: 0.455-0.657) for BI-RADS. Diagnostic performance using Tree (AUC: 0.889-0.943) was similar to BI-RADS (AUC: 0.872-0.953). Less experienced radiologists achieved AUC: improvements up to 4.7 % using Tree (P-values: 0.042 0.698); an expert's performance did not change (P = 0.526). The least experienced reader improved in specificity using Tree (16 %, P = 0.001). No further sensitivity and specificity differences were found (P > 0.1). CONCLUSION: The Tree scoring system improves inter-reader agreement and achieves a diagnostic performance similar to that of BI-RADS. Less experienced radiologists, in particular, benefit from Tree. KEY POINTS: * The Tree scoring system shows high diagnostic accuracy in mass and non-mass lesions. * The Tree scoring system reduces inter-reader variability related to reader experience. * The Tree scoring system improves diagnostic accuracy in non-expert readers. PMID- 26511632 TI - Modeling Spontaneous Metastasis following Surgery: An In Vivo-In Silico Approach. AB - Rapid improvements in the detection and tracking of early-stage tumor progression aim to guide decisions regarding cancer treatments as well as predict metastatic recurrence in patients following surgery. Mathematical models may have the potential to further assist in estimating metastatic risk, particularly when paired with in vivo tumor data that faithfully represent all stages of disease progression. Herein, we describe mathematical analysis that uses data from mouse models of spontaneous metastasis developing after surgical removal of orthotopically implanted primary tumors. Both presurgical (primary tumor) growth and postsurgical (metastatic) growth were quantified using bioluminescence and were then used to generate a mathematical formalism based on general laws of the disease (i.e., dissemination and growth). The model was able to fit and predict pre/postsurgical data at the level of the individual as well as the population. Our approach also enabled retrospective analysis of clinical data describing the probability of metastatic relapse as a function of primary tumor size. In these data-based models, interindividual variability was quantified by a key parameter of intrinsic metastatic potential. Critically, our analysis identified a highly nonlinear relationship between primary tumor size and postsurgical survival, suggesting possible threshold limits for the utility of tumor size as a predictor of metastatic recurrence. These findings represent a novel use of clinically relevant models to assess the impact of surgery on metastatic potential and may guide optimal timing of treatments in neoadjuvant (presurgical) and adjuvant (postsurgical) settings to maximize patient benefit. PMID- 26511633 TI - A Preclinical Model of Malignant Peripheral Nerve Sheath Tumor-like Melanoma Is Characterized by Infiltrating Mast Cells. AB - Human melanomas exhibit considerable genetic, pathologic, and microenvironmental heterogeneity. Genetically engineered mice have successfully been used to model the genomic aberrations contributing to melanoma pathogenesis, but their ability to recapitulate the phenotypic variability of human disease and the complex interactions with the immune system have not been addressed. Here, we report the unexpected finding that immune cell-poor pigmented and immune cell-rich amelanotic melanomas developed simultaneously in Cdk4R24C-mutant mice upon melanocyte-specific conditional activation of oncogenic BrafV600E and a single application of the carcinogen 7,12-dimethylbenz(a)anthracene. Interestingly, amelanotic melanomas showed morphologic and molecular features of malignant peripheral nerve sheath tumors (MPNST). A bioinformatic cross-species comparison using a gene expression signature of MPNST-like mouse melanomas identified a subset of human melanomas with a similar histomorphology. Furthermore, this subset of human melanomas was found to be highly associated with a mast cell gene signature, and accordingly, mouse MPNST-like melanomas were also extensively infiltrated by mast cells and expressed mast cell chemoattractants similar to human counterparts. A transplantable mouse MPNST-like melanoma cell line recapitulated mast cell recruitment in syngeneic mice, demonstrating that this cell state can directly reconstitute the histomorphologic and microenvironmental features of primary MPNST-like melanomas. Our study emphasizes the importance of reciprocal, phenotype-dependent melanoma-immune cell interactions and highlights a critical role for mast cells in a subset of melanomas. Moreover, our BrafV600E Cdk4R24C model represents an attractive system for the development of therapeutic approaches that can target the heterogeneous tumor microenvironment characteristic of human melanomas. PMID- 26511629 TI - Meiotic Recombination: The Essence of Heredity. AB - The study of homologous recombination has its historical roots in meiosis. In this context, recombination occurs as a programmed event that culminates in the formation of crossovers, which are essential for accurate chromosome segregation and create new combinations of parental alleles. Thus, meiotic recombination underlies both the independent assortment of parental chromosomes and genetic linkage. This review highlights the features of meiotic recombination that distinguish it from recombinational repair in somatic cells, and how the molecular processes of meiotic recombination are embedded and interdependent with the chromosome structures that characterize meiotic prophase. A more in-depth review presents our understanding of how crossover and noncrossover pathways of meiotic recombination are differentiated and regulated. The final section of this review summarizes the studies that have defined defective recombination as a leading cause of pregnancy loss and congenital disease in humans. PMID- 26511634 TI - Allogeneic and Autogenous Bone Grafts Are Affected by Historical Donor Environmental Exposure. AB - BACKGROUND: Bone graft materials are routinely evaluated for infectious agents; however, data regarding contamination of bone graft from environmental exposure of the donors to osteotoxic substances such as lead are not routinely available. In animal models, stored lead in bone has been shown to impair fracture healing and osteocyte function. In clinical studies, lead is linked to skeletal disease at relatively low concentrations. Presumably the levels of lead in allografts mirror the level of lead in bone in the population; however, the degree to which processing might decrease this and the frequency with which potentially osteotoxic levels appear in bone grafts have not been studied. QUESTIONS/PURPOSES: (1) Does processing of donor bone for allografts result in lower concentrations of lead in commercial allograft when compared with autologous bone graft; and (2) what proportion of bone grafts contain potentially osteotoxic levels of lead from > 2.0 to 20.0 ug/g corresponding to environmental exposure? METHODS: Allograft from commercial sources and autologous bone graft materials were examined for lead content using ICP- atomic absorption spectrophotometric analysis. We analyzed bone graft specimens from 42 donors, including 26 corticocancellous tibial specimens from commercially available bone graft materials and 16 autograft corticocancellous tibial specimens. Lead levels were determined for the cortical (n = 42) and cancellous (n = 42) portions of each specimen. For quality control, all instruments, plastic and glassware, were regularly tested for lead contamination by atomic absorption spectrophotometry throughout the experiments. In addition, spectrophotometer calibration was verified using Standard Reference Material 1486 bone meal (NIST, Gaithersburg, MD, USA). Descriptive statistical analysis was performed using SPSS 20 (SPSS Inc, Chicago, IL, USA). Using these techniques, a lead level > 2 ug/g to 20 ug/g corresponds to some degree of environmental exposure to lead. RESULTS: With the numbers available in the present study, there were no differences in mean lead level between commercial bone graft materials and autogenous bone graft, 2.1 ug/g (95% confidence interval [CI], 1.6-3.3 ug/g) versus 2.0 ug/g (95% CI, 1.0-4.5 ug/g; p = 0.86). The range for all tested samples varied from < 0.1 to 5.0 ug/g. Likewise, there were no differences in mean lead level between cortical bone grafts, which contained 2.2 ug/g (95% CI, 1.5-3.7 ug/g), and cancellous grafts, which contained 1.9 ug/g (95% CI, 1.2-3.4 ug/g; p = 0.58). Thirty-eight percent (16 of 42) of the specimens had levels between 2.0 ug/g and 20 ug/g within a range expected for individuals with known environmental exposure to lead. CONCLUSIONS: This study demonstrates that lead is present in up to one-third of tibial allograft and autograft bone specimens at potentially osteotoxic levels regardless of the source or screening. Further research is needed to delineate the relationship with nonunion or pseudoarthrosis after procedures in which allograft is used. In addition, further study would examine concentrations of lead and other environmental contaminants in other graft types. CLINICAL RELEVANCE: Comparable levels of lead exposure have been associated with toxic effects on skeletal tissue. Further study of bone graft used in fusion procedures and other procedures is necessary to define the magnitude of osteotoxic effects in the setting of fracture care or fusion procedures. PMID- 26511635 TI - Medicolegal Sidebar: Blowback: The Unintended Consequences of Medical Liability Reform. PMID- 26511636 TI - Sixty seconds on . . . high fructose corn syrup. PMID- 26511638 TI - Biomechanical comparison of pin and tension-band wire fixation with a prototype locking plate fixation in a transverse canine patellar fracture model. AB - OBJECTIVE: To compare a locking plate (LP) with pin and tension-band wire (pin/TBW) for fixation of mid-patellar transverse fractures. MATERIALS AND METHODS: Cadaveric canine stifle joints from 10 adult mixed breed dogs (23-36 kg) were used. Mid-patellar transverse osteotomies were randomly stabilized (in pairs) with either pin/TBW or a prototype LP. Cyclic loads (1 Hz, 500 cycles) at 100% body weight (90 degrees -135 degrees stifle joint extension), were applied. Survival or failure of constructs was defined as <2 mm fracture gap distraction at 500 cycles, or >=2 mm fracture gap distraction at the number of cycles sustained, respectively. Number of cycles at failure and distraction gap were compared with a paired Student's t-test, and a survival analysis performed with a Mantel-Cox test. All constructs that survived cyclic testing were tested in single cycle load to failure (1.0 mm/sec; 110 degrees stifle joint extension); yield strength was compared with a Wilcoxon rank sum test. Significance was set at p <0.05. RESULTS: All 10/10 LP and three out of 10 pin/TBW fixations survived cyclic testing. Survival analysis, number of cycles at failure, and distraction gap all were significantly different between the two groups (p = 0.0011, p = 0.0013, and p <0.0001, respectively). Construct yield strength was not significantly different (p = 0.1273). CONCLUSIONS: The failure mode with pin/TBW was consistently similar to failures observed clinically. The LP demonstrated consistent, reliable and stable fixation. PMID- 26511639 TI - Deviation between self-reported and measured occupational physical activity levels in office employees: effects of age and body composition. AB - OBJECTIVES: Whether occupational physical activity (PA) will be assessed via questionnaires or accelerometry depends on available resources. Although self reported data collection seems feasible and inexpensive, obtained information could be biased by demographic determinants. Thus, we aimed at comparing self reported and objectively measured occupational sitting, standing, and walking times adjusted for socio-demographic variables. METHODS: Thirty-eight office employees (eight males, 30 females, age 40.8 +/- 11.4 years, BMI 23.9 +/- 4.2 kg/m(2)) supplied with height-adjustable working desks were asked to report sitting, standing, and walking times using the Occupational Sitting and Physical Activity Questionnaire during one working week. The ActiGraph wGT3X-BT was used to objectively measure occupational PA during the same week. Subjectively and objectively measured data were compared computing the intra-class correlation coefficients, paired t tests and Bland-Altman plots. Furthermore, repeated measurement ANOVAs for measurement (subjective vs. objective) and socio demographic variables were calculated. RESULTS: Self-reported data yielded a significant underestimation of standing time (13.3 vs. 17.9%) and an overestimation of walking time (12.7 vs. 5.0%). Significant interaction effects of age and measurement of standing time (F = 6.0, p = .02, etap(2) = .14) and BMI group and measurement of walking time were found (F = 3.7, p = .04, etap(2) = .17). Older employees (>39 years) underestimated their standing time, while underweight workers (BMI < 20 kg/m(2)) overestimated their walking time. CONCLUSIONS: Self-reported PA data differ from objective data. Demographic variables (age, BMI) affect the amount of self-reported misjudging of PA. In order to improve the validity of self-reported data, a correction formula for the economic assessment of PA by subjective measures is needed, considering age and BMI. PMID- 26511640 TI - Final height in Italian patients with congenital hypothyroidism detected by neonatal screening: a 20-year observational study. AB - BACKGROUND: Linear growth and final height are reported as normal in congenital hypothyroid patients in the neonatal screening era. METHODS: We evaluated the final height in 215 patients with congenital hypothyroidism to assess if it improved over the last 2 decades. RESULTS: Final height (-0.1 +/- 1.0 SDS) was higher than target height (-0.8 +/- 1.0 SDS, p < 0.001) and not different among the 4 quartiles for birthdate. It was correlated with target height (r(2) = 0.564, p < 0.001) and height at puberty onset (r(2) = 0.685, p < 0.001), but not with age at diagnosis or the starting LT4/kg/day dose. The curve fitting analysis showed that the age at diagnosis progressively decreased during the 20-year study period, while the target height and the starting LT4/kg/day increased. Final height was not affected by the birthdate, the age at diagnosis, the starting LT4 dose. CONCLUSIONS: The final height is higher than the target height, but despite the improvement in the screening and the treatment, it did not improve over the last 20 years. These findings are in keeping with the described secular trend and suggest that earlier diagnosis and replacement therapy do not significantly modify final height in these patients. PMID- 26511641 TI - Sialic acids in biological and therapeutic processes: opportunities and challenges. AB - It is now well documented that carbohydrates play multiple roles in biological processes, and hence are interesting targets for chemical biology and medicinal chemistry programs. This review focuses on a subset of carbohydrates, specifically sialic acid containing carbohydrates. It highlights their occurrence and diversity, and presents evidence for their roles in a range of biological pathways. It illustrates that they are targets for novel medicinal chemistry strategies for a range of therapeutic areas, including cancer and immunity. Case studies highlight opportunities and challenges in this area, and sialic acid based drugs that have entered clinical practice and are promising candidates for future disease intervention schemes, are discussed. The review concludes by highlighting perspectives and emerging roles for these targets. PMID- 26511643 TI - Human germ line editing-roles and responsibilities. PMID- 26511642 TI - SENP3 regulates the global protein turnover and the Sp1 level via antagonizing SUMO2/3-targeted ubiquitination and degradation. AB - SUMOylation is recently found to function as a targeting signal for the degradation of substrates through the ubiquitin-proteasome system. RNF4 is the most studied human SUMO-targeted ubiquitin E3 ligase. However, the relationship between SUMO proteases, SENPs, and RNF4 remains obscure. There are limited examples of the SENP regulation of SUMO2/3-targeted proteolysis mediated by RNF4. The present study investigated the role of SENP3 in the global protein turnover related to SUMO2/3-targeted ubiquitination and focused in particular on the SENP3 regulation of the stability of Sp1. Our data demonstrated that SENP3 impaired the global ubiquitination profile and promoted the accumulation of many proteins. Sp1, a cancer-associated transcription factor, was among these proteins. SENP3 increased the level of Sp1 protein via antagonizing the SUMO2/3-targeted ubiquitination and the consequent proteasome-dependent degradation that was mediated by RNF4. De-conjugation of SUMO2/3 by SENP3 attenuated the interaction of Sp1 with RNF4. In gastric cancer cell lines and specimens derived from patients and nude mice, the level of Sp1 was generally increased in parallel to the level of SENP3. These results provided a new explanation for the enrichment of the Sp1 protein in various cancers, and revealed a regulation of SUMO2/3 conjugated proteins whose levels may be tightly controlled by SENP3 and RNF4. PMID- 26511644 TI - Could humic acid relieve the biochemical toxicities and DNA damage caused by nickel and deltamethrin in earthworms (Eisenia foetida)? AB - The aim of the study was to determine whether humic acid (HA) prevented gene and biochemical toxic effects in earthworms (Eisenia foetida) exposed to nickel and deltamethrin (at 100 and 1 mg kg(-1), respectively) in soil. Cellular- and molecular-level toxic effects of nickel and deltamethrin in earthworms were evaluated by measuring damage to lipid membranes and DNA and the production of protein carbonyls over 42 days of exposure. Nickel and deltamethrin induced significant levels of oxidative stress in earthworms, increasing the production of peroxidation products (malondialdehyde and protein carbonyls) and increasing the comet assay tail DNA% (determined by single-cell gel electrophoresis). DNA damage was the most sensitive of the three indices because it gave a higher sample/control ratio than did the other indices. The presence of HA alleviated (in decreasing order of effectiveness) damage to DNA, proteins, and lipid membranes caused by nickel and deltamethrin. A low HA dose (0.5-1% HA in soil) prevented a great deal of lipid membrane damage, but the highest HA dose (3% HA in soil) prevented still more DNA damage. However, the malondialdehyde concentrations in earthworms were higher at the highest HA dose than at the lower HA doses. The amounts of protein carbonyls produced at different HA doses were not significantly different. The toxic effects to earthworms caused by increased oxidizable nickel concentrations could be relieved by adding HA. PMID- 26511645 TI - Reclassifying colorectal cancer subtypes. PMID- 26511646 TI - Total body exam or lesion detection screening for skin cancer? PMID- 26511647 TI - Modified gastric cancer chemotherapy: more effective, less toxic. PMID- 26511648 TI - Cisplatin-induced renal toxicity magn...ified: role of magnesium deficiency in AKI onset. PMID- 26511649 TI - Mini-review: regulation of the renal NaCl cotransporter by hormones. AB - The renal thiazide-sensitive NaCl cotransporter, NCC, is the major pathway for salt reabsorption in the distal convoluted tubule. The activity of this cotransporter is critical for regulation of several physiological variables such as blood pressure, serum potassium, acid base metabolism, and urinary calcium excretion. Therefore, it is not surprising that numerous hormone-signaling pathways regulate NCC activity to maintain homeostasis. In this review, we will provide an overview of the most recent evidence on NCC modulation by aldosterone, angiotensin II, vasopressin, glucocorticoids, insulin, norepinephrine, estradiol, progesterone, prolactin, and parathyroid hormone. PMID- 26511650 TI - Recent Arctic tundra fire initiates widespread thermokarst development. AB - Fire-induced permafrost degradation is well documented in boreal forests, but the role of fires in initiating thermokarst development in Arctic tundra is less well understood. Here we show that Arctic tundra fires may induce widespread thaw subsidence of permafrost terrain in the first seven years following the disturbance. Quantitative analysis of airborne LiDAR data acquired two and seven years post-fire, detected permafrost thaw subsidence across 34% of the burned tundra area studied, compared to less than 1% in similar undisturbed, ice-rich tundra terrain units. The variability in thermokarst development appears to be influenced by the interaction of tundra fire burn severity and near-surface, ground-ice content. Subsidence was greatest in severely burned, ice-rich upland terrain (yedoma), accounting for ~50% of the detected subsidence, despite representing only 30% of the fire disturbed study area. Microtopography increased by 340% in this terrain unit as a result of ice wedge degradation. Increases in the frequency, magnitude, and severity of tundra fires will contribute to future thermokarst development and associated landscape change in Arctic tundra regions. PMID- 26511651 TI - Subcutaneous Transplantation of Neural Precursor Cells in Experimental Autoimmune Encephalomyelitis Reduces Chemotactic Signals in the Central Nervous System. AB - Neural precursor cell (NPC) transplantation has been proposed as a therapy for multiple sclerosis (MS) and other degenerative disorders of the central nervous system (CNS). NPCs are suggested to exert immune modulation when they are transplanted in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Herein, we explore whether the effect of NPC transplantation on the clinical course and the pathological features of EAE is combined with the modulation of chemokines levels expressed in the inflamed CNS. NPCs were isolated from brains of neonatal C57/Bl6 mice and were subcutaneously administered in female mice with myelin oligodendrocyte glycoprotein (MOG)-induced EAE. Clinical signs of the disease and transcript analysis of the CNS in the acute phase were performed. In addition, the presence of inflammatory components in the spinal cord was evaluated and ex vivo proliferation of lymphocytes was measured. NPC recipients exhibited ameliorated clinical outcome and less pronounced pathological features in their spinal cord. Downregulation of chemokine mRNA levels throughout the CNS was correlated with diminished Mac-3-, CD3-, and CD4 positive cells and reduced expression levels of antigen-presenting molecules in the spinal cord. Moreover, NPC transplantation resulted in lymphocyte-related, although not splenocyte-related, peripheral immunosuppression. We conclude that NPCs ameliorated EAE potentially by modulating the levels of chemokines expressed in the inflamed CNS, thus resulting in the impaired recruitment of immune cells. These findings further contribute to the better understanding of NPCs' immunomodulatory properties in neuroinflammatory disorders, and may lead to faster translation into potential clinical use. SIGNIFICANCE: Endogenous neural precursor cells of the central nervous system are able to migrate and differentiate toward mature cells to repair an injury. There is increasing evidence that autologous transplantation of these cells in experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, may have a beneficial effect on the disease process. Several mechanisms have been proposed among them, the potentiation of endogenous precursor cell differentiation of the central nervous system and the modulation of demyelinating and neurodegenerative immune-mediated processes. This article provides evidence of interference in immune signaling within the central nervous system as a potential mechanism underlying the immunomodulatory properties of transplanted neural precursor cells. PMID- 26511652 TI - Fluorine-19 Labeling of Stromal Vascular Fraction Cells for Clinical Imaging Applications. AB - Stromal vascular fraction (SVF) cells are used clinically for various therapeutic targets. The location and persistence of engrafted SVF cells are important parameters for determining treatment failure versus success. We used the GID SVF 1 platform and a clinical protocol to harvest and label SVF cells with the fluorinated ((19)F) agent CS-1000 as part of a first-in-human phase I trial (clinicaltrials.gov identifier NCT02035085) to track SVF cells with magnetic resonance imaging during treatment of radiation-induced fibrosis in breast cancer patients. Flow cytometry revealed that SVF cells consisted of 25.0% +/- 15.8% CD45+, 24.6% +/- 12.5% CD34+, and 7.5% +/- 3.3% CD31+ cells, with 2.1 +/- 0.7 * 105 cells per cubic centimeter of adipose tissue obtained. Fluorescent CS-1000 (CS-ATM DM Green) labeled 87.0% +/- 13.5% of CD34+ progenitor cells compared with 47.8% +/- 18.5% of hematopoietic CD45+ cells, with an average of 2.8 +/- 2.0 * 1012 19F atoms per cell, determined using nuclear magnetic resonance spectroscopy. The vast majority (92.7% +/- 5.0%) of CD31+ cells were also labeled, although most coexpressed CD34. Only 16% +/- 22.3% of CD45-/CD31-/CD34- (triple-negative) cells were labeled with CS-ATM DM Green. After induction of cell death by either apoptosis or necrosis, >95% of 19F was released from the cells, indicating that fluorine retention can be used as a surrogate marker for cell survival. Labeled-SVF cells engrafted in a silicone breast phantom could be visualized with a clinical 3-Tesla magnetic resonance imaging scanner at a sensitivity of approximately 2 * 106 cells at a depth of 5 mm. The current protocol can be used to image transplanted SVF cells at clinically relevant cell concentrations in patients. SIGNIFICANCE: Stromal vascular fraction (SVF) cells harvested from adipose tissue offer great promise in regenerative medicine, but methods to track such cell therapies are needed to ensure correct administration and monitor survival. A clinical protocol was developed to harvest and label SVF cells with the fluorinated (19F) agent CS-1000, allowing cells to be tracked with (19)F magnetic resonance imaging (MRI). Flow cytometry evaluation revealed heterogeneous 19F uptake in SVF cells, confirming the need for careful characterization. The proposed protocol resulted in sufficient 19F uptake to allow imaging using a clinical MRI scanner with point-of-care processing. PMID- 26511653 TI - A Universal and Robust Integrated Platform for the Scalable Production of Human Cardiomyocytes From Pluripotent Stem Cells. AB - Recent advances in the generation of cardiomyocytes (CMs) from human pluripotent stem cells (hPSCs), in conjunction with the promising outcomes from preclinical and clinical studies, have raised new hopes for cardiac cell therapy. We report the development of a scalable, robust, and integrated differentiation platform for large-scale production of hPSC-CM aggregates in a stirred suspension bioreactor as a single-unit operation. Precise modulation of the differentiation process by small molecule activation of WNT signaling, followed by inactivation of transforming growth factor-beta and WNT signaling and activation of sonic hedgehog signaling in hPSCs as size-controlled aggregates led to the generation of approximately 100% beating CM spheroids containing virtually pure (~90%) CMs in 10 days. Moreover, the developed differentiation strategy was universal, as demonstrated by testing multiple hPSC lines (5 human embryonic stem cell and 4 human inducible PSC lines) without cell sorting or selection. The produced hPSC CMs successfully expressed canonical lineage-specific markers and showed high functionality, as demonstrated by microelectrode array and electrophysiology tests. This robust and universal platform could become a valuable tool for the mass production of functional hPSC-CMs as a prerequisite for realizing their promising potential for therapeutic and industrial applications, including drug discovery and toxicity assays. SIGNIFICANCE: Recent advances in the generation of cardiomyocytes (CMs) from human pluripotent stem cells (hPSCs) and the development of novel cell therapy strategies using hPSC-CMs (e.g., cardiac patches) in conjunction with promising preclinical and clinical studies, have raised new hopes for patients with end-stage cardiovascular disease, which remains the leading cause of morbidity and mortality globally. In this study, a simplified, scalable, robust, and integrated differentiation platform was developed to generate clinical grade hPSC-CMs as cell aggregates under chemically defined culture conditions. This approach resulted in approximately 100% beating CM spheroids with virtually pure (~90%) functional cardiomyocytes in 10 days from multiple hPSC lines. This universal and robust bioprocessing platform can provide sufficient numbers of hPSC-CMs for companies developing regenerative medicine technologies to rescue, replace, and help repair damaged heart tissues and for pharmaceutical companies developing advanced biologics and drugs for regeneration of lost heart tissue using high-throughput technologies. It is believed that this technology can expedite clinical progress in these areas to achieve a meaningful impact on improving clinical outcomes, cost of care, and quality of life for those patients disabled and experiencing heart disease. PMID- 26511654 TI - Model-specification uncertainty in future forest pest outbreak. AB - Climate change will modify forest pest outbreak characteristics, although there are disagreements regarding the specifics of these changes. A large part of this variability may be attributed to model specifications. As a case study, we developed a consensus model predicting spruce budworm (SBW, Choristoneura fumiferana [Clem.]) outbreak duration using two different predictor data sets and six different correlative methods. The model was used to project outbreak duration and the uncertainty associated with using different data sets and correlative methods (=model-specification uncertainty) for 2011-2040, 2041-2070 and 2071-2100, according to three forcing scenarios (RCP 2.6, RCP 4.5 and RCP 8.5). The consensus model showed very high explanatory power and low bias. The model projected a more important northward shift and decrease in outbreak duration under the RCP 8.5 scenario. However, variation in single-model projections increases with time, making future projections highly uncertain. Notably, the magnitude of the shifts in northward expansion, overall outbreak duration and the patterns of outbreaks duration at the southern edge were highly variable according to the predictor data set and correlative method used. We also demonstrated that variation in forcing scenarios contributed only slightly to the uncertainty of model projections compared with the two sources of model specification uncertainty. Our approach helped to quantify model-specification uncertainty in future forest pest outbreak characteristics. It may contribute to sounder decision-making by acknowledging the limits of the projections and help to identify areas where model-specification uncertainty is high. As such, we further stress that this uncertainty should be strongly considered when making forest management plans, notably by adopting adaptive management strategies so as to reduce future risks. PMID- 26511655 TI - Comparison of doxycycline with azithromycin in treatment of pharyngeal chlamydia infection. AB - Recent data suggest that azithromycin may not be as effective as doxycycline in eradication of genital chlamydial infection. The aim of this study was to compare the eradication rate of pharyngeal Chlamydia trachomatis infection after treatment with azithromycin 1 g stat with that of doxycycline 100 mg twice a day for seven days. A prospective open-label observational study was conducted on patients with pharyngeal Chlamydia trachomatis diagnosed at Whittall Street Clinic, University Hospitals Birmingham, Birmingham, UK, between July 2012 and July 2013. We confirmed eradication of pharyngeal Chlamydia trachomatis with a negative test of cure. We treated all our patients with azithromycin 1 g stat until February 2013. At that stage, we offered doxycycline to patients with pharyngeal Chlamydia trachomatis A total of 398 patients (52 men, 346 women) were diagnosed with pharyngeal Chlamydia trachomatis during the study period. Of the 172 patients included in the final analysis, 78 were treated with azithromycin and 64 with doxycycline. Treatment failure was identified among 8/78 (10%) patients treated with azithromycin and 1/64 (2%) treated with doxycycline (absolute difference: 8 percentage points, 95% CI: 0-17%, p = 0.041). In our study, doxycycline 100 mg twice a day for seven days was associated with less treatment failure of oropharyngeal chlamydia compared with azithromycin 1 g stat Future randomised studies should investigate whether patients with pharyngeal Chlamydia trachomatis should be followed up with a test of cure when treated with azithromycin, or be treated with doxycycline. PMID- 26511656 TI - Crystal Vue technique for imaging fetal spine and ribs. PMID- 26511657 TI - [Denis Parsons Burkitt: A passion for knowledge]. PMID- 26511658 TI - The behaviour and recovery of juvenile lemon sharks Negaprion brevirostris in response to external accelerometer tag attachment. AB - Behavioural responses of lemon sharks Negaprion brevirostris to a fin-mounted tag package (CEFAS G6A tri-axial accelerometer with epoxied Sonotronics PT4 acoustic transmitter) were measured in a controlled captive environment (n = 10, total length, LT range 80-140 cm) and in free-ranging sharks upon release (n = 7, LT range 100-160 cm). No changes were detected in behaviour (i.e. swimming speed, tailbeat frequency, time spent resting and frequency of chafing) between control and tagged captive shark trials, suggesting that the tag package itself does not alter behaviour. In the free-ranging trials, an initial period of elevated swimming activity was found in all individuals (represented by overall dynamic body acceleration). Negaprion brevirostris, however, appeared to recover quickly, returning to a steady swimming state between 2 and 35 min after release. Post release tracking found that all sharks swim immediately for the shoreline and remain within 100 m of shore for prolonged periods. Hence, although N. brevirostris are capable of quick adaptation to stressors and demonstrate rapid recovery in terms of activity, tracking data suggest that they may modify their spatial use patterns post release. This research is important in separating deviation in behaviour due to environmental stressors from artefacts caused by experimental techniques. PMID- 26511659 TI - Transforming cardiac rehabilitation into broad-based healthy lifestyle programs to combat noncommunicable disease. AB - The current incidence and prevalence of noncommunicable diseases (NCDs) is currently a cause for great concern on a global scale; future projections are no less disconcerting. Unhealthy lifestyle patterns are at the core of the NCD crisis; physical inactivity, excess body mass, poor nutrition and tobacco use are the primary lifestyle factors that substantially increase the risk of developing one or more NCDs. We have now come to recognize that healthy lifestyle interventions are a medical necessity that should be prescribed to all individuals. Perhaps the most well-established model for healthy lifestyle interventions in the current healthcare model is cardiac rehabilitation. To have any hope of improving the outlook for NCDs on a global scale, what is currently known as cardiac rehabilitation must transform into broad-based healthy lifestyle programing, with a shifted focus on primordial and primary prevention. PMID- 26511660 TI - Multiblock copolymers exhibiting spatio-temporal structure with autonomous viscosity oscillation. AB - Here we report an ABA triblock copolymer that can express microscopic autonomous formation and break-up of aggregates under constant condition to generate macroscopic viscoelastic self-oscillation of the solution. The ABA triblock copolymer is designed to have hydrophilic B segment and self-oscillating A segment at the both sides by RAFT copolymerization. In the A segment, a metal catalyst of chemical oscillatory reaction, i.e., the Belousov-Zhabotinsky (BZ) reaction, is introduced as a chemomechanical transducer to change the aggregation state of the polymer depending on the redox states. Time-resolved DLS measurements of the ABA triblock copolymer confirm the presence of a transitional network structure of micelle aggregations in the reduced state and a unimer structure in the oxidized state. This autonomous oscillation of a well-designed triblock copolymer enables dynamic biomimetic softmaterials with spatio-temporal structure. PMID- 26511661 TI - Stem and progenitor cell division kinetics during postnatal mouse mammary gland development. AB - The cycling properties of mammary stem and progenitor cells is not well understood. To determine the division properties of these cells, we administered synthetic nucleosides for varying periods of time to mice at different stages of postnatal development and monitored the rate of uptake of these nucleosides in the different mammary cell compartments. Here we show that most cell division in the adult virgin gland is restricted to the oestrogen receptor-expressing luminal cell lineage. Our data also demonstrate that the oestrogen receptor-expressing, milk and basal cell subpopulations have telomere lengths and cell division kinetics that are not compatible with these cells being hierarchically organized; instead, our data indicate that in the adult homeostatic gland, each cell type is largely maintained by its own restricted progenitors. We also observe that transplantable stem cells are largely quiescent during oestrus, but are cycling during dioestrus when progesterone levels are high. PMID- 26511662 TI - Neurocognitive Development and Predictors of L1 and L2 Literacy Skills in Dyslexia: A Longitudinal Study of Children 5-11 Years Old. AB - The aim of this study was to find valid neurocognitive precursors of literacy development in first language (L1, Norwegian) and second language (L2, English) in a group of children during their Pre-literacy, Emergent Literacy and Literacy stages, by comparing children with dyslexia and a typical group. Children who were 5 years old at project start were followed until the age of 11, when dyslexia was identified and data could be analysed in retrospect. The children's neurocognitive pattern changed both by literacy stage and domain. Visuo-spatial recall and RAN appeared as early precursors of L1 literacy, while phonological awareness appeared as early precursor of L2 English. Verbal long term memory was associated with both L1 and L2 skills in the Literacy stage. Significant group differences seen in the Pre-literacy and Emergent literacy stages decreased in the Literacy stage. The developmental variations by stage and domain may explain some of the inconsistencies seen in dyslexia research. Early identification and training are essential to avoid academic failure, and our data show that visuo spatial memory and RAN could be suitable early markers in transparent orthographies like Norwegian. Phonological awareness was here seen as an early precursor of L2 English, but not of L1 Norwegian. PMID- 26511663 TI - Professional karate-do and mixed martial arts fighters present with a high prevalence of temporomandibular disorders. AB - BACKGROUND/AIM: Facial trauma in sports has been associated with temporomandibular disorders. Because of the intensity and duration of training needed for elite-level competitions, high-performance athletes can have two to five times more traumatic injuries than recreational athletes. This study aimed to investigate the prevalence of temporomandibular disorders in high-performance martial arts fighters and compare it with the prevalence in recreational athletes and non-athletes. MATERIAL AND METHODS: The Research Diagnostic Criteria for Temporomandibular Disorders was used to diagnose and classify professional karate do practitioners (group I; n = 24), amateur karate-do practitioners (group II; n = 17), high-performance mixed martial arts fighters (group III; n = 13), and non athletes (n = 28). The groups were compared with the chi-square test and tested for the difference between two proportions using a significance level of 5% (P < 0.05). RESULTS: The prevalence of temporomandibular disorders in groups I (54.2%; P = 0.003) and III (61.5%; P = 0.002) was significantly higher than in group IV (14.3%). The prevalence in group II was similar to that in group IV (P > 0.05). A diagnosis of arthralgia from disk displacement was made more frequently in groups I (45.8%; P = 0.013) and III (38.5%; P = 0.012) than in group IV (7.1%). The chronic pain associated with TMD was low intensity and low disability. CONCLUSIONS: While there was a high prevalence of temporomandibular disorders in the professional athletes in our study, the prevalence of the condition in recreational athletes was similar to that in individuals who did not practice martial arts. PMID- 26511664 TI - Metabolic and oxidative status of Saanen goats of different parity during the peripartum period. AB - The aim of this study was to research changes in metabolic and antioxidative status of Saanen goats of different parity occurring during the peripartum period. Blood samples were taken on 10-7 and 3-1 d prepartally and 1-3, 14 and 28 d postpartally from goats allocated in three groups according to their parity: primiparous (PRIM), goats that kidded the 2nd or 3rd time (MID), and goats that kidded 4 or more times (MULTI)). Metabolic profile parameters (non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHB), glucose, triglycerides, albumin and urea) and indicators of oxidative stress ((superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA)) were determined. Intense metabolic changes associated with late pregnancy and onset of lactation were pronounced the most in MULTI goats that also had the biggest litter per goat. Significant differences were found in metabolic parameters NEFA, BHB, glucose, triglycerides within groups during peripartum period, as well as between them (the effect of parity). MDA concentrations were indicative of increased lipid peroxidation around parturition, especially pronounced in MULTI group 1-3 d prepartally, when the highest GSH-Px/SOD ratio was also found. Postpartally, antioxidant enzymes ratio in MID and MULTI group decreased while MDA concentrations remained high, suggesting antioxidant system inefficiency. Significant time * group interaction was observed for most of the parameters. The obtained results show that the goats of higher parity display higher levels of metabolism intensity and consequently, varying levels of oxidative stress during the peripartum period. Further studies should determine applicability of NEFA and BHB in periparturient metabolic profiling in dairy goats as well as establish normal ranges and cut-off levels for these biomarkers. PMID- 26511665 TI - Variation of milk components in the Italian Brown cattle. AB - The aim of this study was to evaluate the variations of protein, casein, saturated (SFA), unsaturated (UFA), monounsaturated (MUFA), polyunsaturated (PUFA) fatty acids contents and cheese yield in the milk of two groups of Italian Brown cows conventionally reared in indoor period of housing or consuming pasture during the summer months in 2008 and 2013. Milk components were obtained from samples collected during the national routine (conventionally reared) and 'extraordinary' (pasture period) milk recording scheme in herds located near Sondrio (Lombardia, Italy). Milk samples were processed with the MilkoScanTM FT6000 for the identification of milk casein, SFA, UFA, MUFA and PUFA composition. The groups were analysed separately per year and the environmental factors affecting milk protein, casein, and fatty acids contents (pasture/indoor, parity, data of sampling, days in milk, days from collection to analysis) were included in the MIXED procedure of SAS 9.3. A total of 778 milk samples were available, including 234 records from indoor and 544 observations from pasture feeding. Pasture intake affected the content of casein (%) and the proportion of fat in milk (g/100 g), enhancing milk casein levels (from 2.90 to 3) and reducing the concentration of milk SFA in milk from grazing cows (from 2.29 to 1.92). Additionally, the cheese yield was calculated as 'kg of cheese per 100 kg of milk' and resulted to be 10.4 and 12 in 2008 from milk of cows reared indoor and with pasture based diet, respectively. The dairy industry should take advantage of the milk production during grazing periods from which high quality products may be obtained. PMID- 26511666 TI - Qualitative variations on Calabrian Provola cheeses stored under different packaging conditions. AB - Calabrian Provola cheese, an Italian typical dairy product, is commonly sold unwrapped with an expiry date of 45 d. The influence of different packagings and subsequent storage at 4 and 7 degrees C on maintaining cheese quality and prolonging its shelf life was evaluated. The following packaging systems were used: Polyamide/Polyethylene pouch under vacuum; Polyethylene/Polyethylene terephthalate lid over a Polyethylene/Ethylene vinyl alcohol/Polyvinyl Chloride + Polyvinyl alcohol thermoformed tray; Polyethylene/Ethylene vinyl alcohol/Polyamide/Polyethylene pouch. Concerning the two last systems, cheeses were packaged in a modified atmosphere (70:30 N2:CO2). All studied packaging prolonged Calabrian Provola cheese shelf life to 65 d. In particular, the packaging in modified atmosphere with Polyethylene/Ethylene vinyl alcohol/Polyamide/Polyethylene pouch preserved Provola cheeses best, not only showing a decrease of the original total microbial count but also showing the lowest peroxide value and hardness at both temperatures of storage. The results of this study will help local Italian firms to expand their business in more distant markets. PMID- 26511667 TI - Weight management care practices of English and Chinese nurses. AB - BACKGROUND: Obesity is a growing global public health problem which requires all healthcare professionals to deliver weight management care within their roles. AIM: To describe nurses' perceived barriers, skills and practices regarding weight-related care and explore differences between English and Chinese nurses. METHODS: A cross-sectional, self-administered questionnaire survey was distributed to 588 English nurses employed in a range of clinical settings and healthcare organizations and attending a large university in London (October November 2010), and 519 Chinese nurses working in one of the largest hospitals in Shanghai, China (February-April 2011). Perceived barriers, skills and practices regarding weight-related care were measured. Data analysis was undertaken using responses from 399 English and 466 Chinese nurses. RESULTS: English and Chinese nurses reported similar barriers to undertaking weight-related care practices which included two relatively new barriers, namely complex patients and the absence of clear practice guidelines. Both English and Chinese nurses reported being moderately skilled to perform weight-related care practices with the most mean skill scores at the moderate level. Up to 11-54% of the English nurses and 10-25% of the Chinese nurses reported providing recommended weight-related interventions for most of their patients. Generally, the English nurses reported more barriers, high-level skills and practices regarding weight-related care than the Chinese nurses. LIMITATIONS: The convenience samples and self-report data may have been sources of bias. CONCLUSIONS: A variety of barriers and limited skills may help explain the suboptimal weight-related practices among the nurses. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Skill development of pre-registration and qualified nurses is indicated as well as the development of the nurse role to include weight management care of obese patients. Evidence-based guidelines should be readily accessible to support the nurse role in weight-related care. PMID- 26511668 TI - Patterns of recurrence in early-stage oesophageal cancer after chemoradiotherapy and surgery compared with surgery alone. AB - BACKGROUND: Patterns of disease recurrence in patients with oesophageal cancer following treatment with neoadjuvant chemoradiotherapy and surgery (nCRTS) or surgery alone are poorly reported. An understanding of patterns of disease recurrence is important for subsequent treatment planning. METHODS: An analysis was undertaken of patterns of disease recurrence from a phase III multicentre randomized trial (FFCD9901) comparing nCRTS with surgery alone in patients with stage I and II oesophageal cancer. RESULTS: Some 170 patients undergoing surgical resection were included in the study. R0 resection rates were similar in the two groups: 94 per cent following nCRTS versus 92 per cent after surgery alone (P = 0.749). After a median follow-up of 94.2 months, recurrent disease was found in 39.4 per cent of the overall cohort (31 per cent after nCRTS versus 47 per cent following surgery alone; P = 0.030). Locoregional recurrence was diagnosed in 41 patients (17 versus 30 per cent respectively; P = 0.047) and distant metastatic recurrence in 47 (23 versus 31 per cent respectively; P = 0.244). Metastatic recurrence was more frequent in patients with adenocarcinoma than in those with squamous cell cancer (40 versus 23.1 per cent respectively; P = 0.032). ypT0 N0 category was associated with prolonged time to mixed locoregional and metastatic recurrence (P = 0.009), and time to locoregional (P = 0.044) and metastatic (P = 0.055) recurrence. In multivariable analysis, node-positive disease predicted both locoregional (P = 0.001) and metastatic (P < 0.001) recurrence. CONCLUSION: Locoregional disease control following nCRTS indicated a local field effect not related solely to completeness of resection. pN+ disease was strongly predictive of time to locoregional and metastatic disease recurrence. PMID- 26511669 TI - Consistency in adult reporting of adverse childhood experiences. AB - BACKGROUND: Many studies have used retrospective reports to assess the long-term consequences of early life stress. However, current individual characteristics and experiences may bias the recall of these reports. In particular, depressed mood may increase the likelihood of recall of negative experiences. The aim of the study was to assess whether specific factors are associated with consistency in the reporting of childhood adverse experiences. METHOD: The sample comprised 7466 adults from Canada's National Population Health Survey who had reported on seven childhood adverse experiences in 1994/1995 and 2006/2007. Logistic regression was used to explore differences between those who consistently reported adverse experiences and those whose reports were inconsistent. RESULTS: Among those retrospectively reporting on childhood traumatic experiences in 1994/1995 and 2006/2007, 39% were inconsistent in their reports of these experiences. The development of depression, increasing levels of psychological distress, as well as increasing work and chronic stress were associated with an increasing likelihood of reporting a childhood adverse experience in 2006/2007 that had not been previously reported. Increases in mastery were associated with reduced likelihood of new reporting of a childhood adverse experience in 2006/2007. The development of depression and increases in chronic stress and psychological distress were also associated with reduced likelihood of 'forgetting' a previously reported event. CONCLUSIONS: Concurrent mental health factors may influence the reporting of traumatic childhood experiences. Studies that use retrospective reporting to estimate associations between childhood adversity and adult outcomes associated with mental health may be biased. PMID- 26511671 TI - PdPt bimetallic nanoparticles enabled by shape control with halide ions and their enhanced catalytic activities. AB - In this study, a new and convenient one step approach is described for synthesizing shape controlled PdPt bimetallic nanoparticles. It is found that the resultant morphologies of these PdPt nanoparticles can be well controlled by simply altering the participation of different halide ions that serve as shape controlling agents in the reaction solution. The dendritic core-shell PdPt bimetallic nanoparticles generated with Pt atoms adopt usual island growth pattern in the presence of Cl(-) ions, whereas the introduction of Br(-) ions with a relatively strong adsorption effect facilitate the formation of a layered core-shell structure due to the layered growth mode of Pt atoms on the exterior surface of the central Pd core. Moreover, the stronger adsorption function of I( ) ions and the resulting fast atomic diffusion promoted the generation of mesoporous core-shell PdPt bimetallic nanoparticles with many pore channels. In addition, the size of these synthesized PdPt nanoparticles exhibited a significant dependence on the concentration of the halide ions involved. Due to their specific structural features and synergistic effects, these PdPt catalysts exhibited shape-dependent catalytic performance and drastically enhanced electrocatalytic activities relative to that of commercial Pt black and Pt/C toward methanol oxidation. PMID- 26511672 TI - Thermal conductivity of biaxial-strained MoS2: sensitive strain dependence and size dependent reduction rate. AB - The effect of biaxial tensile strain on the thermal transport properties of MoS(2) is investigated by combining first-principles calculations and the Boltzmann transport equation. The thermal conductivities of single layer MoS(2) are found to be heavily suppressed by the applied strains; even a moderate biaxial tensile strain, 2 ~ 4%, could result in a 10 ~ 20% reduction in the thermal conductivity. Most interestingly, the reduction rate of thermal conductivity is size dependent,which is due to different dominant phonon scattering mechanisms at different sizes of MoS(2) samples. The sensitive strain dependence of thermal conductivity indicates that strain engineering could be an effective method to enhance the figure of merit for thermoelectric applications of MoS(2). PMID- 26511673 TI - Prevalence and risk of diabetes based on family history in the Shanghai High-Risk Diabetic Screen (SHiDS) study. AB - AIMS: To evaluate the prevalence and risk of diabetes based on family history in high-risk subjects and also to evaluate insulin sensitivity and insulin secretion in these subjects. METHODS: Data were analysed from 9756 participants in the Shanghai High-Risk Diabetic Screen (SHiDS) Project. Family history of diabetes was classified according to parental and sibling diabetes status. The prevalence and odds ratios were calculated for each grouping after adjusting for other risk factors. Insulin resistance and sensitivity were evaluated using oral glucose tolerance test-derived indices that were validated by hyperinsulinaemic euglycaemic and hyperglycaemic clamps. RESULTS: A total of 30.4% of the subjects had a family history of diabetes in a first-degree relative. The proportions of subjects with a father, mother or sibling with diabetes were 7.5, 11.9 and 5.5%, respectively. The prevalence rates of diabetes in subjects with sibling history, maternal history or paternal history of diabetes were 39.3, 38.3 and 36.4%, respectively. Sibling history was a strong risk factor for diabetes (odds ratio 1.53, 95% CI 1.27-1.84; P < 0.05). Insulin secretion was significantly lower in those with a maternal or sibling history of diabetes; however, insulin sensitivity was not significantly different among subjects with a family history of diabetes. CONCLUSIONS: Sibling history of diabetes was more strongly associated with diabetes risk than parental history among high-risk subjects. Subjects with a sibling or maternal history of diabetes had significantly lower insulin secretion. Sibling history is an important and independent risk factor for diabetes even among multi-risk populations. Those with a sibling history of diabetes warrant intensive care and follow-up screening. PMID- 26511674 TI - Changes in Relationship-Specific Attachment in Emotionally Focused Couple Therapy. AB - Emotionally focused couple therapy (EFT; Johnson, The practice of emotionally focused couple therapy (1st/2nd edition). Brunner-Routledge, New York, 2004) is an effective treatment of relationship distress (Johnson et al., Clinical Psychology: Science and Practice, 1999; 6, 67). However, less is known about EFT's impact on couples' relationship-specific attachment bond. Using hierarchical linear modeling with a sample of 32 couples, we examined session-by session changes in couples' relationship-specific attachment anxiety and avoidance and pre- to posttherapy changes in their relationship-specific attachment behaviors. Couples significantly decreased in relationship-specific attachment avoidance, and those who completed a blamer softening significantly decreased in relationship-specific attachment anxiety. Couples' attachment behavior significantly increased toward security. Finally, session-by-session decreases in relationship-specific attachment anxiety and avoidance were significant associated with increases in relationship satisfaction across sessions. These results provide empirical support for the attachment-based assumptions of EFT. Video abstract accessible by clicking here. PMID- 26511675 TI - Synthesis of FMRFaNV, a Photoreleasable Caged Transmitter Designed to Study Neuron-Glia Interactions in the Central Nervous System. AB - Neuroscience studies require technologies able to deliver compounds with both scale and timing compatibility with morphological and physiological synaptic properties. In this light, two-photon flash photolysis has been extensively used to successfully apply glutamate or other neurotransmitters at the synaptic level. However, the set of commercially available caged compounds is restricted and incompatible with studies demanding high cell specificity. The gain in cell specificity is especially relevant and challenging when studying neuron-glia interactions in the central nervous system. Here we develop a system to mimic the metabotropic glutamate receptor-dependent response of astrocytes, a glial cell type, following synaptic glutamate release. For this, we expressed an exogeneous orphan Gq-coupled protein of the Mas-related-gene (Mrg) family in glial cells and generated an MrgR's agonist peptide (FMRFa) that was chemically caged with a nitroveratryl photolabile protecting group (NV). NV has an appropriate quantum yield and a high absorption maximum that makes it very adapted to experiments with very short irradiation time. This novel caged compound allowed the activation of MrgR with both single- and two-photon light sources. Indeed, MrgR activation induced calcium transients and morphological changes in astrocytes as described previously. Thus, FMRFaNV is a very promising tool to study neuron-glia interactions. PMID- 26511676 TI - What Factors Influence the Decision to Share Suicidal Thoughts? A Multilevel Social Network Analysis of Disclosure Among Individuals with Serious Mental Illness. AB - Nondisclosure of suicidal thoughts limits suicide risk management. Consistent with disclosure models for other stigmatized statuses, understanding suicidal disclosure requires accounting for features of the discloser (individual factors) and the discloser-recipient relationship (relational factors). In a sample of 30 adults with schizophrenia, bipolar disorder, or major depressive disorder (Level 2) who nominated 436 social network members (Level 1), we examined disclosure patterns and identified individual and relational correlates of disclosure intent. Most individuals disclosed in the past (77%; n = 23) and all intended on disclosing (100%; n = 30). Disclosure was highly selective, with 14% (n = 62) of network members identified as prior confidants and 23% (n = 99) identified as intended confidants. Multilevel modeling indicated that relational factors were more central to disclosure than individual factors. Network members who were prior confidants and who provided social support were attractive targets for intended disclosure. Our findings suggest that "targeted" gatekeeper training may be a promising strategy and reveal relational characteristics to identify "high probability confidants." PMID- 26511677 TI - The prognostic role of E-cadherin and beta-catenin overexpression in laryngeal squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: Epithelial-to-mesenchymal transition (EMT) consists of a rapid and reversible change in the cellular phenotype toward the mesenchymal cell phenotype that facilitates cell migration and invasion of the tumor into surrounding tissues followed by metastasis. In the present study, we sought to determine the clinical significance of E-cadherin, N-cadherin, beta-catenin, alpha-catenin, gamma-catenin, caveolin-1, and vimentin in a cohort of patients with stage I to IVA laryngeal squamous cell carcinoma (LSCC) treated with surgery with or without adjuvant therapy using immunohistochemical analyses. STUDY DESIGN: Individual retrospective cohort study. METHODS: E-cadherin, N-cadherin, beta-catenin, alpha-catenin, gamma-catenin, caveolin-1, and vimentin immunohistochemical expression were evaluated in a cohort of 82 patients with stages I to IVA LSCC. The Fisher exact test was used for categorical variables, and the Mann-Whitney test where appropriate for continuous variables. Survival comparisons was performed using the log-rank test. A multivariate analysis using the Cox proportional hazards model was performed and considered all EMT markers. RESULTS: In multivariate analysis, T stage was an independent risk factor for adverse disease-specific survival (DSS) and overall survival (OS) (P = .025 and .019, respectively). Cytoplasmic beta-catenin overexpression was independently associated with a longer DSS (P = .0007), and E-cadherin overexpression was found to be an independent risk factor for poor OS (P = .030). CONCLUSIONS: E-cadherin and beta-catenin pathways could represent future therapeutic targets in the treatment of LSCC. However, validation of our results in prospective cohorts of patients with LSCCs is required before their clinical implementation. LEVEL OF EVIDENCE: NA. PMID- 26511678 TI - Triazole-gold promoted intermolecular propargyl alcohol addition to alkyne: the reaction cascade toward substituted allenes. AB - Gold-catalyzed intermolecular propargyl alcohol addition to alkyne was achieved. The reaction of propargyl alcohol with a typical gold catalyst gave the hydration product almost exclusively. The triazole gold catalyst (TA-Au) successfully prevented the hydration, giving the vinyl ether followed by a 3,3-rearrangement. Synthetically useful substituted allenes were formed with high efficiency, substrate tolerability and chemoselectivity. Also, more than 95% chirality transfer from propargyl alcohol to allene was obtained. PMID- 26511679 TI - Prenatal arsenic exposure and drowning among children in Bangladesh. AB - There is increasing concern regarding adverse effects of prenatal arsenic exposure on the neurodevelopment of children. We analyzed mortality data for children, who were born to 11,414 pregnant women between 2002 and 2004, with an average age of 5 years of follow-up. Individual drinking-water arsenic exposure during pregnancy was calculated using tubewell water arsenic concentration between last menstrual period and date of birth. There were 84 drowning deaths registered, with cause of death ascertained using verbal autopsy (International Classification of Diseases, 10th revision, codes X65-X70). The prenatal water arsenic exposure distribution was tertiled, and the risk of drowning mortality was estimated by Cox proportional hazard models, adjusted for potential confounders. We observed a significant association between prenatal arsenic exposure and drowning in children aged 1-5 years in the highest exposure tertile (HR=1.74, 95% CI: 1.03-2.94). This study showed that in utero arsenic exposure might be associated with excess mortality among children aged 1-5 years due to drowning. PMID- 26511680 TI - Bakkenolide-IIIa Protects Against Cerebral Damage Via Inhibiting NF-kappaB Activation. AB - AIMS: This study was designed to examine the neuroprotective effects of bakkenolide-IIIa, a major novel compound extracted from the rhizome of P. trichinous. METHODS: Transient focal cerebral damage model in rats and oxygen glucose deprivation (OGD) in cultured hippocampal neurons were performed. The amount of apoptotic neurons was determined using TUNEL assay. The expressions of Bcl-2, Bax, Akt, ERK1/2, IKKbeta, IkappaBalpha were measured using Western blot. The nuclear translocation and activation of NF-kappaB was measured using a fluorescence microscope and electrophoretic mobility shift assay (EMSA). RESULTS: Bakkenolide-IIIa (4, 8, 16 mg/kg; i.g.) was administered immediately after reperfusion could reduce the brain infarct volume, and the neurological deficit, as well as a high dose of bakkenolide-IIIa, increases the 72 h survival rate in cerebrally damaged rats. In vitro data demonstrated that bakkenolide-IIIa could increase cell viability and decrease the amount of apoptotic cells in cultured primary hippocampal neurons exposed to OGD. Bakkenolide-IIIa also dose dependently increased the ratio of Bcl-2 to Bax. These results indicated that inhibition of apoptosis partly mediated the neuroprotection of bakkenolide-IIIa. Furthermore, bakkenolide-IIIa inhibited the phosphorylation of Akt, ERK1/2, IKKbeta, IkappaBalpha, and p65 in cultured hippocampal neurons exposed to OGD. Bakkenolide-IIIa not only inhibited the nuclear translocation of NF-kappaB in cultured neurons exposed to OGD, but also inhibited the activation of NF-kappaB in peri-infarct area in cerebrally damaged rats. CONCLUSION: Collectively, our findings indicated that bakkenolide-IIIa protects against cerebral damage by inhibiting AKT and ERK1/2 activation and inactivated NF-kappaB signaling. PMID- 26511681 TI - Differential characteristics of young and midlife adult users of psychotherapy, psychotropic medications, or both: information from a population representative sample in Sao Paulo, Brazil. AB - OBJECTIVE: While the personal characteristics of users of psychotherapy and/or psychotropic medications have been examined, direct user comparison of these treatment approaches appears to be rare. Our aim is to ascertain extent of receipt of these services, and identify basic distinguishing characteristics of users. METHODS: Information on demographics, lifetime and past 12 month use of mental health services, and presence of common mental disorders (CMD), was gathered in 2002 using a multi-stage sampling procedure that yielded a population representative, community-resident sample (N = 2000, age 18-65) for Sao Paulo, Brazil. Analysis used descriptive statistics and logistic regression. RESULTS: Overall, 9.3% reported receiving psychotherapy and/or psychotropic medication, 54.3% of whom did not meet CMD criteria. Of those meeting criteria for CMD (n = 455, 22.8%), 2.9% reported only psychotherapy, 10.1% reported only psychotropic medication, and 5.7% reported both. CMD was associated with use of psychotropic medication (psychotropic medication alone, Odds Ratio (OR) 3.58, 95% CI 2.33 5.52; together with psychotherapy, OR 4.17, 95% CI 2.34-7.44). CMD was not associated with use of psychotherapy. Users' distinguishing characteristics were: psychotherapy only--not married; psychotropics only--increasing age, female, not married; using both--only CMD status. Neither education nor income was associated with use. CONCLUSIONS: Nearly 10% of all community residents age 18-65, but less than a fifth of the 23% with CMD, received psychotherapy and/or psychotropic medication. Non-married status increased odds of all treatment types, but CMD presence increased only odds of psychotropic and combined psychotherapy/psychotropic use, with odds of psychotropic only use increasing with age, and for women. Use was equitable with respect to education and income. PMID- 26511682 TI - Posterior cruciate ligament reconstruction via tibial inlay technique in multiligament knee injuries. AB - OBJECTIVE: The aim of this study is to report our institution's experience regarding the use of open tibial inlay technique in patients undergoing single stage combined posterior cruciate ligament (PCL) reconstruction. METHODS: Records of 17 patients who underwent PCL reconstruction with tibial inlay technique were retrospectively reviewed. Patients with ipsilateral femoral or tibial osteochondral avulsion fractures or ipsilateral concomitant tibia and femur shaft fractures were excluded. Out of these 17 patients, six cases underwent anterior cruciate ligament (ACL) + PCL reconstruction, nine cases underwent ACL+ PCL + posterolateral corner reconstruction, one case underwent ACL + PCL + MCL reconstruction and one case underwent ACL+ PCL + posterolateral corner + MCL reconstruction. Mean follow-up was 14.27+/-6.77 (range: 6-30) months. RESULTS: In preoperative assessments, all patients had 3+ posterior laxity in posterior drawer test; at final follow-up, 6 patients had 0 laxity, 7 patients had 1+ laxity, and 4 patients had 2+ laxity (p<0.001). International Knee Documentation Committee (IKDC) objective evaluation showed severe disability in all patients preoperatively, whereas 5 knees were grade A, 8 knees were grade B, 3 knees were grade C, and 1 knee was grade D at final follow-up. Mean IKDC subjective score was 75.22+/-7.53 at final follow-up. Postoperatively, mean side-to-side difference in KT-1000 arthrometer measurement was 2.45+/-1.80 mm. At final follow up, mean range of motion (ROM) was 0o on extension and 123.56+/-6.31o on flexion. CONCLUSION: Open tibial inlay approach is beneficial during PCL reconstruction. Further study is warranted to establish its effectiveness on functional outcomes and prevention of complications. PMID- 26511683 TI - Mini-midvastus versus mini-medial parapatellar approach in simultaneous bilateral total knee arthroplasty with 24-month follow-up. AB - OBJECTIVE: Comparisons of mini-midvastus (mMV) with mini-medial parapatellar (mMPP) approach in total knee arthroplasty (TKA) have been performed in the past but were often compromised by variables such as disease, pain tolerance, bone quality, and surgeon. The aim of this study was to minimize the influence of these factors in order to more accurately evaluate these 2 approaches. METHODS: Forty-five patients who had bilateral arthritis of the knee with similar deformity and preoperative range of motion (ROM) on both sides agreed to have 1 knee replaced via mMV approach (Group I) and the other via mMPP approach (Group II) were evaluated. Postoperative clinical outcomes, postoperative complications, perioperative parameters, and knee component positioning were analyzed. RESULTS: No significant differences were found between the mMV and mMPP groups with regards to functional assessment, patient satisfaction, postoperative complication, quadricep strength, pain at the point of incision, degree of soft tissue release, as well as ROM. Nor were significant differences found between the 2 groups in terms of perioperative parameters and radiographic component positioning. CONCLUSION: The present study did not detect any substantive difference between the mMV and mMPP approaches for TKA. The decision between the 2 surgical approaches should be based on surgeon experience and preference. PMID- 26511684 TI - Return to driving after total knee arthroplasty. AB - OBJECTIVE: The aim of this study was to ascertain the duration from time of surgery to resumption of driving after total knee arthroplasty (TKA) and to examine recommendations in the literature. METHODS: All patients who underwent primary unilateral TKA and were driving within 6 months preceding the arthroplasty were included. The patients' age, gender and side of the TKA were noted. The time taken to resume driving by each patient as well as the type of vehicle were noted. RESULTS: Ninety-eight patients were included in our survey. Fifty-five patients (56%) underwent TKA on their left knee and 94 (96%) were manual car drivers. Seventy-seven patients (79%) were able to resume driving within 6 weeks of TKA; 18 patients (18%) were able to do so at Week 12 postoperatively. The remaining 3 patients (3%) did not feel confident enough to drive at Week 12 postoperatively. No patient reported deterioration in driving ability, whereas 27 patients (27%) felt a subjective improvement in their driving ability. CONCLUSION: The vast majority of patient resumed driving by 6 weeks postoperatively. Only a small number did not return to regular driving. Patients are advised to resume driving after 6 weeks but should wait until they feel comfortable and confident enough to do so. PMID- 26511685 TI - The midterm and long-term effects of acetabular roof ring and Burch-Schneider anti-protusio cages in acetabular revisions for patients with acetabular bone deficiency. AB - OBJECTIVE: The purpose of this study was to investigate the mid-term and long term effects of the acetabular roof ring (ARR) and Burch-Schneider anti-protrusio cage (BSAPC) in acetabular revision for patients with acetabular bone deficiency and acetabular component loosening. METHODS: Between 1988 and 2007, ARR revisions were performed in 51 patients (25 women; average age: 46.9 years) and BSAPC in 18 patients (16 women; average age: 62.1 years). Grafts were used in all revisions. The patients were evaluated retrospectively. The bone defects were classified according to the classification of the American Academy of Orthopaedic Surgeons (AAOS). Harris Hip Score (HHS) was used for clinical evaluation. Radiolucent lines, implant sizes, osseointegration, and heterotopic ossification in the 3 regions defined by DeLee and Charnley were evaluated radiologically. RESULTS: The success rate of ARR revisions after an average follow-up of 8.93+/-4.10 years (range: 4-23 years) was 87.9%, and the cumulative survival rate at year 10 postoperatively was 91%. Average HHS score increased to 83.70+/-8.98 postoperatively, from 40.10+/-2.49 preoperatively (p<0.01). The success rate of BSAPC revisions after an average follow-up of 7.06+/-2.39 years (range: 4-12 years) was 83.3%, and the cumulative survival rate was 78%. Average HHS score increased from 42.55 preoperatively to 73.86 postoperatively (p<0.01). All failures of ARR revisions occurred in type 3 defects (p<0.05). In 40 of the 47 patients in which an allograft was used, osseointegration occurred. No statistically significant difference was found between the increase in HHS scores of patients who underwent femoral component revision with acetabular revision and those who did not (p=0.06). Patients who underwent more than 1 revision had statistically significantly higher failure rates in comparison to patients undergoing revision for the first time (p=0.008). CONCLUSION: The mid-term and long-term results of the use of ARR and BSAPC with allografts in bone deficient acetabular revisions are satisfactory. The implants facilitate graft osseointegration, increase the bone stock, and make future revisions easier. ARR should be preferred in type 1 and type 2 acetabular bone defects, while BSAPC should be preferred in type 3 and 4 defects. PMID- 26511686 TI - Reliability and variability in the interpretation of lumbar high intensity zone. AB - OBJECTIVE: The aim of this study was to evaluate the reliability of high intensity zone (HIZ) and to assess discrepancy in the interpretation, as well as investigate the effects of parameters of HIZ on interobserver variation. METHODS: Four spine surgeons made independent observations on lumbar magnetic resonance imaging (MRI) from 207 consecutive patients from 3 institutions. The kappa statistic was used to characterize inter- and intraobserver reliability for visual assessments of HIZ. The corresponding MRI was provided to 2 additional spine surgeons for quantitative measurements. The parameters of HIZ, including signal intensity (SI) and area ratio (HIZ%), were used to assess the interobserver variation of HIZ. RESULTS: The overall interobserver agreement for visual assessments was substantial (kappa=0.62 at L4-5 and 0.61 at L5-S1), and intraobserver agreement was excellent (kappa=0.84 at L4-5 and 0.86 at L5-S1). Of 93 observed HIZ, 17 instances (18.3%) were agreed upon by all visual observers. The SI with full agreement was significantly brighter than all the others (p<0.01). The HIZ% with 2 agreements was significantly smaller than those with 4 agreements (p=0.04) and 3 agreements (p=0.03). Although fewer observers with consensus were associated with smaller HIZ%, the difference was not significant (p>0.05). CONCLUSION: The reliability in the interpretation of HIZ was sufficient for spine surgeons with differing levels of experience. This study highlighted that signal intensity was the primary cause of variability in visual observation. PMID- 26511687 TI - Transverse decompression technique in the surgical treatment of degenerative lumbar canal stenosis. AB - OBJECTIVE: The aim of this study was to assess the outcomes of fusion technique via posterior instrumentation in combination with transverse decompression in the surgical treatment of degenerative lumbar canal stenosis. METHODS: Forty-five patients-39 women (86.7%) and 6 men (13.3%)-were included. Mean age was 58.68+/ 8.63 years with mean follow-up of 51.71+/-20.96 months. Preoperative and postoperative clinical evaluation was performed using the Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) for overall pain. Preoperative and postoperative imaging studies were used to measure the degree of spondylolisthesis and the angle of scoliosis and lumbar lordosis. The presence of preoperative facet joint arthrosis and changes in the diameter of anterior, posterior, and transverse spinal canal were assessed by computed tomography (CT). Preoperative disc degeneration, disk herniation, and spondylolisthesis were examined by magnetic resonance imaging (MRI). RESULTS: Mean preoperative ODI and VAS scores were 59.2% and 7.06, respectively, while postoperative ODI and VAS scores were 14.4% and 1.7%, respectively (p=0.001). Anteroposterior diameter of the central canal increased from 10.43+/-2.18 mm preoperatively to 19.63+/-2.01 mm postoperatively (p=0.0001). Mean preoperative and postoperative spondylolisthesis were 5.81+/-4.88 mm and 3.87+/-4.53 mm, respectively (p=0.0001). Mean preoperative and postoperative scoliosis angles were 5.84 degrees +/-10.14 degrees and 2.04 degrees +/-5.08 degrees , respectively (p=0.0002). Mean preoperative and postoperative lordosis angles were 22.47 degrees +/-13.98 degrees and 33.73 degrees +/-10.89 degrees , respectively (p=0.0001). Complications included pulmonary embolism in 1 patient (2.2%), superficial injury site infection in 1 patient (2.2%), and deep surgical site infection in 1 patient (2.2%). Two patients (4.4%) experienced dural tears. One patient (2.2%) had intraoperative radix damage. CONCLUSION: The results of the present study suggest that the fusion technique via posterior instrumentation, in combination with transverse decompression, offers a clinical improvement in patients with lumbar canal stenosis. PMID- 26511688 TI - Factors affecting adherence with foot abduction orthosis following Ponseti method. AB - OBJECTIVE: The Ponseti method is an effective protocol for treatment of congenital idiopathic clubfoot. Foot abduction orthosis (FAO) is sometimes necessary to preserve the correction achieved with the serial casting and tenotomy. Patient and family adherence to brace use is a common problem, as nonadherence is directly related to relapse. The aim of this study was to investigate patient and parent characteristics related to relapse. METHODS: One hundred and fifty-three children who were treated with Ponseti method (mean age: 44.62 months; range: 16-104 months) and their parents were included in the study. Thirty-one patients experienced relapse at an average follow-up of 32 months (range: 6-84 months) since beginning orthosis use. At the time of follow-up visits, parents were questioned about brace use adherence. Satisfaction with Symptoms Scale in the American Academy of Orthopaedic Surgeons (AAOS) Pediatric Outcomes Data Collection Instrument (PODCI) was used. RESULTS: Difficulties with brace use were encountered in 122 children. Children of parents who were satisfied with the treatment had relapse at an average of 69.13+/-2.64 months, and those of parents who were not satisfied at 32.83+/-7.51 months. The most important variable was the child's adaptation to the orthosis treatment without an adverse reaction. Additionally, better compliance was found in children with higher-educated parents. CONCLUSION: Non-compliance with periods of intolerance is very common for children during orthosis treatment. Parents' coping strategies are very important to avoid relapses. It is important to develop strategies to guide parents. PMID- 26511689 TI - Preliminary report on amputation versus reconstruction in treatment of tibial hemimelia. AB - OBJECTIVE: Tibial hemimelia is a rare disorder characterized by the absence or hypoplasia of the tibia with associated rigidity. The aim of this study was to retrospectively evaluate the affectivity of reconstructive surgeries including centralization of the knee-ankle joints and lengthening with Ilizarov principles, as well as physical and functional results of amputation and reconstruction. METHODS: This is an IRB-approved retrospective review of all patients diagnosed with tibial hemimelia who required surgery at a single institution between 1998 and 2011. Charts were analyzed for clinical and radiographical findings. At final follow-up, patients underwent physical and radiographic examination. Patients and their parents were asked to complete the SF-10TM health survey (QualityMetric Inc., Lincoln, RI, USA). RESULTS: Twenty-one patients (12 male, 9 female) with 30 affected extremities were included. Mean age was 4.8+/-3.1 years at initial surgery. Knee level disarticulation was performed in 6 extremities of 4 patients. One patient with type III underwent transtibial amputation. Mean number of surgeries for each patient was 6.4+/-3.3, and mean duration of external fixator and casting was 17+/-6 months. Mean lengthening was 4.9+/-1.3 cm, and mean limb length discrepancy was 3.1+/-1.7 cm at 5.8+/-3.7 years at follow-up. SF-10TM scores were similar in disarticulated and reconstructed patients (p=0.63). All scores were significantly higher when disarticulation was performed in cases of knee instability (p<0.01). CONCLUSION: When stability of the knee joint is present, treatment modality should be chosen according to the existence of the proximal tibia. Amputation should be preferred in cases of knee joint instability. PMID- 26511690 TI - Surgical management of bone metastases from urological malignancies: an analysis of 70 cases. AB - OBJECTIVE: The purpose of this study was to evaluate symptomatic bone metastases from urological malignancies and the efficacy of surgical treatment of bone metastases in achieving local tumor control. METHODS: This was a retrospective observational study of patients diagnosed with bone metastases from urological malignancies who died from their diseases between 2002 and 2013. Data on clinicopathology, number and sites of bone metastasis, time to first and subsequent metastasis, survival after metastasis, nature of metastasis (blastic, mixed, lytic), type of surgical reconstruction, systemic affections, and visceral organ metastasis for 70 bone metastases from deceased urological malignancies patients (55 male, 15 female) with evidence of bone metastasis were statistically analyzed. RESULTS: Forty-three patients (61.42%) had renal cell carcinoma (RCC), 15 patients (21.43%) had prostate cancer, and 12 patients (17.15%) had bladder carcinoma as primary diagnosis. Osteolytic lesions were most prevalent (n=61; 87%). The most common surgical modality for extremities was wide resection with prosthetic replacement (42 patients), followed by wide resection or wide resection with bone cement application with internal fixation (21 patients); 65 patients were treated with limb salvage procedures, and 2 patients were treated with amputation. Overall median survival was 13 months for RCC, 16 months for prostate carcinoma, and 11 months for bladder carcinoma patients. CONCLUSION: Detection of bone metastases in patients with urological malignancies influences the treatment strategy. Diagnosis of bone metastases may be delayed in urologic malignities; thus, these patients receive long-term clinical follow-up. PMID- 26511691 TI - Proximal row carpectomy for Lichtman stage III Kienbock's disease. AB - OBJECTIVE: The purpose of this study was to investigate the objective and subjective outcomes of proximal row carpectomy (PRC) for stage III Kienbock's disease and determine if the physician's objective measurements correlate with the patients' subjective outcomes. METHODS: Twenty-four patients who underwent PRC for stage III Kienbock's disease with a follow-up period of more than 18 months were enrolled in the study. Clinical evaluation included preoperative and postoperative Quick Disabilities of the Arm, Shoulder and Hand (Q-DASH) questionnaire, postoperative Mayo wrist score, postoperative total joint range of motion (ROM), as well as grip and pinch strength measurements of the operated and normal side. Radiographic criteria such as carpal height ratio, subchondral cyst, and osteophyte formation were assessed during the follow-up period. Mean follow up period was 41.7 months (range: 18-106 months). RESULTS: No wrists underwent total arthrodesis. Reflex sympathetic dystrophy was observed in 2 patients (8.3%). Postoperative ROM measurements, power grip, and pinch strength values significantly decreased in both stages (IIIA and IIIB) on the operated side compared to the normal side. In contrast, Q-DASH scores significantly increased in both stages compared to preoperative values. Average Mayo wrist score was 67.3 (range: 10-90). CONCLUSION: PRC is a well-tolerated procedure for stage III Kienbock's disease with certain complications. While subjective values improved significantly, there was no correlation between this improvement in subjective values and objective measurements. PRC was not able to restore motion postoperatively to that of the normal side, even though this feature did not affect postoperative subjective patient satisfaction. PMID- 26511692 TI - Modified Simmonds-Menelaus procedure for moderate or severe adult hallux valgus. AB - OBJECTIVE: The purpose of this study was to present the clinical and radiological results of modified Simmonds-Menelaus technique, performed as a proximal, medially-based, open-wedge osteotomy of the first metatarsal, in cases of moderate or severe adult hallux valgus deformity. METHODS: Fifty-one feet of 47 patients underwent surgery due to hallux valgus. Mean age was 41.2+/-14.0 years, and mean follow-up period was 99.5+/-36.0 months. Patients were evaluated with standing anteroposterior (AP) and lateral radiographies obtained in the preoperative and early postoperative periods, and during final follow-up. The parameters of hallux valgus angle (HVA), intermetatarsal angle (IA), metatarsal distal phalangeal angle (MDPA), and first metatarsal length (ML) were measured. For clinical evaluation, American Orthopaedic Foot and Ankle Society (AOFAS) hallux metatarsophalangeal-interphalangeal (MTP-IP) scale was used. RESULTS: Mean preoperative HVA was 36.9 degrees +/-7.3 degrees , mean early postoperative HVA was 16.6 degrees +/-6.2 degrees , and mean final postoperative HVA was 28.9 degrees +/-11.5 degrees . Mean preoperative IA was 17.3 degrees +/-4.5 degrees , mean early postoperative IA was 8.8 degrees +/-3.6 degrees , and mean final postoperative IA was 14.3 degrees +/-4.9 degrees . Mean AOFAS hallux MTP-IP score was 71.9+/-20.1 at final follow-up. CONCLUSION: From studies in the available literature, it is not clear whether the proximal open-wedge osteotomy technique itself is unsuccessful in adults or the lack of internal fixation led to failure. Application of an adequate fixation material should be used in order to avoid the collapse of the graft and to maintain the correction of the radiological parameters. PMID- 26511693 TI - Tension band wiring through double-cannulated screws as a new internal fixation method for treatment of olecranon fractures: a randomized comparative study. AB - OBJECTIVE: The aim of this study was to assess the therapeutic effects and complications of tension band wiring (TBW) through the use of double-cannulated screws versus conventional TBW in the treatment of olecranon fractures. METHODS: Eligible participants were randomly assigned to 2 groups to undergo different methods of fixation. The related indices and data of the 2 groups were collected for comparative analysis after an average follow-up of 32.7+/-6.6 months. RESULTS: Average fracture healing time was 11.4 weeks in the double-screw TBW group and 12.6+/-1.8 weeks in the conventional TBW group (p=0.000). There was significant difference in complications related to fixation between the 2 groups. In the double-screw TBW group (42 patients), 2 patients felt screw head prominence with no pain and requested no further intervention; in contrast, 21 patients experienced complications associated with internal fixation in the conventional TBW group. Mean Mayo Elbow Performance Score (MEPS) score was 87.90+/-6.0 in the double-screw TBW group, compared to 83.67+/-6.6 in the conventional TBW group at 24-month follow-up (p=0.002). The rate of elbow function in the double-screw TBW group (29/42, 69.05%) was higher than that of the conventional TBW group (16/46, 34.78%) (p=0.000). CONCLUSION: In comparison with conventional TBW, TBW with double-cannulated screws can significantly reduce complications, lower reoperation rate, improve elbow function, shorten healing time, as well as diminish surgical trauma. PMID- 26511694 TI - Percutaneous repair of acute Achilles tendon rupture: a functional evaluation study with a minimum 10-year follow-up. AB - OBJECTIVE: The purpose of this study was to present the functional outcomes of percutaneous tenorrhaphy of the Achilles tendon with a minimum follow-up of 10 years. METHODS: The medical records of patients who underwent percutaneous surgery for acute unilateral Achilles tendon rupture between 2000 and 2004 were retrospectively reviewed. RESULTS: A total of 11 male patients met the inclusion criteria and were followed for a mean of 12.6 years (range: 10-13 years). The average age at the time of surgery was 39.3 years (range: 29-53 years). Patients returned to work at an average of 2.7 months (range: 1-4 months) after surgery and to normal daily activities (NDA) at an average of 4.1 months (range: 3-6 months) postoperatively. The mean strength ratio between the injured and normal sides was 90%. Compared with the contralateral normal side, the thickness of the operated tendon increased by a mean of 0.7 cm, while the circumference of the affected calf diminished by a mean of 1.1 cm. No difference in active and passive range of motion (ROM) was recorded between the affected and the contralateral normal ankle joints. Isometric plantar flexion was 87% of normal. Sensory impairment in the territory of the sural nerve was identified in 1 patient immediately after surgery. The sensory defect had completely resolved by 6 months postoperatively. CONCLUSION: Long-term outcomes of our series support the effectiveness of percutaneous tenorrhaphy in Achilles function rehabilitation of patients with acute ruptures. PMID- 26511695 TI - Exchanging reamed nailing versus augmentative compression plating with autogenous bone grafting for aseptic femoral shaft nonunion: a retrospective cohort study. AB - OBJECTIVE: The purpose of this study was to compare the outcomes of exchanging reamed nailing (ERN) and augmentative compression plating (ACP) with autogenous bone grafting (BG) for the treatment of aseptic femoral shaft nonunion secondary to the treatment of intramedullary nailing (IMN). METHODS: A multicenter retrospective study was performed for 178 patients (180 cases) of aseptic femoral shaft nonunion secondary to first treatment of IMN. All cases were fixed with either ERN (n=87) or ACP (n=93). In the ERN group, 42 cases (48.3%) were nonisthmal nonunions and 45 (51.7%) were isthmal nonunions. In the ACP group, 46 cases (49.5%) were nonisthmal nonunions, and 47 (50.5%) were isthmal nonunions. Operation time, blood loss, time to union, union rate, volume of drainage, time to renonunion, and complication rate were compared between the 2 groups. RESULTS: All patients were followed up, with a mean period of 4.1 years (range: 1-7.1 years). Bone union occurred in 93/93 cases (100%) in the ACP group versus 75/87 cases (86.2%) in the ERN group (odds ratio [OR]=3.28, 95% confidence interval [CI] 0.8-14). Of the 12 cases involved with renonunion in the ERN group, 10 were nonisthmal nonunions, and 2 were isthmal nonunions with cortical bone defect >3 cm. The union time, blood loss, and complication rate of the ERN group were significantly higher than those of the ACP group (p=0.028, p=0.035, and p=0.021, respectively). No significant difference was found in the average operation time of the 2 groups (p=0.151). However, for the nonisthmal nonunions, a significant difference was found between the ERN and ACP groups (p=0.018). CONCLUSION: ACP with autogenous BG can obtain a higher bone union rate and shorter time to union than ERN in the treatment of aseptic femoral shaft nonunion after failed IMN. Especially for nonisthmal femoral shaft nonunions or isthmal nonunions with larger bone defects, ACP with autogenous BG can be more advantageous than ERN for patients. A future prospective observational study should be conducted. PMID- 26511696 TI - Effect of pentoxifylline on healing of segmental bone defects and angiogenesis. AB - OBJECTIVE: The aim of this study was to determine the effect of pentoxifylline (PTX) on angiogenesis and the healing of a critical-sized segmental defect of the radius diaphysis in a rat model, using radiological and histological grading systems. METHODS: The study included 24 female Sprague-Dawley rats (weight: 300+/ 20 g) divided into 4 groups. A critical-sized segmental defect was created in the radius diaphysis in all rats. In Group 1, morcellized iliac crest autografts were used to fill the segmental bone defect. In Group 2, segmental bone defects were filled using morcellized iliac crest autografts, and 25 mg/kg/day PTX was applied intraperitoneally. In Group 3, the segmental bone defects were not filled, and in Group 4 the segmental bone defects were left unfilled, and an intraperitoneal (IP) dose of 25 mg/kg/day PTX was applied. Rats were sacrificed at postoperative Week 8, and defects were evaluated using radiographic, histological and immunohistochemical methods. RESULTS: There were significant differences between Group 1 and 2 according to radiological evaluation (p=0.003) and quality of union at the defect site (p=0.01). Union quality was higher in Group 4 than Group 3 (p=0.01). Cluster of differentiation 31 (CD31) and vascular endothelial growth factor (VEGF) levels were higher in Group 2 than in Groups 3 and 4. CONCLUSION: According to radiological and histological parameters, PTX appears to improve angiogenesis and healing of segmental cortical bone defects of the radius in a rat model. PMID- 26511697 TI - Histopathological and biomechanical evaluation of bone healing properties of DBM and DBM-G90 in a rabbit model. AB - OBJECTIVE: The present study was designed to investigate the effects of DBM and DBM-G90 on bone healing in a rabbit model. METHODS: Thirty male white albino rabbits were used in this study. An incision was made in all rabbits under general anesthesia directly over the radius in order to expose it. A 10-mm segmental defect was created on the middle portion of each radius. The defects of 10 rabbits (Group I) were filled with DBM Block and Strip (Zimmer, Inc., Warsaw, IN, USA), the defects of 10 rabbits (Group II) were filled with DBM soaked in G90, and the defects of 10 rabbits (Group III/control) were left empty. The rabbits were euthanized at 60 days postoperatively for histopathological and biomechanical evaluation. RESULTS: At the histopathologic level, the defects of the animals in the DBM and DBM-G90 groups showed more advanced healing criteria than those of the control group. In biomechanical findings, there was a statistically significant difference between the injured bones and contralateral normal bones of the control group in terms of measured strength. There was not a statistically significant difference between the treated bones of the DBM and DBM G90 groups with contralateral normal bones, nor was there a statistically significant difference between the treated bones of the DBM and DBM-G90 groups with the treated bones of the control group, in terms of other biomechanical tests. CONCLUSION: Based on the histopathological and biomechanical findings, the DBM and DBM-G90 groups demonstrated superior osteogenic potential; however, G90 shows no superiority over DBM on bone healing. PMID- 26511698 TI - A new surgical technique for traumatic dislocation of posterior tibial tendon with avulsion fracture of medial malleolus. AB - We introduce a case of traumatic dislocation of the posterior tibial tendon with avulsion fracture of the medial malleolus in a 52-year-old female patient who was treated surgically with periosteal flap and suture anchor fixation. Based in the posteromedial ridge of the distal tibia, a quadrilateral periosteal flap was created and folded over the tendon, followed by fixation on the lateral aspect of the groove by use of multiple suture anchors. Clinical and radiological findings 25 months postoperatively showed well-preserved function of the ankle joint with stable tendon gliding. PMID- 26511699 TI - Mosaicplasty for the treatment of osteochondritis dissecans following Legg-Calve Perthes disease: a case report and literature review. AB - Legg-Calve-Perthes disease leads to hip joint deformity. Osteochondritis dissecans following Perthes disease (OCDP) is a less common entity. Treatment options of OCDP are limited. Osteochondral autologous transfer (OATS) is an established method of treatment of full thickness cartilage defects in different locations. This paper presents the case of a 42-year-old patient diagnosed with symptomatic OCDP and treated with lesion fixation using autologous osteochondral grafts via surgical hip dislocation. At the most recent follow-up, 5.5 years after the surgery, the patient did not complain of any pain during rest or activity. He had painless motion with persisting abduction and internal rotation reduction. Harris hip score (HHS) improved from preoperative 62 to 92 points at most recent follow-up. Treatment protocol was discussed in relation to the literature regarding this clinical topic. PMID- 26511700 TI - Coalition of trapezoid, capitate, and metacarpal: a case report. AB - Carpal coalition is a rare wrist anomaly. A coalition can be an isolated condition, but it can be observed as a component of a congenital syndrome as well. Carpal coalition is usually asymptomatic and detected incidentally. It is most frequently encountered as lunate-triquetral coalition, followed by capito hamate coalition. Other coalition types are very rare. In this case report, we present a case in which the patient applied with complaints of pain, and in whom a coalition of capitate-trapezoid- second and third metacarpal was detected. PMID- 26511701 TI - Radial collateral ligament reconstruction of the proximal interphalangeal joint of a finger with severe bony defect: revising a failed ligament reconstruction--a case report. AB - Chronic proximal interphalangeal joint (PIPJ) instability of the finger is rare, and when it occurs usually requires surgical reconstruction. Complications arising from failed ligament reconstruction may result in a situation more difficult to address than the initial reconstruction. This situation is more likely for the finger than other orthopaedic reconstructions because the phalangeal bones are so small. We present a case of chronic radial PIPJ instability of the finger and severe bony defect caused by multiple failed ligament reconstructions that was treated successfully using a modification of the bone-ligament-bone graft technique. PMID- 26511702 TI - Cell-in-Cell: A Century-Old Mystery Comes to the Table. PMID- 26511703 TI - Emperipolesis is a potential histological hallmark associated with chronic hepatitis B. AB - Although emperipolesis exists in infectious liver diseases, the diagnostic value of emperipolesis in chronic hepatitis B is not exactly known. The aim of this study is to evaluate the histological characteristics and laboratory parameters of emperipolesis in chronic hepatitis B. Totally 402 patients with hepatitis B and other liver diseases were processed in a retrospective assessment. Inflammatory severity of hepatitis B was evaluated with Ishak Scoring System. Immunofluorescent staining was performed for CD8 (T cells), CD20 (B cells), CD56 (NK cells), CD68 (macrophages) and MPO (neutrophils). Emperipolesis was observed in 74.0% of patients with chronic hepatitis B (CHB) and 82.8% of patients with acute hepatitis B (AHB). In emperipolesis, CD8(+) T cell was the main cell type. Patients with emperipolesis in CHB got high scores of inflammatory activity. Among patients with CHB, emperipolesis was present with higher serum ALT, AST and GGT levels. HBV DNA Load in patients with emperipolesis was as 10 times high as those without emperipolesis. HBeAb was significantly correlated with the evidence of emperipolesis. In chronic hepatitis B, emperipolesis was associated with severity of liver injury. The presence of emperipolesis was an indicator of active liver inflammation. PMID- 26511704 TI - The physics for the formation of cell-in-cell structures. AB - The formations of cell-in-cell structures have been found in several important biological processes. Recent studies have shed light on the biochemical signaling pathways as well as the quantitative understandings of the underlying physics. Multiple new features that regulate the cellular engulfment have been identified. However, the driving forces promoting the structural formation are still under debate. This review focuses on the recent progress and discusses the potential significance of the existing physical models. PMID- 26511705 TI - Phagoptosis - Cell Death By Phagocytosis - Plays Central Roles in Physiology, Host Defense and Pathology. AB - Cell death by phagocytosis - termed 'phagoptosis' for short - is a form of cell death caused by the cell being phagocytosed i.e. recognised, engulfed and digested by another cell. Phagocytes eat cells that: i) expose 'eat-me' signals, ii) lose 'don't-eat-me' signals, and/or iii) bind opsonins. Live cells may express such signals as a result of cell stress, damage, activation or senescence, which can result in phagoptosis. Phagoptosis may be the most abundant form of cell death physiologically as it mediates erythrocyte turnover. It also regulates: reproduction by phagocytosis of sperm, development by removal stem cells and excess cells, and immunity by removal of activated neutrophils and T cells. Phagoptosis mediates the recognition of non-self and host defence against pathogens and cancer cells. However, in inflammatory conditions, excessive phagoptosis may kill our cells, leading to conditions such as hemophagy and neuronal loss. PMID- 26511706 TI - Thymic Nurse Cells Participate in Heterotypic Internalization and Repertoire Selection of Immature Thymocytes; Their Removal from the Thymus of Autoimmune Animals May be Important to Disease Etiology. AB - Thymic nurse cells (TNCs) are specialized epithelial cells that reside in the thymic cortex. The initial report of their discovery in 1980 showed TNCs to contain up to 200 thymocytes within specialized vacuoles in their cytoplasm. Much has been reported since that time to determine the function of this heterotypic internalization event that exists between TNCs and developing thymocytes. In this review, we discuss the literature reported that describes the internalization event and the role TNCs play during T cell development in the thymus as well as why these multicellular complexes may be important in inhibiting the development of autoimmune diseases. PMID- 26511707 TI - Suicidal emperipolesis: a process leading to cell-in-cell structures, T cell clearance and immune homeostasis. AB - "Suicidal emperipolesis" is one of the most recently reported processes leading to cell-in-cell structures that promote cell death. This process was discovered in studies investigating the fate of autoreactive CD8 T cells activated within the liver. Recently, we reported that activated T cells invaded hepatocytes, formed transient cell-in-cell structures, and were rapidly degraded within endosomal/lysosomal compartments by a non-apoptotic pathway. Importantly, pharmacological inhibition of this process caused intrahepatic accumulation of tissue-reactive T cells and breach of immune tolerance. The characterization of the molecular mechanisms of suicidal emperipolesis is still in its infancy, but initial studies suggest this phenomenon is distinct from other reported cell-in cell structures. As opposed to the formation of other cell-in-cell structures, suicidal emperipolesis takes place in a non-malignant environment, and without obvious pathology. It is therefore the first cell-in-cell structure described to have a role in maintaining homeostasis in normal physiology in higher organisms. T cell emperipolesis within hepatocytes has also been observed by pathologists in a range of chronic human liver pathologies. As T cell-in-hepatocyte structures resulting from suicidal emperipolesis are very transiently observed in normal physiology, their accumulation during liver disease would suggest that severe tissue injury is promoted by, or associated with, defective T cell clearance. In this review, we compare "suicidal emperipolesis" to other processes leading to cell-in-cell structures, and consider its potential biological roles in maintaining immune homeostasis and tolerance in the context of the hepatic environment. PMID- 26511708 TI - Mammalian Cell Competitions, Cell-in-Cell Phenomena and Their Biomedical Implications. AB - Cell competition was first identified four decades ago as a mechanism to eliminate less fit cells during development in Drosophila melanogaster, and later postulated to be involved in tumorigenesis of human beings. However, evidence for a similar mechanism functional in mammals and tumors was missed until recent years. Like cell competition in fly, multiple forms of competition mechanisms were reported in mammalian system, and some of them were found participating in tumor initiation. Lately, entosis, a mechanism of cell cannibalisms responsible for the formation of cell-in-cell structures in human tumors, was identified as a novel member of ever-expanding family of mammalian cell competitions (MaCCs), and proposed to be able to promote clonal selection and tumor evolution. Thus, engulfment by neighboring cells other than the professional phagocytes, an issue still in debate in fly, was clearly demonstrated in mammals to be responsible for loser elimination. Competition mediated by cell-in-cell structures, formed by multiple cannibal mechanisms, constitutes a novel class of MaCCs. This review will summarize current research on mammalian cell competitions, followed by feature and mechanism analysis and their potential implications in the pathology and treatment of human tumors. PMID- 26511709 TI - Cancer Cell Cannibalism: A Primeval Option to Survive. AB - Cancer cell cannibalism is currently defined as a phenomenon in which an ensemble of a larger cell containing a smaller one, often in a big cytoplasmic vacuole, is detected in either cultured tumor cells or a tumor sample. After almost one century of considering this phenomenon as a sort of neglected curiosity, some recent studies have first proposed tumor cell cannibalism as a sort of "aberrant phagocytosis", making malignant cells very similar to professional phagocytes. Later, further research has shown that, differently to macrophages, exclusively ingesting exogenous material, apoptotic bodies, or cell debris, tumor cells are able to engulf other cells, including lymphocytes and erythrocytes, either dead or alive, with the main purpose to feed on them. This phenomenon has been associated to the malignancy of tumors, mostly exclusive of metastatic cells, and often associated to poor prognosis. The cannibalistic behavior increased depending on the microenvironmental condition of tumor cells, such as low nutrient supply or low pH, suggesting its key survival option for malignant cancers. However, the evidence that malignant cells may cannibalize tumor infiltrating lymphocytes that act as their killers, suggests that tumor cell cannibalism could be a very direct and efficient way to neutralize immune response, as well. Tumor cell cannibalism may represent a sign of regression to a simpler, ancestral or primeval life style, similar to that of unicellular microorganisms, such as amoebas, where the goal is to survive and propagate in an overcrowded and very hostile microenvironment. In fact, we discovered that metastatic melanoma cells share with amoebas a transmembrane protein TM9SF4, indeed related to the cannibal behavior of these cells. This review attempts to provide a comprehensive description of the current knowledge about the role of TM9SF4 in cancer, highlighting its role as a key player in the cannibal behavior of malignant cancer cells. Moreover, we discuss differences and similarities between tumor cannibalism, entosis, phagocytosis and emperipolesis. PMID- 26511710 TI - Entosis and Related Forms of Cell Death within Cells. AB - By eliminating the unneeded or mutant cells, programmed cell death actively participates in a wide range of biological processes from embryonic development to homeostasis maintenance in adult. Continuing efforts have identified multiple cell death pathways, with apoptosis, necrosis and autophage the mostly studied. Recently a unique cell death pathway called "cell-in-cell death" has been defined. Unlike traditional cell death pathways, cell-in-cell death, characterized by cell death within another cell, is triggered by the invasion of one cell into its neighbor and executed by either lysosome-dependent degradation or caspase-dependent apoptosis. With remarkable progresses on cell-in-cell over past few years, multiple mechanisms, including entosis, cannibalism and emperitosis, are found to be responsible for cell-in-cell death. Some key questions, such as specific biochemical markers to distinguish precisely the properties of different cell-in-cell structures and the physiological and pathological relevance, remain to be addressed. In light of this situation and a surge of interests, leading scientists in this field intend to share with readers current research progresses on cell-in-cell structures from different model systems through this special edition on cell-in-cell. The mechanistic advances will be highlighted while the future researches be speculated. PMID- 26511711 TI - Entosis: Cell-in-Cell Formation that Kills Through Entotic Cell Death. AB - Entosis is a cell-in-cell formation mechanism that targets viable cells for uptake in epithelial cell cultures and human tumors. Entotic cells control their own engulfment, by invading into their hosts in a Rho-GTPase and actomyosin dependent manner. Although entotic cells are internalized while alive, most eventually undergo a non-apoptotic form of cell death, called entotic cell death, that is executed non-cell-autonomously by autophagy proteins and lysosomes. Here we review the current understanding of entosis and entotic cell death and discuss the potential roles of this process in cancer. PMID- 26511712 TI - Cell-in-cell phenomenon: A New Paradigm in Life Sciences. AB - Cell-in-cell, a phenomenon characterized by one or more viable cells entering actively into another cell, was observed more than a century and has only attracted more attention in recent years and is becoming a new hot topic in the biological field, owing its biological significance in evolutionary as well as physiological and pathological relevance in development, homeostasis and diseases. In this paper we focus on the diversity, evolutionary conservatism and clinical implication of cell-in-cell as well as latest opinions on the research strategies. Based on the findings from our laboratory and other research groups three working models of cell-in-cell are also proposed. PMID- 26511713 TI - Box Isolation of Fibrotic Areas (BIFA): A Patient-Tailored Substrate Modification Approach for Ablation of Atrial Fibrillation. AB - BACKGROUND: Catheter ablation strategies beyond pulmonary vein isolation (PVI) for treatment of atrial fibrillation (AF) are less well defined. Increasing clinical data indicate that atrial fibrosis is a critical common left atrial (LA) substrate in AF patients (pts). OBJECTIVE: We applied a new substrate modification concept according to the individual fibrotic substrate as estimated from electroanatomic voltage mapping (EAVM) in 41 pts undergoing catheter ablation of AF. RESULTS: First, EAVM during sinus rhythm was done in redo cases of 10 pts with paroxysmal AF despite durable PVI. Confluent low-voltage areas (LVA) were found in all pts and were targeted with circumferential isolation, so called box isolation of fibrotic areas (BIFA). This strategy led to stable sinus rhythm in 9/10 pts and was transferred prospectively to first procedures of 31 pts with nonparoxysmal AF. In 13 pts (42%), no LVA (<0.5 mV) were identified, and only PVI was performed. In 18 pts (58%), additional BIFA strategies were applied (posterior box in 5, anterior box in 7, posterior plus anterior box in 5, no box in 1 due to diffuse fibrosis). Mean follow-up was 12.5 +/- 2.4 months. Single procedure freedom from AF/atrial tachycardia was achieved in 72.2% of pts and in 83.3% of pts with 1.17 procedures/patient. CONCLUSIONS: In approximately 40% of pts with nonparoxysmal AF, no substantial LVA were identified, and PVI alone showed high success rate. In pts with paroxysmal AF despite durable PVI and in approximately 60% of pts with nonparoxysmal AF, individually localized LVA were identified and could be targeted successfully with the BIFA strategy. PMID- 26511714 TI - Throat and nasal swabs for molecular detection of respiratory viruses in acute pharyngitis. AB - BACKGROUND: Detection of specific respiratory viruses is important for surveillance programs, where nasopharyngeal or nasal swabs have traditionally been used. Our objective was to determine whether sampling with a throat swab provides incremental benefit-when used in conjunction with a nasal swab-to detect respiratory viruses among patients with acute pharyngitis in the outpatient setting. FINDINGS: Among 83 university students with acute pharyngitis, we detected respiratory viruses with molecular assays on two samples collected per student: with a flocked nasal mid-turbinate swab and a rayon throat swab. Forty eight (58 %) patients had virus-positive samples, with 49 virus positives detected by either swab (one patient had a dual viral co-infection). The most common viruses were rhinovirus, coronavirus, and influenza A virus. Specifically, 29 virus positives were detected by both swabs, 14 exclusively by the nasal swab, and six exclusively by the throat swab. The additional six virus positives detected by the throat swab corresponded to an absolute increase in viral detection of 7.1 % (95 % CI: 1.2-12.9 %); the specific viruses detected were four rhinoviruses and two coronaviruses. CONCLUSIONS: The flocked nasal swab samples respiratory viruses well, even among patients whose primary complaint is a sore throat. The rayon throat swab has modest incremental value over and above using the flocked nasal mid-turbinate swab alone, which suggests that while throat swabs alone would not be adequate for respiratory viral surveillance, they may have value as a supplementary test. PMID- 26511715 TI - Synthesis of Chiral Tertiary Alcohols by Cu(I) -Catalyzed Enantioselective Addition of Organomagnesium Reagents to Ketones. AB - Catalytic enantioselective addition of organometallic nucleophiles to ketones is among the most straightforward approaches to the synthesis of chiral tertiary alcohols. The first such catalytic methodologies using the highly reactive organomagnesium reagents, which are the preferred organometallic reagents in terms of cost, availability, atom efficiency, and structural diversity, were developed only during the last five years. This Concept article highlights the fundamental breakthrough that made the development of methodologies for highly enantioselective Cu(I) -catalyzed alkylation of ketones using organomagnesium reagents possible. PMID- 26511716 TI - Ancestral role of Pax2/5/8 in molluscan brain and multimodal sensory system development. AB - BACKGROUND: Mollusks represent the largest lophotrochozoan phylum and exhibit highly diverse body plans. Previous studies have demonstrated that transcription factors such as Pax genes play important roles during their development. Accordingly, in ecdysozoan and vertebrate model organisms, orthologs of Pax2/5/8 are among others involved in the formation of the midbrain/hindbrain boundary, the auditory/geosensory organ systems, and the excretory system. METHODS: Pax2/5/8 expression was investigated by in situ hybridization during the development of representatives of the two major molluscan subclades, Aculifera and Conchifera. RESULTS: Compared to the investigated polyplacophoran and bivalve species that lack larval statocysts as geosensory organs and elaborate central nervous systems (CNS), cephalopods possess highly centralized brains and statocysts. Pax2/5/8 is expressed in regions where sensory cells develop subsequently during ontogenesis. Expression domains include esthetes and the ampullary system in polyplacophorans as well as the eyes of cephalopods. No Pax2/5/8 expression was observed in the less centralized CNS of bivalve, polyplacophoran, and gastropod embryos, thus arguing for a loss of Pax2/5/8 involvement in CNS development in these lineages. In contrast, Pax2/5/8 is expressed among others in brain lobes along the trajectory of the esophagus that divides the cephalopod brain. CONCLUSIONS: Our results, along with those on Otx- and Hox-gene expression, demonstrate that the cephalopod condition is similar to that in mouse and fruit fly, with Otx being expressed in the anterior-most brain region (except for the vertical lobe) and a Pax2/5/8 expression domain separating the Otx-domain from a Hox-gene expressing posterior brain region. Thus, Pax2/5/8 appears to have been recruited independently into regionalization of non homologous complex brains of organisms as different as squid, fruit fly, and mouse. In addition, Pax2/5/8 is expressed in multimodal sensory systems in mollusks such as the esthetes and the ampullary system of polyplacophorans as well as the eyes of cephalopods. Pax2/5/8-expressing cells are present in regions where the future sensory cells such as the polyplacophoran esthetes are situated and hence Pax2/5/8 expression probably predates sensory cell development during ontogeny. In mollusks, Pax2/5/8 is only expressed in derivatives of the ectoderm and hence an ancestral role in molluscan ectoderm differentiation is inferred. PMID- 26511717 TI - Haemophilus parasuis: infection, immunity and enrofloxacin. AB - Haemophilus parasuis is an early colonizer of the porcine upper respiratory tract and is the etiological agent of Glasser's disease. The factors responsible for H. parasuis colonization and systemic infection are not yet well understood, while prevention and control of Glasser's disease continues to be challenging. Recent studies on innate immunity to H. parasuis have demonstrated that porcine alveolar macrophages (PAMs) are able to differentially up-regulate several genes related to inflammation and phagocytosis, and several pro-inflammatory cytokines are produced by porcine cells upon exposure to H. parasuis. The susceptibility of H. parasuis strains to phagocytosis by PAMs and the bactericidal effect of complement are influenced by the virulent phenotype of the strains. While non virulent strains are susceptible to phagocytosis and complement, virulent strains are resistant to both. However, in the presence of specific antibodies against H. parasuis, virulent strains become susceptible to phagocytosis. More information is still needed, though, in order to better understand the host immune responses to H. parasuis. Antimicrobials are commonly used in the swine industry to help treat and control Glasser's disease. Some of the common antimicrobials have been shown to reduce colonization by H. parasuis, which may have implications for disease dynamics, development of effective immune responses and immunomodulation. Here, we provide the current state of research on innate and adaptive immune responses to H. parasuis and discuss the potential effect of enrofloxacin on the development of a protective immune response against H. parasuis infection. PMID- 26511718 TI - Case report: atypical presentation of Mycobacterium tuberculosis uveitis preceding nodular scleritis. AB - BACKGROUND: Intraocular tuberculosis is uncommon and has various clinical presentations. Lack of specific clinical clues can make the diagnosis challenging. The purpose of this study is to report a clinical presentation of tuberculous iridocyclitis that mimics phacolytic glaucoma and has a distinctive inflammatory deposit in the inner side of the cornea. This report is the first to describe the progression of tuberculous iridocyclitis to nodular scleritis without evidence for extraocular tuberculous infection. CASE PRESENTATION: A 78 year-old, immunocompetent woman presented with subacute intraocular inflammation with high intraocular pressure, mimicking phacolytic glaucoma. Distinct pigment keratic precipitates were noted on the first visit. Even though the cataract extraction was uneventful and adequate anti-inflammatory drugs were given, the inflammation did not subside as expected. Seven weeks later, she developed two scleral abscesses, which were subsequently explored for microbiological investigation. The smears of the pus revealed positive acid-fast bacilli stain and PCR for Mycobacterium tuberculosis complex. Eventually, the pus culture grew Mycobacterium tuberculosis. Anti-tuberculosis medications were prescribed. After 1 month of treatment, the abscesses were cured. However, her visual acuity did not improve at the last visit. CONCLUSIONS: This case revealed an unusual presentation and untreated course of tuberculosis iridocyclitis. Pattern of keratic precipitates may indicate the presence of tuberculosis. PMID- 26511719 TI - The Diagnostic Yield of Array Comparative Genomic Hybridization Is High Regardless of Severity of Intellectual Disability/Developmental Delay in Children. AB - Microarray-based comparative genomic hybridization is a method of molecular analysis that identifies chromosomal anomalies (or copy number variants) that correlate with clinical phenotypes. The aim of the present study was to apply a clinical score previously designated by de Vries to 329 patients with intellectual disability/developmental disorder (intellectual disability/developmental delay) referred to our tertiary center and to see whether the clinical factors are associated with a positive outcome of aCGH analyses. Another goal was to test the association between a positive microarray based comparative genomic hybridization result and the severity of intellectual disability/developmental delay. Microarray-based comparative genomic hybridization identified structural chromosomal alterations responsible for the intellectual disability/developmental delay phenotype in 16% of our sample. Our study showed that causative copy number variants are frequently found even in cases of mild intellectual disability (30.77%). We want to emphasize the need to conduct microarray-based comparative genomic hybridization on all individuals with intellectual disability/developmental delay, regardless of the severity, because the degree of intellectual disability/developmental delay does not predict the diagnostic yield of microarray-based comparative genomic hybridization. PMID- 26511720 TI - Neurologic Complications Caused by Epstein-Barr Virus in Pediatric Patients. AB - We retrospectively analyzed the medical documentation of 194 children infected with Epstein-Barr virus. The diagnosis was based on clinical symptoms and the presence of the viral capsid antigen IgM antibody. Patients with severe neurologic complications also underwent neurologic examination, magnetic resonance imaging (MRI), and electroencephalography (EEG). There were 2 peaks in incidence of infection; the first one in young children aged 1 to 5 years represented 62.0% of cases. The second peak (24.6% of patients) occurred in teenagers. Febrile seizures were confirmed in 3.1% of affected children younger than 5 years and headaches in 24.2% patients, mostly older children. Ten children presented severe, neurologic complications: meningoencephalitis, acute encephalitis, acute cerebellitis, transverse myelitis, and myeloradiculitis. Our study identified a variety of Epstein-Barr virus-related neurologic complications. Epstein-Barr virus should be routinely tested for when a child presents with an apparent neuroinfection as it is a common pathogen that can induce a wide variety of signs and symptoms. PMID- 26511721 TI - Inter-professional in-situ simulated team and resuscitation training for patient safety: Description and impact of a programmatic approach. AB - BACKGROUND: Inter-professional teamwork is key for patient safety and team training is an effective strategy to improve patient outcome. In-situ simulation is a relatively new strategy with emerging efficacy, but best practices for the design, delivery and implementation have yet to be evaluated. Our aim is to describe and evaluate the implementation of an inter-professional in-situ simulated team and resuscitation training in a teaching hospital with a programmatic approach. METHODS: We designed and implemented a team and resuscitation training program according to Kern's six steps approach for curriculum development. General and specific needs assessments were conducted as independent cross-sectional surveys. Teamwork, technical skills and detection of latent safety threats were defined as specific objectives. Inter-professional in situ simulation was used as educational strategy. The training was embedded within the workdays of participants and implemented in our highest acuity wards (emergency department, intensive care unit, intermediate care unit). Self perceived impact and self-efficacy were sampled with an anonymous evaluation questionnaire after every simulated training session. Assessment of team performance was done with the team-based self-assessment tool TeamMonitor applying Van der Vleuten's conceptual framework of longitudinal evaluation after experienced real events. Latent safety threats were reported during training sessions and after experienced real events. RESULTS: The general and specific needs assessments clearly identified the problems, revealed specific training needs and assisted with stakeholder engagement. Ninety-five interdisciplinary staff members of the Children's Hospital participated in 20 in-situ simulated training sessions within 2 years. Participant feedback showed a high effect and acceptance of training with reference to self-perceived impact and self-efficacy. Thirty-five team members experiencing 8 real critical events assessed team performance with TeamMonitor. Team performance assessment with TeamMonitor was feasible and identified specific areas to target future team training sessions. Training sessions as well as experienced real events revealed important latent safety threats that directed system changes. CONCLUSIONS: The programmatic approach of Kern's six steps for curriculum development helped to overcome barriers of design, implementation and assessment of an in-situ team and resuscitation training program. This approach may help improve effectiveness and impact of an in-situ simulated training program. PMID- 26511722 TI - A comparison of commercial and custom-made electronic tracking systems to measure patient flow through an ambulatory clinic. AB - BACKGROUND: Understanding how patients move through outpatient clinics is important for optimizing clinic processes. This study compares the costs, benefits, and challenges of two clinically important methods for measuring patient flow: (1) a commercial system using infrared (IR) technology that passively tracks patient movements and (2) a custom-built, low cost, networked radio frequency identification (RFID) system that requires active swiping by patients at proximity card readers. METHODS: Readers for both the IR and RFID systems were installed in the General Eye Service of the Wilmer Eye Institute. Participants were given both IR and RFID tags to measure the time they spent in various clinic stations. Simultaneously, investigators recorded the times at which patients moved between rooms. These measurements were considered the standard against which the other methods were compared. RESULTS: One hundred twelve patients generated a total of 252 events over the course of 6 days. The proportion of events successfully recorded by the RFID system (83.7%) was significantly greater than that obtained with the IR system (75.4%, p < 0.001). The cause of the missing events using the IR method was found to be a signal interruption between the patient tags and the check-in desk receiver. Excluding those data, the IR system successfully recorded 94.4% of events (p = 0.002; OR = 3.83 compared to the RFID system). There was no statistical difference between the IR, RFID, and manual time measurements (p > 0.05 for all comparisons). CONCLUSIONS: Both RFID and IR methods are effective at providing patient flow information. The custom-made RFID system was as accurate as IR and was installed at about 10% the cost. Given its significantly lower costs, the RFID option may be an appealing option for smaller clinics with more limited budgets. PMID- 26511724 TI - Exploring overweight and obesity in pre-school children using routinely collected data: a case study of Halton, Northwest England. AB - BACKGROUND: A growing body of evidence suggests that childhood overweight may have its roots in early life. This study aimed to explore patterns of weight in children from birth to 40 months, born between 1994 and 2006, in Halton, Northwest England. METHODS: Halton infants were compared with the UK-90 reference population at four time points (birth, 2 months, 8 months and 40 months) by converting heights and weights into age-sex adjusted SD scores. The mean and SD of Halton SD scores were calculated for each time point and sex. Cohort trends and gender differences in rates of children above the 85th and 95th centiles at each time point were tested for using Poisson regression modelling. RESULTS: A total of 16 381 births were analysed. At birth, 8 months and 40 months, proportions of Halton children above the 85th and 95th centiles were consistently higher than reference data. Proportions above the 85th and 95th centiles at birth did not change significantly year on year, but for all other time points the proportions increased with subsequent cohorts. CONCLUSIONS: This study may provide evidence that the development of overweight and obesity has its roots in very early life and has highlighted patterns of infant overweight and obesity not previously reported. PMID- 26511723 TI - Engineering Corynebacterium glutamicum for the production of 2,3-butanediol. AB - BACKGROUND: 2,3-Butanediol is an important bulk chemical with a wide range of applications. In bacteria, this metabolite is synthesised from pyruvate via a three-step pathway involving alpha-acetolactate synthase, alpha-acetolactate decarboxylase and 2,3-butanediol dehydrogenase. Thus far, the best producers of 2,3-butanediol are pathogenic strains, hence, the development of more suitable organisms for industrial scale fermentation is needed. Herein, 2,3-butanediol production was engineered in the Generally Regarded As Safe (GRAS) organism Corynebacterium glutamicum. A two-stage fermentation process was implemented: first, cells were grown aerobically on acetate; in the subsequent production stage cells were used to convert glucose into 2,3-butanediol under non-growing and oxygen-limiting conditions. RESULTS: A gene cluster, encoding the 2,3 butanediol biosynthetic pathway of Lactococcus lactis, was assembled and expressed in background strains, C. glutamicum DeltaldhA, C. glutamicum DeltaaceEDeltapqoDeltaldhA and C. glutamicum DeltaaceEDeltapqoDeltaldhADeltamdh, tailored to minimize pyruvate-consuming reactions, i.e., to prevent carbon loss in lactic, acetic and succinic acids. Producer strains were characterized in terms of activity of the relevant enzymes in the 2,3-butanediol forming pathway, growth, and production of 2,3-butanediol under oxygen-limited conditions. Productivity was maximized by manipulating the aeration rate in the production phase. The final strain, C. glutamicum DeltaaceEDeltapqoDeltaldhADeltamdh(pEKEx2 als,aldB,Ptuf butA), under optimized conditions produced 2,3-butanediol with a 0.66 mol mol(-1) yield on glucose, an overall productivity of 0.2 g L(-1) h(-1) and a titer of 6.3 g L(-1). CONCLUSIONS: We have successfully developed C. glutamicum into an efficient cell factory for 2,3-butanediol production. The use of the engineered strains as a basis for production of acetoin, a widespread food flavour, is proposed. PMID- 26511726 TI - Accessible and continuous primary care may help reduce rates of emergency department use. An international survey in 34 countries. AB - BACKGROUND: Part of the visits to emergency departments (EDs) is related to complaints that may well be treated in primary care. OBJECTIVES: (i) To investigate how the likelihood of attending an ED is related to accessibility and continuity of primary care. (ii) To investigate the reasons for patients to visit EDs in different countries. METHODS: Data were collected within the EU Seventh Framework project Quality and Costs in Primary Care (QUALICOPC) in 31 European countries, Australia, New Zealand and Canada. The data were collected between 2011 and 2013 and contain survey data from 60991 patients and 7005 GPs, within 7005 general practices. OUTCOME MEASURE: whether the patient visited the ED in the previous year (yes/no). Multilevel logistic regression analyses were carried out to analyse the data. RESULTS: Some 29.4% had visited the ED in the past year. Between countries, the percentages varied between 18% and 40%. ED visits show a significant and negative relation with better accessibility of primary care. Patients with a regular doctor who knows them personally were less likely to attend EDs. Only one-third of all patients who visited an ED indicated that the main reason for this was that their complaint could not be treated by a GP. CONCLUSIONS: Good accessibility and continuity of primary care may well reduce ED use. In some countries, it may be worthwhile to invest in more continuous relationships between patients and GPs or to eliminate factors that hamper people to use primary care (e.g. for costs or travelling). PMID- 26511727 TI - Assessing the satisfaction levels among doctors who embark on after-hours home visits in Australia. AB - BACKGROUND: Despite the growing popularity of after-hours house calls (AHHCs) in Australia, no previous study had ever looked at satisfaction among the involved practitioners. The high number of overseas-trained doctors in Australia makes this a subject of international significance. OBJECTIVE: To determine the levels of satisfaction and its significant associations among doctors in AHHCs. METHODS: DESIGN, SETTING AND PARTICIPANTS: A quantitative, questionnaire-based survey of all 300 doctors engaged in AHHCs through the National Home Doctor Service (NHDS), Australia's largest home-visit doctor service provider. MAIN OUTCOME MEASURE: Satisfaction was assessed using the modified, 10-item Warr-Cook-Wall tool. RESULTS: A total of 168 valid responses (56.0% response rate) were received. Mean satisfaction scores for each of the 10 items ranged from 3.02 to 3.86, indicating 'moderate' to 'very satisfied' levels. Overall satisfaction was 85.9%, mostly related to 'freedom of work and independence', 'amount of responsibility' and 'income'. Doctors in existing legal unions are more satisfied than the single, separated or widowed ones on the 'amount of responsibility' [odds ratio (OR) = 6.50, P = 0.02, confidence interval (CI): 1.33-31.72], while those engaged for <24 hours/week are less satisfied on 'income' than full-time ones (OR = 0.30, P = 0.01, CI: 0.13-0.71). The 'adoption of protective measures', being 'aged >40', being 'male' and 'working in Brisbane, Adelaide or the Gold Coast' are other doctor variables associated with increased satisfaction. CONCLUSIONS: Satisfaction levels among AHHC GPs in Australia are comparable to the levels seen among their colleagues in regular-hour jobs, but there is still room for improvement. PMID- 26511728 TI - Head lice predictors and infestation dynamics among primary school children in Norway. AB - BACKGROUND: Health providers need to know which measures to take and children to prioritize in order to decrease costs associated with head lice infestations. OBJECTIVE: Our aim was to determine the most important predictors for head lice and identify the major drivers of an infestation outbreak in a low-prevalence area. METHODS: The study was based on three datasets of head lice prevalence (retrospective, point prevalence and prospective approach) from primary school children (ages 6-12) at 12 schools in Oslo, Norway. The tested predictors were siblings with lice, individual and household characteristics as well as class and school affiliation. Self-reported monthly incidences (prospective approach) of head lice were used to evaluate infestation dynamics. RESULTS: Infested siblings strongly increased the odds of head lice infestation of school children (odds ratio 36, 26 and 7 in the three datasets) whereas having short hair halved the odds. Household characteristics were of minor importance, and class affiliation proved more important than school affiliation. Having head lice in one school term increased the odds of an infestation in the next, but this effect diminished over time. About 97% of all self-reported infestations were noted in two consecutive months or less. CONCLUSIONS: With the exception of hair length, we have found that individual and household characteristics are of minor importance to predict head lice infestations in a low-prevalence country and that unnoticed transmissions in school classes and families are likely to be the major driver upon outbreaks. PMID- 26511729 TI - MeCP2 regulation of cardiac fibroblast proliferation and fibrosis by down regulation of DUSP5. AB - Cardiac fibrosis is a complex pathological process that includes the abnormal proliferation of cardiac fibroblasts and deposition of the extracellular matrix (ECM) proteins and collagens. Methyl-CpG-binding protein 2 (MeCP2) is a multifunctional nuclear protein, and plays a key role in the fibrotic diseases. However, the potential role of MeCP2 in cardiac fibrosis remains unclear. We report that MeCP2 modulates cardiac fibrosis via down-regulation of dual specificity phosphatase 5 (DUSP5), a nuclear phosphatase that negatively regulates prohypertrophic signaling by ERK1/2. MeCP2 is a critical participant in the epigenetic silencing of regulatory genes. Here, we found that down-regulation of DUSP5 in cardiac fibrosis is associated with MeCP2 over-expression. Treatment of cardiac fibroblasts with MeCP2-siRNA blocked proliferation. Knockdown of MeCP2 elevated DUSP5 expression in activated cardiac fibroblasts. Moreover, we investigated the effect of DUSP5 on the ERK1/2 activation. Our results demonstrated that MeCP2 modulates DUSP5 mediated activation of ERK1/2 in cardiac fibrosis. Taken together, these results indicated that MeCP2 acts as a key regulator of pathological cardiac fibrosis, promotes cardiac fibroblasts proliferation and fibrosis by down-regulation of DUSP5. PMID- 26511730 TI - MRI-associated classification to evaluate the outcome after autologous reconstruction of the medial patellofemoral ligament: a preliminary study. AB - PURPOSE: Purpose of this study was to establish and validate an MRI-associated classification to graduate postoperative results of MPFL reconstructions. METHODS: 30 autologous MPFL reconstructions of 28 patients were evaluated by two independent raters using MRI. All grafts were assigned to a novel graduation system respecting the graft's anchoring insertions, its MRI signal appearance, continuity and tension and the differentiation relating to the surrounding soft tissue. RESULTS: All grafts could reliably be assigned to one of the subgroups by both raters. 86.6 % of the grafts could be classified A1 or B1, reflecting a correct positioning and a low to intermediate signal intensity. Only one graft had to be classified C3 (malpositioned, elongated). CONCLUSION: We were able to establish and validate an MRI-associated classification to graduate the postoperative outcome after MPFL reconstructions. Foresighted, the presented classification might support further decision making in case of unsatisfying postoperative results. PMID- 26511731 TI - Septic arthritis caused by Mycobacterium marinum. AB - The incidence of infection by Mycobacterium marinum is rising, mainly due to the increasing popularity of home aquariums. The infection typically manifests as skin lesions, with septic arthritis being a rare presentation form. The disease is difficult to diagnose even when there is a high clinical suspicion, as culture in specific media may not yield positive findings. Thus, establishment of appropriate treatment is often delayed. Synovectomy, capsular thinning, and joint drainage together with prolonged, combined antibiotic therapy may be needed to cure the infection. PMID- 26511732 TI - Rapid alteration of protein phosphorylation during postmortem: implication in the study of protein phosphorylation. AB - Protein phosphorylation is an important post-translational modification of proteins. Postmortem tissues are widely being utilized in the biomedical studies, but the effects of postmortem on protein phosphorylation have not been received enough attention. In the present study, we found here that most proteins in mouse brain, heart, liver, and kidney were rapidly dephosphorylated to various degrees during 20 sec to 10 min postmortem. Phosphorylation of tau at Thr212 and glycogen synthase kinase 3beta (GSK-3beta) at Ser9 was reduced by 50% in the brain with 40 sec postmortem, a regular time for tissue processing. During postmortem, phosphorylation of cAMP-dependent protein kinase (PKA) and AMP activated kinase (AMPK) was increased in the brain, but not in other organs. Perfusion of the brain with cold or room temperature phosphate-buffered saline (PBS) also caused significant alteration of protein phosphorylation. Cooling down and maintaining mouse brains in the ice-cold buffer prevented the alteration effectively. This study suggests that phosphorylation of proteins is rapidly changed during postmortem. Thus, immediate processing of tissues followed by cooling down in ice cold buffer is vitally important and perfusion has to be avoided when protein phosphorylation is to be studied. PMID- 26511733 TI - History of spine surgery for tuberculous spondylodiscitis. AB - For those stricken with tuberculosis, a disease that was present in ancient times, treatment was originally limited to conservative treatment including high altitude, fresh air, rest, and immobilization, manual reduction devices, and surgical procedures. Mortality and morbidity were high until the advent of antitubercular chemotherapy in the 1940s. Today multidrug regimen enable good disease clearance and also make direct surgical debridement without complications possible. Antitubercular drugs have reduced mortality by 72.5%. Surgical intervention is reserved for selected situations. PMID- 26511734 TI - An Update on Clostridium difficile Toxinotyping. AB - Toxinotyping is a PCR-restriction fragment length polymorphism (RFLP)-based method for differentiation of Clostridium difficile strains according to the changes in the pathogenicity locus (PaLoc), a region coding for toxins A and B. Toxinotypes are a heterogenous group of strains that are important in the development of molecular diagnostic tests and vaccines and are a good basis for C. difficile phylogenetic studies. Here we describe an overview of the 34 currently known toxinotypes (I to XXXIV) and some changes in nomenclature. PMID- 26511735 TI - High Prevalence of Mycoplasma faucium DNA in the Human Oropharynx. AB - Mycoplasma faucium has recently been associated with brain abscesses and seems to originate from the mouth. We evaluated its prevalence by quantitative real-time PCR (qPCR) in the oropharynxes of 644 subjects and found that 25% harbored M. faucium, probably constituting the gateway for entrance of the bacteria into cerebral abscesses. PMID- 26511725 TI - Use of multilocus sequence typing to infer genetic diversity and population structure of Lactobacillus plantarum isolates from different sources. AB - BACKGROUND: Lactobacillus plantarum is a lactic acid bacterium (LAB) of considerable industrial interest since it has an important role in the production of fermented food. In the present study, the genetic diversity and population structure within 186 L. plantarum isolates was determined based on a novel MLST scheme employing eight housekeeping genes. These isolates had originated from different sources and geographic regions: 179 isolates were from our own culture collection and originated from China and Mongolia and seven isolates were type or reference isolates from other collections. RESULTS: The results showed that 179 isolates and seven reference isolates could be assigned to 73 different sequence types (STs), forming ten clonal complexes (CCs) and 23 singletons. There were 158 polymorphic sites detected in total, and the nucleotide diversity per site varied from 0.00401 in clpX to 0.03220 in groEL. The minimum spanning tree analyses suggested that the evolution of L. plantarum isolates have little relationship with ecological sources have similar nucleotide diversity. Phylogenetic trees and structure indicated that there were six lineages in the L. plantarum isolates used in our study. Split-decomposition and ClonalFrame analysis indicated that recombination had occurred throughout the population of L. plantarum, but it occurred at a low frequency in these eight loci. CONCLUSION: We deduced that L. plantarum isolates from the same ecological niches have similar genetic diversity and population structure. The MLST scheme presented in this study provides abundant sequence data for L. plantarum and enabled global comparisons of isolates associated with various environmental origins to be made. This will further advance our understanding of the microbial ecology of this industrially important LAB. PMID- 26511736 TI - Laboratory-Acquired Infection with Salmonella enterica Serovar Typhimurium Exposed by Whole-Genome Sequencing. AB - Despite advances in laboratory design, professional training, and workplace biosafety guidelines, laboratory-acquired infections continue to occur. Effective tools are required to investigate cases and prevent future illness. Here, we demonstrate the value of whole-genome sequencing as a tool for the identification and source attribution of laboratory-acquired salmonellosis. PMID- 26511737 TI - Direct Screening of Blood by PCR and Pyrosequencing for a 16S rRNA Gene Target from Emergency Department and Intensive Care Unit Patients Being Evaluated for Bloodstream Infection. AB - Here we compared the results of PCR/pyrosequencing to those of culture for detecting bacteria directly from blood. DNA was extracted from 1,130 blood samples from 913 patients suspected of bacteremia (enrollment criteria were physician-ordered blood culture and complete blood count [CBC]), and 102 controls (healthy blood donors). Real-time PCR assays for beta-globin and Universal 16S rRNA gene targets were performed on all 1,232 extracts. Specimens identified by Universal 16S rRNA gene PCR/pyrosequencing as containing staphylococci, streptococci, or enteric Gram-negative rods had target-specific PCR/pyrosequencing performed. Amplifiable beta-globin (melting temperature [Tm], 87.2 degrees C +/- 0.2 degrees C) occurred in 99.1% (1,120/1,130) of patient extracts and 100% (102/102) of controls. Concordance between PCR/pyrosequencing and culture was 96.9% (1,085/1,120) for Universal 16S rRNA gene targets, with positivity rates of 9.4% (105/1,120) and 11.3% (126/1,120), respectively. Bacteria cultured included staphylococci (59/126, 46.8%), Gram-negative rods (34/126, 27%), streptococci (32/126, 25.4%), and a Gram-positive rod (1/126, 0.8%). All controls screened negative by PCR/pyrosequencing. Clinical performance characteristics (95% confidence interval [CI]) for Universal 16S rRNA gene PCR/pyrosequencing included sensitivity of 77.8% (69.5 to 84.7), specificity of 99.3% (98.6 to 99.7), positive predictive value (PPV) of 93.3% (86.8 to 97.3), and negative predictive value (NPV) of 97.2% (96.0 to 98.2). Bacteria were accurately identified in 77.8% (98/126) of culture-confirmed sepsis samples with Universal 16S PCR/pyrosequencing and in 76.4% (96/126) with follow-up target specific PCR/pyrosequencing. The initial PCR/pyrosequencing took ~5.5 h to complete or ~7.5 h when including target-specific PCR/pyrosequencing compared to 27.9 +/- 13.6 h for Gram stain or 81.6 +/- 24.0 h for phenotypic identification. In summary, this molecular approach detected the causative bacteria in over three quarters of all culture-confirmed cases of bacteremia directly from blood in significantly less time than standard culture but cannot be used to rule out infection. PMID- 26511738 TI - Characterization of Staphylococcus caprae Clinical Isolates Involved in Human Bone and Joint Infections, Compared with Goat Mastitis Isolates. AB - Staphylococcus caprae is an emerging microorganism in human bone and joint infections (BJI). The aim of this study is to describe the features of S. caprae isolates involved in BJI (H for human) compared with those of isolates recovered in goat mastitis (A for animal). Fourteen isolates of each origin were included. Identifications were performed using a Vitek 2 GP ID card, tuf gene sequencing, and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) Vitek MS. Molecular typing was carried out using pulsed-field gel electrophoresis (PFGE) and DiversiLab technology. The crystal violet method was used to determine biofilm-forming ability. Virulence factors were searched by PCR. Vitek MS technology provides an accurate identification for the two types of isolates compared to that of gold-standard sequencing (sensitivity, 96.4%), whereas the Vitek 2 GP ID card was more effective for H isolates. Molecular typing methods revealed two distinct lineages corresponding to the origin despite few overlaps: H and A. In our experimental conditions, no significant difference was observed in biofilm production ability between H and A isolates. Nine isolates (5 H isolates and 4 A isolates) behaved as weak producers while one A isolate was a strong producer. Concerning virulence factors, the autolysin atlC and the serine aspartate adhesin (sdrZ) genes were detected in 24 isolates (86%), whereas the lipase gene was always detected, except in one H isolate (96%). The ica operon was present in 23 isolates (82%). Fibrinogen-binding (fbe) or collagen-binding (cna) genes were not detected by using primers designed for Staphylococcus aureus or Staphylococcus epidermidis, even in low stringency conditions. Although S. caprae probably remains underestimated in human infections, further studies are needed to better understand the evolution and the adaptation of this species to its host. PMID- 26511739 TI - Microscopic Observation Drug Susceptibility Assay for Rapid Diagnosis of Lymph Node Tuberculosis and Detection of Drug Resistance. AB - In this study, 132 patients with lymphadenopathy were investigated. Fifty-two (39.4%) were diagnosed with tuberculosis (TB). The microscopic observation drug susceptibility (MODS) assay provided rapid (13 days), accurate diagnosis (sensitivity, 65.4%) and reliable drug susceptibility testing (DST). Despite its lower sensitivity than that of other methods, its faster results and simultaneous DST are advantageous in resource-poor settings, supporting the incorporation of MODS into diagnostic algorithms for extrapulmonary TB. PMID- 26511740 TI - Microbiological Characteristics of Chlamydia trachomatis and Neisseria gonorrhoeae Infections in South African Women. AB - We analyzed data of 263 women with at least one genital or anorectal sexually transmitted infection from a cross-sectional study conducted in rural South Africa. We provide new insights concerning the concurrence of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, and Trichomonas vaginalis infections as well as the characteristics of bacterial loads. PMID- 26511741 TI - Are Pathogenic Leptospira Species Agents of Community-Acquired Pneumonia? Case Reports of Leptospirosis Presenting as Pneumonia. AB - We report four Indonesian cases meeting the clinical and radiological criteria for community-acquired pneumonia and other findings suggestive of leptospirosis. Quantitative PCR (qPCR) analyses of serum and urine samples and serology confirmed the diagnosis of leptospirosis in each. Results of qPCR analysis of throat swabs were concordant with those obtained with acute-phase serum samples, which suggests its potential for use as a noninvasive diagnostic tool for leptospirosis. PMID- 26511742 TI - Clinical Utility of Laboratory Detection of Clostridium difficile Strain BI/NAP1/027. AB - Clostridium difficile strain BI/NAP1/027 is associated with increased C. difficile infection (CDI) rates and severity, and the efficacy of some CDI therapies may be strain dependent. Although cultured C. difficile isolates can be reliably subtyped by various methods, the long turnaround times, high cost, and limited availability of strain typing preclude their routine use. Nucleic acid amplification tests identify BI/NAP1/027 rapidly from stool, but the emergence of closely related strains compromises test specificity. Although detection of epidemiologically significant pathogens is generally useful for infection control programs, specific data supporting use of rapid detection of BI/NAP1/027 as an infection control tool are still awaited. PMID- 26511743 TI - Meningitis and Bacteremia Due to Neisseria cinerea following a Percutaneous Rhizotomy of the Trigeminal Ganglion. AB - Neisseria cinerea is a human commensal. The first known case of meningitis and bacteremia due to Neisseria cinerea following percutaneous glycerol instillation of the trigeminal ganglion is reported. Conventional phenotypic methods and complete 16S RNA gene sequencing accurately identified the pathogen. Difficulties in differentiation from pathogenic neisseriae are discussed. PMID- 26511744 TI - Oxygen Reduction with a Bifunctional Iridium Dihydride Complex. AB - The iridium dihydride [Ir(H)2 (HPNP)](+) (PNP=N(CH2 CH2 PtBu2 )2 ) reacts with O2 to give the unusual, square-planar iridium(III) hydroxide [Ir(OH)(PNP)](+) and water. Regeneration of the dihydride with H2 closes a quasi-catalytic synthetic oxygen-reduction reaction (ORR) cycle that can be run several times. Experimental and computational examinations are in agreement with an oxygenation mechanism via rate-limiting O2 coordination followed by H-transfer at a single metal site, facilitated by the cooperating pincer ligand. Hence, the four electrons required for the ORR are stored within the two covalent M?H bonds of a mononuclear metal complex. PMID- 26511745 TI - Healthcare workers and skin sensitization: north-eastern Italian database. AB - BACKGROUND: Working in healthcare is regarded as a risk factor for occupational skin disease. Workers are exposed to disinfectants, soaps, detergents and latex and need to wash their hands frequently and thoroughly. AIMS: To investigate the association between healthcare work and patch test reactions to various potential sensitizers in a population of contact dermatitis patients in various dermatology and occupational medicine units in north-eastern Italy. METHODS: Patients with suspected allergic dermatitis underwent patch testing. Odds ratios (ORs) and 95% confidence intervals (CIs), adjusted by age and sex, were calculated for healthcare workers (HCWs), using white-collar workers as control group. RESULTS: HCWs represented 14% of the sample of 19088 patients (68% women, 32% men). Among HCWs, both sexes had a higher risk of developing hand/forearm dermatitis (females: OR 2.1, 95% CI 1.8-2.5; males: OR 1.6, 95% CI 1.3-2.1). HCWs had an increased risk of sensitization to formaldehyde (OR 1.65; 95% CI 1.2-2.3) and to p-phenylenediamine (OR 1.6; CI 1.1-2.3). CONCLUSIONS: Our study suggests a significant association between healthcare work, hand/forearm dermatitis and sensitization to formaldehyde and p-phenylenediamine. PMID- 26511746 TI - UK asbestos imports and mortality due to idiopathic pulmonary fibrosis. AB - BACKGROUND: Previous studies have demonstrated that the rising mortality due to mesothelioma and asbestosis can be predicted from historic asbestos usage. Mortality due to idiopathic pulmonary fibrosis (IPF) is also rising, without any apparent explanation. AIMS: To compare mortality due to these conditions and examine the relationship between mortality and national asbestos imports. METHODS: Mortality data for IPF and asbestosis in England and Wales were available from the Office for National Statistics. Data for mesothelioma deaths in England and Wales and historic UK asbestos import data were available from the Health & Safety Executive. The numbers of annual deaths due to each condition were plotted separately by gender, against UK asbestos imports 48 years earlier. Linear regression models were constructed. RESULTS: For mesothelioma and IPF, there was a significant linear relationship between the number of male and female deaths each year and historic UK asbestos imports. For asbestosis mortality, a similar relationship was found for male but not female deaths. The annual numbers of deaths due to asbestosis in both sexes were lower than for IPF and mesothelioma. CONCLUSIONS: The strength of the association between IPF mortality and historic asbestos imports was similar to that seen in an established asbestos related disease, i.e. mesothelioma. This finding could in part be explained by diagnostic difficulties in separating asbestosis from IPF and highlights the need for a more accurate method of assessing lifetime occupational asbestos exposure. PMID- 26511747 TI - Self-reported workplace perception as indicators of work anxieties. AB - BACKGROUND: Work anxiety is a potentially disabling mental health problem, which can cause (long-term) sickness absence. In many cases patients do not openly report their anxieties and tend to give externalizing explanations of inner problems. Therefore people with work anxiety may perceive their workplace more negatively than those without such anxiety. AIMS: To investigate the relation between subjective work description and work anxiety. METHODS: Work anxiety was investigated with a standardized interview in a sample of employed psychosomatic rehabilitation inpatients suffering from common mental disorders. We assessed their subjective perception and evaluation of workplace conditions with the 'Short Questionnaire for Job Analysis' (KFZA) and compared their results with those from a sample of employees in the general population. RESULTS: There were 148 inpatient participants and 8015 general population controls. Patients with work anxiety described their workplace significantly more negatively than patients without work anxiety and employees in the general population, with no differences in workplace descriptions between psychosomatic patients without work anxiety and the general population sample. The type of complaint about work conditions was related to the specific type of work anxiety. CONCLUSIONS: Reports about workplace burdens can be indicative of work anxiety and should prompt further in-depth assessments. The content of complaints about work conditions may point to the type of underlying work anxiety. PMID- 26511748 TI - Low yield of surveillance imaging after surgery for T1 kidney cancer. AB - PURPOSE: To examine the mode of relapse detection and subsequent treatment after partial or radical nephrectomy in patients with low-risk (pT1, N0, Nx) kidney cancer. METHODS: Retrospective study on 1404 patients treated with partial or radical nephrectomy for low-risk kidney cancer from the years 2000-2012. Scans for chest imaging (X-ray or CT) and abdominal imaging (CT, MRI, or ultrasound) are tabulated. For those patients with relapse, the site, mode of detection, and symptoms were recorded. RESULTS: Twenty-one patients relapsed with a median follow-up of 4.1 years for patients who did not relapse. In 17 (81 %) patients, relapse was detected by imaging alone, while 4 (19 %) patients presented with symptoms. Of the patients who relapsed by imaging, 13 (76 %) were treated immediately, while 4 (24 %) continued observation. During the first 3 years of follow-up, 5762 imaging studies were performed to detect 8 relapses, with 6 patients receiving immediate treatment. The median number of imaging studies per patient per year for the first 3 years was 1.7 (interquartile range 1.0, 2.3) including 30 % CT, 3 % MRI, 36 % X-ray, and 31 % ultrasounds. CONCLUSION: We found a low yield of surveillance imaging in the first 3 years for pT1 kidney cancer. Nearly 1000 imaging studies were performed to detect one relapse that required treatment. Further studies are needed to evaluate the clinical impact of imaging surveillance according to recent guidelines. PMID- 26511749 TI - Extended-spectrum beta-lactamase-producing Enterobacteriaceae in hospital urinary tract infections: incidence and antibiotic susceptibility profile over 9 years. AB - PURPOSE: Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are an increasing concern regarding antibiotic resistance and their potential to cause serious infections which are difficult to treat. The purpose of this surveillance programme was to assess the incidence of ESBL in adults amongst urinary isolates, identify risk factors, and detail the antibiotic susceptibility profile in order to guide empirical treatment. METHODS: From 2006 to 2014, we reviewed 21,414 positive urine cultures for E. coli and Klebsiella sp. from a University hospital in the UK and found 1420 ESBL-positive specimens. Susceptibility testing was performed by British Society of Antimicrobial Chemotherapy disc diffusion testing. ESBL screening was performed on samples resistant to cefpodoxime and confirmed by double disc diffusion (Oxoid Ltd, Basingstoke, UK). Patient gender, age, inpatient status, and catheterisation were assessed as risk factors. RESULTS: ESBL production amongst E. coli urine cultures increased 44 %, from 4.6 to 6.6 % of all E. coli isolates. ESBL-positive organisms were associated with increases in drug resistance, particularly amongst fluoroquinolones, trimethoprim, and cephalexin. Multidrug resistance was a feature with 75 % of ESBL+ Klebsiella sp.-resistant >=6 antibiotic classes. ESBL producers remained largely susceptible to carbapenems. Male gender, urinary catheterisation, inpatient status, and increasing age were identified as risk factors for ESBL infection or colonisation. CONCLUSION: We demonstrate that the incidence of ESBL-producing E. coli in urine cultures is increasing and that such isolates are multidrug resistant. Carbapenems and nitrofurantoin for E. coli infections remain effective, which may guide empirical antibiotic therapy. PMID- 26511750 TI - First findings of gap junction proteins in human urothelial carcinoma. PMID- 26511751 TI - Postoperative drainage does not prevent complications after robotic partial nephrectomy. AB - OBJECTIVES: We aimed to assess the impact of a postoperative drainage after RPN. METHODS: A retrospective multicentric study included RPN performed at eight centers between 2010 and 2014. Three centers stopped using postoperative drainage early in their RPN experience, whereas other institutions systematically left a drain. Preoperative characteristics, complication rates, need for postoperative imaging or procedure (surgical or radiological) and length of hospital stay were compared between the two groups [drainage (D) and no drainage (ND)]. RESULTS: Among 636 RPNs, 140 were done without drainage (22 %). In the ND group, surgeons were more experienced (>50 cases: 55.7 vs. 15.1 %; p < 0.0001), and tumors were more complex (RENAL score: 7.6 vs. 6.5; p < 0.0001). Complication rates were similar in both groups (21.9 vs. 20.2 %; p = 0.67). The omission of postoperative drainage did not increase requirement of CT scan (RR = 1.03; 95 % CI 0.64-1.67). Length of hospital stay was shorter in the ND group (4.5 vs. 5.5 days; p = 0.007). There were six urinary fistulas: four in the D group (0.8 %) and two in the ND group (1.4 %; p = 0.49). A CT scan was done to confirm the diagnosis of fistula in every case. In multivariate analysis, the omission of drainage was not associated with increased need of postoperative CT scan or major complications but was a predictor of decreased length of stay. CONCLUSION: The omission of postoperative drainage does not seem to increase the risk of postoperative complications and could safely be omitted after RPN. PMID- 26511752 TI - Turing Pattern Formation in a Semiarid Vegetation Model with Fractional-in-Space Diffusion. AB - A fractional power of the Laplacian is introduced to a reaction-diffusion system to describe water's anomalous diffusion in a semiarid vegetation model. Our linear stability analysis shows that the wavenumber of Turing pattern increases with the superdiffusive exponent. A weakly nonlinear analysis yields a system of amplitude equations, and the analysis of these amplitude equations shows that the spatial patterns are asymptotic stable due to the supercritical Turing bifurcation. Numerical simulations exhibit a bistable regime composed of hexagons and stripes, which confirm our analytical results. Moreover, the characteristic length of the emergent spatial pattern is consistent with the scale of vegetation patterns observed in field studies. PMID- 26511753 TI - A response to "Comments on torsional testing". PMID- 26511754 TI - Ambient temperature effect on pulse rate variability as an alternative to heart rate variability in young adult. AB - Pulse rate variability (PRV) is a promising physiological and analytic technique used as a substitute for heart rate variability (HRV). PRV is measured by pulse wave from various devices including mobile and wearable devices but HRV is only measured by an electrocardiogram (ECG). The purpose of this study was to evaluate PRV and HRV at various ambient temperatures and elaborate on the interchangeability of PRV and HRV. Twenty-eight healthy young subjects were enrolled in the experiment. We prepared temperature-controlled rooms and recorded the ECG and photoplethysmography (PPG) under temperature-controlled, constant humidity conditions. The rooms were kept at 17, 25, and 38 degrees C as low, moderate, and high ambient temperature environments, respectively. HRV and PRV were derived from the synchronized ECG and PPG measures and they were studied in time and frequency domain analysis for PRV/HRV ratio and pulse transit time (PTT). Similarity and differences between HRV and PRV were determined by a statistical analysis. PRV/HRV ratio analysis revealed that there was a significant difference between HRV and PRV for a given ambient temperature; this was with short-term variability measures such as SDNN SDSD or RMSSD, and HF-based variables including HF, LF/HF and normalized HF. In our analysis the absolute value of PTT was not significantly influenced by temperature. Standard deviation of PTT, however, showed significant difference not only between low and moderate temperatures but also between low and high temperatures. Our results suggest that ambient temperature induces a significant difference in PRV compared to HRV and that the difference becomes greater at a higher ambient temperature. PMID- 26511755 TI - Tackling fear about exercise produces long term benefit in chronic fatigue syndrome. PMID- 26511756 TI - Recent developments and applications of clickable photoprobes in medicinal chemistry and chemical biology. AB - Photoaffinity labeling is a well-known biochemical technique that has grown significantly since the turn of the century, principally due to its combination with bioorthogonal/click chemistry reactions. This review highlights new developments and applications of clickable photoprobes in medicinal chemistry and chemical biology. In particular, recent examples of clickable photoprobes for target identification, activity- or affinity-based protein profiling (ABPP or AfBPP), characterization of sterol- or lipid-protein interactions and characterization of ligand-binding sites are presented. PMID- 26511757 TI - Effects of post-suckling n-3 polyunsaturated fatty acids: prevention of dyslipidemia and liver steatosis induced in rats by a sucrose-rich diet during pre- and post-natal life. AB - The interaction between fetal programming and the post-natal environment suggests that the post-natal diet could amplify or attenuate programmed outcomes. We investigated whether dietary n-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) at weaning resulted in an amelioration of dyslipidemia, adiposity and liver steatosis that was induced by a sucrose-rich diet (SRD; where the fat source is corn oil) from the onset of pregnancy up to adulthood. During pregnancy and lactation, dams were fed an SRD or the standard powdered rodent commercial diet (RD). At weaning and until 150 days of life, male offspring from SRD-dams were divided into two groups and fed an SRD or SRD-with-fish oil [where 6% of the corn oil was partially replaced by fish oil (FO) 5% and corn oil (CO) 1%], forming SRD-SRD or SRD-FO groups. Male offspring from RD-dams continued with RD up to the end of the experimental period, forming an RD-RD group. The presence of FO in the weaning diet showed the following: prevention of hypertriglyceridemia and liver steatosis, together with increased lipogenic enzyme activity caused by a maternal SRD; the complete normalization of CPT I activity and PPARalpha protein mass levels; a slight but not statistically significant accretion of visceral adiposity; and limited body fat content and reduced plasma free fatty acid levels. All of these results were observed even in the presence of a high sucrose diet challenge after weaning. SRD-dams' breast milk showed a more saturated fatty acid composition. These results suggest the capacity of n-3 PUFAs to overcome some adverse outcomes induced by a maternal and post-weaning sucrose rich diet. PMID- 26511758 TI - Stunted PFC activity during neuromuscular control under stress with obesity. AB - OBJECTIVE: Obesity is an established risk factor for impaired cognition, which is primarily regulated by the prefrontal cortex (PFC). However, very little is known about the neural pathways that underlie obesity-related declines in neuromuscular control, particularly under stress. The purpose of this study was to determine the role of the PFC on neuromuscular control during handgrip exertions under stress with obesity. METHODS: Twenty non-obese and obese young adults performed submaximal handgrip exertions in the absence and presence of a concurrent stressful task. Primary dependent measures included oxygenated hemoglobin (HbO2: a measure of PFC activity) and force fluctuations (an indicator of neuromuscular control). RESULTS: Higher HbO2 levels in the PFC were observed in the non-obese compared to the obese group (P = 0.009). In addition, higher HbO2 levels were observed in the stress compared to the control condition in the non-obese group; however, this trend was reversed in the obese group (P = 0.043). In general, force fluctuations increased by 26% in the stress when compared to the control condition (P = 0.001) and obesity was associated with 39% greater force fluctuation (P = 0.024). Finally, while not significant, obesity-related decrements in force fluctuations were magnified under stress (P = 0.063). CONCLUSION: The current study provides the first evidence that neuromuscular decrements with obesity were associated with impaired PFC activity and this relationship was augmented in stress conditions. These findings are important because they provide new information on obesity-specific changes in brain function associated with neuromuscular control since the knowledge previously focused largely on obesity-specific changes in peripheral muscle capacity. PMID- 26511759 TI - Prevalence, prenatal screening and neonatal features in children with Down syndrome: a registry-based national study. AB - BACKGROUND: Down syndrome (DS) is one of the most common chromosomal abnormalities among newborns. In recent years advances in perinatal and neonatal care have improved chance of survival for the children with DS. The objective of this Registry-Based study was to get more accurate data of DS prevalence with evaluation of antenatal screening, neonatal and maternal features among total births in Croatia from 2009 to 2012. METHODS: We used retrospectively collected data for DS newborns from the medical birth database and perinatal mortality database for the period of 2009-2012. Differences between DS and the referent population for each year in quantitative measures were assessed with the independent t-test. Other differences in nominal and categorical values were analyzed with the chi-square test. RESULTS: The total prevalence for DS in the period of 2009-2012 was 7.01 per 10,000 births, while the live-birth prevalence was 6.49 per 10,000 births. The significant differences (p < 0.05) between the DS and reference populations for each year were noticed for birth weight and length, gestational age, mother age, Apgar score of >=6 after 5 min and breastfeeding. Among newborns with DS, there were 64 (53.33 %) males and 56 (46.67 %) females versus 88,587 (51.76 %) males and 82,553 (48.23 %) females in the reference population. In the DS group compared to the reference population the mean birth weight was 2845 grams versus 3467 grams in males and 2834 grams versus 3329 grams in females, respectively, with a mean birth length of 47 cm versus 50 cm for both genders. The mean gestational age of the DS births was 37 weeks and the mean age of the mothers was 32.6 years, versus 39 weeks and 29.1 years, respectively, in the reference population. Only 68.3 % of children with DS were breastfed from birth, compared with 94.72 % of children in the reference population. CONCLUSIONS: The significant differences for neonatal and maternal features between DS and the referent population were found similar to other studies. The total prevalence of DS in Croatia in the period of 2009-2012 was lower than the previously estimated prevalence based on EUROCAT data. The establishment of a new national registry of congenital malformations covering 99 % of all births in Croatia is necessary to improve the health and prosperity of children, adolescents and adults with DS in Croatia. PMID- 26511760 TI - Noninvasive Antenatal Determination of Fetal Blood Group Using Next-Generation Sequencing. AB - Hemolytic disease of the fetus and newborn (HDFN) is a condition characterized by a decreased lifespan of fetal red blood cells caused by maternally produced allospecific antibodies transferred to the fetus during pregnancy. The antibodies bind to the corresponding blood group antigens on fetal red blood cells and induce hemolysis. Cell-free DNA derived from the conceptus circulates in maternal blood. Using next-generation sequencing (NGS), it can be determined if this cell free fetal DNA encodes the corresponding blood group antigen that is the target of the maternal allospecific antibodies. This determination carries no risk to the fetus. It is important to determine if the fetus is at risk of hemolysis to enable timely intervention. Many tests for blood groups are based solely on the presence or absence of a single nucleotide polymorphism (SNP). Antenatal determination of fetal blood group by NGS analysis holds advantages over polymerase chain reaction (PCR) determination based on allele specific amplification. PMID- 26511762 TI - The Regulatory T Cell: Jack-Of-All-Trades. AB - Foxp3(+) regulatory T (Treg) cells suppress auto-reactive and inflammatory T cells to maintain immune homeostasis. In a recent study, Rudensky and colleagues demonstrate the ability of Treg cells to facilitate tissue repair, a non canonical Treg cell function accomplished by amphiregulin and mediated by cytokines interleukin (IL)-18 and IL-33. PMID- 26511761 TI - The Woodchuck, a Nonprimate Model for Immunopathogenesis and Therapeutic Immunomodulation in Chronic Hepatitis B Virus Infection. AB - The woodchuck hepatitis virus (WHV) and its host, the eastern woodchuck, is a very valuable model system for hepatitis B virus infection. Many aspects of WHV replication and pathogenesis resemble acute and chronic hepatitis B infection in patients. Since the establishment of immunological tools, woodchucks were used to develop new therapeutic vaccines and immunomodulatory approaches to treat chronic hepadnaviral infections. Combination therapy of nucleos(t)ide analogs, with prime boost vaccination and triple therapy, including immunomodulatory strategies by blocking the interaction of the programmed death-1 (PD-1) receptor with its ligand inducing a potent T-cell response in chronic WHV carrier woodchucks, suppression of viral replication, and complete elimination of the virus in 30% of the animals. Both strategies may be used for future therapies in patients with chronic hepatitis B. PMID- 26511763 TI - PVP-Assisted Solvothermal Synthesis of High-Yielded Bi2Te3 Hexagonal Nanoplates: Application in Passively Q-Switched Fiber Laser. AB - High-yielded Bi2Te3 hexagonal nanoplates were fabricated via a facile solvothermal method with the assistance of poly (vinyl pyrrolidone) (PVP). Effects of PVP molecular weight and concentration on the morphology and size distribution of the products were illustrated in this study. Molecular weight of PVP is significant for determining the morphology of Bi2Te3. The hexagonal nanoplates with high yield were obtained in the presence of PVP with molecular weight of 40000-45000. The average size and size distribution of Bi2Te3 nanoplates can be slightly varied by controlling concentration of PVP. High yielded Bi2Te3 nanoplates exhibit characteristics of saturable absorption, identified by open-aperture Z-scan technique. The synthesized Bi2Te3 nanoplates with large saturation intensity of 4.6 GW/cm(2) and high modulation depth of 45.95% generated a stable passively Q-switched fiber laser pulse at 1.5 MUm. In comparison with recently reported Q-switched fiber lasers utilizing exfoliated Bi2Te3 nanosheets, our passive Q-switching operations could be conducted at a relatively low threshold power of 30.2 mW or a quite high output power of 99.45 mW by tuning the cavity parameters. PMID- 26511764 TI - Reducing worry and subjective health complaints: A randomized trial of an internet-delivered worry postponement intervention. AB - OBJECTIVES: Several studies have shown that perseverative, worrisome thoughts are prospectively related to subjective health complaints (SHC) and that a short worry postponement intervention can decrease these complaints. As SHC and worry are prevalent and costly, we tested whether the intervention can be offered online to reduce these complaints in the general population. DESIGN: A randomized parallel-group trial was conducted with self-selected participants from the general population. METHODS: Via the research website, 996 participants were instructed to register their worrying for 6 consecutive days. The intervention group was instructed to postpone worry to a special 30-min period in the early evening. The Subjective Health Complaints inventory, as administered before and after the intervention, and daily worry frequency and duration were considered the primary outcomes. RESULTS: Three hundred and sixty-one participants completed the study. Contrary to our expectation, the registration group (n = 188) did not differ from the intervention group (n = 163) in SHC (etap2 = .000, CI [0.000 0.003]), or in worry frequency or duration. Nevertheless, the different worry parameters were moderately related to SHC (r between .238 and .340, p <= .001). CONCLUSIONS: In contrast to previous studies using pen-and-pencil versions of the worry postponement intervention, this study suggests that a direct online implementation was not effective in reducing SHC and worry. Overall, participants had high trait worry levels and reported difficulty with postponing worrying. Reducing SHC and worries via the Internet might require more elaborate interventions that better incorporate the advantages of delivering interventions online. STATEMENT OF CONTRIBUTION: What is already known on this subject? The perseverative cognition hypothesis argues that perseverative cognition, such as worry and rumination, acts as a mediator by which psychosocial stress may produce negative health effects. Prior research has indeed shown that worry and subjective health complaints (SHC) are prospectively related, but causality studies - that is, showing that changes in worry induce changes in health outcomes - are scarce and have mainly been conducted in young samples. These studies showed that reducing worry, using a worry postponement intervention, can reduce daily worrying and SHC. What does this study add? Trait and daily worrying are associated with SHC. An online worry postponement intervention is ineffective in reducing worry and SHC. Paper-and-pencil interventions cannot directly be used as online interventions. PMID- 26511765 TI - Prediction of microcephaly at birth using three reference ranges for fetal head circumference: can we improve prenatal diagnosis? AB - OBJECTIVE: To evaluate the prediction of microcephaly at birth (micB) using established and two new reference ranges for fetal head circumference (HC) and to assess whether integrating additional parameters can improve prediction. METHODS: Microcephaly in utero was defined as a fetal HC 3SD below the mean for gestational age according to Jeanty et al.'s reference range. The records of cases with fetal microcephaly (Fmic) were evaluated for medical history, imaging findings, biometry and postnatal examination/autopsy findings. Microcephaly was confirmed at birth (micB) by an occipitofrontal circumference (OFC) or a brain weight at autopsy 2SD below the mean for gestational age. The new INTERGROWTH 21(st) Project and a recent Israeli reference for fetal growth were applied for evaluation of the Fmic positive predictive value (PPV) for diagnosis of micB cases. Optimal HC cut-offs were determined for each of the new references with the aim of detecting all micB cases whilst minimizing the number of false positives found to have a normal HC at birth. We also assessed the difference between the Z-scores of the prenatal HC and the corresponding OFC at birth, the frequency of small-for-gestational age (SGA), decreased HC/abdominal circumference (AC) and HC/femur length (FL) ratios, the prevalence of associated malformations and family history. RESULTS: Forty-two fetuses were diagnosed as having Fmic according to the Jeanty reference, but micB was confirmed in only 24 (PPV, 57.1%). The optimal INTERGROWTH and Israeli reference HC cut-offs for micB diagnosis were mean - 3SD and mean - 2.3SD, resulting in a statistically non significant improvement in PPV to 61.5% and 66.7%, respectively. The presence of a family history of microcephaly, SGA, associated malformations and application of stricter HC cut-offs resulted in a higher PPV of micB, although not statistically significant and with a concurrent increase in the number of false negative results. The deviation of the HC from the mean, by all references, was significantly larger compared with the actual deviation of the OFC at birth, with mean differences between the corresponding Z-scores of -1.15, -1.95 and -0.74 for the Jeanty, INTERGROWTH and Israeli references, respectively. CONCLUSIONS: The evaluated reference ranges all result in considerable over-diagnosis of fetal microcephaly. The use of the two new HC reference ranges did not significantly improve micB prediction compared with that of Jeanty et al., whilst use of additional characteristics and stricter HC cut-offs could improve the PPV with an increase in false negatives. The postnatal OFC deviates significantly less from the mean compared with the prenatal HC, and we propose that adjustment for this would enable better prediction of the actual OFC deviation at birth. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26511767 TI - Extraordinary capture of a Randall's snapper Randallichthys filamentosus in the temperate south-eastern Indian Ocean and its molecular phylogenetic relationship within the Etelinae. AB - The capture of a rarely encountered Randall's snapper Randallichthys filamentosus (female, 587 mm fork length) from the upper continental slope (c. 350 m) off the south coast of Western Australia (c. 34.5 degrees S; 122.5 degrees E) in January 2014 represents its first record from the temperate Indian Ocean and a southern range extension. This record suggests that spawning of this predominantly tropical species may probably be occurring in the eastern Indian Ocean, considering the extensive, and unlikely, distance the progeny would have otherwise travelled from its typical distribution in the western and central Pacific Ocean. PMID- 26511766 TI - Short term health-related quality of life improvement during opioid agonist treatment. AB - BACKGROUND: Opioid dependence is associated with high levels of morbidity, yet sparse data exists regarding the health-related quality of life (HRQoL) of individuals with opioid dependence, particularly following treatment initiation. To inform cost-effectiveness analyses of treatment modalities, this study investigates short-term changes in HRQoL following enrollment into opioid agonist treatment (OAT), across treatment modalities and patient subgroups. METHODS: Data was analyzed from the Starting Treatment with Agonist Replacement Therapies (START) and Prescription Opioid Addiction Treatment Studies (POATS) randomized controlled trials. Participants included individuals dependent on prescription opioids (POs) or heroin, receiving limited-term or time-unlimited treatment. PO- or heroin-users in START received buprenorphine/naloxone (BUP/NX) or methadone (MET) over 24 weeks. PO-users in POATS received psychosocial care and short-term (4-week) taper with BUP/NX, with non-responders offered subsequent extended (12 week) stabilization and taper. HRQoL was assessed using the short-form SF-6D while in and out of OAT, with distinction between MMT and BUP/NX in START. Linear mixed effects regression models were fitted to determine the independent effects of OAT on HRQoL and characterize HRQoL trajectories. RESULTS: Treatment had a similar immediate and modest positive association with HRQoL in each patient subgroup. The association of OAT on HRQoL was statistically significant in each model, with effect sizes between 0.039 (heroin-users receiving BUP/NX) and 0.071 (PO-users receiving MET). After initial improvement, HRQoL decreased slightly, or increased at a diminished rate. CONCLUSIONS: OAT, whether delivered in time limited or unlimited form, using BUP/NX or MET, is associated with modest immediate HRQoL improvements, with diminishing benefits thereafter. PMID- 26511768 TI - Estimating the direct and indirect costs associated with Parkinson's disease. AB - Parkinson's disease (PD) is a progressive, neurodegenerative disorder whose symptoms and manifestations greatly deteriorate the health, functional status and quality of life of patients, has severe consequences on their families and caregivers and supposes a challenge for the healthcare system and society. The aim of this paper is to comprehensively and descriptively review studies on the economic impact of the disease and interventions, analyzing major contributing factors to direct and indirect costs in PD. Cost-of-illness studies have shown that costs of PD are high, mainly due to drug, hospitalization and productivity loss, and tend to increase as the disease progresses. Studies on PD treatment have suggested that therapies for advanced PD (levodopa/carbidopa intestinal gel and apomorphine) and surgical procedures are cost-effective and cost saving, despite their high expenditures; however, further research such as on the economic impact of non-motor manifestations or on the cost-effectiveness of non medical interventions is still needed. PMID- 26511769 TI - CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells. AB - IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens but also drive numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10 producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFNgamma-producing Th17 cells. However, their distinct developmental requirements, functions and trafficking mechanisms in vivo remain poorly understood. Here we identify a temporally regulated IL-23-dependent switch from CCR6 to CCR2 usage by developing Th17 cells that is critical for pathogenic Th17 cell-driven inflammation in experimental autoimmune encephalomyelitis (EAE). This switch defines a unique in vivo cell surface signature (CCR6(-)CCR2(+)) of GM-CSF/IFNgamma-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, we identify an IL-23/IL-1/IFNgamma/TNFalpha/T-bet/Eomesodermin driven circuit driving GM-CSF/IFNgamma-producing Th17 cell formation in vivo. Thus, our data identify a unique cell surface signature, trafficking mechanism and T-cell intrinsic regulators of GM-CSF/IFNgamma-producing Th17 cells. PMID- 26511770 TI - Fractional Solitons in Excitonic Josephson Junctions. AB - The Josephson effect is especially appealing to physicists because it reveals macroscopically the quantum order and phase. In excitonic bilayers the effect is even subtler due to the counterflow of supercurrent as well as the tunneling between layers (interlayer tunneling). Here we study, in a quantum Hall bilayer, the excitonic Josephson junction: a conjunct of two exciton condensates with a relative phase phi0 applied. The system is mapped into a pseudospin ferromagnet then described numerically by the Landau-Lifshitz-Gilbert equation. In the presence of interlayer tunneling, we identify a family of fractional sine-Gordon solitons which resemble the static fractional Josephson vortices in the extended superconducting Josephson junctions. Each fractional soliton carries a topological charge Q that is not necessarily a half/full integer but can vary continuously. The calculated current-phase relation (CPR) shows that solitons with Q = phi0/2pi is the lowest energy state starting from zero phi0 - until phi0 > pi - then the alternative group of solitons with Q = phi0/2pi - 1 takes place and switches the polarity of CPR. PMID- 26511771 TI - Retrograde solubility of formamidinium and methylammonium lead halide perovskites enabling rapid single crystal growth. AB - Here we show the retrograde solubility of various hybrid perovskites through the correct choice of solvent(s) and report their solubility curves. Retrograde solubility enables to develop inverse temperature crystallization of FAPbX3 (FA = HC(NH2)2(+), X = Br(-)/I(-)). FAPbI3 crystals exhibit a 1.4 eV bandgap- considerably narrower than their polycrystalline counterparts. PMID- 26511772 TI - Solicited kidney donors: Are they coerced? AB - Most non-directed donors (NDDs) decide to donate on their own and contact the transplant centre directly. Some NDDs decide to donate in response to community solicitation such as newspaper ads or donor drives. We wished to explore whether subtle coercion might be occurring in such NDDs who are part of a larger community. One successful organization in a community in Brooklyn, NY, provides about 50 NDDs per year for recipients within that community. The donors answer ads in local papers and attend donor drives. Herein, we evaluated the physical and emotional outcomes of community-solicited NDDs in comparison to traditional NDDs who come from varied communities and are not responding to a specific call for donation. An assessment of coercion was used as well. PMID- 26511773 TI - Transplant considerations in a man with von Hippel-Lindau disease with bilateral renal cell carcinoma and a pancreatic neuroendocrine tumour. PMID- 26511774 TI - Influence of abutment tooth position and adhesive point dimension on the rigidity of a dental trauma wire-composite splint. AB - BACKGROUND/AIM: The influence of abutment tooth position and adhesive point dimension on rigidity of wire-composite splints, used in dental trauma, was evaluated in vitro. MATERIALS AND METHODS: A commercial artificial resin model was used. The central incisors served as injured teeth with increased mobility (degrees of loosening II tooth 21 and III tooth 11), whereas teeth 12/22 or teeth 13/23 served as non-injured teeth with physiological mobility. Horizontal and vertical tooth mobility before and after splinting was assessed, using a universal testing machine. Teeth were splinted with a wire-composite splint (0.8 mm). Four groups were assigned with respective abutment tooth position and adhesive point dimension: group 1 (13-11-21-23, 2 * 2 mm(2) ), group 2 (12-11-21 22, 2 * 2 mm(2) ), group 3 (12-11-21-22, 3 * 3 mm(2) ), group 4 (12-11-21-22, 4 * 4 mm(2) ). RESULTS: For each group, tooth mobility after splinting was significantly higher than the physiological tooth mobility (P < 0.05). For teeth 11 and 12, no significant differences between Group 1 and 2 (P > 0.05) were found in tooth mobility after splinting. Significant differences were found in horizontal tooth mobility after splinting of tooth 11 between Group 2 and 3, Group 2 and 4 and Group 3 and 4, respectively (P < 0.05), whereas significant difference was found in vertical dimension for tooth 11 only between Group 2 and 4 (P < 0.05). Significant differences were found in horizontal mobility of tooth 21 between Group 2 and 3, and Group 2 and 4 (P < 0.05). CONCLUSION: Splinting the injured teeth 11 and 21 and the bilateral uninjured abutment teeth (teeth 12/22 or teeth 13/23) with the stainless steel wire-composite splint (0.8 mm), can be considered flexible splinting. While mobility was still higher than in unaffected teeth, increase in size of the adhesive splinting point decreased horizontal but not vertical mobility in most cases. PMID- 26511775 TI - Randomized trial to examine procedure-to-procedure transfer in laparoscopic simulator training. AB - BACKGROUND: Laparoscopic simulation has become a standard component of surgical training, but there is limited knowledge regarding skills transfer between procedural tasks. The objective was to investigate the specificity of procedural simulator training. METHODS: This was randomized single-centre educational superiority trial. Surgical novices practised basic skills on a laparoscopic virtual reality simulator. On reaching proficiency, participants were randomized to proficiency-based training. The intervention group practised two procedures on the simulator (appendicectomy followed by salpingectomy), whereas the control group trained on only one procedure (salpingectomy). The main outcomes were number of repetitions and time to proficiency for the second procedure. RESULTS: Ninety-six participants were randomized, of whom 74 per cent were women, with a median age of 26 years. The intervention group needed significantly fewer attempts than the control group to reach proficiency in the second procedure: median (i.q.r.) 22 (17-34) versus 32 (26-41) attempts, which corresponded to 24.1 per cent fewer attempts as assessed by multivariable analysis (P = 0.004). The intervention group required significantly less time than the control group to reach proficiency: median (i.q.r.) 88 (63-127) versus 131 (101-153) min respectively, corresponding to a difference of 31.1 min as assessed by multivariable analysis (P = 0.001). CONCLUSION: Practising two procedures, compared with only one, reduced the number of attempts and time to reach proficiency in the second procedure. Skills transfer is seen between two tasks in laparoscopic simulator training; however, task specificity is still present when practising procedures. REGISTRATION NUMBER: NCT02069951 (http://www.clinicaltrials.gov). PMID- 26511776 TI - The Role of Ceramide in the Pathogenesis of Alcoholic Liver Disease. AB - AIMS: Ceramide is an important second messenger in the sphingomyelin signaling pathway. In this review, we will focus on the potential role of ceramide in the pathogenesis of alcoholic liver disease (ALD). METHODS: We have summarized the relevant studies and reviews about the role of ceramide in ALD. In addition, we have discussed the role of acid sphingomyelinase and protein phosphatase 2A in ALD, which are associated with ceramide and hepatic steatosis. RESULTS: Recent studies have proved that the immunoreactivity and content of ceramide were increased, both in experimental models of chronic alcohol-induced steatohepatitis and human livers with severe chronic alcohol-related liver disease. Consistent with that, the levels of protein phosphatase 2A and acid sphingomyelinase were increased. Of relevance, the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) was inhibited, which could block the fatty acid oxidation and promote its synthesis. CONCLUSIONS: It was hypothesized that ethanol promoted ceramide accumulation and increased PP2A activity by activating ASMase, which may be an important mechanism in the inhibitory effect on AMPK phosphorylation and then contributed to the progression of steatosis. ASMase, a specific mechanism of ceramide generation, was proved to be a regulator of steatosis, fibrosis, lipotoxicity and endoplasmic reticulum stress. PMID- 26511777 TI - Personality Predictors of Drinking Outcomes in Depressed Alcohol-Dependent Patients. AB - AIM: To evaluate the role of personality dimensions as predictors of drinking outcomes in depressed alcohol-dependent patients. METHODS: Temperament and character inventory (TCI) scores were obtained at baseline in a 24-week study of 127 depressed alcohol-dependent patients who received open-label naltrexone and were randomized to citalopram or placebo. The association between TCI personality dimensions and alcohol outcomes during follow-up was examined using general linear mixed models. RESULTS: Low novelty seeking, high self-directedness and high cooperativeness predicted less alcohol consumption on drinking days during follow-up. Temperament and character variables had no effect on the percentage of days abstinent from alcohol. Depression mediated the effects of self-directedness and cooperativeness on alcohol outcomes while the effect of novelty seeking remained after adjusting for depression scores in follow-up. CONCLUSION: Identifying personality characteristics at baseline predicts drinking outcomes in depressed, alcohol-dependent patients. In particular patients with high novelty seeking drank more heavily on drinking days and they may therefore need more intensive intervention to achieve good treatment outcomes. PMID- 26511779 TI - Radical nursing and the emergence of technique as healthcare technology. AB - The integration of technology in care is core business in nursing and this role requires that we must understand and use technology informed by evidence that goes much deeper and broader than actions and behaviours. We need to delve more deeply into its complexity because there is nothing minor or insignificant about technology as a major influence in healthcare outcomes and experiences. Evidence is needed that addresses technology and nursing from perspectives that examine the effects of technology, especially related to increasing demands for efficiency, the relationship of technology to nursing and caring, and a range of philosophical questions associated with empowering people in their healthcare choices. Specifically, there is a need to confront in practice the ways technique influences care. Technique is the creation of a kind of thinking that is necessary for contemporary healthcare technology to develop and be applied in an efficient and rational manner. Technique is not an entity or specific thing, but rather a way of thinking that seeks to shape and organize nursing activity, and manage efficiently individual difference(s) in care. It emphasizes predetermined causal relationships, conformity, and sameness of product, process, and thought. In response is needed a radical vision of nursing that attempts in a real sense to ensure we meet the needs of individuals and their community. Activism and advocacy are needed, and a willingness to create a certain detachment from the imperatives that technique demands. It is argued that our responsibility as nurses is to respond in practice to the errors, advantages, difficulties, and temptations of technology for the benefit of those who most need our assistance and care. PMID- 26511778 TI - Depression in Mexican Americans with diagnosed and undiagnosed diabetes. AB - BACKGROUND: Depression and diabetes commonly co-occur; however, the strength of the physiological effects of diabetes as mediating factors towards depression is uncertain. METHOD: We analyzed extensive clinical, epidemiological and laboratory data from n = 2081 Mexican Americans aged 35-64 years, recruited from the community as part of the Cameron County Hispanic Cohort (CCHC) divided into three groups: Diagnosed (self-reported) diabetes (DD, n = 335), Undiagnosed diabetes (UD, n = 227) and No diabetes (ND, n = 1519). UD participants denied being diagnosed with diabetes, but on testing met the 2010 American Diabetes Association and World Health Organization definitions of diabetes. Depression was measured using the Center for Epidemiological Studies - Depression (CES-D) scale. Weighted data were analyzed using dimensional and categorical outcomes using univariate and multivariate models. RESULTS: The DD group had significantly higher CES-D scores than both the ND and UD (p ? 0.001) groups, whereas the ND and UD groups did not significantly differ from each other. The DD subjects were more likely to meet the CES-D cut-off score for depression compared to both the ND and UD groups (p = 0.001), respectively. The UD group was also less likely to meet the cut-off score for depression than the ND group (p = 0.003). Our main findings remained significant in models that controlled for socio-demographic and clinical confounders. CONCLUSIONS: Meeting clinical criteria for diabetes was not sufficient for increased depressive symptoms. Our findings suggest that the 'knowing that one is ill' is associated with depressive symptoms in diabetic subjects. PMID- 26511780 TI - Chemical Signals of Synthetic Disaccharide Derivatives Dominate Rhamnolipids at Controlling Multiple Bacterial Activities. AB - Microbes secrete molecules that modify their environment. Here, we demonstrate a class of synthetic disaccharide derivatives (DSDs) that mimics and dominates the activity of naturally secreted rhamnolipids by Pseudomonas aeruginosa. The DSDs exhibit the dual function of activating and inhibiting the swarming motility through a concentration-dependent activity reversal that is characteristic of signaling molecules. Whereas DSDs tethered with a saturated farnesyl group exhibit inhibition of both biofilm formation and swarming motility, with higher activities than rhamnolipids, a saturated farnesyl tethered with a sulfonate group only inhibits swarming motility but promote biofilm formation. These results identified important structural elements for controlling swarming motility, biofilm formation, and bacterial adhesion and suggest an effective chemical approach to control intertwined signaling processes that are important for biofilm formation and motilities. PMID- 26511781 TI - Inflammatory cytokine biomarkers to identify women with asymptomatic sexually transmitted infections and bacterial vaginosis who are at high risk of HIV infection. AB - BACKGROUND: Untreated sexually transmitted infections (STIs) and bacterial vaginosis (BV) cause genital inflammation and increase the risk of HIV infection. WHO-recommended syndromic STI and BV management is severely limited as many women with asymptomatic infections go untreated. The purpose of this cross-sectional study was to evaluate genital cytokine profiles as a biomarker of STIs and BV to identify women with asymptomatic, treatable infections. METHODS: Concentrations of 42 cytokines in cervicovaginal lavages from 227 HIV-uninfected women were measured using Luminex. All women were screened for BV by microscopy and STIs using molecular assays. Multivariate analyses were used to identify cytokine profiles associated with STIs/BV. RESULTS: A multivariate profile of seven cytokines (interleukin (IL)-1alpha, IL-1beta, tumour necrosis factor-beta, IL-4, fractalkine, macrophage-derived chemokine, and interferon-gamma) most accurately predicted the presence of a treatable genital condition, with 77% classification accuracy and 75% cross-validation accuracy (sensitivity 72%; specificity 81%, positive predictive value (PPV) 86%, negative predictive value (NPV) 64%). Concomitant increased IL-1beta and decreased IP-10 concentrations predicted the presence of a treatable genital condition without a substantial reduction in predictive value (sensitivity 77%, specificity 72%, PPV 82% and NPV 65%), correctly classifying 75% of the women. This approach performed substantially better than clinical signs (sensitivity 19%, specificity 92%, PPV 79% and NPV 40%). CONCLUSIONS: Supplementing syndromic management with an assessment of IL 1beta and IP-10 as biomarkers of genital inflammation may improve STI/BV management for women, enabling more effective treatment of asymptomatic infections and potentially reducing their risk of HIV infection. PMID- 26511782 TI - Tunnelling conductive hybrid films of gold nanoparticles and cellulose and their applications as electrochemical electrodes. AB - Conductive hybrid films of metal nanoparticles and polymers have practical applications in the fields of sensing, microelectronics and catalysis, etc. Herein, we present the electrochemical availability of tunnelling conductive hybrid films of gold nanoparticles (GNPs) and cellulose.The hybrid films were provided with stable tunnelling conductive properties with 12 nm GNPs of 12.7% (in weight). For the first time, the conductive hybrid films were used as substrates of electrochemical electrodes to load calmodulin (CaM) proteins for sensing of calcium cations.The electrodes of hybrid films with 20 nm GNPs of 46.7% (in weight) exhibited stable electrochemical properties, and showed significant responses to calcium cations with concentrations as low as 10(-9) M after being loaded with CaM proteins. PMID- 26511786 TI - Peer Review Week 2015. PMID- 26511783 TI - Quality of care in patients with diabetic kidney disease in Asia: The Joint Asia Diabetes Evaluation (JADE) Registry. AB - AIMS: Diabetic kidney disease independently predicts cardiovascular disease and premature death. We examined the burden of chronic kidney disease (CKD, defined as an estimated GFR < 60 ml/min/1.73 m(2) ) and quality of care in a cross sectional survey of adults (age >= 18 years) with Type 2 diabetes across Asia. METHODS: The Joint Asia Diabetes Evaluation programme is a disease-management programme implemented using an electronic portal that systematically captures clinical characteristics of all patients enrolled. Between July 2007 and December 2012, data on 28 110 consecutively enrolled patients (China: 3415, Hong Kong: 15 196, India: 3714, Korea: 1651, Philippines: 3364, Vietnam: 692, Taiwan: 78) were analysed. RESULTS: In this survey, 15.9% of patients had CKD, 25.0% had microalbuminuria and 12.5% had macroalbuminuria. Patients with CKD were less likely to achieve HbA1c < 53 mmol/mol (7.0%) (36.0% vs. 42.3%) and blood pressure < 130/80 mmHg (20.8% vs. 35.3%), and were more likely to have retinopathy (26.2% vs. 8.7%), sensory neuropathy (29.0% vs. 7.7%), cardiovascular disease (26.6% vs. 8.7%) and self-reported hypoglycaemia (18.9% vs. 8.2%). Despite high frequencies of albuminuria (74.8%) and dyslipidaemia (93.0%) among CKD patients, only 49.0% were using renin-angiotensin system inhibitors and 53.6% were on statins. On logistic regression, old age, male gender, tobacco use, long disease duration, high HbA1c , blood pressure and BMI, and low LDL cholesterol were independently associated with CKD (all P < 0.05). CONCLUSIONS: The poor control of risk factors, suboptimal use of organ-protective drugs and high frequencies of hypoglycaemia highlight major treatment gaps in patients with diabetic kidney disease in Asia. PMID- 26511787 TI - Assessment of contribution of other users to own total whole-body RF absorption in train environment. AB - For the first time, the contribution of radio-frequent radiation originating from other people's devices to total own whole-body absorption is assessed in a simulation study. Absorption in a train environment due to base station's downlink is compared with absorption due to uplink (UL) of the user's own mobile device and absorption due to the UL of 0, 1, 5, or 15 other nearby active users. In a Global System for Mobile Communications (GSM) macro cell connection scenario, UL of 15 other users can cause up to 19% of total absorption when calling yourself and up to 100% when not calling yourself. In a Universal Mobile Telecommunications System (UMTS) femtocell connection scenario, UL of 15 other users contributes to total absorption of a non-calling user for no more than 1.5%. For five other users in the train besides the considered person, median total whole-body Specific Absorption Rate is reduced by a factor of about 400000 when deploying a UMTS femtocell base station instead of relying on the GSM macrocell. PMID- 26511788 TI - Suicide and Suicidal Attempts in the United States: Costs and Policy Implications. AB - The national cost of suicides and suicide attempts in the United States in 2013 was $58.4 billion based on reported numbers alone. Lost productivity (termed indirect costs) represents most (97.1%) of this cost. Adjustment for under reporting increased the total cost to $93.5 billion or $298 per capita, 2.1-2.8 times that of previous studies. Previous research suggests that improved continuity of care would likely reduce the number of subsequent suicidal attempts following a previous nonfatal attempt. We estimate a highly favorable benefit cost ratio of 6 to 1 for investments in additional medical, counseling, and linkage services for such patients. PMID- 26511789 TI - Microstructural white matter changes mediate age-related cognitive decline on the Montreal Cognitive Assessment (MoCA). AB - Although the relationship between aging and cognitive decline is well established, there is substantial individual variability in the degree of cognitive decline in older adults. The present study investigates whether variability in cognitive performance in community-dwelling older adults is related to the presence of whole brain or tract-specific changes in white matter microstructure. Specifically, we examine whether age-related decline in performance on the Montreal Cognitive Assessment (MoCA), a cognitive screening tool, is mediated by the white matter microstructural decline. We also examine if this relationship is driven by the presence of cardiovascular risk factors or variability in cerebral arterial pulsatility, an index of cardiovascular risk. Sixty-nine participants (aged 43-87) completed behavioral and MRI testing including T1 structural, T2-weighted FLAIR, and diffusion-weighted imaging (DWI) sequences. Measures of white matter microstructure were calculated using diffusion tensor imaging analyses on the DWI sequence. Multiple linear regression revealed that MoCA scores were predicted by radial diffusivity (RaD) of white matter beyond age or other cerebral measures. While increasing age and arterial pulsatility were associated with increasing RaD, these factors did not mediate the relationship between total white matter RaD and MoCA. Further, the relationship between MoCA and RaD was specific to participants who reported at least one cardiovascular risk factor. These findings highlight the importance of cardiovascular risk factors in the presentation of cognitive decline in old age. Further work is needed to establish whether medical or lifestyle management of these risk factors can prevent or reverse cognitive decline in old age. PMID- 26511790 TI - Reasons for Thiomicrospira crunogena's recalcitrance towards previous attempts to detect its hydrogen consumption ability. AB - The first Thiomicrospira species was isolated in 1972 and was described as a sulfur-oxidizing chemolithoautotroph. Since then, several other Thiomicrospira species have been recovered from around the globe and have been classified as common sulfur oxidizers. In the past, attempts to demonstrate hydrogen consumption of a Thiomicrospira species have failed. However, recently, we showed that some Thiomicrospira strains can indeed consume hydrogen. Here, we discuss why Thiomicrospira species have likely resisted efforts to consume hydrogen under the offered conditions. It appears that their hydrogen consumption ability is closely tied to the concentration of nickel in the medium. Investigated carbonate and thiosulfate concentrations did not appear to be critical for hydrogen utilization under the tested conditions. PMID- 26511791 TI - Dynamic weight bearing is an efficient and predictable method for evaluation of arthritic nociception and its pathophysiological mechanisms in mice. AB - The assessment of articular nociception in experimental animals is a challenge because available methods are limited and subject to investigator influence. In an attempt to solve this problem, the purpose of this study was to establish the use of dynamic weight bearing (DWB) as a new device for evaluating joint nociception in an experimental model of antigen-induced arthritis (AIA) in mice. AIA was induced in Balb/c and C57BL/6 mice, and joint nociception was evaluated by DWB. Western Blotting and real-time PCR were used to determine protein and mRNA expression, respectively. DWB detected a dose- and time-dependent increase in joint nociception during AIA and was able to detect the dose-response effects of different classes of analgesics. Using DWB, it was possible to evaluate the participation of spinal glial cells (microglia and astrocytes) and cytokines (IL 1beta and TNFalpha) for the genesis of joint nociception during AIA. In conclusion, the present results indicated that DWB is an effective, objective and predictable test to study both the pathophysiological mechanisms involved in arthritic nociception in mice and for evaluating novel analgesic drugs against arthritis. PMID- 26511792 TI - Development of an instrument to measure medical students' perceptions of the assessment environment: initial validation. AB - INTRODUCTION: Assessment environment, synonymous with climate or atmosphere, is multifaceted. Although there are valid and reliable instruments for measuring the educational environment, there is no validated instrument for measuring the assessment environment in medical programs. This study aimed to develop an instrument for measuring students' perceptions of the assessment environment in an undergraduate medical program and to examine the psychometric properties of the new instrument. METHOD: The Assessment Environment Questionnaire (AEQ), a 40 item, four-point (1=Strongly Disagree to 4=Strongly Agree) Likert scale instrument designed by the authors, was administered to medical undergraduates from the authors' institution. The response rate was 626/794 (78.84%). To establish construct validity, exploratory factor analysis (EFA) with principal component analysis and varimax rotation was conducted. To examine the internal consistency reliability of the instrument, Cronbach's alpha was computed. Mean scores for the entire AEQ and for each factor/subscale were calculated. Mean AEQ scores of students from different academic years and sex were examined. RESULTS: Six hundred and eleven completed questionnaires were analysed. EFA extracted four factors: feedback mechanism (seven items), learning and performance (five items), information on assessment (five items), and assessment system/procedure (three items), which together explained 56.72% of the variance. Based on the four extracted factors/subscales, the AEQ was reduced to 20 items. Cronbach's alpha for the 20-item AEQ was 0.89, whereas Cronbach's alpha for the four factors/subscales ranged from 0.71 to 0.87. Mean score for the AEQ was 2.68/4.00. The factor/subscale of 'feedback mechanism' recorded the lowest mean (2.39/4.00), whereas the factor/subscale of 'assessment system/procedure' scored the highest mean (2.92/4.00). Significant differences were found among the AEQ scores of students from different academic years. CONCLUSIONS: The AEQ is a valid and reliable instrument. Initial validation supports its use to measure students' perceptions of the assessment environment in an undergraduate medical program. PMID- 26511793 TI - Targeting TGR5 in cholangiocyte proliferation: default topic. PMID- 26511794 TI - TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice. AB - OBJECTIVE: Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible remain incompletely defined. VSG increases circulating bile acid concentrations and bile acid signalling through TGR5 improves glucose homeostasis. Therefore, we investigated the role of TGR5 signalling in mediating the glucoregulatory benefits of VSG. DESIGN: VSG or sham surgery was performed in high-fat-fed male Tgr5+/+ (wild type) and Tgr5-/- (knockout) littermates. Sham-operated mice were fed ad libitum or food restricted to match their body weight to VSG-operated mice. Body weight, food intake, energy expenditure, insulin signalling and circulating bile acid profiles were measured and oral glucose tolerance testing, islet immunohistochemistry and gut microbial profiling were performed. RESULTS: VSG decreased food intake and body weight, increased energy expenditure and circulating bile acid concentrations, improved fasting glycaemia, glucose tolerance and glucose-stimulated insulin secretion, enhanced nutrient-stimulated glucagon-like peptide 1 secretion and produced favourable shifts in gut microbial populations in both genotypes. However, the body weight-independent improvements in fasting glycaemia, glucose tolerance, hepatic insulin signalling, hepatic inflammation and islet morphology after VSG were attenuated in Tgr5-/- relative to Tgr5+/+ mice. Furthermore, VSG produced metabolically favourable alterations in circulating bile acid profiles that were blunted in Tgr5-/- relative to Tgr5+/+ mice. TGR5-dependent regulation of hepatic Cyp8b1 expression may have contributed to TGR5-mediated shifts in the circulating bile acid pool after VSG. CONCLUSIONS: These results suggest that TGR5 contributes to the glucoregulatory benefits of VSG surgery by promoting metabolically favourable shifts in the circulating bile acid pool. PMID- 26511796 TI - A rare cause of upper GI bleeding and wasting disease. PMID- 26511795 TI - The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia. AB - OBJECTIVE: Pneumonia accounts for more deaths than any other infectious disease worldwide. The intestinal microbiota supports local mucosal immunity and is increasingly recognised as an important modulator of the systemic immune system. The precise role of the gut microbiota in bacterial pneumonia, however, is unknown. Here, we investigate the function of the gut microbiota in the host defence against Streptococcus pneumoniae infections. DESIGN: We depleted the gut microbiota in C57BL/6 mice and subsequently infected them intranasally with S. pneumoniae. We then performed survival and faecal microbiota transplantation (FMT) experiments and measured parameters of inflammation and alveolar macrophage whole-genome responses. RESULTS: We found that the gut microbiota protects the host during pneumococcal pneumonia, as reflected by increased bacterial dissemination, inflammation, organ damage and mortality in microbiota-depleted mice compared with controls. FMT in gut microbiota-depleted mice led to a normalisation of pulmonary bacterial counts and tumour necrosis factor-alpha and interleukin-10 levels 6 h after pneumococcal infection. Whole-genome mapping of alveolar macrophages showed upregulation of metabolic pathways in the absence of a healthy gut microbiota. This upregulation correlated with an altered cellular responsiveness, reflected by a reduced responsiveness to lipopolysaccharide and lipoteichoic acid. Compared with controls, alveolar macrophages derived from gut microbiota-depleted mice showed a diminished capacity to phagocytose S. pneumoniae. CONCLUSIONS: This study identifies the intestinal microbiota as a protective mediator during pneumococcal pneumonia. The gut microbiota enhances primary alveolar macrophage function. Novel therapeutic strategies could exploit the gut-lung axis in bacterial infections. PMID- 26511798 TI - Impeding Sudden Cardiac Death Despite Subcutaneous Implantable Defibrillator Due to Fatal Crosstalk. PMID- 26511797 TI - Bacterial infection in compensated viral cirrhosis impairs 5-year survival (ANRS CO12 CirVir prospective cohort). AB - OBJECTIVE: To assess incidence and prognostic significance of bacterial infections (BIs) occurring in compensated viral cirrhosis. DESIGN: This prospective study involved 35 French centres. Inclusion criteria were biopsy proven HCV or HBV cirrhosis, Child-Pugh A and no previous hepatic complications. Cumulative incidence (CumI) of events was estimated in a competing risks framework. RESULTS: 1672 patients were enrolled (HCV 1323, HBV 318, HCV-HBV 31). During a median follow-up of 43 months, 234 BIs occurred in 171 patients (5 year CumI: 12.9%), among whom 14.6% had septic shock. Main localisations included the urinary tract (27.4%), lung (25.2%) and peritoneum (10.7%) (other, 86 (36.7%)). Most BIs occurred as a first event prior to liver decompensation (n=140, 81.8%) and were community-acquired (CA, 84.2%). The risk of BI was higher in patients with HCV than in patients with HBV (5 year CumI: 15.2% vs 5.5%, p=0.0008). Digestive localisation, concomitant interferon-based treatment, isolation of resistant bacteria and non-CA BIs were associated with lowest probability of resolution. The occurrence of a first BI impaired survival in patients infected with HCV (5 year survival: 60.2% vs 90.4%, p<0.001) and patients infected with HBV (5 year survival: 69.2% vs 97.6%, p<0.001). BIs represented the third cause of death (14.1%) after liver failure and liver cancer. BI risk factors comprised older age, lower albumin, proton pump inhibitor intake and absence of virological eradication/control. CONCLUSION: BI mostly occurs as a first complication and represents a turning point in the course of compensated viral cirrhosis. Its occurrence impacts long-term prognosis and may define a subgroup of patients in whom adaptation of management is warranted. PMID- 26511799 TI - Self-wise, Other-wise, Streetwise (SOS) training: a novel intervention to reduce victimization in dual diagnosis psychiatric patients with substance use disorders: protocol for a randomized controlled trial. AB - BACKGROUND: Psychiatric patients are more likely to be victims of crime than others in the community. Dual diagnosis patients with comorbid psychiatric and substance use disorders are especially prone to victimization. Victimization is associated with substance abuse, more severe symptomatology and homelessness. There is a strong need for interventions to reduce victimization in this population. We developed the Self-wise, Other-wise, Streetwise (SOS) training to reduce victimization in patients with dual diagnosis. METHODS/DESIGN: This study is a randomized controlled trial using a parallel group design to determine the effectiveness of adding the SOS training to care as usual. Patients with dual diagnosis (N = 250) will be allocated to either care as usual plus SOS training (N = 125) or care as usual only (N = 125) using computer-generated stratified block randomization. To compare effectiveness participants will be interviewed at baseline and 2, 8 and 14 months follow-up. The primary outcome measure is treatment response (yes/no), defined as either no victimization at 14 months follow-up or at least a 50% reduction in incidents of victimization at 14 months follow-up compared to baseline assessment. Victimization is measured with the Safety Monitor, an adequate self-report instrument used by Statistics Netherlands to measure victimization on a large scale in the Netherlands. Outcome assessors are blind to treatment allocation. An economic evaluation will be performed alongside the randomized controlled trial and will take the societal perspective. DISCUSSION: This study is the first randomized controlled trial to examine the effectiveness of an intervention that aims to reduce victimization in patients with dual diagnosis. If the intervention is effective it can be implemented in mental health care and contribute to the safety and well-being of patients. TRIAL REGISTRATION: Dutch Trial Register (NTR): 4472, date of registration: 24-03-2014. PMID- 26511800 TI - Adjuvant Treatment after Surgery in Stage IIIA Endometrial Adenocarcinoma. AB - PURPOSE: We evaluated the role of adjuvant therapy in stage IIIA endometrioid adenocarcinoma patients who underwent surgery followed by radiotherapy (RT) alone or chemoradiotherapy (CTRT) according to risk group. MATERIALS AND METHODS: A multicenter retrospective study was conducted including patients with surgical stage IIIA endometrial cancertreated by radical surgery and adjuvant RT or CTRT. Disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: Ninety-three patients with stage IIIA disease were identified. Nineteen patients (20.4%) experienced recurrence, mostly distant metastasis (17.2%). Combined CTRT did not affect DFS (74.1% vs. 82.4%, p=0.130) or OS (96.3% vs. 91.9%, p=0.262) in stage IIIA disease compared with RT alone. Patients with age >= 60 years, grade G2/3, and lymphovascular space involvement had a significantly worse DFS and those variables were defined as risk factors. The high-risk group showed a significant reduction in 5-year DFS (>= 2 risk factors) (49.0% vs. 88.0%, p < 0.001) compared with the low-risk group (< 2). Multivariate analysis confirmed that more than one risk factor was the only predictor of worse DFS (hazard ratio, 5.45; 95% confidence interval, 2.12 to 13.98; p < 0.001). Of patients with no risk factors, a subset treated with RT alone showed an excellent 5-year DFS and OS (93.8% and 100%, respectively). CONCLUSION: We identified a low-risk subset of stage IIIA endometrioid adenocarcinoma patients who might be reasonable candidates for adjuvant RT alone. Further randomized studies are needed to determine which subset might benefit from combined CTRT. PMID- 26511801 TI - Delay of Treatment Initiation Does Not Adversely Affect Survival Outcome in Breast Cancer. AB - PURPOSE: Previous studies examining the relationship between time to treatment and survival outcome in breast cancer have shown inconsistent results. The aim of this study was to analyze the overall impact of delay of treatment initiation on patient survival and to determine whether certain subgroups require more prompt initiation of treatment. MATERIALS AND METHODS: This study is a retrospective analysis of stage I-III patients who were treated in a single tertiary institution between 2005 and 2008. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of interval between diagnosis and treatment initiation in breast cancer and various subgroups. RESULTS: A total of 1,702 patients were included. Factors associated with longer delay of treatment initiation were diagnosis at another hospital, medical comorbidities, and procedures performed before admission for surgery. An interval between diagnosis and treatment initiation as a continuous variable or with a cutoff value of 15, 30, 45, and 60 days had no impact on disease-free survival (DFS). Subgroup analyses for hormone-responsiveness, triple-negative breast cancer, young age, clinical stage, and type of initial treatment showed no significant association between longer delay of treatment initiation and DFS. CONCLUSION: Our results show that an interval between diagnosis and treatment initiation of 60 days or shorter does not appear to adversely affect DFS in breast cancer. PMID- 26511802 TI - In Vitro Adenosine Triphosphate-Based Chemotherapy Response Assay as a Predictor of Clinical Response to Fluorouracil-Based Adjuvant Chemotherapy in Stage II Colorectal Cancer. AB - PURPOSE: We evaluated the usefulness of the in vitro adenosine triphosphate-based chemotherapy response assay (ATP-CRA) for prediction of clinical response to fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer. MATERIALS AND METHODS: Tumor specimens of 86 patients with pathologically confirmed stage II colorectal adenocarcinoma were tested for chemosensitivity to fluorouracil. Chemosensitivity was determined by cell death rate (CDR) of drug-exposed cells, calculated by comparing the intracellular ATP level with that of untreated controls. RESULTS: Among the 86 enrolled patients who underwent radical surgery followed by fluorouracil-based adjuvant chemotherapy, recurrence was found in 11 patients (12.7%). The CDR >= 20% group was associated with better disease-free survival than the CDR < 20% group (89.4% vs. 70.1%, p=0.027). Multivariate analysis showed that CDR < 20% and T4 stage were poor prognostic factors for disease-free survival after fluorouracil-based adjuvant chemotherapy. CONCLUSION: In stage II colorectal cancer, the in vitro ATP-CRA may be useful in identifying patients likely to benefit from fluorouracil-based adjuvant chemotherapy. PMID- 26511803 TI - What Is the Ideal Tumor Regression Grading System in Rectal Cancer Patients after Preoperative Chemoradiotherapy? AB - PURPOSE: Tumor regression grade (TRG) is predictive of therapeutic response in rectal cancer patients after chemoradiotherapy (CRT) followed by curative resection. However, various TRG systems have been suggested, with subjective categorization, resulting in interobserver variability. This study compared the prognostic validity of four different TRG systems in order to identify the most ideal TRG system. MATERIALS AND METHODS: This study included 933 patients who underwent preoperative CRT and curative resection. Primary tumors alone were graded according to the American Joint Committee on Cancer (AJCC), Dworak, and Ryan TRG systems, and both primary tumors and regional lymph nodes were graded according to a modified Dworak TRG system. The ability of each TRG system to predict recurrence-free survival (RFS) and overall survival (OS) was analyzed using chi-square and C statistics. RESULTS: All four TRG systems were significantly predictive of both RFS and OS (p < 0.001 each), however none was a better predictor of prognosis than ypStage. Among the four TRGs, the mDworak TRG system was a better predictor of RFS and OS than the AJCC, Dworak, and Ryan TRG systems, and both the chi-square and C statistics were higher for the former, although the differences were not statistically significant. The combination of ypStage and the modified Dworak TRG better predicted RFS and OS than ypStage alone. CONCLUSION: The modified Dworak TRG system for evaluation of entire tumors including regional lymph nodes is a better predictor of survival than current TRG systems for evaluation of the primary tumor alone. PMID- 26511804 TI - Changing Patterns of Primary Treatment in Korean Men with Prostate Cancer Over 10 Years: A Nationwide Population Based Study. AB - PURPOSE: We investigated changing patterns of primary treatment in Korean men with prostate cancer (PC) and impact of sociodemographic factors on treatment choice from a nationwide cohort over 10 years. MATERIALS AND METHODS: We conducted a cohort study of a 2% nationwide random sample of Korean National Health Insurance. A total of 1,382 patients who had undergone active treatments for newly diagnosed PC between 2003 and 2013 were included. Time trends in primary treatment of PC, including radical surgery, radiation therapy (RT), and androgen deprivation therapy (ADT) were analyzed. RESULTS: Total number of patients undergoing active treatments increased significantly (162%). Surgery cases showed the most significant increase, from 22.4% in 2003 to 45.4% in 2013, while the relative proportion of ADT showed a tendency to decrease from 60.3% in 2003 to 45.4% in 2013, and the relative proportion of RT was variable over 10 years (from 7.2% to 18.4%). While treatment patterns differed significantly according to age (p < 0.001) and income classes (p=0.014), there were differences in primary treatment according to residential area. In multinomial logistic regression analysis, older patients showed significant association with ADT or RT compared to surgery, while patients with higher income showed significant association with surgery. CONCLUSION: Treatment pattern in Korean PC patients has changed remarkably over the last 10 years. Sociodemographic factors do affect the primary treatment choice. Our results will be valuable in overviewing changing patterns of primary treatment in Korean PC patients and planning future health policy for PC. PMID- 26511805 TI - Concurrent Chemoradiotherapy Versus Chemotherapy Alone for Unresectable Locally Advanced Pancreatic Cancer: A Retrospective Cohort Study. AB - PURPOSE: The optimal treatment strategy for locally advanced pancreatic cancer (LAPC), particularly the role of concurrent chemoradiotherapy (CCRT), remains debatable. We compared the clinical outcomes of CCRT and palliative chemotherapy alone (CA) in patients with unresectable LAPC. MATERIALS AND METHODS: Patients with LAPC who were consecutively treated between 2003 and 2010 were included. Resectability was evaluated according to National Comprehensive Cancer Network ver. 1.2012. The clinical outcomes for each treatment group (CCRT vs. CA) were evaluated retrospectively. RESULTS: Sixty-three patients (58.9%) and 44 patients (41.1%) were treated with CCRT and CA, respectively. The CCRT cohort included patients who were treated with CCRT with or without chemotherapy backbone (CCRT alone, induction chemotherapy-CCRT, CCRT-maintenance chemotherapy, and induction CCRT-maintenance chemotherapy). Median progression-free survival (PFS) and overall survival (OS) of all patients were 7.2 months and 13.1 months. PFS of the CCRT and CA groups was 9.0 months and 4.4 months, respectively (p=0.020). OS of the CCRT and CA groups was 15.4 months and 9.3 months, respectively (p=0.011). In multivariate analysis, the adjusted hazard ratio of CCRT was 0.536 (p=0.003) for OS and 0.667 (p=0.078) for PFS. Although the pattern of failure was similar in the CCRT and CA groups, the times to both local and distant failure were significantly longer in the CCRT group. CONCLUSION: In patients with unresectable LAPC, those who underwent CCRT during their entire treatment courses had longer OS than patients treated with chemotherapy alone. PMID- 26511806 TI - The Overexpression of CCAR1 in Hepatocellular Carcinoma Associates with Poor Prognosis. AB - PURPOSE: Cell division cycle and apoptosis regulator 1 (CCAR1) plays a dynamic role in regulation of cell growth and apoptosis by serving as a cofactor of steroid/thyroid nuclear receptors, beta-catenin, and p53 in a variety of cell types including different cancer cells. However, whether CCAR1 protein is overexpressed in hepatocellular carcinoma (HCC) and the prognostic significance of CCAR1 protein expression in HCC have not been reported. MATERIALS AND METHODS: In 167 HCC patients with long-term follow-up, CCAR1 protein expression was examined by immunohistochemistry. RESULTS: High CCAR1 protein expression was observed in 149 of the 167 HCC cases (89.2%) and showed significant correlation with microvascular invasion, intrahepatic metastasis, higher American Joint Committee on Cancer (AJCC) T stage, and early recurrence. High CCAR1 expression showed an unfavorable effect on recurrence-free survival (RFS) (p=0.002). In subgroup analysis, among patients with alpha-fetoprotein <= 20 ng/mL (n=54) and patients with AJCC T stage 1 (n=62), significant differences in RFS were observed between high CCAR1 expression groups and low CCAR1 expression groups (p=0.015 and p=0.004, respectively). High CCAR1 expression tended to be an independent predictor of shorter RFS (p=0.054) and showed an unfavorable effect on overall survival (OS) (p=0.015). In subgroup analysis, among patients with alpha fetoprotein <= 20 ng/mL (n=54), significant difference in OS was observed between high CCAR1 expression group and low CCAR1 expression group (p=0.046). CONCLUSION: CCAR1 protein could be a potential biomarker predicting RFS in HCC patients after curative hepatectomy. In addition, CCAR1 had prognostic values in HCC patients with normal serum alpha-fetoprotein levels or early stage HCC. PMID- 26511807 TI - Tolerability and Outcomes of First-Line Pemetrexed-Cisplatin Followed by Gefitinib Maintenance Therapy Versus Gefitinib Monotherapy in Korean Patients with Advanced Nonsquamous Non-small Cell Lung Cancer: A Post Hoc Descriptive Subgroup Analysis of a Randomized, Phase 3 Trial. AB - PURPOSE: We recently reported on a randomized, open-label, phase 3 trial comparing pemetrexed-cisplatin chemotherapy followed by gefitinib maintenance therapy (PC/G) with gefitinib monotherapy in patients with non-small cell lung cancer (NSCLC). Here, we report on a post hoc subgroup analysis of that study assessing the demographics and disposition of the Korean patient subgroup, and comparing the tolerability of PC/G and gefitinib monotherapy and the tumor response with respect to epidermal growth factor receptor (EGFR) status. MATERIALS AND METHODS: Patients, who were >= 18 years, chemonaive, Korean, light ex-smokers/never-smokers with advanced NSCLC, were randomly assigned (1:1) to PC/G or gefitinib monotherapy. Treatment-emergent adverse events (TEAEs) were graded, and tumor response was measured as change in lesion sum from baseline at best response. The study was registered with ClinicalTrials. gov, NCT01017874. RESULTS: Overall, 111 Korean patients were treated (PC/G, 51; gefitinib, 60). Between-arm characteristics were balanced and similar to those of the overall population. Treatment discontinuations due to adverse events were low (PC/G: 1, 2.0%; gefitinib: 7, 11.7%). Overall, 92 patients (82.9%) reported >= 1 TEAE (PC/G, 44; gefitinib, 48); few patients (PC/G, 16; gefitinib, 7) reported severe TEAEs; the most frequent was neutropenia (PC/G arm) and elevated alanine aminotransferase (gefitinib arm). The lesion sum was decreased by PC/G treatment in most patients, regardless of EGFR mutation status, while gefitinib monotherapy reduced the lesion sum in EGFR-positive patients but had no effect in EGFR negative patients. CONCLUSION: Our results confirm that both PC/G and gefitinib were well tolerated in Korean patients, regardless of EGFR status; however, patients with EGFR wild-type NSCLC may not benefit from gefitinib monotherapy. PMID- 26511808 TI - Adopting Advance Directives Reinforces Patient Participation in End-of-Life Care Discussion. AB - PURPOSE: In Korea, most terminal cancer patients have still not been included in end-of-life (EOL) discussions. The purpose of this study was to evaluate the proportion of patients participating in EOL discussions after adopting advance directives. MATERIALS AND METHODS: Medical records of 106 hospice patients between July 2012 and February 2013 were reviewed retrospectively. The proportion of patient participation in EOL discussions, barriers, and favorable factors for completion of advance directives, as well as outcomes of advance directives were evaluated. RESULTS: Patient participation in EOL discussion had increased from 16/53 (30%) to 27/53 (51%) since adopting advance directives (p < 0.001). Median time between completion of an advance directive and death increased from 8 days (range, 0 to 22 days) to 14.5 days (range, 0 to 47 days). Patients' poor condition after late referral was the main barrier to missing EOL discussions; however, family members' concerns about patient's distress was also a main reason for excluding the patient from EOL discussions. In univariate analysis, patient age, education status, and time from diagnosis to completion of an advance directive influenced advance directive completion favorably. Following multivariate analysis, higher education and periods of more than 2 years from diagnosis to completion of an advance directive remained favorable (odds ratio [OR], 9.586, p=0.024 and OR, 70.312; p=0.002). Preferences of all patients regarding cardiopulmonary resuscitation or hemodialysis were carried out by physicians. Orders for nutrition and palliative sedation showed discordance, with concordance rates of 74.2% and 51.6%, respectively. CONCLUSION: Our results suggested that the use of advance directive promote patient participation in EOL discussion. PMID- 26511809 TI - Dental Anomalies as Late Adverse Effect among Young Children Treated for Cancer. AB - PURPOSE: The aim of this study was to compare the incidence of dental complications in childhood cancer survivors with that of healthy control subjects, and to determine the possible influence of various factors associated with patient and treatment. MATERIALS AND METHODS: Sixty-one panoramic radiographs of the dentition of cancer survivors were compared with 521 radiographs of healthy patients at a similar age, between 5 and 18 years. The mean period from termination of therapy was 4.9 years (58.9 +/- 34.3 months), and 51 children (83.60%) were under age 5 when therapy began. RESULTS: Dental anomalies were found in 38 cancer survivors (62.29%) and 69 control subjects (13.24%) (p < 0.001). Agenesis of teeth was found in 19 cancer patients (31.14%) and in 48 control subjects (9.21%). Microdontic teeth were found in 22 cancer survivors (36.06%) and 15 control subjects (2.87%) (p < 0.001), whereas teeth with short roots were found in seven cancer patients (11.47%) and 15 control subjects (2.87%) (p < 0.01). Dental anomalies in cancer patients were more common in some tooth groups and were not observed in others. The frequency of dental anomalies did not show correlation with age at the beginning or termination or time of therapy. CONCLUSION: Children under the age of 5 are in a high risk group for dental complications after anticancer treatment. Rudimentary chemotherapy has a considerable impact on the occurrence of dental anomalies. PMID- 26511810 TI - Association between Health Behaviors and a Family History of Cancer among Korean Women. AB - PURPOSE: The aim of this study was to examine the health-related behaviors related to a family history of cancer (FHCA) among Korean women underwent cancer screening. MATERIALS AND METHODS: A total of 8,956 women who underwent cancer screenings during 2001-2011 at the National Cancer Center, Korea, were analyzed. The association between health-related behaviors and a FHCA were assessed using multivariate logistic regression. RESULTS: Compared to women with no FHCA, women with FHCA were more likely to smoke (adjusted odds ratio [aOR], 1.32; 95% confidence interval [CI], 1.06 to 1.65), to be exposed to passive smoking (aOR, 1.21; 95% CI, 1.15 to 1.65), and less likely to engage in regular exercise (aOR, 1.20; 95% CI, 1.01 to 1.41). Combined effects of selected health behaviors for FHCA were significant, although no statistically significant interactions were observed between selected health behaviors. Compared to women with no FHCA, women with FHCA were more likely to simultaneously smoke and be exposed to passive smoking (aOR, 1.65; 95% CI, 1.17 to 2.31) and to simultaneously smoke and be physically inactive (aOR, 1.62; 95% CI, 1.00 to 2.64). CONCLUSION: The study found that women with a FHCA exhibited unhealthy behaviors compared to women without FHCA. Higher emphasis on lifestyle modifications using a new standardized tool is strongly recommended for those with a FHCA, as well as individuals who are at high risk, together with their family members. PMID- 26511811 TI - Aberrant Epigenetic Modifications of LPHN2 Function as a Potential Cisplatin Specific Biomarker for Human Gastrointestinal Cancer. AB - PURPOSE: Epigenetic alterations of specific genes have recently been identified as diagnostic biomarkers for human cancers. However, there are currently no standardized epigenetic biomarkers for drug sensitivity in human gastrointestinal cancer. Therefore, the aim of this study is to identify a novel epigenetic biomarker in gastrointestinal cancer. MATERIALS AND METHODS: Using bisulfite sequencing and pyrosequencing analysis, DNA methylation patterns of gastric, colon primary tissues and their cancer cells were analyzed, and histone modifications were analyzed using chromatin immunoprecipitation assay. In addition, cancer cells were exposed to cisplatin and treated with a DNA methyltransferase inhibitor. RESULTS: We report that in human gastric and colon cancers, latrophilin 2 (LPHN2) is silenced by epigenetic modifications, including CpG island methylation and aberrant histone modifications. We also confirmed that LPHN2 was silenced by DNA hypermethylation in primary gastric and colon tumor tissues compared to their normal counterparts. Interestingly, we found that cancer cells with methylated LPHN2 showed higher sensitivity to cisplatin. Also, 5-aza- 2'-deoxycytidine combined with cisplatin decreased the cytotoxicity of cisplatin in cancer cells with methylated LPHN2. In addition, LPHN2 knockdown in cancer cells with high LPHN2 expression sensitized these cells to the anti proliferative effects of cisplatin. CONCLUSION: In human gastrointestinal cancer, we found that LPHN2 is regulated by epigenetic modifications, and that cancer cells with lower LPHN2 expression show higher sensitivity to cisplatin. Therefore, the methylation status of LPHN2 is a potential novel epigenetic biomarker for cisplatin treatment in human gastric and colon cancers. PMID- 26511812 TI - Endoscopic Criteria for Evaluating Tumor Stage after Preoperative Chemoradiation Therapy in Locally Advanced Rectal Cancer. AB - PURPOSE: Local excision may be an another option for selected patients with markedly down-staged rectal cancer after preoperative chemoradiation therapy (CRT), and proper evaluation of post-CRT tumor stage (ypT) is essential prior to local excision of these tumors. This study was designed to determine the correlations between endoscopic findings and ypT of rectal cancer. MATERIALS AND METHODS: In this study, 481 patients with locally advanced rectal cancer who underwent preoperative CRT followed by surgical resection between 2004 and 2013 at a single institution were evaluated retrospectively. Pathological good response (p-GR) was defined as ypT <= 1, and pathological minimal or no response (p-MR) as ypT >= 2. The patients were randomly classified according to two groups, a testing (n=193) and a validation (n=288) group. Endoscopic criteria were determined from endoscopic findings and ypT in the testing group and used in classifying patients in the validation group as achieving or not achieving p-GR. RESULTS: Based on findings in the testing group, the endoscopic criteria for p-GR included scarring, telangiectasia, and erythema, whereas criteria for p-MR included nodules, ulcers, strictures, and remnant tumors. In the validation group, the kappa statistic was 0.965 (p < 0.001), and the sensitivity, specificity, positive predictive value, and negative predictive value were 0.362, 0.963, 0.654, and 0.885, respectively. CONCLUSION: The endoscopic criteria presented are easily applicable for evaluation of ypT after preoperative CRT for rectal cancer. These criteria may be used for selection of patients for local excision of down-staged rectal tumors, because patients with p-MR could be easily ruled out. PMID- 26511813 TI - Caveolin-1 Modulates Docetaxel-Induced Cell Death in Breast Cancer Cell Subtypes through Different Mechanisms. AB - PURPOSE: Caveolin-1 (CAV-1) expression is more associated with basal-like cancers than estrogen receptor- or ErbB-2-expressing breast cancers. However, the biological relevance of different levels of CAV-1 expression according to subtype in the epithelial compartment of breast cancer remains unclear. MATERIALS AND METHODS: We investigated whether CAV-1 functions as a tumor suppressor and/or modulator of the cytotoxic activity of docetaxel (DTX) in subtypes of breast cancer using in vitro and xenograft models. RESULTS: The levels of CAV-1 expression were closely associated with DTX sensitivity in triple-negative breast cancer cells. In addition, CAV-1 significantly inhibited cell proliferation and modulated DTX-induced apoptosis through cell cycle arrest in the G2/M phase. The mechanisms underlying DTX-induced apoptosis differed in breast cancers according to the levels of CAV-1 expression. DTX robustly enhanced Bcl-2 inactivation by CAV-1 in MDA-MB-231 cells, while p53-mediated cell cycle arrest by DTX was more pronounced in CAV-1-low but p53-functional MCF-7 cells. In parallel with the data from breast cancer cell lines, CAV-1-transfected MCF-7 cells showed higher efficacy of DTX treatment in a xenograft model. CONCLUSION: We clearly demonstrated cooperative effects between CAV-1 and DTX in mediating apoptosis, suggesting that the levels of CAV-1 expression might be an important indicator for DTX use in breast cancer. PMID- 26511814 TI - Association Between PD-L1 and HPV Status and the Prognostic Value of PD-L1 in Oropharyngeal Squamous Cell Carcinoma. AB - PURPOSE: Oropharyngeal squamous cell carcinoma (OSCC) has been recognized as an immunosuppressive disease. Various mechanisms have been proposed for immune escape, including dysregulation of immune checkpoints such as the PD-1:PD-L1 pathway. We investigated the expression of programmed cell death-ligand 1 (PD-L1) in HPV-negative and HPV-positive OSCC to determine its prevalence and prognostic relevance. MATERIALS AND METHODS: Using immunohistochemistry, 133 cases of OSCC were evaluated for expression of PD-L1. Formalin-fixed paraffin-embedded tumor samples were stained with monoclonal antibody (clone 5H1) to PD-L1. PD-L1 positivity was defined as membrane staining in >=20% of tumor cells. Correlations between PD-L1 expression and HPV status and survival parameters were analyzed. RESULTS: Of the 133 patients, 68% showed PD-L1 expression, and 67% of patients were positive for p16 expression by immunohistochemistry. No significant difference in PD-L1 expression was observed between HPV(-) and HPV(+) tumors (61% vs. 71%, p=0.274). No significant difference in age, gender, smoking history, location of tumor origin, or stage was observed according to PD-L1 status. With a median follow-up period of 44 months, older age (>=65) (p=0.017) and T3-4 stage (p<0.001) were associated with poor overall survival (OS), whereas PD-L1 expression did not affect OS in univariate and multivariate analysis. CONCLUSION: PD-L1 expression was observed in the majority of OSCC patients regardless of HPV status. Further large prospective studies are required to determine the role of PD-L1 expression as a prognostic or predictive biomarker, and clinical studies of immune checkpoint inhibitors in OCSS are warranted regardless of HPV status. PMID- 26511815 TI - A Korean Nationwide Survey for Breakthrough Cancer Pain in an Inpatient Setting. AB - PURPOSE: We evaluated the prevalence and characteristics of breakthrough cancer pain (BTcP) in Korean patients admitted with cancer pain. MATERIALS AND METHODS: In-hospital patients with cancer pain completed a questionnaire concerning severity of background cancer pain (BCP), prevalence and treatment for BTcP, sleep disorders, and satisfaction with cancer pain treatment. Medical records showing medications for BCP and BTcP were also evaluated. RESULTS: Total 609 patients with controlled BCP enrolled. Mean age of the patients was 59.5 years old, and 59% were male. Of all patients, 177 (29%) complained of BTcP. No clinical characteristic predicted BTcP. Of the 177 patients with BTcP, 56% did not receive treatment for BTcP. Patients with BTcP showed significant association with a sleep disorder and dissatisfaction with pain control, compared to those without BTcP (p < 0.0001 and p=0.0498, respectively). Oxycodone-immediate release was the most commonly used short-acting analgesic, followed by intravenous morphine. CONCLUSION: The prevalence of BTcP was 29% in patients admitted with controlled BCP. Although the patients had well-controlled BCP, BTcP showed association with a lower quality of life in patients with cancer. More medical attention is needed for detection and management of BTcP. PMID- 26511816 TI - Anti-cancer Effect of Luminacin, a Marine Microbial Extract, in Head and Neck Squamous Cell Carcinoma Progression via Autophagic Cell Death. AB - PURPOSE: The purpose of this study is to determine whether luminacin, a marine microbial extract from the Streptomyces species, has anti-tumor effects on head and neck squamous cell carcinoma (HNSCC) cell lines via autophagic cell death. MATERIALS AND METHODS: Inhibition of cell survival and increased cell death was measured using cell viability, colony forming, and apoptosis assays. Migration and invasion abilities of head and cancer cells were evaluated using wound healing, scattering, and invasion assays. Changes in the signal pathway related to autophagic cell death were investigated. Drug toxicity of luminacin was examined in in vitro HaCaT cells and an in vivo zebrafish model. RESULTS: Luminacin showed potent cytotoxicity in HNSCC cells in cell viability, colony forming, and fluorescence-activated cell sorting analysis. In vitro migration and invasion of HNSCC cells were attenuated by luminacin treatment. Combined with Beclin-1 and LC3B, Luminacin induced autophagic cell death in head and neck cancer cells. In addition, in a zebrafish model and human keratinocyte cell line used for toxicity testing, luminacin treatment with a cytotoxic concentration to HNSCC cells did not cause toxicity. CONCLUSION: Taken together, these results demonstrate that luminacin induces the inhibition of growth and cancer progression via autophagic cell death in HNSCC cell lines, indicating a possible alternative chemotherapeutic approach for treatment of HNSCC. PMID- 26511817 TI - Conditional Survival and Associated Prognostic Factors in Patients with Upper Tract Urothelial Carcinoma after Radical Nephroureterectomy: A Retrospective Study at a Single Institution. AB - PURPOSE: The purpose of this study is to evaluate the changes of conditional survival (CS) probabilities and to identify the prognostic parameters that significantly affect CS over time post-surgery in upper tract urothelial carcinoma (UTUC) patients. MATERIALS AND METHODS: A total of 330 patients were examined in the final analysis. Primary end point was conditional cancer-specific survival (CSS), overall survival (OS), and intravesical recurrence-free survival (IVRFS) after surgery. The Kaplan-Meier method was used for calculation of CS. Cox regression hazard ratio model was used to determine the predictors of CS. RESULTS: UTUC patients who had already survived 5 years after radical nephroureterectomy had a more favorable CS probability in all given survivorships compared to those with shorter survival times. Patients with unfavorable pathologic features showed a higher increment of 5-year conditional CSS and OS compared to their counterparts. For 5-year conditional CSS, several factors, including high-grade tumor, lymphovascular invasion, and tumor location showed significant association with risk elevation over time. Only age remained as a predictor of 5-year conditional OS with increased risk in all given survivorships. For 5-year IVRFS, no variables remained as significant predictive factors over time after surgery. CONCLUSION: Our study provides valuable information for practical survival estimation and relevant prognostic factors for patients with UTUC after surgery. PMID- 26511818 TI - (18)F-FDG/PET May Help to Identify a Subgroup of Patients with T1-T2 Breast Cancer and 1-3 Positive Lymph Nodes Who Are at a High Risk of Recurrence after Mastectomy. AB - PURPOSE: The purpose of this study is to assess the utility of positron emission tomography (PET) for predicting recurrence among patients with T1-T2/N1 breast cancer who were treated with mastectomy. MATERIALS AND METHODS: Of 712 consecutive patients with T1-T2/N1 breast cancer treated during 2003-2012, 109 had undergone preoperative (18)F-fluorodeoxyglucose/PET and were included. Metabolic (maximum standardized uptake value [SUVmax]), volumetric (metabolic tumor volume [MTV]), and combined (total lesion glycolysis [TLG]) indices were measured. The resulting values were analyzed and compared with clinical outcome. RESULTS: At the median follow-up of 46.7 months, the 3-year relapse-free survival (RFS) rate was 95.2%. SUVmax (area under curve, 0.824) was more useful than MTV or TLG as a means of identifying patients at high risk for any recurrence. In multivariate analysis, SUVmax remained an independent risk factor for RFS (p=0.006). Using the method of Contal and O'Quigley, a SUVmax threshold of 5.36 showed the best predictive performance. The PET-based high-risk group (>= 5.36 in either breast or nodes) had more T1c-T2, high-grade, hormone-receptor negative, and invasive ductal carcinoma tumors than the low-risk group (< 5.36 in both breast and nodes). The prognosis was much worse when high SUVmax (>= 5.36) was detected in nodes (p < 0.001). In the no-radiotherapy cohort, the PET-based high risk group had increased risk of locoregional recurrence when compared to the low risk group (p=0.037). CONCLUSION: High SUVmax on preoperative PET showed association with elevated risk of locoregional recurrence and any recurrence. Pre treatment PET may improve assessments of recurrence risk and clarify indications for post-mastectomy radiotherapy in this subset of patients. PMID- 26511819 TI - Dermatoepidemiology; what's up people? PMID- 26511820 TI - Measuring quality of dermatology care from the patient's perspective: how was it for you? PMID- 26511821 TI - Nails - more than just an ectodermal appendage: the genetics behind isolated nail disorders. PMID- 26511822 TI - Interleukin-23 inhibition for the treatment of psoriasis: the next frontier for high-efficacy biologic therapy. PMID- 26511823 TI - Resin lacquer: a cheaper alternative to amorolfine for onychomycosis? PMID- 26511824 TI - Atopic eczema and nonatopic eczema show the same pattern in an adolescent general population. PMID- 26511825 TI - Measuring cutaneous symptoms of dermatomyositis: an important step towards objective monitoring of disease course and treatment response as a basis for clinical trials. PMID- 26511826 TI - Causality for depression and psoriasis is a sex-specific two-way process. PMID- 26511827 TI - A fresh look at T cells in psoriasis. PMID- 26511828 TI - The cutaneous side-effect iceberg. PMID- 26511829 TI - How best to manage acral naevi. PMID- 26511830 TI - CARE guidelines and how to improve case reporting. Does one size fit all? PMID- 26511831 TI - Diphenylcyclopropenone in patients with alopecia areata. A critically appraised topic. AB - AIM: To assess the efficacy and safety of topical diphenylcyclopropenone (DPCP) in patients with alopecia areata. SETTING AND DESIGN: Study selection, data extraction, risk of bias assessment and analyses were carried out independently by two authors. The quality of evidence was rated with Grading of Recommendations Assessment, Development and Evaluation (GRADE). No randomised trials were identified, but 11 case series, conducted in dermatology departments in the Netherlands, UK, Iran, Italy, Egypt and Greece were included. STUDY EXPOSURE: Patients with mainly extensive and long-lasting alopecia totalis and universalis were treated. Most often one side of the scalp was treated with DPCP whilst the other side received no treatment. Treatment duration varied from 4 to 48 months with a follow up of 6 to 36 months. OUTCOMES: Outcomes included quality of life, patient satisfaction, adverse events, treatment effect and duration of remission. RESULTS: Eleven studies, with sample sizes of 18-139 comprising 500 patients, were retrieved. Our critical outcomes quality of life and patient satisfaction, were not or hardly addressed. In about half of the patients DPCP appeared to be effective, with transient side effects such as contact eczema, blistering, oedema of eyelids, headache and flu-like symptoms. If treatment was satisfactory the effect was maintained for more than a year. The overall quality of the evidence was rated very low. CONCLUSION: There is very low quality evidence for the effectiveness and safety in extensive resistant alopecia areata. Well-designed and well-conducted randomised controlled trials, with subsequent adequate reporting, including high-quality descriptions of all aspects of methodology are required. PMID- 26511835 TI - Acute exposure to wood smoke from incomplete combustion--indications of cytotoxicity. AB - BACKGROUND: Smoke from combustion of biomass fuels is a major risk factor for respiratory disease, but the underlying mechanisms are poorly understood. The aim of this study was to determine whether exposure to wood smoke from incomplete combustion would elicit airway inflammation in humans. METHODS: Fourteen healthy subjects underwent controlled exposures on two separate occasions to filtered air and wood smoke from incomplete combustion with PM1 concentration at 314 MUg/m(3) for 3 h in a chamber. Bronchoscopy with bronchial wash (BW), bronchoalveolar lavage (BAL) and endobronchial mucosal biopsies was performed after 24 h. Differential cell counts and soluble components were analyzed, with biopsies stained for inflammatory markers using immunohistochemistry. In parallel experiments, the toxicity of the particulate matter (PM) generated during the chamber exposures was investigated in vitro using the RAW264.7 macrophage cell line. RESULTS: Significant reductions in macrophage, neutrophil and lymphocyte numbers were observed in BW (p < 0.01, <0.05, <0.05, respectively) following the wood smoke exposure, with a reduction in lymphocytes numbers in BAL fluid (<0.01. This unexpected cellular response was accompanied by decreased levels of sICAM-1, MPO and MMP-9 (p < 0.05, <0.05 and <0.01). In contrast, significant increases in submucosal and epithelial CD3+ cells, epithelial CD8+ cells and submucosal mast cells (p < 0.01, <0.05, <0.05 and <0.05, respectively), were observed after wood smoke exposure. The in vitro data demonstrated that wood smoke particles generated under these incomplete combustion conditions induced cell death and DNA damage, with only minor inflammatory responses. CONCLUSIONS: Short-term exposure to sooty PAH rich wood smoke did not induce an acute neutrophilic inflammation, a classic hallmark of air pollution exposure in humans. While minor proinflammatory lymphocytic and mast cells effects were observed in the bronchial biopsies, significant reductions in BW and BAL cells and soluble components were noted. This unexpected observation, combined with the in vitro data, suggests that wood smoke particles from incomplete combustion could be potentially cytotoxic. Additional research is required to establish the mechanism of this dramatic reduction in airway leukocytes and to clarify how this acute response contributes to the adverse health effects attributed to wood smoke exposure. TRIAL REGISTRATION: NCT01488500. PMID- 26511836 TI - Novel Therapeutic Approach for Autism Spectrum Disorder: Focus on SHANK3. AB - SHANK3 is a synaptic scaffolding protein and plays an important role in neuronal development. SHANK3 interacts with various synaptic molecules, including post synaptic density-95 (PSD-95), homer and GluR1 AMPA receptor. SHANK3 gene is a causable gene of the Phelan- McDermid syndrome (also known as the 22q13.3 deletion syndrome), whose manifestation is global developmental delay and autistic behavior, especially shows severe speech and language deficit. Additionally since cumulative gene analysis in autistic subjects identified several mutations in SHANK3 gene, including deletion and duplication in a particular region, abnormality of SHANK3 gene is thought the be related with the neuropathology of autism spectrum disorder (ASD). We here review the recent findings in regard to the roles of SHANK3 in higher brain functions, molecular biologic studies of the complex expression of Shank3 transcripts and production of SHANK3 isoforms, and behavioral studies of Shank3-mutant mice, including our recent findings, and discuss a novel therapeutic approach for ASD. PMID- 26511837 TI - Characterizing selective pressures on the pathway for de novo biosynthesis of pyrimidines in yeast. AB - BACKGROUND: Selection on proteins is typically measured with the assumption that each protein acts independently. However, selection more likely acts at higher levels of biological organization, requiring an integrative view of protein function. Here, we built a kinetic model for de novo pyrimidine biosynthesis in the yeast Saccharomyces cerevisiae to relate pathway function to selective pressures on individual protein-encoding genes. RESULTS: Gene families across yeast were constructed for each member of the pathway and the ratio of nonsynonymous to synonymous nucleotide substitution rates (dN/dS) was estimated for each enzyme from S. cerevisiae and closely related species. We found a positive relationship between the influence that each enzyme has on pathway function and its selective constraint. CONCLUSIONS: We expect this trend to be locally present for enzymes that have pathway control, but over longer evolutionary timescales we expect that mutation-selection balance may change the enzymes that have pathway control. PMID- 26511838 TI - Dynamics of the natural transmission of bovine spongiform encephalopathy within an intensively managed sheep flock. AB - Sheep are susceptible to the bovine spongiform encephalopathy (BSE) agent and in the UK they may have been exposed to BSE via contaminated meat and bone meal. An experimental sheep flock was established to determine whether ovine BSE could be naturally transmitted under conditions of intensive husbandry. The flock consisted of 113 sheep of different breeds and susceptible PRNP genotypes orally dosed with BSE, 159 sheep subsequently born to them and 125 unchallenged sentinel controls. BSE was confirmed in 104 (92%) orally dosed sheep and natural transmission was recorded for 14 of 79 (18%) lambs born to BSE infected dams, with rates varying according to PRNP genotype. The likelihood of natural BSE transmission was linked to stage of incubation period of the dam: the attack rate for lambs born within 100 days of the death of BSE infected dams was significantly higher (9/22, 41%) than for the rest (5/57, 9%). Within the group of ewes lambing close to death, those rearing infected progeny (n = 8, for 9/12 infected lambs) showed a significantly greater involvement of lymphoid tissues than those rearing non-infected offspring (n = 8, for 0/10 infected lambs). Horizontal transmission to the progeny of non-infected mothers was recorded only once (1/205, 0.5%). This low rate of lateral transmission was attributed, at least partly, to an almost complete absence of infected placentas. We conclude that, although BSE can be naturally transmitted through dam-lamb close contact, the infection in this study flock would not have persisted due to low-efficiency maternal and lateral transmissions. PMID- 26511839 TI - Differential outcome of an antimicrobial stewardship audit and feedback program in two intensive care units: a controlled interrupted time series study. AB - BACKGROUND: Antimicrobial decision making in intensive care units (ICUs) is challenging. Unnecessary antimicrobials contribute to the development of resistant pathogens, Clostridium difficile infection and drug related adverse events. However, inadequate antimicrobial therapy is associated with mortality in critically ill patients. Antimicrobial stewardship programs are increasingly being implemented to improve antimicrobial prescribing, but the optimal approach in the ICU setting is unknown. We assessed the impact of an audit and feedback antimicrobial stewardship intervention on antimicrobial use, antimicrobial costs, clinical outcomes and microbiologic outcomes in two ICUs with different patient populations. METHODS: The audit and feedback intervention was implemented in a trauma and neurosurgery ICU (TNICU) and a medical surgical ICU (MSICU) at a 465 bed teaching hospital in Toronto, Canada. ICU patients were reviewed Monday to Friday by a physician and pharmacist with infectious diseases training. Recommendations related to appropriate antimicrobial use were presented to ICU teams during a dedicated daily meeting. A controlled interrupted time series analysis was used to compare outcomes in the 12 months before and after the intervention. Cardiovascular and coronary care ICUs served as control units. RESULTS: Mean total monthly antimicrobial use in defined daily doses (DDD) per 1000 patient days was reduced 28% in the TNICU (1433 vs. 1037) but increased 14% in the MSICU (1705 vs. 1936). In the time series analysis, total monthly antimicrobial use in the TNICU decreased by 375 DDD per 1000 patient days (p < 0.0009) immediately following the intervention, followed by a non-significant downward trend in use of -9 DDD per 1000 patient days (p = 0.56). No significant changes in antimicrobial use were identified in the MSICU. Antimicrobial use temporarily increased in one control unit and remained unchanged in the other. There were no changes in mortality, length of stay, readmission rate, incidence of C. difficile infection or resistance patterns of E. coli and P. aeruginosa in either intervention unit. CONCLUSIONS: Audit and feedback antimicrobial stewardship programs can lead to significant reductions in total antimicrobial use in the ICU setting. However, this effect may be context-dependent and further work is needed to determine the ingredients necessary for success. PMID- 26511840 TI - Low intensity microwave radiation induced oxidative stress, inflammatory response and DNA damage in rat brain. AB - Over the past decade people have been constantly exposed to microwave radiation mainly from wireless communication devices used in day to day life. Therefore, the concerns over potential adverse effects of microwave radiation on human health are increasing. Until now no study has been proposed to investigate the underlying causes of genotoxic effects induced by low intensity microwave exposure. Thus, the present study was undertaken to determine the influence of low intensity microwave radiation on oxidative stress, inflammatory response and DNA damage in rat brain. The study was carried out on 24 male Fischer 344 rats, randomly divided into four groups (n=6 in each group): group I consisted of sham exposed (control) rats, group II-IV consisted of rats exposed to microwave radiation at frequencies 900, 1800 and 2450 MHz, specific absorption rates (SARs) 0.59, 0.58 and 0.66 mW/kg, respectively in gigahertz transverse electromagnetic (GTEM) cell for 60 days (2h/day, 5 days/week). Rats were sacrificed and decapitated to isolate hippocampus at the end of the exposure duration. Low intensity microwave exposure resulted in a frequency dependent significant increase in oxidative stress markers viz. malondialdehyde (MDA), protein carbonyl (PCO) and catalase (CAT) in microwave exposed groups in comparison to sham exposed group (p<0.05). Whereas, levels of reduced glutathione (GSH) and superoxide dismutase (SOD) were found significantly decreased in microwave exposed groups (p<0.05). A significant increase in levels of pro-inflammatory cytokines (IL-2, IL-6, TNF-alpha, and IFN-gamma) was observed in microwave exposed animal (p<0.05). Furthermore, significant DNA damage was also observed in microwave exposed groups as compared to their corresponding values in sham exposed group (p<0.05). In conclusion, the present study suggests that low intensity microwave radiation induces oxidative stress, inflammatory response and DNA damage in brain by exerting a frequency dependent effect. The study also indicates that increased oxidative stress and inflammatory response might be the factors involved in DNA damage following low intensity microwave exposure. PMID- 26511841 TI - Puerarin attenuates learning and memory impairments and inhibits oxidative stress in STZ-induced SAD mice. AB - Puerarin (PUE), an isoflavone purified from the root of Pueraria lobata (Chinese herb), has been reported to attenuate learning and memory impairments in the transgenic mouse model of Alzheimer's disease (AD). In the present study, we tested PUE in a sporadic AD (SAD) mouse model which was induced by the intracerebroventricular injection of streptozotocin (STZ). The mice were administrated PUE (25, 50, or 100mg/kg/d) for 28 days. Learning and memory abilities were assessed by the Morris water maze test. After behavioral test, the biochemical parameters of oxidative stress (glutathione peroxidase (GSH-Px), superoxide dismutases (SOD), and malondialdehyde (MDA)) were measured in the cerebral cortex and hippocampus. The SAD mice exhibited significantly decreased learning and memory ability, while PUE attenuated these impairments. The activities of GSH-Px and SOD were decreased while MDA was increased in the SAD animals. After PUE treatment, the activities of GSH-Px and SOD were elevated, and the level of MDA was decreased. The middle dose PUE was more effective than others. These results indicate that PUE attenuates learning and memory impairments and inhibits oxidative stress in STZ-induced SAD mice. PUE may be a promising therapeutic agent for SAD. PMID- 26511842 TI - Human papillomavirus mediated inhibition of DNA damage sensing and repair drives skin carcinogenesis. AB - BACKGROUND: The failure to mount an effective DNA damage response to repair UV induced cyclobutane pyrimidine dimers (CPDs) results in an increased propensity to develop cutaneous squamous cell carcinoma (cSCC). High-risk patient groups, such as organ transplant recipients (OTRs) frequently exhibit field cancerization at UV exposed body sites from which multiple human papillomavirus (HPV) associated cSCCs develop rapidly, leading to profound morbidity and increased mortality. In vitro molecular evidence indicates that HPV of genus beta papillomavirus (beta-PV) play an important role in accelerating the early stages of skin tumorigenesis. METHODS: We investigated the effects of UV induced DNA damage in murine models of beta-PV E6 oncoprotein driven skin tumorigenesis by crossing K14-HPV8-E6wt mice (developing skin tumors after UV treatment) with K14 CPD-photolyase animals and by generating the K14-HPV8-E6-K136N mutant mouse strain. Thymine dimers (marker for CPDs) and gammaH2AX (a marker for DNA double strand breaks) levels were determined in the murine skin and organotypic skin cultures of E6 expressing primary human keratinocytes after UV-irradiation by immunohistochemistry and in cell lines by In Cell Western blotting. Phosphorylation of ATR/Chk1 and ATM were assessed in cell lines and organotypic skin cultures by Western blots and immunohistochemistry. RESULTS: Skin tumor development after UV-irradiation in K14-HPV8-E6wt mice could completely be blocked through expression of CPD-photolyase. Through quantification of thymine dimers after UV irradiation in cells expressing E6 proteins with point mutations at conserved residues we identified a critical lysine in the C-terminal part of the protein for prevention of DNA damage repair and p300 binding. Whereas all K14 HPV8-E6wt animals develop skin tumors after UV expression of the HPV8-E6-K136N mutant significantly blocked skin tumor development after UV treatment. The persistence of CPDs in hyperproliferative epidermis K14-HPV8-E6wt skin resulted in the accumulation of gammaH2AX foci. DNA damage sensing was impaired in E6 positive cells grown as monolayer culture and in organotypic cultures, due to lack of phosphorylation of ATM, ATR and Chk1. CONCLUSION: We showed that cells expressing E6 fail to sense and mount an effective response to repair UV-induced DNA lesions and demonstrated a physiological relevance of E6-mediated inhibition of DNA damage repair for tumor initiation. These are the first mechanistical in vivo data on the tumorigenicity of HPV8 and demonstrate that the impairment of DNA damage repair pathways by the viral E6 protein is a critical factor in HPV driven skin carcinogenesis. PMID- 26511843 TI - Why and how do general practitioners teach? An exploration of the motivations and experiences of rural Australian general practitioner supervisors. AB - BACKGROUND: In medical education, a learner-centred approach is recommended. There is also a trend towards workplace-based learning outside of the hospital setting. In Australia, this has resulted in an increased need for General Practitioner (GP) supervisors who are receptive to using adult learning principles in their teaching. Little is known about what motivates Australian GP supervisors and how they currently teach. METHODS: A qualitative study involving semi-structured interviews with 20 rural GP supervisors who work within one Regional Training Provider region in Australia explored their reasons for being a supervisor and how they performed their role. Data was analysed using a thematic analysis approach. RESULTS: GP supervisors identified both personal and professional benefits in being a supervisor, as well as some benefits for their practice. Supervision fulfilled a perceived broader responsibility to the profession and community, though they felt it had little impact on rural retention of doctors. While financial issues did not provide significant motivation to teach, the increasing financial inequity compared with providing direct patient care might impact negatively on the decision to be or to remain a supervisor in the future. The principal challenge for supervisors was finding time for teaching. Despite this, there was little evidence of supervisors adopting strategies to reduce teaching load. Teaching methods were reported in the majority to be case-based with styles extending from didactic to coach/facilitator. The two-way collegiate relationship with a registrar was valued, with supervisors taking an interest in the registrars beyond their development as a clinician. CONCLUSION: Supervisors report positively on their teaching and mentoring roles. Recruitment strategies that highlight the personal and professional benefits that supervision offers are needed. Practices need assistance to adopt models of supervision and teaching that will help supervisors productively manage the increasing number of learners in their practices. Educational institutions should facilitate the development and maintenance of supportive supervision and a learning culture within teaching practices. Given the variety of teaching approaches, evaluation of in-practice teaching is recommended. PMID- 26511844 TI - Bilateral Symmetrical Idiopathic Necrotizing Encephalopathy: A New Syndrome in Sprague-Dawley Rats. AB - This article describes the occurrence of a bilaterally symmetrical encephalopathy in Sprague-Dawley rats, which occurred over the period 2005 to 2012 in our laboratory in both untreated control rats and rats treated with different pharmacologically active compounds. The acute brain lesions consisted of degeneration/necrosis in the ventral areas of the brain mostly with little inflammatory response; in the more rare chronic cases there were numerous lipid laden macrophages. The areas most consistently affected were the crus cerebri, the ventral midbrain, the pyramids, and the internal capsule. Other areas less frequently affected were the mammillary bodies, the fimbria, the olfactory tubercles, the optic tracts, and the ventral hippocampus. All available data, including clinical signs, gross pathology, clinical pathology, diet, breeding, and housing were collected and are presented. Our investigations did not elucidate the pathogenesis of the lesions, although the infarction-type changes are suggestive of a vascular etiology. To our knowledge, this particular lesion with its consistent distribution pattern has not been reported in the rat literature and its publication is therefore important to the toxicological pathology community, because an unbalanced group distribution in a toxicology study could potentially confound the safety assessment of a compound. PMID- 26511845 TI - Utilizing Whole Slide Images for Pathology Peer Review and Working Groups. AB - This article describes the results of comparisons of digitally scanned whole slide images (WSIs) and glass microscope slides for diagnosis of tissues under peer review by the National Toxicology Program. Findings in this article were developed as a result of the data collected from 6 pathology working groups (PWGs), 1 pathology peer review, and survey comments from over 25 participating pathologists. For each PWG, 6-14 pathologists examined 10-143 tissues per study from 6- and 9-month perinatal studies and 2-year carcinogenicity studies. Overall it was found that evaluation of WSIs is generally equivalent to using glass slides. Concordance of PWG consensus diagnoses based upon review of WSIs versus glass slides ranged from 74% to 100% (median 86%). The intra- and interobserver diagnostic variation did not appear to influence the conclusions of any study. Based upon user opinions collected from surveys, WSIs may be less optimal than glass slides for evaluation of subtle lesions, large complex lesions, small lesions in a large section of tissue, and foci of altered hepatocytes. These results indicate that, although there may be some limitations, the use of WSIs can effectively accomplish the objectives of a conventional glass slide review and definitely serves as a useful adjunct to the conduct of PWGs. PMID- 26511846 TI - Immunohistochemical Detection of Markers for Translational Studies of Lung Disease in Pigs and Humans. AB - Genetically engineered pigs are increasingly recognized as valuable models for the study of human disease. Immunohistochemical study of cellular markers of disease is an important tool for the investigation of these novel models so as to evaluate genotype and treatment differences. Even so, there remains a lack of validated markers for pig tissues that can serve as a translational link to human disease in organs such as the lung. Herein, we evaluate markers of cellular inflammation (cluster of differentiation [CD]3, CD79a, B cell lymphoma [BCL] 6, ionized calcium-binding adapter molecule [IBA]1, and myeloperoxidase) and those that may be involved with tissue remodeling (alpha-smooth muscle actin, beta tubulin-III, lactoferrin, mucin [MUC]5AC, MUC5B, and cystic fibrosis transmembrane conductance regulator [CFTR]) for study of lung tissues. We compare the utility of these markers between pig and human lungs to validate translational relevance of each marker. Our results suggest these markers can be a useful addition in the pathological evaluation of porcine models of human disease. PMID- 26511847 TI - Tailored Pig Models for Preclinical Efficacy and Safety Testing of Targeted Therapies. AB - Despite enormous advances in translational biomedical research, there remains a growing demand for improved animal models of human disease. This is particularly true for diseases where rodent models do not reflect the human disease phenotype. Compared to rodents, pig anatomy and physiology are more similar to humans in cardiovascular, immune, respiratory, skeletal muscle, and metabolic systems. Importantly, efficient and precise techniques for genetic engineering of pigs are now available, facilitating the creation of tailored large animal models that mimic human disease mechanisms at the molecular level. In this article, the benefits of genetically engineered pigs for basic and translational research are exemplified by a novel pig model of Duchenne muscular dystrophy and by porcine models of cystic fibrosis. Particular emphasis is given to potential advantages of using these models for efficacy and safety testing of targeted therapies, such as exon skipping and gene editing, for example, using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system. In general, genetically tailored pig models have the potential to bridge the gap between proof-of-concept studies in rodents and clinical trials in patients, thus supporting translational medicine. PMID- 26511848 TI - Artesunate-amodiaquine versus artemether-lumefantrine for the treatment of acute uncomplicated malaria in Congolese children under 10 years old living in a suburban area: a randomized study. AB - BACKGROUND: The Republic of Congo adopted a new anti-malarial treatment policy in 2006, with artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) as the first- and second-line anti-malarial drugs, respectively. Only three clinical studies had been conducted before the policy change. A randomized study on these two artemisinin-based combinations was conducted, and the effect that sickle cell trait may have on treatment outcomes was evaluated in children under 10 years old followed during 12 months in Brazzaville in 2010-2011. METHODS: A cohort of 330 children under 10 years of age living in a suburban area in the south of Brazzaville were passively followed for registration of malaria episodes. Uncomplicated Plasmodium falciparum episodes were randomly treated with co formulated ASAQ (Coarsucam((r))) or AL (Coartem((r))). Patients were followed according to the 2009 World Health Organization protocol for the evaluation of anti-malarial drug efficacy. Plasmodium falciparum recrudescent isolates were compared to pre-treatment isolates by polymerase chain reaction (PCR) to distinguish between re-infection and recrudescence. PCR-uncorrected and PCR corrected responses to treatment were determined using per protocol analysis. Haemoglobin type (AA, AS, SS) was determined by PCR. RESULTS: Of 282 clinical malaria episodes registered during 1-year follow-up period, 262 children with uncomplicated malaria were treated with ASAQ (129 patients) or AL (133 patients). The PCR-corrected efficacy, expressed as the percentage of adequate clinical and parasitological response, was 97.0 % for ASAQ and 96.4 % for AL. Among ASAQ treated patients, 112 (86.8 %) carried AA genotype and 17 (13.2 %) were AS carriers. The PCR-corrected efficacy was 96.4 % for AA-carriers and 100 % for AS carriers treated with ASAQ [relative risk (RR) = 0.96; 95 % confidence interval, 0.93-1.00, p = 0.5]. Among 133 AL-treated children, 109 (82 %) carried AA, and 24 (18 %) AS genotypes. The PCR-corrected efficacy was 96.7 % among AA-carriers and 95.2 % among AS-carriers [RR = 1.01 (0.92-1.12), p = 0.6]. Nausea, jaundice, headache, dizziness, vomiting, pruritus, abdominal pain, and diarrhoea were registered as adverse events in both groups. ASAQ was associated with significantly more frequent adverse events (P < 0.05). CONCLUSION: This first randomized study in Brazzaville confirmed the excellent efficacy of these co formulated anti-malarial drugs in children. Sickle cell genotype did not influence the treatment efficacy of artemisinin-based combination therapy. PMID- 26511849 TI - One amino acid makes the difference: the formation of ent-kaurene and 16alpha hydroxy-ent-kaurane by diterpene synthases in poplar. AB - BACKGROUND: Labdane-related diterpenoids form the largest group among the diterpenes. They fulfill important functions in primary metabolism as essential plant growth hormones and are known to function in secondary metabolism as, for example, phytoalexins. The biosynthesis of labdane-related diterpenes is mediated by the action of class II and class I diterpene synthases. Although terpene synthases have been well investigated in poplar, little is known about diterpene formation in this woody perennial plant species. RESULTS: The recently sequenced genome of Populus trichocarpa possesses two putative copalyl diphosphate synthase genes (CPS, class II) and two putative kaurene synthase genes (KS, class I), which most likely arose through a genome duplication and a recent tandem gene duplication, respectively. We showed that the CPS-like gene PtTPS17 encodes an ent-copalyl diphosphate synthase (ent-CPS), while the protein encoded by the putative CPS gene PtTPS18 showed no enzymatic activity. The putative kaurene synthases PtTPS19 and PtTPS20 both accepted ent-copalyl diphosphate (ent-CPP) as substrate. However, despite their high sequence similarity, they produced different diterpene products. While PtTPS19 formed exclusively ent-kaurene, PtTPS20 generated mainly the diterpene alcohol, 16alpha-hydroxy-ent-kaurane. Using homology-based structure modeling and site-directed mutagenesis, we demonstrated that one amino acid residue determines the different product specificity of PtTPS19 and PtTPS20. A reciprocal exchange of methionine 607 and threonine 607 in the active sites of PtTPS19 and PtTPS20, respectively, led to a complete interconversion of the enzyme product profiles. Gene expression analysis revealed that the diterpene synthase genes characterized showed organ-specific expression with the highest abundance of PtTPS17 and PtTPS20 transcripts in poplar roots. CONCLUSIONS: The poplar diterpene synthases PtTPS17, PtTPS19, and PtTPS20 contribute to the production of ent-kaurene and 16alpha-hydroxy-ent kaurane in poplar. While ent-kaurene most likely serves as the universal precursor for gibberellins, the function of 16alpha-hydroxy-ent-kaurane in poplar is not known yet. However, the high expression levels of PtTPS20 and PtTPS17 in poplar roots may indicate an important function of 16alpha-hydroxy-ent-kaurane in secondary metabolism in this plant organ. PMID- 26511850 TI - Impact of personal protective equipment on clinical output and perceived exertion. AB - BACKGROUND AND AIM: Safe clinical care within Ebola Virus Disease Treatment Units (EVDTUs) mandate the use of personal protective equipment (PPE), comprising a fluid impermeable hooded suit, visor, gloves and rubber boots. The aim of this study was to assess the impact of this PPE on clinical personnel's performance in the EVDTU, Kerry Town, Sierra Leone. METHODS: An anonymous questionnaire was administered to healthcare professionals (HCPs) entering the EVDTU ward area (Red Zone (RZ)), during a 2-week period to assess perceived exertion using the Borg Rating of Perceived Exertion Scale. RESULTS: A total of 62 clinical episodes undertaken by 20 HCPs were analysed. There were no episodes of heat illness during the study. HCPs spent a median of 74 (IQR 55-95) minutes within the RZ. Median durations of RZ activity were similar throughout the 24 h period (p=0.22), but Borg scores were significantly higher between 11:00 and 14:59 compared with RZ entry between 15:00 and 10:59, respectively (12 (6-15), n=13; 8 (6-9), n=48; p=0.022). Rates of weight loss per minute spent within the RZ were significantly greater between 11:00 and 14:59 compared with 15:00-10:59, respectively (0.014 (0.009-0.023) kg/min, n=6; 0.007 (0.004-0.013) kg/min, n=37; p=0.037). CONCLUSIONS: Despite acclimatisation and proactive clinical tasking, HCPs in the EVDTU experienced significantly greater rates of weight loss and perceived exertion scores during the hottest times of the day. These findings should be considered by those planning healthcare facilities for future humanitarian missions where HCPs will provide clinical care in full PPE. PMID- 26511851 TI - Influence of volcanic activity and anthropic impact in the trace element contents of fishes from the North Patagonia in a global context. AB - The elemental contents in salmonid muscle and liver tissues from different lakes around the world were investigated. Fish from pristine areas were compared with those fishes from impacted environments, both by volcanic and anthropogenic activities. Within the data, special attention was given to fishes from the Andean Patagonian lakes in two contexts: local and global. The local evaluation includes geological and limnological parameters and diet composition which were obtained through a data search from published works. The volcanic influence in Andean Patagonian lakes was mainly observed by an increase of cesium (Cs) and rubidium (Rb) concentrations in fishes, influenced by calcium (Ca) and potassium (K) water contents. Zinc (Zn), selenium (Se), iron (Fe), silver (Ag), and mercury (Hg) contents in fishes showed the effect of the geological substratum, and some limnological parameters. The diet composition was another factor which affects the elemental concentration in fishes. The analyzed data showed that the fishes from Andean Patagonian lakes had elemental content patterns corresponding to those of pristine regions with volcanic influence. Selenium and Ag contents from Andean Patagonian fishes were the highest reported. PMID- 26511852 TI - Multilevel analysis of a riverscape under rapid urbanization in the Yangtze delta plain, China: 1965-2006. AB - River networks are the typical hydrological characteristic of the Yangtze delta plain. They have important ecological service functions and a unique landscape, which has been significantly degraded during the past 50 years. Qingpu District in Shanghai has been used as study area to develop an integrated method for riverscape assessment in floodplain areas with a dense river network. This integrated method bridges geomorgraphy, landscape, and regional planning. Indicators of sinuosity, connectivity, and circuitry have been integrated into a three-level framework, including river, intersection, and river network level. Furthermore, this method was integrated by the geographic information system method and stepwise regression to identify the riverscape response to the changes in the use of the land. The spatial and temporal changes of the riverscape and land use were calculated for each grid (3000 m*3000 m) from 1965 to 2006. The results indicated that the riverscape had been significantly degraded during the study period in terms of sinuosity, connectivity, and circuitry reducing. The land use changed significantly with more building areas and less water regions and agricultural land. Additionally, the regression results indicated that several specific land use conversion types had had strong effects on the change in the riverscape structure. Finally, according to the assessing method, we have proposed specific planning and management recommendations based on the pressure state-response model to protect the riverscape from the impact of rapid urbanization. PMID- 26511853 TI - Isotopic and geochemical characterization of invader tilapia fishes from water bodies of West Bengal and Karnataka, India. AB - The otoliths (N = 12) of freshwater invasive species tilapia (Tilapia mossambicus) collected from two water bodies located at Kolkata and Bangalore, India, were analyzed for stable isotopes (delta18O, delta14C) and major and trace elements in order to assess the suitability of using otoliths as a tracer of aquatic environmental changes. The stable isotope analysis was done using the dual inlet system of a Finnigan-MAT 253 isotope ratio mass spectrometer (Thermo Fisher, Bremen, Germany). Concentrations of major and trace elements were determined using a Thermo X-Series II quadrupole mass spectrometer. The stable isotope composition in tilapia otolith samples from Bangalore and Kolkata water bodies are quite good agreeing with that of the respective lake/pond and rain water. Elemental composition revealed in a pattern of Ca>Fe>Na>Sr>K>Ba>Cr>Mg>As>Mn>Zn>Co>Cu>Cd>Pb. The otoliths from Kolkata pond water are more enriched in Ba, Zn, Pb, Mn, Se, Cu, Zn, Cd, and Ni whereas Cr and As were found to be higher in otolith samples from Bangalore lake. The enrichment factor (EF) values of Cr were higher for both the sampling location in comparison with other metals, although all the studied metals exhibited EF values>1. The PCA shows clustering of metals in the otolith which are related either with the metabolic and physiological attributes or waterborne source. The study demonstrated the potential of stable isotope techniques to distinguish otolith specimens from varied climatic zone, while elemental composition recorded the quality of water at both the locations. The role of climate driving the quality of water can be understood by detailed and continuous monitoring of otolith specimens in the future. Future method allows reconstruction of climate and water quality from old specimens from field exposures or museum collection. PMID- 26511854 TI - Promoting an obesity education program among minority patients in a single urban pediatric Emergency Department (ED). AB - BACKGROUND: The purpose of this study was to assess the feasibility of the Emergency Department (ED) as a place for obesity education and to evaluate its impact on patient's lifestyle modification. METHODS: In this study, children between 8 and 18 years of age, who presented to the ED for non-urgent reasons in a single urban hospital, were enrolled. Parents' perception of their child's diet and exercise were assessed prior to the intervention. Both parents and children attended a brief audio-visual presentation that provided educational information on age-appropriate diet and exercise. Following the intervention, the participants were asked about their impressions regarding the ED as a place to receive obesity education and whether they plan to make any changes in diet and exercise. RESULTS: One hundred children and their parents participated in this study. Of these, 76 were Latino and 21 were African-Americans. The mean age was 14 years, and the mean body mass index (BMI) was 25.6. Following the intervention, 21 (100 %) of the African-American parents and 73 (98.6 %) of the Latino parents felt that the ED should provide obesity education. Eighteen (85.7 %) of the African-American parents and 72 (97.3 %) of the Latino parents planned to make changes in their child's diet and exercise. Among the children, 21 (100 %) of African-American participants and 76 (100 %) of Latino participants reported that they found the audio-visual useful. Seventeen (81.0 %) of the African-American children and 73 (96.1 %) of Latino children stated learning new information from the intervention program. CONCLUSIONS: This study suggests the ED may have a role in primary health promotion and obesity prevention. An ED based intervention may be used to provide education about obesity prevention and has the potential to impact life style modifications, including diet and exercise. PMID- 26511855 TI - Nanoparticle Targeting and Cholesterol Flux Through Scavenger Receptor Type B-1 Inhibits Cellular Exosome Uptake. AB - Exosomes are nanoscale vesicles that mediate intercellular communication. Cellular exosome uptake mechanisms are not well defined partly due to the lack of specific inhibitors of this complex cellular process. Exosome uptake depends on cholesterol-rich membrane microdomains called lipid rafts, and can be blocked by non-specific depletion of plasma membrane cholesterol. Scavenger receptor type B 1 (SR-B1), found in lipid rafts, is a receptor for cholesterol-rich high-density lipoproteins (HDL). We hypothesized that a synthetic nanoparticle mimic of HDL (HDL NP) that binds SR-B1 and removes cholesterol through this receptor would inhibit cellular exosome uptake. In cell models, our data show that HDL NPs bind SR-B1, activate cholesterol efflux, and attenuate the influx of esterified cholesterol. As a result, HDL NP treatment results in decreased dynamics and clustering of SR-B1 contained in lipid rafts and potently inhibits cellular exosome uptake. Thus, SR-B1 and targeted HDL NPs provide a fundamental advance in studying cholesterol-dependent cellular uptake mechanisms. PMID- 26511856 TI - High cell-specific rates of nitrogen and carbon fixation by the cyanobacterium Aphanizomenon sp. at low temperatures in the Baltic Sea. AB - Aphanizomenon is a widespread genus of nitrogen (N2)-fixing cyanobacteria in lakes and estuaries, accounting for a large fraction of the summer N2-fixation in the Baltic Sea. However, information about its cell-specific carbon (C)- and N2 fixation rates in the early growth season has not previously been reported. We combined various methods to study N2-fixation, photosynthesis and respiration in field-sampled Baltic Sea Aphanizomenon sp. during early summer at 10 degrees C. Stable isotope incubations at in situ light intensities during 24 h combined with cell-specific secondary ion mass spectrometry showed an average net N2-fixation rate of 55 fmol N cell(-1) day(-1). Dark net N2-fixation rates over a course of 12 h were 20% of those measured in light. C-fixation, but not N2-fixation, was inhibited by high ambient light intensities during daytime. Consequently, the C:N fixation ratio varied substantially over the diel cycle. C- and N2-fixation rates were comparable to those reported for Aphanizomenon sp. in August at 19 degrees C, using the same methods. High respiration rates (23% of gross photosynthesis) were measured with (14)C-incubations and O2-microsensors, and presumably reflect the energy needed for high N2-fixation rates. Hence, Aphanizomenon sp. is an important contributor to N2-fixation at low in situ temperatures in the early growth season. PMID- 26511857 TI - Pulsed electromagnetic field (PEMF) promotes collagen fibre deposition associated with increased myofibroblast population in the early healing phase of diabetic wound. AB - The present study evaluated the effects of PEMF on collagen fibre deposition, collagen fibril alignment and collagen fibre orientation. The potential relationships between collagen fibre deposition and myofibroblast population in diabetic wound healing were also examined. Forty young male streptozotocin induced diabetic Sprague-Dawley rats were randomly assigned to PEMF group or control group. 2 cm * 2 cm square wounds were made at their back. The PEMF group received daily exposure of PEMF to the wounds, while control group was handled in the same manner except that the PEMF device was not activated. Wound tissues harvested on post-wounding day 7, 10 and 14 were fixed, processed and sectioned. The abundance, fibril alignment and fibre orientation of type I collagen were quantified with picro-sirius polarization method and image analysis software (Nikon NIS Element AR). Myofibroblast population data were adopted from our previous study. Correlation between myofibroblast population and collagen fibre deposition was examined. There was significantly greater abundance of type I collagen fibre in the PEMF group than in the control on day 7 (P = .013), but not on day 10 or 14. No significant between-group differences were found in collagen fibril alignment and collagen fibre orientation at any measured time points. Positive correlation was found between collagen fibre deposition and myofibroblast population only on day 7 (r = .729, P = .007). In conclusion, PEMF can significantly increase collagen fibre in the early phase of diabetic wound healing, which is associated with the enhancement of myofibroblast population. PMID- 26511858 TI - Morphological risk factors for the rupture of anterior communicating artery aneurysms: the significance of fenestration. AB - INTRODUCTION: The purpose of this study was to evaluate morphological factors associated with rupture in anterior communicating artery (AcomA) aneurysms and to investigate the significance of AcomA fenestration as a risk factor for aneurysm rupture. METHODS: The clinical and radiologic findings of 255 patients with AcomA aneurysms treated with coil embolization between January 2005 and March 2014 were retrospectively reviewed. We performed univariate and multivariate analyses to evaluate the associations between morphological variables and rupture status. RESULTS: The number of patients with AcomA fenestration was 17 out of 255 (6.6 %). There were no statistically significant differences between the fenestration group and non-fenestration group in clinical and morphological characteristics. Multivariate logistic regression tests showed that superior direction of aneurysm dome (OR 2.802, p = 0.023), presence of a bleb (OR 5.998, p < 0.001), high aspect ratio (OR 3.138, p = 0.009), size greater than 7 mm (OR 3.356, p = 0.013), and AcomA fenestration (OR 4.135, p = 0.026) were significantly associated with AcomA aneurysm rupture. CONCLUSIONS: The results of this study demonstrated that a fenestrated AcomA is associated with risk of aneurysm rupture. Therefore, AcomA fenestration can be considered as an important morphological risk factor for rupture, along with other known risk factors such as the direction of aneurysm dome, a bleb, high aspect ratio, and size. PMID- 26511859 TI - Trapping the delta Isomer of the Polyoxometalate-Based Keggin Cluster with a Tripodal Ligand. AB - We report the synthesis, structural, and electronic characterization of the theoretically predicted, but experimentally elusive delta-isomer of the Keggin polyoxometalate polyanion. A family of delta-Keggin polyoxoanions of the general formula, (TEA)Hp Naq [H2 M12 (XO4 )O33 (TEA)]?r H2 O where p, q, r=[2,3,8] for 1 and [4,1,4] for 2 were isolated by the reaction of tungstate(VI) and vanadium(V) with triethanolammonium ions (TEAH), acting as a tripodal ligand grafted to the surface of the cluster thereby stabilizing the polyanionic delta-Keggin archetype. The delta-Keggin species were characterized by single-crystal X-ray diffraction, FT-IR, UV/Vis, NMR, and ESI-MS spectrometry. Electronic structure and structure-stability correlations were evaluated by means of DFT calculations. The compounds exhibited multi-electron transfer and reversible photochromic properties by undergoing single-crystal-to-single-crystal (SC-SC) transformations accompanied with color changes under light. PMID- 26511860 TI - Biodistribution and Toxicity of X-Ray Iodinated Contrast Agent in Nano-emulsions in Function of Their Size. AB - PURPOSE: This study aimed to investigate the impact of the size of X-ray iodinated contrast agent in nano-emulsions, on their toxicity and fate in vivo. METHODS: A new compound, triiodobenzoate cholecalciferol, was synthetized, formulated as nano-emulsions, and followed after i.v. administration in mice by X ray imaging (micro computed tomography). Physicochemical characterization and process optimization allowed identifying a good compromise between X-ray contrasting properties, monodispersity and stability. This also allowed selecting two formulations with different sizes, hydrodynamic diameters of 55 and 100 nm, but exactly the same composition. In vitro experiments were performed on two cell lines, namely hepatocytes (BNL-CL2) and macrophages (RAW264.7). RESULTS: Cell viability studies, cell uptake observations by confocal microscopy, and uptake quantification by fluorimetry, disclosed clear differences between two formulations, as well as between two types of cell lines. After i.v. injection of the two iodinated nano-emulsions in mice, CT scans provided the quantification of the pharmacokinetics and biodistributions. We finally showed that the size in the nano-emulsions has not a real impact on the pharmacokinetics and biodistributions, but has a strong influence on their toxicity, corroborating the in vitro results. CONCLUSIONS: This study shows that the size of the nanocarrier significantly matters, likely due to highly different interactions with cells and tissues. Graphical Abstract A study on the effect of the size of cholecciferol nano-emulsions, on their in vivo becoming, through X-ray imaging modality. PMID- 26511862 TI - Nectar Attracts Foraging Honey Bees with Components of Their Queen Pheromones. AB - Floral nectar often contains chemicals that are deterrent to pollinators, presenting potential challenges to outcrossing plant species. Plants may be able to co-opt pollinator chemical signals to mitigate the negative effects of nectar deterrent compounds on pollination services. We found that buckwheat (Fagopyrum esculentum) and Mexican sunflower (Tithonia diversifolia) produce nectar with abundant phenolics, including three components of the Apis honeybee queen mandibular pheromone (QMP). In addition, these nectars contain a non-pheromonal phenolic, chlorogenic acid (CA), which was toxic to honeybees, and T. diversifolia nectar also contained isochlorogenic acid (IA). Fresh nectar or solutions containing nectar phenolics reduced Apis individual feeding compared to sucrose solutions. However, freely foraging bees preferred solutions with QMP components to control solutions, and QMP components over-rode or reversed avoidance of CA and IA. Furthermore, prior exposure to the presence or just the odor of QMP components removed the deterrent effects of CA and IA. By mimicking the honey bee pheromone blend, nectar may maintain pollinator attraction in spite of deterrent nectar compounds. PMID- 26511861 TI - Inflammatory Cell Migration in Rheumatoid Arthritis: A Comprehensive Review. AB - Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects the joints. Self-reactive B and T lymphocytes cooperate to promote antibody responses against self proteins and are major drivers of disease. T lymphocytes also promote RA independently of B lymphocytes mainly through the production of key inflammatory cytokines, such as IL-17, that promote pathology. While the innate signals that initiate self-reactive adaptive immune responses are poorly understood, the disease is predominantly caused by inflammatory cellular infiltration and accumulation in articular tissues, and by bone erosions driven by bone-resorbing osteoclasts. Osteoclasts are giant multinucleated cells formed by the fusion of multiple myeloid cells that require short-range signals, such as the cytokines MCSF and RANKL, for undergoing differentiation. The recruitment and positioning of osteoclast precursors to sites of osteoclast differentiation by chemoattractants is an important point of control for osteoclastogenesis and bone resorption. Recently, the GPCR EBI2 and its oxysterol ligand 7a, 25 dihydroxycholesterol, were identified as important regulators of osteoclast precursor positioning in proximity to bone surfaces and of osteoclast differentiation under homeostasis. In chronic inflammatory diseases like RA, osteoclast differentiation is also driven by inflammatory cytokines such as TNFa and IL-1, and can occur independently of RANKL. Finally, there is growing evidence that the chemotactic signals guiding osteoclast precursors to inflamed articular sites contribute to disease and are of great interest. Furthering our understanding of the complex osteoimmune cell interactions should provide new avenues of therapeutic intervention for RA. PMID- 26511863 TI - Feeding on Leaves of the Glucosinolate Transporter Mutant gtr1gtr2 Reduces Fitness of Myzus persicae. AB - As aphids are a pest on various crops worldwide, a better understanding of the interaction between aphids and plant host defenses is required. The green peach aphid (Myzus persicae) feeds on a variety of plant species, including the model plant Arabidopsis thaliana (Arabidopsis), in which glucosinolates function as a major part of the chemical defense. Several studies have shown that glucosinolates play a role in interactions between Arabidopsis and the green peach aphid. In this work, we used a recently identified Arabidopsis glucosinolate transporter mutant (gtr1gtr2 dKO), with altered glucosinolate content in the vasculature, to investigate the role of defense compound transport in aphid infestation. By monitoring aphid performance on caged leaves and analyzing glucosinolates in leaf tissue and phloem sap, as well as inside aphids, we examined if a change in spatial distribution of glucosinolates within a leaf influences aphid performance. Based on reduced glucosinolate content in the phloem sap of the transporter mutant, we hypothesized that aphids would perform better on gtr1gtr2 dKO leaves compared to WT. Unexpectedly, aphids performed poorly on gtr1gtr2 dKO leaves. Our data suggest that higher glucosinolate content in tissues surrounding the phloem of the double transporter mutant may play a role in reducing aphid performance on this genotype. PMID- 26511864 TI - Acceptability and Feasibility of HIV Self-Testing Among Transgender Women in San Francisco: A Mixed Methods Pilot Study. AB - An estimated one in four transgender women (trans women) in the U.S. are infected with HIV. Rates of HIV testing are not commensurate with their risk, necessitating alternative strategies for early detection and care. We explored the feasibility and acceptability of HIV self-testing (HIVST) with 50 HIV negative adult trans women in San Francisco. Participants received three self test kits to perform once a month. Acceptability and behavioral surveys were collected as were 11 in-depth interviews (IDIs). Among 50 participants, 44 reported utilizing HIVST at least once; 94 % reported the test easy to use; 93 % said results were easy to read; and 91 % would recommend it to others. Most participants (68 %) preferred HIVST to clinic-based testing, although price was a key barrier to uptake. IDIs revealed a tension between desires for privacy versus support found at testing sites. HIVST for trans women was acceptable and feasible and requires careful consideration of linkage to support services. PMID- 26511865 TI - HIV-Alcohol Risk Reduction Interventions in Sub-Saharan Africa: A Systematic Review of the Literature and Recommendations for a Way Forward. AB - Sub-Saharan Africa bears 69 % of the global burden of HIV, and strong evidence indicates an association between alcohol consumption, HIV risk behavior, and HIV incidence. However, characteristics of efficacious HIV-alcohol risk reduction interventions are not well known. The purpose of this systematic review is to summarize the characteristics and synthesize the findings of HIV-alcohol risk reduction interventions implemented in the region and reported in peer-reviewed journals. Of 644 citations screened, 19 met the inclusion criteria for this review. A discussion of methodological challenges, research gaps, and recommendations for future interventions is included. Relatively few interventions were found, and evidence is mixed about the efficacy of HIV-alcohol risk reduction interventions. There is a need to further integrate HIV-alcohol risk reduction components into HIV prevention programming and to document results from such integration. Additionally, research on larger scale, multi-level interventions is needed to identify effective HIV-alcohol risk reduction strategies. PMID- 26511866 TI - Chemical genetics and regeneration. AB - Regeneration involves interactions between multiple signaling pathways acting in a spatially and temporally complex manner. As signaling pathways are highly conserved, understanding how regeneration is controlled in animal models exhibiting robust regenerative capacities should aid efforts to stimulate repair in humans. One way to discover molecular regulators of regeneration is to alter gene/protein function and quantify effect(s) on the regenerative process: dedifferentiation/reprograming, stem/progenitor proliferation, migration/remodeling, progenitor cell differentiation and resolution. A powerful approach for applying this strategy to regenerative biology is chemical genetics, the use of small-molecule modulators of specific targets or signaling pathways. Here, we review advances that have been made using chemical genetics for hypothesis-focused and discovery-driven studies aimed at furthering understanding of how regeneration is controlled. PMID- 26511869 TI - Novartis agrees to pay $390m in US kickback case. PMID- 26511868 TI - Recombinant IgA production for mucosal passive immunization, advancing beyond the hurdles. AB - Vaccination is a successful strategy to proactively develop immunity to a certain pathogen, but most vaccines fail to trigger a specific immune response at the mucosal surfaces, which are the first port of entry for infectious agents. At the mucosal surfaces, the predominant immunoglobulin is secretory IgA (SIgA) that specifically neutralizes viruses and prevents bacterial colonization. Mucosal passive immunization, i.e. the application of pathogen-specific SIgAs at the mucosae, can be an effective alternative to achieve mucosal protection. However, this approach is not straightforward, mainly because SIgAs are difficult to obtain from convalescent sources, while recombinant SIgA production is challenging due to its complex structure. This review provides an overview of manufacturing difficulties presented by the unique structural diversity of SIgAs, and the innovative solutions being explored for SIgA production in mammalian and plant expression systems. PMID- 26511867 TI - The emerging role of aryl hydrocarbon receptor in the activation and differentiation of Th17 cells. AB - The aryl hydrocarbon receptor (AHR) is a cytoplasmic transcription factor, which plays an essential role in the xenobiotic metabolism in a wide variety of cells. The AHR gene is evolutionarily conserved and it has a central role not only in the differentiation and maturation of many tissues, but also in the toxicological metabolism of the cell by the activation of metabolizing enzymes. Several lines of evidence support that both AHR agonists and antagonists have profound immunological effects; and recently, the AHR has been implicated in antibacterial host defense. According to recent studies, the AHR is essential for the differentiation and activation of T helper 17 (Th17) cells. It is well known that Th17 cells have a central role in the development of inflammation, which is crucial in the defense against pathogens. In addition, Th17 cells play a major role in the pathogenesis of several autoimmune diseases such as rheumatoid arthritis. Therefore, the AHR may provide connection between the environmental chemicals, the immune regulation, and autoimmunity. In the present review, we summarize the role of the AHR in the Th17 cell functions. PMID- 26511870 TI - Magnetic-charge ordering and phase transitions in monopole-conserved square spin ice. AB - Magnetic-charge ordering and corresponding magnetic/monopole phase transitions in spin ices are the emergent topics of condensed matter physics. In this work, we investigate a series of magnetic-charge (monopole) phase transitions in artificial square spin ice model using the conserved monopole density algorithm. It is revealed that the dynamics of low monopole density lattices is controlled by the effective Coulomb interaction and the Dirac string tension, leading to the monopole dimerization which is quite different from the dynamics of three dimensional pyrochlore spin ice. The condensation of the monopole dimers into monopole crystals with staggered magnetic-charge order can be predicted clearly. For the high monopole density cases, the lattice undergoes two consecutive phase transitions from high-temperature paramagnetic/charge-disordered phase into staggered charge-ordered phase before eventually toward the long-range magnetically-ordered phase as the ground state which is of staggered charge order too. A phase diagram over the whole temperature-monopole density space, which exhibits a series of emergent spin and monopole ordered states, is presented. PMID- 26511871 TI - Polymorphism of CAG and GGN repeats of androgen receptor gene in women with polycystic ovary syndrome. AB - One characteristic of polycystic ovary syndrome (PCOS) is hyperandrogenism, which may be related to the activity of androgen receptor (AR). This study was designed to investigate the polymorphism of CAG and GGN repeats in the AR gene in women with PCOS. The frequency distributions of CAG and GGN repeat alleles, as well as their X-inactivation patterns, were compared between 76 age-matched normal women (control group) and 80 women with PCOS (PCOS group). The expression of AR mRNA in the ovarian tissues of seven patients with PCOS and five normal women was also tested using real-time quantitative PCR. It was found that PCOS patients had significantly higher frequency of longer GGN biallelic mean (29.8%) and X weighted biallelic mean (33.3%) than controls (6.1% and 3.2%, respectively, P = 0.002, P = 0.003). The odds ratio of the long GGN repeat length (n > 16) before and after X-chromosome inactivation (XCI) in the PCOS group was significantly higher than in controls (P = 0.0001, P = 0.005). AR-GGN repeat mRNA expression was higher in the ovarian tissue of controls compared with PCOS patients (P = 0.022). In conclusion, the data suggest that the GGN repeat polymorphism in the AR gene is associated with PCOS. PMID- 26511872 TI - Meiotic behaviour and sperm aneuploidy in an infertile man with a mosaic 45,X/46,XY karyotype. AB - The meiotic behaviour of the germ cells in 45,X/46,XY men has not been extensively studied. This study investigated the meiotic events and sperm aneuploidy in an azoospermic man with a 45,X/46,XY (50/50) mosaic karyotype to better understand the fate of the 45,X cells and the production of chromosomally abnormal spermatozoa. Combining immunofluorescence techniques and fluorescence in situ hybridization, meiotic recombination, synapsis, meiotic sex chromosome inactivation (MSCI) and configuration were analysed, as well as sperm aneuploidy in the patient and 10 normal, fertile men. Despite the 50:50 somatic mosaicism in the patient, 25% of pachytene cells analysed were 45,X. Furthermore, 63% of pachytene cells were 46,XY with paired sex chromosomes, and 12% were 46,XY with unpaired sex chromosomes, which displayed abnormal MCSI patterns. Although the patient's testicular spermatozoa showed increased aneuploidy, the majority were of normal constitution. The X:Y sperm ratio was significantly increased compared with the controls (P < 0.001), which may indicate that some 45,X cells gave rise to X-bearing spermatozoa. The findings provide insight into the fate of 45,X/46,XY cells in meiosis, supporting the hypothesis that stringent checkpoints ensure the favourable production of spermatozoa with normal chromosomal constitution despite an individual's abnormal karyotype. PMID- 26511873 TI - The place of reconstructive tubal surgery in the era of assisted reproductive techniques. AB - Assisted reproductive techniques yield high rates of success for women with tubal factor infertility. Because they are potentially effective for all categories of infertility, for two decades, clinical and basic research in infertility has been focused on IVF techniques and outcomes, rather than developing surgical techniques or training infertility subspecialists in tubal microsurgery. Nonetheless, in comparison with IVF, reconstructive tubal surgery is inexpensive and offers multiple opportunities to attempt conception. Performing laparoscopic salpingostomy prior to IVF in women with good prognosis tubal disease may improve the outcome of subsequent IVF, while offering the potential for spontaneous conception. Tubo-tubal anastomosis for reversal of tubal ligation, performed either by a microsurgical technique through a mini-laparotomy or by laparoscopy, is preferable to IVF in younger women with no other fertility factors, because it offers potentially higher cumulative pregnancy rates. Surgery is the only alternative for women with tubal factor infertility who for personal or other reasons are unable to undergo assisted reproductive techniques. Tubal reconstructive surgery and assisted reproductive techniques must be considered complementary forms of treatment for women with tubal factor infertility, and training in tubal reconstructive surgery should be an integral part of subspecialty training in reproductive endocrinology and infertility. PMID- 26511875 TI - Isolating single cells in a neurosphere assay using inertial microfluidics. AB - Sphere forming assays are routinely used for in vitro propagation and differentiation of stem cells. Because the stem cell clusters can become heterogeneous and polyclonal, they must first be dissociated into a single cell suspension for further clonal analysis or differentiation studies. The dissociated population is marred by the presence of doublets, triplets and semi cleaved/intact clusters which makes identification and further analysis of differentiation pathways difficult. In this work, we use inertial microfluidics to separate the single cells and clusters in a population of chemically dissociated neurospheres. In contrast to previous microfluidic sorting technologies which operated at high flow rates, we implement the spiral microfluidic channel in a novel focusing regime that occurs at lower flow rates. In this regime, the curvature-induced Dean's force focuses the smaller, single cells towards the inner wall and the larger clusters towards the center. We further demonstrate that sorting in this low flow rate (and hence low shear stress) regime yields a high percentage (>90%) of viable cells and preserves multipotency by differentiating the sorted neural stem cell population into neurons and astrocytes. The modularity of the device allows easy integration with other lab-on-a-chip devices for upstream mechanical dissociation and downstream high-throughput clonal analysis, localized electroporation and sampling. Although demonstrated in the case of the neurosphere assay, the method is equally applicable to other sphere forming assays. PMID- 26511876 TI - Heart rate variability is an indicator for intradialytic hypotension among chronic hemodialysis patients. AB - BACKGROUND: Intradialytic hypotension (IDH) carries adverse impact. Heart rate variability (HRV) represents autonomic cardiac regulation which influences intradialytic blood pressure. We aimed to evaluate the association between IDH and HRV. METHODS: This prospective study was carried out in a teaching hospital in Taiwan from June to August 2010. Adult patients on chronic hemodialysis without active medical conditions were enrolled and received HRV measurements for 4 times (before and during an index hemodialysis session). Patients were categorized by the changes of systolic blood pressure during the index hemodialysis into Group 1 (elevation >20 mmHg), Group 2 (decrease >20 mmHg), and Group 3 (others). Then we compared HRV indices among the three groups, and determined the indicators for IDH. RESULTS: One hundred and seventy-one patients (96 women, mean age 64.9 years) were enrolled and categorized into Group 1 (n = 47, 27.5 %), Group 2 (n = 45, 26.3 %) and Group 3 (n = 79, 46.2 %). Comparing with Group 1 and/or Group 3, Group 2 had significantly higher blood pressure at hemodialysis initiation (most p < 0.001) and statistically lower levels of HRV indices including variance, total power, very low-frequency, low-frequency and high-frequency since the middle phase of the hemodialysis. By logistic regression method, higher systemic blood pressure [odds ratio (OR) 1.048; p < 0.001], heart rate (OR 1.093; p = 0.021), low-frequency/high-frequency ratio (OR 1.715; p = 0.022), as well as lower variance (OR 0.639; p = 0.048) at hemodialysis initiation were independently associated with intradialytic blood pressure changes. CONCLUSIONS: HRV is a useful indicator for IDH among hemodialysis patients. PMID- 26511877 TI - Early response to erythropoiesis-stimulating agents in non-dialysis chronic kidney disease patients. AB - BACKGROUND: Renal anemia complicated with chronic kidney disease is usually treated with erythropoiesis-stimulating agents (ESAs). However, few studies have compared the early response of hemoglobin (Hb) to different kinds of ESAs. METHODS: The effects of three types of ESAs-epoetin alfa or beta (EPO), darbepoetin alfa (DPO), and epoetin beta pegol (EPObp)-on renal anemia were followed in 416 pre-dialysis chronic kidney disease (CKD) patients. After the initial 12-week administration of ESAs, DeltaHb/ESA dose/kg was calculated as an index of efficacy of each ESA. Furthermore, independent variables associated with DeltaHb/ESA dose/kg (dependent variable) were determined using multiple linear regression analysis. The ten independent variables selected for analysis were: presence of diabetic nephropathy, estimated glomerular filtration rate (eGFR), Hb, albumin, iron (Fe), transferrin saturation (TSAT), ferritin, phosphate (P), intact parathyroid hormone (iPTH), and C-reactive protein. RESULTS: The efficacy of DPO and EPObp were similar and higher than EPO. TSAT was most strongly correlated with DeltaHb/EPO dose/kg in all three types of ESAs. Other significant independent factors were Hb, albumin, P, iPTH, and diabetic nephropathy in the EPO group, eGFR in the DPO group, and Fe in the EPObp group. The adjusted coefficient of determination (R (2)) ranged from 0.415 to 0.520 in the three ESA groups. CONCLUSIONS: The study results suggest that TSAT is the best predictor of the initial 12-week responsiveness to ESA, irrespective of the type. Variables not investigated in this study also affect responsiveness to ESA in Japanese pre dialysis CKD patients. PMID- 26511878 TI - Biomarkers from distinct biological pathways improve early risk stratification in medical emergency patients: the multinational, prospective, observational TRIAGE study. AB - INTRODUCTION: Early risk stratification in the emergency department (ED) is vital to reduce time to effective treatment in high-risk patients and to improve patient flow. Yet, there is a lack of investigations evaluating the incremental usefulness of multiple biomarkers measured upon admission from distinct biological pathways for predicting fatal outcome and high initial treatment urgency in unselected ED patients in a multicenter and multinational setting. METHOD: We included consecutive, adult, medical patients seeking ED care into this observational, cohort study in Switzerland, France and the USA. We recorded initial clinical parameters and batch-measured prognostic biomarkers of inflammation (pro-adrenomedullin [ProADM]), stress (copeptin) and infection (procalcitonin). RESULTS: During a 30-day follow-up, 331 of 7132 (4.6 %) participants reached the primary endpoint of death within 30 days. In logistic regression models adjusted for conventional risk factors available at ED admission, all three biomarkers strongly predicted the risk of death (AUC 0.83, 0.78 and 0.75), ICU admission (AUC 0.67, 0.69 and 0.62) and high initial triage priority (0.67, 0.66 and 0.58). For the prediction of death, ProADM significantly improved regression models including (a) clinical information available at ED admission (AUC increase from 0.79 to 0.84), (b) full clinical information at ED discharge (AUC increase from 0.85 to 0.88), and (c) triage information (AUC increase from 0.67 to 0.83) (p <0.01 for each comparison). Similarly, ProADM also improved clinical models for prediction of ICU admission and high initial treatment urgency. Results were robust in regard to predefined patient subgroups by center, main diagnosis, presenting symptoms, age and gender. CONCLUSIONS: Combination of clinical information with results of blood biomarkers measured upon ED admission allows early and more adequate risk stratification in individual unselected medical ED patients. A randomized trial is needed to answer the question whether biomarker-guided initial patient triage reduces time to initial treatment of high-risk patients in the ED and thereby improves patient flow and clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01768494 . Registered January 9, 2013. PMID- 26511880 TI - Homelessness and ED use: myths and facts. PMID- 26511879 TI - Prophylactic mesh placement to prevent parastomal hernia, early results of a prospective multicentre randomized trial. AB - PURPOSE: Parastomal hernia (PSH) is a common complication after colostomy formation. Recent studies indicate that mesh implantation during formation of a colostomy might prevent a PSH. To determine if placement of a retromuscular mesh at the colostomy site is a feasible, safe and effective procedure in preventing a parastomal hernia, we performed a multicentre randomized controlled trial in 11 large teaching hospitals and three university centres in The Netherlands. METHODS: Augmentation of the abdominal wall with a retromuscular light-weight polypropylene mesh (Parietene LightTM, Covidien) around the trephine was compared with traditional colostomy formation. Patients undergoing elective open formation of a permanent end-colostomy were eligible. 150 patients were randomized between 2010 and 2012. Primary endpoint of the PREVENT trial is the incidence of parastomal hernia. Secondary endpoints are morbidity, pain, quality of life, mortality and cost-effectiveness. This article focussed on the early results of the PREVENT trial and, therefore, operation time, postoperative morbidity, pain, and quality of life were measured. RESULTS: Outcomes represent results after 3 months of follow-up. A total of 150 patients were randomized. Mean operation time of the mesh group (N = 72) was significantly longer than in the control group (N = 78) (182.6 vs. 156.8 min; P = 0.018). Four (2.7 %) peristomal infections occurred of which one (1.4 %) in the mesh group. No infection of the mesh occurred. Most of the other infections were infections of the perineal wound, equally distributed over both groups. No statistical differences were discovered in stoma or mesh-related complications, fistula or stricture formation, pain, or quality of life. CONCLUSIONS: During open and elective formation of an end colostomy, primary placement of a retromuscular light-weight polypropylene mesh for prevention of a parastomal hernia is a safe and feasible procedure. The PREVENT trial is registered at: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2018 . PMID- 26511881 TI - Effect of time delays for appendectomy as observed on computed tomography in patients with noncomplicated appendicitis. AB - OBJECTIVES: Delaying appendectomy is a controversial issue. This study aimed at identifying the effect of time delays in surgery, especially for patients with noncomplicated appendicitis on computed tomography (CT). METHODS: Postappendectomy patients were analyzed from October 2013 to August 2014. Among the patients, data of those with findings of noncomplicated appendicitis on CT were gathered and the following time parameters were reviewed: CT examination time and appendectomy time. Other basic information and postoperative complications were checked. Patients were divided into a noncomplicated appendicitis group and a complicated appendicitis group. Perforated appendicitis and periappendiceal abscesses were regarded as complicated appendicitis. All other appendicitis from simple, focal to suppurative, and gangrenous appendicitis were regarded as noncomplicated appendicitis. RESULTS: In total, 397 patients were enrolled. The mean age was 33.2 years and the number of male/female patients was 216:181, respectively. The mean times from CT to operation were 5.9 vs 6.3hours for both the noncomplicated and complicated appendicitis groups (P=.758). The time from CT to operation showed no statistical relation to occurrences of complicated appendicitis, or postoperative complications such as ileuses, wound complications, and length of hospital stay. CONCLUSIONS: The time from CT to operation has no effect on the results of appendicitis. Further study in large-scaled, multicenter setting might yield more reliable results. PMID- 26511882 TI - Evaluation of the accuracy of the Emergency Coma Scale: E-COMET STEP II. PMID- 26511883 TI - HDlive imaging in diagnosis of uterine artery pseudoaneurysm during pregnancy. PMID- 26511884 TI - Recombinant modified vaccinia virus Ankara-based malaria vaccines. AB - A safe and effective malaria vaccine is a crucial part of the roadmap to malaria elimination/eradication by the year 2050. Viral-vectored vaccines based on adenoviruses and modified vaccinia virus Ankara (MVA) expressing malaria immunogens are currently being used in heterologous prime-boost regimes in clinical trials for induction of strong antigen-specific T-cell responses and high-titer antibodies. Recombinant MVA is a safe and well-tolerated attenuated vector that has consistently shown significant boosting potential. Advances have been made in large-scale MVA manufacture as high-yield producer cell lines and high-throughput purification processes have recently been developed. This review describes the use of MVA as malaria vaccine vector in both preclinical and clinical studies in the past 5 years. PMID- 26511885 TI - A mutational signature in gastric cancer suggests therapeutic strategies. AB - Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer and demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Our results suggest that 7-12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors. PMID- 26511886 TI - Chronic kidney disease among adult participants of the ELSA-Brasil cohort: association with race and socioeconomic position. AB - BACKGROUND: There is increased interest in understanding why chronic kidney disease (CKD) rates vary across races and socioeconomic groups. We investigated the distribution of estimated glomerular filtration rate (eGFR), urinary albumin creatinine ratio (ACR) and CKD according to these factors in Brazilian adults. METHODS: Using baseline data (2008-2010) of 14,636 public sector employees (35-74 years) enrolled in the Brazilian Longitudinal Study of Adult Health (ELSA)-Brasil multicentre cohort, we estimated the prevalence of CKD by sex, age, race and socioeconomic factors. CKD was defined as ACR >= 30 mg/g and/or eGFR < 60 mL/min/1.73 m(2). GFR was estimated by CKD epidemiology collaboration without correction for race. We used logistic regression to estimate the association of race and socioeconomic position (education, income, social class and occupational nature) with CKD after adjusting for sex, age and several health-related factors. RESULTS: The prevalence of high ACR or low eGFR, in isolation and combined, increased with age, and was higher in individuals with lower socioeconomic position and among black individuals and indigenous individuals. The overall prevalence of CKD was 8.9%. After full adjustments, it was similar in men and women (OR=0.90; 95% CI 0.79 to 1.02) and increased with age (OR=1.07; 95% CI 1.06 to 1.08). Compared to white individuals, black individuals (OR=1.23; 95% CI 1.03 to 1.47), 'pardos' (OR=1.16; 95% CI 1.00 to 1.35) and Indigenous (OR=1.72; 95% CI 1.07 to 2.76) people had higher odds for CKD. Having high school (OR=1.15; 95% CI 1.00 to 1.34) or elementary education (OR=1.23; 95% CI 1.03 to 1.47) increased the odds for CKD compared to those having a university degree. CONCLUSIONS: There were marked discrepancies in the increases in reduced eGFR and high ACR with age and race. The higher prevalences of CKD in individuals with lower educational status and in non-whites were not explained by differences in health-related factors. PMID- 26511887 TI - Wealth and mortality at older ages: a prospective cohort study. AB - BACKGROUND: Despite the importance of socioeconomic position for survival, total wealth, which is a measure of accumulation of assets over the life course, has been underinvestigated as a predictor of mortality. We investigated the association between total wealth and mortality at older ages. METHODS: We estimated Cox proportional hazards models using a sample of 10,305 community dwelling individuals aged >= 50 years from the English Longitudinal Study of Ageing. RESULTS: 2401 deaths were observed over a mean follow-up of 9.4 years. Among participants aged 50-64 years, the fully adjusted HRs for mortality were 1.21 (95% CI 0.92 to 1.59) and 1.77 (1.35 to 2.33) for those in the intermediate and lowest wealth tertiles, respectively, compared with those in the highest wealth tertile. The respective HRs were 2.54 (1.27 to 5.09) and 3.73 (1.86 to 7.45) for cardiovascular mortality and 1.36 (0.76 to 2.42) and 2.53 (1.45 to 4.41) for other non-cancer mortality. Wealth was not associated with cancer mortality in the fully adjusted model. Similar but less strong associations were observed among participants aged >= 65 years. The use of repeated measurements of wealth and covariates brought about only minor changes, except for the association between wealth and cardiovascular mortality, which became less strong in the younger participants. Wealth explained the associations between paternal occupation at age 14 years, education, occupational class, and income and mortality. CONCLUSIONS: There are persisting wealth inequalities in mortality at older ages, which only partially are explained by established risk factors. Wealth appears to be more strongly associated with mortality than other socioeconomic position measures. PMID- 26511888 TI - Previous anxiety and depression as risk factors for early labour force exit. AB - BACKGROUND: Individuals with a history of mental illness have lower earnings than individuals without. A possible reason is that those with prior anxiety or depression may be more likely to exit the labour force prior to retirement age, but evidence has been mixed and limited. Our objective was to compare risk of early labour force exit between employed adults with a history of depression or anxiety versus those without, separately for men and women. METHODS: We used data from the Baltimore Epidemiological Catchment Area Follow-up Cohort, which collected baseline data in 1981 and follow-up data 1993-1996 and 2004-2005. Cox proportional hazards models estimated the relative risk of labour force exit comparing those with versus without prior history of anxiety or depressive disorders. RESULTS: Women with prior anxiety or depression are at 37% increased risk of dropping out of the labour force as compared to women without, controlling for age, socioeconomic status, race and marital status (HR: 1.37, 95% CI 1.04 to 1.79). Men with prior anxiety or depression are 18% more likely to subsequently drop out of the labour force as compared to men without, controlling for the above confounders as well as veteran status, but this association is not statistically significant (HR: 1.18, 95% CI 0.72 to 1.27). CONCLUSIONS: Prior anxiety or depression increases risk of early labour force exit for women. These findings may help explain previously reported lower earnings among female individuals with a history of mental illness and highlight the importance of considering anxiety and depressive disorders in policies supporting labour force participation. PMID- 26511889 TI - Gas-phase acidity and dynamics of the protonation processes of carbidopa and levodopa. A QM/QD study. AB - The present work details, our efforts to investigate and compare the acid-base properties of levodopa (LD) and carbidopa (CD), a drug combination being used in the treatment of Parkinson's disease. Protonation and deprotonation were examined for all possible sites in the two drugs. Proton affinity and proton detachment enthalpies were computed at the B3LYP/6-311++G** level of theory. Results of the present work reveal that CD is more basic and can abstract protons in solution much more efficiently than LD. Furthermore, at all deportation sites considered, CD is more acidic than LD. DFT-based ADMP, dynamic simulations have been performed to explore the dynamics of the protonation processes in LD and CD. Thus, while the dynamics of the protonation process of LD is very straightforward leading to the formation of the corresponding cation, the protonation process in CD is very complex involving a major geometry change and rearrangement. Results of the present work reveal that the active species in acid medium is not CD in its normal geometry but a carbonyl hydrazine form instead. The presence of the carbonyl group beta to the hydrazine group may very well underlie its enhanced activity which allows it to bind to the active site of the DDC enzyme. The relative stabilities of various water-water-CD complexes have been computed and compared. PMID- 26511890 TI - Bending light via adiabatic optical transition in longitudinally modulated photonic lattices. AB - Bending light in a controllable way is desired in various applications such as beam steering, navigating and cloaking. Different from the conventional way to bend light by refractive index gradient, transformation optics or special beams through wavefront design such as Airy beams and surface plasmons, we proposed a mechanism to bend light via resonant adiabatic optical transition between Floquet Bloch (FB) modes from different FB bands in longitudinally modulated photonic lattices. The band structure of longitudinally modulated photonic lattices was calculated by employing the concept of quasi-energy based on the Floquet-Bloch theory, showing the existence of band discontinuities at specific resonant points which cannot be revealed by the coupled-mode theory. Interestingly, different FB bands can be seamlessly connected at these resonant points in longitudinally modulated photonic lattices driven by adiabatically varying the longitudinal modulation period along the propagation direction, which stimulates the adiabatic FB mode transition between different FB bands. PMID- 26511891 TI - The increased CO2 adsorption performance of chitosan-derived activated carbons with nitrogen-doping. AB - Highly porous nitrogen-doped activated carbons (NACs) were prepared by the chemical activation of chitosan using alkali carbonates. The NACs exhibited extremely high CO2 capacities of 1.6 mmol g(-1) (15 kPa) and 4.9 mmol g(-1) (100 kPa) at 25 degrees C. Nitrogen atoms doped into carbon frameworks clearly enhanced CO2 adsorption at low partial pressures. PMID- 26511892 TI - KHA-CARI guideline recommendations for the diagnosis and management of autosomal dominant polycystic kidney disease. PMID- 26511893 TI - Lesion Pattern in Patients With Erectile Dysfunction of Suspected Arterial Origin: An Angiographic Study. AB - PURPOSE: To determine the specific lesion pattern of supplying arteries in patients with cardiovascular risk factors suffering from treatment-refractory erectile dysfunction (ED). METHODS: From May 2012 to August 2013, 26 men (median age 55 years) poorly responsive to phosphodiesterase-5 inhibitor therapy were evaluated for a possible vascular cause for their ED. The men were examined with penile duplex sonography and digital subtraction angiography (DSA). Arterial lesions in the common and internal iliac arteries and the internal pudendal arteries considered amenable to endovascular therapy were treated with angioplasty +/- stents. Retrospectively, 2 blinded investigators independently evaluated the DSA images and categorized the vascular patterns of the erection related arteries as normal, macroangiopathy (occlusive lesions of the internal pudendal arteries), or microangiopathy (smaller caliber arteries distal to the internal pudendal circulation with no distal arterial reconstitution). RESULTS: Seventeen macroangiopathic lesions were successfully treated by angioplasty in 11 patients. The treated arterial lesions were mainly located in the internal (n=10) and common iliac arteries (n=2), whereas the internal pudendal artery were involved in 5 cases. Microangiopathic lesions lacking distal reconstitution were present in 7 patients, and the remaining 8 patients had normal vessels supplying the penis. Patients with macroangiopathy undergoing angioplasty had a higher prevalence of peripheral artery disease (63.6% vs 6.7%, p=0.003). CONCLUSION: In this preliminary series of ED patients with cardiovascular risk factors and pathologic duplex sonographic flow parameters, roughly 40% exhibited arterial lesions amenable to endovascular revascularization. In the patients with macroangiopathy, vessels upstream of the internal pudendal artery were most commonly affected. More studies are warranted to define the role of endovascular procedures in this ED subpopulation. PMID- 26511894 TI - Thoracic Endovascular Repair of Complicated Penetrating Aortic Ulcer: An 11-Year Single-Center Experience. AB - PURPOSE: To analyze an 11-year single-center experience of treating complicated penetrating aortic ulcer (PAU) using thoracic endovascular aortic repair (TEVAR). METHODS: This study included 63 consecutive patients (mean age 69.1+/-11.5 years; 40 men) with complicated PAU (42 symptomatic, 22 with rupture) who underwent TEVAR between 2002 and 2013. The PAUs were located in the aortic arch (n=11), the descending thoracic aorta (n=43), and the thoracoabdominal aorta (n=9). RESULTS: TEVAR was performed within 14 days of diagnosis in 33 (52.3%) cases (19 ruptures treated immediately); the other 30 (47.6%) patients had an average interval between diagnosis and intervention of 40+/-39 days. Technical success was 98.4% (62/63). One patient had a type I endoleak after stent-graft repair of a PAU in the aortic arch without great vessel transposition; another procedure was required for carotid-subclavian bypass and proximal stent-graft extension. No patient experienced spinal cord ischemia after TEVAR. Five (7.9%) patients died in-hospital; 3 had severe cardiac complications, 1 died from complications of aortic rupture, and the other succumbed to septic shock. Mean follow-up was 45.6+/-47.2 months, during which 12 (19.0%) patients needed a secondary intervention because of late endoleaks (n=4, 6.3%) or new complications due to disease progression. Multivariate analysis indicated that a PAU depth >15 mm was an independent predictor of mortality (hazard ratio 6.92, p=0.03). In the biomarker analysis, symptomatic patients had significantly higher D-dimer and troponin levels compared to asymptomatic patients [559.5+/-460.7 vs 283.2+/-85.2 ug/L (p=0.016) and 0.22+/-0.61 vs 0.02+/-0.03 ng/mL (p=0.04), respectively]. CONCLUSION: Patients with PAU suffer from underlying severe atherosclerotic disease and have a significant number of cardiovascular comorbidities that lead to relevant mortality and morbidity after TEVAR. As a PAU diameter >15 mm represented high risk for disease progression, these patients may be candidates for early intervention. D-dimer levels may help identify patients at risk and with progression of PAU. PMID- 26511895 TI - Externalized Guidewires to Facilitate Fenestrated Endograft Deployment in the Aortic Arch. AB - PURPOSE: To describe a precannulated fenestrated endograft system utilizing externalized guidewires to facilitate aortic arch endovascular repair and to report its use in 2 patients with challenging anatomy. TECHNIQUE: For distal arch repair, a fenestration for the left subclavian artery (LSA) is made onsite in a standard thoracic endograft tailored to the patient anatomy; it is precannulated with a nitinol guidewire (NGw), which is passed from the femoral artery and externalized from the left brachial artery prior to endograft delivery system introduction over a parallel stiff guidewire. Steps are then taken to remove guidewire intertwining, prevent NGw wrapping around the delivery system, and orient the LSA fenestration superiorly when the delivery system moves into the arch. Gentle traction on the ends of the NGw during endograft deployment facilitates proper fenestration alignment. A covered stent is deployed in the LSA fenestration. The technique is illustrated in a patient with congenital coarctation of the aorta and descending aortic aneurysm. For total arch repair, endograft fenestrations are made for all 3 arch branches; the left common carotid artery (LCCA) and LSA fenestrations are each cannulated with NGws, which travel together from the femoral artery, pass through a LSA snare loop, and are exteriorized from the LCCA. After endograft deployment, the innominate artery fenestration is separately cannulated using right brachial access. Placement of a parallel externalized hydrophilic guidewire passing through the LCCA fenestration (but not the LSA snare loop) and removal of the LCCA fenestration NGw allows exteriorization of the LSA fenestration NGw from the left brachial artery by pulling the LSA snare. Covered stents are deployed in all 3 fenestrations. The technique is presented in a patient with type B aortic dissection. CONCLUSION: Use of the precannulated fenestrated endograft system described is feasible and has the potential to make aortic arch endovascular repair simpler, more reliable, and safer. PMID- 26511896 TI - Paclitaxel-Eluting Balloon vs Standard Angioplasty to Reduce Restenosis in Diabetic Patients With In-Stent Restenosis of the Superficial Femoral and Proximal Popliteal Arteries: Three-Year Results of the DEBATE-ISR Study. AB - PURPOSE: To report the 3-year safety and effectiveness outcomes from the prospective all-comers DEBATE-ISR study (ClinicalTrials.gov identifier NCT01558531) of symptomatic diabetic patients with femoropopliteal in-stent restenosis (ISR) undergoing treatment with paclitaxel-eluting balloons compared with historical diabetic controls. METHODS: From January 2010 to December 2011, 44 consecutive diabetic patients (mean age 74+/-11 years; 32 men) were treated with drug-eluting balloons (DEBs) and enrolled in the study. The control group comprised 42 consecutive diabetic patients (age 76+/-7 years; 23 men) treated with conventional balloon angioplasty (BA) from 2008 to 2009. RESULTS: No significant differences in terms of clinical, angiographic, or procedural characteristics were observed between the study groups. Critical limb ischemia was present in the majority of patients. Tosaka class III ISR was observed in more than half of the patients. Mean lesion length was 132+/-86 and 137+/-82 mm in the DEB and BA groups, respectively (p=0.7). At 3-year follow-up, the rate of target lesion revascularization (TLR) was 40% in the DEB group vs 43% in the BA group (p=0.8); Kaplan-Meier analysis showed no significant differences in terms of freedom from TLR. The presence of a Tosaka class III occlusion was associated with a worse outcome in both study groups (odds ratio 3.96, 95% confidence interval 1.55 to 10.1, p=0.004). CONCLUSION: Using DEBs for femoropopliteal ISR yielded similar results to BA in terms of TLR at 3-year follow-up. The treatment of more complex ISR lesions was associated with an increased rate of TLR, irrespective of the technology used. PMID- 26511897 TI - Does Helping Keep Teens Protected? Longitudinal Bidirectional Relations Between Prosocial Behavior and Problem Behavior. AB - The current study examined bidirectional, longitudinal links between prosocial and problem behavior. Participants (N = 500) were recruited from a Northwestern city in the United States and assessed for 3 consecutive years from 2009 to 2011 (M(age) of youth at Time 1 = 13.32, SD = 1.05; 52% girls; 67% European American, 33% single-parent families). Results suggested that effects of earlier prosocial behavior toward family and strangers were predictive of fewer problem behaviors 2 years later, while results for prosocial behavior toward friends were more mixed. Results also suggested depression predicted lower prosocial behavior toward family members and anxiety predicted higher prosocial behavior toward friends. Findings show a complex pattern of relations that demonstrate the need to consider targets of helping. PMID- 26511899 TI - Thickness-Dependent Charge Carrier Dynamics in CdSe/ZnSe/CdS Core/Barrier/Shell Nanoheterostructures. AB - We report the synthesis of CdSe/ZnSe/CdS heterostructures composed of type I and type II band alignments, where ZnSe acts as a barrier for charge carriers between the CdSe core and the CdS shell as well as being an active component of the type I (CdSe/ZnSe) and type II (ZnSe/CdS) structure simultaneously. We investigated the effect of the thickness of the barrier and the shell on the charge carrier dynamics by using UV/Vis absorbance, photoluminescence (PL), and time-resolved fluorescence techniques. The experimental data are supported by simple theoretical calculations based on effective mass approximation (EMA). PL results indicate the emission from both type I and type II structures. Time-resolved fluorescence studies show that the lifetime of the core emission decreases with increasing barrier width, owing to a greater confinement of the exciton to the core, whereas it increases with shell width because of the tunneling of charge carriers, primarily electrons, delaying the recombination of the exciton. The lifetime of the shell emission decreases with shell width as well as barrier width and height, with a larger effect being observed for the barrier width and negligible for the associated changes in the barrier height. PMID- 26511900 TI - Editorial : une revue canadienne au rayonnement international. PMID- 26511901 TI - Synthesis of alpha-haloenamides via zinc halide mediated direct addition of benzhydryl halides to ynamides. AB - A regio- and stereoselective synthesis of highly substituted alpha-haloenamides was described via the zinc halide mediated direct addition of benzhydryl halides to ynamides under mild conditions. The products alpha-haloenamides were further transformed into multisubstituted enamides via Suzuki and Sonogashira cross coupling reactions. PMID- 26511902 TI - Simulations of radiation pressure experiments narrow down the energy and momentum of light in matter. AB - Consensus on a single electrodynamic theory has yet to be reached. Discord was seeded over a century ago when Abraham and Minkowski proposed different forms of electromagnetic momentum density and has since expanded in scope with the gradual introduction of other forms of momentum and force densities. Although degenerate sets of electrodynamic postulates can be fashioned to comply with global energy and momentum conservation, hope remains to isolate a single theory based on detailed comparison between force density predictions and radiation pressure experiments. This comparison is two-fold challenging because there are just a handful of quantitative radiation pressure measurements over the past century and the solutions developed from different postulates, which consist of approximate expressions and inferential deductions, are scattered throughout the literature. For these reasons, it is appropriate to conduct a consolidated and comprehensive re-analysis of past experiments under the assumption that the momentum and energy of light in matter are degenerate. We create a combined electrodynamic/fluid dynamic simulation testbed that uses five historically significant sets of electrodynamic postulates, including those by Abraham and Minkowski, to model radiation pressure under diverse configurations with minimal assumptions. This leads to new interpretations of landmark investigations of light momentum, including the Balazs thought experiment, the Jones-Richards and Jones-Leslie measurements of radiation pressure on submerged mirrors, observations of laser deformed fluid surfaces, and experiments on optical trapping and tractor beaming of dielectric particles. We discuss the merits and demerits of each set of postulates when compared to available experimental evidence and fundamental conservation laws. Of the five sets of postulates, the Abraham and Einstein-Laub postulates provide the greatest consistency with observations and the most physically plausible descriptions of electrodynamic interactions. Force density predictions made by these two postulates are unique under many conditions and their experimental isolation is potentially within reach. PMID- 26511903 TI - The neuroprotective and anti-apoptotic effects of melatonin on hemolytic hyperbilirubinemia-induced oxidative brain damage. AB - Melatonin exerts protection in several inflammatory and neurodegenerative disorders. To investigate the neuroprotective effects of melatonin in an experimental hemolysis-induced hyperbilirubinemia, newborn Sprague-Dawley rats (25-40 g, n = 72) were injected with phenylhydrazine hydrochloride (PHZ; 75 mg/kg) and the injections were repeated at the 24th hour. Rats were treated with saline or melatonin (10 mg/kg) 30 min before the first and second PHZ injections and 24 h after the 2nd PHZ injections. Control rats (n = 24) were injected with saline, but not PHZ. At sixth hours after the last injections of saline or melatonin, all rats were decapitated. Tumor necrosis factor (TNF)-alpha, IL 1beta, IL-10 and brain-derived neurotrophic factor (BDNF) and S100B levels in the plasma were measured. Brain tissue malondialdehyde (MDA), glutathione (GSH) levels and myeloperoxidase (MPO) activities were measured, and brain tissues were evaluated for apoptosis by TUNEL method. In the saline-treated PHZ group, hemoglobin, hematocrit levels were reduced, and total/direct bilirubin levels were elevated when compared to control group. Increased plasma TNF-alpha, IL 1beta levels, along with decreased BDNF, S100B and IL-10 values were observed in the saline-treated PHZ group, while these changes were all reversed in the melatonin-treated group. Increased MDA levels and MPO activities in the brain tissues of saline-treated hyperbilirubinemic rats, concomitant with depleted brain GSH stores, were also reversed in the melatonin-treated hyperbilirubinemic rats. Increased TUNEL(+) cells in the hippocampus of saline-treated PHZ group were reduced by melatonin treatment. Melatonin exerts neuroprotective and anti apoptotic effects on the oxidative neuronal damage of the newborn rats with hemolysis and hyperbilirubinemia. PMID- 26511904 TI - Concentrating Solar Power. PMID- 26511905 TI - Development of novel in vitro photosafety assays focused on the Keap1-Nrf2-ARE pathway. AB - Although photoallergens require UV energy for antigen formation, the subsequent immune response is considered to be the same as in ordinary skin sensitization. Therefore, in vitro tests for skin sensitization should also be applicable for photoallergy testing. In this study, we examined whether activation of the Keap1 (Kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor-erythroid 2-related factor 2)-ARE (antioxidant response element) pathway could be used to assess the photoallergenic potential of chemicals, using the reporter cell line AREc32 or KeratinoSens(TM) . First, we identified an appropriate UVA irradiation dose [5 J cm(-2) irradiation in phosphate-buffered saline (PBS)] by investigating the effect of UV irradiation on ARE-dependent gene induction using untreated or 6 methylcoumarin (6-MC)-treated cells. Irradiation of well-known photoallergens under this condition increased ARE-dependent gene expression by more than 50% compared with both vehicle and non-irradiated controls. When the cut-off value for detecting photoallergens was set at 50% induction, the accuracy of predicting photoallergenic/phototoxic chemicals was 70% in AREc32 cells and 67% in KeratinoSens(TM) cells, and the specificity was 100% in each case. We designate these assays as a photo-ARE assay and photo-KeratinoSens(TM) , respectively. Our results suggest that activation of the Keap1-Nrf2-ARE pathway is an effective biomarker for evaluating both photoallergenic and phototoxic potentials. Either of the above tests might be a useful component of a battery of in vitro tests/in silico methods for predicting the photoallergenicity and phototoxicity of chemicals. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26511906 TI - Metabolic predispositions and increased risk of colorectal adenocarcinoma by anatomical location: a large population-based cohort study in Norway. AB - Whether different definitions of metabolic syndrome (MetS) are differently associated with colorectal adenocarcinoma (CA) by anatomical location is unclear. A population-based cohort study, the Cohort of Norway (CONOR) Study, was conducted in Norway from 1995 to 2010. Anthropometric measurements, blood samples, and lifestyle data were collected at recruitment. CAs were identified through linkage to the Norwegian Cancer Register. A composite index of MetS as defined by the International Diabetes Federation (IDF) or/and the National Cholesterol Education Program's Adult Treatment Panel III (ATP III) and single components of MetS, including anthropometric factors, blood pressure, lipids, triglycerides, and glucose, were analyzed. Cox proportional hazards regression was performed to estimate hazard ratios and 95% confidence intervals. Significant associations between single MetS components and CA, except for reduced high density lipoprotein cholesterol and nonfasting glucose levels, were observed. MetS defined by 2 criteria separately showed a similar association with CA in general, and MetS defined by both the IDF and ATP III showed consistent results. Stronger associations were observed in the proximal colon among men (IDF: hazard ratio (HR) = 1.51, 95% confidence interval (CI): 1.24, 1.84; ATP III: HR = 1.40, 95% CI: 1.15, 1.70) and in the rectum among women (IDF: HR = 1.42, 95% CI: 1.07, 1.89; ATP III: HR = 1.43, 95% CI: 1.08, 1.90). PMID- 26511907 TI - The effect of obesity on inflammatory cytokine and leptin production following acute mental stress. AB - Obesity may contribute to cardiovascular disease (CVD) risk by eliciting chronic systemic inflammation and impairing the immune response to additional stressors. There has been little assessment of the effect of obesity on psychological stress, an independent risk factor for CVD. Therefore, it was of interest to examine interleukin-6, tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), interleukin-1 receptor antagonist (IL-1Ra), and leptin following an acute mental stress task in nonobese and obese males. Twenty college-aged males (21.3 +/- 0.56 years) volunteered to participate in a 20-min Stroop color-word and mirror tracing task. Subjects were recruited for obese (body mass index: BMI > 30) and nonobese (BMI < 25) groups, and blood samples were collected for enzyme-linked immunosorbent assay analysis. The acute mental stress task elicited an increase in heart rate, catecholamines, and IL-1beta in all subjects. Additionally, acute mental stress increased cortisol concentrations in the nonobese group. There was a significant reduction in leptin in obese subjects 30 min posttask compared with a decrease in nonobese subjects 120 min posttask. Interestingly, the relationship between the percent change in leptin and IL-1Ra at 120 min posttask in response to an acute mental stress task was only observed in nonobese individuals. This is the first study to suggest that adiposity in males may impact leptin and inflammatory signaling mechanisms following acute mental stress. PMID- 26511908 TI - Methotrexate for the Management of Crohn's Disease in Children. AB - OBJECTIVE: To review the literature evaluating methotrexate as a treatment option for Crohn's disease (CD) in pediatric patients. DATA SOURCES: A search of PubMed electronic database (1966 to August 2015) and secondary resources was performed using the terms methotrexate, Crohn's, and inflammatory bowel disease. Other relevant articles cited within identified articles were also utilized. STUDY SELECTION AND DATA EXTRACTION: Data sources were limited to English-language studies that included children less than 18 years of age. In total, 10 clinical studies met the criteria. DATA SYNTHESIS: Awareness of the risk of hepatosplenic T-cell lymphoma associated with anti-tumor necrosis factor and thiopurine therapies has renewed interest in methotrexate to treat CD in children. According to data from 10 predominantly retrospective studies, children treated with oral or subcutaneous methotrexate once weekly had remission rates of 25% to 53% at 1 year. Adverse effects most often included nausea and vomiting, elevated liver function tests, headache, and hematological toxicity. The evidence to support methotrexate is limited by inconsistent study design and poorly described dosage regimens. It has been most frequently evaluated in patients with prior thiopurine exposure and has not been thoroughly evaluated as first-line therapy. CONCLUSIONS: Based on results of retrospective studies, methotrexate is useful in the treatment of pediatric CD in those who fail thiopurine therapy. Remission rates with methotrexate are similar to those for thiopurine therapy, although no studies directly compare these agents. Although preliminary results are promising, prospective studies are needed to assess the use of methotrexate as initial first-line therapy in the pediatric CD population. PMID- 26511909 TI - Role of Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase in Patients with Recurrent Miscarriage. AB - PROBLEM: An indoleamine 2,3-dioxygenase (IDO) and a tryptophan 2,3-dioxygenase (TDO) lead to dysfunction of T cell and immunological tolerance between fetus and mother in early pregnancy. We investigated the role of IDO and TDO in patients with recurrent miscarriage. METHODS OF STUDY: Cervical mucus, decidua, and villi were surgically collected from patients with recurrent miscarriage from April 2010 to March 2013. Samples of cervical mucus were divided into two groups: the delivery group and the miscarriage group. The samples of cervical mucus in the miscarried group and tissue of villi and decidua were divided into normal chromosome group (normal chromosome analysis of villi) and abnormal chromosome group (abnormal chromosome analysis of villi). We performed immunohistochemistry, SDS-PAGE, and Western Blot analysis and measured the activity of IDO and TDO. RESULTS: The activity of IDO and TDO in cervical mucus was not significantly different between the delivery group and the miscarriage group, and between the normal chromosome group and abnormal chromosome group. The expression of TDO in villi and decidua was not significantly different between the normal chromosome group and the abnormal chromosome group. The activity of IDO and TDO in villi and decidua was not significantly different between the normal chromosome group and the abnormal chromosome group. The expression of IDO in villi was significantly higher in the normal chromosome group than in the abnormal chromosome group. CONCLUSION: Our results suggest that the difference of expression of IDO and dysfunctional activation of IDO in villi may play an important role in unexplained recurrent miscarriage. PMID- 26511910 TI - Stress reactions after a patient suicide and their relations to the profile of mental health professionals. AB - BACKGROUND: Patient suicide is a professional hazard for mental health professionals and an event likely to trigger stress reactions among them. This study aimed to identify typical profiles of professionals after a patient suicide to address the severity of stress reactions and its discriminant variables. METHODS: Mental health professionals (N = 666) working in institutional settings or private practice in the French-speaking part of Switzerland filled out a self administered questionnaire including the IES-R (Impact of Event Scale-Revised). Profiles were identified by cluster analysis. RESULTS: The interplay of variables pertaining to the relationship to the patient, exposure to suicide, support and training contributed to explaining the severity of stress reactions after a patient suicide. Five profiles of professionals were identified. Low-impacted professionals (55.8% of the sample) were characterised either by high support and anticipation (anticipators with support), emotional distance to the patient (distant professionals) or no contact with the patient at the time of death (no more contact with patient professionals). Emotional closeness to, and responsibility for the patient were typical of moderately-impacted professionals (36.6%, concerned professionals), while highly-impacted professionals felt emotionally close to the patient and lacked support although more than half of them sought it (7.7%, unsupported professionals). CONCLUSIONS: Differences in the professionals' profiles relate prominently to the interplay between risk and protective factors. Professionals who were appropriately supported, i.e., according to their risk profile, were able to cope with the event. Taking into account the profiles of professionals and the severity of stress reactions may enable the screening of those professionals most in need of support. Those most impacted sought out help more frequently. However, only a minority of them were offered sufficient support. Institutional or vocational bodies should take measures to ensure that professionals seeking help find it easily and promptly. The combination of training and support seems to be crucial for mitigating risk factors since the three low impacted subgroups had received the most training and support. PMID- 26511911 TI - The modulation effect of longitudinal acupuncture on resting state functional connectivity in knee osteoarthritis patients. AB - Recent advances in brain imaging have contributed to our understanding of the neural activity associated with acupuncture treatment. In this study, we investigated functional connectivity across longitudinal acupuncture treatments in older patients with knee osteoarthritis (OA). Over a period of 4 weeks (six treatments), we collected resting state functional magnetic resonance imaging (fMRI) scans from 30 patients before and after their first, third and sixth treatments. Clinical outcome showed a significantly greater pain subscore on the Knee Injury and Osteoarthritis Outcome Score (KOOS) (indicative of improvement) with verum acupuncture than with sham acupuncture. Independent component analysis (ICA) of the resting state fMRI data showed that the right frontoparietal network (rFPN) and the executive control network (ECN) showed enhanced functional connectivity (FC) with the rostral anterior cingulate cortex/medial prefrontal cortex, a key region in the descending pain modulatory system, in the verum groups as compared to the sham group after treatments. We also found that the rFPN connectivity with the left insula is (1) significantly associated with changes in KOOS pain score after treatments, and (2) significantly enhanced after verum acupuncture treatments as compared to sham treatment. Analysis of the acupuncture needle stimulation scan showed that compared with sham treatment, verum acupuncture activated the left operculum/insula, which also overlaps with findings observed in resting state analysis. Our results suggest that acupuncture may achieve its therapeutic effect on knee OA pain by modulating functional connectivity between the rFPN, ECN and the descending pain modulatory pathway. CLINICAL TRIAL NUMBER: NCT01079390. PMID- 26511912 TI - SUPPRESSOR OF APICAL DOMINANCE1 of Sporisorium reilianum Modulates Inflorescence Branching Architecture in Maize and Arabidopsis. AB - The biotrophic fungus Sporisorium reilianum causes head smut of maize (Zea mays) after systemic plant colonization. Symptoms include the formation of multiple female inflorescences at subapical nodes of the stalk because of loss of apical dominance. By deletion analysis of cluster 19-1, the largest genomic divergence cluster in S. reilianum, we identified a secreted fungal effector responsible for S. reilianum-induced loss of apical dominance, which we named SUPPRESSOR OF APICAL DOMINANCE1 (SAD1). SAD1 transcript levels were highly up-regulated during biotrophic fungal growth in all infected plant tissues. SAD1-green fluorescent protein fusion proteins expressed by recombinant S. reilianum localized to the extracellular hyphal space. Transgenic Arabidopsis (Arabidopsis thaliana) expressing green fluorescent protein-SAD1 displayed an increased number of secondary rosette-leaf branches. This suggests that SAD1 manipulates inflorescence branching architecture in maize and Arabidopsis through a conserved pathway. Using a yeast (Saccharomyces cerevisiae) two-hybrid library of S. reilianum-infected maize tissues, we identified potential plant interaction partners that had a predicted function in ubiquitination, signaling, and nuclear processes. Presence of SAD1 led to an increase of the transcript levels of the auxin transporter PIN-FORMED1 in the root and a reduction of the branching regulator TEOSINTE BRANCHED1 in the stalk. This indicates a role of SAD1 in regulation of apical dominance by modulation of branching through increasing transcript levels of the auxin transporter PIN1 and derepression of bud outgrowth. PMID- 26511913 TI - Polyploidy Enhances F1 Pollen Sterility Loci Interactions That Increase Meiosis Abnormalities and Pollen Sterility in Autotetraploid Rice. AB - Intersubspecific autotetraploid rice (Oryza sativa ssp. indica * japonica) hybrids have greater biological and yield potentials than diploid rice. However, the low fertility of intersubspecific autotetraploid hybrids, which is largely caused by high pollen abortion rates, limits their commercial utility. To decipher the cytological and molecular mechanisms underlying allelic interactions in autotetraploid rice, we developed an autotetraploid rice hybrid that was heterozygous (S(i)S(j)) at F1 pollen sterility loci (Sa, Sb, and Sc) using near isogenic lines. Cytological studies showed that the autotetraploid had higher percentages (>30%) of abnormal chromosome behavior and aberrant meiocytes (>50%) during meiosis than did the diploid rice hybrid control. Analysis of gene expression profiles revealed 1,888 genes that were differentially expressed between the autotetraploid and diploid hybrid lines at the meiotic stage, among which 889 and 999 were up- and down-regulated, respectively. Of the 999 down regulated genes, 940 were associated with the combined effect of polyploidy and pollen sterility loci interactions (IPE). Gene Ontology enrichment analysis identified a prominent functional gene class consisting of seven genes related to photosystem I (Gene Ontology 0009522). Moreover, 55 meiosis-related or meiosis stage-specific genes were associated with IPE in autotetraploid rice, including Os02g0497500, which encodes a DNA repair-recombination protein, and Os02g0490000, which encodes a component of the ubiquitin-proteasome pathway. These results suggest that polyploidy enhances epistatic interactions between alleles of pollen sterility loci, thereby altering the expression profiles of important meiosis related or meiosis stage-specific genes and resulting in high pollen sterility. PMID- 26511914 TI - Engineering Monolignol p-Coumarate Conjugates into Poplar and Arabidopsis Lignins. AB - Lignin acylation, the decoration of hydroxyls on lignin structural units with acyl groups, is common in many plant species. Monocot lignins are decorated with p-coumarates by the polymerization of monolignol p-coumarate conjugates. The acyltransferase involved in the formation of these conjugates has been identified in a number of model monocot species, but the effect of monolignol p-coumarate conjugates on lignification and plant growth and development has not yet been examined in plants that do not inherently possess p-coumarates on their lignins. The rice (Oryza sativa) p-COUMAROYL-Coenzyme A MONOLIGNOL TRANSFERASE gene was introduced into two eudicots, Arabidopsis (Arabidopsis thaliana) and poplar (Populus alba * grandidentata), and a series of analytical methods was used to show the incorporation of the ensuing monolignol p-coumarate conjugates into the lignin of these plants. In poplar, specifically, the addition of these conjugates did not occur at the expense of the naturally incorporated monolignol p hydroxybenzoates. Plants expressing the p-COUMAROYL-Coenzyme A MONOLIGNOL TRANSFERASE transgene can therefore produce monolignol p-coumarate conjugates essentially without competing with the formation of other acylated monolignols and without drastically impacting normal monolignol production. PMID- 26511915 TI - MicroRNA857 Is Involved in the Regulation of Secondary Growth of Vascular Tissues in Arabidopsis. AB - MicroRNAs (miRNAs) are endogenous small RNAs that repress target gene expression posttranscriptionally, and are critically involved in various developmental processes and responses to environmental stresses in eukaryotes. MiRNA857 is not widely distributed in plants and is encoded by a single gene, AtMIR857, in Arabidopsis (Arabidopsis thaliana). The functions of miR857 and its mechanisms in regulating plant growth and development are still unclear. Here, by means of genetic analysis coupled with cytological studies, we investigated the expression pattern and regulation mechanism of miR857 and its biological functions in Arabidopsis development. We found that miR857 regulates its target gene, Arabidopsis LACCASE7, at the transcriptional level, thereby reducing laccase activity. Using stimulated Raman scattering and x-ray microtomography three dimensional analyses, we showed that miR857 was involved in the regulation of lignin content and consequently morphogenesis of the secondary xylem. In addition, miR857 was activated by SQUAMOSA PROMOTER BINDING PROTEIN-LIKE7 in response to low copper conditions. Collectively, these findings demonstrate the role of miR857 in the regulation of secondary growth of vascular tissues in Arabidopsis and reveal a unique control mechanism for secondary growth based on the miR857 expression in response to copper deficiency. PMID- 26511916 TI - Hyphal Branching during Arbuscule Development Requires Reduced Arbuscular Mycorrhiza1. AB - During arbuscular mycorrhizal symbiosis, arbuscule development in the root cortical cell and simultaneous deposition of the plant periarbuscular membrane generate the interface for symbiotic nutrient exchange. The transcriptional changes that accompany arbuscule development are extensive and well documented. By contrast, the transcriptional regulators that control these programs are largely unknown. Here, we provide a detailed characterization of an insertion allele of Medicago truncatula Reduced Arbuscular Mycorrhiza1 (RAM1), ram1-3, which reveals that RAM1 is not necessary to enable hyphopodium formation or hyphal entry into the root but is essential to support arbuscule branching. In ram1-3, arbuscules consist only of the arbuscule trunk and in some cases, a few initial thick hyphal branches. ram1-3 is also insensitive to phosphate-mediated regulation of the symbiosis. Transcript analysis of ram1-3 and ectopic expression of RAM1 indicate that RAM1 regulates expression of EXO70I and Stunted Arbuscule, two genes whose loss of function impacts arbuscule branching. Furthermore, RAM1 regulates expression of a transcription factor Required for Arbuscule Development (RAD1). RAD1 is also required for arbuscular mycorrhizal symbiosis, and rad1 mutants show reduced colonization. RAM1 itself is induced in colonized root cortical cells, and expression of RAM1 and RAD1 is modulated by DELLAs. Thus, the data suggest that DELLAs regulate arbuscule development through modulation of RAM1 and RAD1 and that the precise transcriptional control essential to place proteins in the periarbuscular membrane is controlled, at least in part, by RAM1. PMID- 26511918 TI - Heterocyclic Secretase Inhibitors for the Treatment of Alzheimer's Disease: An Overview. AB - Alzheimer's disease (AD), the most common neurodegenerative disorder and demands to find a way for prevention and delayed onset. The development of therapeutics for AD is based on the amyloid cascade hypothesis (vaccines, beta- and gamma-Secretase inhibitors), or targeting tau and neurofibrillary tangle formation, neuroinflammation, etc. Cholinesterase, BACE-1, amyloid-beta 1-42, gamma and beta-Secretase, Phosphodiesterase type IV (PDE4) inhibitors are the reported treatment strategies. Among these, the gamma- and beta-Secretase inhibitors can be clustered in several heterocyclic classes (imidazoles, thiazoles, indoles, benzaldehydes, pyrimidine, etc), with subsequent description of the structure-activity relationships, and extended to the pharmacological profile in order to evaluate their drug-likeness, with special attention to toxicity and bioavailability. This article discusses the approaches proposed by several research groups working on the synthesis of enzyme inhibitors, based on modelling studies and the way these findings were used to obtain new drugs for the treatment of AD. PMID- 26511917 TI - Ethylene Control of Fruit Ripening: Revisiting the Complex Network of Transcriptional Regulation. AB - The plant hormone ethylene plays a key role in climacteric fruit ripening. Studies on components of ethylene signaling have revealed a linear transduction pathway leading to the activation of ethylene response factors. However, the means by which ethylene selects the ripening-related genes and interacts with other signaling pathways to regulate the ripening process are still to be elucidated. Using tomato (Solanum lycopersicum) as a reference species, the present review aims to revisit the mechanisms by which ethylene regulates fruit ripening by taking advantage of new tools available to perform in silico studies at the genome-wide scale, leading to a global view on the expression pattern of ethylene biosynthesis and response genes throughout ripening. Overall, it provides new insights on the transcriptional network by which this hormone coordinates the ripening process and emphasizes the interplay between ethylene and ripening-associated developmental factors and the link between epigenetic regulation and ethylene during fruit ripening. PMID- 26511919 TI - Preliminary Study on Nematocyst Types and Venom Isolation of Cassiopea andromeda Forskal, 1775 (Scyphozoa, Cnidaria) from Turkey. AB - Nematocyst types of Cassiopea andromeda were investigated. Medusae samples were taken from Gulluk Bay, Mugla, Turkey. Nematocyst samples from oral arms of C. andromeda were observed on light microscope and photographed. Birhopaloid and a isorhiza nematocyst types were found in C. andromeda. Moreover, it was seen that nematocyst sizes increased with increasing the bell diameters of the individuals. Also, the venom of the species was isolated and injected intramuscularly to Cyprinus carpio juveniles. Signs of partial paralysis, raking, and immobilized fins were observed in the juveniles consequently. Death was observed for the fishes which were 3-4 g in the range of weight. This study is a preliminary work on nematocysts and venom of C. andromeda. Further studies on neurotoxic effects of nematocyst venoms of this species should follow. PMID- 26511920 TI - Psychomotor Seizure Screening and in vitro Neuroprotection Assay of Hydrazones Derived from 2-Acetyl Thiophene. AB - BACKGROUND: Hydrazone core is a versatile structural linker for the development of various classes of antiepileptic agents. The aim of this study was to investigate the anticonvulsant activity of thiophene based hydrazones according to the antiepileptic drug development program protocol. METHODS: The maximal electroshock-induced seizure and 6 Hz "Psychomotor" seizure test models in mice were performed. Additionally, the active compounds in the screening test were subsequently subjected to the maximal electroshock-induced seizure test that allowed determination of their median effective doses and median toxic doses. The most active compound was also subjected to the In vitro Hippocampal slice culture neuroprotection assay. RESULTS: Among the synthesized compounds, 1-(thiophen-2 yl) ethylidene] hydrazine carboxamides (THb) and 1-(thiophen-2-yl) ethylidene] hydrazine carbothioamide (THc) showed a broad-spectrum anticonvulsant activity since they were active in both maximal electroshock-induced seizure and 6Hz Psychomotor induced seizure models with no neurotoxicity. In the mice maximal electroshock-induced seizure screen, compound THb gave an ED50 of 11.8 mg/kg and a TD50 of 39.47 mg/kg, resulting in a good protection index (PI), that is, TD50/ED50, of 3.3 when compared to Phenobarbital and Valproate. THb (100MUM) was also found to be effectively suppressing network hyperexcitability in the in vitro mEC-HC spontaneous bursting model, as determined by effects on spontaneous burst activity and duration. CONCLUSION: The suggested pharmacophore model for lead compounds from thiophene based hydrazones is explained by the hydrophobic domain-thiophene, electron donor-imine and hydrogen bonding domain-carboxamide or carbothioamide unit. PMID- 26511921 TI - Biogeographic history and high-elevation adaptations inferred from the mitochondrial genome of Glyptosternoid fishes (Sisoridae, Siluriformes) from the southeastern Tibetan Plateau. AB - BACKGROUND: The distribution of the Chinese Glyptosternoid catfish is limited to the rivers of the Tibetan Plateau and peripheral regions, especially the drainage areas of southeastern Tibet. Therefore, Glyptosternoid fishes are ideal for reconstructing the geological history of the southeastern Tibet drainage patterns and mitochondrial genetic adaptions to high elevations. RESULTS: Our phylogenetic results support the monophyly of the Sisoridae and the Glyptosternoid fishes. The reconstructed ancestral geographical distribution suggests that the ancestral Glyptosternoids was widely distributed throughout the Brahmaputra drainage in the eastern Himalayas and Tibetan area during the Late Miocene (c. 5.5 Ma). We found that the Glyptosternoid fishes lineage had a higher ratio of nonsynonymous to synonymous substitutions than those found in non-Glyptosternoids. In addition, omegapss was estimated to be 10.73, which is significantly higher than 1 (p-value 0.0002), in COX1, which indicates positive selection in the common ancestral branch of Glyptosternoid fishes in China. We also found other signatures of positive selection in the branch of specialized species. These results imply mitochondrial genetic adaptation to high elevations in the Glyptosternoids. CONCLUSIONS: We reconstructed a possible scenario for the southeastern Tibetan drainage patterns based on the adaptive geographical distribution of the Chinese Glyptosternoids in this drainage. The Glyptosternoids may have experienced accelerated evolutionary rates in mitochondrial genes that were driven by positive selection to better adapt to the high-elevation environment of the Tibetan Plateau. PMID- 26511922 TI - Multifunctional roles of leader protein of foot-and-mouth disease viruses in suppressing host antiviral responses. AB - Foot-and-mouth disease virus (FMDV) leader protein (L(pro)) is a papain-like proteinase, which plays an important role in FMDV pathogenesis. L(pro) exists as two forms, Lab and Lb, due to translation being initiated from two different start codons separated by 84 nucleotides. L(pro) self-cleaves from the nascent viral polyprotein precursor as the first mature viral protein. In addition to its role as a viral proteinase, L(pro) also has the ability to antagonize host antiviral effects. To promote FMDV replication, L(pro) can suppress host antiviral responses by three different mechanisms: (1) cleavage of eukaryotic translation initiation factor 4 gamma (eIF4G) to shut off host protein synthesis; (2) inhibition of host innate immune responses through restriction of interferon alpha/beta production; and (3) L(pro) can also act as a deubiquitinase and catalyze deubiquitination of innate immune signaling molecules. In the light of recent functional and biochemical findings regarding L(pro), this review introduces the basic properties of L(pro) and the mechanisms by which it antagonizes host antiviral responses. PMID- 26511923 TI - Axonal dysfunction in internal capsule is closely associated with early motor deficits after intracerebral hemorrhage in mice. AB - Previously we showed that expansion of intracerebral hemorrhage (ICH) into the internal capsule greatly aggravated neurological symptoms in mice. Here we examined ICH-associated events in the internal capsule with relation to neurological dysfunction. Corticospinal axons labeled by biotinylated dextran amine exhibited fragmented appearance after ICH induced by local injection of collagenase into the internal capsule. Fragmentation of axonal structures was confirmed by neurofilament-H immunostaining, which was evident from 6h after induction of ICH. We also observed accumulation of amyloid precursor protein, which indicated compromised axonal transport, from 3h after induction of ICH. The early defect in axonal transport was accompanied by a robust decline in motor performance. Local application of an axonal transport inhibitor colchicine to the internal capsule induced a prompt decline in motor performance, suggesting that compromised axonal transport is closely associated with early neurological dysfunction in ICH. Arrest of axonal transport and fragmentation of axonal structures were also induced by local injection of thrombin, but not by thrombin receptor activator peptide-6, a protease-activated receptor-1 agonist. These results suggest that receptor-independent actions of thrombin mediate disruption of structure and function of axons by hemorrhage expansion into the internal capsule, which leads to severe neurological dysfunction. PMID- 26511924 TI - FGF/MAPK signaling sets the switching threshold of a bistable circuit controlling cell fate decisions in embryonic stem cells. AB - Intracellular transcriptional regulators and extracellular signaling pathways together regulate the allocation of cell fates during development, but how their molecular activities are integrated to establish the correct proportions of cells with particular fates is not known. Here we study this question in the context of the decision between the epiblast (Epi) and the primitive endoderm (PrE) fate that occurs in the mammalian preimplantation embryo. Using an embryonic stem cell (ESC) model, we discover two successive functions of FGF/MAPK signaling in this decision. First, the pathway needs to be inhibited to make the PrE-like gene expression program accessible for activation by GATA transcription factors in ESCs. In a second step, MAPK signaling levels determine the threshold concentration of GATA factors required for PrE-like differentiation, and thereby control the proportion of cells differentiating along this lineage. Our findings can be explained by a simple mutual repression circuit modulated by FGF/MAPK signaling. This might be a general network architecture to integrate the activity of signal transduction pathways and transcriptional regulators, and serve to balance proportions of cell fates in several contexts. PMID- 26511925 TI - Neurogenesis in sea urchin embryos and the diversity of deuterostome neurogenic mechanisms. AB - A single origin to the diverse mechanisms of metazoan neurogenesis is suggested by the involvement of common signaling components and similar classes of transcription factors. However, in many forms we lack details of where neurons arise, patterns of cell division, and specific differentiation pathway components. The sea urchin larval nervous system is composed of an apical organ, which develops from neuroepithelium and functions as a central nervous system, and peripheral neurons, which differentiate in the ciliary band and project axons to the apical organ. To reveal developmental mechanisms of neurogenesis in this basal deuterostome, we developed antibodies to SoxC, SoxB2, ELAV and Brn1/2/4 and used neurons that develop at specific locations to establish a timeline for neurogenesis. Neural progenitors express, in turn, SoxB2, SoxC, and Brn1/2/4, before projecting neurites and expressing ELAV and SynB. Using pulse-chase labeling of cells with a thymidine analog to identify cells in S-phase, we establish that neurons identified by location are in their last mitotic cycle at the time of hatching, and S-phase is coincident with expression of SoxC. The number of cells expressing SoxC and differentiating as neurons is reduced in embryos injected with antisense morpholino oligonucleotides to SoxC, SoxB2 or Six3. Injection of RNA encoding SoxC into eggs does not enhance neurogenesis. In addition, inhibition of FGF receptors (SU5402) or a morpholino to FGFR1 reduces expression of SoxC. These data indicate that there are common features of neurogenesis in deuterostomes, and that sea urchins employ developmental mechanisms that are distinct from other ambulacraria. PMID- 26511926 TI - A new Xist allele driven by a constitutively active promoter is dominated by Xist locus environment and exhibits the parent-of-origin effects. AB - The dosage difference of X-linked genes between the sexes in mammals is compensated for by genetic inactivation of one of the X chromosomes in XX females. A noncoding RNA transcribed from the Xist gene at the onset of X chromosome inactivation coats the X chromosome in cis and induces chromosome-wide heterochromatinization. Here, we report a new Xist allele (Xist(CAG)) driven by a CAG promoter, which is known to be constitutively active in many types of cells. The paternal transmission of Xist(CAG) resulted in the preferential inactivation of the targeted paternal X (Xp) not only in the extra-embryonic but also the embryonic lineage, whereas maternal transmission ended with embryonic lethality at the early postimplantation stage with a phenotype that resembled mutant embryos carrying a maternal deficiency in Tsix, an antisense negative regulator of Xist, in both sexes. Interestingly, we found that the upregulation of Xist(CAG) in preimplantation embryos temporally differed depending on its parental origin: its expression started at the 4- to 8-cell stages when paternally inherited, and Xist(CAG) was upregulated at the blastocyst stage when maternally inherited. This might indicate that the Xist locus on Xp is permissive to transcription, but the Xist locus on the maternal X (Xm) is not. We extrapolated from these findings that the maternal Xist allele might manifest a chromatin structure inaccessible by transcription factors relative to the paternal allele. This might underlie the mechanism for the maternal repression of Xist at the early cleavage stage when Tsix expression has not yet occurred on Xm. PMID- 26511928 TI - CRISPR/Cas9-mediated mutagenesis in the sea lamprey Petromyzon marinus: a powerful tool for understanding ancestral gene functions in vertebrates. AB - Lamprey is one of only two living jawless vertebrates, a group that includes the first vertebrates. Comparisons between lamprey and jawed vertebrates have yielded important insights into the origin and evolution of vertebrate physiology, morphology and development. Despite its key phylogenetic position, studies of lamprey have been limited by their complex life history, which makes traditional genetic approaches impossible. The CRISPR/Cas9 system is a bacterial defense mechanism that was recently adapted to achieve high-efficiency targeted mutagenesis in eukaryotes. Here we report CRISPR/Cas9-mediated disruption of the genes Tyrosinase and FGF8/17/18 in the sea lamprey Petromyzon marinus, and detail optimized parameters for producing mutant F0 embryos. Using phenotype and genotype analyses, we show that CRISPR/Cas9 is highly effective in the sea lamprey, with a majority of injected embryos developing into complete or partial mutants. The ability to create large numbers of mutant embryos without inbred lines opens exciting new possibilities for studying development in lamprey and other non-traditional model organisms with life histories that prohibit the generation of mutant lines. PMID- 26511927 TI - Evidence for the involvement of fibroblast growth factor 10 in lipofibroblast formation during embryonic lung development. AB - Lipid-containing alveolar interstitial fibroblasts (lipofibroblasts) are increasingly recognized as an important component of the epithelial stem cell niche in the rodent lung. Although lipofibroblasts were initially believed merely to assist type 2 alveolar epithelial cells in surfactant production during neonatal life, recent evidence suggests that these cells are indispensable for survival and growth of epithelial stem cells during adulthood. Despite increasing interest in lipofibroblast biology, little is known about their cellular origin or the molecular pathways controlling their formation during embryonic development. Here, we show that a population of lipid-droplet-containing stromal cells emerges in the developing mouse lung between E15.5 and E16.5. This is accompanied by significant upregulation, in the lung mesenchyme, of peroxisome proliferator-activated receptor gamma (master switch of lipogenesis), adipose differentiation-related protein (marker of mature lipofibroblasts) and fibroblast growth factor 10 (previously shown to identify a subpopulation of lipofibroblast progenitors). We also demonstrate that although only a subpopulation of total embryonic lipofibroblasts derives from Fgf10(+) progenitor cells, in vivo knockdown of Fgfr2b ligand activity and reduction in Fgf10 expression lead to global reduction in the expression levels of lipofibroblast markers at E18.5. Constitutive Fgfr1b knockouts and mutants with conditional partial inactivation of Fgfr2b in the lung mesenchyme reveal the involvement of both receptors in lipofibroblast formation and suggest a possible compensation between the two receptors. We also provide data from human fetal lungs to demonstrate the relevance of our discoveries to humans. Our results reveal an essential role for Fgf10 signaling in the formation of lipofibroblasts during late lung development. PMID- 26511929 TI - Intestinal decolonization of Enterobacteriaceae producing extended-spectrum beta lactamases (ESBL): a retrospective observational study in patients at risk for infection and a brief review of the literature. AB - BACKGROUND: Multidrug-resistant Escherichia coli and other enteric bacteria producing extended-spectrum beta-lactamases (ESBL) have emerged as an important cause of invasive infection. Targeting the primary (intestinal) niche by decolonization may be a valuable approach to decrease the risk of relapsing infections and to reduce transmission of ESBL-producing enteric pathogens. METHODS: In a retrospective observational study we evaluated the efficacy of intestinal decolonization treatment using orally administered colistin or other non-absorbable agents given for 2 to 4 weeks in adult patients with previous relapsing infection and persistent intestinal colonization with ESBL-positive Enterobacteriaceae (ESBL-E). Eradication success was defined as negative rectal swab or stool culture at the end of treatment and at follow up-2 weeks after treatment discontinuation. RESULTS: First-line decolonization treatment led to eradication of ESBL-E in 19/45 patients (42%, 7/18 low-dose [4 * 1 million units] colistin, 3/12 high-dose [4 * 2 million units] colistin, 9/15 rifaximin [2 * 400 mg]), and secondary/salvage treatment was successful in 8/13 patients (62 %, 20 treatment episodes). Late follow-up showed that 7/13 patients (54%) with successful initial or salvage decolonization became recolonized within 3 months after post-treatment assessment while all eight of the patients failing initial or salvage decolonization treatment with late follow-up remained colonized. A narrative review of the literature confirms the limited efficacy of non absorbable antibiotics including conventional selective digestive tract decolonization (SDD)-like combination regimens for eradicating multidrug resistant enteric bacteria from the intestinal tract. CONCLUSIONS: At present, there is no clear evidence of a significant decolonization efficacy using single drug treatment with oral non-absorbable antibiotics. More effective regimens are needed and a better definition of at risk patients is required for planning meaningful randomized controlled studies in this field. PMID- 26511930 TI - Effects of two-months balanced diet in metabolically healthy obesity: lipid correlations with gender and BMI-related differences. AB - BACKGROUND: Nowadays no researches has been performed on fatty acid profile (FA) and desaturase activity in metabolically healthy obesity (MHO). The aim of this study was to assessed gender and BMI-related difference in FA, estimated desaturase activities and the efficacy on metabolic changes produced by 2-months well-balance diet in MHO subjects. METHODS: In 103 MHO subjects (30/73 M/F; age:42.2 +/- 9.5) FA, estimated desaturase activity, body composition (by DXA), Body Mass Index (BMI), lipid profile, adipokines (leptin, adiponectin, grelin, glucagon-like peptide-1), insulin resistence (by Homestasis metabolic assessment), C-reactive proteine, Atherogenic index of plasma (AIP) and Body Shape Index (ABSI) have been assessed. Gender and BMI related difference have been evaluated and the efficacy produced by 2-months well-balance diet has been considered. RESULTS: At baseline, obese subjects, compared to overweight, show a significantly higher oleic (p <0.050), monounsaturated fatty acids (p <0.040), C18:0 delta-9 desaturase activity (D9D) (p <0.040) and lower linoleic acid (p <0.020), polyunsaturated fatty acids (p <0.020) and n-6 LCPUFA (p <0.010). Concerning gender-related difference, women show a significantly higher arachidonic acid (p <0.001), polyunsaturated fatty acids (p <0.001), n-6 LCPUFA (p <0.002), and lower monounsaturated fatty acids (p <0.001), D6D activity (p <0.030), C18:0 D9D (0.000) and C16:0 D9D (p <0.030). The 2-months diet was associated with a significantly increase in arachidonic acid (p = 0.007), eicosapentaenoic acid (p = 0.030), docosahexaenoic acid (p <0.001), long chain omega 3 polyunsaturated fatty acids (n-3 LCPUFA) (p <0.001), delta-5 desaturase activity (D5D) (p = 0.002), glucagon like peptide-1 (p <0.001) and a significant decrease in palmitoleic acid (p = <0.030), n-6/n-3 LCPUFA (p <0.001), insulin resistance (p = 0.006), leptin (p = 0.006), adiponectin (p <0.001), grelin (p = 0.030), CRP (p = 0.004), BMI (p <0.001) and android fat mass (p <0.001). CONCLUSIONS: The balanced diet intervention was effective in improving metabolic indices. PMID- 26511931 TI - Pathways to multidrug-resistant tuberculosis diagnosis and treatment initiation: a qualitative comparison of patients' experiences in the era of rapid molecular diagnostic tests. AB - BACKGROUND: Although new molecular diagnostic tests such as GenoType MTBDRplus and Xpert(r) MTB/RIF have reduced multidrug-resistant tuberculosis (MDR-TB) treatment initiation times, patients' experiences of diagnosis and treatment initiation are not known. This study aimed to explore and compare MDR-TB patients' experiences of their diagnostic and treatment initiation pathway in GenoType MTBDRplus and Xpert(r) MTB/RIF-based diagnostic algorithms. METHODS: The study was undertaken in Cape Town, South Africa where primary health-care services provided free TB diagnosis and treatment. A smear, culture and GenoType MTBDRplus diagnostic algorithm was used in 2010, with Xpert(r) MTB/RIF phased in from 2011-2013. Participants diagnosed in each algorithm at four facilities were purposively sampled, stratifying by age, gender and MDR-TB risk profiles. We conducted in-depth qualitative interviews using a semi-structured interview guide. Through constant comparative analysis we induced common and divergent themes related to symptom recognition, health-care access, testing for MDR-TB and treatment initiation within and between groups. Data were triangulated with clinical information and health visit data from a structured questionnaire. RESULTS: We identified both enablers and barriers to early MDR-TB diagnosis and treatment. Half the patients had previously been treated for TB; most recognised recurring symptoms and reported early health-seeking. Those who attributed symptoms to other causes delayed health-seeking. Perceptions of poor public sector services were prevalent and may have contributed both to deferred health seeking and to patient's use of the private sector, contributing to delays. However, once on treatment, most patients expressed satisfaction with public sector care. Two patients in the Xpert(r) MTB/RIF-based algorithm exemplified its potential to reduce delays, commencing MDR-TB treatment within a week of their first health contact. However, most patients in both algorithms experienced substantial delays. Avoidable health system delays resulted from providers not testing for TB at initial health contact, non-adherence to testing algorithms, results not being available and failure to promptly recall patients with positive results. CONCLUSION: Whilst the introduction of rapid tests such as Xpert(r) MTB/RIF can expedite MDR-TB diagnosis and treatment initiation, the full benefits are unlikely to be realised without reducing delays in health-seeking and addressing the structural barriers present in the health-care system. PMID- 26511932 TI - Performance of four HRP-2/pLDH combination rapid diagnostic tests and field microscopy as screening tests for malaria in pregnancy in Indonesia: a cross sectional study. AB - BACKGROUND: Malaria in pregnancy poses a major public health problem in Indonesia with an estimated six million pregnancies at risk of Plasmodium falciparum or Plasmodium vivax malaria annually. In 2010, Indonesia introduced a screen and treat policy for the control of malaria in pregnancy at first antenatal visit using microscopy or rapid diagnostic tests (RDTs). A diagnostic study was conducted in Sumba, Indonesia to compare the performance of four different RDTs in predominately asymptomatic pregnant women under field condition. METHODS: Women were screened for malaria at antenatal visits using field microscopy and four HRP-2/pLDH combination RDTs (CarestartTM, First-Response((r)), Parascreen((r)) and SD-Bioline((r))). The test results were compared with expert microscopy and nested PCR. End user experience of the RDTs in the field was assessed by questionnaire. RESULTS: Overall 950 were recruited and 98.7 % were asymptomatic. The prevalence of malaria was 3.0-3.4 % by RDTs, and 3.6, 5.0 and 6.6 % by field microscopy, expert microscopy and PCR, respectively. The geometric mean parasite density was low (P. falciparum = 418, P. vivax = 147 parasites/uL). Compared with PCR, the overall sensitivity of the RDTs and field microscopy to detect any species was 24.6-31.1 %; specificities were >98.4 %. Relative to PCR, First-Response((r)) had the best diagnostic accuracy (any species): sensitivity = 31.1 %, specificity = 98.9 % and diagnostic odds ratio = 39.0 (DOR). The DOR values for CarestartTM, Parascreen((r)), SD-Bioline((r)), and field microscopy were 23.4, 23.7, 23.5 and 29.2, respectively. The sensitivity of Pan-pLDH bands to detect PCR confirmed P. vivax mono-infection were 8.6-13.0 %. The sensitivity of the HRP-2 band alone to detect PCR confirmed P. falciparum was 10.3-17.9 %. Pan-pLDH detected P. falciparum cases undetected by the HRP-2 band resulting in a better test performance when both bands were combined. First Response((r)) was preferred by end-users for the overall practicality. CONCLUSION: The diagnostic accuracy to detect malaria among mostly asymptomatic pregnant women and perceived ease of use was slightly better with First-Response((r)), but overall, differences between the four RDTs were small and performance comparable to field microscopy. Combination RDTs are a suitable alternative to field microscopy to screen for malaria in pregnancy in rural Indonesia. The clinical relevance of low density malaria infections detected by PCR, but undetected by RDTs or microscopy needs to be determined. PMID- 26511933 TI - Psychological Aspects of the Israeli-Palestinian Conflict: A Systematic Review. AB - Despite ongoing local and international peace efforts, the Jews, Arabs, and other residents of Israel and the Palestinian territories (i.e., the West Bank and Gaza) have endured decades of political, social, and physical upheaval, with periodic eruptions of violence. It has been theorized that the psychological impact of the Israeli-Palestinian conflict extends beyond the bounds of psychiatric disorders such as posttraumatic stress disorder (PTSD). Exposure to the ongoing conflict may lead to changes in the way Israelis and Palestinians think, feel, and act; while these changes may not meet the thresholds of PTSD or depression, they nonetheless could have a strong public health impact. It is unclear whether existing studies have found associations between exposure to the conflict and nonclinical psychological outcomes. We conducted a systematic review to synthesize the empirical research on the Israeli-Palestinian conflict and its psychological consequences. As a whole, the body of literature we reviewed suggests that exposure to regional political conflict and violence may have detrimental effects on psychological well-being and that these effects likely extend beyond the psychiatric disorders and symptoms most commonly studied. We found evidence that exposure to the conflict informs not only the way Israelis and Palestinians think, feel, and act but also their attitudes toward different religious and ethnic groups and their degree of support for peace or war. We also found that Palestinians may be at particularly high risk of experiencing psychological distress as a result of the conflict, though more research is needed to determine the extent to which this is due to socioeconomic stress. Our review suggests the need for more studies on the nonclinical psychological aspects of the Israeli-Palestinian conflict as well as for longitudinal studies on the impact of the conflict on both Israelis and Palestinians. PMID- 26511934 TI - Misplacement of left-sided double-lumen tubes into the right mainstem bronchus: incidence, risk factors and blind repositioning techniques. AB - BACKGROUND: Double-lumen endobronchial tubes (DLTs) are commonly advanced into the mainstem bronchus either blindly or by fiberoptic bronchoscopic guidance. However, blind advancement may result in misplacement of left-sided DLTs into the right bronchus. Therefore, incidence, risk factors, and blind repositioning techniques for right bronchial misplacement of left-sided DLTs were investigated. METHODS: This was an observational cohort study performed on the data depository consecutively collected from patients who underwent intubation of left-sided DLTs for 2 years. Patients' clinical and anatomical characteristics were analyzed to investigate risk factors for DLT misplacements with logistic regression analysis. Moreover, when DLTs were misplaced into the right bronchus, the bronchial tube was withdrawn into the trachea and blindly readvanced without rotation, or with 90 degrees or 180 degrees counterclockwise rotation while the patient's head was turned right. RESULTS: DLTs were inadvertently advanced into the right bronchus in 48 of 1135 (4.2 %) patients. DLT misplacements occurred more frequently in females, in patients of short stature or with narrow trachea and bronchi, and when small-sized DLTs were used. All of these factors were significantly inter-correlated each other (P < 0.001). In 40 of the 48 (83.3 %) patients, blind repositioning was successful. CONCLUSIONS: Smaller left-sided DLTs were more frequently misplaced into the right mainstem bronchus than larger DLTs. Moreover, we were usually able to reposition the misplaced DLTs into the left bronchus by using the blind techniques. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01371773. PMID- 26511935 TI - Transperitoneal repair of a juxtarenal abdominal aortic aneurysm and co-existent horseshoe kidney with division of the renal isthmus. AB - The co-existence of abdominal aortic aneurysm (AAA) and horseshoe kidney (HSK) is rare. We report a 67-year-old man with an expanding juxtarenal AAA associated with a HSK. The aneurysm had a severely angulated neck and contained a significant amount of mural thrombus. The isthmus of HSK closely lied over the aneurysm, making its exposure extremely difficult. The aneurysm was successfully repaired using transperitoneal approach with division of the renal isthmus and without any need for the renal artery reconstruction. Despite the potential complications, particularly renal insufficiency, associated with division of the renal isthmus and suprarenal cross-clamping of the abdominal aorta, in our case, post-operative period was uneventful and the patient's recovery was satisfactory. PMID- 26511936 TI - Investigation of Thermal and Viscoelastic Properties of Polymers Relevant to Hot Melt Extrusion, IV: AffinisolTM HPMC HME Polymers. AB - Most cellulosic polymers cannot be used as carriers for preparing solid dispersion of drugs by hot melt extrusion (HME) due to their high melt viscosity and thermal degradation at high processing temperatures. Three HME-grade hydroxypropyl methylcelluloses, namely AffinisolTM HPMC HME 15 cP, AffinisolTM HPMC HME 100 cP, and AffinisolTM HPMC HME 4 M, have recently been introduced by The Dow Chemical Co. to enable the preparation of solid dispersion at lower and more acceptable processing temperatures. In the present investigation, physicochemical properties of the new polymers relevant to HME were determined and compared with that of Kollidon((r)) VA 64. Powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), thermogravimetric analysis (TGA), moisture sorption, rheology, and torque analysis by melt extrusion were applied. PXRD and mDSC showed that the AffinisolTM polymers were amorphous in nature. According to TGA, the onset of degradation for all polymers was >220 degrees C. The AffinisolTM polymers exhibited less hygroscopicity than Kollidon((r)) VA 64 and another HPMC polymer, MethocelTM K100LV. The complex viscosity profiles of the AffinisolTM polymers as a function of temperature were similar. The viscosity of the AffinisolTM polymers was highly sensitive to the shear rate applied, and unlike Kollidon((r)) VA 64, the viscosity decreased drastically when the angular frequency was increased. Because of the very high shear rate encountered during melt extrusion, AffinisolTM polymers showed capability of being extruded at larger windows of processing temperatures as compared to that of Kollidon((r)) VA 64. PMID- 26511937 TI - Transfersomal Nanoparticles for Enhanced Transdermal Delivery of Clindamycin. AB - The aim of this work was to study the potential of delivering clindamycin phosphate, as an efficient antibiotic drug, into a more absorbed, elastic ultradeformable form, transfersomes (TRSs). These vesicles showed an enhanced penetration through ex vivo permeation characters. TRSs were prepared using thin film hydration method. Furthermore, they were evaluated for their entrapment efficiency, size, zeta potential, and morphology. Also, the prepared TRSs were converted into suitable gel formulation using carbopol 934 and were evaluated for their gel characteristics like pH, viscosity, spreadability, homogeneity, skin irritation, in vitro release, stability, and ex vivo permeation studies in rats. TRSs were efficiently formulated in a stable bilayer vesicle structure. Furthermore, clindamycin phosphate showed higher entrapment efficiency within the TRSs reaching about 93.3% +/- 0.8 and has a uniform particle size. Moreover, the TRSs surface had a high negative charge which indicated the stability of the produced vesicles and resistance of aggregation. Clindamycin phosphate showed a significantly higher in vitro release (p < 0.05; ANOVA/Tukey) compared with the control carbopol gel. Furthermore, the transfersomal gel showed a significantly higher (p < 0.05; ANOVA/Tukey) cumulative amount of drug permeation and flux than both the transfersomal suspension and the control carbopol gel. In conclusion, the produced results suggest that TRS-loaded clindamycin are promising carriers for enhanced dermal delivery of clindamycin phosphate. PMID- 26511938 TI - Effect of Food Status on the Gastrointestinal Transit of Amphotericin B Containing Solid Lipid Nanoparticles in Rats. AB - Amphotericin B (AmB) is poorly absorbed from the gastrointestinal tract. Recent studies have suggested enhanced drug absorption from solid lipid nanoparticles (SLN). Little is known of the fate of AmB absorption within the gastrointestinal tract, and no gastrointestinal transit study has yet been performed on AmB containing nano-formulations. We aimed to investigate the effect of food on the gastrointestinal transit properties of an AmB-containing SLN in rats. Three SLNs containing AmB, paracetamol, or sulfasalazine were formulated using cocoa butter and beeswax as lipid matrices and simultaneously administered orally to Sprague Dawley rats. Paracetamol and sulfapyridine were used as marker drugs for estimating gastric emptying and cecal arrival, respectively. The pharmacokinetic data generated for paracetamol and sulfapyridine were used in estimating the absorption of the AmB SLNs in the small and large intestines, respectively. A delayed rate of AmB absorption was observed in the fed state; however, the extent of absorption was not affected by food. Specifically, the percentages of AmB absorption during the fasted state in the stomach, small intestine, and colon were not significantly different from absorption within the respective regions in the fed state. In both states, however, absorption was highest in the colon and appeared to be a combination of absorption from the small intestine plus absorption proper within the colon. The study suggests that AmB SLN, irrespective of food status, is slowly but predominantly taken up by the lymph, making the small intestine the most favorable site for the delivery of the AmB SLNs. PMID- 26511939 TI - Carbetocin versus oxytocin in the management of atonic post partum haemorrhage (PPH) after vaginal delivery: a randomised controlled trial. AB - OBJECTIVE: The objective of this study is to compare the effectiveness and safety of carbetocin vs. oxytocin in the management of atonic post partum haemorrhage (PPH) after vaginal delivery. METHODS: A prospective randomised study was conducted in which 100 pregnant women were randomised into 2 equal groups: group 1 received Carbetocin 100 ugm (Pabal((r)) Ferring, UK) and group 2 received oxytocin 5 IU (Syntocinon((r)), Novartis, Switzerland). RESULTS: The amount of blood loss and the need for other uterotonics were significantly lower in the carbetocin group (811 +/- 389.17 vs. 1010 +/- 525.66 and 10/50 vs. 21/50). There was no significant difference between the carbetocin and oxytocin groups regarding occurrence of major PPH (6 vs. 11), the need for blood transfusion (6 vs. 9), the difference between blood haemoglobin levels before delivery and 24 h after delivery (0.6 +/- 0.28 vs. 0.56 +/- 0.25), respectively. There was no significant difference between the 2 study groups regarding both systolic and diastolic blood pressure measured immediately after the drug administration and at 30 and 60 min later. Regarding the drugs side effects, there was no significant difference between the 2 groups in the occurrence of nausea, vomiting, tachycardia, flushing, dizziness, headache, shivering, metallic taste, dyspnea, palpitations and itching. CONCLUSIONS: Carbetocin is a better alternative to oxytocin in management of atonic PPH with non-significant hemodynamic changes or side effects . PMID- 26511940 TI - Genetic characteristics of inflammatory bowel disease in a Japanese population. AB - BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are two major forms of inflammatory bowel disease (IBD). Meta-analyses of genome-wide association studies (GWAS) have identified 163 susceptibility loci for IBD among European populations; however, there is limited information for IBD susceptibility in a Japanese population. METHODS: We performed a GWAS using imputed genotypes of 743 IBD patients (372 with CD and 371 with UC) and 3321 controls. Using 100 tag single-nucleotide polymorphisms (SNPs) (P < 5 * 10(-5)), a replication study was conducted with an independent set of 1310 IBD patients (949 with CD and 361 with UC) and 4163 controls. In addition, 163 SNPs identified by a European IBD GWAS were genotyped, and genetic backgrounds were compared between the Japanese and European populations. RESULTS: In the IBD GWAS, two East Asia-specific IBD susceptibility loci were identified in the Japanese population: ATG16L2-FCHSD2 and SLC25A15-ELF1-WBP4. Among 163 reported SNPs in European IBD patients, significant associations were confirmed in 18 (8 CD-specific, 4 UC-specific, and 6 IBD-shared). In Japanese CD patients, genes in the Th17-IL23 pathway showed stronger genetic effects, whereas the association of genes in the autophagy pathway was limited. The association of genes in the epithelial barrier and the Th17-IL23R pathways were similar in the Japanese and European UC populations. CONCLUSIONS: We confirmed two IBD susceptibility loci as common for CD and UC, and East Asian-specific. The genetic architecture in UC appeared to be similar between Europeans and East Asians, but may have some differences in CD. PMID- 26511941 TI - Gastrointestinal stromal tumors in Japanese patients with neurofibromatosis type I. AB - BACKGROUND: Neurofibromatosis type I (NF1) predisposes patients to various neoplasias, including gastrointestinal stromal tumors (GISTs). Little is known about the risk of developing GISTs for NF1 patients or the clinicopathologic features and prognosis of NF1-GIST. METHODS: We conducted a multi-detector computed tomography screen for adult NF1 patients between 2003 and 2012. Clinicopathologic data of sporadic GISTs from patients who underwent surgery between 2001 and 2010 were retrospectively collected from 32 hospitals in Japan. RESULTS: CT screening identified 6 GIST patients from the 95 NF1 patients screened, suggesting that the prevalence rate of GISTs was approximately 6.3/100 in NF1 patients. All 6 NF1 patients exhibited hyperplasia of the interstitial cells of Cajal in the adjoining small intestine. NF1-GISTs may account for 1.1 1.3 % of primary sporadic GISTs and present as multiple tumors in the small intestine, with low mitotic activity and no KIT or PDGFRA mutations. The risk of recurrence and mortality is very similar between NF1 and non-NF1 patients after surgical resection of GISTs. CONCLUSIONS: NF1 patients may be predisposed to developing small intestinal GISTs, which may appear as multiple GISTs without KIT and PDGFRA mutations. The prognosis of patients with NF1-GISTs is similar to patients with conventional GISTs. PMID- 26511942 TI - Health promotion implementation capacities in hospitals matter: results from the PRICES-HPH study. AB - In this article, organizational implementation capacities are discussed as facilitators for hospital health promotion (HP) activities, based on data from 159 sampled hospitals of the PRICES-HPH study. PRICES-HPH is a cross-sectional evaluation study of the International Network of Health Promoting Hospitals and Health Services (HPH-Network) and was conducted from 2008 to 2012. Hospitals applying elaborated HP implementation capacities such as 'regular health promotion projects and organization-wide programs', 'established health promotion management systems' or the 'integration of health promotion in existing quality management systems' have better HP activity scores as compared with hospitals that implement HP on the basis of occasional projects only. Organizational capacities are associated with considerably higher chances for the successful implementation of a multiplicity of different HP activities in hospitals. The results add further evidence to the importance of capacity building in hospital HP. PMID- 26511943 TI - Barriers to promote cardiovascular health in community pharmacies: a systematic review. AB - Community pharmacists play an important role in the provision of health promotion services, and community pharmacies are considered as a potentially ideal site for cardiovascular health promotion. Information based on a systematic review of barriers to promoting cardiovascular health in community pharmacy is currently lacking. We have sought to identify the most important barriers to cardiovascular health promotion in the community pharmacy. We have systematically searched PubMed and International Pharmaceutical Abstracts for a period of 15 years from 1 April 1998 to 1 April 2013, contacted subject experts and hand-searched bibliographies. We have included peer-reviewed articles, with English abstracts in the analysis, if they reported community pharmacists' perceptions of the barriers to cardiovascular health promotion activities in a community pharmacy setting. Two reviewers have independently extracted study characteristics and data. We identified 24 studies that satisfy the eligibility criteria. The main barriers to cardiovascular health promotion in the community pharmacy included pharmacist-related factors; practice site factors; financial factors; legal factors; and patient-related factors. This review will help to provide reliable evidence for health promotion practitioners of the barriers to promoting cardiovascular health in the community pharmacy setting. This knowledge is valuable for the improvement of cardiovascular health promotion in this setting and guiding future research. PMID- 26511944 TI - Research and the health of indigenous populations in low- and middle-income countries. AB - In low- and middle-income countries (LMICs)-when there are available data-a 'health divide' exists between indigenous and non-indigenous populations living in the same society. Despite the limited available evidence suggesting that indigenous populations have high levels of health needs, there is scant research on indigenous health, especially in Africa, China and South Asia. Pursuing research, however, is clouded by the prior negative experiences that indigenous populations have had with researchers. In this paper, we describe the current evidence base on indigenous health in LMICs, propose practical strategies for undertaking future research, and conclude by describing how global health researchers can contribute to improving the health of indigenous populations. PMID- 26511945 TI - Analysis of drug-related problems in three departments of a German University hospital. AB - BACKGROUND: During the last decades, pharmaceutical care services have been developed and implemented to optimize drug therapies and ensure medication safety. To investigate the need for pharmaceutical care services, drug-related problems can be measured. OBJECTIVE: Thus, the aim of this study was to analyse number, type and occurrence of drug-related problems in different clinical departments. SETTING: A pharmaceutical care service was established on general wards in Urology, Neurology and Gastroenterology at the University Hospital RWTH Aachen, Germany. METHOD: For each of a total of 306 patients, a pharmacist conducted an extended medication history, performed medication reconciliation, conducted medication safety checks and if drug-related problems were discovered, gave valid recommendations to the attending healthcare team. Drug-related problems were classified using the APS-Doc system. For statistical analyses, SAS((r)) 9.1.3, SAS Institute, Cary NC, USA was applied. The project was approved by the local ethics committee. MAIN OUTCOME MEASURE: Type, occurrence and frequency of DRP in different medical departments. RESULTS: On average, 2.3 drug related problems per patient were documented for all three departments. Drug related problems were found in each category of the APS-Doc system. The most pronounced drug-related problems found were drug-drug interactions (34.6 %). 37 % of the identified drug-related problems occurred before hospital admission, 27 % during transitional care, and 36 % on the ward. Subgroup analysis revealed specific drug-related problem patterns for each clinical department. The number of drug-related problems was found to be associated with the number of drugs and age. CONCLUSION: Drug-related problems frequently occur in all investigated clinical departments. A holistic pharmaceutical care service could be an option to address this issue. In case of limited resources, individual drug-related problem patterns can be used as a basis for a tailored pharmaceutical care service. As number of drugs and age have been shown to be significant risk factors, it is crucial that the healthcare team including the pharmacist pays special attention to elderly patients and those with polymedication. PMID- 26511946 TI - The use of theory in research. AB - All researchers should consider the theoretical basis for their studies very early on in the planning stage. The aim of this paper is to describe and discuss how theory (a 'comprehensive explanation of some aspect of nature that is supported by a body of evidence') can inform and improve the quality and relevance of pharmacy-based research. Theories can be applied at many stages of quantitative and qualitative (and mixed) research processes, including: providing rationale for the study; defining the aim and research questions; considering the methodological stance; developing data collection and generation tools; providing a framework for data analysis, and interpretation. The focus of the paper is on the use of theoretical lenses, their selection and application. Two key theoretical lenses and their potential applications are described: the Theoretical Domains Framework in studies of behavioural change, and Normalization Process Theory in implementing, embedding and integrating interventions. PMID- 26511947 TI - Long-term effects of growth hormone (GH) replacement therapy on hematopoiesis in a large cohort of children with GH deficiency. AB - The aim of our prospective case-control study was to evaluate long-term effects of GH replacement therapy on erythrocytes parameters, leukocytes, and platelets numbers in a large cohort of children with isolated GH deficiency (GHD). Hemoglobin (Hb) concentration, hematocrit (Hct), mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution width, number of erythrocytes, leukocytes, neutrophils, lymphocytes, monocytes and platelets, ferritin, and C reactive protein were evaluated in 85 children with isolated GHD (10.20 +/- 3.50 years) before and annually during the first 5 years of GH replacement therapy and in 85 healthy children age and sex comparable to patients during 5 years of follow-up. Compared with controls, GHD children at study entry showed lower Hb ( 1.18 +/- 0.87 vs. -0.40 +/- 0.90 SDS, p < 0.0001), red cells number (-0.24 +/- 0.81 vs. 0.25 +/- 1.14 SDS, p < 0.0001), and Hct (-1.18 +/- 0.86 vs. -0.68 +/- 0.99 SDS, p < 0.0001). Twelve GHD patients (14 %) showed a normocytic anemia. GH therapy was associated with a significant increase in Hb, Hct, and red cells number which became all comparable to controls within the first 2 years of treatment. Moreover, hemoglobin levels normalized in all anemic GHD patients after 5 years of therapy. No difference between patients and controls was found in leukocytes and platelets numbers neither at baseline nor during the study. GHD in childhood is associated with an impairment of erythropoiesis which causes a normocytic anemia in a considerable percentage of patients. GH replacement therapy exerts a beneficial effect leading to a significant increase of erythrocytes parameters and recovery from anemia. Neither GHD nor GH replacement treatment exerts effects on leukocytes or platelets numbers. PMID- 26511948 TI - Serum but not salivary cortisol levels are influenced by daily glycemic oscillations in type 2 diabetes. AB - Diurnal salivary and plasma cortisol variations are considered valid expression of circadian cortisol rhythmicity. The aim of this study was to assess the reliability of salivary and plasma cortisol and if glycemia and glycemic oscillations may interfere with their concentration. Forty-seven type 2 diabetic patients and 31 controls were studied for glycemic profile and diurnal salivary and plasma cortisol variations on two contemporary samples taken at 08:00 a.m. 11:00 p.m (Late Night, LN). Glucose variability was evaluated in diabetic patients by considering the standard deviation of blood glucose (BGSD) readings, by calculating the mean amplitude of glycemic excursions (MAGEs) and continuous overlapping net glycemic action (CONGA). A significant correlation between LN serum cortisol and morning fasting glycemia (r = 0.78; p = 0.004) was observed in T2DM group but not in the control group (r = 0.09; p = 0.74). While LN serum cortisol significantly correlated with CONGA in diabetic patients (r = 0.50; p < 0.001), LN salivary cortisol did not correlate with any indices of glucose variability. Moreover, a highly significant correlation between LN salivary and LN serum cortisol concentrations was found in control group (r = 0.80; p < 0.001) but not in diabetic patients (r = 0.07; p = 0.62). This study shows for the first time that LN salivary rather than plasma cortisol may give information on the dynamics of adrenal function of type 2 diabetic patients, as it is not significantly influenced by glycemic variations. However, our preliminary results need to be confirmed by further studies with more complete evaluations including many more patients. PMID- 26511950 TI - Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with Low-Dose Cisplatin and Doxorubicin in Gastric Peritoneal Metastasis. AB - BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique of intraperitoneal chemotherapy. First results obtained with PIPAC in patients with advanced peritoneal metastasis (PM) from gastric cancer (GC) are presented. METHODS: Retrospective analysis: Sixty PIPAC were applied in 24 consecutive patients with PM from GC. 67 % patients had previous surgery, and 79 % previous platinum-based systemic chemotherapy. Mean Peritoneal Carcinomatosis Index (PCI) of 16 +/- 10 and 18/24 patients had signet-ring GC. Cisplatin 7.5 mg/m(2) and doxorubicin 1.5 mg/m(2) were given for 30 min at 37 degrees C and 12 mmHg at 6 week intervals. Outcome criteria were survival, adverse events, and histological tumor response. RESULTS: Median follow-up was 248 days (range 105 748), and median survival time was 15.4 months. Seventeen patients had repeated PIPAC, and objective tumor response was observed in 12 (12/24 = 50 %): no vital tumor cells = 6, major pathological response = 6, minor response = 3. Postoperative adverse events > CTCAE 2 were observed in 9 patients (9/24, 37.5 %). In 3/17 patients, a later PIPAC could not be performed due to non-access. Two patients (ECOG 3 and 4) died in the hospital due to disease progression. CONCLUSION: PIPAC with low-dose cisplatin and doxorubicin was safe and induced objective tumor regression in selected patients with PM from recurrent, platinum resistant GC. First survival data are encouraging and justify further clinical studies in this indication. PMID- 26511951 TI - Bacterial community and proteome analysis of fresh-cut lettuce as affected by packaging. AB - With the growing demand of fresh-cut vegetables, a variety of packaging films are produced specifically to improve safety and quality of the fresh vegetables over the storage period. The aim of our work was to evaluate the influence of different packaging films on the quality of fresh-cut lettuce analyzing changes in bacterial community composition and modifications at the proteome level, by means of culture-dependent/culture-independent methods and differential gel electrophoresis combined with mass spectrometry analysis. Total viable counts indicated the presence of a highly variable and complex microbial flora, around a mean value of 6.26 log10 CFU g(-1). Analysis of terminal-restriction fragment length polymorphism data indicated that bacterial communities changed with packaging films and time, showing differences in community composition and diversity indices between the commercially available package (F) and the new packages (A and C), in the first days after packaging. Also proteomic analysis revealed significant changes, involving proteins related to energy metabolism, photosynthesis, plant defense and oxidative stress processes, between F and A/C packages. In conclusion, microbiological and proteomic analysis have proved to be powerful tools to provide new insights into both the composition of leaf associated bacterial communities and protein content of fresh-cut lettuce during the shelf-life storage process. PMID- 26511949 TI - Cardiovascular risk in adult hypopituitaric patients with growth hormone deficiency: is there a role for vitamin D? AB - Hypovitaminosis D represent an environmental risk factors for cardiovascular (CV) disease. To investigate the prevalence of hypovitaminosis D and the correlation between GH/IGF-I deficiency and hypovitaminosis D with CV risk in GH deficiency (GHD) patients. A link between these hormones has been shown. Forty-one hypopituitaric patients with GHD (22 males, age 18-84 years) and 41 controls were enrolled in the study. Anthropometric parameters, blood pressure, glucose and lipid profile, parathyroid hormone (PTH), 25(OH) vitamin D (vitamin D), metabolic syndrome (MS), GH peak after GHRH + ARG, IGF-I, and standard deviation score (SDS) of IGF-I (zIGF-I) were assessed. Vitamin D levels were lower in patients than in controls (21.3 +/- 12.3 vs. 28.2 +/- 9.4, p = 0.006). Deficiency was found in 51 % of patients versus 14.6 % of controls (p < 0.01), insufficiency in 26.8 versus 41.4 % (p = 0.269) and normal vitamin D levels in 21.9 versus 43.9 % (p = 0.060). The prevalence of dyslipidemia was 51.2 % in patients versus 12.1 % in controls (p < 0.001), type 2 diabetes mellitus (DM) was 7.3 versus 17 % (p = 0.292), hypertension was 44 versus 22 % (p = 0.060), and MS was 17 versus 14.6 % (p = 0.957). In patients, an association was found between the presence of hypovitaminosis D and the prevalence of dyslipidemia, hypertension and MS and between zIGF-I and the prevalence of hypertension. Hypovitaminosis D was the most powerful predictor of the prevalence of dyslipidemia and hypertension. GHD patients have an increased prevalence of hypovitaminosis D compared with controls. The presence of hypovitaminosis D was the most powerful predictor of the prevalence of dyslipidemia and hypertension in GHD patients, suggesting the involvement of both factors in the CV risk in these patients. PMID- 26511952 TI - Structure-function analysis of the Bacillus megaterium GerUD spore germinant receptor protein. AB - Germination of Bacillus spores is triggered by the interaction of germinant molecules with specialized receptor proteins localized to the spore inner membrane. Germinant receptors (GRs) are comprised typically of three interacting protein subunits, each of which is essential for receptor function. At least some GRs appear to have a fourth component, referred to as a D-subunit protein. A number of D-subunit proteins were shown previously to be capable of modulating the activity of associated GRs. Here, we investigate the topology and structure function relationships of the Bacillus megaterium QM B1551 GerUD protein, which is associated with the GerU GR. The presented data demonstrate that GerUD can be subjected to relatively extensive structural modifications while retaining function. Indeed, the presence of either of the two transmembrane spanning domains is sufficient to modulate an efficient GerU-mediated germinative response. The precise function of D-subunit proteins has yet to be established, although they may act as molecular chaperones within the spore inner-membrane environment. PMID- 26511953 TI - SYBR Gold Fluorescence Quenching is a Sensitive Probe of Chitosan-microRNA Interactions. AB - Competitive dye displacement titration has previously been used to characterize chitosan-DNA interactions using ethidium bromide. In this work, we aim to develop a fast and reliable method using SYBR Gold as a fluorescent probe to evaluate the binding affinity between ssRNA and chitosan. The interaction of chitosan with ssRNA was investigated as a function of temperature, molecular weight and degree of acetylation of chitosan, using competitive dye displacement titrations with fluorescence quenching. Affinity constants are reported, showing the high sensitivity of the interaction to the degree of acetylation of chitosan and barely dependent on the molecular weight. We propose that the mechanism of SYBR Gold fluorescence quenching is governed by both static and dynamic quenching. PMID- 26511954 TI - Enhanced Sensitivity for Hydrogen Peroxide Detection: Polydiacetylene Vesicles with Phenylboronic Acid Head Group. AB - It was recently reported that, besides UV irradiated polymerization, polymerization of diacetylene compounds could also been initiated by radicals generated from enzyme catalyzed hydrogen peroxide (H2O2) decomposition. A new optical sensing method for H2O2 was proposed based on this phenomenon. However, the sensitivity of this method is relatively lower than existed ones. In the present work, phenylboronic acid (PBA) functionalized 10, 12-pentacosadiynoic acid (PDA-PBA) was synthesized and its vesicles were formed successfully as colorimetric sensor for H2O2 detection. It was found that color change during the polymerization of vesicles composed of the PBA modified monomer is much stronger than that of the non-modified one. The response of PDA-PBA vesicles to H2O2 is 16 times more sensitive than that of the PDA. The absorption of PDA-PBA at 650 nm is linearly related to the concentration of H2O2 and a detection limit of ~5 MUM could be achieved. PMID- 26511955 TI - Aliidiomarina minuta sp. nov., a haloalkaliphilic bacterium that forms ultra small cells under non-optimal conditions. AB - An aerobic haloalkaliphilic bacterium, designated strain MLST1(T), was isolated from filtered (0.22 um) Mono Lake (USA) waters. The isolate was observed to grow primarily on yeast extract, peptone and tryptone. Optimal growth occurred in media at pH 9.5 containing 5-11 g/l yeast extract, and 70-100 g/l NaCl. When in log phase of growth, cells were found to be mostly curved motile rods (1-3 um length by 0.4-1 um diameter). Phylogenetic analysis of the 16S rRNA gene and chemotaxonomic data revealed that the isolate belonged to the family Idiomarinaceae, and is closely related to Aliidiomarina maris (96.67 % sequence similarity). The major fatty acids were identified to be iso-C17:1 omega9c (27.1 %), iso-C17:0 (21.3 %) and iso-C15:0 (12.2 %). Predominant polar lipids included phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, and the major respiratory quinone was identified as Q8. The DNA base composition was 46.3 mol% G+C. Survival studies indicated that strain MLST1(T) remains viable after exposure to adverse conditions, particularly in the prolonged absence of a carbon source, at low temperatures and with no NaCl. Under these conditions, the cells shrunk to around 0.2 um in length by 0.1 um in diameter and passed through 0.22 um filters. The ultra-small cells could only be resuscitated in media with low levels of yeast extract, up to 0.6 g/l. Once resuscitated, cells were able to grow to full size. Strain MLST1(T) is clearly a unique bacterium in the waters of Mono Lake and the name Aliidiomarina minuta sp. nov. is proposed. The type strain is MLST1(T) (=JCM 17425(T) = KCTC 23357(T)). PMID- 26511957 TI - Respiratory syncytial virus trials and beyond. PMID- 26511956 TI - Efficacy of motavizumab for the prevention of respiratory syncytial virus disease in healthy Native American infants: a phase 3 randomised double-blind placebo controlled trial. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections in children. We aimed to assess the safety and efficacy of an anti-RSV monoclonal antibody (motavizumab) in healthy term (>=36 weeks' gestational age) infants for the prevention of medically attended RSV acute lower respiratory tract infections. METHODS: This phase 3, double-blind, placebo-controlled, randomised trial enrolled healthy Native American infants aged 6 months or younger who were born at 36 weeks' gestational age in southwestern USA, on the Navajo Nation, the White Mountain Apache reservation, and the San Carlos Apache Indian reservation. Participants were randomly assigned (2:1) to receive either five monthly intramuscular doses of motavizumab (15 mg/kg) or placebo. They were followed up for 150 days after the first dose, and the primary endpoints were respiratory admission to hospital with a positive result for RSV by RT-PCR and death caused by RSV. Participants were followed up for medically attended wheezing until they reached age 3 years. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00121108. FINDINGS: During the autumn seasons (October to December) between 2004 and 2007, 2127 infants of the 2596 infants enrolled were randomly assigned to receive either motavizumab (1417) or placebo (710). After ITT analysis, motavizumab resulted in an 87% relative reduction (relative risk [RR] 0.13, 95% CI 0.08-0.21) in the proportion of infants admitted to hospital with RSV (21 [2%] of 1417 participants who received motavizumab; 80 [11%] of 710 participants who received placebo, p<0.0001). Serious adverse events were less common in particpants taking motavizumab (212 [15%]) than particpants on placebo (148 [21%]). Six deaths occurred in study participants (motavizumab, n=4 [0.3%]; placebo, n=2 [0.3%]); none were deemed to be related to the study product. Hypersensitivity events were more common in patients given motavizumab (208 [14.7%]) than in placebo recipients (87 [12.3%]; p=0.14). There was no effect on rates of medically attended wheezing in children aged 1-3 years (190 [14.9%] of participants randomly assigned to receive motavizumab vs 90 [14.0%] participants randomly assigned to receive placebo). INTERPRETATION: To our knowledge, this is the only trial of an anti-RSV antibody to prevent serious RSV disease in healthy term infants. Motavizumab significantly reduced the RSV-associated inpatient and outpatient burden and set a benchmark for the efficacy of RSV prevention strategies. The findings do not support a direct, generalisable, causal association between RSV lower respiratory tract infection and subsequent long term wheezing in term infants. FUNDING: MedImmune. PMID- 26511958 TI - Tackling neglect: treating schistosomiasis in pregnancy. PMID- 26511959 TI - Efficacy and safety of praziquantel for the treatment of human schistosomiasis during pregnancy: a phase 2, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Despite WHO recommendations to offer pregnant women treatment with praziquantel, many nations continue to withhold treatment, awaiting data from controlled trials addressing safety and efficacy. The objectives of this study were to assess whether treatment of pregnant women with schistosomiasis at 12-16 weeks gestation leads to improved maternal and newborn outcomes and to collect maternal and newborn safety data. METHODS: This phase 2, randomised, double blind, placebo-controlled trial was done in 72 baranguays (villages) serviced by six municipal health centres in a schistosomiasis endemic region of northeastern Leyte, Philippines. Pregnant women (at 12-16 weeks gestation) who were otherwise healthy but infected with Schistosoma japonicum were enrolled and randomly assigned (1:1) to receive either over-encapsulated praziquantel (total dose 60 mg/kg given as two split doses) or placebo. Participants, investigators, midwives, and laboratory staff were all masked to treatment. The primary outcome was birthweight. Safety data were collected including immediate reactogenicity, post-dosing toxicology ascertained 24 h after study drug administration, and maternal and newborn serious adverse events. Analysis followed the intention-to treat principle. Analyses were done using hierarchical generalised linear models to adjust for identified confounders and account for potential clustering of observations within villages and municipalities. This trial is registered with ClinicalTrials.gov, number NCT00486863. FINDINGS: Between Aug 13, 2007, and Dec 3, 2012, 370 pregnant women were enrolled and randomly assigned to each treatment group (184 to the placebo group, 186 to the praziquantel group). Most women had low-intensity infections (n=334, 90%). Treatment with praziquantel did not have a significant effect on birthweight (2.85 kg in both groups, beta=-0.002 [95% CI 0.088 to 0.083]; p=0.962). Treatment was well tolerated with reactogenicity rates similar to those seen in non-pregnant participants (severe reactions occurred in five patients in the praziquantel group and two in the placebo group, and included headache, fever, and malaise). There were no significant differences in key safety outcomes including abortion, fetal death in utero, and congenital anomalies. INTERPRETATION: Results from this study provide important data from a controlled trial in support of the expansion of treatment policies to include pregnant women as recommended by WHO. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases (U01AI066050). PMID- 26511960 TI - Clinicians and patients need to be convinced that benefits of big data outweigh risks, MPs are told. PMID- 26511962 TI - Learning through instructions vs. learning through practice: flanker congruency effects from instructed and applied S-R mappings. AB - We compared flanker congruency effects (FCE) for flanker stimuli that were part of merely instructed S-R mappings or S-R mappings that had already been practiced. Four new S-R mappings were instructed before each block of trials. In applied flanker blocks, each instructed stimulus could appear as target and as flanker. In merely instructed flanker blocks, two stimuli only served as targets, whereas the other two exclusively appeared as flankers. Significant FCEs were observed for both flanker conditions even though the instruction-based FCE was (a) smaller than the FCE from applied mappings and (b) decreased with task practice. These results suggest that instructions alone can induce S-R associations that lead to automatic response activation when instructed stimuli appear as flankers. Execution of instructed rules seems to strengthen the instructed associations, leading to increased response conflict. PMID- 26511963 TI - Early alterations in platelet mitochondrial function are associated with survival and organ failure in patients with septic shock. AB - INTRODUCTION: The objective of the study is to determine if changes in platelet mitochondrial function in patients with sepsis are present early after presentation and the association of these changes with clinical outcomes and systemic metabolic function. MATERIALS AND METHODS: This is a prospective observational cohort study of a convenience sample of patients with severe sepsis. Mitochondrial function of intact, nonpermeabilized platelets suspended in their own plasma was estimated using high-resolution respirometry. Unstimulated basal respiration, oligomycin-induced state 4, and maximal respiratory rate after serial titrations of carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone were measured. Organ failure was estimated using Sequential Organ Failure Assessment score, and patients were followed up until 28 days to determine survival. Lactate levels were measured in all patients, and a subset of patients had lactate/pyruvate (L/P) ratios measured. RESULTS: Twenty-eight patients were enrolled, 21 of whom survived. Initial Sequential Organ Failure Assessment score and lactate levels were 8.5 (interquartile range [IQR], 6-10) and 2.3 (IQR, 1.2 3.5) respectively, whereas the median L/P ratio was 23.4 (IQR, 15.2-38). Basal and maximal respiratory rates were significantly higher among nonsurvivors compared to survivors (P = .02 and P = .04), whereas oligomycin-induced state 4 respiration was not statistically different between groups (P = .15). We found a significant association between maximal respiration and organ failure (P = .03) and both basal and maximal rates with initial lactate level (P = .04, P = .02), but not with L/P ratio. CONCLUSIONS: Differences in platelet mitochondrial function between survivors and nonsurvivors are present very early in the hospital course and are associated with organ failure and lactate. PMID- 26511964 TI - Mulberry extract to modULate Blood glucosE Responses in noRmoglYcaemic adults (MULBERRY): study protocol for a randomised controlled trial. AB - BACKGROUND: Worldwide sugar consumption has tripled during the last fifty years. High sugar intake is associated with weight gain and increased incidence of diabetes and has been linked with increased cardiovascular mortality. Reducing the health impact of dietary sugar and poor quality carbohydrate intake is a public health priority. IminoNorm(r), a proprietary mulberry leaf extract (ME), may reduce blood glucose responses following dietary sugar and carbohydrate intake by reducing absorption of glucose from the gut. Previous research has shown that ME can reduce blood glucose and improve insulin responses in healthy subjects and also in subjects with raised fasting blood glucose levels. Mulberry leaf has an excellent safety profile. This pilot study will test a novel, safe, water soluble product in normoglycaemic adults in the UK to determine if it can reduce glucose absorption without increasing plasma insulin concentration. METHODS/DESIGN: The trial will be a double-blind, individually randomised, four arm single-dose crossover design to test the effect of three doses of ME in order to determine efficacy, dose response relationship and gastrointestinal side effects with respect to placebo. A total of 40 subjects will participate in this study and attend for four visits receiving each of the four interventions in random order. DISCUSSION: We aim to test the evidence that mulberry leaf extract can reduce blood glucose without a disproportionate increase in blood insulin responses in healthy individuals in a high-quality research study based in the UK. It is hoped that this will lead to further randomised controlled trials and an effective dietary supplement to lower blood glucose concentrations. TRIAL REGISTRATION: ISRCTN: ISRCTN14597438 (21 April 2015). PMID- 26511965 TI - Jumping into the deep-end: results from a pilot impact evaluation of a community based aquatic exercise program. AB - This multi-center quasi-experimental pilot study aimed to evaluate changes in pain, joint stiffness, physical function, and quality of life over 12 weeks in adults with musculoskeletal conditions attending 'Waves' aquatic exercise classes. A total of 109 adults (mean age, 65.2 years; range, 24-93 years) with musculoskeletal conditions were recruited across 18 Australian community aquatic centers. The intervention is a peer-led, 45 min, weekly aquatic exercise class including aerobic, strength, flexibility, and balance exercises (n = 67). The study also included a control group of people not participating in Waves or other formal exercise (n = 42). Outcomes were measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and EuroQoL five dimensions survey (EQ-5D) at baseline and 12 weeks. Satisfaction with Waves classes was also measured at 12 weeks. Eighty two participants (43 Waves and 39 control) completed the study protocol and were included in the analysis. High levels of satisfaction with classes were reported by Waves participants. Over 90 % of participants reported Waves classes were enjoyable and would recommend classes to others. Waves participants demonstrated improvements in WOMAC and EQ-5D scores however between-group differences did not reach statistical significance. Peer-led aquatic exercise classes appear to improve pain, joint stiffness, physical function and quality of life for people with musculoskeletal conditions. The diverse study sample is likely to have limited the power to detect significant changes in outcomes. Larger studies with an adequate follow-up period are needed to confirm effects. PMID- 26511966 TI - Garre's sclerosing osteomyelitis caused by salmonella group D in a patient with systemic lupus erythematosus: an unusual complication. AB - We report the case of a 35-year-old male, who was diagnosed with systemic lupus erythematosus (SLE) in 2010 based on the presence of articular, serous, renal, immune, and hematologic involvement. He also had secondary antiphospholipid syndrome (APS). He was treated with prednisone 10 mg per day, hydroxychloroquine 200 mg per day, methotrexate 12.5 mg per week, leflunomide 20 mg per day, and oral anticoagulation previous to the present event. He presented to emergency room with a 7 day disease duration characterized by pain in the left thigh, which increased with physical activity, resulting in claudication; he also had malaise and fever. The X-ray films showed periostitis of the lower half of the left femur with bone marrow narrowing; the scintigraphy showed marked increased uptake in the middle and distal thirds of the left femur, and magnetic resonance imaging (MRI) showed thickening and hyperintensity of the cortex of the diaphysis and distal epiphysis of the femur and endosteal irregularity. Empirical treatment was started with vancomycin for 3 weeks. Femur biopsy and cultures were performed, isolating Salmonella spp. group "D" Vi (-); treatment with cotrimoxazole and ceftazidime for 4 weeks followed by doxycycline and cotrimoxazole for 4 months were given with a favorable functional outcome. This is an unusual case of a young adult with Garre's sclerosing osteomyelitis associated to SLE and caused by salmonella. The literature is reviewed and the clinical conditions predisposing to this infection are discussed, particularly in patients with SLE. PMID- 26511967 TI - Identifying real and perceived barriers to therapeutic education programs for individuals with inflammatory arthritis. AB - Therapeutic Education Programs (TEPs) grounded in self-management principles have been shown to improve quality of life of patients with chronic conditions and reduce patient-related healthcare costs. Though these programs are becoming more readily available, patients often experience barriers in participating. This study sought to identify barriers faced by inflammatory arthritis (IA) patients in attending a TEP and understand how patients overcame perceived barriers. A mixed-method study design was used. Questionnaires were distributed to individuals with IA who were invited to attend a TEP between 2010 and 2013. Respondents were those that chose not to attend (group A), individuals who attended <=4 of 10 sessions (group B), individuals who attended >=5 of 10 sessions prior to May 2013 (group C), and individuals who attended >=5 of 10 sessions from June 2013 to November 2013 (group D). Individuals in group D were also invited to participate in focus groups to discuss how they had overcome perceived barriers. Real barriers identified by individuals in groups A and B included time, distance, and cost associated with attendance. Individuals who overcame perceived barriers (groups C and D) discussed strategies they used to do so. Aspects of the overall program experience and access to clinic and program also contributed to patients being able to overcome barriers. Time, distance, and cost are external barriers that prevented individuals from utilizing self management education opportunities. These barriers were overcome if and when individuals had resources available to them. Readiness for behavior change also influenced commitment to participate in the program. PMID- 26511968 TI - Endostatin combined with radiotherapy suppresses vasculogenic mimicry formation through inhibition of epithelial-mesenchymal transition in esophageal cancer. AB - The growth of solid tumors requires angiogenesis to provide oxygen and nutrients and to support cell proliferation. The switch from an avascular to a vascular phenotype is typically related to acceleration of tumor growth. Anti-angiogenic therapy is becoming a very promising way for malignant tumors. Meanwhile, malignant tumor cells themselves were able to develop the formation of cell-lined vessels that contribute to tumor neovascularization and supply the nutrients and oxygen, which is called vasculogenic mimicry (VM). However, the molecular mechanism of VM remains unclear. The purpose of this study was to investigate the efficacy of the novel recombinant human endostatin (rh-Endo) protein combined with radiotherapy on human esophageal squamous cell carcinoma (ESCC) cell lines Eca-109 and TE13. Our results showed that rh-Endo combined with radiotherapy significantly inhibited the proliferation, migration, invasion, and VM of human esophageal cancer cells in a dose-dependent manner; however, it has no direct effect on apoptosis of carcinoma cells, which indicated that rh-Endo combined with radiotherapy significantly changed the microenvironment of esophageal carcinoma, and played an important role in preventing distant metastasis. Our findings suggested that rh-Endo inhibited the metastasis of esophageal cancer and the activation of AKT pathway, and the down-regulation of epithelial-mesenchymal transition (EMT) may be associated with such effect of rh-Endo. These results also supported the bright prospect of rh-Endo combined with radiotherapy for clinical applications in the future. PMID- 26511969 TI - MiR-429 induces apoptosis of glioblastoma cell through Bcl-2. AB - An essential role of microRNAs (miRNAs) has been acknowledged in the tumorigenesis of glioblastoma multiforme (GBM). Very recently, miR-429 was reported to have a potential of suppressing cancer growth. However, whether miR 429 may similarly regulate growth of GBM remains unknown. Here, we analyzed the levels of miR-429 and anti-apoptotic protein Bcl-2 in GBM specimens. We combined bioinformatics analyses and luciferase reporter assay to determine the relationship between miR-429 and Bcl-2 in GBM cells. Cell survival upon temozolomide treatment was analyzed in a CCK assay. Cell apoptosis was measured by fluorescein isothiocyanate (FITC) Annexin V apoptosis detection assay. We found that miR-429 levels were significantly decreased and Bcl-2 levels were significantly increased in GBM specimens, compared to the paired adjacent non tumor brain tissue. Moreover, the levels of miR-429 and Bcl-2 inversely correlated. Low-miR-429 subjects had an overall inferior survival, compared to high-miR-429 subjects. MiR-429 targeted the 3'-UTR of Bcl-2 mRNA to inhibit its translation. Overexpression of miR-429 inhibited Bcl-2-mediated cell survival against temozolomide-induced apoptosis, while depletion of miR-429 augmented it. Together, our data suggest that miR-429 suppression in GBM promotes Bcl-2 mediated cancer cell survival against chemotherapy-induced cell death. Re expression of miR-429 levels in GBM cells may improve the outcome of chemotherapy. PMID- 26511970 TI - Expression of prostaglandin E2 and EP receptors in human papillary thyroid carcinoma. AB - The objective of the present study is to determine the role of prostaglandin E2 (PGE2) and downstream EP receptors in the development of human papillary thyroid carcinoma (PTC). A total of 90 thyroid specimens excised from patients undergoing total or subtotal thyroidectomy in the Department of General Surgery, the Fifth Affiliated Hospital of Sun Yat-sen University, China, from August 2013 to September 2014, were analyzed. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical analyses were employed to examine the messenger RNA (mRNA) and protein expression, respectively. The expressions and significances of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), PGE2, and EP receptors in PTC and nodular goiter were investigated. The COX-2 mRNA and protein expression level significantly increased in the PTC tissues than in the paired noncarcinoma tissues adjacent to the PTC or nodular goiter tissues. The mPGES-1 protein expression was also significantly upregulated in the PTC tissues. All the four subtypes of EP receptors (EP1-4) could express in the thyroid tissues, while only the EP4 mRNA and protein levels significantly increased in the PTC tissues. The local production of PGE2 had a higher-level expression in the PTC tissues than in the noncarcinoma thyroid tissues adjacent to the PTC lesion and the benign nodular goiter tissues. The induction of PGE2 biosynthesis as well as the overexpression of EP4 in PTC suggested that this pathway might play an important role in the carcinogenesis and progression of PTC. These observations raise the possibility that pharmacological inhibition of mPGES-1 and/or EP4 may hold therapeutic promise in this common cancer. PMID- 26511971 TI - Differential interference of vitamin D analogs PRI-1906, PRI-2191, and PRI-2205 with the renewal of human colon cancer cells refractory to treatment with 5 fluorouracil. AB - This study was aimed to determine whether hypocalcemic analogs of active forms of vitamins D modulate expression of genes related to stem-like phenotype in colon cancer cell lines HT-29 and HCT-116 undergoing renewal after the treatment with 5 fluorouracil (5-FU). Both lines express vitamin D receptor, but differ in differentiation stage and vitamin D sensitivity. Cells that resisted the 5-FU exposure were treated with synthetic analog of 1,25-dihydroxyvitamin D2 (PRI 1906) and analogs of 1,25-dihydroxyvitamin D3 (PRI-2191 and PRI-2205). Proliferative activity was more profoundly affected by vitamin D analogs in HT 29/5-FU than in HCT-116/5-FU cells. In HT-29/5-FU cells, analogs PRI-1906 and PRI 2191 downregulated the expression of genes related to survival, re-growth, and invasiveness during renewal, while PRI-2205 increased expression of genes related to differentiation only. In HCT-116/5-FU cells, PRI-2191 decreased the expression of stemness- and angiogenesis-related genes, whereas PRI-1906 augmented their expression. The effects in HCT-116/5-FU cells were observed at higher concentrations of the analogs than those used for HT-29/5-FU cells. Out of the series of analogs studied, PRI-2191 might be used to counteract the renewal of both moderately and poorly differentiated cancer cells following conventional treatment. PMID- 26511972 TI - MicroRNA-195 inhibits proliferation of cervical cancer cells by targeting cyclin D1a. AB - Cervical cancer is one of the most frequent gynecological malignancies in women worldwide. MicroRNA-195 (miR-195) was recently found highly expressed in cervical cancer. However, the role of miR-195 in the pathology of cervical cancer remains poorly understood. In this study, we first confirmed the downregulation of miR 195 in primary cervical cancer tissues. For the functional study, we introduced the sequences of miR-195 or miR-195 inhibitor into Hela and SiHa cervical cancer cell lines. Overexpression of miR-195 inhibited the proliferation of both Hela and SiHa cells. In contrast, reducing the endogenous miR-195 level by miR-195 inhibitor promoted the proliferation of cervical cancer cells. Flow cytometric assay showed that overexpression of miR-195 induced G1 phase arrest, whereas miR 195 inhibitor shortened G1 phase of cervical cancer cells. In addition, the suppressive role of miR-195 in cell cycle was also demonstrated by the western blot results of various cell cycle indicators, such as phosphorylated retinoblastoma (p-Rb) and proliferating cell nuclear antigen (PCNA), in the gain and loss of function experiments. Furthermore, Dual-Luciferase Reporter Assay revealed that miR-195 targeted the 3'-untranslated region of cyclin D1a transcript, such as to regulate cyclin D1 expression. In summary, our results suggest that miR-195 acts as a suppressor in the proliferation and cell cycle of cervical cancer cells by directly targeting cyclin D1a mRNA. PMID- 26511973 TI - Insulin is an important risk factor of endometrial cancer among premenopausal women: a case-control study in China. AB - The aim of the article was to evaluate the important role played by insulin in the development of endometrial cancer (EC) among Chinese premenopausal women. In this study, 128 endometrial cancer patients and 294 controls who were all premenopausal were included. Baseline characteristics data were collected and serum insulin, C-peptide, sex hormone-binding globulin, C-reaction protein, interleukin-6, and tumor necrosis factor-alpha levels were measured. Paired t test, chi(2) test, Spearman correlation coefficients, and univariate and multivariate logistic regression models were used in data analysis. Furthermore, insulin levels were categorized into quartiles, and likelihood ratio was calculated for the four categories. Blood insulin levels of the patients were significantly higher than those of the controls (P < 0.001). Factor analysis identified insulin (OR = 2.46; 95 % confidence interval (CI) = 1.55-3.91; P < 0.001) as the independent risk factor of EC. When insulin levels were categorized into quartiles, we found that insulin was positively associated with endometrial cancer risk [HR comparing extreme quartiles (HR q4-q1) = 4.44; 95 % CI = 2.59 7.62; P trend = 0.025]. After adjustment for body mass index (BMI) or waist-hip ratio (WHR), this association was attenuated, but still significant. In conclusion, insulin plays an important role in the carcinogenesis of EC among premenopausal women. Treatment targeting down-regulation of blood insulin levels seems effective in the prevention of this malignancy. PMID- 26511974 TI - A review of progress in single particle tracking: from methods to biophysical insights. AB - Optical microscopy has for centuries been a key tool to study living cells with minimum invasiveness. The advent of single molecule techniques over the past two decades has revolutionized the field of cell biology by providing a more quantitative picture of the complex and highly dynamic organization of living systems. Amongst these techniques, single particle tracking (SPT) has emerged as a powerful approach to study a variety of dynamic processes in life sciences. SPT provides access to single molecule behavior in the natural context of living cells, thereby allowing a complete statistical characterization of the system under study. In this review we describe the foundations of SPT together with novel optical implementations that nowadays allow the investigation of single molecule dynamic events with increasingly high spatiotemporal resolution using molecular densities closer to physiological expression levels. We outline some of the algorithms for the faithful reconstruction of SPT trajectories as well as data analysis, and highlight biological examples where the technique has provided novel insights into the role of diffusion regulating cellular function. The last part of the review concentrates on different theoretical models that describe anomalous transport behavior and ergodicity breaking observed from SPT studies in living cells. PMID- 26511976 TI - Transcriptomic Effects of Estrogen Starvation and Induction in the MCF7 Cells. The Meta-analysis of Microarray Results. AB - Estrogen is one of the most important signaling molecules which targets a number of genes. Estrogen levels regulate cell proliferation and a plethora of metabolic processes, which may interfere with a range of medical conditions and drug metabolism. The MCF7 breast cancer cell line, expressing the estrogen receptor alpha, is a well-studied model of cellular answer to estrogen. The aim of this study was to characterize transcriptomic responses to estrogen in a broad time range. We performed a meta-analysis of microarray data on gene expression in the MCF7 cells under estrogen exposure and deprivation. As the result we distinguished three major phases of transcriptomic response to stimulation with 17beta- estradiol: the early (1-2 h), with the activation of the MAPK signaling pathway; the intermediate (3-12 h), with enhanced expression of genes participating in cell surface receptor linked signal transduction and cellular homeostasis; and the late one (24-48 h), with the induction of genes involved in mitotic cell division. Two main phases under estrogen starvation were indicated as the early (1-3 days), with elevated expression of genes associated with cell projection and repression of those responsible for cell cycle regulation, and the late (15-180 days), with increased expression of genes of cell adhesion proteins. The meta-analysis displayed how different gene sets are either induced or repressed following either estrogen exposure or deprivation, and how the gene expression changes are orchestrated by estrogen in time dependent manner, indicating that proper understanding of estrogen impact on transcriptional gene activity requires an extensive time perspective. PMID- 26511975 TI - Identification and characterization of a high kernel weight mutant induced by gamma radiation in wheat (Triticum aestivum L.). AB - BACKGROUND: Inducing mutations are considered to be an effective way to create novel genetic variations and hence novel agronomical traits in wheat. This study was conducted to assess the genetic differences between Shi4185 and its mutant line Fu4185, produced by gamma radiation with larger grain, and to identify quantitative trait loci (QTLs) for thousand kernel weight (TKW). RESULTS: Phenotypic analysis revealed that the TKW of Fu4185 was much higher than that of Shi4185 under five different environments. At the genomic level, 110 of 2019 (5.4%) simple sequence repeats (SSR) markers showed polymorphism between Shi4185 and Fu4185. Notably, 30% (33 out of 110) polymorphic SSR markers were located on the D-genome, which was higher than the percentage of polymorphisms among natural allohexaploid wheat genotypes, indicating that mutations induced by gamma radiation could be a potential resource to enrich the genetic diversity of wheat D-genome. Moreover, one QTL, QTkw.cau-5D, located on chromosome 5DL, with Fu4185 contributing favorable alleles, was detected under different environments, especially under high temperature conditions. CONCLUSIONS: QTkw.cau-5D is an environmental stable QTL, which may be a desired target for genetic improvement of wheat kernel weight. PMID- 26511977 TI - Ideal and Reality: Barricade in the Delivery of Small Interfering RNA for Cancer Therapy. AB - Small interfering RNA (siRNA) has been demonstrated to be a powerful tool for silencing post-transcriptional gene expression, and thus exhibits great potential in cancer gene therapy. However, siRNA technology has not become an established strategy for cancer treatment, as it is a considerable challenge to deliver siRNA to the targeting sites. In this review, barricades in the systemic delivery of siRNA were systematically introduced, from pharmacokinetics, biodistribution and intracellular behavior. Meanwhile, current and potential strategies for overcoming the barricades were elucidated, including chemical modification of siRNA, nanomaterial-based delivery systems, and targeting and stimuli-responsive smart carriers. In conclusion, the siRNA-based gene silencing drug will gain an important position for treating human diseases if we can solve the gap between ideal and reality. PMID- 26511978 TI - Investigation of Chitosan for Prevention of Diabetic Progression Through Gut Microbiota Alteration in Sugar Rich Diet Induced Diabetic Rats. AB - Sugar rich diet induces inflammation and insulin resistance mainly through gut microbiota alteration. Gut microflora dysbiosis increases plasma lipopolysaccharide and reduces short chain fatty acids to impair the insulin signaling cascades by different molecular pathways to progress into diabetes. Chitosan based formulations have major significance in insulin delivery system due to their ability to protect the insulin from enzymatic degradation and its efficient inter-epithelial transport. This study was designed to investigate the effect of chitosan administration on gut microflora mediated signaling pathways to prevent the diet induced diabetes. Male wistar rats were divided into non diabetic group with a normal diet (CD), diabetic group with high sucrose diet (HSD) and treatment group with HSD and chitosan (60 mg/kg). After 8 weeks of the study, significant alterations in two major gut dominant microbial phyla i.e Firmicutes and Bacteroides and four dominant microbial species i.e. Lactobacilli, Bifidobacteria, Escherichia and Clostridia were observed in HSD group compared to CD. This microbial dysbiosis in dominant phyla was significantly prevented in chitosan administrated HSD group. Chitosan administration had also reduced the HSD induced activation of Toll like receptors and Nod like receptors signaling pathways compared to HSD control group to reduce the inflammation. These suggest that chitosan can prevent the progression of Type 2 Diabetes through gut microbiota alteration, reducing endotoxin and microbes mediated inflammation. PMID- 26511979 TI - Small Amine Molecules: Solvent Design Toward Facile Improvement of Protein Stability Against Aggregation and Inactivation. AB - Proteins are prone to inactivation in aqueous solutions because chemical modification and aggregation usually occur, particularly at high temperature. This review focuses on the recent advance in practical application with amine compounds that prevent the heat-induced inactivation and aggregation of proteins. Coexistence of amine solutes, typically diamines, polyamines, amino acid esters, and amidated amino acids decreases the heat-induced inactivation rate of proteins by one order of magnitude compared with that in the absence of additives under low concentrations of proteins at physiological pH. The amine compounds mainly suppress chemical modification, typically the beta-elimination of disulfide bond and deamidation of asparagine side chain, thereby preventing heat-induced inactivation of proteins. Polyamines do not improve the refolding yield of proteins, owing to decrease in the solubility of unfolded proteins. In contrast, arginine is the most versatile additive for various situations, such as refolding of recombinant proteins, solubilized water-insoluble compounds, and prevention of nonspecific binding to solid surfaces; however, it is not always effective for preventing heat-induced aggregation. Amine compounds will be a key to prevent protein inactivation in solution additives. PMID- 26511980 TI - Determination of Water Content in Dehydrated Mammalian Cells Using Terahertz Pulsed Imaging: A Feasibility Study. AB - Mammalian cells are involved in a range of biotechnological applications and more recently have been increasingly exploited in regenerative medicine. Critical to successful applications involving mammalian cells are their long-term storage and transport, for which cryopreservation in liquid nitrogen is the most frequently used strategy. However, cryopreservation suffers from high costs, difficulties in transport logistics and the use of undesirable additives (e.g. animal sera or DMSO). An alternative approach, proposed as low cost, low maintenance and process compatible, is viable desiccation of mammalian cells. Several groups claim to have achieved this, but the extent of desiccation in the cell samples concerned is not always clear, in part because of difficulties in determining very low water content. Although several techniques exist that are frequently used to quantify the amount of water in samples (e.g. FTIR spectroscopy, thermogravimetric analysis (TGA), NMR spectroscopy), the complexity of sample preparation, as well as the costs and time constraints involved are disadvantageous. Here, we assess a novel, rapid and low cost technique, i.e. terahertz (THz) spectroscopy, for the quantification of water content within dehydrated mammalian cell samples. PMID- 26511981 TI - Atmospheric Humidity Influences Oviposition Rate of Tetranychus urticae (Acari: Tetranychidae) Through Morphological Responses of Host Cucumis sativus Leaves. AB - We investigated the effects of morphology of host cucumber, Cucumis sativus L., leaves acclimatized to different atmospheric humidity levels on oviposition by adult females of the twospotted spider mite, Tetranychus urticae Koch. Cucumber seedlings were grown at a vapor pressure deficit (VPD) of 0.4, 1.9, or 3.0 kPa at 28 degrees C (90%, 50%, or 20% relative humidity, respectively) in growth chambers until the second true leaves had expanded. Adult females of T. urticae were released on the adaxial surfaces of leaf squares cut from first and second true leaves in each treatment group, and held in the same humidity condition. Eggs were counted 2 d after release. The lower acclimatization humidity (higher VPD) increased trichome (leaf hair) density of the host leaves and oviposition rate, but the relationship between the trichome and oviposition differed between leaf positions. The leaf mass per area (LMA) was greater in first true leaves than in second true leaves, but was not influenced by VPD. A linear regression model with oviposition rate as the dependent variable and trichome density and LMA as independent variables showed that both variables influenced the oviposition rate approximately equally. We conclude that oviposition was accelerated under low humidity (high VPD) conditions indirectly probably through an increase in the trichome density of host leaves. PMID- 26511982 TI - Introduction and Establishment of Pissodes castaneus (Coleoptera: Curculionidae) in the Andean Patagonia of Argentina. AB - The pine weevils that occur in plantations of Pinus spp. in Andean Patagonia of Argentina belong to the species Pissodes castaneus (De Geer), a Eurasian endemic species, according to the identification based on molecular and morphological characters. Sequences of the mitochondrial Cytochrome oxidase subunit I and nuclear genes (28 S rDNA and ITS2) were obtained for individuals of 13 afforestations, covering the entire distribution area of the established populations in the Andean Patagonia of Argentina. Sequence comparison with representative species of the genus (European, North American, and Chinese species) shows that Patagonian specimens are conspecific to those of P. castaneus sequenced from Europe. Phylogenetic analyses indicate that all terminals from Patagonia form a monophyletic unit without evident subclades, eliminating the possibility of existence of more than one species of Pissodes Germar in this area, including cryptic ones. Moreover, the very low genetic divergence between the Patagonian populations suggests that it is plausible that P. castaneus was introduced into Patagonia from just one location. Mitochondrial DNA analysis shows that Patagonian terminals group together with a French haplotype and are clearly separated from other P. castaneus individuals represented in our sample, and reveal that established populations in Andean Patagonia originated via a limited introduction. PMID- 26511983 TI - Dominant Inheritance of Field-Evolved Resistance to Fipronil in Plutella xylostella (Lepidoptera: Plutellidae). AB - A field-collected strain (HF) of Plutella xylostella (L.) showed 420-fold resistance to fipronil compared with a susceptible laboratory strain (Roth). The HF-R strain, derived from the HF strain by 25 generations of successive selection with fipronil in the laboratory, developed 2,200-fold resistance to fipronil relative to the Roth strain. The F(1) progeny of the reciprocal crosses between HF-R and Roth showed 640-fold (R? * S?) and 1,380-fold (R? * S?) resistance to fipronil, indicating resistance is inherited as an incompletely dominant trait. Analysis of progeny from a backcross (F1? * S?) suggests that resistance is controlled by one major locus. The LC(50) of the R? * S? cross F(1) progeny is slightly but significantly higher than that of the R? * S? cross F(1) progeny, suggesting a minor resistance gene on the Z chromosome. Sequence analysis of PxGABARalpha1 (an Rdl-homologous GABA receptor gene of P. xylostella) from the HF R strain identified two mutations A282S and A282G (corresponding to the A302S mutation of the Drosophila melanogaster Rdl gene), which have been previously implicated in fipronil resistance in several insect species including P. xylostella. PxGABARalpha1 was previously mapped to the Z chromosome of P. xylostella. In conclusion, fipronil resistance in the HF-R strain of P. xylostella was incompletely dominant, and controlled by a major autosomal locus and a sex-linked minor gene (PxGABARalpha1) on the Z chromosome. PMID- 26511984 TI - Effect of Planting Date and Maturity Group on Soybean Yield Response to Injury by Megacopta cribraria (Hemiptera: Plataspidae). AB - The kudzu bug, Megacopta cribraria (F.), is an invasive member of the family Plataspidae originating from Asia. Since its discovery in Georgia in 2009, its distribution has increased to 13 southern and eastern states. In the United States, M. cribraria is bivoltine and has two primary developmental hosts, kudzu and soybean. Here, we evaluated the yield response of soybean to M. cribraria feeding injury in relation to planting date and soybean maturity group. The study contained four replicated trials in Griffin, Tifton, and Midville, GA, in 2012 and 2013. Four planting dates from April to July, served as the whole plot of a split-plot design with maturity group five and seven soybean and insecticide (lambda-cyhalothrin) randomized within planting date. Egg masses, nymphs, and adults were enumerated weekly to biweekly until soybean reached maturity. Two generations were observed in April and May plantings, but only one generation was evident in June and July soybean plantings. Insecticide-protected plots had consistently higher yields than unprotected plots. Grain yield was greatest in the May planting and lowest in the July planting. Season-long feeding by M. cribraria reduced grain yield in April, May, and June plantings but not in the July planting. Maturity group and planting date had significant effects on yield components in most comparisons. This study indicated that early-planted soybean are at greater risk of yield loss from M. cribraria injury compared with later planted soybean. PMID- 26511985 TI - Comparison of analytical methods for profiling N- and O-linked glycans from cultured cell lines : HUPO Human Disease Glycomics/Proteome Initiative multi institutional study. AB - The Human Disease Glycomics/Proteome Initiative (HGPI) is an activity in the Human Proteome Organization (HUPO) supported by leading researchers from international institutes and aims at development of disease-related glycomics/glycoproteomics analysis techniques. Since 2004, the initiative has conducted three pilot studies. The first two were N- and O-glycan analyses of purified transferrin and immunoglobulin-G and assessed the most appropriate analytical approach employed at the time. This paper describes the third study, which was conducted to compare different approaches for quantitation of N- and O linked glycans attached to proteins in crude biological samples. The preliminary analysis on cell pellets resulted in wildly varied glycan profiles, which was probably the consequence of variations in the pre-processing sample preparation methodologies. However, the reproducibility of the data was not improved dramatically in the subsequent analysis on cell lysate fractions prepared in a specified method by one lab. The study demonstrated the difficulty of carrying out a complete analysis of the glycome in crude samples by any single technology and the importance of rigorous optimization of the course of analysis from preprocessing to data interpretation. It suggests that another collaborative study employing the latest technologies in this rapidly evolving field will help to realize the requirements of carrying out the large-scale analysis of glycoproteins in complex cell samples. PMID- 26511986 TI - Endothelial progenitor cells as a biological marker of peripheral artery disease. AB - The role of endothelial progenitor cells (EPCs) in peripheral artery disease (PAD) remains unclear. We hypothesized that EPC mobilization and function play a central role in the development of endothelial dysfunction and directly influence the degree of atherosclerotic burden in peripheral artery vessels. The number of circulating EPCs, defined as CD34(+)/KDR(+) cells, were assessed by flow cytometry in 91 subjects classified according to a predefined sample size of 31 non-diabetic PAD patients, 30 diabetic PAD patients, and 30 healthy volunteers. Both PAD groups had undergone endovascular treatment in the past. As a functional parameter, EPC colony-forming units were determined ex vivo. Apart from a broad laboratory analysis, a series of clinical measures using the ankle-brachial index (ABI), flow-mediated dilatation (FMD) and carotid intima-media thickness (cIMT) were investigated. A significant reduction of EPC counts and proliferation indices in both PAD groups compared to healthy subjects were observed. Low EPC number and pathological findings in the clinical assessment were strongly correlated to the group allocation. Multivariate statistical analysis revealed these findings to be independent predictors of disease appearance. Linear regression analysis showed the ABI to be a predictor of circulating EPC number (p=0.02). Moreover, the functionality of EPCs was correlated by linear regression (p=0.017) to cIMT. The influence of diabetes mellitus on EPCs in our study has to be considered marginal in already disease-affected patients. This study demonstrated that EPCs could predict the prevalence and severity of symptomatic PAD, with ABI as the determinant of the state of EPC populations in disease affected groups. PMID- 26511987 TI - Evaluation of health-related quality of life with EORTC QLQ-C30 and QLQ-H&N35 in Romanian laryngeal cancer patients. AB - The aims of this study were to evaluate the health-related quality of life (HRQL) according to: type of surgery, adjuvant oncological treatment and postoperative complications. We performed a retrospective case-control study between October 2013 and November 2014 at the Ear Nose and Throat Clinic of Cluj-Napoca. We included patients diagnosed with laryngeal or hypopharyngeal cancer treated with total or partial laryngectomy, and a sample of healthy volunteers recruited from the hospital stuff. We used the European Organisation for Research and Treatment of Cancer (EOTRC) core questionnaires (the QLQ-C30 version 3) and the head and neck cancer module (the QLQ-H&N35). We included in the study 80 patients diagnosed and surgically treated for laryngeal/hypopharyngeal squamous cell carcinoma and 20 healthy volunteers. Median age of the patients was 59.90 years. The most common location was the larynx, in 72 (90 %) of cases and the hypopharynx in 8 (10 %) cases. Sixty-six (82, 50 %) underwent total laryngectomy and 14 (17, 50 %) a partial laryngectomy. Forty-eight patients had received external radiation therapy, with adjuvant chemotherapy in 25 patients. Postoperative complication rates were 14 (17, 50 %) cases. We found a low score in total laryngectomy group regarding functional scales: role (28.03), emotional (37.75) and social (37.88) and a high score on insomnia (35.86) and financial difficulties (45.45). Partial laryngectomy group had a high score on functional scales: role (47.62), emotional (51.19) and social (52.38). These two QOL instruments were effective for Romanian patients. The QLQ-H&N35 questionnaire discriminating better the problems between groups compared with QLQ-C30. PMID- 26511988 TI - Different anesthetic agents-soaked sinus packings on pain management after functional endoscopic sinus surgery: which is the most effective? AB - In the present study, we investigated the efficacy of local anesthetics soaked non-absorbable sinus packs on pain management after functional endoscopic surgery (FESS). One hundred and fifty patients with the diagnosis of bilateral chronic sinusitis with or without nasal polyps who underwent FESS were included into the study. Their pre-operative Lund-Mackay computerized tomography (CT) Scores were similar. We applied anesthetic agents of 2 % lidocaine HCl, 0.25 % Bupivacaine HCl, 0.2 % Ropivacaine, 2 % Prilocaine and 0.9 % NaCl (Saline) in groups 1-5 onto the sinus packs after FESS. At postoperative period, acetaminophen (250 mg/5 ml) was used in 10-15 mg/kg per dose (4 times a day). Bleeding grade, operation duration, postoperative number of gauze/24 h, additional painkiller need, pain values at 1, 2, 4, 8, 12 and 24 h were noted. Lund-Kennedy endoscopic scores were also evaluated at 1st, 2nd and 4th weeks postoperatively. In saline group, 93.3 % of the patients needed additional painkiller. Whereas, in Bupivacaine group, additional painkiller use (20.0 %) is less than the other groups. In Bupivacaine group, number of gauze/24 h use was lower than lidocaine, ropivacaine and prilocaine groups. In our study, except 1st and 24th hours, pain values of groups can be written in ascending order (from less to higher) as Bupivacaine, Lidocaine, Prilocaine, Ropivacaine and Saline. In the first hour, pain values of groups can be written in ascending order (from less to higher) as Lidocaine, Prilocaine, Bupivacaine, Ropivacaine and Saline. In the 2nd week, in the Bupivacaine and Lidocaine Groups separately, postoperative Lund-Kennedy scores were lower than the Prilocaine and Saline Groups. In the 1st month, Lidocaine Group's Lund-Kennedy scores were significantly lower than the Saline Group. Synechia values were not different between groups. Bupivacaine help the lower pain values and less additional painkiller need after FESS. Therefore, we recommend to use Bupivacaine soaked sinus packs after FESS for achieve less pain values and to improve patient satisfaction. PMID- 26511989 TI - CRISPR/Cas9-based tools for targeted genome editing and replication control of HBV. AB - Hepatitis B virus (HBV) infection remains a major global health problem because current therapies rarely eliminate HBV infections to achieve a complete cure. A different treatment paradigm to effectively clear HBV infection and eradicate latent viral reservoirs is urgently required. In recent years, the development of a new RNA-guided gene-editing tool, the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9) system, has greatly facilitated site-specific mutagenesis and represents a very promising potential therapeutic tool for diseases, including for eradication of invasive pathogens such as HBV. Here, we review recent advances in the use of CRISPR/Cas9, which is designed to target HBV specific DNA sequences to inhibit HBV replication and to induce viral genome mutation, in cell lines or animal models. Advantages, limitations and possible solutions, and proposed directions for future research are discussed to highlight the opportunities and challenges of CRISPR/Cas9 as a new, potentially curative therapy for chronic hepatitis B infection. PMID- 26511990 TI - The preventive effect of vaccine prophylaxis on severe respiratory syncytial virus infection: A meta-analysis. AB - Respiratory syncytial virus (RSV) is the key underlying cause of acute lower respiratory tract infection in infants; however, no licensed vaccine against RSV infection is currently available. This study was undertaken to assess the preventive effect of vaccine on RSV infection. In this metaanalysis, 1,792 published randomized clinical trials of RSV vaccines from Jan 1973 to Sep 2015 were examined. Among thirteen studies that met the inclusion criteria, eleven studies estimated the impact of RSV vaccines and four studies estimated the effect of adjuvants. The odds ratios (ORs) were 0.31 (95% CI, 0.15-0.67) and 0.62 (95% CI, 0.29-1.34), respectively. We found that RSV subunit vaccines can significantly reduce the incidence of RSV infection and that whether vaccination with adjuvant therapy was an effective strategy still remained to be studied. This analysis of the preventive effect of vaccines on RSV infection has direct applications for the prevention of RSV infections. PMID- 26511991 TI - The challenging diagnosis of haemophagocytic lymphohistiocytosis in an HIV infected patient. AB - The differential diagnosis of febrile pancytopenia in the setting of HIV infection can be challenging. The authors report a case of a 34-year-old man with advanced HIV infection (TCD4=8 cells/mm(3)) and a 2-month history of fever, weight loss and asthaenia. On observation, he was emaciated, hyperthermic and pale, with a haemorrhagic oropharyngeal lesion, penile violaceous lesions and palpable hepatosplenomegaly. Blood tests showed pancytopenia, hyperferritinaemia and hypertriglyceridaemia; imaging confirmed hepatosplenomegaly and a bone marrow biopsy revealed HIV-associated dyshematopoiesis. Biopsy of the aforementioned lesions displayed Kaposi sarcoma; extensive investigation was negative for other opportunistic infections or lymphoproliferative disease. Despite only a posteriori histological documentation, haemophagocytic lymphohistiocytosis (HLH) was considered; chemotherapy and antiretrovirals were started, with excellent response. There was, however, disease relapse requiring an intensification course, with sustained remission at 18-month follow-up. HLH is a rare disease, with non-specific presentation, requiring a high index of suspicion since treatment delay can be fatal. PMID- 26511992 TI - Impella left ventricular assist device in cardiac arrest after spinal anaesthesia for caesarean section. AB - Cardiac arrest after neuraxial anaesthesia is very well described. Inhibition of the sympathetic efferent system and vagal activation leading to decrease preload and severe bradycardia results in cardiac arrest. Pregnant patients undergoing spinal anaesthesia are at increased risk for vasovagal events due to aortocaval compression and higher level of spinal block. A 36-year-old pregnant woman at 39 weeks presented for an elective caesarean section. She underwent spinal anaesthesia. Immediately after, she had severe bradycardia followed by asystole cardiac arrest. She had spontaneous return of circulation. The patient was in cardiogenic shock causing pulmonary oedema and required four vasopressors to maintain her blood pressure. An Impella 2.5 percutaneous microaxial left ventricle (LV) support device was inserted to support her haemodynamics. She fully recovered and was discharged in stable condition. To the best of our knowledge, this is first case report of the use of an LV-assist device in a patient postcardiac arrest from spinal anaesthesia. PMID- 26511993 TI - Bilateral hip pain in a young man? It may be worth considering juvenile-onset ankylosing spondylitis (JAS). AB - A 15-year-old boy with severe bilateral hip joint pain and restriction of mobility presented to the casualty ward. He had earlier been treated for tuberculosis of the hip, with no relief. Our work up revealed a case of severe juvenile-onset ankylosing spondylitis with predominant hip involvement and accompanying sacroiliitis. PMID- 26511994 TI - Oral manifestations of Crohn's disease. PMID- 26511995 TI - Concurrent perforated Meckel's diverticulum and intestinal malrotation in an 8 year-old boy. AB - An 8-year-old boy with a history of recurrent abdominal pain presented with a 12 h history of severe periumbilical pain, nausea and vomiting. On examination, he was found to have a tender, erythematous, paraumbilical mass. At operative exploration, an abscess cavity was identified and followed to reveal a gangrenous Meckel's diverticulum, perforated at its tip to create the abscess. Around this Meckel's diverticulum, the small bowel had torted to produce a significant small bowel volvulus on a shortened mesentery. The caecum and ascending colon were found to be in the left upper quadrant and an intraoperative diagnosis of malrotation was made. Following resection of the Meckel's diverticulum and surgical correction of the malrotation, the child made an excellent recovery. His abdominal pain has not recurred in 6 months of follow-up since the operation. PMID- 26511997 TI - Remission in SLE: closing in on the target. PMID- 26511996 TI - Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. AB - OBJECTIVES: The efficacy of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, has not previously been evaluated in a population consisting exclusively of patients with early rheumatoid arthritis (RA). METHODS: In a double-blind randomised controlled trial (FUNCTION), 1162 methotrexate (MTX) naive patients with early progressive RA were randomly assigned (1:1:1:1) to one of four treatment groups: 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo and placebo+MTX (comparator group). The primary outcome was remission according to Disease Activity Score using 28 joints (DAS28-erythrocyte sedimentation rate (ESR) <2.6) at week 24. Radiographic and physical function outcomes were also evaluated. We report results through week 52. RESULTS: The intent-to-treat population included 1157 patients. Significantly more patients receiving 8 mg/kg TCZ+MTX and 8 mg/kg TCZ+placebo than receiving placebo+MTX achieved DAS28-ESR remission at week 24 (45% and 39% vs 15%; p<0.0001). The 8 mg/kg TCZ+MTX group also achieved significantly greater improvement in radiographic disease progression and physical function at week 52 than did patients treated with placebo+MTX (mean change from baseline in van der Heijde-modified total Sharp score, 0.08 vs 1.14 (p=0.0001); mean reduction in Health Assessment Disability Index, -0.81 vs -0.64 (p=0.0024)). In addition, the 8 mg/kg TCZ+placebo and 4 mg/kg TCZ+MTX groups demonstrated clinical efficacy that was at least as effective as MTX for these key secondary endpoints. Serious adverse events were similar among treatment groups. Adverse events resulting in premature withdrawal occurred in 20% of patients in the 8 mg/kg TCZ+MTX group. CONCLUSIONS: TCZ is effective in combination with MTX and as monotherapy for the treatment of patients with early RA. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT01007435. PMID- 26511998 TI - The efficacy of continuous subcostal transversus abdominis plane block for analgesia after living liver donation: a retrospective study. AB - PURPOSE: Postoperative pain management for living liver donors has become a major concern as a result of the increasing number of living liver donations. Transversus abdominis plane (TAP) block has been known to provide effective analgesia for abdominal surgery. The aim of this study was to evaluate the efficacy of ultrasound-guided continuous subcostal TAP block as a part of a multimodal analgesic regimen in comparison with conventional intravenous (IV) fentanyl-based analgesia in living liver donors. METHODS: Thirty-two donors were retrospectively classified into either the continuous subcostal TAP block group (TAP group) or the IV fentanyl-based analgesia group (control group). TAP group donors received bilateral continuous subcostal TAP infusion of 0.125 % levobupivacaine at 6 ml/h. Control group donors did not receive any neural blockade. RESULTS: Cumulative fentanyl consumption was significantly lower in the TAP group for 48 h (P < 0.01) as compared to the control group. Further, the donors in the TAP group had significantly lower incidence of nausea and vomiting during 24-48 h postoperatively (P < 0.01) and fewer delays in the initiation of oral intake than those in the control group (P = 0.02). CONCLUSIONS: In conclusion, continuous subcostal TAP block provided an effective opioid-sparing analgesia for living liver donors. PMID- 26511999 TI - The correct renal function evaluation in patients with thyroid dysfunction. AB - Thyroid dysfunction induces several renal derangements involving all nephron portions. Furthermore, dysthyroidism is a recognized risk factor associated with the development of chronic kidney disease. Current data, in fact, demonstrate that either subclinical or overt thyroid disease is associated with significant changes in creatinine, estimated glomerular filtration rate, measured glomerular filtration rate and Cystatin C. Herein, we systematically reviewed several relevant studies aiming at the identification of the most sensitive and specific parameter for the correct renal function evaluation in patients with thyroid dysfunction, that are usually treated as outpatients. Our systematic review indicates that estimated glomerular filtration rate, preferably with CKD-EPI equation, appears to be the most reliable and wieldy renal function parameter. Instead, Cystatin C should be better used in the grading of thyroid dysfunction severity. PMID- 26512001 TI - Using Rasch-models to compare the 30-, 20-, and 12-items version of the general health questionnaire taking four recoding schemes into account. AB - BACKGROUND: The present study compares the 30-, 20-, and 12-items versions of the General Health Questionnaire (GHQ) in the original coding and four different recoding schemes (Bimodal, Chronic, Modified Likert and a newly proposed Modified Chronic) with respect to their psychometric qualities. METHODS: The dichotomized versions (i.e. Bimodal, Chronic and Modified Chronic) were evaluated with the Rasch-Model and the polytomous original version and the Modified Likert version were evaluated with the Partial Credit Model. RESULTS: In general, the versions under consideration showed agreement with the model assumption. However, the recoded versions exhibited some deficits with respect to the Outfit index. CONCLUSIONS: Because of the item deficits and for theoretical reasons we argue in favor of using the any of the three length versions with the original four categorical coding scheme. Nevertheless, any of the versions appears apt for clinical use from a psychometric perspective. PMID- 26512000 TI - Neural circuitry and immunity. AB - Research during the last decade has significantly advanced our understanding of the molecular mechanisms at the interface between the nervous system and the immune system. Insight into bidirectional neuro-immune communication has characterized the nervous system as an important partner of the immune system in the regulation of inflammation. Neuronal pathways, including the vagus nerve based inflammatory reflex, are physiological regulators of immune function and inflammation. In parallel, neuronal function is altered in conditions characterized by immune dysregulation and inflammation. Here, we review these regulatory mechanisms and describe the neural circuitry modulating immunity. Understanding these mechanisms reveals possibilities to use targeted neuromodulation as a therapeutic approach for inflammatory and autoimmune disorders. These findings and current clinical exploration of neuromodulation in the treatment of inflammatory diseases define the emerging field of Bioelectronic Medicine. PMID- 26512002 TI - Caspases and osteogenic markers--in vitro screening of inhibition impact. AB - Caspases, well-known players in apoptosis or inflammation, appear to have roles also in other processes such as cell differentiation. Caspase-3, in particular, was recently demonstrated to have non-apoptotic functions in osteogenesis. However, the molecular pathways involved are not yet known. Therefore, we used osteogenic PCR arrays to provide a comprehensive screening of possible interactions of caspases in general and specifically of caspase-3 in osteogenic networks. Embryonic micromass cultures derived from mouse forelimbs were established and pharmacological fluoromethylketone (FMK) inhibitors applied. Alterations were observed in expression of several genes after caspase inhibition (Bmp1, Bmp5, Bmp6, Col10a1, Col2a1, Comp, Egf, Fgfr2, Gli1, Igf1, Nog, Phex, Sox9, Spp1). The list suggests molecular interactions of caspases and osteogenic molecules and creates a background for further temporospatial and functional studies. PMID- 26512003 TI - Control of enzymatic degradation of biodegradable polymers by treatment with biosurfactants, mannosylerythritol lipids, derived from Pseudozyma spp. yeast strains. AB - Cutinase-like esterase from the yeasts Pseudozyma antarctica (PaE) shows strong degradation activity in an agricultural biodegradable plastic (BP) model of mulch films composed of poly(butylene succinate-co-adipate) (PBSA). P. antarctica is known to abundantly produce a glycolipid biosurfactant, mannosylerythritol lipid (MEL). Here, the effects of MEL on PaE-catalyzed degradation of BPs were investigated. Based on PBSA dispersion solution, the degradation of PBSA particles by PaE was inhibited in the presence of MEL. MEL behavior on BP substrates was monitored by surface plasmon resonance (SPR) using a sensor chip coated with polymer films. The positive SPR signal shift indicated that MEL readily adsorbed and spread onto the surface of a BP film. The amount of BP degradation by PaE was monitored based on the negative SPR signal shift and was decreased 1.7-fold by MEL pretreatment. Furthermore, the shape of PBSA mulch films in PaE-containing solution was maintained with MEL pretreatment, whereas untreated films were almost completely degraded and dissolved. These results suggest that MEL covering the surface of BP film inhibits adsorption of PaE and PaE-catalyzed degradation of BPs. We applied the above results to control the microbial degradation of BP mulch films. MEL pretreatment significantly inhibited BP mulch film degradation by both PaE solution and BP-degradable microorganism. Moreover, the degradation of these films was recovered after removal of the coated MEL by ethanol treatment. These results demonstrate that the biodegradation of BP films can be readily and reversibly controlled by a physical approach using MEL. PMID- 26512004 TI - Role of malate transporter in lipid accumulation of oleaginous fungus Mucor circinelloides. AB - Fatty acid biosynthesis in oleaginous fungi requires the supply of reducing power, NADPH, and the precursor of fatty acids, acetyl-CoA, which is generated in the cytosol being produced by ATP: citrate lyase which requires citrate to be, transported from the mitochondrion by the citrate/malate/pyruvate transporter. This transporter, which is within the mitochondrial membrane, transports cytosolic malate into the mitochondrion in exchange for mitochondrial citrate moving into the cytosol (Fig. 1). The role of malate transporter in lipid accumulation in oleaginous fungi is not fully understood, however. Therefore, the expression level of the mt gene, coding for a malate transporter, was manipulated in the oleaginous fungus Mucor circinelloides to analyze its effect on lipid accumulation. The results showed that mt overexpression increased the lipid content for about 70 % (from 13 to 22 % dry cell weight, CDW), whereas the lipid content in mt knockout mutant decreased about 27 % (from 13 to 9.5 % CDW) compared with the control strain. Furthermore, the extracellular malate concentration was decreased in the mt overexpressing strain and increased in the mt knockout strain compared with the wild-type strain. This work suggests that the malate transporter plays an important role in regulating lipid accumulation in oleaginous fungus M. circinelloides. PMID- 26512005 TI - Identification and characterization of a flavin-containing monooxygenase MoA and its function in a specific sophorolipid molecule metabolism in Starmerella bombicola. AB - The yeast Starmerella bombicola CGMCC 1576 can produce abundant sophorolipids (SLs) including almost equal proportion of acidic and lactonic SLs. In this study, a monooxygenase MoA responsible for the metabolism of a sophorolipid molecule, C18:2 diacetylated acidic sophorolipid (C18:2 DASL), was identified, through genomic analysis, protein modeling, and gene knocking out strategy. The yield and compositions of SLs produced by the deletion mutant ?moA changed dramatically. In HPLC chromatogram, the UV absorption area of C18:2 DASL (one major acidic sophorolipid component) increased from 9.84 * 10(6) mAU * s to 34.26 * 10(6) mAU * s by an increase of 248.17 % when oleic acid was used as hydrophobic carbon source. Moreover, when linoleic acid was used as hydrophobic carbon source, the content of C18:2 DASL component produced by the overexpressed strain Peno::moA decreased significantly compared with that of wild type and ?moA. Furthermore, the MoA enzyme was heterologously expressed in Escherichia coli JM109 (DE3) with a recombinant plasmid named pMAL-c2x-moA, and the purified enzyme was obtained through a maltose-binding protein (MBP) affinity chromatography column. The purified C18:2 DASL and C18:1 DASL were applied to be catalyzed by MoA enzyme, respectively; it turned to be that C18:1 DASL still remained in the MoA reaction system, but C18:2 DASL disappeared. PMID- 26512006 TI - Monomeric Corynebacterium glutamicum N-acetyl glutamate kinase maintains sensitivity to L-arginine but has a lower intrinsic catalytic activity. AB - N-acetyl glutamate kinase (NAGK) is a key enzyme in the synthesis of L-arginine, and L-arginine-sensitive NAGK typically has hexameric architecture. Defining the relationship between this architecture and L-arginine inhibition can provide a foundation to identify the key amino acids involved in the allosteric regulation network of L-arginine. In the present study, the key amino acids in the N terminal helix (N-helix) of Corynebacterium glutamicum (Cg) NAGK required for hexamer formation were determined using structural homology modeling and site directed mutagenesis. It was also verified that hexameric architecture is required for the positive cooperativity of inhibition by L-arginine and for efficient catalysis, but that it is not the determinant of inhibition by L arginine. Monomeric mutants retained a similar sensitivity to L-arginine as the hexameric form, indicating that monomers contain an independent, sensitive signal transduction network of L-arginine to mediate allosteric regulation. Mutation studies of CgNAGKs also revealed that amino acid residues 18-23 of the N-helix are required for inhibition by L-arginine, and that E19 may be an essential amino acid influencing the apparent affinity of L-arginine. Collectively, these studies may illuminate the basic mechanism of metabolic homeostasis of C. glutamicum. PMID- 26512007 TI - Anti-Staphylococcus aureus single-chain variable region fragments provide protection against mastitis in mice. AB - Staphylococcus aureus is a leading causative agent of bovine mastitis, which can result in significant economic losses to the dairy industry. However, available vaccines against bovine mastitis do not confer adequate protection, although passive immunization with antibodies may be useful to prevent disease. Hence, we constructed a bovine single-chain variable region fragment (scFv) phage display library using cDNAs from peripheral blood lymphocytes of cows with S. aureus induced mastitis. After four rounds of selection, eight scFvs that bound S. aureus antigens with high affinity were obtained. The framework regions of the variable domains (VH and VL) of the eight scFvs were highly conserved, and the complementarity-determining regions (CDRs) displayed significant diversity, especially CDR3 of the VH domain. All eight scFvs inhibited S. aureus growth in culture medium. Lactating mice were challenged by injecting S. aureus into the fourth mammary gland. Histopathological analysis showed that treatment with these scFvs prior to bacterial challenge maintained the structure of the mammary acini, decreased infiltration of polymorphonuclear neutrophils, increased levels of interferon-gamma and interleukin-4, and reduced tumor necrosis factor-alpha levels in mammary tissues, as compared with mice treatment with physiological saline (P < 0.05). These novel bovine scFvs may be suitable candidates for therapeutic agents for the prevention of S. aureus-induced bovine mastitis. PMID- 26512008 TI - High zinc ion supplementation of more than 30 MUM can increase monoclonal antibody production in recombinant Chinese hamster ovary DG44 cell culture. AB - Effects of high ZnSO4.7H2O supplementation on cell growth and monoclonal antibody (mAb) production in chemically defined suspension cultures of recombinant Chinese hamster ovary (rCHO) DG44 cells were examined. The supplementation of ZnSO4.7H2O up to 120 MUM gradually increased specific mAb production rate of rCHO DG44 cells in the early growth phase (0-4 days of culture). The ZnSO4.7H2O concentration for enhancing mAb production without any cytotoxic effects on cell growth was 30-60 MUM. In addition of 60 MUM ZnSO4.7H2O to in-house protein-free medium and in house chemically defined medium, mAb production was increased 2.0-fold and 6.5 fold, respectively. Moreover, addition of ZnSO4.7H2O to three kinds of commercial chemically defined media yielded a greater than 1.2-fold enhancement of mAb production. These data indicate that simple supplementation of a relatively high zinc ion concentration to cell culture media without significant changes of rCHO DG44 cell culture process can be useful for achieving high production of mAb. PMID- 26512009 TI - Biodegradation kinetics of thin-stillage treatment by Aspergillus awamori and characterization of recovered chitosan. AB - An attempt has been made to provide solution for distillery wastewater using fungal pretreatment followed by an anaerobic process to achieve higher organic matter removal, which is a challenge at present with currently adopted technologies. Submerged growth kinetics of distillery wastewater supernatant by Aspergillus awamori was also evaluated. The proposed kinetic models using a logistic equation for fungal growth and the Leudeking-Piret equation for product formation were validated experimentally, and substrate consumption equation was derived using estimated kinetic coefficients. Up to 59.6 % chemical oxygen demand (COD) and 70 % total organic carbon (TOC) removals were observed in 96 h of fungal incubation. Maximum specific growth rate of fungi, coefficient of biomass yield on substrate and growth-associated product formation coefficient were estimated to be 0.07 +/- 0.01 h(-1), 0.614 kg biomass/kg utilized COD and 0.215 kg CO2/kg utilized TOC, respectively. The chitosan recovery of 0.072-0.078 kg/kg of dry mycelium was obtained using dilute sulphuric acid extraction, showing high purity and characteristic chitosan properties according to FTIR and XRD analyses. After anaerobic treatment of the fungal pretreated effluent with COD concentration of 7.920 +/- 0.120 kg COD/m(3) (organic loading rate of 3.28 kg COD/m(3) day), overall COD reduction of 91.07 % was achieved from distillery wastewater. PMID- 26512011 TI - Integrated Care Pathways for Schizophrenia: A Scoping Review. AB - This paper summarizes the existing evidence for integrated care pathways (ICPs) for the treatment of schizophrenia. Scoping review methods following PRISMA guidelines were employed due to the variable nature of the evidence in this area. The review identified 13 papers. Of these papers, 7 focused on describing ICP content and process-related data and 6 examined clinical outcomes. Of the 6 studies providing outcome data, 2 reported improved outcomes associated with ICPs. Conceptually, ICPs hold great promise for improving the quality of schizophrenia care. However, in contrast with other specialty healthcare domains, the schizophrenia ICP evidence base is very limited and has not fulsomely begun to address ICPs for effectiveness. PMID- 26512010 TI - Biotechnological production and application of the antibiotic pimaricin: biosynthesis and its regulation. AB - Pimaricin (natamycin) is a small polyene macrolide antibiotic used worldwide. This efficient antimycotic and antiprotozoal agent, produced by several soil bacterial species of the genus Streptomyces, has found application in human therapy, in the food and beverage industries and as pesticide. It displays a broad spectrum of activity, targeting ergosterol but bearing a particular mode of action different to other polyene macrolides. The biosynthesis of this only antifungal agent with a GRAS status has been thoroughly studied, which has permitted the manipulation of producers to engineer the biosynthetic gene clusters in order to generate several analogues. Regulation of its production has been largely unveiled, constituting a model for other polyenes and setting the leads for optimizing the production of these valuable compounds. This review describes and discusses the molecular genetics, uses, mode of action, analogue generation, regulation and strategies for increasing pimaricin production yields. PMID- 26512012 TI - Reasons Why Individuals Remain Uninsured Under the Affordable Care Act: Experiences of Patients at a Student-Run Free Clinic in Michigan, a Medicaid Expansion State. AB - Since the enactment of the Affordable Care Act (ACA), many people remain uninsured. While studies have examined this population, few have explored patients' experiences seeking insurance. To elucidate these individuals' perspectives, we surveyed patients (n = 80) at the University of Michigan Student Run Free Clinic concerning their activity accessing insurance. Over half of respondents had sought insurance in the past 6 months; 57 % of respondents qualified for Medicaid by self-reported income (<=138 % FPL) and all but one were eligible for tax credits on the Health Insurance Marketplace. However, only 35 % of apparently Medicaid-eligible respondents had recently applied. There was no significant difference in the rate of applying for those above the income cutoff (p = 0.901). Perceived expense of plans and belief of ineligibility for Medicaid discouraged respondents from actively seeking insurance. Personalized outreach emphasizing new Medicaid eligibility requirements and tax credits may be needed to facilitate Medicaid enrollment for some uninsured persons under the ACA. PMID- 26512013 TI - Coliform Contamination of Peri-urban Grown Vegetables and Potential Public Health Risks: Evidence from Kumasi, Ghana. AB - Peri-urban vegetable farming in Ghana is an important livelihood activity for an increasing number of people. However, increasing quality and public health concerns have been raised, partly because freshwater availability for irrigation purposes is a major constraint. This paper investigated on-farm vegetable contamination and potential health risks using samples of lettuce, spring onions and cabbage randomly selected from 18 vegetable farms in peri-urban Kumasi, Ghana. Vegetable samples were tested for total coliform, fecal coliform, Escherichia coli and Salmonella spp. bacteria contamination using the Most Probable Number method. Results show high contamination levels of total and fecal coliforms, and Escherichia coli bacteria in all 18 vegetable samples. The mean total coliform/100 ml concentration for spring onions, lettuce and cabbage were 9.15 * 10(9), 4.7 * 10(7) and 8.3 * 10(7) respectively. The mean fecal coliform concentration for spring onions, lettuce and cabbage were also 1.5 * 10(8), 4.15 * 10(7) and 2.15 * 10(7) respectively, while the mean Escherichia coli bacteria contamination for spring onions, lettuce and cabbage were 1.4 * 10(8), 2.2 * 10(7) and 3.2 * 10(7) respectively. The level of total coliform, fecal coliform and Escherichia coli bacteria contamination in all the vegetable samples however declined as the distance between the main water source (Wiwi River) and farms increases. Nonetheless, all contamination levels were well above acceptable standards, and could therefore pose serious public health risks to consumers. Increased education and supervision of farmers, as well as public health and food hygiene education of consumers, are critical to reducing on-farm vegetable contamination and the health risks associated with consumption of such vegetables. PMID- 26512014 TI - Third-Hand Smoke: Old Smoke, New Concerns. AB - While the effects of active smoking and second-hand smoke (SHS) are well documented, the concept of third-hand smoke (THS) is a relatively new phenomenon in the environmental and public health field. This notion was coined in 2009 (Winickoff et al. in Pediatrics 123(1):e74-e79, 2009) but was not really brought to light until the New York Times published an article on the topic (Rabin in A new cigarette hazard: 'third-hand smoke'. The New York Times, http://www.nytimes.com/2009/01/03/health/research/03smoke.html?_r=0 , 2009). Research on THS is fairly new and currently only limited animal studies have been performed that explore the health impacts associated with an individual THS specific component. The public at large has a limited understanding of this new concept. As such, attitudes and beliefs surrounding THS exposure are still immature. Future research must be conducted to facilitate hazard identification, exposure and risk assessment to address its health impact on susceptible populations and to differentiate THS versus active smoking and SHS. In addition, policies and laws concerning tobacco smoke will need to be reviewed, possibly revised with the role of THS considered as an indispensable component of a broader tobacco control strategy. PMID- 26512015 TI - Variability in the temporal parameters in the song of the Bengalese finch (Lonchura striata var. domestica). AB - Birdsong provides a unique model for studying the control mechanisms of complex sequential behaviors. The present study aimed to demonstrate that multiple factors affect temporal control in the song production. We analyzed the song of Bengalese finches in various time ranges to address factors that affected the duration of acoustic elements (notes) and silent intervals (gaps). The gaps showed more jitter across song renditions than did notes. Gaps had longer duration in branching points of song sequence than in stereotypic transitions, and the duration of a gap was correlated with the duration of the note that preceded the gap. When looking at the variation among song renditions, we found notable factors in three time ranges: within-day drift, within-bout changes, and local jitter. Note durations shortened over time from morning to evening. Within each song bout note durations lengthened as singing progressed, while gap durations lengthened only during the late part of song bout. Further analysis after removing these drift factors confirmed that the jitter remained in local song sequences. These results suggest distinct sources of temporal variability exist at multiple levels on the basis of this note-gap relationship, and that song comprised a mixture of these sources. PMID- 26512016 TI - Landscape vision and zonal orientation in the Equatorial sandhopper Talorchestia martensii. AB - We investigate the role of the landscape in the zonal recovery of the Equatorial sandhopper Talorchestia martensii Weber. It is known that this species uses the sun and the magnetic compasses to return to the belt of damp sand of the beach following the shortest route (the sea-land axis). However, the sun is not always easy to use at Equatorial latitudes because of astronomical reasons (its zenithal culmination and its hourly azimuthal speed) at least during the central time of the day (around noon) and close to the equinox. Our experiments were performed in Kenya, during the equinoctial period. We tested adult individuals, belonging to Malindi (Kenya) population, in a confined environment with and without the vision of the landscape of their home beach and with the vision of the prominent landscape of a different-orientated shore (Temple Point). Releases were carried out with either natural or zeroed magnetic field. Results clearly show the importance of the landscape as an orienting factor mainly during the central hours of the day when it seems to assume a greater importance than magnetic cues. PMID- 26512017 TI - Liam Donaldson: Proud of smoke-free public places. PMID- 26512020 TI - Risk factor burden in midlife: is it water under the bridge? PMID- 26512019 TI - Computational fluid dynamics modelling in cardiovascular medicine. AB - This paper reviews the methods, benefits and challenges associated with the adoption and translation of computational fluid dynamics (CFD) modelling within cardiovascular medicine. CFD, a specialist area of mathematics and a branch of fluid mechanics, is used routinely in a diverse range of safety-critical engineering systems, which increasingly is being applied to the cardiovascular system. By facilitating rapid, economical, low-risk prototyping, CFD modelling has already revolutionised research and development of devices such as stents, valve prostheses, and ventricular assist devices. Combined with cardiovascular imaging, CFD simulation enables detailed characterisation of complex physiological pressure and flow fields and the computation of metrics which cannot be directly measured, for example, wall shear stress. CFD models are now being translated into clinical tools for physicians to use across the spectrum of coronary, valvular, congenital, myocardial and peripheral vascular diseases. CFD modelling is apposite for minimally-invasive patient assessment. Patient-specific (incorporating data unique to the individual) and multi-scale (combining models of different length- and time-scales) modelling enables individualised risk prediction and virtual treatment planning. This represents a significant departure from traditional dependence upon registry-based, population-averaged data. Model integration is progressively moving towards 'digital patient' or 'virtual physiological human' representations. When combined with population scale numerical models, these models have the potential to reduce the cost, time and risk associated with clinical trials. The adoption of CFD modelling signals a new era in cardiovascular medicine. While potentially highly beneficial, a number of academic and commercial groups are addressing the associated methodological, regulatory, education- and service-related challenges. PMID- 26512021 TI - Experimental inflammation following dural application of complete Freund's adjuvant or inflammatory soup does not alter brain and trigeminal microvascular passage. AB - BACKGROUND: Migraine is a paroxysmal, disabling primary headache that affects 16 % of the adult population. In spite of decades of intense research, the origin and the pathophysiology mechanisms involved are still not fully known. Although triptans and gepants provide effective relief from acute migraine for many patients, their site of action remains unidentified. It has been suggested that during migraine attacks the leakiness of the blood-brain barrier (BBB) is altered, increasing the passage of anti-migraine drugs. This study aimed to investigate the effect of experimental inflammation, following dural application of complete Freund's adjuvant (CFA) or inflammatory soup (IS) on brain and trigeminal microvascular passage. METHODS: In order to address this issue, we induced local inflammation in male Sprague-Dawley-rats dura mater by the addition of CFA or IS directly on the dural surface. Following 2, 24 or 48 h of inflammation we calculated permeability-surface area product (PS) for [(51)Cr] EDTA in the trigeminal ganglion (TG), spinal trigeminal nucleus, cortex, periaqueductal grey and cerebellum. RESULTS: We observed that [(51)Cr]-EDTA did not pass into the central nervous system (CNS) in a major way. However, [(51)Cr] EDTA readily passed the TG by >30 times compared to the CNS. Application of CFA or IS did not show altered transfer constants. CONCLUSIONS: With these experiments we show that dural IS/CFA triggered TG inflammation, did not increase the BBB passage, and that the TG is readily exposed to circulating molecules. The TG could provide a site of anti-migraine drug interaction with effect on the trigeminal system. PMID- 26512022 TI - A review of the generalized uncertainty principle. AB - Based on string theory, black hole physics, doubly special relativity and some 'thought' experiments, minimal distance and/or maximum momentum are proposed. As alternatives to the generalized uncertainty principle (GUP), the modified dispersion relation, the space noncommutativity, the Lorentz invariance violation, and the quantum-gravity-induced birefringence effects are summarized. The origin of minimal measurable quantities and the different GUP approaches are reviewed and the corresponding observations are analysed. Bounds on the GUP parameter are discussed and implemented in the understanding of recent PLANCK observations of cosmic inflation. The higher-order GUP approaches predict minimal length uncertainty with and without maximum momenta. Possible arguments against the GUP are discussed; for instance, the concern about its compatibility with the equivalence principles, the universality of gravitational redshift and the free fall and law of reciprocal action are addressed. PMID- 26512023 TI - n-3 Fatty Acids Induce Neurogenesis of Predominantly POMC-Expressing Cells in the Hypothalamus. AB - Apoptosis of hypothalamic neurons is believed to play an important role in the development and perpetuation of obesity. Similar to the hippocampus, the hypothalamus presents constitutive and stimulated neurogenesis, suggesting that obesity-associated hypothalamic dysfunction can be repaired. Here, we explored the hypothesis that n-3 polyunsaturated fatty acids (PUFAs) induce hypothalamic neurogenesis. Both in the diet and injected directly into the hypothalamus, PUFAs were capable of increasing hypothalamic neurogenesis to levels similar or superior to the effect of brain-derived neurotrophic factor (BDNF). Most of the neurogenic activity induced by PUFAs resulted in increased numbers of proopiomelanocortin but not NPY neurons and was accompanied by increased expression of BDNF and G-protein-coupled receptor 40 (GPR40). The inhibition of GPR40 was capable of reducing the neurogenic effect of a PUFA, while the inhibition of BDNF resulted in the reduction of global hypothalamic cell. Thus, PUFAs emerge as a potential dietary approach to correct obesity-associated hypothalamic neuronal loss. PMID- 26512024 TI - Variations in Brain Volume and Growth in Young Children With Type 1 Diabetes. AB - Early-onset type 1 diabetes may affect the developing brain during a critical window of rapid brain maturation. Structural MRI was performed on 141 children with diabetes (4-10 years of age at study entry) and 69 age-matched control subjects at two time points spaced 18 months apart. For the children with diabetes, the mean (+/-SD) HbA1c level was 7.9 +/- 0.9% (63 +/- 9.8 mmol/mol) at both time points. Relative to control subjects, children with diabetes had significantly less growth of cortical gray matter volume and cortical surface area and significantly less growth of white matter volume throughout the cortex and cerebellum. For the population with diabetes, the change in the blood glucose level at the time of scan across longitudinal time points was negatively correlated with the change in gray and white matter volumes, suggesting that fluctuating glucose levels in children with diabetes may be associated with corresponding fluctuations in brain volume. In addition, measures of hyperglycemia and glycemic variation were significantly negatively correlated with the development of surface curvature. These results demonstrate that early onset type 1 diabetes has widespread effects on the growth of gray and white matter in children whose blood glucose levels are well within the current treatment guidelines for the management of diabetes. PMID- 26512025 TI - Obesity in MENX Rats Is Accompanied by High Circulating Levels of Ghrelin and Improved Insulin Sensitivity. AB - Ghrelin, the natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing epsilon-cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7.5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin's proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion in MENX rats, while insulin sensitivity is improved. In summary, we provide a novel nontransgenic rat model with high endogenous ghrelin plasma levels and, interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases, including type 2 diabetes. PMID- 26512026 TI - Skeletal Muscle Phospholipid Metabolism Regulates Insulin Sensitivity and Contractile Function. AB - Skeletal muscle insulin resistance is an early defect in the development of type 2 diabetes. Lipid overload induces insulin resistance in muscle and alters the composition of the sarcoplasmic reticulum (SR). To test the hypothesis that skeletal muscle phospholipid metabolism regulates systemic glucose metabolism, we perturbed choline/ethanolamine phosphotransferase 1 (CEPT1), the terminal enzyme in the Kennedy pathway of phospholipid synthesis. In C2C12 cells, CEPT1 knockdown altered SR phospholipid composition and calcium flux. In mice, diet-induced obesity, which decreases insulin sensitivity, increased muscle CEPT1 expression. In high-fat diet-fed mice with skeletal muscle-specific knockout of CEPT1, systemic and muscle-based approaches demonstrated increased muscle insulin sensitivity. In CEPT1-deficient muscles, an altered SR phospholipid milieu decreased sarco/endoplasmic reticulum Ca(2+) ATPase-dependent calcium uptake, activating calcium-signaling pathways known to improve insulin sensitivity. Altered muscle SR calcium handling also rendered these mice exercise intolerant. In obese humans, surgery-induced weight loss increased insulin sensitivity and decreased skeletal muscle CEPT1 protein. In obese humans spanning a spectrum of metabolic health, muscle CEPT1 mRNA was inversely correlated with insulin sensitivity. These results suggest that high-fat feeding and obesity induce CEPT1, which remodels the SR to preserve contractile function at the expense of insulin sensitivity. PMID- 26512027 TI - The Relationship Between the Use of Complementary and Alternative Medicine and the Use of Biomedical Services: Evidence From East Asian Medical Systems. AB - To provide East Asian evidence to the relationship between the use of complementary and alternative medicine (CAM) and the use of biomedicine, this article examines the institutionalization of traditional East Asian medicine (EM) in China, Korea, and Japan and how it affects the relationship between EM use and biomedicine use. It uses the 2010 East Asian Social Survey. Logistic regressions specify the statistical association between EM use and biomedical physician visits. These models show that the high institutional acceptance of EM promotes the concurrent use of EM and biomedicine. In addition, since these countries feature different ways of institutionalizing EM (unification in China, equalization in Korea, and subjugation in Japan), the concurrent use is more obvious under the Chinese and the Korean system than the Japanese system. It concludes that the CAM use can be complementary to biomedicine, depending on how CAM and biomedicine are institutionalized in medical systems. PMID- 26512028 TI - Prescription Drug Use Among Adults With Chronic Conditions in South Korea: Dual Burden of Health Care Needs and Socioeconomic Vulnerability. AB - The aim of this study is to identify the social determinants of prescription drug use among adults with chronic diseases by examining the associations between socioeconomic position and prescription medicine use and perceived burden for pharmaceutical expenditure, using a sample of the Korean population from the 2008 Korea Health Panel, with 4 analytic models. Controlled with health status and the type of health insurance, the probability of using prescription drugs and overall spending on drugs significantly increased with rising income level, while perceived burden for out-of-pocket payment significantly decreased. These results imply that the poor are likely to underuse prescription drugs compared with their wealthier counterparts with the same need for health care, probably due to economic barriers. PMID- 26512029 TI - Knowledge, Attitudes, and Practices on Lifestyle and Cardiovascular Risk Factors Among Metabolic Syndrome Patients in an Urban Tertiary Care Institute in Sri Lanka. AB - Metabolic syndrome (MetS) is a significant predictor of cardiovascular diseases (CVDs). A pretested questionnaire was used to assess knowledge, attitudes, and practice (KAP) of CVD and its risks among Sri Lankan urban adults (35-55 years) with MetS. KAP scores were predefined as high, moderate, and low. Of the participants (n = 423), 13% were males and 87% were females. Attitudes scores were high among this population, though their knowledge and practices scores on CVD risk factors were moderate. Participants with high mean knowledge scores had significantly lower waist circumference (WC) and showed a trend toward reduced fasting blood glucose levels. Participants with high practice scores had significantly lower BMI and WC, which signify that better knowledge and practices are associated with decrease in CVD risk markers in these patients. The study reveals that urban MetS patients have a moderate knowledge and practice score, though their attitude score is high regarding CVD risk factors. PMID- 26512030 TI - Incremental Cost-Effectiveness Analysis of Gestational Diabetes Mellitus Screening Strategies in Singapore. AB - The objective of this study was to conduct an incremental cost-effectiveness analysis from the payer's perspective in Singapore of 3 gestational diabetes mellitus screening strategies: universal, targeted, or no screening. A decision tree model assessed the primary outcome: incremental cost per quality-adjusted life year (QALY) gained. Probabilities, costs, and utilities were derived from the literature, the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort study, and the KK Women's and Children's Hospital's database. Relative to targeted screening using risk factors, universal screening generates an incremental cost-effectiveness ratio (ICER) of $USD10,630/QALY gained. Sensitivity analyses show that disease prevalence rates and intervention effectiveness of glycemic management have the biggest impacts on the ICERs. Based on the model and best available data, universal screening is a cost-effective approach for reducing the complications of gestational diabetes mellitus in Singapore as compared with the targeted screening approach or no screening. PMID- 26512031 TI - Correlation Between New Cooperative Medical Scheme Policy Design and Catastrophic Medical Payment: Evidence From 25 Counties in Rural China. AB - Few studies have examined the association between the New Cooperative Medical Scheme (NCMS) policy design and its achievement of providing financial protection to rural residents. This study collected data on NCMS policy design and health care spending from 25 counties and rural households in their catchment areas. It shows that on average, NCMS has a growing but small effect on the reduction of catastrophic medical payment (CMP) incidence. If outpatient spending can be reimbursed from an NCMS pooled account, the incidence of CMP before a reimbursement and that after a reimbursement will be reduced. Higher nominal reimbursement rate for inpatient spending at provincial hospitals is correlated with higher incidence of CMP before a reimbursement. Higher ceiling for annual reimbursement from NCMS is associated with lower incidence of CMP after a reimbursement. Thus, NCMS policy design can be improved to strengthen its effects on the reduction of CMP incidence. PMID- 26512032 TI - Assessment of eHealth capabilities and utilization in residential care settings. AB - The US National Survey of Residential Care Facilities was used to conduct cross sectional analyses of residential care facilities (n = 2302). Most residential care facilities lacked computerized capabilities for one or more of these capabilities in 2010. Lacking computerized systems supporting electronic health information exchange with pharmacies was associated with non-chain affiliation (p < .05). Lacking electronic health information exchange with physicians was associated with being a small-sized facility (vs large) (p < .05). Lacking computerized capabilities for discharge/transfer summaries was associated with for-profit status (p < .05) and small-sized facilities (p < .05). Lacking computerized capabilities for medical provider information was associated with non-chain affiliation (p < .05), small- or medium-sized facilities (p < .05), and for-profit status (p < .05). Lack of electronic health record was associated with non-chain affiliation (p < .05), small- or medium-sized facilities (p < .05), for profit status (p < .05), and location in urban areas (p < .05). eHealth disparities exist across residential care facilities. As the older adult population continues to grow, resources must be in place to provide an integrated system of care across multiple settings. PMID- 26512034 TI - CXCL10, CXCL11, HLA-A and IL-1beta are induced in peripheral blood mononuclear cells from women with Chlamydia trachomatis related infertility. AB - Chlamydia trachomatis infections can result in the development of serious sequelae such as pelvic inflammatory disease and tubal infertility. In this study, peripheral blood mononuclear cells from women who were undergoing or had recently undergone IVF treatment were cultured ex vivo with C. trachomatis to identify the immune responses associated with women who had serological evidence of a history of Chlamydia infection. Cytokines secreted into the supernatant from the cultures were measured using ELISA, and the level of IL-1beta was found to be significantly higher in Chlamydia positive women than Chlamydia negative women. qRT-PCR analysis of the expression of 88 immune-related genes showed trends towards an upregulation of CXCL10, CXCL11 and HLA-A in Chlamydia positive women compared with Chlamydia negative women. These findings support that some women launch a more marked proinflammatory response upon infection with C. trachomatis and this may be associated with why C. trachomatis induces infertility in some infected women. PMID- 26512035 TI - MSF hospital is destroyed in Yemen airstrikes. PMID- 26512033 TI - Building a KATalogue of acetyllysine targeting and function. AB - Acetylation is a dynamic post-translational modification that is attached to protein substrates by lysine acetyltransferases (KATs) and removed by lysine deacetylases (KDACs). While these enzymes are best characterized as histone modifiers and regulators of gene transcription, work in a number of systems highlights that acetylation is a pervasive modification and suggests a broad scope for KAT and KDAC functions in the cell. As we move beyond generating lists of acetylated proteins, the acetylation field is in dire need of robust tools to connect acetylation and deacetylation machineries to their respective substrates and to dissect the function of individual sites. The Saccharomyces cerevisiae model system provides such a toolkit in the context of both tried and true genetic techniques and cutting-edge proteomic and cell imaging methods. Here, we review these methods in the context of their contributions to acetylation research thus far and suggest strategies for addressing lingering questions in the field. PMID- 26512036 TI - Solitaire salvage: a stent retriever-assisted catheter reduction technical report. AB - The endovascular management of giant aneurysms often proves difficult with standard techniques. Obtaining distal access to allow catheter reduction is often key to approaching these aneurysms, but several anatomic challenges make this task unsafe and not feasible. Obtaining distal anchor points and performing catheter reduction maneuvers using adjunctive devices is not a novel concept, however using the Solitaire in order to do so may have some distinct advantages compared with previously described methods. Here we describe our novel Solitaire salvage technique, which allowed successful reduction of a looped catheter within an aneurysm in three cases. While this technique is expensive and therefore best performed after standard maneuvers have failed, in our experience it was effective, safe, and more efficient than other methods. PMID- 26512037 TI - Tackling a case of a stent lost in calcified right coronary artery: a novel implication of intravascular ultrasound. PMID- 26512038 TI - Successful device closure of a ruptured sinus of Valsalva aneurysm presenting with acute heart failure. PMID- 26512039 TI - Acute Kidney Injury Predicts Major Adverse Outcomes in Diabetes: Synergic Impact With Low Glomerular Filtration Rate and Albuminuria. AB - OBJECTIVE: Subjects with diabetes are prone to the development of cardiovascular and noncardiovascular complications. In separate studies, acute kidney injury (AKI), albuminuria, and low estimated glomerular filtration rate (eGFR) were shown to predict adverse outcomes, but, when considered together, their respective prognostic value is unknown. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes consecutively recruited in the SURDIAGENE cohort were prospectively followed up for major diabetes-related events, as adjudicated by an independent committee: death (with cause), major cardiovascular events (myocardial infarction, stroke, congestive heart failure, amputation, and arterial revascularization), and renal failure (i.e., sustained doubling of serum creatinine level or end-stage renal disease). RESULTS: Intrahospital AKI occurred in 411 of 1,371 patients during the median follow-up period of 69 months. In multivariate analyses, AKI was significantly associated with cardiovascular and noncardiovascular death, including cancer-related death. In multivariate analyses, AKI was a powerful predictor of major adverse cardiovascular events, heart failure requiring hospitalization, myocardial infarction, stroke, lower limb amputation or revascularization, and carotid artery revascularization. AKI, eGFR, and albuminuria, even when simultaneously considered in multivariate models, predicted all-cause and cardiovascular deaths. All three renal biomarkers were also prognostic of most adverse outcomes and of the risk of renal failure. CONCLUSIONS: AKI, low eGFR, and elevated albuminuria, separately or together, are compelling biomarkers of major adverse outcomes and death in diabetes. PMID- 26512040 TI - Impact of Extended Combination Antiretroviral Therapy on the Decline of HIV Prevalence in Pregnant Women in Malawi. AB - Combination antiretroviral therapy has been shown to reduce HIV transmission and incident infections. In recent years, Malawi has significantly increased the number of individuals on combination antiretroviral drugs through more inclusive treatment policies. Using a retrospective observational cohort design, records with HIV test results were reviewed for pregnant women attending a referral hospital in Malawi over a 5-year period, with viral load measurements recorded. HIV prevalence over time was determined, and results correlated with population viral load. A total of 11 052 women were included in this analysis, with 440 (4.1%) HIV infections identified. HIV prevalence rates in pregnant women in Malawi halved from 6.4% to 3.0% over 5 years. Mean viral loads of adult patients decreased from 120 000 copies/mL to less than 20 000 copies/mL. Results suggest that community viral load has an effect on HIV incidence rates in the population, which in turn correlates with reduced HIV prevalence rates in pregnant women. PMID- 26512041 TI - Liraglutide in people treated for type 2 diabetes with multiple daily insulin injections: randomised clinical trial (MDI Liraglutide trial). AB - STUDY QUESTION: What are the effects of liraglutide, an incretin based treatment, on glycaemic control in people with type 2 diabetes treated with multiple daily insulin injections? METHODS: The study was a randomised, double blind, placebo controlled trial with a parallel group design carried out at 13 hospital based outpatient clinics and one primary care unit in Sweden. Patients were considered eligible for inclusion if they had type 2 diabetes and inadequate glycaemic control (HbA1c concentrations >= 58 mmol/mol (7.5%) and <= 102 mmol/mol (11.5%)), a body mass index of 27.5-45 kg/m(2), and required multiple daily insulin injections. Overall, 124 participants were randomised 1:1 to subcutaneous liraglutide or placebo by minimisation allocation. The main outcome measure was change in HbA1c level from baseline to week 24. STUDY ANSWER AND LIMITATIONS: Liraglutide was associated with a significant reduction of 16.9 mmol/mol (1.5%) in HbA1c versus 4.6 mmol/mol (0.4%) for placebo, difference -12.3 mmol/mol (95% confidence interval -15.8 to -8.8 mmol/mol; -1.13%, -1.45 to -0.81 mmol/mol). Body weight was significantly reduced in participants in the liraglutide compared with placebo group (3.8 v 0.0 kg, difference -3.8, -4.9 to -2.8 kg), and total daily insulin doses were significantly reduced, by 18.1 units and 2.3 units (difference -15.8, -23.1 to -8.5 units). Reductions in mean and standard deviation of glucose levels estimated by masked continuous glucose monitoring were significantly greater in the liraglutide group than placebo group (-1.9 and 0.5 mmol/L). Neither group experienced severe hypoglycaemic events nor were there any significant differences in symptomatic or asymptomatic non-severe hypoglycaemia (<4.0 or <3.0 mmol/L). The mean number of non-severe symptomatic hypoglycaemic events (<4.0 mmol/L) during follow-up was 1.29 in the liraglutide group and 1.24 in the placebo group (P=0.96). One of the study's limitations was its relatively short duration. Sustained effects of liraglutide have, however, been found over lengthier periods in connection with other treatment regimens. Cardiovascular safety and potential adverse events during longer exposure to liraglutide need to be evaluated. Nausea was experienced by 21 (32.8%) participants in the liraglutide group and 5 (7.8%) in the placebo group and 3 (5%) and 4 (7%) participants in these groups, respectively, had any serious adverse event. WHAT THIS STUDY ADDS: Adding liraglutide to multiple daily insulin injections in people with type 2 diabetes improves glycaemic control without an increased risk of hypoglycaemia, reduces body weight, and enables patients to lower their insulin doses. FUNDING, COMPETING INTERESTS, DATA SHARING: This study was an investigator initiated trial, supported in part by Novo Nordisk and InfuCare. Potential competing interests have been reported and are available on the bmj.com. STUDY REGISTRATION: EudraCT 2012-001941-42. PMID- 26512042 TI - In Vitro Kinetic Characterization of Axitinib Metabolism. AB - N-Methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide (axitinib) is an oral inhibitor of vascular endothelial growth factor receptors 1 3, which is approved for the treatment of advanced renal cell cancer. Human [(14)C]-labeled clinical studies indicate axitinib's primary route of clearance is metabolism. The aims of the in vitro experiments presented herein were to identify and characterize the enzymes involved in axitinib metabolic clearance. In vitro biotransformation studies of axitinib identified a number of metabolites including an axitinib sulfoxide, several less abundant oxidative metabolites, and glucuronide conjugates. The most abundant NADPH- and UDPGA-dependent metabolites, axitinib sulfoxide (M12) and axitinib N-glucuronide (M7) were selected for phenotyping and kinetic study. Phenotyping experiments with human liver microsomes (HLMs) using chemical inhibitors and recombinant human cytochrome P450s demonstrated axitinib was predominately metabolized by CYP3A4/5, with minor contributions from CYP2C19 and CYP1A2. The apparent substrate concentration at half-maximal velocity (Km) and Vmax values for the formation of axitinib sulfoxide by CYP3A4 or CYP3A5 were 4.0 or 1.9 uM and 9.6 or 1.4 pmol.min( 1).pmol(-1), respectively. Using a CYP3A4-specific inhibitor (Cyp3cide) in liver microsomes expressing CYP3A5, 66% of the axitinib intrinsic clearance was attributable to CYP3A4 and 15% to CYP3A5. Axitinib N-glucuronidation was primarily catalyzed by UDP-glucuronosyltransferase (UGT) UGT1A1, which was verified by chemical inhibitors and UGT1A1 null expressers, with lesser contributions from UGTs 1A3, 1A9, and 1A4. The Km and Vmax values describing the formation of the N-glucuronide in HLM or rUGT1A1 were 2.7 uM or 0.75 uM and 8.9 or 8.3 pmol.min(-1).mg(-1), respectively. In summary, CYP3A4 is the major enzyme involved in axitinib clearance with lesser contributions from CYP3A5, CYP2C19, CYP1A2, and UGT1A1. PMID- 26512043 TI - BMJ launches publishing portal in China. PMID- 26512044 TI - Genomic Profiling in Gastrointestinal Cancer: Are We Ready To Use These Data to Make Treatment Decisions? AB - Remarkable strides have been made in the past 10-15 years in identifying the molecular events that drive cancer. With an enormous amount of new data, including those from The Cancer Genome Atlas Project, therapies are increasingly being developed and tested in clinical trials specifically designed to target some of these molecular events. Often, molecular signatures have become more important than the histologic features in making treatment choices. The success rate of these therapies depends on many factors but, perhaps most importantly, on patient selection according to the genetic analysis results of their individual tumors. PMID- 26512045 TI - Distance as a Barrier to Cancer Diagnosis and Treatment: Review of the Literature. AB - The burden of travel from a patient's residence to health care providers is an important issue that can influence access to diagnosis and treatment of cancer. Although several studies have shown that the travel burden can result in delays in diagnosis and treatment of many common cancers, its role appears underestimated in the treatment of patients in clinical practice. Therefore, we performed a review of the published data on the role of travel burden influencing four items: delay of diagnosis, adequate treatment of cancer, outcome, and quality of life of cancer patients. Forty-seven studies published up to December 2014 were initially identified. Twenty studies were excluded because they did not regard specifically the four items of our review. Twenty-seven studies formed the basis of our study and involved 716,153 patients. The associations between travel burden and (a) cancer stage at diagnosis (12 studies), (b) appropriate treatment (8 studies), (c) outcome (4 studies), and (d) quality of life (1 study) are reported. In addition, in two studies, the relation between travel burden and compliance with treatment was examined. The results of our review show that increasing travel requirements are associated with more advanced disease at diagnosis, inappropriate treatment, a worse prognosis, and a worse quality of life. These results suggest that clinical oncologists should remember the specific travel burden problem for cancer patients, who often need health care services every week or every month for many years. PMID- 26512046 TI - Ramosetron Versus Ondansetron in Combination With Aprepitant and Dexamethasone for the Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: A Multicenter, Randomized Phase III Trial, KCSG PC10-21. AB - BACKGROUND: A combination of serotonin receptor (5-hydroxytryptamine receptor type 3) antagonists, NK-1 receptor antagonist, and steroid improves the complete response (CR) of chemotherapy-induced nausea and vomiting (CINV) in cancer patients. Ramosetron's efficacy in this triple combination regimen has not been investigated. This prospective, multicenter, single-blind, randomized, phase III study compares a combination of ramosetron, aprepitant, and dexamethasone (RAD) with a combination of ondansetron, aprepitant, and dexamethasone (OAD) to prove the noninferiority of RAD in controlling highly emetogenic CINV. METHODS: Aprepitant and dexamethasone were orally administered for both arms. Ramosetron and ondansetron were intravenously given to the RAD and OAD groups. The primary endpoint was no vomiting and retching and no need for rescue medication during the acute period (day 1); the noninferiority margin was -15%. RESULTS: A total of 299 modified intention-to-treat cancer patients who received RAD (144 patients) and OAD (155 patients) were eligible for the efficacy analysis. The CR rates of RAD versus OAD were 97.2% versus 93.6% during the acute period, 77.8% versus 73.6% during the delayed period (day 2-5), and 77.1% versus 71.6% during the overall period. Furthermore, RAD was noninferior to OAD in subgroups stratified by age, cancer type, chemotherapeutic agents, and schedule. Repeated measures analysis showed that in male patients, RAD was superior to OAD. Profiles of adverse events were similar in both groups. CONCLUSION: RAD is as effective and tolerable as OAD for CINV prevention in patients receiving highly emetogenic chemotherapy. Ramosetron could be considered one of the best partners for aprepitant. PMID- 26512047 TI - Enumeration of Gut-Homing beta7-Positive, Pathogen-Specific Antibody-Secreting Cells in Whole Blood from Enterotoxigenic Escherichia coli- and Vibrio cholerae Infected Patients, Determined Using an Enzyme-Linked Immunosorbent Spot Assay Technique. AB - Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC) are noninvasive mucosal pathogens that cause acute watery diarrhea in people in developing countries. Direct assessment of the mucosal immune responses to these pathogens is problematic. Surrogate markers of local mucosal responses in blood are increasingly being studied to determine the mucosal immune responses after infection. However, the volume of blood available in children and infants has limited this approach. We assessed whether an approach that first isolates beta7 positive cells from a small volume of blood would allow measurement of the antigen-specific immune responses in patients with cholera and ETEC infection. beta7 is a cell surface marker associated with mucosal homing. We isolated beta7 expressing cells from blood on days 2, 7, and 30 and used an enzyme-linked immunosorbent spot (ELISPOT) assay to assess the gut-homing antibody-secreting cells (ASCs) specific to pathogen antigens. Patients with ETEC diarrhea showed a significant increase in toxin-specific gut-homing ASCs at day 7 compared to the levels at days 2 and 30 after onset of illness and to the levels in healthy controls. Similar elevations of responses to the ETEC colonization factors (CFs) CS6 and CFA/I were observed in patients infected with CS6- and CFA/I-positive ETEC strains. Antigen-specific gut-homing ASCs to the B subunit of cholera toxin and cholera-specific lipopolysaccharides (LPS) were also observed on day 7 after the onset of cholera using this approach. This study demonstrates that a simple ELISPOT assay can be used to study the mucosal immunity to specific antigens using a cell-sorting protocol to isolate mucosal homing cells, facilitating measurement of mucosal responses in children following infection or vaccination. PMID- 26512048 TI - Naturally Acquired HMW1- and HMW2-Specific Serum Antibodies in Adults and Children Mediate Opsonophagocytic Killing of Nontypeable Haemophilus influenzae. AB - The HMW1 and HMW2 proteins are highly immunogenic adhesins expressed by approximately 75% of nontypeable Haemophilus influenzae (NTHi) strains, and HMW1- and HMW2-specific antibodies can mediate opsonophagocytic killing of NTHi. In this study, we assessed the ability of HMW1- and HMW2-specific antibodies in sera from healthy adults and convalescent-phase sera from children with NTHi otitis media to mediate killing of homologous and heterologous NTHi. The serum samples were examined pre- and postadsorption on HMW1 and HMW2 affinity columns, and affinity-purified antibodies were assessed for ability to mediate killing of homologous and heterologous strains. Adult serum samples mediated the killing of six prototype NTHi strains at titers of <1:10 to 1:1,280. HMW1- and HMW2-adsorbed sera demonstrated unchanged to 8-fold decreased opsonophagocytic titers against the homologous strains. Each affinity-purified antibody preparation mediated the killing of the respective homologous strain at titers of <1:10 to 1:320 and of the five heterologous strains at titers of <1:10 to 1:320, with most preparations killing most heterologous strains to some degree. None of the acute-phase serum samples from children mediated killing, but each convalescent-phase serum sample mediated killing of the infecting strain at titers of 1:40 to 1:640. HMW1- and HMW2-adsorbed convalescent-phase serum samples demonstrated >=4-fold decreases in titer. Three of four affinity-purified antibody preparations mediated killing of the infecting strain at titers of 1:20 to 1:320, but no killing of representative heterologous strains was observed. HMW1- and HMW2-specific antibodies capable of mediating opsonophagocytic killing are present in the serum from normal adults and develop in convalescent-phase sera of children with NTHi otitis media. Continued investigation of the HMW1 and HMW2 proteins as potential vaccine candidates for the prevention of NTHi disease is warranted. PMID- 26512049 TI - Display of Antigens on Polyester Inclusions Lowers the Antigen Concentration Required for a Bovine Tuberculosis Skin Test. AB - The tuberculin skin test is the primary screening test for the diagnosis of bovine tuberculosis (TB), and use of this test has been very valuable in the control of this disease in many countries. However, the test lacks specificity when cattle have been exposed to environmental mycobacteria or vaccinated with Mycobacterium bovis bacille Calmette-Guerin (BCG). Recent studies showed that the use of three or four recombinant mycobacterial proteins, including 6-kDa early secretory antigenic target (ESAT6), 10-kDa culture filtrate protein (CFP10), Rv3615c, and Rv3020c, or a peptide cocktail derived from those proteins, in the skin test greatly enhanced test specificity, with minimal loss of test sensitivity. The proteins are present in members of the pathogenic Mycobacterium tuberculosis complex but are absent in or not expressed by the majority of environmental mycobacteria and the BCG vaccine strain. To produce a low-cost skin test reagent, the proteins were displayed at high density on polyester beads through translational fusion to a polyhydroxyalkanoate synthase that mediates the formation of antigen-displaying inclusions in recombinant Escherichia coli. Display of the proteins on the polyester beads greatly increased their immunogenicity, allowing for the use of very low concentrations of proteins (0.1 to 3 MUg of mycobacterial protein/inoculum) in the skin test. Polyester beads simultaneously displaying all four proteins were produced in a single fermentation process. The polyester beads displaying three or four mycobacterial proteins were shown to have high sensitivity for detection of M. bovis-infected cattle and induced minimal responses in animals exposed to environmental mycobacteria or vaccinated with BCG. PMID- 26512050 TI - A Hyperresponsive HPA Axis May Confer Resilience Against Persistent Paclitaxel Induced Mechanical Hypersensitivity. AB - Paclitaxel (PAC) treatment is associated with persistent, debilitating neuropathic pain that affects the hands and feet. Female sex and biological stress responsivity are risk factors for persistent pain, but it is unclear whether these important biologically based factors confer risk for PAC-induced neuropathic pain. To determine the relative contributions of sex and hypothalamic pituitary-adrenal (HPA)-axis stress responsivity to PAC-induced mechanical hypersensitivity, we employed a PAC protocol consisting of three, 2-week cycles of every-other-day doses of PAC 1 mg/kg versus saline (Week 1) and recovery (Week 2), totaling 42 days, in mature male and female Fischer 344, Lewis, and Sprague Dawley (SD) rats, known to differ in HPA axis stress responsivity. Mechanical sensitivity was operationalized using von Frey filaments, per the up-down method. Among PAC-injected rats, SD rats exhibited significantly greater mechanical hypersensitivity relative to accumulative PAC doses compared to Fischer 344 rats. Lewis rats were not significantly different in mechanical hypersensitivity from SD or Fischer 344 rats. At the end of the protocol, PAC-injected SD rats exhibited profound mechanical hypersensitivity, whereas the PAC-injected Fischer 344 rats appeared relatively resilient to the long-term effects of PAC and exhibited mechanical sensitivity that was not statistically different from their saline-injected counterparts. Sex differences were mixed and noted only early in the PAC protocol. Moderate HPA axis stress responsivity may confer additional risk for the painful effects of PAC. If these findings hold in humans, clinicians may be better able to identify persons who may be at increased risks for developing neuropathic pain during PAC therapy. PMID- 26512051 TI - Sleep Fragmentation and Biomarkers in Juvenile Idiopathic Arthritis. AB - OBJECTIVES: (1) To compare sleep (nighttime sleep duration and sleep efficiency) and sleep fragmentation (movement and fragmentation index), as measured by actigraphy, and symptoms (pain and fatigue) in 8- to 14-year-old children with polyarticular and extended oligoarticular juvenile idiopathic arthritis (JIA) and (2) to examine the associations between sleep fragmentation (movement and fragmentation index) and the calcium-binding protein biomarkers S100A12 and myeloid-related protein (MRP8/14). METHOD: Participants included 40 children with extended oligoarticular (n = 15) or polyarticular (n = 25) JIA and their parents. Serum protein samples were obtained during routine rheumatology clinic visits. Children completed the PedsQL Multidimensional Fatigue Scale and daily pain and sleep diaries and wore actigraphy monitors for 9 consecutive days. Parents completed the Children's Sleep Habits Questionnaire (CSHQ). RESULTS: Of the 40 children, 68% scored above the CSHQ clinical cutoff score for sleep disturbances. Mean nighttime sleep duration was 7.5 hr, and mean sleep efficiency was 85.3%. Group differences were not found for nighttime sleep duration, sleep efficiency, movement and fragmentation index, or S100A12 and MRP8/14 protein concentrations. In a stepwise regression, medications, joint count, and movement and fragmentation index explained 21% of the variance in MRP8/14 concentration. CONCLUSION: Decreased nighttime sleep duration, poor sleep efficiency, and fragmented sleep were observed in our sample, regardless of JIA category. Sleep fragmentation was a significant predictor of MRP8/14 protein concentration. Additional research is needed to understand the interrelations among sleep fragmentation, effects of medication, and S100A12 and MRP8/14 protein biomarkers in JIA. PMID- 26512052 TI - Lung Disease, Oxidative Stress, and Oxygen Requirements in Preterm Infants. AB - BACKGROUND: The role of oxidative stress remains unclear in the multifactorial pathophysiologic mechanism of lung disease in preterm infants. AIMS: The aim of this study was to examine the associations among chronic lung disease (CLD), oxidative stress, and oxygen requirements in preterm infants. DESIGN: Prospective, longitudinal, and correlational design. SUBJECTS: Preterm infants born at <32 weeks' gestation (N = 31), median gestation of 29.0 weeks (range 24.9 31.7). MEASUREMENTS: The diagnosis of CLD was obtained from the medical record. Oxidative stress was measured using 8-hydroxydeoxyguanosine (8-OHdG) in the cord blood at birth and urine on Days 1 and 7. Oxygen requirements were measured using fraction of inspired oxygen (FIO2) recorded in the first hour after birth/admission and the average FIO2 during the first 12 hr and 7 days after birth. Descriptive statistics are presented. Comparison analyses were performed using Kruskal-Wallis and Fisher's exact tests. RESULTS: Infants with CLD (n = 12) had lower gestational age (p = .04) and weight (p = .04) at birth, more days on the ventilator (p = .004), and longer neonatal intensive care unit stay (p = .04) compared to infants without CLD (n = 19). CLD was associated with lower oxidative stress levels (p = .03) and higher oxygen requirements during the first 12 hr (p = .025) and on Day 7 (p = .001). Lower oxidative stress levels on Day 7 were associated with higher oxygen requirements in the first 12 hr (p = .01) and on Day 7 (p = .03). CONCLUSION: Our results linking CLD and higher oxygen requirements with low oxidative stress contradict previous reports. Findings identify a gap in knowledge for postresuscitation oxygen therapy in preterm infants and expose the role of oxidative stress from inflammation and intermittent hypoxia in the etiology of CLD. PMID- 26512053 TI - CRH as a Predictor of Preterm Birth in Minority Women. AB - OBJECTIVE: To determine the predictive capability of corticotropin-releasing hormone (CRH) as a biomarker of preterm birth (PTB) in minority women. STUDY DESIGN: Venous blood samples were obtained at 22-24 weeks' gestation in a prospective, descriptive study of 707 minority women experiencing low-risk pregnancies. CRH was analyzed using a radioimmunoassay and methanol extraction protocol. RESULT: CRH predicted PTB in both African American and Hispanic women. The odds ratio was 1.8 times greater for having a PTB if the CRH level was >24 pg/ml. The median CRH for African American women having a PTB was 46.6 pg/ml and for Hispanic women was 35.03 pg/ml. Using a receiver-operating characteristic curve, the threshold for CRH among the African American women was 30.6 pg/ml and among the Hispanic women was 27.4 pg/ml. CONCLUSION: CRH may be an important biomarker for predicting PTB in minority women, especially when combined with other predictors. PMID- 26512054 TI - Clinicopathologic Risk Factor Distributions for MLH1 Promoter Region Methylation in CIMP-Positive Tumors. AB - BACKGROUND: The CpG island methylator phenotype (CIMP) is a major molecular pathway in colorectal cancer. Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1. METHODS: We assessed the associations between age, sex, tumor-site, MSI status BRAF and KRAS mutations, and family colorectal cancer history with MLH1 methylation status in a large population-based sample of CIMP-positive colorectal cancers defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables. RESULTS: Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger, more likely to be male, and more likely to have distal colon or rectal primaries and the MSI-L phenotype. CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation. MLH1 methylation was associated with significantly better overall survival (HR, 0.50; 95% confidence interval, 0.31 0.82). CONCLUSIONS: These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis. IMPACT: MLH1 DNA methylation status should be taken into account in etiologic studies. PMID- 26512055 TI - An A20/AN1-type zinc finger protein modulates gibberellins and abscisic acid contents and increases sensitivity to abiotic stress in rice (Oryza sativa). AB - The plant hormones gibberellins (GA) and abscisic acid (ABA) play important roles in plant development and stress responses. Here we report a novel A20/AN1-type zinc finger protein ZFP185 involved in GA and ABA signaling in the regulation of growth and stress response. ZFP185 was constitutively expressed in various rice tissues. Overexpression of ZFP185 in rice results in a semi-dwarfism phenotype, reduced cell size, and the decrease of endogenous GA3 content. By contrast, higher GA3 content was observed in RNAi plants. The application of exogenous GA3 can fully rescue the semi-dwarfism phenotype of ZFP185 overexpressing plants, suggesting the negative role of ZFP185 in GA biosynthesis. Besides GA, overexpression of ZFP185 decreased ABA content and expression of several ABA biosynthesis-related genes. Moreover, it was found that ZFP185, unlike previously known A20/AN1-type zinc finger genes, increases sensitivity to drought, cold, and salt stresses, implying the negative role of ZFP185 in stress tolerance. ZFP185 was localized in the cytoplasm and lacked transcriptional activation potential. Our study suggests that ZFP185 regulates plant growth and stress responses by affecting GA and ABA biosynthesis in rice. PMID- 26512056 TI - Phase change and flowering in woody plants of the New Zealand flora. PMID- 26512057 TI - Soybean fruit development and set at the node level under combined photoperiod and radiation conditions. AB - In soybean, long days during post-flowering increase seed number. This positive photoperiodic effect on seed number has been previously associated with increments in the amount of radiation accumulated during the crop cycle because long days extend the duration of the crop cycle. However, evidence of intra-nodal processes independent of the availability of assimilates suggests that photoperiodic effects at the node level might also contribute to pod set. This work aims to identify the main mechanisms responsible for the increase in pod number per node in response to long days; including the dynamics of flowering, pod development, growth and set at the node level. Long days increased pods per node on the main stems, by increasing pods on lateral racemes (usually dominated positions) at some main stem nodes. Long days lengthened the flowering period and thereby increased the number of opened flowers on lateral racemes. The flowering period was prolonged under long days because effective seed filling was delayed on primary racemes (dominant positions). Long days also delayed the development of flowers into pods with filling seeds, delaying the initiation of pod elongation without modifying pod elongation rate. The embryo development matched the external pod length irrespective of the pod's chronological age. These results suggest that long days during post-flowering enhance pod number per node through a relief of the competition between pods of different hierarchy within the node. The photoperiodic effect on the development of dominant pods, delaying their elongation and therefore postponing their active growth, extends flowering and allows pod set at positions that are usually dominated. PMID- 26512058 TI - Complex molecular mechanisms underlying seedling salt tolerance in rice revealed by comparative transcriptome and metabolomic profiling. AB - To understand the physiological and molecular mechanisms underlying seedling salt tolerance in rice (Oryza sativa L.), the phenotypic, metabolic, and transcriptome responses of two related rice genotypes, IR64 and PL177, with contrasting salt tolerance were characterized under salt stress and salt+abscisic acid (ABA) conditions. PL177 showed significantly less salt damage, lower Na(+)/K(+) ratios in shoots, and Na(+) translocation from roots to shoots, attributed largely to better salt exclusion from its roots and salt compartmentation of its shoots. Exogenous ABA was able to enhance the salt tolerance of IR64 by selectively decreasing accumulation of Na(+) in its roots and increasing K(+) in its shoots. Salt stress induced general and organ-specific increases of many primary metabolites in both rice genotypes, with strong accumulation of several sugars plus proline in shoots and allantoin in roots. This was due primarily to ABA mediated repression of genes for degradation of these metabolites under salt. In PL177, salt specifically up-regulated genes involved in several pathways underlying salt tolerance, including ABA-mediated cellular lipid and fatty acid metabolic processes and cytoplasmic transport, sequestration by vacuoles, detoxification and cell-wall remodeling in shoots, and oxidation-reduction reactions in roots. Combined genetic and transcriptomic evidence shortlisted relatively few candidate genes for improved salt tolerance in PL177. PMID- 26512059 TI - Major latex protein-like protein 43 (MLP43) functions as a positive regulator during abscisic acid responses and confers drought tolerance in Arabidopsis thaliana. AB - Drought stress is one of the disadvantageous environmental conditions for plant growth and reproduction. Given the importance of abscisic acid (ABA) to plant growth and abiotic stress responses, identification of novel components involved in ABA signalling transduction is critical. In this study, we screened numerous Arabidopsis thaliana mutants by seed germination assay and identified a mutant mlp43 (major latex protein-like 43) with decreased ABA sensitivity in seed germination. The mlp43 mutant was sensitive to drought stress while the MLP43 overexpressed transgenic plants were drought tolerant. The tissue-specific expression pattern analysis showed that MLP43 was predominantly expressed in cotyledons, primary roots and apical meristems, and a subcellular localization study indicated that MLP43 was localized in the nucleus and cytoplasm. Physiological and biochemical analyses indicated that MLP43 functioned as a positive regulator in ABA- and drought-stress responses in Arabidopsis through regulating water loss efficiency, electrolyte leakage, ROS levels, and as well as ABA-responsive gene expression. Moreover, metabolite profiling analysis indicated that MLP43 could modulate the production of primary metabolites under drought stress conditions. Reconstitution of ABA signalling components in Arabidopsis protoplasts indicated that MLP43 was involved in ABA signalling transduction and acted upstream of SnRK2s by directly interacting with SnRK2.6 and ABF1 in a yeast two-hybrid assay. Moreover, ABA and drought stress down-regulated MLP43 expression as a negative feedback loop regulation to the performance of MLP43 in ABA and drought stress responses. Therefore, this study provided new insights for interpretation of physiological and molecular mechanisms of Arabidopsis MLP43 mediating ABA signalling transduction and drought stress responses. PMID- 26512060 TI - Reduced PLP2 expression increases ER-stress-induced neuronal apoptosis and risk for adverse neurological outcomes after hypoxia ischemia injury. AB - Both genetic and environmental factors contribute to the development of intellectual disability (ID). Previously, we identified a promoter variant ( 113C>A) in PLP2 (proteolipid protein 2) that results in an ~4-fold reduction of transcript and protein and is overly represented in males with X-linked ID (XLID). The functional connection between reduced PLP2 expression and increased risk to XLID is unknown. To investigate the pathophysiological mechanisms, we studied a Plp2-loss-of-function murine model and fibroblasts from XLID patients hemizygous for PLP2-(-113C>A). We found that Plp2-deficient mouse embryonic fibroblast and human fibroblasts carrying PLP2-(-113C>A) have similarly defective endoplasmic reticulum (ER) trafficking, increased basal ER stress and exaggerated susceptibility to inducers of ER stress. Plp2-deficient mice show increased neuronal death to ER stress and hypoxia in vitro and in a neonatal hypoxia ischemia model in vivo. Finally, we provide evidence that up-regulation of PLP2 directly promotes resistance to ER stressors. Results of our studies support the hypothesis that reduced PLP2 expression increase susceptibility of neurons to environmental ER stressors such as hypoxia and ischemia and that increased apoptosis and neuronal death contribute to the risks to ID in humans. PMID- 26512061 TI - Dlx5 and Dlx6 control uterine adenogenesis during post-natal maturation: possible consequences for endometriosis. AB - Dlx5 and Dlx6 are two closely associated homeobox genes which code for transcription factors involved in the control of steroidogenesis and reproduction. Inactivation of Dlx5/6 in the mouse results in a Leydig cell defect in the male and in ovarian insufficiency in the female. DLX5/6 are also strongly expressed by the human endometrium but their function in the uterus is unknown. The involvement of DLX5/6 in human uterine pathology is suggested by their strong downregulation in endometriotic lesions and upregulation in endometrioid adenocarcinomas. We first show that Dlx5/6 expression begins in Mullerian ducts epithelia and persists then in the uterine luminal and glandular epithelia throughout post-natal maturation and in the adult. We then use a new mouse model in which Dlx5 and Dlx6 can be simultaneously inactivated in the endometrium using a Pgr(cre/+) allele. Post-natal inactivation of Dlx5/6 in the uterus results in sterility without any obvious ovarian involvement. The uteri of Pgr(cre/+); Dlx5/6(flox/flox) mice present very few uterine glands and numerous abnormally large and branched invaginations of the uterine lumen. In Dlx5/6 mutant uteri, the expression of genes involved in gland formation (Foxa2) and in epithelial remodelling during implantation (Msx1) is significantly reduced. Furthermore, we show that DLX5 is highly expressed in human endometrial glandular epithelium and that its expression is affected in endometriosis. We conclude that Dlx5 and Dlx6 expression determines uterine architecture and adenogenesis and is needed for implantation. Given their importance for female reproduction, DLX5 and DLX6 must be regarded as interesting targets for future clinical research. PMID- 26512063 TI - Venous Thromboembolism in Patients With Thrombocytopenia: Risk Factors, Treatment, and Outcome. AB - BACKGROUND: Venous thromboembolism (VTE) is a frequent and potentially lethal condition. Venous thrombi are mainly constituted of fibrin and red blood cells, but platelets also play an important role in VTE formation. Information about VTE in patients with thrombocytopenia is, however, missing. OBJECTIVES: To identify VTE risk factors and describe treatment and outcome (bleeding episodes and mortality) in patients with thrombocytopenia. PATIENTS/METHODS: Patients with thrombocytopenia (platelet count <100 * 109/L) admitted to Odense University Hospital, Denmark, between April 2000 and April 2012 were included. Fifty cases had experienced VTE. Controls without VTE were matched 3:1 with cases on sex and hospital department. Medical records were examined, and data were analyzed using conditional logistic regression. RESULTS: In multivariate analysis, platelet count <50 * 109/L (odds ratio [OR] 0.22, P < .05) and chronic liver disease (OR 0.05, 95% confidence interval [CI] 0.01-0.58) reduced the risk of VTE. Surgery (OR 6.44, 95% CI 1.37-30.20) and previous thromboembolism (OR 6.16, 95% CI 1.21 31.41) were associated with an increased VTE risk. Ninety-two percent of cases were treated with anticoagulants. There was no difference in bleeding incidence between cases and controls. CONCLUSIONS: Several known VTE risk factors also seems to apply in patients with thrombocytopenia. Also, patients with thrombocytopenia may be VTE risk stratified based on platelet count and comorbidities. Finally, patients having thrombocytopenia with VTE seem to be safely treated with anticoagulants without increased occurrence of bleeding. PMID- 26512062 TI - Whole-genome bisulfite sequencing maps from multiple human tissues reveal novel CpG islands associated with tissue-specific regulation. AB - CpG islands (CGIs) are one of the most widely studied regulatory features of the human genome, with critical roles in development and disease. Despite such significance and the original epigenetic definition, currently used CGI sets are typically predicted from DNA sequence characteristics. Although CGIs are deeply implicated in practical analyses of DNA methylation, recent studies have shown that such computational annotations suffer from inaccuracies. Here we used whole genome bisulfite sequencing from 10 diverse human tissues to identify a comprehensive, experimentally obtained, single-base resolution CGI catalog. In addition to the unparalleled annotation precision, our method is free from potential bias due to arbitrary sequence features or probe affinity differences. In addition to clarifying substantial false positives in the widely used University of California Santa Cruz (UCSC) annotations, our study identifies numerous novel epigenetic loci. In particular, we reveal significant impact of transposable elements on the epigenetic regulatory landscape of the human genome and demonstrate ubiquitous presence of transcription initiation at CGIs, including alternative promoters in gene bodies and non-coding RNAs in intergenic regions. Moreover, coordinated DNA methylation and chromatin modifications mark tissue-specific enhancers at novel CGIs. Enrichment of specific transcription factor binding from ChIP-seq supports mechanistic roles of CGIs on the regulation of tissue-specific transcription. The new CGI catalog provides a comprehensive and integrated list of genomic hotspots of epigenetic regulation. PMID- 26512064 TI - Anecdotes to the life and times of Sir Richard Owen (1804-1892) in Lancaster. AB - Sir Richard Owen, a Lancastrian, was a prominent biologist, comparative anatomist, geologist, palaeontologist and known for coining the term dinosaur. His expertise in anatomical dissection proved to be one of his biggest assets and aided his career progression at the Royal College of Surgeons and the Zoological Society. Owen's apprenticeship in Lancaster helped him to gain expertise in anatomy and anatomical dissection. The authors aim to provide some novel contextual background to his childhood in Lancaster, his affection for his hometown and his contribution to Lancaster's sanitary reform. The latter aspect of his scientific accomplishments is typically overlooked. PMID- 26512065 TI - The forgotten French: The 'heroic' era of kidney transplantation. AB - The efforts in the late 1940s to 1960s of two Parisian pioneers in kidney transplantation, Rene Kuss, a surgeon, and Jean Hamburger, a nephrologist, have largely been forgotten. Kuss developed the operation that is basically unchanged today. Both groups initiated clinical transplant programs in January 1951, and both were among the first to carry out kidney transplantation (i) without immunosuppressive therapy, (ii) between living-related and unrelated donors, (iii) with organs from deceased donors, (iv) with irradiation and immunosuppressive drugs, and (v) with long-term survival. In the opinion of many, the French did not receive full credit for their work internationally. PMID- 26512066 TI - Turhan Baytop (1920-2002): A pioneer historian of pharmacy from Turkey. AB - Turhan Baytop, a Turkish professor of pharmacognosy (the scientific study of crude drugs of animal, vegetable, and mineral origin), received international acclaim not only for his contributions in collecting and identifying the Anatolian plants, but also for his extensive research shedding light on the history of Turkish pharmacy. As a devoted researcher, collector, and lecturer, T Baytop was a genuine pioneer of the history of pharmacy as a discipline in Turkey. PMID- 26512067 TI - Physicians of the Bear-Flag Republic. AB - In the mid-nineteenth century, three events coincided to make California the 31st state of the USA: The Mexican-American war of 1846-1848, The Bear Flag Revolt of 1846 and the discovery of gold in 1848. Within a few years a population explosion had occurred and with it came the need for organization of the practice of medicine. This paper outlines the biographies of some physicians who were instrumental in the early years of the Golden State. PMID- 26512068 TI - The modulatory effect of anandamide on nitroglycerin-induced sensitization in the trigeminal system of the rat. AB - BACKGROUND: One of the human and animal models of migraine is the systemic administration of the nitric oxide donor (NO) nitroglycerin (NTG). NO can provoke migraine-like attacks in migraineurs and initiates a self-amplifying process in the trigeminal system, probably leading to central sensitization. Recent studies suggest that the endocannabinoid system is involved in nociceptive signal processing and cannabinoid receptor (CB) agonists are able to attenuate nociception in animal models of pain. AIM: The purpose of the present study was to investigate the modulatory effects of a CB agonist anandamide (AEA) on the NTG induced expression of transient receptor potential vanilloid type 1 (TRPV1), neuronal nitric oxide synthase (nNOS), nuclear factor kappa B (NF-kappaB), cyclooxygenase-2 (COX-2) and kynurenine aminotransferase-II (KAT-II) in the upper cervical spinal cord (C1-C2) of the rat, where most of the trigeminal nociceptive afferents convey. METHODS: A half hour before and one hour after NTG (10 mg/kg) or placebo injection, adult male Sprague-Dawley rats (n = 44) were treated with AEA (2 * 5 mg/kg). Four hours after placebo/NTG injection, the animals were perfused and the cervical spinal cords were removed for immunohistochemistry and Western blotting. RESULTS AND CONCLUSION: Our results show that NTG is able to increase TRPV1, nNOS, NF-kappaB and COX-2 and decrease KAT-II expression in the C1-C2 segments. On the other hand, we have found that AEA modulates the NTG induced changes, thus it influences the activation and central sensitization process in the trigeminal system, probably via CBs. PMID- 26512069 TI - Behavioral Analysis of Bitter Taste Perception in Drosophila Larvae. AB - Insect larvae, which recognize food sources through chemosensory cues, are a major source of global agricultural loss. Gustation is an important factor that determines feeding behavior, and the gustatory receptors (Grs) act as molecular receptors that recognize diverse chemicals in gustatory receptor neurons (GRNs). The behavior of Drosophila larvae is relatively simpler than the adult fly, and a gustatory receptor-to-neuron map was established in a previous study of the major external larval head sensory organs. Here, we extensively study the bitter taste responses of larvae using 2-choice behavioral assays. First, we tested a panel of 23 candidate bitter compounds to compare the behavioral responses of larvae and adults. We define 9 bitter compounds which elicit aversive behavior in a dose dependent manner. A functional map of the larval GRNs was constructed with the use of Gr-GAL4 lines that drive expression of UAS-tetanus toxin and UAS-VR1 in specific gustatory neurons to identify bitter tastants-GRN combinations by suppressing and activating discrete subsets of taste neurons, respectively. Our results suggest that many gustatory neurons act cooperatively in larval bitter sensing, and that these neurons have different degrees of responsiveness to different bitter compounds. PMID- 26512070 TI - Comparison of Olfactory Identification Patterns among Parkinson's Disease Patients from Different Countries. AB - Olfactory function assessment is an important screening tool and also may differentiate Parkinson's disease (PD) patients from other parkinsonisms, including nondegenerative ones, such as, normal pressure hydrocephalus, vascular, drug induced, or infectious parkinsonism. Several authors in different countries have reported various sets of odors that best differentiate between these conditions. It is debated if distinctive patterns of "restrictive" or "selective" hyposmia in PD may be affected by cultural aspects. To compare the olfactory identification function in PD across different countries, we analyzed Sniffin' Sticks identification task results between 112 PD patients from Argentina and previously reported data of PD patients from Brazil (106 patients), the Netherlands (400 patients), Germany (40 patients), China (110 patients), and Sri Lanka (89 patients). Categorical principal component analysis (CATPCA) was performed to find components reflecting groups of odors similarly perceived across subjects. CATPCA analysis found 2 components for each group which shared 10 out of 16 odors amongst each other. We found that only the shared items of component 2 (orange, mint, banana, garlic, coffee, cloves, and fish) showed uniform results across all of the included countries, whereas variations in component 1 (licorice, turpentine, and apple) were attributed mostly to differences across control groups. PMID- 26512071 TI - A Case of Colocalized Vitiligo and Psoriasis. AB - BACKGROUND: Psoriasis and vitiligo are common dermatologic conditions with underlying autoimmune etiologies. There are few reports of concomitant and colocalized disease. Several theories have been proposed to explain this rare presentation. OBJECTIVE: The objective of this study was to present a rare case of a concomitant and colocalized presentation of vitiligo and psoriasis. METHODS: Case report. RESULTS: A 72-year-old male was referred for treatment of a 30-year history of psoriasis and 5-year history of colocalized vitiligo. The patient had no other underlying autoimmune diseases including psoriatic arthritis. CONCLUSION: Clinicians should be aware of the possible concomitance and colocalization of psoriasis and vitiligo. Further research is needed to elucidate the common pathways leading to the concomitance and colocalization of these diseases. PMID- 26512072 TI - Observational studies, statistical tests and bias arising from case-control comparisons. PMID- 26512073 TI - Reply: Modified natural cycles for poor responders: addressing misconceptions and fallacies. PMID- 26512074 TI - Modified natural cycle IVF for poor ovarian responders: rethink before concluding. PMID- 26512075 TI - Patient-reported outcomes on the agenda in cardiovascular clinical practice. PMID- 26512076 TI - Modulation of Mitochondrial Antiviral Signaling by Human Herpesvirus 8 Interferon Regulatory Factor 1. AB - Mitochondrial lipid raft-like microdomains, experimentally also termed mitochondrial detergent-resistant membrane fractions (mDRM), play a role as platforms for recruiting signaling molecules involved in antiviral responses such as apoptosis and innate immunity. Viruses can modulate mitochondrial functions for their own survival and replication. However, viral regulation of the antiviral responses via mDRM remains incompletely understood. Here, we report that human herpesvirus 8 (HHV-8) gene product viral interferon regulatory factor 1 (vIRF-1) is targeted to mDRM during virus replication and negatively regulates the mitochondrial antiviral signaling protein (MAVS)-mediated antiviral responses. The N-terminal region of vIRF-1 interacts directly with membrane lipids, including cardiolipin. In addition, a GxRP motif within the N terminus of vIRF-1, conserved in the mDRM-targeting region of mitochondrial proteins, including PTEN-induced putative kinase 1 (PINK1) and MAVS, was found to be important for vIRF-1 association with mitochondria. Furthermore, MAVS, which has the potential to promote vIRF-1 targeting to mDRM possibly by inducing cardiolipin exposure on the outer membrane of mitochondria, interacts with vIRF 1, which, in turn, inhibits MAVS-mediated antiviral signaling. Consistent with these results, vIRF-1 targeting to mDRM contributes to promotion of HHV-8 productive replication and inhibition of associated apoptosis. Combined, our results suggest novel molecular mechanisms for negative-feedback regulation of MAVS by vIRF-1 during virus replication. IMPORTANCE: Successful virus replication is in large part achieved by the ability of viruses to counteract apoptosis and innate immune responses elicited by infection of host cells. Recently, mitochondria have emerged to play a central role in antiviral signaling. In particular, mitochondrial lipid raft-like microdomains appear to function as platforms in cell apoptosis signaling. However, viral regulation of antiviral signaling through the mitochondrial microdomains remains incompletely understood. The present study demonstrates that HHV-8-encoded vIRF-1 targets to the mitochondrial detergent-resistant microdomains via direct interaction with cardiolipin and inhibits MAVS protein-mediated apoptosis and type I interferon gene expression in a negative-feedback manner, thus promoting HHV-8 productive replication. These results suggest that vIRF-1 is the first example of a viral protein to inhibit mitochondrial antiviral signaling through lipid raft-like microdomains. PMID- 26512077 TI - Single Mutations in the VP2 300 Loop Region of the Three-Fold Spike of the Carnivore Parvovirus Capsid Can Determine Host Range. AB - Sylvatic carnivores, such as raccoons, have recently been recognized as important hosts in the evolution of canine parvovirus (CPV), a pandemic pathogen of domestic dogs. Although viruses from raccoons do not efficiently bind the dog transferrin receptor (TfR) or infect dog cells, a single mutation changing an aspartic acid to a glycine at capsid (VP2) position 300 in the prototype raccoon CPV allows dog cell infection. Because VP2 position 300 exhibits extensive amino acid variation among the carnivore parvoviruses, we further investigated its role in determining host range by analyzing its diversity and evolution in nature and by creating a comprehensive set of VP2 position 300 mutants in infectious clones. Notably, some position 300 residues rendered CPV noninfectious for dog, but not cat or fox, cells. Changes of adjacent residues (residues 299 and 301) were also observed often after cell culture passage in different hosts, and some of the mutations mimicked changes seen in viruses recovered from natural infections of alternative hosts, suggesting that compensatory mutations were selected to accommodate the new residue at position 300. Analysis of the TfRs of carnivore hosts used in the experimental evolution studies demonstrated that their glycosylation patterns varied, including a glycan present only on the domestic dog TfR that dictates susceptibility to parvoviruses. Overall, there were significant differences in the abilities of viruses with alternative position 300 residues to bind TfRs and infect different carnivore hosts, demonstrating that the process of infection is highly host dependent and that VP2 position 300 is a key determinant of host range. IMPORTANCE: Although the emergence and pandemic spread of canine parvovirus (CPV) are well documented, the carnivore hosts and evolutionary pathways involved in its emergence remain enigmatic. We recently demonstrated that a region in the capsid structure of CPV, centered around VP2 position 300, varies after transfer to alternative carnivore hosts and may allow infection of previously nonsusceptible hosts in vitro. Here we show that VP2 position 300 is the most variable residue in the parvovirus capsid in nature, suggesting that it is a critical determinant in the cross-species transfer of viruses between different carnivores due to its interactions with the transferrin receptor to mediate infection. To this end, we demonstrated that there are substantial differences in receptor binding and infectivity of various VP2 position 300 mutants for different carnivore species and that single mutations in this region can influence whether a host is susceptible or refractory to virus infection. PMID- 26512078 TI - Identification of Positively Charged Residues in Enterovirus 71 Capsid Protein VP1 Essential for Production of Infectious Particles. AB - Enterovirus 71 (EV71), a positive-stranded RNA virus, is the major cause of hand, foot, and mouth disease (HFMD) in children, which can cause severe central nervous system disease and death. The capsids of EV71 consist of 60 copies of each of four viral structural proteins (VP1 to VP4), with VP1, VP2, and VP3 exposed on the surface and VP4 arranged internally. VP1 plays a central role in particle assembly and cell entry. To gain insight into the role of positively charged residues in VP1 function in these processes, a charged-to-alanine scanning analysis was performed using an infectious cDNA clone of EV71. Twenty seven mutants containing single charged-to-alanine changes were tested. Sixteen of them were not viable, seven mutants were replication defective, and the remaining four mutants were replication competent. By selecting revertants, second-site mutations which could at least partially restore viral infectivity were identified within VP1 for four defective mutations and two lethal mutations. The resulting residue pairs represent a network of intra- and intermolecular interactions of the VP1 protein which could serve as a potential novel drug target. Interestingly, mutation K215A in the VP1 GH loop led to a significant increase in thermal stability, demonstrating that conditional thermostable mutants can be generated by altering the charge characteristics of VP1. Moreover, all mutants were sensitive to the EV71 entry inhibitor suramin, which binds to the virus particle via the negatively charged naphthalenetrisulfonic acid group, suggesting that single charged-to-alanine mutation is not sufficient for suramin resistance. Taken together, these data highlight the importance of positively charged residues in VP1 for production of infectious particles. IMPORTANCE: Infection with EV71 is more often associated with neurological complications in children and is responsible for the majority of fatalities. No licensed vaccines or antiviral therapies are currently available for the prevention or treatment of EV71 infection. Understanding the determinants of virion assembly and entry will facilitate vaccine development and drug discovery. Here, we identified 23 out of 27 positively charged residues in VP1 which impaired or blocked the production of infectious particles. The defect could be rescued by second-site mutations within the VP1 protein. Our findings highlight the importance of positively charged residues in VP1 during infectious particle production and reveal a potential strategy for blocking EV71 infections by inhibiting intra- or intermolecular interactions of the VP1 protein. PMID- 26512079 TI - Conserved Role of an N-Linked Glycan on the Surface Antigen of Human Immunodeficiency Virus Type 1 Modulating Virus Sensitivity to Broadly Neutralizing Antibodies against the Receptor and Coreceptor Binding Sites. AB - HIV-1 establishes persistent infection in part due to its ability to evade host immune responses. Occlusion by glycans contributes to masking conserved sites that are targets for some broadly neutralizing antibodies (bNAbs). Previous work has shown that removal of a highly conserved potential N-linked glycan (PNLG) site at amino acid residue 197 (N7) on the surface antigen gp120 of HIV-1 increases neutralization sensitivity of the mutant virus to CD4 binding site (CD4bs)-directed antibodies compared to its wild-type (WT) counterpart. However, it is not clear if the role of the N7 glycan is conserved among diverse HIV-1 isolates and if other glycans in the conserved regions of HIV-1 Env display similar functions. In this work, we examined the role of PNLGs in the conserved region of HIV-1 Env, particularly the role of the N7 glycan in a panel of HIV-1 strains representing different clades, tissue origins, coreceptor usages, and neutralization sensitivities. We demonstrate that the absence of the N7 glycan increases the sensitivity of diverse HIV-1 isolates to CD4bs- and V3 loop directed antibodies, indicating that the N7 glycan plays a conserved role masking these conserved epitopes. However, the effect of the N7 glycan on virus sensitivity to neutralizing antibodies directed against the V2 loop epitope is isolate dependent. These findings indicate that the N7 glycan plays an important and conserved role modulating the structure, stability, or accessibility of bNAb epitopes in the CD4bs and coreceptor binding region, thus representing a potential target for the design of immunogens and therapeutics. IMPORTANCE: N linked glycans on the HIV-1 envelope protein have been postulated to contribute to viral escape from host immune responses. However, the role of specific glycans in the conserved regions of HIV-1 Env in modulating epitope recognition by broadly neutralizing antibodies has not been well defined. We show here that a single N-linked glycan plays a unique and conserved role among conserved glycans on HIV-1 gp120 in modulating the exposure or the stability of the receptor and coreceptor binding site without affecting the integrity of the Env in mediating viral infection or the ability of the mutant gp120 to bind to CD4. The observation that the antigenicity of the receptor and coreceptor binding sites can be modulated by a single glycan indicates that select glycan modification offers a potential strategy for the design of HIV-1 vaccine candidates. PMID- 26512080 TI - Prion Type-Dependent Deposition of PRNP Allelic Products in Heterozygous Sheep. AB - Susceptibility or resistance to prion infection in humans and animals depends on single prion protein (PrP) amino acid substitutions in the host, but the agent's modulating role has not been well investigated. Compared to disease incubation times in wild-type homozygous ARQ/ARQ (where each triplet represents the amino acids at codons 136, 154, and 171, respectively) sheep, scrapie susceptibility is reduced to near resistance in ARR/ARR animals while it is strongly enhanced in VRQ/VRQ carriers. Heterozygous ARR/VRQ animals exhibit delayed incubation periods. In bovine spongiform encephalopathy (BSE) infection, the polymorphism effect is quite different although the ARR allotype remains the least susceptible. In this study, PrP allotype composition in protease-resistant prion protein (PrP(res)) from brain of heterozygous ARR/VRQ scrapie-infected sheep was compared with that of BSE-infected sheep with a similar genotype. A triplex Western blotting technique was used to estimate the two allotype PrP fractions in PrP(res) material from BSE-infected ARR/VRQ sheep. PrP(res) in BSE contained equimolar amounts of VRQ- and ARR-PrP, which contrasts with the excess (>95%) VRQ PrP fraction found in PrP in scrapie. This is evidence that transmissible spongiform encephalopathy (TSE) agent properties alone, perhaps structural aspects of prions (such as PrP amino acid sequence variants and PrP conformational state), determine the polymorphic dependence of the PrP(res) accumulation process in prion formation as well as the disease-associated phenotypic expressions in the host. IMPORTANCE: Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative and transmissible diseases caused by prions. Amino acid sequence variants of the prion protein (PrP) determine transmissibility in the hosts, as has been shown for classical scrapie in sheep. Each individual produces a separate PrP molecule from its two PrP gene copies. Heterozygous scrapie-infected sheep that produce two PrP variants associated with opposite scrapie susceptibilities (136V-PrP variant, high; 171R PrP variant, very low) contain in their prion material over 95% of the 136V PrP variant. However, when these sheep are infected with prions from cattle (bovine spongiform encephalopathy [BSE]), both PrP variants occur in equal ratios. This shows that the infecting prion type determines the accumulating PrP variant ratio in the heterozygous host. While the host's PrP is considered a determining factor, these results emphasize that prion structure plays a role during host infection and that PrP variant involvement in prions of heterozygous carriers is a critical field for understanding prion formation. PMID- 26512081 TI - Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain. AB - HIV-1 uses cellular machinery to bud from infected cells. This cellular machinery is comprised of several multiprotein complexes known as endosomal sorting complexes required for transport (ESCRTs). A conserved late domain motif, Pro-Thr Ala-Pro (PTAP), located in the p6 region of Gag (p6(Gag)), plays a central role in ESCRT recruitment to the site of virus budding. Previous studies have demonstrated that PTAP duplications are selected in HIV-1-infected patients during antiretroviral therapy; however, the consequences of these duplications for HIV-1 biology and drug resistance are unclear. To address these questions, we constructed viruses carrying a patient-derived PTAP duplication with and without drug resistance mutations in the viral protease. We evaluated the effect of the PTAP duplication on viral release efficiency, viral infectivity, replication capacity, drug susceptibility, and Gag processing. In the presence of protease inhibitors, we observed that the PTAP duplication in p6(Gag) significantly increased the infectivity and replication capacity of the virus compared to those of viruses bearing only resistance mutations in protease. Our biochemical analysis showed that the PTAP duplication, in combination with mutations in protease, enhances processing between the nucleocapsid and p6 domains of Gag, resulting in more complete Gag cleavage in the presence of protease inhibitors. These results demonstrate that duplication of the PTAP motif in p6(Gag) confers a selective advantage in viral replication by increasing Gag processing efficiency in the context of protease inhibitor treatment, thereby enhancing the drug resistance of the virus. These findings highlight the interconnected role of PTAP duplications and protease mutations in the development of resistance to antiretroviral therapy. IMPORTANCE: Resistance to current drug therapy limits treatment options in many HIV-1-infected patients. Duplications in a Pro-Thr-Ala Pro (PTAP) motif in the p6 domain of Gag are frequently observed in viruses derived from patients on protease inhibitor (PI) therapy. However, the reason that these duplications arise and their consequences for virus replication remain to be established. In this study, we examined the effect of PTAP duplication on PI resistance in the context of wild-type protease or protease bearing PI resistance mutations. We observe that PTAP duplication markedly enhances resistance to a panel of PIs. Biochemical analysis reveals that the PTAP duplication reverses a Gag processing defect imposed by the PI resistance mutations in the context of PI treatment. The results provide a long-sought explanation for why PTAP duplications arise in PI-treated patients. PMID- 26512082 TI - HIV-1 Adapts To Replicate in Cells Expressing Common Marmoset APOBEC3G and BST2. AB - Previous studies have shown that a major block to HIV-1 replication in common marmosets operates at the level of viral entry and that this block can be overcome by adaptation of the virus in tissue-cultured cells. However, our current studies indicate that HIV-1 encounters additional postentry blocks in common marmoset peripheral blood mononuclear cells. Here, we show that the common marmoset APOBEC3G (A3G) and BST2 proteins block HIV-1 in cell cultures. Using a directed-evolution method that takes advantage of the natural ability of HIV-1 to mutate during replication, we have been able to overcome these blocks in tissue cultured cells. In the adapted viruses, specific changes were observed in gag, vif, env, and nef. The contribution of these changes to virus replication in the presence of the A3G and BST2 restriction factors was studied. We found that certain amino acid changes in Vif and Env that arise during adaptation to marmoset A3G and BST2 allow the virus to replicate in the presence of these restriction factors. The changes in Vif reduce expression levels and encapsidation of marmoset APOBEC3G, while the changes in Env increase viral fitness and discretely favor cell-to-cell transmission of the virus, allowing viral escape from these restriction factors. IMPORTANCE: HIV-1 can infect only humans and chimpanzees. The main reason for this narrow tropism is the presence in many species of dominant-acting factors, known as restriction factors, that block viral replication in a species-specific way. We have been exploring the blocks to HIV-1 in common marmosets, with the ultimate goal of developing a new animal model of HIV-1 infection in these monkeys. In this study, we observed that common marmoset APOBEC3G and BST2, two known restriction factors, are able to block HIV-1 in cell cultures. We have adapted HIV-1 to replicate in the presence of these restriction factors and have characterized the mechanisms of escape. These studies can help in the development of a novel animal model for in vivo infection of marmosets with HIV-1-like viruses. PMID- 26512083 TI - Chemical Cross-Linking Stabilizes Native-Like HIV-1 Envelope Glycoprotein Trimer Antigens. AB - Major neutralizing antibody immune evasion strategies of the HIV-1 envelope glycoprotein (Env) trimer include conformational and structural instability. Stabilized soluble trimers such as BG505 SOSIP.664 mimic the structure of virion associated Env but nevertheless sample different conformational states. Here we demonstrate that treating BG505 SOSIP.664 trimers with glutaraldehyde or a heterobifunctional cross-linker introduces additional stability with relatively modest effects on antigenicity. Thus, most broadly neutralizing antibody (bNAb) epitopes were preserved after cross-linking, whereas the binding of most weakly or nonneutralizing antibodies (non-NAb) was reduced. Cross-linking stabilized all Env conformers present within a mixed population, and individual conformers could be isolated by bNAb affinity chromatography. Both positive selection of cross linked conformers using the quaternary epitope-specific bNAbs PGT145, PGT151, and 3BC315 and negative selection with non-NAbs against the V3 region enriched for trimer populations with improved antigenicity for bNAbs. Similar results were obtained using the clade B B41 SOSIP.664 trimer. The cross-linking method may, therefore, be useful for countering the natural conformational heterogeneity of some HIV-1 Env proteins and, by extrapolation, also vaccine immunogens from other pathogens. IMPORTANCE: The development of a vaccine to induce protective antibodies against HIV-1 is of primary public health importance. Recent advances in immunogen design have provided soluble recombinant envelope glycoprotein trimers with near-native morphology and antigenicity. However, these trimers are conformationally flexible, potentially reducing B-cell recognition of neutralizing antibody epitopes. Here we show that chemical cross-linking increases trimer stability, reducing binding of nonneutralizing antibodies while largely maintaining neutralizing antibody binding. Cross-linking followed by positive or negative antibody affinity selection of individual stable conformational variants further improved the antigenic and morphological characteristics of the trimers. This approach may be generally applicable to HIV 1 Env and also to other conformationally flexible pathogen antigens. PMID- 26512084 TI - Herpes Simplex Virus 1 Infection of Tree Shrews Differs from That of Mice in the Severity of Acute Infection and Viral Transcription in the Peripheral Nervous System. AB - Studies of herpes simplex virus (HSV) infections of humans are limited by the use of rodent models such as mice, rabbits, and guinea pigs. Tree shrews (Tupaia belangeri chinensis) are small mammals indigenous to southwest Asia. At behavioral, anatomical, genomic, and evolutionary levels, tree shrews are much closer to primates than rodents are, and tree shrews are susceptible to HSV infection. Thus, we have studied herpes simplex virus 1 (HSV-1) infection in the tree shrew trigeminal ganglion (TG) following ocular inoculation. In situ hybridization, PCR, and quantitative reverse transcription-PCR (qRT-PCR) analyses confirm that HSV-1 latently infects neurons of the TG. When explant cocultivation of trigeminal ganglia was performed, the virus was recovered after 5 days of cocultivation with high efficiency. Swabbing the corneas of latently infected tree shrews revealed that tree shrews shed virus spontaneously at low frequencies. However, tree shrews differ significantly from mice in the expression of key HSV-1 genes, including ICP0, ICP4, and latency-associated transcript (LAT). In acutely infected tree shrew TGs, no level of ICP4 was observed, suggesting the absence of infection or a very weak, acute infection compared to that of the mouse. Immunofluorescence staining with ICP4 monoclonal antibody, and immunohistochemistry detection by HSV-1 polyclonal antibodies, showed a lack of viral proteins in tree shrew TGs during both acute and latent phases of infection. Cultivation of supernatant from homogenized, acutely infected TGs with RS1 cells also exhibited an absence of infectious HSV-1 from tree shrew TGs. We conclude that the tree shrew has an undetectable, or a much weaker, acute infection in the TGs. Interestingly, compared to mice, tree shrew TGs express high levels of ICP0 transcript in addition to LAT during latency. However, the ICP0 transcript remained nuclear, and no ICP0 protein could be seen during the course of mouse and tree shrew TG infections. Taken together, these observations suggest that the tree shrew TG infection differs significantly from the existing rodent models. IMPORTANCE: Herpes simplex viruses (HSVs) establish lifelong infection in more than 80% of the human population, and their reactivation leads to oral and genital herpes. Currently, rodent models are the preferred models for latency studies. Rodents are distant from primates and may not fully represent human latency. The tree shrew is a small mammal, a prosimian primate, indigenous to southwest Asia. In an attempt to further develop the tree shrew as a useful model to study herpesvirus infection, we studied the establishment of latency and reactivation of HSV-1 in tree shrews following ocular inoculation. We found that the latent virus, which resides in the sensory neurons of the trigeminal ganglion, could be stress reactivated to produce infectious virus, following explant cocultivation and that spontaneous reactivation could be detected by cell culture of tears. Interestingly, the tree shrew model is quite different from the mouse model of HSV infection, in that the virus exhibited only a mild acute infection following inoculation with no detectable infectious virus from the sensory neurons. The mild infection may be more similar to human infection in that the sensory neurons continue to function after herpes reactivation and the affected skin tissue does not lose sensation. Our findings suggest that the tree shrew is a viable model to study HSV latency. PMID- 26512085 TI - A Molecular Sensor To Characterize Arenavirus Envelope Glycoprotein Cleavage by Subtilisin Kexin Isozyme 1/Site 1 Protease. AB - Arenaviruses are emerging viruses including several causative agents of severe hemorrhagic fevers in humans. The advent of next-generation sequencing technology has greatly accelerated the discovery of novel arenavirus species. However, for many of these viruses, only genetic information is available, and their zoonotic disease potential remains unknown. During the arenavirus life cycle, processing of the viral envelope glycoprotein precursor (GPC) by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P) is crucial for productive infection. The ability of newly emerging arenaviruses to hijack human SKI-1/S1P appears, therefore, to be a requirement for efficient zoonotic transmission and human disease potential. Here we implement a newly developed cell-based molecular sensor for SKI-1/S1P to characterize the processing of arenavirus GPC-derived target sequences by human SKI-1/S1P in a quantitative manner. We show that only nine amino acids flanking the putative cleavage site are necessary and sufficient to accurately recapitulate the efficiency and subcellular location of arenavirus GPC processing. In a proof of concept, our sensor correctly predicts efficient processing of the GPC of the newly emergent pathogenic Lujo virus by human SKI 1/S1P and defines the exact cleavage site. Lastly, we employed our sensor to show efficient GPC processing of a panel of pathogenic and nonpathogenic New World arenaviruses, suggesting that GPC cleavage represents no barrier for zoonotic transmission of these pathogens. Our SKI-1/S1P sensor thus represents a rapid and robust test system for assessment of the processing of putative cleavage sites derived from the GPCs of newly discovered arenavirus by the SKI-1/S1P of humans or any other species, based solely on sequence information. IMPORTANCE: Arenaviruses are important emerging human pathogens that can cause severe hemorrhagic fevers with high mortality in humans. A crucial step in productive arenavirus infection of human cells is the processing of the viral envelope glycoprotein by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P). In order to break the species barrier during zoonotic transmission and cause severe disease in humans, newly emerging arenaviruses must be able to hijack human SKI-1/S1P efficiently. Here we implement a newly developed cell based molecular sensor for human SKI-1/S1P to characterize the processing of arenavirus glycoproteins in a quantitative manner. We further use our sensor to correctly predict efficient processing of the glycoprotein of the newly emergent pathogenic Lujo virus by human SKI-1/S1P. Our sensor thus represents a rapid and robust test system with which to assess whether the glycoprotein of any newly emerging arenavirus can be efficiently processed by human SKI-1/S1P, based solely on sequence information. PMID- 26512086 TI - Fluid Spatial Dynamics of West Nile Virus in the United States: Rapid Spread in a Permissive Host Environment. AB - The introduction of West Nile virus (WNV) into North America in 1999 is a classic example of viral emergence in a new environment, with its subsequent dispersion across the continent having a major impact on local bird populations. Despite the importance of this epizootic, the pattern, dynamics, and determinants of WNV spread in its natural hosts remain uncertain. In particular, it is unclear whether the virus encountered major barriers to transmission, or spread in an unconstrained manner, and if specific viral lineages were favored over others indicative of intrinsic differences in fitness. To address these key questions in WNV evolution and ecology, we sequenced the complete genomes of approximately 300 avian isolates sampled across the United States between 2001 and 2012. Phylogenetic analysis revealed a relatively star-like tree structure, indicative of explosive viral spread in the United States, although with some replacement of viral genotypes through time. These data are striking in that viral sequences exhibit relatively limited clustering according to geographic region, particularly for those viruses sampled from birds, and no strong phylogenetic association with well-sampled avian species. The genome sequence data analyzed here also contain relatively little evidence for adaptive evolution, particularly of structural proteins, suggesting that most viral lineages are of similar fitness and that WNV is well adapted to the ecology of mosquito vectors and diverse avian hosts in the United States. In sum, the molecular evolution of WNV in North America depicts a largely unfettered expansion within a permissive host and geographic population with little evidence of major adaptive barriers. IMPORTANCE: How viruses spread in new host and geographic environments is central to understanding the emergence and evolution of novel infectious diseases and for predicting their likely impact. The emergence of the vector-borne West Nile virus (WNV) in North America in 1999 represents a classic example of this process. Using approximately 300 new viral genomes sampled from wild birds, we show that WNV experienced an explosive spread with little geographical or host constraints within birds and relatively low levels of adaptive evolution. From its introduction into the state of New York, WNV spread across the United States, reaching California and Florida within 4 years, a migration that is clearly reflected in our genomic sequence data, and with a general absence of distinct geographical clusters of bird viruses. However, some geographically distinct viral lineages were found to circulate in mosquitoes, likely reflecting their limited long-distance movement compared to avian species. PMID- 26512087 TI - Structure and Function of the N-Terminal Domain of the Vesicular Stomatitis Virus RNA Polymerase. AB - Viruses have various mechanisms to duplicate their genomes and produce virus specific mRNAs. Negative-strand RNA viruses encode their own polymerases to perform each of these processes. For the nonsegmented negative-strand RNA viruses, the polymerase is comprised of the large polymerase subunit (L) and the phosphoprotein (P). L proteins from members of the Rhabdoviridae, Paramyxoviridae, and Filoviridae share sequence and predicted secondary structure homology. Here, we present the structure of the N-terminal domain (conserved region I) of the L protein from a rhabdovirus, vesicular stomatitis virus, at 1.8 A resolution. The strictly and strongly conserved residues in this domain cluster in a single area of the protein. Serial mutation of these residues shows that many of the amino acids are essential for viral transcription but not for mRNA capping. Three-dimensional alignments show that this domain shares structural homology with polymerases from other viral families, including segmented negative strand RNA and double-stranded RNA (dsRNA) viruses. IMPORTANCE: Negative-strand RNA viruses include a diverse set of viral families that infect animals and plants, causing serious illness and economic impact. The members of this group of viruses share a set of functionally conserved proteins that are essential to their replication cycle. Among this set of proteins is the viral polymerase, which performs a unique set of reactions to produce genome- and subgenome-length RNA transcripts. In this article, we study the polymerase of vesicular stomatitis virus, a member of the rhabdoviruses, which has served in the past as a model to study negative-strand RNA virus replication. We have identified a site in the N terminal domain of the polymerase that is essential to viral transcription and that shares sequence homology with members of the paramyxoviruses and the filoviruses. Newly identified sites such as that described here could prove to be useful targets in the design of new therapeutics against negative-strand RNA viruses. PMID- 26512088 TI - Hemagglutinin Stalk- and Neuraminidase-Specific Monoclonal Antibodies Protect against Lethal H10N8 Influenza Virus Infection in Mice. AB - Between November 2013 and February 2014, China reported three human cases of H10N8 influenza virus infection in the Jiangxi province, two of which were fatal. Using hybridoma technology, we isolated a panel of H10- and N8-directed monoclonal antibodies (MAbs) and further characterized the binding reactivity of these antibodies (via enzyme-linked immunosorbent assay) to a range of purified virus and recombinant protein substrates. The H10-directed MAbs displayed functional hemagglutination inhibition (HI) and neutralization activity, and the N8-directed antibodies displayed functional neuraminidase inhibition (NI) activity against H10N8. Surprisingly, the HI-reactive H10 antibodies, as well as a previously generated, group 2 hemagglutinin (HA) stalk-reactive antibody, demonstrated NI activity against H10N8 and an H10N7 strain; this phenomenon was absent when virus was treated with detergent, suggesting the anti-HA antibodies inhibited neuraminidase enzymatic activity through steric hindrance. We tested the prophylactic efficacy of one representative H10-reactive, N8-reactive, and group 2 HA stalk-reactive antibody in vivo using a BALB/c challenge model. All three antibodies were protective at a high dose (5 mg/kg). At a low dose (0.5 mg/kg), only the anti-N8 antibody prevented weight loss. Together, these data suggest that antibody targets other than the globular head domain of the HA may be efficacious in preventing influenza virus-induced morbidity and mortality. IMPORTANCE: Avian H10N8 and H10N7 viruses have recently crossed the species barrier, causing morbidity and mortality in humans and other mammals. Although these reports are likely isolated incidents, it is possible that more cases may emerge in future winter seasons, similar to H7N9. Furthermore, regular transmission of avian influenza viruses to humans increases the risk of adaptive mutations and reassortment events, which may result in a novel virus with pandemic potential. Currently, no specific therapeutics or vaccines are available against the H10N8 influenza virus subtype. We generated a panel of H10- and N8 reactive MAbs. Although these antibodies may practically be developed into therapeutic agents, characterizing the protective potential of MAbs that have targets other than the HA globular head domain will provide insight into novel antibody-mediated mechanisms of protection and help to better understand correlates of protection for influenza A virus infection. PMID- 26512089 TI - Extracellular Vesicles Mediate Receptor-Independent Transmission of Novel Tick Borne Bunyavirus. AB - Severe fever with thrombocytopenia syndrome (SFTS) virus is a newly recognized member of the genus Phlebovirus in the family Bunyaviridae. The virus was isolated from patients presenting with hemorrhagic manifestations and an initial case fatality rate of 12 to 30% was reported. Due to the recent emergence of this pathogen, there is limited knowledge on the molecular virology of SFTS virus. Recently, we reported that the SFTS virus NSs protein inhibited the activation of the beta interferon (IFN-beta) promoter. Furthermore, we also found that SFTS virus NSs relocalizes key components of the IFN response into NSs-induced cytoplasmic structures. Due to the important role these structures play during SFTS virus replication, we conducted live cell imaging studies to gain further insight into the role and trafficking of these cytoplasmic structures during virus infection. We found that some of the SFTS virus NSs-positive cytoplasmic structures were secreted to the extracellular space and endocytosed by neighboring cells. We also found that these secreted structures isolated from NSs expressing cells and SFTS virus-infected cells were positive for the viral protein NSs and the host protein CD63, a protein associated with extracellular vesicles. Electron microscopy studies also revealed that the isolated CD63 immunoprecipitated extracellular vesicles produced during SFTS virus infection contained virions. The virions harbored within these structures were efficiently delivered to uninfected cells and were able to sustain SFTS virus replication. Altogether, these results suggest that SFTS virus exploits extracellular vesicles to mediate virus receptor-independent transmission to host cells and open the avenue for novel therapeutic strategies against SFTS virus and related pathogens. IMPORTANCE: SFTS virus is novel bunyavirus associated with hemorrhagic fever illness. Currently, limited information is available about SFTS virus. In the present study, we demonstrated that extracellular vesicles produced by SFTS virus infected cells harbor infectious virions. We sought to determine whether these "infectious" extracellular vesicles can mediate transmission of the virus and confirmed that the SFTS virions were efficiently transported by these secreted structures into uninfected cells and were able to sustain efficient replication of SFTS virus. These results have significant impact on our understanding of how the novel tick-borne phleboviruses hijack cellular machineries to establish infection and point toward a novel mechanism for virus replication among arthropod-borne viruses. PMID- 26512090 TI - Knockout of the Host Resistance Gene Pkr Fully Restores Replication of Murine Cytomegalovirus m142 and m143 Mutants In Vivo. AB - Murine cytomegalovirus (MCMV) proteins m142 and m143 are essential for viral replication. They bind double-stranded RNA and prevent protein kinase R-induced protein synthesis shutoff. Whether the two viral proteins have additional functions such as their homologs in human cytomegalovirus do remained unknown. We show that MCMV m142 and m143 knockout mutants attain organ titers equivalent to those attained by wild-type MCMV in Pkr knockout mice, suggesting that these viral proteins do not encode additional PKR-independent functions relevant for pathogenesis in vivo. PMID- 26512091 TI - VP24 Is a Chitin-Binding Protein Involved in White Spot Syndrome Virus Infection. AB - Oral ingestion is the major route of infection for the white spot syndrome virus (WSSV). However, the mechanism by which virus particles in the digestive tract invade host cells is unknown. In the present study, we demonstrate that WSSV virions can bind to chitin through one of the major envelope proteins (VP24). Mutagenesis analysis indicated that amino acids (aa) 186 to 200 in the C terminus of VP24 were required for chitin binding. Moreover, the P-VP24186-200 peptide derived from the VP24 chitin binding region significantly inhibited the VP24 chitin interaction and the WSSV-chitin interaction, implying that VP24 participates in WSSV binding to chitin. Oral inoculation experiments showed that P-VP24186-200 treatment reduced the number of virus particles remaining in the digestive tract during the early stage of infection and greatly hindered WSSV proliferation in shrimp. These data indicate that binding of WSSV to chitin through the viral envelope protein VP24 is essential for WSSV per os infection and provide new ideas for preventing WSSV infection in shrimp farms. IMPORTANCE: In this study, we show that WSSV can bind to chitin through the envelope protein VP24. The chitin-binding domain of VP24 maps to amino acids 186 to 200 in the C terminus. Binding of WSSV to chitin through the viral envelope protein VP24 is essential for WSSV per os infection. These findings not only extend our knowledge of WSSV infection but also provide new insights into strategies to prevent WSSV infection in shrimp farms. PMID- 26512092 TI - Dengue Virus prM-Specific Human Monoclonal Antibodies with Virus Replication Enhancing Properties Recognize a Single Immunodominant Antigenic Site. AB - The proposed antibody-dependent enhancement (ADE) mechanism for severe dengue virus (DENV) disease suggests that non-neutralizing serotype cross-reactive antibodies generated during a primary infection facilitate entry into Fc receptor bearing cells during secondary infection, resulting in enhanced viral replication and severe disease. One group of cross-reactive antibodies that contributes considerably to this serum profile target the premembrane (prM) protein. We report here the isolation of a large panel of naturally occurring human monoclonal antibodies (MAbs) obtained from subjects following primary DENV serotype 1, 2, or 3 or secondary natural DENV infections or following primary DENV serotype 1 live attenuated virus vaccination to determine the antigenic landscape on the prM protein that is recognized by human antibodies. We isolated 25 prM-reactive human MAbs, encoded by diverse antibody-variable genes. Competition-binding studies revealed that all of the antibodies bound to a single major antigenic site on prM. Alanine scanning-based shotgun mutagenesis epitope mapping studies revealed diverse patterns of fine specificity of various clones, suggesting that different antibodies use varied binding poses to recognize several overlapping epitopes within the immunodominant site. Several of the antibodies interacted with epitopes on both prM and E protein residues. Despite the diverse genetic origins of the antibodies and differences in the fine specificity of their epitopes, each of these prM-reactive antibodies was capable of enhancing the DENV infection of Fc receptor-bearing cells. IMPORTANCE: Antibodies may play a critical role in the pathogenesis of enhanced DENV infection and disease during secondary infections. A substantial proportion of enhancing antibodies generated in response to natural dengue infection are directed toward the prM protein. The fine specificity of human prM antibodies is not understood. Here, we isolated a panel of dengue prM-specific human monoclonal antibodies from individuals after infection in order to define the mode of molecular recognition by enhancing antibodies. We found that only a single antibody molecule can be bound to each prM protein at any given time. Distinct overlapping epitopes were mapped, but all of the epitopes lie within a single major antigenic site, suggesting that this antigenic domain forms an immunodominant region of the protein. Neutralization and antibody-dependent enhanced replication experiments showed that recognition of any of the epitopes within the major antigenic site on prM was sufficient to cause enhanced infection of target cells. PMID- 26512095 TI - A Complicated Case of Sepsis Involving a Rare Organism in a 46-Year-Old White Woman with Asplenia and a History of Drug Abuse. PMID- 26512096 TI - Acute Myelogenous Leukemia with Cuplike Nuclei. PMID- 26512097 TI - Extreme electron polaron spatial delocalization in pi-conjugated materials. AB - The electron polaron, a spin-1/2 excitation, is the fundamental negative charge carrier in pi-conjugated organic materials. Large polaron spatial dimensions result from weak electron-lattice coupling and thus identify materials with unusually low barriers for the charge transfer reactions that are central to electronic device applications. Here we demonstrate electron polarons in pi conjugated multiporphyrin arrays that feature vast areal delocalization. This finding is evidenced by concurrent optical and electron spin resonance measurements, coupled with electronic structure calculations that suggest atypically small reorganization energies for one-electron reduction of these materials. Because the electron polaron dimension can be linked to key performance metrics in organic photovoltaics, light-emitting diodes, and a host of other devices, these findings identify conjugated materials with exceptional optical, electronic, and spintronic properties. PMID- 26512098 TI - Bantu history: Big advance, although with a chronological contradiction. PMID- 26512093 TI - Assessing global risk factors for non-fatal injuries from road traffic accidents and falls in adults aged 35-70 years in 17 countries: a cross-sectional analysis of the Prospective Urban Rural Epidemiological (PURE) study. AB - OBJECTIVES: To assess risk factors associated with non-fatal injuries (NFIs) from road traffic accidents (RTAs) or falls. METHODS: Our study included 151 609 participants from the Prospective Urban Rural Epidemiological study. Participants reported whether they experienced injuries within the past 12 months that limited normal activities. Additional questions elicited data on risk factors. We employed multivariable logistic regression to analyse data. RESULTS: Overall, 5979 participants (3.9% of 151 609) reported at least one NFI. Total number of NFIs was 6300: 1428 were caused by RTAs (22.7%), 1948 by falls (30.9%) and 2924 by other causes (46.4%). Married/common law status was associated with fewer falls, but not with RTA. Age 65-70 years was associated with fewer RTAs, but more falls; age 55-64 years was associated with more falls. Male versus female was associated with more RTAs and fewer falls. In lower-middle-income countries, rural residence was associated with more RTAs and falls; in low-income countries, rural residence was associated with fewer RTAs. Previous alcohol use was associated with more RTAs and falls; current alcohol use was associated with more falls. Education was not associated with either NFI type. CONCLUSIONS: This study of persons aged 35-70 years found that some risk factors for NFI differ according to whether the injury is related to RTA or falls. Policymakers may use these differences to guide the design of prevention policies for RTA-related or fall related NFI. PMID- 26512099 TI - Microscale kin discrimination in a famous soil bacterium. PMID- 26512100 TI - Library preparation methodology can influence genomic and functional predictions in human microbiome research. AB - Observations from human microbiome studies are often conflicting or inconclusive. Many factors likely contribute to these issues including small cohort sizes, sample collection, and handling and processing differences. The field of microbiome research is moving from 16S rDNA gene sequencing to a more comprehensive genomic and functional representation through whole-genome sequencing (WGS) of complete communities. Here we performed quantitative and qualitative analyses comparing WGS metagenomic data from human stool specimens using the Illumina Nextera XT and Illumina TruSeq DNA PCR-free kits, and the KAPA Biosystems Hyper Prep PCR and PCR-free systems. Significant differences in taxonomy are observed among the four different next-generation sequencing library preparations using a DNA mock community and a cell control of known concentration. We also revealed biases in error profiles, duplication rates, and loss of reads representing organisms that have a high %G+C content that can significantly impact results. As with all methods, the use of benchmarking controls has revealed critical differences among methods that impact sequencing results and later would impact study interpretation. We recommend that the community adopt PCR-free-based approaches to reduce PCR bias that affects calculations of abundance and to improve assemblies for accurate taxonomic assignment. Furthermore, the inclusion of a known-input cell spike-in control provides accurate quantitation of organisms in clinical samples. PMID- 26512101 TI - KH domain protein RCF3 is a tissue-biased regulator of the plant miRNA biogenesis cofactor HYL1. AB - The biogenesis of microRNAs (miRNAs), which regulate mRNA abundance through posttranscriptional silencing, comprises multiple well-orchestrated processing steps. We have identified the Arabidopsis thaliana K homology (KH) domain protein REGULATOR OF CBF GENE EXPRESSION 3 (RCF3) as a cofactor affecting miRNA biogenesis in specific plant tissues. MiRNA and miRNA-target levels were reduced in apex-enriched samples of rcf3 mutants, but not in other tissues. Mechanistically, RCF3 affects miRNA biogenesis through nuclear interactions with the phosphatases C-TERMINAL DOMAIN PHOSPHATASE-LIKE1 and 2 (CPL1 and CPL2). These interactions are essential to regulate the phosphorylation status, and thus the activity, of the double-stranded RNA binding protein and DICER-LIKE1 (DCL1) cofactor HYPONASTIC LEAVES1 (HYL1). PMID- 26512102 TI - Producing desired ice faces. AB - The ability to prepare single-crystal faces has become central to developing and testing models for chemistry at interfaces, spectacularly demonstrated by heterogeneous catalysis and nanoscience. This ability has been hampered for hexagonal ice, Ih--a fundamental hydrogen-bonded surface--due to two characteristics of ice: ice does not readily cleave along a crystal lattice plane and properties of ice grown on a substrate can differ significantly from those of neat ice. This work describes laboratory-based methods both to determine the Ih crystal lattice orientation relative to a surface and to use that orientation to prepare any desired face. The work builds on previous results attaining nearly 100% yield of high-quality, single-crystal boules. With these methods, researchers can prepare authentic, single-crystal ice surfaces for numerous studies including uptake measurements, surface reactivity, and catalytic activity of this ubiquitous, fundamental solid. PMID- 26512103 TI - Interrogating the activities of conformational deformed enzyme by single-molecule fluorescence-magnetic tweezers microscopy. AB - Characterizing the impact of fluctuating enzyme conformation on enzymatic activity is critical in understanding the structure-function relationship and enzymatic reaction dynamics. Different from studying enzyme conformations under a denaturing condition, it is highly informative to manipulate the conformation of an enzyme under an enzymatic reaction condition while monitoring the real-time enzymatic activity changes simultaneously. By perturbing conformation of horseradish peroxidase (HRP) molecules using our home-developed single-molecule total internal reflection magnetic tweezers, we successfully manipulated the enzymatic conformation and probed the enzymatic activity changes of HRP in a catalyzed H2O2-amplex red reaction. We also observed a significant tolerance of the enzyme activity to the enzyme conformational perturbation. Our results provide a further understanding of the relation between enzyme behavior and enzymatic conformational fluctuation, enzyme-substrate interactions, enzyme substrate active complex formation, and protein folding-binding interactions. PMID- 26512104 TI - Robustness of sensory-evoked excitation is increased by inhibitory inputs to distal apical tuft dendrites. AB - Cortical inhibitory interneurons (INs) are subdivided into a variety of morphologically and functionally specialized cell types. How the respective specific properties translate into mechanisms that regulate sensory-evoked responses of pyramidal neurons (PNs) remains unknown. Here, we investigated how INs located in cortical layer 1 (L1) of rat barrel cortex affect whisker-evoked responses of L2 PNs. To do so we combined in vivo electrophysiology and morphological reconstructions with computational modeling. We show that whisker evoked membrane depolarization in L2 PNs arises from highly specialized spatiotemporal synaptic input patterns. Temporally L1 INs and L2-5 PNs provide near synchronous synaptic input. Spatially synaptic contacts from L1 INs target distal apical tuft dendrites, whereas PNs primarily innervate basal and proximal apical dendrites. Simulations of such constrained synaptic input patterns predicted that inactivation of L1 INs increases trial-to-trial variability of whisker-evoked responses in L2 PNs. The in silico predictions were confirmed in vivo by L1-specific pharmacological manipulations. We present a mechanism consistent with the theory of distal dendritic shunting-that can regulate the robustness of sensory-evoked responses in PNs without affecting response amplitude or latency. PMID- 26512105 TI - Fly LMBR1/LIMR-type protein Lilipod promotes germ-line stem cell self-renewal by enhancing BMP signaling. AB - Limb development membrane protein-1 (LMBR1)/lipocalin-interacting membrane receptor (LIMR)-type proteins are putative nine-transmembrane receptors that are evolutionarily conserved across metazoans. However, their biological function is unknown. Here, we show that the fly family member Lilipod (Lili) is required for germ-line stem cell (GSC) self-renewal in the Drosophila ovary where it enhances bone morphogenetic protein (BMP) signaling. lili mutant GSCs are lost through differentiation, and display reduced levels of the Dpp transducer pMad and precocious activation of the master differentiation factor bam. Conversely, overexpressed Lili induces supernumerary pMad-positive bamP-GFP-negative GSCs. Interestingly, differentiation of lili mutant GSCs is bam-dependent; however, its effect on pMad is not. Thus, although it promotes stem cell self-renewal by repressing a bam-dependent process, Lilipod enhances transduction of the Dpp signal independently of its suppression of differentiation. In addition, because Lili is still required by a ligand-independent BMP receptor, its function likely occurs between receptor activation and pMad phosphorylation within the signaling cascade. This first, to our knowledge, in vivo characterization of a LMBR1/LIMR type protein in a genetic model reveals an important role in modulating BMP signaling during the asymmetric division of an adult stem cell population and in other BMP signaling contexts. PMID- 26512106 TI - Reply to Healy et al.: Value of ex ante predictions and independent tests for assessing false-positive results. PMID- 26512107 TI - Determining false-positives requires considering the totality of evidence. PMID- 26512108 TI - Transient conformers of LacY are trapped by nanobodies. AB - The lactose permease of Escherichia coli (LacY), a highly dynamic membrane protein, catalyzes symport of a galactopyranoside and an H(+) by using an alternating access mechanism, and the transport cycle involves multiple conformational states. Single-domain camelid nanobodies (Nbs) developed against a LacY mutant immobilized in an outward (periplasmic)-open conformation bind to the flexible WT protein and stabilize the open-outward conformation(s). Here, we use site-directed, distance-dependent Trp quenching/unquenching of fluorescent probes inserted on opposite surfaces of LacY to assess the conformational states of the protein complexed with each of eight unique Nbs that bind exclusively to the periplasmic side and block transport, but increase the accessibility of the sugar binding site. Nb binding involves conformational selection of LacY molecules with exposed binding epitopes. Each of eight Nbs induces quenching with three pairs of cytoplasmic Trp/fluorophore probes, indicating closing of cytoplasmic cavity. In reciprocal fashion, the same Nbs induce unquenching of fluorescence in three pairs of periplasmic probes due to opening of the periplasmic cavity. Because the extent of fluorescence change with various Nbs differs and the differences correlate with changes in the rate of sugar binding, it is also concluded that the Nbs stabilize several different outward-open conformations of LacY. PMID- 26512109 TI - Growing the terrestrial planets from the gradual accumulation of submeter-sized objects. AB - Building the terrestrial planets has been a challenge for planet formation models. In particular, classical theories have been unable to reproduce the small mass of Mars and instead predict that a planet near 1.5 astronomical units (AU) should roughly be the same mass as Earth. Recently, a new model called Viscously Stirred Pebble Accretion (VSPA) has been developed that can explain the formation of the gas giants. This model envisions that the cores of the giant planets formed from 100- to 1,000-km bodies that directly accreted a population of pebbles-submeter-sized objects that slowly grew in the protoplanetary disk. Here we apply this model to the terrestrial planet region and find that it can reproduce the basic structure of the inner solar system, including a small Mars and a low-mass asteroid belt. Our models show that for an initial population of planetesimals with sizes similar to those of the main belt asteroids, VSPA becomes inefficient beyond ~ 1.5 AU. As a result, Mars's growth is stunted, and nothing large in the asteroid belt can accumulate. PMID- 26512110 TI - Structure and two-metal mechanism of a eukaryal nick-sealing RNA ligase. AB - ATP-dependent RNA ligases are agents of RNA repair that join 3'-OH and 5'-PO4 RNA ends. Naegleria gruberi RNA ligase (NgrRnl) exemplifies a family of RNA nick sealing enzymes found in bacteria, viruses, and eukarya. Crystal structures of NgrRnl at three discrete steps along the reaction pathway-covalent ligase-(lysyl Nzeta)-AMP*Mn(2+) intermediate; ligase*ATP*(Mn(2+))2 Michaelis complex; and ligase*Mn(2+) complex-highlight a two-metal mechanism of nucleotidyl transfer, whereby (i) an enzyme-bound "catalytic" metal coordination complex lowers the pKa of the lysine nucleophile and stabilizes the transition state of the ATP alpha phosphate; and (ii) a second metal coordination complex bridges the beta- and gamma-phosphates. The NgrRnl N domain is a distinctively embellished oligonucleotide-binding (OB) fold that engages the gamma-phosphate and associated metal complex and orients the pyrophosphate leaving group for in-line catalysis with stereochemical inversion at the AMP phosphate. The unique domain architecture of NgrRnl fortifies the theme that RNA ligases have evolved many times, and independently, by fusions of a shared nucleotidyltransferase domain to structurally diverse flanking modules. The mechanistic insights to lysine adenylylation gained from the NgrRnl structures are likely to apply broadly to the covalent nucleotidyltransferase superfamily of RNA ligases, DNA ligases, and RNA capping enzymes. PMID- 26512111 TI - RNA sensing by conventional dendritic cells is central to the development of lupus nephritis. AB - Glomerulonephritis is a common and debilitating feature of systemic lupus erythematosus (SLE). The precise immune mechanisms that drive the progression from benign autoimmunity to glomerulonephritis are largely unknown. Previous investigations have shown that a moderate increase of the innate Toll-like receptor 7 (TLR7) is sufficient for the development of nephritis. In these systems normalization of B-cell TLR7 expression or temporal depletion of plasmacytoid dendritic cells (pDCs) slow progression; however, the critical cell that is responsible for driving full immunopathology remains unidentified. In this investigation we have shown that conventional DC expression of TLR7 is essential for severe autoimmunity in the Sle1Tg7 model of SLE. We show that a novel expanding CD11b(+) conventional DC subpopulation dominates the infiltrating renal inflammatory milieu, localizing to the glomeruli. Moreover, exposure of human myeloid DCs to IFN-alpha or Flu increases TLR7 expression, suggesting they may have a role in self-RNA recognition pathways in clinical disease. To our knowledge, this study is the first to highlight the importance of conventional DC TLR7 expression for kidney pathogenesis in a murine model of SLE. PMID- 26512112 TI - Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress. AB - Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7(Deltapan) mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7(Deltapan) mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7(Deltapan) mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures. PMID- 26512113 TI - Crohn's disease-derived monocytes fail to induce Paneth cell defensins. AB - Crohn's disease (CD) is associated with a multitude of genetic defects, many of which likely affect Paneth cell function. Paneth cells reside in the small intestine and produce antimicrobial peptides essential for the host barrier, principally human alpha-defensin 5 (HD5) and HD6. Patients with CD of the ileum are characterized by reduced constitutive expression of these peptides and, accordingly, compromised antimicrobial barrier function. Here, we present a previously unidentified regulatory mechanism of Paneth cell defensins. Using cultures of human ileal tissue, we showed that the secretome of peripheral blood mononuclear cells (PBMCs) from healthy controls restored the attenuated Paneth cell alpha-defensin expression characteristic of patients with ileal CD. Analysis of the Wnt pathway in both cultured biopsies and intestinal epithelial cells implicated Wnt ligands driving the PBMC effect, whereas various tested cytokines were ineffective. We further detected another defect in patients with ileal CD, because the PBMC secretomes derived from patients with CD were unable to restore the reduced HD5/HD6 expression. Accordingly, analysis of PBMC subtypes showed that monocytes of patients with CD express significantly lower levels of canonical Wnt ligands, including Wnt3, Wnt3a, Wnt1, and wntless Wnt ligand secretion mediator (Evi/Wls). These studies reveal an important cross-talk between bone marrow-derived cells and epithelial secretory Paneth cells. Defective Paneth cell-mediated innate immunity due to inadequate Wnt ligand stimulation by monocytes provides an additional mechanism in CD. Because defects of Paneth cell function stemming from various etiologies are overcome by Wnt ligands, this mechanism is a potential therapeutic target for this disease. PMID- 26512114 TI - LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts through downregulation of Etv2. AB - The hemangioblast is a progenitor cell with the capacity to give rise to both hematopoietic and endothelial progenitors. Currently, the regulatory mechanisms underlying hemangioblast formation are being elucidated, whereas those controllers for the selection of hematopoietic or endothelial fates still remain a mystery. To answer these questions, we screened for zebrafish mutants that have defects in the hemangioblast expression of Gata1, which is never expressed in endothelial progenitors. One of the isolated mutants, it627, showed not only down regulation of hematopoietic genes but also up-regulation of endothelial genes. We identified the gene responsible for the it627 mutant as the zebrafish homolog of Lys-specific demethylase 1 (LSD1/KDM1A). Surprisingly, the hematopoietic defects in lsd1(it627) embryos were rescued by the gene knockdown of the Ets variant 2 gene (etv2), an essential regulator for vasculogenesis. Our results suggest that the LSD1-dependent shutdown of Etv2 gene expression may be a significant event required for hemangioblasts to initiate hematopoietic differentiation. PMID- 26512115 TI - A priori calculations of the free energy of formation from solution of polymorphic self-assembled monolayers. AB - Modern quantum chemical electronic structure methods typically applied to localized chemical bonding are developed to predict atomic structures and free energies for meso-tetraalkylporphyrin self-assembled monolayer (SAM) polymorph formation from organic solution on highly ordered pyrolytic graphite surfaces. Large polymorph-dependent dispersion-induced substrate-molecule interactions (e.g., -100 kcal mol(-1) to -150 kcal mol(-1) for tetratrisdecylporphyrin) are found to drive SAM formation, opposed nearly completely by large polymorph dependent dispersion-induced solvent interactions (70-110 kcal mol(-1)) and entropy effects (25-40 kcal mol(-1) at 298 K) favoring dissolution. Dielectric continuum models of the solvent are used, facilitating consideration of many possible SAM polymorphs, along with quantum mechanical/molecular mechanical and dispersion-corrected density functional theory calculations. These predict and interpret newly measured and existing high-resolution scanning tunnelling microscopy images of SAM structure, rationalizing polymorph formation conditions. A wide range of molecular condensed matter properties at room temperature now appear suitable for prediction and analysis using electronic structure calculations. PMID- 26512116 TI - HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. AB - Increased expression of CD47 has been reported to enable cancer cells to evade phagocytosis by macrophages and to promote the cancer stem cell phenotype, but the molecular mechanisms regulating CD47 expression have not been determined. Here we report that hypoxia-inducible factor 1 (HIF-1) directly activates transcription of the CD47 gene in hypoxic breast cancer cells. Knockdown of HIF activity or CD47 expression increased the phagocytosis of breast cancer cells by bone marrow-derived macrophages. CD47 expression was increased in mammosphere cultures, which are enriched for cancer stem cells, and CD47 deficiency led to cancer stem cell depletion. Analysis of datasets derived from thousands of patients with breast cancer revealed that CD47 expression was correlated with HIF target gene expression and with patient mortality. Thus, CD47 expression contributes to the lethal breast cancer phenotype that is mediated by HIF-1. PMID- 26512117 TI - p27kip1 controls H-Ras/MAPK activation and cell cycle entry via modulation of MT stability. AB - The cyclin-dependent kinase (CDK) inhibitor p27(kip1) is a critical regulator of the G1/S-phase transition of the cell cycle and also regulates microtubule (MT) stability. This latter function is exerted by modulating the activity of stathmin, an MT-destabilizing protein, and by direct binding to MTs. We recently demonstrated that increased proliferation in p27(kip1)-null mice is reverted by concomitant deletion of stathmin in p27(kip1)/stathmin double-KO mice, suggesting that a CDK-independent function of p27(kip1) contributes to the control of cell proliferation. Whether the regulation of MT stability by p27(kip1) impinges on signaling pathway activation and contributes to the decision to enter the cell cycle is largely unknown. Here, we report that faster cell cycle entry of p27(kip1)-null cells was impaired by the concomitant deletion of stathmin. Using gene expression profiling coupled with bioinformatic analyses, we show that p27(kip1) and stathmin conjunctly control activation of the MAPK pathway. From a molecular point of view, we observed that p27(kip1), by controlling MT stability, impinges on H-Ras trafficking and ubiquitination levels, eventually restraining its full activation. Our study identifies a regulatory axis controlling the G1/S phase transition, relying on the regulation of MT stability by p27(kip1) and finely controlling the spatiotemporal activation of the Ras-MAPK signaling pathway. PMID- 26512118 TI - Dynamic membrane protein topological switching upon changes in phospholipid environment. AB - A fundamental objective in membrane biology is to understand and predict how a protein sequence folds and orients in a lipid bilayer. Establishing the principles governing membrane protein folding is central to understanding the molecular basis for membrane proteins that display multiple topologies, the intrinsic dynamic organization of membrane proteins, and membrane protein conformational disorders resulting in disease. We previously established that lactose permease of Escherichia coli displays a mixture of topological conformations and undergoes postassembly bidirectional changes in orientation within the lipid bilayer triggered by a change in membrane phosphatidylethanolamine content, both in vivo and in vitro. However, the physiological implications and mechanism of dynamic structural reorganization of membrane proteins due to changes in lipid environment are limited by the lack of approaches addressing the kinetic parameters of transmembrane protein flipping. In this study, real-time fluorescence spectroscopy was used to determine the rates of protein flipping in the lipid bilayer in both directions and transbilayer flipping of lipids triggered by a change in proteoliposome lipid composition. Our results provide, for the first time to our knowledge, a dynamic picture of these events and demonstrate that membrane protein topological rearrangements in response to lipid modulations occur rapidly following a threshold change in proteoliposome lipid composition. Protein flipping was not accompanied by extensive lipid-dependent unfolding of transmembrane domains. Establishment of lipid bilayer asymmetry was not required but may accelerate the rate of protein flipping. Membrane protein flipping was found to accelerate the rate of transbilayer flipping of lipids. PMID- 26512119 TI - Membrane Proteome-Wide Response to the Antifungal Drug Clotrimazole in Candida glabrata: Role of the Transcription Factor CgPdr1 and the Drug:H+ Antiporters CgTpo1_1 and CgTpo1_2. AB - Azoles are widely used antifungal drugs. This family of compounds includes triazoles, mostly used in the treatment of systemic infections, and imidazoles, such as clotrimazole, often used in the case of superficial infections. Candida glabrata is the second most common cause of candidemia worldwide and presents higher levels of intrinsic azole resistance when compared with Candida albicans, thus being an interesting subject for the study of azole resistance mechanisms in fungal pathogens.Since resistance often relies on the action of membrane transporters, including drug efflux pumps from the ATP-binding cassette family or from the Drug:H(+) antiporter (DHA)(1) family, an iTRAQ-based membrane proteomics analysis was performed to identify all the membrane-associated proteins whose abundance changes in C. glabrata cells exposed to the azole drug clotrimazole. Proteins found to have significant expression changes in this context were clustered into functional groups, namely: glucose metabolism, oxidative phosphorylation, mitochondrial import, ribosome components and translation machinery, lipid metabolism, multidrug resistance transporters, cell wall assembly, and stress response, comprising a total of 37 proteins. Among these, the DHA transporter CgTpo1_2 (ORF CAGL0E03674g) was identified as overexpressed in the C. glabrata membrane in response to clotrimazole. Functional characterization of this putative drug:H(+) antiporter, and of its homolog CgTpo1_1 (ORF CAGL0G03927g), allowed the identification of these proteins as localized to the plasma membrane and conferring azole drug resistance in this fungal pathogen by actively extruding the drug to the external medium. The cell wall protein CgGas1 was also shown to confer azole drug resistance through cell wall remodeling. Finally, the transcription factor CgPdr1 in the clotrimazole response was observed to control the expression of 20 of the identified proteins, thus highlighting the existence of additional unforeseen targets of this transcription factor, recognized as a major regulator of azole drug resistance in clinical isolates. PMID- 26512120 TI - Saviour Siblings: reply to critics. PMID- 26512121 TI - Into the blue: the importance of murine lacZ gene expression profiling in understanding and treating human disease. AB - The International Mouse Phenotyping Consortium (IMPC) is a major international effort to explore the effects of knocking out 20,000 genes in the mouse. A new study by White and colleagues, published in the current issue of Disease Models & Mechanisms, demonstrates the usefulness of lacZ in situ reporter expression patterns in extending our understanding of genotype-phenotype relationships as part of the IMPC high-throughput screen. In situ gene expression profiling is invaluable for evaluating compartment-specific gene expression patterns, and these enrich our understanding of the role of genes in a great number of biological processes in multiple organ systems. Furthermore, the complexity of gene expression patterns informs our understanding of how genes influence lethality. This Editorial aims to highlight ways in which the lacZ expression profiles can impact on biomedical research by uncovering as-yet-unknown genotype phenotype relationships, and through predicting the role of genes in health and disease. PMID- 26512122 TI - Exploring cell apoptosis and senescence to understand and treat cancer: an interview with Scott Lowe. AB - Scott W. Lowe is currently principal investigator at the Memorial Sloan-Kettering Cancer Center. After beginning his studies in chemical engineering, he decided to take another path and became fascinated by biochemistry, genetics and molecular biology, which ultimately led to an interest in human disease, particularly cancer. During his PhD at the Massachusetts Institute of Technology (MIT), Scott had the opportunity to benefit from the exceptional mentorship of Earl Ruley, David Housman and Tyler Jacks, and contributed to elucidating how the p53 (TP53) tumor suppressor gene limits oncogenic transformation and modulates the cytotoxic response to conventional chemotherapy. This important work earned him a fellowship from the Cold Spring Harbor Laboratory, which helped to launch his independent career. Scott is now a leading scientist in the cancer field and his work has helped to shed light on mechanisms of cell apoptosis and senescence to better understand and treat cancer. In this interview, he talks about this incredible scientific journey. PMID- 26512124 TI - Clinician-educators in emerging graduate medical education systems: description, roles and perceptions. AB - OBJECTIVES: To describe clinician-educators (CEs) in new graduate medical education (GME) systems and characterize perception of preparedness, roles and rewards, and factors affecting job satisfaction and retention. METHODS: A cross sectional survey of all CEs of institutions using competency-based GME and accredited by the Accreditation Council for Graduate Medical Education International (ACGME-I). RESULTS: 274 of 359 eligible participants (76.3%) responded, representing 47 residency programs across 17 specialties. CEs were predominantly married men aged in their 40s, employed at their current institution 9.3 years (+/-6.4 years). CEs judged themselves competent or expert in teaching skills (91.5%), trainee assessment (82%) and mentoring (75%); less so in curriculum development (44%) and educational research skills (32%). Clinical productivity was perceived by the majority (62%) as the item most valued by their institutions, with little or no perceived value for teaching or educational efforts. Overall, 58.3% were satisfied or very satisfied with their roles, and 77% expected to remain in academic medicine for 5 years. A strong negative correlation was found between being a program or associate program director and likelihood of staying in academic medicine (aOR 0.42; 0.22 to 0.80). CONCLUSIONS: In the GME systems studied, CEs, regardless of country or programme, report working in environments that value clinical productivity over educational efforts. CEs feel competent and prepared for many aspects of their roles, have positive attitudes towards teaching, and report overall job satisfaction, with most likely to remain in academic medicine. As medical training advances internationally, the impact on and by CEs requires ongoing attention. PMID- 26512123 TI - Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models. AB - A low level of tissue oxygen (hypoxia) is a physiological feature of a wide range of diseases, from cancer to infection. Cellular hypoxia is sensed by oxygen sensitive hydroxylase enzymes, which regulate the protein stability of hypoxia inducible factor alpha (HIF-alpha) transcription factors. When stabilised, HIF alpha binds with its cofactors to HIF-responsive elements (HREs) in the promoters of target genes to coordinate a wide-ranging transcriptional programme in response to the hypoxic environment. This year marks the 20th anniversary of the discovery of the HIF-1alpha transcription factor, and in recent years the HIF mediated hypoxia response is being increasingly recognised as an important process in determining the outcome of diseases such as cancer, inflammatory disease and bacterial infections. Animal models have shed light on the roles of HIF in disease and have uncovered intricate control mechanisms that involve multiple cell types, observations that might have been missed in simpler in vitro systems. These findings highlight the need for new whole-organism models of disease to elucidate these complex regulatory mechanisms. In this Review, we discuss recent advances in our understanding of hypoxia and HIFs in disease that have emerged from studies of zebrafish disease models. Findings from such models identify HIF as an integral player in the disease processes. They also highlight HIF pathway components and their targets as potential therapeutic targets against conditions that range from cancers to infectious disease. PMID- 26512125 TI - Improving outcomes in patients with Acute Kidney Injury: the impact of hospital based automated AKI alerts. AB - BACKGROUND: Acute kidney injury (AKI) is a significant cause of morbidity and mortality. Early identification may improve the outcome and in 2012 our hospital introduced an automated AKI alert system for early detection and management of AKI. OBJECTIVES: Using an automated AKI alert system we analysed whether early review and intervention by the Critical Care and Outreach (CCOT) team improved patient outcomes in AKI and whether serum bicarbonate was useful in predicting outcomes in patients with AKI. METHODS: In a retrospective analysis we identified patients who triggered an AKI alert from 20 April 2012 to 20 September 2013 and collected data on mortality, length of stay, need for intensive care admission and renal replacement therapy (RRT). RESULTS: 994 AKI alerts were generated and analysed. Patients with bicarbonate outside the normal range had significantly higher mortality. Bicarbonate <22 mmol/L was associated with a mortality of 25.7% (49/191) compared with 16.9% (39/231) when 22-29 mmol/L (p=0.047, chi(2)). Those patients reviewed >=1 day after AKI alert by CCOT compared with those seen on the day of the alert had a 2.4 times increase in mortality and were 7 times more likely to require RRT acutely. CONCLUSIONS: Electronically identified AKI alerts identify patients at high risk of morbidity and mortality. In this group AKI alerts preceded CCOT review by a mean of 2 days. This represents a window for supportive interventions, which may explain improved outcomes in those reviewed earlier. The addition of serum bicarbonate offers a further method of risk stratifying patients at greater risk of death. PMID- 26512127 TI - Crystal structure of Mycobacterium tuberculosis O6-methylguanine-DNA methyltransferase protein clusters assembled on to damaged DNA. AB - Mycobacterium tuberculosis O(6)-methylguanine-DNA methyltransferase (MtOGT) contributes to protect the bacterial GC-rich genome against the pro-mutagenic potential of O(6)-methylated guanine in DNA. Several strains of M. tuberculosis found worldwide encode a point-mutated O(6)-methylguanine-DNA methyltransferase (OGT) variant (MtOGT-R37L), which displays an arginine-to-leucine substitution at position 37 of the poorly functionally characterized N-terminal domain of the protein. Although the impact of this mutation on the MtOGT activity has not yet been proved in vivo, we previously demonstrated that a recombinant MtOGT-R37L variant performs a suboptimal alkylated-DNA repair in vitro, suggesting a direct role for the Arg(37)-bearing region in catalysis. The crystal structure of MtOGT complexed with modified DNA solved in the present study reveals details of the protein-protein and protein-DNA interactions occurring during alkylated-DNA binding, and the protein capability also to host unmodified bases inside the active site, in a fully extrahelical conformation. Our data provide the first experimental picture at the atomic level of a possible mode of assembling three adjacent MtOGT monomers on the same monoalkylated dsDNA molecule, and disclose the conformational flexibility of discrete regions of MtOGT, including the Arg(37)-bearing random coil. This peculiar structural plasticity of MtOGT could be instrumental to proper protein clustering at damaged DNA sites, as well as to protein-DNA complexes disassembling on repair. PMID- 26512126 TI - The Exosporium Layer of Bacterial Spores: a Connection to the Environment and the Infected Host. AB - Much of what we know regarding bacterial spore structure and function has been learned from studies of the genetically well-characterized bacterium Bacillus subtilis. Molecular aspects of spore structure, assembly, and function are well defined. However, certain bacteria produce spores with an outer spore layer, the exosporium, which is not present on B. subtilis spores. Our understanding of the composition and biological functions of the exosporium layer is much more limited than that of other aspects of the spore. Because the bacterial spore surface is important for the spore's interactions with the environment, as well as being the site of interaction of the spore with the host's innate immune system in the case of spore-forming bacterial pathogens, the exosporium is worthy of continued investigation. Recent exosporium studies have focused largely on members of the Bacillus cereus family, principally Bacillus anthracis and Bacillus cereus. Our understanding of the composition of the exosporium, the pathway of its assembly, and its role in spore biology is now coming into sharper focus. This review expands on a 2007 review of spore surface layers which provided an excellent conceptual framework of exosporium structure and function (A. O. Henriques and C. P. Moran, Jr., Annu Rev Microbiol 61:555-588, 2007, http://dx.doi.org/10.1146/annurev.micro.61.080706.093224). That review began a process of considering outer spore layers as an integrated, multilayered structure rather than simply regarding the outer spore components as independent parts. PMID- 26512128 TI - Orthotopic heart transplantation: the bicaval technique. AB - Heart transplantation still remains the gold standard therapy for end-stage heart failure, although several other approaches have emerged, such as biventricular pacing, left ventricular assist devices (LVADs) and total artificial heart. Moreover, the increasing use of LVADs as a bridge to transplant is posing the technical challenge of LVAD removal during the procedure. We in this paper describe the bicaval technique, which currently represents the routine approach for orthotopic heart transplantation. PMID- 26512129 TI - Mutations in adenine-binding pockets enhance catalytic properties of NAD(P)H dependent enzymes. AB - NAD(P)H-dependent enzymes are ubiquitous in metabolism and cellular processes and are also of great interest for pharmaceutical and industrial applications. Here, we present a structure-guided enzyme engineering strategy for improving catalytic properties of NAD(P)H-dependent enzymes toward native or native-like reactions using mutations to the enzyme's adenine-binding pocket, distal to the site of catalysis. Screening single-site saturation mutagenesis libraries identified mutations that increased catalytic efficiency up to 10-fold in 7 out of 10 enzymes. The enzymes improved in this study represent three different cofactor binding folds (Rossmann, DHQS-like, and FAD/NAD binding) and utilize both NADH and NADPH. Structural and biochemical analyses show that the improved activities are accompanied by minimal changes in other properties (cooperativity, thermostability, pH optimum, uncoupling), and initial tests on two enzymes (ScADH6 and EcFucO) show improved functionality in Escherichia coli. PMID- 26512130 TI - Qualitative complaints and their relation to overall hospital rating using an H CAHPS-derived instrument. AB - BACKGROUND AND OBJECTIVES: Due to the multitude of questions in the Hospital Consumer Assessment of Healthcare Providers and Systems (H-CAHPS) survey, it may be difficult to decide where quality improvement efforts should be focused. Our organisation has supplemented the survey with a 'patient complaints' section. The study objectives were to determine (1) the frequency of qualitative complaints and the demographic/clinical profile of patients lodging them, (2) the most frequent complaint themes and their association with overall experience scores and (3) whether overall experience scores varied based upon the complaint action taken by the patient or the degree of patient satisfaction in the handling of complaints. METHODS: From April 2013 to March 2014, 8929 telephone surveys were completed by patients discharged from 93 acute care hospitals in Alberta, Canada. These were successfully linked with the corresponding inpatient record. Open ended complaints were themed into categories. Mean differences in overall inpatient experience were assessed for each complaint theme, including overall and multiple complaints. RESULTS: 1870 patients (20.9%) reported at least one open-ended complaint. Most frequent complaint themes were nursing (n=491; 5.5% of cohort), medications (n=219; 2.5%) and food (n=193; 2.2%). Increased odds of having a complaint were associated with younger age, being born in Canada and having no documented medical comorbidities. Protective factors were male gender, lower education level, urgent hospital admission, lower resource intensity and length of stay (LOS) <3 days. CONCLUSIONS: This is the first investigation of its type using H-CAHPS-based data in a Canadian context. Through replication of this study, other healthcare organisations may determine the association between open ended complaints and their own overall experience scores. PMID- 26512131 TI - Development and testing of a text-mining approach to analyse patients' comments on their experiences of colorectal cancer care. AB - BACKGROUND: Quality of cancer care may greatly impact on patients' health-related quality of life (HRQoL). Free-text responses to patient-reported outcome measures (PROMs) provide rich data but analysis is time and resource-intensive. This study developed and tested a learning-based text-mining approach to facilitate analysis of patients' experiences of care and develop an explanatory model illustrating impact on HRQoL. METHODS: Respondents to a population-based survey of colorectal cancer survivors provided free-text comments regarding their experience of living with and beyond cancer. An existing coding framework was tested and adapted, which informed learning-based text mining of the data. Machine-learning algorithms were trained to identify comments relating to patients' specific experiences of service quality, which were verified by manual qualitative analysis. Comparisons between coded retrieved comments and a HRQoL measure (EQ5D) were explored. RESULTS: The survey response rate was 63.3% (21 802/34 467), of which 25.8% (n=5634) participants provided free-text comments. Of retrieved comments on experiences of care (n=1688), over half (n=1045, 62%) described positive care experiences. Most negative experiences concerned a lack of post treatment care (n=191, 11% of retrieved comments) and insufficient information concerning self-management strategies (n=135, 8%) or treatment side effects (n=160, 9%). Associations existed between HRQoL scores and coded algorithm retrieved comments. Analysis indicated that the mechanism by which service quality impacted on HRQoL was the extent to which services prevented or alleviated challenges associated with disease and treatment burdens. CONCLUSIONS: Learning-based text mining techniques were found useful and practical tools to identify specific free-text comments within a large dataset, facilitating resource-efficient qualitative analysis. This method should be considered for future PROM analysis to inform policy and practice. Study findings indicated that perceived care quality directly impacts on HRQoL. PMID- 26512132 TI - Natural History of Elderly-onset Ulcerative Colitis: Results from a Territory wide Inflammatory Bowel Disease Registry. AB - BACKGROUND AND AIMS: Data on the natural history of elderly-onset ulcerative colitis [UC] are limited. We aimed to investigate clinical features and outcomes of patients with elderly-onset UC. METHODS: Patients with a confirmed diagnosis of UC between 1981 and 2013, from 13 hospitals within a territory-wide Hong Kong Inflammatory Bowel Disease Registry, were included. Clinical features and outcomes of elderly-onset patients, defined as age >= 60 years at diagnosis, were compared with those of non-elderly-onset disease [< 60 years at diagnosis]. RESULTS: We identified 1225 patients, of whom 12.8% [157/1225; 56.1% male] had elderly-onset UC. Median duration of follow-up was 11 years [interquartile range, 6-16 years]. Age-specific incidence of elderly-onset UC increased from 0.1 per 100000 persons before 1991 to 1.3 per 100000 persons after 2010. There were more ex-smokers [32.2% vs. 12.2%, p < 0.001] and higher proportion of comorbidities [p < 0.001] in elderly-onset than non-elderly-onset patients. Disease extent, corticosteroids, immunosuppressants use, and colectomy rates were similar between the two groups. Elderly-onset disease was an independent risk factor for cytomegalovirus infection [odds ratio 2.9, 95% confidence interval 1.6-5.2, p < 0.001]. More elderly-onset patients had Clostridium difficile infection [11.0% vs. 5.4%, p = 0.007], hospitalisation for UC exacerbation [50.6% vs. 41.8%, p = 0.037], colorectal cancer [3.2% vs. 0.9%, p = 0.033], all-cause mortality [7.0% vs. 1.0%, p < 0.001], and UC-related mortality [1.9% vs. 0.2%, p = 0.017] than non-elderly-onset patients. CONCLUSIONS: Elderly-onset UC patients are increasing in number. These patients have higher risk of opportunistic infections, hospitalisation, colorectal cancer, and mortality than non-elderly-onset patients. Management and therapeutic strategies in this special group need careful attention. PMID- 26512133 TI - A Meta-analysis of Percutaneous Drainage Versus Surgery as the Initial Treatment of Crohn's Disease-related Intra-abdominal Abscess. AB - BACKGROUND AND AIMS: Spontaneous intra-abdominal abscess formation is a common complication of Crohn's disease. Percutaneous drainage [PD] may avoid surgery and preserve bowel length, although there is no consensus on its efficacy as the initial treatment and the associated outcomes if unsuccessful. This study uses meta-analytical techniques to compare the outcomes of PD alone versus primary surgery for Crohn's-related intra-abdominal abscess. METHODS: A comprehensive search for comparative studies examining the use of PD and surgery for spontaneous Crohn's-related intra-abdominal abscess was performed. Each study was reviewed and data extracted. Random-effects methods were used to combine data. RESULTS: There were six studies including a total of 333 patients that met the inclusion criteria. Surgery was performed initially in 184 patients, PD was performed in 149. Groups were similar in demographics and abscess characteristics. There was a significantly higher risk of abscess recurrence following PD (odds ratio [OR]: 6.544, 95% confidence interval [CI]: 1.783-24.010, p: 0.005]. The pooled proportion of PD patients requiring subsequent surgery was 70.7%. There was no significant difference between approaches in post-procedural complication rate [OR: 0.657, 95% CI: 0.175-2.476, p: 0.535], ultimate permanent stoma requirement [OR: 0.557, 95% CI: 0.147-2.111, p: 0.389] or length of hospital stay [difference in means: -1.006 days, 95% CI: -28.762-26.749, p: 0.943]. CONCLUSIONS: PD can avoid surgery in up to 30% of patients presenting with spontaneous Crohn's-related intra-abdominal abscesses. However, the suggested advantages over surgery in relation to complications and length of stay were not apparent. Further studies in this area are needed. PMID- 26512134 TI - Classifying Back Pain and Peripheral Joint Complaints in Inflammatory Bowel Disease Patients: A Prospective Longitudinal Follow-up Study. AB - BACKGROUND AND AIMS: Peripheral joint complaints [pJTC] and chronic back pain [CBP] are the most common extra-intestinal manifestations in patients with inflammatory bowel disease [IBD]. This prospective study evaluates variables associated with joint/back pain, including IBD disease activity. METHODS: IBD patients with back pain >= 3 months and/or peripheral joint pain/swelling [n = 155], and IBD patients without joint complaints [n = 100; controls], were followed for a period of 1 year. Patients were classified as having SpondyloArthritis [SpA] according to several sets of criteria. Statistical analysis included logistic regression models and linear mixed model analysis. RESULTS: Of the 155 patients with joint/back pain, 13 had chronic back pain, 80 peripheral joint complaints, and 62 axial and peripheral joint complaints. Smoking, female gender, and IBD disease activity were independently associated with IBD joint/back pain. The Assessment in Spondyloarthritis International Society criteria for axial and peripheral SpA were fulfilled in 12.3% of patients, with 9.7% [n = 15] receiving a rheumatological diagnosis of arthritis. During the 12-month follow-up, the majority of the patients reporting joint/back pain remained stable. CONCLUSIONS: In our cohort, the majority of IBD patients reported joint/back pain and SpA was relatively common. To facilitate effective care, gastroenterologists should be aware of the various features of SpA to classify joint complaints and, by making use of an efficient referral algorithm, to refer CBP patients to the rheumatologist. PMID- 26512135 TI - IBD Genetic Risk Profile in Healthy First-Degree Relatives of Crohn's Disease Patients. AB - BACKGROUND: Family history provides important information on risk of developing inflammatory bowel disease [IBD], and genetic profiling of first-degree relatives [FDR] of Crohn's disease [CD]- affected individuals might provide additional information. We aimed to delineate the genetic contribution to the increased IBD susceptibility observed in FDR. METHODS: N = 976 Caucasian, healthy, non-related FDR; n = 4997 independent CD; and n = 5000 healthy controls [HC]; were studied. Genotyping for 158 IBD-associated single nucleotide polymorphisms [SNPs] was performed using the Illumina Immunochip. Risk allele frequency [RAF] differences between FDR and HC cohorts were correlated with those between CD and HC cohorts. CD and IBD genetic risk scores [GRS] were calculated and compared between HC, FDR, and CD cohorts. RESULTS: IBD-associated SNP RAF differences in FDR and HC cohorts were strongly correlated with those in CD and HC cohorts, correlation coefficient 0.63 (95% confidence interval [CI] 0.53 - 0.72), p = 9.90 x 10(-19). There was a significant increase in CD-GRS [mean] comparing HC, FDR, and CD cohorts: 0.0244, 0.0250, and 0.0257 respectively [p < 1.00 x 10(-7) for each comparison]. There was no significant difference in the IBD-GRS between HC and FDR cohorts [p = 0.81]; however, IBD-GRS was significantly higher in CD compared with FDR and HC cohorts [p < 1.00 x 10(-10) for each comparison]. CONCLUSION: FDR of CD-affected individuals are enriched with IBD risk alleles compared with HC. Cumulative CD-specific genetic risk is increased in FDR compared with HC. Prospective studies are required to determine if genotyping would facilitate better risk stratification of FDR. PMID- 26512136 TI - Defunctioning Ileostomy is not Associated with Reduced Leakage in Proctocolectomy and Ileal Pouch Anastomosis Surgeries for IBD. AB - BACKGROUND: Anastomotic leakage is a serious complication after restorative proctocolectomy with ileal pouch-anal anastomosis. Previous studies have shown significantly decreased leak rates in diverted patients with less severe clinical consequences. The aim of this study was to evaluate short- and long-term outcome of selective ileostomy formation in a multicentre cohort of patients undergoing pouch surgery. METHODS: In a retrospective study, 621 patients undergoing pouch surgery for inflammatory bowel disease [IBD] were identified from three large centres. Anastomotic leakage was defined as any leak confirmed by either contrast extravasation on imaging or during surgical re-intervention. RESULTS: In 305 patients [49.1%], primary defunctioning ileostomy was created during pouch surgery and 41 [6.6%] patients received a secondary ileostomy because of a leaking non-diverted pouch. Primary ileostomy formation was associated with male sex, weight loss, American Society of Anesthesiologists score [ASA] > 2, steroid use, one-stage surgery, hand-sewn anastomosis, and blood transfusion. Leak rates were comparable between diverted and non-diverted patients [16.7% vs 17.1%, p = 0.92], which remained unchanged in subgroups with immunosuppressive medication. Having had an ileostomy was demonstrated to be an independent predictor of small bowel obstruction (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.45 - 4.67) and pouch fistulas [OR 3.05, 95%CI 1.06 - 8.73]. The 10-year pouch survival was comparable for patients with and without ileostomy [89% versus 88%, p = 0.718]. CONCLUSIONS: Leakage rates of diverted and non-diverted pouches in IBD patients were similar and relatively high. Defunctioning was independently associated with long-term complications. A staged approach without defunctioning might be the best strategy. PMID- 26512137 TI - Thymic Epithelial Cells Are a Nonredundant Source of Wnt Ligands for Thymus Development. AB - Wnt signaling has been implicated in T cell development. However, it remained unclear which cell type is the major source of Wnt ligands and to what extent thymic epithelial cell (TEC) development is dependent on Wnt signaling. In this study, we analyzed the role of Wnt ligands provided by TECs for the development of T cells and TECs without manipulating the intracellular Wnt signaling machinery in either cell type. To this end, we used conditional knockout mice (FoxN1-Gpr177) in which TECs are unable to secrete Wnt ligands. Gpr177 (Evi/Wls) is a Wnt-specific cargo receptor that is required for the secretion of Wnt ligands. We found that TECs are the main source of Wnt ligands in the thymus, which serves a nonredundant role, and lack of TEC-provided Wnt ligands led to thymic hypotrophy, as well as a reduced peripheral T cell pool. Despite being reduced in numbers, T cells that developed in the absence of TEC-secreted Wnt ligands were functionally competent, and the subset composition of the peripheral T cell pool was not affected. Thus, our data suggest that T cell development is not directly dependent on TEC-provided Wnt ligands. Rather, TEC-secreted Wnt ligands are essential for normal thymus development and normal peripheral T cell frequencies but are dispensable for T cell function in the periphery. PMID- 26512138 TI - Revisiting the Timing of Action of the PAG Adaptor Using Quantitative Proteomics Analysis of Primary T Cells. AB - The protein tyrosine kinase LCK plays a key role in TCR signaling, and its activity is dynamically controlled by the tyrosine kinase C-terminal Src kinase (CSK) and the tyrosine phosphatase CD45. CSK is brought in contiguity to LCK via binding to a transmembrane adaptor known as phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG). The lack of a blatant phenotype in PAG-deficient mice has impeded our understanding of the mechanisms through which PAG exerts its negative-regulatory role in TCR signaling. We used quantitative mass spectrometry and both thymocytes and CD4(+) T cells from mice in which a tag for affinity purification was knocked in the gene coding for PAG to determine the composition and dynamics of the multiprotein complexes that are found around PAG over 5 min of activation. Most of the high-confidence interactions that we observed were previously unknown. Using phosphoproteomic analysis, PAG showed low levels of tyrosine phosphorylation in resting primary mouse CD4(+) T cells; the levels of tyrosine phosphorylation increased and reached a maximum 2 min after stimulation. Analysis of the dynamics of association of the protein tyrosine phosphatase PTPN22 and lipid phosphatase SHIP-1 with PAG following T cell activation suggests that both cooperate with CSK to terminate T cell activation. Our findings provide a model of the role for PAG in mouse primary CD4(+) T cells that is consistent with recent phosphoproteomic studies of the Jurkat T cell line but difficult to reconcile with former biochemical studies indicating that PAG is constitutively phosphorylated in resting T cells and rapidly dephosphorylated once the TCR is engaged. PMID- 26512139 TI - Development and Characterization of Monoclonal Antibodies Specific for Mouse and Human Fcgamma Receptors. AB - FcgammaRs are key regulators of the immune response, capable of binding to the Fc portion of IgG Abs and manipulating the behavior of numerous cell types. Through a variety of receptors, isoforms, and cellular expression patterns, they are able to fine-tune and direct appropriate responses. Furthermore, they are key determinants of mAb immunotherapy, with mAb isotype and FcgammaR interaction governing therapeutic efficacy. Critical to understanding the biology of this complex family of receptors are reagents that are robust and highly specific for each receptor. In this study, we describe the development and characterization of mAb panels specific for both mouse and human FcgammaR for use in flow cytometry, immunofluorescence, and immunocytochemistry. We highlight key differences in expression between the two species and also patterns of expression that will likely impact on immunotherapeutic efficacy and translation of therapeutic agents from mouse to clinic. PMID- 26512140 TI - CCR5-Delta32 Heterozygosity, HIV-1 Reservoir Size, and Lymphocyte Activation in Individuals Receiving Long-term Suppressive Antiretroviral Therapy. AB - We conducted a case-controlled study of the associations of CCR5-Delta32 heterozygosity with human immunodeficiency virus type 1 (HIV-1) reservoir size, lymphocyte activation, and CCR5 expression in 114 CCR5(Delta32/WT) and 177 wild type CCR5 AIDS Clinical Trials Group participants receiving suppressive antiretroviral therapy. Overall, no significant differences were found between groups for any of these parameters. However, higher levels of CCR5 expression correlated with lower amounts of cell-associated HIV-1 RNA. The relationship between CCR5-Delta32 heterozygosity, CCR5 expression, and markers of HIV-1 persistence is likely to be complex and may be influenced by factors such as the duration of ART. PMID- 26512141 TI - Decreased Flight Activity in Culex pipiens (Diptera: Culicidae) Naturally Infected With Culex flavivirus. AB - Insect-specific flaviviruses (ISFVs) commonly infect vectors of mosquito-borne arboviruses. To investigate whether infection with an ISFV might affect mosquito flight behavior, we quantified flight behavior in Culex pipiens L. naturally infected with Culex flavivirus (CxFV). We observed a significant reduction in the scotophase (dark hours) flight activity of CxFV-positive mosquitoes relative to CxFV-negative mosquitoes, but only a marginal reduction in photophase (light hours) flight activity, and no change in the circadian pattern of flight activity. These results suggest that CxFV infection alters the flight activity of naturally infected Cx. pipiens most dramatically when these vectors are likely to be host seeking and may therefore affect the transmission of medically important arboviruses. PMID- 26512142 TI - Consistent individual differences in the social phenotypes of wild great tits, Parus major. AB - Despite growing interest in animal social networks, surprisingly little is known about whether individuals are consistent in their social network characteristics. Networks are rarely repeatedly sampled; yet an assumption of individual consistency in social behaviour is often made when drawing conclusions about the consequences of social processes and structure. A characterization of such social phenotypes is therefore vital to understanding the significance of social network structure for individual fitness outcomes, and for understanding the evolution and ecology of individual variation in social behaviour more broadly. Here, we measured foraging associations over three winters in a large PIT-tagged population of great tits, and used a range of social network metrics to quantify individual variation in social behaviour. We then examined repeatability in social behaviour over both short (week to week) and long (year to year) timescales, and investigated variation in repeatability across age and sex classes. Social behaviours were significantly repeatable across all timescales, with the highest repeatability observed in group size choice and unweighted degree, a measure of gregariousness. By conducting randomizations to control for the spatial and temporal distribution of individuals, we further show that differences in social phenotypes were not solely explained by within-population variation in local densities, but also reflected fine-scale variation in social decision making. Our results provide rare evidence of stable social phenotypes in a wild population of animals. Such stable social phenotypes can be targets of selection and may have important fitness consequences, both for individuals and for their social-foraging associates. PMID- 26512143 TI - Electrocardiographic findings in pulmonary embolism. AB - Pulmonary embolism (PE) poses a challenge to physicians, as it can be difficult to diagnose but results in significant mortality and morbidity in patients. Diagnosing PE requires an integrated approach using clinical findings, electrocardiography (ECG), blood investigations and imaging modalities. Abnormalities in ECG are common among patients with massive acute PE and can serve as a prognostic indicator. In this article, we describe the ECG presentations of two patients diagnosed with PE, and review the literature on the various types of ECG presentations and their role in predicting the prognosis of PE. PMID- 26512144 TI - A practical approach to perioperative management of cardiac implantable electronic devices. AB - With the increased use of cardiac implantable electronic devices (CIEDs), it is increasingly important to recognise the unique challenges involved in the management of patients with CIEDs who are undergoing surgery. Practice advisories and consensus statements have been issued by the American Society of Anesthesiologists and the Heart Rhythm Society, advocating a multidisciplinary approach. This review discusses and presents a practical approach to perioperative CIED management in the Singapore context. PMID- 26512145 TI - Clinics in diagnostic imaging (163). Transient lateral patellar dislocation with trochlear dysplasia. AB - A 14-year-old girl presented with left knee pain and swelling after an injury. Magnetic resonance (MR) imaging showed a transient lateral patellar dislocation with patellar osteochondral fracture, medial patellofemoral ligament tear and underlying femoral trochlear dysplasia. Open reduction and internal fixation of the osteochondral fracture, plication of the medial patellar retinaculum and lateral release were performed. As lateral patellar dislocation is often clinically unsuspected, an understanding of its characteristic imaging features is important in making the diagnosis. Knowledge of the various predisposing factors for patellar instability may also influence the choice of surgical management. We also discuss signs of acute injury and chronic instability observed on MR imaging, and the imaging features of anatomical variants that predispose an individual to lateral patellar dislocation. Treatment options and postsurgical imaging appearances are also briefly described. PMID- 26512146 TI - Incidence of postoperative wound infections after open tendo Achilles repairs. AB - INTRODUCTION: Tendo Achilles (TA), which is the confluence of the gastrocnemius and soleus muscles, is one of the most commonly injured tendons. The surgical repair of TA ruptures is associated with a significant risk of infection. This study examined several factors (i.e. gender, age, body mass index, history of diabetes mellitus, steroid use, acute or chronic TA injuries, type of surgical incision and type of sutures used) that may be associated with postoperative wound infection after open TA repair. METHODS: This was a retrospective study involving 60 patients who underwent open TA repair over an 18-month period. Patients who had prior TA surgery or open TA injuries, or who needed soft tissues flaps were excluded. RESULTS: Among the patients, 7 (11.7%) developed superficial wound infections that were successfully treated with oral antibiotics, while 3 (5.0%) developed deep wound infections that required at least one debridement procedure. No significant association was found between the risk of postoperative wound infection and gender, age, the presence of diabetes mellitus, acute or chronic ruptures, site of surgical incision and type of deep or superficial sutures used. CONCLUSION: While diabetes mellitus and age did not appear to be associated with postoperative wound infections after open TA repair, obese patients were found to be two times more likely to develop a wound infection than normal-weight patients. The incidence of superficial wound infections in this study was similar to previously published results (11.7% vs. 8.2%-14.6%), but the incidence of deep infections was higher (5% vs. 1%-2%). PMID- 26512147 TI - Intramuscular schwannoma: clinical and magnetic resonance imaging features. AB - INTRODUCTION: Schwannomas that arise within the muscle plane are called intramuscular schwannomas. The low incidence of these tumours and the lack of specific clinical features make preoperative diagnosis difficult. Herein, we report our experience with intramuscular schwannomas. We present details of the clinical presentation, radiological diagnosis and management of these tumours. METHODS: Between January 2011 and December 2013, 29 patients were diagnosed and treated for histologically proven schwannoma at the National University Hospital, Singapore. Among these 29 patients, eight (five male, three female) had intramuscular schwannomas. RESULTS: The mean age of the eight patients was 40 (range 27-57) years. The most common presenting feature was a palpable mass. The mean interval between surgical treatment and the onset of clinical symptoms was 17.1 (range 4-72) months. Six of the eight tumours (75.0%) were located in the lower limb, while 2 (25.0%) were located in the upper limb. None of the patients had any preoperative neurological deficits. Tinel's sign was present in one patient. Magnetic resonance (MR) imaging showed that the findings of split-fat sign, low signal margin and fascicular sign were present in all patients. The entry and exit sign was observed in 4 (50.0%) patients, a hyperintense rim was observed in 7 (87.5%) patients and the target sign was observed in 5 (62.5%) patients. All patients underwent microsurgical excision of the tumour and none developed any postoperative neurological deficits. CONCLUSION: Intramuscular schwannomas demonstrate the findings of split-fat sign, low signal margin and fascicular sign on MR imaging. These findings are useful for the radiological diagnosis of intramuscular schwannoma. PMID- 26512148 TI - Clinical presentations as predictors of prolonged mechanical ventilation in Guillain-Barre syndrome in an institution with limited medical resources. AB - INTRODUCTION: Severe Guillain-Barre syndrome (GBS) causes ventilatory insufficiency and the need for prolonged artificial ventilation. Under circumstances where medical care for patients with severe GBS is required in a resource-limited institution, identifying initial clinical presentations in GBS patients that can predict respiratory insufficiency and the need for prolonged mechanical ventilation (> 15 days) may be helpful for advanced care planning. METHODS: The medical records of patients diagnosed with GBS in a tertiary care and medical teaching hospital from January 2001 to December 2010 were retrospectively reviewed. The demographic data and clinical presentations of the patients were summarised using descriptive statistics. Clinical predictors of respiratory insufficiency and the need for prolonged mechanical ventilation (> 15 days) were identified using univariate logistic regression analysis. RESULTS: A total of 55 patients with GBS were included in this study. Mechanical ventilation was needed in 28 (50.9%) patients. Significant clinical predictors for respiratory insufficiency were bulbar muscle weakness (odds ratio [OR] 5.08, 95% confidence interval [CI] 1.31-21.60, p = 0.007) and time to peak limb weakness <= 5 days (OR 0.75, 95% CI 0.62-0.91, p < 0.001). Bulbar muscle weakness (p = 0.006) and time to peak limb weakness <= 5 days (p < 0.001) were also found to be significantly associated with the need for prolonged mechanical ventilation (> 15 days). CONCLUSION: Bulbar weakness and time to peak limb weakness <= 5 days were able to predict respiratory insufficiency and the need for prolonged mechanical ventilation in patients with GBS. PMID- 26512149 TI - Comparison of the therapeutic effects of Garcin((r)) and fluconazole on Candida vaginitis. AB - INTRODUCTION: This study aimed to determine and compare the effects of garlic tablets (Garcin((r))) and fluconazole on Candida vaginitis in women who presented to a health centre in Koohdasht, Iran, from August 2011 to March 2012. METHODS: The clinical trial was conducted on 110 married women (aged 18-44 years) who had complaints of itching or a burning sensation in the vaginal area. Candida vaginitis was diagnosed by pH measurement of vaginal secretions, direct microscopic evaluation and Sabouraud dextrose agar cultures of the vaginal discharge. On confirmation of diagnosis, the patients were randomly divided into two groups (n = 55). One group received 1,500 mg of Garcin tablets daily and the other received fluconazole tablets 150 mg daily, over a period of seven days. Four to seven days after the completion of treatment, patients were examined for treatment response and possible side effects. RESULTS: Complaints related to the disease improved by about 44% in the Garcin group and 63.5% in the fluconazole group (p < 0.05). The overall symptoms of the disease (i.e. redness of vulva and vagina, cheesy discharge, pustulopapular lesions and abnormal cervix) improved by about 60% in the Garcin group and 71.2% in the fluconazole group (p > 0.05). Results of microscopic evaluation and vaginal discharge culture showed significant differences before and after intervention in both groups (p < 0.05). CONCLUSION: The present study shows that Garcin tablets could be a suitable alternative to fluconazole for the treatment of Candida vaginitis. PMID- 26512150 TI - Effect of a high fat diet on ovary morphology, in vitro development, in vitro fertilisation rate and oocyte quality in mice. AB - INTRODUCTION: The aim of this study was to determine the effect of a high-fat diet (HFD) on oocyte maturation and quality in a mouse model. METHODS: Female BALB/c mice were allocated to one of the following groups: (a) control group (n = 40), which received a controlled diet; or (b) HFD group (n = 40), which received an HFD for 12 weeks. Sections of the ovary were examined histologically. The number of follicles and corpora lutea were counted. In vitro maturation and in vitro fertilisation (IVF) were assessed in germinal vesicle (GV) and metaphase II (MII) oocytes, respectively. The expression of bone morphogenetic protein 15 (BMP15) and leptin receptor genes in GV and MII oocytes was evaluated using reverse transcription real-time polymerase chain reactions. RESULTS: In the HFD group, there was a decreased number of primordial and Graafian follicles, as well as corpora lutea (p < 0.05). The rate of oocyte development to the MII stage was also reduced (p < 0.001). Cumulus expansion was observed more frequently in the control group than the HFD group (p < 0.05). The IVF rate in the HFD group was lower than that in the control group (p < 0.05). In the HFD group, BMP15 and leptin receptor genes were upregulated in the GV stage (p > 0.05) and MII stage (p < 0.05), compared to the control group. CONCLUSION: An HFD reduces folliculogenesis in the primordial and Graafian stages, in vitro maturation and in vitro fertilisation rates, as well as oocyte quality in mice. PMID- 26512151 TI - Initial experience of subcutaneous implantable cardioverter defibrillators in Singapore: a case series and review of the literature. AB - Transvenous implantable cardioverter defibrillators are a type of implantable cardiac device. They are effective at reducing total and arrhythmic mortality in patients at risk of sudden cardiac death. Subcutaneous implantable cardioverter defibrillators (S-ICDs) are a new alternative that avoids the disadvantages of transvenous lead placement. In this case series, we report on the initial feasibility and safety of S-ICD implantation in Singapore. PMID- 26512152 TI - George Papanicolaou (1883-1962): Discoverer of the Pap smear. PMID- 26512153 TI - Comment on: Vitamin D deficiency. PMID- 26512154 TI - Authors' reply: Vitamin D deficiency. PMID- 26512155 TI - Superficial siderosis of the central nervous system with seizures onset. PMID- 26512156 TI - Wavelet-Based Scalar-on-Function Finite Mixture Regression Models. AB - Classical finite mixture regression is useful for modeling the relationship between scalar predictors and scalar responses arising from subpopulations defined by the di ering associations between those predictors and responses. The classical finite mixture regression model is extended to incorporate functional predictors by taking a wavelet-based approach in which both the functional predictors and the component-specific coefficient functions are represented in terms of an appropriate wavelet basis. By using the wavelet representation of the model, the coefficients corresponding to the functional covariates become the predictors. In this setting, there are typically many more predictors than observations. Hence a lasso-type penalization is employed to simultaneously perform feature selection and estimation. Specification of the model is discussed and a fitting algorithm is provided. The wavelet-based approach is evaluated on synthetic data as well as applied to a real data set from a study of the relationship between cognitive ability and di usion tensor imaging measures in subjects with multiple sclerosis. PMID- 26512157 TI - The effect of a sentence comprehension treatment on discourse comprehension in aphasia. AB - BACKGROUND: While it is well understood that individuals with aphasia have difficulty with discourse comprehension, very few studies have examined the nature of discourse comprehension deficits in aphasia and the potential for improvement in discourse comprehension after rehabilitation. To address the first goal, we previously developed the Test of Syntactic Effects on Discourse Comprehension (TSEDC), which provides a measure of the extent to which a participant's sentence comprehension ability aids in comprehending passages (Levy et al., 2012). AIMS: The goal of this study was to examine the effect of a sentence comprehension treatment on the TSEDC to assess if training participants to understand sentences of different syntactic complexity would improve their ability to understand passages that vary by their level of syntactic complexity. METHODS & PROCEDURES: Forty participants with aphasia received sentence comprehension treatment using one of two syntactic comprehension tasks: object manipulation (OM) or sentence to picture matching (SPM). The dependent measure was improved sentence comprehension of one sentence type in one task-related protocol, with the order of task and structure counterbalanced across participants. Before and after treatment, participants also completed a self paced auditory story comprehension task which involved 9 passages that contained either semantically reversible canonical sentences (simple passages) or semantically reversible noncanonical sentences (complex passages). At the end of each passage, participants were asked explicit or implicit questions about the story. Accuracy and reaction times were measured for each patient for each story before and after treatment. OUTCOMES & RESULTS: Analysis of the treatment data revealed that participants improved in their ability to understand trained sentences (both in terms of effect size and percent change on trained structure), irrespective of whether the trained task was SPM or OM. There was no significant relationship between treatment improvements on the SPM/OM treatment (even when the task targeted in treatment was controlled for) and changes in performance on the TSEDC. Also, there was no significant improvement in TSEDC accuracy after treatment, even when various aspects of the narrative passages, including passage complexity (simple/complex), the nature of sentence type (semantically constrained/semantically reversible) and the nature of questions asked (explicit or implicit) were accounted for. CONCLUSIONS: Inherent differences between the sentence comprehension treatment and the TSEDC may have precluded generalization. PMID- 26512158 TI - Miniature Dual-Corona Ionizer for Bipolar Charging of Aerosol. AB - A corona-based bipolar charger has been developed for use in compact, field portable mobility size spectrometers. The charger employs an aerosol flow cavity exposed to two corona ionizers producing ions of opposite polarity. Each corona ionizer houses two electrodes in parallel needle-mesh configuration and is operated at the same magnitude of corona current. Experimental measurement of detailed charge distribution of near-monodisperse particles of different diameter in the submicrometer size range showed that the charger is capable of producing well-defined, consistent bipolar charge distributions for flow rates up to 1.5 L/min and aerosol concentration up to 107 per cm3. For particles with preexisting charge of +1, 0, and -1, the measured charge distributions agreed well with the theoretical distributions within the range of experimental and theoretical uncertainties. The transmission efficiency of the charger was measured to be 80% for 10 nm particles (at 0.3 L/min and 5 MUA corona current) and increased with increasing diameter beyond this size. Measurement of uncharged fractions at various combinations of positive and negative corona currents showed the charger performance to be insensitive to fluctuations in corona current. Ion concentrations under positive and negative unipolar operation were estimated to be 8.2 * 107 and 3.37 * 108 cm-3 for positive and negative ions; the n.t product value under positive corona operation was independently estimated to be 8.5 * 105 s/cm3. The ion concentration estimates indicate the charger to be capable of "neutralizing" typical atmospheric and industrial aerosols in most measurement applications. The miniature size, simple and robust operation makes the charger suitable for portable mobility spectrometers. PMID- 26512159 TI - Finding Bayesian Optimal Designs for Nonlinear Models: A Semidefinite Programming Based Approach. AB - This paper uses semidefinite programming (SDP) to construct Bayesian optimal design for nonlinear regression models. The setup here extends the formulation of the optimal designs problem as an SDP problem from linear to nonlinear models. Gaussian quadrature formulas (GQF) are used to compute the expectation in the Bayesian design criterion, such as D-, A- or E-optimality. As an illustrative example, we demonstrate the approach using the power-logistic model and compare results in the literature. Additionally, we investigate how the optimal design is impacted by different discretising schemes for the design space, different amounts of uncertainty in the parameter values, different choices of GQF and different prior distributions for the vector of model parameters, including normal priors with and without correlated components. Further applications to find Bayesian D-optimal designs with two regressors for a logistic model and a two-variable generalised linear model with a gamma distributed response are discussed, and some limitations of our approach are noted. PMID- 26512160 TI - New VLBI2010 scheduling strategies and implications on the terrestrial reference frames. AB - In connection with the work for the next generation VLBI2010 Global Observing System (VGOS) of the International VLBI Service for Geodesy and Astrometry, a new scheduling package (Vie_Sched) has been developed at the Vienna University of Technology as a part of the Vienna VLBI Software. In addition to the classical station-based approach it is equipped with a new scheduling strategy based on the radio sources to be observed. We introduce different configurations of source based scheduling options and investigate the implications on present and future VLBI2010 geodetic schedules. By comparison to existing VLBI schedules of the continuous campaign CONT11, we find that the source-based approach with two sources has a performance similar to the station-based approach in terms of number of observations, sky coverage, and geodetic parameters. For an artificial 16 station VLBI2010 network, the source-based approach with four sources provides an improved distribution of source observations on the celestial sphere. Monte Carlo simulations yield slightly better repeatabilities of station coordinates with the source-based approach with two sources or four sources than the classical strategy. The new VLBI scheduling software with its alternative scheduling strategy offers a promising option with respect to applications of the VGOS. PMID- 26512161 TI - Comparison of Low-Level Laser Therapy versus Ozone Therapy in the Treatment of Oral Lichen Planus. AB - BACKGROUND: The treatment options for oral lichen planus (OLP) are numerous and include topical and systemic agents. Intralesional and systemic corticosteroids are used; however, the therapeutic results are often disappointing. OBJECTIVE: To compare the influence of ozone, laser, and topical corticosteroid therapies in the treatment of OLP. METHODS: One hundred twenty adult patients with <=3 cm atrophic-erosive biopsy-proven OLPs in the tongue or buccal mucosa were recruited into the study. They were randomly assigned, by preoperative envelope drawing, to be treated with low-level laser therapy (LLLT group), ozone therapy (ozonated group), and topical corticosteroid therapy (positive control group). A placebo treatment containing base ointment without the active corticosteroid component was administered to patients in the negative control group. Response rate scores were determined on the basis of changes in the appearance score and pain score of the lesions between baseline and after each treatment. RESULTS: The study subjects consisted of 56 male and 64 female OLP patients with a combined mean age of 42.6+/-8.3 years (range, 28~55 years). No statistically significant difference was detected in clinical severity among the groups. The sign scores decreased in almost all scoring groups; however, statistically significant improvement was found in the ozonated and corticosteroid-treated groups. Symptom improvement was achieved after treatment with LLLT, ozone, and corticosteroid (p<0.05). The efficacy indices were significantly higher in the ozonated and corticosteroid treated groups. CONCLUSION: Ozone and corticosteroid therapies were more effective than 808-nm LLLT in the treatment of OLP. PMID- 26512162 TI - Quality of Life Assessment in Korean Patients with Pemphigus. AB - BACKGROUND: Measuring the quality of life (QOL) is important in the evaluation of nonclinical aspects of diseases, for the discovery of functional and psychological limitations, and in choosing treatment in the initial phase of the disease. Pemphigus is a potentially fatal autoimmune bullous disease caused by autoantibodies against desmogleins (cadherin family proteins in desmosomes). Thus far, there has been no published study on QOL in Korean patients with pemphigus. OBJECTIVE: To study the impact of pemphigus on the QOL in a large number of Korean patients. METHODS: Sixty-six patients enrolled at the Gangnam Severance Hospital from March 2012 to March 2013 were assessed for QOL by using the Dermatology Life Quality Index (DLQI), and for anxiety and depression by using the General Health Questionnaire (GHQ). Spearman's rank-order correlation, t test, and ANOVA were used to identify the relations between the DLQI score and other clinical variables. RESULTS: Pemphigus vulgaris and pemphigus foliaceus significantly reduced the QOL of patients. The average DLQI score for all patients was 10.18. The mean DLQI score was 13.45 in patients in the active state and 5.15 in the patients in the remission state. The DLQI score highly correlated with disease severity, titer of anti-desmoglein 1 in enzyme-linked immunosorbent assay, and the corticosteroid dose. However, the QOL was not affected by sex, age, subtype of pemphigus, duration of disease, or comorbidities. Forty-two percent of the patients showed a positive result in the GHQ, reflecting probable minor psychiatric nonpsychotic conditions, and the GHQ score positively correlated to the DLQI score. CONCLUSION: Pemphigus significantly impairs the QOL of patients. The QOL of Korean pemphigus patients significantly correlates with clinical severity. Therefore, considerable attention should be paid to the patients' QOL and psychological states as well as clinical status. PMID- 26512163 TI - Topical Corticosteroid Phobia among Parents of Children with Atopic Eczema in Korea. AB - BACKGROUND: Topical corticosteroids (TCS) are the first-line agents for the treatment of atopic dermatitis (AD). However, a vague phobia concerning the use of TCS exists among parents of children with AD because of misinformation, and studies on the subject are insufficient. OBJECTIVE: To assess the current state of steroid phobia among parents of atopic children in Korea and to investigate the importance of education in its reduction. METHODS: By using a structured questionnaire, 126 parents of children with AD (22.2% fathers, 77.8% mothers) were interviewed. After the questionnaire administration, all participants were educated about TCS use. RESULTS: Overall, 67.5% of the parents showed steroid phobia. A statistical correlation was found between steroid phobia and knowledge of potential adverse events, experience of TCS use, and adherence to treatment (p<0.05). Adherence to treatment tended to be lower among parents with steroid phobia. The most recognized adverse effects of TCS were skin atrophy and thinning (71.9%). The most prevalent information source leading to steroid phobia was the Internet (49.2%). The risk factors for steroid phobia were AD severity (odds ratio [OR]=5.332 [moderate], 9.040 [severe] vs. mild; p=0.001) and the knowledge of potential adverse events (OR=2.658; p=0.021). CONCLUSION: We found a high prevalence of steroid phobia among parents of patients with AD, and here show the impact of this phobia on treatment adherence. We emphasize the important role of dermatologists as providers of accurate information and appropriate education about the use of TCS. PMID- 26512164 TI - Oxidative Damage and Nuclear Factor Erythroid 2-Related Factor 2 Protein Expression in Normal Skin and Keloid Tissue. AB - BACKGROUND: Reactive oxygen species (ROS) play an important role in the induction of apoptosis under pathological conditions. Recently, a significant increase in ROS production and disrupted apoptosis mechanisms in keloids have been reported. Nuclear factor erythroid 2-related factor 2 (Nrf2) represents one of the most important cellular defense mechanisms against oxidative stress and is implicated in the regulation of apoptosis. Recently, it has been reported that Nrf2 upregulates Bcl-2, an anti-apoptotic protein. OBJECTIVE: To compare Nrf2 protein expression in normal skin tissues to keloid tissues. METHODS: ROS generation in keloid tissues was evaluated with OxyBlot analysis. Western blotting and/or immunohistochemical staining approaches were used to study expression of Nrf2 or Bcl-2 in keloid and normal skin tissues. Cellular fractionation was performed to examine subcellular distribution of Nrf2. Transfection of fibroblasts with Nrf2 specific small interfering RNA (siRNA) was conducted to understand the relationship between Nrf2 expression and apoptosis induction. RESULTS: Protein oxidation, a marker of oxidative stress, is increased in keloid tissues. Western blot analysis clearly showed that Nrf2 and Bcl-2 are downregulated in keloid tissues. Immunohistochemical staining of Nrf2 confirmed the results of the western blot analysis. Transfection of fibroblasts with the Nrf2-specific siRNA results in increased apoptosis and decreased cell viability. CONCLUSION: Collectively, our data indicate that Nrf2 expression is downregulated in keloid tissues, and that Nrf2 is involved in the development of apoptosis in Nrf2 siRNA transfected fibroblasts. We propose that a defective antioxidant system and apoptotic dysregulation may participate in keloid pathogenesis. PMID- 26512165 TI - Efficacy and Safety of Hair Removal with a Long-Pulsed Diode Laser Depending on the Spot Size: A Randomized, Evaluators-Blinded, Left-Right Study. AB - BACKGROUND: The efficacy of the long-pulsed diode laser (LPDL) in hair removal is determined with various physical parameters. Recently, LPDLs with a larger spot size are commercially available; however, the independent effect of spot size on hair removal has not been studied. OBJECTIVE: This study aimed to compare the efficacy of the LPDL in hair removal depending on the spot size. METHODS: A randomized, evaluators-blind, intrapatient comparison (left vs. right) trial was designed. Ten healthy Korean women received three hair removal treatment sessions on both armpits with the 805-nm LPDL and followed for 3 months. A 10*10 mm handpiece (D1) or a 10*30 mm handpiece (D3) was randomly assigned to the right or left axilla. The fluence, pulse duration, and epidermal cooling temperature were identical for both armpits. Hair clearance was quantified with high-resolution photos taken at each visit. Postprocedural pain was quantified on a visual analogue scale. Adverse events were evaluated by physical examination and the patients' self-report. RESULTS: The mean hair clearance at 3 months after three treatment sessions was 38.7% and 50.1% on the armpits treated with D1 and D3, respectively (p=0.028). Procedural pain was significantly greater in the side treated with D3 (p=0.009). Serious adverse events were not observed. CONCLUSION: Given that the pulse duration, fluence, and epidermal cooling were identical, the 805-nm LPDL at the three times larger spot size showed an efficacy improvement of 29.5% in axillary hair removal without serious adverse events. PMID- 26512166 TI - Maintenance Therapy of Facial Seborrheic Dermatitis with 0.1% Tacrolimus Ointment. AB - BACKGROUND: Topical calcineurin inhibitors (TCIs) have been successfully used to treat seborrheic dermatitis (SD) patients. Meanwhile, treatment of atopic dermatitis (AD) with low-dose, intermittent TCI has been proved to reduce disease flare-ups. This regimen is known as a maintenance treatment. OBJECTIVE: The aim of this trial was to investigate the efficacy and tolerability of a maintenance treatment with tacrolimus ointment in patients with facial SD. METHODS: During the initial stabilization period, patients with facial SD or AD applied 0.1% tacrolimus ointment twice daily for up to 4 weeks. Clinical measurements were evaluated on either in the whole face or on separate facial regions. When an investigator global assessment score 1 was achieved, the patient applied tacrolimus twice weekly for 20 weeks. We also compared our results with recent published data of placebo controlled study to allow an estimation of the placebo effect. RESULTS: The time to the first relapse during phase II was similar in both groups otherwise significantly longer than the placebo group. The recurrence free curves of two groups were not significantly different from each other; otherwise the curve of the placebo group was significantly different. There were no significant differences between the 2 groups in the number of DEs, and treatment days for disease exacerbations (DEs). The adverse event profile was also similar between the 2 groups. During the 20 weeks of treatment, the study population tolerated tacrolimus ointment well. CONCLUSION: The results of this study suggest that maintenance treatment with tacrolimus may be effective in preventing the occurrence of facial SD exacerbations. PMID- 26512167 TI - Awareness, Knowledge, and Vaccine Acceptability of Herpes Zoster in Korea: A Multicenter Survey of 607 Patients. AB - BACKGROUND: Herpes zoster (HZ) infection can significantly impair the quality of life of the affected individuals, and its treatment imposes a considerable cost burden on the health-care system and on society at large. However, there is little information on the perception of this disease and the acceptability of vaccines in Korea. OBJECTIVE: The aim of this study is to determine the awareness of HZ and its vaccine, and to identify factors associated with the acceptability of the HZ vaccine among outpatients of dermatology clinics. METHODS: A questionnaire-based survey was conducted on 607 outpatients who visited the dermatologic clinics. RESULTS: The responses of the patients revealed a high awareness of HZ (85.4%) but a relatively low knowledge about HZ and its vaccine (42.3%). The HZ vaccination rate among patients aged >=50 years was 9%. A history of HZ infection, being older, and greater knowledge about HZ and its vaccine were associated with a higher HZ vaccine acceptability. Of those who had not been vaccinated, 58.3% were interested in receiving the vaccine. The most frequent reason for this interest was "severe sequelae," followed by "knowing someone who has HZ" and "recommendation from a doctor." High cost was the most common reason for unwillingness to receive the vaccination. CONCLUSION: Despite a high awareness of HZ, vaccine acceptability was extremely low among this study cohort. Vaccination acceptability would be improved by encouraging doctors to educate elderly patients about the disease and the availability of vaccination, and by the provision of insurance coverage for HZ vaccination. PMID- 26512168 TI - Trichoscopic Findings of Hair Loss in Koreans. AB - BACKGROUND: Trichoscopic findings of hair loss have been well described for the differential diagnosis of alopecia; however, critical findings were not thoroughly investigated or compared among all ethnic groups, including Asians. OBJECTIVE: We aimed to find any characteristic trichoscopic findings in Korean alopecia patients and to verify whether those findings are closely related to previously reported observations. METHODS: Three hundred and twenty-seven patients with hair loss of various causes and 160 normal scalps were analyzed. Trichoscopic examination was performed with a polarized-light handheld dermoscope. RESULTS: A total of 35 patterns of trichoscopic features were represented, and certain features were significantly common or observed exclusively in a particular type of alopecia as follows: yellow dots, exclamation mark hairs, and proximal tapering hairs (alopecia areata), trichoptilosis and pointed hairs (trichotillomania), corkscrew hairs, septate hyphae hairs, and comma hairs (tinea capitis), diffuse white area, fibrotic white dots, and tufting hairs (primary cicatricial alopecia), hair diameter diversity and peripilar sign (androgenetic alopecia), and short nonvellus hairs (telogen effluvium). CONCLUSION: The characteristic trichoscopic features for the differential diagnosis of alopecia in Koreans, shown as follicular, perifollicular, and hair shaft patterns, are similar to those of Caucasians; however, the frequencies of the pigment patterns are different between Koreans and Caucasians because of the contrast effect of the skin and hair color. Therefore, racial difference should be considered in the trichoscopic evaluation for differential diagnosis. PMID- 26512169 TI - In Vitro Antimicrobial Activities of Fusidic Acid and Retapamulin against Mupirocin- and Methicillin-Resistant Staphylococcus aureus. AB - BACKGROUND: The in vitro activities of retapamulin and fusidic acid against clinical isolates of mupirocin-resistant and methicillin-resistant Staphylococcus aureus (MRSA) from Korea are not well understood. OBJECTIVE: This study aimed to determine the activities of retapamulin and fusidic acid against clinical isolates of mupirocin-resistant MRSA. METHODS: Clinical isolates of mupirocin resistant MRSA were collected from two tertiary hospitals. The minimal inhibitory concentrations of mupirocin, fusidic acid, and retapamulin were determined using agar dilution method. Polymerase chain reaction was used to confirm the identity of the species and the presence of resistance genes. Pulsed-field gel electrophoresis (PFGE) patterns of chromosomal DNA were used to determine the genetic similarity of high-level mupirocin-resistant isolates. RESULTS: Of the 497 MRSA isolates tested, 22 (4.4%) were mupirocin-resistant. Of these, 9 (1.8%) and 13 (2.6%) had high-level and low-level mupirocin resistance, respectively. Analysis of the PFGE patterns of the high-level mupirocin-resistant MRSA isolates identified five clusters. All 13 of the low-level mupirocin-resistant isolates were resistant to fusidic acid but susceptible to retapamulin. However, among the 9 high-level mupirocin-resistant isolates, 56% were resistant to fusidic acid, and all were susceptible to retapamulin. CONCLUSION: Retapamulin is highly active in vitro against Korean clinical isolates of high-level mupirocinand methicillin resistant Staphylococcus aureus with different genetic backgrounds. Fusidic acid is more active against high-level mupirocin-resistant MRSA than low-level mupirocin-resistant MRSA. PMID- 26512170 TI - Reduction of Inter-Rater and Intra-Rater Variability in Psoriasis Area and Severity Index Assessment by Photographic Training. AB - BACKGROUND: Severity grading is important for the assessment of psoriasis treatment efficacy. This is most commonly achieved by using the psoriasis area and severity index (PASI), a subjective tool with inherent inter-rater and intra rater variability. PASI-naive dermatologists require training to properly conduct a PASI assessment. OBJECTIVE: In the present study, we aimed to investigate whether photographic training improves inter-rater and intra-rater variabilities. We also determined which PASI component has the greatest impact on variability. METHODS: Twenty-one dermatologists received 1 hour of PASI training. They were tested before and after the training to evaluate intra-rater variability. The physicians were further tested after training by using a reference photograph. RESULTS: The mean of each PASI component was underevaluated compared with scoring by a PASI expert. The concordance rate with the expert's grading was highest for thickness followed by erythema, scaling, and area. The scaling score showed the greatest improvement after training. After training, the distribution of deviation from the expert's grading, which signifies inter-rater variability, improved only for the PASI area component. The deviation of scaling grading improved upon retesting by using a reference photograph. CONCLUSION: PASI assessment training improved variabilities to some degree but not for every PASI component. The development of an objective psoriasis severity assessment tool will help overcome the subjective variabilities in PASI assessment, which can never be completely eliminated via training. PMID- 26512171 TI - Consensus Guidelines for the Treatment of Atopic Dermatitis in Korea (Part I): General Management and Topical Treatment. AB - BACKGROUND: Since the treatment guidelines for atopic dermatitis (AD) were released by the Korean Atopic Dermatitis Association (KADA) work group in 2006, there have been several advances in AD management. OBJECTIVE: We aimed to establish updated evidence- and experience-based treatment guidelines for Korean AD. METHODS: We collected a database of references from relevant systematic AD reviews and guidelines regarding general AD management such as bathing and skin care, avoidance of exacerbating factors, education and psychosocial support, and the use of moisturizers and topical anti-inflammatory and antipruritic drugs. Evidence for each statement was graded and the strength of the recommendation for each statement classified. Thirty-nine KADA council members participated in three rounds of voting to establish an expert consensus of recommendations. RESULTS: Basic AD treatment includes proper bathing and skin care, avoidance of exacerbating factors, proper education and psychosocial support, and use of moisturizers. The regular use of moisturizer has a steroid-sparing effect and reduces relapse episodes. The short- and long-term use of topical corticosteroids and calcineurin inhibitors improves AD symptoms and should be encouraged to use in an active and proactive treatment. Wet-wrap therapy can be used for rapid recovery of acute exacerbation. Topical antipruritic drugs cannot be recommended for the treatment of AD. CONCLUSION: This report provides up-to-date evidence- and experience-based treatment guidelines for AD regarding general management and topical treatment. In addition, the average agreement scores obtained by a panel of experts based on the Korean healthcare system and patient adherence are presented. PMID- 26512172 TI - Consensus Guidelines for the Treatment of Atopic Dermatitis in Korea (Part II): Systemic Treatment. AB - BACKGROUND: Since the treatment guidelines for atopic dermatitis (AD) were issued by the Korean Atopic Dermatitis Association (KADA) work group in 2006, there have been further advances in the systemic treatment of AD. OBJECTIVE: We aimed to establish updated evidence- and experience-based systemic treatment guidelines for Korean AD. METHODS: We compiled a database of references from relevant systematic reviews and guidelines regarding the systemic management of AD, including antihistamines, antimicrobials, systemic immunomodulators, allergen specific immunotherapy, phototherapy, adjunctive treatment, and complementary and alternative medicines. Evidence for each statement was graded and classified based on the strength of the recommendation. Thirty-nine council members of KADA participated in the three rounds of votes and expert consensus recommendations were established. RESULTS: The use of antihistamines is recommended to relieve pruritus and to prevent exacerbation due to scratching in AD patients. Infection should be controlled as needed and long-term medication should be avoided. For moderate to severe AD patients, concomitant active treatments with systemic immunomodulators are indicated. Cyclosporine is the first choice among systemic immunomodulators and others should be considered as second-line alternatives. Allergen-specific immunotherapy could be effective in AD patients with aeroallergen hypersensitivity. Phototherapy can be useful for moderate to severe AD patients and narrow-band ultraviolet B is the most effective option. Complementary and alternative medicines cannot be recommended for treating AD. CONCLUSION: We expect these recommendations to be a reference guide for physicians and AD patients in choosing the appropriate treatment to improve quality of life and decrease unnecessary social medical costs. PMID- 26512173 TI - Folliculocystic and Collagen Hamartoma: A New Entity? AB - Folliculocystic and collagen hamartoma is a newly described complex hamartoma characterized by abundant collagen deposition, concentric perifollicular fibrosis, and keratin- filled infundibular cysts that are visible on histopathological examination. Here, we report the case of a 19-year-old Korean man who had large brownish infiltrated plaques with numerous follicular comedo like openings and subcutaneous cystic masses on his right temporal scalp and ear since birth. Histopathological examination showed abundant collagen deposition in the dermis that extended up to the subcutaneous fat layer, multifocal infundibular cysts packed with keratin, and perifollicular inflammation and fibrosis. Hence, we describe a new type of hamartoma with folliculocystic and collagen components but without tuberous sclerosis. PMID- 26512174 TI - Congenital Dermatofibrosarcoma Protuberans: A Case Report and Literature Review. AB - Congenital dermatofibrosarcoma protuberans (DFSP) is an extremely rare skin tumor that is commonly misdiagnosed, or is often diagnosed long after the initial presentation. Although many cases of DFSP are diagnosed in adulthood, there are some differences between adult DFSP and congenital DFSP. We report a case of congenital DFSP that was initially misdiagnosed as a simple vascular lesion. The delay in diagnosis led to the considerable growth of the lesion, such that a huge scar was left after the surgical treatment. The major differences between adult and congenital DFSP are discussed through a literature review. Clinicians should be aware of the characteristics of congenital DFSP, to reduce misdiagnosis and the delay of diagnosis from the initial presentation. PMID- 26512175 TI - Composite Tumor Associating Trichoblastoma and Seborrheic Keratosis. AB - Seborrheic keratosis is a common benign epidermal tumor histologically composed of basaloid and squamous cells. It mainly occurs on the face, scalp, and trunk, and presents clinically as a well-circumscribed, brownish to black papule, nodule, or plaque. Trichoblastoma is a relatively rare benign, slow-growing tumor showing differentiation toward the primitive hair follicle. It clinically manifests as a solitary, skin to erythematous colored, well-circumscribed dermal nodule located predominantly on the head and neck with a predilection for the scalp. Histologically, a well-demarcated mass of follicular germinative cells that show various degrees of differentiation, arranged in lobules, sheets, and nests, is located in the dermis or subcutaneous fat layer. We report the case of a 28-year-old female patient with a solitary, 2.0*4.0-cm black plaque with a 0.7 cm skin-colored nodule on the scalp. Histologically, the entire black plaque had prominent hyperkeratosis, acanthosis, and papillomatosis with horn cysts. The central nodule showed well-circumscribed, various-sized dermal tumor lobules without a connection to the overlying epidermis. The lobular aggregation was composed of numerous basaloid epithelial nests and multiple primitive papillary structures with distinct peripheral palisading of nuclei. According to these findings, the scalp lesion was diagnosed as a composite tumor associating trichoblastoma and seborrheic keratosis. PMID- 26512176 TI - Nodular Vasculitis That Developed during Etanercept (Enbrel) Treatment in a Patient with Psoriasis. AB - Nodular vasculitis was introduced by Montgomery for cases of erythema induratum like lesions that were not associated with tuberculosis. Nodular vasculitis has been associated with both nontuberculous infections and noninfectious conditions. However, there has been no report on the development of nodular vasculitis during tumor necrosis factor-alpha inhibitor treatment. A 28-year-old man visited our clinic for the treatment of severe psoriasis with a 20-year history. Subcutaneous injection of etanercept (25 mg, twice weekly) was started. One year later, erythematous nodules developed on his lower leg. A skin biopsy showed lobular panniculitis with extensive necrosis and vasculitis. To exclude latent tuberculosis, an assay specific for Mycobacterium tuberculosis antigens was performed, with a negative result. After stopping etanercept under the diagnosis of nodular vasculitis associated with etanercept, the lesions gradually disappeared, leaving depressed scars in 3 months. There has been no recurrence after 6 months of follow-up. PMID- 26512177 TI - Preceding Annular Skin Lesions in a Patient with Hemophagocytic Lymphohistiocytosis. AB - The cutaneous manifestations of hemophagocytic lymphohistiocytosis (HLH) are variable and nonspecific. A 42-year-old man presented with multiple annular, erythematous patches on the trunk for 3 months. Two months later, he presented with bullae along with high fever. The laboratory examination showed pancytopenia, hypertriglyceridemia, and hypofibrinogenemia. The bone marrow biopsy specimen showed an active hemophagocytosis. On the basis of these findings, a diagnosis of HLH was concluded. After five cycles of chemotherapy, his skin lesion completely resolved. Taking the results together, we suggest that annular skin lesion can be added to the list of cutaneous manifestations of HLH. PMID- 26512178 TI - Multiple Autoimmune Skin Manifestations in a Patient with Crohn's Disease Treated with a Tumor Necrosis Factor-Alpha Blocker. PMID- 26512179 TI - Successful Treatment of Livedoid Vasculitis with Primary Antiphospholipid Syndrome by Using Aspirin and Low Dose Warfarin Combination Therapy. PMID- 26512180 TI - Generalized Pustulosis Diagnosed as Acute Generalized Exanthematous Pustulosis: Tzanck Smear and Pathological Evaluation of the Pustule Roof Can Provide Evidence for Early Diagnosis. PMID- 26512181 TI - CD56-Negative Extranodal NK/T-Cell Lymphoma, Nasal Type, with Extranasal Cutaneous Involvement. PMID- 26512182 TI - Development of Vitiligo during Treatment with Adalimumab: A Plausible or Paradoxical Response? PMID- 26512183 TI - Adult Multiple Myofibromas on an Atrophic Patch on the Thigh. PMID- 26512184 TI - Pyodermatitis-Pyostomatitis Vegetans Associated with Crohn's Disease. PMID- 26512185 TI - Possible Involvement of Keratinocyte Growth Factor in the Persistence of Hyperpigmentation in both Human Facial Solar Lentigines and Melasma. PMID- 26512186 TI - A Case of Focal Eosinophilic Myositis Associated with Hypereosinophilic Syndrome: A Rare Case Report. PMID- 26512187 TI - Psoriatic Arthritis Complicating Systemic Sclerosis: Possible Involvement of M2 Macrophages. PMID- 26512188 TI - A Case of Multiple Epidermolytic Acanthoma of the Scrotum: Is the Human Papillomavirus a Culprit? PMID- 26512189 TI - Creeping Hair in the Beard Area. PMID- 26512190 TI - Hypertrichosis and Hyperpigmentation in the Periocular Area Associated with Travoprost Treatment. PMID- 26512191 TI - Mycobacterium marinum Infection on the Face Diagnosed by Polymerase Chain Reaction Amplification and Direct Sequencing. PMID- 26512192 TI - Imatinib Mesylate-Induced Erythema Multiforme: Recurrence after Rechallenge with 200 mg/day Imatinib. PMID- 26512193 TI - A Giant, Deep, Benign Fibrous Histiocytoma with a Palisading Pattern. PMID- 26512194 TI - Male Cohabiting Partners as Primary Coparents in Low-Income Black Stepfamilies. AB - Male cohabiting partners in low-income urban Black single mother families may represent an extreme case of stepfathers who have been characterized as "polite strangers" in the household. The purpose of this study was twofold: To examine who serves as a coparent in these families; and to determine if identification of a coparent in addition to or instead of the MCP would be associated with the level of MCP involvement in the family. Participants were 121 mothers and adolescents from cohabiting families. The MCP was identified as a coparent in 75% of the families, an additional coparent was identified in only 30% of the families, and, when the MCP did not serve as a coparent, another individual was identified in this role in only 24% of the families. The identification of an MCP as a coparent was associated with higher levels of MCP childrearing activities, coparenting support provided by the MCP, and relationship quality with the mother relative to no coparent being identified. The identification of another coparent in addition to the MCP was not associated with changes in the higher levels of family involvement found when the MCP was a coparent. The importance of a male cohabiting partner for coparenting of an adolescent is emphasized in the discussion of the findings. PMID- 26512195 TI - Intergenerational Transmission of Externalizing Behavior. AB - This prospective longitudinal investigation examined the predictors of generation 2 (G2) parental substance use as related to their generation 3 (G3) offspring's externalizing behavior. The sample comprised 281 mother- or father- child (G2/G3) pairs. The results indicated that the G1/G2 (generations 1 and 2) parent-child relationship during G2's adolescence predicted externalizing behavior in the G2 young adults which correlated with G2 parental substance use. G2 parental substance use was related to subsequent G2 substance use disorders (SUDS), and to the G2/G3 parent-child relationship. The G2/G3 parent-child relationship and G2's SUDS each predicted G3 externalizing behavior. The results highlight the significance of breaking the chain of transmission of externalizing behavior across generations. Implications for policy and programs addressing the etiology of externalizing behavior in the offspring are discussed within a developmental framework. PMID- 26512196 TI - Moving back: The radiation dose received from lumbar spine quantitative fluoroscopy compared to lumbar spine radiographs with suggestions for dose reduction. AB - PURPOSE: Quantitative fluoroscopy is an emerging technology for assessing continuous inter-vertebral motion in the lumbar spine, but information on radiation dose is not yet available. The purposes of this study were to compare the radiation dose from quantitative fluoroscopy of the lumbar spine with lumbar spine radiographs, and identify opportunities for dose reduction in quantitative fluoroscopy. METHODS: Internationally reported dose area product (DAP) and effective dose data for lumbar spine radiographs were compared with the same for quantitative fluoroscopy and with data from a local hospital for functional radiographs (weight bearing AP, lateral, and/or flexion and extension) (n = 27). The effects of procedure time, age, weight, height and body mass index on the fluoroscopy dose were determined by multiple linear regression using SPSS v19 software (IBM Corp., Armonck, NY, USA). RESULTS AND CONCLUSION: The effective dose (and therefore the estimated risk) for quantitative fluoroscopy is 0.561 mSv which is lower than in most published data for lumbar spine radiography. The dose area product (DAP) for sagittal (flexion + extension) quantitative fluoroscopy is 3.94 Gy cm2 which is lower than local data for two view (flexion and extension) functional radiographs (4.25 Gy cm2), and combined coronal and sagittal dose from quantitative fluoroscopy (6.13 Gy cm2) is lower than for four view functional radiography (7.34 Gy cm2). Conversely DAP for coronal and sagittal quantitative fluoroscopy combined (6.13 Gy cm2) is higher than that published for both lumbar AP or lateral radiographs, with the exception of Nordic countries combined data. Weight, procedure time and age were independently positively associated with total dose, and height (after adjusting for weight) was negatively associated, thus as height increased, the DAP decreased. PMID- 26512197 TI - USING THE THEORY OF PLANNED BEHAVIOR TO DETERMINE THE CONDOM USE BEHAVIOR AMONG COLLEGE STUDENTS. AB - The study utilized the Theory of Planned Behavior (TPB) to determine condom use behavior among college students. A total of 218 college students with mean age of 20.9 years old participated in the study. A 32- item cross-sectional survey was administered among the participants. The constructs of attitude towards behavior, perceived behavioral control, and subjective norm (p<0.001) significantly predicted intention to use condoms and they accounted for 64% of the variance. Behavioral intention significantly predicted condom use and it accounted for 15% of the variance. The TPB could be used to guide programs in promoting condom use among college students. PMID- 26512198 TI - B-Cell and Monocyte Contribution to Systemic Lupus Erythematosus Identified by Cell-Type-Specific Differential Expression Analysis in RNA-Seq Data. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by complex interplay among immune cell types. SLE activity is experimentally assessed by several blood tests, including gene expression profiling of heterogeneous populations of cells in peripheral blood. To better understand the contribution of different cell types in SLE pathogenesis, we applied the two methods in cell-type-specific differential expression analysis, csSAM and DSection, to identify cell-type-specific gene expression differences in heterogeneous gene expression measures obtained using RNA-seq technology. We identified B-cell-, monocyte-, and neutrophil-specific gene expression differences. Immunoglobulin-coding gene expression was altered in B-cells, while a ribosomal signature was prominent in monocytes. On the contrary, genes differentially expressed in the heterogeneous mixture of cells did not show any functional enrichment. Our results identify antigen binding and structural constituents of ribosomes as functions altered by B-cell- and monocyte-specific gene expression differences, respectively. Finally, these results position both csSAM and DSection methods as viable techniques for cell-type-specific differential expression analysis, which may help uncover pathogenic, cell-type specific processes in SLE. PMID- 26512199 TI - Machine Learning Methods for Predicting HLA-Peptide Binding Activity. AB - As major histocompatibility complexes in humans, the human leukocyte antigens (HLAs) have important functions to present antigen peptides onto T-cell receptors for immunological recognition and responses. Interpreting and predicting HLA peptide binding are important to study T-cell epitopes, immune reactions, and the mechanisms of adverse drug reactions. We review different types of machine learning methods and tools that have been used for HLA-peptide binding prediction. We also summarize the descriptors based on which the HLA-peptide binding prediction models have been constructed and discuss the limitation and challenges of the current methods. Lastly, we give a future perspective on the HLA-peptide binding prediction method based on network analysis. PMID- 26512200 TI - The Genetic Architecture of Domestication in Animals. AB - Domestication has been essential to the progress of human civilization, and the process itself has fascinated biologists for hundreds of years. Domestication has led to a series of remarkable changes in a variety of plants and animals, in what is termed the "domestication phenotype." In domesticated animals, this general phenotype typically consists of similar changes in tameness, behavior, size/morphology, color, brain composition, and adrenal gland size. This domestication phenotype is seen in a range of different animals. However, the genetic basis of these associated changes is still puzzling. The genes for these different traits tend to be grouped together in clusters in the genome, though it is still not clear whether these clusters represent pleiotropic effects, or are in fact linked clusters. This review focuses on what is currently known about the genetic architecture of domesticated animal species, if genes of large effect (often referred to as major genes) are prevalent in driving the domestication phenotype, and whether pleiotropy can explain the loci underpinning these diverse traits being colocated. PMID- 26512201 TI - Molecular Assay and Genotyping of Hepatitis C Virus among Infected Egyptian and Saudi Arabian Patients. AB - Hepatitis C virus (HCV) infection is a major health problem recognized globally. HCV is a common cause of liver fibrosis that may lead to liver cirrhosis or hepatocellular carcinoma. The aim of this study was to estimate the prevalence of HCV infection and genotyping among Egyptian and Saudi Arabian chronic patients using different molecular techniques. HCV RNA viral load was assessed by real time polymerase chain reaction (RT-PCR) technology. For HCV genotyping, RT-PCR hybridization fluorescence-based method and reverse hybridization line probe assay (INNO-LiPA) were used. A total of 40 anti-HCV-positive patients with chronic hepatitis C were examined for HCV RNA, genotyping, and different laboratory investigations. In the present study, HCV genotypes 4, mixed 4.1b, and 1 were detected in patients of both countries, while genotype 2 was only detected in Saudi Arabian patients. Genotyping methods for HCV showed no difference in the classification at the genotype level. With regard to HCV subtypes, INNO-LiPA assay was a reliable test in HCV genotyping for the detection of major genotypes and subtypes, while RT-PCR-based assay was a good test at the genotype level only. HCV genotype 4 was found to be the predominant genotype among Egyptian and Saudi Arabian chronic patients. In conclusion, data analysis for detecting and genotyping HCV was an important factor for understanding the epidemiology and treatment strategies of HCV among Egyptian and Saudi Arabian chronic patients. PMID- 26512202 TI - Birth and Neonatal Outcomes Following Opioid Use in Pregnancy: A Danish Population-Based Study. AB - BACKGROUND: Few population-based data exist on birth outcomes in women who received opioid maintenance treatment during pregnancy. We therefore examined adverse birth outcomes in women exposed to methadone or buprenorphine during pregnancy and the risk of neonatal abstinence syndrome (NAS) among neonates exposed to buprenorphine, methadone, and/or heroin in utero. PATIENTS AND METHODS: This study included all female Danish residents with a live birth or a stillbirth from 1997 to 2011. We identified the study population, use of opioids and opioid substitution treatment, birth outcomes, and NAS through medical registers. Birth outcomes included preterm birth (born before 38th gestational week), low-birth weight (LBW) (<2,500 g, restricted to term births), small for gestational age (SGA) (weight <2 standard deviations from the sex- and gestational-week-specific mean), congenital malformations, and stillbirths. We used log-binomial regression to estimate the prevalence ratio (PR) for birth outcomes. RESULTS: Among 950,172 pregnancies in a total of 571,823 women, we identified 557 pregnancies exposed to buprenorphine, methadone, and/or heroin (167 to buprenorphine, 197 to methadone, 28 to self-reported heroin, and 165 to combinations). Compared with nonexposed pregnancies, prenatal opioid use was associated with greater prevalence of preterm birth (PR of 2.8 (95% confidence interval (CI), 2.3-3.4)), LBW among infants born at term (PR of 4.3 (95% CI, 3.0 6.1)), and being SGA (PR of 2.7 (95% CI, 1.9-4.3)). Restricting the analyses to women who smoked slightly lowered these estimates. The prevalence of congenital malformations was 8.3% in opioid-exposed women compared with 4.2% in nonexposed women (PR of 2.0 (95% CI, 1.5-2.6)). The risk of NAS ranged from 7% in neonates exposed to buprenorphine only to 55% in neonates exposed to methadone only or to opioid combinations. CONCLUSION: The maternal use of buprenorphine and methadone during pregnancy was associated with increased prevalence of adverse birth outcomes, and this increase could only be explained to a smaller extent by increased prevalence of smoking. The risk of NAS was eight-fold higher in methadone-exposed neonates than that in buprenorphine-exposed neonates, but this difference may at least partly be explained by differences in underlying indications (analgesic versus opioid maintenance treatment) between the two groups. PMID- 26512203 TI - To Cause Harm and to be Harmed by Others: New Perspectives on Alcohol's Harms to Others. AB - OBJECTIVE: To examine how sociodemographic factors and alcohol consumption are related to a four-way typology of causing harm to others and/or being harmed by others' and one's own drinking. DATA AND METHODS: Data from the 2011 Danish national survey (n = 2,569) were analyzed with multi nomial logistic regression. RESULTS: Younger age and heavy drinking were significant correlates of both causing harm and being harmed. Women and better educated respondents were more likely to report negative effects on relationship and family from another's drinking. Better educated respondents had higher risks for work, financial, or injury harms from another's drinking. Mean alcohol consumption and risky single occasion drinking were related to both causing harm and being harmed from one's own drinking. CONCLUSIONS: Drinking variables were the strongest correlates of causing harm and being harmed. Efforts to reduce risky drinking may also help reduce exposures to collateral harm. PMID- 26512204 TI - Vannellid Species Isolated from Freshwater Source in a Park in Jamaica, West Indies. AB - Free-living amoebae (FLA) occupy a wide range of freshwater, marine, and soil habitats, and are opportunistic pathogens in human beings. While Acanthamoeba spp., Naegleria fowleri, and Balamuthia mandrillaris are well-known opportunistic organisms, Vannella epipetala is nonpathogenic. Sediments were collected from a freshwater source from a park in Jamaica to investigate the presence of FLA. Acanthamoeba and Naegleria spp. were not recovered; however, a Vannellid species identified by microscopy and PCR analysis as V. epipetala was isolated. These nonpathogens pose a threat to human beings as they may act as Trojan horses for microsporidian parasites and other pathogens, thereby facilitating their transmission to human beings. PMID- 26512205 TI - Mutant K-RAS Promotes Invasion and Metastasis in Pancreatic Cancer Through GTPase Signaling Pathways. AB - Pancreatic ductal adenocarcinoma is one of the most aggressive malignancies, characterized by the local invasion into surrounding tissues and early metastasis to distant organs. Oncogenic mutations of the K-RAS gene occur in more than 90% of human pancreatic cancers. The goal of this study was to investigate the functional significance and downstream effectors of mutant K-RAS oncogene in the pancreatic cancer invasion and metastasis. We applied the homologous recombination technique to stably disrupt K-RAS oncogene in the human pancreatic cell line MiaPaCa-2, which carries the mutant K-RAS (G12C) oncogene in both alleles. Using in vitro assays, we found that clones with disrupted mutant K-RAS gene exhibited low RAS activity, reduced growth rates, increased sensitivity to the apoptosis inducing agents, and suppressed motility and invasiveness. In vivo assays showed that clones with decreased RAS activity had reduced tumor formation ability in mouse xenograft model and increased survival rates in the mouse orthotopic pancreatic cancer model. We further examined molecular pathways downstream of mutant K-RAS and identified RhoA GTP activating protein 5, caveolin 1, and RAS-like small GTPase A (RalA) as key effector molecules, which control mutant K-RAS-dependent migration and invasion in MiaPaCa-2 cells. Our study provides rational for targeting RhoA and RalA GTPase signaling pathways for inhibition of pancreatic cancer metastasis. PMID- 26512206 TI - Drosophila Neuronal Injury Follows a Temporal Sequence of Cellular Events Leading to Degeneration at the Neuromuscular Junction. AB - Neurodegenerative diseases affect millions of people worldwide, and as the global population ages, there is a critical need to improve our understanding of the molecular and cellular mechanisms that drive neurodegeneration. At the molecular level, neurodegeneration involves the activation of complex signaling pathways that drive the active destruction of neurons and their intracellular components. Here, we use an in vivo motor neuron injury assay to acutely induce neurodegeneration in order to follow the temporal order of events that occur following injury in Drosophila melanogaster. We find that sites of injury can be rapidly identified based on structural defects to the neuronal cytoskeleton that result in disrupted axonal transport. Additionally, the neuromuscular junction accumulates ubiquitinated proteins prior to the neurodegenerative events, occurring at 24 hours post injury. Our data provide insights into the early molecular events that occur during axonal and neuromuscular degeneration in a genetically tractable model organism. Importantly, the mechanisms that mediate neurodegeneration in flies are conserved in humans. Thus, these studies have implications for our understanding of the cellular and molecular events that occur in humans and will facilitate the identification of biomedically relevant targets for future treatments. PMID- 26512207 TI - Csf2 and Ptgs2 Epigenetic Dysregulation in Diabetes-prone Bicongenic B6.NODC11bxC1tb Mice. AB - In Type 1 diabetic (T1D) human monocytes, STAT5 aberrantly binds to epigenetic regulatory sites of two proinflammatory genes, CSF2 (encoding granulocyte macrophage colony-stimulating factor) and PTGS2 (encoding prostaglandin synthase 2/cyclooxygenase 2). Bicongenic B6.NOD C11bxC1tb mice re-create this phenotype of T1D monocytes with only two nonobese diabetic (NOD) Idd subloci (130.8 Mb-149.7 Mb, of Idd5 on Chr 1 and 32.08-53.85 Mb of Idd4.3 on Chr11) on C57BL/6 genetic background. These two Idd loci interact through STAT5 binding at upstream regulatory regions affecting Csf2 (Chr 11) and Ptgs2 (Chr 1) expression. B6.NODC11bxC1tb mice exhibited hyperglycemia and immune destruction of pancreatic islets between 8 and 30 weeks of age, with 12%-22% penetrance. Thus, B6.NODC11bxC1tb mice embody NOD epigenetic dysregulation of gene expression in myeloid cells, and this defect appears to be sufficient to impart genetic susceptibility to diabetes in an otherwise genetically nonautoimmune mouse. PMID- 26512208 TI - Emerging Novel Therapies for Heart Failure. AB - Heart function fails when the organ is unable to pump blood at a rate proportional to the body's need for oxygen or when this function leads to elevated cardiac chamber filling pressures (cardiogenic pulmonary edema). Despite our sophisticated knowledge of heart failure, even so-called ejection fraction preserved heart failure has high rates of mortality and morbidity. So, novel therapies are sorely needed. This review discusses current standard therapies for heart failure and launches an exploration into emerging novel treatments on the heels of recently-approved sacubitril and ivbradine. For example, Vasoactive Intestinal Peptide (VIP) is protective of the heart, so in the absence of VIP, VIP knockout mice have dysregulation in key heart failure genes: 1) Force Generation and Propagation; 2) Energy Production and Regulation; 3) Ca(+2) Cycling; 4) Transcriptional Regulators. VIP administration leads to coronary dilation in human subjects. In heart failure patients, VIP levels are elevated as a plausible endogenous protective effect. With the development of elastin polymers to stabilize VIP and prevent its degradation, VIP may therefore have a chance to satisfy the unmet need as a potential treatment for acute heart failure. PMID- 26512210 TI - Sparsifying the Fisher Linear Discriminant by Rotation. AB - Many high dimensional classification techniques have been proposed in the literature based on sparse linear discriminant analysis (LDA). To efficiently use them, sparsity of linear classifiers is a prerequisite. However, this might not be readily available in many applications, and rotations of data are required to create the needed sparsity. In this paper, we propose a family of rotations to create the required sparsity. The basic idea is to use the principal components of the sample covariance matrix of the pooled samples and its variants to rotate the data first and to then apply an existing high dimensional classifier. This rotate-and-solve procedure can be combined with any existing classifiers, and is robust against the sparsity level of the true model. We show that these rotations do create the sparsity needed for high dimensional classifications and provide theoretical understanding why such a rotation works empirically. The effectiveness of the proposed method is demonstrated by a number of simulated and real data examples, and the improvements of our method over some popular high dimensional classification rules are clearly shown. PMID- 26512211 TI - Synthesis, Characterization, and Reactivity of Functionalized Trinuclear Iron Sulfur Clusters - A New Class of Bioinspired Hydrogenase Models. AB - The air- and moisture-stable iron-sulfur carbonyl clusters Fe3S2(CO)7(dppm) (1) and Fe3S2(CO)7(dppf) (2) carrying the bisphosphine ligands bis(diphenylphosphanyl)methane (dppm) and 1,1'-bis(diphenylphosphanyl)ferrocene (dppf) were prepared and fully characterized. Two alternative synthetic routes based on different thionation reactions of triiron dodecacarbonyl were tested. The molecular structures of the methylene-bridged compound 1 and the ferrocene functionalized derivative 2 were determined by single-crystal X-ray diffraction. The catalytic reactivity of the trinuclear iron-sulfur cluster core for proton reduction in solution at low overpotential was demonstrated. These deeply colored bisphosphine-bridged sulfur-capped iron carbonyl systems are discussed as promising candidates for the development of new bioinspired model compounds of iron-based hydrogenases. PMID- 26512209 TI - Interstitial Lung Disease in Childhood: Clinical and Genetic Aspects. AB - Interstitial lung disease (ILD) in childhood is a heterogeneous group of rare pulmonary conditions presenting chronic respiratory disorders. Many clinical features of ILD still remain unclear, making the treatment strategies mainly investigative. Guidelines may provide physicians with an overview on the diagnosis and therapeutic directions. However, the criteria used in different clinical studies for the classification and diagnosis of ILDs are not always the same, making the development of guidelines difficult. Advances in genetic testing have thrown light on some etiologies of ILD, which were formerly classified as ILDs of unknown origins. The need of genetic testing for unexplained ILD is growing, and new classification criteria based on the etiology should be adopted to better understand the disease. The purpose of this review is to give an overview of the clinical and genetic aspects of ILD in children. PMID- 26512212 TI - Smoking, smoking cessation, and 7-year mortality in a cohort of Thai adults. AB - BACKGROUND: Smoking is a strong risk factor for mortality in both the developed and the developing world. However, there is still limited research to examine the impact of smoking cessation and mortality in middle-income Southeast Asian populations. METHODS: We use longitudinal data from a large Thai cohort of adult Open University students residing nationwide, linked with official death records to assess the association of smoking status and mortality risks during a 7-year follow-up. The log-rank test was used to evaluate the statistical probability of differential survival according to baseline smoking status. Multivariate hazard ratios (HR) were reported for smoking status and all-cause and cause-specific mortality. RESULTS: From 2005 baseline to 2012, current smokers were more likely to die than cohort members who ceased smoking and never smokers (1.9 vs 1.3 vs 0.6 %, p < 0.05). The hazard of all-cause mortality increased with the daily amount of cigarette consumption among both current and former smokers. Cause of death analyses showed that current male smokers had a significantly increased risk of cardiovascular disease related mortality (HR 3.9 [95 % CI 1.8-8.1]). Former male smokers had a moderate increase in risk of dying from cardiovascular diseases compared to never smokers (HR 1.6 [95 % CI 0.7-3.4]). Current male smokers between 2005 and 2009 experienced highest subsequent mortality hazards during the period 2009-2012 compared to never smokers (HR 2.1 [95 % CI 1.4-3.4]). The higher risk of dying reduced if people quit smoking during the 2005-2009 follow-up period (HR 1.5 [95 % CI 0.7-3.3]). Risk for mortality fell even further among long-term quitters (HR 1.4 [95 % CI 0.9-2.2]). CONCLUSION: Among a large nationwide cohort of Thai adults, current smokers were at a significantly and substantially higher risk of all-cause mortality, especially cardiovascular related mortality. The higher risk of dying fell if people quit smoking and the risk for mortality was even lower among long-term quitters. Promotion of smoking cessation will contribute substantially to the reduction in avoidable mortality in Thailand. PMID- 26512213 TI - Three ideas to advance our research base. PMID- 26512214 TI - Nuggets: findings shared in multiple clinical case reports. AB - OBJECTIVE: The researchers assessed prevalence in the clinical case report literature of multiple reports independently reporting the same (or nearly the same) main finding. METHODS: Results from forty-five PubMed queries were examined for incidence and features of main findings ("nuggets") shared in at least four case reports. RESULTS: The authors found that nuggets are surprisingly prevalent and large in the case report literature, the largest found so far was reported in seventeen articles. In most cases, the main findings of case reports were evident from examining titles alone. CONCLUSIONS: Our curated examples should serve as gold standards for developing specific automated methods for finding nuggets. Nuggets potentially enable finding-based (instead of topic-based) information retrieval. PMID- 26512215 TI - Electronic resources preferred by pediatric hospitalists for clinical care. AB - OBJECTIVES: There is little research on pediatric hospitalists' use of evidence based resources. The aim of this study was to determine the electronic resources that pediatric hospitalists prefer. METHODS: Using a web-based survey, the authors determined hospitalists' preferred electronic resources, as well as their attitudes toward lifelong learning, practice, and experience characteristics. RESULTS: One hundred sixteen hospitalists completed the survey. The most preferred resource for general information, patient handouts, and treatment was UpToDate. Online search engines were ranked second for general information and patient handouts. CONCLUSIONS: Pediatric hospitalists tend to utilize less rigorous electronic resources such as UpToDate and Google. These results can set a platform for discussing the quality of resources that pediatric hospitalists use. PMID- 26512216 TI - Identifying and removing duplicate records from systematic review searches. AB - OBJECTIVE: The purpose of this study was to compare effectiveness of different options for de-duplicating records retrieved from systematic review searches. METHODS: Using the records from a published systematic review, five de duplication options were compared. The time taken to de-duplicate in each option and the number of false positives (were deleted but should not have been) and false negatives (should have been deleted but were not) were recorded. RESULTS: The time for each option varied. The number of positive and false duplicates returned from each option also varied greatly. CONCLUSION: The authors recommend different de-duplication options based on the skill level of the searcher and the purpose of de-duplication efforts. PMID- 26512217 TI - Database choices in endocrine systematic reviews. AB - OBJECTIVE: The choice of bibliographic database during the systematic review search process has been an ongoing conversation among information specialists. With newer information sources, such as Google Scholar and clinical trials registries, we were interested in which databases were utilized by information specialists and systematic review researchers. METHOD: We retrieved 144 systematic reviews and meta-analyses from 4 clinical endocrinology journals and extracted all information sources used during the search processes. RESULTS: Findings indicate that traditional bibliographic databases are most often used, followed by regional databases, clinical trials registries, and gray literature databases. CONCLUSIONS: This study informs information specialists about additional resources that may be considered during the search process. PMID- 26512218 TI - Database trial impact on graduate nursing comprehensive exams. AB - While the authors were doing a test period of databases, the question of whether or not databases affect outcomes of graduate nursing comprehensive examinations came up. This study explored that question through using citation analysis of exams that were taken during a database trial and exams that were not. The findings showed no difference in examination pass/fail rates. While the pass/fail rates did not change, a great deal was learned in terms of citation accuracy and types of materials that students used, leading to discussions about changing how citation and plagiarism awareness were taught. PMID- 26512219 TI - Developing an evidence-based public health informatics course. AB - OBJECTIVES: This study assessed the need to develop a public health informatics (PHI) introductory course and determine contents of such a course. METHODS: Community assessments employing focus group interviews and an online survey were utilized to determine course need and content. RESULTS: Results revealed a need to provide PHI training to graduate public health students and suggested broad course content requirements. Results indicated lack of awareness of libraries and librarians as sources of public health information. CONCLUSIONS: A graduate PHI course was developed and delivered. Additionally, implementation of a subject guide increased the library's profile. PMID- 26512220 TI - Correction. PMID- 26512221 TI - Information and informatics literacies of first-year medical students. AB - PURPOSE: The study evaluated medical students' familiarity with information literacy and informatics during the health sciences library orientation. METHODS: A survey was fielded at the start of the 2013 school year. RESULTS: Seventy-two of 77 students (94%) completed the survey. Over one-half (57%) expected to use library research materials and services. About half (43%) expected to use library physical space. Students preferred accessing biomedical research on laptops and learning via online-asynchronous modes. CONCLUSIONS: The library identified areas for service development and outreach to medical students and academic departments. PMID- 26512222 TI - Continuing education for medical students: a library model. AB - PURPOSE: The research assessed a three-year continuing medical education-style program for medical students in a Midwestern academic medical library. METHODS: A mixed methods approach of a survey and two focus groups comparing attendees versus non-attendees assessed the program. RESULTS: Eleven students participated in the focus groups. Attendance was driven by topic interest and lunch. Barriers included lack of interest, scheduling, location, and convenience. CONCLUSIONS: Although attendance was a challenge, students valued opportunities to learn new skills. This study show cases a reproducible method to engage students outside the curriculum. PMID- 26512223 TI - Evaluation of instructive texts on searching medical databases. PMID- 26512224 TI - Library resource discovery. PMID- 26512225 TI - It's the end of the world and we feel fine. PMID- 26512226 TI - Bibliometrics basics. PMID- 26512227 TI - Bibliometric indicators: opportunities and limits. PMID- 26512228 TI - Enhancing library impact through technology. PMID- 26512230 TI - Scalable Evaluation of Polarization Energy and Associated Forces in Polarizable Molecular Dynamics: II.Towards Massively Parallel Computations using Smooth Particle Mesh Ewald. AB - In this paper, we present a scalable and efficient implementation of point dipole based polarizable force fields for molecular dynamics (MD) simulations with periodic boundary conditions (PBC). The Smooth Particle-Mesh Ewald technique is combined with two optimal iterative strategies, namely, a preconditioned conjugate gradient solver and a Jacobi solver in conjunction with the Direct Inversion in the Iterative Subspace for convergence acceleration, to solve the polarization equations. We show that both solvers exhibit very good parallel performances and overall very competitive timings in an energy-force computation needed to perform a MD step. Various tests on large systems are provided in the context of the polarizable AMOEBA force field as implemented in the newly developed Tinker-HP package which is the first implementation for a polarizable model making large scale experiments for massively parallel PBC point dipole models possible. We show that using a large number of cores offers a significant acceleration of the overall process involving the iterative methods within the context of spme and a noticeable improvement of the memory management giving access to very large systems (hundreds of thousands of atoms) as the algorithm naturally distributes the data on different cores. Coupled with advanced MD techniques, gains ranging from 2 to 3 orders of magnitude in time are now possible compared to non-optimized, sequential implementations giving new directions for polarizable molecular dynamics in periodic boundary conditions using massively parallel implementations. PMID- 26512231 TI - Design of an Optically Controlled MR-Compatible Active Needle. AB - An active needle is proposed for the development of magnetic resonance imaging (MRI)-guided percutaneous procedures. The needle uses a low-transition temperature shape memory alloy (LT SMA) wire actuator to produce bending in the distal section of the needle. Actuation is achieved with internal optical heating using laser light transported via optical fibers and side coupled to the LT SMA. A prototype, with a size equivalent to a standard 16-gauge biopsy needle, exhibits significant bending, with a tip deflection of more than 14 degrees in air and 5 degrees in hard tissue. A single-ended optical sensor with a gold coated tip is developed to measure the curvature independently of temperature. The experimental results in tissue phantoms show that human tissue causes fast heat dissipation from the wire actuator; however, the active needle can compensate for typical targeting errors during prostate biopsy. PMID- 26512232 TI - Why do - or don't - patients with urinary tract infection participate in a clinical trial? A qualitative study in German family medicine. AB - BACKGROUND: Insufficient patient recruitment can impair the conduct of clinical trials substantially, not least because a significant number of eligible patients decline trial participation. Though barriers and motivational factors have been worked out for patients with cancer or chronic diseases, little is known about primary care patients' perceptions towards trial participation when visiting their family practitioner (FP) with acute uncomplicated conditions. This study aims to assess primary care patients' motivation and barriers to participate in trials, and to identify factors that optimize patient recruitment in future trials. METHODS: This study was embedded in a drug trial comparing two treatment strategies for women with uncomplicated urinary tract infection in primary care. Semi-structured telephone interviews both with trial participants and decliners were conducted. The interview guideline focused on patients' personal motivational or hampering factors. Further topics were study theme, FPs' role, randomization, trial procedures, and potential motivational factors or barriers presumed to be relevant for other patients. Transcripts were analyzed by summarizing content analysis. RESULTS: 20 interviews with trial participants and 5 interviews with trial decliners were conducted. RESULTS show various reasons for trial participation from three categories: personal aspects, trial related aspects and patient-physician-relationship. A relevant trial topic and perceived personal benefit promotes participation as well as the wish to support research in general. Additionally, a maximum of safety concerning symptom relief reassures patients significantly. Trust in the FP plays also an important role in the decision process. Trial decliners show strong individual treatment preferences, which, together with individual reasons, lead to trial refusals. CONCLUSIONS: To optimize recruitment conditions for further clinical trials on acute and common conditions in family medicine, the following key issues should be considered: emphasizing patients' personal benefit, featuring patient relevant trial topics, providing a maximum of safety, keeping effort by trial procedures comfortable. PMID- 26512233 TI - Pallial patterning and the origin of the isocortex. AB - Together with a complex variety of behavioral, physiological, morphological, and neurobiological innovations, mammals are characterized by the development of an extensive isocortex (also called neocortex) that is both laminated and radially organized, as opposed to the brain of birds and reptiles. In this article, we will advance a developmental hypothesis in which the mechanisms of evolutionary brain growth remain partly conserved across amniotes (mammals, reptiles and birds), all based on Pax6 signaling or related morphogens. Despite this conservatism, only in mammals there is an additional upregulation of dorsal and anterior signaling centers (the cortical hem and the anterior forebrain, respectively) that promoted a laminar and a columnar structure into the neocortex. It is possible that independently, some birds also developed an upregulated dorsal pallium. PMID- 26512234 TI - Secondary cardiovascular prevention in older adults: an evidence based review. PMID- 26512235 TI - Perioperative care in older adults. PMID- 26512236 TI - PARADIGM-HF trial: will LCZ696 change the current treatment of systolic heart failure? PMID- 26512237 TI - Early prediction of myocardial viability after acute myocardial infarction by two dimensional speckle tracking imaging. AB - BACKGROUND: Identifying the transmural extent of myocardial necrosis and the degree of myocardial viability in acute myocardial infarction (AMI) is important clinically. The aim of this study was to assess myocardial viability using two dimensional speckle tracking imaging (2D-STI) in patients with AMI. METHODS: 2D STI was performed at initial presentation, three days, and six months after primary percutaneous coronary intervention (PCI) in 30 patients with AMI, who had a left anterior descending coronary artery (LAD) culprit lesion. In addition, 20 patients who had minimal stenotic lesions (< 30% stenosis) on coronary angiography were also included in the control group. At six months dobutamine echocardiography was performed for viability assessment in seven segments of the LAD territory. According to the recovery of wall motion abnormality, segments were classified as viable or non-viable. RESULTS: A total of 131 segments were viable, and 44 were nonviable. Multivariate analysis revealed significant differences between the viable and nonviable segments in the peak systolic strain, the peak systolic strain rate at initial presentation, and peak systolic strain rate three days after primary PCI. Among these, the initial peak systolic strain rate had the highest predictive value for myocardial viability (hazard ratio: 31.22, P < 0.01). CONCLUSIONS: 2D-STI is feasible for assessing myocardial viability, and the peak systolic strain rate might be the most reliable predictor of myocardial viability in patients with AMI. PMID- 26512238 TI - Defective recovery of QT dispersion following transcatheter aortic valve implantation: frequency, predictors and prognosis. AB - BACKGROUND: Corrected QT dispersion (cQTD) has been correlated with non-uniform ventricular repolarisation and increased mortality. In patients with aortic stenosis, cQTD has been shown improved after surgical valve replacement, but the effects of transcatheter aortic valve implantation (TAVI) are unknown. Therefore, we sought to explore the frequency, predictors and prognostic effects of defective cQTD recovery at 6 months after TAVI. METHODS: A total of 222 patients underwent TAVI with the Medtronic-CoreValve System between November 2005 and January 2012. Patients who were on class I or III antiarrhythmics or on chronic haemodialysis or who developed atrial fibrillation, a new bundle branch block or became pacemaker dependent after TAVI were excluded. As a result, pre-, post- and follow-up ECG (median: 6 months) analysis was available in 45 eligible patients. Defective cQTD recovery was defined as any progression beyond the baseline cQTD at 6 months. RESULTS: In the 45 patients, the mean cQTD was 47 +/- 23 ms at baseline, 45 +/- 17 ms immediately after TAVI and 40 +/- 16 ms at 6 months (15% reduction, P = 0.049). Compared to baseline, cQTD at 6 months was improved in 60% of the patients whereas defective cQTD recovery was present in 40%. cQTD increase immediately after TAVI was an independent predictor of defective cQTD recovery at 6 months (per 10 ms increase; OR: 1.89, 95% CI: 1.15-3.12). By univariable analysis, defective cQTD recovery was associated with late mortality (HR: 1.52, 95% CI: 1.05-2.17). CONCLUSIONS: Despite a gradual reduction of cQTD after TAVI, 40% of the patients had defective recovery at 6 months which was associated with late mortality. More detailed ECG analysis after TAVI may help to avoid late death. PMID- 26512239 TI - Transradial versus transfemoral rotablation for heavily calcified coronary lesions in contemporary drug-eluting stent era. AB - BACKGROUND: Although radial access for drug-eluting stent (DES) combined with rotational atherectomy (RA) in patients with calcified coronary lesions may be associated with a lower risk of major bleeding complications and obtain favorable clinical results compared with femoral access, the long-term outcome data of this approach were limited in contemporary DES era. METHODS & RESULTS: This retrospective study sought to compare in-hospital and long-term outcomes for patients undergoing RA via the transradial (TR) and transfemoral (TF) route in 126 consecutive patients (59 radial, 67 femoral) from 2009 to 2014. TR RA procedures were performed in 44/62 (71%) by the three TR operators, compared with 15/64 (23%) by the four TF operators in the present study. Significantly smaller diameter guide catheters and burrs (1.39 +/- 0.16 mm vs. 1.53 +/- 0.24 mm, P = 0.001) were used in the TR group. Procedural success rates were similar in both TR and TF groups. There was a significantly less major access site bleeding complications in favor of radial artery access (2% vs. 16%, P = 0.012). The incidence of in-hospital death or myocardial infarction was low in both groups. Although a trend of lower adverse event rate was demonstrated in the TR group compared with the TF one, no statistical significance (21% vs. 27%, P = 0.135) was detected. CONCLUSIONS: Radial access, a useful alternative to femoral access for RA and DES, can be safely and successfully performed on up to 71% of the patients with heavily calcified coronary lesions needing RA by experienced TR operators. PMID- 26512240 TI - Is cardiac resynchronisation therapy feasible, safe and beneficial in the very elderly? AB - OBJECTIVE: To evaluate whether cardiac resynchronisation therapy (CRT) implantation was feasible and safe in octogenarians and the association with symptoms. METHODS: Consecutive patients undergoing CRT implantation were recruited from two UK centers. Patients grouped according to age: < 80 & >= 80 years. Baseline demographics, complications and outcomes were compared between those groups. RESULTS: A total of 439 patients were included in this study, of whom 26% were aged >= 80 years. Octogenarians more often received cardiac resynchronization therapy pacemaker in comparison to cardiac resynchronisation therapy-defibrillator. Upgrade from pacemaker was common in both groups (16% < 80 years vs. 22% >= 80 years, P = NS). Co-morbidities were similarly common in both groups (overall diabetes: 25%, atrial fibrillation: 23%, hypertension: 45%). More patient age >= 80 years had significant chronic kidney disease (CKD, estimated glomerular filtration rate < 45 mL/min per 1.73 m(2), 44% vs. 22%, P < 0.01). Overall complication rates (any) were similar in both groups (16% vs. 17%, P = NS). Both groups demonstrated symptomatic benefit. One-year mortality rates were almost four fold greater in octogenarians as compared with the younger cohort (13.9% vs. 3.7%, P < 0.01). CONCLUSIONS: CRT appears to be safe in the very elderly despite extensive co-morbidity, and in particular frequent severe CKD. Symptomatic improvement appears to be meaningful. Strategies to increase the appropriate identification of elderly patients with CHF who are potential candidates for CRT are required. PMID- 26512241 TI - Incidence and in-hospital mortality of acute aortic dissection in China: analysis of China Health Insurance Research (CHIRA) Data 2011. AB - OBJECTIVE: Acute aortic dissection (AAD) is a catastrophic event with high early mortality rate, but to date, no data on the incidence of AAD in Mainland China is available. This study aimed to estimate the incidence of AAD in China and characterize the clinical profile, management and in-hospital outcomes of this vascular event. METHODS: We used the China Health Insurance Research Data (the CHIRA Data) 2011 which comprises all inpatient hospital records (300,886) during the period of Jan. 1st 2011 to Dec. 31 2011 of 3,335,000 randomly sampled beneficiaries (1,718,500 men and 1,616,500 women) from 25 cities and counties in different economic-geographic regions of Mainland China. Patients with acute aortic dissection were identified according to International Classification of Disease 10(th) Revision (ICD-10) of I71.0. The estimated incidence of AAD was calculated using the equation: estimated incidence = 2.0 * (40% * hospital admission rate) + 60% * hospital admission rate. RESULTS: The hospital admission rate was 2.0/100,000 (65/3,325,000, 95% CI: 1.2-2.8). The estimated annual incidence of AAD was 2.8/100,000 (95% CI: 1.9-3.6) and was higher in male than in female (3.7 vs. 1.5, P < 0.001). The mean age was 58.9 +/- 13.4 years. During the mean hospital stay of 23 +/- 6 days, the overall in-hospital mortality was 13.9% (9/65). CONCLUSIONS: Our study showed relatively lower but not negligible incidence and in-hospital mortality of AAD in the mainland of China. The mean age of patients with AAD in Chinese was younger than that reported by researches from west countries, while the male to female incidence ratio is similar to those reported by other studies. PMID- 26512242 TI - Long-term stroke rates after catheter ablation or antiarrhythmic drug therapy for atrial fibrillation: a meta-analysis of randomized trials. AB - BACKGROUND: Atrial fibrillation (AF) is an independent risk factor for ischemic stroke and is associated with increased risk of death. Randomized studies suggest improved quality of life for patients with AF after successful catheter ablation compared to antiarrhythmic drug therapy. The value of ablation in long-term risk of ischemic stroke, however, has not been assessed. We conducted a meta-analysis to determine whether AF ablation reduces the long-term risk of stroke compared to antiarrhythmic drug therapy in randomized controlled trials. METHODS & RESULTS: PubMed and the Cochrane Central Register were searched for randomized trials from January 1990 to December 2014 comparing AF catheter ablation to drug therapy. The results are reported as risk differences (RDs) and 95% CI. Thirteen trials were analyzed with 1097 patients treated by catheter ablation and 855 patients received antiarrhythmic drug therapy. Overall, seven patients (0.64%) in the catheter ablation group had ischemic stroke or transient ischemic attacks vs. two patients (0.23%) in the drug therapy group. No difference was shown in the rate of stroke or transient ischemic attack between ablation and drug therapy (RD: 0.003, 95% CI: -0.006 to 0.012, P = 0.470), and no evidence of heterogeneity was observed (I (2) = 0, P = 0.981). No potential publication bias was found. There was also no difference in mortality between the two groups (RD: -0.004, 95% CI: 0.014 to 0.006, P = 0.472). CONCLUSIONS: This meta-analysis of randomized controlled trials showed similar rates of ischemic stroke or transient ischemic attack and death in AF patients undergoing catheter ablation compared to drug therapy. A larger prospective randomized trial to confirm this finding is warranted. PMID- 26512243 TI - Serum uric acid as a prognostic marker in the setting of advanced vascular disease: a prospective study in the elderly. AB - BACKGROUND: Many epidemiological studies analyze the relationship between hyperuricemia and cardiovascular outcomes. This observational prospective study investigates the association of serum uric acid (SUA) levels with adverse cardiovascular events and deaths in an elderly population affected by advanced atherosclerosis. METHODS: Two hundred and seventy six elderly patients affected by advanced atherosclerosis (217 males and 59 females; aged 71.2 +/- 7.8 years) were included. All patients were assessed for history of cardiovascular disease, cancer, obesity and traditional risk factors. Patients were followed for approximately 31 +/- 11 months. Major events were recorded during follow-up, defined as myocardial infarction, cerebral ischemia, myocardial and/or peripheral revascularization and death. RESULTS: Mean SUA level was 5.47 +/- 1.43 mg/dL; then we further divided the population in two groups, according to the median value (5.36 mg/dL). During a median follow up of 31 months (5 to 49 months), 66 cardiovascular events, 9 fatal cardiovascular events and 14 cancer-related deaths have occurred. The patients with increased SUA level presented a higher significant incidence of total cardiovascular events (HR: 1.867, P = 0.014, 95% CI: 1.134-3.074). The same patients showed a significant increased risk of cancer related death (HR: 4.335, P = 0.025, 95% CI: 1.204-15.606). CONCLUSIONS: Increased SUA levels are independently and significantly associated with risk of cardiovascular events and cancer related death in a population of mainly elderly patients affected by peripheral vasculopathy. PMID- 26512244 TI - Effect of probucol on insulin resistance in patients with non-diabetic chronic kidney disease. AB - BACKGROUND: Insulin resistance (IR) is present at all stages of chronic kidney disease (CKD) and is associated with CKD progression. Probucol can improve the prognosis of IR in diabetes mellitus (DM) patients. This study aimed to observe the effect of probucol on IR and kidney protection in non-diabetic CKD patients. METHODS: This was an open-label, non-placebo-controlled, randomized study. A total of 59 patients were randomized to the probucol group (0.5 g, twice daily) or the control group using a 1: 1 treatment ratio. IR was determined using a homeostatic model assessment-IR (HOMA-IR) index. An Excel database was established to analyze follow-up data at weeks 0, 12, and 24. The primary outcome of interest was changes in the HOMA-IR, and the secondary outcomes of interest were changes in the estimated glomerular filtration rate (eGFR), body mass index (BMI), cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and 24-h urinary protein. RESULTS: The HOMA-IR index of the probucol group after 24 weeks was significantly decreased (P < 0.001) compared to the value before treatment (average decrease: 1.45; range: -2.90 to -0.43). The HOMA-IR index in the control group increased (average increase: 0.54; range: 0.38 to 1.87). For the secondary outcomes of interest, the changes between these two groups also exhibited significant differences in eGFR (P = 0.041), cholesterol (P = 0.001), fasting insulin (P < 0.001), and fasting C-peptide (P = 0.001). CONCLUSIONS: Compared to angiotensin receptor blockers alone, the combination with probucol ameliorates IR in non-diabetic CKD patients and delays disease progression. PMID- 26512245 TI - Dexamethasone, tetrahydrobiopterin and uncoupling of endothelial nitric oxide synthase. AB - OBJECTIVE: To find out whether dexamethasone induces an uncoupling of the endothelial nitric oxide synthase (eNOS). METHODS & RESULTS: A major cause of eNOS uncoupling is a deficiency of its cofactor tetrahydrobiopterin (BH4). Treatment of human EA.hy 926 endothelial cells with dexamethasone decreased mRNA and protein expression of both BH4-synthesizing enzymes: GTP cyclohydrolase I and dihydrofolate reductase. Consistently, a concentration- and time-dependent reduction of BH4, dihydrobiopterin (BH2) as well as BH4: BH2 ratio was observed in dexamethasone-treated cells. Surprisingly, no evidence for eNOS uncoupling was found. We then analyzed the expression and phosphorylation of the eNOS enzyme. Dexamethasone treatment led to a down-regulation of eNOS protein and a reduction of eNOS phosphorylation at serine 1177. A reduction of eNOS expression may lead to a relatively normal BH4: eNOS molar ratio in dexamethasone-treated cells. Because the BH4-eNOS stoichiometry rather than the absolute BH4 amount is the key determinant of eNOS functionality (i.e., coupled or uncoupled), the down regulation of eNOS may represent an explanation for the absence of eNOS uncoupling. Phosphorylation of eNOS at serine 1177 is needed for both the NO producing activity of the coupled eNOS and the superoxide-producing activity of the uncoupled eNOS. Thus, a reduction of serine 1177 phosphorylation may render a potentially uncoupled eNOS hardly detectable. CONCLUSIONS: Although dexamethasone reduces BH4 levels in endothelial cells, eNOS uncoupling is not evident. The reduction of NO production in dexamethasone-treated endothelial cells is mainly attributable to reduced eNOS expression and decreased eNOS phosphorylation at serine 1177. PMID- 26512246 TI - Panax quinquefolium saponin attenuates cardiomyocyte apoptosis induced by thapsigargin through inhibition of endoplasmic reticulum stress. AB - BACKGROUND: Endoplasmic reticulum (ER) stress-related apoptosis is involved in the pathophysiology of many cardiovascular diseases, and Panax quinquefolium saponin (PQS) is able to inhibit excessive ER stress-related apoptosis of cardiomyocytes following hypoxia/reoxygenation and myocardial infarction. However, the pathway by which PQS inhibits the ER stress-related apoptosis is not well understood. To further investigate the protective effect of PQS against ER stress-related apoptosis, primary cultured cardiomyocytes were stimulated with thapsigargin (TG), which is widely used to model cellular ER stress, and it could induce apoptotic cell death in sufficient concentration. METHODS: Primary cultured cardiomyocytes from neonatal rats were exposed to TG (1 umol/L) treatment for 24 h, following PQS pre-treatment (160 ug/mL) for 24 h or pre treatment with small interfering RNA directed against protein kinase-like endoplasmic reticulum kinase (Si-PERK) for 6 h. The viability and apoptosis rate of cardiomyocytes were detected by cell counting kit-8 and flow cytometry respectively. ER stress-related protein expression, such as glucose-regulated protein 78 (GRP78), calreticulin, PERK, eukaryotic translation initiation factor 2alpha (eIF2alpha), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) were assayed by western blotting. RESULTS: Both PQS pre treatment and PERK knockdown remarkably inhibited the cardiomyocyte apoptosis induced by TG, increased cell viability, decreased phosphorylation of both PERK and eIF2alpha, and decreased protein levels of both ATF4 and CHOP. There was no statistically significant difference between PQS pre-treatment and PERK knockdown in the cardioprotective effect. CONCLUSIONS: Our data indicate that the PERK eIF2alpha-ATF4-CHOP pathway of ER stress is involved in the apoptosis induced by TG, and PQS might prevent TG-induced cardiomyocyte apoptosis through a mechanism involving the suppression of this pathway. These findings provide novel data regarding the molecular mechanisms by which PQS inhibits cardiomyocyte apoptosis. PMID- 26512247 TI - A review on atrioventricular junction ablation and pacing for heart rate control of atrial fibrillation. AB - Atrioventricular junction ablation with permanent pacemaker implantation is a highly effective treatment approach in patients with atrial fibrillation and high ventricular rates resistant to other treatment modalities, especially in the elderly or those with severe comorbidities. Compared with pharmacological therapy alone, the so-called "ablate and pace" approach offers the potential for more robust control of ventricular rate. Atrioventricular junction ablation and pacing strategy is associated with improvement in symptoms, quality of life, and exercise capacity. Given the close relationship between atrial fibrillation and heart failure, there is a particular benefit of such a rate control in patients with atrial fibrillation and reduced systolic function. There is increasing evidence that cardiac resynchronization therapy devices may be beneficial in selected populations after atrioventricular junction ablation. The present review article focuses on the current recommendations for atrioventricular junction ablation and pacing for heart rate control in patients with atrial fibrillation. The technique, the optimal implantation time, and the proper device selection after atrioventricular junction ablation are also discussed. PMID- 26512248 TI - Coronary revascularization in the elderly with stable angina. AB - A proportion of elderly with coronary artery disease is rapidly growing. They have more severe coronary artery disease, therefore, derive more benefit from revascularization and have a greater need for it. The elderly is a heterogeneous group, but compared to the younger cohort, the choice of the optimal revascularization method is much more complicated among them. In recent decades, results has improved dramatically both in surgery and percutaneous coronary intervention (PCI), even in very old persons. Despite the lack of evidence in elderly, it is obvious, that coronary artery bypass surgery (CABG) has a more pronounced effect on long-term survival in price of more strokes, while PCI is certainly less invasive. Age itself is not a criterion for the selection of treatment strategy, but the elderly are often more interested in quality of life and personal independence instead of longevity. This article discusses the factors that influence the choice of the revascularization method in the elderly with stable angina and presents a complex algorithm for making an individual risk benefit profile. As a consequence the features of CABG and PCI in elderly patients are exposed. Emphasis is centered on the frailty and non-medical factors, including psychosocial, as essential components in making the decision of what strategy to choose. Good communication with the patients and giving them unbiased information is encouraged. PMID- 26512249 TI - Impact of miRNAs on cardiovascular aging. AB - Aging is a multidimensional process that leads to an increased risk of developing severe diseases, such as cancer and cardiovascular, neurodegenerative, and immunological diseases. Recently, small non-coding RNAs known as microRNAs (miRNAs) have been shown to regulate gene expression, which contributes to many physiological and pathophysiological processes in humans. Increasing evidence suggests that changes in miRNA expression profiles contribute to cellular senescence, aging and aging-related diseases. However, only a few miRNAs whose functions have been elucidated have been associated with aging and/or aging related diseases. This article reviews the currently available findings regarding the roles of aging-related miRNAs, with a focus on cardiac and cardiovascular aging. PMID- 26512250 TI - Gender differences in the efficacy of cardiovascular rehabilitation in patients after cardiac surgery procedures. PMID- 26512251 TI - Calcific degeneration and rupture of the aortic valve and ascending aorta: from cardiac auscultation to multimodality imaging. PMID- 26512252 TI - An uncommon cause of hypoxemia: platypnea-orthodeoxia syndrome. PMID- 26512253 TI - The oldest patient with takotsubo cardiomyopathy. PMID- 26512254 TI - Atrial fibrillation may be a hidden factor for the development of cognitive impairment in patients with heart failure. PMID- 26512255 TI - Between the Living and the Dead: Trauma Medicine and Forensic Medicine in the Mid Qing. AB - This paper analyzes the influence of forensic medicine on therapeutic medicine through a case study of Qian Xiuchang and Hu Tingguang, two Chinese doctors who specialized in treating traumatic injuries. During the early nineteenth century, both men compiled medical treatises that sought to improve on a scholarly model of "rectifying bones" articulated in 1742 by the Imperially-Compiled Golden Mirror of the Medical Lineage. Both texts also incorporated information from forensic medicine, including official inquest diagrams and checklists promulgated by the Qing government. I show that they drew on these forensic materials to help address two interlinked medical issues: understanding the effects of injury on different parts of the body, and clarifying the location and form of the body's bones. Overall, I suggest that the exchange of ideas between the realm of therapeutic medicine and forensic medicine was an important epistemological strategy that doctors and officials alike employed to improve their knowledge of the material body. PMID- 26512256 TI - Kabuki syndrome: clinical and molecular characteristics. AB - Kabuki syndrome (KS) is a rare syndrome characterized by multiple congenital anomalies and mental retardation. Other characteristics include a peculiar facial gestalt, short stature, skeletal and visceral abnormalities, cardiac anomalies, and immunological defects. Whole exome sequencing has uncovered the genetic basis of KS. Prior to 2013, there was no molecular genetic information about KS in Korean patients. More recently, direct Sanger sequencing and exome sequencing revealed KMT2D variants in 11 Korean patients and a KDM6A variant in one Korean patient. The high detection rate of KMT2D and KDM6A mutations (92.3%) is expected owing to the strict criteria used to establish a clinical diagnosis. Increased awareness and understanding of KS among clinicians is important for diagnosis and management of KS and for primary care of KS patients. Because mutation detection rates rely on the accuracy of the clinical diagnosis and the inclusion or exclusion of atypical cases, recognition of KS will facilitate the identification of novel mutations. A brief review of KS is provided, highlighting the clinical and genetic characteristics of patients with KS. PMID- 26512257 TI - Vitamin D serum levels in children with allergic and vasomotor rhinitis. AB - PURPOSE: In addition to regulating calcium and phosphorus homeostasis and bone metabolism, vitamin D is known as an immune modulator. Recently, there has been increased worldwide interest in the association between low levels of vitamin D and allergic diseases. The purpose of this study was to assess the relationship between serum vitamin D levels and allergic/vasomotor rhinitis (AR/VR) in children. METHODS: This study included 164 patients. The sample included 59 patients with AR, 42 patients with VR, and 63 controls. Their ages ranged from 0 to 16 years. We examined the levels of 25-hydroxyvitamin D, Immunoglobulin E, specific IgE, and eosinophil cationic protein; peripheral blood eosinophil count; and the results of a skin prick test. RESULTS: Serum 25-hydroxyvitamin D levels were 19.0+/-8.5 ng/mL in the AR group, 25.5+/-10.9 ng/mL in the VR group, and 26.9+/-10.7 ng/mL in the control group. After adjustment for body mass index and season at the time of blood sampling, vitamin D levels in the AR group were lower than those of the VR group (P=0.003) and control group (P<0.001). Vitamin D levels were inversely correlated with Immunoglobulin E levels (r=-0.317, P<0.001). AR patients with food allergy or atopic dermatitis did not have lower levels of 25-hydroxyvitamin D than AR patients without these diseases. CONCLUSION: This study demonstrates a possible relationship between vitamin D levels and allergic rhinitis in Korean children. PMID- 26512258 TI - Food allergen sensitization in young children with typical signs and symptoms of immediate-type food allergies: a comparison between monosensitized and polysensitized children. AB - PURPOSE: The clinical interpretation of children sensitized to allergens is challenging, particularly in children with food allergies. We aimed to examine clinical differences between children with monosensitization and those with polysensitization to common food allergens and to determine risk factors for polysensitization in young children <10 years of age with immediate-type food allergies. METHODS: The study included children <10 years of age with signs and symptoms indicative of immediate-type food allergies. Serum total IgE level was measured, and ImmunoCAP analysis for food allergens was performed. RESULTS: The mean age of the study subjects was 1.6+/-1.6 years (75 boys and 51 girls). Thirty eight children (30.2%) were monosensitized and 88 children (69.8%) were polysensitized. Multivariate logistic regression analysis showed that the development of polysensitization to common food allergens was positively associated with a parental history of allergic rhinitis (adjusted odds ratio [aOR], 6.28; 95% confidence interval [CI], 1.78-22.13; P=0.004), season of birth (summer/fall) (aOR, 3.10; 95% CI, 1.10-8.79; P=0.033), and exclusive breastfeeding in the first 6 months of age (aOR, 3.51; 95% CI, 1.20-10.25; P=0.022). CONCLUSION: We found significant clinical differences between children with monosensitization and those with polysensitization to common food allergens and identified risk factors for the development of polysensitization in young children with immediate-type food allergies. Clinicians should consider these clinical risk factors when evaluating, counseling, treating, and monitoring young children with food allergies. PMID- 26512259 TI - Change in the height of Korean children and adolescents: analysis from the Korea National Health and Nutrition Survey II and V. AB - PURPOSE: The mean adult height of Koreans has increased since nationwide anthropological measurements began in 1967. The objective of this study was to evaluate differences in heights of Korean late adolescents and young adults within and between the Second and Fifth Korea National Health and Nutrition Examination Surveys (KNHANES II and V). METHODS: Koreans aged <=22 years with available measurements of height were enrolled from the KNHANES surveys (KNHANES II: n=3,372 [1,732 males and 1,640 females]; KNHANES V: n=6,190 [3,198 males and 2,992 females]). Differences in the height of KNHANES respondents within and between surveys were evaluated according to age and sex. RESULTS: In KNHANES II, there was no significant difference in height between males aged 17-19 years and those aged 20-22 years (174.3+/-0.5 cm vs. 174.3+/-0.6 cm, P=0.995). Females aged 20-22 years were taller than those aged 17-19 years (159.8+/-0.4 cm vs. 161.0+/ 0.4 cm, P=0.017). Females aged 17-19 years were significantly taller in KNHANES V than in KNHANES II (161.2+/-0.3 cm vs. 159.8+/-0.4 cm, P=0.004). Respondents aged 20-22 years were taller in KNHANES V than in KNHANES II, although not significantly so; the difference was 0.3+/-0.8 cm in males (P=0.721) and 0.5+/ 0.6 cm in females (P=0.386). CONCLUSION: Koreans appear to continue growing even in their late adolescence and early twenties. Consequently, it may be necessary to expand the reference age ranges of the Korean growth chart. Additionally, a longitudinal growth survey is needed to determine growth patterns and secular trend in height among Koreans. PMID- 26512260 TI - Evaluation of new American Academy of Pediatrics guideline for febrile urinary tract infection. AB - PURPOSE: To evaluate the practical applications of the diagnosis algorithms recommended by the American Academy of Pediatrics urinary tract infection (UTI) guideline. METHODS: We retrospectively reviewed the medical records of febrile UTI patients aged between 2 and 24 months. The patients were divided into 3 groups: group I (patients with positive urine culture and urinalysis findings), group II (those with positive urine culture but negative urinalysis findings), and group III (those with negative urine culture but positive urinalysis findings). Clinical, laboratory, and imaging results were analyzed and compared between the groups. RESULTS: A total of 300 children were enrolled. The serum C reactive protein level was lower in children in group II than in those in groups I and III (P<0.05). Children in group I showed a higher frequency of hydronephrosis than those in groups II and III (P<0.05). However, the frequencies of acute pyelonephritis (APN), vesicoureteral reflux (VUR), renal scar, and UTI recurrence were not different between the groups. In group I, recurrence of UTI and presence of APN were associated with the incidence of VUR (recurrence vs. no recurrence: 40% vs.11.4%; APN vs. no APN: 23.3% vs. 9.2%; P<0.05). The incidence of VUR and APN was not related to the presence of hydronephrosis. CONCLUSION: UTI in febrile children cannot be ruled out solely on the basis of positive urinalysis or urine culture findings. Recurrence of UTI and presence of APN may be reasonable indicators of the presence of VUR. PMID- 26512261 TI - The efficacy and safety of Montelukast sodium in the prevention of bronchopulmonary dysplasia. AB - PURPOSE: The purpose of this study was to evaluate the efficacy and safety of Montelukast sodium in the prevention of bronchopulmonarydysplasia (BPD). METHODS: The Interventional study was designed as a multicenter, prospective, and randomized trial, with open labeled and parallel-experimental groups, 66 infants were enrolled and allocated to either the case group (n=30) or the control group (n=36) based on gestational age (GA). Infants in the case group were given Montelukast sodium (Singulair) based on their body weight (BW). Zero week was defined as the start time of the study. RESULTS: The incidence of moderate to severe BPD was not different between the groups (case group: 13 of 30 [43.3%] vs. control group: 19 of 36 [52.8%], P=0.912). Additionally, secondary outcomes such as ventilation index, mean airway pressure and resort to systemic steroids were not significantly different. There were no serious adverse drug reactions in either group, and furthermore the rate of occurrence of mild drug related-events were not significantly different (case group: 10 of 42 [23.8%] vs. control group: 6 of 48 (15.8%), P=0.414). CONCLUSION: Montelukast was not effective in reducing moderate or severe BPD. There were no significant adverse drug events associated with Montelukast treatment. PMID- 26512262 TI - Parry-Romberg syndrome with ipsilateral hemipons involvement presenting as monoplegic ataxia. AB - Parry-Romberg syndrome (PRS) is a rare, acquired disorder characterized by progressive unilateral facial atrophy of the skin, soft tissue, muscles, and underlying bony structures that may be preceded by cutaneous induration. It is sometimes accompanied by ipsilateral brain lesions and neurological symptoms. Here we present the case of a 10-year-old girl with right-sided PRS and recurrent monoplegic ataxia of the left leg. At 4 years of age, she presented with localized scleroderma over the right parietal region of her scalp; her face gradually became asymmetric as her right cheek atrophied. Brain magnetic resonance imaging revealed hemiatrophy of the face and skull base, and T2 weighted images showed increased signal in the right hemipons and hemicerebellar peduncle. Magnetic resonance angiography findings were unremarkable. She was treated with oral prednisolone, and her recurrent gait ataxia diminished within 2 months of the follow-up period. To the best of our knowledge, this is only the second case of PRS presenting with an abnormal involvement of the ipsilateral hemipons. PMID- 26512263 TI - Hemophagocytic lymphohistiocytosis diagnosed by brain biopsy. AB - Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever, splenomegaly, jaundice, and pathologic findings of hemophagocytosis in bone marrow or other tissues such as the lymph nodes and liver. Pleocytosis, or the presence of elevated protein levels in cerebrospinal fluid, could be helpful in diagnosing HLH. However, the pathologic diagnosis of the brain is not included in the diagnostic criteria for this condition. In the present report, we describe the case of a patient diagnosed with HLH, in whom the brain pathology, but not the bone marrow pathology, showed hemophagocytosis. As the diagnosis of HLH is difficult in many cases, a high level of suspicion is required. Moreover, the pathologic diagnosis of organs other than the bone marrow, liver, and lymph nodes may be a useful alternative. PMID- 26512264 TI - Experimental Set Up of P300 Based Brain Computer Interface Using a Bioamplifier and BCI2000 System for Patients with Spinal Cord Injury. AB - OBJECTIVE: Brain computer interface (BCI) is one of the most promising technologies for helping people with neurological disorders. Most current BCI systems are relatively expensive and difficult to set up. Therefore, we developed a P300-based BCI system with a cheap bioamplifier and open source software. The purpose of this study was to describe the setup process of the system and preliminary experimental results. METHODS: Ten spinal cord-injured patients were recruited. We used a sixteen-channel EEG(KT88-1016, Contec, China) and BCI2000 software (Wadsworth center, NY, USA). Subjects were asked to spell a 5-character word using the P300-based BCI system with 10 minutes of training. EEG data were acquired during the experiment. After subjects spelled the word for ten trials, the spelling accuracy and information transfer rate (ITR) were obtained in each patients. RESULTS: All subjects performed the experiment without difficulty. The mean accuracy was 59.4+/-22.8%. The spelling accuracy reversely correlated with the age. Younger subjects spelled with higher accuracy than older subjects (p=0.018). However, sex, injury level, time since injury and ASIA scale were not correlated with the accuracy. The mean of ITR was 2.26+/-1.22 bit/min. CONCLUSION: This study showed that a BCI system can be set up inexpensively with a low-price bioamplifier and open-source software. The spelling accuracy was moderately achieved with our system. P300-based BCI is useful in young patients, but modification is necessary in old patients who have low ability of recognition and concentration. PMID- 26512265 TI - Treatment of Spinal Epidural Abscess and Predisposing Factors of Motor Weakness: Experience with 48 Patients. AB - OBJECTIVE: Spinal epidural abscess (SEA) can be fatal if untreated, so early diagnosis and treatment are essential. We conducted a retrospective study to define its clinical features and evaluate the risk factors of motor weakness. METHODS: We retrospectively analyzed the medical records and images of patients with SEA who had been hospitalized in our institute from January 2005 to June 2012. Pyogenic SEA patients were categorized as patients without motor weakness (Group A) and with motor weakness (Group B). Abscess volume was measured using the Gamma-Plan program. Intervertebral foramen height and posterior disc height were measured to evaluate degree of spinal stenosis. RESULTS: Of 48 patients with pyogenic SEA, 33 (68%) were treated surgically, and 15 (32%) were treated with antibiotics. Eleven patients had weakness and abscess volume was unrelated to motor weakness. Old age, 'spare room' (abscess volume subtracted from spinal volume) and intervertebral foramen height and posterior disc height were statistically significant. Among the 48 patients, 43 (85%) had good outcome and erythrocyte sedimentation rate (ESR) was the only meaningful prognostic factor (p=0.014). The cut-off value of ESR was 112mm/h with 80% sensitivity and 79% specificity and had borderline significance (p=0.062). CONCLUSION: SEA needs emergent diagnosis and treatment. Motor weakness is the most important factor in treatment decision. By careful image reading, early surgical treatment can be an option for selected patients with severe spinal stenosis for prevent motor weakness. Inflammatory markers, especially ESR, are valuable to identify worsening of SEA. PMID- 26512266 TI - The Actual Level of Symptomatic Soft Disc Herniation in Patients with Cervical Disc Herniation. AB - OBJECTIVE: The aim of this study was to predict the relationship between the symptomatic disc herniation level and the osteophyte level or decreased disc height in patients with cervical disc herniation. METHODS: Between January 2011 and December 2012, 69 patients with an osteophyte of the cervical spine underwent surgery at a single center due to soft cervical disc herniation. Data including soft disc herniation level, osteophyte level in the posterior vertebral margin, Cobb's angle, and symptom duration were retrospectively assessed. The patients were divided into three groups according to the relationship between the degenerative change level and the level of reported symptoms. RESULTS: Among the 69 patients, 48 (69.6%) showed a match between osteophyte level and soft disc herniation level. Disc herniation occurred at the adjacent segment to degenerative osteophyte level in 12 patients (17.4%) and at both the adjacent and the osteophyte level in nine (13.0%). There was no significant difference in Cobb's angle or duration among the three groups. Osteophyte type was not significant. The mean disc height of the prominent degenerative change level group was lower than the adjacent segment level, but this was not significant. CONCLUSION: Soft cervical disc herniation usually occurs at the level an osteophyte forms. However, it may also occur at segments adjacent to that of the osteophyte level. Therefore, in patients with cervical disc herniation, although a prominent osteophyte alone may appear on plain radiography, we must suspect the presence of soft disc herniation at other levels. PMID- 26512267 TI - The Effect of Different Pillow Heights on the Parameters of Cervicothoracic Spine Segments. AB - OBJECTIVE: To investigate the effect of different pillow heights on the slope of the cervicothoracic spine segments. METHODS: A prospective analysis of data from 16 asymptomatic adults (aged 20 to 30 years) was carried out. Exclusion criteria were history of injury or accident to the cervicothoracic spine, cervicothoracic spine surgery, or treatment for neck symptoms. We used three different pillow heights: flat (0 cm), 10-cm, and 20-cm pillows. Cervical sagittal parameters, measured with radiography, included; C2-7 Cobb's angle, T1 slope (T1S), thoracic inlet angle (TIA), and neck tilt (NT). Statistical analyses were performed using Spearman correlation coefficients. RESULTS: As the height of the pillow increased, the T1S & C2-7 Cobb's angle increased while the NT values tended to decrease. The TIA values, however, remained constant. Additionally, there was a statistically significant sex difference in T1S with the 0-cm pillow (p=0.01), and in NT with the 20-cm pillow (p=0.01). CONCLUSION: From the data obtained in this study, we recommend that the most suitable pillow height is 10 cm, considering the normal cervical lordosis. PMID- 26512268 TI - Rapidly Progressive Gas-containing Lumbar Spinal Epidural Abscess. AB - Gas-containing (emphysematous) infections of the abdomen, pelvis, and extremities are well-known disease entities, which can potentially be life-threatening. They require aggressive medical and often surgical treatment. In the neurosurgical field, some cases of gas-containing brain abscess and subdural empyema have been reported. Sometimes they progress rapidly and even can cause fatal outcome. However, gas-containing spinal epidural abscess has been rarely reported and clinical course is unknown. We report on a case of rapidly progressive gas containing lumbar spinal epidural abscess due to Enterococcus faecalis in a 72 year-old male patient with diabetes mellitus. PMID- 26512269 TI - Lumbar Disc Herniation Combined with Posterior Apophyseal Ring Separation in a Young Child: A Case Report. AB - Lumbar disc herniation in children aged 10 years or less is extremely uncommon and posterior apophyseal ring separation is not a common injury that usually occurs in adolescents or young adults after a sports-related microtraumatism. The authors report an unique case of 10-year-old boy who presented with low back pain and radiating pain on both legs. The boy received conservative treatment, which included anti-inflammatory medication, muscle relaxants, and physical therapy, but symptoms were not improved. Computed tomography and magnetic resonance imaging revealed a huge central disc herniation combined with posterior apophyseal ring separation. Microscopic lumbar discectomy with the removal of apophyseal ring separation was performed due to the intractable pain. At six months after surgery, the child was symptom free. PMID- 26512270 TI - Delayed or Missed Diagnosis of Cervical Instability after Traumatic Injury: Usefulness of Dynamic Flexion and Extension Radiographs. AB - Prompt and accurate diagnosis of cervical spine injury is important to prevent the catastrophic results that can be caused by undetected lesions. Delayed or missed diagnosis of cervical spine injury occurs with an incidence of 5 to 20% according to previous studies. In this study, we report four cases of cervical instability without initial radiologic evidence. These cases demonstrate that dynamic flexion and extension radiographies can be a proper choice of modality to diagnose and exclude the possibility of cervical instability in a patient with a suspicious ligament injury on the static radiographies following acute cervical trauma. PMID- 26512271 TI - Intracranial Hypertension in a Patient with a Chiari Malformation Accompanied by Hyperthyroidism. AB - The Chiari malformation is an infrequently detected congenital anomaly characterized by the downward displacement of the cerebellum with a tonsillar herniation below the foramen magnum that may be accompanied by either syringomyelia or hydrocephalus. Surgery, such as foramen magnum decompression, is indicated for a symptomatic Chiari malformation, although an incidental lesion may be followed-up without further treatment. Infrequently, increased intracranial pressure emerges due to hyperthyroidism. A nineteen-year-old girl visited our outpatient clinic presented with a headache, nausea and vomiting. A brain and spinal magnetic resonance image study (MRI) indicated that the patient had a Chiari I malformation without syringomyelia or hydrocephalus. An enlarged thyroid gland was detected on a physical examination, and serum markers indicated Graves' disease. The patient started anti-hyperthyroid medical treatment. Subsequently, the headache disappeared after the medical treatment of hyperthyroidism without surgical intervention for the Chiari malformation. A symptomatic Chiari malformation is indicated for surgery, but a surgeon should investigate other potential causes of the symptoms of the Chiari malformation to avoid unnecessary surgery. PMID- 26512272 TI - An Incidental Finding of a Radiopaque Pill following Cervical Spinal Surgery in a Parkinson's Disease Patient. AB - There are previous reports of the identification of radiopaque medications on abdominal X-rays or computed tomography (CT). We describe an interesting case of the incidental identification of a radiopaque medication on cervical spinal CT following cervical spinal surgery. A sixty seven-year-old male patient with Parkinson's disease (PD) visited our emergency center with a C5-6 dislocation and fracture. Surgery was performed with open reduction and pedicle screw fixation through the posterior approach. No abnormal events occurred during the perioperative period. However, a radiopaque incidental foreign body in front of the C6 vertebrae was found on a cervical spinal CT and X-rays that were performed as routine examinations on postoperative day 3. After 6 hours, we performed gastrofibroscopy (GFS) but were unable to find anything. Therefore, we checked all of his medications related to the neck and check X-ray again. One enteric coated pill he had taken exhibited strong radiodensity. Although our patient underwent an unnecessary GFS, every spinal surgeon should keep in mind that radiopaque pills can appear similar to spinal instruments on X-ray and CT. In addition, we should also know the associated dysphagia is a possible cause of the delayed passage of medicine in PD with or without cervical osteophytes. PMID- 26512273 TI - Syringomyelia Associated with a Huge Retrocerebellar Arachnoid Cyst: A Case Report. AB - Occasionally, a posterior fossa arachnoid cyst can induce compression of the spinal cord and cause syringomyelia. Here, we report the case of a 29-year-old man with both progressive shoulder pain and gait disturbance, who was found to have a huge retrocerebellar arachnoid cyst associated with syringomyelia. Accordingly, posterior fossa decompression and arachnoid cyst excision were performed. Post-operative MRI showed a marked reduction in the size of the arachnoid cyst and syringomyelia. The patient's symptoms were clearly improved compared to before surgery. In our view, treatment in such patients should focus on decompressing the foramen magnum and include the removal of the coexistent arachnoid cyst walls, which appear to be the crucial factor in development of syringomyelia. In this report, we discuss the pathogenic mechanisms underlying syringomyelia-associated retrocerebellar arachnoid cyst and review the current literature on this topic. PMID- 26512274 TI - Primary Spinal Cord Oligodendroglioma with Postoperative Adjuvant Radiotherapy: A Case Report. AB - Primary spinal cord oligodendrogliomas are rare tumors comprising two percent of all spinal cord tumors. Although a treatment guideline has yet to be established, maximal surgical resection is primary in the treatment of spinal cord oligodendrogliomas. Adjuvant radiotherapy has remained controversial, and it is unclear whether chemotherapy adds any benefit. In this case report, the authors present a 24-year-old male who had a seven-year history of left leg weakness and a radiating pain in both legs. Magnetic resonance image (MRI) showed an intramedullary mass at the T4-T8 level. He underwent subtotal removal of the tumor and pathologic diagnosis revealed a WHO grade II oligodendroglioma. The patient was treated with radiotherapy postoperatively and followed up with MRI annually. Clinical and radiological status of the patient had been stationary for four years after the surgery. The five-year follow-up MRI showed an increase in the size and extent of the residual tumor. Despite radiological progression, considering that symptoms and the performance status of the patient had remained unchanged, further treatment has not been performed. Given the clinical outcome of this patient, close observation after subtotal removal with adjuvant radiotherapy is one of the acceptable treatment options for WHO grade II spinal cord oligodendrogliomas. PMID- 26512275 TI - Epithelioid Sarcoma in the Cervical Spine: A Case Report. AB - Epithelioid sarcoma is a rare and highly malignant soft tissue neoplasm that most commonly occurs in the long bones. This uncommon tumor has a poor clinical outcome, and the modality of its treatment has not yet been fully established. The authors report an extremely rare presentation of epithelioid sarcoma in the cervical spine, along with its clinical progression, imaging, and pathology. The patient underwent three surgical procedures and adjuvant radiochemical management. He survived for 25 months with a good general condition and adapted well to his social activity. Systemic metastasis was not found, but the patient died of respiratory failure due to direct tracheal invasion of the tumor. PMID- 26512276 TI - Idiopathic Hypertrophic Pachymeningitis in the Craniocervical Junction. AB - Idiopathic hypertrophic pachymeningitis (IHP) is a rare disease, and it is characterized by chronic progressive inflammatory fibrosis and thickening of the dura mater with resultant compression of the spinal cord or neural structure without any identifiable cause. It can occur in the intracranial or spinal dura mater alone or as a craniospinal form. The spinal form is rarer than the cranial form and the craniospinal form is extremely rare. We report a rare case of IHP in the craniocervical junction involving both the cranial and spinal dura mater and discuss the diagnosis and management of the disease. PMID- 26512277 TI - Spontaneous Spinal Epidural Hematoma on the Ventral Portion of Whole Spinal Canal: A Case Report. AB - Spontaneous spinal epidural hematoma is an uncommon but disabling disease. This paper reports a case of spontaneous spinal epidural hematoma and treatment by surgical management. A 32-year-old male presented with a 30-minute history of sudden headache, back pain, chest pain, and progressive quadriplegia. Whole spinal sagittal magnetic resonance imaging (MRI) revealed spinal epidural hematoma on the ventral portion of the spinal canal. Total laminectomy from T5 to T7 was performed, and hematoma located at the ventral portion of the spinal cord was evacuated. Epidural drainages were inserted in the upper and lower epidural spaces. The patient improved sufficiently to ambulate, and paresthesia was fully recovered. Spontaneous spinal epidural hematoma should be considered when patients present symptoms of spinal cord compression after sudden back pain or chest pain. To prevent permanent neurologic deficits, early and correct diagnosis with timely surgical management is necessary. PMID- 26512278 TI - A Rare Case of Malignant Lymphoma Occurred at Spinal Epidural Space: A Case Report. AB - The sacral spinal epidural space is an uncommon site for primary malignant lymphomas, presenting with symptoms associated with cauda equina compression. Especially, lumbo-sacral epidural lymphoma has been reported to be very rare. We present a rare case of 29-year-old male with sacral spinal epidural malignant lymphoma. The patient complained of tingling sensation in his buttocks that was radiating to his calf. The neurological examination was normal. Magnetic resonance imaging (MRI) with contrast showed a well-defined extradural mass lesion at the mid L5 to mid S2 level. The lesion was iso- to hypointense on T1 and T2 weighted images and showed homogenous enhancement and a focal enhancement in the L5 vertebral body on post-contrast images. The patient underwent a L5-S2 laminectomy and subtotal excision of the lesion. Intra-operatively, the lesion was extradural and not densely adherent to the dura; the lesion was friable, not firm, fleshy, brownish and hypervascular. The histologic diagnosis was grade 2 non-Hodgkin's follicular lymphoma. Even though the primary spinal epidural non Hodgkin's lymphoma is a very rare disease, clinicians should take it into consideration in the differential diagnosis of patients with spinal epidural tumor. PMID- 26512279 TI - Posterior Spinal Reconstruction with Pedicle Screws, Multiple Iliac Screws and Wisconsin Spinal Wires in a Patient with Neurofibromatosis Scoliosis: A Case Report. AB - A 54-year-old female with neurofibromatosis type 1 presented with progressing truncal shift owing to spinal deformity. On plain radiograph, the Cobb angle was 54 degree in coronal plane. Radiological examinations showed severe dystrophic change with dysplastic pedicles, bony scalloping, neural foraminal widening from dural ectasia. The patient underwent deformity correction and reconstruction surgery from the T9 to the pelvis using multiple iliac screws and Wisconsin interspinous segmental instrumentation by wiring due to maximize fixation points. The postoperative course was uneventful. One-year follow-up radiographs showed a successful curve correction with solid fusion. We report a case of pedicle dysplasia and dystrophic change treated by posterior segmental spinal instrumentation and fusion with help of multiple iliac screws and modified Wisconsin interspinous segmental wiring. PMID- 26512280 TI - Free Vascularized Fibular Strut Autografts to the Lumbar Spine in Complex Revision Surgery: A Report of Two Cases. AB - This case report presents two patients who underwent fibular strut grafting for complex revisions of previous lumbar spine arthrodeses. A case review of the Electronic Medical Record at the index institution was performed to evaluate the timeline of events of the two patients who underwent fibular strut grafting for complex revisions of previous lumbar spine arthrodesis, including imaging studies, progress notes, and laboratory results. One patient had developed chronic L3 vertebral body osteomyelitis from a prior fibular allograft and instrumentation placed for a traumatic burst fracture. The second patient had a severe scoliosis recalcitrant to prior arthrodeses in the context of Marfan syndrome and a persistent L4-5 pseudarthrosis. Both patients underwent free vascularized fibular autograft revision arthrodeses. At most recent long-term follow-up, both patients had improved clinically and neither had required further revision. The use of free vascularized fibular grafting is an excellent option for a variety of spinal indications, and these two reports indicate that the technology may have an indication for use after multiple failed surgeries for osteomyelitis or correction of a multi-level large spinal deformity secondary to Marfan syndrome. PMID- 26512281 TI - A Tethered Cord with Hemivertebra: A Case Report and Review of Literature. AB - Spinal dysraphisms are defined as open and closed dysraphisms. A hemivertebra is a congenital condition seen in 61% of patients with congenital anomalies. The first report of the excision of a hemivertebra was by Royle in 1928. A sixteen year-old girl was admitted to our clinic with a congenital stain on the waist and a normal neurological examination. No new cases have been reported in recent literature. Our case, which is also rare, is associated with a tethered cord only and no other congenital abnormalities. PMID- 26512282 TI - Rare Thoracolumbar Facet Synovial Cyst Presenting as Paraparesis. AB - Spinal cord compressing syndrome due to synovial cyst (SC) of the thoracolumbar spine is a rare clinical condition. In this report we aim to heighten awareness of the thoracolumbar facet synovial cyst as a possible cause of thoracic myelopathy. The SC was removed thoroughly by laminectomy. The patient had an excellent recovery. The etiological and therapeutic aspects are discussed. PMID- 26512283 TI - An Intramuscular Hemangioma at the Cervical Muscle: A Case Report. AB - Intramuscular hemangioma (IMH) primarily develops in the skeletal muscles of the limbs or trunk. The occurrence of IMH in the neck muscle is very rare. In the present report, we describe a case of IMH in the posterior neck muscle. A 58-year old woman presented with a mass on the right posterior neck area, which had developed 2 years previously. The tumor was round in shape, had a size of 3.5*3.0 cm, and was fixed to the surrounding soft tissue. The patient complained of mild dull pain and tenderness at the mass without reddish discoloration. The mass showed a diurnal variation in size - the mass grew in size in the morning and became smaller in the afternoon. Preoperative study confirmed the vascular nature of the tumor. During peritumoral dissection, the mass shrank rapidly following profuse bleeding and arterial cauterization, and hence, it was difficult to distinguish the mass from the surrounding tissues. A total resection was possible with careful dissection of its fibrotic boundary. Based on the histological findings, a definitive diagnosis of cavernous type IMH was made. An initial suspicion of IMH, according to the clinical findings, would be helpful for decision making of further evaluations and surgical plan. PMID- 26512284 TI - Delayed Bilateral C5 Palsy following Circumferential Decompression and Fusion in Patient with Cervical Spondylotic Myelopathy. AB - C5 palsy is a common complication after cervical decompressive surgery, which have 0 to 30% complication rate. A 61-year-old female patient with cervical spondylotic myelopathy showed bilateral C5 palsy following circumferential decompression and fusion. Unexpectedly, bilateral C5 palsy was noted in different time points on postoperative day 2 and 8, respectively. Steroid injection and physical therapy were performed, and her motor function is recovering. Surgeons should make an effort to prevent possible C5 palsy when performing cervical decompression surgery. PMID- 26512285 TI - Erector Spinal Muscular Schwannoma of the Dorsal Ramus Nerve: A Case Report. AB - We present a rare case of intramuscular schwannoma originating from the dorsal ramus nerve in a 62-year-old woman. The mass grew slowly, with pain developing upon touch five years prior. No neurological deficit was detected. The mass was observed in the erector spinae muscles in magnetic resonance imaging (MRI), and surgical excision was performed. The mass was well encapsulated with clear margin. The lesion appeared to originate from the cranial side. We completely removed the mass including the origin. Histopathology confirmed a schwannoma diagnosis. This is the first report, to our knowledge, of a dorsal ramus-nerve schwannoma within the erector spinae muscles. PMID- 26512286 TI - Migration of an Intracranial Subdural Hematoma to the Spinal Subdural Space: A Case Report. AB - A 57-year-old man complained of severe lower back pain and radicular pain in both legs for 1 week after falling from a ladder. Magnetic resonance imaging (MRI) of the spine showed a subdural hematoma (SDH), which was surgically removed. The patient had no back pain or the radicular leg pain at 2 weeks post-surgery. However, he complained of diffuse headaches upon follow-up. Brain computed tomography (CT) and MRI revealed an intracranial SDH, which was immediately removed by surgery. During his 1-year follow-up, he reported that the pain had resolved without recurrence. Simultaneous spinal and intracranial SDH are rare and no standard treatment exists for this condition. This case suggests that it is possible that an intracranial SDH can migrate into the cerebrospinal fluid (CSF) space through an arachnoid tear. CSF circulation allows the intracranial SDH to enter subarachnoid spaces encasing the spinal cord. In order to prevent irreversible damage, surgical intervention should be considered for case of spinal SDH with progressive neurological deficits. PMID- 26512287 TI - Isolated Painless Foot Drop due to Cerebral Infarction Mimicking Lumbar Radiculopathy: A Case Report. AB - Although they usually originate from peripheral problems, foot drop is caused by lesions affecting the neural pathway related to dorsiflexor muscles, whether of central or peripheral origin. We present a patient with sudden isolated foot drop caused by a small infarct in the primary motor cortex mimicking a peripheral origin. This report indicates that patients presenting isolated foot drop should be managed carefully and the possibility of both central and peripheral causes should be considered. To our knowledge, this is the first report of sudden isolated foot drop caused by a cortical infarction mimicking lumbar radiculopathy. PMID- 26512288 TI - Spontaneous Spinal Subdural Hematoma causing Brown-Sequard Syndrome with Thrombocytopenic Myelodysplastic Syndrome. AB - Spontaneous spinal subdural hematoma (SSDH) is a very rare condition. We report a case of SSDH presenting with Brown-Sequard syndrome, treated by surgical evacuation. A 77-year-old woman was hospitalized for back pain without trauma history. As she showed progressive sensory loss and right-side dominant paraparesis, we performed magnetic resonance imaging and confirmed the SSDH in the thoracic area. Therefore, she underwent emergent operation and the hematoma was evacuated successfully. After the operation, the patient showed improvement in neurologic function. PMID- 26512289 TI - Symptomatic Large Spinal Extradural Arachnoid Cyst: A Case Report. AB - Spinal extradural arachnoid cysts (SEACs) are relatively rare cause of compressive myelopathy. SEACs can be either congenital or acquired, but the etiology and the mechanism for their development are still unclear. A number of cases have been reported in the literature, and the one-way valve mechanism is the most widely accepted theory which explains the expansion of cysts and spinal cord compression. We report two cases of SEAC in this article. Patients had intermittent, progressive cord compressing symptoms. MRI image showed large SEAC which caused compression of the spinal cord. Pre-operative cystography and CT myelography were performed to identify the communicating tract. Pre-operative epidural cystography showed a fistulous tract. The patients underwent primary closure of the dural defect which was a communicating tract. The operative finding (nerve root herniation through the tract) suggested that the SEAC developed through a checkvalve mechanism. Postoperatively, the patients had no surgical complications and symptoms were relieved. Based on our experience, preoperative identification of the communicating tract is important in surgical planning. Although surgical excision is the standard surgical treatment, primary closure of the dural defect which was a communicating tract can be an acceptable surgical strategy. PMID- 26512290 TI - Spinal Burkitt's Lymphoma Mimicking Dumbbell Shape Neurogenic Tumor: A Case Report and Review of the Literature. AB - Non-Hodgkin's lymphoma (NHL), a disease which may involve the spine, is frequently associated with advanced disease. Radiculopathy caused by spinal root compression as the initial presentation in patients with NHL is very rare and thought to occur in less than 5% of cases. A 69-year-old woman complained of a history of low back pain with right sciatica for 1 month prior to admission. Computed tomography and magnetic resonance imaging of the lumbar spine showed a dumbbell-shape epidural mass lesion extending from L2 to L3, which was suggestive of a neurogenic tumor. After paraspinal approach and L2 lower half partial hemilaminectomy, total excision of the tumor was achieved, followed by rapid improvement of back pain and radiating pain. The lesion was confirmed to be Burkitt's lymphoma by histopathological examination. We then checked whole-body PET-CT, which showed multifocal malignant lesions in the intestine, liver, bone and left supraclavicular lymph node. Although a rare situation, Burkitt's lymphoma should be considered in the differential diagnosis for patients presenting with back and lumbar radicular pain without a prior history of malignancy. Burkitt's lymphoma could be the cause of dumbbell-shape spinal tumor. PMID- 26512291 TI - Two Cases of Klippel-Feil Syndrome with Cervical Myelopathy Successfully Treated by Simple Decompression without Fixation. AB - Klippel-Feil syndrome (KFS) is a congenital developmental disorder of cervical spine, showing short neck with restricted neck motion, low hairline, and high thoracic cage due to multilevel cervical fusion. Radiculopathy or myelopathy can be accompanied. There were 2 patients who were diagnosed as KFS with exhibited radiological and physical characteristics. Both patients had stenosis and cord compression at C1 level due to anterior displacement of C1 posterior arch secondary to kyphotic deformity of upper cervical spine, which has been usually indicative to craniocervical fixation. One patient was referred due to quadriparesis detected after surgery for aortic arch aneurysmal dilatation. The other patient was referred to us due to paraparesis and radiating pain in all extremities developed during gynecological examinations. Decompressive C1 laminectomy was done for one patient and additional suboccipital craniectomy for the other. No craniocervical fixation was done because there was no spinal instability. Motor power improved immediately after the operation in both patients. Motor functions and spinal stability were well preserved in both patients for 2 years. In KFS patients with myelopathy at the C1 level without C1 2 instability, a favorable outcome could be achieved by a simple decompression without spinal fixation. PMID- 26512292 TI - Two Cases of Dedifferentiated Chordoma in the Sacrum. AB - Dedifferentiated chordoma (DC) is defined as a chordoma containing sarcoma components. DC is distinguished from conventional chordoma by the rapidity of tumor growth and the potential for distant metastasis. We report two cases of DC, which are developed in the sacrum. We reviewed the medical records and imaging studies of 2 patients diagnosed with DC and the literature published. In the first case, percutaneous biopsy revealed that it was conventional chordoma in the sacrum. Patient underwent radiation therapy (RT). Six years after the RT, the tumor recurred. Surgical removal was performed and the recurrent tumor was diagnosed as DC in histopathologic examination. In the second case, a patient underwent gross total resection of sacral tumor, which was diagnosed with conventional chordoma. Aggravated tumor was detected after 4 months, and patient underwent reoperation. The second operation revealed the transformation of the tumor into DC. The survival time of the patients after the diagnosis was 10 and 31 months. Dedifferentiated chordoma is a rare and highly aggressive tumor. De novo type exists, but it usually transformed from recurrent chordoma after surgical resection or radiation. PMID- 26512293 TI - Three Cases of Calcifying Pseudoneoplasm which Involve the Epidural Space of the Spine. AB - Calcifying psuedoneoplasm of the spine is a rare non-neoplastic lesion of unknown origin. Radiologic and histologic manifestations are very variable and clinical symptoms include isolated pain, myelopathy, and radiculopathy. Surgical resection is the preferred option of treatment. This report describes three cases of calcifying pseudoneoplasm in the spine. The first case is a 77-year-old female with pain in both legs. The second case is a 67-year-old woman who presented as right leg pain. The third case is a 78-year-old woman with isolated back pain. The involved sites of each of cases were T12, L2-3, and L1, respectively. Surgical resection of the involved masses relieved symptoms. PMID- 26512294 TI - Identification of hypertensive patients with dominant affective temperaments might improve the psychopathological and cardiovascular risk stratification: a pilot, case-control study. AB - BACKGROUND: Although mood disorders and cardiovascular diseases have widely studied psychosomatic connections, data concerning the influence of the psychopathologically important affective temperaments in hypertension are scarce. To define a possibly higher cardiovascular risk subpopulation we investigated in well-treated hypertensive patients with dominant affective temperaments (DOM) and in well-treated hypertensive patients without dominant temperaments the level of depression and anxiety, arterial stiffness and serum Brain-derived Neurotrophic Factor (seBDNF). METHODS: 175 hypertensive patients, free of the history of psychiatric diseases, completed the TEMPS-A, Beck Depression Inventory and Hamilton Anxiety Scale questionnaires in two primary care practices. Of those 175 patients, 24 DOM patients and 24 hypertensive controls (matched in age, sex and the presence of diabetes) were selected for measurements of arterial stiffness and seBDNF level. RESULTS: Beck and Hamilton scores in DOM patients were higher compared with controls. Pulse wave velocity and augmentation index did not differ between the groups while in the DOM patients decreased brachial systolic and diastolic and central diastolic blood pressures were found compared with controls. SeBDNF was lower in the DOM group than in the controls (22.4 +/- 7.2 vs. 27.3 +/- 7.8 ng/mL, p < 0.05). CONCLUSIONS: Although similar arterial stiffness parameters were found in DOM patients, their increased depression and anxiety scores, the decreased brachial and central diastolic blood pressures as well as the decreased seBDNF might refer to their higher vulnerability regarding the development not only of major mood disorders, but also of cardiovascular complications. These data suggest that the evaluation of affective temperaments should get more attention both with regard to psychopathology and cardiovascular health management. PMID- 26512295 TI - Erratum to: Physical activity of elderly patients with rheumatoid arthritis and healthy individuals: an actigraphy study. AB - [This corrects the article DOI: 10.1186/s13030-015-0046-0.]. PMID- 26512296 TI - Proximal interphalangeal replantation with arthrodesis facilitates favorable esthetics and functional outcome. AB - PURPOSE: Management of finger amputations of the proximal interphalangeal (PIP) joint is still controversial. Regrettably, injured PIP joints seldom regain normal active motion; thus, many investigators recommend revision amputation with skeletal injury at or proximal to the PIP joint. We report the functional outcome of patients with replantation or revascularization following complete or incomplete amputations of the PIP joint. METHODS: A total of 15 digital replantations or revascularization were performed on 11 patients (9 males and 2 females, age, 26-69 years) with severe finger injuries at the PIP joint at our Medical Center from 2010 through 2012. Seven patients with 10 complete amputations underwent replantations, and 4 with 5 incomplete avulsion amputations underwent revascularization. PIP arthrodesis was performed in all cases. Routine postoperative evaluation was performed in 13 successfully treated patients. RESULTS: The 13 successfully treated cases were tracked over a follow-up of 12 to 55 months. Arthrodesis of PIP caused significantly lower total active range of motion (TAM; 85-120 degrees ). The mean DASH score was 37/100 (range: 10-64 points). Although mobility is poorer in PIP replantations, adequate PIP joint fixation improves DASH score and hand function. CONCLUSIONS: PIP replantation along with arthrodesis at a functional position for a finger amputation should be performed when the patient wishes to undergo replantation, which facilitates patient satisfaction. PMID- 26512297 TI - Dynamics of Rex3 in the genomes of endangered Iberian Leuciscinae (Teleostei, Cyprinidae) and their natural hybrids. AB - BACKGROUND: Iberian Leuciscinae are greatly diverse comprising taxa of hybrid origin. With highly conservative karyotypes, Iberian Chondrostoma s.l. have recently demonstrated sub-chromosomal differentiation and rapid genome restructuring in natural hybrids, which was confirmed by ribosomal DNA (rDNA) transposition and/or multiplication. To understand the role of repetitive DNAs in the differentiation of their genomes, a genetic and molecular cytogenetic survey was conducted in Achondrostoma oligolepis, Anaecypris hispanica, Iberochondrostoma lemmingii, I. lusitanicum, Pseudochondrostoma duriense, P. polylepis, Squalius pyrenaicus and hybrids between A. oligolepis x (P. duriense/P. polylepis), representing 'alburnine', chondrostomine and Squalius lineages. RESULTS: Partial Rex3 sequences evidenced high sequence homology among Leuciscinae (>=98 %) and different fish families (80-95 %) proposing a relatively recent activity of these elements in the species inspected. Low nucleotide substitution rates (<20 %) and intact ORFs suggests that Rex3 may in fact be active in these genomes. The chromosomal distribution of Rex3 retroelement was found highly concentrated at pericentromeric and moderately at subtelomeric blocks, co-localizing with 5S rDNA loci, and correlating with blocks of heterochromatin and C0t-1 DNA. This accumulation was evident in at least 10 chromosome pairs, a pattern that seemed to be shared among the different species, likely pre-dating their divergence. Nevertheless, species-specific clusters were detected in I. lusitanicum, P. duriense, P. polylepis and S. pyrenaicus demonstrating rapid and independent differentiation. Natural hybrids followed the same patterns of accumulation and association with repetitive sequences. An increased number of Rex3 clusters now associating also with translocated 45S rDNA clusters vouched for other genomic rearrangements in hybrids. Rex3 sequence phylogeny did not agree with its hosts' phylogeny but the observed distribution pattern is congruent with an evolutionary tendency to protect its activity, a robust regulatory system and/or events of horizontal transfer. CONCLUSIONS: This is the first report directed at retroelement physical mapping in Cyprinidae. It helped outlining conceivable ancestral homologies and recognizing retrotransposon activation in hybrids, being possibly associated with genome diversification within the subfamily. The extensive diversity of Iberian Leuciscinae makes them excellent candidates to explore the processes and mechanisms behind the great plasticity distinguishing vertebrate genomes. PMID- 26512298 TI - Pathological variations in mummified feet between two near-distance/long-time populations in Ancient Egypt. AB - BACKGROUND: In ancient populations, a significant quantity of foot pathology was related either to the type of footwear they used or the underlying terrain they walked on. Our study was carried out to analyze these parameters with the foot pathologies the mummies presented. METHODS: Between 2006 and 2012, more than 650 individuals were recovered from the Sharuna and Qarara necropolis (Middle Egypt) dating from the VIth Dynasty of the first Ptolemaic Period to the second Coptic Period. From among them, a total of 73 mummified feet (41 from Sharuna and 32 from Qarara) were studied. We took into account the differences existing between both sites in location (15 km apart) and in time (2500 years apart). RESULTS: Almost all feet from Sharuna were wrapped and impregnated with a preservative substance (anthropological mummification), while the mummification process in Qarara was quite natural. Pathologies were found in 36 of the 73 ft (20 from Sharuna and 16 from Qarara). The differences in foot pathologies between the two sites were analysed. CONCLUSIONS: The foot pathologies we found in both necropolises have led us to hypothesise that the majority of the diachronic differences could be related more to progressive changes in the type of the terrain brought out through droughts, than the changes in footwear habits. PMID- 26512299 TI - Homocysteine levels in women with a history of gestational diabetes mellitus. AB - BACKGROUND: Previous gestational diabetes (pGDM) is a risk factor of type 2 diabetes, hypertension and cardiovascular diseases. Homocysteine is one of markers of cardiovascular risk. The aim of this study was to assess the homocysteine levels in women with pGDM and to evaluate its relationship with current carbohydrate metabolism and nourishment status. METHODS: The study group comprised 199 women at 7.8 +/- 1.0 years after pGDM and 50 control women in whom pGDM was excluded. The analyzed parameters: BMI, WHR, body composition (Tanita SC 330S analyzer), glucose and insulin levels in oral glucose tolerance test (OGTT), insulin resistance index (HOMA-IR), HbA1c, lipid profile, homocysteine, creatinine and creatinine clearance. The Mann-Whitney test and Chi-squared test were used for comparison of continuous and nominal variables, respectively. Correlations between continuous variables in each group were analyzed using Spearman's rank correlation coefficient (Rs). A logarithmic transformation was applied for variables with non-normal distribution. RESULTS: There were no differences between the pGDM women and controls in terms of age, number of childbirths, time from indexed pregnancy, pre-pregnancy BMI, or current anthropometric parameters. In pGDM women HbA1c and all glucose levels in OGTT were significantly higher, but still within the normal range. No significant differences were found in homocysteine levels, HOMA-IR, blood lipids, creatinine and creatinine clearance. Homocysteine levels did not differ significantly in subgroups categorized according to the current OGTT results or BMI. Carbohydrate metabolism disorders, overweight and obesity were associated with higher creatinine clearance. Positive correlation between homocysteine and creatinine (r = 0.21, p < 0.004), and a negative correlation with creatinine clearance (r = 0.16, p < 0.03) were found. CONCLUSIONS: In women with pGDM, homocysteine is not a marker of glucose tolerance disturbances and cardiovascular risk. Increased glomerular filtration rate, observed in more severe disorders of carbohydrate metabolism and greater BMI, may temporarily protect against an increase of proatherogenic homocysteine. PMID- 26512300 TI - Large eccrine angiomatous hamartoma: a novel clinical presentation of disease. AB - BACKGROUND: Eccrine angiomatous hamartoma is a rare benign cutaneous malformation with a diverse clinical appearance, therefore likely to be misdiagnosed and underreported. MAIN OBSERVATIONS: A 44-year-old man presented with a congenital erythematous hyperhidrotic plaque on the left upper back measuring 18 x 25 cm. No pain or tenderness nor hypertrichosis were observed. Histopathology was consistent with the mucinous variant of eccrine angiomatous hamartoma. Intralesional injection of botulinum toxin type A greatly reduced localized sweating, improving patient quality of life. CONCLUSIONS: This article describes a novel clinical presentation of eccrine angiomatous hamartoma: large, erythematous, and slightly indurated plaque localized on the upper back. It emphasizes the role of histopathology in the diagnostic process and botulinum toxin as a viable treatment option. PMID- 26512301 TI - Disseminated refractory pyoderma gangraenosum during an ulcerative colitis flare. Treatment with infliximab. AB - BACKGROUND: Pyoderma gangraenosum is an immune-mediated, inflammatory, neutrophilic dermatosis of unknown etiology, which represents one of the extraintestinal manifestations of inflammatory bowel disease. It is a rare disease that occurs in less than 1% of patients with inflammatory bowel disease and with the same ratio in patients with Crohn's disease and ulcerative colitis. MAIN OBSERVATIONS: A 36-year-old woman was diagnosed with ulcerative colitis 6 years before admission to our dermatology department with an acute disseminated pyoderma gangraenosum with mucosal involvement, during a flare of ulcerative colitis. Disease progression was interrupted by intravenous administration of the tumor necrosis factor-alpha inhibitor infliximab at 5 mg/kg at weeks 0, 2, and 6 (1st cycle) and every 8 weeks thereafter. Improvement of intestinal, skin and oral manifestations was evident already after the 1st cycle of treatment and has been maintained since (at least 16 months). CONCLUSIONS: This case report is one of very few on disseminated pyoderma gangraenosum with oral involvement complicating ulcerative colitis, where infliximab was shown to have a rapid efficacy on skin, mucosal and bowel symptoms. PMID- 26512302 TI - Brooke-Spiegler Syndrome - an underrecognized cause of multiple familial scalp tumors: report of a new germline mutation. AB - BACKGROUND: Brooke-Spiegler syndrome (BSS) is probably an underdiagnosed genodermatosis that predisposes for the development of cylindromas, spiradenomas and trichoepitheliomas mainly of the head and neck. Wide phenotypic variability regarding the number and type of lesions can be observed within a family. Mutations of the CYLD gene are identified in the vast majority of cases and play a key role in BSS pathogenesis. MAIN OBSERVATIONS: Two first degree relatives with numerous erythematous telangiectatic nodules of the scalp present for decades, with recurring tendency regardless the multiple previous excisions. Histopathological review of the lesions revealed predominantly "spiradenocylindromas" in the proband and cylindromas in her sister. The suspicion of BSS was confirmed after detection of a new nonsense germline mutation of CYLD (c.1783C>T pGln 595*) in the proband. CONCLUSIONS: BSS diagnosis can be challenging and is based on clinical-pathological correlation, positive familial association and identification of CYLD mutations. CYLD exerts antineoplastic effects by downregulating intracellular NF-kappaB signalling pathways. The reported mutation affecting the ubiquitin-specific protease domain leads to a truncated and catalytically inactive enzyme. Despite the expanding list of CYLD mutations no firm genotype-phenotype correlation is known so far. Early recognition and treatment of BSS avoid disfiguring changes like "turban tumor". PMID- 26512303 TI - Long-term ustekinumab therapy of psoriasis in patients with coexisting rheumatoid arthritis and Sjogren syndrome. Report of two cases and review of literature. AB - BACKGROUND: Inteleukin (IL)12 and IL23 are two main cytokines involved in the pathogenesis of immune-mediated disease. IL12 is produced by macrophages and B lymphocytes and mediates differentiation of Th1 lymphocytes, while IL23 is a pro inflammatory cytokine essential for the differentiation of Th17 cells. Ustekinumab is a human monoclonal antibody directed against the p40 protein subunit shared by IL12 and IL23, therefore it blocks the signal transmission of both cytokines. MAIN OBSERVATIONS: We present two cases and discuss the long-term efficacy of ustekinumab as a treatment of psoriasis in patients affected by autoimmune diseases, rheumatoid arthritis and Sjogren's syndrome, who presented with severe psoriasis after anti-TNF treatment. CONCLUSIONS: To the best of our knowledge, these are the first cases reported in the literature describing the long-term good efficacy of ustekinumab not only on paradoxical forms of psoriasis induced by anti-TNF-alpha drugs, but also on the articular involvement in a patient affected by RA and in a patient affected by Sjogren syndrome. PMID- 26512304 TI - Cryptococcal panniculitis in a renal transplant recipient: case report and review of literature. AB - BACKGROUND: Cryptococcosis is a deep fungal infection caused by Cryptococcus neoformans. The infection usually involves the lungs, the central nervous system as well as the skin, the bones and the urinary tract. Immunocompromised individuals, including solid organ transplant recipients, are at higher risk for cryptococcal infections. MAIN OBSERVATIONS: We present a 40-year-old renal transplant recipient who developed a slightly painful, erythematous, indurated plaque on his thigh several years after a kidney transplant. Histopathology revealed cryptococcal panniculitis and cryptococcus neoformans subsequently grew from the tissue culture. There was no other systemic involvement. CONCLUSION: The primary cutaneous form of cryptococcosis is extremely rare and early diagnosis and treatment is essential in view of possible dissemination and variable nonspecific clinical manifestations. PMID- 26512305 TI - Pityriasis rosea-like cutaneous eruption as the presenting symptom of Hodgkin lymphoma. Case report and review of the literature. AB - BACKGROUND: Cutaneous involvement by Hodgkin lymphoma is extremely rare and usually follows extensive involvement of the lymph nodes. Cutaneous manifestations of Hodgkin lymphoma may be divided into specific and non-specific. Generalized pruritus is one of the most common non-specific presentations of Hodgkin lymphoma as is cutaneous granulomas. Such signs and symptoms should prompt thorough physical exam, including evaluation of lymph nodes, especially in a young patient. MAIN OBSERVATION: We report a case of a 22-year-old man who presented with night sweats, weight loss, dry cough, and generalized maculopapular eruption that started with a large patch in the center of the chest and spread to the extremities. Biopsy of the rash revealed pityriasis rosea-like findings. A computerized tomography scan of the chest revealed a mediastinal mass. Biopsy of the mediastinal mass revealed Reed-Sternberg cells in a fibrotic background, diagnostic of Hodgkin lymphoma, nodular sclerosis type. CONCLUSION: In conclusion, the presentation of Hodgkin lymphoma as a pityriasis rosea-like cutaneous eruption is rare and clinicians should be aware of this presentation. In this paper we review the non-specific cutaneous manifestations of Hodgkin lymphoma in an effort to raise awareness of the diversity of early cutaneous signs of Hodgkin lymphoma. PMID- 26512306 TI - Photoletter to the editor: Exogenous pigmentation after Diplopoda exposure leading to a dermatoscopic parallel ridge pattern on the plantar region. AB - The millipedes (also known as "gongolos") are arthropods characterized by a cylindrical body consisting of rings. When threatened, they release chemicals that can cause erythema and hyperpigmentation. We report the case of a patient who developed a darkened macule on the plantar region after stepping on a millipede. Dermatoscopic examination showed a parallel-ridge pattern, which is considered typical for acral melanoma. A detailed history was essential for the diagnosis, as the clinical and dermatoscopic features suggested a malignant melanocytic lesion. PMID- 26512307 TI - Photoletter to the editor: Topical 0.5% brimonidine gel to camouflage redness of immature scars. AB - Cutaneous scars develop as a result of a defective wound healing process. Scars are commonly visible as erythematous, sometimes disfiguring lesions which might be stigmatizing for the affected patient. Only a few therapies to improve the appearance of scars are available. Recently, brimonidine - a selective alpha2 receptor-agonist which causes vasoconstriction of small cutaneous vessels - was approved for the treatment of erythemato-telangiectatic rosacea. Topical brimonidine might also be helpful to improve redness of immature scars. Here we report on the effect of brimonidine 0.5% gel on a flat, erythematous scar in a 25 year-old female patient. Whitening of the scar could be observed immediately after application of brimonidine 0.5% gel and a good clinical result was observed within one hour. This effect lasted for up to three hours. We conclude that brimonidine 0.5% gel is a suitable topical therapy to reduce erythema in visible cutaneous scars. PMID- 26512308 TI - Filamentous Basidiomycetes in the Clinical Laboratory. AB - Filamentous basidiomycetes are difficult to identify in the clinical laboratory, mostly due to lack of sporulation, and their role as agents of fungal infection can be difficult to assess. More cases of infection with these agents are being reported as more laboratories gain proficiency with the recognition of their subtle morphologic features and the use of DNA-based methods for identification. Most infections occur in the respiratory tract and sinuses, although brain infection has been reported. Susceptibility testing suggests that these agents will respond well to azole drugs other than fluconazole. PMID- 26512309 TI - Partial genome sequence of Thioalkalivibrio thiocyanodenitrificans ARhD 1(T), a chemolithoautotrophic haloalkaliphilic sulfur-oxidizing bacterium capable of complete denitrification. AB - Thioalkalivibrio thiocyanodenitrificans strain ARhD 1(T) is a motile, Gram negative bacterium isolated from soda lakes that belongs to the Gammaproteobacteria. It derives energy for growth and carbon fixation from the oxidation of sulfur compounds, most notably thiocyanate, and so is a chemolithoautotroph. It is capable of complete denitrification under anaerobic conditions. The draft genome sequence consists of 3,746,647 bp in 3 scaffolds, containing 3558 protein-coding and 121 RNA genes. T. thiocyanodenitrificans ARhD 1(T) was sequenced as part of the DOE Joint Genome Institute Community Science Program. PMID- 26512310 TI - Partial genome sequence of the haloalkaliphilic soda lake bacterium Thioalkalivibrio thiocyanoxidans ARh 2(T). AB - Thioalkalivibrio thiocyanoxidans strain ARh 2(T) is a sulfur-oxidizing bacterium isolated from haloalkaline soda lakes. It is a motile, Gram-negative member of the Gammaproteobacteria. Remarkable properties include the ability to grow on thiocyanate as the sole energy, sulfur and nitrogen source, and the capability of growth at salinities of up to 4.3 M total Na(+). This draft genome sequence consists of 61 scaffolds comprising 2,765,337 bp, and contains 2616 protein coding and 61 RNA-coding genes. This organism was sequenced as part of the Community Science Program of the DOE Joint Genome Institute. PMID- 26512311 TI - The standard operating procedure of the DOE-JGI Microbial Genome Annotation Pipeline (MGAP v.4). AB - The DOE-JGI Microbial Genome Annotation Pipeline performs structural and functional annotation of microbial genomes that are further included into the Integrated Microbial Genome comparative analysis system. MGAP is applied to assembled nucleotide sequence datasets that are provided via the IMG submission site. Dataset submission for annotation first requires project and associated metadata description in GOLD. The MGAP sequence data processing consists of feature prediction including identification of protein-coding genes, non-coding RNAs and regulatory RNA features, as well as CRISPR elements. Structural annotation is followed by assignment of protein product names and functions. PMID- 26512312 TI - High-quality permanent draft genome sequence of Bradyrhizobium sp. strain WSM1743 - an effective microsymbiont of an Indigofera sp. growing in Australia. AB - Bradyrhizobium sp. strain WSM1743 is an aerobic, motile, Gram-negative, non-spore forming rod that can exist as a soil saprophyte or as a legume microsymbiont of an Indigofera sp. WSM1743 was isolated from a nodule recovered from the roots of an Indigofera sp. growing 20 km north of Carnarvon in Australia. It is slow growing, tolerates up to 1 % NaCl and is capable of growth at 37 degrees C. Here we describe the features of Bradyrhizobium sp. strain WSM1743, together with genome sequence information and its annotation. The 8,341,956 bp high-quality permanent draft genome is arranged into 163 scaffolds and 167 contigs, contains 7908 protein-coding genes and 75 RNA-only encoding genes and was sequenced as part of the Root Nodule Bacteria chapter of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 26512313 TI - Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families. AB - BACKGROUND: Previous studies have demonstrated aggregation of autistic traits in undiagnosed family members of children with autism spectrum disorder (ASD), which has significant implications for ASD risk in their offspring. This study capitalizes upon a large, quantitatively characterized clinical-epidemiologic family sample to establish the extent to which family transmission pattern and sex modulate ASD trait aggregation. METHODS: Data were analyzed from 5515 siblings (2657 non-ASD and 2858 ASD) included in the Interactive Autism Network. Autism symptom levels were measured using the Social Responsiveness Scale (SRS) and by computing Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) symptom scores based on items from the SRS and Social Communication Questionnaire. Generalized estimating equation models evaluated the influence of family incidence types (single versus multiple incidence families; male-only ASD-affected families versus families with female ASD-affected children), diagnostic group (non-ASD children with and without a history of language delay with autistic speech and ASD-affected children), and sibling sex on ASD symptom levels. RESULTS: Non-ASD children manifested elevated ASD symptom burden when they were members of multiple incidence families-this effect was accentuated for male children in female ASD-containing families-or when they had a history of language delay with autistic qualities of speech. In this sample, ASD-affected children from multiple incidence families had lower symptom levels than their counterparts in single incidence families. Recurrence risk for ASD was higher for children from female ASD-containing families than for children from male-only families. CONCLUSIONS: Sex and patterns of family transmission modulate the risk of autism symptom burden in undiagnosed siblings of ASD-affected children. Identification of these symptoms/traits and their molecular genetic causes may have significant implications for genetic counseling and for understanding inherited liabilities that confer risk for ASD in successive generations. Autism symptom elevations were more dramatic in non-ASD children from multiple incidence families and those with a history of language delay and autistic qualities of speech, identifying sub-groups at substantially greater transmission risk. Higher symptom burden and greater recurrence in children from female ASD-containing families indicate that familial aggregation patterns are further qualified by sex-specific thresholds, supportive of the notion that females require a higher burden of deleterious liability to cross into categorical ASD diagnosis. PMID- 26512314 TI - Aberrant functioning of the theory-of-mind network in children and adolescents with autism. AB - BACKGROUND: Theory-of-mind (ToM), the ability to infer people's thoughts and feelings, is a pivotal skill in effective social interactions. Individuals with autism spectrum disorders (ASD) have been found to have altered ToM skills, which significantly impacts the quality of their social interactions. Neuroimaging studies have reported altered activation of the ToM cortical network, especially in adults with autism, yet little is known about the brain responses underlying ToM in younger individuals with ASD. This functional magnetic resonance imaging (fMRI) study investigated the neural mechanisms underlying ToM in high functioning children and adolescents with ASD and matched typically developing (TD) peers. METHODS: fMRI data were acquired from 13 participants with ASD and 13 TD control participants while they watched animations involving two "interacting" geometrical shapes. RESULTS: Participants with ASD showed significantly reduced activation, relative to TD controls, in regions considered part of the ToM network, the mirror network, and the cerebellum. Functional connectivity analyses revealed underconnectivity between frontal and posterior regions during task performance in the ASD participants. CONCLUSIONS: Overall, the findings of this study reveal disruptions in the brain circuitry underlying ToM in ASD at multiple levels, including decreased activation and decreased functional connectivity. PMID- 26512315 TI - The effectiveness of manual therapy for the management of musculoskeletal disorders of the upper and lower extremities: a systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. AB - BACKGROUND: Musculoskeletal disorders (MSDs) of the upper and lower extremities are common in the general population and place a significant burden on the health care system. Manual therapy is recommended by clinical practice guidelines for the management of these injuries; however, there is limited evidence to support its effectiveness. The purpose of our review was to investigate the effectiveness of manual therapy in adults or children with MSDs of the upper or lower extremity. METHODS: Randomized controlled trials (RCTs), cohort studies, and case control studies evaluating the effectiveness of manual therapy were eligible. We searched MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Central Register of Controlled Trials from 1990 to 2015. Paired reviewers screened studies for relevance and critically appraised relevant studies using the Scottish Intercollegiate Guidelines Network criteria. Studies with low risk of bias were synthesized following best-evidence synthesis principles. Where available, we computed mean changes between groups, relative risks and 95 % CI. RESULTS: We screened 6047 articles. Seven RCTs were critically appraised and three had low risk of bias. For adults with nonspecific shoulder pain of variable duration, cervicothoracic spinal manipulation and mobilization in addition to usual care may improve self-perceived recovery compared to usual care alone. For adults with subacromial impingement syndrome of variable duration, neck mobilization in addition to a multimodal shoulder program of care provides no added benefit. Finally, for adults with grade I-II ankle sprains of variable duration, lower extremity mobilization in addition to home exercise and advice provides greater short-term improvements in activities and function over home exercise and advice alone. No studies were included that evaluated the effectiveness of manual therapy in children or for the management of other extremity injuries in adults. CONCLUSIONS: The current evidence on the effectiveness of manual therapy for MSDs of the upper and lower extremities is limited. The available evidence supports the use of manual therapy for non-specific shoulder pain and ankle sprains, but not for subacromial impingement syndrome in adults. Future research is needed to determine the effectiveness of manual therapy and guide clinical practice. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42014009899. PMID- 26500764 TI - MicroRNA levels quantified in whole blood varies from PBMCs. AB - MicroRNAs are non-coding RNAs that negatively regulate mRNA expression and play significant roles in both health and disease. Differential microRNA expression has been used to aid diagnosis and discriminate disease stages. The accuracy and reliability of microRNA expression measurement is of utmost importance. Quantification of microRNA expression in human peripheral blood is commonly detected using total RNA extracted via different methods. To date, no convincing data are available showing whether microRNA quantification results can be influenced by the use of total RNA extracted from whole blood or peripheral blood mononuclear cells (PBMCs). This study examined miR-146a-5p and miR-155-5p expression using total RNA extracted in parallel from whole blood and PBMCs of 14 healthy volunteers. The data showed that the quantification of miRNA using total RNA extracted from whole blood varied from that of PBMCs, indicating that the miRNA expression was a result of all the different cell-types present in whole blood. Our results suggested that the source of total RNA and the statistical analyses performed are crucial considerations when designing miRNA research. PMID- 26500764 TI - MicroRNA levels quantified in whole blood varies from PBMCs. AB - MicroRNAs are non-coding RNAs that negatively regulate mRNA expression and play significant roles in both health and disease. Differential microRNA expression has been used to aid diagnosis and discriminate disease stages. The accuracy and reliability of microRNA expression measurement is of utmost importance. Quantification of microRNA expression in human peripheral blood is commonly detected using total RNA extracted via different methods. To date, no convincing data are available showing whether microRNA quantification results can be influenced by the use of total RNA extracted from whole blood or peripheral blood mononuclear cells (PBMCs). This study examined miR-146a-5p and miR-155-5p expression using total RNA extracted in parallel from whole blood and PBMCs of 14 healthy volunteers. The data showed that the quantification of miRNA using total RNA extracted from whole blood varied from that of PBMCs, indicating that the miRNA expression was a result of all the different cell-types present in whole blood. Our results suggested that the source of total RNA and the statistical analyses performed are crucial considerations when designing miRNA research. PMID- 26500764 TI - MicroRNA levels quantified in whole blood varies from PBMCs. AB - MicroRNAs are non-coding RNAs that negatively regulate mRNA expression and play significant roles in both health and disease. Differential microRNA expression has been used to aid diagnosis and discriminate disease stages. The accuracy and reliability of microRNA expression measurement is of utmost importance. Quantification of microRNA expression in human peripheral blood is commonly detected using total RNA extracted via different methods. To date, no convincing data are available showing whether microRNA quantification results can be influenced by the use of total RNA extracted from whole blood or peripheral blood mononuclear cells (PBMCs). This study examined miR-146a-5p and miR-155-5p expression using total RNA extracted in parallel from whole blood and PBMCs of 14 healthy volunteers. The data showed that the quantification of miRNA using total RNA extracted from whole blood varied from that of PBMCs, indicating that the miRNA expression was a result of all the different cell-types present in whole blood. Our results suggested that the source of total RNA and the statistical analyses performed are crucial considerations when designing miRNA research. PMID- 26512319 TI - Tourette Syndrome research highlights 2014. AB - About 200 journal articles reported research on Tourette syndrome and other tic disorders in 2014. Here we briefly summarize a few of the reports that seemed most important or interesting, ranging from animal models to human studies. Readers can comment on our choices or provide their own favorites using the tools on the online article. PMID- 26512320 TI - The ubiquitous and ancient ER membrane protein complex (EMC): tether or not? AB - The recently discovered endoplasmic reticulum (ER) membrane protein complex (EMC) has been implicated in ER-associated degradation (ERAD), lipid transport and tethering between the ER and mitochondrial outer membranes, and assembly of multipass ER-membrane proteins. The EMC has been studied in both animals and fungi but its presence outside the Opisthokont clade (animals + fungi + related protists) has not been demonstrated. Here, using homology-searching algorithms, I show that the EMC is truly an ancient and conserved protein complex, present in every major eukaryotic lineage. Very few organisms have completely lost the EMC, and most, even over 2 billion years of eukaryote evolution, have retained a majority of the complex members. I identify Sop4 and YDR056C in Saccharomyces cerevisiae as Emc7 and Emc10, respectively, subunits previously thought to be specific to animals. This study demonstrates that the EMC was present in the last eukaryote common ancestor (LECA) and is an extremely important component of eukaryotic cells even though its primary function remains elusive. PMID- 26512321 TI - Bone antiresorptive agents in the treatment of bone metastases associated with solid tumours or multiple myeloma. AB - Skeletal lesions contribute substantially to morbidity and mortality in patients with cancer. The disease manifestation course during metastatic bone disease is driven by tumour cells in the bone marrow, which alter the functions of bone resorbing (osteoclasts) and bone-forming (osteoblasts) cells, promoting skeletal destruction. Successful therapeutic strategies for the treatment of metastatic bone disease include bisphosphonates and denosumab that inhibit osteoclast mediated bone resorption. Inhibitors of cathepsin K, Src and activin A are under clinical investigation as potential anti-osteolytics. In this review, we describe current knowledge and future directions of antiresorptive therapies that may reduce or prevent destructive bone lesions from solid tumours and multiple myeloma. PMID- 26512322 TI - Communication of bone cells with hematopoiesis, immunity and energy metabolism. AB - The bone contains the bone marrow. The functional communication between bone cells and hematopoiesis has been extensively studied in the past decade or so. Osteolineage cells and their modulators, such as the sympathetic nervous system, macrophages and osteoclasts, form a complex unit to maintain the homeostasis of hematopoiesis, called the 'microenvironment'. Recently, bone-embedded osteocytes, the sensors of gravity and mechanical stress, have joined the microenvironment, and they are demonstrated to contribute to whole body homeostasis through the control of immunity and energy metabolism. The inter-organ communication orchestrated by the bone is summarized in this article. PMID- 26512323 TI - Cationic surface modification of gold nanoparticles for enhanced cellular uptake and X-ray radiation therapy. AB - A challenge of X-ray radiation therapy is that high dose X-ray can damage normal cells and cause side effects. This paper describes a new nanoparticle-based method to reduce X-ray dose in radiation therapy by internalization of gold nanoparticles that are modified with cationic molecules into cancer cells. A cationic thiol molecule is synthesized and used to modify gold nanoparticles in a one-step reaction. The modified nanoparticles can penetrate cell membranes at high yield. By bring radio-sensitizing gold nanoparticles closer to nuclei where DNA is stored, the total X-ray dose needed to kill cancer cells has been reduced. The simulation of X-ray-gold nanoparticle interaction also indicates that Auger electrons contribute more than photoelectrons. PMID- 26512324 TI - Heavy metals removal from aqueous environments by electrocoagulation process- a systematic review. AB - Heavy metals pollution has become a more serious environmental problem in the last several decades as a result releasing toxic materials into the environment. Various techniques such as physical, chemical, biological, advanced oxidation and electrochemical processes were used for the treatment of domestic, industrial and agricultural effluents. The commonly used conventional biological treatments processes are not only time consuming but also need large operational area. Accordingly, it seems that these methods are not cost-effective for effluent containing toxic elements. Advanced oxidation techniques result in high treatment cost and are generally used to obtain high purity grade water. The chemical coagulation technique is slow and generates large amount of sludge. Electrocoagulation is an electrochemical technique with many applications. This process has recently attracted attention as a potential technique for treating industrial wastewater due to its versatility and environmental compatibility. This process has been applied for the treatment of many kinds of wastewater such as landfill leachate, restaurant, carwash, slaughterhouse, textile, laundry, tannery, petroleum refinery wastewater and for removal of bacteria, arsenic, fluoride, pesticides and heavy metals from aqueous environments. The objective of the present manuscript is to review the potential of electrocoagulation process for the treatment of domestic, industrial and agricultural effluents, especially removal of heavy metals from aqueous environments. About 100 published studies (1977-2016) are reviewed in this paper. It is evident from the literature survey articles that electrocoagulation are the most frequently studied for the treatment of heavy metal wastewater. PMID- 26512325 TI - Prevalence of diabetes and impaired fasting glucose in Peru: report from PERUDIAB, a national urban population-based longitudinal study. AB - OBJECTIVES: We aimed to estimate the prevalences of diabetes and impaired fasting glucose (IFG) in a national sample in Peru and assess the relationships with selected sociodemographic variables. METHODS: We estimated prevalence in PERUDIAB study participants, a nationwide, stratified urban and suburban population selected by random cluster sampling. Between 2010 and 2012, questionnaires were completed and blood tests obtained from 1677 adults >=25 years of age. Known diabetes was defined as participants having been told so by a doctor or nurse and/or receiving insulin or oral antidiabetic agents. Newly diagnosed diabetes was defined as fasting plasma glucose >=126 mg/dL determined during the study and without a previous diabetes diagnosis. IFG was defined as fasting plasma glucose of 100-125 mg/dL. RESULTS: The estimated national prevalence of diabetes was 7.0% (95% CI 5.3% to 8.7%) and it was 8.4% (95% CI 5.6% to 11.3%) in metropolitan Lima. No gender differences were detected. Known and newly diagnosed diabetes prevalences were estimated as 4.2% and 2.8%, respectively. A logistic regression response surface model showed a complex trend for an increased prevalence of diabetes in middle-aged individuals and in those with no formal education. Diabetes prevalence was higher in coastal (8.2%) than in highlands (4.5%; p=0.03), and jungle (3.5%; p<0.02) regions. The estimated national prevalence of IFG was 22.4%, higher in males than in females (28.3% vs 19.1%; p<0.001), and higher in coastal (26.4%) than in highlands (17.4%; p=0.03), but not jungle regions (14.9%; p=0.07). CONCLUSIONS: This study confirms diabetes as an important public health problem, especially for middle-aged individuals and those with no formal education. 40% of the affected individuals were undiagnosed. The elevated prevalence of IFG shows that nearly a quarter of the adult population of Peru has an increased risk of diabetes. PMID- 26512326 TI - Does the CHA2DS2-Vasc score predict procedural and short-term outcomes in patients undergoing transcatheter aortic valve implantation? AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is associated with periprocedural and postprocedural morbidity and mortality. Currently, there is a paucity of risk stratification models for potential TAVI candidates. We employed the CHA2DS2-Vasc score to quantify the risk of 30-day mortality and morbidity in patients undergoing TAVI. METHODS AND RESULTS: A retrospective analysis of registry data for consecutive patients undergoing TAVI at 3 tertiary centres in Northwest England between 2008 and 2013. The CHA2DS2-Vasc score and its modification-the R2CHA2DS2-Vasc score, which includes pre-existing renal impairment and pre-existing conduction abnormality (right bundle branch block/left bundle branch block, RBBB/LBBB)-were calculated for all patients. A total of 313 patients with a mean age of 80 (79.1-80.8) years underwent TAVI. The implanted devices were either the CoreValve or the Edwards-SAPIEN prosthesis. The 30-day mortality was 14.3% in those with a CHA2DS2-Vasc score >=6, whereas it was only 6.2% in those with a score <6 (p=0.04). Using the R2-CHA2DS2-Vasc score, the difference was more pronounced with a 30-day mortality of 22.6% in those patients with an R2-CHA2DS2-Vasc score >=7 compared to 6.0% in those with a R2-CHA2DS2 Vasc score <7 (p=0.001). In multivariable Cox regression analyses, there was a significant and independent relationship between the CHA2DS2-Vasc score (hazard ratio (HR)= 2.71, (1.01 to 7.31); p<0.05) and the modified R2CHA2DS2-Vasc score (HR=4.27 (1.51 to 12.07); p=0.006) with 30-day mortality. CONCLUSIONS: Our study demonstrates the potential use of the CHA2DS2-Vasc or the R2CHA2DS2-Vasc score to quantify the risk of mortality in patients undergoing TAVI. This could have significant implications in terms of clinical as well as patients' decision making. PMID- 26512327 TI - Sympathetic autonomic dysfunction and impaired cardiovascular performance in higher risk surgical patients: implications for perioperative sympatholysis. AB - OBJECTIVE: Recent perioperative trials have highlighted the urgent need for a better understanding of why sympatholytic drugs intended to reduce myocardial injury are paradoxically associated with harm (stroke, myocardial infarction). We hypothesised that following a standardised autonomic challenge, a subset of patients may demonstrate excessive sympathetic activation which is associated with exercise-induced ischaemia and impaired cardiac output. METHODS: Heart rate rise during unloaded pedalling (zero workload) prior to the onset of cardiopulmonary exercise testing (CPET) was measured in 2 observation cohorts of elective surgical patients. The primary outcome was exercise-evoked, ECG-defined ischaemia (>1 mm depression; lead II) associated with an exaggerated increase in heart rate (EHRR >=12 bpm based on prognostic data for all-cause cardiac death in preceding epidemiological studies). Secondary outcomes included cardiopulmonary performance (oxygen pulse (surrogate for left ventricular stroke volume), peak oxygen consumption (VO2peak), anaerobic threshold (AT)) and perioperative heart rate. RESULTS: EHRR was present in 40.4-42.7% in both centres (n=232, n=586 patients). Patients with EHRR had higher heart rates perioperatively (p<0.05). Significant ST segment depression during CPET was more common in EHRR patients (relative risk 1.7 (95% CI 1.3 to 2.1); p<0.001). EHRR was associated with 11% (95%CI 7% to 15%) lower predicted oxygen pulse (p<0.0001), consistent with impaired left ventricular function. CONCLUSIONS: EHRR is common and associated with ECG-defined ischaemia and impaired cardiac performance. Perioperative sympatholysis may further detrimentally affect cardiac output in patients with this phenotype. PMID- 26512328 TI - MRI and serum high-sensitivity C reactive protein predict long-term mortality in non-ischaemic cardiomyopathy. AB - OBJECTIVE: Myocardial fibrosis related to non-specific inflammation can be detected using late gadolinium-enhancement cardiovascular MR (LGE-CMR), which is an important prognostic indicator for dilated cardiomyopathy (DCM). The aims of this study were to define the prognostic factors for DCM with LGE-CMR, and to evaluate the impact of the prognostic factors on adverse effects. METHODS: We performed a retrospective analysis of a prospectively maintained single centre registry. We analysed the data from 76 patients with DCM who had been admitted for acute heart failure. The primary combined end point was defined as all-cause mortality and rehospitalisation. RESULTS: LGE-CMR was present in 39 patients (51%), and the mean follow-up period was 813+/-54 days. The primary end point occurred in 20 patients (5 (13.5%) patients without LGE-CMR and 15 (38.5%) patients with LGE-CMR, p=0.006). Sixteen of 39 patients with LGE-CMR exhibited elevated high-sensitivity C reactive protein (hs-CRP >0.3 mg/dL). Patients with elevated hs-CRP and LGE-CMR had a significantly higher incidence of the primary end point compared with patients with normal hs-CRP and LGE-CMR (62.5%; 10 patients, 22.7%; 5 patients, respectively, p=0.001). Elevated hs-CRP was significantly associated with the primary end point (HR: 4.04; 95% CI 1.67 to 9.76; p=0.002). After elevated hs-CRP was adjusted for known predictors of DCM, it was still associated with the primary end point (HR: 2.91; 95% CI 1.19 to 7.15; p=0.02). CONCLUSIONS: Among patients with DCM, LGE-CMR and elevated hs-CRP are associated with a higher incidence of the long-term combined end point of all cause mortality and hospitalisation. TRIAL REGISTRATION NUMBER: UMIN000001171. PMID- 26512329 TI - Physiology-guided myocardial revascularisation in complex multivessel coronary artery disease: beyond the 2014 ESC/EACTS guidelines on myocardial revascularisation. AB - For patients with multivessel coronary artery disease there are two options for revascularisation: Percutaneous coronary intervention (PCI) or Coronary Artery Bypass Graft Surgery (CABG). In daily clinical practice, a heart team consisting of an interventional cardiologist and a cardiothoracic surgeon decide on the most appropriate mode of revascularization. The current European guidelines on myocardial revascularisation include updated recommendations for patients with multivessel coronary artery disease. In patients with stable angina, three-vessel disease and a SYNTAX score of 23-32 or >32 a class I level of evidence A recommendation for CABG was issued as compared to PCI which received a class III recommendation. Although the authors of this viewpoint greatly appreciate the efforts of the guideline committee, we believe that it was an oversight not to include recommendations on physiology-guided PCI in multivessel disease (MVD). In this viewpoint, it is argued that physiology-guided revascularization using current-generation drug-eluting stents is a reasonable alternative for complex multivessel disease. PMID- 26512330 TI - Coenzyme Q10 for the treatment of heart failure: a review of the literature. AB - Coenzyme Q10 (CoQ10) is an endogenously synthesised and diet-supplied lipid soluble cofactor that functions in the mitochondrial inner membrane to transfer electrons from complexes I and II to complex III. In addition, its redox activity enables CoQ10 to act as a membrane antioxidant. In patients with congestive heart failure, myocardial CoQ10 content tends to decline as the degree of heart failure worsens. A number of controlled pilot trials with supplemental CoQ10 in heart failure found improvements in functional parameters such as ejection fraction, stroke volume and cardiac output, without side effects. Subsequent meta-analyses have confirmed these findings, although the magnitude of benefit tends to be less notable in patients with severe heart failure, or within the context of ACE inhibitor therapy. The multicentre randomised placebo-controlled Q-SYMBIO trial has assessed the impact of supplemental CoQ10 on hard endpoints in heart failure. A total of 420 patients received either CoQ10 (100 mg three times daily) or placebo and were followed for 2 years. Although short-term functional endpoints were not statistically different in the two groups, CoQ10 significantly reduced the primary long-term endpoint-a major adverse cardiovascular event-which was observed in 15% of the treated participants compared to 26% of those receiving placebo (HR=0.50, CI 0.32 to 0.80, p=0.003). Particularly in light of the excellent tolerance and affordability of this natural physiological compound, supplemental CoQ10 has emerged as an attractive option in the management of heart failure, and merits evaluation in additional large studies. PMID- 26512332 TI - Catecholaminergic polymorphic ventricular tachycardia: a rare cause of recurrent syncope. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia characterized by adrenergically induced polymorphic or bidirectional ventricular tachycardia (VT). Although a rare disease, its recognition is important because of its high mortality rate when left untreated. We report an index case of a 32-year-old woman who presented with recurrent syncope. The diagnosis was confirmed by exercise-induced polymorphic ventricular premature beats and episodes of non-sustained VT, in the absence of structural heart abnormalities. She remained event free with beta-blocker therapy. CPVT is a potentially life-threatening disease and should be considered in the case of recurrent syncope, in young individuals. Diagnosis is based on clinical history and exercise testing, which is the gold standard. Therapy is mandatory in all diagnosed individuals. Exercise testing in first-degree relatives is recommended, even in the case of a mutation-negative index patient. PMID- 26512331 TI - Acarbose: safe and effective for lowering postprandial hyperglycaemia and improving cardiovascular outcomes. AB - alpha-Glucosidase inhibitors (AGIs) are a class of oral glucose-lowering drugs used exclusively for treatment or prevention of type 2 diabetes mellitus. AGIs act by altering the intestinal absorption of carbohydrates through inhibition of their conversion into simple sugars (monosaccharides) and thus decrease the bioavailability of carbohydrates in the body, significantly lowering blood glucose levels. The three AGIs used in clinical practice are acarbose, voglibose and miglitol. This review will focus on the cardiovascular properties of acarbose. The current available data suggest that AGIs (particularly acarbose) may be safe and effective for the treatment of prediabetes and diabetes. PMID- 26512333 TI - A vicious cycle of acute catecholamine cardiomyopathy and circulatory collapse secondary to pheochromocytoma. AB - Acute catecholamine cardiomyopathy is an uncommon, life-threatening manifestation of pheochromocytoma. The massive release of catecholamines from the adrenal medulla and their toxic effects on the coronary vessels and the cardiac myocytes play a significant role in the pathogenesis of cardiomyopathy in patients with pheochromocytoma. Severe manifestations, such as acute catecholamine cardiomyopathy, may be the initial presentation, especially in unsuspected and untreated pheochromocytoma cases. The clinical course of catecholamine-induced cardiomyopathy is unpredictable as patients may rapidly deteriorate into circulatory collapse and multisystem crisis. We report a case of a 25-year-old man who presented with catecholamine-induced cardiomyopathy. PMID- 26512334 TI - A case of diffuse pulmonary lymphangiomatosis with unilateral lung invasion. AB - Diffuse pulmonary lymphangiomatosis (DPL) is a rare interstitial lung disease characterized by intrathoracic lymphatic system abnormalities often with involvement of both lungs. Here, we report a 24-year-old male patient with DPL initially located in one lung, presenting only with transient fever. Resection of the right middle and lower lobes was performed for diagnosis and complete removal of the lesions. The pathologic features shown by diffuse smooth thickening of the interlobular septa, bronchovascular bundles, infiltration of patchy ground glass opacities and specific immunohistologic D2-40 and CD34 positive staining confirmed the diagnosis of DPL. The patient did not show signs of relapse during the 2-year follow-up period, which suggests that surgery is an effective and reasonable method for treating DPL with relatively localized lesions. PMID- 26512335 TI - Kindling Kindness for Compassionate Disaster Management. AB - In the health sector, it has become clear that staff who feel better supported deliver better care. Can disaster management learn from this drive to ensure compassionate care to avoid the perils of burnout and empathy exhaustion? PMID- 26512336 TI - Improved Discrimination of Influenza Forecast Accuracy Using Consecutive Predictions. AB - INTRODUCTION: The ability to predict the growth and decline of infectious disease incidence has advanced considerably in recent years. In particular, accurate forecasts of influenza epidemiology have been developed using a number of approaches. METHODS: Within our own group we produce weekly operational real-time forecasts of influenza at the municipal and state level in the U.S. These forecasts are generated using ensemble simulations depicting local influenza transmission dynamics, which have been optimized prior to forecast with observations of influenza incidence and data assimilation methods. The expected accuracy of a given forecast can be inferred in real-time through quantification of the agreement (e.g. the variance) among the ensemble of simulations. RESULTS: Here we show that forecast expected accuracy can be further discriminated with the additional consideration of the streak or persistence of the forecast-the number of consecutive weeks the forecast has converged to the same outcome. DISCUSSION: The findings indicate that the use of both the streak and ensemble agreement provides a more detailed and informative assessment of forecast expected accuracy. PMID- 26512337 TI - Sleep Disorders in Postmenopausal Women. AB - One of the core symptoms of the menopausal transition is sleep disturbance. Peri menopausal women often complain of difficulties initiating and/or maintaining sleep with frequent nocturnal and early morning awakenings. Factors that may play a role in this type of insomnia include vasomotor symptoms, changing reproductive hormone levels, circadian rhythm abnormalities, mood disorders, coexistent medical conditions, and lifestyle. Other common sleep problems in this age group, such as obstructive sleep apnea and restless leg syndrome, can also worsen the sleep quality. Exogenous melatonin use reportedly induces drowsiness and sleep and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age and the menopausal transition. Recently, more potent melatonin analogs (selective melatonin-1 (MT1) and melatonin-2 (MT2) receptor agonists) with prolonged effects and slow-release melatonin preparations have been developed. They were found effective in increasing total sleep time and sleep efficiency as well as in reducing sleep latency in insomnia patients. The purpose of this review is to give an overview on the changes in hormonal status to sleep problems among menopausal and postmenopausal women. PMID- 26512338 TI - A Systematic Review of the Acute Effects of Exercise on Immune and Inflammatory Indices in Untrained Adults. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of global mortality. Although the incidence may be reduced with regular exercise, the health benefits of a single bout of exercise on selected CVD risk factors are not well understood. The primary objective of this review is to consider the transient effects of exercise on immune (neutrophil count) and inflammatory (interleukin-6 [IL-6], C-reactive protein [CRP]) markers in untrained adults. METHODS: MEDLINE, EMBASE, CINAHL, Sports Discus and Cochrane were searched for relevant studies published from January 1946 to May 2013. Randomised controlled or crossover studies which measured any of these parameters in untrained but otherwise healthy participants in the 48 h following about of exercise, less than 1 h in duration were included. RESULTS: Ten studies met the inclusion criteria. The results indicate a single bout of aerobic or resistance exercise of moderate to high intensity promotes an increase in IL-6 (145 %) and neutrophil counts (51 %). It appears that 30-60 min of moderate to high intensity exercise is necessary to elicit such changes although variables such as the mode, intensity and pattern of exercise also affect the response. The acute response of CRP within the included studies is equivocal. CONCLUSIONS: Although responses to CRP are inconsistent, a single bout of exercise can increase the activity of both circulating IL-6 and neutrophil counts in untrained adults. These immune and inflammatory responses to a single bout of exercise may be linked to a range of health benefits. PMID- 26512339 TI - Effects of High-Intensity Training on Anaerobic and Aerobic Contributions to Total Energy Release During Repeated Supramaximal Exercise in Obese Adults. AB - BACKGROUND: Studying relative anaerobic and aerobic metabolism contributions to total energy release during exercise may be valuable in understanding exercise energetic demands and the energetic adaptations that occur in response to acute or chronic exercise in obese adults. The aim of the present study is to evaluate the effects of 6 weeks of high-intensity training (HIT) on relative anaerobic and aerobic contributions to total energy release and on peak power output during repeated supramaximal cycling exercises (SCE) in obese adults. METHODS: Twenty four obese adults (body mass index = +/- 33 kg.m-2) were randomized into a control group (n = 12) and an HIT group (n = 12). Accumulated oxygen deficits (ml.min-1) and anaerobic and aerobic contributions (%) were measured in all groups before and after training via repeated SCE. In addition, the peak power output performed during SCE was determined using the force-velocity test. RESULTS: Before HIT, anaerobic contributions to repeated SCE did not differ between the groups and decreased significantly during the third and fourth repetitions. After HIT, anaerobic contributions increased significantly in the HIT group (+11 %, p < 0.01) and were significantly higher than those of the control group (p < 0.01). Moreover, the peak power obtained during SCE increased significantly in the HIT group (+110 W.kg-1, p < 0.01) and correlated positively with increases in anaerobic contributions (r = 0.9, p < 0.01). CONCLUSIONS: In obese adults, HIT increased anaerobic contributions to energy release which were associated with peak power enhancement in response to repeated SCE. Consequently, HIT may be an appropriate approach for improving energy contributions and muscle power among obese adults. PMID- 26512341 TI - Nonoperative Management of a Multi-Regional Epidural Abscess with Neurological Dysfunction. AB - Spinal epidural abscesses are uncommon, but their incidence is increasing. They represent a collection of purulent material in the epidural space and most commonly occur in the lumbar spine, where they remain localised. Abscesses that affect all three spinal levels (holospinal or multiregional abscesses) are extremely rare, with only a few cases published in the literature. Epidural abscesses are particularly high risk infections as progressive neurological dysfunction can occur rapidly; early diagnosis and treatment is therefore essential to avoid long term neurological complications and reduce potential mortality. Given the uncommon nature of this condition, the treatment remains controversial with no definitive guidance on conservative versus surgical management. The literature mostly recommends surgical decompression along with intravenous antibiotics in patients with neurological abnormalities. We describe a case of a 77-year-old patient presenting with a delayed diagnosis of a multi regional epidural abscess with associated upper motor neurone signs. The patient was successfully treated nonoperatively with a course of antibiotics resulting in complete radiological resolution of the abscess and full neurological recovery. PMID- 26512340 TI - Effect of Low-intensity Exercise on Physical and Cognitive Health in Older Adults: a Systematic Review. AB - BACKGROUND: It is well known that physical exercise is important to promote physical and cognitive health in older population. However, inconsistent research findings were shown regarding exercise intensity, particularly on whether low intensity exercise (1.5 metabolic equivalent tasks (METs) to 3.0 METs) can improve physical and cognitive health of older adults. This systematic review aimed to fill this research gap. The objective of this study is to conduct a systematic review of the effectiveness of low-intensity exercise interventions on physical and cognitive health of older adults. METHODS: Published research was identified in various databases including CINAHL, MEDLINE, PEDro, PubMed, Science Direct, SPORTDiscus, and Web of Science. Research studies published from January 01, 1994 to February 01, 2015 were selected for examination. Studies were included if they were published in an academic peer-reviewed journal, published in English, conducted as randomized controlled trial (RCT) or quasi-experimental studies with appropriate comparison groups, targeted participants aged 65 or above, and prescribed with low-intensity exercise in at least one study arm. Two reviewers independently extracted the data (study, design, participants, intervention, and results) and assessed the quality of the selected studies. Fifteen studies met the inclusion criteria. Quality index ranged from 15 to 18 mean = 18.3 with a full score of 28, indicating a moderate quality. Most of the outcomes reported in these studied were lower limb muscle strength (n = 9), balancing (n = 7), flexibility (n = 4), and depressive symptoms (n = 3). RESULTS: Out of the 15 selected studies, 11 reported improvement in flexibility, balancing, lower limb muscle strength, or depressive symptoms by low-intensity exercises. CONCLUSIONS: The current literature suggests the effectiveness of low intensity exercise on improved physical and cognitive health for older adults. It may be a desired intensity level in promoting health among older adults with better compliance, lower risk of injuries, and long-term sustainability. PMID- 26512342 TI - Lateral Pressure and VAS Pain Score Analysis for the Lateral Lumbar Interbody Fusion Procedure. AB - BACKGROUND: The lateral lumbar interbody fusion (LLIF) procedure is a minimally invasive procedure that has become widely utilized. The LLIF procedure typically involves bending the table to access the disc spaces of interest due to anatomical constraints. It is unknown if this bending process is painful or what pressures are exhibited on the downside part of the body. The goal of the study was to determine whether sex, height, weight, body mass index, bed angle, or positioning relative to the break of the bed affects the downside skin pressures and VAS pain scores in awake volunteers. METHODS: Fifty-six volunteers were placed in the lateral decubitus position and pressure sensors were placed at the downside part of their anatomy (shoulder, T10 rib , iliac crest, and greater trochanter). The pressures were checked with the iliac crest or greater trochanter at 0, 10, 20, 30, 40 degree bed angles. VAS scores were checked when the iliac crest or greater trochanter were at the maximum bed break angles. RESULTS: A significant positive association was found between increased bed angle and pressure at all five areas on the downside body locations (p<0.0001). The greatest pressures were located at the iliac crest and greater trochanter when these specific locations were centered over the break of the bed (p<0.0001). When the iliac crest was placed at maximal bed break, each unit increase in BMI increased the VAS pain by 0.13 (p<0.0001)and men had 1.96 (p=0.0009)higher VAS scores then women. When the greater trochanter was placed at the maximal bed break, each unit increase in BMI decreased VAS pain by 0.19 (p<0.0001) and women had 1.55 (p=0.0002)higher VAS pain scores then men. CONCLUSIONS: In awake volunteers, the pressure at the iliac crest or greater trochanter at the break of the bed increases by increasing the bed angle. Women with a lower BMI had high VAS pain scores when their greater trochanter was at maximal bed break. Men with higher BMI had high VAS pain scores when their iliac crest was at maximal bed break. An awareness of the iliac crest or greater trochanter at the break of the bed should be considered to prevent pain and increased pressure based on the patient's sex and BMI. PMID- 26512343 TI - Clinical outcomes after treatment with disc prostheses in three lumbar segments compared to one- or two segments. AB - BACKGROUND: Fusion surgery in the rare patients suffering from symptomatic degenerative disc disease (DDD) at three segments has been reported to produce poor results and a high frequency of complications, why patients suffering from DDD at three segments are seldom offered surgical treatment. PURPOSE: To compare clinical outcome after one- and two years, between patients that have undergone disc replacement surgery (TDR) at three segments and patients that have been treated at less segments. METHODS: The present study is based on data recorded in the Swedish Spine Registry (SweSpine). The study group consisted of 30 patients who underwent three-segment TDR, the comparative group of 700 patients treated in one or two segments. Analyses included comparisons of preoperative data, postoperative results and improvement from baseline. RESULTS: Our results showed no differences in outcome between groups at one- and two years postoperatively. Improvements achieved after surgery in both groups well exceeded established values for minimally clinically important difference (MCID). CONCLUSIONS: The results of this study show that patients with a diagnosis of therapy-resistant chronic low back pain (CLBP) due to DDD in one, two or even three lumbar segments achieve similar and good results after TDR surgery. CLINICAL RELEVANCE: The rare patients with severe and convincing DDD from three segments might in carefully selected cases be offered surgery, with a reasonable chance of a beneficial outcome. PMID- 26512344 TI - Surgical Treatment Strategies for High-Grade Spondylolisthesis: A Systematic Review. AB - BACKGROUND: HGS is a severe deformity most commonly affecting L5-S1 vertebral segment. Treatment available for HGS includes a range of different surgical options: full or partial reduction of translation and/or abnormal alignment and in situ fusion with or without decompression. Various instrumented or non instrumented constructs are available, and surgical approach varies from anterior/posterior to combined depending on surgeon preference and experience. The aim of this systematic review was to review the literature on lumbosacral high-grade spondylolisthesis (HGS), identify patients at risk for progression to higher-grade slip and evaluate various surgical strategies to report on complications and radiographic and clinical outcomes. METHODS: Systematic search of PubMed, Cochrane and Google Scholar for papers relevant to HGS was performed. 19 articles were included after title, abstract, and full-text review and grouped to analyze baseline radiographic parameters and the effect of surgical approach, instrumentation, reduction and decompression on patient radiographic and clinical outcomes. RESULTS: There is a lack of high-quality studies pertaining to surgical treatment for HGS, and a majority of included papers were Level III or IV based on the JBJS Levels of Evidence Criteria. CONCLUSIONS: Surgical treatment for HGS can vary depending on patient age. There is strong evidence of an association between increased pelvic incidence (PI) and presence of HGS and moderately strong evidence that patients with unbalanced pelvis can benefit from correction of lumbopelvic parameters with partial reduction. Surgeons need to weigh the benefits of fixing the deformity with the risks of potential complications, assessing patient satisfaction as well as their understanding of the possible complications. However, further research is necessary to make more definitive conclusions on surgical treatment guidelines for HGS. LEVEL OF EVIDENCE: II. PMID- 26512345 TI - The Effects of Exercise on Dopamine Neurotransmission in Parkinson's Disease: Targeting Neuroplasticity to Modulate Basal Ganglia Circuitry. AB - Animal studies have been instrumental in providing evidence for exercise-induced neuroplasticity of corticostriatal circuits that are profoundly affected in Parkinson's disease. Exercise has been implicated in modulating dopamine and glutamate neurotransmission, altering synaptogenesis, and increasing cerebral blood flow. In addition, recent evidence supports that the type of exercise may have regional effects on brain circuitry, with skilled exercise differentially affecting frontal-striatal related circuits to a greater degree than pure aerobic exercise. Neuroplasticity in models of dopamine depletion will be reviewed with a focus on the influence of exercise on the dorsal lateral striatum and prefrontal related circuitry underlying motor and cognitive impairment in PD. Although clearly more research is needed to address major gaps in our knowledge, we hypothesize that the potential effects of exercise on inducing neuroplasticity in a circuit specific manner may occur through synergistic mechanisms that include the coupling of an increasing neuronal metabolic demand and increased blood flow. Elucidation of these mechanisms may provide important new targets for facilitating brain repair and modifying the course of disease in PD. PMID- 26512346 TI - Screening newborns for metabolic disorders based on targeted metabolomics using tandem mass spectrometry. AB - The main purpose of newborn screening is to diagnose genetic, metabolic, and other inherited disorders, at their earliest to start treatment before the clinical manifestations become evident. Understanding and tracing the biochemical data obtained from tandem mass spectrometry is vital for early diagnosis of metabolic diseases associated with such disorders. Accordingly, it is important to focus on the entire diagnostic process, including differential and confirmatory diagnostic options, and the major factors that influence the results of biochemical analysis. Compared to regular biochemical testing, this is a complex process carried out by a medical physician specialist. It is comprised of an integrated program requiring multidisciplinary approach such as, pediatric specialist, expert scientist, clinical laboratory technician, and nutritionist. Tandem mass spectrometry is a powerful tool to improve screening of newborns for diverse metabolic diseases. It is likely to be used to analyze other treatable disorders or significantly improve existing newborn tests to allow broad scale and precise testing. This new era of various screening programs, new treatments, and the availability of detection technology will prove to be beneficial for the future generations. PMID- 26512347 TI - Body mass index and body composition scaling to height in children and adolescent. AB - Childhood obesity prevalence has been increased and known to be related to various diseases and mortality in adult and body mass index (BMI) has been widely used as a screening tool in children with obesity. It is important to understand what BMI is and its limitations. BMI is a measure of weight adjusted for height. Weight scales to height with a power of about 2, is the basis of BMI (weight/height(2)) as the scaling of body weight to height across adults provides powers rounded to 2. BMI has the advantage of a simple and noninvasive surrogate measure of body fat, but it has limitation in differentiating body fat from lean (fat free) mass and low-moderate sensitivity is problematic for clinical applications. Among overweight children higher BMI levels can be a result of increased either fat or fat-free mass. BMI could be divided into fat-free mass index and fat mass index. Monitoring of the changes in body composition is important as distinguishing changes in each component occur with rapid growth in adolescents as it is occur in concert with changes in the hormonal environment. Reference values for each body composition indexes and chart created with selected percentiles of a normal adolescent population could be helpful in growth assessment and health risk evaluation. PMID- 26512348 TI - The effect of early menarche on the sexual behaviors of Korean female adolescents. AB - PURPOSE: This study examined the relationships between early menarche and sexual behaviors among Korean female adolescents. METHODS: We analyzed data from the eighth Korea Youth Risk Behavior Web-based survey that was conducted on female high school students in grades 10-12. The survey included 17,867 students, and 974 students were assigned to the early menarche group because they had experienced menarche when they were in grade four or below, and 16,893 students were assigned to the normal menarche group because they had experienced menarche during or after grade five. The characteristics of the sexual behaviors in the early menarche and normal menarche group were analyzed. RESULTS: The early menarche group was at a higher risk of intersexual kissing or petting (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.28-1.87), intersexual intercourse (OR, 2.35; 95% CI, 1.65-3.36), homosexual kissing or petting (OR, 3.53; 95% CI, 2.22-5.59), homosexual intercourse (OR, 7.70; 95% CI, 4.04-14.66), being the victim (OR, 2.89; 95% CI, 1.98-4.22) or the assailant (OR, 13.55; 95% CI, 6.61 27.78) of sexual assaults, intercourse without any contraception (OR, 1.92; 95% CI, 1.06-3.46), and pregnancy (OR, 5.72; 95% CI, 2.31-14.15) than the normal menarche group. CONCLUSION: Early menarche is associated with risky sexual behaviors among adolescent females; therefore, developing comprehensive sexual health education programs and tools for early intervention are required for children who are expected to experience early menarche. PMID- 26512349 TI - Metabolic effects of polycystic ovary syndrome in adolescents. AB - PURPOSE: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenic anovulation in women of reproductive age. We investigated the metabolic effects of lean and overweight adolescents with PCOS. METHODS: Anthropometric measurements and biochemical parameters were evaluated in 49 adolescents with PCOS and 40 age- and body mass index (BMI)-matched controls. We further divided both PCOS and control groups into those having BMI within the normal range of less than 85(th) percentile and those being overweight and obese with a BMI greater than 85(th) percentile. RESULTS: Hemoglobin, gamma-glutamyl transferase (r-GT), total cholesterol, low-density lipoprotein-cholesterol and 2-hour postglucose load plasma insulin levels were significantly elevated in the lean PCOS group than in the lean control group. In the overweight/obese PCOS group, hemoglobin and r-GT levels were significantly elevated than in the overweight/obese control group. In the normal weight group, none of the subjects had metabolic syndrome according to the Adult Treatment Panel III criteria, but the incidence of metabolic syndrome in the overweight/obese PCOS group was 8.3% and that in the overweight/obese control group was 6.7%. CONCLUSION: PCOS in adolescents causes metabolic abnormalities, underscoring the importance of early diagnosis of PCOS in oligomenorrheic adolescents. PMID- 26512350 TI - Qualitative assessment of precocious puberty-related user-created contents on YouTube. AB - PURPOSE: User-created content (UCC) has provided a considerable amount of medical information and become an important source. We aimed to evaluate the quality and scientific accuracy of precocious puberty-related UCC on YouTube. METHODS: The keywords "precocious puberty", "early puberty", "sexual precocity", and "precocity" were searched for on YouTube during June and July 2014. More than 1,500 UCC matched the keywords. According to the information provider, UCC was classified as medical, oriental, or commercial & others. We evaluated the quality and scientific accuracy of the information provided in UCC using the DISCERN instrument and information scores, respectively. RESULTS: We selected 51 UCC, which were categorized into three types: medical (n=17), oriental (n=17), or commercial & others (n=17). The overall quality score for medical UCC (3.4) was significantly higher relative to those of oriental and commercial & others UCC (2.8 and 2.3, respectively) (P<0.001). In the assessment of scientific accuracy, the mean information score for medical UCC (30.7) was significantly higher than those of oriental and commercial & others UCC (15.9 and 5.1, respectively) (P<0.001). The mean duration of oriental UCC was the longest (P<0.001), however, it was viewed less frequently among them (P=0.086). CONCLUSION: The quality and accuracy of precocious puberty-related health information in UCC were variable and often unreliable. The overall quality of UCC regarding precocious puberty was moderate. Only medical UCC provided scientifically accurate information. As UCC becomes a popular source of health information, it is important to provide reliable, scientifically accurate information. PMID- 26512351 TI - Bone mineral density change during adjuvant chemotherapy in pediatric osteosarcoma. AB - PURPOSE: Osteoporosis is currently receiving particular attention as a sequela in survivors of childhood osteosarcoma. The aim of this study was to evaluate bone mineral density (BMD) changes during methotrexate-based chemotherapy in children and adolescents with osteosarcoma. METHODS: Nine patients with osteosarcoma were included in this retrospective study and compared with eight healthy controls. BMD of the lumbar spine and unaffected femur neck of patients was serially measured by dual-energy x-ray absorptiometry (DXA) before and just after chemotherapy and compared with controls. RESULTS: Four patients (44%) showed decreased lumbar spine BMD and seven patients (78%) showed decreased femur neck BMD, while all controls showed increased lumbar and femur BMD (P=0.024 and P=0.023). The femur neck BMD z-scores decreased from -0.49+/-1.14 to -1.63+/-1.50 (P=0.032). At the end of therapy, five patients (56%) showed femur neck BMD z scores below -2.0. CONCLUSION: The bone metabolism is disturbed during therapy in children with osteosarcoma, resulting in a reduced BMD with respect to healthy controls. Since a reduced BMD predisposes to osteoporosis, specific attention and therapeutic interventions should be considered. PMID- 26512352 TI - Clinical manifestations of testicular adrenal rest tumor in males with congenital adrenal hyperplasia. AB - PURPOSE: In male patients with congenital adrenal hyperplasia (CAH), the presence of testicular adrenal rest tumors (TARTs) have been reported, however their prevalence and clinical manifestations are not well known. Untreated TARTs may lead to testicular structural damage and infertility. This study was conducted to investigate the prevalence of TARTs in male patients with CAH, and characterize the manifestations to identify contributing factors to TART. METHODS: Among 102 CAH patients aged 0-30 years, 24 male patients have been regularly followed up in our outpatient clinic at Severance Children's Hospital from January 2000 to December 2014. In order to reveiw the characteristics of TART patients, we calculated the mean levels of hormones during the 5 years before the time of investigation. Five patients underwent follow-up scrotal ultrasonography (US) after adjusting the dosage of glucocorticoids. RESULTS: TARTs were detected in 8 of the 13 patients (61.5%). The median age of TARTs diagnosis was 20.2 years with the youngest case being 15.5 years old. The mean serum level of adrenocorticotropic hormone (ACTH) was higher in the TARTs patient group compared to the non-TARTs group (P<0.05). The tumor size decreased in 3 cases, slightly increased in 1 case, and had no change in another case. CONCLUSION: The serum ACTH level might be associated with the growth promoting factor for TARTs, but the exact mechanism has not been clearly identified. Screening for TARTs using US is important in male patients with CAH for early-detection and prevention of ongoing complications, such as infertility. PMID- 26512353 TI - A Leri-Weill dyschondrosteosis patient confirmed by mutation analysis of SHOX gene. AB - Leri-Weill dyschondrosteosis is characterized by SHOX deficiency, Madelung deformity, and mesomelic short stature. In addition, SHOX deficiency is associated with idiopathic short stature, Turner syndrome, and Langer mesomelic dysplasia. We report the first case of a Leri-Weill dyschondrosteosis patient confirmed by SHOX gene mutation analysis in Korea. The patient, who was a 7-year old female, showed short stature. Her height and weight were 108.9 cm (<3rd percentile) and 19.7 kg (5th-10th percentile), respectively. Her arm span, height of trunk, leg length, and sitting length were 100.5 cm, 58 cm, 50.9 cm, and 62.5 cm, respectively. Her body proportion was 1.13:1. Extremities to trunk ratio was 2.61. Her hand radiograph showed Madelung deformity. And the growth hormone stimulation test showed a normal response. Furthermore, because of Madelung deformity with idiopathic short stature, she was suspected of SHOX deficiency. We performed SHOX gene mutation analysis and found a c.491G>A (p.W164X) mutation of the SHOX gene. Accordingly, this patient was diagnosed with Leri-Weill dyschondrosteosis. Recently, many mutations have been reported in the SHOX gene. However, to date, mutation analysis of the SHOX gene for Leri-Weill dyschondrosteosis has not been reported in Korea as yet. We report the first case of a Leri-Weill dyschondrosteosis patient confirmed by mutation analysis of the SHOX gene. PMID- 26512354 TI - Hypotonic hyponatremia by primary polydipsia caused brain death in a 10-year-old boy. AB - Hypotonic hyponatremia by primary polydipsia can cause severe neurologic complications due to cerebral edema. A 10-year-and-4-month-old boy with a psychiatric history of intellectual disability and behavioral disorders who presented with chief complaints of seizure and mental change showed severe hypotonic hyponatremia with low urine osmolality (serum sodium, 101 mmol/L; serum osmolality, 215 mOsm/kg; urine osmolality, 108 mOsm/kg). The patient had been polydipsic for a few months prior, and this had been worse in the previous few days. A diagnosis of hypotonic hyponatremia caused by primary polydipsia was made. The patient was in a coma, and developed respiratory arrest and became brain death shortly after admission, despite the treatment. The initial brain magnetic resonance imaging showed severe brain swelling with tonsillar and uncal herniation, and the patient was declared as brain death. It has been reported that antidiuretic hormone suppression is inadequate in patients with chronic polydipsia, and that this inadequate suppression of antidiuretic hormone is aggravated in patients with acute psychosis. Therefore, hyponatremia by primary polydipsia, although it is rare, can cause serious and life-threatening neurologic complications. PMID- 26512355 TI - XYY syndrome: a 13-year-old boy with tall stature. AB - When evaluating the underlying causes of tall stature, it is important to differentiate pathologic tall stature from familial tall stature. Various pathologic conditions leading to adult tall stature include excess growth hormone secretion, Marfan syndrome, androgen or estrogen deficiency, testicular feminization, and sex chromosome anomaly, such as Klinefelter syndrome and XYY syndrome. Men with 47,XYY syndrome can exhibit multiple phenotypes. A 13-year-old boy visited the hospital for evaluation of tall stature. The boy had no other physical abnormalities except tall stature. All biochemical and imaging studies were within the normal ranges. He was diagnosed with XYY syndrome in this chromosome study. When evaluating men with tall stature, XYY syndrome should be ruled out. PMID- 26512356 TI - Integrating Antiretroviral Strategies for Human Immunodeficiency Virus Prevention: Post- and Pre-Exposure Prophylaxis and Early Treatment. AB - Best practices for integrating human immunodeficiency virus (HIV) testing and antiretroviral interventions for prevention and treatment are suggested based on research evidence and existing normative guidance. The goal is to provide high impact prevention services during periods of substantial risk. Antiretroviral medications are recommended for postexposure prophylaxis (PEP), pre-exposure prophylaxis (PrEP), and treatment of HIV infection. We reviewed research evidence and current normative guidelines to identify best practices for integrating these high-impact prevention strategies. More sensitive HIV tests used for screening enable earlier diagnosis and treatment of HIV infection, more appropriate counseling, and help limit drug resistance. A fully suppressive PEP regimen should be initiated based on exposure history or physical findings when sensitive diagnostic testing is delayed or not available and antibody tests are negative. Transitions from PEP to PrEP are often warranted because HIV exposure events may continue to occur. This algorithmic approach to integrating PEP, PrEP, and early treatment decisions may increase the uptake of these interventions by a greater number and diversity of knowledgeable healthcare providers. PMID- 26512357 TI - In-Hospital Pneumococcal Polysaccharide Vaccination Is Associated With Detection of Pneumococcal Vaccine Serotypes in Adults Hospitalized for Community-Acquired Pneumonia. AB - During an etiology study of adults hospitalized for pneumonia, in which urine specimens were examined for serotype-specific pneumococcal antigen detection, we observed that some patients received 23-valent pneumococcal polysaccharide vaccine before urine collection. Some urine samples became positive for specific vaccine pneumococcal serotypes shortly after vaccination, suggesting false positive test results. PMID- 26512358 TI - Interpretation of Negative Molecular Test Results in Patients With Suspected or Confirmed Ebola Virus Disease: Report of Two Cases. AB - Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) is the most sensitive quantitative diagnostic assay for detection of Ebola virus in multiple body fluids. Despite the strengths of this assay, we present 2 cases of Ebola virus disease (EVD) and highlight the potential for false-negative results during the early and late stages of EVD. The first case emphasizes the low negative-predictive value of qRT-PCR during incubation and the early febrile stage of EVD, and the second case emphasizes the potential for false-negative results during recovery and late neurologic complications of EVD. Careful interpretation of test results are needed to guide difficult admission and discharge decisions in suspected or confirmed EVD. PMID- 26512359 TI - Intensifying Antiretroviral Therapy With Raltegravir and Maraviroc During Early Human Immunodeficiency Virus (HIV) Infection Does Not Accelerate HIV Reservoir Reduction. AB - Background. Persistent human immunodeficiency virus (HIV) within the CD4(+) T cell reservoir is an obstacle to eradication. We hypothesized that adding raltegravir and maraviroc to standard combination antiretroviral therapy (cART) during early HIV infection could substantially reduce viral reservoirs as a step towards eradication. Methods. A prospective, randomized, double-blinded, placebo controlled pilot trial enrolled 32 participants with documented early (<6 months) HIV infection to either standard cART (emtricitabine/tenofovir/lopinavir/ritonavir) or intensive cART (standard regimen + raltegravir/maraviroc). Human immunodeficiency virus reservoirs were assessed at baseline and at 48 weeks by (1) proviral DNA, (2) cell-associated RNA, and (3) replication-competent virus, all from purified blood CD4(+) T cells, and (4) gut proviral DNA. A multiassay algorithm (MAA) on baseline sera estimated timing of infection. Results. Thirty individuals completed the study to the 48-week endpoint. The reduction in blood proviral burden was -1.03 log DNA copies/10(6) CD4(+) T cells versus -.84 log in the standard and intensive groups, respectively (P = .056). Overall, there was no significant difference in the rate of decline of HIV-associated RNA, replication-competent virus in blood CD4(+) T cells, nor proviral gut HIV DNA to 48 weeks. Individuals who presented with more recent HIV infection had significantly lower virus reservoirs, and cART tended to reduce their reservoirs to a greater extent. Conclusions. Intensive cART led to no additional reduction in the blood virus reservoir at 48 weeks compared with standard cART. Human immunodeficiency virus reservoir size is smaller earlier in HIV infection. Other novel treatment strategies in combination with early cART will be needed to eliminate the HIV latent reservoir. PMID- 26512360 TI - Description of a Working Day as a Senior Emergency Medicine Resident; Burning Candle at Both Ends! PMID- 26512361 TI - Management of Dysrhythmia in Emergency Department. PMID- 26512362 TI - Ebola Hemorrhagic Fever as a Public Health Emergency of International Concern; a Review Article. AB - Ebola hemorrhagic fever (EHF) was first reported in 1976 with two concurrent outbreaks of acute viral hemorrhagic fever centered in Yambuku (near the Ebola river), Democratic Republic of Congo, and in Nzara, Sudan. The current outbreak of the Ebola virus was started by reporting the first case in March 2014 in the forest regions of southeastern Guinea. Due to infection rates raising over 13,000% within a 6-month period, Ebola is now considered as a global public health emergency and on August 8(th), 2014 the World Health Organization (WHO) declared the epidemic to be a Public Health Emergency of International Concern. With more than 5000 involved cases and nearly 3000 deaths, this event has turned into the largest and most dangerous Ebola virus outbreak in the world. Based on the above-mentioned, the present article aimed to review the virologic characteristics, transmission, clinical manifestation, diagnosis, treatment, and prevention of Ebola virus disease. PMID- 26512364 TI - The Most Important Causes of Death in Iranian Population; a Retrospective Cohort Study. AB - INTRODUCTION: Health care providers and health policy managers need updated and valid information regarding causes of death (COD) for development the health care facilities, directing primary prevention, assigning funds, and promoting public health. The major causes of death and its burden have not been yet appropriately identified in Iran. Although several studies had been carried out in this area, most of them were local or performed in the past years and need to be update. Thus, the present study aimed to address the major causes of death and its burden in Iran. METHODS: The present cross-sectional study was performed on graduate students and their families from February to March 2014. Through a two-stage random sampling procedure, data on 11315 subjects were obtained. The corresponding age of death, gender, and calendar year of death were inquired. All causes of death were categorized in nine groups including major cardiovascular disease, cancers, motor vehicle accidents, unintentional injuries, intentional injuries, stroke, lower respiratory infections, diabetes, and other reasons. Years of life lost (YLL) and person years of life lost were computed as the burden of diseases. RESULTS: Totally, 11315 (50.4% male) subjects were studied. The results regarding death of relatives revealed that 360 deaths occurred (66.9% male). COD in 95 cases (26.4%) was cardiovascular diseases, 64 (17.8%) motor vehicle accidents, 41 (11.4%) cancers, 23 (6.4%) unintentional injuries, 22 (6.1%) intentional injuries, 10 (2.8%) stroke, 8 (2.2%) lower respiratory infections, 6 (1.8%) diabetes, and 91 (25.3%) other reasons. The average YLL due to all COD was 34.4+/-18.5. YLL for motor vehicle accidents and injuries (unintentional and intentional) were higher than cardiovascular diseases (p<0.001). In addition, person years of life lost for motor vehicle accidents were 2613.1 years. Cardiovascular diseases (2159.4 years), cancers (1321.0 years), and unintentional injuries (990.4 years) were in the next ranks. CONCLUSION: Based on the findings, it seems that cardiovascular diseases, motor vehicle accidents, cancers, intentional and unintentional injuries are the major causes of death in Iranian population. Most of years of life lost were due to motor vehicle accidents, cardiovascular diseases and cancers, intentional and unintentional injuries, respectively. PMID- 26512363 TI - Infantile Apparent Life-Threatening Events, an Educational Review. AB - Many physicians have received a frantic call from anxious parents stating that their child had stopped breathing, become limp, or turned blue but then had recovered quickly. An apparent life-threatening event (ALTE) is defined as "an episode that is frightening to the observer, and is characterized by some combination of apnea, color change, marked change in muscle tone, choking, gagging, or coughing". The incidence of ALTE is reported to be 0.05% to 6%. The knowledge about the most common causes and factors associated with higher risk of ALTE could be resulted in a more purposeful approach, improving the decision making process, and benefiting both children and parents. The aim of this review article was to report the epidemiology, etiology, evaluation, management, and disposition of ALTE. Infants with an ALTE might present no signs of acute illness and are commonly managed in the emergency settings that often require significant medical attention; hence, the emergency medicine personnel should be aware of the its clinical importance. There is no specific treatment for ALTE; therefore, the clinical evaluations should be focused on the detection of the underlying causes, which will define the outcomes and prognosis. ALTE is a confusing entity, representing a constellation of descriptive symptoms and signs; in other words, it is not a diagnosis. There are multiple possible etiologies and difficulties in evaluating and managing infants with these events, which are challenges to primary care physicians, emergency medicine specialists, and subspecialty pediatricians. The evaluation of these events in infants includes a detailed history, appropriate physical examination, diagnostic tests guided by obtained clues from the history and physical examination, and observation in the emergency department. PMID- 26512365 TI - Rectal Thiopental versus Intramuscular Ketamine in Pediatric Procedural Sedation and Analgesia; a Randomized Clinical Trial. AB - INTRODUCTION: Physicians frequently deal with procedures which require sedation of pediatric patients. Laceration repair is one of them. No study has been performed regarding the comparison between induction of sedation with sodium thiopental and ketamine in laceration repair. Therefore, the present study was aimed to comparison of induced sedation by rectal sodium thiopental and muscular injection of hydrochloride ketamine in pediatric patients need laceration repair. METHODS: The presented study is a single-blinded clinical trial performed through 2013 to 2014 in Ayatollah Kashani and Alzahra Hospitals, Isfahan, Iran. Patients from 3 months to 14 years, needed sedation for laceration repair, were entered. Patients were sequentially evaluated and randomly categorized in two groups of hydrochloride ketamine with dose of 2-4 milligram per kilogram and sodium thiopental with dose of 25 milligram per kilogram. Demographic data and vital signs before drug administration and after induction of sedation, Ramsey score, time to onset of action, and sedation recovery time were evaluated. Chi-squared, Mann-Whitney, and Non-parametric analysis of covariance tests were used. P<0.05 was considered as a significant level. RESULTS: In this study 60 pediatric patients were entered. 30 patients with mean age of 42.8+/-18.82 months were received sodium thiopental and the rest with mean age of 30.08+/-16.88 months given ketamine. Mann-Whitney test was showed that time to onset of action in sodium thiopental group (28.23+/-5.18 minutes) was significantly higher than ketamine (7.77+/-4.13 minutes), (p<0.001). The sedation recovery time in ketamine group (29.83+/-7.70) was higher than sodium thiopental. Depth of sedation had no significant difference between two groups based on Ramsey score (p=0.87). No significant difference was seen between two groups in the respiratory rate (df=1, 58; F=0.002; P=0.96) and heart rate (df=1, 58; F=0.98; P=0.33). However, arterial oxygen saturation level (df=1, 58; F=6.58; P=0.013) was significantly higher in ketamine group. CONCLUSION: The findings of the present study show that Although the recovery time from sedation by ketamine is more than sodium thiopental, it's fast-acting function without effecting on the oxygen saturation level causes that ketamine is considered as the better choice for induction of sedation in pediatric patients need laceration repair. In addition, long-term effect of ketamine provides more time for the physician to do the procedure and this issue decreases the need probability to the repeated-dose. However, effectiveness of both drugs to decrease the agitation was equal, based on the Ramsey score. PMID- 26512366 TI - Epidemiology of Alcohol Poisoning and Its Outcome in the North-West of Iran. AB - INTRODUCTION: Alcohol poisoning is one of the main preventable causes of death, disability, and injury in many societies. Ethanol and methanol are the most prevalent kinds of alcohol used. There is no any exact reports of alcohol poisoning and its outcome in Iranian society. Therefore, the present study was assessed the status of alcohol poisoning and its outcome in referees to the emergency department. METHODS: This is a cross-sectional study, which was done from July 2013 to 2014 in Sina Trauma Center, Tabriz, Iran. The studied population included all alcohol-poisoning cases referred to this center. Demographic variables, clinical evaluation, laboratory tests, and patient's outcome were evaluated. To assess the relation between evaluated factors and outcome of alcohol poisoning. After univariate analysis, a multivariate logistic regression was applied to evaluate independent risk factors for death. P<0.05 was considered as a significant level. RESULTS: Lastly, 81 patients with alcohol poisoning were entered to the study (91.4% male) with the mean age of 27.9+/-10.4 years. Ten (12.3%) subjects were dialyzed and 34 (42%) cases hospitalized that 3 (3.7%) of them died. The multivariate logistic regression test displayed that plasma creatinine level (OR=2.2 95%Cl: 1.8-2.5; p=0.015) and need for dialysis (OR=6.4; 95%Cl: 5.3-7.5; p<0.001) were the only risk factors of death among these patients. CONCLUSION: The findings of the present study revealed that total mortality rate of referees to the emergency with alcohol poisoning was 3.7% all of whom related to methanol poisoning. Based on this result, the mortality rate of methanol poisoning was estimated 20%. Need for dialysis and increasing the creatinine level were accounted as independent risk factors of death. PMID- 26512367 TI - Knowledge and Attitude Regarding Organ Donation among Relatives of Patients Referred to the Emergency Department. AB - INTRODUCTION: Organ donation is one of the surviving procedures, which can increase the life expectancy of end-stage patients. Inappropriate beliefs and attitude of individuals to organ donation, their poor knowledge, and the socio economic level are one of the most important barriers for organ donation. Therefore, here knowledge and attitude levels among relatives of trauma patients regarding organ donation were evaluated. METHODS: This cross-sectional study was done on relatives of trauma patients referred to the emergency department of Sina Hospital, Tabriz, Iran, through 2013 to 2014. The questionnaire included parts of demographic data and socio-economic situations as well as status of knowledge and attitude regarding organ donation. A score between 0-7 was belonged to each person based on his/her level of knowledge. Attitude level had a score between 0 12. Chi- square, Fisher, and Mann-Whitney U test were performed to assess the relation between demographic variables and the level of knowledge and attitude. P<0.05 was considered as a significant level. RESULTS: 79 persons (57.1% male) with the mean age of 31.3+/-11.3 years were evaluated. 57 (73.1%) of subjects agreed with organ transplant. The main causes of disagreement among relatives regarding organ donation were dissatisfaction of the donor's relatives (25%) and religious issues (15%). 49 (62.02%) studied people had inappropriate attitude and 27 (34.2%) ones had good knowledge. male gender (OR=5.87; 95%CI: 3.32-8.42; p=0.001) and self-employed job (OR=7.78; 95%CI: 4.64-10.92; p=0.001) are independent factors associated with poor knowledge about organ donation. Self employed job (OR=3.86; 95%CI: 1.41-6.11; p=0.009) and poor knowledge (OR=15.3; 95%CI: 9.03-21.57; p<0.001) were related to inappropriate attitude toward organ donation. CONCLUSION: The present study showed that 73.1% of participants agreed with organ donation. The major causes of disagreements were dissatisfaction of other relatives and religious beliefs. 62.0% of the studied people had positive view regarding organ donation and 34.2% of them well informed about. The most important causative factors for poor knowledge in this context were male gender and self-employed occupation. In addition, poor knowledge and self-employed job were two factors associated with inappropriate attitude toward organ donation. PMID- 26512368 TI - Independent Predictive Factors of Hospitalization in a North-West Burn Center of Iran; an Epidemiologic Study. AB - INTRODUCTION: A high-grade burn is one of the most devastating injuries with several medical, social, economic, and psychological effects. These injuries are the most common cause of accidental deaths after traffic injuries in both the developed and developing countries. Therefore, this research was aimed to determine demographic characteristics of patients with burn injury admitted to the emergency department and identify predictive factors of hospitalization. METHODS: This is a cross sectional descriptive study, which is done in 20 March up to 20 September 2011 in emergency department of Sina Hospital, Tabriz, Iran. Patients' information including demographic characteristic, cause of burn, place of accident, anatomical areas burned, grading and percent of burning and disposition were gathered and analyzed using SPSS version 18.0 statistical software. Stepwise multivariate regression analysis was used for recognition of independent predictive factors of hospitalization in burned patients. RESULTS: One hundred and sixty patients were enrolled (54.4% female). The average age of those was 20.47+/-13.5 years. The prevalence of burn was significantly higher in ages under 20 years (p<0.001). Lower limb (37.5%), head and neck (21.25%) and upper limb (17.5%) were three frequent site of burn. The most common cause of burns was boiling water scalding (34.4%). Home related burn was significantly higher than other place (p<0.001). The most frequent percent of burn was <5% (46.25%). Finally, 50 (31.25%) cases hospitalized. Univariate analysis demonstrated that age under 20 years old (p=0.02) female gender (p=0.02), burning site (p=0.002), cause (p=0.005), place (p<0.001), grade (p<0.001), and percent (p<0.001) was related to disposition of patients. Stepwise multiple logistic regression showed female gender (OR=3.52; 95% CI: 1.57-7.88; p=0.002), work related burning (OR=1.78; 95% CI: 1.26-2.52; p=0.001), and burning over 5 percent (OR=2.15; 95% CI: 1.35-3.41; p=0.001) as independent predictive factors of hospitalization. CONCLUSION: The results of present study showed that burns injury are most frequent in age under 20 year old, lower limbs, with boiling water, and at home. In addition, the most frequent type and percentage of burned area were second degree and <5% of total body surface area, respectively. Among age under 20 years old, female gender, burning site, cause, place, grade, and percent only female gender, work related burning, and burning over 5% were detected as independent predictive factors of hospitalization. PMID- 26512370 TI - Preface. PMID- 26512369 TI - Rupture of Hydatid Liver Cyst into Peritoneal Cavity Following Blunt Abdominal Trauma; a Case Report. AB - Hydatid cyst is a serious parasitic infection in places, which people has a close contact with dogs or sheep. They may be found as an incidental findings during routine clinical examination or even followed by radiographic or ultrasonography evaluation. The disease becomes more complicated if rupture of the cysts occurs due to blunt trauma or spontaneously increases of intra-cystic pressure. Here, we reported a case of hydatid liver cyst that ruptured into the peritoneal cavity after blunt abdominal trauma. PMID- 26512371 TI - Preface. PMID- 26512372 TI - Reply to Dr. James G. O'Brien. PMID- 26512373 TI - [Not Available]. PMID- 26512374 TI - [Not Available]. PMID- 26512375 TI - [Not Available]. PMID- 26512376 TI - Preface. PMID- 26512377 TI - Preface. T-Cell Development. PMID- 26512378 TI - Authors' response. PMID- 26512379 TI - Small cell lung cancer mimicking high-grade lymphoma in a patient with concurrent B-cell lymphoproliferative disorder. PMID- 26512380 TI - Diagnosing Plasmodium falciparum in a teenage traveler by peripheral blood smear. PMID- 26512381 TI - Preface. PMID- 26512382 TI - Volume 15: noncommunicable diseases. PMID- 26512384 TI - Preface. PMID- 26512383 TI - Phenotyping in Plants. Preface. PMID- 26512385 TI - Volume 13: pulmonary function. PMID- 26512386 TI - Preface. PMID- 26512387 TI - Volume 3: environmental exposure to pollutants. PMID- 26512388 TI - Preface. PMID- 26512389 TI - Volume 2: lung cancer and autoimmune disorders. PMID- 26512390 TI - [Not Available]. PMID- 26512391 TI - Yes, we need mechanistic biophysical models! PMID- 26512410 TI - G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment of Diabetes: Recent Progress and Prevailing Challenges. AB - In this Perspective, recent advances and challenges in the development of GPR119 agonists as new oral antidiabetic drugs will be discussed. Such agonists are expected to exhibit a low risk to induce hypoglycemia as well as to have a beneficial impact on body weight. Many pharmaceutical companies have been active in the search for GPR119 agonists, making it a highly competitive area in the industrial environment. Several GPR119 agonists have been entered into clinical studies, but many have failed either in phase I or II and none has progressed beyond phase II. Herein we describe the strategies chosen by the different medicinal chemistry teams in academia and the pharmaceutical industry to improve potency, physicochemical properties, pharmacokinetics, and the safety profile of GPR119 agonists in the discovery phase in order to improve the odds for successful development. PMID- 26512411 TI - A Switchable Molecular Dielectric with Two Sequential Reversible Phase Transitions: [(CH3)4P]4[Mn(SCN)6]. AB - A new organic-inorganic hybrid switchable and tunable dielectric compound, [(CH3)4P]4[Mn(SCN)6] (1), exhibits three distinct dielectric states above room temperature and undergoes two reversible solid-state phase transitions, including a structural phase transition at 330 K and a ferroelastic phase transition with the Aizu notation of mmmF2/m at 352 K. The variable-temperature structural analyses disclose that the origin of the phase transitions and dielectric anomalies can be ascribed to the reorientation or motion of both the [(CH3)4P](+) cations and [Mn(SCN)6](4-) anions in solid-state crystals. PMID- 26512412 TI - Environmentally Relevant Concentrations of the Flame Retardant Tris(1,3-dichloro 2-propyl) Phosphate Inhibit Growth of Female Zebrafish and Decrease Fecundity. AB - Bioconcentrations of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) in brain, gonad, and liver as well as effects on fecundity and development of zebrafish (Danio rerio) were determined. Zebrafish (1-month old) were exposed to environmentally relevant concentrations of 29 +/- 2.1, 600 +/- 21, or 6300 +/- 130 ng TDCIPP/L. After 120 days of exposure, TDCIPP accumulated in the brain, gonad, and liver with bioconcentration factors of 460, 38, and 87 in females and 26, 55, and 110 in males, respectively. TDCIPP accumulated to a greater extent in brains of females than those of males. Exposure to 6300 +/- 130 ng TDCIPP/L resulted in significantly (P < 0.05) fewer eggs being produced, but the histology of the gonad, plasma concentrations of estradiol and 11-ketotestosterone, and expression of genes involved in hypothalamic-pituitary-gonadal-liver axis were not significantly (P > 0.05) different between individuals exposed to TDCIPP and the unexposed control fish. Exposure to TDCIPP resulted in shorter body length, lighter body mass, and lower gonadal-somatic index in females. These effects were possibly due to down-regulation of expression of genes along the growth hormone/insulin-like growth factor (GH/IGF) axis. Correlations between the production of eggs and developmental parameters or expression of genes along the GH/IGF axis further suggested that environmentally relevant concentrations of TDCIPP could have adverse effects on reproduction, possibly due to the inhibition of the growth of females. PMID- 26512413 TI - Genome-wide identification and characterization of tissue-specific RNA editing events in D. melanogaster and their potential role in regulating alternative splicing. AB - RNA editing is a widespread mechanism that plays a crucial role in diversifying gene products. Its abundance and importance in regulating cellular processes were revealed using new sequencing technologies. The majority of these editing events, however, cannot be associated with regulatory mechanisms. We use tissue-specific high-throughput libraries of D. melanogaster to study RNA editing. We introduce an analysis pipeline that utilises large input data and explicitly captures ADAR's requirement for double-stranded regions. It combines probabilistic and deterministic filters and can identify RNA editing events with a low estimated false positive rate. Analyzing ten different tissue types, we predict 2879 editing sites and provide their detailed characterization. Our analysis pipeline accurately distinguishes genuine editing sites from SNPs and sequencing and mapping artifacts. Our editing sites are 3 times more likely to occur in exons with multiple splicing acceptor/donor sites than in exons with unique splice sites (p-value < 2.10(-15)). Furthermore, we identify 244 edited regions where RNA editing and alternative splicing are likely to influence each other. For 96 out of these 244 regions, we find evolutionary evidence for conserved RNA secondary-structures near splice sites suggesting a potential regulatory mechanism where RNA editing may alter splicing patterns via changes in local RNA structure. PMID- 26512414 TI - Photoresponsive molecular switch for regulating transmembrane proton-transfer kinetics. AB - To control proton delivery across biological membranes, we synthesized a photoresponsive molecular switch and incorporated it in a lipid layer. This proton gate was reversibly activated with 390 nm light (Z-isomer) and then deactivated by 360 nm irradiation (E-isomer). In a lipid layer this stimuli responsive proton gate allowed the regulation of proton flux with irradiation to a lipid-buried O2 reduction electrocatalyst. Thus, the catalyst was turned on and off with the E-to-Z interconversion. This light-induced membrane proton delivery system may be useful in developing any functional device that performs proton coupled electron-transfer reactions. PMID- 26512415 TI - Gene transfer by pulsed electric field is highly promising in cutaneous wound healing. AB - INTRODUCTION: Tremendous progress has been achieved during the last decades in electroporation-based technologies for medicine. Understanding the basic underlying mechanisms of gene delivery opens the way for clinical gene therapy and DNA vaccination. AREAS COVERED: This review focuses on the use of gene electrotherapy in cutaneous tissue repair and how it affects healing. EXPERT OPINION: Gene electrotherapy is safe, efficient and promising as shown by the increasing number of publications reporting evidence for its potential in wound healing. Going deeper into the mechanisms of DNA delivery and expression as well as into skin regeneration at the molecular, cellular and tissues levels will help make it an attractive approach for the treatment of skin pathologies in general. PMID- 26512416 TI - Tailor-Made Distribution of Nanoparticles in Blend Structure toward Outstanding Electromagnetic Interference Shielding. AB - Engineering blend structure with tailor-made distribution of nanoparticles is the prime requisite to obtain materials with extraordinary properties. Herein, a unique strategy of distributing nanoparticles in different phases of a blend structure has resulted in >99% blocking of incoming electromagnetic (EM) radiation. This is accomplished by designing a ternary polymer blend structure using polycarbonate (PC), poly(vinylidene fluoride) (PVDF), and poly(methyl methacrylate) (PMMA) to simultaneously improve the structural, electrical, and electromagnetic interference shielding (EMI). The blend structure was made conducting by preferentially localizing the multi-wall nanotubes (MWNTs) in the PVDF phase. By taking advantage of "pi-pi stacking" MWNTs was noncovalently modified with an imidazolium based ionic liquid (IL). Interestingly, the enhanced dispersion of IL-MWNTs in PVDF improved the electrical conductivity of the blends significantly. While one key requisite to attenuate EM radiation (i.e., electrical conductivity) was achieved using MWNTs, the magnetic properties of the blend structure was tuned by introducing barium ferrite (BaFe) nanoparticles, which can interact with the incoming EM radiation. By suitably modifying the surface of BaFe nanoparticles, we can tailor their localization under the macroscopic processing condition. The precise localization of BaFe nanoparticles in the PC phase, due to nucleophilic substitution reaction, and the MWNTs in the PVDF phase not only improved the conductivity but also facilitated in absorption of the incoming microwave radiation due to synergetic effect from MWNT and BaFe. The shielding effectiveness (SE) was measured in X and Ku band, and an enhanced SE of -37 dB was noted at 18 GHz frequency. PMMA, which acted as an interfacial modifier in PC/PVDF blends further, resulting in a significant enhancement in the mechanical properties besides retaining high SE. This study opens a new avenue in designing mechanically strong microwave absorbers with a suitable combination of materials. PMID- 26512417 TI - NaI-Mediated Acetamidosulphenylation of Alkenes with Nitriles as the Nucleophiles: A Direct Access to Acetamidosulfides. AB - An example of a transition-metal-free, direct, and efficient acetamidosulphenylation reaction of alkenes using nitriles as the nucleophiles via a radical process is presented. This reaction shows a broad substrate scope and high regioselectivity and provides straightforward access to acetamidosulfide derivatives in moderate to high yields. PMID- 26512418 TI - Neutral-Color Semitransparent Organic Solar Cells with All-Graphene Electrodes. AB - Graphene has been considered as a promising material for transparent electrodes due to its advantages including ultrahigh carrier mobilities, high optical transmittance, excellent mechanical flexibility, and good stability. Solar cells with all-graphene electrodes are potentially low-cost, high-performance, and environmental friendly, which however have not been realized until now. Here, we report the fabrication of semitransparent organic photovoltaics (OPVs) with graphene transparent electrodes as both cathode and anode, which can absorb light from both sides with the power conversion efficiency up to 3.4%. Meanwhile, the OPVs have a neutral color and show the transmittance of ~40% in the visible region, making them suitable for some special applications, such as power generating windows and building integrated photovoltaics. This work demonstrates the great potential of graphene for the applications in carbon-based optoelectronic devices. PMID- 26512419 TI - Effect of promoter and noble metals and suspension pH on catalytic nitrate reduction by bimetallic nanoscale Fe(0) catalysts. AB - Experiments were conducted to investigate the effect of experimental factors (types of promotor and noble metals, H2 injection, and suspension pH) on catalytic nitrate reduction by bimetallic catalysts supported by nanoscale zero valent iron (NZVI). NZVI without H2 injection showed 71% of nitrate reduction in 1 h. Cu/NZVI showed the almost complete nitrate reduction (96%) in 1 h, while 67% of nitrate was reduced by Ni/NZVI. The presence of noble metals (Pd and Pt) on Cu/NZVI without H2 injection resulted in the decrease of removal efficiency to 89% and 84%, respectively, due probably to the electron loss of NZVI for formation of metallic Pd and Pt. H2 injection into Cu-Pd/NZVI suspension significantly improved both catalytic nitrate reduction (>97% in 30 min) and N2 selectivity (18%), indicating that adsorbed H on active Pd sites played an important role for the enhanced nitrate reduction and N2 selectivity. The rapid passivation of NZVI surface resulted in a dramatic decrease in nitrate reduction (79-28%) with an increase in N2 selectivity (8-66%) as the suspension pH increased from 8 to 10. PMID- 26512420 TI - Asthma management practices in adults--findings from the German Health Update (GEDA) 2010 and the German National Health Interview and Examination Survey (DEGS1) 2008-2011. AB - OBJECTIVES: In Germany, population-wide data on adherence to national asthma management guidelines are lacking, and performance measures (PM) for quality assurance in asthma care are systematically monitored for patients with German national asthma disease management program (DMP) enrollment only. We used national health survey data to assess variation in asthma care PM with respect to patient characteristics and care context, including DMP enrollment. METHODS: Among adults 18-79 years with self-reported physician-diagnosed asthma in the past 12 months identified from a recent German National Health Interview Survey (GEDA 2010: N = 1096) and the German National Health interview and Examination Survey 2008-2011 (DEGS1: N = 333), variation in asthma care PM was analyzed using logistic regression analysis. RESULTS: Overall, 38.4% (95% confidence interval: 32.5-44.6%) of adults with asthma were on current inhaled corticosteroid therapy. Regarding non-drug asthma management, low coverage was observed for inhaler technique monitoring (35.2%; 31.2-39.3%) and for provision of an asthma management plan (27.3%; 24.2-30.7%), particularly among those with low education. Specific PM were more complete among persons with than without asthma DMP enrollment (adjusted odds ratios ranging up to 10.19; 5.23-19.86), even if asthma patients were regularly followed in a different care context. CONCLUSIONS: Guideline adherence appears to be suboptimal, particularly with respect to PM related to patient counseling. Barriers to the translation of recommendations into practice need to be identified and continuous monitoring of asthma care PM at the population level needs to be established. PMID- 26512421 TI - Effect of cocaine dependence on brain connections: clinical implications. AB - Cocaine dependence (CD) is associated with several cognitive deficits. Accumulating evidence, based on human and animal studies, has led to models for interpreting the neural basis of cognitive functions as interactions between functionally related brain regions. In this review, we focus on magnetic resonance imaging (MRI) studies using brain connectivity techniques as related to CD. The majority of these brain connectivity studies indicated that cocaine use is associated with altered brain connectivity between different structures, including cortical-striatal regions and default mode network. In cocaine users some of the altered brain connectivity measures are associated with behavioral performance, history of drug use, and treatment outcome. The implications of these brain connectivity findings to the treatment of CD and the pros and cons of the major brain connectivity techniques are discussed. Finally potential future directions in cocaine use disorder research using brain connectivity techniques are briefly described. PMID- 26512422 TI - Role of TLR gene expression and cytokine profiling in the immunopathogenesis of viral hepatitis E. AB - BACKGROUND: The clinical manifestations of Hepatitis E virus (HEV) range from self-limiting acute viral hepatitis (AVH) to acute liver failure (ALF). The varied clinical course is thought to be immune-mediated. Toll-like receptors (TLRs) play a central role in sensing and initiating innate antiviral-response and downstream signaling of TLRs modulates cytokine production, thereby playing an important role in determining the disease course. OBJECTIVES: The present study was designed to elucidate the role of TLRs and cytokine production in the immunopathogenesis of HEV. STUDY DESIGN: Peripheral blood mono-nuclear cells were separated from 50 AVH-HEV, 30 ALF-HEV patients and 50 healthy-controls. One-part of the PBMC was processed for RNA-extraction another pulsed with HEV-ORF2 peptide. Gene-expression levels of TLR (2-4, 7, and 8) were checked using semi quantitative Real-time-PCR. Cytokine levels were analyzed using Cytokine-Bead Array. TLR3-silencing experiments were performed and post-silencing cytokine levels were estimated. RESULTS: TLR3 gene-expression in AVH was significantly higher than ALF (202.4+/-36.36 Vs 13.71+/-5.01; p<0.0001). Higher amount of both anti-and pro-inflammatory cytokines; IFNgamma, TNF-alpha, IL10 and TGF-beta were detected in the PBMC culture-supernatant of AVH Vs ALF (p<0.0001, p=0.0008, p=0.0002, p<0.0001 respectively). Post-silencing TLR3, significant decrease in IFNgamma level was observed in the PBMC culture-supernatant (4.08+/-1.06 Vs 23.20+/-12.51; p=N0.0213). CONCLUSIONS: TLR3 and IFNgamma were found to play an important role in HEV disease pathogenesis. Patients capable of expressing high levels of TLR 3 and robust IFNgamma response are able to limit the disease and recover uneventfully; while the patients with lower expression of TLR3 and IFNgamma progress to ALF. PMID- 26512423 TI - Early serum markers of pre-eclampsia: are we stepping forward? AB - Pre-eclampsia (PE) is a multisystemic disorder of human pregnancy, clinically characterized by hypertension, proteinuria, oedema and platelet aggregation; the syndrome includes vasoconstriction, resulting in maternal hypertension, reduced uterine blood flow, impairment of placenta-vascular endothelial integrity with increased permeability and activation of the coagulation cascade. The aetiopathogenesis of PE remains still unknown, although the central role played by the placenta seems to be crucial. To date, increasing efforts are trying to create an unique and robust biochemical pattern in serum to predict PE. Although the recent data, the definition of an early biochemical pattern in serum to predict PE is still far from reaching the final shape. This stalemate could be due, at least in part, to lack of robust and reproducible methodology (inclusion/exclusion criteria during enrolment, period and type of sample collection, type of sample analysis and interpretation of results) across the different studies. Considering these assumptions, the aim of the current paper is to review the available data about early serum markers of PE. PMID- 26512424 TI - Control of the Aquaporin-4 Channel Water Permeability by Structural Dynamics of Aromatic/Arginine Selectivity Filter Residues. AB - The aquaporins (AQPs) make up a family of integral membrane proteins that control cellular water flow. Gating of the water channel by conformational changes induced by phosphorylation or protein-protein interactions is an established regulatory mechanism for AQPs. Recent in silico and crystallographic analyses of the structural biology of AQPs suggest that the rate of water flow can also be controlled by small movements of single-amino acid side chains lining the water pore. Here we use measurements of the membrane water permeability of mammalian cells expressing AQP4 mutants to provide the first in vitro evidence in support of this hypothesis. PMID- 26512425 TI - Environmental pollutions associated to conflicts in Iraq and related health problems. AB - Several wars and a 13-year embargo as well as several years of civil war with the recent war on terrorism have cumulatively damaged Iraq's land, air, water, and health infrastructure. The sand particles in Iraq contain toxic substances, which dates back to the pollution caused by military actions that disassemble the desert sands and turn it into light dust. This dust reaches cities as dust storms that effect most Iraqi cities. The presence of depleted uranium (DU) in the Iraqi food chain is documented by measuring the uranium in animals organs in different Iraqi cities with the highest concentration in the south of Iraq. One of the major sites of pollution in Iraq is the Al-twaitha nuclear research site. The nuclear research reactors were destroyed in the 1991 Gulf War. Barrels containing radioactive materials and sources were stolen from the site in the 2003 war. This resulted in considerable radioactive pollution at the site and in its surrounding areas. Soil sample have been found to be contaminated by Cs-137and Co-60. Cancer and birth defects are most associated with the environmental pollution caused by the conflicts. All studies related to this by Iraqi researchers are discussed in this review. From studying the Iraqi scientific publications, we can conclude that Basrah, Baghdad, Faluja, Mosul and Thi-Qar are the most effected cities in Iraq. This review concludes that the presence of a heavily contaminated environment with war related pollutants in most of the Iraqi cities needs much attention and huge effort to reduce the related health problems. PMID- 26512426 TI - Protective effects of forced exercise against nicotine-induced anxiety, depression and cognition impairment in rat. AB - BACKGROUND: Nicotine is one of the psychostimulant agents displaying parasympathomimetic activity; the chronic neurochemical and behavioral effects of nicotine remain unclear. Exercise lowers stress and anxiety and can act as a non pharmacologic neuroprotective agent. In this study, the protective effects of exercise in nicotine withdrawal syndrome-induced anxiety, depression, and cognition impairment were investigated. METHODS: Seventy adult male rats were divided randomly into five groups. Group 1 served as negative control and received normal saline (0.2 mL/rat, i.p.) for 30 days, whereas group 2 (as positive control) received nicotine (6 mg/kg/day, s.c.) for the first 15 days. Groups 4, 5, and 6 were treated with nicotine (6 mg/kg/day, s.c.) for the first 15 days and then were treated with forced exercise, bupropion (20 mg/kg/day, i.p.), or a combination of the two for the following 15 days. Between day 25 and day 30, Morris water maze was used to evaluate spatial learning and memory. From days 31 to 35, the elevated plus maze (EPM), open field test (OFT), forced swim test (FST), and tail suspension test (TST) were used to investigate the level of anxiety and depression in the subjects. RESULTS: Nicotine-dependent animals indicated a reflective depression and anxiety in a dose-dependent manner in FST, EPM, and TST, which were significantly different from the control group and also can significantly attenuate the motor activity and anxiety in OFT. CONCLUSIONS: Forced exercise, bupropion, or their combination can attenuate nicotine cessation induced anxiety, depression, and motor activity in the mentioned behavioral assay. We conclude that forced exercise can protect the brain against nicotine withdrawal-induced anxiety, depression, and cognitive alteration. PMID- 26512427 TI - Somatic stem cell aging and malignant transformation--impact on therapeutic application. AB - Somatic stem cells possess unique properties of self-renewal and plasticity which make them promising candidates for use in tissue engineering and regenerative medicine, in addition to serving as efficient delivery vehicles in site-specific therapy. In the case of therapeutic application, it is essential to isolate and culture stem cells in vitro, to obtain them in sufficient quantities. Although long-term cultivation provides an adequate number of cells, it has been shown that this approach is associated with increased risk of transformation of cultured cells, which presents a significant biological hazard. This article reviews information about biological features and cellular events which occur during long-term cultivation of somatic stem cells, with respect to their safe utilization in potential clinical practice. PMID- 26512428 TI - Attitudes and Beliefs About the Acceptability and Justness of Peer Victimization of Lesbian and Gay University Students. AB - We evaluated the acceptability and justness of anti-lesbian and gay victimization among 473 undergraduates. Participants were assigned to one of four vignette conditions that described an individual being verbally victimized in a typical college setting. Each vignette varied by victim gender (male; female) and sexual orientation (lesbian/gay; heterosexual). Participants completed background questionnaires and a measure that assessed the acceptability of the actions described in the vignettes. Overall, victimization was rated as unacceptable regardless of the sexual orientation and gender of the victim. However, participants rated the victimization of lesbian and gay students as more harmful and unjust than victimization of heterosexual students. Although the acceptability of anti-lesbian and gay victimization was low, 3%-12% of participants rated anti-lesbian and gay victimization as slightly or completely acceptable and just. Given that victimization is associated with long-term negative outcomes, college administrators should consider interventions aimed at decreasing the acceptability of victimization among students. PMID- 26512429 TI - Iron deficiency in sports - definition, influence on performance and therapy. AB - Iron deficiency is frequent among athletes. All types of iron deficiency may affect physical performance and should be treated. The main mechanisms by which sport leads to iron deficiency are increased iron demand, elevated iron loss and blockage of iron absorption due to hepcidin bursts. As a baseline set of blood tests, haemoglobin, haematocrit, mean cellular volume, mean cellular haemoglobin and serum ferritin levels help monitor iron deficiency. In healthy male and female athletes >15 years, ferritin values <15 mcg are equivalent to empty, values from 15 to 30 mcg/l to low iron stores. Therefore a cut-off of 30 mcg/l is appropriate. For children aged from 6-12 years and younger adolescents from 12-15 years, cut-offs of 15 and 20 mcg/l, respectively, are recommended. As an exception in adult elite sports, a ferritin value of 50 mcg/l should be attained in athletes prior to altitude training, as iron demands in these situations are increased. Treatment of iron deficiency consists of nutritional counselling, oral iron supplementation or, in specific cases, by intravenous injection. Athletes with repeatedly low ferritin values benefit from intermittent oral substitution. It is important to follow up the athletes on an individual basis, repeating the baseline blood tests listed above twice a year. A long-term daily oral iron intake or i.v. supplementation in the presence of normal or even high ferritin values does not make sense and may be harmful. PMID- 26512431 TI - Strength-based crisis programming: Evaluating the process of care. AB - In this study, a utilization-focused process evaluation framework was used to explore client and service providers' experiences of Crisis Management Services (CMS), their perceptions of the services provided, and the process of client engagement CMS offers. CMS is a strength-based program that targets individuals who experience crises every day. The Community-University Institute for Social Research facilitated the evaluation by engaging academic expertise in a coordinated collaborative approach to community-university partnerships. Semi structured interviews were conducted with the clients and service providers. The general inductive approach was used for transcript analysis with seven themes emerging. A conceptual model of service delivery is presented, which integrates the interviews conducted with clients and service providers. Results affirm that the establishment of a close personal strength-based relationship is key to client engagement. Collaborative goal setting with informal and formal community resources viewed as potential assets, characterizes the process that enables clients to live at their optimal level of independence. This study is unique as it provides valuable insight on the perspectives of vulnerable individuals in crisis situations. Through the establishment of community-university partnerships the gap between scholarly research and its applicability to community organizations is narrowed with opportunities for improving the quality of life enhanced. PMID- 26512432 TI - Readmissions related to antihypertensive medications used in chronic hemodialysis. AB - BACKGROUND: In hemodialysis, hypertension is treated by removing excess fluid and antihypertensive therapy. Commonly, the antihypertensives used to treat hypertension in earlier stages of kidney disease are continued as the patient progresses into end-stage renal disease and begins dialysis, without much evidence for benefit. METHODS: This study is a single center, retrospective chart review that included hemodialysis patients admitted for congestive heart failure (CHF), fluid overload, or pulmonary edema as determined by ICD-9 code (428.x, 276.6, 518.4, 506.1). The primary objective was to determine if the number or class of antihypertensives used in the chronic hemodialysis population increased the number of readmissions related to CHF, fluid overload, or pulmonary edema. Patients were separated into two groups based on total number of antihypertensive medications, less than or equal to 2 medications for group 1 and greater than two medications for group 2. The primary endpoint was 30-day readmission for CHF, fluid overload, or pulmonary edema. RESULTS: For the study period, 85 individual patient charts met inclusion criteria. Group 1 (n = 44) experienced seven readmissions (16%) and group 2 (n = 41) experienced eight readmissions (18%) (p = 0.663). The most common antihypertensives at discharge were ACE inhibitors for group 1 (45%) and dihydropyridine calcium channel blockers for group 2 (66%). No difference in systolic blood pressures before, during and after hemodialysis was found between groups. CONCLUSIONS: Antihypertensive medications continue to play an important role in the hemodialysis population. This study suggests that drug class and quantity of antihypertensives do not alter readmission rate in the setting of fluid overload. PMID- 26512433 TI - Preserved priming effect in individuals with schizophrenia: cues towards rehabilitation. AB - INTRODUCTION: Individuals with schizophrenia and affective disorders show relatively intact implicit memory as compared to declarative memory. Implicit memory is usually assessed with skill learning and priming tasks. Whereas priming is thought to involve storage changes in the posterior neocortex, skill learning is thought to rely more on the corticostriatal pathway. Since frontostriatal and frontotemporal dysfunctions are, respectively, found in schizophrenia and affective disorders, we hypothesised that individuals with schizophrenia and first-episode psychosis would exhibit disturbances in skill learning, but not priming. METHODS: Thirty-five patients (11 first-episode psychosis; 11 schizophrenia; 13 affective disorders) and 10 controls completed a procedural learning and priming task. Participants had to identify fragmented images throughout five training sessions. The improvement of the threshold at which the images could be identified between the first and last session was used as an index of procedural learning. In a final session, the identification thresholds for old and new images were compared to assess the priming effect. RESULTS: Whereas individuals with schizophrenia and first-episode psychosis showed impaired skill learning, the priming effect was similar in all groups. CONCLUSION: Even though some aspects of learning and memory are affected in schizophrenia, our results suggest that the posterior cortical pathway remains efficient at modulating the priming effect. This intact ability could be used to guide the elaboration of new rehabilitation programmes. PMID- 26512434 TI - Uptake of non-invasive prenatal testing in Chinese women: money matters. AB - OBJECTIVE: To determine the influence of free invasive prenatal testing on the uptake of non-invasive prenatal testing (NIPT). STUDY DESIGN: Over a 2-year period at a Chinese tertiary prenatal diagnostic unit, women at risk of fetal trisomy were given the option of NIPT or invasive prenatal testing. Invasive prenatal testing was offered free of charge to women with a local Hukou (household registration); however, women without a local Hukou were charged for invasive prenatal testing. Both women with and without a local Hukou were charged for NIPT. RESULTS: During the first year, 2647 women with a positive trisomy 21 screening test were referred (474 women with a local Hukou and 2173 women without a local Hukou). Only 1.6% of the women with a local Hukou underwent NIPT, while this proportion was 20.6% in the women without a local Hukou. During the second year, the price of NIPT was reduced. The total number of women referred was 3047 (502 women with a local Hukou and 2545 women without a local Hukou). The uptake of NIPT in women without a local Hukou doubled, but the uptake of NIPT remained stable in women with a local Hukou. CONCLUSION: The financial impact on the uptake of NIPT should not be underestimated. PMID- 26512435 TI - Can urethrolysis resolve outlet obstruction related symptoms after Burch colposuspension for stress urinary incontinence? AB - OBJECTIVE: Bladder outlet obstruction may occur after any incontinence surgery and may present as OAB, hesitancy and or the feeling of incomplete emptying. Aim of this study was to analyze the clinical and urodynamical outcome after urethrolysis in patients presenting with various clinical symptoms after Burch colposuspension for stress urinary incontinence. STUDY DESIGN: Between January 2005 and December 2014, all patients who presented with symptoms and with bladder outlet obstruction were included. All patients had undergone Burch or Cowan colposuspension for stress urinary incontinence previously. Primary endpoint was the visual analogue scale (VAS) as measurement of patient perceived disease impact. Secondary endpoints were the various domains of the King's Health Questionnaire, urodynamic parameters as detrusor pressure at maximum flow, residual urine and sonographic bladder wall thickness before and six months after intervention. RESULTS: Seventy-two female patients were included in this study whereof 42 suffered from urgency and urge incontinence, 20 from hesitancy and/or slow stream, seven from residual urine of more than 100ml and three from a combination of urgency and residual urine. VAS improved significantly (p<0.0001). Quality of life as determined by the King's Health Questionnaire improved for the domains general health, role limitations, emotions, physical limitations, personal limitations and incontinence impact significantly. Micturition pressure dropped significantly from 43cmH2O (95% CI 19-59cmH2O) to 18cmH2O (95% CI 16-23.5 H2O). Residual urine changed from 110ml (range 20-380ml) to 32ml (20-115ml). Bladder wall thickness decreased from 7mm (95% CI 6.235-7.152) to 5mm (95% CI 5.037-5.607; p<0.01). CONCLUSION: Urethrolysis may resolve patients' symptoms and lower micturition pressure but irritative symptoms may persist. PMID- 26512436 TI - Intergenerational transmission of macrosomia in women with gestational diabetes and normal glucose tolerance. AB - OBJECTIVES: It has been suggested that neonatal macrosomia may contribute to increased risk of obesity and type 2 diabetes in later life. Much less is known about the association between maternal birth weight (MBW) and offspring birth weight (OBW). This retrospective study evaluated the prevalence of macrosomia in women with treated gestational diabetes mellitus (GDM) and normal glucose tolerance during pregnancy. The study also investigated associations between MBW and OBW. STUDY DESIGN: Medical records of 519 pregnant women with treated GDM and 766 women with normal glucose tolerance, referred to the Gestational Diabetes Outpatient Clinic in Szczecin, Poland, were analyzed. The following data were assessed: maternal age, pregravid body weight, height, gestational weight gain, prior GDM, prior macrosomia, MBW and OBW. Birth weight was classified as small for gestational age (SGA), appropriate for gestational age (AGA), large for gestational age (LGA) and macrosomia (>=4000g). OBW was obtained from birth certificates, and MBW was obtained from birth certificates or self-report. RESULTS: The overall prevalence of macrosomia was 8.1%, and was comparable in subgroups of women with and without GDM (7.7% and 8.4%, respectively; p=0.905). The frequencies of SGA, AGA and LGA did not differ between study groups. A positive correlation was found between MBW and OBW in women with treated GDM (r=0.211, p<0.001) and in women with normal glucose tolerance (r=0.220, p<0.001). Regardless of glucose tolerance status during pregnancy, the greatest proportion of macrosomic babies were born to mothers who were themselves born macrosomic (26.5% in mothers with GDM and 20.0% in mothers with normal glucose tolerance; p=0.631). On logistic regression, MBW was found to be a robust predictor of macrosomia in offspring [odds ratio (OR) 1.64, 95% confidence interval (CI) 1.15 2.36 in women with treated GDM; OR 1.35, 95% CI 1.07-1.76 in women with normal glucose tolerance). Other independent predictors of fetal macrosomia were gestational weight gain, prior macrosomia and pregravid body mass index (BMI). CONCLUSIONS: MBW, prior macrosomia, pregravid BMI and gestational weight gain were predictors of macrosomia in offspring, but GDM was not. High MBW seems to contribute to intergenerational transmission of macrosomia. PMID- 26512437 TI - An update on new orally administered contraceptives for women. AB - INTRODUCTION: The focus in contraception is shifting from oral contraceptives to more effective methods, such as implants and intrauterine devices. Generics are favored by third-party payors. As a result, potentially exciting developments in branded pills to increase safety or to reduce side effects may have gone unnoticed. AREAS COVERED: This article reviews the features of each of the four new oral contraceptives that have been introduced in the United States and/or Europe in the last few years. The motivation for the development of each product is outlined as is its efficacy, safety, tolerability and the noncontraceptive applications that have been explored are described. EXPERT OPINION: The hypothesis that using estradiol in place of ethinyl estradiol would reduce the risk of venous thromboembolism is still to be proven. However, the stronger progestogens used in these formulations may offer other tangible benefits for selected women. The new products for extended cycle pill use may have less impact. The flexible regimen can be adopted using any pill, but the approved product does provide convenience to patients. Cost will continue to be the determining factor in the acceptance of these new products, unless substantial health benefits can be conclusively proven. PMID- 26512438 TI - The Morcellation Debate: The History and the Science. AB - Intracorporeal electromechanical morcellation has been available for nearly 2 decades, and has allowed hundreds of thousands of women to undergo hysterectomy and myomectomy in a minimally invasive approach. Despite gains in postoperative pain, complications, quality of life, hospital stay, and return to work, it has recently come under attack. The risk of inadvertent morcellation of a uterine malignancy, and subsequent dissemination of occult cancer, must be balanced by the risks of increased numbers of laparotomies. Power morcellation should be available to appropriate surgical candidates. PMID- 26512439 TI - Vaginal Mesh in Pelvic Reconstructive Surgery: Controversies, Current Use, and Complications. AB - In 2001, the Food and Drug Administration approved the first surgical mesh product specifically designed for the surgical repair of pelvic organ prolapse and between 2004 and 2008, the use of vaginal mesh in gynecologic surgery was at its peak. Unfortunately, the rise in transvaginal mesh use was accompanied by a surge of adverse events and mesh-related complications. As a result, the Food and Drug Administration put forth several efforts to regulate the manufacturing of vaginal mesh products. These notifications have been supported by several gynecologic societies, and recommendations now exist not only on the placement of mesh and patient selection, but also on the evaluation and management of mesh related complications. In addition, data on outcomes following management of these complications are now emerging. PMID- 26512440 TI - Controversies in the Management of Endometrioma: To Cure Sometimes, to Treat Often, to Comfort Always? AB - Endometriomas are common in reproductive-aged women, but controversy exists regarding their management. PubMed was searched to identify pertinent studies on outcomes of medical and surgical management of endometrioma, with focus on randomized controlled trials and meta-analyses. Surgical excision is more effective than fenestration/coagulation of endometrioma for pelvic pain but decreases antimullerian hormone. It may modestly improve the chances of spontaneous pregnancy, but does not impact chances of success with in vitro fertilization. Oral contraceptive pills improve dysmenorrhea but not dyspareunia or noncyclic pelvic pain. Management of the patient with endometrioma should be individualized based on each patient's particular symptoms and short-term and long-term fertility goals. PMID- 26512441 TI - Management of Postoperative Abdominal Wall Pain. AB - Postoperative incisional pain is expected after surgery. However, when a patient is complaining of pain months after surgery, this can be a source of frustration and confusion to the patient and the surgeon. Whether the pain is a result of myofascial pain, incisional hernia, or nerve injury, understanding potential sources of abdominal wall pain can simplify this diagnostic dilemma. This chapter will focus on the diagnosis, treatment, and prevention of postsurgical abdominal wall pain. PMID- 26512442 TI - Breast Pain: Engorgement, Nipple Pain, and Mastitis. AB - This review explores current concepts surrounding breastfeeding complications including nipple pain and trauma, breast engorgement, mastitis, and breast abscess. The review discusses possible etiologies, risk factors, incidence, differential diagnosis, and suggested treatment strategies. The evidence that supports these management options is discussed. PMID- 26512443 TI - Educating the Obstetrician About Breastfeeding. AB - Obstetricians and other obstetric providers play a critical role in promoting, protecting, and supporting breastfeeding. Most obstetricians agree that they have a role in breastfeeding support and promotion; however, they often feel unprepared to do so. Breastfeeding support from clinicians is a highly modifiable barrier to breastfeeding success and physician education in breastfeeding medicine is vital to the provision of optimal obstetric care. Obstetricians can easily utilize numerous existing online and print resources to improve their own knowledge, making them an invaluable resource to their patients. PMID- 26512447 TI - Aggressive Palliation and Survival in Anaplastic Thyroid Carcinoma. AB - IMPORTANCE: Anaplastic thyroid carcinoma is an undifferentiated aggressive tumor with a high rate of regional and distant spread and a grave prognosis (median survival, 3 months) with no standardized treatment. OBJECTIVE: To review the effect of an active treatment policy on the outcome of anaplastic thyroid carcinoma. DESIGN, SETTING, AND PARTICIPANTS: Retrospective comparative study of all patients diagnosed as having anaplastic thyroid carcinoma and undergoing treatment from January 1, 2008, through December 31, 2013, in a tertiary university-affiliated medical center. Data were collected by medical record review. Final follow-up was completed on November 30, 2014. Data were analyzed from December 1 to 3, 2014. INTERVENTIONS: Treatment options included surgery and adjuvant concomitant radiotherapy and chemotherapy with doxorubicin hydrochloride or paclitaxel for local disease; full-dose chemoradiotherapy (70 Gy to the gross tumor) for local disease when surgery was not feasible; aggressive palliative radiotherapy (50 Gy to the gross tumor) for metastatic disease; and palliative radiotherapy (<= 30 Gy) for metastatic disease with a low performance status. MAIN OUTCOMES AND MEASURES: Survival time and quality of life. RESULTS: Of the 26 patients (including 15 women) who met the inclusion criteria, 11 underwent radiotherapy with curative intent. These patients included 5 who underwent curative surgery (5 with chemotherapy) and 6 who received primary chemotherapy. Nine patients received aggressive palliative radiotherapy, and 3 received palliative radiotherapy. The remaining 3 patients were not treated. Curative radiotherapy was associated with a significantly longer overall median (95% CI) survival time (11 [8.1-13.9] months) than aggressive palliative radiotherapy (6 [3.1-8.9] months), palliative radiotherapy (3 [0.0-7.8] months), and no treatment (1 month) (P < .001). Chemotherapy in 10 patients had a significant effect on survival (mean [95% CI], 11 [1.2-6.8] vs 4 [8.1-13.9] months for patients who did not receive chemotherapy; P = .01). Among the patients who underwent surgery and curative radiotherapy, 3 were alive after more than 3 years of follow-up. No association of survival with patient sex (median [95% CI] survival for men and women, 9 [3.6-14.4] and 5 [0.3-9.7] months, respectively; P = .54) or a history of thyroid disease (median [95% CI] survival for those with and without, 4 [1.0 6.9] and 9 [5.4-12.5] months, respectively; P = .15) was found. CONCLUSIONS AND RELEVANCE: Anaplastic thyroid carcinoma has a grave prognosis, but an aggressive approach, including surgery, chemotherapy, and radiotherapy, seems to improve survival. Higher doses of radiotherapy may have a survival benefit in candidates for palliative treatment and may be considered for patients with extensive disease. PMID- 26512448 TI - Villitis of unknown etiology - prevalence and clinical associations. AB - OBJECTIVES: We aimed to determine the association of villitis of unknown etiology (VUE) in complicated and uncomplicated pregnancies. METHODS: Placentas from term pregnancies (>=37 weeks) were sent to histopathology evaluation. Maternal and labor characteristics and pathological reports were compared between placentas with VUE (VUE group) and without VUE (controls). Immunohistochemical studies were performed to identify T-cells infiltration in foci of VUE. Placentas were analyzed for concomitant lesions consistent with maternal malperfusion, fetal vascular supply and inflammatory lesions. Small for gestational age (SGA) was defined as birth weight below the 10th %. RESULTS: A total of 1203 placentas were obtained, in which VUE was diagnosed in 5% (n = 60). Compared to controls ((n = 1143), the VUE group was characterized by lower birth weights, p < 0.001, higher rate of SGA, p = 0.009 and lower placental weight, p < 0.001. By logistic regression analysis, after controlling for gestational age, nulliparity, pregnancy complications, obesity, smoking and SGA, only SGA was found to be independently associated with VUE, aOR: 2.3, 95% CI: 1.2-4.4, p = 0.012. Additionally, VUA and maternal malperfusion lesions were found to be independent risk factors for the development SGA. CONCLUSIONS: VUE is associated with lower birth weights, SGA and lower placental weight. Both VUE and maternal malperfusion lesions are risk factors for the development of SGA. PMID- 26512449 TI - Patterns of long-term and short-term responses in adult patients with attention deficit/hyperactivity disorder in a completer cohort of 12 weeks or more with atomoxetine. AB - BACKGROUND: Atomoxetine is a well-established pharmacotherapy for adult ADHD. Long-term studies show incremental reductions in symptoms over time. However, clinical experience suggests that patients differ in their response patterns. METHODS: From 13 Eli Lilly-sponsored studies, we pooled and analyzed data for adults with ADHD who completed atomoxetine treatment at long-term (24 weeks; n=1443) and/or short-term (12 weeks; n=2830) time-points, and had CAARS-Inv:SV total and CGI-S data up to or after these time-points and at Week 0 (i.e. at baseline, when patients first received atomoxetine). The goal was to identify and describe distinct trajectories of response to atomoxetine using hierarchical clustering methods and linear mixed modelling. RESULTS: Based on the homogeneity of changes in CAARS-Inv:SV total scores, 5 response clusters were identified for patients who completed long-term (24 weeks) treatment with atomoxetine, and 4 clusters were identified for patients who completed short-term (12 weeks) treatment. Four of the 5 long-term clusters (comprising 95% of completer patients) showed positive trajectories: 2 faster responding clusters (L1 and L2), and 2 more gradually responding clusters (L3 and L4). Responses (i.e.>=30% reduction in CAARS-Inv:SV total score, and CGI-S score<=3) were observed at 8 and 24 weeks in 80% and 95% of completers in Cluster L1, versus 5% and 48% in Cluster L4. CONCLUSIONS: While many adults with ADHD responded relatively rapidly to atomoxetine, others responded more gradually without a clear plateau at 24 weeks. Longer-term treatment may be associated with greater numbers of responders. PMID- 26512450 TI - Social networking sites and mental health problems in adolescents: The mediating role of cyberbullying victimization. AB - BACKGROUND: Previous research has suggested an association between the use of social networking sites (SNSs) and mental health problems such as psychological distress, suicidal ideation and attempts in adolescents. However, little is known about the factors that might mediate these relationships. The present study examined the link between the use of social networking sites and psychological distress, suicidal ideation and suicide attempts, and tested the mediating role of cyberbullying victimization on these associations in adolescents. METHODS: The sample consisted of a group of 11-to-20-year-old individuals (n=5126, 48% females; mean+/-SD age: 15.2+/-1.9 years) who completed the mental health portion of the Ontario Student Drug Use and Health Survey (OSDUHS) in 2013. Multiple logistic regression analyses were used to test the mediation models. RESULTS: After adjustment for age, sex, ethnicity, subjective socioeconomic status (SES), and parental education, use of SNSs was associated with psychological distress (adjusted odds ratio, 95% confidence interval=2.03, 1.22-3.37), suicidal ideation (3.44, 1.54-7.66) and attempts (5.10, 1.45-17.88). Cyberbullying victimization was found to fully mediate the relationships between the use of SNSs with psychological distress and attempts; whereas, it partially mediated the link between the use of SNSs and suicidal ideation. CONCLUSION: Findings provide supporting evidence that addressing cyberbullying victimization and the use of SNSs among adolescents may help reduce the risk of mental health problems. PMID- 26512451 TI - Electron-dense deposit in renal transplant patients on eculizumab may be drug derived. AB - Eculizumab is a monoclonal antibody that inhibits the conversion of complement protein C5 to C5a and C5b. Eculizumab has been used to treat some disorders of complement regulation owing to its ability to inhibit terminal complement activation. The efficacy of eculizumab in reducing complement-mediated microvascular injury in renal allografts is currently the subject of trials. Electron-dense deposit was detected in allograft biopsies from three highly sensitized recipients of renal transplants, all of whom had received prophylactic eculizumab therapy. In two cases, the deposit was probably drug-derived whilst in the third case the deposit was probably derived from recurrent disease. The cases demonstrate the potential difficulty in interpreting electron-dense deposit in renal allograft biopsies, particularly in the setting of eculizumab therapy. PMID- 26512452 TI - Celecoxib prevents pressure overload-induced cardiac hypertrophy and dysfunction by inhibiting inflammation, apoptosis and oxidative stress. AB - To explore the effects of celecoxib on pressure overload-induced cardiac hypertrophy (CH), cardiac dysfunction and explore the possible protective mechanisms. We surgically created abdominal aortic constrictions (AAC) in rats to induce CH. Rats with CH symptoms at 4 weeks after surgery were treated with celecoxib [2 mg/100 g body-weight(BW)] daily for either 2 or 4 weeks. Survival rate, blood pressure and cardiac function were evaluated after celecoxib treatment. Animals were killed, and cardiac tissue was examined for morphological changes, cardiomyocyte apoptosis, fibrosis, inflammation and oxidative stress. Four weeks after AAC, rats had significantly higher systolic, diastolic and mean blood pressure, greater heart weight and enlarged cardiomyocytes, which were associated with cardiac dysfunction. Thus, the CH model was successfully established. Two weeks later, animals had impaired cardiac function and histopathological abnormalities including enlarged cardiomyocytes and cardiac fibrosis, which were exacerbated 2 weeks later. However, these pathological changes were remarkably prevented by the treatment of celecoxib, independent of preventing hypertension. Mechanistic studies revealed that celecoxib-induced cardiac protection against CH and cardiac dysfunction was due to inhibition of apoptosis via the murine double mimute 2/P53 pathway, inhibition of inflammation via the AKT/mTOR/NF-kappaB pathway and inhibition of oxidative stress via increases in nuclear factor E2-related factor-2-mediated gene expression of multiple antioxidants. Celecoxib suppresses pressure overload-induced CH by reducing apoptosis, inflammation and oxidative stress. PMID- 26512453 TI - What is the DNA repair defect underlying Fanconi anemia? AB - Fanconi anemia (FA) is a rare human genetic disease characterized by bone marrow failure, cancer predisposition, and genomic instability. It has been known for many years that FA patient-derived cells are exquisitely sensitive to DNA interstrand cross-linking agents such as cisplatin and mitomycin C. On this basis, it was widely assumed that failure to repair endogenous interstrand cross links (ICLs) causes FA, although the endogenous mutagen that generates these lesions remained elusive. Recent genetic evidence now suggests that endogenous aldehydes are the driving force behind FA. Importantly, aldehydes cause a variety of DNA lesions, including ICLs and DNA protein cross-links (DPCs), re-kindling the debate about which DNA lesions cause FA. In this review, we discuss new developments in our understanding of DPC and ICL repair, and how these findings bear on the question of which DNA lesion underlies FA. PMID- 26512454 TI - Lenalidomide: deciphering mechanisms of action in myeloma, myelodysplastic syndrome and beyond. AB - Lenalidomide and its related 'analogues' modulate the substrate specificity of the CRL4(CRBN) E3 ubiquitin ligase complex. Polyubiquitination and subsequent proteasomal degradation of IKZF1 and IKZF3 in multiple myeloma and CK1alpha in del(5q) MDS has recently been linked to therapeutic efficacy of this class of compounds. Harnessing ubiquitin ligase substrate specificity, may in time facilitate the degradation of other 'undruggable' proteins and allow for separation of detrimental side effects of IMiD compounds from those associated with therapeutic efficacy. PMID- 26512455 TI - Polymorphs of layered assemblies of hydrogen-bonded hexagonal networks caused by conformational frustration. AB - Generation of four polymorphs of 2D-nCOF crystals that are formed through stacking of a hydrogen-bonded, hexagonally-networked framework is revealed for the first time. The structural diversity is caused not from the topology or the stacking manner of the framework but from subtle structural factors such as rotational conformation and location of conformational frustration within the framework. PMID- 26512456 TI - Free 25-Hydroxyvitamin D Concentrations in Cystic Fibrosis. AB - BACKGROUND: Vitamin D deficiency is common in cystic fibrosis (CF), but there is no previous data on free 25-hydroxyvitamin D (25[OH]D) in CF or in relation to healthy individuals. METHODS: We assessed total serum 25(OH)D concentration by chemiluminescence and serum free 25(OH)D concentration by both direct measurement (ELISA) and calculation, using serum albumin and vitamin D binding protein (VDBP) levels in 80 subjects (28 healthy adults, 25 clinically stable adults and children with CF and 27 adults experiencing a CF exacerbation). RESULTS: Serum albumin and VDBP concentrations were lower in CF compared with healthy controls. Total serum 25(OH)D concentrations were positively correlated with both calculated and measured free 25(OH)D (P < 0.001 for both). Calculated and directly measured serum free 25(OH)D levels were positively correlated (P < 0.001). CONCLUSIONS: Serum levels of directly measured free 25(OH)D positively correlated with total 25(OH)D, suggesting that achieving sufficient total serum 25(OH)D may result in adequate free 25(OH)D levels in CF. PMID- 26512457 TI - Chronotype, sports and public health. PMID- 26512458 TI - A context-intensive approach to imputation of missing values in data sets from networks of environmental monitors. AB - Although networks of environmental monitors are constantly improving through advances in technology and management, instances of missing data still occur. Many methods of imputing values for missing data are available, but they are often difficult to use or produce unsatisfactory results. I-Bot (short for "Imputation Robot") is a context-intensive approach to the imputation of missing data in data sets from networks of environmental monitors. I-Bot is easy to use and routinely produces imputed values that are highly reliable. I-Bot is described and demonstrated using more than 10 years of California data for daily maximum 8-hr ozone, 24-hr PM2.5 (particulate matter with an aerodynamic diameter <2.5 MUm), mid-day average surface temperature, and mid-day average wind speed. I Bot performance is evaluated by imputing values for observed data as if they were missing, and then comparing the imputed values with the observed values. In many cases, I-Bot is able to impute values for long periods with missing data, such as a week, a month, a year, or even longer. Qualitative visual methods and standard quantitative metrics demonstrate the effectiveness of the I-Bot methodology. IMPLICATIONS: Many resources are expended every year to analyze and interpret data sets from networks of environmental monitors. A large fraction of those resources is used to cope with difficulties due to the presence of missing data. The I-Bot method of imputing values for such missing data may help convert incomplete data sets into virtually complete data sets that facilitate the analysis and reliable interpretation of vital environmental data. PMID- 26512459 TI - Broadband mid-infrared frequency comb generation in a Si(3)N(4) microresonator. AB - We demonstrate broadband frequency comb generation in the mid-infrared (MIR) from 2.3 to 3.5 MUm in a Si(3)N(4) microresonator. We engineer the dispersion of the structure in the MIR using a Sellmeier equation we derive from experimental measurements performed on Si(3)N(4) films from the UV to the IR. We use deposition-anneal cycling to decrease absorption losses due to vibrational transitions in the MIR and achieve a Q-factor of 1.0*10(6). To our knowledge, this is the highest Q reported in this wavelength range for any on-chip resonator. PMID- 26512460 TI - High-dimensional structured light coding/decoding for free-space optical communications free of obstructions. AB - Bessel beams carrying orbital angular momentum (OAM) with helical phase fronts exp(ilphi)(l=0;+/-1;+/-2;...), where phi is the azimuthal angle and l corresponds to the topological number, are orthogonal with each other. This feature of Bessel beams provides a new dimension to code/decode data information on the OAM state of light, and the theoretical infinity of topological number enables possible high-dimensional structured light coding/decoding for free-space optical communications. Moreover, Bessel beams are nondiffracting beams having the ability to recover by themselves in the face of obstructions, which is important for free-space optical communications relying on line-of-sight operation. By utilizing the OAM and nondiffracting characteristics of Bessel beams, we experimentally demonstrate 12 m distance obstruction-free optical m-ary coding/decoding using visible Bessel beams in a free-space optical communication system. We also study the bit error rate (BER) performance of hexadecimal and 32 ary coding/decoding based on Bessel beams with different topological numbers. After receiving 500 symbols at the receiver side, a zero BER of hexadecimal coding/decoding is observed when the obstruction is placed along the propagation path of light. PMID- 26512461 TI - Optimization of adiabaticity in coupled-waveguide devices using shortcuts to adiabaticity. AB - Conventional strategies to design adiabatic coupled-waveguide devices focus on optimizing the system adiabaticity but can only guarantee 100% efficiency at specific lengths. We establish a simple technique allowing the optimization of device adiabaticity and ensuring 100% coupling/conversion efficiency at any physically realizable length. Specifically, we use the shortcuts-to-adiabaticity technique to represent the system state precisely and engineer the system evolution to be as close to the adiabatic state as possible. Smooth parameters are derived for coupled-waveguide devices, which feature good robustness against wavelength and fabrication variations at the same time. The proposed device is verified with beam propagation simulations. PMID- 26512462 TI - Carrier-envelope phase stabilization of a 16 TW, 10 Hz Ti:sapphire laser. AB - We propose and demonstrate a simple and promising method for stabilizing the carrier-envelope phase (CEP) of a high-energy ultrashort pulse laser operating at a low repetition rate. The method was successfully applied to a Ti:sapphire laser operating at 10 Hz with 400 mJ pulse energy and 25 fs pulse duration (16 TW). The laser system consists of a 1 kHz front-end preamplifier and a 10 Hz back-end power amplifier. By sampling a 500 Hz reference pulse from a 1 kHz seed pulse, the measured single-shot CEP noise of a 10 Hz amplified pulse is stabilized to 670 mrad rms. Our proposed CEP stabilization concept can be applied to single shot ultrahigh-power lasers, such as a petawatt laser system. PMID- 26512463 TI - Spatial frequency-domain multiplexed microscopy for simultaneous, single-camera, one-shot, fluorescent, and quantitative-phase imaging. AB - Multimodal imaging is a crucial tool when imaging biological phenomena that cannot be comprehensively captured by a single modality. Here, we introduce a theoretical framework for spatial-frequency-multiplexed microscopy via off-axis interference as a novel wide-field imaging technique that enables true simultaneous multimodal and multichannel wide-field imaging. We experimentally demonstrate this technique for single-camera, simultaneous two-channel fluorescence and one-channel quantitative-phase imaging for fluorescent microspheres and fixed cells stained for F-actin and nuclear fluorescence. PMID- 26512464 TI - High-base vector beam encoding/decoding for visible-light communications. AB - Polarization is a basic property of light. Different from well-known linear, circular, and elliptical polarizations, which are spatially homogeneous, a vector light beam with spatially variant polarization states has received increasing interest for its expanded functionalities. In this Letter, we present a visible light communication link exploiting high-base vector beam encoding/decoding. Using a single phase-only spatial light modulator, we generate 16 states of vector beams representing hexadecimal numbers. In the visible-light communication link experiment, we transmit a random high-base number sequence with 10,000 hexadecimal numbers and a 64*64 pixel Lena gray image with 8192 hexadecimal numbers. The bit error rate is evaluated, and zero error among all received hexadecimal numbers is achieved, showing favorable link communication performance using the high-base vector beam encoding/decoding. PMID- 26512465 TI - Wide-field three-dimensional optical imaging using temporal focusing for holographically trapped microparticles. AB - A contemporary challenge across the natural sciences is the simultaneous optical imaging or stimulation of small numbers of cells or colloidal particles organized into arbitrary geometries. We demonstrate the use of temporal focusing with holographic optical tweezers in order to achieve depth-resolved two-photon imaging of trapped objects arranged in arbitrary three-dimensional (3D) geometries using a single objective. Trapping allows for the independent position control of multiple objects by holographic beam shaping. Temporal focusing of ultrashort pulses provides the wide-field two-photon depth-selective activation of fluorescent samples. We demonstrate the wide-field depth-resolved illumination of both trapped fluorescent beads and trapped HL60 cells in suspension with full 3D positioning control. These approaches are compatible with implementation through scattering media and can be beneficial for emergent studies in colloidal science and particularly optogenetics, offering targeted photoactivation over a wide area with micrometer-precision depth control. PMID- 26512466 TI - Single-mode monolithic fiber laser with 200 W output power at a wavelength of 1018 nm. AB - We report on an ytterbium-doped monolithic fiber laser at a wavelength of 1018 nm with an output power of 200 W in continuous wave operation. The optimal parameters for setting up such a high-power fiber laser with an ytterbium-doped fiber are investigated and discussed in detail. An in-house-developed pump light stripper and a single-mode fused fiber coupler were applied to use the fiber laser for core-pumping of ytterbium-doped high-power fiber amplifiers in a monolithic setup. PMID- 26512467 TI - Watt-level passively mode-locked Er(3+)-doped ZBLAN fiber laser at 2.8 MUm. AB - We experimentally demonstrated a stable, high-average-power, continuous-wave (CW) passively mode-locked Er(3+)-doped ZBLAN fiber laser at 2.8 MUm based on a semiconductor saturable absorber mirror. A stable mode-locked laser with a signal to-noise ratio of 52 dB and a slope efficiency of 14% was obtained. The highest average output power in excess of 1 W was generated at the incident pump power of 8.2 W, with a pulse repetition rate of 22.56 MHz and pulse duration of 25 ps. To the best of our knowledge, this is the highest average output power of a CW mode locked ZBLAN fiber laser in the mid-infrared wavelength regime up to now. PMID- 26512468 TI - Total internal reflection optical switch using the reverse breakdown of a pn junction in silicon. AB - We demonstrate a new type of silicon total-internal-reflection optical switch with a simple pn junction functioning both as a reflector and a heater. The reflector is placed between asymmetrically y-branched multimode waveguides with an inclination angle corresponding to half of the branch angle. When the reflector is at rest, incident light is reflected in accordance to the refractive index difference due to the plasma dispersion effect of the pre-doped carriers. Switching to the transmission state is attained under a reverse breakdown of the pn junction by the thermo-optic effect which smears the refractive index difference. From this switching scheme, we confirmed the switching operation with a shallow total-internal-reflection region of 1 MUm width. At a 6 degrees branch angle, an extinction ratio of 12 dB and an insertion loss of -4.2 dB are achieved along with a thermal heating power of 151.5 mW. PMID- 26512469 TI - Photonic radio frequency phase-shift amplification by radio frequency interferometry. AB - We present a new technique for radio frequency (RF) phase-shift amplification based on RF interferometry and demonstrate it in an optical system. A striking feature of this amplifier is that the input phase noise is not amplified together with the input phase signal, so the phase sensitivity improves with higher phase amplification. We also predict that in the case of correlated amplitude noise, the sensitivity is not affected by the amplitude noise. With 600 MHz of modulated light and a phase amplification of 100, we demonstrate a phase resolution of 0.2 mrad, giving a distance resolution of 8 MUm. We postulate that nanometric distance resolution can be achieved with sub-gigahertz modulation. PMID- 26512470 TI - Analysis of lossy mode resonances on thin-film coated cladding removed plastic fiber. AB - In this work, the modal transition induced by lossy mode resonances has been analyzed as a function of wavelength for thin-film coated cladding removed fibers. The wavelength dependence of the modal structure allows us to explain the resonance phenomenon. The numerical data obtained were calculated with a method based on the exact calculation of core modes. Theoretical simulations have been compared with experimental results showing good agreement. PMID- 26512471 TI - Weak and strong interactions between dark solitons and dispersive waves. AB - The effect of mutual interactions between dark solitons and dispersive waves is investigated numerically and analytically. The condition of the resonant scattering of dispersive waves on dark solitons is derived and compared against the results of the numerical simulations. It is shown that the interaction with intense dispersive waves affects the dynamics of the solitons by accelerating, decelerating, or destroying them. It is also demonstrated that two dark solitons can form a cavity for dispersive waves bouncing between the two dark solitons. The differences of the resonant scattering of the dispersive waves on dark and bright solitons are discussed. In particular, we demonstrate that two dark solitons and a dispersive wave bouncing in between them create a solitonic cavity with convex "mirrors," unlike the concave "mirror" in the case of bright solitons. PMID- 26512472 TI - High-speed femtosecond laser beam shaping based on binary holography using a digital micromirror device. AB - In this Letter, we present a digital micromirror device (DMD)-based ultrafast beam shaper, i.e., DUBS. To our knowledge, the DUBS is the first binary laser beam shaper that can generate high-resolution (1140*912 pixels) arbitrary beam modes for femtosecond lasers at a rate of 4.2 kHz; the resolution and pattern rate are limited by the DMD. In the DUBS, the spectrum of the input pulsed laser is first angularly dispersed by a transmission grating and subsequently imaged to a DMD with beam modulation patterns; the transmission grating and a high reflectivity mirror together compensate the angular dispersion introduced by the DMD. The mode of the output beam is monitored by a CCD camera. In the experiments, the DUBS is programmed to generate four different beam modes, including an Airy beam, Bessel beam, Laguerre-Gaussian (LG) beam, and a custom designed "peace-dove" beam via the principle of binary holography. To verify the high shaping rate, the Airy beam and LG beam are generated alternately at 4.2 kHz, i.e., the maximum pattern rate of our DMD. The overall efficiency of the DUBS is measured to be 4.7%. With the high-speed and high-resolution beam-shaping capability, the DUBS may find important applications in nonlinear microscopy, optical manipulation, and microscale/nanoscale laser machining, etc. PMID- 26512473 TI - Polarization and phase characteristics of nonresonant sum-frequency generation response from a silicon (111) surface. AB - Silicon (111) [Si(111)] surfaces both with and without a thin film of polystyrene are investigated with sum-frequency generation (SFG) spectroscopy with s polarized visible and p-polarized infrared inputs. On uncoated Si, the nonresonant polarization changes from s to p, with the maximum signal in each polarization component repeating every 60 degrees of sample rotation. With polystyrene on Si(111), the resonant features go in and out of phase with the nonresonant signal every 120 degrees . The resonant response is only s polarized, as expected; however, the nonresonant response again switches between s and p polarizations. Implications for proper collection and interpretation of SFG spectra from crystalline substrates are discussed. PMID- 26512474 TI - Direct measurements of forces induced by Bloch surface waves in a one-dimensional photonic crystal. AB - An experimental study of the interaction between a single dielectric microparticle and the evanescent field of the Bloch surface wave in a one dimensional (1D) photonic crystal is reported. The Bloch surface wave-induced forces on a 1 MUm polystyrene sphere were measured by photonic force microscopy. The results demonstrate the potential of 1D photonic crystals for the optical manipulation of microparticles and suggest a novel approach for utilizing light in lab-on-a-chip devices. PMID- 26512475 TI - Using the nonseparability of vector beams to encode information for optical communication. AB - In this work, it is experimentally demonstrated that the nonseparability of vector beams (e.g., radial and azimuthal polarization) can be used to encode information for optical communication. By exploiting the nonseparability of a vector beam's space and polarization degrees of freedom using conventional wave plates, it is shown that 2 bits of information can be encoded when applying the identity and three Pauli operators to its polarization degree of freedom. It is also shown that vector beams can be efficiently decoded with as low as 2.7% cross talk using a Mach-Zehnder interferometer that exploits a higher-order Pancharatnam-Berry phase and liquid crystal q-plates. PMID- 26512476 TI - Ultra-high sensitivity Fabry-Perot interferometer gas refractive index fiber sensor based on photonic crystal fiber and Vernier effect. AB - An ultra-high sensitivity open-cavity Fabry-Perot interferometer (FPI) gas refractive index (RI) sensor based on the photonic crystal fiber (PCF) and Vernier effect is proposed and demonstrated. The sensor is prepared by splicing a section of PCF to a section of fiber tube fused with a section of single mode fiber. The air holes running along the cladding of the PCF enable the gas to enter or leave the cavity freely. The reflection beam from the last end face of the PCF is used to generate the Vernier effect, which significantly improves the sensitivity of the sensor. Experimental results show that the proposed sensor can provide an ultra-high RI sensitivity of 30899 nm/RIU. This sensor has potential applications in fields such as gas concentration analyzing and humidity monitoring. PMID- 26512477 TI - Microwave photonic comb filter with ultra-fast tunability. AB - A microwave comb filter with ultra-fast tunability is proposed based on the fundamental delay-line microwave photonic filter. The central frequency of the passband or stopband in such a filter can be rapidly adjusted, along with the independent tunability of the free spectral range (FSR). Experimental results show that the central frequency of the transfer function is electronically tuned with a frequency difference of half of the FSR at a speed of <100 ps. Such high speed tunability is vital for high-speed microwave switching, frequency hopping, cognitive radio, and next-generation radar systems. PMID- 26512478 TI - Optical channel de-aggregation of quadrature-phase-shift-keying and eight-phase shift-keying data using mapping onto constellation axes. AB - An eight-phase-shift-keying signal is experimentally de-aggregated onto two four pulse amplitude modulation signals using nonlinear processes in optical elements. Quadrature-phase-shift-keying signals are similarly de-multiplexed into two binary phase shift keying signals by mapping the data points onto the constellation axes. De-multiplexing performance is evaluated as a function of the optical signal-to-noise ratio of the incoming signals. The effect of phase noise is also studied. PMID- 26512479 TI - High-order harmonics in a quantum dot and metallic nanorod complex. AB - We investigate the high-order harmonic generation (HHG) in a semiconductor quantum dot (SQD) and metallic nanorod (MNR) complex driven by a moderate intensity (<10(12) W/cm(2)) frequency-chirped Gaussian few-cycle pulse. Our numerical results indicate that the cutoff energy of the HHG can be controlled by optimizing the shape of the MNR and surface-to-surface distance between the SQD and the MNR. We also show that the extreme ultraviolet supercontinuum harmonics (25 eV maximal photon energy) and isolated ultrashort pulses (2.67-4.36 fs FWHM) are achievable. PMID- 26512480 TI - Basic categories of dual-contour reflective-refractive aplanats. AB - We derive, illustrate, and analyze previously unrecognized basic categories of dual-contour reflective-refractive aplanats, evaluated for solar concentration. PMID- 26512481 TI - Noninvasive, in vivo imaging of subcortical mouse brain regions with 1.7 MUm optical coherence tomography. AB - A spectral/Fourier domain optical coherence tomography (OCT) intravital microscope using a supercontinuum light source at 1.7 MUm was developed to study subcortical structures noninvasively in the living mouse brain. The benefits of 1.7 MUm for deep tissue brain imaging are demonstrated by quantitatively comparing OCT signal attenuation characteristics of cortical tissue across visible and near-infrared wavelengths. Imaging of hippocampal tissue architecture and white matter microvasculature are demonstrated in vivo through thinned-skull, glass coverslip-reinforced cranial windows in mice. Applications of this novel platform include monitoring disease progression and pathophysiology in rodent models of Alzheimer's disease and subcortical dementias, including vascular dementia. PMID- 26512482 TI - Absolute two-photon excitation spectra of red and far-red fluorescent probes. AB - Efficient use of two-photon excitation (TPE) microscopy requires knowledge of the absolute TPE action cross sections (ATACSs) of fluorescent probes. However, these values are not available for recently developed dyes, which exhibit superior properties in many modern microscopy applications. We report ATACSs of five red to far-red organic dyes, ATTO 647N, STAR 635P, silicon rhodamine, ATTO 594, and ATTO 590. The dyes were found to have large ATACSs (>100 GM) at their respective wavelength peaks, thus supporting their use as bright fluorescent markers in TPE microscopy. PMID- 26512483 TI - Investigation of thermo-optical characteristics of magneto-active crystal Na(0.37)Tb(0.63)F(2.26). AB - Thermo-optical characteristics of a new magneto-active material, Na(0.37)Tb(0.63)F(2.26) crystal, were investigated in this Letter. This crystal has a high value of magneto-optical figure-of-merit and negative optical anisotropy parameter that makes it a promising material for development of Faraday isolators for high-power lasers; in particular it gives opportunities for the realization of new schemes of optical isolators. PMID- 26512484 TI - Interrogation of a linearly chirped fiber Bragg grating sensor with high resolution using a linearly chirped optical waveform. AB - An approach to the interrogation of a linearly chirped fiber Bragg grating (LCFBG) sensor using a linearly frequency-modulated (or chirped) optical waveform (LFMOW) with a high resolution is proposed and experimentally demonstrated. An LFMOW is generated at a laser diode through linear frequency modulation. The generated LFMOW is then launched into an LCFBG pair consisting of two identical LCFBGs, with one serving as a sensing LCFBG and the other as a reference LCFBG. The reflection of the LFMOW from the two LCFBGs would lead to two time delayed LFMOWs. By beating the LFMOWs at a photodetector, a microwave signal with a beat frequency that is proportional to the time delay difference between the two reflected LFMOWs is generated. By measuring the frequency change of the beat signal, the strain applied to the sensing LCFBG is estimated. The proposed approach is experimentally evaluated. An LCFBG sensor with a resolution of 0.25 MUepsilon is experimentally demonstrated. PMID- 26512485 TI - Efficient diode-pumped acousto-optic Q-switched Er:Yb:GdAl(3)(BO(3))(4) pulse laser at 1522 nm. AB - End-pumped by a continuous-wave 976 nm diode laser, efficient 1522 nm laser operation was demonstrated in an Er:Yb:GdAl(3)(BO(3))(4) crystal when a sapphire crystal was used as a heat diffuser. A continuous-wave 1522 nm laser with a maximum output power of 750 mW and slope efficiency of 36% was realized at an absorbed pump power of 4.1 W. The pulse performances of an acousto-optic Q switched laser with various repetition frequencies were investigated in detail. In a repetition frequency range of 1-10 kHz, 1522 nm pulse lasers with a slope efficiency of about 10%, peak output power at the kilowatt level, and width of about 50 ns were first obtained in an Er:Yb:GdAl(3)(BO(3))(4) crystal pumped by a continuous-wave diode laser. The results indicate that the crystal is a promising gain medium for an actively Q-switched 1.5 MUm laser. PMID- 26512486 TI - Spectroscopic microscopy can quantify the statistics of subdiffractional refractive-index fluctuations in media with random rough surfaces. AB - We previously established that spectroscopic microscopy can quantify subdiffraction-scale refractive index (RI) fluctuations in a label-free dielectric medium with a smooth surface. However, to study more realistic samples, such as biological cells, the effect of rough surface should be considered. In this Letter, we first report an analytical theory to synthesize microscopic images of a rough surface, validate this theory by finite-difference time-domain (FDTD) solutions of Maxwell's equations, and characterize the spectral properties of light reflected from a rough surface. Then, we report a technique to quantify the RI fluctuations beneath a rough surface and demonstrate its efficacy on FDTD-synthesized spectroscopic microscopy images, as well as experimental data obtained from biological cells. PMID- 26512487 TI - Near-wavelength diffraction gratings for surface plasmon polaritons. AB - In this Letter, we study numerically diffraction gratings for surface plasmon polaritons. Investigated plasmonic gratings consist of a periodic set of dielectric ridges located on the metal surface. The grating period is comparable with the wavelength of the incident wave. The simulation results obtained within the rigorous coupled-wave analysis framework have shown that the SPP diffraction on a plasmonic grating with parasitic scattering suppression is remarkably close to the diffraction of a TE-polarized plane wave on a conventional grating. A compact and efficient reflecting plasmonic grating is considered as an example. The presented results can be used for the design of high-efficiency two dimensional optical elements for steering surface plasmon propagation. PMID- 26512488 TI - Nonlinear optical memory for manipulation of orbital angular momentum of light. AB - We report on the demonstration of a nonlinear optical memory (NOM) for storage and on-demand manipulation of orbital angular momentum (OAM) of light via higher order nonlinear processes in cold cesium atoms. A spatially resolved phase matching technique is used to select each order of the nonlinear susceptibility associated, respectively, with time-delayed four-, six-, and eight-wave mixing processes. For a specific configuration of the stored OAM of the incident beams, we demonstrated that the OAM of the retrieved beam can be manipulated according to the order of the nonlinear process chosen by the operator for reading out the NOM. This demonstration indicates new pathways for applications in classical and quantum information processing where OAM of light is used to encode optical information. PMID- 26512489 TI - Volumetric structured illumination microscopy enabled by a tunable-focus lens. AB - We present a mechanical-scan-free method for volumetric imaging of biological tissue. The optical sectioning is provided by structured illumination, and the depth of the imaging plane is varied using an electrically tunable-focus lens. We characterize and evaluate the ability of this axial-scanning mechanism in structured illumination microscopy and demonstrate its ability to perform subcellular resolution imaging in oral mucosa ex vivo. The proposed mechanism can potentially convert any wide-field microscope to a 3D-imaging platform without the need for mechanical scanning of imaging optics and/or sample. PMID- 26512490 TI - Generation of chi(2) solitons from the Airy wave through the parametric instability. AB - Spontaneous creation of solitons in quadratic media by the downconversion (i.e., parametric instability against the generation of fundamental-frequency excitations) from the truncated Airy-wave (AW) mode in the second-harmonic component is studied. Parameter regions are identified for the generation of one, two, and three solitons, with additional small-amplitude "jets." Shares of the total power carried by individual solitons are found. Also considered are soliton patterns generated by the downconversion from a pair of AWs bending in opposite directions. PMID- 26512491 TI - Signatures of periodicity and randomness in the angular emission profile of a 2-D on-average periodic optofluidic random laser. AB - Angle-dependent emission from a dye infiltrated 2-D on-average periodic structured optofluidic random laser is studied. Distinct signatures of periodicity and randomness are observed in the angle-resolved emission spectra of the device. Emission patterns composed of concentric ellipses are observed on transverse excitation of the device, attributed to the in-plane diffraction of light by a 2-D square lattice. The effect of randomness on the emission spectra is demonstrated by a highly resolved angle-dependent spectral scan of a single diffraction fringe. Finally, we conclude that the randomness in the size of the scatterers resolves the random lasing modes angularly. PMID- 26512492 TI - Parity-time-symmetric coupled microring lasers operating around an exceptional point. AB - The behavior of a parity-time-symmetric coupled microring system is studied when operating in the vicinity of an exceptional point. Using the abrupt phase transition around this point, stable single-mode lasing is demonstrated in spectrally multimoded microring arrangements. PMID- 26512493 TI - Core/shell-structured upconversion nanophosphor and cadmium-free quantum-dot bilayer-based near-infrared photodetectors. AB - The core/shell-structured upconversion nanophosphors (UCNPs) and Cd-free CuInS(2)/ZnS quantum dots (QDs) were synthesized via coprecipitation and hot injection methods, respectively, and they were applied to near infrared (NIR) photodetectors. The beta-NaYF(4):Yb,Er/beta-NaYF(4) UCNPs emitted intense visible light peaking at 522, 542, and 656 nm via (2)H(11/2), (4)S(3/2), and (4)F(9/2) >(4)I(15/2) transitions under excitation with 980 nm NIR light. The core/shell UCNPs showed 6.4 times higher emission intensity than core UCNPs. Charge carriers can be generated from CuInS(2)/ZnS QDs in the QD-UCNP mixture due to their broad absorption in the visible spectral region shorter than 600 nm. The photodetector devices were fabricated by spin-coating CuInS(2)/ZnS QDs on a SiO(2)/Si substrate with patterned gold electrodes followed by spin-coating UCNPs on the QD layer. The fabricated QD-UCNP-bilayer-based device showed a drastically increased photocurrent (128 MUA) compared with the QD-layer-based device under 980 nm NIR light illumination. Additionally, the fabricated device showed stable ON-OFF switching properties against on and off NIR light. PMID- 26512494 TI - Security authentication using the reflective glass pattern imaging effect. AB - The reflective glass pattern imaging effect is investigated experimentally for the utility in forming a synthetic 3D image as a security authentication device in this Letter. An array of homogeneously randomly distributed reflective elements and a corresponding micropattern array are integrated onto a thin layer of polyester film aiming to create a vivid image floating over a substrate surface, which can be clearly visible to the naked eye. By using the reflective type configuration, the micro-optic system can be realized on a thinner substrate and is immune to external stain due to its flat working plane. A novel gravure like doctor blading technique can realize a resolution up to 12,000 dpi and a stringent 2D alignment requirement should be imposed. Such devices can find applications in document security and banknotes or other valuable items to protect them against forgery. PMID- 26512495 TI - Dynamic polarization flip in nanoripples on photoexcited Ti surface near its surface plasmon resonance. AB - Both normal and abnormal sub-100-nanometer ripples (wavenumber ~10 MUm(-1)) were separately observed on Ti surfaces excited by linearly polarized IR femtosecond laser pulses at lower and higher fluences. Numerical modeling of dispersion curves for surface plasmon-polaritons on the photoexcited Ti surfaces demonstrates its surface plasmon resonance with the peak wavenumber ~8 MUm(-1) spectrally tuned by prompt surface optical response, prompt surface charging, and pre-oxidation, with normal/abnormal nanoripples appearing at its red/blue shoulders, respectively. PMID- 26512496 TI - Ultralow-threshold cascaded Brillouin microlaser for tunable microwave generation. AB - We experimentally demonstrate an ultralow-threshold cascaded Brillouin microlaser for tunable microwave generation in a high-Q silica microsphere resonator. The threshold of the Brillouin microlaser is as low as 8 MUW, which is close to the theoretical prediction. Moreover, the fifth-order Stokes line with a frequency shift up to 55 GHz is achieved with a coupled pump power of less than 0.6 mW. Benefiting from resonant wavelength shifts driven by thermal dynamics in the microsphere, we further realized tunable microwave signals with tuning ranges of 40 MHz at an 11 GHz band and 20 MHz at a 22 GHz band. To the best of our knowledge, it was the first attempt for tunable microwave source based on the whispering-gallery-mode Brillouin microlaser. Such a tunable microwave source from a cascaded Brillouin microlaser could find significant applications in aerospace, communication engineering, and metrology. PMID- 26512497 TI - Dynamic lossless polarization gate using a coherently prepared atomic medium. AB - We propose a dynamic lossless all-optical polarization gate using coherently prepared atomic media. We show that the loss/gain of two circularly polarized components of a linearly polarized probe field can be simultaneously eliminated by locking the power of the pump field and the external magnetic field intensity simultaneously. Using the polarization selective Kerr phase shift method, we can write pi/2 (-pi/2) phase shift to the right (left) circularly polarized component of the linearly polarized probe field with a choice of "magic" wavelength for the probe field. Consequently, the linear polarization state for the probe field acquires a 90 degrees rotation at the exit of the medium. The scheme proposed in this Letter is helpful for applications in optical and quantum information processing and computation. PMID- 26512498 TI - Angle-insensitive plasmonic color filters with randomly distributed silver nanodisks. AB - Plasmonic color filters inherently suffer from angular sensitiveness, which hinder them from practical applications. Here, we present a plasmonic subtractive color filter incorporating two-dimensional randomly distributed silver nanodisks on top of a glass substrate. Due to the elimination of structural periodicity, the proposed plasmonic color filter works via localized surface plasmon resonances (LSPRs) and thus enables excellent angle-insensitive (up to 60 degrees ) performance. In addition, uncoupled LSPRs between nanodisks guarantee stability and reproducibility of the color filter. Finally, a palette of colors across the visible region was obtained with the proposed color filters by simply varying the diameter of nanodisks, exhibiting a promising and robust applicability in digital imaging and sensing industries. PMID- 26512499 TI - Magnetic-field sensor based on whispering-gallery modes in a photonic crystal fiber infiltrated with magnetic fluid. AB - In this work, a magnetic-field sensor was designed to take advantage of the tunability of the resonance wavelengths of a cylindrical whispering-gallery-mode microresonator. The microresonator is based on a 1.3 cm length of photonic crystal fiber infiltrated with a magnetic fluid containing nanoparticles with diameters of either 5 or 10 nm. The Q-factor achieved for the microresonators was 4.24*10(3) or higher. When a magnetic field is applied, the whispering-gallery mode resonances shift toward longer wavelengths. The experimentally demonstrated sensitivity of the proposed sensor was as high as 110 pm/mT in the magnetic field range from 0 to 38.7 mT. PMID- 26512500 TI - Assessment of the metastable electronic state approach as a microscopically self consistent description for the nonlinear response of atoms. AB - This Letter presents the first quantitative assessment of the recently proposed metastable electronic state approach (MESA) for calculation of the nonlinear optical response of noble gas atoms. Based on the single active electron potentials for several atomic species, Stark resonant states are used to extract the nonlinear polarization and ionization rates free of any additional fitting parameters. It is shown that even the simplest version of the method provides a viable, first-principle-based, and self-consistent alternative to the standard model commonly used for simulations in the field of extreme nonlinear optics. PMID- 26512501 TI - Implementation of a new scanning method for high-resolution fluorescence tomography using thermo-sensitive fluorescent agents. AB - Conventional fluorescence tomography provides images of the distribution of fluorescent agents within highly scattering media, but suffers from poor spatial resolution. Previously, we introduced a new method termed "temperature-modulated fluorescence tomography" (TM-FT) that generates fluorescence images with high spatial resolution. TM-FT first uses focused ultrasound to locate the distribution of temperature-sensitive fluorescence probes. Afterward, this a priori information is utilized to improve the performance of the inverse solver for conventional fluorescence tomography and reveal quantitatively accurate fluorophore concentration maps. However, the disadvantage of this novel method is the long data acquisition time as the ultrasound beam was scanned in a step-and shoot mode. In this Letter, we present a new, fast scanning method that reduces the imaging time 40 fold. By continuously scanning the ultrasound beam over a 50 mm by 25 mm field-of-view, high-resolution fluorescence images are obtained in less than 29 min, which is critical for in vivo small animal imaging. PMID- 26512502 TI - Hybrid spiral-ring microlaser vertically coupled to silicon waveguide for stable and unidirectional output. AB - A hybrid spiral-ring laser vertically coupled to a silicon waveguide is demonstrated to achieve stable and unidirectional output theoretically and experimentally. The mode competition between clockwise (CW) and counter-clockwise (CCW) modes is eliminated due to the mode coupling in a spiral resonator. The simulation results indicate that the CCW and CW direction traveling waves are dominant components, respectively, for the spiral resonator without and with an output waveguide. A hybrid AlGaInAs/Si spiral-ring laser is designed and fabricated vertically coupled to a silicon waveguide. For a spiral-ring laser with a radius of 30 MUm and a ring width of 5 MUm, the continuous-wave lasing threshold of 9.5 mA is obtained with the threshold current density of 1.1 kA/cm(2) at a temperature of 285 K. The output power fluctuations due to the mode competition between CW and CCW modes are eliminated. The output power from CCW direction is five times that from CW direction. PMID- 26512503 TI - Pulse front adaptive optics in two-photon microscopy. AB - Adaptive optics has been extensively studied for the correction of phase front aberrations in optical systems. In systems using ultrafast lasers, distortions can also exist in the pulse front (contour of constant intensity in space and time), but until now their correction has been mostly unexplored due to technological limitations. In this Letter, we apply newly developed pulse front adaptive optics, for the first time to our knowledge, to practical compensation of a two-photon fluorescence microscope. With adaptive correction of the system induced pulse front distortion, improvements beyond conventional phase correction are demonstrated. PMID- 26512504 TI - High-sensitivity distributed transverse load sensor with an elliptical-core fiber based on Brillouin dynamic gratings. AB - A high-sensitivity distributed transverse load sensor based on Brillouin dynamic gratings (BDGs) is proposed and demonstrated experimentally for the first time, to the best of our knowledge. The principle is to measure the transverse-load induced birefringence change through exciting and probing a BDG in an elliptical core polarization-maintaining fiber. A distributed measurement of transverse load is demonstrated experimentally using a 10 m sensing fiber, which features high sensitivity to a transverse load with a measurement accuracy as high as 0.8*10( 3) N/mm at a 20 cm spatial resolution. PMID- 26512505 TI - Quantitative shear-wave optical coherence elastography with a programmable phased array ultrasound as the wave source. AB - The purpose of this study is to implement a beam-steering ultrasound as the wave source for shear-wave optical coherence elastography (SW-OCE) to achieve an extended range of elastic imaging of the tissue sample. We introduce a linear phased array ultrasound transducer (LPAUT) as the remote and programmable wave source and a phase-sensitive optical coherence tomography (OCT) as the sensitive shear-wave detector. The LPAUT is programmed to launch acoustic radiation force impulses (ARFI) focused at desired locations within the range of OCT imaging, upon which the elasticity map of the entire OCT B-scan cross section is recovered by spatial compounding of the elastic maps derived from each launch of AFRIs. We also propose a directional filter to separate the shear-wave propagation at different directions in order to reduce the effect of tissue heterogeneity on the shear-wave propagation within tissue. The feasibility of this proposed approach is then demonstrated by determining the stiffness of tissue-mimicking phantoms with agarose concentrations of 0.5% and 1% and also by imaging the Young's modulus of retinal and choroidal tissues within a porcine eye ball ex vivo. The approach opens up opportunities to combine medical ultrasound imaging and SW-OCE for high-resolution localized quantitative assessment of tissue biomechanical property. PMID- 26512506 TI - High-energy large-aperture Ti:sapphire amplifier for 5 PW laser pulses. AB - We report on the generation of 192.3 J centered at 800 nm wavelength from a chirped-pulse amplification (CPA) Ti:sapphire laser system. The experimental results demonstrate that parasitic lasing can be suppressed successfully in the final amplifier based on a Ti:sapphire crystal of 150 mm in diameter. An over 50% pump-to-signal conversion efficiency was measured for the final amplifier by optimizing the time delay of two pump pulses and enhancing the injected seed energy. With 72% compressor throughput efficiency and 27 fs long compressed pulse duration obtained at a lower energy level, this laser could potentially support a compressed laser pulse of 5.13 PW peak power. The experimental results represent notable progress regarding the CPA laser. PMID- 26512507 TI - Differential-interference-contrast digital in-line holography microscopy based on a single-optical-element. AB - Both digital in-line holography (DIH) and zone plate-based microscopy have received considerable interest as powerful imaging tools. However, the former suffers from a twin-image noise problem. The latter suffers from low efficiency and difficulty in fabrication. Here, we present an effective and efficient phase contrast imaging approach, named differential-interference-contrast digital in line holography (DIC-DIH), by using a single optical element to split the incident light into a plane wave and a converging spherical wave and generate a two-dimensional (2D) DIC effect simultaneously. Specifically, to improve image contrast, we present a new single optical element, termed 2D DIC compound photon sieves, by combining two overlaid binary gratings and a compound photon sieve through two logical XOR operations. The proof-of-concept experiments demonstrate that the proposed technique can eliminate the twin-image noise problem and improve image contrast with high efficiency. Additionally, we present an example of the phase-contrast imaging nonuniform thick photoresist development process. PMID- 26512508 TI - Single-shot photofragment imaging by structured illumination. AB - A laser method to suppress background interferences in pump-probe measurements is presented and demonstrated. The method is based on structured illumination, where the intensity profile of the pump beam is spatially modulated to make its induced photofragment signal distinguishable from that created solely by the probe beam. A spatial lock-in algorithm is then applied on the acquired data, extracting only those image components that are characterized by the encoded structure. The concept is demonstrated for imaging of OH photofragments in a laminar methane/air flame, where the signal from the OH photofragments produced by the pump beam is spatially overlapping with that from the naturally present OH radicals. The purpose was to perform for the first time, to the best of our knowledge, single shot imaging of HO(2) in a flame. These results show an increase in signal-to interference ratio of about 20 for single-shot data. PMID- 26512509 TI - Nanoshock wave resonance enhancement on stimulated Raman scattering of H(2)O(2) in liquid water. AB - This study investigates the stimulated Raman scattering (SRS) of H(2)O(2)-H(2)O mixtures. The laser-induced plasma nanoshock wave is formed by focusing an intense pulsed 532 nm laser beam on the mixtures. An enhancement at the low frequency 1715 cm(-1) SRS line of the bending mode of H(2)O(2) is observed. The mechanism of enhancement was attributed to nanoshock wave resonance with the bending mode, which would preferentially excite phonon and lower energy molecular vibrations. PMID- 26512510 TI - Large mode area multi-trench fiber for UV and visible transmission. AB - We experimentally demonstrate all-solid 10 and 20 MUm core diameter multi-trench fibers for UV and visible wavelengths. Measurements ensure an effective single mode operation over a wide range of bend radii, which is suitable for applications such as beam delivery. Both fibers were fabricated by the conventional modified chemical vapor deposition process, which is suitable for mass production. Moreover, all-solid fiber design ensures easy cleaving and splicing. PMID- 26512511 TI - Single- and few-moded lithium aluminosilicate optical fiber for athermal Brillouin strain sensing. AB - Results are presented toward realizing a true single-mode fiber whose Brillouin frequency shift is independent of temperature, while its dependence on strain is comparable to conventional high-silica-content single-mode fibers. Demonstrated here is a fiber with a negative thermal sensitivity dnu/dT of -0.26 MHz/K and a strain sensitivity of +406 MHz/%. The suppression of the Brillouin thermal response is enabled by the large thermal expansion coefficient of the group I oxide-containing silica glass network. PMID- 26512512 TI - Bulk plasmon-polariton gap solitons in defective metamaterial photonic superlattices. AB - We show the existence of a defect mode within the plasmon-polariton gap in 1D defective photonic superlattices, composed by alternating layers of conventional dielectric (A) and negative refractive (B) material slabs with a dielectric defective layer (D), which, in the nonlinear regime, can be tuned by means of the incident field intensity. Also, we have shown that the self-induced transparency phenomena can be only observed when gap-soliton modes, coupled through the defective layer, are excited in both mirror systems around the defective slab. PMID- 26512513 TI - Cascade photonic integrated circuit architecture for electro-optic in-phase quadrature/single sideband modulation or frequency conversion. AB - A photonic integrated circuit architecture for implementing frequency upconversion is proposed. The circuit consists of a 1*2 splitter and 2*1 combiner interconnected by two stages of differentially driven phase modulators having 2*2 multimode interference coupler between the stages. A transfer matrix approach is used to model the operation of the architecture. The predictions of the model are validated by simulations performed using an industry standard software tool. The intrinsic conversion efficiency of the proposed design is improved by 6 dB over the alternative functionally equivalent circuit based on dual parallel Mach Zehnder modulators known in the prior art. A two-tone analysis is presented to study the linearity of the proposed circuit, and a comparison is provided over the alternative. The proposed circuit is suitable for integration in any platform that offers linear electro-optic phase modulation such as LiNbO(3), silicon, III V, or hybrid technology. PMID- 26512514 TI - Refractive index sensitivity characteristics near the dispersion turning point of the multimode microfiber-based Mach-Zehnder interferometer. AB - The turning point of the refractive index (RI) sensitivity based on the multimode microfiber (MMMF) in-line Mach-Zehnder interferometer (MZI) is observed. By tracking the resonant wavelength shift of the MZI generated between the HE(11) and HE(12) modes in the MMMF, the surrounding RI (SRI) could be detected. Theoretical analysis demonstrates that the RI sensitivity will reach +/-infinity on either side of the turning point due to the group effective RI difference (G) approaching zero. Significantly, the positive sensitivity exists in a very wide fiber diameter range, while the negative sensitivity can be achieved in a narrow diameter range of only 0.3 MUm. Meanwhile, the experimental sensitivities and variation trend at different diameters exhibit high consistency with the theoretical results. High RI sensitivity of 10777.8 nm/RIU (RI unit) at the fiber diameter of 4.6 MUm and the RI around 1.3334 is realized. The discovery of the sensitivity turning points has great significance on trace detection due to the possibility of ultrahigh RI sensitivity. PMID- 26512515 TI - Physical manifestation of extreme events in random lasers. AB - We report our studies on exponentially-tempered Levy sums that explain coherent random lasers based on nonresonant feedback. We investigate the hierarchy in the sums and identify the contribution of the extremes over a wide range of excitation energies and disorder strengths. Subsequently, we carry out experiments in which the physical manifestation of these extremes is revealed. At the appropriate gain and disorder, the extremes manifest as the sharp ultranarrow modes in the spectrum. At stronger excitation and disorder, the peaks disappear due to the reduced rarity of the extremes, compounded by the decreased magnitude effected by the tempering. PMID- 26512516 TI - Diffraction technique for testing the resolution and sensitivity of Hartmann and Shack-Hartmann sensors. AB - A diffraction technique for testing the resolution and sensitivity of Hartmann and Shack-Hartmann sensors is proposed, substantiated theoretically, and studied experimentally. It is based on the generation and measuring of the wavefronts of monochromatic plane waves with a weak, one-dimensional, damped chirp modulation and without this modulation. The modulated and nonmodulated wavefronts are produced by the insertion of a half-plane straight-edge screen into the field of a plane wave and by withdrawal of the screen out of the field. Also, the respective intensity distributions of these waves are measured. Testing the resolution and sensitivity of the sensors is performed by analyzing the difference patterns of the phase and intensity distributions recorded with the induced wavefield modulation and without it. PMID- 26512517 TI - Three optical cycle mid-IR Kerr-lens mode-locked polycrystalline Cr(2+):ZnS laser. AB - We report Kerr-lens mode-locked polycrystalline Cr(2+):ZnS lasers at 2.4 MUm central wavelength optimized for short pulse duration. By control of the second- and third-order dispersion within 500 nm bandwidth we obtained pulses of three optical cycles (<29 fs) at 100 MHz repetition rate with 0.44 W average power. The emission spectrum is 240 nm broad at -3 dB level and spans 950 nm at -30 dB level. Transform-limited 38 fs pulses were obtained at 300 MHz repetition rate with 700 mW average power. To the best of our knowledge these are the shortest reported to-date pulses from Cr(2+):ZnS and Cr(2+):ZnSe lasers. PMID- 26512518 TI - Visualizing surface plasmon polaritons by their gradient force. AB - A new method is presented for visualizing the electric field distributions associated with propagating surface-plasmon-polariton (SPP) modes directly in the near-field. The method is based on detecting the photo-induced gradient force exerted by the evanescent field onto a sharp and polarizable tip. Using a photo induced force microscope (PiFM), images of propagating SPPs are obtained on flat gold surfaces. PMID- 26512519 TI - Single-layer optical bandpass filter technology. AB - Resonant periodic surfaces and films enable new functionalities with wide applicability in practical optical systems. Their material sparsity, ease of fabrication, and minimal interface count provide environmental and thermal stability and robustness in applications. Here, we report an experimental bandpass filter fashioned in a single patterned silicon layer on a quartz substrate. Its performance corresponds to bandpass filters requiring 15 traditional Si/SiO(2) thin-film layers. The feasibility of sparse narrowband high efficiency bandpass filters with extremely wide, flat, and low sidebands is thereby demonstrated. This class of devices is designed with rigorous solutions of Maxwell's equations while engaging the physical principles of resonant waveguide gratings. An experimental filter presented exhibits a transmittance of ~72%, bandwidth of ~0.5 nm, and low sidebands spanning ~100 nm. The proposed technology is integration-friendly and opens doors for further development in various disciplines and spectral regions where thin-film solutions are traditionally applied. PMID- 26512520 TI - Investigating the self-healing property of an optical Airy beam. AB - We report the theoretical and experimental study of the self-healing property of an Airy beam related to its phase. We find that, even when the phase of an Airy beam is not preserved, the beam still exhibits the self-healing property but undergoes a severe diffraction. To decrease the diffraction effect, we utilize an electromagnetically induced transparency (EIT) image-cloning system based on position selective absorption effect to further demonstrate the self-healing phenomenon. Our experimental results show excellent agreement with the theoretical analysis. PMID- 26512521 TI - Generalization of electromagnetic scattering by charged grains through incorporation of interband and intraband effects. AB - Scattering of electromagnetic radiation by electrically charged spherical particles is treated theoretically. A generalization of the approach is performed by incorporating both intraband and interband effects, while a new oscillatory term corresponding to the classical dispersion theory and the semi-quantum approach is considered. It is shown through a set of numerical experiments that interband effects may reduce the amplitude of resonant peaks for scattering, Q(sca), and absorption, Q(abs), and cause a shift of peak positions to longer wavelengths. In general, the resonant features due to interband and intraband effects can occur at different frequencies; thus, both together may result in qualitatively and quantitatively new optical signatures of electrically charged particles. This is a motivating factor for experimentalists who can use the particles as targeted probes, for example, in mapping the electric fields in different media based on scattering and/or absorption properties of electrified particulate systems. PMID- 26512522 TI - Low-loss, robust fusion splicing of silica to chalcogenide fiber for integrated mid-infrared laser technology development. AB - We demonstrate a low-loss, repeatable, and robust splice between single-mode silica fiber and single-mode chalcogenide (CHG) fiber. These splices are particularly difficult to create because of the significant difference in the two fibers' glass transition temperatures (~1000 degrees C) as well as the large difference in the coefficients of thermal expansion between the fibers (~20*10( 6)/ degrees C). With 90% light coupled through the silica-CHG fiber splice, predominantly in the fundamental circular-symmetric mode, into the core of the CHG fiber and with 0.5 dB of splice loss measured around the wavelength of 2.5 MUm, after correcting only for the Fresnel loss, the silica-CHG splice offers excellent beam quality and coupling efficiency. The tensile strength of the splice is greater than 12 kpsi, and the laser damage threshold is greater than 2 W (CW) and was limited by the available laser pump power. We also utilized this splicing technique to demonstrate 2 to 4.5 MUm ultrabroadband supercontinuum generation in a monolithic all-fiber system comprising a CHG fiber and a high peak power 2 MUm pulsed Raman-shifted thulium fiber laser. This is a major development toward compact form factor commercial applications of soft-glass mid IR fibers. PMID- 26512523 TI - Watt-level, mid-infrared output from a BaWO(4) external-cavity Raman laser at 2.6 MUm. AB - An external-cavity Raman laser with a BaWO(4) crystal is reported to generate a high-brightness, mid-infrared output at 2.6 MUm. An actively Q-switched Ho:YAG laser at 2.097 MUm is used as the pump source. The first Stokes output from the Raman laser reached 1.35 W with a near-diffraction-limited beam quality. Pulse widths as short as 8.5 ns are measured at a repetition rate of 5 kHz. Maximum conversion efficiency with respect to the incident pump power is measured as 14%. This simplified external-cavity configuration facilitates the realization of Raman-shifted sources within the water absorption window, using fixed and tunable Tm- and Ho-doped solid-state and fiber lasers. PMID- 26512524 TI - High-energy infrared femtosecond pulses generated by dual-chirped optical parametric amplification. AB - We demonstrate high-energy infrared femtosecond pulse generation by a dual chirped optical parametric amplification (DC-OPA) scheme [Opt. Express19, 7190 (2011)]. By employing a 100 mJ pump laser, a signal pulse energy exceeding 20 mJ at a wavelength of 1.4 MUm was achieved before dispersion compensation. A total output energy of 33 mJ was recorded. Under a further energy scaling condition, the signal pulse was compressed to an almost transform-limited duration of 27 fs using a fused silica prism compressor. Since the DC-OPA scheme is efficient and energy scalable, design parameters for obtaining 100 mJ level infrared pulses are presented, which are suitable as driver lasers for the energy scaling of high order harmonic generation with sub-keV photon energy. PMID- 26512525 TI - Optical parametric amplification via non-Hermitian phase matching. AB - We introduce the notion of dissipative optical parametric amplifiers (DOPA) and demonstrate that, even in the absence of the Hermitian phase-matching condition in these structures, the signal beam can be amplified when the idler mode suffers optical attenuation. We discuss the optical implementation of this concept in waveguide platforms, and we propose different methods to control the optical loss of these configurations only at the wavelength of the idler component. Surprisingly, this spectrally selective dissipation process allows the signal beam to draw more energy from the pump and, as a result, attains net amplification. Similar results also apply if the losses are introduced only to the signal component. This intriguing feature can open new avenues for building long wavelength light sources and parametric amplifiers by using semiconductor planar structures, where Hermitian phase-matching requirements can be difficult to satisfy without adding stringent geometric constraints or relatively complex fabrication steps. PMID- 26512526 TI - Phase locking of 2.324 and 2.959 terahertz quantum cascade lasers using a Schottky diode harmonic mixer. AB - The 23rd and 31st harmonics of a microwave signal generated in a novel THz balanced Schottky diode mixer were used as a frequency stable reference source to phase lock solid-nitrogen-cooled 2.324 and 2.959 THz quantum cascade lasers. Hertz-level frequency stability was achieved, which was maintained for several hours. PMID- 26512527 TI - Regenerative amplification and bifurcations in a burst-mode Nd:YAG laser. AB - An Nd:YAG-based burst-mode regenerative amplifier laser was developed that offers high extraction efficiency at high repetition rates with low seed energies. The regenerative amplification technique, combined with the burst-mode laser technology, shows promise as an efficient method for amplification of femtojoule nanojoule pulses up to millijoule energies at repetition rates exceeding 100 kHz. Output energies at repetition rates near the inverse upper state lifetime are limited by bifurcations in the pulse energies of the burst. A model is developed and advantages and limitations are discussed. PMID- 26512528 TI - Low voltage blue phase liquid crystal for spatial light modulators. AB - We demonstrated a low-voltage polymer-stabilized blue phase liquid crystal (BPLC) for phase-only modulation with a liquid-crystal-on-silicon (LCoS). A new device configuration was developed, which allows the incident laser beam to traverse the BPLC layer four times before exiting the LCoS. As a result, the 2pi phase change voltage is reduced to below 24 V in the visible region. The response time remains relatively fast (~3 ms). The proposed device configuration enables widespread applications of BPLC spatial light modulators. PMID- 26512529 TI - Demonstration of polarization mode selection and coupling efficiency of optofluidic ring resonator lasers. AB - We demonstrate the polarization mode selection and the dependence of coupling efficiency on polarization state of pump light for an optofluidic ring resonator (OFRR) laser. An optical fiber is chosen to serve as the ring resonator and surrounded by rhodamine 6G dye solution of lower refractive index as the fluidic gain medium. When the ring resonator is pumped by a linearly s-polarized laser, the emitted whispering gallery mode (WGM) lasing is of parallel polarization (TM mode), while p-polarized laser excitation generates a vertically polarized lasing emission (TE mode), both TM and TE mode lasing emission coexist simultaneously if the ring resonator is pumped by the s- and p-mixed polarized light. Further investigation reveals that the lasing intensity of the TM mode is approximately twice that of the TE mode for the same pump energy density, meaning an obvious difference of coupling efficiency on the polarization state of pump light; the experimental results of coupling efficiency are well explained by an induced dipole model. PMID- 26512530 TI - Timing jitter of Raman solitons. AB - We study the relative intensity noise (RIN) and timing jitter of a Raman soliton. We demonstrate that the RIN of an excitation pulse causes center-wavelength fluctuations of the resulting Raman soliton which translates by fiber dispersion into relative timing jitter (RTJ) between the Raman soliton and the excitation pulse. The Raman soliton's absolute timing jitter is dominated by the excitation pulse's timing jitter at low frequency and by the RTJ at high frequency. The experimental study reveals that RTJ can be significantly reduced by reducing the accumulated fiber dispersion (e.g., using less dispersive fibers with shorter length) experienced by the Raman soliton. PMID- 26512531 TI - Simple method for generation of vector beams using a small-angle birefringent beam splitter. AB - A simple and practical system for generation of vector beams with arbitrary polarization and complex-amplitude distributions is proposed. The system mainly consists of a scalar computer-generated hologram (CGH), a small-angle birefringent beam splitter (BBS), and a Fourier lens with a filtering aperture (FA). The CGH is placed in front of the Fourier lens. The BBS is inserted between the CGH and the Fourier lens. When the CGH specially designed according to the method described in this Letter is illuminated by a plane beam or a Gaussian beam, a desired vector beam can be obtained through the FA placed at the back focal plane of the Fourier lens. Because no coupling element and half-wave plate are to be placed between the CGH and the BBS, the extinction ratios of both the two orthogonal polarization components for the vector beam can be better than 10( 5) and so high-quality vector beams can be generated. PMID- 26512532 TI - Fiber nonlinearity-induced penalty reduction in CO-OFDM by ANN-based nonlinear equalization. AB - We experimentally demonstrate ~2 dB quality (Q)-factor enhancement in terms of fiber nonlinearity compensation of 40 Gb/s 16 quadrature amplitude modulation coherent optical orthogonal frequency-division multiplexing at 2000 km, using a nonlinear equalizer (NLE) based on artificial neural networks (ANN). Nonlinearity alleviation depends on escalation of the ANN training overhead and the signal bit rate, reporting ~4 dBQ-factor enhancement at 70 Gb/s, whereas a reduction of the number of ANN neurons annihilates the NLE performance. An enhanced performance by up to ~2 dB in Q-factor compared to the inverse Volterra-series transfer function NLE leads to a breakthrough in the efficiency of ANN. PMID- 26512533 TI - Octave-spanning coherent supercontinuum generation in a silicon nitride waveguide. AB - We demonstrate the generation of a supercontinuum spanning more than 1.4 octaves in a silicon nitride waveguide using sub-100-fs pulses at 1 MUm generated by either a 53-MHz, diode-pumped ytterbium (Yb) fiber laser or a 1-GHz, Yb:CaAlGdO(4) (Yb:CALGO) laser. Our numerical simulations show that the broadband supercontinuum is fully coherent, and a spectral interference measurement is used to verify that the supercontinuum generated with the Yb:CALGO laser possesses a high degree of coherence over the majority of its spectral bandwidth. This coherent spectrum may be utilized for optical coherence tomography, spectroscopy, and frequency metrology. PMID- 26512534 TI - Toward the optical "magic carpet": reducing the divergence of a light sheet below the diffraction limit. AB - In 3D, diffraction-free or Bessel beams are well known and have found applications in diverse fields. An analog in 2D, or pseudonondiffracting (PND) beams, is a nontrivial problem, and existing methods suffer from deficiencies. For example, Airy beams are not highly localized, some PND beams have significant side lobes, and a cosine beam has to be truncated by a very narrow aperture thus discarding most of the energy. We show, both theoretically and experimentally, that it is possible to generate a quasi-nondiffracting 2D light beam in a simple and efficient fashion. This is achieved by placing a mask consisting of a pair of double slits on a cylindrical lens. The applications include light sheet microscopy/optical sectioning and particle manipulation. PMID- 26512535 TI - 100-kHz-rate gas-phase thermometry using 100-ps pulses from a burst-mode laser. AB - Temperature measurements based on gas-phase coherent anti-Stokes Raman scattering (CARS) spectroscopy are demonstrated in reacting flows at a rate of 100 kHz employing a burst-mode laser with a pulse duration of ~100 ps. The recently developed picosecond-duration, high-energy burst-mode laser is used to pump an optical parametric generator/optical parametric amplifier that produces broadband light centered at ~680 nm to provide the Stokes beams for excitation of the rovibrational Raman transitions of H(2). The 532-nm output of the picosecond burst-mode laser is then utilized as a pump beam for the CARS process that generates 100 single-shot spectra at a rate of 100 kHz during the 1-ms duration burst. Coherent spectroscopy-based temperature measurements at 100 kHz will significantly aid the understanding of transient and unsteady flow phenomena related to turbulent combustion, transonic and hypersonic flows, high-enthalpy flows, and the dynamics of energetic materials. PMID- 26512537 TI - Assessment of an implant-skin interface scoring system for external skeletal fixation of dogs. AB - OBJECTIVE To assess intraobserver repeatability and interobserver and in vivo versus photographic agreement of a scoring system for the implant-skin interface (ISI) of external skeletal fixation (ESF). SAMPLE 42 photographs of ISIs from 18 dogs for interobserver agreement and intraobserver repeatability and 27 photographs of ISIs from 6 dogs for in vivo versus photograph agreement. PROCEDURES An ISI inflammation scoring system was developed. It included scales for 6 metrics (erythema, drainage amount, drainage type, swelling, hair loss or lack of hair regrowth, and granulation tissue). Photographs of the ISI of ESF were obtained by use of a standard protocol and evaluated to determine intraobserver repeatability and interobserver agreement (Cronbach alpha; 4 raters) of the ISI score. Agreement between in vivo and photographic ISI scores (2 raters) and correlation between median scores across metrics were evaluated. RESULTS 42 photographs met the inclusion criteria. Overall intraclass correlation coefficients ranged from 0.922 to 0.975. Interobserver overall Cronbach alpha ranged from 0.835 to 0.943. For in vivo versus photographic assessment, 27 ISIs in 6 dogs and their photographs were evaluated. The Cronbach alpha for both raters ranged from 0.614 to 0.938. Overall, the Cronbach alpha ranged from 0.725 to 0.932. Mean photographic scores were greater than mean in vivo scores for each metric. Pearson correlation coefficients ranged from 0.221 to 0.923. Erythema, swelling, and granulation were correlated with all other metrics. CONCLUSIONS AND CLINICAL RELEVANCE In this study, an ISI scoring system used in this study had high repeatability and agreement and may therefore be considered for use in clinical situations. Photographic scores were not equivalent to in vivo scores and should not be used interchangeably. PMID- 26512538 TI - Effect of histologic processing on dimensions of skin samples obtained from cat cadavers. AB - OBJECTIVE To determine changes in dimensions of feline skin samples as a result of histologic processing and to identify factors that contributed to changes in dimensions of skin samples after sample collection. SAMPLE Cadavers of 12 clinically normal cats. PROCEDURES Skin samples were obtained bilaterally from 3 locations (neck, thorax, and tibia) of each cadaver; half of the thoracic samples included underlying muscle. Length, width, and depth were measured at 5 time points (before excision, after excision, after application of ink to mark tissue margins, after fixation in neutral-buffered 10% formalin for 36 hours, and after completion of histologic processing and staining with H&E stain). Measurements obtained after sample collection were compared with measurements obtained before excision. RESULTS At the final time point, tissue samples had decreased in length (mean decrease, 32.40%) and width (mean decrease, 34.21%) and increased in depth (mean increase, 54.95%). Tissue from the tibia had the most shrinkage in length and width and that from the neck had the least shrinkage. Inclusion of underlying muscle on thoracic skin samples did not affect the degree of change in dimensions. CONCLUSIONS AND CLINICAL RELEVANCE In this study, each step during processing from excision to formalin fixation and histologic processing induced changes in tissue dimensions, which were manifested principally as shrinkage in length and width and increase in depth. Most of the changes occured during histologic processing. Inclusion of muscle did not affect thoracic skin shrinkage. Shrinkage should be a consideration when interpreting surgical margins in clinical cases. 945). PMID- 26512539 TI - Pharmacokinetics and bioavailability of orbifloxacin oral suspension in New Zealand White rabbits (Oryctolagus cuniculus). AB - OBJECTIVE To evaluate the pharmacokinetics and bioavailability of 2 doses of orbifloxacin in rabbits. ANIMALS 6 healthy purpose-bred adult female New Zealand White rabbits (Oryctolagus cuniculus). PROCEDURES Each of 3 rabbits received orbifloxacin at either 10 or 20 mg/kg, PO. Then, after a 1-week washout period, they received the same dose IV. Blood samples were collected from each rabbit at 0, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 hours after drug administration. Plasma orbifloxacin concentration was measured with liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis for data obtained following PO administration and noncompartmental and compartmental analyses for data obtained following IV administration. RESULTS Following oral administration, the mean +/- SD peak plasma orbifloxacin concentration was 1.66 +/- 0.51 MUg/mL for rabbits administered the 10 mg/kg dose and 3.00 +/- 0.97 MUg/mL for rabbits administered the 20 mg/kg dose and was attained at 2 hours after drug administration. The mean +/- SD half-life of orbifloxacin in plasma was 7.3 +/- 1.1 hours for rabbits administered the 10 mg/kg dose and 8.6 +/- 0.55 hours for rabbits administered the 20 mg/kg dose. Mean bioavailability was 52.5% for rabbits administered the 10 mg/kg dose and 46.5% for rabbits administered the 20 mg/kg dose. CONCLUSIONS AND CLINICAL RELEVANCE Results provided pharmacokinetic properties for 2 doses (10 mg/kg and 20 mg/kg) of orbifloxacin oral suspension in rabbits. Further studies are necessary to determine the protein-binding activity of orbifloxacin in rabbits before dosages for the treatment of common pathogens in this species are recommended. PMID- 26512540 TI - Influence of biomechanical parameters on cranial cruciate ligament-deficient or intact canine stifle joints assessed by use of a computer simulation model. AB - OBJECTIVE To investigate the influence of 4 biomechanical parameters on canine cranial cruciate ligament (CrCL)-intact and -deficient stifle joints. SAMPLE Data for computer simulations of a healthy 5-year-old 33-kg neutered male Golden Retriever in a previously developed 3-D rigid body pelvic limb computer model simulating the stance phase during walking. PROCEDURES Canine stifle joint biomechanics were assessed when biomechanical parameters (CrCL stiffness, CrCL prestrain, body weight, and stifle joint friction coefficient) were altered in the pelvic limb computer simulation model. Parameters were incrementally altered from baseline values to determine the influence on stifle joint outcome measures (ligament loads, relative tibial translation, and relative tibial rotation). Stifle joint outcome measures were compared between CrCL-intact and -deficient stifle joints for the range of parameters evaluated. RESULTS In the CrCL-intact stifle joint, ligament loads were most sensitive to CrCL prestrain. In the CrCL deficient stifle joint, ligament loads were most sensitive to body weight. Relative tibial translation was most sensitive to body weight, whereas relative tibial rotation was most sensitive to CrCL prestrain. CONCLUSIONS AND CLINICAL RELEVANCE In this study, computer model sensitivity analyses predicted that CrCL prestrain and body weight influenced stifle joint biomechanics. Cranial cruciate ligament laxity may influence the likelihood of CrCL deficiency. Body weight could play an important role in management of dogs with a CrCL-deficient stifle joint. PMID- 26512541 TI - Risk factors for carriage of antimicrobial-resistant Salmonella spp and Escherichia coli in pet dogs from volunteer households in Ontario, Canada, in 2005 and 2006. AB - OBJECTIVE To determine pet-related management factors associated with the carriage of antimicrobial-resistant Salmonella spp and Escherichia coli in a population of pet dogs. SAMPLE 138 dogs from 84 households in Ontario, Canada. PROCEDURES From October 2005 through May 2006, dogs and households in Ontario, Canada, were recruited to participate in a cross-sectional study. Fecal samples were submitted for culture of Salmonella spp and E coli, which provided 515 bacterial isolates for antimicrobial susceptibility testing. Multilevel logistic regression models with random effects for household and dog were created to identify pet-related management factors associated with antimicrobial resistance. RESULTS Bacterial species, feeding a homemade diet or adding homemade food to the diet, feeding a raw diet or adding anything raw to the diet, feeding a homemade raw food diet, and feeding raw chicken in the past week were significant risk factors for antimicrobial resistance in this population of dogs. CONCLUSIONS AND CLINICAL RELEVANCE In this study, several potentially important pet-related risk factors for the carriage of antimicrobial-resistant Salmonella spp and E coli in pet dogs were identified. Further evaluation of risk factors for antimicrobial resistance in dogs may lead to development of evidence-based guidelines for safe and responsible dog ownership and management to protect the public, especially pet owners who are immunocompromised. PMID- 26512542 TI - Effect of leukoreduction on concentrations of interleukin-8, interleukin-1beta, and tumor necrosis factor-alpha in canine packed red blood cells during storage. AB - OBJECTIVE To measure changes in interleukin-8 (IL-8), interleukin-1beta (IL 1beta), and tumor necrosis factor-alpha (TNF-alpha) concentrations in stored canine packed RBCs (PRBCs) over time and assess the effect of leukoreduction on these cytokine concentrations. ANIMALS 12 anesthetized healthy Greyhounds. PROCEDURES 1 unit of whole blood from each dog was processed into PRBCs. Half of each PRBCs unit was passed through a leukoreduction filter to produce a leukoreduced unit, and the remaining blood was kept as a nonleukoreduced unit. All units had a CBC performed on day 0 (day of collection) and were stored at 2 degrees to 6 degrees C. Samples were collected from leukoreduced and nonleukoreduced units on days 0, 10, 20, 30, and 37 and centrifuged; the supernatant was stored at -80 degrees C until analysis. Canine TNF-alpha and IL-8 concentrations were assessed with a multiplexed genomic and proteomic biomarker analyzer, and canine IL-1beta concentration was measured by ELISA. RESULTS Leukocyte counts were decreased by >= 99.9% in all leukoreduced units. Median TNF alpha and IL-1beta concentrations were not significantly different between leukoreduced and nonleukoreduced units and did not change significantly during storage; median IL-8 concentration was significantly higher in nonleukoreduced versus leukoreduced units on all days, and was greater at all time points after >= 10 days of storage than on day 0. Median IL-8 concentration in leukoreduced units did not increase during storage. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that leukoreduction was effective for the removal of leukocytes from canine PRBCs and prevented significant increases in IL-8 concentration during storage. Further studies are needed to evaluate whether leukoreduction reduces cytokine-associated complications of transfusion. PMID- 26512543 TI - Effect of in ovo administration of inulin and Lactococcus lactis on immune related gene expression in broiler chickens. AB - OBJECTIVE To evaluate the effect of in ovo administration of inulin and Lactococcus lactis on immune-related gene expression in broiler chickens. ANIMALS 45 Ross broilers. PROCEDURES On day 12 of embryonic development, 360 eggs were equally allocated among 3 treatment groups and injected with 0.2 mL of a solution that contained 1.76 mg of inulin (prebiotic group) or 1.76 mg of inulin enriched with 1,000 CFUs of L lactis subsp lactis 2955 (synbiotic group), or they were injected with 0.2 mL of saline (0.9% NaCl) solution (control). At 1, 14, and 35 days after hatching, 5 male birds from each group were euthanized, and the spleen and cecal tonsils were harvested for determination of interleukin (IL)-4, IL-6, IL-8, IL-12p40, IL-18, cluster of differentiation 80, interferon-beta, and interferon-gamma expression by means of a reverse transcription quantitative PCR assay. Gene expressions in the cecal tonsils and spleens of chickens in the prebiotic and synbiotic groups were compared with those of control chickens at each tissue collection time. RESULTS Compared with control birds, immune-related gene expression was downregulated in birds in the prebiotic and synbiotic groups, and the magnitude of that downregulation was more pronounced in the cecal tonsils than in the spleen and increased with age. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that in ovo administration of a prebiotic or synbiotic to broilers was associated with downregulation of immune-related gene expression in the cecal tonsils and spleen. The magnitude of that downregulation increased with age and was most likely caused by stabilization of the gastrointestinal microbiota. PMID- 26512544 TI - Serum alpha-1 acid glycoprotein and serum amyloid A concentrations in cats receiving antineoplastic treatment for lymphoma. AB - OBJECTIVE To characterize serum alpha-1 acid glycoprotein (AGP) and serum amyloid A (SAA) concentrations at diagnosis and during treatment in cats with lymphoma. ANIMALS 16 cats with various anatomic forms of lymphoma and 25 healthy cats. PROCEDURES Blood samples were collected from healthy cats once and from cats with lymphoma at diagnosis and 2-week intervals until the 12th week of antineoplastic treatment. Serum harvested from blood samples was assessed for AGP and SAA concentrations. Differences in serum AGP and SAA values were investigated between healthy cats and cats with lymphoma (at diagnosis) and, for cats with lymphoma, between diagnosis and various points during treatment. RESULTS Serum AGP and SAA concentrations were higher in cats with lymphoma at diagnosis (median, 832.60 and 1.03 MUg/mL, respectively), compared with those in healthy cats (median, 269.85 and 0.10 MUg/mL). Treatment resulted in a gradual decrease in serum AGP concentration after 4 weeks and in SAA concentration after 8 weeks of treatment, and these concentrations returned to values comparable with those of healthy cats by 12 weeks of treatment, by which point all cats had achieved complete remission of the disease. CONCLUSIONS AND CLINICAL RELEVANCE Serum AGP and SAA concentrations in cats with lymphoma were higher at diagnosis than after antineoplastic treatment. Decreases to values established for healthy cats corresponded with achievement of complete disease remission. Serum AGP and SAA may be useful protein markers for monitoring of antineoplastic treatment in cats with lymphoma. PMID- 26512545 TI - Evaluation of species differences and the effects of storage duration and temperature on the anticollagenase efficacy of canine, feline, and equine serum on in vitro corneal degradation. AB - OBJECTIVE To evaluate species differences and effects of storage duration and temperature on the anticollagenase efficacy of canine, feline, and equine serum on in vitro corneal degradation. SAMPLES Corneas and serum from dogs, cats, and horses. PROCEDURES Clinically normal corneas from dogs, cats, and horses were harvested within 2 hours after euthanasia. Serum samples from dogs, cats, and horses were collected and pooled by species. Corneal specimens were incubated with collagenase derived from Clostridium histolyticum, 5mM calcium chloride in saline (0.9% NaCl) solution, and feline, canine, or equine serum that had been stored for 0, 30, 90, or 180 days at -20 degrees or -80 degrees C. Following incubation, the corneal weight loss percentage and hydroxyproline concentration in the incubation fluid were calculated and compared among experimental combinations. RESULTS Feline serum was more effective than canine or equine serum for minimizing corneal weight loss. Incubation with feline or equine, but not canine, serum significantly reduced hydroxyproline production. Serum storage duration did not affect corneal weight loss, but the hydroxyproline concentration was greater for corneal specimens that were incubated with serum that was stored for 90 days, compared with that for corneal specimens incubated with serum that was stored for 0, 30, or 180 days. Serum storage temperature did not affect corneal weight loss or hydroxyproline concentration. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that serum reduced corneal degradation in vitro, and the duration and temperature at which serum was stored did not affect its anticollagenase efficacy. PMID- 26512546 TI - Iron metabolism following intravenous transfusion with stored versus fresh autologous erythrocyte concentrate in healthy dogs. AB - OBJECTIVE To determine effects of IV transfusion with fresh (3-day-old) or stored (35-day-old) autologous erythrocyte concentrate on serum labile iron concentration, iron-binding capacity, and protein interaction with iron in dogs. ANIMALS 10 random-source healthy dogs. PROCEDURES Dogs were randomly assigned to receive autologous erythrocyte concentrate stored for 3 days (n = 5) or 35 days (5). One unit of whole blood was collected from each dog, and erythrocyte concentrates were prepared and stored as assigned. After erythrocyte storage, IV transfusion was performed, with dogs receiving their own erythrocyte concentrate. Blood samples were collected from each dog before and 5, 9, 24, 48, and 72 hours after transfusion. Serum was harvested for measurement of total iron, labile iron, transferrin, ferritin, hemoglobin, and haptoglobin concentrations. RESULTS For dogs that received fresh erythrocytes, serum concentrations of the various analytes largely remained unchanged after transfusion. For dogs that received stored erythrocytes, serum concentrations of total iron, labile iron, hemoglobin, and ferritin increased markedly and serum concentrations of transferrin and haptoglobin decreased after transfusion. CONCLUSIONS AND CLINICAL RELEVANCE Transfusion with autologous erythrocyte concentrate stored for 35 days resulted in evidence of intravascular hemolysis in healthy dogs. The associated marked increases in circulating concentrations of free iron and hemoglobin have the potential to adversely affect transfusion recipients. PMID- 26512547 TI - Erratum: Vol. 64, No. 34. PMID- 26512548 TI - Chemical Composition and Antioxidant Capacity of Brazilian Passiflora Seed Oils. AB - The seed oils of different varieties of 4 Passiflora species cultivated in Brazil were analyzed and compared regarding their physicochemical parameters, fatty acid composition and the presence of minor components, such as phytosterols, tocopherols, total carotenoids, and phenolic compounds. The antioxidant capacities of the oil extracts were determined using the 2,2'azinobis [3 ethylbenzothiazoline-6-sulfonic acid] and oxygen radical absorbance capacity methods. The results revealed that all studied Passiflora seed oils possessed similar physicochemical characteristics, except for color, and predominantly contained polyunsaturated fatty acids with a high percentage of linolenic acid (68.75% to 71.54%). Other than the total phytosterol content, the extracted oil from Passiflora setacea BRS Perola do Cerrado seeds had higher quantities (% times higher than the average of all samples), of carotenoids (44%), phenolic compounds (282%) and vitamin E (215%, 56%, 398%, and 100% for the alpha tocopherol, beta-tocopherol, gamma-tocopherol, and delta-tocopherol isomers, respectively). The methanolic extracts from Passiflora setacea BRS Perola do Cerrado seed oil also showed higher antioxidant activity, which was positively correlated with the total phenolic, delta-tocopherol, and vitamin E contents. For the first time, these results indicate that Passiflora species have strong potential regarding the use of their seeds for oil extraction. Due to their interesting composition, the seed oils may be used as a raw material in manufacturing industries in addition to other widely used vegetable oils. PMID- 26512549 TI - Detection of Strabismus by Non-Health Care Professionals in an Ethnically Diverse Set of Images. AB - IMPORTANCE: Understanding the criteria for when strabismus becomes detectable by non-health care professionals could influence the goals for determining the success of surgical intervention and how patients with such misalignments are counseled. OBJECTIVE: To examine the magnitude at which strabismus is detectable by lay observers in an ethnically diverse set of images. DESIGN, SETTING, AND PARTICIPANTS: Photographs of 12 ethnically diverse models (black, white, and Asian) were simulated to have strabismus from esotropia of 21 prism diopters (?) to exotropia of 21?. From July 1, 2007, to October, 1, 2008, images were presented to 120 non-health care professionals aged 21 years or older from the general community in Boston, Massachusetts, who were asked whether strabismus was present. Analysis was conducted from November 1, 2008, to March 31, 2009. MAIN OUTCOMES AND MEASURES: The threshold angle for detecting strabismus to enable 70% of lay observers to make a positive determination whether strabismus is present. RESULTS: In white and black models, the threshold allowing a 70% positive detection rate was higher for esotropia than for exotropia (P < .001 for both). For white models, the threshold was 23.2? (95% CI, 21.0? to 26.5?) for esotropia and 13.5? (95% CI, 12.5? to 14.6?) for exotropia. For black models, the threshold was 20.8? (95% CI, 19.2? to 22.2?) for esotropia and 16.3? (95% CI, 15.5? to 17.2?) for exotropia. Asian models showed an opposite trend, with the threshold allowing a 70% positive detection rate for esotropia (14.3?; 95% CI, 13.2? to 15.7?) being lower than that for exotropia (20.9?; 95% CI, 18.0? to 24.6?) (P < .001). CONCLUSIONS AND RELEVANCE: Esotropia was easier for lay observers to detect than exotropia in Asian models, and exotropia was easier to detect than esotropia in white and black models. This information should be considered when managing patients who have concerns about the social significance of their strabismus. Future studies should include diverse individuals and make an effort to account for individual factors that may alter the perception of strabismus. PMID- 26512550 TI - Advanced age and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor. AB - ESSENTIALS: Dual antiplatelet therapy (DAPT) in elderly patients requires balancing bleedings and thrombosis. Impact of age on high residual on-treatment platelet reactivity (HRPR) on DAPT was studied. A reduced effectiveness of adenosine diphosphate antagonists was observed over 70 years of age. The occurrence of HRPR was increased among elderly patients with both clopidogrel and ticagrelor. BACKGROUND: The aim of the present study was to evaluate the impact of age on platelet function and the occurrence of high residual on-treatment platelet reactivity (HRPR) in patients treated with dual antiplatelet therapy (DAPT) using acetylsalicilic acid (ASA) and clopidogrel or ticagrelor. METHODS: Patients treated with DAPT (ASA and clopidogrel or ticagrelor) were scheduled for platelet function assessment at 30-90 days post-discharge. By whole blood impedance aggregometry, HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values > 417 AU*min (for ADP antagonists). Elderly patients were defined as those aged >= 70 years. RESULTS: Among 494 patients on DAPT, 224 (45.3%) were >= 70 years old. ADP-mediated platelet aggregation increased with decades of age (279.3 +/- 148.6 vs. 319.6 +/- 171.1 vs. 347.3 +/- 190.1 vs. 345.7 +/- 169.2), whereas no difference was observed for ASA response. A reduced effectiveness of ADP antagonists was observed among elderly patients; in fact, among the 117 patients displaying HRPR (23.7%), a higher prevalence was observed among patients over 70 years old (30.4% vs. 18.1%; adjusted odds ratio (OR) [95% confidence interval (CI)] = 2.19 [1.29 3.71]). Similar results were obtained among the 266 clopidogrel-treated patients (38.5% vs. 27.9%; adjusted OR [95% CI] = 2.91 [1.46-5.8]) and in the 228 patients receiving ticagrelor (19.1% vs. 8.1%; adjusted OR [95% CI] = 2.55 [1.02-8.59]). CONCLUSION: In patients receiving dual antiplatelet therapy, advanced age is independently associated with a reduced effectiveness of ADP antagonists and a higher rate of HRPR with both clopidogrel and ticagrelor. PMID- 26512551 TI - Long term motor function after neonatal stroke: Lesion localization above all. AB - Motor outcome is variable following neonatal arterial ischemic stroke (NAIS). We analyzed the relationship between lesion characteristics on brain MRI and motor function in children who had suffered from NAIS. Thirty eight full term born children with unilateral NAIS were investigated at the age of seven. 3D T1- and 3D FLAIR-weighted MR images were acquired on a 3T MRI scanner. Lesion characteristics were compared between patients with and without cerebral palsy (CP) using the following approaches: lesion localization either using a category based analysis, lesion mapping as well as voxel-based lesion-symptom mapping (VLSM). Using diffusion-weighted imaging the microstructure of the cortico-spinal tract (CST) was related to the status of CP by measuring DTI parameters. Whereas children with lesions sparing the primary motor system did not develop CP, CP was always present when extensive lesions damaged at least two brain structures involving the motor system. The VLSM approach provided a statistical map that confirmed the cortical lesions in the primary motor system and revealed that CP was highly correlated with lesions in close proximity to the CST. In children with CP, diffusion parameters indicated microstructural changes in the CST at the level of internal capsule and the centrum semiovale. White matter damage of the CST in centrum semiovale was a highly reproducible marker of CP. This is the first description of the implication of this latter region in motor impairment after NAIS. In conclusion, CP in childhood was closely linked to the location of the infarct in the motor system. PMID- 26512552 TI - Cardiovascular Involvement in Erdheim-Chester Disease: A Case Report and Review of the Literature. AB - Erdheim-Chester disease (ECD) is a rare, multiorgan, non-Langerhans cell histiocytosis of uncertain origin, characterized by systemic xanthogranulomatous infiltration from CD68+CD1a- histiocytes. Skeletal involvement is present in up to 96% of cases with bilateral osteosclerosis of meta-diaphysis of long bones. Furthermore, in more than 50% of cases there is 1 extraskeletal manifestation. In this case report, we describe an interesting case of ECD with an extensive pan cardiac and vascular involvement, in addition to skeletal, retro-orbital, and retroperitoneum one.A 44-year-old woman with a long history of exophthalmos referred to our hospital for elective surgical orbital decompression. At preoperative examinations a large pericardial effusion was discovered. Echocardiography, computed tomography (CT), and magnetic resonance imaging (MRI) described an inhomogeneous mass involving pericardium and the right heart, abdominal aorta and its main branches and the retroperitoneum, suggestive for a systemic inflammatory disorder. Histological examination on a biopsy sample confirmed the diagnosis of ECD. Radiology showed the pathognomonic long-bone involvement. Surgical orbital decompression was performed and medical therapy with interferon-alpha (INF-alpha) was started.Among extraskeletal manifestations of ECD, cardiovascular involvement is often asymptomatic and thus under-diagnosed but linked to poor prognosis. This is why clinician should always look for it when a new case of ECD is diagnosed. PMID- 26512553 TI - Evaluation of Lymphatic and Vascular Invasion in Relation to Clinicopathological Factors and Treatment Outcome in Oral Cavity Squamous Cell Carcinoma. AB - This study evaluated the associations between lymphatic and vascular invasion of oral cavity squamous cell carcinoma (OSCC) and clinicopathological manifestations, as well as their impact on patient outcomes after treatment.In total, 571 patients with primary OSCC who underwent surgery with or without adjuvant therapy were enrolled.Lymphatic and vascular invasion were found in 28 (5%) and 16 (3%) patients, respectively. Significant associations were found between lymphatic and vascular invasion and overall stage (P < 0.001 and P = 0.020, respectively), tumor stage (P = 0.009 and P = 0.025, respectively), nodal metastasis (both P < 0.001), extracapsular spread (both P < 0.001), perineural invasion (both P < 0.001), bone invasion (P = 0.004 and P = 0.001, respectively), depth of invasion (P < 0.001 and P = 0.001, respectively), and pathologic differentiation (P = 0.002 and P < 0.001, respectively). In the analysis of adverse events during follow-up, neither lymphatic nor vascular invasion was statistically associated with local recurrence, neck recurrence, and distant metastasis. Although lymphatic invasion exhibited significant associations with poorer overall survival (P < 0.001), disease-specific survival (P < 0.001), and disease-free survival (P = 0.01), it was not demonstrated to be an independent prognostic factor in all multivariate analyses.Although both lymphatic and vascular invasion are associated with many clinicopathological manifestations, neither affects the occurrence of locoregional recurrence and distant metastasis in patients with OSCC after treatment. PMID- 26512554 TI - Time-course of Changes in Activation Among Facial Nerve Injury: A Functional Imaging Study. AB - Patients suffering different intervals of facial nerve injury were investigated by functional magnetic resonance imaging to study changes in activation within cortex.Forty-five patients were divided into 3 groups based on intervals of facial nerve injury. Another 16 age and sex-matched healthy participants were included as a control group. Patients and healthy participants underwent task functional magnetic resonance imaging (eye blinking and lip pursing) examination.Functional reorganization after facial nerve injury is dynamic and time-dependent. Correlation between activation in sensorimotor area and intervals of facial nerve injury was significant, with a Pearson correlation coefficient of -0.951 (P < 0.001) in the left sensorimotor area and a Pearson correlation coefficient of 0.333 (P = 0.025) in the right sensorimotor area.Increased activation in integration areas, such as supramarginal gyrus and precunes lobe, could be detected in the early-middle stage of facial dysfunction compared with normal individuals. Decreased activation in sensorimotor area contralateral to facial nerve injury could be found in late stage of facial dysfunction compared with normal individuals. Dysfunction in the facial nerve has devastating effects on the activity of sensorimotor areas, whereas enhanced intensity in the sensorimotor area ipsilateral to the facial nerve injury in middle stage of facial dysfunction suggests the possible involvement of interhemispheric reorganization. Behavioral or brain stimulation technique treatment in this stage could be applied to alter reorganization within sensorimotor area in the rehabilitation of facial function, monitoring of therapeutic efficacy, and improvement in therapeutic intervention along the course of recovery. PMID- 26512555 TI - Oral Contraceptives Use and Liver Cancer Risk: A Dose-Response Meta-Analysis of Observational Studies. AB - Studies about the association between oral contraceptives use and liver cancer risk have generated controversial results. Therefore, a meta-analysis of cohort and case-control studies was performed to quantitatively summarize the existing evidence.Eligible studies were identified by a computer search of PubMed and Embase databases and handed-search of reference lists, without any limitations. Study-specific risk estimates (RRs) with 95% confidence intervals (CIs) were combined with random-effects model.A total of 17 articles were included in this meta-analysis. Overall, there was no statistically significant association between oral contraceptives use and liver cancer risk (RR: 1.23, 95% CI: 0.93 1.63). In a dose-analysis of meta-analysis, a linear relationship between oral contraceptives use and liver cancer risk (P for linearity = 0.391) was found, although this correlation was not statistically significant.Oral contraceptives use was not positively associated with the risk of liver cancer. PMID- 26512556 TI - Prognostic Value and Grading of MRI-Based T Category in Patients With Nasopharyngeal Carcinoma Without Lymph Node Metastasis Undergoing Intensity Modulated Radiation Therapy. AB - We investigated the prognostic value and gradation of the T category in N0 nasopharyngeal carcinoma (NPC) patients undergoing magnetic resonance imaging (MRI) and intensity-modulated radiotherapy (IMRT).A total of 749 patients were retrospectively reviewed, and a total of 181 N0 NPC patients were included in this retrospective study. All patients were restaged according to the 7th edition of the American Joint Committee on Cancer staging system. The following endpoints were estimated: overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS).The 5-year survival rates for T1 to T4 were: OS (97.3%, 100.0%, 86.1%, and 82.8%; P = 0.007), PFS (94.6%, 96.9%, 76.5%, and 76.7%; P = 0.002), LRFS (98.5%, 100.0%, 92.2%, and 86.7%; P < 0.001), and DMFS (97.3%, 96.9%, 85.5%, and 85.7%; P = 0.042), respectively. Pairwise comparisons showed that the OS, PFS, and LRFS rates were significantly poorer in the advanced T categories (T3 and T4) than the early ones (T1 and T2), and no significant differences between T1 and T2, and T3 and T4 were found. In Cox's proportional hazard analysis, T category was found to be an independent prognostic factor only for PFS (P = 0.003). According to the primary tumor extent, we then graded all 181 N0 patients into 3 groups: group 1, early T category (n = 107); group 2, low-risk advanced T category (n = 35); and group 3, high-risk advanced T category (n = 39). The 5-year survival rates for the 3 groups were: OS (98.1%, 94.1%, and 76.3%; P < 0.001), PFS (95.3%, 88.2%, and 66.2%; P < 0.001), LRFS (99.0%, 97.0%, and 83.4%; P < 0.001), and DMFS (97.2%, 91.1%, and 80.4%; P = 0.002). The 5-year OS, PFS, and LRFS rates of group 3 differed significantly from those of groups 1 and 2, and a significant difference was observed in the DMFS rate only between groups 3 and 1. In Cox's proportional hazard analysis, the 3-grade T category was an independent prognostic factor for OS (P = 0.002), PFS (P < 0.001), and LRFS (P = 0.002).The 3 grade T category, using MRI according to the site of invasion, has prognostic value for the outcome of IMRT treatment in N0 NPC, and could aid in developing individualized treatment strategies. PMID- 26512557 TI - Invasion Types Are Associated With Poor Prognosis in Lung Squamous Carcinoma Patients. AB - Although the prognostic significance of the histologic patterns in lung adenocarcinoma is being identified, no significant prognostic indicators in lung squamous carcinoma are accepted as a standard universally. The aim of this study was to evaluate the histologic characteristics incorporating the defined invasion types and distinguish the features that can reflect prognosis.We reviewed all slices of 132 patients with lung squamous carcinoma. The cases were classified according to the World Health Organization (WHO) classification and were evaluated for tumor budding, single cell invasion, large cell invasion, cytologic atypia degree, mitotic count, number of buds, tumor nest size, fibrosis, and necrosis.In univariate analysis, overall survival was associated significantly with age (P = 0.023), lymph nodes metastasis (P < 0.001), distant organ metastasis (P < 0.001), pleural invasion (P < 0.001), tumor budding (P = 0.003), single cell invasion (P = 0.001), mitotic count (P < 0.001), and the cytologic atypia degree (P = 0.009). However, the subtypes of 2004 WHO classification showed no association with outcome (P = 0.209). In multivariate analysis, the independent significant prognostic indicators of lung squamous carcinoma were tumor budding (hazard ratio [HR] = 0.466, P = 0.005), single cell invasion (HR = 0.447, P = 0.003), mitotic count (HR = 0.502, P = 0.048) and cytologic atypia degree (HR = 0.479, P = 0.024).Lung squamous carcinomas with the invasion types were associated with a poor prognosis. PMID- 26512558 TI - Endoscopic Resection Versus Surgical Resection for Early Gastric Cancer: A Systematic Review and Meta-Analysis. AB - Endoscopic resection (ER) has been widely accepted to treat early gastric cancer (EGC) in place of surgical resection (SR). The aim of this meta-analysis was to conduct a comprehensive comparison between the two methods.Four literature databases, including PubMed, Web of Science, the Cochrane Library, and EMBASE, were searched for studies that compared ER with SR to treat EGC. In this meta analysis, primary and secondary endpoints were compared between the two groups. Primary endpoints included overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and recurrence-free survival (RFS). Secondary endpoints included operation-related death, local recurrence, metachronous lesions, procedure-related complication, bleeding, hospital stay, operation time, and cost.Nineteen studies consisting of a total of 6118 patients were identified and selected for evaluation. Meta-analysis showed that long-term outcomes of ER versus SR for EGC were comparable in terms of 5-year OS (risk ratio [RR] 1.00, 95% confidence interval [CI] 0.98-1.02), DSS (RR 0.98, 95% CI 0.89-1.08), DFS (RR 0.95, 95% CI 0.86-1.05), and RFS (RR 0.98, 95% CI 0.94-1.01). However, ER had shorter operation time (standardized mean difference [SMD] -3.39, 95% CI -3.58 to 3.20), hospital stay (SMD -2.86, 95% CI -4.02 to -1.69), lower costs (SMD -5.30, 95% CI -10.37 to -0.22), and fewer procedure-related complications (RR 0.43, 95% CI 0.28-0.65) compared to SR. Nevertheless, ER had higher incidences of local recurrence (risk difference 0.01, 95% CI 0.00-0.02) and metachronous lesions (RR 6.81, 95% CI 3.80-12.19).Endoscopic resection was associated with similar long term outcomes and considerable advantages concerning operation time, hospital stay, costs, and complications, compared with SR, and was also associated with disadvantages such as higher incidence of local recurrence and metachronous lesions. Further high-quality studies from more countries are required to confirm these results. PMID- 26512559 TI - Risk Factors, Coronary Severity, Outcome and ABO Blood Group: A Large Chinese Han Cohort Study. AB - ABO blood type locus has been reported to have ethnic difference and to be a pivotal genetic determinant of cardiovascular risk, whereas few prospective data regarding the impact on cardiovascular outcomes are available in a large cohort of patients with angiography-proven coronary artery disease, especially from the Chinese population. The objective of this study was to assess the prognostic role of blood type in future cardiovascular events (CVEs) in Chinese Han patients undergoing coronary angiography.The population of this prospective cohort study consisted of 3823 eligible patients, and followed annually to capture all CVEs. Baseline characteristics and ABO blood type were obtained. Cox proportional hazards models were used to evaluate the risk of ABO blood type on CVEs.New CVEs occurred in 348 patients [263 (10.3%) non-O and 85 (7.8%) O] during a median period of 24.6 months follow-up. Significantly, non-O blood group was related to the presence and severity of coronary atherosclerosis and several risk factors including inflammatory markers. The log-rank test revealed that there was a significant difference between non-O and O blood groups in event-free survival analysis (P = 0.026). In particular, the Cox proportional hazards models revealed that non-O blood type was associated with increased CVEs risk [hazard ratio (95% confidence interval) 1.320 (1.033-1.685)], even after adjusting for potential confounders [adjusted hazard ratio (95% confidence interval) non-O: 1.289 (1.003 1.656); A: 1.083 (0.797-1.472); B: 1.481 (1.122-1.955); AB: 1.249 (0.852-1.831), respectively].Non-O blood type is associated with future CVEs in Chinese Han patients undergoing coronary angiography. PMID- 26512560 TI - Effect of Probiotics on Blood Lipid Concentrations: A Meta-Analysis of Randomized Controlled Trials. AB - Previous clinical studies have reported mixed results regarding the effect of probiotics on lipid metabolism. Therefore, we conducted a meta-analysis of randomized controlled trials to quantify the direction and magnitude of the potential effect of probiotics on blood lipid concentrations.Eligible studies were randomized, placebo-controlled trials whose interventions were probiotic products containing live bacteria. The studies reported net changes in lipid profiles (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) and their associated standard deviations (or the data to calculate them). The probiotic products did not contain prebiotics or other active ingredients, and the full article was accessible in English.The pooled mean net change in lipid profiles and 95% confidence intervals (95% CIs) were calculated. Q statistics and I were calculated to examine heterogeneity. Potential sources of heterogeneity were investigated via subgroup and sensitivity analyses, and publication biases were estimated.A total of 30 randomized controlled trials with 1624 participants (828 in intervention groups and 796 in placebo groups) were included in this analysis. Subjects treated with probiotics demonstrated reduced total cholesterol and LDL cholesterol compared to control subjects by 7.8 mg/dL (95% CI: -10.4, 5.2) and 7.3 mg/dL (95% CI: -10.1, -4.4), respectively. There was no significant effect of probiotics on HDL cholesterol or triglycerides. The effect of probiotics on total cholesterol and LDL cholesterol depended on a variety of factors. The significant effects were greater for higher baseline total cholesterol levels, longer treatment durations, and certain probiotic strains. In addition, these associations seem stronger in studies supported by probiotics companies.The studies included in this meta-analysis showed significant heterogeneity as indicated by the Q statistics and I. In addition, industry sponsorship may affect study findings.These results suggest that the use of probiotics may improve lipid metabolism by decreasing total and LDL cholesterol concentrations. However, both the efficacy of probiotics for cholesterol lowering and safety should be investigated further in well-designed clinical trials. PMID- 26512561 TI - Second-Line HIV Therapy Outcomes and Determinants of Mortality at the Largest HIV Referral Center in Southern Vietnam. AB - The growing numbers of HIV-infected patients requiring second-line antiretroviral therapy (ART) in Vietnam make essential the evaluation of treatment efficacy to guide treatment strategies.We evaluated all patients aged >=15 years who initiated second-line ART after documented failure of first-line therapy at the Hospital for Tropical Diseases in Ho Chi Minh City. The primary outcome was time from second-line ART initiation to death, or to a new or reoccurrence of a WHO defined immunological or clinical failure event, whichever occurred first. Risks of treatment failure and death were evaluated using Cox proportional hazards modeling.Data from 326 of 373 patients initiating second-line ART between November 2006 and August 2011 were included in this analysis. The median age was 32 years (IQR: 28-36). Eighty one percent were men. The median CD4 count was 44 cells/MUL (IQR: 16-84). During a median follow-up of 29 months (IQR: 15-44), 60 (18.4%) patients experienced treatment failure, including 12 immunological failures, 4 WHO stage IV AIDS events, and 44 deaths (13.5%). Sixty percent of deaths occurred during the first 6-12 months. The Kaplan-Meier estimates of treatment failure after 1, 2, 3, and 4 years were 13.1% (95% CI: 9.2-16.8), 18.6% (95% CI: 14.0-23.1), 20.4% (95% CI: 15.4-25.1), and 22.8% (95% CI: 17.2-28.1), respectively. Older age, history of injection drug use, lower CD4 count, medication adherence <95%, and previous protease inhibitor use independently predicted treatment failure.While treatment efficacy was similar to that reported from other resource-limited settings, mortality was higher. Early deaths may be averted by prioritizing second-line therapy for those with lower CD4 counts and by improving treatment adherence support. PMID- 26512562 TI - Prognostic Nomogram for Prediction of Axillary Pathologic Complete Response After Neoadjuvant Chemotherapy in Cytologically Proven Node-Positive Breast Cancer. AB - To develop a nomogram predicting probability of axillary pathologic complete response (pCR) in patients with cytologically proven axillary node-positive breast cancer who received neoadjuvant chemotherapy (NAC).The current management of axillary intervention in node-positive breast cancer patients who received NAC is axillary lymph node dissection (ALND) regardless of axillary pCR.We reviewed the records of 415 patients with cytologically proven node-positive breast cancer that were treated with NAC followed by surgery between 2008 and 2012 at Severance Hospital, Yonsei University Health System. Baseline patient and tumor characteristics, chemotherapy regimen, and tumor and nodal responses were analyzed. A nomogram was developed using a binary logistic regression model with a training cohort and validated in an independent cohort of 110 patients.Axillary pCR was achieved in 38.8% of the patients who underwent ALND after NAC. Axillary pCR was associated with initial clinical nodal status, negative estrogen receptor status, positive human epidermal growth factor receptor 2 (HER2) status with trastuzumab, and clinical nodal and tumor responses. A nomogram was developed based on the clinical and statistically significant predictors. It had good discrimination performance (AUC 0.82, 95% CI, 0.78-0.86) and calibration fit. The nomogram was independently validated, indicating the good predictive power of the model (AUC 0.80, 95% CI, 0.72-0.88).Our nomogram might help predict axillary pCR after NAC in patients with initially node-positive breast cancer. Patients with a high probability of achieving axillary pCR could be spared ALND, avoiding postoperative morbidity. PMID- 26512563 TI - Intraoperative Dexmedetomidine Promotes Postoperative Analgesia and Recovery in Patients after Abdominal Colectomy: A CONSORT-Prospective, Randomized, Controlled Clinical Trial. AB - Surgery-induced acute postoperative pain and stress response may lead to prolonged convalescence. The present study was designed to investigate the effects of intraoperative dexmedetomidine on postoperative analgesia and recovery after abdominal colectomy surgeries.Sixty-seven patients scheduled for abdominal colectomy under general anesthesia were divided into two groups, which were maintained using propofol/remifentanil/dexmedetomidine (PRD) or propofol/remifentanil/saline (PRS).During surgery, patients in the PRD group had a lower bispectral index value, which indicated a deeper anesthetic state and a higher sedation score right after extubation, than patients in the PRS group. During the first 24 hours after surgery, PRD patients consumed less morphine in patient-controlled analgesia, and had a lower score in visual analog scale, than their controls from the PRS group. The global 40-item quality of recovery questionnaire and 9-question fatigue severity score both showed a higher recovery score from day 3 after surgery in the PRD group.Intraoperative administration of dexmedetomidine seems to promote the analgesic property of morphine-based patient controlled analgesia, and speed recovery from surgery in patients after abdominal colectomy. PMID- 26512564 TI - Registry of the Spanish Network for Systemic Sclerosis: Survival, Prognostic Factors, and Causes of Death. AB - Systemic sclerosis (SSc) is a rare, multisystem disease showing a large individual variability in disease progression and prognosis. In the present study, we assess survival, causes of death, and risk factors of mortality in a large series of Spanish SSc patients. Consecutive SSc patients fulfilling criteria of the classification by LeRoy were recruited in the survey. Kaplan Meier and Cox proportional-hazards models were used to analyze survival and to identify predictors of mortality. Among 879 consecutive patients, 138 (15.7%) deaths were registered. Seventy-six out of 138 (55%) deceased patients were due to causes attributed to SSc, and pulmonary hypertension (PH) was the leading cause in 23 (16.6%) patients. Survival rates were 96%, 93%, 83%, and 73% at 5, 10, 20, and 30 years after the first symptom, respectively. Survival rates for diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc were 91%, 86%, 64%, and 39%; and 97%, 95%, 85%, and 81% at 5, 10, 20, and 30 years, respectively (log rank: 67.63, P < 0.0001). The dcSSc subset, male sex, age at disease onset older than 65 years, digital ulcers, interstitial lung disease (ILD), PH, heart involvement, scleroderma renal crisis (SRC), presence of antitopoisomerase I and absence of anticentromere antibodies, and active capillaroscopic pattern showed reduced survival rate. In a multivariate analysis, older age at disease onset, dcSSc, ILD, PH, and SRC were independent risk factors for mortality. In the present study involving a large cohort of SSc patients, a high prevalence of disease-related causes of death was demonstrated. Older age at disease onset, dcSSc, ILD, PH, and SRC were identified as independent prognostic factors. PMID- 26512565 TI - Outcomes of Early Decompressive Craniectomy Versus Conventional Medical Management After Severe Traumatic Brain Injury: A Systematic Review and Meta Analysis. AB - This meta-analysis examined whether early decompressive craniectomy (DC) can improve control of intracranial pressure (ICP) and mortality in patients with traumatic brain injury (TBI).Medline, Cochrane, EMBASE, and Google Scholar databases were searched until May 14, 2015, using the following terms: traumatic brain injury, refractory intracranial hypertension, high intracranial pressure, craniectomy, standard care, and medical management. Randomized controlled trials in which patients with TBI received DC and non-DC medical treatments were included.Of the 84 articles identified, 8 studies were selected for review, with 3 randomized controlled trials s having a total of 256 patients (123 DCs, 133 non DCs) included in the meta-analysis. Patients receiving DC had a significantly greater reduction of ICP and shorter hospital stay. They also seemed to have lower odds of death than patients receiving only medical management, but the P value did not reach significance (pooled odds ratio 0.531, 95% confidence interval 0.209-1.350, Z = 1.95, P = 0.183) with respect to the effect on overall mortality; a separate analysis of 3 retrospective studies yielded a similar result.Whereas DC might effectively reduce ICP and shorten hospital stay in patients with TBI, its effect in decreasing mortality has not reached statistical significance. PMID- 26512566 TI - Chronic Indwelling Urinary Catheter Increase the Risk of Bladder Cancer, Even in Patients Without Spinal Cord Injury. AB - Chronic indwelling urinary catheters (CIDCs) are known as a risk factor for bladder cancer in patients with spinal cord injury (SCI). This study examined the potential risk of bladder cancer from CIDCs in patients without SCI.The National Health Insurance Research Database in Taiwan was used to identify SCI patients (N = 1816). This group was compared against a control CIDC cohort without SCI (N = 1816) and a reference cohort with normal individuals without SCI and a record of CIDC (N = 7264). Comparisons were made based on age and gender matching over a maximum of 11 follow-up years. The incidence risk and hazard ratio (HR) of bladder cancer were estimated in all 3 groups.During the follow-up period, the bladder cancer incidence rates were 68.90 and 102.53 per 100,000 person-years in the SCI and CIDC-non-SCI groups, respectively. These values were both higher than that of the reference cohort (12.00 per 100,000 person-years). Patients who had history of SCI (HR: 6.51; 95% CI, 2.56-16.52) or CIDC without SCI (HR: 9.11; 95% CI, 3.9-21.29) had a higher risk of bladder cancer compared with the reference cohort.Patients with CIDCs may have an increased risk of bladder cancer development, especially in older aged and male patients compared with general population. PMID- 26512567 TI - Does Once-Daily Raltegravir Have Any Role in the Antiretroviral Treatment? AB - Administering raltegravir once daily would make adherence to antiretroviral treatment easier, especially if the concomitant drugs are also administered once daily. We report our experience on the use of raltegravir, both once- and twice daily.Retrospective review of HIV-infected patients on treatment with raltegravir 800 mg once or 400 mg twice a day plus 2 analogs. Patients were classified as group A (subjects switched to raltegravir due to adverse events on a previous regimen or drug-drug interactions) and group B (subjects who restarted antiretroviral treatment after a previous drop-out). The primary clinical endpoint was the percentage of subjects with virological suppression after 96 weeks. Treatment's effectiveness (noncomplete/missing equals failure) was also evaluated. Pharmacokinetic study was performed in unselected patients. Plasma raltegravir concentrations were determined by high-performance liquid chromatography coupled with mass spectrometry.A total of 133 patients were included in the study (74 and 59 on raltegravir once- and twice-daily). There were only 4 virological failures in the entire cohort during the follow-up. Thus, the Kaplan-Meier estimation of efficacy by on-treatment analysis was 96.3% (CI95, 92.8-99.8) at week 96, independently of the dosing regimen and of the raltegravir concentrations. Similar exposures to raltegravir based on AUC0-tau, but higher Cmax and significantly lower Ctrough were observed when raltegravir was given once daily compared with 400 mg twice daily. In fact, 14 out of 56 Ctrough concentrations (25%) from patients taking raltegravir once daily were below the IC95 of wild-type HIV-1 clinical isolates while only 2 samples from patients receiving 400 mg twice a day were below this value, although no relationship between Ctrough and efficacy was found. The main limitations of the study are that the raltegravir dosing regimen was not randomized and more than 50% of the patients were virologically suppressed at baseline.Regimens comprising raltegravir 800 mg once daily plus 2 nucleos(t)ide reverse transcriptase inhibitors can be an efficacious and safe option, particularly in virologically suppressed patients and those with a viral load <100,000 copies/mL. PMID- 26512568 TI - Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Terms of Major Cardiovascular Disease Outcomes in Elderly Patients: A Nationwide Population-Based Cohort Study. AB - Renin and aldosterone activity levels are low in elderly patients, raising concerns about the benefits and risks of angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARB) use. However, data from direct comparisons of the effects of ACEIs on ARBs in the elderly population remain inconclusive.In this nationwide study, all patients aged >= 70 years were retrieved from the Taiwan National Health Insurance database for the period 2000 to 2009 and were followed up until the end of 2010. The ARB cohort (12,347 patients who continuously used ARBs for >= 90 days) was matched to ACEI cohort using high-dimensional propensity score (hdPS). Intention-to-treat (ITT) and as treated (AT) analyses were conducted.In the ITT analysis, after considering death as a competing risk, the ACEI cohort had similar risks of myocardial infarction (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.79-1.06), ischemic stroke (HR 0.98, 95% CI 0.90-1.07), and heart failure (HR 0.93, 95% CI 0.83-1.04) compared with the ARB cohort. No difference in adverse effects, such as acute kidney injury (HR 0.99, 95% CI 0.89-1.09) and hyperkalemia (HR 1.02, 95% CI 0.87 1.20), was observed between cohorts. AT analysis produced similar results to those of ITT analysis. We were unable to demonstrate a survival difference between cohorts (HR 1.03, 95% CI 0.88-1.21) after considering drug discontinuation as a competing risk in AT analysis.Our study supports the notion that ACEI and ARB users have similar risks of major adverse cardiovascular events (MACE), even in elderly populations. PMID- 26512569 TI - A Case Report of Catatonia and Neuroleptic Malignant Syndrome With Multiple Treatment Modalities: Short Communication and Literature Review. AB - We describe a case with complicated clinical presentations who was difficult to treat. We described the possible etiologies and differential diagnosis of neuroleptic malignant syndrome (NMS), catatonia, and infection, in details. This patient was also referred to neuro-intensive care unit for extensive workup and treatments by neurologist guidelines. In addition, we also used lorazepam diazepam protocol and antipsychotics, but both failed to completely relieve her symptoms. She eventually responded to electroconvulsive therapy (ECT).A 60-year old female patient with schizophrenia was diagnosed to suspected pneumonia, urinary tract infection, and retarded catatonia at first. The brain computed tomography revealed no significant finding. She developed NMS caused by the administration of low-dose quetiapine (200 mg) after carbamazepine was discontinued. The Francis-Yacoub NMS rating scale (F-Y scale) total score was 90. We utilized lorazepam-diazepam protocol and prescribed bromocriptine and amantadine, but NMS was not improved. Meanwhile, we arranged the brain magnetic resonance imaging to survey the physical problem, which revealed agenesis of septum pellucidum and dilated lateral ventricles. She was then transferred to the neuro-intensive care unit on the 15th hospital day for complete study. The results of cerebrospinal fluid study and electroencephalography were unremarkable. She was transferred back to psychiatric ward on the 21st hospital day with residual catatonic and parkinsonian symptoms of NMS, and the F-Y scale total score was 63. Finally, her residual catatonic condition that followed NMS got improved after 11 sessions of ECT. On the 47th hospital day, the F-Y scale total score was 9.This report underscores that the ECT is an effective treatment for a patient of NMS when other treatments have failed. PMID- 26512570 TI - A Case Report of Churg-Strauss Syndrome Presenting With Cardiogenic Shock Treated With Extracorporeal Membrane Oxygenation. AB - Churg-Strauss Syndrome (CSS) complicated with cardiogenic shock is rare. Few case reports have described successful treatment of this rare disease. However, no one has reported on the application of mechanical life support with extracorporeal membrane oxygenation (ECMO) to treat this life-threatening disease.A 36-year-old female with limb numbness for >10 days, chest tightness for 2 days, and worsening dyspnea for 5 h presented in the emergency room. Vital signs showed a low blood pressure (104/60 mm Hg), increased heart rate (158 bpm), and respiration rate (28 bpm). Laboratory tests revealed that eosinophil was significantly increased (WBC: 34.46 * 10/L, neutrophil: 7.56 * 10/L[21.9%], eosinophil: 23.84 * 10/L[69.2%]), and serum myocardial enzymes was abnormal (CK 1049U/L, CKMB-mass 145.1 MUg/L, cTnI 16.24 MUg/L). Myocardial injury (tachycardia with ST elevation) and poor heart function (LVEF 31%) were found by electrocardiogram and transthoracic echocardiography. On the next day, cardiogenic shock had been developed as demonstrated by deteriorating the perfusion index.Churg-Strauss Syndrome with cardiogenic shock.A series of conservative therapy with drugs such as corticosteroids, anticoagulant, antiplatelet, nitrates, calcium antagonists, inotrope, and vasopressors were initiated on the day of admission. The treatment was ineffective and a cardiogenic shock developed on the next day. Thus, ECMO was initiated immediately to stabilize circulation and perfusion. At the same time, high-dose corticosteroids combined with immunosuppressive therapy were continuously used.Symptoms of cardiogenic shock were gradually improved after ECMO treatment. Elevated values of cardiac enzymes were decreased and the dose of vasoactive drugs was reduced. Extracorporeal membrane oxygenation was discontinued after 8 days, and the patient was eventually weaned off the ventilator. The patient was discharged after 40 days treatment.Once a CSS develops into a cardiogenic shock, the ECMO should be considered as an alternative therapeutics in that it stabilizes hemodynamic status, maintains effective tissue perfusion, and provides an opportunity for the recovery of cardiac function. PMID- 26512571 TI - Vacuum Sealing Drainage as Treatment of Severe Buttocks and Perianal Infection: A Case Report and Review of the Literature (Care-Compliant). AB - Vacuum sealing is a therapeutic concept to achieve secure and rapid wound healing in traumatic soft tissue damage. Its application and effect in the treatment of severe buttocks and perianal infection are unclear.We describe a case of buttocks and perianal infection using the vacuum sealing drainage (VSD) technique. A 58 year-old man was admitted with buttocks and perianal severe infection, which was caused by injection. The size of the wounds was 40 * 30 cm. Colostomy was applied prior to the prompt surgical debridement to prevent defecation and keep the perianal region clean. Emergency debridement was then conducted. After the wounds were thoroughly washed with conventional disinfection solution, they were then covered by VSD system.The infection was controlled 9 days after the first surgery by prompt surgical debridement, the application of VSD treatment, and the use of narrow-spectrum antibiotics based on susceptibility result. After 3 applications of VSD treatment, skin grafting harvested from the left leg was conducted. All free skin grafts survived at 8 weeks. Colon was placed back into the abdominal cavity finally.Initial colostomy and debridement, the temporary VSD cover followed after several days by skin grafting is a reliable treatment regimen for severe buttocks and perianal infection. PMID- 26512572 TI - Traumatic Posterior Atlantoaxial Dislocation Without Associated Fracture but With Neurological Deficit: A Case Report and Literature Review. AB - Posterior atlantoaxial dislocation without odontoid fracture is extremely rare and often results in fatal spinal cord injury. According to the reported literature, all cases presented mild or no neurologic deficit, with no definite relation to upper spinal cord injury. Little is reported about traumatic posterior atlantoaxial dislocation, with incomplete quadriplegia associated with a spinal cord injury.We present a case of posterior atlantoaxial dislocation without associated fracture, but with quadriplegia, and accompanying epidural hematoma and subarachnoid hemorrhage.The patient underwent gentle traction in the neutral position until repeated cranial computed tomography revealed no progression of the epidural hematoma. Thereafter, the atlantoaxial dislocation was reduced by using partial odontoidectomy via a video-assisted transcervical approach and maintained with posterior polyaxial screw-rod constructs and an autograft. Neurological status improved immediately after surgery, and the patient recovered completely after 1 year.Posterior fusion followed by closed reduction is the superior strategy for posterior atlantoaxial dislocation without odontoid fracture, according to literature. But for cases with severe neurological deficit, open reduction may be the safest choice to avoid the lethal complication of overdistraction of the spinal cord. Also, open reduction and posterior srew-rod fixation are safe and convenient strategies in dealing with traumatic posterior atlantoaxial dislocation patients with neurological deficit. PMID- 26512573 TI - Incidence of and Predictors for Early Return Visits to the Emergency Department: A Population-Based Survey. AB - The aim of this study is to estimate the proportion of and predictors for early return visits (ERVs) to the emergency department (ED) in Taiwan.This is a population-based study using data of 1 million people randomly selected from all beneficiaries of the Taiwan National Health Insurance. All ED visits in 2012 were analyzed. The ERVs to the ED were defined as those ED revisits within 3 days after the initial ED visit. We employed a generalized estimation equation model to investigate the independent effects of various characteristics associated with the initial ED visit on ERVs.The overall proportion of ERVs within 3 days with a same dichotomous diagnostic category according to injury or noninjury was 4.3% (6740/158,132), and the overall proportion of hospitalizations after ERVs was 24.1% (1627/6740). Male subjects (4.3%) were more likely to have ERVs with an adjusted odds ratio (AOR) of 1.10 (95% confidence interval [CI]: 1.04-1.16). Compared with patients aged 18 to 64 years (4.0%), those aged >64 years had a significantly increased risk of ERVs (6.2%, AOR: 1.49, 95% CI: 1.39-1.59). In comparison to patients with injury diagnoses (2.2%), those with noninjury diagnoses had a higher risk of ERVs (5.2%, AOR: 2.50, 95% CI: 2.33-2.70). Compared with patients initially treated at medical centers (3.7%), those initially treated at regional (4.5%, AOR: 1.28, 95% CI: 1.20-1.37) or district hospitals (4.5%, AOR: 1.38, 95% CI: 1.27-1.49) had significantly higher risks of ERVs. Among the 6740 patients with ERVs, 2622 (38.9%) returned to a different hospital, and these patients tended to be those aged 18 to 64 years and initially treated at district hospitals.The risk of ERVs was associated with demographic characteristics and accreditation level of hospital. We noted a large proportion of patients with ERVs to a different hospital. The reason underlying this phenomenon warrants further investigations. PMID- 26512574 TI - A Phase II Study of Gemcitabine, Vincristine, and Cisplatin As Second-Line Treatment for Patients with Advanced Soft Tissue Sarcoma. AB - Patients with advanced soft tissue sarcoma (aSTS) typically have a poor prognosis. Patients progressing to doxorubicin-based regimen have limited therapeutic options. Monotherapy with cytotoxic drugs appears to have only modest activity in the second-line setting. The purpose of this phase II study was to prospectively evaluate the safety and efficacy of combination regimen with gemcitabine, vincristine, and cisplatin (GVP) as a salvage treatment for patients with aSTS.Eligible patients were female with 18~75 years old, and had aSTS that had progressed after 1 prior anthracyclines-based chemotherapy regimen. Patients were treated with 1,000 mg/m gemcitabine intravenously (IV) on days 1 and 8, 1.4 mg/m (max 2 mg) vincristine IV on day 1 and 25 mg/m cisplatin IV on days 1 through 3 every 21 days until disease progression, unacceptable toxicity or up to 6 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), over response rate (ORR) and safety. This trial was registered with http://www.clinicaltrials.gov (no. NCT01192633).A total of 26 patients with a median age 47 years (21-72) were recruited. ORR was 23.1% [1 complete response and 5 partial responses]. The median PFS and OS were 4.8 (95% CI, 0.1-9.5) months and 15.0 (95% CI, 6.1-23.9) months, respectively. Grade 3/4 hematologic toxicities included neutropenia (34.6%), leukopenia (23.1%), thrombocytopenia (11.5%) and anemia (3.8%). No febrile neutropenia and grade 3/4 non-hematologic toxicities occurred. The most frequent non-hematologic toxicities were nausea/vomiting (50.0%), fatigue (30.8%), and fever (11.5%).We conclude that GVP regimen is effective with a favorable safety profile as the second-line chemotherapy in aSTS patients, which warrants further investigation in a phase III study. PMID- 26512575 TI - Secondary Primary Malignancy Risk in Patients With Cervical Cancer in Taiwan: A Nationwide Population-Based Study. AB - To evaluate the risk of secondary primary malignancy (SPM) in patients with cervical cancer using a nationwide population-based dataset.Patients newly diagnosed with cervical cancer between 1997 and 2011 were identified using Taiwan's National Health Insurance database. Patients with antecedent malignancies were excluded. Standardized incidence ratios (SIRs) for SPM were calculated by comparing with the cancer incidence in the general population. Risk factors for cancer development were analyzed using Cox proportional hazard models.During the 14-year study period (follow-up of 223,062 person-years), 2004 cancers developed in 35,175 patients with cervical cancer. The SIR for all cancers was 1.56 (95% confidence interval, 1.50-1.63, P < 0.001). SIRs for follow up periods of >10, 5 to 10, 1 to 5, and <1 year were 1.37, 1.51, 1.34, and 2.59, respectively. After the exclusion of SPM occurring within 1 year of cervical cancer diagnosis, SIRs were significantly higher for cancers of the esophagus (2.05), stomach (1.38), colon, rectum, and anus (1.36); lung and mediastinum (2.28), bone and soft tissue (2.23), uterus (3.76), bladder (2.26), and kidneys (1.41). Multivariate analysis showed that age >=60 was a significant SPM risk factor (hazard ratio [HR] 1.59). Different treatments for cervical cancer, including radiotherapy (HR 1.41) and chemotherapy (HR 1.27), had different impacts on SPM risk. Carboplatin and fluorouracil independently increased SPM risk in cervical cancer patients.Patients with cervical cancer are at increased risk of SPM development. Age >=60 years, chemotherapy, and radiotherapy are independent risk factors. Carboplatin and fluorouracil also increased SPM risk independently. Close surveillance of patients at high risk should be considered for the early detection of SPMs. PMID- 26512576 TI - When to Perform Surgical Resection or Radiofrequency Ablation for Early Hepatocellular Carcinoma?: A Nomogram-guided Treatment Strategy. AB - Radiofrequency ablation (RFA) is indicated for early-stage hepatocellular carcinoma (HCC), but the comparative efficacy between RFA and surgical resection (SR) is inconclusive. We aim to develop a prognostic nomogram for predicting recurrence-free survival (RFS) after RFA. We also evaluate the possibility of using nomogram in improving treatment algorithm.We retrospectively enrolled 836 patients with Barcelona Clinic Liver Cancer very-early/early-stage HCC receiving SR or RFA. A visually-orientated nomogram was constructed with Cox proportional hazards model, and number and size of tumor, platelet count, albumin level, and model for end-stage liver disease score were included. The concordance index of the nomogram was 0.69.Radiofrequency ablation patients were stratified into low and high-risk groups by the median of nomogram scores. The RFS and overall survival (OS) of 2 risk groups were compared with SR patients with propensity score matching analysis. SR provided better RFS and OS compared with high-risk (nomogram score >=9.8) RFA patients in the propensity model. The 5-year RFS rates were 36% versus 11%, whereas the 5-year OS rates were 74% versus 60% for SR and high-risk RFA groups, respectively (both P < 0.05). However, SR was associated with better RFS (5-year RFS rates 41% vs 29%), but similar OS (5-year OS rates 80% vs 81%), compared with low-risk (nomogram score <9.8) RFA patients in the propensity model (P < 0.05 and P > 0.05, respectively).In conclusion, this user friendly nomogram offers individualized recurrence risk estimation and stratification for early HCC patients receiving curative RFA. The nomogram can be integrated into current treatment algorithm. SR should be considered the first line treatment for high-risk patients to achieve better long-term survival. PMID- 26512577 TI - Efficacy and Safety of Topiramate for Essential Tremor: A Meta-Analysis of Randomized Controlled Trials. AB - Essential tremor (ET) is the most common movement disorder that is frequently treated by propranolol or primidone. However, 30% of patients with ET do not respond to either propranolol or primidone. The objective of this study was to assess the efficacy and safety of topiramate for ET.We searched the MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for relevant randomized controlled trials on the effects of topiramate for ET. A meta-analysis technique was applied to estimate the efficacy and safety of topiramate. The primary outcome was the change in the Fahn-Tolosa-Marin tremor rating scale (TRS). The secondary outcomes included the respective change in the location, motor tasks/function and function disability scores, and adverse events.We included 3 randomized controlled trials with a total of 294 participants. Topiramate was significantly better than placebo in reducing TRS of patients with ET (mean difference [MD] -8.58, 95% confidence interval [CI] -15.46 to -1.70). Changes from the scales of upper limb tremor severity (MD -5.12, 95% CI -7.79 to 2.45), motor tasks/function (MD -5.07, 95% CI -7.12 to -3.03), and functional disability (MD -4.72, 95% CI -6.77 to -2.67) were significantly greater with topiramate than with placebo. More participants taking topiramate experienced adverse events leading to withdrawal than those taking placebo (risk difference 19%, 95% CI 11%-27%).There is consistent evidence supporting the efficacy of topiramate in treating ET; however, a significant proportion of participants withdrew due to its adverse effects. PMID- 26512578 TI - Impact of Arterial Reconstruction With Recipient's Own Internal Iliac Artery for Multiple Graft Arteries on Living Donor Kidney Transplantation: Strobe Study. AB - The aim of this study is to investigate the usefulness of arterial reconstruction using the recipient's own internal iliac artery for multiple kidney graft arteries.The safety and efficacy of various arterial reconstruction methods have been demonstrated. Although some reports have documented arterial reconstruction with the recipient's own internal iliac artery for multiple kidney graft arteries using the interposition method, usefulness of this technique has not yet been investigated compared with other arterial reconstruction methods.Between January 2008 and April 2014, 532 living donor kidney transplants in adult recipients were performed at 1 center. Of these, 389 kidney grafts had a single artery and did not need arterial reconstruction (nonarterial reconstruction group). Among the bench surgery patients, 19 kidney grafts for multiple arteries were performed using the interposition method with the recipient's own internal iliac artery (interposition group). Seventy-nine kidney grafts were performed using conjoined reconstruction (conjoined group) and 15 kidney grafts were performed using end-to side reconstruction (end-to-side group). Total ischemic time (the period between arterial clamp and blood reperfusion), time to initial urination, perioperative and postoperative estimated glomerular filtration rate (eGFR), and complication rates between the interposition group and other 3 groups were retrospectively investigated. This study was based on the STROBE compliant.Warm ischemic time (the period between arterial clamp and beginning of the cold perfusion) of interposition group was significantly longer than that of nonarterial reconstruction group. Total ischemic time of the interposition group was significantly longer than those of other 3 groups. But time to initial urination, perioperative and postoperative eGFR, and complications were similar to other 3 groups.The interposition method was shown to be a useful standard method for multiple kidney graft arteries of living donor kidney transplantation in carefully selected recipients without calcification of the iliac arteries. PMID- 26512579 TI - Implementation of Out-of-Office Blood Pressure Monitoring in the Netherlands: From Clinical Guidelines to Patients' Adoption of Innovation. AB - Out-of-office blood pressure monitoring is promoted by various clinical guidelines toward properly diagnosing and effectively managing hypertension and engaging the patient in their care process. In the Netherlands, however, the Dutch cardiovascular risk management (CVRM) guidelines do not explicitly prescribe 24-hour ambulatory blood pressure measurement (ABPM) and home BP measurement (HBPM). The aim of this descriptive study was to develop an understanding of patients' and physicians' acceptance and use of out-of-office BP monitoring in the Netherlands given the CVRM recommendations.Three small focus group discussions (FGDs) with patients and 1 FGD with physicians were conducted to explore the mechanisms behind the acceptance and use of out-of-office BP monitoring and reveal real-world challenges that limit the implementation of out of-office BP monitoring methods. To facilitate the FGDs, an analytical framework based on the technology acceptance model (TAM), the theory of planned behavior and the model of personal computing utilization was developed to guide the FGDs and analysis of the transcriptions of each FGD.ABPM was the out-of-office BP monitoring method prescribed by physicians and used by patients. HBPM was not offered to patients even with patients' feedback of poor tolerance of ABPM. Even as there was little awareness about HBPM among patients, there were a few patients who owned and used sphygmomanometers. Patients professed and seemed to exhibit self-efficacy, whereas physicians had reservations about (all of their) patients' self-efficacy in properly using ABPM. Since negative experience with ABPM impacted patients' acceptance of ABPM, the interaction of factors that determined acceptance and use was found to be dynamic among patients but not for physicians.In reference to the CVRM guidelines, physicians implemented out-of office BP monitoring but showed a strong preference for ABPM even where there is poor tolerance of the method. We found that physicians' positive attitude to ABPM enabled the use of the method by patients which, in turn, impeded the diffusion of HBPM. For patients, the acceptance process of HBPM can only begin after the physician has adopted the innovation. Physicians are in a position to encourage as well as hinder out-of-office BP monitoring and self-management. PMID- 26512580 TI - Association of Bisphenol A Exposure With Hypertension and Early Macrovascular Diseases in Chinese Adults: A Cross-Sectional Study. AB - Bisphenol A (BPA) is an environmental endocrine disruptor that has been associated with cardiovascular outcomes in previous observational studies. We aimed to examine the relationships of urinary BPA levels with hypertension and early macrovascular diseases.This is a cross-sectional study. From June through August 2009, 3246 participants ages 40 years or older were enrolled from Baoshan District, Shanghai, China. Logistic regression modes were used to estimate the odds ratios (ORs) for prevalent risk of hypertension, elevated carotid intima media thickness (CIMT), arterial stiffness, and peripheral artery disease (PAD) with multivariable adjustment. We also performed stratification analysis by age and sex.The median (interquartile range) for BPA was 0.81 (0.48, 1.45) ng/mL, which is notably lower than previously reported in the United States and other Western countries. Urinary BPA concentrations were negatively associated with hypertension (multivariable-adjusted OR for the highest versus lowest BPA quartile = 0.61; 95% confidence interval [CI]: 0.46, 0.80), elevated CIMT (OR = 0.64; 95% CI: 0.47, 0.87), and arterial stiffness (OR = 0.62; 95% CI: 0.44, 0.87). The corresponding OR for PAD (60 cases total) was not significant (OR = 0.89; 95% CI: 0.28, 2.80). The negative associations of BPA with hypertension, elevated CIMT, and arterial stiffness were consistent by age and sex stratifications, and were stronger among participants >=60 versus <60 years of age, and among women than men.In contrast with previous investigations, our study suggests negative associations of BPA exposure with hypertension and early macrovascular diseases among middle-aged and elderly Chinese. Future investigations are needed to draw more definite conclusions and generalize to other populations. PMID- 26512581 TI - The Correlation of Hepatic and Systemic Hemodynamics During Liver Transplantation: Quantification of Hepatic Resistance as an Actual Value. AB - The correlation between portal vein pressure (PVP) and flow (PVF) has not been established, and there is still lack of consensus about the optimal hemodynamics during liver transplantation (LT). We aimed to establish the correlation between systemic and hepatic hemodynamics during LT by applying the hepatokinetic power hypothesis, based on the law of energy conservation and hydrodynamics.A total of 103 adult liver transplant recipients were enrolled in this study from September 2012 to December 2014. Systemic and hepatic hemodynamics were assessed intraoperatively to calculate the hepatokinetic power status. Severe surgical complications (Clavien-Dindo grade >=III) were recorded as the main outcome measure, and potential covariates were evaluated including recipient, donor, donor-recipient match, surgery-related factors, conventional hemodynamics, and the intraoperative hepatokinetic power profile.In multivariate analysis, hepatokinetic power gradient >4260 mL mmHg min100 g graft weight (P = 0.001), 2.2 < ratio of hepatokinetic power from the portal vein to the hepatic artery <=8.7 (P = 0.012), and hepatic resistance of partial grafts <=0.006 or >0.015 min mmHg mL (P = 0.012) were associated with a higher risk. None of the conventional hemodynamic parameters, such as PVP, PVF, and hepatic venous pressure gradient, entered into this regression model (c-statistic = 0.916) when competing with hepatokinetic power indexes.The hepatokinetic power hypothesis clarifies the correlation of systemic and hepatic hemodynamics in a simple, rational manner. The hepatic resistance, derived from the hepatokinetic power equation, can be quantified and has an effect on the incidence of severe surgical complications. This finding offers a new objective clinical approach to evaluate graft quality during transplantation. PMID- 26512583 TI - Molecular Etiology of Hereditary Single-Side Deafness: Its Association With Pigmentary Disorders and Waardenburg Syndrome. AB - Unilateral sensorineural hearing loss (USNHL)/single-side deafness (SSD) is a frequently encountered disability in children. The etiology of a substantial portion of USNHL/SSD still remains unknown, and genetic causes have not been clearly elucidated. In this study, the authors evaluated the heritability of USNHL/SSD.The authors sequentially recruited 50 unrelated children with SSD. For an etiologic diagnosis, we performed a rigorous review on the phenotypes of family members of all children and conducted, if necessary, molecular genetic tests including targeted exome sequencing of 129 deafness genes.Among the 50 SSD children cohort, the authors identify 4 (8%) unrelated SSD probands from 4 families (SH136, SB173, SB177, and SB199) with another hearing impaired family members. Notably, all 4 probands in our cohort with a familial history of SSD also have pigmentary abnormalities such as brown freckles or premature gray hair within first degree relatives, which may indicate that genes whose products are involved with pigmentary disorder could be candidates for heritable SSD. Indeed, SH136 and SB199 turned out to segregate a mutation in MITF and PAX3, respectively, leading to a molecular diagnosis of Waardenburg syndrome (WS).We report, for the first time in the literature, a significant heritability of pediatric SSD. There is a strong association between the heritability of USNHL/SSD and the pigmentary abnormality, shedding a new light on the understanding of the molecular basis of heritable USNHL/SSD. In case of children with congenital SSD, it would be mandatory to rigorously screen pigmentary abnormalities. WS should also be included in the differential diagnosis of children with USNHL/SSD, especially in a familial form. PMID- 26512584 TI - Assessment of Activity of Crohn Disease by Diffusion-Weighted Magnetic Resonance Imaging. AB - To assess the diagnostic efficacy of diffusion-weighted MR imaging (DWI) for evaluating inflammatory activity in patients with Crohn's disease (CD). A total of 47 CD patients underwent MR enterography (MRE) and DWI using 3 b values of 50, 400, and 800 s/mm. Apparent diffusion coefficients (ADCs) of inflamed and normal bowel wall were calculated. The conventional MRE findings and DWI signal intensities were qualitatively scored from 0 to 3. The correlation between Crohn disease activity index (CDAI) and both ADCs and magnetic resonance imaging scores was analyzed. Receiver-operating characteristic curve analysis was used to determine the diagnostic accuracy of CD activity. Of the 47 patients, 25 were active CD (CDAI>=150) and 22 were inactive (CDAI<150). Diffusion-weighted MR imaging and MRE + DWI scores of active CD were significantly higher than that of inactive CD (both P < 0.001). Apparent diffusion coefficients in inflamed segments of active CD were lower than that of inactive CD (P < 0.001). The DWI scores (r = 0.74, P < 0.001), ADCs (r = -0.71, P < 0.001), MRE scores (r = 0.54, P < 0.001), and MRE + DWI scores (r = 0.66, P < 0.001) were all correlated with CDAI. The areas under the receiver-operating characteristics curves for ADCs, DWI scores, MRE scores, and MRE + DWI scores ranged from 0.83 to 0.98. The threshold ADC value of 1.17 * 10 mm/s allowed differentiation of active from inactive CD with 100% sensitivity and 88% specificity. Diffusion-weighted MR imaging and ADC correlated with CD activity, and had excellent diagnostic accuracy for differentiating active from inactive CD. PMID- 26512582 TI - Current Epidemiology and Outcome of Infective Endocarditis: A Multicenter, Prospective, Cohort Study. AB - The aim of the study was to describe the epidemiologic and clinical characteristics and identify the risk factors of short-term and 1-year mortality in a recent cohort of patients with infective endocarditis (IE).From January 2008, multidisciplinary teams have prospectively collected all consecutive cases of IE, diagnosed according to the Duke criteria, in 25 Spanish hospitals.Overall, 1804 patients were diagnosed. The median age was 69 years (interquartile range, 55-77), 68.0% were men, and 37.1% of the cases were nosocomial or health care related IE. Gram-positive microorganisms accounted for 79.3% of the episodes, followed by Gram-negative (5.2%), fungi (2.4%), anaerobes (0.9%), polymicrobial infections (1.9%), and unknown etiology (9.1%). Heart surgery was performed in 44.2%, and in-hospital mortality was 28.8%. Risk factors for in-hospital mortality were age, previous heart surgery, cerebrovascular disease, atrial fibrillation, Staphylococcus or Candida etiology, intracardiac complications, heart failure, and septic shock. The 1-year independent risk factors for mortality were age (odds ratio [OR], 1.02), neoplasia (OR, 2.46), renal insufficiency (OR, 1.59), and heart failure (OR, 4.42). Surgery was an independent protective factor for 1-year mortality (OR, 0.44).IE remains a severe disease with a high rate of in-hospital (28.9%) and 1-year mortality (11.2%). Surgery was the only intervention that significantly reduced 1-year mortality. PMID- 26512585 TI - Association Between Heme Oxygenase-1 Promoter Polymorphisms and the Development of Albuminuria in Type 2 Diabetes: A Case-Control Study. AB - Heme oxygenase (HO)-1 is a key enzyme in cytoprotective mechanisms against oxidative stress in the cardiovascular-renal system. The T(-413)A single nucleotide polymorphism (SNP) and (GT)n microsatellite polymorphism in the HO-1 gene promoter modulate the HO-1 gene transcriptional activity and these polymorphisms are associated with various human diseases.We investigated the association between HO-1 promoter polymorphisms and nephropathy in type 2 diabetes. We sequenced the T(-413)A SNP and (GT)n repeat segments of the HO-1 gene promoter in 536 patients with type 2 diabetes. (GT)n alleles were divided into 2 groups: short (S, <=25 GT repeats) and long (L, >25 GT repeats) alleles. The presence of albuminuria was used as a marker of diabetic nephropathy.Patients with the TT genotype in the T(-413)A SNP were significantly more susceptible to albuminuria development than those carrying the A allele, with an odds ratio of 1.577 (95% confidence interval, 1.088 - 2.285; P = 0.016). Subgroup analysis showed that patients carrying the TT genotype with long duration of diabetes (>=20 years), poor glycemic control, male gender and without hypertension had higher odds ratios for the development of albuminuria. In vitro, promoter activity of the T(-413)A SNP was higher with A allele than T allele. Regarding to the (GT)n repeats, the LL genotype showed a higher odds ratio for the development of albuminuria only in patients with hypertension when compared to the S allele.In conclusion, the T(-413)A SNP in the HO-1 promoter is significantly associated with albuminuria development in type 2 diabetes patients, especially with longer duration and poor glycemic control. PMID- 26512586 TI - Dental Procedures and the Risk of Infective Endocarditis. AB - Infective endocarditis (IE) is an uncommon but potentially devastating disease. Recently published data have revealed a significant increase in the incidence of IE following the restriction on indications for antibiotic prophylaxis as recommended by the revised guidelines. This study aims to reexamine the basic assumption behind the rationale of prophylaxis that dental procedures increase the risk of IE.Using the Longitudinal Health Insurance Database of Taiwan, we retrospectively analyzed a total of 739 patients hospitalized for IE between 1999 and 2012. A case-crossover design was conducted to compare the odds of exposure to dental procedures within 3 months preceding hospitalization with that during matched control periods when no IE developed.In the unadjusted model, the odds ratio (OR) was 0.93 for tooth extraction (95% confidence interval [CI] 0.54 1.59), 1.64 for surgery (95% CI 0.61-4.42), 0.92 for dental scaling (95% CI 0.59 1.42), 1.69 for periodontal treatment (95% CI 0.88-3.21), and 1.29 for endodontic treatment (95% CI 0.72-2.31). The association between dental procedures and the risk of IE remained insignificant after adjustment for antibiotic use, indicating that dental procedures did not increase the risk of IE.Therefore, this result may argue against the conventional assumption on which the recommended prophylaxis for IE is based. PMID- 26512587 TI - Morphine for Intravenous Patient-Controlled Analgesia May Inhibit Delirium Tremens: A Case Report and Literature Review. AB - Alcoholism is common among trauma patients and often lacks the appropriate monitoring. Alcohol withdrawal syndrome (AWS), including delirium tremens (DT), can be associated with significant postoperative morbidity and mortality. However, appropriate acute pain management may protect against delirium; the administration of intravenous patient-controlled analgesia (IV - PCA) may not only alleviate pain, but also reduce the incidence of post-operative delirium. IV PCA is widely used today; however, little attention has been paid to its influence on the development of AWS or DT post-surgery. Here we present a case in which the administration of IV-PCA may have delayed the onset of DT that interfered with postoperative care and the initiation of psychiatric consultation. The literature was reviewed to determine the potential mechanisms behind the effects of IV-PCA on the onset of AWS or DT.IV-PCA may delay the onset of DT. It is imperative to take into consideration trauma patients' psychiatric history including answers to questions on alcoholism, so that when an IV-PCA is administered and then discontinued, adequate interventions to prevent further morbidity associated with AWS and DT can be initiated in sufficient time. PMID- 26512588 TI - Outcome of Preterm Infants With Postnatal Cytomegalovirus Infection via Breast Milk: A Two-Year Prospective Follow-Up Study. AB - Approximately 15% of preterm infants may develop postnatal cytomegalovirus (CMV) infection from seropositive mothers via breast milk and are at risk for neurological sequelae in childhood. The aims of this study were to assess the effects and outcomes on growth, neurodevelopmental status, and hearing in very low birth weight (VLBW) premature infants with postnatal CMV infection via breast milk at the corrected age of 12 and 24 months.The prospective follow-up study population comprised all living preterm children (n = 55) with a birth weight <=1500 g and gestational age of <=35 weeks, who had been participated in our "postnatal CMV infection via breast milk" studies in 2000 and 2009, respectively. The cohort of children was assessed at 12 and 24 months. Clinical outcomes were documented during hospitalization and after discharge. Long-term outcomes included anthropometry, audiologic tests, gross motor quotient, Infant International Battery, and neurodevelopmental outcomes; all were assessed at postcorrected age in 12 and 24 months during follow-up visits.Of the 55 infants enrolled in the study (4 noninfected infants were excluded because their parents did not join this follow-up program later), 14 infants postnatally acquired CMV infection through breast-feeding (infected group) and were compared with 41 infants without CMV infection (control group). No significant differences were observed between the groups with regard to baseline characteristics, clinical outcomes, anthropometry, or psychomotor and mental development on the Bayley scale of infant development. None of the infants had CMV-related death or permanent sensorineural hearing loss.Transmission of CMV from seropositive mother via breast milk to preterm infants does not appear at this time to have major adverse effects on clinical outcomes, growth, neurodevelopmental status, and hearing function at 12 and 24 months corrected age. PMID- 26512589 TI - Association Between Hearing Impairment and Albuminuria in the Korean Adults: The 2011-2012 Korea National Health and Nutrition Examination Survey. AB - Although the associations between albuminuria and renal and cardiovascular diseases, including diabetes and hypertension, have been extensively studied, few studies have investigated the association between albuminuria and hearing impairment. In this study, we assessed the relationship between albuminuria and hearing impairment in 9786 adult Korean subjects, using data from the Korea National Health and Nutrition Examination Survey (KNHANES) performed in 2011 2012. The range of urinary albumin-to-creatinine ratio (UACR) was divided into 4 grades: grade 1 (first tertile of low-grade albuminuria [LGA]), 0.00 to 1.99 mg/g Cr; grade 2 (second tertile of LGA), 2.00 to 5.49 mg/g Cr; grade 3 (third tertile of LGA), 5.50 to 29.99 mg/g Cr; grade 4 (albuminuria), >=30.00 mg/g Cr.The age- and sex-adjusted weighted UACR was higher in subjects with hearing impairment compared with those without hearing impairment (26.2 +/- 4.7 mg/g Cr vs 14.1 +/- 1.5 mg/g Cr, P = 0.020). The age- and sex-adjusted weighted prevalence of albuminuria was also higher in subjects with hearing impairment compared with subjects without hearing impairment. (8.3 +/- 0.9% vs 5.8 +/- 0.4%, P = 0.013) The age- and sex-adjusted weighted percentage of hearing impairment increased as UACR increased (18.0% +/- 0.6%, 20.0% +/- 0.8%, 22.2% +/- 0.9%, 25.3% +/- 2.0%, respectively; P < 0.001). Logistic regression analyses were performed for hearing impairment by albuminuria, with age, sex, tobacco use, heavy alcohol use, educational background, occupational noise exposure, obesity, hypertension, diabetes, total serum cholesterol, and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m as covariates. Using grade 1 of UACR as the control, grade 3 (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.05-1.53, P = 0.005) and grade 4 (OR 1.41, 95% CI 1.04-1.90, P = 0.026) of UACR were correlated with hearing impairment, respectively. When the level of hearing impairment (dB) was analyzed as a continuous variable, it was positively correlated with log UACR (Spearman correlation, unadjusted r = 0.226, adjusted r = 0.076, P < 0.001).In conclusion, we are the first to demonstrate that albuminuria is associated with hearing impairment in the Korean general population, using nationally representative data. Screening for albuminuria would allow for interventions for the prevention of hearing impairment. PMID- 26512590 TI - Comparison of Short-Course Radiotherapy Versus Long-Course Radiotherapy for Treatment of Metastatic Spinal Cord Compression: A Systematic Review and Meta Analysis. AB - In this study, we evaluate the efficacy of short-course radiotherapy (SCRT) versus long-course radiotherapy (LCRT) in the treatment of metastatic spinal cord compression (MSCC).PubMed, EMBASE, and Web of Science were searched up to April 2015. Relevant data were extracted based on inclusion and exclusion criteria. Methodological quality of randomized controlled trial (RCT) was evaluated using modified Jadad scale; non-RCT was evaluated using Newcastle-Ottawa Scale. Meta analysis was performed using RevMan 5.3 software.Fourteen studies with 2239 patients were included. Results of meta-analysis showed that there were no significant differences between SCRT and long-course radiotherapy LCRT in 6-month overall survival rate (risk ratio [RR] = 0.97, 95% confidence interval [CI] 0.88, 1.07, P = 0.55), 1-year overall survival rate (RR = 0.94, 95% CI 0.85, 1.04, P = 0.22), motor function improvement (RR = 0.96, 95% CI 0.81, 1.13, P = 0.63), no change on motor function (RR = 0.98, 95% CI (0.88, 1.09), P = 0.74], and deterioration on motor function (RR = 0.96, 95% CI 0.71, 1.31, P = 0.78). Compared with SCRT, LCRT significantly increased 6-month local control rate (RR = 0.87, 95% CI 0.80, 0.95, P = 0.002), 1-year local control rate (RR = 0.83, 95% CI 0.71, 0.97, P = 0.02), and 2-year local control rate (RR = 0.83, 95% CI 0.79, 0.87, P < 0.00001).Both LCRT and SCRT provided similar survival rates and functional outcome, but LCRT showed better local control rates than SCRT. However, considering low cost and good patient's compliance, SCRT may be a better choice. PMID- 26512591 TI - Atypical Presentation of Intracardiac Floating Thrombi in Hypereosinophilic Syndrome Complicated With Stroke and Systemic Embolization: A Case Report. AB - Hypereosinophilic syndrome (HES) describes a disorder characterized by persistent peripheral blood eosinophilia with evidence of multiple target organs damage caused by eosinophilia. HES most commonly involves the heart, and cardiac involvement typically presents in the form of endomyocarditis or myocarditis with apical mural thrombus formation.We present a case with atypical cardiac presentation with massive intracardiac fragile thrombi, causing peripheral emboli and strokes.HES can present as floating thrombi with thin attachment to the left ventricle, and clinicians should also be vigilant of thromboembolic complications and initiate early therapy to prevent or reduce the potential complications of HES. PMID- 26512592 TI - Factors Associated With Age-related Hearing Impairment: A Retrospective Cohort Study. AB - Age-related hearing impairment (ARHI) is a complex degenerative disease in the elderly. As multiple factors interact during the development of ARHI, it is important to elucidate the major influencing factors to understand and prevent ARHI. We aimed to identify risk factors associated with the development of ARHI with a retrospective cohort from 2001 to 2010. The records of the adult subjects over 40 years of age who consecutively underwent a comprehensive health checkup including pure-tone audiometry at the Health Promotion Center were reviewed. During this period, 1560 subjects who underwent pure-tone audiometry more than twice, had no other otologic diseases, and were followed-up more than 2 years were included. A pure-tone average (PTA: 0.5, 1, 2, 4 kHz) was calculated. Development of ARHI was defined as a PTA at follow-up more than 10 dB greater than the baseline PTA. Times to the first development of ARHI were investigated. Overall, 12.7% of subjects developed ARHI within the first 4 years. High blood ionized calcium (hazard ratio [HR] 0.084), albumin (HR 0.239), systolic blood pressure (HR 0.577), thyroid hormone (T3) (HR 0.593), and alpha fetoprotein levels (HR 0.883) were associated with decreased hazard for the development of ARHI. In contrast, high blood high-density lipoprotein (HR 2.105), uric acid (HR 1.684), total protein (HR 1.423), and total bilirubin levels (HR 1.220) were potential risk factors for the development of ARHI. Development of ARHI is common among the aged population, and a variety of factors may interact during this process. The results of this study can be used for counseling of adults at high risk of developing ARHI with regard to regular audiological check-up. PMID- 26512593 TI - Incidence and Outcomes of Acute Respiratory Distress Syndrome: A Nationwide Registry-Based Study in Taiwan, 1997 to 2011. AB - Most epidemiological studies of acute respiratory distress syndrome (ARDS) have been conducted in western countries, and studies in Asia are limited. The aim of our study was to evaluate the incidence, in-hospital mortality, and 1-year mortality of ARDS in Taiwan.We conducted a nationwide inpatient cohort study based on the Taiwan National Health Insurance Research Database between 1997 and 2011. A total of 40,876 ARDS patients (68% male; mean age 66 years) were identified by International Classification of Diseases, 9th edition coding and further analyzed for clinical characteristics, medical costs, and mortality.The overall crude incidence of ARDS was 15.74 per 100,000 person-years, and increased from 2.53 to 19.26 per 100,000 person-years during the study period. The age adjusted incidence of ARDS was 15.19 per 100,000 person-years. The overall in hospital mortality was 57.8%. In-hospital mortality decreased from 59.7% in 1997 to 47.5% in 2011 (P < 0.001). The in-hospital mortality rate was lowest (33.5%) in the youngest patients (age 18-29 years) and highest (68.2%) in the oldest patients (>80 years, P < 0.001). The overall 1-year mortality rate was 72.1%, and decreased from 75.8% to 54.7% during the study period. Patients who died during hospitalization were older (69 +/- 17 versus 62 +/- 19, P < 0.001) and predominantly male (69.8% versus 65.3%, P < 0.001). In addition, patients who died during hospitalization had significantly higher medical costs (6421 versus 5825 US Dollars, P < 0.001) and shorter lengths of stay (13 versus 19 days, P < 0.001) than patients who survived.We provide the first large-scale epidemiological analysis of ARDS incidence and outcomes in Asia. Although the overall incidence was lower than has been reported in a prospective US study, this may reflect underdiagnosis by International Classification of Diseases, 9th edition code and identification of only patients with more severe ARDS in this analysis. Overall, there has been a decreasing trend in in-hospital and 1-year mortality rates in recent years, likely because of the implementation of lung protective ventilation. PMID- 26512594 TI - Anterior Lumbar Interbody Fusion for Degenerative Discogenic Low Back Pain: Evaluation of L4-S1 Fusion. AB - The treatment of degenerative discogenic pain is controversial, and anterior lumbar fusion for the treatment of degenerative discogenic low back pain has also been a controversial topic for over a generation.The aim of this systematic review was to evaluate the outcome of different anterior lumbar fusion levels for degenerative discogenic low back pain.In this study, we performed a clinical outcome subgroup analysis. The outcomes of 84 consecutive patients who underwent anterior lumbar interbody fusion from 2004 to 2009 were reviewed. The operative time, intraoperative blood loss, hospital stay, Oswestry Disability Index (ODI), visual analog scale (VAS) results, and complication rate were recorded separately.Medical indications were degenerative disc disease (73.8%), postdiscectomy disc disease (16.1%), and disc herniation (9.5%). Patients with severe spondylolysis or disc degeneration, with more than 3 or multilevel lesions, were excluded.The mean operative time was 124.5 +/- 10.9 min (range 51 248 min), the mean intraoperative blood loss was 242.1 +/- 27.7 mL (range 50-2700 mL), the mean hospital stay was 3.9 +/- 1.1 days (range 3-6 days), the mean preoperative VAS score was 7.5 +/- 1.4, and the mean preoperative ODI score was 60.0 +/- 5.7. At the 1-year follow-up, the mean postoperative VAS score was 3.3 +/- 1.3 and the mean postoperative ODI score was 13.6 +/- 3.4 (P < 0.05). L4-L5 disc fusion led to better clinical results than 2-level L4-L5/L5-S1 disc fusion. Additionally, the 2-level fusion of L4-L5/L5-S1 had better clinical results than the L5-S1 disc fusion at both the 1 and 2-year postoperative follow-ups regarding the VAS score and the ODI score. The rate of complications was more frequent in the 2-level L4-L5/L5-S1 group (27.3%) (group C) than in the L4-L5 group (9.1%) (group A) and the L5-S1 group (12.5%) (group B). There was no difference between the L4-L5 group (9.1%) and the L5-S1 group (12.5%). A venous tear occurred during surgery and was successfully repaired in 6 of the 84 patients. Also, out of the 84 patients, 6 were found with pseudarthrosis during the follow-up, and these patients underwent a spinal fusion with instrumentation, with a posterior approach after a mean of 1 year. The complications secondary to the surgical approach were persistent abdominal pain (1/84, 1.2%) and wound dehiscence (1/84, 1.2%).Anterior lumbar interbody fusion for L4-L5 had better clinical results than the 2-segmental L4-L5/L5-S1 disc fusion, and the 2-segmental L4-L5/L5-S1 disc fusion had better clinical results than the L5-S1 disc fusion. Also, the 2 segmental L4-L5/L5-S1 disc fusion had a higher complication rate (27.3%), but there was no difference between the L4-L5 group (9.1%) and the L5-S1 group (12.5%). PMID- 26512595 TI - Pure Laparoscopic Versus Open Liver Resection for Primary Liver Carcinoma in Elderly Patients: A Single-Center, Case-Matched Study. AB - Pure laparoscopic liver resection (PLLR) has been reported to be as safe and effective as open liver resection (OLR) for liver lesions, and it is associated with less intraoperative blood loss, shorter hospital stay, and lower complication rate. However, studies comparing PLLR with OLR in elderly patients were limited. The aim of this study was to analyze the short-term outcome of PLLR versus OLR for primary liver carcinoma (PLC) in elderly patients.Between January 2008 and October 2014, 30 consecutive elderly patients (>=70 years) who underwent PLLR for PLC were included into analysis. Sixty patients who received OLR for PLC during the same study period were also included as a case-matched control group. Patients were well matched in terms of age, sex, comorbid illness, Child Pugh class, American Society of Anesthesiologists grade, tumor size, tumor location, and extent of hepatectomy.No significant differences were observed with regard to patient preoperative baseline status, median tumor size (Group PLLR 4.0 cm vs Group OLR 5.0 cm, P = 0.125), tumor location, extent of hepatectomy, and operation time (Group PLLR 133 minutes vs Group OLR 170 minutes, P = 0.073). Compared with OLR, the PLLR group displayed a significantly less frequent Pringle maneuver application (10.0% vs 70.0%, P < 0.001), less blood loss (100 vs 300 mL; P < 0.001), shorter hospital stay (5 vs 10 days; P < 0.001), and lower total hospitalization cost ($9147.50 vs $10,867.10, P = 0.008). The postoperative complication rates were similar between groups (Group PLLR 10.0% vs Group OLR 16.7%; P = 0.532). There was no hospital mortality in both groups.PLLR for PLC is as safe and feasible as OLR, but with less blood loss, shorter hospital stay, and lower hospitalization cost for selected elderly patients. PMID- 26512596 TI - Assessment of Left Ventricular Ejection Fraction Calculation on Long-axis Views From Cardiac Magnetic Resonance Imaging in Patients With Acute Myocardial Infarction. AB - To assess left ventricular ejection fraction (LVEF) accurately, cardiac magnetic resonance (CMR) can be indicated and lays on the evaluation of multiple slices of the left ventricle in short axis (CMRSAX). The objective of this study was to assess another method consisting of the evaluation of 2 long-axis slices (CMRLAX) for LVEF determination in acute myocardial infarction.One hundred patients underwent CMR 2 to 4 days after acute myocardial infarction. LVEF was computed by the area-length method on horizontal and vertical CMRLAX images. Those results were compared to reference values obtained on contiguous CMRSAX images in one hand, and to values obtained from transthoracic echocardiography (TTE) in the other hand. For CMRSAX and TTE, LVEF was computed with Simpson method. Reproducibility of LVEF measurements was additionally determined. The accuracy of volume measurements was assessed against reference aortic stroke volumes obtained by phase-contrast MR imaging.LVEF from CMRLAX had a mean value of 47 +/- 8% and were on average 5% higher than reference LVEF from CMRSAX (42 +/- 8%), closer to routine values from TTELAX (49 +/- 8%), much better correlated with the reference LVEF from CMRSAX (R = 0.88) than that from TTE (R = 0.58), obtained with a higher reproducibility than with the 2 other techniques (% of interobserver variability: CMRLAX 5%, CMRSAX 11%, and TTE 13%), and obtained with 4-fold lower recording and calculation times than for CMRSAX. Apart from this, CMRLAX stroke volume was well correlated with phase-contrast values (R = 0.81).In patients with predominantly regional contractility abnormalities, the determination of LVEF by CMRLAX is twice more reproducible than the reference CMRSAX method, even though the LVEF is consistently overestimated compared with CMRSAX. However, the CMRLAX LVEF determination provides values closer to TTE measurements, the most available and commonly used method in clinical practice, clinical trials, and guidelines in ischemic cardiomyopathy. Moreover, LVEF determination by CMRLAX allows a 63% gain of acquisition/reading time compared with CMRSAX. Thus, despite the fact that LVEF obtained from CMRSAX remains the gold standard, CMRLAX should be considered to shorten the overall imaging acquisition and reading time as a putative replacement. PMID- 26512597 TI - Planned FDG PET-CT Scan in Follow-Up Detects Disease Progression in Patients With Locally Advanced NSCLC Receiving Curative Chemoradiotherapy Earlier Than Standard CT. AB - The role of positron emission tomography-computed tomography (PET-CT) in surveillance of patients with nonsmall cell lung cancer (NSCLC) treated with curatively intended chemoradiotherapy remains controversial. However, conventional chest X-ray and computed tomography (CT) are of limited value in discriminating postradiotherapy changes from tumor relapse. The aim of this study was to evaluate the clinical value of PET-CT scan in the follow-up for patients with locally advanced (LA) NSCLC receiving concomitant chemoradiotherapy (CCRT).Between 2009 and 2013, eligible patients with stages IIB-IIIB NSCLC were enrolled in the clinical trial NARLAL and treated in Odense University Hospital (OUH). All patients had a PET-CT scan scheduled 9 months (PET-CT9) after the start of the radiation treatment in addition to standard follow-up (group A). Patients who presented with same clinical stage of NSCLC and received similar treatment, but outside protocol in OUH during this period were selected as control group (group B). Patients in group B were followed in a conventional way without PET-CT9. All patients were treated with induction chemotherapy followed by CCRT.Group A included 37 and group B 55 patients. The median follow-up was 16 months. Sixty-six (72%) patients were diagnosed with progression after treatment. At the time of tumor progression, patients in group A had better performance status (PS) than those in group B (P = 0.02). Because of death (2 patients), poor PS (3) or retreatment of relapse (9), only 23 patients had PET-CT9 in group A. Eleven (48%) patients were firstly diagnosed with progression by PET-CT9 without any clinical symptoms of progression. The median progression-free survival (PFS) was 8.8 months in group A and 12.5 months in group B (P = 0.04). Hazard function PFS showed that patients in group A had higher risk of relapse than in group B.Additional FDG PET-CT scan at 9 months in surveillance increases probability of early detection of disease progression in advanced NSCLC patients treated with curatively intended CCRT. PMID- 26512598 TI - Association Between the Neutrophil/Lymphocyte Ratio and Acute Kidney Injury After Cardiovascular Surgery: A Retrospective Observational Study. AB - A high neutrophil-lymphocyte ratio (N/L ratio) was associated with the development of acute kidney injury (AKI) in patients with severe sepsis. We sought to investigate the association between the perioperative N/L ratios and postoperative AKI in patients undergoing high-risk cardiovascular surgery.A retrospective medical chart review was performed of 590 patients who underwent cardiovascular surgeries, including coronary artery bypass, valve replacement, patch closure for atrial or ventricular septal defect and surgery on the thoracic aorta with cardiopulmonary bypass (CPB). Baseline perioperative clinical parameters, including N/L ratios measured before surgery, immediately after surgery, and on postoperative day (POD) one were obtained. Multivariate logistic regression analysis was used to evaluate risk factors.A total of 166 patients (28.1%) developed AKI defined by the KDIGO (kidney disease improving global outcomes) criteria in the first 7 PODs. Independent risk factors for AKI included old age, decreased left ventricular systolic function, preoperative high serum creatinine, low serum albumin and high uric acid levels, intraoperative large transfusion amount, oliguria, hyperglycemia, and elevated N/L ratio measured immediately after surgery and on POD one. The quartiles of immediately postoperative N/L ratio were associated with graded increase in risk of AKI development (fourth quartile [N/L ratio>=10] multivariate odds ratio 5.90, 95% confidence interval [CI] 2.74-12.73; P < 0.001), a longer hospital stay, and a higher in-hospital and 1-year mortality rate (fourth quartile [N/L ratio>=10] adjusted hazard ratio for 1-year mortality [8.40, 95% CI 2.50-28.17]; P < 0.001).In patients undergoing cardiovascular surgery with CPB, elevated N/L ratios in the immediately postoperative period and on POD one were associated with an increased risk of postoperative AKI and 1-year mortality. The N/L ratio, which is easily calculable from routine work-up, can therefore assist with risk stratification of AKI and mortality in high-risk surgical patients. PMID- 26512599 TI - Characterization of Benign Myocarditis Using Quantitative Delayed-Enhancement Imaging Based on Molli T1 Mapping. AB - Delayed contrast enhancement after injection of a gadolinium-chelate (Gd-chelate) is a reference imaging method to detect myocardial tissue changes. Its localization within the thickness of the myocardial wall allows differentiating various pathological processes such as myocardial infarction (MI), inflammatory myocarditis, and cardiomyopathies. The aim of the study was first to characterize benign myocarditis using quantitative delayed-enhancement imaging and then to investigate whether the measure of the extracellular volume fraction (ECV) can be used to discriminate between MI and myocarditis.In 6 patients with acute benign myocarditis (32.2 +/- 13.8 year-old, subepicardial late gadolinium enhancement [LGE]) and 18 patients with MI (52.3 +/- 10.9 year-old, subendocardial/transmural LGE), myocardial T1 was determined using the Modified Look-Locker Imaging (MOLLI) sequence at 3 Tesla before and after Gd-chelate injection. T1 values were compared in LGE and normal regions of the myocardium. The myocardial T1 values were normalized to the T1 of blood, and the ECV was calculated from T1 values of myocardium and blood pre- and post-Gd injection.In both myocarditis and MI, the T1 was lower in LGE regions than in normal regions of the left ventricle. T1 of LGE areas was significantly higher in myocarditis than in MI (446.8 +/- 45.8 vs 360.5 +/- 66.9 ms, P = 0.003) and ECV was lower in myocarditis than in MI (34.5 +/- 3.3 vs 53.8 +/- 13.0 %, P = 0.004).Both inflammatory process and chronic fibrosis induce LGE (subepicardial in myocarditis and subendocardial in MI). The present study demonstrates that the determination of T1 and ECV is able to differentiate the 2 histological patterns.Further investigation will indicate whether the severity of ECV changes might help refine the predictive risk of LGE in myocarditis. PMID- 26512600 TI - The Risk of Depressive Disorder Among Contacts of Tuberculosis Patients in a TB endemic Area: A Population-based Cohort Study. AB - Tuberculosis (TB) disease may be transmitted to close contacts of index cases, causing physical illness. No studies have investigated the risk of developing depressive disorder among TB contacts in a TB-endemic area.Adult participants with a new diagnosis of TB contact (ICD-9-CM codes V01.1 plus chest radiographic order) since January 1, 2008, were identified from the National Health Insurance Research Database in Taiwan. A control cohort matched for age (+/-5 y), sex, enrolled years, and income level was selected. These 2 cohorts were followed until December 31, 2012, and observed for the development of depressive disorder. The Kaplan-Meier method and the log-rank test were used to examine the difference in cumulative incidences of depressive disorder between groups. Cox proportional hazard models were used to calculate adjusted hazard ratios (aHRs) for depressive disorder.The TB contact cohort consisted of 9046 patients and matched controls of 36,184 ones. The mean age of TB contacts was 44.7 years, and 56.0% of them were women. During a mean follow-up period of 2.5 years, 127 (1.40%) TB contacts and 521 (1.44%) matched controls developed depressive disorder. TB exposure was found to be an independent risk factor of depressive disorder in women (aHR 1.34, 95% confidence interval [CI] 1.07-1.68), but not in men (aHR 0.71, 95% CI 0.48-1.06) after adjusting for age, comorbidities, and income levels. The risk of depression was significantly higher for female TB contacts than for matched controls in the first and second years (aHR 1.49, 95% CI 1.03-2.14; and aHR 1.53, 95% CI 1.05 2.23, respectively), but not thereafter. Of note, 67 (0.74%) TB contacts and 88 (0.24%) matched controls developed active TB, but none of them had subsequent depressive disorder during follow-up periods.Female TB contacts had an increased risk of depression within the first 2 years after exposure. Clinicians should consider conducting depression evaluations in addition to routine TB contact investigations in this subgroup population. PMID- 26512601 TI - Dynamic of Mixed HCV Infection in Plasma and PBMC of HIV/HCV Patients Under Treatment With Peg-IFN/Ribavirin. AB - The extent of mixed hepatitis C virus (HCV) genotype in different compartments (plasma and peripheral blood mononuclear cell, PBMC) and possible association with treatment efficacy in HIV/HCV coinfected patients remains to be unknown.The objective of this study was to elucidate the frequency of mixed genotype infection (MG), its profile in different compartments during anti-HCV treatment, and the possible influence of different genotypes on the response rate.The compartmentalization of HCV population was investigated by next-generation sequencing in 19 HIV/HCV coinfected patients under anti-HCV treatment with peginterferon/ribavirin (P-R). Ten individuals were nonresponder (NR) or relapser (RE) to P-R treatment and 9 had a sustained virological response (SVR).Eleven/nineteen (58%) patients had MG in plasma compartment. Ten or 12 patients infected by a difficult to treat genotype (DTG) 1 or 4 as dominant strain, had an MG, whereas only 1/7 individuals infected by easy to treat genotype (ETG) harbored a mixed genotype, P = 0.006. HCV-RNA was more frequently detected in PBMC of NR (10/10) than in those of SVR (5/9), P = 0.032. Mixed genotype infection was detected in 6/15 (40%) PBMC-positive cases and was not associated with P-R treatment response. By multivariate analysis, MG in plasma samples was the most important viral factor affecting the treatment response (P = 0.0237).Detection of MG in plasma of HIV/HCV coinfected patients seems to represent the major determinant of response to P-R treatment. This finding may have important clinical implication in light of the new therapeutic approach in HIV/HCV coinfected individuals suggesting that combination treatment with direct acting antivirals could be less effective in MG. PMID- 26512602 TI - Epidemiologic Properties of Pediatric Fractures in a Metropolitan Area of Turkey. AB - Occurrence of fractures is highly dependent on lifestyle. Domestic data should be used when needed. In this cross-sectional study, the authors aim to find the most recent distribution of pediatric fracture types and the attributes of fracture occurrence within a large sample size in a metropolitan area of Turkey.This study consists of 4879 pediatric age patients with a fracture who took advantage of the emergency service of a trauma center in a metropolitan area between March 2010 and December 2013 (1397 days). Date, hour, age, sex, fracture type, and social security status of the patients were studied.A total of 65% of the patients were men and 35% were women. A total of 81% of the fractures were in the upper extremities, whereas 19% of them were in the lower extremities. In 22 patients (0.5%), there were open fractures. Fractures showed some seasonal, daily, and circadian variations. Different types of fractures showed some specific patterns in different age groups. Ankle, elbow, and shoulder fractures were more common in girls, whereas wrist and forearm fractures were more in boys and the difference was statistically significant (P < 0.05).Fractures in pediatric ages vary depending on the age, sex, season, and the hour of the day. Types of fractures show some obvious patterns especially depending on the age. This data can be useful in making optimizations in fracture care units. Considering these specific patterns would enable more effective planning of providing preventive measures for pediatric injuries. PMID- 26512603 TI - Association Between Genetic Polymorphisms in the Promoter Regions of Let-7 and Risk of Papillary Thyroid Carcinoma: A Case-Control Study. AB - The aim of this study was to investigate the association between 2 polymorphisms (ie, rs10877887 and rs13293512) in the promoter regions of let-7 and the risk of papillary thyroid carcinoma (PTC).A case-control study of 618 PTC patients and 562 controls was conducted. The rs10877887 polymorphism was genotyped by using polymerase chain reaction-restriction fragment length polymorphism and the rs13293512 polymorphism was genotyped by using a TaqMan Genotyping Assay. The results were confirmed by DNA sequencing.The rs10877887 polymorphism had reduced risks of PTC in heterozygous comparison, dominant model, and overdominant model (TC vs TT: adjusted odds ratio [OR] = 0.73, 95% confidence interval [95% CI] = 0.58-0.94, P = 0.01; TC/CC vs TT: adjusted OR = 0.79, 95% CI = 0.63-1.00, P = 0.047; TC vs TT/CC: adjusted OR = 0.73, 95% CI = 0.57-0.92, P = 0.007, respectively). Stratified analyses showed that PTC patients carrying the rs10877887 CC genotype were more likely to have multiple tumors (adjusted OR = 1.71, 95% CI = 1.03-2.86, P = 0.04), and PTC patients carrying the rs13293512 TC + CC or CC were more likely to develop N0 status (TC/CC vs TT: adjusted OR = 0.64, 95% CI = 0.43-0.94, P = 0.02; CC vs TC/TT: adjusted OR = 0.50, 95% CI = 0.33-0.77, P = 0.001, respectively).Our study suggests that the rs10877887 polymorphism may be associated with the risk of PTC and the rs13293512 polymorphism may correlate to lymph node metastasis in PTC. PMID- 26512604 TI - Comparison Between the Use of Ropivacaine Alone and Ropivacaine With Sufentanil in Epidural Labor Analgesia. AB - To compare the analgesic efficacy and safety of the sole local anesthetic ropivacaine with the combination of both local anesthetic ropivacaine and opioidergic analgesic sufentanil given epidurally on the labor pain control.After institutional review board approval and patient consent, a total of 500 nulliparas requesting epidural labor analgesia were enrolled and 481 eventually were randomized into 2 groups: a sole local anesthetic group (ropivacaine 0.125%) and a combination of local anesthetic and opioidergic analgesic group (0.125% ropivacaine + 0.3 MUg/mL sufentanil). After the test dose, a 10-mL epidural analgesic solution was given in a single bolus, followed by intermittent bolus injection of 10 to 15 mL of the solution. The primary outcome was the analgesic efficacy measured using Numerical Rating Scale (NRS) of pain. Other maternal and infant variables were evaluated as secondary outcomes.A total of 346 participants completed the study. The median NRS pain score during the 1st stage of labor was significantly lower in the combination group 2.2 (interquartile range [IQR]: 1.8 2.7) comparing to the sole local analgesic group 2.4 (IQR: 2.0-2.8) (P < 0.0001). No significant difference was observed in NRS pain score prior epidural analgesia and during the 2nd stage of labor. Patients in both groups rated same satisfaction of analgesia. Patients in the sole local analgesic group experienced fewer side effects than those in the combination group (37.7% vs 47.2%, P = 0.082). The individual analgesia-related cost in the sole local analgesic group was less ($5.7 +/- 2.06) than that in the combination group ($9.76 +/- 3.54) (P < 0.0001). The incidence of 1-minute Apgar <= 7 was lower in the sole local analgesic group 2 (1.2%) than the combination group 10 (5.5%) (P = 0.038). No difference was found between other secondary outcomes.The sole local anesthetic ropivacaine produces a comparable labor analgesic effect as the combination of both local anesthetic ropivacaine and opioidergic analgesic sufentanil at different stages of labor (DeltaNRS = 0.2) but the former has less side effects, lower cost, and less incidence of lower 1-minute Apgar scoring. These results imply the necessity of a systematic reevaluation of epidural labor analgesia with sole local anesthetics against combination regimens of local anesthetics and other opioids. PMID- 26512605 TI - Normal Myocardial Flow Reserve in HIV-Infected Patients on Stable Antiretroviral Therapy: A Cross-Sectional Study Using Rubidium-82 PET/CT. AB - Studies have found HIV-infected patients to be at increased risk of myocardial infarction, which may be caused by coronary microvascular dysfunction. For the first time among HIV-infected patients, we assessed the myocardial flow reserve (MFR) by Rubidium-82 (82Rb) positron emission tomography (PET), which can quantify the coronary microvascular function. MFR has proved highly predictive of future coronary artery disease and cardiovascular events in the general population.In a prospective cross-sectional study, HIV-infected patients all receiving antiretroviral therapy (ART) with full viral suppression and HIV uninfected controls were scanned using 82Rb PET/computed tomography at rest and adenosine-induced stress, thereby obtaining the MFR (stress flow/rest flow), stratified into low <=1.5, borderline >1.5 to 2.0, or normal >2.0.Fifty-six HIV infected patients and 25 controls were included. The HIV-infected patients had a mean age of 53 years (range 37-68 years) with 23% active smokers. The controls had a mean age of 52 years (range 36-68 years) and 26% active smokers. In the HIV infected group 73% had a normal MFR, 17% borderline, and 10% low values of MFR. Among controls these values were 71%, 19%, and 10%, respectively (P = 0.99). However, the HIV-infected group had lower values of stress myocardial blood flow (MBF) (2.63 +/- 0.09 mL/g/min vs 2.99 +/- 0.14 mL/g/min; P = 0.03). We found no evidence of decreased MFR as assessed by 82Rb PET among HIV-infected patients on stable ART with full viral suppression compared with HIV-uninfected controls. We did notice a decreased MBF during stress. PMID- 26512606 TI - Metabolic Syndrome and Chronic Laryngitis: The Korean National Health and Nutrition Examination Survey 2008 to 2010. AB - Metabolic syndrome (MetS) is associated with a higher risk of morbidity and/or mortality for various chronic diseases. The aim of this study was to investigate the relationship of chronic laryngitis (CL) with MetS and its components in a representative Korean population.Data from the Korean National Health and Nutrition Examination Survey (2008-2010) were analyzed. A total of 10,360 adults who had undergone otolaryngological examination were evaluated.The prevalence of CL in the study population was 3.1%. The prevalence of MetS was significantly higher in patients with CL than in those without CL for both sexes (men: 34.7 +/- 4.0% versus 25.9 +/- 0.8%, P = 0.0235; women: 40.6 +/- 5.3% versus 23.7 +/- 0.7%, P = 0.0003). Elevated fasting glucose, triglycerides, and blood pressure, however, were only significantly associated with CL in women. After controlling for confounders, CL was only significantly associated with MetS in women (odds ratio: 2.159; 95% confidence interval: 1.2974, 3.594). Furthermore, the association between CL and MetS was most robust in women who were classified as obese.In Korea, MetS and its components are significantly associated with CL in women. PMID- 26512607 TI - Prospective Multicenter Feasibility Study of Laparoscopic Sentinel Basin Dissection for Organ Preserving Surgery in Gastric Cancer: Quality Control Study for Surgical Standardization Prior to Phase III Trial. AB - The clinical application of sentinel node biopsies in early gastric cancer is still controversial even though it appears promising. This study was conducted as a prerequisite quality control for surgical standardization of laparoscopic sentinel basin dissection (SBD) prior to the initiation of a phase III trial.Laparoscopic SBD was performed in patients with preoperative stage T1-2N0 and tumor size <4 cm in diameter. Intraoperative endoscopic submucosal injection of a standardized dual tracer was administered. All retrieved sentinel basin nodes (SBN) were investigated with intraoperative frozen hematoxylin and eosin (H&E) staining. A strict checklist consisting of 7 essential steps was followed during laparoscopic SBD as the quality control study for a phase III trial. Completion of all essential steps in the checklist for 10 cases was used to define a qualified institution.Seven institutions participated and 112 patients were enrolled in this study. However, 4 patients were excluded owing to screening failure. The mean number of cases required for institutional qualification was 15 cases (range, 13-20 cases). Sentinel basins (SB) were detected and dissected in 100 of the 108 patients (92.6%); the median number of SB and SBN was 2 and 7, respectively. Lymph node metastases were detected in 10 patients by postoperative permanent H&E staining and they were detected by SBD in all 10 patients. Frozen results of SBN were compatible with permanent staining reports.Laparoscopic SBD is feasible and demonstrated improved sensitivity in detecting metastatic lymph nodes compared to the previous study. A future phase III randomized trial comparing laparoscopic SBD with organ-preserving gastrectomy and laparoscopic standard gastrectomy seems promising for qualified institutions. PMID- 26512608 TI - Remote Ischemic Preconditioning Fails to Benefit Pediatric Patients Undergoing Congenital Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials. AB - Remote ischemic preconditioning (RIPC) has been proven to reduce the ischemia reperfusion injury. However, its effect on children receiving congenital cardiac surgery (CCS) was inconsistent. We therefore performed the current meta-analysis of randomized controlled trials (RCTs) to comprehensively evaluate the effect of RIPC in pediatric patients undergoing CCS.PubMed, Embase, and Cochrane library were searched to identify RCTs assessing the effect of RIPC in pediatric patients undergoing CCS. The outcomes included the duration of mechanical ventilation (MV), intensive care unit (ICU) length of stay, postoperative cardiac troponin (cTnI) level, hospital length of stay (HLOS), postoperative inotropic score, and mortality. Subgroup and sensitivity analysis were also performed as predesigned. The meta-analysis was performed with random-effects model despite of heterogeneity. Sensitivity and subgroup analysis were predesigned to identify the robustness of the pooled estimate.Nine RCTs with 697 pediatric patients were included in the meta-analysis. Overall, RIPC failed to alter clinical outcomes of duration of MV (standard mean difference [SMD] -0.03, 95% confidence interval [CI] -0.23-0.17), ICU length of stay (SMD -0.22, 95% CI -0.47-0.04), or HLOS (SMD -0.14, 95% CI -0.55-0.26). Additionally, RIPC could not reduce postoperative cTnI (at 4-6 hours: SMD -0.25, 95% CI -0.73-0.23; P = 0.311; at 20-24 hours: SMD 0.09, 95% CI -0.51-0.68; P = 0.778) or postoperative inotropic score (at 4-6 hours: SMD -0.19, 95% CI -0.51-0.14; P = 0.264; at 24 hours: SMD -0.15, 95% CI -0.49-0.18; P = 0.365).RIPC may have no beneficial effects in children undergoing CCS. However, this finding should be interpreted with caution because of heterogeneity and large-scale RCTs are still needed. PMID- 26512609 TI - Short-Term Prognosis of Mechanically Ventilated Patients With Guillain-Barre Syndrome Is Worsened by Corticosteroids as an Add-On Therapy. AB - Intravenous immunoglobulin (IVIg) has been proven most effective in treating Guillain-Barre syndrome (GBS). Corticosteroids as an add-on therapy have been prescribed in severe GBS cases. However, the efficacy of intravenous corticosteroids combined with IVIg in dealing with severe GBS remains unclear. We explored the therapeutic effects of different therapeutic regimens on the short term prognosis of GBS patients, especially the severe cases.We retrospectively analyzed the clinical data of 527 adult patients with GBS who were prescribed to different treatments from 2003 to 2014. The therapeutic effect of a treatment was evaluated by the improvement of Hughes Functional Grading Scale (HFGS) and Medical Research Council (MRC) sum score.With comparable incidence of infectious complications (P > 0.05), more mechanically ventilated patients were found improvement after IVIg treatment than combination IVIg with intravenous corticosteroids (MRC: 97% vs. 72.4%, P < 0.05; HFGS: 97% vs. 72.4%, P < 0.05). As to bedridden patients without mechanical ventilation, incidence of infectious complications (P > 0.05) and ratio of patients who were improved after IVIg were insignificantly different from the combination therapy (MRC: 89.6% vs. 86.5%; HFGS: 69.6% vs. 61.5%; both P > 0.05), even if the intravenous corticosteroids were initiated within 7 days after onset (P > 0.05). In addition, supportive treatment was sufficient for patients who were able to walk with help (HFGS = 3) and mildly affected (HFGS < 3) when compared with IVIg and intravenous corticosteroids.IVIg is sufficient to GBS patients who are unable to walk (HFGS > 3), while corticosteroids are detrimental for short-term prognosis in mechanically ventilated patients when used in combination with IVIg. Further prospective and randomized studies are warranted to validate this finding. PMID- 26512610 TI - Association Between the MUC5B Promoter Polymorphism rs35705950 and Idiopathic Pulmonary Fibrosis: A Meta-analysis and Trial Sequential Analysis in Caucasian and Asian Populations. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. A number of studies reported the association between MUC5B promoter polymorphism rs35705950 and IPF, but substantial inconsistent findings were observed and the strength of association remains unclear.The aim of the study was to investigate the association between rs35705950 and IPF in different ethnic populations.PubMed, EMBASE, Web of Science, and CENTRAL were searched from their inception to April 15, 2015. Allelic and phenotypic comparisons were conducted separately, as were comparisons in Caucasian and Asian populations. A meta analysis with trial sequential analysis was conducted.Nine studies presented in 7 full-text articles were included, encompassing 2733 IPF patients and 5044 controls. Six studies were carried out in the Caucasian population, and 3 in the Asian population. Minor T allele was associated with an increased risk of IPF compared with G allele (odds ratio [OR] 4.85, 95% confidence interval [CI] 3.79 6.21, P = 5.88 * 10), as were TG and TT genotypes compared with GG genotype (TG vs GG: OR 6.20, 95% CI 5.14-7.48, P = 1.70 * 10; TT vs GG: OR 11.29, 95% CI 5.69 22.40, P = 4.22 * 10), in an allele dose-dependent manner. These observations were confirmed in trial sequential analysis in both populations. The strength of association was more remarkable in the Caucasian population than in the Asian population, and no homozygous TT genotype was detected in the Asian population in our study.Our study revealed strong association between the MUC5B promoter rs35705950 polymorphism and the risk of IPF. The strength of association between rs35705950 minor T allele and IPF susceptibility was particularly evident in the Caucasian population, and milder but still significant in the Asian population. PMID- 26512611 TI - Identification of Biologically Effective Dose-Volumetric Parameters That Predict Radiation-Induced Hepatic Toxicity in Patients Treated With Helical Tomotherapy for Unresectable Locally Advanced Hepatocellular Carcinoma. AB - The purpose of this study is to identify dose-volumetric parameters that predict radiation-induced hepatic toxicity (RIHT) by analyzing the relationship between the biologically effective dose (BED) delivered to the normal liver and RIHT.The clinical and dosimetric data from 123 patients with unresectable hepatocellular carcinoma (HCC) treated with helical tomotherapy were analyzed. The median radiation dose was a 50 Gy in 4.5 Gy fractions (range, 30-60 Gy in 1.8-5.0 Gy fractions) to 95% of the planning target volume. RIHT was defined as a Child-Pugh score increase of at least 2 points within 3 months of helical tomotherapy completion.RIHT developed in 60 patients (48.7%). Multivariate logistic regression analysis showed that VBED20 (percentage of nontarget normal liver volume that received more than a BED of 20 Gy) was a significant parameter (P < 0.001), and the cut-off value was 40.8% with a sensitivity and specificity of 0.833 and 0.698, respectively, according to the receiver operating characteristic curve (P < 0.001).Maintaining a VBED20 below 40.8% will reduce the risk of RIHT, and the proposed normal liver tolerance curve could be a useful guideline when treating unresectable HCC patients with various radiotherapy dose schedules. PMID- 26512612 TI - Risk Factors and Microbiological Features of Patients Hospitalized for Microbial Keratitis: A 10-Year Study in a Referral Center in Taiwan. AB - We conducted a retrospective, cross-sectional study to analyze predisposing factors, clinical features, and microbiological characteristics of patients with microbial keratitis hospitalized over 10 years.The medical records of 558 patients who were diagnosed with microbial keratitis and admitted to Chang Gung Memorial Hospital (CGMH), a referral center in Taiwan, from January 1, 2003 to December 31, 2012 were reviewed. Demographics, predisposing factors, isolated organisms, treatment, and hospital stay were recorded. Yearly trends were tested using a linear-by-linear association.Contact lens wear was the most common predisposing factor (31.4%), followed by ocular and systemic diseases (26.3%) and trauma (23.5%). Contact lens-related infectious keratitis increased year by year (P = 0.011). Pseudomonas aeruginosa was the most commonly isolated organism (28%), followed by fungi (17.6%) and coagulase-negative Staphylococcus (5.4%). Except for Serratia marcescens, the identified organisms did not change over 10 years. Most bacterial infections were controlled using antimicrobial treatment, but more than half of patients with fungal keratitis required surgical interventions. The mean hospital stay was 13.7 +/- 11.5 days. Previous ocular surgery, large ulcer size, nontuberculous myycobacteris infection, and surgery during admission were related to prolonged hospital stay.In Taiwan, contact lens related pseudomonal keratitis remained the most common cause of microbial keratitis in patients hospitalized from 2003 to 2012. PMID- 26512613 TI - Dipeptidyl Peptidase-4 Inhibitors and the Risk of Acute Pancreatitis in Patients With Type 2 Diabetes in Taiwan: A Population-Based Cohort Study. AB - To investigate the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on the risk of acute pancreatitis in patients with type 2 diabetes.This nationwide population-based cohort study used the diabetes patients dataset of Taiwan's National Health Research Insurance Research Database. Patients with newly diagnosed type 2 diabetes between January 1, 2008 and December 31, 2009 and no history of acute pancreatitis were selected. This cohort was followed from the index date to the onset of acute pancreatitis or December 31, 2011. The main outcome measure was the hazard ratio (HR) for acute pancreatitis associated with DPP-4 inhibitor use. Cox proportional-hazards regression analyses were adjusted for alcohol use, hypertriglyceridemia, cholelithiasis, neoplasm, and Diabetes Complications Severity Index (DCSI) score. Subgroup analyses stratified by age and sex were conducted.The study cohort comprised 114,141 patients. Significant interaction effects were observed between sex and age (HR 0.80, 95% confidence interval [CI] 0.64-0.99) and age and DCSI score (HR 0.83, 95% CI: 0.71-0.97). In subgroup analyses, significant risks of acute pancreatitis were noted in female and elderly DPP-4 inhibitor users. Among women, the risk of acute pancreatitis was significantly higher among DPP-4 inhibitor users than among nonusers (HR 2.27, 95% CI: 1.30-3.97). This risk was also significantly higher in users than in nonusers among patients aged >65 years (HR 2.39, 95% CI: 1.11-5.15).Female and elderly DPP-4 inhibitor users had significantly elevated risks of acute pancreatitis development. Further well-conducted studies are needed to confirm our findings. PMID- 26512614 TI - DTI Study of Cerebral Normal-Appearing White Matter in Hereditary Neuropathy With Liability to Pressure Palsies (HNPP). AB - The majority of previous studies on hereditary neuropathy with liability to pressure palsies (HNPP) were focused on peripheral nerves, whereas cerebral alterations in HNPP have been less attended to. In this work, Diffusion tensor imaging (DTI) was used to detect the changes in WM, especially in the normal appearing white matter (NAWM) in HNPP patients for its sensitivity in probing the microstructure of WM, the sensitive metric was searched for probing cerebral alterations and the regional distribution of cerebral abnormalities was identified. Twelve HNPP patients and 12 age- and gender-matched healthy controls underwent the conventional MRI, DTI scan, and electrophysiological examination. The conventional MRI images were first analyzed to identify abnormal intense regions and the NAWM regions. NAWM refers to the white matter regions that do not include the lesions on conventional MRI. The apparent diffusion coefficient and fractional anisotropy (FA) values of the NAWM were then measured and compared between patient and control groups. The sensitivity and specificity of 3 methods and the cerebral regional distribution of MR signal abnormalities were further analyzed. Hyperintense foci were observed on T2 weighted image and fluid attenuated inversion recovery images in 6 patients. Compared to the controls, FA values of the patients were significantly lower in bilateral frontal, orbitofrontal, and temporal NAWMs; whereas the electrophysiological examination results of patients and controls exhibited no statistically significant difference. The sensitivity of FA value was higher than that of electrophysiological examination and conventional MRI. The majority of abnormal signals on conventional MRI images and abnormal FA values were located in the frontal and temporal lobes. The results of our study show cerebral WM changes in HNPP patients. FA value in DTI has been shown to be sensitive to the cerebral microstructural changes in HNPP. The frontal lobe is the predilection site that is most involved in HNPP. PMID- 26512615 TI - Clinicopathologic Significance and Prognostic Value of B7 Homolog 1 in Gastric Cancer: A Systematic Review and Meta-Analysis. AB - Immunologic checkpoint marker B7 homolog 1 (B7-H1) plays a fundamental role in the initiation and progression of gastric cancer (GC); however, the clinicopathologic significance and prognostic value of B7-H1 in GC remains controversial. In this study, we aimed to assess their relationship through a meta-analysis.Medline/PubMed, EMBASE, the Cochrane Library databases, and Grey literature were searched up to August 10, 2015, for eligible studies of the association between B7-H1 expression and overall survival in GC. The hazard ratio and its 95% confidence interval (CI) were calculated from the included studies. Moreover, the odds ratio (OR) was also extracted to evaluate the association between the clinicopathologic parameters of participants and B7-H1 expression.Five studies involving 481 patients were included in the meta analysis. The pooled results showed that positive B7-H1 expression was a negative predictor for overall survival with hazard ratio of 1.74 (95% CI: 1.40-2.17; Pheterogeneity = 0.146) in GC. Additionally, increased B7-H1 was found to be significantly associated with positive lymph node metastasis (OR = 2.61, 95% CI: 1.78-3.84; Pheterogeneity = 0.004) and poorer tumor stage (OR = 2.28, 95% CI: 1.39-3.74; Pheterogeneity = 0.006); however, higher B7-H1 expression was not significantly correlated with poorer tumor differentiation (OR = 1.29, 95% CI: 0.90-1.86; Pheterogeneity = 0.013) and bigger tumor size (OR = 1.18, 95% CI: 0.81 1.73; Pheterogeneity = 0.104).The meta-analysis suggested that B7-H1 could act as a significant biomarker in the poor prognosis of gastric carcinoma. PMID- 26512616 TI - Distribution of High-Density Lipoprotein Subfractions and Hypertensive Status: A Cross-Sectional Study. AB - The exact mechanisms of hypertension contributing to atherosclerosis have not been fully elucidated. Although multiple studies have clarified the association with low-density lipoprotein (LDL) subfractions, uncertainty remains about its relationship with high-density lipoprotein (HDL) subfractions. Therefore, we aimed to comprehensively determine the relationship between distribution of HDL subfractions and hypertensive status.A total of 953 consecutive subjects without previous lipid-lowering drug treatment were enrolled and were categorized based on hypertension history (with hypertension [n = 550] or without hypertension [n = 403]). Baseline clinical and laboratory data were collected. HDL separation was performed using the Lipoprint System.Plasma large HDL-cholesterol (HDL-C) and large HDL percentage were dramatically lower whereas the small HDL-C and small HDL percentage were higher in patients with hypertension (all P < 0.05). The antihypertensive drug therapy was not associated with large or small HDL subfractions (on treatment vs not on treatment, P > 0.05; combination vs single drug therapy, P > 0.05). However, the blood pressure well-controlled patients have significantly lower small HDL subfraction (P < 0.05). Moreover, large HDL-C and percentage were inversely whereas small HDL percentage was positively associated with incident hypertension after adjusting potential confounders (all P < 0.05). In the multivariate model conducted in patients with and without hypertension separately, the cardio-protective value of large HDL-C was disappeared in patients with hypertension (OR 95%CI: 1.011 [0.974-1.049]).The distribution of HDL subfractions is closely associated with hypertensive status and hypertension may potentially impact the cardio-protective value of large HDL subfraction. PMID- 26512617 TI - Adult Onset Asthma and Periocular Xanthogranuloma (AAPOX), a Rare Entity With a Strong Link to IgG4-Related Disease: An Observational Case Report Study. AB - Adult onset asthma and periocular xanthogranuloma (AAPOX) is a rare non Langerhans histiocytosis characterized histopathologically by a periocular infiltration of foamy histiocytes and Touton giant cells. Benign hyperplasia with plasma cell infiltration is classically described in eyelids or lymph nodes of AAPOX patients. It is also a characteristic feature of IgG4-related disease (IgG4 RD), a new entity defined by an IgG4-bearing plasma cell infiltration of organs.To determine if AAPOX syndrome shares clinical, biological, and histopathological characteristics with IgG4-RD, we used the comprehensive clinical diagnostic criteria for IgG4-RD in a retrospective case series of three consecutive patients with histologically-proven AAPOX. Patients who were diagnosed with AAPOX at a French academic referral center for orbital inflammation between November 1996 and March 2013 were enrolled. Biopsies from ocular adnexa or other organs were systematically reexamined. For each patient, clinical and serological data, radiologic findings, and treatment were retrospectively analyzed.Two AAPOX patients fulfilled all of the diagnostic criteria for a definite IgG4-RD. One patient who lacked the serological criteria fulfilled the criteria of a probable IgG4-RD.These 3 cases of AAPOX patients fulfilled the IgG4-RD comprehensive clinical diagnostic criteria. To our knowledge, this is the first observational case report study to clearly show a strong relationship between IgG4-RD and AAPOX syndrome. PMID- 26512618 TI - Is Atrial Fibrillation a Risk Factor for Gastroesophageal Reflux Disease Occurrence? AB - Recent studies have reported an association between gastroesophageal reflux disease (GERD) and atrial fibrillation (AF). The objective of the present study was to evaluate whether AF is one of the risk factors for GERD occurrence.In this hospital-based, retrospective, case-control study, the patients were classified into 2 groups. The patients diagnosed with new AF were assigned to the AF group (n = 1612); those diagnosed without AF and GERD were assigned to the control group (n = 1612). The subjects in the control group were selected from outpatients of total healthcare center without a history of AF or GERD, and matched for age and gender. We evaluated the incidence of GERD and risk factors for GERD occurrence between the 2 groups.The number of patients experiencing occurrence of GERD during the follow-up period was significantly higher in the AF group than those in the control group, respectively (129 patients vs 98 subjects, P = 0.037). The incidence of GERD was significantly higher in the AF group than in the control group by Kaplan-Meier analysis with log-rank test (P = 0.008). The AF group's adjusted hazard ratio of GERD occurrence against that of the control group was 1.37 (95% confidence interval [CI]: 1.16-1.57; P = 0.009) according to Cox's proportional hazard model.The presence of AF appears to increase the incidence of GERD and may be considered a risk factor for the development of GERD. Further, large prospective and cohort studies will be required to better establish the correlation of GERD with AF. PMID- 26512619 TI - Vinorelbine Plus Platinum in Patients with Metastatic Triple Negative Breast Cancer and Prior Anthracycline and Taxane Treatment. AB - Currently, there is no preferred standard chemotherapy regimen available for patients with metastatic triple negative breast cancer (mTNBC) and no cohort studies on the efficacy of vinorelbine plus platinum (NP) regimen in patients with mTNBC who failed to anthracyclines and/or taxanes have been reported. We present the single-center, retrospective experience of NP regimen in a total of 41 patients with mTNBC.All patients were treated with NP regimen, main combination used was vinorelbine-cisplatin in 34 patients (82.9%).The median follow-up was 36.8 months. Objective response rate was 34.1% (n = 14) in the whole study group. Three patients experienced complete response (7.3%), 11 patients acquired partial response (26.8%), stable disease was observed in 14 patients (34.1%), and 10 patients (24.4%) had progressive disease. Response evaluation was not applicable in 3 patients who received the treatment of NP regimen after surgical removal of the metastatic lesions. The median overall survival and progression-free survival were 18.9 months (95% confidence interval, 15.6-22.1 months) and 6.7 months (95% confidence interval, 2.9-10.5 months), respectively. The main adverse events were grade 3/4 neutropenia (n = 20, 48.8%) and grade 1/2 gastrointestinal toxicity (n = 20, 48.8%).NP regimen is active and tolerable in patients with mTNBC pretreated with anthracyclines and/or taxanes. Therefore, among other chemotherapy regimens, NP combination may provide a rational treatment option for this patient subset. PMID- 26512620 TI - Prognosis of Early-Stage Hepatocellular Carcinoma: The Clinical Implications of Substages of Barcelona Clinic Liver Cancer System Based on a Cohort of 1265 Patients. AB - The prognostic implication of Barcelona Clinic Liver Cancer (BCLC) substages in Asian patients with hepatocellular carcinoma (HCC) is still obscure.The aim to this study is to compare the prognoses among HCC patients in different substages of the BCLC stage 0 and A.We enrolled 1265 treatment-naive HCC patients with BCLC stage 0 or A from 2007 to 2014. Factors in terms of prognoses were analyzed by multivariate analysis.There were 184, 446, 271, 92, and 272 patients in substage 0, A1, A2, A3, and A4, respectively. After a median follow-up period of 21.0 months, patients in stages 0 and A1 had comparable prognoses (P = 0.136). Both of them had significantly higher overall survival rates than those in stages A2-A4 (all P < 0.001). Multivariate analysis revealed that the factors associated with mortality were serum albumin <=3.5 g/dL (hazard ratio [HR] 1.459), alpha fetoprotein >20 ng/mL (HR 1.863), tumor size >3 cm (HR 1.542), BCLC stage A2-A4 (HR 1.488), and treatment modality. Surgical resection had the highest overall survival rate followed by radiofrequency ablation (RFA) (HR 1.598), transarterial chemoembolization (HR 2.224), and other treatments (HR 3.707). Verus patients receiving RFA, those who underwent resection had a higher overall survival rate and lower recurrence rate especially in BCLC stages A2-A4.The BCLC-staging system provided good prognostic stratification for early-stage HCC. Patients with a single tumor >2 cm but without portal hypertension or jaundice had similar prognosis to those in BCLC stage 0. Curative therapies-especially hepatic resection-are suggested in early-stage HCC. PMID- 26512621 TI - Clinical Characteristics and Mortality of Life-Threatening Events Requiring Cardiopulmonary Resuscitation in Gastrointestinal Endoscopy Units. AB - Little is known about life-threatening events during gastrointestinal endoscopy (GIE). This study aimed to evaluate the clinical characteristics of emergency conditions requiring cardiopulmonary resuscitation (CPR) in GIE units and to assess the risk factors for mortality in these cases.We retrospectively collected life-threatening cases that occurred in the GIE units of 6 tertiary hospitals from January 2012 to June 2014. Cases were defined as alert calls for resuscitation teams in emergency situations of respiratory failure or cardiac arrest. Demographic data, clinical features, and probable causes were assessed. Factors associated with mortality were elucidated using logistic regression analysis.Among 263,426 endoscopies, 40 cases of CPR (0.015%) occurred during the period (male 67.5%, median age 62 yr). Gastrointestinal bleeding (GIB), such as hematemesis or melena, was the most common indication for endoscopy (55%). The types of clinical situations encountered were as follows: respiratory insufficiency (47.5%), decreased blood pressure (25%), and cardiac arrhythmia (25%). Although most of these conditions were detected during endoscopy (67.5%), one-third of cases (32.5%) were found before or after procedures. The most frequent probable cause of cases was aggravation of underlying diseases (57.5%), such as uncontrolled bleeding or exacerbation of lung disease. Despite efforts to resuscitate, 18 patients (45%) died. GIB was the single independent risk factor for mortality (odds ratio 28.45, 95% confidence interval 1.55-523.33, P = 0.024).Life-threatening situations requiring CPR can occur during endoscopy, even before or after the procedure. Greater attention should be paid while endoscopy is performed for GIB. PMID- 26512622 TI - A Comparison of Transthroracic Echocardiograpy and Transcranial Doppler With Contrast Agent for Detection of Patent Foramen Ovale With or Without the Valsalva Maneuver. AB - Patent foramen ovale (PFO) is a remnant of the fetal circulation exist in 20% of the general population. The purpose of our study was to compare of transthoracic echocardiography (TTE) and contrast-transcranial Doppler sonography (c-TCD) in the diagnosis and quantification of PFO with or without the Valsalva maneuver (VM).We studied 106 patients with a high clinical suspicion for PFO prospectively. Simultaneous c-TCD and TTE were conducted using agitated saline solution to detect right to left shunt (RLS). To classify RLS, mainly PFO, we applied a 4-level visual classification for c-TCD test: no occurrence of micro embolic signals; grade I, 1 to 10 signals; grade II, 10 to 30 signals but not curtain; and grade III, curtain pattern. We used the number of micro-bubbles appeared in left atrium per frame image to define classification for TTE test: no occurrence of micro-bubbles; grade I, 1 to 10 micro-bubbles; grade II, 10 to 30 micro-bubbles; and grade III, more than 30 micro-bubbles or left atrium nearly filled with micro-bubbles or left atrial opacity. Statistical analyses were performed using SPSS Version 18.0.RLS was detected in 36.0% in c-TCD test and in 46% in TTE test at rest (P = 0.158). And during the VM, RLS was detected in 99.0% in c-TCD test and in 83.0% in TTE test (P < 0.001). Compared with the positive results of c-TCD and TTE at rest, the positive results of them with VM is more higher, respectively (all P < 0.001). The VM obviously increased the number of micro-bubbles shunting.Both c-TCD and TTE should used as initial screening tool for PFO. VM increases the size of shunt. VM resulted in detection of more RLS both in c-TCD and TTE tests. PMID- 26512623 TI - A Simple Evaluation Tool (ET-CET) Indicates Increase of Diagnostic Skills From Small Bowel Capsule Endoscopy Training Courses: A Prospective Observational European Multicenter Study. AB - Small bowel capsule endoscopy (SBCE) has become a first line diagnostic tool. Several training courses with a similar format have been established in Europe; however, data on learning curve and training in SBCE remain sparse.Between 2008 and 2011, different basic SBCE training courses were organized internationally in UK (n = 2), Italy (n = 2), Germany (n = 2), Finland (n = 1), and nationally in Germany (n = 10), applying similar 8-hour curricula with 50% lectures and 50% hands-on training. The Given PillCam System was used in 12 courses, the Olympus EndoCapsule system in 5, respectively. A simple evaluation tool for capsule endoscopy training (ET-CET) was developed using 10 short SBCE videos including relevant lesions and normal or irrelevant findings. For each video, delegates were required to record a diagnosis (achievable total score from 0 to 10) and the clinical relevance (achievable total score 0 to 10). ET-CET was performed at baseline before the course and repeated, with videos in altered order, after the course.Two hundred ninety-four delegates (79.3% physicians, 16.3% nurses, 4.4% others) were included for baseline analysis, 268 completed the final evaluation. Forty percent had no previous experience in SBCE, 33% had performed 10 or less procedures. Median scores for correct diagnosis improved from 4.0 (IQR 3) to 7.0 (IQR 3) during the courses (P < 0.001, Wilcoxon), and for correct classification of relevance of the lesions from 5.0 (IQR 3) to 7.0 (IQR 3) (P < 0.001), respectively. Improvement was not dependent on experience, profession, SBCE system, or course setting. Previous experience in SBCE was associated with higher baseline scores for correct diagnosis (P < 0.001; Kruskal-Wallis). Additionally, independent nonparametric partial correlation with experience in gastroscopy (rho 0.33) and colonoscopy (rho 0.27) was observed (P < 0.001).A simple ET-CET demonstrated significant improvement of diagnostic skills on completion of formal basic SBCE courses with hands-on training, regardless of preexisting experience, profession, and course setting. Baseline scores for correct diagnoses show a plateau after interpretation of 25 SBCE before courses, supporting this number as a compromise for credentialing. Experience in flexible endoscopy may be useful before attending an SBCE course. PMID- 26512624 TI - Comparison of Diagnostic Accuracy of MRI with and Without Contrast in Diagnosis of Traumatic Spinal Cord Injuries. AB - Acute spinal cord injury (SCI) is one of the most common causes of severe disability and mortality after trauma. Magnetic resonance imaging (MRI) can identify different levels of SCI, but sometimes unable to detect the associated soft tissue injuries. The role of MRI with contrast in patients with SCI has not been studied. This is the first study in human to compare the efficacy of MRI with and without contrast in diagnosis and prognosis evaluation of SCIs.In this cross-sectional diagnostic study, MRI with and without contrast was performed on 40 patients with acute spinal injury. In these patients, 3 different types of MRI signal patterns were detected and compared.The most common cases of spinal injuries were accident (72.5%) and the after fall (27.5%). The prevalence of lesions detected includes spine fracture (70%), spinal stenosis (32.5%), soft tissue injuries (30%), and tearing of the spinal cord (2.5%). A classification was developed using 3 patterns of SCIs. Type I, seen in 2 (5.0%) of the patients, demonstrated a decreased signal intensity consistent with acute intraspinal hemorrhage. Type II, seen in 8 (20.0%) of the patients, demonstrated a bright signal intensity consistent with acute cord edema. Type III, seen in 1 (2.5%) of the patients, demonstrated a mixed signal of hypointensity centrally and hyperintensity peripherally consistent with contusion. In the diagnosis of all injuries, MRI with contrast efficacy comparable to noncontrast MRI, except in the diagnosis of soft tissue, which was significantly higher sensitivity (P < 0.05).So given that is not significant differences between noncontrast and contrast-enhanced MRI in the diagnosis of major injuries (hematoma, edema, etc.) and contrast-enhanced MRI just better in soft tissues. We recommend to the MRI with contrast only used in cases of suspected severe soft tissue injury, which have been ignored by detection MRI without contrast. PMID- 26512625 TI - Narratives of Food Insecurity in Tippecanoe County, Indiana: Economic Constraints in Local Meanings of Hunger. AB - Food insecurity and its most extreme form, hunger, have increased exponentially in the United States since 2006. This essay seeks to contribute to our understanding of hunger by attending to the context of the financial crisis as an organizing frame for understanding local meanings of hunger. Within a broader framework of the culture-centered approach (CCA) that works to identify and develop locally rooted solutions to food insecurity, we describe through locally grounded stories of food insecurity the financial climate where large percentages of U.S. households have been cast into poverty because of the crash of an unregulated economy. These local understandings of hunger in the context of the economy offer entry points for organizing a food-insecure coalition that seeks to address the stigma around food insecurity. PMID- 26512626 TI - LETTER TO THE EDITOR: A response to Wamai et al. PMID- 26512627 TI - Oxygen supplementation before induction of general anaesthesia in horses. AB - REASONS FOR PERFORMING STUDY: Hypoventilation or apnoea, caused by the induction of general anaesthesia, may cause hypoxaemia. Preoxygenation may lengthen the period before this happens. No scientific studies are published on preoxygenation in equine anaesthesia. OBJECTIVES: To determine whether supplementation of oxygen at a flow rate of 15 l/min for 3 min via a nasal cannula before induction of general anaesthesia is effective in elevating the arterial partial pressure of oxygen (PaO2 ) directly after induction. STUDY DESIGN: Randomised, prospective clinical trial. METHODS: A total of 18 American Society of Anesthesiologists physical status 1 or 2 adult horses undergoing elective anaesthesia were randomly allocated to one of 2 groups. The first group (control) received no oxygen supplementation before induction of general anaesthesia, whereas the second group (oxygen) did. All horses were anaesthetised with intravenous detomidine, butorphanol, ketamine, midazolam and isoflurane. Directly after induction (T = 0) and 30 min later (T = 30) an arterial blood sample was taken for blood gas analysis. At T = 30 an estimate of intrapulmonary shunt fraction (Qs/Qt) was calculated. RESULTS: At T = 0 arterial partial pressure of oxygen (PaO2 ) was significantly higher in the oxygen group compared with the control group (11.0 +/ 2.6 kPa vs. 7.4 +/- 1.6 kPa; mean +/- s.d., P = 0.005) and at T = 30 differences were not statistically significant. Partial pressure of carbon dioxide (PaCO2 ) and Qs/Qt did not differ between groups. CONCLUSIONS: Supplementing oxygen by a nasal cannula before induction of general anaesthesia in horses is feasible and does effectively elevate the PaO2 immediately after induction. Future research is needed to determine whether supplementation of oxygen before induction of general anaesthesia in horses will affect outcomes. PMID- 26512629 TI - Evolution and Function of Dinosaur Teeth at Ultramicrostructural Level Revealed Using Synchrotron Transmission X-ray Microscopy. AB - The relationship between tooth form and dietary preference is a crucial issue in vertebrate evolution. However, the mechanical properties of a tooth are influenced not only by its shape but also by its internal structure. Here, we use synchrotron transmission X-ray microscopy to examine the internal microstructures of multiple dinosaur teeth within a phylogenetic framework. We found that the internal microstructures of saurischian teeth are very different from advanced ornithischian teeth, reflecting differences in dental developmental strategies. The three-tissue composition (enamel-mantle dentin-bulk dentin) near the dentinoenamel junction (DEJ) in saurischian teeth represents the primitive condition of dinosaur teeth. Mantle dentin, greatly reduced or absent from DEJ in derived ornithischian teeth, is a key difference between Saurischia and Ornithischia. This may be related to the derived herbivorous feeding behavior of ornithischians, but interestingly, it is still retained in the herbivorous saurischian sauropods. The protective functions of mantle dentin with porous microstructures between enamel and bulk dentin inside typical saurischian teeth are also discussed using finite-element analysis method. Evolution of the dental modifications in ornithischian dinosaurs, with the absence of mantle dentin, may be related to changes in enamel characteristics with enamel spindles extending through the DEJ. PMID- 26512630 TI - Residential mobility and associated factors in relation to the assessment of exposure to naturally occurring radiation in studies of childhood cancer. AB - Migration, that is the study subjects moving from one residential address to another, is a complication for epidemiological studies where exposures to the agent of interest depend on place of residence [corrected]. In this paper we explore migration in cases from a large British case-control study of childhood cancer and natural background radiation. We find that 44% of cases had not moved house between birth and diagnosis, and about two-thirds were living within 2 km of their residence at birth. The estimated dose at the diagnosis address was strongly correlated with that at the birth address, suggesting that use of just the birth address in this case-control study does not lead to serious bias in risk estimates. We also review other individual-based studies of naturally occurring radiation, with particular emphasis on those from Great Britain. Interview-based case-control and cohort studies can potentially establish full residential histories for study subjects and make direct measurements of radiation levels in the dwellings in question. However, in practice, because of study size and difficulties in obtaining adequate response rates, interview-based studies generally do not use full residential histories, and a substantial proportion of dose estimates often derive from models rather than direct measurements. More seriously, problems of incomplete response may lead to bias, not just to loss of power. Record-based case-control studies, which do not require direct contact with study subjects, avoid such problems, but at the expense of having only model-based exposure estimates that use databases of measurements. PMID- 26512631 TI - Microbial signatures in post-infectious irritable bowel syndrome--toward patient stratification for improved diagnostics and treatment. AB - Irritable bowel syndrome (IBS) is a multifactorial and heterogeneous disorder estimated to affect over 10% of the Western population. A subset of the patients reports the start of the disease after an episode of gastroenteritis. The alterations in the intestinal microbiota of the post-infectious IBS (PI-IBS) patients were recently investigated in a British cohort and shown to differentiate from the healthy controls and resemble that of diarrhea-predominant IBS (IBS-D) patients. The altered 27 genus-like groups created a microbial signature, which could be used to objectively stratify patients and healthy controls. In this addendum, we combine the microbiota data derived from the British cohort with that of a recently reported Swedish PI-IBS cohort. Remarkably, robust and reproducible microbiota signatures were observed in these PI-IBS patients. We discuss these results with attention on the emerging role of microbiota in the classification, development and treatment of PI-IBS. PMID- 26512632 TI - Highly Selective Bioconversion of Ginsenoside Rb1 to Compound K by the Mycelium of Cordyceps sinensis under Optimized Conditions. AB - Compound K (CK), a highly active and bioavailable derivative obtained from protopanaxadiol ginsenosides, displays a wide variety of pharmacological properties, especially antitumor activity. However, the inadequacy of natural sources limits its application in the pharmaceutical industry. In this study, we firstly discovered that Cordyceps sinensis was a potent biocatalyst for the biotransformation of ginsenoside Rb1 into CK. After a series of investigations on the biotransformation parameters, an optimal composition of the biotransformation culture was found to be lactose, soybean powder and MgSO4 without controlling the pH. Also, an optimum temperature of 30 degrees C for the biotransformation process was suggested in a range of 25 degrees C-50 degrees C. Then, a biotransformation pathway of Rb1->Rd->F2->CK was established using high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS). Our results demonstrated that the molar bioconversion rate of Rb1 to CK was more than 82% and the purity of CK produced by C. sinensis under the optimized conditions was more than 91%. In conclusion, the combination of C. sinensis and the optimized conditions is applicable for the industrial preparation of CK for medicinal purposes. PMID- 26512633 TI - A CuAAC-Hydrazone-CuAAC Trifunctional Scaffold for the Solid-Phase Synthesis of Trimodal Compounds: Possibilities and Limitations. AB - We present a trifunctional scaffold designed for the solid-phase synthesis of trimodal compounds. This scaffold holds two alkyne arms in a free and TIPS protected form for consecutive CuAAC (copper(I)-catalyzed azide-alkyne cycloaddition), one Fmoc-protected hydrazide arm for reaction with aldehydes, and one carboxylic acid arm with CF2 groups for attachment to the resin and (19)F-NMR quantification. This scaffold was attached to a resin and derivatized with model azides and aliphatic, electron-rich or electron-poor aromatic aldehydes. We identified several limitations of the scaffold caused by the instability of hydrazones in acidic conditions, in the presence of copper during CuAAC, and when copper accumulated in the resin. We successfully overcame these drawbacks by optimizing synthetic conditions for the derivatization of the scaffold with aromatic aldehydes. Overall, the new trifunctional scaffold combines CuAAC and hydrazone chemistries, offering a broader chemical space for the development of bioactive compounds. PMID- 26512634 TI - Poly(Propylene Imine) Dendrimers and Amoxicillin as Dual-Action Antibacterial Agents. AB - Besides acting as antimicrobial compounds, dendrimers can be considered as agents that improve the therapeutic effectiveness of existing antibiotics. In this work we present a new approach to using amoxicillin (AMX) against reference strains of common Gram-negative pathogens, alone and in combination with poly(propylene imine) (PPI) dendrimers, or derivatives thereof, in which 100% of the available hydrogen atoms are substituted with maltose (PPI 100%malG3). The concentrations of dendrimers used remained in the range non-toxic to eukaryotic cells. The results indicate that PPI dendrimers significantly enhance the antibacterial effect of amoxicillin alone, allowing antibiotic doses to be reduced. It is important to reduce doses of amoxicillin because its widespread use in medicine could lead to the development of bacterial resistance and environmental pollution. This is the first report on the combined antibacterial activity of PPI surface-modified maltose dendrimers and amoxicillin. PMID- 26512635 TI - Analysis of the Photophysical Behavior and Rotational-Relaxation Dynamics of Coumarin 6 in Nonionic Micellar Environments: The Effect of Temperature. AB - The photodynamics of Coumarin 6 have been investigated in three nonionic micellar assemblies, i.e., n-dodecyl-beta-D-maltoside (beta-C12G2), p-tert-octyl-phenoxy polyethylene (9.5) ether (Triton X-100 or TX100) and n-dodecyl-hexaethylene glycol (C12E6), to assess their potential use as encapsulation vehicles for hydrophobic drugs. To evaluate the effect of the micellar size and hydration, the study used a broad temperature range (293.15-323.15 K). The data presented here include steady-state absorption and emission spectra of the probe, dynamic light scattering, together with fluorescence lifetimes and both steady-state, as well as time-resolved fluorescence anisotropies. The time-resolved fluorescence anisotropy data were analyzed on the basis of the well-established two-step model. Our data reveal that the molecular probe in all of the cases is solubilized in the hydration layer of micelles, where it would sense a relatively polar environment. However, the probe was found to undergo a slower rotational reorientation when solubilized in the alkylpolyglycoside surfactant, as a result of a more compact microenvironment around the probe. The behavior of the parameters of the reorientation dynamics with temperature was analyzed on the basis of both micellar hydration and the head-group flexibility of the surfactants. PMID- 26512636 TI - Design, Synthesis, Activity and Docking Study of Sorafenib Analogs Bearing Sulfonylurea Unit. AB - Two series of novel sorafenib analogs containing a sulfonylurea unit were synthesized and their chemical structures were confirmed by 1H-NMR, 13C-NMR, MS spectrum and elemental analysis. The synthesized compounds were evaluated for the cytotoxicity against A549, Hela, MCF-7, and PC-3 cancer cell lines. Some of the compounds showed moderate cytotoxic activity, especially compounds 1-(2,4 difluorophenylsulfonyl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (6c) and 1-(4-bromophenylsulfonyl)-3-(4-(2-(methylcarbamoyl)pyridin-4 yloxy)phenyl)urea (6f) with the IC50 values against four cancer cell lines ranging from 16.54+/-1.22 to 63.92+/-1.81 MUM, respectively. Inhibitory rates against vascular endothelial growth factor receptor-2 (VEGFR2/KDR) kinase at 10 MUM of target compounds were further carried out in this paper in order to investigate the target of these compounds. Structure-activity relationships (SARs) and docking studies indicated that the sulfonylurea unit was important to these kinds of compounds. None of the substitutions in the phenoxy group and small halogen atoms such as 2,4-difluoro substitution of the aryl group contributed to the activity. The results suggested that sulfonylurea sorafenib analogs are worthy of further study. PMID- 26512637 TI - Purification and Partial Characterization of beta-Glucosidase in Chayote (Sechium edule). AB - beta-Glucosidase (EC 3.2.1.21) is a prominent member of the GH1 family of glycoside hydrolases. The properties of this beta-glucosidase appear to include resistance to temperature, urea, and iodoacetamide, and it is activated by 2-ME, similar to other members. beta-Glucosidase from chayote (Sechium edule) was purified by ionic-interchange chromatography and molecular exclusion chromatography. Peptides detected by LC-ESI-MS/MS were compared with other beta glucosidases using the BLAST program. This enzyme is a 116 kDa protein composed of two sub-units of 58 kDa and shows homology with Cucumis sativus beta glucosidase (NCBI reference sequence XP_004154617.1), in which seven peptides were found with relative masses ranging from 874.3643 to 1587.8297. The stability of beta-glucosidase depends on an initial concentration of 0.2 mg/mL of protein at pH 5.0 which decreases by 33% in a period of 30 h, and then stabilizes and is active for the next 5 days (pH 4.0 gives similar results). One hundred MUg/mL beta-D-glucose inhibited beta-glucosidase activity by more than 50%. The enzyme had a Km of 4.88 mM with p-NPG and a Kcat of 10,000 min(-1). The optimal conditions for the enzyme require a pH of 4.0 and a temperature of 50 degrees C. PMID- 26512638 TI - A Practical Route for the Preparation of 1,4,7-Triazacyclononanyl Diacetates with a Hydroxypyridinonate Pendant Arm. AB - The preparation of triazamacrocyclic hydroxypyridinonate (HOPO-TACN) derivatives as potential chelators for metals in biomedical applications was reported. The synthesis is based on a convergent synthetic approach, in which the key intermediate di-tert-butyl-2,2'-(1,4,7-triazonane-1,4-diyl) diacetate was coupled with a hydroxypyridinonate pendant arm. The method is suitable for rapid syntheses of metal chelator HOPO-TACNs of biomedical interest. PMID- 26512639 TI - Effects of Flavonoids from Food and Dietary Supplements on Glial and Glioblastoma Multiforme Cells. AB - Quercetin, catechins and proanthocyanidins are flavonoids that are prominently featured in foodstuffs and dietary supplements, and may possess anti-carcinogenic activity. Glioblastoma multiforme is the most dangerous form of glioma, a malignancy of the brain connective tissue. This review assesses molecular structures of these flavonoids, their importance as components of diet and dietary supplements, their bioavailability and ability to cross the blood-brain barrier, their reported beneficial health effects, and their effects on non malignant glial as well as glioblastoma tumor cells. The reviewed flavonoids appear to protect glial cells via reduction of oxidative stress, while some also attenuate glutamate-induced excitotoxicity and reduce neuroinflammation. Most of the reviewed flavonoids inhibit proliferation of glioblastoma cells and induce their death. Moreover, some of them inhibit pro-oncogene signaling pathways and intensify the effect of conventional anti-cancer therapies. However, most of these anti-glioblastoma effects have only been observed in vitro or in animal models. Due to limited ability of the reviewed flavonoids to access the brain, their normal dietary intake is likely insufficient to produce significant anti cancer effects in this organ, and supplementation is needed. PMID- 26512640 TI - The Multiple Roles of Microrna-223 in Regulating Bone Metabolism. AB - Bone metabolism is a lifelong process for maintaining skeletal system homeostasis, which is regulated by bone-resorbing osteoclasts and bone-forming osteoblasts. Aberrant differentiation of osteoclasts and osteoblasts leads to imbalanced bone metabolism, resulting in ossification and osteolysis diseases. MicroRNAs (miRNAs) are pivotal factors in regulating bone metabolism via post transcriptional inhibition of target genes. Recent studies have revealed that miR 223 exerts multiple effects on bone metabolism, especially in the processes of osteoclast and osteoblasts differentiation. In this review, we highlight the roles of miR-223 during the processes of osteoclast and osteoblast differentiation, as well as the potential clinical applications of miR-223 in bone metabolism disorders. PMID- 26512641 TI - Selective Halogen-Lithium Exchange of 1,2-Dihaloarenes for Successive [2+4] Cycloadditions of Arynes and Isobenzofurans. AB - Successive [2+4] cycloadditions of arynes and isobenzofurans by site-selective halogen-lithium exchange of 1,2-dihaloarenes were developed, allowing the rapid construction of polycyclic compounds which serve as a useful synthetic intermediates for the preparation of various polyacene derivatives. PMID- 26512642 TI - Comparative Study of the Optical and Textural Properties of Tetrapyrrole Macrocycles Trapped Within ZrO2, TiO2, and SiO2 Translucent Xerogels. AB - The entrapping of physicochemical active molecules inside mesoporous networks is an appealing field of research due to the myriad of potential applications in optics, photocatalysis, chemical sensing, and medicine. One of the most important reasons for this success is the possibility of optimizing the properties that a free active species displays in solution but now trapped inside a solid substrate. Additionally it is possible to modulate the textural characteristics of substrates, such as pore size, specific surface area, polarity and chemical affinity of the surface, toward the physical or chemical adhesion of a variety of adsorbates. In the present document, two kinds of non-silicon metal alkoxides, Zr and Ti, are employed to prepare xerogels containing entrapped tetrapyrrolic species that could be inserted beforehand in analogue silica systems. The main goal is to develop efficient methods for trapping or binding tetrapyrrole macrocycles inside TiO2 and ZrO2 xerogels, while comparing the properties of these systems against those of the SiO2 analogues. Once the optimal synthesis conditions for obtaining translucent monolithic xerogels of ZrO2 and TiO2 networks were determined, it was confirmed that these substrates allowed the entrapment, in monomeric form, of macrocycles that commonly appear as aggregates within the SiO2 network. From these experiments, it could be determined that the average pore diameters, specific surface areas, and water sorption capacities depicted by each one of these substrates, are a consequence of their own nature combined with the particular structure of the entrapped tetrapyrrole macrocycle. Furthermore, the establishment of covalent bonds between the intruding species and the pore walls leads to the obtainment of very similar pore sizes in the three different metal oxide (Ti, Zr, and Si) substrates as a consequence of the templating effect of the encapsulated species. PMID- 26512643 TI - Relevant Aspects of Nutritional and Dietary Interventions in Non-Alcoholic Fatty Liver Disease. AB - Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver disease worldwide. NAFLD is linked to circumstances such as type 2 diabetes, insulin resistance, obesity, hyperlipidemia, and hypertension. Since the obesity figures and related comorbidities are increasing, NAFLD has turned into a liver problem that has become progressively more common. Currently, there is no effective drug therapy for NAFLD; therefore, interventions in lifestyles remain the first line of treatment. Bearing in mind that adherence rates to this type of treatment are poor, great efforts are currently focused on finding novel therapeutic agents for the prevention in the development of hepatic steatosis and its progression to nonalcoholic steatohepatitis and cirrhosis. This review presents a compilation of the scientific evidence found in the last years showing the results of interventions in lifestyle, diet, and behavioral therapies and research results in human, animal and cell models. Possible therapeutic agents ranging from supplementation with vitamins, amino acids, prebiotics, probiotics, symbiotics, polyunsaturated fatty acids and polyphenols to interventions with medicinal plants are analyzed. PMID- 26512644 TI - miR-134 Modulates the Proliferation of Human Cardiomyocyte Progenitor Cells by Targeting Meis2. AB - Cardiomyocyte progenitor cells play essential roles in early heart development, which requires highly controlled cellular organization. microRNAs (miRs) are involved in various cell behaviors by post-transcriptional regulation of target genes. However, the roles of miRNAs in human cardiomyocyte progenitor cells (hCMPCs) remain to be elucidated. Our previous study showed that miR-134 was significantly downregulated in heart tissue suffering from congenital heart disease, underlying the potential role of miR-134 in cardiogenesis. In the present work, we showed that the upregulation of miR-134 reduced the proliferation of hCMPCs, as determined by EdU assay and Ki-67 immunostaining, while the inhibition of miR-134 exhibited an opposite effect. Both up- and downregulation of miR-134 expression altered the transcriptional level of cell cycle genes. We identified Meis2 as the target of miR-134 in the regulation of hCMPC proliferation through bioinformatic prediction, luciferase reporter assay and western blot. The over-expression of Meis2 mitigated the effect of miR-134 on hCMPC proliferation. Moreover, miR-134 did not change the degree of hCMPC differentiation into cardiomyocytes in our model, suggesting that miR-134 is not required in this process. These findings reveal an essential role for miR-134 in cardiomyocyte progenitor cell biology and provide new insights into the physiology and pathology of cardiogenesis. PMID- 26512645 TI - Graphene Functionalized with Arginine Decreases the Development of Glioblastoma Multiforme Tumor in a Gene-Dependent Manner. AB - Our previous studies revealed that graphene had anticancer properties in experiments in vitro with glioblastoma multiforme (GBM) cells and in tumors cultured in vivo. We hypothesized that the addition of arginine or proline to graphene solutions might counteract graphene agglomeration and increase the activity of graphene. Experiments were performed in vitro with GBM U87 cells and in vivo with GBM tumors cultured on chicken embryo chorioallantoic membranes. The measurements included cell morphology, mortality, viability, tumor morphology, histology, and gene expression. The cells and tumors were treated with reduced graphene oxide (rGO) and rGO functionalized with arginine (rGO + Arg) or proline (rGO + Pro). The results confirmed the anticancer effect of graphene on GBM cells and tumor tissue. After functionalization with amino acids, nanoparticles were distributed more specifically, and the flakes of graphene were less agglomerated. The molecule of rGO + Arg did not increase the expression of TP53 in comparison to rGO, but did not increase the expression of MDM2 or the MDM2/TP53 ratio in the tumor, suggesting that arginine may block MDM2 expression. The expression of NQO1, known to be a strong protector of p53 protein in tumor tissue, was greatly increased. The results indicate that the complex of rGO + Arg has potential in GBM therapy. PMID- 26512647 TI - Increased Uptake of Chelated Copper Ions by Lolium perenne Attributed to Amplified Membrane and Endodermal Damage. AB - The contributions of mechanisms by which chelators influence metal translocation to plant shoot tissues are analyzed using a combination of numerical modelling and physical experiments. The model distinguishes between apoplastic and symplastic pathways of water and solute movement. It also includes the barrier effects of the endodermis and plasma membrane. Simulations are used to assess transport pathways for free and chelated metals, identifying mechanisms involved in chelate-enhanced phytoextraction. Hypothesized transport mechanisms and parameters specific to amendment treatments are estimated, with simulated results compared to experimental data. Parameter values for each amendment treatment are estimated based on literature and experimental values, and used for model calibration and simulation of amendment influences on solute transport pathways and mechanisms. Modeling indicates that chelation alters the pathways for Cu transport. For free ions, Cu transport to leaf tissue can be described using purely apoplastic or transcellular pathways. For strong chelators (ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA)), transport by the purely apoplastic pathway is insufficient to represent measured Cu transport to leaf tissue. Consistent with experimental observations, increased membrane permeability is required for simulating translocation in EDTA and DTPA treatments. Increasing the membrane permeability is key to enhancing phytoextraction efficiency. PMID- 26512646 TI - Diabetic Cardiovascular Disease Induced by Oxidative Stress. AB - Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD), cardiac hypertrophy, and heart failure (HF). HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS). ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease. PMID- 26512648 TI - Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer. AB - We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC) and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs), bisphenols (BPs), and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA) and phthalates, increased the summary odds ratio for breast cancer and endometriosis. Bioinformatics analysis of gene-EDC interactions and disease associations identified several hundred genes that were altered by exposure to PCBs, phthalate or BPA. EDCs-modified genes in breast neoplasms and endometriosis are part of steroid hormone signaling and inflammation pathways. All three EDCs-PCB 153, phthalates, and BPA influenced five common genes-CYP19A1, EGFR, ESR2, FOS, and IGF1-in breast cancer as well as in endometriosis. These genes are environmentally and estrogen responsive, altered in human breast and uterine tumors and endometriosis lesions, and part of Mitogen Activated Protein Kinase (MAPK) signaling pathways in cancer. Our findings suggest that breast cancer and endometriosis share some common environmental and molecular risk factors. PMID- 26512649 TI - Membranotropic Cell Penetrating Peptides: The Outstanding Journey. AB - The membrane bilayer delimits the interior of individual cells and provides them with the ability to survive and function properly. However, the crossing of cellular membranes constitutes the principal impediment to gaining entry into cells, and the potential therapeutic application of many drugs is predominantly dependent on the development of delivery tools that should take the drug to target cells selectively and efficiently with only minimal toxicity. Cell penetrating peptides are short and basic peptides are widely used due to their ability to deliver a cargo across the membrane both in vitro and in vivo. It is widely accepted that their uptake mechanism involves mainly the endocytic pathway, the drug is catched inside endosomes and lysosomes, and only a small quantity is able to reach the intracellular target. In this wide-ranging scenario, a fascinating novel hypothesis is that membranotropic peptides that efficiently cross biological membranes, promote lipid-membrane reorganizing processes and cause a local and temporary destabilization and reorganization of the membrane bilayer, may also be able to enter cells circumventing the endosomal entrapment; in particular, by either favoring the escape from the endosome or by direct translocation. This review summarizes current data on membranotropic peptides for drug delivery. PMID- 26512650 TI - A Parallel Biological Optimization Algorithm to Solve the Unbalanced Assignment Problem Based on DNA Molecular Computing. AB - The unbalanced assignment problem (UAP) is to optimally resolve the problem of assigning n jobs to m individuals (m < n), such that minimum cost or maximum profit obtained. It is a vitally important Non-deterministic Polynomial (NP) complete problem in operation management and applied mathematics, having numerous real life applications. In this paper, we present a new parallel DNA algorithm for solving the unbalanced assignment problem using DNA molecular operations. We reasonably design flexible-length DNA strands representing different jobs and individuals, take appropriate steps, and get the solutions of the UAP in the proper length range and O(mn) time. We extend the application of DNA molecular operations and simultaneity to simplify the complexity of the computation. PMID- 26512651 TI - Structure-Functional Study of Tyrosine and Methionine Dipeptides: An Approach to Antioxidant Activity Prediction. AB - Quantum chemical methods allow screening and prediction of peptide antioxidant activity on the basis of known experimental data. It can be used to design the selective proteolysis of protein sources in order to obtain products with antioxidant activity. Molecular geometry and electronic descriptors of redox active amino acids, as well as tyrosine and methionine-containing dipeptides, were studied by Density Functional Theory method. The calculated data was used to reveal several descriptors responsible for the antioxidant capacities of the model compounds based on their experimentally obtained antioxidant capacities against ABTS (2,2'-Azino-bis-(3-ethyl-benzothiazoline-6-sulfonate)) and peroxyl radical. A formula to predict antioxidant activity of peptides was proposed. PMID- 26512652 TI - MicroRNA-214 and MicroRNA-126 Are Potential Biomarkers for Malignant Endothelial Proliferative Diseases. AB - Malignant endothelial proliferative diseases including human angiosarcoma (AS) and canine hemangiosarcoma (HSA) are serious diseases with a grave prognosis. Establishing liquid biopsy-based biomarkers for screening has definite clinical utility; however, plasma miRNAs up- or down-regulated in these sarcomas have been unclear. For identifying possible diagnostic plasma miRNAs for these sarcomas, we investigated whether plasma miR-214 and miR-126, which miRNAs play important roles in angiogenesis and tumorigenesis, were elevated in malignant endothelial proliferative diseases. For this investigation, human angiosarcoma and canine hemangiosarcoma cell lines and clinical plasma samples of canine hemangiosarcoma were examined by performing miRNA qRT-PCR. We report here that human angiosarcoma and canine hemangiosarcoma cell lines over-secreted miR-214 and miR-126 via microvesicles; in addition, their levels in the plasma samples from canines with hemangiosarcoma were increased. Moreover, the surgical resection of primary tumors decreased the levels of plasma miR-214 and miR-126. Our findings suggest that these malignant endothelial proliferative diseases over-secreted miR-214 and miR-126, thus suggesting that these miRNAs have potential as diagnostic biomarkers for malignant endothelial proliferative diseases in canine and possible in human angiosarcoma. PMID- 26512654 TI - Characterization of Peripheral Immune Cell Subsets in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study. AB - Immune cells (IC) play a crucial role in murine stroke pathophysiology. However, data are limited on the role of these cells in ischemic stroke in humans. We therefore aimed to characterize and compare peripheral IC subsets in patients with acute ischemic stroke/transient ischemic attack (AIS/TIA), chronic cerebrovascular disease (CCD) and healthy volunteers (HV). We conducted a case control study of patients with AIS/TIA (n = 116) or CCD (n = 117), and HV (n = 104) who were enrolled at the University Hospital Wurzburg from 2010 to 2013. We determined the expression and quantity of IC subsets in the three study groups and performed correlation analyses with demographic and clinical parameters. The quantity of several IC subsets differed between the AIS/TIA, CCD, and HV groups. Several clinical and demographic variables independently predicted the quantity of IC subsets in patients with AIS/TIA. No significant changes in the quantity of IC subsets occurred within the first three days after AIS/TIA. Overall, these findings strengthen the evidence for a pathophysiologic role of IC in human ischemic stroke and the potential use of IC-based biomarkers for the prediction of stroke risk. A comprehensive description of IC kinetics is crucial to enable the design of targeted treatment strategies. PMID- 26512655 TI - TP53inp1 Gene Is Implicated in Early Radiation Response in Human Fibroblast Cells. AB - Tumor protein 53-induced nuclear protein-1 (TP53inp1) is expressed by activation via p53 and p73. The purpose of our study was to investigate the role of TP53inp1 in response of fibroblasts to ionizing radiation. gamma-Ray radiation dose dependently induces the expression of TP53inp1 in human immortalized fibroblast (F11hT) cells. Stable silencing of TP53inp1 was done via lentiviral transfection of shRNA in F11hT cells. After irradiation the clonogenic survival of TP53inp1 knockdown (F11hT-shTP) cells was compared to cells transfected with non-targeting (NT) shRNA. Radiation-induced senescence was measured by SA-beta-Gal staining and autophagy was detected by Acridine Orange dye and microtubule-associated protein 1 light chain 3 (LC3B) immunostaining. The expression of TP53inp1, GDF-15, and CDKN1A and alterations in radiation induced mitochondrial DNA deletions were evaluated by qPCR. TP53inp1 was required for radiation (IR) induced maximal elevation of CDKN1A and GDF-15 expressions. Mitochondrial DNA deletions were increased and autophagy was deregulated following irradiation in the absence of TP53inp1. Finally, we showed that silencing of TP53inp1 enhances the radiation sensitivity of fibroblast cells. These data suggest functional roles for TP53inp1 in radiation-induced autophagy and survival. Taken together, we suppose that silencing of TP53inp1 leads radiation induced autophagy impairment and induces accumulation of damaged mitochondria in primary human fibroblasts. PMID- 26512653 TI - Changes in Regenerative Capacity through Lifespan. AB - Most organisms experience changes in regenerative abilities through their lifespan. During aging, numerous tissues exhibit a progressive decline in homeostasis and regeneration that results in tissue degeneration, malfunction and pathology. The mechanisms responsible for this decay are both cell intrinsic, such as cellular senescence, as well as cell-extrinsic, such as changes in the regenerative environment. Understanding how these mechanisms impact on regenerative processes is essential to devise therapeutic approaches to improve tissue regeneration and extend healthspan. This review offers an overview of how regenerative abilities change through lifespan in various organisms, the factors that underlie such changes and the avenues for therapeutic intervention. It focuses on established models of mammalian regeneration as well as on models in which regenerative abilities do not decline with age, as these can deliver valuable insights for our understanding of the interplay between regeneration and aging. PMID- 26512656 TI - Photodynamic Therapy (PDT) with Chemotherapy for Advanced Lung Cancer with Airway Stenosis. AB - Intractable advanced lung cancer can be treated palliatively with photodynamic therapy (PDT) combined with chemotherapy to remove central and peripheral (lobar or segmental bronchi) bronchial stenosis and obstruction. We present data for 12 (eight men, four women) consecutive patients with 13 advanced non-small cell lung carcinomas in whom curative operations were contraindicated, who underwent PDT combined with chemotherapy for local control of the intraluminal lesions. The mean age was 73.3 years (range, 58-80 years), and the stages of cancer were IIA IV. The median stenosis rates before treatment, one week post-treatment, and one month post-treatment were 60% (range, 30%-100%), 15% (range, 15%-99%), and 15% (range 15%-60%), respectively. The mean and median survival times were 9.3 and 5.9 months, respectively. The overall 1-year survival rate was 30.0%. No PDT related morbidity or mortality occurred. In this single-institution study, all patients experienced improved symptoms and quality of life at one week after treatment; furthermore, an objective response was evidenced by the substantial increase in the openings of the bronchial lumen and prevention of obstructive pneumonia. Therefore, PDT with chemotherapy was useful and safe for the treatment of bronchial obstruction. PMID- 26512658 TI - The Fab Fragment of a Humanized Anti-Toll Like Receptor 4 (TLR4) Monoclonal Antibody Reduces the Lipopolysaccharide Response via TLR4 in Mouse Macrophage. AB - Lipopolysaccharides (LPS) can induce acute inflammation, sepsis, or chronic inflammatory disorders through the Toll receptor 4 (TLR4) signaling pathway. The TLR4/MD2 (myeloid differentiation protein 2) complex plays a major role in the immune response to LPS. However, there is not a good method to suppress the immune response induced by LPS via this complex in macrophages. In this article, we aimed to evaluate the effects of humanized anti-TLR4 monoclonal antibodies on LPS-induced responses in mouse macrophages. The peritoneal macrophages of mice were incubated with anti-TLR4 monoclonal antibodies and stimulated with LPS. The expression levels of cytokines were analyzed by quantitative polymerase chain reaction and enzyme-linked immunosorbent assays. Additionally, activation of various signaling pathways was evaluated by Western blotting. The results showed that the humanized anti-TLR4 monoclonal antibody blocked the inflammatory cytokines expression at both the mRNA and protein level. We also found that the Fab fragment significantly inhibited the nuclear factor kappaB signaling pathway by reducing the phosphorylation of the inhibitor of kappaBalpha and decreasing the translocation of p65, resulting in the suppression of p38, extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase 1/2, and IFN-beta regulatory factor 3 phosphorylation. Therefore, our study showed that this humanized anti TLR4 monoclonal antibody could effectively protect against LPS-induced responses by blocking the TLR4 signaling pathway in mouse peritoneal macrophages. PMID- 26512657 TI - Stem Cells in Skin Regeneration, Wound Healing, and Their Clinical Applications. AB - The skin is the largest organ of the body and has an array of functions. Skin compartments, epidermis, and hair follicles house stem cells that are indispensable for skin homeostasis and regeneration. These stem cells also contribute to wound repair, resulting in restoration of tissue integrity and function of damaged tissue. Unsuccessful wound healing processes often lead to non-healing wounds. Chronic wounds are caused by depletion of stem cells and a variety of other cellular and molecular mechanisms, many of which are still poorly understood. Current chronic wound therapies are limited, so the search to develop better therapeutic strategies is ongoing. Adult stem cells are gaining recognition as potential candidates for numerous skin pathologies. In this review, we will discuss epidermal and other stem cells present in the skin, and highlight some of the therapeutic applications of epidermal stem cells and other adult stem cells as tools for cell/scaffold-based therapies for non-healing wounds and other skin disorders. We will also discuss emerging concepts and offer some perspectives on how skin tissue-engineered products can be optimized to provide efficacious therapy in cutaneous repair and regeneration. PMID- 26512659 TI - Molecular Cloning and Characterization of DXS and DXR Genes in the Terpenoid Biosynthetic Pathway of Tripterygium wilfordii. AB - 1-Deoxy-d-xylulose-5-phosphate synthase (DXS) and 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) genes are the key enzyme genes of terpenoid biosynthesis but still unknown in Tripterygium wilfordii Hook. f. Here, three full-length cDNA encoding DXS1, DXS2 and DXR were cloned from suspension cells of T. wilfordii with ORF sizes of 2154 bp (TwDXS1, GenBank accession no.KM879187), 2148 bp (TwDXS2, GenBank accession no.KM879186), 1410 bp (TwDXR, GenBank accession no.KM879185). And, the TwDXS1, TwDXS2 and TwDXR were characterized by color complementation in lycopene accumulating strains of Escherichia coli, which indicated that they encoded functional proteins and promoted lycopene pathway flux. TwDXS1 and TwDXS2 are constitutively expressed in the roots, stems and leaves and the expression level showed an order of roots > stems > leaves. After the suspension cells were induced by methyl jasmonate, the mRNA expression level of TwDXS1, TwDXS2, and TwDXR increased, and triptophenolide was rapidly accumulated to 149.52 ug.g(-1), a 5.88-fold increase compared with the control. So the TwDXS1, TwDXS2, and TwDXR could be important genes involved in terpenoid biosynthesis in Tripterygium wilfordii Hook. f. PMID- 26512661 TI - Non-Alcoholic Steatohepatitis (NASH): Risk Factors in Morbidly Obese Patients. AB - The aim was to investigate the prevalence of non-alcoholic steatohepatitis (NASH) and risk factors for hepatic fibrosis in morbidly obese patients submitted to bariatric surgery. This retrospective study recruited all patients submitted to bariatric surgery from January 2007 to December 2012 at a reference attendance center of Southern Brazil. Clinical and biochemical data were studied as a function of the histological findings of liver biopsies done during the surgery. Steatosis was present in 226 (90.4%) and NASH in 176 (70.4%) cases. The diagnosis of cirrhosis was established in four cases (1.6%) and fibrosis in 108 (43.2%). Risk factors associated with NASH at multivariate analysis were alanine aminotransferase (ALT) >1.5 times the upper limit of normal (ULN); glucose >= 126 mg/dL and triglycerides >= 150 mg/dL. All patients with ALT >=1.5 times the ULN had NASH. When the presence of fibrosis was analyzed, ALT > 1.5 times the ULN and triglycerides >= 150 mg/dL were risk factors, furthermore, there was an increase of 1% in the prevalence of fibrosis for each year of age increase. Not only steatosis, but NASH is a frequent finding in MO patients. In the present study, ALT >= 1.5 times the ULN identifies all patients with NASH, this finding needs to be further validated in other studies. Moreover, the presence of fibrosis was associated with ALT, triglycerides and age, identifying a subset of patients with more severe disease. PMID- 26512660 TI - Cell Death Conversion under Hypoxic Condition in Tumor Development and Therapy. AB - Hypoxia, which is common during tumor progression, plays important roles in tumor biology. Failure in cell death in response to hypoxia contributes to progression and metastasis of tumors. On the one hand, the metabolic and oxidative stress following hypoxia could lead to cell death by triggering signal cascades, like LKB1/AMPK, PI3K/AKT/mTOR, and altering the levels of effective components, such as the Bcl-2 family, Atg and p62. On the other hand, hypoxia-induced autophagy can serve as a mechanism to turn over nutrients, so as to mitigate the adverse condition and then avoid cell death potentially. Due to the effective role of hypoxia, this review focuses on the crosstalk in cell death under hypoxia in tumor progression. Additionally, the illumination of cell death in hypoxia could shed light on the clinical applications of cell death targeted therapy. PMID- 26512662 TI - Microengineered Conductive Elastomeric Electrodes for Long-Term Electrophysiological Measurements with Consistent Impedance under Stretch. AB - In this research, we develop a micro-engineered conductive elastomeric electrode for measurements of human bio-potentials with the absence of conductive pastes. Mixing the biocompatible polydimethylsiloxane (PDMS) silicone with other biocompatible conductive nano-particles further provides the material with an electrical conductivity. We apply micro-replica mold casting for the micro structures, which are arrays of micro-pillars embedded between two bulk conductive-PDMS layers. These micro-structures can reduce the micro-structural deformations along the direction of signal transmission; therefore the corresponding electrical impedance under the physical stretch by the movement of the human body can be maintained. Additionally, we conduct experiments to compare the electrical properties between the bulk conductive-PDMS material and the microengineered electrodes under stretch. We also demonstrate the working performance of these micro-engineered electrodes in the acquisition of the 12 lead electrocardiographs (ECG) of a healthy subject. Together, the presented gel less microengineered electrodes can provide a more convenient and stable bio potential measurement platform, making tele-medical care more achievable with reduced technical barriers for instrument installation performed by patients/users themselves. PMID- 26512663 TI - Highly Sensitive Measurement of Bio-Electric Potentials by Boron-Doped Diamond (BDD) Electrodes for Plant Monitoring. AB - We describe a sensitive plant monitoring system by the detection of the bioelectric potentials in plants with boron-doped diamond (BDD) electrodes. For sensor electrodes, we used commercially available BDD, Ag, and Pt plate electrodes. We tested this approach on a hybrid species in the genus Opuntia (potted) and three different trees (ground-planted) at different places in Japan. For the Opuntia, we artificially induced bioelectric potential changes by the surface potential using the fingers. We detected substantial changes in bioelectric potentials through all electrodes during finger touches on the surface of potted Opuntia hybrid plants, although the BDD electrodes were several times more sensitive to bioelectric potential change compared to the other electrodes. Similarly for ground-planted trees, we found that both BDD and Pt electrodes detected bioelectric potential change induced by changing environmental factors (temperature and humidity) for months without replacing/removing/changing electrodes, BDD electrodes were 5-10 times more sensitive in this detection than Pt electrodes. Given these results, we conclude that BDD electrodes on live plant tissue were able to consistently detect bioelectrical potential changes in plants. PMID- 26512664 TI - Highly Sensitive Liquid Core Temperature Sensor Based on Multimode Interference Effects. AB - A novel fiber optic temperature sensor based on a liquid-core multimode interference device is demonstrated. The advantage of such structure is that the thermo-optic coefficient (TOC) of the liquid is at least one order of magnitude larger than that of silica and this, combined with the fact that the TOC of silica and the liquid have opposite signs, provides a liquid-core multimode fiber (MMF) highly sensitive to temperature. Since the refractive index of the liquid can be easily modified, this allows us to control the modal properties of the liquid-core MMF at will and the sensor sensitivity can be easily tuned by selecting the refractive index of the liquid in the core of the device. The maximum sensitivity measured in our experiments is 20 nm/ degrees C in the low temperature regime up to 60 degrees C. To the best of our knowledge, to date, this is the largest sensitivity reported for fiber-based MMI temperature sensors. PMID- 26512665 TI - AMA- and RWE- Based Adaptive Kalman Filter for Denoising Fiber Optic Gyroscope Drift Signal. AB - An improved double-factor adaptive Kalman filter called AMA-RWE-DFAKF is proposed to denoise fiber optic gyroscope (FOG) drift signal in both static and dynamic conditions. The first factor is Kalman gain updated by random weighting estimation (RWE) of the covariance matrix of innovation sequence at any time to ensure the lowest noise level of output, but the inertia of KF response increases in dynamic condition. To decrease the inertia, the second factor is the covariance matrix of predicted state vector adjusted by RWE only when discontinuities are detected by adaptive moving average (AMA).The AMA-RWE-DFAKF is applied for denoising FOG static and dynamic signals, its performance is compared with conventional KF (CKF), RWE-based adaptive KF with gain correction (RWE-AKFG), AMA- and RWE- based dual mode adaptive KF (AMA-RWE-DMAKF). Results of Allan variance on static signal and root mean square error (RMSE) on dynamic signal show that this proposed algorithm outperforms all the considered methods in denoising FOG signal. PMID- 26512666 TI - An Ultrasonic Multi-Beam Concentration Meter with a Neuro-Fuzzy Algorithm for Water Treatment Plants. AB - Ultrasonic concentration meters have widely been used at water purification, sewage treatment and waste water treatment plants to sort and transfer high concentration sludges and to control the amount of chemical dosage. When an unusual substance is contained in the sludge, however, the attenuation of ultrasonic waves could be increased or not be transmitted to the receiver. In this case, the value measured by a concentration meter is higher than the actual density value or vibration. As well, it is difficult to automate the residuals treatment process according to the various problems such as sludge attachment or sensor failure. An ultrasonic multi-beam concentration sensor was considered to solve these problems, but an abnormal concentration value of a specific ultrasonic beam degrades the accuracy of the entire measurement in case of using a conventional arithmetic mean for all measurement values, so this paper proposes a method to improve the accuracy of the sludge concentration determination by choosing reliable sensor values and applying a neuro-fuzzy learning algorithm. The newly developed meter is proven to render useful results from a variety of experiments on a real water treatment plant. PMID- 26512667 TI - Computerised Analysis of Telemonitored Respiratory Sounds for Predicting Acute Exacerbations of COPD. AB - Chronic obstructive pulmonary disease (COPD) is one of the commonest causes of death in the world and poses a substantial burden on healthcare systems and patients' quality of life. The largest component of the related healthcare costs is attributable to admissions due to acute exacerbation (AECOPD). The evidence that might support the effectiveness of the telemonitoring interventions in COPD is limited partially due to the lack of useful predictors for the early detection of AECOPD. Electronic stethoscopes and computerised analyses of respiratory sounds (CARS) techniques provide an opportunity for substantial improvement in the management of respiratory diseases. This exploratory study aimed to evaluate the feasibility of using: (a) a respiratory sensor embedded in a self-tailored housing for ageing users; (b) a telehealth framework; (c) CARS and (d) machine learning techniques for the remote early detection of the AECOPD. In a 6-month pilot study, 16 patients with COPD were equipped with a home base-station and a sensor to daily record their respiratory sounds. Principal component analysis (PCA) and a support vector machine (SVM) classifier was designed to predict AECOPD. 75.8% exacerbations were early detected with an average of 5 +/- 1.9 days in advance at medical attention. The proposed method could provide support to patients, physicians and healthcare systems. PMID- 26512668 TI - Fault Diagnosis of Demountable Disk-Drum Aero-Engine Rotor Using Customized Multiwavelet Method. AB - The demountable disk-drum aero-engine rotor is an important piece of equipment that greatly impacts the safe operation of aircraft. However, assembly looseness or crack fault has led to several unscheduled breakdowns and serious accidents. Thus, condition monitoring and fault diagnosis technique are required for identifying abnormal conditions. Customized ensemble multiwavelet method for aero engine rotor condition identification, using measured vibration data, is developed in this paper. First, customized multiwavelet basis function with strong adaptivity is constructed via symmetric multiwavelet lifting scheme. Then vibration signal is processed by customized ensemble multiwavelet transform. Next, normalized information entropy of multiwavelet decomposition coefficients is computed to directly reflect and evaluate the condition. The proposed approach is first applied to fault detection of an experimental aero-engine rotor. Finally, the proposed approach is used in an engineering application, where it successfully identified the crack fault of a demountable disk-drum aero-engine rotor. The results show that the proposed method possesses excellent performance in fault detection of aero-engine rotor. Moreover, the robustness of the multiwavelet method against noise is also tested and verified by simulation and field experiments. PMID- 26512669 TI - Why does the Conductivity of a Nickel Catalyst Increase during Sulfidation? An Exemplary Study Using an In Operando Sensor Device. AB - In order to study the sulfidation of a catalyst fixed bed, an in operando single pellet sensor was designed. A catalyst pellet from the fixed bed was electrically contacted and its electrical response was correlated with the catalyst behavior. For the sulfidation tests, a nickel catalyst was used and was sulfidized with H2S. This catalyst had a very low conductivity in the reduced state. During sulfidation, the conductivity of the catalyst increased by decades. A reaction from nickel to nickel sulfide occurred. This conductivity increase by decades during sulfidation had not been expected since both nickel and nickel sulfides behave metallic. Only by assuming a percolation phenomenon that originates from a volume increase of the nickel contacts when reacting to nickel sulfides, this effect can be explained. This assumption was supported by sulfidation tests with differently nickel loaded catalysts and it was quantitatively estimated by a general effective media theory. The single pellet sensor device for in operando investigation of sulfidation can be considered as a valuable tool to get further insights into catalysts under reaction conditions. PMID- 26512670 TI - Nanostructured Tungsten Oxide Composite for High-Performance Gas Sensors. AB - We report the results of composite tungsten oxide nanowires-based gas sensors. The morphologic surface, crystallographic structures, and chemical compositions of the obtained nanowires have been investigated using scanning electron microscopy (SEM), X-ray diffraction (XRD), and Raman scattering, respectively. The experimental measurements reveal that each wire consists of crystalline nanoparticles with an average diameter of less than 250 nm. By using the synthesized nanowires, highly sensitive prototypic gas sensors have been designed and fabricated. The dependence of the sensitivity of tungsten oxide nanowires to the methane and hydrogen gases as a function of time has been obtained. Various sensing parameters such as sensitivity, response time, stability, and repeatability were investigated in order to reveal the sensing ability. PMID- 26512671 TI - Fabrication and Characterization of a Micro Methanol Sensor Using the CMOS-MEMS Technique. AB - A methanol microsensor integrated with a micro heater manufactured using the complementary metal oxide semiconductor (CMOS)-microelectromechanical system (MEMS) technique was presented. The sensor has a capability of detecting low concentration methanol gas. Structure of the sensor is composed of interdigitated electrodes, a sensitive film and a heater. The heater located under the interdigitated electrodes is utilized to provide a working temperature to the sensitive film. The sensitive film prepared by the sol-gel method is tin dioxide doped cadmium sulfide, which is deposited on the interdigitated electrodes. To obtain the suspended structure and deposit the sensitive film, the sensor needs a post-CMOS process to etch the sacrificial silicon dioxide layer and silicon substrate. The methanol senor is a resistive type. A readout circuit converts the resistance variation of the sensor into the output voltage. The experimental results show that the methanol sensor has a sensitivity of 0.18 V/ppm. PMID- 26512672 TI - An Accurate and Fault-Tolerant Target Positioning System for Buildings Using Laser Rangefinders and Low-Cost MEMS-Based MARG Sensors. AB - Target positioning systems based on MEMS gyros and laser rangefinders (LRs) have extensive prospects due to their advantages of low cost, small size and easy realization. The target positioning accuracy is mainly determined by the LR's attitude derived by the gyros. However, the attitude error is large due to the inherent noises from isolated MEMS gyros. In this paper, both accelerometer/magnetometer and LR attitude aiding systems are introduced to aid MEMS gyros. A no-reset Federated Kalman Filter (FKF) is employed, which consists of two local Kalman Filters (KF) and a Master Filter (MF). The local KFs are designed by using the Direction Cosine Matrix (DCM)-based dynamic equations and the measurements from the two aiding systems. The KFs can estimate the attitude simultaneously to limit the attitude errors resulting from the gyros. Then, the MF fuses the redundant attitude estimates to yield globally optimal estimates. Simulation and experimental results demonstrate that the FKF-based system can improve the target positioning accuracy effectively and allow for good fault tolerant capability. PMID- 26512673 TI - A Novel Multilayered RFID Tagged Cargo Integrity Assurance Scheme. AB - To minimize cargo theft during transport, mobile radio frequency identification (RFID) grouping proof methods are generally employed to ensure the integrity of entire cargo loads. However, conventional grouping proofs cannot simultaneously generate grouping proofs for a specific group of RFID tags. The most serious problem of these methods is that nonexistent tags are included in the grouping proofs because of the considerable amount of time it takes to scan a high number of tags. Thus, applying grouping proof methods in the current logistics industry is difficult. To solve this problem, this paper proposes a method for generating multilayered offline grouping proofs. The proposed method provides tag anonymity; moreover, resolving disputes between recipients and transporters over the integrity of cargo deliveries can be expedited by generating grouping proofs and automatically authenticating the consistency between the receipt proof and pick proof. The proposed method can also protect against replay attacks, multi-session attacks, and concurrency attacks. Finally, experimental results verify that, compared with other methods for generating grouping proofs, the proposed method can efficiently generate offline grouping proofs involving several parties in a supply chain using mobile RFID. PMID- 26512674 TI - An Indoor Obstacle Detection System Using Depth Information and Region Growth. AB - This study proposes an obstacle detection method that uses depth information to allow the visually impaired to avoid obstacles when they move in an unfamiliar environment. The system is composed of three parts: scene detection, obstacle detection and a vocal announcement. This study proposes a new method to remove the ground plane that overcomes the over-segmentation problem. This system addresses the over-segmentation problem by removing the edge and the initial seed position problem for the region growth method using the Connected Component Method (CCM). This system can detect static and dynamic obstacles. The system is simple, robust and efficient. The experimental results show that the proposed system is both robust and convenient. PMID- 26512675 TI - An LPV Adaptive Observer for Updating a Map Applied to an MAF Sensor in a Diesel Engine. AB - In this paper, a new method for mass air flow (MAF) sensor error compensation and an online updating error map (or lookup table) due to installation and aging in a diesel engine is developed. Since the MAF sensor error is dependent on the engine operating point, the error model is represented as a two-dimensional (2D) map with two inputs, fuel mass injection quantity and engine speed. Meanwhile, the 2D map representing the MAF sensor error is described as a piecewise bilinear interpolation model, which can be written as a dot product between the regression vector and parameter vector using a membership function. With the combination of the 2D map regression model and the diesel engine air path system, an LPV adaptive observer with low computational load is designed to estimate states and parameters jointly. The convergence of the proposed algorithm is proven under the conditions of persistent excitation and given inequalities. The observer is validated against the simulation data from engine software enDYNA provided by Tesis. The results demonstrate that the operating point-dependent error of the MAF sensor can be approximated acceptably by the 2D map from the proposed method. PMID- 26512676 TI - Interferon (IFN) and Cellular Immune Response Evoked in RNA-Pattern Sensing During Infection with Hepatitis C Virus (HCV). AB - Hepatitis C virus (HCV) infects hepatocytes but not dendritic cells (DCs), but DCs effectively mature in response to HCV-infected hepatocytes. Using gene disrupted mice and hydrodynamic injection strategy, we found the MAVS pathway to be crucial for induction of type III interferons (IFNs) in response to HCV in mouse. Human hepatocytes barely express TLR3 under non-infectious states, but frequently express it in HCV infection. Type I and III IFNs are induced upon stimulation with polyI:C, an analog of double-stranded (ds)RNA. Activation of TLR3 and the TICAM-1 pathway, followed by DC-mediated activation of cellular immunity, is augmented during exposure to viral RNA. Although type III IFNs are released from replication-competent human hepatocytes, DC-mediated CTL proliferation and NK cell activation hardly occur in response to the released type III IFNs. Yet, type I IFNs and HCV-infected hepatocytes can induce maturation of DCs in either human or mouse origin. In addition, mouse CD8+ DCs mature in response to HCV-infected hepatocytes unless the TLR3/TICAM-1 pathway is blocked. We found the exosomes containing HCV RNA in the supernatant of the HCV infected hepatocytes act as a source of TLR3-mediated DC maturation. Here we summarize our view on the mechanism by which DCs mature to induce NK and CTL in a status of HCV infection. PMID- 26512677 TI - Simultaneous Determination of Fucoxanthin and Its Deacetylated Metabolite Fucoxanthinol in Rat Plasma by Liquid Chromatography-Tandem Mass Spectrometry. AB - Fucoxanthin and its deacetylated metabolite fucoxanthinol are two major carotenoids that have been confirmed to possess various pharmacological properties. In the present study, fucoxanthinol was identified as the deacetylated metabolite of fucoxanthin, after intravenous (i.v.) and intragastric gavage (i.g.) administration to rats at doses of 2 and 65 mg/kg, respectively, by liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. Next, an accurate and precise LC-MS/MS method was developed to quantitatively determine fucoxanthin and fucoxanthinol in rat plasma. Plasma samples were resolved by LC MS/MS on a reverse-phase SB-C18 column that was equilibrated and eluted with acetonitrile (A)/aqueous 0.1% formic acid (B; 92/8, v/v) at a flow rate of 0.5 mL/min. Analytes were monitored by multiple-reaction monitoring (MRM) under positive electrospray ionization mode. The precursor/product transitions (m/z) were 659.3->109.0 for fucoxanthin, 617.2->109.0 for fucoxanthinol, and 429.4 >313.2 for the internal standard (IS). Calibration curves for fucoxanthin and fucoxanthinol were linear over concentrations ranging from 1.53 to 720 and 1.17 to 600 ng/mL, respectively. The inter- and intraday accuracy and precision were within +/-15%. The method was applied successfully in a pharmacokinetic study and the resulting oral fucoxanthin bioavailability calculated. PMID- 26512678 TI - Production of Hyaluronic Acid by Streptococcus zooepidemicus on Protein Substrates Obtained from Scyliorhinus canicula Discards. AB - This work investigates the production of hyaluronic acid (H) by Streptococcus equi subsp. zooepidemicus in complex media formulated with peptones obtained from Scyliorhinus canicula viscera by-products. Initially, in batch cultures, the greatest productions were achieved using commercial media (3.03 g/L) followed by peptones from alcalase hydrolyzed viscera (2.32 g/L) and peptones from non hydrolyzed viscera (2.26 g/L). An increase of between 12% and 15% was found in subsequent fed-batch cultures performed on waste peptones. Such organic nitrogen sources were shown to be an excellent low-cost substrate for microbial H, saving more than 50% of the nutrient costs. PMID- 26512679 TI - Middle East Respiratory Syndrome and Medical Students: Letter from China. AB - OBJECTIVES: The present study aimed to investigate the knowledge of Middle East Respiratory Syndrome (MERS) among Chinese medical students. METHODS: A structured questionnaire on MERS was conducted among 214 medical students in China. RESULTS: The average correction of the single question varied from 36.0% to 89.7%. There is a significant difference on MERS knowledge among different majors of medical students (p < 0.05). Management students scored significantly higher than students of other majors (p < 0.05). CONCLUSION: Chinese medical students had good knowledge of MERS. The MERS knowledge score varied among students of different majors. Education on disease control should be included in the school curriculum. PMID- 26512680 TI - Climate Change Effects on Heat- and Cold-Related Mortality in the Netherlands: A Scenario-Based Integrated Environmental Health Impact Assessment. AB - Although people will most likely adjust to warmer temperatures, it is still difficult to assess what this adaptation will look like. This scenario-based integrated health impacts assessment explores baseline (1981-2010) and future (2050) population attributable fractions (PAF) of mortality due to heat (PAFheat) and cold (PAFcold), by combining observed temperature-mortality relationships with the Dutch KNMI'14 climate scenarios and three adaptation scenarios. The 2050 model results without adaptation reveal a decrease in PAFcold (8.90% at baseline; 6.56%-7.85% in 2050) that outweighs the increase in PAFheat (1.15% at baseline; 1.66%-2.52% in 2050). When the 2050 model runs applying the different adaptation scenarios are considered as well, however, the PAFheat ranges between 0.94% and 2.52% and the PAFcold between 6.56% and 9.85%. Hence, PAFheat and PAFcold can decrease as well as increase in view of climate change (depending on the adaptation scenario). The associated annual mortality burdens in 2050-accounting for both the increasing temperatures and mortality trend-show that heat-related deaths will range between 1879 and 5061 (1511 at baseline) and cold-related deaths between 13,149 and 19,753 (11,727 at baseline). Our results clearly illustrate that model outcomes are not only highly dependent on climate scenarios, but also on adaptation assumptions. Hence, a better understanding of (the impact of various) plausible adaptation scenarios is required to advance future integrated health impact assessments. PMID- 26512681 TI - On the Science-Policy Bridge: Do Spatial Heat Vulnerability Assessment Studies Influence Policy? AB - Human vulnerability to heat varies at a range of spatial scales, especially within cities where there can be noticeable intra-urban differences in heat risk factors. Mapping and visualizing intra-urban heat vulnerability offers opportunities for presenting information to support decision-making. For example the visualization of the spatial variation of heat vulnerability has the potential to enable local governments to identify hot spots of vulnerability and allocate resources and increase assistance to people in areas of greatest need. Recently there has been a proliferation of heat vulnerability mapping studies, all of which, to varying degrees, justify the process of vulnerability mapping in a policy context. However, to date, there has not been a systematic review of the extent to which the results of vulnerability mapping studies have been applied in decision-making. Accordingly we undertook a comprehensive review of 37 recently published papers that use geospatial techniques for assessing human vulnerability to heat. In addition, we conducted an anonymous survey of the lead authors of the 37 papers in order to establish the level of interaction between the researchers as science information producers and local authorities as information users. Both paper review and author survey results show that heat vulnerability mapping has been used in an attempt to communicate policy recommendations, raise awareness and induce institutional networking and learning, but has not as yet had a substantive influence on policymaking or preventive action. PMID- 26512682 TI - Perceived and Objective Measures of Neighborhood Walkability and Physical Activity among Adults in Japan: A Multilevel Analysis of a Nationally Representative Sample. AB - Although associations between a person's neighborhood and their health have been studied internationally, most studies have been limited to a few cities or towns. Therefore, we used a nationally representative sample to explore whether perceived and objective neighborhood walkability was associated with the physical activity of residents. Data were analyzed from the Japanese General Social Surveys of 2010 (n = 2395; 1114 men and 1281 women). Perceived walkability was scored using factor analysis for the respondents' perceptions of neighborhood conditions, while objective walkability was measured using the geographic information system approach. Finally, multilevel logistic regression analysis was performed to examine whether neighborhood walkability was associated with the frequency of leisure-time physical activity (LTPA) among respondents. We found that perceived walkability was positively associated with the frequency of LTPA (odds ratio of the highest quartile was 1.53 (1.14-2.05) compared with the lowest quartile); however, objective walkability showed no association. When stratified by gender, an association between perceived walkability and LTPA was observed among women, but only a marginally significant association was present between objective walkability and LTPA among men. We conclude that the association between neighborhood walkability and LTPA can be partially generalized across Japan. PMID- 26512683 TI - Geographic Elevation and Cognitive Function among Elderly Residents in Rural Mountainous Areas: Shimane CoHRE Study. AB - The aim of this study was to test whether there is an association between elevation and cognitive function among elderly residents in rural mountainous areas. Data were collected in 2012 from a cross-sectional study conducted in Ohnan Town, which is located in a rural mountainous area in the southern part of Shimane Prefecture, Japan. Cognitive function was evaluated using CADi (Cognitive Assessment for Dementia, iPad version) and elevation was estimated by using Geographic Information Systems according to the participant's address. After excluding subjects with missing data, 866 participants were analyzed. After adjustment for potential confounding factors, higher elevation was significantly associated with decreased cognitive function. This finding suggests that it is important to consider the physical environment, i.e., elevation, that would affect accessibility to health-promoting goods, services, and resources when seeking to maintain cognitive function in elderly people living in rural mountainous areas. PMID- 26512684 TI - Level and Contamination Assessment of Soil along an Expressway in an Ecologically Valuable Area in Central Poland. AB - Express roads are a potential source of heavy metal contamination in the surrounding environment. The Warsaw Expressway (E30) is one of the busiest roads in the capital of Poland and cuts through the ecologically valuable area (Mazowiecki Natural Landscape Park). Soil samples were collected at distances of 0.5, 4.5 and 25 m from the expressway. The concentrations of cadmium (Cd), copper (Cu), nickel (Ni), lead (Pb), and zinc (Zn) were determined in the soils by the flame atomic absorption spectrometry method (FAAS). Soils located in the direct proximity of the analyzed stretch of road were found to have the highest values of pH and electrical conductivity (EC), which decreased along with an increase in the distance from the expressway. The contents of Cd, Cu and Zn were found to be higher than Polish national averages, whereas the average values of Ni and Pb were not exceeded. The pollution level was estimated based on the geo accumulation index (Igeo), and the pollution index (PI). The results of Igeo and PI indexes revealed the following orders: Cu < Zn < Ni < Cd < Pb and Cu < Ni < Cd < Zn < Pb, and comparison with geochemical background values showed higher concentration of zinc, lead and cadmium. PMID- 26512685 TI - Focusing on the Environment to Improve Youth Participation: Experiences and Perspectives of Occupational Therapists. AB - The environment plays a key role in supporting children's participation and can serve as a focus of intervention. This study aimed to elicit the perceptions and experiences of occupational therapists who had applied the PREP approach- Pathways and Resources for Engagement and Participation. PREP is a novel 12-week intervention for youth with physical disabilities, aimed at improving participation in leisure community-based activities by modifying aspects of the environment. Using a qualitative post-intervention only design, 12 therapists took part in individual semi-structured interviews, in which the therapists reflected on their experience using PREP to enable participation. A thematic analysis was conducted. Four themes emerged from the data; two of which were informative in nature, describing elements of the PREP intervention that target multi-layered composition of the environment and use strategies that involve leveraging resources and problem solving. The two remaining themes were reflective in nature, illustrating a new take on the Occupational Therapy role and re-positioning the concept of participation in therapy practices. Results emphasize aspects of the environment that can serve as effective targets of intervention, guided by the PREP approach. Findings can broaden the scope and focus of occupational therapy practice by redefining views on participation and the environment. PMID- 26512686 TI - Assessment of the Physicochemical Qualities and Prevalence of Escherichia coli and Vibrios in the Final Effluents of Two Wastewater Treatment Plants in South Africa: Ecological and Public Health Implications. AB - The final effluents of two wastewater treatment plants (WWTPs) in the Eastern Cape Province of South Africa were evaluated for their physicochemical and microbiological qualities over a period of 12 months. The physicochemical parameters assessed ranged as follows both plants. The ranges of values for the physicochemical are: pH (3.9-8.6), total dissolved solids (86.50-336.3 mg/L), electrical conductivity (13.57-52.50 mS/m), temperature (13-28 degrees C), nitrate (0-21.73 mg/L), nitrite (0.01-0.60 mg/L), orthophosphate (1.29-20.57 mg/L), turbidity (4.02-43.20 NTU), free chlorine (0.05-7.18 mg/L), dissolve oxygen (3.91-9.60 mg/L), biochemical oxygen demand (0.1-9.0 mg/L) and chemical oxygen demand (4.67-211 mg/L). The microbiological assessment for both WWTPs revealed the presence of E. coli in counts ranging between 0 and 1.86 * 104 CFU/100 mL and Vibrio counts ranging between 0 and 9.93 * 103 CFU/100 mL. We conclude that these WWTPs are important point sources of pollution in surface water with potential public health and ecological risks. PMID- 26512687 TI - The Role of Cytokines and Chemokines in Filovirus Infection. AB - Ebola- and marburgviruses are highly pathogenic filoviruses and causative agents of viral hemorrhagic fever. Filovirus disease is characterized by a dysregulated immune response, severe organ damage, and coagulation abnormalities. This includes modulation of cytokines, signaling mediators that regulate various components of the immune system as well as other biological processes. Here we examine the role of cytokines in filovirus infection, with an emphasis on understanding how these molecules affect development of the antiviral immune response and influence pathology. These proteins may present targets for immune modulation by therapeutic agents and vaccines in an effort to boost the natural immune response to infection and/or reduce immunopathology. PMID- 26512688 TI - Identifying Recent HIV Infections: From Serological Assays to Genomics. AB - In this paper, we review serological and molecular based methods to identify HIV infection recency. The accurate identification of recent HIV infection continues to be an important research area and has implications for HIV prevention and treatment interventions. Longitudinal cohorts that follow HIV negative individuals over time are the current gold standard approach, but they are logistically challenging, time consuming and an expensive enterprise. Methods that utilize cross-sectional testing and biomarker information have become an affordable alternative to the longitudinal approach. These methods use well characterized biological makers to differentiate between recent and established HIV infections. However, recent results have identified a number of limitations in serological based assays that are sensitive to the variability in immune responses modulated by HIV subtypes, viral load and antiretroviral therapy. Molecular methods that explore the dynamics between the timing of infection and viral evolution are now emerging as a promising approach. The combination of serological and molecular methods may provide a good solution to identify recent HIV infection in cross-sectional data. As part of this review, we present the advantages and limitations of serological and molecular based methods and their potential complementary role for the identification of HIV infection recency. PMID- 26512689 TI - Comparative Genomic Analysis of Classical and Variant Virulent Parental/Attenuated Strains of Porcine Epidemic Diarrhea Virus. AB - Since 2010, the variant porcine epidemic diarrhea virus (PEDV) has been the etiological agent responsible for the outbreak of porcine epidemic diarrhea (PED) worldwide. In this study, a variant PEDV strain YN1 was isolated, serially propagated on the Vero cells and was characterized for 200 passages. To better elucidate the molecular basis of Vero cell adaptation of variant PEDV strains, we sequenced, compared, and analyzed the full-genome sequences of parental YN1 and passages 15, 30, 60, 90, 144, and 200. The results showed that the variations increased with the viral passage. The nucleotides sequences of non-structural protein (NSP)2, NSP4-7, NSP10, NSP12 and NSP13 genes did not change during the Vero cell adaptation process. After comparison of the variation characteristic of classical, variant virulent/attenuated strains, it was found that attenuation of PEDV virus was associated with 9-26 amino acid (aa) changes in open reading frames (ORF) 1a/b and S protein, early termination in ORF3, 1-3 aa changes in E, M and N protein and some nucleotide sequences' synonymous mutations. The aa deletion at about 144 aa of S protein could be the attenuation marker for the PEDV. The pig study showed that the early termination in ORF3 was more important for virus cell adaptation than virus attenuation. PMID- 26512690 TI - Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Inhibits RNA-Mediated Gene Silencing by Targeting Ago-2. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) infection strongly modulates the host's immune response. The RNA silencing pathway is an intracellular innate response to viral infections. However, it is unknown whether PRRSV interacts with cellular RNA silencing to facilitate the viral infection. Here, we report for the first time the interaction between PRRSV and RNA silencing in both the porcine macrophages and African green monkey kidney cell line (MARC-145) cell line, which were derived from African green monkey kidney cells and highly permissive for PRRSV infection. Our data demonstrated that PRRSV suppressed RNA silencing induced by short-hairpin (sh) RNA, double-strand (ds) RNA and microRNA (miRNA) and downregulated the expression of argonaute protein-2 (Ago-2), which is a key protein of the RNA silencing pathway in animal cells. Further, exogenous introduction of siRNA and shRNA downregulated Dicer or Ago-2 proteins of the cellular RNA silencing apparatus in MARC-145 cells and porcine macrophages, which, in turn, increased the viral replication and titers. The viral non-structure protein 1alpha (nsp-1alpha) and nsp11 of PRRSV were identified as the suppressors for cellular RNA silencing (RSSs) to downregulate the Ago-2 protein. Our results identify that PRRSV, through its nsp proteins, suppresses the cellular RNA silencing apparatus in favor of viral infection and supports a co-evolutionary process of the virus and the cellular RNA silencing process. PMID- 26512691 TI - No Effect of Added Sugar Consumed at Median American Intake Level on Glucose Tolerance or Insulin Resistance. AB - Excess sugar consumption may promote adverse changes in hepatic and total body insulin resistance. Debate continues over the effects of sugars at more typically consumed levels and whether the identity of the sugar consumed is important. In the present study participants (20-60 years old) were randomly assigned to one of five groups, three that consumed low fat milk with added fructose containing sugars in amounts equivalent to the 50th percentile of fructose consumption (US), one which consumed low-fat milk sweetened with glucose, and one unsweetened low fat milk control group. The intervention lasted ten weeks. In the entire study population there was less than 1 kg increase in weight (73.6 +/-13.0 vs. 74.5 +/- 13.3 kg, p < 0.001), but the change in weight was comparable among groups (p > 0.05). There were no changes in fasting glucose (49 +/- 0.4 vs. 5.0 +/- 0.5 mmol/L), insulin (56.9 +/- 38.9 vs. 61.8 +/- 50.0 pmol/L), or insulin resistance, as measured by the Homeostasis Model Assessment method (1.8 +/- 1.3 vs. 2.0 +/- 1.5, all p > 0.05). These data suggest that added sugar consumed at the median American intake level does not produce changes in measures of insulin sensitivity or glucose tolerance and that no sugar has more deleterious effects than others. PMID- 26512692 TI - Detoxification of Aflatoxin-Contaminated Maize by Neutral Electrolyzed Oxidizing Water. AB - Aflatoxins, a group of extremely toxic mycotoxins produced by Aspergillus flavus, A. parasiticus and A. nomius, can occur as natural contaminants of certain agricultural commodities, particularly maize. These toxins have been shown to be hepatotoxic, carcinogenic, mutagenic and cause severe human and animal diseases. The effectiveness of neutral electrolyzed oxidizing water (NEW) on aflatoxin detoxification was investigated in HepG2 cells using several validation methodologies such as the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide assay, the induction of lipid peroxidation, the oxidative damage by means of glutathione modulation, the Ames test and the alkaline Comet assay. Our results showed that, after the aflatoxin-contaminated maize containing 360 ng/g was soaked in NEW (60 mg/L available chlorine, pH 7.01) during 15 min at room temperature, the aflatoxin content did not decrease as confirmed by the immunoaffinity column and ultra performance liquid chromatography methods. Aflatoxin fluorescence strength of detoxified samples was similar to untreated samples. However, aflatoxin-associated cytotoxicity and OPEN ACCESS Toxins 2015, 7 4295 genotoxicity effects were markedly reduced upon treatment. According to these results, NEW can be effectively used to detoxify aflatoxin-contaminated maize. PMID- 26512693 TI - Menadione-Induced Oxidative Stress Re-Shapes the Oxylipin Profile of Aspergillus flavus and Its Lifestyle. AB - Aspergillus flavus is an efficient producer of mycotoxins, particularly aflatoxin B1, probably the most hepatocarcinogenic naturally-occurring compound. Although the inducing agents of toxin synthesis are not unanimously identified, there is evidence that oxidative stress is one of the main actors in play. In our study, we use menadione, a quinone extensively implemented in studies on ROS response in animal cells, for causing stress to A. flavus. For uncovering the molecular determinants that drive A. flavus in challenging oxidative stress conditions, we have evaluated a wide spectrum of several different parameters, ranging from metabolic (ROS and oxylipin profile) to transcriptional analysis (RNA-seq). There emerges a scenario in which A. flavus activates several metabolic processes under oxidative stress conditions for limiting the ROS-associated detrimental effects, as well as for triggering adaptive and escape strategies. PMID- 26512694 TI - AFM1 in Milk: Physical, Biological, and Prophylactic Methods to Mitigate Contamination. AB - Aflatoxins (AFs) are toxic, carcinogenic, immunosuppressive secondary metabolites produced by some Aspergillus species which colonize crops, including many dietary staple foods and feed components. AFB1 is the prevalent and most toxic among AFs. In the liver, it is biotransformed into AFM1, which is then excreted into the milk of lactating mammals, including dairy animals. AFM1 has been shown to be cause of both acute and chronic toxicoses. The presence of AFM1 in milk and dairy products represents a worldwide concern since even small amounts of this metabolite may be of importance as long-term exposure is concerned. Contamination of milk may be mitigated either directly, decreasing the AFM1 content in contaminated milk, or indirectly, decreasing AFB1 contamination in the feed of dairy animals. Current strategies for AFM1 mitigation include good agricultural practices in pre-harvest and post-harvest management of feed crops (including storage) and physical or chemical decontamination of feed and milk. However, no single strategy offers a complete solution to the issue. PMID- 26512695 TI - Targeting the Hedgehog Pathway in Pediatric Medulloblastoma. AB - Medulloblastoma (MB), a primitive neuroectomal tumor of the cerebellum, is the most common malignant pediatric brain tumor. The cause of MB is largely unknown, but aberrant activation of Hedgehog (Hh) pathway is responsible for ~30% of MB. Despite aggressive treatment with surgical resection, radiation and chemotherapy, 70%-80% of pediatric medulloblastoma cases can be controlled, but most treated patients suffer devastating side effects. Therefore, developing a new effective treatment strategy is urgently needed. Hh signaling controls transcription of target genes by regulating activities of the three Glioma-associated oncogene (Gli1-3) transcription factors. In this review, we will focus on current clinical treatment options of MB and discuss mechanisms of drug resistance. In addition, we will describe current known molecular pathways which crosstalk with the Hedgehog pathway both in the context of medulloblastoma and non-medulloblastoma cancer development. Finally, we will introduce post-translational modifications that modulate Gli1 activity and summarize the positive and negative regulations of the Hh/Gli1 pathway. Towards developing novel combination therapies for medulloblastoma treatment, current information on interacting pathways and direct regulation of Hh signaling should prove critical. PMID- 26512696 TI - Hypermethylation of MAPK13 Promoter in Oesophageal Squamous Cell Carcinoma Is Associated with Loss of p38delta MAPK Expression. AB - The loss of tumour suppressor gene function is a hallmark of malignant transformation and can occur by a variety of genetic and/or epigenetic alterations. We have previously characterised p38delta mitogen-activated protein kinase (MAPK) as a tumour suppressor in oesophageal squamous cell carcinoma (OESCC) and outlined how loss of p38delta MAPK expression promotes increased proliferation and migration, as well as reduced chemosensitivity. Our aim was to investigate the underlying molecular causes of loss of p38delta MAPK expression in OESCC. Sequence analysis of DNA from p38delta MAPK positive and p38delta MAPK negative OESCC cell lines was used to investigate potential loss of function causing mutations. Epigenetic control of p38delta expression in OESCC was examined using methylation-specific PCR and sequencing of bisulfite-converted DNA. We did not identify any mutations in the MAPK13 sequence in OESCC cell lines which lack p38delta MAPK expression. However, we identified a differential pattern of methylation between p38delta MAPK positive and p38delta MAPK negative cell lines. We outline here for the first time differential MAPK13 promoter methylation in OESCC. Our results suggest that epigenetic alterations are responsible, in part, for the suppression of p38delta MAPK expression and promotion of tumourigenesis in OESCC. PMID- 26512697 TI - Roles of TRPM8 Ion Channels in Cancer: Proliferation, Survival, and Invasion. AB - The goal of this article is to provide a critical review of the transient receptor potential melastatin-subfamily member 8 (TRPM8) in cancers, with an emphasis on its roles in cellular proliferation, survival, and invasion. The TRPM8 ion channels regulate Ca2+ homeostasis and function as a cellular sensor and transducer of cold temperature. Accumulating evidence has demonstrated that TRPM8 is aberrantly expressed in a variety of malignant solid tumors. Clinicopathological analysis has shown that over-expression of TRPM8 correlates with tumor progression. Experimental data have revealed important roles of TRPM8 channels in cancer cells proliferation, survival, and invasion, which appear to be dependent on the cancer type. Recent reports have begun to reveal the signaling mechanisms that mediate the biological roles of TRPM8 in tumor growth and metastasis. Determining the mechanistic roles of TRPM8 in cancer is expected to elucidate the impact of thermal and chemical stimuli on the formation and progression of neoplasms. Translational research and clinical investigation of TRPM8 in malignant diseases will help exploit these ion channels as molecular biomarkers and therapeutic targets for developing precision cancer medicine. PMID- 26512698 TI - COBRA-Seq: Sensitive and Quantitative Methylome Profiling. AB - Combined Bisulfite Restriction Analysis (COBRA) quantifies DNA methylation at a specific locus. It does so via digestion of PCR amplicons produced from bisulfite treated DNA, using a restriction enzyme that contains a cytosine within its recognition sequence, such as TaqI. Here, we introduce COBRA-seq, a genome wide reduced methylome method that requires minimal DNA input (0.1-1.0 mg) and can either use PCR or linear amplification to amplify the sequencing library. Variants of COBRA-seq can be used to explore CpG-depleted as well as CpG-rich regions in vertebrate DNA. The choice of enzyme influences enrichment for specific genomic features, such as CpG-rich promoters and CpG islands, or enrichment for less CpG dense regions such as enhancers. COBRA-seq coupled with linear amplification has the additional advantage of reduced PCR bias by producing full length fragments at high abundance. Unlike other reduced representative methylome methods, COBRA-seq has great flexibility in the choice of enzyme and can be multiplexed and tuned, to reduce sequencing costs and to interrogate different numbers of sites. Moreover, COBRA-seq is applicable to non model organisms without the reference genome and compatible with the investigation of non-CpG methylation by using restriction enzymes containing CpA, CpT, and CpC in their recognition site. PMID- 26512699 TI - Reproductive Behavior and Basic Biology of the Oriental Bamboo-Inhabiting Anoplomus rufipes and a Comparison with Frugivorous Dacinae Fruit Flies. AB - The reproductive behaviors and mating systems of the fruit-infesting species of the Dacinae tribes Ceratitidini and Dacini are increasingly well understood, while in the non-frugivorous tribe Gastrozonini, data are lacking. In the present study, the reproductive behavior of Anoplomus rufipes from North Thailand was studied in the field, other behaviors also in the laboratory. A. rufipes mated on young bamboo plants growing in areas destroyed by fire. Exudates of extrafloral nectaries produced by the young bamboo plants provided food for the females. Factors affecting the choice of the mating site were favorable microclimatic conditions and food. Courtship behavior was performed on the upper sides of bamboo leaves and included pheromone calling (abdominal elevation, anal pouch eversion, abdominal pleural distention), anal dabbing, looping flights and a specific lofting/body swaying behavior. The males searched individually for females or formed leks containing up to four males. The reproductive behaviors and lek formation of A. rufipes are compared to other Dacinae (Ceratitis, Bactrocera), and their functions are discussed. Hitherto unknown data on the general biology of A. rufipes are also included. A. rufipes larvae infested living bamboo shoots of Cephalostachyum pergracile, and the observed behaviors of the adults included locomotion, grooming, feeding, oral droplet deposition, bubbling and agonistic behavior. PMID- 26512700 TI - Differential Contributions of the Complement Anaphylotoxin Receptors C5aR1 and C5aR2 to the Early Innate Immune Response against Staphylococcus aureus Infection. AB - The complement anaphylatoxin C5a contributes to host defense against Staphylococcus aureus. In this study, we investigated the functional role of the two known C5a receptors, C5aR1 and C5aR2, in the host response to S. aureus. We found that C5aR1(-/)(-) mice exhibited greater susceptibility to S. aureus bloodstream infection than wild type and C5aR2(-/)(-) mice, as demonstrated by the significantly higher bacterial loads in the kidneys and heart at 24 h of infection, and by the higher levels of inflammatory IL-6 in serum. Histological and immunohistochemistry investigation of infected kidneys at 24 h after bacterial inoculation revealed a discrete infiltration of neutrophils in wild type mice but already well-developed abscesses consisting of bacterial clusters surrounded by a large number of neutrophils in both C5aR1(-/)(-) and C5aR2(-/)(-) mice. Furthermore, blood neutrophils from C5aR1(-/)(-) mice were less efficient than those from wild type or C5aR2(-/)(-) mice at killing S. aureus. The requirement of C5aR1 for efficient killing of S. aureus was also demonstrated in human blood after disrupting C5a-C5aR1 signaling using specific inhibitors. These results demonstrated a role for C5aR1 in S. aureus clearance as well as a role for both C5aR1 and C5aR2 in the orchestration of the inflammatory response during infection. PMID- 26512701 TI - High Temperature Stable Separator for Lithium Batteries Based on SiO2 and Hydroxypropyl Guar Gum. AB - A novel membrane based on silicon dioxide (SiO2) and hydroxypropyl guar gum (HPG) as binder is presented and tested as a separator for lithium-ion batteries. The separator is made with renewable and low cost materials and an environmentally friendly manufacturing processing using only water as solvent. The separator offers superior wettability and high electrolyte uptake due to the optimized porosity and the good affinity of SiO2 and guar gum microstructure towards organic liquid electrolytes. Additionally, the separator shows high thermal stability and no dimensional-shrinkage at high temperatures due to the use of the ceramic filler and the thermally stable natural polymer. The electrochemical tests show the good electrochemical stability of the separator in a wide range of potential, as well as its outstanding cycle performance. PMID- 26512702 TI - Membrane and Protein Interactions of the Pleckstrin Homology Domain Superfamily. AB - The human genome encodes about 285 proteins that contain at least one annotated pleckstrin homology (PH) domain. As the first phosphoinositide binding module domain to be discovered, the PH domain recruits diverse protein architectures to cellular membranes. PH domains constitute one of the largest protein superfamilies, and have diverged to regulate many different signaling proteins and modules such as Dbl homology (DH) and Tec homology (TH) domains. The ligands of approximately 70 PH domains have been validated by binding assays and complexed structures, allowing meaningful extrapolation across the entire superfamily. Here the Membrane Optimal Docking Area (MODA) program is used at a genome-wide level to identify all membrane docking PH structures and map their lipid-binding determinants. In addition to the linear sequence motifs which are employed for phosphoinositide recognition, the three dimensional structural features that allow peripheral membrane domains to approach and insert into the bilayer are pinpointed and can be predicted ab initio. The analysis shows that conserved structural surfaces distinguish which PH domains associate with membrane from those that do not. Moreover, the results indicate that lipid binding PH domains can be classified into different functional subgroups based on the type of membrane insertion elements they project towards the bilayer. PMID- 26512703 TI - Nephroprotection by Hypoglycemic Agents: Do We Have Supporting Data? AB - Current therapy directed at delaying the progression of diabetic nephropathy includes intensive glycemic and optimal blood pressure control, renin angiotensin aldosterone system blockade and multifactorial intervention. However, the renal protection provided by these therapeutic modalities is incomplete. There is a scarcity of studies analysing the nephroprotective effect of antihyperglycaemic drugs beyond their glucose lowering effect and improved glycaemic control on the prevention and progression of diabetic nephropathy. This article analyzes the exisiting data about older and newer drugs as well as the mechanisms associated with hypoglycemic drugs, apart from their well known blood glucose lowering effect, in the prevention and progression of diabetic nephropathy. Most of them have been tested in humans, but with varying degrees of success. Although experimental data about most of antihyperglycemic drugs has shown a beneficial effect in kidney parameters, there is a lack of clinical trials that clearly prove these beneficial effects. The key question, however, is whether antihyperglycemic drugs are able to improve renal end-points beyond their antihyperglycemic effect. Existing experimental data are post hoc studies from clinical trials, and supportive of the potential renal-protective role of some of them, especially in the cases of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. Dedicated and adequately powered renal trials with renal outcomes are neccessary to assess the nephrotection of antihyperglycaemic drugs beyond the control of hyperglycaemia. PMID- 26512704 TI - Circulating microRNA Biomarkers as Liquid Biopsy for Cancer Patients: Pros and Cons of Current Assays. AB - An increasing number of studies have focused on circulating microRNAs (cmiRNA) in cancer patients' blood for their potential as minimally-invasive biomarkers. Studies have reported the utility of assessing specific miRNAs in blood as diagnostic/prognostic biomarkers; however, the methodologies are not validated or standardized across laboratories. Unfortunately, there is often minimum limited overlap in techniques between results reported even in similar type studies on the same cancer. This hampers interpretation and reliability of cmiRNA as potential cancer biomarkers. Blood collection and processing, cmiRNA extractions, quality and quantity control of assays, defined patient population assessment, reproducibility, and reference standards all affect the cmiRNA assay results. To date, there is no reported definitive method to assess cmiRNAs. Therefore, appropriate and reliable methodologies are highly necessary in order for cmiRNAs to be used in regulated clinical diagnostic laboratories. In this review, we summarize the developments made over the past decade towards cmiRNA detection and discuss the pros and cons of the assays. PMID- 26512705 TI - Functional Analysis of Cotton Leaf Curl Kokhran Virus/Cotton Leaf Curl Multan Betasatellite RNA Silencing Suppressors. AB - In South Asia, Cotton leaf curl disease (CLCuD) is caused by a complex of phylogenetically-related begomovirus species and a specific betasatellite, Cotton leaf curl Multan betasatellite (CLCuMuB). The post-transcriptional gene silencing (PTGS) suppression activities of the transcriptional activator protein (TrAP), C4, V2 and betaC1 proteins encoded by Cotton leaf curl Kokhran virus (CLCuKoV)/CLCuMuB were assessed in Nicotiana benthamiana. A variable degree of local silencing suppression was observed for each viral protein tested, with V2 protein exhibiting the strongest suppression activity and only the C4 protein preventing the spread of systemic silencing. The CLCuKoV-encoded TrAP, C4, V2 and CLCuMuB-encoded betaC1 proteins were expressed in Escherichia coli and purified. TrAP was shown to bind various small and long nucleic acids including single stranded (ss) and double-stranded (ds) RNA and DNA molecules. C4, V2, and betaC1 bound ssDNA and dsDNA with varying affinities. Transgenic expression of C4 under the constitutive 35S Cauliflower mosaic virus promoter and betaC1 under a dexamethasone inducible promoter induced severe developmental abnormalities in N. benthamiana. The results indicate that homologous proteins from even quite closely related begomoviruses may differ in their suppressor activity and mechanism of action. The significance of these findings is discussed. PMID- 26512706 TI - Novel Implications of DNA Damage Response in Drug Resistance of Malignant Cancers Obtained from the Functional Interaction between p53 Family and RUNX2. AB - During the lifespan of cells, their genomic DNA is continuously exposed to theendogenous and exogenous DNA insults. Thus, the appropriate cellular response to DNAdamage plays a pivotal role in maintaining genomic integrity and also acts as a molecularbarrier towards DNA legion-mediated carcinogenesis. The tumor suppressor p53 participatesin an integral part of proper regulation of DNA damage response (DDR). p53 is frequentlymutated in a variety of human cancers. Since mutant p53 displays a dominant-negative behavioragainst wild-type p53, cancers expressing mutant p53 sometimes acquire drug-resistantphenotype, suggesting that mutant p53 prohibits the p53-dependent cell death pathwayfollowing DNA damage, and thereby contributing to the acquisition and/or maintenance ofdrug resistance of malignant cancers. Intriguingly, we have recently found that silencing ofpro oncogenic RUNX2 enhances drug sensitivity of aggressive cancer cells regardless of p53status. Meanwhile, cancer stem cells (CSCs) have stem cell properties such as drug resistance.Therefore, the precise understanding of the biology of CSCs is quite important to overcometheir drug resistance. In this review, we focus on molecular mechanisms behind DDR as wellas the serious drug resistance of malignant cancers and discuss some attractive approachesto improving the outcomes of patients bearing drug-resistant cancers. PMID- 26512707 TI - ATM-Dependent Phosphorylation of All Three Members of the MRN Complex: From Sensor to Adaptor. AB - The recognition, signalling and repair of DNA double strand breaks (DSB) involves the participation of a multitude of proteins and post-translational events that ensure maintenance of genome integrity. Amongst the proteins involved are several which when mutated give rise to genetic disorders characterised by chromosomal abnormalities, cancer predisposition, neurodegeneration and other pathologies. ATM (mutated in ataxia-telangiectasia (A-T) and members of the Mre11/Rad50/Nbs1 (MRN complex) play key roles in this process. The MRN complex rapidly recognises and locates to DNA DSB where it acts to recruit and assist in ATM activation. ATM, in the company of several other DNA damage response proteins, in turn phosphorylates all three members of the MRN complex to initiate downstream signalling. While ATM has hundreds of substrates, members of the MRN complex play a pivotal role in mediating the downstream signalling events that give rise to cell cycle control, DNA repair and ultimately cell survival or apoptosis. Here we focus on the interplay between ATM and the MRN complex in initiating signaling of breaks and more specifically on the adaptor role of the MRN complex in mediating ATM signalling to downstream substrates to control different cellular processes. PMID- 26512708 TI - Competing Interactions of RNA-Binding Proteins, MicroRNAs, and Their Targets Control Neuronal Development and Function. AB - Post-transcriptional mechanisms play critical roles in the control of gene expression during neuronal development and maturation as they allow for faster responses to environmental cues and provide spatially-restricted compartments for local control of protein expression. These mechanisms depend on the interaction of cis-acting elements present in the mRNA sequence and trans-acting factors, such as RNA-binding proteins (RBPs) and microRNAs (miRNAs) that bind to those cis elements and regulate mRNA stability, subcellular localization, and translation. Recent studies have uncovered an unexpected complexity in these interactions, where coding and non-coding RNAs, termed competing endogenous RNAs (ceRNAs), compete for binding to miRNAs. This competition can, thereby, control a larger number of miRNA target transcripts. However, competing RNA networks also extend to competition between target mRNAs for binding to limited amounts of RBPs. In this review, we present evidence that competitions between target mRNAs for binding to RBPs also occur in neurons, where they affect transcript stability and transport into axons and dendrites as well as translation. In addition, we illustrate the complexity of these mechanisms by demonstrating that RBPs and miRNAs also compete for target binding and regulation. PMID- 26512709 TI - Engineering and Characterization of a Fluorescent Native-Like HIV-1 Envelope Glycoprotein Trimer. AB - Generation of a stable, soluble mimic of the HIV-1 envelope glycoprotein (Env) trimer on the virion surface has been considered an important first step for developing a successful HIV-1 vaccine. Recently, a soluble native-like Env trimer (BG505 SOSIP.664) has been described. This protein has facilitated major advances in the HIV-1 vaccine field, since it was the first Env immunogen that induced consistent neutralizing antibodies against a neutralization-resistant (tier 2) virus. Moreover, BG505 SOSIP.664 enabled elucidation of the atomic resolution structure of the Env trimer and facilitated the isolation and characterization of new broadly neutralizing antibodies against HIV-1. Here, we designed and characterized the BG505 SOSIP.664 trimer fused to fluorescent superfolder GFP (sfGFP), a GFP variant that allows efficient folding (BG505 SOSIP.664-sfGFP). Despite the presence of the sfGFP, the Env protein largely retained its morphology, antigenicity, glycan composition, and thermostability. In addition, we show that BG505 SOSIP.664-sfGFP can be used for fluorescence-based assays, such as flow cytometry. PMID- 26512710 TI - Epidemiology of children with acquired immune deficiency syndrome (stage 3): A referral hospital-based study in Iran. AB - Lack of recognition of human immunodeficiency virus (HIV) infection especially in children and delayed implementation of effective control programs makes HIV infection as a major cause for concern. Information on HIV epidemiology in Iran as well as other Islamic countries is limited. The aim of our study was to describe the clinical manifestation and laboratory finding of HIV infected children who were admitted to a referral Children Medical Center (CMC) in Tehran, Iran, during 11 years from January 2002 to January 2013. This was a retrospective study carried out over a period of 11 years. The records of all patients attending to the CMC with confirmed acquired immunodeficiency syndrome (AIDS) were screened. The patients were evaluated for social circumstance, family history, age, gender, clinical, and laboratory features. Clinical data including fever, respiratory distress, diarrhea, rash, etc. as well as laboratory tests including complete blood count, serum glucose level, electrolytes, liver function test, cultures, CD4 lymphocyte count were evaluated. During the study period, 32 HIV positive children were enrolled. The majority of patients were presented with weight loss, prolonged fever, respiratory infection and chronic diarrhea. In this study, salmonella infections as well as streptococcal pneumonia and candida infections followed by, tuberculosis and Pseudomonas aeruginosa infections were the predominant opportunistic infections. Since the number of HIV-positive children has been alarmingly increasing in recent years and perinatal transmission is the most common route of HIV infection in children, essential recommendations for prenatal HIV testing as well as appropriate antiretroviral therapy by HIV infected mothers are needed. PMID- 26512711 TI - Human coronaviruses in severe acute respiratory infection (SARI) cases in southwest India. AB - Acute viral respiratory infections (AVRI) are a leading cause of morbidity and mortality among all age groups globally. Except for Influenza virus and Respiratory Syncytial virus, mostly viral aetiology of AVRI remains undiagnosed. Lately, human coronaviruses (HCoVs) have emerged as an important aetiology of AVRI. A laboratory based retrospective cross sectional study was conducted in which respiratory samples (throat swabs) of patients (n = 864), with Influenza negative SARI, of all age groups between Jan 2011-Dec 2012 were tested for HCoVs including MERS-CoV using Conventional and real time PCR assays. The prevalence of HCoV among SARI cases was 1.04% (9/864) [95% CI: 0.36-1.72]. Of these four (44.44%) were identified as HCoV OC43, three (33.33%) as HCoV NL63 and two (22.22%) as HCoV 229E. No HCoV HKU1 was detected. The samples were also negative for SARS-CoV and MERS-CoV. The results of this study documents low prevalence of human coronaviruses in SARI cases in south western India and the absence of highly pathogenic human coronaviruses. As the study included only SARI cases the prevalence reported could be an under estimate when it is extrapolated to community. PMID- 26512712 TI - Group trajectory analysis helps to identify older cancer survivors who benefit from distance-based lifestyle interventions. AB - BACKGROUND: The number of older cancer survivors is increasing as more adults survive to older ages. The objectives of this study were to examine trajectories of physical activity (PA) and physical function (PF) over a 2-year lifestyle counseling study and to identify characteristics of the trajectory groups. METHODS: This was a secondary analysis of Reach Out to Enhance Wellness, a randomized controlled trial of home-based lifestyle counseling. The 641 participants were older (>=65 years), overweight (body mass index [BMI], 25 to <40 kg/m(2)), long-term community-dwelling survivors (>5 years) of breast, prostate, and colorectal cancer from Canada, the United Kingdom, and the United States (21 states) who had been randomly assigned to an immediate intervention or a 12-month-wait-listed control arm. The main outcome measures were PA and PF trajectory group membership. RESULTS: Three PA groups and 5 PF trajectory groups were observed. The baseline BMI (P < .001) and self-efficacy for performing strength (P < .0001) and endurance exercises (P < .0002) were the strongest predictors of achieving the highest amount of PA and the most favorable functional trajectory over 2 years. Individuals with low baseline self-efficacy, no PA, and a Short Form 36 PF subscale score < 65 did not benefit from the intervention. CONCLUSIONS: This study identified characteristics of survivors who benefited from home-based interventions and suggested alternative approaches for survivors requiring more structured and intensive interventions to promote behavioral changes. PMID- 26512713 TI - Safety of Intraperitoneal Injection of Adipose Tissue-Derived Autologous Mesenchymal Stem Cells in Cats. AB - BACKGROUND: Chronic inflammatory diseases are common in cats and mesenchymal stem cells (MSC) are a promising therapeutic approach for management of these disorders. The purpose of this study was to evaluate the safety of intraperitoneal injection of MSC in cats. HYPOTHESIS: Intrapertioneal injection of autologous MSC in cats is safe. ANIMALS: Ten healthy adult purpose-bred cats. METHODS: Mesenchymal stem cells were isolated from subcutaneous adipose tissue collected during ovariohysterectomy and characterized for expression of CD90, CD105 and CD44 and trilineage differentiation. Three weeks postoperatively a complete blood count, serum chemistry profile, urinalysis, and abdominal ultrasound were performed. Five cats then received 1 * 10(6) of autologous MSC/kg of body weight intraperitoneally with ultrasound guidance; 5 additional cats were sham injected. Cats were monitored for 6 weeks with daily physical examinations and weekly clinicopathological evaluations. Abdominal ultrasonography was repeated at weeks 1 and 5 after injection. RESULTS: Serious adverse effects were not observed in any MSC-injected cat. Two animals developed transient lethargy and decreased activity. Jejunal lymph node size was increased in MSC-injected cats compared to controls at weeks 1 (1.38 +/- 0.25 versus 0.88 +/- 0.25 cm(2); P = .036) and 5 (1.75 +/- 0.82 versus 0.79 +/- 0.12 cm(2); P = .047). A hyperechoic renal segmental cortical lesion was observed in 1 MSC-injected cat. CONCLUSIONS AND CLINICAL RELEVANCE: Intraperitoneal MSC injection was well tolerated with only mild, self-limiting adverse effects being observed in 2 cats. This route provides a safe means of administration for cell-based treatment in cats. PMID- 26512714 TI - Bronchogenic cyst in the omental bursa: A case report. PMID- 26512715 TI - GipA Factor Supports Colonization of Peyer's Patches by Crohn's Disease associated Escherichia Coli. AB - BACKGROUND: Adherent-invasive Escherichia coli (AIEC) associated with Crohn's disease target M cells lining Peyer's patches (PPs) through the expression of long polar fimbriae (LPF) and survive macrophage killing. Invasion of PPs constitutes a way to colonize the mucosa for bacteria able to escape or resist killing of underlying immune cells. We aimed to identify new virulence factors involved in PPs colonization by AIEC. METHODS: The presence of gipA (Growth in PPs) gene was determined by polymerase chain reaction. In vivo experiments were performed using CEABAC10 transgenic mice. Intramacrophagic behavior of AIEC was assessed in murine bone marrow-derived macrophages and human monocyte-derived macrophages. Cytokines production was quantified by ELISA. RESULTS: A higher prevalence of gipA-positive E. coli was observed in patients with Crohn's disease (27.3%) compared with controls (17.2%). Unlike non-AIEC strains, all gipA positive AIEC strains also harbored lpfA. GipA deletion impaired AIEC translocation across M cells and their replication inside macrophages. GipA expression was induced by gastrointestinal (bile salts) and phagolysosomal (reactive oxygen species and acid pH) conditions. GipA deletion decreased lpfA mRNA level in AIEC bacteria. Survival of AIEC-DeltagipA bacteria was reduced in medium containing H2O2 or acidic pH. GipA deletion impaired AIEC colonization of PPs and dissemination to mesenteric lymph nodes in mice. CONCLUSIONS: GipA is required for optimal colonization of mouse PPs and survival within macrophages by AIEC, suggesting that this factor plays a role in AIEC promotion of Crohn's disease. Detection of gipA and lpfA could be a predictor for the presence of AIEC. PMID- 26512716 TI - From Genes to Mechanisms: The Expanding Spectrum of Monogenic Disorders Associated with Inflammatory Bowel Disease. AB - Inborn errors of the intestinal epithelial barrier function as well as the innate and adaptive mucosal immune responses toward the intestinal microbiota are a group of genetic disorders that confer susceptibility to monogenic and syndromal forms of inflammatory bowel disease (IBD). There is a continuous spectrum of genetic susceptibility from monogenic causative variants with complete Mendelian inheritance, over NOD2 variants with moderate penetrance to minute penetrance in most common susceptibility variants predisposing to conventional polygenic IBD. We discuss advances to understand monogenic IBD and review recently identified genetic defects. We describe an integrative model for genetic susceptibility variants of conventional IBD and monogenic IBD-like intestinal inflammation in the context of microbial commensal colonization and infection susceptibility. PMID- 26512717 TI - Unhealthy Behaviours: An International Comparison. AB - In the current global economy, chronic non-communicable diseases (NCDs) have become the leading cause of death and a major health concern for both developed and developing countries. Among other factors, the worldwide spread of NCDs is driven by the globalisation of unhealthy habits. The purpose of this paper is to develop a simple statistic to measure, at the national level, the average population's exposure to the main NCDs modifiable risk factors. The approach and methodology followed by the United Nations Development Programme to compute the Human Development Index (HDI) is applied to four basic indicators of NCD-related preventable risk factors (alcohol consumption, excess caloric intake, non balanced diet and tobacco use) in 112 countries worldwide in 2012-14. We obtain a summary composite index, which we call the Unhealthy Behaviour Index (UBI), which ranks countries by the average level of the unhealthy habits (drinking, eating and smoking) of their populations. We find that Belarus and Russian federation are the two countries with the unhealthiest NCD-related lifestyle. With the exception of Canada, the first twenty populations more exposed to the main NCDs preventable risk factors all live in European countries, and mainly in countries of Eastern Europe. Overall, the UBI tends to increase along with the level of human development. In medium, high and very high HDI countries, however, the same level of human development may be associated with very different kinds of NCD related lifestyles. Finally, economic growth may push populations toward either more unhealthy or healthy habits, depending on the countries' level of development; the elasticity of unhealthy habits with respect to income per capita is positive (but less than one: on average 0.6) until $30,000, decreases as income rises, and becomes negative (around -0.3) in very high income countries. PMID- 26512718 TI - Role of MiR-3619-5p in beta-Catenin-Mediated Non-Small Cell Lung Cancer Growth and Invasion. AB - BACKGROUND/AIMS: The malignancy of non-small cell lung cancer (NSCLC) is largely due to its fast growth and invasion. WNT/beta-catenin signaling plays a critical role in regulating NSCLC carcinogenesis. Hence, suppression of beta-catenin signal transduction in NSCLC cells may improve the therapeutic outcome. METHODS: We analyzed the levels of beta-catenin and miR-3619-5p in NSCLC specimens, compared to paired non-tumor normal lung tissue (NT). We did Bioinformatics analyses on the binding sites of 3'-UTR of beta-catenin mRNA by miR-3619-5p. We modified the levels of miR-3619-5p in NSCLC cells and examined their effects on beta-catenin levels, and on the growth and invasion of NSCLC cells in an MTT assay and a transwell cell migration assay, respectively. RESULTS: NSCLC specimens had significant higher levels of beta-catenin, and significantly lower levels of miR-3619-5p, compared to NT. The levels of beta-catenin and miR-3619-5p were inversely correlated in NSCLC specimens. Bioinformatics analyses showed that miR-3619-5p bound to 3'-UTR of beta-catenin mRNA in NSCLC cells to inhibit its translation. Overexpression of miR-3619-5p decreased beta-catenin protein, while depletion of miR-3619-5p increased beta-catenin protein in NSCLC cells, without altering beta-catenin mRNA levels. Overexpression of miR-3619-5p in NSCLC cells inhibited cell growth and invasion, while depletion of miR-3619-5p in NSCLC lines increased cell growth and invasion. CONCLUSION: Our data demonstrate a previously unappreciated role for miR-3619-5p in suppression of beta-catenin-mediated cancer growth and invasion in NSCLC cells, and highlight miR-3619-5p as a novel cancer suppressor in NSCLC. PMID- 26512719 TI - Strong Local Scientific Communities Are Essential to Reach the Millennium Development Goals. PMID- 26512720 TI - New Isoform of Cardiac Myosin Light Chain Kinase and the Role of Cardiac Myosin Phosphorylation in alpha1-Adrenoceptor Mediated Inotropic Response. AB - BACKGROUND & AIMS: Cardiac myosin light chain kinase (cMLCK) plays an obligatory role in maintaining the phosphorylation levels of regulatory myosin light chain (MLC2), which is thought to be crucial for regulation of cardiac function. To test this hypothesis, the role played by ventricular MLC2 (MLC2v) phosphorylation was investigated in the phenylephrine-induced increase in twitch tension using the naturally-occurring mouse strain, C57BL/6N, in which cMLCK is down regulated. METHODS AND RESULTS: By Western blot and nanoLC-MS/MS analysis, cMLCKs with molecular mass of 61-kDa (cMLCK-2) and/or 86-kDa were identified in mice heart. Among various mouse strains, C57BL/6N expressed cMLCK-2 alone and the closest relative strain C57BL/6J expressed both cMLCKs. The levels of MLC2v phosphorylation was significantly lower in C57BL/6N than in C57BL/6J. The papillary muscle twitch tension induced by electrical field stimulation was smaller in C57BL/6N than C57BL/6J. Phenylephrine had no effect on MLC2v phosphorylation in either strains but increased the twitch tension more potently in C57BL/6J than in C57BL/6N. Calyculin A increased papillary muscle MLC2v phosphorylation to a similar extent in both strains but increased the phenylephrine-induced inotropic response only in C57BL/6N. There was a significant positive correlation between the phenylephrine-induced inotropic response and the levels of MLC2v phosphorylation within ranges of 15-30%. CONCLUSIONS: We identified a new isoform of cMLCK with a molecular mass of 61kDa(cMLCK-2) in mouse heart. In the C57BL/6N strain, only cMLCK-2 was expressed and the basal MLC2v phosphorylation levels and the phenylephrine-induced inotropic response were both smaller. We suggest that a lower phenylephrine induced inotropic response may be caused by the lower basal MLC2v phosphorylation levels in this strain. PMID- 26512721 TI - Correction: Resistance to Nucleotide Excision Repair of Bulky Guanine Adducts Opposite Abasic Sites in DNA Duplexes and Relationships between Structure and Function. PMID- 26512722 TI - The Mycoplasma hyorhinis p37 Protein Rapidly Induces Genes in Fibroblasts Associated with Inflammation and Cancer. AB - The p37 protein at the surface of Mycoplasma hyorhinis cells forms part of a high affinity transport system and has been found associated with animal and human cancers. Here we show in NIH3T3 fibroblasts, p37 rapidly induces the expression of genes implicated in inflammation and cancer progression. This gene activation was principally via the Tlr4 receptor. Activity was lost from p37 when the C terminal 20 amino acids were removed or the four amino acids specific for the hydrogen bonding of thiamine pyrophosphate had been replaced by valine. Blocking the IL6 receptor or inhibiting STAT3 signalling resulted in increased p37-induced gene expression. Since cancer associated fibroblasts support growth, invasion and metastasis via their ability to regulate tumour-related inflammation, the rapid induction in fibroblasts of pro-inflammatory genes by p37 might be expected to influence cancer development. PMID- 26512723 TI - An Anti-Influenza Virus Antibody Inhibits Viral Infection by Reducing Nucleus Entry of Influenza Nucleoprotein. AB - To date, four main mechanisms mediating inhibition of influenza infection by anti hemagglutinin antibodies have been reported. Anti-globular-head-domain antibodies block either influenza virus receptor binding to the host cell or progeny virion release from the host cell. Anti-stem region antibodies hinder the membrane fusion process or induce antibody-dependent cytotoxicity to infected cells. In this study we identified a human monoclonal IgG1 antibody (CT302), which does not inhibit both the receptor binding and the membrane fusion process but efficiently reduced the nucleus entry of viral nucleoprotein suggesting a novel inhibition mechanism of viral infection by antibody. This antibody binds to the subtype-H3 hemagglutinin globular head domain of group-2 influenza viruses circulating throughout the population between 1997 and 2007. PMID- 26512724 TI - The Safety and Pharmacokinetics of Carprofen, Flunixin and Phenylbutazone in the Cape Vulture (Gyps coprotheres) following Oral Exposure. AB - The following study evaluates the overt toxic potential of carprofen (CRP), flunixin (FXN) and phenylbutazone (PBZ) in Old world vultures in relation to historic toxicity data for diclofenac and ketoprofen, with the Cape vulture (Gyps coprotheres) being the indicator species. The toxic potential of a single oral dose of CRP (11.5 mg/kg), FXN (1 mg/kg),PBZ (1.7 mg/kg) or water was evaluated by means of a four-way parallel study (n = 2), as means of ascertaining if these drugs were as toxic as diclofenac in the vulture. No unscheduled deaths or pathological lesions were noted following exposure. Clinical signs of lethargy and depression were, however, noted in one CRP, two FXN and one PBZ treated birds. Mild reversible inhibition of UA excretion was evident in all three groups, although UA remained within the population reference interval in contrast to the effects previously described for diclofenac and ketoprofen. All treatment groups had a drug concentration responsive increase in alanine transferase activity. CRP, FXN and PBZ were characterised by a maximum plasma concentration (Cmax) of 1051.8 +/- 620.7 ng/ml, 335.9 +/- 36.3 ng/ml and 11150 +/- 2474.9 ng/ml at 4 +/- 4.3, 0.45 +/- 0.02 and 5.3 +/- 5.2 hours (Tmax) respectively and a half life of elimination of 13.3 +/-5, 1.8+/-1 and 18.7 +/-11.4 hours respectively. While we could not demonstrate a lethal effect of the tested substances, the presence of toxic clinical signs, clinical pathological changes and/or long half lives of elimination suggests that all three drugs have a potential for toxicity in a larger population or on repeat administration. In conclusion while the studied substances were not as overtly toxic as diclofenac, they are of safety concern. PMID- 26512725 TI - Prediction of Acute Radiation Mucositis using an Oral Mucosal Dose Surface Model in Carbon Ion Radiotherapy for Head and Neck Tumors. AB - PURPOSE: To evaluate the dose-response relationship for development of acute radiation mucositis (ARM) using an oral mucosal dose surface model (OMDS-model) in carbon ion radiotherapy (C-ion RT) for head and neck tumors. METHODS: Thirty nine patients receiving C-ion RT for head and neck cancer were evaluated for ARM (once per week for 6 weeks) according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and the Radiation Therapy Oncology Group (RTOG) scoring systems. The irradiation schedule typically used was 64 Gy [relative biological effectiveness (RBE)] in 16 fractions for 4 weeks. Maximum point doses in the palate and tongue were compared with ARM in each patient. RESULTS: The location of the ARM coincided with the high-dose area in the OMDS model. There was a clear dose-response relationship between maximum point dose and ARM grade assessed using the RTOG criteria but not the CTCAE. The threshold doses for grade 2-3 ARM in the palate and tongue were 43.0 Gy(RBE) and 54.3 Gy(RBE), respectively. CONCLUSIONS: The OMDS-model was useful for predicting the location and severity of ARM. Maximum point doses in the model correlated well with grade 2-3 ARM. PMID- 26512726 TI - Relational Memory Is Evident in Eye Movement Behavior despite the Use of Subliminal Testing Methods. AB - While it is generally agreed that perception can occur without awareness, there continues to be debate about the type of representational content that is accessible when awareness is minimized or eliminated. Most investigations that have addressed this issue evaluate access to well-learned representations. Far fewer studies have evaluated whether or not associations encountered just once prior to testing might also be accessed and influence behavior. Here, eye movements were used to examine whether or not memory for studied relationships is evident following the presentation of subliminal cues. Participants assigned to experimental or control groups studied scene-face pairs and test trials evaluated implicit and explicit memory for these pairs. Each test trial began with a subliminal scene cue, followed by three visible studied faces. For experimental group participants, one face was the studied associate of the scene (implicit test); for controls none were a match. Subsequently, the display containing a match was presented to both groups, but now it was preceded by a visible scene cue (explicit test). Eye movements were recorded and recognition memory responses were made. Participants in the experimental group looked disproportionately at matching faces on implicit test trials and participants from both groups looked disproportionately at matching faces on explicit test trials, even when that face had not been successfully identified as the associate. Critically, implicit memory-based viewing effects seemed not to depend on residual awareness of subliminal scene cues, as subjective and objective measures indicated that scenes were successfully masked from view. The reported outcomes indicate that memory for studied relationships can be expressed in eye movement behavior without awareness. PMID- 26512727 TI - Use of Modern Family Planning Methods in Fishing Communities of Lake Victoria, Uganda. AB - INTRODUCTION: Fishing communities (FCs) in Uganda have high HIV infection rates but poor access to health services including family planning (FP). Although FP is a cost-effective public health intervention, there is a paucity of data on knowledge and use of modern FP in FCs. This study determined knowledge and use of modern FP methods in FCs of Uganda. METHODS: Data were accrued from a 12-month follow up of 1,688 HIV-uninfected individuals, 18-49 years from 8 FCs along Lake Victoria, between September 2011 and March 2013. Data on knowledge and use of modern FP were collected through a semi-structured questionnaire. Prevalence Risk Ratios with corresponding 95% CIs were used to determine factors associated with Modern FP knowledge and use. RESULTS: The mean age was 31.4 years, with nearly half (48.8%) being females while more than half (58.6%) had attained up to primary education level. Knowledge of modern FP was high, 87.5% (1477/1688); significantly higher among females [adj. PRR = 4.84 (95% CI; 3.08, 7.61)], among older respondents (25-29 years) [adj. PRR = 1.83 (95% CI; 1.12, 2.99)] compared to younger ones (18-24 years) and among those conducting business [adj. PRR = 2.42(95% CI; 1.02, 5.74)] relative to those primarily in fishing. Just over a third (35.2%, 595/1688) reported use of at least one modern FP method. Use of modern FP methods was significantly higher among females [adj. PRR = 2.04 (95% CI; 1.56, 2.65, and among those reporting multiple sexual partnerships [adj. PRR = 2.12, 95% CI; 1.63, 2.76)]. Nonuse of modern methods was mostly due to desire for more children (30.6%), fear of side effects (12.2%) and partner refusal (5.2%). CONCLUSION: Despite their high knowledge of FP, FCs have low use of modern FP methods. Key barriers to use of modern FP methods were high fertility desires, fear of perceived side effects and partner refusal of methods. PMID- 26512728 TI - Conservation of sigma28-Dependent Non-Coding RNA Paralogs and Predicted sigma54 Dependent Targets in Thermophilic Campylobacter Species. AB - Assembly of flagella requires strict hierarchical and temporal control via flagellar sigma and anti-sigma factors, regulatory proteins and the assembly complex itself, but to date non-coding RNAs (ncRNAs) have not been described to regulate genes directly involved in flagellar assembly. In this study we have investigated the possible role of two ncRNA paralogs (CjNC1, CjNC4) in flagellar assembly and gene regulation of the diarrhoeal pathogen Campylobacter jejuni. CjNC1 and CjNC4 are 37/44 nt identical and predicted to target the 5' untranslated region (5' UTR) of genes transcribed from the flagellar sigma factor sigma54. Orthologs of the sigma54-dependent 5' UTRs and ncRNAs are present in the genomes of other thermophilic Campylobacter species, and transcription of CjNC1 and CNC4 is dependent on the flagellar sigma factor sigma28. Surprisingly, inactivation and overexpression of CjNC1 and CjNC4 did not affect growth, motility or flagella-associated phenotypes such as autoagglutination. However, CjNC1 and CjNC4 were able to mediate sequence-dependent, but Hfq-independent, partial repression of fluorescence of predicted target 5' UTRs in an Escherichia coli-based GFP reporter gene system. This hints towards a subtle role for the CjNC1 and CjNC4 ncRNAs in post-transcriptional gene regulation in thermophilic Campylobacter species, and suggests that the currently used phenotypic methodologies are insufficiently sensitive to detect such subtle phenotypes. The lack of a role of Hfq in the E. coli GFP-based system indicates that the CjNC1 and CjNC4 ncRNAs may mediate post-transcriptional gene regulation in ways that do not conform to the paradigms obtained from the Enterobacteriaceae. PMID- 26512729 TI - Carbon Nanotube Synaptic Transistor Network for Pattern Recognition. AB - Inspired by the human brain, a neuromorphic system combining complementary metal oxide semiconductor (CMOS) and adjustable synaptic devices may offer new computing paradigms by enabling massive neural-network parallelism. In particular, synaptic devices, which are capable of emulating the functions of biological synapses, are used as the essential building blocks for an information storage and processing system. However, previous synaptic devices based on two terminal resistive devices remain challenging because of their variability and specific physical mechanisms of resistance change, which lead to a bottleneck in the implementation of a high-density synaptic device network. Here we report that a three-terminal synaptic transistor based on carbon nanotubes can provide reliable synaptic functions that encode relative timing and regulate weight change. In addition, using system-level simulations, the developed synaptic transistor network associated with CMOS circuits can perform unsupervised learning for pattern recognition using a simplified spike-timing-dependent plasticity scheme. PMID- 26512730 TI - Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self Resistance Element in Streptomyces flavoviridis ATCC21892. AB - The bleomycins (BLMs), tallysomycins (TLMs), phleomycin, and zorbamycin (ZBM) are members of the BLM family of glycopeptide-derived antitumor antibiotics. The BLM producing Streptomyces verticillus ATCC15003 and the TLM-producing Streptoalloteichus hindustanus E465-94 ATCC31158 both possess at least two self resistance elements, an N-acetyltransferase and a binding protein. The N acetyltransferase provides resistance by disrupting the metal-binding domain of the antibiotic that is required for activity, while the binding protein confers resistance by sequestering the metal-bound antibiotic and preventing drug activation via molecular oxygen. We recently established that the ZBM producer, Streptomyces flavoviridis ATCC21892, lacks the N-acetyltransferase resistance gene and that the ZBM-binding protein, ZbmA, is sufficient to confer resistance in the producing strain. To investigate the resistance mechanism attributed to ZbmA, we determined the crystal structures of apo and Cu(II)-ZBM-bound ZbmA at high resolutions of 1.90 and 1.65 A, respectively. A comparison and contrast with other structurally characterized members of the BLM-binding protein family revealed key differences in the protein-ligand binding environment that fine tunes the ability of ZbmA to sequester metal-bound ZBM and supports drug sequestration as the primary resistance mechanism in the producing organisms of the BLM family of antitumor antibiotics. PMID- 26512731 TI - Brominated Variant of the Lantibiotic NAI-107 with Enhanced Antibacterial Potency. AB - We identified an Actinoallomurus strain producing NAI-107, a chlorinated lantibiotic effective against multidrug-resistant Gram-positive pathogens and previously reported from the distantly related genus Microbispora. Inclusion of KBr in the production medium of either the Actinoallomurus or the Microbispora producer readily afforded brominated variants of NAI-107, which were designated as NAI-108. The other post-translational modifications naturally occurring in this lantibiotic family (i.e., hydroxylation of Pro-14 and C-terminal decarboxylation) were unaffected by the presence of a brominated tryptophan. In addition to being the first example of a bromine-containing lantibiotic, NAI-108 displayed a small but consistent improvement in antibacterial activity against all tested strains. The brominated lantibiotic maintained the same rapid bactericidal activity as NAI-107 but at reduced concentrations, consistent with its increased potency and with the role played by the hydrophobicity of the first lanthionine ring. NAI-108 thus represents an interesting addition to a promising family of potent and effective lantibiotics. PMID- 26512732 TI - Catalytic Aldol-Cyclization Cascade of 3-Isothiocyanato Oxindoles with alpha Ketophosphonates for the Enantioselective Synthesis of beta-Amino-alpha hydroxyphosphonates. AB - A cascade aldol-cyclization reaction between 3-isothiocyanato oxindoles and alpha ketophosphonates has been developed for the synthesis of beta-amino-alpha hydroxyphosphonate derivatives. Catalyzed by a quinine-based tertiary amino thiourea derivative, this reaction delivers 2-thioxooxazolidinyl phosphonates based on a spirooxindole scaffold bearing two contiguous quaternary stereogenic centers in high yields with excellent diastereo- (up to >20:1 dr) and enantioselectivities (up to >99:1 er). PMID- 26512733 TI - Azide vs Alkyne Functionalization in Pt(II) Complexes for Post-treatment Click Modification: Solid-State Structure, Fluorescent Labeling, and Cellular Fate. AB - Tracking of Pt(II) complexes is of crucial importance toward understanding Pt interactions with cellular biomolecules. Post-treatment fluorescent labeling of functionalized Pt(II)-based agents using the bioorthogonal Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC) reaction has recently been reported as a promising approach. Here we describe an azide-functionalized Pt(II) complex, cis-[Pt(2 azidobutyl)amido-1,3-propanediamine)Cl2] (1), containing the cis geometry and difunctional reactivity of cisplatin, and present a comparative study with its previously described alkyne-functionalized congener. Single-crystal X-ray diffraction reveals a dramatic change in the solid-state arrangement with exchange of the alkyne for an azide moiety wherein 1 is dominated by a pseudo chain of Pt-Pt dimers and antiparallel alignment of the azide substituents, in comparison with a circular arrangement supported by CH/pi(C=C) interactions in the alkyne version. In vitro studies indicate similar DNA binding and click reactivity of both congeners observed by fluorescent labeling. Interestingly, complex 1 shows in vitro enhanced click reactivity in comparison to a previously reported azide-appended Pt(II) complex. Despite their similar behavior in vitro, preliminary in cellulo HeLa studies indicate a superior imaging potential of azide-functionalized 1. Post-treatment fluorescent labeling of 1 observed by confocal fluorescence microscopy shows nuclear and intense nucleolar localization. These results demonstrate the potential of 1 in different cell line localization studies and for future isolation and purification of Pt-bound targets. PMID- 26512734 TI - Large-Deformation Curling Actuators Based on Carbon Nanotube Composite: Advanced Structure Design and Biomimetic Application. AB - In recent years, electroactive polymers have been developed as actuator materials. As an important branch of electroactive polymers, electrothermal actuators (ETAs) demonstrate potential applications in the fields of artificial muscles, biomimetic devices, robotics, and so on. Large-shape deformation, low voltage-driven actuation, and ultrafast fabrication are critical to the development of ETA. However, a simultaneous optimization of all of these advantages has not been realized yet. Practical biomimetic applications are also rare. In this work, we introduce an ultrafast approach to fabricate a curling actuator based on a newly designed carbon nanotube and polymer composite, which completely realizes all of the above required advantages. The actuator shows an ultralarge curling actuation with a curvature greater than 1.0 cm(-1) and bending angle larger than 360 degrees , even curling into a tubular structure. The driving voltage is down to a low voltage of 5 V. The remarkable actuation is attributed not only to the mismatch in the coefficients of thermal expansion but also to the mechanical property changes of materials during temperature change. We also construct an S-shape actuator to show the possibility of building advanced-structure actuators. A weightlifting walking robot is further designed that exhibits a fast-moving motion while lifting a sample heavier than itself, demonstrating promising biomimetic applications. PMID- 26512735 TI - Comparison of Asian Aquaculture Products by Use of Statistically Supported Life Cycle Assessment. AB - We investigated aquaculture production of Asian tiger shrimp, whiteleg shrimp, giant river prawn, tilapia, and pangasius catfish in Bangladesh, China, Thailand, and Vietnam by using life cycle assessments (LCAs), with the purpose of evaluating the comparative eco-efficiency of producing different aquatic food products. Our starting hypothesis was that different production systems are associated with significantly different environmental impacts, as the production of these aquatic species differs in intensity and management practices. In order to test this hypothesis, we estimated each system's global warming, eutrophication, and freshwater ecotoxicity impacts. The contribution to these impacts and the overall dispersions relative to results were propagated by Monte Carlo simulations and dependent sampling. Paired testing showed significant (p < 0.05) differences between the median impacts of most production systems in the intraspecies comparisons, even after a Bonferroni correction. For the full distributions instead of only the median, only for Asian tiger shrimp did more than 95% of the propagated Monte Carlo results favor certain farming systems. The major environmental hot-spots driving the differences in environmental performance among systems were fishmeal from mixed fisheries for global warming, pond runoff and sediment discards for eutrophication, and agricultural pesticides, metals, benzalkonium chloride, and other chlorine-releasing compounds for freshwater ecotoxicity. The Asian aquaculture industry should therefore strive toward farming systems relying upon pelleted species-specific feeds, where the fishmeal inclusion is limited and sourced sustainably. Also, excessive nutrients should be recycled in integrated organic agriculture together with efficient aeration solutions powered by renewable energy sources. PMID- 26512736 TI - 2-Azetidinones as Precursors of Pincer Ligands: Preparation, Structure, and Spectroscopic Properties of CC'N-Osmium Complexes. AB - A metal-promoted degradation of 2-azetidinones to afford CC'N-pincer ligands is reported. The hexahydride complex OsH6(P(i)Pr3)2 (1) reacts with (+/-)-cis-1-(4 methoxyphenyl)-3-phenoxy-4-(pyridin-2-yl)azetidin-2-one (I), (+/-)-cis-1-(4 methoxyphenyl)-3-phenoxy-4-(isoquinolin-2-yl)azetidin-2-one (II), and (+/-)-cis-1 (4-methoxyphenyl)-3-phenoxy-4-(quinolin-2-yl)azetidin-2-one (III) to give the respective OsH2(P(i)Pr3)2(CC'N) (2-4) complexes, which add HBF4.OEt2 to yield [OsH2(P(i)Pr3)2(CC"N)]BF4 (5-7). These salts are the result of the addition of the proton of the acid to the dianionic CC'N-pincer ligand. The hydride ligands of these compounds undergo quantum mechanical exchange coupling, which has been experimentally quantified according to a two-dimensional harmonic oscillator model, where Jex is determined by the separation between the hydrides, their hard sphere radius, and a nu parameter describing the H-M-H vibrational wag mode allowing the movement along the H-H vector. The comparison of the results reveals that the phenomenon is particularly intense for 5-7. Furthermore, in these compounds, the separation between the hydrides is ~0.1 A shorter than in the respective neutral species 2-4, whereas the hydride hard sphere radius increases by ~10%, and the nu value decreases by ~20%. PMID- 26512737 TI - Hydrogen Bonding Interactions in Amorphous Indomethacin and Its Amorphous Solid Dispersions with Poly(vinylpyrrolidone) and Poly(vinylpyrrolidone-co-vinyl acetate) Studied Using (13)C Solid-State NMR. AB - Hydrogen bonding interactions in amorphous indomethacin and amorphous solid dispersions of indomethacin with poly(vinylpyrrolidone), or PVP, and poly(vinylpyrrolidone-co-vinyl acetate), or PVP/VA, were investigated quantitatively using solid-state NMR spectroscopy. Indomethacin that was (13)C isotopically labeled at the carboxylic acid carbon was used to selectively analyze the carbonyl region of the spectrum. Deconvolution of the carboxylic acid carbon peak revealed that 59% of amorphous indomethacin molecules were hydrogen bonded through carboxylic acid cyclic dimers, 15% were in disordered carboxylic acid chains, 19% were hydrogen bonded through carboxylic acid and amide interactions, and the remaining 7% were free of hydrogen bonds. The standard dimerization enthalpy and entropy of amorphous indomethacin were estimated to be 38 kJ/mol and -91 J/(mol . K), respectively, using polystyrene as the "solvent". Polymers such as PVP and PVP/VA disrupted indomethacin self-interactions and formed hydrogen bonds with the drug. The carboxylic acid dimers were almost completely disrupted with 50% (wt) of PVP or PVP/VA. The fraction of disordered carboxylic acid chains also decreased as the polymer content increased. The solid state NMR results were compared with molecular dynamics (MD) simulations from the literature. The present work highlights the potential of (13)C solid-state NMR to detect and quantify various hydrogen bonded species in amorphous solid dispersions as well as to serve as an experimental validation of MD simulations. PMID- 26512738 TI - Figure of Merit for Carbon Nanotube Photothermoelectric Detectors. AB - Carbon nanotubes (CNTs) have emerged as promising materials for visible, infrared, and terahertz photodetectors. Further development of these photodetectors requires a fundamental understanding of the mechanisms that govern their behavior as well as the establishment of figures of merit for technology applications. Recently, a number of CNT detectors have been shown to operate based on the photothermoelectric effect. Here we present a figure of merit for these detectors, which includes the properties of the material and the device. In addition, we use a suite of experimental characterization methods for the thorough analysis of the electrical, thermoelectric, electrothermal, and photothermal properties of the CNT thin-film devices. Our measurements determine the quantities that enter the figure of merit and allow us to establish a path toward future performance improvements. PMID- 26512739 TI - A novel chemical/biological combined technique for N, N-dimethylformamide wastewater treatment. AB - N, N-Dimethylformamide (DMF) is a widely used organic solvent whose wastewater is difficult to biodegrade directly. In this paper, a novel chemical/biological combined technique consisting of alkaline hydrolysis stripping, activated sludge and a bio-trickling filter (BTF) was developed for DMF wastewater treatment. The main pollutant, DMF, was decomposed to dimethylamine and formate under alkaline conditions, and the dimethylamine was stripped out by the BTF. The pretreated wastewater was then degraded in an activated sludge process. The operation performances of alkaline hydrolysis, activated sludge and BTF processes were investigated separately. At the optimal conditions of an alkali dosage of 40 g/L, an air/liquid ratio of 3000:1 and 5 h in the air-stripping process, the removal of total organic carbon and DMF was found to be 58% and 96%, respectively. A chemical oxygen demand removal efficiency of 80-90% was obtained in the activated sludge process. The performance of BTF was excellent with a dimethylamine removal efficiency close to 90% even at a high loading of 16 g/d. PMID- 26512740 TI - Bupropion-SR plus naltrexone-SR for the treatment of mild-to-moderate obesity. AB - Naltrexone-bupropion is a recently approved drug combination for chronic weight management. In this article, we discuss the rationale for its use as a combination followed by a comprehensive review of safety and efficacy data from major preclinical, phase II and III clinical trials. PMID- 26512741 TI - Trial of labor after cesarean versus repeat cesarean in women with small-for gestational age neonates: a secondary analysis. AB - OBJECTIVE: The objective of this study was to determine whether trial of labor after cesarean (TOLAC) is associated with increased risk of adverse outcomes for small-for-gestational-age (SGA) neonates. METHODS: This secondary analysis of a multicenter prospective observational study evaluated SGA neonates born to women with a single prior cesarean delivery. Nonanomalous, singleton pregnancies delivered at 24-41 weeks were included. The primary exposure was whether women underwent planned cesarean versus attempted TOLAC. Log-linear regression models were developed to characterize the relationship between TOLAC and neonatal outcomes. The primary outcome was a composite measure of neonatal morbidity and/or mortality, including death, respiratory complications, treated hypoglycemia, sepsis, neonatal intensive care unit (NICU) admission and hospital stay >5 days. RESULTS: Of 1009 patients identified, 258 underwent repeat cesarean; 751 attempted TOLAC. Controlling for age, race, body mass index, smoking, maternal disease, prior vaginal birth after cesarean, corticosteroids, prematurity and nonreassuring fetal status as indication for delivery, the composite adverse outcome was similarly likely in both groups (adjusted risk ratio (RR) 0.99, 95% confidence interval (95% CI) 0.88-1.12, p = 0.93). CONCLUSIONS: SGA infants born to women who TOLAC have similar neonatal outcomes to those who deliver by planned repeat cesarean. We conclude that TOLAC is an acceptable option for women with a prior cesarean and suspected SGA neonates. PMID- 26512742 TI - Transporter assays as useful in vitro tools in drug discovery and development. AB - INTRODUCTION: Drug transporters are transmembrane proteins that facilitate the transfer of substances in and out of cells and play a substantial role in drug absorption, distribution and elimination. During the drug discovery and development phases, in vitro assays are important tools to identify substrates and inhibitors of transporters. AREAS COVERED: This article provides an overview of in vitro transporter assays, discussing their advantages, limitations, and sources of variability. Membrane-based assays take advantage of the location of efflux transporters for measurements of drug interactions. Cell-based systems are functional transporter assays that measure the passage of drugs across cell membranes and transporter proteins. EXPERT OPINION: Use of optimized and validated in vitro transporter assays during drug discovery and development leads to a greater confidence in their results in determining whether a new compound is a substrate or inhibitor. The concept of transporter method suitability provides a general scheme to improve predictability and reduce variability of the in vitro assays by incorporating assay validation, acceptance criteria, and probe substrates and inhibitors. Such a scheme can potentially improve assay reproducibility and allow in vitro transporter assays to aid in defining a test compound as a substrate or inhibitor of efflux and uptake transporters. PMID- 26512743 TI - Health-related quality of life in men with metastatic castration-resistant prostate cancer. AB - Metastatic castration-resistant prostate cancer (MCRPC) is a chronic disease with several therapeutic options. By definition, all approaches to treatment are palliative in intent and improving health-related quality of life (HRQoL) is an important goal of therapy. Several tools exist for the assessment of HRQoL in MCRPC enabling cross-trial comparisons. In this article agents currently used in the management of MCRPC are reviewed from a HRQoL perspective. PMID- 26512744 TI - Current treatment options for hereditary angioedema due to C1 inhibitor deficiency. AB - INTRODUCTION: Hereditary angioedema (HAE) usually results from C1 inhibitor (C1 INH) deficiency or dysfunction. It is a rare autosomal dominant disorder characterized by localized, non-pitting edema of the skin and submucosal tissues of the upper respiratory and gastrointestinal tracts, without significant wheals or pruritus, due to a temporary increase in vascular permeability. Other forms of HAE have been described, but therapies are approved only for HAE with C1-INH deficiency: hence, this review focuses on C1-INH-HAE. AREAS COVERED: The aim of this review article is to present current available therapies for treatment of acute attacks as well as for short- and long-term prophylaxis of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE). The Authors highlight also critical issues on the management of C1-INH-HAE, which is continuously evolving thanks to evidence from clinical trials, post-marketing experience and ongoing studies. EXPERT OPINION: In the last decade, the quality of life of C1 INH-HAE patients has significantly improved due to increased knowledge and awareness of the disease, improved patient support and major progress in pharmacotherapy. Ongoing research will probably provide patients with other new effective therapeutic agents in the near future. PMID- 26512745 TI - Limited treatment adaptation despite poor asthma control in asthma patients treated with inhaled corticosteroids. AB - OBJECTIVE: Current asthma guidelines recommend use of inhaled corticosteroids (ICS) in patients with persistent disease. This study was designed to investigate (1) the proportion of patients prescribed ICS-containing maintenance treatment who achieve asthma control, (2) determinants of control and (3) how physicians adapt treatment to the level of control. METHODS: General practitioners (GPs) and chest physicians (CPs) in France recruited patients consulting for asthma and prescribed an ICS. Over a 2-year follow-up period, asthma symptoms in the previous 3 months and treatments prescribed were documented at each visit. Variables independently associated with asthma control were determined by multiple logistic regression. RESULTS: Data were available for 924 patients recruited by GPs and 455 recruited by CPs. Asthma control was acceptable in only 24% of patients at inclusion, and in 33.6% at the last follow-up visit. Five factors were independently associated with asthma control: age (or time since diagnosis), gender, smoking status, allergic aetiology of asthma and treatment. Most patients (56.3%) were prescribed the same ICS dose regimen at the end of follow-up as at inclusion. The intensity of controller therapy had been increased in only 12.2% of patients unacceptably controlled at inclusion. CONCLUSIONS: Asthma was unacceptably controlled in most patients receiving ICS-containing maintenance treatment and remained so during follow-up. Despite this, treatment adaptations by GPs and CPs were very infrequent. This unsatisfactory situation may be improved by adopting a more dynamic approach to tailoring controller therapy to the needs of the patient. PMID- 26512747 TI - Matrix-type transdermal films to enhance simvastatin ex vivo skin permeability. AB - This study aimed at employing Plackett-Burman design in screening formulation variables that affect quality of matrix-type simvastatin (SMV) transdermal film. To achieve this goal, 12 formulations were prepared by casting method. The investigated variables were Eudragit RL percentage, polymer mixture percentage, plasticizer type, plasticizer percentage, enhancer type, enhancer percentage and dichloromethane fraction in organic phase. The films were evaluated for physicochemical properties and ex vivo SMV permeation. SMV initial, delayed flux, diffusivity and permeability coefficient were calculated on the delayed flux phase with constraint to minimize the initial flux and approaching steady-state flux. The obtained results revealed flat films with homogeneous distribution of SMV within the films. Thickness values changed from 65 to 180 MUm by changing the factors' combinations. Most of the permeation profiles showed sustained release feature with fast permeation phase followed by slow phase. Analysis of variance (ANOVA) showed significant effects (p < 0.05) of the investigated variables on the responses with Prob > F values of 0.0147, 0.0814, 0.0063 and 0.0142 for the initial and delayed fluxes, permeability coefficients and diffusivities, respectively. The findings of screening study showed the importance of the significant variables to be scaled up for full optimization study as a promising alternative drug delivery system. PMID- 26512748 TI - HuR antagonizes the effect of an intronic pyrimidine-rich sequence in regulating WT1 +/-KTS isoforms. AB - WT1 + KTS and -KTS isoforms only differ in 3 amino acids in protein sequence but show significant functional difference. The +/-KTS isoforms were generated by alternative usage of 2 adjacent 5' splice sites at RNA level, however, how these 2 isoforms are regulated is still elusive. Here we report the identification of an intronic pyrimidine-rich sequence that is critical for the ratio of +/-KTS isoforms, deletion or partial replacement of the sequence led to full/significant shift to -KTS isoform. To identify trans-factors that can regulate +/-KTS isoforms via the binding to the element, we performed RNP assembly using in vitro transcribed RNA with or without the pyrimidine-rich sequence. Mass spectrometry analysis of purified RNPs showed that the element associated with many splicing factors. Co-transfection of these factors with WT1 reporter revealed that HuR promoted the production of -KTS isoform at the reporter level. RNA immuno precipitation experiment indicated that HuR interacted with the pyrimidine-rich element in WT1 intron 9. We further presented evidence that transient or stable over-expression of HuR led to enhanced expression of endogenous -KTS isoform. Moreover, knockdown of HuR resulted in decreased expression of endogenous -KTS isoform in 293T, SW620, SNU-387 and AGS cell lines. Together, these data indicate that HuR binds to the pyrimidine-rich sequence and antagonize its effect in regulating WT1 +/-KTS isoforms. PMID- 26512749 TI - Assessing the Mismatch Between Incubation and Latent Periods for Vector-Borne Diseases: The Case of Sharka. AB - The relative durations of the incubation period (the time between inoculation and symptom expression) and of the latent period (the time between inoculation and infectiousness of the host) are poorly documented for plant diseases. However, the extent of asynchrony between the ends of these two periods (i.e., their mismatch) can be a key determinant of the epidemic dynamics for many diseases and consequently it is of primary interest in the design of disease management strategies. In order to assess this mismatch, an experimental approach was developed and applied using sharka, a severe disease caused by Plum pox virus (PPV, genus Potyvirus, family Potyviridae) affecting trees belonging to the genus Prunus. Leaves of infected young peach trees were used individually as viral sources in aphid-mediated transmission tests carried out at different time points postinoculation in order to bracket symptom onset. By fitting a nonlinear logistic model to the obtained transmission rates, we demonstrated that the first symptoms appear on leaves 1 day before they rapidly become infectious. In addition, among symptomatic leaves, symptom intensity and transmission rate are positively correlated. These results strengthen the conclusion that, under our experimental conditions, incubation and latent periods of PPV infection are almost synchronous. PMID- 26512750 TI - Prolactin as an Adjunct for Type 1 Diabetes Immunotherapy. AB - Type 1 diabetes is caused by autoimmune destruction of beta-cells. Although immunotherapy can restore self-tolerance thereby halting continued immune mediated beta-cell loss, residual beta-cell mass and function is often insufficient for normoglycemia. Using a growth factor to boost beta-cell mass can potentially overcome this barrier and prolactin (PRL) may fill this role. Previous studies have shown that PRL can stimulate beta-cell proliferation and up regulate insulin synthesis and secretion while reducing lymphocytic infiltration of islets, suggesting that it may restore normoglycemia through complementary mechanisms. Here, we test the hypothesis that PRL can improve the efficacy of an immune modulator, the anticluster of differentiation 3 monoclonal antibody (aCD3), in inducing diabetes remission by up-regulating beta-cell mass and function. Diabetic nonobese diabetic (NOD) mice were treated with a 5-day course of aCD3 with or without a concurrent 3-week course of PRL. We found that a higher proportion of diabetic mice treated with the aCD3 and PRL combined therapy achieved diabetes reversal than those treated with aCD3 alone. The aCD3 and PRL combined group had a higher beta-cell proliferation rate, an increased beta-cell fraction, larger islets, higher pancreatic insulin content, and greater glucose stimulated insulin release. Lineage-tracing analysis found minimal contribution of beta-cell neogenesis to the formation of new beta-cells. Although we did not detect a significant difference in the number or proliferative capacity of T cells, we observed a higher proportion of insulitis-free islets in the aCD3 and PRL group. These results suggest that combining a growth factor with an immunotherapy may be an effective treatment paradigm for autoimmune diabetes. PMID- 26512751 TI - Ultrastructural changes in the pulmonary mechanical barriers in a rat model of severe acute pancreatitis-associated acute lung injury. AB - This study examined the ultrastructural changes in the pulmonary mechanical barriers in a rat model of severe acute pancreatitis (SAP)-associated acute lung injury (ALI). Animals were randomized into the SAP group (n = 60) and the control group (n = 60). SAP was induced by retrograde injection of 5% taurocholic acid into the biliopancreatic duct. The morphological abnormalities assessed by histology and the lung wet/dry weight ratio and the ultrastructural abnormalities assessed by transmission electron microscope and scanning electron microscope examinations plus lanthanum nitrate tracing were compared between the two groups at 6, 12, and 24 h post-SAP induction (n = 10/group/time point). The SAP group had significantly greater extravascular effusion than the control group at each time point as assessed by the lung wet/dry weight ratio (p < .001). The severity of the tissue damage increased in the lung and pancreas over time in the SAP group (all p < .001). In the SAP group, ultrastructural damages to the endothelial, epithelial, and pleural barriers were apparent and the damages to the endothelial barrier were detected earlier than the other two barriers, suggesting its fundamental role in preventing the further development of SAP associated ALI. Moreover, the ultrastructural abnormalities were detected earlier than symptoms and morphological changes. The ultrastructural damages in the endothelial, epithelial, and pleural barriers occurred in the early stage of SAP. The endothelial barrier is likely to be the first line to prevent the further development in this rat model of SAP-associated ALI. PMID- 26512752 TI - Circadian regulation gene polymorphisms are associated with sleep disruption and duration, and circadian phase and rhythm in adults with HIV. AB - Genes involved in circadian regulation, such as circadian locomotor output cycles kaput [CLOCK], cryptochrome [CRY1] and period [PER], have been associated with sleep outcomes in prior animal and human research. However, it is unclear whether polymorphisms in these genes are associated with the sleep disturbances commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Thus, the purpose of this study was to describe polymorphisms in selected circadian genes that are associated with sleep duration or disruption as well as the sleep-wake rhythm strength and phase timing among adults living with HIV/AIDS. A convenience sample of 289 adults with HIV/AIDS was recruited from HIV clinics and community sites in the San Francisco Bay Area. A wrist actigraph was worn for 72 h on weekdays to estimate sleep duration or total sleep time (TST), sleep disruption or percentage of wake after sleep onset (WASO) and several circadian rhythm parameters: mesor, amplitude, the ratio of mesor to amplitude (circadian quotient), and 24-h autocorrelation. Circadian phase measures included clock time for peak activity (acrophase) from actigraphy movement data, and bed time and final wake time from actigraphy and self-report. Genotyping was conducted for polymorphisms in five candidate genes involved in circadian regulation: CLOCK, CRY1, PER1, PER2 and PER3. Demographic and clinical variables were evaluated as potential covariates. Interactions between genotype and HIV variables (i.e. viral load, years since HIV diagnosis) were also evaluated. Controlling for potentially confounding variables (e.g. race, gender, CD4+ T-cell count, waist circumference, medication use, smoking and depressive symptoms), CLOCK was associated with WASO, 24-h autocorrelation and objectively-measured bed time; CRY1 was associated with circadian quotient; PER1 was associated with mesor and self-reported habitual wake time; PER2 was associated with TST, mesor, circadian quotient, 24-h autocorrelation and bed and wake times; PER3 was associated with amplitude, 24-h autocorrelation, acrophase and bed and wake times. Most of the observed associations involved a significant interaction between genotype and HIV. In this chronic illness population, polymorphisms in several circadian genes were associated with measures of sleep disruption and timing. These findings extend the evidence for an association between genetic variability in circadian regulation and sleep outcomes to include the sleep-wake patterns experienced by adults living with HIV/AIDS. These results provide direction for future intervention research related to circadian sleep wake behavior patterns. PMID- 26512753 TI - Grape seed proanthocyanidin extract protects human umbilical vein endothelial cells from indoxyl sulfate-induced injury via ameliorating mitochondrial dysfunction. AB - OBJECTIVE: To investigate the effects of grape seed proanthocyanidin extract (GSPE) on indoxyl sulfate-induced Human Umbilical Vein Endothelial Cells (HUVECs) injury in vitro and study its mechanism. METHODS: HUVECs were incubated with indoxyl sulfate at concentrations in the range found in uremic patients. Then we determined the effect of indoxyl sulfate on endothelial phenotype, endothelial function, ROS (reactive oxygen species), cell apoptosis and mitochondrial function. In addition, we detected whether GSPE can suppress the injury of HUVECs induced by indoxyl sulfate and probe the mechanism underlying the protective effects of GSPE by analyzing mitochondrial dysfunction. RESULTS: GSPE treatment significantly attenuated indoxyl sulfate-induced HVUECs injury in a dose- and time-dependent manner. GSPE-enhanced eNOS and VE-cadherin expression, inhibited intracellular ROS level and cell apoptosis, adjust mitochondrial membrane potential and reduced 8-hydroxy-desoxyguanosine (8-OHdG) level induced by indoxyl sulfate. CONCLUSION: These results suggest that GSPE prevents HUVECs from indoxyl sulfate-induced injury by ameliorating mitochondrial dysfunction and may be a promising agent for treating uremia toxin-induced injury. PMID- 26512754 TI - Urban traffic pollution reduction for sedan cars using petrol engines by hydro oxide gas inclusion. AB - Petrol cars, in particular nonhybrid cars, contribute significantly to the pollution problem as compared with other types of cars. The originality of this article falls in the direction of using hydro-oxy gas to reduce pollution from petrol car engines. Experiments were performed in city areas at low real speeds, with constant engine speeds in the average of 2500 rpm and at variable velocity ratios (first speed was 10-20 km/hr, second speed was 20-35 km/hr, and third speed was 35-50 km/hr). Results indicated that through using hydro-oxy gas, a noticeable reduction in pollution was recorded. Oxygen (O2) percentage has increased by about 2.5%, and nitric oxide (NO) level has been reduced by about 500 ppm. Carbon monoxide (CO) has decreased by about 2.2%, and also CO2 has decreased by 2.1%. It's worth mentioning that for hybrid system in cars at speeds between 10 and 50 km/hr, the emission percentage change is zero. However, hybrid cars are less abundant than petrol cars. IMPLICATIONS: The originality of this paper falls in the direction of using hydro-oxy gas to reduce pollution from petrol car engines. Experiments were performed in city areas at low real speeds, with constant engine speeds in the average of 2500 rpm and at variable velocity ratios (first speed was 10-20 km/hr, second speed was 20-35 km/hr, and third speed was 35-50 km/h). PMID- 26512756 TI - Increased RhoA/Rho-Kinase Activity and Markers of Endothelial Dysfunction in Young Adult Subjects with Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome, a chronic condition associated with higher risk of cardiovascular diseases, is increasingly prevalent in young adults. Dyslipidemia, proinflammatory cytokines, endothelial dysfunction signs, and RhoA/Rho-kinase (ROCK) activation are considered risk factors of cardiovascular diseases. The occurrence of these factors in young patients with metabolic syndrome but without type 2 diabetes or hypertension has not been fully studied. The objective of this study was to evaluate young subjects with enlarged waist circumference and dyslipidemia but without type 2 diabetes or hypertension,for markers associated with a higher risk of cardiovascular diseases. METHODS: Thirty two male patients aged 31 +/- 1.3 years diagnosed with metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III guide for enlarged waist circumference, elevated triglycerides, and low HDL levels, but with blood pressure and fasting glucose within normal ranges, were evaluated for RhoA/ROCK activity in leukocytes, serum fatty acid methyl esters profile, proinflammatory cytokines, and oxidative stress markers in addition to thrombin generation and biochemical analysis. Age- and gender-matched healthy subjects were equivalently evaluated. RESULTS: Patients showed higher RhoA/ROCK activity, elevated levels of interleukin-6, soluble CD40L, monocyte chemoattractant protein, and high-sensitivity C-reactive protein (P < 0.001) as well as parameters of endogenous thrombin generation potential (P < 0.05) compared with healthy subjects. Increased thiobarbituric acid reactive substances, advanced oxidation protein product, and insulin levels and low nitric oxide biodisponibility (P < 0.001) were also found in patients as compared with controls. Palmitic acid was one of the saturated fatty acids found to be significantly elevated in patients compared with control subjects (P = 0.0087). CONCLUSIONS: Increased markers of cardiovascular risk are already present in young adults with metabolic syndrome but without type 2 diabetes or hypertension. PMID- 26512757 TI - Orthodontics is temporomandibular disorder-neutral. AB - OBJECTIVES: To assess if subjects with a clinical diagnosis of temporomandibular disorders (TMDs) have a similar prevalence of orthodontic history as a population of TMD-free individuals and to assess if those subjects who have a history of ideal orthodontics have fewer symptoms than those with a history of nonideal orthodontics. MATERIALS AND METHODS: Two groups of age- and sex-matched individuals belonging to either a study ("TMD") or a control group were recruited. Subjects who underwent orthodontic treatment were classified as having a history of ideal or nonideal orthodontics based on the current presence of normal values in five reference occlusal features. RESULTS: The correlation with a history of orthodontic treatment was not clinically significant for any of the TMD diagnoses (ie, muscle pain, joint pain, disc displacement, arthrosis), with Phi (Phi) coefficient values within the -0.120 to 0.058 range. Within the subset of patients with a history of orthodontics, the correlation of ideal or nonideal orthodontic treatment with TMD diagnoses was, in general, not clinically relevant or was weakly relevant. CONCLUSIONS: Findings confirmed the substantial absence of clinically significant effects of orthodontics as far as TMD is concerned. The very low correlation values of a negative or positive history of ideal or nonideal orthodontics with the different TMD diagnoses suggest that orthodontic treatment could not have a true role for TMD. PMID- 26512760 TI - Correlates of Cancer Information Overload: Focusing on Individual Ability and Motivation. AB - The present study defined cancer information overload (CIO) as an aversive disposition wherein a person is confused and overwhelmed by cancer information, which occurs when he or she fails to effectively categorize new information due to a lack of resources for effective learning. Based on the definition and informed by previous studies on information overload and the cognitive mediation model, we hypothesized that low ability and motivation to process cancer information would lead to CIO. We used education level and trait anxiety as factors related to ability. Cancer history and the use of active media channels (such as the Internet and print media) were adopted as motivational factors. Four samples (three from the United States and one from South Korea) were used to explore the relationship between ability/motivation and CIO. Among them, only Sample 4 participants answered questions about stomach cancer, and other participants were asked about cancer in general. In all four samples, trait anxiety was positively associated with CIO. Health information use from active media channels (print or the Internet) was negatively associated with CIO in three samples. The associations between family history and CIO, and between education and CIO, were found in two samples. In short, the present study demonstrated that CIO partly depends on individual ability and motivation, thereby showing that CIO is influenced by personal characteristics as well as environmental factors. PMID- 26512761 TI - The influence of age, playing position, anthropometry and fitness on career attainment outcomes in rugby league. AB - This study evaluated the influence of annual-age category, relative age, playing position, anthropometry and fitness on the career attainment outcomes of junior rugby league players originally selected for a talent identification and development (TID) programme. Junior rugby league players (N = 580) were grouped retrospectively according to their career attainment level (i.e., amateur, academy and professional). Anthropometric (height, sitting height, body mass, sum of four skinfolds), maturational (age at peak height velocity; PHV) and fitness (power, speed, change of direction speed, estimated[Formula: see text]) characteristics were assessed at the Under 13s, 14s and 15s annual-age categories. Relative age (Q2 = 8.5% vs. Q4 = 25.5%) and playing position (Pivots = 19.5% vs. Props = 5.8%) influenced the percentage of players attaining professional status. Anthropometry and fitness had a significant effect on career attainment at the Under 14 (P = 0.002, eta(2) = 0.16) and 15 (P = 0.01, eta(2) = 0.12) annual-age categories. Findings at the Under 14s showed future professional players were significantly later maturing compared to academy and amateur players. Findings suggest that relative age, playing position, anthropometry and fitness can influence the career attainment of junior rugby league players. TID programmes within rugby league, and other related team sports, should be aware and acknowledge the factors influencing long-term career attainment, and not delimit development opportunities during early adolescence. PMID- 26512759 TI - APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction. AB - Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer's disease. PMID- 26512762 TI - HPV vaccines: Translating immunogenicity into efficacy. AB - Currently available human papillomavirus (HPV) vaccines are very successful at preventing persistent HPV infection and premalignant cervical lesions. In part due to the unique aspects of HPV immunogenicity and high levels of efficacy no immune correlate has been identified for HPV vaccination. Serum neutralizing antibodies are used to measure vaccine response, but their role as a correlate has not been verified, and this theory fails to explain the prevention of HPV related non-mucosal lesions. Identifying a true correlate would aid in future work in this area but will be difficult in the setting of a highly efficacious vaccine. PMID- 26512763 TI - Chernobyl cleanup workers from Estonia: cohort description and related epidemiological research. AB - The Estonian study of Chernobyl cleanup workers was one of the first investigations to evaluate the possible health consequences of working in the Chernobyl area (the 30 km exclusion zone and/or adjacent territories) after the 1986 reactor accident. The cohort consists of 4831 men who were dispatched in 1986-1991 for tasks involving decontamination, construction of buildings, transport, radiation measurement, guard duty or other activities. By 31 December 2012, the follow-up of the cohort yielded 102 158 person-years of observation. Exposure and health data were collected by postal questionnaires, biodosimetry evaluations, thyroid screenings, and record-linkages with cancer, causes of death and health insurance reimbursement registers and databases. These data cover socio-demographic factors, employment history, aspects of health behaviour, medical history, work and living conditions in the Chernobyl area, biomarkers of exposure, cancer and non-cancer disease occurrence and causes of death. Cancer incidence data were obtained for 1986-2008, mortality data for 1986-2011 and non cancer morbidity data for 2004-2012. Although the cohort is relatively small, it has been extensively examined and benefited from comprehensive nationwide population and health registers. The major finding was an increased risk of suicide. Thyroid examinations did not reveal an association with thyroid nodular disease and radiation dose, but did indicate the importance of accounting for screening when making comparisons with unscreened populations. No risk of leukaemia was observed and risks higher than 2.5-fold could be excluded with 95% confidence. Biodosimetry included GPA analyses and chromosomal translocation analyses and indicated that the Estonian cleanup workers experienced a relatively low mean exposure of the order of 0.1 Gy. One value of the Estonian study is in the methodologic processes brought to bear in addressing possible health effects from the Chernobyl accident. Twenty-five years of research are summarised and opportunities for the future listed. PMID- 26512764 TI - Influence of interface stabilisers and surrounding aqueous phases on nematic liquid crystal shells. AB - We investigate the nematic-isotropic (N-I) transition in shells of the liquid crystal 5CB, surrounded by aqueous phases that conventionally are considered to be immiscible with 5CB. The aqueous phases contain either sodium dodecyl sulfate (SDS) or polyvinyl alcohol (PVA) as stabiliser, the former additionally promoting homeotropic director alignment. For all shell configurations we find a depression of the clearing point compared to pure 5CB, indicating that a non-negligible fraction of the constituents of the surrounding phases enter the shell, predominantly water. In hybrid-aligned shells, with planar outer and homeotropic inner boundary (or vice versa), the N-I transition splits into two steps, with a consequent three-step textural transformation. We explain this as a result of the order-enhancing effect of a monolayer of radially aligned SDS molecules adsorbed at the homeotropic interface. PMID- 26512765 TI - Capillary Index Score in acute ischemic stroke: interobserver reliability and correlation with neurological outcomes. AB - BACKGROUND: Collateral blood flow has been identified as a possible factor to evaluate when predicting neurological outcomes or selecting patients for endovascular therapy in acute ischemic stroke. The Capillary Index Score (CIS) has recently been proposed as a tool to select patients with sufficient collateral blood flow for vascularization and to predict good neurological outcomes. We investigated the inter-rater agreement among reviewers of CIS and compared consensus scores to neurological outcomes. METHODS: We conducted a retrospective review of 29 randomly selected patients undergoing endovascular therapy for an occlusion in the middle cerebral artery or intracranial internal carotid artery. Patients' angiograms were reviewed by four reviewers of varying experience levels and given a CIS ranging from 0-3. A favorable CIS was 2 or 3 and an unfavorable CIS was 0 or 1. The inter-agreement of the reviewers was calculated using the kappa statistic. A consensus CIS was compared with good neurological outcome, defined as modified Rankin Scale scores (mRS<=2) at 90 days. RESULTS: The agreement between reviewers for the CIS ranged from kappa=0.66 0.97, indicating good to very good agreement. 92% of patients with favorable CIS had a positive neurological outcome compared to only 14% of unfavorable CIS patients. The number of patients with a favorable neurological outcome (mRS<=2) at 90 days was higher in the favorable CIS group (P<0.0001). CONCLUSIONS: CIS was a reproducible metric among physicians of varying experiences. Favorable CIS scores were a predictor of good neurological outcome and lower rates of intracranial hemorrhage. We believe that the Capillary Index Score can be used alongside other tools to improve patient selection for endovascular treatment. PMID- 26512766 TI - Middle Ear Response of Muc5ac and Muc5b Mucins to Nontypeable Haemophilus influenzae. AB - IMPORTANCE: Chronic otitis media with effusion is characterized by middle ear secretion of mucin glycoproteins, predominantly MUC5B; MUC5AC, the other secretory mucin studied frequently, has also been identified in the middle ear. Emerging evidence suggests a dichotomous role for these mucins in innate immune responses. We hypothesized that MUC5AC is an acute responder and MUC5B is expressed at later time points, reflecting a chronic situation. OBJECTIVE: To determine middle ear regulation of MUC5B and MUC5AC following in vitro bacterial and cytokine exposure. DESIGN, SETTING, AND SAMPLES: An in vitro cell-based model of mucin gene regulation was conducted in a basic science laboratory at a tertiary pediatric hospital. The study was conducted from July 1, 2014, to June 30, 2015; data analysis was performed in July 2015. INTERVENTIONS: Nontypeable Haemophilus influenzae (NTHi) lysates were generated and used to stimulate mouse middle ear epithelial cells (mMEECs) for 2 hours during 3 weeks. MAIN OUTCOMES AND MEASURES: Real-time quantitative polymerase chain reaction, luciferase assays, Western blot assay, and immunofluorescence techniques were performed to determine Muc5ac and Muc5b expression over time, Cxcl2 chemokine response, and nuclear factor-kappaB activation. Luciferase reporter assays were performed to evaluate specific promoter responses after NTHi exposure. RESULTS: Nontypeable H influenzae lysates (200 MUg/mL) drove differential mucin gene activation, with Muc5ac being induced up to 2.04 fold at 24 hours and 2.79 fold at 96 hours (P < .05) and Muc5b being induced only at more long-term points: 1.61 fold at 96 hours, 1.41 fold at 1 week, and 1.53 fold at 3 weeks (P < .05). Although NTHi lysates induced robust, early nuclear factor-kappaB nuclear translocation with nuclear factor-kappaB-dependent induction of Cxlc2 expression, the lysates had minimal to no effect on Muc5ac and Muc5b promoter activity. However, in contrast to NTHi lysates, CXCL2 induced significant transcription of both Muc5b and Muc5ac as early as 24 hours. CONCLUSIONS AND RELEVANCE: Nontypeable H influenzae lysates activate differential mucin gene activation in mMEECs. Although Muc5ac is an early response mucin gene, Muc5b appears to react as a chronic response mucin. PMID- 26512767 TI - Duramycin-induced calcium release in cancer cells. AB - Duramycin, through binding with phosphatidylethanolamine (PE), has shown potential to be an effective antitumour agent. However, its mode of action in relation to tumour cells is not fully understood. PE expression on the surface of a panel of cancer cell lines was analysed using duramycin and subsequent antibody labelling, and then analysed by flow cytometry. Cell viability was also assessed by flow cytometry using annexin V and propidium iodide. Calcium ion (Ca) release by tumour cells in response to duramycin was determined by spectrofluorometry following incubation with Fluo-3, AM. Confocal microscopy was performed on the cancer cell line AsPC-1 to assess real-time cell response to duramycin treatment. Duramycin could detect cell surface PE expression on all 15 cancer cell lines screened, which was shown to be duramycin concentration dependent. However, higher concentrations induced necrotic cell death. Duramycin induced calcium ion (Ca) release from the cancer cell lines also in a concentration-dependent and time-dependent manner. Confocal microscopy showed an influx of propidium iodide into the cells over time and induced morphological changes. Duramycin induces Ca release from cancer cell lines in a time-dependent and concentration-dependent manner. PMID- 26512768 TI - An overview of normocalcemic primary hyperparathyroidism. AB - PURPOSE OF REVIEW: Normocalcemic primary hyperparathyroidism (PHPT) received special attention in the publication of the conference proceedings from the Fourth International Workshop on the Management of Asymptomatic PHPT, although much remains unknown about the disorder. RECENT FINDINGS: Observational studies have found that despite maintaining normocalcemia, patients with normocalcemic PHPT have a high incidence of kidney stones and osteoporosis. Small studies focusing on the cardiovascular implications of normocalcemic PHPT have shown a possible association with hypertension and an atherogenic lipid profile, but not insulin resistance. Recent data from small cohorts show that subjects with normocalcemic PHPT respond to medical therapy and have a positive densitometric response following parathyroid surgery. SUMMARY: The available evidence suggests that patients with normocalcemic PHPT develop complications of PHPT, despite having normal calcium levels. Most data come from referral populations and information regarding a mild, asymptomatic form of the disease is lacking. Future research requires a standardized approach to the diagnostic criteria of normocalcemic PHPT. PMID- 26512769 TI - Diabetes and bone: biological and environmental factors. AB - PURPOSE OF REVIEW: Type 1 and type 2 diabetes mellitus are known to increase fracture risk. It is known that type 1 diabetes mellitus is associated with lower bone mineral density, but for type 2 diabetes mellitus, the real risk of increasing osteoporotic fractures is not explained by bone mineral density, which was found to be normal or paradoxically higher than controls in several studies, thus claiming for further investigations. This review summarizes some of the newest findings about factors that contribute to bone alterations in diabetic patients. RECENT FINDINGS: Most recent evidences showed that bone of diabetic patients presents a cortical porosity which is not captured by the bidimensional densitometric measurements as performed by dual energy X-ray absorptiometry. Other studies investigated bone matrix searching for molecular mechanisms underlying the reduced bone strength in diabetic patients. The loss of bone biomechanical properties in diabetes has been associated to the glycated collagen matrix induced by hyperglycemia. Other studies analyzed the effect on bone microarchitecture of the most common antidiabetic drugs. SUMMARY: Disease management of fracture risk in diabetic patients needs new methodologies of assessment that also take into account bone quality and evaluation of clinical risk factors, including balance, visual, and neurological impairments. PMID- 26512770 TI - Bone disease in post-transplant patients. AB - PURPOSE OF REVIEW: Mineral and bone disorders are common problems in organ transplant recipients. Successful transplantation solves many aspects of abnormal mineral and bone metabolism, but the degree of improvement is frequently incomplete. Posttransplant bone disease can affect long-term outcomes as well as increase the likelihood of fracture. In this article, we reviewed the major posttransplant bone diseases and recent advances in treatment strategies. RECENT FINDINGS: Pretransplant bone disease and immunosuppressants are important risk factors for posttransplant bone disease. Corticosteroid withdrawal may result in minimal or no protection against fractures, with increased risk for acute rejection. Vitamin D analogue and bisphosphonate are frequently used to prevent and treat posttransplant osteoporosis. Posttransplant hyperparathyroidism increases the risk for all-cause mortality and graft loss, but not major cardiovascular events. Cinacalcet was well tolerated and effectively controlled hypercalcemic hyperparathyroidism; however, it did not improve bone mineral density and discontinuation led to parathyroid hormone rebound. Six-month paricalcitol supplementation reduced parathyroid hormone levels and attenuated bone remodeling and mineral loss in case of posttransplant hyperparathyroidism. SUMMARY: Posttransplant bone diseases present in various forms, including osteoporosis, hyperparathyroidism, adynamic bone disease, and osteonecrosis. Prophylactic and therapeutic approaches to both pretransplant and posttransplant periods should be considered. PMID- 26512771 TI - Bone in trans persons. AB - PURPOSE OF REVIEW: We provide an update of bone health in trans persons on cross sex hormonal therapy. This drastic hormonal reversal will have direct but also indirect effects on bone, through body composition changes. RECENT FINDINGS: Recent evidence suggests that trans women, even before the start of any hormonal intervention, already have a lower bone mass, a higher frequency of osteoporosis, and a smaller bone size vs. natal men. During cross-sex hormonal treatment, bone mass was maintained or gained in trans women. In trans men, bone metabolism seemed to increase during short-term testosterone therapy, but no major changes have been found in bone density. On long-term testosterone therapy, larger cortical bone size was observed in trans men vs. natal women. SUMMARY: Follow-up of bone health and osteoporosis prevention in trans persons is important. We advise active assessment of osteoporosis risk factors including the (previous) use of hormonal therapy. Based on this risk profile and the intended therapy, bone densitometry may be indicated. Long-term use of antiandrogens or gonadotropin-releasing hormone agonists alone should be monitored as trans women may have low bone mass, even prior to treatment. Therapy compliance with the cross-sex hormones is of major concern, especially after gonadectomy. Large scaled, multicenter, and long-term research is needed to determine a well tolerated dosage of cross-sex hormonal treatment, also in elderly trans persons. PMID- 26512772 TI - Update on menopausal hormone therapy. AB - PURPOSE OF REVIEW: Menopause management has undergone an eventful journey over the past decade; some dogmas got refuted, some new hypotheses took life, and the review is timely and relevant to the practice of clinical medicine in 2015. RECENT FINDINGS: The field stepped out of an era of absolutes into times of patient centeredness and an individualized perspective. SUMMARY: The onus now is to tailor management to address patient's needs while keeping in perspective individualized symptom burden and risks that may be unique to each aging woman. PMID- 26512773 TI - Update on primary ovarian insufficiency. AB - PURPOSE OF REVIEW: Despite an incidence of 1% among women under the age of 40, primary ovarian insufficiency (POI) is still poorly understood. As the variable cause and presentation of POI complicate its management, a standard regimen for treatment remains to be established. However, emerging research has provided new insight on current mainstays of treatment as well as novel management approaches and therapeutic interventions. RECENT FINDINGS: Recent clinical trials in women with POI indicate that the widely used regimen of transdermal estradiol and medroxyprogesterone acetate restores bone mineral density to a level equal to women with normal ovarian function. Further research verifies that compounded bioidentical hormones and androgen supplementation are inadequate in treating POI and lowering risk for long-term sequelae. Additionally, assessing changes in bone turnover markers may be useful for monitoring bone mineral density. Alternative therapies such as acupuncture, dehydroepiandrosterone, and bupropion may be effective in treating the effects of estrogen deficiency at some level, but require further investigation. SUMMARY: Recent updates show promise in improving management methods and reducing risk of long-term sequelae. Additional research that expands upon the most current literature is critical to achieve an evidence based standard of best practice. PMID- 26512774 TI - Bone health after menopause. AB - PURPOSE OF REVIEW: This article reviews recent publications (January 2014-June 2015) on bone health and menopause. RECENT FINDINGS: Recent articles suggest that simple instruments, such as the osteoporosis self-assessment tool based on age and weight may identify women age 50-64 for bone mineral density (BMD) testing. Rescreening of women age 50-64 is not recommended because their overall risk of fracture is quite low. A novel risk factor for hip fracture among non-Caucasian women is socioeconomic status. Midlife women with low serum 25-hydroxyvitamin D (<20 ng/ml) have an increased risk of fracture over the menopausal transition and vitamin D supplementation is warranted. Wrist fractures are the most common fracture in women age 50-64. Women who experience a wrist fracture have an increased risk of subsequent fracture and should have a BMD scan. Results of studies using composite measures of femoral neck strength relative to load emphasize the need for osteoporotic research to move beyond BMD. SUMMARY: This recent research has provided new and important findings improving our understanding of osteoporosis during the menopausal transition. PMID- 26512775 TI - Progesterone or progestin as menopausal ovarian hormone therapy: recent physiology-based clinical evidence. AB - PURPOSE OF REVIEW: Provide evidence-based recent data on oral micronized progesterone (OMP) and progestins in menopausal hormonal therapy (MHT). RECENT FINDINGS: Medroxyprogesterone acetate (MPA) increases breast cancer acting through the glucocorticoid receptor; progestins in MHT increase thrombosis more than oral estrogens; MPA, but not OMP or other progestins, increase monocyte cell endothelium adhesion; MPA and estradiol (E2)/MPA have negative brain effects, whereas E2/progesterone (P4) has neuroregenerative brain effects. The 'window of opportunity' cardiovascular disease hypothesis is not supported by a randomized controlled trial showing that transdermal estradiol with sequential OMP in early menopause does not prevent increased carotid intimal media thickness; P4 in the cardiac electrical system opposes E2 effects and prevents sudden death/long QT syndrome; transdermal estradiol/OMP does not increase venous thromboembolism in observational data. P4 decreases breast cell proliferation and improves prognosis through P4 receptor alteration of estrogen receptor alpha genetic effects; OMP with conjugated equine estrogen (CEE)/estrogen (E)/E2 does not increase breast cancer in two prospective cohorts, one population-based. Endometrial cancer is increased in MHT of CEE/E/E2+cyclic OMP at 200 mg/day. SUMMARY: New data show CEE/E/E2+MPA/P mechanisms for negative breast cancer, venous thromboembolism, cardiovascular system, and brain effects. OMP/P4 counterbalances CEE/E/E2-related negative effects on breast cancer and long QT syndrome. OMP effectively treats vasomotor symptoms and sleep disturbances, and could safely be used alone for symptomatic menopause. PMID- 26512777 TI - TIP60-miR-22 axis as a prognostic marker of breast cancer progression. AB - MicroRNAs (miRNAs) are 22- to 24-nucleotide, small, non-coding RNAs that bind to the 3'UTR of target genes to control gene expression. Consequently, their dysregulation contributes to many diseases, including diabetes and cancer. miR-22 is up-regulated in numerous metastatic cancers and recent studies have suggested a role for miR-22 in promoting stemness and metastasis. TIP60 is a lysine acetyl transferase reported to be down-regulated in cancer but the molecular mechanism of this reduction is still unclear. In this study, we identify TIP60 as a target of miR-22. We show a negative correlation in the expression of TIP60 and miR-22 in breast cancer patients, and show that low levels of TIP60 and high levels of miR-22 are associated with poor overall survival. Furthermore, pathway analysis using high miR-22/low TIP60 and low miR-22/high TIP60 breast cancer patient datasets suggests association of TIP60/miR-22 with epithelial-mesenchymal transition (EMT), a key alteration in progression of cancer cells. We show that blocking endogenous miR-22 can restore TIP60 levels, which in turn decreases the migration and invasion capacity of metastatic breast cancer cell line. These results provide mechanistic insight into TIP60 regulation and evidence for the utility of the combination of TIP60 and miR-22 as prognostic indicator of breast cancer progression. PMID- 26512778 TI - Ki67/SATB1 ratio is an independent prognostic factor of overall survival in patients with early hormone receptor-positive invasive ductal breast carcinoma. AB - Biological diversity of breast cancer presents challenges for personalized therapy and necessitates multiparametric approaches to understand and manage the disease. Multiple protein biomarkers tested by immunohistochemistry (IHC), followed by digital image analysis and multivariate statistics of the data, have been shown to be effective in exploring latent profiles of tumor tissue immunophenotype. In this study, based on tissue microarrays of 107 patients with hormone receptor (HR) positive invasive ductal breast carcinoma, we investigated the prognostic value of the integrated immunophenotype to predict overall survival (OS) of the patients. A set of 10 IHC markers (ER, PR, HER2, Ki67, AR, BCL2, HIF-1alpha, SATB1, p53, and p16) was used. The main factor of the variance was characterized by opposite loadings of ER/PR/AR/BCL2 and Ki67/HIF-1alpha; it was associated with histological grade but did not predict OS. The second factor was driven by SATB1 expression along with moderate positive HIF-1alpha and weak negative Ki67 loadings. Importantly, this factor did not correlate with any clinicopathologic parameters, but was an independent predictor of better OS. Ki67 and SATB1 did not reach statistical significance as single predictors; however, high Ki67/SATB1 ratio was an independent predictor of worse OS. In addition, our data indicate potential double prognostic meaning of HIF-1alpha expression in breast cancer and necessitate focused studies, taking into account the immunophenotype interactions and tissue heterogeneity aspects. PMID- 26512779 TI - Doxycycline reverses epithelial-to-mesenchymal transition and suppresses the proliferation and metastasis of lung cancer cells. AB - The gelatinase inhibitor doxycycline is the prototypical antitumor antibiotic. We investigated the effects of doxycycline on the migration, invasion, and metastasis of human lung cancer cell lines and in a mouse model. We also measured the effect of doxycycline on the transcription of epithelial-mesenchymal transition (EMT) markers, and used immunohistochemistry to determine whether EMT reversal was associated with doxycycline inhibition. Doxycycline dose-dependently inhibited proliferation, migration, and invasion of NCI-H446 human small cell lung cancer cells. It also suppressed tumor growth from NCI-H446 and A549 lung cancer cell xenografts without altering body weight, inhibited Lewis lung carcinoma cell migration, and prolonged survival. The activities of the transcription factors Twist1/2, SNAI1/2, AP1, NF-kappaB, and Stat3 were suppressed by doxycycline, which reversed EMT and inhibited signal transduction, thereby suppressing tumor growth and metastasis. Our data demonstrate functional targeting of transcription factors by doxycycline to reverse EMT and suppress tumor proliferation and metastasis. Thus, doxycycline selectively targets malignant tumors and reduces its metastatic potential with less cytotoxicity in lung cancer patients. PMID- 26512780 TI - Anti-cancer efficacy of SREBP inhibitor, alone or in combination with docetaxel, in prostate cancer harboring p53 mutations. AB - Mutant p53 proteins (mutant p53s) have oncogenic gain-of-function properties correlated with tumor grade, castration resistance, and prostate cancer (PCa) tumor recurrence. Docetaxel is a standard first-line treatment for metastatic castration-resistant PCa (mCRPC) after the failure of hormone therapy. However, most mCRPC patients who receive docetaxel experience only transient benefits and rapidly develop incurable drug resistance, which is closely correlated with the p53 mutation status. Mutant p53s were recently reported to regulate the metabolic pathways via sterol regulatory element-binding proteins (SREBPs). Therefore, targeting the SREBP metabolic pathways with docetaxel as a combination therapy may offer a potential strategy to improve anti-tumor efficacy and delay cellular drug resistance in mCRPC harboring mutant p53s. Our previous data showed that fatostatin, a new SREBP inhibitor, inhibited cell proliferation and induced apoptosis in androgen receptor (AR)-positive PCa cell lines and xenograft mouse models. In this study, we demonstrated that mutant p53s activate the SREBP mediated metabolic pathways in metastatic AR-negative PCa cells carrying mutant p53s. By blocking the SREBP pathways, fatostatin inhibited cell growth and induced apoptosis in metastatic AR-negative PCa cells harboring mutant p53s. Furthermore, the combination of fatostatin and docetaxel resulted in greater proliferation inhibition and apoptosis induction compared with single agent treatment in PCa cells in vitro and in vivo, especially those with mutant p53s. These data suggest for the first time that fatostatin alone or in combination with docetaxel could be exploited as a novel and promising therapy for metastatic PCa harboring p53 mutations. PMID- 26512781 TI - A set of defined oncogenic mutation alleles seems to better predict the response to cetuximab in CRC patient-derived xenograft than KRAS 12/13 mutations. AB - Cetuximab is a standard of care for treating EGFR-expressing metastatic colorectal carcinoma (mCRC) exclusive of those with KRAS mutations at codons 12/13. However, retrospective analysis has recently suggested that KRAS-G13D patients can still benefit, while only a fraction of KRAS wild-type patients can benefit, from the treatment. We set out to test this contradicting issue experimentally in an independent cohort of patient derived xenograft (PDX) diseases. We conducted a mouse clinical trial (MCT) enrolling a random cohort of 27 transcriptome sequenced CRC-PDXs to evaluate cetuximab activity. The treatment responses were analyzed against the KRAS 12/13 mutation alleles, as well as several other well-known oncogenic alleles. If the response is defined by >80% tumor growth inhibition, 8/27 PDXs (~30%) are responders versus 19/27 non /partial responders (~70%). We found that indeed there are no significantly fewer KRAS-12/13-allele responders (4/8 or 50%) than non-/partial responders (7/19, or 37%). In particular, there are actually no fewer G13D responders (4/8, or 50%) than in non-/partial responders (2/19 or 10.5%) statistically. Furthermore, majority of the non-/partial responders tend to have certain activating oncogenic alleles (one or more of the following common ones: K/N-RAS-G12V/D, -A146T, Q61H/R, BRAF-V600E, AKT1-L52R and PIK3CA-E545G/K). Our data on an independent cohort support the recent clinical observation, but against the current practiced patient stratification in the cetuximab CRC treatment. Meanwhile, our data seem to suggest that a set of the six-oncogenic alleles may be of better predictive value than the current practiced stratification, justifying a new prospective clinical investigation on an independent cohort for confirmation. PMID- 26512782 TI - A Predictive Model for Parametrial Invasion in Patients With FIGO Stage IB Cervical Cancer: Individualized Approach for Primary Treatment. AB - OBJECTIVE: The aim of this study was to preoperatively identify high- and low risk subgroups of patients with parametrial involvement in those with FIGO (International Federation of Gynecology and Obstetrics) stage IB cervical cancer treated with radical hysterectomy according to menopause. MATERIALS AND METHODS: We retrospectively reviewed data of 197 patients with FIGO stage IB cervical cancer. None of the patients had definite evidence of parametrial invasion in a preoperative examination and underwent type III radical hysterectomy between February 2006 and March 2015. Preoperative risk criteria predicting parametrial involvement were identified in premenopausal and postmenopausal women, respectively. RESULTS: Tumor size on magnetic resonance imaging (MRI) more than 4 cm (odds ratio [OR], 10.029; 95% confidence interval [95% CI], 2.300-43.741; P = 0.002) and serum squamous cell carcinoma-antigen level of 3.60 ng/mL or more (OR, 4.132; 95% CI, 1.086-5.723; P = 0.037) were independent factors for parametrial invasion in premenopausal women. Significant factors associated with parametrial involvement in postmenopausal women were tumor size on MRI more than 3 cm (OR, 11.353; 95% CI, 2.614-49.306; P = 0.001) and Cyfra 21-1 level of 2.40 ng/mL or more (OR, 8.048; 95% CI, 1.240-52.221; P = 0.029). Patients were categorized into low- and high-risk groups according to risk criteria. Significant differences in the rates of parametrial invasion were observed between the groups (2.3% vs 38.6% in the premenopausal group, P < 0.001; 11.1% vs 77.3% in the postmenopausal group, P < 0.001). CONCLUSIONS: A model using preoperative tumor size on MRI, serum squamous cell carcinoma-antigen, and Cyfra 21-1 level was highly predictive of parametrial invasion in patients with FIGO stage IB cervical cancer. In particular, postmenopausal women were likely to have microscopic parametrial invasion, even among tumors 3 cm or less. Therefore, individualized approaches considering several preoperative factors are needed. PMID- 26512783 TI - Patient Support Groups Identifying Clinical Equipoise in UK Gynaecological Oncology Surgeons as the Basis for Trials in Ultraradical Surgery for Advanced Ovarian Cancer. AB - "Clinical equipoise" is defined as the genuine uncertainty by the expert medical community of the most beneficial treatment. A survey performed in 2013 by a patient support group, Ovacome, of gynaecological oncologists in the UK on ultra radical surgery in advanced ovarian cancer has shown that there is a wide variation in surgical practice across the country. In addition, there were mixed views on the quality of published evidence justifying it's performance, signifying a state of clinical equipoise. The survey also identified widespread insufficient infra-structural resources and lack of surgical training and skills. The majority of respondents would be prepared to undertake additional training to acquire the surgical skills and/or refer to other centres/surgeons already performing the surgery and/or recruit to surgical trials investigating ultra radical surgery in advanced ovarian cancer. PMID- 26512784 TI - Intraoperative Diagnosis Support Tool for Serous Ovarian Tumors Based on Microarray Data Using Multicategory Machine Learning. AB - OBJECTIVES: Serous borderline ovarian tumors (SBOTs) are a subtype of serous ovarian carcinoma with atypical proliferation. Frozen-section diagnosis has been used as an intraoperative diagnosis tool in supporting the fertility-sparing surgery by diagnosing SBOTs with accuracy of 48% to 79%. Using DNA microarray technology, we designed multicategory classification models to support frozen section diagnosis within 30 minutes. MATERIALS AND METHODS: We systematically evaluated 6 machine learning algorithms and 3 feature selection methods using 5 fold cross-validation and a grid search on microarray data obtained from the National Center for Biotechnology Information. To validate the models and selected biomarkers, expression profiles were analyzed in tissue samples obtained from the Yonsei University College of Medicine. RESULTS: The best accuracy of the optimal machine learning model was 97.3%. In addition, 5 features, including the expression of the putative biomarkers SNTN and AOX1, were selected to differentiate between normal, SBOT, and serous ovarian carcinoma groups. Different expression levels of SNTN and AOX1 were validated by real-time quantitative reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemistry. A multinomial logistic regression model using SNTN and AOX1 alone was used to construct a simple-to-use equation that gave a diagnostic test accuracy of 91.9%. CONCLUSIONS: We identified 2 biomarkers, SNTN and AOX1, that are likely involved in the pathogenesis and progression of ovarian tumors. An accurate diagnosis of ovarian tumor subclasses by application of the equation in conjunction with expression analysis of SNTN and AOX1 would offer a new accurate diagnosis tool in conjunction with frozen-section diagnosis within 30 minutes. PMID- 26512785 TI - The Factors Predicting Recurrence in Patients With Serous Borderline Ovarian Tumor. AB - OBJECTIVE: In this study, we aimed to demonstrate the characteristics, recurrence rates, survival, and factors associated with survival of patients with serous borderline ovarian tumor (BOT) who were operated on in a single institution. Our secondary goal was to evaluate the necessity of staging surgery and the importance of a comprehensive lymphadenectomy in these patients. MATERIALS AND METHODS: The patients who were diagnosed in our institution between January 1990 and April 2014 with a final diagnosis of serous BOT were evaluated retrospectively. Kaplan-Meier method was used for analysis of progression-free survival (PFS). Univariate Cox proportional hazards model and log rank test were used for analysis of continuous and categorical variables affecting survival, respectively. RESULTS: One hundred twenty-one (75%) patients underwent staging surgery. Stage I disease was observed in 63%, stage III was observed in 11% of the patients, and only 0.6% of patients had stage II disease. Among 162 patients, 72 patients (44%) had conservative surgery. Eight (4.9%) patients had recurrence, one of which was invasive. All recurrences were in the patients who had conservative surgery. Median follow-up of the patients was 57 months (range, 37 270 years). Five- and 10-year PFS rates were 94.9% and 92.8%, respectively. In the univariate analysis of patients with serous BOT, PFS was worse in the presence of positive para-aortic lymph nodes, positive abdominal cytology, and conservative surgery (P = 0.008, P < 0.001, P = 0.007, respectively). The patients having noninvasive implant and advanced-stage disease had a tendency to have worse PFS (P = 0.067, P = 0.069, respectively). CONCLUSIONS: Staging surgery generally gives us an idea of the probability of recurrence but not an idea of overall survival. Therefore, staging surgery including lymphadenectomy could be suggested to have information about the probability of recurrence and to be able to detect patients with an invasive implant that is the only probable factor affecting overall survival. PMID- 26512786 TI - Clinical Characteristics of Gestational Trophoblastic Neoplasia: A 15-Year Hospital-Based Study. AB - OBJECTIVE: To analyze the clinical profile of invasive mole (IM) and choriocarcinoma (CCA) in the past 15 years in Western China. MATERIALS AND METHODS: A retrospective study was performed on 221 patients with IM and 70 patients with CCA treated in the First Affiliated Hospital of Xi'an Jiaotong University from 1994 to 2009. Patients were assigned into 3 groups by 5 years, and the clinical characteristics were compared among these groups. RESULTS: The incidence was not significantly changed in the past 15 years, whereas the mean age of gestational trophoblastic neoplasia (GTN) was increased significantly, especially for the patients 40 years or older. The symptoms of the patients with GTN did not show significant variation, but the number of patients with CCA without clinical symptoms was increased significantly. The mean values of beta human chorionic gonadotropin in the patients with IM and those with CCA were 459.43 and 661.70 mIu/L, respectively, and the size of uterine lesion was concentrated at 4 cm or less in both the patients with IM and those with CCA, without significant differences. CONCLUSIONS: In the past 15 years, the incidence of GTN was still higher than in other countries from 1994 to 2009, and the mean age of patients with GTN was increased significantly, especially for the patients older than 40 years. Furthermore, patients with no clinical manifestations increased significantly, which should be paid more attention in the future works. Serum level of beta human chorionic gonadotropin and pelvic ultrasonography are still 2 important indexes for diagnosing and monitoring condition of GTN. PMID- 26512787 TI - Pregnancy Outcomes After Abdominal Radical Trachelectomy for Early-Stage Cervical Cancer: A 13-Year Experience in a Single Tertiary-Care Center. AB - OBJECTIVE: To investigate pregnancy outcomes in women after abdominal radical trachelectomy (RT) for early-stage cervical cancer. METHODS: The patients' background, fertility, and pregnancy outcomes were reviewed in a total of 61 pregnancies in 48 of 172 women who underwent abdominal RT at Keio University Hospital between September 2002 and December 2013. RESULTS: There were 5 women with stage IA1, 2 with stage IA2, and 41 with stage IB1. Histological types were as follows: squamous cell carcinoma (n = 36), adenocarcinoma (n = 10), and adenosquamous cell carcinoma (n = 2). The pregnancy rate of women attempting to conceive after abdominal RT was 44% (48/109). The mean +/- SD duration from abdominal RT to conception was 3.1 +/- 1.9 years. Of 61 pregnancies, 42 pregnancies were achieved by fertility treatment (in vitro fertilization-embryo transfer, 39; intrauterine insemination, 3). After excluding one pregnancy without detailed clinical information, there were 42 live births (5 in 22-27 weeks, 11 in 28-33weeks, 20 in 34-36 weeks, and 6 in 37-38 weeks), 13 miscarriages, and 5 ongoing pregnancies. While there were 10 first trimester miscarriages, 3 pregnancies ended in the second trimester owing to chorioamnionitis. The mean gestational age at birth was 33 weeks of pregnancy. Thirty-seven neonates were appropriate-for-date, and one was small-for-date. Six pregnancies exhibited massive bleeding from the residual cervix in the late pregnancy. Preterm birth less than 34 weeks of pregnancy was related to premature rupture of the membrane (P < 0.05). Chorioamnionitis was evident in 9 of 11 pregnancies with preterm premature rupture of the membrane followed by birth at less than 34 weeks of pregnancy. No parturients exhibited lochiometra and endometritis postpartum. CONCLUSIONS: Abdominal RT provided favorable pregnancy outcomes, and fertility treatment could be advantageous to conception. Massive bleeding from the residual cervix as well as ascending infection might be characteristic features during pregnancy after abdominal RT. PMID- 26512788 TI - Overexpression of Siah2 Is Associated With Poor Prognosis in Patients With Epithelial Ovarian Carcinoma. AB - OBJECTIVES: Seven in absentia homolog 2 (Siah2) is an E3 ubiquitin ligase that is expressed in mammals and is homologous to seven in absentia in Drosophila. Siah2 is involved in the progression of many malignancies. However, the role of Siah2 in ovarian cancer remains unclear. This study aims to evaluate the prognostic value of Siah2 expression for epithelial ovarian carcinoma (EOC) patients. MATERIALS AND METHODS: Immunohistochemical analysis was conducted using 32 normal ovarian specimens and 122 ovarian carcinoma specimens, respectively. We analyzed the correlations of Siah2 expression with the clinicopathological factors and prognosis of ovarian cancer patients. chi Analysis, Kaplan-Meier method, and multivariate Cox proportional hazard analysis were conducted for statistical analyses. RESULTS: Immunohistochemical staining demonstrated that the expression of Siah2 was higher in the EOC tissues than in the normal tissues. High Siah2 expression positively correlated with histological grade and lymph node metastasis but not with age, histologic type, International Federation of Gynecology and Obstetrics staging, and CA125. Patients with positive Siah2 expression showed lower overall survival and disease-free survival rates than those with negative Siah2 expression (P < 0.05 for both). Multivariate Cox analysis indicated that Siah2 was an independent parameter for overall survival (hazards ratio, 2.166; 95% confidence interval, 1.182-3.970; P = 0.012) and disease-free survival (hazards ratio, 1.819; 95% confidence interval, 1.030 3.216; P = 0.039). CONCLUSIONS: Siah2 is possibly involved in tumor development and progression in EOC. Thus, Siah2 is a promising biomarker for predicting the prognosis of ovarian cancer patients and may serve as a novel target for treating ovarian carcinoma. PMID- 26512789 TI - Regulatory T Cells Suppress Natural Killer Cell Immunity in Patients With Human Cervical Carcinoma. AB - OBJECTIVE: To determine the functional attributes of CD4 CD25 regulatory T (Treg) cells by suppressing natural killer (NK) cell activity in human cervical cancer (CC). METHODS: Triple-color flow cytometry was used to study the phenotypic expression of CD4 CD25 Treg cells and NK cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs). In vitro coculture assays were performed to illustrate the cytokine immunoregulations between Treg cells and NK cells. RESULTS: Significantly lower expression ratio of NK cells and higher expression ratio of Treg cells in TILs than PBLs were found. The NK cells displayed significantly higher expression ratio of inhibitory NK receptors (CD158a, CD158b, and NKG2A) and lower expression ratio of activating NK receptors (NKG2D, NKp46, and NKp30) as well as perforin in TILs than PBLs, suggesting the suppressed cytotoxicity of the NK cells in the CC tumor milieu. The expression ratio of transforming growth factor-beta1 (TGF-beta1) on Treg cells as well as TGF-betaRII on Treg cells and NK cells was significantly higher in TILs than PBLs. Further functional in vitro assays demonstrated that NK cell function was suppressed by Treg cells, mimicking the inhibition of TGF-beta on NK cells, and interleukin-2/interleukin-15 stimulation was able to restore the NK cell activity. CONCLUSIONS: These findings indicate that Treg cells in TILs may abrogate NK cell cytotoxicity through TGF-beta pathway, and therefore, Treg cell elimination may enhance NK cell activity and be a novel therapeutic strategy for CC. PMID- 26512790 TI - Utility Serum Marker HE4 for the Differential Diagnosis Between Endometriosis and Adnexal Malignancy. AB - OBJECTIVE: The aim of the study was to assess the utility of serum human epididymal secretory protein E4 (HE4) biomarker in the differential diagnosis of endometriosis and adnexal malignancies. METHODS: Multicentric prospective observational study between January 2010 and December 2011 in 4 European centers (Italy, Portugal, Latvia, and Spain) was carried out. We collected 981 healthy patients diagnosed with adnexal patology and selected 65 patients diagnosed with endometriosis and analyzed their serum markers CA125, HE4, and Risk of Ovarian Malignancy Algorithm (ROMA) index. We also analyzed all cases of malignant histology and divided them according to CA125 levels (negative, <=35 U/mL; intermediate, >35-150 U/mL; and highly positive, >150 U/mL). RESULTS: HE4 was positive only in 1.5% of cases, CA125 in 64.6%, and ROMA index in 14.1%. In the subgroup intermediate CA125 values, positive HE4 is very specific (91.2%) correctly classifying patients with benign disease, but with lower sensibility (66.1%); however, ROMA index showed a high sensibility (89.3%), with a false positive rate of 42.8%. CONCLUSIONS: HE4 can be a very useful biomarker to exclude malignant disease in patients with endometriosis. PMID- 26512791 TI - Granulomatous nephritis and dermatitis in a patient with BRAF V600E mutant metastatic melanoma treated with dabrafenib and trametinib. AB - A 61-year-old man was diagnosed with stage IIIB BRAF V600E mutant melanoma in October 2012. He was treated with a combination therapy of dabrafenib and trametinib. He remained in complete remission for 18 months and the treatment was well tolerated after dose reduction because of pyrexia. In March 2013, he developed bilateral pitting edema of the legs with an erythematous, slightly infiltrated rash on his back and upper arms. His face was edematous, with a heliotrope rash-like aspect. Eye examination showed bilateral blepharitis. Additional blood test showed inflammation and acute kidney injury Rifle category failure. A skin and kidney biopsy indicated a granulomatous inflammation. A complete workup for other causes of granulomatous inflammation was negative. Treatment with dabrafenib and trametinib was stopped and corticosteroids were initiated, with a rapid beneficial effect on both the kidney function and skin rash. When corticosteroids were halted after 1 month, a rapid decline in the kidney function was observed. After reintroduction of corticosteroids, kidney function normalized and steroids could be tapered gradually over 6 months. To our knowledge, interstitial nephritis has not been described in patients on BRAF targeted nor MEK-targeted therapy for melanoma, although it has been described in a melanoma patient treated with the immune checkpoint inhibitor, ipilimumab. Currently, the patient has no sign of local or distal recurrence of melanoma, notwithstanding that treatment with dabrafenib and trametinib has been stopped for 10 months and no other antimelanoma therapy was initiated. PMID- 26512792 TI - Finely tuning MOFs towards high-performance post-combustion CO2 capture materials. AB - CO2 capture science and technology, particularly for the post-combustion CO2 capture, has become one of very important research fields, due to great concern of global warming. Metal-organic frameworks (MOFs) with a unique feature of structural fine-tunability, unlike the traditional porous solid materials, can provide many and powerful platforms to explore high-performance adsorbents for post-combustion CO2 capture. Until now, several strategies for finely tuning MOF structures have been developed, in which either the larger quadrupole moment and polarizability of CO2 are considered: metal ion change (I), functional groups attachment (II) and functional group insertion (III), vary the electronic nature of the pore surface; or targeting the smaller kinetic diameter of CO2 over N2 is focused on: framework interpenetration (IV), ligand shortening (V) and coordination site shifting (VI) contract the pore size of frameworks to improve their CO2 capture properties. In this review, from the viewpoint of synthetic materials scientists/chemists, we would like to introduce and summarize these strategies based upon recent work published by other groups and ourselves. PMID- 26512793 TI - Predicted Indirectly Recognizable HLA Epitopes Presented by HLA-DRB1 Are Related to HLA Antibody Formation During Pregnancy. AB - Pregnancy can prime maternal immune responses against inherited paternal HLA of the fetus, leading to the production of child-specific HLA antibodies. We previously demonstrated that donor-specific HLA antibody formation after kidney transplantation is associated with donor-derived HLA epitopes presented by recipient HLA class II (predicted indirectly recognizable HLA epitopes presented by HLA class II [PIRCHE-II]). In the present study, we evaluated the role of PIRCHE-II in child-specific HLA antibody formation during pregnancy. A total of 229 mother-child pairs were HLA typed. For all mismatched HLA class I molecules of the child, we subsequently predicted the number of HLA epitopes that could be presented by maternal HLA class II molecules. Child-specific antigens were classified as either immunogenic or nonimmunogenic HLA based on the presence of specific antibodies and correlated to PIRCHE-II numbers. Immunogenic HLA contained higher PIRCHE-II numbers than nonimmunogenic HLA. Moreover, the probability of antibody production during pregnancy increased with the number of PIRCHE-II. In conclusion, our data suggest that the number of PIRCHE-II is related to the formation of child-specific HLA antibodies during pregnancy. Present confirmation of the role of PIRCHE-II in antibody formation outside the transplantation setting suggests the PIRCHE-II concept is universal. PMID- 26512794 TI - Low-Bandgap Small-Molecule Donor Material Containing Thieno[3,4-b]thiophene Moiety for High-Performance Solar Cells. AB - By replacing the central thiophene of STDR, a sepithiophene terminated with two 3 ethylrhodanine moieties, with 2-ethylhexyl 3-fluorothieno[3,4-b]thiophene-2 carboxylate, an A-D-Q-D-A-type small molecule has been developed for high performance organic solar cells with improved photocurrent. STDR-TbT exhibits a significant bathochromic shift with a low optical bandgap of approximately 1.60 eV in the thin film. Accordingly, STDR-TbT shows broad external quantum efficiency spectral response up to 800 nm. A high short circuit current (Jsc) of 10.90 mA cm(-2) was achieved for STDR-TbT:PC71BM-based devices; this is significantly higher than that of STDR:PC71BM-based devices, Jsc: 5.61 mA cm(-2), with a power-conversion efficiency (PCE) of 5.05%. Compared with STDR-based devices, STDR-TbT-based devices show balanced charge carrier transport, better thin-film morphology, and favorable charge separation/collection. PMID- 26512795 TI - Detailed Monte Carlo Simulation of electron transport and electron energy loss spectra. AB - A computer program for detailed Monte Carlo simulation of the transport of electrons with kinetic energies in the range between about 0.1 and about 500 keV in bulk materials and in thin solid films is presented. Elastic scattering is described from differential cross sections calculated by the relativistic (Dirac) partial-wave expansion method with different models of the scattering potential. Inelastic interactions are simulated from an optical-data model based on an empirical optical oscillator strength that combines optical functions of the solid with atomic photoelectric data. The generalized oscillator strength is built from the adopted optical oscillator strength by using an extension algorithm derived from Lindhard's dielectric function for a free-electron gas. It is shown that simulated backscattering fractions of electron beams from bulk (semi-infinite) specimens are in good agreement with experimental data for beam energies from 0.1 keV up to about 100 keV. Simulations also yield transmitted and backscattered fractions of electron beams on thin solid films that agree closely with measurements for different film thicknesses and incidence angles. Simulated most probable deflection angles and depth-dose distributions also agree satisfactorily with measurements. Finally, electron energy loss spectra of several elemental solids are simulated and the effects of the beam energy and the foil thickness on the signal to background and signal to noise ratios are investigated. SCANNING 38:475-491, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26512796 TI - Oral Fluoroquinolones and the Risk of Uveitis. AB - IMPORTANCE: Fluoroquinolones are the most commonly prescribed antibiotic class in the outpatient setting. Recent reports have implicated an association between oral fluoroquinolones and an increased risk of uveitis. OBJECTIVE: To determine the hazard of uveitis with oral fluoroquinolone use. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted using medical claims data from a large national US insurer (N = 4,387,651). Cohorts from ambulatory care centers across the United States were created including every new user of an oral fluoroquinolone or beta-lactam antibiotic prescription with at least 24 months of data prior to the date of the prescription from January 1, 2000, to January 30, 2013. Exclusion criteria consisted of any previous diagnosis of uveitis or a uveitis-associated systemic illness. Participants were censored for a new diagnosis of a uveitis-associated systemic illness, the end of an observation period, use of the other class of antibiotic, or removal from the insurance plan. Data analysis was performed from January 2 through March 15, 2015. MAIN OUTCOMES AND MEASURES: The hazard of a uveitis diagnosis after a fluoroquinolone prescription compared with a beta-lactam prescription using multivariate regression with Cox proportional hazards models. RESULTS: Of the 4,387,651 patients in the database, 843,854 individuals receiving a fluoroquinolone and 3,543,797 patients receiving a beta-lactam were included in the analysis. After controlling for age, race, and sex using multivariate analysis, no hazard for developing uveitis at the 30-, 60-, or 90-day observation windows was seen (hazard ratio [HR] range, 0.96; 95% CI, 0.82-1.13; to 1.05; 95% CI, 0.95-1.16; P > .38 for all comparisons). The 365-day observation period showed a small increase in the HR for the fluoroquinolone cohort (1.11; 95% CI, 1.05-1.17; P < .001). Moxifloxacin produced an increased hazard for uveitis at every time point (HR range, 1.47-1.75; 95% CI, 1.27-2.37; P < .001 for all comparisons). Secondary analysis demonstrated a similar hazard at 365 days for a later diagnosis of a uveitis-associated systemic illness after fluoroquinolone use (HR range, 1.46-1.96; 95% CI, 1.42-2.07; P < .001 for all comparisons). CONCLUSIONS AND RELEVANCE: These data do not support an association between oral fluoroquinolone use and uveitis. Instead, this study shows an association between oral fluoroquinolone use and the risk for uveitis-associated systemic illnesses, which is a possible source of bias that could explain the findings of previous studies. PMID- 26512797 TI - The clinical management of COPD exacerbations: an update. AB - Clinical management of chronic obstructive pulmonary disease (COPD) exacerbations is of high importance because exacerbations reduce quality of life, increase mortality and carry high socioeconomic costs. Still, a quarter of patients with an acute exacerbation do not respond adequately to initial exacerbation treatment. Yet, research from recent years has advanced the clinical management of COPD exacerbations. Prediction of exacerbations can be improved by asking patients about their exacerbation history. The duration of oral corticosteroid treatment has been optimized, new oral- and inhalation medication has become available and important knowledge has been gathered about the risks and benefits of inhalation corticosteroids, which we will discuss in this editorial. Still, future research is needed to tailor treatment strategies for specific COPD phenotypes. PMID- 26512798 TI - Commercial Scale Cucumber Fermentations Brined with Calcium Chloride Instead of Sodium Chloride. AB - Development of low salt cucumber fermentation processes present opportunities to reduce the amount of sodium chloride (NaCl) that reaches fresh water streams from industrial activities. The objective of this research was to translate cucumber fermentation brined with calcium chloride (CaCl2 ) instead of NaCl to commercial scale production. Although CaCl2 brined cucumber fermentations were stable in laboratory experiments, commercial scale trials using 6440 L open-top tanks rapidly underwent secondary cucumber fermentation. It was understood that a limited air purging routine, use of a starter culture and addition of preservatives to the cover brine aids in achieving the desired complete cucumber fermentation. The modified process was used for subsequent commercial trials using 12490 and 28400 L open-top tanks packed with variable size cucumbers and from multiple lots, and cover brines containing CaCl2 and potassium sorbate to equilibrated concentrations of 100 and 6 mM, respectively. Lactobacillus plantarum LA0045 was inoculated to 10(6) CFU/mL, and air purging was applied for two 2-3 h periods per day for the first 10 d of fermentation and one 2-3 h period per day between days 11 and 14. All fermentations were completed, as evidenced by the full conversion of sugars to lactic acid, decrease in pH to 3.0, and presented microbiological stability for a minimum of 21 d. This CaCl2 process may be used to produce fermented cucumbers intended to be stored short term in a manner that reduces pollution and waste removal costs. PMID- 26512799 TI - Genes involved in the regulation of intestinal permeability and their role in ulcerative colitis. AB - OBJECTIVE: Genome-wide association studies have identified single nucleotide polymorphisms in genes that might influence intestinal barrier function (HNF4A, ECM1, CDH1 and LAMB1) to increase the risk for ulcerative colitis (UC). The aim of our study was to detect causative sequence alterations and provide a functional link to a disturbed intestinal permeability (IP) in UC. METHODS: A total of 19 UC patients with increased IP (lactulose/mannitol ratio measured by sugar drink test) were identified from a large database, and exon/intron boundaries, coding and promoter regions of HNF4A, ECM1, CDH1 and LAMB1 were sequenced. Variants with putative protein alterations were studied for an association with IP in 82 UC patients. A case-control analysis including a genotype phenotype correlation was performed in 743 patients with inflammatory bowel disease (IBD) and 473 healthy controls. RESULTS: In UC patients, we identified 11 missense-mutations, 12 synonymous mutations, one putative promoter variant and three variants in introns close to the intron/exon boundaries (CDH1, HNF4A). For several variants prediction tools revealed damaging protein alterations. None of the studied variants, however, showed an association with an increased IP in UC. In the case-control analysis, the frequency of all investigated variants did not differ between UC or Crohn's disease and healthy controls. Furthermore, no significant association was found to a distinct phenotype. CONCLUSIONS: Despite our large sequencing approach, we could not identify protein altering variants in the genes HNF4A, ECM1, CDH1 and LAMB1 which could explain an impaired intestinal barrier function in UC. The functional relevance of these genes in IBD remains unknown. PMID- 26512800 TI - Life cycle cost of a hybrid forward osmosis - low pressure reverse osmosis system for seawater desalination and wastewater recovery. AB - In recent years, forward osmosis (FO) hybrid membrane systems have been investigated as an alternative to conventional high-pressure membrane processes (i.e. reverse osmosis (RO)) for seawater desalination and wastewater treatment and recovery. Nevertheless, their economic advantage in comparison to conventional processes for seawater desalination and municipal wastewater treatment has not been clearly addressed. This work presents a detailed economic analysis on capital and operational expenses (CAPEX and OPEX) for: i) a hybrid forward osmosis - low-pressure reverse osmosis (FO-LPRO) process, ii) a conventional seawater reverse osmosis (SWRO) desalination process, and iii) a membrane bioreactor - reverse osmosis - advanced oxidation process (MBR-RO-AOP) for wastewater treatment and reuse. The most important variables affecting economic feasibility are obtained through a sensitivity analysis of a hybrid FO LPRO system. The main parameters taken into account for the life cycle costs are the water quality characteristics (similar feed water and similar water produced), production capacity of 100,000 m(3) d(-1) of potable water, energy consumption, materials, maintenance, operation, RO and FO module costs, and chemicals. Compared to SWRO, the FO-LPRO systems have a 21% higher CAPEX and a 56% lower OPEX due to savings in energy consumption and fouling control. In terms of the total water cost per cubic meter of water produced, the hybrid FO-LPRO desalination system has a 16% cost reduction compared to the benchmark for desalination, mainly SWRO. Compared to the MBR-RO-AOP, the FO-LPRO systems have a 7% lower CAPEX and 9% higher OPEX, resulting in no significant cost reduction per m(3) produced by FO-LPRO. Hybrid FO-LPRO membrane systems are shown to have an economic advantage compared to current available technology for desalination, and comparable costs with a wastewater treatment and recovery system. Based on development on FO membrane modules, packing density, and water permeability, the total water cost could be further reduced. PMID- 26512801 TI - Study of the photochemical transformation of 2-ethylhexyl 4 (dimethylamino)benzoate (OD-PABA) under conditions relevant to surface waters. AB - We studied the aquatic environmental fate of 2-ethylhexyl 4 (dimethylamino)benzoate (OD-PABA), a widespread sunscreen, to assess its environmental persistence and photoinduced transformation. Direct photolysis is shown to play a key role in phototransformation, and this fast process is expected to be the main attenuation route of OD-PABA in sunlit surface waters. The generation of transformation products (TPs) was followed via HPLC/HRMS. Five (or four) TPs were detected in the samples exposed to UVB (or UVA) radiation, respectively. The main detected TPs of OD-PABA, at least as far as HPLC-HRMS peak areas are concerned, would involve a dealkylation or hydroxylation/oxidation process in both direct photolysis and indirect phototransformation. The latter was simulated by using TiO2-based heterogeneous photocatalysis, involving the formation of nine additional TPs. Most of them resulted from the further degradation of the primary TPs that can also be formed by direct photolysis. Therefore, these secondary TPs might also occur as later transformation intermediates in natural aquatic systems. PMID- 26512802 TI - Monitoring and statistical modelling of sedimentation in gully pots. AB - Gully pots are essential assets designed to relief the downstream system by trapping solids and attached pollutants suspended in runoff. This study applied a methodology to develop a quantitative gully pot sedimentation and blockage model. To this end, sediment bed level time series from 300 gully pots, spanning 15 months, were collected. A generalised linear mixed modelling (GLMM) approach was applied to model and quantify the accumulation of solids in gully pots and to identify relevant physical and catchment properties that influence the complex trapping processes. Results show that the retaining efficiency decreases as sediment bed levels increase. Two typical silting evolutions were identified. Approximately 5% of all gully pots experienced progressive silting, eventually resulting in a blockage. The other gully pots show stabilising sediment bed levels. The depth of the sand trap, elapsed time since cleaning and the road type were identified to be the main properties discriminating progressive accumulation from stabilising sediment bed levels. Furthermore, sediment bed levels exhibit no residual spatial correlation, indicating that the vulnerability to a blockage is reduced as adjacent gully pots provide a form of redundancy. The findings may aid to improve maintenance strategies in order to safeguard the performance of gully pots. PMID- 26512803 TI - Efficient nitro reduction and dechlorination of 2,4-dinitrochlorobenzene through the integration of bioelectrochemical system into upflow anaerobic sludge blanket: A comprehensive study. AB - Bioelectrochemical system (BES) coupled upflow anaerobic sludge blanket (UASB) was developed for the removal of recalcitrant pollutants but lack of a comprehensive study. Thus in this study an integrated UASB-BES system was operated continuously for 240 d to systematically investigate the feasibility of the enhanced reduction of 2,4-dinitrochlorobenzene (DNCB), with the key operation parameters, the system stability as well as the microbial biodiversity emphasized. The results indicate that high voltage supplied had a positive effect on DNCB reduction but a negative impact for the overhigh voltage (>1.6 V). The ability to resist shock loading was strengthened in the UASB-BES system in comparison with the control UASB system. High-throughput sequencing analysis suggested that the enhanced reduction of DNCB in UASB-BES could be attributed to higher diversity and the enrichment of reduction-related species, potential electroactive species and fermentative species. Both DNCB removal and dechlorination gradually increased with the increase of operation time, indicating the improved performance of the coupled UASB-BES system. The heatmap visualized only slight differences in the microbial community during long-term operation, indicating the stability of the microbial community. The observed efficient and stable performance highlights the potential for long-term operation and full-scale application of the UASB-BES coupled system particularly for highly recalcitrant pollutants removal. PMID- 26512804 TI - Bioelectricity inhibits back diffusion from the anolyte into the desalinated stream in microbial desalination cells. AB - Microbial desalination cells (MDCs) taking advantage of energy in wastewater to drive desalination represent a promising approach for energy-efficient desalination, but concerns arise whether contaminants in wastewater could enter the desalinated stream across ion exchange membranes. Such back diffusion of contaminants from the anolyte into the desalinated stream could be controlled by two mechanisms, Donnan effect and molecule transport. This study attempted to understand those mechanisms for inorganic and organic compounds in MDCs through two independently conducted experiments. Donnan effect was found to be the dominant mechanism under the condition without current generation. Under open circuit condition, the MDC fed with 5 g L(-1) salt solution exhibited 1.9 +/- 0.7%, 10.3 +/- 1.3%, and 1.8 +/- 1.2% back diffusion of acetic, phosphate, and sulfate ions, respectively. Current generation effectively suppressed Donnan effect from 68.2% to 7.2%, and then molecule transport became more responsible for back diffusion. A higher initial salt concentration (35 g L(-1)) and a shorter HRT (1.0 d) led to the highest concentration gradient, resulting in the most back diffusion of 7.1 +/- 1.2% and 6.8 +/- 3.1% of phosphate and sulfate ions, respectively. Three representative organic compounds were selected for test, and it was found that organic back diffusion was intensified with a higher salt concentration gradient and molecular weight played an important role in compound movement. Principal component analysis confirmed the negative correlation between Donnan effect and current, and the positive correlation between molecule transport and concentration gradient related conditions. PMID- 26512805 TI - Critical role of surface roughness on colloid retention and release in porous media. AB - This paper examines the critical role of surface roughness (both nano- and micro scale) on the processes of colloid retention and release in porous media under steady-state and transient chemical conditions. Nanoscale surface roughness (NSR) in the order of a few nanometers, which is common on natural solid surfaces, was incorporated into extended-DLVO calculations to quantify the magnitudes of interaction energy parameters (e.g. the energy barrier to attachment, DeltaPhia , and detachment, DeltaPhid , from a primary minimum). This information was subsequently used to explain the behavior of colloid retention and release in column and batch experiments under different ionic strength (IS) and pH conditions. Results demonstrated that the density and height of NSR significantly influenced the interaction energy parameters and consequently the extent and kinetics of colloid retention and release. In particular, values of DeltaPhia and DeltaPhid significantly decreased in the presence of NSR. Therefore, consistent with findings of column experiments, colloid retention in the primary minimum was predicted to occur at some specific locations on the sand surface, even at low IS conditions. However, NSR yielded a much weaker primary minimum interaction compared with that of smooth surfaces. Colloid release from primary minima upon decreasing IS and increasing pH was attributed to the impact of NSR on the values of DeltaPhid . Pronounced differences in the amount of colloid retention in batch and column experiments indicated that primary minimum interactions were weak even at high IS conditions. Negligible colloid retention in batch experiments was attributed to hydrodynamic torques overcoming adhesive torques, whereas significant colloid retention in column experiments was attributed to nano- and micro-scale roughness which would dramatically alter the lever arms associated with hydrodynamic and adhesive torques. PMID- 26512806 TI - Nanocarbon-based membrane filtration integrated with electric field driving for effective membrane fouling mitigation. AB - Membrane filtration provides an effective solution for removing pollutants from water but is limited by serious membrane fouling. In this work, an effective approach was used to mitigate membrane fouling by integrating membrane filtration with electropolarization using an electroconductive nanocarbon-based membrane. The electropolarized membrane (EM) by alternating square-wave potentials between +1.0 V and -1.0 V with a pulse width of 60 s exhibited a permeate flux 8.1 times as high as that without electropolarization for filtering feed water containing bacteria, which confirms the ability of the EM to achieve biofouling mitigation. Moreover, the permeate flux of EM was 1.5 times as high as that without electropolarization when filtrating natural organic matter (NOM) from water, and demonstrated good performance in organic fouling mitigation with EM. Furthermore, the EM was also effective for complex fouling mitigation in filtering water containing coexisting bacteria and NOM, and presented an increased flux rate 1.9 times as high as that without electropolarization. The superior fouling mitigation performance of EM was attributed to the synergistic effects of electrostatic repulsion, electrochemical oxidation and electrokinetic behaviors. This work opens an effective avenue for membrane fouling mitigation of water treatment membrane filtration systems. PMID- 26512807 TI - Microbial responses to membrane cleaning using sodium hypochlorite in membrane bioreactors: Cell integrity, key enzymes and intracellular reactive oxygen species. AB - Sodium hypochlorite (NaClO) is a commonly used reagent for membrane cleaning in membrane bioreactors (MBRs), while it, being a kind of disinfectant (oxidant), may impair viability of microbes or even totally inactivate them upon its diffusion into mixed liquor during membrane cleaning. In this study, we systematically examine the effects of NaClO on microorganisms in terms of microbial cell integrity, metabolism behaviours (key enzymes), and intracellular reactive oxygen species (ROS) under various NaClO concentrations. Different proportions of microbial cells in activated sludge were damaged within several minutes dependent on NaClO dosages (5-50 mg/g-SS), and correspondingly organic matters were released to bulk solution. Inhibition of key enzymes involved in organic matter biodegradation, nitrification and denitrification was observed in the presence of NaClO above 1 mg/g-SS, and thus organic matter and nitrogen removal efficiencies were decreased. It was also demonstrated that intracellular ROS production was increased with the NaClO dosage higher than 1 mg/g-SS, which likely induced further damage to microbial cells. PMID- 26512808 TI - Inhibition of alkaline flocculation by algal organic matter for Chlorella vulgaris. AB - Alkaline flocculation is a promising strategy for the concentration of microalgae for bulk biomass production. However, previous studies have shown that biological changes during the cultivation negatively affect flocculation efficiency. The influence of changes in cell properties and in the quality and composition of algal organic matter (AOM) were studied using Chlorella vulgaris as a model species. In batch cultivation, flocculation was increasingly inhibited over time and mainly influenced by changes in medium composition, rather than biological changes at the cell surface. Total carbohydrate content of the organic matter fraction sized bigger than 3 kDa increased over time and this fraction was shown to be mainly responsible for the inhibition of alkaline flocculation. The monosaccharide identification of this fraction mainly showed the presence of neutral and anionic monosaccharides. The addition of 30-50 mg L(-1) alginic acid, as a model for anionic carbohydrate polymers containing uronic acids, resulted in a complete inhibition of flocculation. These results suggest that inhibition of alkaline flocculation was caused by interaction of anionic polysaccharides leading to an increased flocculant demand over time. PMID- 26512809 TI - Prioritisation of odorants emitted from sewers using odour activity values. AB - Volatile sulfur and volatile organic compound (VSC and VOC, respectively) emissions were measured over a 3.5 year period from 21 field monitoring sites across Australia to determine their potential contribution to sewer odours and support the evaluation of odour abatement processes used to treat sewer emissions. Measured VOC concentrations were generally less than 250 MUg/m(3), although some VOCs (toluene, trimethylbenzene and cymene) were present at higher concentrations. In general, sewer headspace VOCs are unlikely to be a significant contributor to sewer odours and VOC monitoring is only recommended for sites with a history of significant trade waste discharges or where odour character descriptors are typical of VOCs. A range of VSCs were identified, including hydrogen sulfide, ethyl mercaptan, methyl mercaptan, dimethyl sulfide, dimethyl disulfide, dimethyl trisulfide, carbon disulfide, and carbonyl sulfide. From a concentration perspective, the VSCs were dominated by hydrogen sulfide, followed by methyl mercaptan, and then a range of sulfides. Significant variations in VSC concentration and relative importance were observed between the cities and all identified VSCs were potentially odorous. An odorant prioritisation methodology to identify key and high priority odorants was developed and successfully demonstrated. While some high priority VOCs were identified, VSCs (hydrogen sulfide, methyl mercaptan, dimethyl sulfide, and dimethyl disulfide) were the dominant priority odorants. A wider range of VSCs should be assessed in addition to hydrogen sulfide to improve the evaluation of odour abatement processes. PMID- 26512810 TI - Rapid degradation of sulphamethoxazole and the further transformation of 3-amino 5-methylisoxazole in a microbial fuel cell. AB - Sulphamethoxazole (SMX) is extensively used in humans and livestock, but its appearance in natural water raises environmental concerns. This study demonstrated that SMX and its degradation product, 3-amino-5-methylisoxazole (3A5MI), could be effectively degraded in microbial fuel cell (MFC) reactors. Approximately 85% of 20 ppm SMX was degraded within 12 h, and this was a more rapid biodegradation rate than has been previously shown in the literature. In addition, 3A5MI, a toxic chemical that forms in the SMX degradation process, can be further mineralized. The degradation products of SMX were detected by mass spectrometry, and three speculated by-products were confirmed with chemical standards. It was observed that nitrogen atoms of SMX were progressively eliminated during the degradation process, which may relate with the degradation of SMX and 3A5MI. An antibacterial activity test showed that the biotoxicity of SMX towards Shewanella oneidensis MR-1 and Escherichia coli DH5alpha was greatly reduced after MFC treatment. Moreover, the ATP level of the MFC microbe was nearly threefold higher than that in open-circuit controls, which may be related to the rapid degradation of SMX in MFCs. This study can facilitate further investigations about the biodegradation of SMX. PMID- 26512811 TI - Simultaneous nitritation-denitritation for the treatment of high-strength nitrogen in hypersaline wastewater by aerobic granular sludge. AB - Fish processing industries produce wastewater containing high amounts of salt, organic matter and nitrogen. Biological treatment of such wastewaters could be problematic due to inhibitory effects exerted by high salinity levels. In detail, high salt concentrations lead to the accumulation of nitrite due to the inhibition of nitrite-oxidizing bacteria. The feasibility of performing simultaneous nitritation and denitritation in the treatment of fish canning wastewater by aerobic granular sludge was evaluated, and simultaneous nitritation denitritation was successfully sustained at salinities up to 50 gNaCl L(-1), with a yield of over 90%. The total nitrogen concentration in the effluent was less than 10 mg L(-1) at salinities up to 50 gNaCl L(-1). Nitritation collapsed above 50 gNaCl L(-1), and then, the only nitrogen removal mechanism was represented by heterotrophic synthesis. In contrast, organic matter removal was not affected by salinity but was instead affected by the organic loading rate (OLR). Both COD and BOD removal efficiencies were over 90%. The COD fractionation analysis indicated that aerobic granules were able to remove more than 95% of the particulate organic matter. Finally, results obtained in this work noted that aerobic granular sludge had an excellent ability to adapt under adverse environmental conditions. PMID- 26512812 TI - Membrane biofouling in a wastewater nitrification reactor: Microbial succession from autotrophic colonization to heterotrophic domination. AB - Membrane biofouling is a complex process that involves bacterial adhesion, extracellular polymeric substances (EPS) excretion and utilization, and species interactions. To obtain a better understanding of the microbial ecology of biofouling process, this study conducted rigorous, time-course analyses on the structure, EPS and microbial composition of the fouling layer developed on ultrafiltration membranes in a nitrification bioreactor. During a 14-day fouling event, three phases were determined according to the flux decline and microbial succession patterns. In Phase I (0-2 days), small sludge flocs in the bulk liquid were selectively attached on membrane surfaces, leading to the formation of similar EPS and microbial community composition as the early biofilms. Dominant populations in small flocs, e.g., Nitrosomonas, Nitrobacter, and Acinetobacter spp., were also the major initial colonizers on membranes. In Phase II (2-4 d), fouling layer structure, EPS composition, and bacterial community went through significant changes. Initial colonizers were replaced by fast-growing and metabolically versatile heterotrophs (e.g., unclassified Sphingobacteria). The declining EPS polysaccharide to protein (PS:PN) ratios could be correlated well with the increase in microbial community diversity. In Phase III (5-14 d), heterotrophs comprised over 90% of the community, whereas biofilm structure and EPS composition remained relatively stable. In all phases, AOB and NOB were constantly found within the top 40% of the fouling layer, with the maximum concentrations around 15% from the top. The overall microbial succession pattern from autotrophic colonization to heterotrophic domination implied that MBR biofouling could be alleviated by forming larger bacterial flocs in bioreactor suspension (reducing autotrophic colonization), and by designing more specific cleaning procedures targeting dominant heterotrophs during typical filtration cycles. PMID- 26512813 TI - An 'omics' approach towards the characterisation of laboratory scale anaerobic digesters treating municipal sewage sludge. AB - In this study, laboratory scale digesters were operated to simulate potential shocks to the Anaerobic Digestion (AD) process at a 350 ML/day wastewater treatment plant. The shocks included high (42 degrees C) and low (32 degrees C) temperature (either side of mesophilic 37 degrees C) and a 20% loading of fats, oil and grease (FOG; 20% w:v). These variables were explored at two sludge retention times (12 and 20 days) and two organic loading rates (2.0 and 2.5 kgTS/m(3)day OLR). Metagenomic and metabolomic approaches were then used to characterise the impact of operational shocks in regard to temperature and FOG addition, as determined through monitoring of biogas production, the microbial profile and their metabolism. Results showed that AD performance was not greatly affected by temperature shocks, with the biggest impact being a reduction in biogas production at 42 degrees C that persisted for 32 +/- 1 days. The average biogas production across all digesters at the completion of the experiment was 264.1 +/- 76.5 mL/day, with FOG addition observed to significantly promote biogas production (+87.8 mL/day). Metagenomic and metabolomic analyses of the digesters indicated that methanogens and methane oxidising bacteria (MOB) were low in relative abundance, and that the ratio of oxidising bacteria (methane, sulphide and sulphate) with respect to sulphate reducing bacteria (SRB) had a noticeable influence on biogas production. Furthermore, increased biogas production correlated with an increase in short chain fatty acids, a product of the addition of 20% FOG. This work demonstrates the application of metagenomics and metabolomics to characterise the microbiota and their metabolism in AD digesters, providing insight to the resilience of crucial microbial populations when exposed to operational shocks. PMID- 26512814 TI - Resistance identification and rational process design in Capacitive Deionization. AB - Capacitive Deionization (CDI) is an electrochemical method for water desalination employing porous carbon electrodes. To enhance the performance of CDI, identification of electronic and ionic resistances in the CDI cell is important. In this work, we outline a method to identify these resistances. We illustrate our method by calculating the resistances in a CDI cell with membranes (MCDI) and by using this knowledge to improve the cell design. To identify the resistances, we derive a full-scale MCDI model. This model is validated against experimental data and used to calculate the ionic resistances across the MCDI cell. We present a novel way to measure the electronic resistances in a CDI cell, as well as the spacer channel thickness and porosity after assembly of the MCDI cell. We identify that for inflow salt concentrations of 20 mM the resistance is mainly located in the spacer channel and the external electrical circuit, not in the electrodes. Based on these findings, we show that the carbon electrode thickness can be increased without significantly increasing the energy consumption per mol salt removed, which has the advantage that the desalination time can be lengthened significantly. PMID- 26512816 TI - Imaging charge transfer in a cation-pi system: velocity-map imaging of Ag(+)(benzene) photodissociation. AB - Ag(+)(benzene) complexes are generated in the gas phase by laser vaporization and mass selected in a time-of-flight spectrometer. UV laser excitation at either 355 or 266 nm results in dissociative charge transfer (DCT), leading to neutral silver atom and benzene cation products. Kinetic energy release in translationally hot benzene cations is detected using a new instrument designed for photofragment imaging of mass-selected ions. Velocity-map imaging and slice imaging techniques are employed. In addition to the expected translational energy release, DCT of Ag(+)(benzene) produces a distribution of internally hot benzene cations. Compared with experiments at 355 nm, 266 nm excitation produces only slightly higher translational excitation and a much greater fraction of internally hot benzene ions. The maximum kinetic energy release in the photodissociation sets an upper limit on the Ag(+)(benzene) dissociation energy of 32.8 (+1.4/-1.5) kcal/mol. PMID- 26512815 TI - Clinicopathologic features of breast cancers that develop in women with previous benign breast disease. AB - BACKGROUND: Women with benign breast disease (BBD) have an increased risk of developing breast cancer (BC). Nearly 30% of all BCs develop in women with prior BBD. Information regarding features of the expected number of BCs after BBD would enhance individualized surveillance and prevention strategies for these women. In the current study, the authors sought to characterize BCs developing in a large cohort of women with BBD. METHODS: The current study cohort included 13,485 women who underwent breast biopsy for mammographic or palpable concerns between 1967 and 2001. Biopsy slides were reviewed and classified as nonproliferative disease, proliferative disease without atypia, or atypical hyperplasia. BCs were identified by follow-up questionnaires, medical records, and Tumor Registry data. BC tissues were obtained and reviewed. RESULTS: With median follow-up of 15.8 years, 1273 women developed BC. The majority of BCs were invasive (81%), of which 61% were ductal, 13% were mixed ductal/lobular, and 14% were lobular. Approximately two-thirds of the BC cases were intermediate or high grade, and 29% were lymph node positive. Cancer characteristics were similar across the 3 histologic categories of BBD, with a similar frequency of ductal carcinoma in situ, invasive disease, tumor size, time to invasive BC, histologic type of BC, lymph node positivity, and human epidermal growth factor receptor 2 positivity. Women with atypical hyperplasia were found to have a higher frequency of estrogen receptor-positive BC (91%) compared with women with proliferative disease without atypia (80%) or nonproliferative disease (85%) (P = .02). CONCLUSIONS: A substantial percentage of all BCs develop in women with prior BBD. The majority of BCs after BBD are invasive tumors of ductal type, with a substantial number demonstrating lymph node positivity. Of all the BCs in the current study, 84% were estrogen receptor positive. Prevention therapy should be strongly encouraged in higher-risk women with BBD. PMID- 26512817 TI - Combined impact of healthy lifestyle factors on risk of atrial fibrillation: Prospective study in men and women. AB - BACKGROUND: The combined impact of multiple lifestyle factors on risk of atrial fibrillation (AF) remains unclear. We investigated the joint association of four modifiable lifestyle factors on incidence of AF in a prospective study of men and women. METHODS: The study cohort comprised 39 300 men in the Cohort of Swedish Men and 33 090 women in the Swedish Mammography Cohort who were 45-83 years of age and free from atrial fibrillation at baseline. Healthy lifestyle was defined as body mass index <25 kg/m(2), regular exercise for >= 20 min/day, no or light to-moderate alcohol consumption (<= 2 drinks/day for men and <= 1 drink/day for women), and not smoking. Incident AF cases were identified through linkage with the Swedish National Inpatient Register. RESULTS: During a mean follow-up of 10.9 years, AF occurred in 4028 men and 2539 women. Compared with men and women with no healthy lifestyle factors, the multivariable relative risks (95% confidence interval) of AF were 0.83 (0.65-1.07) for one, 0.74 (0.58-0.94) for two, 0.62 (0.49-0.79) for three, and 0.50 (0.39-0.64) for four healthy lifestyle factors (P for trend <0.0001). The inverse association was similar in men and women. CONCLUSIONS: Four healthy lifestyle factors combined were associated with a halving of the risk of AF. PMID- 26512818 TI - Four episodes of takotsubo cardiomyopathy in one patient. PMID- 26512819 TI - A new policy by achieving bonus points to pass the medical licensing examination. PMID- 26512820 TI - Critical appraisal of international guidelines on chronic heart failure: Can China AGREE? PMID- 26512821 TI - Early age at natural menopause and risk of cardiovascular and all-cause mortality: A meta-analysis of prospective observational studies. PMID- 26512822 TI - Casual diagnosis of anomalous origin of the left coronary artery from the pulmonary artery. PMID- 26512823 TI - Shifts in the distribution of body mass index among children and adolescents in Shandong, China, 1985-2014. PMID- 26512824 TI - Obstructive cardiomyopathy with persistent marked elevation of troponin T in myasthenia gravis. PMID- 26512825 TI - P-wave dispersion predicts atrial fibrillation following cardiac surgery. PMID- 26512826 TI - Influence of stent positioning on coronary blood flow after primary percutaneous coronary intervention. PMID- 26512827 TI - Late gadolinium enhancement image masquerading as hypertrophic cardiomyopathy in Fabry disease receiving enzyme replacement therapy. PMID- 26512828 TI - Myocardial infarction in grown up patients with congenital heart disease: An emerging high-risk combination. PMID- 26512829 TI - An evaluation of 20 year survival in patients with diabetes mellitus and acute myocardial infarction. AB - BACKGROUND: Diabetes mellitus (DM) is an established adverse prognostic factor in patients sustaining myocardial infarction (MI). However, its impact on long-term survival remains less clear. The aim of this observational study was to quantify lifetime mortality and years of life lost after MI in patients with and without DM. METHODS: In 1995, 2153 individuals with MI were recruited from 20 adjacent hospitals within Yorkshire, UK. Median survival, all-cause mortality at 20 years and lost years of life when compared to actuarial predictions were compared in patients with and without DM. Landmark analyses were conducted to define the ongoing impact of DM beyond specified time points. RESULTS: 13% (279/2153) had known DM. They experienced higher mortality at 30 days (33.1% vs 24.6%; p<0.0001) and at 20 years (84.9% vs 75.7%; p<0.0001). Overall, there was a 48% increased risk of death (p<0.0001), which persisted after adjustment for potential confounders. There was no interaction between DM and prior MI in predicting mortality (p=0.67). Median survival decreased by 3.3 years (p<0.0001). The adverse impact of DM persisted in sequential landmark analyses at 1, 5 and 10 years. Presence of DM conferred 2 extra years of life lost when compared with actuarial predictions (8 vs 6 years; p<0.0001). CONCLUSIONS: DM remains an independent adverse prognostic factor in the long-term after MI. Persistently diverging survival curves support enduring efforts to reduce mortality late after MI. PMID- 26512830 TI - p38alpha MAPK inhibits stretch-induced JNK activation in cardiac myocytes through MKP-1. AB - Mechanical stretch is a major determinant that leads to heart failure, which is associated with a steady increase in myocardial angiotensinogen (Aogen) expression and formation of the biological peptide angiotensin II (Ang II). c-jun NH2-terminal kinase (JNK) and p38alpha have been found to have opposing roles on stretch-induced Aogen gene expression in neonatal rat ventricular myocytes (NRVM). JNK negatively regulated Aogen expression in NRVM following acute stretch, whereas with prolonged stretch, JNK phosphorylation was downregulated and p38alpha was found responsible for upregulation of Aogen expression. However, the mechanisms responsible for regulation of these kinases, especially the cross talk between p38 and JNK1/2, remain to be determined. In this study, a combination of pharmacologic and molecular approaches (adenovirus-mediated gene transfer) were used to examine the mechanisms by which p38 regulates JNK phosphorylation in NRVM under stretch and non-stretch conditions. Pharmacologic inhibition of p38 significantly increased JNK phosphorylation in NRVM at 15 min, whereas overexpression of wild-type p38alpha significantly decreased JNK phosphorylation. While p38alpha overexpression prevented stretch-induced JNK phosphorylation, pharmacologic p38 inhibition abolished the JNK dephosphorylation during 15-60 min of stretch. Expression of constitutively-active MKK3 (MKK3CA), the upstream activator of p38, abolished JNK phosphorylation in both basal and stretched NRVM. Pharmacologic inhibition of MAP kinase phosphatase-1 (MKP-1) or protein phosphatase-1 (PP1) increased JNK phosphorylation in NRVM, suggesting the involvement of these phosphatases on reversing stretch-induced JNK activation. Inhibition of MKP-1, but not PP1, reduced JNK phosphorylation in NRVM overexpressing MKK3CA under basal conditions (no-stretch). Inhibition of MKP-1 also enhanced stretch-induced JNK phosphorylation in NRVM at 15 to 60 min. In summary, these results indicate that MKP-1 inhibits JNK phosphorylation in stretched NRVM through p38 dependent and independent mechanisms, whereas PP1 regulates JNK through a p38-independent mechanism. PMID- 26512831 TI - Successful use of 20mm SAPIEN 3 for valve-in-valve intervention within a 19 mm degenerated aortic bioprosthetic valve. PMID- 26512832 TI - A sign of lateral myocardial infarction: TV2 taller than TV6. PMID- 26512833 TI - TRPC3 regulates the automaticity of embryonic stem cell-derived cardiomyocytes. AB - BACKGROUND: Cardiac pacemaking is a complex phenomenon that is not completely understood. Canonical transient receptor potential isoform 3 (TRPC3) channel is a cation channel that permeates both Ca(2+) and Na(+). TRPC3 was previously found to express in adult cardiomyocytes. However, its role in cardiac pacemaking is unexplored. Here we used mouse embryonic stem cell-derived cardiomyocytes (mESC CMs) to investigate whether TRPC3 regulates the spontaneous automaticity and the underlying mechanism involved. METHODS AND RESULTS: Immunocytochemistry results showed that TRPC3 is expressed at the T-tubules of mESC-CMs. Whole-cell patch clamping showed that single mESC-CMs contain TRPC3 current. Confocal Ca(2+) imaging showed that the TRPC3-specific blocker Pyr3 decreased Ca(2+) transients and local Ca(2+) release (LCR) of mESC-CMs. Combined current and voltage clamp recordings from the same cell showed that reducing the TRPC3 current, either by Pyr3 or a dominant negative (loss-of-function) construct of TRPC3, decreased the pacemaker activity of mESC-CMs as reflected by a decrease in action potential rate, a depolarized maximum diastolic potential and a decrease in slope of phase 4 diastolic depolarization. Furthermore, decreasing the TRPC3 current diminished, while increasing the TRPC3 current augmented the sodium-calcium exchanger (NCX) current in mESC-CMs. Lastly, decrease in TRPC3 current decreased the phosphorylation of ryanodine receptor isoform 2 at Ser2809 and phospholamban at Thr17. CONCLUSIONS: TRPC3 positively regulates diastolic depolarization of spontaneous action potential by increasing LCR and NCX current and therefore is an important determinant in pacemaking of mESC-CMs. PMID- 26512834 TI - Mitral annuloplasty ring and two MitraClip(r) devices: Quintuple diastolic filling orifice. PMID- 26512835 TI - Do we need further clinical-effectiveness estimates to support the use of primary prevention implantable cardioverter-defibrillators in New York Heart Association class III patients? PMID- 26512836 TI - Renal sympathetic denervation suppresses atrial fibrillation induced by acute atrial ischemia/infarction through inhibition of cardiac sympathetic activity. AB - OBJECTIVE: This study aims to explore the effects of renal sympathetic denervation (RSD) on atrial fibrillation (AF) inducibility and sympathetic activity induced by acute atrial ischemia/infarction. METHODS: Acute ischemia/infarction was induced in 12 beagle dogs by ligating coronary arteries that supply the atria. Six dogs in the sham-RSD group did not undergo RSD, and six dogs without coronary artery ligation served as controls. AF induction rate, sympathetic discharge, catecholamine concentration and densities of tyrosine hydroxylase-positive nerves were measured. RESULTS: Acute atrial ischemia/infarction resulted in a significant increase of AF induction rate, which was decreased by RSD compared to controls (P<0.05). The root-mean-square peak value, peak area and number of sympathetic discharges were significantly augmented by atrial ischemia relative to the baseline and control (P<0.05). The number of sympathetic discharges was significantly reduced in the RSD group, compared to the control and sham-RSD groups (P<0.05). Norepinephrine and epinephrine concentrations in the atria, ventricle and kidney were elevated by atrial ischemia/infarction, but were reduced by RSD (P<0.05). CONCLUSIONS: Sympathetic hyperactivity was associated with pacing-induced AF after acute atrial ischemia/infarction. RSD has the potential to reduce the incidence of new onset AF after acute atrial ischemia/infarction. The inhibition of cardiac sympathetic activity by RSD may be one of the major underlying mechanisms for the marked reduction of AF inducibility. PMID- 26512837 TI - National administrative data produces an accurate and stable risk prediction model for short-term and 1-year mortality following cardiac surgery. AB - OBJECTIVES: Various risk models exist to predict short-term risk-adjusted outcomes after cardiac surgery. Statistical models constructed using clinical registry data usually perform better than those based on administrative datasets. We constructed a procedure-specific risk prediction model based on administrative hospital data for England and we compared its performance with the EuroSCORE (ES) and its variants. METHODS: The Hospital Episode Statistics (HES) risk prediction model was developed using administrative data linked to national mortality statistics register of patients undergoing CABG (35,115), valve surgery (18,353) and combined CABG and valve surgery (8392) from 2008 to 2011 in England and tested using an independent dataset sampled for the financial years 2011-2013. Specific models were constructed to predict mortality within 1-year post discharge. Comparisons with EuroSCORE models were performed on a local cohort of patients (2580) from 2008 to 2013. RESULTS: The discrimination of the HES model demonstrates a good performance for early and up to 1-year following surgery (c stats: CABG 81.6%, 78.4%; isolated valve 78.6%, 77.8%; CABG & valve 76.4%, 72.0%), respectively. Extended testing in subsequent financial years shows that the models maintained performance outside the development period. Calibration of the HES model demonstrates a small difference (CABG 0.15%; isolated valve 0.39%; CABG & valve 0.63%) between observed and expected mortality rates and delivers a good estimate of risk. Discrimination for the HES model for in-hospital deaths is similar for CABG (logistic ES 79.0%) and combined CABG and valve surgery (logistic ES 71.6%) patients and superior for valve patients (logistic ES 70.9%) compared to the EuroSCORE models. The C-statistics of the EuroSCORE models for longer periods are numerically lower than that of the HES model. CONCLUSION: The national administrative dataset has produced an accurate, stable and clinically useful early and 1-year mortality prediction after cardiac surgery. PMID- 26512838 TI - Peripheral arterial disease and atrial fibrillation and risk of stroke, heart failure hospitalization and cardiovascular death: A nationwide cohort study. AB - BACKGROUND: Peripheral arterial disease (PAD) and atrial fibrillation (AF) share several comorbidities and contribute to similar cardiovascular (CV) outcomes. Only few studies have evaluated the correlation between PAD, AF, and their interaction effects on CV outcomes. METHODS: We included 597,164 adults from Taiwan's National Health Insurance Research Database to conduct a cohort study to assess whether PAD was an independent risk factor of AF and vice versa. We also examined if PAD and AF increased the incident stroke, heart failure hospitalization and CV death. RESULTS: People with PAD had a significant higher risk of incident AF than those without PAD [adjusted hazard ratio (HR): 1.29, 95% confidence interval (CI): 1.17-1.42]. Meanwhile, people with AF did not have an increased risk of incident PAD compared to those without AF (adjusted HR: 1.00, 95% CI: 0.89-1.11). Both AF and PAD increased the risk of stroke [adjusted HR being 1.29 (95% CI: 1.17-1.43) and 1.41 (95% CI: 1.35-1.47), respectively], heart failure hospitalization [adjusted HR being 1.96 (95% CI: 1.77-2.17) and 1.35 (95% CI: 1.28-1.42), respectively], and CV death [adjusted HR being 3.33 (95% CI: 2.58 4.30) and 2.08 (95% CI: 1.80-2.41), respectively]. However, we found no interaction effects of AF and PAD on these outcomes. CONCLUSIONS: PAD is an independent risk factor of incident AF but not vice versa. Both PAD and AF are independent risk factors for stroke, heart failure hospitalization, and CV death. PMID- 26512839 TI - Rapid improvement of pulmonary hemodynamics following combined tadalafil and inotropic treatment in a patient with pulmonary hypertension secondary to left ventricular dysfunction. PMID- 26512840 TI - Down-regulation of lncRNA MALAT1 reduces cardiomyocyte apoptosis and improves left ventricular function in diabetic rats. PMID- 26512841 TI - Kounis Syndrome: An analysis of spontaneous reports from international pharmacovigilance database. AB - INTRODUCTION: The coincidental occurrence of a cardiac symptomatology (e.g. an acute coronary syndrome or a myocardial infarction), during an anaphylactic or anaphylactoid episode is known as Kounis Syndrome. A variety of drugs, substances, food and environmental exposures are associated with this reaction. There is an exponential increase in the number of published scientific articles reports on this syndrome, but since it is rare, the largest case series published so far included only 10 and 6 patients. METHODS: We searched the global World Health Organization database called VigiBaseTM to detect all cases of Kounis Syndrome ever reported (last update December 31st 2014). RESULTS: We identified 51 cases of Kounis Syndrome reported to International Pharmacovigilance Agency (VigiBaseTM). All these cases were reported in the period 2010-2014 and almost half cases (22 reports) belonged to the year 2014. Most cases occurred in the USA and non-steroidal anti-inflammatory drugs were the most frequent trigger drugs. DISCUSSION: We collected pharmacovigilance international data representing the largest case series ever published on the recently identified Kounis Syndrome. PMID- 26512842 TI - The combination of percutaneous transapical and transseptal closure of cardiac apex and prosthetic mitral paravalvular leak with loop technique. PMID- 26512843 TI - Acute coronary syndrome (ACS) in patients with essential thrombocytemia (ET). What is the best treatment? PMID- 26512844 TI - Crystal Structures, Magnetic Properties, and Electrochemical Properties of Coordination Polymers Based on the Tetra(4-pyridyl)-tetrathiafulvalene Ligand. AB - Seven new coordination polymers based on the redox-active tetra(4-pyridyl) tetrathiafulvalene ligand (TTF(py)4) and different transition-metal ions, namely, {[Cu(hfac)2][TTF(py)4].2(CH2Cl2)}n (1), {[Co(acac)2][TTF(py)4]0.5.(CHCl3)}n (2), {[Mn(hfac)2][TTF(py)4]0.5}n (3), {[Cu2(OAc)4][TTF(py)4]0.5.1.5(CHCl3).0.5(H2O).(CH3CN)}n (4), {[Mn(SCN)2][TTF(py)4].6(CH2Cl2)}n (5), {[Mn(SeCN)Cl][TTF(py)4]}n (6), and {Cu2[TTF(py)4]2.(ClO4)2.2.5(CH2Cl2).1.5(CH3CN)}n (7), were synthesized and characterized. The tetrapyridyl ligand coordinates to metal ions in a bidentate or tetradentate fashion, forming complexes 1-7 with different structures. Complex 1 exhibits a one-dimensional chain structure. Complexes 2, 3, and 4 possess similar (4,2)-connected binodal two-dimensional networks, while complexes 5 and 6 have similar (4,4)-connected binodal two-dimensional networks with two different rings. Complex 7 shows a 2-fold interpenetrated (4,4)-connected binodal PtS-type three-dimensional framework. Meanwhile, these complexes feature diverse nonclassical hydrogen bonding interactions. In addition, magnetic and solid-state electrochemical properties for typical complexes have been studied. PMID- 26512845 TI - [Genetics and Surgical Therapy in Strabismus: New Strategies]. PMID- 26512846 TI - [Recruitment of Suitable Families to Identify Causative Genes in Hereditary Strabismus]. AB - PURPOSE: The cause and origin of primary strabismus are not well understood. It is thought that there is multifactorial genetic inheritance. Only linkage analysis has been applied to study the genetic causes and correlations. The objective of this study was the compilation and statistical evaluation of a useful cohort of families for linkage analysis. METHODS: The archives of the Department of Ophthalmology of the Justus-Liebig-University Giebetaen were used as a database for this study. Medical records of visits between January 2001 and July 2008 were analysed. Evaluation was based on the medical history form. The data set was scanned for index families in which at least two members had any form of primary strabismus. Patients were classified according to their type of primary strabismus. Families who were most suitable for linkage analysis were approached. A disease specific questionnaire was developed to complete the data. RESULTS: Between January 2001 and July 2008, 20,813 patients affected by primary strabismus were treated. The data set contained 2380 patients with a positive family history of primary strabismus. The majority presented with esotropia (67 %), followed by exotropia (21 %). In most cases (80 %), two family members were affected and the child-parent relationship contributed the largest group, including 948 cases (40 %). Affected siblings were found in 397 families (17 %). Three affected patients were identified in 432 (18 %) families. In these, the relationship parent-child-sibling occurred most frequently, with 143 cases (6 %). A positive family history of at least four related patients was found in 46 families (2 %). Forty-two families were particularly suitable for linkage analysis. Seventeen of the 42 families answered a questionnaire aimed at improving the data set. Three families finally participated in ophthalmic examinations and agreed to blood sampling to perform linkage analysis. CONCLUSION: The fraction of families with strabismus patients in more than two consecutive generations was extremely low. If these families are included in any study, this should be coupled to treatment to improve compliance. PMID- 26512847 TI - [Intermittent Exotropia]. AB - Intermittent exotropia (IXT) is a congenital form of divergent strabismus. Its incidence is estimated to be 32 per 100 000. Most often, IXT is first noted in early childhood when intermittently manifest outward deviation of the eyes is seen. Patients with IXT can control the deviation and keep the eyes aligned; this ability can be measured with "control scores". Complications such as amblyopia and loss of binocular functions are rare but should be looked for and need to be avoided. IXT can have a negative impact on quality of life. Conservative treatment includes the correction of refractive errors, (alternating) occlusion, over-minus lenses and orthoptic exercises. By injecting an extraocular muscle with botulinum toxin (to weaken its function) or with bupivacaine (to strengthen its function), IXT can be treated pharmacologically. Diagnostic occlusion and prism adaptation are strategies to uncover the true (largest) angle. Eye muscle surgery aims at eliminating the condition, but recurrences are common. The literature on large, randomized prospective trials for IXT is scarce. However, there are trials underway in the United Kingdom and in North America to better understand the natural course of IXT and to determine the most appropriate therapeutic approach. PMID- 26512848 TI - [Induced Incomitance of one Muscle Strabismus Surgery in Comparison to Unilateral Recess-Resect Procedures]. AB - BACKGROUND: Surgical correction of intermediate squint angles may be performed on one muscle alone or as a combined unilateral recess-resect procedure. No larger case series has yet systematically measured the amount of induced incomitance that could potentially lead to visual disturbances. METHODS: 31 patients with strabismus and binocular vision (phoria or intermittent strabismus) were operated on one extraocular eye muscle; 30 patients underwent a unilateral recess-resect procedure. Preoperatively and three months postoperatively, we measured the latent angle of squint on a tangent screen over the horizontal 60 degrees in 10 degrees increments and then calculated the amount of induced incomitance. RESULTS: After one muscle surgery, the induced incomitance was 1.7 degrees over a 20 degrees gaze range, 3.2 degrees over a 40 degrees gaze range and 3.8 degrees over a 60 degrees gaze range. For recess-resect procedures, the induced incomitance was 1.4 degrees , 2.6 degrees and 3.4 degrees , respectively. A significant correlation between the surgical dose and the induced incomitance was only seen in one muscle surgery for the 40 degrees and 60 degrees gaze range, but not for the 20 degrees gaze range. A subgroup analysis of patients with an identical surgical dose in one and two muscle procedures (6-8 mm) found greater induced incomitance in one muscle procedures, but only for the 40 degrees and 60 degrees gaze range (p = 0.02). Double vision in any gaze direction was reported by 16 % of patients after one muscle surgery and 10 % of patients after unilateral recess-resect surgery (p > 0.05). CONCLUSION: One muscle surgery is a viable option in small and intermediate angles of squint. The induced incomitance is rather small and does not lead to significant visual disturbances in the central gaze range. PMID- 26512849 TI - [Contralateral Recession of the Inferior Oblique Muscle in Grave's Disease Patients with Mild M. rectus inferior fibrosis]. AB - INTRODUCTION: The aim of this study was to evaluate the dose effect and the resulting binocular single vision for inferior oblique muscle recession in patients with Grave's orbitopathy. METHODS AND PATIENTS: The evaluation covered all patients (n = 13) between 2010-2013 treated with recession of the inferior oblique muscle for vertical deviation caused by inferior fibrosis of the contralateral eye. The inclusion criterion was a small vertical squint angle with excyclotorsion. The corrected vertical squint angle was 3.75 degrees [7 pdpt] (median, min 1.5 degrees [3 pdpt], max 8 degrees [16 pdpt]) in primary position and 5.5 degrees in adduction [11pdpt] (median, min 3 degrees [6 pdpt], max 9 degrees [18pdpt]). Excyclotorsion was 4 degrees [8 pdpt] (median, min 1 degrees [2 pdpt], max 9 degrees [18 pdpt]). Elevation was only slightly impaired and the side difference was 5 degrees (median). The recession distance was preoperatively determined: 0.5 degrees squint angle reduction per mm recession distance (calculation from patients who received surgery before 2010). RESULTS: Inferior oblique recession generated a good field of binocular single vision (BSV) for all patients. All patients reached BSV in the central area (20 degrees ) and within 30 degrees of downgaze. Sixty nine percent of the patients were completely diplopia free in downgaze. Diplopia persisted in more than half of the patients in up gaze outside 15 degrees . Squint reduction was 0.5 degrees [1 pdpt] [0.45-0.67]/per mm recession distance in primary position and 0.65 degrees [1.3 pdpt] [0.55-0.76]/per mm for the vertical deviation in adduction. Excyclotorsion was reduced to <= 2 degrees in 77 % of the patients. CONCLUSION: Inferior oblique muscle recession can be very successfully performed on the contralateral eye in patients with mild inferior rectus muscle fibrosis. Surgery at the contralateral yoke muscle prevents the risk of overeffect with resulting diplopia in downgaze, which could occur if small distance recession had been performed at the inferior rectus muscle. An overeffect in relation to inferior oblique recession will only cause diplopia in upgaze, which is much less troublesome in daily routine. PMID- 26512850 TI - [Dynamic Contour Tonometry and Goldmann Applanation Tonometry: Difference of Intraocular Pressure Values Between Eyes with and without Glaucomatous Damage in Thin Corneas]. AB - BACKGROUND: To examine the differences in intraocular pressure (IOP) measurements obtained with Goldmann applanation tonometry (GAT) and Pascal dynamic contour tonometry (DCT) in subjects with thin corneas and to correlate these with structural and functional parameters of glaucoma damage. PATIENTS AND METHODS: One hundred and thirty participants (130 eyes) with central corneal thickness lower than 500 um were included in five groups in this cross-sectional observational study: 52 eyes with primary open angle glaucoma (POAG), 19 eyes with normal tension glaucoma (NTG), 27 eyes with ocular hypertension (OHT), 21 participants suspected of having glaucoma (GS), and 11 healthy subjects. The measurements were obtained with GAT and DCT in a masked fashion. The corrected GAT-IOP for central corneal thickness (CCT), the difference between DCT and GAT (DeltaIOP = DCT-GAT) and corrected DeltaIOP (corrected DeltaIOP = DCT-corrected GAT) were calculated. Age, mean deviation (MD) from the most recent reliable visual field examination, average retinal nerve fibre layer thickness (RNFL), cup to-disc ratio (CDR), ocular pulse amplitude (OPA), and treatment status were recorded for statistical analysis. RESULTS: In all of the subjects (n = 130), the mean DCT, GAT and corrected GAT values were 17.6 +/- 3.4 mmHg, 13.2 +/- 3.8 mmHg, and 15.5 +/- 2.1 mmHg, respectively. DeltaIOP and corrected DeltaIOP were 4.4 +/- 2 mmHg and 1.7 +/- 2 mmHg, respectively. DeltaIOP was correlated negatively with MD (rs = -0.32, p < 0.0001) and average RNFL thickness (r = -0.46, p < 0.0001) and positively with CDR (rs = 0.50, p < 0.0001). The mean IOP measured by GAT differed statistically significantly between eyes with glaucoma (n = 71, POAG and NTG) and eyes without damage (n = 59; OHT, GS, and healthy) (p < 0.0001), whereas the mean IOP by DCT did not (p = 0.935). The mean DeltaIOP values were also statistically significantly higher in the glaucomatous group, with and without correction for CCT (p < 0.001). OPA and glaucoma diagnoses statistically significantly predicted DeltaIOP (R(2) = 0.41, F2.127 = 47.46, p < 0.0001). CONCLUSION: Greater underestimation of IOP by GAT was observed in the glaucomatous eyes with thin corneas. Performing DCT on patients with thin corneas might be advantageous in establishing the need for more aggressive treatment. PMID- 26512851 TI - [Trabeculectomy Ab Interno in Primary Open Angle Glaucoma and Exfoliative Glaucoma]. AB - BACKGROUND: To assess the outcome of routine trabectomy surgery in the treatment of primary (POAG) and secondary open angle glaucoma. PATIENTS/METHODS: 296 eyes of 296 patients with diagnosed open angle glaucoma and exfoliative glaucoma were analysed from June 2012 until June 2014. IOP readings (intraocular pressure) and the number of antiglaucoma medications was evaluated at every follow-up visit. For statistical analysis, 4 study cohorts were built (cohort 1 = trabectomy in POAG, cohort 2 = trabectomy in exfoliative glaucoma (PEX), cohort 3 = trabectomy + IOL in POAG, cohort 4 = trabectomy + IOL in PEX glaucoma). RESULTS: Mean IOP before trabectomy surgery was 19.8 +/- 5.9 mmHg and 23.7 +/- 9.5 mmHg in cohorts 1 and 2, respectively. At 1 year follow-up, IOP was reduced to normal level for cohorts 1 and 2 (14.8 +/- 3.2 mmHg (p = 0.001) and 14.0 +/- 3.3 mmHg (p = 0.046), respectively). The number of topical antiglaucoma medications changed to 2.1 +/- 1.2 (p = 0.004) and 2.4 +/- 1.2, respectively (p = 0.593) at one year follow-up, respectively, for POAG and exfoliative glaucoma. In study cohort 3 and 4, mean IOP before trabectomy surgery was 19.2 +/- 4.0 mmHg and 23.2 +/- 9.2 mmHg, respectively. At 1 year follow-up, IOP was reduced to normal levels in cohorts 3 and 4 (11.8 +/- 3.1 mmHg (p < 0.01) and 12.6 +/- 1.1 mmHg, respectively (p = 0.043)); the number of topical antiglaucoma medications changed to 2.3 +/- 1.4 (p = 0.469) and 1.4 +/- 0.8, respectively, (p = 0.102) at 1 year follow-up. A significant difference in IOP reduction could be demonstrated in POAG between the trabectomy + IOL group and the trabectomy cohort 1 year postoperative (p = 0.017); in the PEX trabectomy + IOL versus PEX trabectomy cohort no statistically significant difference (p = 0.678) could be demonstrated. No serious postoperative complications were recorded. CONCLUSION: Trabectomy surgery seemed to be a reliable and effective tool for the management of mild and moderate primary and secondary open angle glaucoma with uncontrolled IOP in daily routine. One year follow-up showed a significant reduction in intraocular pressure in all cohorts. PMID- 26512852 TI - Effects of salinity build-up on the performance and bacterial community structure of a membrane bioreactor. AB - This study investigated the effects of salinity increase on bacterial community structure in a membrane bioreactor (MBR) for wastewater treatment. The influent salt loading was increased gradually to simulate salinity build-up in the bioreactor during the operation of a high retention-membrane bioreactor (HR-MBR). Bacterial community diversity and structure were analyzed using 454 pyrosequencing of 16S rRNA genes of MBR mixed liquor samples. Results show that salinity increase reduced biological performance but did not affect microbial diversity in the bioreactor. Unweighted UniFrac and taxonomic analyses were conducted to relate the reduced biological performance to the change of bacterial community structure. In response to the elevated salinity condition, the succession of halophobic bacteria by halotolerant/halophilic microbes occurred and thereby the biological performance of MBR was recovered. These results suggest that salinity build-up during HR-MBR operation could be managed by allowing for the proliferation of halotolerant/halophilic bacteria. PMID- 26512853 TI - Biomethanization of sugar beet byproduct by semi-continuous single digestion and co-digestion with cow manure. AB - Dried pellet of exhausted sugar beet cossettes were digested alone and combined with cow manure as co-substrate in a mesophilic semi-continuous anaerobic system. In single digestion assay, the stable biogas production and stable reactor operation was observed at the hydraulic retention time (HRT) of 20days (OLR: 3.26gVS/Lreactord) which was the minimum HRT tolerated by the system. However, co digestion with cow manure allowed to decrease the HRT until 15days (OLR: 4.97gVS/Lreactord) with 32% higher biogas generation and efficient reactor operation. Propionic acid was the predominant VFA observed during single digestion assay failure, while acetic acid accumulation was observed in the co digestion assay. In both single and co-digestion assays, the recovery of digesters was possible by ceasing the feeding and re-inoculation with a well adapted inoculum. PMID- 26512854 TI - Study on demetalization of sewage sludge by sequential extraction before liquefaction for the production of cleaner bio-oil and bio-char. AB - Demetalization of sewage sludge (SS) by sequential extraction before liquefaction was implemented to produce cleaner bio-char and bio-oil. Demetalization steps 1 and 2 did not cause much organic matter loss on SS, and thus the bio-oil and bio char yields and the compositions of bio-oils were also not affected significantly. However, the demetalization procedures resulted in the production of cleaner bio-chars and bio-oils. The total concentrations and the acid soluble/exchangeable fraction (F1 fraction, the most toxic heavy metal fraction) of heavy metals (Cu, Cr, Pb, Zn, and Cd) in these products were significantly reduced and the environmental risks of these products were also relived considerably compared with those produced from raw SS, respectively. Additionally, these bio-oils had less heavy fractions. Demetalization processes with removal of F1 and F2 fractions of heavy metals would benefit the production of cleaner bio-char and bio-oil by liquefaction of heavy metal abundant biomass like SS. PMID- 26512855 TI - Hydrodynamic optimization of membrane bioreactor by horizontal geometry modification using computational fluid dynamics. AB - Geometry property would affect the hydrodynamics of membrane bioreactor (MBR), which was directly related to membrane fouling rate. The simulation of a bench scale MBR by computational fluid dynamics (CFD) showed that the shear stress on membrane surface could be elevated by 74% if the membrane was sandwiched between two baffles (baffled MBR), compared with that without baffles (unbaffled MBR). The effects of horizontal geometry characteristics of a bench-scale membrane tank were discussed (riser length index Lr, downcomer length index Ld, tank width index Wt). Simulation results indicated that the average cross flow of the riser was negatively correlated to the ratio of riser and downcomer cross-sectional area. A relatively small tank width would also be preferable in promoting shear stress on membrane surface. The optimized MBR had a shear elevation of 21.3-91.4% compared with unbaffled MBR under same aeration intensity. PMID- 26512856 TI - A thermogravimetric analysis of the combustion kinetics of karanja (Pongamia pinnata) fruit hulls char. AB - The combustion characteristics of Karanj fruit hulls char (KFH-char) was investigated with thermogravimetry analysis (TGA). The TGA outlined the char combustion thermographs at a different heating rate and isoconversional methods expressed the combustion kinetics. The Kissinger-Akahira-Sunose (KAS) and Flynn Wall-Ozawa (FWO) methods authenticated the char average activation energy at 62.13 and 68.53kJ/mol respectively, enough to derive the char to burnout. However, the Coats-Redfern method verified the char combustion via complex multi step mechanism; the second stage mechanism has 135kJ/mol average activation energy. The TGA thermographs and kinetic parameters revealed the adequacy of the KFH-char as fuel substrate than its precursor, Karanj fruit hulls (KFH). PMID- 26512857 TI - Application of microbial electrolysis cells to treat spent yeast from an alcoholic fermentation. AB - Spent yeast (SY), a major challenge for the brewing industry, was treated using a microbial electrolysis cell to recover energy. Concentrations of SY from bench alcoholic fermentation and ethanol were tested, ranging from 750 to 1500mgCOD/L and 0 to 2400mgCOD/L respectively. COD removal efficiency (RE), coulombic efficiency (CE), coulombic recovery (CR), hydrogen production and current density were evaluated. The best treatment condition was 750mgCOD/LSY+1200mgCOD/L ethanol giving higher COD RE, CE, CR (90+/-1%, 90+/-2% and 81+/-1% respectively), as compared with 1500mgCOD/LSY (76+/-2%, 63+/-7% and 48+/-4% respectively); ethanol addition was significantly favorable (p value=0.011), possibly due to electron availability and SY autolysis. 1500mgCOD/LSY+1200mgCOD/L ethanol achieved higher current density (222.0+/-31.3A/m(3)) and hydrogen production (2.18+/-0.66 [Formula: see text] ) but with lower efficiencies (87+/-2% COD RE, 71.0+/-.4% CE). Future work should focus on electron sinks, acclimation and optimizing SY breakdown. PMID- 26512858 TI - Activated carbon derived from carbon residue from biomass gasification and its application for dye adsorption: Kinetics, isotherms and thermodynamic studies. AB - In this work, activated carbon (AC) as an effective and low-cost adsorbent was successfully prepared from carbon residue (or char, one of the by-products from woody biomass gasification) via physical activation. The surface area of char was significantly increased from 172.24 to 776.46m(2)/g after steam activation at 900 degrees C. The obtained activated carbons were then employed for the adsorption of dye (Rhodamine B) and it was found that activated carbon obtained from steam activation exhibited the highest adsorption capability, which is mainly attributed to the higher surface area and the abundance of hydroxyl (-OH) and carboxyl (-COOH) groups on the activated carbon surface. Moreover, it was also found that the adsorption capability significantly increased under the basic condition, which can be attributed to the increased electrostatic interaction between the deprotonated (negatively charged) activated carbon and dye molecules. Furthermore, the equilibrium data were fitted into different adsorption isotherms and found to fit well with Langmuir model (indicating that dye molecules form monolayer coverage on activated carbon) with a maximum monolayer adsorption capability of 189.83mg/g, whereas the adsorption kinetics followed the pseudo second-order kinetics. PMID- 26512859 TI - Continuous harvesting of microalgae by new microfluidic technology for particle separation. AB - A new microfluidic chip based on a trilobite structure, designed for continuously concentrating particles in moving fluids, was investigated as a pre-concentration method for microalgal harvesting. The chip has a 5-MUm gap limit and was tested for concentrating the microalgae Rhodomonas baltica, Chaetoceros sp. and Thalassiosira weissflogii. The chip was able to concentrate rigid cells and to sort them according to size. However, optimization with respect to cell properties, such as size and flexibility, needs further work. Although no clogging of the chip was seen for R. baltica and Chaetoceros sp., production of exopolymers by T. weissflogii made harvesting challenging for this species. The TrilobiteTM microfluidic chip appears to be a promising tool for pre concentrating microalgae that are difficult to harvest due to their repelling properties or small size. PMID- 26512860 TI - Hydrolysis-acidogenesis of food waste in solid-liquid-separating continuous stirred tank reactor (SLS-CSTR) for volatile organic acid production. AB - The use of conventional continuous stirred tank reactor (CSTR) can affect the methane (CH4) recovery in a two-stage anaerobic digestion of food waste (FW) due to carbon short circuiting in the hydrolysis-acidogenesis (Hy-Aci) stage. In this research, we have designed and tested a solid-liquid-separating CSTR (SLS-CSTR) for effective Hy-Aci of FW. The working conditions were pH 6 and 9 (SLS-CSTR-1 and -2, respectively); temperature-37 degrees C; agitation-300rpm; and organic loading rate (OLR)-2gVSL(-1)day(-1). The volatile fatty acids (VFA), enzyme activities and bacterial population (by qPCR) were determined as test parameters. Results showed that the Hy-Aci of FW at pH 9 produced ~35% excess VFA as compared to that at pH 6, with acetic and butyric acids as major precursors, which correlated with the high enzyme activities and low lactic acid bacteria. The design provided efficient solid-liquid separation there by improved the organic acid yields from FW. PMID- 26512861 TI - Improvement of Sporobolomyces ruberrimus carotenoids production by the use of raw glycerol. AB - The red yeast Sporobolomyces ruberrimus H110 was able to use glycerol as a carbon source. The highest concentration (0.51gL(-1)) and productivity (0.0064gL(-1)h( 1)) of carotenoids were achieved when raw glycerol from biodiesel production, containing around 1gL(-1) of fatty acids, was used as the carbon source, which represented increases of 27% and 1.5*, respectively, in relation to pure glycerol. Mass spectrometry analysis led to the identification of four carotenoids in the fermented samples, torularhodin, torulene, beta-carotene and gamma-carotene. The use of raw glycerol also enhanced the proportion of torularhodin (69% against 59% in pure glycerol). The addition of individual fatty acids (palmitic, stearic, oleic and linoleic acids) to pure glycerol resulted in increases between 15% and 25% in maximum concentration and between 1.6* and 2.0* in productivity of carotenoids. The presence of palmitic and oleic acids increased the torularhodin proportion to 66%. PMID- 26512862 TI - Nitrification and aerobic denitrification in anoxic-aerobic sequencing batch reactor. AB - The aim of this study was to evaluate the feasibility of achieving nitrogen (N) removal using a lab-scale sequencing batch reactor (SBR) exposed to anoxic/aerobic (AN/OX) phases, focusing to achieve aerobic denitrification. This process will minimize emissions of N2O greenhouse gas. The effects of different operating parameters on the reactor performance were studied: cycle duration, AN/OX ratio, pH, dissolved oxygen concentration (DOC), and organic load. The highest inorganic N removal (NiR), close to 70%, was obtained at pH=7.5, low organic load (440mgCOD/(Lday)) and high aeration given by 12h cycle, AN/OX ratio=0.5:1.0 and DOC higher than 4.0mgO2/L. Nitrification followed by high-rate aerobic denitrification took place during the aerobic phase. Aerobic denitrification could be attributed to Tetrad-forming organisms (TFOs) with phenotype of glycogen accumulating organisms using polyhydroxyalkanoate and/or glycogen storage. The proposed AN/OX system constitutes an eco-friendly N removal process providing N2 as the end product. PMID- 26512863 TI - Biotic and abiotic roles of leachate recirculation in batch mode solid-state anaerobic digestion of cattle manure. AB - Solid state anaerobic digestion, with leachate recirculation, is suitable for exploiting manure with a high solid content. The biotic and abiotic effects of the leachates were studied in lab-scale leach bed reactors (LBRs). LBRs were fed with cow manure and four leachates either biologically active or inert. The biotic impact of leachate was assessed by monitoring the microbial communities in the manure and in the leachates. LBRs with biologically active leachates, regardless to their origin, produced equivalent methane volumes (114.52+/-19.05 and 99.79+/-6.4NL/kgVS) while LBRs with inert leachates produced half less methane (60.22+/-5.71 and 58.87+/-13.2NL/kgVS) attesting to the biotic role of leachate. Moreover, its beneficial abiotic role is mainly due to its initial nutrient content, pH, and buffering capacity. The microbial community in the manure was strongly involved in methane production, and no transfer of microorganisms from the liquid phase was found (p<0.05). PMID- 26512864 TI - A grey box model of glucose fermentation and syntrophic oxidation in microbial fuel cells. AB - In this work, the fermentative and oxidative processes taking place in a microbial fuel cell (MFC) fed with glucose were studied and modeled. The model accounting for the bioelectrochemical processes was based on ordinary, Monod-type differential equations. The model parameters were estimated using experimental results obtained from three H-type MFCs operated at open or closed circuits and fed with glucose or ethanol. The experimental results demonstrate that similar fermentation processes were carried out under open and closed circuit operation, with the most important fermentation products being ethanol (with a yield of 1.81molmol(-1) glucose) and lactic acid (with a yield of 1.36molmol(-1) glucose). A peak in the electricity generation was obtained when glucose and fermentation products coexisted in the liquid bulk. However, almost 90% of the electricity produced came from the oxidation of ethanol. PMID- 26512865 TI - Methane enhancement through oxidative cleavage and alkali solubilization pre treatments for corn stover with anaerobic activated sludge. AB - In the present study, thermo-chemical pre-treatment was adopted to evaluate methane production potential from corn stover by co-digesting it with anaerobic activated sludge. Three chemicals H2O2, Ca(OH)2 and NaOH were selected with two levels of concentration. All thermo-chemical pre-treatments were found significant (P<0.05) to enhance lignocellulosic digestibility and methane production. The results indicated that the methane yield by H2O2-1, H2O2-2, and NaOH-2 treated corn stover were 293.52, 310.50 and 279.42ml/g.VS which were 57.18%, 66.27% and 49.63% higher than the untreated corn stover respectively. In the previous studies pre-treatment time was reported in days but our method had reduced it to about one hour. H2O2-2 and NaOH-2 treatments remained prominent to increase lignocellulosic degradation vigorously up to 45% and 42% respectively. Process biochemistry during the anaerobic digestion process was taken into consideration to optimize the most feasible thermo-chemical pre-treatment for corn stover. PMID- 26512866 TI - Production of co-polymers of polyhydroxyalkanoates by regulating the hydrolysis of biowastes. AB - Production of polyhydroxyalkanoate (PHA) co-polymers by Bacillus spp. was studied by feeding defined volatile fatty acids (VFAs) obtained through controlled hydrolysis of various wastes. Eleven mixed hydrolytic cultures (MHCs) each containing 6 strains could generate VFA from slurries of (2% total solids): pea shells (PS), potato peels (PP), apple pomace (AP) and onion peels (OP). PS hydrolysates (obtained with MHC2 and MHC5) inoculated with Bacillus cereus EGU43 and Bacillus thuringiensis EGU45 produced co-polymers of PHA at the rate of 15 60mg/L with a 3HV content of 1%w/w. An enhancement in PHA yield of 3.66-fold, i.e. 205-550mg/L with 3HV content up to 7.5%(w/w) was observed upon addition of OP hydrolysate and 1% glucose (w/v) to PS hydrolysates. This is the first demonstration, where PHA co-polymer composition, under non-axenic conditions, could be controlled by customizing VFA profile of the hydrolysate by the addition of different biowastes. PMID- 26512867 TI - Evaluation of energy-distribution of a hybrid microbial fuel cell-membrane bioreactor (MFC-MBR) for cost-effective wastewater treatment. AB - A low-cost hybrid system integrating a membrane-less microbial fuel cell (MFC) with an anoxic/oxic membrane bioreactor (MBR) was studied for fouling mitigation. The appended electric field in the MBR was supplied by the MFC with continuous flow. Supernatant from an anaerobic reactor with low dissolved oxygen was used as feed to the MFC in order to enhance its performance compared with that fed with synthetic wastewater. The voltage output of MFC maintained at 0.52+/-0.02V with 1000Omega resister. The electric field intensity could reach to 0.114Vcm(-1). Compared with the conventional MBR (CMBR), the contents rather than the components of foulants on the cake layer of fouled MFC-MBR system was significantly reduced. Although only 0.5% of the feed COD was translated into electricity and applied to MBR, the hybrid system showed great feasibility without additional consumption but extracting energy from waste water and significantly enhancing the membrane filterability. PMID- 26512868 TI - Biodegradation of phenolic compounds and their metabolites in contaminated groundwater using microbial fuel cells. AB - This is the first study demonstrating the biodegradation of phenolic compounds and their organic metabolites in contaminated groundwater using bioelectrochemical systems (BESs). The phenols were biodegraded anaerobically via 4-hydroxybenzoic acid and 4-hydroxy-3-methylbenzoic acid, which were retained by electromigration in the anode chamber. Oxygen, nitrate, iron(III), sulfate and the electrode were electron acceptors for biodegradation. Electro-active bacteria attached to the anode, producing electricity (~1.8mW/m(2)), while utilizing acetate as an electron donor. Electricity generation started concurrently with iron reduction; the anode was an electron acceptor as thermodynamically favorable as iron(III). Acetate removal was enhanced by 40% in the presence of the anode. However, enhanced removal of phenols occurred only for a short time. Field-scale application of BESs for in situ bioremediation requires an understanding of the regulation and kinetics of biodegradation pathways of the parent compounds to relevant metabolites, and the syntrophic interactions and carbon flow in the microbial community. PMID- 26512869 TI - Crystal Structures of Mycobacterium tuberculosis CysQ, with Substrate and Products Bound. AB - In many organisms, 3'-phosphoadenosine 5'-phosphate (PAP) is a product of two reactions in the sulfur activation pathway. The sulfurylation of biomolecules, catalyzed by sulfotransferases, uses 3'-phosphoadenosine 5'-phosphosulfate (PAPS) as a sulfate donor, producing the sulfated biomolecule and PAP product. Additionally, the first step in sulfate reduction for many bacteria and fungi reduces the sulfate moiety of PAPS, producing PAP and sulfite, which is subsequently reduced to sulfide. PAP is removed by the phosphatase activity of CysQ, a 3',5'-bisphosphate nucleotidase, yielding AMP and phosphate. Because excess PAP alters the equilibrium of the sulfur pathway and inhibits sulfotransferases, PAP concentrations can affect the levels of sulfur-containing metabolites. Therefore, CysQ, a divalent cation metal-dependent phosphatase, is a major regulator of this pathway. CysQ (Rv2131c) from Mycobacterium tuberculosis (Mtb) was successfully expressed, purified, and crystallized in a variety of ligand-bound states. Here we report six crystal structures of Mtb CysQ, including a ligand-free structure, a lithium-inhibited state with substrate PAP bound, and a product-bound complex with AMP, phosphate, and three Mg(2+) ions bound. Comparison of these structures together with homologues of the superfamily has provided insight into substrate specificity, metal coordination, and catalytic mechanism. PMID- 26512870 TI - Polymer-Supported Optically Active fac(S)-Tris(thiotato)rhodium(III) Complex for Sulfur-Bridging Reaction With Precious Metal Ions. AB - The optically active mixed-ligand fac(S)-tris(thiolato)rhodium(III) complexes, DeltaL -fac(S)-[Rh(aet)2 (L-cys-N,S)](-) (aet = 2-aminoethanethiolate, L-cys = L cysteinate) () and DeltaLL -fac(S)-[Rh(aet)(L-cys-N,S)2 ](2-) were newly prepared by the equatorial preference of the carboxyl group in the coordinated L-cys ligand. The amide formation reaction of with 1,10-diaminodecane and polyallylamine gave the diamine-bridged dinuclear Rh(III) complex and the single chain polymer-supported Rh(III) complex with retention of the DeltaL configuration of , respectively. These Rh(III) complexes reacted with Co(III) or Co(II) to give the linear-type trinuclear structure with the S-bridged Co(III) center and the two Delta-Rh(III) terminal moieties. The polymer-supported Rh(III) complex was applied not only to the CD spectropolarimetric detection and determination of a trace of precious metal ions such as Au(III), Pt(II), and Pd(II) but also to concentration and extraction of these metal ions into the solid polymer phase. Chirality 28:85-91, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26512871 TI - Nanotopography applications in drug delivery. AB - Refinement of micro- and nanofabrication in the semiconductor field has led to innovations in biomedical technologies. Nanotopography, in particular, shows great potential in facilitating drug delivery. The flexibility of fabrication techniques has created a diverse array of topographies that have been developed for drug delivery applications. Nanowires and nanostraws deliver drug cytosolically for in vitro and ex vivo applications. In vivo drug delivery is limited by the barrier function of the epithelium. Nanowires on microspheres increase adhesion and residence time for oral drug delivery, while also increasing permeability of the epithelium. Low aspect ratio nanocolumns increase paracellular permeability, and in conjunction with microneedles increase transdermal drug delivery of biologics in vivo. In summary, nanotopography is a versatile tool for drug delivery. It can deliver directly to cells or be used for in vivo delivery across epithelial barriers. This editorial highlights the application of nanotopography in the field of drug delivery. PMID- 26512872 TI - Low frequency steady-state brain responses modulate large scale functional networks in a frequency-specific means. AB - Neural oscillations are essential for brain functions. Research has suggested that the frequency of neural oscillations is lower for more integrative and remote communications. In this vein, some resting-state studies have suggested that large scale networks function in the very low frequency range (<1 Hz). However, it is difficult to determine the frequency characteristics of brain networks because both resting-state studies and conventional frequency tagging approaches cannot simultaneously capture multiple large scale networks in controllable cognitive activities. In this preliminary study, we aimed to examine whether large scale networks can be modulated by task-induced low frequency steady-state brain responses (lfSSBRs) in a frequency-specific pattern. In a revised attention network test, the lfSSBRs were evoked in the triple network system and sensory-motor system, indicating that large scale networks can be modulated in a frequency tagging way. Furthermore, the inter- and intranetwork synchronizations as well as coherence were increased at the fundamental frequency and the first harmonic rather than at other frequency bands, indicating a frequency-specific modulation of information communication. However, there was no difference among attention conditions, indicating that lfSSBRs modulate the general attention state much stronger than distinguishing attention conditions. This study provides insights into the advantage and mechanism of lfSSBRs. More importantly, it paves a new way to investigate frequency-specific large scale brain activities. PMID- 26512873 TI - Cadmium Stabilization Efficiency and Leachability by CdAl4O7 Monoclinic Structure. AB - This study investigated the stabilization efficiencies of using an aluminum-rich precursor to incorporate simulated cadmium-bearing waste sludge and evaluated the leaching performance of the product phase. Cadmium oxide and gamma-alumina mixtures with various Cd/Al molar ratios were fired at 800-1000 degrees C for 3 h. Cadmium could be crystallochemically incorporated by gamma-alumina into CdAl4O7 monoclinic phase and the reaction was strongly controlled by the treatment temperature. The crystal structure details of CdAl4O7 were solved and refined with the Rietveld refinement method. According to the structural refinement results, the stabilization efficiencies were quantified and expressed as a transformation ratio (TR) with optimized processing parameters. The preferred treatment temperature was found to be 950 degrees C for mixtures with a Cd/Al molar ratio of 1/4, as its TR value indicated the cadmium incorporation was nearly completed after a 3 h treatment scheme. Constant-pH leaching tests (CPLT) were conducted by comparing the leachability of the CdO and CdAl4O7 phases in a pH 4.0 environment. A remarkable reduction in cadmium leachability could be achieved via monoclinic CdAl4O7 structure formation to effectively stabilize hazardous cadmium in the waste stream. The CPLT and X-ray photoelectron spectroscopy (XPS) results suggested incongruent dissolution behavior during the leaching of the CdAl4O7 phase. PMID- 26512874 TI - Colossal Dielectric Behavior of Ga+Nb Co-Doped Rutile TiO2. AB - Stimulated by the excellent colossal permittivity (CP) behavior achieved in In+Nb co-doped rutile TiO2, in this work we investigate the CP behavior of Ga and Nb co doped rutile TiO2, i.e., (Ga(0.5)Nb(0.5))(x)Ti(1-x)O2, where Ga(3+) is from the same group as In(3+) but with a much smaller ionic radius. Colossal permittivity of up to 10(4)-10(5) with an acceptably low dielectric loss (tan delta = 0.05 0.1) over broad frequency/temperature ranges is obtained at x = 0.5% after systematic synthesis optimizations. Systematic structural, defect, and dielectric characterizations suggest that multiple polarization mechanisms exist in this system: defect dipoles at low temperature (~10-40 K), polaronlike electron hopping/transport at higher temperatures, and a surface barrier layer capacitor effect. Together these mechanisms contribute to the overall dielectric properties, especially apparent observed CP. We believe that this work provides comprehensive guidance for the design of new CP materials. PMID- 26512875 TI - Pancreatic preneoplastic lesions plasma signatures and biomarkers based on proteome profiling of mouse models. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a mortality that is almost identical to incidence. Because early detected PDAC is potentially curable, blood-based biomarkers that could detect currently developing neoplasia would improve patient survival and management. PDAC develops from pancreatic intraepithelial neoplasia (PanIN) lesions, graded from low grade (PanIN1) to high grade (PanIN3). We made the hypothesis that specific proteomic signatures from each precancerous stage exist and are detectable in plasma. METHODS: We explored the peptide profiles of microdissected PanIN cells and of plasma samples corresponding to the different PanIN grade from genetically engineered mouse models of PDAC using capillary electrophoresis coupled to mass spectrometry (CE-MS) and Chip-MS/MS. RESULTS: We successfully characterised differential peptides profiles from PanIN microdissected cells. We found that plasma from tumor-bearing mice and age matched controls exhibit discriminative peptide signatures. We also determined plasma peptide signatures corresponding to low- and high-grade precancerous step present in the mice pancreas using the two mass spectrometry technologies. Importantly, we identified biomarkers specific of PanIN3. CONCLUSIONS: We demonstrate that benign and advanced PanIN lesions display distinct plasma peptide patterns. This strongly supports the perspectives of developing a non invasive screening test for prediction and early detection of PDAC. PMID- 26512876 TI - Phase I study of afatinib combined with nintedanib in patients with advanced solid tumours. AB - BACKGROUND: This Phase I study evaluated continuous- and intermittent-dosing (every other week) of afatinib plus nintedanib in patients with advanced solid tumours. METHODS: In the dose-escalation phase (n=45), maximum tolerated doses (MTDs) were determined for continuous/intermittent afatinib 10, 20, 30 or 40 mg once daily plus continuous nintedanib 150 or 200 mg twice daily. Secondary objectives included safety and efficacy. Clinical activity of continuous afatinib plus nintedanib at the MTD was further evaluated in an expansion phase (n=25). RESULTS: The most frequent dose-limiting toxicities were diarrhoea (11%) and transaminase elevations (7%). Maximum tolerated doses were afatinib 30 mg continuously plus nintedanib 150 mg, and afatinib 40 mg intermittently plus nintedanib 150 mg. Treatment-related adverse events (mostly Grade?3) included diarrhoea (98%), asthenia (64%), nausea (62%) and vomiting (60%). In the dose escalation phase, two patients had partial responses (PRs) and 27 (60%) had stable disease (SD). In the expansion phase, one complete response and three PRs were observed (all non-small cell lung cancer), with SD in 13 (52%) patients. No pharmacokinetic interactions were observed. CONCLUSIONS: MTDs of continuous or intermittent afatinib plus nintedanib demonstrated a manageable safety profile with proactive management of diarrhoea. Antitumour activity was observed in patients with solid tumours. PMID- 26512877 TI - Interplay between cadherins and alpha2beta1 integrin differentially regulates melanoma cell invasion. AB - BACKGROUND: Malignant transformation of melanocytes frequently coincides with an alteration in the expression of cell-cell adhesion molecules (cadherins) and cell extracellular matrix proteins (integrins). How these two adhesion systems interplay to impact on cell invasion remains to be described in melanoma. METHODS: Cell adhesion networks were localised by immunofluorescence in human primary cutaneous melanoma, metastatic melanoma in the lymph nodes, and melanoma cell lines. The role of these cell adhesion networks was assessed both in vivo, by analysing their impact on tumour growth in mice, and in vitro, with the use of functional tests including cell aggregation and cell migration. RESULTS: We found that alpha2beta1 integrin associates with both E-cadherin and N-cadherin to form two adhesive networks, distinguishable by the interaction-or not-of alpha2beta1 integrin with type I collagen. N-cadherin/alpha2beta1 integrin and E cadherin/alpha2beta1 integrin networks differently participated towards tumour growth in mice. The N-cadherin/alpha2beta1 integrin network showed specific involvement in melanoma cell invasion and migration towards type I collagen. On the other hand, the E-cadherin/alpha2beta1 network regulated cell-cell adhesion. CONCLUSIONS: This suggests that different signalling environments can be generated, depending on the type and/or local concentration of cadherin present in the adhesion complex, which potentially leads to differential cell responses. Further clarification of how these adhesive networks are regulated is fundamental to understanding important physiological and pathological processes such as morphogenesis, wound healing, tumour invasion and metastasis. PMID- 26512878 TI - TIM-4 promotes the growth of non-small-cell lung cancer in a RGD motif-dependent manner. AB - BACKGROUND: T-cell immunoglobulin domain and mucin domain 4 (TIM-4) is exclusively expressed in antigen-presenting cells and involved in immune regulation. However, the role of TIM-4 expressed in tumour cells remains completely unknown. METHODS: Immunohistochemistry staining was used to examine TIM-4 or Ki-67 expression in tumour tissues. Real-time PCR or RT-PCR was performed to detect TIM-4 mRNA expression. Lung cancer cell growth and proliferation were conducted by CCK-8 assay and EdU staining. Cell cycle progression was analysed by flow cytometry. The PCNA and cell cycle-related proteins were verified by western blot. Co-IP assay was used to identify the interaction of TIM-4 and integrin alphavbeta3. The efficacy of TIM-4 in vivo was evaluated using xenograft tumour model. RESULTS: The expression of TIM-4 in non small-cell lung cancer (NSCLC) tissues was significantly higher than that of the adjacent tissues. Enhanced TIM-4 expression was negatively correlated with histological differentiation of lung carcinoma and lifespan of patients. Overexpression of TIM-4 promoted lung cancer cell growth and proliferation, and upregulated the expression of PCNA, cyclin A, cyclin B1 and cyclin D1, accompanied by accumulation of lung cancer cells in S phase. Interestingly, Arg Gly-Asp (RGD) motif mutation abolished the effect of TIM-4 on lung cancer cells, which was further verified by tumour xenografts in mice. Furthermore, we found that TIM-4 interacted with alphavbeta3 integrin through RGD motif. CONCLUSIONS: This finding suggests that TIM-4 might be a potential biomarker for NSCLC that promotes lung cancer progression by RGD motif. PMID- 26512879 TI - Zopolrestat Induced Suicidal Death of Human Erythrocytes. AB - BACKGROUND/AIMS: The aldose reductase inhibitor zopolrestat has been shown to either decrease or increase apoptosis, the suicidal death of nucleated cells. Erythrocytes may similarly enter suicidal death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include oxidative stress, Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i), and ceramide formation. The present study explored, whether and how zopolrestat induces eryptosis. METHODS: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, oxidative stress from DCFDA dependent fluorescence, [Ca2+]i from Fluo3 fluorescence, and ceramide abundance utilizing specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to zopolrestat (>= 150 ug/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter (>= 125 ug/ml), significantly increased Fluo3-fluorescence (200 ug/ml), significantly increased ceramide abundance (150 ug/ml), but did not significantly modify DCFDA fluorescence. The effect of zopolrestat on annexin-V binding was significantly blunted, but not abolished by removal of extracellular Ca2+. CONCLUSIONS: Exposure of human erythrocytes to zopolrestat triggers cell shrinkage and cell membrane scrambling, an effect in part due to Ca2+ entry and ceramide. PMID- 26512880 TI - Effect of standardized perioperative dabigatran interruption on the residual anticoagulation effect at the time of surgery or procedure. AB - ESSENTIALS: Anticoagulants need to be stopped preprocedure so there is little or no remaining anticoagulant effect. We assessed the residual anticoagulant effect with standardized interruption for patients on dabigatran. With this protocol, 80 86% of patients had no residual anticoagulant effect at the time of a procedure. A standardized perioperative dabigatran protocol appears to be safe, but requires further study. BACKGROUND: In patients taking dabigatran who require treatment interruption for a surgery/procedure, a sufficient interruption interval is needed so that there is little or no residual anticoagulant effect at the time of the surgery/procedure. METHODS: A prospective cohort study of patients receiving dabigatran (110 mg or 150 mg twice daily) who required an elective surgery/procedure and received a standardized dabigatran interruption protocol based on surgery/procedure bleeding risk and renal function was performed. Before the surgery/procedure, a blood sample was taken for measurement of the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and dilute thrombin time (dTT). We determined the proportion of all patients and those having a high bleeding risk surgery/procedure with normal coagulation test results at the time of the surgery/procedure. The APTT and dTT were considered to be most likely to reflect a dabigatran anticoagulant effect. Patients were followed up for 30 days postprocedure to assess for bleeding and thromboembolism. RESULTS: One hundred and eighty-one patients were studied: 118 with low bleeding risk, and 63 with high bleeding risk. For all patients, the proportions with normal PT, APTT, TT dTT levels were 92.8%, 79.6%, 33.1%, and 80.7%, respectively. In patients with high bleeding risk, the proportions with normal PT, APTT, TT dTT levels were 93.7%, 85.7%, 57.1%, and 87.3%, respectively. During follow-up, there was one (0.6%) major bleed, there were nine (5.0%) minor bleeds, and there was one (0.6%) transient ischemic attack. CONCLUSIONS: In patients receiving dabigatran who require an elective surgery/procedure, a standardized interruption protocol yielded 80-86% of patients with no residual anticoagulant effect at the time of surgery/procedure, and with a low incidence of bleeding. PMID- 26512881 TI - Development of a Sendai virus vector-based AIDS vaccine inducing T cell responses. AB - Virus-specific CD8(+) T-cell responses play a major role in the control of HIV replication, and induction of HIV-specific T-cell responses is an important strategy for AIDS vaccine development. Optimization of the delivery system and immunogen would be the key for the development of an effective T cell-based AIDS vaccine. Heterologous prime-boost vaccine regimens using multiple viral vectors are a promising protocol for efficient induction of HIV-specific T-cell responses, and the development of a variety of potent viral vectors have been attempted. This review describes the current progress of the development of T cell-based AIDS vaccines using viral vectors, focusing on Sendai virus vectors, whose phase I clinical trials have been performed. PMID- 26512882 TI - Nickel-Catalyzed Reductive Cross-Coupling of (Hetero)Aryl Iodides with Fluorinated Secondary Alkyl Bromides. AB - A mild and efficient nickel-catalyzed reductive cross-coupling between fluorinated secondary alkyl bromides and (hetero)aryl iodides is described. The use of FeBr2 as an additive successfully overcomes the hydrodebromination and beta-fluorine elimination of fluorinated substrates and allows the efficient synthesis of a wide range of trifluoromethyl and difluoroalkyl containing aliphatic compounds with a fluoroalkyl substituted tertiary carbon center. The notable features of this protocol are the synthetic and operational simplicity without preparation of moisture sensitive organometallic reagents and excellent functional group compatibility, even toward active proton containing substrates. PMID- 26512883 TI - Molecular Mechanisms and Novel Therapeutic Approaches to Rhabdomyolysis-Induced Acute Kidney Injury. AB - Rhabdomyolysis is a syndrome caused by injury to skeletal muscle that usually leads to acute kidney injury (AKI). Rhabdomyolysis has been linked to different conditions, including severe trauma and intense physical exercise. Myoglobin induced renal toxicity plays a key role in rhabdomyolysis-associated kidney damage by increasing oxidative stress, inflammation, endothelial dysfunction, vasoconstriction, and apoptosis. New drugs that target the harmful effects of myoglobin have been recently developed, and some have been proven to be successful in animal models of acute renal failure secondary to rhabdomyolysis. This review aims to provide a comprehensive and updated overview of the pathological mechanisms of renal damage and describes new therapeutic approaches to this condition based on novel compounds that target key pathways involved in myoglobin-mediated kidney damage. PMID- 26512884 TI - Counterion-Mediated Ligand Exchange for PbS Colloidal Quantum Dot Superlattices. AB - In the past years, halide capping became one of the most promising strategies to passivate the surface of colloidal quantum dots (CQDs) in thin films to be used for electronic and optoelectronic device fabrication. This is due to the convenient processing, strong n-type characteristics, and ambient stability of the devices. Here, we investigate the effect of three counterions (ammonium, methylammonium, and tetrabutylammonium) in iodide salts used for treating CQD thin films and shed light on the mechanism of the ligand exchange. We obtain two- and three-dimensional square-packed PbS CQD superlattices with epitaxial merging of nearest neighbor CQDs as a direct outcome of the ligand-exchange reaction and show that the order in the layer can be controlled by the nature of the counterion. Furthermore, we demonstrate that the acidity of the environment plays an important role in the substitution of the carboxylates by iodide ions at the surface of lead chalcogenide quantum dots. Tetrabutylammonium iodide shows lower reactivity compared to methylammonium and ammonium iodide due to the nonacidity of the cation, which eventually leads to higher order but also poorer carrier transport due to incomplete removal of the pristine ligands in the QD thin film. Finally, we show that single-step blade-coating and immersion in a ligand exchange solution such as the one containing methylammonium iodide can be used to fabricate well performing bottom-gate/bottom-contact PbS CQD field effect transistors with record subthreshold swing. PMID- 26512885 TI - Pre-eclampsia and preterm birth in Reunion Island: a 13 years cohort-based study. Comparison with international data. AB - OBJECTIVES: To assess the prevalence of preterm birth in pre-eclamptic deliveries in Reunion Island, a tropical overseas French department (departements d'outre mer, DOM) and to compare this prevalence with that of international literature. METHODS: All singleton live-born deliveries referred to three maternity centers in Reunion Island over 13 years were eligible. Data for comparison were found through searches of MEDLINE, bibliographies of identified studies, proceedings of meetings on pre-eclampsia and contact with relevant researchers. Incidence of pre eclampsia, proportion of preterm (<37(0/7) weeks gestation), late (34(0/7) 36(6/7) weeks) and early (<34(0/7) weeks) preterm birth in pre-eclamptic deliveries were analyzed. RESULTS: Pre-eclampsia occurred in 2.3% of 51 927 singleton live-born deliveries in Reunion Island. The prevalence of preterm birth among pre-eclamptic deliveries was 59.8% (28.6% late and 31.2% early preterm birth). Among identified reports, only one prospective study from Canada (1986 1995) described preterm and early preterm birth rates higher than Reunion Island. A cohort-based report from Guadeloupe, another tropical French DOM, showed a preterm birth prevalence of 60.9%, with 30.8% of early preterm birth. CONCLUSIONS: Predominance of early- or late-onset pre-eclampsia has huge geographical differences. Further investigations are required to address risk factors for preterm birth and early onset pre-eclampsia in French DOM. PMID- 26512886 TI - The Rho-guanine nucleotide exchange factor PDZ-RhoGEF governs susceptibility to diet-induced obesity and type 2 diabetes. AB - Adipose tissue is crucial for the maintenance of energy and metabolic homeostasis and its deregulation can lead to obesity and type II diabetes (T2D). Using gene disruption in the mouse, we discovered a function for a RhoA-specific guanine nucleotide exchange factor PDZ-RhoGEF (Arhgef11) in white adipose tissue biology. While PDZ-RhoGEF was dispensable for a number of RhoA signaling-mediated processes in mouse embryonic fibroblasts, including stress fiber formation and cell migration, it's deletion led to a reduction in their proliferative potential. On a whole organism level, PDZ-RhoGEF deletion resulted in an acute increase in energy expenditure, selectively impaired early adipose tissue development and decreased adiposity in adults. PDZ-RhoGEF-deficient mice were protected from diet-induced obesity and T2D. Mechanistically, PDZ-RhoGEF enhanced insulin/IGF-1 signaling in adipose tissue by controlling ROCK-dependent phosphorylation of the insulin receptor substrate-1 (IRS-1). Our results demonstrate that PDZ-RhoGEF acts as a key determinant of mammalian metabolism and obesity-associated pathologies. PMID- 26512887 TI - pp32 and APRIL are host cell-derived regulators of influenza virus RNA synthesis from cRNA. AB - Replication of influenza viral genomic RNA (vRNA) is catalyzed by viral RNA dependent RNA polymerase (vRdRP). Complementary RNA (cRNA) is first copied from vRNA, and progeny vRNAs are then amplified from the cRNA. Although vRdRP and viral RNA are minimal requirements, efficient cell-free replication could not be reproduced using only these viral factors. Using a biochemical complementation assay system, we found a novel activity in the nuclear extracts of uninfected cells, designated IREF-2, that allows robust unprimed vRNA synthesis from a cRNA template. IREF-2 was shown to consist of host-derived proteins, pp32 and APRIL. IREF-2 interacts with a free form of vRdRP and preferentially upregulates vRNA synthesis rather than cRNA synthesis. Knockdown experiments indicated that IREF-2 is involved in in vivo viral replication. On the basis of these results and those of previous studies, a plausible role(s) for IREF-2 during the initiation processes of vRNA replication is discussed. PMID- 26512888 TI - Fucosylation and protein glycosylation create functional receptors for cholera toxin. AB - Cholera toxin (CT) enters and intoxicates host cells after binding cell surface receptors using its B subunit (CTB). The ganglioside (glycolipid) GM1 is thought to be the sole CT receptor; however, the mechanism by which CTB binding to GM1 mediates internalization of CT remains enigmatic. Here we report that CTB binds cell surface glycoproteins. Relative contributions of gangliosides and glycoproteins to CTB binding depend on cell type, and CTB binds primarily to glycoproteins in colonic epithelial cell lines. Using a metabolically incorporated photocrosslinking sugar, we identified one CTB-binding glycoprotein and demonstrated that the glycan portion of the molecule, not the protein, provides the CTB interaction motif. We further show that fucosylated structures promote CTB entry into a colonic epithelial cell line and subsequent host cell intoxication. CTB-binding fucosylated glycoproteins are present in normal human intestinal epithelia and could play a role in cholera. PMID- 26512889 TI - Filopodial dynamics and growth cone stabilization in Drosophila visual circuit development. AB - Filopodial dynamics are thought to control growth cone guidance, but the types and roles of growth cone dynamics underlying neural circuit assembly in a living brain are largely unknown. To address this issue, we have developed long-term, continuous, fast and high-resolution imaging of growth cone dynamics from axon growth to synapse formation in cultured Drosophila brains. Using R7 photoreceptor neurons as a model we show that >90% of the growth cone filopodia exhibit fast, stochastic dynamics that persist despite ongoing stepwise layer formation. Correspondingly, R7 growth cones stabilize early and change their final position by passive dislocation. N-Cadherin controls both fast filopodial dynamics and growth cone stabilization. Surprisingly, loss of N-Cadherin causes no primary targeting defects, but destabilizes R7 growth cones to jump between correct and incorrect layers. Hence, growth cone dynamics can influence wiring specificity without a direct role in target recognition and implement simple rules during circuit assembly. PMID- 26512890 TI - Deficient and Null Variants of SERPINA1 Are Proteotoxic in a Caenorhabditis elegans Model of alpha1-Antitrypsin Deficiency. AB - alpha1-antitrypsin deficiency (ATD) predisposes patients to both loss-of-function (emphysema) and gain-of-function (liver cirrhosis) phenotypes depending on the type of mutation. Although the Z mutation (ATZ) is the most prevalent cause of ATD, >120 mutant alleles have been identified. In general, these mutations are classified as deficient (<20% normal plasma levels) or null (<1% normal levels) alleles. The deficient alleles, like ATZ, misfold in the ER where they accumulate as toxic monomers, oligomers and aggregates. Thus, deficient alleles may predispose to both gain- and loss-of-function phenotypes. Null variants, if translated, typically yield truncated proteins that are efficiently degraded after being transiently retained in the ER. Clinically, null alleles are only associated with the loss-of-function phenotype. We recently developed a C. elegans model of ATD in order to further elucidate the mechanisms of proteotoxicity (gain-of-function phenotype) induced by the aggregation-prone deficient allele, ATZ. The goal of this study was to use this C. elegans model to determine whether different types of deficient and null alleles, which differentially affect polymerization and secretion rates, correlated to any extent with proteotoxicity. Animals expressing the deficient alleles, Mmalton, Siiyama and S (ATS), showed overall toxicity comparable to that observed in patients. Interestingly, Siiyama expressing animals had smaller intracellular inclusions than ATZ yet appeared to have a greater negative effect on animal fitness. Surprisingly, the null mutants, although efficiently degraded, showed a relatively mild gain-of-function proteotoxic phenotype. However, since null variant proteins are degraded differently and do not appear to accumulate, their mechanism of proteotoxicity is likely to be different to that of polymerizing, deficient mutants. Taken together, these studies showed that C. elegans is an inexpensive tool to assess the proteotoxicity of different AT variants using a transgenic approach. PMID- 26512891 TI - Development and Characterization of 1,906 EST-SSR Markers from Unigenes in Jute (Corchorus spp.). AB - Jute, comprising white and dark jute, is the second important natural fiber crop after cotton worldwide. However, the lack of expressed sequence tag-derived simple sequence repeat (EST-SSR) markers has resulted in a large gap in the improvement of jute. Previously, de novo 48,914 unigenes from white jute were assembled. In this study, 1,906 EST-SSRs were identified from these assembled uingenes. Among these markers, di-, tri- and tetra-nucleotide repeat types were the abundant types (12.0%, 56.9% and 21.6% respectively). The AG-rich or GA-rich nucleotide repeats were the predominant. Subsequently, a sample of 116 SSRs, located in genes encoding transcription factors and cellulose synthases, were selected to survey polymorphisms among12 diverse jute accessions. Of these, 83.6% successfully amplified at least one fragment and detected polymorphism among the 12diverse genotypes, indicating that the newly developed SSRs are of good quality. Furthermore, the genetic similarity coefficients of all the 12 accessions were evaluated using 97 polymorphic SSRs. The cluster analysis divided the jute accessions into two main groups with genetic similarity coefficient of 0.61. These EST-SSR markers not only enrich molecular markers of jute genome, but also facilitate genetic and genomic researches in jute. PMID- 26512892 TI - All Military Adolescents Are Not the Same: Sexuality and Substance Use among Adolescents in the U.S. Military Healthcare System. AB - Data examining sexuality and substance use among active duty and military dependent youth is limited; however, these psychosocial factors have military implications. Adolescents and young adults aged 12-23 were recruited from an active-duty trainee clinic (n = 225) and a military pediatric clinic (n = 223). Active duty participants were more likely to be older, male, White, previous tobacco users, and report a history of sexual activity and less contraception use at their most recent intercourse, compared to the dependent group. Over 10% of all participants indicated attraction to members of the same gender or both genders. In logistic regression analysis, non-White participants were less likely to use contraception compared to White participants. Adolescents and young adults seen in military clinics frequently engage in high-risk behavior. Clinicians who care for military youth should assess their patient's psychosocial history. Further study of this population is warranted to identify factors that may influence risk and resilience. PMID- 26512893 TI - The YHS-Domain of an Adenylyl Cyclase from Mycobacterium phlei Is a Probable Copper-Sensor Module. AB - YHS-domains are small protein modules which have been proposed to bind transition metal ions like the related TRASH-domains. They are found in a variety of enzymes including copper-transporting ATPases and adenylyl cyclases. Here we investigate a class IIIc adenylyl cyclase from Mycobacterium phlei which contains a C terminal YHS-domain linked to the catalytic domain by a peptide of 8 amino acids. We expressed the isolated catalytic domain and the full-length enzyme in E. coli. The catalytic domain requires millimolar Mn2+ as a cofactor for efficient production of cAMP, is unaffected by low micromolar concentrations of Cu2+ and inhibited by concentrations higher than 10 MUM. The full-length enzyme also requires Mn2+ in the absence of an activator. However, 1-10 MUM Cu2+ stimulate the M. phlei adenylyl cyclase sixfold when assayed with Mn2+. With Mg2+ as the probable physiological cofactor of the adenylyl cyclase Cu2+ specifically switches the enzyme from an inactive to an active state. Other transition-metal ions do not elicit activity with Mg2+. We favor the view that the YHS-domain of M. phlei adenylyl cyclase acts as a sensor for copper ions and signals elevated levels of the transition-metal via cAMP. By analogy to TRASH-domains binding of Cu2+ probably occurs via one conserved aspartate and three conserved cysteine residues in the YHS-domain. PMID- 26512894 TI - Extracting Diffusive States of Rho GTPase in Live Cells: Towards In Vivo Biochemistry. AB - Resolving distinct biochemical interaction states when analyzing the trajectories of diffusing proteins in live cells on an individual basis remains challenging because of the limited statistics provided by the relatively short trajectories available experimentally. Here, we introduce a novel, machine-learning based classification methodology, which we call perturbation expectation-maximization (pEM), that simultaneously analyzes a population of protein trajectories to uncover the system of diffusive behaviors which collectively result from distinct biochemical interactions. We validate the performance of pEM in silico and demonstrate that pEM is capable of uncovering the proper number of underlying diffusive states with an accurate characterization of their diffusion properties. We then apply pEM to experimental protein trajectories of Rho GTPases, an integral regulator of cytoskeletal dynamics and cellular homeostasis, in vivo via single particle tracking photo-activated localization microscopy. Remarkably, pEM uncovers 6 distinct diffusive states conserved across various Rho GTPase family members. The variability across family members in the propensities for each diffusive state reveals non-redundant roles in the activation states of RhoA and RhoC. In a resting cell, our results support a model where RhoA is constantly cycling between activation states, with an imbalance of rates favoring an inactive state. RhoC, on the other hand, remains predominantly inactive. PMID- 26512895 TI - Correlates of Regular Participation in Sports Groups among Japanese Older Adults: JAGES Cross-Sectional Study. AB - BACKGROUND: Participation in a sports group is key for the prevention of incident functional disability. Little is known about the correlates of older adults' participation in sports groups, although this could assist with the development of effective health strategies. The purpose of this study was to identify the demographic and biological, psychosocial, behavioral, social and cultural, and environmental correlates of sports group participation among Japanese older adults. METHODS: Data were obtained from the Japan Gerontological Evaluation study, which was a population-based cohort of people aged >=65 years without disability enrolled from 31 municipalities across Japan (n = 78,002). Poisson regression analysis was used to determine the associations between the factors and participation in sports groups. RESULTS: Non-regular participation in sports groups was associated with lower educational level, being employed, and working the longest in the agricultural/forestry/fishery industry among the demographic and biological factors and poor self-rated health and depression among the psychosocial factors. Of the behavioral factors, current smoking was negatively associated and current drinking was positively associated with regular participation in sports groups. Among the social and cultural factors, having emotional social support and participating in hobby clubs, senior citizen clubs, or volunteer groups were associated with a high prevalence of participation in sports groups. Perceptions of the presence of parks or sidewalks, good access to shops, and good accessibility to facilities were positively associated with participation in sports groups among the environmental factors. CONCLUSIONS: Our study suggests that the promotion of activities that could increase older adults' participation in sports groups should consider a broad range of demographic and biological, psychosocial, behavioral, social and cultural, and environmental factors. Although future longitudinal studies to elucidate the causal associations are needed, encouraging participation in community groups through social networks might be effective for participation in sports groups. PMID- 26512896 TI - Correction: Efficacy of Albendazole-Chitosan Microsphere-based Treatment for Alveolar Echinococcosis in Mice. AB - [This corrects the article DOI: 10.1371/journal.pntd.0003950.]. PMID- 26512897 TI - Correction: Expression Analysis of All Protease Genes Reveals Cathepsin K to Be Overexpressed in Glioblastoma. PMID- 26512898 TI - Inhibition on Proteasome beta1 Subunit Might Contribute to the Anti-Cancer Effects of Fangchinoline in Human Prostate Cancer Cells. AB - Fangchinoline is a bisbenzylisoquinoline alkaloid isolated from Radix Stephaniae tetrandrae S. Moore. Fangchinoline and its structure analogue, tetrandrine, exhibited direct binding affinity with recombinant human proteasome beta1 subunit and also inhibited its activity in vitro. In cultured prostate PC-3 cells and LnCap cells, fangchinoline could dose-dependently inhibit cell proliferation and caspase-like activity of cellular proteasome which was mediated by proteasome beta1 subunit. The inhibitive effect of fangchinoline on caspase-like activity of proteasome was also observed in purified human erythrocyte 20S proteasome. In PC 3 cells, fangchinoline induced cell cycle arrest at G0/G1 phase and apoptosis. Treatment of PC-3 tumor-bearing nude mice with fangchinoline inhibited tumor growth, induced apoptosis and also caused decrease in proteasome activities in tumor xenografts. Dose-dependent and time-dependent accumulation of ubiquitinated proteins and important proteasome substrates such as p27, Bax and IkappaB-alpha were observed in fangchinoline-treated cells. Over-expression of proteasome beta1 subunit by plasmid transfection increased sensitivity of cells to the cytotoxicity of fangchinoline while knockdown of proteasome beta1 subunit ameliorated cytotoxicity of fangchinoline in PC-3 cells. Results of the present study suggested that proteasome inhibition was involved in the anti-cancer effects of fangchinoline. Fangchinoline and its structure analogues might be new natural proteasome inhibitors targeting beta1 subunit. PMID- 26512899 TI - Incidence of fetal bradycardia and effect of placental injury on fetal heart rate during second-trimester genetic amniocentesis. AB - A prospective study was conducted for comparing the incidence of fetal bradycardia and level of fetal heart rate change following a second-trimester genetic amniocentesis with and without placental injury. A total of 257 and 495 participants in injured and non-injured groups were analysed. The incidence of fetal bradycardia following amniocentesis was not statistically different between the two groups (1.17%, [95% CI 0.24, 3.37] and 0.20%, [95% CI 0.005, 1.12]) in injured and non-injured placenta groups, respectively; p = 0.118). The mean change in baseline fetal heart rate before and after amniocentesis was also not significantly different between the two groups (p = 0.844). No fetal death or pregnancy loss occurred within 4 weeks after the procedure. All 4 bradycardia participants were normal and healthy and had an appropriate weight for their gestational age. We conclude that placental injury during a second-trimester genetic amniocentesis due to advanced maternal age poses only a low risk of fetal bradycardia, and there is no evidence of differences between subjects with injured and non-injured placenta in the changes in fetal heart rate. PMID- 26512900 TI - Posterior Teeth Occlusion Associated with Cognitive Function in Nursing Home Older Residents: A Cross-Sectional Observational Study. AB - Early detection and subsequent reduction of modifiable risk factors for cognitive decline is important for extending healthy life expectancy in the currently aging society. Although a recent increase in studies on the state or number of the teeth and cognitive function, few studies have focused on the association between posterior teeth occlusion necessary to maintain chewing function and cognitive function among older adults. This study examined the association between posterior teeth occlusion and cognitive function in nursing home older residents. In this cross-sectional study, 279 residents aged >=60 years from eight nursing homes in Aso City, Japan participated in cognitive function and dental status assessments and completed a comprehensive questionnaire survey in 2014. Cognitive function was measured using a Mini-Mental State Examination (MMSE). Posterior teeth occlusion was assessed using a total number of functional tooth units (total-FTUs), depending on the number and location of the remaining natural and artificial teeth on implant-supported, fixed, and removable prostheses. Linear regression models were used to assess univariate and multivariate associations between total-FTUs and MMSE scores. Models were sequentially adjusted for demographic characteristics, number of natural teeth, socioeconomic status, health behaviors, comorbidities, physical function, and nutritional status. Among the 200 residents included in our analysis, mean MMSE scores and total-FTUs were 11.0 +/- 8.6 and 9.3 +/- 4.6, respectively. Higher total-FTUs were significantly associated with higher MMSE scores after adjustment for demographics and teeth number (B = 0.48, 95% confidence interval [CI] = 0.22-0.74). The association remained significant even after adjustment for all covariates (B = 0.25, 95% CI = 0.01-0.49). The current findings demonstrated that loss of posterior teeth occlusion was independently associated with cognitive decline in nursing home older residents in Japan. Maintenance and restoration of posterior teeth occlusion may be a preventive factor against cognitive decline in aged populations. PMID- 26512901 TI - Gabapentin Effects on PKC-ERK1/2 Signaling in the Spinal Cord of Rats with Formalin-Induced Visceral Inflammatory Pain. AB - Currently, the clinical management of visceral pain remains unsatisfactory for many patients suffering from this disease. While preliminary animal studies have suggested the effectiveness of gabapentin in successfully treating visceral pain, the mechanism underlying its analgesic effect remains unclear. Evidence from other studies has demonstrated the involvement of protein kinase C (PKC) and extracellular signal-regulated kinase1/2 (ERK1/2) in the pathogenesis of visceral inflammatory pain. In this study, we tested the hypothesis that gabapentin produces analgesia for visceral inflammatory pain through its inhibitory effect on the PKC-ERK1/2 signaling pathway. Intracolonic injections of formalin were performed in rats to produce colitis pain. Our results showed that visceral pain behaviors in these rats decreased after intraperitoneal injection of gabapentin. These behaviors were also reduced by intrathecal injections of the PKC inhibitor, H-7, and the ERK1/2 inhibitor, PD98059. Neuronal firing of wide dynamic range neurons in L6-S1 of the rat spinal cord dorsal horn were significantly increased after intracolonic injection of formalin. This increased firing rate was inhibited by intraperitoneal injection of gabapentin and both the individual and combined intrathecal application of H-7 and PD98059. Western blot analysis also revealed that PKC membrane translocation and ERK1/2 phosphorylation increased significantly following formalin injection, confirming the recruitment of PKC and ERK1/2 during visceral inflammatory pain. These effects were also significantly reduced by intraperitoneal injection of gabapentin. Therefore, we concluded that the analgesic effect of gabapentin on visceral inflammatory pain is mediated through suppression of PKC and ERK1/2 signaling pathways. Furthermore, we found that the PKC inhibitor, H-7, significantly diminished ERK1/2 phosphorylation levels, implicating the involvement of PKC and ERK1/2 in the same signaling pathway. Thus, our results suggest a novel mechanism of gabapentin-mediated analgesia for visceral inflammatory pain through a PKC-ERK1/2 signaling pathway that may be a future therapeutic target for the treatment of visceral inflammatory pain. PMID- 26512902 TI - Low Incidence of HIV-1C Acquired Drug Resistance 10 Years after Roll-Out of Antiretroviral Therapy in Ethiopia: A Prospective Cohort Study. AB - The emergence of HIV-1 drug resistance mutations has mainly been linked to the duration and composition of antiretroviral treatment (ART), as well as the level of adherence. This study reports the incidence and pattern of acquired antiretroviral drug resistance mutations and long-term outcomes of ART in a prospective cohort from Northwest Ethiopia. Two hundred and twenty HIV-1C infected treatment naive patients were enrolled and 127 were followed-up for up to 38 months on ART. ART initiation and patients' monitoring was based on the WHO clinical and immunological parameters. HIV viral RNA measurement and drug resistance genotyping were done at baseline (N = 160) and after a median time of 30 (IQR, 27-38) months on ART (N = 127). Viral suppression rate (HIV RNA levels <= 400 copies/ml) after a median time of 30 months on ART was found to be 88.2% (112/127), which is in the range for HIV drug resistance prevention suggested by WHO. Of those 15 patients with viral load >400 copies/ml, six harboured one or more drug resistant associated mutations in the reverse transcriptase (RT) region. Observed NRTIs resistance associated mutations were the lamivudine induced mutation M184V (n = 4) and tenofovir associated mutation K65R (n = 1). The NNRTIs resistance associated mutations were K103N (n = 2), V106M, Y181S, Y188L, V90I, K101E and G190A (n = 1 each). Thymidine analogue mutations and major drug resistance mutations in the protease (PR) region were not detected. Most of the patients (13/15) with virologic failure and accumulated drug resistance mutations had not met the WHO clinical and/or immunological failure criteria and continued the failing regimen. The incidence and pattern of acquired antiretroviral drug resistance mutations is lower and less complex than previous reports from sub Saharan Africa countries. Nevertheless, the data suggest the need for virological monitoring and resistance testing for early detection of failure. Moreover, adherence reinforcement will contribute to improving overall treatment outcomes. PMID- 26512903 TI - Correction to Relaxometry and Dephasing Imaging of Superparamagnetic Magnetite Nanoparticles Using a Single Qubit. PMID- 26512904 TI - Home dust microbiota is disordered in homes of low-income asthmatic children. AB - OBJECTIVE: Exposure to microorganisms has repeatedly been found to influence development of atopic diseases, such as asthma. Innovative techniques have been developed that can comprehensively characterize microbial communities. The objective of this study was to characterize the home microbiota of asthmatic children utilizing 16S rRNA-based phylogenetic analysis by microarray. METHODS: In this cross-sectional study, DNA was extracted from home dust and bacterial 16S rRNA genes amplified. Bacterial products were hybridized to the PhyloChip Array and scanned using a GeneArray scanner (Affymetrix, Santa Clara, CA). The Adonis test was used to determine significant differences in the whole microbiome. Welch's t-test was used to determine significant abundance differences and genus level richness differences. RESULTS: Nineteen homes were included in the analysis (14 asthma and five no asthma). About 1741 operational taxonomic units (OTUs) were found in at least one sample. Bacterial genus richness did not differ in the homes of asthmatics and non-asthmatics (p = 0.09). The microbial profile was significantly different between the two groups (p = 0.025). All the top 12 OTUs with significant abundance differences were increased in homes of asthmatics and belonged to one of the five phyla (p = 0.001 to p = 7.2 * 10(-6)). Nearly half of significant abundance differences belonged to the phylum Cyanobacteria or Proteobacteria. CONCLUSIONS: These results suggest that home dust has a characteristic microbiota which is disturbed in the homes of asthmatics, resulting in a particular abundance of Cyanobacteria and Proteobacteria. Further investigations are needed which utilize high-throughput technology to further clarify how home microbial exposures influence human health and disease. PMID- 26512905 TI - Increased serum levels of serine enantiomers in patients with depression. AB - OBJECTIVE: Glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor is integral to the pathophysiology of depression. This study was performed to examine whether amino acids related to NMDA receptor neurotransmission are altered in the serum of patients with depression. METHOD: We measured the serum levels of d-serine, l-serine, glycine, glutamate and glutamine in patients with depression (n=70), and age-matched healthy subjects (n=78). RESULTS: Serum levels of d-serine and l-serine in patients with depression were significantly higher than those of healthy controls (p<0.001). In contrast, serum levels of glycine, glutamate and glutamine did not differ between the two groups. Interestingly, the ratio of l-serine to glycine in patients was significantly higher than that of healthy controls (p<0.001). CONCLUSION: This study suggests that serine enantiomers may be peripheral biomarkers for depression, and that abnormality in the d-serine-l-serine-glycine cycle plays a role in the pathophysiology of depression. PMID- 26512906 TI - The effects of ultraviolet C radiation on the ultrastructure of the liver cells of mole rats. AB - The aim of this study was to elucidate the ultrastructural changes in the liver cells of mole rats (Spalax leucodon) exposed to ultraviolet radiation (UVR). Thirteen mole rats used in this study were caught from nature. They were divided into four groups. The first group was separated as a control and was not given any radiation. The rest were exposed to ultraviolet C (UVC) radiation for 7, 14, and 21 days. The electron microscopic examinations revealed that significant ultrastructural changes occurred in the liver tissue. These changes were the reduction in cytoplasmic organelles, dilatation in rough endoplasmic reticulum, impairment of nucleus membrane, and broadened and vacuolated mitochondria in the cytoplasm. Also, UVC radiation caused significant changes in liver enzymes of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gama-glutamiltransferase values. After long-term exposure to radiation, some excessive ultrastructural changes occurred. These results indicated that longer exposure to UVR would cause more ultrastructural effects on the liver cells and liver enzymes. PMID- 26512907 TI - Erratum: Quantitative analysis of magnetic spin and orbital moments from an oxidized iron (1 1 0) surface using electron magnetic circular dichroism. PMID- 26512908 TI - Avoiding Management Errors in Patients with Obesity Hypoventilation Syndrome. AB - The prevalence of obesity hypoventilation syndrome and obstructive sleep apnea are increasing rapidly in the United States in parallel with the obesity epidemic. As the pathogenesis of this chronic illness is better understood, effective evidence-based therapies are being deployed to reduce morbidity and mortality. Nevertheless, patients with obesity hypoventilation still fall prey to at least four avoidable types of therapeutic errors, especially at the time of hospitalization for respiratory or cardiovascular decompensation: (1) patients with obesity hypoventilation syndrome may develop acute hypercapnia in response to administration of excessive supplemental oxygen; (2) excessive diuresis for peripheral edema using a loop diuretic such as furosemide exacerbates metabolic alkalosis, thereby worsening daytime hypoventilation and hypoxemia; (3) excessive or premature pharmacological treatment of psychiatric illnesses can exacerbate sleep-disordered breathing and worsen hypercapnia, thereby exacerbating psychiatric symptoms; and (4) clinicians often erroneously diagnose obstructive lung disease in patients with obesity hypoventilation, thereby exposing them to unnecessary and potentially harmful medications, including beta-agonists and corticosteroids. Just as literary descriptions of pickwickian syndrome have given way to greater understanding of the pathophysiology of obesity hypoventilation, clinicians might exercise caution to consider these potential pitfalls and thus avoid inflicting unintended and avoidable complications. PMID- 26512909 TI - An update on chemotherapy for osteosarcoma. AB - INTRODUCTION: In the early seventies chemotherapy significantly improved survival in osteosarcoma. Since then minor innovations have occurred although recent years have offered insights of clinical and scientific relevance. AREAS COVERED: This review focuses on the most recent results of phase 3 and 2 studies. Published data or presentations at International meetings are discussed. A specific section discusses recent insights from studies supporting the hypothesis of a possible personalized chemotherapy approach. EXPERT OPINION: Osteosarcoma is a rare tumor and any effort should be made to improve the level of International collaboration. The MAP (methotrexate, doxorubicin and cisplatin) regimen has become the treatment of choice. Poor pathological response to primary chemotherapy is confirmed as a predictive factor of survival and, presently with the available drugs, it is not recommended to intensify or change post-operative treatment on the basis of pathological response to primary chemotherapy. The genomic complexity and the heterogeneity of osteosarcoma makes active and effective molecularly targeted therapies unlikely to be available in the near future. A relation between pharmacogenetic profile and chemotherapy toxicity and prognosis has been reported. The new frontier for clinical research in osteosarcoma is to optimize the use of the active drugs available by personalizing chemotherapy treatment. PMID- 26512910 TI - The daily rhythms of mitochondrial gene expression and oxidative stress regulation are altered by aging in the mouse liver. AB - The circadian clock regulates many cellular processes, notably including the cell cycle, metabolism and aging. Mitochondria play essential roles in metabolism and are the major sites of reactive oxygen species (ROS) production in the cell. The clock regulates mitochondrial functions by driving daily changes in NAD(+) levels and Sirt3 activity. In addition to this central route, in the present study, we find that the expression of some mitochondrial genes is also rhythmic in the liver, and that there rhythms are disrupted by the Clock(Delta19) mutation in young mice, suggesting that they are regulated by the core circadian oscillator. Related to this observation, we also find that the regulation of oxidative stress is rhythmic in the liver. Since mitochondria and ROS play important roles in aging, and mitochondrial functions are also disturbed by aging, these related observations prompt the compelling hypothesis that circadian oscillators influence aging by regulating ROS in mitochondria. During aging, the expression rhythms of some mitochondrial genes were altered in the liver and the temporal regulation over the dynamics of mitochondrial oxidative stress was disrupted. However, the expression of clock genes was not affected. Our results suggested that mitochondrial functions are combinatorially regulated by the clock and other age-dependent mechanism(s), and that aging disrupts mitochondrial rhythms through mechanisms downstream of the clock. PMID- 26512911 TI - Identification of novel proteins binding the AU-rich element of alpha-prothymosin mRNA through the selection of open reading frames (RIDome). AB - We describe here a platform for high-throughput protein expression and interaction analysis aimed at identifying the RNA-interacting domainome. This approach combines the selection of a phage library displaying "filtered" open reading frames with next-generation DNA sequencing. The method was validated using an RNA bait corresponding to the AU-rich element of alpha-prothymosin, an RNA motif that promotes mRNA stability and translation through its interaction with the RNA-binding protein ELAVL1. With this strategy, we not only confirmed known RNA-binding proteins that specifically interact with the target RNA (such as ELAVL1/HuR and RBM38) but also identified proteins not previously known to be ARE-binding (R3HDM2 and RALY). We propose this technology as a novel approach for studying the RNA-binding proteome. PMID- 26512912 TI - Evidence-based post-exercise recovery strategies in basketball. AB - Basketball can be described as a moderate-to-long duration exercise including repeated bouts of high-intensity activity interspersed with periods of low to moderate active recovery or passive rest. A match is characterized by repeated explosive activities, such as sprints, jumps, shuffles and rapid changes in direction. In top-level modern basketball, players are frequently required to play consecutive matches with limited time to recover. To ensure adequate recovery after any basketball activity (i.e., match or training), it is necessary to know the type of fatigue induced and, if possible, its underlying mechanisms. Despite limited scientific evidence to support their effectiveness in facilitating optimal recovery, certain recovery strategies are commonly utilized in basketball. It is particularly important to optimize recovery because players spend a much greater proportion of their time recovering than they do in training. Therefore, the main aim of this report is to facilitate useful information that may lead to practical application, based on the scientific evidence and applied knowledge specifically in basketball. PMID- 26512913 TI - The Use of Superlatives in Cancer Research. PMID- 26512914 TI - Early changes in Achilles tendon behaviour in vivo following downhill backwards walking. AB - Downhill backwards walking causes repeated, cyclical loading of the muscle-tendon unit. The effect this type of repeated loading has on the mechanical behaviour of the Achilles tendon is presently unknown. This study aimed to investigate the biomechanical response of the Achilles tendon aponeurosis complex following a downhill backwards walking protocol. Twenty active males (age: 22.3 +/- 3.0 years; mass: 74.7 +/- 5.6 kg; height: 1.8 +/- 0.7 m) performed 60 min of downhill (8.5 degrees ), backwards walking on a treadmill at -0.67 m . s(-1). Data were collected before, immediately post, and 24-, 48- and 168-h post-downhill backwards walking. Achilles tendon aponeurosis elongation, strain and stiffness were measured using ultrasonography. Muscle force decreased immediately post downhill backward walking (P = 0.019). There were increases in Achilles tendon aponeurosis stiffness at 24-h post-downhill backward walking (307 +/- 179.6 N . mm(-1), P = 0.004), and decreases in Achilles tendon aponeurosis strain during maximum voluntary contraction at 24 (3.8 +/- 1.7%, P = 0.008) and 48 h (3.9 +/- 1.8%, P = 0.002) post. Repeated cyclical loading of downhill backwards walking affects the behaviour of the muscle-tendon unit, most likely by altering muscle compliance, and these changes result in tendon stiffness increases. PMID- 26512915 TI - Connecting the self to traumatic and positive events: links to identity and well being. AB - Self-event connections in autobiographical narratives help integrate specific episodes from memory into the life story, which has implications for identity and well-being. Previous research has distinguished differential relations between positive and negative self-event connections to psychological well-being but less research has examined identity. In this study, examining self-event connections in emerging adults' narratives, 225 participants narrated a traumatic and an intensely positive experience and completed questionnaires assessing identity development and well-being. Participants who described more negative connections to self overall had higher psychological distress and identity distress, compared to those who described fewer negative connections. Participants who described positive connections to the self in traumatic events were more likely to have lower psychological distress, higher post-traumatic growth, and higher identity commitment, whereas positive connections in positive events was related to higher identity exploration and marginally higher post-traumatic growth. These findings contribute to a growing body of literature that suggests linking autobiographical memories to self can have differential effects on identity and well-being depending on the valence of the event and the connections made. PMID- 26512916 TI - How Health Risks Are Pinpointed (or Not) on Social Media: The Portrayal of Waterpipe Smoking on Pinterest. AB - Waterpipe tobacco is among the most rapidly growing trends in tobacco smoking, the growing use and acceptance of which are taking place at a time when cigarette smoking is regarded in an increasingly negative manner (Martinasek, McDermott, & Martini, 2011). Given the health risks and the misperceptions associated with waterpipe smoking, this study focuses on how waterpipe smoking is portrayed and represented on the social media platform Pinterest. In total, 800 Pinterest pins were content analyzed. The vast majority of the sampled pins were primarily image based. More than half of the pins linked to a website external to Pinterest that often redirected the pinner to a commercial website. Waterpipe-focused pins portrayed waterpipe smoking more in a positive light than in a negative light, and conveyed a sense of pleasure, aesthetic, and relaxation, which tended to trigger more repins, likes, and higher levels of engagement. Overall, the risks of waterpipe smoking were not represented on Pinterest, indicating that the social media portrayal of waterpipe smoking needs improvement and could benefit from a public health perspective. PMID- 26512917 TI - Evaluation of Gafchromic EBT-XD film, with comparison to EBT3 film, and application in high dose radiotherapy verification. AB - There is renewed interest in film dosimetry for the verification of dose delivery of complex treatments, particularly small fields, compared to treatment planning system calculations. A new radiochromic film, Gafchromic EBT-XD, is available for high-dose treatment verification and we present the first published evaluation of its use. We evaluate the new film for MV photon dosimetry, including calibration curves, performance with single- and triple-channel dosimetry, and comparison to existing EBT3 film. In the verification of a typical 25 Gy stereotactic radiotherapy (SRS) treatment, compared to TPS planned dose distribution, excellent agreement was seen with EBT-XD using triple-channel dosimetry, in isodose overlay, maximum 1.0 mm difference over 200-2400 cGy, and gamma evaluation, mean passing rate 97% at 3% locally-normalised, 1.5 mm criteria. In comparison to EBT3, EBT-XD gave improved evaluation results for the SRS-plan, had improved calibration curve gradients at high doses, and had reduced lateral scanner effect. The dimensions of the two films are identical. The optical density of EBT-XD is lower than EBT3 for the same dose. The effective atomic number for both may be considered water-equivalent in MV radiotherapy. We have validated the use of EBT-XD for high-dose, small-field radiotherapy, for routine QC and a forthcoming multi-centre SRS dosimetry intercomparison. PMID- 26512918 TI - Interplay between YB-1 and IL-6 promotes the metastatic phenotype in breast cancer cells. AB - Epithelial to mesenchymal transition (EMT) induces cell plasticity and promotes metastasis. The multifunctional oncoprotein Y-box binding protein-1 (YB-1) and the pleiotropic cytokine interleukin 6 (IL-6) have both been implicated in tumor cell metastasis and EMT, but via distinct pathways. Here, we show that direct interplay between YB-1 and IL-6 regulates breast cancer metastasis. Overexpression of YB-1 in breast cancer cell lines induced IL-6 production while stimulation with IL-6 increased YB-1 expression and YB-1 phosphorylation. Either approach was sufficient to induce EMT features, including increased cell migration and invasion. Silencing of YB-1 partially reverted the EMT and blocked the effect of IL-6 while inhibition of IL-6 signaling blocked the phenotype induced by YB-1 overexpression, demonstrating a clear YB-1/IL-6 interdependence. Our findings describe a novel signaling network in which YB-1 regulates IL-6, and vice versa, creating a positive feed-forward loop driving EMT-like metastatic features during breast cancer progression. Identification of signaling partners or pathways underlying this co-dependence may uncover novel therapeutic opportunities. PMID- 26512919 TI - Silencing of E2F3 suppresses tumor growth of Her2+ breast cancer cells by restricting mitosis. AB - The E2F transcriptional activators E2F1, E2F2 and E2F3a regulate many important cellular processes, including DNA replication, apoptosis and centrosome duplication. Previously, we demonstrated that silencing E2F1 or E2F3 suppresses centrosome amplification (CA) and chromosome instability (CIN) in Her2+ breast cancer cells without markedly altering proliferation. However, it is unknown whether and how silencing a single E2F activator, E2F3, affects malignancy of human breast cancer cells. Thus, we injected HCC1954 Her2+ breast cancer cells silenced for E2F3 into mammary fat pads of immunodeficient mice and demonstrated that loss of E2F3 retards tumor growth. Surprisingly, silencing of E2F3 led to significant reductions in mitotic indices relative to vector controls, while the percentage of cells undergoing S phase were not affected. Nek2 is a mitotic kinase commonly upregulated in breast cancers and a critical regulator of Cdk4- or E2F-mediated CA. In this report, we found that Nek2 overexpression rescued back the CA caused by silencing of shE2F3. However, the effects of Nek2 overexpression in affecting tumor growth rates of shE2F3 and shE2F3; GFP cells were inconclusive. Taken together, our results indicate that E2F3 silencing decreases mammary tumor growth by reducing percentage of cells undergoing mitosis. PMID- 26512920 TI - A biotherapy based on PSCs-in-3D spheroid-ameliorated biologics depletes in vivo cancer-sustaining stem cells. AB - CSCs are able to survive routine anticancer procedures and peripheral-immune attack. Here we develop and detail a framework of CSC elimination governed by 3D biologics. Pluripotent cells-engineered 3D-biologics (PMSB) and control non-3D biologics were prepared from placenta-based somatic stem cells (PSCs) and inoculated respectively into senile hosts bearing progressive mammary, lung, colon carcinomas and melanoma. We demonstrate that PMSB evokes in vivo central immune microenvironment with subsequent re-expression of thymosin-alpha1 ~ beta4 in thymic cortex-medulla borderline for rapid MHC-unrestricted renewal of gammadeltaT-dominated immunocompetence. The post-renewal gammadeltaT-subsets could accurately bind and drive CSCs into apoptosis. Finally, with central/peripheral integral microenvironment renewal and TERT/Wnt/beta-catenin pathway blockade, the CSC-subsets are fully depleted, leading to substantial cure of diverse tumors by PMSB inoculation (P < 0.01), yet not by non-3D-biologics. Thus, our study may contribute to open up a new avenue for tumor remission via pluripotent cells-engineered 3D-biologics addressing quick renewal of central thymus and peripheral immune-microenvironment. PMID- 26512921 TI - MicroRNA-29B (mir-29b) regulates the Warburg effect in ovarian cancer by targeting AKT2 and AKT3. AB - Epithelial ovarian cancer (EOC) is the most lethal and aggressive gynecological malignancy, and abnormal cellular metabolism significantly contributes to cancer onset and progression. Here, we report that miR-29b negatively regulates AKT2/AKT3 expression, causing HK2/PKM2 downregulation and leading to a decreased Warburg effect and slowed ovarian cancer progression. Compared to normal ovaries, ovaries with epithelial cancer exhibited lower miR-29b expression at both cellular/histological levels. Glucose consumption and lactate production experiments confirmed miR-29b's regulation of EOC metabolism. A luciferase reporter assay confirmed the direct binding of miR-29b to AKT2/AKT3 3' UTRs. miR 29b silencing correlated with increased expression of AKT2/3, pAKT2/3, HK2, and PKM2. Pyruvic acid and NAD+/NADH levels also changed when miR-29b expression was suppressed; this effect could be blocked by specific AKT inhibitors, suggesting the miR-29b-AKT axis regulates the Warburg effect in ovarian cancer. In xenograft mouse models, miR-29b inhibited tumor formation in vivo. In vivo imaging also demonstrated that miR-29b agomir inhibited the relative uptake of 18F-FDG in the xenograft tumors, suggesting that miR-29b over-expression could negatively modulate tumor glucose metabolism in vivo. Taken together, our study suggests that miR-29b regulates the Warburg effect in EOC via AKT2/AKT3 and may provide novel options for future treatments for EOC. PMID- 26512923 TI - Correlating conduction properties with the molecular symmetry: segregation of Z and E isomers in the charge-assisted, halogen-bonded cocrystal [(Z,E) Me2I2TTF]2Br. AB - The Z and E isomers of the iodinated TTF derivative (Z,E)-Me2I2-TTF co crystallize in a mixed-valence salt with Br(-) anions, and are segregated into Z and E stacks, each of them with a different charge localization pattern, which also revealed charge-assisted halogen bonding. PMID- 26512922 TI - Combining plasma Epstein-Barr virus DNA and nodal maximal standard uptake values of 18F-fluoro-2-deoxy-D-glucose positron emission tomography improved prognostic stratification to predict distant metastasis for locoregionally advanced nasopharyngeal carcinoma. AB - BACKGROUND: This study aimed to evaluate the value of combining the nodal maximal standard uptake values (SUVmax) of (18) F-fluoro-2-deoxy-D-glucose positron emission tomography with Epstein-Barr virus DNA(EBV DNA) levels to predict distant metastasis for nasopharyngeal carcinoma (NPC) patients. PATIENTS AND METHODS: Eight hundred seventy-four patients with stage III-IVa-b NPC were evaluated for the effects of combining SUVmax and EBV DNA levels on distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS). RESULTS: The optimal cutoff value was 6,220 copies/mL for EBV DNA and 7.5 for SUVmax-N. Patients with lower EBV DNA levels or SUVmax-N had a significantly better 3-year DMFS, DFS, and OS. Patients were divided into four groups based on EBV DNA and SUVmax-N, as follows: low EBV DNA and low SUVmax-N (LL), low EBV DNA and high SUVmax-N (LH), high EBV DNA and low SUVmax-N (HL), and high EBV DNA and high SUVmax-N (HH). There were significant differences between the four mentioned groups in 3-year DMFS: 95.7%, 92.2%, 92.3%, and 80.1%, respectively (P(trend) < 0.001). When looking at the disease stage, the 3-year DMFS in group LL, LH, HL, HH were 94.2%, 92.9%, 95.0%, and 81.1%, respectively, in stage III patients (P(trend) < 0.001) and 92.7%, 87.2%, 86.3%, and 77.0% in stage IVa-b patients (P(trend) = 0.026). CONCLUSION: Pretreatment EBV DNA and SUVmax of neck lymph nodes were independent prognostic factors for distant metastasis in NPC patients. Combining EBV DNA and SUVmax-N led to an improved risk stratification for distant metastasis in advanced-stage disease. PMID- 26512924 TI - Thermal-structural relationship of individual titania nanotubes. AB - The thermal properties of nano-scale materials are largely influenced by their geometry. The zero, one and quasi one dimensional forms of the same material could exhibit unique thermal transport properties depending upon the shape and nano-scale feature size. In order to gain a clear understanding of the contributions from geometrical scattering effects on thermal transport, it is required to study these nano-materials in a single isolated form rather than in clusters or films. In the past decade, titanium dioxide nanotube arrays fabricated by anodic oxidation of titanium emerged as a useful semiconductor architecture for a variety of applications, particularly for solar energy conversion. Nonetheless, the thermal properties of individual nanotubes that are important for their use in high temperature applications have not been clearly understood. Here we report the thermal transport properties of individual titania nanotubes as revealed by our preliminary study using a suspended microdevice that facilitates the thermal conductivity measurements and crystal structure investigation on the same nanotube. The nanotubes were prepared by anodic oxidation of a titanium foil in HF-DMSO electrolyte at 60 V, having outer diameters in the range of 200 to 300 nm and wall thicknesses of ~30 to 70 nm in either amorphous or polycrystalline anatase phase. The thermal conductivity of single nanotubes was found to be very close to that of the amorphous phase (1.5 W mK(-1) and 0.85 W mK(-1) respectively) and it was only half of the thermal conductivity of the nanotube arrays in the film form. The thermal conductivity of bulk TiO2 is known to be almost six times higher. The observed thermal conductivity suppression in single nanotubes was explained using a transport model developed by considering diffuse phonon-surface scattering and scattering of phonons by ionized impurities of concentrations in the order of 10(18)-10(19) cm(-3). PMID- 26512925 TI - Applications of GPS-tracked personal and fixed-location PM(2.5) continuous exposure monitoring. AB - Continued development of personal air pollution monitors is rapidly improving government and research capabilities for data collection. In this study, we tested the feasibility of using GPS-enabled personal exposure monitors to collect personal exposure readings and short-term daily PM2.5 measures at 15 fixed locations throughout a community. The goals were to determine the accuracy of fixed-location monitoring for approximating individual exposures compared to a centralized outdoor air pollution monitor, and to test the utility of two different personal monitors, the RTI MicroPEM V3.2 and TSI SidePak AM510. For personal samples, 24-hr mean PM2.5 concentrations were 6.93 MUg/m3 (stderr = 0.15) and 8.47 MUg/m3 (stderr = 0.10) for the MicroPEM and SidePak, respectively. Based on time-activity patterns from participant journals, exposures were highest while participants were outdoors (MicroPEM = 7.61 ug/m3, stderr = 1.08, SidePak = 11.85 ug/m3, stderr = 0.83) or in restaurants (MicroPEM = 7.48 ug/m3, stderr = 0.39, SidePak = 24.93 ug/m3, stderr = 0.82), and lowest when participants were exercising indoors (MicroPEM = 4.78 ug/m3, stderr = 0.23, SidePak = 5.63 ug/m3, stderr = 0.08). Mean PM(2.5) at the 15 fixed locations, as measured by the SidePak, ranged from 4.71 ug/m3 (stderr = 0.23) to 12.38 ug/m3 (stderr = 0.45). By comparison, mean 24-h PM(2.5) measured at the centralized outdoor monitor ranged from 2.7 to 6.7 ug/m3 during the study period. The range of average PM(2.5) exposure levels estimated for each participant using the interpolated fixed-location data was 2.83 to 19.26 ug/m3 (mean = 8.3, stderr = 1.4). These estimated levels were compared with average exposure from personal samples. The fixed-location monitoring strategy was useful in identifying high air pollution microclimates throughout the county. For 7 of 10 subjects, the fixed-location monitoring strategy more closely approximated individuals' 24-hr breathing zone exposures than did the centralized outdoor monitor. Highlights are: Individual PM(2.5) exposure levels vary extensively by activity, location and time of day; fixed-location sampling more closely approximated individual exposures than a centralized outdoor monitor; and small, personal exposure monitors provide added utility for individuals, researchers, and public health professionals seeking to more accurately identify air pollution microclimates. IMPLICATIONS: Personal air pollution monitoring technology is advancing rapidly. Currently, personal monitors are primarily used in research settings, but could they also support government networks of centralized outdoor monitors? In this study, we found differences in performance and practicality for two personal monitors in different monitoring scenarios. We also found that personal monitors used to collect outdoor area samples were effective at finding pollution microclimates, and more closely approximated actual individual exposure than a central monitor. Though more research is needed, there is strong potential that personal exposure monitors can improve existing monitoring networks. PMID- 26512927 TI - Impact of vaccination on meningococcal epidemiology. AB - Neisseria meningitidis may cause invasive disease (meningitis and sepsis), leading to considerable disease burden and mortality. However, effective vaccines are available against most pathogenic serogroups. Large-scale vaccination campaigns with the MCC vaccine conducted in UK and with MenAfriVac in the Sahel have clearly demonstrated the direct and indirect effect of immunization programmes on disease and carriage. Moreover, the introduction of novel subcapsular vaccines against serogroup B, which may cross-protect against other serogroups, is likely to have a further effect on trends. Accurate data collection is key to elaborate vaccination strategies able to reduce meningococcal disease burden through direct protection and herd immunity. PMID- 26512928 TI - Conflicting results of robot-assisted versus usual gait training during postacute rehabilitation of stroke patients: a randomized clinical trial. AB - Robot gait training has the potential to increase the effectiveness of walking therapy. Clinical outcomes after robotic training are often not superior to conventional therapy. We evaluated the effectiveness of a robot training compared with a usual gait training physiotherapy during a standardized rehabilitation protocol in inpatient participants with poststroke hemiparesis. This was a randomized double-blind clinical trial in a postacute physical and rehabilitation medicine hospital. Twenty-eight patients, 39.3% women (72+/-6 years), with hemiparesis (<6 months after stroke) receiving a conventional treatment according to the Bobath approach were assigned randomly to an experimental or a control intervention of robot gait training to improve walking (five sessions a week for 5 weeks). Outcome measures included the 6-min walk test, the 10 m walk test, Functional Independence Measure, SF-36 physical functioning and the Tinetti scale. Outcomes were collected at baseline, immediately following the intervention period and 3 months following the end of the intervention. The experimental group showed a significant increase in functional independence and gait speed (10 m walk test) at the end of the treatment and follow-up, higher than the minimal detectable change. The control group showed a significant increase in the gait endurance (6-min walk test) at the follow-up, higher than the minimal detectable change. Both treatments were effective in the improvement of gait performances, although the statistical analysis of functional independence showed a significant improvement in the experimental group, indicating possible advantages during generic activities of daily living compared with overground treatment. PMID- 26512929 TI - Topical treatment of actinic keratosis with 3.0% diclofenac in 2.5% hyaluronan gel: review of the literature about the cumulative evidence of its efficacy and safety. AB - BACKGROUND: Topical 3% diclofenac in 2.5% hyaluronic acid (HA) gel is a nonsteroidal anti-inflammatory drug approved for the treatment of actinic keratosis (AK). It has been shown to be a safe and effective for treatment of AK on both skin and mucosal lip. EVIDENCE ACQUISITION: A PubMed search was carried out from 1997 to 2015 using key words in multiple combinations. EVIDENCE SYNTHESIS: Different studies from the literature shown the efficacy and safety of HA in both immunocompetent and immunosuppressed patients, with important impact on preventing field cancerization. In different clinical trials, the product was effective in significantly reducing lesions when applied for 60 or 90 days. CONCLUSIONS: Despite the effectiveness of the treatment with topical 3% diclofenac in 2.5% HA, the patients who achieve the complete clinical response should be adequately educated to continue their photoprotection in order to minimize recurrence of AK. PMID- 26512930 TI - New insights into immune mechanisms of vitiligo. AB - Vitiligo is the most common depigmenting disorder, affecting 0.5% of the population. This stigmatizing disease has a major social impact with high unmet needs, and no real curative intervention has been reported so far. Vitiligo is characterized by the development of white macules resulting from a loss of epidermal melanocytes, which can result from cell destruction through melanocyte specific cytotoxic immune response and melanocyte detachment through a defective adhesion system. Multiple mechanisms have been suggested to be involved in melanocyte disappearance: genetic predisposition, environmental triggers, metabolic abnormalities, altered inflammatory and immune responses. The autoimmune and inflammatory theory is the leading hypothesis. Indeed, vitiligo is often associated with autoimmune diseases; genome-wide association studies and functional pathway analyses have shown that most vitiligo susceptibility loci encode components of the immune system; and immune cells are found in the perilesional margin of actively depigmenting skin of vitiligo patients. However, studies support melanocytes intrinsic abnormalities in vitiligo associated with increased melanocytes stress leading to the release of dangers signals important for the activation of the immune system. This review aimed to overview the link between cellular stress, melanocyte function, and the abnormal inflammatory immune response in vitiligo. The involvement of innate and adaptive immune cells in the pathomechanisms leading to melanocyte loss observed in vitiligo will be discussed. PMID- 26512931 TI - Protective effects of leflunomide on renal lesions in a rat model if diabetic nephropathy. AB - Diabetic nephropathy is one of the most common chronic complications of diabetes with poor efficacy of clinical treatment. This study investigated the protective effects of leflunomide, a new immunosuppressant, on tubulointerstitial lesions in a rat model of diabetic nephropathy. Diabetes was induced with streptozotocin (STZ, 50 mg/kg) by intraperitoneal injection in male Wistar rats. Two weeks after STZ injection, diabetic rats were treated daily for 8 weeks with low (5 mg/kg) and high dose (10 mg/kg) of leflunomide, and benazepril hydrochloride (4 mg/kg) as a positive control. In diabetic rats, the 24-h urine volume, urine protein and microalbumin, blood creatinine and urea nitrogen significantly increased, which were attenuated by leflunomide treatment in a dose-dependent manner (all p < 0.05). The increase of kidney weight/body weight and the histopathological findings of tubulointerstitial lesion in diabetic rats were mitigated by leflunomide treatment. Immunohistochemistry study and real-time polymerase chain reaction results demonstrated that osteopontin (OPN), transforming growth factor beta 1 (TGF-beta1), alpha-smooth muscle actin and CD68 expression in the renal tubulointerstitial region were significantly increased in the diabetic rats, while these increases were inhibited by leflunomide treatment. These findings suggest that leflunomide protects the kidney injury of diabetic rats might through its inhibition of OPN/TGF-beta1 mediated extracellular matrix deposition and tubulointerstitial fibrosis, as well as its inhibition on tubular epithelial myofibroblast transdifferentiation. PMID- 26512932 TI - Enhancing tyrosine hydroxylase and tryptophan hydroxylase expression and improving oxidative stress involved in the antidepressant effect of sodium valproate on rats undergoing chronic unpredicted stress. AB - Depression is a common worldwide mental disorder whose etiology remains unclear; there is also a lack of effective therapeutic agents. Sodium valproate (VPA) is a traditional antiepileptic drug with mood-stabilization effect and is increasingly being used to treat bipolar disorders and depression, but its antidepressant mechanism remains unknown. The aim of the present study was to investigate the possible mechanisms of antidepressant action by studying malondialdehyde level, catalase, and superoxide dismutase activities in the serum and the mRNA and protein expression of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) in the prefrontal cortex of rats exposed to chronic unpredicted stress (CUS). Male Sprague-Dawley rats were used to establish a depression model by CUS. VPA (300 mg/kg once daily) and an equivalent volume of vehicle were administered to rats by an intragastric gavage. Rat behaviors, serum malondialdehyde level, serum catalase and superoxide dismutase activities, and the mRNA and protein expressions of TH and TPH in the prefrontal cortex were determined. The results showed that VPA treatment led to a significant decrease in depression-like behaviors, improvement in oxidative stress imbalance, and enhancement of TH, TPH mRNA, and protein expression in stressed rats, but failed to show any significant changes in control rats. This could indicate that the antidepressant mechanism of VPA is perhaps linked to upregulation of TH and TPH expression and inhibition of oxidative damage in CUS rats. PMID- 26512933 TI - Effects of binge ethanol exposure during first-trimester equivalent on corticothalamic neurons in Swiss Webster outbred mice. AB - Fetal alcohol spectrum disorders range in severity depending on the amount, timing, and frequency of alcohol exposure. Regardless of severity, sensorimotor defects are commonly reported. Sensorimotor information travels through three tracts of the internal capsule: thalamocortical axons, corticothalamic axons, and corticospinal axons. Here we describe the effects of binge ethanol exposure during the first-trimester equivalent on corticothalamic neurons using Swiss Webster mice. We injected pregnant mice with ethanol (2.9 g/kg, intraperitoneal, followed by 1.45 g/kg, intraperitoneal, 2 h later) on embryonic days (E) 11.5, 12.5, and 13.5. Our paradigm resulted in a mean maternal blood ethanol content of 294.8+/-15.4 mg/dl on E12.5 and 258.3+/-22.2 mg/dl on E13.5. Control dams were injected with an equivalent volume of PBS. Bromodeoxyuridine birthdating was carried out on E11.5 to label S-phase neurons. The days of injection were chosen because they are at the onset of neurogenesis and axon extension for corticothalamic, thalamocortical, and corticospinal neurons. Ethanol-exposed pups exhibited no differences compared with controls on day of birth in litter size, body weight, or brain weight. Corticothalamic neurons labeled with bromodeoxyuridine and T-box brain 1 were located in the deep layers of the cortex and did not differ in number in both groups. These results contrast several studies demonstrating alcohol-related differences in these parameters using chronic ethanol exposure paradigms and inbred mouse strains. Therefore, our findings highlight the importance of expanding the mouse strains used to model fetal alcohol spectrum disorder to enhance our understanding of its complex etiology. PMID- 26512934 TI - Functional columns in superior temporal sulcus areas of the common marmoset. AB - Cortical areas in the superior temporal sulcus (STS) of primates have been recognized as a part of the 'social brain'. In particular, biological motion stimuli elicit neuronal responses in the STS, indicating their roles in the ability to understand others' actions. However, the spatial organization of functionally identified STS cells is not well understood because it is difficult to identify the precise locations of cells in sulcal regions. Here, using a small New World monkey, the common marmoset (Callithrix jacchus) that has a lissencephalic brain, we investigated the spatial organization of the cells responsive to other's actions in STS. The neural responses to movies showing several types of other's actions were recorded with multicontact linear-array electrodes that had four shanks (0.4 mm spacing), with eight electrode contacts (0.2 mm spacing) for each shank. The four shanks were penetrated perpendicular to the cortical surface. We found that STS cells significantly responded to other's goal-directed actions, such as when an actor marmoset was reaching for and grasping a piece of food. The response profiles to the movies were more similar between the vertically positioned electrodes than horizontally positioned electrodes when the distances between electrodes were matched. This indicates that there are functional columns in the higher-order visual areas in STS of the common marmoset. PMID- 26512935 TI - The relationship between dizziness and cervical artery stenosis. AB - Dizziness is a common complaint in neurology departments. We sought to identify the relationship between dizziness and cervical artery stenosis, as assessed using cervical computed tomographic angiography. From 1 January 2012 to 20 April 2014, we prospectively and continuously collected the demographic characteristics, clinical data, and chief complaints of all hospitalized patients aged between 20 and 80 years who underwent computed tomographic angiography at our medical center. Altogether, 5796 hospitalized patients were enrolled in this study. After propensity-score matching, a matched cohort of 1139 patients in a dizziness group and 1139 patients in a nondizziness group was created. The proportion of patients with vertebrobasilar artery stenosis was larger in the dizziness group than in the nondizziness group (13.3 vs. 7.6% in the matched cohort) and was especially larger among patients with stroke histories (19.4 vs. 11.2% in the matched cohort). In the logistic regression, dizziness did not significantly predict carotid artery stenosis (P>0.01). Age, male sex, and hypertension, diabetes, myocardial infarction, cerebral infarction, or demyelinating diseases were the predictors of carotid artery stenosis that remained after adjustment (P<0.01). Patients with dizziness faced nearly twice the risk for vertebrobasilar artery stenosis than did those without dizziness (P<0.01). The other independent predictors of vertebrobasilar artery stenosis were age, male sex, hypertension, coronary artery disease, cerebral infarction, and hemorrhage (P<0.01). Patients with dizziness faced nearly twice the risk for vertebrobasilar artery stenosis than did those without dizziness, whereas dizziness did not significantly predict carotid artery stenosis. PMID- 26512936 TI - Kinesin light chain-1 isoform E does not interact with calsyntenin-1. AB - beta-Amyloid is generated by the sequential cleavage of amyloid precursor protein. Calsyntenin-1 and kinesin light chain-1 splice variant E (KLC1-E) have been proposed to regulate beta-amyloid production from amyloid precursor protein. Vesicles containing calsyntenin-1 are transported from the Golgi apparatus to axons by interaction between calsyntenin-1 and KLC1 in their C-terminal regions. However, it is unclear whether KLC1 isoform E influences the interaction between KLC1 and calsyntenin-1, resulting in the impaired axonal transport of calsyntenin 1 vesicles. Here, we show that KLC1-E does not interact with calsyntenin-1 using a pull-down assay, coimmunoprecipitation, and immunocytochemistry. These findings suggest that KLC1-E enrichment may impair the axonal transport of calsyntenin-1 vesicles. PMID- 26512937 TI - EDUCATION AND IMAGING. Gastrointestinal: Endoscopic submucosal tunnel dissection of a giant cardiac leiomyoma. PMID- 26512938 TI - Pharmacokinetic studies of antimalarials: recent developments. AB - Pharmacokinetic studies are essential for the development of safe and effective antimalarial treatment regimens, but there are clinical situations in which there are limited data on drug disposition. These include very young children, pregnant women, and where drug interactions may alter treatment response. New approaches such as sampling methods involving low volumes and minimal preparation such as dried blood spots, highly sensitive and specific multidrug assays, and population PK analyses which can evaluate the influence of covariates such as age, pregnancy and coadministered therapies, can generate robust data that inform treatment in the most challenging situations in the tropics. PMID- 26512940 TI - The Antibody Response to HLA Mismatch: Putting Together the Pieces of a Puzzle. PMID- 26512939 TI - Comparison of Aflibercept, Bevacizumab, and Ranibizumab for Treatment of Diabetic Macular Edema: Extrapolation of Data to Clinical Practice. AB - IMPORTANCE: The Diabetic Retinopathy Clinical Research Network (DRCR Network), sponsored by the National Eye Institute, reported the results of a comparative effectiveness randomized clinical trial (RCT) evaluating the 3 anti-vascular endothelial growth factor (anti-VEGF) agents aflibercept (2.0 mg), bevacizumab (1.25 mg), and ranibizumab (0.3 mg) for treatment of diabetic macular edema (DME) involving the center of the retina and associated with visual acuity loss. The many important findings of the RCT prompted the American Society of Retina Specialists to convene a group of experts to provide their perspective regarding clinically relevant findings of the study. OBJECTIVES: To describe specific outcomes of the RCT judged worthy of highlighting, to discuss how these and other clinically relevant results should be considered by specialists treating DME, and to identify unanswered questions that merit consideration before treatment. EVIDENCE REVIEW: The DRCR Network-authored publication on primary outcomes of the comparative effectiveness RCT at 89 sites in the United States. The study period of the RCT was August 22, 2012, to August 28, 2013. FINDINGS: On average, all 3 anti-VEGF agents led to improved visual acuity in eyes with DME involving the center of the retina and with visual acuity impairment, including mean (SD) improvements by +13.3 (11.1) letters with aflibercept vs +9.7 (10.1) letters with bevacizumab (P < .001) and +11.2 (9.4) letters with ranibizumab (P = .03). Worse visual acuity when initiating therapy was associated with greater visual acuity benefit of aflibercept (+18.9 [11.5]) over bevacizumab (+11.8 [12.0]) or ranibizumab (14.2 [10.6]) 1 year later (P < .001 for interaction with visual acuity as a continuous variable, and P = .002 for interaction with visual acuity as a categorical variable). It is unknown whether different visual acuity outcomes associated with the use of the 3 anti-VEGF agents would be noted with other treatment regimens or with adequately repackaged bevacizumab, as well as in patients with criteria that excluded them from the RCT, such as persistent DME despite recent anti-VEGF treatment. CONCLUSIONS AND RELEVANCE: On average, all 3 anti-VEGF agents led to improved visual acuity in eyes with DME involving the center of the retina and visual acuity impairment. Worse visual acuity when initiating therapy was associated with greater visual acuity benefit of aflibercept over bevacizumab or ranibizumab 1 year later. Care needs to be taken when attempting to extrapolate outcomes of this RCT to differing treatment regimens. With access to adequately repackaged bevacizumab, many specialists might initiate therapy with bevacizumab when visual acuity is good (ie, 20/32 to 20/40 as measured in the DRCR Network), recognizing that the cost-effectiveness of bevacizumab outweighs that of aflibercept or ranibizumab. PMID- 26512941 TI - Analysis of Scientific Production in Food Science from 2003 to 2013. AB - Food Science is an active discipline in scientific research. The improvements in Food Technology constitute a challenge for society to eradicate hunger, while achieving food safety. This work analyses the scientific production in Food Science of the 25 countries with the greatest output in this subject area in the period 2003 to 2013. The growth of China's production was striking, with the country becoming top-ranked by the end of the period. Some developing countries (such as Nigeria) achieved a major increase in production but reducing their proportion of scientific collaboration and their works' impact. There appear to be 2 international collaboration networks that get good results--one European and the other Pacific. PMID- 26512942 TI - Altered Machinery of Protein Synthesis in Alzheimer's: From the Nucleolus to the Ribosome. AB - Ribosomes and protein synthesis have been reported to be altered in the cerebral cortex at advanced stages of Alzheimer's disease (AD). Modifications in the hippocampus with disease progression have not been assessed. Sixty-seven cases including middle-aged (MA) and AD stages I-VI were analyzed. Nucleolar chaperones nucleolin, nucleophosmin and nucleoplasmin 3, and upstream binding transcription factor RNA polymerase I gene (UBTF) mRNAs are abnormally regulated and their protein levels reduced in AD. Histone modifications dimethylated histone H3K9 (H3K9me2) and acetylated histone H3K12 (H3K12ac) are decreased in CA1. Nuclear tau declines in CA1 and dentate gyrus (DG), and practically disappears in neurons with neurofibrillary tangles. Subunit 28 ribosomal RNA (28S rRNA) expression is altered in CA1 and DG in AD. Several genes encoding ribosomal proteins are abnormally regulated and protein levels of translation initiation factors eIF2alpha, eIF3eta and eIF5, and elongation factor eEF2, are altered in the CA1 region in AD. These findings show alterations in the protein synthesis machinery in AD involving the nucleolus, nucleus and ribosomes in the hippocampus in AD some of them starting at first stages (I-II) preceding neuron loss. These changes may lie behind reduced numbers of dendritic branches and reduced synapses of CA1 and DG neurons which cause hippocampal atrophy. PMID- 26512943 TI - The Impact of Tobacco Smoke Exposure on Childhood Asthma in a Medicaid Managed Care Plan. AB - BACKGROUND: Tobacco smoke exposure increases breathing problems of children. Texas Children's Health Plan is a Managed Medicaid and Children's Health Insurance Program (CHIP) managed care provider. The aim of this study is to determine associations among tobacco smoke exposure, asthma prevalence, and asthma health-care utilization. METHODS: Texas Children's Health Plan conducts an annual survey of members who have a physician visit. Questions were added to the survey in March 2010 about asthma and tobacco smoke exposure. Survey results for children < 18 years of age were matched to health plan claims data for the 12 months following the date of the physician visit. RESULTS: A total of 22,470 parents of unique members/patients from birth to < 18 years of age participated in the survey. More whites than African Americans or Hispanics report that the child's mother is a smoker (19.5% vs 9.1% and vs 2.3%, respectively; P < .001). Compared with children whose mother does not smoke, parent report of asthma diagnosis and claims for dispensing of short-acting beta agonist medication are greater if the mother is a smoker (adjusted OR, 1.20 [95% CI, 1.03-1.40] and 1.24 [95% CI, 1.08-1.42], respectively). In contrast to Medicaid, in which there are no out-of-pocket costs, the CHIP line of business requires copays for ED visits. ED visits are influenced by maternal smoking only in the CHIP line of business (adjusted OR, 4.40; 95% CI, 1.69-11.44). CONCLUSION: Maternal smoking increases risk for asthma diagnosis and prescription of asthma quick relief medication. Maternal smoking predicted asthma-related ED visits only for the CHIP line of business. PMID- 26512944 TI - Cutaneous metastases: clinical and dermatoscopically simulating multiple dermatofibromas. PMID- 26512945 TI - Early atherosclerosis in ulcerative colitis: cross-sectional case-control study. AB - OBJECTIVE: To study the extent of early atherosclerosis in ulcerative colitis (UC) patients by measuring carotid intima-media thickness (CIMT) and the correlation between CIMT, serum homocysteine level and homeostasis model assessment-insulin resistance (HOMA-IR) in UC. METHODS: We studied 60 UC patients and 60 healthy controls. Individuals with risk factors for atherosclerosis were excluded from the study. Fasting blood glucose, lipid profile, HOMA-IR, erythrocyte sedimentation rate (ESR), serum vitamin B12 and homocysteine levels were measured in all participants. CIMT was measured using a B-mode duplex imaging study. RESULTS: UC patients had significantly higher CIMT than controls (P < 0.05). ESR, fasting insulin, HOMA-IR and serum homocysteine levels were also significantly higher in UC patients (P < 0.05). Pearson's correlation coefficient showed significant correlations between: (i) CIMT and patients' age, duration of UC, HOMA-IR, and homocysteine level (P < 0.05); (ii) serum homocysteine and duration of UC, fasting insulin level, HOMA-IR and CIMT (P < 0.01); (iii) HOMA-IR and age, duration of UC, serum homocysteine and CIMT (P < 0.01). Multi-regression models showed that serum homocysteine affects CIMT and duration of UC independently, whereas participants' age and duration of UC affects HOMA-IR independently. CONCLUSIONS: Higher CIMT might indicate subclinical atherosclerosis in UC patients. Patients' age, duration of UC, HOMA-IR and homocysteine levels are important factors associated with increased CIMT. PMID- 26512946 TI - Strain tuning of ferroelectric polarization in hybrid organic inorganic perovskite compounds. AB - Metal-organic frameworks (MOFs) are hybrid crystalline compounds comprised of an extended ordered network made up of organic molecules, organic linkers and metal cations. In particular, MOFs with the same topology as inorganic perovskites have been shown to possess interesting properties, e.g., coexistence of ferroelectric and magnetic ordering. Using first-principles density functional theory, we have investigated the effect of strain on the compounds C(NH2)3Cr(HCOO)3 and (CH3CH2NH3)Mn(HCOO)3. Here, we show that compressive strain can substantially increase the ferroelectric polarization by more than 300%, and we discuss the mechanism involved in the strain enhancement of polarization. Our study highlights the complex interplay between strain and organic cations' dipoles and put forward the possibility of tuning of ferroelectric polarization through appropriate thin film growing. PMID- 26512947 TI - Occurrence, distribution, and sources of antimicrobials in a mixed-use watershed. AB - The release into the environment of antimicrobial compounds from both human and agricultural sources is a growing global concern. The Grand River watershed, the largest mixed-use watershed in southern Ontario, receives runoff from intensive animal production as well as municipal wastewater effluents from a rapidly increasing human population. A survey of surface waters and wastewater effluents was conducted across the watershed to assess the occurrence and distribution of several antimicrobials (i.e., trimethoprim, sulfamethoxazole, sulfamethazine, lincomycin, and monensin) and chemical indicators (i.e., ammonia, nitrate, ibuprofen, venlafaxine, atrazine) and to characterize exposure levels. The human antimicrobials trimethoprim and sulfamethoxazole were detected in the urban areas of the main channel at mean concentrations of 8 +/- 7 ng/L and 31 +/- 24 ng/L, respectively, but at much lower concentrations in the agricultural tributaries. In contrast, the veterinary antimicrobial sulfamethazine was detected at a mean concentration of 11 +/- 9 ng/L in the main channel, and at a much higher concentration in the agricultural tributaries. Lincomycin was detected in only two river samples and not in the effluents while monensin was not detected in all samples. The herbicide atrazine was detected at very low concentrations in the surface waters of both the tributaries and the main channel. The concentrations of the antimicrobials and chemical indicators generally increased downstream of the confluences with agricultural tributaries and effluent outfalls. In the wastewater effluents, the concentrations of trimethoprim, sulfamethoxazole, ibuprofen, and venlafaxine decreased with increasing treatment levels (i.e., secondary to tertiary) as indicated by ammonia/nitrate concentrations. There was a strong correlation among trimethoprim, sulfamethoxazole, and venlafaxine in the main channel and in the wastewater effluents. While the environmental concentrations of antimicrobials in the watershed are low relative to toxicity thresholds, their persistence in the environment may be an important consideration in defining strategies for future water management. PMID- 26512948 TI - Rocuronium versus succinylcholine for rapid sequence induction intubation. AB - BACKGROUND: Patients often require a rapid sequence induction (RSI) endotracheal intubation technique during emergencies or electively to protect against aspiration, increased intracranial pressure, or to facilitate intubation. Traditionally succinylcholine has been the most commonly used muscle relaxant for this purpose because of its fast onset and short duration; unfortunately, it can have serious side effects. Rocuronium has been suggested as an alternative to succinylcholine for intubation. This is an update of our Cochrane review published first in 2003 and then updated in 2008 and now in 2015. OBJECTIVES: To determine whether rocuronium creates intubating conditions comparable to those of succinylcholine during RSI intubation. SEARCH METHODS: In our initial review we searched all databases until March 2000, followed by an update to June 2007. This latest update included searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 2), MEDLINE (1966 to February Week 2 2015), and EMBASE (1988 to February 14 2015 ) for randomized controlled trials (RCTs) or controlled clinical trials (CCTs) relating to the use of rocuronium and succinylcholine. We included foreign language journals and handsearched the references of identified studies for additional citations. SELECTION CRITERIA: We included any RCT or CCT that reported intubating conditions in comparing the use of rocuronium and succinylcholine for RSI or modified RSI in any age group or clinical setting. The dose of rocuronium was at least 0.6 mg/kg and succinylcholine was at least 1 mg/kg. DATA COLLECTION AND ANALYSIS: Two authors (EN and DT) independently extracted data and assessed methodological quality for the 'Risk of bias' tables. We combined the outcomes in Review Manager 5 using a risk ratio (RR) with a random-effects model. MAIN RESULTS: The previous update (2008) had identified 53 potential studies and included 37 combined for meta analysis. In this latest update we identified a further 13 studies and included 11, summarizing the results of 50 trials including 4151 participants. Overall, succinylcholine was superior to rocuronium for achieving excellent intubating conditions: RR 0.86 (95% confidence interval (CI) 0.81 to 0.92; n = 4151) and clinically acceptable intubation conditions (RR 0.97, 95% CI 0.95 to 0.99; n = 3992, 48 trials). A high incidence of detection bias amongst the trials coupled with significant heterogeneity provides moderate-quality evidence for these conclusions, which are unchanged from the previous update. Succinylcholine was more likely to produce excellent intubating conditions when using thiopental as the induction agent: RR 0.81 (95% CI: 0.73 to 0.88; n = 2302, 28 trials). In the previous update, we had concluded that propofol was the superior induction agent with succinylcholine. There were no reported incidences of severe adverse outcomes. We found no statistical difference in intubation conditions when succinylcholine was compared to 1.2 mg/kg rocuronium; however, succinylcholine was clinically superior as it has a shorter duration of action. AUTHORS' CONCLUSIONS: Succinylcholine created superior intubation conditions to rocuronium in achieving excellent and clinically acceptable intubating conditions. PMID- 26512950 TI - Inhalable nanocomposite microparticles: preparation, characterization and factors affecting formulation. AB - INTRODUCTION: Nanocomposite microparticles are intelligent carriers utilised for pulmonary drug delivery. These carriers are composed of drug-encapsulated nanoparticles dispersed in microstructures of polysaccharides. Upon administration, the inhaled microparticles can penetrate and be deposited deeply in the lung due to their adjusted aerodynamic particle size. Subsequently, the nanoparticles are released into the lung and are retained there for a prolonged time due to their resistance to immunological opsonisation, engulfment and digestion. AREA COVERED: Nanocomposite microparticles may be prepared by spray drying, spray freeze drying, spray drying fluidised bed granulation or dry coating techniques. The selection of the included excipients, preparation technique and optimisation of the operational parameter play a significant role in the determination of the aerodynamic particle size, redispersibility of the nanoparticles, morphology, yield, moisture content, flowability and in vitro drug release. Moreover, the in vivo behaviour of this novel carrier may be optimised and traced by studying the lung deposition of the inhaled particles and the biological activity of the encapsulated drug. EXPERT OPINION: Nanocomposite microparticles have been found to be superior to both nanoparticles and microparticles and may represent a promising carrier for pulmonary drug delivery. PMID- 26512949 TI - Lentiviral vector-mediated insertional mutagenesis screen identifies genes that influence androgen independent prostate cancer progression and predict clinical outcome. AB - Prostate cancer (PC) is the second leading cause of cancer related deaths in US men. Androgen deprivation therapy (ADT) improves clinical outcome, but tumors often recur and progress to androgen independent prostate cancer (AIPC) which no longer responds to ADT. The progression to AIPC is due to genetic alterations that allow PC cancer cells to grow in the absence of androgen. Here we performed an insertional mutagenesis screen using a replication-incompetent lentiviral vector (LV) to identify the genes that promote AIPC in an orthotopic mouse model. Androgen sensitive PC cells, LNCaP, were mutagenized with LV and injected into the prostate of male mice. After tumor development, mice were castrated to select for cells that proliferate in the absence of androgen. Proviral integration sites and nearby dysregulated genes were identified in tumors developed in an androgen deficient environment. Using publically available datasets, the expression of these candidate androgen independence genes in human PC tissues were analyzed. A total of 11 promising candidate AIPC genes were identified: GLYATL1, FLNA, OBSCN, STRA13, WHSC1, ARFGAP3, KDM2A, FAM83H, CLDN7, CNOT6, and B3GNT9. Seven out the 11 candidate genes; GLYATL1, OBSCN, STRA13, KDM2A, FAM83H, CNOT6, and B3GNT6, have not been previously implicated in PC. An in vitro clonogenic assay showed that knockdown of KDM2A, FAM83H, and GLYATL1 genes significantly inhibited the colony forming ability of LNCaP cells. Additionally, we showed that a combination of four genes, OBSCN, FAM83H, CLDN7, and ARFGAP3 could significantly predicted the recurrence risk in PC patients after prostatectomy (P = 5.3 * 10-5 ). (c) 2015 Wiley Periodicals, Inc. PMID- 26512951 TI - Effects of glomerular filtration rate estimating equations derived from different reference methods on staging and long term mortality risks of chronic kidney disease in a Southeast Asian cohort. AB - AIM: There are limited data on the risks of chronic kidney disease (CKD) in Southeast Asian populations. Several GFR estimating equations have been developed in diverse Asian populations, but they produce markedly discrepant results. We investigated the impact of Asian equations on the mortality risk of CKD in a Thai cohort during long term follow-up, and explored the differences between equations grouped according to the reference GFR methods used to develop them. METHODS: Employees of the Electricity Generating Authority of Thailand (n = 3430) were enrolled in a health survey and followed up for 22 years. The risks for all-cause mortality for each GFR stage classified by CKD-EPI or different Asian equations were assessed by using Cox proportional hazard models. RESULTS: Equations derived from DTPA clearance (Chinese MDRD, Thai GFR, Singapore CKD-EPI) produced higher GFR, whereas equations from inulin clearance (Japanese CKD-EPI, Taiwan MDRD or Taiwan CKD-EPI) produced lower GFR compared to CKD-EPI. (Average DeltaGFR: inulin, -14.9 vs. DTPA +5.80 mL/min per 1.73 m(2) , P < 0.001). CKD prevalence varied widely (0.7 to 24 %) with inulin-based equations being higher than DTPA based. GFR stage concordance was over 80% for equations using similar reference method compared to less than 40% between inulin and DTPA-based equations. Low GFR (<45) was an independent mortality risk factor when DTPA-based equations were used, but not when inulin-based equations were used. CONCLUSION: Chronic kidney disease prevalence and prognosis in Thais varied widely depending on the equation used. Differences in the reference GFR methods could be an important cause for the discrepancies between Asian equations. PMID- 26512952 TI - Multiplex PMA-qPCR Assay with Internal Amplification Control for Simultaneous Detection of Viable Legionella pneumophila, Salmonella typhimurium, and Staphylococcus aureus in Environmental Waters. AB - Pathogenic microorganisms are responsible for many infectious diseases, and pathogen monitoring is important and necessary for water quality control. This study for the first time explored a multiplex quantitative real-time PCR (qPCR) technique combined with propidium monoazide (PMA) to simultaneously detect viable Legionella pneumophila, Salmonella typhimurium, and Staphylococcus aureus in one reaction from water samples. Sodium lauroyl sarcosinate (sarkosyl) was applied to enhance the dead bacterial permeability of PMA. The sensitivity of the multiplex PMA-qPCR assay achieved two colony-forming units (CFU) per reaction for L. pneumophila and three CFU per reaction for S. typhimurium and S. aureus. No PCR products were amplified from all nontarget control samples. Significantly, with comparable specificity and sensitivity, this newly invented multiplex PMA-qPCR assay took a much shorter time than did conventional culture assays when testing water samples with spiked bacteria and simulated environmental water treatment. The viable multiplex PMA-qPCR assay was further successfully applied to pathogen detection from rivers, canals, and tap water samples after simple water pretreatment. PMID- 26512953 TI - Surface-Engineered Contact Lens as an Advanced Theranostic Platform for Modulation and Detection of Viral Infection. AB - We have demonstrated an entirely new concept of a wearable theranostic device in the form of a contact lens (theranostic lens) with a dual-functional hybrid surface to modulate and detect a pathogenic attack, using a the corneal HSV serotype-1 (HSV-1) model. The theranostic lenses were constructed using a facile layer-by-layer surface engineering technique, keeping the theranostic lenses with good surface wettability, optically transparency, and nontoxic toward human corneal epithelial cells. The theranostic lenses were used to capture and concentrate inflammatory cytokines such as interleukin-1alpha (IL-1alpha), which is upregulated during HSV-1 reactivation, for sensitive, noninvasive diagnostics. The theranostic lens also incorporated an antiviral coating to serve as a first line of defense to protect patients against disease. Our strategy tackles major problems in tear diagnostics that are mainly associated with the sampling of a relatively small volume of fluid and the low concentration of biomarkers. The theranostic lenses show effective anti-HSV-1 activity and good analytical performance for the detection of IL-1alpha, with a limit of detection of 1.43 pg mL(-1) and a wide linear range covering the clinically relevant region. This work offers a new paradigm for "wearable" noninvasive healthcare devices combining "diagnosis" and "protection" against disease, while supporting patient compliance. We believe that this approach holds immense promise as a next generation point-of-care and decentralized diagnostic/theranostic platform for a range of biomarkers. PMID- 26512954 TI - NBR1 is dispensable for PARK2-mediated mitophagy regardless of the presence or absence of SQSTM1. AB - Degradation of malfunctional mitochondria by mitophagy is a pivotal component of mitochondrial quality control to maintain cellular homeostasis. Mitochondrial clearance through the PINK1/PARK2 pathway is mediated by autophagic adaptor proteins. Previous studies revealed a significant involvement, but not an absolute requirement for SQSTM1 in PARK2-dependent mitophagy, suggesting that the existence of redundant adaptor proteins may compensate for the loss of SQSTM1. Here we investigated whether NBR1, a functional homolog of SQSTM1, has a role in PARK2-mediated mitophagy, either alone or as a compensatory mechanism. We showed that NBR1 does not appear to be required for mitochondrial clustering following mitochondrial depolarization. Moreover, we demonstrated that deletion of NBR1 alone or in combination with SQSTM1 does not prevent the degradation of damaged mitochondria. Our data suggest that NBR1 is dispensable for PARK2-dependent mitophagy and additional autophagic adaptor proteins, other than NBR1, are responsible for mitochondrial degradation in cells depleted of SQSTM1. PMID- 26512955 TI - A conserved MADS-box phosphorylation motif regulates differentiation and mitochondrial function in skeletal, cardiac, and smooth muscle cells. AB - Exposure to metabolic disease during fetal development alters cellular differentiation and perturbs metabolic homeostasis, but the underlying molecular regulators of this phenomenon in muscle cells are not completely understood. To address this, we undertook a computational approach to identify cooperating partners of the myocyte enhancer factor-2 (MEF2) family of transcription factors, known regulators of muscle differentiation and metabolic function. We demonstrate that MEF2 and the serum response factor (SRF) collaboratively regulate the expression of numerous muscle-specific genes, including microRNA-133a (miR-133a). Using tandem mass spectrometry techniques, we identify a conserved phosphorylation motif within the MEF2 and SRF Mcm1 Agamous Deficiens SRF (MADS) box that regulates miR-133a expression and mitochondrial function in response to a lipotoxic signal. Furthermore, reconstitution of MEF2 function by expression of a neutralizing mutation in this identified phosphorylation motif restores miR 133a expression and mitochondrial membrane potential during lipotoxicity. Mechanistically, we demonstrate that miR-133a regulates mitochondrial function through translational inhibition of a mitophagy and cell death modulating protein, called Nix. Finally, we show that rodents exposed to gestational diabetes during fetal development display muscle diacylglycerol accumulation, concurrent with insulin resistance, reduced miR-133a, and elevated Nix expression, as young adult rats. Given the diverse roles of miR-133a and Nix in regulating mitochondrial function, and proliferation in certain cancers, dysregulation of this genetic pathway may have broad implications involving insulin resistance, cardiovascular disease, and cancer biology. PMID- 26512956 TI - Autophagy dysregulation by mutant fused in sarcoma--implications for amyotrophic lateral sclerosis. PMID- 26512957 TI - P53-dependent upregulation of neutral sphingomyelinase-2: role in doxorubicin induced growth arrest. AB - Neutral sphingomyelinase-2 (nSMase2) is a ceramide-generating enzyme that has been implicated in growth arrest, apoptosis and exosome secretion. Although previous studies have reported transcriptional upregulation of nSMase2 in response to daunorubicin, through Sp1 and Sp3 transcription factors, the role of the DNA damage pathway in regulating nSMase2 remains unclear. In this study, we show that doxorubicin induces a dose-dependent induction of nSMase2 mRNA and protein with concomitant increases in nSMase activity and ceramide levels. Upregulation of nSMase2 was dependent on ATR, Chk1 and p53, thus placing it downstream of the DNA damage pathway. Moreover, overexpression of p53 was sufficient to transcriptionally induce nSMase2, without the need for DNA damage. DNA-binding mutants as well as acetylation mutants of p53 were unable to induce nSMase2, suggesting a role of nSMase2 in growth arrest. Moreover, knockdown of nSMase2 prevented doxorubicin-induced growth arrest. Finally, p53-induced nSMase2 upregulation appears to occur via a novel transcription start site upstream of exon 3. These results identify nSMase2 as a novel p53 target gene, regulated by the DNA damage pathway to induce cell growth arrest. PMID- 26512959 TI - IRAK1 mediates TLR4-induced ABCA1 downregulation and lipid accumulation in VSMCs. AB - The activation of Toll-like receptor 4 (TLR4) signaling has an important role in promoting lipid accumulation and pro-inflammatory effects in vascular smooth muscle cells (VSMCs), which facilitate atherosclerosis development and progression. Previous studies have demonstrated that excess lipid accumulation in VSMCs is due to an inhibition of the expression of ATP-binding cassette transporter A1 (ABCA1), an important molecular mediator of lipid efflux from VSMCs. However, the underlying molecular mechanisms of this process are unclear. The purpose of this study was to disclose the underlying molecular mechanisms of TLR4 signaling in regulating ABCA1 expression. Primary cultured VSMCs were stimulated with 50 MUg/ml oxidized low-density lipoprotein (oxLDL). We determined that enhancing TLR4 signaling using oxLDL significantly downregulated ABCA1 expression and induced lipid accumulation in VSMCs. However, TLR4 knockout significantly rescued oxLDL-induced ABCA1 downregulation and lipid accumulation. In addition, IL-1R-associated kinase 1 (IRAK1) was involved in the effects of TLR4 signaling on ABCA1 expression and lipid accumulation. Silencing IRAK1 expression using a specific siRNA reversed TLR4-induced ABCA1 downregulation and lipid accumulation in vitro. These results were further confirmed by our in vivo experiments. We determined that enhancing TLR4 signaling by administering a 12 week-long high-fat diet (HFD) to mice significantly increased IRAK1 expression, which downregulated ABCA1 expression and induced lipid accumulation. In addition, TLR4 knockout in vivo reversed the effects of the HFD on IRAK1 and ABCA1 expression, as well as on lipid accumulation. In conclusion, IRAK1 is involved in TLR4-mediated downregulation of ABCA1 expression and lipid accumulation in VSMCs. PMID- 26512958 TI - A novel miR-371a-5p-mediated pathway, leading to BAG3 upregulation in cardiomyocytes in response to epinephrine, is lost in Takotsubo cardiomyopathy. AB - Molecular mechanisms protecting cardiomyocytes from stress-induced death, including tension stress, are essential for cardiac physiology and defects in these protective mechanisms can result in pathological alterations. Bcl2 associated athanogene 3 (BAG3) is expressed in cardiomyocytes and is a component of the chaperone-assisted autophagy pathway, essential for homeostasis of mechanically altered cells. BAG3 ablation in mice results in a lethal cardiomyopathy soon after birth and mutations of this gene have been associated with different cardiomyopathies including stress-induced Takotsubo cardiomyopathy (TTC). The pathogenic mechanism leading to TTC has not been defined, but it has been suggested that the heart can be damaged by excessive epinephrine (epi) spillover in the absence of a protective mechanism. The aim of this study was to provide more evidence for a role of BAG3 in the pathogenesis of TTC. Therefore, we sequenced BAG3 gene in 70 TTC patients and in 81 healthy donors with the absence of evaluable cardiovascular disease. Mutations and polymorphisms detected in the BAG3 gene included a frequent nucleotide change g2252c in the BAG3 3' untranslated region (3'-UTR) of Takotsubo patients (P<0.05), resulting in loss of binding of microRNA-371a-5p (miR-371a-5p) as evidenced by dual-luciferase reporter assays and argonaute RNA-induced silencing complex catalytic component 2/pull-down assays. Moreover, we describe a novel signaling pathway in cardiomyocytes that leads to BAG3 upregulation on exposure to epi through an ERK dependent upregulation of miR-371a-5p. In conclusion, the presence of a g2252c polymorphism in the BAG3 3'-UTR determines loss of miR-371a-5p binding and results in an altered response to epi, potentially representing a new molecular mechanism that contributes to TTC pathogenesis. PMID- 26512960 TI - Considering autophagy, beta-Catenin and E-Cadherin as innovative therapy aspects in AML. PMID- 26512961 TI - miR-300 mediates Bmi1 function and regulates differentiation in primitive cardiac progenitors. AB - B lymphoma Mo-MLV insertion region 1 (Bmi1) is a polycomb-family transcriptional factor critical for self-renewal in many adult stem cells and human neoplasia. We sought to identify microRNAs regulated by Bmi1 that could play a role in multipotent cardiac progenitor cell (CPC) decisions. We found that miR-300, a poorly characterized microRNA mapping in the Dlk1-Dio3 microRNA cluster, was positively regulated by Bmi1 in CPCs. Forced expression of miR-300 in CPCs promoted an improved stemness signature with a significant increase in Oct4 levels, a reduction in senescence progression and an enhanced proliferative status via p19 activation and inhibition of p16 accumulation. Endothelial and cardiogenic differentiation were clearly compromised by sustained miR-300 expression. Additionally, RNA and protein analysis revealed a significant reduction in key cardiac transcription factors, including Nkx2.5 and Tbx5. Collectively, these results suggest that some functions attributed to Bmi1 are due to induction of miR-300, which decreases the cardiogenic differentiation potential of multipotent CPCs in vitro and promotes self-renewal. PMID- 26512962 TI - K(+) regulates Ca(2+) to drive inflammasome signaling: dynamic visualization of ion flux in live cells. AB - P2X7 purinergic receptor engagement with extracellular ATP induces transmembrane potassium and calcium flux resulting in assembly of the NLRP3 inflammasome in LPS primed macrophages. The role of potassium and calcium in inflammasome regulation is not well understood, largely due to limitations in existing methods for interrogating potassium in real time. The use of KS6, a novel sensor for selective and sensitive dynamic visualization of intracellular potassium flux in live cells, multiplexed with the intracellular calcium sensor Fluo-4, revealed a coordinated relationship between potassium and calcium. Interestingly, the mitochondrial potassium pool was mobilized in a P2X7 signaling, and ATP dose dependent manner, suggesting a role for mitochondrial sensing of cytosolic ion perturbation. Through treatment with extracellular potassium we found that potassium efflux was necessary to permit sustained calcium entry, but not transient calcium flux from intracellular stores. Further, intracellular calcium chelation with BAPTA-AM indicated that P2X7-induced potassium depletion was independent of calcium mobilization. This evidence suggests that both potassium efflux and calcium influx are necessary for mitochondrial reactive oxygen generation upstream of NLRP3 inflammasome assembly and pyroptotic cell death. We propose a model wherein potassium efflux is necessary for calcium influx, resulting in mitochondrial reactive oxygen generation to trigger the NLRP3 inflammasome. PMID- 26512963 TI - DAB2IP loss confers the resistance of prostate cancer to androgen deprivation therapy through activating STAT3 and inhibiting apoptosis. AB - Loss of DAB2IP, a novel tumor suppressor gene, is associated with the high risk of aggressive prostate cancer (PCa). Previously, we reported that DAB2IP modulated androgen receptor activation in the development of castration-resistant PCa; however, its direct action on the failure of androgen deprivation therapy (ADT) remains largely unknown. In this study, we showed that DAB2IP knockdown could significantly enhance in vitro growth and colony formation of PCa cells following ADT as well as tumorigenicity in pre-castrated nude mice. In addition, DAB2IP loss stabilized mitochondrial transmembrane potential, prevented release of cytochrome c, Omi/HtrA2 and Smac from the mitochondria to the cytoplasm and inhibited intrinsic apoptosis induced by ADT. Mechanistically, DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. Moreover, the luminal epithelia in DAB2IP(-/-) mice with more activated STAT3 and survivin expression were resistant to castration-induced apoptosis. Consistently, DAB2IP expression inversely correlated with STAT3 phosphorylation and survivin expression in PCa patients. Together, our data indicate that DAB2IP loss reprograms intracellular signal transduction and anti-apoptotic gene expression, which potentiates PCa cell survival from ADT-induced cell death. PMID- 26512964 TI - Succinate dehydrogenase/complex II activity obligatorily links mitochondrial reserve respiratory capacity to cell survival in cardiac myocytes. PMID- 26512965 TI - Adding another piece to the retinoblastoma puzzle. PMID- 26512966 TI - Evaluation of low doses BPA-induced perturbation of glycemia by toxicogenomics points to a primary role of pancreatic islets and to the mechanism of toxicity. AB - Epidemiologic and experimental studies have associated changes of blood glucose homeostasis to Bisphenol A (BPA) exposure. We took a toxicogenomic approach to investigate the mechanisms of low-dose (1 * 10(-9 )M) BPA toxicity in ex vivo cultures of primary murine pancreatic islets and hepatocytes. Twenty-nine inhibited genes were identified in islets and none in exposed hepatocytes. Although their expression was slightly altered, their impaired cellular level, as a whole, resulted in specific phenotypic changes. Damage of mitochondrial function and metabolism, as predicted by bioinformatics analyses, was observed: BPA exposure led to a time-dependent decrease in mitochondrial membrane potential, to an increase of ROS cellular levels and, finally, to an induction of apoptosis, attributable to the bigger Bax/Bcl-2 ratio owing to activation of NF kappaB pathway. Our data suggest a multifactorial mechanism for BPA toxicity in pancreatic islets with emphasis to mitochondria dysfunction and NF-kappaB activation. Finally, we assessed in vitro the viability of BPA-treated islets in stressing condition, as exposure to high glucose, evidencing a reduced ability of the exposed islets to respond to further damages. The result was confirmed in vivo evaluating the reduction of glycemia in hyperglycemic mice transplanted with control and BPA-treated pancreatic islets. The reported findings identify the pancreatic islet as the main target of BPA toxicity in impairing the glycemia. They suggest that the BPA exposure can weaken the response of the pancreatic islets to damages. The last observation could represent a broader concept whose consideration should lead to the development of experimental plans better reproducing the multiple exposure conditions. PMID- 26512967 TI - Coexpression of Multiple ABC-Transporters is Strongly Associated with Treatment Response in Childhood Acute Myeloid Leukemia. AB - BACKGROUND: To analyze whether expression of ABC-transporters is associated with remission rate and long-term outcome in a prospective clinical trial of childhood acute myeloid leukemia (AML). PROCEDURE: The expression of four ABC-transporter genes (ABCA3 encoding drug transporter ABCA3, ABCB1 encoding multidrug resistance protein 1, ABCC3 encoding multidrug resistance-associated protein 3, and ABCG2 encoding breast cancer resistance protein) was measured by TaqMan real time polymerase chain reaction in pretreatment samples from 112 children with AML. Patients were treated according to multicenter study AML-Berlin, Frankfurt, Munich (BFM) 2004. RESULTS: ABCC3 (P = 0.009) and ABCG2 (P = 0.03) were associated with a lower chance to achieve remission after the first course of chemotherapy. ABCC3 was associated with lower relapse free survival (RFS) (P = 0.02). ABCG2 was expressed at higher levels in subtypes of AML with favorable outcome but within standard- and high-risk patients, it was associated with poor outcome (P = 0.02). A strong association was observed between the number of overexpressed ABC-transporters and the chance to achieve remission (P = 0.01) or the chance of RFS (P < 0.001). CONCLUSIONS: The intensive treatment regimen of AML-BFM 2004 did not readily overcome drug resistance caused by ABC-transporters. Inhibition of ABC-transporters might be particularly useful in patients who express multiple of these genes. PMID- 26512968 TI - Secondary metabolite perturbations in Phaseolus vulgaris leaves due to gamma radiation. AB - Oxidative stress is a condition in which the balance between the production and elimination of reactive oxygen species (ROS) is disturbed. However, plants have developed a very sophisticated mechanism to mitigate the effect of ROS by constantly adjusting the concentration thereof to acceptable levels. Electromagnetic radiation is one of the factors which results in oxidative stress. In the current study, ionizing gamma radiation generated from a Cobalt-60 source was used to induce oxidative stress in Phaseolus vulgaris seedlings. Plants were irradiated with several radiation doses, with 2 kGy found to be the optimal, non-lethal dose. Metabolite distribution patterns from irradiated and non-irradiated plants were analyzed using UHPLC-qTOF-MS and multivariate data models such as principal component analysis (PCA) and orthogonal projection to latent structures discriminate analysis (OPLS-DA). Metabolites such as hydroxycinnamic phenolic acids, flavonoids, terpenes, and a novel chalcone were found to be perturbed in P. vulgaris seedlings treated with the aforementioned conditions. The results suggest that there is a compensatory link between constitutive protectants and inducible responses to injury as well as defense against oxidative stress induced by ionizing radiation. The current study is also the first to illustrate the power of a metabolomics approach to decipher the effect of gamma radiation on crop plants. PMID- 26512969 TI - Phosphomimetic mutation of a conserved serine residue in Arabidopsis thaliana 14 3-3omega suggests a regulatory role of phosphorylation in dimerization and target interactions. AB - 14-3-3s are evolutionarily conserved eukaryotic regulatory proteins that are involved in diverse biological processes. The common mode of action for the 14-3 3 proteins is through the binding of phosphorylated target proteins. In many species, multiple 14-3-3 isoforms exist and these different isoforms can exhibit distinct ranges of target interactions. The dimerization of 14-3-3s is central to their function. 14-3-3 isoforms can form different combinations of homo- and heterodimers, which contribute to the broad functional diversity of the family. In this study, we showed that phosphomimetic mutation of a conserved serine residue in the dimerization interface of 14-3-3 isoforms, Ser-62, not only affects the ability of Arabidopsis 14-3-3omega to form homodimers, but alters the range of 14-3-3 family members with which it can form heterodimers. Furthermore, we demonstrated that the phosphorylation status of Ser-62 can regulate the binding of 14-3-3omega to target proteins, suggesting that Ser-62 might be a conserved key element to modulate target binding in both plants and animals. PMID- 26512970 TI - Anthocyanin composition and expression analysis of anthocyanin biosynthetic genes in kidney bean pod. AB - Kidney bean (Phaseolus vulgaris L.) is an important dietary legume crop cultivated and consumed worldwide. A purple cultivar (Zi Bawang) and a green cultivar (Chun Qiu), the main difference of which is in the pod skin color, were selected for the study. Malvidin 3, 5-diglucoside is identified as the major anthocyanin in the pod skin of Zi Bawang by HPLC-ESI-MS/MS. Three regulatory genes PvMYB1, PvMYB2, PvTT8-1 and most structural genes are dramatically up regulated in purple pod skin compared to those in other materials. Significantly decreased expression levels of all regulatory genes and most biosynthetic genes are also detected in the purple skin of pods covered with bags compared to non covered ones. All the results suggest that PvMYB1, PvMYB2 and PvTT8-1 might play a critical role in transcriptional activation of most anthocyanin biosynthetic genes in purple kidney bean pod. PMID- 26512971 TI - Salt stress-induced production of reactive oxygen- and nitrogen species and cell death in the ethylene receptor mutant Never ripe and wild type tomato roots. AB - The salt stress triggered by sublethal, 100 mM and lethal, 250 mM NaCl induced ethylene production as well as rapid accumulation of superoxide radical and H2O2 in the root tips of tomato (Solanum lycopersicum cv. Ailsa Craig) wild type and ethylene receptor mutant, Never ripe (Nr/Nr) plants. In the wild type plants superoxide accumulation confined to lethal salt concentration while H2O2 accumulated more efficiently under sublethal salt stress. However, in Nr roots the superoxide production was higher and unexpectedly, H2O2 level was lower than in the wild type under sublethal salt stress. Nitric oxide production increased significantly under sublethal and lethal salt stress in both genotypes especially in mutant plants, while peroxynitrite accumulated significantly under lethal salt stress. Thus, the nitro-oxidative stress may be stronger in Nr roots, which leads to the programmed death of tissues, characterized by the DNA and protein degradation and loss of cell viability under moderate salt stress. In Nr mutants the cell death was induced in the absence of ethylene perception. Although wild type roots could maintain their potassium content under moderate salt stress, K(+) level significantly declined leading to small K(+)/Na(+) ratio in Nr roots. Thus Nr mutants were more sensitive to salt stress than the wild type and the viability of root cells decreased significantly under moderate salt stress. These changes can be attributed to a stronger ionic stress due to the K(+) loss from the root tissues. PMID- 26512973 TI - Dracaena marginata biofilter: design of growth substrate and treatment of stormwater runoff. AB - The purpose of this research was to investigate the efficiency of Dracaena marginata planted biofilters to decontaminate urban runoff. A new biofilter growth substrate was prepared using low-cost and locally available materials such as red soil, fine sand, perlite, vermiculite, coco-peat and Sargassum biomass. The performance of biofilter substrate was compared with local garden soil based on physical and water quality parameters. Preliminary analyses indicated that biofilter substrate exhibited desirable characteristics such as low bulk density (1140 kg/m(3)), high water holding capacity (59.6%), air-filled porosity (7.82%) and hydraulic conductivity (965 mm/h). Four different biofilter assemblies, with vegetated and non-vegetated systems, were examined for several artificial rain events (un-spiked and metal-spiked). Results from un-spiked artificial rain events suggested that concentrations of most of the chemical components in effluent were highest at the beginning of rain events and thereafter subsided during the subsequent rain events. Biofilter growth substrate showed superior potential over garden soil to retain metal ions such as Al, Fe, Cu, Cr, Ni, Zn, Cd and Pb during metal-spiked rain events. Significant differences were also observed between non-vegetated and vegetated biofilter assemblies in runoff quality, with the latter producing better results. PMID- 26512974 TI - Downregulation of MicroRNA-145 Caused by Hepatitis B Virus X Protein Promotes Expression of CUL5 and Contributes to Pathogenesis of Hepatitis B Virus Associated Hepatocellular Carcinoma. AB - BACKGROUND: Hepatitis B viral infection-induced hepatocellular carcinoma (HCC) is a major threat to human health in China. Hepatitis B virus X protein (HBX), an HBV protein, has been reported to be involved in regulating the cellular activities of the host cells and is responsible for HCC oncogenesis. METHODS AND RESULTS: In this study, we performed real-time PCR in tumor tissue samples collected from 53 HCC patients (25 HBV-positive cases and 28 HBV-negative cases) to screen the candidate miRNAs that have previously been reported to be aberrantly expressed in HBV-associated HCC and found that miR-145 was significantly downregulated. The following computational analysis identified CUL5 and RAB5C as virtual targets of miR-145, whereas only CUL5 was verified as a validated target gene of miR-145 in liver cells via luciferase reporter assay. In line with this result, we found that both the mRNA and protein expression levels of CUL5 were significantly higher in HBV-positive than in HBV-negative HCC. An in vitro experiment demonstrated a significant decrease in the expression of miRNA 145, a substantial increase in the mRNA and protein expression of CUL5, and an enhanced proliferation of HBX over-expressing HepG2 cells compared with the control. In HepG2.2.15, we found significant decreases in both the expression of CUL5 and the cell growth rate of H cells transfected with 60 nM miR-145 mimics compared with the scramble controls. CONCLUSION: HBV infection promotes cell growth, at least partially, through the HBX-induced downregulation of miRNA-145 expression, which is responsible for the oncogenesis of HBV-associated HCC. PMID- 26512975 TI - Synthesis of Highly Fluorescent Copper Clusters Using Living Polymer Chains as Combined Reducing Agents and Ligands. AB - We present the synthesis of colloidally stable ultrasmall (diameter of 1.5 +/- 0.6 nm) and fluorescent copper clusters (Cu-clusters) exhibiting outstanding quantum efficiencies (up to 67% in THF and approximately 30% in water). For this purpose, an amphiphilic block copolymer poly(ethylene glycol)-block poly(propylene sulfide) (MPEG-b-PPS) was synthesized by living anionic ring opening polymerization. When CuBr is mixed with the living polymer chains in THF, the formation of Cu-clusters is detected by the appearance of the fluorescence. The cluster growth is quenched by the addition of water, followed by THF removal. The structural features of the MPEG-b-PPS copolymer control the cluster formation and the stabilization: the poly(propylene sulfide) segment acts as coordinating and reducing agent for the copper ions in THF, and imparts a hydrophobic character. This hydrophobic block protects the Cu-clusters from water exposure, thus allowing to obtain a stable emission in water. The PEG segment instead provides the hydrophilicity, rendering the Cu-clusters water-soluble. To obtain fluorescent and stable Cu-clusters exhibiting outstanding quantum efficiencies, the removal of the excess of free polymer and copper salt was crucial. The Cu clusters are also colloidally and optically stable in physiological media and showed bright fluorescence even when taken up by HeLa cells, being noncytotoxic when administered at a Cu dose between 10 nM and 1.6 MUM. Given the very small size of the Cu-clusters, localization and fluorescent staining of cell nucleus is achieved, as demonstrated by confocal cell imaging performed at different Cu cluster doses and at different incubation temperatures. PMID- 26512976 TI - Amniotic fluid prostaglandin E2 in pregnancies complicated by preterm prelabor rupture of the membranes. AB - OBJECTIVE: To determine amniotic fluid prostaglandin E2 concentrations in women preterm prelabor rupture of the membranes (PPROM) with respect to microbial invasion of the amniotic cavity (MIAC), intraamniotic inflammation (IAI), microbial-associated IAI, histological chorioamnionitis, and short-term neonatal morbidity. METHODS: One hundred forty-five women with singleton pregnancies were included in this study. Amniotic fluid samples were obtained by transabdominal amniocentesis and were assayed for prostaglandin E2 concentrations by ELISA. IAI was defined as amniotic fluid interleukin-6 >745 pg/mL. Microbial-associated IAI was defined as the presence of both MIAC and IAI. RESULT: No differences in prostaglandin E2 concentrations were found between women with and without MIAC (p = 0.27). Women with IAI (p = 0.0008) and microbial-associated IAI (p = 0.01) had higher prostaglandin E2 concentrations than women without these complications. Women with histological chorioamnionitis had higher prostaglandin E2 concentrations only in crude analysis (p = 0.02), but not after adjustment for gestational age at sampling (p = 0.10). No associations between amniotic fluid prostaglandin E2 concentrations and the selected conditions of severe neonatal morbidity were found. CONCLUSIONS: The intraamniotic inflammatory response either to infectious or to non-infectious stimulus, but not MIAC per se, seems to be a main factor associated with the elevation of the amniotic fluid PGE2 concentrations in women with PPROM. PMID- 26512977 TI - The Changing Pattern of Admission of Allograft Patients to the Intensive Care Unit. PMID- 26512978 TI - Prognosis of Allogeneic Haematopoietic Stem Cell Recipients Admitted to the Intensive Care Unit: A Retrospective, Single-Centre Study. AB - BACKGROUND: Allogeneic haematopoietic stem cell transplantation (HSCT) is a procedure with inherent complications and intensive care may be necessary. We evaluated the short- and long-term outcomes of the HSCT recipients requiring admission to the intensive care unit (ICU). METHODS: We retrospectively examined the outcome of 54 adult haematological HSCT recipients admitted to the ICU at the University Hospital Rigshospitalet between January 2007 and March 2012. RESULTS: The overall in-ICU, in-hospital, 6-month and 1-year mortality rates were 46.3, 75.9, 79.6 and 86.5%, respectively. Mechanical ventilation had a statistically significant effect on in-ICU (p = 0.02), 6-month (p = 0.049) and 1-year (p = 0.014) mortality. Renal replacement therapy also had a statistically significant effect on in-hospital (p = 0.038) and 6-month (p = 0.026) mortality. Short ICU admissions, i.e. <10 days, had a statistically significant positive effect on in hospital, 6-month and 1-year mortality (all p < 0.001). The SAPS II, APACHE II and SOFA scoring systems grossly underestimated the actual in-hospital mortality observed for these patients. CONCLUSION: The poor prognosis of critically ill HSCT recipients admitted to the ICU was confirmed in our study. Mechanical ventilation, renal replacement therapy and an ICU admission of >=10 days were each risk factors for mortality in the first year after ICU admission. PMID- 26512979 TI - Stem Cell Transplantation Procedures Are Becoming Affordable for Individuals Living in Developing (Middle-Income) Countries. PMID- 26512980 TI - Esculentin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance. AB - The frog skin host-defense peptide esculentin-2CHa (GFSSIFRGVA10KFASKGLGK D20LAKLGVDLVA30CKISKQC) displays antimicrobial, antitumor, and immunomodulatory properties. This study investigated the antidiabetic actions of the peptide and selected analogues. Esculentin-2CHa stimulated insulin secretion from rat BRIN BD11 clonal pancreatic beta-cells at concentrations greater than 0.3 nM without cytotoxicity by a mechanism involving membrane depolarization and increase of intracellular Ca2+. Insulinotropic activity was attenuated by activation of KATP channels, inhibition of voltage-dependent Ca2+ channels and chelation of extracellular Ca2+. The [L21K], [L24K], [D20K, D27K] and [C31S,C37S] analogues were more potent but less effective than esculentin-2CHa whereas the [L28K] and [C31K] analogues were both more potent and produced a significantly (P < 0.001) greater maximum response. Acute administration of [L28K]esculentin-2CHa (75 nmol/kg body weight) to high fat fed mice with obesity and insulin resistance enhanced glucose tolerance and insulin secretion. Twice-daily administration of this dose of [L28K]esculentin-2CHa for 28 days had no significant effect on body weight, food intake, indirect calorimetry or body composition. However, mice exhibited decreased non-fasting plasma glucose (P < 0.05), increased non-fasting plasma insulin (P < 0.05) as well as improved glucose tolerance and insulin secretion (P < 0.01) following both oral and intraperitoneal glucose loads. Impaired responses of isolated islets from high fat fed mice to established insulin secretagogues were restored by [L28K]esculentin-2CHa treatment. Peptide treatment was accompanied by significantly lower plasma and pancreatic glucagon levels and normalization of alpha-cell mass. Circulating triglyceride concentrations were decreased but plasma cholesterol and LDL concentrations were not significantly affected. The data encourage further investigation of the potential of esculentin-2CHa related peptides for treatment of patients with type 2 diabetes. PMID- 26512981 TI - Complete mitochondrial genome of the Pseudopleuronectes yokohamae (Pleuronectiforll: Pleuronectidae). AB - In this study, the complete mitochondrial genome of the Pseudopleuronectes yokohamae was sequenced. The mitochondrial genome is 17 383 bp in length, consisting of 13 protein-coding genes, 2 ribosomal RNA genes (rRNAs), 22 transfer RNA genes (tRNAs) and a control region (D-loop). The gene order and composition of P. yokohamae mitochondrial genome was similar to that of most other vertebrates. Two rRNA genes for 12S rRNA (949 bases) and 16S rRNA (1716 bases) are located between tRNA-Phe (GAA) and tRNA-Leu (TAA) and separated by the tRNA Val. The control region of P. yokohamae, is located after tRNA-Pro and found to be 1679 bp. The overall nucleotides base composition of the heavy strand is A (27.55%), T (26.45%), G (28.75%), C (17.26%). With the exception of the NADH dehydrogenase subunit 6 (ND6) and eight tRNA genes, all other mitochondrial genes are encoded on the heavy strand. The 22 tRNA genes could be folded into a typical clover-leaf secondary structure. The phylogenetic trees consistently show that P. yokohama, Kareius bicoloratus and Platichthys stellatus from the same genus clustered into one branch. The complete mitogenome sequence information of P. yokohamae would provide useful data for further studies on population genetics and molecular systematics. PMID- 26512982 TI - Body Acceleration as Indicator for Walking Economy in an Ageing Population. AB - BACKGROUND: In adults, walking economy declines with increasing age and negatively influences walking speed. This study aims at detecting determinants of walking economy from body acceleration during walking in an ageing population. METHODS: 35 healthy elderly (18 males, age 51 to 83 y, BMI 25.5+/-2.4 kg/m2) walked on a treadmill. Energy expenditure was measured with indirect calorimetry while body acceleration was sampled at 60Hz with a tri-axial accelerometer (GT3X+, ActiGraph), positioned on the lower back. Walking economy was measured as lowest energy needed to displace one kilogram of body mass for one meter while walking (WCostmin, J/m/kg). Gait features were extracted from the acceleration signal and included in a model to predict WCostmin. RESULTS: On average WCostmin was 2.43+/-0.42 J/m/kg and correlated significantly with gait rate (r2 = 0.21, p<0.01) and regularity along the frontal (anteroposterior) and lateral (mediolateral) axes (r2 = 0.16, p<0.05 and r2 = 0.12, p<0.05 respectively). Together, the three variables explained 46% of the inter-subject variance (p<0.001) with a standard error of estimate of 0.30 J/m/kg. WCostmin and regularity along the frontal and lateral axes were related to age (WCostmin: r2 = 0.44, p<0.001; regularity: r2 = 0.16, p<0.05 and r2 = 0.12, p<0.05 respectively frontal and lateral). CONCLUSIONS: The age associated decline in walking economy is induced by the adoption of an increased gait rate and by irregular body acceleration in the horizontal plane. PMID- 26512983 TI - The Prevalence of Non-Alcoholic Fatty Liver Disease in Children and Adolescents: A Systematic Review and Meta-Analysis. AB - BACKGROUND & AIMS: Narrative reviews of paediatric NAFLD quote prevalences in the general population that range from 9% to 37%; however, no systematic review of the prevalence of NAFLD in children/adolescents has been conducted. We aimed to estimate prevalence of non-alcoholic fatty liver disease (NAFLD) in young people and to determine whether this varies by BMI category, gender, age, diagnostic method, geographical region and study sample size. METHODS: We conducted a systematic review and meta-analysis of all studies reporting a prevalence of NAFLD based on any diagnostic method in participants 1-19 years old, regardless of whether assessing NAFLD prevalence was the main aim of the study. RESULTS: The pooled mean prevalence of NAFLD in children from general population studies was 7.6% (95%CI: 5.5% to 10.3%) and 34.2% (95% CI: 27.8% to 41.2%) in studies based on child obesity clinics. In both populations there was marked heterogeneity between studies (I2 = 98%). There was evidence that prevalence was generally higher in males compared with females and increased incrementally with greater BMI. There was evidence for differences between regions in clinical population studies, with estimated prevalence being highest in Asia. There was no evidence that prevalence changed over time. Prevalence estimates in studies of children/adolescents attending obesity clinics and in obese children/adolescents from the general population were substantially lower when elevated alanine aminotransferase (ALT) was used to assess NAFLD compared with biopsies, ultrasound scan (USS) or magnetic resonance imaging (MRI). CONCLUSIONS: Our review suggests the prevalence of NAFLD in young people is high, particularly in those who are obese and in males. PMID- 26512984 TI - Local but Not Systemic Administration of Uridine Prevents Development of Antigen Induced Arthritis. AB - OBJECTIVE: Uridine has earlier been show to down modulate inflammation in models of lung inflammation. The aim of this study was to evaluate the anti-inflammatory effect of uridine in arthritis. METHODS: Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice pre-immunized with mBSA. Uridine was either administered locally by direct injection into the knee joint or systemically. Systemic treatment included repeated injections or implantation of a pellet continuously releasing uridine during the entire experimental procedure. Anti-mBSA specific immune responses were determined by ELISA and cell proliferation and serum cytokine levels were determined by Luminex. Immunohistochemistry was used to identify cells, study expression of cytokines and adhesion molecules in the joint. RESULTS: Local administration of 25-100 mg/kg uridine at the time of arthritis onset clearly prevented development of joint inflammation. In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis. Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro inflammatory cytokines associated with the triggering of arthritis. In contrast, local uridine treatment efficiently inhibited synovial expression of ICAM-1 and CD18, local cytokine production and recruitment of leukocytes to the synovium. CONCLUSION: Local, but not systemic administration of uridine efficiently prevented development of antigen-induced arthritis. The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation. Further, uridine is a small, inexpensive molecule and may thus be a new therapeutic option to treat joint inflammation in RA. PMID- 26512985 TI - The Trigger Factor Chaperone Encapsulates and Stabilizes Partial Folds of Substrate Proteins. AB - How chaperones interact with protein chains to assist in their folding is a central open question in biology. Obtaining atomistic insight is challenging in particular, given the transient nature of the chaperone-substrate complexes and the large system sizes. Recent single-molecule experiments have shown that the chaperone Trigger Factor (TF) not only binds unfolded protein chains, but can also guide protein chains to their native state by interacting with partially folded structures. Here, we used all-atom MD simulations to provide atomistic insights into how Trigger Factor achieves this chaperone function. Our results indicate a crucial role for the tips of the finger-like appendages of TF in the early interactions with both unfolded chains and partially folded structures. Unfolded chains are kinetically trapped when bound to TF, which suppresses the formation of transient, non-native end-to-end contacts. Mechanical flexibility allows TF to hold partially folded structures with two tips (in a pinching configuration), and to stabilize them by wrapping around its appendages. This encapsulation mechanism is distinct from that of chaperones such as GroEL, and allows folded structures of diverse size and composition to be protected from aggregation and misfolding interactions. The results suggest that an ATP cycle is not required to enable both encapsulation and liberation. PMID- 26512986 TI - Quality of Life after Post-Prostatectomy Intensity Modulated Radiation Therapy: Pelvic Nodal Irradiation Is Not Associated with Worse Bladder, Bowel, or Sexual Outcomes. AB - BACKGROUND: Limited data exist regarding toxicity and quality of life (QOL) after post-prostatectomy intensity modulated radiation therapy (IMRT) and whether pelvic nodal RT influences these outcomes. METHODS: 118 men were treated with curative-intent RT after radical prostatectomy. 69 men (58%) received pelvic nodal RT. QOL data and physician-assigned toxicity were prospectively collected. Changes in QOL from baseline were assessed with Wilcoxon signed-rank tests and risk factors associated with each domain were identified with generalized estimating equation (GEE) models. Late freedom from (FF) toxicity was estimated by the Kaplan-Meier method and comparisons were tested using the log-rank test. RESULTS: Urinary irritation/obstruction, bowel, and sexual domain scores declined at 2 months (all P <= 0.01) but were no different than baseline at subsequent visits through 4 years of follow-up. At 4 years, FF grade 2+ GI toxicity was 90% and FF grade 2+ GU toxicity was 89%. On GEE analysis, pelvic nodal RT was associated with decreased bowel function (P = 0.09) and sexual function (P = 0.01). On multivariate analysis, however, there was no significant association with either decreased bowel (P = 0.31) or sexual (P = 0.84) function. There was also no association with either FF grade 2+ GI toxicity (P = 0.24) or grade 2+ GU toxicity (P = 0.51). CONCLUSIONS: Receipt of pelvic nodal RT was not associated with inferior QOL or toxicity compared to prostate bed alone RT. For the entire cohort, RT was associated with only temporary declines in patient-reported urinary, bowel, or sexual QOL. PMID- 26512987 TI - Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis. AB - Paracoccidioidomycosis (PCM), is a pulmonary fungal disease whose severity depends on the adequate development of T cell immunity. Although regulatory T (Treg) cells were shown to control immunity against PCM, deleterious or protective effects were described in different experimental settings. To clarify the function of Treg cells in pulmonary PCM, loss-and gain-of-function approaches were performed with Foxp3GFP knock-in mice and immunodeficient Rag1-/- mice, respectively, which were intratracheally infected with 106 yeast cells. The activity of Foxp3-expressing Treg cells in pulmonary PCM was determined in Foxp3GFP transgenic mice. First, it was verified that natural Treg cells migrate to the lungs of infected mice, where they become activated. Depletion of Treg cells led to reduced fungal load, diminished pathogen dissemination and increased Th1/Th2/Th17 immunity. Further, adoptive transfer of diverse T cell subsets to Rag1-/- mice subsequently infected by the pulmonary route demonstrated that isolated CD4+Foxp3+ Treg cells were able to confer some degree of immunoprotection and that CD4+Foxp3- T cells alone reduced fungal growth and enhanced T cell immunity, but induced vigorous inflammatory reactions in the lungs. Nevertheless, transfer of Treg cells combined with CD4+Foxp3- T cells generated more efficient and balanced immune Th1/Th2/Th17 responses able to limit pathogen growth and excessive tissue inflammation, leading to regressive disease and increased survival rates. Altogether, these loss- and gain-of-function approaches allow us to clearly demonstrate the dual role of Treg cells in pulmonary PCM, their deleterious effects by impairing T cell immunity and pathogen eradication, and their protective role by suppressing exacerbated tissue inflammation. PMID- 26512988 TI - Effectively Communicating the Uncertainties Surrounding Ebola Virus Transmission. AB - The current Ebola virus outbreak has highlighted the uncertainties surrounding many aspects of Ebola virus virology, including routes of transmission. The scientific community played a leading role during the outbreak-potentially, the largest of its kind-as many of the questions surrounding ebolaviruses have only been interrogated in the laboratory. Scientists provided an invaluable resource for clinicians, public health officials, policy makers, and the lay public in understanding the progress of Ebola virus disease and the continuing outbreak. Not all of the scientific communication, however, was accurate or effective. There were multiple instances of published articles during the height of the outbreak containing potentially misleading scientific language that spurred media overreaction and potentially jeopardized preparedness and policy decisions at critical points. Here, we use articles declaring the potential for airborne transmission of Ebola virus as a case study in the inaccurate reporting of basic science, and we provide recommendations for improving the communication about unknown aspects of disease during public health crises. PMID- 26512989 TI - Premature Mortality from Cardiovascular Disease in the Americas - Will the Goal of a Decline of "25% by 2025" be Met? AB - BACKGROUND: Cardiovascular diseases (CVD) are the underlying cause 1.6 million deaths per year in the Americas, accounting for 30% of total mortality and 38% of by non-communicable deaths diseases (NCDs). A 25% reduction in premature mortality due four main NCDs was targeted by the 2011 High-level Meeting of the General Assembly on the Prevention and Control of NCDs. While overall CVD mortality fell in the Americas during the past decade, trends in premature CVD mortality during the same period have not been described, particularly in the countries of Latin America and the Caribbean. METHODS: This is a population-based trend-series study based on a total of 6,133,666 deaths to describe the trends and characteristics of premature mortality due to CVD and to estimates of the average annual percentage of change during the period 2000-2010 in the Americas. FINDINGS: Premature mortality due to CVD in the Americas fell by 21% in the period 2000-2010 with a -2.5% average annual rate of change in the last 5 year-a statistically significant reduction of mortality-. Mortality from ischemic diseases, declined by 25% - 24% among men and 26% among women. Cerebrovascular diseases declined by 27% -26% among men and 28% among women. Guyana, Trinidad and Tobago, the Dominican Republic, Bahamas, and Brazil had CVD premature mortality rates over 200 per 100,000 population, while the average for the Region was 132.7. US and Canada will meet the 25% reduction target before 2025. Mexico, Costa Rica, Venezuela, Dominican Republic, Panama, Guyana, and El Salvador did not significantly reduce premature mortality among men and Guyana, the Dominican Republic, and Panama did not achieve the required annual reduction in women. CONCLUSIONS: Trends in premature mortality due to CVD observed in last decade in the Americas would indicate that if these trends continue, the Region as a whole and a majority of its countries will be able to reach the goal of a 25% relative reduction in premature mortality even before 2025. PMID- 26512990 TI - Predose and Postdose Blood Gene Expression Profiles Identify the Individuals Susceptible to Acetaminophen-Induced Liver Injury in Rats. AB - The extent of drug-induced liver injury (DILI) can vary greatly between different individuals. Thus, it is crucial to identify susceptible population to DILI. The aim of this study was to determine whether transcriptomics analysis of predose and postdose rat blood would allow prediction of susceptible individuals to DILI using the widely applied analgesic acetaminophen (APAP) as a model drug. Based on ranking in alanine aminotransferase levels, five most susceptible and five most resistant rats were identified as two sub-groups after APAP treatment. Predose and postdose gene expression profiles of blood samples from these rats were determined by microarray analysis. The expression of 158 genes innately differed in the susceptible rats from the resistant rats in predose data. In order to identify more reliable biomarkers related to drug responses for detecting individuals susceptibility to APAP-induced liver injury (AILI), the changes of these genes' expression posterior to APAP treatment were detected. Through the further screening method based on the trends of gene expression between the two sub-groups before and after drug treatment, 10 genes were identified as potential predose biomarkers to distinguish between the susceptible and resistant rats. Among them, four genes, Incenp, Rpgrip1, Sbf1, and Mmp12, were found to be reproducibly in real-time PCR with an independent set of animals. They were all innately higher expressed in resistant rats to AILI, which are closely related to cell proliferation and tissue repair functions. It indicated that rats with higher ability of cell proliferation and tissue repair prior to drug treatment might be more resistant to AILI. In this study, we demonstrated that combination of predose and postdose gene expression profiles in blood might identify the drug related inter-individual variation in DILI, which is a novel and important methodology for identifying susceptible population to DILI. PMID- 26512991 TI - Microbial Contaminants of Cord Blood Units Identified by 16S rRNA Sequencing and by API Test System, and Antibiotic Sensitivity Profiling. AB - Over a period of ten months a total of 5618 cord blood units (CBU) were screened for microbial contamination under routine conditions. The antibiotic resistance profile for all isolates was also examined using ATB strips. The detection rate for culture positive units was 7.5%, corresponding to 422 samples.16S rRNA sequence analysis and identification with API test system were used to identify the culturable aerobic, microaerophilic and anaerobic bacteria from CBUs. From these samples we recovered 485 isolates (84 operational taxonomic units, OTUs) assigned to the classes Bacteroidia, Actinobacteria, Clostridia, Bacilli, Betaproteobacteria and primarily to the Gammaproteobacteria. Sixty-nine OTUs, corresponding to 447 isolates, showed 16S rRNA sequence similarities above 99.0% with known cultured bacteria. However, 14 OTUs had 16S rRNA sequence similarities between 95 and 99% in support of genus level identification and one OTU with 16S rRNA sequence similarity of 90.3% supporting a family level identification only. The phenotypic identification formed 29 OTUs that could be identified to the species level and 9 OTUs that could be identified to the genus level by API test system. We failed to obtain identification for 14 OTUs, while 32 OTUs comprised organisms producing mixed identifications. Forty-two OTUs covered species not included in the API system databases. The API test system Rapid ID 32 Strep and Rapid ID 32 E showed the highest proportion of identifications to the species level, the lowest ratio of unidentified results and the highest agreement to the results of 16S rRNA assignments. Isolates affiliated to the Bacilli and Bacteroidia showed the highest antibiotic multi-resistance indices and microorganisms of the Clostridia displayed the most antibiotic sensitive phenotypes. PMID- 26512992 TI - Changes in Levels of Seminal Nitric Oxide Synthase, Macrophage Migration Inhibitory Factor, Sperm DNA Integrity and Caspase-3 in Fertile Men after Scrotal Heat Stress. AB - BACKGROUND: This study observes changes in levels of seminal nitric oxide (NO), nitric oxide synthase (NOS), macrophage migration inhibitory factor (MIF), sperm DNA integrity, chromatin condensation and Caspase-3in adult healthy men after scrotal heat stress (SHS). METHODS: Exposure of the scrotum of 25 healthy male volunteers locally at 40-43 degrees C SHS belt warming 40 min each day for successive 2 d per week. The course of SHS was continuously 3 months. Routine semen analysis, hypo-osmotic swelling (HOS) test, Aniline blue (AB) staining, HOS/AB and terminal deoxynucleotidyl transferase-mediated d UDP nick-end labeling (TUNEL) were carried out before, during and after SHS. Seminal NO and NOS contents were determined by nitrate reduction method. The activated Caspase-3 levels of spermatozoa and MIF in seminal plasma were measured by the enzyme linked immunosorbent assay (ELISA) method. Statistical significance between mean values was determined using statistical ANOVA tests. RESULTS: The mean parameters of sperm concentration, motile and progressive motile sperm and normal morphological sperm were significantly decreased in groups during SHS 1, 2 and 3 months compared with those in groups of pre-SHS (P<0.001). Statistically significant differences of sperm DNA fragmentation, normal sperm membrane, and Caspase-3 activity as well as the level of NO, NOS and MIF in semen were observed between the groups before SHS and after SHS 3 months and the groups during SHS 1, 2 and 3 months (P<0.001). After three months of the SHS, various parameters recovered to the level before SHS. WBC in semen showed a positively significant correlation with the levels of NO, NOS, MIF and Caspase-3 activity. The percentage of abnormal sperm by using the test of HOS showed a positively significant correlation with that of HOS/AB. CONCLUSIONS: The continuously constant SHS can impact the semen quality and sperm DNA and chromatin, which may be contributed to the high level of NO, NOS, MIF and Caspase-3 by SHS. PMID- 26512993 TI - Chromium speciation in human blood samples based on acetyl cysteine by dispersive liquid-liquid biomicroextraction and in-vitro evaluation of acetyl cysteine/cysteine for decreasing of hexavalent chromium concentration. AB - A rapid and efficient method based on ionic liquid dispersive liquid-liquid biomicroextraction (IL-DLLBME) was used for speciation and preconcentration of Chromium (III, VI) in human blood samples before determination by electro-thermal atomic absorption spectrometer (ET-AAS). In this method, 1-hexyl-3 methylimidazolium hexafluorophosphate as a ionic liquid was dissolved in acetone as a dispersant solvent and then the binary solution was rapidly injected by a syringe into the blood samples containing Cr(III), which have already complexed by acetyl cysteine (NAC) at optimized pH. Under the optimal conditions, the linear range (LR), limit of detection (LOD) and preconcentration factor (PF) were obtained 0.03-4.4 MUg L(-1), 0.005 MUg L(-1) and 10 respectively (RSD <5%). In vitro study show us, the cysteine (Cys) as a prodrug of NAC can decrease the concentration of Cr(VI) in blood samples and human body. Validation of methodology was confirmed by standard reference material (SRM). PMID- 26512994 TI - Ultra-high-pressure liquid chromatography tandem mass spectrometry determination of antidepressant and anxiolytic drugs in neonatal meconium and maternal hair. AB - A procedure based on ultra-high-pressure liquid chromatography tandem mass spectrometry has been developed for the determination of 22 antidepressant and anxiolytic drugs ad metabolites in the three consecutive maternal hair segments representing the pregnancy trimesters and paired neonatal meconium samples. After hair washing with methyl alcohol and diethyl ether and subsequent addition of internal standards, hair samples were treated with 500 MUl VMA-T M3 reagent for 1h at 100 degrees C. After cooling, 100 MUl M3 extract were diluted with 400 MUl water and a volume of 10 MUl was injected into chromatographic system. Meconium samples were firstly treated with 1 ml methyl alcohol and the organic layer back extracted twice with 1.5 ml of a mixture of ethylacetate:hexane (80:20, v/v). Chromatographic separation was achieved at ambient temperature using a reverse phase column and a linear gradient elution with two solvents: 0.3% formic acid in acetonitrile and 5mM ammonium formate pH 3. The mass spectrometer was operated in positive ion mode, using multiple reaction monitoring via positive electrospray ionization. The method was linear from the limit of quantification (0.05-1 ng/mg hair and 5-25 ng/g meconium depending on analyte under investigation;) to 10 ng/mg hair and 1000 ng/g meconium, with an intra- and inter-assay imprecision and inaccuracy always less than 20% and an analytical recovery between 66.6% and 95.3%, depending on the considered analyte and biological matrix. Using the validated method, 7 mothers were found positive to one or more hair segments and 5 meconium samples were found positive to one or more antidepressant and anxiolytic drugs, assessing prenatal exposure to these drugs following maternal consumption in one or more pregnancy trimesters. PMID- 26512995 TI - Simultaneous determination of ceftaroline, daptomycin, linezolid and rifampicin concentrations in human plasma by on-line solid phase extraction coupled to high performance liquid chromatography-tandem mass spectrometry. AB - Methicillin-resistant Staphylococcus aureus infection is a serious clinical problem worldwide. Ceftaroline, daptomycin, linezolid in combination with rifampicin are particularly used in this indication. To allow monitoring of these antibiotics, an on-line solid phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometry assay requiring a 100 MUL aliquot of human plasma has been developed. Besides, significance of 25-O desacetylrifampicin concentrations was evaluated. Sample pre-treatment is limited to protein precipitation with methanol. After centrifugation 10 MUL of supernatant are injected into the chromatographic system, which consists of an on line solid phase extraction followed by a separation on a phenyl-hexyl column and detected by a tandem mass spectrometer. Plasma drug concentrations were determined by multiple reaction monitoring in positive ion mode, and assay performance was evaluated. 25-O-Desacetylrifampicin activity, was compared to rifampicin using a microbiological method. Sample preparation using methanol precipitation followed by solid-phase extraction yielded good recovery and ionization efficiency, with chromatographic separation achieved within 3 min per sample. Within-run and between-run precisions ranged respectively from 1.22% to 9.35% and from 1.61% to 9.36%. Lower limits of quantification were 0.04 mg/L for linezolid, 0.1mg/L for rifampicin, 0.2mg/L for ceftaroline and 0.5mg/L for daptomycin. It appears that 25-O-desacetylrifampicin displays a substantial intrinsic bactericidal activity against S. aureus. This assay provides simple, rapid, sensitive and accurate quantification of the four antibiotic drugs and one metabolite and can be routinely used to monitor drug concentration in methicillin resistant S. aureus infected patients. PMID- 26512996 TI - On-line comprehensive two-dimensional HepG2 cell membrane chromatographic analysis system for charactering anti-hepatoma components from rat serum after oral administration of Radix scutellariae: A strategy for rapid screening active compounds in vivo. AB - Cell membrane chromatography (CMC) is a bioaffinity chromatography technique for characterizing interactions between drugs and membrane receptors and has been widely used to screen active components from complex samples such as herbal medicines (HMs). However, it has never been applied in vivo due to its relatively high limit of detection (LOD) and the matrix interferences. In this study, a novel on-line comprehensive two-dimensional HepG2/CMC/enrich columns/high performance liquid chromatography/time-of-flight mass spectrometry system was developed to rapidly screen potential anti-hepatoma components from drug containing serum of rats after oral administration of Radix scutellariae. A matrix interference deduction method with a home-written program in MATLAB was developed, which could successfully eliminate the interference of endogenous substances in serum. Baicalein, wogonin, chrysin, oroxylin A, neobaicalein and rivularin from Radix scutellariae extraction were significantly retained in the HepG2/CMC column. Three potential active components, wogonin, oroxylin A and neobaicalein were firstly screened from the drug-containing serum as well. The cell counting kit-8 assay demonstrated that wogonin, oroxylin A and chrysin showed high inhibitory activities in a dose-dependent manner on HepG2 cells at the concentration of 12.5-200 MUM (p<0.05) and the IC50 values were 69.83, 16.66 and 51.6 MUM, respectively. Wogonin and oroxylin A, which were screened both from Radix scutellariae extraction and the drug-containing serum, could be selected as lead compounds to obtain good anti-hepatoma effects. The proposed comprehensive 2D CMC system and matrix interference elimination strategy have significant advantages for in vivo screening of active components from complex biological samples and could be applied to other biochromatography models. PMID- 26512997 TI - Quantitation of a low level coeluting impurity present in a modified oligonucleotide by both LC-MS and NMR. AB - This paper describes the use of two complementary techniques, LC-MS and NMR, to quantify a low level mono phosphate substituted impurity in an oligonucleotide drug substance. This impurity is the result of a sulphurisation failure, leading to the production of a sequence where a phosphorothioate linkage is replaced by a phosphate. Few quantitative methods are possible to analyse these challenging molecules especially if reversed phase ion pair chromatography, one of the most commonly used techniques for the separation of oligonucleotides, is unable to resolve the impurity in question. With the use of a standard addition method it could be demonstrated that both analytical techniques show equivalency and furthermore, the LC-MS method alone with additional validation has the potential to perform this quantitative assay with a high degree of accuracy. PMID- 26512998 TI - Simultaneous determination of eleven compounds related to metabolism of bioamines in rat cortex and hippocampus by HPLC-ECD with boron-doped diamond working electrode. AB - A simple and rapid high-performance liquid chromatography method with electrochemical detection employing boron-doped diamond electrode (BDD) was established for simultaneous determination of eleven bioamines with their precursor amino acids and metabolites, including two precursors (tyrosine and tryptophan), three catecholamines (dopamine, norepinephrine and epinephrine) and their four metabolites (3,4-dihydroxyphenylacetic acid, 3-methoxytyramine, homovanillic acid, and 3-methoxy-4-hydroxyphenylglycol), as well as serotonin and its metabolite (5-hydroxyindoleacetic acid), in a single run of 20 min using vanillic acid as internal standard. The separation was performed on an ODS2 column (250 mm * 4.6 mm, 5.0 MUm) with column oven temperature of 30 degrees C. Quantification was accomplished at an oxidation potential of 700 mV vs Ag/AgCl reference electrode after a range of applied voltages were tested. Several parameters of this new chromatographic method were validated after optimizaton of the analytical conditions. The new method was successfully applied to test cortex and hippocampus samples from Sprague-Dawley rats with good separation. These eleven compounds in cortices and hippocampi were compared, which was used for monitoring their variations in neuroscience research. PMID- 26512999 TI - Structural peculiarity and antithrombin binding region profile of mucosal bovine and porcine heparins. AB - The major compositional differences between bovine mucosal heparin (BMH) and the currently employed porcine mucosal heparin (PMH) have been reported to essentially consist of reduced 6-O-sulfation of the glucosamine residues in BMH and somewhat lower 2-O-sulfation of the iduronate residues in PMH. The present work is based on direct comparison of several BMH and PMH commercial preparations. A combined study by 2D (heteronuclear single quantum coherence, HSQC) NMR and ion-pair reversed-phase high performance liquid chromatography (IPRP-HPLC) coupled with electrospray ionization mass spectrometry (ESI-MS) on the heparins, extended to the analysis of their heparinases digests and fractions separated by affinity chromatography on antithrombin (AT), confirmed the previously reported lower degree of 6-O-sulfation and showed lower 3-O-sulfated glucosamine content in BMH. More detailed studies allowed the identification of structural variants of AT-binding region (ATBR) structural variants, showing higher content of the N-sulfated components in BMH than in PMH. PMID- 26513000 TI - A computational prediction for the effective drug and stem cell treatment of human airway burns. AB - Burns in the airway from inhaling hot gases lead to one of the most common causes of death in the United States. In order to navigate tissues with large burn areas, the velocity, temperature, and heat flux distributions throughout the human airway system are computed for the inhalation of hot air using the finite element method. From there, the depth of burned tissue is estimated for a range of exposure times. Additionally, the effectiveness of drug or stem cell delivery to the burned airway tissue is considered for a range of drug or cell sizes. Results showed that the highest temperature and lowest heat flux regions are observed near the pharynx and just upstream of the glottis. It was found that large particles such as stem cells (>20 MUm) are effective for treatment of the upper airways, whereas small particles (<10 MUm) such as drug nanoparticles are effective in the lower airways. PMID- 26513001 TI - Diurnal and seasonal variation of cough episodes in healthy young adults. AB - SETTING: We developed an algorithm to assess recorded cough episodes and differentiate them from similar, non-cough sounds. OBJECTIVE: To measure cough episodes in healthy young adults, cigarette smokers and non-smokers over a 24 hour recording period, during the course of normal activity. DESIGN: The study subjects were students, aged 20-40 years old. 24-hour sound recordings were conducted by a portable recorder. Analysis used an algorithm that was developed and tested in the study. RESULTS: Seventy students were recruited. Recordings included 2628 cough episodes in 1704 h of recording. The cough detection algorithm successfully detected 88.5% of recorded cough episodes and 95.6% of non cough sounds. There was a clear tendency for more coughs among smokers. Autumn was the season with the highest mean cough episodes per day (58.65), while summer had the lowest (14.19). There was a strong correlation between self-reported cough episodes and recorded coughs. Cough episodes were significantly more frequent between noon and midnight (p < 0.0001). CONCLUSION: There is a very large range in daily coughs among healthy young adults. During sleeping hours there are less cough episodes. In autumn and spring there are more cough episodes compared to summer and winter, probably secondary to environmental factors. In smokers, the coughing rate is relatively high. If the cough detection device will be able to discriminate between cough variants (i.e., healthy versus patient), and stringent validation will confirm sensitivity and specificity, valuable data from this device may ease the decision regarding medications, or any other changes in order to improve outcome. PMID- 26513002 TI - Maternal Body Weight and Gestational Diabetes Differentially Influence Placental and Pregnancy Outcomes. AB - CONTEXT: Maternal obesity and gestational diabetes mellitus (GDM) can both contribute to adverse neonatal outcomes. The extent to which this may be mediated by differences in placental metabolism and nutrient transport remains to be determined. OBJECTIVE: Our objective was to examine whether raised maternal body mass index (BMI) and/or GDM contributed to a resetting of the expression of genes within the placenta that are involved in energy sensing, oxidative stress, inflammation, and metabolic pathways. METHODS: Pregnant women from Spain were recruited as part of the "Study of Maternal Nutrition and Genetics on the Foetal Adiposity Programming" survey at the first antenatal visit (12-20 weeks of gestation) and stratified according to prepregnancy BMI and the incidence of GDM. At delivery, placenta and cord blood were sampled and newborn anthropometry measured. RESULTS: Obese women with GDM had higher estimated fetal weight at 34 gestational weeks and a greater risk of preterm deliveries and cesarean section. Birth weight was unaffected by BMI or GDM; however, women who were obese with normal glucose tolerance had increased placental weight and higher plasma glucose and leptin at term. Gene expression for markers of placental energy sensing and oxidative stress, were primarily affected by maternal obesity as mTOR was reduced, whereas SIRT-1 and UCP2 were both upregulated. In placenta from obese women with GDM, gene expression for AMPK was also reduced, whereas the downstream regulator of mTOR, p70S6KB1 was raised. CONCLUSIONS: Placental gene expression is sensitive to both maternal obesity and GDM which both impact on energy sensing and could modulate the effect of either raised maternal BMI or GDM on birth weight. PMID- 26513003 TI - Reducing the Risk of OHSS by GnRH Agonist Triggering. AB - CONTEXT: Overstimulation of follicle development in assisted reproductive technology cycles can lead to the development of life-threatening ovarian hyperstimulation syndrome (OHSS). There is evidence that administration of GnRH agonist as the trigger for final follicular maturation, instead of the usual human chorionic gonadotropin trigger, will reduce the risk of OHSS by shortening the duration of luteal stimulation, lowering estrogen levels by inducing luteolysis and reducing the secretion of vascular endothelial growth factor (VEGF). EVIDENCE ACQUISITION: The paper by Miller et al (1) in this month's issue of the Journal of Clinical Endocrinology and Metabolism (JCEM) demonstrates that GnRH agonist may directly reduce the activity of VEGF by stimulation of granulosa cell expression and secretion of pigment epithelial-derived factor (PEDF). EVIDENCE SYNTHESIS: The increased expression and secretion of PEDF in response to a bolus of GnRH agonist may antagonize the adverse effects of VEGF on ovarian vascular permeability and may contribute to luteolysis by reducing corpus luteum vascularity, thereby reducing the risk of OHSS. In addition, stimulation of PEDF may also be part of the protective mechanism of dopamine agonists used for prevention of OHSS. CONCLUSIONS: The new data presented by Miller et al (1) propose a likely mechanism for the reduced risk of OHSS following GnRH agonist triggering of follicle maturation in assisted reproductive technology cycles. PMID- 26513004 TI - Corrigendum: Photosystem I cyclic electron flow via chloroplast NADH dehydrogenase-like complex performs a physiological role for photosynthesis at low light. PMID- 26513005 TI - Effects of acute postexercise chocolate milk consumption during intensive judo training on the recovery of salivary hormones, salivary SIgA, mood state, muscle soreness, and judo-related performance. AB - This study examined the effects of postexercise chocolate milk (CM) or water (W) consumption during 5 days of intensive judo training with concomitant weight loss on salivary cortisol and testosterone, salivary secretory immunoglobulin A (SIgA), delayed-onset muscle soreness (DOMS), and judo-related performance. Twelve trained male judo athletes engaged in 5 days of intensive judo training followed by a simulated judo competition, on 2 separate training weeks 14 days apart. The athletes consumed 1000 mL of W (week 1) or CM (week 2) immediately post-training. During both weeks, athletes were instructed to "make weight" for the upcoming competition. Performance in timed push-ups and the Special Judo Fitness Test improved by 14.6% and 6.8%, respectively, at the end of the training week with CM consumption (both p < 0.001). Decreased salivary cortisol (p < 0.01) and a trend for an increased salivary testosterone/cortisol ratio (p = 0.07) were also observed midweek in the CM condition. Saliva flow rate was higher during the week with CM intake compared with W intake (p < 0.001). DOMS (p < 0.001) and mood disturbance (p < 0.0001) increased after the first day of training in the W condition but not in the CM condition. Salivary testosterone and SIgA responses were similar between treatments (p > 0.05). Body mass decreased by 1.9% in the W condition and by 1.1% in the CM condition, with no significant difference between treatments. This study indicates that postexercise CM consumption during short term intensive judo training enhances aspects of recovery without affecting intentional weight loss. PMID- 26513006 TI - Effect of electrical stimulation-induced resistance exercise on mitochondrial fission and fusion proteins in rat skeletal muscle. AB - It is well known that resistance exercise increases muscle protein synthesis and muscle strength. However, little is known about the effect of resistance exercise on mitochondrial dynamics, which is coupled with mitochondrial function. In skeletal muscle, mitochondria exist as dynamic networks that are continuously remodeling through fusion and fission. The purpose of this study was to investigate the effect of acute and chronic resistance exercise, which induces muscle hypertrophy, on the expression of proteins related to mitochondrial dynamics in rat skeletal muscle. Resistance exercise consisted of maximum isometric contraction, which was induced by percutaneous electrical stimulation of the gastrocnemius muscle. Our results revealed no change in levels of proteins that regulate mitochondrial fission (Fis1 and Drp1) or fusion (Opa1, Mfn1, and Mfn2) over the 24-h period following acute resistance exercise. Phosphorylation of Drp1 at Ser616 was increased immediately after exercise (P < 0.01). Four weeks of resistance training (3 times/week) increased Mfn1 (P < 0.01), Mfn2 (P < 0.05), and Opa1 (P < 0.01) protein levels without altering mitochondrial oxidative phosphorylation proteins. These observations suggest that resistance exercise has little effect on mitochondrial biogenesis but alters the expression of proteins involved in mitochondrial fusion and fission, which may contribute to mitochondrial quality control and improved mitochondrial function. PMID- 26513007 TI - Resistance training minimizes catabolic effects induced by sleep deprivation in rats. AB - Sleep deprivation (SD) can induce muscle atrophy. We aimed to investigate the changes underpinning SD-induced muscle atrophy and the impact of this condition on rats that were previously submitted to resistance training (RT). Adult male Wistar EPM-1 rats were randomly allocated into 1 of 5 groups: control, sham, SD (for 96 h), RT, and RT+SD. The major outcomes of this study were muscle fiber cross-sectional area (CSA), anabolic and catabolic hormone profiles, and the abundance of select proteins involved in muscle protein synthesis and degradation pathways. SD resulted in muscle atrophy; however, when SD was combined with RT, the reduction in muscle fiber CSA was attenuated. The levels of IGF-1 and testosterone were reduced in SD animals, and the RT+SD group had higher levels of these hormones than the SD group. Corticosterone was increased in the SD group compared with the control group, and this increase was minimized in the RT+SD group. The increases in corticosterone concentrations paralleled changes in the abundance of ubiquitinated proteins and the autophagic proteins LC3 and p62/SQSTM1, suggesting that corticosterone may trigger these changes. SD induced weight loss, but this loss was minimized in the RT+SD group. We conclude that SD induced muscle atrophy, probably because of the increased corticosterone and catabolic signal. High-intensity RT performed before SD was beneficial in containing muscle loss induced by SD. It also minimized the catabolic signal and increased synthetic activity, thereby minimizing the body's weight loss. PMID- 26513008 TI - Multimodal high-intensity interval training increases muscle function and metabolic performance in females. AB - High-intensity interval training (HIIT) is a time-efficient method of improving aerobic and anaerobic power and capacity. In most individuals, however, HIIT using modalities such as cycling, running, and rowing does not typically result in increased muscle strength, power, or endurance. The purpose of this study is to compare the physiological outcomes of traditional HIIT using rowing (Row-HIIT) with a novel multimodal HIIT (MM-HIIT) circuit incorporating multiple modalities, including strength exercises, within an interval. Twenty-eight recreationally active women (age 24.7 +/- 5.4 years) completed 6 weeks of either Row-HIIT or MM HIIT and were tested on multiple fitness parameters. MM-HIIT and Row-HIIT resulted in similar improvements (p < 0.05 for post hoc pre- vs. post-training increases for each group) in maximal aerobic power (7% vs. 5%), anaerobic threshold (13% vs. 12%), respiratory compensation threshold (7% vs. 5%), anaerobic power (15% vs. 12%), and anaerobic capacity (18% vs. 14%). The MM-HIIT group had significant (p < 0.01 for all) increases in squat (39%), press (27%), and deadlift (18%) strength, broad jump distance (6%), and squat endurance (280%), whereas the Row-HIIT group had no increase in any muscle performance variable (p values 0.33-0.90). Post-training, 1-repetition maximum (1RM) squat (64.2 +/- 13.6 vs. 45.8 +/- 16.2 kg, p = 0.02), 1RM press (33.2 +/- 3.8 vs. 26.0 +/- 9.6 kg, p = 0.01), and squat endurance (23.9 +/- 12.3 vs. 10.2 +/- 5.6 reps, p < 0.01) were greater in the MM-HIIT group than in the Row-HIIT group. MM-HIIT resulted in similar aerobic and anaerobic adaptations but greater muscle performance increases than Row-HIIT in recreationally active women. PMID- 26513009 TI - Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib. AB - BACKGROUND AND OBJECTIVE: Several studies have reported an association between type 2 diabetes mellitus and hepatocellular carcinoma (HCC). Data from several retrospective studies and meta-analyses have highlighted a reduction of about 50% in the risk of developing HCC in cirrhotic patients treated with metformin for diabetes. The aim of this study was to evaluate the different outcomes of patients who received or did not receive metformin during treatment with sorafenib. METHODS: We analyzed 93 patients consecutively treated with sorafenib. Forty-two (45.2%) patients were diabetic, of whom 31 were on metformin. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: The concomitant use of sorafenib and metformin was associated with a median PFS of 2.6 months (95% CI 1.9-3.3) compared to 5.0 months (95% CI 2.5-8.2) for patients receiving sorafenib alone (p = 0.029). The median OS of patients treated with the combination was 10.4 months (95% CI 3.9-14.4) compared to 15.1 months (95% CI 11.7-17.8) for those who were not given metformin (p = 0.014). CONCLUSIONS: Our findings could be the result of increased tumor aggressiveness and resistance to sorafenib in metformin-treated patients. PMID- 26513010 TI - Effects of starvation, re-feeding and timing of food supply on daily rhythm features of gut melatonin in carp (Catla catla). AB - Influences of starvation, re-feeding and time of food supply on daily rhythm features of melatonin (5-methoxy-N-acetyltryptamine) and its key regulator AANAT (arylalkylamine N-acetyltransferase) protein in the gut tissues were separately evaluated in carp Catla catla. The first experiment was aimed at demonstration of duration dependent effects of starvation and re-feeding after starvation on the daily profiles and rhythm features of gut melatonin and AANAT. Accordingly, juvenile carp were randomly distributed in three groups, which were (a) provided with balanced diet daily at a fixed time, that is, 10:00 clock hour or zeitgeber time (ZT) 4 (control), or (b) starved (for 2-, 4-, 6- or 8 days), or (c) initially starved for 8 days and then re-fed (for 2-, 4-, 6-, 8-, 12- or 16 days) daily with the same food and at the time (ZT4) used for control fish. The carp in each group were sampled for collection of gut tissues at six different time points at a regular interval of 4 h in a daily cycle. In another experiment, the influences of timing of food supply were separately examined in four fish groups, which were provided with a fixed amount of food once daily either at 06:00 or 12:00 or 18:00 or 24:00 clock hour corresponding to ZT0 or ZT6 or ZT12 or ZT18, respectively, for 7 days before sampling at 12 different time points with a regular interval of 2 h in a 24-h cycle. The study revealed a gradual increase in the mesor and amplitude values of melatonin and AANAT in gut with the progress of starvation till their values reached maximum at day-6 and remained steady thereafter. In contrast, re-feeding of 8-day starved fish resulted in a sharp decrease in their mesor and amplitude values after 2 days and then followed by a steady-state increase till re-attainment of their values close to control fish at the end of 16 days. The acrophase of these gut variables in each control, starved and re-fed fish was noted mostly at midday or ZT6. However, the results of another experiment demonstrated that a shift of food supply time led to a shift in their acrophase. The amount of residual food in the gut lumen in each, but not starved, fish by showing a significant positive correlation independently with the gut levels of melatonin and AANAT also indicated possible role of food as the synchronizer for their daily rhythms. Collectively, it appears reasonable to argue that daily profiles of gut melatonin and AANAT are strongly influenced by the availability of food, while their daily rhythm features seem to be dependent mostly on the time of food supply in carp. PMID- 26513011 TI - One-step solvothermal synthesis of magnetic Fe3O4-graphite composite for Fenton like degradation of levofloxacin. AB - A novel Fe3O4-graphite composite was prepared, characterized, and investigated as a heterogeneous Fenton-like catalyst for the degradation of levofloxacin (LEV) in an aqueous solution. The results revealed that the Fe3O4-graphite composite exhibited excellent properties for the degradation and mineralization of LEV, achieving a nearly complete degradation of 50 mg L(-1) LEV in 15 min and 48% of total organic carbon removal in 60 min under optimal conditions. A large electronic conjugation structure exists in graphite, which may lead to the fast production of *OH radical species because of the easy reduction of Fe(III) to Fe(II). In addition, we observed that the graphite can degrade LEV in the presence of H2O2. Therefore, the synergistic results of the graphite structure and Fe3O4 magnetic nanoparticles (MNPs) may contribute to the high catalytic activity of the Fe3O4-graphite composite. Compared with pure Fe3O4 MNPs, lesser iron leaching of the Fe3O4-graphite composite was observed during the degradation of LEV. The degradation efficiency of LEV remained approximately 80% at the fifth recycling run, which indicates that the Fe3O4-graphite composite has potential applications in water treatment for removing organic pollutants. PMID- 26513012 TI - Chronic exercise preserves brain function in masters athletes when compared to sedentary counterparts. AB - OBJECTIVE: Exercise is beneficial for both the body and the mind, and it has been associated with protective neurocognitive effects, such as increased levels of brain-derived neurotrophic factor and neurogenesis. These effects are linked to the attenuation of age-related mental decline and the preservation of mental capacities in older, physically active adults. This study evaluated whether masters athletes, a highly active population, have better cognitive function compared to age-matched non-athletes based on the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) tool. METHODS: Masters athletes and sedentary controls were recruited and screened for eligibility. All subjects were excluded if they had preexisting neurological diseases, psychiatric disorders, substance abuse disorders, learning disorders, and/or a history of traumatic brain injury, and in addition, control subjects were excluded if they performed >1 h/week of aerobic exercise. All participants completed a health and activity survey which includes the SF-12 and the ImPACT neurocognitive test which measures verbal and visual memory as well as reaction time. Differences between masters athletes and the control population were determined by ImPACT score composites. RESULTS: 51 pairs of athletes and non-athletes were analyzed. Athletes had significantly higher verbal memory scores (85.9 +/- 7.7 vs 79.9 +/- 13.9, p = 0.01) and faster reaction times (0.71 +/- 0.12 vs 0.76 +/- 0.15 s, p = 0.04) on the ImPACT test. Athletes also scored significantly higher on the physical components summary score of the SF-12 (55.0 +/- 3.3 vs 51.8 +/- 6.7, p = 0.004). CONCLUSION: Masters athletes performed better on verbal memory and reaction time test, as well as on physical function as evaluated by the SF-12, compared to non athlete controls. Chronic physical activity may preserve neurocognitive processes and increase physical health, which are protective factors for the negative effects of the aging process. PMID- 26513013 TI - Comparison of Adverse Events for Endoscopic vs Percutaneous Biliary Drainage in the Treatment of Malignant Biliary Tract Obstruction in an Inpatient National Cohort. AB - IMPORTANCE: Nonsurgical biliary drainage in malignant biliary tract obstruction can be performed endoscopically by endoscopic retrograde cholangiopancreatography (ERCP) or by percutaneous transhepatic biliary drainage (PTBD). The published body of literature to support either approach is surprisingly sparse, is conflicting on the preferred approach, and is limited by small studies with heterogeneous groups. OBJECTIVE: To evaluate the procedure-related adverse event rate with endoscopic vs percutaneous drainage in patients with malignant biliary tract obstruction. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis from the National Inpatient Sample (NIS) database from 2007 through 2009. Data analysis was performed in 2015. Patients from the NIS database are representative of the US population and are included from both community and tertiary care hospitals in the United States. MAIN OUTCOMES AND MEASURES: Procedure-related adverse event rates. RESULTS: A total of 7445 patients were included for ERCP and 1690 for PTBD. The overall adverse event rate was 8.6% for endoscopic drainage (640 events) and 12.3% for percutaneous biliary drainage (208 events) (P < .001). When analyzed by type of malignant neoplasm, ERCP was associated with a lower rate of adverse events compared with PTBD for pancreatic cancer (2.9% vs 6.2%; odds ratio [OR], 0.46 [95% CI, 0.35-0.61]; P < .001) and cholangiocarcinoma (2.6% vs 4.2% OR, 0.62 [95% CI, 0.35-1.10]; P = .10). For pancreatic cancer, endoscopic procedures were associated with a lower rate of adverse events regardless of the volume of percutaneous procedures performed by a center. For cholangiocarcinoma, centers that performed a low volume of percutaneous biliary drainage procedures were more likely to have adverse events compared with endoscopic procedures performed at the same center (5.7% vs 2.5%; OR, 2.28 [95% CI, 1.02-5.11]; P = .04). In centers that performed a high volume of percutaneous drainage procedures, rates of adverse events were similar to those of endoscopic adverse events (3.5% vs 3.0%; OR, 1.18 [95% CI, 0.53-2.66]; P = .68). CONCLUSIONS AND RELEVANCE: Our results support the finding that endoscopic biliary drainage for malignant biliary obstruction is a first-line intervention. Endoscopic drainage is superior to percutaneous drainage, in regard to adverse event rate, for patients with pancreatic cancer. For patients with cholangiocarcinoma, endoscopic drainage is superior in centers that perform a low volume of percutaneous biliary drainage procedures. PMID- 26513015 TI - Real-time Cherenkov emission portal imaging during CyberKnife(r) radiotherapy. AB - The feasibility of real-time portal imaging during radiation therapy, through the Cherenkov emission (CE) effect is investigated via a medical linear accelerator (CyberKnife((r))) irradiating a partially-filled water tank with a 60 mm circular beam. A graticule of lead/plywood and a number of tissue equivalent materials were alternatively placed at the beam entrance face while the induced CE at the exit face was imaged using a gated electron-multiplying-intensified-charged coupled device (emICCD) for both stationary and dynamic scenarios. This was replicated on an Elekta Synergy((r)) linear accelerator with portal images acquired using the iViewGT(TM) system. Profiles across the acquired portal images were analysed to reveal the potential resolution and contrast limits of this novel CE based portal imaging technique and compared against the current standard. The CE resolution study revealed that using the lead/plywood graticule, separations down to 3.4 +/- 0.5 mm can be resolved. A 28 mm thick tissue equivalent rod with electron density of 1.69 relative to water demonstrated a CE contrast of 15% through air and 14% through water sections, as compared to a corresponding contrast of 19% and 12% using the iViewGT(TM) system. For dynamic scenarios, video rate imaging with 30 frames per second was achieved. It is demonstrated that CE-based portal imaging is feasible to identify both stationary and dynamic objects within a CyberKnife((r)) radiotherapy treatment field. PMID- 26513016 TI - Lapatinib increases motility of triple-negative breast cancer cells by decreasing miRNA-7 and inducing Raf-1/MAPK-dependent interleukin-6. AB - Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), has been approved for HER2-positive breast cancer patients. Nevertheless, its inhibitory effect on EGFR did not deliver clinical benefits for triple-negative breast cancer (TNBC) patients even EGFR overexpression was frequently found in this disease. Moreover, lapatinib was unexpectedly found to enhance metastasis of TNBC cells, but the underlying mechanisms are not fully understood. In this study, we explored that the level of interleukin-6 (IL-6) was elevated in lapatinib-treated TNBC cells. Treatment with IL-6 antibody abolished the lapatinib-induced migration. Mechanistically, the signaling axis of Raf-1/mitogen-activated protein kinases (MAPKs), c-Jun N terminal kinases (JNKs), p38 MAPK, and activator protein 1 (AP-1) was activated in response to lapatinib treatment to induce IL-6 expression. Furthermore, our data showed that microRNA-7 directly binds and inhibits Raf-1 3'UTR activity, and that down-regulation of miR-7 by lapatinib contributes to the activation of Raf-1 signaling pathway and the induction of IL-6 expression. Our results not only revealed IL-6 as a key regulator of lapatinib-induced metastasis, but also explored the requirement of miR7/Raf-1/MAPK/AP-1 axis in lapatinib-induced IL-6 expression. PMID- 26513017 TI - Traditional Chinese patent medicines for cancer treatment in China: a nationwide medical insurance data analysis. AB - Based on the nationwide survey into inpatients' utilization of the health service covered by China's urban basic medical insurance from 2008 to 2010, we analyzed the use rate, cancer profile and combined use of anticancer Chinese patent medicines (CPMs) on 51,382 insured cancer patients by using statistical, bi clustering and network methods. We found that 42.4% of 51,382 cancer patients used 33 anticancer CPMs, and 51.7% used 71 anticancer Western medicines (WMs). The CPMs were most often used in lung (52%) and nasopharynx (52%) cancer patients, and least in bladder cancer (21%) and leukemia of unspecified cell type (21%) patients. The cost per patient for all 33 anticancer CPMs was 2069RMB, lower than that of the WMs (3458RMB). The cancer profile of commonly used CPMs and WMs for the top 17 cancers (>500 sampled patients) were provided, indicating anticancer CPMs had a broad spectrum of cancers and lacked selectivity in cancer treatment (CPM mean CV = 49%; WM mean CV = 152%). Moreover, 24.8% of the cancer patients used both CPMs and WMs, and CPM-WM combined use networks were constructed for four major cancers. This first nationwide analysis revealed the use characteristics and herb-drug combined use patterns of insurance covered anticancer CPMs in China. The study offers valuable information to guide future studies of the precision, safety and standard use of CPMs. PMID- 26513019 TI - UCHL1 is a biomarker of aggressive multiple myeloma required for disease progression. AB - The success of proteasome inhibition in multiple myeloma highlights the critical role for the ubiquitin-proteasome system (UPS) in this disease. However, there has been little progress in finding more specific targets within the UPS involved in myeloma pathogenesis. We previously found the ubiquitin hydrolase UCH-L1 to be frequently over-expressed in B-cell malignancies, including myeloma, and showed it to be a potent oncogene in mice. Here we show that UCH-L1 is a poor prognostic factor that is essential for the progression of myeloma. We found high levels of UCHL1 to predict early progression in newly diagnosed patients; a finding reversed by the inclusion of bortezomib. We also found high UCHL1 levels to be a critical factor in the superiority of bortezomib over high-dose dexamethasone in relapsed patients. High UCHL1 partially overlaps with, but is distinct from, known genetic risks including 4p16 rearrangement and 1q21 amplification. Using an orthotopic mouse model, we found UCH-L1 depletion delays myeloma dissemination and causes regression of established disease. We conclude that UCH-L1 is a biomarker of aggressive myeloma that may be an important marker of bortezomib response, and may itself be an effective target in disseminated disease. PMID- 26513021 TI - Structure and dynamics of aqueous 2-propanol: a THz-TDS, NMR and neutron diffraction study. AB - Aqueous liquid mixtures, in particular, those involving amphiphilic species, play an important role in many physical, chemical and biological processes. Of particular interest are alcohol/water mixtures; however, the structural dynamics of such systems are still not fully understood. Herein, a combination of terahertz time-domain spectroscopy (THz-TDS) and NMR relaxation time analysis has been applied to investigate 2-propanol/water mixtures across the entire composition range; while neutron diffraction studies have been carried out at two specific concentrations. Excellent agreement is seen between the techniques with a maximum in both the relative absorption coefficient and the activation energy to molecular motion occurring at ~90 mol% H2O. Furthermore, this is the same value at which well-established excess thermodynamic functions exhibit a maximum/minimum. Additionally, both neutron diffraction and THz-TDS have been used to provide estimates of the size of the hydration shell around 2-propanol in solution. Both methods determine that between 4 and 5 H2O molecules per 2 propanol are found in the 2-propanol/water clusters at 90 mol% H2O. Based on the acquired data, a description of the structure of 2-propanol/water across the composition range is presented. PMID- 26513020 TI - NF-kappaB contributes to MMP1 expression in breast cancer spheroids causing paracrine PAR1 activation and disintegrations in the lymph endothelial barrier in vitro. AB - RELA, RELB, CREL, NFKB1 and NFKB2, and the upstream regulators NEMO and NIK were knocked-down in lymph endothelial cells (LECs) and in MDA-MB231 breast cancer spheroids to study the contribution of NF-kappaB in vascular barrier breaching. Suppression of RELA, NFKB1 and NEMO inhibited "circular chemo-repellent induced defects" (CCIDs), which form when cancer cells cross the lymphatic vasculature, by ~20-30%. Suppression of RELB, NFKB2 and NIK inhibited CCIDs by only ~10-15%. In MDA-MB231 cells RELA and NFKB1 constituted MMP1 expression, which caused the activation of PAR1 in adjacent LECs. The knock-down of MMP1 in MDA-MB231 spheroids and pharmacological inhibition of PAR1 in LECs inhibited CCID formation by ~30%. Intracellular Ca(2+) release in LECs, which was induced by recombinant MMP1, was suppressed by the PAR1 inhibitor SCH79797, thereby confirming a functional intercellular axis: RELA/NFKB1 - MMP1 (MDA-MB231) - PAR1 (LEC). Recombinant MMP1 induced PAR1-dependent phosphorylation of MLC2 and FAK in LECs, which is indicative for their activity and for directional cell migration such as observed during CCID formation. The combined knock-down of the NF-kappaB pathways in LECs and MDA-MB231 spheroids inhibited CCIDs significantly stronger than knock down in either cell type alone. Also the knock-down of ICAM-1 in LECs (a NF kappaB endpoint with relevance for CCID formation) and knock-down of MMP1 in MDA MB231 augmented CCID inhibition. This evidences that in both cell types NF-kappaB significantly and independently contributes to tumour-mediated breaching of the lymphatic barrier. Hence, inflamed tumour tissue and/or vasculature pose an additional threat to cancer progression. PMID- 26513022 TI - The feasibility and acceptability of a chaplain-led intervention for caregivers of seriously ill patients: A Caregiver Outlook pilot study. AB - OBJECTIVE: When caring for a loved one with a life-limiting illness, a caregiver's own physical, emotional, and spiritual suffering can be profound. While many interventions focus on physical and emotional well-being, few caregiver interventions address existential and spiritual needs and the meaning that caregivers ascribe to their role. To evaluate the feasibility and acceptability of the process and content of Caregiver Outlook, we employed a manualized chaplain-led intervention to improve well-being by exploring role related meaning among caregivers of patients with a life-limiting illness. METHOD: We conducted a single-arm pre-post pilot evaluation among caregivers of patients with advanced cancer or amyotrophic lateral sclerosis (ALS). Caregivers completed three chaplain-led intervention sessions focusing on (1) a relationship review, (2) forgiveness, and (3) legacy. Outcomes administered at baseline and at 1 and 2 weeks after the intervention included quality of life, anxiety, depression, spiritual well-being, religious coping, caregiver burden, and grief. RESULTS: The sample (N = 31) included a range of socioeconomic status groups, and the average age was approximately 60 years. A third of them worked full-time. Some 74% of our participants cared for a spouse or partner, and the other quarter of the sample cared for a parent (13%), child (10%), or other close family member (3%). At baseline, participants did not demonstrate clinical threshold levels of anxiety, depression, or other indicators of distress. Outcomes were stable over time. The qualitative results showed the ways in which Caregiver Outlook was assistive: stepping back from day-to-day tasks, the opportunity to process emotions, reflecting on support received, provoking thoughts and emotions between sessions, discussing role changes, stimulating communication with others, and the anonymity of a phone conversation. Both religious and nonreligious participants were pleased with administration of the chaplain intervention. SIGNIFICANCE OF RESULTS: The acceptability and feasibility of Caregiver Outlook were demonstrated among caregivers of patients with an advanced illness. Our pilot findings suggest minor modifications to study participant screening, interventionist guidance, and the study measures. PMID- 26513023 TI - A Smartphone-based Decision Support Tool Improves Test Performance Concerning Application of the Guidelines for Managing Regional Anesthesia in the Patient Receiving Antithrombotic or Thrombolytic Therapy. AB - BACKGROUND: The American Society of Regional Anesthesia and Pain Medicine (ASRA) consensus statement on regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy is the standard for evaluation and management of these patients. The authors hypothesized that an electronic decision support tool (eDST) would improve test performance compared with native physician behavior concerning the application of this guideline. METHODS: Anesthesiology trainees and faculty at 8 institutions participated in a prospective, randomized trial in which they completed a 20-question test involving clinical scenarios related to the ASRA guidelines. The eDST group completed the test using an iOS app programmed to contain decision logic and content of the ASRA guidelines. The control group completed the test by using any resource in addition to the app. A generalized linear mixed-effects model was used to examine the effect of the intervention. RESULTS: After obtaining institutional review board's approval and informed consent, 259 participants were enrolled and randomized (eDST = 122; control = 137). The mean score was 92.4 +/- 6.6% in the eDST group and 68.0 +/- 15.8% in the control group (P < 0.001). eDST use increased the odds of selecting correct answers (7.8; 95% CI, 5.7 to 10.7). Most control group participants (63%) used some cognitive aid during the test, and they scored higher than those who tested from memory alone (76 +/- 15% vs. 57 +/- 18%, P < 0.001). There was no difference in time to completion of the test (P = 0.15) and no effect of training level (P = 0.56). CONCLUSIONS: eDST use improved application of the ASRA guidelines compared with the native clinician behavior in a testing environment. PMID- 26513025 TI - Current Perspectives in Health Literacy Research. PMID- 26513024 TI - Peptide/protein vaccine delivery system based on PLGA particles. AB - Due to the excellent safety profile of poly (D,L-lactide-co-glycolide) (PLGA) particles in human, and their biodegradability, many studies have focused on the application of PLGA particles as a controlled-release vaccine delivery system. Antigenic proteins/peptides can be encapsulated into or adsorbed to the surface of PLGA particles. The gradual release of loaded antigens from PLGA particles is necessary for the induction of efficient immunity. Various factors can influence protein release rates from PLGA particles, which can be defined intrinsic features of the polymer, particle characteristics as well as protein and environmental related factors. The use of PLGA particles encapsulating antigens of different diseases such as hepatitis B, tuberculosis, chlamydia, malaria, leishmania, toxoplasma and allergy antigens will be described herein. The co delivery of antigens and immunostimulants (IS) with PLGA particles can prevent the systemic adverse effects of immunopotentiators and activate both dendritic cells (DCs) and natural killer (NKs) cells, consequently enhancing the therapeutic efficacy of antigen-loaded PLGA particles. We will review co-delivery of different TLR ligands with antigens in various models, highlighting the specific strengths and weaknesses of the system. Strategies to enhance the immunotherapeutic effect of DC-based vaccine using PLGA particles can be designed to target DCs by functionalized PLGA particle encapsulating siRNAs of suppressive gene, and disease specific antigens. Finally, specific examples of cellular targeting where decorating the surface of PLGA particles target orally administrated vaccine to M-cells will be highlighted. PMID- 26513026 TI - Health Literacy and Patient-Reported Outcomes: A Cross-Sectional Study of Underserved English- and Spanish-Speaking Patients With Type 2 Diabetes. AB - This study examined associations between patient characteristics, health behaviors, and health outcomes and explored the role of health literacy as a potential mediator of outcomes. English- and Spanish-speaking adults with Type 2 diabetes used a bilingual multimedia touchscreen to complete questionnaires. The behavioral model for vulnerable populations guided multivariable regression and mediation testing. Dependent variables were diabetes self-care, health status, and satisfaction with communication. Independent variables included sociodemographic and clinical characteristics, health literacy, health beliefs, and self-efficacy. Spanish speakers had lower health literacy and poorer physical, mental, and overall health compared to English speakers. Higher health literacy was associated with less social support for diet, fewer diet and medication barriers, younger age, higher diabetes knowledge, and talking with health care professionals to get diabetes information. In contrast to expectations, health literacy was not associated with diabetes self-care, health status, or satisfaction with communication, and it did not mediate the effects of other factors on these outcomes. Diabetes self-efficacy was significantly associated with health behaviors and outcomes. The association between Spanish language preference and poorer health was not mediated by this group's lower health literacy. Increasing health-related self-efficacy might be an important clinical strategy for improving outcomes in underserved patients with Type 2 diabetes. PMID- 26513027 TI - A Cross-Sectional Comparison of Health Literacy Deficits Among Patients With Chronic Kidney Disease. AB - Inadequate health literacy in people with chronic kidney disease (CKD) is associated with poorer disease management and greater complications. There are limited data on the health literacy deficits of people with CKD. The aim of this study was to investigate the types and extent of health literacy deficits in patients with CKD using the multidimensional Health Literacy Management Scale (HeLMS) and to identify associations between patient characteristics and the domains of health literacy measured by the HeLMS. Invitations to participate were sent to patients with CKD attending the renal unit of a regional Australian hospital. These patients included predialysis, dialysis (peritoneal and hemodialysis), and kidney transplant patients. This study identified that inadequate health literacy--especially in the domains relating to attending to one's health needs, understanding health information, social support, and socioeconomic factors--was common. Male gender and education level were significantly associated with inadequate health literacy. The type and extent of health literacy deficits varied among CKD groups, and transplant patients had more deficits than other CKD patient groups. This study provides useful information for health professionals treating patients with CKD, especially with regard to the design of self-management interventions and health information. PMID- 26513028 TI - Health Literacy, Smoking, and Health Indicators in African American Adults. AB - We examined cross-sectional associations of health literacy (HL) with smoking and other established health indicators among 1,467 African American adults. Data emanated from a longitudinal cohort study designed to investigate cancer risk factors among church-going African American adults. We conducted linear and logistic regression analyses to assess associations between HL and health indicators. HL was assessed using an established single-item screening question. Outcomes included indicators of poor physical health (cigarette smoking, self rated general and physical health) and mental health (self-rated mental health, depressive symptoms, perceived stress). Nearly 19% of participants had low HL. Low HL was significantly associated with current smoking, poorer self-rated general and physical health, and higher perceived stress (ps < .05) even after we controlled for demographic variables (i.e., age, gender, relationship status) and indicators of socioeconomic status (i.e., education, income, insurance status). Low HL appears to be an independent risk factor for smoking and other indicators of poor physical and mental health in a large sample of African American adults. Future directions and clinical implications are discussed. PMID- 26513029 TI - Medication Nonadherence Before Hospitalization for Acute Cardiac Events. AB - Medication nonadherence increases the risk of hospitalization and poor outcomes, particularly among patients with cardiovascular disease. The purpose of this study was to examine characteristics associated with medication nonadherence among adults hospitalized for cardiovascular disease. Patients in the Vanderbilt Inpatient Cohort Study who were admitted for acute coronary syndrome or heart failure completed validated assessments of self-reported medication adherence (the Adherence to Refills and Medications Scale), demographic characteristics, health literacy, numeracy, social support, depressive symptoms, and health competence. We modeled the independent predictors of nonadherence before hospitalization, standardizing estimated effects by each predictor's interquartile range. Among 1,967 patients studied, 70.7% indicated at least some degree of medication nonadherence leading up to their hospitalization. Adherence was significantly lower among patients with lower health literacy (0.18-point change in adherence score per interquartile range change in health literacy), lower numeracy (0.28), lower health competence (0.30), and more depressive symptoms (0.52) and those of younger age, of non-White race, of male gender, or with less social support. Medication nonadherence in the period before hospitalization is more prevalent among patients with lower health literacy, numeracy, or other intervenable psychosocial factors. Addressing these factors in a coordinated care model may reduce hospitalization rates. PMID- 26513030 TI - Predictors of Health Literacy and Numeracy Concordance Among Adolescents With Special Health Care Needs and Their Parents. AB - Parent and teen health literacies (HLs) are employed as teens with chronic illnesses transition to health self-management and the adult health system. This study explores the relationships between parent and teen HL. Teens ages 12-18 with chronic conditions and their parents, sampled from a pediatric Medicaid accountable care organization, completed an interview assessing HL and self reported competence with written and numerical health information. Rates of teen and parent HL, degree of concordance, and the relationship between concordance and teen-reported competence with health materials were measured. Half (52%) of teens had adequate HL, 62% of teens reported competence with written health materials, and 69% reported competence with numerical information. The correlation between parent and teen HL was modest but significant (phi = 0.13, p = .03): 47% of parent-teen dyads were concordant for adequate HL, and 10% were concordant for inadequate HL. Adequate teen HL was associated with parental adequate HL and parental education. Discordance was associated with self-reported competence with written material and numerical material. More than half of parent teen dyads had at least 1 member with less than adequate HL, and parent-teen HL concordance was associated with teen perception of HL. These findings support the consideration of both independent and dyad HL levels in adolescent care. PMID- 26513031 TI - Parent Health Literacy and Communication With Diabetes Educators in a Pediatric Diabetes Clinic: A Mixed Methods Approach. AB - Low health literacy is associated with poor communication between adults and providers, but little is known about how parents' health literacy influences communication in pediatric encounters. We examined how parent health literacy affected communication between parents and diabetes educators in a pediatric diabetes clinic. A mixed methods study was conducted including a cross-sectional survey of 162 parents and semi-structured interviews with a subsample of 24 parents of a child with Type 1 diabetes. Parent and child characteristics, parents' report of quality of communication, and parent health literacy were assessed. Logistic regression was performed to determine associations between health literacy and 4 subscales of the Interpersonal Processes of Care (IPC) survey; directed content analyses of interview data were completed. Although health literacy was not significantly associated with the IPC subscales, results from directed content analyses revealed different communication experiences for parents by health literacy classification. Low health literate parents were confused by diabetes jargon, preferred hands-on teaching, and wished for information to be communicated in simple language, broken down into key points, and repeated. Parents with adequate health literacy wanted comprehensive information communicated through ongoing dialogue. Findings indicate that learner driven curricula may be most appropriate for diabetes education. PMID- 26513032 TI - Empowering Women's Prenatal Communication: Does Literacy Matter? AB - This study was designed to evaluate the impact of an interactive computer program developed to empower prenatal communication among women with restricted literacy skills. A total of 83 women seeing 17 clinicians were randomized to a computer based communication activation intervention (Healthy Babies Healthy Moms [HBHM]) or prenatal education (Baby Basics [BB]) prior to their prenatal visit. Visit communication was coded with the Roter Interaction Analysis System, and postvisit satisfaction was reported. Participants were on average 24 years of age and 25 weeks pregnant; 80% were African American. Two thirds scored <=8th grade on a literacy screener. Women with literacy deficits were more verbally active, disclosed more medical and psychosocial/lifestyle information, and were rated as more dominant by coders in the HBHM group relative to their counterparts in the BB group (all ps < .05). Clinicians were less verbally dominant and more patient centered with literate HBHM relative to BB group women (p < .05); there was a similar, nonsignificant trend (p < .1) for lower literate women. Clinicians communicated less medical information and made fewer reassurance statements to lower literate women in the HBHM relative to the BB group (p < .05). There was a trend toward lower visit satisfaction for women with restricted literacy in the HBHM relative to the BB group (p < .1); no difference in satisfaction was evident for more literate women. The HBHM intervention empowered communication of all women and facilitated verbal engagement and relevant disclosure of medical and psychosocial information of women with literacy deficits. Satisfaction, however, tended to be lower for these women. PMID- 26513033 TI - Using the Health Literacy Universal Precautions Toolkit to Improve the Quality of Patient Materials. AB - Patient materials are often written above the reading level of most adults. Tool 11 of the Health Literacy Universal Precautions Toolkit ("Design Easy-to-Read Material") provides guidance on ensuring that written patient materials are easy to understand. As part of a pragmatic demonstration of the Toolkit, we examined how four primary care practices implemented Tool 11 and whether written materials improved as a result. We conducted interviews to learn about practices' implementation activities and assessed the readability, understandability, and actionability of patient education materials collected during pre- and postimplementation site visits. Interview data indicated that practices followed many action steps recommended in Tool 11, including training staff, assessing readability, and developing or revising materials, typically focusing on brief documents such as patient letters and information sheets. Many of the revised and newly developed documents had reading levels appropriate for most patients and- in the case of revised documents--better readability than the original materials. In contrast, the readability, understandability, and actionability of lengthier patient education materials were poor and did not improve over the 6-month implementation period. Findings guided revisions to Tool 11 and highlighted the importance of engaging multiple stakeholders in improving the quality of patient materials. PMID- 26513034 TI - The Influence of Health Literacy and Patient Activation on Patient Information Seeking and Sharing. AB - This study provided an assessment of how patients looked for information to prepare for a clinical appointment and whether they shared those findings with their provider. A cross-sectional survey allowed insight into patient attitudes, motivations, and behavior in clinical real time. At two hospital-based clinics, 243 patients completed surveys before and after clinical appointments. Younger patients with higher communicative and critical health literacy prepared for clinical appointments with information searches. The predicted association of health literacy and patient activation with information sharing was not supported. This study shows that patients with higher patient activation perceived that their providers responded more positively to patient-obtained medical information. The role of critical health literacy may show that individuals choosing to seek information are considering not just their ability to conduct the search but also their ability to synthesize and critically analyze the results of the information search. An implication for providers is to become skilled in directly asking or passively surveying what outside information sources the patient has engaged with, no matter if the patient does or does not introduce the information. PMID- 26513035 TI - Effect of Health Literacy on Research Follow-Up. AB - Previous research has not examined the effect of health literacy on research subjects' completion of scheduled research follow-up. This article evaluates patient factors associated with incomplete research follow-up at three time points after enrollment in a large, hospital-based prospective cohort study. Predictor variables included health literacy, age, race, gender, education, employment status, difficulty paying bills, hospital diagnosis, length of stay, self-reported global health status, depression, perceived health competence, medication adherence, and health care system distrust. In a sample of 2,042 patients, multivariable models demonstrated that lower health literacy and younger age were significantly associated with a lower likelihood of completing research follow-up interviews at 2-3 days, 30 days, and 90 days after hospital discharge. In addition, patients who had less education, were currently employed, and had moderate financial stress were less likely to complete 90-day follow-up. This study is the first to demonstrate that lower health literacy is a significant predictor of incomplete research follow-up. PMID- 26513036 TI - Assessing Health Literacy in Deaf American Sign Language Users. AB - Communication and language barriers isolate Deaf American Sign Language (ASL) users from mass media, health care messages, and health care communication, which, when coupled with social marginalization, places them at a high risk for inadequate health literacy. Our objectives were to translate, adapt, and develop an accessible health literacy instrument in ASL and to assess the prevalence and correlates of inadequate health literacy among Deaf ASL users and hearing English speakers using a cross-sectional design. A total of 405 participants (166 Deaf and 239 hearing) were enrolled in the study. The Newest Vital Sign was adapted, translated, and developed into an ASL version (ASL-NVS). We found that 48% of Deaf participants had inadequate health literacy, and Deaf individuals were 6.9 times more likely than hearing participants to have inadequate health literacy. The new ASL-NVS, available on a self-administered computer platform, demonstrated good correlation with reading literacy. The prevalence of Deaf ASL users with inadequate health literacy is substantial, warranting further interventions and research. PMID- 26513037 TI - Blending Health Literacy With an English as a Second Language Curriculum: A Systematic Literature Review. AB - About 21% of the U.S. population ages 5 and older speaks a language other than English at home, and many of them cannot communicate in English fluently. A possible intervention to improve health literacy for people with limited English proficiency is the use of an English as a second language curriculum. The purpose of this systematic review is to assess the characteristics (e.g., theoretical framework, developing processes, classroom activities, goals and topics) and effectiveness of English as a second language health literacy curricula that are currently available in English-dominant countries. We searched the online databases of ERIC, Sage, Springer, PubMed, Medline, and Scopus, identifying 7 curricula within 18 published reports. We synthesize the strengths and weaknesses of the reviewed curricula and provide recommendations for improving future health literacy interventions and research. PMID- 26513038 TI - Modern Measurement Approaches to Health Literacy Scale Development and Refinement: Overview, Current Uses, and Next Steps. AB - There are currently more than 100 health literacy instruments. The procedures used to develop and test the measures are primarily guided by classical test theory. However, a small and growing number (n = 13) of health literacy measures are guided by modern measurement theories such as item response theory. This article briefly describes (a) the benefits of using modern measurement approaches for the development of health literacy measures, (b) how these approaches have been used with existing health literacy measures, and (c) some considerations for how modern measurement theory can help strengthen future work in health literacy measurement. Ultimately, this article provides evidence to support an assertive shift toward the use of modern measurement approaches in health literacy instrument development. PMID- 26513039 TI - Rapid and selective detection of viruses using virus-imprinted polymer films. AB - We prepared a nanopatterned polymer film of polydimethylsiloxane (PDMS) via virus imprinting. The imprinted surface exhibited nanoscale cavities with the mean size of 120 +/- 4 nm. These cavities demonstrated the ability to preferentially capture a target virus from an aqueous suspension of ultralow volume (5 MUL) after only 1 minute of contact. Two inactivated viruses with similar shape, Influenza A (HK68) and Newcastle Disease Virus (NDV), were employed as model pathogens. The polymer film, which was first imprinted with HK68 and exposed sequentially to suspensions containing fluorescently labeled NDV and HK68, was able to preferentially bind HK68 at a capture ratio of 1 : 8.0. When we reversed the procedure and imprinted with NDV, the capture ratio was 1 : 7.6. These results were obtained within 20 minutes of static exposure. The suspensions contained viruses at concentrations close to those occurring physiologically in influenza infections. The limit of detection was approximately 8 fM. Production of virus-imprinted films can be readily scaled to large quantities and yields a disposable, simple-to-use device that allows for rapid detection of viruses. PMID- 26513040 TI - Enhancing Effect of Intermittent Parathyroid Hormone Administration on Bone Formation After Titanium Implant Placement in an Ovariectomized Rat Maxilla. AB - OBJECTIVE: This study examined the effect of intermittent parathyroid hormone (PTH) administration on the bone response around implant on the maxilla of rats with ovariectomy-induced osteoporosis. MATERIAL AND METHODS: A total of 27 female Sprague-Dawley rats were divided into 3 groups (n = 9) and were ovariectomized (OVX). Eight weeks after, upper right molar was extracted and an implant was placed at 4 weeks after extraction. The PTH group received PTH, and the OVX group and the control group received vehicle only. Beginning after implant placement, 30 MUg/kg of PTH was subcutaneously administered in the dorsum 3 times a week. Three rats in each group were killed at 1, 2, and 4 weeks and histologic sections were evaluated. RESULTS: After 4 weeks, the amount of newly formed bone around implants in the PTH group was comparable with the control group, with bone covering the implant surface in both groups. However, the OVX group displayed relatively small amount of new bone. CONCLUSION: Intermittent PTH has the potential to increase new bone formation around implant. These findings have clinical implications in prosthetic restoration by implants with poor bone quality. PMID- 26513041 TI - Efficacy and tolerability of nitric-zinc complex in the treatment of external genital warts and "difficult-to-treat" warts: a "proof of concept", prospective, multicentre, open study. AB - AIM: Treatment of plantar and periungueal warts (so called "difficult-to-treat" warts, DTW) and external genital warts (EGW) remains unsatisfactory. Medical or invasive procedures are partially effective and/or painful. Furthermore recurrences rates after treatments are still a relevant problem for all the available therapies. Nitric-zinc complex is a solution for topical application containing nitric acid, zinc, copper and organic acids able to induce a caustic effect of the wart trough mummification and proteins denaturation/coagulation action. Nitric-zinc complex has been shown to be an effective and well tolerated treatment of common warts. METHODS: We evaluated in a prospective open label 4 centre trial, the efficacy and local tolerability of nitric-zinc complex in the treatment of EGW and DTW. A total of 37 immunocompetent subjects (20 men and 17 women; mean age: 45 years) with single or multiple lesions, were enrolled, after their informed consent. A total of 30 subjects had EGW, 2 subjects had plantar warts, 2 warts of the hand and 3 periungueal lesions. Nitric-zinc aqueous solution was applied topically using a 30 mL capillary tube over the lesions until a whitening/yellowish reaction appeared. A second (or more, if needed) application was performed at two-week interval until a complete clinical cure rate was observed. Primary outcome of the study was the clinical evaluation with picture documentation of the evolution of lesions classified as total cure, partial disappearance or no effect. Topical tolerability was evaluated through patient's reported adverse events. RESULTS: All subjects completed the study. A complete cure of lesions was observed in 31 subjects (90%) after one and up to four applications. Three patients with EGW (8%) showed a partial disappearance of lesions and one (2%) subject was no responder to four nitric-zinc complex applications. The product was well tolerated. No serious adverse events were observed or recorded. CONCLUSION: Nitric-zinc complex topical solution has shown to be an effective and well tolerated treatment of EGW and "difficult-to-treat" warts with a 90% of subjects with a total cure after one or up to four applications. A total or partial response was observed in 99% of the subjects. Nitric-zinc complex could be considered an easy-to-use effective treatment strategy of "difficult-to-treat" warts and external genital warts. Additional studies comparing nitric-zinc complex to other strategies are warranted. PMID- 26513042 TI - Skin aging. PMID- 26513043 TI - Hidradenitis suppurativa: guidelines of the Italian Society of Dermatology and Venereology (SIDeMaST) for the use of anti-TNF-alpha agents. AB - Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by nodules, abscesses and sinus tracts, primarily affecting the intertriginous areas. The occlusion of the upper part of the folliculopilosebaceous unit, leading to rupture of the sebofollicular canal with the consequent development of perifollicular lympho-histiocytic inflammation, is believed to be the initial pathogenic event in HS. Giving the chronic nature of HS, its destructive impact on social, working and daily life of patients, its management is often frustrating both for patients and physicians. The HS treatment choices are influenced by disease severity and its individual subjective impact. In this article, the Board of the Italian Society of Dermatology and Venereology (SIDeMaST) on HS has prepared a document focusing on the role of biologic drugs (anti-TNF-alpha) in HS management, providing also a flow-chart for HS handling and the inclusion and exclusion criteria for HS treatment with anti-TNF-alpha. PMID- 26513044 TI - Nevus anemicus associated with neurofibromatosis type 1 in a neonate: a case report. AB - Neurofibromatosis type 1 (NF1) is a multisystemic autosomal dominant disease affecting approximately 1 individual in 3500. The diagnostic criteria developed by NIH in 1988 allow unequivocal diagnosis in all cases but the youngest children. Due to the variable phenotypic expression, the diagnosis of NF1 in the youngest may be challenging, particularly when the distinctive cutaneous lesions are missing. We describe the case of a neonate who presented at birth solely with a nevus anemicus. Although this is not considered a diagnostic feature, given the presence of a few cafe au lait lesions in the patient's father, the genetic test was performed and the diagnosis of NF1 confirmed. To our knowledge, the association between nevus anemicus and NF1 is only anedoctal. The peculiarity clinical manifestation of this case highlights the high variable expressivity of the NF1 gene mutation and reinforces the importance of genetic counseling in affected individuals. PMID- 26513045 TI - Atrophoderma of Pasini and Pierini in zosteriform distribution. PMID- 26513046 TI - Phenol 8% solution for the treatment of epidermal growth factor receptor inhibitor-induced periungual pyogenic granulomas. PMID- 26513047 TI - Reversible skin hypopigmentation after topical application of high potency glucocorticosteroids. PMID- 26513048 TI - Psoriasiform nail lesions in a patient with artificial nails. PMID- 26513049 TI - A case of lichenoid drug eruption in a child treated with carbamazepine for idiopathic epilepsy. PMID- 26513050 TI - The association of bullous pemphigoid and malignancy: a case control study. PMID- 26513051 TI - Subcutaneous fat necrosis in a newborn. PMID- 26513052 TI - Leonardo Martinotti: the biography on the fiftieth anniversary of his death. PMID- 26513053 TI - Inhibitory effect of post-hemorrhagic shock mesenteric lymph drainage on the HMGB1 and RAGE in mouse kidney. AB - BACKGROUND: Excessively inflammatory response is one of mechanisms that underlie the acute kidney injury (AKI) induced by severe hemorrhagic shock, which could be ameliorated by post-hemorrhagic shock mesenteric lymph (PHSML) blockage. Recent studies demonstrate that high mobility group box 1 (HMGB1) and the receptor for advanced glycation end products (RAGE) are critical mediators of local inflammations. The present study was sought to investigate whether the PHSML drainage inhibits the HMGB1 and RAGE in mouse kidney to ameliorate the renal inflammatory responses. METHODS: A mouse hemorrhagic shock model (40 +/- 2 mmHg for 90 min, fluid resuscitation for 30 min) was employed, and the PHMSL drainage was performed at the end of the resuscitation. After 3 h of resuscitation, the expressions of mRNA and protein for the renal HMGB1 and RAGE and the levels of interleukin (IL)-1beta and IL-18 were assessed by the real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: Hemorrhagic shock elicited significant increases in the mRNA expressions of HMGB1 and RAGE and in the protein expressions of HMGB1, RAGE, IL-1beta and IL-18 in kidney. The PHSML drainage abolished these potentiating effects. CONCLUSION: The present study demonstrates that PHSML blockade reduces the increased HMGB1 and RAGE and pro-inflammatory factors following hemorrhagic shock, suggesting that the PHSML elicits the inflammatory responses via enhancing the HMGB1 and RAGE production in the kidney. PMID- 26513054 TI - Quantitative assessment of early liver fibrosis in rats using 13N-NH3.H2O PET/CT. AB - OBJECTIVE: To investigate the value of N-NH3.H2O PET/computed tomography (CT) and the inhibitor, acetazolamide (ACZ), in the quantitative diagnosis of early liver fibrosis and the assessment of liver fibrosis stage. MATERIALS AND METHODS: Twenty-four male Wistar rats (293.54+/-37.99 g) were used in this study and grouped by pathology after biopsy. Using N-NH3.H2O as an imaging agent and ACZ as an aquaporin 1 inhibitor, the rats were subjected to a dynamic PET/CT scan for 45 min. According to data reconstruction and imaging analysis, we calculated the mean standard uptake value (SUVmean) of the liver at the time points of 20, 90 s, 5, 10, 15, 20, and 25 min. From the results of N-NH3.H2O, the liver SUVmean in the control group and the liver fibrosis model group at different time points were compared. In addition, blood perfusion, interstitial diffusion, and N NH3.H2O metabolism of the two groups were compared. Single-factor analysis of variance was used to analyze the differences between the SUVs in the groups at any time point and the paired-sample t-test was used to compare the SUVs before and after addition of the inhibitor. RESULTS: We included four rats in the control group (S0) and 20 rats in the liver fibrosis group (which included early stage S1: 11 rats, progressive-stage S2+S3+S4: nine rats). Three rats in S0, seven rats in S1, and six rats in S2+S3+S4 were paired. The SUVmean at 90 s was statistically different (P<0.05); however, the other groups showed statistical difference at all time points (P>0.05). After the addition of the inhibitor, ACZ, the SUVmean of S0 and S2+S3+S4 at 10, 15, 20, and 25 min was statistically different (P<0.05). CONCLUSION: N-NH3.H2O PET/CT may aid the diagnosis of liver fibrosis. N-NH3.H2O PET/CT combined with ACZ may help distinguish between the early stage and the progressive stage of liver fibrosis. PMID- 26513055 TI - Risk of second primary breast cancer after radioactive iodine treatment in thyroid cancer: a systematic review and meta-analysis. AB - The aim of this study was to determine whether the risk of second primary breast cancer (SPBC) is increased in thyroid cancer patients treated with radioactive iodine (RAI). We searched the MEDLINE, EMBASE, and the Cochrane Library and Chinese database for studies that reported the risk of SPBC in thyroid cancer patients treated with RAI and patients not treated with RAI. Two independent reviewers screened citations and reviewed full-text papers. A meta-analysis was carried out using the Review Manager software. Six cohort studies (three from Europe, one from America, and two from east Asia) with 17,914 patients were included in this review. The relative risk of SPBC in thyroid cancer survivors treated with RAI was 0.61 (95% confidence interval 0.47-0.79) relative to thyroid cancer survivors not treated with RAI. The risk of SPBC in thyroid cancer survivors treated with RAI is not increased compared with thyroid cancer survivors not treated with RAI. PMID- 26513056 TI - Evaluation of a new motion correction algorithm in PET/CT: combining the entire acquired PET data to create a single three-dimensional motion-corrected PET/CT image. AB - PURPOSE: This study evaluated the potential of Q.Freeze algorithm for reducing motion artifacts, in comparison with ungated imaging (UG) and respiratory-gated imaging (RG). PATIENTS AND METHODS: Twenty-nine patients with 53 lesions who had undergone RG F-FDG PET/CT were included in this study. Using PET list mode data, five series of PET images [UG, RG, and QF images with an acquisition duration of 3 min (QF3), 5 min (QF5), and 10 min (QF10)] were reconstructed retrospectively. The image quality was evaluated first. Next, quantitative metrics [maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), SD, metabolic tumor volume, signal to noise ratio, or lesion to background ratio] were calculated for the liver, background, and each lesion, and the results were compared across the series. RESULTS: QF10 and QF5 showed better image quality compared with all other images. SUVmax in the liver, background, and lesions was lower with QF10 and QF5 than with the others, but there were no statistically significant differences in SUVmean and the lesion to background ratios. The SD with UG and RG was significantly higher than that with QF5 and QF10. The metabolic tumor volume in QF3 and QF5 was significantly lower than that in UG. CONCLUSION: The Q.Freeze algorithm can improve the quality of PET imaging compared with RG and UG. PMID- 26513057 TI - Evaluating the effect of a third-party implementation of resolution recovery on the quality of SPECT bone scan imaging using visual grading regression. AB - AIM: The aim of this study was to evaluate the benefits to SPECT bone scan image quality when applying resolution recovery (RR) during image reconstruction using software provided by a third-party supplier. METHODS: Bone SPECT data from 90 clinical studies were reconstructed retrospectively using software supplied independent of the gamma camera manufacturer. The current clinical datasets contain 120*10 s projections and are reconstructed using an iterative method with a Butterworth postfilter. Five further reconstructions were created with the following characteristics: 10 s projections with a Butterworth postfilter (to assess intraobserver variation); 10 s projections with a Gaussian postfilter with and without RR; and 5 s projections with a Gaussian postfilter with and without RR. Two expert observers were asked to rate image quality on a five-point scale relative to our current clinical reconstruction. Datasets were anonymized and presented in random order. The benefits of RR on image scores were evaluated using ordinal logistic regression (visual grading regression). RESULTS: The application of RR during reconstruction increased the probability of both observers of scoring image quality as better than the current clinical reconstruction even where the dataset contained half the normal counts. Type of reconstruction and observer were both statistically significant variables in the ordinal logistic regression model. CONCLUSION: Visual grading regression was found to be a useful method for validating the local introduction of technological developments in nuclear medicine imaging. RR, as implemented by the independent software supplier, improved bone SPECT image quality when applied during image reconstruction. In the majority of clinical cases, acquisition times for bone SPECT intended for the purposes of localization can safely be halved (from 10 s projections to 5 s) when RR is applied. PMID- 26513058 TI - Is there a role for PET/CT in the evaluation of primary and secondary hyperparathyroidism? PMID- 26513059 TI - Clopidogrel, prasugrel, ticagrelor or vorapaxar in patients with renal impairment: do we have a winner? AB - The optimal utilization of antiplatelet therapy in patients with renal impairment (RI) following acute coronary syndromes (ACS) represents an urgent, unmet and yet unsolved need with regards to the choice of agents, duration of treatment and potential dose/regimen adjustment. The lack of any large randomized trials designed and powered specifically in such high-risk patients, absence of the uniformed efficacy and safety data reporting policy to the FDA and endless overoptimistic publications based on post hoc analyses of primary trials sometimes exaggerating benefits and hiding risks, clouds reality. In addition, triaging RI patients is problematic due to ongoing kidney deterioration and the fact that such patients are prone to both vascular occlusions and bleeding. The authors summarize available FDA-confirmed evidence from the latest trials with approved antiplatelet agents, namely clopidogrel (CAPRIE, CURE, CREDO, CLARITY, CHARISMA); prasugrel (TRITON, TRILOGY); ticagrelor (PLATO, and PEGASUS); and vorapaxar (TRACER and TRA2P) in RI patient cohorts on top of aspirin as part of dual antiplatelet therapy (DAPT). We deliberately avoided any results unless they were verified by the FDA, with the exception of the recent PEGASUS, since Agency reviews are not yet available. Despite differences among the trials and DAPT choices, RI patients universally experience much higher (HR = 1.3-3.1) rates of primary endpoint events, and bleeding risks (HR = 1.7-3.6). However, only ticagrelor increases creatinine and uric acid levels above that of clopidogrel; has the worst incidence of serious adverse events, more adverse events, and inferior outcomes in patients with severe (eGFR <30 ml/min), especially in the lowest (eGFR <15 ml/min) RI subsets. Clopidogrel, prasugrel and vorapaxar appear safer. Moreover, less aggressive half dose (5 mg/daily) prasugrel and strict DAPT, are well justified in RI, but not predominantly triple strategies with vorapaxar as tested in TRA2P and especially in TRACER. In conclusion, data from clinical trials, their sub-studies and affiliated FDA reviews indicate that RI cause more vascular occlusions and bleeding in ACS patients treated with DAPT. Among the novel antiplatelet agents, prasugrel and vorapaxar, but probably not ticagrelor, offer advantage in RI patients. PMID- 26513060 TI - Intracellular mechanisms underlying lipid accumulation (white opaque substance) in gastric epithelial neoplasms: A pilot study of expression profiles of lipid metabolism-associated genes. AB - BACKGROUND AND AIM: White opaque substance (WOS) is a novel endoscopic finding in gastric neoplasms, indicating the intracellular accumulation of lipid droplets (LDs). However, gastric lipid metabolism has not been extensively investigated, even in normal mucosa. We investigated the expression profiles of lipid metabolism-associated genes in gastric neoplasms. METHODS: Thirty-four patients with early gastric cancer or adenoma were enrolled in this study. Paired biopsy samples from tumor and adjacent non-tumor areas were obtained and analyzed by real-time polymerase chain reaction. Endoscopically resected specimens were evaluated histopathologically. RESULTS: Genes associated with beta-oxidation (peroxisome proliferator-activated receptor alpha, carnitine palmitoyltransferase 1A, and hydroxyacyl-CoA dehydrogenase), lipoprotein excretion (apolipoprotein B, microsomal triglyceride transfer protein, and acyl-CoA:cholesterol acyltransferase 2), fatty acid transport (fatty acid-binding protein), construction of triglycerides in the endoplasmic reticulum (acyl CoA:diacylglycerol acyltransferase 1), and LD degradation/lipolysis (comparative gene identification-58, adipose triglyceride lipase) were significantly downregulated in neoplasms compared with non-tumor areas. Pyruvate dehydrogenase lipoamide kinase isozyme 4 (negative regulator of glycolysis) and adipophilin (LD surface component) were also repressed. Conversely, expression levels of genes associated with de novo lipogenesis (sterol regulatory element-binding protein 1c, acyl-CoA:diacylglycerol acyltransferase 2) were significantly enhanced in neoplasms. There was no significant difference in gene expression levels between carcinomas and adenomas, or between WOS-positive and WOS-negative neoplasms. CONCLUSION: Gene expression profiles in neoplasms suggest a predominance of lipid storage (lipogenesis/LD formation) over consumption (beta oxidation/excretion/lipolysis). Lipid accumulation and WOS in gastric epithelial neoplasms may be caused by impaired mitochondrial oxidation, lipoprotein excretion, and LD degradation. PMID- 26513061 TI - Association of Patient Self-esteem With Perceived Outcome After Face-lift Surgery. AB - IMPORTANCE: It is well understood that optimal psychological health is imperative to success in aesthetic surgical procedures. Self-esteem is a very sensitive psychological factor that can influence patients' motivations for seeking surgery as well as their perceptions of outcomes. OBJECTIVE: To use the Rosenberg Self Esteem Scale (RSES) to correlate the outcome of rhytidectomy as perceived by the patient to further understand the association of self-esteem and the results of aesthetic facial rejuvenation. DESIGN, SETTING, AND PARTICIPANTS: A prospective study was conducted of 59 consecutive patients undergoing rhytidectomy performed by a single surgeon at a private practice from July 1 to October 31, 2013. The RSES was used to establish preoperative baseline scores and scores at a 6-month postoperative follow-up. A paired t test was used to compare statistical data before and after surgery. Change in self-esteem and the patient's evaluation of the surgical outcome was assessed. Analysis was conducted from July 1 to December 1, 2014. MAIN OUTCOMES AND MEASURES: Patients' change in self-esteem level after rhytidectomy, as assessed by the RSES. RESULTS: Of the 59 patients, 50 completed a 6-month postoperative questionnaire; mean age was 58 years (range, 37-73 years); 48 were women; and 44 were nonsmokers. The mean difference between baseline and 6-month scores showed an increase of 0.3 (baseline, 24.3; 6-month follow-up, 24.6), which was not statistically significant (P = .69). Subdivision of patients into groups by self-esteem level showed a statistically significant improvement in self-esteem after surgery in the group with low self-esteem, with a mean difference in the RSES score of 3.7 (P = .01), whereas the group with high self-esteem showed a decrease in the RSES score of -3.1 (P = .03) and the group with average self-esteem showed a nonsignificant increase of 0.5 in the RSES score (P = .59). The perceived change in youthful appearance (mean, 8.9 years) did not correlate with self-esteem changes. CONCLUSIONS AND REVELANCE: Patient's self-esteem before surgery may partially determine the quality-of-life outcome after surgery. Patients with low preoperative self-esteem saw an increase in self esteem after surgery, those with average preoperative self-esteem experienced no change, and those with high preoperative self-esteem experienced a decrease in self-esteem after surgery. In our study, self-esteem measurements did not correlate directly with the positive effect of the surgical outcome, as patients showed no mean change in self-esteem, but patients thought that they appeared a mean of 8.9 years younger after their face-lift surgery. These findings underscore the complex nature of the human psyche as it relates to aesthetic surgery and demonstrates that patients exhibit a wide spectrum of psychological reactions after face-lift surgery. LEVEL OF EVIDENCE: 2. PMID- 26513062 TI - [Not Available]. PMID- 26513063 TI - [Not Available]. PMID- 26513065 TI - Contact dermatitis: relevant differential diagnoses, simulators, and variants. AB - Similar to all eczematous disorders, irritant and allergic contact dermatitis are primarily defined by their morphology. In addition, the diagnosis of this specific reaction pattern on the skin (and mucous membranes) also requires prior exposure (direct or indirect) to an allergen or irritant. While it is quite easy to give a textbook description of the typical features of eczema, its clinical manifestations in daily practice are diverse and frequently uncharacteristic. Contact reactions may present as lichenoid, lymphomatoid, granulomatous, pigmented, purpuric, and erythema multiforme-like lesions, thus lacking the typical eczematous appearance and broadening the spectrum of differential diagnoses to be considered. Moreover, a considerable number of agents, acting by mechanisms other than contact, may trigger adverse reactions mimicking the eczematic morphology and distribution pattern of contact dermatitis. Increasingly used in oncology, this is especially true for drugs such as kinase inhibitors. Knowledge of these associations is crucial for the adequate diagnostic and therapeutic care of patients with supposed or actual contact dermatitis. PMID- 26513067 TI - Vasculitic wheel - an algorithmic approach to cutaneous vasculitides. AB - BACKGROUND: Previous classifications of vasculitides suffer from several defects. First, classifications may follow different principles including clinicopathologic findings, etiology, pathogenesis, prognosis, or therapeutic options. Second, authors fail to distinguish between vasculitis and coagulopathy. Third, vasculitides are systemic diseases. Organ-specific variations make morphologic findings difficult to compare. Fourth, subtle changes are recognized in the skin, but may be asymptomatic in other organs. Our aim was to use the skin and subcutis as a model and the clinicopathologic correlation as the basic process for classification. METHODS AND RESULTS: We use an algorithmic approach with pattern analysis, which allows for consistent reporting of microscopic findings. We first differentiate between small and medium vessel vasculitis. In the second step, we differentiate the subtypes of small (capillaries versus postcapillary venules) and medium-sized (arterioles/arteries versus veins) vessels. In the final step, we differentiate, according to the predominant cell type, into leukocytoclastic and/or granulomatous vasculitis. CONCLUSIONS: Starting from leukocytoclastic vasculitis as a central reaction pattern of cutaneous small/medium vessel vasculitides, its relations or variations may be arranged around it like spokes of a wheel around the hub. This may help establish some basic order in this rather complex realm of cutaneous vasculitides, leading to a better understanding in a complicated field. PMID- 26513068 TI - Epidermal barrier in hereditary ichthyoses, atopic dermatitis, and psoriasis. AB - Several skin disorders are associated with impaired skin barrier function. Primary dysfunction is caused by monogenic defects in key components of the epidermis (for example ichthyoses). Secondary barrier impairment occurs in inflammatory dermatoses marked by disturbed epidermal homeostasis (eczema, psoriasis, etc.). In these disorders, inflammation impedes the synthesis or maintenance of skin barrier components. Recent evidence suggests a combination of primary and secondary barrier dysfunction in atopic dermatitis and, to a lesser extent, also in psoriasis. In the future, subtypes of atopic dermatitis may likely be defined, in which one or the other is prevalent. PMID- 26513070 TI - Hereditary epidermolysis bullosa. AB - The term epidermolysis bullosa (EB) includes a group of rare genodermatoses characterized by mutational impairment of the structural and functional integrity of intraepidermal adhesion and dermoepidermal anchorage. Clinically, these disorders are marked by increased skin fragility as well as characteristic mechanically inducible blisters on the skin and mucous membranes. Extracutaneous manifestations and their complications in other epithelialized organs render EB a multi-system disease associated with significant morbidity and mortality. Cornerstones of a dynamically changing healthcare structure include precise and early diagnosis; coordinated, multidisciplinary, individually adjusted patient care at specialized centers; optimized symptomatic therapies; and access to research-based, potentially curative therapeutic strategies. PMID- 26513072 TI - Gonococcal infections in Austria: a long-term observation of prevalence and resistance profiles from 1999 to 2014. AB - BACKGROUND AND OBJECTIVES: The increase in minimum inhibitory concentrations (MICs) of cephalosporins for Neisseria gonorrhoeae has given rise to concerns regarding potentially untreatable gonococcal infections. The goal was to ascertain the prevalence of gonorrhea in a Viennese patient group and determine resistance patterns. Another objective was to evaluate resistance profiles and MIC values of gonococcal isolates in an Austria-wide surveillance project. PATIENTS AND METHODS: From 1999 to 2014, 350,000 individuals were tested for gonococci at the Viennese Outpatient Clinic. In addition, from 2010 to 2014, the MICs of recommended antibiotics was determined in 3,584 gonococcal isolates, initially by agar dilution and breakpoint determination, and, from 2012 onwards, by Etest(r). RESULTS: During the observation period, the prevalence of gonorrhea increased eightfold, with a significantly greater number of quinolone, penicillin, and tetracycline- resistant strains. In gonococcal strains isolated from across Austria, there was an increase in cefixime and ceftriaxone MICs toward breakpoints. Twenty-one isolates showed cefixime resistance, and while there was an increase in azithromycin resistance from 0.9 % (2013) to 3.2 % (2014), no resistance to ceftriaxone was observed. CONCLUSION: Currently, there is no imminent risk of untreatable gonorrhea in Austria. However, continuing the use of gonococcal cultures as a diagnostic tool for establishing resistance profiles is essential in order to monitor trends in the development of Neisseria (N.) gonorrhoeae resistance. PMID- 26513075 TI - Phrynoderma and acquired acrodermatitis enteropathica in breastfeeding women after bariatric surgery. AB - BACKGROUND AND OBJECTIVES: Women who have undergone bariatric surgery are susceptible to nutritional deficiencies in subsequent pregnancies. We highlight the importance of dermatologists in the early recognition of cutaneous signs of malnutrition occurring in this specific clinical setting. PATIENTS AND METHODS: We compare clinical characteristics of two young women with dermatological signs of combined post-gestational nutritional deficiencies following Roux-en-Y gastric bypass surgery. RESULTS: Patient 1 exhibited follicular papules on the extremities, perianal eczema, perleche, alopecia, and depigmentation of hair. Patient 2 showed erythematous plaques in genitoanal and acral areas, perleche, diffuse alopecia, and depigmentation of hair. Based on clinical and histopathological findings, decreased vitamin A (patient 1) and zinc levels (patient 2), we diagnosed phrynoderma and acquired acrodermatitis enteropathica, respectively. Comparison of the two patients revealed that both (i) were lacking follow-up after gastric bypass surgery, (ii) developed skin lesions as primary symptoms with (iii) mixed clinical manifestations due to combined deficiencies, and (iv) experienced initial symptoms during lactation suggesting a causal relationship. CONCLUSIONS: Our observations highlight the potentially increased risk of women to develop post-gestational dermatological manifestations of malnutrition following bariatric surgery. The awareness of dermatologists with respect to this emerging, susceptible patient group may help avert damage to mother and child. PMID- 26513076 TI - Patient perspectives on treating psoriasis with classic inpatient dithranol therapy: a retrospective patient survey. AB - BACKGROUND: Evidence of the efficacy of dithranol and patient perspectives on the treatment is scant. PATIENTS AND METHODS: Using a telephone interview survey, we collected retrospective data from 63 patients (41 men [65.1 %] and 22 women [34.9 %]) who had been treated with classic inpatient dithranol (CID). PsoRA (www.psoriasisregistry.at) was used to obtain clinical data and treatment responses, which were then correlated with the interview responses. RESULTS: Fifty-two (82.5 %) patients achieved a PASI75 and 51 (81 %) a PASI90 response within a median of 12.5 (range: 3 to 25) days. Ten out of twelve (83 %) patients showed a satisfactory response to CID (PASI75 or greater reduction) despite the fact that they had previously failed to adequately respond to methotrexate, oral retinoids, cyclosporine, or ustekinumab. Overall, patients recalled a median recurrence-free interval of four (95 % CI: 3-9) months after responding to CID, which was positively correlated with the patients' recommendation of (p = 0.018) and their overall high satisfaction with the treatment (p = 0.012). CONCLUSIONS: Despite the known limitations of CID, this survey indicates that dithranol remains a highly efficacious and valuable treatment option as induction therapy in psoriasis. CID can be effective in patients who have failed to respond to systemic therapy, including traditional agents and biologics. PMID- 26513078 TI - Matriptase-1 expression is lost in psoriatic skin lesions and is downregulated by TNFalpha in vitro. AB - BACKGROUND AND OBJECTIVES: Matriptase-1 participates in terminal keratinocyte (KC) differentiation. Knockdown of matriptase-1 in skin equivalent cultures leads to impaired KC differentiation and retention of nuclei in the stratum corneum. Here, we investigated the expression and regulation of matriptase-1 in psoriatic skin and in KC in vitro. PATIENTS AND METHODS: Matriptase-1 expression in healthy and psoriatic skin and its regulation in skin equivalents were analyzed by Western blotting, immunofluorescence staining, qRT-PCR, and activity assays. Involvement of the nuclear factor kappa B (NFkappaB) signaling pathway was investigated by adenoviral overexpression of a dominant-negative form of IKK2. RESULTS: Matriptase-1 expression was detected in the stratum granulosum of healthy human skin and in skin equivalent cultures. Its expression and activity was strongly reduced in lesional skin of patients with psoriasis. Addition of TNFalpha to skin equivalent cultures resulted in complete loss of matriptase-1 expression accompanied by disturbed KC differentiation. Mechanistically, we were able to show that TNFalpha-induced downregulation of matriptase-1 was inhibited by blocking the IKK2/NFkappaB signaling pathway. CONCLUSIONS: Given that matriptase-1 participates in terminal KC differentiation, its absence in psoriatic skin lesions indicates that this contributes to the barrier disturbances in this disease. Our data suggests that blocking the IKK2/NFkappaB pathway represents a potential target for the treatment of psoriasis. PMID- 26513080 TI - Unclear swelling of the lips and left cheek. PMID- 26513082 TI - Phacomatosis pigmentovascularis. PMID- 26513084 TI - Condyloma-like Darier's disease of the inguinal region: resolution after surgical excision and CO2 laser ablation. PMID- 26513086 TI - Pyoderma gangrenosum-like necrotizing panniculitis associated with alpha-1 antitrypsin deficiency: a lethal course. PMID- 26513089 TI - Multiple miliary osteoma cutis of the scalp. PMID- 26513090 TI - Extensive purpuric lesions on the face. PMID- 26513092 TI - Generalized pustulosis in a 5-year-old girl. PMID- 26513094 TI - Xanthoma-like lesions in a 52-year-old female patient. PMID- 26513096 TI - Modified subcutaneously pedicled flap. AB - The subcutaneously pedicled flap, also known as V-Y flap, belongs to the group of island flaps whose blood supply (unlike the horizontally perfused advancement and transposition flaps) comes from subcutaneous blood vessels perpendicular to the skin surface. Because of the outstanding perfusion of this type of flap, we remove up to one-third of the cranial flap pedicle to form a skin flap (3-4 mm thick), resulting in a significant increase in the defect size able to be covered by the V-Y flap. Moreover, in the infraorbital region - as far as topographically feasible - this flap is pulled further cranially (in the direction of the defect to be closed) by an obliquely placed periosteal suture. This offsets any potential distal tension on the flap and has thus proven beneficial in preventing an ectropion. PMID- 26513099 TI - [Not Available]. PMID- 26513100 TI - [Not Available]. PMID- 26513101 TI - [Not Available]. PMID- 26513102 TI - [Not Available]. PMID- 26513103 TI - [Not Available]. PMID- 26513104 TI - [Not Available]. PMID- 26513105 TI - [Not Available]. PMID- 26513106 TI - [Not Available]. PMID- 26513107 TI - [Not Available]. PMID- 26513109 TI - Food Protein Functionality--A New Model. AB - Proteins in foods serve dual roles as nutrients and structural building blocks. The concept of protein functionality has historically been restricted to nonnutritive functions--such as creating emulsions, foams, and gels--but this places sole emphasis on food quality considerations and potentially overlooks modifications that may also alter nutritional quality or allergenicity. A new model is proposed that addresses the function of proteins in foods based on the length scale(s) responsible for the function. Properties such as flavor binding, color, allergenicity, and digestibility are explained based on the structure of individual molecules; placing this functionality at the nano/molecular scale. At the next higher scale, applications in foods involving gelation, emulsification, and foam formation are based on how proteins form secondary structures that are seen at the nano and microlength scales, collectively called the mesoscale. The macroscale structure represents the arrangements of molecules and mesoscale structures in a food. Macroscale properties determine overall product appearance, stability, and texture. The historical approach of comparing among proteins based on forming and stabilizing specific mesoscale structures remains valid but emphasis should be on a common means for structure formation to allow for comparisons across investigations. For applications in food products, protein functionality should start with identification of functional needs across scales. Those needs are then evaluated relative to how processing and other ingredients could alter desired molecular scale properties, or proper formation of mesoscale structures. This allows for a comprehensive approach to achieving the desired function of proteins in foods. PMID- 26513110 TI - Directed Self-Assembly of Diblock Copolymer Thin Films on Prepatterned Metal Nanoarrays. AB - The sequential layer by layer self-assembly of block copolymer (BCP) nanopatterns is an effective approach to construct 3D nanostructures. Here large-scale highly ordered metal nano-arrays prepared from solvent annealed thin films of polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP) diblock copolymer are used to direct the assembly of the same BCP. The influence of initial loading concentration of metal precursor, the type of metal nanoparticle (gold, platinum, and silver), and the nanoparticle-substrate interaction on the directed assembly behavior of the upper BCP layer have been focused. It is found that the upper BCP film can be completely directed by the gold nanoarray with P2VP domain exclusively located between two adjacent gold nanowires or nanodots, which behaves the same way as on the platinum nanoarray. While the silver nanoarray can be destroyed during the upper BCP self-assembly with the silver nanoparticles assembled into the P2VP domain. Based on the discussions of the surface energy of nanoparticles and the interplay between nanoparticle-substrate interaction and nanoparticle-polymer interaction, it is concluded that the effect of immobilization of nanoparticles on the substrate, together with entropy effect to minimize the energetically unfavorable chain stretching contributes to the most effective alignment between each layer. PMID- 26513111 TI - Persistent hepatitis C viral replication despite priming of functional CD8+ T cells by combined therapy with a vaccine and a direct-acting antiviral. AB - Exhaustion of antiviral CD8(+) T cells contributes to persistence of hepatitis C viral (HCV) infection. This immune response has proved difficult to restore by therapeutic vaccination, even when HCV replication is suppressed using antiviral regimens containing type I interferon. Because immunomodulatory effects of type I interferon may be a factor in poor T-cell priming, we undertook therapeutic vaccination in two chronically infected chimpanzees during treatment with a direct-acting antiviral (DAA) targeting the HCV NS5b polymerase protein. Immunization with genetic vaccines encoding the HCV NS3-NS5b nonstructural proteins during DAA treatment resulted in a multifunctional CD8(+) T-cell response. However, these antiviral CD8(+) T cells did not prevent persistent replication of DAA-resistant HCV variants that emerged during treatment. Most vaccine-induced CD8(+) T cells targeted class I epitopes that were not conserved in the circulating virus. Exhausted intrahepatic CD8(+) T-cell targeting conserved epitopes did not expand after vaccination, with a notable exception. A sustained, multifunctional CD8(+) T-cell response against at least one intact class I epitope was detected in blood after vaccination. Persistence of HCV was not due to mutational escape of this epitope. Instead, failure to control HCV replication was likely caused by localized exhaustion in the liver, where CD8(+) T-cell expression of the inhibitory receptor programmed cell death 1 increased 25 fold compared with those in circulation. CONCLUSION: Treatment with a DAA during therapeutic vaccination provided transient control of HCV replication and a multifunctional T-cell response, primarily against nonconserved class I epitopes; exhaustion of liver-infiltrating CD8(+) T cells that target conserved epitopes may not be averted when DAA therapy fails prematurely due to emergence of resistant HCV variants. PMID- 26513112 TI - The COPD Assessment Test: What Do We Know So Far?: A Systematic Review and Meta Analysis About Clinical Outcomes Prediction and Classification of Patients Into GOLD Stages. AB - BACKGROUND: The COPD Assessment Test (CAT) was developed as a simple instrument to assess health status in patients with COPD. This study aimed to systematically review the determinants of the CAT score, its ability to predict clinical outcomes, and the agreement between CAT (>= 10) and the modified Medical Research Council scale (mMRC >= 2) to categorize patients into the new Global Initiative for Chronic Obstructive Lung Disease classification system. METHODS: From January 1, 2009, to June 30, 2015, databases were searched for studies using CAT in adults with COPD and in general populations aiming to detect COPD. Two investigators independently screened, selected, and extracted data by using a standardized form. Where appropriate, the results were combined in a random effects meta-analysis. RESULTS: Of 453 studies, 17 were included, and eight were used in the meta-analysis. The models to predict the CAT score were able to explain < 50% of its variance. CAT scores can indicate risk of exacerbation, depression, acute deterioration in health status, and mortality. All studies found a different proportion of patients in each Global Initiative for Chronic Obstructive Lung Disease category using CAT >= 10 or mMRC >= 2. On average, the distribution was 13% different according to the instrument used. The kappa agreement between CAT and mMRC ranged from 0.13 to 0.77. CONCLUSIONS: CAT may be used as a complementary tool in a patient's clinical assessment to predict COPD exacerbation, health status deterioration, depression, and mortality. The interpretation of this meta-analysis does not support the use of the recommended cutoff points of >=10 for CAT and >=2 for mMRC as equivalents for the purpose of assessing patient symptoms. PMID- 26513113 TI - Predictive factors of splanchnic vein thrombosis in acute pancreatitis: A 6-year single-center experience. AB - OBJECTIVE: Splanchnic vein thrombosis (SVT) is a potentially severe complication of pancreatitis. The aim of this single-center, retrospective cohort study was to investigate the incidence of SVT and to determine the connected risk factors. METHODS: All consecutive patients with acute pancreatitis (AP) managed in our hospital were included. The primary outcome was the occurrence of SVT and data was collected in accordance with Ranson's criteria. RESULTS: A total of 318 patients were included, of whom 124 (39.0%) were women. Biliary lithiasis was the main cause of pancreatitis (n = 156, 49.1%). A total of 19 (6.0%) SVT were identified. In univariate analysis, alcohol intake, smoking and male gender were associated with SVT (P = 0.005, 0.003 and 0.007, respectively). Biological parameters significantly associated with thrombosis were lactate dehydrogenase (LDH) < 500 U/L and hyperglycemia (>= 10 mmol/L) (P = 0.009 and 0.016, respectively). In multivariate analysis, prothrombin time >75% was a protective factor against thrombosis (OR 0.148, P = 0.019). Leukocytes >10 * 10(9)/L (OR 6.397, P = 0.034), hyperglycemia (>= 10 mmol/L) (OR 6.845, P = 0.023), LDH < 500 U/L ((OR 22.61, P = 0.001) and alcoholic etiology (OR 8.960, P = 0.041) were risk factors for SVT. CONCLUSIONS: Alcohol intake, male gender and smoking should focus the physician's attention on the risk of SVT. When further associated with certain biological parameters, the physicians should consider therapeutic anticoagulation to prevent SVT. PMID- 26513114 TI - Acral hyperkeratotic and verrucous plaques in a 77-year-old male patient. PMID- 26513115 TI - Is the sexual behaviour of young people in sub-Saharan Africa influenced by their peers? A systematic review. AB - Adolescents in sub-Saharan Africa are highly vulnerable to HIV, other sexually transmitted infections (STIs) and unintended pregnancies. Evidence for the effectiveness of individual behaviour change interventions in reducing incidence of HIV and other biological outcomes is limited, and the need to address the social conditions in which young people become sexually active is clear. Adolescents' peers are a key aspect of this social environment and could have important influences on sexual behaviour. There has not yet been a systematic review on the topic in sub-Saharan Africa. We searched 4 databases to find studies set in sub-Saharan Africa that included an adjusted analysis of the association between at least one peer exposure and a sexual behaviour outcome among a sample where at least 50% of the study participants were aged between 13 and 20 years. We classified peer exposures using a framework to distinguish different mechanisms by which influence might occur. We found 30 studies and retained 11 that met quality criteria. There were 3 cohort studies, 1 time to event and 7 cross-sectional. The 11 studies investigated 37 different peer exposure-outcome associations. No studies used a biological outcome and all asked about peers in general rather than about specific relationships. Studies were heterogeneous in their use of theoretical frameworks and means of operationalizing peer influence concepts. All studies found evidence for an association between peers and sexual behaviour for at least one peer exposure/outcome/sub-group association. Of all 37 outcome/exposure/sub-group associations tested, there was evidence for 19 (51%). There were no clear patterns by type of peer exposure, outcome or adolescent sub-group. There is a lack conclusive evidence about the role of peers in adolescent sexual behaviour in Sub-Saharan. We argue that longitudinal designs, use of biological outcomes and approaches from social network analysis are priorities for future studies. PMID- 26513116 TI - Does a college education reduce depressive symptoms in American young adults? AB - Higher levels of educational attainment are consistently associated with better mental health. Whether this association represents an effect of education on mental health, however, is less clear as omitted variable bias remains a pressing concern with education potentially serving as a proxy for unobserved factors including family background and genetics. To combat this threat and come closer to a causal estimate of the effect of education on depressive symptoms, this study uses data on 231 monozygotic twin pairs from The National Longitudinal Study of Adolescent to Adult Health and employs a twin-pair difference-in difference design to account for both unobserved shared factors between twin pairs (e.g. home, school, and neighborhood environment throughout childhood) and a number of observed non-shared but theoretically relevant factors (e.g. cognitive ability, personality characteristics, adolescent health). We find an inverse association between possessing a college degree and depressive symptoms in both conventional and difference-in-difference models. Results of this study also highlight the potentially overlooked role of personality characteristics in the education and mental health literature. PMID- 26513117 TI - Community trust and household health: A spatially-based approach with evidence from rural Honduras. AB - What is the relationship between community trust and household health? Scholars working to understand the effects of trust and social capital on human health tend to focus on individual characteristics or social environments, frequently without integrating these two dimensions. In light of this, the present paper makes contributions in both conceptualization and measurement. First, I develop a spatially-based approach for operationalizing community trust as the product of individual orientation and social environment. This approach highlights the need for a household to trust its neighbors and for those neighbors to reciprocate trust in order to constitute the psychological and material mechanisms critical for linking social context to individual health. Second, I illustrate the utility of this measure by evaluating the relationship between community trust and self rated health status using an original population census survey from 2009 to 2010 for two municipalities in western Honduras (approximately 2800 households with a response rate of 94.9%). I implement spatial regression analysis and show that there is a positive and substantively meaningful relationship between community trust and household health; households that are trusting and surrounded by similarly trusting neighbors report better health status, while those in uncertain or mutually distrusting environments report worse health. The theory and results presented here suggest an important link between trust and social capital at the community level, which is particularly salient for rural regions in developing countries where health resources are scarce and community-based interventions are common. PMID- 26513118 TI - The path of least resistance? Jurisdictions, responsibility and professional asymmetries in pharmacists' accounts of antibiotic decisions in hospitals. AB - The misuse of antibiotics has become a major public health problem given the global threat of multi-resistant organisms and an anticipated 'antimicrobial perfect storm' within the next few decades. Despite recent attempts by health service providers to optimise antibiotic usage, widespread inappropriate use of antibiotics continues in hospitals internationally. In this study, drawing on qualitative interviews with Australian pharmacists, we explore how they engage in antibiotic decisions in the hospital environment. We develop a sociological understanding of pharmacy as situated within evolving interprofessional power relations, inflected by an emerging milieu whereby antibiotic optimisation is organisationally desired but interprofessionally constrained. We argue that the case of antibiotics articulates important interprofessional asymmetries, positioning pharmacists as delimited negotiators within the context of medical prescribing power. We conclude that jurisdictional uncertainties, and the resultant interprofessional dynamics between pharmacy and medicine, are vital delimiting factors in the emerging role of pharmacists as 'antimicrobial stewards' in the hospital environment. Moreover, we argue that a nuanced understanding of the character of interprofessional negotiations is key to improving the use of antibiotics within and beyond the hospital. PMID- 26513119 TI - Serum aflatoxin B1-lysine adduct level in adult women from Eastern Province in Kenya depends on household socio-economic status: A cross sectional study. AB - BACKGROUND: Notwithstanding the growing concern about the negative impact of aflatoxin (AF) on human health, there is a dearth of evidence on the socio economic determinants of AF exposure in low and middle income countries. OBJECTIVES: We used detailed socio-economic data to quantify to what extent socio economic characteristics explained differences in serum AFB1-lysine adduct level in adult women from a rural area in Kenya's Eastern Province. METHODS: We first explored the relationship between serum aflatoxin level and a number of household, farm, and individual characteristics using cross-sectional data on 884 mothers (pregnant or with a child under 24 months). We then used regression analyses to estimate the extent to which the combined characteristics could predict serum aflatoxin levels. We finally used the estimated regression models to predict changes in AF level when changing a women's characteristics from the most disadvantaged group (setting all socio-economic characteristics to the lowest tertile) to the most advantaged group (highest tertile). RESULTS: AF was detected in all women. The median level of serum AB1-lysine adduct was 7.47 pg/mg albumin. Higher exposure levels were significantly associated with poverty: predicted serum aflatoxin levels in women living in the worst socio-economic conditions were 4.7-7.1 times higher than those with the best socio-economic status. CONCLUSIONS: The results of our study, the first to show the significant association between poverty and aflatoxin exposure, highlight the need to better understand the strategies used by better-off families to mitigate AF exposure. PMID- 26513120 TI - The long-term mortality impact of combined job strain and family circumstances: A life course analysis of working American mothers. AB - BACKGROUND: Work stress and family composition have been separately linked with later-life mortality among working women, but it is not known how combinations of these exposures impact mortality, particularly when exposure is assessed cumulatively over the life course. We tested whether, among US women, lifelong work stress and lifelong family circumstances would jointly predict mortality risk. PROCEDURES: We studied formerly working mothers in the US Health and Retirement Study (HRS) born 1924-1957 (n = 7352). We used sequence analysis to determine five prototypical trajectories of marriage and parenthood in our sample. Using detailed information on occupation and industry of each woman's longest-held job, we assigned each respondent a score for job control and job demands. We calculated age-standardized mortality rates by combined job demands, job control, and family status, then modeled hazard ratios for death based on family constellation, job control tertiles, and their combination. RESULTS: Married women who had children later in life had the lowest mortality risks (93/1000). The highest-risk family clusters were characterized by spells of single motherhood (132/1000). Generally, we observed linear relationships between job control and mortality hazard within each family trajectory. But while mortality risk was high for all long-term single mothers, we did not observe a job control-mortality gradient in this group. The highest-mortality subgroup was previously married women who became single mothers later in life and had low job control (HR 1.91, 95% CI 1.38,2.63). PRACTICAL IMPLICATIONS: Studies of associations between psychosocial work characteristics and health might consider heterogeneity of effects by family circumstances. Worksite interventions simultaneously considering both work and family characteristics may be most effective in reducing health risks. PMID- 26513121 TI - Neighborhood crime and depressive symptoms among African American women: Genetic moderation and epigenetic mediation of effects. AB - INTRODUCTION: Social scientists have long recognized the important role that neighborhood crime can play in stress-related disease, but very little is known about potential biosocial mechanisms that may link the experience of living in high-crime neighborhoods with depression. OBJECTIVE: The current study introduces an integrated model that combines neighborhood, genetic, and epigenetic factors. METHODS: Hypotheses were tested with a sample of 99 African American women from the Family and Community Health Study (FACHS). RESULTS: Allele variants of the serotonin transporter gene (5-HTT) interact with neighborhood crime to predict depressive symptoms in a manner consonant with the differential susceptibility perspective. Furthermore, this association is mediated by DNA methylation of the promoter region of the serotonin transporter gene. CONCLUSION: The findings provide support for an integrated model in which changes in DNA methylation, resulting from neighborhood crime, can result in an increase or decrease in gene activity which, in turn, influences depressive symptoms. PMID- 26513122 TI - Social support attenuates the harmful effects of stress in healthy adult women. AB - OBJECTIVE: The purpose of this study was to test the hypothesis that social support buffers the effects of perceived stress on physical symptoms in healthy women. METHODS: The study was conducted in the Southwest United States and data were collected from 2006 to 2010. Participants were 52 healthy adult women who completed a baseline questionnaire and a 21-day daily diary. Social support was assessed in the baseline questionnaire and perceived stress and physical symptoms were assessed in the daily diary. Multilevel analyses were used to predict both same day and next day physical symptoms from baseline social support and daily perceived stress. RESULTS: The hypotheses were supported when predicting both same and next day physical symptoms. For the same day, perceived stress and the social support * perceived stress interaction were both related to physical symptoms. For the next day, the social support * perceived stress interaction but not perceived stress was related to physical symptoms when controlling for previous day physical symptoms. The interactions were such that women higher in social support had smaller increases in same and next day physical symptoms on days of higher perceived stress than women lower in social support. CONCLUSIONS: Social support may buffer the effects of daily perceived stress on physical symptoms in healthy women. Future research should investigate what aspects and in what contexts social support may reduce the effects of perceived stress on physical symptoms and examine how social support may affect the development of long-term health problems through increases in daily physical symptoms. PMID- 26513123 TI - HIV serostatus disclosure: development and validation of indicators considering target and modality. Results from a community-based research in 5 countries. AB - RATIONALE: HIV serostatus disclosure is a complex challenge for persons living with HIV (PLHIV). Despite its beneficial effects, it can also lead to stigmatization and rejection. The current lack of multi-dimensional measurement tools impede an in-depth understanding of the dynamic of disclosure. OBJECTIVE: To develop and validate complex measures of serostatus disclosure. METHODS: This international community based research study was performed by joint research teams (researchers/community based organizations (CBO)) in five countries (Democratic Republic of the Congo, Ecuador, Mali, Morocco and Romania). A convenience sample of 1500 people living with HIV (PLHIV) in contact with local CBO were recruited in 2011 (300 in each country). Face-to-face interviews were performed using a 125-item questionnaire covering HIV status disclosure to 23 potential disclosure targets and related issues (including personal history with HIV, people's reaction to disclosure, sexuality). A principal component analysis and a hierarchical cluster analysis were performed, in order to identify the main components of HIV disclosure, create measures and classify participants into profiles. RESULTS: Patterns of disclosure were summarized using two main measures: direct and indirect disclosure. Disclosure to sexual partners, whether steady or not, was different from patterns of disclosure to other targets. Among the participants, three profiles emerged - labelled Restricted disclosure, Mainly indirect disclosure and Mainly direct disclosure, respectively representing 61%, 13% and 26% of the total sample. The profiles were associated with different aspects of PLHIV's lives, including self-efficacy, functional limitations and social exclusion. Patterns varied across the five studied countries. CONCLUSION: Results suggest that multi-dimensional constructs should be used to measure disclosure in order to improve understanding of the disclosure process. PMID- 26513124 TI - Predicting the mortality from asbestos-related diseases based on the amount of asbestos used and the effects of slate buildings in Korea. AB - Asbestos has been used since ancient times, owing to its heat-resistant, rot proof, and insulating qualities, and its usage rapidly increased after the industrial revolution. In Korea, all slates were previously manufactured in a mixture of about 90% cement and 10% chrysotile (white asbestos). This study used a Generalized Poisson regression (GPR) model after creating databases of the mortality from asbestos-related diseases and of the amount of asbestos used in Korea as a means to predict the future mortality of asbestos-related diseases and mesothelioma in Korea. Moreover, to predict the future mortality according to the effects of slate buildings, a comparative analysis based on the result of the GPR model was conducted after creating databases of the amount of asbestos used in Korea and of the amount of asbestos used in making slates. We predicted the mortality from asbestos-related diseases by year, from 2014 to 2036, according to the amount of asbestos used. As a result, it was predicted that a total of 1942 people (maximum, 3476) will die by 2036. Moreover, based on the comparative analysis according to the influence index, it was predicted that a maximum of 555 people will die from asbestos-related diseases by 2031 as a result of the effects of asbestos-containing slate buildings, and the mortality was predicted to peak in 2021, with 53 cases. Although mesothelioma and pulmonary asbestosis were considered as asbestos-related diseases, these are not the only two diseases caused by asbestos. However the results of this study are highly important and relevant, as, for the first time in Korea, the future mortality from asbestos related diseases was predicted. These findings are expected to contribute greatly to the Korean government's policies related to the compensation for asbestos victims. PMID- 26513125 TI - The metallic state in neutral radical conductors: dimensionality, pressure and multiple orbital effects. AB - Pressure-induced changes in the solid-state structures and transport properties of three oxobenzene-bridged bisdithiazolyl radicals 2 (R = H, F, Ph) over the range 0-15 GPa are described. All three materials experience compression of their pi-stacked architecture, be it (i) 1D ABABAB pi-stack (R = Ph), (ii) quasi-1D slipped pi-stack (R = H), or (iii) 2D brick-wall pi-stack (R = F). While R = H undergoes two structural phase transitions, neither of R = F, Ph display any phase change. All three radicals order as spin-canted antiferromagnets, but spin canted ordering is lost at pressures <1.5 GPa. At room temperature, their electrical conductivity increases rapidly with pressure, and the thermal activation energy for conduction Eact is eliminated at pressures ranging from ~3 GPa for R = F to ~12 GPa for R = Ph, heralding formation of a highly correlated (or bad) metallic state. For R = F, H the pressure-induced Mott insulator to metal conversion has been tracked by measurements of optical conductivity at ambient temperature and electrical resistivity at low temperature. For R = F compression to 6.2 GPa leads to a quasiquadratic temperature dependence of the resistivity over the range 5-300 K, consistent with formation of a 2D Fermi liquid state. DFT band structure calculations suggest that the ease of metallization of these radicals can be ascribed to their multiorbital character. Mixing and overlap of SOMO- and LUMO-based bands affords an increased kinetic energy stabilization of the metallic state relative to a single SOMO-based band system. PMID- 26513126 TI - The interplay of socio-psychological factors on school engagement among early adolescents. AB - The study examined a conceptual model integrating existing knowledge on the linkages between life satisfaction, affect, purpose in life, and resilience with school engagement. This model posits direct relationships between all the social psychological variables and school engagement, and also indirect relationships between life satisfaction and school engagement as mediated by all the other variables in the study. The participants were 2381 students (1119 boys and 1262 girls) with average age of 15 years, from 40 national secondary schools in Malaysia. The findings supported the theoretical conceptualization. All variables were positively associated with school engagement. The strongest relationship was observed between overall life satisfaction and school engagement. The mediating model was partially supported. The study reiterates the adage that "it takes a village to raise a child". Implications for practice and future research are discussed in the context of engagement in school learning. PMID- 26513127 TI - Children's online coping strategies: Rethinking coping typologies in a risk specific approach. AB - Understanding how children deal with problematic situations online is helpful in developing efficient awareness raising and online resilience building initiatives. In this article, we will discuss and develop typologies for online coping strategies. In a school survey, 2046 Flemish children aged 10-16 were asked about how they (would) respond when confronted with different types of online risks. Using principal component analyses and multi-dimensional scaling, we identified different types of cross-risk and risk-specific coping strategies, and explored which types of coping have similar underlying meanings. The results suggest to distinguish behavioral avoidance tactics from mere passive responses or indifference. Young people tend to perceive online coping strategies along two dimensions: engagement versus disengagement and technical versus non-technical measures. Behavioral avoidance is popular among younger children and is associated with a medium level of active engagement and often combined with communicative approaches. Girls are more communicative and respond more proactively. PMID- 26513128 TI - Pharmacological interventions for cognitive decline in people with Down syndrome. AB - BACKGROUND: People with Down syndrome are vulnerable to developing dementia at an earlier age than the general population. Alzheimer's disease and cognitive decline in people with Down syndrome can place a significant burden on both the person with Down syndrome and their family and carers. Various pharmacological interventions, including donepezil, galantamine, memantine and rivastigmine, appear to have some effect in treating cognitive decline in people without Down syndrome, but their effectiveness for those with Down syndrome remains unclear. OBJECTIVES: To assess the effectiveness of anti-dementia pharmacological interventions and nutritional supplements for treating cognitive decline in people with Down syndrome. SEARCH METHODS: In January 2015, we searched CENTRAL, ALOIS (the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group), Ovid MEDLINE, Embase, PsycINFO, seven other databases, and two trials registers. In addition, we checked the references of relevant reviews and studies and contacted study authors, other researchers and relevant drug manufacturers to identify additional studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of anti-dementia pharmacological interventions or nutritional supplements for adults (aged 18 years and older) with Down syndrome, in which treatment was administered and compared with either placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias of included trials and extracted the relevant data. Review authors contacted study authors to obtain missing information where necessary. MAIN RESULTS: Only nine studies (427 participants) met the inclusion criteria for this review. Four of these (192 participants) assessed the effectiveness of donepezil, two (139 participants) assessed memantine, one (21 participants) assessed simvastatin, one study (35 participants) assessed antioxidants, and one study (40 participants) assessed acetyl-L-carnitine.Five studies focused on adults aged 45 to 55 years, while the remaining four studies focused on adults aged 20 to 29 years. Seven studies were conducted in either the USA or UK, one between Norway and the UK, and one in Japan. Follow-up periods in studies ranged from four weeks to two years. The reviewers judged all included studies to be at low or unclear risk of bias.Analyses indicate that for participants who received donepezil, scores in measures of cognitive functioning (standardised mean difference (SMD) 0.52, 95% confidence interval (CI) -0.27 to 1.13) and measures of behaviour (SMD 0.42, 95% CI -0.06 to 0.89) were similar to those who received placebo. However, participants who received donepezil were significantly more likely to experience an adverse event (odds ratio (OR) 0.32, 95% CI 0.16 to 0.62). The quality of this body of evidence was low. None of the included donepezil studies reported data for carer stress, institutional/home care, or death.For participants who received memantine, scores in measures of cognitive functioning (SMD 0.05, 95% CI -0.43 to 0.52), behaviour (SMD -0.17, 95% CI -0.46 to 0.11), and occurrence of adverse events (OR 0.45, 95% CI 0.18 to 1.17) were similar to those who received placebo. The quality of this body of evidence was low. None of the included memantine studies reported data for carer stress, institutional/home care, or death.Due to insufficient data, it was possible to provide a narrative account only of the outcomes for simvastatin, antioxidants, and acetyl-L-carnitine. Results from one pilot study suggest that participants who received simvastatin may have shown a slight improvement in cognitive measures. AUTHORS' CONCLUSIONS: Due to the low quality of the body of evidence in this review, it is difficult to draw conclusions about the effectiveness of any pharmacological intervention for cognitive decline in people with Down syndrome. PMID- 26513130 TI - Molecular Chromophore-Catalyst Assemblies for Solar Fuel Applications. PMID- 26513129 TI - Anandamide-induced endoplasmic reticulum stress and apoptosis are mediated by oxidative stress in non-melanoma skin cancer: Receptor-independent endocannabinoid signaling. AB - Endocannabinoids are neuromodulatory lipids that regulate central and peripheral physiological functions. Endocannabinoids have emerged as effective antitumor drugs due to their ability to induce apoptosis in various cancer studies. The G protein coupled cannabinoid receptors (CB1 and CB2) and the TRPV1 ion channel were reported to mediate the antiproliferative activity of endocannabinoids. However, receptor-independent effects also account for their activity. Our previous studies showed that the antiproliferative activity of anandamide (AEA) was regulated by cyclooxygenase-2 (COX-2) via induction of endoplasmic reticulum (ER) stress. We also determined that AEA induced oxidative stress. However, the role of oxidative stress, the cannabinoid receptors, and TRPV1 in AEA-induced ER stress-apoptosis was unclear. Therefore, the current study examines the role of oxidative stress in ER stress-apoptosis and investigates whether this effect is modulated by CB1, CB2, or TRPV1. In non-melanoma skin cancer (NMSC) cells, AEA reduced the total intracellular level of glutathione and induced oxidative stress. To evaluate the importance of oxidative stress in AEA-induced cell death, the antioxidants, N-acetylcysteine (NAC) and Trolox, were utilized. Each antioxidant ameliorated the antiproliferative effect of AEA. Furthermore, Trolox inhibited AEA-induced CHOP10 expression and caspase 3 activity, indicating that oxidative stress was required for AEA-induced ER stress-apoptosis. On the other hand, selective blockade of CB1, CB2, and TRPV1 did not inhibit AEA-induced oxidative stress or ER stress-apoptosis. These findings suggest that AEA-induced ER stress-apoptosis in NMSC cells is mediated by oxidative stress through a receptor-independent mechanism. Hence, receptor-independent AEA signaling pathways may be targeted to eliminate NMSC. (c) 2015 Wiley Periodicals, Inc. PMID- 26513131 TI - SGLT2 inhibition: efficacy and safety in type 2 diabetes treatment. AB - INTRODUCTION: Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) offer a new opportunity for the management of type 2 diabetes mellitus. These agents reduce hyperglycemia by decreasing the renal glucose threshold and thereby increasing urinary glucose excretion. Subsequent reduction of glucotoxicity improves beta-cell sensitivity to glucose and tissue insulin sensitivity. AREAS COVERED: This article analyzes the efficacy and safety data of canagliflozin, dapagliflozin and empagliflozin in randomized controlled trials of 24 - 104 weeks duration, compared with placebo or an active comparator, in patients treated with diet/exercise, metformin, dual oral therapy or insulin. EXPERT OPINION: SGLT2 inhibitors significantly and consistently reduce glycated hemoglobin, with a minimal risk of hypoglycemia. The improvement of glucose control is similar or slightly better compared with metformin, sulfonylureas or sitagliptin, with the add-on value of significant reductions in body weight and blood pressure. However, caution is recommended in fragile elderly patients and patients with chronic kidney disease. An increased risk of genital mycotic infections is observed, but urinary tract infections are rare. Concern about an unexpected risk of euglycemic ketoacidosis has been recently reported. A possible renal protection deserves further attention. A remarkable reduction in cardiovascular mortality was reported in EMPA-REG OUTCOME with empagliflozin. PMID- 26513132 TI - Inadequate sociomedical evaluation of possible abusive head trauma in Yokohama. AB - BACKGROUND: There have been no previous studies on the adequacy of combined evaluation of possible abusive head trauma cases by frontline medical personnel, hospital-based child protection teams, and child protective services in local districts of Japan. METHODS: We conducted a questionnaire survey of hospitalized patients under 24 months old with a diagnosis of intracranial hemorrhage (ICH) from January 2011 to December 2013. Eleven large-scale general hospitals in Yokohama, Japan were surveyed, which provide centralized inpatient care to moderately-severely ill children. RESULTS: A total of 51 ICH patients were listed from eight hospitals. Median patient age was 7 months, and 84% were younger than 12 months. The most common diagnosis on computed tomography was subdural hematoma (n = 26; 51%). Of a total of 51 cases, 31 (61%) occurred inside the home; the injury scene was unknown in six cases (12%). We reviewed these 37 cases from the viewpoint of evaluation with concern for suspected child abuse. Three out of 37 patients (8%) were not examined for inflicted skin lesions, and skeletal surveys and funduscopy were not conducted in 14 (38%) and 15 (41%), respectively. Thirteen out of 37 cases (35%) were not reported to hospital-based child protection teams and 22 (59%) were not reported to regional child protective services. CONCLUSION: The sociomedical evaluation of possible child abuse appears to be systematically inadequate in Yokohama. PMID- 26513133 TI - Synthesis and Characterization of Aluminum Complexes of Redox-Active Pyridyl Nitroxide Ligands. AB - The aluminum complexes ((R)pyNO(-))2AlCl ((R)pyNO(-) = N-tert-butyl-N-(2 pyridyl)nitroxyl; R = H (1), CH3 (2), CF3 (3)) were prepared in 80-98% yield through the protonolysis reaction between the pyridyl hydroxylamine ligand precursors (R)pyNOH and dimethylaluminum chloride. Complex 1 was also prepared using a salt metathesis route in 92% yield. Complexes 1-3 were characterized using (1)H and (13)C NMR spectroscopies. Single-crystal X-ray diffraction analysis of the complexes revealed that 1-3 are isostructural, with the Al(III) cation in all cases being five coordinate with distorted square pyramidal geometries. The geometry of complex 1 was studied using DFT, which showed primarily ligand-based frontier molecular orbitals. Reaction of 1 with NaOt-Bu gave (pyNO(-))2AlOt-Bu (4), while reaction of 1 with AgBPh4 gave [(pyNO( ))2Al(THF)2][BPh4] (5) in 54% and 87% yields, respectively. Compounds 4 and 5 were both characterized using (1)H and (13)C NMR spectroscopies and compound 5 by X-ray diffraction. Complexes 1-5 were also characterized by UV-vis electronic absorption spectroscopy and electrochemistry. The cyclic voltammograms of the complexes show two separate oxidation process, the potentials of which are dependent on both the substitution pattern of the (R)pyNO(-) ligands and the anion that completes the aluminum coordination sphere. A correlation was determined between the chemical shift of the t-Bu of the (R)pyNO(-) ligand in the (1)H NMR spectroscopy and the potentials of the redox events for complexes 1-4. PMID- 26513134 TI - Development, validation, and comparison of four methods to simultaneously quantify l-arginine, citrulline, and ornithine in human plasma using hydrophilic interaction liquid chromatography and electrospray tandem mass spectrometry. AB - To understand the role of l-arginine depletion in impaired nitric oxide synthesis in disease, it is important to simultaneously quantify arginine, citrulline, and ornithine in the plasma. Because the three amino acids are endogenous analytes, true blank matrix for them is not available. It is necessary and valuable to compare the performance of different approaches due to lack of regulatory clarity for validation. A two-step sample preparation method using methanol as protein precipitation reagent was developed in this study is used for sample preparation. Because true blank matrix for endogenous analytes is not available, water as blank matrix, 1% BSA in PBS as blank matrix, surrogate analyte, and background subtraction were designed to establish successful quantification methods. Four methods to simultaneously quantify arginine, citrulline, and ornithine in human plasma using hydrophilic interaction liquid chromatography and electrospray tandem mass spectrometry were developed, validated, and compared. The developed two-step sample preparation method using methanol as protein precipitation reagent in this study needs less time and provides higher recovery comparing with other approaches. Three of the four methods, water as blank matrix, 1% BSA in PBS as blank matrix, and surrogate analyte, have been successful in fulfilling all the criteria, while background subtraction has failed. Results of the measured concentrations in 97 human plasma samples using the three methods show that the difference between any two methods or among the three methods presents 100% of samples with less than 20% for all the three amino acids and majority of them are under 10%. The developed two-step sample preparation method using methanol as protein precipitation reagent is simple and convenient. Three of the four methods are fully validated and the validation is successful. The BSA functioned effectively as a blank matrix for these three amino acids, considering cost, data quality, matrix similarity, and practicality. PMID- 26513135 TI - Simultaneous determination of 70 pesticide residues in leek, leaf lettuce and garland chrysanthemum using modified QuEChERS method with multi-walled carbon nanotubes as reversed-dispersive solid-phase extraction materials. AB - Leek, leaf lettuce and garland chrysanthemum are troublesome vegetables containing large amount of pigments which may bring serious matrix interferences in mass spectrometry analysis. Multi-walled carbon nanotubes (MWCNTs) have a good effect for the cleanup of troublesome matrix. So the study was designed to develop a multi-residue method for the determination of 70 pesticide residues in leek, leaf lettuce and garland chrysanthemum based on a modified QuEChERS procedure using MWCNTs as reversed-dispersive solid phase extraction (r-DSPE) materials to remove the interferences of pigments. PSA and GCB were used as comparison. LC-MS/MS was used to identify and quantify the residue levels of multi-pesticides. The clean-up performance of MWCNTs was demonstrated to be obviously superior to GCB and PSA. This method was validated on leek, leaf lettuce and garland chrysanthemum spiked at the concentration of 10, 50 and 100MUgkg(-1) with five replicates. The recoveries of 70 pesticides ranged from 74% to 119%, with relative standard deviations (RSDs) lower than 14.2%. Good linearity (R(2)>=0.9903) was obtained at the range of 10-1000MUg/L for all pesticides in the selected matrices. The limit of quantification (LOQs) and limit of detection (LODs) of the 70 pesticides for the selected matrices ranged from 0.3 to 7.9MUgkg(-1) and from 0.1 to 2.4MUgkg(-1) respectively. The method was successfully applied to the routine monitoring of pesticide residues in market samples. PMID- 26513136 TI - Highly Transparent and Toughened Poly(methyl methacrylate) Nanocomposite Films Containing Networks of Cellulose Nanofibrils. AB - Cellulose nanofibrils (CNFs) are a class of cellulosic nanomaterials with high aspect ratios that can be extracted from various natural sources. Their highly crystalline structures provide the nanofibrils with excellent mechanical and thermal properties. The main challenges of CNFs in nanocomposite applications are associated with their high hydrophilicity, which makes CNFs incompatible with hydrophobic polymers. In this study, highly transparent and toughened poly(methyl methacrylate) (PMMA) nanocomposite films were prepared using various percentages of CNFs covered with surface carboxylic acid groups (CNF-COOH). The surface groups make the CNFs interfacial interaction with PMMA favorable, which facilitate the homogeneous dispersion of the hydrophilic nanofibrils in the hydrophobic polymer and the formation of a percolated network of nanofibrils. The controlled dispersion results in high transparency of the nanocomposites. Mechanical analysis of the resulting films demonstrated that a low percentage loading of CNF-COOH worked as effective reinforcing agents, yielding more ductile and therefore tougher films than the neat PMMA film. Toughening mechanisms were investigated through coarse-grained simulations, where the results demonstrated that a favorable polymer-nanofibril interface together with percolation of the nanofibrils, both facilitated through hydrogen bonding interactions, contributed to the toughness improvement in these nanocomposites. PMID- 26513137 TI - Potassium-Competitive Acid Blockers (P-CABs): Are They Finally Ready for Prime Time in Acid-Related Disease? AB - The need for new acid suppressing agents with improved pharmacology and superior antisecretory effects to address unmet clinical needs in acid-related disorders has been evident for over a decade. Recent new antisecretory drugs (IR-omeprazole and MR-dexlansoprazole) only provide a small incremental advance in control of acid secretion over the delayed-release proton pump inhibitors. Vonoprazan (a new potassium-competitive acid blocker) displays more potent and extended 24 h acid suppression and preliminary Japanese trials translate this into meaningful clinical benefits in gastro-esophageal reflux disease and Helicobacter pylori eradication. We review the vonoprazan information to date and the indications, benefits, and concerns of more effective therapeutic control of acid secretion. PMID- 26513138 TI - Skin Cancer Surveillance Behaviors Among Childhood Cancer Survivors. AB - The risk of developing skin cancer is elevated among childhood cancer survivors (CCS), particularly among those treated with radiation. This survey study examined the skin cancer surveillance behaviors of 94 CCS. Approximately 48% of CCS had ever conducted skin self-examination (SSE) and 31% had ever received a physician skin examination. Rates of physician skin examination were 2.5 times higher among CCS treated with radiation compared to those without radiation. However, rates of SSEs did not differ based on treatment history. These findings highlight the need to promote skin cancer surveillance as an important aspect of CCS survivorship care. PMID- 26513140 TI - Binary Crystallized Supramolecular Aerogels Derived from Host-Guest Inclusion Complexes. AB - Aerogels with low density and high porosity show outstanding properties such as large surface area and low thermal and acoustic conductivity. However, great challenges remain to convert hydrophilic polymer based hydrogels to corresponding aerogels. Here, we report a structurally new type of aerogels, supramolecular aerogels (SMAs), derived from supramolecular hydrogels formed by self-assembling of poly(ethylene glycol) and alpha-/gamma-cyclodextrin. The SMAs posses a characteristic binary crystallized nanosheet structure due to their supramolecular cross-linking nature, and their specific surface areas and nanosheet structures are tunable. Furthermore, we demonstrated application of the aerogels as solid-solid phase change materials with tunable latent heat, reversible melting-crystallization cycle while keeping the microstructure of the SMAs unchanged. PMID- 26513141 TI - A Neutron Diffraction Study of the Electrochemical Double Layer Capacitor Electrolyte Tetrapropylammonium Bromide in Acetonitrile. AB - Neutron diffraction with isotopic substitution has been used to characterize the bulk liquid structure of the technologically relevant electrolyte solution, 1 M tetrapropylammonium bromide (TPA Br) in acetonitrile (acn), and of pure deuterated acetonitrile. Empirical potential structure refinement modeling procedures have been used to extract detailed structural information about solvent-solvent, solvent-ion, and ion-ion correlations. Analysis of the refined data shows the expected local dipolar conformation of acn in the pure solvent. This short-range dipolar ordering is also present within the solutions of TPA Br in acn, and it affects how the solvent orders itself around the ions. The solvation numbers of the TPA cations and the bromide anions are deduced, 8 and 5, respectively, as are the orientations of the solvent molecules that surround the ions. Evidence for ion association is also presented, with nearly two-thirds of the ions in the system being in associated pairs or clusters. PMID- 26513142 TI - Fatty acids composition of human milk fed to small for gestational age infants. AB - OBJECTIVES: To test the null hypothesis that mothers of asymmetric small for gestational age (SGA) infants produce milk with fatty acids composition similar to that of lactating mothers of appropriate-for-gestational-age (AGA) infants. METHODS: We obtained human milk (HM) from 2 groups of lactating volunteers that gave birth to asymmetric SGA (study group) or AGA infants (control group). Each mother was asked to contribute by manual expression at least one of 3 samples: first 72 hours after labor (colostrum), day 2-7 postpartum (transitional milk) and 14 days post partum (mature milk). After lipid extraction using Folch's cold extraction procedure fatty acids were analyzed using gas chromatography. RESULTS: A total of 108 samples were obtained in 60 women. In univariate analysis, there were no significant differences in any of the fatty acids concentrations examined between groups. This remained true when timing of the sample (colostrum, transitional or mature milk) or gestational age were introduced as confounders in analysis of variance (general linear model). CONCLUSION: Fatty acid composition of human milk is not affected by whether or not the infant was fetal growth restricted. We suggest that mothers of SGA infants may be reassured about the fat quality of their milk. PMID- 26513143 TI - Prognostic Role of Tumor-Infiltrating Lymphocytes in Lung Cancer: a Meta Analysis. AB - BACKGROUND/AIMS: The role of Tumor-infiltrating lymphocytes (TILs) in the prognosis of patients with lung cancer is still controversial. We performed a meta-analysis to evaluate the prognostic role of TILs in lung cancer. METHODS: Studies were recruited by searching PubMed, Embase and the Cochrane Library and assessed by further quality evaluation. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to investigate the association between TIL subsets and lung cancer patients' outcome. RESULTS: A total of 29 articles including 8,600 patients were enrolled into the meta-analysis. Our results indicated that high level of CD8+ cells infiltration in tumor stroma (TS) or tumor nest (TN) was associated with better OS in lung cancer patients (HR = 0.76, 95% CI 0.62-0.93, P = 0.006; HR = 0.80, 95% CI 0.67-0.96; P = 0.018, respectively). Similar results could be also observed in CD3+ T cells infiltration. High CD4+ T lymphocytes infiltration in TS was explicitly accompanied by better OS (HR = 0.65, 95% CI 0.46-0.91; P = 0.013), rather than in TN. In contrast, high density of FOXP3+ T cells infiltration in TS showed a poor PFS (HR = 2.67, 95% CI, 1.74-4.08, P < 0.001). CONCLUSION: This meta-analysis clarified that high level of CD8+ and CD3+ T cells infiltration in TS or TN, and high CD4+ T lymphocytes infiltration in TS showed better OS in lung cancer patients, whereas high density of FOXP3+ T cells infiltration in TS could be recognized as a negative prognostic factor. PMID- 26513144 TI - Complete mitochondrial genome of the guava fruit fly, Bactrocera correcta (Diptera: Tephritidae). AB - Bactrocera correcta (Diptera: Tephritidae) is one of the most serious pest insects in south China and surrounding Southeast Asian countries. The family Tephritidae includes over 4257 species distributed worldwide, so the complete mitochondrial genome would be helpful for bio-identification, biogeography and phylogeny. The B. correcta genome consists of 15 936 bp. Annotation indicated that the structure and orientation of 13 protein-coding genes (PCGs), 22 tRNA and 2 rRNA sequences were typical of, and similar to, the ten closely related tephritid species. The nucleotide composition shows heavily biased toward As and Ts accounting 73.2% and exhibits a slightly positive AT skew, which is similar to other known tephritid species and other insects. The phylogenetic tree indicated the presence of three distinct families (Tephritidae, Muscidae, Drosophilidae) in Order Diptera. PMID- 26513145 TI - Tissue-Specific Regulation of Drosophila NF-x03BA;B Pathway Activation by Peptidoglycan Recognition Protein SC. AB - In Drosophila, peptidoglycan (PGN) is detected by PGN recognition proteins (PGRPs) that act as pattern recognition receptors. Some PGRPs such as PGRP-LB or PGRP-SCs are able to cleave PGN, therefore reducing the amount of immune elicitors and dampening immune deficiency (IMD) pathway activation. The precise role of PGRP-SC is less well defined because the PGRP-SC genes (PGRP-SC1a, PGRP SC1b and PGRP-SC2) lie very close on the chromosome and have been studied using a deletion encompassing the three genes. By generating PGRP-SC-specific mutants, we reevaluated the roles of PGRP-LB, PGRP-SC1 and PGRP-SC2, respectively, during immune responses. We showed that these genes are expressed in different gut domains and that they follow distinct transcriptional regulation. Loss-of function mutant analysis indicates that PGRP-LB is playing a major role in IMD pathway activation and bacterial load regulation in the gut, although PGRP-SCs are expressed at high levels in this organ. We also demonstrated that PGRP-SC2 is the main negative regulator of IMD pathway activation in the fat body. Accordingly, we showed that mutants for either PGRP-LB or PGRP-SC2 displayed a distinct susceptibility to bacteria depending on the infection route. Lastly, we demonstrated that PGRP-SC1 and PGRP-SC2 are required in vivo for full Toll pathway activation by Gram-positive bacteria. PMID- 26513146 TI - Low Goiter Rate Associated with Small Average Thyroid Volume in Schoolchildren after the Elimination of Iodine Deficiency Disorders. AB - BACKGROUND: After the implementation of the universal salt iodization (USI) program in 1996, seven cross-sectional school-based surveys have been conducted to monitor iodine deficiency disorders (IDD) among children in eastern China. OBJECTIVES: This study aimed to examine the correlation of total goiter rate (TGR) with average thyroid volume (Tvol) and urinary iodine concentration (UIC) in Jiangsu province after IDD elimination. DESIGN: Probability-proportional-to size sampling was applied to select 1,200 children aged 8-10 years old in 30 clusters for each survey in 1995, 1997, 1999, 2001, 2002, 2005, 2009 and 2011. We measured Tvol using ultrasonography in 8,314 children and measured UIC (4,767 subjects) and salt iodine (10,184 samples) using methods recommended by the World Health Organization. Tvol was used to calculate TGR based on the reference criteria specified for sex and body surface area (BSA). RESULTS: TGR decreased from 55.2% in 1997 to 1.0% in 2009, and geometric means of Tvol decreased from 3.63 mL to 1.33 mL, along with the UIC increasing from 83 MUg/L in 1995 to 407 MUg/L in 1999, then decreasing to 243 MUg/L in 2005, and then increasing to 345 MUg/L in 2011. In the low goiter population (TGR < 3.9%), TGR was positively associated with average Tvol (r = 0.99); UIC showed a non-linear association with average Tvol, and UIC > 300 MUg/L was associated with a smaller average Tvol in children. CONCLUSIONS: After IDD elimination in Jiangsu province in 2001, lower TGR was associated with smaller average Tvol. Average Tvol was more sensitive than TGR in detecting the fluctuation of UIC. A UIC of 300 MUg/L may be defined as a critical value for population level iodine status monitoring. PMID- 26513147 TI - The Risk Factors for Failure of an Upper Extremity Replantation: Is the Use of Cigarettes/Tobacco a Significant Factor? AB - BACKGROUND: The purpose of this study was to explore the potential risk factors associated with the failure of an upper extremity replantation with a focus on cigarette or tobacco use. PATIENTS AND METHODS: A cohort of 102 patients with 149 replants (6 extremities, 143 digits) and a mean age of 41 years (range 5 to 72 years) was enrolled in this study. The data collected included age, gender, tobacco/cigarettes use, trauma mechanism, underlying disease (e.g., hypertension (HTN), diabetes mellitus (DM), etc.), and vein graft use. An analysis with a multivariable regression was conducted to identify the risk factors of replant failure and their respective odds ratios (ORs). RESULTS: Multilevel generalized linear mixed models (GLMMs) with a binomial distribution and logit link showed that smoking did not increase the risk of replant failure (p = 0.234). In addition, the survival of replants was not affected by DM or HTN (p = 0.285 and 0.938, respectively). However, the replantation results were significantly affected by the age of the patients and the mechanism of injury. Patients older than 50 years and those with avulsion or crush injuries tended to have a higher risk of replant failure (OR = 2.29, 6.45, and 5.42, respectively; p = 0.047, 0.028, and 0.032, respectively). CONCLUSIONS: This study showed that the use of cigarettes/tobacco did not affect the replantation outcome. The main risks for replant failure included being older than 50 years and the trauma mechanism (avulsion or crush injuries). PMID- 26513148 TI - Functional Trait Changes, Productivity Shifts and Vegetation Stability in Mountain Grasslands during a Short-Term Warming. AB - Plant functional traits underlie vegetation responses to environmental changes such as global warming, and consequently influence ecosystem processes. While most of the existing studies focus on the effect of warming only on species diversity and productivity, we further investigated (i) how the structure of community plant functional traits in temperate grasslands respond to experimental warming, and (ii) whether species and functional diversity contribute to a greater stability of grasslands, in terms of vegetation composition and productivity. Intact vegetation turves were extracted from temperate subalpine grassland (highland) in the Eastern Pyrenees and transplanted into a warm continental, experimental site in Lleida, in Western Catalonia (lowland). The impacts of simulated warming on plant production and diversity, functional trait structure, and vegetation compositional stability were assessed. We observed an increase in biomass and a reduction in species and functional diversity under short-term warming. The functional structure of the grassland communities changed significantly, in terms of functional diversity and community-weighted means (CWM) for several traits. Acquisitive and fast-growing species with higher SLA, early flowering, erect growth habit, and rhizomatous strategy became dominant in the lowland. Productivity was significantly positively related to species, and to a lower extent, functional diversity, but productivity and stability after warming were more dependent on trait composition (CWM) than on diversity. The turves with more acquisitive species before warming changed less in composition after warming. Results suggest that (i) the short-term warming can lead to the dominance of acquisitive fast growing species over conservative species, thus reducing species richness, and (ii) the functional traits structure in grassland communities had a greater influence on the productivity and stability of the community under short-term warming, compared to diversity effects. In summary, short-term climate warming can greatly alter vegetation functional structure and its relation to productivity. PMID- 26513149 TI - Do We Need Surveillance Urethro-Cystoscopy in Patients with Neurogenic Lower Urinary Tract Dysfunction? AB - PURPOSE: To examine the value of surveillance urethro-cystoscopy in patients with neurogenic lower urinary tract dysfunction (NLUTD) in regard to the conflicting literature as it is generally agreed that patients with NLUTD are at increased risk for bladder cancer. MATERIALS AND METHODS: In a cross-sectional study, a consecutive series of 129 patients (50 females, 79 males, mean age 51, range 18 88) suffering from NLUTD for at least 5 years was prospectively investigated using urethro-cystoscopy and bladder washing cytology at a single university spinal cord injury (SCI) center. RESULTS: Due to suspicious urethro-cystoscopy and/or bladder washing cytology findings, 13 (10%) of 129 patients underwent transurethral resection of the bladder lesion and/or random bladder biopsies. Overall, 9 relevant histological findings were found in 5% (7/129) of our patients: bladder melanosis (n = 1), nephrogenic adenoma (n = 3), keratinizing squamous metaplasia (n = 1), intestinal metaplasia (n = 3), and muscle-invasive adenocarcinoma of the bladder (n = 1). CONCLUSIONS: Using surveillance urethro cystoscopy, we found relevant histological findings in 5% of our patients suffering from NLUTD for at least 5 years. Thus, surveillance urethro-cystoscopy might be warranted, although the ideal starting point and frequency remain to be determined in further prospective studies. PMID- 26513150 TI - Dendritic Pooling of Noisy Threshold Processes Can Explain Many Properties of a Collision-Sensitive Visual Neuron. AB - Power laws describe brain functions at many levels (from biophysics to psychophysics). It is therefore possible that they are generated by similar underlying mechanisms. Previously, the response properties of a collision sensitive neuron were reproduced by a model which used a power law for scaling its inhibitory input. A common characteristic of such neurons is that they integrate information across a large part of the visual field. Here we present a biophysically plausible model of collision-sensitive neurons with eta-like response properties, in which we assume that each information channel is noisy and has a response threshold. Then, an approximative power law is obtained as a result of pooling these channels. We show that with this mechanism one can successfully predict many response characteristics of the Lobula Giant Movement Detector Neuron (LGMD). Moreover, the results depend critically on noise in the inhibitory pathway, but they are fairly robust against noise in the excitatory pathway. PMID- 26513151 TI - Influence of Schistosoma mansoni and Hookworm Infection Intensities on Anaemia in Ugandan Villages. AB - BACKGROUND: The association of anaemia with intestinal schistosomiasis and hookworm infections are poorly explored in populations that are not limited to children or pregnant women. METHODS: We sampled 1,832 individuals aged 5-90 years from 30 communities in Mayuge District, Uganda. Demographic, village, and parasitological data were collected. Infection risk factors were compared in ordinal logistic regressions. Anaemia and infection intensities were analyzed in multilevel models, and population attributable fractions were estimated. FINDINGS: Household and village-level predictors of Schistosoma mansoni and hookworm were opposite in direction or significant for single infections. S. mansoni was found primarily in children, whereas hookworm was prevalent amongst the elderly. Anaemia was more prevalent in individuals with S. mansoni and increased by 2.86 fold (p-value<0.001) with heavy S. mansoni infection intensity. Individuals with heavy hookworm were 1.65 times (p-value = 0.008) more likely to have anaemia than uninfected participants. Amongst individuals with heavy S. mansoni infection intensity, 32.0% (p-value<0.001) of anaemia could be attributed to S. mansoni. For people with heavy hookworm infections, 23.7% (p-value = 0.002) of anaemia could be attributed to hookworm. A greater fraction of anaemia (24.9%, p-value = 0.002) was attributable to heavy hookworm infections in adults (excluding pregnant women) as opposed to heavy hookworm infections in school-aged children and pregnant women (20.2%, p-value = 0.001). CONCLUSION: Community-based surveys captured anaemia in children and adults affected by S. mansoni and hookworm infections. For areas endemic with schistosomiasis or hookworm infections, WHO guidelines should include adults for treatment in helminth control programmes. PMID- 26513152 TI - A Systematic Review of Waterborne Disease Outbreaks Associated with Small Non Community Drinking Water Systems in Canada and the United States. AB - BACKGROUND: Reports of outbreaks in Canada and the United States (U.S.) indicate that approximately 50% of all waterborne diseases occur in small non-community drinking water systems (SDWSs). Summarizing these investigations to identify the factors and conditions contributing to outbreaks is needed in order to help prevent future outbreaks. OBJECTIVES: The objectives of this study were to: 1) identify published reports of waterborne disease outbreaks involving SDWSs in Canada and the U.S. since 1970; 2) summarize reported factors contributing to outbreaks, including water system characteristics and events surrounding the outbreaks; and 3) identify terminology used to describe SDWSs in outbreak reports. METHODS: Three electronic databases and grey literature sources were searched for outbreak reports involving SDWSs throughout Canada and the U.S. from 1970 to 2014. Two reviewers independently screened and extracted data related to water system characteristics and outbreak events. The data were analyzed descriptively with 'outbreak' as the unit of analysis. RESULTS: From a total of 1,995 citations, we identified 50 relevant articles reporting 293 unique outbreaks. Failure of an existing water treatment system (22.7%) and lack of water treatment (20.2%) were the leading causes of waterborne outbreaks in SDWSs. A seasonal trend was observed with 51% of outbreaks occurring in summer months (p<0.001). There was large variation in terminology used to describe SDWSs, and a large number of variables were not reported, including water source and whether water treatment was used (missing in 31% and 66% of reports, respectively). CONCLUSIONS: More consistent reporting and descriptions of SDWSs in future outbreak reports are needed to understand the epidemiology of these outbreaks and to inform the development of targeted interventions for SDWSs. Additional monitoring of water systems that are used on a seasonal or infrequent basis would be worthwhile to inform future protection efforts. PMID- 26513153 TI - Eating Quality of Carrots (Daucus carota L.) Grown in One Conventional and Three Organic Cropping Systems over Three Years. AB - The eating quality of carrots (Daucus carota L.) was investigated to evaluate the impact of cropping systems (one conventional and three organic systems) and growing years (2007, 2008, and 2009) on root size, chemical composition, and sensory quality. The content of dry matter, sugars, polyacetylenes, and terpenes as well as the sensory quality and root size were related to the climate during the three growing years. A higher global radiation and a higher temperature sum in 2009 as compared to 2007 and 2008 resulted in larger roots, higher contents of dry matter, sucrose, total sugars, and total polyacetylenes, and lower contents of terpenes, fructose, and glucose. No differences were found between conventional and organic carrots with regard to the investigated parameters. This result shows that organically grown carrots have the same eating quality as conventionally grown carrots, while being produced in a more sustainable way. PMID- 26513154 TI - Syringe life and memory effects in isotopic analyses performed by liquid water isotopic analysers - a case study for natural waters from central Europe. AB - Syringes are the most expensive consumables for analyses in the Liquid Water Isotope Analyser using commercial Cavity Ring-Down Spectroscopy (CRDS) systems. Our experience shows that although the syringe life significantly varies, it is not an exception that a syringe performs many thousands of injections. A simple maintenance procedure consisting of replacing the syringes two times per day and keeping them in the deionised water resulted in an average syringe life of over 3500 injections. Number of injections per sample affects the between-sample memory effect and the cost of the analysis (duration, energy, consumption of syringes). We studied the influence of the number of injections (six and nine) on the final delta(18)O and delta(2)H values using two sets of samples covering the ranges of isotopic composition typical for the natural waters of the highest part of the Carpathians (streams, springs, soil water and precipitation). The differences in the final delta-values between nine and six injections were within 0.1 0/00 for delta(18)O and 1.0 0/00 for delta(2)H for the Picarro 2120i and 2130i CRDS systems. PMID- 26513155 TI - Dimensions of Horizontal Gene Transfer in Eukaryotic Microbial Pathogens. PMID- 26513156 TI - Protein and messenger RNA expression of interleukin 1 system members in bovine ovarian follicles and effects of interleukin 1beta on primordial follicle activation and survival in vitro. AB - This study aimed to investigate the expression of interleukin 1 (IL-1) system members (proteins and messenger RNA of ligands and receptors) and its distribution in ovarian follicles of cyclic cows and to evaluate the effects of IL-1beta on the survival and activation of primordial follicles in vitro. The ovaries were processed for localization of IL-1 system in preantral and antral follicles by immunohistochemical, real-time polymerase chain reaction, and Western blot analysis. For in vitro studies, ovarian fragments were cultured in alpha-MEM(+) supplemented with IL-1beta (0, 1, 10, 50, or 100 ng/mL), and after 6 d, the cultured tissues were processed for histologic analysis. Immunohistochemical results showed that the IL-1 system proteins IL-1beta, IL 1RA, IL-1RI, and IL-1RII were detected in the cytoplasm of oocytes and granulosa cells from all follicular categories and theca cells of antral follicles. Variable levels of messenger RNA for the IL-1 system members were observed at different stages of development. After 6 d of culture, the presence of IL-1beta (10 or 50 ng/mL) was effective in maintaining the percentage of normal follicles and in promoting primordial follicle activation. In conclusion, IL-1 system members are differentially expressed in ovarian follicles according to their stage of development. Moreover, IL-1beta promotes the development of primordial follicles. These results indicate an important role of the IL-1 system in the regulation of bovine folliculogenesis. PMID- 26513157 TI - MicroRNA-10b suppresses goat granulosa cell proliferation by targeting brain derived neurotropic factor. AB - Brain-derived neurotropic factor (BDNF) and its high-affinity receptor, tyrosine kinase receptor B, have been assumed to be involved in female reproduction and have recently shown to play an essential role in follicle activation and oocyte maturation. In this study, we analyzed the expression of miR-10b and BDNF in the ovary and discovered that the expression of miR-10b was higher in monotocous goat ovaries than in polytocous goat ovaries, whereas the expression pattern of BDNF in ovary was opposite. Moreover, human chorionic gonadotropin induced rapid and transient expression of BDNF messenger RNA and protein. In contrast, human chorionic gonadotropin upregulated miR-10b expression in a time-dependent manner. The BDNF gene was identified as a direct target of miR-10b using a dual luciferase reporter assay. Transfection of granulosa cells with miR-10b decreased BDNF messenger RNA and protein levels. MiR-10b overexpression inhibited cell proliferation, whereas BDNF promoted cell proliferation. However, a combined treatment with miR-10b and BDNF promoted cell proliferation, indicating that the reintroduction of BDNF reversed the suppressive effect of miR-10b. These results demonstrate that miR-10b downregulates BDNF expression in granulosa cells by directly targeting the 3' untranslated regions and plays an important role in inhibiting granulosa cell proliferation by targeting BDNF. PMID- 26513158 TI - The oxytocin-CD38-vitamin A axis in pregnant women involves both hypothalamic and placental regulation. AB - OBJECTIVE: Oxytocin, a hypothalamic hormone secreted upon release of ectoenzyme CD38, plays a vital role in interpersonal bonding behaviors. Reduced plasma oxytocin characterizes autistic individuals. CD38 levels, which were found to be low in LBCs derived from autistic patients, is upregulated upon the addition of a vitamin A derivative. During pregnancy, oxytocin is also secreted by placenta. Recent controversial studies have suggested an increased risk for autism when oxytocin is used during induction and augmentation of labor. We aimed to examine the tripartite relationship between oxytocin, CD38 and vitamin A in pregnant women and their newborns. METHODS: Thirty-one healthy expectant mothers were enlisted for this study. Levels of oxytocin, CD38 and ATRA were measured in both maternal peripheral and newborn cord blood, and the tripartite relationship between these parameters examined. Estrogen and progesterone levels of the mothers were also recorded. Several clinical measures were also noted. RESULTS: Mean maternal oxytocin and vitamin A levels were approximately 8- and 4-fold higher, respectively, than neonatal levels. CD38 expression, however, was 9 times higher in neonates than in the maternal group. Positive correlation was found between maternal and cord blood for both oxytocin and CD38. CONCLUSIONS: This establishment of normative values for oxytocin, CD38 and vitamin A in healthy pregnant women and newborns may serve as a reference in the investigation of developing pathologies of disorders such as autism. PMID- 26513159 TI - Annual Reproductive Cycle and Unusual Embryogenesis of a Temperate Coral in the Mediterranean Sea. AB - The variety of reproductive processes and modes among coral species reflects their extraordinary regeneration ability. Scleractinians are an established example of clonal animals that can exhibit a mixed strategy of sexual and asexual reproduction to maintain their populations. This study provides the first description of the annual reproductive cycle and embryogenesis of the temperate species Caryophyllia inornata. Cytometric analyses were used to define the annual development of germ cells and embryogenesis. The species was gonochoric with three times more male polyps than female. Polyps were sexually mature from 6 to 8 mm length. Not only females, but also sexually inactive individuals (without germ cells) and males were found to brood their embryos. Spermaries required 12 months to reach maturity, while oogenesis seemed to occur more rapidly (5-6 months). Female polyps were found only during spring and summer. Furthermore, the rate of gamete development in both females and males increased significantly from March to May and fertilization was estimated to occur from April to July, when mature germ cells disappeared. Gametogenesis showed a strong seasonal influence, while embryos were found throughout the year in males and in sexually inactive individuals without a defined trend. This unusual embryogenesis suggests the possibility of agamic reproduction, which combined with sexual reproduction results in high fertility. This mechanism is uncommon and only four other scleractinians (Pocillopora damicornis, Tubastraea diaphana, T. coccinea and Oulastrea crispata) have been shown to generate their broods asexually. The precise nature of this process is still unknown. PMID- 26513160 TI - Impact of Pregnancy-Related Deaths on Female Life Expectancy in Zambia: Application of Life Table Techniques to Census Data. AB - INTRODUCTION: Since 2000, the world has been coalesced around efforts to reduce maternal mortality. However, few studies have estimated the significance of eliminating maternal deaths on female life expectancy. We estimated, based on census data, the potential gains in female life expectancy assuming complete elimination of pregnancy-related mortality in Zambia. METHODS: We used data on all-cause and pregnancy-related deaths of females aged 15-49 reported in the Zambia 2010 census, and evaluated, adjusted and smoothed them using existing and verified techniques. We used associated single decrement life tables, assuming complete elimination of pregnancy-related deaths to estimate the potential gains in female life expectancy at birth, at age 15, and over the ages 15-49. We compared these gains with the gains from eliminating deaths from accidents, injury, violence and suicide. RESULTS: Complete elimination of pregnancy-related deaths would extend life expectancy at birth among Zambian women by 1.35 years and life expectancy at age 15 by 1.65 years. In rural areas, this would be 1.69 years and 2.19 years, respectively, and in urban areas, 0.78 years and 0.85 years. An additional 0.72 years would be spent in the reproductive age group 15 49; 1.00 years in rural areas and 0.35 years in urban areas. Eliminating deaths from accidents, injury, suicide and violence among women aged 15-49 would cumulatively contribute 0.55 years to female life expectancy at birth. CONCLUSION: Eliminating pregnancy-related mortality would extend female life expectancy in Zambia substantially, with more gains among adolescents and females in rural areas. The application of life table techniques to census data proved very valuable, although rigorous evaluation and adjustment of reported deaths and age was necessary to attain plausible estimates. The collection of detailed high quality cause-specific mortality data in future censuses is indispensable. PMID- 26513161 TI - One-Carbon Metabolic Factors and Risk of Renal Cell Cancer: A Meta-Analysis. AB - BACKGROUND: Nutrients related to one-carbon metabolism were previously shown to be significantly associated with the risk of cancer. The aim of this meta analysis was to evaluate potential relationships between one-carbon metabolic factors and renal cell cancer (RCC) risk. METHODS: PubMed, EMBASE, and Cochrane Library databases were searched through March 2015 for observational studies of quantitative RCC risk estimates in relation to one-carbon metabolic factors. The relative risks (RRs) with 95% confidence intervals (CIs) measured the relationship between one-carbon metabolic factors and RCC risk using a random effects model. RESULTS: Of the 463 citations and abstracts identified by database search, seven cohorts from five observational studies reported data on 133,995 individuals, and included 2,441 RCC cases. Comparing the highest with the lowest category, the pooled RRs of RCC were 0.72 (95%CI: 0.52-1.00; P = 0.048) for vitamin B12. In addition, an increase in folic acid supplementation of 100 MUg/day was associated with a 3% lower risk of RCC (RR, 0.97; 95%CI: 0.93-1.00; P = 0.048). Similarly, an increase of 5 nmol/L of vitamin B2 was associated with a reduced risk of RCC 0.94 (95%CI: 0.89-1.00; P = 0.045). Sensitivity analyses suggested that a higher serum vitamin B6 might contribute to a reduced risk of RCC (RR, 0.83; 95%CI: 0.77-0.89; P < 0.001). CONCLUSIONS: Higher levels of serum vitamin B2, B6, B12, and folic acid supplementation lowered the risk of RCC among the study participants. PMID- 26513162 TI - Erratum: Electric-field control of magnetic moment in Pd. PMID- 26513163 TI - Analysis of the Complete Chloroplast Genome of a Medicinal Plant, Dianthus superbus var. longicalyncinus, from a Comparative Genomics Perspective. AB - Dianthus superbus var. longicalycinus is an economically important traditional Chinese medicinal plant that is also used for ornamental purposes. In this study, D. superbus was compared to its closely related family of Caryophyllaceae chloroplast (cp) genomes such as Lychnis chalcedonica and Spinacia oleracea. D. superbus had the longest large single copy (LSC) region (82,805 bp), with some variations in the inverted repeat region A (IRA)/LSC regions. The IRs underwent both expansion and constriction during evolution of the Caryophyllaceae family; however, intense variations were not identified. The pseudogene ribosomal protein subunit S19 (rps19) was identified at the IRA/LSC junction, but was not present in the cp genome of other Caryophyllaceae family members. The translation initiation factor IF-1 (infA) and ribosomal protein subunit L23 (rpl23) genes were absent from the Dianthus cp genome. When the cp genome of Dianthus was compared with 31 other angiosperm lineages, the infA gene was found to have been lost in most members of rosids, solanales of asterids and Lychnis of Caryophyllales, whereas rpl23 gene loss or pseudogization had occurred exclusively in Caryophyllales. Nevertheless, the cp genome of Dianthus and Spinacia has two introns in the proteolytic subunit of ATP-dependent protease (clpP) gene, but Lychnis has lost introns from the clpP gene. Furthermore, phylogenetic analysis of individual protein-coding genes infA and rpl23 revealed that gene loss or pseudogenization occurred independently in the cp genome of Dianthus. Molecular phylogenetic analysis also demonstrated a sister relationship between Dianthus and Lychnis based on 78 protein-coding sequences. The results presented herein will contribute to studies of the evolution, molecular biology and genetic engineering of the medicinal and ornamental plant, D. superbus var. longicalycinus. PMID- 26513164 TI - Progress and challenges in improving the nutritional quality of rice (Oryza sativa L.). AB - Rice is a staple food for more than 3 billion people in more than 100 countries of the world but ironically it is deficient in many bioavailable vitamins, minerals, essential amino- and fatty-acids and phytochemicals that prevent chronic diseases like type 2 diabetes, heart disease, cancers, and obesity. To enhance the nutritional and other quality aspects of rice, a better understanding of the regulation of the processes involved in the synthesis, uptake, transport, and metabolism of macro-(starch, seed storage protein and lipid) and micronutrients (vitamins, minerals and phytochemicals) is required. With the publication of high quality genomic sequence of rice, significant progress has been made in identification, isolation, and characterization of novel genes and their regulation for the nutritional and quality enhancement of rice. During the last decade, numerous efforts have been made to refine the nutritional and other quality traits either by using the traditional breeding with high through put technologies such as marker assisted selection and breeding, or by adopting the transgenic approach. A significant improvement in vitamins (A, folate, and E), mineral (iron), essential amino acid (lysine), and flavonoids levels has been achieved in the edible part of rice, i.e., endosperm (biofortification) to meet the daily dietary allowance. However, studies on bioavailability and allergenicity on biofortified rice are still required. Despite the numerous efforts, the commercialization of biofortified rice has not yet been achieved. The present review summarizes the progress and challenges of genetic engineering and/or metabolic engineering technologies to improve rice grain quality, and presents the future prospects in developing nutrient dense rice to save the everincreasing population, that depends solely on rice as the staple food, from widespread nutritional deficiencies. PMID- 26513165 TI - Molecular characterization of human thyroid hormone receptor beta isoform 4. AB - Thyroid hormone exerts a pleiotropic effect on development, differentiation, and metabolism through thyroid hormone receptor (TR). A novel thyroid hormone receptor beta isoform (TRbeta4) was cloned using PCR from a human pituitary cDNA library as a template. We report here the characterization of TRbeta4 from a molecular basis. Temporal expression of TRbeta4 during the fetal period is abundant in the brain and kidney, comparable with the adult pattern. Western blot analysis revealed that TRs are ubiquitination labile proteins, while TRbeta1 is potentially stable. TRbeta1, peroxisome proliferator-activated receptors (PPAR), and vitamin D receptor (VDR), which belong to class II transcription factors that function via the formation of heterodimeric complexes with retinoid X receptor (RXR), were suppressed by TRbeta4 in a dose-dependent manner. Thus, TRbeta4 exhibits ligand-independent transcriptional silencing, possibly as a substitute for dimerized RXR. In this study, TRbeta1 and TRbeta4 transcripts were detected in several cell lines. Quantitative RT-PCR assay showed that the expression of TRbeta4 in human embryonic carcinoma cells of the testis was suppressed by sex hormone in a reciprocal manner to TRbeta1. In contrast, TRbeta4 was expressed under a high dose of triiodothyronine (T3) in a reciprocal manner to TRbeta1. Finally, in transiently transfected NIH-3T3 cells, green fluorescence protein (GFP)-tagged TRbeta4 was mostly nuclear in both the absence and the presence of T3. By mutating defined regions of both TRbetas, we found that both TRbeta1 and TRbeta4 had altered nuclear/cytoplasmic distribution as compared with wild-type, and different to T3 and the nuclear receptor corepressor (NCoR). Thus, site specific DNA binding is not essential for maintaining TRbetas within the nucleus. PMID- 26513166 TI - Development of indirect competitive ELISA using egg yolk-derived immunoglobulin (IgY) for the detection of Gentamicin residues. AB - Gentamicin (Gent) is an aminoglycoside antibiotic being used in livestock sector. Gent residues could cause some genetic disorders by nonsense mutations. This study aimed to develop IgY-based ELISA for the detection of Gent in animal products. Gent was conjugated with Bovine serum albumin (BSA) by carbodiimide method for further immunization in the laying chickens. PEG-6000 extraction method was employed to extract IgY from the egg yolk. The titer of anti-Gent-IgY attained the peak of 1:256,000 after the 5(th) booster immunization. Checkerboard titration confirmed that, anti-Gent IgY in 1:2,000 dilution could give an Optical Density (OD) 1.0 at 2 ug mL(-1) of Gent-OVA coating concentration. IgY-based indirect competitive ELISA (Ic-ELISA) showed that, the IC50 value of anti-Gent IgY was 2.69 ng mL(-1) and regression curve equation was y = -16.27x + 56.97 (R(2) = 0.95, n = 3), confirming that, the detection limit (LOD, IC10 value) was 0.01 ng mL(-1). Recoveries from fresh milk, pork and chicken samples were ranged from 69.82% to 94.32%, with relative standard deviation lower than 10.88%. Our results suggested that generated anti-Gent IgY antibodies can be used in routine screening analysis of Gent residues in food samples. PMID- 26513167 TI - Approach to the pediatric athlete with back pain: more than just the pars. AB - Back pain in a pediatric patient can present a worrisome and challenging diagnostic dilemma for any physician. Although most back pain can be attributed to muscle strains and poor mechanics, it is necessary to appreciate the full differential of etiologies causing back pain in the pediatric population. The physician must recognize areas of mechanical weakness in the skeletally immature spine and the sport specific forces that can predispose a patient to injury. A comprehensive history involves determining the onset, chronicity, and location of the pain. A focused physical exam includes a neurological exam as well as provocative testing. The combination of a thorough history and focused physical exam should guide appropriate imaging. Radiographic tests are instrumental in narrowing the differential, making a diagnosis, and uncovering associated pathology. Treatment modalities such as activity modification, heat/cold compresses, and NSAIDs can provide pain relief and allow for effective physical therapy. In most cases nonoperative methods are successful in providing a safe and quick return to activities. Failure of conservative measures requires referral to an orthopedic surgeon, as surgical intervention may be warranted. PMID- 26513168 TI - Current Therapy and New Directions in the Treatment of Hairy Cell Leukemia: A Review. AB - Hairy cell leukemia (HCL) is a chronic B-cell leukemia noted for an indolent course that ultimately results in cytopenias and massive splenomegaly. Whereas treatment with the nucleoside purine analogues cladribine and pentostatin results in lengthy remissions in nearly all patients with HCL, most patients will experience relapse while a small percentage of patients' disease fails to respond to therapy in the first place. Retreatment with a purine nucleoside analogue often leads to an effective but limited response. For decades, few other viable therapeutic options were available to these patients who required retreatment. Recently, new insights into the mechanism of disease of HCL have led to research in new potential treatment agents, either alone or with a purine nucleoside analogue. Clinical trials with rituximab, bendamustine, and conjugate immunotoxins will reveal what role these therapies will have in HCL treatment. A better understanding of the BRAF/MEK/ERK pathway and the B-cell signaling pathway has allowed further exploration into the novel drugs vemurafenib, dabrafenib, trametinib, and ibrutinib. PMID- 26513169 TI - Event-related potentials reveal the relations between feature representations at different levels of abstraction. AB - In this paper, we use behavioural methods and event-related potentials (ERPs) to explore the relations between informational and instantiated features, as well as the relation between feature abstraction and rule type. Participants are trained to categorize two species of fictitious animals and then identify perceptually novel exemplars. Critically, two groups are given a perfectly predictive counting rule that, according to Hannah and Brooks (2009. Featuring familiarity: How a familiar feature instantiation influences categorization. Canadian Journal of Experimental Psychology/Revue Canadienne de Psychologie Experimentale, 63, 263 275. Retrieved from http://doi.org/10.1037/a0017919), should orient them to using abstract informational features when categorizing the novel transfer items. A third group is taught a feature list rule, which should orient them to using detailed instantiated features. One counting-rule group were taught their rule before any exposure to the actual stimuli, and the other immediately after training, having learned the instantiations first. The feature-list group were also taught their rule after training. The ERP results suggest that at test, the two counting-rule groups processed items differently, despite their identical rule. This not only supports the distinction that informational and instantiated features are qualitatively different feature representations, but also implies that rules can readily operate over concrete inputs, in contradiction to traditional approaches that assume that rules necessarily act on abstract inputs. PMID- 26513170 TI - NOX5-L can stimulate proliferation and apoptosis depending on its levels and cellular context, determining cancer cell susceptibility to cisplatin. AB - The NADPH oxidase, NOX5, is known to stimulate cell proliferation in some cancers by generating reactive oxygen species (ROS). We show here that the long form of NOX5 (NOX5-L) also promotes cell death, and thus determines the balance of proliferation and death, in skin, breast and lung cancer cells. Moderate expression of NOX5-L induced cell proliferation accompanied by AKT and ERK phosphorylation, whereas an increase in NOX5-L above a certain threshold promoted cancer cell death accompanied by caspase-3 activation. Notably, cisplatin treatment increased NOX5-L levels through CREB activation and enhanced NOX5-L activity through augmentation of Ca2+ release and c-Abl expression, ultimately triggering ROS-mediated cancer cell death-a distinct pathway absent in normal cells. These results indicate that NOX5-L determines cellular responses in a concentration- and context-dependent manner. PMID- 26513171 TI - Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline. AB - Cabergoline (CAB), the first-line drug for treatment of prolactinomas, is effective in suppressing prolactin hypersecretion, reducing tumor size, and restoring gonadal function. However, mechanisms for CAB-mediated tumor shrinkage are largely unknown. Here we report a novel cytotoxic mechanism for CAB. CAB induced formation of autophagosome in rat pituitary tumor MMQ and GH3 cells at the early stage through inhibiting mTOR pathway, resulting in higher conversion rates of LC3-I to LC3-II, GFP-LC3 aggregation, and increased autophagosome formation. Interestingly, CAB treatment augmented lysosome acidification and resulted in impaired proteolytic degradation within autolysosomes. This blocked the autophagic flux, leading to the accumulation of p62 aggregation and undigested autolysosomes. Knockdown of ATG7, ATG5, or Becn1, could significantly rescue the CAB-mediated cell death of MMQ cells (p < 0.05). CAB-induced autophagy and blockade of autophagy flux participated in antitumoral action in vivo. In conclusion, our study provides evidence that CAB concomitantly induces autophagy and inhibits the autophagic flux, leading to autophagy-dependent cell death. These findings elucidate novel mechanisms for CAB action. PMID- 26513172 TI - Celecoxib increases lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1. AB - The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Using lung cancer cell lines (A549, H460) and metastatic cells derived from a lung cancer patient, the present study investigates the impact of celecoxib on the expression of intercellular adhesion molecule 1 (ICAM-1) and cancer cell lysis by lymphokine-activated killer (LAK) cells. Celecoxib, but not other structurally related selective COX-2 inhibitors (i.e., etoricoxib, rofecoxib, valdecoxib), was found to cause a substantial upregulation of ICAM-1 protein levels. Likewise, ICAM-1 mRNA expression was increased by celecoxib. Celecoxib enhanced the susceptibility of cancer cells to be lysed by LAK cells with the respective effect being reversed by a neutralizing ICAM-1 antibody. In addition, enhanced killing of celecoxib-treated cancer cells was reversed by preincubation of LAK cells with an antibody to lymphocyte function associated antigen 1 (LFA-1), suggesting intercellular ICAM-1/LFA-1 crosslink as crucial event within this process. Finally, celecoxib elicited no significant increase of LAK cell-mediated lysis of non-tumor bronchial epithelial cells, BEAS-2B, associated with a far less ICAM-1 induction as compared to cancer cells. Altogether, our data demonstrate celecoxib-induced upregulation of ICAM-1 on lung cancer cells to be responsible for intercellular ICAM-1/LFA-1 crosslink that confers increased cancer cell lysis by LAK cells. These findings provide proof for a novel antitumorigenic mechanism of celecoxib. PMID- 26513173 TI - Depletion of the thiol oxidoreductase ERp57 in tumor cells inhibits proliferation and increases sensitivity to ionizing radiation and chemotherapeutics. AB - Rapidly growing tumor cells must synthesize proteins at a high rate and therefore depend on an efficient folding and quality control system for nascent secretory proteins in the endoplasmic reticulum (ER). The ER resident thiol oxidoreductase ERp57 plays an important role in disulfide bond formation. Lentiviral, doxycycline-inducible ERp57 knockdown was combined with irradiation and treatment with chemotherapeutic agents. The knockdown of ERp57 significantly enhanced the apoptotic response to anticancer treatment in HCT116 colon cancer cells via a p53 dependent mechanism. Instead of a direct interaction with p53, depletion of ERp57 induced cell death via a selective activation of the PERK branch of the Unfolded Protein Response (UPR). In contrast, apoptosis was reduced in MDA-MB-231 breast cancer cells harboring mutant p53. Nevertheless, we observed a strong reduction of proliferation in response to ERp57 knockdown in both cell lines regardless of the p53 status. Depletion of ERp57 reduced the phosphorylation activity of the mTOR-complex1 (mTORC1) as demonstrated by reduction of p70S6K phosphorylation. Our data demonstrate that ERp57 is a promising target for anticancer therapy due to synergistic p53-dependent induction of apoptosis and p53-independent inhibition of proliferation. PMID- 26513174 TI - MDP, a database linking drug response data to genomic information, identifies dasatinib and statins as a combinatorial strategy to inhibit YAP/TAZ in cancer cells. AB - Targeted anticancer therapies represent the most effective pharmacological strategies in terms of clinical responses. In this context, genetic alteration of several oncogenes represents an optimal predictor of response to targeted therapy. Integration of large-scale molecular and pharmacological data from cancer cell lines promises to be effective in the discovery of new genetic markers of drug sensitivity and of clinically relevant anticancer compounds. To define novel pharmacogenomic dependencies in cancer, we created the Mutations and Drugs Portal (MDP, http://mdp.unimore.it), a web accessible database that combines the cell-based NCI60 screening of more than 50,000 compounds with genomic data extracted from the Cancer Cell Line Encyclopedia and the NCI60 DTP projects. MDP can be queried for drugs active in cancer cell lines carrying mutations in specific cancer genes or for genetic markers associated to sensitivity or resistance to a given compound. As proof of performance, we interrogated MDP to identify both known and novel pharmacogenomics associations and unveiled an unpredicted combination of two FDA-approved compounds, namely statins and Dasatinib, as an effective strategy to potently inhibit YAP/TAZ in cancer cells. PMID- 26513175 TI - The role of font size and font style in younger and older adults' predicted and actual recall performance. AB - We examined how font sizes (18pt., 48 pt.) and font styles (regular, italic, bold) influenced younger and older adults' judgments of learning (JOLs) and recall. In Experiment 1 younger adults gave higher JOLs and obtained higher recall than older adults. However, JOLs and recall varied for both age groups as a function of font size and font style manipulations despite a tendency for both groups to predict higher recall for items in large and in regular and italic styles than for small and bold fonts and achieve higher recall for regular than italic or bold items. No age differences were found in relative accuracy, with near-perfect calibration in absolute accuracy for younger and older adults. Experiment 2 presented a description of Experiment 1 and asked participants to predict recall for the various font size/style combinations. Younger and older adults predicted higher recall for large than small font items, regardless of font style, and higher recall for bold than regular or italic styles, regardless of font size. Memory predictions did not align across experiments, suggesting that memory beliefs combine with processing fluency to affect JOLs and recall. PMID- 26513176 TI - Quantitative imaging of protein targets in the human brain with PET. AB - PET imaging of proteins in the human brain with high affinity radiolabelled molecules has a history stretching back over 30 years. During this period the portfolio of protein targets that can be imaged has increased significantly through successes in radioligand discovery and development. This portfolio now spans six major categories of proteins; G-protein coupled receptors, membrane transporters, ligand gated ion channels, enzymes, misfolded proteins and tryptophan-rich sensory proteins. In parallel to these achievements in radiochemical sciences there have also been significant advances in the quantitative analysis and interpretation of the imaging data including the development of methods for image registration, image segmentation, tracer compartmental modeling, reference tissue kinetic analysis and partial volume correction. In this review, we analyze the activity of the field around each of the protein targets in order to give a perspective on the historical focus and the possible future trajectory of the field. The important neurobiology and pharmacology is introduced for each of the six protein classes and we present established radioligands for each that have successfully transitioned to quantitative imaging in humans. We present a standard quantitative analysis workflow for these radioligands which takes the dynamic PET data, associated blood and anatomical MRI data as the inputs to a series of image processing and bio-mathematical modeling steps before outputting the outcome measure of interest on either a regional or parametric image basis. The quantitative outcome measures are then used in a range of different imaging studies including tracer discovery and development studies, cross sectional studies, classification studies, intervention studies and longitudinal studies. Finally we consider some of the confounds, challenges and subtleties that arise in practice when trying to quantify and interpret PET neuroimaging data including motion artifacts, partial volume effects, age effects, image registration and normalization, input functions and metabolites, parametric imaging, receptor internalization and genetic factors. PMID- 26513177 TI - LASSBio-579, a prototype antipsychotic drug, and clozapine are effective in novel object recognition task, a recognition memory model. AB - Previous studies on the N-phenylpiperazine derivative LASSBio-579 have suggested that LASSBio-579 has an atypical antipsychotic profile. It binds to D2, D4 and 5 HT1A receptors and is effective in animal models of schizophrenia symptoms (prepulse inhibition disruption, apomorphine-induced climbing and amphetamine induced stereotypy). In the current study, we evaluated the effect of LASSBio 579, clozapine (atypical antipsychotic) and haloperidol (typical antipsychotic) in the novel object recognition task, a recognition memory model with translational value. Haloperidol (0.01 mg/kg, orally) impaired the ability of the animals (CF1 mice) to recognize the novel object on short-term and long-term memory tasks, whereas LASSBio-579 (5 mg/kg, orally) and clozapine (1 mg/kg, orally) did not. In another set of experiments, animals previously treated with ketamine (10 mg/kg, intraperitoneally) or vehicle (saline 1 ml/100 g, intraperitoneally) received LASSBio-579, clozapine or haloperidol at different time-points: 1 h before training (encoding/consolidation); immediately after training (consolidation); or 1 h before long-term memory testing (retrieval). LASSBio-579 and clozapine protected against the long-term memory impairment induced by ketamine when administered at the stages of encoding, consolidation and retrieval of memory. These findings point to the potential of LASSBio-579 for treating cognitive symptoms of schizophrenia and other disorders. PMID- 26513197 TI - What can we learn about dementia from research in Indigenous populations? PMID- 26513198 TI - Au13-nAgn clusters: a remarkably simple trend. AB - The planar to three dimensional transition of Au13-nAgn clusters is investigated. To do so the low lying energy configurations for all possible concentrations (n values) are evaluated. Many thousands of possible conformations are examined. They are generated using the procedure developed by Rogan et al. in combination with the semi-empirical Gupta potential. A large fraction of these (the low lying energy ones) are minimized by means of Density Functional Theory (DFT) calculations. We employ the Tao, Perdew, Staroverov, and Scuseria (TPSS) meta-GGA functional and the Perdew, Burke and Ernzerhof (PBE) GGA functional, and compare their results. The effect of spin-orbit coupling is studied as well as the s-d hybridization. As usual in this context the results are functional-dependent. However, both functionals lead to agreement as far as trends are concerned, yielding just two relevant motifs, but their results differ quantitatively. PMID- 26513199 TI - Determination of pressure drop across activated carbon fiber respirator cartridges. AB - Activated carbon fiber (ACF) is considered as an alternative adsorbent to granular activated carbon (GAC) for the development of thinner, lighter, and efficient respirators because of their larger surface area and adsorption capacities, thinner critical bed depth, lighter weight, and fabric form. This study aims to measure the pressure drop across different types of commercially available ACFs in respirator cartridges to determine the ACF composition and density that will result in acceptably breathable respirators. Seven ACF types in cloth (ACFC) and felt (ACFF) forms were tested. ACFs in cartridges were challenged with pre-conditioned constant air flow (43 LPM, 23 degrees C, 50% RH) at different compositions (single- or combination-ACF type) in a test chamber. Pressure drop across ACF cartridges were obtained using a micromanometer, and compared among different cartridge configurations, to those of the GAC cartridge, and to the NIOSH breathing resistance requirements for respirator cartridges. Single-ACF type cartridges filled with any ACFF had pressure drop measurements (23.71-39.93 mmH2O) within the NIOSH inhalation resistance requirement of 40 mmH2O, while those of the ACFC cartridges (85.47+/-3.67 mmH2O) exceeded twice the limit due possibly to the denser weaving of ACFC fibers. All single ACFF-type cartridges had higher pressure drop compared to the GAC cartridge (23.13+/-1.14 mmH2O). Certain ACF combinations (2 ACFF or ACFC/ACFF types) resulted to pressure drop (26.39-32.81 mmH2O) below the NIOSH limit. All single-ACFF type and all combination-ACF type cartridges with acceptable pressure drop had much lower adsorbent weights than GAC (<=15.2% of GAC weight), showing potential for light weight respirator cartridges. 100% ACFC in cartridges may result to respirators with high breathing resistance and, thus, is not recommended. The more dense ACFF and ACFC types may still be possibly used in respirators by combining them with less dense ACFF materials and/or by reducing cartridge bed depth to reduce pressure drop to acceptable levels. ACFF by itself may be more appropriate as adsorbent materials in ACF respirator cartridges in terms of acceptable breathing resistance. PMID- 26513200 TI - Dendritic cell targeted vaccines: Recent progresses and challenges. AB - Dendritic cells (DCs) are known to be a set of morphology, structure and function of heterogeneous professional antigen presenting cells (APCs), as well as the strongest functional antigen presenting cells, which can absorb, process and present antigens. As the key regulators of innate and adaptive immune responses, DCs are at the center of the immune system and capable of interacting with both B cells and T cells, thereby manipulating the humoral and cellular immune responses. DCs provide an essential link between the innate and adaptive immunity, and the strong immune activation function of DCs and their properties of natural adjuvants, make them a valuable target for antigen delivery. Targeting antigens to DC-specific endocytic receptors in combination with the relevant antibodies or ligands along with immunostimulatory adjuvants has been recently recognized as a promising strategy for designing an effective vaccine that elicits a strong and durable T cell response against intracellular pathogens and cancer. This opinion article provides a brief summary of the rationales, superiorities and challenges of existing DC-targeting approaches. PMID- 26513201 TI - Compliance with recommendations made in a multidisciplinary ALS clinic. AB - Multidisciplinary ALS clinics provide recommendations at each visit, but these do little good unless recalled and followed. This study was conducted to determine recall of, and compliance with, these recommendations, and to study factors affecting compliance. Patients were contacted by telephone six weeks after their ALS clinic visit and asked about recommendations made by the multidisciplinary team. Themes for recall and compliance were generated by three coders using qualitative analysis, and validated using triangulation and consensual validation. Pearson correlation coefficients were calculated for the relationship of function and quality of life to recommendation categories. Results demonstrated that most recommendations centered around physical needs, whereas few were provided for Caregiver Support and Mental Health. Fewer than 40% of all recommendations were recalled, with the highest category being Physical Function. Compliance was highest for this category as well (mean 4.27/5). Monitoring of patients between clinic visits appeared to enhance compliance. In conclusion, for ALS clinic teams seeking to maximize the impact of recommendations, discussions to facilitate understanding, instruction in problem-solving skills, and closer follow-up between clinic visits should facilitate better recall and compliance, and thus improve care. The potential benefits of greater emphasis on mental health and caregiver well-being should be explored. PMID- 26513202 TI - A randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of venlafaxine extended release and a long-term extension study for patients with major depressive disorder in Japan. AB - The aim of this study was to assess antidepressant efficacy and safety of venlafaxine extended release in Japanese patients with major depressive disorder (MDD). We carried out a double-blinded, placebo-controlled, randomized study using fixed (75 mg/day) and flexible (75-225 mg/day, most patients attained to 225 mg/day) doses, followed by the long-term, open-labeled, extension study. Outpatients aged at least 20 years diagnosed with MDD were included. The primary efficacy measure was change from baseline in the Hamilton Rating Scale for Depression (HAM-D17) score at week 8; secondary efficacy measures included the Montgomery-Asberg Depression Rating Scale, the Quick Inventory of Depressive Symptomatology self-report version, HAM-D6, and Clinical Global Impression scales in the double-blinded study. Overall, 538 patients were randomized; significant differences were observed in the primary efficacy variable in the fixed-dose group (-10.76; P=0.031), but not in the flexible-dose (-10.37; P=0.106) group compared with placebo (-9.25). However, the flexible-dose group showed significant efficacy in several secondary measures. Treatment-related adverse events in the treatment period were 51.7 and 67.8% in the fixed-dose and flexible dose groups, respectively, versus 38.8% with placebo. Throughout the study period, no Japanese-specific adverse events were observed. Thus, venlafaxine extended release was efficacious and safe for MDD treatment in Japan. PMID- 26513204 TI - A novel PDE1A coupled to M2AChR at plasma membranes from bovine tracheal smooth muscle. AB - Muscarinic antagonists, via muscarinic receptors increase the cAMP/cGMP levels at bovine tracheal smooth muscle (BTSM) through the inhibition of phosphodiesterases (PDEs), displaying a similar behavior of vinpocetine (a specific-PDE1 inhibitor). The presence of PDE1 hydrolyzing both cyclic nucleotides in BTSM strips was revealed. Moreover, a vinpocetine and muscarinic antagonists inhibited PDE1 located at plasma membranes (PM) fractions from BTSM showing such inhibition, an M(2)AChR pharmacological profile. Therefore, a novel Ca(2+)/CaM dependent and vinpocetine inhibited PDE1 was purified and characterized at PM fractions from BTSM. This PDE1 activity was removed from PM fractions using a hypotonic buffer and purified some 38 fold using two columns (Q-Sepharose and CaM-agarose). This PDE1 was stimulated by CaM and inhibited by vinpocetine showing two bands in PAGE SDS (56, 58 kDa) being the 58 kDa identified as PDE1A by Western blotts. This PDE1A activity was assayed with [(3)H]cGMP and [(3)H]cAMP exhibiting a higher affinity as Km (MUM) for cGMP than cAMP but being close values with V(max) cAMP/cGMP ratio of 1.5. The co-factor Mg(2+) showed similar K(A) (mM) for both cyclic nucleotides. Vinpocetine showed similar inhibition concentration 50% (IC(50) of 4.9 and 4.6 MUM) for cAMP and cGMP, respectively. CaM stimulated the cyclic nucleotides hydrolysis by PDE1A exhibiting similar activation constant as K(CaM), in nM range. The original finding was the identification and purification of a vinpocetine and muscarinic antagonist-inhibited and CaM-activated PM-bound PDE1A, linked to M(2)AChR. A model of this novel signal transducing cascade for the regulation of cyclic nucleotides levels at BTSM is proposed. PMID- 26513203 TI - Research as a Standard of Care in the PICU. AB - OBJECTIVES: Excellence in clinical care coupled with basic and applied research reflects the maturation of a medical subspecialty, advances that field, and provides objective data for identifying best practices. PICUs are uniquely suited for conducting translational and clinical research. In addition, multiple investigations have reported that a majority of parents are interested in their children's participation in clinical research, even when the research offers no direct benefit to their child. However, such activity may generate ethical conflict with bedside care providers trying to acutely identify the best approach for an individual critically ill child. Ultimately, this conflict may diminish enthusiasm for the generation of scientific evidence that supports the application of evidence-based medicine into PICU clinical standard work. Accordingly this review endeavors to provide an overview of current state PICU clinical research strengths, liabilities, opportunities, and barriers and contrast this with an established pediatric hematology-oncology iterative research model that constitutes a learning healthcare system. DATA SOURCES, DATA EXTRACTION, AND DATA SYNTHESIS: Narrative review of medical literature published in English. CONCLUSIONS: Currently, most PICU therapy is not evidence based. Developing a learning healthcare system in the PICU integrates clinical research into usual practice and fosters a culture of evidence-based learning and continual care improvement. As PICU mortality has significantly decreased, identification and validation of patient-centered, clinically relevant research outcome measures other than mortality is essential for future clinical trial design. Because most pediatric critical illness may be classified as rare diseases, participation in research networks will facilitate iterative, collaborative, multiinstitutional investigations that over time identify the best practices to improve PICU outcomes. Despite real ethical challenges, critically ill children and their families should have the opportunity to participate in translational/clinical research whenever feasible. PMID- 26513205 TI - John Paul Jones: An Overlooked Autopsy Finding that May Explain His Terminal Illness. AB - A finding in the autopsy of John Paul Jones, the American Revolutionary War naval hero, may explain his terminal illness. During his last 2 years, he had a persistent productive cough and dyspnea. Ten days before death, he developed rapidly progressive dependent edema and ascites. He died in France in 1792. His body, preserved in alcohol in a lead coffin, was, in 1905, removed to the United States. Glomerulonephritis was noted on an autopsy, performed in France, but there was no comment then or since about ventricular wall thickness being the same in both ventricles at 5-6 mm. Hypertrophy and dilatation with biventricular failure followed by tissue shrinkage during 113 years in alcohol could have resulted in these ventricular wall findings. Systemic hypertension and left ventricular failure are consistent with his respiratory symptoms complicated perhaps by pulmonary emboli, right ventricular failure with tricuspid regurgitation, peripheral congestion, and jaundice. PMID- 26513206 TI - Influence of marital status on the survival of patients with gastric cancer. AB - BACKGROUND AND AIMS: The influence of marital status on gastric cancer (GC) survival is controversial. The aim of our study was to investigate the relationship between marital status and the survival of GC patients. METHODS: The data of current study was from the Surveillance, Epidemiology, and End-Results database. We identified 18,815 GC patients between 2004 and 2009, who were categorized into married, never married, widowed, and divorced/separated groups. Kaplan-Meier analysis was performed to compare gastric cancer specific survival (GCSS), and Cox regression analysis was used to estimate the risk factors for different survival outcomes in four groups with diverse marital status. RESULTS: Married patients had better 5-year GCSS compared with patients who were never married, separated/widowed, or divorced. In stratified analyses by histological type and pathological differentiation, unmarried patients with gastric adenocarcinoma, signet ring cell carcinoma, moderately differentiated caicinoma, and poorly differentiated/undifferentiated carcinoma had an increased risk of cancer mortality. Widowed patients had the highest percentage of women and elderly, and were more susceptible to well and moderately differentiated gastric carcinomars and gastric adenocarcinoma with earlier TNM stage and lowest rate of surgery and radiation therapy. In addition, they also had the worst 5-year GCSS. CONCLUSIONS: Our study suggests that unmarried GC patients, especially widowed patients, are at a high risk of GCSS. Additionally, the survival benefit is more significant among married GC patients in higher malignancy status. PMID- 26513207 TI - A Global Perspective of Beauty in a Multicultural World. PMID- 26513208 TI - Revealing Hearing Loss: A Survey of How People Verbally Disclose Their Hearing Loss. AB - OBJECTIVE: Hearing loss is the most common sensory deficit and congenital anomaly, yet the decision-making processes involved in disclosing hearing loss have been little studied. To address this issue, we have explored the phrases that adults with hearing loss use to disclose their hearing loss. DESIGN: Since self-disclosure research has not focused on hearing loss-specific issues, we created a 15-question survey about verbally disclosing hearing loss. English speaking adults (>18 years old) with hearing loss of any etiology were recruited from otology clinics in a major referral hospital. Three hundred and thirty-seven participants completed the survey instrument. Participants' phrase(s) used to tell people they have hearing loss were compared across objective characteristics (age; sex; type, degree, and laterality of hearing loss; word recognition scores) and self-reported characteristics (degree of hearing loss; age of onset and years lived with hearing loss; use of technology; hearing handicap score). RESULTS: Participants' responses revealed three strategies to address hearing loss: Multipurpose disclosure (phrases that disclose hearing loss and provide information to facilitate communication), Basic disclosure (phrases that disclose hearing loss through the term, a label, or details about the condition), or nondisclosure (phrases that do not disclose hearing loss). Variables were compared between patients who used and who did not use each disclosure strategy using chi or Wilcoxon rank sum tests. Multipurpose disclosers were mostly female (p = 0.002); had experienced reactions of help, support, and accommodation after disclosing (p = 0.008); and had experienced reactions of being overly helpful after disclosing (p=0.039). Basic disclosers were predominantly male (p = 0.004); reported feeling somewhat more comfortable disclosing their hearing loss over time (p = 0.009); had not experienced reactions of being treated unfairly or discriminated against (p = 0.021); and were diagnosed with mixed hearing loss (p = 0.004). Nondisclosers tended not to disclose in a group setting (p = 0.002) and were diagnosed with bilateral hearing loss (p = 0.005). In addition, all of the variables were examined to build logistic regression models to predict the use of each disclosure strategy. CONCLUSIONS: Our results reveal three simple strategies for verbally addressing hearing loss that can be used in a variety of contexts. We recommend educating people with hearing loss about these strategies-this could improve the experience of disclosing hearing loss, and could educate society at large about how to interact with those who have a hearing loss. PMID- 26513209 TI - Long-term Follow-up of Mycobacterium avium Complex Lung Disease in Patients Treated With Regimens Including Clofazimine and/or Rifampin. AB - BACKGROUND: Mycobacterium avium complex (MAC) lung disease requires prolonged treatment with multiple antibiotics. Drug intolerances and interactions are common with the current recommended treatment. There is limited information on outcomes with alternative medications. METHODS: Retrospective review including adult patients with MAC lung disease who were treated and monitored for at least 6 months posttreatment. The aim was to evaluate the clinical and microbiologic outcomes in patients treated with regimens including clofazimine and/or rifampin. RESULTS: One hundred and seven patients were included (79% were female; mean age, 67 years). Sputum samples were smear positive in 54% of patients. The majority (84%) were treated with clofazimine in combination with a macrolide and ethambutol. Fourteen patients (13%) were treated with rifampin, macrolide, and ethambutol. Most patients (95%) converted from positive to negative sputum culture results in an average of 4.5 +/- 4.2 months (range, 0-30 months). A significantly greater proportion of patients treated with clofazimine converted to negative culture results compared with those treated with rifampin (100% vs 71%; P = .0002). Microbiologic relapse occurred in 52 of 107 patients (49%). Thirty-six percent of patients required retreatment. There was no difference in microbiologic relapse or re-treatment rates between the two treatment groups. CONCLUSIONS: The majority of patients with MAC lung disease achieve negative sputum culture results. Re-treatment is needed in approximately one-third of patients. In this cohort, both initial outcomes and re-treatment rates were at least as good in patients treated with clofazimine-containing regimens as in patients receiving rifampin-containing regimens. Clofazimine should be considered as an alternative drug for the treatment of MAC lung disease. PMID- 26513210 TI - Predicting cardiovascular disease from handgrip strength: the potential clinical implications. AB - The measurement of handgrip strength has proven prognostic value for all-cause and cardiovascular death, and for cardiovascular disease. It is also an important indicator of frailty and vulnerability. The measurement of handgrip strength may be most useful in the context of multi-morbidity, where it may be a simple tool to identify the individual at particularly high risk of adverse outcomes, who may benefit from closer clinical attention. Research into dietary, exercise, and pharmacologic strategies to increase muscle strength is ongoing. Important issues will be the feasibility and sustainability of increases in muscle strength, and whether these increases translate into clinical benefit. PMID- 26513211 TI - Commentary: From global campaign to global commitment. PMID- 26513212 TI - Changes in balance function with chronic antiepileptic drug therapy: A twin and sibling study. AB - OBJECTIVE: To investigate cross-sectional and longitudinal differences in static and dynamic standing balance measures and lower limb muscle strength in patients who are treated chronically with antiepileptic drugs (AEDs). METHODS: Twenty-six AED exposure-discordant same-gender twin and sibling pairs were studied. Clinical and laboratory balance examinations were conducted twice, separated by at least 1 year. The mean within-pair differences in balance measures were calculated cross sectionally at baseline and follow-up, and longitudinally. RESULTS: No significant mean within-pair difference was found at baseline in age (44 years), weight, and height (p > 0.05). Between study assessments, the median (interquartile range [IQR]) interval was 3.0 (2.1-4.3) years in users and 2.9 (2.0-4.4) years in nonusers. The median duration of AED therapy was 19 (11-21) years. At baseline and follow-up, cross-sectional sway measures from posturography (Chattecx Balance System) and clinical static balance tests showed poorer performance in users compared to nonusers on several test conditions (p = 0.002-0.032). At follow-up, the users took longer than nonusers to complete the Four-Square-Step Test (p = 0.005) and Five-Times-Sit-to-Stand Test (p = 0.018). A greater annual rate of deterioration in sway was found in users compared to nonusers using posturography on the anteroposterior tilting platform task with distraction (p = 0.032). In both groups, higher baseline sway predicted greater annual deterioration in sway in all platform conditions (beta = 0.3-0.5, p < 0.001-0.013). The annual change in measures did not differ between groups in the clinical balance and lower limb strength assessments. SIGNIFICANCE: In this longitudinal twin and sibling study, chronic AED users had poorer standing balance compared to nonusers. Users showed greater deterioration in postural sway with one dynamic platform condition. AEDs may progressively impair balance mechanisms, although this requires further investigations. Repeated dynamic posturography could provide a basis for preventive trials for maintaining or improving balance. PMID- 26513213 TI - Neurocysticercosis: An uncommon cause of drug-refractory epilepsy in North Indian population. AB - OBJECTIVE: Being a common cause of epilepsy in endemic areas, neurocysticercosis (NCC) is expected to account for a sizable proportion of patients with drug refractory epilepsy (DRE) as well. However, data regarding prevalence of DRE in NCC are sparse. This study aimed to determine the prevalence of DRE as well as identification of clinical and radiologic factors that lead to DRE in patients with NCC. METHODS: This study was conducted in a tertiary-care postgraduate teaching institute in Northern India from July 2011 to July 2013. Two hundred patients with epilepsy due to NCC (definite [n = 59, 29.5%] or probable [n = 141, 70.5%]) based on diagnostic criteria by Del Brutto et al. were enrolled in the study in both a prospective (n = 51 [25.5%]) and a retrospective manner (n = 149 [74.5%]), and were followed for a minimum period of 1 year. RESULTS: Thirteen patients with NCC were found to be refractory to drug therapy. Prevalence of DRE was found to be 65 of 1,000 NCC patients with epilepsy in the present study. The risk factors associated with high risk of DRE were male sex (p = 0.035), older age (p = 0.016), pig-raising practices (p = 0.003), pork eating (p = 0.04), and presence of multiple (>2) (p = 0.0001) or mixed stage lesions (p = 0.007) on neuroimaging. On multivariate analysis, it was found that residing in an area where pig raising is prevalent (p = 0.01) and presence of multiple (>2) (p = 0.004) lesions on neuroimaging are associated with increased risk of DRE. SIGNIFICANCE: NCC is only rarely associated with the development of DRE. The common risk factors associated with increased chance of DRE include pig-rearing practices and presence of multiple (>2) lesions on neuroimaging. PMID- 26513214 TI - LQT, HCN, and epilepsy model. PMID- 26513215 TI - In response: LQT, HCN, and epilepsy model. PMID- 26513216 TI - Tolerance induction using nanoparticles bearing HY peptides in bone marrow transplantation. AB - Allogeneic cell therapies have either proven effective or have great potential in numerous applications, though the required systemic, life-long immunosuppression presents significant health risks. Inducing tolerance to allogeneic cells offers the potential to reduce or eliminate chronic immunosuppression. Herein, we investigated antigen-loaded nanoparticles for their ability to promote transplant tolerance in the minor histocompatibility antigen sex-mismatched C57BL/6 model of bone marrow transplantation. In this model, the peptide antigens Dby and Uty mediate rejection of male bone marrow transplants by female CD4+ and CD8+ T cells, respectively, and we investigated the action of nanoparticles on these T cell subsets. Antigens were coupled to or encapsulated within poly(lactide-co glycolide) (PLG) nanoparticles with an approximate diameter of 500 nm. Delivery of the CD4-encoded Dby epitope either coupled to or encapsulated within PLG particles prevented transplant rejection, promoted donor-host chimerism, and suppressed proliferative and IFN-gamma responses in tolerized recipients. Nanoparticles modified with the Uty peptide did not induce tolerance. The dosing regimen was investigated with Dby coupled particles, and a single dose delivered the day after bone marrow transplant was sufficient for tolerance induction. The engraftment of cells was significantly affected by PD-1/PDL-1 costimluation, as blockade of PD-1 reduced engraftment by ~50%. In contrast, blockade of regulatory T cells did not impact the level of chimerism. The delivery of antigen on PLG nanoparticles promoted long-term engraftment of bone marrow in a model with a minor antigen mismatch in the absence of immunosuppression, and this represents a promising platform for developing a translatable, donor-specific tolerance strategy. PMID- 26513217 TI - Assessing services with communicatively impaired bilingual adults in culturally and linguistically diverse neurorehabilitation programs. AB - The combined effect of the steady increase in cultural and linguistic diversity and epidemiological factors in minority populations is estimated to continue having an impact on adult neurorehabilitation programs in the country, particularly in the number of bilingual individuals receiving clinical services. No comprehensive assessment of the present professional and clinical realities in service delivery to communicatively impaired adults in culturally and linguistically diverse (CLD) neurorehabilitation contexts has been conducted. The current survey research was undertaken to examine current professional training, clinical practices, and challenges in the services rendered to the steadily increasing numbers of communicatively disordered adults in CLD neurorehabilitation programs with a special focus on bilingual persons. A 36 question, 6-section survey was administered to health care-based SLPs working with adults to examine multiple factors regarding work setting and caseload, professional training, clinical tools and procedures, service delivery issues, and suggestions to improve clinical work with bilingual adults in CLD neurorehabilitation environments. Results support that SLPs presently make sensible decisions to serve communicatively disordered bilingual adults with neuropathologies despite training gaps and scant clinical resources. Responses additionally highlight critical areas to improve professional preparation and available resources. Results are discussed in terms of strengths and weaknesses as well as their implications to professional education and target research areas in order to minimize present gaps in service delivery with bilingual speakers in CLD adult neurorehabilitation programs. LEARNING OUTCOMES: As a result of this activity, the reader will be able to: (1) Discuss the demographic and epidemiological factors that suggest a continued increase in the number of communicatively impaired bilingual adults in CLD neurorehabilitation programs. (2) Describe current strengths and weaknesses in the diagnostic and therapeutic practices employed by SLPs with bilingual clients in CLD adult neurorehabilitation programs. (3) Describe possible strategies to improve current limitations in professional training and clinical resources that would strengthen the current services given to bilingual adults in CLD neurorehabilitation programs. PMID- 26513218 TI - Supporting culturally and linguistically diverse children with speech, language and communication needs: Overarching principles, individual approaches. AB - Speech-language pathologists (SLPs) are working with an increasing number of families from culturally and linguistically diverse backgrounds as the world's population continues to become more internationally mobile. The heterogeneity of these diverse populations makes it impossible to identify and document a one size fits all strategy for working with culturally and linguistically diverse families. This paper explores approaches to practice by SLPs identified as specialising in multilingual and multicultural practice in culturally and linguistically diverse contexts from around the world. Data were obtained from ethnographic observation of 14 sites in 5 countries on 4 continents. The sites included hospital settings, university clinics, school-based settings, private practices and Indigenous community-based services. There were 652 individual artefacts collected from the sites which included interview transcripts, photographs, videos, narrative reflections, informal and formal field notes. The data were analysed using Cultural-Historical Activity Theory (Engestrom, 1987). From the analysis six overarching Principles of Culturally Competent Practice (PCCP) were identified. These were: (1) identification of culturally appropriate and mutually motivating therapy goals, (2) knowledge of languages and culture, (3) use of culturally appropriate resources, (4) consideration of the cultural, social and political context, (5) consultation with families and communities, and (6) collaboration between professionals. These overarching principles align with the six position statements developed by the International Expert Panel on Multilingual Children's Speech (2012) which aim to enhance the cultural competence of speech pathologists and their practice. The international examples provided in the current study demonstrate the individualised ways that these overarching principles are enacted in a range of different organisational, social, cultural and political contexts. Tensions experienced in enacting the principles are also discussed. This paper emphasises the potential for individual SLPs to enhance their practice by adopting these overarching principles to support the individual children and families in diverse contexts around the world. PMID- 26513219 TI - Human Papillomavirus Vaccination Coverage Among Female Adolescents in Managed Care Plans - United States, 2013. AB - Human papillomavirus (HPV) is the most common sexually transmitted infection, with a reported 79 million persons aged 15-59 years in the United States currently infected with HPV, and approximately 14 million new cases diagnosed each year. Although most HPV infections are asymptomatic, transient, and do not cause disease, persistent HPV infection can lead to cervical, vulvar, vaginal, anal, penile, and oropharyngeal cancer. In the United States, approximately 27,000 HPV-attributable cancers occur each year. HPV vaccination is an effective primary prevention strategy that can reduce many of the HPV infections that lead to cancer, and is routinely recommended for adolescents aged 11-12 years. To determine whether the recommended HPV vaccination series is currently being administered to adolescents with health insurance, CDC and the National Committee for Quality Assurance (NCQA) assessed 2013 data from the Healthcare Effectiveness Data and Information Set (HEDIS). The HEDIS HPV Vaccine for Female Adolescents performance measure evaluates the proportion of female adolescent members in commercial and Medicaid health plans who receive the recommended 3-dose HPV vaccination series by age 13 years. In 2013, in the United States, the median HPV vaccination coverage levels for female adolescents among commercial and Medicaid plans were 12% and 19%, respectively (ranges = 0%-34% for commercial plans; 5% 52% for Medicaid plans). Improving HPV vaccination coverage and understanding of what health plans might do to support HPV vaccination are needed, including understanding the barriers to, and facilitators for, vaccination coverage. PMID- 26513220 TI - Nickel has biochemical, physiological, and structural effects on the green microalga Ankistrodesmus falcatus: An integrative study. AB - In recent years, the release of chemical pollutants to water bodies has increased due to anthropogenic activities. Ni(2+) is an essential metal that causes damage to aquatic biota at high concentrations. Phytoplankton are photosynthesizing microscopic organisms that constitute a fundamental community in aquatic environments because they are primary producers that sustain the aquatic food web. Nickel toxicity has not been characterized in all of the affected levels of biological organization. For this reason, the present study evaluated the toxic effects of nickel on the growth of a primary producer, the green microalga Ankistrodesmus falcatus, and on its biochemical, enzymatic, and structural levels. The IC50 (96h) was determined for Ni(2+). Based on this result, five concentrations were determined for additional tests, in which cell density was evaluated daily. At the end of the assay, pigments and six biomarkers, including antioxidant enzymes (catalase [CAT], glutathione peroxidase [GPx], superoxide dismutase [SOD]), and macromolecules (proteins, carbohydrates and lipids), were quantified; the integrated biomarker response (IBR) was determined also. The microalgae were observed by SEM and TEM. Population growth was affected starting at 7.5 MUg L(-1) (0.028 MUM), and at 120 MUg L(-1) (0.450 MUM), growth was inhibited completely; the determined IC50 was 17 MUg L(-1). Exposure to nickel reduced the concentration of pigments, decreased the content of all of the macromolecules, inhibited of SOD activity, and increased CAT and GPx activities. The IBR revealed that Ni(2+) increased the antioxidant response and diminished the macromolecules concentration. A. falcatus was affected by nickel at very low concentrations; negative effects were observed at the macromolecular, enzymatic, cytoplasmic, and morphological levels, as well as in population growth. Ni(2+) toxicity could result in environmental impacts with consequences on the entire aquatic community. Current regulations should be revised to protect primary producers. PMID- 26513221 TI - Prediction of acute toxicity of cadmium and lead to zebrafish larvae by using a refined toxicokinetic-toxicodynamic model. AB - The biotic ligand model (BLM) and the toxicokinetic-toxicodynamic (TK-TD) model are essential in predicting the acute toxicity of metals in various species and exposure conditions; however, these models are usually separately utilized. In this study, a mechanistic TK-TD model was developed to predict the acute toxicity of 10(-6)M Cd and 10(-6)M Pb to zebrafish (Danio rerio) larvae. The novel approach links the BLM with relevant TK processes to simulate the bioaccumulation processes of Cd or Pb as a function of the maximum uptake rate of each metal, the affinity constants, and the concentrations of free metal ions and H(+) in test solutions. Results showed that the refined TK-TD model can accurately predict the accumulation and acute toxicity of Cd and Pb to zebrafish larvae at pH 5.5, 6.5, and 7.0. PMID- 26513222 TI - Effects of copper, hypoxia and acute temperature shifts on mitochondrial oxidation in rainbow trout (Oncorhynchus mykiss) acclimated to warm temperature. AB - Temperature fluctuations, hypoxia and metals pollution frequently occur simultaneously or sequentially in aquatic systems and their interactions may confound interpretation of their biological impacts. With a focus on energy homeostasis, the present study examined how warm acclimation influences the responses and interactions of acute temperature shift, hypoxia and copper (Cu) exposure in fish. Rainbow trout (Oncorhynchus mykiss) were acclimated to cold (11 degrees C; control) and warm (20 degrees C) temperature for 3 weeks followed by exposure to environmentally realistic levels of Cu and hypoxia for 24h. Subsequently, mitochondrial electron transport system (ETS) respiratory activity supported by complexes I-IV (CI-IV), plasma metabolites and condition indices were measured. Warm acclimation reduced fish condition, induced aerobic metabolism and altered the responses of fish to acute temperature shift, hypoxia and Cu. Whereas warm acclimation decelerated the ETS and increased the sensitivity of maximal oxidation rates of the proximal (CI and II) complexes to acute temperature shift, it reduced the thermal sensitivity of state 4 (proton leak). Effects of Cu with and without hypoxia were variable depending on the acclimation status and functional index. Notably, Cu stimulated respiratory activity in the proximal ETS segments, while hypoxia was mostly inhibitory and minimized the stimulatory effect of Cu. The effects of Cu and hypoxia were modified by temperature and showed reciprocal antagonistic interaction on the ETS and plasma metabolites, with modest additive actions limited to CII and IV state 4. Overall, our results indicate that warm acclimation came at a cost of reduced ETS efficiency and increased sensitivity to added stressors. PMID- 26513223 TI - High-intensity versus low-intensity physical activity or exercise in people with hip or knee osteoarthritis. AB - BACKGROUND: Exercise or physical activity is recommended for improving pain and functional status in people with knee or hip osteoarthritis. These are complex interventions whose effectiveness depends on one or more components that are often poorly identified. It has been suggested that health benefits may be greater with high-intensity rather than low-intensity exercise or physical activity. OBJECTIVES: To determine the benefits and harms of high- versus low intensity physical activity or exercise programs in people with hip or knee osteoarthritis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; issue 06, 2014), MEDLINE (194 8 to June 2014) , EMBASE (198 0 to June 2014), CINAHL (1982 to June 2014), PEDro (1929 to June 2014), SCOPUS (to June 2014) and the World Health Organization (WHO) International Clinical Registry Platform (to June 2014) for articles, without a language restriction. We also handsearched relevant conference proceedings, trials, and reference lists and contacted researchers and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomized controlled trials of people with knee or hip osteoarthritis that compared high- versus low-intensity physical activity or exercise programs between the experimental and control group.High-intensity physical activity or exercise programs training had to refer to an increase in the overall amount of training time (frequency, duration, number of sessions) or the amount of work (strength, number of repetitions) or effort/energy expenditure (exertion, heart rate, effort). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and extracted data on trial details. We contacted authors for additional information if necessary. We assessed the quality of the body of evidence for these outcomes using the GRADE approach. MAIN RESULTS: We included reports for six studies of 656 participants that compared high- and low-intensity exercise programs; five studies exclusively recruited people with symptomatic knee osteoarthritis (620 participants), and one study exclusively recruited people with hip or knee osteoarthritis (36 participants). The majority of the participants were females (70%). No studies evaluated physical activity programs. We found the overall quality of evidence to be low to very low due to concerns about study limitations and imprecision (small number of studies, large confidence intervals) for the major outcomes using the GRADE approach. Most of the studies had an unclear or high risk of bias for several domains, and we judged five of the six studies to be at high risk for performance, detection, and attrition bias.Low-quality evidence indicated reduced pain on a 20-point Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain scale (mean difference (MD) -0.84, 95% confidence interval (CI) -1.63 to -0.04; 4% absolute reduction, 95% CI -8% to 0%; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 14 to 22) and improved physical function on the 68 point WOMAC disability subscale (MD -2.65, 95% CI -5.29 to -0.01; 4% absolute reduction; NNTB 10, 95% CI 8 to 13) immediately at the end of the exercise programs (from 8 to 24 weeks). However, these results are unlikely to be of clinical importance. These small improvements did not continue at longer-term follow-up (up to 40 weeks after the end of the intervention). We are uncertain of the effect on quality of life, as only one study reported this outcome (0 to 200 scale; MD 4.3, 95% CI -6.5 to 15.2; 2% absolute reduction; very low level of evidence).Our subgroup analyses provided uncertain evidence as to whether increased exercise time (duration, number of sessions) and level of resistance (strength or effort) have an impact on the exercise program effects.Three studies reported withdrawals due to adverse events. The number of dropouts was small. Only one study systematically monitored adverse effects, but four studies reported some adverse effects related to knee pain associated with an exercise program. We are uncertain as to whether high intensity increases the number of adverse effects (Peto odds ratio 1.72, 95% CI 0.51 to 5.81; - 2% absolute risk reduction; very low level of evidence). None of the included studies reported serious adverse events. AUTHORS' CONCLUSIONS: We found very low-quality to low quality evidence for no important clinical benefit of high-intensity compared to low-intensity exercise programs in improving pain and physical function in the short term. There was insufficient evidence to determine the effect of different types of intensity of exercise programs.We are uncertain as to whether higher intensity exercise programs may induce more harmful effects than those of lower intensity; this must be evaluated by further studies. Withdrawals due to adverse events were poorly monitored and not reported systematically in each group. We downgraded the evidence to low or very low because of the risk of bias, inconsistency, and imprecision.The small number of studies comparing high- and low-intensity exercise programs in osteoarthritis underscores the need for more studies investigating the dose-response relationship in exercise programs. In particular, further studies are needed to establish the minimal intensity of exercise programs needed for clinical effect and the highest intensity patients can tolerate. Larger studies should comply with the Consolidated Standards of Reporting Trials (CONSORT) checklist and systematically report harms data to evaluate the potential impact of highest intensities of exercise programs in people with joint damage. PMID- 26513224 TI - Use of endoanal ultrasound for reducing the risk of complications related to anal sphincter injury after vaginal birth. AB - BACKGROUND: During childbirth, many women sustain trauma to the perineum, which is the area between the vaginal opening and the anus. These tears can involve the perineal skin, the pelvic floor muscles, the external and internal anal sphincter muscles as well as the rectal mucosa (lining of the bowel). When these tears extend beyond the external anal sphincter they are called 'obstetric anal sphincter injuries' (OASIS). When women sustain an OASIS, they are at increased risk of developing anal incontinence either immediately following birth or later in life. Anal incontinence is associated with significant medical, hygiene and social problems. Endoanal ultrasound (EAUS) can be performed with a bedside scanner by inserting a small probe into the anus and the structures of the anal canal and perineum can be reviewed in real-time. We proposed that by examining the perineum with EAUS after the birth of the baby and before the tear has been repaired, there would be an increase in detection of OASIS. This increased detection could lead to improved primary repair of the external and internal anal sphincter resulting in reduced rates of anal incontinence and improved quality of life for women. EAUS may also have a role after perineal repair in the evaluation of residual injury and may help guide a woman's management in subsequent pregnancies and allow for early referral to specialised units, minimising long term complications. OBJECTIVES: To evaluate the effectiveness of EAUS in the detection of OASIS following vaginal birth and in reducing the risk of anal sphincter complications related to OASIS. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2015) and reference list of the one retrieved study. SELECTION CRITERIA: Randomised control trials (RCTs) comparing EAUS versus no ultrasound in women prior to repair of perineal trauma and EAUS performed after perineal repair. RCTs published in abstract form only and trials using a cluster-randomised design were eligible for inclusion, but none were identified.Trials using a cross-over design and quasi RCTs were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: The two review authors independently assessed the single trial for inclusion and assessed trial quality. Both review authors independently extracted data. Data were checked for accuracy. MAIN RESULTS: We included one trial that randomised 752 primiparous women with clinically detectable second-degree perineal tears to either further assessment with EAUS prior to perineal repair or standard care. We assessed this trial as being at a low risk of bias. The trial reported women's anal incontinence at three and 12 months as well as their pain scores and quality of life assessment. The trial authors reported outcomes at three months for 719 women (364 in the experimental group, 355 in the control group, 4% loss to follow up), and an outcome at 12 months for 684 women (342 in the experimental group, 342 in the control group, 9% loss to follow-up). Primary outcomeCompared with clinical examination (routine care), the use of EAUS prior to perineal repair was associated with a reduction in the rate of severe anal incontinence (defined as involuntary loss of faeces or flatus that constitutes social and/or hygiene problems, or as defined by authors), at greater than six months postpartum (risk ratio (RR) 0.48, 95% confidence interval (CI) 0.24 to 0.97, 684 women at the 12 month time point). Secondary outcomes Severe anal incontinence at less than six months was reduced with the use of EAUS prior to repair when compared with clinical examination (routine care) (RR 0.38, 95% CI 0.20 to 0.72, 719 women). However, increased perineal pain at three months was associated with the use of EAUS prior to perineal repair when compared with routine care (RR 5.86, 95% CI 1.74 to 19.72, 684 women). There was no clear difference in the number of women who reported any anal incontinence at either less than six months or equal to or greater than six months (outcomes not prespecified in our published protocol). Similarly, there was no clear difference between groups in terms of faecal incontinence, flatal incontinence, faecal urgency, or maternal quality of life. The study did not report any data on the need for secondary repair of external anal sphincter, dyspareunia, women's satisfaction with care or the planned or actual mode of birth in any subsequent pregnancy. We were unable to assess the detection rates of OASIS with EAUS from the included study because women with clinically-detected OASIS were excluded from randomisation. AUTHORS' CONCLUSIONS: There is some evidence to suggest that EAUS prior to perineal repair is associated with reduced risk of severe anal incontinence but an increase in the incidence of perineal pain at three months postpartum. However, these results are based on one small study involving 752 women. The study took place in a large teaching hospital with an average to busy labour ward. The trial participants were similar to those found in most large obstetric units in developed countries, thus increasing applicability of the evidence, but were restricted to primiparous women.More research is needed to further evaluate the effectiveness of EAUS in the detection of OASIS following vaginal birth and in reducing the risk of anal sphincter complications related to OASIS. More high-quality RCTs are needed to fully evaluate the intervention before the routine use of EAUS on the labour ward could be supported. It would be particularly useful if future trials could assess detection rates of OASIS with EAUS versus clinical examination alone as this is the basis of the theory for improved outcomes with this intervention. Cost and the training required to implement EAUS should be considered, along with maternal quality of life and individual symptoms experienced by postnatal women . It would also be useful to follow up women after their subsequent vaginal births to determine if subsequent mode of delivery affects long-term outcomes. Future studies in multiparous women may also be useful. PMID- 26513225 TI - Reduced SLC27A2 induces cisplatin resistance in lung cancer stem cells by negatively regulating Bmi1-ABCG2 signaling. AB - Platinum-based chemotherapies have long been used as a standard treatment in non small cell lung cancer (NSCLC). However, cisplatin resistance is a major problem that restricts the use of cisplatin. Lung cancer stem cells (LCSCs) represent a subpopulation that is responsible for chemo-resistance. We aim to investigate the biological function of SLC27A2 and its underlying mechanisms in regulating chemo resistance to cisplatin in LCSCs. Here, our findings testified that CD166+ cells which were derived from fresh primary NSCLC samples displayed stem cell-like features and were resistant to chemotherapy drug cisplatin. In patient cohort, we found the presence of a variable fraction of CD166+ cells in 24 out of 25 primary NSCLC samples. Significantly, SLC27A2 expression was reduced in CD166+ LCSCs. Reduced SLC27A2 correlated chemo-response and poor patient survival. Our results indicated that enhanced SLC27A2 expression sensitized CD166+ LCSCs to cisplatin by in vitro and in vivo experiments. Microarray profiling showed that the expression of Bmi1 and ABCG2 was enhanced in p-SLC27A2-LCSCs compared with that in pc3.1DNA-LCSCs. Furthermore, we demonstrated that reduced SLC27A2 induced chemo-resistance in CD166+ LCSCs by negatively regulating Bmi1-ABCG2 signaling, and ABCG2 was a direct transcriptional target of Bmi1. Thus, this study widens the window for identification and targeting of a cisplatin-resistant population and contributes to the development of potential therapeutics to improve the current treatment modalities in NSCLC. (c) 2015 Wiley Periodicals, Inc. PMID- 26513226 TI - Intelligent sensing sensory quality of Chinese rice wine using near infrared spectroscopy and nonlinear tools. AB - The approach presented herein reports the application of near infrared (NIR) spectroscopy, in contrast with human sensory panel, as a tool for estimating Chinese rice wine quality; concretely, to achieve the prediction of the overall sensory scores assigned by the trained sensory panel. Back propagation artificial neural network (BPANN) combined with adaptive boosting (AdaBoost) algorithm, namely BP-AdaBoost, as a novel nonlinear algorithm, was proposed in modeling. First, the optimal spectra intervals were selected by synergy interval partial least square (Si-PLS). Then, BP-AdaBoost model based on the optimal spectra intervals was established, called Si-BP-AdaBoost model. These models were optimized by cross validation, and the performance of each final model was evaluated according to correlation coefficient (Rp) and root mean square error of prediction (RMSEP) in prediction set. Si-BP-AdaBoost showed excellent performance in comparison with other models. The best Si-BP-AdaBoost model was achieved with Rp=0.9180 and RMSEP=2.23 in the prediction set. It was concluded that NIR spectroscopy combined with Si-BP-AdaBoost was an appropriate method for the prediction of the sensory quality in Chinese rice wine. PMID- 26513227 TI - Antimicrobial activity, structural evaluation and vibrational (FT-IR and FT Raman) study of pyrrole containing vinyl derivatives. AB - In this paper we present structural and vibrational study of three vinylpyrrole derivatives: 2-Cyano-3-(1H-pyrrol-2-yl)-acrylamide (CPA), 1-(1H-Pyrrol-2-yl)-Pent 1-en-3-one (PP) and 1-(1H-Pyrrol-2-yl)-but-1-en-3-one (PB), using ab initio, DFT and experimental approaches. The quantum chemical calculation have been performed on B3LYP method and 6-311+G(d,p) basis set. The experimental FT-IR and Raman wavenumbers were compared with the respective theoretical values obtained from DFT calculations and found to agree well. The experimental FT-IR and Raman study clearly indicate that the compound exist as dimer in solid state. The binding energies of (CPA), (PP) and (PB) dimers are found to be 20.95, 18.75 and 19.18 kcal/mol, respectively. The vibrational analysis shows red shifts in v(N-H) and v(C=O) stretching as result of dimer formation. Stability of the molecule arising from hyperconjugative interactions and charge delocalization has been analyzed using NBO analysis. Topological and energetic parameters reveal the nature of interactions in dimer. The local electronic descriptors analyses were used to predict the reactive sites in the molecule. Calculated first static hyperpolarizability of CPA, PP and PB is found to be 10.41*10(-30), 18.93*10( 30), 18.29*10(-30) esu, respectively, shows that investigated molecules will have non-linear optical response and might be used as non-linear optical (NLO) material. These vinylpyrrole compounds (CPA), (PP) and (PB) showed antifungal and antibacterial activity against Aspergillus niger and gram-positive bacteria Bacillus subtili. PMID- 26513228 TI - Advanced stability indicating chemometric methods for quantitation of amlodipine and atorvastatin in their quinary mixture with acidic degradation products. AB - Two advanced, accurate and precise chemometric methods are developed for the simultaneous determination of amlodipine besylate (AML) and atorvastatin calcium (ATV) in the presence of their acidic degradation products in tablet dosage forms. The first method was Partial Least Squares (PLS-1) and the second was Artificial Neural Networks (ANN). PLS was compared to ANN models with and without variable selection procedure (genetic algorithm (GA)). For proper analysis, a 5 factor 5-level experimental design was established resulting in 25 mixtures containing different ratios of the interfering species. Fifteen mixtures were used as calibration set and the other ten mixtures were used as validation set to validate the prediction ability of the suggested models. The proposed methods were successfully applied to the analysis of pharmaceutical tablets containing AML and ATV. The methods indicated the ability of the mentioned models to solve the highly overlapped spectra of the quinary mixture, yet using inexpensive and easy to handle instruments like the UV-VIS spectrophotometer. PMID- 26513229 TI - Analysis of a Brazilian baroque sculpture using Raman spectroscopy and FT-IR. AB - In this study, samples were taken from the sculpture of Our Lady of Sorrows and analyzed by Raman spectroscopy and FT-IR. This sculpture has been dated to the early eighteenth century. Samples were also examined using optical microscopy and Energy Dispersive Spectroscopy (EDS). Based on chemical analysis, the pigments vermilion [HgS], massicot [PbO] and azurite [Cu3(CO3)2(OH)2]were found in the sculpture polychrome. The results indicate that the green polychrome of the sculpture's mantle comes from the blending of massicot and azurite. Because the literature reports that the mantle of the Our Lady of Sorrows sculpture is blue, the mixing of these pigments results from a production error. The results also indicate the presence of Au in the sculpture, which indicates the originality of the piece. The results from this study helped restorers to choose the appropriate procedures for intervening in the sculpture and contributed to the knowledge about the manufacturing process of Brazilian baroque sculptures. PMID- 26513230 TI - Synthesis and photoluminescence of novel red-emitting ZnWO4: Pr3+, Li+ phosphors. AB - Zn0.997WO4: Pr(3+)(0.003) and different concentrations (0.1 mol% to 0.9 mol%) of Pr, Li co-doped ZnWO4 red phosphors were prepared by means of solid-state reaction process. The crystalline, surface morphology and luminescent properties of Zn0.997WO4: Pr(3+)(0.003) and Zn(1-x-y)WO4: xPr(3+), yLi(+) phosphors were investigated by the X-ray diffraction patterns (XRD), scanning electron microscope (SEM) and fluorescent measurements. From powder XRD analysis, the formation of monoclinic structure with C(2/h) point-group symmetry and P(2/c) space group of the as-synthesized samples is confirmed. The SEM image showed that surface morphology of the phosphor powder is irregular cylindricality. The luminescent spectra are dominated by the red emission peaks at 607, 621 and 643 nm, respectively, radiated from the (1)D2->(3)H4, (3)P0->(3)H6 and (3)P0->(3)F2 transitions of Pr(3+) ions. The concentrations of the highest luminescent intensity is determined at 0.3 mol% Pr(3+) and 0.3 mol% Li co-doped ZnWO4 powder crystal, and the peak intensity is improved more than 3 times in comparison with that of 0.3 mol% Pr(3+) single-doped ZnWO4. The enhanced luminescence comes from the improved crystalline and from the charge compensation of Li(+) ions. The decay curve and CIE chromaticity coordinates of as-prepared samples are also studied in detail. PMID- 26513231 TI - Renal impairment in patients with chronic hepatitis C treated with first generation protease inhibitors. AB - BACKGROUND: The incidence, course and risk factors associated with renal impairment (RI) in patients treated with triple therapy (TT) with pegylated interferon, ribavirin and telaprevir/boceprevir (PR/TVR/BOC) vs. dual therapy (DT) with PR were analyzed in this study. The association between RI and the decline of hemoglobin (Hb) was also examined. METHODS: Retrospective analysis included 110 patients with genotype 1b chronic HCV infection, aged 18 - 80 years, who underwent TT (48TVR/14BOC) or DT (48 patients). The estimated glomerular filtration rate (eGFR), serum creatinine concentration (SCr) and Hb were measured at baseline, at weeks 4, 12, 24, 48 of treatment, and post-treatment week 24. RESULTS: RI occurred in 9/62 (14.5%) patients who underwent TT, eight of whom were treated with TVR, one with BOC, and none treated with DT. The risk factors associated with RI were the following: TT (p = 0.0078), usage of nephrotoxic drugs (p = 0.0288), and older age (p < 0.0001). RI was reversible. A drop of Hb was associated with RI, older age and TT. CONCLUSIONS: RI is not a rare but a reversible complication of TT. It is necessary to monitor SCr and eGFR, especially in patients with a potential risk factor of RI occurrence. The Hb drop is more severe in patients with RI than in those without it. PMID- 26513232 TI - Causative pathogens and antibiotic resistance in children hospitalized for urinary tract infection. AB - BACKGROUND: Urinary tract infections (UTI) are one of the most common bacterial infections in children and a major cause of hospitalization. In this study we investigated the clinical characteristics, causative uropathogens; their antibiotic susceptibility and resistance patterns, treatment modalities and efficacy in children hospitalized for UTI in a tertiary care setting. METHODS: Patients hospitalized for an upper UTI between March 2009 and July 2014 were enrolled. The urine culture-antibiogram results and accompanying urinary tract abnormalities were recorded retrospectively. RESULTS: A total of 142 patients (104 girls, 73.2%; 38 boys, 26.8%) were enrolled. Mean patient age was 32.6 +/- 4.1 months. History of recurrent UTI was present in 45.8% (n = 65), with prior hospitalization in 12.0% (n = 17). Frequency of vesicoureteral reflux was 18.3% (n = 26). Gram-negative enteric microorganisms yielded growth in all culture positive UTI and the most common microorganism was Escherichia coli (n = 114, 80.3%). Extended spectrum beta-lactamase-producing (ESBL (+)) bacterial strains were detected in 49.3% (n = 70), with third-generation cephalosporin resistance in all and increased duration of hospitalization. CONCLUSIONS: The prevalence of UTI with ESBL (+) bacterial strains with multi-drug resistance is increasing in the hospitalized pediatric population, therefore rational use of antibiotics is essential. PMID- 26513233 TI - Explorations of New SHG Materials in the Alkali-Metal-Nb(5+)-Selenite System. AB - Standard high-temperature solid-state reactions of NaCl, Nb2O5, and SeO2 resulted in two new sodium selenites containing a second-order Jahn-Teller (SOJT) distorted Nb(5+) cation, namely, Na2Nb4O7(SeO3)4 (P1; 1) and NaNbO(SeO3)2 (Cmc21; 2). Compound 1 exhibits an unusual 3D [Nb4O7(SeO3)4](2-) anionic network composed of 2D [Nb4O11(SeO3)2](6-) layers which are further bridged by additional SeO3(2-) anions via corner sharing; the 2D [Nb4O11(SeO3)2](6-) layer is formed by unusual quadruple [Nb4O17](14-) niobium oxide chains of corner-sharing NbO6 octahedra being further interconnected by selenite anions via Nb-O-Se bridges. The polar compound 2 features a 1D [NbO(SeO3)2](-) anionic chain in which two neighboring Nb(5+) cations are bridged by one oxo and two selenite anions. The alignments of the polarizations from the NbO6 octahedra in 2 led to a strong SHG response of ~7.8 * KDP (~360 * alpha-SiO2), which is the largest among all phases found in metal-Nb(5+)-Se(4+)/metal-Nb(5+)-Te(4+)-O systems. Furthermore, the material is also type I phase matchable. The above experimental results are consistent with those based on DFT theoretical calculations. Thermal stabilities and optical properties for both compounds are also reported. PMID- 26513234 TI - Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies. AB - The possible interrelations between human leukocyte antigen (HLA)-DQ, non-HLA single-nucleotide polymorphisms (SNPs) and islet autoantibodies were investigated at clinical onset in 1-34-year-old type 1 diabetes (T1D) patients (n=305) and controls (n=203). Among the non-HLA SNPs reported by the Type 1 Diabetes Genetics Consortium, 24% were supported in this Swedish replication set including that the increased risk of minor PTPN22 allele and high-risk HLA was modified by GAD65 autoantibodies. The association between T1D and the minor AA+AC genotype in ERBB3 gene was stronger among IA-2 autoantibody-positive patients (comparison P=0.047). The association between T1D and the common insulin (AA) genotype was stronger among insulin autoantibody (IAA)-positive patients (comparison P=0.008). In contrast, the association between T1D and unidentified 26471 gene was stronger among IAA-negative (comparison P=0.049) and IA-2 autoantibody-negative (comparison P=0.052) patients. Finally, the association between IL2RA and T1D was stronger among IAA-positive than among IAA-negative patients (comparison P=0.028). These results suggest that the increased risk of T1D by non-HLA genes is often modified by both islet autoantibodies and HLA-DQ. The interactions between non-HLA genes, islet autoantibodies and HLA-DQ should be taken into account in T1D prediction studies as well as in prevention trials aimed at inducing immunological tolerance to islet autoantigens. PMID- 26513235 TI - Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. AB - Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon production downstream of Toll-like receptor (TLR)3. In the present study, we used whole-exome sequencing to investigate the genetic profile of 16 adult patients with a history of HSE. We identified novel mutations in IRF3, TYK2 and MAVS, molecules involved in generating innate antiviral immune responses, which have not previously been associated with HSE. Moreover, data revealed mutations in TLR3, TRIF, TBK1 and STAT1 known to be associated with HSE in children but not previously described in adults. All discovered mutations were heterozygous missense mutations, the majority of which were associated with significantly decreased antiviral responses to HSV-1 infection and/or the TLR3 agonist poly(I:C) in patient peripheral blood mononuclear cells compared with controls. Altogether, this study demonstrates novel mutations in the TLR3 signaling pathway in molecules previously identified in children, suggesting that impaired innate immunity to HSV-1 may also increase susceptibility to HSE in adults. Importantly, the identification of mutations in innate signaling molecules not directly involved in TLR3 signaling suggests the existence of innate immunodeficiencies predisposing to HSE beyond the TLR3 pathway. PMID- 26513236 TI - Discordant responses to cART in HIV-1 patients in the era of high potency antiretroviral drugs: clinical evaluation, classification, management prospects. AB - The goal of antiretroviral treatment (ART) in HIV-1 patients is immune reconstitution following control of viral replication. CD4+ cell number/proportions are a crude but essential correlate of immune reconstitution. Despite suppression of HIV replication, a fraction of ART-treated patients still fails to fully reconstitute CD4+ T cell numbers (immunological nonresponders, INRs). New drugs, regimens and treatment strategies led to increased efficacy, lower side effects and higher virological success rates in clinical practice. The multitude of described immune defects and clinical events accompanying INR opposed to the marginal effect of antiretroviral intensification or immunotherapy trials underline the need for continuing efforts at understanding the mechanisms that underlie INR. Here, we reassess INR definition, frequency, and the achievements of active clinical and translational research suggesting a shared definition for insufficient, partial and complete CD4+ cell number recovery thus improving homogeneity in patient selection and mechanism identification. PMID- 26513237 TI - Trends in End-of-Life Care in Pediatric Hematology, Oncology, and Stem Cell Transplant Patients. AB - BACKGROUND: Decisions about end-of-life care may be influenced by cultural and disease-specific features. We evaluated associations of demographic variables (race, ethnicity, language, religion, and diagnosis) with end-of-life characteristics (Phase I enrollment, do-not-resuscitate (DNR) orders, hospice utilization, location of death), and trends in palliative care services delivered to pediatric hematology, oncology, and stem cell transplant (SCT) patients. PROCEDURE: In this single-center retrospective cohort study, inclusion criteria were as follows: patients aged 0-35 who died between January 1, 2002 and March 1, 2014, and had been cared for in the pediatric hematology, oncology, and SCT divisions. The era of 2002-2014 was divided into quartiles to assess trends over time. RESULTS: Of the 445 included patients, 64% of patients had relapsed disease, 45% were enrolled in hospice, and 16% had received palliative care consultation. Patients with brain or solid tumors enrolled in hospice (P < 0.0001) and died at home more frequently than patients with leukemia/lymphoma (P < 0.0001). Patients who received Phase I therapy or identified as Christian/Catholic religion enrolled in hospice more frequently (P < 0.0001 and P = 0.03, respectively). When patient deaths were analyzed over quartiles, the frequency of DNR orders (P = 0.02) and palliative care consultation (P = 0.04) increased over time. Hospice enrollment, location of death, and Phase I trial enrollment did not change significantly. CONCLUSIONS: Despite increases in palliative care consultation and DNR orders over time, utilization remains suboptimal. No increase in hospice enrollment or shift in death location was observed. These data will help target future initiatives to achieve earlier discussions of goals of care and improved palliative care for all patients. PMID- 26513238 TI - Influence of Texture and Colour in Breast TMA Classification. AB - Breast cancer diagnosis is still done by observation of biopsies under the microscope. The development of automated methods for breast TMA classification would reduce diagnostic time. This paper is a step towards the solution for this problem and shows a complete study of breast TMA classification based on colour models and texture descriptors. The TMA images were divided into four classes: i) benign stromal tissue with cellularity, ii) adipose tissue, iii) benign and benign anomalous structures, and iv) ductal and lobular carcinomas. A relevant set of features was obtained on eight different colour models from first and second order Haralick statistical descriptors obtained from the intensity image, Fourier, Wavelets, Multiresolution Gabor, M-LBP and textons descriptors. Furthermore, four types of classification experiments were performed using six different classifiers: (1) classification per colour model individually, (2) classification by combination of colour models, (3) classification by combination of colour models and descriptors, and (4) classification by combination of colour models and descriptors with a previous feature set reduction. The best result shows an average of 99.05% accuracy and 98.34% positive predictive value. These results have been obtained by means of a bagging tree classifier with combination of six colour models and the use of 1719 non-correlated (correlation threshold of 97%) textural features based on Statistical, M-LBP, Gabor and Spatial textons descriptors. PMID- 26513239 TI - MiR-429 Induces Gastric Carcinoma Cell Apoptosis Through Bcl-2. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) play an essential role in the tumorigenesis of gastric carcinoma (GC). MiR-429 has been recently reported to inhibit GC growth, but the underlying mechanisms are not clear. METHODS: Here, we studied the levels of miR-429 and anti-apoptotic protein Bcl-2 in GC specimens. We performed bioinformatics analyses and used luciferase-reporter assay to analyze the relationship between miR-429 and Bcl-2 in GC cells. Cell survival upon Fluorouracil treatment was analyzed in a CCK assay. Cell apoptosis was measured by flow cytometry based FITC Annexin V apoptosis detection assay. RESULTS: MiR 429 levels were significantly decreased and Bcl-2 levels were significantly increased in GC specimens, compared to the paired adjacent non-tumor gastric tissue. Moreover, the levels of miR-429 and Bcl-2 inversely correlated in GC specimens. MiR-429-low subjects had an overall inferior survival, compared to miR 429-high subjects. Bioinformatics analyses showed that miR-429 targeted the 3' UTR of Bcl-2 mRNA to inhibit its translation, which was confirmed by luciferase reporter assay. Overexpression of miR-429 inhibited Bcl-2-mediated cell survival against apoptosis induced by Fluorouracil, while depletion of miR-429 augmented it. CONCLUSION: Our data suggest that miR-429 suppression in GC promotes Bcl-2 mediated cancer cell survival against chemotherapy-induced cell death. Re expression of miR-429 levels in GC cells may enhance cancer apoptosis during chemotherapy. PMID- 26513240 TI - A Cluster Randomised Trial on the Impact of Integrating Early Infant HIV Diagnosis with the Expanded Programme on Immunization on Immunization and HIV Testing Rates in Rural Health Facilities in Southern Zambia. AB - BACKGROUND: We assessed the integration of early infant HIV diagnosis with the expanded programme for immunization in a rural Zambian setting with the aim of determining whether infant and postpartum maternal HIV testing rates would increase without harming immunization uptake. METHODS: In an unblinded, location stratified, cluster randomised controlled trial, 60 facilities in Zambia's Southern Province were equally allocated to a control group, Simple Intervention group that received a sensitization meeting and the resupply of HIV testing commodities in the event of a stock-out, and a Comprehensive Intervention group that received the Simple Intervention as well as on-site operational support to facilitate the integration of HIV testing services with EPI. FINDINGS: The average change in number of first dose diphtheria, pertussis, and tetanus vaccine (DPT1) provided per month, per facility was approximately 0.86 doses higher [90% confidence interval (CI) -1.40, 3.12] in Comprehensive Intervention facilities compared to the combined average change in the Simple Intervention and control facilities. The interventions resulted in a 16.6% [90% CI: -7%, 46%, P-value = 0.26] and 10% [90% CI: -10%, 36%, P-value = 0.43] greater change in average monthly infant DBS testing compared to control for the Simple and Comprehensive facilities respectively. We also found 15.76 (90% CI: 7.12, 24.41, P-value < 0.01) and 10.93 (90% CI: 1.52, 20.33, P-value = 0.06) additional total maternal re-tests over baseline for the Simple and Comprehensive Facilities respectively. CONCLUSIONS: This study provides strong evidence to support Zambia's policy of integration of HIV testing and EPI services. Actions in line with the interventions, including HIV testing material supply reinforcement, can increase HIV testing rates without harming immunization uptake. In response, Zambia's Ministry of Health issued a memo to remind health facilities to provide HIV testing at under-five clinics and to include under-five HIV testing as part of district performance assessments. TRIAL REGISTRATION: ClinicalTrials.gov REGISTRATION NUMBER: NCT02479659. PMID- 26513241 TI - Seed Germination Ecology of the Cold Desert Annual Isatis violascens (Brassicaceae): Two Levels of Physiological Dormancy and Role of the Pericarp. AB - The occurrence of various species of Brassicaceae with indehiscent fruits in the cold deserts of NW China suggests that there are adaptive advantages of this trait. We hypothesized that the pericarp of the single-seeded silicles of Isatis violascens restricts embryo expansion and thus prevents germination for 1 or more years. Thus, our aim was to investigate the role of the pericarp in seed dormancy and germination of this species. The effects of afterripening, treatment with gibberellic acid (GA3) and cold stratification on seed dormancy-break were tested using intact silicles and isolated seeds, and germination phenology was monitored in an experimental garden. The pericarp has a role in mechanically inhibiting germination of fresh seeds and promotes germination of nondormant seeds, but it does not facilitate formation of a persistent seed bank. Seeds in silicles in watered soil began to germinate earlier in autumn and germinated to higher percentages than isolated seeds. Sixty-two percent of seeds in the buried silicles germinated by the end of the first spring, and only 3% remained nongerminated and viable. Twenty to twenty-five percent of the seeds have nondeep physiological dormancy (PD) and 75-80% intermediate PD. Seeds with nondeep PD afterripen in summer and germinate inside the silicles in autumn if the soil is moist. Afterripening during summer significantly decreased the amount of cold stratification required to break intermediate PD. The presence of both nondeep and intermediate PD in the seed cohort may be a bet-hedging strategy. PMID- 26513242 TI - Hypergravity Provokes a Temporary Reduction in CD4+CD8+ Thymocyte Number and a Persistent Decrease in Medullary Thymic Epithelial Cell Frequency in Mice. AB - Gravity change affects many immunological systems. We investigated the effects of hypergravity (2G) on murine thymic cells. Exposure of mice to 2G for three days reduced the frequency of CD4+CD8+ thymocytes (DP) and mature medullary thymic epithelial cells (mTECs), accompanied by an increment of keratin-5 and keratin-8 double-positive (K5+K8+) TECs that reportedly contain TEC progenitors. Whereas the reduction of DP was recovered by a 14-day exposure to 2G, the reduction of mature mTECs and the increment of K5+K8+ TEC persisted. Interestingly, a surgical lesion of the inner ear's vestibular apparatus inhibited these hypergravity effects. Quantitative PCR analysis revealed that the gene expression of Aire and RANK that are critical for mTEC function and development were up-regulated by the 3-day exposure and subsequently down-regulated by the 14-day exposure to 2G. Unexpectedly, this dynamic change in mTEC gene expression was independent of the vestibular apparatus. Overall, data suggest that 2G causes a temporary reduction of DP and a persistent reduction of mature mTECs in a vestibular system-dependent manner, and also dysregulates mTEC gene expression without involving the vestibular system. These data might provide insight on the impact of gravity change on thymic functions during spaceflight and living. PMID- 26513243 TI - No Effect of Host Species on Phenoloxidase Activity in a Mycophagous Beetle. AB - Ecological immunology is an interdisciplinary field that helps elucidate interactions between the environment and immune response. The host species individuals experience have profound effects on immune response in many species of insects. However, this conclusion comes from studies of herbivorous insects even though species of mycophagous insects also inhabit many different host species. The goal of this study was to determine if fungal host species as well as individual, sex, body size, and host patch predict one aspect of immune function, phenoloxidase activity (PO). We sampled a metapopulation of Bolitotherus cornutus, a mycophagous beetle in southwestern Virginia. B. cornutus live on three species of fungus that differ in nutritional quality, social environment, and density. A filter paper phenoloxidase assay was used to quantify phenoloxidase activity. Overall, PO activity was significantly repeatable among individuals (0.57) in adult B. cornutus. While there was significant variance among individuals in PO activity, there were surprisingly no significant differences in PO activity among subpopulations, beetles living on different host species, or between the sexes; there was also no effect of body size. Our results suggest that other factors such as age, genotype, disease prevalence, or natal environment may be generating variance among individuals in PO activity. PMID- 26513244 TI - Identification of the Mechanisms Causing Reversion to Virulence in an Attenuated SARS-CoV for the Design of a Genetically Stable Vaccine. AB - A SARS-CoV lacking the full-length E gene (SARS-CoV-?E) was attenuated and an effective vaccine. Here, we show that this mutant virus regained fitness after serial passages in cell culture or in vivo, resulting in the partial duplication of the membrane gene or in the insertion of a new sequence in gene 8a, respectively. The chimeric proteins generated in cell culture increased virus fitness in vitro but remained attenuated in mice. In contrast, during SARS-CoV-?E passage in mice, the virus incorporated a mutated variant of 8a protein, resulting in reversion to a virulent phenotype. When the full-length E protein was deleted or its PDZ-binding motif (PBM) was mutated, the revertant viruses either incorporated a novel chimeric protein with a PBM or restored the sequence of the PBM on the E protein, respectively. Similarly, after passage in mice, SARS CoV-?E protein 8a mutated, to now encode a PBM, and also regained virulence. These data indicated that the virus requires a PBM on a transmembrane protein to compensate for removal of this motif from the E protein. To increase the genetic stability of the vaccine candidate, we introduced small attenuating deletions in E gene that did not affect the endogenous PBM, preventing the incorporation of novel chimeric proteins in the virus genome. In addition, to increase vaccine biosafety, we introduced additional attenuating mutations into the nsp1 protein. Deletions in the carboxy-terminal region of nsp1 protein led to higher host interferon responses and virus attenuation. Recombinant viruses including attenuating mutations in E and nsp1 genes maintained their attenuation after passage in vitro and in vivo. Further, these viruses fully protected mice against challenge with the lethal parental virus, and are therefore safe and stable vaccine candidates for protection against SARS-CoV. PMID- 26513246 TI - Application of sequential expanded granular sludge bed reactors for biodegradation of acetate, benzoate, terephtalate and p-toluate in purified terephtalic acid production wastewater. AB - The anaerobic degradation of four major constituents from purified terephtalic acid production wastewater in sequential two expanded granular sludge bed (EGSB) reactors was studied. The performance of the system was evaluated in terms of chemical oxygen demand (COD) removal efficiencies, methane production, stability, granular sludge adaptability as well as reversion of bacterial inhibition. With volumetric loading rates of 1.9-25 kg-COD m(-3) d(-1) and terephtalate and p toluate of 584-821 mg L(-1), average removal efficiencies of 97.6% and 75.2% were achieved in the EGSB reactors, respectively. In these conditions, gas production reached a total methane production rate of 0.33 L g-COD(-1) in the two-stage EGSB reactor system. The disturbance of the EGSB reactors was observed at a feed concentration above around 6.9 g-COD L(-1) because of higher influent COD concentration compared to other experiments. PMID- 26513245 TI - Combining Search, Social Media, and Traditional Data Sources to Improve Influenza Surveillance. AB - We present a machine learning-based methodology capable of providing real-time ("nowcast") and forecast estimates of influenza activity in the US by leveraging data from multiple data sources including: Google searches, Twitter microblogs, nearly real-time hospital visit records, and data from a participatory surveillance system. Our main contribution consists of combining multiple influenza-like illnesses (ILI) activity estimates, generated independently with each data source, into a single prediction of ILI utilizing machine learning ensemble approaches. Our methodology exploits the information in each data source and produces accurate weekly ILI predictions for up to four weeks ahead of the release of CDC's ILI reports. We evaluate the predictive ability of our ensemble approach during the 2013-2014 (retrospective) and 2014-2015 (live) flu seasons for each of the four weekly time horizons. Our ensemble approach demonstrates several advantages: (1) our ensemble method's predictions outperform every prediction using each data source independently, (2) our methodology can produce predictions one week ahead of GFT's real-time estimates with comparable accuracy, and (3) our two and three week forecast estimates have comparable accuracy to real-time predictions using an autoregressive model. Moreover, our results show that considerable insight is gained from incorporating disparate data streams, in the form of social media and crowd sourced data, into influenza predictions in all time horizons. PMID- 26513247 TI - In Vitro Mutational Analysis of the beta2 Adrenergic Receptor, an In Vivo Surrogate Odorant Receptor. AB - Many G-protein coupled receptors (GPCRs), such as odorant receptors (ORs), cannot be characterized in heterologous cells because of their difficulty in trafficking to the plasma membrane. In contrast, a surrogate OR, the GPCR mouse beta2 adrenergic-receptor (mbeta2AR), robustly traffics to the plasma membrane. We set out to characterize mbeta2AR mutants in vitro for their eventual use in olfactory axon guidance studies. We performed an extensive mutational analysis of mbeta2AR using a Green Fluorescent Protein-tagged mbeta2AR (mbeta2AR::GFP) to easily assess the extent of its plasma membrane localization. In order to characterize mutants for their ability to successfully transduce ligand-initiated signal cascades, we determined the half maximal effective concentrations (EC50) and maximal response to isoprenaline, a known mbeta2AR agonist. Our analysis reveals that removal of amino terminal (Nt) N-glycosylation sites and the carboxy terminal (Ct) palmitoylation site of mbeta2AR do not affect its plasma membrane localization. By contrast, when both the Nt and Ct of mbeta2AR are replaced with those of M71 OR, plasma membrane trafficking is impaired. We further analyze three mbeta2AR mutants (RDY, E268A, and C327R) used in olfactory axon guidance studies and are able to decorrelate their plasma membrane trafficking with their capacity to respond to isoprenaline. A deletion of the Ct prevents proper trafficking and abolishes activity, but plasma membrane trafficking can be selectively rescued by a Tyrosine to Alanine mutation in the highly conserved GPCR motif NPxxY. This new loss-of-function mutant argues for a model in which residues located at the end of transmembrane domain 7 can act as a retention signal when unmasked. Additionally, to our surprise, amongst our set of mutations only Ct mutations appear to lower mbeta2AR EC50s revealing their critical role in G-protein coupling. We propose that an interaction between the Nt and Ct is necessary for proper folding and/or transport of GPCRs. PMID- 26513248 TI - TdKT, a new killer toxin produced by Torulaspora delbrueckii effective against wine spoilage yeasts. AB - Microbiological spoilage is a major concern throughout the wine industry, and control tools are limited. This paper addresses the identification and partial characterization of a new killer toxin from Torulaspora delbrueckii with potential biocontrol activity of Brettanomyces bruxellensis, Pichia guilliermondii, Pichia manshurica and Pichia membranifaciens wine spoilage. A panel of 18 different wine strains of T. delbrueckii killer yeasts was analysed, and the strain T. delbrueckii NPCC 1033 (TdKT producer) showed a significant inhibitory effect on the growth of all different spoilage yeasts evaluated. The TdKT toxin was then subjected to a partial biochemical characterization. Its estimated molecular weight was N30 kDa and it showed glucanase and chitinase enzymatic activities. The killer activity was stable between pH 4.2 and 4.8 and inactivated at temperature above 40 degrees C. Pustulan and chitin - but not other cell wall polysaccharides - prevented sensitive yeast cells from being killed by TdKT, suggesting that those may be the first toxin targets in the cell wall. TdKT provoked an increase in necrosis cell death after 3 h treatment and apoptotic cell death after 24 h showing time dependence in its mechanisms of action. Killer toxin extracts were active at oenological conditions, confirming their potential use as a biocontrol tool in winemaking. PMID- 26513249 TI - Genetic diversity analysis of isolates belonging to the Photobacterium phosphoreum species group collected from salmon products using AFLP fingerprinting. AB - An accurate amplified fragment length polymorphism (AFLP) method, including three primer sets for the selective amplification step, was developed to display the phylogenetic position of Photobacterium isolates collected from salmon products. This method was efficient for discriminating the three species Photobacterium phosphoreum, Photobacterium iliopiscarium and Photobacterium kishitanii, until now indistinctly gathered in the P. phosphoreum species group known to be strongly responsible for seafood spoilage. The AFLP fingerprints enabled the isolates to be separated into two main clusters that, according to the type strains, were assigned to the two species P. phosphoreum and P. iliopiscarium. P. kishitanii was not found in the collection. The accuracy of the method was validated by using gyrB-gene sequencing and luxA-gene PCR amplification, which confirmed the species delineation. Most of the isolates of each species were clonally distinct and even those that were isolated from the same source showed some diversity. Moreover, this AFLP method may be an excellent tool for genotyping isolates in bacterial communities and for clarifying our knowledge of the role of the different members of the Photobacterium species group in seafood spoilage. PMID- 26513250 TI - Bacterial consortia at different wine fermentation phases of two typical Central European grape varieties: Blaufrankisch (Frankovka modra) and Gruner Veltliner (Veltlinske zelene). AB - This is the first study focused to bacterial diversity and dynamic during the vinification of two important Central Europe grape vines: Blaufrankisch and Gruner Veltliner. The investigation strategy included culture-dependent and culture-independent approaches. Four different agar media were utilized for the isolation of various bacteria occurring in several fermentation stages. The isolates were clustered by fluorescent-ITS PCR and, one or more representatives of each cluster, were identified by 16 rRNA gene sequencing. The culture independent approach, based on 16S rRNA gene amplification, combined the denaturing gradient gel electrophoresis (DGGE) method and the construction of bacterial clone library for each wine fermentation step. A complex bacterial community was identified, comprising different lactic acid bacteria and acetic acid bacteria, such as Leuconostoc spp., Lactobacillus spp. and Gluconobacter spp. Other OTUs and bacterial isolates embraced the Actinobacteria, Bacilli, Alpha-, Beta- and Gamma-proteobacteria classes. Different taxa already detected by recent studies, such as Sphingomonas, Variovorax, Pantoea, Enterobacter and Tatumella, were detected confirming the continuous occurrence of these kinds of bacteria in wine environment. Moreover, novel genera (Amycolatopsis, Hydrogenophilus, Snodgrassella, Telluria, Gilliamella, Lelliottia, and Lonsdale quercina) never detected before were recognized, too. The role of these, until now anonymous, bacteria during vinification deserves investigation, which could open a new research field in wine technology. PMID- 26513251 TI - Characterization of a transferable bcrABC and cadAC genes-harboring plasmid in Listeria monocytogenes strain isolated from food products of animal origin. AB - In this study, we characterized a bcrABC cassette and its genetic environment harbored by a plasmid in Listeria monocytogenes (L. monocytogenes) 11GZL18, a strain isolated from raw meat in 2011. The bcrABC cassette and its genetic environment were characterized, with a total of 33,727 nt nucleotide sequence obtained. The nucleotide sequences of the bcrABC cassette in strain 11GZL18 exhibited 100% identity to that on plasmid pLM80, which is harbored by L. monocytogenes strain H7550 and H7858, and the neighboring 21,678 nt nucleotide sequence of bcrABC cassette showed 99% identity with plasmid pLM80. The plasmid curing experiment demonstrated the role of the plasmid in conferring benzalkonium chloride (BC) and cadmium (Cd) tolerance in this strain. The bcrABC cassette and cadAC genes from the L. monocytogenes 11GZL18 were harbored by plasmid, functional and transmissible, and led to the acquired tolerance in Gram-negative Escherichia coli (E. coli) DH5alpha by chemical and natural transformation. Besides, the efflux pump activity that is conferring tolerance to BC and Cd was observed in strain 11GZL18, while not in a plasmid-cured strain 11GZL18-C, confirming that efflux pumps play a role in plasmid-mediated tolerance to BC and Cd in L. monocytogenes 11GZL18. In this study we characterized the genetic organization of a novel BC and Cd tolerance determinants-harboring plasmid in a L. monocytogenes strain isolated from raw meat of animal origin, and demonstrated the potential horizontal transferability of this bcrABC cassette-harboring plasmid to E. coli. The findings will further improve our understanding of the adaptations of this organism to disinfectants such as BC and may contribute to elucidating possible dissemination of BC tolerance in foodborne L. monocytogenes. PMID- 26513252 TI - Impact of bacterial biocontrol agents on aflatoxin biosynthetic genes, aflD and aflR expression, and phenotypic aflatoxin B1 production by Aspergillus flavus under different environmental and nutritional regimes. AB - The objectives of this study were to examine the efficacy of four bacterial antagonists against Aspergillus flavus using 50:50 ratio of bacterial cells/conidia for the control of aflatoxin B1 (AFB1) production on two different nutritional matrices, nutrient and maize-based media at different water availabilities (0.98, 0.94 water activity (aw) on nutrient medium; 0.995, 0.98 aw on maize meal agar medium) at 35 degrees C. The indicators of efficacy used were the relative expression of one structural and regulatory gene in the biosynthetic pathway (aflD and aflR respectively) and the production of AFB1. These studies showed that some of the bacterial species could significantly inhibit the relative expression of the aflD and aflR genes at both 0.98 and 0.94 aw on nutrient agar. On maize-based media some of the bacterial antagonists reduced the activity of both genes at 0.94 aw and some at 0.995 aw. However, the results for AFB1 production were not consistent with the effects on gene expression. Some bacterial species stimulated AFB1 production on both nutrient and maize-based media regardless of aw. However, some bacterial treatments did inhibit AFB1 production significantly when compared to the control. Overall, this study suggests that temporal studies are required on the biosynthetic genes under different environmental and nutritional conditions to evaluate the potential of antagonists to control AFB1. PMID- 26513253 TI - Characterization of Cronobacter spp. isolated from food of plant origin and environmental samples collected from farms and from supermarkets in the Czech Republic. AB - The Cronobacter genus (previously known as Enterobacter sakazakii) comprises seven species (Cronobacter sakazakii, Cronobacter malonaticus, Cronobacter muytjensii, Cronobacter turicensis, Cronobacter dublinensis, Cronobacter universalis and Cronobacter condimenti)which cause serious infections in neonates and immunocompromised people.Most of the documented outbreaks of these bacteria have been associated with consumption of contaminated powdered infant formula. The plant environment is considered to be the natural habitat of these bacteria. Therefore, a total number of 563 samples of vegetables, fruit, water and environmental swabs were collected from local farms and supermarkets in the Czech Republic and investigated for the presence of Cronobacter spp. The obtained 45 isolates (8.0%) were further characterized by phenotyping (antimicrobial resistance, capsule and pigment production) and genotyping (fusA sequencing,MLST, PCR-serotyping) methods. Most of the Cronobacter isolates (42.2%) were identified as C. sakazakii, followed by C. turicensis (31.1%), C. dublinensis (22.2%), C. malonaticus (2.2%) and C. universalis (2.2%). The 25 identified sequence types, out of which 17 were unique for only one strain, indicated a high diversity of strains. C. sakazakii sequence type 4 (ST 4), which has been associated with many cases of meningitis, was isolated only in one case. A strong association of C. turicensis and C. dublinensis with the plant environment can be deduced from our results. PMID- 26513254 TI - Molecular characterization of patulin producing and non-producing Penicillium species in apples from Morocco. AB - The isolation of patulin-producing Penicillia in apples collected in different markets in four localities in Morocco is reported. Fungi were identified by beta tubulin sequencing and further characterized using a specific PCR-based method targeting the isoepoxydon dehydrogenase (IDH) gene to discriminate between patulin-producing and non-producing strains. Production of patulin was also evaluated using standard cultural and biochemical methods. Results showed that 79.5% of contaminant fungi belonged to the genus Penicillium and that Penicillium expansum was the most isolated species (83.9%) followed by Penicillium chrysogenum (~9.7%) and Penicillium crustosum (~6.4%). Molecular analysis revealed that 64.5% of the Penicillium species produced the expected IDH-amplicon denoting patulin production in these strains. However, patulin production was not chemically confirmed in all P. expansum strains. The isolation of IDH( )/patulin(+) strains poses the hypothesis that gentisylaldehyde is not a direct patulin precursor, supporting previous observations that highlighted the importance of the gentisyl alcohol in the production of this mycotoxin. Total agreement between IDH-gene detection and cultural/chemical methods employed was observed in 58% of P. expansum strains and for 100% of the other species isolated. Overall the data reported here showed a substantial genetic variability within P. expansum population from Morocco. PMID- 26513255 TI - Efflux pump-mediated benzalkonium chloride resistance in Listeria monocytogenes isolated from retail food. AB - In this study, efflux pump-mediated benzalkonium chloride (BC) resistance, including plasmid-encoded (Qac protein family and BcrABC) and chromosome-borne efflux pumps, was investigated in Listeria monocytogenes from retail food in China. Among the 59 L. monocytogenes strains, 13 (22.0%) strains were resistant to BC. The PCR results showed that bcrABC was harbored by 2 of 13 BC resistant strains. However, none of the qac genes were detected among the 59 strains. The bcrABC was absent in both of the plasmid cured strains, indicating that this BC resistance determinant was plasmid-encoded in the two bcrABC-positive strains. In the presence of reserpine, most of the bcrABC-negative strains had decreases in the MICs of BC, suggesting the existence of other efflux pumps and their role in BC resistance. After exposed to reserpine, the reduction in BC MICs was observed in the two cured strains, indicating that efflux pumps located on chromosome was also involved in BC resistance. Our findings suggest that food products may act as reservoirs for BC resistant isolates of L. monocytogenes and plasmid- and chromosome-encoded efflux pumps could mediate the BC resistance of L. monocytogenes, which is especially relevant to the adaption of this organism in food-related environments with frequent BC use. PMID- 26513256 TI - Heat Shock Factor 1 Deficiency Affects Systemic Body Temperature Regulation. AB - INTRODUCTION: Heat shock factor 1 (HSF1) is a ubiquitous heat-sensitive transcription factor that mediates heat shock protein transcription in response to cellular stress, such as increased temperature, in order to protect the organism against misfolded proteins. In this study, we analysed the effect of HSF1 deficiency on core body temperature regulation. MATERIALS AND METHODS: Body temperature, locomotor activity, and food consumption of wild-type mice and HSF1 deficient mice were recorded. Prolactin and thyroid-stimulating hormone levels were measured by ELISA. Gene expression in brown adipose tissue was analysed by quantitative real-time PCR. Hypothalamic HSF1 and its co-localisation with tyrosine hydroxylase was analysed using confocal laser scanning microscopy. RESULTS: HSF1-deficient mice showed an increase in core body temperature (hyperthermia), decreased overall locomotor activity, and decreased levels of prolactin in pituitary and blood plasma reminiscent of cold adaptation. HSF1 could be detected in various hypothalamic regions involved in temperature regulation, suggesting a potential role of HSF1 in hypothalamic thermoregulation. Moreover, HSF1 co-localises with tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, suggesting a potential role of HSF1 in the hypothalamic control of prolactin release. In brown adipose tissue, levels of prolactin receptor and uncoupled protein 1 were increased in HSF1-deficient mice, consistent with an up-regulation of heat production. CONCLUSION: Our data suggest a role of HSF1 in systemic thermoregulation. PMID- 26513257 TI - Non-Invasive Microbial Metabolic Activity Sensing at Single Cell Level by Perfusion of Calcein Acetoxymethyl Ester. AB - Phase contrast microscopy cannot give sufficient information on bacterial metabolic activity, or if a cell is dead, it has the fate to die or it is in a viable but non-growing state. Thus, a reliable sensing of the metabolic activity helps to distinguish different categories of viability. We present a non-invasive instantaneous sensing method using a fluorogenic substrate for online monitoring of esterase activity and calcein efflux changes in growing wild type bacteria. The fluorescent conversion product of calcein acetoxymethyl ester (CAM) and its efflux indicates the metabolic activity of cells grown under different conditions at real-time. The dynamic conversion of CAM and the active efflux of fluorescent calcein were analyzed by combining microfluidic single cell cultivation technology and fluorescence time lapse microscopy. Thus, an instantaneous and non invasive sensing method for apparent esterase activity was created without the requirement of genetic modification or harmful procedures. The metabolic activity sensing method consisting of esterase activity and calcein secretion was demonstrated in two applications. Firstly, growing colonies of our model organism Corynebacterium glutamicum were confronted with intermittent nutrient starvation by interrupting the supply of iron and carbon, respectively. Secondly, bacteria were exposed for one hour to fatal concentrations of antibiotics. Bacteria could be distinguished in growing and non-growing cells with metabolic activity as well as non-growing and non-fluorescent cells with no detectable esterase activity. Microfluidic single cell cultivation combined with high temporal resolution time lapse microscopy facilitated monitoring metabolic activity of stressed cells and analyzing their descendants in the subsequent recovery phase. Results clearly show that the combination of CAM with a sampling free microfluidic approach is a powerful tool to gain insights in the metabolic activity of growing and non growing bacteria. PMID- 26513258 TI - Association between Lymph Node Ratio and Disease Specific Survival in Breast Cancer Patients with One or Two Positive Lymph Nodes Stratified by Different Local Treatment Modalities. AB - PURPOSE: Results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial indicated that complete axillary node dissection (ALND) may not be warranted in some breast cancer patients with low tumor burden who are undergoing breast-conserving surgery following whole-breast irradiation. However, this study did not address patients undergoing mastectomy or those undergoing breast conserving surgery without whole-breast radiotherapy. Given that lymph node ratio (LNR; ratio of positive lymph nodes to the total number removed) has been shown to be a prognostic factor in breast cancer, we first sought to determine the prognostic value of LNR in a low risk population comparable to that of the Z0011 trial and further to investigate whether the prognostic significance differs with local treatment modality. METHOD: We used the Surveillance Epidemiology and End Results (SEER) database to identify breast cancer patients with T1-T2 tumor and 1 2 positive nodes. Patients were subclassified by the local therapy they underwent for the primary tumor. The prognostic value of LNR in predicting disease-specific survival (DSS) was examined in each treatment group. RESULTS: A total of 53,109 patients were included. In the subgroup of 20,602 patients who underwent lumpectomy following radiotherapy, LNR was not found to be significantly associated with DSS in both the univariate and multivariate model. For the 4,664 patients treated with mastectomy following radiotherapy, 6,811 treated with lumpectomy without radiotherapy and 21,031 with mastectomy without radiotherapy, LNR independently predict DSS in each of these subgroups. CONCLUSIONS: Our results add evidence to the concept that axillary dissection could be omitted in patients with one or two positive nodes following breast-conserving surgery and whole breast radiation. PMID- 26513260 TI - Simultaneous Overexpression of Functional Human HO-1, E5NT and ENTPD1 Protects Murine Fibroblasts against TNF-alpha-Induced Injury In Vitro. AB - Several biomedical applications, such as xenotransplantation, require multiple genes simultaneously expressed in eukaryotic cells. Advances in genetic engineering technologies have led to the development of efficient polycistronic vectors based on the use of the 2A self-processing oligopeptide. The aim of this work was to evaluate the protective effects of the simultaneous expression of a novel combination of anti-inflammatory human genes, ENTPD1, E5NT and HO-1, in eukaryotic cells. We produced an F2A system-based multicistronic construct to express three human proteins in NIH3T3 cells exposed to an inflammatory stimulus represented by tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory cytokine which plays an important role during inflammation, cell proliferation, differentiation and apoptosis and in the inflammatory response during ischemia/reperfusion injury in several organ transplantation settings. The protective effects against TNF-alpha-induced cytotoxicity and cell death, mediated by HO-1, ENTPD1 and E5NT genes were better observed in cells expressing the combination of genes as compared to cells expressing each single gene and the effect was further improved by administrating enzymatic substrates of the human genes to the cells. Moreover, a gene expression analyses demonstrated that the expression of the three genes has a role in modulating key regulators of TNF alpha signalling pathway, namely Nemo and Tnfaip3, that promoted pro-survival phenotype in TNF-alpha injured cells. These results could provide new insights in the research of protective mechanisms in transplantation settings. PMID- 26513262 TI - Erratum: An 80 kyr-long continuous speleothem record from Dim Cave, SW Turkey with paleoclimatic implications for the Eastern Mediterranean. PMID- 26513261 TI - Mesenchymal Stem Cells Exhibit Regulated Exocytosis in Response to Chemerin and IGF. AB - Mesenchymal stem cells (MSCs) play important roles in tissue repair and cancer progression. Our recent work suggests that some mesenchymal cells, notably myofibroblasts exhibit regulated exocytosis resembling that seen in neuroendocrine cells. We now report that MSCs also exhibit regulated exocytosis. Both a G-protein coupled receptor agonist, chemerin, and a receptor tyrosine kinase stimulant, IGF-II, evoked rapid increases in secretion of a marker protein, TGFbetaig-h3. The calcium ionophore, ionomycin, also rapidly increased secretion of TGFbetaig-h3 while inhibitors of translation (cycloheximide) or secretory protein transport (brefeldin A) had no effect, indicating secretion from preformed secretory vesicles. Inhibitors of the chemerin and IGF receptors specifically reduced the secretory response. Confocal microscopy of MSCs loaded with Fluo-4 revealed chemerin and IGF-II triggered intracellular Ca2+ oscillations requiring extracellular calcium. Immunocytochemistry showed co localisation of TGFbetaig-h3 and MMP-2 to secretory vesicles, and transmission electron-microscopy showed dense-core secretory vesicles in proximity to the Golgi apparatus. Proteomic studies on the MSC secretome identified 64 proteins including TGFbetaig-h3 and MMP-2 that exhibited increased secretion in response to IGF-II treatment for 30min and western blot of selected proteins confirmed these data. Gene ontology analysis of proteins exhibiting regulated secretion indicated functions primarily associated with cell adhesion and in bioassays chemerin increased adhesion of MSCs and adhesion, proliferation and migration of myofibroblasts. Thus, MSCs exhibit regulated exocytosis that is compatible with an early role in tissue remodelling. PMID- 26513263 TI - Archaic RDA Methodology for Vitamin C. AB - Frei et al's 2012 review entitled "Authors' Perspective: What is the Optimum Intake of Vitamin C in Humans" is both flawed and misleading. RCTs are ill suited to determining the RDA, it is debatable that there is sufficient scientific evidence to determine the optimum intake of vitamin C in humans, observations regarding high-doses of ascorbate have been ignored, and there are inaccuracies of fact with respect to the saturation of blood plasma following low dose intake. Until the limitations of current knowledge are recognised it is unwise to set limits on the dose. PMID- 26513264 TI - Practical survey on antibiotic-resistant bacterial communities in livestock manure and manure-amended soil. AB - Through livestock manure fertilization, antibiotics, antibiotic-resistant bacteria and genes are transferred to agricultural soils, resulting in a high prevalence of antibiotic-resistant bacteria in the soil. It is not clear, however, whether a correlation exists between resistant bacterial populations in manure and manure-amended soil. In this work, we demonstrate that the prevalence of cephalexin-, amoxicillin-, kanamycin- and gentamicin-resistant bacteria as well as bacteria simultaneously resistant to all four antibiotics was much higher in manure-amended soils than in manure-free soil. 454-pyrosequencing indicated that the ARB and multiple antibiotic-resistant bacteria (MARB) in swine or chicken manure and manure-amended soil were mainly distributed among Sphingobacterium, Myroides, Enterococcus, Comamonas and unclassified Flavobacteriaceae. The genus Sphingobacterium was highly prevalent among ARB from swine manure and manure-amended soil, and was also the most dominant genus among MARB from chicken manure and manure-amended soil. Other dominant genera among ARB or MARB populations in manure samples, including Myroides, Enterococcus and Comamonas, could not be detected or were detected at very low relative abundance in manure-amended soil. The present study suggests the possibility of transfer of ARBs from livestock manures to soils and persistence of ARB in these environments. PMID- 26513265 TI - Cross-Sectional Association Between Number of Teeth and High-Sensitivity C Reactive Protein Among Middle-Aged Germans. AB - BACKGROUND: The association between number of teeth and low-grade systemic inflammation deserves consideration within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam since the association between number of teeth and myocardial infarction has been established. METHODS: Two subsamples (n = 2,439 and 728) were randomly selected from EPIC-Potsdam. Participants provided information on number of natural teeth, anthropometry, lifestyle factors, and illness-related factors. High-sensitivity C-reactive protein (hsCRP) was measured from serum. Adjusted means of hsCRP across five categories of numbers of teeth in each subsample and in the combined sample were determined, and linear trends were checked. Non-linear associations were investigated with restricted cubic spline (RCS) regression. RESULTS: In the first subsample, the full multivariable adjusted model showed that participants with 28 to 32, 24 to 27, 18 to 23, 1 to 17, and 0 teeth had mean hsCRP values of 1.32, 1.39, 1.54, 1.38, and 1.48 mg/L, respectively; in the second subsample, mean hsCRP values were 1.64, 1.67, 1.73, 1.47, and 1.87 mg/L; combined hsCRP values were 1.49, 1.53, 1.64, 1.44, and 1.65 mg/L. No linear trend was observed in these models, and RCS regression showed no non-linear association. CONCLUSION: This study shows that number of teeth has a weak association with hsCRP, if any, thereby excluding this marker of low-grade systemic inflammation as a possible explanation for the association between number of teeth and myocardial infarction. PMID- 26513266 TI - Relationship Among Mothers' Glycemic Level, Periodontitis, and Birth Weight. AB - BACKGROUND: The aim of this study is to determine the influence of glycemic level on the relationship between periodontitis and low birth weight (LBW). METHODS: A case-control study was conducted with 372 females divided into cases (109 mothers of newborns with birth weight < 2,500 g) and controls (263 mothers of newborns with birth weight >= 2,500 g). The birth weight of children was obtained from medical records, whereas information on sociodemographic, lifestyle, and health characteristics of the participants was obtained through an interview. Glycated hemoglobin (HbA1c) levels were measured, and probing depth, clinical attachment levels, and bleeding on probing were used to determine the periodontal status. Results were analyzed using logistic regression. RESULTS: The likelihood of having children with LBW among the mothers with periodontitis was six times greater than that observed among mothers without periodontitis (adjusted odds ratio [OR adjusted] = 6.02, 95% confidence interval [CI] = 2.47 to 15.17), even after adjustment. There was also a strong, statistically significant relationship between periodontitis and LBW in both the normal glycemic-level group (HbA1c levels < 5.6%, unadjusted odds ratio [OR unadjusted] = 8.30, 95% CI = 3.56 to 19.35) and the high glycemic-level group (HbA1c levels >= 5.6% and < 6.5%, OR unadjusted = 5.73, 95% CI = 1.75 to 18.70). After adjustment for confounders, the magnitude of the association continued to be strong in the normal glycemic-level group (OR adjusted = 7.59, 95% CI = 2.7 to 24.28), an increase of 25% when compared to the main association measurement. In those with high glycemic levels (OR adjusted = 4.03, 95% CI = 0.81 to 19.96), the OR decreased almost 50%, and the association lost statistical significance. CONCLUSION: Periodontitis and glycemic levels appeared to have opposing influences on birth weight, with periodontitis being associated with LBW and the magnitude of the association being altered depending on maternal blood glucose level. PMID- 26513267 TI - Abutment Coating With Diamond-Like Carbon Films to Reduce Implant-Abutment Bacterial Leakage. AB - BACKGROUND: The influence of diamond-like carbon (DLC) films on bacterial leakage through the interface between abutments and dental implants of external hexagon (EH) and internal hexagon (IH) designs was evaluated. METHODS: Film deposition was performed by plasma-enhanced chemical vapor deposition. Sets of implants and abutments (n = 30 per group, sets of 180 implants) were divided according to connection design and treatment of the abutment base: 1) no treatment (control); 2) DLC film deposition; and 3) Ag-DLC film deposition. Under sterile conditions, 1 MUL Enterococcus faecalis was inoculated inside the implants, and abutments were tightened. The sets were tested for immediate external contamination, suspended in test tubes containing sterile culture broth, and followed for 5 days. Turbidity of the broth indicated bacterial leakage. At the end of the period, the abutments were removed and the internal content of the implants was collected with paper points and plated in Petri dishes. After 24-hour incubation, they were assessed for bacterial viability and colony-forming unit counting. Bacterial leakage was analyzed by chi(2) and Fisher exact tests (alpha = 5%). RESULTS: The percentage of bacterial leakage was 16.09% for EH implants and 80.71% for IH implants (P <0.0001). The bacterial load was higher inside IH implants (P = 0.000). The type of implant significantly influenced the results (P = 0.000), whereas the films did not (P = 0.487). CONCLUSION: IH implants show a higher frequency of bacterial leakage; and DLC and Ag-DLC films do not significantly reduce the frequency of bacterial leakage and bacteria load inside the implants. PMID- 26513268 TI - Periodontal Pathogens and Risk of Incident Cancer in Postmenopausal Females: The Buffalo OsteoPerio Study. AB - BACKGROUND: Extraoral translocation of oral bacteria may contribute to associations between periodontal disease and cancer. The associations among the presence of three orange-complex periodontal pathogens (Fusobacterium nucleatum, Prevotella intermedia, and Campylobacter rectus), two red-complex periodontal pathogens (Porphyromonas gingivalis and Tannerella forsythia), and cancer risk were investigated. METHODS: A total of 1,252 postmenopausal females enrolled in the Buffalo Osteoporosis and Periodontal Disease Study were followed prospectively. Baseline subgingival plaque samples were assessed for the presence of periodontal pathogens using indirect immunofluorescence. Incident cancer cases were adjudicated by staff physicians via review of medical records. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of periodontal pathogens with total cancer and site-specific cancer risk in unadjusted and multivariable adjusted models. RESULTS: Neither the presence of individual pathogens nor the presence of any red-complex pathogens was associated with total cancer or site specific cancers. Borderline associations were seen among the presence of any orange-complex pathogens (F. nucleatum, P. intermedia, and C. rectus), total cancer risk (HR = 1.35, 95% CI = 1.00 to 1.84), and lung cancer risk (HR = 3.02, 95% CI = 0.98 to 9.29). CONCLUSIONS: No associations were found between the presence of individual subgingival pathogens and cancer risk. However, there were suggestions of borderline positive associations of the presence of any orange complex pathogens with total cancer and lung cancer risk. The study is limited by the small number of cancer cases and the assessment of only five oral bacteria. Additional research is needed to understand the possible role of periodontal disease in carcinogenesis. PMID- 26513269 TI - Non-linear dynamics of stable carbon and hydrogen isotope signatures based on a biological kinetic model of aerobic enzymatic methane oxidation. AB - The non-linear dynamics of stable carbon and hydrogen isotope signatures during methane oxidation by the methanotrophic bacteria Methylosinus sporium strain 5 (NCIMB 11126) and Methylocaldum gracile strain 14 L (NCIMB 11912) under copper rich (8.9 uM Cu(2+)), copper-limited (0.3 uM Cu(2+)) or copper-regular (1.1 uM Cu(2+)) conditions has been described mathematically. The model was calibrated by experimental data of methane quantities and carbon and hydrogen isotope signatures of methane measured previously in laboratory microcosms reported by Feisthauer et al. [ 1 ] M. gracile initially oxidizes methane by a particulate methane monooxygenase and assimilates formaldehyde via the ribulose monophosphate pathway, whereas M. sporium expresses a soluble methane monooxygenase under copper-limited conditions and uses the serine pathway for carbon assimilation. The model shows that during methane solubilization dominant carbon and hydrogen isotope fractionation occurs. An increase of biomass due to growth of methanotrophs causes an increase of particulate or soluble monooxygenase that, in turn, decreases soluble methane concentration intensifying methane solubilization. The specific maximum rate of methane oxidation upsilonm was proved to be equal to 4.0 and 1.3 mM mM(-1) h(-1) for M. sporium under copper rich and copper-limited conditions, respectively, and 0.5 mM mM(-1) h(-1) for M. gracile. The model shows that methane oxidation cannot be described by traditional first-order kinetics. The kinetic isotope fractionation ceases when methane concentrations decrease close to the threshold value. Applicability of the non-linear model was confirmed by dynamics of carbon isotope signature for carbon dioxide that was depleted and later enriched in (13)C. Contrasting to the common Rayleigh linear graph, the dynamic curves allow identifying inappropriate isotope data due to inaccurate substrate concentration analyses. The non-linear model pretty adequately described experimental data presented in the two dimensional plot of hydrogen versus carbon stable isotope signatures. PMID- 26513270 TI - Thermal Adaptability of the Light-Harvesting Complex 2 from Thermochromatium tepidum: Temperature-Dependent Excitation Transfer Dynamics. AB - The photosynthetic purple bacterium Thermochromatium (Tch.) tepidum is a thermophile that grows at an optimal temperature of ~50 degrees C. We have investigated, by means of steady-state and time-resolved optical spectroscopies, the effects of temperature on the near-infrared light absorption and the excitation energy transfer (EET) dynamics of its light-harvesting complex 2 (LH2), for which the mesophilic counterpart of Rhodobacter (Rba.) sphaeroides 2.4.1 (~30 degrees C) was examined in comparison. In a limited range around the physiological temperature (10-55 degrees C), the B800-to-B850 EET process of the Tch. tepidum LH2, but not the Rba. sphaeroides LH2, was found to be characteristically temperature-dependent, mainly because of a temperature-tunable spectral overlap. At 55 degrees C, the LH2 complex from Tch. tepidum maintained efficient near-infrared light harvesting and B800-to-B850 EET dynamics, whereas this EET process was disrupted in the case of Rba. sphaeroides 2.4.1 owing to the structural distortion of the LH2 complex. Our results reveal a remarkable thermal adaptability of the light-harvesting function of Tch. tepidum, which could enhance our understanding of the survival strategy of this thermophile in response to environmental challenges. PMID- 26513271 TI - Role of various DNA repair pathways in chromosomal inversion formation in CHO mutants. AB - PURPOSE: In an effort to better understand the formation of chromosomal inversions, we investigated the role of various DNA repair pathways, including the non-homologous end joining (NHEJ), homologous recombination (HR), and Fanconi Anemia (FA) repair pathways for the formation of radiation induced chromosomal inversions. MATERIALS AND METHODS: CHO10B2 wild type, CHO DNA repair-deficient, and CHO DNA repair-deficient corrected mutant cells were synchronized into G1 phase and exposed to gamma-rays. First post-irradiation metaphase cells were analyzed for chromosomal inversions by a differential chromatid staining technique involving a single cycle pre-irradiation ethynyl-uridine treatment and statistic calculations. RESULTS: It was observed that inhibition of the NHEJ pathway resulted in an overall decrease in the number of radiation-induced inversions, roughly a 50% decrease when compared to the CHO wild type. Interestingly, inhibition of the FA pathway resulted in an increase in both the number of spontaneous inversions and the number of radiation-induced inversions observed after exposure to 2 Gy of ionizing radiation. It was observed that FA deficient cells contained roughly 330% (1.24 inversions per cell) more spontaneous inversions and 20% (0.4 inversions per cell) more radiation-induced inversions than the wild-type CHO cell lines. The HR mutants, defective in Rad51 foci, showed similar number of spontaneous and radiation-induced inversion as the wild-type cells. Gene complementation resulted in both spontaneous and radiation induced inversions resembling the CHO wild-type cells. CONCLUSIONS: We have concluded that the NHEJ repair pathway contributes to the formation of radiation induced inversions. Additionally, through an unknown molecular mechanism it appears that the FA signal pathway prevents the formation of both spontaneous and radiation induced inversions. PMID- 26513272 TI - Blood-Flow Velocity in Glaucoma Patients Measured with the Retinal Function Imager. AB - PURPOSE: Circulatory abnormalities in the retina, optic nerve and choroid have been detected by various technologies in glaucoma patients. However, there is no clear understanding of the role of blood flow in glaucoma. The purpose of this study was to compare retinal blood-flow velocities using the retinal function imager (RFI) between glaucoma and healthy subjects. MATERIALS AND METHODS: Fifty nine eyes of 46 patients with primary open-angle glaucoma (POAG), 51 eyes of 31 healthy individuals and 28 eyes of 23 patients with glaucomatous optic neuropathy (GON) but normal perimetry were recruited for this study. Three eyes of 2 patients in the glaucoma group and 2 eyes of 1 patient in the GON group had normal pressure at the time of diagnosis. Eighty-three percent of the glaucoma patients and 73% of the patients in the GON group were treated with anti-glaucoma medications. All patients were scanned by the RFI. Differences among groups were assessed by mixed linear models. RESULTS: The average venous velocity in the GON group (3.8 mm/s) was significantly faster than in the glaucoma (3.3 mm/s, p = 0.03) and healthy (3.0 mm/s, p = 0.005) groups. The arterial velocity in the GON group was not different from any of the other study groups (4.7 mm/s). The arterial and venous velocity in the POAG eyes was not different than in the healthy eyes (arterial: 4.3 versus 4.2 mm/s, p = 0.7; venous: 3.3 versus 3.0 mm/s, p = 0.3). A subgroup of 13 glaucoma patients who had perimetric glaucoma in 1 eye and normal visual field (VF) in the fellow eye showed a trend of lower velocity in the glaucoma eyes. CONCLUSIONS: Changes in retinal blood-flow velocity were detected only in the pre-perimetric state, but not in perimetric glaucoma. These findings might represent early dysregulation in the retinal vasculature. PMID- 26513273 TI - Antenatal corticosteroids: analytical decision model and economic analysis in a Brazilian cohort of preterm infants. AB - OBJECTIVE: To analyze the hospital costs and the effectiveness of antenatal corticosteroid (ACS) therapy in a cohort of Brazilian preterm infants. METHODS: Infants with gestational age (GA) 26 to 32 weeks, born between 2006 and 2009 in a tertiary university hospital and who survived hospitalization were included. A decision tree was built according to GA (26-27, 28-29, 30-31 and 32 weeks), assuming that each patient exposed or not to ACS may or not develop one of the clinical outcomes included in the model. The cost of each outcome was calculated by microcosting. Sensitivity analysis tested the model stability and calculated outcomes and costs per 1000 patients. RESULTS: The cost-effectiveness analysis indicated that ACS reduced USD 3413 in hospital costs per patient exposed to ACS. Its use decreased oxygen dependency at 36 weeks in 11%, advanced resuscitation in delivery room in 24%, severe peri-intraventricular hemorrhage in 12%, patent ductus arteriosus requiring surgery in 3.6% and retinopathy of prematurity in 0.3%, but increased the probability of late-onset sepsis in 2.5%. The sensitivity analysis indicated that ACS was dominant over no ACS therapy for most outcomes. CONCLUSION: The results indicate that ACS therapy decreases costs and severe neonatal outcomes of preterm infants. PMID- 26513274 TI - Sarcasm and emoticons: Comprehension and emotional impact. AB - Most theorists agree that sarcasm serves some communicative function that would not be achieved by speaking directly, such as eliciting a particular emotional response in the recipient. One debate concerns whether this kind of language serves to enhance or mute the positive or negative nature of a message. The role of textual devices commonly used to accompany written sarcastic remarks is also unclear. The current research uses a rating task to investigate the influence of textual devices (emoticons and punctuation marks) on the comprehension of, and emotional responses to, sarcastic versus literal criticism and praise, for both unambiguous (Experiment 1) and ambiguous (Experiment 2) materials. Results showed that sarcastic criticism was rated as less negative than literal criticism, and sarcastic praise was rated as less positive than literal praise, suggesting that sarcasm serves to mute the positive or negative nature of the message. In terms of textual devices, results showed that emoticons had a larger influence on both comprehension and emotional impact than punctuation marks. PMID- 26513275 TI - The complete mitochondrial genome of the Rana huanrensis (Anura: Ranidae). AB - We first determined complete mitochondrial genomes of R. huanrensis (Anura: Ranidae). The complete mtDNA sequence is 19 253 bp in length, including 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and one displacement loop. The start/stop codons of protein-coding genes are similar to which of R. chensinensis. D-loop region of R. huanrensis is 3448 bp in size, contains many tandem repeat units. The phylogenetic trees of 18 species from Ranidae were reconstructed by BI and ML analyses. The result indicated that R. huanrensis is the most closely related species with other Rana species. The molecular data are expected to provide a useful tool for population genetics studies of this species and further phylogenetic analyses of Ranidae. PMID- 26513276 TI - Capitate glandular trichomes of Paragutzlaffia henryi harbor new phytotoxic labdane diterpenoids. AB - The morphology and chemical profile of the capitate glandular trichomes (CGTs) of Paragutzlaffia henryi (Acanthaceae) were investigated. Four new labdane diterpenoids named paraguhenryisins A-D (1-4), together with the known physacoztomatin (5), were localized to the CGTs using laser microdissection coupled with cryogenic (1)H NMR and HPLC analyses and were traced and isolated from the CGT extract of inflorescences. Their structures were determined by spectroscopic methods and single-crystal X-ray diffraction. Bioassays indicated significant inhibitory effect for these diterpenoids on Arabidopsis thaliana seed germination and seedling root elongation. The most potent inhibitor, paraguhenryisin C (3), was interestingly detected in both the rhizosphere soil and water rinsed inflorescences extract of P. henryi but not the roots, with average contents in the rhizosphere soil relevant to its phytotoxic EC50 values. These results suggested that phytotoxic labdane diterpenoids in the CGTs might be released into the environment as a defensive measure for P. henryi against other competitive plants. PMID- 26513277 TI - Mitochondrial DNA content and function, childhood obesity, and insulin resistance. AB - OBJECTIVES: The objectives of our study were to compare the mitochondrial enzyme activity between obese and non-obese children and to assess the association between mitochondrial DNA content and function and markers of metabolic syndrome. METHODS: Clinical and anthropometric data of obese and normal-weight children ages 2-18 years were collected. We collected buccal swabs for mitochondrial respiratory enzymes (complex I, IV, and Citrate Synthase). In obese children only, serum levels of metabolic parameters and mitochondrial DNA from mononuclear cells were quantitated. RESULTS: We recruited 75 obese and 65 normal-weight children. There was no difference in respiratory complex enzyme activity levels between obese and normal-weight subjects. In obese subjects, mitochondrial to nuclear DNA (mt/nDNA) ratio was significantly correlated with BMI Z-score and BMI percentile (p < 0.05, and p < 0.01, respectively), and the strength of this correlation was proportionate to the degree of obesity. We did not find any association between mt/nDNA ratio and metabolic parameters. We observed a significant positive association between complex IV activity and fasting insulin level (p < 0.05). Finally, fasting insulin explained 45% of the variation in the complex IV activity level (p < 0.05). CONCLUSION: Our findings indicate that mitochondrial DNA content is directly related to obesity, but not to the markers of metabolic syndrome/insulin resistance in children. Longitudinal studies involving larger samples are needed to confirm our findings and help elucidate the relationship between mitochondrial function, adiposity, and insulin resistance. PMID- 26513278 TI - Prebiotics for the management of hyperbilirubinemia in preterm neonates. AB - OBJECTIVE: We evaluated if prebiotics have benefits for the management of hyperbilirubinemia in preterm neonates. METHODS: Preterm neonates were entered into the study when enteral feeding volume met 30 mL/kg/day. They randomly received a mixture of short-chain galacto-oligosacarids/long-chain fructo oligosacarids or distilled water (placebo) for 1 week. Total serum bilirubin level was measured by transcutaneous bilirubinometry. Stool frequency and meeting full enteral feeding during the study period were considered as secondary outcomes. RESULTS: Twenty-five neonates in each group completed the trial. Bilirubin level was decreased with the prebiotic (-1.3 +/- 1.8 mg/dL, p = 0.004), but not placebo (-0.1 +/- 3.3 mg/dL, p = 0.416). Peak bilirubin level was lower with the prebiotic than placebo (8.3 +/- 1.7 versus 10.1 +/- 2.2 mg/dL, p = 0.003). Stool frequency was increased with the prebiotic (0.7 +/- 1.9 defecation/day, p = 0.014), but not with placebo (0.6 +/- 1.5 defecation/day, p = 0.133). Average stool frequency (2.4 +/- 0.4 versus 1.9 +/- 0.5 defecation/day, p = 0.003) and frequently of meeting full enteral feeding (60% versus 16%, p = 0.002) were higher with the prebiotic than placebo. CONCLUSIONS: Prebiotic oligosaccharides increase stool frequency, improve feeding tolerance and reduce bilirubin level in preterm neonates and therefore can be efficacious for the management of neonatal hyperbilirubinemia. PMID- 26513279 TI - Health, Wealth, and the 21st Century Cures Act. PMID- 26513281 TI - A novel signal amplification strategy of an electrochemical aptasensor for kanamycin, based on thionine functionalized graphene and hierarchical nanoporous PtCu. AB - An ultrasensitive electrochemical aptasensor for the quantitative detection of kanamycin antibiotic was fabricated based on a novel signal amplification strategy. This aptasensor was developed using thionine functionalized graphene (GR-TH) and hierarchical nanoporous (HNP) PtCu alloy as biosensing substrates for the first time. HNP-PtCu alloy with controllable bimodal ligament/pore distributions was successfully prepared by two-step dealloying of a well-designed PtCuAl precursor alloy combined with an annealing operation. GR-TH composite was synthesized by one-step reduction of graphene oxide (GO) in TH solution. Greatly amplified sensitivity was achieved by using GR-TH/HNP-PtCu composite owing to its large specific surface and good electron-transfer ability. Under the optimized conditions, the proposed aptasensor exhibited a high sensitivity and a wider linearity to kanamycin in the range 5 * 10(-7)-5 * 10(-2) MUgmL(-1) with a low detection limit of 0.42 pgmL(-1). This aptasensor also displayed a satisfying electrochemical performance with good stability, selectivity and reproducibility. The as-prepared aptasensor was successfully used for the determination of kanamycin in animal derived food. PMID- 26513282 TI - Detection of prostate specific antigen based on electrocatalytic platinum nanoparticles conjugated to a recombinant scFv antibody. AB - Highly sensitive and label free detection of prostate specific antigen (PSA) still remains a challenge in prostate cancer diagnosis. In this paper, we propose a sensitive electrochemical immunosensor based on electrocatalytic platinum nanoparticles conjugated to a recombinant scFv antibody. Gold disc electrodes functionalised with a l-Cysteine (Cys) self-assembled monolayer (SAM) were used to covalently bind PSA specific monoclonal antibody (anti-PSA) using N-ethyl-N' (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide (EDC/NHS) chemistry. Immunosensing was completed using sandwich-type immunoreaction of the PSA-antigen (1-30 ng/mL) between anti-PSA immobilized on the l-Cys modified electrode using label free electrochemical impedance (EIS) technique. Furthermore, highly specific in-house generated scFv fragments as receptor proteins were utilised for one step site-directed immobilisation on the surface of platinum nanoparticles (PtNPs). To improve the sensitivity of the immunoassay, these scFV labelled electrocatalytic PtNPs were then used for covalent hybridisation to the PSA modified electrode and then applied in a hybridisation assay to determine the concentration of the PSA by measuring the faradaic current associated with reduction of peroxide in solution. Semi-log plots of the PSA concentration vs. faradaic current are linear from 1 to 30 ng/mL and pM concentrations can be detected without the need for molecular, e.g., PCR or NASBA, amplification. PMID- 26513283 TI - Preparation of a new nanobiosensor for the determination of some biogenic polyamines and investigation of their interaction with DNA. AB - Biogenic polyamines are small organic polycations involving in a variety of biological processes. They form high affinity complexes with DNA. Here, we have followed two different novel approaches, either fabrication of an electrochemical nanobiosensor for determination of three of the most important biogenic polyamines; spermine (SPM), spermidine (SPD) and putrescine (PUT), or electrochemical investigation of their interaction with DNA. Strong binding of polyamines to DNA makes the DNA a suitable recognition element for construction of a sensitive biosensor. The fabricated biosensor responded to SPM, SPD and PUT over an extended dynamic range of 0.04-100 MUM, 0.01-24 MUM, and 0.08-100 MUM respectively, with low detection limits of a few nM. We also studied the interaction of polyamines with three different DNA sequences with base composition of 100% AT, 80% AT and 100% GC in the presence of [Ru(NH3)6]3(+) as a redox probe. The highest kb values were obtained in the interaction of polyamines with 80% AT (mixed) DNA sequence. The kb values were 5.24 * 10(5), 4.17 * 10(5) and 1.46 * 10(5)M(-1) for SPM, SPD and PUT, respectively, which correlated well with their increasing number of amino groups. In addition, competition study showed the impotence of SPD to replace with histone H1 in histone H1-DNA complex, which indicates the more potent interaction of histone H1 with DNA. In this proof of-principle study, we have proposed an approach for simple, cost-effective, miniaturizable, and direct-readout detection of polyamines, as well as the understanding of the modes of interaction between polyamines and DNA. PMID- 26513284 TI - Fabrication techniques for microfluidic paper-based analytical devices and their applications for biological testing: A review. AB - Paper is increasingly recognized as a user-friendly and ubiquitous substrate for construction of microfluidic devices. Microfluidic paper-based analytical devices (MUPADs) provide an alternative technology for development of affordable, portable, disposable and low-cost diagnostic tools for improving point of care testing (POCT) and disease screening in the developing world, especially in those countries with no- or low-infrastructure and limited trained medical and health professionals. We in this review present fabrication techniques for microfluidic devices and their respective applications for biological detection as reported to date. These include: (i) fabrication techniques: examples of devices fabricated by using two-dimensional (2D) and three-dimensional (3D) methods; (ii) detection application: biochemical, immunological and molecular detection by incorporating efficient detection methods such as, colorimetric detection, electrochemical detection, fluorescence detection, chemiluminescence (CL) detection, electrochemiluninescence (ECL) detection, photoelectrochemi (PEC) detection and so on. In addition, main advantages, disadvantages and future trends for the devices are also discussed in this review. PMID- 26513285 TI - Label-free biomolecular detection at electrically displaced liquid interfaces using interfacial electrokinetic transduction (IET). AB - Biosensors require a biorecognition element that specifically binds to a target analyte, and a signal transducer, which converts this targeted binding event into a measurable signal. While current biosensing methods are capable of sensitively detecting a variety of target analytes in a laboratory setting, there are inherent difficulties in developing low-cost portable biosensors for point-of care diagnostics using traditional optical, mass, or electroanalytical-based signal transducers. It is therefore important to develop new biosensing transducer elements for recognizing binding events at low cost and in portable environments. Here, we demonstrate a novel electrokinetic liquid biosensing method for the sensitive label-free detection of a model biomolecule against a background of serum protein. The biosensor is based on the motion of a microfluidic-generated electrical liquid interface when subjected to an external alternating current electrical field. We demonstrate that the electric field induced motion of the interface can be used as a sensitive and specific transducer for the detection of avidin at femtomolar concentrations in solution. This new detection strategy does not require surface functionalization or fluorescent labels, and has the potential to serve as a sensitive low-cost method for portable biomarker detection. PMID- 26513286 TI - Construction of Au-IDE/CFP10-ESAT6 aptamer/DNA-AuNPs MSPQC for rapid detection of Mycobacterium tuberculosis. AB - Au-IDE/CFP10-ESAT6 aptamer/DNA-AuNPs MSPQC for rapid detection of Mycobacterium tuberculosis was constructed based on specific detection of specific fused antigen CFP10-ESAT6 which secreted only by pathogenic M. tuberculosis in its early culture time. CFP10-ESAT6 aptamer was used as sensor specific probe of CFP10-ESAT6 antigen. Au nanoparticles (NPs) was employed to increase sensor senstivity. The Au-IDE/CFP10-ESAT6 aptamer/DNA-AuNPs electrode probe was prepared by modifying of the complementary DNA-AuNPs on to interdigital array microelectrode with CFP10-ESAT6 aptamer. CFP10-ESAT6 aptamer could specifically catch CFP10-ESAT6 protein and formed a tight complex on the electrode surface and resulted in the DNA-AuNPs fragments fell away from the electrode surface. This change can be sensitively detected by IDE-MSPQC sensor. The detection time was 96.3h. Non-pathogenic Mycobacterium did not affect detection. Compared with conventional methods, this approach was specific, more sensitive, and expected to become a valuable analysis tool for the early detection of M. tuberculosis in clinical sample. PMID- 26513287 TI - Non-protein coding RNA-based genosensor with quantum dots as electrochemical labels for attomolar detection of multiple pathogens. AB - The ability of a diagnostic test to detect multiple pathogens simultaneously is useful to obtain meaningful information for clinical treatment and preventive measures. We report a highly sensitive and specific electrochemical biosensor assay for simultaneous detection of three gene targets using quantum dots (QDs). The targets are novel non-protein coding RNA (npcRNA) sequences of Vibrio cholerae, Salmonella sp. and Shigella sp., which cause diarrheal diseases. QDs (PbS, CdS, ZnS) were synthesized and functionalized with DNA probes that were specific to each pathogen. Electrochemical detection of QDs was performed using square wave anodic stripping voltammetry (SWASV). The QDs gave distinct peaks at 0.5 V (PbS), 0.75 V (CdS) and 1.1 V (ZnS). There was no interference in signal response when all three QDs were mixed and detected simultaneously. The detection limits of single and multiplex assays with linear targets and PCR products were in the attomolar ranges. The high assay sensitivity, in combination with specific npcRNA sequences as novel diagnostic targets, makes it a viable tool for detecting pathogens from food, environment and clinical samples. PMID- 26513288 TI - A high performance Schiff-base fluorescent probe for monitoring Au(3+) in zebrafish based on BODIPY. AB - We designed and synthesized a mono-Schiff-base fluorescent probe (Probe 1) based on a boron-dipyrromethene (BODIPY) dye. By investigating the recognition of Au(3+) through an irreversible C=N bond hydrolysis reaction, Probe 1 exhibited higher properties such as acting as a "naked eye" probe, stability to pH, fast response of 90s, a lower detection limit of 60 nM, stronger antijamming capability, and better live-cells imaging with low cytotoxicity compared with other probes. Even in relatively high temperatures, Probe 1 maintained its own excellent characteristic. More importantly, this is the first time that one chemosensor could be successfully applied to Au(3+) imaging in zebrafish, which demonstrated the performance that Probe 1 exhibited wonderful organism permeability. PMID- 26513289 TI - Label-free electrochemical nucleic acid biosensing by tandem polymerization and cleavage-mediated cascade target recycling and DNAzyme amplification. AB - Owing to the intrinsic importance of nucleic acid as bio-targets, the achievement of its simple and sensitive detection with high confidence is very essential for biological studies and diagnostic purposes. Herein, a label-free, isothermal, and ultrasensitive electrochemical detection of target DNA was developed by using a tandem polymerization and cleavage-mediated cascade target recycling and DNAzyme releasing amplification strategy. Upon sensing of the nucleic acid analyte for the assembled hairpin-like probe DNA on the electrode, the DNA polymerase guided the target recycling and simultaneously triggered the lambda exonuclease cleavage, accompanied by the cascade recycling of the released new complementary strand and the amplified liberation of the G-rich sequence of the HRP-mimicking DNAzyme. The electrocatalytic reduction of H2O2 by the generated hemin/G quadruplex DNAzyme was used for the signal readout and further amplification toward target response. Such tandem functional operation by DNA polymerase, lambda exonuclease and DNAzyme endows the developed biosensor with a high sensitivity and also a high confidence. A low detection limit of 5 fM with an excellent selectivity toward target DNA could be achieved. It also exhibits the distinct advantages of simplicity in probe design and biosensor fabrication, and label-free electrochemical detection, thus may offer a promising avenue for the applications in disease diagnosis and clinical biomedicine. PMID- 26513290 TI - A review of impedance measurements of whole cells. AB - Impedance measurement of live biological cells is widely accepted as a label free, non-invasive and quantitative analytical method to assess cell status. This method is easy-to-use and flexible for device design and fabrication. In this review, three typical techniques for impedance measurement, i.e., electric cell substrate impedance sensing, Impedance flow cytometry and electric impedance spectroscopy, are reviewed from the aspects of theory, to electrode design and fabrication, and applications. Benefiting from the integration of microelectronic and microfluidic techniques, impedance sensing methods have expanded their applications to nearly all aspects of biology, including living cell counting and analysis, cell biology research, cancer research, drug screening, and food and environmental safety monitoring. The integration with other techniques, the fabrication of devices for certain biological assays, and the development of point-of-need diagnosis devices is predicted to be future trend for impedance sensing techniques. PMID- 26513291 TI - Magnesium as a predictor of acute stent thrombosis in patients with ST-segment elevation myocardial infarction who underwent primary angioplasty. AB - BACKGROUND: Although magnesium (Mg) has been proposed as a useful biomarker for predicting atherothrombosis, the association between Mg and acute stent thrombosis (ST) after primary percutaneous coronary intervention (p-PCI) for ST segment elevation myocardial infarction (STEMI) has not yet been defined. OBJECTIVES: We aimed to examine whether admission Mg levels predicted the development of acute ST after p-PCI in STEMI patients. METHODS AND RESULTS: A total of 2633 patients with STEMI who underwent p-PCI were retrospectively analyzed. Acute ST was defined as thrombosis that occurred in the first (0-1) days following primary coronary stenting, and patients who had undergone p-PCI were divided into two groups: ST group and no-ST group. The cut-off value for Mg obtained by the receiver-operating characteristic curve analysis was less than 1.91 mg/dl for the prediction of acute ST (area under the curve was 0.761; 95% confidence interval, 0.706-0.816; P<0.001; sensitivity, 70%; specificity, 69%). Serum Mg levels were significantly lower in the ST group compared with the no-ST group (median 1.80 mg/dl, interquartile range 1.70-2.00 mg/l vs. median 2.10 mg/dl, interquartile range 1.90-2.20 mg/dl, P<0.001). After multivariable adjustment for clinical, laboratory, and angiographic variables, Mg remained a strong independent predictor for acute ST (odds ratio 5.802, 95% confidence interval, 3.069-10.967; P<0.001). CONCLUSION: Serum Mg level is associated independently with the risk of acute ST in patients with STEMI who undergo p-PCI. PMID- 26513292 TI - Extreme late-phase observation using coronary angioscopy until 7 years after sirolimus-eluting stent implantation. AB - BACKGROUND: Little is known about the very late-phase morphological vessel characteristics within the sirolimus-eluting stent (SES). METHODS AND RESULTS: We assessed a total of 12 patients with 15 SES implantations who underwent repeat angiographic and angioscopic procedures after 5 and 7 years. The degree of neointimal stent coverage (NSC) was classified as follows: grade 0, uncovered struts; grade 1, visible struts through a thin neointima; or grade 2, invisible struts with complete neointimal coverage. The maximum and minimum NSC grades were evaluated and the existence of in-stent thrombus was also recorded for all patients. The prevalence of a maximum NSC grade of 2 increased and that of a minimum NSC grade of 0 decreased, although there was no significant difference in prevalence between 5 and 7 years. One of four in-stent thrombus identified at 5 years had disappeared from 5 to 7 years and a new thrombus was found in another patient at 7 years. Thus, the incidence of in-stent thrombus did not change from 5 to 7 years. In one case, a thrombus was observed inside the angiographic aneurysmal change, but none of the thrombi were related to adverse events. CONCLUSION: This angioscopic study reported gradual arterial repair and continuous delayed healing associated with subclinical thrombus formation 7 years after SES deployment. PMID- 26513293 TI - Impact of thrombus burden on procedural and mid-term outcomes after primary percutaneous coronary intervention. AB - OBJECTIVE: Angiographic thrombus burden (TB) can be assessed early and enable a decision on intervention. The aim of this study was to analyze its effect on the incidence of cardiac events after a primary percutaneous coronary intervention. PATIENTS AND METHODS: We carried out a prospective study of 480 consecutive ST segment elevation myocardial infarction patients treated by systematic primary percutaneous coronary intervention. Large TB was defined as thrombus length at least 2 vessel diameters or as solid thrombus obtained through catheter aspiration. The primary outcome measure was a composite of death, reinfarction, or target vessel revascularization. RESULTS: A total of 205 (47%) patients fulfilled the criteria for large TB. These patients were more frequently treated with abciximab (62.0 vs. 35.8%, P<0.001), showed more angiographic complications (26.6 vs. 13.7%, P=0.001), and had larger infarcts (peak troponin I, 74 vs. 50 ng/ml, P=0.015). During a follow-up of 19 +/- 5 months, the rates of primary outcome were similar between groups of small and large TB (16.2 vs. 12.8%, hazard ratio: 0.88, 95% confidence interval: 0.46-1.67, P=0.691). There were no differences in the rates of definite stent thrombosis (0.5 vs. 2.2%, P=0.190). CONCLUSION: Large TB is associated with larger infarct size, but not with worse mid-term outcomes. Selective use of adjuvant therapies according to TB may be an effective approach to reduce thrombotic complications. PMID- 26513294 TI - An inducible transgenic mouse breast cancer model for the analysis of tumor antigen specific CD8+ T-cell responses. AB - In Simian virus 40 (SV40) transgenic BALB/c WAP-T mice tumor development and progression is driven by SV40 tumor antigens encoded by inducible transgenes. WAP T mice constitute a well characterized mouse model for breast cancer with strong similarities to the corresponding human disease. BALB/c mice mount only a weak cellular immune response against SV40 T-antigen (T-Ag). For studying tumor antigen specific CD8+ T-cell responses against transgene expressing cells, we created WAP-TNP mice, in which the transgene additionally codes for the NP118-126 epitope contained within the nucleoprotein of lymphocytic choriomeningitis virus (LCMV), the immune-dominant T-cell epitope in BALB/c mice. We then investigated in WAP-TNP mice the immune responses against SV40 tumor antigens and the NP epitope within the chimeric T-Ag/NP protein (T-AgNP). Analysis of the immune reactivity against T-Ag in WAP-T and of T-AgNP in WAP-TNP mice revealed that, in contrast to wild type (wt) BALB/c mice, WAP-T and WAP-TNP mice were non-reactive against T-Ag. However, like wtBALB/c mice, WAP-T as well as WAP-TNP mice were highly reactive against the immune-dominant LCMV NP-epitope, thereby allowing the analysis of NP-epitope specific cellular immune responses in WAP-TNP mice. LCMV infection of WAP-TNP mice induced a strong, LCMV NP-epitope specific CD8+ T-cell response, which was able to specifically eliminate T-AgNP expressing mammary epithelial cells both prior to tumor formation (i.e. in cells of lactating mammary glands), as well as in invasive tumors. Elimination of tumor cells, however, was only transient, even after repeated LCMV infections. Further studies showed that already non-infected WAP-TNP tumor mice contained LCMV NP-epitope specific CD8+ T-cells, albeit with strongly reduced, though measurable activity. Functional impairment of these 'endogenous' NP-epitope specific T-cells seems to be caused by expression of the programmed death-1 protein (PD1), as anti-PD1 treatment of splenocytes from WAP-TNP tumor mice restored their activity. These characteristics are similar to those found in many tumor patients and render WAP TNP mice a suitable model for analyzing parameters to overcome the blockade of immune checkpoints in tumor patients. PMID- 26513295 TI - Evaluation of pentacyclic triterpenes found in Perilla frutescens for inhibition of skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. AB - A series of pentacyclic tritperpenes found in Perilla frutescens (P. frutescens), including ursolic acid (UA), oleanolic acid (OA), corosolic acid (CA), 3-epi corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) were evaluated for their effects on epidermal cell signaling, proliferation, and skin inflammation in relation to their ability to inhibit skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) and compared to UA as the prototype compound. All compounds were given topically 30 min prior to each TPA application and significantly inhibited skin tumor promotion. 3-epiCA and MA were significantly more effective than UA at inhibiting tumor development. All of these compounds significantly inhibited epidermal proliferation induced by TPA, however, CA, 3-epiCA and MA were more effective than UA. All compounds also reduced skin inflammation (assessed by infiltration of mast cells and T-cells) and inflammatory gene expression induced by TPA, however, 3-epiCA and MA were again more effective than UA. The greater ability of 3-epiCA and MA to inhibit skin tumor promotion was associated with greater reduction of Cox-2 and Twist1 proteins and inhibition of activation (i.e., phosphorylation) of IGF-1R, STAT3 and Src. Further study of these compounds, especially 3-epiCA and MA, for chemopreventive activity in other cancer model systems is warranted. PMID- 26513296 TI - Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus. AB - Despite the development of several new agents for multiple myeloma (MM) therapy over the last decade, drug resistance continues to be a significant problem. Patients with relapsed/refractory disease have high mortality rates and desperately need new precision approaches that directly target specific molecular features that are prevalent in the refractory setting. Reolysin is a proprietary formulation of reovirus for cancer therapy that has demonstrated efficacy in multiple clinical trials. Its selective effects against solid tumors have been largely attributed to RAS-mediated control of reovirus replication. However, the mechanisms regulating its preferential anti-neoplastic effects in MM and other hematological malignancies have not been rigorously studied. Here we report that the reovirus receptor, junctional adhesion molecule-A (JAM-A) is highly expressed in primary cells from patients with MM and the majority of MM cell lines compared to normal controls. A series of experiments demonstrated that JAM-A expression, rather than RAS, was required for Reolysin-induced cell death in MM models. Notably, analysis of paired primary MM specimens revealed that JAM-A expression was significantly increased at relapse compared to diagnosis. Two different models of acquired resistance to bortezomib also displayed both higher JAM-A expression and elevated sensitivity to Reolysin compared to parental cells, suggesting that Reolysin may be an effective agent for patients with relapsed/refractory disease due to their high JAM-A levels. Taken together, these findings support further investigation of Reolysin for the treatment of patients with relapsed/refractory MM and of JAM-A as a predictive biomarker for sensitivity to Reolysin-induced cell death. PMID- 26513297 TI - CUDR promotes liver cancer stem cell growth through upregulating TERT and C-Myc. AB - Cancer up-regulated drug resistant (CUDR) is a novel non-coding RNA gene. Herein, we demonstrate excessive CUDR cooperates with excessive CyclinD1 or PTEN depletion to accelerate liver cancer stem cells growth and liver stem cell malignant transformation in vitro and in vivo. Mechanistically, we reveal the decrease of PTEN in cells may lead to increase binding capacity of CUDR to CyclinD1. Therefore, CUDR-CyclinD1 complex loads onto the long noncoding RNA H19 promoter region that may lead to reduce the DNA methylation on H19 promoter region and then to enhance the H19 expression. Strikingly, the overexpression of H19 increases the binding of TERT to TERC and reduces the interplay between TERT with TERRA, thus enhancing the cell telomerase activity and extending the telomere length. On the other hand, insulator CTCF recruits the CUDR-CyclinD1 complx to form the composite CUDR-CyclinD1-insulator CTCF complex which occupancied on the C-myc gene promoter region, increasing the outcome of oncogene C-myc. Ultimately, excessive TERT and C-myc lead to liver cancer stem cell and hepatocyte-like stem cell malignant proliferation. To understand the novel functions of long noncoding RNA CUDR will help in the development of new liver cancer therapeutic and diagnostic approaches. PMID- 26513299 TI - Reciprocal spin Hall effects in conductors with strong spin-orbit coupling: a review. AB - Spin Hall effect and its inverse provide essential means to convert charge to spin currents and vice versa, which serve as a primary function for spintronic phenomena such as the spin-torque ferromagnetic resonance and the spin Seebeck effect. These effects can oscillate magnetization or detect a thermally generated spin splitting in the chemical potential. Importantly this conversion process occurs via the spin-orbit interaction, and requires neither magnetic materials nor external magnetic fields. However, the spin Hall angle, i.e. the conversion yield between the charge and spin currents, depends severely on the experimental methods. Here we discuss the spin Hall angle and the spin diffusion length for a variety of materials including pure metals such as Pt and Ta, alloys and oxides determined by the spin absorption method in a lateral spin valve structure. PMID- 26513298 TI - E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling. AB - Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have demonstrated clinical proof of concept for cancer treatment. Here, we describe the development of the novel PARP inhibitor E7449, a potent PARP1/2 inhibitor that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1 and 2), important regulators of canonical Wnt/beta-catenin signaling. E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity. Cells deficient in DNA repair pathways beyond homologous recombination were sensitive to E7449 treatment. Chemotherapy was potentiated by E7449 and single agent had significant antitumor activity in BRCA deficient xenografts. Additionally, E7449 inhibited Wnt/beta-catenin signaling in colon cancer cell lines, likely through TNKS inhibition. Consistent with this possibility, E7449 stabilized axin and TNKS proteins resulting in beta-catenin de stabilization and significantly altered expression of Wnt target genes. Notably, hair growth mediated by Wnt signaling was inhibited by E7449. A pharmacodynamic effect of E7449 on Wnt target genes was observed in tumors, although E7449 lacked single agent antitumor activity in vivo, a finding typical for selective TNKS inhibitors. E7449 antitumor activity was increased through combination with MEK inhibition. Particularly noteworthy was the lack of toxicity, most significantly the lack of intestinal toxicity reported for other TNKS inhibitors. E7449 represents a novel dual PARP1/2 and TNKS1/2 inhibitor which has the advantage of targeting Wnt/beta-catenin signaling addicted tumors. E7449 is currently in early clinical development. PMID- 26513300 TI - Solvation effects on the band edge positions of photocatalysts from first principles. AB - The band edge positions of photocatalysts relative to the redox potentials of water play an important role in determining the efficiency of photoelectrochemical cells. These band positions depend on the structure of the solid-liquid interface, but direct ab initio molecular dynamics calculations of these interfaces, while expected to be accurate, are too computationally demanding for high-throughput materials screening. Thus rapid theoretical screening of new photocatalyst materials requires simplified continuum solvation models that are suitable for treating solid-liquid interfaces. In this paper, we evaluate the accuracy of the recently developed CANDLE and SaLSA continuum solvation models for predicting solvation effects on the band positions of several well-studied surfaces [Si(111), TiO2(110), IrO2(110) and WO3(001)] in water. We find that the solvation effects vary considerably, ranging from <0.5 eV for hydrophobic surfaces, 0.5-1 eV for many hydrophilic oxide surfaces, to ~2 eV for oxygen-deficient surfaces. The solvation model predictions are in excellent agreement (within ~0.1 eV) with ab initio molecular dynamics results where available, and in good agreement (within ~0.2-0.3 eV) with experimental measurements. We also predict the energetics for surface oxygen vacancies and their effect on the band positions of the hydrated WO3(001) surface, leading to an explanation for why the solvation shift observed experimentally is substantially larger than predicted for the ideal surface. Based on the correlation between solvation shift and the type of surface and solvent, we suggest approaches to engineer the band positions of surfaces in aqueous and non aqueous solutions. PMID- 26513301 TI - Pain in amyotrophic lateral sclerosis: Patient and physician perspectives and practices. AB - Our objective was to better understand the experience and impact of pain on ALS patients in the U.S., and to survey ALS physicians on their pain assessment and management practices. Individuals with ALS were invited to complete an online survey of pain in ALS. ALS specialist physicians were sent an e-mail survey about their experiences in evaluating and managing patients' pain. Nearly 75% of patients with ALS reported significant pain, and most thought that ALS was the source of at least some of this pain. Pain intensity scores (mean 3.9/10) and pain interference scores (mean 4.3/10) were moderate on average, but nearly 80% of participants were using pain medication, including 22% using opioids. Nearly 25% of patients thought they needed stronger pain medication than they were receiving. Physicians generally assess and manage pain in ALS patients, but few use standardized assessment tools. Nearly two-thirds felt that there is a need for better pain management practices and more than one-third felt better training was needed. In conclusion, pain in patients with ALS is not always well controlled. Improvement in care may be facilitated by a more standardized approach to evaluation, and by additional education and training of ALS health care professionals. PMID- 26513302 TI - The effects of neutralized particles on the sampling efficiency of polyurethane foam used to estimate the extrathoracic deposition fraction. AB - In addition to chemical composition, the site of deposition of inhaled particles is important for determining the potential health effects from an exposure. As a result, the International Organization for Standardization adopted a particle deposition sampling convention. This includes extrathoracic particle deposition sampling conventions for the anterior nasal passages (ET1) and the posterior nasal and oral passages (ET2). This study assessed how well a polyurethane foam insert placed in an Institute of Occupational Medicine (IOM) sampler can match an extrathoracic deposition sampling convention, while accounting for possible static buildup in the test particles. In this way, the study aimed to assess whether neutralized particles affected the performance of this sampler for estimating extrathoracic particle deposition. A total of three different particle sizes (4.9, 9.5, and 12.8 um) were used. For each trial, one particle size was introduced into a low-speed wind tunnel with a wind speed set a 0.2 m/s (~40 ft/min). This wind speed was chosen to closely match the conditions of most indoor working environments. Each particle size was tested twice either neutralized, using a high voltage neutralizer, or left in its normal (non neutralized) state as standard particles. IOM samplers were fitted with a polyurethane foam insert and placed on a rotating mannequin inside the wind tunnel. Foam sampling efficiencies were calculated for all trials to compare against the normalized ET1 sampling deposition convention. The foam sampling efficiencies matched well to the ET1 deposition convention for the larger particle sizes, but had a general trend of underestimating for all three particle sizes. The results of a Wilcoxon Rank Sum Test also showed that only at 4.9 um was there a statistically significant difference (p-value = 0.03) between the foam sampling efficiency using the standard particles and the neutralized particles. This is interpreted to mean that static buildup may be occurring and neutralizing the particles that are 4.9 um diameter in size did affect the performance of the foam sampler when estimating extrathoracic particle deposition. PMID- 26513303 TI - Compensation programs after withdrawal of the recommendation for HPV vaccine in Japan. AB - HPV vaccinations were recommended with the backing of a Japanese government subsidy program in 2010, and were included in the National Immunization Program in April 2013. However, the Ministry of Health, Labour, and Welfare withdrew the recommendation for the HPV vaccination in June 2013. We investigated HPV vaccine injury compensation programs for both the national and local governments. Approximately 3.38 million girls were vaccinated, and 2,584 complained of health problems. The majority of these received the vaccine shot as a non-routine vaccination. In total, 98 people developed health problems and applied for assistance from 2011 to 2014, but no cases have been processed since October 2014. Several local governments are providing their own compensation program for cases of vaccine adverse reactions, but the number is extremely low (16 of 1,741 municipalities and 1 of 47 prefectures). The local governments that are providing compensation are largely those where HPV vaccine victim support groups are prominent. The confusion regarding the national program for HPV vaccine injury was caused by the discrepancy between the compensation programs for those vaccinated under the immunization law and for those who received voluntary vaccinations. The establishment of a new compensation program might be key to finding a lasting resolution. PMID- 26513304 TI - Warfarin resistance associated with genetic polymorphism of VKORC1: linking clinical response to molecular mechanism using computational modeling. AB - The variable response to warfarin treatment often has a genetic basis. A protein homology model of human vitamin K epoxide reductase, subunit 1 (VKORC1), was generated to elucidate the mechanism of warfarin resistance observed in a patient with the Val66Met mutation. The VKORC1 homology model comprises four transmembrane (TM) helical domains and a half helical lid domain. Cys132 and Cys135, located in the N-terminal end of TM-4, are linked through a disulfide bond. Two distinct binding sites for warfarin were identified. Site-1, which binds vitamin K epoxide (KO) in a catalytically favorable orientation, shows higher affinity for S-warfarin compared with R-warfarin. Site-2, positioned in the domain occupied by the hydrophobic tail of KO, binds both warfarin enantiomers with similar affinity. Displacement of Arg37 occurs in the Val66Met mutant, blocking access of warfarin (but not KO) to Site-1, consistent with clinical observation of warfarin resistance. PMID- 26513305 TI - Report on the First PANLAR Rheumatology Review Course Rheumatoid Arthritis: Challenges and Solutions in Latin America. AB - The First PANLAR Rheumatology Review Course was held in Barranquilla, Colombia, in April 2015. Researchers, rheumatologists, epidemiologists, and a variety of allied professionals and patients attended the meeting. The scientific program included plenary sessions and symposia delivered by renowned experts in the field, followed by an interactive forum of discussion during 2 days.A broad spectrum of topics was discussed, reflecting the current challenges and opportunities for diagnosis and treatment of rheumatoid arthritis (RA) in Latin America. The scientific program included not only traditional disease aspects, but also social implications, research projects, and educational characteristics, patient perspectives, and novel care models, emphasizing the need for training human resources and proposing unique approaches to RA health care in Latin America, therefore helping us to increase and improve the knowledge and understanding of the characteristics of this health condition in the region, thus promoting and encouraging equity, quality, and efficiency of RA health care. PMID- 26513306 TI - Agreement of Physicians and Nurses Performing Tender and Swollen Joint Counts in Rheumatoid Arthritis. AB - OBJECTIVE: The aims of this study were to assess the agreement of physicians and nurses performing tender and swollen joint counts (TJCs/SJCs) in rheumatoid arthritis (RA) and identify factors that might influence their examinations including patient age, sex, race, RA disease duration, body mass index, RA disease activity level, comorbid fibromyalgia, comorbid osteoarthritis, and levels of acute-phase reactants. METHODS: Seventy-two RA participants underwent TJCs/SJCs of 28 joints using a standardized protocol by 2 nurses and 2 rheumatologists. Demographic, laboratory, radiographic, and clinical data were obtained to assess the influence of these factors on TJCs/SJCs. Intraclass correlations (ICCs) among examiners were determined for TJCs/SJCs. Nurse physician differences and agreement of individual joints were evaluated using Cohen kappa. Analysis of variance was performed to detect differences in means between examiners for TJCs/SJCs. Intraclass correlation and Fisher Z tests were used to identify factors influencing TJCs/SJCs. RESULTS: Agreement was strong among these nurses and physicians for total TJCs/SJCs (ICC = 0.84/ICC = 0.79, respectively). kappa was best for hand joint tenderness and poorest for shoulder swelling. Some significant differences in mean TJCs/SJCs were found between examiners. Fibromyalgia significantly reduced agreement of both TJCs and SJCs. Agreement of TJC was significantly reduced when patients had lower disease activity, greater work impairment, lower mental health quality of life, and elevated erythrocyte sedimentation rate, whereas female sex, assessor's perception of but not radiographic hand osteoarthritis, and elevated C-reactive protein significantly reduced agreement for SJC. CONCLUSIONS: Strong agreement was found among nurses and physicians for total 28-joint counts, with agreement at individual joints being stronger for tenderness than swelling. Fibromyalgia significantly reduced ICCs of TJCs/SJCs. PMID- 26513307 TI - A Die-Hard Giant Capillary. PMID- 26513308 TI - BIRC4 Mutation: An Important Rare Cause of Uveitis. AB - We report a 6-year-old man with chronic severe recalcitrant bilateral anterior uveitis and a remote history of hemophagocytic lymphocytic histiocytosis secondary to Epstein-Barr virus infection. The patient was treated for idiopathic uveitis after an initial extensive evaluation failed to reveal a specific diagnosis. The patient failed to achieve sustained inactive disease with multiple monotherapies including topical glucocorticoid, methotrexate, infliximab, mycophenolate mofeti, and cyclosporine. Disease control was finally attained with a combination of cyclosporine and adalimumab. After more recent testing, he was found to have a novel deletion on the BIRC4 (baclovirus inhibitor of apoptosis repeat containing protein 4) gene, the causative gene for X-linked lymphoproliferative syndrome type 2. We conclude that male patients with chronic idiopathic uveitis should be questioned about a history of hemophagocytic lymphocytic histiocytosis during their workup and screened for BIRC4 mutation if appropriate. PMID- 26513309 TI - Options to Promote Competitive Generics Markets in the United States. PMID- 26513310 TI - Systemic and alveolar inflammatory response in the dependent and nondependent lung in patients undergoing lung resection surgery: A prospective observational study. AB - BACKGROUND: Measurement of inflammatory mediators in bronchoalveolar lavage (BAL) during lung resection surgery with periods of one-lung ventilation (OLV) has revealed an intense local pulmonary response. The role of each lung in the inflammation that occurs during this procedure has never been investigated. OBJECTIVE(S): The primary objective of our study was to compare the inflammatory response in the dependent lung with that of the nondependent lung by measuring inflammatory markers in BAL. Our secondary objective was to assess the behaviour of these inflammatory mediators in patients with and without postoperative pulmonary complications (PPCs). DESIGN: A prospective, observational study. SETTING: Department of Anaesthesiology in a university hospital. PATIENTS: Forty six consecutive patients undergoing lung resection surgery. INTERVENTION(S): BAL samples were taken from dependent and nondependent lung 10 min before initiating OLV and at the end of OLV (once two-lung ventilation was established). All patients were followed up until 30 days after surgery. MAIN OUTCOME MEASURES: The concentration of cytokines [interleukin (IL)-1, IL-2, IL-6, IL-10, tumour necrosis factor-alpha (TNF-alpha)], nitric oxide, carbon monoxide and matrix metalloproteinase 2 (MMP-2) was analysed in both lungs before and after OLV. PPCs were recorded. RESULTS: In BAL fluid, all measured biomarkers, apart from IL-10, were significantly greater (P < 0.05) at the end of OLV than those obtained before OLV, both for the dependent and nondependent lung. The increase in measured biomarkers was similar in both lungs. Eight patients developed PPC. Patients who developed PPC had higher levels of TNF-alpha (P < 0.05) in BAL from the nondependent lung before and after OLV than patients who did not have PPC. Patients who developed PPC had a smaller increase in MMP-2 levels (P < 0.05) in the dependent lung than patients who did not have PPC. CONCLUSION: In lung resection surgery, the inflammatory response is similar in both lungs. However, the greater increase in TNF-alpha levels in the nondependent lung and the smaller increase of MMP-2 concentration in the dependent lung may increase the susceptibility to develop PPC. PMID- 26513311 TI - Subclassification of Barcelona Clinic Liver Cancer B and C hepatocellular carcinoma: A cohort study of the multicenter registry database. AB - BACKGROUND AND AIM: We aimed to subclassify hepatocellular carcinoma (HCC) using Barcelona Clinic Liver Cancer intermediate and advanced stages, which include a highly heterogeneous population. METHODS: From two registries ("random" and "voluntary" cohorts in the Korean Liver Cancer Study Group), patients who were newly diagnosed as HCC with intermediate or advanced stage between 2003 and 2005 were considered eligible. Overall survival (OS) was analyzed using Kaplan-Meier method with comparison by log-rank test. RESULTS: Patients with intermediate stage HCC (n = 994) were subclassified according to tumor size and Child-Pugh class. Patients with tumor size < 5 cm (B1), those with tumor size >= 5 cm and Child-Pugh A (B2), and those with tumor size >= 5 cm and Child-Pugh B (B3) had median OS of 30.73, 20.60, and 9.23 months, respectively (P < 0.001 by log-rank test). Among patients with advanced stage HCC (n = 1746), patients were subclassified according to presence of significant portal vein invasion (sPVI; defined as portal vein invasion in lobar, main, or contralateral branch) and extrahepatic spread (EHS). Patients with neither sPVI nor EHS (C1), those with either sPVI or EHS (C2), and those with both sPVI and EHS (C3) had median OS of 8.43, 4.63, and 3.63 months, respectively (P < 0.001 by log-rank test). CONCLUSION: Subclassification of Barcelona Clinic Liver Cancer intermediate and advanced stages might be useful for determining patient prognosis and guiding treatment strategies for HCC. PMID- 26513313 TI - Forensic Investigation of Methadone Concentrations in Deceased Breastfed Infants. AB - There is a paucity of data to aid in assessing whether postmortem methadone findings in breastfed infants are clinically and/or toxicologically significant. Two cases are reported in which methadone was detected in deceased neonates whose mothers were enrolled in methadone maintenance programs and were breastfeeding. In addition to a complete autopsy and toxicological testing for alcohol, prescription medications, and drugs of abuse, pharmacogenetic analysis was performed for variants in genes related to methadone metabolism and response. In both cases, the postmortem methadone concentration measured in neonatal heart blood was higher than the maximum serum methadone concentration reported in living breastfed infants whose mothers were receiving methadone. However, additional analysis of antemortem blood indicated postmortem redistribution of methadone. Pharmacogenetic results were suggestive of a potential predisposition to methadone toxicity based on studies in adults; the significance of these findings in breastfed neonates requires further research. The medical cause of death was unascertained in both cases. PMID- 26513314 TI - Erratum: Trop-2 is up-regulated in invasive prostate cancer and displaces FAK from focal contacts. PMID- 26513315 TI - Noninvasive Tissue Characterization of Lung Tumors Using Integrated Backscatter Intravascular Ultrasound: An Ex Vivo Comparative Study With Pathological Diagnosis. AB - BACKGROUND: Endobronchial ultrasonography (EBUS) facilitates a lung cancer diagnosis. However, qualitative tissue characterization of lung tumors is difficult using EBUS. Integrated backscatter (IBS) is an ultrasound technique that calculates the power of the ultrasound signal to characterize tissue components in coronary arteries. We hypothesized that qualitative diagnosis of lung tumors is possible using the IBS technique. The aim of the present study was to elucidate whether the IBS technique can be used in lung tissue diagnoses. METHODS: Thirty-five consecutive patients who underwent surgery for lung cancer were prospectively enrolled. Surgical specimens of the lung and the tumor tissue were obtained, and the IBS values were measured within 48 h after surgery. Histologic images of lung and tumor tissues were compared with IBS values, and the relative interstitial area according to results of Masson's trichrome staining were determined by using an imaging processor. RESULTS: The IBS values in tumor tissue were significantly lower than those in normal lung tissue (-50.9 +/- 2.6 dB and -47.6 +/- 2.6 dB, respectively; P < .001). The IBS values of adenocarcinomas associated with a good 5-year survival rate were higher than those of non-adenocarcinomas (-48.1 +/- 1.6 dB and -52.6 +/- 1.4 dB; P < .001). There were significant correlations between the IBS values and the relative interstitial area or micro air area in tumor (r = 0.53 and r = 0.67; P < .01). After combining normal lung tissue and adenocarcinomas with a good prognosis, the sensitivity and specificity for establishing the presence of lung tumors were 84% and 85%. CONCLUSIONS: Qualitative diagnosis of lung tumors was possible, with a sensitivity of 84% and a specificity of 85%, using the ultrasound IBS technique. PMID- 26513316 TI - Reducing periprocedural complications in transcatheter aortic valve replacement: review of paravalvular leaks, stroke and vascular complications. AB - Transcatheter aortic valve replacement has been established as the standard of care for inoperable patients and a valid alternative for high-risk individuals with severe symptomatic native aortic stenosis. Over the last decade, substantial improvement has been made in the transcatheter technology. Nevertheless, this less-invasive procedure is still associated with complications like paravalvular leaks, strokes and vascular complications. This review article discusses these worrisome complications associated with transcatheter aortic valve replacement and proposes methods to prevent these hurdles. PMID- 26513317 TI - Coupling of acrylic dyeing wastewater treatment by heterogeneous Fenton oxidation in a continuous stirred tank reactor with biological degradation in a sequential batch reactor. AB - This work deals with the treatment of a recalcitrant effluent, from the dyeing stage of acrylic fibres, by combination of the heterogeneous Fenton's process in a continuous stirred tank reactor (CSTR) with biological degradation in a sequential batch reactor (SBR). Three different catalysts (a commercial Fe/ZSM-5 zeolite and two distinct Fe-containing activated carbons - ACs - prepared by wet impregnation of iron acetate and iron nitrate) were employed on the Fenton's process, and afterwards a parametric study was carried out to determine the effect of the main operating conditions, namely the hydrogen peroxide feed concentration, temperature and contact time. Under the best operating conditions found, using the activated carbon impregnated with iron nitrate, 62.7% of discolouration and 39.9% of total organic carbon (TOC) reduction were achieved, at steady-state. Furthermore, a considerable increase in the effluent's biodegradability was attained (BOD5:COD ratio increased from <0.001 to 0.27 and SOUR - specific oxygen uptake rate - from <0.2 to 11.1 mg O2/(gVSS.h)), alongside a major decrease in its toxicity (from 92.1 to 94.0% of Vibrio fischeri inhibition down to 6.9-9.9%). This allowed the application of the subsequent biological degradation stage. The combination of the two processes provided a treated effluent that clearly complies with the legislated discharge limits. It was also found that the iron leaching from the three catalysts tested was very small in all runs, a crucial factor for the stability and long-term use of such materials. PMID- 26513318 TI - Evaluation of the effectiveness of sepiolite, bentonite, and phosphate amendments on the stabilization remediation of cadmium-contaminated soils. AB - A pot trial was conducted to assess the effectiveness of sepiolite, bentonite, and phosphate on the immobilization remediation of cadmium (Cd)-contaminated soils using a set of variables, namely, physiological traits, sequential extraction procedure, plant growth and Cd concentration, and soil enzymatic activities and microbial population. Results showed that superoxide dismutase and peroxidase activities in the leaves of Oryza sativa L. and catalase activities in soils were stimulated after applying the amendments. However, soluble protein contents in leaves and urease and invertase activities in soils were reduced from 7.1% to 31.7%, 1.0%-23.3%, and 21.1%-62.5%, respectively, compared with the control. Results of the sequence extraction procedures revealed that the exchangeable fraction of Cd in soils was mostly converted into carbonated associated forms. The water soluble plus exchangeable fraction (SE) of Cd in soil decreased when treated with single and compound materials of sepiolite, bentonite and phosphate, which resulted in 13.2%-69.2% reduction compared with that of CK (control test). The amendments led to decreased Cd concentrations in roots, stems, leaves, brown rice, and rice hull by 16.2%-54.5%, 16.6%-42.8%, 19.6% 59.6%, 5.0%-68.2%, and 6.2%-20.4%, respectively. Higher bacterial and actinomycete amount indicated that remediation measures improved soil environmental quality. Composite amendments could be more efficiently used for the stabilization remediation of Cd contaminated soils with low Cd uptake and translocation in the plants and available contents of Cd in soil. PMID- 26513319 TI - Shrub recovery after fuel reduction treatments in a gorse shrubland in northern Spain. AB - Land managers need information about the environmental effects of fuel reduction techniques to select the most appropriate treatments in terms of conservation of ecosystem diversity and function. In this study, shrub cover recovery was monitored during the first four years after prescribed burning, clearing and mastication in a gorse shrubland dominated by Ulex gallii Planch. in northern Spain. Twelve experimental plots were installed just before treatments where plant cover was measured. All plant species present were identified, their frequency recorded and alpha diversity, richness and evenness determined. No differences between fuel treatments were observed for total shrub cover during the duration of the study. However, at the end of the study period, cover by Ericaceae shrubs and grasses was almost two times higher than the pre-treatment values, for all treatments. The treatments did not have different effects on gamma diversity or evenness during the four year interval, although higher species richness was measured in the burned plots than in the masticated or cleared ones throughout the study period. However, a redundancy analysis showed that the variation in species frequency during the study period was not related to the type of treatment applied. Fuel treatments significantly affected the shrubland under study in the short and medium term. The increase in Ericaceae shrubs and grasses cover may shift the long-term community composition. Long-term studies are required to establish whether the observed response lasts in time. PMID- 26513320 TI - Fast removal of high quantities of toxic arsenate via cationic p(APTMACl) microgels. AB - Hydrogels are resourceful materials and can be prepared in different morphology, size, surface charge and porosity adopting different polymerization techniques and reaction conditions. The cationic poly(3-acrylamidopropyl)trimethylammonium chloride (p(APTMACl)) microgels were synthesized by photo-initiated inverse suspension polymerization technique. These microgels were utilized as absorbents for the removal of toxic arsenate (As) from different aqueous environments. The experimental parameters affecting absorption efficiency were investigated, and it was demonstrated that these types of microgels are highly efficient in removing arsenate anions from different aqueous environments compared to the previously reported bulk hydrogel, and cryogel of the same material. A removal efficiency of approximately 97.25% was obtained by immersing 0.5 g microgel in 250 ppm 100 mL solution of arsenate anions for 60 min. Both Langmuir and Freundlich adsorption isotherms were applied to adsorption of arsenate anions by p(APTMACl) microgels, and the Langmuir isotherm was a better representation of the adsorption of arsenate with a high value of R(2) (0.9982). Furthermore, mag-p(APTMACl) microgels were synthesized for the adsorption of arsenate anions to provide easy removal of the microgel composite by using an externally applied magnetic field. Furthermore, re-usability of the p(APTMACl) microgels was also investigated for the adsorption of arsenate anions. PMID- 26513321 TI - Production and efficiency of large wildland fire suppression effort: A stochastic frontier analysis. AB - This study examines the production and efficiency of wildland fire suppression effort. We estimate the effectiveness of suppression resource inputs to produce controlled fire lines that contain large wildland fires using stochastic frontier analysis. Determinants of inefficiency are identified and the effects of these determinants on the daily production of controlled fire line are examined. Results indicate that the use of bulldozers and fire engines increase the production of controlled fire line, while firefighter crews do not tend to contribute to controlled fire line production. Production of controlled fire line is more efficient if it occurs along natural or built breaks, such as rivers and roads, and within areas previously burned by wildfires. However, results also indicate that productivity and efficiency of the controlled fire line are sensitive to weather, landscape and fire characteristics. PMID- 26513322 TI - Conceptual basis for an integrated system for the management of a protected area. Examples from its application in a mediterranean area. AB - Improving the efficiency of management in protected areas is imperative in a generalized context of limited conservation budgets. However, this is overlooked due to flaws in problem definition, general disregard for cost information, and a lack of suitable tools for measuring costs and management quality. This study describes an innovative methodological framework, implemented in the web application SIGEIN, focused on maximizing the quality of management against its costs, establishing an explicit justification for any decision. The tool integrates, with this aim, a procedure for prioritizing management objects according to a conservation value, modified by a functional criterion; a project management module; and a module for management of continuous assessment. This appraisal associates the relevance of the conservation targets, the efficacy of the methods employed, both resource and personnel investments, and the resulting costs. Preliminary results of a prototypical SIGEIN application on the Site of Community Importance Chafarinas Islands are included. PMID- 26513323 TI - Forest clearfelling effects on dissolved oxygen and metabolism in peatland streams. AB - Peatlands cover ~3% of the world's landmass and large expanses have been altered significantly as a consequence of land use change. Forestry activities are a key pressure on these catchments increasing suspended sediment and nutrient export to receiving waters. The aim of this study was to investigate stream dissolved oxygen (DO) and metabolic activity response following clearfelling of a 39-year old lodgepole pine and Sitka spruce forestry in an upland peat catchment. Significant effects of clearfelling on water temperature, flows, DO and stream metabolic (photosynthesis, respiration) rates were revealed. Stream temperature and discharge significantly increased in the study stream following clearfelling. Instream ecosystem respiration increased significantly following clearfelling, indicating an increase in the net consumption of organic carbon. PMID- 26513324 TI - Use of cationic polymers to reduce pathogen levels during dairy manure separation. AB - Various separation technologies are used to deal with the enormous amounts of animal waste that large livestock operations generate. When the recycled waste stream is land applied, it is essential to lower the pathogen load to safeguard the health of livestock and humans. We investigated whether cationic polymers, used as a flocculent in the solid/liquid separation process, could reduce the pathogen indicator load in the animal waste stream. The effects of low charge density cationic polyacrylamide (CPAM) and high charge density cationic polydicyandiamide (PDCD) were investigated. Results demonstrated that CPAM was more effective than PDCD for manure coagulation and flocculation, while PDCD was more effective than CPAM in reducing the pathogen indicator loads. However, their combined use, CPAM followed by PDCD, resulted in both improved solids separation and pathogen indicator reduction. PMID- 26513325 TI - Chemical characterization of an alkali-like superatom consisting of a Ta encapsulating Si16 cage. AB - Chemical characterization was performed for an alkali-like superatom consisting of a Ta-encapsulating Si16 cage, Ta@Si16, deposited on a graphite substrate using X-ray photoelectron spectroscopy (XPS) to element-specifically clarify the local electronic structure of the cage atoms. The XPS spectra derived from Ta 4f and Si 2p core levels have been well modeled with a single chemical component, revealing the formation of a symmetric Si cage around the Ta atom in the deposited nanoclusters. On chemical treatments by heating or oxygen exposure, it is found that the deposited Ta@Si16 is thermally stable up to 700 K and is also exceptionally less reactive toward oxygen compared to other Ta-Si nanoclusters, although some heat degradation and oxidation accompany the treatments. These results show the promising possibility of applying Ta@Si16 as a building block to fabricate cluster-assembled materials consisting of naked nanoclusters. PMID- 26513327 TI - The elusive illusion: Do children (Homo sapiens) and capuchin monkeys (Cebus apella) see the Solitaire illusion? AB - One approach to gaining a better understanding of how we perceive the world is to assess the errors that human and nonhuman animals make in perceptual processing. Developmental and comparative perspectives can contribute to identifying the mechanisms that underlie systematic perceptual errors often referred to as perceptual illusions. In the visual domain, some illusions appear to remain constant across the lifespan, whereas others change with age. From a comparative perspective, many of the illusions observed in humans appear to be shared with nonhuman primates. Numerosity illusions are a subset of visual illusions and occur when the spatial arrangement of stimuli within a set influences the perception of quantity. Previous research has found one such illusion that readily occurs in human adults, the Solitaire illusion. This illusion appears to be less robust in two monkey species, rhesus macaques and capuchin monkeys. We attempted to clarify the ontogeny of this illusion from a developmental and comparative perspective by testing human children and task-naive capuchin monkeys in a computerized quantity judgment task. The overall performance of the monkeys suggested that they perceived the numerosity illusion, although there were large differences among individuals. Younger children performed similarly to the monkeys, whereas older children more consistently perceived the illusion. These findings suggest that human-unique perceptual experiences with the world might play an important role in the emergence of the Solitaire illusion in human adults, although other factors also may contribute. PMID- 26513326 TI - Non-symbolic division in childhood. AB - The approximate number system (ANS) underlies representations of large numbers of objects as well as the additive, subtractive, and multiplicative relationships between them. In this set of studies, 5- and 6-year-old children were shown a series of video-based events that conveyed a transformation of a large number of objects into one-half or one-quarter of the original number. Children were able to estimate correctly the outcomes to these halving and quartering problems, and they based their responses on scaling by number, not on continuous quantities or guessing strategies. Children's performance exhibited the ratio signature of the ANS. Moreover, children performed above chance on relatively early trials, suggesting that this scaling operation is easily conveyed and readily performed. The results support the existence of a flexible and substantially untrained capacity to scale numerical amounts. PMID- 26513328 TI - I won't tell: Young children show loyalty to their group by keeping group secrets. AB - Group loyalty is highly valued. However, little is known about young children's loyal behavior. This study tested whether 4- and 5-year-olds (N=96) remain loyal to their group even when betraying it would be materially advantageous. Children and four puppets were allocated to novel groups. Two of these puppets (either in group or out-group members) then told children a group secret and urged them not to disclose the secret. Another puppet (not assigned to either group) then bribed children with stickers to tell the secret. Across ages, children were significantly less likely to reveal the secret in the in-group condition than in the out-group condition. Thus, even young children are willing to pay a cost to be loyal to their group. PMID- 26513329 TI - Active Bacterial Core Surveillance for Legionellosis - United States, 2011-2013. AB - During 2000-2011, passive surveillance for legionellosis in the United States demonstrated a 249% increase in crude incidence, although little was known about the clinical course and method of diagnosis. In 2011, a system of active, population-based surveillance for legionellosis was instituted through CDC's Active Bacterial Core surveillance (ABCs) program. Overall disease rates were similar in both the passive and active systems, but more complete demographic information and additional clinical and laboratory data were only available from ABCs. ABCs data during 2011-2013 showed that approximately 44% of patients with legionellosis required intensive care, and 9% died. Disease incidence was higher among blacks than whites and was 10 times higher in New York than California. Laboratory data indicated a reliance on urinary antigen testing, which only detects Legionella pneumophila serogroup 1 (Lp1). ABCs data highlight the severity of the disease, the need to better understand racial and regional differences, and the need for better diagnostic testing to detect infections. PMID- 26513330 TI - Inhibition of dentine collagen degradation by hesperidin: an in situ study. AB - Dentine caries is a process of demineralization and subsequent degradation of the collagenous matrix. Host-derived proteolytic enzymes, such as matrix metalloproteinases (MMPs), play a role in this process of dentine collagen degradation. Hampering this degradation retards the caries process. Dietary antioxidants, such as the flavonoid hesperidin, can inhibit the proteolytic activity of MMPs and act as natural stabilizers of collagen. The aim of this study was to investigate the anti-collagenolytic activity of hesperidin in an in situ model. A single-blind, split-mouth, in situ experiment was designed. Seventeen participants received two completely demineralized dentine specimens placed contralaterally in the buccal flanges of their partial prosthesis. During the 4-wk experimental period, the participants immersed the dentine specimens in a test solution [1,000 parts per million (p.p.m.) hesperidin] or a control solution (saline), twice daily for 3 min. After the in situ period, the specimens were retrieved and their collagen content was determined. A saliva sample was taken at the start and at the end of the experimental period, to assess collagenolytic activity. A significant protection of collagen, of 24%, was observed in the hesperidin-treated specimens compared with the control-treated specimens. No correlation was found between salivary collagenolytic activity and loss of collagen in the control-treated specimens. The results of this in situ study show that hesperidin could play a role in the preservation of dentine collagen matrix. PMID- 26513331 TI - Montreal Cognitive Assessment for the diagnosis of Alzheimer's disease and other dementias. AB - BACKGROUND: Dementia is a progressive syndrome of global cognitive impairment with significant health and social care costs. Global prevalence is projected to increase, particularly in resource-limited settings. Recent policy changes in Western countries to increase detection mandates a careful examination of the diagnostic accuracy of neuropsychological tests for dementia. OBJECTIVES: To determine the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) at various thresholds for dementia and its subtypes. SEARCH METHODS: We searched MEDLINE, EMBASE, BIOSIS Previews, Science Citation Index, PsycINFO and LILACS databases to August 2012. In addition, we searched specialised sources containing diagnostic studies and reviews, including MEDION (Meta-analyses van Diagnostisch Onderzoek), DARE (Database of Abstracts of Reviews of Effects), HTA (Health Technology Assessment Database), ARIF (Aggressive Research Intelligence Facility) and C-EBLM (International Federation of Clinical Chemistry and Laboratory Medicine Committee for Evidence-based Laboratory Medicine) databases. We also searched ALOIS (Cochrane Dementia and Cognitive Improvement Group specialized register of diagnostic and intervention studies). We identified further relevant studies from the PubMed 'related articles' feature and by tracking key studies in Science Citation Index and Scopus. We also searched for relevant grey literature from the Web of Science Core Collection, including Science Citation Index and Conference Proceedings Citation Index (Thomson Reuters Web of Science), PhD theses and contacted researchers with potential relevant data. SELECTION CRITERIA: Cross-sectional designs where all participants were recruited from the same sample were sought; case-control studies were excluded due to high chance of bias. We searched for studies from memory clinics, hospital clinics, primary care and community populations. We excluded studies of early onset dementia, dementia from a secondary cause, or studies where participants were selected on the basis of a specific disease type such as Parkinson's disease or specific settings such as nursing homes. DATA COLLECTION AND ANALYSIS: We extracted dementia study prevalence and dichotomised test positive/test negative results with thresholds used to diagnose dementia. This allowed calculation of sensitivity and specificity if not already reported in the study. Study authors were contacted where there was insufficient information to complete the 2x2 tables. We performed quality assessment according to the QUADAS-2 criteria.Methodological variation in selected studies precluded quantitative meta-analysis, therefore results from individual studies were presented with a narrative synthesis. MAIN RESULTS: Seven studies were selected: three in memory clinics, two in hospital clinics, none in primary care and two in population-derived samples. There were 9422 participants in total, but most of studies recruited only small samples, with only one having more than 350 participants. The prevalence of dementia was 22% to 54% in the clinic-based studies, and 5% to 10% in population samples. In the four studies that used the recommended threshold score of 26 or over indicating normal cognition, the MoCA had high sensitivity of 0.94 or more but low specificity of 0.60 or less. AUTHORS' CONCLUSIONS: The overall quality and quantity of information is insufficient to make recommendations on the clinical utility of MoCA for detecting dementia in different settings. Further studies that do not recruit participants based on diagnoses already present (case-control design) but apply diagnostic tests and reference standards prospectively are required. Methodological clarity could be improved in subsequent DTA studies of MoCA by reporting findings using recommended guidelines (e.g. STARDdem). Thresholds lower than 26 are likely to be more useful for optimal diagnostic accuracy of MoCA in dementia, but this requires confirmation in further studies. PMID- 26513332 TI - Is the eccrine gland an integral, functionally important component of the human scalp pilosebaceous unit? AB - The pilosebaceous unit (PSU) and the eccrine sweat gland (ESG) are classically described as completely independent skin appendages. However, careful inspection of scalp follicular units reveals that the secretory segment of the ESG spatially approximates the hair follicle in a position below the sebaceous gland and the insertion of the arrector pili muscle. Therefore, we propose here that, contrary to conventional wisdom, the PSU and the ESG should not be viewed in isolation, and may form instead, along with the arrector pili muscle and the apocrine gland (where present),one functional unit. For this, we suggest the more inclusive term of 'Hair Cluster' (HC). If confirmed, e.g. by 3D imaging techniques, the novel concept of a functional HC, whose individual components may communicate via secreted molecules and may share selected progenitor cell populations for HC repair/regeneration, has major physiological and pathological implications, which are briefly discussed. PMID- 26513333 TI - Technetium Incorporation into Goethite (alpha-FeOOH): An Atomic-Scale Investigation. AB - During the processing of low-activity radioactive waste to generate solid waste forms (e.g., glass), technetium-99 (Tc) is of concern because of its volatility. A variety of materials are under consideration to capture Tc from waste streams, including the iron oxyhydroxide, goethite (alpha-FeOOH), which was experimentally shown to sequester Tc(IV). This material could ultimately be incorporated into glass or alternative low-temperature waste form matrices. However, questions remain regarding the incorporation mechanism for Tc(IV) in goethite, which has implications for predicting the long-term stability of Tc in waste forms under changing conditions. Here, quantum-mechanical calculations were used to evaluate the energy of five different charge-compensated Tc(IV) incorporation scenarios in goethite. The two most stable incorporation mechanisms involve direct substitution of Tc(IV) onto Fe(III) lattice sites and charge balancing either by removing one nearby H(+) (i.e., within 5 A) or by creating an Fe(III) vacancy when substituting 3 Tc(IV) for 4 Fe(III), with the former being preferred over the latter relative to gas-phase ions. When corrections for hydrated references phases are applied, the Fe(III)-vacancy mechanism becomes more energetically competitive. Calculated incorporation energies and optimized bond lengths are presented. Proton movement is observed to satisfy undercoordinated bonds surrounding Fe(III)-vacancies in the goethite structure. PMID- 26513334 TI - Risk factors affecting fatal bus accident severity: Their impact on different types of bus drivers. AB - While the bus is generally considered to be a relatively safe means of transportation, the property losses and casualties caused by bus accidents, especially fatal ones, are far from negligible. The reasons for a driver to incur fatalities are different in each case, and it is essential to discover the underlying risk factors of bus fatality severity for different types of drivers in order to improve bus safety. The current study investigates the underlying risk factors of fatal bus accident severity to different types of drivers in the U.S. by estimating an ordered logistic model. Data for the analysis are retrieved from the Buses Involved in Fatal Accidents (BIFA) database from the USA for the years 2006-2010. Accidents are divided into three levels by counting their equivalent fatalities, and the drivers are classified into three clusters by the K-means cluster analysis. The analysis shows that some risk factors have the same impact on different types of drivers, they are: (a) season; (b) day of week; (c) time period; (d) number of vehicles involved; (e) land use; (f) manner of collision; (g) speed limit; (h) snow or ice surface condition; (i) school bus; (j) bus type and seating capacity; (k) driver's age; (l) driver's gender; (m) risky behaviors; and (n) restraint system. Results also show that some risk factors only have impact on the "young and elder drivers with history of traffic violations", they are: (a) section type; (b) number of lanes per direction; (c) roadway profile; (d) wet road surface; and (e) cyclist-bus accident. Notably, history of traffic violations has different impact on different types of bus drivers. PMID- 26513335 TI - Does an on-road motorcycle coaching program reduce crashes in novice riders? A randomised control trial. AB - OBJECTIVES: Motorcycle riding is increasing globally and confers a high risk of crash-related injury and death. There is community demand for investment in rider training programs but no high-quality evidence about its effectiveness in preventing crashes. This randomised trial of an on-road rider coaching program aimed to determine its effectiveness in reducing crashes in novice motorcycle riders. METHODS: Between May 2010 and October 2012, 2399 newly-licensed provisional riders were recruited in Victoria, Australia and completed a telephone interview before randomisation to intervention or control groups. Riders in the intervention group were offered an on-road motorcycle rider coaching program which involved pre-program activities, 4h riding and facilitated discussion in small groups with a riding coach. Outcome measures were collected for all participants via telephone interviews at 3 and 12 months after program delivery (or equivalent for controls), and via linkage to police-recorded crash and offence data. The primary outcome was a composite measure of police-recorded and self-reported crashes; secondary outcomes included traffic offences, near crashes, riding exposure, and riding behaviours and motivations. RESULTS: Follow up was 89% at 3 months and 88% at 12 months; 60% of the intervention group completed the program. Intention-to-treat analyses conducted in 2014 indicated no effect on crash risk at 3 months (adjusted OR 0.90, 95% CI: 0.65-1.27) or 12 months (adjusted OR 1.00, 95% CI: 0.78-1.29). Riders in the intervention group reported increased riding exposure, speeding behaviours and rider confidence. CONCLUSIONS: There was no evidence that this on-road motorcycle rider coaching program reduced the risk of crash, and we found an increase in crash-related risk factors. PMID- 26513336 TI - Hazard prediction discriminates between novice and experienced drivers. AB - Typical hazard perception tests often confound multiple processes in their responses. The current study tested hazard prediction in isolation to assess whether this component can discriminate between novice and experienced drivers. A variant of the hazard perception test, based on the Situation Awareness Global Assessment Technique, found experienced drivers to outperform novices across three experiments suggesting that the act of predicting an imminent hazard is a crucial part of the hazard-perception process. Furthermore three additional hypotheses were tested in these experiments. First, performance was compared across clips of different length. There was marginal evidence that novice drivers' performance suffered with the longest clips, but experienced drivers' performance did not, suggesting that experienced drivers find hazard prediction less effortful. Secondly, predictive accuracy was found to be dependent on the temporal proximity of visual precursors to the hazard. Thirdly the relationship between the hazard and its precursor was found to be important, with less obvious precursors improving the discrimination between novice and experience drivers. These findings demonstrate that a measure of hazard prediction, which is less confounded by the influence of risk appraisal than simple response time measures, can still discriminate between novice and experienced drivers. Application of this methodology under different conditions can produce insights into the underlying processes that may be at work, whilst also providing an alternative test of driver skill in relation to the detection of hazards. PMID- 26513337 TI - Integration of geometric consistency contributory factors in three-leg junctions collision prediction models of Portuguese two-lane national highways. AB - This paper aims at developing a collision prediction model for three-leg junctions located in national roads (NR) in Northern Portugal. The focus is to identify factors that contribute for collision type crashes in those locations, mainly factors related to road geometric consistency, since literature is scarce on those, and to research the impact of three modeling methods: generalized estimating equations, random-effects negative binomial models and random parameters negative binomial models, on the factors of those models. The database used included data published between 2008 and 2010 of 177 three-leg junctions. It was split in three groups of contributing factors which were tested sequentially for each of the adopted models: at first only traffic, then, traffic and the geometric characteristics of the junctions within their area of influence; and, lastly, factors which show the difference between the geometric characteristics of the segments boarding the junctions' area of influence and the segment included in that area were added. The choice of the best modeling technique was supported by the result of a cross validation made to ascertain the best model for the three sets of researched contributing factors. The models fitted with random-parameters negative binomial models had the best performance in the process. In the best models obtained for every modeling technique, the characteristics of the road environment, including proxy measures for the geometric consistency, along with traffic volume, contribute significantly to the number of collisions. Both the variables concerning junctions and the various national highway segments in their area of influence, as well as variations from those characteristics concerning roadway segments which border the already mentioned area of influence have proven their relevance and, therefore, there is a rightful need to incorporate the effect of geometric consistency in the three leg junctions safety studies. PMID- 26513338 TI - Sequencing and de novo draft assemblies of a fathead minnow (Pimephales promelas) reference genome. AB - The present study was undertaken to provide the foundation for development of genome-scale resources for the fathead minnow (Pimephales promelas), an important model organism widely used in both aquatic toxicology research and regulatory testing. The authors report on the first sequencing and 2 draft assemblies for the reference genome of this species. Approximately 120* sequence coverage was achieved via Illumina sequencing of a combination of paired-end, mate-pair, and fosmid libraries. Evaluation and comparison of these assemblies demonstrate that they are of sufficient quality to be useful for genome-enabled studies, with 418 of 458 (91%) conserved eukaryotic genes mapping to at least 1 of the assemblies. In addition to its immediate utility, the present work provides a strong foundation on which to build further refinements of a reference genome for the fathead minnow. PMID- 26513339 TI - S-1-based regimens and the risk of oral and gastrointestinal mucosal injury: a meta-analysis with comparison to other fluoropyrimidines. AB - BACKGROUND: We performed a meta-analysis of the risk of oral and gastrointestinal (GI) mucosal injury associated with S-1-based regimens. PATIENTS AND METHODS: Randomized phase II and III trials of patients with solid tumors on S-1; describing events of all-grade and high-grade stomatitis and diarrhea constituted the eligible studies. RESULTS: After exclusion of ineligible studies, a total of 26 clinical trials were considered eligible for the meta-analysis. The odds ratio (OR) of all-grade and high-grade stomatitis for S-1 vs. non-fluoropyrimidine controls was 4.39 [95% CI: 1.05, 18.37; p = 0.04] and 5.64 [95% CI: 1.46, 21.77; p = 0.01], respectively; while the OR of all-grade and high-grade stomatitis for S-1 vs. infusional 5-fluorouracil (5-FU) control was -1.01 [95% CI: 0.22, 4.63; p = 0.99] and 0.32 [95% CI: 0.20, 0.49; p < 0.00001], respectively. The OR of all grade and high-grade diarrhea for S-1 vs. non-fluoropyrimidine controls was 2.48 [95% CI: 2.12, 2.90; p < 0.00001] and 1.95 [95% CI: 1.29, 2.96; p = 0.002], respectively; while the OR of all-grade and high-grade diarrhea for S-1 vs. infusional 5-FU control was -1.03 [95% CI: 0.87, 1.22; p = 0.76] and 2.52 [95% CI: 1.80, 3.52; p < 0.00001], respectively. CONCLUSIONS: Compared to non fluoropyrimidine control, patients treated with S-1-based regimens have an increased risk of all-grade and high-grade stomatitis and diarrhea; while on the other hand, patients treated with infusional 5-FU have a greater risk of high grade stomatitis and diarrhea compared to patients treated with S-1-based regimens. PMID- 26513340 TI - Surfactant-Free Vanadium Oxides from Reverse Micelles and Organic Oxidants: Solution Processable Nanoribbons with Potential Applicability as Battery Insertion Electrodes Assembled in Different Configurations. AB - Vanadium oxides similar to other metal transition oxides are prototypes of multifunctionality. Implementing new synthesis routes that lead to dry vanadium oxide nanomaterials with good functional and structural properties as well as good processing capabilities is thus of general interest. Here we report a facile method based on reverse micelles for the growth at room temperature and atmospheric pressure of surfactant-free vanadium oxide nanoribbons that retain after drying excellent solution-processable capabilities. Essential for the success of the method is the use of a soluble organic oxidant that acts as oxidant and cosurfactant during the synthesis, and facilitates surfactant removal with a simple washing protocol. Interestingly, this simple surfactant removal protocol could be of general applicability. As a proof-of-concept of the functional, structural, and processing capabilities of the dry vanadium oxide nanoribbons here prepared, we have checked their lithium insertion capabilities as battery cathodes built upon different configurations. Specifically, we show efficient insertion both in dry nanoribbons processed as films using doctor blade and organic solvents and in dry nanoribbons infiltrated in three-dimensional metal collectors from aqueous suspensions. PMID- 26513341 TI - Pediatric extended spectrum beta-lactamase infection: Community-acquired infection and treatment options. AB - BACKGROUND: Infection caused by extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in pediatric patients has been increasing and spreading to the community, compromising the options for effective antibiotics. This retrospective study was conducted to identify which antibiotics ESBL-producing Enterobacteriaceae remain susceptible to. In addition, the prevalence of community-acquired infection caused by these organisms, and the possibility of association between these organisms and septic shock, were explored. METHODS: Antibiotic susceptibility of ESBL-producing and non-ESBL-producing Escherichia coli and Klebsiella pneumoniae strains isolated from pediatric patients were reviewed to determine the rates of susceptibility to various antibiotics. A chart review was performed to clarify the prevalence of community-acquired infection and the severity. RESULTS: Of 849 strains analyzed, 40% were ESBL positive. Apart from cephalosporins, ESBL-producing strains were also less likely to be susceptible to other antibiotics, such as quinolones, gentamicin, netilmicin, and cotrimoxazole, more than 90% of which were still susceptible to amikacin, carbapenems, colistin, and tigecycline. Around 20% of community-acquired infections in the present study were caused by ESBL-producing strains. ESBL producing strains found in the community were more likely to be susceptible to gentamicin, netilmicin, and cefepime than those found in hospital. Infection caused by ESBL-producing strains was not significantly associated with septic shock. CONCLUSION: The increase in infection caused by ESBL-producing Enterobacteriaceae limits the availability of effective antibiotics. Given that carbapenems are necessary for treating serious infections, amikacin, cefepime, and piperacillin/tazobactam are possible options for consolidative therapy or for non-serious infection. PMID- 26513342 TI - Electronic Structure and Optical Properties of BiOI Ultrathin Films for Photocatalytic Water Splitting. AB - As a promising photocatalyst driven by visible light, BiOI suffers from its lower conduction band edge position, which leads to its inability to produce hydrogen from photocatalytic water splitting. However, BiOI has an open layered intergrowth structure, which makes it easily cleavable along (001) plane. Thus, inspired by the progress of graphene-like two-dimensional nanomaterials, researchers believe that single-layer BiOI presents excellent photocatalytic activity for water splitting. To further explore the relationship between intrinsic properties and photocatalytic performance of BiOI ultrathin film, its electronic structure and optical properties as a function of layer thickness are systematically investigated by using first-principle calculations. The calculated results indicate that the quantum confinement effects can cause the following variations: band gap increasing, band edge position upshifting, and built-in electric field strengthening, which are very favorable for enhancement of photocatalytic performance. Importantly, if the layer thickness is less than 3 nm, the conduction band edge position will be higher than the reduction potential of H(+)/H2 and thus appropriate for the overall photocatalytic water-splitting reaction. However, layer thickness also caused disadvantageous reduction of sunlight absorption, which is noticed and avoided in practice. PMID- 26513343 TI - Palladium-Catalyzed Direct Arylation of C(sp(3))-H Bonds of alpha-Cyano Aliphatic Amides. AB - Pd(OAc)2-catalyzed arylation of C(sp(3))-H bonds in alpha-cyano-alpha-methyl aliphatic amides is achieved in the presence of 8-aminoquinoline, as a removable directing group, using Mn(OAc)2 and Na2CO3. The current strategy enables the placement of an aryl/heteroaryl group at the beta-position of alpha-cyano aliphatic acids for the first time. Wide functional group tolerance and easily accessible starting materials provide an efficient protocol for the synthesis of arylated alpha-cyano amides. Furthermore, the synthetic utility of the products has been demonstrated by their efficient conversions to medicinally important alpha,alpha-dialkylated acid and beta-amino acid derivatives. PMID- 26513344 TI - Suppression in PHLPP2 induction by morin promotes Nrf2-regulated cellular defenses against oxidative injury to primary rat hepatocytes. AB - Recent advances indicate a possible role of phytochemicals as modulatory factors in signaling pathways. We have previously demonstrated PHLPP2-mediated suppression of Nrf2 responses during oxidant attack. The present study was designed to explore Nrf2-potentiating mechanism of morin, a flavonol, via its possible role in intervening PHLPP2-regulated Akt/GSK3beta/Fyn kinase axis. Efficacy of morin was evaluated against oxidative stress-mediated damage to primary hepatocytes by tert-butyl hydroperoxide (tBHP) and acetaminophen. The anti-cytotoxic effects of morin were found to be a consequence of fortification of Nrf2-regulated antioxidant defenses since morin failed to sustain activities of redox enzyme in Nrf2 silenced hepatocytes. Morin promoted Nrf2 stability and its nuclear retention by possibly modulating PHLPP2 activity which subdues cellular Nrf2 responses by activating Fyn kinase. Pull-down assay using morin conjugated beads indicated the binding affinity of morin towards PHLPP2. Molecular docking also revealed the propensity of morin to occupy the active site of PHLPP2 enzyme. Thus, dietary phytochemical morin was observed to counteract oxidant-induced hepatocellular damage by promoting Nrf2-regulated transcriptional induction. The findings support the novel role of morin in potentiating Nrf2 responses by limiting PHLPP2 and hence Fyn kinase activation. Therefore, morin may be exploited in developing novel therapeutic strategy aimed at enhancing Nrf2 responses. PMID- 26513345 TI - Decrease of serum total ghrelin in extensive atrophic gastritis: comparison with pepsinogens in histological reference. AB - OBJECTIVE: Ghrelin is mainly secreted by the gastric oxyntic mucosa and its production is impaired in chronic atrophic gastritis. This study aimed at evaluating how serum total ghrelin correlates with the extent of atrophy, and to compare its performance as a serologic marker with that of pepsinogen (PG). MATERIAL AND METHODS: Data were collected from 154 patients with atrophic gastritis. The histological extent of atrophy was assessed by three paired biopsies from the antrum, corpus lesser curvature (CLC), and corpus greater curvature (CGC). Fasting serum concentrations of total ghrelin, pepsinogen I and II were measured. Regression analysis was performed to evaluate the factors associated with serum total ghrelin. The serologic performance was compared with that of pepsinogen using receiver-operating characteristic (ROC) curves. RESULTS: The Helicobacter pylori infection rate was 85%, and extensive atrophic gastritis involving CGC was found in 24%. Serum total ghrelin was significantly decreased in patients with extensive CGC atrophy (median: 170.4 pg/mL, vs 201.1 pg/mL in patients without atrophy; p < 0.001), and its levels correlated with those of pepsinogen I and I/II ratio. The decrease of serum total ghrelin was independent of age, gender, body mass index (BMI), and H. pylori infection status. The sensitivity and specificity of serum total ghrelin in predicting extensive atrophy were 57% and 79%, respectively. The discriminatory ability was similar to that of pepsinogen I/II ratio (p = 0.612), and lower than that of pepsinogen I (p = 0.040). CONCLUSIONS: Serum total ghrelin is decreased during extensive atrophy involving CGC. The serologic performance is lower than that of pepsinogen I. PMID- 26513346 TI - Efficacy of endoscopic ultrasonography and endoscopic ultrasonography-guided fine needle aspiration for the diagnosis and grading of pancreatic neuroendocrine tumors. AB - BACKGROUND AND AIM: Pancreatic neuroendocrine tumors (pNETs) are histologically categorized according to the WHO 2010 classification by their mitotic index or Ki 67 index as G1, G2, or G3. The present study examined the efficacy of endoscopic ultrasonography (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) in the diagnosis and grading of pNET. METHODS: We retrospectively reviewed 61 pNETs in 51 patients who underwent EUS between January 2007 and June 2014. All lesions were pathologically diagnosed by surgical resection or EUS-FNA. We evaluated the detection rates of EUS for pNET and sensitivity of EUS-FNA, and compared the Ki 67 index between EUS-FNA samples and surgical specimens. EUS findings were compared between G1 and G2/G3 tumors. RESULTS: EUS showed significantly higher sensitivity (96.7%) for identifying pNET than CT (85.2%), MRI (70.2%), and ultrasonography (75.5%). The sensitivity of EUS-FNA for the diagnosis of pNET was 89.2%. The concordance rate of WHO classification between EUS-FNA and surgical specimens was 69.2% (9/13). The concordance rate was relatively high (87.5%, 5/6) in tumors <20 mm but lower (57.1%; 4/7) in tumors >=20 mm. Regarding EUS findings, G2/G3 tumors were more likely to be large (>20 mm), heterogeneous, and have main pancreatic duct (MPD) obstruction than G1 tumors. Multivariate analysis showed large diameter and MPD obstruction were significantly associated with G2/G3 tumors. CONCLUSIONS: EUS and EUS-FNA are highly sensitive and accurate diagnostic methods for pNET. Characteristic EUS findings such as large tumor size and MPD obstruction are suggestive of G2/G3 tumors and would be helpful for grading pNETs. PMID- 26513347 TI - Bias in CFTR screening panels. PMID- 26513348 TI - Response to Sosnay et al. PMID- 26513349 TI - Perceived economic burden associated with an inherited cardiac condition: a qualitative inquiry with families affected by arrhythmogenic right ventricular cardiomyopathy. AB - PURPOSE: Significant gaps remain in the literature on the economic burden of genetic illness. We explored perceived economic burden associated with one inherited cardiac condition, arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS: Semistructured interviews were held with individuals from families affected by ARVC. Data on the perceived financial and economic impacts of ARVC were used to identify emerging categories and themes using the method of constant comparison. RESULTS: Data analysis revealed four themes that described participants' perceptions of the economic impact ARVC had on them and their families: (i) economic impact during childhood, (ii) impact on current and future employment, (iii) impact on current and future financial well-being, and (iv) no perceived economic impact. CONCLUSIONS: This study is the first to explore the economic burden of ARVC from the perspective of affected families. It revealed a number of perceived burdens, from employment and career choices to worry about insurance for self and children, decreased household spending, and the need for childhood employment. Findings highlight potential areas of discussion for genetic counseling sessions, as well as areas for future research.Genet Med 18 6, 584-592. PMID- 26513350 TI - Spiders Tune Glue Viscosity to Maximize Adhesion. AB - Adhesion in humid conditions is a fundamental challenge to both natural and synthetic adhesives. Yet, glue from most spider species becomes stickier as humidity increases. We find the adhesion of spider glue, from five diverse spider species, maximizes at very different humidities that matches their foraging habitats. By using high-speed imaging and spreading power law, we find that the glue viscosity varies over 5 orders of magnitude with humidity for each species, yet the viscosity at maximal adhesion for each species is nearly identical, 10(5) 10(6) cP. Many natural systems take advantage of viscosity to improve functional response, but spider glue's humidity responsiveness is a novel adaptation that makes the glue stickiest in each species' preferred habitat. This tuning is achieved by a combination of proteins and hygroscopic organic salts that determines water uptake in the glue. We therefore anticipate that manipulation of polymer-salts interaction to control viscosity can provide a simple mechanism to design humidity responsive smart adhesives. PMID- 26513351 TI - Addendum. PMID- 26513353 TI - Erythropoietin Decreases the Occurrence of Myocardial Fibrosis by Inhibiting the NADPH-ERK-NF-x03BA;B Pathway. AB - OBJECTIVES: The aim of this study was to investigate the protective role of erythropoietin (EPO) against myocardial fibrosis (MF). METHODS: Pressure overloaded rats were established by abdominal aortic constriction, the rats were randomly divided in a double-blind manner into 3 groups (n = 12 for each group): sham-operated rats (sham), operated rats receiving physiological saline (vehicle) and operated rats receiving 4,000 U/kg rhEPO (EPO group). The vehicle and drugs were administered to rats by intraperitoneal injection. In addition, cultured adult rat cardiac fibroblasts (CFs) were utilized to investigate the role of EPO in CF proliferation and collagen secretion. RESULTS: After 4 weeks, besides an increase in blood pressure, myocardial hypertrophy, collagen deposition in the myocardium and decreased cardiac function were observed in the pressure overloaded rats. The expression of NADPH oxidase (Nox2 and Nox4) and inflammatory cytokines (CD45, F4/80 and MCP-1) was also significantly increased. All these alterations were prevented by EPO. TGF-beta promoted CF proliferation, collagen secretion, ROS production and Nox2/Nox4 expression, which was inhibited by EPO. In addition, the TGF-beta-induced increase of ERK1/2 phosphorylation and NF x03BA;B expression were attenuated by EPO. CONCLUSION: EPO inhibited rat MF induced by pressure overload and improved myocardial function by decreasing CF proliferation and differentiation via inhibition of the NADPH-ERK-NF-x03BA;B pathway. PMID- 26513352 TI - Learning-Induced Gene Expression in the Hippocampus Reveals a Role of Neuron Astrocyte Metabolic Coupling in Long Term Memory. AB - We examined the expression of genes related to brain energy metabolism and particularly those encoding glia (astrocyte)-specific functions in the dorsal hippocampus subsequent to learning. Context-dependent avoidance behavior was tested in mice using the step-through Inhibitory Avoidance (IA) paradigm. Animals were sacrificed 3, 9, 24, or 72 hours after training or 3 hours after retention testing. The quantitative determination of mRNA levels revealed learning-induced changes in the expression of genes thought to be involved in astrocyte-neuron metabolic coupling in a time dependent manner. Twenty four hours following IA training, an enhanced gene expression was seen, particularly for genes encoding monocarboxylate transporters 1 and 4 (MCT1, MCT4), alpha2 subunit of the Na/K ATPase and glucose transporter type 1. To assess the functional role for one of these genes in learning, we studied MCT1 deficient mice and found that they exhibit impaired memory in the inhibitory avoidance task. Together, these observations indicate that neuron-glia metabolic coupling undergoes metabolic adaptations following learning as indicated by the change in expression of key metabolic genes. PMID- 26513354 TI - What makes a movement a gesture? AB - Theories of how adults interpret the actions of others have focused on the goals and intentions of actors engaged in object-directed actions. Recent research has challenged this assumption, and shown that movements are often interpreted as being for their own sake (Schachner & Carey, 2013). Here we postulate a third interpretation of movement-movement that represents action, but does not literally act on objects in the world. These movements are gestures. In this paper, we describe a framework for predicting when movements are likely to be seen as representations. In Study 1, adults described one of three scenes: (1) an actor moving objects, (2) an actor moving her hands in the presence of objects (but not touching them) or (3) an actor moving her hands in the absence of objects. Participants systematically described the movements as depicting an object-directed action when the actor moved objects, and favored describing the movements as depicting movement for its own sake when the actor produced the same movements in the absence of objects. However, participants favored describing the movements as representations when the actor produced the movements near, but not on, the objects. Study 2 explored two additional features-the form of an actor's hands and the presence of speech-like sounds-to test the effect of context on observers' classification of movement as representational. When movements are seen as representations, they have the power to influence communication, learning, and cognition in ways that movement for its own sake does not. By incorporating representational gesture into our framework for movement analysis, we take an important step towards developing a more cohesive understanding of action-interpretation. PMID- 26513355 TI - Where are the cookies? Two- and three-year-olds use number-marked verbs to anticipate upcoming nouns. AB - We tested toddlers' and adults' predictive use of English subject-verb agreement. Participants saw pairs of pictures differing in number and kind (e.g., one apple, two cookies), and heard sentences with a target noun naming one of the pictures. The target noun was the subject of a preceding agreeing verb in informative trials (e.g., Wherearethe good cookies?), but not in uninformative trials (Do you see the good cookies?). In Experiment 1, 3-year-olds and adults were faster and more likely to shift their gaze from distractor to target upon hearing an informative agreeing verb. In Experiment 2, 2.5-year-olds were faster to shift their gaze from distractor to target in response to the noun in informative trials, and were more likely to be fixating the target already at noun onset. Thus, toddlers used agreeing verbs to predict number features of an upcoming noun. These data provide strong new evidence for the broad scope of predictive processing in online language comprehension. PMID- 26513356 TI - Individual consistency in the accuracy and distribution of confidence judgments. AB - We examine which aspects of the confidence distributions - its shape, its bias toward higher or lower values, and its ability to distinguish correct from erred trials - are idiosyncratic of the who (individual specificity), the when (variability across days) and the what (task specificity). Measuring confidence across different sessions of four different perceptual tasks we show that: (1) Confidence distributions are virtually identical when measured in different days for the same subject and the same task, constituting a subjective fingerprint, (2) The capacity of confidence reports to distinguish correct from incorrect responses is only modestly (but significantly) correlated when compared across tasks, (3) Confidence distributions are very similar for tasks that involve different sensory modalities but have similar structure, (4) Confidence accuracy is independent of the mean and width of the confidence distribution, (5) The mean of the confidence distribution (an individual's confidence bias) constitutes the most efficient indicator to infer a subject's identity from confidence reports and (6) Confidence bias measured in simple perceptual decisions correlates with an individual's optimism bias measured with standard questionnaire. PMID- 26513357 TI - Profile of an HIV Testing and Counseling Unit in Bangladesh: Majority of New Diagnoses among Returning Migrant Workers and Spouses. AB - INTRODUCTION: Analysis of data from HIV testing and counseling (HTC) services provides an opportunity to identify important populations for targeting of HIV prevention efforts. Our primary aim was to describe the demographics of clients presenting to HTC in Bangladesh, a low HIV prevalence country. Our secondary aim was to determine the risk factors for HIV positivity among returning migrant workers who were tested. METHODS: We performed a cross-sectional study of data collected between 2002 and 2010 from the first HTC service established in Bangladesh, located in three large cities. RESULTS: 8973 individuals attended HTC services, with 558 (6.2%) of clients testing positive for HIV, including 33 children. The majority of those who tested positive were aged 25-44 (71%), male (70%), and married (68%). Key populations considered at increased risk of HIV, such as female sex workers, people who inject drugs, and males who have sex with males accounted for only 11% of adults who tested positive. Notably, 75% of adults testing positive had a history of migrant work or was the spouse of a migrant worker. In multivariable logistic regression of those with a migrant work history presenting for HTC, we found rural residence, working in the Middle East, and longer duration of migrant work to be independently associated with testing positive, and female gender and higher level of education to be negatively associated. CONCLUSIONS: These data suggest that in Bangladesh, in addition to targeting traditional key populations, HIV prevention efforts should also focus on migrant workers and their spouses. PMID- 26513358 TI - Change in Care Dependency and Nursing Care Problems in Nursing Home Residents with and without Dementia: A 2-Year Panel Study. AB - Over time, chronic conditions like dementia can lead to care dependency and nursing care problems, often necessitating nursing home admission. This panel study (2012-2014) aims to explore changes in care dependency and nursing care problems (incontinence, malnutrition, decubitus, falls and restraints) in residents with and without dementia over time. In total, nine Austrian nursing homes participated, including 258 residents (178 with, 80 without dementia) who completed all five measurements. Data were collected with the International Prevalence Measurement of Care Problems questionnaire, the Care Dependency Scale and the Mini-Mental State Examination-2. Repeated measures ANOVA and crosstabs were used to analyse changes. The results showed that care dependency in dementia residents increased significantly for all 15 items of the Care Dependency Scale, with the highest increase being residents' day-/night pattern, contact with others, sense of rules/values and communication. In contrast, care dependency in residents without dementia increased for four of the 15 items, with the highest increase being for continence, followed by getting (un)dressed. With respect to the assessed nursing care problems, residents with dementia and those without only differed significantly in terms of an increase in urinary- (12.3% vs. 14.2%), fecal- (17.4% vs. 10%), and double incontinence (16.7% vs. 11.9%). The results indicated that residents with dementia experienced increased care dependency in different areas than residents without dementia. Furthermore, residents with dementia experienced a lower increase in urinary incontinence but a higher increase in fecal- and double incontinence. These results help professionals to identify areas for improvement in dementia care. PMID- 26513359 TI - Resected Brain Tissue, Seizure Onset Zone and Quantitative EEG Measures: Towards Prediction of Post-Surgical Seizure Control. AB - BACKGROUND: Epilepsy surgery is a potentially curative treatment option for pharmacoresistent patients. If non-invasive methods alone do not allow to delineate the epileptogenic brain areas the surgical candidates undergo long-term monitoring with intracranial EEG. Visual EEG analysis is then used to identify the seizure onset zone for targeted resection as a standard procedure. METHODS: Despite of its great potential to assess the epileptogenicty of brain tissue, quantitative EEG analysis has not yet found its way into routine clinical practice. To demonstrate that quantitative EEG may yield clinically highly relevant information we retrospectively investigated how post-operative seizure control is associated with four selected EEG measures evaluated in the resected brain tissue and the seizure onset zone. Importantly, the exact spatial location of the intracranial electrodes was determined by coregistration of pre-operative MRI and post-implantation CT and coregistration with post-resection MRI was used to delineate the extent of tissue resection. Using data-driven thresholding, quantitative EEG results were separated into normally contributing and salient channels. RESULTS: In patients with favorable post-surgical seizure control a significantly larger fraction of salient channels in three of the four quantitative EEG measures was resected than in patients with unfavorable outcome in terms of seizure control (median over the whole peri-ictal recordings). The same statistics revealed no association with post-operative seizure control when EEG channels contributing to the seizure onset zone were studied. CONCLUSIONS: We conclude that quantitative EEG measures provide clinically relevant and objective markers of target tissue, which may be used to optimize epilepsy surgery. The finding that differentiation between favorable and unfavorable outcome was better for the fraction of salient values in the resected brain tissue than in the seizure onset zone is consistent with growing evidence that spatially extended networks might be more relevant for seizure generation, evolution and termination than a single highly localized brain region (i.e. a "focus") where seizures start. PMID- 26513360 TI - Comparisons of Allergenic and Metazoan Parasite Proteins: Allergy the Price of Immunity. AB - Allergic reactions can be considered as maladaptive IgE immune responses towards environmental antigens. Intriguingly, these mechanisms are observed to be very similar to those implicated in the acquisition of an important degree of immunity against metazoan parasites (helminths and arthropods) in mammalian hosts. Based on the hypothesis that IgE-mediated immune responses evolved in mammals to provide extra protection against metazoan parasites rather than to cause allergy, we predict that the environmental allergens will share key properties with the metazoan parasite antigens that are specifically targeted by IgE in infected human populations. We seek to test this prediction by examining if significant similarity exists between molecular features of allergens and helminth proteins that induce an IgE response in the human host. By employing various computational approaches, 2712 unique protein molecules that are known IgE antigens were searched against a dataset of proteins from helminths and parasitic arthropods, resulting in a comprehensive list of 2445 parasite proteins that show significant similarity through sequence and structure with allergenic proteins. Nearly half of these parasite proteins from 31 species fall within the 10 most abundant allergenic protein domain families (EF-hand, Tropomyosin, CAP, Profilin, Lipocalin, Trypsin-like serine protease, Cupin, BetV1, Expansin and Prolamin). We identified epitopic-like regions in 206 parasite proteins and present the first example of a plant protein (BetV1) that is the commonest allergen in pollen in a worm, and confirming it as the target of IgE in schistosomiasis infected humans. The identification of significant similarity, inclusive of the epitopic regions, between allergens and helminth proteins against which IgE is an observed marker of protective immunity explains the 'off-target' effects of the IgE-mediated immune system in allergy. All these findings can impact the discovery and design of molecules used in immunotherapy of allergic conditions. PMID- 26513361 TI - Mitogenomes from Egyptian Cattle Breeds: New Clues on the Origin of Haplogroup Q and the Early Spread of Bos taurus from the Near East. AB - BACKGROUND: Genetic studies support the scenario that Bos taurus domestication occurred in the Near East during the Neolithic transition about 10 thousand years (ky) ago, with the likely exception of a minor secondary event in Italy. However, despite the proven effectiveness of whole mitochondrial genome data in providing valuable information concerning the origin of taurine cattle, until now no population surveys have been carried out at the level of mitogenomes in local breeds from the Near East or surrounding areas. Egypt is in close geographic and cultural proximity to the Near East, in particular the Nile Delta region, and was one of the first neighboring areas to adopt the Neolithic package. Thus, a survey of mitogenome variation of autochthonous taurine breeds from the Nile Delta region might provide new insights on the early spread of cattle rearing outside the Near East. METHODOLOGY: Using Illumina high-throughput sequencing we characterized the mitogenomes from two cattle breeds, Menofi (N = 17) and Domiaty (N = 14), from the Nile Delta region. Phylogenetic and Bayesian analyses were subsequently performed. CONCLUSIONS: Phylogenetic analyses of the 31 mitogenomes confirmed the prevalence of haplogroup T1, similar to most African cattle breeds, but showed also high frequencies for haplogroups T2, T3 and Q1, and an extremely high haplotype diversity, while Bayesian skyline plots pointed to a main episode of population growth ~12.5 ky ago. Comparisons of Nile Delta mitogenomes with those from other geographic areas revealed that (i) most Egyptian mtDNAs are probably direct local derivatives from the founder domestic herds which first arrived from the Near East and the extent of gene flow from and towards the Nile Delta region was limited after the initial founding event(s); (ii) haplogroup Q1 was among these founders, thus proving that it underwent domestication in the Near East together with the founders of the T clades. PMID- 26513363 TI - Phosphorus and Defoliation Interact and Improve the Growth and Composition of the Plant Community and Soil Properties in an Alpine Pasture of Qinghai-Tibet Plateau. AB - Pasture degradation caused by overgrazing and inappropriate fertiliser management is a major production and environmental threat in Qinghai-Tibet Plateau. Previous research has focused on the effects of mixed nitrogen (N) and phosphorus (P) fertiliser and reduced grazing pressure on the plant community of the grassland; however, the role of P and how it interacts with various defoliation (the process of the complete or partial removal of the above-ground parts of plants by grazing or cutting) intensities on the plant and soil of the grassland ecosystem have not been quantified. A field experiment was conducted to quantify how P application in combination of defoliation pressure could impact the dynamic change of the plant and soil in a native alpine grassland ecosystem of the Qinghai-Tibet Plateau, China, from May 2012 to September 2014. A split-plot design with 4 replicates and repeated measures was used to determine the growth and composition of plant community and soil physical and chemical properties under various levels of P fertiliser and defoliation intensity. The results showed that applying 20 kg P/ha increased the herbage yield of Melissitus ruthenica by 68% and total pasture yield by 25%. Close defoliation favoured the growth and plant frequency of the shorter species, whereas lax defoliation favoured that of the taller plant species. Medium P rate and cutting to 3 cm above ground gave an overall best outcome in pasture yield, quality and frequency and soil moisture and nutrient concentration. Application of P fertiliser with a moderate defoliation pressure to promote legume growth and N fixation has the potential to achieve multiple benefits in increasing pasture and livestock production and improving environmental sustainability in the alpine pasture of Qinghai-Tibet Plateau, a fragile and P-deficient ecosystem zone in China and its western neighbouring countries. PMID- 26513362 TI - Calcium Regulation of Hemorrhagic Fever Virus Budding: Mechanistic Implications for Host-Oriented Therapeutic Intervention. AB - Hemorrhagic fever viruses, including the filoviruses (Ebola and Marburg) and arenaviruses (Lassa and Junin viruses), are serious human pathogens for which there are currently no FDA approved therapeutics or vaccines. Importantly, transmission of these viruses, and specifically late steps of budding, critically depend upon host cell machinery. Consequently, strategies which target these mechanisms represent potential targets for broad spectrum host oriented therapeutics. An important cellular signal implicated previously in EBOV budding is calcium. Indeed, host cell calcium signals are increasingly being recognized to play a role in steps of entry, replication, and transmission for a range of viruses, but if and how filoviruses and arenaviruses mobilize calcium and the precise stage of virus transmission regulated by calcium have not been defined. Here we demonstrate that expression of matrix proteins from both filoviruses and arenaviruses triggers an increase in host cytoplasmic Ca2+ concentration by a mechanism that requires host Orai1 channels. Furthermore, we demonstrate that Orai1 regulates both VLP and infectious filovirus and arenavirus production and spread. Notably, suppression of the protein that triggers Orai activation (Stromal Interaction Molecule 1, STIM1) and genetic inactivation or pharmacological blockade of Orai1 channels inhibits VLP and infectious virus egress. These findings are highly significant as they expand our understanding of host mechanisms that may broadly control enveloped RNA virus budding, and they establish Orai and STIM1 as novel targets for broad-spectrum host-oriented therapeutics to combat these emerging BSL-4 pathogens and potentially other enveloped RNA viruses that bud via similar mechanisms. PMID- 26513364 TI - Leading Indicators and the Evaluation of the Performance of Alerts for Influenza Epidemics. AB - BACKGROUND: Most evaluations of epidemic thresholds for influenza have been limited to internal criteria of the indicator variable. We aimed to initiate discussion on appropriate methods for evaluation and the value of cross validation in assessing the performance of a candidate indicator for influenza activity. METHODS: Hospital records of in-patients with a diagnosis of confirmed influenza were extracted from the Canadian Discharge Abstract Database from 2003 to 2011 and aggregated to weekly and regional levels, yielding 7 seasons and 4 regions for evaluation (excluding the 2009 pandemic period). An alert created from the weekly time-series of influenza positive laboratory tests (FluWatch, Public Health Agency of Canada) was evaluated against influenza-confirmed hospitalizations on 5 criteria: lead/lag timing; proportion of influenza hospitalizations covered by the alert period; average length of the influenza alert period; continuity of the alert period and length of the pre-peak alert period. RESULTS: Influenza hospitalizations led laboratory positive tests an average of only 1.6 (95% CI: -1.5, 4.7) days. However, the difference in timing exceeded 1 week and was statistically significant at the significance level of 0.01 in 5 out of 28 regional seasons. An alert based primarily on 5% positivity and 15 positive tests produced an average alert period of 16.6 weeks. After allowing for a reporting delay of 2 weeks, the alert period included 80% of all influenza-confirmed hospitalizations. For 20 out of the 28 (71%) seasons, the first alert would have been signalled at least 3 weeks (in real time) prior to the week with maximum number of influenza hospitalizations. CONCLUSIONS: Virological data collected from laboratories was a good indicator of influenza activity with the resulting alert covering most influenza hospitalizations and providing a reasonable pre-peak warning at the regional level. Though differences in timing were statistically significant, neither time-series consistently led the other. PMID- 26513365 TI - Gas Chromatography-Quadrupole Time-of-Flight Mass Spectrometry-Based Determination of Isotopologue and Tandem Mass Isotopomer Fractions of Primary Metabolites for (13)C-Metabolic Flux Analysis. AB - For the first time an analytical work flow based on accurate mass gas chromatography-quadrupole time-of-flight mass spectrometry (GC-QTOFMS) with chemical ionization for analysis providing a comprehensive picture of (13)C distribution along the primary metabolism is elaborated. The method provides a powerful new toolbox for (13)C-based metabolic flux analysis, which is an emerging strategy in metabolic engineering. In this field, stable isotope tracer experiments based on, for example, (13)C are central for providing characteristic patterns of labeled metabolites, which in turn give insights into the regulation of metabolic pathway kinetics. The new method enables the analysis of isotopologue fractions of 42 free intracellular metabolites within biotechnological samples, while tandem mass isotopomer information is also accessible for a large number of analytes. Hence, the method outperforms previous approaches in terms of metabolite coverage, while also providing rich isotopomer information for a significant number of key metabolites. Moreover, the established work flow includes novel evaluation routines correcting for isotope interference of naturally distributed elements, which is crucial following derivatization of metabolites. Method validation in terms of trueness, precision, and limits of detection was performed, showing excellent analytical figures of merit with an overall maximum bias of 5.8%, very high precision for isotopologue and tandem mass isotopomer fractions representing >10% of total abundance, and absolute limits of detection in the femtomole range. The suitability of the developed method is demonstrated on a flux experiment of Pichia pastoris employing two different tracers, i.e., 1,6(13)C2-glucose and uniformly labeled (13)C-glucose. PMID- 26513366 TI - Poverty indicators and mental health functioning among adults living with HIV in Delhi, India. AB - Poor mental health functioning among persons living with HIV (PLHIV) has gained considerable attention particularly in low-income countries that disproportionately carry the global HIV/AIDS burden. Fewer studies, however, have examined the relationship between poverty indicators and mental health among PHLIV in India. Based on this cross-sectional study of 196 HIV-seropositive adults who received medical services at Shalom AIDS Project in Delhi, India, structural equation modeling and mediation analysis were employed to estimate the associations between poverty indices (household asset index, food security, unemployment, water treatment, sanitation), HIV-health factors (illness in the past 3 months, co-morbid medical conditions), and psychological distress. In the final model, ownership of fewer household assets was associated with higher levels of food insecurity, which in turn was associated with higher psychological distress. Also, the household asset index, food insecurity, and unemployment had a larger effect on psychological distress than new opportunistic infections. These findings build on increasing evidence that support concerted efforts to design, evaluate, and refine HIV mental health interventions that are mainstreamed with livelihood programming in high poverty regions in India. PMID- 26513367 TI - Amyloidosis of the Breast: Three Different and Unusual Presentations of a Rare Entity. AB - BACKGROUND: Amyloidosis involving the breast is a rare finding and it may present as a solitary mass called 'amyloid tumor'. According to the largest case series, the amyloid deposits are usually of the AL type (commonly x03BA; light chain). METHODS: We report 3 cases diagnosed at our institution in the period from 2000 to 2015. Radiological, histological and immunohistochemical studies were performed. RESULTS AND CONCLUSIONS: Together with a case presenting in a patient with multiple myeloma, we describe 2 unique presentations including 1 associated with CREST syndrome in a patient with a previous history of breast carcinoma and another, also associated with cancer, with transthyretin deposits in a woman with a TTR gene mutation and a family history of familial amyloidotic polyneuropathy. These cases are an example of the vast heterogeneity of this disorder regarding its clinical presentation, the type of amyloid deposits and other diseases associated with breast amyloidosis. PMID- 26513368 TI - Impact of Donation Mode on the Proportion and Function of T Lymphocytes in the Liver. AB - BACKGROUND: Liver T-cells respond to the inflammatory insult generated during organ procurement and contribute to the injury following reperfusion. The mode of liver donation alters various metabolic and inflammatory pathways but the way it affects intrahepatic T-cells is still unclear. METHODS: We investigated the modifications occurring in the proportion and function of T-cells during liver procurement for transplantation. We isolated hepatic mononuclear cells (HMC) from liver perfusate of living donors (LD) and donors after brain death (DBD) or cardiac death (DCD) and assessed the frequency of T-cell subsets, their cytokine secretion profile and CD8 T-cell cytotoxicity function, responsiveness to a danger associated molecular pattern (High Mobility Group Box1, HMGB1) and association with donor and recipient clinical parameters and immediate graft outcome. RESULTS: We found that T-cells in healthy human livers were enriched in memory CD8 T-cells exhibiting a phenotype of non-circulating tissue-associated lymphocytes, functionally dominated by more cytotoxicity and IFN-gamma-production in DBD donors, including upon activation by HMGB1 and correlating with peak of post-transplant AST. This liver-specific pattern of CD8 T-cell was prominent in DBD livers compared to DCD and LD livers suggesting that it was influenced by events surrounding brain death, prior to retrieval. CONCLUSION: Mode of liver donation can affect liver T-cells with increased liver damage in DBD donors. These findings may be relevant in designing therapeutic strategies aimed at organ optimization prior to transplantation. PMID- 26513369 TI - Corrigendum: Frankincense and myrrh suppress inflammation via regulation of the metabolic profiling and the MAPK signaling pathway. PMID- 26513370 TI - Usage of Complementary Medicine in Switzerland: Results of the Swiss Health Survey 2012 and Development Since 2007. AB - BACKGROUND: Complementary medicine (CM) is popular in Switzerland. Several CM methods (traditional Chinese medicine/acupuncture, homeopathy, anthroposophic medicine, neural therapy, and herbal medicine) are currently covered by the mandatory basic health insurance when performed by a certified physician. Treatments by non-medical therapists are partially covered by a supplemental and optional health insurance. In this study, we investigated the frequency of CM use including the evolvement over time, the most popular methods, and the user profile. METHODS: Data of the Swiss Health Surveys 2007 and 2012 were used. In 2007 and 2012, a population of 14,432 and 18,357, respectively, aged 15 years or older answered the written questionnaire. A set of questions queried about the frequency of use of various CM methods within the last 12 months before the survey. Proportions of usage and 95% confidence intervals were calculated for these methods and CM in general. Users and non-users of CM were compared using logistic regression models. RESULTS: The most popular methods in 2012 were homeopathy, naturopathy, osteopathy, herbal medicine, and acupuncture. The average number of treatments within the 12 months preceding the survey ranged from 3 for homeopathy to 6 for acupuncture. 25.0% of the population at the age of 15 and older had used at least one CM method in the previous 12 months. People with a chronic illness or a poor self-perceived health status were more likely to use CM. Similar to other countries, women, people of middle age, and those with higher education were more likely to use CM. 59.9% of the adult population had a supplemental health insurance that partly covered CM treatments. CONCLUSIONS: Usage of CM in Switzerland remained unchanged between 2007 and 2012. The user profile in Switzerland was similar to other countries, such as Germany, United Kingdom, United States or Australia. PMID- 26513371 TI - Association between Stock Market Gains and Losses and Google Searches. AB - Experimental studies in the area of Psychology and Behavioral Economics have suggested that people change their search pattern in response to positive and negative events. Using Internet search data provided by Google, we investigated the relationship between stock-specific events and related Google searches. We studied daily data from 13 stocks from the Dow-Jones and NASDAQ100 indices, over a period of 4 trading years. Focusing on periods in which stocks were extensively searched (Intensive Search Periods), we found a correlation between the magnitude of stock returns at the beginning of the period and the volume, peak, and duration of search generated during the period. This relation between magnitudes of stock returns and subsequent searches was considerably magnified in periods following negative stock returns. Yet, we did not find that intensive search periods following losses were associated with more Google searches than periods following gains. Thus, rather than increasing search, losses improved the fit between people's search behavior and the extent of real-world events triggering the search. The findings demonstrate the robustness of the attentional effect of losses. PMID- 26513372 TI - Lipid droplets regulate autophagosome biogenesis. AB - The source of the autophagic membrane and the regulation of autophagosome biogenesis are still elusive open issues in the field of autophagy. In our recent study of the role of lipid droplets (LDs) and their constituents in autophagy, we provided evidence that both the biogenesis of LDs and its lipolysis by specific lipases are important for autophagosome biogenesis. Our study sheds new light on the source of the autophagic membrane and suggests that a flow of membranes from the endoplasmic reticulum (ER) to LDs, and from LDs to the ER, is essential for autophagosome biogenesis. PMID- 26513373 TI - Total antioxidant and oxidant status of plasma and renal tissue of cisplatin induced nephrotoxic rats: protection by floral extracts of Calendula officinalis Linn. AB - The present study was aimed to determine the total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) of plasma and renal tissue in cisplatin (cDDP) induced nephrotoxic rats and its protection by treatments with floral extracts of Calendula officinalis Linn. Treatment with cDDP elevated (p < 0.05) the levels of blood urea nitrogen, creatinine (CR), TOS, OSI and malondialdehyde (MDA) but lowered (p < 0.05) total plasma proteins, TAS, total thiols (TTH), blood glutathione (GSH) and antioxidant enzymes compared to the control group. Pre- and post-treatments of ethanolic floral extract of C. officinalis along with cDDP restored (p > 0.05) CR, albumin, TOS, GSH and activities of antioxidant enzymes in blood and renal tissue. Ethanolic extract treatments reduced (p < 0.05) MDA level in renal tissue without restoring the erythrocyte MDA level following cDDP treatment. These observations were further supported by the histopathological findings in renal tissue. Observations of the present study have shown that treatments with ethanolic floral extract of C. officinalis protect cDDP induced nephrotoxicity by restoring antioxidant system of the renal tissue. PMID- 26513374 TI - Longitudinal observations of typical English voicing acquisition in a 2-year-old child: Stability of the contrast and considerations for clinical assessment. AB - Early assessment of phonetic and phonological development requires knowledge of typical versus atypical speech patterns, as well as the range of individual developmental trajectories. The nature of data reporting in previous literature on typical voicing acquisition left aspects of the developmental process unclear and limited clinical applicability. This work extends a previous four-month group study to present data for one child over 12 months. Words containing initial /b p d t/ were elicited from a monolingual English-speaking 2-year-old child biweekly for 25 sessions. Voice onset time (VOT) was measured for each stop. For each consonant and recording session, we measured range as well as accuracy, overshoot and discreteness calculated for means and individual tokens. The results underscore the value of token-by-token analyses. They further reveal that typical development may involve an extended period of fluctuating voicing patterns, suggesting that the voiced/voiceless contrast may take months or years to stabilise. PMID- 26513375 TI - Induction of labor with an unfavorable cervix: how does BMI affect success? (?). AB - OBJECTIVE: Obesity places women and their babies at risk for obstetric and perinatal morbidity including induction of labor and cesarean delivery. We sought to evaluate the impact of body mass index (BMI) on successful induction of labor using misoprostol at our institution. The primary outcome was time to delivery. Secondary outcomes were number of doses of misoprostol, duration of oxytocin and cesarean delivery. METHODS: A retrospective cohort over two years found 329 patients who were > 37 weeks of gestational age and had a Bishop score < 5 prior to beginning induction. Patients were divided into three categories based on their BMI: Group 1: BMI <= 30 kg/m(2), Group 2: BMI 30 to 39.9 kg/m(2) and Group 3: BMI >= 40 kg/m(2). Statistical analysis included the use of multivariate analysis, contingency tables and Chi-square tests for categorical data and Pearson's correlation coefficient for numerical data. RESULTS: There were no significant differences among the groups when analyzed for gestational age, bishop score, median parity or race. Time to delivery increased significantly with increasing BMI (p < 0.01). Furthermore, women with higher BMIs required more doses of misoprostol (p < 0.01), longer duration of oxytocin administration prior to delivery (p < 0.02) and increased risk of cesarean section (p < 0.0006). CONCLUSION: As BMI increases, obese patients undergoing induction with misoprostol have a longer time to delivery, require more doses of misoprostol, require a longer duration of oxytocin and have higher cesarean delivery rate. PMID- 26513376 TI - Interleukin-17 targeted therapies in axial spondyloarthritis. PMID- 26513377 TI - Attenuated baroreflex sensitivity in normotensive prediabetes and diabetes in Indian adults. AB - PURPOSE/AIM OF THE STUDY: Though attenuated baroreflex sensitivity (BRS) is known to promote cardiovascular disease (CVD) risk in diabetics, its status in prediabetes has not been reported. Also, the link of BRS to CVD risk in normotensive diabetics has not been reported. This study aimed to evaluate the association of BRS to CVD risk in normotensive prediabetics and diabetics. MATERIALS AND METHODS: Participants (n = 154) of 18-45 years were divided into normoglycemics (n = 52), prediabetics (n = 64) and diabetics (n = 38) based on American Diabetes Association criteria. Body mass index, waist-hip ratio, waist height ratio, body fat mass index, basal heart rate, systolic blood pressure, diastolic blood pressure, rate pressure product, BRS, heart rate variability (HRV), fasting plasma glucose, fasting insulin, lipid profile and atherogenic index of plasma (AIP) were measured. Indian Diabetes Risk Score (IDRS) and homeostatic model assessment of insulin resistance were calculated. RESULTS: There was significant increase in all the parameters except BRS, HRV and high density lipoprotein in prediabetics and diabetics compared to normoglycemics. All these parameters were significantly altered in prediabetics compared to diabetics. Significant negative correlation was found between BRS and other parameters in prediabetics and diabetics. CONCLUSIONS: BRS was attenuated in normotensive prediabetics and diabetics with high IDRS, insulin resistance, AIP, dyslipidemia and reduced HRV that predisposes them to CVD risk. The study demonstrates CVD risk quite early in the prediabetics with reduced HRV, high body fat, hyperinsulinemia, insulin resistance, AIP and rate pressure product. PMID- 26513378 TI - Disentangling the effects of word frequency and contextual diversity on serial recall performance. AB - Research shows that contextual diversity (CD; the number of different contexts in which a word appears within a corpus) constitutes a better predictor of reading performance than word frequency (WF), that it mediates the access to lexical representations, and that controlling for contextual CD abolishes the effect of WF in lexical decision tasks. Despite the theoretical relevance of these findings for the study of serial memory, it is not known how CD might affect serial recall performance. We report the first independent manipulation of CD and WF in a serial recall task. Experiment 1 revealed better performance for low CD and for high WF words independently. Both effects affected omissions and item errors, but contrary to past research, word frequency also affected order errors. These results were confirmed in two more experiments comparing pure and alternating lists of low and high CD (Experiment 2) or WF (Experiment 3). The effect of CD was immune to this manipulation, while that of WF was abolished in alternating lists. Altogether the findings suggest a more difficult episodic retrieval of item information for words of high CD, and a role for both item and order information in the WF effect. PMID- 26513379 TI - Model-aided atpE gene knockout strategy in Escherichia coli for enhanced succinic acid production from glycerol. AB - Succinic acid is an important platform chemical with a variety of applications. Model-guided metabolic engineering strategies in Escherichia coli for strain improvement to increase succinic acid production using glucose and glycerol remain largely unexplored. Herein, we report what are, to our knowledge, the first metabolic knockout of the atpE gene to have increased succinic acid production using both glucose and alternative glycerol carbon sources in E. coli. Guided by a genome-scale metabolic model, we engineered the E. coli host to enhance anaerobic production of succinic acid by deleting the atpE gene, thereby generating additional reducing equivalents by blocking H(+) conduction across the mutant cell membrane. This strategy produced 1.58 and .49 g l(-1) of succinic acid from glycerol and glucose substrate, respectively. This work further elucidates a model-guided and/or system-based metabolic engineering, involving only a single-gene deletion strategy for enhanced succinic acid production in E. coli. PMID- 26513380 TI - The association of HLA-G and immune markers in recurrent miscarriages. AB - OBJECTIVE: To determine role of human leukocyte antigen (HLA)-G, CD8, CD16, CD56, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha for recurrent miscarriages in feto-maternal interface. METHOD: Chorion and decidua samples were obtained from 11 women with unwanted pregnancies (healthy pregnancy, HP) and 10 women with missed abortion diagnosis after at least two pregnancy losses (recurrent miscarriage, RM). In addition, endometrial tissues were obtained from 10 non-pregnant women (NonP). The expressions of markers were evaluated using the Western blot analysis. The values obtained between different groups were compared. RESULTS: The highest protein expression of CD56 was found in the HP compared to NonP and RM. Meanwhile, the lowest protein expression of CD16 was observed in the NonP compared to HP and RM. The HLA-G expression exhibited the highest level in HP; however, there was no statistically significant difference between groups. CD8 and IFNgamma expressions were lowest in the NonP group; however, TNF-alpha was highest in the RM group. CONCLUSIONS: The CD56 expression of uterine NK cells may be an indicator of a HP. However, not statistically significant, the increased expression of CD16, CD8, and also significantly increased expression of TNF may be associated with the predominant cytotoxic activity in the maternal immune system in patients with RM. Although there was no change in the expression of HLA-G, this finding may mean that the maternal immune system is unresponsive to HLA-G-mediated immunosuppressive signals originating from the fetus in these cases. PMID- 26513381 TI - Detection of Socially Significant Strabismus in an Ethnically Diverse Model Set. PMID- 26513383 TI - Protective mechanism of grape seed oil on carbon tetrachloride-induced brain damage in gamma-irradiated rats. AB - This study investigated the possible beneficial effects of grape seed oil (GSO) on carbon tetrachloride (CCl4)-induced acute neurotoxicity in gamma-irradiated rats. A statistical significant decrease in superoxide-dismutase (SOD), catalase (CAT), and glutathione-peroxidase (GPx) activities and reduced glutathione (GSH) content were exhibited. Further, a significant elevation in malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and transforming growth factor-beta-1 (TGF-beta1) levels was observed. Furthermore, xanthine oxidase (XO) and inducible nitric oxide synthase (iNOS) gene expression were elevated in the gamma-irradiated animals treated with an acute dose of CCl4. The pretreatment of GSO exerts significant amelioration of the studied parameters. In conclusion, this study demonstrated that GSO has a neuroprotective effect against CCl4-induced brain injury in gamma-irradiated rats, which is likely attributed to its ability to scavenge the free radicals, suppress the inflammatory responses, improve the activity of the antioxidant enzymes and inhibit the XO and iNOS gene expression levels. PMID- 26513384 TI - The contribution of temperature, exposure intensity and visible light to the inhibitory effect of irradiation on acute chlamydial infection. AB - Water-filtered infrared A (wIRA) is radiation with a spectrum ranging from 780 to 1400 nm. Chlamydiaceae are obligate intracellular bacteria associated with various diseases in both animals and humans. A recent in vitro study demonstrated that wIRA combined with visible light (wIRA/VIS) has potential as a non-chemical method for the treatment of chlamydial infections without adversely affecting the cell viability. The aim of this study was to investigate the influence of various factors on the effect of wIRA/VIS on acute chlamydial infection, namely the impact of temperature, exposure intensity and infectious dose (multiplicity of infection) as well as the efficacy of the visible light component.We demonstrate that non-thermal effects contribute to the inhibition of acute chlamydial infection. Visible light enhances the inhibitory effect of wIRA on extracellular bacteria (elementary bodies or EBs).Moreover, the inhibitory effect of wIRA/VIS following treatment of EBs prior to infection correlated with increased irradiation intensity. The infectivity of mature chlamydial inclusions was significantly reduced upon wIRA/VIS exposure at all irradiation intensities investigated, suggesting the contribution of host cell factors to the anti chlamydial effect of wIRA/VIS in the late stage of the developmental cycle. The effect of irradiation was not influenced by the infectious dose. PMID- 26513385 TI - Changing scenario in plant UV-B research:UV-B from a generic stressor to a specific regulator. AB - Although UV-B accounts for <0.5% of total sunlight energy reaching the earth's surface, however, it has multifaceted impact on plants as well as animals. High energy UV-B radiation is reported to have damaging impact on plant growth and productivity. After discovery of UV RESISTANCE LOCUS8 (UVR8), perceptions of biological impact of UV-B radiation on plants, have changed dramatically in last few years. This review focuses on the changing concept about the role of UV-B from a generic stressor to a specific regulator in plant science and has tried compiling the historical aspects of UVR8 starting with discovery, localisation and regulatory role played by UVR8 and also its interaction with other regulators. PMID- 26513386 TI - A Rare Case of Quadratus Femoris Muscle Rupture After Yoga Exercises. AB - We present a case of a female patient with left groin pain after intense yoga exercises. The patient presented abnormal pattern of gait with no swelling over the groin, thigh, or buttock. Magnetic resonance imaging demonstrated a tear of the quadratus femoris muscle with an associated extensive hematoma formation. Patient was treated with a rehabilitation program consisting of nonsteroidal anti inflammatory drugs and physiotherapy. At the follow-up control, the patient had improved her pain and flexibility of the hip, and gradually she returned to daily activities and yoga exercises. Such an entity is a rare cause of hip pain after exercise and should be kept in mind by the orthopedic surgeon, in cases of gluteal pain after intense physical activity. Moreover, such a condition should be included in the diagnostic algorithm of unknown origin hip pain. PMID- 26513387 TI - Cardiorespiratory Exertion While Playing Video Game Exercises in Elderly Individuals With Type 2 Diabetes. AB - OBJECTIVE: To evaluate the suitability of the Wii Fit Plus exergame as a tool to improve cardiorespiratory fitness in individuals with type 2 diabetes. DESIGN: Experimental cross-sectional study. SETTING: Controlled laboratory. PARTICIPANTS: Twelve type 2 diabetic patients (10 male and 2 female; age, 60.2 +/- 7.7 years; body mass index, 30.9 +/- 6.2 kg/m). INTERVENTIONS: At baseline, all participants underwent an all-out cardiopulmonary exercise test on a treadmill to assess peak and average oxygen consumption (V[Combining Dot Above]O2peak and V[Combining Dot Above]O2mean). Forty-eight to 72 hours after the cardiopulmonary exercise test, the same parameters were assessed during three 10-minute bouts of Wii Fit Plus exergaming and converted to percentage of treadmill V[Combining Dot Above]O2peak (%V[Combining Dot Above]O2peak). MAIN OUTCOME MEASURES: V[Combining Dot Above]O2peak and V[Combining Dot Above]O2mean during Wii Fit Plus play relative to V[Combining Dot Above]O2peak achieved during the cardiopulmonary exercise test. RESULTS: All Wii Fit Plus exercises generated a V[Combining Dot Above]O2peak of around 60% and V[Combining Dot Above]O2mean of around 40% of the V[Combining Dot Above]O2peak as established during the cardiopulmonary exercise test. Mean heart rate and resting energy expenditure (respiratory exchange ratio) lay in a range of moderate aerobic exercise. A moderate-to-strong correlation between treadmill V[Combining Dot Above]O2peak and both exergame V[Combining Dot Above]O2peak and exergame V[Combining Dot Above]O2mean was found. CONCLUSIONS: Video gaming has the potential to offer training intensities that concur with established guidelines for type 2 diabetic patients. The training intensity is self-adjusting based on fitness level allowing for an effective workout for different users. PMID- 26513388 TI - Hamstring Injury After Swimming in a Patient With Multiple Hereditary Osteochondromatosis. AB - Reported here is a 20-year-old male suffered a hamstring strain after a prolonged bout of swimming. After ultrasound imaging, the patient's injury was considered to be the result of nearby osteochondromas. Case reports have been previously published concerning anterior cruciate ligament injury, rotator cuff tears, subacromial impingement, or femoroacetabular impingement in multiple osteochondromatosis. However, to the best of our knowledge, this is the first reported case of a hamstring injury secondary to an osteochondroma. PMID- 26513389 TI - Low Back Pain in Young Basketball and Floorball Players. AB - OBJECTIVE: The aim of the study was to investigate the prevalence and risk factors of low back pain (LBP) in young female and male basketball and floorball players. DESIGN: Cross-sectional study. SETTING: Nine basketball teams and 9 floorball teams from Tampere city district, Finland. PARTICIPANTS: Four hundred one young female and male players (mean age: 15.8 +/- 1.9 years). ASSESSMENT OF RISK FACTORS: Age, gender, sport, and family history of musculoskeletal disorders were assessed as risk factors for LBP. Adjustment was made on team level to avoid random effects associated with a team. MAIN OUTCOME MEASURES: Information of players' background factors and LBP episodes was collected by a structured questionnaire. RESULTS: Forty-four percentage of the basketball players and 62% of floorball players had suffered from LBP during the previous 12 months. Prevalence of LBP during the previous year was significantly higher among floorball players (P = 0.001). In both sports, prevalence of pain symptoms was the highest during the competitive playing season. Family history of musculoskeletal disorders [OR (odds ratio), 2.02, 95% confidence interval (CI), 1.22-3.34] and higher age (OR, 1.22, 95% CI, 1.05-1.41) were associated with LBP in players. CONCLUSIONS: The study attested that LBP is a relatively common complaint in young team sport players. Targeted measures to examine causes, risk factors, and prevention of LBP in youth sports are needed. PMID- 26513390 TI - Incidence and Prevalence of Acute Kidney Injury During Multistage Ultramarathons. AB - OBJECTIVE: Determine prevalence, incidence, and risk factors of acute kidney injury (AKI) during multistage ultramarathons. DESIGN: Prospective observational cohort study. SETTING: Jordanian Desert 2012; Atacama Desert, Chile 2012 and 2013; and Gobi Desert 2013 RacingThePlanet 250 km, 6-stage, ultramarathons. PARTICIPANTS: One hundred twenty-eight participants (384 measurements) from the Jordan (25, 19.5%), Gobi (35, 27.3%), 2012 Atacama (24, 18.8%), and 2013 Atacama (44, 34.4%) races. INTERVENTIONS: Blood samples and weights were gathered and analyzed immediately after stage 1 (40 km), 3 (120 km), and 5 (225 km). MAIN OUTCOME MEASURES: Changes in serum creatinine (Cr), cumulative incidence, and prevalence of AKI were calculated for each stage with "risk of injury" defined as 1.5 * baseline Cr and "injury" defined as 2 * Cr. RESULTS: Cumulative incidence of AKI was 41.4%. Stage 1 had 56 (43.8%) with risk of AKI and 24 (18.8%) with injury; in stage 3, 61 (47.7%) were at risk, 41 (32%) had injury; in stage 5, 62 (48.4%) runners were at risk and 36 (28.1%) had injury. Acute kidney injury was significantly associated with females [odds ratio (OR), 4.64; 95% confidence interval (CI), 2.07-10.37; P < 0.001], lower pack weight (OR, 0.71; 95% CI, 0.56 0.91; P < 0.007), and percentage weight loss (OR, 0.87; 95% CI, 0.78-0.97; P < 0.015). Lowest quintile of finishers was less likely to develop AKI (OR, 0.18; 95% CI, 0.04-0.78; P < 0.022). CONCLUSIONS: Prevalence of AKI was 63%-78% during multistage ultramarathons. Female sex, lower pack weight, and greater weight loss were associated with renal impairment. PMID- 26513391 TI - Concussed or Not? An Assessment of Concussion Experience and Knowledge Within Elite and Semiprofessional Rugby Union. AB - OBJECTIVE: The primary aim was to assess experience and knowledge of adult concussion among international, professional and semiprofessional players, coaches, medical staff, and referees within Rugby Union. The secondary aim was to identify preferred education dissemination routes. DESIGN: Questionnaires devised specifically for players, coaches, medical staff, and referees. SETTING AND PARTICIPANTS: A total of 370 players, 44 coaches, 40 medical staff, and 33 referees from within Wales were surveyed. MAIN OUTCOME MEASURES: Knowledge of the signs and symptoms of concussion, return to play guidelines and consequences of concussion were investigated along with experiences of, and attitudes towards, concussion. RESULTS: The respondents had extensive experience of sustaining or witnessing rugby-related concussion. Medical staff had the greatest level of concussion knowledge, with coaches having the least. Players and coaches exhibited a disconnection between being "knocked-out" and practically applying this when managing concussion. Almost half of the players and coaches did not indicate concussion could impair performance. Eighty percent of medical staff had felt pressured to clear a concussed player. Most players (82%), coaches (66%), and referees (64%) incorrectly believed protective equipment prevents concussion. Players and coaches prefer concussion education from medical staff, whereas medical staff and referees prefer such education from governing body Web sites or training courses. CONCLUSIONS: Several role-specific misconceptions and deficiencies in concussion knowledge were identified and should be targeted through education. Medical staff had the highest level of concussion knowledge and were the preferred sources of education for players and coaches. Therefore, they are encouraged to play a greater role in providing concussion education. PMID- 26513392 TI - Sonoelastography of the Achilles Tendon: Prevalence and Prognostic Value Among Asymptomatic Elite Australian Rules Football Players. AB - OBJECTIVE: To investigate the prevalence of sonographic abnormalities at the mid Achilles tendon among a cohort of asymptomatic professional football players and to determine whether these sonographic abnormalities predict midportion Achilles tendon symptoms. DESIGN: Longitudinal study. SETTING: A single competitive season in the Australian Rules Football League. PARTICIPANTS: Forty-two elite Australian Rules football players. MAIN OUTCOME MEASURES: Using ultrasound and sonoelastography, 42 players were examined at baseline and again 9 months later (postseason) for the existence of intratendinous hypoechogenicity, delamination, softening, and neovascularization. The anterio-posterior (AP) thickness and cross sectional area (CSA) were measured. Players reporting Achilles tendon pain or with Victorian Institute of Sports Assessment-Achilles scores below 80 at the end of the season were classified as symptomatic. RESULTS: At preseason, ultrasound and/or sonoelastographic abnormalities were found in 22 (22/42, 52.4%) asymptomatic players. Baseline AP thickness and CSA were significantly greater in symptomatic players at the end season than those in asymptomatic players (0.57 +/ 0.05 cm vs 0.50 +/- 0.03 cm; P < 0.001 and 0.67 +/- 0.07 cm vs 0.57 +/- 0.06 cm; P < 0.001, respectively). The presence of intratendinous softening and delaminations at baseline was associated with pain onset during the season (P = 0.046; P = 0.048, respectively). CONCLUSIONS: Ultrasound and sonoelastography detected abnormalities were relatively common among the asymptomatic footballers. Greater AP thickness and CSA and also the presence of intratendinous softening and delaminations were associated with the increased risk of developing symptoms. CLINICAL RELEVANCE: Conventional ultrasound supplement with sonoelastography may be able to identify elite athletes at risk of Achilles tendon injury, which may, in turn, impact therapeutic decisions. PMID- 26513393 TI - Similar Prevalence of Acetabular Labral Tear in Professional Ballet Dancers and Sporting Participants. AB - OBJECTIVE: To compare the prevalence of acetabular labral tear in male and female professional ballet dancers with age-matched and sex-matched sporting participants and to determine the relationship to clinical findings and cartilage defects. DESIGN: Case-control study. SETTING: Clinical and radiology practices. PARTICIPANTS: Forty-nine (98 hips) male and female professional ballet dancers (current and retired) with median age 30 years (range: 19-64 years) and 49 (98 hips) age-matched and sex-matched sporting participants. INDEPENDENT VARIABLES: Group (ballet or sports), sex, age, hip cartilage defects, history of hip pain, Hip and Groin Outcome Score, passive hip internal rotation (IR), and external rotation range of movement (ROM). MAIN OUTCOME MEASURES: Labral tear identified with 3T magnetic resonance imaging (MRI). RESULTS: Labral tears were identified in 51% of all 196 hips. The prevalence did not differ significantly between the ballet and sporting participants (P = 0.41) or between sexes (P = 0.34). Labral tear was not significantly associated with clinical measures, such as pain and function scores or rotation ROM (P > 0.01 for all). Pain provocation test using IR at 90 degrees of hip flexion had excellent specificity [96%, 95% confidence intervals (CIs), 0.77%-0.998%] but poor sensitivity (50%, 95% CI, 0.26%-0.74%) for identifying labral tear in participants reporting hip pain. Older age and cartilage defect presence were independently associated with an increased risk of labral tear (both P < 0.001). CONCLUSIONS: The prevalence of labral tear in male and female professional ballet dancers was similar to a sporting population. Labral tears were not associated with clinical findings but were related to cartilage defects, independent of aging. CLINICAL RELEVANCE: Caution is required when interpreting MRI findings as labral tear may not be the source of the ballet dancer's symptoms. PMID- 26513394 TI - Enhancement of near-infrared luminescence of ytterbium in triple-stranded binuclear helicates. AB - A bis-beta-diketone, bis(4,4,4-trifluoro-1,3-dioxobutyl)(2,2'-bithienyl) (BTT), which can be looked upon as coupling of two mono-beta-diketones (2 thenoyltrifluoroacetone, TTA) at the 5,5'-position of thiophene ring, has been designed for exploring the advantages of binuclear helical structure in sensitizing the lanthanide NIR luminescence. The Yb(iii) ion was selected as the luminescent center, and its corresponding mono-beta-diketone complex Yb(TTA)3(DMSO) () and bis-beta-diketone complex Yb2(BTT)3(DMSO)4 () were synthesized and isolated. X-ray crystallographical analysis reveals that the bis beta-diketone complex Yb2(BTT)3(DMSO)4 adopts a triple-stranded dinuclear structure, in which the two Yb(iii) ions are helically wrapped by three ligands, and each Yb(iii) ion is eight-coordinated by six oxygen atoms from three ligands and two oxygen atoms from the coordinated DMSO molecules. Whereas, the mono-beta diketone complex Yb(TTA)3(DMSO) is a mononuclear structure, the central Yb(iii) ion is coordinated by seven oxygen atoms from three ligands and a DMSO molecule. The photophysical properties related to the electronic transition are characterized by the absorbance spectra, the emission spectra, the emission quantum yields, the emission lifetimes, and the radiative (kr) and nonradiative rate constants (knr). The luminescence quantum yield experiment reveals that the dinuclear complex has about 10 times luminescence enhancement compared with the mononuclear complex. This enhancement mainly benefits from its helical structure, which effectively depresses the nonradiative transition caused by high-energy oscillators in ligands, and the part-encapsulated structure decreases the probability of solvents entering the metal centers. PMID- 26513395 TI - Sampling efficiency of modified 37-mm sampling cassettes using computational fluid dynamics. AB - In the U.S., most industrial hygiene practitioners continue to rely on the closed face cassette (CFC) to assess worker exposures to hazardous dusts, primarily because ease of use, cost, and familiarity. However, mass concentrations measured with this classic sampler underestimate exposures to larger particles throughout the inhalable particulate mass (IPM) size range (up to aerodynamic diameters of 100 MUm). To investigate whether the current 37-mm inlet cap can be redesigned to better meet the IPM sampling criterion, computational fluid dynamics (CFD) models were developed, and particle sampling efficiencies associated with various modifications to the CFC inlet cap were determined. Simulations of fluid flow (standard k-epsilon turbulent model) and particle transport (laminar trajectories, 1-116 MUm) were conducted using sampling flow rates of 10 L min(-1) in slow moving air (0.2 m s(-1)) in the facing-the-wind orientation. Combinations of seven inlet shapes and three inlet diameters were evaluated as candidates to replace the current 37-mm inlet cap. For a given inlet geometry, differences in sampler efficiency between inlet diameters averaged less than 1% for particles through 100 MUm, but the largest opening was found to increase the efficiency for the 116 MUm particles by 14% for the flat inlet cap. A substantial reduction in sampler efficiency was identified for sampler inlets with side walls extending beyond the dimension of the external lip of the current 37-mm CFC. The inlet cap based on the 37-mm CFC dimensions with an expanded 15-mm entry provided the best agreement with facing-the-wind human aspiration efficiency. The sampler efficiency was increased with a flat entry or with a thin central lip adjacent to the new enlarged entry. This work provides a substantial body of sampling efficiency estimates as a function of particle size and inlet geometry for personal aerosol samplers. PMID- 26513396 TI - Activation of brown adipose tissue in hypothyroidism. AB - BACKGROUND: Brown adipose tissue (BAT) attracts growing interest as a potential therapeutic target for obesity and diabetes. Hyperthyroidism is well-known to increase BAT activity, but the role of hypothyroidism is controversial. We aimed to investigate the association between different thyroid hormone (TH) states and BAT activity. METHODS: FDG-PET studies were retrospectively evaluated in thyroid cancer patients after total thyroidectomy both at euthyroidism during TH replacement or at hypothyroidism after TH cessation. Serum TH levels were compared between patients with active BAT and control patients with non-active BAT matched for age, gender, and body mass index. Additionally, animal experiments with controls (n = 5) and hypothyroid rats (n = 5) were performed. RESULTS: Out of 124 patients, 6 patients with active BAT were identified. These patients showed significantly higher thyroid-stimulating hormone (TSH) levels than matched controls (P < 0.05). In animal experiments, all hypothyroid animals showed BAT activation at room temperature (24 degrees C), whereas controls did not (P < 0.001). Increased BAT activity was also confirmed by increased expression of UCP-1 and D2. CONCLUSIONS: Increased BAT metabolism appears to be related with hypothyroidism, which might be the result of a feedback mechanism to maintain body temperature in a state of reduced basal thermogenesis. Future research needs to explore the underlying mechanistic and biological implications. PMID- 26513398 TI - Protecting Patient Safety: Can Video Monitoring Prevent Falls in High-Risk Patient Populations? AB - Despite implementation of many prevention strategies, patient falls in hospitals continue to be a significant safety problem, causing nursing staff and administrators to seek innovative means to further reduce falls among hospitalized patients. This article describes the feasibility and impact of implementing centralized video monitoring on the safety of patients identified as high risk for falls, as well as implications of video monitoring in the acute care setting. PMID- 26513397 TI - DWI Lesion Patterns Predict Outcome in Stroke Patients with Thrombolysis. AB - BACKGROUND: Lesion patterns may predict prognosis after acute ischemic stroke within the middle cerebral artery (MCA) territory; yet it remains unclear whether such imaging prognostic factors are related to patient outcome after intravenous thrombolysis. AIMS: The aim of this study is to investigate the clinical outcome after intravenous thrombolysis in acute MCA ischemic strokes with respect to diffusion-weighted imaging (DWI) lesion patterns. METHODS: Consecutive acute ischemic stroke cases of the MCA territory treated over a 7-year period were retrospectively analyzed. All acute MCA stroke patients underwent a MRI scan before intravenous thrombolytic therapy was included. DWI lesions were divided into 6 patterns (territorial, other cortical, small superficial, internal border zone, small deep, and other deep infarcts). Lesion volumes were measured by dedicated imaging processing software. Favorable outcome was defined as modified Rankin scale (mRS) of 0-2 at 90 days. RESULTS: Among the 172 patients included in our study, 75 (43.6%) were observed to have territorial infarct patterns or other deep infarct patterns. These patients also had higher baseline NIHSS score (p < 0.001), a higher proportion of large cerebral artery occlusions (p < 0.001) and larger infarct volume (p < 0.001). Favorable outcome (mRS 0-2) was achieved in 89 patients (51.7%). After multivariable analysis, groups with specific lesion patterns, including territorial infarct and other deep infarct pattern, were independently associated with favorable outcome (OR 0.40; 95% CI 0.16-0.99; p = 0.047). CONCLUSIONS: Specific lesion patterns predict differential outcome after intravenous thrombolysis therapy in acute MCA stroke patients. PMID- 26513399 TI - Comparison of patient and caregiver perception of pain from commonly performed accident and emergency services procedures. AB - OBJECTIVE: To compare the perception by naive patients, emergency services clinicians and nurses, of healthcare-induced pain for procedures performed frequently by accident and emergency services. METHODS: A prospective, three-part anonymous survey, given to caregivers and patients at arrival accident and emergency services. The primary endpoint was the a priori estimated pain score for 10 procedures performed frequently by accident and emergency services. The same estimation was performed with the 'willingness to pay' method (amount allocated a priori to avoid this pain). RESULTS: Fifty surveys were analyzed in each group, with a significant difference for pain perception between caregivers and patients concerning four procedures: local anesthesia, fracture or dislocation reduction, dressing change and abscess incision. Caregivers always overestimated pain scores compared with patients. No difference was noted for the remaining five procedures: intravenous line insertion and removal, urethral catheterization, wound suture and nasogastric intubation. CONCLUSION: Caregivers should be aware of the most feared procedures by patients to establish pre emptive analgesia when possible, inform patients and achieve reassurance. PMID- 26513400 TI - The hidden price and possible benefit of repeated traumatic exposure. AB - There is a growing evidence showing that first-responders who are frequently exposed to traumatic events as part of their occupational routine may pay a hidden price. Although they display low to moderate levels of post-traumatic stress disorder (PTSD) symptoms, similar to individuals with full-blown PTSD, they show impaired ability to process and react according to contextual demands. We aimed to test whether this impairment affects performance on simple unrelated tasks and its association with cumulative traumatic exposure and level of PTSD symptoms. Thirty-nine trauma-exposed criminal scene investigator police and 35 unexposed civilians matched for age, gender, and education performed a simple discrimination task in the presence of aversive pictures with low or high intensity. We predicted and found that trauma-exposed individuals failed to modify their behavior in accordance with levels of negative intensity. Hence they were equally distracted in both low and high negative intensity conditions, compared to unexposed controls who showed improved performance in low intensity conditions. Importantly, performance of trauma-exposed individuals on conditions of low intensity negatively correlated with their levels of PTSD symptoms. These results highlight the maladaptive tendency of individuals with repeated traumatic exposure to maintain the same behavior in low-intensity contextual conditions when it is no longer adequate. Interestingly however, in high-intensity conditions trauma-exposed individuals outperformed unexposed controls. Specifically, when completing simple tasks in high intensity conditions. The results suggest that repeated traumatic exposure has both positive and negative consequences on the way individuals interpret and react to their environment. PMID- 26513402 TI - Corrigendum. PMID- 26513401 TI - Mind the gap: Signal movement through plasmodesmata is critical for the manifestation of SAR. AB - Systemic acquired resistance (SAR) is a plant defense response in which an initial localized infection affords enhanced pathogen resistance to distant, uninfected leaves. SAR requires efficient long-distance signaling between the infected leaf, where SAR signals are generated, and the distant uninfected leaves that receive them. A growing body of evidence indicates that the lipid transfer protein DIR1 (Defective in Induced Resistance) is an important mediator of long distance SAR signaling. In a recent publication, we investigated if cell-to-cell movement through plasmodesmata is required for long-distance movement of DIR1 during SAR. We determined that overexpression of Plasmodesmata-Located Proteins (PDLP1 and 5) negatively impacted long-distance DIR1 movement and SAR competence, suggesting that movement through plasmodesmata contributes to long-distance signal movement during SAR. PMID- 26513403 TI - Bond Strength of Thermally Fused Vascular Tissue Varies With Apposition Force. AB - Surgical tissue fusion devices ligate blood vessels using thermal energy and coaptation pressure, while the molecular mechanisms underlying tissue fusion remain unclear. This study characterizes the influence of apposition force during fusion on bond strength, tissue temperature, and seal morphology. Porcine splenic arteries were thermally fused at varying apposition forces (10-500 N). Maximum bond strengths were attained at 40 N of apposition force. Bonds formed between 10 and 50 N contained laminated medial layers; those formed above 50 N contained only adventitia. These findings suggest that commercial fusion devices operate at greater than optimal apposition forces, and that constituents of the tunica media may alter the adhesive mechanics of the fusion mechanism. PMID- 26513405 TI - NF-kappaB and HIF crosstalk in immune responses. AB - Hypoxia and inflammation have been associated with a number of pathological conditions, in particular inflammatory diseases. While hypoxia is mainly associated with the activation of hypoxia-inducible factors (HIFs), inflammation activates the family of transcription factor called nuclear factor-kappa B (NF kappaB). An extensive crosstalk between these two main molecular players involved in hypoxia and inflammation has been demonstrated. This crosstalk includes common activating stimuli, shared regulators and targets. In this review, we discuss the current understanding of the role of NF-kappaB and HIF in the context of the immune response. We review the crosstalk between HIF and NF-kappaB in the control of the immune response in different immune cell types including macrophages, neutrophils and B and T cells. Furthermore the importance of the molecular crosstalk between HIFs and NF-kappaB for a variety of medical conditions will be discussed. PMID- 26513406 TI - Use of macrolides during pregnancy and the risk of birth defects: a population based study. AB - PURPOSE: Macrolides have been linked to the occurrence of congenital heart defects, but findings are inconsistent. We therefore aimed to estimate the risk of major congenital malformations (MCMs) after fetal exposure to macrolides, focusing on cardiac malformations. METHODS: From the Quebec Pregnancy Cohort (1998-2008), women exposed to a macrolide or penicillin in the first trimester and unexposed women were studied. There were 135 859 pregnancies included; 914 were exposed to azithromycin, 734 to erythromycin, 686 to clarithromycin, and 9106 to penicillin during the first trimester. Cases of MCMs were identified within the first year of life. RESULTS: After adjusting for potential confounders, azithromycin (RR = 1.19, 95%CI: 0.98, 1.44; 120 exposed cases), erythromycin (RR = 0.96, 95%CI: 0.74, 1.24; 66 exposed cases) and clarithromycin use (RR = 1.12, 95%CI: 0.99, 1.42; 79 exposed cases) during the first trimester of pregnancy were not statistically significantly associated with the risk of MCMs; no associations were observed for cardiac malformations. CONCLUSIONS: First trimester exposure to any of the macrolides was not associated with an increased risk of overall MCMs or cardiac malformations specifically. PMID- 26513407 TI - Antiarrhythmic drugs in pregnancy. AB - The risk of arrhythmia development or recurrence is increased during pregnancy. For those arrhythmias that are unresponsive to conservative therapy, such as vagal maneuvers or life style interventions, or that present a higher risk to the mother or fetus, medical therapy may be necessary. In each case, the patient and provider must carefully consider the risks and benefits of a particular therapy. This requires an understanding of the data regarding the safety and efficacy of any particular drug, which in some cases may be extensive and in others quite limited. Fortunately, options exist for the treatment of arrhythmias during pregnancy. PMID- 26513408 TI - Characterization of gastrointestinal hemorrhage and prediction of mortality in Asian patients with alcoholic hepatitis. AB - BACKGROUND AND AIM: Gastrointestinal bleeding (GIB) often accompanies alcoholic hepatitis (AH). The study aimed to investigate clinical characteristics of GIB in AH patients and to identify risk factors for mortality in AH patients with GIB. METHODS: Data from 329 patients hospitalized with AH in a single center during 1999-2014 were retrospectively analyzed. Patients with AH were dichotomized into GIB and non-GIB groups. The GIB group was further divided into portal hypertensive bleeding (PHB) and non-PHB groups. Clinical characteristics and survival outcomes were compared between the groups. Risk factors for mortality were analyzed using Cox regression. RESULTS: Among the 329 AH patients, 132 experienced GIB at admission or during hospitalization. The most common cause of GIB was an esophageal varix. The GIB group had worse survival outcomes than the non-GIB group (log-rank test, P = 0.034). The PHB group had worse survival outcomes than the non-PHB group (log-rank test, P = 0.001). On multivariate analysis, alcohol consumption, ascites, encephalopathy, infection, Maddrey's discriminant function, and the model for end-stage liver disease (MELD) score independently predicted mortality in the entire AH cohort. The MELD score (hazard ratio, 1.085; 95% confidence interval, 1.052-1.120; P < 0.001) and PHB (hazard ratio, 2.162; 95% confidence interval, 1.021-4.577; P = 0.044) were significant prognosticators for patients with AH and GIB. CONCLUSIONS: The presence of PHB and a higher MELD score adversely affected survival in AH patients with GIB. Accordingly, prompt endoscopic examination for exploring the etiologies of GIB may alert physicians to predict the risk of death in AH patients with GIB. PMID- 26513409 TI - Identification of COPD Patients at High Risk for Lung Cancer Mortality Using the COPD-LUCSS-DLCO. AB - BACKGROUND: The COPD-Lung Cancer Screening Score (COPD-LUCSS) is a tool designed to help identify patients with COPD with the highest risk of developing lung cancer (LC). The COPD-LUCSS includes the determination of radiological emphysema, a potential limitation for its implementation in clinical practice. The diffusing capacity for carbon monoxide (DLCO) is a surrogate marker of emphysema and correlates well with CT-determined emphysema. OBJECTIVE: To explore the use of the COPD-LUCSS using the DLCO instead of radiological emphysema, as a tool to identify patients with COPD at higher risk of LC death. METHODS: The Body Mass Index, Airflow Obstruction, Dyspnea, Exercise Performance international cohort database was analyzed. By logistic regression analysis, we confirmed that the other parameters included in the COPD-LUCSS (age > 60, pack-years > 60, BMI < 25) were independently associated with LC death. We selected the best cutoff value for DLCO that independently predicted LC death. We then integrated the new COPD LUCSS-DLCO assigning points to each parameter according to its hazard ratio value in the Cox regression model. The score ranges from 0 to 8 points. RESULTS: By regression analysis, age > 60, BMI <25 kg/m(2), pack-year history > 60, and DLCO < 60% were independently associated with LC diagnosis. Two COPD-LUCSS-DLCO risk categories were identified: low risk (scores 0-3) and high risk (scores 3.5-8). In comparison to patients at low risk, risk of death from LC increased 2.4-fold (95% CI, 2.0-2.7) in the high-risk category. CONCLUSIONS: The COPD-LUCSS using DLCO instead of CT-determined emphysema is a useful tool to identify patients with COPD at risk of LC death and may help in its implementation in clinical practice. PMID- 26513410 TI - Microwave pumped high-efficient thermoacoustic tumor therapy with single wall carbon nanotubes. AB - The ultra-short pulse microwave could excite to the strong thermoacoustic (TA) shock wave and deeply penetrate in the biological tissues. Based on this, we developed a novel deep-seated tumor therapy modality with mitochondria-targeting single wall carbon nanotubes (SWNTs) as microwave absorbing agents, which act efficiently to convert ultra-short microwave energy into TA shock wave and selectively destroy the targeted mitochondria, thereby inducing apoptosis in cancer cells. After the treatment of SWNTs (40 MUg/mL) and ultra-short microwave (40 Hz, 1 min), 77.5% of cancer cells were killed and the vast majority were caused by apoptosis that initiates from mitochondrial damage. The orthotopic liver cancer mice were established as deep-seated tumor model to investigate the anti-tumor effect of mitochondria-targeting TA therapy. The results suggested that TA therapy could effectively inhibit the tumor growth without any observable side effects, while it was difficult to achieve with photothermal or photoacoustic therapy. These discoveries implied the potential application of TA therapy in deep-seated tumor models and should be further tested for development into a promising therapeutic modality for cancer treatment. PMID- 26513411 TI - Smart medical stocking using memory polymer for chronic venous disorders. AB - Proper level of pressure or compression generated by medical stocking or hosiery is the key element for successful treatment or management of chronic venous disorders such as oedema, leg ulcers, etc. However achieving the recommended compression level and, more importantly, sustaining it using stockings has been a major challenge to the health practitioners supervising the treatment. This work aims to investigate and design a smart compression stocking using shape-memory polymer that allows externally controlling the pressure level in the wrapped position on the leg. Based on thermodynamical rubber theories, we first derived several criteria that have to be satisfied simultaneously in order to achieve the controlled pressure adjustment using external heat stimuli. We then presented a case where such a stocking is developed using a blend yarn consists of selected shape-memory polyurethane and nylon filaments. Extensive experimental work has also been conducted to demonstrate the feasibility and explore the influencing factors involved. PMID- 26513412 TI - New injectable elastomeric biomaterials for hernia repair and their biocompatibility. AB - Complications associated with implantation of polymeric hernia meshes remain a difficult surgical challenge. We report here on our work, developing for the first time, an injectable viscous material that can be converted to a solid and elastic implant in vivo, thus successfully closing herniated tissue. In this study, long-chain fatty acids were used for the preparation of telechelic macromonomers end-capped with methacrylic functionalities to provide UV curable systems possessing high biocompatibility, good mechanical strength and flexibility. Two different systems, comprising urethane and ester bonds, were synthesized from non-toxic raw materials and then subjected to UV curing after injection of viscous material into the cavity at the abdominal wall during hernioplasty in a rabbit hernia model. No additional fixation or sutures were required. The control group of animals was treated with commercially available polypropylene hernia mesh. The observation period lasted for 28 days. We show here that artificially fabricated defect was healed and no reherniation was observed in the case of the fatty acid derived materials. Importantly, the number of inflammatory cells found in the surrounding tissue was comparable to these found around the standard polypropylene mesh. No inflammatory cells were detected in connective tissues and no sign of necrosis has been observed. Collectively, our results demonstrated that new injectable and photocurable systems can be used for minimally invasive surgical protocols in repair of small hernia defects. PMID- 26513413 TI - Doxorubicin encapsulated in stealth liposomes conferred with light-triggered drug release. AB - Stealth liposomes can be used to extend the blood circulation time of encapsulated therapeutics. Inclusion of 2 molar % porphyrin-phospholipid (PoP) imparted optimal near infrared (NIR) light-triggered release of doxorubicin (Dox) from conventional sterically stabilized stealth liposomes. The type and amount of PoP affected drug loading, serum stability and drug release induced by NIR light. Cholesterol and PEGylation were required for Dox loading, but slowed light triggered release. Dox in stealth PoP liposomes had a long circulation half-life in mice of 21.9 h and was stable in storage for months. Following intravenous injection and NIR irradiation, Dox deposition increased ~ 7 fold in treated subcutaneous human pancreatic xenografts. Phototreatment induced mild tumor heating and complex tumor hemodynamics. A single chemophototherapy treatment with Dox-loaded stealth PoP liposomes (at 5-7 mg/kg Dox) eradicated tumors while corresponding chemo- or photodynamic therapies were ineffective. A low dose 3 mg/kg Dox phototreatment with stealth PoP liposomes was more effective than a maximum tolerated dose of free (7 mg/kg) or conventional long-circulating liposomal Dox (21 mg/kg). To our knowledge, Dox-loaded stealth PoP liposomes represent the first reported long-circulating nanoparticle capable of light triggered drug release. PMID- 26513414 TI - Bioinspired anchoring AgNPs onto micro-nanoporous TiO2 orthopedic coatings: Trap killing of bacteria, surface-regulated osteoblast functions and host responses. AB - The therapeutic applications of silver nanoparticles (AgNPs) against biomedical device-associated infections (BAI), by local delivery, are encountered with risks of detachment, instability and nanotoxicity in physiological milieus. To firmly anchor AgNPs onto modified biomaterial surfaces through tight physicochemical interactions would potentially relieve these concerns. Herein, we present a strategy for hierarchical TiO2/Ag coating, in an attempt to endow medical titanium (Ti) with anticorrosion and antibacterial properties whilst maintaining normal biological functions. In brief, by harnessing the adhesion and reactivity of bioinspired polydopamine, silver nanoparticles were easily immobilized onto peripheral surface and incorporated into interior cavity of a micro/nanoporous TiO2 ceramic coating in situ grown from template Ti. The resulting coating protected the substrate well from corrosion and gave a sustained release of Ag(+) up to 28 d. An interesting germicidal effect, termed "trap-killing", was observed against Staphylococcus aureus strain. The multiple osteoblast responses, i.e. adherence, spreading, proliferation, and differentiation, were retained normal or promoted, via a putative surface-initiated self-regulation mechanism. After subcutaneous implantation for a month, the coated specimens elicited minimal, comparable inflammatory responses relative to the control. Moreover, this simple and safe functionalization strategy manifested a good degree of flexibility towards three-dimensional sophisticated objects. Expectedly, it can become a prospective bench to bedside solution to current challenges facing orthopedics. PMID- 26513415 TI - Development of a biointegrated mandibular reconstruction device consisting of bone compatible titanium fiber mesh scaffold. AB - Coating biomaterials with a thin hydroxyapatite (HA) was proven effective in enhancing bone compatibility. Segmental bone defects are considered as the most difficult defect to repair in bone regeneration therapy. We developed submicron thin HA-coated titanium fiber mesh scaffolds to reconstruct immediately loaded segmental mandibular defects and evaluated their bone compatibility in vitro and in vivo. Human osteoblasts attachment, proliferation, and osteocalcin expression in non- and HA-coated scaffolds were evaluated. A 10-mm long segmental bone defect in a rabbit mandibular bone was reconstructed with non- or HA-coated scaffolds, which were removed at 9 and 21 weeks, to evaluate the mechanical strength of the bone-scaffold connection and the bone formation around the scaffold. Expression of osteocalcin was greater in HA-coated scaffolds. In vivo bone formation in HA-coated scaffolds was greater than that in non-coated scaffolds at 21 weeks. Newly formed bone in HA-coated scaffolds mostly restored bone continuity. Scanning electron microscopy identified strong integration of the bone and HA-coated scaffolds. The mechanical strength of the bone-scaffold connection was 3-fold greater in HA-coated scaffolds than that in non-coated scaffolds. These results suggest that a thin HA-coated titanium fiber mesh scaffold is a bone-compatible mandibular reconstruction device in immediately loaded segmental defects. PMID- 26513417 TI - In situ label-free quantification of human pluripotent stem cells with electrochemical potential. AB - Conventional methods for quantification of undifferentiated pluripotent stem cells such as fluorescence-activated cell sorting and real-time PCR analysis have technical limitations in terms of their sensitivity and recyclability. Herein, we designed a real-time in situ label-free monitoring system on the basis of a specific electrochemical signature of human pluripotent stem cells in vitro. The intensity of the signal of hPSCs highly corresponded to the cell number and remained consistent in a mixed population with differentiated cells. The electrical charge used for monitoring did not markedly affect the proliferation rate or molecular characteristics of differentiated human aortic smooth muscle cells. After YM155 treatment to ablate undifferentiated hPSCs, their specific signal was significantly reduced. This suggests that detection of the specific electrochemical signature of hPSCs would be a valid approach to monitor potential contamination of undifferentiated hPSCs, which can assess the risk of teratoma formation efficiently and economically. PMID- 26513416 TI - Chitosan thermogels for local expansion and delivery of tumor-specific T lymphocytes towards enhanced cancer immunotherapies. AB - The success of promising anti-cancer adoptive cell therapies relies on the abilities of the perfused CD8(+) T lymphocytes to gain access to and persist within the tumor microenvironment to carry out their cytotoxic functions. We propose a new method for their local delivery as a living concentrate, which may not only reduce the numbers of cells required for treatment but also enhance their site-specific mobilization. Using combinations of sodium hydrogen carbonate and phosphate buffer as gelling agents, novel injectable chitosan-based biocompatible thermogels (CTGels) having excellent mechanical properties and cytocompatibility have been developed. Three thermogel formulations with acceptable physicochemical properties, such as physiological pH and osmolality, macroporosity, and gelation rates were compared. The CTGel2 formulation outperformed the others by providing an environment suitable for the encapsulation of viable CD8(+) T lymphocytes, supporting their proliferation and gradual release. In addition, the encapsulated T cell phenotypes were influenced by surrounding conditions and by tumor cells, while maintaining their capacity to kill tumor cells. This strongly suggests that cells encapsulated in this formulation retain their anti-cancer functions, and that this locally injectable hydrogel may be further developed to complement a wide variety of existing immunotherapies. PMID- 26513418 TI - Matrix metalloproteinase-20 mediates dental enamel biomineralization by preventing protein occlusion inside apatite crystals. AB - Reconstruction of enamel-like materials is a central topic of research in dentistry and material sciences. The importance of precise proteolytic mechanisms in amelogenesis to form a hard tissue with more than 95% mineral content has already been reported. A mutation in the Matrix Metalloproteinase-20 (MMP-20) gene results in hypomineralized enamel that is thin, disorganized and breaks from the underlying dentin. We hypothesized that the absence of MMP-20 during amelogenesis results in the occlusion of amelogenin in the enamel hydroxyapatite crystals. We used spectroscopy and electron microscopy techniques to qualitatively and quantitatively analyze occluded proteins within the isolated enamel crystals from MMP-20 null and Wild type (WT) mice. Our results showed that the isolated enamel crystals of MMP-20 null mice had more organic macromolecules occluded inside them than enamel crystals from the WT. The crystal lattice arrangements of MMP-20 null enamel crystals analyzed by High Resolution Transmission Electron Microscopy (HRTEM) were found to be significantly different from those of the WT. Raman studies indicated that the crystallinity of the MMP 20 null enamel crystals was lower than that of the WT. In conclusion, we present a novel functional mechanism of MMP-20, specifically prevention of unwanted organic material entrapped in the forming enamel crystals, which occurs as the result of precise amelogenin cleavage. MMP-20 action guides the growth morphology of the forming hydroxyapatite crystals and enhances their crystallinity. Elucidating such molecular mechanisms can be applied in the design of novel biomaterials for future clinical applications in dental restoration or repair. PMID- 26513419 TI - Highly dense, optically inactive silica microbeads for the isolation and identification of circulating tumor cells. AB - Efficient isolation of circulating tumor cells (CTCs) from whole blood is a major challenge for the clinical application of CTCs. Here, we report an efficient method to isolate CTCs from whole blood using highly dense and transparent silica microbeads. The surfaces of silica microbeads were fully covered with an antibody to capture CTCs, and blocked by zwitterionic moieties to prevent the non-specific adsorption of blood cells. Owing to the high density of the silica microbeads, the complexation of CTCs with silica microbeads resulted in the efficient sedimentation of CTC-microbead complexes, which enabled their discrimination from other blood cells in density gradient media. Model CTCs (MCF-7, HCC827, and SHP 77) with various levels of epithelial cell adhesion molecule (EpCAM) were isolated efficiently, especially those with low EpCAM expression (SHP-77). Moreover, the transparency of silica microbeads enabled CTCs to be clearly identified without interference caused by microbeads. The improved sensitivity resulted in increased CTC recovery from patient samples compared with the FDA approved CellSearch system (14/15 using our method; 5/15 using the CellSearch system). These results indicate that the isolation method described in this report constitutes a powerful tool for the isolation of CTCs from whole blood, which has important applications in clinical practice. PMID- 26513420 TI - The role of miR-135-modified adipose-derived mesenchymal stem cells in bone regeneration. AB - Tissue-engineering technology employing genetically-modified mesenchymal stem cells combined with proper scaffolds represents a promising strategy for bone regeneration. Elucidating the underlying mechanisms that govern the osteogenesis of mesenchymal stem cells will give deeper insights into the regulatory patterns, as well as provide more effective methods to enhance bone regeneration. In this study, miR-135 was identified as an osteogenesis-related microRNA that was up regulated during the osteogenesis of rat adipose-derived stem cells (ADSCs). Gain and loss-of-function experiments using a lentiviral expression system showed that Homeobox A2 (Hoxa2) was negatively regulated by miR-135, and luciferase reporter assay further indicated that miR-135 repressed Hoxa2 expression through binding to the 3'-untranslated region (3'-UTR) of the Hoxa2 mRNA. In vitro analyses showed that the overexpression of miR-135 significantly enhanced the expression of bone markers and extracellular matrix calcium deposition, whereas the knockdown of miR-135 suppressed these processes. Transduced ADSCs were then combined with poly(sebacoyl diglyceride) (PSeD) scaffold to repair a critical sized calvarial defects in rats. The results showed that the overexpression of miR-135 significantly promoted new bone formation with higher bone mineral density (BMD) and number of trabeculae (Tb.N), as well as larger areas of newly formed bone and mineralization labeled by tetracycline, calcein and alizarin red. In contrast, the knockdown of miR-135 attenuated these processes. Additionally, immunohistochemical analyses showed that transduced ADSCs participated in new bone formation and a miR-135/Hoxa2/Runx2 pathway might contribute to the regulation of ADSC osteogenesis and bone regeneration. Taken together, our data suggested that miR-135 positively regulated the osteogenesis and bone regeneration of ADSCs both in vitro and in vivo. Thus, the combination of miR-135 modified ADSCs and the PSeD scaffold may serve as a promising and effective method to repair critical-sized bone defects. PMID- 26513421 TI - Impact of protein pre-coating on the protein corona composition and nanoparticle cellular uptake. AB - Nanoparticles (NPs) are functionalized with targeting ligands to enable selectively delivering drugs to desired locations in the body. When these functionalized NPs enter the blood stream, plasma proteins bind to their surfaces, forming a protein corona that affects NP uptake and targeting efficiency. To address this problem, new strategies for directing the formation of a protein corona that has targeting capabilities are emerging. Here, we have investigated the feasibility of directing corona composition to promote targeted NP uptake by specific types of cells. We used the well-characterized process of opsonin-induced phagocytosis by macrophages as a simplified model of corona mediated NP uptake by a desired cell type. We demonstrate that pre-coating silica NPs with gamma-globulins (gamma-globulins) produced a protein corona that was enriched with opsonins, such as immunoglobulins. Although immunoglobulins are ligands that bind to receptors on macrophages and elicit phagocytois, the opsonin rich protein corona did not increase NP uptake by macrophage RAW 264.7 cells. Immunolabeling experiments indicated that the binding of opsonins to their target cell surface receptors was impeded by other proteins in the corona. Thus, corona mediated NP targeting strategies must optimize both the recruitment of the desired plasma proteins as well as their accessibility and orientation in the corona layer. PMID- 26513422 TI - Selective characterization of proteins on nanoscale concave surfaces. AB - Nanoscale curvature plays a critical role in nanostructure-biomolecule interactions, yet the understanding of such effects in concave nanostructures is still very limited. Because concave nanostructures usually possess convex surface curvatures as well, it is challenging to selectively study the proteins on concave surfaces alone. In this work, we have developed a novel and facile method to address this issue by desorbing proteins on the external surfaces of hollow gold nanocages (AuNG), allowing the selective characterization of retained proteins immobilized on their internal concave surfaces. The selective desorption of proteins was achieved via varying the solution ionic strength, and was demonstrated by both calculation and experimental comparison with non-hollow nanoparticles. This method has created a new platform for the discrete observation of proteins adsorbed inside AuNG hollow cores, and this work suggests an expanded biomedical application space for hollow nanomaterials. PMID- 26513423 TI - Cervical cancer screening in Australia: Past and present. PMID- 26513424 TI - Endoscopic ultrasound-guided fine-needle aspiration of solid lesions on clopidogrel may not be a high-risk procedure for bleeding: A case series. AB - The major gastrointestinal endoscopy society guidelines list endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) as a high-risk procedure for bleeding. However, there are no studies evaluating the risk of bleeding for EUS FNA of solid organs while patients continue to take clopidogrel. The aim of the present case series was to evaluate the rate of bleeding in a cohort of patients who underwent EUS-FNA for solid lesions while on clopidogrel. Bleeding was measured at the time of the procedure by bleeding seen on EUS, endoscopic visualization of blood, or drop in hemoglobin after the procedure. From 2013 to 2015, 10 patients were identified for this case series. Lesions that underwent EUS-FNA included gastric and rectal subepithelial lesions, pancreas masses, and liver masses. No immediate or delayed bleeding was observed in any of the patients. EUS-FNA of solid lesions on clopidogrel may not be a high-risk procedure for bleeding. Larger studies are needed to confirm this finding. PMID- 26513425 TI - State Medicaid Coverage for Tobacco Cessation Treatments and Barriers to Coverage - United States, 2014-2015. AB - Medicaid enrollees have a cigarette smoking prevalence (30.4%) twice as high as that of privately insured Americans (14.7%), placing them at increased risk for smoking-related disease and death. Individual, group, and telephone counseling and seven Food and Drug Administration (FDA)-approved medications are evidence based, effective treatments for helping tobacco users quit. A Healthy People 2020 objective (TU-8) calls for all state Medicaid programs to adopt comprehensive coverage of these treatments. However, a previous MMWR report indicated that, although state Medicaid coverage of cessation treatments had improved during 2008 2014, this coverage was still limited in most states. To monitor the most recent trends in state Medicaid cessation coverage, the American Lung Association collected data on coverage of, and barriers to, accessing all evidence-based cessation treatments except telephone counseling in state Medicaid programs (for a total of nine treatments) during January 31, 2014-June 30, 2015. As of June 30, 2015, all 50 states covered certain cessation treatments for at least some Medicaid enrollees. During 2014-2015, increases were observed in the number of states covering individual counseling, group counseling, and all seven FDA approved cessation medications for all Medicaid enrollees; however, only nine states covered all nine treatments for all enrollees. Common barriers to accessing covered treatments included prior authorization requirements, limits on duration, annual limits on quit attempts, and required copayments. Previous research in both Medicaid and other populations indicates that state Medicaid programs could reduce smoking prevalence, smoking-related morbidity, and smoking related health care costs among Medicaid enrollees by covering all evidence-based cessation treatments, removing all barriers to accessing these treatments, promoting coverage to Medicaid enrollees and health care providers, and monitoring use of covered treatments. PMID- 26513426 TI - Beyond magic traits: Multimodal mating cues in Heliconius butterflies. AB - Species coexistence involves the evolution of reproductive barriers opposing gene flow. Heliconius butterflies display colorful patterns affecting mate choice and survival through warning signaling and mimicry. These patterns are called "magic traits" for speciation because divergent natural selection may promote mimicry shifts in pattern whose role as mating cue facilitates reproductive isolation. By contrast, between comimetic species, natural selection promotes pattern convergence. We addressed whether visual convergence interferes with reproductive isolation by testing for sexual isolation between two closely related species with similar patterns, H. timareta thelxinoe and H. melpomene amaryllis. Experiments with models confirmed visual attraction based on wing phenotype, leading to indiscriminate approach. Nevertheless, mate choice experiments showed assortative mating. Monitoring male behavior toward live females revealed asymmetry in male preference, H. melpomene males courting both species equally while H. timareta males strongly preferred conspecifics. Experiments with hybrid males suggested an important genetic component for such asymmetry. Behavioral observations support a key role for short-distance cues in determining male choice in H. timareta. Scents extracts from wings and genitalia revealed interspecific divergence in chemical signatures, and hybrid female scent composition was significantly associated with courtship intensity by H. timareta males, providing candidate chemical mating cues involved in sexual isolation. PMID- 26513427 TI - Psychological therapies for the management of chronic neuropathic pain in adults. AB - BACKGROUND: Neuropathic pain is thought to arise from damage to the somatosensory nervous system. Its prevalence is increasing in line with many chronic disorders such as diabetes. All treatments have limited effectiveness. Given the evidence regarding psychological treatment for distress and disability in people with various chronic pain conditions, we were interested to investigate whether psychological treatments have any effects for those with chronic neuropathic pain. OBJECTIVES: To assess the effects of psychological treatments on pain experience, disability, mood, and health-care use in adults with chronic neuropathic pain. SEARCH METHODS: We searched for randomised controlled trials (RCTs) published in any language in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and PsycINFO, from database inception to March 2015. SELECTION CRITERIA: Full publications of RCTs on psychological interventions for neuropathic pain. Trials had to have lasted at least three months, had at least 20 participants in each arm at the end of treatment, and compared a psychological intervention with any active or inactive intervention. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: Two small studies (enrolling a total of 105 participants) met the inclusion criteria. One was a standard cognitive behavioural treatment (CBT) programme for 61 people with pain from spinal cord injury, followed up for three months, and compared with a waiting list. The other was weekly group psychotherapy for 44 people with burning mouth syndrome, compared with a daily placebo tablet. The overall risk of bias was high in both trials.The CBT study assessed participants for pain, disability, mood, and quality of life, with improvement in treatment and control groups. However, there was no more improvement in the treatment group than in the control for any outcome, either post-treatment or at follow-up. The group psychotherapy study only assessed pain, classifying participants by pain severity. There is a lack of evidence on the efficacy and safety of psychological interventions for people with neuropathic pain. AUTHORS' CONCLUSIONS: There is insufficient evidence of the efficacy and safety of psychological interventions for chronic neuropathic pain. The two available studies show no benefit of treatment over either waiting list or placebo control groups. PMID- 26513428 TI - Ultraviolet B stimulates proopiomelanocortin signalling in the arcuate nucleus of the hypothalamus in mice. AB - We previously found that ultraviolet B (UVB) could stimulate the paraventricular nucleus (PVN) with activation the systemic hypothalamic-pituitary- adrenal (HPA) axis. To investigate whether UVB can also stimulate other hypothalamic nuclei, we tested its effect on the proopiomelanocortin (POMC) related signalling system in the arcuate nucleus (ARC) of female C57BL/6 and FVB albino mice. The shaved back skin of the mice was irradiated with either 100 or 400 mJ/cm2 of UVB. After 1, 3, 6 and 12 h, blood and hypothalamus were collected and processed for gene and protein expression, and measurement of alpha-MSH and beta-endorphin (beta-END) levels. An in situ immunohistochemical examination was performed for melanocortin receptor 4 (MC4R) and POMC-derived alpha-MSH. The expression of Pomc and MC4R mRNAs was stimulated, whereas that of AgRP was inhibited after exposure to UVB. It was accompanied by an increased number of both alpha-MSH- and MC4R immunoreactive neurons in the ARC, and by increased levels of alpha-MSH and beta END (both found in the hypothalamus and plasma). This surprising discovery of UVB stimulating the POMC system in the ARC, accompanied by the increased plasma levels of alpha-MSH and beta-END, paves the way for exciting areas of research on the communication between the skin and the brain, as well as is suggesting a new role for UVB in regulation of body metabolism. PMID- 26513429 TI - Management of spinal fractures in patients with ankylosing spondylitis. AB - Ankylosing spondlylitis is a seronegative spondyloarthropathy that primarily affects the spinal column and sacroiliac joints. With disease progression autofusion of the spinal column takes place. This combined with the brittle bone quality make patients prone to fractures and spinal cord injury. The typical fracture pattern is extension type and involves all three columns. These fractures and injuries may involve the craniovertebral junction, the subaxial cervical spine, and the thoracolumbar spine. While at times these fractures are challenging to manage especially when they affect the elderly, there is evidence that supports long segment fixation and fusion. This article presents a narrative review on managing spinal fractures in patients with ankylosing spondylitis. PMID- 26513430 TI - A detailed analysis of intracerebral hemorrhages in DBS surgeries. AB - OBJECTIVES: Deep brain stimulation is nowadays a frequently performed surgery in patients with movement disorders, intractable epilepsy, and severe psychiatric disorders. The most feared complication of this surgery is an intracerebral hemorrhage due to the electrode placement, either for intraoperative electrophysiology (microelectrode recording) and/or implantation of the final electrode (macroelectrode). Here, we have investigated the risk of developing an intracerebral hemorrhage in our cohort of deep brain stimulation patients over a period of 15 years. PATIENTS AND METHODS: We have collected demographic data and analyzed the effect of performing surgery with single-electrode versus multiple electrode guided DBS. The effect of using single-dose versus double-dose contrast enhanced MRI to visualize vessels for the electrode trajectory planning has been investigated as well. RESULTS: We have found that the overall calculated risk of an intracerebral hemorrhage in our series was 1.81% per patient, 0.3% per recording electrode and 0.23% per brain insertion. While three out of four patients recovered without neurological deficits, there was one mortality in a patient with cardiovascular comorbidities. Statistical comparisons between the groups of single-electrode versus multiple electrode guided surgery and single dose gadolinium versus double-dose contrast enhanced MRI revealed no significant differences. In addition, there was no meaningful correlation between the age at surgery and the risk of bleeding. CONCLUSION: We have found that the risk of developing an intracerebral hemorrhage due to deep brain stimulation surgery is low. The clinical course of the patients with an intracerebral hemorrhage was generally favorable. PMID- 26513431 TI - Autonomic symptoms in hypertensive patients with post-acute minor ischemic stroke. AB - BACKGROUND: Most studies regarding autonomic dysfunction in ischemic stroke are limited to heart rate and blood pressure changes during the acute phase. However, there are few data on quantitative assessment of autonomic symptoms. We sought to assess autonomic symptoms in hypertensive ischemic stroke patients. METHODS: In 100 hypertensive patients (45 with symptomatic ischemic stroke (6 months after stroke onset) and 55 without stroke), we assessed autonomic symptoms using the Scale for Outcomes in Parkinson disease-Autonomic (SCOPA-AUT). RESULTS: The age (mean +/- standard deviation) for the stroke group was 66 +/- 12 and 63 +/- 15 for the without stroke group (P=0.8). Orthostatic hypotension occurred in 3.6% of the stroke group and 4.4% in the group without stroke. The total SCOPA-AUT score was higher in the stroke group compared with the group without stroke (P=0.001). Domain scores for gastrointestinal (P=0.001), urinary (P=0.005) and cardiovascular (P=0.001) were higher in the stroke group. No differences were found when comparing the total SCOPA-AUT scores for stroke subtypes (P=0.168) and for lateralization (P=0.6). SCOPA AUT scores were correlated with depression scores (P=0.001) but not with stroke severity (P=0.2). CONCLUSION: Autonomic symptoms, especially, gastrointestinal, urinary and cardiovascular function, were significantly increased in hypertensive patients with minor ischemic stroke. Symptoms were associated with depression but not with the characteristic of the stroke. PMID- 26513432 TI - Clinical characteristics and etiology of transient myoclonic state in the elderly. AB - OBJECTIVES: To clarify clinical picture of transient myoclonic state in elderly patients. METHODS: The Aizawa Hospital database was searched to identify all patients with transient myoclonic state with or without asterixis between April 2006 and June 2013. Medical records, brain images and laboratory data including electroencephalograms and electromyograms were reviewed. RESULTS: We found 26 patients: 10 women and 16 men, and their ages ranged from 56 to 96 years (79.7 +/ 9.9 years, mean +/- standard deviation). The affected sites of the myoclonic jerks were predominantly the lower face, neck and upper extremities. The myoclonus appeared at conscious resting condition, slightly exaggerated by posturing or action. Asterixis was observed in eight patients. Single myoclonic bursts were 1.70 +/- 0.94 s long. The interval of myoclonic bursts was 4.47 +/- 2.44 s. Single myoclonic bursts were composed of 9.5 +/- 2.5 Hz myoclonic contractions, and single myoclonic contractions were 44.4 +/- 12.3 ms in duration. Most of the patients suffered from chronic diseases, but they were basically independent in activity of daily living. Oral administration of clonazepam was effective. CONCLUSIONS: Transient myoclonic state has relatively stereotyped features. The pathophysiology may include some metabolic abnormality on a background of age-related arteriosclerotic changes. Its prognosis is benign, and prompt oral administration of clonazepam abolishes it. Further investigations will be needed to clarify its cause and pathophysiology. PMID- 26513433 TI - Predictors of surgical outcome in medically-resistant temporal lobe epilepsy with bilateral features on pre-operative evaluation. AB - OBJECTIVE: This study identifies potential prognostic factors for favorable anterior mesial temporal lobe (AMTL) resection outcomes in patients with medically refractory temporal lobe epilepsy (TLE) with bilateral features on pre operative examination. METHODS: Thirty-one patients demonstrated bilateral features defined as: bilateral independent temporal or bitemporal ictal onsets on surface or intracranial EEG, or bitemporal interictal epileptiform abnormalities on surface EEG with bilateral radiographic mesial temporal sclerosis. Surgical outcomes were classified according to reduction in seizure frequency: I (100% reduction), II (>=75% reduction), III (50-74% reduction), IV (<50% reduction). RESULTS: Of 31 patients, 14 (45%) improved to class I and 9 (29%) had a class II outcome at an average of 4 years after surgery. Eight (26%) patients did not exhibit good surgical outcome (class III, class IV). We found that neuropsychological and Wada memory scores were significantly correlated (p<0.05) with surgical outcome, and logistic regression found neuropsychological evaluation significantly predicted better surgical outcome (p<0.05). CONCLUSIONS: When bilateral features are present on pre-operative evaluation, neuropsychological and Wada test results can provide unique data to better identify those patients more likely to achieve substantial seizure reduction. PMID- 26513434 TI - Efficacy of ultra-short single agent regimen antibiotic chemo-prophylaxis in reducing the risk of meningitis in patients undergoing endoscopic endonasal transsphenoidal surgery. AB - OBJECTIVES: The study aims to evaluate the incidence of infectious complications (namely meningitis) within 30 days after endoscopic endonasal transspheinodal neurosurgery (EETS) in patients receiving an ultra-short peri-operative chemo prophylaxis regimen with 2 doses of 1st generation cephalosporin or macrolide. PATIENTS AND METHODS: We retrospectively analyzed the clinical records of 145 patients who received an ultra-short chemoprophylaxis with two doses of an antibiotic, given 30 min before and 8h after EETS, over a 30-month time-frame. Ninety-seven patients (66.89%) received endovenous cefazolin, a 1st generation cephalosporin, administered at a dosage of 1000 mg, and 48 patients (33.10%) with an history of allergy to various agents, received endovenous clarithromycin at a dosage of 500 mg. RESULTS: No case of peri- and post-operative meningitis occurred in patients receiving the 2 doses of antibiotic. Only one patient (0.68%) developed cerebral fluid leakage on the 7th postoperative day, which required the switching to a broad-spectrum antibiotic prophylaxis for one week; this patient received the ultrashort prophylaxis with a macrolide. In addition, 7 patients (4.82%) developed minor infectious complications such as low-grade fever (3 cases, all of them receiving cefazolin), enlarged submandibular and cervical lymphnodes (3 cases, all of them receiving cefazolin), and upper and lower respiratory tract infection (1 case receiving clarithromycin). The cost of this prophylaxis regimen ranged from 7.76 Euro (cefazolin) to 39.54 Euro (clarithromycin). CONCLUSIONS: This study suggested that an ultra-short single antibiotic prophylaxis is a safe, cheap and effective regimen to prevent post operative meningitis in patients undergoing EETS and who do not require lumbar drainage after surgery. In these patients also the rate of minor infective complications was acceptable when compared with the previous more expensive regimen based on 3rd generation cephalosporin plus aminoglycoside or alone, that could be suitable only for at-risk patients (e.g. smokers, cerebrospinal leak or Cushing's diseases). PMID- 26513435 TI - Smoking bans, cigarette prices and life satisfaction. AB - The consequences of tobacco control policies for individual welfare are difficult to assess, even more so when related consumption choices challenge people's willpower. We therefore evaluate the impact of smoking bans and cigarette prices on subjective well-being by analyzing data for 40 European countries and regions between 1990 and 2011. We exploit the staggered introduction of bans and apply an imputation strategy to study the effect of anti-smoking policies on people with different propensities to smoke. We find that higher cigarette prices reduce the life satisfaction of likely smokers. Overall, smoking bans are barely related to subjective well-being, but increase the life satisfaction of smokers who would like to quit smoking. The latter finding is consistent with cue-triggered models of addiction and the idea of bans as self-control devices. PMID- 26513436 TI - Pharmacokinetic and pharmacodynamic profile of degarelix for prostate cancer. AB - INTRODUCTION: Luteinizing hormone-releasing hormone (LHRH) agonists have been the mainstay of androgen deprivation therapy (ADT) for advanced prostate cancer for over two decades. However, their limitations include a transient initial rise in testosterone, failure to reduce testosterone to castrate levels in some patients, incomplete suppression of follicle-stimulating hormone (FSH), and an increased risk of cardiovascular (CV) events in those with pre-existing CV disease. This article considers whether the LHRH antagonist degarelix offers significant advantages over LHRH agonists. AREAS COVERED: This review covers the development and introduction of degarelix, its pharmacodynamic and pharmacokinetic properties, and the efficacy and safety results of Phase II and III clinical studies. EXPERT OPINION: Degarelix has clear pharmacodynamic advantages over the LHRH agonist leuprolide in terms of almost immediate suppression of testosterone to castrate levels and sustained suppression of FSH levels. It reduces the risk of CV events vs agonists in men with pre-existing CV disease. This finding, which may reflect differential effects on FSH and/or endothelial plaques, requires confirmation in a prospective study; however, it is the view of the author that the differential effects on CV events are real and suggest that men with pre existing CV disease requiring ADT should preferentially be treated with degarelix. PMID- 26513437 TI - Polyelectrolyte Multilayers: A Versatile Tool for Preparing Antimicrobial Coatings. AB - The prevention of pathogen colonization of medical implants represents a major medical and financial issue. The development of antimicrobial coatings aimed at protecting against such infections has thus become a major field of scientific and technological research. Three main strategies are developed to design such coatings: (i) the prevention of microorganisms adhesion and the killing of microorganisms (ii) by contact and (iii) by the release of active compounds in the vicinity of the implant. Polyelectrolyte multilayer (PEM) technology alone covers the entire widespread spectrum of functionalization possibilities. PEMs are obtained through the alternating deposition of polyanions and polycations on a substrate, and the great advantages of PEMs are that (i) they can be applied to almost any type of substrate whatever its shape and composition; (ii) various chemical, physicochemical, and mechanical properties of the coatings can be obtained; and (iii) active compounds can be embedded and released in a controlled manner. In this article we will give an overview of the field of PEMs applied to the design of antimicrobial coatings, illustrating the large versatility of the PEM technology. PMID- 26513438 TI - The State of Evaluation Research on Food Policies to Reduce Obesity and Diabetes Among Adults in the United States, 2000-2011. AB - INTRODUCTION: Improvements in diet can prevent obesity and type 2 diabetes. Although policy changes provide a foundation for improvement at the population level, evidence for the effectiveness of such changes is slim. This study summarizes the literature on recent efforts in the United States to change food related policies to prevent obesity and diabetes among adults. METHODS: We conducted a systematic review of evidence of the impact of food policies. Websites of government, academic, and nonprofit organizations were scanned to generate a typology of food-related policies, which we classified into 18 categories. A key-word search and a search of policy reports identified empirical evaluation studies of these categories. Analyses were limited to strategies with 10 or more reports. Of 422 articles identified, 94 met these criteria. Using publication date, study design, study quality, and dietary outcomes assessed, we evaluated the strength of evidence for each strategy in 3 assessment categories: time period, quality, and study design. RESULTS: Five strategies yielded 10 or more reports. Only 2 of the 5 strategies, menu labeling and taxes on unhealthy foods, had 50% or more studies with positive findings in at least 2 of 3 assessment categories. Most studies used methods that were rated medium quality. Although the number of published studies increased over 11 years, study quality did not show any clear trend nor did it vary by strategy. CONCLUSION: Researchers and policy makers can improve the quality and rigor of policy evaluations to synthesize existing evidence and develop better methods for gleaning policy guidance from the ample but imperfect data available. PMID- 26513439 TI - Depressive Symptoms and Behavior-Related Risk Factors, Italian Population-Based Surveillance System, 2013. AB - INTRODUCTION: Depression may increase the likelihood of adopting behaviors risky to health. Population studies investigating the association between depressive symptoms and behavior-related risk factors are lacking in Italy. The aim of this study was to estimate the prevalence of various self-reported behavior-related risk factors and to study their associations with current depressive symptoms in the Italian adult general population. METHODS: Data collected in 2013 from people aged 18 to 69 years participating in the Italian behavioral risk factor surveillance system were used for the analysis. Indicators of no leisure-time physical activity, obesity, cigarette smoking, and excessive alcohol consumption were investigated. Depressive symptoms were explored through the Patient Health Questionnaire-2. RESULTS: In the survey sample of 39,463 participants, 34.4% of adults engaged in no leisure-time physical activity, 26.2% were cigarette smokers, 11.5% were excessive alcohol consumers, and 10.3% were obese. The prevalence of depressive symptoms was 6.2%. People with depressive symptoms were more likely to be physically inactive (adjusted prevalence ratio [APR], 1.13), cigarette smokers (APR, 1.34), obese (APR, 1.27) and excessive alcohol consumers (APR, 1.43) than those without depressive symptoms. CONCLUSION: The contribution of this study to the existing evidence lies not just in confirming the association between depression and behavior-related risk factors in the Italian context but also in suggesting that programs for simultaneously improving people's mental and physical health should be developed and implemented. PMID- 26513440 TI - Identification of Hypertension Predictors and Application to Hypertension Prediction in an Urban Han Chinese Population: A Longitudinal Study, 2005-2010. AB - INTRODUCTION: Research suggests that targeting high-risk, nonhypertensive patients for preventive intervention may delay the onset of hypertension. We aimed to develop a biomarker-based risk prediction model for assessing hypertension risk in an urban Han Chinese population. METHODS: We analyzed data from 26,496 people with hypertension to extract factors from 11 check-up biomarkers. Then, depending on a 5-year follow-up cohort, a Cox model for predicting hypertension development was built by using extracted factors as predictors. Finally, we created a hypertension synthetic predictor (HSP) by weighting each factor with its risk for hypertension to develop a risk assessment matrix. RESULTS: After factor analysis, 5 risk factors were extracted from data for both men and women. After a 5-year follow-up, the cohort of participants had an area under receiver operating characteristic curve (area under the curve [AUC]) with an odds ratio (OR) of 0.755 (95% confidence interval [CI], 0.746 0.763) for men and an OR of 0.801 (95% CI, 0.792-0.810) for women. After tenfold cross validation, the AUC was still high, with 0.755 (95% CI, 0.746-0.763) for men and 0.800 (95% CI, 0.791-0.810) for women. An HSP-based 5-year risk matrix provided a convenient tool for risk appraisal. CONCLUSION: Hypertension could be explained by 5 factors in a population sample of Chinese urban Han. The HSP may be useful in predicting hypertension. PMID- 26513441 TI - Improving Community Health While Satisfying a Critical Community Need: A Case Study for Nonprofit Hospitals. AB - BACKGROUND: School-based student health screenings identify issues that may affect physical and intellectual development and are an important way to maintain student health. Nonprofit hospitals can provide a unique resource to school districts by assisting in the timely completion of school-based screenings and meet requirements of the Affordable Care Act. This case study describes the collaboration between an academic medical center and a local school district to conduct school-based health screenings. COMMUNITY CONTEXT: Penn State Milton S. Hershey Medical Center and Penn State Hershey PRO Wellness Center collaborated with Lebanon School District to facilitate student health screenings, a need identified in part by a community health needs assessment. METHODS: From June 2012 through February 2013, district-wide student health screenings were planned and implemented by teams of hospital nursing leadership, school district leadership, and school nurses. In fall 2013, students were screened through standardized procedures for height, weight, scoliosis, vision, and hearing. OUTCOMES: In 2 days, 3,105 students (67% of all students in the district) were screened. Letters explaining screening results were mailed to parents of all students screened. Debriefing meetings and follow-up surveys for the participating nurses provided feedback for future screenings. INTERPRETATION: The 2-day collaborative screening event decreased the amount of time spent by school nurses in screening students throughout the year and allowed them more time in their role as school wellness champion. Additionally, parents found out early in the school year whether their child needed physician follow-up. Partnerships between school districts and hospitals to conduct student health screenings are a practical option for increasing outreach while satisfying community needs. PMID- 26513442 TI - Obesogenic Environments: Access to and Advertising of Sugar-Sweetened Beverages in Soweto, South Africa, 2013. AB - INTRODUCTION: Rates of obesity and overweight among South Africans are increasing. Food marketing has a profound impact on children and affects their lifelong eating patterns; in urban areas of South Africa, disposable incomes are growing and ultra-processed food is increasingly available at low cost. The combination of these factors will strain an already fragile health system. Our aim was to investigate the density of outdoor sugar sweetened beverage (SSB) advertising and the number of formal and informal vendors selling SSBs in a transforming, historically disadvantaged urban setting of South Africa. METHODS: A digital camera and global positioning system navigation system were used to record the location of SSB advertisements and food vendors in a demarcated area in Soweto. Data were collected by walking or driving through each street; a food inventory was completed for every food vendor. Spatial analyses were conducted using a geographic information system. RESULTS: A total of 145 advertisements for SSBs were found over a driven or walked distance of 111.9 km. The density of advertisements was 3.6 per km(2) in relation to schools, and 50% of schools had branded advertising of SSBs on their school property. Most (n = 104; 58%) of the 180 vendors in the study sold SSBs. CONCLUSION: This is the first study in South Africa to document the location of billboard advertisements and vendors in relation to schools. Marketing of products that contribute to obesity is common in urban Soweto. Our findings have implications for policies that regulate SSB advertising, especially in the proximity of schools. PMID- 26513443 TI - Technology and Data Collection in Chronic Disease Epidemiology. PMID- 26513444 TI - Estimating HCV disease burden - volume 3 (editorial). PMID- 26513445 TI - Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 3. AB - Detailed, country-specific epidemiological data are needed to characterize the burden of chronic hepatitis C virus (HCV) infection around the world. With new treatment options available, policy makers and public health officials must reconsider national strategies for infection control. In this study of 15 countries, published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates were gathered from the literature and validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Iran and Lebanon to 4.2% in Pakistan. The largest viraemic populations were in Pakistan (7 001 000 cases) and Indonesia (3 187 000 cases). Injection drug use (IDU) and a historically unsafe blood supply were major risk factors in most countries. Diagnosis, treatment and liver transplant rates varied widely between countries. However, comparison across countries was difficult as the number of cases changes over time. Access to reliable data on measures such as these is critical for the development of future strategies to manage the disease burden. PMID- 26513448 TI - Solvothermal Subcomponent Self-Assembly of Cubic Metal-Imidazolate Cages and Their Coordination Polymers. AB - A series of Ni-imidazolate cubic cages, one-dimensional and two-dimensional coordination polymers based on the cubic cages, have been prepared by solvothermal subcomponent self-assembly of 5-methyl-4-formylimidazole, m xylylenediamine, and Ni(II) salts with varied anions. These compounds have been characterized by single-crystal X-ray diffractions, elemental analysis, IR spectra, and powder X-ray diffractions. The formation of an oligomerized coordination cage or an infinite coordination polymer depends on the anions chosen. An oligomerized 8-nuclear Ni-imidazolate cubic cage is formed when the anion Cl(-), Br(-), I(-), SCN(-), NO2(-), or NO3(-) is utilized in the reactions, and a two-dimensional coordination polymer based on the Ni-imidazolate cubic cage will be obtained when N3(-), (CN)2N(-), or (CN)3C(-) act as the anions. When only ClO4(-) or both ClO4(-) and [Ni(C4N2S2)2](2-) (C4N2S2 = dimercaptomaleonitrile) as anions exist in the reaction mixture, a ladder-like one-dimensional coordination polymer based on the Ni-imidazolate cubic cage and formate is formed unpredictably. PMID- 26513449 TI - Palladium-Catalyzed Nucleophilic Substitution/C-H Activation/Aromatization Cascade Reaction: One Approach To Construct 6-Unsubstituted Phenanthridines. AB - A facile and practical palladium-catalyzed nucleophilic substitution/C-H activation/aromatization cascade reaction has been developed. A range of 6 unsubstituted phenanthridines could be obtained in moderate to good yields (31 85%) with readily prepared N-Ms arylamines and commercially available 2 bromobenzyl bromide derivatives as starting materials. The potential application of the protocol was also demonstrated by the expeditious synthesis of the natural alkaloid trisphaeridine. PMID- 26513446 TI - The present and future disease burden of hepatitis C virus infections with today's treatment paradigm - volume 3. AB - The total number, morbidity and mortality attributed to viraemic hepatitis C virus (HCV) infections change over time making it difficult to compare reported estimates from different years. Models were developed for 15 countries to quantify and characterize the viraemic population and forecast the changes in the infected population and the corresponding disease burden from 2014 to 2030. With the exception of Iceland, Iran, Latvia and Pakistan, the total number of viraemic HCV infections is expected to decline from 2014 to 2030, but the associated morbidity and mortality are expected to increase in all countries except for Japan and South Korea. In the latter two countries, mortality due to an ageing population will drive down prevalence, morbidity and mortality. On the other hand, both countries have already experienced a rapid increase in HCV-related mortality and morbidity. HCV-related morbidity and mortality are projected to increase between 2014 and 2030 in all other countries as result of an ageing HCV infected population. Thus, although the total number of HCV countries is expected to decline in most countries studied, the associated disease burden is expected to increase. The current treatment paradigm is inadequate if large reductions in HCV-related morbidity and mortality are to be achieved. PMID- 26513450 TI - Disulfide-based multifunctional conjugates for targeted theranostic drug delivery. AB - Theranostics, chemical entities designed to combine therapeutic effects and imaging capability within one molecular system, have received considerable attention in recent years. Much of this interest reflects the promise inherent in personalized medicine, including disease-targeted treatments for cancer patients. One important approach to realizing this latter promise involves the development of so-called theranostic conjugates, multicomponent constructs that selectively target cancer cells and deliver cytotoxic agents while producing a readily detectable signal that can be monitored both in vitro and in vivo. This requires the synthesis of relatively complex systems comprising imaging reporters, masked chemotherapeutic drugs, cleavable linkers, and cancer targeting ligands. Ideally, the cleavage process should take place within or near cancer cells and be activated by cellular components that are associated with cancer states or specifically expressed at a higher level in cancer cells. Among the cleavable linkers currently being explored for the construction of such localizing conjugates, disulfide bonds are particularly attractive. This is because disulfide bonds are stable in most blood pools but are efficiently cleaved by cellular thiols, including glutathione (GSH) and thioredoxin (Trx), which are generally found at elevated levels in tumors. When disulfide bonds are linked to fluorophores, changes in emission intensity or shifts in the emission maxima are typically seen upon cleavage as the result of perturbations to internal charge transfer (ICT) processes. In well-designed systems, this allows for facile imaging. In this Account, we summarize our recent studies involving disulfide based fluorescent drug delivery conjugates, including preliminary tests of their biological utility in vitro and in vivo. To date, a variety of chemotherapeutic agents, such as doxorubicin, gemcitabine, and camptothecin, have been used to create disulfide-based conjugates, as have a number of fluorophores, including naphthalimide, coumarin, BODIPY, rhodol, and Cy7. The resulting theranostic core (drug-disulfide-fluorophore) can be further linked to any of several site localizing entities, including galactose, folate, biotin, and the RGD (Arg-Gly Asp) peptide sequence, to create systems with an intrinsic selectivity for cancer cells over normal cells. Site-specific cleavage by endogenous thiols serves to release the cytotoxic drug and produce an easy-to-monitor change in the fluorescence signature of the cell. On the basis of the results summarized in this Account, we propose that disulfide-based cancer-targeting theranostics may have a role to play in advancing drug discovery efforts, as well as improving our understanding of cellular uptake and drug release mechanisms. PMID- 26513447 TI - Strategies to manage hepatitis C virus infection disease burden - volume 3. AB - The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries in Europe, the Middle East and Asia, and the relative impact of two scenarios was considered: increased treatment efficacy while holding the annual number of treated patients constant and increased treatment efficacy and an increased annual number of treated patients. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. A 90% reduction in total HCV infections within 15 years is feasible in most countries studied, but it required a coordinated effort to introduce harm reduction programmes to reduce new infections, screening to identify those already infected and treatment with high cure rate therapies. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. Among European countries, the majority of patients were born between 1940 and 1985. A wider range of birth cohorts was seen in the Middle East and Asia (between 1925 and 1995). PMID- 26513451 TI - Regulation of antiapoptotic and cytoprotective pathways in colonic epithelial cells in ulcerative colitis. AB - Ulcerative colitis is an inflammatory bowel disease involving the colon resulting in bloody diarrhea and increased risk of colorectal cancer in certain patient subgroups. Increased apoptosis in the epithelial cell layer causes increased permeability, especially during flares; this leads to translocation of luminal pathogens resulting in a continued inflammatory drive. The present work investigates how epithelial apoptosis is regulated in ulcerative colitis. The main results are that Fas mediated apoptosis is inhibited during flares of ulcerative colitis, probably by an upregulation of cellular inhibitor of apoptosis protein 2 (cIAP2) and cellular FLICE-like inhibitory protein. cIAP2 is upregulated in regenerative epithelial cells both in ulcerative colitis and in experimental intestinal wounds. Inhibition of cIAP2 decreases wound healing in vitro possibly through inhibition of migration. Altogether, it is shown that epithelial cells in ulcerative colitis responds to the hostile microenvironment by activation of cytoprotective pathways that tend to counteract the cytotoxic effects of inflammation. However, the present studies also show that epithelial cells produce increased amounts of reactive oxygen species during stimulation with tumor necrosis factor-alpha and interferon-gamma resulting in DNA instability. The combined effect of increased DNA-instability and decreased apoptosis responses could lead to neoplasia. PMID- 26513452 TI - Reference intervals for reticulocyte parameters of infants during their first 90 days after birth. AB - OBJECTIVE: The automated reticulocyte parameters (absolute reticulocyte count, immature reticulocyte fraction (IRF) and reticulocyte hemoglobin content (RET He)) are of value in managing adults and older children with a variety of hematological disorders. However, the lack of reference intervals for these parameters in neonates and young infants has limited their application to that population. STUDY DESIGN: During a span of 12 months (29 May 2014 to 5 May 2015), a convenience sample of reticulocyte parameters were run from clinically ordered complete blood counts (CBCs) of infants within the first 90 days after birth. Measuring the reticulocyte parameters as a research-only adjunct to the CBC did not require any additional blood or generate a patient charge, and the reticulocyte results were not reported to the provided and did not appear in the clinical records. Values from neonates who had a transfusion or a diagnosis of anemia were subsequently excluded from the reference data set. RESULTS: Nine Intermountain Healthcare clinical laboratories contributed 8438 CBCs to the initial reticulocyte parameter database. From these, 1806 were excluded because of a transfusion or a diagnosis of anemia, leaving 6632 in the reference interval database. The parameters charted over the first 90 days after birth were: (1) blood hemoglobin concentration (g dl(-1)), (2) mean corpuscular volume (fL), (3) reticulocyte count (x10(3) per MUl), (4) IRF (%) and (5) RET-He (pg). CONCLUSIONS: The new reference interval charts can help clinicians identify abnormalities in the reticulocyte parameters. This information could be of value in identifying and following neonates with various hematological problems including hemolytic disorders, occult hemorrhage, or iron deficiency or other limitations of erythrocyte production. PMID- 26513453 TI - Isolated proteinuria is a risk factor for pre-eclampsia: a retrospective analysis of the maternal and neonatal outcomes in women presenting with isolated gestational proteinuria. AB - OBJECTIVE: To examine maternal and neonatal outcomes of isolated proteinuria and define maternal characteristics for progression to pre-eclampsia. STUDY DESIGN: Retrospective cohort study. Data from all hospitalized pregnant women between 2009 and 2014 with new onset isolated proteinuria of over 300 mg/24 h at admission were obtained. Follow-up was performed from the time of admission to the hospital to the time of discharge postpartum. Obstetrical, maternal and neonatal outcomes were obtained. RESULT: Ninety-five pregnant women diagnosed with new onset isolated proteinuria were followed to term. Thirteen women developed pre-eclampsia during pregnancy and eight developed pre-eclampsia postpartum. Maternal characteristics for progression to pre-eclampsia were greater maximal values of proteinuria. Earlier pre-eclampsia onset was associated with early-onset proteinuria and multiple gestation. Although greater values of proteinuria were associated with increased risk for intrauterine growth restriction and lower Apgar scores, maternal outcome was favorable, regardless of pre-eclampsia progression. Isolated proteinuria progressing to pre-eclampsia was associated with late pre-eclampsia onset and favorable maternal and neonatal outcomes. CONCLUSION: A significant proportion of women with new onset isolated proteinuria will develop pre-eclampsia. In these women, close follow-up is recommended until after delivery. PMID- 26513454 TI - Neonatal outcomes in twin pregnancies complicated by gestational diabetes compared with non-diabetic twins. AB - OBJECTIVE: To compare neonatal outcomes of twin pregnancies with gestational diabetes (GDM) and preexisting diabetes with non-diabetic twin pregnancies. STUDY DESIGN: US birth data from 2006 to 2009 was used to compare twin pregnancies of 16 562 GDM and 2137 preexisting diabetic with 258 857 non-diabetic twin gestations. Adjusted odds ratios (aORs) were calculated to assess effects of GDM and preexisting diabetes on neonatal outcomes. RESULT: Twin pregnancies with GDM vs non-diabetic twin pregnancies demonstrated decreased 5-min Apgar scores <4 (aOR 0.8, 95% confidence interval (CI) 0.68-0.94), fewer births before 32 weeks gestation (aOR 0.72, 95% CI 0.68-0.76), decreased birth weight less than the tenth percentile (aOR 0.84, 95% CI 0.81-0.89) and fifth percentile (aOR 0.85, 95% CI 0.81-0.89) and a trend toward lower rates of neonatal death (aOR 0.84, 95% CI 0.68-1.02). CONCLUSION: Certain adverse outcomes in pregnancies with GDM may be attenuated in twin gestations; however, further investigation is warranted. PMID- 26513455 TI - Factors promoting diabetes self-care among low-income, minority pregnant women. AB - OBJECTIVE: To prospectively identify factors promoting healthy self-management of gestational and type 2 diabetes mellitus among underserved pregnant women. STUDY DESIGN: Twenty-nine in-depth, semi-structured interviews were performed over the course of pregnancy for 10 women with diabetes. Interviews on factors promoting diabetes self-management used cognitive load theory to frame questions. Qualitative analysis of longitudinal interview data applied grounded theory techniques to generate themes. RESULT: Half this cohort of minority, low-income, public aid-supported women had type 2 diabetes. Four themes, comprised of both internal self-driven motivators and external sources of support, were identified. These themes were: (1) disease familiarity and diabetes self-efficacy; (2) external motivation (for health of fetus and responsibilities to older children); (3) supportive social and physical environment; and (4) self-regulatory behavior, including goal responsiveness and long-term goal-setting. CONCLUSION: Low-income women used multiple internal and external resources to promote health during a pregnancy complicated by diabetes. Successful behavior modification and achievement of diabetes care goals require leveraging these resources. PMID- 26513456 TI - Multi-professional training for obstetric emergencies in a U.S. hospital over a 7 year interval: an observational study. AB - OBJECTIVE: Birth is less safe than it can be. We adapted the UK-developed PROMPT (PRactical Obstetric Multi-Professional Training) course to local practices and initiated annual training. STUDY DESIGN: This observational study used quality assurance data from University of Kansas Hospital 2 years before and 7 years after intervention encompassing 14,309 consecutive deliveries from January 2006 through December 2014. An events/trials approach was applied to changes in proportions over time. RESULT: PROMPT was associated with progressive decreases in rates (P<0.05) of brachial plexus injury and umbilical artery pH <7.00 exclusive of catastrophic events. Reduced rates (P<0.05) of cesarean section, episiotomy and higher perception of nurse/physician communication were documented. Hypoxic ischemic encephalopathy (HIE) rates declined progressively by >50% (P=NS). These improvements occurred despite younger faculty and higher rates of complicated pregnancies (P<0.05). Estimated health-care costs avoided exceeded annual training costs. CONCLUSION: Local annual multi-professional training as provided by PROMPT was temporally associated with improved obstetric outcomes. PMID- 26513457 TI - Tracking of Inhaled Near-Infrared Fluorescent Nanoparticles in Lungs of SKH-1 Mice with Allergic Airway Inflammation. AB - Molecular imaging of inflammatory lung diseases, such as asthma, has been limited to date. The recruitment of innate immune cells to the airways is central to the inflammation process. This study exploits these cells for imaging purposes within the lung, using inhaled polystyrene nanoparticles loaded with the near-infrared fluorescence dye Itrybe (Itrybe-NPs). By means of in vivo and ex vivo fluorescence reflectance imaging of an ovalbumin-based allergic airway inflammation (AAI) model in hairless SKH-1 mice, we show that subsequent to intranasal application of Itrybe-NPs, AAI lungs display fluorescence intensities significantly higher than those in lungs of control mice for at least 24 h. Ex vivo immunofluorescence analysis of lung tissue demonstrates the uptake of Itrybe NPs predominantly by CD68(+)CD11c(+)ECF-L(+)MHCII(low) cells, identifying them as alveolar M2 macrophages in the peribronchial and alveolar areas. The in vivo results were validated by confocal microscopy, overlapping tile analysis, and flow cytometry, showing an amount of Itrybe-NP-containing macrophages in lungs of AAI mice significantly larger than that in controls. A small percentage of NP containing cells were identified as dendritic cells. Flow cytometry of tracheobronchial lymph nodes showed that Itrybe-NPs were negligible in lung draining lymph nodes 24 h after inhalation. This imaging approach may advance preclinical monitoring of AAI in vivo over time and aid the investigation of the role that macrophages play during lung inflammation. Furthermore, it allows for tracking of inhaled nanoparticles and can hence be utilized for studies of the fate of potential new nanotherapeutics. PMID- 26513458 TI - A chloroplast-localized S1 domain-containing protein SRRP1 plays a role in Arabidopsis seedling growth in the presence of ABA. AB - Although the roles of S1 domain-containing proteins have been characterized in diverse cellular processes in the cytoplasm, the functional roles of a majority of S1 domain-containing proteins targeted to the chloroplast are largely unknown. Here, we characterized the function of a nuclear-encoded chloroplast-targeted protein harboring two S1 domains, designated SRRP1 (for S1 RNA-binding ribosomal protein 1), in Arabidopsis thaliana. Subcellular localization analysis of SRRP1 GFP fusion proteins revealed that SRRP1 is localized to the chloroplast. The T DNA tagged loss-of-function srrp1 mutants displayed poorer seedling growth and less cotyledon greening than the wild-type plants on MS medium supplemented with abscisic acid (ABA), suggesting that SRRP1 plays a role in seedling growth in the presence of ABA. Splicing of the trnL intron and processing of 5S rRNA in chloroplasts were altered in the mutant plants. Importantly, SRRP1 complemented the growth-defective phenotypes of an RNA chaperone-deficient Escherichia coli mutant at low temperatures and had nucleic acid-melting ability, indicating that SRRP1 possesses RNA chaperone activity. Taken together, these results suggest that SRRP1, the chloroplast-localized S1 domain-containing protein, harboring RNA chaperone activity affects the splicing and processing of chloroplast transcripts and plays a role in Arabidopsis seedling growth in the presence of ABA. PMID- 26513459 TI - Involvement of AOX and UCP pathways in the post-harvest ripening of papaya fruits. AB - Enhanced respiration during ripening in climacteric fruits is sometimes associated with an uncoupling between the ATP synthesis and the mitochondrial electron transport chain. While the participation of two energy-dissipating systems, one of which is mediated by the alternative oxidase (AOX) and the other mediated by the uncoupling protein (UCP), has been linked to fruit ripening, the relation between the activation of both mitochondrial uncoupling systems with the transient increase of ethylene synthesis (ethylene peak) remains unclear. To elucidate this question, ethylene emission and the two uncoupling (AOX and UCP) pathways were monitored in harvested papaya fruit during the ripening, from green to fully yellow skin. The results confirmed the typical climacteric behavior for papaya fruit: an initial increase in endogenous ethylene emission which reaches a maximum (peak) in the intermediate ripening stage, before finally declining to a basal level in ripe fruit. Respiration of intact fruit also increased and achieved higher levels at the end of ripening. On the other hand, in purified mitochondria extracted from fruit pulp the total respiration and respiratory control decrease while an increase in the participation of AOX and UCP pathways was markedly evident during papaya ripening. There was an increase in the AOX capacity during the transition from green fruit to the intermediate stage that accompanied the transient ethylene peak, while the O2 consumption triggered by UCP activation increased by 80% from the beginning to end stage of fruit ripening. Expression analyses of AOX (AOX1 and 2) and UCP (UCP1-5) genes revealed that the increases in the AOX and UCP capacities were linked to a higher expression of AOX1 and UCP (mainly UCP1) genes, respectively. In silico promoter analyses of both genes showed the presence of ethylene-responsive cis-elements in UCP1 and UCP2 genes. Overall, the data suggest a differential activation of AOX and UCP pathways in regulation related to the ethylene peak and induction of specific genes such as AOX1 and UCP1. PMID- 26513460 TI - Chlorophyll b in angiosperms: Functions in photosynthesis, signaling and ontogenetic regulation. AB - Chlorophyll b (Chlb) is an antenna chlorophyll. The binding of Chlb by antenna proteins is crucial for the correct assembly of the antenna complexes in thylakoid membranes. Since the levels of the proteins of major and minor antenna are affected to different extents by Chlb binding, the availability of Chlb influences the composition and the size of antenna complexes which in turn determine the supramolecular organization of the thylakoid membranes in grana. Therefore, Chlb synthesis levels have a major impact on lateral mobility and diffusion of membrane molecules, and thus affect not only light harvesting and thermal energy dissipation processes, but also linear electron transport and repair processes in grana. Furthermore, in angiosperms Chlb synthesis affects plant functions beyond chloroplasts. First, the stability of pigment-protein complexes in the antennae, which depends on Chlb, is an important factor in the regulation of plant ontogenesis, and Chlb levels were recently shown to influence plant ontogenetic signaling. Second, the amounts of minor antenna proteins in chloroplasts, which depend on the availability of Chlb, were recently shown to affect ABA levels and signaling in plants. These mechanisms can be examined in mutants where Chlb synthesis is reduced or abolished. The dramatic effects caused by the lack of Chlb on plant productivity are interpreted in this review in light of the pleiotropic effects on photosynthesis and signaling, and the potential to manipulate Chlb biosynthesis for the improvement of crop production is discussed. PMID- 26513461 TI - L-Citrulline Protects Skeletal Muscle Cells from Cachectic Stimuli through an iNOS-Dependent Mechanism. AB - Dietary L-citrulline is thought to modulate muscle protein turnover by increasing L-arginine availability. To date, the direct effects of increased L-citrulline concentrations in muscle have been completely neglected. Therefore, we determined the role of L-citrulline in regulating cell size during catabolic conditions by depriving mature C2C12 myotubes of growth factors (serum free; SF) or growth factors and nutrients (HEPES buffered saline; HBS). Cells were treated with L citrulline or equimolar concentrations of L-arginine (positive control) or L alanine (negative control) and changes in cell size and protein turnover were assessed. In myotubes incubated in HBS or SF media, L-citrulline improved rates of protein synthesis (HBS: +63%, SF: +37%) and myotube diameter (HBS: +18%, SF: +29%). L-citrulline treatment substantially increased iNOS mRNA expression (SF: 350%, HBS: 750%). The general NOS inhibitor L-NAME and the iNOS specific inhibitor aminoguanidine prevented these effects in both models. Depriving myotubes in SF media of L-arginine or L-leucine, exacerbated wasting which was not attenuated by L-citrulline. The increased iNOS mRNA expression was temporally associated with increases in mRNA of the endogenous antioxidants SOD1, SOD3 and catalase. Furthermore, L-citrulline prevented inflammation (LPS) and oxidative stress (H2O2) induced muscle cell wasting. In conclusion, we demonstrate a novel direct protective effect of L-citrulline on skeletal muscle cell size independent of L-arginine that is mediated through induction of the inducible NOS (iNOS) isoform. This discovery of a nutritional modulator of iNOS mRNA expression in skeletal muscle cells could have substantial implications for the treatment of muscle wasting conditions. PMID- 26513462 TI - Trends in Social Inequality in Tooth Brushing among Adolescents: 1991-2014. AB - This study examines whether social inequality in tooth brushing frequency among adolescents changed from 1991 to 2014. The data material was seven comparable cross-sectional studies of nationally representative samples of 11- to 15-year olds in Denmark with data about frequency of tooth brushing and occupation of parents. The total number of participants was 31,464, of whom 21.7% brushed their teeth less than the recommended 2 times a day. The absolute social inequality measured as prevalence difference between low and high social class increased from 7.7% in 1991 to 14.6% in 2014. The relative social inequality assessed by odds ratios for infrequent tooth brushing also increased from 1991 to 2014. PMID- 26513463 TI - Assessment of Model Based (Input) Impedance, Pulse Wave Velocity, and Wave Reflection in the Asklepios Cohort. AB - OBJECTIVES: Arterial stiffness and wave reflection parameters assessed from both invasive and non-invasive pressure and flow readings are used as surrogates for ventricular and vascular load. They have been reported to predict adverse cardiovascular events, but clinical assessment is laborious and may limit widespread use. This study aims to investigate measures of arterial stiffness and central hemodynamics provided by arterial tonometry alone and in combination with aortic root flows derived by echocardiography against surrogates derived by a mathematical pressure and flow model in a healthy middle-aged cohort. METHODS: Measurements of carotid artery tonometry and echocardiography were performed on 2226 ASKLEPIOS study participants and parameters of systemic hemodynamics, arterial stiffness and wave reflection based on pressure and flow were measured. In a second step, the analysis was repeated but echocardiography derived flows were substituted by flows provided by a novel mathematical model. This was followed by a quantitative method comparison. RESULTS: All investigated parameters showed a significant association between the methods. Overall agreement was acceptable for all parameters (mean differences: -0.0102 (0.033 SD) mmHg*s/ml for characteristic impedance, 0.36 (4.21 SD) mmHg for forward pressure amplitude, 2.26 (3.51 SD) mmHg for backward pressure amplitude and 0.717 (1.25 SD) m/s for pulse wave velocity). CONCLUSION: The results indicate that the use of model-based surrogates in a healthy middle aged cohort is feasible and deserves further attention. PMID- 26513464 TI - A Membrane-Based Electro-Separation Method (MBES) for Sample Clean-Up and Norovirus Concentration. AB - Noroviruses are the leading cause of acute gastroenteritis and foodborne illnesses in the United States. Enhanced methods for detecting noroviruses in food matrices are needed as current methods are complex, labor intensive and insensitive, often resulting in inhibition of downstream molecular detection and inefficient recovery. Membrane-based electro-separation (MBES) is a technique to exchange charged particles through a size-specific dialysis membrane from one solution to another using electric current as the driving force. Norovirus has a net negative surface charge in a neutrally buffered environment, so when placed in an electric field, it moves towards the anode. It can then be separated from the cathodic compartment where the sample is placed and then collected in the anodic compartment for downstream detection. In this study, a MBES-based system was designed, developed and evaluated for concentrating and recovering murine norovirus (MNV-1) from phosphate buffer. As high as 30.8% MNV-1 migrated from the 3.5 ml sample chamber to the 1.5 ml collection chamber across a 1 MUm separation membrane when 20 V was applied for 30 min using 20 mM sodium phosphate with 0.01% SDS (pH 7.5) as the electrolyte. In optimization of the method, weak applied voltage (20 V), moderate duration (30 min), and low ionic strength electrolytes with SDS addition were needed to increase virus movement efficacy. The electric field strength of the system was the key factor to enhance virus movement, which could only be improved by shortening the electrodes distance, instead of increasing system applied voltage because of virus stability. This study successfully demonstrated the norovirus mobility in an electric field and migration across a size-specific membrane barrier in sodium phosphate electrolyte. With further modification and validation in food matrixes, a novel, quick, and cost-effective sample clean-up technique might be developed to separate norovirus particles from food matrices by electric force. PMID- 26513466 TI - Photoprotection Mechanism of p-Methoxy Methylcinnamate: A CASPT2 Study. AB - p-Methoxy methylcinnamate (p-MMC) shares the same molecular skeleton with octyl methoxycinnamate sunscreen. It is recently found that adding one water to p-MMC can significantly enhance the photoprotection efficiency. However, the physical origin is elusive. Herein we have employed multireference complete active space self-consistent field (CASSCF) and multistate complete active-space second-order perturbation (MS-CASPT2) methods to scrutinize the photophysical and photochemical mechanism of p-MMC and its one-water complex p-MMC-W. Specifically, we optimize the stationary-point structures on the (1)pipi*, (1)npi*, and S0 potential energy surfaces to locate the (1)pipi*/S0 and (1)pipi*/(1)npi* conical intersections and to map (1)pipi* and (1)npi* excited-state relaxation paths. On the basis of the results, we find that, for the trans p-MMC, the major (1)pipi* deactivation path is decaying to the dark (1)npi* state via the in-plane (1)pipi*/(1)npi* crossing point, which only need overcome a small barrier of 2.5 kcal/mol; the minor one is decaying to the S0 state via the (1)pipi*/S0 conical intersection induced by out-of-plane photoisomerization. For the cis p-MMC, these two decay paths are comparable (1)pipi* deactivation paths: one is decaying to the dark (1)npi* state via the (1)pipi*/(1)npi* crossing point, and the second is decaying to the ground state via the (1)pipi*/S0 conical intersection. One-water hydration stabilizes the (1)pipi* state and meanwhile destabilizes the (1)npi* state. As a consequence, the (1)pipi* deactivation path to the dark (1)npi* state is heavily inhibited. The related barriers are increased to 5.8 and 3.3 kcal/mol for the trans and cis p-MMC-W, respectively. In comparison, the barriers associated with the photoisomerization-induced (1)pipi* decay paths are reduced to 2.5 and 1.3 kcal/mol for the trans and cis p-MMC-W. Therefore, the (1)pipi* decay paths to the S0 state are dominant relaxation channels when adding one water molecule. Finally, the present work contributes a lot of knowledge to understanding the photoprotection mechanism of methylcinnamate derivatives. PMID- 26513467 TI - Construction of quality-assured infant feeding process of care data repositories: definition and design (Part 1). AB - This is the first paper of a series of two regarding the construction of data quality (DQ) assured repositories for the reuse of information on infant feeding from birth until two years old. This first paper justifies the need for such repositories and describes the design of a process to construct them from Electronic Health Records (EHR). As a result, Part 1 proposes a computational process to obtain quality-assured datasets represented by a canonical structure extracted from raw data from multiple EHR. For this, 13 steps were defined to ensure the harmonization, standardization, completion, de-duplication, and consistency of the dataset content. Moreover, the quality of the input and output data for each of these steps is controlled according to eight DQ dimensions: predictive value, correctness, duplication, consistency, completeness, contextualization, temporal-stability and spatial-stability. The second paper of the series will describe the application of this computational process to construct the first quality-assured repository for the reuse of information on infant feeding in the perinatal period aimed at the monitoring of clinical activities and research. PMID- 26513468 TI - Development of an automatic identification algorithm for antibiogram analysis. AB - Routinely, diagnostic and microbiology laboratories perform antibiogram analysis which can present some difficulties leading to misreadings and intra and inter reader deviations. An Automatic Identification Algorithm (AIA) has been proposed as a solution to overcome some issues associated with the disc diffusion method, which is the main goal of this work. AIA allows automatic scanning of inhibition zones obtained by antibiograms. More than 60 environmental isolates were tested using susceptibility tests which were performed for 12 different antibiotics for a total of 756 readings. Plate images were acquired and classified as standard or oddity. The inhibition zones were measured using the AIA and results were compared with reference method (human reading), using weighted kappa index and statistical analysis to evaluate, respectively, inter-reader agreement and correlation between AIA-based and human-based reading. Agreements were observed in 88% cases and 89% of the tests showed no difference or a <4mm difference between AIA and human analysis, exhibiting a correlation index of 0.85 for all images, 0.90 for standards and 0.80 for oddities with no significant difference between automatic and manual method. AIA resolved some reading problems such as overlapping inhibition zones, imperfect microorganism seeding, non-homogeneity of the circumference, partial action of the antimicrobial, and formation of a second halo of inhibition. Furthermore, AIA proved to overcome some of the limitations observed in other automatic methods. Therefore, AIA may be a practical tool for automated reading of antibiograms in diagnostic and microbiology laboratories. PMID- 26513469 TI - Automated assessment of synovitis in 0.2T magnetic resonance images of the wrist. AB - According to the current recommendations in diagnosis of rheumatoid arthritis (RA), Magnetic Resonance (MR) images of wrist joints are used to evaluate three main types of lesions: synovitis, bone edema and bone erosions. In the clinical practice, the RA-related lesions seen in MR images are assessed manually with the semi-quantitative RAMRIS scoring system. In this paper we present an automated method for inflamed synovial membrane volume determination, based on the analysis of pre- and post-contrast MR images and segmentation of wrist bones seen in MR images. We found that the correlation between the automatically quantified volume of synovitis and RAMRIS scores was in the range from 0.76 to 0.87 for the total RAMRIS synovitis score. This can be compared with the correlation between the manually quantified volume of synovitis and RAMRIS scores which was in the range from 0.75 to 0.81 for the total synovitis score. The results of the study demonstrate that computer assisted methods for assessment of synovitis have great potential for clinical applications. PMID- 26513470 TI - Structural Insights into Separase Architecture and Substrate Recognition through Computational Modelling of Caspase-Like and Death Domains. AB - Separases are large proteins that mediate sister chromatid disjunction in all eukaryotes. They belong to clan CD of cysteine peptidases and contain a well conserved C-terminal catalytic protease domain similar to caspases and gingipains. However, unlike other well-characterized groups of clan CD peptidases, there are no high-resolution structures of separases and the details of their regulation and substrate recognition are poorly understood. Here we undertook an in-depth bioinformatical analysis of separases from different species with respect to their similarity in amino acid sequence and protein fold in comparison to caspases, MALT-1 proteins (mucosa-associated lymphoidtissue lymphoma translocation protein 1) and gingipain-R. A comparative model of the single C-terminal caspase-like domain in separase from C. elegans suggests similar binding modes of substrate peptides between these protein subfamilies, and enables differences in substrate specificity of separase proteins to be rationalised. We also modelled a newly identified putative death domain, located N-terminal to the caspase-like domain. The surface features of this domain identify potential sites of protein-protein interactions. Notably, we identified a novel conserved region with the consensus sequence WWxxRxxLD predicted to be exposed on the surface of the death domain, which we termed the WR motif. We envisage that findings from our study will guide structural and functional studies of this important protein family. PMID- 26513471 TI - The Impact of Heat on an Emergency Department in Italy: Attributable Visits among Children, Adults, and the Elderly during the Warm Season. AB - INTRODUCTION: Recent studies suggest that heat is associated with an increase in the number of ambulance calls and emergency department visits. We investigated the association between heat and daily number of emergency department visits at the University Hospital of Verona during the warm seasons 2011-2012 and we assessed the magnitude of the impact in terms of attributable events, focusing on the role of age and triage codification. MATERIALS AND METHODS: We used a Poisson model to analyse the association between daily number of visits and daily mean apparent temperature, accounting for air pollution level and seasonality. The analyses were stratified by age group and were performed both on the total number of emergency department visits and on the subsample of high-priority visits. Impact estimates were obtained only for this subsample, using a Monte Carlo approach to account for sampling variability. Number of attributable events and attributable community rate were calculated. RESULTS: We found a positive and immediate association between event occurrence and mean apparent temperatures exceeding a threshold located around 28-29 degrees C. The estimated percent change in the total number of visits per 1 degrees C increase of exposure above the threshold was equal to 3.75 (90% CI: 3.01; 4.49). Focusing only on high priority visits, the estimated percent change was larger and the greatest effect was among children. We estimated that apparent temperatures above the threshold were responsible for 1177 high-priority visits during the study period. Due to the record high temperatures observed in 2012 in Italy and in Europe, the impact in 2012 was much larger than in 2011, and consisted in 34 high-priority visits every 10000 children, 30 every 10000 people aged 15-64, and 38 every 10000 people aged 65 and over. DISCUSSION: Our results indicate that heat affects not only the elderly, but also children and non-elderly adults, stressing the need for developing public health preparedness plans for the entire community. PMID- 26513472 TI - The mediating role of depression in the association between disability and quality of life in Alzheimer's disease. AB - BACKGROUND: An understanding of the determinants of quality of life in Alzheimer's disease (AD) is required in order to develop effective interventions to promote patients' well-being. Most studies have pointed out depression, functional ability and environmental factors. However, unmeasured confounders can jeopardize the interpretation of the results. OBJECTIVES: To explore the mediating role of depression in the association between functional status and QoL, and establish a procedure to detect confounding variables. METHODS: A sample of 192 AD patients and their respective caregivers were recruited from day centers and health care centers in the region of Murcia (Spain). The mediating effect was evaluated using causal mediation analysis. Covariates were introduced into the model in a stepwise fashion and sensitivity analyses were performed to assess the influence of potential confounders. RESULTS: Self-rated depression acted as a partial mediator between functional status and quality of life. The mediating effect was positive and significant even after including both patient- and caregiver-related covariates. Only if confounders explained more than 80% of the residual variance in the mediator or in the outcome, the mediating effects would not be positive. CONCLUSIONS: The effect of lack of autonomy on the QoL is mostly explained by the negative consequences on mood status. The sensitivity analysis confirms the robustness of this finding. PMID- 26513473 TI - Optical Control of Peroxisomal Trafficking. AB - The blue-light-responsive LOV2 domain of Avena sativa phototropin1 (AsLOV2) has been used to regulate activity and binding of diverse protein targets with light. Here, we used AsLOV2 to photocage a peroxisomal targeting sequence, allowing light regulation of peroxisomal protein import. We generated a protein tag, LOV PTS1, that can be appended to proteins of interest to direct their import to the peroxisome with light. This method provides a means to inducibly trigger peroxisomal protein trafficking in specific cells at user-defined times. PMID- 26513475 TI - Corrigendum: Ursolic acid exerts anti-cancer activity by suppressing vaccinia related kinase 1-mediated damage repair in lung cancer cells. PMID- 26513474 TI - Distinct Macrophage Fates after in vitro Infection with Different Species of Leishmania: Induction of Apoptosis by Leishmania (Leishmania) amazonensis, but Not by Leishmania (Viannia) guyanensis. AB - Leishmania is an intracellular parasite in vertebrate hosts, including man. During infection, amastigotes replicate inside macrophages and are transmitted to healthy cells, leading to amplification of the infection. Although transfer of amastigotes from infected to healthy cells is a crucial step that may shape the outcome of the infection, it is not fully understood. Here we compare L. amazonensis and L. guyanensis infection in C57BL/6 and BALB/c mice and investigate the fate of macrophages when infected with these species of Leishmania in vitro. As previously shown, infection of mice results in distinct outcomes: L. amazonensis causes a chronic infection in both strains of mice (although milder in C57BL/6), whereas L. guyanensis does not cause them disease. In vitro, infection is persistent in L. amazonensis-infected macrophages whereas L. guyanensis growth is controlled by host cells from both strains of mice. We demonstrate that, in vitro, L. amazonensis induces apoptosis of both C57BL/6 and BALB/c macrophages, characterized by PS exposure, DNA cleavage into nucleosomal size fragments, and consequent hypodiploidy. None of these signs were seen in macrophages infected with L. guyanensis, which seem to die through necrosis, as indicated by increased PI-, but not Annexin V-, positive cells. L. amazonensis induced macrophage apoptosis was associated to activation of caspases-3, -8 and 9 in both strains of mice. Considering these two species of Leishmania and strains of mice, macrophage apoptosis, induced at the initial moments of infection, correlates with chronic infection, regardless of its severity. We present evidence suggestive that macrophages phagocytize L. amazonensis-infected cells, which has not been verified so far. The ingestion of apoptotic infected macrophages by healthy macrophages could be a way of amastigote spreading, leading to the establishment of infection. PMID- 26513476 TI - In Vitro Mutational and Bioinformatics Analysis of the M71 Odorant Receptor and Its Superfamily. AB - We performed an extensive mutational analysis of the canonical mouse odorant receptor (OR) M71 to determine the properties of ORs that inhibit plasma membrane trafficking in heterologous expression systems. We employed the use of the M71::GFP fusion protein to directly assess plasma membrane localization and functionality of M71 in heterologous cells in vitro or in olfactory sensory neurons (OSNs) in vivo. OSN expression of M71::GFP show only small differences in activity compared to untagged M71. However, M71::GFP could not traffic to the plasma membrane even in the presence of proposed accessory proteins RTP1S or mbeta2AR. To ask if ORs contain an internal "kill sequence", we mutated ~15 of the most highly conserved OR specific amino acids not found amongst the trafficking non-OR GPCR superfamily; none of these mutants rescued trafficking. Addition of various amino terminal signal sequences or different glycosylation motifs all failed to produce trafficking. The addition of the amino and carboxy terminal domains of mbeta2AR or the mutation Y289A in the highly conserved GPCR motif NPxxY does not rescue plasma membrane trafficking. The failure of targeted mutagenesis on rescuing plasma membrane localization in heterologous cells suggests that OR trafficking deficits may not be attributable to conserved collinear motifs, but rather the overall amino acid composition of the OR family. Thus, we performed an in silico analysis comparing the OR and other amine receptor superfamilies. We find that ORs contain fewer charged residues and more hydrophobic residues distributed throughout the protein and a conserved overall amino acid composition. From our analysis, we surmise that it may be difficult to traffic ORs at high levels to the cell surface in vitro, without making significant amino acid modifications. Finally, we observed specific increases in methionine and histidine residues as well as a marked decrease in tryptophan residues, suggesting that these changes provide ORs with special characteristics needed for them to function in olfactory neurons. PMID- 26513478 TI - Lithium Interferes with the Urinary Excretion of Phenolsulfonphthalein in Rats: Involvement of a Reduced Content of alpha-Ketoglutarate, the Driving Force for Organic Anion Transporters OAT1 and OAT3, in the Kidney Cortex. AB - AIMS: Lithium is effective in the treatment for bipolar disorder and is known to influence renal functions. The purpose of this study was to examine the effects of lithium on the renal organic anion transport system. METHODS: Pharmacokinetic experiments using rats and Western blotting were conducted. RESULTS: Until 60 min after the intravenous injection of phenolsulfonphthalein, a typical substrate of the renal organic anion transporters, as a bolus, 41.2% of the dose was recovered in the urine, and the infusion of lithium chloride dose-dependently interfered with its renal excretion. No significant changes were observed in the expression levels of rat organic anion transporters rOAT1 and rOAT3, and the content of alpha-ketoglutarate, the driving force for both transporters, was significantly decreased in the kidney cortex of rats administered lithium. CONCLUSION: These findings represented the dysfunction of the renal organic anion transport system in rats by lithium. As the mechanism, the reduced driving force for rOAT1 and rOAT3 was suggested to be involved at least in part. PMID- 26513477 TI - AKP-11 - A Novel S1P1 Agonist with Favorable Safety Profile Attenuates Experimental Autoimmune Encephalomyelitis in Rat Model of Multiple Sclerosis. AB - Sphingosine-1-phosphate receptor 1 (S1P1) mediated regulation of lymphocyte egress from lymphoid organs is recognized as the mechanism of FTY720 (Fingolimod, Gilenya) efficacy in relapsing-remitting forms of multiple sclerosis (RRMS). In this study we describe a novel S1P1 agonist AKP-11, next generation of S1P1 agonist, with immunomodulatory activities in cell culture model and for therapeutic efficacy against an animal model of MS, i.e. experimental autoimmune encephalomyelitis (EAE) but without the adverse effects observed with FTY720. Like FTY720, AKP-11 bound to S1P1 is internalized and activates intracellular AKT and ERKs cellular signaling pathways. In contrast to FTY720, AKP-11 mediated S1P1 downregulation is independent of sphingosine kinase activity indicating it to be a direct agonist of S1P1. The S1P1 loss and inhibition of lymphocyte egress by FTY720 leads to lymphopenia. In comparison with FTY720, oral administration of AKP-11 caused milder and reversible lymphopenia while providing a similar degree of therapeutic efficacy in the EAE animal model. Consistent with the observed reversible lymphopenia with AKP-11, the S1P1 recycled back to cell membrane in AKP-11 treated cells following its withdrawal, but not with withdrawal of FTY720. Accordingly, a smaller degree of ubiquitination and proteolysis of S1P1 was observed in AKP-11 treated cells as compared to FTY720. Consistent with previous observations, FTY720 treatment is associated with adverse effects of bradycardia and lung vascular leaks in rodents, whereas AKP-11 treatment had undetectable effects on bradycardia and reduced lung vascular leaks as compared to FTY720. Taken together, the data documents that AKP-11 treatment cause milder and reversible lymphopenia with milder adverse effects while maintaining therapeutic efficacy similar to that observed with FTY720, thus indicating therapeutic potential of AKP-11 for treatment of MS and related autoimmune disorders. PMID- 26513480 TI - Correction: Interobserver Agreement in Detecting Spectral-Domain Optical Coherence Tomography Features of Diabetic Macular Edema. PMID- 26513479 TI - Prevalence of and Factors Associated with Rectal-Only Chlamydia and Gonorrhoea in Women and in Men Who Have Sex with Men. AB - BACKGROUND: Both anorectal Chlamydia trachomatis (CT) and Neisseria gonorrhoea (NG) can occur as a rectal-only infection or concurrently with simultaneous urogenital infection with the same pathogen. Characterising the target groups in which rectal-only infections occur may improve the efficacy of screening practices. METHODS: We analysed data from two Dutch outpatient sexually transmitted infection (STI) clinics between 2011 and 2012. We included all men who have sex with men (MSM) (n = 9549) and women (n = 11113), >=18 years, who had been tested for anorectal and urogenital CT and/or NG (either as a result of reporting anal sex/symptoms or via routine universal testing). Factors associated with rectal-only CT and NG infections were assessed using univariable and multivariable logistic regression. RESULTS: In MSM, anorectal CT prevalence was 9.8% (693/7094), anorectal NG prevalence was 4.2% (397/9534). In women this was 9.5% overall (439/4597) and 0.9% (96/10972) respectively. Anorectal CT prevalence among women who were routinely universally tested was 10.4% (20/192), for selective testing this was 9.5% (419/4405) (p = 0.68). Anorectal NG infections were not detected among women who were routinely universally tested (p = 0.19). Among CT or NG positive MSM, rectal-only CT infections were found in 85.9% (595/693), for NG this was 85.6% (340/397) respectively. In positive women these figures were 22.1% (97/439)for CT and 20.8% (20/96) for NG, respectively. In MSM, independent factors associated with rectal-only CT were: being a sex worker (OR0.4,CI0.2-1.0), exclusively having sex with men (OR3.4,CI1.7-6.8), and absence of urogenital symptoms (OR0.2,CI0.2-0.4). In women, these factors were: older age (OR2.3, CI1.3-4.0) and non-Western nationality (OR1.8, CI1.0-3.5). Factors associated with rectal-only NG in MSM were: having been warned for STIs by an (ex) partner (OR2.9,CI1.1-7.5), oropharyngeal NG infection (OR2.4,CI1.0-5.3), and absence of urogenital symptoms (OR0.02,CI0.01-0.04), while in women no significant factors were identified. CONCLUSIONS: The prevalence of anorectal CT and NG was substantial in MSM and prevalence of anorectal CT was also substantial in women. Anorectal infections occurred mostly as rectal-only infections in MSM and mostly concurrent with other infections in women. Given the lack of useful indicators for rectal-only infections, selective screening based on a priori patient characteristics will have low discriminatory power both in relation to MSM and women. PMID- 26513481 TI - Measurement of Ensemble TRPV1 Ion Channel Currents Using Droplet Bilayers. AB - Electrophysiological characterization of ion channels is useful for elucidation of channel function as well as quantitative assessment of pharmaceutical effects on ion channel conductance. We used droplet bilayers to measure ensemble ion channel currents from membrane preparations made from TRPV1-expressing HEK cells. Conductance measurements showed rectification, activation by acid and capsaicin, and inhibition by capsazepine, SB 452533, and JNJ 17293212. We also quantitatively measured concentration-dependent inhibition of channel conductance through determination of capsazepine IC50 in agreement with previously published studies using patch clamp. These results, combined with the reduced apparatus and material requirements of droplet bilayers, indicate that this platform could be used for study of other physiologically relevant ion channels. PMID- 26513482 TI - Lessons From Reparative Therapy Applied to Post-Abortion Grief Counseling. AB - There is evidence from the legislative, judicial, and counseling sectors that the sun is setting on therapies designed to change sexual orientation. Despite this evidence, there is also evidence that similar pseudoscientific interventions continue to be used in at least one other area-post-abortion counseling. The key factor shared by both interventions is their dependence on unvalidated explanations of behavior. In the case of changing the expression of sexual orientation, the harm at the personal and communal levels is clear. In the case of post-abortion counseling, the harm is hypothesized, and the reasons why a communal response is lacking in the post-abortion community are described. Steps clinicians can take to alleviate the probable harm caused by the use of unvalidated/unvalidatable interventions, with a particular emphasis on identifying and expunging culturally derived and oppressive interventions currently used, are delineated as clinical and social justice activities to reduce human suffering. PMID- 26513484 TI - Cross-cultural Adaptation, Reliability, and Validity of the BICAMS in Brazil. AB - OBJECTIVE: To investigate the reliability and validity of a Brazilian-Portuguese adaptation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). METHOD: A Brazilian sample of 58 multiple sclerosis (MS) patients and 58 healthy controls (HC) were administered the Brazilian-Portuguese BICAMS test battery, comprising the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test Second Edition (CVLT2), and the Brief Visuospatial Memory Test Revised (BVMTR). Mean differences between groups on BICAMS tests were assessed using analysis of covariance (ANCOVA), controlling for age, gender, education, anxiety, and depression. Test-retest data were obtained from 49 of the MS patients, two weeks after the initial assessment. RESULTS: The MS patient group scored significantly lower on all BICAMS tests (CVLT2 F1,110 = 28.99, p < .001; BVMTR F1,110 = 7.77, p < .01; SDMT F1,110 = 21.09, p < .001). Mixed-factor ANCOVAs tested differences in learning curves across trials for CVLT2 and BVMTR. HCs had significantly steeper learning curves on both CVLT2 (F1,111 = 10.82, p < .01) and BVMTR (F1,110 = 7.816, p < .01). These findings support diagnostic validity of the Brazilian-Portuguese adaptation. Test-retest reliability was satisfactory for SDMT, CVLT2, and BVMTR (.86, .84, and .77, respectively). CONCLUSION: The results suggest that this Brazilian version of the BICAMS will be a valid and reliable measure once complete normative data become available. PMID- 26513483 TI - Food safety knowledge on the Bt mutant protein Cry8Ka5 employed in the development of coleopteran-resistant transgenic cotton plants. AB - Insecticidal Cry proteins from Bacillus thuringiensis (Bt) have been exploited in the development of genetically modified (GM) crops for pest control. However, several pests are still difficult to control such as the coleopteran boll weevil Anthonomus grandis. By applying in vitro molecular evolution to the cry8Ka1 gene sequence, variants were generated with improved activity against A. grandis. Among them, Cry8Ka5 mutant protein showed coleoptericidal activity 3-fold higher (LC50 2.83 MUg/mL) than that of the original protein (Cry8Ka1). Cry8Ka5 has been used in breeding programs in order to obtain coleopteran-resistant cotton plants. Nevertheless, there is some concern in relation to the food safety of transgenic crops, especially to the heterologously expressed proteins. In this context, our research group has performed risk assessment studies on Cry8Ka5, using the tests recommended by Codex as well as tests that we proposed as alternative and/or complementary approaches. Our results on the risk analysis of Cry8Ka5 taken together with those of other Cry proteins, point out that there is a high degree of certainty on their food safety. It is reasonable to emphasize that most safety studies on Cry proteins have essentially used the Codex approach. However, other methodologies would potentially provide additional information such as studies on the effects of Cry proteins and derived peptides on the indigenous gastrointestinal microbiota and on intestinal epithelial cells of humans. Additionally, emerging technologies such as toxicogenomics potentially will offer sensitive alternatives for some current approaches or methods. PMID- 26513485 TI - The temporal primacy of self-related stimuli and negative stimuli: an ERP-based comparative study. AB - Numerous studies have shown there exist attention biases for self-related and negative stimuli. Few studies, however, have been carried out to compare the effects of such stimuli on the neural mechanisms of early attentional alertness and subsequent cognitive processing. The purpose of the present study was to examine the temporal primacy of both self-related stimuli and negative stimuli in the neurophysiologic level. In a modified oddball task, event-related potentials of the deviant stimuli (i.e., self-face, negative face and neutral face) were recorded. Results revealed that larger P2 amplitudes were elicited by self related and negative stimuli than by neutral stimuli. Negative stimuli, however, elicited shorter P2 latencies than self-related and neutral stimuli. As for the N2 component, self-related and negative stimuli elicited smaller amplitudes and shorter latencies than neutral stimuli, but otherwise did not differ. Self related stimuli also elicited larger P3 and late positive component (LPC) amplitudes than negative and neutral stimuli. The pattern of results suggests that the primacy of negative stimuli occurred at an early attention stage of processing, while the primacy of self-related stimuli occurred at the subsequent cognitive evaluation and memory stage. PMID- 26513486 TI - Zinc-induced heterodimer formation between metal-binding domains of intact and naturally modified amyloid-beta species: implication to amyloid seeding in Alzheimer's disease? AB - Zinc ions and modified amyloid-beta peptides (Abeta) play a critical role in the pathological aggregation of endogenous Abeta in Alzheimer's disease (AD). Zinc induced Abeta oligomerization is mediated by the metal-binding domain (MBD) which includes N-terminal residues 1-16 (Abeta1-16). Earlier, it has been shown that Abeta1-16 as well as some of its naturally occurring variants undergoes zinc induced homodimerization via the interface in which zinc ion is coordinated by Glu11 and His14 of the interacting subunits. In this study using surface plasmon resonance technique, we have found that in the presence of zinc ions Abeta1-16 forms heterodimers with MBDs of two Abeta species linked to AD: Abeta containing isoAsp7 (isoAbeta) and Abeta containing phosphorylated Ser8 (pS8-Abeta). The heterodimers appear to possess the same interface as the homodimers. Simulation of 200 ns molecular dynamic trajectories in two constructed models of dimers ([Abeta1-16/Zn/Abeta1-16] and [isoAbeta1-16/Zn/Abeta1-16]), has shown that conformational flexibility of the N-terminal fragments of the dimer subunits is controlled by the structure of corresponding sites 6-8. The data suggest that isoAbeta and pS8-Abeta can be involved in the AD pathogenesis by means of their zinc-dependent interactions with endogenous Abeta resulting in the formation of heterodimeric seeds for amyloid aggregation. PMID- 26513487 TI - Protective effects of thymoquinone against apoptosis and oxidative stress by arsenic in rat kidney. AB - We aimed to investigate the protective role of thymoquinone (TQ) by targeting its antiapoptotic and antioxidant properties against kidney damage induced by arsenic in rats. We have used the 24 male Sprague-Dawley rats. Rats were divided into three groups. Physiological serum in 10 mL/kg dose as intragastric was given to the control group. Sodium arsenite (10 mg/kg, intragastric by gavage for fifteen days) was given to the arsenic group. Sodium arsenite (10 mg/kg, intragastric by gavage for fifteen days) and TQ (10 mg/kg, intragastric by gavage for 15 days) was given to the arsenic + TQ group. After 15 days, the animals' kidneys were taken theirs, then we have performed histological and apoptotic assessment. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) enzyme activities and malondialdehyde (MDA) levels have examined as the oxidative stress parameters. We have determined the levels of arsenic. Increased renal injury and apoptotic cells have been detected in the arsenic group. Degenerative changes in the arsenic + TQ group were diminished. Although the MDA levels were augmented in the arsenic group, SOD, CAT and GSH-Px enzyme activities were lessened than the other groups. Our findings suggest that TQ may impede the oxidative stress, the cells have been damaged and also the generation of apoptotic cells arisen from arsenic. TQ plays a protective role against arsenic induced toxicity in kidney and may potentially be used as a remedial agent. PMID- 26513488 TI - Obesity during pregnancy and long-term risk for ophthalmic morbidity - a population-based study with a follow-up of more than a decade. AB - OBJECTIVE: To investigate whether patients with a history of obesity during pregnancy have an increased risk for subsequent long-term ophthalmic complications, after controlling for diabetes and preeclampsia. METHODS: A population-based study compared the incidence of long-term maternal ophthalmic complications in a cohort of women with and without a history of obesity during pregnancy. Deliveries occurred between the years 1988 and 2013, with a mean follow-up duration of 12 years. RESULTS: During the study period 106 220 deliveries met the inclusion criteria; 2.2% (n = 2353) occurred in patients with a diagnosis of obesity during at least one of their pregnancies. These patients had a significantly higher incidence of ophthalmic complications in total and specifically of diabetic retinopathy. Using a Kaplan-Meier survival curve, we found that patients with a history of obesity during pregnancy had a significantly higher cumulative incidence of ophthalmic complications. Using a Cox proportional hazards model, adjusted for confounders such as maternal age, preeclampsia and diabetes mellitus, we found obesity during pregnancy remained independently associated with ophthalmic complications (adjusted HR, 2.4; 95% CI, 1.4-4.2; p = 0.003). CONCLUSION: Obesity during pregnancy is an independent risk factor for long-term ophthalmic complications, and specifically diabetic retinopathy. PMID- 26513490 TI - Relationships between transporter expression and the status of BRAF V600E mutation and F-18 FDG uptake in papillary thyroid carcinomas. AB - PURPOSE: The purpose of this study was to evaluate the expression of the glucose transporters GLUT1 and GLUT3 in papillary thyroid carcinomas (PTCs) and to elucidate their relationship with the BRAF V600E mutation and F-18 FDG uptake. MATERIALS AND METHODS: We retrospectively analyzed data of 52 PTC patients (41 women and 11 men; mean age, 52.4 +/- 14.5 years). F-18 FDG PET/CT was performed preoperatively, and the maximum standardized uptake value (SUVmax) was calculated. GLUT1/GLUT3 expression was determined immunohistochemically, and the BRAF V600E mutation was detected using DNA sequencing. RESULTS: GLUT1 and GLUT3 were expressed in 82.7% (43/52) and 59.6% (31/52) PTCs, respectively. The BRAF V600E mutation was detected in 65.4% (34/52) PTCs. The odds ratio between GLUT1 expression and the BRAF V600E mutation was 5.2 (95% CI, 1.11-24.05; p < 0.05), and that between GLUT3 expression and the BRAF V600E mutation was 3.8 (95% CI, 1.14-12.53; p < 0.05). The SUVmax of PTCs was significantly higher if they carried the BRAF V600E mutation (11.3 +/- 2.0, compared with 5.7 +/- 1.4 for wild type BRAF tumors, Mann-Whitney test, p = 0.016). Neither GLUT1 nor GLUT3 expression was significantly associated with the SUVmax of F-18 FDG PET/CT in PTCs. CONCLUSIONS: Our findings confirmed that both GLUT1 and GLUT3 are strongly expressed by PTCs, although their expression was not significantly associated with the SUVmax of F-18 FDG PET/CT. However, GLUT1 and GLUT3 expressions were significantly associated with the presence of the BRAF V600E mutation, and the SUVmax of tumors was significantly higher in the presence of the mutated BRAF gene. PMID- 26513489 TI - Antiphospholipid Antibodies and Recurrent Thrombotic Events: Persistence and Portfolio. AB - BACKGROUND: There are very limited prospective data on the significance of persistent antiphospholipid antibodies (aPL) and recurrent thrombo-occlusive events (TOEs). We investigated the prognostic value of (1) 2 newer aPL assays, (2) an aPL portfolio and (3) persistent aPL positivity following stroke. METHODS: A total of 1,770 subjects from the APASS-WARSS study underwent further aPL testing for antibodies to phosphatidylserine (aPS) and anti-beta2-glycoprotein-I (anti-beta2GPI) from stored sera. Follow-up aPL status was also tested in a subset of subjects. Primary analysis was based on time to any TOE (ischemic stroke, myocardial infarction, transient ischemic attack, deep vein thrombosis, pulmonary embolism or systemic arterial occlusion)/death at 2 years. Cox proportional hazard analyses assessed whether aPL independently related to outcome. RESULTS: Persistent anti-beta2GPI decreased the time to TOE/death after adjustment for potential confounders (hazards ratio (HR) 2.86, 95% CI 1.21-6.76, p = 0.017). When persistent anti-beta2GPI was combined with another persistently positive aPL, time to TOE/death was also reduced (HR 3.79, 95% CI 1.18-12.14, p = 0.025). Neither persistent anticardiolipin antibodies nor persistent aPS alone nor a single positive anti-beta2GPI nor aPS was associated with decreased time to TOE/death. No single positive aPL, portfolio of baseline aPL or any persistent aPL increased the rate of TOE/death. CONCLUSIONS: Rates of TOE/death were not influenced by aPL results at baseline or follow-up. Persistent anti-beta2GPI alone, and with persistent second aPL, was independently associated with decreased time to TOE/death. Persistent aPL, an aPL portfolio and newer aPL in ischemic stroke patients are not helpful in predicting an increased rate of recurrent TOEs. PMID- 26513491 TI - Risk of gastrointestinal complications in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. AB - AIM: We performed a meta-analysis of the risk of selected gastrointestinal toxicities associated with immune checkpoint inhibitors. PATIENTS & METHODS: Eligible studies included randomized trials of patients with solid tumors on ipilimumab, nivolumab, pembrolizumab, tremelimumab, pidilizumab and atezolizumab, describing events of diarrhea, vomiting or colitis. RESULTS: After exclusion of ineligible studies, a total of ten clinical trials were considered eligible for the meta-analysis. The relative risk of all-grade diarrhea, vomiting and colitis was 1.64 (95% CI: 1.19-2.26; p = 0.002), 0.72 (95% CI: 0.49-1.07; p = 0.1), 10.35 (95% CI: 5.78-18.53; p < 0.00001), respectively. CONCLUSION: Our meta-analysis has demonstrated that immune checkpoint inhibitors are associated with a significantly increased risk of all grade and high-grade colitis. PMID- 26513492 TI - Controversy Surrounding the Proposed Ocular Adverse Events of Fluoroquinolones. PMID- 26513493 TI - The longitudinal change of extracellular antioxidant status during pregnancy using an electron spin resonance method. AB - OBJECTIVE: To evaluate the longitudinal change of extracellular antioxidant status during pregnancy. METHODS: A longitudinal study involving 21 cases of pregnant women without medical disorders and had a vaginal birth was undertaken. Blood was obtained at early, mid and late pregnancy, labor onset, and postpartum day 1 and 5. We measured oxygen radical absorbance capacity (ORAC) and superoxide radical-eliminating ability (SREA) in serum using an electron spin resonance method. Twelve healthy volunteers were recruited as controls. Longitudinal and temporal changes were compared. RESULTS: ORAC increased significantly during the antepartum period (at early, mid and late pregnancy), decreased once during the peripartum period (in labor and day 1), and then recovered at day 5. SREA showed a similar tendency as ORAC. Interestingly, the ORAC of controls (919.7 +/- 48.2 umol TE/L) was significantly higher than those pregnant women at early pregnancy (early pregnancy: 699.2 +/- 127.5, p < 0.01) and day 1 (740.3 +/- 101.0, p < 0.01). The ORAC of controls was comparable to at late pregnancy and day 5 (1066.4 +/- 189.6 and 920.3 +/- 106.6, respectively). The SREA of controls (77.8 +/- 31.2 arbitrary unit) was high, but there was no significant difference against the study group. CONCLUSION: Antioxidant ability of serum clearly fluctuated during periods that may be critical, namely, early pregnancy and peripartum period. PMID- 26513494 TI - The causal epileptic network identifies the primary epileptogenic zone in Lennox Gastaut syndrome. AB - PURPOSE: Lennox-Gastaut syndrome (LGS) can be successfully treated by resective surgery in patients with a primary epileptogenic zone. This study aimed to identify the primary epileptogenic zone based on the causal epileptic network using direct directed transfer function (dDTF) analysis. METHODS: We reviewed the dDTF findings for generalized sharp and wave discharges (GSW) from the preoperative electroencephalography (EEG) of 12 LGS patients (group A) with unilateral focal pathology who were successfully treated with resective surgery. These findings were compared with preoperative dDTF findings for the GSW from 15 LGS patients with bilateral non-resectable pathology (group B) who exhibited persistent bilateral independent diffuse sharp and wave discharges, even after corpus callosotomy. RESULTS: The dDTF analysis of the GSW revealed concordant findings of localization or lateralization with the primary epileptogenic zone in 83.3% (10/12 cases) of group A patients and bilateral or multifocal localization in 93.3% (14/15) of group B patients (p<0.01). The regions identified by dDTF analysis were included in the resected areas of all patients in group A, and complete matches of the resected areas without other foci were observed in 7 patients (58.3%) in group A. The region of GSW most frequently identified by dDTF analysis was the frontal area, which was identified in 91.7% (11/12) of group A and in 100% of group B, while extra-frontal areas were identified in 36.1% and 24.5% of groups A and B, respectively. CONCLUSIONS: The dDTF analysis of GSW could provide additional information to identify resective surgery candidates for patients with LGS. PMID- 26513495 TI - The impact of cranioplasty on cerebral blood perfusion in patients treated with decompressive craniectomy for severe traumatic brain injury. AB - BACKGROUND: A large cranial defect following decompressive craniectomy (DC) is a common sequela in patients with severe traumatic brain injury (TBI). Such a defect can cause severe disturbance of cerebral blood flow (CBF) regulation. This study investigated the impact of cranioplasty on CBF in these patients. METHODS: Patients who underwent DC and secondary cranioplasty were prospectively studied for a severe TBI. CT perfusion was used to measure CBF before and after cranioplasty. The basal ganglia, parietal lobe and occipital lobe on the decompressed side were chosen as zones of interest for CBF evaluation. RESULTS: Nine patients representing nine cranioplasty procedures were included in the study. Before cranioplasty, CBF on the decompressed side was lower than that on the contralateral side. During the early stage (10 days) after cranioplasty, CBF on the decompressed side was increased and this increase was significant in the parietal and occipital lobe. CBF was also increased on the contralateral side. In addition, the difference in CBF between the contralateral side and the decompressed side was reduced after cranioplasty. Further, the CT perfusion showed that the CBFs decreased again 3 months post-cranioplasty among four cases, but was still higher than those before cranioplasty. CONCLUSIONS: This study indicates that cranioplasty may increase CBF and benefit the recovery in patients with DC for TBI. PMID- 26513496 TI - Translation regulation by ribosomes: Increased complexity and expanded scope. AB - The primary function of ribosomes is to decode mRNAs into polypeptide chains; however, this description is overly simplistic. Accumulating evidence shows that ribosomes themselves can affect the relative efficiency with which various mRNAs are translated and indicates that these effects can be modulated by ribosome heterogeneity. The notion that ribosomes have regulatory capabilities was elaborated more than a decade ago in the ribosome filter hypothesis. Various lines of evidence support this idea and have shown that the translation of some mRNAs is affected by discrete binding interactions with rRNA or ribosomal proteins. Recent work from our laboratory has demonstrated that base-pairing of the Hepatitis C Virus (HCV) internal ribosome entry site (IRES) to 18S rRNA is required for IRES function, but only in the context of more complex ribosomal interactions. The HCV IRES provides an example of the ribosome filter that involves multiple binding interactions between mRNAs and ribosomal subunits. PMID- 26513497 TI - Impact of Wet Macular Degeneration on the Execution of Natural Actions. AB - PURPOSE: To use eye movements to investigate how people with a central scotoma might be impaired in the execution of natural actions and whether task familiarity affects performance. METHODS: Sixteen participants with AMD and 16 age-matched controls performed two natural actions: (1) a familiar sandwich making task and (2) a less familiar model-building task. In each action, task relevant and task-irrelevant objects were placed on a table, covering 90 degrees . The participants were asked to execute the actions without a time constraint. Eye movements were recorded. RESULTS: The people with AMD were significantly slower than the controls, both in the exploration phase (before the first reaching movement) and in the working phase (execution of action), especially in the unfamiliar task. Gaze duration was longer on relevant than irrelevant objects in both groups and tasks, as might be expected. However, for the participants with AMD, gaze durations were longer on all of the objects, whether relevant or irrelevant, except in the more familiar task. This suggests that participants with AMD take longer to extract the information they need but that this can be counteracted when the task items are familiar. The number of saccades/min of the task was significantly greater for the people with AMD than for the controls. CONCLUSIONS: The present results show that people with AMD can accomplish natural actions efficiently, but need longer gaze durations and more eye movements than normally sighted people. This effect can be reduced when executing a familiar task. PMID- 26513498 TI - Efficacy of VIP as Treatment for Bacteria-Induced Keratitis Against Multiple Pseudomonas aeruginosa Strains. AB - PURPOSE: Previous studies have demonstrated the efficacy of vasoactive intestinal peptide (VIP) treatment in regulating inflammation following bacterial keratitis induced by the P. aeruginosa strain 19660. However, in the current study we assessed whether disease outcome is specific to 19660 or if VIP treatment is effective against multiple P. aeruginosa strains. METHODS: B6 mice received daily IP injections of VIP from -1 through 5 days post injection (p.i.). Control mice were similarly injected with PBS. Corneal infection was induced using PA 19660, PAO1 or KEI 1025. Disease response was documented and bacterial plate counts and myeloperoxidase assays were performed. Expression of select inflammatory mediators as well as enzymes associated with lipid mediator production was assessed after VIP treatment. KEI 1025 was characterized by cytotoxicity and invasion assays and then confirmed for ExoS/ExoU expression. RESULTS: VIP treatment converted the susceptible response to resistant for the three P. aeruginosa strains tested. Disease response was significantly reduced with no corneal perforation. Anti-inflammatory mediators were enhanced after VIP treatment, while pro-inflammatory molecules were reduced compared to controls. Furthermore, VIP reduced inflammatory cell persistence in the cornea after infection with each of the P. aeruginosa strains. CONCLUSIONS: VIP treatment is effective at ameliorating disease pathogenesis for multiple P. aeruginosa strains, both cytotoxic and invasive. This study is also the first to indicate a possible role for VIP regarding lipid mediator expression in the eye. In addition, the clinical isolate, KEI 1025, was characterized as an invasive strain. Overall, this study strengthens the preclinical development of VIP as a therapeutic agent for ocular infectious disease. PMID- 26513499 TI - Quantitative Analysis of Corneal Energy Dissipation and Corneal and Orbital Deformation in Response to an Air-Pulse in Healthy Eyes. AB - PURPOSE: To examine and evaluate ocular biomechanical metrics and additionally derived corneal and orbital components using a noncontact Scheimpflug-based tonometer (CorVis ST) in a population of healthy eyes. METHODS: A total of 152 eyes of 152 participants were examined by slit-lamp biomicroscopy, corneal tomography, and the CorVis ST (CST). This determined the distribution of outputs from the CST, such as deformation amplitude (DA), and additionally derived parameters, including maximum corneal deformation (MCD), maximum orbital deformation (MOD), and corneal energy dissipation (CED). RESULTS: The mean age of participants was 35.88 +/- 13.8 years. Deformation amplitude significantly correlated with age (r = 0.24, P = 0.002) but not sex or ethnicity (P > 0.05). Multiple linear regression analysis revealed significant correlations between DA and age (r = 0.19, P = 0.006) and DA and IOP (r = -0.59, P < 0.001). Age correlated with MCD (r = 0.20, P = 0.01), MOD (r = 0.18, P = 0.03), and CED (r = 0.39, P < 0.001). Males had a lower MOD than females (0.24 vs. 0.26 mm, respectively, P = 0.01); however, there were no differences in MCD or CED between sexes (P > 0.05). There were no significant differences between ethnicities for MCD, MOD, and CED (P > 0.05). Multiple linear regression analysis revealed significant correlations between MCD and IOP (r = -0.65, P < 0.001), CED and age (r = 0.41, P < 0.001), CED and IOP (r = 0.28, P = 0.001), and between CED and central corneal thickness (CCT) (r = -0.36, P < 0.001). CONCLUSIONS: The isolation of the corneal component (MCD) should be used when analyzing deformation characteristics in diseases that only affect the cornea. This study establishes a baseline for a population of healthy eyes. Future publications will identify differences in MCD, MOD, and CED between healthy and diseased populations. PMID- 26513500 TI - IGF-1 Regulates the Extracellular Level of Active MMP-2 and Promotes Muller Glial Cell Motility. AB - PURPOSE: In ischemic proliferative retinopathies, Muller glial cells (MGCs) acquire migratory abilities. However, the mechanisms that regulate this migration remain poorly understood. In addition, proliferative disorders associated with enhanced activities of matrix metalloproteinases (MMPs) also involve insulin-like growth factor (IGF)-1 participation. Therefore, the main interest of this work was to investigate the IGF-1 effect on the extracellular proteolytic activity in MGCs. METHODS: Cell culture supernatants and cell lysates of the human MGC line MIO-M1 stimulated with IGF-1 were analyzed for MMP-2 by zymographic and Western blot analysis. The MGCs' motility was evaluated by scratch wound assay. The MMP 2, beta1-integrin, and focal adhesions were detected by confocal microscopy. The localization of active MMPs and actin cytoskeleton were evaluated by in situ zymography. RESULTS: The IGF-1 induced the activation of canonical signaling pathways through the IGF-1R phosphorylation. Culture supernatants showed a relative decrease in the active form of MMP-2, correlating with an increased accumulation of MMP-2 protein in the MGCs' lysate. The IGF-1 effect on MMP-2 was abolished by an IGF-1R blocking antibody, alphaIR3, as well as by the PI3-kinase inhibitor, LY294002. The IGF-1 increased the migratory capacity of MGCs, which was blocked by the GM6001 MMP inhibitor, LY294002 and alphaIR3. Finally, IGF-1 induced the intracellular distribution of MMP-2 toward cellular protrusions and the partial colocalization with beta1-integrin and phospo-focal adhesion kinase signals. Gelatinase activity was concentrated along F-actin filaments. CONCLUSIONS: Taken together, these data indicate that IGF-1, through its receptor activation, regulates MGCs' motility by a mechanism that involves the MMP-2 and PI3K signaling pathway. PMID- 26513501 TI - In Vivo Visualization of Endoplasmic Reticulum Stress in the Retina Using the ERAI Reporter Mouse. AB - PURPOSE: Endoplasmic reticulum (ER) stress activates inositol requiring enzyme 1 (IRE1), a key regulator of the unfolded protein response. The ER stress activated indicator (ERAI) transgenic mouse expresses a yellow fluorescent GFP variant (Venus) when IRE1 is activated by ER stress. We tested whether ERAI mice would allow for real-time longitudinal studies of ER stress in living mouse eyes. METHODS: We chemically and genetically induced ER stress, and qualitatively and quantitatively studied the Venus signal by fluorescence ophthalmoscopy. We determined retinal cell types that contribute to the signal by immunohistology, and we performed molecular and biochemical assays using whole retinal lysates to assess activity of the IRE1 pathway. RESULTS: We found qualitative increase in vivo in fluorescence signal at sites of intravitreal tunicamycin injection in ERAI eyes, and quantitative increase in ERAI mice mated to RhoP23H mice expressing ER stress-inducing misfolded rhodopsin protein. As expected, we found that increased Venus signal arose primarily from photoreceptors in RhoP23H/+;ERAI mice. We found increased Xbp1S and XBP1s transcriptional target mRNA levels in RhoP23H/+;ERAI retinas compared to Rho+/+;ERAI retinas, and that Venus signal increased in ERAI retinas as a function of age. CONCLUSIONS: Fluorescence ophthalmoscopy of ERAI mice enables in vivo visualization of retinas undergoing ER stress. ER stress activated indicator mice enable identification of individual retinal cells undergoing ER stress by immunohistochemistry. ER stress activated indicator mice show higher Venus signal at older ages, likely arising from amplification of basal retinal ER stress levels by GFP's inherent stability. PMID- 26513502 TI - Pathological Effects of Mutant C1QTNF5 (S163R) Expression in Murine Retinal Pigment Epithelium. AB - PURPOSE: The mutation S163R in complement C1q tumor necrosis factor-related protein-5 (C1QTNF5) causes an autosomal dominant disorder known as late-onset retinal degeneration (L-ORD). In this study, our goal is to evaluate the consequences of mutant S163R C1QTNF5 expression in mouse RPE following its delivery using an adeno-associated viral (AAV) vector. METHODS: We generated AAV vectors containing either human wild-type C1QTNF5 or mutant S163R C1QTNF5 driven by an RPE-specific BEST1 promoter, and delivered them subretinally into one eye of adult C57BL/6 mice. Transgene expression was detected by immunohistochemistry. Retinal function was assessed by full-field ERG. Pathological changes were further examined by digital fundus imaging and spectral-domain optical coherence tomography (SD-OCT). RESULTS: We show that the AAV-expressed mutant S163R leads to pathological effects similar to some of those found in patients with advanced L-ORD, including RPE thinning, RPE cell loss, and retinal degeneration. In addition, we provide in vivo evidence that mutant S163R C1QTNF5 can form large, transparent, spherical intracellular aggregates throughout the RPE, which are detectable by light microscopy. In contrast to AAV-expressed wild-type C1QTNF5, which is secreted apically from the RPE toward the photoreceptor cells and the outer limiting membrane, the S163R mutant is primarily routed toward the basal side of RPE, where it forms thick, extracellular deposits over time. CONCLUSIONS: Adeno-associated viral-targeted expression of mutant S163R in the RPE represents a useful approach for quickly generating animal models that mimic pathological features of L-ORD and offers the potential to understand disease mechanisms and develop therapeutic strategies. PMID- 26513504 TI - Erratum. M2 Macrophages Enhance Pathological Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy. PMID- 26513503 TI - Denervation of the Lacrimal Gland Leads to Corneal Hypoalgesia in a Novel Rat Model of Aqueous Dry Eye Disease. AB - PURPOSE: Some dry eye disease (DED) patients have sensitized responses to corneal stimulation, while others experience hypoalgesia. Many patients have normal tear production, suggesting that reduced tears are not always the cause of DED sensory dysfunction. In this study, we show that disruption of lacrimal innervation can produce hypoalgesia without changing basal tear production. METHODS: Injection of a saporin toxin conjugate into the extraorbital lacrimal gland of male Sprague Dawley rats was used to disrupt cholinergic innervation to the gland. Tear production was assessed by phenol thread test. Corneal sensory responses to noxious stimuli were assessed using eye wipe behavior. Saporin DED animals were compared to animals treated with atropine to produce aqueous DED. RESULTS: Cholinergic innervation and acetylcholine content of the lacrimal gland were significantly reduced in saporin DED animals, yet basal tear production was normal. Saporin DED animals demonstrated normal eye wipe responses to corneal application of capsaicin, but showed hypoalgesia to corneal menthol. Corneal nerve fiber density was normal in saporin DED animals. Atropine-treated animals had reduced tear production but normal responses to ocular stimuli. CONCLUSIONS: Because only menthol responses were impaired, cold-sensitive corneal afferents appear to be selectively altered in our saporin DED model. Hypoalgesia is not due to reduced tear production, since we did not observe hypoalgesia in an atropine DED model. Corneal fiber density is unaltered in saporin DED animals, suggesting that molecular mechanisms of nociceptive signaling may be impaired. The saporin DED model will be useful for exploring the mechanism underlying corneal hypoalgesia. PMID- 26513505 TI - Evaluation of Fluorophotometry to Assess the Vitreal Pharmacokinetics of Protein Therapeutics. AB - PURPOSE: In this work, we assessed the ability of fluorophotometry to measure the vitreal pharmacokinetics (PK) of fluorescently-labeled ranibizumab in the rabbit after intravitreal injection. We compared these values to those obtained using enzyme-linked immunosorbent assays (ELISA). Data obtained in this study were also compared to historical ranibizumab ocular PK data, either measured in-house or previously published. METHODS: Three individual in vivo studies were performed in New Zealand White rabbits to assess the feasibility of using fluorophotometry to measure rabbit ocular PK of ranibizumab; explore the dynamic range of dosing fluorescently-labeled ranibizumab; and directly compare ranibizumab concentrations and calculated PK parameters measured by vitreal fluorophotometry to those measured using ELISA. RESULTS: In direct comparisons between fluorophotometry and ELISA, the calculated clearance (CL) values were 0.26 and 0.21 mL/day, the volumes of distribution at steady state (Vss) were 0.80 and 0.94 mL, the half-lives (t1/2) were 3.1 and 2.9 days and the dose normalized areas under the curve (AUC/D) were 4.7 and 3.9 MUg.day/mL/MUg, respectively. These values fell within the ranges of 0.13 to 0.44 mL/day for CL, 0.5 to 1.8 mL for Vss, 2.8 to 3.5 days for t1/2, and 2.3 to 7.9 MUg.day/mL/MUg for AUC/D that have been either measured previously in-house or published elsewhere. CONCLUSIONS: Although not suitable for measuring retinal concentrations, fluorophotometry is a valuable, noninvasive method to measure vitreous concentrations of protein therapeutics after intravitreal injection. PMID- 26513507 TI - Molecular simulation of low temperature argon adsorption in several models of IRMOF-1 with defects and structural disorder. AB - Defects and inclusions in metal-organic frameworks (MOFs) have captured the attention of the scientific community as a possible new source of interesting functionalities. Currently, little is known about how the presence of defects and guest molecules affects adsorptive, catalytic, mechanical and other properties of a MOF crystal and there is a clear need for a comprehensive theoretical framework. In this article we offer several conceptual models of IRMOF-1 with defects and guest molecules and explore properties of these models using computational structure characterization methods and molecular simulation of argon adsorption at 78 K. PMID- 26513506 TI - Effect of Age and Glaucoma on the Detection of Darks and Lights. AB - PURPOSE: We have shown previously that normal observers detect dark targets faster and more accurately than light targets, when presented in noisy backgrounds. We investigated how these differences in detection time and accuracy are affected by age and ganglion cell pathology associated with glaucoma. METHODS: We asked 21 glaucoma patients, 21 age-similar controls, and 5 young control observers to report as fast as possible the number of 1 to 3 light or dark targets. The targets were positioned at random in a binary noise background, within the central 30 degrees of the visual field. RESULTS: We replicate previous findings that darks are detected faster and more accurately than lights. We extend these findings by demonstrating that differences in detection of darks and lights are found reliably across different ages and in observers with glaucoma. We show that differences in detection time increase at a rate of approximately 55 msec/dB at early stages of glaucoma and then remain constant at later stages at approximately 800 msec. In normal subjects, differences in detection time increase with age at a rate of approximately 8 msec/y. We also demonstrate that the accuracy to detect lights and darks is significantly correlated with the severity of glaucoma and that the mean detection time is significantly longer for subjects with glaucoma than age-similar controls. CONCLUSIONS: We conclude that differences in detection of darks and lights can be demonstrated over a wide range of ages, and asymmetries in dark/light detection increase with age and early stages of glaucoma. PMID- 26513510 TI - "Give Sorrow Words": Working With Bereavement in Senior Residential Settings. AB - Bereavement and its consequent grief are frequent in senior residential settings. Failure to manage grief appropriately can have serious medical consequences, principally clinical depression. Focused talk with a grieving person can help ease the pain of grief; it can also help prevent complications that often lead to depression. Along with mental health professionals, staff members and volunteers can be important, and less expensive, participants in reaching this goal. PMID- 26513511 TI - Anger and Paranoia in Mentally Disordered Offenders. AB - Previous studies have identified a positive relationship between aggression and paranoia, yet the relationship between the emotion of anger and paranoia in forensic populations has not been examined. Possible confounding variables, such as social desirability and mood, should also be considered. Sixty-six participants who had a violent conviction and mental disorder completed self report questionnaires that measured anger, paranoid ideation, socially desirable responding, anxiety, and depression. The findings indicated that increased anger was associated with increased paranoia. Partial correlations showed that anger remained significantly associated with paranoia after socially desirable responding, anxiety, depression, gender, and violence history were controlled, suggesting anger and paranoia were not associated due to indirect relationships with these constructs. This could suggest that integrative psychological interventions that consider experiences of both anger and paranoia may be beneficial with forensic populations. PMID- 26513508 TI - A critical review of neonicotinoid insecticides for developmental neurotoxicity. AB - A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT). These insecticides have favorable safety profiles, due to their preferential affinity for nicotinic receptor (nAChR) subtypes in insects, poor penetration of the mammalian blood-brain barrier, and low application rates. Nevertheless, examination of this issue is warranted, due to their insecticidal mode of action and potential exposure with agricultural and residential uses. This review identified in vitro, in vivo, and epidemiology studies in the literature and studies performed in rats in accordance with GLP standards and EPA guidelines with imidacloprid, acetamiprid, thiacloprid, clothianidin, thiamethoxam, and dinotefuran, which are all the neonicotinoids currently registered in major markets. For the guideline-based studies, treatment was administered via the diet or gavage to primiparous female rats at three dose levels, plus a vehicle control (>=20/dose level), from gestation day 0 or 6 to lactation day 21. F1 males and females were evaluated using measures of motor activity, acoustic startle response, cognition, brain morphometry, and neuropathology. The principal effects in F1 animals were associated with decreased body weight (delayed sexual maturation, decreased brain weight, and morphometric measurements) and acute toxicity (decreased activity during exposure) at high doses, without neuropathology or impaired cognition. No common effects were identified among the neonicotinoids that were consistent with DNT or the neurodevelopmental effects associated with nicotine. Findings at high doses were associated with evidence of systemic toxicity, which indicates that these insecticides do not selectively affect the developing nervous system. PMID- 26513512 TI - Response and Remission After Cognitive and Exposure Therapy for Hypochondriasis. AB - Cognitive behavioral therapy has demonstrated large effect sizes for the treatment of hypochondriasis. However, response and remission rates, which provide important additional information about clinically significant improvements, have seldom been reported. In the current study, rates of response and remission after cognitive therapy and exposure therapy were evaluated. The study was based on a randomized controlled trial that treated patients with hypochondriasis (N = 75). The primary outcome measure was a clinician administered structured interview for hypochondriasis. At posttreatment, response was found for 72.0% and remission for 45.3% of the patients. At 12-month follow up, the response rate was 68.0%, and the remission rate was 54.7%. No significant differences in the frequency of response/remission were found between the cognitive therapy and the exposure therapy groups. Patients' and therapists' perspectives of clinical improvement corresponded with remission rather than response rates. Improvement rates were compared with those of other mental disorders, and implications for the treatment of hypochondriasis were discussed. PMID- 26513513 TI - "You should (not) do that": An Evaluative Model of Normative Appeals (EMNA). AB - Normative appeals refer to those messages that indicate that one should (or should not) engage in a certain action in a given situation. According to the psychosocial research, the decision to fulfill a normative appeal depends on both the extent to which it has captured our attention and the evaluation of what we may gain or lose by doing so. However, according to the Evaluative Model of Normative Appeals (EMNA), between these two processes we carry out an evaluation (normative appraisal) that strongly influences the decision that is ultimately made. Specifically, this normative appraisal, which is done in accordance with the dimensions of formality and protection, transforms the appeal into a particular normative representation (i.e., custom, coercive law, prescription, or legitimate law) that, in turn, influences the willingness toward compliance or violation. The results of three studies support these basic premises of EMNA. PMID- 26513514 TI - DICER1 deletion and 14q32 microdeletion syndrome: an additional case and a review of the literature. PMID- 26513515 TI - Mardini-Nyhan association (LACHT syndrome) with intrauterine fetal demise. PMID- 26513516 TI - Penile duplication as genital abnormality in OEIS complex: a fetal autopsy case report. PMID- 26513517 TI - The Efficacy of Vigorous-Intensity Exercise as an Aid to Smoking Cessation in Adults With High Anxiety Sensitivity: A Randomized Controlled Trial. AB - OBJECTIVES: High anxiety sensitivity predicts poor smoking cessation outcomes. Aerobic exercise reduces anxiety sensitivity and aspects of the risk conferred by anxiety sensitivity. In the current study, we examined whether exercise can aid smoking cessation in adults with high anxiety sensitivity. METHODS: Participants were sedentary and low-activity adult daily smokers (n = 136) with elevated prescreen anxiety sensitivity. Participants received 15 weeks of standard smoking cessation treatment (ST; cognitive behavioral therapy plus nicotine replacement therapy). In addition, participants were simultaneously randomized to 15 weeks of either an exercise intervention (ST + EX; n = 72) or a wellness education control condition (ST + CTRL; n = 64). Self-reported smoking abstinence was assessed weekly during the intervention, at the end of treatment (10 weeks after the target quit date), and at 4 and 6 months after the target quit date. Abstinence was verified by expired carbon monoxide readings and saliva cotinine. RESULTS: Results indicated that point prevalence abstinence (PPA) and prolonged abstinence (PA) rates were significantly higher for ST + EX than for ST + CTRL at each of the major end points among persons with high anxiety sensitivity (PPA: b = -0.91, standard error [SE] = 0.393, t(1171) = -2.33, p = .020; PA: b = -0.98, SE = 0.346, t(132) = -2.84, p = .005), but not among those with low anxiety sensitivity (PPA: b = -0.23, SE = 0.218, t(1171) = -1.06, p = .29; PA: b = -0.31, SE = 0.306, t(132) = -1.01, p = .32). CONCLUSIONS: The present results suggest that exercise facilitates the odds of quit success for smokers with high levels of anxiety sensitivity and therefore may be a useful therapeutic tactic for this high-risk segment of the smoking population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01065506. PMID- 26513518 TI - The Editors Respond. PMID- 26513519 TI - Sex and Gender Issues in Cardiovascular Research. PMID- 26513520 TI - Crystal structure of D-stereospecific amidohydrolase from Streptomyces sp. 82F2 - insight into the structural factors for substrate specificity. AB - D-Stereospecific amidohydrolase (DAH) from Streptomyces sp. 82F2, which catalyzes amide bond formation from d-aminoacyl esters and l-amino acids (aminolysis), can be used to synthesize short peptides with a dl-configuration. We found that DAH can use 1,8-diaminooctane and other amino compounds as acyl acceptors in the aminolysis reaction. Low concentrations of 1,8-diaminooctane inhibited acyl-DAH intermediate formation. By contrast, excess 1,8-diaminooctane promoted aminolysis by DAH, producing d-Phe-1,8-diaminooctane via nucleophilic attack of the diamine on enzyme-bound d-Phe. To clarify the mechanism of substrate specificity and amide bond formation by DAH, the crystal structure of the enzyme that binds 1,8 diaminooctane was determined at a resolution of 1.49 A. Comparison of the DAH crystal structure with those of other members of the S12 peptidase family indicated that the substrate specificity of DAH arises from its active site structure. The 1,8-diaminooctane molecule binds at the entrance of the active site pocket. The electrkon density map showed that another potential 1,8 diaminooctane binding site, probably with lower affinity, is present close to the active site. The enzyme kinetics and structural comparisons suggest that the location of enzyme-bound diamine can explain the inhibition of the acyl-enzyme intermediate formation, although the bound diamine is too far from the active site for aminolysis. Despite difficulty in locating the diamine binding site for aminolysis definitively, we propose that the excess diamine also binds at or near the second binding site to attack the acyl-enzyme intermediate during aminolysis. DATABASE: The coordinates and structure factors for d-stereospecific amidohydrolase have been deposited in the Protein Data Bank at the Research Collaboratory for Structural Bioinformatics under code: 3WWX. PMID- 26513521 TI - Neutrophil-to-lymphocyte ratio for predicting fibrosis in nonalcoholic fatty liver disease. PMID- 26513522 TI - Arterial stiffness in patients with celiac disease. PMID- 26513524 TI - Association of vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D levels with Crohn's disease in Chinese patients. AB - BACKGROUND AND AIM: The vitamin D receptor (VDR) regulates immune responses and inflammation through binding with 1,25-dihydroxyvitamin D, the active form of vitamin D. The serum 25-hydroxyvitamin D (25(OH)D) level clinically reflects vitamin D status in the human body. We investigated the association of VDR polymorphisms and 25(OH)D levels in Chinese patients with Crohn's disease (CD). METHODS: Vitamin D receptor polymorphisms (FokI, BsmI, ApaI, and TaqI) were genotyped by SNaPshot. Serum 25(OH)D levels were measured by electro chemiluminescence immunoassay. RESULTS: A total of 297 patients with CD and 446 controls were recruited. Compared with controls, mutant alleles and genotypes of BsmI and TaqI were less prevalent in patients with CD (all P < 0.05/4 = 0.0125). The AAC haplotype formed by BsmI, ApaI, and TaqI was also less prevalent in patients with CD (P = 0.004). Furthermore, 124 patients and 188 controls were randomly selected for measurements of 25(OH)D levels. Average 25(OH)D level was lower in patients with CD than in controls (15.46 +/- 8.11 vs 21.64 +/- 9.45 ng/mL, P < 0.001) and negatively linked to CD activity index (beta = -0.829, P < 0.001), platelet count (beta = -0.253, P < 0.001) and neutrophil percentage (beta = -0.136, P = 0.005) in patients with CD. The ApaI mutant genotype and vitamin D deficiency (<20 ng/mL) were independently associated with CD (P = 0.009, P < 0.001, respectively). In patients with CD, vitamin D deficiency interacted with FokI, ApaI, and TaqI mutant genotypes (P = 0.027, P = 0.024, and P = 0.040, respectively). CONCLUSIONS: Vitamin D receptor (BsmI, ApaI, and TaqI) mutations and lower 25(OH)D levels are associated with CD in Chinese patients. Moreover, VDR (FokI, ApaI, and TaqI) mutations and vitamin D deficiency may have a combined impact on CD. PMID- 26513526 TI - Interactions of Apolipoproteins AI, AII, B and HDL, LDL, VLDL with Polyurethane and Polyurethane-PEO Surfaces. AB - The lipoproteins (HDL, LDL, VLDL) are important components of blood present in high concentration. Surprisingly, their role in blood-biomaterial interactions has been largely ignored. In previous work apolipoprotein AI (the main protein component of HDL) was identified as a major constituent of protein layers adsorbed from plasma to biomaterials having a wide range of surface properties, and quantitative data on the adsorption of apo AI to a biomedical grade polyurethane were reported. In the present communication quantitative data on the adsorption of apo AI, apo AII and apoB (the latter being a constituent of LDL and VLDL), as well as the lipoprotein particles themselves (HDL, LDL, VLDL), to a biomedical segmented polyurethane (PU) with and without an additive containing poly(ethylene oxide) (material referred to as PEO) are reported. Using radiolabeled apo AI, apo AII, and apoB, adsorption levels on PU from buffer at a protein concentration of 50 MUg/mL were found to be 0.34, 0.40, and 0.14 MUg/cm(2) (12, 23, and 0.25 nmol/cm(2)) respectively. Adsorption to the PEO surface was <0.02 MUg/cm(2) for all three apolipoproteins demonstrating the strong protein resistance of this material. In contrast to the apolipoproteins, significant amounts of the lipoproteins were found to adsorb to the PEO as well as to the PU surface. X-ray photoelectron spectra, following exposure of the surfaces to the lipoproteins, showed a strong phosphorus signal, confirming that adsorption had occurred. It therefore appears that a PEO-containing surface that is resistant to apolipoproteins may be less resistant to the corresponding lipoproteins. PMID- 26513525 TI - Amyloid-associated Cystic Lung Disease. AB - BACKGROUND: Amyloid-associated cystic lung disease is rare. It can be associated with collagen vascular disease (CVD). We aimed to describe the clinical, radiology, and pathology findings of this entity. METHODS: We reviewed the records of subjects having biopsy-proven pulmonary amyloidosis with cystic lung disease demonstrated at high-resolution computed tomography (HRCT). Demographic characteristics, association with CVD and lymphoproliferative disorders, pulmonary function, and pathology results were reviewed. HRCT appearance was analyzed for number, size, distribution, and morphology of cysts and nodules. RESULTS: Twenty-one subjects (13 female, eight male; median age, 61 years) with cystic pulmonary amyloidosis were identified. The most common pulmonary function patterns were normal (42%) and obstructive (32%). The most common associated CVD was Sjogren syndrome (10 of 12). Nine subjects had no CVD. Cysts tended to be multiple (>= 10 in 14 of 21, 67%), round (21 of 21, 100%), or lobulated (20 of 21, 95%); thin-walled (< 2 mm in 17 of 21, 81%); and of small (< 1 cm in 21 of 21, 100%) to moderate (1-2 cm in 17 of 21, 81%) size. Peribronchovascular (19 of 21, 90%) and subpleural (19 of 21, 90%) cysts were typically present. Seventeen (81%) subjects had lung nodules, which tended to be numerous (>= 10 in 10 of 17, 59%; 4-9 in six of 17, 35%). At least one calcified nodule was present in 14 of 17 subjects (82%). Pulmonary mucosa-associated lymphoid tissue lymphoma (MALToma) was diagnosed in seven subjects (33%). CONCLUSIONS: Amyloid-associated cystic lung disease can occur with or without underlying CVD. Cystic lesions in the lung are commonly numerous, often are peribronchovascular or subpleural, and are frequently associated with nodular lesions that are often calcified. MALToma was a relatively frequent association. PMID- 26513527 TI - Environmental variables across Pan troglodytes study sites correspond with the carbon, but not the nitrogen, stable isotope ratios of chimpanzee hair. AB - Diet influences the stable isotope ratios of carbon and nitrogen (delta(13) C and delta(15) N values) in animal tissue; but here we explore the influences of particular aspects of the local environment on those values in chimpanzees (Pan troglodytes). In this article we present new delta(13) C and delta(15) N values in Gombe chimpanzees using hairs collected from night nests in 1989. Then, we explore the influence of environmental factors by comparing our Gombe data to those from eight additional Pan study sites with previously published stable isotope data. We compare chimpanzee delta(13) Chair and delta(15) Nhar values to specific characteristics of local site ecology (biome and ecoregion) and to local Mean Annual Precipitation (MAP) to test hypotheses based on known effects of these variables on the delta(13) C and delta(15) N values in plant tissues. The comparison shows that hair from chimpanzees living in savanna sites with lower MAP have higher delta(13) Chair values than do chimpanzees living in woodland and forested sites with higher MAP. These results demonstrate the potential of using delta(13) C values in primate tissue to indicate aspects of their local ecology in cases where the ecology is uncertain, such as samples collected early in the last century and in fossil hominins. In contrast to expectations, however, chimpanzee delta(15) Nhair values from some savanna sites with lower MAP are lower, not higher, than those living in more forested areas with higher MAP. It is likely that diet selectivity by chimpanzees affects delta(15) Nhair values to a greater extent than does the influence of precipitation on plants. Am. J. Primatol. 78:1055-1069, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26513528 TI - Sulfur decreases cadmium translocation and enhances cadmium tolerance by promoting sulfur assimilation and glutathione metabolism in Brassica chinensis L. AB - We investigated the ameliorative role of sulfur (S) in protecting plants against cadmium (Cd) toxicity by using two pakchoi (Brassica chinensis L.) cultivars with different Cd tolerance levels. The exposure of pakchoi seedlings to 100MUM Cd inhibited plant growth, increased superoxide content, enhanced membrane lipid peroxidation, and induced Cd accumulation in the roots and shoots. Application of S to Cd-stressed plants alleviated Cd-induced oxidative stress by promoting the capacity of the ascorbate (AsA)-glutathione (GSH) cycle, enhanced S assimilation by increasing the activity of ATP sulfurylase (ATPS) and o acetylserine(thiol)lyase (OASTL), and decreased Cd translocation from the roots to the shoots by enhancing phytochelatins (PCs) biosynthesis. Results suggested that S reversed Cd-induced growth inhibition and oxidative stress by restraining Cd translocation from the roots to the shoots and upregulating S assimilation and GSH metabolism, including the AsA-GSH cycle and PCs synthesis. PMID- 26513529 TI - Uptake of azoles by lamb's lettuce (Valerianella locusta L.) grown in hydroponic conditions. AB - An uptake and translocation study of azole compounds was performed in lamb's lettuce (Valerianella locusta L.) grown in nutrient solution fortified with different azoles. Three azoles, (clotrimazole, fluconazole and propiconazole), which have different physico-chemical properties and are ubiquitous in the aquatic environment, were the compounds selected. An analytical method, based on matrix solid phase dispersion (MSPD) followed by LC-MS/MS determination, was developed to quantify these compounds in aqueous solution and in roots and leaves. The physicochemical properties of azoles are the main factors governing the uptake and plant accumulation. These azoles were detected in leaves indicating their transport within lamb's lettuce. Translocation from nutrient solution to the aerial part of lamb's lettuce was found to be highly dependent on the hydrophobicity of the azole. Clotrimazole accumulates in roots causing necrosis in roots and leaves, whereas fluconazole was the azole with the highest concentration in leaves without causing apparent phytotoxicity symptoms. The assessment of the levels of these azoles in leaves indicates that the risk for human health is negligible. PMID- 26513530 TI - Increased formation of halomethanes during chlorination of chloramphenicol in drinking water by UV irradiation, persulfate oxidation, and combined UV/persulfate pre-treatments. AB - Ultraviolet/persulfate (UV/PS) has been widely used to generate sulfate radicals for degradation of water organic pollutants in previous studies. However, its impacts on disinfection byproduct formation during post-chlorination of degraded compounds is unclear. The objective of this study was to evaluate the impacts of UV irradiation, PS oxidation, and the combined UV/PS advanced oxidation process (AOP) pre-treatments on halomethane formation during the following chlorination of chloramphenicol (CAP), a model antibiotic commonly found in wastewater impacted water. Results showed that CAP could be transformed to more trichloromethane (TCM) than monochloromethane (MCM) and dichloromethane (DCM) in the presence of excess chlorine. UV photolysis, PS oxidation and UV/PS AOP all directly decomposed CAP to produce halomethanes (HMs) before post-chlorination. Moreover, UV and UV/PS pre-treatments both enhanced the formation of all the HMs in the subsequent chlorination. PS pre-oxidation decreased the TCM formation during post-chlorination, but increased the yields of MCM, DCM and total HMs. UV pre-irradiation significantly increased the bromide utilization of HMs, whereas UV/PS pre-oxidation decreased the bromine incorporation and utilization of HMs from the chlorination of CAP in a low-bromide water. UV irradiation, PS oxidation, and UV/PS AOP can inactivate pathogens and degrade organic pollutants, but this benefit should be weighed against a potential risk of the increased halomethane formation from degraded organic pollutants with and without post chlorination. PMID- 26513531 TI - Human health risk assessment of mercury vapor around artisanal small-scale gold mining area, Palu city, Central Sulawesi, Indonesia. AB - Emissions of elemental mercury, Hg(0), from artisanal small-scale gold mining activities accounted for 37% of total global Hg(0) emissions in 2010. People who live near gold-mining areas may be exposed to high concentrations of Hg(0). Here, we assessed the human health risk due to Hg(0) exposure among residents of Palu city (Central Sulawesi Province, Indonesia). The area around the city has more than 60t of gold reserves, and the nearby Poboya area is the most active gold mining site in Indonesia. Owing to its geography, the city experiences alternating land and sea breezes. Sampling was done over a period of 3 years (from 2010 Aug. to 2012 Dec.) intermittently with a passive sampler for Hg(0), a portable handheld mercury analyzer, and a mercury analyzer in four areas of the city and in the Poboya gold-processing area, as well as wind speeds and directions in one area of the city. The 24-h average concentration, wind speed, and wind direction data show that the ambient air in both the gold-processing area and the city was always covered by high concentration of mercury vapor. The Hg(0) concentration in the city was higher at night than in the daytime, owing to the effect of land breezes. These results indicate that the inhabitants of the city were always exposed to high concentrations of Hg(0). The average daytime point-sample Hg(0) concentrations in the city, as measured with a handheld mercury analyzer over 3 days in July 2011, ranged from 2096 to 3299ngm(-3). In comparison, the average daytime Hg(0) concentration in the Poboya gold-processing area was 12,782ngm(-3). All of these concentrations are substantially higher than the World Health Organization air-quality guideline for annual average Hg exposure (1000ngm(-3)). We used the point-sample concentrations to calculate hazard quotient ratios by means of a probabilistic risk assessment method. The results indicated that 93% of the sample population overall was at risk (hazard quotient ratio >=1 and cut off at the 95th percentile value of the sample population) of mercury toxicity, that is, damage to the central nervous system due to chronic exposure. The corresponding percentages for the northern, central, southern, and western areas of the city were 83%, 84%, 95%, and 95%, respectively. Our results indicate that the residents of Palu city are at serious risk from exposure to high concentrations of atmospheric Hg(0). PMID- 26513532 TI - Nonfullerene Polymer Solar Cells with 8.5% Efficiency Enabled by a New Highly Twisted Electron Acceptor Dimer. AB - Fullerene-free and processing additive-free 8.5% efficient polymer solar cells are achieved by using a new 3,4-ethylenedioxythiophene-linked arylene diimide dimer with a 76 degrees twist angle. The devices combine high (78-83%) external quantum efficiency with high (0.91-0.95 V) photovoltages and thus have relatively low optical bandgap energy loss. PMID- 26513533 TI - Escape from the competence state in Streptococcus mutans is governed by the bacterial population density. AB - Horizontal gene transfer through natural DNA transformation is an important evolutionary mechanism among bacteria. Transformation requires that the bacteria are physiologically competent to take and incorporate free DNA directly from the environment. Although natural genetic transformation is a remarkable feature of many naturally competent bacteria, the process is energetically expensive for the cells. Consequently, a tight control of the competence state is necessary. The objective of the present work was to help decipher the molecular mechanisms regulating the escape from the competence state in Streptococcus mutans, the principal etiological agent responsible for tooth decay in humans. Our results showed that the cessation of competence in S. mutans was abrupt, and did not involve the accumulation of a competence inhibitor nor the depletion of a competence activator in the extracellular environment. The competence state was repressed at high cell population density via concomitant repression of sigX gene encoding the master regulator of the competence regulon. Co-culture experiments performed with oral and non-oral bacteria showed that S. mutans assesses its own population density and also the microbial density of its surroundings to regulate its competence escape. Interestingly, neither the intra-species and extra-species quorum-sensing systems nor the other 13 two-component regulatory systems identified in S. mutans were involved in the cell-density-dependent escape of the competence state. Altogether, our results suggest a complex mechanism regulating the competence shut-off involving cell-density-dependent repression of sigX through an as yet undefined system, and possibly SigX protein stability. PMID- 26513534 TI - Update on Multistate Outbreak of Fungal Infections Associated with Contaminated Methylprednisolone Injections, 2012-2014. AB - During September 2012, CDC, in collaboration with state and local health departments and the Food and Drug Administration (FDA), investigated a multistate outbreak of fungal meningitis and other infections caused by injections of contaminated methylprednisolone acetate solution (MPA). After this unprecedented outbreak, scientists in the CDC Mycotic Diseases Branch, along with infectious diseases specialists who cared for patients from the outbreak, clinical experts, and public health officials from affected states, have continued to monitor the recovery of affected patients. A long-term follow-up study involving these patients was initiated and is being conducted by the Mycoses Study Group Education and Research Consortium (MSGERC). This update summarizes subsequent information about the current state of the outbreak. PMID- 26513535 TI - A Selective Association between Central and Peripheral Lithium Levels in Remitters in Bipolar Depression: A 3T-(7) Li Magnetic Resonance Spectroscopy Study. AB - OBJECTIVE: The objective of this study was to evaluate brain lithium levels using (7) Li magnetic resonance spectroscopy after 6 weeks of lithium therapy in bipolar depression to test the hypothesis that brain and plasma lithium are correlated. It was also tested whether responders and remitters have different pharmacokinetics, blood and brain lithium levels (ratio) compared with those presenting suboptimal antidepressant improvement. METHOD: Twenty-three patients with bipolar disorder (I and II) during depressive episodes were included and followed up for 6 weeks at the University of Sao Paulo using flexible dose of lithium (450-900 mg/day). Sixteen patients were drug-naive. At endpoint, patients underwent a (7) Li-MRS scan and brain lithium concentrations were calculated. RESULTS: A significant association between central and peripheral lithium levels was found only in remitters (r = 0.7, P = 0.004) but not in non-remitters (r = 0.12, P = 0.76). Also, brain lithium (but not plasma) was inversely correlated with age (r = -0.46, P = 0.025). Plasma lithium did not correlate with any clinical outcome, lithium dosage or adverse effects. CONCLUSION: These findings suggest that non-remitters may not transport lithium properly to the brain, which may underlie treatment resistance to lithium in BD. Future studies with (7) Li MRS integrated with the evaluation of blood-brain barrier transport mechanisms and longitudinal clinical outcomes in BD and aging are warranted. PMID- 26513536 TI - Selective CD28 antagonist prevents Aldara-induced skin inflammation in non-human primates. PMID- 26513537 TI - Lyotropic Cubic Phases for Drug Delivery: Diffusion and Sustained Release from the Mesophase Evaluated by Electrochemical Methods. AB - Lyotropic liquid crystalline systems are excellent carriers for drugs due to their biocompatibility, stability in aqueous environment, and well-defined structure that allow them to host significantly larger amounts of drugs than carriers such as liposomes or gold nanoparticles. Incorporating the drug within the mesophase gel, or the cubosome/hexosome nanoparticles, decreased its toxic effects toward healthy cells, while appropriate mechanisms can stimulate the release of the drug from the carrier when it approaches the cancerous cell environment. Electrochemical methods-chronocoulometry and voltammetry at micro and normal size electrodes-are used for the first time to simultaneously determine the diffusion coefficients and effective concentrations of a toxic anticancer drug, doxorubicin, in the channels of three liquid-crystalline lipidic cubic phases. This approach was instrumental in demonstrating that the drug diffusion and kinetics of release from the mesophases depend on the aqueous channel size, which in turn is related to the identity and structure of the amphiphilic molecules used for the formation of the mesophase. Structural parameters of the cubic phases with the incorporated drug were characterized by small-angle X-ray scattering (SAXS), and molecular dynamics simulations were applied in order to describe the differences in the distribution of doxorubicin in the cubic phase matrix at acidic and neutral pH. The release of the drug from the phase was retarded at physiological pH, while at lower pH, corresponding to the cancer environment, it was accelerated, provided that suitable amphiphilic molecules were employed for the construction of the liquid crystal drug delivery system. PMID- 26513538 TI - Advances in the pharmacologic treatment of ventricular arrhythmias. AB - INTRODUCTION: Despite many advances in nonpharmacologic management of ventricular arrhythmias, antiarrhythmic drugs remain important in both the acute conversion and chronic prevention of ventricular arrhythmias. AREAS COVERED: Key trials related to antiarrhythmic drug use are reviewed, emphasizing the impact of recent discoveries. Sodium channel blockers are discussed with an emphasis on recently identified specialized uses. Beta blockers, amiodarone, sotalol, and dofetilide are discussed together in the context of structural heart disease, because they do not increase mortality in this group of patients. Other medications found to reduce ventricular arrhythmia burden are discussed last. EXPERT OPINION: Since most patients with ventricular arrhythmias have structural heart disease, pharmacologic treatment is limited to amiodarone, d-,l-sotalol, and dofetilide (off-label indication), in conjunction with defibrillator implantation. While amiodarone has superior reduction in arrhythmias, its long-term extracardiac toxicities can cause significant morbidity. A trial of sotalol is reasonable if there are no contraindications, recognizing that over 20% of patients have to discontinue it because of adverse effects. Beta blockers are first line therapy for most patients. Genetic testing is particularly informative regarding treatment approach in long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic VT. Research should continue to focus on developing more effective antiarrhythmic medications with less long-term toxicity. PMID- 26513539 TI - Magnetic Interactions in the Double Perovskites R2NiMnO6 (R = Tb, Ho, Er, Tm) Investigated by Neutron Diffraction. AB - R2NiMnO6 (R = Tb, Ho, Er, Tm) perovskites have been prepared by soft-chemistry techniques followed by high oxygen-pressure treatments; they have been investigated by X-ray diffraction, neutron powder diffraction (NPD), and magnetic measurements. In all cases the crystal structure is defined in the monoclinic P21/n space group, with an almost complete order between Ni(2+) and Mn(4+) cations in the octahedral perovskite sublattice. The low temperature NPD data and the macroscopic magnetic measurements indicate that all the compounds are ferrimagnetic, with a net magnetic moment different from zero and a distinct alignment of Ni and Mn spins depending on the nature of the rare-earth cation. The magnetic structures are different from the one previously reported for La2NiMnO6, with a ferromagnetic structure involving Mn(4+) and Ni(2+) moments. This spin alignment can be rationalized taking into account the Goodenough Kanamori rules. The magnetic ordering temperature (TCM) decreases abruptly as the size of the rare earth decreases, since TCM is mainly influenced by the superexchange interaction between Ni(2+) and Mn(4+) (Ni(2+)-O-Mn(4+) angle) and this angle decreases with the rare-earth size. The rare-earth magnetic moments participate in the magnetic structures immediately below TCM. PMID- 26513540 TI - Heat and desiccation are the predominant factors affecting inactivation of Bacillus licheniformis and Bacillus thuringiensis spores during simulated composting. AB - AIMS: The suitability of composting for disposal of livestock mortalities due to Bacillus anthracis was assessed by measuring viability of surrogate spores from two strains each of Bacillus licheniformis and Bacillus thuringiensis after a heating cycle modelled on a cattle composting study. METHODS AND RESULTS: Sporulation was attempted from 10 to 37 degrees C, but poor yields at lower temperatures resulted in 25, 30 and 37 degrees C being selected to generate sufficient spores (8 log10 CFU ml(-1) ) for experiments. Spores were inoculated into 3 g autoclaved dried-ground compost rehydrated with 6 ml water or silica beads in a factorial design for each strain, sporulation temperature, matrix and sampling day (0, 25, 50, 100, 150). Maximum incubation temperature was 62 degrees C, but spores were maintained at >=55 degrees C for 78 of 150 days. Although significant differences existed among Bacillus strains and sporulation temperatures, numbers of viable spores after 150 days averaged 1.3 log10 CFU g( 1) , a 5.2 log10 reduction from day 0. CONCLUSIONS: Spore inactivation was likely due to heat and desiccation as matrices were autoclaved prior to incubation, negating impacts of microflora. SIGNIFICANCE AND IMPACT OF STUDY: Results support composting for disposal of anthrax mortalities, provided long-term thermophillic heating is achieved. Due to limited sporulation at 10 degrees C, livestock mortalities from anthrax at this or lower ambient temperatures would likely be of lower risk for disease transmission. PMID- 26513541 TI - Mental wellness in Canada's Aboriginal communities: striving toward reconciliation. PMID- 26513542 TI - Treatment-resistant depression in later life. PMID- 26513543 TI - Exit exceptionalism: mental disease is like any other medical disease. PMID- 26513544 TI - Exit exceptionalism: mental disease is like any other medical disease - Author response. PMID- 26513545 TI - Total Synthesis and Tentative Structural Elucidation of Cryptomoscatone E3: Interplay of Experimental and Computational Studies. AB - A successful combination of computational chemistry and total synthesis was explored to tentatively elucidate the absolute configuration of cryptomoscatone E3, a polyketide isolated from the Brazilian tree Cryptocarya mandiocanna. Two independent synthetic approaches are discussed based on asymmetric allylation, ring closing metathesis, and aldol reactions. PMID- 26513546 TI - Essure a novel option for the treatment of hydrosalpinx: a case series and literature review. AB - OBJECTIVE: The aim of this study is to evaluate the use of hysteroscopic Essure device placement for the treatment of hydrosalpinx (HS)-related infertility in patients with laparoscopic contraindications and compared their pregnancy outcomes following IVF-ICSI treatment with those patients having had laparoscopic tubal occlusion (LTO). PATIENTS: From 2008 to 2014 a total of 50 patients were diagnosed with unilateral or bilateral hydrosalpinges: 29 patients had laparoscopic contraindications and were treated hysteroscopically and 21 patients were treated with laparoscopical salpingectomy. RESULTS: Of the 29 patients who underwent treatment with Essure((r)), 21 began a cycle of in vitro fertilization (IVF), and 13 finished in embryo transfer that resulted in seven clinical pregnancies. Furthermore, in the group of women treated with salpingectomy, 17 started an IVF cycle that resulted in 12 clinical pregnancies. The clinical pregnancy rate per patient with an IVF cycle started was 33.3% and 70.6%, the live-birth rate per patient was 14.3% and 52.9%, the miscarriage rate was 57.1% and 18.2%, and the implantation rate was 16.3% and 34.1% for hysteroscopy and laparoscopy, respectively. CONCLUSION: Essure((r)) placement is an alternative method for occlusion of hydrosalpinges before IVF. Monitoring the live-birth rate confirms that this option may be considered when laparoscopy is impossible or contraindicated. PMID- 26513547 TI - Genetic differentials of child abuse: Is your case rare or real? AB - The clinical geneticist can be called upon to play a role in the medical evaluation of children with clinical findings concerning for child abuse. This Introduction describes a case of suspected child abuse in an 8-month-old baby referred to clinical genetics to exclude osteogenesis imperfecta. The experience from this case raised medical and ethical considerations and prompted consideration of the role of the clinical geneticist in distinguishing rare mimics of child abuse from real cases. From this single case, and a discussion regarding similar cases, arose the idea of this issue in Seminars in Medical Genetics, Genetic Differentials of Child Abuse: Is Your Case Rare or Real? In thinking about child abuse from a clinical genetics perspective, we categorize clinical presentations into fractures, skin lesions, hemorrhage, growth disturbances, and concern for caregiver-fabricated illness (previously known as Munchausen syndrome by proxy). In this Introduction, we also discuss recent questions regarding Ehlers-Danlos syndrome and infantile fractures and concerns about caregiver-fabricated illness in the context of mitochondrial or other rare diseases. The goal is that this issue on child abuse and genetics will serve as a resource to help distinguish the rare causes from the real cases of child abuse, and those critical distinctions and correct diagnoses may be life-saving for some infants and children. PMID- 26513548 TI - BrowserGenome.org: web-based RNA-seq data analysis and visualization. PMID- 26513549 TI - TransVar: a multilevel variant annotator for precision genomics. PMID- 26513550 TI - Avoiding abundance bias in the functional annotation of post-translationally modified proteins. PMID- 26513551 TI - Nanopores: a sequencer in your backpack. PMID- 26513552 TI - Detecting nano-scale protein clustering. PMID- 26513554 TI - In Vivo Differentiation of Therapeutic Insulin-Producing Cells from Bone Marrow Cells via Extracellular Vesicle-Mimetic Nanovesicles. AB - The current diabetes mellitus pandemic constitutes an important global health problem. Reductions in the mass and function of beta-cells contribute to most of the pathophysiology underlying diabetes. Thus, physiological control of blood glucose levels can be adequately restored by replacing functioning beta-cell mass. Sources of functional islets for transplantation are limited, resulting in great interest in the development of alternate sources, and recent progress regarding cell fate change via utilization of extracellular vesicles, also known as exosomes and microvesicles, is notable. Thus, this study investigated the therapeutic capacity of extracellular vesicle-mimetic nanovesicles (NVs) derived from a murine pancreatic beta-cell line. To differentiate insulin-producing cells effectively, a three-dimensional in vivo microenvironment was constructed in which extracellular vesicle-mimetic NVs were applied to subcutaneous Matrigel platforms containing bone marrow (BM) cells in diabetic immunocompromised mice. Long-term control of glucose levels was achieved over 60 days, and differentiation of donor BM cells into insulin-producing cells in the subcutaneous Matrigel platforms, which were composed of islet-like cell clusters with extensive capillary networks, was confirmed along with the expression of key pancreatic beta-cell markers. The resectioning of the subcutaneous Matrigel platforms caused a rebound in blood glucose levels and confirmed the source of functioning beta-cells. Thus, efficient differentiation of therapeutic insulin producing cells was attained in vivo through the use of extracellular vesicle mimetic NVs, which maintained physiological glucose levels. PMID- 26513553 TI - Focused ion beams in biology. AB - A quiet revolution is under way in technologies used for nanoscale cellular imaging. Focused ion beams, previously restricted to the materials sciences and semiconductor fields, are rapidly becoming powerful tools for ultrastructural imaging of biological samples. Cell and tissue architecture, as preserved in plastic-embedded resin or in plunge-frozen form, can be investigated in three dimensions by scanning electron microscopy imaging of freshly created surfaces that result from the progressive removal of material using a focused ion beam. The focused ion beam can also be used as a sculpting tool to create specific specimen shapes such as lamellae or needles that can be analyzed further by transmission electron microscopy or by methods that probe chemical composition. Here we provide an in-depth primer to the application of focused ion beams in biology, including a guide to the practical aspects of using the technology, as well as selected examples of its contribution to the generation of new insights into subcellular architecture and mechanisms underlying host-pathogen interactions. PMID- 26513556 TI - Doxycycline supplementation allows for the culture of human ESCs/iPSCs with media changes at 3-day intervals. AB - Culturing human embryonic stem and induced pluripotent stem cells (hESCs/iPSCs) is one of the most costly and labor-intensive tissue cultures, as media containing expensive factors/cytokines should be changed every day to maintain and propagate undifferentiated hESCs/iPSCs in vitro. We recently reported that doxycycline, an anti-bacterial agent, had dramatic effects on hESC/iPSC survival and promoted self-renewal. In this study, we extended the effects of doxycycline to a more practical issue to save cost and labor in hESC/iPSC cultures. Regardless of cultured cell conditions, hESCs/iPSCs in doxycycline-supplemented media were viable and proliferating for at least 3 days without media change, while none or few viable cells were detected in the absence of doxycycline in the same conditions. Thus, hESCs/iPSCs supplemented with doxycycline can be cultured for a long period of time with media changes at 3-day intervals without altering their self-renewal and pluripotent properties, indicating that doxycycline supplementation can reduce the frequency of media changes and the amount of media required by 1/3. These findings strongly encourage the use of doxycycline to save cost and labor in culturing hESCs/iPSCs. PMID- 26513555 TI - MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells. AB - Neural stem cell (NSC)-based carriers have been presented as promising therapeutic tools for the treatment of infiltrative brain tumors due to their intrinsic tumor homing property. They have demonstrated the ability to migrate towards distant tumor microsatellites and effectively deliver the therapeutic payload, thus significantly improving survival in experimental animal models for brain tumor. Despite such optimistic results, the efficacy of NSC-based anti cancer therapy has been limited due to the restricted tumor homing ability of NSCs. To examine this issue, we investigated the mechanisms of tumor-tropic migration of an FDA-approved NSC line, HB1.F3.CD, by performing a gene expression analysis. We identified vascular endothelial growth factor-A (VEGFA) and membrane bound matrix metalloproteinase (MMP14) as molecules whose expression are significantly elevated in migratory NSCs. We observed increased expression of VEGF receptor 2 (VEGFR2) in the focal adhesion complexes of migratory NSCs, with downstream activation of VEGFR2-dependent kinases such as p-PLCgamma, p-FAK, and p-Akt, a signaling cascade reported to be required for cellular migration. In an in vivo orthotopic glioma xenograft model, analysis of the migratory trail showed that NSCs maintained expression of VEGFR2 and preferentially migrated within the perivascular space. Knockdown of VEGFR2 via shRNAs led to significant downregulation of MMP14 expression, which resulted in inhibited tumor-tropic migration. Overall, our results suggest, the involvement of VEGFR2-regulated MMP14 in the tumor-tropic migratory behavior of NSCs. Our data warrant investigation of MMP14 as a target for enhancing the migratory properties of NSC carriers and optimizing the delivery of therapeutic payloads to disseminated tumor burdens. PMID- 26513557 TI - Osteogenic differentiation of mesenchymal stem cells from dental bud: Role of integrins and cadherins. AB - Several studies have reported the beneficial effects of mesenchymal stem cells (MSCs) in tissue repair and regeneration. New sources of stem cells in adult organisms are continuously emerging; dental tissues have been identified as a source of postnatal MSCs. Dental bud is the immature precursor of the tooth, is easy to access and we show in this study that it can yield a high number of cells with >=95% expression of mesenchymal stemness makers and osteogenic capacity. Thus, these cells can be defined as Dental Bud Stem Cells (DBSCs) representing a promising source for bone regeneration of stomatognathic as well as other systems. Cell interactions with the extracellular matrix (ECM) and neighboring cells are critical for tissue morphogenesis and architecture; such interactions are mediated by integrins and cadherins respectively. We characterized DBSCs for the expression of these adhesion receptors and examined their pattern during osteogenic differentiation. Our data indicate that N-cadherin and cadherin-11 were expressed in undifferentiated DBSCs and their expression underwent changes during the osteogenic process (decreasing and increasing respectively), while expression of E-cadherin and P-cadherin was very low in DBSCs and did not change during the differentiation steps. Such expression pattern reflected the mesenchymal origin of DBSCs and confirmed their osteoblast-like features. On the other hand, osteogenic stimulation induced the upregulation of single subunits, alphaV, beta3, alpha5, and the formation of integrin receptors alpha5beta1 and alphaVbeta3. DBSCs differentiation toward osteoblastic lineage was enhanced when cells were grown on fibronectin (FN), vitronectin (VTN), and osteopontin (OPN), ECM glycoproteins which contain an integrin-binding sequence, the RGD motif. In addition we established that integrin alphaVbeta3 plays a crucial role during the commitment of MSCs to osteoblast lineage, whereas integrin alpha5beta1 seems to be dispensable. These data suggest that functionalization of biomaterials with such ECM proteins would improve bone reconstruction therapies starting from dental stem cells. PMID- 26513558 TI - Au/BiOCl heterojunction within mesoporous silica shell as stable plasmonic photocatalyst for efficient organic pollutants decomposition under visible light. AB - A new mesoporous silica protected plasmonic photocatalyst, Au/BiOCl@mSiO2, was prepared by a modified AcHE method and a subsequent UV light induced photodeposition process. The surfactant-free heterojunction allows the electrons spontaneously flow from Au to nearby BiOCl surface, leading to the accumulation of positive charges on Au surface, and negative charges on Bi species under visible light. Au/BiOCl@mSiO2 exhibits high visible light photocatalytic efficiency in complete oxidation of aqueous formaldehyde and Rhodamin B. We showed that a positive relationship exists between the LSPR effect and rate enhancements, and leads to a hypothesis that the metallic Au LSPR enhances the photocatalytic rates on nearby semiconductors by transferring energetic electrons to BiOCl and increasing the steady-state concentration of active OH species by a multi-electron reduction of molecular oxygen. The OH species is the main oxidant in photocatalytic transformations, whose intensity is greatly enhanced in the dye involving systems due to the synergetic effect between LSPR and dye sensitization processes. In addition, the mesoporous SiO2 shell not only inhibits the over growth of BiOCl nanocrystals within the silica frameworks, but also protects the dissolution of chloride or Au species into aqueous solution, which ultimately makes the Au/BiOCl@mSiO2 catalysts rather stable during photocatalysis. PMID- 26513559 TI - Aluminium fumarate metal-organic framework: A super adsorbent for fluoride from water. AB - Potential of aluminium fumarate metal organic framework (MOF) for fluoride removal from groundwater has been explored in this work. The laboratory produced MOF exhibited characteristics similar to the commercial version. MOF was found to be micro-porous with surface area of 1156 m(2)/g and average pore size 17A. Scanning electron micrograph of the AlFu MOF showed minute pores and texture was completely different from either of the parent materials. Change in the composition of AlFu MOF after fluoride adsorption was evident from powder X-ray diffraction analysis. Thermal stability of the AlFu MOF up to 700K was established by thermo-gravimetric analysis. Incorporation of fluoride phase after adsorption was confirmed by X-ray fluorescence analysis. As observed from FTIR study, hydroxyl ions in AlFu MOF were substituted by fluoride. 0.75 g/l AlFu MOF was good enough for complete removal of 30 mg/l fluoride concentration in feed solution. The maximum adsorption capacity for fluoride was 600, 550, 504 and 431 mg/g, respectively, at 293, 303, 313 and 333K. PMID- 26513561 TI - A Quantitative Structure Activity Relationship for acute oral toxicity of pesticides on rats: Validation, domain of application and prediction. AB - Quantitative Structure Activity Relationship (QSAR) models are expected to play an important role in the risk assessment of chemicals on humans and the environment. In this study, we developed a validated QSAR model to predict acute oral toxicity of 329 pesticides to rats because a few QSAR models have been devoted to predict the Lethal Dose 50 (LD50) of pesticides on rats. This QSAR model is based on 17 molecular descriptors, and is robust, externally predictive and characterized by a good applicability domain. The best results were obtained with a 17/9/1 Artificial Neural Network model trained with the Quasi Newton back propagation (BFGS) algorithm. The prediction accuracy for the external validation set was estimated by the Q(2)ext and the root mean square error (RMS) which are equal to 0.948 and 0.201, respectively. 98.6% of external validation set is correctly predicted and the present model proved to be superior to models previously published. Accordingly, the model developed in this study provides excellent predictions and can be used to predict the acute oral toxicity of pesticides, particularly for those that have not been tested as well as new pesticides. PMID- 26513560 TI - Derivation of soil thresholds for lead applying species sensitivity distribution: A case study for root vegetables. AB - The combination of food quality standard and soil-plant transfer models can be used to derive critical limits of heavy metals for agricultural soils. In this paper, a robust methodology is presented, taking the variations of plant species and cultivars and soil properties into account to derive soil thresholds for lead (Pb) applying species sensitivity distribution (SSD). Three species of root vegetables (four cultivars each for radish, carrot, and potato) were selected to investigate their sensitivity differences for accumulating Pb through greenhouse experiment. Empirical soil-plant transfer model was developed from carrot New Kuroda grown in twenty-one soils covering a wide variation in physicochemical properties and was used to normalize the bioaccumulation data of non-model cultivars. The relationship was then validated to be reliable and would not cause over-protection using data from field experimental sites and published independent studies. The added hazardous concentration for protecting 95% of the cultivars not exceeding the food quality standard (HC5add) were then calculated from the Burr Type III function fitted SSD curves. The derived soil Pb thresholds based on the added risk approach (total soil concentration subtracting the natural background part) were presented as continuous or scenario criteria depending on the combination of soil pH and CEC. PMID- 26513562 TI - Mitigation of micropollutants for black water application in agriculture via composting of anaerobic sludge. AB - The excess sludge from Up-flow anaerobic sludge bed (UASB) reactor operated on source separated toilet wastewater is a potential source of nutrients and organic matter. It can be further stabilized and dried by composting and applied as a soil amendment. Presence of pathogens, heavy metals and micropollutants in the compost derived from anaerobic sludge is thus undesirable. This paper focuses on removal of micropollutants, typically present in domestic wastewater, via composting of UASB sludge with waste wood. Estrone, diclofenac, ibuprofen, metoprolol, carbamazepine, galaxolide and triclosan were spiked to a mixture of UASB sludge and waste wood. Their concentrations were monitored during 92 days of composting at controlled temperature conditions. All studied micropollutants were removed at various rates with overall removal ranging from 99.9% for ibuprofen, diclofenac and estrone to 87.8% for carbamazepine. Accumulation of methyltriclosan as by-product of triclosan degradation was observed. The prospects and limitations of the integration of a composting process into Source Separated Sanitation concepts are discussed. PMID- 26513563 TI - Novel electrostatic precipitator using unipolar soft X-ray charger for removing fine particles: Application to a dry de-NOX process. AB - The novel electrostatic precipitator (ESP), consisting of a soft X-ray charger and a collection part, was demonstrated and applied to a dry de-NOX process to evaluate its performance in by-product particle removal. NOX gas was oxidized by ozone (O3) and neutralized by ammonia (NH3) sequentially, and finally converted to an ammonium nitrate (NH4NO3) aerosol with ~ 100-nm peak particle diameter. The unipolar soft X-ray charger was introduced for charging the by-product particles in this dry de-NOX process. For the highest particle collection efficiency, the optimal operating conditions of the soft X-ray charger and collection part were investigated by adjusting the applied voltage of each device. The results showed that ~ 99% of NOX was removed when the O3/NOX ratio was increased to 2 (i.e., the maximum production conditions of the NH4NO3 by-product particles by the gas-to particle conversion process). The highest removal efficiency of particle (~ 90%) was observed with operating conditions of positive polarity and an applied voltage of ~ 2-3 kV in the charger chamber. The unipolar soft X-ray charger has potential for particle removal systems in industrial settings because of its compact size, ease of operation, and non-interruptive charging mechanism. PMID- 26513564 TI - Interaction of ciprofloxacin and probe compounds with palygorskite PFl-1. AB - The adsorption of ciprofloxacin (CIP) as well as probe compounds, phenylpiperazine (PP) (NH) and fluorochloroquinolone carboxylic acid (FCQCA) (COOH), on palygorskite (PFl-1) obeyed the Langmuir isotherm at pH 2, 7, and 11 except the FCQCA adsorption at pH 2. The CIP and PP adsorption onto PFl-1 was 98 160 mmol/kg. In neutral solution the total amount of exchangeable cations desorbed correlated with the adsorbed amount of CIP and PP well with a slope of 0.9-1, indicating a cation-exchange mechanism. A low amount of FCQCA adsorption of 27-57 mmol/kg was observed and the amount of exchangeable cations desorbed negatively correlate with the amount of FCQCA adsorbed as influenced by surface complexation or cation bridging. FTIR band shifting due to the ring-stretch vibration of PP and the keto-carbonyl group stretching of FCQCA suggested strong interactions as PP and FCQCA absorbed on PFl-1 in neutral solution. In the interaction of CIP with PFl-1, the piperazine-amine group played an important role in cation-exchange interaction in acidic to neutral solution, while the deprotonated keto carbonyl group actively partook in cation bridging or surface complexation with metal cations adsorbed on PFl-1 when the CIP was in anionic form in alkaline solution. PMID- 26513565 TI - Photocatalytic degradation of terephthalic acid on sulfated titania particles and identification of fluorescent intermediates. AB - Terephthalic acid (TA) is toxic and known as an endocrine disruptor. In this paper, the photocatalytic degradation of TA using sulfated titanium dioxide SO4(2 )/TiO2 photocatalysts was investigated. The photocatalysts were prepared by sol gel method and characterized by XRD, SEM, BET, ICP/MS and spectroscopic methods. Their activities were compared with bare TiO2 and Degussa P25. The effects of catalyst sulfur content, the initial TA concentration and pre-treatment conditions (O2, N2 or non-pretreated) were studied. O2 functions were also explored. Since there had been no comprehensive study of fluorescent intermediates reported yet, we investigated the intermediates and discovered 5 new intermediates (4 fluorescent and 1 non-fluorescent) which were identified by gas chromatography-mass spectrometry (GC/MS) and fluorescence spectroscopy. These intermediates are complementary to the previously identified carboxylic acid intermediates and might provide new insights to the mechanism of photocatalytic degradation of TA. Since TA is widely used as a probing molecule for photocatalytically generated (.)OH radicals, the ratios of fluorescent intermediates of TA degradation may provide new clues to the photocatalytic activity and mechanism. Based on the results obtained, the possible destruction pathway of TA is also proposed. PMID- 26513566 TI - Arsenic impacted the development, thyroid hormone and gene transcription of thyroid hormone receptors in bighead carp larvae (Hypophthalmichthys nobilis). AB - Arsenic (As) contamination in aquatic environment adversely impacts aquatic organisms. The present study assessed the toxicity of different As species and concentrations on bighead carp (Hypophthalmichthys nobilis) at early life stage, a major fish in Yangtze River, China. We measured the changes in embryo and larvae survival rate, larvae aberration, concentrations of thyroid hormone thyroxine, and transcription levels of thyroid hormone receptors (TRs) in fish larvae after exposing to arsenite (AsIII) or arsenate (AsV) at 0, 10, 30, 50, 100, or 150 MUg L(-1) for 78 h. As concentrations <= 150 MUg L(-1) had limited effect on embryo survival rate (6-8% inhibition), but larvae survival rate decreased to 53-57% and larvae aberration rate increased to 20-24% after As exposure. Moreover, thyroxine levels elevated by 23% and 50% at 100 MUg L(-1) AsIII and 150 MUg L(-1) AsV. Besides, AsIII and AsV decreased the transcriptional levels of TRalpha by 72 and 53%, and TRbeta by 91 and 81% at 150 MUg L(-1) As. Our data showed that AsIII and AsV had limited effect on carp embryo survival, but they were both toxic to carp larvae, with AsIII showing more effect than AsV. As concentrations <150MUg L(-1) adversely influenced the development of bighead carp larvae and disturbed their thyroid hormone homeostasis. PMID- 26513567 TI - Treatment of gaseous toluene in three biofilters inoculated with fungi/bacteria: Microbial analysis, performance and starvation response. AB - Bacteria and fungi are often utilized for the biodegradation of organic pollutants. This study compared fungal and/or bacterial biofiltration in treating toluene under both steady and unsteady states. Fungal biofilter (F-BF) removed less toluene than both bacterial biofilters (B-BF) and fungal & bacterial biofilters (F&B-BF) (<20% vs >60% vs >90%). The mineralization ratio was also lower in F-BF-levels were 2/3 and 1/2 of those values obtained by the other biofilters. Microbial analysis showed that richer communities were present in B BF and F&B-BF, and that the Hypocreales genus which Trichoderma viride belongs to was much better represented in F&B-BF. The F&B-BF also supported enhanced robustness after 15-day starvation episodes; 1 day later the performance recovered to 80% of the original removal level. The combination of bacteria and fungi makes biofiltration a good option for VOC treatment including better removal and performance stability versus individual biofilters (bacteria or fungi dominated). PMID- 26513568 TI - Detection of dimethyl methylphosphonate by thin water film confined surface enhanced Raman scattering method. AB - It is important and necessary to effectively detect the chemical warfare agents, such as highly toxic never agent sarin. However, based on the surface-enhanced Raman scattering (SERS) effect, detection of nerve agent simulant dimethyl methylphosphonate (DMMP) which is weakly interacted with SERS-active substrate has been the most challenge for the routine SERS detection method. To overcome this challenge, we put forward a thin water film confined SERS strategy. Under the space-confinement of water film, Raman measurements are carried out in the water evaporation process. The subsequent water evaporation induces concentrating of the DMMP molecules, which are thus successfully restricted within the strong electromagnetic field enhanced area above the SERS substrates, leading to the enhancement of their Raman signals. This study provides a new way to achieve the efficient SERS-based detection of the target molecules weakly interacted with the metal substrates. PMID- 26513569 TI - Reductive reactivity of borohydride- and dithionite-synthesized iron-based nanoparticles: A comparative study. AB - In this study sodium dithionite (NaS2O4) and sodium borohydride (NaBH4) were employed as reducing agents for the synthesis of nanosized iron-based particles. The particles formed using NaBH4 (denoted nFe(BH4)) principally contained (as expected) Fe(0) according to XAS and XRD analyses while the particles synthesized using NaS2O4, (denoted nFe(S2O4)) were dominated by the mixed Fe(II)/Fe(III) mineral magnetite (Fe3O4) though with possible presence of Fe(0). The ability of both particles to reduce trichloroethylene (TCE) under analogous conditions demonstrated remarkable differences with nFe(BH4) resulting in complete reduction of 1.5mM of TCE in 2h while nFe(S2O4) were unable to effect complete reduction of TCE in 120 h. Moreover, acetylene was the major reaction product formed in the presence of nFe(S2O4) while the major reaction product formed following reaction with nFe(BH4) was ethylene, which was further reduced to ethane as the reaction proceeded. Considering that effective Pd reduction to Pd(0) requires the presence of Fe(0), this is consistent with our finding that Fe(0) is not the dominant phase formed when employing dithionite as a reducing agent under the conditions employed in this study. PMID- 26513570 TI - Decomposition of perfluorooctanoic acid by ultraviolet light irradiation with Pb modified titanium dioxide. AB - Perfluorooctanoic acid (PFOA, C7H15COOH) is widely used in industrial and commercial applications. It has become a global concern due to its widespread occurrence in water bodies and adverse environmental impact. PFOA could not be effectively removed by the conventional UV/TiO2 system. This study synthesized Pb modified TiO2 catalyst and used it as a catalyst with light irradiation for PFOA decomposition. It was found that the Pb-TiO2 catalyst could produce traps to capture photo-induced electrons or holes that lead to better photocatalytic efficiencies. Rate constant values for PFOA decomposition by the UV/TiO2 and UV/Pb-TiO2 systems were determined to be 0.0158 and 0.5136 h(-1), respectively. The PFOA decomposition in the UV/Pb-TiO2 system is 32.5 times faster than that in the UV/TiO2 system. The UV/Pb-TiO2 system yielded a better performance than those of the UV/Fe-TiO2 and UV/Cu-TiO2 systems. During the reaction, PFOA decomposed stepwisely into shorter-chain perfluorocarboxylic acids and F(-). PMID- 26513572 TI - Wavepacket Dynamics of the Axially Chiral Molecule Cl-O-O-Cl under Coherent Radiative Excitation and Including Electroweak Parity Violation. AB - We report detailed calculations of the quantum wavepacket dynamics of Cl-O-O-Cl, which serves as a prototype molecule for the stereomutation dynamics of an axially chiral molecule. We include the effects both from electroweak parity violation and from the interaction with a coherent monochromatic laser field. We use the quasiadiabatic channel reaction path Hamiltonian approach to approximately solve the six-dimensional Schrodinger equation describing the vibrational motion, including rotation by an effective Hamiltonian. We calculate time-dependent wave functions based on the time-dependent Schrodinger equation. We study stereomutation dynamics due to tunneling motion and laser-induced population transfer and show results on efficient methods for selectively populating single molecular states in chiral molecules by frequency-modulated laser pulses. We also discuss laser-induced stereomutation (LISM) and a process that may be called resonance Raman induced stereomutation (RRISM). The results are discussed in relation to current experimental attempts to measure the parity violating energy difference DeltapvE between the enantiomers of chiral molecules. Furthermore, we show detailed quantitative simulations of a selection of well defined parity levels in chiral molecules ("parity isomers") that form the basis of a possible measurement of DeltapvE by the time evolution of parity. PMID- 26513573 TI - Counterintuitive DNA Sequence Dependence in Supercoiling-Induced DNA Melting. AB - The metabolism of DNA in cells relies on the balance between hybridized double stranded DNA (dsDNA) and local de-hybridized regions of ssDNA that provide access to binding proteins. Traditional melting experiments, in which short pieces of dsDNA are heated up until the point of melting into ssDNA, have determined that AT-rich sequences have a lower binding energy than GC-rich sequences. In cells, however, the double-stranded backbone of DNA is destabilized by negative supercoiling, and not by temperature. To investigate what the effect of GC content is on DNA melting induced by negative supercoiling, we studied DNA molecules with a GC content ranging from 38% to 77%, using single-molecule magnetic tweezer measurements in which the length of a single DNA molecule is measured as a function of applied stretching force and supercoiling density. At low force (<0.5pN), supercoiling results into twisting of the dsDNA backbone and loop formation (plectonemes), without inducing any DNA melting. This process was not influenced by the DNA sequence. When negative supercoiling is introduced at increasing force, local melting of DNA is introduced. We measured for the different DNA molecules a characteristic force Fchar, at which negative supercoiling induces local melting of the dsDNA. Surprisingly, GC-rich sequences melt at lower forces than AT-rich sequences: Fchar = 0.56pN for 77% GC but 0.73pN for 38% GC. An explanation for this counterintuitive effect is provided by the realization that supercoiling densities of a few percent only induce melting of a few percent of the base pairs. As a consequence, denaturation bubbles occur in local AT-rich regions and the sequence-dependent effect arises from an increased DNA bending/torsional energy associated with the plectonemes. This new insight indicates that an increased GC-content adjacent to AT-rich DNA regions will enhance local opening of the double-stranded DNA helix. PMID- 26513574 TI - Patient-Reported Outcome Measurement in Clinical Dermatological Practice: Relevance and Feasibility of a Web-Based Portal. AB - BACKGROUND/AIMS: Patient-reported outcomes (PROs) are increasingly considered important. We developed a web-based application to electronically assess PROs in routine dermatological practice. We assessed (1) the relevance of PRO measurement according to health care providers and patients, (2) the feasibility of our application in routine practice according to health care providers, supporting staff and patients, and (3) barriers/facilitators for implementation according to health care providers and supporting staff. METHODS: Health care providers, supporting staff and patients completed study-specific questionnaires. Also, website statistics were analysed. RESULTS: 3/6 clinics participated, including 9 professionals and 80 patients. Both health care providers and patients rated PRO measurement as relevant. However, implementation was only moderately feasible. Time constraints and logistical problems were mentioned as barriers, and motivated patients and supportive staff as facilitators. CONCLUSION: Electronic PRO assessment in routine practice is not self-evident. Adjustments in logistics are recommended to optimize implementation, using a plan-do-study-act approach. PMID- 26513576 TI - The Intensity of Victimization: Associations with Children's Psychosocial Well Being and Social Standing in the Classroom. AB - The association between experienced victimization and students' psychological and social adjustment depends on the intensity of victimization. We examined how frequency and multiplicity of victimization, and the number of bullies involved, account for differences in students' psychosocial well-being and social standing in the classroom. Multilevel analyses were conducted on the control group of an intervention study among students in grades 3-6 of Dutch elementary schools (N = 2859 students from 124 classes and 33 schools; ages 8-12; 49.6% boys). It was found that victims of frequent and multiple victimization, and victims who were victimized by several bullies, had higher levels of psychosocial adjustment problems than victims of less frequent and non-multiple victimization, and victims with only one bully. Moreover, these more severe victims turned out to be least accepted and most rejected among their classmates. The findings illustrate that it can be fruitful to use several measures of victimization so that (differences in) adjustment problems can be better understood. Moreover, the results suggest that it is important to find out who is victimized, in what ways, and by whom. Anti-bullying interventions should provide resources to do this. PMID- 26513577 TI - Functional identification of an exon 1 substitution in the myostatin gene and its expression in breast and leg muscle of the Bian chicken. AB - 1. The objective of this study was to verify the functional effects of the c.234G>A substitution in the myostatin (MSTN) gene and ascertain the mechanism by which the variant affects growth traits in the Bian chicken. 2. The c.234G>A substitution was detected by PCR-RFLP analysis in the 7th-generation Bian chickens and three genotypes (AA, AG and GG) were identified. Results showed that the substitution was significantly associated with all studied growth traits, except first-d-weight, in female Bian chickens. 3. Based on these results, the substitution was used in gene-assisted selection for growth traits and thus fast growth (AA genotype) and slow-growth (GG genotype) lines were successfully established. Significant differences in growth traits were detected between the fast-growth and slow-growth lines from 6 to 16 weeks of age. Furthermore, all slaughter traits, except leg muscle rate, were significantly different between the fast-growth and slow-growth lines. 4. Expression analysis showed that the relative expression level of MSTN in chickens with GG and AG genotypes were significantly higher than that in chickens with an AA genotype, both in breast and leg muscle. Chickens in the slow-growth line had significantly higher relative expression level of MSTN compared to chickens in the fast-growth line, both in breast and leg muscle. 5. The results suggest that the c.234G>A substitution in the myostatin (MSTN) gene negatively regulates the expression of MSTN in the Bian chicken and that it may be used in marker-assisted selection to accelerate the chicken breeding process. PMID- 26513575 TI - Pharmacological Mechanisms of Cortical Enhancement Induced by the Repetitive Pairing of Visual/Cholinergic Stimulation. AB - Repetitive visual training paired with electrical activation of cholinergic projections to the primary visual cortex (V1) induces long-term enhancement of cortical processing in response to the visual training stimulus. To better determine the receptor subtypes mediating this effect the selective pharmacological blockade of V1 nicotinic (nAChR), M1 and M2 muscarinic (mAChR) or GABAergic A (GABAAR) receptors was performed during the training session and visual evoked potentials (VEPs) were recorded before and after training. The training session consisted of the exposure of awake, adult rats to an orientation specific 0.12 CPD grating paired with an electrical stimulation of the basal forebrain for a duration of 1 week for 10 minutes per day. Pharmacological agents were infused intracortically during this period. The post-training VEP amplitude was significantly increased compared to the pre-training values for the trained spatial frequency and to adjacent spatial frequencies up to 0.3 CPD, suggesting a long-term increase of V1 sensitivity. This increase was totally blocked by the nAChR antagonist as well as by an M2 mAChR subtype and GABAAR antagonist. Moreover, administration of the M2 mAChR antagonist also significantly decreased the amplitude of the control VEPs, suggesting a suppressive effect on cortical responsiveness. However, the M1 mAChR antagonist blocked the increase of the VEP amplitude only for the high spatial frequency (0.3 CPD), suggesting that M1 role was limited to the spread of the enhancement effect to a higher spatial frequency. More generally, all the drugs used did block the VEP increase at 0.3 CPD. Further, use of each of the aforementioned receptor antagonists blocked training-induced changes in gamma and beta band oscillations. These findings demonstrate that visual training coupled with cholinergic stimulation improved perceptual sensitivity by enhancing cortical responsiveness in V1. This enhancement is mainly mediated by nAChRs, M2 mAChRs and GABAARs. The M1 mAChR subtype appears to be involved in spreading the enhancement of V1 cortical responsiveness to adjacent neurons. PMID- 26513578 TI - Corrigendum: Decreased LKB1 predicts poor prognosis in Pancreatic Ductal Adenocarcinoma. PMID- 26513579 TI - Relating Cortical Atrophy in Temporal Lobe Epilepsy with Graph Diffusion-Based Network Models. AB - Mesial temporal lobe epilepsy (TLE) is characterized by stereotyped origination and spread pattern of epileptogenic activity, which is reflected in stereotyped topographic distribution of neuronal atrophy on magnetic resonance imaging (MRI). Both epileptogenic activity and atrophy spread appear to follow white matter connections. We model the networked spread of activity and atrophy in TLE from first principles via two simple first order network diffusion models. Atrophy distribution is modeled as a simple consequence of the propagation of epileptogenic activity in one model, and as a progressive degenerative process in the other. We show that the network models closely reproduce the regional volumetric gray matter atrophy distribution of two epilepsy cohorts: 29 TLE subjects with medial temporal sclerosis (TLE-MTS), and 50 TLE subjects with normal appearance on MRI (TLE-no). Statistical validation at the group level suggests high correlation with measured atrophy (R = 0.586 for TLE-MTS, R = 0.283 for TLE-no). We conclude that atrophy spread model out-performs the hyperactivity spread model. These results pave the way for future clinical application of the proposed model on individual patients, including estimating future spread of atrophy, identification of seizure onset zones and surgical planning. PMID- 26513581 TI - 3-D bone models to improve treatment initiation among patients with osteoporosis: A randomised controlled pilot trial. AB - OBJECTIVE: To investigate the efficacy of 3-D printed bone models as a tool to facilitate initiation of bisphosphonate treatment among individuals who were newly diagnosed with osteoporosis. DESIGN: Fifty eight participants with estimated fracture risk above that at which guidelines recommend pharmacological intervention were randomised to receive either a standard physician interview or an interview augmented by the presentation of 3-D bone models. MAIN OUTCOME MEASURES: Participants' beliefs about osteoporosis and bisphosphonate treatment, initiation of bisphosphonate therapy assessed at two months using self-report and pharmacy dispensing data. RESULTS: Individuals in the 3-D bone model intervention condition were more emotionally affected by osteoporosis immediately after the interview (p = .04) and reported a greater understanding of osteoporosis at follow-up (p = .04), than the control group. While a greater proportion of the intervention group initiated an oral bisphosphonate regimen (alendronate) (52%) in comparison with the control group (21%), the overall initiation of medication for osteoporosis, including infusion (zoledronate), did not differ significantly (intervention group 62%, control group 45%, p = .19). CONCLUSION: The presentation of 3-D bone models during a medical consultation can modify cognitive and emotional representations relevant to treatment initiation among people with osteoporosis and might facilitate commencement of bisphosphonate treatment. PMID- 26513580 TI - Multiple Lattice Model for Influenza Spreading. AB - Behavioral differences among age classes, together with the natural tendency of individuals to prefer contacts with individuals of similar age, naturally point to the existence of a community structure in the population network, in which each community can be identified with a different age class. Data on age dependent contact patterns also reveal how relevant is the role of the population age structure in shaping the spreading of an infectious disease. In the present paper we propose a simple model for epidemic spreading, in which a contact network with an intrinsic community structure is coupled with a simple stochastic SIR model for the epidemic spreading. The population is divided in 4 different age-communities and hosted on a multiple lattice, each community occupying a specific age-lattice. Individuals are allowed to move freely to nearest neighbor empty sites on the age-lattice. Different communities are connected with each other by means of inter-lattices edges, with a different number of external links connecting different age class populations. The parameters of the contact network model are fixed by requiring the simulated data to fully reproduce the contact patterns matrices of the Polymod survey. The paper shows that adopting a topology which better implements the age-class community structure of the population, one gets a better agreement between experimental contact patterns and simulated data, and this also improves the accordance between simulated and experimental data on the epidemic spreading. PMID- 26513583 TI - Sources of Discrimination and Their Associations With Health in Sexual Minority Adults. AB - Health disparities exist between sexual minorities and heterosexuals. These health disparities may be due to stressful social situations and environments that are created by discrimination. The current study recruited 277 sexual minorities to complete an online survey to examine the effects of discrimination on health. Discrimination from family and friends, compared to non-family and friends, was found to be more strongly associated with poorer health. This effect was partially statistically mediated by perceived stress reactivity. Findings from this study highlight the importance of distinguishing between different sources of discrimination when examining the effect of discrimination on health in sexual minority adults. PMID- 26513582 TI - Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy. AB - OBJECTIVE: Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset. METHODS: A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up. RESULTS: Patients were followed up to an average age of 15.9 +/- 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027). CONCLUSIONS: We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts. PMID- 26513584 TI - Characterization of Zebrafish Green Cone Photoresponse Recorded with Pressure Polished Patch Pipettes, Yielding Efficient Intracellular Dialysis. AB - The phototransduction enzymatic cascade in cones is less understood than in rods, and the zebrafish is an ideal model with which to investigate vertebrate and human vision. Therefore, here, for the first time, the zebrafish green cone photoresponse is characterized also to obtain a firm basis for evaluating how it is modulated by exogenous molecules. To this aim, a powerful method was developed to obtain long-lasting recordings with low access resistance, employing pressure polished patch pipettes. This method also enabled fast, efficient delivery of molecules via a perfusion system coupled with pulled quartz or plastic perfusion tubes, inserted very close to the enlarged pipette tip. Sub-saturating flashes elicited responses in different cells with similar rising phase kinetics but with very different recovery kinetics, suggesting the existence of physiologically distinct cones having different Ca2+ dynamics. Theoretical considerations demonstrate that the different recovery kinetics can be modelled by simulating changes in the Ca2+-buffering capacity of the outer segment. Importantly, the Ca2+-buffer action preserves the fast response rising phase, when the Ca2+ dependent negative feedback is activated by the light-induced decline in intracellular Ca2+. PMID- 26513585 TI - Genetic Differentiation and Spatial Structure of Phellinus noxius, the Causal Agent of Brown Root Rot of Woody Plants in Japan. AB - Phellinus noxius is a pathogenic fungus that causes brown root rot disease in a variety of tree species. This fungus is distributed in tropical and sub-tropical regions of Southeast and East Asia, Oceania, Australia, Central America and Africa. In Japan, it was first discovered on Ishigaki Island in Okinawa Prefecture in 1988; since then, it has been found on several of the Ryukyu Islands. Recently, this fungus was identified from the Ogasawara (Bonin) Islands, where it has killed trees, including rare endemic tree species. For effective control or quarantine methods, it is important to clarify whether the Japanese populations of P. noxius are indigenous to the area or if they have been introduced from other areas. We developed 20 microsatellite markers from genome assembly of P. noxius and genotyped 128 isolates from 12 of the Ryukyu Islands and 3 of the Ogasawara Islands. All isolates had unique genotypes, indicating that basidiospore infection is a primary dissemination method for the formation of new disease foci. Genetic structure analyses strongly supported genetic differentiation between the Ryukyu populations and the Ogasawara populations of P. noxius. High polymorphism of microsatellite loci suggests that Japanese populations are indigenous or were introduced a very long time ago. We discuss differences in invasion patterns between the Ryukyu Islands and the Ogasawara Islands. PMID- 26513586 TI - Evaluation of Computed Tomography for Lymph Node Staging in Bladder Cancer Prior to Radical Cystectomy. AB - OBJECTIVES: To retrospectively evaluate the value of CT for lymph node (LN) staging in bladder cancer. METHODS: Two uroradiologists reviewed CT scans of 231 patients who underwent radical cystectomy and pelvic lymphadenectomy according to a predefined 12-field template. A 5-step model was used to grade the radiological likelihood of a LN to represent malignant spread based on size, configuration and structure as well as regional clustering. Statistical analyses were performed both on patient- and field-based levels. RESULTS: LN metastases were found in 59 of 231 patients (25.5%). On a patient-based level, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were 52.6, 93.6, 73.2, 85.6 and 83.4%, respectively. Using the field-based approach, a total of 1,649 anatomical fields were evaluable, of which 114 fields showed malignancy (6.9%). On a field basis, sensitivity, specificity, PPV, NPV and accuracy were 30.2, 98, 51.5, 94.5 and 93.3%, respectively. Concerning local staging (pT category), the overall accuracy was 78%; overstaging occurred in 6% and understaging in 16%. CONCLUSIONS: In line with prior studies, the sensitivity of CT imaging for the detection of LN metastases was low, while high values for specificity were achieved. This was further underlined by analyzing standardized anatomical fields. Concerning local staging, postoperative changes after TURB-T rarely led to overstaging. PMID- 26513587 TI - A Preliminary Investigation of Individual Differences in Subjective Responses to D-Amphetamine, Alcohol, and Delta-9-Tetrahydrocannabinol Using a Within-Subjects Randomized Trial. AB - Polydrug use is common, and might occur because certain individuals experience positive effects from several different drugs during early stages of use. This study examined individual differences in subjective responses to single oral doses of d-amphetamine, alcohol, and delta-9-tetrahydrocannabinol (THC) in healthy social drinkers. Each of these drugs produces feelings of well-being in at least some individuals, and we hypothesized that subjective responses to these drugs would be positively correlated. We also examined participants' drug responses in relation to personality traits associated with drug use. In this initial, exploratory study, 24 healthy, light drug users (12 male, 12 female), aged 21-31 years, participated in a fully within-subject, randomized, counterbalanced design with six 5.5-hour sessions in which they received d amphetamine (20mg), alcohol (0.8 g/kg), or THC (7.5 mg), each paired with a placebo session. Participants rated the drugs' effects on both global measures (e.g. feeling a drug effect at all) and drug-specific measures. In general, participants' responses to the three drugs were unrelated. Unexpectedly, "wanting more"? alcohol was inversely correlated with "wanting more"? THC. Additionally, in women, but not in men, "disliking"? alcohol was negatively correlated with "disliking"? THC. Positive alcohol and amphetamine responses were related, but only in individuals who experienced a stimulant effect of alcohol. Finally, high trait constraint (or lack of impulsivity) was associated with lower reports of liking alcohol. No personality traits predicted responses across multiple drug types. Generally, these findings do not support the idea that certain individuals experience greater positive effects across multiple drug classes, but instead provide some evidence for a "drug of choice"? model, in which individuals respond positively to certain classes of drugs that share similar subjective effects, and dislike other types of drugs. PMID- 26513588 TI - Perceived social pressure not to experience negative emotion is linked to selective attention for negative information. AB - Social norms and values may be important predictors of how people engage with and regulate their negative emotional experiences. Previous research has shown that social expectancies (the perceived social pressure not to feel negative emotion (NE)) exacerbate feelings of sadness. In the current research, we examined whether social expectancies may be linked to how people process emotional information. Using a modified classical flanker task involving emotional rather than non-emotional stimuli, we found that, for those who experienced low levels of NE, social expectancies were linked to the selective avoidance of negative emotional information. Those who experienced high levels of NE did not show a selective avoidance of negative emotional information. The findings suggest that, for people who experience many NEs, social expectancies may lead to discrepancies between how they think they ought to feel and the kind of emotional information they pay attention to. PMID- 26513590 TI - Correction: Biotic and Climatic Velocity Identify Contrasting Areas of Vulnerability to Climate Change. PMID- 26513589 TI - Cardioversion and Risk of Adverse Events with Dabigatran versus Warfarin-A Nationwide Cohort Study. AB - AIM: Cardioversion can rapidly and effectively restore sinus rhythm in patients with persistent atrial fibrillation. Since 2011 dabigatran has been available as an alternative to warfarin to prevent thromboembolic events in patients with non valvular atrial fibrillation undergoing cardioversion. We studied time to cardioversion, risk of adverse events, and risk of readmission with atrial fibrillation after cardioversion according to anticoagulation therapy. METHODS AND RESULTS: Through the nationwide Danish registries we included 1,230 oral anticoagulation naive patients with first time non-valvular atrial fibrillation and first time cardioversion from 2011 to 2012; 37% in the dabigatran group (n = 456), and 63% in the warfarin group (n = 774). Median time to cardioversion was 4.0 (interquartile range [IQR] 2.9 to 6.5) and 6.9 (IQR 3.9 to 12.1) weeks in the dabigatran and warfarin groups respectively, and the adjusted odds ratio of cardioversion within the first 4 weeks was 2.3 (95% confidence interval [CI] 1.7 to 3.1) in favor of dabigatran. The cumulative incidence of composite endpoint of stroke, bleeding or death were 2.0% and 1.0% at 30 weeks in the warfarin and dabigatran groups respectively, with an adjusted hazard ratio of 1.33 (95% CI 0.33 to 5.42). Cumulative incidence of readmission with atrial fibrillation after 30 weeks were 9% and 11% in the warfarin and dabigatran groups, respectively, and an adjusted hazard ratio of 0.66 (95% CI 0.41 to 1.08). CONCLUSION: Anticoagulation treatment with dabigatran allows shorter time to cardioversion for atrial fibrillation than warfarin, and appears to be an effective and safe alternative treatment strategy to warfarin. PMID- 26513591 TI - Engineering the glycolytic pathway: A potential approach for improvement of biocatalyst performance. AB - The glycolytic pathway is a main driving force in the fermentation process as it produces energy, cell component precursors, and fermentation products. Given its importance, the glycolytic pathway can be considered as an attractive target for the metabolic engineering of industrial microorganisms. However, many attempts to enhance glycolytic flux, by overexpressing homologous or heterologous genes encoding glycolytic enzymes, have been unsuccessful. In contrast, significant enhancement in glycolytic flux has been observed in studies with bacteria, specifically, Corynebacterium glutamicum. Although there has been a recent increase in the number of successful applications of this technology, little is known about the mechanisms leading to the enhancement of glycolytic flux. To explore the rational applications of glycolytic pathway engineering in biocatalyst development, this review summarizes recent successful studies as well as past attempts. PMID- 26513592 TI - Processing emotional body expressions: state-of-the-art. AB - Processing emotional body expressions has become recently an important topic in affective and social neuroscience along with the investigation of facial expressions. The objective of the study is to review the literature on emotional body expressions in order to discuss the current state of knowledge on this topic and identify directions for future research. The following electronic databases were searched: PsychINFO, Ebsco, ERIC, ProQuest, Sagepub, and SCOPUS using terms such as "body," "bodily expression," "body perception," "emotions," "posture," "body recognition" and combinations of them. The synthesis revealed several research questions that were addressed in neuroimaging, electrophysiological and behavioral studies. Among them, one important question targeted the neural mechanisms of emotional processing of body expressions to specific subsections regarding the time course for the integration of emotional signals from face and body, as well as the role of context in the perception of emotional signals. Processing bodily expression of emotion is similar to processing facial expressions, and the holistic processing is extended to the whole person. The current state-of-the-art in processing emotional body expressions may lead to a better understanding of the underlying neural mechanisms of social behavior. At the end of the review, suggestions for future research directions are presented. PMID- 26513593 TI - Oral manifestations in chronic uremia patients. AB - The incidence of chronic renal failure (CRF) is approximately 200 cases per million people in different Western countries. Recent data indicate that the incidences of these pathologies are increasing. Ninety percent of patients with CRF report oral signs and symptoms that affect both the bone and soft tissues. A broad range of lesions may be observed in chronic uratemia patients, including the following: gingival hyperplasia, enamel hypoplasia, petechiae, gingival bleeding, and others lesions. These patients require various types of treatment ranging from dietary and lifestyle changes to dialysis and kidney transplantation. CRF often leads to multiple oral manifestations that are difficult for dentists to manage. The present study examined the characteristics of this disease, the existing therapeutic options and the relevant considerations for dental professionals. PMID- 26513594 TI - C-Nucleosides To Be Revisited. AB - Two new C-nucleoside analogues, BCX4430, an imino-C-nucleoside, and GS-6620, a phosphoramidate derivative of 1'-cyano-2'-C-methyl-4-aza-7,9-dideazaadenosine C nucleoside, have been recently described as effective against filovirus infections (Marburg) and hepatitis C virus (HCV), respectively. The first C nucleoside analogues were described about half a century ago. The C-nucleoside pseudouridine is a natural component of RNA, and various other C-nucleoside analogues have been reported previously for their antiviral and/or anticancer potential, the most prominent being pyrazofurin, tiazofurin, and selenazofurin. In the meantime, showdomycin, formycin, and various triazole, pyrazine, pyridine, dihydroxyphenyl, thienopyrimidine, pyrazolotriazine, and porphyrin C-nucleoside analogues have been described. It would be worth revisiting these C-nucleosides and derivatives thereof, including their phosphoramidates, for their therapeutic potential in the treatment of virus infections and, where appropriate, cancer as well. PMID- 26513595 TI - E-pharmacophore filtering and molecular dynamics simulation studies in the discovery of potent drug-like molecules for chronic kidney disease. AB - Chronic kidney disease (CKD) is a prominent health issue reported globally. The level of the vitamin D receptor (VDR) and cytochrome P450 enzyme 24-hydroxylase (CYP24A1) are crucial in the pathogenesis of secondary hyperparathyroidism (sHPT) in CKD. An elevated expression of the CYP24A1 leads to the deficiency of vitamin D and resistance to vitamin D therapy. Hence, VDR agonists and CYP24A1 antagonists are suggested to CKD patients for the management of biochemical complications. CTA-018 is a recently reported analog and acts as a potent CYP24A1 inhibitor. It inhibits CYP24A1 with an IC50 27 +/- 6 nM, about 10 times more potentially than the non-selective inhibitor ketoconazole (253 +/- 20 nM), and it is also been reported to induce the VDR expression. Thus, CTA-018 is under clinical trial among CKD patients. In this study, combined molecular docking and pharmacophore filtering were employed to identify compounds better than CTA-018. A huge set of 9127 compounds from Sweet Lead database were docked into the active site of VDR using Glide XP program. E-pharmacophore was developed from both the targets along with CTA-018. The compounds retrieved from the two different pharmacophore-based screening were re-docked into the active site of CYP24A1. The hits that bind well at both the active sites and matched with the pharmacophore models were considered as possible dual functional molecules against VDR and CYP24A1. Further, molecular dynamics simulation and subsequent energy decomposition analyses were also performed to study the role of specific amino acids in the active site of both VDR and CYP24A1. PMID- 26513596 TI - Optical Coherence Tomography Angiography of Acute Macular Neuroretinopathy and Paracentral Acute Middle Maculopathy. PMID- 26513597 TI - A qualitative geographical information systems approach to explore how older people over 70 years interact with and define their neighbourhood environment. AB - A growing body of literature explores the relationship between the built environment and health, and the methodological challenges of understanding these complex interactions across the lifecourse. The impact of the neighbourhood environment on health and behaviour amongst older adults has received less attention, despite this age group being potentially more vulnerable to barriers in their surrounding social and physical environment. A qualitative geographical information systems (QGIS) approach was taken to facilitate the understanding of how older people over 70 in 5 UK towns interact with their local neighbourhood. The concept of neighbourhood changed seasonally and over the lifecourse, and was associated with social factors such as friends, family, or community activities, rather than places. Spaces stretched further than the local, which is problematic for older people who rely on variable public transport provision. QGIS techniques prompted rich discussions on interactions with and the meanings of 'place' in older people. PMID- 26513598 TI - Pronounced Photovoltaic Response from Multilayered Transition-Metal Dichalcogenides PN-Junctions. AB - Transition metal dichalcogenides (TMDs) are layered semiconductors with indirect band gaps comparable to Si. These compounds can be grown in large area, while their gap(s) can be tuned by changing their chemical composition or by applying a gate voltage. The experimental evidence collected so far points toward a strong interaction with light, which contrasts with the small photovoltaic efficiencies eta <= 1% extracted from bulk crystals or exfoliated monolayers. Here, we evaluate the potential of these compounds by studying the photovoltaic response of electrostatically generated PN-junctions composed of approximately 10 atomic layers of MoSe2 stacked onto the dielectric h-BN. In addition to ideal diode-like response, we find that these junctions can yield, under AM-1.5 illumination, photovoltaic efficiencies eta exceeding 14%, with fill factors of ~70%. Given the available strategies for increasing eta such as gap tuning, improving the quality of the electrical contacts, or the fabrication of tandem cells, our study suggests a remarkable potential for photovoltaic applications based on TMDs. PMID- 26513599 TI - Evaluation of the Melody transcatheter pulmonary valve and Ensemble delivery system for the treatment of dysfunctional right ventricle to pulmonary artery conduits. AB - Synthetic conduits and bioprosthetic valves are used in the treatment of patients with congenital heart disease involving the right ventricular outflow tract and pulmonary valve. In-situ time-dependent degradation uniformly results in conduit and valve dysfunction. The abnormal hemodynamics imposed by valve and conduit dysfunction have been linked to exercise intolerance, arrhythmia, right heart failure, and sudden death. Starting in childhood, affected patients are subjected to repeated open-heart surgeries to restore valve function and potentially reduce morbidity and mortality. Percutaneous transcatheter pulmonary valve replacement with the Melody Transcatheter Pulmonary Valve (Medtronic, Inc., Minneapolis, MN) has been performed in ~8000 patients worldwide. The valve and implant procedure provide a far less invasive means of restoring valve and conduit function and allow patients to forego multiple operations. Recent clinical trials have shown excellent and durable results in terms of valve function, relief of obstruction, and improvement in functional class up to 7 years from implant. PMID- 26513600 TI - Amniotic fluid levels of phospholipase A2 in fetal rats with retinoic acid induced myelomeningocele: the potential "second hit" in neurologic damage. AB - OBJECTIVES: There is growing evidence of ongoing, in utero neurological damage in fetuses with myelomeningocele (MMC). Phospholipase A2 (PLA2) has known neurotoxic properties and is predominantly present in its secretory isoform (sPLA2) in meconium, the passage of which is increased in MMC fetuses. The objective of this study was to determine if amniotic fluid (AF) levels of PLA2 are elevated in a rat model of MMC. METHODS: Timed pregnant Sprague-Dawley rats were gavage fed 60 mg/kg/bodyweight retinoic acid (RA) in olive oil at embryonic day 10 (E10). Amniocentesis was performed at multiple gestational time points on MMC fetuses, RA-exposed fetuses without MMC and control fetuses. AF PLA2 levels were analyzed by a fluorescent enzyme activity assay. PLA2 isoforms were determined by measuring activity in the presence of specific inhibitors. RESULTS: There was no difference in AF PLA2 activity between groups on E15. PLA2 activity was significantly increased in MMC fetuses on E17, E19 and E21 (p < 0.001). Secretory PLA2 primarily accounted for the overall greater activity. CONCLUSIONS: PLA2 levels are elevated in the AF of fetal rats with MMC and may contribute to ongoing neural injury. This pathway may be a useful drug target to limit ongoing damage and better preserve neurologic function. PMID- 26513601 TI - Antifungal prophylaxis with liposomal amphotericin B and caspofungin in high-risk patients after liver transplantation: impact on fungal infections and immune system. AB - Antifungal prophylaxis may be required in high-risk patients undergoing liver transplantation and for that reason we aimed to verify its role and its related impact on the graft. From January 2006 throughout 2012, 250 liver transplants were evaluated and 54 patients identified as being at higher risk were randomly selected to undergo the following schedule: 28 patients received liposomal amphotericin B and 26 received caspofungin. We evaluated, throughout 12 months, renal and liver function tests, bacterial and fungal infection episodes, and intensive care unit (ICU) stay, as well as the Th1 and Th2 cytokine network. Differences were analyzed according to non-parametric tests (two-tailed p values). Neither of the groups showed episodes of invasive fungal infection during the 12 months follow-up; however, patients receiving prophylaxis with liposomal amphotericin B had reduced episodes of bacterial infections coupled with an improved immune system response compared with those receiving caspofungin. Finally, a reduced stay in the ICU was also observed. In conclusion, even if the results of liposomal amphotericin B and caspofungin prophylaxis strategies did not differ in terms of invasive fungal infection rate, patients receiving prophylaxis with liposomal amphotericin B had a reduced ICU stay and an improved Th2 status, as well as a reduced number of post-transplant bacterial infections. Further studies are required to better address and evaluate these findings. PMID- 26513602 TI - Management of mastitis and breast engorgement in breastfeeding women. AB - OBJECTIVE: To identify the best management approaches to mastitis management in breastfeeding women and heavy breast engorgement in the early postnatal period. METHODS: We compared various international guidelines and reviews on mastitis management in breastfeeding women and breast engorgement treatment. RESULTS: Effective milk removal is recommended as a first step in mastitis management. Active emptying of the breasts can prevent mastitis development in most cases. If it fails, antibiotics should be administered for 10-14 days with continuing breastfeeding. Russian guidelines recommend antibiotic therapy during 5-7 days with temporary bromocriptine-induced breastfeeding suppression. In case of heavy breast engorgement after lactation is initiated, Progesterone-containing gel can be administered. Application of the progesterone-containing gel on the breast skin improves swelling, and reduces engorgement and tenderness in 15-20 minutes. CONCLUSIONS: Antibiotics with temporary suppression of breastfeeding are more effective than with continuing breastfeeding in mastitis management. The progesterone-containing gel is recommended on the 3rd-4th days after childbirth in heavy breast engorgement to prevent mastitis. PMID- 26513603 TI - Design considerations for an underwater soft-robot inspired from marine invertebrates. AB - This article serves as an overview of the unique challenges and opportunities made possible by a soft, jellyfish inspired, underwater robot. We include a description of internal pressure modeling as it relates to propulsive performance, leading to a desired energy-minimizing volume flux program. Strategies for determining optimal actuator placement derived from biological body motions are presented. In addition a feedback mechanism inspired by the epidermal line sensory system of cephalopods is presented, whereby internal pressure distribution can be used to determine pertinent deformation parameters. PMID- 26513604 TI - Limited usefulness of the Rey Fifteen-Item Test in detection of invalid performance in veterans suspected of mild traumatic brain injury. AB - OBJECTIVE: This study explored using the FIT as a measure of performance validity among veterans undergoing neuropsychological evaluation for mild traumatic brain injury (mTBI). BACKGROUND: The Rey Fifteen-Item Memory Test (FIT) is a performance validity measure criticized for poor sensitivity. METHODS: Two hundred and fifty-seven veterans completed the FIT and Wechsler Adult Intelligence Scale, Fourth Edition, Digit Span (DS); 109 of whom completed the Test of Memory Malingering (TOMM). FIT cut-offs of <9, <8 and stricter cut-offs were examined using DS and/or TOMM as criterion performance validity measures. RESULTS: Only four participants scored below the standard cut score of 9 on the FIT. Among the 13 veterans failing both criterion tests, only two scored below 9 on the FIT. Regardless of which FIT cut-off was used, the FIT had poor diagnostic accuracy. CONCLUSION: Despite its popularity, the FIT is not supported as an appropriate measure of performance validity in veterans undergoing evaluation for possible mTBI. Therefore, inferences regarding neuropsychological data reliability with adequate statistical certainty require use of other measures of performance validity with greater sensitivity. PMID- 26513605 TI - Cadmium or cadmium compounds and chronic kidney disease in workers and the general population: a systematic review. AB - BACKGROUND: Cadmium (Cd) is abundantly documented as a metal mainly affecting tubular function both in workers and in the general population indirectly exposed via the environment. Results from epidemiological studies linking Cd exposure and risk of progression to chronic kidney disease (CKD) are, however, conflicting. OBJECTIVES: To perform a systematic review of the association between Cd exposure and CKD. METHODS: A systematic appraisal of publications found in MEDLINE (1946 2014), EMBASE (1974-2012) and an in-house database (1986-2013) was conducted. Additional studies were searched for by contacting experts and checking reference lists. Search terms used key and text words. No language restriction was applied. Cohort, case-control and case-series with follow-up including individual and objective assessment of occupational or environmental exposure were eligible. Studies were selected and data extracted by two independent reviewers using predefined forms. Study characteristics and results were extracted to structured tables. Synthesis was qualitative and results appraised with causality criteria. RESULTS: Thirty-four exposed groups, totaling more than 3000 participants, were eligible. Overall, results disclosed no convincing evidence supporting a risk of progression to CKD in populations exposed to Cd. Lack of information about methods, risk of bias and heterogeneity were identified as limitations and precluded conducting a meta-analysis. Publication bias did not appear as a major problem. CONCLUSIONS: This qualitative systematic review does not support the contention that human exposure to Cd leads to progressive CKD. PMID- 26513607 TI - Protective Effects of Antiplacental Growth Factor Antibody Against Light-Induced Retinal Damage in Mice. AB - PURPOSE: Placental growth factor (PlGF) is part of the VEGF family and is known to be involved in angiogenesis, vasopermeability, and neuroprotection. Recently, PlGF has been reported as a novel therapeutic target for wet AMD. However, there are few reports about the effect of PlGF against dry AMD. Previously, we reported that PlGF has protective effects against retinal neuronal cell damage in vitro. Therefore, we investigated the effects of PlGF against photoreceptor degeneration. METHODS: In this study, mice were exposed to white light at 8000 lx for 3 hours to induce retinal damage, which was evaluated by recording the electroretinogram amplitude and measuring the outer nuclear layer (ONL) thickness. The mice were injected intravitreally with PlGF before light exposure, PlGF after light exposure, or anti-PlGF antibody before light exposure. RPE choroid-sclera flat mounts were immunostained with anti-ZO-1 antibody to evaluate the disruption of retinal pigmented epithelium (RPE) cell-cell junctional integrity after light exposure. Furthermore, the expression of VEGF receptor in the retina and RPE-choroid complex after light exposure was measured using Western blot analysis. RESULTS: Contrary to the expected outcome, PlGF treatment exacerbated the light-induced retinal functional damage and ONL thinning. In contrast, anti-PlGF treatment significantly improved the light-induced retinal degeneration. The disruption of RPE cell-cell junctional integrity after light exposure was suppressed by anti-PlGF treatment. Moreover, the VEGF receptor, which is involved in blood-retinal barrier breakdown, was up-regulated after light exposure. CONCLUSIONS: These findings suggest that anti-PlGF antibody has protective effects against light-induced retinal degeneration in the murine retina through inhibition of RPE breakdown after light exposure. Thus, anti-PlGF antibody may be useful therapeutic agents in dry AMD. PMID- 26513606 TI - Convergent evolution of twintron-like configurations: One is never enough. AB - Introns inserted within introns are commonly referred to as twintrons, however the original definition for twintron implied that splicing of the external member of the twintron could only proceed upon splicing of the internal member. This review examines the various types of twintron-like arrangements that have been reported and assigns them to either nested or twintron categories that are subdivided further into subtypes based on differences of their mode of splicing. Twintron-like arrangements evolved independently by fortuitous events among different types of introns but once formed they offer opportunities for the evolution of new regulatory strategies and/or novel genetic elements. PMID- 26513608 TI - Theoretical characterization of a series of N5-based aromatic hyperhalogen anions. AB - Hyperhalogens are a class of highly electronegative molecules whose electron affinities even exceed those of their superhalogen ligands. Such species can serve as new oxidizing agents, biocatalysts, and building blocks of unusual salts, and hence are important to the chemical industry. Utilizing stable N5(-) as the ligand, a series of aromatic hyperhalogen anions, namely mononuclear M(N5)(k+1)(-) (M = Li, Be, B) and dinuclear M2(N5)(2k+1)(-) (M = Li, Be), have been reported here for the first time. Calculation results based on the density functional theory revealed that all the N5(-) subunits preserve their structural and electronic integrity as well as aromatic characteristics in these anions. Especially, these anionic molecules exhibit larger vertical electron detachment energies (6.76-7.86 eV) than that of the superhalogen ligand N5(-), confirming their hyperhalogen nature. The stability of these studied anions is guaranteed by their large HOMO-LUMO gaps, and positive dissociation energies of predetermined fragmentation pathways. We hope this work will not only provide evidence of a new type of hyperhalogen molecule but also stimulate more research interest and efforts in the amazing superatom realm. PMID- 26513609 TI - Mapping Adolescent Cancer Services: How Do Young People, Their Families, and Staff Describe Specialized Cancer Care in England? AB - BACKGROUND: Specialized cancer services for adolescents and young adults (AYAs) are being developed in a number of countries to address the particular needs of this population. However, the evidence base to inform service design and associated care delivery is inadequate. OBJECTIVE: The aim of this study was to undertake a mapping study to identify the main components of AYA cancer care to be studied further to reflect the range of approaches to service delivery currently provided in England. METHODS: Semistructured interviews were conducted with young people, their family members, and staff in 11 AYA principal treatment centers. Using different levels of extraction, these data were drawn together to illuminate the main components of AYA cancer care and the range of approaches to service delivery. RESULTS: Young people, family members, and staff consistently identified and valued similar areas of AYA cancer care: caring and supportive staff, activities designed for AYAs, and an environment that feels like home. CONCLUSION: The mapping exercise successfully informed the selection of 4 sites for an in-depth case study. The main components of specialized AYA care have been described. IMPLICATIONS FOR PRACTICE: This description can assist clinical teams interested in developing or refining their approach to AYA cancer care. It could also offer a way to agree priorities, based on the key components young people consider as being essential for their care, and facilitate services to benchmark against these key components, and it could also go some way to address international AYA goals to support global change to reduce the current disparities in care. PMID- 26513610 TI - Thromboembolism as an important complication of inflammatory bowel disease. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) have a higher risk of developing thromboembolic events (TE) compared with the healthy population. AIM: This study aimed to describe a cohort of IBD patients with a history of TE focusing on recurrence of TE, disease activity and IBD medication at the time of TE and surgery before TE. MATERIALS AND METHODS: In a retrospective monocentric cohort study, we included IBD patients in whom an arterial and/or venous TE occurred. RESULTS: Eighty-four IBD patients with a history of TE (63% Crohn's disease, 44% men) and a mean age of 45+/-15 years were included; 25/84 patients (30%) were identified to have recurrent TE. Seventy out of 84 (83%) developed a venous TE, with a deep vein thrombosis as the major manifestation (28/70, 40%), followed by a pulmonary embolism (16/70, 23%). At the time of TE, 60/84 (71%) patients were diagnosed with active disease. In all, 23% patients were on 5 aminosalicylic acids, 36% on steroids, 18% on azathioprine, 5% on methotrexate, 12% on biologicals and 23% were not receiving specific IBD treatment. Moreover, within a 6-month period preceding the TE, 28/84 (33%) patients underwent surgery, of whom 17% received thromboprophylaxis at hospital discharge. CONCLUSION: We confirm the association between disease activity and the occurrence of TE. A substantial number of patients had additional risk factors such as recurrence of TE. In all, 36% received steroids at the time of TE and 33% underwent recent surgery, of whom only a minority received thromboprophylaxis at hospital discharge. Further efforts are required to increase thromboprophylaxis in at-risk patients. PMID- 26513611 TI - Efficacy and safety of anticoagulation in more advanced portal vein thrombosis in patients with liver cirrhosis. AB - BACKGROUND AND AIM: Portal vein thrombosis (PVT) is a frequent event in patients with cirrhosis. The effects of anticoagulation on these patients were still unclear, especially for more advanced PVT. The aim of this study was to retrospectively assess the resolution of PVT and liver disease progression in a large cohort of cirrhotic patients with PVT with or without anticoagulation therapy. METHODS: We analyzed data from 66 cirrhotic patients with PVT from January 2002 to June 2014. Thirty patients were anticoagulated with warfarin and 36 patients were untreated. PVT and hepatic decompensation were evaluated. RESULTS: For anticoagulated patients, the thrombosis had improved in 15 (68.2%) patients, was stable in four patients (18.2%), and progressed in three patients (13.6%). For untreated patients, the thrombosis had improved in four patients (25%), was stable in six patients (37.5%), and progressed in six patients (37.5%). The anticoagulation group had significantly better recanalization rates than the untreated group (P=0.011). Degree of superior mesenteric vein (P=0.032, hazard ratio: 15.4; 95% confidence interval: 1.3-200) was a significant predictor. In addition, anticoagulation can effectively improve PVT with a degree less than 75% in the main portal vein compared with untreated patients (6/6 vs. 2/6, P=0.030). The probability of hepatic decompensation at 1 year was 15.6 and 17.9% between the anticoagulation and the untreated groups (P=0.847). Albumin (P=0.06, hazard ratio: 0.860; 95% confidence interval: 0.772-0.959) was a significant predictor. CONCLUSION: Anticoagulation with warfarin might result in the resolution of more advanced PVT effectively and safely in patients with liver cirrhosis. In addition, we did not demonstrate the benefit of anticoagulation for the decompensation or death. PMID- 26513612 TI - Serum beta-trophin level as a new marker for noninvasive assessment of nonalcoholic fatty liver disease and liver fibrosis. AB - OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease and evaluation of fibrosis is important. We aimed to investigate the utility of serum beta-trophin in NAFLD and its ability to predict liver fibrosis. PATIENTS AND METHODS: Serum samples of consecutive patients with biopsy-proven NAFLD and age-matched and sex-matched healthy controls were used to measure beta trophin using ELISA. Correlations between histopathological features of NAFLD and beta-trophin were analyzed. Whereas patients with fibrosis scores less than 2 were grouped in the mild fibrosis group, patients with scores of 2 or more were grouped in the significant fibrosis group. Univariate/multivariate logistic regression analyses were carried out to evaluate the independent predicting factors of liver fibrosis. Receiver operating characteristics (ROCs) were assessed to determine the best cut-off values for NAFLD and fibrosis. RESULTS: Sixty-nine patients with NAFLD and 69 healthy controls were enrolled in the study. Serum beta-trophin levels were lower in NAFLD patients compared with the controls (2.34+/-0.06 vs. 1.94+/-0.09 ng/ml, respectively, P<0.001). In NAFLD, serum beta-trophin was related to liver fibrosis and inflammation. The mild fibrosis group had higher serum beta-trophin levels than the significant fibrosis group (2.11+/-0.12 vs. 1.72+/-0.11, respectively, P<0.001). In multivariate analysis, beta-trophin remained an independent predictor of significant fibrosis (odds ratio, 0.237; 95% confidence interval, 0.059-0.949; P<0.001). ROC analysis showed that serum beta-trophin was statistically significant in the identification of significant fibrosis (area under receiver operating characteristic, 0.844; 95% confidence interval, 0.718-0.970; P<0.001). The best cut-off value was 1.786, with the best sensitivity (71.43%) and specificity (95.65%). CONCLUSION: Serum beta-trophin may be a potential noninvasive marker for the identification of NAFLD and significant liver fibrosis. PMID- 26513613 TI - Lung Pathology in U.S. Coal Workers with Rapidly Progressive Pneumoconiosis Implicates Silica and Silicates. AB - RATIONALE: Recent reports of progressive massive fibrosis and rapidly progressive pneumoconiosis in U.S. coal miners have raised concerns about excessive exposures to coal mine dust, despite reports of declining dust levels. OBJECTIVES: To evaluate the histologic abnormalities and retained dust particles in available coal miner lung pathology specimens, and to compare these findings with those derived from corresponding chest radiographs. METHODS: Miners with severe disease and available lung tissue were identified through investigator outreach. Demographic as well as smoking and work history information was obtained. Chest radiographs were interpreted according to the International Labor Organization classification scheme to determine if criteria for rapidly progressive pneumoconiosis were confirmed. Pathology slides were scored by three expert pulmonary pathologists using a standardized nomenclature and scoring system. MEASUREMENTS AND MAIN RESULTS: Thirteen cases were reviewed, many of which had features of accelerated silicosis and mixed dust lesions. Twelve had progressive massive fibrosis, and 11 had silicosis. Only four had classic lesions of simple coal workers' pneumoconiosis. Four had diffuse interstitial fibrosis with chronic inflammation, and two had focal alveolar proteinosis. Polarized light microscopy revealed large amounts of birefringent mineral dust particles consistent with silica and silicates; carbonaceous coal dust was less prominent. On the basis of chest imaging studies, specimens with features of silicosis were significantly associated (P = 0.047) with rounded (type p, q, or r) opacities, whereas grade 3 interstitial fibrosis was associated (P = 0.02) with the presence of irregular (type s, t, or u) opacities. CONCLUSIONS: Our findings suggest that rapidly progressive pneumoconiosis in these miners was associated with exposure to coal mine dust containing high concentrations of respirable silica and silicates. PMID- 26513615 TI - Possible association between the prolactin receptor gene and callous-unemotional traits among aggressive children. AB - This study examined the possible association between prolactin (PRL) system genes and callous-unemotional (CU) traits in childhood-onset aggression. Two markers for the PRL peptide gene and three markers for the prolactin receptor (PRLR) gene were genotyped. The participants were assessed on the CU subscale using five items from the Antisocial Process Screening Device. Genotype analysis showed nominally significant results with PRLR_rs187490 (uncorrected P=0.01), with the GG genotype associated with higher CU scores. This is the first paper to evaluate the relationship of PRL system genes with CU traits in childhood-onset aggression. PMID- 26513617 TI - Functional Gastrointestinal Disorders Dominate Pediatric Gastroenterology Outpatient Practice. AB - OBJECTIVES: Symptom-based diagnostic criteria have improved recognition and standardization of pediatric functional gastrointestinal disorders (FGIDs). We used Rome 3 diagnostic criteria to determine the prevalence of FGIDs in pediatric gastroenterology clinic. In the process, we developed a diagnostic questionnaire for infants and toddlers. METHODS: We enrolled new patients <=18 years referred during 19 months to a pediatric gastroenterology clinic. Subjects or parents completed a demographic survey and a the Questionnaire on Pediatric Gastrointestinal symptoms, Rome 3 Version (if >=4 years, or a new infant-toddler questionnaire) before their appointment. RESULTS: We acquired data from 976 subjects: 476 boys, 592 white. Of 332 subjects <4 years, 172 (52%) met diagnostic criteria for >=1 FGIDs. Of 644 subjects >=4 years, 486 (75%) met diagnostic criteria for >=1 FGIDs. Thirty one (9%) subjects <4 years and 170 (26%) subjects >=4 years met the criteria for >=2 FGIDs. Of the total sample of subjects <4 years, common FGIDs included functional constipation (29%), infant regurgitation (13%), and cyclic vomiting syndrome (10%). Of the total sample of subjects >=4 years, common FGIDs included irritable bowel syndrome (36%), abdominal migraine (19%), functional constipation (17%), cyclic vomiting syndrome (8%), functional abdominal pain syndrome (7%), aerophagia (7%), and functional dyspepsia (7%). CONCLUSIONS: More than half of new pediatric gastrointestinal clinic patients met the Rome 3 criteria for >=1 FGIDs. Satisfying the criteria may facilitate diagnosis on the first visit. PMID- 26513616 TI - Lack of association of SNPs from the FADS1-FADS2 gene cluster with major depression or suicidal behavior. AB - Fatty acid desaturase genes (FADS1-FADS2) encode desaturases participating in the biosynthesis of long-chain polyunsaturated fatty acids. As long-chain polyunsaturated fatty acids are implicated in major depressive disorder (MDD) and suicide risk, and as both are partly heritable, we studied the association of FADS1-FADS2 polymorphisms with MDD (635 cases, 480 controls) and suicide attempt status (291 attempters, 344 MDD nonattempters). Eighteen FADS-related single nucleotide polymorphisms were genotyped from Caucasians enrolled in Madrid (n=791) or New York City (n=324) and entered as predictors into logistic regression analyses with diagnostic group or suicide attempt history as outcomes and location and sex as covariates. No associations were observed between any single-nucleotide polymorphisms and diagnosis or attempt status. As statistical power was adequate, we conclude that FADS1-FADS2 genetic variants may not be a common determinant of MDD. PMID- 26513618 TI - Colon Casts Excreted in a Child. PMID- 26513619 TI - A Pilot Study of Confocal Laser Endomicroscopy to Predict Barrier Dysfunction and Relapse in Pediatric Inflammatory Bowel Disease. AB - OBJECTIVES: Probe-based confocal laser endomicroscopy (pCLE) is a novel imaging modality that enables virtual optical biopsy in vivo. Loss of barrier function of the small bowel observed via pCLE as increased density of epithelial gaps (extrusion zones left in the intestinal lining after cells are shed) is predictive of relapse in adult patients with inflammatory bowel disease (IBD). This study aims to determine whether such observations on pCLE are similarly predictive of disease relapse in pediatric patients with IBD. METHODS: Pediatric patients with biopsy-proven IBD underwent pCLE during colonoscopy and subsequent clinical follow-up every 6 months. Relapse was defined as moderate to severe flare with endoscopic evidence of inflammation during the follow-up period. The relations between epithelial gap density, disease relapse, and imaging parameters were determined using Cox models. RESULTS: Twenty-four patients with IBD (13 with Crohn disease, 11 with ulcerative colitis) with a median age of 14 years (range 10-21) were studied for a median of 13 (4-33) months. The median duration of disease was 2.9 years (range 0-9). Increased epithelial gap density in the terminal ileum on pCLE of normal endoscopic appearing terminal ileum mucosa (N = 19) was predictive of disease relapse when 3 or more areas were imaged (N = 6, log-rank P = 0.02, C-statistic = 0.94). CONCLUSIONS: In pediatric patients with IBD, barrier dysfunction observed on pCLE imaging of the small bowel was predictive of disease relapse. PMID- 26513620 TI - Should Partial Hydrolysates Be Used as Starter Infant Formula? A Working Group Consensus. AB - Partially hydrolyzed formulas (pHFs) are increasingly used worldwide, both in the prevention of atopic disease in at-risk infants and in the therapeutic management of infants with functional gastrointestinal manifestations. Because prevention is always preferable to treatment, we reviewed the literature aiming to find an answer for the question whether pHF may be recommended for feeding all infants if breast-feeding is not possible. PubMed and Cochrane databases were searched up to December 2014. In addition, to search for data that remained undetected by the searches, we approached authors of relevant articles and major producers of pHFs asking for unpublished data. Because few data were found, nonrandomized, controlled trials and trials in preterm infants were included as well. Overall, only limited data could be found on the efficacy and safety of pHF in healthy term infants. Available data do not indicate that pHFs are potentially harmful for healthy, term infants. With respect to long-term outcomes, particularly referring to immune, metabolic and hormonal effects, data are, however, nonexistent. From a regulatory point of view, pHFs meet the nutrient requirements to be considered as standard formula for term healthy infants. Cost, which is different from country to country, should be considered in the decision-making process. Based on limited available data, the use of pHF in healthy infants is safe with regard to growth. The lack of data, in particular for metabolic consequences and long-term outcomes, is, however, the basis for our recommendation that health authorities should develop and support long-term follow-up studies. Efficacy and long-term safety data are required before a recommendation of this type of formula for all infants can be made. PMID- 26513621 TI - Dynamics of Vitamin D Metabolism in Maternal-Fetal Dyads. AB - OBJECTIVES: Metabolites of vitamin D in maternal-neonatal dyads remain relatively unexplored. The goal of this study was to evaluate concentrations of 25(OH)D3, 24,25(OH)2D3, and 3-epi-25(OH)D3 in maternal-infant pairs at delivery. METHODS: Serum samples of maternal and infant cord blood were collected on 131 mother infant pairs at delivery. Vitamin D metabolites were analyzed in triplicate using liquid chromatography-tandem mass spectrometry. Statistical analysis was conducted using the Fisher exact test, Wilcoxon rank sum test, and Spearman correlation coefficients. RESULTS: Mean 25(OH)D3 concentrations in maternal and cord blood were 32.9 and 18.5 ng/mL, respectively; mean maternal and cord 24,25(OH)2D3 were 2.0 versus 1.1 ng/mL, respectively. Absolute concentrations of 3-epi-25(OH)D3 were similar in maternal and cord samples (2.4 vs 2.2 ng/mL), whereas the proportion of the total 25(OH)D as the 3-epimer was 6.5% in maternal samples and 10.5% in cord samples. This suggests that the fetus contributes significantly to 3-epi-25(OH)D3 production. In contrast, the ratio of 25(OH)D3:24,25(OH)2D3 was identical in maternal and cord samples (18.5) suggesting equivalent CYP24A1 activity in mother and fetus. Maternal and cord metabolite levels were highly correlated (r = 0.78, 0.90, 0.89 for 25(OH)D3, 24,25(OH)2D3, and 3-epi-25(OH)D3, respectively, P = 0.001 for all). Serum concentrations of all metabolites were lower in nonwhite infants compared with white infants. Maternal and cord concentrations of 25(OH)D3 were positively associated with birth weight (r = 0.21, P = 0.02; r = 0.25, P = 0.003, respectively). CONCLUSIONS: This data suggests that although maternal and cord concentrations of vitamin D metabolites are highly correlated, regulation of specific vitamin D metabolites in the mother and the neonate may be mediated independently. PMID- 26513622 TI - High Prevalence of Response to Proton-pump Inhibitor Treatment in Children With Esophageal Eosinophilia. AB - OBJECTIVES: Proton-pump inhibitor-responsive esophageal eosinophilia is a newly recognized entity with an unclear prevalence in children, as only retrospective data are available. The aim of this study was to determine the prevalence and clinical features of proton-pump inhibitor-responsive esophageal eosinophilia in children. METHODS: This prospective study enrolled patients with esophageal symptoms and esophageal eosinophilic counts as 15 or more than 15 eos/hpf (eosinophils per high-power field). Children received treatment with esomeprazole 1 mg . kg per dose twice daily for 8 weeks and the endoscopy was repeated. Complete response to proton-pump inhibitor (PPI) was defined as 5 or less than 5 eos/hpf, and a partial response as >5 and <15 eos/hpf in post-treatment biopsies. RESULTS: Fifty-one children (74.5% boys) were included. Histological response was observed in 35 children (68.6%): 24 children (47%) had a complete response and 11 children (21.6%) had a partial response. Only 16 children (31.4%) were diagnosed with eosinophilic esophagitis (EoE). There were no differences in history of atopy, allergy tests, pH study results, and endoscopic scores. Clinical symptoms were similar, with the exception of food impaction, which was more frequent in children with EoE (56.2% vs 20%, P = 0.01). The mean pretreatment peak eosinophil count was higher in patients with EoE (74.8 +/- 36.2 vs 46.3 +/- 30.7, P = 0.007). Eleven of the 14 patients (78.6%) on a lower PPI treatment maintenance dose remained in clinicopathologic remission at 1-year follow-up. CONCLUSIONS: A significant proportion of children with esophageal eosinophilia responded to high dose PPI treatment. Clinical, endoscopic, and pH study results were similar, with exception of patients with EoE, who were more likely to experience food impaction and have higher esophageal eosinophil counts. PMID- 26513623 TI - Anti-Glypican 3, a Novel Ancillary Maker in the Histological Assessment of Hirschsprung's Disease. AB - OBJECTIVES: Hirschsprung's disease (HSCR) results from a malformation of the enteric nervous system. A congenital absence of intrinsic ganglion cells from the distal rectum and a variable length of the contiguous bowel is the required diagnostic feature of Hirschsprung's disease and total colonic aganglionosis (TCA). We evaluated the utility of a monoclonal antibody directed against glypican 3 (GPC-3), a membrane bound protein involved in regulation of the signaling of Wingless-types (WNTs), Hedgehogs (Hh), Fibroblast Growth Factors (FGFs), and Bone Morphogenetic Proteins (BMPs), in the detection of ganglion cells in formalin-fixed, paraffin-embedded tissue sections. METHODS: The presence/absence of ganglion cells was evaluated retrospectively by immunohistochemical staining for calretinin and GPC-3 in tissue specimens; a total of 15 patients who underwent colectomy (total or sub-total) for histologically proven aganglionosis (14 HSCR, 1 TCA) and 5 rectal suction biopsies (4HSCR-B, 1 TCA-B) were considered. Of the 20 considered cases, a total of 60 tissue specimens (3 for each patient) were selected. A total of 30 additional normal (N) colonic mucosa biopsy samples were also included. RESULTS: GPC-3 constantly identified ganglion cell bodies in all but 2 normal biopsies (with normal presentation of ganglion cells on hematoxylin and eosin (H&E) stain), and was negative in all 60 aganglionotic biopsies; these results were reflective of calretinin staining pattern. CONCLUSIONS: The present study indicates that monoclonal anti-GPC-3 might prove to be useful immunohistochemical marker in the identification of ganglion cells in paraffin-embedded rectal tissue specimens and suction biopsies. Further studies in larger series will contribute to demonstrate its utility as an ancillary marker in the histological assessment of HSCR aganglionosis. PMID- 26513624 TI - The change in motor unit firing rates at de-recruitment relative to recruitment is correlated with type I myosin heavy chain isoform content of the vastus lateralis in vivo. AB - AIM: To investigate the change in motor unit (MU) firing rates (FR) at de recruitment relative to recruitment and the relation to % type I myosin heavy chain isoform content (type I %MHC) of the vastus lateralis (VL) in vivo. METHODS: Ten subjects performed a 22-s submaximal isometric trapezoid muscle action that included a linearly increasing, steady force at 50% maximal voluntary contraction, and linearly decreasing segments. Surface electromyographic signals were collected from the VL and were decomposed into constituent MU action potentials trains. A tissue sample from the VL was taken to calculate type I %MHC. The y-intercepts and slopes were calculated for the changes (Delta) in FR at de-recruitment (FRDEREC ) relative to FR at recruitment (FRREC ) vs. FRREC relationship for each subject. Correlations were performed between the y intercepts and slopes with type I %MHC. RESULTS: The majority of MUs had greater FRDEREC than FRREC . The y-intercepts (r = -0.600, P = 0.067) were not significantly correlated, but the slopes (r = -0.793, P = 0.006) were significantly correlated with type I %MHC. CONCLUSION: The majority of the motoneuron pool had greater FRDEREC than FRREC , however, individuals with higher type I %MHC had a greater propensity to have MUs with FRREC > FRDEREC as indicated by the slope values. Overall, the contractile properties of the muscle (MHC) could partially explain the differences in MU firing rates at de recruitment relative to recruitment. Thus, suggesting the fatigability of the muscle influences the alterations in MU firing rates from recruitment to de recruitment. PMID- 26513625 TI - The influence of nonconscious processes on perceptions of downsizing and terminations. AB - Although social and cognitive psychologists have developed a large body of research on priming and other nonconscious processes, relatively little research has focused on how these issues influence organizationally relevant phenomena. The current research sought to partially fill this void by examining the influence of nonconscious processes on perceptions of organizational downsizing. In three studies, individuals were primed with traits of self-reliance or employer-reliance either supraliminally (Study 1) or subliminally (Studies 2 and 3). Studies 1 and 2 found that individuals primed with self-reliance had less negative views of downsizing. Experiment 3 found that those primed with self reliance reported greater perceptions of fair treatment, respect for their boss, and decreased levels of anger in response to a termination scenario. Implications and future directions are discussed. PMID- 26513626 TI - Influence of the delivery modus on subpopulations and replication of lymphocytes in mothers and newborns. AB - BACKGROUND: Several studies reported that the mode of delivery may induce changes to the immune system. Our hypothesis was that the delivery mode may influence mainly the naive T cell subpopulation. AIMS: Particular focus was set on the proportions and peripheral replicative history of naive T cells and cord blood serum concentrations of IL-7, a cytokine involved in peripheral naive T cell homeostasis. STUDY DESIGN, SUBJECTS AND OUTCOME MEASURES: In a prospective cohort study, proportions of lymphocyte populations were measured in mothers and newborns delivered by spontaneous vaginal delivery (SD), vacuum extraction (VE), primary (PCS) and secondary Cesarean sections (SCS) by flow cytometry. T-cell receptor-excision-circles (TRECs) and relative telomere lengths (RTLs) were used to estimate the replicative history of peripheral naive T cells. The cytokine profile was assessed by ELISA. RESULTS: The study demonstrated that leukocytes, neutrophils and NK cells were increased in spontaneously delivered newborns compared to PCS, whereas circulating T cells were relatively lower. TRECs and RTLs were not significantly influenced by the delivery mode. IL-2, IL-8 and IFN gamma were increased in VD. IL-7 production tends to be increased in more stress associated delivery modes, such as VE and SCS. CONCLUSIONS: Our results demonstrate proportional changes in newborns delivered by PCS and diminished cytokine production. It has to be proven whether these alterations may be of disadvantage regarding early defense of infectious diseases. Understanding the physiological role of these changes may help to find preventive strategies for neonatal infectious risks and the development of atopy or other immune diseases. PMID- 26513627 TI - Validation of the Chilean version of the Ages and Stages Questionnaire (ASQ-CL) in Community Health Settings. AB - OBJECTIVE: To validate the translated and cross culturally adapted Chilean version of the 8 and 18month Ages and Stages Questionnaire (ASQ-CL) in a community sample. METHODS: PARTICIPANTS: Parents of 1572 term children (82.9%) and 324 children at risk for developmental delay (17.1%) were included. INSTRUMENT: ASQ-3rd edition translated and culturally adapted for Chilean urban population. MAIN MEASURES: 8 and 18months ASQ-CL reliability, validity and mean scores. Feasibility was assessed using qualitative methods in healthcare professionals and mothers. RESULTS: ASQ-CL mean scores were comparable to U.S. normative data. The overall total score and all domains were reliable (Cronbach alpha 0.66-0.85). Test-retest and inter-rater reliability were high (Pearson's r range 0.73-0.94; intraclass correlation r range 0.68-0.93). Early preterm infants were more likely to fail on several criteria. Qualitative methods confirmed ASQ CL as a feasible tool in this Chilean urban community. CONCLUSIONS: ASQ-CL is a valid, reliable and feasible tool for assessing development in children at 8 and 18months in Chilean urban population. PMID- 26513628 TI - The role of elevated central-peripheral temperature difference in early detection of late-onset sepsis in preterm infants. AB - AIMS: The study investigated the association between clinical symptoms and late onset sepsis (LOS) in preterm infants with the aim of identifying a non-invasive tool for the early detection of LOS. METHODS: This was a prospective study of 83 episodes of suspected LOS in 67 preterm infants. At the time LOS was suspected, we recorded a standardized set of clinical symptoms. A diagnosis of "clinical LOS" (Clin-LOS), "culture-proven LOS" (Prov-LOS) or "LOS not present" (No-LOS) was made on the basis of C-reactive protein (CrP) and blood culture results where Clin-LOS was defined as CrP>10mg/l, Prov-LOS was defined as CrP>10mg/l AND positive blood cultures, or it was established that there was no sepsis present (No-LOS). We examined univariable associations between clinical signs and LOS using odds ratio (OR) analysis and then adjusted the odds ratio (adOR) through binary regression analysis. RESULTS: Clin-LOS was diagnosed in 20/83 episodes, 19 cases were found to have Prov-LOS. Clinical signs which had a significant association with Clin-LOS were capillary refill time >2s (OR 2.9) and decreased responsiveness (OR 5.2), whereas there was a negative association between gastric residuals and LOS (OR 0.35). However, the most marked association was found for a greater central-peripheral temperature difference (cpTD) >2 degrees C (OR 9). In Prov-LOS an increased heart rate (OR 3.1), prolonged capillary refill time (OR 3.3) and again an increased cpTD (OR 16) had a significant association with LOS, whereas gastric residuals were negatively associated (OR 0.29). Regression analysis showed that cpTD was the most striking clinical sign associated with both Clin- (adOR 6.3) and Prov-LOS (adOR 10.5). CONCLUSIONS: Prolonged capillary refill time and - more impressive - elevated cpTD were the most useful clinical symptoms for detection of LOS in preterm infants. We especially suggest using cpTD as a predictor of LOS. It is a cheap, non-invasive and readily available tool for daily routines. PMID- 26513629 TI - Trajectories of general movements from birth to term-equivalent age in infants born <30 weeks' gestation. AB - BACKGROUND: General movements (GMs) is an assessment with good predictive validity for neurodevelopmental outcomes in preterm infants. However, there is limited information describing the early GMs of very preterm infants, particularly prior to term. AIMS: To describe the early GMs trajectory of very preterm infants (born <30weeks' gestation) from birth to term-equivalent age, and to assess the influence of known perinatal risk factors on GMs. STUDY DESIGN: Prospective cohort study. SUBJECTS: 149 very preterm infants born <30weeks' gestation. OUTCOME MEASURES: GMs were recorded weekly from birth until 32weeks' postmenstrual age, and then fortnightly until 38weeks' postmenstrual age. GMs were also assessed at term-equivalent age. Detailed perinatal data were collected. RESULTS: Of 669 GMs assessed, 551 were preterm and 118 were at term equivalent age. Prior to term, 15% (n=82) of GMs were normal and 85% (n=469) were abnormal, with the proportion of abnormal GMs decreasing with increasing postmenstrual age (p for trend <0.001). By term-equivalent 30% (n=35) of GMs were normal. On univariable analysis, lower gestational age (p<0.001), postnatal infection (p<0.001) and bronchopulmonary dysplasia (p=0.001) were associated with abnormal GMs. Postnatal infection was the only independent perinatal association with abnormal GMs on multivariable analysis. All four infants with grade III/IV intraventricular haemorrhage (IVH) had persistently abnormal GMs. CONCLUSIONS: GMs were predominantly abnormal in very preterm infants, with a higher proportion of normal GMs at term-equivalent age than prior to term. Abnormal GMs were associated with postnatal infection and IVH. PMID- 26513630 TI - Challenges of neurodevelopmental follow-up for extremely preterm infants at two years. AB - AIM: This study examined the rates of follow-up for a cohort of extremely preterm (EP -<28weeks gestation) and/or extremely low birthweight (ELBW -<1000g) children at two years with related perinatal and geographical factors. The secondary aim was to determine the rates of developmental delay and disability. METHODS: A retrospective review of two year follow-up data for all EP and/or ELBW infants born in a large tertiary neonatal hospital over a two year period was undertaken. Neurodevelopmental outcome was assessed using the Bayley Scales of Infant and Toddler Development Scale - 3rd edition (Bayley-III) and neurosensory disability was assessed by a paediatrician using a standard proforma. Rates of delay (composite score>=1SD below mean) were determined using the Bayley-III test norms and a local cohort normative group. Attrition rates and reasons for loss to follow-up were determined. RESULTS: Only 50% (109/219) of eligible children participated in the follow-up. The follow-up rate for children engaged in an ongoing research project was excellent at 98% (58/59), however it was only 32% (51/160) for children following the clinical pathway. The main reason for not attending the follow-up was loss of contact. Factors associated with attendance included a lower gestation, sepsis and living in the metropolitan areas. The rates of delay in this cohort were greater with reference to local cohort normative data compared to Bayley-III test norms with an overall rate of delay of 72% (95%CI, 63% to 81%) compared to 38% (95%CI, 29% to 50%). CONCLUSIONS: Follow up of EP/ELBW infants to two years is an important part of clinical care, however the high rate of attrition in routine clinical follow-up and consequent difficulty in accurately determining rates of delay highlight challenges for centres providing ongoing care. PMID- 26513631 TI - Bioinspired Oil Core/Silica Shell Nanocarriers with Tunable and Multimodal Functionalities. AB - The application of multimodal systems in the field of nanomedicine is advantageous as they can perform two or more tasks simultaneously. Here a robust approach is presented mimicking biogenic silica to design a multilayered nanocarrier system with a central oil core encapsulated within a polymer-silica shell. The outermost silica shell has been deposited through a biosilicification process induced by poly-L-lysine molecules immobilized on the surface of emulsion droplets. This system can be simultaneously loaded with high amount of hydrophobic molecules or contrasting agents in the inner oil core, while the polymeric-silica layers can be easily tagged with at least two different contrasting agents. Additionally, the zwitterionic nature of the silica precipitating peptide (poly-L-lysine) has been efficiently exploited to modulate and entirely reverse the surface charge of the nanocarrier without using any additional coating material. It has been demonstrated experimentally that the designed nanocapsular system is monodisperse, nontoxic, cargo protective, tunable in thickness, fluorescent, and magnetic resonance imaging (MRI) active so highly versatile for multiple applications in the field of drug delivery and in vivo imaging. PMID- 26513632 TI - Cervical Lymphadenopathy. PMID- 26513633 TI - Natalizumab in multiple sclerosis: discontinuation, progressive multifocal leukoencephalopathy and possible use in children. AB - In the early 1990s, attention was drawn to the migration of immune cells into the central nervous system via the blood-brain barrier. The literature showed that lymphocytes binding to the endothelium were successfully inhibited by an antibody against alpha4beta1 integrin. These biological findings resulted in the development of a humanized antibody to alpha4 integrin - natalizumab (NTZ) - to treat multiple sclerosis (MS). Here, we provide a systematic review and meta analysis on the efficacy and safety of natalizumab, trying to answer the question whether its use may be recommended both in adult and in pediatric age groups as standard MS treatment. Our results highlight the improvement of clinical and radiological findings in treated patients (p < 0.005), confirming NTZ efficacy. Nevertheless, if NTZ is shown to be efficient, further studies should be performed to evaluate its safety and to target the MS profile that could benefit from this treatment. PMID- 26513634 TI - The attraction of evil and the destruction of meaning. AB - Does the concept of evil deserve special formulation in the realm of psychoanalytic thought? In agreement with authors such as Meltzer (1992) and De Masi (2003) and through selected moments from a boy's long analysis, I will propose a definition of evil as a state of mind, characterized by disregard for the human quality of the object and the destruction of meaning and meaningfulness of life in and for others. Evil drains, perverts and strips symbols of intentions and goals, leaving them empty of emotional significance. In my patient, the state of mind that he called evil exerted a seductive appeal and was accompanied by a sadistic excitement that he elevated into a state of sexualized well-being, which progressively perverted and destroyed emotional meaning, contributing to his confusion and desperation. Confronting this pathological configuration and describing the situation that I felt existed within his mind and between us, and rearticulating emotional meaning where it had been perverted, cannibalized or left empty, was the principal - and at times only - clinical instrument available to lead him out of his descent into nothingness. PMID- 26513635 TI - Mutually enhancing anti-inflammatory activities of dimethyl fumarate and NF kappaB inhibitors--implications for dose-sparing combination therapies. AB - Fumaric acid esters, dimethyl fumarate (DMF) in particular, have been established for the therapy of psoriasis and, more recently, multiple sclerosis. In the light of therapy-limiting dose-dependent side effects, such as gastrointestinal irritation, reducing the effective doses of FAE is a worthwhile goal. In search of strategies to maintain the anti-inflammatory activity of DMF at reduced concentrations, we found that NF-kappaB inhibition augmented key anti inflammatory effects of DMF in two complementary experimental settings in vitro. At non-toxic concentrations, both proteasome inhibition with bortezomib as well as blocking NF-kappaB activation through KINK-1, a small molecule inhibitor of IKKbeta-profoundly enhanced DMF-dependent inhibition of nuclear NF-kappaB translocation in TNFalpha-stimulated human endothelial cells. This resulted in significant and selective co-operative down-regulation of endothelial adhesion molecules crucial for leucocyte extravasation, namely E-selectin (CD62E), VCAM-1 (CD106) and ICAM-1 (CD54), on both mRNA and protein levels. Functionally, these molecular changes led to synergistically decreased rolling and firm adhesion of human lymphocytes on TNF-activated endothelial cells, as demonstrated in a dynamic flow chamber system. If our in vitro findings can be translated into clinical settings, it is conceivable that anti-inflammatory effects of DMF can be achieved with lower doses than currently used, thus potentially reducing unwanted side effects. PMID- 26513636 TI - Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. AB - In this article, the American Cancer Society provides an overview of female breast cancer statistics in the United States, including data on incidence, mortality, survival, and screening. Approximately 231,840 new cases of invasive breast cancer and 40,290 breast cancer deaths are expected to occur among US women in 2015. Breast cancer incidence rates increased among non-Hispanic black (black) and Asian/Pacific Islander women and were stable among non-Hispanic white (white), Hispanic, and American Indian/Alaska Native women from 2008 to 2012. Although white women have historically had higher incidence rates than black women, in 2012, the rates converged. Notably, during 2008 through 2012, incidence rates were significantly higher in black women compared with white women in 7 states, primarily located in the South. From 1989 to 2012, breast cancer death rates decreased by 36%, which translates to 249,000 breast cancer deaths averted in the United States over this period. This decrease in death rates was evident in all racial/ethnic groups except American Indians/Alaska Natives. However, the mortality disparity between black and white women nationwide has continued to widen; and, by 2012, death rates were 42% higher in black women than in white women. During 2003 through 2012, breast cancer death rates declined for white women in all 50 states; but, for black women, declines occurred in 27 of 30 states that had sufficient data to analyze trends. In 3 states (Mississippi, Oklahoma, and Wisconsin), breast cancer death rates in black women were stable during 2003 through 2012. Widening racial disparities in breast cancer mortality are likely to continue, at least in the short term, in view of the increasing trends in breast cancer incidence rates in black women. PMID- 26513637 TI - Temperature Dependence of the Piezotronic and Piezophototronic Effects in a-axis GaN Nanobelts. AB - The temperature dependence of the piezotronic and piezophototronic effects in a axis GaN nanobelts from 77 to 300 K is investigated. The piezotronic effect is enhanced by over 440% under lower temp-eratures. Two independent processes are discovered to form a competing mechanism through the investigation of the temperature dependence of the piezophototronic effect in a-axis GaN nanobelts. PMID- 26513638 TI - Outbreak of Escherichia coli O157:H7 Infections Associated with Dairy Education Event Attendance - Whatcom County, Washington, 2015. AB - On April 27, 2015, the Whatcom County Health Department (WCHD) in Bellingham, Washington, was notified by a local laboratory regarding three children with presumptive Escherichia coli O157 infection. WCHD interviewed the parents, who indicated that all three children had attended a dairy education event held in a barn April 20-24, 2015, during a school field trip. WCHD, the Washington State Department of Health, and CDC investigated to determine the magnitude of the outbreak, identify risk factors and potential environmental sources of infection, and develop recommendations. A total of 60 cases (25 confirmed and 35 probable) were identified, and 11 patients were hospitalized. PMID- 26513639 TI - Methadone related deaths compared to all prescription related deaths. AB - BACKGROUND: Methadone is increasingly implicated in unintentional overdose deaths. Despite major interventions, rates continue to remain high. One primary intervention, Prescription Drug Monitoring Programs (PDMP) are limited in their ability to impact this epidemic due to federal law restricting Opioid Treatment Programs (OTPs) from sharing data to PDMPs, despite being a major source of Methadone dispensing. METHODS: This retrospective, observational study analyzed all prescription-related deaths occurring in San Diego County during the year 2013 with a specific focus on methadone-related deaths. All patients designated by medical examiner to have died by unintentional prescription were then referenced in the California PDMP, the Controlled Substance Utilization Review and Evaluation System (CURES). RESULTS: As a whole, patients who died had a high number of average prescriptions, 21, and averaged 4.5 different providers, and three different pharmacies. Methadone-related deaths (MRD) accounted for 46 out of the 254 total patient deaths (18.1%). Methadone prescriptions were found in 14 patients with PDMP reports, 10 of who had methadone on toxicology report. Notably, 100% of methadone prescribed by primary care specialists. MRD patients were less likely to have toxicology reports matching PDMP data compared to other related drug deaths (20.6 vs. 61.2%, p<0.0001). Of the 46 methadone deaths, only 10 (29.4%) had prescriptions for methadone recorded in the database. Out of the 51 patients with only one drug recorded at death, methadone was most common (n=12; 23.5%). While all deaths had a notably high rate of chronic prescriptions at death (68.8% compared to 2% for all patients in CURES), there was no significant difference between MRD and other drug-related deaths (73.5 vs. 67.8%, p=0.68, respectively). MRD patients were less likely than other drug patients to have matching PDMP data without any illicit substance or alcohol (14.7 vs. 41.4%, p=0.003, respectively). CONCLUSION: Methadone is a long-acting opioid that carries a higher risk profile than other opioids. In San Diego, the great majority of MRD had no data on methadone in the statewide PDMP database, bringing to question the restriction of OTP clinics from uploading information into the database. A risk-benefit analysis should be made to consider changing laws that would allow for OTP to input data into PDMP. OTP should make it standard of care to check PDMP data on their patients. Methadone prescribed for pain management should be limited to the most compliant patients. PMID- 26513640 TI - 2-Amino-thiophene derivatives present antileishmanial activity mediated by apoptosis and immunomodulation in vitro. AB - This study evaluated the effects of 2-amino-thiophene derivatives on the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis and their possible mechanisms of action. Initially, we evaluated the antileishmanial activity of ten 2-amino-thiophene derivatives on promastigote and axenic amastigote forms of Leishmania amazonensis and their cytotoxicity against murine macrophages and human red blood cells. Three promising compounds were selected for studies of the cell death process using flow cytometry analysis and a DNA fragmentation assay. The effects of the compounds were assessed on intramacrophagic amastigotes, and the modulation of cytokine and NO production was investigated. All thiophene derivatives showed antileishmanial activity against promastigotes and axenic amastigotes with less toxicity for murine macrophages and human red blood cells. The best values were obtained for compounds containing a lateral indole ring. Docking studies suggested that these compounds played an important role in inhibiting trypanothione reductase (TryR) activity. The selected compounds SB-200, SB-44, and SB-83 induced apoptosis in promastigotes involving phosphatidylserine externalization and DNA fragmentation in a pattern similar to that observed for the positive control. Additionally, SB 200, SB-44, and SB-83 significantly reduced the infection index of macrophages by the parasites; for compounds SB-200 and SB-83 this reduction was associated with increased TNF-alpha, IL-12, and NO levels. This study demonstrated the effective and selective action of 2-amino-thiophene derivatives against L. amazonensis, resulting in apoptosis-like cell death and immunomodulation in vitro. The results suggest that they are promising compounds for the development of new leishmanicidal drugs. PMID- 26513641 TI - Design and synthesis of fused tetrahydroisoquinoline-iminoimidazolines. AB - In the aim of identifying new privileged structures, we describe the 5-steps synthesis of cyclic guanidine compounds "tetrahydroisoquinoline iminoimidazolines" derived from tetrahydroisoquinoline-hydantoin core. In order to evaluate this new minimal structure and the impact of replacing a carbonyle by a guanidine moiety, their affinity towards adenosine receptor A2A was evaluated and compared to those of tetrahydroisoquinoline-hydantoin compounds. PMID- 26513642 TI - Highly functionalized tetrahydropyridines are cytotoxic and selective inhibitors of human puromycin sensitive aminopeptidase. AB - Efficient one-pot five-component synthetic protocols for highly functionalized tetrahydropyridines (THPs) and their biological evaluation have been illustrated. Synthesis of novel functionalized tetrahydropyridines containing differential substitutions at 2,6-positions has been achieved via a modified MCR. Cytotoxic studies of 23 synthesized compounds have been carried out against three different cell lines, namely A-549, HeLa and HepG2, wherein some compounds have displayed appreciable cytotoxicity. Further, investigation of enzyme inhibition by the synthesized THPs has been carried out against four members of M1 family aminopeptidases. Several compounds have selectively inhibited only one member of this enzyme family i.e., human puromycin sensitive aminopeptidase (hPSA). Among the compounds; 4b, 9b, 9e and 10a demonstrated best inhibition against hPSA. PMID- 26513643 TI - Tryptophan dendrimers that inhibit HIV replication, prevent virus entry and bind to the HIV envelope glycoproteins gp120 and gp41. AB - Dendrimers containing from 9 to 18 tryptophan residues at the peryphery have been efficiently synthesized and tested against HIV replication. These compounds inhibit an early step of the replicative cycle of HIV, presumably virus entry into its target cell. Our data suggest that HIV inhibition can be achieved by the preferred interaction of the compounds herein described with glycoproteins gp120 and gp41 of the HIV envelope preventing interaction between HIV and the (co)receptors present on the host cells. The results obtained so far indicate that 9 tryptophan residues on the periphery are sufficient for efficient gp120/gp41 binding and anti-HIV activity. PMID- 26513644 TI - Cement As a Waste Form for Nuclear Fission Products: The Case of (90)Sr and Its Daughters. AB - One of the main challenges faced by the nuclear industry is the long-term confinement of nuclear waste. Because it is inexpensive and easy to manufacture, cement is the material of choice to store large volumes of radioactive materials, in particular the low-level medium-lived fission products. It is therefore of utmost importance to assess the chemical and structural stability of cement containing radioactive species. Here, we use ab initio calculations based on density functional theory (DFT) to study the effects of (90)Sr insertion and decay in C-S-H (calcium-silicate-hydrate) in order to test the ability of cement to trap and hold this radioactive fission product and to investigate the consequences of its beta-decay on the cement paste structure. We show that (90)Sr is stable when it substitutes the Ca(2+) ions in C-S-H, and so is its daughter nucleus (90)Y after beta-decay. Interestingly, (90)Zr, daughter of (90)Y and final product in the decay sequence, is found to be unstable compared to the bulk phase of the element at zero K but stable when compared to the solvated ion in water. Therefore, cement appears as a suitable waste form for (90)Sr storage. PMID- 26513645 TI - Reconstruction of the ankle complex wound with a fabricated superficial circumflex iliac artery chimeric flap including the sartorius muscle: A case report. AB - Free flap reconstruction of the foot and ankle can be challenging in that it must fulfill functional and esthetic demands. Injury of this region is often associated with fractures, and muscle flaps are sometimes preferred. Here we present a case of the use of superficial circumflex iliac artery (SCIA) chimeric flap for reconstruction of ankle complex wound. A 78-year-old lady sustained open fractures of the left distal tibia, fibula, and talus, with a 10 * 6 cm2 soft tissue defect over the lateral aspect of her left ankle due to an automobile accident. A 7 * 3 cm2 sartorius muscle component was inset to cover the exposed left ankle joint capsule, and a 5 * 10 cm2 SCIP skin paddle was used for coverage of the defect. The postoperative course was uneventful, and the sartorius muscle component and the SCIP skin paddle survived completely. Six months after the reconstruction, the flap and the donor site showed pleasing cosmesis, and the patient could ambulate with a supple ankle without crutches. The sartorius muscle component was elevated based on the deep branch of the SCIA, and was chimerically combined with a SCIP skin paddle for reconstruction of a complex ankle injury. (c) 2015 Wiley Periodicals, Inc. Microsurgery 37:421-425, 2017. PMID- 26513646 TI - Biotinylated Cubosomes: A Versatile Tool for Active Targeting and Codelivery of Paclitaxel and a Fluorescein-Based Lipid Dye. AB - The functionalization of cubosomes with biotin is reported here as an alternative method for the preparation of drug delivery systems capable of active targeting specific receptors that are (over)expressed by cancer cells. We describe the design, synthesis, assembly, and characterization of these novel cubosome nanoparticles by small-angle X-ray scattering (SAXS) and dynamic laser light scattering (DLS) and show their application to human adenocarcinoma cell line HeLa. These cubosomes are stabilized and functionalized with a novel, designed biotin-based block copolymer and are able to simultaneously transport paclitaxel, a potent anticancer drug, and a hydrophobic fluorescent dye in the active targeting of cancer cells. Such biotinylated cubosomes are potentially applicable in diagnosis, drug delivery, and monitoring of the therapeutic response for active targeting versus cancer cells. PMID- 26513647 TI - Pharmacotherapy of head and neck cancer. AB - INTRODUCTION: There are over 55,000 new cases of head and neck cancer diagnosed annually in the United States. Historically surgical resection was the standard of care, but due to vital structures in the head and neck region this led to severe morbidity. The integration of pharmacotherapy has rapidly expanded over the years into a multimodality treatment paradigm for locally advanced head and neck cancer, allowing organ-sparing treatment approaches. Here we discuss the various approaches and settings in which chemotherapy can be incorporated into the management of head and neck squamous cell carcinoma (HNSCC). AREAS COVERED: Chemotherapy in HNSCC can be administered in several different treatment circumstances: in the metastatic setting for palliation of symptoms and prolongation of survival, before definitive local treatment (induction), as part of definitive treatment simultaneously with radiation (concurrent) or after definitive local therapy (adjuvant). EXPERT OPINION: The incorporation of chemotherapy into the management of patients with head and neck cancer has allowed organ preservation approaches and improved survival. Because of the toxicities of chemotherapy, it is imperative that chemotherapy is only administered to the appropriate patient population who are more likely to benefit. Cisplatin 100 mg/m(2) given in combination with radiation in the non metastatic setting is the most widely tested regimen and remains the reference regimen. Cetuximab is also an alternative, but there is no data to support the use of cetuximab in a laryngeal preservation approach or in the postoperative setting. PMID- 26513648 TI - MicroRNA 17-5p regulates autophagy in Mycobacterium tuberculosis-infected macrophages by targeting Mcl-1 and STAT3. AB - Autophagy plays a crucial role in the control of bacterial burden during Mycobacterium tuberculosis infection. MicroRNAs (miRNAs) are small non-coding RNAs that regulate immune signalling and inflammation in response to challenge by pathogens. Appreciating the potential of host-directed therapies designed to control autophagy during mycobacterial infection, we focused on the role of miRNAs in regulating M. tuberculosis-induced autophagy in macrophages. Here, we demonstrate that M. tuberculosis infection leads to downregulation of miR-17 and concomitant upregulation of its targets Mcl-1 and STAT3, a transcriptional activator of Mcl-1. Forced expression of miR-17 reduces expression of Mcl-1 and STAT3 and also the interaction between Mcl-1 and Beclin-1. This is directly linked to enhanced autophagy, because Mcl-1 overexpression attenuates the effects of miR-17. At the same time, transfection with a kinase-inactive mutant of protein kinase C delta (PKCdelta) (an activator of STAT3) augments M. tuberculosis-induced autophagy, and miR-17 overexpression diminishes phosphorylation of PKCdelta, suggesting that an miR-17/PKC delta/STAT3 axis regulates autophagy during M. tuberculosis infection. PMID- 26513649 TI - Reversible Single-Crystal to Single-Crystal Transformations of a Zn(II) Salicyaldimine Coordination Polymer Accompanying Changes in Coordination Sphere and Network Dimensionality upon Dehydration and Rehydration. AB - A fluorescent Zn(II)-salicyaldimine coordination polymer, [Zn(L(salpyca))(H2O)]n (1; H2L(salpyca) = 4-hydroxy-3-(((pyridin-2-yl)methylimino)methyl)benzoic acid), showing a one-dimensional (1D) zigzag chain structure has been hydro(solvo)thermally synthesized. Removal of coordination water molecules in 1 by thermal dehydration gives rise to the dehydration product [Zn(L(salpyca))]n (1'), which has a dizinc-based two-dimensional (2D) gridlike (4,4)-layer structure. X-ray powder diffraction (XRPD) patterns, thermogravimetric (TG) analyses, and infrared (IR) spectra all clearly indicate that the structure of 1 is quite flexible as a result of a reversible 1D-2D single-crystal to single crystal (SCSC) transformation upon removal and rebinding of coordination water molecules, which accompanies changes in coordination sphere and network dimensionality. Additionally, Zn(II)-salicyaldimine polymers 1 and 1' exhibit different solid-state photoluminescences at 458 and 480 nm, respectively. This is reasonably attributed to the close-packing effect and/or the influences of the differences on the conformation and the coordination mode of the L(salpyca) ligand and the coordination geometry around the Zn(II) center. PMID- 26513650 TI - Angiogenic Gene Expression in Down Syndrome Fetal Hearts. AB - INTRODUCTION: Forty percent of Down syndrome (DS) fetuses have congenital heart defects (CHD). An abnormal angiogenic environment has been described in euploid fetuses with CHD. However, the underlying pathophysiologic pathway that contributes to CHD in DS remains unknown. The objective was to compare the expression of angiogenic factors and chronic hypoxia genes in heart tissue from DS and euploid fetuses with and without CHD. METHODS: The gene expression profile was determined by real-time PCR quantification in heart tissue from 33 fetuses with DS, 23 euploid fetuses with CHD and 23 control fetuses. RESULTS: Angiogenic factors mRNA expression was significantly increased in the DS group compared to the controls (soluble fms-like tyrosine kinase-1, 81%, p = 0.007; vascular endothelial growth factor A, 57%, p = 0.006, and placental growth factor, 32%, p = 0.0227). Significant increases in the transcript level of hypoxia-inducible factor-2alpha and heme oxygenase 1 were also observed in the DS group compared to the controls. The expression of angiogenic factors was similar in DS fetuses and CHD euploid fetuses with CHD. CONCLUSION: Abnormal angiogenesis was detected in the hearts of DS fetuses with and without CHD. Our results suggest that DS determines an intrinsically angiogenic impairment that may be present in the fetal heart. PMID- 26513651 TI - Right Limbic FDG-PET Hypometabolism Correlates with Emotion Recognition and Attribution in Probable Behavioral Variant of Frontotemporal Dementia Patients. AB - The behavioural variant of frontotemporal dementia (bvFTD) is a rare disease mainly affecting the social brain. FDG-PET fronto-temporal hypometabolism is a supportive feature for the diagnosis. It may also provide specific functional metabolic signatures for altered socio-emotional processing. In this study, we evaluated the emotion recognition and attribution deficits and FDG-PET cerebral metabolic patterns at the group and individual levels in a sample of sporadic bvFTD patients, exploring the cognitive-functional correlations. Seventeen probable mild bvFTD patients (10 male and 7 female; age 67.8+/-9.9) were administered standardized and validated version of social cognition tasks assessing the recognition of basic emotions and the attribution of emotions and intentions (i.e., Ekman 60-Faces test-Ek60F and Story-based Empathy task-SET). FDG-PET was analysed using an optimized voxel-based SPM method at the single subject and group levels. Severe deficits of emotion recognition and processing characterized the bvFTD condition. At the group level, metabolic dysfunction in the right amygdala, temporal pole, and middle cingulate cortex was highly correlated to the emotional recognition and attribution performances. At the single-subject level, however, heterogeneous impairments of social cognition tasks emerged, and different metabolic patterns, involving limbic structures and prefrontal cortices, were also observed. The derangement of a right limbic network is associated with altered socio-emotional processing in bvFTD patients, but different hypometabolic FDG-PET patterns and heterogeneous performances on social tasks at an individual level exist. PMID- 26513653 TI - Crack Detection in Fibre Reinforced Plastic Structures Using Embedded Fibre Bragg Grating Sensors: Theory, Model Development and Experimental Validation. AB - In a fibre-reinforced polymer (FRP) structure designed using the emerging damage tolerance and structural health monitoring philosophy, sensors and models that describe crack propagation will enable a structure to operate despite the presence of damage by fully exploiting the material's mechanical properties. When applying this concept to different structures, sensor systems and damage types, a combination of damage mechanics, monitoring technology, and modelling is required. The primary objective of this article is to demonstrate such a combination. This article is divided in three main topics: the damage mechanism (delamination of FRP), the structural health monitoring technology (fibre Bragg gratings to detect delamination), and the finite element method model of the structure that incorporates these concepts into a final and integrated damage monitoring concept. A novel method for assessing a crack growth/damage event in fibre-reinforced polymer or structural adhesive-bonded structures using embedded fibre Bragg grating (FBG) sensors is presented by combining conventional measured parameters, such as wavelength shift, with parameters associated with measurement errors, typically ignored by the end-user. Conjointly, a novel model for sensor output prediction (virtual sensor) was developed using this FBG sensor crack monitoring concept and implemented in a finite element method code. The monitoring method was demonstrated and validated using glass fibre double cantilever beam specimens instrumented with an array of FBG sensors embedded in the material and tested using an experimental fracture procedure. The digital image correlation technique was used to validate the model prediction by correlating the specific sensor response caused by the crack with the developed model. PMID- 26513652 TI - The Impact of Comorbid Depression on Educational Inequality in Survival after Acute Coronary Syndrome in a Cohort of 83 062 Patients and a Matched Reference Population. AB - BACKGROUND: Patients with low socioeconomic position have higher rates of mortality after diagnosis of acute coronary syndrome (ACS), but little is known about the mechanisms behind this social inequality. The aim of the present study was to examine whether any educational inequality in survival after ACS was influenced by comorbid conditions including depression. METHODS: From 2001 to 2009 all first-time ACS patients were identified in the Danish National Patient Registry. This cohort of 83 062 ACS patients and a matched reference population were followed for incident depression and mortality until December 2012 by linkage to person, patients and prescription registries. Educational status was defined at study entry and the impact of potential confounders and mediators (age, gender, cohabitation status, somatic comorbidity and depression) on the relation between education and mortality were identified by drawing a directed acyclic graph and analysed using multiple Cox regression analyses. FINDINGS: During follow-up, 29 583(35.6%) of ACS patients and 19 105(22.9%) of the reference population died. Cox regression analyses showed an increased mortality in the lowest educated compared to those with high education in both ACS patients and the reference population. Adjustment for previous and incident depression or other covariables only attenuated the relations slightly. This pattern of associations was seen for mortality after 30 days, 1 year and during total follow up. CONCLUSION: In this study the relative excess mortality rate in lower educated ACS patients was comparable with the excess risk associated with low education in the background population. This educational inequality in survival remained after adjustment for somatic comorbidity and depression. PMID- 26513654 TI - Exhalation immediately before inhalation optimizes dry powder inhaler use. AB - OBJECTIVE: Although exhalation immediately prior to inhalation (EPI) from dry powder inhalers (DPIs) is universally advised, its benefit has not been investigated. The objective of this study to assess the effects of EPI on inhaled flow from a DPI. METHODS: We measured peak inhaled flow rate (PIFR) and inhaled gas volume of 25 volunteers unfamiliar with DPIs. They inhaled strongly and deeply through a flow meter either with or without EPI before and after connecting Turbuhaler or Diskus. RESULTS: Median PIFR increased significantly with EPI both without connection to DPIs (178.8 versus 140.4 L min(-1)), and with connection to Diskus (75.6 versus 67.8 L min(-1)), or to Turbuhaler (51.0 versus 48.0 L min(-1)). As a result, the number of subjects whose PIFR exceeded 60 L min(-1) was significantly increased with connection to either Diskus (76 versus 64%) or to Turbuhaler (24 versus 4%). EPI significantly increased median inhaled volume both without connection to DPIs (2.84 versus 1.84 L), and with connection to Diskus (1.95 versus 1.66 L), or to Turbuhaler (1.86 versus 1.28 L). EPI significantly increased F0.2 (flow at 0.2 s after onset of inhalation) and AC30 (flow acceleration at 30 L min(-1)), parameters representing the rate of flow increase during the early phase of inhalation, in all the three groups. CONCLUSIONS: EPI increases PIFR which may augment drug dispersion and facilitate fine particle generation from a DPI. PMID- 26513655 TI - A Theoretical Analysis of the Geography of Schistosomiasis in Burkina Faso Highlights the Roles of Human Mobility and Water Resources Development in Disease Transmission. AB - We study the geography of schistosomiasis across Burkina Faso by means of a spatially explicit model of water-based disease dynamics. The model quantitatively addresses the geographic stratification of disease burden in a novel framework by explicitly accounting for drivers and controls of the disease, including spatial information on the distributions of population and infrastructure, jointly with a general description of human mobility and climatic/ecological drivers. Spatial patterns of disease are analysed by the extraction and the mapping of suitable eigenvectors of the Jacobian matrix subsuming the stability of the disease-free equilibrium. The relevance of the work lies in the novel mapping of disease burden, a byproduct of the parametrization induced by regional upscaling, by model-guided field validations and in the predictive scenarios allowed by exploiting the range of possible parameters and processes. Human mobility is found to be a primary control at regional scales both for pathogen invasion success and the overall distribution of disease burden. The effects of water resources development highlighted by systematic reviews are accounted for by the average distances of human settlements from water bodies that are habitats for the parasite's intermediate host. Our results confirm the empirical findings about the role of water resources development on disease spread into regions previously nearly disease free also by inspection of empirical prevalence patterns. We conclude that while the model still needs refinements based on field and epidemiological evidence, the proposed framework provides a powerful tool for large-scale public health planning and schistosomiasis management. PMID- 26513656 TI - Bone regeneration in critical bone defects using three-dimensionally printed beta tricalcium phosphate/hydroxyapatite scaffolds is enhanced by coating scaffolds with either dipyridamole or BMP-2. AB - Bone defects resulting from trauma or infection need timely and effective treatments to restore damaged bone. Using specialized three-dimensional (3D) printing technology we have created custom 3D scaffolds of hydroxyapatite (HA)/beta-tri-calcium phosphate (beta-TCP) to promote bone repair. To further enhance bone regeneration we have coated the scaffolds with dipyridamole, an agent that increases local adenosine levels by blocking cellular uptake of adenosine. Nearly 15% HA:85% beta-TCP scaffolds were designed using Robocad software, fabricated using a 3D Robocasting system, and sintered at 1100 degrees C for 4 h. Scaffolds were coated with BMP-2 (200 ng mL-1 ), dypiridamole 100 uM or saline and implanted in C57B6 and adenosine A2A receptor knockout (A2AKO) mice with 3 mm cranial critical bone defects for 2-8 weeks. Dipyridamole release from scaffold was assayed spectrophotometrically. MicroCT and histological analysis were performed. Micro-computed tomography (microCT) showed significant bone formation and remodeling in HA/beta-TCP-dipyridamole and HA/beta-TCP-BMP-2 scaffolds when compared to scaffolds immersed in vehicle at 2, 4, and 8 weeks (n = 5 per group; p <= 0.05, p <= 0.05, and p <= 0.01, respectively). Histological analysis showed increased bone formation and a trend toward increased remodeling in HA/beta-TCP- dipyridamole and HA/beta-TCP-BMP-2 scaffolds. Coating scaffolds with dipyridamole did not enhance bone regeneration in A2AKO mice. In conclusion, scaffolds printed with HA/beta-TCP promote bone regeneration in critical bone defects and coating these scaffolds with agents that stimulate A2A receptors and growth factors can further enhance bone regeneration. These coated scaffolds may be very useful for treating critical bone defects due to trauma, infection or other causes. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 366-375, 2017. PMID- 26513657 TI - Proteomic Analysis of the Relationship between Metabolism and Nonhost Resistance in Soybean Exposed to Bipolaris maydis. AB - Nonhost resistance (NHR) pertains to the most common form of plant resistance against pathogenic microorganisms of other species. Bipolaris maydis is a non adapted pathogen affecting soybeans, particularly of maize/soybean intercropping systems. However, no experimental evidence has described the immune response of soybeans against B. maydis. To elucidate the molecular mechanism underlying NHR in soybeans, proteomics analysis based on two-dimensional polyacrylamide gel electrophoresis (2-DE) was performed to identify proteins involved in the soybean response to B. maydis. The spread of B. maydis spores across soybean leaves induced NHR throughout the plant, which mobilized almost all organelles and various metabolic processes in response to B. maydis. Some enzymes, including ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), mitochondrial processing peptidase (MPP), oxygen evolving enhancer (OEE), and nucleoside diphosphate kinase (NDKs), were found to be related to NHR in soybeans. These enzymes have been identified in previous studies, and STRING analysis showed that most of the protein functions related to major metabolic processes were induced as a response to B. maydis, which suggested an array of complex interactions between soybeans and B. maydis. These findings suggest a systematic NHR against non-adapted pathogens in soybeans. This response was characterized by an overlap between metabolic processes and response to stimulus. Several metabolic processes provide the soybean with innate immunity to the non-adapted pathogen, B. maydis. This research investigation on NHR in soybeans may foster a better understanding of plant innate immunity, as well as the interactions between plant and non adapted pathogens in intercropping systems. PMID- 26513659 TI - Erratum: Structural Mechanism for Regulation of Bcl-2 protein Noxa by phosphorylation. PMID- 26513658 TI - Insights into the Immunological Properties of Intrinsically Disordered Malaria Proteins Using Proteome Scale Predictions. AB - Malaria remains a significant global health burden. The development of an effective malaria vaccine remains as a major challenge with the potential to significantly reduce morbidity and mortality. While Plasmodium spp. have been shown to contain a large number of intrinsically disordered proteins (IDPs) or disordered protein regions, the relationship of protein structure to subcellular localisation and adaptive immune responses remains unclear. In this study, we employed several computational prediction algorithms to identify IDPs at the proteome level of six Plasmodium spp. and to investigate the potential impact of protein disorder on adaptive immunity against P. falciparum parasites. IDPs were shown to be particularly enriched within nuclear proteins, apical proteins, exported proteins and proteins localised to the parasitophorous vacuole. Furthermore, several leading vaccine candidates, and proteins with known roles in host-cell invasion, have extensive regions of disorder. Presentation of peptides by MHC molecules plays an important role in adaptive immune responses, and we show that IDP regions are predicted to contain relatively few MHC class I and II binding peptides owing to inherent differences in amino acid composition compared to structured domains. In contrast, linear B-cell epitopes were predicted to be enriched in IDPs. Tandem repeat regions and non-synonymous single nucleotide polymorphisms were found to be strongly associated with regions of disorder. In summary, immune responses against IDPs appear to have characteristics distinct from those against structured protein domains, with increased antibody recognition of linear epitopes but some constraints for MHC presentation and issues of polymorphisms. These findings have major implications for vaccine design, and understanding immunity to malaria. PMID- 26513660 TI - Understanding Recession and Self-Rated Health with the Partial Proportional Odds Model: An Analysis of 26 Countries. AB - INTRODUCTION: Self-rated health is demonstrated to vary substantially by both personal socio-economic status and national economic conditions. However, studies investigating the combined influence of individual and country level economic indicators across several countries in the context of recent global recession are limited. This paper furthers our knowledge of the effect of recession on health at both the individual and national level. METHODS: Using the Life in Transition II study, which provides data from 19,759 individuals across 26 European nations, we examine the relationship between self-rated health, personal economic experiences, and macro-economic change. Data analyses include, but are not limited to, the partial proportional odds model which permits the effect of predictors to vary across different levels of our dependent variable. RESULTS: Household experiences with recession, especially a loss of staple good consumption, are associated with lower self-rated health. Most individual-level experiences with recession, such as a job loss, have relatively small negative effects on perceived health; the effect of individual or household economic hardship is strongest in high income nations. Our findings also suggest that macroeconomic growth improves self-rated health in low-income nations but has no effect in high-income nations. Individuals with the greatest probability of "good" self-rated health reside in wealthy countries ($23,910 to $50, 870 GNI per capita). CONCLUSION: Both individual and national economic variables are predictive of self-rated health. Personal and household experiences are most consequential for self-rated health in high income nations, while macroeconomic growth is most consequential in low-income nations. PMID- 26513661 TI - Transcriptomic Characterization of an Infection of Mycobacterium smegmatis by the Cluster A4 Mycobacteriophage Kampy. AB - The mycobacteriophages, phages that infect the genus Mycobacterium, display profound genetic diversity and widespread geographical distribution, and possess significant medical and ecological importance. However, most of the majority of functions of mycobacteriophage proteins and the identity of most genetic regulatory elements remain unknown. We characterized the gene expression profile of Kampy, a cluster A4 mycobacteriophage, during infection of its host, Mycobacterium smegmatis, using RNA-Seq and mass spectrometry. We show that mycobacteriophage Kampy transcription occurs in roughly two phases, an early phase consisting of genes for metabolism, DNA synthesis, and gene regulation, and a late phase consisting of structural genes and lysis genes. Additionally, we identify the earliest genes transcribed during infection, along with several other possible regulatory units not obvious from inspection of Kampy's genomic structure. The transcriptional profile of Kampy appears similar to that of mycobacteriophage TM4 but unlike that of mycobacteriophage Giles, a result which further expands our understanding of the diversity of mycobacteriophage gene expression programs during infection. PMID- 26513662 TI - Prodrug AST-003 Improves the Therapeutic Index of the Multi-Targeted Tyrosine Kinase Inhibitor Sunitinib. AB - Patients have responded well to the multi-targeted tyrosine kinase inhibitor (TKI) Sunitinib in the clinic. But the severe toxic side effects associated with Sunitinib limit its therapeutic index. To improve the therapeutic index of Sunitinib, a prodrug strategy was employed to modify Sunitinib. The inactive prodrug AST-003 can be converted to Sunitinib in vitro and in vivo. Compared with Sunitinib, AST-003 has unique biochemical, cellular and pharmacokinetic properties with improved tolerability in mice and yield higher efficacy in tumor xenograft models. This prodrug strategy may constitute a novel paradigm to improve the therapeutic index of Sunitinib and other TKI or anti-angiogenesis drugs in general. PMID- 26513663 TI - Correction: The Value of BISAP Score for Predicting Mortality and Severity in Acute Pancreatitis: A Systematic Review and Meta-Analysis. PMID- 26513664 TI - Topology of Plant - Flower-Visitor Networks in a Tropical Mountain Forest: Insights on the Role of Altitudinal and Temporal Variation. AB - Understanding the factors determining the spatial and temporal variation of ecological networks is fundamental to the knowledge of their dynamics and functioning. In this study, we evaluate the effect of elevation and time on the structure of plant-flower-visitor networks in a Colombian mountain forest. We examine the level of generalization of plant and animal species and the identity of interactions in 44 bipartite matrices obtained from eight altitudinal levels, from 2200 to 2900 m during eight consecutive months. The contribution of altitude and time to the overall variation in the number of plant (P) and pollinator (A) species, network size (M), number of interactions (I), connectance (C), and nestedness was evaluated. In general, networks were small, showed high connectance values and non-nested patterns of organization. Variation in P, M, I and C was better accounted by time than elevation, seemingly related to temporal variation in precipitation. Most plant and insect species were specialists and the identity of links showed a high turnover over months and at every 100 m elevation. The partition of the whole system into smaller network units allowed us to detect small-scale patterns of interaction that contrasted with patterns commonly described in cumulative networks. The specialized but erratic pattern of network organization observed in this tropical mountain suggests that high connectance coupled with opportunistic attachment may confer robustness to plant flower-visitor networks occurring at small spatial and temporal units. PMID- 26513665 TI - Long Non-Coding RNA Expression Profiling in Aging Rats with Erectile Dysfunction. AB - BACKGROUND/AIMS: Erectile dysfunction (ED) in aged people remains a topic of interest to andrological physicians. Long non-coding RNAs (lncRNAs), which form the largest group of non-coding RNAs, have been shown to regulate various biological processes. The function of lncRNAs in age-related erectile dysfunction (A-ED) pathogenesis remains poorly understood. METHODS: This study aims to assess the differential expression profiles of mRNAs and lncRNAs between A-ED and normal control (NC) samples. Using a second-generation lncRNA microarray, we detected a total of 8,744 lncRNAs and 13,585 coding transcripts. RESULTS: We identified 608 up-regulated and 406 down-regulated lncRNAs in A-ED compared with NC samples, by setting a filter of fold-change >2.0. Gene Ontology and pathway analysis revealed that a muscle contraction disorder induced by abnormal ion channels might play a critical role in the pathogenesis of A-ED. CONCLUSION: Our results show significantly altered expression profiles of lncRNAs and mRNAs between A-ED and NC. This study may provide information for further research on A-ED and may be helpful for finding a new therapeutic target for A-ED. PMID- 26513666 TI - Multilocus sequence analysis for Mycoplasma synoviae molecular genotyping. AB - The aim of this study was to identify molecular techniques which enable clear discrimination between Mycoplasma synoviae isolates for improved epidemiology. Multilocus sequence analysis (MLSA) of 6 M. synoviae loci was conducted for genotyping of isolates with previously determined 5'-vlhA sequences. Sequencing of three polymorphic genes (5'-vlhA, cysP and nanH) enables good discrimination between isolates with different genotypes. Such a genotyping scheme revealed 10 distinct genotypes, which were confirmed by sequencing of an additional three loci of the M. synoviae genome. Epidemiologically linked strains formed clusters with the same genotypes which clearly differed between clusters. MLSA used in this study is a promising tool for epidemiology of M. synoviae isolates, but it should be evaluated by further investigations using a much higher number of M. synoviae strains. PMID- 26513667 TI - Single Nanoparticle Mass Spectrometry as a High Temperature Kinetics Tool: Sublimation, Oxidation, and Emission Spectra of Hot Carbon Nanoparticles. AB - In single nanoparticle mass spectrometry, individual charged nanoparticles (NPs) are trapped in a quadrupole ion trap and detected optically, allowing their mass, charge, and optical properties to be monitored continuously. Previous experiments of this type probed NPs that were either fluorescent or large enough to detect by light scattering. Alternatively, small NPs can be heated to temperatures where thermally excited emission is strong enough to allow detection, and this approach should provide a new tool for measurements of sublimation and surface reaction kinetics of materials at high temperatures. As an initial test, we report a study of carbon NPs in the 20-50 nm range, heated by 10.6 MUm, 532 nm, or 445 nm lasers. The kinetics for sublimation and oxidation of individual carbon NPs were studied, and a model is presented for the factors that control the NP temperature, including laser heating, and cooling by sublimation, buffer gas collisions, and radiation. The estimated NP temperatures were in the 1700-2000 K range, and the NP absorption cross sections ranged from ~0.8 to 0.2% of the geometric cross sections for 532 nm and 10.6 MUm excitation, respectively. Emission spectra of single NPs and small NP ensembles show a feature in the IR that appears to be the high energy tail of the thermal (blackbody-like) emission expected from hot particles but also a discrete feature peaking around 750 nm. Both the IR tail and 750 nm peak are observed for all particles and for both IR and visible laser excitation. No significant difference was observed between graphite and amorphous carbon NPs. PMID- 26513668 TI - Catalytic C-H bond silylation of aromatic heterocycles. AB - This protocol describes a method for the direct silylation of the carbon-hydrogen (C-H) bond of aromatic heterocycles using inexpensive and abundant potassium tert butoxide (KOt-Bu) as the catalyst. This catalytic cross-dehydrogenative coupling of simple hydrosilanes and various electron-rich aromatic heterocycles enables the synthesis of valuable silylated heteroarenes. The products thus obtained can be used as versatile intermediates, which facilitate the divergent synthesis of pharmaceutically relevant compound libraries from a single Si-containing building block. Moreover, a variety of complex Si-containing motifs, such as those produced by this protocol, are being actively investigated as next-generation therapeutic agents, because they can have improved pharmacokinetic properties compared with the original all-carbon drug molecules. Current competing methods for C-H bond silylation tend to be incompatible with functionalities, such as Lewis-basic heterocycles, that are often found in pharmaceutical substances; this leaves de novo synthesis as the principal strategy for preparation of the target sila-drug analog. Moreover, competing methods tend to be limited in the scope of hydrosilane that can be used, which restricts the breadth of silicon-containing small molecules that can be accessed. The approach outlined in this protocol enables the chemoselective and regioselective late-stage silylation of small heterocycles, including drugs and drug derivatives, with a broad array of hydrosilanes in the absence of precious metal catalysts, stoichiometric reagents, sacrificial hydrogen acceptors or high temperatures. Moreover, H2 is the only by product generated. The procedure normally requires 48-75 h to be completed. PMID- 26513669 TI - Sample preparation for high-resolution 3D confocal imaging of mouse skeletal tissue. AB - High-resolution confocal imaging is a vital tool for analyzing the 3D architecture and detailed spatial distribution of cells in situ. However, imaging of skeletal tissue has remained technically challenging because of its calcified nature. Here we describe a protocol that allows high-resolution imaging of skeletal tissue with preservation of cellular morphology and tissue architecture. The procedure involves tissue fixation, decalcification and cryosectioning of the mouse skeletal tissue to generate thick sections. The thick sections generated by this procedure are not only compatible with the analysis of genetically expressed fluorescent proteins but they also preserve antigenicity, thus enabling diverse combinations of antibody labeling. Further, this procedure also permits other fluorescence techniques such as TUNEL and ethynyl deoxyuridine (EdU) incorporation assays. Images resulting from the confocal imaging can be assessed qualitatively and quantitatively to analyze various parameters such as distribution and interrelationships of cell types. The technique is straightforward and robust, highly reproducible and can be completed in ~11 d. PMID- 26513670 TI - TARDIS, a targeted RNA directional sequencing method for rare RNA discovery. AB - High-throughput transcriptional analysis has unveiled a myriad of novel RNAs. However, technical constraints in RNA sequencing library preparation and platform performance hamper the identification of rare transcripts contained within the RNA repertoire. Herein we present targeted-RNA directional sequencing (TARDIS), a hybridization-based method that allows subsets of RNAs contained within the transcriptome to be interrogated independently of transcript length, function, the presence or absence of poly-A tracts, or the mechanism of biogenesis. TARDIS is a modular protocol that is subdivided into four main phases, including the generation of random DNA traps covering the region of interest, purification of input RNA material, DNA trap-based RNA capture, and finally RNA-sequencing library construction. Importantly, coupling RNA capture to strand-specific RNA sequencing enables robust identification and reconstruction of novel transcripts, the definition of sense and antisense RNA pairs and, by the concomitant analysis of long and natural small RNA pools, it allows the user to infer potential precursor-product relations. TARDIS takes ~10 d to implement. PMID- 26513671 TI - Human norovirus culture in B cells. AB - Human noroviruses (HuNoVs) are a leading cause of foodborne disease and severe childhood diarrhea, and they cause a majority of the gastroenteritis outbreaks worldwide. However, the development of effective and long-lasting HuNoV vaccines and therapeutics has been greatly hindered by their uncultivability. We recently demonstrated that a HuNoV replicates in human B cells, and that commensal bacteria serve as a cofactor for this infection. In this protocol, we provide detailed methods for culturing the GII.4-Sydney HuNoV strain directly in human B cells, and in a coculture system in which the virus must cross a confluent epithelial barrier to access underlying B cells. We also describe methods for bacterial stimulation of HuNoV B cell infection and for measuring viral attachment to the surface of B cells. Finally, we highlight variables that contribute to the efficiency of viral replication in this system. Infection assays require 3 d and attachment assays require 3 h. Analysis of infection or attachment samples, including RNA extraction and RT-qPCR, requires ~6 h. PMID- 26513672 TI - Overinflation of a King LT Extraglottic Airway Device Mimicking Ludwig's Angina. AB - In this report, we describe the case of a young female with Down syndrome who presented to the anesthesia service after pulseless electrical activity arrest with a King LT(S)-D extraglottic airway device in situ. She had multiple predictors of difficult intubation, including what appeared to be a submental mass consistent with Ludwig's angina. She went on to receive an urgent tracheotomy because of those predictors but had full resolution of the submental mass on removal of the extraglottic airway device, which had been overinflated at the time of insertion. We outline the various techniques to establish a definitive airway with an extraglottic device in place. PMID- 26513673 TI - Unintentional Infusion of Phenylephrine into the Epidural Space. AB - We describe a patient who received an unintentionally prolonged epidural infusion of phenylephrine. The patient experienced no major morbidity. However, this case highlights the continuing problem of wrong-route drug administration and the urgent need to adopt route-specific connections. PMID- 26513674 TI - Harlequin Syndrome After Thoracic Paravertebral Block. AB - Harlequin syndrome is characterized by the sudden onset of unilateral facial flushing and sweating, often preceded by exercise, excessive heat, or, rarely, regional anesthesia. Although the exact mechanism remains unclear, it is often referred to as transient or permanent interruption of the sympathetic nervous system. We present a case of Harlequin syndrome without Horner syndrome in a patient with unilateral right-sided facial flushing that started shortly after a left-sided thoracic paravertebral nerve block for a mastectomy. We discuss the interruption of the sympathetic and parasympathetic nervous system and the levels of spinal nerve block associated with a thoracic paravertebral nerve block. PMID- 26513675 TI - Direct Laryngoscopy and Endotracheal Intubation Complicated by Anterior Tracheal Laceration Secondary to Protrusion of Preloaded Endotracheal Tube Stylet. AB - Tracheal wall disruption is a rare complication of endotracheal intubation, typically occurring in the posterior (membranous) trachea lacking cartilaginous support. We present the case of a 68-year-old man who developed an anterior tracheal tear after routine endotracheal intubation, most likely occurring secondary to protrusion of a factory-preloaded stylet beyond the distal orifice of the endotracheal tube. Tracheal disruption should be considered in any patient with subcutaneous emphysema and respiratory distress after tracheal extubation and confirmed with bronchoscopy. Conservative management may be appropriate for those with small tears, hemodynamic stability, and the ability to isolate the tear from positive pressure ventilation. PMID- 26513676 TI - Symptoms of Central Anticholinergic Syndrome After Glycopyrrolate Administration in a 5-Year-Old Child. AB - Anesthesia-related central anticholinergic syndrome (CAS) is most commonly associated with administration of atropine or scopolamine, whereas glycopyrrolate is an extremely rare cause of CAS. Here, we report a case of CAS in a 5-year-old boy admitted to the intensive care unit. Immediately after the administration of glycopyrrolate, he became agitated and developed apnea, hypertension, tachycardia, and anuria. Although the present case describes a rare cause of CAS, it is an important reminder of an iatrogenic condition that is presumably underdiagnosed in the operating theater as well as the intensive care unit. PMID- 26513677 TI - A High-Fidelity Codon Set for the T4 DNA Ligase-Catalyzed Polymerization of Modified Oligonucleotides. AB - In vitro selection of nucleic acid polymers can readily deliver highly specific receptors and catalysts for a variety of applications; however, it is suspected that the functional group deficit of nucleic acids has limited their potential with respect to proteinogenic polymers. This has stimulated research toward expanding their chemical diversity to bridge the functional gap between nucleic acids and proteins to develop a superior biopolymer. In this study, we investigate the effect of codon library size and composition on the sequence specificity of T4 DNA ligase in the DNA-templated polymerization of both unmodified and modified oligonucleotides. Using high-throughput DNA sequencing of duplex pairs, we have uncovered a 256-membered codon set that yields sequence defined modified ssDNA polymers in high yield and with high fidelity. PMID- 26513678 TI - Spiritual and Sexual Identity: Exploring Lesbian, Gay, and Bisexual Clients' Perspectives of Counseling. AB - Although religious and spiritual issues have emerged as areas of focus in counseling, very few scholars have explored the meaning and experiences of lesbian, gay, and bisexual (LGB) clients who addressed their sexual and religious/spiritual identities in counseling. Using consensual qualitative research (CQR; Hill, 2012), the current study explores the perspectives of 12 LGB persons who sought counseling that involved religious/spiritual concerns. Four themes in participant interviews are identified, including (a) self-acceptance, (b) goals of counseling, (c) identification with counselor, and (d) counseling environment and relationship. Implications of findings for the counseling field are discussed. PMID- 26513679 TI - Overexpression of immunosuppressive cytokines is associated with poorer clinical stage of oral squamous cell carcinoma. AB - OBJECTIVE: The aim of this study was to evaluate the expression of IL-10 and TGF beta2 in oral squamous cell carcinoma (OSCC) and its relationship with prognostic clinical and microscopic parameters. DESIGN: Immunohistochemistry was used to assess the expression of IL-10 and TGF-beta2 in OSCC samples from 43 patients who had undergone surgical excision and neck dissection. Metastatic lymph nodes were included in the study (n=23). Samples of healthy oral mucosa (n=20) were used as controls. The sections were evaluated using a semi-quantitative method in conjunction with staining intensity. RESULTS: Our findings showed that the expression of IL-10 and TGF-beta2 by neoplastic and stromal cells was high in most of the OSCC samples (>70% of samples), especially when compared to the controls (?10% of samples) (P<0.05). OSCC neoplastic cells in cervical lymph nodes were also positive for IL-10 and TGF-beta2. An association between high expression of IL-10 by neoplastic cells and advanced clinical stage (T3-T4) was verified (P=0.02). Although not statistically significant, the expression of TGF beta2 was also augmented in advanced stage tumours. CONCLUSIONS: These data suggest that the ability of OSCC neoplastic cells to secrete immunosuppressive cytokines could contribute to clinical progression by maintaining a microenvironment conducive to evasion and tumour proliferation. PMID- 26513680 TI - Interferon-gamma stimulates CD14, TLR2 and TLR4 mRNA expression in gingival fibroblasts increasing responsiveness to bacterial challenge. AB - OBJECTIVE: To investigate the potential effects of IFN-03A5 on the responsiveness of human gingival fibroblasts to bacterial challenge. DESIGN: mRNA and protein expression of CD14, TLR2 and TLR4 in human gingival fibroblasts was detected by quantitative polymerase chain reaction (Q-PCR) and flow cytometry. The effect of preincubation with IFN-03A5 on subsequent bacterial LPS-induced expression of IL 6 and IL-8 by gingival fibroblasts was determined by ELISA. Bacterial LPS-induced IkappaBalpha degradation in human gingival fibroblasts was investigated by western blot. RESULTS: Human gingival fibroblasts express CD14, TLR2 and TLR4 mRNAs. IFN-03A5, but not IL-103B2, induced mRNA expression of all three receptors and the expression of membrane bound CD14 protein. Pre-incubation of fibroblasts with IFN-03A5 and subsequent stimulation with Escherichia coli LPS or Porphyromonas gingivalis LPS led to increased production of IL-6 and IL-8. LPS induced pro-inflammatory cytokine production was abrogated by a blocking antibody to CD14. Both E. coli LPS and P. gingivalis LPS induced IkappaBalpha degradation in human gingival fibroblasts. CONCLUSION: Our data indicate that IFN-03A5 primes human gingival fibroblasts, through the upregulation of CD14 expression, which results in increased responsiveness to bacterial LPS challenge, as determined by pro-inflammatory cytokine production. PMID- 26513681 TI - The effect of rheumatoid arthritis and functional loading on the structure of the mandibular condyle in a transgenic mouse model: An FTIR study. AB - OBJECTIVE: The objective of the present study was to investigate the effect of rheumatoid arthritis and functional loading through diet modification on the biochemical properties of the mandibular condyle in a transgenic mouse model and compare with healthy littermates. DESIGN: Twenty three, 4-week old hybrid male mice were used. Eleven were of transgenic line hTNF 197 (Tg 197 - with rheumatoid arthritis - RA) and 12 healthy littermates, both from mixed background CBAxC57BL/6. Four groups of mice were formed. Group 1 [n =5, RA-hard] included transgenic mice and received ordinary (hard) diet; group 2 [n=6, RA-soft] included transgenic line and received soft diet; group 3 [n=6, control-hard] were healthy littermates receiving ordinary (hard) diet and group 4 [n=6, control soft] were healthy littermates with soft diet. Experimental period was 28 days. Following sacrifice, the mandibular condyles were subjected to micro-attenuated reflection Fourier transform infrared spectroscopy (micro-ATR FTIR) to reveal collagen/proteoglycan conformation of the condylar cartilage, while resin embedded and metallographically polished specimens were evaluated through reflection FTIR microscopy to identify mineralization status of the corresponding condylar bone. RESULTS: The multivariable analysis revealed significantly lower a helix to amide I percentage area ratio for the transgenic animals after adjusting for diet (beta=-4.29, 95% CIs: -8.52, -0.06; p=0.04). Mineral phase indices did not differ significantly between RA and control groups regardless the type of diet. CONCLUSIONS: Internal derangement of the anatomical structure with denaturation in the collagen structural components of the mandibular condyles of the RA animals was found, while no association with functional loading through diet modification was recorded. PMID- 26513682 TI - The role of aryl hydrocarbon receptor (AhR) in the pathology of pleomorphic adenoma in parotid gland. AB - OBJECTIVES: Pleomorphic adenoma (benign mixed tumor) is one of the most common salivary gland tumors. However, molecular mechanisms implicated in its development are not entirely defined. Therefore, the study aimed at definition of aryl hydrocarbon receptor (AhR) involvement in pleomorphic adenoma pathology, as the AhR controlled gene system was documented to play a role in development of various human tumors. DESIGN: The study was carried out in pleomorphic adenoma and control parotid gland tissues where gene expression of AHR, AhR nuclear translocator (ARNT), AhR repressor (AHRR), as well as AhR controlled genes: CYP1A1 and CYP1B1, at mRNA and protein (immunohistochemistry) levels were studied. Functional evaluation of AhR system was evaluated in HSY cells (human parotid gland adenocarcinoma cells) using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as AhR specific inducer. RESULTS: Pleomorphic adenoma specimens showed cytoplasmic and nuclear AhR expression in epithelial cells as well as in mesenchymal cells. In parotid gland AhR was expressed in cytoplasm of duct cells. Quantitative expression at mRNA level showed significantly higher expression of AHR, ARNT and CYP1B1, and comparable levels of CYP1A1 in pleomorphic adenoma tissue in comparison to healthy parotid gland. The HSY cell study revealed significantly higher expression level of AHRR in HSY as compared with MCF-7 cells (human breast adenocarcinoma cell line used as reference). Upon TCDD stimulation a drop in AHRR level in HSY cells and an increase in MCF-7 cells were observed. The HSY and MCF-7 cell proliferation rate (measured by WST-1 test) was not affected by TCDD. CONCLUSIONS: Summarizing both in vitro and in vivo observations it can be stated that AhR system may play a role in the pathology of pleomorphic adenoma. PMID- 26513683 TI - Bone regeneration by low-level laser therapy and low-intensity pulsed ultrasound therapy in the rabbit calvarium. AB - OBJECTIVE: We evaluated the efficacy of low-level laser therapy (LLLT) and low intensity pulsed ultrasound (LIPUS), alone and in combination, in triggering new bone formation. STUDY DESIGN: Sixteen New Zealand white rabbits were given two calvarial defects by using a 6-mm trephine bur, then divided into four treatment groups: control, LLLT, LIPUS, and LLLT+LIPUS. The LLLT and LIPUS groups were treated three times a week for two weeks. The LLLT+LIPUS group received each treatment on the same day, 12h apart, three days a week for two weeks. The animals were sacrificed after three weeks. RESULTS: LLLT and LIPUS, alone and in combination, enhanced new bone formation in comparison to the untreated controls after three weeks (P<0.05); the combined therapy did not produce an additive effect. CONCLUSIONS: Our results demonstrate the efficacy of LLLT or LIPUS in triggering bone regeneration. Therapeutic dose and duration requires further study. PMID- 26513684 TI - Systemic Safety of Prolonged Monthly Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Anti-vascular endothelial growth factor (VEGF) therapy is commonly used to treat numerous retinal conditions and appears safe, yet controversy remains regarding systemic safety. OBJECTIVE: To evaluate the systemic safety of intravitreous anti-VEGF injections in high-risk patients with diabetic macular edema (DME) and to investigate separately the subgroup of these patients with the highest level of exposure to anti-VEGF monthly treatment for 2 years. DATA SOURCES: A search of MEDLINE, Cochrane Central Register of Controlled Trials, clincaltrials.gov, and ophthalmology congress abstracts January 1, 1947, to May 19, 2015. STUDY SELECTION: Randomized clinical trials were selected that evaluated monthly anti-VEGF injections for DME for 2 years and reported the outcome measures of cerebrovascular accidents, myocardial infarctions, arteriothrombotic events, and mortality. DATA EXTRACTION AND SYNTHESIS: Two reviewers collected data independently from each study for the meta-analysis. Data were pooled using a fixed-effects model and analyzed from November 6, 2014, to June 28, 2015. Peto odds ratios with 95% CIs were calculated. MAIN OUTCOMES AND MEASURES: Primary end points included cerebrovascular accidents and all-cause mortality in the highest-dose arms. Secondary outcomes included myocardial infarctions, arteriothrombotic events, and vascular-related death. RESULTS: Of 1126 articles reviewed, 598 were removed as duplicate studies and 524, for lack of monthly treatment data for 2 years, leaving 4 studies for the meta-analysis that met the search criteria: 2 trials using monthly aflibercept and 2 using monthly ranibizumab, representing 1328 patients. The primary evaluation (1078 patients) combined the monthly aflibercept and the 0.5-mg ranibizumab arms and yielded an increased risk for death compared with sham and laser treatments (odds ratio [OR], 2.98; 95% CI, 1.44-6.14; P = .003). Analysis including monthly aflibercept and 0.5-mg ranibizumab yielded an increased risk for cerebrovascular accidents (OR, 2.33; 95% CI, 1.04-5.22; P = .04) and vascular death (OR, 2.51; 95% CI, 1.08-5.82; P = .03). No definitive increased risk for myocardial infarctions and arteriothrombotic events was seen with all dose combinations. CONCLUSIONS AND RELEVANCE: In this meta-analysis of anti-VEGF agents for patients with DME, assessment of the highest-level exposure group (those high-risk patients with DME who received 2 years of monthly treatment) revealed a possible increased risk for death and potentially for cerebrovascular accidents. Consideration of total exposure to anti-VEGF agents when treating those at high risk for vascular disease may be important. PMID- 26513685 TI - Five glutamic acid residues in the C-terminal domain of the ChlD subunit play a major role in conferring Mg(2+) cooperativity upon magnesium chelatase. AB - Magnesium chelatase catalyzes the first committed step in chlorophyll biosynthesis by inserting a Mg(2+) ion into protoporphyrin IX in an ATP-dependent manner. The cyanobacterial (Synechocystis) and higher-plant chelatases exhibit a complex cooperative response to free magnesium, while the chelatases from Thermosynechococcus elongatus and photosynthetic bacteria do not. To investigate the basis for this cooperativity, we constructed a series of chimeric ChlD proteins using N-terminal, central, and C-terminal domains from Synechocystis and Thermosynechococcus. We show that five glutamic acid residues in the C-terminal domain play a major role in this process. PMID- 26513686 TI - Kidney disease progression in patients of upper tract urothelial carcinoma following unilateral radical nephroureterectomy. AB - OBJECTIVES: To compare the renal outcomes in patients of unilateral renal cell carcinoma (RCC) with upper tract urothelial carcinoma (UTUC) following surgical resection of the tumor-bearing kidney, and to investigate the potential predictors in renal function decline. PATIENTS AND METHODS: In this retrospective cohort study, 319 RCC patients undergoing radical nephrectomy (RN) and 297 UTUC patients undergoing radical nephroureterectomy were recruited from a tertiary medical center between 2001 and 2010. Demographic data, co-morbidity, smoking habit, baseline estimated glomerular filtration rate (eGFR) calculated by chronic kidney disease-epidemiology equation, as well as tumor staging of RCC and UTUC, were recorded. The primary endpoint was serum creatinine doubling and/or end stage renal disease (ESRD) necessitating long-term dialysis. Cox proportional hazard model and Fine and Gray's competing risk regression accounting for death were used to model renal outcome. RESULTS: UTUC patients had a higher incidence rate of renal function deterioration than RCC patients did (15.01 vs. 2.68 per 100 person-years, p<0.001). In Cox proportional hazard model and Fine and Gray's competing risk regression, UTUC was significantly associated with increased risk of creatinine doubling and/or ESRD necessitating dialysis (hazard ratio, 3.13; 95% confidence interval, 2.01-4.87) as compared to RCC following unilateral RN. Nevertheless, our study is observational in nature and cannot prove causality. CONCLUSIONS: UTUC per se is strongly associated with kidney disease progression as compared to RCC following unilateral nephrectomy. Further studies are needed to elucidate this association. PMID- 26513687 TI - Editorial. PMID- 26513688 TI - Wireless Solar Water Splitting Device with Robust Cobalt-Catalyzed, Dual-Doped BiVO4 Photoanode and Perovskite Solar Cell in Tandem: A Dual Absorber Artificial Leaf. AB - A stand-alone, wireless solar water splitting device without external energy supply has been realized by combining in tandem a CH3NH3PbI3 perovskite single junction solar cell with a cobalt carbonate (Co-Ci)-catalyzed, extrinsic/intrinsic dual-doped BiVO4 (hydrogen-treated and 3 at% Mo-doped). The photoanode recorded one of the highest photoelectrochemical water oxidation activity (4.8 mA/cm(2) at 1.23 VRHE) under simulated 1 sun illumination. The oxygen evolution Co-Ci co-catalyst showed similar performance to best known cobalt phosphate (Co-Pi) (5.0 mA/cm(2) at 1.23 VRHE) on the same dual-doped BiVO4 photoanode, but with significantly better stability. A tandem artificial-leaf type device produced stoichiometric hydrogen and oxygen with an average solar-to hydrogen efficiency of 4.3% (wired), 3.0% (wireless) under simulated 1 sun illumination. Hence, our device based on a D4 tandem photoelectrochemical cell represents a meaningful advancement in performance and cost over the device based on a triple-junction solar cell-electrocatalyst combination. PMID- 26513689 TI - The influence of oxidative stress induced by iron on telomere length. AB - Oxidative stress can be induced by increased concentrations of iron in the body and consequently can cause shortening of telomeres. Telomeres, called mitotic clocks, are non-coding fragments at the end of chromosomes. During the replication of genetic material they are shortened, playing the role of ageing biomarkers in eukaryotes. In human endothelial cells, oxidative stress causes a decrease in telomerase activity. Shortening of chromosomes in telomeric parts was found in patients with primary hemochromatosis and in patients taking supplements containing iron. Increased level of transferrin saturation is associated with the presence of shorter telomeres in the chromosomes of leukocytes. The relationship between iron status and telomere length is still not fully understood. PMID- 26513690 TI - Effects of zinc oxide nanoparticles on bioaccumulation and oxidative stress in different organs of tilapia (Oreochromis niloticus). AB - Nano-size zinc oxide particles (ZnO NPs) are used in diverse industrial and commercial fields. However, the information from existing studies is not sufficient in evaluating the potential toxic effects of ZnO NPs. In this study, tilapia fish (Oreochromis niloticus) were exposed to different concentrations of small and large ZnO NPs in vivo. Accumulation in various organs/tissues (liver, gill, intestine, kidney, brain and muscle) and possible oxidative stress mechanisms were investigated comparatively. Fish were exposed to 1 and 10mg/L concentrations of small (10-30 nm) and large (100 nm) ZnO NPs semi-statically for 14 days. Both small and large ZnO NPs accumulated substantially in the tissues. Accumulation for the small ZnO NPs was significantly higher compared to larger NPs under same exposure regimes. Significant fluctuations were observed in antioxidant defense system biomarkers, including Superoxide dismutase (SOD), Catalase (CAT) and Glutathione (GSH) levels depending on particle size, exposure time and concentration. Lipid peroxidation measured with TBARS levels were higher in groups exposed to the suspensions of small ZnO NPs than that of large ZnO NPs and controls. These results imply that colloidal suspensions of small ZnO NPs induce elevated oxidative stress and toxic effects on tilapia compared to the larger NPs. PMID- 26513691 TI - Selective blockade of cancer cell proliferation and anchorage-independent growth by Plk1 activity-dependent suicidal inhibition of its polo-box domain. AB - Polo-like kinase 1 (Plk1) plays a critical role in proper M-phase progression and cell proliferation. Plk1 is overexpressed in a broad spectrum of human cancers and is considered an attractive anticancer drug target. Although a large number of inhibitors targeting the catalytic domain of Plk1 have been developed, these inhibitors commonly exhibit a substantial level of cross-reactivity with other structurally related kinases, thus narrowing their applicable dose for patient treatment. Plk1 contains a C-terminal polo-box domain (PBD) that is essentially required for interacting with its binding targets. However, largely due to the lack of both specific and membrane-permeable inhibitors, whether PBD serves as an alternative target for the development of anticancer therapeutics has not been rigorously examined. Here, we used an intracellularly expressed 29-mer-long PBIP1 derived peptide (i.e., PBIPtide), which can be converted into a "suicidal" PBD inhibitor via Plk1-dependent self-priming and binding. Using this highly specific and potent system, we showed that Plk1 PBD inhibition alone is sufficient for inducing mitotic arrest and apoptotic cell death in cancer cells but not in normal cells, and that cancer cell-selective killing can occur regardless of the presence or absence of oncogenic RAS mutation. Intriguingly, PBD inhibition also effectively prevented anchorage-independent growth of malignant cancer cells. Thus, targeting PBD represents an appealing strategy for anti-Plk1 inhibitor development. Additionally, PBD inhibition-induced cancer cell-selective killing may not simply stem from activated RAS alone but, rather, from multiple altered biochemical and physiological mechanisms, which may have collectively contributed to Plk1 addiction in cancer cells. PMID- 26513692 TI - EN2RN - transitioning to a new scope of practice. AB - BACKGROUND: In Australia, newly graduated registered nurses enter the workforce and a number of these have previous experience as enrolled nurses. For all newly graduated registered nurses, transitioning to the new role can be challenging. AIM: The aim of this study was to explore the experiences of enrolled nurses transitioning to the role of registered nurses to support the development of effective transition programs. DESIGN: An exploratory qualitative design. METHODS: In-depth interviews with a purposive sample from one health service in South East Queensland, Australia. Data were analysed thematically. FINDINGS: The three main themes emerging from analysis: a new scope of practice, perceptions of capability, building on experience and knowledge. CONCLUSIONS: We recommend assessment of individual learning needs and support during the transition period which acknowledges previous experience and recognises learning required to effectively transition to the role of a registered nurse. PMID- 26513693 TI - Evaluation of obstetrical patients with disseminated intravascular coagulopathy - tertiary center experience. AB - OBJECTIVE: The purpose of the present study is twofold: (a) to investigate the etiology of disseminated intravascular coagulopathy (DIC) caused by obstetrical conditions and (b) to present parameters that can be used in predicting DIC related mortality in obstetrical patients. MATERIAL AND METHOD: Obstetrical patients who had a delivery at or were referred (after delivery) to Obstetrics and Gynecology Clinic of Dicle University between July 2006 and December 2013 were retrospectively analyzed in this study. Those patients diagnosed with DIC were included in the study. RESULTS: Fifty-six obstetrical patients carrying the diagnosis of DIC were included in this study. The overall mortality rate was 25% among these patients. More specifically, the mortality rate was 10.7% among patients with a DIC score <=5 and 40.7% among those with a DIC score > 5. Multiple logistic regression analysis resulted in the finding that international normalized ratio (INR) and urea were among those factors affecting mortality in obstetrical DIC [OR: 8.44 (CI: 1.9-36.8), OR: 1.05 (CI: 1.0-1.1), respectively]. CONCLUSION: DIC is a syndrome that might be caused by obstetrical conditions. It is associated with high mortality and morbidity rates. In obstetrical DIC, urea is the most important factor affecting mortality. In addition, we are of the opinion that DIC score might guide mortality predictions as a determinant of prognosis. PMID- 26513694 TI - Tumor treating fields therapy device for glioblastoma: physics and clinical practice considerations. AB - Alternating electric fields therapy, as delivered by the tumor treating fields device, is a new modality of cancer treatment that has been approved by the US FDA for recurrent glioblastoma. At a frequency of 200 kHz, these fields emanate from transducer arrays on the surface of the patient's scalp into the brain and perturb processes necessary for cytokinesis during tumor cell mitosis. In the registration Phase III trial for recurrent glioblastoma patients, the efficacy of the tumor treating fields as monotherapy was equivalent to chemotherapy, while scalp irritation was its major adverse event compared with systemic toxicities that were associated with cytotoxic chemotherapies. Alternating electric fields therapy is, therefore, an essential option for the treatment of recurrent glioblastoma. Here, we summarize our current knowledge of the physics, cell biology and clinical data supporting the use of the tumor treating fields therapy. PMID- 26513695 TI - Organocatalytic Aerobic Oxidation of Benzylic sp(3) C-H Bonds of Ethers and Alkylarenes Promoted by a Recyclable TEMPO Catalyst. AB - An entirely metal-free catalyst system consisting of an easily prepared recyclable new TEMPO derived sulfonic salt catalyst, and mineral acids (NaNO2 and HCl) has been developed for selective aerobic oxidation of structurally diverse benzylic sp(3) C-H bonds of ethers and alkylarenes. The mild reaction conditions allow for the generation of synthetically and biologically valued isochromanones and xanthones from readily accessible alkyl aromatic precursors in good yields. PMID- 26513696 TI - Phase coordination and phase-velocity relationship in metameric robot locomotion. AB - This research proposes a new approach for the control of metameric robot locomotion via phase coordination. Unlike previous studies where global wave-like rules were pre-specified to construct the actuation sequence of segments, this phase coordination method generates robot locomotion by assigning the actuation phase differences between adjacent segments without any global prerequisite rules. To effectively coordinate the phase differences, different symmetry properties are introduced. Optimization is then carried out on various symmetrically coordinated phase-difference patterns to maximize the average steady-state velocity of the robot. It is shown that the maximum average velocity is always achieved when the reflectional symmetry is included in the phase difference pattern, and the identical-phase-difference (IPD) pattern is preferred for implementation because it reduces the number of independent phase variables to only one without significant loss in locomotion performance. Extensive analytical investigations on the IPD pattern reveal the relationship between the average locomotion velocity and some important parameters. Theoretical findings on the relationship between the average velocity and the phase difference in the IPD pattern are verified via experimental investigations on an 8-segment earthworm-like metameric robot prototype. Finally, this paper reveals an interesting result that the optimized phase-difference pattern can naturally generate peristalsis waves in metameric robot locomotion without global prerequisite wave-like rules. PMID- 26513697 TI - Vemurafenib-induced pityriasis amiantacea: a case report. AB - Vemurafenib, a novel treatment for patients with BRAF-positive metastatic melanoma, is associated with a wide spectrum of cutaneous adverse events both benign and malignant. Vemurafenib-induced pityriasis amiantacea (PA), a scaling reaction of the scalp that may cause temporary or cicatricial alopecia, has not yet been reported in the literature. In the present case, PA was observed two months after the initiation of vemurafenib therapy for metastatic melanoma and managed with symptomatic treatment without the need to cease or modify the vemurafenib dosage. PMID- 26513698 TI - Blood pressure changes in patients with chronic heart failure undergoing slow breathing training. AB - BACKGROUND: Slow breathing training (SBT) has been proposed as a new non pharmacological treatment able to induce favorable effects in patients with chronic heart failure (CHF). However, no information is available regarding its effects on orthostatic blood pressure (BP) changes in these patients, an issue of practical relevance given the reported BP-lowering effect of SBT. The aim of this study is to evaluate the influence of SBT on BP and whether SBT induces orthostatic hypotension (OH) or changes in quality of life (QoL) in CHF patients. METHODS: The analysis was performed as part of an ongoing crossover open trial aimed at assessing the clinical effectiveness of SBT in treated patients with CHF. The patients underwent 10-12 weeks of SBT with the RESPeRATE device and 10 12 week follow-up under usual care. Patients were randomly divided into two groups: group I began with SBT, followed by usual care; group II began with usual care, followed by SBT. Patients undergoing SBT were asked to perform each day two separate 15 min sessions of device-guided SBT at a breathing frequency of 6 breaths/min. In all patients, before the enrollment and after each study phase, clinical data collection and BP measurements in sitting, supine and standing position were performed. OH was defined as a decrease of >= 20 mmHg in systolic blood pressure (SBP) or >= 10 mmHg in diastolic blood pressure (DBP) within 3 min of standing. QoL was assessed three times at the beginning, and after each phase of the study by the Minnesota Living with Heart Failure (MLHF) questionnaire. RESULTS: Forty patients (two equal groups) completed the study, with the following baseline characteristics: 32 males/eight females, age 63.3 +/- 13.4 years, 25 with ischemic CHF, 37 in New York Heart Association class II and three in class III, left ventricular ejection fraction 30.8 +/- 6.7%, mean BP 138.7 +/- 16.5/83.1 +/- 11.5 mmHg, 23 with arterial hypertension and four with a history of stroke. There were no significant differences between the groups in clinical characteristics, SBP and DBP at rest, while seated and before and after standing up. OH prevalence was low and did not change during the study (10% vs 10%). No significant difference in average SBP and DBP changes secondary to body position were found when comparing the two study phases. Decrease in MLHF score was observed in group I during SBT (p = 0.002), but not in group II. CONCLUSIONS: Our data indicate that SBT is safe, does not affect the prevalence of OH in CHF patients and shows a non-significant tendency to improve QoL. These results should be confirmed in a larger sample of patients to support the safety of SBT and its possible benefits as a novel component of cardiorespiratory rehabilitation programs in CHF. PMID- 26513699 TI - Magnesium sulphate can prolong pregnancy in patients with severe early-onset preeclampsia. AB - OBJECTIVE: To assess whether long-term use of magnesium sulphate prolongs pregnancy in patients with severe early-onset preeclampsia. METHODS: Retrospective cohort study included all singleton pregnancies with severe early onset preeclampsia, expectantly managed in our institution between 2005 and 2013. Obstetric and perinatal outcomes were compared between patients managed using a current protocol that tolerates long-term (over 48 h) use of magnesium sulphate (long-term group, n = 26) and a historical control group (control group, n = 15) that underwent conventional treatment (up to 48 h use of magnesium sulphate). RESULTS: Long-term group showed significant prolongation of pregnancy compared with the control group (9.2 +/- 7.9 versus 16.6 +/- 9.3 d, log-rank test, p = 0.021), which was also observed in patients with severe preeclampsia occurring before 28 weeks' gestation (n = 11, 4.5 +/- 5.2 versus 13.2 +/- 6.8 d, log-rank test, p = 0.035). In contrast to a progressive decrease of platelet count in patients managed without magnesium sulphate, administration of magnesium sulphate for 7 d prevented the decrease of platelet count (p = 0.001). Thirty two percent of patients (13/41) experienced a major complication irrespective of duration of magnesium sulphate use. CONCLUSIONS: Long-term use of magnesium sulphate prolonged pregnancy in patients with severe early-onset preeclampsia and can help alleviate progression of preeclampsia. PMID- 26513700 TI - Astonishing advances in mouse genetic tools for biomedical research. AB - The humble house mouse has long been a workhorse model system in biomedical research. The technology for introducing site-specific genome modifications led to Nobel Prizes for its pioneers and opened a new era of mouse genetics. However, this technology was very time-consuming and technically demanding. As a result, many investigators continued to employ easier genome manipulation methods, though resulting models can suffer from overlooked or underestimated consequences. Another breakthrough, invaluable for the molecular dissection of disease mechanisms, was the invention of high-throughput methods to measure the expression of a plethora of genes in parallel. However, the use of samples containing material from multiple cell types could obfuscate data, and thus interpretations. In this review we highlight some important issues in experimental approaches using mouse models for biomedical research. We then discuss recent technological advances in mouse genetics that are revolutionising human disease research. Mouse genomes are now easily manipulated at precise locations thanks to guided endonucleases, such as transcription activator-like effector nucleases (TALENs) or the CRISPR/Cas9 system, both also having the potential to turn the dream of human gene therapy into reality. Newly developed methods of cell type-specific isolation of transcriptomes from crude tissue homogenates, followed by detection with next generation sequencing (NGS), are vastly improving gene regulation studies. Taken together, these amazing tools simplify the creation of much more accurate mouse models of human disease, and enable the extraction of hitherto unobtainable data. PMID- 26513701 TI - Transmission electron microscopic analysis of malathion-induced cytotoxicity in granulosa cells of caprine antral follicles. AB - Malathion, one of the most abundantly used organophosphate pesticides, has immoderate potency as a cytotoxic and genotoxic compound that induces toxicity in granulosa cells, resulting in its apoptosis. Thus, the present study aims to employ ultrastructural analysis for assessing the cytotoxicity of malathion at nanomolar concentrations (1 nM and 10 nM) in granulosa cells of caprine antral follicles at different exposure durations. Transmission electron microscopy revealed diminished cell-cell contact and cellular integrity, presence of crescent-shaped nucleus, chromatin condensation, and pyknosis with nuclear membrane folding, accumulation of lipid droplets with occurrence of cytoplasmic protrusions in granulosa cells treated with 1 nM malathion, whereas at 10 nM concentration, along with apoptotic attributes, prominent association of nucleus, endoplasmic reticulum, mitochondria and lipid droplets, nucleus invagination into lipid droplets, apical localization of lipid bodies, and occurrence of autophagic body were observed as compared to healthy granulosa cells in control with normal intact cellular integrity, well-developed cellular association, and doubled membrane nuclear lamina with homogenously dispersed chromatin surrounded by intact mitochondria with well-developed cristae. Thus, the results of ultrastructural analysis clearly suggest that nanomolar concentration of malathion induces apoptotic hallmarks within the granulosa cells of antral follicles that play a consequential role in increasing the incidence of follicular atresia, thereby affecting the overall fertility. PMID- 26513702 TI - EXTENDED CYTOPROTECTIVE EFFECT OF AUTOPHAGY IN THE LATE STAGES OF SEPSIS AND FLUCTUATIONS IN SIGNAL TRANSDUCTION PATHWAYS IN A RAT EXPERIMENTAL MODEL OF KIDNEY INJURY. AB - The impact of a potential autophagy (LC3a/b) deregulation in hyper and in hypo stages during sepsis-induced kidney injury and the temporal profile of phosphorylated extracellular signal-related kinase, P38 (pP38), Akt (pAKT), and 13-3-3beta protein were investigated in the current study, using a rat cecal ligation and puncture (CLP) model, by means of flow cytometry and immunohistochemistry. Cell viability was assessed by protein C zymogen concentrate (PC), 7-aminoactinomycin D (7-AAD) staining and inflammation by S100 protein immunostaining. The impact of reduced kidney inflammation in autophagy was assessed by PC administration, an anti-inflammatory and cytoprotective substance. Sepsis induction increased LC3a/b expression, which presented two peaks at 6 and 36 h after CLP, both in the percentage of positive cells (P = 0.024, P = 0.025, respectively) and in fluorescence intensity. At 6 h when inflammation was already apparent, LC3a/b increase was escorted by phosphorylated extracellular signal-related kinase stimulation and high cell viability (65%), designating autophagy as a cytoprotective mechanism against microbial infection. The phosphorylation of P38 was delayed to 12 h after CLP, when autophagy was reduced. pAkt and 14-3-3beta expression was stimulated between 6 and 36 h after CLP, although a slight inhibition of pAkt within each cell was detected (lower MnIX value). During the second peak, inflammation was intensified, necrosis was significantly increased with LC3a/b+/7-AAD + cells to present a 1.5-fold increase. Protein C zymogen concentrate administration declined autophagy at 6 and 36 h after CLP and reduced necrosis, whereas double positive LC3a/b and 7-AAD cells were increased by 1.68 and 2.78-fold, respectively. These data open new prospectives in sepsis treatment, since they further support that autophagy represents a cytoprotective mechanism triggered by stress conditions, rather than an alternative cell death pathway. PMID- 26513703 TI - DANGER IN THE INTENSIVE CARE UNIT: DAMPS IN CRITICALLY ILL PATIENTS. AB - Danger-associated molecular patterns (DAMPs) that are released by injured, threatened, or dead cells, or that originate from the extracellular matrix, influence the immune system. This is of great relevance in critically ill patients, in whom trauma or surgery-related cell damage, hypoxia, ischemia, and infections can result in extensive release of DAMPs. As many patients at the intensive care unit suffer from immune system-related complications, DAMPs could serve as markers for the prognosis of these patients and represent possible therapeutic targets. In the present review, we provide an overview of several well known DAMPs (high-mobility group box 1, heat-shock proteins, s100 proteins, nucleic acids, and hyaluronan) and their effects on the immune system. Furthermore, we discuss the role of DAMPs as markers or therapeutic targets in several conditions frequently encountered in critically ill patients, such as sepsis, trauma, ventilator-induced lung injury, and cardiac arrest. PMID- 26513704 TI - CIRCULATING MICROPARTICLES, BLOOD CELLS, AND ENDOTHELIUM INDUCE PROCOAGULANT ACTIVITY IN SEPSIS THROUGH PHOSPHATIDYLSERINE EXPOSURE. AB - Sepsis is invariably accompanied by altered coagulation cascade; however, the precise role of phosphatidylserine (PS) in inflammation-associated coagulopathy in sepsis has not been well elucidated. We explored the possibility of exposed PS on microparticles (MPs), blood cells, as well as on endothelium, and defined its role in procoagulant activity (PCA) in sepsis. PS-positive MPs and cells were detected by flow cytometry, while PCA was assessed with clotting time, purified coagulation complex, and fibrin formation assays. Plasma levels of PS MPs derived from platelets, leukocytes (including neutrophils, monocytes, and lymphocytes), erythrocytes, and endothelial cells were elevated by 1.49-, 1.60-, 2.93-, and 1.53-fold, respectively, in septic patients. Meanwhile, PS exposure on blood cells was markedly higher in septic patients than in controls. Additionally, we found that the endothelial cells (ECs) treated with septic serum in vitro exposed more PS than with healthy serum. Isolated MPs/blood cells from septic patients and cultured ECs treated with septic serum in vitro demonstrated significantly shortened coagulation time, greatly enhanced intrinsic/extrinsic FXa generation, and increased thrombin formation. Importantly, confocal imaging of MPs or septic serum-treated ECs identified binding sites for FVa and FXa to form prothrombinase, and further supported fibrin formation in the area where PS exposure was abundant. Pretreatment with lactadherin blocked PS on MPs/blood cells/ECs, prolonged coagulation time by at least 25%, reduced FXa/thrombin generation, and inhibited fibrin formation by approximately 85%. Our findings suggest a key role for PS exposed on MPs, blood cells, and endothelium in augmenting coagulation in sepsis. Therefore, therapies targeting PS may be of particular importance. PMID- 26513705 TI - IMPACTS OF SYSTEMIC HYPERTENSION AND LEFT VENTRICULAR HYPERTROPHY ON OUTCOME OF CARDIOPULMONARY RESUSCITATION AND THERAPEUTIC HYPOTHERMIA IN A CARDIAC ARREST MODEL OF RAT. AB - BACKGROUND: Systemic hypertension and left ventricular hypertrophy (LVH) are major risk factors of cardiac arrest. However, the impacts of hypertension and LVH on the outcome of cardiopulmonary resuscitation (CPR) and post-resuscitation hypothermia are still undetermined. METHODS: After 4 min of untreated ventricular fibrillation (VF) and 4 min of CPR, defibrillation was attempted in 16 male spontaneously hypertensive rats (SHR) with LVH and 16 male normotensive Wistar Kyoto (WKY) rats. When restoration of spontaneous circulation (ROSC) was achieved, animals were randomized into either hypothermia or normothermia. For animals subjected to hypothermia, rapid cooling was started immediately after ROSC and a temperature of 33.0 +/- 0.4 degrees C was maintained for 2 h. Normothermic animals were maintained at 37.0 +/- 0.4 degrees C. RESULTS: Baseline mean arterial pressure, heart rate, and left ventricle mass were significantly higher but ejection fraction was lower for hypertensive animals. Coronary perfusion pressure was higher for SHR, but no differences in duration of CPR and number of defibrillations required for resuscitation compared with WKY. All of the animals were successfully resuscitated but post-resuscitation cardiac function was severely impaired in hypertensive animals. Serum levels of cardiac troponin T, amino-terminal pro-brain natriuretic peptide, and S100B measured after ROSC were also markedly higher in SHR groups. Fourteen WKY rats (87.5%) survived, whereas only 1 SHR (6.3%, P < 0.001) survived to 96 h. CONCLUSIONS: In this rat model, systemic hypertension and LVH did not affect ROSC. However, survival was dismal due to elevated severity of cardiac and cerebral injury in hypertensive animals regardless of short-duration hypothermia. PMID- 26513706 TI - OBESITY AND CRITICAL ILLNESS: INSIGHTS FROM ANIMAL MODELS. AB - Critical illness is a major cause of morbidity and mortality around the world. While obesity is often detrimental in the context of trauma, it is paradoxically associated with improved outcomes in some septic patients. The reasons for these disparate outcomes are not well understood. A number of animal models have been used to study the obese response to various forms of critical illness. Just as there have been many animal models that have attempted to mimic clinical conditions, there are many clinical scenarios that can occur in the highly heterogeneous critically ill patient population that occupies hospitals and intensive care units. This poses a formidable challenge for clinicians and researchers attempting to understand the mechanisms of disease and develop appropriate therapies and treatment algorithms for specific subsets of patients, including the obese. The development of new, and the modification of existing animal models, is important in order to bring effective treatments to a wide range of patients. Not only do experimental variables need to be matched as closely as possible to clinical scenarios, but animal models with pre-existing comorbid conditions need to be studied. This review briefly summarizes animal models of hemorrhage, blunt trauma, traumatic brain injury, and sepsis. It also discusses what has been learned through the use of obese models to study the pathophysiology of critical illness in light of what has been demonstrated in the clinical literature. PMID- 26513707 TI - THE GLYCOCALYX AND TRAUMA: A REVIEW. AB - In the United States trauma is the leading cause of mortality among those under the age of 45, claiming approximately 192,000 lives each year. Significant personal disability, lost productivity, and long-term healthcare needs are common and contribute 580 billion dollars in economic impact each year. Improving resuscitation strategies and the early acute care of trauma patients has the potential to reduce the pathological sequelae of combined exuberant inflammation and immune suppression that can co-exist, or occur temporally, and adversely affect outcomes. The endothelial and epithelial glycocalyx has emerged as an important participant in both inflammation and immunomodulation. Constituents of the glycocalyx have been used as biomarkers of injury severity and have the potential to be target(s) for therapeutic interventions aimed at immune modulation. In this review, we provide a contemporary understanding of the physiologic structure and function of the glycocalyx and its role in traumatic injury with a particular emphasis on lung injury. PMID- 26513708 TI - AP39, A Mitochondrially Targeted Hydrogen Sulfide Donor, Exerts Protective Effects in Renal Epithelial Cells Subjected to Oxidative Stress in Vitro and in Acute Renal Injury in Vivo. AB - This study evaluated the effects of AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol 5yl) phenoxy)decyl) triphenyl phosphonium bromide], a mitochondrially targeted donor of hydrogen sulfide (H2S) in an in vitro model of hypoxia/oxidative stress injury in NRK-49F rat kidney epithelial cells (NRK cells) and in a rat model of renal ischemia-reperfusion injury. Renal oxidative stress was induced by the addition of glucose oxidase, which generates hydrogen peroxide in the culture medium at a constant rate. Glucose oxidase (GOx)-induced oxidative stress led to mitochondrial dysfunction, decreased intracellular ATP content, and, at higher concentrations, increased intracellular oxidant formation (estimated by the fluorescent probe 2, 7-dichlorofluorescein, DCF) and promoted necrosis (estimated by the measurement of lactate dehydrogenase release into the medium) of the NRK cells in vitro. Pretreatment with AP39 (30-300 nM) exerted a concentration dependent protective effect against all of the above effects of GOx. Most of the effects of AP39 followed a bell-shaped concentration-response curve; at the highest concentration of GOx tested, AP39 was no longer able to afford cytoprotective effects. Rats subjected to renal ischemia/reperfusion responded with a marked increase (over four-fold over sham control baseline) blood urea nitrogen and creatinine levels in blood, indicative of significant renal damage. This was associated with increased neutrophil infiltration into the kidneys (assessed by the myeloperoxidase assay in kidney homogenates), increased oxidative stress (assessed by the malondialdehyde assay in kidney homogenates), and an increase in plasma levels of IL-12. Pretreatment with AP39 (0.1, 0.2, and 0.3 mg/kg) provided a dose-dependent protection against these pathophysiological alterations; the most pronounced protective effect was observed at the 0.3 mg/kg dose of the H2S donor; nevertheless, AP39 failed to achieve a complete normalization of any of the injury markers measured. The partial protective effects of AP39 correlated with a partial improvement of kidney histological scores and reduced TUNEL staining (an indicator of DNA damage and apoptosis). In summary, the mitochondria-targeted H2S donor AP39 exerted dose-dependent protective effects against renal epithelial cell injury in vitro and renal ischemia-reperfusion injury in vivo. We hypothesize that the beneficial actions of AP39 are related to the reduction of cellular oxidative stress, and subsequent attenuation of various positive feed-forward cycles of inflammatory and oxidative processes. PMID- 26513709 TI - EFFECT OF INTRAPERITONEAL RESUSCITATION WITH DIFFERENT CONCENTRATIONS OF SODIUM PYRUVATE ON INTESTINAL ISCHEMIA REPERFUSION INJURY IN HEMORRHAGIC SHOCK RAT. AB - OBJECTIVE: To determine the effects of intraperitoneal resuscitation (PR) with different concentrations of sodium pyruvate (PY) on intestinal ischemia reperfusion injury in rats hemorrhagic shock (HS). METHODS: Sixty rats were randomly assigned to six groups. These included: group SHAM, intravenous resuscitation only (VR) group, and four PR groups based on resuscitation fluid: glucose-lactate-based peritoneal dialysis solution (LA), and PY-1.1%, PY-1.6%, and PY-2.2% (concentrations in grams/dL). Mean arterial pressure (MAP) was monitored continuously. Blood pH, base excess (BE), lactate, intestinal myeloperoxidase (MPO), malondialdehyde (MDA), tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), activated caspase-3, and zonula occludens-1 (ZO-1) were measured; intestinal mucosal damage index (IMDI) and subcellular changes were observed; apoptotic index (AI) was calculated. RESULTS: Three hours after resuscitation, in PY groups, MPO, MDA, IMDI, AI, TNF-alpha, and IL-6 were significantly lower than VR and LA groups, while pH and BE were higher. PY groups showed less expression of activated caspase-3 but elevated ZO-1. Among PY groups, group PY-1.1% had the lowest MPO, MDA and TNF-alpha, and had less pathological damage and subcellular changes than other experimental groups. CONCLUSIONS: PR using PY solution combined with VR provided protection against intestinal ischemia-reperfusion injury following HS and resuscitation. Under the same hypertonic condition, 1.1% PY solution showed significant advantages compared with 2.2% and 1.6% solutions. The underlying mechanisms may include the maintenance of hemodynamic stability, regulation of homeostasis, inhibition of oxidative stress and inflammation, and protection of intestinal epithelial tight junction barrier function. PMID- 26513710 TI - Acute Lung Injury Causes Asynchronous Alveolar Ventilation That Can Be Corrected by Individual Sighs. AB - RATIONALE: Improved ventilation strategies have been the mainstay for reducing mortality in acute respiratory distress syndrome. Their unique clinical effectiveness is, however, unmatched by our understanding of the underlying mechanobiology, and their impact on alveolar dynamics and gas exchange remains largely speculative. OBJECTIVES: To assess changes in alveolar dynamics and associated effects on local gas exchange in experimental models of acute lung injury (ALI) and their responsiveness to sighs. METHODS: Alveolar dynamics and local gas exchange were studied in vivo by darkfield microscopy and multispectral oximetry in experimental murine models of ALI induced by hydrochloric acid, Tween instillation, or in antibody-mediated transfusion-related ALI. MEASUREMENTS AND MAIN RESULTS: Independent of injury mode, ALI resulted in asynchronous alveolar ventilation characteristic of alveolar pendelluft, which either spontaneously resolved or progressed to a complete cessation or even inversion of alveolar ventilation. The functional relevance of the latter phenomena was evident as impaired blood oxygenation in juxtaposed lung capillaries. Individual sighs (2 * 10 s at inspiratory plateau pressure of 30 cm H2O) largely restored normal alveolar dynamics and gas exchange in acid-induced ALI, yet not in Tween-induced surfactant depletion. CONCLUSIONS: We describe for the first time in detail the different forms and temporal sequence of impaired alveolar dynamics in the acutely injured lung and report the first direct visualization of alveolar pendelluft. Moreover, we identify individual sighs as an effective strategy to restore intact alveolar ventilation by a mechanism independent of alveolar collapse and reopening. PMID- 26513712 TI - tRNA fragmentation and protein translation dynamics in the course of kidney injury. AB - Cells under stressful microenvironmental conditions initiate integrated molecular circuitries that aim at reducing general protein translation rates while redirecting protein synthesis toward a selective set of stress-response proteins. The consequence of the activation of this dynamic system is a reduction of the energy expenditure of the cell, and a metabolic rewiring that shapes adaptation under stress, which will, in fine, promote cell survival. In general, the translation initiation step is the prime target of translation reduction, with 2 molcular modules inhibiting translation initiation: the mechanistic target of Rapamycin complex 1, and the stress related kinases eIF2 kinases, which are all involved in the cellular responses to kidney injuries. tRNA (tRNA) dynamics and fragmentation have recently gained a considerable weight in the field of the non coding RNA biology, and emerge as an important system for protein translation modulation under cellular stress. More precisely, stress-induced tRNA (tiRNA), the cleavage products of the ribonuclease angiogenin, are generated under various stress conditions, including oxidative stress and endoplasmic reticulum stress, and contribute to protein translation reprogramming in mammal cells. Current clinical and experimental evidence indicates that the angiogenin-tRNA fragmentation system is initiated under renal insults, and is involved in the tissue adaptation upon kidney injury. In addition, this system represents a potential source for minimally-invasive or non invasive biomarkers of early kidney injury. Besides RNA interference, tRNA fragments are likely involved in other fundamental cellular functions, including inflammation, and a better understanding of the molecular basis of tRNA functions will drive discoveries on the fundamental role of non coding RNA biology, as exemplified by microRNA, in the regulation of kidney homeostasis. PMID- 26513713 TI - Higher survival drives the success of nitrogen-fixing trees through succession in Costa Rican rainforests. AB - Trees capable of symbiotic nitrogen (N) fixation ('N fixers') are abundant in many tropical forests. In temperate forests, it is well known that N fixers specialize in early-successional niches, but in tropical forests, successional trends of N-fixing species are poorly understood. We used a long-term census study (1997-2013) of regenerating lowland wet tropical forests in Costa Rica to document successional patterns of N fixers vs non-fixers, and used an individual based model to determine the demographic drivers of these trends. N fixers increased in relative basal area during succession. In the youngest forests, N fixers grew 2.5 times faster, recruited at a similar rate and were 15 times less likely to die as non-fixers. As succession proceeded, the growth and survival disparities decreased, whereas N fixer recruitment decreased relative to non fixers. According to our individual-based model, high survival was the dominant driver of the increase in basal area of N fixers. Our data suggest that N fixers are successful throughout secondary succession in tropical rainforests of north east Costa Rica, and that attempts to understand this success should focus on tree survival. PMID- 26513714 TI - Current screening approaches for antibody deficiency. AB - PURPOSE OF REVIEW: Diagnostic delay is a major problem for rare diseases including primary antibody deficiency (PAD). The aim of this review is to discuss the opportunities and challenges of current and future screening approaches for antibody deficiency, to reduce the delay and its impact on patients. (Figure is included in full-text article.) RECENT FINDINGS: Diagnostic delay in PAD is known to result in increased morbidity, mortality, and permanent functional impairment. Approaches to prevent this have been only partially successful and the delay may still be many years as the clinical presentation of PAD is highly variable and may be at any age, making screening difficult. Patients often have numerous healthcare encounters generating repeated cycles of laboratory and clinical data before the diagnosis is made. Low immunoglobulin levels result in alterations in laboratory tests not directly aimed at measuring immunoglobulins. We describe these and highlight the growing evidence in support of using calculated globulin which is part of the liver function test profile as a screening tool for antibody deficiency. Additional approaches include using embedded algorithms to analyse data generated by repeated clinical encounters (e.g. infections, antibiotics, cytopenias), potentially in combination with laboratory results such as calculated globulin, to help bring forward the diagnosis of PAD in patients in whom this has not yet been considered. SUMMARY: There is a strong case for the use of calculated globulin in screening for antibody deficiency. Further work is required to integrate laboratory results with clinical data to reduce diagnostic delay in patients with hitherto unsuspected antibody deficiency. PMID- 26513715 TI - Effect of Continued Medical Therapy on Productivity Costs for Refractory Chronic Rhinosinusitis. AB - IMPORTANCE: It is estimated that lost productivity related to chronic rhinosinusitis (CRS) costs society in excess of $13 billion per year in the United States. Given this tremendous cost to society, it is important to evaluate the effect of current interventions on improving this productivity loss. OBJECTIVE: To define the change in productivity costs in patients with refractory CRS who select continued medical therapy. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study. Thirty-eight patients with a guideline-based diagnosis of CRS whose initial appropriate medical therapy failed were enrolled from 4 tertiary-level rhinology clinics. The study was conducted from December 6, 2010, to April 23, 2013, and data analysis was performed from December 6, 2010, to June 1, 2015. INTERVENTIONS: Continued medical therapy for CRS. MAIN OUTCOMES AND MEASURES: The human capital approach was applied to quantify productivity costs. Absenteeism, presenteeism, and lost leisure time were quantified to define annual lost productive time, which was measured at enrollment (baseline) and at a minimum of 6 months after treatment. Lost productive time was monetized using the annual daily wage rates obtained from the 2012 US National Census and the 2013 US Department of Labor statistics. RESULTS: Thirty-eight patients with refractory CRS who selected continued medical therapy had a mean (SD) baseline annual productivity cost of $3464 ($4900) per patient. After continued medical therapy for a mean of 12.8 (4.8) months, productivity costs were $2730 ($3720) (before vs after continued medical therapy productivity cost, P = .74). Mean annual absenteeism was reduced from 5 (12) days to 2 (8) days (P = .02). Mean annual presenteeism (17 [27] days reduced to 15 [23] days; P = .93) and mean annual household days lost (7 [7] days reduced to 6 [6] days; P = .51) were maintained at baseline levels. There were no significant differences in productivity outcomes based on endoscopy, the 22-item Sinonasal Outcome Test score, age, or polyp status (all P >= .11). CONCLUSIONS AND RELEVANCE: Patients with refractory CRS often make treatment decisions based on the degree of quality-of-life and productivity impairment. Outcomes from this study suggest that productivity in patients with refractory CRS who have minor reductions in baseline productivity can remain stable with continued medical therapy. Physicians can use this information to inform appropriate patients with CRS of their expected outcomes from continued medical therapy. PMID- 26513716 TI - Radiopacity of Esthetic Post Materials: Evaluation with Digital Analysis Technique. AB - PURPOSE: To evaluate the radiopacity of five post materials using a digital image analysis method. MATERIALS AND METHODS: Twelve specimens from each post type (two zirconia and three fiber based) of 2 mm in thickness were obtained using a diamond blade mounted on a cutting machine, and digital radiographs were taken along with aluminum step-wedge and dentin discs under standard exposure conditions. The mean gray-values of specimens were measured using a computer graphics program. Data were analyzed using one-way ANOVA followed by Holm-Sidak multicomparison test (p = 0.05). RESULTS: The highest radiopacity was observed in custom zirconia (5.842 millimeters of equivalent Al [mmAl]), and the lowest value was detected with FRC-Postec (Ivoclar Vivadent) (1.716 mmAl). Significant differences were revealed between the radiopacity values among all groups (p < 0.05), except the Zr post materials (p = 0.56). CONCLUSIONS: All tested post materials had higher radiopacity than dentin. Further studies will be required to clarify optimum radiopacity properties of the post materials to provide a precise clinical observation. PMID- 26513717 TI - Penetrating and Intrastromal Corneal Arcuate Incisions in Rabbit and Human Cadaver Eyes: Manual Diamond Blade and Femtosecond Laser-Created Incisions. AB - OBJECTIVES: To compare morphologic differences between freehand diamond or femtosecond laser-assisted penetrating and intrastromal arcuate incisions. METHODS: Freehand diamond blade, corneal arcuate incisions (180 degrees apart, 60 degrees arc lengths) and 150 kHz femtosecond laser (80% scheimpflug pachymetry depth corneal thickness) arcuate incisions were performed in rabbits. Intrastromal arcuate incisions (100 MUm above Descemet's membrane, 100 MUm below epithelium) were performed in rabbit corneas (energy 1.2 MUJ, spot line separation 3 * 3 MUm, 90 degrees side cut angle). Eyes were examined by slit lamp and light microscopy up to 47 days post-procedure. Freehand diamond blade penetrating incisions, and femtosecond laser penetrating and intrastromal arcuate incisions (energy 1.8 MUJ, spot line separation 2 * 2 MUm) were performed in cadaver eyes. Optical coherence tomography was performed immediately after surgery and the corneas were fixed for light scanning and transmission electron microscopy. RESULTS: The rabbit model showed anterior stromal inflammation with epithelial hyperplasia in penetrating blade and laser penetrating wounds. The laser intrastromal and penetrating incisions showed localized constriction of the stromal layers of the cornea near the wound. In cadaver eyes, penetrating wound morphology was similar between blade and laser whereas intrastromal wounds did not affect the cornea above or below incisions. CONCLUSION: Penetrating femtosecond laser arcuate incisions have more predictable and controlled outcomes shown by less post-operative scarring than incisions performed with a diamond blade. Intrastromal incisions do not affect uncut corneal layers as demonstrated by histopathology. The femtosecond laser has significant advantages in its ability to make intrastromal incisions which are not achievable by traditional freehand or mechanical diamond blades. PMID- 26513718 TI - Exophiala phaeomuriformis Fungal Keratitis: Case Report and In Vivo Confocal Microscopy Findings. AB - PURPOSE: Corneal infections, particularly fungal keratitis due to rare fungal species, pose a diagnostic and therapeutic challenge because of difficulty in identification and varying susceptibility profiles. In this study, we report the first case of fungal keratitis because of Exophiala phaeomuriformis. METHODS: We report the clinical findings and microbial identification techniques of a case of fungal keratitis due to E. phaeomuriformis. An 84-year-old woman presented with redness, pain, and itching in the left eye for 2 weeks. Slit-lamp biomicroscopy revealed one broken suture from previous penetrating keratoplasty (PKP), black infiltrates at the 4-o'clock position, without an overlying epithelial defect and hypopyon. Microbial identification was based cultures on Sabouraud dextrose agar and DNA sequencing and correlations to laser in vivo confocal microscopy (IVCM; Heidelberg Retinal Tomograph 3/Rostock Cornea Module, Heidelberg Engineering) and multiphoton microscopy (Ultima Microscope; Prairie Technologies) images. RESULTS: Slit-lamp biomicroscopy revealed one broken suture from previous PKP, black infiltrates at the 4-o'clock position, without an overlying epithelial defect and hypopyon. Based on a clinical suspicion of fungal keratitis, antifungals and fortified antibiotics were started. However, the patient did not respond to therapy and required urgent PKP. After surgery, the patient was maintained on topical and systemic voriconazole and also topical 2% cyclosporine for 5 months because of possibility of scleral involvement noticed during surgery. At the end of the treatment period, her vision improved from hand motion to 20/40, with no recurrence observed in a follow-up period of 1 year. Results of diagnostic tests were supported by fungal elements in stroma on IVCM. Culture from the infiltrate grew black yeast. DNA sequencing led to the diagnosis of E. phaeomuriformis keratitis. Antifungal susceptibility testing revealed sensitivity to voriconazole. CONCLUSION: This is, to our knowledge, the first reported case of E. phaeomuriformis fungal keratitis. Diagnostic testing included slit-lamp biomicroscopy, which revealed pigmented infiltrates, culture plates grew black yeast, microscopy showed branched fungal hyphae with budding conidia, and physiological features showed tolerance to high temperatures, nitrate assimilation, and ribosomal DNA sequencing. Collectively, these tests demonstrate unique features seen for this microorganism. High suspicion should be kept with pigmented infiltrates and with dark yeast on culture plates. Prompt and aggressive medical management with voriconazole or therapeutic PKP in nonresponsive cases is essential to prevent irreversible loss of vision. PMID- 26513719 TI - Myopia Control: A Review. AB - Slowing the progression of myopia has become a considerable concern for parents of myopic children. At the same time, clinical science is rapidly advancing the knowledge about methods to slow myopia progression. This article reviews the peer reviewed literature regarding several modalities attempting to control myopia progression. Several strategies have been shown to be ineffective for myopia control, including undercorrection of myopic refractive error, alignment fit gas permeable contact lenses, outdoor time, and bifocal of multifocal spectacles. However, a recent randomized clinical trial fitted progressing myopic children with executive bifocals for 3 years and found a 39% slowing of myopia progression for bifocal-only spectacles and 50% treatment effect for bifocal spectacles with base-in prism, although there was not a significant difference in progression between the bifocal-only and bifocal plus prism groups. Interestingly, outdoor time has shown to be effective for reducing the onset of myopia but not for slowing the progression of myopic refractive error. More effective methods of myopia control include orthokeratology, soft bifocal contact lenses, and antimuscarinic agents. Orthokeratology and soft bifocal contact lenses are both thought to provide myopic blur to the retina, which acts as a putative cue to slow myopic eye growth. Each of these myopia control methods provides, on average, slightly less than 50% slowing of myopia progression. All studies have shown clinically meaningful slowing of myopia progression, including several randomized clinical trials. The most investigated antimuscarinic agents include pirenzepine and atropine. Pirenzepine slows myopia progression by approximately 40%, but it is not commercially available in the United States. Atropine provides the best myopia control, but the cycloplegic and mydriatic side effects render it a rarely prescribed myopia control agent in the United States. However, low concentration atropine has been shown to provide effective myopia control with far fewer side effects than 1.0% atropine. Finally, two agents, low-concentration atropine and outdoor time have been shown to reduce the likelihood of myopia onset. Over the past few years, much has been learned about how to slow the progression of nearsightedness in children, but we still have a lot to learn. PMID- 26513720 TI - Tear Osmolarity and Tear Film Parameters in Patients With Ocular Rosacea. AB - OBJECTIVES: The aim of this study was to evaluate tear osmolarity and tear film parameters in patients with ocular rosacea. METHODS: In a single center, 25 eyes of 25 patients with ocular rosacea (group 1), 25 eyes of 25 patients with rosacea without ocular involvement (group 2), and 20 eyes of 20 healthy individuals (group 3) were evaluated using the Ocular Surface Disease Index (OSDI) questionnaire, Schirmer I test, tear film break-up time (TBUT), scoring of ocular surface fluorescein staining using modified Oxford scale, and tear osmolarity. RESULTS: Tear osmolarity values, OSDI and Oxford scale scores were significantly higher in group 1 than in groups 2 and 3 (P<0.001 for all). Schirmer I test and TBUT in group 1 were significantly lower than in groups 2 and 3 (P<0.001 for all). There were no significant differences in OSDI, Schirmer I test, TBUT, Oxford scores, or tear osmolarity between groups 2 and 3 (P=0.629, P=0.175, P=0.713, P=865, and P=0.388, respectively). CONCLUSIONS: This study showed that ocular rosacea is associated with tear hyperosmolarity and tear film dysfunction. PMID- 26513721 TI - The Effect of Temperature on Soft Contact Lens Diameter. AB - PURPOSE: The diameters of soft contact lenses are conventionally measured at room temperature (RT), however, all soft lenses shrink when raised to eye temperature (ET). The purpose of this study was to evaluate RT to ET shrinkage in a representative sample of contemporary spherical soft contact lenses. METHODS: Twenty-four reusable and daily disposable lens types (10 hydrogel and 14 silicone hydrogel) in three powers were measured for total diameter at RT (20 degrees C+/ 1 degrees C) and ET (34 degrees C+/-1 degrees C). Lens diameter measurements were undertaken after equilibration in ISO saline in a temperature controlled lens analyzer (Optimec Ltd, Malvern, UK). Theoretical changes in base curve radii were also calculated. RESULTS: All lens types reduced in diameter when raised to ET. The largest mean changes with silicone hydrogel and hydrogel lenses were with Avaria (Delta0.33 mm) and SofLens Daily Disposable (Delta0.69 mm), respectively. The smallest mean changes for silicone hydrogel and hydrogel lenses were with 1 DAY ACUVUE TruEye (Delta0.04 mm) and SofLens 38 (Delta0.11 mm), respectively. There was, however, a wide range in change between the different lenses tested. CONCLUSIONS: This study has identified the levels of shrinkage in current soft contact lenses. In many cases, these shrinkage levels can be expected to have significant effects on clinical performance. PMID- 26513722 TI - Neurologic Deficits Including Auditory Loss and Recovery of Function in Horses with Temporohyoid Osteoarthropathy. AB - BACKGROUND: Auditory loss is a common deficit in horses with temporohyoid osteoarthropathy (THO), however, recovery of function is unknown. HYPOTHESIS/OBJECTIVES: To investigate neurologic function with emphasis in audition in horses with THO after treatment. To describe anatomical alterations of the petrous temporal bone that might result in auditory loss. ANIMALS: Twenty four horses with a clinical diagnosis of THO. METHODS: Prospective study. A brainstem auditory evoked response (BAER) study was done as part of the criteria for inclusion in horses with a clinical diagnosis of THO from the years of 2005 to 2014. Physical and neurologic status and BAER findings were recorded. Brainstem auditory evoked response variables were compared by using Wilcoxon sign test. Fisher's exact test was also used. Significance was set at P < 0.05. RESULTS: The most common signs included auditory loss (100% of horses), vestibular and facial nerve dysfunction (83%), and exposure ulcerative keratitis (71%). Concurrent left laryngeal hemiparesis was observed in 61% of horses through endoscopy. Auditory dysfunction was bilateral in 50% of the cases (complete and partial), and unilateral affecting more commonly the right ear (R = 8, L = 4). Short- and long-term follow-up revealed persistent auditory loss in all horses based on abnormal response to sound, and further confirmed through a BAER in 8 horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Auditory dysfunction appears to be a permanent neurologic deficit in horses diagnosed with THO despite overall neurologic improvement. PMID- 26513723 TI - The Role of Structural Elements of the 5'-Terminal Region of p53 mRNA in Translation under Stress Conditions Assayed by the Antisense Oligonucleotide Approach. AB - The p53 protein is one of the major factors responsible for cell cycle regulation and stress response. In the 5'-terminal region of p53 mRNA, an IRES element has been found which takes part in the translational regulation of p53 expression. Two characteristic hairpin motifs are present in this mRNA region: G56-C169, with the first AUG codon, and U180-A218, which interacts with the Hdm2 protein (human homolog of mouse double minute 2 protein). 2'-OMe modified antisense oligomers hybridizing to the 5'-terminal region of p53 mRNA were applied to assess the role of these structural elements in translation initiation under conditions of cellular stress. Structural changes in the RNA target occurring upon oligomers' binding were monitored by the Pb2+-induced cleavage method. The impact of antisense oligomers on the synthesis of two proteins, the full-length p53 and its isoform Delta40p53, was analysed in HT-29, MCF-7 and HepG2 cells, under normal conditions and under stress, as well as in vitro conditions. The results revealed that the hairpin U180-A218 and adjacent single-stranded region A219-A228 were predominantly responsible for high efficacy of IRES-mediated translation in the presence of stress factors. These motifs play a role of cis-acting elements which are able to modulate IRES activity, likely via interactions with protein factors. PMID- 26513724 TI - Mincle, an Innate Immune Receptor, Is Expressed in Urothelial Cancer Cells of Papillomavirus-Associated Urothelial Tumors of Cattle. AB - BACKGROUND: Mincle, macrophage-inducible C-type lectin, is a member of C-type lectin receptors. It plays an important role in anti-mycobacterial and anti fungal immunity. Furthermore it senses dead cells through its primary ligand SAP130. MATERIALS AND FINDINGS: We examined ten urothelial tumors of the urinary bladder of cattle. Eight of them expressed E5 cDNA of bovine papillomaviruses type 2 (BPV-2) and type 13 (BPV-13) that belong to Deltapapillomavirus genus. Two of them were not examined for detection of E5 cDNA. Mincle expression appeared to occur in urothelial neoplastic cells only. No mincle expression was detected in urothelial cells from healthy cattle. Mincle expression was characterized by a membranous pattern in papillary urothelial cancers; isolated and/or clustered urothelial cells showing a strong cytoplasmic immunoreactivity were primarily seen in invasive urothelial cancers. CONCLUSION: This is the first study about the expression of mincle in veterinary oncology and the first report which describes the expression of functional mincle receptor in neoplastic cells in medical literature. As it has been shown that urothelial cancer cells have the ability to function as antigen-presenting cells (APCs), it is conceivable that mincle expression is involved in the presentation of cancer cell antigens to cells of the immune system. Furthermore, since expression of mincle contributes to the control of Mycobacterium bovis BCG infection, this study has exciting clinical implications in comparative medicine keeping in mind that Bacillus Calmette-Guerin (BCG) immunotherapy is currently the most effective treatment of non-muscle invasive bladder cancer in man. Mincle expression in urothelial tumor cells warrants further study to better understand the role, if any, of this receptor in bladder cancer. Future studies will provide insights in the role of mincle receptor of urothelial cancer cells in antitumor immunotherapy. PMID- 26513725 TI - The arms of the chimeras. AB - This article seeks to compare the approach developed in 1974 by Michel de M'Uzan to the concept of the 'chimera' with Thomas Ogden's (, ) reflections on 'the analytic third'. This comparison shows that in spite of the different theoretical approaches, unconscious to unconscious communication - a subject of interest in contemporary psychoanalytic research - makes it possible to grasp the intersubjective data deployed in the field of the session. After reviewing M. de M'Uzan's conception of the 'chimera' - a product of the unconsciouses of patient and analyst alike, and which emerges during a process of depersonalization in the analyst - the author proposes her hypothesis of the chimera as a particular intersubjective third whose creation, in a hallucinatory state, makes it possible to gain access to the bodily and emotional basis of the trauma. The author describes the chimera as a mental 'squiggle' between the two members of the pair which finds expression in different forms; further, she considers that the chimera that seizes the analyst is underpinned by the unconscious affinities of traumatic zones in both protagonists, which permit the grounding, configuration and sharing of the territories of suffering, as apprehended in this paper. PMID- 26513726 TI - Substance Use in Patients With First-Episode Psychosis: Is Gender Relevant? AB - OBJECTIVE: Only a few studies in patients with first-episode psychosis have included gender in the study hypothesis or considered this a primary study variable. The aim of this study was to explore the influence of gender in the pattern of substance use in patients with first-episode psychosis. METHODS: This is a sub-analysis of a randomized open clinical trial that compared 1-year treatment retention rates of patients with first-episode psychosis randomized to haloperidol, olanzapine, quetiapine, risperidone, or ziprasidone. Our sub analysis included 85 men and 29 women. RESULTS: Substance use was relatively high among these patients and differed significantly by gender. Men were more likely to use substances overall than women (89.4% for men vs. 55.2% for women), chi(2) = 16.2, df = 1, p <.001, and were also more likely to use alcohol (chi(2) = 13, df = 1, p <.001), cannabis (chi(2) = 9.9; df = 1, p <.002), and cocaine (chi(2) = 10.3; df = 1, p <.001), compared to women. While there were no gender differences in age at first consumption of alcohol or cocaine, men were significantly younger at first consumption of cannabis (M = 16.08 years, SD = 2.1) than women (M = 18.0 years, SD = 3.8), F(1, 59) = 5, p <.02. When analyzed separately by gender, women showed no significant differences in the influence of number of substances used on age at onset of psychosis, F(3, 29) = 1.2, p =.30. However, there was a significant difference among men, with earlier onset of psychosis noted in men consuming multiple substances; F(4, 85) = 5.8, p <.0001. Regarding prediction of age at onset of psychosis, both male gender and the use of a higher number of substances significantly predicted an earlier age at onset of psychosis. CONCLUSIONS: Our study provides some evidence of gender differences in the pattern of substance use in patients with first-episode psychosis, suggesting the possible need for gender-specific approaches in the interventions performed in these patients. This study is registered as #12610000954022 with the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au). PMID- 26513727 TI - The Relationship of Metabolic Syndrome and Body Composition in Children with Premature Adrenarche: Is It Age Related? AB - BACKGROUND: Studies that evaluate both body composition and metabolic syndrome (MeS) risk in prepubertal children with premature adrenarche (PA) are limited. METHODS: Fifty-eight prepubertal children (aged 5-9 years, 33 female and 25 male), 30 with PA and 28 controls, were evaluated for the presence of MeS as defined by age-modified National Cholesterol Education Program Adult Treatment Panel III criteria. A subset had dual-energy X-ray absorptiometry and bone markers (n = 23/58) to evaluate the effect of hyperandrogenism on metabolic abnormalities and body composition. RESULTS: There was no difference in the prevalence of MeS between PA and controls (p = 0.138). Children with MeS were obese with an increased waist circumference (WC) and decreased high-density lipoprotein levels. Androgens were not associated with having more than one criterion for MeS (p = 0.08) but were associated with triglycerides and WC (p = 0.029 and p = 0.041, respectively). Lean mass was greater in PA subjects (p = 0.039), and androgens correlated with bone mineral density (p = 0.029) and total body fat (p = 0.008). Subjects with a higher percent of body fat were more likely to have more than one MeS risk factor (p = 0.005). CONCLUSIONS: MeS was seen only in obese subjects whether or not they had PA. Thus, it appears that obesity drives metabolic risk in the prepubertal population rather than PA. Our findings are important in determining how the prepubertal patient with PA should be evaluated for metabolic risk. PMID- 26513728 TI - Chemical chaperone therapy, a new strategy for genetic skin fragility disorders. PMID- 26513729 TI - Socio-Economic Differences in Cardiovascular Health: Findings from a Cross Sectional Study in a Middle-Income Country. AB - BACKGROUND: A relatively consistent body of literature, mainly from high-income countries, supports an inverse association between socio-economic status (SES) and risk of cardiovascular disease (CVD). Data from low- and middle-income countries are scarce. This study explores SES differences in cardiovascular health (CVH) in the Republic of Srpska (RS), Bosnia and Herzegovina, a middle income country. METHODS: We collected information on SES (education, employment status and household's relative economic status, i.e. household wealth) and the 7 ideal CVH components (smoking status, body mass index, physical activity, diet, blood pressure, total cholesterol, and fasting blood glucose) among 3601 participants 25 years of age and older, from the 2010 National Health Survey in the RS. Based on the sum of all 7 CVH components an overall CVH score (CVHS) was calculated ranging from 0 (all CVH components at poor levels) to 14 (all CVH components at ideal levels). To assess the differences between groups the chi square test, t-test and ANOVA were used where appropriate. The association between SES and CVHS was analysed with multivariate linear regression analyses. The dependent variable was CVHS, while independent variables were educational level, employment status and wealth index. RESULTS: According to multiple linear regression analysis CVHS was independently associated with education attainment and employment status. Participants with higher educational attainment and those economically active had higher CVHS (b = 0.57; CI = 0.29-0.85 and b = 0.27; CI = 0.10-0.44 respectively) after adjustment for sex, age group, type of settlement, and marital status. We failed to find any statistically significant difference between the wealth index and CVHS. CONCLUSION: This study presents the novel information, since CVHS generated from the individual CVH components was not compared by socio-economic status till now. Our finding that the higher overall CVHS was independently associated with a higher education attainment and those economically active supports the importance of reducing socio-economic inequalities in CVH in RS. PMID- 26513730 TI - Aqueous synthesis of high bright and tunable near-infrared AgInSe2-ZnSe quantum dots for bioimaging. AB - Efficient synthetic methods for near-infrared quantum dots with good biophysical properties as bioimaging agents are urgently required. In this work, a simple and fast synthesis of highly luminescent, near-infrared AgInSe2-ZnSe quantum dots (QDs) with tunable emissions in aqueous media is reported. This method avoids high temperature and pressure and organic solvents to directly generate water dispersible AgInSe2-ZnSe QDs. The photoluminescence emission peak of the AgInSe2 ZnSe QDs ranged from 625 to 940nm, with quantum yields up to 31%. The AgInSe2 ZnSe QDs with high quantum yield, near-infrared and low cytotoxic could be used as good cell labels, showing great potential applications in bio-imaging. PMID- 26513731 TI - Surface tension supported floating of heavy objects: Why elongated bodies float better? AB - Floating of bodies heavier than the supporting liquid is discussed. Floating of cylindrical, ellipsoidal bodies and rectangular plates possessing lateral dimensions smaller than the capillary length is treated. It is demonstrated that more elongated bodies of a fixed volume are better supported by capillary forces, due to the increase in the perimeter of the triple line. Thus, floating of metallic needles obtains reasonable explanation. PMID- 26513732 TI - High catalytic active palladium nanoparticles gradually discharged from multilayer films to promote Suzuki, Heck and Sonogashira cross coupling reactions. AB - To improve the catalytic activity and reduce the dosage of noble metal catalysts has attracted much more attention for organic synthetic chemists. We facilely fabricated multilayer films of PEI-(PdCl2/1)n through layer-by-layer (LBL) self assembly method (PEI=polyethylenmine, 1=2,2',7,7'-tetra(4-pyridyl)-9,9' spirobifluorene, psf). UV-vis spectroscopy, atomic force microscopy (AFM) and scanning electron microscopy (SEM) were used to monitor the growth of multilayer films. X-ray photoelectron spectroscopy (XPS) proved the palladium and ligand 1 were deposited on the film. The PEI-(PdCl2/1)n multilayer films were used as the cisterns of catalysts to gradually discharge high active catalytic moieties in the Suzuki-Miyaura, Heck and Sonogashira cross-coupling reactions. The Pd-loading was as low as 12.1*10(-6)mol% measured by inductively coupled plasma OES spectrometer (ICP), and gave high yields in the typical reactions of bromobenzenes with phenylboronic acids. The LbL catalyst featured the simplicity of fabrication, high efficiency, reusability, convenient control and no sensitive to air in the reactions. PMID- 26513733 TI - Photo-responsive polyethyleneimine microcapsules cross-linked by ortho nitrobenzyl derivatives. AB - Intelligent capsules are widely used as carriers for loading small molecules and particles for their capacity to respond to environmental stimuli. In this study, photo-responsive polyethyleneimine (PEI) microcapsules were fabricated using 4 bromomethyl-3-nitrobenzoic acid (BNBA) bearing a photodegradable ortho nitrobenzyl group as a cross-linker. PEI-doped CaCO3 particles were used as the sacrificial templates, in which the PEI molecules were cross-linked by BNBA molecules under the activation of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 methylmorpholinium chloride (DMT-MM) and N,N-diisopropylethylamine (DIEA). After the removal of CaCO3 particles by hydrochloric acid, the PEI-BNBA capsules were obtained. Since the C-N bond that formed via reaction of benzyl bromide and amine is photo-cleavable, the capsules could be decomposed under UV irradiation at 365nm. The loaded macromolecules could be released upon UV irradiation, exhibiting the microcapsules' potential applications in the field of controlled release. PMID- 26513734 TI - Ionic liquid crosslinkers for chiral imprinted nanoGUMBOS. AB - Molecularly imprinted polymers (MIPs) are an important class of selective materials for molecular specific sensors and separations. Molecular imprinting using non-covalent interactions in aqueous conditions still remains a difficult challenge due to interruption of hydrogen-bonding or electrostatic interactions water. Newly developed crosslinking ionic liquids are demonstrated herein to overcome problems of synthesizing aqueous MIPs, adding to previous examples of ionic liquids used as monomers in non-aqueous conditions or used as MIP solvents. Vinylimidazole ionic liquid crosslinkers were synthesized and subsequently explored as matrix supports for fabrication of molecularly imprinted polymeric nanoGUMBOS (nanoparticles derived from a group of uniform materials based on organic salts). Each of the four crosslinkers incorporated a unique functional spacer between the vinylimidazole groups, and the performance of the corresponding molecularly imprinted polymers was evaluated using chiral recognition as the diagnostic. High uptake values for l-tryptophan were found in the 13-87MUmol/g range; and chiral recognition was determined via binding ratios of l-tryptophan over d-tryptophan that ranged from 5:1 to 13:1 for polymers made using different crosslinkers. Not only are these materials good for chiral recognition, but the results highlight the utility of these materials for imprinting aqueous templates such as biological targets for theranostic agents. PMID- 26513735 TI - Toward a durable superhydrophobic aluminum surface by etching and ZnO nanoparticle deposition. AB - Fabrication of suitable roughness is a fundamental step for acquiring superhydrophobic surfaces. For this purpose, a deposition of ZnO nanoparticles on Al surface was carried out by simple immersion and ultrasound approaches. Then, surface energy reduction was performed using stearic acid (STA) ethanol solution for both methods. The results demonstrated that ultrasound would lead to more stable superhydrophobic Al surfaces (STA-ZnO-Al-U) in comparison with simple immersion method (STA-ZnO-Al-I). Besides, etching in HCl solution in another sample was carried out before ZnO deposition for acquiring more mechanically stable superhydrophobic surface. The potentiodynamic measurements demonstrate that etching in HCl solution under ultrasound leads to superhydrophobic surface (STA-ZnO-Al(E)-U). This sample shows remarkable decrease in corrosion current density (icorr) and long-term stability improvement versus immersion in NaCl solution (3.5%) in comparison with the sample prepared without etching (STA-ZnO Al-U). Scanning electron micrograph (SEM) and energy-dispersive X-ray spectroscopy (EDX) confirmed a more condense and further particle deposition on Al substrate when ultrasound was applied in the system. The crystallite evaluation of deposited ZnO nanoparticles was carried out using X-ray diffractometer (XRD). Finally, for STA grafting verification on Al surface, Fourier transform infrared in conjunction with attenuated total reflection (FTIR ATR) was used as a proper technique. PMID- 26513736 TI - Synthesis of halogen-doped reduced graphene oxide nanosheets as highly efficient metal-free electrocatalyst for oxygen reduction reaction. AB - We demonstrate F-, Cl-, Br- and I-doped reduced graphene oxide (XRGO) as metal free graphene electro-catalysts for oxygen reduction reaction (ORR) in alkaline media. Reduced graphene oxide (GO) is prepared from graphite electrode using electrochemical exfoliation. In situ doping of halide in a graphene film has many problems. In this technique, different halides individually or all of them were mixed with the RGO and ionic liquids precursor at H2SO4 solution. Then we have evaluated the effectiveness of doping and performed electrochemical measurements of the ORR activity on XRGO. Fourier-transform infrared spectroscopy spectra show a variety of the halogen-containing functional groups. Energy-dispersive X-ray spectroscopy analysis confirmed the presence of doped halogens in RGO. Raman spectroscopy shows a high density of defects in the RGO layer. The electrochemical properties of the XRGO catalysts on carbon paper as a gas diffusion electrode (GDE) are investigated by several electrochemical methods in oxygen saturated alkaline solutions. The catalytic activity of the XRGO and Pt-C electrodes for ORR is 50 and 30mAcm(-2) at -1V in GDEs. This enhanced efficiency is the result of the influence of the nature and percentage of the halogen, especially fluorine presence in the graphene layer. PMID- 26513737 TI - In vitro and in vivo evaluation of effect of excipients in local delivery of paclitaxel using microporous infusion balloon catheters. AB - Drug-infusion balloons are one of the currently used local drug delivery devices for preventing restenosis after endovascular treatments. An antiproliferative drug (paclitaxel, PAT) is infused through the balloon using a cremophor-based formulation to control restenosis. However, the major limitations of this approach are poor in vivo drug uptake and a limit in the amount of PAT delivered because of cremophor toxicity. In this study, we have investigated the use of different excipients for effectively infusing PAT out of the balloon for improved drug uptake in the tissue. The excipients include nanoparticle albumin-bound PAT (nab-PAT, a nanobiomaterial used in cancer therapy), urea (a hydrophilic agent used for faster drug transfer), iodixanol (a contrast agent used for coronary angiography), and cremophor-PAT (the most commonly used PAT formulation). An in vitro drug release, smooth muscle cell (SMC) response, endothelial cell (EC) response, and in vivo drug uptake were investigated for all the different excipients of PAT infused through the balloon. The nab-PAT was as effective as cremophor in infusing out of the balloon and inhibiting SMC growth. Also, nab-PAT showed a significantly greater amount of in vivo PAT uptake than that of cremophor-PAT. Urea and iodixanol were not effective in delivering a clinically relevant dose of PAT due to the poor solubility of PAT in these excipients. Urea eradicated all the SMCs and ECs, suggesting a toxic effect, which impedes its use in balloon-based therapy. Thus, this study demonstrated that nab-PAT is an effective formulation to locally deliver PAT through infusion balloons. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 376-390, 2017. PMID- 26513738 TI - The NADPH Oxidase Nox4 mediates tumour angiogenesis. AB - AIM: The aim of this work was to identify the role of the NADPH oxidase Nox4 for tumour angiogenesis in a slow-growing tumour model in mice. METHODS: Tumour angiogenesis was studied in tumours induced by the carcinogen 3 methylcholanthrene (MCA) in wild-type and Nox knockout mice. Mice were killed when the tumour reached a diameter of 1.5 cm and tumour tissue was used for histological and molecular analysis. RESULTS: 3-methylcholanthrene induced fibrosarcoma in wild-type, Nox1y/-, Nox2y/- and Nox4-/- mice. Histological analysis of vessel density using anti-CD31 staining showed a significant 38% reduction in tumour vascularization in fibrosarcomas of Nox4-/- mice. In contrast, tumour angiogenesis was doubled in Nox1 knockout mice, whereas knockout of Nox2 had no effect on tumour-vessel density. As underlying mechanisms, we identified a defect in hypoxia signalling in Nox4-/- mice. Hypoxia-inducible factor 1-alpha (Hif-1alpha) accumulation in the tumours was attenuated as was the expression of the Hif-1alpha-dependent pro-angiogenic genes vascular endothelial growth factor-A, glucose transporter 1 and adrenomedullin. CONCLUSION: By regulating the tumour-vessel density through stabilization of Hif-1alpha and induction of VEGF expression, Nox4 promotes tumour angiogenesis and may represent a novel target for anti-angiogenic tumour therapy. PMID- 26513739 TI - IDENTIFICATION OF THE FGL-AMIDE ALLATOSTATIN GENE OF THE PRIMITIVE TERMITE Mastotermes darwiniensis AND THE WOODROACH Cryptocercus darwini. AB - Allatostatins with the C-terminal ending Tyr/Phe-Xaa-Phe-Gly-Leu/Ile-amide (FGLa/ASTs) are widespread neuropeptides with multiple functions. The gene encoding the FGLa/AST polypeptide precursor was first isolated from cockroaches and since then could be identified in many insects and crustaceans. With its strictly conserved regions in combination with variable regions the gene seems to be a good candidate for phylogenetic analyses between closely and distantly related species. Here, the structure of the FGLa/AST gene of the most primitive termite, the giant northern termite Mastotermes darwiniensis Froggatt, was identified. The FGLa/AST gene of the woodroach Cryptocercus darwini was also determined. Precursor sequences of both species possess the general organization of dictyopteran FGLa/AST precursors containing 14 putative FGLa/AST peptides. In M. darwiniensis, only 11 out of the 14 FGLa/AST-like peptides possess the C terminal conserved region Y/FXFGL/I/V/M and four of the putative peptide structures are not followed by a Gly residue that would lead to nonamidated peptides. Phylogenetic analyses show the high degree of similarity of dictyopteran FGLa/AST sequences. The position of termites, nested within the Blattaria, confirms that termites have evolved from primitive cockroaches. PMID- 26513740 TI - Morphing technique reveals intact perception of object motion and disturbed perception of emotional expressions by low-functioning adolescents with Autism Spectrum Disorder. AB - A morphing procedure has been designed to compare directly the perception of emotional expressions and of moving objects. Morphing tasks were presented to 12 low-functioning teenagers with Autism Spectrum Disorder (LF ASD) compared to 12 developmental age-matched typical children and a group presenting ceiling performance. In a first study, when presented with morphed stimuli of objects and emotional faces, LF ASD showed an intact perception of object change of state together with an impaired perception of emotional facial change of state. In a second study, an eye-tracker recorded visual exploration of morphed emotional stimuli displayed by a human face and a robotic set-up. Facing the morphed robotic stimuli, LF ASD displayed equal duration of fixations toward emotional regions and toward mechanical sources of motion, while the typical groups tracked the emotional regions only. Altogether the findings of the two studies suggest that individuals with ASD process motion rather than emotional signals when facing facial expressions. PMID- 26513741 TI - The reliability and validity of the Developmental Coordination Disorder Questionnaire'07 for children aged 4-6 years in mainland China. AB - An effective population-based screening tool is needed to identify possible cases of Developmental Coordination Disorder (DCD) among preschool children in mainland China. We examined the psychometric properties of the DCD questionnaire'07 (DCDQ'07) in Chinese children aged 4-6. A total of 3316 children from 10 nursery schools were involved in the study. Internal consistency and test-retest reliability of the DCDQ'07 were estimated using Cronbach's alpha, item-total correlation and intraclass correlation co-efficient (ICC). The construct validity was evaluated using the exploratory and confirmatory factor analysis. Receiver operating characteristic (ROC) analysis was used to measure the accuracy of the DCDQ'07. The results showed that both internal consistency (Cronbach's alpha value of all items were above 0.85) and test-retest reliability (ICCs of 13 items and subscales were above 0.9) were excellent. Confirmatory factor analysis showed that each goodness-of-fit indices of the 3-factor model was above 0.9, indicating a satisfactory fit of the data to the model. Area under the ROC curve was comparatively small (0.641). With the exception of construct validity in younger children (4 years old) and discriminative validity, the Chinese version of the DCDQ'07 achieves satisfactory reliability and construct validity in mainland China. Nevertheless, the questionnaire should be not used in younger children, and further studies are needed to explore the use of Little DCD-Q in Chinese preschool children. PMID- 26513742 TI - Semantic conflicts are resolved differently by adults with and without ADHD. AB - Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurobehavioral disorder characterized by various behavioral and cognitive difficulties. Previous studies indicated that children with ADHD have language difficulties, including difficulties in metaphor understanding but the relation between metaphor processing and specific cognitive functions needs further investigation. In the current study we examined how adults with and without ADHD resolve semantic conflicts between a metaphorical prime and a metaphorical or literal target sentence. Twenty-six adults with ADHD and 24 age-matched control participants underwent a thorough evaluation of neuropsychological skills, as well as assessment of various aspects of attention. Results suggested that people with ADHD were less efficient than controls in resolving conflicts between metaphorical and literal meanings of sentence pairs. In addition they showed deficient sustained attention and executive attention. Moreover, the ability to resolve semantic conflicts was related to semantic fluency in the ADHD group, but to executive attention in the control group. These findings emphasize the various specific difficulties of adults with ADHD and shed light on the different role of attention in the resolution of semantic conflicts among ADHD individuals as compared to controls. PMID- 26513743 TI - A Spatiotemporal Analysis of Brazilian Science from the Perspective of Researchers' Career Trajectories. AB - The growth of Brazilian scientific production in recent years is remarkable, which motivates an investigation on the factors, inside and outside the country, that helped shape this wealthy research environment. This article provides a thorough analysis of the education of researchers that constitute the main Brazilian research groups, using data on about 6,000 researchers involved in the country's National Institutes of Science and Technology (INCT) initiative. Data on the steps taken by each researcher in her education, from the bachelor's degree to doctorate, including a possible postdoctoral experience, and employment, are extracted from an official curriculum vitae repository. The location and the time at which each career step occurred define spatiotemporal career trajectories. We then analyze such trajectories considering additional data, including the area of knowledge of the INCTs to which each researcher is associated. We found an increasing prevalence of Brazilian institutions in the education of Brazilian scientists, as the number of doctorates earned abroad is decreasing over time. Postdoctoral stages, on the other hand, often take place in Europe or in the United States. Taking an international postdoctoral position after a full education in Brazil suggests a drive towards seeking higher-level exchange and cooperation with foreign groups in a more advanced career stage. Results also show that Brazilian researchers tend to seek employment in regions that are close to the institutions at which they received their bachelor's degrees, suggesting low mobility within the country. This study can be instrumental in defining public policies for correcting distortions, and can help other developing countries that aim to improve their national science systems. PMID- 26513744 TI - Solution Structural Studies of GTP:Adenosylcobinamide-Phosphateguanylyl Transferase (CobY) from Methanocaldococcus jannaschii. AB - GTP:adenosylcobinamide-phosphate (AdoCbi-P) guanylyl transferase (CobY) is an enzyme that transfers the GMP moiety of GTP to AdoCbi yielding AdoCbi-GDP in the late steps of the assembly of Ado-cobamides in archaea. The failure of repeated attempts to crystallize ligand-free (apo) CobY prompted us to explore its 3D structure by solution NMR spectroscopy. As reported here, the solution structure has a mixed alpha/beta fold consisting of seven beta-strands and five alpha helices, which is very similar to a Rossmann fold. Titration of apo-CobY with GTP resulted in large changes in amide proton chemical shifts that indicated major structural perturbations upon complex formation. However, the CobY:GTP complex as followed by 1H-15N HSQC spectra was found to be unstable over time: GTP hydrolyzed and the protein converted slowly to a species with an NMR spectrum similar to that of apo-CobY. The variant CobYG153D, whose GTP complex was studied by X-ray crystallography, yielded NMR spectra similar to those of wild-type CobY in both its apo- state and in complex with GTP. The CobYG153D:GTP complex was also found to be unstable over time. PMID- 26513745 TI - Comparison of NK-1 Receptor Antagonist (Maropitant) to Morphine as a Pre Anaesthetic Agent for Canine Ovariohysterectomy. AB - OBJECTIVE: To compare the NK-1 receptor antagonist maropitant to morphine during and after surgery in dogs undergoing ovariohysterectomy (OHE). METHODS: 30 healthy female dogs were randomly divided to receive either a pre-anaesthetic dose of morphine (0.5 mg/kg SQ) or maropitant (1 mg/kg, SQ) prior to OHE. Anaesthesia was induced with propofol and maintained with isoflurane. Expired isoflurane concentration, heart rate (HR), systolic arterial pressure (SAP) and respiratory rate were measured. Post-operative pain scores and appetite were evaluated during the recovery period. Rescue analgesia (morphine 0.1 mg/kg IV) was administered as needed post-operatively based on blinded pain score assessments. RESULTS: Although clinically comparable; during surgical stimulation, the maropitant group had lower HR (108+/-18 vs 115+/-24 bpm; p = 0.04), lower SAP (114+/-23 vs 125+/-23 mmHg; p = 0.003) and required slightly lower percent of isoflurane anaesthetic (1.35+/-0.2 vs 1.51+/-0.4%; p = 0.005), when compared to the morphine group. In the recovery period, the maropitant group had lower pain scores at extubation (1.7+/-0.7 vs 3.4+/-2.3; p = 0.0001) and were more likely to eat within 3 hours after extubation (64.7 vs 15.3%). However, post operative rescue analgesia requirements were similar between groups. All other measured parameters were similar between groups. The overall difference observed between groups was small and all monitored and measured parameters were within the expected range for anesthetized dogs. CLINICAL SIGNIFICANCE: No major differences in cardiorespiratory parameters or anaesthetic requirements were observed between maropitant and morphine when used as a pre-anesthetic agent for OHE. Further studies are necessary to fully elucidate the benefits of maropitant as a pre-anaesthetic agent for canine OHE. PMID- 26513746 TI - A Four Dimensional Spatio-Temporal Analysis of an Agricultural Dataset. AB - While a variety of statistical models now exist for the spatio-temporal analysis of two-dimensional (surface) data collected over time, there are few published examples of analogous models for the spatial analysis of data taken over four dimensions: latitude, longitude, height or depth, and time. When taking account of the autocorrelation of data within and between dimensions, the notion of closeness often differs for each of the dimensions. Here, we consider a number of approaches to the analysis of such a dataset, which arises from an agricultural experiment exploring the impact of different cropping systems on soil moisture. The proposed models vary in their representation of the spatial correlation in the data, the assumed temporal pattern and choice of conditional autoregressive (CAR) and other priors. In terms of the substantive question, we find that response cropping is generally more effective than long fallow cropping in reducing soil moisture at the depths considered (100 cm to 220 cm). Thus, if we wish to reduce the possibility of deep drainage and increased groundwater salinity, the recommended cropping system is response cropping. PMID- 26513748 TI - Correction: Passage-Based Bibliographic Coupling: An Inter-Article Similarity Measure for Biomedical Articles. PMID- 26513747 TI - Probing Difference in Binding Modes of Inhibitors to MDMX by Molecular Dynamics Simulations and Different Free Energy Methods. AB - The p53-MDMX interaction has attracted extensive attention of anti-cancer drug development in recent years. This current work adopted molecular dynamics (MD) simulations and cross-correlation analysis to investigate conformation changes of MDMX caused by inhibitor bindings. The obtained information indicates that the binding cleft of MDMX undergoes a large conformational change and the dynamic behavior of residues obviously change by the presence of different structural inhibitors. Two different methods of binding free energy predictions were employed to carry out a comparable insight into binding mechanisms of four inhibitors PMI, pDI, WK23 and WW8 to MDMX. The data show that the main factor controlling the inhibitor bindings to MDMX arises from van der Waals interactions. The binding free energies were further divided into contribution of each residue and the derived information gives a conclusion that the hydrophobic interactions, such as CH-CH, CH-pi and pi-pi interactions, are responsible for the inhibitor associations with MDMX. PMID- 26513749 TI - Risk Factors for Intracranial Haemorrhage in Accidents Associated with the Shower or Bathtub. AB - BACKGROUND: There has been little research on bathroom accidents. It is unknown whether the shower or bathtub are connected with special dangers in different age groups or whether there are specific risk factors for adverse outcomes. METHODS: This cross-sectional analysis included all direct admissions to the Emergency Department at the Inselspital Bern, Switzerland from 1 January 2000 to 28 February 2014 after accidents associated with the bathtub or shower. Time, age, location, mechanism and diagnosis were assessed and special risk factors were examined. Patient groups with and without intracranial bleeding were compared with the Mann-Whitney U test.The association of risk factors with intracranial bleeding was investigated using univariate analysis with Fisher's exact test or logistic regression. The effects of different variables on cerebral bleeding were analysed by multivariate logistic regression. RESULTS: Two hundred and eighty (280) patients with accidents associated with the bathtub or shower were included in our study. Two hundred and thirty-five (235) patients suffered direct trauma by hitting an object (83.9%) and traumatic brain injury (TBI) was detected in 28 patients (10%). Eight (8) of the 27 patients with mild traumatic brain injuries (GCS 13-15), (29.6%) exhibited intracranial haemorrhage. All patients with intracranial haemorrhage were older than 48 years and needed in-hospital treatment. Patients with intracranial haemorrhage were significantly older and had higher haemoglobin levels than the control group with TBI but without intracranial bleeding (p<0.05 for both).In univariate analysis, we found that intracranial haemorrhage in patients with TBI was associated with direct trauma in general and with age (both p<0.05), but not with the mechanism of the fall, its location (shower or bathtub) or the gender of the patient. Multivariate logistic regression analysis identified only age as a risk factor for cerebral bleeding (p<0.05; OR 1.09 (CI 1.01;1.171)). CONCLUSION: In patients with ED admissions associated with the bathtub or shower direct trauma and age are risk factors for intracranial haemorrhage. Additional effort in prevention should be considered, especially in the elderly. PMID- 26513750 TI - Metro system in Guangzhou as a hazardous reservoir of methicillin-resistant Staphylococci: findings from a point-prevalence molecular epidemiologic study. AB - Staphylococci are common causes of healthcare-associated and community-associated infections. However, limited data are available on the prevalence, phenotypes and molecular characteristics of Staphylococci in metro system around the world. 320 surface samples were collected from the Guangzhou metro system to isolate and characterize Staphylococci strains. Of the samples, 75.6% (242/320) were contaminated with Staphylococci. The Staphylococci isolates, especially the methicillin resistant isolates, were resistance to most of the antibiotics, with 79.8% (193/242) classified as multidrug resistant (MDR) strains. 8 strains of methicillin-resistant Staphylococcus aureus (MRSA) carried a range of staphylococcal cassette chromosome mec (SCCmec) types [I (1), II (3), III (2) and NT (2)]. Staphylococcus aureus isolates were classified into several ST types and showed possible cross transmissions of strains from various sources. All MRSA strains were positive for the qac gene, and only one methicillin-susceptible Staphylococci aureus (MSSA) strain was positive for the Panton-Valentine leukocidin (PVL) genes. This study demonstrated that environmental surfaces in the Guangzhou metro system may be a hazardous reservoir for transmission of Staphylococci to passengers. The resistance to antibiotics and disinfectants observed among isolates was also noteworthy. PMID- 26513751 TI - Self-assembled mPEG-PCL-g-PEI micelles for multifunctional nanoprobes of doxorubicin delivery and magnetic resonance imaging and optical imaging. AB - In this paper, a novel bifunctional nanoprobe based on polyethylene glycol(MPEG) poly(epsilon-caprolactone)(epsilon-CL)-polyethylenimine(PEI) labeled with FITC (MPEG-PCL-PEI-FITC, PCIF) were prepared to provide tumor therapy and simultaneous diagnostic information via magnetic resonance imaging (MRI) and optical imaging. Superparamagnetic iron oxide (SPIO) and doxorubicin (DOX) loaded PCIF (PCIF/SPIO/DOX) nanoprobes were prepared by self-assembling into micelles, which had uniformly distributed particle size of 130 +/- 5 nm and a zeta potential of +35 +/- 2 mV. Transmission electronic microscopy(TEM) showed that SPIO NPs were loaded into PCIF micelles. The PCIF/SPIO/DOX nanoprobes were superparamagnetic at 300 K with saturated magnetization of 20.5 emu/g Fe by vibrating-sample magnetomete (VSM). Studies on cellular uptake of PCIF/SPIO/DOX nanoprobes demonstrated that SPIO NPs, DOX and FITC labeled MPEG-PCL-PEI were simultaneously taken up by the breast cancer (4T1) cells. After intravenous injection of PCIF/SPIO/DOX nanoprobes in 4T1 tumor-bearing mice, SPIO NPs, DOX and FITC labeled MPEG-PCL-PEI micelles were simultaneously delivered into tumor tissue by histochemisty. This work is important for the applications to multimodal diagnostic and theragnosis as nanomedicine. PMID- 26513752 TI - Multistage vector delivery of sulindac and silymarin for prevention of colon cancer. AB - Familial adenomatous polyposis (FAP) is an inherited condition secondary to germline mutations in the APC gene, thus resulting in the formation of hundreds of colonic adenomas that eventually progress into colon cancer. Surgical removal of the colon remains the only treatment option to avoid malignancy, as long-term exposure to chemopreventive agents such as sulindac (a non-steroidal anti inflammatory drug) and silymarin (phytoestrogen) is not feasible. Here, we have developed a multistage silicon-based drug delivery platform for sulindac and silymarin that preferentially interacts with colon cancer cells as opposed to normal intestinal mucosa. Preferential binding and internalization of these drugs into colon cancer cells was obtained using a targeting strategy against the protein meprin A, which we demonstrate is overexpressed in human colon cancer cells and in the small intestine of Apc(Min/+) mice. We propose that this delivery system could potentially be used to reduce drug-induced side effects in FAP patients, thus enabling long-term prevention of adenoma formation. PMID- 26513753 TI - Bioactive compounds immobilized on Ti and TiNbHf: AFM-based investigations of biofunctionalization efficiency and cell adhesion. AB - Implant materials require optimal biointegration, including strong and stable cell-material interactions from the early stages of implantation. Ti-based alloys with low elastic modulus are attracting a lot of interest for avoiding stress shielding, but their osseointegration potential is still very low. In this study, we report on how cell adhesion is influenced by linear RGD, cyclic RGD, and recombinant fibronectin fragment III8-10 coated on titanium versus a novel low modulus TiNbHf alloy. The bioactive molecules were either physisorbed or covalently coupled to the substrates and their conformation on the surfaces was investigated with atomic force microscopy (AFM). The influence of the different bioactive coatings on the adhesion of rat mesenchymal stem cells was evaluated using cell culture assays and quantitatively analyzed at the single cell level by AFM-based single-cell force spectroscopy. Our results show that bioactive moieties, particularly fibronectin fragment III8-10, improve cell adhesion on titanium and TiNbHf and that the covalent tethering of such molecules provides the most promising strategy to biofunctionalize these materials. Therefore, the use of recombinant protein fragments is of high importance for improving the osseointegration potential of implant materials. PMID- 26513754 TI - Magnetic field activated drug release system based on magnetic PLGA microspheres for chemo-thermal therapy. AB - Controlled drug delivery systems have been extensively investigated for cancer therapy in order to obtain better specific targeting and therapeutic efficiency. Herein, we developed doxorubicin-loaded magnetic PLGA microspheres (DOX-MMS), in which DOX was encapsulated in the core and high contents (28.3 wt%) of gamma Fe2O3 nanoparticles (IOs) were electrostatically assembled on the surface of microsphere to ensure the high sensitivity to response of an external alternating current magnetic field (ACMF). The IOs in PLGA shell can both induce the heat effect and trigger shell permeability enhancement to release drugs when DOX-MMs was activated by ACMF. Results show that the cumulative drug release from DOX-MMs exposed to ACMF for 30 min (21.6%) was significantly higher (approximately 7 times higher) than that not exposed to ACMF (2.8%). The combination of hyperthermia and enhanced DOX release from DOX-MMS is beneficial for in vitro 4T1 breast cancer cell apoptosis as well as effective inhibition of tumor growth in 4T1 tumor xenografts. Therefore, the DOX-MMS can be optimized as powerful delivery system for efficient magnetic responsive drug release and chemo-thermal therapy. PMID- 26513755 TI - Fabrication of MPEG-b-PMAA capped YVO4:Eu nanoparticles with biocompatibility for cell imaging. AB - A novel nanoparticle with multilayer core-shell architecture for cell imaging is designed and synthesized by coating a fluorescent YVO4:Eu core with a diblock copolymer, MPEG-b-PMAA. The synthesis of YVO4:Eu core, which further makes MPEG-b PMAA-YVO4:Eu NPs adapt for cell imaging, is guided by the model determined upon the evaluation of pH and CEu%. The PMAA block attached tightly on the YVO4:Eu core forms the inner shell and the MPEG block forms the biocompatible outermost shell. Factors including reaction time, reaction temperature, CEu% and pH are optimized for the preparation of the YVO4:Eu NPs. A precise defined model is established according to analyzing the coefficients of pH and CEu% during the synthesis. The MPEG-b-PMAA-YVO4:Eu NPs, with an average diameter of 24 nm, have a tetragonal structure and demonstrate luminescence in the red region, which lies in a biological window (optical imaging). Significant enhancement in luminescence intensity by MPEG-b-PMAA-YVO4:Eu NPs formation is observed. The capping copolymer MPEG-b-PMAA improves the dispersibility of hydrophobic YVO4:Eu NPs in water, making the NPs stable under different conditions. In addition, the biocompatibility MPEG layer reduces the cytotoxicity of the nanoparticles effectively. 95% cell viability can be achieved at the NPs concentration of 800 mgL(-1) after 24h of culture. Cellular uptake of the MPEG-b-PMAA-YVO4:Eu NPs is evaluated by cell imaging assay, indicating that the NPs can be taken up rapidly and largely by cancerous or non-cancerous cells through an endocytosis mechanism. PMID- 26513756 TI - Targeted polymer-drug conjugates: Current progress and future perspective. AB - The combination of polymer technology and targeted drug delivery may pave the way for more effective yet safer therapeutic options for cancer therapy. Polymer-drug conjugates belonging to polymer therapeutics represent an emerging approach for drug delivery. The development of smart targeted polymer-drug conjugates that can specifically deliver drugs at a sustained rate to tumor cells may substantially improve the therapeutic index of anticancer agents. In this update, we provide an overview of the most important targeting molecules, and systemically summarize the recent advances in the development of tumor-targeted polymer-drug conjugates. Additionally, several promising approaches for the future will also be presented. PMID- 26513757 TI - Postmortem Propofol Levels: A Case of Residual Detection Long After Administration. AB - Propofol has gained notoriety in recent years because of its involvement in high profile deaths and has increasingly become a drug of misuse and abuse particularly by health care personnel with easy access to it. In addition, propofol has also been used for more nefarious purposes such as murder and suicide. These, coupled with the drug's routine use for both major and minor medical procedures, provide ample opportunities for it to be implicated as a cause of death or contributing factor. In such instances, forensic investigators may be faced with the task of not only detecting the presence of propofol on postmortem toxicology screening, but also determining if it was indeed responsible for the decedent's demise. While propofol has a high volume of distribution, it is thought to equilibrate and be eliminated rapidly and not show significant tissue accumulation. However, this article presents a case illustrating that propofol can accumulate in the tissues and may be found up to a week after administration. This capacity to accumulate implies that postmortem detection does not necessarily confirm administration near the time of death, and further investigation needs to be undertaken to determine the timeline of events in order to rule out other factors, such as recent medical interventions, before attributing the cause of death to the presence of the drug. PMID- 26513758 TI - Comparative analysis of N-glycans in the ungerminated and germinated stages of Oryza sativa. AB - All fundamental information such as signal transduction, metabolic control, infection, cell-to-cell signaling, and cell differentiation related to the growth of plants are preserved in germs. In preserving these information, glycans have a key role and are involved in the development and differentiation of organisms. Glycans which exist in rice germ are expected to have an important role in germination. In this study, we performed structural and correlation analysis of the N-glycans in rice germ before and after germination. Our results confirmed that the N-glycans in the ungerminated stage of the rice germ had low number of N glycans consisting only of six kinds especially with high-mannose and paucimannose type N-glycans being 16.0% and 76.7%, respectively. On the other hand, after 48 hours germinated germ stage, there was an increase in the complex type N-glycans with the appearance of Lewis a structure, the most complex type and a decrease in paucimannose types. These results suggest that at least six kinds of N-glycans are utilized for long time preservation of rice seed, while the diversification of most complex types of N-glycans is produced an environment dependent for shoot formation of rice. PMID- 26513759 TI - Synthesis and immunodetection of 6-O-methyl-phosphoramidyl-alpha-D-galactose: a Campylobacter jejuni antigenic determinant. AB - Campylobacter jejuni is a leading cause of traveler's diarrhea. Previously, we have shown that a C. jejuni capsule polysaccharide (CPS) conjugate vaccine can fully prevent C.jejuni diarrhea in non-human primates. C.jejuni CPSs are decorated with non-stoichiometric amounts of O-methyl phosphoramidate (MeOPN) units that are key serospecific markers. In the case of C.jejuni serotype complex HS23/36, the MeOPN are at positions 2 and 6 of the CPS galactose (Gal). We describe here the synthesis of the p-methoxyphenyl glycoside of MeOPN->6-alpha-D Galp, and its immunodetection by antisera raised by C.jejuni CPS conjugates with MeOPN at primary positions. The synthetic approach in this work served as the foundation for a similar MeOPN->6-Gal construct used in a conjugate vaccine, whose synthesis, immunogenicity and efficacy will be described elsewhere. PMID- 26513760 TI - Expanded acceptor substrates flexibility study of flavonol 7-O rhamnosyltransferase, AtUGT89C1 from Arabidopsis thaliana. AB - Acceptor substrates flexibility of previously characterized flavonol 7-O rhamnosyltransferase (AtUGT89C1) from Arabidopsis thaliana was explored with an endogenous nucleotide diphosphate sugar and five different classes of flavonoids (flavonols, flavones, flavanones, chalcone and stilbenes) through a biotransformation approach. In contrast to the previous reports, this study highlights the expanded acceptor substrate promiscuity of AtUGT89C1 for the regiospecific glycosylation of diverse class of flavonoids at 7-hydroxyl position using microbial thymidine diphosphate (TDP)-L-rhamnose as sugar donor instead of uridine diphosphate-L-rhamnose. We examine the biocatalytic potential of AtUGT89C1 using endogenous sugar (TDP-L-rhamnose) from E. coli to generate a library of flavonoid 7-O-rhamnosides. PMID- 26513761 TI - An efficient planar-heterojunction solar cell based on wide-bandgap CH3NH3PbI2.1Br0.9 perovskite film for tandem cell application. AB - A dense and homogenous flat wide-bandgap (1.75 eV) CH3NH3PbI2.1Br0.9 perovskite film was prepared via a facile halide exchange route. The planar-heterojunction solar cell shows an optimal power conversion efficiency of 12.67% with negligible current hysteresis due to the film's large grains and vertically oriented grain boundaries. PMID- 26513762 TI - Molecular epidemiology of hepatitis B and Delta virus strains that spread in the Mediterranean North East Coast of Tunisia. AB - BACKGROUND: Tunisia is classified as an area of middle endemic for hepatitis B virus (HBV) infection, however little is known about hepatitis Delta virus (HDV) infection. OBJECTIVES: This study aimed to address the prevalence of HDV infection, to identify possible risks factors, and to analyze the genetic diversity of HDV strains that are spreading in Tunisia. STUDY DESIGN: A retrospective large-scale study including 1615 HBsAg positive patients, native of the North East coast of Tunisia, recruited from Gastroenterology departments, was conducted. Demographic, epidemiological, ethnical, clinical and biological data were recorded. HBV and HDV serological analyses and DNA and RNA viral load quantification were performed. Genotyping of HBV and HDV strains was performed using nucleotide sequencing followed by phylogenetic analyses. RESULTS: The study population included 819 (50.7%) men and 796 (49.3%) women; aged 12-90 years (mean age 41+/-13 years). A very low prevalence of HDV infection, 2% was observed. No risk factor, except a history of hospitalization for surgery was found. All HDV strains belonged to genotype 1, with a wide distribution within the HDV-1 group. They all share the African amino acid marker, a serine at position 202 of the large Delta protein. HBV genotypes were distributed as follows: HBV/D1 (56.8%), HBV/D7 (40.9%), and HBV/A2 (2.3%). CONCLUSION: Tunisia is a low endemic region for HDV infection, due to an efficient policy of HBV infection control. HDV-1 is the sole genotype found, with a high diversity within this group. Further studies are ongoing in order to better characterize and manage the HBV/HDV-infected patients according to the genetic variability of the viral strains. PMID- 26513763 TI - Comparison of three quantitative HCV RNA assays in samples from HCV genotype 1- or 4-infected patients treated with the NS3/4A protease inhibitor simeprevir. AB - BACKGROUND: Monitoring HCV RNA levels during treatment is an important tool for managing protease-inhibitor-based regimens, and different assays used in clinical practice can impact treatment decisions. OBJECTIVES: The concordance of three HCV RNA assays was determined, and their impact on treatment decisions assessed using samples from HCV genotype (GT) 1- and GT4-infected patients treated with the NS3/4A inhibitor simeprevir in combination with pegylated interferon alpha/ribavirin. STUDY DESIGN: Plasma samples collected during the simeprevir Phase III studies QUEST-1 and QUEST-2 (GT1), and RESTORE (GT4) were analyzed with the Roche High-Pure-System COBAS((r)) TaqMan((r)) HCV v2.0 (HPS), the Roche AmpliPrep COBAS((r)) TaqMan((r)) HCV v2.0 (CAP), and the Abbott RealTime HCV (ART) assay. RESULTS: In GT1, of the 440 samples, 81% were undetectable (rapid virological response; RVR) by HPS at Week 4, 76% by CAP and 44% by ART. In GT4 (103 samples), RVR rates were 67% by HPS and 24% by ART. HCV RNA <25IU/mL at Week 4 was observed for 95-96% and 92% GT1 samples and 86% and 74% GT4 samples by HPS/CAP and ART, respectively. At Week 12, assay concordance for undetectability was high in GT1 and GT4, (95-98% and 93%, respectively). CONCLUSIONS: While different HCV RNA assays can lead to substantially different RVR rates, a good concordance was observed with a cut-off of 25IU/mL. Sustained virologic response rates among GT1 patients achieving RVR or <25IU/mL at Week 4 were high and similar between assays used. At later time points, when viremia is low, assay concordance was high. PMID- 26513764 TI - Impact of rapid influenza diagnostic test on physician estimation of viral infection probability in paediatric emergency department during epidemic period. AB - BACKGROUND: The clinical diagnosis of influenza is difficult in the younger children. OBJECTIVES: Evaluate the impact of rapid influenza diagnostic test (RIDT) on clinicians' estimation of the clinical probability of influenza in children. STUDY DESIGN: This prospective study included children aged from 1 month to 5 years who were admitted in a university paediatric emergency department during an influenza epidemic period and presented with fever without source. The RIDT Quickvue((r)) was performed on nasopharyngeal aspiration and results were confirmed with immunofluorescence and/or PCR. The clinical probability of influenza and serious bacterial infection (SBI) was evaluated for each child before and after the physician(s) was informed of the RIDT results. RESULTS: 170 children were included from January 15th through March 18th, 2013. After the only clinical examination, the overall clinical probability of influenza was 66.0% [CI 95%: 63.04-68.4], and was significantly increased at 92.4% [CI 95%: 89.5-95.3] in case of positive RIDT and significantly decreased at 30.8% [CI 95%: 29.0-32.5] in case of negative RIDT without knowing the results of laboratory tests. Whereas the initial clinical probability of influenza were appropriate regarding the prevalence (66.0% vs. 57.0%), the probability of SBI was overestimated (30.2% vs. 8.8%). The RIDT result positive enabled a significant decrease in orders for chest X-rays (64,4% vs. 45.8%, p<0,05) and laboratory tests (71,1% vs. 41.1%, p<0,05). CONCLUSIONS: The RIDT seems to be a useful diagnostic tool for ED clinicians in epidemic conditions. Improving clinician estimation of flu probability would reduce orders for imaging and testing. PMID- 26513765 TI - Central nervous system and muscle involvement in dengue patients: A study from a tertiary care center. AB - BACKGROUND: Neurological involvement in dengue virus (DENV) infection is being increasingly reported. There is paucity of studies evaluating the relative frequency of central nervous system (CNS) and muscle involvement in dengue. OBJECTIVES: To evaluate the frequency and prognosis of neurological and muscle involvement in dengue, and correlate these with dengue subtypes. STUDY DESIGN: Consecutive dengue patients were included, and their clinical features, laboratory investigations and cerebrospinal fluid (CSF) findings were recorded. Cranial MRI was done in unconscious patients and electromyography and nerve conduction study in patients with flaccid weakness. Patients were categorized into encephalopathy, encephalitis, immune mediated and dengue associated muscle dysfunction (DAMD). Outcome at 1 month and its predictors were evaluated. RESULTS: 116 patients aged 5-70 years were included; 82 had dengue fever (DF), 18 had dengue hemorrhagic fever (DHF), and 16 had dengue shock syndrome (DSS). Neurological manifestations were present in 92 (79%); encephalopathy in 17 (15%), encephalitis in 22 (19%), transverse myelitis in 1 (1%) and DAMD in 52 (45%) patients. Central nervous system (CNS) involvement was commoner in DHF/DSS compared to DF (44% vs 26%). 10 patients with CNS involvement died versus 1 with DAMD. The patients in the CNS group had more frequent hypotension, renal dysfunction and respiratory failure compared to the DAMD group, and had worse outcome. DENV2 and DENV3 were the commonest serotypes, but serotypes did not differ between CNS and DAMD groups. CONCLUSIONS: DAMD is commoner than CNS involvement in dengue. CNS involvement however, is associated with more serious illness and predicts poorer outcome. PMID- 26513766 TI - Automated Assembly of Vascular-Like Microtube With Repetitive Single-Step Contact Manipulation. AB - Fabricated vessel-mimetic microtubes are essential for delivering sufficient nutrient to engineered composite tissues. In this paper, vascular-like microtubes are engineered by automated assembly of donut-shaped micromodules that embed fibroblast cells. A microrobotic system is set up with dual manipulators of 30-nm positioning resolution under an optical microscope. The system assembles the micromodules by repeated single-step pick-up motions. This process is specifically designed to avoid human interference and ensure high reproducibility for automation. We optimized the single-step motion by calibrating the key parameters (the micromodule dimensions) in a force analysis. The optimal motion achieved a 98% pick-up success rate. The automated repetitive single-step assembly is achieved by an algorithm that acquires the 3-D location and tracks the micromanipulator without being affected by low contrast. The accuracy of the acquired 3-D location was experimentally determined as approximately 1 pixel (2 MUm under 4* magnification), and the tracking under different observation conditions is proved effective. Finally, we automatically assembled microtubes at 6 micromodules/min, sufficiently fast for fabricating macroscopic vessel-mimetic substitutes in biological applications. PMID- 26513767 TI - Filtered Virtual Reference: A New Method for the Reduction of Power Line Interference With Minimal Distortion of Monopolar Surface EMG. AB - GOAL: This study tests and validates a new method to remove power line interference from monopolar EMGs detected by multichannel systems: the filtered virtual reference (FVR). FVR is an adaptation of the virtual reference (VR) method, which consists in referencing signals detected by each electrode in a grid to their spatial average. Signals may however be distorted with the VR approach, in particular when the skin region where the detection system is positioned does not cover the entire muscle. METHODS: Simulated and experimental EMGs were used to compare the performance of FVR and VR in terms of interference reduction and distortion of monopolar signals referred to a remote reference. RESULTS: Simulated data revealed the monopolar EMG signals processed with FVR were significantly less distorted than those filtered by VR. These results were similarly observed for experimental signals. Moreover, FVR method outperformed VR in removing power line interference when it was distributed unevenly across the signals of the grid. CONCLUSION: Key results demonstrated that FVR improves the VR method as it reduces interference while preserving the information content of monopolar signals. SIGNIFICANCE: Although the actual distribution of motor unit action potential is represented in monopolar EMGs, collecting high quality monopolar signals is challenging. This study presents a possible solution to this issue; FVR provides undistorted monopolar signals with negligible interference and is insensitive to muscle architecture. It is therefore relevant for EMG applications benefiting from a clean monopolar detection (e.g., decomposition, control of prosthetic devices, motor unit number estimation). PMID- 26513768 TI - Chagas disease: are we there yet? PMID- 26513769 TI - Chagas disease and transfusion medicine: a perspective from non-endemic countries. AB - In the last decades, increasing international migration and travel from Latin America to Europe have favoured the emergence of tropical diseases outside their "historical" boundaries. Chagas disease, a zoonosis endemic in rural areas of Central and South America represents a clear example of this phenomenon. In the absence of the vector, one of the potential modes of transmission of Chagas disease in non-endemic regions is through blood and blood products. As most patients with Chagas disease are asymptomatic and unaware of their condition, in case of blood donation they can inadvertently represent a serious threat to the safety of the blood supply in non-endemic areas. Since the first cases of transfusion-transmitted Chagas disease were described in the last years, non endemic countries began to develop ad hoc strategies to prevent and control the spread of the infection. United States, Spain, United Kingdom and France first recognised the need for Trypanosoma cruzi screening in at-risk blood donors. In this review, we trace an up-to-date perspective on Chagas disease, describing its peculiar features, from epidemiological, pathological, clinical and diagnostic points of view. Moreover, we describe the possible transmission of Chagas disease through blood or blood products and the current strategies for its control, focusing on non-endemic areas. PMID- 26513770 TI - The impact of deep vein thrombosis in critically ill patients: a meta-analysis of major clinical outcomes. AB - BACKGROUND: Critically ill patients appear to be at high risk of developing deep vein thrombosis (DVT) and pulmonary embolism during their stay in the intensive care unit (ICU). However, little is known about the clinical course of venous thromboembolism in the ICU setting. We therefore evaluated, through a systematic review of the literature, the available data on the impact of a diagnosis of DVT on hospital and ICU stay, duration of mechanical ventilation and mortality in critically ill patients. We also tried to determine whether currently adopted prophylactic measures need to be revised and improved in the ICU setting. MATERIALS AND METHODS: MEDLINE and EMBASE databases were searched up to week 4 of June 2012. Two reviewers selected studies and extracted data. Pooled results are reported as relative risks and weighted mean differences and are presented with 95% confidence intervals (CI). RESULTS: Seven studies for a total of 1,783 patients were included. A diagnosis of DVT was frequent in these patients with a mean rate of 12.7% (95% CI: 8.7-17.5%). DVT patients had longer ICU and hospital stays compared to those without DVT (7.28 days; 95% CI: 1.4-13.15; and 11.2 days; 95% CI: 3.82-18.63 days, respectively). The duration of mechanical ventilation was significantly increased in DVT patients (weighted mean difference: 4.85 days; 95% CI: 2.07-7.63). DVT patients had a marginally significant increase in the risk of hospital mortality (relative risk 1.31; 95% CI: 0.99-1.74; p=0.06), and a not statistically significant increase in the risk of ICU mortality (RR 1.64; 95% CI: 0.91-2.93; p=0.10). CONCLUSIONS: A diagnosis of DVT upon ICU admission appears to affect clinically important outcomes including duration of ICU and hospital stay and hospital mortality. Larger, prospective studies are warranted. PMID- 26513771 TI - Spurious hyperglycaemia impairs automated leucocyte counting. A pilot study with two different haematological analysers. PMID- 26513772 TI - Stimulation Frequency Alters the Dorsal Root Ganglion Neurite Growth and Directionality In Vitro. AB - OBJECTIVE: To improve peripheral nerve repair, new techniques to increase the speed of regeneration are required. Studies have shown that the electrical stimulation can enhance nerve regeneration; however, stimulation parameters that regulate the growth increases are unknown. The objective of this study was to examine dorsal root ganglion (DRG) neurite extension, directionality, and density after using methods to specifically control ac electrical field intensity and frequency exposure. METHODS: Chick DRG explants were exposed to 20-Hz, 200-Hz, 1 MHz, and 20-MHz sinusoidal electric field of 17.86 V/m, and tissue parameters were measured. RESULTS: Results show that neurite extension and directionality were influenced by frequency; however, the ratio of support cell emigration with respect to neurite extension from the DRG body was not. These results were further verified through finite-element modeling of intracellular calcium, which show that higher frequencies have minimal effect on intracellular calcium. CONCLUSION: In conclusion, these results demonstrate that 1) directional growth of neurites within EFs can be achieved, 2) high-frequency stimulation in megahertz does not enhance or impair the neurite growth, and 3) low-frequency stimulation affects the growth and directionality. SIGNIFICANCE: The significance of this study is the direct comparison of neurite extension after high stimulation frequencies (megahertz) with typical low-frequency fields (20 and 200 Hz), and modeling the results with finite-element modeling. PMID- 26513773 TI - Unsupervised Trajectory Segmentation for Surgical Gesture Recognition in Robotic Training. AB - Dexterity and procedural knowledge are two critical skills that surgeons need to master to perform accurate and safe surgical interventions. However, current training systems do not allow us to provide an in-depth analysis of surgical gestures to precisely assess these skills. Our objective is to develop a method for the automatic and quantitative assessment of surgical gestures. To reach this goal, we propose a new unsupervised algorithm that can automatically segment kinematic data from robotic training sessions. Without relying on any prior information or model, this algorithm detects critical points in the kinematic data that define relevant spatio-temporal segments. Based on the association of these segments, we obtain an accurate recognition of the gestures involved in the surgical training task. We, then, perform an advanced analysis and assess our algorithm using datasets recorded during real expert training sessions. After comparing our approach with the manual annotations of the surgical gestures, we observe 97.4% accuracy for the learning purpose and an average matching score of 81.9% for the fully automated gesture recognition process. Our results show that trainees workflow can be followed and surgical gestures may be automatically evaluated according to an expert database. This approach tends toward improving training efficiency by minimizing the learning curve. PMID- 26513774 TI - Application-Driven No-Reference Quality Assessment for Dermoscopy Images With Multiple Distortions. AB - GOAL: Dermoscopy images often suffer from blur and uneven illumination distortions that occur during acquisition, which can adversely influence consequent automatic image analysis results on potential lesion objects. The purpose of this paper is to deploy an algorithm that can automatically assess the quality of dermoscopy images. Such an algorithm could be used to direct image recapture or correction. METHODS: We describe an application-driven no-reference image quality assessment (IQA) model for dermoscopy images affected by possibly multiple distortions. For this purpose, we created a multiple distortion dataset of dermoscopy images impaired by varying degrees of blur and uneven illumination. The basis of this model is two single distortion IQA metrics that are sensitive to blur and uneven illumination, respectively. The outputs of these two metrics are combined to predict the quality of multiply distorted dermoscopy images using a fuzzy neural network. Unlike traditional IQA algorithms, which use human subjective score as ground truth, here ground truth is driven by the application, and generated according to the degree of influence of the distortions on lesion analysis. RESULTS: The experimental results reveal that the proposed model delivers accurate and stable quality prediction results for dermoscopy images impaired by multiple distortions. CONCLUSION: The proposed model is effective for quality assessment of multiple distorted dermoscopy images. SIGNIFICANCE: An application-driven concept for IQA is introduced, and at the same time, a solution framework for the IQA of multiple distortions is proposed. PMID- 26513775 TI - Separation and Analysis of Fetal-ECG Signals From Compressed Sensed Abdominal ECG Recordings. AB - OBJECTIVE: Analysis of fetal electrocardiogram (f-ECG) waveforms as well as fetal heart-rate (fHR) evaluation provide important information about the condition of the fetus during pregnancy. A continuous monitoring of f-ECG, for example using the technologies already applied for adults ECG tele-monitor-ing (e.g., Wireless Body Sensor Networks (WBSNs)), may increase early detection of fetal arrhythmias. In this study, we propose a novel framework, based on compressive sensing (CS) theory, for the compression and joint detection/classification of mother and fetal heart beats. METHODS: Our scheme is based on the sparse representation of the components derived from independent component analysis (ICA), which we propose to apply directly in the compressed domain. Detection and classification is based on the activated atoms in a specifically designed reconstruction dictionary. RESULTS: Validation of the proposed compression and detection framework has been done on two publicly available datasets, showing promising results (sensitivity S = 92.5 %, P += 92 % , F1 = 92.2 % for the Silesia dataset and S = 78 % , P += 77 %, F1 = 77.5 % for the Challenge dataset A, with average reconstruction quality PRD = 8.5 % and PRD = 7.5 %, respectively). CONCLUSION: The experiments confirm that the proposed framework may be used for compression of abdominal f-ECG and to obtain real-time information of the fHR, providing a suitable solution for real time, very low-power f-ECG monitoring. SIGNIFICANCE: To the authors' knowledge, this is the first time that a framework for the low power CS compression of fetal abdominal ECG is proposed combined with a beat detector for an fHR estimation. PMID- 26513776 TI - Characterization of Subdural Stimulation-Induced Afterdischarge Activity Using the Continuous Wavelet Transform. AB - OBJECTIVE: We address the problem of characterization of afterdischarges (ADs) that often arise in patients with intractable focal epilepsy who, as part of their evaluation, undergo cortical electrical stimulation: A standard diagnostic and evaluation procedure before respective surgery. RESULTS: A total of 1333 channels of data recorded in 17 trials of seven patients whose EEG showed ADs (on a total of 156 channels) during cortical stimulation were examined in the time scale domain using a complex Morlet scalogram. We found excellent characterization of the AD channels based on the distribution functions of the sum of the wavelet coefficients in the two lowest scales corresponding to the frequency range [20, 80] Hz, i.e., the beta and gamma ranges of EEG. CONCLUSION: We suggest that the transient Morlet wavelet and the scale domain activity function of the EEG in the two lowest scales (as defined in this paper) could serve as a very useful decision aid in the identification of ADs during and after cortical electrical stimulation. SIGNIFICANCE: In patients undergoing cortical electrical stimulation, AD waveforms can cause misleading test results by altering the ongoing electroencephalogram (EEG), and can become unwanted seizures. Any process to suppress the ADs rests on a reliable method to distinguish them from normal EEG channels, a task that is usually performed by visual inspection, and that is complicated by the fact that ADs have multiple distinct morphologies. The single feature of the EEG in our study resulted in average probability of detection of 0.99 with an average false alarm probability of 0.04. It is likely that the addition of one or two more features to our decision aid could improve sensitivity and selectivity to near perfection. PMID- 26513777 TI - High Accuracy Monocular SFM and Scale Correction for Autonomous Driving. AB - We present a real-time monocular visual odometry system that achieves high accuracy in real-world autonomous driving applications. First, we demonstrate robust monocular SFM that exploits multithreading to handle driving scenes with large motions and rapidly changing imagery. To correct for scale drift, we use known height of the camera from the ground plane. Our second contribution is a novel data-driven mechanism for cue combination that allows highly accurate ground plane estimation by adapting observation covariances of multiple cues, such as sparse feature matching and dense inter-frame stereo, based on their relative confidences inferred from visual data on a per-frame basis. Finally, we demonstrate extensive benchmark performance and comparisons on the challenging KITTI dataset, achieving accuracy comparable to stereo and exceeding prior monocular systems. Our SFM system is optimized to output pose within 50 ms in the worst case, while average case operation is over 30 fps. Our framework also significantly boosts the accuracy of applications like object localization that rely on the ground plane. PMID- 26513778 TI - HCP: A Flexible CNN Framework for Multi-label Image Classification. AB - Convolutional Neural Network (CNN) has demonstrated promising performance in single-label image classification tasks. However, how CNN best copes with multi label images still remains an open problem, mainly due to the complex underlying object layouts and insufficient multi-label training images. In this work, we propose a flexible deep CNN infrastructure, called Hypotheses-CNN-Pooling (HCP), where an arbitrary number of object segment hypotheses are taken as the inputs, then a shared CNN is connected with each hypothesis, and finally the CNN output results from different hypotheses are aggregated with max pooling to produce the ultimate multi-label predictions. Some unique characteristics of this flexible deep CNN infrastructure include: 1) no ground-truth bounding box information is required for training; 2) the whole HCP infrastructure is robust to possibly noisy and/or redundant hypotheses; 3) the shared CNN is flexible and can be well pre-trained with a large-scale single-label image dataset, e.g., ImageNet; and 4) it may naturally output multi-label prediction results. Experimental results on Pascal VOC 2007 and VOC 2012 multi-label image datasets well demonstrate the superiority of the proposed HCP infrastructure over other state-of-the-arts. In particular, the mAP reaches 90.5% by HCP only and 93.2% after the fusion with our complementary result in [44] based on hand-crafted features on the VOC 2012 dataset. PMID- 26513779 TI - Recognizing Focal Liver Lesions in CEUS With Dynamically Trained Latent Structured Models. AB - This work investigates how to automatically classify Focal Liver Lesions (FLLs) into three specific benign or malignant types in Contrast-Enhanced Ultrasound (CEUS) videos, and aims at providing a computational framework to assist clinicians in FLL diagnosis. The main challenge for this task is that FLLs in CEUS videos often show diverse enhancement patterns at different temporal phases. To handle these diverse patterns, we propose a novel structured model, which detects a number of discriminative Regions of Interest (ROIs) for the FLL and recognize the FLL based on these ROIs. Our model incorporates an ensemble of local classifiers in the attempt to identify different enhancement patterns of ROIs, and in particular, we make the model reconfigurable by introducing switch variables to adaptively select appropriate classifiers during inference. We formulate the model learning as a non-convex optimization problem, and present a principled optimization method to solve it in a dynamic manner: the latent structures (e.g. the selections of local classifiers, and the sizes and locations of ROIs) are iteratively determined along with the parameter learning. Given the updated model parameters in each step, the data-driven inference is also proposed to efficiently determine the latent structures by using the sequential pruning and dynamic programming method. In the experiments, we demonstrate superior performances over the state-of-the-art approaches. We also release hundreds of CEUS FLLs videos used to quantitatively evaluate this work, which to the best of our knowledge forms the largest dataset in the literature. Please find more information at "http://vision.sysu.edu.cn/projects/fllrecog/". PMID- 26513780 TI - Compressive Deconvolution in Medical Ultrasound Imaging. AB - The interest of compressive sampling in ultrasound imaging has been recently extensively evaluated by several research teams. Following the different application setups, it has been shown that the RF data may be reconstructed from a small number of measurements and/or using a reduced number of ultrasound pulse emissions. Nevertheless, RF image spatial resolution, contrast and signal to noise ratio are affected by the limited bandwidth of the imaging transducer and the physical phenomenon related to US wave propagation. To overcome these limitations, several deconvolution-based image processing techniques have been proposed to enhance the ultrasound images. In this paper, we propose a novel framework, named compressive deconvolution, that reconstructs enhanced RF images from compressed measurements. Exploiting an unified formulation of the direct acquisition model, combining random projections and 2D convolution with a spatially invariant point spread function, the benefit of our approach is the joint data volume reduction and image quality improvement. The proposed optimization method, based on the Alternating Direction Method of Multipliers, is evaluated on both simulated and in vivo data. PMID- 26513781 TI - Histopathological Image Classification Using Discriminative Feature-Oriented Dictionary Learning. AB - In histopathological image analysis, feature extraction for classification is a challenging task due to the diversity of histology features suitable for each problem as well as presence of rich geometrical structures. In this paper, we propose an automatic feature discovery framework via learning class-specific dictionaries and present a low-complexity method for classification and disease grading in histopathology. Essentially, our Discriminative Feature-oriented Dictionary Learning (DFDL) method learns class-specific dictionaries such that under a sparsity constraint, the learned dictionaries allow representing a new image sample parsimoniously via the dictionary corresponding to the class identity of the sample. At the same time, the dictionary is designed to be poorly capable of representing samples from other classes. Experiments on three challenging real-world image databases: 1) histopathological images of intraductal breast lesions, 2) mammalian kidney, lung and spleen images provided by the Animal Diagnostics Lab (ADL) at Pennsylvania State University, and 3) brain tumor images from The Cancer Genome Atlas (TCGA) database, reveal the merits of our proposal over state-of-the-art alternatives. Moreover, we demonstrate that DFDL exhibits a more graceful decay in classification accuracy against the number of training images which is highly desirable in practice where generous training is often not available. PMID- 26513782 TI - Real-Time Automatic Artery Segmentation, Reconstruction and Registration for Ultrasound-Guided Regional Anaesthesia of the Femoral Nerve. AB - The goal is to create an assistant for ultrasound- guided femoral nerve block. By segmenting and visualizing the important structures such as the femoral artery, we hope to improve the success of these procedures. This article is the first step towards this goal and presents novel real-time methods for identifying and reconstructing the femoral artery, and registering a model of the surrounding anatomy to the ultrasound images. The femoral artery is modelled as an ellipse. The artery is first detected by a novel algorithm which initializes the artery tracking. This algorithm is completely automatic and requires no user interaction. Artery tracking is achieved with a Kalman filter. The 3D artery is reconstructed in real-time with a novel algorithm and a tracked ultrasound probe. A mesh model of the surrounding anatomy was created from a CT dataset. Registration of this model is achieved by landmark registration using the centerpoints from the artery tracking and the femoral artery centerline of the model. The artery detection method was able to automatically detect the femoral artery and initialize the tracking in all 48 ultrasound sequences. The tracking algorithm achieved an average dice similarity coefficient of 0.91, absolute distance of 0.33 mm, and Hausdorff distance 1.05 mm. The mean registration error was 2.7 mm, while the average maximum error was 12.4 mm. The average runtime was measured to be 38, 8, 46 and 0.2 milliseconds for the artery detection, tracking, reconstruction and registration methods respectively. PMID- 26513783 TI - An Underwater Color Image Quality Evaluation Metric. AB - Quality evaluation of underwater images is a key goal of underwater video image retrieval and intelligent processing. To date, no metric has been proposed for underwater color image quality evaluation (UCIQE). The special absorption and scattering characteristics of the water medium do not allow direct application of natural color image quality metrics especially to different underwater environments. In this paper, subjective testing for underwater image quality has been organized. The statistical distribution of the underwater image pixels in the CIELab color space related to subjective evaluation indicates the sharpness and colorful factors correlate well with subjective image quality perception. Based on these, a new UCIQE metric, which is a linear combination of chroma, saturation, and contrast, is proposed to quantify the non-uniform color cast, blurring, and low-contrast that characterize underwater engineering and monitoring images. Experiments are conducted to illustrate the performance of the proposed UCIQE metric and its capability to measure the underwater image enhancement results. They show that the proposed metric has comparable performance to the leading natural color image quality metrics and the underwater grayscale image quality metrics available in the literature, and can predict with higher accuracy the relative amount of degradation with similar image content in underwater environments. Importantly, UCIQE is a simple and fast solution for real-time underwater video processing. The effectiveness of the presented measure is also demonstrated by subjective evaluation. The results show better correlation between the UCIQE and the subjective mean opinion score. PMID- 26513784 TI - Robust Face Recognition via Minimum Error Entropy-Based Atomic Representation. AB - Representation-based classifiers (RCs) have attracted considerable attention in face recognition in recent years. However, most existing RCs use the mean square error (MSE) criterion as the cost function, which relies on the Gaussianity assumption of the error distribution and is sensitive to non-Gaussian noise. This may severely degrade the performance of MSE-based RCs in recognizing facial images with random occlusion and corruption. In this paper, we present a minimum error entropy-based atomic representation (MEEAR) framework for face recognition. Unlike existing MSE-based RCs, our framework is based on the minimum error entropy criterion, which is not dependent on the error distribution and shown to be more robust to noise. In particular, MEEAR can produce discriminative representation vector by minimizing the atomic norm regularized Renyi's entropy of the reconstruction error. The optimality conditions are provided for general atomic representation model. As a general framework, MEEAR can also be used as a platform to develop new classifiers. Two effective MEE-based RCs are proposed by defining appropriate atomic sets. The experimental results on popular face databases show that MEEAR can improve both the recognition accuracy and the reconstructed results compared with the state-of-the-art MSE-based RCs. PMID- 26513785 TI - Global Color Sparseness and a Local Statistics Prior for Fast Bilateral Filtering. AB - The property of smoothing while preserving edges makes the bilateral filter a very popular image processing tool. However, its non-linear nature results in a computationally costly operation. Various works propose fast approximations to the bilateral filter. However, the majority does not generalize to vector input as is the case with color images. We propose a fast approximation to the bilateral filter for color images. The filter is based on two ideas. First, the number of colors, which occur in a single natural image, is limited. We exploit this color sparseness to rewrite the initial non-linear bilateral filter as a number of linear filter operations. Second, we impose a statistical prior to the image values that are locally present within the filter window. We show that this statistical prior leads to a closed-form solution of the bilateral filter. Finally, we combine both ideas into a single fast and accurate bilateral filter for color images. Experimental results show that our bilateral filter based on the local prior yields an extremely fast bilateral filter approximation, but with limited accuracy, which has potential application in real-time video filtering. Our bilateral filter, which combines color sparseness and local statistics, yields a fast and accurate bilateral filter approximation and obtains the state of-the-art results. PMID- 26513786 TI - Closed-Loop Restoration Approach to Blurry Images Based on Machine Learning and Feedback Optimization. AB - Blind image deconvolution (BID) aims to remove or reduce the degradations that have occurred during the acquisition or processing. It is a challenging ill-posed problem due to a lack of enough information in degraded image for unambiguous recovery of both point spread function (PSF) and clear image. Although recently many powerful algorithms appeared; however, it is still an active research area due to the diversity of degraded images as well as degradations. Closed-loop control systems are characterized with their powerful ability to stabilize the behavior response and overcome external disturbances by designing an effective feedback optimization. In this paper, we employed feedback control to enhance the stability of BID by driving the current estimation quality of PSF to the desired level without manually selecting restoration parameters and using an effective combination of machine learning with feedback optimization. The foremost challenge when designing a feedback structure is to construct or choose a suitable performance metric as a controlled index and a feedback information. Our proposed quality metric is based on the blur assessment of deconvolved patches to identify the best PSF and computing its relative quality. The Kalman filter-based extremum seeking approach is employed to find the optimum value of controlled variable. To find better restoration parameters, learning algorithms, such as multilayer perceptron and bagged decision trees, are used to estimate the generic PSF support size instead of trial and error methods. The problem is modeled as a combination of pattern classification and regression using multiple training features, including noise metrics, blur metrics, and low-level statistics. Multi objective genetic algorithm is used to find key patches from multiple saliency maps which enhance performance and save extra computation by avoiding ineffectual regions of the image. The proposed scheme is shown to outperform corresponding open-loop schemes, which often fails or needs many assumptions regarding images and thus resulting in sub-optimal results. PMID- 26513787 TI - A Novel Multi-Purpose Matching Representation of Local 3D Surfaces: A Rotationally Invariant, Efficient, and Highly Discriminative Approach With an Adjustable Sensitivity. AB - In this paper, a novel approach to local 3D surface matching representation suitable for a range of 3D vision applications is introduced. Local 3D surface patches around key points on the 3D surface are represented by 2D images such that the representing 2D images enjoy certain characteristics which positively impact the matching accuracy, robustness, and speed. First, the proposed representation is complete, in the sense, there is no information loss during their computation. Second, the 3DoF 2D representations are strictly invariant to all the 3DoF rotations. To optimally avail surface information, the sensitivity of the representations to surface information is adjustable. This also provides the proposed matching representation with the means to optimally adjust to a particular class of problems/applications or an acquisition technology. Each 2D matching representation is a sequence of adjustable integral kernels, where each kernel is efficiently computed from a triple of precise 3D curves (profiles) formed by intersecting three concentric spheres with the 3D surface. Robust techniques for sampling the profiles and establishing correspondences among them were devised. Based on the proposed matching representation, two techniques for the detection of key points were presented. The first is suitable for static images, while the second is suitable for 3D videos. The approach was tested on the face recognition grand challenge v2.0, the 3D twins expression challenge, and the Bosphorus data sets, and a superior face recognition performance was achieved. In addition, the proposed approach was used in object class recognition and tested on a Kinect data set. PMID- 26513788 TI - Segmentation of Overlapping Elliptical Objects in Silhouette Images. AB - Segmentation of partially overlapping objects with a known shape is needed in an increasing amount of various machine vision applications. This paper presents a method for segmentation of clustered partially overlapping objects with a shape that can be approximated using an ellipse. The method utilizes silhouette images, which means that it requires only that the foreground (objects) and background can be distinguished from each other. The method starts with seedpoint extraction using bounded erosion and fast radial symmetry transform. Extracted seedpoints are then utilized to associate edge points to objects in order to create contour evidence. Finally, contours of the objects are estimated by fitting ellipses to the contour evidence. The experiments on one synthetic and two different real data sets showed that the proposed method outperforms two current state-of-art approaches in overlapping objects segmentation. PMID- 26513789 TI - Local Wavelet Pattern: A New Feature Descriptor for Image Retrieval in Medical CT Databases. AB - A new image feature description based on the local wavelet pattern (LWP) is proposed in this paper to characterize the medical computer tomography (CT) images for content-based CT image retrieval. In the proposed work, the LWP is derived for each pixel of the CT image by utilizing the relationship of center pixel with the local neighboring information. In contrast to the local binary pattern that only considers the relationship between a center pixel and its neighboring pixels, the presented approach first utilizes the relationship among the neighboring pixels using local wavelet decomposition, and finally considers its relationship with the center pixel. A center pixel transformation scheme is introduced to match the range of center value with the range of local wavelet decomposed values. Moreover, the introduced local wavelet decomposition scheme is centrally symmetric and suitable for CT images. The novelty of this paper lies in the following two ways: 1) encoding local neighboring information with local wavelet decomposition and 2) computing LWP using local wavelet decomposed values and transformed center pixel values. We tested the performance of our method over three CT image databases in terms of the precision and recall. We also compared the proposed LWP descriptor with the other state-of-the-art local image descriptors, and the experimental results suggest that the proposed method outperforms other methods for CT image retrieval. PMID- 26513790 TI - A Benchmark and Comparative Study of Video-Based Face Recognition on COX Face Database. AB - Face recognition with still face images has been widely studied, while the research on video-based face recognition is inadequate relatively, especially in terms of benchmark datasets and comparisons. Real-world video-based face recognition applications require techniques for three distinct scenarios: 1) Videoto-Still (V2S); 2) Still-to-Video (S2V); and 3) Video-to-Video (V2V), respectively, taking video or still image as query or target. To the best of our knowledge, few datasets and evaluation protocols have benchmarked for all the three scenarios. In order to facilitate the study of this specific topic, this paper contributes a benchmarking and comparative study based on a newly collected still/video face database, named COX(1) Face DB. Specifically, we make three contributions. First, we collect and release a largescale still/video face database to simulate video surveillance with three different video-based face recognition scenarios (i.e., V2S, S2V, and V2V). Second, for benchmarking the three scenarios designed on our database, we review and experimentally compare a number of existing set-based methods. Third, we further propose a novel Point-to Set Correlation Learning (PSCL) method, and experimentally show that it can be used as a promising baseline method for V2S/S2V face recognition on COX Face DB. Extensive experimental results clearly demonstrate that video-based face recognition needs more efforts, and our COX Face DB is a good benchmark database for evaluation. PMID- 26513791 TI - Simultaneous Camera Path Optimization and Distraction Removal for Improving Amateur Video. AB - A major difference between amateur and professional video lies in the quality of camera paths. Previous work on video stabilization has considered how to improve amateur video by smoothing the camera path. In this paper, we show that additional changes to the camera path can further improve video aesthetics. Our new optimization method achieves multiple simultaneous goals: 1) stabilizing video content over short time scales; 2) ensuring simple and consistent camera paths over longer time scales; and 3) improving scene composition by automatically removing distractions, a common occurrence in amateur video. Our approach uses an L(1) camera path optimization framework, extended to handle multiple constraints. Two passes of optimization are used to address both low level and high-level constraints on the camera path. The experimental and user study results show that our approach outputs video that is perceptually better than the input, or the results of using stabilization only. PMID- 26513792 TI - Image Denoising With Edge-Preserving and Segmentation Based on Mask NHA. AB - In this paper, we propose a zero-mean white Gaussian noise removal method using a high-resolution frequency analysis. It is difficult to separate an original image component from a noise component when using discrete Fourier transform or discrete cosine transform for analysis because sidelobes occur in the results. The 2D non-harmonic analysis (2D NHA) is a high-resolution frequency analysis technique that improves noise removal accuracy because of its sidelobe reduction feature. However, spectra generated by NHA are distorted, because of which the signal of the image is non-stationary. In this paper, we analyze each region with a homogeneous texture in the noisy image. Non-uniform regions that occur due to segmentation are analyzed by an extended 2D NHA method called Mask NHA. We conducted an experiment using a simulation image, and found that Mask NHA denoising attains a higher peak signal-to-noise ratio (PSNR) value than the state of-the-art methods if a suitable segmentation result can be obtained from the input image, even though parameter optimization was incomplete. This experimental result exhibits the upper limit on the value of PSNR in our Mask NHA denoising method. The performance of Mask NHA denoising is expected to approach the limit of PSNR by improving the segmentation method. PMID- 26513793 TI - A Survey of Colormaps in Visualization. AB - Colormaps are a vital method for users to gain insights into data in a visualization. With a good choice of colormaps, users are able to acquire information in the data more effectively and efficiently. In this survey, we attempt to provide readers with a comprehensive review of colormap generation techniques and provide readers a taxonomy which is helpful for finding appropriate techniques to use for their data and applications. Specifically, we first briefly introduce the basics of color spaces including color appearance models. In the core of our paper, we survey colormap generation techniques, including the latest advances in the field by grouping these techniques into four classes: procedural methods, user-study based methods, rule-based methods, and data-driven methods; we also include a section on methods that are beyond pure data comprehension purposes. We then classify colormapping techniques into a taxonomy for readers to quickly identify the appropriate techniques they might use. Furthermore, a representative set of visualization techniques that explicitly discuss the use of colormaps is reviewed and classified based on the nature of the data in these applications. Our paper is also intended to be a reference of colormap choices for readers when they are faced with similar data and/or tasks. PMID- 26513794 TI - Improving the Robustness of Myoelectric Pattern Recognition for Upper Limb Prostheses by Covariate Shift Adaptation. AB - Fundamental changes over time of surface EMG signal characteristics are a challenge for myocontrol algorithms controlling prosthetic devices. These changes are generally caused by electrode shifts after donning and doffing, sweating, additional weight or varying arm positions, which results in a change of the signal distribution-a scenario often referred to as covariate shift. A substantial decrease in classification accuracy due to these factors hinders the possibility to directly translate EMG signals into accurate myoelectric control patterns outside laboratory conditions. To overcome this limitation, we propose the use of supervised adaptation methods. The approach is based on adapting a trained classifier using a small calibration set only, which incorporates the relevant aspects of the nonstationarities, but requires only less than 1 min of data recording. The method was tested first through an offline analysis on signals acquired across 5 days from seven able-bodied individuals and four amputees. Moreover, we also conducted a three day online experiment on eight able bodied individuals and one amputee, assessing user performance and user-ratings of the controllability. Across different testing days, both offline and online performance improved significantly when shrinking the training model parameters by a given estimator towards the calibration set parameters. In the offline data analysis, the classification accuracy remained above 92% over five days with the proposed approach, whereas it decreased to 75% without adaptation. Similarly, in the online study, with the proposed approach the performance increased by 25% compared to a test without adaptation. These results indicate that the proposed methodology can contribute to improve robustness of myoelectric pattern recognition methods in daily life applications. PMID- 26513795 TI - Analysis of Vibration Exercise at Varying Frequencies by Different Fatigue Estimators. AB - Vibration exercise (VE) has been suggested to improve muscle strength and power performance, due to enhanced neuromuscular demand. However, understanding of the most appropriate VE protocols is lacking, limiting the optimal use of VE in rehabilitation programs. In this study, the fatiguing effect of vibration at different frequencies was investigated by employing a force-modulation VE system. Twenty volunteers performed 12-s isometric contractions of the biceps brachii with a load consisting of a baseline force of 80% of their maximum voluntary contraction (MVC) and a superimposed sinusoidal force at 0 (control condition with no vibration), 20, 30, and 40 Hz. Mechanical fatigue was estimated by assessment of MVC decay after each task while myoelectric fatigue was estimated by analysis of multichannel electromyography (EMG) signals recorded during VE. EMG conduction velocity, spectral compression, power, and fractal dimension were estimated as indicators of myoelectric fatigue. Our results suggest vibration, in particular at 30 Hz, to produce a larger degree of fatigue as compared to control condition. These results motivate further research aiming at introducing VE in rehabilitation programs with improved training protocols. PMID- 26513797 TI - The DNA-Based Algorithms of Implementing Arithmetical Operations of Complex Vectors on a Biological Computer. AB - Here we show that arithmetical operations of complex vectors can be implemented by means of the proposed DNA-based algorithms. PMID- 26513796 TI - Breast Cancer Ultrasound Images' Sequence Exploration Using BI-RADS Features' Extraction: Towards an Advanced Clinical Aided Tool for Precise Lesion Characterization. AB - This research concerned a clinical need for precise breast cancer lesion characterization imaged by ultrasound sequences. Using therefore BI-RADS features that would be carefully extracted, the purpose of this study could be mainly to prove and to demonstrate the possibility of surveying precisely the changing characteristics of a breast cancer lesion within a considered ultrasound images' sequence. This was in fact a clinical need of a computer aided diagnosis (CAD) system permitting flexible and convivial clinical analysis of multi-slices' ultrasound breast cancer lesion with greater precision. The obtained results of our images' sequence breast cancer ultrasound analysis had shown the lesion form changing depending on the treated slice, as well as the values' differences for the morphological and the textural features. This would allow extracting more information about breast cancer lesions helping then radiologist to converge more rapidly and with a certain reinforced precision to the accurate clinical action to conduct. Such results would be reassembled and rearranged for constituting one computer aided diagnosis (CAD) system that could be provided for clinical explorations permitting on the other hand to avoid possible confusion between benign and malignant masses. PMID- 26513798 TI - Multi-View Clustering of Microbiome Samples by Robust Similarity Network Fusion and Spectral Clustering. AB - Microbiome datasets are often comprised of different representations or views which provide complementary information, such as genes, functions, and taxonomic assignments. Integration of multi-view information for clustering microbiome samples could create a comprehensive view of a given microbiome study. Similarity network fusion (SNF) can efficiently integrate similarities built from each view of data into a unique network that represents the full spectrum of the underlying data. Based on this method, we develop a Robust Similarity Network Fusion (RSNF) approach which combines the strength of random forest and the advantage of SNF at data aggregation. The experimental results indicate the strength of the proposed strategy. The method substantially improves the clustering performance significantly comparing to several state-of-the-art methods in several datasets. PMID- 26513799 TI - A Versatile Embedded Platform for EMG Acquisition and Gesture Recognition. AB - Wearable devices offer interesting features, such as low cost and user friendliness, but their use for medical applications is an open research topic, given the limited hardware resources they provide. In this paper, we present an embedded solution for real-time EMG-based hand gesture recognition. The work focuses on the multi-level design of the system, integrating the hardware and software components to develop a wearable device capable of acquiring and processing EMG signals for real-time gesture recognition. The system combines the accuracy of a custom analog front end with the flexibility of a low power and high performance microcontroller for on-board processing. Our system achieves the same accuracy of high-end and more expensive active EMG sensors used in applications with strict requirements on signal quality. At the same time, due to its flexible configuration, it can be compared to the few wearable platforms designed for EMG gesture recognition available on market. We demonstrate that we reach similar or better performance while embedding the gesture recognition on board, with the benefit of cost reduction. To validate this approach, we collected a dataset of 7 gestures from 4 users, which were used to evaluate the impact of the number of EMG channels, the number of recognized gestures and the data rate on the recognition accuracy and on the computational demand of the classifier. As a result, we implemented a SVM recognition algorithm capable of real-time performance on the proposed wearable platform, achieving a classification rate of 90%, which is aligned with the state-of-the-art off-line results and a 29.7 mW power consumption, guaranteeing 44 hours of continuous operation with a 400 mAh battery. PMID- 26513800 TI - Photoplethysmography-Based Method for Automatic Detection of Premature Ventricular Contractions. AB - This work introduces a method for detection of premature ventricular contractions (PVCs) in photoplethysmogram (PPG). The method relies on 6 features, characterising PPG pulse power, and peak-to-peak intervals. A sliding window approach is applied to extract the features, which are later normalized with respect to an estimated heart rate. Artificial neural network with either linear and non-linear outputs was investigated as a feature classifier. PhysioNet databases, namely, the MIMIC II and the MIMIC, were used for training and testing, respectively. After annotating the PPGs with respect to synchronously recorded electrocardiogram, two main types of PVCs were distinguished: with and without the observable PPG pulse. The obtained sensitivity and specificity values for both considered PVC types were 92.4/99.9% and 93.2/99.9%, respectively. The achieved high classification results form a basis for a reliable PVC detection using a less obtrusive approach than the electrocardiography-based detection methods. PMID- 26513801 TI - A Neuromorphic Event-Based Neural Recording System for Smart Brain-Machine Interfaces. AB - Neural recording systems are a central component of Brain-Machince Interfaces (BMIs). In most of these systems the emphasis is on faithful reproduction and transmission of the recorded signal to remote systems for further processing or data analysis. Here we follow an alternative approach: we propose a neural recording system that can be directly interfaced locally to neuromorphic spiking neural processing circuits for compressing the large amounts of data recorded, carrying out signal processing and neural computation to extract relevant information, and transmitting only the low-bandwidth outcome of the processing to remote computing or actuating modules. The fabricated system includes a low-noise amplifier, a delta-modulator analog-to-digital converter, and a low-power band pass filter. The bio-amplifier has a programmable gain of 45-54 dB, with a Root Mean Squared (RMS) input-referred noise level of 2.1 MUV, and consumes 90 MUW . The band-pass filter and delta-modulator circuits include asynchronous handshaking interface logic compatible with event-based communication protocols. We describe the properties of the neural recording circuits, validating them with experimental measurements, and present system-level application examples, by interfacing these circuits to a reconfigurable neuromorphic processor comprising an array of spiking neurons with plastic and dynamic synapses. The pool of neurons within the neuromorphic processor was configured to implement a recurrent neural network, and to process the events generated by the neural recording system in order to carry out pattern recognition. PMID- 26513802 TI - Adaptive Neural Network-Based Event-Triggered Control of Single-Input Single Output Nonlinear Discrete-Time Systems. AB - This paper presents a novel adaptive neural network (NN) control of single-input and single-output uncertain nonlinear discrete-time systems under event sampled NN inputs. In this control scheme, the feedback signals are transmitted, and the NN weights are tuned in an aperiodic manner at the event sampled instants. After reviewing the NN approximation property with event sampled inputs, an adaptive state estimator (SE), consisting of linearly parameterized NNs, is utilized to approximate the unknown system dynamics in an event sampled context. The SE is viewed as a model and its approximated dynamics and the state vector, during any two events, are utilized for the event-triggered controller design. An adaptive event-trigger condition is derived by using both the estimated NN weights and a dead-zone operator to determine the event sampling instants. This condition both facilitates the NN approximation and reduces the transmission of feedback signals. The ultimate boundedness of both the NN weight estimation error and the system state vector is demonstrated through the Lyapunov approach. As expected, during an initial online learning phase, events are observed more frequently. Over time with the convergence of the NN weights, the inter-event times increase, thereby lowering the number of triggered events. These claims are illustrated through the simulation results. PMID- 26513803 TI - Identification of Nonlinear Spatiotemporal Dynamical Systems With Nonuniform Observations Using Reproducing-Kernel-Based Integral Least Square Regulation. AB - The identification of nonlinear spatiotemporal dynamical systems given by partial differential equations has attracted a lot of attention in the past decades. Several methods, such as searching principle-based algorithms, partially linear kernel methods, and coupled lattice methods, have been developed to address the identification problems. However, most existing methods have some restrictions on sampling processes in that the sampling intervals should usually be very small and uniformly distributed in spatiotemporal domains. These are actually not applicable for some practical applications. In this paper, to tackle this issue, a novel kernel-based learning algorithm named integral least square regularization regression (ILSRR) is proposed, which can be used to effectively achieve accurate derivative estimation for nonlinear functions in the time domain. With this technique, a discretization method named inverse meshless collocation is then developed to realize the dimensional reduction of the system to be identified. Thereafter, with this novel inverse meshless collocation model, the ILSRR, and a multiple-kernel-based learning algorithm, a multistep identification method is systematically proposed to address the identification problem of spatiotemporal systems with pointwise nonuniform observations. Numerical studies for benchmark systems with necessary discussions are presented to illustrate the effectiveness and the advantages of the proposed method. PMID- 26513804 TI - Optimizing Single-Trial EEG Classification by Stationary Matrix Logistic Regression in Brain-Computer Interface. AB - In addition to the noisy and limited spatial resolution characteristics of the electroencephalography (EEG) signal, the intrinsic nonstationarity in the EEG data makes the single-trial EEG classification an even more challenging problem in brain-computer interface (BCI). Variations of the signal properties within a session often result in deteriorated classification performance. This is mainly attributed to the reason that the routine feature extraction or classification method does not take the changes in the signal into account. Although several extensions to the standard feature extraction method have been proposed to reduce the sensitivity to nonstationarity in data, they optimize different objective functions from that of the subsequent classification model, and thereby, the extracted features may not be optimized for the classification. In this paper, we propose an approach that directly optimizes the classifier's discriminativity and robustness against the within-session nonstationarity of the EEG data through a single optimization paradigm, and show that it can greatly improve the performance, in particular for the subjects who have difficulty in controlling a BCI. Moreover, the experimental results on two benchmark data sets demonstrate that our approach significantly outperforms the compared approaches in reducing classification error rates. PMID- 26513805 TI - Twin Neurons for Efficient Real-World Data Distribution in Networks of Neural Cliques: Applications in Power Management in Electronic Circuits. AB - Associative memories are data structures that allow retrieval of previously stored messages given part of their content. They, thus, behave similarly to the human brain's memory that is capable, for instance, of retrieving the end of a song, given its beginning. Among different families of associative memories, sparse ones are known to provide the best efficiency (ratio of the number of bits stored to that of the bits used). Recently, a new family of sparse associative memories achieving almost optimal efficiency has been proposed. Their structure, relying on binary connections and neurons, induces a direct mapping between input messages and stored patterns. Nevertheless, it is well known that nonuniformity of the stored messages can lead to a dramatic decrease in performance. In this paper, we show the impact of nonuniformity on the performance of this recent model, and we exploit the structure of the model to improve its performance in practical applications, where data are not necessarily uniform. In order to approach the performance of networks with uniformly distributed messages presented in theoretical studies, twin neurons are introduced. To assess the adapted model, twin neurons are used with the real-world data to optimize power consumption of electronic circuits in practical test cases. PMID- 26513806 TI - L1-Minimization Algorithms for Sparse Signal Reconstruction Based on a Projection Neural Network. AB - This paper presents several L1-minimization algorithms for sparse signal reconstruction based on a continuous-time projection neural network (PNN). First, a one-layer projection neural network is designed based on a projection operator and a projection matrix. The stability and global convergence of the proposed neural network are proved. Then, based on a discrete-time version of the PNN, several L1-minimization algorithms for sparse signal reconstruction are developed and analyzed. Experimental results based on random Gaussian sparse signals show the effectiveness and performance of the proposed algorithms. Moreover, experimental results based on two face image databases are presented that reveal the influence of sparsity to the recognition rate. The algorithms are shown to be robust to the amplitude and sparsity level of signals as well as efficient with high convergence rate compared with several existing L1-minimization algorithms. PMID- 26513807 TI - Feature Extraction Using Memristor Networks. AB - Crossbar arrays of memristive elements are investigated for the implementation of dictionary learning and sparse coding of natural images. A winner-take-all training algorithm, in conjunction with Oja's rule, is used to learn an overcomplete dictionary of feature primitives that resemble Gabor filters. The dictionary is then used in the locally competitive algorithm to form a sparse representation of input images. The impacts of device nonlinearity and parameter variations are evaluated and a compensating procedure is proposed to ensure the robustness of the sparsification. It is shown that, with proper compensation, the memristor crossbar architecture can effectively perform sparse coding with distortion comparable with ideal software implementations at high sparsity, even in the presence of large device-to-device variations in the excess of 100%. PMID- 26513808 TI - Exponential Stability and Stabilization of Delayed Memristive Neural Networks Based on Quadratic Convex Combination Method. AB - This paper is concerned with the exponential stability and stabilization of memristive neural networks (MNNs) with delays. First, we present some generalized double-integral inequalities, which include some existing inequalities as their special cases. Second, combining with quadratic convex combination method, these double-integral inequalities are employed to formulate a delay-dependent stability condition for MNNs with delays. Third, a state-dependent switching control law is obtained for MNNs with delays based on the proposed stability conditions. The desired feedback gain matrices are accomplished by solving a set of linear matrix inequalities. Finally, the feasibility and effectiveness of the proposed results are tested by two numerical examples. PMID- 26513809 TI - Parameter as a Switch Between Dynamical States of a Network in Population Decoding. AB - Population coding is a method to represent stimuli using the collective activities of a number of neurons. Nevertheless, it is difficult to extract information from these population codes with the noise inherent in neuronal responses. Moreover, it is a challenge to identify the right parameter of the decoding model, which plays a key role for convergence. To address the problem, a population decoding model is proposed for parameter selection. Our method successfully identified the key conditions for a nonzero continuous attractor. Both the theoretical analysis and the application studies demonstrate the correctness and effectiveness of this strategy. PMID- 26513810 TI - Asymptotically Stable Adaptive-Optimal Control Algorithm With Saturating Actuators and Relaxed Persistence of Excitation. AB - This paper proposes a control algorithm based on adaptive dynamic programming to solve the infinite-horizon optimal control problem for known deterministic nonlinear systems with saturating actuators and nonquadratic cost functionals. The algorithm is based on an actor/critic framework, where a critic neural network (NN) is used to learn the optimal cost, and an actor NN is used to learn the optimal control policy. The adaptive control nature of the algorithm requires a persistence of excitation condition to be a priori validated, but this can be relaxed using previously stored data concurrently with current data in the update of the critic NN. A robustifying control term is added to the controller to eliminate the effect of residual errors, leading to the asymptotically stability of the closed-loop system. Simulation results show the effectiveness of the proposed approach for a controlled Van der Pol oscillator and also for a power system plant. PMID- 26513811 TI - Content-Adaptive Region-Based Color Texture Descriptors for Medical Images. AB - The design of computer-assisted decision (CAD) systems for different biomedical imaging scenarios is a challenging task in computer vision. Sometimes, this challenge can be attributed to the image acquisition mechanisms since the lack of control on the cameras can create different visualizations of the same imaging site under different rotation, scaling, and illumination parameters, with a requirement to get a consistent diagnosis by the CAD systems. Moreover, the images acquired from different sites have specific colors, making the use of standard color spaces highly redundant. In this paper, we propose to tackle these issues by introducing novel region-based texture, and color descriptors. The proposed texture features are based on the usage of analytic Gabor filters (for compensation of illumination variations) followed by the calculation of first- and second-order statistics of the filter responses and making them invariant using some trivial mathematical operators. The proposed color features are obtained by compensating for the illumination variations in the images using homomorphic filtering followed by a bag-of-words approach to obtain the most typical colors in the images. The proposed features are used for the identification of cancer in images from two distinct imaging modalities, i.e., gastroenterology and dermoscopy . Experiments demonstrate that the proposed descriptors compares favorably to several other state-of-the-art methods, elucidating on the effectiveness of adapted features for image characterization. PMID- 26513812 TI - Speckle Patch Similarity for Echogenicity-Based Multiorgan Segmentation in Ultrasound Images of the Thyroid Gland. AB - Ultrasound (US) imaging deals with forming a brightness image from the amplified backscatter echo when an ultrasound wave is triggered at the region of interest. Imaging artifacts and speckles occur in the image as a consequence of backscattering and subsequent amplification. We demonstrate the usefulness of speckle-related pixels and imaging artifacts as sources of information to perform multiorgan segmentation in US images of the thyroid gland. The speckle-related pixels are clustered based on a similarity constraint to quantize the image. The quantization results are used to locate useful anatomical landmarks that aid the detection of multiple organs in the image, which are the thyroid gland, the carotid artery, the muscles, and the trachea. The spatial locations of the carotid artery and the trachea are used to estimate the boundaries of the thyroid gland in transverse US scans. Experiments performed on a multivendor dataset yield good quality segmentation results with probabilistic Rand index > 0.83 and boundary error 1 mm, and an average accuracy greater than 94%. Analysis of the results using the Dice coefficient as the metric shows that the proposed method performs better than the state-of-the-art methods. Further, experiments conducted on 971 images of a publicly available dataset prove the effectiveness of the algorithm to track the carotid artery for guided interventions. In addition to US guided interventions, the algorithm can be used as a general framework in applications pertaining to volumetric analysis and computer-aided diagnosis. PMID- 26513813 TI - Automated GPR Rebar Analysis for Robotic Bridge Deck Evaluation. AB - Ground penetrating radar (GPR) is used to evaluate deterioration of reinforced concrete bridge decks based on measuring signal attenuation from embedded rebar. The existing methods for obtaining deterioration maps from GPR data often require manual interaction and offsite processing. In this paper, a novel algorithm is presented for automated rebar detection and analysis. We test the process with comprehensive measurements obtained using a novel state-of-the-art robotic bridge inspection system equipped with GPR sensors. The algorithm achieves robust performance by integrating machine learning classification using image-based gradient features and robust curve fitting of the rebar hyperbolic signature. The approach avoids edge detection, thresholding, and template matching that require manual tuning and are known to perform poorly in the presence of noise and outliers. The detected hyperbolic signatures of rebars within the bridge deck are used to generate deterioration maps of the bridge deck. The results of the rebar region detector are compared quantitatively with several methods of image-based classification and a significant performance advantage is demonstrated. High rates of accuracy are reported on real data that includes thousands of individual hyperbolic rebar signatures from three real bridge decks. PMID- 26513814 TI - $n$ -Dimensional Discrete Cat Map Generation Using Laplace Expansions. AB - Different from existing methods that use matrix multiplications and have high computation complexity, this paper proposes an efficient generation method of n dimensional ( [Formula: see text]) Cat maps using Laplace expansions. New parameters are also introduced to control the spatial configurations of the [Formula: see text] Cat matrix. Thus, the proposed method provides an efficient way to mix dynamics of all dimensions at one time. To investigate its implementations and applications, we further introduce a fast implementation algorithm of the proposed method with time complexity O(n4) and a pseudorandom number generator using the Cat map generated by the proposed method. The experimental results show that, compared with existing generation methods, the proposed method has a larger parameter space and simpler algorithm complexity, generates [Formula: see text] Cat matrices with a lower inner correlation, and thus yields more random and unpredictable outputs of [Formula: see text] Cat maps. PMID- 26513815 TI - Hand-Eye Calibration in Visually-Guided Robot Grinding. AB - Visually-guided robot grinding is a novel and promising automation technique for blade manufacturing. One common problem encountered in robot grinding is hand-eye calibration, which establishes the pose relationship between the end effector (hand) and the scanning sensor (eye). This paper proposes a new calibration approach for robot belt grinding. The main contribution of this paper is its consideration of both joint parameter errors and pose parameter errors in a hand eye calibration equation. The objective function of the hand-eye calibration is built and solved, from which 30 compensated values (corresponding to 24 joint parameters and six pose parameters) are easily calculated in a closed solution. The proposed approach is economic and simple because only a criterion sphere is used to calculate the calibration parameters, avoiding the need for an expensive and complicated tracking process using a laser tracker. The effectiveness of this method is verified using a calibration experiment and a blade grinding experiment. The code used in this approach is attached in the Appendix. PMID- 26513816 TI - Policy Search for the Optimal Control of Markov Decision Processes: A Novel Particle-Based Iterative Scheme. AB - Classical approximate dynamic programming techniques based on state-space gridding become computationally impracticable for high-dimensional problems. Policy search techniques cope with this curse of dimensionality issue by searching for the optimal control policy in a restricted parameterized policy space. We here focus on the case of discrete action space and introduce a novel policy parametrization that adopts particles to describe the map from the state space to the action space, each particle representing a region of the state space that is mapped into a certain action. The locations and actions associated with the particles describing a policy can be tuned by means of a recently introduced policy gradient method with parameter-based exploration. The task of selecting an appropriately sized set of particles is here solved through an iterative policy building scheme that adds new particles to improve the policy performance and is also capable of removing redundant particles. Experiments demonstrate the scalability of the proposed approach as the dimensionality of the state-space grows. PMID- 26513817 TI - Enhanced Local Gradient Order Features and Discriminant Analysis for Face Recognition. AB - Robust descriptor-based subspace learning with complex data is an active topic in pattern analysis and machine intelligence. A few researches concentrate the optimal design on feature representation and metric learning. However, traditionally used features of single-type, e.g., image gradient orientations (IGOs), are deficient to characterize the complete variations in robust and discriminant subspace learning. Meanwhile, discontinuity in edge alignment and feature match are not been carefully treated in the literature. In this paper, local order constrained IGOs are exploited to generate robust features. As the difference-based filters explicitly consider the local contrasts within neighboring pixel points, the proposed features enhance the local textures and the order-based coding ability, thus discover intrinsic structure of facial images further. The multimodal features are automatically fused in the most discriminant subspace. The utilization of adaptive interaction function suppresses outliers in each dimension for robust similarity measurement and discriminant analysis. The sparsity-driven regression model is modified to adapt the classification issue of the compact feature representation. Extensive experiments are conducted by using some benchmark face data sets, e.g., of controlled and uncontrolled environments, to evaluate our new algorithm. PMID- 26513818 TI - Edge-Aware Filtering with Local Polynomial Approximation and Rectangle-Based Weighting. AB - This paper presents a novel method for performing guided image filtering using local polynomial approximation (LPA) with range guidance. In our method, the LPA is introduced into a multipoint framework for reliable model regression and better preservation on image spatial variation which usually contains the essential information in the input image. In addition, we develop a weighting scheme which has the spatial flexibility during the filtering process. All components in our method are efficiently implemented and a constant computation complexity is achieved. Compared with conventional filtering methods, our method provides clearer boundaries and performs especially better in recovering spatial variation from noisy images. We conduct a number of experiments for different applications: depth image upsampling, joint image denoising, details enhancement, and image abstraction. Both quantitative and qualitative comparisons demonstrate that our method outperforms state-of-the-art methods. PMID- 26513819 TI - An Interpretable Fuzzy System Learned Through Online Rule Generation and Multiobjective ACO With a Mobile Robot Control Application. AB - This paper proposes a new multiobjective optimization approach to designing a fuzzy logic system (FLS) using process data and applies it to the wall-following control of a mobile robot. The objectives considered include both the interpretability and control performance of the FLS. It is assumed that no off line training data are available in advance, and the rule base is initially empty. All rules are generated through an online clustering and fuzzy set merging (OCFM) algorithm using data generated online during the FLS evaluation process. The OCFM builds a reference rule base that flexibly partitions the input space with distinguishable fuzzy sets (FSs). Based on the reference rule base, a new multiobjective front-guided continuous ant-colony optimization (MO-FCACO) algorithm is proposed to optimize the FLS structure and parameters. In addition to the objective functions defined to evaluate the FLS control performance, a transparency-oriented objective function is defined with constraints imposed on the FS parameters to obtain an interpretable FLS with transparent FSs. The MO FCACO solves the constrained multiobjective optimization problem by optimizing all of the free parameters in an FLS through ant-path selection, sampling operation, and front-guided optimization processes. The multiobjective FLS design approach is applied to control the orientation and moving speed of a mobile robot in performing the wall-following task. Optimization performance of the MO-FCACO is verified through comparisons with various multiobjective population-based optimization algorithms. Experimental results verify the effectiveness of the designed FLSs in controlling a real robot. PMID- 26513820 TI - Prototype Generation Using Multiobjective Particle Swarm Optimization for Nearest Neighbor Classification. AB - The nearest neighbor (NN) classifier suffers from high time complexity when classifying a test instance since the need of searching the whole training set. Prototype generation is a widely used approach to reduce the classification time, which generates a small set of prototypes to classify a test instance instead of using the whole training set. In this paper, particle swarm optimization is applied to prototype generation and two novel methods for improving the classification performance are presented: 1) a fitness function named error rank and 2) the multiobjective (MO) optimization strategy. Error rank is proposed to enhance the generation ability of the NN classifier, which takes the ranks of misclassified instances into consideration when designing the fitness function. The MO optimization strategy pursues the performance on multiple subsets of data simultaneously, in order to keep the classifier from overfitting the training set. Experimental results over 31 UCI data sets and 59 additional data sets show that the proposed algorithm outperforms nearly 30 existing prototype generation algorithms. PMID- 26513821 TI - A Decentralized Event-Triggered Dissipative Control Scheme for Systems With Multiple Sensors to Sample the System Outputs. AB - This paper is concerned with decentralized event-triggered dissipative control for systems with the entries of the system outputs having different physical properties. Depending on these different physical properties, the entries of the system outputs are grouped into multiple nodes. A number of sensors are used to sample the signals from different nodes. A decentralized event-triggering scheme is introduced to select those necessary sampled-data packets to be transmitted so that communication resources can be saved significantly while preserving the prescribed closed-loop performance. First, in order to organize the decentralized data packets transmitted from the sensor nodes, a data packet processor (DPP) is used to generate a new signal to be held by the zero-order-hold once the signal stored by the DPP is updated at some time instant. Second, under the mechanism of the DPP, the resulting closed-loop system is modeled as a linear system with an interval time-varying delay. A sufficient condition is derived such that the closed-loop system is asymptotically stable and strictly (Q0,S0,R0) -dissipative, where Q0,S0 , and R0 are real matrices of appropriate dimensions with Q0 and R0 symmetric. Third, suitable output-based controllers can be designed based on solutions to a set of a linear matrix inequality. Finally, two examples are given to demonstrate the effectiveness of the proposed method. PMID- 26513822 TI - Discrimination Between Native and Non-Native Speech Using Visual Features Only. AB - Accent is a soft biometric trait that can be inferred from pronunciation and articulation patterns characterizing the speaking style of an individual. Past research has addressed the task of classifying accent, as belonging to a native language speaker or a foreign language speaker, by means of the audio modality only. However, features extracted from the visual stream of speech have been successfully used to extend or substitute audio-only approaches that target speech or language recognition. Motivated by these findings, we investigate to what extent temporal visual speech dynamics attributed to accent can be modeled and identified when the audio stream is missing or noisy, and the speech content is unknown. We present here a fully automated approach to discriminating native from non-native English speech, based exclusively on visual cues. A systematic evaluation of various appearance and shape features for the target problem is conducted, with the former consistently yielding superior performance. Subject independent cross-validation experiments are conducted on mobile phone recordings of continuous speech and isolated word utterances spoken by 56 subjects from the challenging MOBIO database. High performance is achieved on a text-dependent (TD) protocol, with the best score of 76.5% yielded by fusion of five hidden Markov models trained on appearance features. Our framework is also efficient even when tested on examples of speech unseen in the training phase, although performing less accurately compared to the TD case. PMID- 26513823 TI - Emergence of Rotavirus G12P[8] in St. Louis During the 2012-2013 Rotavirus Season. AB - BACKGROUND: We observed an increase in the number of rotavirus cases in the St. Louis area during the 2012-2013 rotavirus season compared with recent seasons. We aimed to determine whether the rotavirus cases during the 2012-2013 rotavirus season were of types not included in licensed vaccines. METHODS: Microbiology laboratories of 3 children's hospitals in St. Louis provided samples that were positive using rapid antigen tests from 2010 to 2013. The majority of samples were from St. Louis Children's Hospital. We determined rotavirus genotypes by polymerase chain reaction tests and further characterized a subset of viruses by genome sequencing and comparative sequence analysis. RESULTS: Eighty-six percent (24 of 28) of typed viruses analyzed from the 2012-2013 rotavirus season were G12. We performed whole genome sequencing on 8 G12 viruses, all of which were VP4 type P[8]. The sequenced viruses showed differences from vaccine strains in major antigenic epitopes on the VP7 protein, but most epitopes on VP4 were conserved. Rotavirus vaccine histories were available for 11 G12 cases, of whom 10 had not been vaccinated. CONCLUSIONS: G12 was a dominant community-wide genotype in 2013. Most of the G12 cases for whom vaccine histories were available had not received rotavirus vaccine. The experience demonstrates the potential for rapid shifts in rotavirus genotype distribution and underscores the need for vigilant surveillance to detect unusual genotypes that might escape from vaccine protection. PMID- 26513824 TI - [Probing the Utility of Ultrasonography for Assessing Degree of Functional Dyspepsia]. PMID- 26513825 TI - [Colonic Endometriosis]. PMID- 26513826 TI - [Hope for Cirrhosis Patients with Genotype 1 Hepatitis C Virus Who Failed the Previous Treatment]. PMID- 26513827 TI - Address by Chair of the ADEA Board of Directors. PMID- 26513828 TI - Address by Chair-elect of the ADEA Board of Directors. PMID- 26513829 TI - Report of ADEA President and CEO: ADEA on the Move. PMID- 26513831 TI - [How can the community pharmacist improve the adherence to anti-osteoporotic treatments]. AB - Adherence of patients with chronic conditions to their treatment is generally low. However, poor medication adherence or persistence reduces therapeutic effectiveness and increases morbidity and health care costs. This is also the case for anti-osteoporotic treatments that, in order to be effective, must be taken correctly, regularly and long-term. The community pharmacist can play an important role in encouraging long-term adherence to antiosteoporotic treatments. To promote adherence, it is essential, from the beginning, to give to the patient the information needed for a good understanding and a proper course of treatment. The repeated contact between pharmacist and patient creates an opportunity to regularly assess adherence. In order to improve adherence, one needs to identify the causes of non-adherence and adapt the interventions accordingly. Persistence also requires follow-up of the patient. Regular reassessment of patient's adherence, taking into account changes that may affect his expectations, preferences and priorities, is essential to adjust interventions to his new needs. This article suggests ways and tools to improve therapeutic adherence, particularly in osteoporotic patients. PMID- 26513832 TI - [Composition of the Belgian influenza vaccines for the 2015-2016 season]. AB - This article gives an update on how the composition of the influenza virus vaccine is determined, how the infection spreads, and what the consequences are of the disease. Next flu season for the first time a quadrivalent and intranasal vaccine will be available on the Belgian market. What is the difference with what we know until now? Is there an added value? How about the contraindications? Furthermore we elaborate on the composition of the influenza vaccine on the Belgian market for the season 2015-2016 and we give a reminder of the patient groups with a high risk for complications. As pharmacists we should motivate these patients to get themselves vaccinated. Finally, we discuss the reimbursement conditions of the National Institute for Health and Disability Insurance INIHDII. PMID- 26513833 TI - [Preliminary study for the implementation of standardized rounded doses of cytotoxic druqs]. AB - BACKGROUND: "Dose-banding" is a concept of cytotoxic drugs standardization allowing the preparation in advance of standardized rounded doses (SRD covering the most frequently prescribed doses rounded to +/-5%. Standard doses will be prepared in advance by batch in order to increase production capacity and at the same time to regulate pharmacy workflow as well as to reduce patient waiting time. PURPOSE: To identify anticancer drugs suitable for dose banding and to fix standardized doses. METHODS: The interesting molecules are first selected in accordance with several criteria: preparations frequency, long-term physicochemical stability after reconstitution, repetition of the prescribed doses and savings opportunity. The selected molecules were: Carboplatin, Cetuximab, Cisplatin, Cyclophosphamide, Doxorubicin, 5-Fluorouracil, Gemcitabine, Oxaliplatine, Paclitaxel, Rituximab, Trastuzumab and Vinorelbine. We established an inventory of the prescriptions retrospectively for a period of six months in order to highlight the most often prescribed doses. For the analysis, we fixed bands with a standard deviation of +/- 5%, 7% and +/- 10%. RESULTS: Standardization of doses of chemotherapy was deemed interesting if > or =60% of the doses were standardisable with a maximum of five SRD and a minimum of one delivery per week, in order to guarantee a good turnover of the batch. A maximum of 5% standard deviation is added to those three criteria, the deviation currently accepted among our medical staff. After analyzing 3506 prescriptions, 7 molecules are eligible: Doxorubicine, 5-Fluorouracil infusion, 5-Fluorouracil pump, Gemcitabine, Paclitaxel, Rituximab, Trastuzumab and Vinorelbine, with a percentage of standardisation of 77% [SRD: 30 mg), 61% [SRD: 700 mg, 750 mg, 800 mgl, 75% (SRD: 4000 mg, 4500 mg, 5000 mg), 72% [SRD: 1600 mg, 1800 mg, 2000 mg), 61% [SRD: 140 mg, 150 mg, 160 mgl, 64% (SRD: 600 mg, 700 mg, 750 mg], 71% (SRD: 350 mg, 400 mg. 450 mgl et 62% [SRD: 40 mg, 50 mg] respectively. CONCLUSION: This preliminary study allows us to consider implementing the dose banding concept in order to optimize the chemotherapy circuit at our institution. PMID- 26513834 TI - [The long-term chemical stability of injectable drugs reconstituted in Hospital Pharmacy]. AB - BACKGROUND: Other injectable preparations than parenteral nutrition admixture and injectable cytotoxic drugs could be prepared by Centralised IntraVenous Admixture Service (CIVAS) if the Long-term stability of the drugs is known. However, this information is not always available. PURPOSE: To develop a program of chemical drug stability analysis in collaboration between Hospital Pharmacy, Medical Laboratory and Scientific Support Unit to determine the long-term stability of largely used injectable anti-infectious and non-anti-infectious drugs. MATERIAL AND METHODS: After a setup of the High Performance Liquid Chromatography (HPLCI method, 28 drugs were reconstituted in laminar air flow hood, 17 of them stored directly at 5 +/- 3 degrees C and 19 stored in the freezer at -20 degrees C, thawed by microwave following a standardised procedure and stored at 5 +/- 3 degrees C before use. Concentration stability was evaluated by regression analysis. RESULTS: For each drug, long-term stability has varied from 11 days to 180 days. The freeze-thaw treatment by microwave may enhance the stability (from 30 to 120 days) and allow batch-scale production of intravenous drugs, less expensive in term of manpower and sterile device than a drug reconstitution at the ward. The results were published by 55 posters in international congress and by 36 publications in national and international pharmaceutical journals. CONCLUSIONS: Our findings contribute to enhance the scale of drugs that may be take on by a CIVAS. PMID- 26513835 TI - [Dolutegravir (Tivicay) orally]. PMID- 26513836 TI - [Teriflunomide (Aubagio), oral administration]. PMID- 26513838 TI - [Facial nerve outcome after vestibular schwannoma surgery: About 89 patients]. AB - OBJECTIVES: We evaluated the postoperative facial nerve function after vestibular schwannoma (VS) surgery and analyzed factors causing it. MATERIAL AND METHODS: We included 89 consecutive patients undergoing surgical excision of unilateral VS. Patient and tumor characteristics, surgical approaches, facial nerve function, extent of tumor resection and complications were analyzed. RESULTS: Complete tumor resection was achieved in 85% of cases. Anatomic preservation of the facial nerve was achieved in 96% of patients. In all tumor stages, 88.2% of patients, have a normal or subnormal facial function within one year of the intervention, the rate was 100% in patients carrying a VS stage I or II. No severe complication or death was reported. CONCLUSION: Short- and long-term facial nerve outcome was comparable with results of other recent series reported in literature. The facial nerve function after surgery was better with small VS compared to large VS. The intraoperative decision of near-total excision of the tumor followed by adjuvant radiotherapy, in some cases, can prove to be a good option in the interest of better preservation of the facial nerve function. The adhesion of the facial nerve and its complex relationship with the tumor remain mysterious; RMI can bring significant refinements, helping to get the best preservation offacial function rate, in the coming years. PMID- 26513839 TI - [Facial nerve monitoring during middle ear surgery: Results of a French survey]. AB - INTRODUCTION: Facial nerve injury is a rare complication of middle ear surgery. To date there is no widely accepted consensus on the use of intraoperative facial nerve monitoring during middle ear surgery, whereas its use has been proved as a valuable adjunct in neurotologic surgery. The purpose of our study was to identify introperative facial nerve monitoring practice patterns in France for middle ear surgery. METHODS: A 19-item survey has been made up by three experienced otologists under the auspices of the French Otology and Neurotology Association. With the support of the French Society of Otolaryngology--Head and Neck Surgery, the survey was electronically sent by email to 1249 practicing ENT with a valid email address. Answers were analyzed two months later. RESULTS: Among 1249 email sent, 299 were opened (24%) and 83 answers were collected (6,6%). Of the respondents, 66% had access to intraoperative facial nerve monitoring. Otolaryngologists involved in academic setting were influenced by their teaching duty in 27%. Intraoperative facial nerve monitoring should not be required for stapes surgery, ossiculoplasty, myringoplasty for, respectively, 92%, 93 % and 98% of the respondents. In cochlear implantation, 78% of ear surgeons used facial nerve monitoring. Answers were more controversial for chronic ear surgery, ear atresia and middle ear implant. Revision surgery and CT scan can influence answers. CONCLUSION: Despite a low response rate, results of this national survey revealed interesting findings. For most of the respondents, intraoperative facial nerve monitoring was not indicated in stapes surgery, myringoplasty and ossiculoplasty. The use of intraoperative facial nerve monitoring for cochlear implantation was supported by the majority of respondents. Variations in response rate were more significant for chronic ear surgery, including middle ear cholesteatoma, and for ear atresia surgery. PMID- 26513840 TI - [Benefit of skull vibration-induced nystagmus test in occupational medicine]. AB - BACKGROUND: Nystagmus induced by vibrations (NIV), has been optimized by the present authors this last decade. The skull vibration-induced nystagmus test (SVINT) can be designated as a high-frequency global "vestibular Weber test" and can be considered as an office-based examination to detect vestibular asymmetry. The aim of this study is to define the tolerance of the SVINT as well as its comparison to the simplified caloric test of Veits (CTV) in normal workers during the pre-employment visit at the occupational medicine center. MATERIAL AND METHODS: The vestibular function has been evaluated by the SVINT and the CTV in 87 healthy workers. The tolerance of the two procedures has been evaluated by a 4 items questionnaire (nausea, vomiting, sweating, asthenia). RESULTS: The caloric test was normal in each worker. The SVINT was positive in one patient who had a partial unilateral vestibular dysfunction related to trauma. The mean duration of the procedure was 15 min for CTV and 1 min for SVINT. Side effects (nausea, vomiting, sweating, asthenia) were present in 50% of the workers following CTV and in only one patient after SVINT. The SVINT demonstrated significantly less side effects for each item (p < 0.0001). CONCLUSIONS: SVINT is a valid, rapid, low-cost clinical screening test and does not cause patient discomfort. It is suggested that this test which explores vestibular high frequencies and is not modified by vestibular compensation is useful for the diagnostic screening of workers' vestibular dysfunction, when combined with other vestibular tests and complements the CTV. PMID- 26513841 TI - [Acute acoustic trauma, a retrospective analysis about 225 military cases]. AB - OBJECTIVES: Studying the epidemiology, the evolutionary audiometric profile and the after-effects of acute acoustic trauma managed in military environment. Assessing the influence beyond the audiometric recovery of earplugs, precocity of the treatment and hyperbaric oxygen therapy. MATERIALS AND METHODS: This retrospective cohort gathered 225 military cases of acute acoustic trauma hospitalized between 2003 and 2008. The cochlear supportive therapy associated intravenous methyl-prednisolone and pentoxyfilline, completed sometimes with hyperbaric oxygen therapy. The evolution was appreciated with pure-tone audiometry at the admission, at the end of hospitalization and one month after. Perceptive deafness and recovery shifts were statically calculated on 109 ears. RESULTS: On the 225 cases, 90% were males, middle-aged of 23 years. Initially 95% of the patients complained about tinnitus, associated with hearing loss felt for 71%. The left ear was more frequently affected. The initial audiometric loss was average of 34 dB HL, concentrated on 4000 and 6000 Hz frequencies. The therapy allowed an average recovery of +18,3 dB in a month. The audiometric sequela concerned 40% of the cases, and residual tinnitus a third. These rates were significantly higher with people whose initial hearing loss average exceeded 40 dB HL. Concerning the audiometric recovery and the after-effects, no significantly difference was found between the groups treated before or after 12 hours. There were either no difference with the earplugs and hyperbaric oxygen groups. CONCLUSION: Despite the effectiveness of early corticotherapy, after effects of acute acoustic trauma remain frequent and invalidating. Its prevention suffers from non-observance and malposition of earplugs. PMID- 26513842 TI - [Retrospective evaluation of short tympanostomy tubes efficacy in case of recurrent acute otitis media on an infant population]. AB - INTRODUCTION: The aim of this study is to appreciate the results of short tympanostomy tubes (ST) in case of recurrent acute otitis media (AOM), and to appreciate the risk factors of recurrent AOM. METHODS: This retrospective chart study concerns infants who had STT placement surgery forrecurrent AOM, between 2007 and 2011. Demographic data, anamnesis, efficacy and postoperative follow-up were analyzed. RESULTS: Forty-nine children were included in the study (30 boys, 19 girls; 7 months to 2 years-old, median age 1.4 year). Two-thirds attended a day-care center, one third was an onlychild. One quarter had an anemia. Anti Haemophilus and anti-pneumococcus vaccinations were up-to-date in 87.5%. After STT placement, 20 children (40.8%) did not present any new episode of AOM. This result did not vary with adenoidectomy. Among the ones that relapsed AOM after STT, 48.3% presented with only one episode. For two thirds of the patients, no general antibiotic treatment was necessary as long as the STT were in place. Half STT have been spontaneously expulsed between 6 and 12 months. Thirteen infants (37.1%) had new episodes of AOM after STT expulsion and 5 (38.5%) needed new tube placement. CONCLUSION: This study confirms that day care and siblings are risk factors of recurrent AOM, but does not confirm potential role of the anemia. STT placement decreased effectively AOM recurrences, their severity and the need for antibiotics prescriptions. No residual perforation was encountered in this study. PMID- 26513843 TI - [Tympanoplasty: Experience of the ENT department in Yopougon hospital (Ivory Cost)]. AB - PURPOSE: Perform an analysis of epidemiological, diagnostic and therapeutic aspects of tympanoplasty in Ivory Coast. MATERIALS AND METHODS: Retro and prospective study over 13 years conducted in the ENT department of Yopougon Teaching Hospital. Our study concerned 104 patients. RESULTS: The study population was dominated by young adults with an average age of 30.61 years. Chronic otitis media accounted for 80.76% of past medical history, a condition that was also the main indication (74.04%). Otoscopy pre- and intraoperative found essentially a non-marginal tympanic perforation (74.03%) and preoperative hearing assessment noted a conductive hearing loss in 72% of cases. The retroauricular surgical incision was performed in all patients. Surgical treatment consisted of a tympanoplasty type I in 76.3% of cases. The anatomical results were good in 81% of cases and functionally, 75% of our patients had interaural intensity difference of less than 20 decibels. CONCLUSION: The tympanoplasty performed in our hospital apparently gives results that are similar to those of western countries to the patients who got a post operative control. PMID- 26513844 TI - [Post operative Caldwell-Luc procedure maxillary cyst: Report of a case]. AB - Rare complication of radical surgery (Caldwell Luc procedure) of the maxillary sinus, maxillary cyst can occurred several years after. We describe the case of a patient 56 years old, who came to our consultationfor repeated pain in the right maxillary region with moderate facial asymmetry. In her history we noted a previous sinus surgery (Caldwell Luc) more than 10 years before. The imaging showed an expansive process filled with proteinic tissue of the posterior wall of the maxillary. With the history of the former surgery, we suspected the existence of a mucocele. She underwent an endonasal surgery and the pathological examination of the specimen revealed an intra osseous cyst lined with ciliated respiratory type mucosa post surgery of the maxillary sinus. The diagnosis of a maxillary cyst complicating a Caldwell Luc was established based on the results obtained with the clinico-radiological and pathological results. PMID- 26513845 TI - The Cochrane review of water fluoridation; a commentary. PMID- 26513846 TI - Relationship between family characteristics and children's regular toothbrushing with fluoride toothpaste. AB - OBJECTIVE: To examine the association between toothbrushing habits of 8-9 year olds and maternal behaviours and attitudes towards oral health in a sample of Japanese population. METHODS: Cross-sectional data on mothers' behaviours and attitudes towards oral health and children's toothbrushing habits were collected from 378 mother-child pairs by self-administered questionnaires. Logistic regression examined the association of children's daily brushing with fluoride toothpaste with family characteristics, mother's behaviour (toothbrushing frequency, use of interdental aids and supervision of children's toothbrushing), and mother's attitudes towards oral health (priority for toothbrushing and dental fear). RESULTS: Children's favourable brushing habits were positively associated with child's gender (female) (OR 1.29; 95%CI:1.09,1.53), child's order of birth (first) (OR 1.53; 95%CI:1.05,2.23), maternal brushing habits (OR 2.42; 95%CI:1.73,3.40), and maternal dental fear (OR 1.45; 95%CI:1.10,1.90). None of the other examined factors were significantly associated with child toothbrushing behaviour. CONCLUSIONS: Matemal oral hygiene practice and attitude towards dentists appear to be important predictors of children's toothbrushing habits in this Japanese community sample. PMID- 26513847 TI - Effect of family caregiver oral care training on stroke survivor oral and respiratory health in Taiwan: a randomised controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of home-based oral care training programs on tongue coating (TC), dental plaque (DP), and symptoms of respiratory infection (SRI) in stroke survivors. METHODS: A single-blind, randomised, controlled trial conducted in a home-based setting over 2 months. Stroke survivors (n=48, experimental group) and their family caregivers received home based oral care training programme while a control group of 46 stroke survivors and family caregivers received routine oral care education with swabs. TC, DP, and SRI were assessed at baseline and after one and two months, with results analysed using Mixed Model ANOVA. RESULTS: Poor oral hygiene and overall neglect of home oral care practices were observed at baseline. TC and DP scores were significantly reduced in the experimental group receiving the home-base oral care training program compared to the control group, who received only routine oral care education (P<0.001). The groupxtime interaction was significant, with decreased TC and DP scores for both groups at one month and at two months of additional care (when compared to baseline). The SRI scores were not significantly different between groups (P>0.05). The groupxtime interaction did not correlate with SRI for either group when compared to the baseline and to one month and two months of additional care. No adverse events were encountered and there was no external funding. CONCLUSIONS: Home-based oral care training programme had a beneficial effect on oral health as measured by TC and DP scores. The effect on SRI requires further longitudinal study. PMID- 26513848 TI - Exploring the association between oral health literacy and alexithymia. AB - Low health literacy and alexithymia have separately been emphasized as barriers to patient-practitioner communication, but the association between the two concepts has not been explored. OBJECTIVE: To test the hypothesis that low oral health literacy and alexithymia are associated. METHOD: Adults (n=127) aged 21-80 years (56% women) participated in this cross-sectional study. Oral health literacy was assessed using the interview-based Adult Health Literacy Instrument for Dentistry (AHLID) with scores from 1-5. The self-administered Toronto Alexithymia Scale (TAS-20) was used to assess three distinct TAS-20 factors and TAS-20 total score. RESULTS: Significant negative correlations between AHLID scores and TAS-20 factors 2, 3 and TAS-20 total score were found. Regression analyses showed that TAS-20 factor 3, externally-oriented thinking (beta=-0.21, SE=0.02, p=0.017), and TAS-20 total score (beta=-0.18, SE=0.01, p=0.036) were significant predictors of AHLID level. CONCLUSION: The hypothesis that low oral health literacy is associated with alexithymia was supported. This finding proposes that alexithymia may be considered as a possible factor for low oral health literacy. However, the correlations are not strong, and the results should be regarded as a first step to provide evidence with additional research on this topic being needed. PMID- 26513849 TI - Association of oral health literacy with oral health behaviour and oral health status in Belarus. AB - OBJECTIVES: To explore the level of oral health literacy among adults in Belarus, a former part of the Soviet Union, and to analyse the associations between oral health literacy, socio-demographics, health behaviour and oral health status. BASIC RESEARCH DESIGN: A cross-sectional study. Participants: 281 adult (18-60 years old) dental patients. MAIN OUTCOME MEASURE: The participants completed a self-administered questionnaire collecting information about socio-demographics and health behaviours, and oral health literacy test (the R-OHLI). Clinical oral examination followed the questionnaire survey. RESULTS: Among participants, 68.7% had adequate, 18.9% had marginal and 12.4% inadequate oral health literacy levels. Females and those with higher education were more likely to have adequate oral health literacy (p<0.05 and p<0.001). Participants with adequate oral health literacy had fewer missing and more filled teeth than those with inadequate literacy (p<0.001). This association remained significant after adjusting for socio-demographics, behavioural characteristics and oral hygiene status (p<0.05 and p<0.001). CONCLUSIONS: Adequate oral health literacy was strongly related with better oral health status. Improvement of oral health literacy should be addressed when developing community oral health promotions. PMID- 26513850 TI - Association between childhood socioeconomic position and periodontitis in Korean adults. AB - OBJECTIVE: To examine the relationship of early life socioeconomic position (SEP) and adulthood periodontitis in the middle aged Korean representative sample. METHODS: The 4th Korea National Health and Nutrition Examination Survey data were used. Multivariate logistic regression analyses were conducted on adults aged 30 59 years to estimate the association between parental SEP (education, occupation) and periodontitis and assess the relative impacts of own SEP (education, income and occupation) on periodontitis. Periodontitis (Community Periodontal Index) was dependent variable and parental SEPs were independent variables. RESULTS: Own SEP was associated with periodontitis (OR of own education=1.94, OR of own occupation=1.67; OR of the lowest income=1.52). Income was associated with periodontitis after adjustment for own SEPs and parental SEPs simultaneously (adjusted OR of the lowest income=1.68). Parental SEP was associated with periodontitis (OR of father's education=1.66, OR of mother's education=l.64; OR of father's occupation=1.38, OR of mother's occupation=1.44). CONCLUSIONS: Early life socioeconomic disadvantages were significantly associated with adulthood periodontitis in the representative Korean sample (p<0.05). The results also indicated that systematic oral health program and oral education would be needed from early childhood throughout the whole life time to improve periodontal health in adulthood. PMID- 26513851 TI - Clustering of risk indicators for periodontal disease: A population-based study. AB - BACKGROUND: To assess the prevalence of clustering of risk indicators for periodontal disease and association of clustering of the risk indicators with sociodemographic factors and the prevalence of moderate/severe periodontal disease in rural Indian 35-54 year-olds. BASIC RESEARCH DESIGN: A multi-stage cluster random sampling design was used for this population-based cross-sectional study. METHOD: Data were collected through in-person interviews relating to sociodemographic factors and habits. Plaque index and periodontal findings were recorded from oral examination. Clustering of risk indicators such as smoking, tobacco chewing, alcohol and plaque were assessed for association with periodontal disease and various other sociodemographic indicators using logistic regression models. Results: Of 1,401 people approached, 873 completed data; a response rate of 62.3%. Clustering of two or more risk indicators was present in 31% of the population. Prevalence of moderate-severe periodontal disease was 46.6%. Simultaneous presence of two/more risk indicators was strongly associated with sociodemographic factors and periodontal disease. CONCLUSIONS: Clustering of two or more of the factors plaque, smoking, chewing tobacco and alcohol, was strongly associated with periodontitis. PMID- 26513852 TI - Dental caries in Iraqi 12-year-olds and background fluoride exposure. AB - OBJECTIVE: The aim of this study was to assess the prevalence and severity of dental caries among 12-year-old Iraqi schoolchildren ingesting water and beverages with low fluoride content. METHOD: A total of 1,526 twelve-year-olds were clinically examined in autumn 2013 for dental caries in accordance with the WHO criteria. Two questionnaires were distributed to gather data concerning daily intakes of drinking water, beverages and tea extracts and how often participants brushed their teeth, visiting doctors and eating snacks between meals. The fluoride content of 279 brands of drinking water, beverages, tea, toothpaste and table salts were determined using fluoride ion selective electrode. Results The mean DMFT and SIC index were 1.6 (SD 1.7) and 3.5 (SD 1.4) respectively. The caries prevalence was 64.0%, and the Care Index was 1.9%. The average fluoride content of drinking water, beverages, toothpaste and food was less than 0.50 mg/kg. CONCLUSION: The mean DMFT value for Iraqi 12-year-olds is still higher than the WHO category of very low caries (<1.2). The daily fluoride exposure by 12-year-old Iraqi children was too low for caries prevention. In order to improve the oral health status, the Iraqi health authorities had to focus more care on the preventive oral health programme. PMID- 26513853 TI - Fluoride content and labelling of toothpastes marketed in India. AB - OBJECTIVE: To enumerate the fluoride content and labelling practices of toothpastes marketed in India and to determine if the content is in accordance with the information provided on the packaging. METHOD: In vitro analysis of total and free available fluoride in 5 adult and 5 children's fluoride toothpastes in India using fluoride ion electrode. Information on the tube and carton was checked to assess the labelling. RESULTS: The mean Total Fluoride concentrations (TF) in the toothpastes labelled 1,000 ppm, 500ppm and 458 ppm were 1,000, 500 and 449mg/L (sd values 3, 5 and 4mg/L) respectively. The toothpastes' Total Soluble Fluoride (TSF) concentration was generally slightly less than the TF concentration. Overall mean percentage of TSF concentration was 94% sd 9%. The mean percentage of TSF concentration in SMFP (sodium monofluorophosphate)/CaCO3 (calcium carbonate) containing toothpastes was 86% sd 16% while that in NaF (sodium fluoride)/Si (silica) based toothpastes was 98% sd 1% and 95% sd 1% in the remaining toothpastes with unknown abrasive. NaF/Si based toothpastes had more TSF concentration than the others (p<0.05). All the information required by the Indian regulations was shown on all 10 toothpastes. CONCLUSION: The available fluoride content of one of the ten toothpastes was substantially less than the total fluoride content. Although the toothpastes were labelled following the guidelines of the regulatory body of India, 3 of the 10 failed to mention the abrasive present. PMID- 26513854 TI - Attitudes and practices regarding preventive dentistry among Libyan dentists. AB - PURPOSE: To assess the attitudes towards and practices related to preventive dentistry among Libyan dentists. METHODS: A cross-sectional, questionnaire-based survey was conducted among dentists working in Benghazi. All dentists registered with the Dental Association of Benghazi and with two or more years of practice were invited to participate. The questionnaire enquired about dentists' demographic (gender and age) and professional characteristics (practice sector and years of service), attitudes towards preventive dentistry using nine semantic differential scales and the frequency with which they performed eight preventive measures to patients. Non-parametric tests were used to compare attitudes towards and practices related to preventive dentistry by participants' demographic and professional characteristics. RESULTS: Of the 175 dentists returning questionnaires (response rate 79%), 166 had complete information on all the variables needed for analysis (75%). Dentists felt preventive dentistry was useful and essential to the community as well as of scientific merit for dentists. As for practices, oral hygiene instruction and recommending fluoridated toothpaste were the most commonly reported preventive measures performed by dentists whereas the application of topical fluoride and fissure sealants were the least reported. Attitudes towards and practices related to preventive dentistry varied by professional but not demographic characteristics. CONCLUSION: Dentists showed a generally positive attitude towards preventive dentistry. However, certain preventive measures, particularly those that incur costs, were less frequently practised. PMID- 26513855 TI - Comparing UK, USA and Australian values for EQ-5D as a health utility measure of oral health. AB - OBJECTIVES: Using generic measures to examine outcomes of oral disorders can add additional information relating to health utility. However, different algorithms are available to generate health states. The aim was to assess UK-, US- and Australian-based algorithms for the EuroQol (EQ-5D) in relation to their discriminative and convergent validity. Methods: Data were collected from adults in Australia aged 30-61 years by mailed survey in 2009-10, including the EQ-5D and a range of self-reported oral health variables, and self-rated oral and general health. RESULTS: Responses were collected from n=1,093 persons (response rate 39.1%). UK-based EQ-5D estimates were lower (0.85) than the USA and Australian estimates (0.91). EQ-5D was associated (p<0.01) with all seven oral health variables, with differences in utility scores ranging from 0.03 to 0.06 for the UK, from 0.04 to 0.07 for the USA, and from 0.05 to 0.08 for the Australian-based estimates. The effect sizes (ESs) of the associations with all seven oral health variables were similar for the UK (ES=0.26 to 0.49), USA (ES=0.31 to 0.48) and Australian-based (ES=0.31 to 0.46) estimates. EQ-5D was correlated with global dental health for the UK (rho=0.29), USA (rho=0.30) and Australian-based estimates (rho=0.30), and correlations with global general health were the same (rho=0.42) for the UK, USA and Australian-based estimates. CONCLUSIONS: EQ-5D exhibited equivalent discriminative validity and convergent validity in relation to oral health variables for the UK, USA and Australian based estimates. PMID- 26513856 TI - Socioeconomic inequalities in dental caries among 5-year-olds in four Chinese provinces. AB - OBJECTIVE: To explore socioeconomic inequalities in dental caries among 5-year olds in four Chinese provinces. METHODS: This study used data from 1,732 children living in Guangxi, Hubei, Jilin and Shanxi who participated in the Third National Oral Health Survey in 2005. Questionnaires were completed by parents to collect information on family socioeconomic position (parental education and household income) and children's dental behaviours (toothbrushing frequency, sugar intake frequency and last dental visit). Children were clinically examined for dental caries, which was reported using the dmft index. Socioeconomic inequalities in children's caries experience were assessed in negative binomial regression models. RESULTS: There were significant gradients in children's dmft by household income. Children's dmft increased from 2.63 in the highest income group to 4.70 in the lowest income group. However, parental education was not significantly related to childhood dental caries. CONCLUSION: Clear social gradients in caries experience of deciduous teeth were found by household income but not parental education. PMID- 26513857 TI - Dental survey of the Falkland Islands' child population. AB - In November 2013 the first dental epidemiological survey of 5, 12 and 15 year old children was undertaken on The Falkland Islands. The census survey used the ICDAS II system and achieved an overall response rate of 87.4%. To allow international comparisons obvious decay experience is reported. The mean dmft of 5-year-olds was 1.2 teeth, the prevalence of decay experience was 34.6%. The mean DMFT of 12 year-old children was 0.9 teeth, the prevalence of decay experience was 36.7%. The mean DMFT of 15-year-olds was 1.78 teeth, and the prevalence of decay experience was 66.7%. This first dental survey showed that levels of child dental decay in the Falkland Islands are similar to western European countries. The results can now be used as a baseline and benchmark to follow future trends in dental health in this British Overseas Territory. PMID- 26513858 TI - [Medical support-of the military parade on the Red Square]. AB - Medical Service of Western Military District provided training and medical support for a ceremonial crew during the parade on the Red Square in honour of the 69th anniversary of the victory in the Great Patriotic War. Medical support was organized at all stages of the preparation and conduct of the parade: the first stage--preparatory, the second stage--conducting training, the third stage- medical care of the parade and the fourth--stage withdrawal in places of permanent deployment. Well-planned activities, training of personnel allowed to organize high quality health care, to prevent mass disorders personnel front calculation. PMID- 26513859 TI - [The value of surgical experience gained during the Great Patriotic War for the modern military surgery]. AB - The surgical experience gained during the Great Patriotic War (1941-1945) is a basis of the modern Russian military surgery, which allows providing any options for surgical care to the wounded. The article describes the main achievements of the military surgeons in our country during the Great Patriotic War, which helped the Soviet (Russian) military field surgery to achieve a leading position in the world of military medicine. The role of the united martial medical doctrine, three editions of "Guidelines for the military surgery", the qualified surgical assistance as a mean that helped to deliver surgical care to the wounded, the introduction of specialized medical care, technology development of medical triage, as well as the origins of the tactics of a multi-stage surgical treatment of combat trauma and special treatment of minimally wounded during the war. The problems in establishing registers of combat injuries. and training military surgeons are analysed. PMID- 26513860 TI - [The historical experience of therapeutic service in the Army and Navy during the Great Patriotic War]. AB - The author presents the experience of therapeutic services of the army and navy during the Great Patriotic War (1941-1945) and its importance for the present. This experience became a-general methodological framework-for the development of principles for the organization of work of military physicians in a modern warfare and the application of new weapons. The history of development, aims and objectives of the new section of Military Medicine--the Military Field Therapy as a unified system of organization and delivery of health care to servicemen based on the principles of a unified military field medical doctrine. A problem of organization of new health facilities (hospitals, hospital databases), their acquisition of trained personnel, especially the structure of internal medicine in the war years, the treatment and the early rehabilitation of wounded and sick, between the military and civilian medical institutions-is highlighted. There is an information that 90.6%, or more than 6.5 million soldiers and officers who were treated in hospitals with various diseases, were returned to duty. The experience of the medical service in World War II and the actual demand and is now planning for a package of measures aimed at further improvement of the health status of military-personnel. PMID- 26513861 TI - [A "difficult" pneumonia: problems of differential diagnosis]. AB - There is a significant number of diseases that occur in the guise of community acquired pneumonia (CAP), so the progressive course, slowly allowed or unresolved CAP search for an alternative disease becomes crucial. In more than 20% of patients with the syndrome of "protracted" pneumonia alternative diagnosis are established. List of the main pathological processes occurring under the guise of pneumonia include: infiltrative pulmonary tuberculosis, acute interstitial pneumonia, acute eosinophilic pneumonia, thromboembolism, pulmonary artery branches, systemic vasculitis, and a number. of other lung diseases. This publication attempts to organize a brief series of problems that practicing physicians often face in the management of patients with "difficult" pneumonia. PMID- 26513862 TI - [The modern state and improvement prospects of community-acquired pneumonia and pulmonary tuberculosis differential diagnostics]. AB - The current article is dedicated to the modem state and improvement prospects of community-acquired pneumonia and pulmonary tuberculosis differential diagnostics. According to the official domestic statistics pulmonary tuberculosis continues to be a serious problem for the Russian Federation. One of the tuberculosis prevention most important factors is its early diagnostics. Unrecognized pulmonary tuberculosis is the leading factor of the in-hospital tuberculosis dissemination. On the basis of the current international and domestic guidelines it is shown that in order to improve the community-acquired pneumonia and pulmonary tuberculosis differential diagnostics it is necessary to introduce mandatory sputum specimens light-emitting diode microscopy and Xpert-testing of all patients admitted with pulmonary tuberculosis suspecion with airspace opacity/consolidation on chest x-ray as well as their isolation until tuberculosis exclusion. PMID- 26513863 TI - [Disease control in the Red Army during the final stages of the Great Patriotic War]. AB - Forms and methods of disease, control in troops were fully developed during the Great Patriotic War 1941-1945 years. An improvement of anti-epidemic organization in the Red Army was based on military medical doctrine, which demanded united views on methods of disease prevention and in accordance with the 'main tasks of medical support of the army, including prevention of epidemic outbreaks in the army. Disease control system in the Red Army during the war was a series of targeted, science-based and proved by military practice measures .aimed at both the prevention and the immediate elimination of epidemic diseases. when they occur. The questions of disease control forces in the final stage of the Great Patriotic War (January 1944 - May 1945). Depending on the progress of the war and the conditions of the fighting, given the period laid down in the principles of disease control of military operations, discussed aspects of the organization of sanitary-epidemiological (preventive) measures in the armed forces. PMID- 26513864 TI - [About experience of medidine of the Navy during the Great Patriotic War]. AB - The article is devoted activity of the Medical Service of the Navy during the Great Patriotic War. During the war the Navy has performed as an integral part of the Armed Forces, played a major role in the defensive and offensive operations. From the first days of the war medical service fleet faced extreme difficulties, to demand from the medical staff of hard work. During the war many problems of medical support for combat operations of the Navy were successfully solved. It was also important to solve complex problems in organizing and conducting medical evacuations via sea. A great attention during: the war was played to the search for optimal system medical evacuation support of naval forces. PMID- 26513865 TI - [The contributin of medical supply experts into military health care during the Great Patriotic War]. AB - During the Great Patriotic War edical supply experts to solve complex problems for the "smooth and full achievement of medical supplies of the army, the development of official documents, creation of new samples of complete- standard issue equipment, ambulance and medical equipment. The experience gained on the battlefield and during the post-war period, allowed progressively improving the functioning of. the medical supply troops (forces), successfully and consistently carried out in the framework of its organizational planning and other activities. PMID- 26513866 TI - [The Military Medical Academy during the Great Patriotic War]. AB - The article is devoted to the 70th anniversary of Victory in the Great Patriotic War of 1941-1945. Presented the contribution of the"Military Medical Academy. Examined the activities of the academy and the fulfillment of its employees on the eve of the war, the conditions under which employees had to work in the first months of the war in Leningrad. Described the evacuation of the Academy to the rear of the' country and especially educational, scientific and practical activities of employees Academy in Samarkand; activities clinics Academy remaining in the besieged Leningrad; radical reorganization of the Academy during the war. Presented briefly the history of creation of command and the Medical Faculty. Paying tribute to the faculty of the Academy in the field of research, teaching activities and practical work in the army. PMID- 26513867 TI - [An activity of forensic services during the Great Patriotic War: events, facts, people]. AB - This article was prepared for the 70th anniversary of the victory in the Great Patriotic War of 1941-1945. Provides information about the historical aspects of the formation of a military forensics in the early years of the war, the creation in 1943 and in the subsequent operation of the war years forensics as an independent service in the system of military medicine. PMID- 26513868 TI - [Unique exhibits and collections dedicated to the Great patriotic War in funds of the Military-medical museum]. AB - The Military Medical Museum, where concentrated materials reflecting the multifaceted activities of the medical service at the front of the bloodiest war in human history, was established in the midst of the Great Patriotic War. For targeted collection of materials were formed special front brigades, which included artists, photographers, a pathologist, a spokesman for the museum. Thanks to their work, the museum has a collection of unique materials--genuine evidence of war, reflecting all aspects of the health departments of fronts, armies, parts and cities in the form of drawings, products, models, models, photographs, charts, medical supplies, documents, etc. On the basis of materials of the museum was prepared 35-volume work < 0.05). CONCLUSION: The results showed that maspin gene can significantly inhibit human cervical SCC SiHa cell proliferation and effectively slow cancer growth. Maspin may be a new molecular target in the gene therapy of human cervical SCC. PMID- 26513879 TI - Extracellular matrix metalloproteinase inducer (EMMPRIN) remodels the extracellular matrix through enhancing matrix metalloproteinases (MMPs) and inhibiting tissue inhibitors of MMPs expression in HPV-positive cervical cancer cells. AB - PUPOSE OF INVESTIGATION: To study the expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), and tissue inhibitors of MMP (TIMPs) in uterine cervical cancer cell lines in vitro. MATERIALS AND METHODS: EMMPRIN, MMPs, and TIMPs expression were assessed by Western blot and real-time RT-PCR from cervical carcinoma SiHa, HeLa, and C33-A cells. RESULTS: EMMPRIN recombinant significantly increased MMP-2, MMP-9 protein and mRNA expression in SiHa and Hela cells, but not in C33-A cells by Western blot analysis and real-time RT-PCR. EMMPRIN recombinant significantly inhibited TIMP-1 protein and mRNA levels in SiHa and Hela cells, but not in C33-A cells. There was no difference on the TIMP-2 expression in those cells with the treatment of EMMPRIN recombinant. EMMPRIN RNAi decreased MMP-2 and MMP-9 and increased TIMP-1 expression in SiHa and HeLa cells, but not in C33-A cells. There was no change on the expression of TIMP-2 mRNA levels in SiHa, HeLa and C33-A cells transfected with siEMMPRIN. CONCLUSION: EMMPRIN may induce MMP-2 and MMP-9, and downregulate TIMP-1 in HPV-positive cervical cancer cells in vitro. PMID- 26513880 TI - Association of EBV and HPV co-infection with the development of cervical cancer in ethnic Uyghur women. AB - OBJECTIVE: Study on the role of Epstein-Barr virus (EBV) and human papillomavirus (HPV) infection in the development of cervical cancer. MATERIALS AND METHODS: We collected 178 cases of cervical tissue specimens of Uyghur women with cervicitis, cervical intraepithelial neoplasia (CIN I, CIN II-III), and cervical squamous cell carcinoma (CSCC). EBV- and HPV-DNA were detected by PCR of tissue DNA. EBV protein expression was checked by immunohistochemistry. RESULTS: HPV-DNA was detectable in 2.5, 12.5, 68.0, and 96.4% of cases of cervicitis, CIN I, CIN II III, and cervical cancer, respectively. For EBV-DNA, these numbers were 0, 3.1, 28.0, and 69.6%. There was a significant difference between the groups of cervicitis, CIN II-III, and cancer with respect to both HPV and EBV positivity rates (p < 0.05). Further analysis indicated that cervical lesion pathogenesis was not only accompanied by a gradually increasing rate of HPV or EBV-DNA alone, but also by an increasing rate of HPV-EBV dual infection (r = 0.46; p < 0.0 1). EBV protein expression was positive in 89.7% of EBV-DNA positive cases (34/39) and 6% of EBV-DNA negative cases (1/17). CONCLUSION: Cervical cancer development and progression may be closely associated with the dual-infection by HPV and EBV. PMID- 26513881 TI - Human papillomavirus effect on the development of endometrial polyps. AB - AIM: Although the association of human papillomavirus (HPV) with warts arising in different parts of the human body has been well-demonstrated, the association of HPV with endometrial polyps has never been studied in the literature up to now. MATERIALS AND METHODS: Detection of the HPV DNA was carried out by using 13 high risk HPV real-time PCR Kit and five low-risk HPV real-time PCR Kit. RESULTS: Among 50 endometrial polyp samples, one endometrial polyp sample revealed a positive result for the presence of HPV type 18. CONCLUSIONS: This first study in the medical literature investigating the possible effect of HPV on the development of endometrial polyps has demonstrated that HPV might have a role in the development of some of the endometrial polyps. If the present authors' hypothesis that endometrial polyps caused by carcinogenic HPV types are prone to proceed to endometrial cancer if left untreated is correct, HPV vaccine has a potential to prevent development of at least some of the endometrial polyps and endometrial cancers. PMID- 26513882 TI - Modified radical vaginal hysterectomy for cervical cancer treatment. AB - OBJECTIVES: The aim of this study was to modify vaginal radical hysterectomy (VRH), design a series of surgical instruments specialised for this procedure, and to study the feasibility, morbidity, and outcome of cervical cancer patients treated with modified laparoscopic-assisted radical vaginal hysterectomy (LARVH). MATERIALS AND METHODS: A total of 86 patients with early-stage cervical cancer (IB 1-IAl) underwent modified VRH and laparoscopic pelvic lymphadenectomy and para-aortic lymphadenectomy. Special instruments and modified procedures were used in VRH. Data were collected on operating time, blood loss, ureter separation time, nodal count, hospital stay, and complication recurrence and survival rates. RESULTS: All patients successfully completed LARVH. Median operating time was 238 minutes, mean blood loss was 283 ml, median time for ureter separation was 18.5 minutes, median time to post-operative exhaustion was 23 hours, urine recovery was 10.3 days, and median hospital stay was 9.2 days. On average, 23.2 lymph nodes were harvested. Except for one case of left internal iliac vein with intraoperative and postoperative complications, no other major complications occurred, particularly no bladder and ureter injury. Surgical margins were negative in all cases. After median follow-up of 46 months, recurrence rate and overall survival for 84 patients were 3.57% and 97.62%, respectively. DISCUSSION: Modified VRH with laparoscopic pelvic lymphadenectomy is an oncologically valid alternative for early stage cervical cancer treatment with minimal intraoperative and postoperative complications. The modification of this procedure and special instruments can enhance the feasibility and the safety of treatment. PMID- 26513883 TI - New method: Are tumor markers in vaginal-washing fluid significant in the diagnosis of primary ovarian carcinoma? AB - OBJECTIVE: Ovarian cancer is the seventh most common cancer in women worldwide, with nearly a quarter of a million women diagnosed every year. The serum tumor markers cancer antigens CA 125, CA 19-9, and carcinoembryonic antigen (CEA) are potentially of clinical value for the diagnosis of ovarian cancer. A diagnostic tool that is noninvasive, simple to perform, and specific is needed to predict primary ovarian cancer. The purpose of this study was to evaluate the diagnostic sensivitity and specificity of vaginal-washing tumor markers CA 125, CA 19-9, and CEA for diagnosis of primary ovarian cancer. MATERIALS AND METHODS: In the current prospective study, 30 patients with advanced primary ovarian cancer and 30 patients with benign ovarian cysts were enrolled. The vaginal-washing fluid samples were obtained the day before surgery and were immediately centrifuged and stored at -80 degrees C until analysis. Measurements of CA 125, CA 19-9, and CEA were determined using fully-automated chemiluminescent microparticle immunoassays. RESULTS: The vaginal fluid concentrations of CA 125, CA 19-9, and CEA in patients with primary ovarian carcinoma were significantly higher (p < 0.001) compared to those in patients with benign adnexal masses (p < 0.001). In the ROC curve analysis, the optimal cut-off values for the detection of primary ovarian cancer were >295 for CA 125 (p < 0.001), > 101 for CA 19-9 (p < 0.001), and >135 for CEA (p < 0.001). CONCLUSION: Vaginal-washing tumor markers CA 125, CA 19-9, and CEA are simple, noninvasive, and reliable diagnostic tests for the detection of primary ovarian cancer. PMID- 26513884 TI - Human papillomavirus infection among Uyghur women with cervical intraepithelial neoplasia in Xinjiang area. AB - OBJECTIVE: To obtain the baseline data of Uyghur women for human papillomavirus (HPV) vaccination in Xinjiang. MATERIALS AND METHODS: The authors analyzed the infection and distribution characteristics of HPV genotypes in genital tracts among Uyghur women with cervical intraepithelial neoplasia (CIN) in Urumqi of Xinjiang. A total of 1,431 eligible cases involved in this trial. All cervical samples from these patients were detected for HPV genotype. RESULTS: High-risk HPV was identified in 24.7% of 979 histologically confirmed normal samples and 89.2% of 452 samples with CIN (p < 0.05). The prevalence of one single high-risk type, low-risk type, and multiple HPV types were 74.6%, 10.4%, and 4.2%, respectively. A single high risk HPV infection progressively increased with the severity of cervical lesions significantly (chi2 = 31.53, p < 0.01). While interestingly multiple infection and single low risk HPV infection were decreased with the severity of cervical lesions, and there was significant difference chi2 = 6.44, p <0.05; chi2 = 4.85, p < 0.05). The major prevalent high-risk HPV genotypes in 346 samples of CIN II-III were HPV-16, -58, -31, -33, -68,-18,-45, and -39. The comparison of HPV genotype distributions between normal cytology and CIN II-III was analyzed. The estimated risks for progression from viral infection to CIN II-III was highest in HPV-33 (prevalence ratio (PR), 2.62), followed by HPV-31 (2.27), HPV-16 (1.92), HPV-58 (1.62), HPV-18 (1.51), HPV-68 (1.05), and HPV-39 (1.05), suggesting that the six genotypes of HPV-31, -16, -58, -18, -68, and -39 (PR > 1) are higher-risk HPV types in Uyghur women with CIN in Urumqi of Xinjiang. There was no association between multiple infection and cervical lesion progression (0.31, PR < 1). CONCLUSION: Except for the common HPV-16, -58, -31, 33, -18 in Xinjiang, HPV-68 and HPV-39 may be the oncogenic subtypes to Uyghur female with CIN in Xinjiang. Distinguishing these HPV subtypes may have implications for future cervical screening strategies and vaccine implementation. Multiple infections were not association with an increased risk of high-grade cervical neoplasia. PMID- 26513885 TI - Primary HPV test screening in cervical cancer: a two-year experience of a single screening center in Latina (Italy). AB - OBJECTIVE: The aim of this study was to evaluate the effect and performance of the new algorithm in cervical cancer screening program in two years' experience of Latina (Italy). MATERIALS AND MTHODS: The female population was divided into two groups, the first group was referred to PAP test and the second one to hr-HPV test according to national guidelines. RESULTS: In two years the participation mean rate increased among women aged 35-64 compared to women aged 25-34. The primary PAP test positive rate and hr-HPV test positive rate were 4.0% and 5.2%, respectively. The PAP test positive rate among hr-HPV+ women decreased from 2012 to 2013. Women with hr-HPV+/PAP+ were referred immediately to colposcopy and this rate was 1.2%. The predictive positive value for CIN2+ to colposcopy was 10.9% in 2012 and 9.1% in 2013, while the detection rate for CIN2+ was 1.6% in 2012 and 1.4% in 2013. CONCLUSION: The stratification of the female population leads to a decreased inappropriate therapeutic path while the combination of hr-HPV test with PAP test in woman aged 35-64 lets obtain high levels specificity and sensitivity results. PMID- 26513886 TI - DVP parametric imaging for characterizing ovarian masses in contrast-enhanced ultrasound. AB - AIM: To evaluate whether parametric imaging with contrast-enhanced ultrasound is an approach capable of for the differential diagnosis of ovarian masses. MATERIALS AND METHODS: The authors analysed 50 cases of ovarian masses by routine ultrasound and contrast-enhanced ultrasound with a new dedicated parametric image processing software-Sonoliver. The angiogenesis and blood perfusion mode on a digital video recorder were recorded and the morphological characteristics of time-intensity curve (TIC) and dynamic vascular pattern (DVP) curve were subsequently described. The quantity factor, including time to peak (TTP), maximum intensity (IMAX), rise time, (RT), mean transit time (mTT), generated by Sonoliver software were compared in both histological gradings. RESULTS: There were 24 cases (86%) displaying mainly hypo-enhanced with blue imaging in those with benign masses and 15 cases (68%) displaying mainly hyper-enhanced imaging with red in those with malignant masses. The difference was statistically significant (p < 0.05). DVP curves were unipolar below the baseline in 23 cases (82%) of benign masses and unipolar above the baseline in 15 cases (68%) of malignant masses. IMAX, TTP, and mTT were all significantly higher in those with malignant masses than those with benign ones (all p < 0.05), but, no statistical difference in the RT between the two groups was found (p > 0.05). CONCLUSIONS: According to the results, DVP parametric imaging is a new approach capable of differential diagnoses of overian masses with contrast-enhanced ultrasound. PMID- 26513887 TI - Assessment of primary radical hysterectomy and neoadjuvant chemotherapy followed by radical hysterectomy in Stage IB2, IIA bulky cervical cancer. AB - OBJECTIVE: Uncertainty concerning the treatment of Stage IB2-IIA (bulky) cervical cancer is still continuing. In this study, an analysis of Stage IB2-IIA (bulky) cervical cancer was performed. The efficacy of primary radical surgery and neoadjuvant chemotherapy followed by a radical surgery was investigated. MATERIALS AND METHODS: Medical data of 50 patients who were diagnosed with Stage 1B2-IIA (bulky) cervical cancer and treated between 2002-2009 were retrospectively assessed. In the radical surgery group, radical hysterectomy + bilateral pelvic + para-aortic lymphadenectomy were performed. In the neoadjuvant chemotherapy group, a combination of cisplatin/topotecan or paclitaxel/carboplatin was given to the patients and then radical surgery was performed. Each group was evaluated individually. Prognostic factors were determined and survival rates were compared between the groups. Ap value was taken < 0.05 for the statistical significance level for all results. RESULTS: Radical surgery after neoadjuvant chemotherapy was performed in 21 and primary radical surgery in 29 patients. Median follow-up time was 36.0 +/- 14.0 months. Average of the tumor size before treatment was 50.2 +/- 7.6 mm. In the radical surgery after neoadjuvant chemotherapy group, lymphovascular space invasion (LVSI) and tumor size (before and after treatment) were determined to be significant factors for each of disease-free survival (DFS) and overall survival (OS). On multivariate analysis, tumor size (before treatment) was found to be an independent prognostic factor for both of DFS (p = 0.006) and OS (p = 0.010). No significant difference in survival periods was observed among the groups. CONCLUSION: There was no significant superiority among the two treatment options. Nonetheless, further studies are needed to compare the multimodal approaches in these stages of cervical cancer. PMID- 26513888 TI - The presence of advanced lesions and associating risk factors for advanced cervical carcinoma in patients with atypical sguamous cells of undetermined significance. AB - PURPOSE OF INVESTIGATION: To characterize histopathological status, high-risk human papillomavirus (hr-HPV) infection status, and associated risk factors in patients with atypical squamous cells of undetermined significance (ASCUS). MATERIALS AND METHODS: Cervical biopsies obtained from 130 ASCUS patients were subjected to histopathological examination and hr-HPV testing. Associations between advanced lesions and hr-HPV load or age were analyzed, and the confounding factors for high-grade cervical lesions were identified. RESULTS: Cervical biopsies from ASCUS patients had a wide range of pathological states, ranging from normal to invasive cervical carcinoma. High-risk HPV infection was significantly associated with advanced cervical lesions in ASCUS patients; hr-HPV infection and the number of gestations were risk factors for developing advanced cervical disease. CONCLUSIONS: A significant portion of ASCUS patients harbor advanced cervical lesions. The number of gestations and hr-HPV infection can increase the risk of developing advanced cervical lesions in ASCUS patients. PMID- 26513889 TI - The construction of cDNA library and the screening of related antigen of ascitic tumor cells of ovarian cancer. AB - OBJECTIVE: To construct the cDNA library of the ascites tumor cells of ovarian cancer, which can be used to screen the related antigen for the early diagnosis of ovarian cancer and therapeutic targets of immune treatment. MATERIALS AND METHODS: Four cases of ovarian serous cystadenocarcinoma, two cases of ovarian mucinous cystadenocarcinoma, and two cases of ovarian endometrial carcinoma in patients with ascitic tumor cells which were used to construct the cDNA library. To screen the ovarian cancer antigen gene, evaluate the enzyme, and analyze nucleotide sequence, serological analysis of recombinant tumor cDNA expression libraries (SEREX) and suppression subtractive hybridization technique (SSH) techniques were utilized. The detection method of recombinant expression-based serological mini-arrays (SMARTA) was used to detect the ovarian cancer antigen and the positive reaction of 105 cases of ovarian cancer patients and 105 normal women's autoantibodies correspondingly in serum. RESULTS: After two rounds of serologic screening and glycosides sequencing analysis, 59 candidates of ovarian cancer antigen gene fragments were finally identified, which corresponded to 50 genes. They were then divided into six categories: (1) the homologous genes which related to the known ovarian cancer genes, such as BARD 1 gene, etc; (2) the homologous genes which were associated with other tumors, such as TM4SFI gene, etc; (3) the genes which were expressed in a special organization, such as ILF3, FXR1 gene, etc; (4) the genes which were the same with some protein genes of special function, such as TIZ, ClD gene; (5) the homologous genes which possessed the same source with embryonic genes, such as PKHD1 gene, etc; (6) the remaining genes were the unknown genes without the homologous sequence in the gene pool, such as OV-189 genes. CONCLUSION: SEREX technology combined with SSH method is an effective research strategy which can filter tumor antigen with high specific character; the corresponding autoantibodies of TM4SFl, ClD, TIZ, BARDI, FXRI, and OV-189 gene's recombinant antigen in serum can be regarded as the biomarkers which are used to diagnose ovarian cancer. The combination of multiple antigen detection can improve diagnostic efficiency. PMID- 26513890 TI - Do we understand the pathophysiology of endometrial cancer? AB - Endometrial carcinoma is the fourth most common cancer in U.K. women. Previous literature describes local, haematological or lymphatic dissemination to common sites including vaginal vault, lungs, liver, bones and brain. The authors present two unusual cases of endometrial cancer metastases to the psoas major muscle and laparoscopic port sites. Case 1 involves a 71-year-old female who underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and peritoneal washings (TAH, BSO, PW) for Grade 1 endometrial cancer, Stage lB. Three years later she represented with lower back and right hip pain, with MRI imaging revealing psoas muscle metastases. Case 2 describes a 60-year-old female who underwent laparoscopic-assisted vaginal hysterectomy (LAVH), BSO+ PW for Grade 1 endometrial cancer, Stage 1B. Three years postoperatively she presented with a lateral abdominal mass overlying the laparoscopic port site scar, which was Grade 1 endometrial cancer on biopsy. These rare metastatic locations question our traditional understanding of the pathophysiology of endometrial carcinoma. PMID- 26513891 TI - Endometrial cancer in unicornuate uterus: a case report. AB - PURPOSE OF INVESTIGATION: Miillerian anomalies have not been implicated as a significant risk factor for the development of cervical, uterine, and ovarian cancers; in the present literature, there are only a few reports of endometrial cancer arising in patients with Miillerian abnormalities. To the best of the authors' knowledge, this is the first reported case of endometrial cancer arising in a patient with unicornuate uterus. CASE REPORT: A 69-year-old Caucasian woman underwent clinical examination and office hysteroscopy with endometrial biopsy because of abnormal post-menopausal bleeding. The diagnosis was endometrial cancer in unicornuate uterus, hence the patient underwent total hysterectomy with pelvic lymphadenectomy. CONCLUSION: Uterine malformations and genetic disorders may cause a delayed diagnosis of gynaecological cancers. Gynaecological examination in asymptomatic patients and differential diagnosis in abnormal uterine bleeding patients should be considered. PMID- 26513892 TI - Isolated brain metastasis from uterine cervical cancer: a case report and review of literature. AB - The metastasis of cervical cancer to the brain is usually associated with systemic involvement such as lungs, liver and bones, and isolated brain metastasis is very rare because the primary mechanism of spread is by hematogenous dissemination of tumor cells. Although a few cases of isolated brain metastasis from cervical cancer have been reported, isolated brain metastasis from neuroendocrine cell carcinoma, which is characterized with aggressive and early metastatic features, has never been reported. A 44-year-old woman with cervical cancer composed of large neuroendocrine cell carcinoma was diagnosed with isolated brain metastasis at eight months after the definitive treatment with surgery followed by adjuvant chemotherapy. Careful evaluation would be needed during follow-up for the patients with cervical cancer with aggressive histologic type. PMID- 26513893 TI - Granular cells tumor of the vulva: an exceptional entity. AB - INTRODUCTION: Granular cells tumor (GCT) is a rare tumor that develops on skin and soft tissues. Only 1-2% of these tumors present malignant behavior. MATERIAL AND METHODS: The authors report three cases of GCT and review the management of these tumors. CASE REPORT: The first case is a 73-year-old woman who was diagnosed with an atypical GCT. She was treated with local excision and then presented a local recurrence 21 months after the surgery. The other two cases are 60- and 58-year-old women diagnosed with a benign GCT. They were treated with single excision; both patients underwent second surgery due to margin affectation. CONCLUSION: Management of GCT is not clear nowadays. The careful selection of patients with poor prognostic factors is very important. Follow-up for early diagnosis of local recurrence and metastases of these tumors is of utmost importance. PMID- 26513894 TI - Primary malignant melanoma of the cervix: a case report. AB - Primary malignant melanomas of the uterine cervix are extremely rare tumors. Diagnosis is confirmed by immunohistochemical methods and by exclusion of other primary sites of melanoma. The treatment of this condition is not yet standardized and the overall prognosis of these patients is very poor. The authors report a case of primary malignant melanoma of the uterine cervix. PMID- 26513895 TI - Aggressive angiomyxoma of the pelvis: a series of four cases and literature review. AB - The purpose of this study was to evaluate the value of CT and MRI in aggressive angiomyxoma (AAM) of the pelvis. A series of four cases from three institutions are reviewed. Among the four cases, three were initially misdiagnosed, and local recurrence necessitated reoperation or angiographic embolization. The fourth case, with accurate preoperative diagnosis, was followed with no recurrence. CT and MR imaging demonstrated a well-defined mass, which displaced adjacent structures. Attenuation of the mass was less than that of muscle on unenhanced CT, and a swirling or layering internal architecture was found using both enhanced CT and TI-weighted MR imaging. In one patient, a layering internal architecture was seen on unenhanced CT images. MRI demonstrated the relation of the tumor to the pelvic floor better than CT. The authors concluded that both CT and MRI show the characteristic imaging pattern and trans-diaphragmatic extent of these tumors, and the diagnosis should be considered in any young woman presenting with a well-defined mass arising from the pelvis or perineum. PMID- 26513896 TI - A successful management of a giant mucinous ovarian tumor with intraoperative controlled fluid aspiration. AB - BACKGROUND: The aim of this article was to present management of a giant ovarian mass. CASE REPORT: A 61-year-old patient was admitted with compliants of abdominal swelling and dyspnea. Ultrasound revealed a giant ovarian mass with dimesnions 47x43x30 cm. The patient underwent laparatomy and the cyst's content was aspirated before total cyst excision. The total weight of the mass was calculated to be 42.5 kg. Postoperatively, the patient was discharged on her postoperative seventh day. CONCLUSION: Giant ovarian cysts can be managed with controlled aspiration before total cyst excision. PMID- 26513897 TI - Carcinosarcoma of the fallopian tube with disappearance of carcinoma cells by neoadjuvant chemotherapy: case study. AB - The authors report a case of carcinosarcoma (CS) of the fimbria of the fallopian tube in which carcinoma cells disappeared with neoadjuvant chemotherapy (NAC). A 74-year-old woman visited the present hospital with a large pelvic mass and pleural effusion. A magnetic resonance image of the tumor was highly suggestive of ovarian carcinoma. Due to the presence of both serous.adenocarcinoma cells in pleural effusion and pulmonary thrombosis, the patient was given NAC consisting of carboplatin plus paclitaxel (TC) and anticoagulant therapy with warfarin potassium. With six courses of NAC, the pleural effusion and pulmonary thrombosis disappeared, and the tumor decreased 36.2% in greatest diameter. Maximum debulking surgery was then performed. The tumor was found to be located in the fimbria of the right fallopian tube. Hysterectomy and bilateral salpingo oophorectomy were performed, and histologic examination revealed chondrosarcoma with the presence of necrotic epithelial cells. The necrotic areas were interspersed with papillary structures, and immunohistochemical study showed positivity for CK7 and negativity for CK20, p53, and estrogen receptor (ER), indicating serous adenocarcinoma. Thus, heterologous CS with disappearance of viable carcinoma cells by NAC was diagnosed. The patient was given adjuvant chemotherapy consisting of three courses of TC, and there has been no evidence of disease for 20 months. The authors' experience in this case of gynecologic CS indicates that a serous adenocarcinomatous component of tubal CS can be well cured by TC-based NAC. PMID- 26513898 TI - A COMPLICATED CASE OF STRONGYLOIDIASIS PRESENTING WITH INTESTINAL LYMPHADENOPATHY OBSTRUCTION: MOLECULAR IDENTIFICATION. AB - Strongyloides stercoralis is an intestinal nematode, which can cause complications in immune-compromised hosts. We present a rare case of intestinal obstruction due to mesenteric lymphadenopathy, a complication due to strongyloidiasis, developing in a male subject chronically receiving corticosteroid for pemphigus vulgaris. DNA was extracted from biopsied lymph nodes containing nematode larvae and PCR amplified using primers specific for S. stercoralis 18S rDNA. Nucleotide sequence of the amplicon showed identity with that of S. stercoralis deposited in GenBank. To the best of our knowledge, this is the first report of a diagnosis of strongyloidiasis from biopsied samples using molecular techniques. PMID- 26513899 TI - PEDIATRIC OCULAR TOXOCARIASIS IN JIANGSU PROVINCE, EASTERN CHINA. AB - Ocular toxocariasis is caused by migration of a Toxocara larva through the posterior eye. We report the first case of pediatric ocular toxocariasis caused by T. canis in Jiangsu Province, eastern China. A 6-year-old girl presented to Suzhou Municipal Children's Hospital with a complaint of right eye redness, minimal white discharge, no photophobia, eye pain, visual impairment, fever or arthralgia. She was initially diagnosed as having conjunctivitis; however, a 2 month treatment with lomefloxacin 0.3% eye drops gave no improvements. The diagnosis was made based on medical history (contact with dogs), clinical features and detection of T. canis IgG antibodies with an enzyme-linked immunosorbent assay (ELISA). Anthelmintic therapy with albendazole in combination with prednisolone resulted in improvement of the ocular symptoms. Ocular toxocariasis is rarely reported in China. However, the rapid economic development in China, could mean an increase in pet dogs with the potential increased risk of contracting toxocariasis if no control measures are taken. Disposal of pet litter, deworming of infected pets, complete cooking of meats, thorough rinsing of fruits and vegetables, and good hand-washing may help prevent human infections. Ocular toxocariasis should be considered in the differential diagnosis of patients with conjunctivitis that does not resolve with treatment. PMID- 26513900 TI - OPHTHALMIC MANIFESTATIONS OF PAEDERUS DERMATITIS. AB - A 30-year-old Chinese female presented with progressive periorbital swelling of unknown cause and redness of her left eye. She was given an antibiotic eyedrop and oral cloxacillin to treat periorbital cellulitis. The clinical picture did not improve and she returned with swelling of the fellow eye. We stopped the medication and sent her to a dermatologist because of the abnormal periorbital skin pattern. Her diagnosis was Paederus dermatitis. Intramuscular dexamethasone was administered due to severe periorbital edema. The skin lesion was improved one week later. The ophthalmic manifestations of Paederus dermatitis are periorbital dermatitis, conjunctivitis and persistent epithelial defects. The challenge in diagnosis of this condition is that it can mimic other diseases, such as infectious periorbital cellulitis and Herpes viral infection. Therefore, a clear appreciation of the clinical manifestations will lead us to the proper management of the condition and minimize complications. PMID- 26513901 TI - COMPARISON OF THAI GOVERNMENT MANUFACTURED TENOFOVIR (TENOFOVIR GPO300) WITH PRIVATELY MANUFACTURED TENOFOVIR (VIREAD) USED ALONG WITH LAMIVUDINE AND EFAVIRENZ TO TREAT THAI HIV PATIENTS. AB - The Thai Government Pharmaceutical Organization (GPO) has produced a nucleotide reverse transcriptase inhibitor, tenofovir disoproxil fumarate (Tenofovir GPO300). No clinical trial to date has compared plasma tenofovir concentrations, renal function, and treatment responses in HIV-infected patients who received Teno- fovir GPO300 versus Viread (original tenofovir) as part of an antiretroviral regimen. We studied 129 antiretroviral treatment (ART)-naive HIV-1 infected patients who received an antiretroviral regimen of lamivudine, efavirenz and Tenofovir GPO300 (n = 65) or Viread (n = 64). We examined plasma tenofovir concentrations (12 hours after dosing), serum creatinine, estimated glomerular filtration rate (eGFR) using the Modification in Diet in Renal Disease (MDRD) study formula, fractional excretion of phosphate (FEphos), CD4 and plasma HIV-1 RNA levels at 12 weeks, and CD4 and plasma HIV-1 RNA levels at 24 weeks after initiating the drugs. At baseline, the mean +/- SD subject body weight was 54 +/- 10 kilograms and the mean +/- SD subject age was 37 +/- 8 years. At baseline, the median (IQR) CD4 count was 44 (18-120) cells/ mm3 and the median (IQR) HIV-1 RNA level was 5.8 log copies/ml. At baseline, the mean +/- SD eGFR was 134.8 +/- 43.6 ml/min/1.73 m2. The baseline values for the two groups were not significantly different from each other (p > 0.05). At 12 weeks, the mean +/- SD plasma tenofovir concentration was 106.9 +/- 41.5 ng/ml among the patients who received Tenofovir GPO300 and 100.7 +/- 49.4 ng/ml among those who received Viread (p = 0.437). At week 12, there were no differences between those who rceived Tenofovir GPO300 and Vilead in mean serum creatinine (0.78 vs 0.81 mg/dl, p = 0.283), mean eGFR (117.9 vs 109.1 ml/min/1.73 m2, p = 0.089), decline in eGFR from baseline ( 21.8 vs -20.6 ml/min/1.73 m2, p = 0.860) or mean FEphos (11.4 vs 11.2, p = 0.923). The median CD4 cell counts and number of patients with undetectable plasma HIV-1 RNA at week 24 were not significantly different (p > 0.05) between those who took Tenofovir GPO300 and Viread. In summary, plasma tenofovir concentrations, changes in renal function, urinary phosphate excretion and treatment responses were comparable between HIV-infected patients who received Tenofovir GPO300 and Viread-containing non-nucleoside reverse transcriptase regimens. PMID- 26513902 TI - ATYPICAL PRESENTATION OF RECURRENT VARICELLA ZOSTER VIRUS INFECTION: A CASE REPORT AND REVIEW OF THE LITERATURE. AB - Recurrent varicella infection is rare but has been reported in immunocompromised patients. We present a patient with atypical recurrent varicella infection who had disseminated central crusting papular lesions without dermatomal distribution. Serology showed previous varicella zoster virus (VZV) infection and the lesions were positive for VZV DNA, consistent with recurrent VZV infection. Atypical recurrent varicella infection is probably an under-recognized condition. VZV infection should be considered in the differential diagnosis of ecthyma-like lesions in an immunocompromised host. PMID- 26513903 TI - A PCR-BASED DETECTION OF BURKHOLDERIA PSEUDOMALLEI DIVERSITY USING MYOVIRIDAE PROPHAGE TYPING. AB - PCR-based detection of Myoviridae lysogenic phages in Burkholderia pseudomallei was developed using primers targeting K96243 prophage GI2, phiE12-2 and phi52237/phiX216. Investigation of 50 clinical and 50 environmental (soil) isolates revealed that K96243 prophage GI2 was the most common (48%) among the isolates, followed by phiE12-2 (38%) and phi52237/phiX216 (35%), with K96243 prophage GI2 being significantly more frequent in soil (64%) than clinical (32%) samples. Twenty-four percent of soil isolates contained all three prophage types, while clinical isolates harbored no more than two types. Although B. pseudomallei isolates from soil were found to be more diverse based on prophage typing, all isolates were equally susceptible to a battery of lytic phages (although to different extents), suggesting the possibility of using lytic phages to control environmental B. pseudomallei. PMID- 26513904 TI - THE CONTRIBUTION OF SOIL PHYSICOCHEMICAL PROPERTIES TO THE PRESENCE AND GENETIC DIVERSITY OF BURKHOLDERIA PSEUDOMALLEI. AB - Burkholderia pseudomallei (Bp), the causative agent of melioidosis, is unevenly distributed in the complex soil environment. Physicochemical factors in the soil have been reported to affect microbial communities in the soil. The effect of physicochemical factors on the number and diversity of organisms in the soil has not been reported. Twenty-five each B. pseudomallei-positive and -negative soil samples were collected from a melioidosis-endemic area. The amount of Bp in each soil sample was measured by culture and quantitative PCR (qPCR). The following physicochemical properties from each soil sample were measured: pH, total organic carbon (TOC), total nitrogen (TN), carbon to nitrogen ratio (C:N ratio), exchangeable calcium (EC) and extractable iron (EI). All the physico- chemical properties measured were significantly different between the Bp-positive and negative soil samples. The Bp-positive soil samples had lower C:N ratios and lower EC and a higher EI (p < 0.05) than the Bp-negative samples. The average pH was lower (3.7-5.0) in the Bp-negative samples. Among the Bp-positive soil samples, the EC was negatively correlated with the PCR copy number. The amount of bacteria detected with the qPCR method was higher than with the culture method, suggesting the presence of unculturable forms of bacteria that might re-grow when the environmental conditions was suitable. A total of 117 Bp isolates obtained from the soil samples were classified into 25 groups using BOX-PCR. The genetic diversity of Bp, did not correlate with the physicochemical factors investigated. A suitable pH range and C:N ratio may be important for the presence of Bp. The EI supports the needs and EC probably alters the growth of Bp. The genetic diversity of the bacteria was not influenced by the soil factors investigated in this study. This information shows the environment conducive to the growth of Bp. This gives us information about how to potentially control or decrease Bp in the soil in the future. PMID- 26513905 TI - EMERGENCY ROOM: AN UNRECOGNIZED SOURCE OF EXTENDED-SPECTRUM beta-LACTAMASE PRODUCING ESCHERICHIA COLI AND KLEBSIELLA PNEUMONIAE. AB - Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae are the leading causes of hospital-associated infections, but community-acquired cases are increasingly being reported. This study determined the prevalence of ESBL-producing E. coli and K. pneumoniae carriers, their bla genes and risk factors of 452 patients admitted to the emergency room (ER) of Ramathibodi Hospital, Mahidol University, Bangkok, Thailand between April and August 2011. Prevalence of ESBL-producing E. coli and K. pneumoniae from rectal swabs was 16.5% and 1.0%, respectively. Factors associated with ESBL-producing carriers were a previous history of hospital admission (p = 0.001) and visits to health care facilities (p = 0.002) during the previous 3 months. All ESBL producing isolates were susceptible to imipenem, meropenem and ertapenem. The majority (78%) of ESBL-producing E. coli isolates showed very high resistance to cefotaxime and ceftriaxone (MIC50 and MIC90 > 256 ug/ml). ESBL-producing E. coli harbored chromosomal blaTEM (96%), blaCTX-M (70%) and blaSHV (1%), while 8%, 73% and 3%, respectively, were located on plasmid. The prevalence of these genes in ESBL-producing K. pneumoniae was 75%, 50% and 25%, respectively on chromosome; and 100%, 25% and 50%, respectively on plasmid. Nucleotide sequence analysis revealed that these bla genes were of the type blaTEM-1' blaTEM-116' blaCTX-M-15' blaCTX-M-161' blaSHV-12, blaSHV-28 and blaSHV-148. Detailed epidemiologic and clinical characteristics of ER patients with history of prior hospital visits should be carried out to identify the ESBL-producing organisms they have acquired in order to institute appropriate treatment for these patients as well as control measures against further dissemination of these life-threatening organisms. PMID- 26513906 TI - DOUBLE-STEP MULTIPLEX REAL TIME PCR WITH MELTING CURVE ANALYSIS FOR DETECTION AND DIFFERENTIATION OF MYCOBACTERIA IN SPUTUM. AB - Mycobacterium tuberculosis (M. tb) is a causative agent of tuberculosis, a worldwide public health problem. In recent years, the incidence of human mycobacterial infection due to species other than M. tb has increased. However, the lack of specific, rapid, and inexpensive methods for identification of mycobacterial species remains a pressing problem. A diagnostic test was developed for mycobacterial strain differentiation utilizing a double-step multiplex real time PCR together with melting curve analysis for identifying and distinguishing among M. tb, M. bovis BCG, other members of M. tb. complex, M. avium, and non tuberculosis mycobacteria. The assay was tested using 167 clinical sputum samples in comparison with acid-fast staining and culturing. Using only the first step (step A) the assay achieved sensitivity and specificity of 81% and 95%, respectively. The detection limit was equivalent to 50 genome copies. PMID- 26513907 TI - DIFFERENCES OF MRI FEATURES BETWEEN TUBERCULOUS AND BACTERIAL SPONDYLITIS IN A TB ENDEMIC AREA. AB - Pyogenic and tuberculous spondylitis are common causes of infectious spondylitis. The purpose of this study was to determine the specific MRI findings that can differentiate these two types of infectious spondylitis. This study retrospectively analyzed MRIs in patients diagnosed with infectious spondylitis from January 1, 2005 to December 31, 2009. Tuberculous spondylitis was diagnosed by histopathological findings of caseous granuloma, while pyogenic spondylitis was diagnosed by positive cultures of tissue, fluid, or blood. Locations and extents of the lesions, and the findings using individual imaging criteria were recorded. Statistical analysis was performed with the Fisher's exact test. A significant difference was considered at.p < 0.05. During the study period, 33 patients met the criteria. Of those, 24 patients had tuberculous spondylitis and nine had pyogenic spondylitis. Two suggestive findings for tuberculous spondylitis were abscesses with thin and smooth walls (75% in tuberculous spondylitis vs 0% in pyogenic spondylitis, p < 0.001) and well-defined paraspinal soft tissue (66.7% in tuberculous vs 11.1% in pyogenic spondylitis, p = 0.007). These two MRI findings may be helpful for differentiating between tuberculous and pyogenic spondylitis. PMID- 26513908 TI - PRIMARY STERNAL TUBERCULOSIS: A CASE REPORT AND LITERATURE REVIEW. AB - Mycobacterium tuberculosis can infect multiple organs and may rarely cause osteomyelitis of the sternum. We report a patient with primary sternal tuberculosis who presented with a chest wall mass. A core needle biopsy confirmed the diagnosis-of tuberculosis. We review the literature regarding tuberculous osteomyelitis of the sternum. PMID- 26513909 TI - METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS FROM READY-TO-EAT FOODS IN A HOSPITAL CANTEEN, SOUTHERN THAILAND: VIRULENCE CHARACTERIZATION AND GENETIC RELATIONSHIP. AB - Due to the existence of sporadic cases caused by methicillin-resistant Staphylococcus aureus (MRSA) in Songklanagarind Hospital, Songkhla, southern Thailand where a canteen is located in close vicinity, this study investigated the presence of MRSA, including mecA-carrying S. aureus (MCSA), contamination in 105 ready-to-eat (RTE) food samples sold in this canteen. Coagulase-negative MRSA (MR-CoN) and coagulase-negative MCSA (MCSA-CoN) contaminations were observed in various RTE foods with unriped-papaya salad having significantly highest incidence of MCSA-CoN contamination (p < 0.05). The majority of MCSA-CoN isolates were resistant to clindamycin and fusidic acid. Two MCSA-CoN strains PSU172 and PSU180 were subsequently shown to be MR-CoN. Staphy- lococcal enterotoxins (SEs) carrying MCSA-CoN strain PSU109 was isolated from seasoned rice. The SE-carrying MCSA-CoN strain PSU109, MR-CoN strain PSU172 and MCSA-CoN strain PSU173 were able to survive in the acidic unriped-papaya salad sauce (pH 4.0-4.5) for up to 6 hours. Typing by pulsed-field gel electrophoresis revealed 80% genetic relatedness among MCSA-CoN strains from RTE food and clinical strains. This study suggests the plausibility of RTE foods sold in a hospital canteen as vehicles of hospital-acquired MR-CoN and of MCSA-CoN. PMID- 26513910 TI - PHENOTYPIC AND GENOTYPIC DETECTION OF ENTEROTOXINS, TOXIC SHOCK SYNDROME TOXIN-1 AND OF METHICILLIN RESISTANCE IN STAPHYLOCOCCUS AUREUS ISOLATED FROM RETAIL READY TO-EAT FOODS IN NORTHEASTERN THAILAND. AB - Toxigenic Staphylococcus aureus contamination of ready-to-eat (RTE) foods is a leading cause of foodborne illness in Thailand. From 151 RTE food samples randomly collected from food vendors and food shops in Khon Kaen municipality, Thailand and after culture-based identification of S. aureus isolates, pentaplex PCR was used for simultaneous detection of super-antigenic toxin (SE) genes (sea, seb, sec, sed and tst-1) and presence of their toxins by reversed passive latex agglutination assay. S. aureus was identified in 57 isolates, of which 60% and 25% was positive for presence of super-antigenic toxin genes and toxins, respectively; and among the former isolates sea was the most common (46%), as well as its product (SEA) (14%) among the latter group. Methicillin resistance S. aureus mecA was not found in any of the isolates using both PCR and disk diffusion methods. These results showed that pentaplex PCR is a useful tool for detection of SE-encoding genes in S. aureus isolates from RTE food. PMID- 26513911 TI - CHROMOBLASTOMYCOSIS MASQUERADING AS DERMATOPHYTOSIS, WITH THE DESCRIPTION OF A NEW OPPORTUNISTIC SPECIES. AB - An unusual case of chromoblastomycosis is reported, it resembled dermatophytosis, tinea faciei due to the presence of a well-demarcated scaly ery- thematous patch on the face. The patient was a 63-year-old farmer from central Thailand, who had the skin lesion for 10 years. Mycological and histopathologi- cal investigations of scales and skin biopsy specimen revealed a granulomatous infiltrate with sclerotic bodies, the hallmark of chromoblastomycosis. The infec- tion showed only localized superficial expansion with a scaly patch suggesting a new clinical type of the disease. The causative organism was identified by DNA sequencing as Rhinocladiella phaeophora. R.phaeophora originally was a saprophytic dematiaceous fungus recovered from maize field soil from Colombia. The case was unusual in its clinical presentation and this is the first case of chromoblastomycosis reported to be caused by a new opportunistic species of the genus Rhinocladiella. The disease was not responsive to itraconazole, but was later treated successfully with terbinafine. PMID- 26513912 TI - DETECTION OF DELETION alpha(+)-THALASSEMIA MUTATION [-alpha (3.7), -alpha (4.2)] BY QUANTITATIVE PCR ASSAY. AB - In Thailand, Hb H (alpha0(-thal/alpha(+)-thal) disease is highly prevalent. We designed 3 primer sets (A, B and C) to detect -alpha (3.7) and -alpha (4.2) deletion types of alpha(+)-thal by quantitative (q)PCR. The A and C primer sets were used to amplify DNA sequences at the 3' terminal regions of HBA2 and HBA1 gene, respectively, and the B primer set was used to amplify an upstream DNA sequence at the 5' flanking region of HBA1 gene. The relative quantities of the PCR products (based on threshold cycle (CT) values) of the 3 primer sets were calculated according to the equation R = 2-DeltaDeltaCT, and these values were used to distinguish between -alpha (3.7) and -alpha (4.2) deletion mutations. The type of alpha(+)-thal mutations was determined by calculating the difference between R (C-A) and R (C-B), yielding a value either of 0.5 or 1.0, which indicates the copy number of the target DNA compared with normal diploid control. Measured values that are close to 0.5 indicate there is a single allele of the target DNA. This method was applied to 250 DNA samples recruited for this study, and the R (C-A) and R (C-B) value determined for 185 cases of non alpha-thal was 1.03 +/- 0.04 and 0.95 +/- 0.08, respectively, for 41 cases of -alpha (3.7) alpha thal trait 0.49 +/- 0.04 and 0.45 +/- 0.04, respectively, and for 2 cases of alpha (4.2) alpha(+)-thal trait 0.5 +/- 0.1 and 1.01 +/- 0.06, respectively. The allele frequency of -alpha (3.7) and -alpha (4.2) mutation was 0.092 and 0.004, respectively. These results were in con- cordance with those obtained by conventional gap-PCR. The method described here is simple, accurate and feasible for screening of alpha(+)-thal carriers and should provide valuable information for genetic counselling of patients at risk of having a child with Hb H disease. PMID- 26513913 TI - PLASMA LEPTIN LEVELS AND A RESTRICTIVE LUNG IN OBESE THAI CHILDREN AND ADOLESCENTS. AB - Morbid obesity, the most significant risk factor for development of sev- eral respiratory diseases, is linked to decreased pulmonary function. The aim of this study was to determine the relationships between pulmonary function and plasma levels of homeostasis model assessment-insulin resistance (HOMA-IR), insulin, leptin, hs-CRP and fasting glucose. Values were measured in 39 Thai children and adolescents, divided into three groups according to lung function (forced expiratory volume in one second, FEV1); normal (Group A) FEV1 >= 80% (n = 19), obese normal (Group B) FEV1 >= 80% (n = 14) and obese (Group C) FEV1 < 80% (n = 6). Body mass index was highest in group C. Groups A and B were comparable for FEV1, forced vital capacity (FVC), maximal voluntary ventilation (MVV) and FEV1/FVC, whereas Group C exhibited significantly reduced FEV1, FVC and MVV but a normal FEV1/FVC ratio. All values except the FEV1/FVC ratio were significantly lower than in groups A and B. Group C had significantly higher levels of leptin, insulin, FG and HOMA-IR than Groups A and B (p < 0.001). There was a significant negative correlation between FEV1 and MVV with leptin, insulin and HOMA-IR, but not with high-sensitivity C-reactive protein (hs-CRP). We conclude that FEV1 is reduced in obese children and adolescents and inversely correlates with plasma leptin, insulin and HOMA-IR levels. We have shown that the most important factor in inducing a restrictive lung in these patients may be related to leptin status. PMID- 26513914 TI - DIFFERENCES IN MORTALITY BY EDUCATION LEVEL AMONG PATIENTS IN DIABETIC REGISTRY FOR THAILAND. AB - This study was conducted in order to determine the impact of education on mortality due cardiovascular, infectious and renal disease, and cancer among Thai diabetics using data from the Thailand diabetes registry cohort prospected and conducted between April 2003 and February 2006. The study population consisted of 9,370 registered diabetic patients attending ten diabetes clinics at tertiary medical centers in Bangkok and major provinces. The population was classified by education level: those who had not yet attained a bachelor's degree classified as having "lower education" (7,684: 82%) and those with a bachelor's degree or higher classified as having "higher education" (1,686:18%). The overall mortality rate among those in the higher education group was lower than those in the lower education group (8.9 vs 20.5 per 1,000 patient-years, respectively) with a hazard ratio (HR) of 0.43 (0.31-0.61). The higher education group also had lower mortality rates due to infectious disease [HR 0.10 (0.02-0.41)], renal disease [HR 0.24 (0.06-0.99)] and cardiovascular disease [HR 0.42 (0.22-0.80)]. There was no difference in cancer mortality between the two groups [HR 1.25 (0.74-2.11)]. PMID- 26513915 TI - HUMAN HEALTH EFFECTS FROM CADMIUM EXPOSURE: COMPARISON BETWEEN PERSONS LIVING IN CADMIUM-CONTAMINATED AND NON-CONTAMINATED AREAS IN NORTHWESTERN THAILAND. AB - Environmental cadmium contamination is present in some rural villages of Mae Sot District, Tak Province, northwestern Thailand. We compared the health of 751 persons aged >= 35 years living in 3 contaminated villages with 682 people from 3 non-contaminated villages with similar socio-demographic and lifestyle characteristics in the same district. All the subjects were screened for urinary cadmium (a biomarker for long-term cadmium exposure), renal function, hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia, urinary tract stone disease and bone mineral density in 2012. The study renal functions included urinary excretion of beta2-microglobulin (early tubular effect), total urine protein and glomerular filtration rate (glomerular effects). The geometric mean of urinary cadmium level was significantly higher among persons living in the contaminated areas (2.96 MUg/g creatinine) than those in the non-contaminated areas (0.60 MUg/g creatinine). Persons living in contaminated areas had a significantly higher prevalence of renal dysfunction, bone mineral loss, hypertension and urinary stones than those living in non-contaminated areas. There were no significant differences between the 2 groups in the prevalence of diabetes, hypercholesterolemia and hypertriglyceridemia. This study shows health effects due to environmental cadmium exposure. The prevalences of diabetes, hypercholesterolemia, and hypertriglyceridemia were not associated with cadmium exposure. PMID- 26513916 TI - EVALUATING PESTICIDE USE AND SAFETY PRACTICES AMONG FARMWORKERS IN GALLIPOLI PENINSULA, TURKEY. AB - Unsafe pesticide use among farmworkers is a major public health problem in Turkey. This study aimed to investigate pesticide use and safety practices of farmers in a village of Gallipoli Peninsula, Turkey. This cross sectional study was conducted with 117 farmers. The questionnaire included questions on demographic data, knowledge, attitudes, and safety practices concerning pesticides. The mean age of participants was 42.8 years, and 38.5% was female participants. Of the total 177 respondents, 77.8% reported that they prepared the chemical mixture at a public fountain, whereas 22.2% prepared it in their houses. Almost half (44.4%) reported that they experienced at least one health problem after pesticide application in the previous one year. Total scores for pesticide safety practices of the subjects, who declared that they experienced at least one health problem after the application in the previous one year, were statistically significantly lower (p < 0.001). Their responses about safe use of pesticides and storage conditions were very striking. Our findings indicated that there is a need to increase health promotion activities through training, and the local administrations should promote safe use of pesticides by farm workers. PMID- 26513917 TI - EVALUATION OF QUIT-CALENDAR IN SMOKING CESSATION AT SAPASITHIPRASONG HOSPITAL, UBON RATCHATHANI. AB - This study aimed to investigate the demographics, smoking behavior, and benefits of the calendar for a group of participants involved in smoking cessation. The Quit-Calendar, containing 37 question items, was developed to promote smoking cessation. Its use was assessed by the implementation of a study involving 80 participants: 40 in a study group and 40 in a control group. The participants in the study group underwent a routine cessation counseling process with additional Quit-Calendars, whereas those in the control group received routine cessation counseling only. The effectiveness of the Quit-Calendar, duration of quit times (known as survival times), and attitudes to the Quit-Calendar and regular cessation counseling were evaluated via descriptive and analytical statistics. The study found that most participants were male, aged between 30 and 41, and had completed primary to senior high school education. The members of the control group had a significantly higher intention to quit smoking compared to those in the study group (X = 4.20 and 3.35, respectively; p < 0.001). Survival times were measured at days 14 and 60. The results indicated that there were significant differences between the study and control groups on these specific days (p = 0.002 and 0.003, respectively). PMID- 26513918 TI - EFFICACY OF FLUORIDE MOUTHRINSE CONTAINING TRICALCIUM PHOSPHATE ON PRIMARY ENAMEL LESIONS: A POLARIZED LIGHT MICROSCOPIC STUDY. AB - The aim of this study was to evaluate the effect of fluoride mouthrinse containing tricalcium phosphate (TCP) on remineralization of primary teeth enamel lesions compared with fluoride mouthrinse alone to determine if the addition of TCP gives additional benefit. Thirty-six sound primary incisors were immersed in a demineralizing solution (pH 4.4) for 96 hours at 37 degrees C to create demineralized lesions. After artificial caries formation, the specimens were randomly assigned to one of three groups (n = 12): Group A: deionized water; Group B: 0.05% sodium fluoride (NaF) plus 20 ppm tricalcium phosphate mouthrinse and Group C: 0.05% sodium fluoride (NaF) only mouthrinse. A pH-cycling process was carried out for 7 days at 37 degrees C. During pH-cycing, all the specimens were immersed for 1 minute; 3 times a day, in the respective mouthrinse. The specimens were then evaluated by polarized light microscopy with the computerized Image Pro Plus program. Data were analyzed using paired-t, one-way ANOVA and Tukey's multiple comparison tests at a 95% level of confidence. The depth of the lesions were significantly different between pre- and post-treatment for all groups (p = 0.00). The lesion depth in the Group A (control) increased by 102% (+/-15), in Group B by 34% (+/-12) and Group C by 36% (+/-9). The lesion depths differed significantly between the control (Group A) and treatment groups (Group B,C) (p < 0.05). Group A had a significantly greater increase in lesion depth compared to the other groups. There was no significant difference in the percent change in lesion depths between Groups B and C. We concluded that the fluoride mouthrinse containing tricalcium phosphate provides no additional benefit over the mouthrinse containing fluoride alone. PMID- 26513919 TI - HEPATIC VISCERAL LARVA MIGRANS DUE TO TOXOCARA CANIS IN A 72-YEAR-OLD MAN. AB - Hepatic toxocariasis is visceral larva migrans caused by Toxocara. We report a case of hepatic toxocariasis detected incidentally during a health checkup. The patient had elevated levels of eosinophils, total IgE, and anti-Toxocara IgG antibodies. On contrast-enhanced computed tomography (CT) imaging he had a single, 2.16 cm, oval, ill-defined, low-attenuation hepatic nodule which was best appreciated during the portal venous phase of the scan. Clinicians should consider hepatic toxocariasis as a possible diagnosis in any individual who presents with eosinophilia of unknown etiology and an ill-defined hepatic lesion on CT imaging. PMID- 26513920 TI - GENETIC SUBTYPES OF BLASTOCYSTIS ISOLATED FROM THAI HOSPITALIZED PATIENTS IN NORTHEASTERN THAILAND. AB - Blastocystis sp is probably the most common intestinal protozoan of humans. This taxon is known to include more than 17 subtypes, some of which likely cause human disease. We investigated the distribution of Blastocystis subtypes in Thai patients admitted for a variety of conditions at a hospital in northeastern Thailand. Fresh fecal samples, positive for Blastocystis by microscopy, were individually cultured in Jones' medium (n = 20) and each sample was used for amplification and sequencing a fragment of 18S rDNA. BLAST search and phylogenetic analysis demonstrated that Blastocystis subtypes ST1 (20%), ST3 (60%), ST6 (10%) and ST7 (10%) were present. No clear link between gastro intestinal symptoms and any particular subtype of Blastocystis was apparent. Thus, there is a need to extend the work to evaluate clinical signs and subtypes in a larger cohort of patients. PMID- 26513921 TI - HUMAN TRICHOSTRONGYLIASIS: A HOSPITAL CASE SERIES. AB - Trichostrongylus is a common nematode found to infect livestock throughout the tropics and can cause accidental zoonosis in humans. In the Lao PDR and Thailand, cases of human trichostrongyliasis have been reported sporadically but clinical data are limited. We retrospectively reviewed 41 cases of trichostrongyliasis who presented to Srinagarind Hospital, Thailand from 2005 to 2012. The diagnosis of trichostrongyliasis was made by finding their eggs in the stool of patients. Of the 41 cases reviewed, 30 were Thais and 11 from the Lao PDR; their age range was 26-86 years. Fifty-eight point five percent of the cases were male, 56.1% had a primary school or a lower education level, 56.1% were farmers or laborers, 63.4% lived in a rural area and 95.1% had underlying disease. Twenty-one patients were co-infected with Opisthorchis viverrini (14/21; 66.7%) and Strongyloides stercoralis (10/21; 47.6%) while the remaining (n = 20) had a single infection with Trichostrongylus only. All the trichostrongyliasis only patients who had underlying disease not related to the gastrointestinal (GI) tract had normal bowel habits and normal grossly appearing stool. GI symptoms, such as abdominal pain, flatulence, bloating, nausea, vomiting, anorexia, diarrhea and constipation, were not found in these patients suggesting they had a light infection. This study is the first report of the clinical features of a trichostrongyliasis case series from tertiary care hospital in Thailand. PMID- 26513922 TI - CORRELATION OF HOST SPECIFICITY, ENVIRONMENTAL FACTORS AND ORIENTAL RAT FLEA ABUNDANCE. AB - Fleas are the vectors of many communicable diseases that are normally found in oriental rats. Climate and environmental changes influence the habitat and migration patterns of vectors. In this study, the oriental rat flea abundance, represented as total flea index, was determined in correlation to host specificity and various environmental factors. The number of hosts and fleas calculated from 3 specific habitats (shipping area, decayed area, and market area) from July 2010 to June 2011. The results showed that the common hosts in the shipping area and decayed area were Rattus rattus and R. exulans, with the total flea indexes of 3.36 and 1.58. R. norvegicus was the most common host identified in the market area. Fleas were virtually absent in rat hosts collected from the market area. Both the density of reservoir hosts and the total flea index were positively correlated with the mean annual rainfall and temperature. These data could be useful for control of rat populations in each specific habitat. PMID- 26513923 TI - PHYLOGENETIC ANALYSIS REVEALS GENETIC VARIATIONS OF DENSOVIRUS ISOLATED FROM FIELD MOSQUITOES IN BANGKOK AND SURROUNDING REGIONS. AB - Screening for densoviruses (DNVs) from Aedes, Culex and Toxorhynchites mosquitoes collected in Bangkok and surrounding regions identified two clades of Aedes DNV; Ae. aegypti DNV (AaeDNV) and Ae. albopictus DNV (AalDNV) by PCR-restriction fragment length polymorphism (PCR-RFLP). From nucleotide sequencing and phylogenetic analysis of PCR amplicons of a fragment of DNV capsid gene, these DNVs were shown to be new DNV genetic variations similar to AaeDNV. Isolation and identification of densoviruses from indigenous field mosquitoes reside in natural habitat should be helpful in monitoring the distribution of DNVs in important mosquitoes, especially Ae. aegypti and Ae. albopictus, vector for dengue and yellow fever viruses. PMID- 26513924 TI - INFLUENZA VACCINATION UPTAKE AMONG HEALTHCARE WORKERS AT A MALAYSIAN TEACHING HOSPITAL. AB - Annual influenza vaccination is the most important preventive strategy against influenza illness in healthcare workers (HCWs), who could acquire influenza from and transmit influenza to patients and other HCWs. Despite the well established benefits and strong recommendations for influenza vaccination for all HCWs, influenza vaccination uptake at the Universiti Kebangsaan Malaysia Medical Centre (UKMMC) for the past 3 years has been low and is decreasing. We aimed to determine the factors associated with influenza vaccination uptake among HCWs at UKMMC. We conducted a cross sectional study via questionnaire among 211 randomly selected HCWs, consisting of 106 HCWs who were vaccinated in 2011 and 105 HCWs who were not vaccinated in 2010 or 2011. We had a 100% response rate. Influenza vaccination uptake was significantly associated with age and previous vaccination history, with older HCWs being more likely to be vaccinated (adjusted OR = 12.494; 95% CI:6.278-24.863; p < 0.001) and HCWs with previous vaccination history being more likely to be vaccinated (adjusted OR = 1.038; 95% CI:1.001 1.077; p = 0.045). Influenza vaccination uptake was not associated with gender (p = 0.926) or job category (p = 0.220). Publicity at the workplace was the main source of information about the vaccine (51.2% of respondents), followed by colleagues (29.9%). Despite the low uptake, 85.3% of respondents believed influenza vaccination was important for disease prevention. The most common reason given for vaccination was protection against influenza infection (73.6%). The most common reason for not having the vaccine was time constraints (56.2%). An evidenced-based strategy needs to be developed to improve vaccine uptake or having mandatory vaccination. PMID- 26513925 TI - PARVOVIRUS B19 INFECTION PRESENTING AS ACUTE HEPATITIS AND TRANSIENT ANEMIA IN A PREVIOUSLY HEALTHY CHILD. AB - Acute hepatitis has been noted as a manifestation of parvovirus B19 infection in children and adults, although its pathogenesis remains unclear. In this report, we present a case of an 11-year old Thai boy with parvovirus B19-associated acute hepatitis who presented with jaundice, hepatomegaly and transient aplastic crisis. Our report underscores the need to consider parvovirus B19 as the causative pathogen in patients with increased liver enzymes, jaundice and anemia. PMID- 26513926 TI - FACTORS ASSOCIATED WITH THE DECISION TO HAVE HIV ANTIBODY TESTING AMONG THAI MEN WHO HAVE SEX WITH MEN. AB - The aim of this study was to assess the factors associated with the deci- sion to have HIV antibody testing among Thai men who have sex with men (MSM) during the previous 12 months. MSM were recruited by systematic sampling from the M-REACH membership registry. Variables collected were demographics, sexual behavior, health behavior, knowledge about HIV/AIDS prevention and attitudes about HIV antibody testing. Data were collected via a self-administered questionnaire and in-depth interviews. About one third of participants reported having HIV antibody testing during the previous 12 months. Of those, 65% were aged > 24 years. Participants aged > 24 years were significantly more likely to have HIV testing than those aged < 24 years (AOR = 3.04, 95% CI: 1.12-8.28; p < 0.005). Most participants exhibited a good knowledge and attitude (levels regarding HIV antibody testing and AIDS). Those with a good attitude level about HIV were more likely to have been tested than those with a poor attitude level (AOR = 3.19; 95% CI: 1.24-8.22; p < 0.005). A programs that improves attitude and knowledge levels about HIV testing need to be developed for MSM in Thailand to improve HIV antibody testing rates. PMID- 26513927 TI - IMMUNO-MAGNETIC ISOLATION, CHARACTERIZATION AND GENETIC RELATIONSHIP OF ESCHERICHIA COLI O26 FROM RAW MEATS, HAT YAI CITY, SONGKHLA, THAILAND. AB - Escherichia coli O26 is the most important serotype in non-O157 group, which plays a significant role in gastrointestinal illnesses. However, information regarding the prevalence and its characteristics are lacking in Thailand. As raw meat is frequently a source of diarrheagenic E. coli, a total of 1,279 E. coli colonies were obtained from 157 raw meat samples obtained from retail markets in Hat Yai City, Songkhla Province, Thailand and E. coli O26 isolated using an immunemagnetic separation technique. Twenty-seven E. coli O26 strains were isolated from 18 samples of raw beef, chicken and pork meats. These E. coli O26 strains could not be classified into the six diarrheagenic E. coli categories and did not harbor virulence genes, except 5 strains carrying escV, encoding type III secretion system component. Phylogenetic group examination demonstrated that 26 strains belonged to phylogenetic group A, and one to group D. Antimicrobial susceptibility test revealed that the E. coli O26 strains were the multi-drug resistant strains. Genetic relatedness employing (GTG)5-PCR and ERIC2-PCR showed that some of O26 which isolated from different samples and different time intervals revealed the identical fingerprint pattern, suggesting that they were derived from the same clone. Examination of five stx2-containing phage integration sites showed that 6 strains had prophage occupancy at sbcB, suggesting that these isolates have the potential in horizontal gene transfer of virulence trait. Moreover, the intactness of yecE and wrbA, the important integration sites in E. coli O26, indicated the possibility of stx2-phage lysogenization in the future. PMID- 26513928 TI - TEM-1 AND ROB-1 PRESENCE AND ANTIMICROBIAL RESISTANCE IN HAEMOPHILUS INFLUENZAE STRAINS, ISTANBUL, TURKEY. AB - Resistance of 235 Haemophilus influenzae clinical isolates from Istanbul Medical Faculty Hospital, Turkey were determined against 19 antibiotics by disc diffusion method, and minimum inhibitory concentrations (MICs) of those found resistant to ampicillin, cefuroxim, chloramphenicol and meropenem were measured using E-test. Ampicillin-resistant isolates producing beta-lactamase as demonstrated by a nitrocefin assay were analyzed for the presence of TEM-1 and ROB-1 genes by PCR. Eleven percent of the isolates were resistant to ampicillin (10 ug/ml), of which 73% were beta-lactamase positive and carried TEM-1 gene, but none were positive for ROB-1 gene. All isolates susceptible to amoxicillin-clavulanate (20/10 ug/ml), azithromycin (15 ug/ml), aztreonam (30 ug/ml), cefotaxime (30 ug/ml), ceftriaxone (30 ug/ml), ciprofloxacin (5 ug/ml), levofloxacin (5 ug/ml), and telithromycin (15 ug/ml) but 24%, 15%, 4%, 4%, 2%, 1%, 1%, 0.5%, 0.5% and 0.5% were resistant to trimethoprim-sulfamethoxazole (1.25/23.75 ug/ml), tetracycline (30 ug/ml), cefaclor (30 ug/ml), clarithromycin (15 ug/ml), cefuroxime (30 ug/ml), meropenem (10 ug/ml), chloramphenicol (30 ug/ml), ampicillin-sulbactam (10/10 ug/ml), nalidixic acid (30 ug/ml), and fosfomycin (30 ug/ml), respectively. MIC values of three cefuroxime-resistant isolates was 24, 48 and > 256 ug/ml, respectively; of two meropenem-resistant strains > 256 ug/ml; and of two chloramphenicol-susceptible isolates (by disc diffusion method) 6 ug/ml (considered as intermediate susceptible). Multiple- antibiotics resistance was detected in 15% of the strains, with resistance to 2, 3, 4, 5 and 6 antibiotics in 8.5%, 4%, 2%, 0.5% and 0.5% of the isolates, respectively. By identifying beta lactamase-negative ampicillin-resistant H. influenzae, empirical therapy with beta-lactam/beta-lactamase inhibitor combinations and second generation cephalosporins would be inappropriate for such patients (approximately 3%). Our findings will contribute to the epidemiological and clinical data regarding H. influenzae infection in Turkey. PMID- 26513929 TI - MOLECULAR CHARACTERIZATION OF FLAB FOR LEPTOSPIRA IDENTIFICATION. AB - PCR amplification of the nearly full-length of virulence flagellin gene (flaB) was employed for rapid identification of Leptospira spp and of Leptospira specific 16S rDNA (rrs) for differentiation from other bacteria. This approach distinguished pathogenic from non-pathogenic Leptospira strains, and the generation of restriction fragment length polymorphism profiles using a combination of restriction endonucleases allowed identification of pathogenic Leptospira species. PCR-based identification of Leptospira flaB provides an accurate and rapid tool for identification of leptospires and can be used as a means for rapidly identifying animal reservoirs responsible for leptospirosis outbreaks. Furthermore, these techniques could be applied to clinical diagnosis without the need for leptospiral isolation. PMID- 26513930 TI - INDUCTION BY EPIDERMOPHYTON FLOCCOSUM OF HUMAN FIBROBLAST MATRIX METALLOPROTEINASE-9 SECRETION IN VITRO. AB - Skin infection from pathogenic dermatophyte, Epidermophytonfloccosum, can cause serious health complications, especially in immuno-compromised patients. Proteolytic enzymes secreted from E. floccosum are required for host tissue degradation, facilitating fungal invasion. However, little is known regarding host matrix metalloproteinase (MMP) expression during E. floccosum infection. In this study human foreskin fibroblast (HFF) cell line was used to determine MMP-9 protease activity by gelatin zymography and amount by ELISA. E. floccosum-induced HFF secretion of MMP-9 in a time dependent manner, but HFF cell viability decreased. Treatment with an MMP inhibitor (SB-3CT) caused reduction in E. floccosum-induced secreted MMP-9 and improvement in HFF cell viability. These findings indicate a possible control measure for protecting skin from E. floccosum infection. PMID- 26513931 TI - FREQUENCY AND ANTIMICROBIAL SUSCEPTIBILITY OF PATHOGENS AT TERTIARY PUBLIC HOSPITAL, SAO PAULO, BRAZIL. AB - Nosocomial infections are one of the leading causes of morbidity and mortality. This study determined both prevalence and antimicrobial susceptibility of microorganisms identified during January to December 2012 at a tertiary public hospital, Sao Paulo, Brazil. Data, hospital length of stay, age, identity of microorganisms, and antimicrobial susceptibilities were obtained from patients' records. A total of 724 positive strains were obtained from different body sites. Gram-negative microorganisms are significantly more prevalent than gram-positive microorganisms (p = 0.001). In all clinics analyzed, coagulase-negative Staphylococcus (CoNS) was the most prevalent microorganism isolated (21.6%), followed by Pseudomonas aeruginosa (12.4%). Extended spectrum beta-lactamase Klebsiella pneumoniae was present in 62.7% of the strains and 18.9% were resistant to carbapenem/meropenem. Acinetobacter baumannii showed multidrug resistance. The majority of Escherichia coli isolates were obtained from positive urinary tract cultures (63.4%), with 27.5% resistant against cefepime. Elderly patients, long periods of hospital stay and continuous usage of a single antibiotic should be kept in mind of possible causes for infection of A. baumannii, ESBL and carbapenem-resistant K. pneumoniae and the worrisome E. coli with increased resistance to cefepime. The data allowed us to implement monitoring programs as part of the prevention strategy against pathogens prevalence and antibiotic resistance burden at Ipiranga Hospital, Sao Paulo, Brazil. PMID- 26513932 TI - PREDICTING CLINICALLY DIAGNOSED DYSENTERY INCIDENCE OBTAINED FROM MONTHLY CASE REPORTING BASED ON METEOROLOGICAL VARIABLES IN DALIAN, LIAONING PROVINCE, CHINA, 2005-2011 USING A DEVELOPED MODEL. AB - This study describes our development of a model to predict the incidence of clinically diagnosed dysentery in Dalian, Liaoning Province, China, using time series analysis. The model was developed using the seasonal autoregressive integrated moving average (SARIMA). Spearman correlation analysis was conducted to explore the relationship between meteorological variables and the incidence of clinically diagnosed dysentery. The meteorological variables which significantly correlated with the incidence of clinically diagnosed dysentery were then used as covariables in the model, which incorporated the monthly incidence of clinically diagnosed dysentery from 2005 to 2010 in Dalian. After model development, a simulation was conducted for the year 2011 and the results of this prediction were compared with the real observed values. The model performed best when the temperature data for the preceding month was used to predict clinically diagnosed dysentery during the following month. The developed model was effective and reliable in predicting the incidence of clinically diagnosed dysentery for most but not all months, and may be a useful tool for dysentery disease control and prevention, but further studies are needed to fine tune the model. PMID- 26513933 TI - PULMONARY TB AMONG MYANMAR MIGRANTS IN SAMUT SAKHON PROVINCE, THAILAND: A. PROBLEM OR NOT FOR THE TB CONTROL PROGRAM? AB - Most transnational migrant workers in Thailand are from Myanmar, a country with a high tuberculosis prevalence. We investigated the prevalence of suspected pulmonary tuberculosis (TB) among Myanmar migrants in communities of Mueang District, Samut Sakhon Province, Thailand. Symptom screening for those with a productive cough of more than 2 weeks was conducted by face-to-face home interviews with 4,874 participants aged at least 15 years. Most subjects (75%) were aged 15-34 years (75%), 52% were male and 60% were married. Subjects typically lived with fellow nationals in crowded, poorly ventilated apartments or row houses. Ten subjects had suspected TB, giving a prevalence rate of 0.2%. Ninety-seven percent were working in Thailand legally but 80% had no health insurance. None had sought community health services; all preferred self medication and private clinics due to stigma associated with TB, medication costs and health center waiting times. Providing information about health insurance and introducing TB prevention and control in this group should be considered. Further studies are needed to develop a TB control program and communicable disease surveillance among migrant communities, in Thailand. PMID- 26513934 TI - THE PREVALENCE OF ANEMIA IN CENTRAL AND EASTERN CHINA: EVIDENCE FROM THE CHINA HEALTH AND NUTRITION SURVEY. AB - Although China has experienced rapid economic growth over the past few decades, significant health and nutritional problems remain. Little work has been done to track basic diseases, such as iron-deficiency anemia, so the exact prevalence of these health problems is unknown. The goals of this study were to assess the prevalence of anemia in China and identify individual, household and community based factors associated with anemia. We used data from the 2009 China Health and Nutrition Survey (CHNS), including the measurement of hemoglobin levels among 7,261 individuals from 170 communities and 7 provinces in central and eastern China. The overall prevalence of anemia was 13.4% using the WHO's blood hemoglobin thresholds (1968). This means in China's more developed central and eastern regions up to 180 million people may be anemic. Some vulnerable subgroups were disproportionately affected by anemia. Seniors (aged 60 years and above) were more likely to be anemic than younger age cohorts, and females had higher anemia prevalence among all age groups except among children aged 7 to 14 years. We found a negative correlation between household wealth and the presence of anemia, suggesting anemia prevalence may decline as China's economy grows. However, the prevalence of anemia was greater in migrant households, which should be experiencing an improved economic status. PMID- 26513935 TI - FACTORS ASSOCIATED WITH DIABETIC RETINOPATHY AMONG TYPE 2 DIABETIC PATIENTS: A HOSPITAL BASED CASE-CONTROL STUDY. AB - The objective of this study was to determine factors associated with diabetic retinopathy (DR) among type 2 diabetics in Thailand. We conducted a hospital based case-control study in Nakhon Nayok Province, between August 2008 and July 2010. The subjects were comprised of 230 cases (with DR) and 230 controls (without DR) who were gender and age matched. All subjects were interviewed and their medical records were reviewed. Seventy-five percent of subjects were married and 42% were aged 60-69 years. Fifty-five percent had a primary school education, 27% had no occupation and 67% had family income > 10,000 Baht per month. On multiple logistic regression analysis, factors associated with DR were: having a fasting plasma glucose (FPG) of 141-160 mg/dl, 161-180 mg/dl and > 180 mg/dl [OR = 7.23; 95% confidence interval CI: 2.80-18.72; OR = 4.33; 95% CI: 1.66 11.33, and OR = 3.76; 95% CI: 1.39-10.18], having a HbA1c > 9% (OR = 2.26; 95% CI: 1.15-4.43), having a BMI >= 30 kg/m2 (OR = 2.09; 95% CI: 1.04-4.19), and having hypertension (OR = 1.80; 95% CI: 1.19-2.71). Elevated blood sugar, blood pressure and body weight are all associated with DR. Further study is needed to determine if controlling these factors could reduce the prevalence of DR. PMID- 26513936 TI - BURNOUT LEVELS OF ASSISTANT PHYSICIANS WORKING AT A TURKISH UNIVERSITY HOSPITAL. AB - The purpose of the present study was to determine their current levels of burnout and to identify the factors associated with burnout syndrome among assistant physicians who are undergoing further training in medical specialties. The present descriptive study was conducted on assistant physicians at a Turkish university hospital. The participants were subject to a 26-item questionnaire and the Maslach Burnout Inventory (MBI). The mean age of the participants was 29.95 +/- 3.79 years. Their mean scores in the three sub-scales of the MBI were as follows: 22.33 +/- 8.37 in emotional exhaustion (EE), 8.72 +/- 4.74 in depersonalization (D), and 18.76 +/- 5.87 in personal accomplishment (PA). While there were no significant discrepancies among the respondents in terms of their mean scores in EE, D and PA depending on their gender, age groups and marital status, those who considered their monthly income levels as "poor" differed significantly from those who regarded their monthly income levels as "good" in terms of their mean scores in EE, D, and PA. In addition, there was a significant difference in terms of the mean scores in EE, D, and PA between the participants who were appreciated by their superiors and those who were not. The participants had high, low and average mean scores in EE, PA and D, respectively, suggesting that they had high levels of burnout in reference to EE and PA and average levels of burnout in reference to D. PMID- 26513937 TI - DEVELOPMENT AND IMPLEMENTATION OF A PRACTICAL PUBLIC HEALTH TRAINING SYSTEM IN CHINA. AB - Public health education is becoming an increasing priority among educators of medicine. In China, little attention has been paid to public health education reform. A new public health training system was introduced in China in 2007. We conducted this study during 2006-2012 to evaluate the graduate core competencies under the new system. Data were collected from 231 graduates and 49 public health agencies. The 144 graduates who enrolled in 2006 and were trained under the old system constituted the control group; the 87 graduates who enrolled in 2007 and were trained under the new system constituted the experimental group. Surveys of graduate core competencies found analyzing and solving problems in the laboratory, conducting on-site practice and learning new technologies were the top three abilities most expected by public health agencies. After 5-year practical ability training, the graduates in the experimental group had better performance; on-site practical ability and laboratory practical ability increased significantly by 24.5% and 20.0%, respectively. Three other important competencies also improved: designing epidemiologic surveys, collecting information from the literature and doing statistical analyses. However, preventing and controlling common diseases and dealing with emergencies remained weak. These results show the new training system should be continued, but revisions are needed to improve this training system, especially in the areas of preventing and controlling common diseases and dealing with emergencies. PMID- 26513938 TI - EFFECT OF RELIGIOUS BELIEFS ON SUBSTANCE USE AMONG SOUTH AFRICAN HIGH SCHOOL STUDENTS. AB - Substance use is a common problem among South African youth. We conducted this study to determine whether religious beliefs influenced substance use among South African youth. We conducted a cross sectional study of 704 students from five high schools in South Africa. We used a questionnaire to assess self reported substance use and religious beliefs among the study subjects. We used binary logistic regression analysis to evaluate the relationship between the subjects' religious beliefs and substance use. Thirty-six point six percent of students reported being very religious. More female students reported being very religious than male students (p = 0.039). Fifty-four percent of students had ever consumed alcohol. Comparing alcohol and drug use between religious and non-religious students, it was found that alcohol and drug use were more common among non religious students (28.3%, 30.4%) than very religious students (8.4%, 11.5%) (p < 0.05). Those who considered themselves religious had lower odds of substance use. Religious beliefs had an influence on substance use among South African youth in our study. PMID- 26513939 TI - EFFECTIVENESS OF AN ORAL HYGIENE EDUCATION PROGRAM COMBINED WITH FLUORIDE MOUTHRINSE AMONG VISUALLY IMPAIRED STUDENTS IN BANGKOK, THAILAND. AB - The objective of this study was to assess the effectiveness of oral hygiene education kits (OHE kits) and 0.05% sodium fluoride mouth rinse among visually impaired students (VIS) in Bangkok, Thailand. Seventy-five VIS aged 10-12 years were included in the study and examined for plaque index (PI), gingival index (GI) and mutans streptococci (MS) salivary levels at baseline and after intervention. The subjects were then randomly divided into three groups. Group 1 received OHE kits and 0.05% NaF mouth rinse and brushing instructions. Group 2 received only the OHE kits and brushing instructions. Group 3 (control) received only brushing instructions. PI, GI and MS levels, were reassessed 3 months after intervention. Pre- and post-intervention evaluation data were compared with the Wilcoxon match-pairs test (p < 0.05). The post-intervention results were significantly better in all 3 groups compared to the pre-intervention result (p < 0.01). Group 1 had the lowest PI and the PI was significantly lower than the other groups (p < 0.05). The GI was significantly lower in Group 1 than Group 3, Group 2 than Group 3 (p < 0.05). MS level was reduced significantly in group 1 and 2 compared to control (p < 0.001, p = 0.038, respectively). All groups showed the reduction of PI, GI, and MS levels. However, students who either received OHE kits with or without sodium fluoride mouthrinse showed significantly lower gingival index and lower number of MS than control group. PMID- 26513940 TI - DENTAL FLUOROSIS AND ITS RELATION TO SOCIOECONOMIC STATUS, PARENTS' KNOWLEDGE AND AWARENESS AMONG 12-YEAR-OLD SCHOOL CHILDREN IN QUETTA, PAKISTAN. AB - This study aimed to determine the prevalence of dental fluorosis and its relationship to socioeconomic status, knowledge, and awareness among 12-year-old school children in Quetta, Pakistan. A cross sectional study was conducted among 349 school children aged 12 years in Quetta, Pakistan. By interviewing children and questionnaire for parents, socioeconomic status, knowledge, and awareness of fluorosis were collected. Dental fluorosis was examined using Dean's Index and Community Fluorosis Index. Prevalence of dental fluorosis was high (63.6%) among children with a majority of moderate and mild degree at 32.1% and 27.5%, respectively. The community fluorosis index was 1.6. While most children and parents had low-to-moderate levels of fluorosis knowledge, the majority of them worried about dental fluorosis. Most parents (84.8%) were uncertain about the condition of fluorosis in their children, and 87.4% did not know about fluorosis before. Dental fluorosis was found significantly associated with gender, family income, and parents' awareness (p <= 0.05). Multivariate analysis indicated that gender, and parent's awareness significantly predicted children's dental fluorosis. Knowledge and basic information regarding dental fluorosis is lacking in the community. Efforts in dissemination and communication about dental fluorosis should be increased in order to raise awareness and prevent the dental fluorosis in Pakistan. PMID- 26513941 TI - Recruitment and activation of circulating neutrophils after sinus surgery. AB - OBJECTIVE: After failure of pharmacological treatment, sinus surgery is the recommended alternative treatment for chronic sinusitis with or without nasal polyps. During post-operative healing, adequate local neutrophil activation plays an important role in the repair process. This pilot study aimed to systematically explore the participation of circulating neutrophils in early-phase wound repair of the nasal and paranasal mucosa after sinus surgery, with a special focus on neutrophil recruitment and activation patterns. METHODOLOGY: We conducted a single-center outcome study of patients undergoing sinus surgery. Whole blood samples were collected from eleven patients before surgery and at post-surgical time points of 1 hour and 1, 7, 14, and 30 days. Hematological analysis was conducted to count circulating neutrophils and evaluate their overall activation status. Using flow cytometry, neutrophil expression of membrane CD11b, CD11c, and CD15 was also measured, and oxidative burst analysis was performed. RESULTS: After sinus surgery, neutrophilia increased by 1 hour after surgery, reached a maximum at Day 1, and showed a gradual return toward baseline by Day 30. The oxidative burst initially decreased during the first hours after surgery, increased at Day 14, and returned toward normal by Day 30. Lewis X factor and the expression of CD11b and CD11c exhibited a bimodal change over time, in an inverted phase compared to the oxidative reaction. CONCLUSIONS: Circulating neutrophils are involved in the first phase of wound healing after sinus surgery as indicated by increased abundance, early membrane changes, and the modulation of their oxidative capacities. PMID- 26513942 TI - Rupatadine relieves allergic rhinitis: a prospective observational study. AB - BACKGROUND: Allergic rhinitis has reached epidemic levels for years in Belgium and substantially impacts the quality of life of patients. Observational, non interventional studies can provide valuable data, supplementing findings from double-blind trials, on the true value of a drug therapy in daily practice. Rupatadine is a new, second-generation, selective oral H1-antihistamine. The primary objective of.this study was to evaluate the evolution of quality of life in patients treated with rupatadine in clinical practice. The impact of rupatadine on the severity of allergic rhinitis symptoms, the subject's evaluation of the treatment, and the safety of rupatadine were also evaluated. METHODS: This prospective, non-interventional, observational, multicenter study included 2,838 adults aged over 18 years. The diagnosis of moderate to severe allergic rhinitis was confirmed. Patients were assessed with validated scales at baseline and after 6 weeks of treatment with rupatadine (10 mg, once daily). RESULTS: All outcome parameters improved significantly: mini-rhinoconjunctivitis quality of life questionnaire (mini- RQLQ, p < 0.001), total 5-symptom score (T5SS) severity (p < 0.001), visual analog scale (VAS) of symptom severity (p < 0.001), and the allergic rhinitis and its impact on asthma (ARIA) severity classification (p < 0.001). Compliance was very good in 72.2% of patients, and only a few minor adverse effects were reported. The therapeutic responses, evaluated by the patients, were complete relief in 21% and strong relief in 62%. CONCLUSION: This study, which included a wide cohort of allergic-rhinitis patients, confirmed the clinical benefit of rupatadine when prescribed in clinical practice, even for the most severe symptoms, including nasal congestion. PMID- 26513943 TI - Preoperative anxiety and postoperative pain in patients undergoing septoplasty. AB - OBJECTIVE: The aim of the study was to determine whether psychological variables such as preoperative anxiety could serve as predictors of the postoperative pain response. METHODS: Sixty consecutive patients with deviated nasal septum were evaluated in the pre- and postoperative periods. A questionnaire that included sociodemographic features was administered to patients. Preoperative anxiety was assessed by the Spielberger State-Trait Anxiety Index. The severity of pain was recorded with a ten-point Visual Analog Scale at the immediate postoperative period (baseline) and at postoperative hours 2, 4, 6, 12, and 24. RESULTS: Sixty patients met the eligibility criteria for the study. Of the 60 patients (39 men and 21 women) whose charts were reviewed, the mean age was 30.9 +/- 12.6 years for men and 32.8 +/- 10.4 years for women. The mean State-Trait Anxiety Index score was 44.3 +/- 7.5 (range 29-67). No significant relationship was found between the patients' self-reports of postoperative pain and sociodemographic variables such as age and educational status. Men and women showed significant differences with respect to pain in the immediate and late postoperative periods. Correlation tests identified a significant relationship between patients' preoperative anxiety and postoperative pain in both the immediate and late periods. CONCLUSIONS: The results of this study suggest that early interventions to minimize the preoperative anxiety stress response may affect the postoperative pain response. PMID- 26513944 TI - The relationship between serum urea levels and outcome in acute epistaxis. AB - OBJECTIVES: To establish whether, for the patient presenting with epistaxis, there is a relationship between clinical outcome and serum urea levels measured on initial attendance at the accident and emergency (A&E) department. METHODOLOGY: Records were reviewed from all patients attending a single teaching hospital A&E department between 1st January 2010 and 11st February 2011 with a diagnosis of epistaxis. Patients were analysed according to their admission serum urea and creatinine levels and then grouped according to clinical outcome. RESULTS: We identified 278 patients (145 males, 133 females), 82 of which required hospital admission. Eleven required blood transfusion, and five required surgical arrest of the haemorrhage. No patients died. Serum urea and creatinine levels were measured in 119/278 patients. The mean serum urea level was significantly higher in patients admitted for further management of epistaxis than in patients who were discharged from the A&E department (9.35 mmol/l vs. 6.74 mmol/l, respectively; p = 0.003). There was no significant difference in mean serum urea levels between patients who were transfused and patients who were not, or between patients who went to the operating theatre and patients who did not. CONCLUSIONS: Elevated serum urea levels on hospital admission are related to more severe clinical outcome in epistaxis. PMID- 26513945 TI - Correlation of Otorhinolaryngologic Symptoms with Physical Findings in Behcet's Disease. AB - OBJECTIVE: Behcet's disease is a chronic systemic inflammatory disease of unknown etiology. We examined the correlation between otorhinolaryngologic symptoms and otorhinolaryngologic physical findings in patients with Behcet's disease, in search of strategies to reduce the morbidity rates. METHODS: Seventy-two patients diagnosed with Behcet's disease were included. After giving a detailed history of oropharyngeal, nasal, laryngeal, and otic symptoms, patients were examined endoscopically by an otolaryngologist, and the findings were recorded. RESULTS: Thirty-nine of the patients were male, and thirty-three were female. The mean age was 39.2 +/- 3.4, and the mean disease duration was 8.24 +/- 4.2 years. Statistically significant correlations were observed between ear lesions and ear symptoms (crusting and otic pain), nasal lesions and nasal symptoms (crusting and nasal pain), oropharyngeal lesions and oropharyngeal symptoms (pain and difficulty in swallowing), and laryngeal lesions and laryngeal symptoms (hoarseness, difficulty in swallowing, and pain). CONCLUSION: The results demonstrated a positive correlation between symptoms and otorhinolaryngeal examination findings in Behcet's disease. Potential morbidities can be prevented by routine endoscopic otorhinolaryngeal examinations and symptom screening of patients with Behcet's disease and arranging the therapy accordingly. PMID- 26513946 TI - Hyperbaric oxygen as salvage treatment for idiopathic sudden sensorineural hearing loss. AB - OBJECTIVE: To investigate the efficacy of hyperbaric oxygen therapy as a salvage treatment for patients with sudden sensorineural hearing loss (SSHL). MATERIALS AND METHODS: Fifteen patients affected by sudden hearing loss and treated with hyperbaric oxygen after steroid and vasodilator therapy failed constituted the study group. A control group of 30 patients who were treated with steroids and vasodilator alone was also included. Hyperbaric oxygen was administered once daily for 15 sessions at a constant pressure of 2.2 atmospheres. Pure-tone hearing thresholds were obtained for both groups before and after each treatment and frequency-specific thresholds 3 months after the end of hyperbaric oxygen therapy. RESULTS: Salvage hyperbaric oxygen therapy was performed with a mean delay of 24 days from the onset of SSHL. The overall rate of hearing improvement was higher in the study group (7/15 cases, 46.6%) compared with the control group (4/30 cases, 13.3%). The mean pure-tone hearing average thresholds after salvage treatment in the study group was 53.4 dB HL (mean gain, 12.1 dB HL), which was significantly lower than that in the control group of 67.9 dB HL (mean gain, 2.7 dB HL). Hearing recovery was found to be better at low frequencies (250-500 Hz). CONCLUSION: Hyperbaric oxygen therapy should be suggested to all patients for whom initial conventional medical treatment for SSHL has failed. PMID- 26513947 TI - Lip-reading abilities in a subject with congenital prosopagnosia. AB - We present the case of an individual with congenital prosopagnosia or "face blindness", a disorder where the ability to recognize faces is impaired. We studied the lip-reading ability and audiovisual perception of this subject using a DVD with four conditions (audiovisual congruent, auditory, visual, and audiovisual incongruent) and compared results with a normal patient cohort. The patient had no correct responses in the visual lip-reading task; whereas, he improved in the audiovisual congruent task. In the audiovisual incongruent task, the patient provided one response; thus, he was able to lip-read. (He was able to use lip-reading/to use labial informations) This patient perceived only global dynamic facial movements, not the fine ones. He had a sufficient complementary use of lip-reading in audiovisual tasks, but not visual ones. These data are consistent with abnormal development of the pathways used for visual speech perception and associated with second-order face processing disorders and normal development of the audiovisual network for speech perception. PMID- 26513948 TI - Free tissue transfer in head and neck reconstruction: 100 consecutive cases. AB - OBJECTIVES: Free flap reconstruction of head and neck defects is a rapidly changing field. We present a case series in this field in which we critically assess our survival rates and complications, and we highlight specific technical variables that may be associated with improved outcomes. METHODOLOGY: This case series from a tertiary medical centre comprises 100 consecutive head and neck microvascular free flap reconstructions. Medical notes were reviewed specifically for indications, adjuvant and neoadjuvant chemoradiotherapy, complications, and outcome of the free flap. RESULTS: The overall flap survival rate was 99%, with a 6% return-to-theatre rate. Three cases had a general complication in the form of a non-flap compromising haematoma that necessitated a return to theatre for an evacuation. Specific microvascular anastomosis-related complication rate was 2% requiring salvage revision. One flap was lost due to infection. Of the 100 cases, 87% were fasciocutaneous free flaps, 7% were musculocutaneous, 5% were osseocutaneous, and one was a skin/cartilage free flap. With regard to indications for reconstruction, oncological resection accounted for 86% of cases; a total of 12% had mandibular bone involvement that required osseocutaneous reconstruction. CONCLUSIONS: We have highlighted specific technical steps we used that may have contributed to our positive results. Moreover, we encourage the use of standardised postoperative monitoring guidelines for all multidisciplinary surgical teams involved in head and neck patients; they facilitate communication and increase early detection of complications, permitting timely intervention, which may be critical for flap survival. PMID- 26513949 TI - Endoscopic Holmium:YAG laser-assisted lithotripsy: A Preliminary Report. AB - PROBLEM/OBJECTIVE: Laser-assisted lithotripsy under sialendoscopy has the potential to overcome the limitations of traditional sialendoscopic lithotripsy when facing salivary stones. In this preliminary study, we report our experience with Holmium:YAG laser-assisted lithotripsy. METHODS: Data from 11 Asian patients receiving sialendoscopies for laser-assisted lithotripsy performed in our department from August 2013 to June 2014 were recorded and reviewed. RESULTS: A total of 18 procedures were performed in 11 Taiwanese patients with symptoms of obstructive sialoadenitis who were diagnosed with sialolithiasis. The sizes of the stones ranged between 3 mm and 13 mm. The endoscopic lithotomy procedures were performed in all 11 patients, and stone fragmentation with the Holmium:YAG laser was done successfully in all patients. All patients were followed for a minimum of 3 months, and there was no evidence of complications or recurrences over the follow up period. CONCLUSION: The Holmium:YAG laser allowed successful fragmentation of stones in all 11 patients. Our experience with this procedure supports the use of Holmium:YAG laser-assisted lithotripsy through sialendoscopy in Asian patients. PMID- 26513950 TI - Megaesophagus associated with Myasthenia Gravis: a rare condition in humans. AB - We present the case of a 79 year-old patient with megaesophagus and aphagia, who required percutaneous endoscopic gastrostomy (PEG) feeding. Megaesophagus was considered the sole cause of aphagia by the referring secondary hospital. Solid state sensor videofluoromanometry (VFM) showed a substantial decrease in manometric values within the hypopharynx along with good relaxation of the upper esophageal sphincter (UES). This led to electromyography (EMG), which showed features compatible with the diagnosis of Myasthenia Gravis (MG). The diagnosis of MG was confirmed by an intravenous injection of edrophonium chloride, performed under VFM monitoring. The co-existence of MG and megaesophagus rarely occurs in humans; although, most small animals, such as dogs, cats, and rodents, present with megaesophagus as an initial symptom of MG. PMID- 26513951 TI - Wegener granulomatosis as possible cause of vertigo: case report and review. AB - OBJECTIVE: Wegener granulomatosis (WG) or granulomatosis with polyangiitis (GPA) is a multi-system necrotizing granulomatous vasculitis that classically affects the upper respiratory tract, lungs and kidneys. We report the unusual clinical course of a patient with WG, and we present a literature review on the association between WG and vertigo. RESULTS: In our case, a 56-year-old female presented with a several-month history of chronic sinusitis and otalgia that was refractory to all initiated outpatient therapies. During hospitalization, a diagnostic evaluation revealed serious nasal crusting, chronic otitis media, and hematuria. Serologic testing showed elevated anti-neutrophil cytoplasmic antibodies (c-ANCAs). The tentative diagnosis of Wegener granulomatosis was confirmed by renal biopsy. Upon admission, the patient developed an acute vertigo with nystagmus, nausea, and vomiting, accompanied by sensorineural hearing loss in one ear. CONCLUSIONS: Vestibular symptoms may be associated with Wegener granulomatosis. PMID- 26513952 TI - Secondary non-Hodgkin lymphoma of the ethmoid sinus after temozolomide. AB - The paranasal sinuses are rarely the site of malignancy, especially non-Hodgkin lymphoma. In such cases, the ethmoid sinus is the second most frequently involved paranasal sinus. Diagnosis of these malignancies is difficult because the early symptoms often mimic benign sinus pathology. Thus, most cases are diagnosed at an advanced stage, and their prognosis is poor. Here we describe the case of a 58 year-old man with a secondary high-grade B-cell non-Hodgkin lymphoma of the ethmoid sinus. This malignancy was diagnosed two years after the patient had received treatment with temozolomide for a glioblastoma multiforme. This case highlights that malignant tumours of the paranasal sinuses should always be included in the differential diagnosis of sinus disease. Additionally, patients treated with temozolomide should receive regular follow-up care including vigilant evaluation for secondary tumours, such as non-Hodgkin lymphoma. PMID- 26513953 TI - Mucocutaneous leishmaniasis of the nose: a case report. AB - Mucocutaneous leishmaniasis of the nose: a case report. Leishmaniasis is a parasitic infection that is rarely seen in Belgium. The majority of new diagnoses are seen in patients living in or visiting endemic regions, which are mostly developing countries. Here we describe the case of a 60-year-old male patient who was referred to an ENT specialist because of an erythematous swelling of the left side of the nose tip, which had persisted for 3 months. Biopsies showed the presence of leishmaniasis. This case report alerts ENT physicians that leishmaniasis is part of the differential diagnosis in patients who present with an uncommon persistent lesion in the head and neck region and who have travelled to endemic regions or are immunodeficient. PMID- 26513954 TI - [Anemia: From Basic Knowledge to Up-to-Date Treatment. Anemia-recent advances in basic and clinical aspects]. PMID- 26513955 TI - [Anemia: From Basic Knowledge to Up-to-Date Treatment. Topic: I. Physiological function and regulated production of erythrocytes]. PMID- 26513956 TI - [Anemia: From Basic Knowledge to Up-to-Date Treatment. Topic: II. Evaluation and classification of anemia]. PMID- 26513957 TI - [Anemia: From Basic Knowledge to Up-to-Date Treatment. Topic: III. Iron metabolism and iron deficiency anemia--Recent findings]. PMID- 26513958 TI - [Anemia: From Basic Knowledge to Up-to-Date Treatment. Topic: IV. Hemolytic anemia: Diagnosis and treatment]. PMID- 26513959 TI - [Anemia: From Basic Knowledge to Up-to-Date Treatment. Topics: V. Paroxysmal nocturnal hemoglobinuria: The pathophysiology and the current treatment]. PMID- 26513960 TI - [Anemia: From Basic Knowledge to Up-to-Date Treatment. Topics: VI. Pathophysiology and management of aplastic anemia and pure red cell aplasia]. PMID- 26513961 TI - [Anemia: From Basic Knowledge to Up-to-Date Treatment. Topic: VII. Anemia in chronic kidney disease]. PMID- 26513962 TI - [From Basic Knowledge to Up-to-Date Treatment. Topics: VIII. Myelodysplastic syndromes]. PMID- 26513963 TI - [Discussion Meeting on anemia in daily clinical practice: Important points for accurate diagnosis and treatment]. PMID- 26513964 TI - [Case Report; Influenza vaccination-associated acute lung injury: two cases report]. PMID- 26513965 TI - [Case Report; A case of tongue angioedema induced by angiotensin-converting enzyme inhibitor]. PMID- 26513966 TI - [Case Report; A case of tetanus with dysphagia as an initial symptom]. PMID- 26513967 TI - [The Cutting-edge of Medicine; Progress in clinical genetics of inherited neuropathy]. PMID- 26513968 TI - [The Cutting-edge of Medicine; Nutrition therapy of anorexia nervosa]. PMID- 26513969 TI - [The Cutting-edge of Medicine; Endocrine disorders and renal disease]. PMID- 26513970 TI - [Report from 18th Shikoku Chapter Educational Seminar: The significance of detailed clinical history in the differential diagnosis of patients with impaired consciousness]. PMID- 26513971 TI - "Chief roles failing to attract enough nurses". PMID- 26513972 TI - Chief nurse crisis 'deeply worrying'. PMID- 26513973 TI - Staff shortage leads to warning for Essex trust. PMID- 26513974 TI - Senior nurses hit out against cap on agency staff spending. PMID- 26513975 TI - Research reveals efficacy of nurse-led discharge. PMID- 26513977 TI - New framework set to prioritise end-of-life care. PMID- 26513976 TI - Experts claim NICE diabetes guidance puts patients at risk. PMID- 26513978 TI - Nurses struck off for causing death of nursing home residents. PMID- 26513979 TI - Pressure on breast cancer nurses increases. PMID- 26513980 TI - "Seven-day service plans must not be used to cut NHS staff pay". PMID- 26513981 TI - "The nursing profession can sometimes behave like a cult". PMID- 26513982 TI - "Limited training places could render district nurses extinct". PMID- 26513983 TI - How to reduce the risk of surgical site infection. AB - Surgical site infections (SSIs) are an important cause of healthcare- associated infection and are associated with considerable morbidity and mortality. Although intrinsic factors in patients--such as age, underlying illness and site of the procedure--increase the risk, the quality of care delivered during the perioperative period is critical to preventing SSI. This article explores what is known about the epidemiology and pathogenesis of SSI, and practices that are effective in reducing the risk of SSI. PMID- 26513984 TI - Standardising infection control precautions. AB - To minimise the risk of infection transmission, standard infection control precautions must be practised whether a patient is known to have an infection. The main aim of any infection control guideline or policy should, therefore, be to make it easy for staff to do the right thing at the right time. This article outlines standard precautions, explains their importance and presents the critical elements that should be applied in all care settings. PMID- 26513985 TI - Effects of long working hours and alcohol intake. PMID- 26513987 TI - 60 seconds with Pauline Evans. PMID- 26513986 TI - Enhancing patient safety in enteral feeding. AB - Misconnection of enteral feeding tubes to intravenous devices has occurred a number of times and could be life-threatening, or even fatal. A new connector has been designed to make misconnection impossible. This article outlines the development of ENFit, how its use will be introduced into the UK and how this will affect nurses' clinical practice. PMID- 26513988 TI - Where there's a will.... PMID- 26513990 TI - [The comparison of arytenoid resection surgical effect between endoscopic laser approach and external cervical approach for bilateral vocal cord fold paralysis]. AB - OBJECTIVE: To investigate the surgical effect and complications of arytenoid resection in bilateral vocal cord fold paralysis(BVFP) patients via endoscopic laser approach and external cervical approach. METHOD: A total seventy-eight BVFP patients who underwent arytenoid resection surgery via endoscopic laser approach (laser group, n=30) or external cervical approach (external cervical group, n=48) were enrolled in this study. Videostroboscopy, vocal perception evaluation, maximum phonation time (MPT) text were preformed in all patients both preoperatively and postoperatively. The decannulation rate was also calculated. RESULT: Videostroboscopy showed that vocal fold on the operated side in both groups could abduct to various extent postoperatively, which showed significant difference when compared with preoperative abductive movements (P<0. 05). Postoperative glottal closure showed various increment in both groups. However, when with preoperative glottal closure, external cervical group showed significant difference (P < 0. 05), while laser group showed no significant difference (P> 0. 05). Postoperative videostroboscopy showed no significant difference in vocal fold position and glottal closure between these two groups(P>0. 05). Vocal perceptual evaluation(RBH score) showed a significant deterioration in voice quality postoperatively in both groups respectively (P<. 05). Postoperative MPT values showed no significant difference between the two groups (P>. 05). However, they were significantly shorten/shorter than preoperative ones in these two groups respectively (P<0. 05). The overall decannulation rate were 90. 0% and 95. 8% for laser group and external cervical group respectively. In Both groups, patients presented aspiration symptoms postoperatively, except one patient of external cervical group who developed pneumonia due to recurrent aspiration. CONCLUSION: Arytenoid resection surgery via both endoscopic laser approach and external cervical approach can both enlarge glottic area so as to solve respiration problems, in BVFP patients. Two kinds of surgery have obvious voice damage. PMID- 26513989 TI - [Preliminary application of video head impulse test in the diagnosis of vertigo]. AB - OBJECTIVE: To investigate clinical application of head impulse test with video recording eye movements in the diagnosis of vertigo. METHOD: The video head impulse test(vHIT) was used to measure the eye saccades and velocity gain in 95 patients with vertigo which were divided into two groups, peripheral vertigo (47 cases) and central vertigo(48 cases); the characteristics of eye saccades and velocity gain of six semicircular canals in different patients with vertigo were analyzed, and were compared between the two groups. RESULT: The vHIT result in patients with peripheral vertigo: in 22 patients (23 affected ears) with Meniere's disease, 21 ears were abnormal (91. 3%); the vHIT results in 4 patients with vestibular schwannoma, 2 patients with vestibular neuritis, 5 patients with delayed endolymphatic hydrops, 6 patients with sudden hearing loss accompanied vertigo, and 8 patients with vestibular dysfunction, were abnormal with correct saccades and/or lower velocity gain of vHIT. The abnormal vHIT results were also found in 35 of 48 patients (72. 9%) with central vertigo, which including posterior cerebral circulation ischemia(7 patients), cerebral infarction/stroke(6 patients), and dizziness with vertigo(17 patients) and others(18 patients). Abnormal rate of vHIT in patients with peripheral vertigo was 95. 7% (45/47), which was significantly higher than that (72. 9%) in patients with central vertigo. CONCLUSION: It is easy to perform the vHIT which without adverse reactions. We can record high-frequency characteristics of vestibular-ocular reflex among six semicircular canals through vHIT. The vHIT results which show the function of vestibular ocular reflex in different diseases with vertigo, can help discriminate peripheral vertigo from central vertigo, and it is a practical assessment method for vertigo. PMID- 26513991 TI - [Short-term efficacy observation on Chinese traditional medicine used after functional endoscopic sinus surgery for chronic sinusitis]. AB - OBJECTIVE: To evaluate the efficacy of chinese traditional treatment after functional endoscopic sinus surgery (FESS) for patients with chronic sinusitis. METHOD: Eighty-eight cases of patients with chronic sinusitis were randomly divided into control group and treatment group after FESS and followed for 3 months. The control group received routine treatment. The treatment group received Chinese traditional treatment on the basis of routine treatment. VAS scores, Lund-Kennedy scores and Lund-Mackay scores were employed to conduct the subjective and objective assessment, comprehensively evaluate the clinical efficacy before and after treatment. RESULT: (1) After 3 months of treatment, the two groups of VAS scores and Lund-Mackay scores were significantly improved before treatment (P<0. 05). (2)After 3 months of treatment, the effectiveness of the control group was 81. 8%, treatment group was 97. 7%, the difference was statistically significant(P<0. 05). CONCLUSION: Chinese traditional treatment after FESS can reduce postoperative mucosal edema and promote the postoperative recovery of sinus mucosal inflammation, is effective in preventing the recurrence of postoperative. PMID- 26513992 TI - [The expression and clinical significance of hyaluronan synthase in nasal polyps]. AB - OBJECTIVE: To study the expression of hyaluronan synthasel-3 (HAS1-3) in nasal polyps, and discuss their clinical significance. METHOD: The expression of HA, HAS1, HAS2 and HAS3 in nasal polyps group (25 cases) and inferior turbinate group (15 cases) was detected by immunohistochemistry and semi-quantitative RT-PCR. RESULT: Compared with the control, the expression of HA, HAS1 and HAS3 was higher in nasal polyps (P<0. 05), while there was no significant difference in HAS2 expression (P>0. 05). CONCLUSION: The increase of HASI and HAS3 expression may be the main cause of the excessive deposition of HA in nasal polyps, which may play an important role in the pathogenic process of nasal polyps, and become a potential target for therapy of nasal polyps. PMID- 26513994 TI - [Efficacy of endoscopic nasal lateral wall dissection approach in the treatment of maxillary sinus diseases]. AB - OBJECTIVE: A retrospective analysis of the clinical efficacy on the surgery of maxillary sinus diseases via the endoscopic lateral nasal wall incision, and a discussion on the clinical application of this approach. METHOD: Eighteen cases of the maxillary sinus diseases diagnosed on the basis of the preoperative nasal endoscopy, CT scan or MRI, and pathologic finding. Among 13 patients underwent routine lateral nasal wall incision approach, including 4 of maxillary sinus hemorrhagic and necrotic polyps, 4 of maxillary sinus cyst, and 3 of the maxillary sinus fungal infection. Five patients underwent lateral nasal wall resection approach and thorough maxillary sinus lesions resection by nasal endoscope, including 3 of inverted maxillary sinus papilloma, a nasal sinus bone giant cell tumor and a spindle cell tumor. Patients were followed up for more than half a year, and the postoperative efficacy were observed. RESULT: The surgical cavity of the lateral nasal wall incision approach have luminal epithelium, well shapes of inferior turbinate, no recurrence of the lesion, and the lateral nasal wall resection patients with well luminal epithelium, without recurrence. All patients had no complications such as numbness, tears, etc. CONCLUSION: Endoscopic incision of lateral nasal wall keep the nasolacrimal duct and inferior turbinate, help remove the entire sinus cavity lesion and retain the physiological function of the nasal cavity. Resection of the lateral nasal wall can reveal an ideal vision approach, which perform certain clinical value for the treatment of the inverted maxillary sinus papilloma and sinus cancer. PMID- 26513993 TI - [Expression and clinical significance of MMP9 in sinonasal squamous cell carcinoma]. AB - OBJECTIVE: We detected expression of MMP9 to discuss its role in the occurrence and development of sinonasal squamous cell carcinoma. METHOD: The immunohistochemical staining, real-time PCR and Western blot were used to measure the expression of MMP9 in sinonasal squamous cell carcinoma tissues (Experimental group) and corresponding normal mucosa tissues (Control group). Relationship between MMP9 and the main clinical features of patients with sinonasal squamous cell carcinoma was analysed. RESULT: Positive expression rates of MMP9 in sinonasal squamous cell carcinoma tissues and corresponding normal mucosa tissues were 81. 25% and 18. 52% respectively. Positive expression rate of MMP9 was not significantly correlated with patient's age and gender (P>0. 05), but correlated with pathological type (P<0. 05). The expression of MMP9 mRNA in sinonasal squamous carcinoma tissues was 30. 66 times of tissues adjacent to carcinoma (P<0. 05). Western blot analysis also showed that the expression of MMP9 protein in squamous carcinoma tissues was significantly higher than tissues adjacent to carcinoma (P<. 05). CONCLUSION: The expression of MMP9 was significantly higher in the sinonasal squamous cell carcinoma and correlated with the degree of differentiation. The results suggest that MMP9 may play a role in the occurrence and development of sinonasal squamous cell carcinoma and degree of malignancy from the protein and cellular and molecular level. The higher degree of malignancy, the stronger expression. PMID- 26513995 TI - [The anatomy study of the frontal beak approach of Draf II b frontal sinusotomy]. AB - OBJECTIVE: To investigate the possibility and anatomy landmark of the frontal beak approach of endoscopic frontal sinusotomy to the frontal sinus lesions. METHOD: (1)Twenty cases of frozen cadaveric head underwent spiral computed tomography scans. Then data were transferred into the Mimics image workstation to reorganize CT images in the coronal, sagittal, and axial planes. The anatomic parameters related to surgical approach points were measured, such as the distance between vertical plate of the middle turbinate and lamina papyracea and the thickness of the frontal beak. (2) 3D visual model of the frontal cell and the drainage way of the frontal sinus was produced with the application of Sinuses Trachea I software. (3)The endoscopic frontal sinus surgery were performed on 20 cases of subjects (objects)to find out the anatomy landmarks of the frontal beak approach, measure the parameters such as the distance between middle turbinate and lamina papyracea, and evaluate the potential surgical complications during operation. RESULT: (1)The frontal beak is a white bony arcs located at the attachment point of middle turbinate front inserted to the skull base. Its position was relatively constant, before frontal sinus above. (2)The distance between the middle turbinate vertical plate and lamina papyracea was (7. 61 +/- 1. 34) mm. The thickness of the frontal beak in surgical approach was (3. 27 +/- 0. 91) mm. (3) 3D visual structure of the frontal sinus and its ventilation pathway: the shape of unilateral frontal sinus looked like the cone, which was transited by the drainage pathway of the frontal sinus. The front part of the frontal sinus ostium is surrounded by the frontal beak. The upper part the frontal beak connected to the floor of the frontal sinus. (4) Frontal beak can be used as an landmark of frontal beak approach in the endoscopic frontal sinus surgery. But the lateral view of frontal sinus still was limited in the operation. CONCLUSION: The endoscopic frontal sinus surgery with the approach of the frontal beak is easy to operate and learn. In this area between the double "L", the operation is safe. PMID- 26513996 TI - [Long-term efficacy of nasal endoscopic opticnerve decompression for traumatic optic neuropathy]. AB - OBJECTIVE: To analyze the long-term efficacy of nasal endoscopic opticnerve decompression for traumatic optic neuropathy(TON) and to explore its possible influencing factors. METHOD: To summarize the clinical data of 39 cases underwent transnasal decompression, which were followed-up for more than 1 year. The data, including optic canal CT scanning, flashed-elicited visual-evoked potential (FVEP), preoperational vision and visual field examination were reviewed. Nasal endoscopic optic nerve decompression was preformed. Whether or not optic nerve sheath incision decided to perform was according to preoperative CT and situations in operation. Postoperative follow-up including vision, visual field, funduscopy, nasal endoscopy were performed. RESULT: Total efficacy rate was 30. 77% (12/39), inefficacy rate was 69. 23%(27/39). The efficacy rate was 85. 71% with better than nolight perception, and the efficacy rate was 18. 75% with nolight perception, the clinical effect in the group of preoperative better than nolight perception was better than that of nolight perception, the difference was statistically significant (P<0. 05). The efficacy rate was 34. 38% with duration of less than 7 days from the traumatic point to the operation point, and the efficacy rate was 14. 29% for more than 7 days, but the difference was not statistically significant (P> 0. 05). The efficacy rate was 26. 32% with optic nerve sheathincision, while the efficacy rate was 35. 00% without optic nerve sheath incision, and there was no statistically significant difference (P>0. 05); Postoperative vision tended to stabilize until about 6 months post-operation, without complications. CONCLUSION: The long-term efficacy of nasal endoscopic opticnerve decompression for TON was certain; The efficacy with preoperative residual vision was better than that of nolight perception, the factor of long or short duration from the trauma point to the operation point and the factor of optic nerve sheath incision didn't influence long curative effect. To avoid the secondary damage to the optic nerve after trauma was the key to increase long curative effect in TON. PMID- 26513997 TI - [Expression level and significance of IL-17 and IL-23 in serum and nasal secretion of patients with allergic rhinitis and non-allergrie rhinitis]. AB - OBJECTIVE: To investigate the effect of IL-17 and IL-23 in the pathogenesis of allergic rhinitis(AR) and non. allergic rhinitis(NAR). METHOD: Selected 156 cases of patients with allergic rhinitis (AR group) and 59 cases of patients with non allergic rhinitis (NAR group), 60 cases of healthy people (control group). All cases in AR group and NAR groups were evaluated by a visual analog scale (VAS) score of nasal symptoms. Collected peripheral blood and nasal secretions in all cases and then detected IL-17 and IL-23 expression levels. RESULT: There was no significant difference in VAS score of AR group and NAR group (P>0. 05). IL-17 and IL-23 levels of serum and nasal secretions in AR group and NAR group were both higher than control group, with a highly significant difference (P <0. 05). The research showed a clear correlation between expression of IL-17 and IL-23 both in serum and nasal secretions of AR group and NAR(P<0. 05). CONCLUSION: IL 17 and IL-23 may be important cytokines and IL-23/IL-17 pathway may play a significant role in the pathogenesis of allergic rhinitis and non-allergic rhinitis. PMID- 26513998 TI - [The effect research of specific immunotherapy of allergic rhinitis and allergic rhinitis combined bronchial asthma]. AB - OBJECTIVE: To study the therapeutic effects of the specific immunotherapy (SIT) on allergic rhinitis and allergic rhinitis combined bronchial asthma. METHED: All patients were classified into allergic rhinitis group (AR group) with 32 patients and allergic rhinitis combined bronchial asthma group (AR+BA group) with 32 patients. Another health control group with 32 cases was designed as well. The allergens,symptom scores and therapeutic effects of the former two-group patients were analysis, and the serums of all three-group cases were extracted to evaluate the specific Immunoglobin E(sIgE), Interleukin-4 (IL-4). The SPSS13. 0 package was applied to conduct t-test and chi-square test, and the difference of P<0. 05 was regarded as statistical significance. RESULT: The main allergens of 64 patients were dermatophagoides farinae and dermatophagoides pteronyssinus. The improvement of symptom scores before and after SIT was statistical significant with P<0. 05. Although total effective rate reached 100% , AR group was superior than AR+BA group in term of the efficacy comparison, and P<0. 05 indicated the statistical significance. The serum sIgE, IL-4 values of three groups were brought into comparison, and P<0. 05 indicated the statistical significance of the difference. CONCLUSION: The SIT on the AR, AR+BA is a safe and effective treatment, but different disease responds diversely. The long-term treatment course is recommended. PMID- 26513999 TI - [Efficacy of sublingual immunotherapy with Dermatophagoides farina drops in monosensitized and polysensitized patients with allergic rhinitis]. AB - OBJECTIVE: To evaluate the efficacy of sublingual immunotherapy (SLIT) with standardized Dermatophagoides farina drops in monosensitized and polysensitized patients with allergic rhinitis. METHOD: The clinical data of 162 patients treated with standardized Dermatophagoides farina drops were analyzed retrospectively. These patients were divided into the monoallergen sensitized group and polyallergen sensitized group according to the results of skin prick tests. The total nasal symptoms score (TNSS), the total medication score (TMS) and adverse effects (AEs) were evaluated before treatment, 2 year after SLIT treatment and 3 year after drug discontinuance. Result:After SLIT treatment for 2 years and drug discontinuance for 3 years, the TNSS (3. 14[2. 47; 3. 65], 3. 45 [2. 76; 3. 92], respectively) and TMS (0. 42[0. 36; 0. 57],0. 35[0. 26; 0. 44], respectively) in the monoallergen sensitized group were lower than that before the treatment (TNSS: 9. 00 [8. 00; 10. 00], TMS: 2. 16 [1. 88; 2. 37]), which have showed a statistically significant difference(P<0. 05). Similarly, after SLIT treatment for 2 years and drug discontinuance for 3 years, the TNSS (3. 14[2. 46; 3. 63], 4. 23[3. 65; 4. 96], respectively) and TMS (0. 42[0. 36; 0. 58], 0. 50[0. 34; 0. 72], respectively) in the polyallergen sensitized group were lower than that before the treatment (TNSS: 9. 00[8. 00; 10. 00], TMS: 2. 18[1. 95; 2. 37]), which have showed a statistically significant difference(P<0. 05). No statistically significant finding could be observed in monoallergen and polyallergen sensitized group before the treatment and 2 years after treatment, respectively. However, a statistically significant finding could be observed between two groups in the drug discontinuance for 3 years (P<0. 05). Eleven patients suffered local adverse effects, and the incidence of adverse effects showed no significantly difference (P>0. 05). CONCLUSION: SLIT with standardized Dermatophagoides farina drops has a long-term efficacy in monosensitized and polysensitized patients with allergic rhinitis. Moreover, a longer SLIT treatment (>2 years) may be necessary to consolidate its efficacy. PMID- 26514000 TI - [Relationship between allergic factors and eosinophilic nasal polyps]. AB - OBJECTIVE: To explore the effects of allergic factores in eosinophilic nasal polyps. METHOD: Clinical characters of 67 eosinophilic nasal polyps patients and 26 lymphocyte nasal polyps patients were restrospeetively analyzed. Allergic factors, allergens and nasal anatomic variations were compared between two groups. RESULT: Allergic factors are proned to present in eosinophilic nasal polyps group compared with lymphocyte nasal polyps group; The positive rates of allergen skin test between eosinophilic nasal polyps group and lymphocyte nasal polyps group showed significant difference; Allergens in eosinophilic nasal polyps group are different from lymphocyte nasal polyps group; Nasal anatomic variations are different between two groups. CONCLUSION: Different pathogenesis maybe exist in different pathological type nasal polyps. Allergic factors are closely relative to eosinophilic nasal polyps and nasal anatomic variations play a more important role in the formation of lymhocyte nasal polyps. PMID- 26514001 TI - [The influence of Xuanfeijiedu granules on trace elements, IgE, ECP of allergic rhinitis]. AB - OBJECTIVE: To study the influence of Xuanfeijiedu granules on trace elements, immunoglobulin E (IgE), eosinophil cationic protein (ECP) of allergic rhinitis. METHOD: One hundred and ten cases of allergic rhinitis ere randomly divided into two groups, 55 cases of the observation group were treated with budesonide, 55 cases of the control group were treated with Xuanfeijiedu granules, the treatment efficacy and serum trace elements, IgE, ECP level were observed. RESULT: The total effective rate of observation group and control group were 92. 7% and 96. 4%, there was no significant difference between two groups (P>0. 05). Before treatment, the serum zinc (Zn), copper (Cu), manganese (Mn) and IgE, ECP levels of two groups were compared, there was no significant difference (P>0. 05); after treatment, the serum Zn level was significantly increased, the serum Cu, Mn, IgE, ECP levels were significantly reduced, and the observation group changed more significantly, there were significant differences between two groups (P<. 05). CONCLUSION: Xuanfeijiedu granules in the treatment of allergic rhinitis can significantly improve the patient's serum trace elements and IgE, ECP levels, improve the state of patient's disease, and promote the rehabilitation of patients. PMID- 26514002 TI - [Study on the correlation between chronic sinusitis with nasal septum deviation]. AB - OBJECTIVE: Study on the correlation between chronic sinusitis with nasal septum deviation. METHOD: Randomly selected 722 patients with coronal sinuses CT, statistics the number of cases of nasal septum deviation, cases of nasal septum deviation with chronic sinusitis, the wide and narrow side cases of nasal septum deviation complicated with sinusitis. The number of sinusitis without deviation, and paired test. RESULT: The incidence of sinusitis between deviation of nasal septum and non deviation were 54. 13% and 44. 66%, the difference between two groups was statistically significant (P<. 05), the incidence of sinusitis with nasal septum deviation of wide and narrow side were 31. 65% and 32. 12%, no significant difference between the two groups (P>0. 01). The incidence of sinusitis high deviation and non high deviation were 59. 54% and 46. 97%, the difference between the two groups was statistically significant (P<0. 05). The number of wide side of upper nasal septum deviation with sinusitis was 54, the narrow side was 66, there is no significant difference between the two groups (P>0. 05). CONCLUSION: The deviation of nasal septum is associated with the formation of chronic sinusitis, the high deviation is more prone to sinusitis, The incidence of sinusitis and nasal septum deviation on both sides was no different. PMID- 26514003 TI - [The long-term clinical efficacy of endoscopic surgery of primary sinonasal malignant neoplasms]. AB - OBJECTIVE: To assess the long-term clinical efficacy of endoscopic surgery of primary sinonasal malignant neoplasms and find out the potential postoperative prognostic factors. METHOD: Forty-three clinical cases of primary sinonasal malignant neoplasms treated under endoscopy were analyzed retrospectively. RESULT: Fifteen patients died. The 1-year, 2-year, 3-year and 5-year survival rates were 83. 7% (36/43), 74. 4% (32/43), 69. 8% (30/43) and 65. 1% (28/43), respectively. Kaplan-Meier single-variable analysis showed that gender, T grade, TNM stage and pathological types of olfactory neuroblastoma were statistically significant prognostic factors (P< 0. 05). COX Pro-Portional hazard models showed that TNM stage was an independent prognostic factors. CONCLUSION: Endoscopic surgery for primary sinonasal malignant neoplasms is a safe and effective minimally invasive surgical treatment, and it is an important supplement to the traditional surgery. Gender, T grade, TNM stage and pathological types of olfactory neuroblastoma might be significant prognostic factors. PMID- 26514004 TI - [Study on the factors impacting on early cochlear implantation between the eastern and western region of China]. AB - OBJECTIVE: To describe tne regional different factors which impact on early cochlear implantation in prelingual deaf children between eastern and western regions of China. METHOD: The charts of 113 children who received the cochlear implantation after 24 months old were reviewed and analyzed. Forty-five of them came from the eastern region (Jiangsu, Zhejiang or Shanghai) while 68 of them came from the western region (Ningxia or Guizhou). Parental interviews were conducted to collect information regarding the factors that impact on early cochlear implantation. Result:Based on the univariate logistic regression analysis, the odds ratio (OR) value of universal newborn hearing screening (UNHS) was 5. 481, which indicated the correlation of UNHS with early cochlear implantation is significant. There was statistical difference between the 2 groups (P<0. 01). For the financial burden, the OR value was 3. 521(strong correlation) and there was statistical difference between the 2 groups (P<0. 01). For the communication barriers and community location, the OR value was 0. 566 and 1. 128 respectively, and there was no statistical difference between the 2 groups (P>0. 05). The multivariate analysis indicated that the UNHS and financial burden are statistically different between the eastern and western regions (P=0. 00 and 0. 040 respectively). CONCLUSION: The UNHS and financial burden are statistically different between the eastern reinforced in the western region. In addition, the government and society should provide powerful policy and more financial support in the western region of China. The innovation of management system is also helpful to the early cochlear implantation. PMID- 26514005 TI - [The clinical characters and surgical management of nasopharyngeal teratoma in infants]. AB - OBJECTIVE: To describe and analyze the clinical characteristics of nasopharyngeal teratoma in infants and improve the levels of diagnosis and treatment to reduce misdiagnosis. METHOD: The clinical data of 11 cases of nasopharyngeal teratoma in infants were reviewed retrospectively and summarized the clinical features. After the preoperative examination of nasopharyngeal endoscopy and imaging (CT or MRI), all patients were under general anesthesia of nasopharyngeal teratoma surgical resection. Of them, 8 cases were used radiofrequency ablation, 3 cases used conventional power systems. RESULT: Eleven cases with neoformation were completely removed, the operation time was 5-15 min, blood loss was 1-5 ml, patients had no significant nasal obstruction, bleeding, eating nasopharyngeal regurgitation, breathing difficulties or other complications. No recurrence was found after 10 months to 9 years followed up. CONCLUSION: The nasopharyngeal mass must be kept in mind in the differential diagnosis of breathing difficulties in infants, especially when it exists together with upper airway obstruction symptoms; The low-temperature radiofrequency ablation with endoscopic had the advantages of short time, precise control, less bleeding, clear operative field, little injury and pain, low recurrence, providing a new clinical treatments. PMID- 26514006 TI - [An in vitro study on substance P-stimulated neuro-immune mechanism of mast cell degranulation]. AB - OBJECTIVE: The goal of this study was to study the mechanism of substance P (SP) mediated the neural control of mast cell (MC) degranulation. METHOD: Bone marrow mast cells from mice were cultured with stem cell factor (SCF), IL-3 and IL-4 (group A) and SCF, IL-3 (group B) for four weeks. Then the cells were harvested and reserved for studies. Western Blot hybridization technique was used to detect the expression of FcepsilonR I alpha and NK-1R on MCs from the two groups. Then such cells were activated with SP (0, 0. 01, 0. 10, 1. 00, 10. 00 ug/ml, respectively) for 30 min. The histamine released into the supernatant and stored in the protoplasm was quantified by enzyme linked immunosorbent assay (ELISA). And the percentage of histamine release was calculated as a percent of total histamine content. RESULT: The expressions of FcepsilonR I alpha and NK-1R on these mast cells in group A were statistically higher than in group B (P<0. 05). The MCs from two groups can be actived when stimulated by SP, but the level of MC degranulation in group A was higher than group B (P<0. 05). CONCLUSION: Neuropeptide may stimulate MC degranulation through immunological and non immunological pathways. In summary, the current study provides us with better understanding of the mechanism of neuropeptide-controlled MC deranulation, and this should be helpful for the further research involved in the mechanism and treatmemt of airway hyper-reactivity. PMID- 26514007 TI - [Effect of dexamethasone on the expression of Tregs in allergic rhinitis mice]. AB - OBJECTIVE: To investigate the effect of dxamethasone (DEX) on the expression of Tregs in allergic rhinitis (AR) mice, and explore the mechanism of glucocorticoid in the treatment of AR. METHOD: AR murine model was established by sensitization and challenge with OVA, besides intervention treatment with DEX was carried out in AR model. The behavior observation was used to evaluate the improvement effect of DEX on AR symptoms. The morphological characteristics of nasal tissues were observed by HE staining after fixation and decalcification. The mononuclear cells were obtained by grinding spleens, and the total RNA was extracted for reverse transcriptase polymerase chain reaction to investigate the level of mRNA expression of Foxp3. The changes of CD4+ Foxp3+ Tcells in spleen of mice were analyzed by flow cytometry. RESULT: BALB/c mice received OVA sensitization followed by OVA intranasal challenge, the frequencies of sneezing and nose scratching increased significantly in AR group (44. 50 +/- 5. 61 and 72. 94 +/- 8. 76) compared with control group (12. 68 +/- 1. 87 and 26. 76 +/- .2. 89), P<0. 01; The frequencies decreased significantly in DEX group (26. 04 +/- 3. 93 and 56. 79 +/- 5. 64), P< 0. 05 compared with AR group. The continuity of nasal mucosa ciliated columnar epithelium in AR group was destroyed and appeared to be repaired in DEX group. Inflammatory cells infiltration was also markedly decreased by DEX treatment. The proportion of CD4+ Foxp3+ T cells in AR group (3. 89 +/- 0. 39)% decreased, P<0. 01 vs control group (4. 63 +/- 0. 15) %. DEX treatment induced production of Tregs (6. 89 +/- 0. 49)%, P<0. 05 vs control group. DEX significantly increased the expression of Foxp3 mRNA (P<0. 05) compared with AR and control group. CONCLUSION: DEX reduce upper airway allergic inflammation effectively, which may be mediated by promoting the expression of Foxp3 and inducing the amplification of Tregs in vivo. PMID- 26514008 TI - [The application of expandible and soluble chitosan sponge in patients with the disease of haematology nasal bleeding]. PMID- 26514009 TI - [The extraction of foreign body in nasal sinus and bases of skull: craniotomy or not?]. PMID- 26514010 TI - [Intranasal endoscopic coblation exairesis for nasal vestibular cyst]. PMID- 26514011 TI - [A case report of endoscopic assisted unilateral infraorbital nerve decompression]. AB - Patients of infraorbital nerve injury often appear in the sensory abnormalities of corresponding position, such as numbness or pain. We present a case with numbness of the left cheek because of the injury. The patient were treated by endoscopic assisted on the left infraorbital nerve decompression through the approach of the canine fossa. The symptom shows improvement after the operation. The patient feels numbness significantly ease on 4 months after the operation. PMID- 26514012 TI - [Nasopharynx pleomorphic adenoma report]. AB - The patient was a 42 years old female. And the reason why she was addmited to the hospital was progressive bilateral nasal congestion for one year, and bilateral nasal bleeding for one day. Physical examination showed no surgical contraindication so the patient got the nasal endoscope by plasma radiofrequency ablation surgery with general anesthesia on 3rd Dec. 2013. And the result of potholegical examination was nasopharynx pleomorphic adenoma. PMID- 26514013 TI - [Digestive system carcinoma metastatic to the nasal cavity: two case report]. AB - Metastatic tumors to the nasal cavity and paranasal sinuses are far less common than primary cancer in this location. The digestive system malignant tumor metastasis to the nose is rarer. The clinical presentation of metastases is similar to that of primary tumors and common symptoms include recurrent epistaxis, nasal obstruction and facial pain. Metastases to the nose and paranasal sinuses usually respond poorly to treatment and have a poor prognosis. PMID- 26514014 TI - [Pyogenic granuloma of inferior turbinate: a case report]. AB - A case of pyogenic granuloma occurred in inferior turbinate was reported and the literatures were reviewed. A 32 years old male patient with left side progressive stuffy nose and repeated epistaxis. Nasal endoscopic examination showed a dark red neoplasm in left nasal cavity and blocked the anterior naris. Nasal cavity enhanced CT showed the neoplasm located in the front of left nasal cavity with marked enhancement. Bilateral sinuses were normal and there was no significant bone destruction. Nasal endoscopic surgery was performed under local anesthesia. Postoperative pathology report showed pyogenic granuloma (granulation tissue type of angioneoplasm). PMID- 26514015 TI - [One case of human nasal myiasis]. AB - Human myiasis is caused by the parasitic maggots of flies. We report a case of nasal myiasis in a 37-year-old woman in Henan. The patient presented with nasal foreign-body sensation, nansal itching sneezing, snuffle and such allergic symptoms in nasal cavity. Based on maggots that were bowed from the right nasal cavity, a detailed endoscopic examination, sinus CT scan and identification of the maggot's species done by parapsychologists of the parasitology teaching and reseach section of the Zhengzhou University School of Medicine, the diagnosis of human nasal infestation by oestrus ovis was definited. PMID- 26514016 TI - [The research status of probiotic treatment of allergic rhinitis]. AB - Allergic rhinitis is nasal mucosa of immediate hypersensitivity, and the current treatment is not satisfied. With the increasing incidence in recent years, we pay more attention on the effective treatments. There are some published studies indicate the benefit of probiotic for allergic rhinitis. Refer to the related literature in recent years, the paper will discuss probiotic species, safety, route of administration, mechanism and efficacy, pointing out a new direction for the treatment of allergic rhinitis. PMID- 26514017 TI - It's the LEAVING! PMID- 26514018 TI - Evidence-Based Palliative Care 13 Years On: Has anything changed? AB - There is a paucity of data on whether interventions in individual palliative care units are evidence-based. Thirteen years ago an initial study evaluated the evidence base of interventions in palliative care. Using similar methodology in the present study, we evaluated the evidence for interventions performed in an inpatient palliative care setting, looking at level of evidence as well as quality and outcome of evidence. More than half of all the interventions (47 interventions, 59 percent) we looked at in a Brisbane, Australia, inpatient palliative care setting were based on a high level of evidence in the form of systematic reviews of randomized controlled trials (level I or level II). There were only a few interventions (10 percent) for which no evidence could be retrieved. Our results show that the evidence base for interventions in palliative care continues to evolve, but that there are still areas for which further high-quality studies are needed. PMID- 26514019 TI - The Practice of Continuous Palliative Sedation in Long-Term Care for Frail Patients with Existential Suffering. AB - Some guidelines and recommendations identify existential suffering as a potential refractory symptom for which continuous palliative sedation (CPS) can be administered under certain conditions. However, there has been little research on the characteristics of patients with existential suffering treated with CPS and the degree to which the preconditions are fulfilled. The aim of this study was to provide insight into this specific indication for CPS. Questionnaires were sent to nursing home physicians in The Netherlands, who described 314 patients. Existential suffering was a refractory symptom in 83 of the patients. For most of the patients with refractory existential suffering, other refractory symptoms were also reported, and life expectancy was seven days or less; informed consent for initiating CPS had been obtained in all cases. Consultation and intermittent sedation before the start of CPS were far less frequently reported than one would expect based on the guidelines. Multivariate analysis showed that being male, having previously requested euthanasia, having a nervous system disease, or having an other diagnosis were positively correlated with the administration of CPS for existential suffering. We conclude that more attention should be paid to the suggested preconditions and to the presence of existential suffering in male patients or patients with a nervous system disease. PMID- 26514020 TI - Healthcare Needs of Patients with Amyotrophic Lateral Sclerosis (ALS) in Singapore: A patient-centred qualitative study from multiple perspectives. AB - BACKGROUND: One challenge for those who manage amyotrophic lateral sclerosis (ALS) is to understand patients' needs. AIM: The aim of this study was to examine the needs of Singapore ALS patients from their perspective as well as that of their caregivers and healthcare professionals in order to develop a template for better services. METHODS: A cross-sectional qualitative study was conducted, with one-to-one interviews and focus group discussions. RESULTS: All 30 participants, key stakeholders in the field of caring for ALS patients, identified these needs categories: psychological--diagnosis must be staged and comfortably paced, and efforts must be made to encourage patients' resilience; social--positive relationships, open communication, and spiritual support must be developed; physical--attention should be paid to alleviating discomfort and disability; and environmental--appropriate services should be made available. CONCLUSION: The identified needs categories do overlap, but there are significant differences. Our findings provide a template for developing individualized patient services, which should be done within the framework of a comprehensive palliative care program. PMID- 26514021 TI - Defining a Good Death: A deliberative democratic view. AB - Many attempts to define a good death have been recorded in the academic literature. In most of these attempts, the methods used have been surveys, interviews, and focus groups. These methods have yielded important information, but they have failed to provide an opportunity for public deliberation, whereby people engage collectively with an issue, consider it from all sides, and struggle to understand it. We believe that a well-orchestrated public deliberation could contribute to defining a good death. We gathered data from four deliberative forums implemented in Finland in November 2013. The results paint a picture that differs from those painted by the previous research, which focused mainly on individual and idealized views of a good death. Our findings have brought to light the messy reality of a good death. Deliberation elicited the concern that society could not provide a good death for all and in the process highlighted the lack of proper palliative care and the dominant role of healthcare professionals in defining a good death. Participants also came to terms with the inherent complexity of dying well and gained a better understanding of the challenges related to providing a good death via euthanasia. Their perspectives broadened, proving that defining a good death is a dynamic process rather than a static one. PMID- 26514022 TI - Intimations of Dying: A visible and invisible process. PMID- 26514023 TI - Is There a Role for Statins in Palliative Care for Patients Suffering from Hepatocellular Carcinoma? PMID- 26514024 TI - Paraneoplastic Syndromes in Palliative Care: A literature review from a nursing perspective. PMID- 26514025 TI - Hope in Palliative Care: Cultural implications. PMID- 26514026 TI - Janet Frame's "An Electric Blanket": Love, loss, and "the bitter seed of moment". PMID- 26514027 TI - End-of-life care for those on skid row. PMID- 26514028 TI - Preface. Sports Medicine and Sports Injuries. PMID- 26514029 TI - Being a Team Doctor. PMID- 26514030 TI - Preparticipation Physical Evaluation. AB - Preparticipation physical evaluations are often a challenge for physicians. A recent study examined the PPE in clinical practice among pediatricians and family physicians in the state of Washington. Unfortunately, many physicians in this study perceived significant barriers to effective performance of the PPE. These barriers included uncertainty about how to perform the PPE, the relative importance of each PPE component, and the lack of a standardized approach and time for appropriate performance of the PPE. Although these concerns are shared by physicians beyond the borders of Washington, those who are aware of the information contained in the PPE monograph are able to use current best practices to enhance the effectiveness and efficiency of this examination and report greater comfort and satisfaction with these evaluations. PMID- 26514031 TI - Concussion in Teenage Athletes. PMID- 26514032 TI - Musculoskeletal Injuries Not to Miss in Teens. PMID- 26514033 TI - Overuse and Overtraining Injuries in Teenage Athletes. PMID- 26514034 TI - Rehabilitation of Musculoskeletal Injuries in Young Athletes. AB - Caring for young athletes challenges the physician to use primary preventive measures to prevent injury and to respond with secondary measures when injuries do occur. An enhanced knowledge of the rehabilitation process will assist the physician in making the appropriate referrals and in evaluating the patient's condition before clearing that athlete. Use of criteria-based testing may aid the primary care physician in determining an athlete's readiness for sport. PMID- 26514035 TI - The Female Athlete Triad: Energy Deficiency, Physiologic Consequences, and Treatment. PMID- 26514036 TI - The Adolescent Dancer: Common Medical Concerns and Relevant Anticipatory Guidance. PMID- 26514037 TI - Mental Health and Pressures in Teen Sports. PMID- 26514038 TI - Performance-Enhancing Substances. PMID- 26514039 TI - The Traveling Athlete. PMID- 26514040 TI - Extreme Sports and the Adolescent Athlete. PMID- 26514041 TI - [A Proposal for Natural Resilience Theory in Psychopharmacotherapy: To Deter High dose Antipsychotic Polypharmacy]. PMID- 26514042 TI - [Behavioral Activation for Depression: Theory and Practice]. AB - Behavioral activation (BA) has recently attracted marked attention. While cognitive therapy focuses on the cognitive distortion of patients with depression and asks them to change their behaviors as the process of altering the cognitive distortion, BA pays attention to behavior to avoid an unpleasant situation or social situation as a key symptom that leads to persistence of the depression. Avoidance behaviors are often seen during every process of depression, from onset to recurrence. Avoidance behaviors, a decrease in pleasant phenomena, or increase in unpleasant phenomena, result in reinforcing a depressive mood. If patients can set appropriate behavioral targets and achieve them, the beneficial behaviors will be further promoted with positive feed-back. The behavioral change, as-a consequence, will result in improvement of the mood, cognition, and depression itself. In this manuscript, the author presents two clinical cases, in which BA assisted the patients in recovering from their depression. The first case was a male in his thirties who repeatedly took sick leave from his work because of maladjustment, which resulted in persistent depression. The second case was a female in her thirties who suffered from OCD and then became maladjusted to her place of work, depressive, and emotionally unstable. In both cases, avoidant behaviors caused their conditions to persist. Appropriate activities formed by BA improved their moods, and their self-efficacies were gradually regained. It was suggested that BA is markedly effective, especially in patients whose avoidant behaviors mainly cause the persistence of their depressive symptoms. PMID- 26514043 TI - [Practice of Behavioral Activation in Cognitive-behavioral Therapy]. AB - An approach focusing on behavioral activation (BA) was adopted in the cognitive therapy of A. T. Beck, and it came to be considered that BA can play an important role in cognitive-behavioral therapy (CBT) for depression. Therefore, in recent years, BA based on clinical behavior analysis has been developed as a new treatment (Martell, et al.). The core characteristics are as follows: 1) focusing attention on context in daily life to promote the behavior control of patients and avoidance of a hatred experience ; 2) breaking the vicious circle; 3) promoting the behavior according to the purpose that the patients originally expect; 4) recognizing a relationship between behavior and the situation (contingency), thereby recovering self-efficacy tied to the long-term results that one originally expects. This does not increase pleasant activity at random when the patient is inactive, or give a sense of accomplishment. We know that depression is maintained by conducting functional analysis of detailed life behavior, and encourage the patients to have healthy behavior according to individual values. We help them to complete schedules regardless of mood and reflect on the results patiently. It is considered that those processes are important. BA may be easy to apply in clinical practice and effective for the chronic cases, or the patients in a convalescent stage. Also, in principle in the CBT for major depression, it may be effective that behavioral activation is provided in an early stage, and cognitive reconstruction in a latter stage. However, an approach to carry out functional analysis by small steps with careful activity monitoring is essential when the symptoms are severe. Furthermore, it should be considered that the way of psychoeducation requires caution because we encourage rest in the treatment of depression in our country. In particular, we must be careful not to take an attitude that an inactive behavior pattern is unproductive only based model cases. PMID- 26514044 TI - [Morita Therapy to Treat Depression: When and How to Encourage Patients to Join Activities]. AB - The author discusses how Morita therapy is used to treat depression, illustrated with a clinical case, and makes comparisons between Morita therapy and behavioral activation (BA). The author further examines the issue of when and how to encourage patients to join activities in clinical practice in Japan. Both Morita therapy and BA share at least a common view that it is effective to activate patients' constructive behavior at a certain point in depression treatment. However, BA therapists, compared to Morita therapists, seem to pay less attention to the necessity of resting and the appropriate timing for introducing behavioral activation. There may be some contextual differences between depressive patients in Japan and those in North America. In the case of Japanese patients, exhaustion from overwork is often considered a factor triggering the development of depression. At the same time, the Morita-based pathogenic model of depression seems different from BA's model of the same disorder. BA's approach to understanding depression may be considered a psychological (behavioristic) model. In this model, the cause of depression lies in: (a) a lack of positive reinforcement, and (b) negative reinforcement resulting from avoidance of the experience of discomfort. Therefore, the basic strategy of BA is to release depressive patients from an avoidant lifestyle, which serves as a basis for negative reinforcement, and to redirect the patients toward activities which offer the experience of positive reinforcement BA is primarily practiced by clinical psychologists in the U. S. while psychiatrists prescribe medication as a medical service. On the other hand, the clinical practice of treating depression in Japan is based primarily on medical models of depression. This is also true of Morita therapy, but in a broad sense. While those who follow medical models in a narrow sense try to identify the cause of illness and then remove it, Morita therapists pay more attention to the recovery process rather than the pathogeneses of depression, and attempt to foster patients' natural healing power and resilience. Therefore, it may be more appropriate to refer to the model used in Morita therapy as "a health-recovery model." Moreover, the Moritian model of depression partially incorporates a psychological model because patients' dogmatic thinking (e. g., perfectionistic self-expectations and high demands on self) is regarded as a factor hindering their recovery, which Morita therapists try to modify. In conclusion, it is recommended that we reconsider the importance of incorporating psychological help which is compatible with the initial treatment principle based on resting and pharmacotherapy in clinical practice in Japan. PMID- 26514045 TI - [Evidence for the Efficacy of Behavioral Activation against Depressive Disorder: A Literature Review]. AB - A growing body of evidence suggests the significant efficacy of behavioral activation therapy (BA) for the treatment of depression, although BA had formerly been regarded as only a part of the techniques for cognitive-behavioral treatment (CBT). The aim of this article is to review the effectiveness, indications, and limitations of BA for the psychosocial treatment of depression. The research group of Washington University in St. Louis, who previously suggested the marked efficacy of BA based on component analysis of CBT, performed a large-scale study to compare the effect of BA and cognitive therapy (CT) or antidepressant medication on the acute phase of depression. As the results, BA was superior to CT and comparable to antidepressant medication in acute-phase treatment for a subgroup of patients with relatively severe depression. Moreover, a long-term follow-up study revealed a benefit of BA compared to pharmacological treatment in regard to the persistence of the effect and cost-effectiveness. More recently, a number of meta-analyses have indicated no significant difference among BA and other psychotherapies regarding their efficacy for the treatment of depression. Because BA does not require patients or therapists to learn complex skills and is also time-efficient, it is recommended as the first-line treatment for mild or moderate depression. However, further studies are needed to consider indications, the timing of induction, and variation in BA techniques if it is applied for the treatment of depression in a general clinical setting in Japan. PMID- 26514046 TI - [Drug Interactions and Pharmacokinetics of Psychotropic Drugs]. AB - Pharmacokinetics is the field dedicated to investigating the absorption, distribution, metabolism and excretion of drugs. Absorption of drugs is affected when they are taken together with a meal. Depending on the drug, the area under the concentration curve is affected by whether a medication is taken before or after a meal. Combined use of drugs with a high plasma protein binding fraction may be dangerous, since drug efficacy is impacted by efficiency, which in turn is affected by the degree to which it binds to proteins. Even more significant is the issue of "drug/drug" interactions that arise due to inhibition of the cytochrome P450 (CYP) hepatic microsomal enzyme system. Some antidepressants, such as paroxetine and fluvoxamine, are strong inhibitors of the CYP system. In the case of a medication that depends on renal clearance for elimination, caution is required when taking such a drug if it influences renal function. When a medicinal effect changes, pharmacodynamic changes must also be considered. PMID- 26514047 TI - [Optical Topography as an Auxiliary Laboratory Test for Differential Diagnosis of Depressive State: Clinical Application of Near-infrared Spectroscopy (NIRS) as the First Trial for Approved Laboratory Tests in Psychiatry]. AB - The lack of clinical laboratory tests is a major obstacle in the reliable diagnosis and quantitative treatment assessment and prevention of psychiatric disorders and in the development of patient-centric psychiatric practices. Optical topography has been approved as an insurance-covered auxiliary laboratory test for differential diagnosis of depressive state by Ministry of Health, Labour and Welfare in Japan since 2014. Near-infrared spectroscopy (NIRS), theoretical basis of optical topography, is one of functional neuroimaging techniques that has been increasingly employed in psychology and psychiatry. Because NIRS can detect only cerebral cortex reactivities with low spatial resolution and may suffer from contaminating signals from skin and skull, its data should be interpreted as a global index of cerebral cortex reactivities. Within these limitations, the advantages of NIRS over fMRI such as complete non-invasiveness, small measurement apparatus, high time resolution, and natural examination setting lead it to one of the preferred methods in studies of brain substrates of psychiatric disorders. Two-thirds of the original articles on NIRS application in psychiatry have been published by Japanese researchers. NIRS examination of major depressive disorder, bipolar disorder, and schizophrenia using a verbal fluency task of only three minutes demonstrated diagnosis-specific characteristics of frontal lobe function. These characteristics have been established as suggesting potential diagnosis of bipolar disorder or schizophrenia in clinically diagnosed major depressive disorder. In order to establish the application of NIRS as clinically useful laboratory tests in psychiatry, auxiliary nature of NIRS examination for differential diagnosis should be properly recognized both by patients and psychiatrists. PMID- 26514048 TI - [Clinical Introduction of Repetitive Transcranial Magnetic Stimulation for Major Depression in Japan]. AB - Therapeutic applications of repetitive transcranial magnetic stimulation (rTMS) have long been awaited for not only neurological but also psychiatric disorders as a low-invasive transcranial brain stimulation. In 2008, the Food and Drug Administration (FDA) of the United States finally approved repetitive transcranial magnetic stimulation (rTMS) for medication-resistant patients with major depression. More recently, at the beginning of 2013, a deep TMS device with the H-coil received FDA approval as the second TMS device for major depression. In Japan, it is estimated that more than 200,000 patients with medication resistant major depression could be candidates for rTMS treatment. To promote the clinical introduction of rTMS for major depression, joint discussion has been ongoing including the Japanese Society of Psychiatry and Neurology (JSPN), the Japanese Ministry of Health, Labour, and Welfare (MHLW), and the Pharmaceutical and Medical Devices Agency (PMDA). On the other hand, some corporate efforts have begun to get MHLW/PMDA approval for a few types of rTMS device. In 2013, the JSPN established a new committee in order to discuss the introduction of neuromodulation methods such as rTMS in Japan. The committee has been discussing how rTMS should be introduced appropriately with expedition, considering the MHLW regulations for the expedited introduction or provisional use of advanced medical technology. Also, the MHLW has required related psychiatric societies to formulate clinical guidelines of rTMS for major depression in order to avoid any potential overuse or misuse. A number of controversies are ongoing, such as standards for the appropriate clinical application of rTMS, a suitable position of rTMS within the comprehensive treatment algorithm of major depression, and bioethical standards for brain stimulation (neuroethics). Moreover, there are some pragmatic issues. For instance, the Japanese Society of Clinical Neurophysiology (JSCN) has restricted repetitive TMS administration to medical doctors due to safety concerns. In order to disseminate rTMS in Japan, it should be discussed how to reduce the work-load of psychiatrists who administer rTMS on a daily basis. For this purpose, standards should be established by the JSCN to qualify non-MD rTMS operators under the supervision of psychiatrists. In this paper, recent progress in the clinical introduction of rTMS for major depression in Japan is reported, in order to facilitate future discussion about how rTMS should be introduced for patients with major depression in Japan. PMID- 26514049 TI - [Clinical Application and Safety of rTMS in Japan and Overseas]. AB - Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that can stimulate the cerebral cortex and alter cortical and subcortical activities, and it has been approved to treat depression in the USA, Australia, and Europe. In Japan, several manufacturers have focused on obtaining approval for rTMS. In terms of the safety and tolerability of rTMS, headache, stimulation pain, and discomfort occur at relatively high frequencies during rTMS, but these events usually improve rapidly as the number of treatment days increases. The induction of seizures is the most severe side effect of rTMS, and its rate is less than approximately 0.1%. In the practice of rTMS, it is critically important to check for medications known to modify the seizure threshold and any metal in the body, and to assess the risk of seizures. PMID- 26514050 TI - [What are Considerations for Clinical Investigation of New Drugs and Treatment Techniques for Major Depressive Disorders?]. AB - Major depressive disorder treatments remain unsatisfactory, and the development of novel antidepressants is continuing. Therefore, not only the establishment of therapeutic strategies to accumulate evidence on existing therapies, but also the development of novel therapies is required in order to improve the medical standards. In principle, parallel, double-blind, randomized, placebo-controlled trials are necessary to assess new compounds for the treatment of major depressive disorders from a scientific perspective. To provide unambiguous evidence of antidepressant activity, well-controlled studies with adequate designs must show efficacy with a statistically significant effect on a clinically meaningful endpoint. For this purpose, it is important to examine all aspects of factors that adversely affect the efficacy and safety assessment in the planning stage of clinical trials and reduce these factors. There are several specific characteristics of clinical trials for neuropsychiatric disorders. Some typical features are as follows: 1) a high and variable response, 2) impact on the effect of the baseline severity of disorders, 3) high dropout rates, 4) biases related to subjective measures of clinical symptoms. In this paper, considerations for the planning and performing of clinical trials for major depressive disorders will be discussed based on these features. PMID- 26514051 TI - [Toward the Introduction of Repetitive Transcranial Magnetic Stimulation in Japan to Treat Antidepressant-resistant Depression]. AB - Treatment of major depressive disorder (MDD) can include a variety of biopsychosocial approaches. In medical practice, antidepressant drugs are the most common treatment for moderate to severe depressive episodes; however, their efficacy is limited. Many depressed patients are considered treatment-resistant, with 33% failing to achieve remission after >= 3 treatment trials. A systemic review and meta-analysis revealed that repetitive transcranial magnetic stimulation (rTMS) may be reasonably considered for patients with MDD and >= 2 prior failures of antidepressant treatment. No rTMS devices have been approved by the Japanese Pharmaceuticals and Medical Devices Agency, which has resulted in its off-label use; therefore, to offer better care for cases of treatment resistant MDD, we should continue efforts to seek the introduction of rTMS to Japan. PMID- 26514052 TI - [The Problems with Domestic Introduction of rTMS from the Three Viewpoints of Scientific Evidence, Specialty and Social Responsibility]. AB - The domestic introduction of rTMS is expected as a new treatment option for treatment-resistant depression. I discussed some problems with the introduction from three viewpoints : scientific evidence, specialty, and social responsibility. I surveyed scientific evidence for rTMS regarding the action mechanism, effectiveness, side effects, and its positioning in the treatment guidelines. To secure the quality of rTMS treatment, I proposed rTMS guidelines, nurturing of the specialists, and a center hospital plan, and pointed out some medium-term problems after its introduction and the consistency of rTMS treatment and standard depression treatment. From the viewpoint of social responsibility, rTMS treatment should be a medical service covered by health insurance to avoid its misuse. We should prepare to overcome the public suspicion of brain stimulation treatment for mental disease. PMID- 26514053 TI - [What Lessons Should We Learn from the Death of Patients on Xeplion?]. AB - From the launch of the long-acting injectable antipsychotic paliperidone palmitate (XEPLION) on November 19, 2013, 32 fatal cases had been reported up to May 18, 2014 (estimated number of users is approximately 11,000 patients) in the Early Post-marketing Phase Vigilance. The most common cause of death was sudden death (12 cases were sudden death defined by ICD-10 codes 96.0 and 96.1 and 4 cases suspected sudden death), followed by suicide (7 cases), and neuroleptic malignant syndrome (4 cases). Several deaths occurred involving patients with serious somatic disorder, such as a malignant tumor or pneumonia. The risk of all cause mortality on XEPLION was not high in comparison with other investigations; the sudden death risk on XEPLION may be higher than on ZODIAC. According to many reports from foreign countries, mortality rates associated with schizophrenia are two to three times higher than those of the general population, corresponding to a 10-25-year reduction in life expectancy. Natural deaths account for about 60% of the excess mortality of schizophrenia patients, and such patients are more likely to die from ischemic heart disease. Since it has been suggested that more than half of sudden deaths in schizophrenic patients have a cardiac origin, sudden cardiac deaths are chiefly responsible for their reduced life expectancy. This sudden death-related problem of patients with schizophrenia has been forgotten or ignored in the psychiatric care of Japan. Taking advantage of this opportunity, we should tackle this problem seriously, and make an effort to reduce the mortality gap. PMID- 26514054 TI - Bullying in adolescence linked to depression in young adults. PMID- 26514055 TI - Optimising the management of bronchiolitis in infants. AB - Bronchiolitis shows a seasonal pattern with peak incidence occurring in the winter. Around 2-3% of children require admission to hospital. Admission rates are highest in infants less than three months old and those with underlying comorbidities. It typically affects children in the first year of life peaking between three and six months of age. Infants will have a coryzal prodrome lasting one to three days before developing a persistent cough. Fever and reduced feeding are common and very young infants may present with apnoeic episodes. Symptoms normally peak between days three to five of the illness. There will be evidence of increased work of breathing such as tachypnoea, in drawing/recession, head bobbing, grunting, nasal flaring or tracheal tug. Auscultation typically reveals wheeze and/or crepitations throughout both lung fields. Most children with bronchiolitis do not need to be referred to secondary care and can be managed safely at home. Immediate referral to hospital should be arranged if there is: apnoea (observed or reported), the child looks seriously unwell, severe respiratory distress, marked chest recession or a respiratory rate >70 breaths/minute, central cyanosis or persistent oxygen saturation < 92% when breathing room air. PMID- 26514056 TI - Managing the child with a fever. AB - Most illnesses associated with fever are self-limiting and children recover with no specific treatment. However, fever can also be the presenting feature of serious illness, which may be life threatening if not diagnosed and treated appropriately. It is important to establish whether the temperature has been measured and, if so, how. The height of the temperature should be recorded, and always enquire what device has been used, as a reading from a forehead thermometer may not be accurate. While many families will use a thermometer the impression of the child being hot to touch without formal measurement should still be taken seriously. Check whether the child is still feeding or taking fluids adequately. Any child may be irritable when their temperature is high, but a constantly irritable or inconsolable child, or one who is extremely lethargic, drowsy or difficult to rouse is a cause for concern. Ask about any skin changes or rashes the parent may have noticed. Find out what measures the parent may already have taken to manage the fever, and in particular, whether, and at what time, antipyretics have been given. Enquire about contact with infectious illnesses, and foreign travel. Other vital signs, including heart rate, respiratory rate and capillary refill time should also be recorded. The child should be examined for focal signs indicating the site of infection, and hydration should be assessed. Posture, tone, fontanelle (if patent), presence of a rash, neck stiffness and level of consciousness should also be assessed. If the diagnosis is unclear, potentially serious, and specific treatment may be needed to prevent deterioration, the child should be referred. PMID- 26514057 TI - Improving detection of non-melanoma skin cancer Non-melanoma skin cancer. AB - Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are clinically and pathologically distinct and both are locally invasive. However, while BCCs rarely metastasise, SCCs have the potential to do so especially when they arise on the ears or lips. UV radiation is the most important risk factor for non melanoma skin cancer (NMSC). The tumours most commonly arise in fair-skinned individuals on sun-damaged skin, especially the face. Incidence rises with age. Patients with one NMSC have a higher risk of developing another NMSC and of malignant melanoma. SCCs are frequently more difficult to diagnose than BCCs. Well differentiated lesions have a pronounced keratotic element. Poorly differentiated SCCs tend to be pink or red papules or nodules, lacking keratin, which may ulcerate. Around 5% of SCCs metastasise. High-risk SCCs include those: on the ear, lip, or sites unexposed to the sun and in chronic ulcers, scars or Bowen's disease. SCCs > 20 mm in diameter or > 4 mm in depth are high risk. Patients who are immunosuppressed, have poorly differentiated tumours or recurrent disease are also at increased risk. Patients with a slowly evolving or persistent skin lesion where cancer is a possibility should be referred to a dermatologist. Lesions suspected of being BCC should be referred routinely. Urgent referral should be reserved for cases where there is concern that a delay may have a significant impact because of the size or site of the lesion. Any non healing lesions >1 cm with marked induration on palpation, showing significant expansion over eight weeks, should be referred urgently as they may be SCCs. PMID- 26514058 TI - Sun damage. PMID- 26514059 TI - We need to learn how to stop medication. PMID- 26514060 TI - Phytoextraction of HG by parsley (Petroselinum crispum) and its growth responses. AB - The effect of mercury (Hg) on the growth and survival of parsley (Petroselinum crispum) was explored at various treatments. The plants were grown in pots having Hoagland's solution to which various Hg treatments were applied and placed under greenhouse conditions. The treatments were: no metal applied (control) and six doses of Hg as mercuric chloride for 15 days. Linear trend of Hg accumulation was noted in roots, stems, and leaves with increasing Hg treatments. The maximum Hg concentration in root, stem and leaf was 8.92, 8.27, and 7.88 at Hg treatments of 25 mg l(-1), respectively. On the whole, Hg accumulation in different plant parts was in the following order: leaves > stem > roots. Linear trend was also observed for Bioaccumulation Factor (BF) and Translocation Factor (TF) with increasing Hg concentrations in the growth medium. The highest respective BFHg and TFHg values were 9.32 and 2.02 for the Hg treatments of 25 and 50 mg l(-1). In spite of the reduced growth in the presence of Hg, the plant has phytoremediation potential. It is recommended that parsley should not be cultivated in Hg contaminated sites in order to avoid dietary toxicity. PMID- 26514062 TI - An Odyssey to Viral Pathogenesis. AB - This odyssey is mine from early junior high school, where my dreams for adventure were shaped by Arthur Conan Doyle's Sherlock Holmes, Percival Christopher Wren's Beau Geste, and best of all the remarkable explorers in Paul de Kruif's Microbe Hunters. My birth site was in Manhattan (my mother was a Vogue model and my father worked in retail), and I traveled to college at the University of Alabama, Tuscaloosa, where my love of history and English literature was shaped along with a sufficient exposure to biology, chemistry, and genetics to meet requirements for entering medical school. By the second year at the University of Maryland School of Medicine, through expert teachers such as Theodore (Ted) Woodward and Sheldon (Shelly) Greisman in medicine and Charles Weissmann in virology and microbiology, I found that understanding why and how people became ill was more my cup of tea than identifying and treating their illnesses. Although I was becoming competent in diagnosis and treatment, I left medical school at the end of my sophomore year to seek a more basic understanding of biology and chemistry. I achieved this by working toward a PhD in biochemistry at Johns Hopkins McCollum Pratt Institute combined with study of rickettsial toxin at Maryland. This was a very important time in my life, because it convinced me that addressing biologic and medical questions in a disciplined scientific manner was what my life voyage should be. That voyage led me initially, through Woodward's contact, to work a summer in Joe Smadel's unit at Walter Reed (Smadel being one of the deans of American virology) and to meet several times with Carleton Gajdusek and then John Enders at Harvard, who pointed me to Frank Dixon at Scripps in La Jolla, California, for postdoctoral training. Dixon was among the founders of modern immunology and a pathfinder for immunopathology. Training by and association with Dixon and his other postdoctoral fellows, my independent position at Scripps, early polishing by Karl Habel (a superb senior virologist who left the National Institutes of Health and came to Scripps), and the gifted postdoctoral fellows who joined my laboratory over four decades form the log of my scientific voyage. The strong friendships and collaborations developed with other young but growing experimentalists like Bernie Fields and Abner Notkins are the fabric of the tale I will weave and were pivotal in the establishment of viral pathogenesis as a discipline. PMID- 26514061 TI - Synthesis of 2,5-Diaryl-1,5-dienes from Allylic Bromides Using Visible-Light Photoredox Catalysis. AB - Visible-light photoreductive coupling of 2-arylallyl bromides in the presence of the photocatalyst Ru(bpy)3(PF6)2, a Hantzsch ester, and i-Pr2NEt gives 2,5-diaryl 1,5-dienes in high yield. This method avoids the use of stoichiometric metal reductants and is compatible with the presence of halogen, alkyl, electron donating, and electron-withdrawing substituents on the aromatic ring. PMID- 26514063 TI - Antibiotic Prescribing in Psychiatric Hospitals and Interactions between Antibiotics and Psychotropic Drugs: A Prospective Observational Study. PMID- 26514064 TI - Antidiarrhoeal activity of aqueous leaf extract of Caladium bicolor (Araceae) and its possible mechanisms of action. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Caladium bicolor (Araceae) is a horticulture plant also used by some traditional medicine practitioners in the treatment of diarrhoea and other gastrointestinal disorders. This study was conducted to evaluate the antidiarrhoeal activity of the aqueous leaf extract of C. bicolor and its possible mechanisms of action in rodents. MATERIALS AND METHODS: Normal and castor oil-induced intestinal transit and castor oil-induced diarrhoea tests were carried out in mice while gastric emptying and enteropooling tests were conducted in rats following the administration of distilled water (10 ml/kg, p.o.), C. bicolor extract (1-50mg/kg, p.o.) and loperamide (5mg/kg, p.o.). The probable mechanisms of action of C. bicolor was investigated following pre treatment with yohimbine (10mg/kg, s.c.; alpha2-adrenoceptor antagonist), pilocarpine (1mg/kg, s.c.; non-selective muscarinic receptor agonist), prazosin (1mg/kg, s.c.; alpha1-adrenoceptor antagonist) and propranolol (1mg/kg, i.p.; non selective beta-adrenoceptor antagonist) 15 min prior to administration of C. bicolor extract (50mg/kg, p.o.). After 30 min of pre-treatment with these drugs, the mice were subjected to the castor oil-induced intestinal transit test. RESULTS: C. bicolor extract did not produce significant (p>0.05) effect on normal intestinal transit unlike loperamide which caused significant (p<0.001) inhibition (61.57%). The extract caused significant (p<0.001) dose-dependent inhibition of castor oil-induced intestinal transit with peak effect, 100% inhibition, elicited at the dose of 50mg/kg compared to 86.97% inhibition for loperamide. Yohimbine and pilocarpine most significantly (p<0.001) reversed this effect of the extract. In the castor oil-induced diarrhoea test, the extract (1mg/kg) and loperamide significantly (p<0.05, 0.01) delayed the onset of diarrhoea. For diarrhoea score, the extract (1 and 50mg/kg) inhibited diarrhoea development (47.53% and 43.83% inhibition, respectively) like loperamide (5mg/kg; 54.94%). The in vivo antidiarrhoeal index of the extract at 1 and 50mg/kg was 50.07% and 42.81% respectively compared to 58.15% for loperamide. CONCLUSIONS: The results obtained in this study suggest that the aqueous leaf extract of C. bicolor possess antidiarrhoeal activity due to its anti-motility effect possibly via antagonist action on intestinal muscarinic receptors and agonist action on intestinal alpha2-adrenoceptors. This justifies the use of the extract in traditional medicine for the treatment of diarrhoea. PMID- 26514065 TI - Patterns of Change in Interpersonal Problems During and After Short-term and Long term Psychodynamic Group Therapy: A Randomized Clinical Trial. AB - OBJECTIVE: In this study, we compared the patterns of change in interpersonal problems between short-term and long-term psychodynamic group therapy. METHOD: A total of 167 outpatients with mixed diagnoses were randomized to 20 or 80 weekly sessions of group therapy. Interpersonal problems were assessed with the Inventory of Interpersonal Problems at six time points during the 3-year study period. Using linear mixed models, change was linearly modelled in two steps. Earlier (within the first 6 months) and later (during the last 2.5 years) changes in five subscales were estimated. RESULTS AND CONCLUSION: Contrary to what we expected, short-term therapy induced a significantly larger early change than long-term therapy on the cold subscale and there was a trend on the socially avoidant subscale, using a Bonferroni-adjusted alpha. There was no significant difference between short-term and long-term group therapy for improving problems in the areas cold, socially avoidant, nonassertive, exploitable, and overly nurturant over the 3 years. PMID- 26514066 TI - Identification of a novel canine distemper virus B-cell epitope using a monoclonal antibody against nucleocapsid protein. AB - Canine distemper virus (CDV) is a member of the genus Morbillivirus within the family Paramyxoviridae and has caused severe economic losses in China. Nucleocapsid protein (N) is the major structural viral protein and can be used to diagnose CDV and other morbilliviruses. In this study, a specific monoclonal antibody, 1N8, was produced against the CDV N protein (amino acids 277-471). A linear N protein epitope was identified by subjecting a series of partially overlapping synthesized peptides to enzyme-linked immunosorbent assay (ELISA) analysis. The results indicated that (350)LNFGRSYFDPA(360) was the minimal linear epitope that could be recognized by mAb 1N8. ELISA assays revealed that mouse anti-CDV sera could also recognize the minimal linear epitope. Alignment analysis of the amino acid sequences indicated that the epitope was highly conserved among CDV strains. Furthermore, the epitope was conserved among other morbilliviruses, which was confirmed with PRRV using western blotting. Taken together, the results of this study may have potential applications in the development of suitable diagnostic techniques for CDV or other morbilliviruses. PMID- 26514067 TI - Unaided trifluoroacetic acid pretreatment solubilizes polyglutamine peptides and retains their biophysical properties of aggregation. AB - Understanding the biophysical mechanism of polyglutamine (polyGln) aggregation is important to unravel the role of aggregates in the pathology of polyGln repeat disorders. To achieve this, synthetic polyGln peptides are widely used. Their disaggregation and solubilization is essential because it plays a crucial role in reproducing biophysical experimental data under in vitro conditions. Pretreatment with trifluoroacetic acid (TFA) and hexafluoroisopropanol (HFIP) at a 1:1 ratio is currently the method of choice to achieve solubility of polyGln peptides. Here we report that the disaggregation and solubilization of polyGln peptides can be achieved by TFA alone. We tested TFA due to the close similarity of it with HFIP in the nature of H-bond breakage and formation, higher cost, and the problems faced by us in the availability of HFIP. Our results demonstrate that the TFA disaggregated polyGln sequences give similar solubilization yield, aggregation kinetics, thioflavin T (ThT) binding, and structural features in comparison with the TFA/HFIP method. Furthermore, we show by limited validation studies that the proposed TFA method can replace the existing TFA/HFIP disaggregation method of polyGln sequences. PMID- 26514068 TI - Comments on "Endoscopic Transpterygoid Approach and Skull Base Repair After Sphenoid Meningoencephalocele Resection". PMID- 26514069 TI - Development of processes allowing near real-time refinement and validation of triage tools during the early stage of an outbreak in readiness for surge: the FLU-CATs Study. AB - BACKGROUND: During pandemics of novel influenza and outbreaks of emerging infections, surge in health-care demand can exceed capacity to provide normal standards of care. In such exceptional circumstances, triage tools may aid decisions in identifying people who are most likely to benefit from higher levels of care. Rapid research during the early phase of an outbreak should allow refinement and validation of triage tools so that in the event of surge a valid tool is available. The overarching study aim is to conduct a prospective near real-time analysis of structured clinical assessments of influenza-like illness (ILI) using primary care electronic health records (EHRs) during a pandemic. This abstract summarises the preparatory work, infrastructure development, user testing and proof-of-concept study. OBJECTIVES: (1) In preparation for conducting rapid research in the early phase of a future outbreak, to develop processes that allow near real-time analysis of general practitioner (GP) assessments of people presenting with ILI, management decisions and patient outcomes. (2) As proof of concept: conduct a pilot study evaluating the performance of the triage tools 'Community Assessment Tools' and 'Pandemic Medical Early Warning Score' to predict hospital admission and death in patients presenting with ILI to GPs during inter-pandemic winter seasons. DESIGN: Prospective near real-time analysis of structured clinical assessments and anonymised linkage to data from EHRs. User experience was evaluated by semistructured interviews with participating GPs. SETTING: Thirty GPs in England, Wales and Scotland, participating in the Clinical Practice Research Datalink. PARTICIPANTS: All people presenting with ILI. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Study outcome is proof of concept through demonstration of data capture and near real-time analysis. Primary patient outcomes were hospital admission within 24 hours and death (all causes) within 30 days of GP assessment. Secondary patient outcomes included GP decision to prescribe antibiotics and/or influenza-specific antiviral drugs and/or refer to hospital - if admitted, the need for higher levels of care and length of hospital stay. DATA SOURCES: Linked anonymised data from a web-based structured clinical assessment and primary care EHRs. RESULTS: In the 24 months to April 2015, data from 704 adult and 159 child consultations by 30 GPs were captured. GPs referred 11 (1.6%) adults and six (3.8%) children to hospital. There were 13 (1.8%) deaths of adults and two (1.3%) of children. There were too few outcome events to draw any conclusions regarding the performance of the triage tools. GP interviews showed that although there were some difficulties with installation, the web-based data collection tool was quick and easy to use. Some GPs felt that a minimal monetary incentive would promote participation. CONCLUSIONS: We have developed processes that allow capture and near real-time automated analysis of GP's clinical assessments and management decisions of people presenting with ILI. FUTURE WORK: We will develop processes to include other EHR systems, attempt linkage to data on influenza surveillance and maintain processes in readiness for a future outbreak. STUDY REGISTRATION: This study is registered as ISRCTN87130712 and UK Clinical Research Network 12827. FUNDING: The National Institute for Health Research Health Technology Assessment programme. MGS is supported by the UK NIHR Health Protection Research Unit in Emerging and Zoonotic Infections. PMID- 26514070 TI - Physical features and chitin content of eggs from the mosquito vectors Aedes aegypti, Anopheles aquasalis and Culex quinquefasciatus: Connection with distinct levels of resistance to desiccation. AB - Mosquito eggs are laid in water but freshly laid eggs are susceptible to dehydration, if their surroundings dry out at the first hours of development. During embryogenesis of different mosquito vectors the serosal cuticle, an extracellular matrix, is produced; it wraps the whole embryo and becomes part of the eggshell. This cuticle is an essential component of the egg resistance to desiccation (ERD). However, ERD is variable among species, sustaining egg viability for different periods of time. While Aedes aegypti eggs can survive for months in a dry environment (high ERD), those of Anopheles aquasalis and Culex quinquefasciatus in the same condition last, respectively, for one day (medium ERD) or a few hours (low ERD). Resistance to desiccation is determined by the rate of water loss, dehydration tolerance and total amount of water of a given organism. The ERD variability observed among mosquitoes probably derives from diverse traits. We quantified several attributes of whole eggs, potentially correlated with the rate of water loss: length, width, area, volume, area/volume ratio and weight. In addition, some eggshell aspects were also evaluated, such as absolute and relative weight, weight/area relationship (herein called surface density) and chitin content. Presence of chitin specifically in the serosal cuticle as well as aspects of endochorion external surface were also investigated. Three features could be related to differences on ERD levels: chitin content, directly related to ERD, the increase in the egg volume during embryogenesis and the eggshell surface density, which were both inversely related to ERD. Although data suggest that the amount of chitin in the eggshell is relevant for egg impermeability, the participation of other yet unidentified eggshell attributes must be considered in order to account for the differences in the ERD levels observed among Ae. aegypti, An. aquasalis and Cx. quinquefasciatus. PMID- 26514071 TI - Evaluation of knowledge and confidence following opioid overdose prevention training: A comparison of types of training participants and naloxone administration methods. AB - BACKGROUND: The purpose of the current study was to assess the effect of opioid overdose prevention training on participants' knowledge about opioid overdose and confidence to recognize and respond to opioid overdose situations as a function of naloxone administration (i.e., injection vs. intranasal spray) and participant type (friend/family, provider, "other"). METHODS: Opioid overdose prevention trainings were offered throughout a mid-sized metropolitan area in the northeast. Participants (n = 428) were trained to administer naloxone via intramuscular injection (n = 154) or intranasal spray (n = 274). All training participants were given pre-post assessments of knowledge about opioid overdose and confidence to recognize and respond to opioid overdose situations. RESULTS: Participants' overall knowledge and confidence increased significantly from pre- to post training (ps < .001). There was no significant association between knowledge and route of administration or participant type. Knowledge significantly increased from pre- to post-training in all participant types (ps < .001). Confidence improved significantly from pre- to post-training across both routes of administration (ps < .001). However, confidence was higher among those who were trained using the intranasal naloxone compared to those who were trained using the intramuscular injection naloxone at pre- (p = .011) and post-training (p < .001). Confidence increased from pre- to post-training in each of the participant types (ps < .001). Post-hoc tests revealed that confidence was higher among providers and friends/family members compared to "other" participants, such as first responders, only at post-training (p < .05). CONCLUSIONS: Opioid overdose trainings are effective in increasing knowledge and confidence related to opioid overdose situations. Findings suggest that trainees are more confident administering naloxone via intranasal spray compared to injection. Future research should attempt to identify other factors that may increase the likelihood of trainees' effectively intervening in opioid overdose situations. PMID- 26514072 TI - Maternal hemoglobin decline following 'uneventful' cesarean delivery. AB - OBJECTIVE: To assess hemoglobin (Hb) decline following elective and non-elective uneventful cesarean section (CS). METHODS: A retrospective cohort study of all women with singleton pregnancy who underwent uneventful CS defined as clinical estimation of intra-operative bleeding < 1000 ml. Hemoglobin decline (pre- and post-CS levels difference) of women with non-elective CS (during labor/delivery process) were compared to those who underwent elective CS (no labor). Cases complicated by placenta previa/abruption were excluded. RESULTS: Overall 2767 women underwent uneventful CS, of them, 954 (34.5%) were non-elective and 1813 (65.5%) were elective. Hemoglobin decline was higher in the non-elective group (1.5 +/- 1.3 versus 1.0 +/- 1.2 g/dL, p < 0.001). This was also observed in the nulliparous patients as well as in those with previous single CS subgroups. The rate of Hb decline >=3 g/dL and the rate of post-CS Hb < 7 g/dL were higher in the non-elective group (8.9% versus 3.1%, p < 0.001 and 2.3% versus 0.4%, p = 0.001, respectively). On multivariable analysis, non-elective CS was found to be significantly associated with Hb decline of >=3 g/dl after surgery (aOR = 2.10, 95% CI 1.36-3.23, p = 0.001) and need for blood products transfusion (aOR = 2.24, 95% CI 1.04-4.83, p = 0.03). CONCLUSION: Non-elective CS was associated with an increased risk of Hb decline and blood product transfusion even in an apparent uneventful operation. PMID- 26514073 TI - Risk factors for the severity of injury incurred in crashes involving on-duty police cars. AB - OBJECTIVE: This article explores the risk factors associated with police cars on routine patrol and/or on an emergency run and their effects on the severity of injuries in crashes. METHODS: The binary probit model is used to examine the effects of important factors on the risk of injuries sustained in crashes involving on-duty police cars. RESULTS: Several factors significantly increase the probability of crashes that cause severe injuries. Among those causes are police officers who drive at excessive speeds, traffic violations during emergency responses or pursuits, and driving during the evening (6 to 12 p.m.) or in rainy weather. Findings also indicate some potential issues associated with an increase in the probability of crashes that cause injuries. Younger police drivers were found to be more likely to be involved in crashes causing injuries than middle-aged drivers were. Distracted driving by on-duty police officers as well as civilian drivers who did not pull over to let a police car pass in emergency situations also caused serious crashes. CONCLUSIONS: Police cars are exempted from certain traffic laws under emergency circumstances. However, to reduce the probability of being involved in a crash resulting in severe injuries, officers are still obligated to drive safely and follow safety procedures when responding to emergencies or pursuing a car. Enhancement of training techniques for emergency situations or driving in pursuit of an offender and following the safety procedures are essential for safety in driving during an emergency run by police. PMID- 26514074 TI - Gender differences in appraisal of stress and coping 5 years after heart transplantation. AB - OBJECTIVES: We examined whether gender differences exist regarding stress, symptom distress, coping, adherence, and social support 5 years after heart transplantation. BACKGROUND: Differences exist in health-related quality of life outcomes by gender after heart transplantation; women report poorer outcomes. METHODS: Patients (n = 210, female = 42), were from a prospective, multi-site, study of health-related quality of life long-term after heart transplantation. Patients completed self-report instruments 5 years after heart transplantation (mean = 4.98 +/- 0.17 years after transplant). Statistical analyses included two sample t-tests, Chi-square or Fisher's exact test, and multivariable modeling. RESULTS: Women did not report more overall stress or symptom distress, but reported more difficulty adhering to the transplant regimen, yet more actual adherence than men. Women reported using more negative coping styles, but reported more satisfaction with social support. CONCLUSIONS: Gender differences exist regarding appraisal of stress, coping styles, and coping resources long term after heart transplantation. These differences may guide tailoring therapy regarding stress, poor coping, and lack of resources. PMID- 26514075 TI - Consolidating new paradigms in large-scale monitoring and assessment of forest ecosystems. AB - Forests provide a wide range of ecosystem services from which people benefit, and upon which all life depends. However, any rational decision related to the maintenance and enhancement of the multiple functions provided by the forests needs to be based on objective, reliable information. As such, forest monitoring and assessment are rapidly evolving as new information needs arise or new techniques and tools become available. Global change issues and utilities from ecosystem management are distinctively to be considered, so that forest inventory and mapping are broadening their scope towards multipurpose resources surveys. Recent changes in forest management perspective have promoted the consideration of forests as complex adaptive systems, thereby highlighting the need to account that such approaches actually work: forest monitoring and assessment are then expected to address and fully incorporate this perspective at global scale, seeking to support planning and management decisions that are evidence-based. This contribution provides selected considerations on the above mentioned issues, in the form of a commented discussion with examples from the literature produced in the last decade. PMID- 26514076 TI - Identification of intrinsically metronidazole-resistant clades of Gardnerella vaginalis. AB - Gardnerella vaginalis is associated with bacterial vaginosis (BV), the most common cause of vaginal discharge. Metronidazole is a front-line therapy for BV, and treatment failure and recurrent disease are common problems. Whole-genome sequencing studies have revealed that G. vaginalis has a population structure that consists of 4 clades: clades 1 and 3 are associated with BV, whereas clades 2 and 4 are not. To determine if metronidazole susceptibility is associated with population structure, we analyzed 87 clinical isolates and found that metronidazole resistance (MIC >=32 MUg/mL) was highly associated with clade (P<0.0001), as 14/14 clade 3 isolates (100%) and 22/22 clade 4 isolates (100%) exhibited resistance, compared to only 16/37 clade 1 isolates (35%) and 1/14 clade 2 isolates (7.1%). The identification of intrinsically metronidazole resistant G. vaginalis clades will facilitate future studies on the relationship between metronidazole resistance and BV treatment failure. PMID- 26514077 TI - Augmented recovery of microorganisms from swabs by homogenization: a novel standardizable high-throughput approach. AB - A new approach introducing a quantitative and standardizable step into sample processing was evaluated by homogenizing in vitro inoculated swab tips with Precellys 24 high-throughput homogenizer. Recovery of microorganisms from homogenized swab tips was significantly higher as compared to conventional processing methods. Thus, swab homogenization is a promising approach introducing a new quality in microbial analysis. PMID- 26514078 TI - SentiHealth-Cancer: A sentiment analysis tool to help detecting mood of patients in online social networks. AB - BACKGROUND: Cancer is a critical disease that affects millions of people and families around the world. In 2012 about 14.1 million new cases of cancer occurred globally. Because of many reasons like the severity of some cases, the side effects of some treatments and death of other patients, cancer patients tend to be affected by serious emotional disorders, like depression, for instance. Thus, monitoring the mood of the patients is an important part of their treatment. Many cancer patients are users of online social networks and many of them take part in cancer virtual communities where they exchange messages commenting about their treatment or giving support to other patients in the community. Most of these communities are of public access and thus are useful sources of information about the mood of patients. Based on that, Sentiment Analysis methods can be useful to automatically detect positive or negative mood of cancer patients by analyzing their messages in these online communities. OBJECTIVE: The objective of this work is to present a Sentiment Analysis tool, named SentiHealth-Cancer (SHC-pt), that improves the detection of emotional state of patients in Brazilian online cancer communities, by inspecting their posts written in Portuguese language. The SHC-pt is a sentiment analysis tool which is tailored specifically to detect positive, negative or neutral messages of patients in online communities of cancer patients. We conducted a comparative study of the proposed method with a set of general-purpose sentiment analysis tools adapted to this context. METHODS: Different collections of posts were obtained from two cancer communities in Facebook. Additionally, the posts were analyzed by sentiment analysis tools that support the Portuguese language (Semantria and SentiStrength) and by the tool SHC-pt, developed based on the method proposed in this paper called SentiHealth. Moreover, as a second alternative to analyze the texts in Portuguese, the collected texts were automatically translated into English, and submitted to sentiment analysis tools that do not support the Portuguese language (AlchemyAPI and Textalytics) and also to Semantria and SentiStrength, using the English option of these tools. Six experiments were conducted with some variations and different origins of the collected posts. The results were measured using the following metrics: precision, recall, F1-measure and accuracy RESULTS: The proposed tool SHC-pt reached the best averages for accuracy and F1-measure (harmonic mean between recall and precision) in the three sentiment classes addressed (positive, negative and neutral) in all experimental settings. Moreover, the worst accuracy value (58%) achieved by SHC-pt in any experiment is 11.53% better than the greatest accuracy (52%) presented by other addressed tools. Finally, the worst average F1 (48.46%) reached by SHC-pt in any experiment is 4.14% better than the greatest average F1 (46.53%) achieved by other addressed tools. Thus, even when we compare the SHC-pt results in complex scenario versus others in easier scenario the SHC-pt is better. CONCLUSIONS: This paper presents two contributions. First, it proposes the method SentiHealth to detect the mood of cancer patients that are also users of communities of patients in online social networks. Second, it presents an instantiated tool from the method, called SentiHealth-Cancer (SHC-pt), dedicated to automatically analyze posts in communities of cancer patients, based on SentiHealth. This context-tailored tool outperformed other general-purpose sentiment analysis tools at least in the cancer context. This suggests that the SentiHealth method could be instantiated as other disease-based tools during future works, for instance SentiHealth-HIV, SentiHealth-Stroke and SentiHealth-Sclerosis. PMID- 26514079 TI - The value of telemonitoring and ICT-guided disease management in heart failure: Results from the IN TOUCH study. AB - AIM: It is still unclear whether telemonitoring reduces hospitalization and mortality in heart failure (HF) patients and whether adding an Information and Computing Technology-guided-disease-management-system (ICT-guided-DMS) improves clinical and patient reported outcomes or reduces healthcare costs. METHODS: A multicenter randomized controlled trial was performed testing the effects of INnovative ICT-guided-DMS combined with Telemonitoring in OUtpatient clinics for Chronic HF patients (IN TOUCH) with in total 179 patients (mean age 69 years; 72% male; 77% in New York Heart Association Classification (NYHA) III-IV; mean left ventricular ejection fraction was 28%). Patients were randomized to ICT-guided DMS or to ICT-guided-DMS+telemonitoring with a follow-up of nine months. The composite endpoint included mortality, HF-readmission and change in health related quality of life (HR-QoL). RESULTS: In total 177 patients were eligible for analyses. The mean score of the primary composite endpoint was -0.63 in ICT guided-DMS vs. -0.73 in ICT-guided-DMS+telemonitoring (mean difference 0.1, 95% CI: -0.67 +0.82, p=0.39). All-cause mortality in ICT-guided-DMS was 12% versus 15% in ICT-guided-DMS+telemonitoring (p=0.27); HF-readmission 28% vs. 27% p=0.87; all-cause readmission was 49% vs. 51% (p=0.78). HR-QoL improved in most patients and was equal in both groups. Incremental costs were ?1360 in favor of ICT-guided DMS. ICT-guided-DMS+telemonitoring had significantly fewer HF-outpatient-clinic visits (p<0.01). CONCLUSION: ICT-guided-DMS+telemonitoring for the management of HF patients did not affect the primary and secondary endpoints. However, we did find a reduction in visits to the HF-outpatient clinic in this group suggesting that telemonitoring might be safe to use in reorganizing HF-care with relatively low costs. PMID- 26514080 TI - Increasing awareness about HIV prevention among young people who initiated injection drug use in a Canadian setting, 1988-2014. AB - BACKGROUND: Globally, harm reduction interventions, including needle and syringe programs (NSPs), have been shown to reduce HIV risks among people who inject drugs (PWID). However, little is known about the impact of these efforts on the circumstances of first injection. Therefore, we sought to identify changes in the awareness about HIV prevention and syringe borrowing at the time of first injection drug use in Vancouver, Canada, during a period of NSP expansion. METHODS: Data were drawn from prospective cohorts of PWID in Vancouver, who initiated injecting between 1988 and 2014. Multivariable regression was used to assess changes in the awareness about HIV and NSPs and syringe borrowing behaviour at first injection against calendar year of first injection. RESULTS: Among 1044 participants (36.9% female), at the time of first injection 73.9% reported having known syringe sharing was an HIV risk, 54.1% reported having heard of NSPs, and 7.8% reported having borrowed a syringe used by others. In multivariable analyses, calendar year of first injection was independently and positively associated with awareness about HIV (adjusted prevalence ratio [APR]: 1.09; 95% confidence interval [CI]: 1.06, 1.11) and awareness about NSPs (APR: 1.18; 95% CI: 1.13, 1.24). While calendar year of first injection was significantly and negatively associated with syringe borrowing at first injection in bivariable analyses, the association did not remain significant in multivariable analyses (adjusted odds ratio: 0.90; 95% CI: 0.72, 1.14). CONCLUSIONS: We found that awareness about HIV and NSPs at first injection have increased over time amongst PWID in this setting. However, declining trends in syringe borrowing at first injection were not determined after adjustment for socio-demographic characteristics. This suggests that HIV prevention efforts may have contributed to increased awareness about HIV prevention, but further research is needed to identify sub-populations at heightened risk of HIV at first injection. PMID- 26514081 TI - Detection and Quantification of Ribosome Inhibition by Aminoglycoside Antibiotics in Living Bacteria Using an Orthogonal Ribosome-Controlled Fluorescent Reporter. AB - The ribosome is the quintessential antibacterial drug target, with many structurally and mechanistically distinct classes of antibacterial agents acting by inhibiting ribosome function. Detecting and quantifying ribosome inhibition by small molecules and investigating their binding modes and mechanisms of action are critical to antibacterial drug discovery and development efforts. To develop a ribosome inhibition assay that is operationally simple, yet provides direct information on the drug target and the mechanism of action, we have developed engineered E. coli strains harboring an orthogonal ribosome-controlled green fluorescent protein (GFP) reporter that produce fluorescent signal when the orthogonal ribosome is inhibited. As a proof of concept, we demonstrate that these strains, when coexpressing homogeneous populations of aminoglycoside resistant ribosomes, act as sensitive and quantitative detectors of ribosome inhibition by a set of 12 structurally diverse aminoglycoside antibiotics. We suggest that this strategy can be extended to quantifying ribosome inhibition by other drug classes. PMID- 26514082 TI - Nutrition in Heart Failure: More Than Drugs and Devices. PMID- 26514083 TI - Anorexia nervosa: aetiology, assessment, and treatment. AB - Anorexia nervosa is an important cause of physical and psychosocial morbidity. Recent years have brought advances in understanding of the underlying psychobiology that contributes to illness onset and maintenance. Genetic factors influence risk, psychosocial and interpersonal factors can trigger onset, and changes in neural networks can sustain the illness. Substantial advances in treatment, particularly for adolescent patients with anorexia nervosa, point to the benefits of specialised family-based interventions. Adults with anorexia nervosa too have a realistic chance of achieving recovery or at least substantial improvement, but no specific approach has shown clear superiority, suggesting a combination of re-nourishment and anorexia nervosa-specific psychotherapy is most effective. To successfully fight this enigmatic illness, we have to enhance understanding of the underlying biological and psychosocial mechanisms, improve strategies for prevention and early intervention, and better target our treatments through improved understanding of specific disease mechanisms. PMID- 26514084 TI - Caveolin-1 regulates osteoclast differentiation by suppressing cFms degradation. AB - Caveolae are flask-shaped cell-surface membranes, which consist of cholesterol, sphingolipids and caveolin proteins. In a microarray analysis, we found that caveolin-1 (Cav-1) was upregulated by receptor activator of NFkappaB ligand (RANKL), the osteoclast differentiation factor. Silencing of Cav-1 inhibited osteoclastogenesis and also decreased the activation of mitogen-activated protein kinase and the induction of NFATc1 by RANKL. Cav-1 knockdown suppressed the expression of cFms and RANK, two major receptors for osteoclastogenesis. Interestingly, cFms expression was decreased only at the protein level, not at the messenger RNA (mRNA) level, whereas RANK expression was decreased at both the mRNA and protein levels. Furthermore, Cav-1 deficiency increased the lysosomal degradation of cFms. Taken together, these results demonstrate that Cav-1 dependent cFms stabilization contributes to efficient osteoclastogenesis. PMID- 26514085 TI - Norepinephrine-induced calcium signaling in astrocytes in the respiratory network of the ventrolateral medulla. AB - The neuronal activity in the respiratory network of the ventrolateral medulla strongly depends on a variety of different neuromodulators. Since the respiratory activity generated by neurons in the pre-Botzinger complex (preBotC) is stabilized by astrocytes, we investigated potential effects of the neuromodulator norepinephrine (NE) on the astrocytic calcium signaling in the ventral respiratory group. In acutely isolated brainstem slices from wild type mice (postnatal day 1-10) we performed calcium imaging experiments using Oregon Green 488 BAPTA-1 AM as a calcium indicator dye. Astrocytes in the preBotC, which were identified by their unique intracellular calcium rise after the reduction of the extracellular K(+) concentration, showed calcium rises in response to norepinephrine. These calcium signals persisted after blockade of neuronal activity by tetrodotoxin (TTX) indicating that they were independent of neuronal activity. Furthermore, application of the endoplasmic reticulum calcium pump blocker cyclopiazonic acid (CPA) diminished norepinephrine-induced calcium signals. This results could be confirmed using transgenic mice with astrocyte specific expression of GCaMP3. Thus, norepinephrine might, apart from acting directly on neurons, influence and modulate respiratory network activity via the modulation of astroglial calcium signaling. PMID- 26514087 TI - Silica core-polystyrene shell nanoparticle synthesis and assembly in three dimensions. AB - Monodisperse silica nanoparticles (SiNPs) grafted with well-defined and highly dense polystyrene brushes are used as building blocks for the formation of three dimensional (3D) colloidal crystals. By adjusting the refractive indices and the density of the hybrid particles with those of mixed solvents, iridescent microcrystals were formed throughout the entire suspension which were characterised by confocal laser microscopy. These core-shell hybrid particles are not charged and the driving force of the crystallization relies on repulsive forces between the polymer brushes with high grafting density. The interparticle distance is correlated to Bragg's Law and can be controlled by manipulating the grafting density and the length of the polymer brushes. Finally, the uniformity of these unique core-shell particles was exploited to generate 3D assemblies by a rapid and simple process based on centrifugation. PMID- 26514086 TI - Identifying the metabolic perturbations in earthworm induced by cypermethrin using gas chromatography-mass spectrometry based metabolomics. AB - Globally, cypermethrin is one of the most widely used synthetic pyrethroid for agricultural and domestic purposes. Most part of the pesticides used in the agriculture ends up as residues in the soil, making soil dwelling organisms, especially earthworms more susceptible to pesticide intoxication. Cypermethrin is known to be a neurotoxicant to many model organisms, including mammals and insects, but such type of toxicity evidence is not available for invertebrate systems like earthworms. In the present work, metabolomics based approach was utilized to identify the toxic mechanism of action of cypermethrin on earthworm (Metaphire posthuma) and these were exposed to sub-lethal concentrations of cypermethrin such as 2.5 mg/kg, 5 mg/kg, 10 mg/kg and 20 mg/kg (1/40(th), 1/20(th), 1/10(th) and 1/5(th) of LC50, respectively) for fourteen days. The results revealed that 22 metabolites (mainly fatty acids, sugars and amino acids) were shown significant responses in the exposed earthworms and these responses are dose dependent. It is proposed that mainly carbohydrate and fatty acids in neural system metabolism was disturbed. Overall, the results provided that metabolomics can be an effective tool to understand the effects of cypermethrin on the metabolic responses of earthworm Metaphire posthuma. PMID- 26514088 TI - Anxious Children and Adolescents Non-responding to CBT: Clinical Predictors and Families' Experiences of Therapy. AB - : The purpose of the study was to examine clinical predictors of non-response to manualized cognitive behaviour therapy (CBT) among youths (children and adolescents) with anxiety disorders, and to explore families' perspective on therapy, using a mixed methods approach. Non-response to manualized group CBT was determined among 106 youths of Danish ethnicity (7-17 years old) with a primary anxiety disorder, identified with the Clinical Global Impression of Improvement Scale at the 3-month follow-up. Twenty-four youths (22.6 %) had not responded to treatment, and a logistic regression analysis revealed that youths with a primary diagnosis of social phobia were seven times more likely not to respond, whereas youths with a comorbid mood disorder were almost four times more likely. Families of non-responding youths with primary social phobia and/or a comorbid mood disorder (n = 15) were interviewed, and data were analysed through interpretative phenomenological analysis. Two superordinate themes emerged: youths were not involved in therapy work, and manualized group format posed challenges to families. The mixed methods approach provided new perspectives on the difficulties that may be encountered by families of non-responding youths with a primary social phobia diagnosis and youths with a comorbid mood disorder during manualized group CBT. Clinical implications related to youths' clinical characteristics, and families' experience and suggestions are drawn. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGES: Youths with an anxiety disorder, who had a primary social phobia diagnosis and those, who had a comorbid mood disorder, were more likely not to respond to manualized group CBT. Parents of those non-responding youths often considered them as motivated to overcome their difficulties, but due to their symptomatology, they were unreceptive, reluctant and ambivalent and therefore not actively involved in therapy. The non-responding youths with social phobia felt evaluated and nervous of what others thought of them in the group. The parents of the non-responding youths with a comorbid mood disorder felt the group format placed restraints on therapists' ability to focus on their individual needs. PMID- 26514089 TI - Ethnic disparities in risk of cardiovascular disease, end-stage renal disease and all-cause mortality: a prospective study among Asian people with Type 2 diabetes. AB - AIM: To study prospectively the ethnic-specific risks of cardiovascular disease, end-stage renal disease and all-cause mortality in patients with Type 2 diabetes mellitus among native Asian subpopulations. METHODS: A total of 2337 subjects with Type 2 diabetes (70% Chinese, 17% Malay and 13% Asian Indian) were followed for a median of 4.0 years. Time-to-event analysis was used to study the association of ethnicity with adverse outcomes. RESULTS: Age- and gender-adjusted hazard ratios for cardiovascular disease in ethnic Malay and Asian Indian subjects were 2.01 (1.40-2.88; P<0.0001) and 1.60 (1.07-2.41; P=0.022) as compared with Chinese subjects. Adjustment for conventional cardiovascular disease risk factors, including HbA1c , blood pressure and lipid profile, slightly attenuated the hazards in Malay (1.82, 1.23-2.71; P=0.003) and Asian Indian subjects (1.47, 0.95-2.30; P=0.086); However, further adjustment for baseline renal function (estimated GFR) and albuminuria weakened the cardiovascular disease risks in Malay (1.48, 0.98-2.26; P=0.065) but strengthened that in Asian Indian subjects (1.81, 1.14-2.87; P=0.012). Competing-risk regression showed that the age- and gender-adjusted sub-distribution hazard ratio for end-stage renal disease was 1.87 (1.27-2.73; P=0.001) in Malay and 0.39 (0.18 0.83; P=0.015) in Asian Indian subjects. Notably, the difference in end-stage renal disease risk among the three ethnic groups was abolished after further adjustment for baseline estimated GFR and albuminuria. There was no significant difference in risk of all-cause mortality among the three ethnic groups. CONCLUSIONS: Risks of cardiovascular and end-stage renal diseases in native Asian subjects with Type 2 diabetes vary substantially among different ethnic groups. Differences in prevalence of diabetic kidney disease may partially explain the ethnic disparities. PMID- 26514090 TI - Polarization and Thickness Dependent Absorption Properties of Black Phosphorus: New Saturable Absorber for Ultrafast Pulse Generation. AB - Black phosphorus (BP) has recently been rediscovered as a new and interesting two dimensional material due to its unique electronic and optical properties. Here, we study the linear and nonlinear optical properties of BP flakes. We observe that both the linear and nonlinear optical properties are anisotropic and can be tuned by the film thickness in BP, completely different from other typical two dimensional layered materials (e.g., graphene and the most studied transition metal dichalcogenides). We then use the nonlinear optical properties of BP for ultrafast (pulse duration down to ~786 fs in mode-locking) and large-energy (pulse energy up to >18 nJ in Q-switching) pulse generation in fiber lasers at the near-infrared telecommunication band ~1.5 MUm. We observe that the output of our BP based pulsed lasers is linearly polarized (with a degree-of-polarization ~98% in mode-locking, >99% in Q-switching, respectively) due to the anisotropic optical property of BP. Our results underscore the relatively large optical nonlinearity of BP with unique polarization and thickness dependence, and its potential for polarized optical pulse generation, paving the way to BP based nonlinear and ultrafast photonic applications (e.g., ultrafast all-optical polarization switches/modulators, frequency converters etc.). PMID- 26514091 TI - Interpretation of mushroom as a common therapeutic agent for Alzheimer's disease and cardiovascular diseases. AB - Alzheimer's disease (AD) and cardiovascular diseases (CVD) share common etiology and preventive strategies. As the population of old-aged people is increasing worldwide, AD complications tend to afflict global healthcare budget and economy heavily. CVD is the prime cause of global mortality and remains a grave threat to both the developed and the developing nations. Mushroom bio-components may be promising in controlling both diseases. Based mainly on in vitro, ex vivo, cell line and animal studies, this review interprets the polypharmaceutic role of mushrooms treating AD and CVD. PMID- 26514092 TI - Hibiscus sabdariffa polyphenols prevent palmitate-induced renal epithelial mesenchymal transition by alleviating dipeptidyl peptidase-4-mediated insulin resistance. AB - Diabetic nephropathy has a significant socioeconomic impact, but its mechanism is unclear and needs to be examined. Hibiscus sabdariffa polyphenols (HPE) inhibited high glucose-induced angiotensin II receptor-1 (AT-1), thus attenuating renal epithelial mesenchymal transition (EMT). Recently, we reported HPE inhibited dipeptidyl-peptidase-4 (DPP-4, the enzyme degrades type 1 glucagon-like peptide (GLP-1)), which mediated insulin resistance signals leading to EMT. Since free fatty acids can realistically bring about insulin resistance, using the palmitate stimulated cell model in contrast with type 2 diabetic rats, in this study we examined if insulin resistance causes renal EMT, and the preventive effect of HPE. Our findings reveal that palmitate hindered 30% of glucose uptake. Treatment with 1 mg mL(-1) of HPE and the DPP-4 inhibitor linagliptin completely recovered insulin sensitivity and palmitate-induced signal cascades. HPE inhibited DPP-4 activity without altering the levels of DPP-4 and the GLP-1 receptor (GLP-1R). HPE decreased palmitate-induced phosphorylation of Ser307 of insulin receptor substrate-1 (pIRS-1 (S307)), AT-1 and vimentin, while increasing phosphorylation of phosphatidylinositol 3-kinase (pPI3K). IRS-1 knockdown revealed its essential role in mediating downstream AT-1 and EMT. In type 2 diabetic rats, it suggests that HPE concomitantly decreased the protein levels of DPP-4, AT-1, vimentin, and fibronectin, but reversed the in vivo compensation of GLP-1R. In conclusion, HPE improves insulin sensitivity by attenuating DPP-4 and the downstream signals, thus decreasing AT-1-mediated tubular-interstitial EMT. HPE could be an adjuvant to prevent diabetic nephropathy. PMID- 26514093 TI - Pharmacokinetics of Alternative Administration Routes of Melatonin: A Systematic Review. AB - BACKGROUND: Melatonin is traditionally administered orally but has a poor and variable bioavailability. This study aims to present an overview of studies investigating the pharmacokinetics of alternative administration routes of melatonin. METHODS: A systematic literature search was performed and included experimental or clinical studies, investigating pharmacokinetics of alternative administration routes of melatonin in vivo. Alternative administration routes were defined as all administration routes except oral and intravenous. RESULTS: 10 studies were included in the review. Intranasal administration exhibited a quick absorption rate and high bioavailability. Transdermal administration displayed a variable absorption rate and possible deposition of melatonin in the skin. Oral transmucosal administration of melatonin exhibited a high plasma concentration compared to oral administration. Subcutaneous injection of melatonin displayed a rapid absorption rate compared to oral administration. CONCLUSION: Intranasal administration of melatonin has a large potential, and more research in humans is warranted. Transdermal application of melatonin has a possible use in a local application, due to slow absorption and deposition in the skin. Oral transmucosal administration may potentially be a clinically relevant due to avoiding first-pass metabolism. Subcutaneous injection of melatonin did not document any advantages compared to other administration routes. PMID- 26514095 TI - Clinical Outcomes of Patients with HIV Undergoing Lead Extraction for Infectious and Noninfectious Indications. AB - BACKGROUND: With the increasing prevalence of human immunodeficiency virus positive (HIV+) patients in the United States, and the association between HIV and cardiovascular morbidity and mortality, the use of cardiac implantable electronic devices (CIEDs) in patients with HIV has become more common. With the increasing incidence of device-related complications, lead extraction is becoming a topic of importance in this population. As the use of implantable devices increases in the HIV+ population, complications are to be expected; therefore, lead extraction in the HIV population must be addressed. METHODS: From January 2004 to May 2013, 1,018 patients requiring lead extraction were referred to a single, high-volume tertiary cardiovascular center. Within this group of patients, 10 were HIV+. We retrospectively reviewed the charts of this cohort and reported clinical variables of interest. RESULTS: Infection was the most common indication for lead extraction and device removal. Four patients were in advanced heart failure, and the overall average ejection fraction of the sample population was 32.7 +/- 16.3%. In addition, the majority of patients had one or more medical comorbidities. Devices removed, in order of frequency, were implantable cardioverter defibrillators, permanent pacemakers, and cardiac resynchronization therapy devices. On average, 35.6 +/- 41.6 months elapsed from implantation of the oldest lead to the date of extraction. There were no major or minor complications and all procedures were clinically successful. CONCLUSIONS: Laser lead extraction is both safe and effective in patients with HIV. This study sets a level of clinical precedent regarding the management of CIED infection or malfunction in patients with HIV. PMID- 26514094 TI - Microscale insights into pneumococcal antibiotic mutant selection windows. AB - The human pathogen Streptococcus pneumoniae shows alarming rates of antibiotic resistance emergence. The basic requirements for de novo resistance emergence are poorly understood in the pneumococcus. Here we systematically analyse the impact of antibiotics on S. pneumoniae at concentrations that inhibit wild type cells, that is, within the mutant selection window. We identify discrete growth inhibition profiles for bacteriostatic and bactericidal compounds, providing a predictive framework for distinction between the two classifications. Cells treated with bacteriostatic agents show continued gene expression activity, and real-time mutation assays link this activity to the development of genotypic resistance. Time-lapse microscopy reveals that antibiotic-susceptible pneumococci display remarkable growth and death bistability patterns in response to many antibiotics. We furthermore capture the rise of subpopulations with decreased susceptibility towards cell wall synthesis inhibitors (heteroresisters). We show that this phenomenon is epigenetically inherited, and that heteroresistance potentiates the accumulation of genotypic resistance. PMID- 26514096 TI - Influence of extracapsular nodal spread extent on prognosis of oral squamous cell carcinoma. AB - BACKGROUND: An objective definition of clinically relevant extracapsular nodal spread (ECS) in head and neck squamous cell carcinoma (SCC) is unavailable. METHODS: Pathologic review of 245 pathologically positive oral cavity SCC neck dissection specimens was performed. The presence/absence of ECS, its extent (in millimeters), and multiple nodal and primary tumor risk factors were related to disease-specific survival (DSS) at a follow-up of 73 months. RESULTS: ECS was detected in 109 patients (44%). DSS was significantly better for patients without ECS than patients with ECS. Time-dependent receiver operator curve (ROC) analysis identified a prognostic cutoff for ECS extent at 1.7 mm. In multivariate analyses, DSS was significantly lower for patients with major ECS compared with patients with minor ECS, but not significantly different between patients with minor ECS and patients without ECS. CONCLUSION: ECS is clinically relevant in oral cavity SCC when it has extended more than 1.7 mm beyond the nodal capsule. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1192-E1199, 2016. PMID- 26514097 TI - Perception of risk for older people living with a mental illness: Balancing uncertainty. AB - Risk is commonly defined as a negative threat which needs to be controlled and mitigated; as a concept, it takes high priority in contemporary mental health services. Health-care organizations and clinicians are now required to use levels of risk as a benchmark for clinical decision-making. However, perceptions of risk change according to the lens through which it is viewed. A qualitative, exploratory research study was undertaken in an aged persons' mental health programme in Victoria, Australia, to explore the notion of risk from the multiple perspectives of service providers and consumers. Data were obtained through in depth interviews, and analysis was based on the framework of Ritchie and Spencer. Balancing uncertainty emerged as a major theme, and comprised two subthemes: (i) complexity of risk from the perspective of providers of services; and (ii) complexity of safety from the perspectives of recipients of services. These differences emphasize a significant disjuncture between perceptions of risk and the potential for the individual needs and concerns of consumers to be subsumed under broader organizational issues. The uncertainty this tension highlights suggests the need to reconceptualize risk, incorporating the views and experiences of all stakeholders, particularly consumers and carers, to enhance recovery-oriented services and facilitate consumer participation within mental health services. PMID- 26514098 TI - Enantioselective Copper-Catalyzed Quinoline Alkynylation. AB - A highly enantioselective copper-catalyzed alkynylation of quinolinium salts is reported. The reaction employs StackPhos, a newly developed imidazole-based chiral biaryl P,N ligand, and copper bromide to effect a three-component reaction between a quinoline, a terminal alkyne, and ethyl chloroformate. Under the reaction conditions, the desired products are delivered in high yields with ee values of up to 98 %. The transformation tolerates a wide range of functional groups with respect to both the alkyne and the quinoline starting materials and the products are easily transformed into useful synthons. Efficient, enantioselective syntheses of the tetrahydroquinoline alkaloids (+)-galipinine, (+)-angustureine, and (-)-cuspareine are reported. PMID- 26514099 TI - Gravitational Effect on the Formation of Surface Nanodroplets. AB - Nanoscale droplets at a solid-liquid interface are of high relevance for many fundamental phenomena and applied processes. The solvent exchange process is a simple approach to produce, e.g., oil nanodroplets over a large surface area on a substrate, by exchange oil-saturated ethanol by oil-saturated water, which has a lower oil solubility than ethanol. In this process, the size of the nanodroplets is closely related to the flow conditions. To achieve control of the droplet size, it is essential to fully understand the nucleation and growth of nanodroplets under different flow conditions. In this work, we investigate the gravitational effect on the droplet formation by the solvent exchange. We compared the droplet size as the substrate was placed on the upper or lower wall in a horizontal fluid channel or on the sides of a vertical channel with an upward or downward flow. We found significant difference in the droplet size for the three substrate positions in a wide channel with height h = 0.21 mm. The difference of droplet size was eliminated in a narrow channel with height h = 0.07 mm. The relevant dimensional control parameter for the occurrence of the gravitational effects is the Archimedes number Ar and these two heights correspond to Ar = 10 and Ar = 0.35, respectively. The gravitational effects lead to a nonsymmetric parabolic profile of the mixing front, with the velocity maximum being off-center and thus with different distances alpha(Ar)h and (1 - alpha(Ar))h to the lower and upper wall, respectively. The ratio of the total droplet volume on the lower and upper wall is theoretically found to be (alpha(Ar)/(1 - alpha(Ar)))(3). This study thus improves our understanding of the mechanism of the solvent exchange process, providing guidelines for tailoring the volume of surface nanodroplets. PMID- 26514100 TI - Relationships between the structure of wheat gluten and ACE inhibitory activity of hydrolysate: stepwise multiple linear regression analysis. AB - BACKGROUND: Ultrasound pretreatment of wheat gluten (WG) before enzymolysis can improve the angiotensin converting enzyme (ACE) inhibitory activity of the hydrolysates by alerting the structure of substrate proteins. Establishment of a relationship between the structure of WG and ACE inhibitory activity of the hydrolysates to judge the end point of the ultrasonic pretreatment is vital. RESULTS: The results of stepwise multiple linear regression (MLR) showed that the contents of free sulfhydryl, alpha-helix, disulfide bond, surface hydrophobicity and random coil were significantly correlated to ACE Inhibitory activity of the hydrolysate, with the standard partial regression coefficients were 3.729, 0.676, -0.252, 0.022 and 0.156, respectively. The R(2) of this model was 0.970. External validation showed that the stepwise MLR model could well predict the ACE inhibitory activity of hydrolysate based on the content of free sulfhydryl, alpha helix, disulfide bond, surface hydrophobicity and random coil of WG before hydrolysis. CONCLUSION: A stepwise multiple linear regression model describing the quantitative relationships between the structure of WG and the ACE Inhibitory activity of the hydrolysates was established. This model can be used to predict the endpoint of the ultrasonic pretreatment. (c) 2015 Society of Chemical Industry. PMID- 26514101 TI - Comparison of the effect of dabigatran and dalteparin on thrombus stability in a murine model of venous thromboembolism. AB - ESSENTIALS: Does thrombus stability alter the presentation of venous thromboembolism and do anticoagulants alter this? In a murine model, we imaged a femoral vein thrombus and quantified emboli in the pulmonary arteries. Dabigatran decreases thrombus stability via factor XIII increasing embolization and pulmonary emboli. This cautions against the unapproved use of dabigatran for acute initial treatment of deep vein thrombosis. BACKGROUND: Venous thromboembolism (VTE) is a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE). Thrombus instability possibly contributes to progression of DVT to PE, and direct thrombin inhibitors (DTIs) may alter this. AIM: To develop a model to assess thrombus stability and its link to PE burden, and identify whether DTIs, in contrast to low-molecular-weight heparin (LMWH), alter this correlation. METHODS: Twelve minutes after ferric chloride-induced thrombus formation in the femoral vein of female mice, saline, dalteparin (LMWH) or dabigatran (DTI) was administered. Thrombus size and embolic events breaking off from the thrombus were quantified before treatment and at 10-min intervals after treatment for 2 h using intravital videomicroscopy. Lungs were stained for the presence of PE. RESULTS: Thrombus size was similar over time and between treatment groups. Total and large embolic events and pulmonary emboli were highest after treatment with dabigatran. Variations in amounts of pulmonary embolic events were not attributed to variations in thrombus size. Large embolic events correlated with the number of emboli per lung slice independent of treatment. Embolization in factor XIII deficient (FXIII(-/-) ) saline-treated mice was greater than that in wild-type (WT) saline-treated mice, but was similar to WT dabigatran-treated mice. CONCLUSION: We have developed a mouse model of VTE that can quantify emboli and correlate this with PE burden. Consistent with clinical data, dabigatran, a DTI, acutely decreases thrombus stability and increases PE burden compared with LMWH or saline, which is a FXIII-dependent effect. PMID- 26514102 TI - Influence of dust and mud on the optical, chemical, and mechanical properties of a pv protective glass. AB - Recent developments in climate change have increased the frequency of dust storms in the Middle East. Dust storms significantly influence the performances of solar energy harvesting systems, particularly (photovoltaic) PV systems. The characteristics of the dust and the mud formed from this dust are examined using various analytical tools, including optical, scanning electron, and atomic force microscopies, X-ray diffraction, energy spectroscopy, and Fourier transform infrared spectroscopy. The adhesion, cohesion and frictional forces present during the removal of dry mud from the glass surface are determined using a microtribometer. Alkali and alkaline earth metal compounds in the dust dissolve in water to form a chemically active solution at the glass surface. This solution modifies the texture of the glass surface, thereby increasing the microhardness and decreasing the transmittance of the incident optical radiation. The force required to remove the dry mud from the glass surface is high due to the cohesive forces that result from the dried mud solution at the interface between the mud and the glass. The ability altering the characteristics of the glass surface could address the dust/mud-related limitations of protective surfaces and has implications for efficiency enhancements in solar energy systems. PMID- 26514106 TI - 'What the patient wants': an investigation of the methods of ascertaining patient values in evidence-based medicine and values-based practice. AB - Evidence-Based Medicine (EBM), Values-Based Practice (VBP) and Person-Centered Healthcare (PCH) are all concerned with the values in play in the clinical encounter. However, these recent movements are not in agreement about how to discover these relevant values. In some parts of EBM textbooks, the prescribed method for discovering values is through social science research on the average values in a particular population. VBP by contrast always investigates the individually held values of the different stakeholders in the particular clinical encounter, although the account has some other difficulties. I argue that although average values for populations might be very useful in informing questions of resource distribution and policy making, their use cannot replace the individual solicitation of patient (and other stakeholder) values in the clinical encounter. Because of the inconsistency of the EBM stance on values, the incompatibility of some versions of the EBM treatment of values with PCH, and EBM's attempt to transplant research methods from science into the realm of values, I must recommend the use of the VBP account of values discovery. PMID- 26514107 TI - Women Don't Ask. PMID- 26514108 TI - Expanded Payer Coverage for Ultrasound Evaluation of Deep Vein Thrombosis With Sonographer-Obtained Clinical History. PMID- 26514109 TI - Lab-on-fiber technology: a new vision for chemical and biological sensing. AB - The integration of microfluidics and photonic biosensors has allowed achievement of several laboratory functions in a single chip, leading to the development of photonic lab-on-a-chip technology. Although a lot of progress has been made to implement such sensors in small and easy-to-use systems, many applications such as point-of-care diagnostics and in vivo biosensing still require a sensor probe able to perform measurements at precise locations that are often hard to reach. The intrinsic property of optical fibers to conduct light to a remote location makes them an ideal platform to meet this demand. The motivation to combine the good performance of photonic biosensors on chips with the unique advantages of optical fibers has thus led to the development of the so-called lab-on-fiber technology. This emerging technology envisages the integration of functionalized materials on micro- and nano-scales (i.e. the labs) with optical fibers to realize miniaturized and advanced all-in-fiber probes, especially useful for (but not limited to) label-free chemical and biological applications. This review presents a broad overview of lab-on-fiber biosensors, with particular reference to lab-on-tip platforms, where the labs are integrated on the optical fiber facet. Light-matter interaction on the fiber tip is achieved through the integration of thin layers of nanoparticles or nanostructures supporting resonant modes, both plasmonic and photonic, highly sensitive to local modifications of the surrounding environment. According to the physical principle that is exploited, different configurations - such as localized plasmon resonance probes, surface enhanced Raman scattering probes and photonic probes - are classified, while various applications are presented in context throughout. For each device, the surface chemistry and the related functionalization protocols are reviewed. Moreover, the implementation strategies and fabrication processes, either based on bottom-up or top-down approaches, are discussed. In conclusion we highlight some of the further development opportunities, including lab-in-a-needle technology, which could have a direct and disruptive impact in localized cancer treatment applications. PMID- 26514110 TI - Vegetation Greening and Climate Change Promote Multidecadal Rises of Global Land Evapotranspiration. AB - Recent studies showed that anomalous dry conditions and limited moisture supply roughly between 1998 and 2008, especially in the Southern Hemisphere, led to reduced vegetation productivity and ceased growth in land evapotranspiration (ET). However, natural variability of Earth's climate system can degrade capabilities for identifying climate trends. Here we produced a long-term (1982 2013) remote sensing based land ET record and investigated multidecadal changes in global ET and underlying causes. The ET record shows a significant upward global trend of 0.88 mm yr(-2) (P < 0.001) over the 32-year period, mainly driven by vegetation greening (0.018% per year; P < 0.001) and rising atmosphere moisture demand (0.75 mm yr(-2); P = 0.016). Our results indicate that reduced ET growth between 1998 and 2008 was an episodic phenomenon, with subsequent recovery of the ET growth rate after 2008. Terrestrial precipitation also shows a positive trend of 0.66 mm yr(-2) (P = 0.08) over the same period consistent with expected water cycle intensification, but this trend is lower than coincident increases in evaporative demand and ET, implying a possibility of cumulative water supply constraint to ET. Continuation of these trends will likely exacerbate regional drought-induced disturbances, especially during regional dry climate phases associated with strong El Nino events. PMID- 26514111 TI - A Novel Alkylated Indacenodithieno[3,2-b]thiophene-Based Polymer for High Performance Field-Effect Transistors. AB - A novel rigid donor monomer, indacenodithieno[3,2-b]thiophene (IDTT), containing linear alkyl chains, is reported. Its copolymer with benzothiadiazole is an excellent p-type semiconductor, affording a mobility of 6.6 cm(2) V(-1) s(-1) in top-gated field-effect transistors with pentafluorobenzenethiol-modified Au electrodes. Electrode treatment with solution-deposited copper(I) thiocyanate (CuSCN) has a beneficial hole-injection/electron-blocking effect, further enhancing the mobility to 8.7 cm(2) V(-1) s(-1) . PMID- 26514112 TI - Layered Metal Nanoparticle Structures on Electrodes for Sensing, Switchable Controlled Uptake/Release, and Photo-electrochemical Applications. AB - Layered metal nanoparticle (NP) assemblies provide highly porous and conductive composites of unique electrical and optical (plasmonic) properties. Two methods to construct layered metal NP matrices are described, and these include the layer by-layer deposition of NPs, or the electropolymerization of monolayer functionalized NPs, specifically thioaniline-modified metal NPs. The layered NP composites are used as sensing matrices through the use of electrochemistry or surface plasmon resonance (SPR) as transduction signals. The crosslinking of the metal NP composites with molecular receptors, or the imprinting of molecular recognition sites into the electropolymerized NP matrices lead to selective and chiroselective sensing interfaces. Furthermore, the electrosynthesis of redox active, imprinted, bis-aniline bridged Au NP composites yields electrochemically triggered "sponges" for the switchable uptake and release of electron-acceptor substrates, and results in conductive surfaces of electrochemically controlled wettability. Also, photosensitizer-relay-crosslinked Au NP composites, or electrochemically polymerized layered semiconductor quantum dot/metal NP matrices on electrodes, are demonstrated as functional nanostructures for photoelectrochemical applications. PMID- 26514113 TI - Evidence of Cu(I)/Cu(II) Redox Process by X-ray Absorption and EPR Spectroscopy: Direct Synthesis of Dihydrofurans from beta-Ketocarbonyl Derivatives and Olefins. AB - The Cu(I)/Cu(II) and Cu(I)/Cu(III) catalytic cycles have been subject to intense debate in the field of copper-catalyzed oxidative coupling reactions. A mechanistic study on the Cu(I)/Cu(II) redox process, by X-ray absorption (XAS) and electron paramagnetic resonance (EPR) spectroscopies, has elucidated the reduction mechanism of Cu(II) to Cu(I) by 1,3-diketone and detailed investigation revealed that the halide ion is important for the reduction process. The oxidative nature of the thereby-formed Cu(I) has also been studied by XAS and EPR spectroscopy. This mechanistic information is applicable to the copper-catalyzed oxidative cyclization of beta-ketocarbonyl derivatives to dihydrofurans. This protocol provides an ideal route to highly substituted dihydrofuran rings from easily available 1,3-dicarbonyls and olefins. PMID- 26514115 TI - Probing electrode/electrolyte interfaces in situ by X-ray spectroscopies: old methods, new tricks. AB - Electrode/electrolyte interfaces play a vital role in various electrochemical systems, but in situ characterization of such buried interfaces remains a major challenge. Several efforts to develop techniques or to modify existing techniques to study such interfaces are showing great promise to overcome this challenge. Successful examples include electrochemical scanning tunneling microscopy (EC STM), surface-sensitive vibrational spectroscopies, environmental transmission electron microscopy (E-TEM), and surface X-ray scattering. Other techniques such as X-ray core-level spectroscopies are element-specific and chemical-state specific, and are being widely applied in materials science research. Herein we showcase four types of newly developed strategies to probe electrode/electrolyte interfaces in situ with X-ray core-level spectroscopies. These include the standing wave approach, the meniscus approach, and two liquid cell approaches based on X-ray photoelectron spectroscopy and soft X-ray absorption spectroscopy. These examples demonstrate that with proper modifications, many ultra-high-vacuum based techniques can be adapted to study buried electrode/electrolyte interfaces and provide interface-sensitive, element- and chemical-state-specific information, such as solute distribution, hydrogen-bonding network, and molecular reorientation. At present, each method has its own specific limitations, but all of them enable in situ and operando characterization of electrode/electrolyte interfaces that can provide important insights into a variety of electrochemical systems. PMID- 26514114 TI - Acute Brain Imaging in Children: Can MRI Replace CT as a Screening Tool? AB - BACKGROUND AND PURPOSE: To determine if axial T2-weighted imaging can serve as screening tool for pediatric brain imaging. METHODS: We retrospectively evaluated consecutive brain magnetic resonance imaging (MRI) data of 161 children (74 girls) with a mean age of 7.44 +/- 5.71 years. Standard of reference was the final report of neuroradiology attendings. Three readers with different levels of experience were blinded for clinical diagnoses and study indications. First, readers studied only the axial T2-weighted screening sequence. Second, they studied all available anatomical and functional MRI sequences as performed per standard protocol for each clinical indication. The readings were classified as normal or abnormal. Sensitivity and specificity were measured. RESULTS: Axial T2 screening yielded a sensitivity of 77-88% and a specificity of 92%. The full studies/data sets had a sensitivity of 89-95% and a specificity of 86-93%. Nineteen of 167 studies were acquired for acute and 148 of 167 studies for nonacute clinical indication. Twenty-five false-negative diagnoses paneled in three groups were made by all readers together. Readers misread four of 19 studies with acute and 21 of 148 studies with nonacute clinical indication. Four of 21 misread studies with nonacute indications harbored unexpected findings needing management. CONCLUSIONS: Axial T2 screening can detect pediatric brain abnormalities with high sensitivity and specificity and can possibly replace CT as screening tool if the reading physician is aware of possible limitations/pitfalls. The level of experience influences sensitivity and specificity. Adding diffusion-weighted imaging and susceptibility-weighted imaging to a 3-dimensional T2-weighted sequence would most likely further increase sensitivity and specificity. PMID- 26514116 TI - The relative importance of maternal body mass index and glucose levels for prediction of large-for-gestational-age births. AB - BACKGROUND: The risk of gestational diabetes mellitus (GDM) increases substantially with increasing maternal body mass index (BMI). The aim of the present study was to evaluate the relative importance of maternal BMI and glucose levels in prediction of large-for-gestational-age (LGA) births. METHOD: This observational cohort study was based on women giving birth in southern Sweden during the years 2003-2005. Information on 10,974 pregnancies was retrieved from a population-based perinatal register. A 75-g oral glucose tolerance test (OGTT) was performed in the 28 week of pregnancy for determination of the 2-h plasma glucose concentration. BMI was obtained during the first trimester. The dataset was divided into a development set and a validation set. Using the development set, multiple logistic regression analysis was used to identify maternal characteristics associated with LGA. The prediction of LGA was assessed by receiver-operating characteristic (ROC) curves, with LGA defined as birth weight > +2 standard deviations of the mean. RESULTS: In the final multivariable model including BMI, 2-h glucose level and maternal demographics, the factor most strongly associated with LGA was BMI (odds ratio 1.1, 95% confidence interval [CI] 1.08-1.30). Based on the total dataset, the area under the ROC curve (AUC) of 2-h glucose level to predict LGA was 0.54 (95% CI 0.48-0.60), indicating poor performance. Using the validation database, the AUC for the final multiple model was 0.69 (95% CI 0.66-0.72), which was identical to the AUC retrieved from a model not including 2-h glucose (0.69, 95% CI 0.66-0.72), and larger than from a model including 2-h glucose but not BMI (0.63, 95% CI 0.60-0.67). CONCLUSIONS: Both the 2-h glucose level of the OGTT and maternal BMI had a significant effect on the risk of LGA births, but the relative contribution was higher for BMI. The findings highlight the importance of concentrating on healthy body weight in pregnant women and closer monitoring of weight during pregnancy as a strategy for reducing the risk of excessive fetal growth. PMID- 26514117 TI - Novosphingobium oryzae sp. nov., a potential plant-promoting endophytic bacterium isolated from rice roots. AB - A novel endophytic bacterium, strain ZYY112T, isolated from rice roots, was characterized by a polyphasic approach. In phylogenetic analyses based on 16S rRNA gene sequences, ZYY112T showed highest sequence similarity to Novosphingobium sediminicola HU1-AH51T (97.2 %) and less than 97 % similarity with respect to other Novosphingobium species with validly published names. The DNA G+C content of strain ZYY112T was 60.8 mol%. The level of DNA-DNA relatedness between strain ZYY112T and N. sediminicola DSM 27057T was 33.7 % (reciprocal 5.2 %), which supported the suggestion that ZYY112T represented a novel species of the genus Novosphingobium. Ubiquinone Q-10 was the unique respiratory quinone (100 %). The polar lipid profile contained diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, sphingoglycolipid, an unknown aminolipid and an unknown phospholipid. The major fatty acids of strain ZYY112T were summed feature 8 (consisting of C18 : 1omega7c and/or C18 : 1omega6c), summed feature 3 (consisting of C16 : 1omega7c and/or C16 : 1omega6c), C14 : 0 2 OH and C16 : 0. The major polyamine of ZYY112T was spermidine, which is a characteristic trait of the genus Novosphingobium. Characterization by genotypic, chemotaxonomic and phenotypic analysis indicated that strain ZYY112T represents a novel species of the genus Novosphingobium, for which the name Novosphingobium oryzae sp. nov. is proposed. The type strain is ZYY112T ( = ACCC 06131T = JCM 30537T). PMID- 26514118 TI - Robotic or laparoscopic sacrohysteropexy versus open sacrohysteropexy for uterus preservation in pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to compare robotic or laparoscopic sacrohysteropexy (RLSH) and open sacrohysteropexy (OSH) as a surgical treatment for pelvic organ prolapse (POP). METHODS: Among 111 consecutive patients who had undergone sacrohysteropexy for POP, surgical outcomes and postoperative symptoms were compared between the RLSH (n = 54; robotic 14 cases and laparoscopic 40 cases) and OSH (n = 57). groups The medical records of enrolled patients were reviewed retrospectively. RESULTS: Compared with the OSH group, the RLSH group had shorter operating time (120.2 vs 187.5 min, p < 0.0001), less operative bleeding (median estimated blood loss 50 vs 150 ml; p < 0.0001; mean hemoglobin drop 1.4 vs 2.0 g/dl; p < 0.0001), and fewer postoperative symptoms (13 vs 45.6 %; p < 0.0001). Patients' overall satisfaction (94.4 vs 91.2 %; p = 0.717) and required reoperation due to postoperative complications (3.7 vs 1.8 %; p = 0.611) did not differ between groups. CONCLUSIONS: RLSH could be a feasible and safe procedure in patients with POP and should be considered as a surgical option that allows preservation of the uterus. Prospective randomized trials will permit the evaluation of potential benefits of RLSH as a minimally invasive surgical approach. PMID- 26514119 TI - Optimal Timing of Surgical Resection After Radiation in Locally Advanced Rectal Adenocarcinoma: An Analysis of the National Cancer Database. AB - BACKGROUND: In the treatment of rectal cancer, a longer radiation-surgery interval from the end of neoadjuvant radiation therapy to surgery has been associated with higher rates of complete pathologic response (pCR), but the optimal interval with respect to survival has not been established. Data from the National Cancer Database (NCDB) was used to evaluate the impact of radiation surgery interval on oncologic outcomes. METHODS: The NCDB was searched for patients diagnosed with nonmetastatic rectal cancer who underwent preoperative radiation followed by radical surgical resection. A Cox proportional hazards model was constructed to examine the influence of radiation-surgery interval while controlling for potential confounding factors. Sensitivity analysis was used to confirm the results of the model. RESULTS: A cohort of 6397 patients meeting all inclusion and exclusion criteria from 2004-2006 was identified, and the pCR rate for this cohort was 6.9%. Of those who experienced a pCR, 76.2% had done so by 60 days. Intervals greater than 60 days were associated with higher rates of positive surgical margins (6.7 vs. 4.8%, p = 0.009) and lower rates of sphincter-preserving surgery (64.9 vs. 68.9%, p = 0.007). An interval greater than 60 days was associated with significantly shorter survival (hazard ratio (HR), 1.314; 95% CI 1.191-1.449; p < 0.001). CONCLUSIONS: Radiation-surgery interval beyond 60 days is associated with increased rate of positive surgical margins, decreased rate of sphincter-preserving surgery, and decreased survival. Delay of surgery for rectal cancer beyond 60 days after the completion of neoadjuvant therapy should be done with caution. PMID- 26514120 TI - Intraoperative Ultrasound-Guided Lumpectomy Versus Mammographic Wire Localization for Breast Cancer Patients After Neoadjuvant Treatment. AB - BACKGROUND: Intraoperative ultrasound (IOUS)-guided lumpectomy in early breast cancer has shown advantages over other techniques. However, the use of IOUS has been less explored after neoadjuvant treatment (NAT). This study aimed to compare IOUS- and wire localization (WL)-guided surgery in breast cancer patients after NAT. METHODS: The study enrolled patients treated with NAT who underwent breast conserving surgery (BCS) between July 2008 and December 2012. For the patients with a hydrogel marker or residual tumor visible on ultrasound, an IOUS-guided surgery was performed (IOUS group). The patients with a standard marker or hydrogel marker not visible on ultrasound underwent a WL-guided surgery (WL group). RESULTS: The study investigated 214 patients: 145 (67.8 %) in the IOUS group and 69 (32.2 %) in the WL group. The patient and tumor characteristics were comparable between the two groups. For the patients who had a pathologic complete response (pCR) or microscopic disease, the volume excised was lower in the IOUS group (p = 0.03). The rate of reexcision for positive or close margins was similar in the two groups (p = 0.80). After a median follow-up period of 43 months, the local recurrence rates did not differ significantly between the two groups. CONCLUSIONS: Compared with WL surgery, IOUS seems to lower the volume of resection in patients with pCR or minimal microscopic disease after NAT without compromising margins and local recurrences. BCS can easily be achieved with IOUS for patients with a good response after NAT. PMID- 26514121 TI - Benefit of Adjuvant Chemotherapy After Curative Resection of Lung Metastasis in Colorectal Cancer. AB - BACKGROUND: The survival benefit of adjuvant chemotherapy after colorectal cancer (CRC) lung metastasectomy is uncertain. METHODS: We enrolled 221 CRC patients who underwent pulmonary metastasectomy between October 2002 and July 2013, including those with previous liver metastasis that had been curatively resected. Disease free survival (DFS) and overall survival (OS) were calculated from the day of lung metastasectomy. RESULTS: Among all patients, 176 (79.6%) received adjuvant chemotherapy after lung metastasectomy. Median follow-up was 34.7 months from the time of lung metastasectomy [95% confidence interval (95% CI), 7.4-90.9 months]. Patients treated with adjuvant chemotherapy had longer DFS compared with surgery alone (median 32.7 vs 11.2 months respectively, P = 0.076). Multivariate analysis revealed previous liver metastasis, preoperative carcinoembryonic antigen >=5 ng/mL, disease-free interval <24 months, and surgery without adjuvant chemotherapy as independent risk factors for recurrence. Low-risk patients who had 0-1 risk factors received a significant survival benefit from adjuvant chemotherapy [hazard ratio (HR) 0.54; 95% CI 0.32-0.91, P = 0.020]; however, high risk patients with >=2 risk factors did not (HR 1.02; 95% CI 0.48-2.14, P = 0.964). Patients treated with adjuvant chemotherapy showed no OS benefit compared with patients who received surgery alone (median 89.6 vs 86.8 months respectively, P = 0.833). CONCLUSIONS: CRC patients received lung metastasectomy could have a DFS benefit from adjuvant chemotherapy, especially in low-risk patients. Larger, prospective studies are needed to evaluate the role of adjuvant chemotherapy after CRC lung metastasectomy. PMID- 26514123 TI - An Examination of Growing Trends in Land Tenure and Conservation Practice Adoption: Results from a Farmer Survey in Iowa. AB - Tenants and part-owners are farming an increasing number of acres in the United States, while full-owners are farming fewer acres. This shift in ownership is a potential cause for concern because some previous research indicated that tenant and part-owner farmers were less likely to adopt conservation practices than farmers who owned the land they farmed. If that trend persists, ownership changes would signal a national drop in conservation adoption. Here we examine this issue using a survey of agricultural operators in the Clear Creek watershed in Iowa, a state with intensive agricultural production. We compare adoption of conservation practices, and preferences for conservation information sources and communication channels, between farmers who rent some portion of the land they farm (tenants and part-owners) and farmers who own all of the land they farm (full-owners). We find that renters are more likely to practice conservation tillage than full owners, though they are less likely to rotate crops. In addition, renters report using federal government employees (specifically, Natural Resource Conservation Service and Farm Service Agency) as their primary sources of conservation information, while full-owners most frequently rely on neighbors, friends, and County Extension. These findings are significant for conservation policy because, unlike some past research, they indicate that renters are not resistant to all types of conservation practices, echoing recent studies finding an increase in conservation adoption among non-full-owners. Our results emphasize the importance of government conservation communication and can inform outreach efforts by helping tailor effective, targeted conservation strategies for owners and renters. PMID- 26514122 TI - Does "Two is Better Than One" Apply to Surgeons? Comparing Single-Surgeon Versus Co-surgeon Bilateral Mastectomies. AB - BACKGROUND: Bilateral mastectomies (BM) are traditionally performed by single surgeons (SS); a co-surgeon (CS) technique, where each surgeon concurrently performs a unilateral mastectomy, offers an alternative approach. We examined differences in general surgery time (GST), overall surgery time (OST), and patient complications for BM performed by CS and SS. METHODS: Patients undergoing BM with tissue expander reconstruction (BMTR) between January 2010 and May 2014 at our center were identified through operative case logs. GST (incision to end of BM procedure), reconstruction duration (RST) (plastic surgery start to end of reconstruction) and OST (OST = GST + RST) was calculated. Patient age, presence/stage of cancer, breast weight, axillary procedure performed, and 30-day postoperative complications were extracted from medical records. Differences in GST and OST between CS and SS cases were assessed with a t test. A multivariate linear regression was fit to identify factors associated with GST. RESULTS: A total of 116 BMTR cases were performed [CS, n = 67 (57.8 %); SS, n = 49 (42.2 %)]. Demographic characteristics did not differ between groups. GST and OST were significantly shorter for CS cases, 75.8 versus 116.8 min, p < .0001, and 255.2 versus 278.3 min, p = .005, respectively. Presence of a CS significantly reduces BMTR time (beta = -38.82, p < .0001). Breast weight (beta = 0.0093, p = .03) and axillary dissection (beta = 28.69, p = .0003) also impacted GST. CONCLUSIONS: The CS approach to BMTR reduced both GST and OST; however, the degree of time savings (35.1 and 8.3 %, respectively) was less than hypothesized. A larger study is warranted to better characterize time, cost, and outcomes of the CS-approach for BM. PMID- 26514124 TI - Phosphorus ingestion improves oral glucose tolerance of healthy male subjects: a crossover experiment. AB - BACKGROUND: Fasting serum phosphorus (P) was reported to be inversely related to serum glucose and insulin, while the impact of P ingestion is not well documented. The effect of P intake with or before glucose ingestion on postprandial glucose and insulin statuses was investigated. METHOD: Two cross over experiments using healthy male subjects were conducted. Experiment 1: Overnight fasted subjects (n = 7) randomly received: 500 mg of P tablets, glucose (75 g) solution with placebo or 500 mg of P tablets. Experiment 2: Overnight fasted subjects (n = 8) underwent similar procedures to those of experiment 1, except that placebo or 500 mg P tablets were given 60 min prior to glucose ingestion. RESULTS: In both experiments, serum P decreased following glucose ingestion. Co-ingestion of P with glucose improved, at time 60 min, postprandial glucose (P < 0.05), insulin (P < 0.05), and insulin sensitivity index (p < 0.006), while P pre-ingestion failed to exert similar effect. CONCLUSION: This study suggests that postprandial glucose and insulin are affected by exogenous P supply, especially when co-ingested with glucose. PMID- 26514125 TI - Low-dose corticosteroid treatment and mortality in refractory abdominal septic shock after emergency laparotomy. AB - BACKGROUND: The role of low-dose corticosteroid as an adjunctive treatment for abdominal septic shock remains controversial. METHODS: We identified refractory septic shock patients who required noradrenaline and at least one of other vasopressor/inotropic (dopamine, dobutamine or vasopressin) following emergency open laparotomy for perforation of the lower intestinal tract between July 2010 and March 2013 using the Japanese Diagnosis Procedure Combination inpatient database. In-hospital mortality was compared between the low-dose corticosteroid and control groups. RESULTS: There were 2164 eligible patients (155 in the corticosteroid group, 2009 in the control group). We observed no significant difference between the groups in terms of in-hospital mortality in the unadjusted analysis [corticosteroid vs. control groups, 19.4 and 25.1 %, respectively; difference, -5.7 %; 95 % confidence interval (CI), -12.8 to 1.3]; however, a significant difference in in-hospital mortality was evident in the propensity score-weighted analysis (17.6 and 25.0 %, respectively; difference, -7.4 %; 95 % CI -9.9 to -5.0). An instrumental variable analysis with the hospital low-dose corticosteroid prescription proportion showed that receipt of low-dose corticosteroid was significantly associated with reduction in in-hospital mortality (differences, -13.5 %; 95 % CI -24.6 to -2.3). CONCLUSIONS: Low-dose corticosteroid administration may be associated with reduced in-hospital mortality in patients with refractory septic shock following emergency laparotomy for lower intestinal perforation. PMID- 26514126 TI - Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) displays high resistance to conventional chemotherapy. Considering that microRNA-122 (miR-122) performs an essential function to promote chemosensitivity of HCC cells, an effective vehicle mediated miR-122 delivery may represent a promising strategy for HCC chemotherapy. An increasing interest is focused on the use of exosomes as biological vehicles for microRNAs (miRNA) transfer. Mesenchymal stem cells (MSCs) are known for their capacity to produce large amounts of exosomes. This study aimed to determine whether adipose tissue-derived MSC (AMSC) exosomes can be used for miR-122 delivery. METHODS: AMSCs were transfected with a miR-122 expression plasmid. At 48 h after transfection, AMSC-derived exosomes (122-Exo) were harvested and added to recipient HCC cells. Expression levels of miR-122 in AMSCs, exosomes, and HCC cells were quantified by real-time PCR. The mRNA and protein levels of miR-122-target genes in recipient HCC cells were quantified by real-time PCR and Western blot, respectively. The effects of 122-Exo on cell viability, apoptosis, and cell cycle of HCC cells were evaluated by MTT and flow cytometry analysis. Xenograft models were used to determine whether 122-Exo can sensitize HCC cells to sorafenib in vivo. RESULTS: Data showed that miR-122 transfected AMSC can effectively package miR-122 into secreted exosomes, which can mediate miR-122 communication between AMSCs and HCC cells, thereby rendering cancer cells sensitive to chemotherapeutic agents through alteration of miR-122 target gene expression in HCC cells. Moreover, intra-tumor injection of 122-Exo significantly increased the antitumor efficacy of sorafenib on HCC in vivo. CONCLUSIONS: The findings suggest that the export of miR-122 via AMSC exosomes represents a novel strategy to enhance HCC chemosensitivity. PMID- 26514127 TI - The Central Analgesic Mechanism of YM-58483 in Attenuating Neuropathic Pain in Rats. AB - Calcium channel antagonists are commonly used to treat neuropathic pain. Their analgesic effects rely on inhibiting long-term potentiation, and neurotransmitters release in the spinal cord. Store-operated Ca(2+)channels (SOCCs) are highly Ca(2+)-selective cation channels broadly expressed in non excitable cells and some excitable cells. Recent studies have shown that the potent inhibitor of SOCCs, YM-58483, has analgesic effects on neuropathic pain, but its mechanism is unclear. This experiment performed on spinal nerve ligation (SNL)-induced neuropathic pain model in rats tries to explore the mechanism, whereby YM-58483 attenuates neuropathic pain. The left L5 was ligated to produce the SNL neuropathic pain model in male Sprague-Dawley rats. The withdrawal threshold of rats was measured by the up-down method and Hargreaves' method before and after intrathecal administration of YM-58483 and vehicle. The SOCCs in the spinal dorsal horn were located by immunofluorescence. The expression of phosphorylated ERK and phosphorylated CREB, CD11b, and GFAP proteins in spinal level was tested by Western blot, while the release of proinflammatory cytokines (IL-1beta, TNF-alpha, PGE2) was measured by enzyme-linked immunosorbent assay (ELISA). Intrathecal YM-58483 at the concentration of 300 MUM (1.5 nmol) and 1000 MUM (10 nmol) produced a significant central analgesic effect on the SNL rats, compared with control + vehicle (n = 7, P < 0.001). However, both could not prevent the development of neuropathic pain, compared with normal + saline (P < 0.001). Immunofluorescent staining revealed that Orai1 and STIM1 (the two key components of SOCCs) were located in the spinal dorsal horn neurons. Western blot showed that YM-58483 could decrease the levels of P-ERK and P-CREB (n = 10, #P < 0.05), without affecting the expression of CD11b and GFAP (n = 10, #P > 0.05). YM 58483 also inhibited the release of spinal cord IL-1beta, TNF-alpha, and PGE2, compared with control + vehicle (n = 5, #P < 0.001). The analgesic mechanism of YM-58483 may be via inhibiting central ERK/CREB signaling in the neurons and decreasing central IL-1beta, TNF-alpha, and PGE2 release to reduce neuronal excitability in the spinal dorsal horn of the SNL rats. PMID- 26514128 TI - Risk factors for child abuse: levels of knowledge and difficulties in family medicine. A mixed method study. AB - BACKGROUND: Family physicians (FPs) have a central role in the detection and management of child abuse. According to the literature, only 2-5% of initial reports of child abuse come from the medical profession. METHODS: The objective of this study was to assess levels of knowledge of risk factors for child abuse by Family Physicians (FPs) and the attention that the physicians pay to these risk factors. We conducted a mixed-method survey based on semi-structured interviews. 50 FPs practicing in the Somme County (northern France) were interviewed with closed and open questions. The FPs' level of knowledge of risk factors for child abuse and obstacles in the detection of child abuse were assessed. RESULTS: The FPs' level of knowledge of risk factors for child abuse was similar to that reported in the literature. However, FPs knew little about the significant role of prematurity. Likewise, the FP's training did not seem to influence their knowledge of risk factors. Fear of an incorrect diagnosis was the main obstacle to reporting a suspected case. The FPs considered that they were often alone in dealing with a difficult situation and considered that the judicial system and the social services were not sufficiently active. CONCLUSIONS: Few FPs had actually received specific training in the detection and management of child abuse but many stated their need for this type of training. FPs encounter many obstacles in the detection of child abuse, which sometimes make the FP reluctant to report a suspected or potential case. Medical education need to be improved in this field. PMID- 26514129 TI - Endoscopic treatment for iatrogenic achalasia post-laparoscopic adjustable gastric banding. AB - BACKGROUND: Esophageal obstruction is a known complication of laparoscopic adjustable gastric band (LAGB) and usually occurs in the context of band slippage. Current reports of pseudoachalasia post-LAGB describe that in some patients esophageal function improves after band removal. For those without improvement, current treatments include division of the fibrotic band post-LAGB or revisional surgery. Our hypothesis, illustrated in the submitted video, is that an endoscopic division of LAGB-induced stricture will improve esophageal function. METHODS: This video presents the case of a patient presenting with dysphagia post-LAGB removal. The preoperative high-resolution manometry was compatible with a type I achalasia. Using a high-definition endoscope and the equipment used for per-oral endoscopic myotomy (POEM) procedure, the intramural fibrotic tissue caused by the LAGB is divided, thus releasing the stricture and restoring baseline esophageal function. This is demonstrated with intraoperative endoscopic functional lumen imaging probe (EndoFLIP; Crospon Ltd, Galway, Ireland). RESULTS: Similar to the POEM technique, a 12-cm tunnel and 8-cm myotomy were performed. No intra-procedural or post-procedural complications were noted. Using impedance planimetry, the division of the LAGB-induced stricture induced an increase in the minimal diameter from 5.3 to 8.6 mm. The cross-sectional area increased from 22 to 58 mm(2). The patient denies any residual dysphagia, regurgitation, or heartburn at 6-month follow-up. On the postoperative high resolution manometry, significant improvement in LES pressure parameters was seen post-myotomy with return of 30 % peristalsis. DISCUSSION: In LAGB patients with pseudoachalasia in which removal of fluid from the band does not result in clinical or manometric improvement, laparoscopic removal of the band with division of the peri-esophageal scar tissue has been advocated. This video illustrates that an endoscopic division of the LAGB-induced esophageal fibrosis is another potential treatment for adjustable gastric band-induced achalasia. PMID- 26514131 TI - Combined open and laparoscopic technique for extraperitoneal mesh repair of large sac inguinal hernias. AB - BACKGROUND: Laparoscopic total extraperitoneal (TEP) hernia repair has been confirmed as an effective procedure in several studies but is considered technically demanding. Separating the hernial sac and spermatic cord is difficult when a large sac inguinal hernia is encountered. This study aimed to investigate the feasibility and effectiveness of a combined open and laparoscopic TEP repair of large sac inguinal hernias. METHODS: From June 2012 to May 2015, laparoscopic TEP (112 cases) and combined open and laparoscopic TEP (COL-TEP) (44 cases) were performed in patients with large sac hernia. There was no clear definition of large sac inguinal hernia; therefore, we defined a large sac as one with the sac base cranial to or over outer ring that could not be easily resected laparoscopically. Using this definition, the laparoscopic TEP group was divided into a small sac TEP (SS-TEP) group (68 cases) and a large sac TEP (LS-TEP) group (44 cases). Direct hernias were included in the SS-TEP group because the hernial sac was easily dissected laparoscopically. The patient demographics, perioperative parameters, complications, and recurrence were compared between the three groups. RESULTS: No significant differences were found between the groups in mean age, gender, body mass index, comorbidities, number of previous laparotomies, or recurrence rate. Compared with the LS-TEP group, both the SS-TEP and COL-TEP groups had a significantly lower surgical duration (51.4 +/- 10.9 vs. 32.8 +/- 13.1 and 36.2 +/- 11.2 min, respectively), conversion rate (13.6 vs. 0 and 0 %, respectively), and total complication rate (27.3 vs. 13.2 and 11.3 %, respectively). CONCLUSION: The combined technique was safe and effective for repair of large sac inguinal hernias. The combined technique was associated with decreased technical difficulty, surgical duration, and conversion and total complication rates. PMID- 26514130 TI - A robust and non-obtrusive automatic event tracking system for operating room management to improve patient care. AB - BACKGROUND: Optimization of OR management is a complex problem as each OR has different procedures throughout the day inevitably resulting in scheduling delays, variations in time durations and overall suboptimal performance. There exists a need for a system that automatically tracks procedural progress in real time in the OR. This would allow for efficient monitoring of operating room states and target sources of inefficiency and points of improvement. STUDY DESIGN: We placed three wireless sensors (floor-mounted pressure sensor, ventilator-mounted bellows motion sensor and ambient light detector, and a general room motion detector) in two ORs at our institution and tracked cases 24 h a day for over 4 months. RESULTS: We collected data on 238 total cases (107 laparoscopic cases). A total of 176 turnover times were also captured, and we found that the average turnover time between cases was 35 min while the institutional goal was 30 min. Deeper examination showed that 38 % of laparoscopic cases had some aspect of suboptimal activity with the time between extubation and patient exiting the OR being the biggest contributor (16 %). CONCLUSION: Our automated system allows for robust, wireless real-time OR monitoring as well as data collection and retrospective data analyses. We plan to continue expanding our system and to project the data in real time for all OR personnel to see. At the same time, we plan on adding key pieces of technology such as RFID and other radio-frequency systems to track patients and physicians to further increase efficiency and patient safety. PMID- 26514132 TI - Evaluating tactile feedback in robotic surgery for potential clinical application using an animal model. AB - INTRODUCTION: The aims of this study were to evaluate (1) grasping forces with the application of a tactile feedback system in vivo and (2) the incidence of tissue damage incurred during robotic tissue manipulation. Robotic-assisted minimally invasive surgery has been shown to be beneficial in a variety of surgical specialties, particularly radical prostatectomy. This innovative surgical tool offers advantages over traditional laparoscopic techniques, such as improved wrist-like maneuverability, stereoscopic video displays, and scaling of surgical gestures to increase precision. A widely cited disadvantage associated with robotic systems is the absence of tactile feedback. METHODS AND PROCEDURE: Nineteen subjects were categorized into two groups: 5 experts (six or more robotic cases) and 14 novices (five cases or less). The subjects used the da Vinci with integrated tactile feedback to run porcine bowel in the following conditions: (T1: deactivated tactile feedback; T2: activated tactile feedback; and T3: deactivated tactile feedback). The grasping force, incidence of tissue damage, and the correlation of grasping force and tissue damage were analyzed. Tissue damage was evaluated both grossly and histologically by a pathologist blinded to the sample. RESULTS: Tactile feedback resulted in significantly decreased grasping forces for both experts and novices (P < 0.001 in both conditions). The overall incidence of tissue damage was significantly decreased in all subjects (P < 0.001). A statistically significant correlation was found between grasping forces and incidence of tissue damage (P = 0.008). The decreased forces and tissue damage were retained through the third trial when the system was deactivated (P > 0.05 in all subjects). CONCLUSION: The in vivo application of integrated tactile feedback in the robotic system demonstrates significantly reduced grasping forces, resulting in significantly less tissue damage. This tactile feedback system may improve surgical outcomes and broaden the use of robotic-assisted minimally invasive surgery. PMID- 26514133 TI - A comparison of endoscopic treatments in rectal carcinoid tumors. AB - BACKGROUND: Various endoscopic techniques for rectal carcinoid tumors have been developed recently. In this study, we compared the outcomes of conventional endoscopic mucosal resection (EMR), strip biopsy, and EMR after circumferential precutting (EMR-P). METHODS: From March 2004 to July 2014, the medical records of 188 patients (190 rectal carcinoid tumors) who were treated with an endoscopic procedure for rectal carcinoid tumors were investigated retrospectively. The characteristics of the patients and tumors, the selection of the treatment method, the rate of complete resection, and the rate of complications were analyzed retrospectively. RESULTS: Forty-seven, 75 and 68 cases of EMR, strip biopsy and EMR-P were performed, respectively. The mean procedure time was not significantly different between the EMR, strip biopsy and EMR-P cases (5.6, 6.5 and 7.4 min, respectively, P = 0.119). En bloc resection was achieved in most of the cases (97.8, 98.7 and 95.5 % in the EMR, strip biopsy and EMR-P cases, respectively). However, histologic examination showed positive lateral or deep resection margins in 57 out of 190 cases (30.0 %). Multivariate analysis showed that the strip biopsy and EMR-P methods were independent factors for pathologic complete resection (negative in both lateral and deep resection margins), with odds ratios for margin involvement of 0.20 and 0.43 with 95 % confidence intervals from 0.08 to 0.47 and 0.19 to 0.96, respectively. In all the follow-up cases (81 of 190, 42.6 %), no local recurrence or distal metastasis was found. CONCLUSIONS: Compared to conventional EMR, strip biopsy and EMR-P had a lower risk of incomplete resection. The procedure time and complication rate did not differ between the three groups, and no recurrence was detected during the follow up period. Strip biopsy and EMR-P are safe and effective methods for the treatment of rectal carcinoid tumors. PMID- 26514134 TI - Training model for laparoscopic Heller and Dor fundoplication: a tool for laparoscopic skills training and assessment-construct validity using the GOALS score. AB - BACKGROUND: Laparoscopic training demands practice. The transfer of laparoscopic skills from training models to real surgical procedures has been proven. The global operative assessment of laparoscopic skills (GOALS) score is a 5-item global rating scale developed to evaluate laparoscopic skills by direct observation. This scale has been used to demonstrate construct validity of several laparoscopic training models. Here, we present a low-cost model of laparoscopic Heller-Dor for advanced laparoscopic training. The aim of this study was to determine the capability of a training model for laparoscopic Heller-Dor to discriminate between different levels of laparoscopic expertise. METHODS: The performance of two groups with different levels of expertise, novices (<30 laparoscopic procedures PGY1-2) and experts (>300 laparoscopic procedures PGY4-5) was assessed. All participants were instructed to perform two tasks (esophageal myotomy and fundoplication). All the performances were recorded in a digital format. A laparoscopic expert who was blinded to subject's identity evaluated the recordings using the GOALS score. Autonomy, one of the five items of GOALS, was removed since the evaluator and the trainee did not have interaction. The time required to finish each task was also recorded. Performance was compared using the Mann-Whitney U test (p < 0.05 was significant). RESULTS: Twenty subjects were evaluated: ten in each group, using the GOALS score. The mean total GOALS score for novices was 7.5 points (SD: 1.64) and 13.9 points (SD: 1.66) for experts (p < 0.05).The expert group was superior in each domain of the GOALS score compared to novices: depth perception (mean: 3.3 vs 2 p < 0.05), bimanual dexterity (mean 3.4 vs 2.1 p < 0.05), efficiency (mean 3.4 vs 1.7 p < 0.05) and tissue handling (mean 3.6 vs 1.7 p < 0.05). With regard to time, experts were superior in task 1 (mean 9.7 vs 14.9 min p < 0.05) and task 2 (mean 24 vs 47.1 min p < 0.05) compared to novices. CONCLUSIONS: The laparoscopic Heller-Dor training model has construct validity. The model may be used as a tool for training of the surgical resident. PMID- 26514135 TI - Laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma: results of a multicenter cohort study on 196 patients. AB - BACKGROUND: Laparoscopy is widely accepted as a feasible option for distal pancreatectomy. However, the experience in laparoscopic distal pancreatectomy (LDP) for pancreatic ductal adenocarcinoma (PDAC) is limited to a small number of studies, reported by expert centers. The present study aimed to evaluate perioperative and oncological outcomes after LDP for PDAC in a large, multicenter cohort of patients. METHODS: A retrospective analysis of the data on 196 patients with histologically verified PDAC, operated at Oslo University Hospital Rikshospitalet (Oslo, Norway), Asan Medical Center (Seoul, Republic of Korea), Institut Mutualiste Montsouris (Paris, France) and University Hospital Southampton (Southampton, UK) between January 2002 and April 2015 was conducted. The patients with standard (SLDP) and extended (i.e., en bloc with adjacent organ, ELDP) resections were compared in terms of perioperative and oncological outcomes. RESULTS: Out of 196 LDP procedures, 191 (97.4 %) were completed through laparoscopy, while five (2.6 %) were converted to open surgery. ELDP was performed in 30 (15.7 %) cases. Sixty-one (31.9 %) patients experienced postoperative complications, including 48 (25.1 %) with pancreatic fistula. The rate of clinically relevant fistula (grade B/C) was 15.7 %. Median postoperative hospital stay was 8 (2-63) days. Median follow-up was 16 months. Median survival was 31.3 months (95 % CI 22.9-39.6). Three- and 5-year actuarial survival rates were 42.4 and 30 %, respectively. SLDP was associated with significantly higher survival compared with ELDP (p = 0.032). CONCLUSIONS: LDP seems to be a feasible and safe procedure, providing satisfactory oncological outcomes in patients with PDAC. PMID- 26514136 TI - Effect of bariatric surgery on systemic and adipose tissue inflammation. AB - BACKGROUND: Obese patients are predisposed to developing insulin resistance and associated metabolic diseases such as diabetes and cardiovascular disease. The objective of this study was to determine the effect of bariatric surgery on adipose-derived inflammatory cytokines (adipokines), which play a key role in insulin resistance and obesity. We hypothesized that there is a significant increase in serum and tissue anti-inflammatory adiponectin with a decrease in circulating pro-inflammatory TNF-alpha and MCP-1, leading to reduced inflammation post-bariatric surgery. METHODS: In this study, we investigated the effects of laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic gastric band on serum and tissue levels of adiponectin and serum levels of MCP-1 and TNF-alpha. Samples of serum and adipose tissue were collected at the time of surgery, 2 weeks and 6 months postoperatively. Adipokine levels were assayed by ELISA kits. RESULTS: A significant increase in adiponectin levels 2 weeks after surgery was observed in the subcutaneous adipose tissue in both groups combined. Serum adiponectin in LRYGB patients showed an increasing trend, while MCP-1 showed a decreasing trend post-surgery. There was no difference in TNF-alpha among the groups. The number of patients enrolled did not allow for statistical power to be reached. CONCLUSION: Our results show significant and rapid increases in subcutaneous adipose adiponectin as early as 2 weeks post-bariatric surgery demonstrating reduced inflammation and possibly reduced insulin resistance. Future studies are warranted in larger cohorts with additional measurements of insulin sensitivity and inflammation. PMID- 26514137 TI - Long-term oncologic outcome of robotic versus open total thyroidectomy in PTC: a case-matched retrospective study. AB - PURPOSE: The role of the robot in thyroid surgery remains uncertain, and it is unclear whether robotic total thyroidectomy (R-TT) can be justified as a standard treatment for patients with thyroid cancer. This study compared the long-term operative results and oncologic outcomes of R-TT and conventional open TT (O-TT) after propensity score matching of the cohorts. METHODS: This study retrospectively evaluated patients with papillary thyroid cancer (PTC) who underwent TT with central compartment node dissection (CCND) by a single surgeon in tertiary medical center. Of the 833 patients, 94 (11.3 %) were lost to follow up. 245 (33.2 %) underwent R-TT, and 494 (66.8 %) underwent O-TT. The mean follow up duration was 74 (range 61-91) months. Propensity score matching in age, gender, tumor size, extrathyroidal invasion, multiplicity, bilaterality, and TNM stage identified 206 pairs of patients. The long-term oncologic outcomes were assessed in the R-TT and O-TT groups before and after adjustment for baseline covariates. RESULTS: After adjustment for baseline covariates, serum thyroglobulin (Tg) (p = 0.746) and anti-thyroglobulin antibody (TgAb) (p = 0.394) concentrations were similar in the two groups 5 years after surgery. Nine patients experienced locoregional recurrence, six in the O-TT and three in the R TT group, with all recurrences in regional LNs. Disease-free survival (DFS) was similar in the R-TT and O-TT groups before matching (p = 0.890) and after adjustment for baseline covariates (p = 0.882). CONCLUSION: This represents the first report of 5-year surgical outcomes in patients who underwent R-TT for thyroid cancer. Long-term oncologic quality was similar after R-TT and O-TT. PMID- 26514138 TI - Nonintubated transareolar single-port thoracic sympathicotomy with a needle scope in a series of 85 male patients. AB - BACKGROUND: Traditional endoscopic thoracic sympathicotomy is usually performed through an axillary incision with 5-mm thoracoscope under general anesthesia with endotrachea intubation. Nonintubated transareolar single-port thoracic sympathicotomy with a needle scope has rarely been attempted. The objective of this study is to evaluate the feasibility and safety of this minimally invasive technique in managing primary palmar hyperhidrosis (PPH). METHODS: From May 2012 to May 2014, a total of 85 male patients with severe PPH underwent transareolar single-port thoracic sympathicotomy by use of a 2-mm needle scope under total intravenous anesthesia without endotrachea intubation. RESULTS: All procedures were successfully performed with a mean operating time of 13.5 min. The palms of all patients became dry and warm as soon as the sympathetic chain was cut off. There were no sore throat, and all the patients regained consciousness rapidly after surgery. Eighty-two patients (96.5 %) were discharged from the hospital on the first postoperative day. The postoperative complications were minor, and no patients developed Horner's syndrome. At 6 months postoperatively, there is no obvious surgical scar on the chest wall, and none of the patients complained about postoperative pain. Compensatory sweating appeared in 31 patients. No recurrent symptoms were observed in our study. One-year follow-up revealed an excellent cosmetic result and degree of satisfaction. CONCLUSIONS: Nonintubated transareolar single-port needlescopic thoracic sympathicotomy is a safe, effective and minimally invasive therapeutic procedure, which can be performed in routine clinical practice for male PPH patients. PMID- 26514139 TI - New endoscopic platform for endoluminal en bloc tissue resection in the gastrointestinal tract (with videos). AB - BACKGROUND: Endoscopic removal of gastrointestinal tract lesions is increasingly popular around the world. We evaluated feasibility, safety, effectiveness, and user learning curve of new endoscopic platform for complex intraluminal interventions. METHODS: A novel system, consisting of expandable working chamber with two independent instrument guides (LIG), was inserted into colon. Simulated colonic lesions were removed with endoscopic submucosal (ESD) and submuscular (ESmD) dissection. RESULTS: In all nine in vivo models, an intraluminal chamber and its dynamic tissue retractors (via LIG) provided a stable working space with excellent visualization and adequate access to target tissue. Endoscopic platform facilitated successful completion of 11 en bloc ESDs (mean size 43.0 +/- 11.3 mm, mean time 46.3 +/- 41.2 min) and eight ESmD (mean size 50.0 +/- 14.1 mm, mean time 48.0 +/- 21.2 min). The learning curve for ESD using this platform demonstrated three phases: rapid improvement in procedural skills took place during the first three procedures (mean ESD time 98.7 +/- 40.0 min). A plateau phase then occurred (procedures 4-7) with mean procedure time 42.0 +/- 13.4 min (p = 0.04), followed by another sharp improvement in procedural skills (procedures 8-11) requiring only 16.3 +/- 11.4 min (p = 0.03) to complete ESD. Especially dramatic (p = 0.002) was the time difference between the first three procedures (mean time 98.7 +/- 40.0 min) and subsequent eight procedures (mean time 29.1 +/- 17.9 min). CONCLUSIONS: A newly developed endoscopic platform provides stable intraluminal working space, dynamic tissue retraction, and instrument triangulation, improving visualization and access to the target tissue for safer and more effective en bloc endoscopic submucosal and submuscular dissection. The learning curve for ESD was markedly facilitated by this new endoscopic platform. PMID- 26514140 TI - Linked shoulder replacement: current design problems and a new design proposal. AB - BACKGROUND: Totally constrained shoulder replacement with linked components is one of the surgical options in post-tumor resection shoulder reconstruction or in complex shoulder revision operations. In this paper, we intend to shed light on such an implant design, which provides a linked constrained connection between the humeral head and the glenoid, and to show some immediate postoperative complications, implant progression to decrease the chances of implant mechanical postinsertion failure, and a new design proposal. MATERIALS AND METHODS: In our center, we use the linked prosthesis in complex revision situations; however, there have been some complications, which could be attributed mainly to the engineering and the implant design, and hence potentially avoidable by making a different design to cover for those mechanical issues. Two such complications are described in this paper. RESULTS: Early revisions after linked shoulder replacement implantation were needed in two occasions due to implant disconnection: one of them was due to dislodgement from the native glenoid, and the second one was due to the disengagement of the ringlet which secures the linkage mechanism between the humeral head and the implanted glenoid shell. CONCLUSION: There is a need for a more stable design construct to avoid the reported complications that needed early revision surgeries. The new design proposed is an attempt to help providing a better and more stable implant to decrease the chances of revision in those complex situations where the patient already had many major operations, and working to increase the durability of the implant is crucial. PMID- 26514141 TI - Shear fractures of the distal humerus: Is the use of intra-articular screws a safe treatment? AB - BACKGROUND: Coronal shear fractures of the distal humerus are uncommon injuries and are not exempt from complications. The aim of this research is to evaluate the possible advantages and drawbacks using cannulated compression headless screws. MATERIALS AND METHODS: We performed a prospective study including all the consecutive patients who were treated with cannulated screws for coronal shear fractures of the distal humerus between 2010 and 2013. Following the Dubberley's classification, three patients were type 1A, one patient was 1B, three patients were 2B, and one patient was 3B. The mean follow-up was 30 months. The clinical and radiological evaluation included analysis of passive range of motion, functional outcome, radiological evaluation of fracture healing and reduction maintenance, and the occurrence of possible adverse events. RESULTS: All fractures healed, and radiographic union was observed at an average of 3 months. The average elbow range of motion was 125 degrees , with 125 degrees of flexion and 20 of extension. According to the Broberg and Morrey score, there were four excellent and four good results. Using the Mayo Elbow Performance Index, five cases achieved excellent scores and three reported good results. Adverse events reported in three cases were as follows: heterotopic ossification, complex regional pain syndrome and delayed lateral collateral ligament disruption. CONCLUSIONS: The use of cannulated compression headless screws has given satisfactory results, allowing a strong inter-fragmentary compression, early mobilization, with high union rates and good elbow function. However, patients should be counseled about the high proportion of adverse events following these injuries. PMID- 26514142 TI - A study of 44 patients with subtrochanteric fractures treated using long nail and cerclage cables. AB - OBJECTIVE: This study aims to demonstrate that the use of long cephalomedullary nail and cerclage cables represents a good strategy in order to reduce the high risk of nonunion of the most displaced subtrochanteric fractures. METHODS: This retrospective study examines 44 patients with average follow-up of 23 months, with subtrochanteric fracture type SH IIB, IIC, IIIA, IIIB treated by the same operator and with the same nail and cerclage cables. The clinical results which are derived from THRS have been reported. RESULTS: Clinical and radiological consolidation occurred in all 44 cases, without re-intervention. The average evaluation derived from the THRS was 48 which corresponds to good, according to the scale. CONCLUSIONS: Considering the anatomic reduction achieved in all patients and the clinical results, we can define the use of long cephalomedullary nail and cerclage cables as the most useful technique in the armamentarium of a trauma surgeon for the treatment of the subtrochanteric fractures. PMID- 26514143 TI - A conserved RNA structural element within the hepatitis B virus post transcriptional regulatory element enhance nuclear export of intronless transcripts and repress the splicing mechanism. AB - Hepatitis B virus (HBV) infection is a primary cause of hepatocellular carcinoma and liver cirrhosis worldwide. To develop novel antiviral drugs, a better understanding of HBV gene expression regulation is vital. One important aspect is to understand how HBV hijacks the cellular machinery to export unspliced RNA from the nucleus. The HBV post-transcriptional regulatory element (HBV PRE) has been proposed to be the HBV RNA nuclear export element. However, the function remains controversial, and the core element is unclear. This study, therefore, aimed to identify functional regulatory elements within the HBV PRE and investigate their functions. Using bioinformatics programs based on sequence conservation and conserved RNA secondary structures, three regulatory elements were predicted, namely PRE 1151-1410, PRE 1520-1620 and PRE 1650-1684. PRE 1151-1410 significantly increased intronless and unspliced luciferase activity in both HepG2 and COS-7 cells. Likewise, PRE 1151-1410 significantly elevated intronless and unspliced HBV surface transcripts in liver cancer cells. Moreover, motif analysis predicted that PRE 1151-1410 contains several regulatory motifs. This study reported the roles of PRE 1151-1410 in intronless transcript nuclear export and the splicing mechanism. Additionally, these results provide knowledge in the field of HBV RNA regulation. Moreover, PRE 1151-1410 may be used to enhance the expression of other mRNAs in intronless reporter plasmids. PMID- 26514144 TI - [Who exactly are these "persons with limitations in daily living skills"? : Survey of insured persons based on health insurance data]. AB - BACKGROUND: In recent years German long-term care insurance coverage has gradually been extended to include services for people with limitations in daily living skills. Until now, however, it was unclear who exactly people with limited daily living skills are. AIM: The study aimed to characterize people with limited daily living skills who use additional support services as defined by S 45b of the Social Services Code XI (SGB XI). MATERIAL AND METHODS: This study was based on a survey of 1284 people with limited daily living skills who used additional support services (S 45b SGB XI). The data were analyzed descriptively. RESULTS: The average recipient was 81 years old, mainly in care level I and the majority of them were exclusively cared for by relatives. Of these recipients 61 % were diagnosed with dementia, 73.4 % had medium cognitive impairments while more than half could no longer carry out the instrumental activities of daily living (IADL). CONCLUSION: Statistics on people with limited daily living skills should be included in publications and reports so that the need for care and assistance can be estimated more precisely. PMID- 26514145 TI - Fitness training for the old and frail. Effectiveness and impact on daily life coping and self-care abilities. AB - BACKGROUND: Limitations of functionality and mobility due to age-related decrease in muscle strength, balance and physical endurance are closely related to weakness, risk of falls, malnutrition as well as an increase in morbidity and mortality. STUDY PARTICIPANTS AND METHODS: In a pilot study we developed and evaluated an 8-week equipment-based progressive resistance training program for geriatric day hospital patients (> 65 years) to improve strength, endurance and coordination. Of the 38 patients who entered the study, 20 were randomly assigned to the intervention group (ALFIT training) and 18 to the control group who only participated in the routine program of the day hospital. Motivation, experiences during training and the subjective impact on coping with daily life were examined with qualitative interviews. RESULTS: Muscular strength, endurance, coordination and balance improved during the implementation of the ALFIT training program. The most pronounced effects were seen for the leg pressing with an average increase of 27.8 +/- 16 kg (mean +/- SD) in terms of 1 repetition maximum and an increase of 12.6 +/- 23.7 (mean +/- SD) in terms of muscular endurance (number of repetitions). Positive effects were also evident for mobility and nutritional status. The results of the interviews suggest that the ALFIT training leads to noticeably better physical function and confidence and can have a positive impact on coping in daily life and self-care abilities. CONCLUSION: The results show that ALFIT training was appropriate for the needs of geriatric patients and demonstrated beneficial effects on muscular strength, functionality and mobility. The results of the interviews suggest that even frail old people can be motivated to engage in sports. PMID- 26514146 TI - [Structural lag and room for possibilities in old age: Contribution of a novel discipline trialogue between diaconical science, psychology and theology]. PMID- 26514147 TI - [The search for wasted potential]. PMID- 26514148 TI - Drinking and Driving Among Undocumented Latino Immigrants in Miami-Dade County, Florida. AB - There is concern that by failing to understand fully the risks associated with driving under the influence (DUI), some Latino immigrants-undocumented in particular-may be overrepresented in alcohol-related crashes. Until now, data on undocumented immigrants has been absent. Data came from an ongoing longitudinal sample of Latino immigrants to Miami-Dade County, FL. Descriptive analyses and regression techniques were applied. Compared with permanent residents, undocumented drivers are more likely to binge drink, less likely to understand DUI laws, and less likely to perceive the risks associated with DUI-three factors largely associated with high DUI rates. Despite facing these risk factors, undocumented immigrants showed low DUI rates, partly due to their limited amount of driving. Differences in risk perceptions and actual DUI events between Latino immigrants of different residency statuses suggest the possibility of early interventions aimed at reducing DUI among Latino immigrants. PMID- 26514150 TI - Exploring Barriers to Breastfeeding Among Chinese Mothers Living in Madrid, Spain. AB - In Spain, immigrant women have high rates for initiating breastfeeding. In contrast, the case of immigrant Chinese mothers stands out, due to the low rate. In China, breastfeeding has historically been the cultural norm. An ethnographic study was conducted to explore aspects related to the low rate of breastfeeding. Field observations and informal interviews were conducted in two hospitals and a primary care center. Semi-structured interviews were performed with Chinese mothers and health workers. Among Spanish health workers, there is a belief that Chinese women do not breastfeed due to cultural reasons. The rapid return to work and the popular phenomenon of sending babies back to China for grandparents to raise constitute barriers for breastfeeding. Although in China breastfeeding is common practice, in Madrid the prioritization of productivity over reproduction and the existence of the so-called "satellite babies" and transnational maternity make the establishment and maintenance of breastfeeding difficult. PMID- 26514149 TI - Comparisons of Physical Activity and Walking Between Korean Immigrant and White Women in King County, WA. AB - Immigrant and minority women are less physically active than White women particularly during leisure time. However, prior research demonstrates that reported household physical activity (PA) and non-leisure time walking/biking were higher among the former. Using accelerometers, GPS, and travel logs, transport-related, home-based, and leisure time PA were measured objectively for 7 days from a convenience sample of 60 first-generation Korean immigrant women and 69 matched White women from the Travel Assessment and Community Project in King County, Washington. Time spent in total PA, walking, and home-based PA was higher among Whites than Korean immigrants regardless of PA type or location. 58 % of the White women but only 20 % of the Korean women met CDC's PA recommendations. Socio-economic status, psychosocial factors, and participants' neighborhood built environmental factors failed to account for the observed PA differences between these groups. PMID- 26514151 TI - Diet Quality among Preschool-Age Children of Latino Migrant and Seasonal Farmworkers in the United States. AB - Dietary quality has been linked to obesity in children. Obesity among children of farmworker families exceeds that of other US Hispanic children. Knowledge of their dietary quality is needed to understand the origins and prevention of this obesity. Mothers (n = 237) of 3-year old children in farmworker families completed 3 24-hour recalls with trained interviewers using the Nutrition Data System for Research (NDS-R). Output was used to calculate total and component scores of the Revised Children's Diet Quality Index (RC-DQI). Mean total score was 62 (range 36-86) of an optimal score of 90. Scores for total fat, total grains, excess juice and iron were >80 % of the optimum, but scores for added sugar, whole grains, fruits, and vegetables were considerably lower. Children in farmworker families have low overall dietary quality. Intervention targeted to specific food issues may be an efficient way to addressing the problem. PMID- 26514152 TI - Acculturation, Income and Vegetable Consumption Behaviors Among Latino Adults in the U.S.: A Mediation Analysis with the Bootstrapping Technique. AB - This study examined whether household income mediates the relationship between acculturation and vegetable consumption among Latino adults in the U.S. Data from the 2009 to 2010 National Health and Nutrition Examination Survey were analyzed. Vegetable consumption index was created based on the frequencies of five kinds of vegetables intake. Acculturation was measured with the degree of English language use at home. Path model with bootstrapping technique was employed for mediation analysis. A significant partial mediation relationship was identified. Greater acculturation [95 % bias corrected bootstrap confident interval (BCBCI) = (0.02, 0.33)] was associated with the higher income and in turn, greater vegetable consumption. At the same time, greater acculturation was associated with lower vegetable consumption [95 % BCBCI = (-0.88, -0.07)]. Findings regarding the income as a mediator of the acculturation-dietary behavior relationship inform unique intervention programs and policy changes to address health disparities by race/ethnicity. PMID- 26514153 TI - Mycoplasma Infection Alters Cancer Stem Cell Properties in Vitro. AB - Cancer cell lines can be useful to model cancer stem cells. Infection with Mycoplasma species is an insidious problem in mammalian cell culture. While investigating stem-like properties in early passage melanoma cell lines, we noted poorly reproducible results from an aliquot of a cell line that was later found to be infected with Mycoplasma hyorhinis. Deliberate infection of other early passage melanoma cell lines aliquots induced variable and unpredictable effects on expression of putative cancer stem cell markers, clonogenicity, proliferation and global gene expression. Cell lines established in stem cell media (SCM) were equally susceptible. Mycoplasma status is rarely reported in publications using cultured cells to study the cancer stem cell hypothesis. Our work highlights the importance of surveillance for Mycoplasma infection while using any cultured cells to interrogate tumor heterogeneity. PMID- 26514154 TI - Hospital-Level Factors Related to 30-Day Readmission Rates. AB - This study investigates the relationship between inpatient quality of care as measured by the Agency for Healthcare Research and Quality (AHRQ) patient safety indicator (PSI) composite and all-cause, hospital-wide, 30-day readmission rates. Discharge data from 4 statewide databases were analyzed. Linear, repeated measures regressions were performed to predict hospital-level 30-day readmission rates. The mean readmission rate was 12.9%, and the mean PSI composite ratio was 0.95 among 524 hospitals with 2592 observations. In the hospital-level analysis, the risk-adjusted AHRQ PSI composite was not significantly associated with hospital 30-day readmission rate after controlling for hospital-level characteristics, patient case mix, and sociodemographics. Inpatient quality of care appears to have less influence on hospital readmission rates than do clinical and socioeconomic factors. However, these results suggest that a patient safety composite measure that includes postdischarge complications would provide more information to assist hospitals and communities in understanding the association between quality of care and readmission rates. PMID- 26514155 TI - Ranjit Chandra: how reputation bamboozled the scientific community. PMID- 26514156 TI - Revision of Breastfeeding Guidelines in the Setting of Maternal Opioid Use Disorder: One Institution's Experience. AB - Breastfeeding is recommended for women with opioid use disorder who are treated with methadone or buprenorphine. Infants with neonatal abstinence syndrome (NAS) secondary to in-utero opioid exposure have unique challenges related to breastfeeding but also have significant benefits including improved NAS symptoms with a decreased need for pharmacotherapy. Poor understanding of substance use disorder and treatment, lack of evidence-based recommendations, and vague guidelines from national academies create controversy about breastfeeding eligibility for these women. Defining breastfeeding guidelines is often difficult, particularly in large institutions with multiple providers caring for the mother-infant dyad. Based on the available evidence and review of our institutional data, we revised our breastfeeding guidelines for mothers with opioid use disorder. The aims of our new guidelines are (a) to safely promote breastfeeding in all mothers with opioid use disorder who are in recovery, (b) to improve NAS outcomes through use of breastfeeding as a key nonpharmacologic treatment modality, and (c) to improve staff communication and consistency on the subject of breastfeeding in this patient population. PMID- 26514157 TI - Drug transporter gene expression in human colorectal tissue and cell lines: modulation with antiretrovirals for microbicide optimization. AB - OBJECTIVES: The objectives of this study were to comprehensively assess mRNA expression of 84 drug transporters in human colorectal biopsies and six representative cell lines, and to investigate the alteration of drug transporter gene expression after exposure to three candidate microbicidal antiretroviral (ARV) drugs (tenofovir, darunavir and dapivirine) in the colorectal epithelium. The outcome of the objectives informs development of optimal ARV-based microbicidal formulations for prevention of HIV-1 infection. METHODS: Drug transporter mRNA expression was quantified from colorectal biopsies and cell lines by quantitative real-time PCR. Relative mRNA expression was quantified in Caco-2 cells and colorectal explants after induction with ARVs. Data were analysed using Pearson's product moment correlation (r), hierarchical clustering and principal component analysis (PCA). RESULTS: Expression of 58 of the 84 transporters was documented in colorectal biopsies, with genes for CNT2, P glycoprotein (P-gp) and MRP3 showing the highest expression. No difference was noted between individual subjects when analysed by age, gender or anatomical site (rectum or recto-sigmoid) (r = 0.95-0.99). High expression of P-gp and CNT2 proteins was confirmed by immunohistochemical staining. Similarity between colorectal tissue and cell-line drug transporter gene expression was variable (r = 0.64-0.84). PCA showed distinct clustering of human colorectal biopsy samples, with the Caco-2 cells defined as the best surrogate system. Induction of Caco-2 cell lines with ARV drugs suggests that darunavir-based microbicides incorporating tenofovir may result in drug-drug interactions likely to affect distribution of individual drugs to sub-epithelial target cells. CONCLUSIONS: These findings will help optimize complex formulations of rectal microbicides to realize their full potential as an effective approach for pre-exposure prophylaxis against HIV-1 infection. PMID- 26514158 TI - Guilt is associated with acute stress symptoms in children after road traffic accidents. AB - BACKGROUND: Although previous research has consistently found considerable rates of acute stress disorder (ASD) in children with accidental injuries, knowledge about determinants of ASD remains incomplete. Guilt is a common reaction among children after a traumatic event and has been shown to contribute to posttraumatic stress disorder. However, its relationship to ASD has never been examined. OBJECTIVE: This study assessed the prevalence of ASD in children and adolescents following road traffic accidents (RTAs). Moreover, the association between peritraumatic guilt and ASD was investigated relying on current cognitive theories of posttraumatic stress and controlling for female sex, age, socioeconomic status (SES), injury severity, inpatient treatment, pretrauma psychopathology, and maternal posttraumatic stress symptoms (PTSS). METHODS: One hundred and one children and adolescents (aged 7-16 years) were assessed by means of a clinical interview approximately 10 days after an RTA. Mothers were assessed by questionnaires. RESULTS: Three participants (3.0%) met diagnostic criteria for full ASD according to DSM-IV, and 17 (16.8%) for subsyndromal ASD. In a multivariate regression model, guilt was found to be a significant predictor of ASD severity. Female sex, outpatient treatment, and maternal PTSS also predicted ASD severity. Child age, SES, injury severity, and pretraumatic child psychopathology were not related to ASD severity. CONCLUSIONS: Future research should examine the association between peritraumatic guilt and acute stress symptoms in more detail. Moreover, guilt appraisals in the acute phase after an accident might be a relevant target for clinical attention. PMID- 26514159 TI - Refugee blues: a UK and European perspective. AB - In this paper, the numbers of refugees travelling to the European Union are set in a global context. It is argued that the increasing restrictions placed on asylum seekers from the 1980s onwards in the UK and the associated culture of deterrence and prohibition have had the perverse effect of supporting the economic market for people smuggling. It appears that these restrictions were initially designed to deter people, most of whom would have been granted humanitarian assistance had they managed to arrive in the UK, so as to prevent them from accessing the decision-making process on asylum. Policy changes concerning travel, benefits, and other pressures on asylum seekers are also considered in the context of deterrence. The problems facing asylum seekers do not end with their arrival in a safe country. The current methods of determining refugee status are alarmingly weak. Indeed there is evidence suggesting that those who are most traumatised before arrival face systematic disadvantage. The focus of this paper is on the United Kingdom but its conclusions apply to most Western European countries. The paper concludes with some tentative suggestions for change. PMID- 26514160 TI - Optimal Lifestyle Components in Young Adulthood Are Associated With Maintaining the Ideal Cardiovascular Health Profile Into Middle Age. AB - BACKGROUND: Middle-aged adults with ideal blood pressure, cholesterol, and glucose levels exhibit substantially lower cardiovascular mortality than those with unfavorable levels. Four healthy lifestyle components-optimal body weight, diet, physical activity, and not smoking-are recommended for cardiovascular health (CVH). This study quantified associations between combinations of healthy lifestyle components measured in young adulthood and loss of the ideal CVH profile into middle age. METHODS AND RESULTS: Analyses included 2164 young adults in the Coronary Artery Risk Development in Young Adults study with the ideal CVH profile (defined as untreated blood pressure <120/80 mm Hg, total cholesterol <200 mg/dL, fasting blood glucose <100 mg/dL, and absence of cardiovascular disease) at baseline. Cox proportional hazards regression models estimated hazard ratios for loss of the ideal CVH profile over 25 years according to 4 individual and 16 combinations of optimal healthy lifestyle components measured in young adulthood: body mass index, physical activity, nonsmoking status, and diet quality. Models were adjusted for age, sex, race, education, study center, and baseline blood pressure, cholesterol, and glucose. Eighty percent (n=1737) of participants lost the ideal CVH profile by middle age; loss was greatest for young adults with no optimal healthy lifestyle components at baseline. Relative to young adults with no optimal healthy lifestyle components, those with all 4 were less likely to lose the ideal CVH profile (hazard ratio 0.59, 95% CI 0.44 0.80). Combinations that included optimal body mass index and nonsmoking status were each associated with lower risk. CONCLUSIONS: Optimal body mass index and not smoking in young adulthood were protective against loss of the ideal CVH profile through middle age. Importance of diet and physical activity may be included through their effects on healthy weight. PMID- 26514161 TI - Individual Proton Pump Inhibitors and Outcomes in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy: A Systematic Review. AB - BACKGROUND: Observational studies evaluating the possible interaction between proton pump inhibitors (PPIs) and clopidogrel have shown mixed results. We conducted a systematic review comparing the safety of individual PPIs in patients with coronary artery disease taking clopidogrel. METHODS AND RESULTS: Studies performed from January 1995 to December 2013 were screened for inclusion. Data were extracted, and study quality was graded for 34 potential studies. For those studies in which follow-up period, outcomes, and multivariable adjustment were comparable, meta-analysis was performed.The adjusted odds or hazard ratios for the composite of cardiovascular or all-cause death, myocardial infarction, and stroke at 1 year were reported in 6 observational studies with data on individual PPIs. Random-effects meta-analyses of the 6 studies revealed an increased risk for adverse cardiovascular events for those taking pantoprazole (hazard ratio 1.38; 95% CI 1.12-1.70), lansoprazole (hazard ratio 1.29; 95% CI 1.09-1.52), or esomeprazole (hazard ratio 1.27; 95% CI 1.02-1.58) compared with patients on no PPI. This association was not significant for omeprazole (hazard ratio 1.16; 95% CI 0.93-1.44). Sensitivity analyses for the coronary artery disease population (acute coronary syndrome versus mixed) and exclusion of a single study due to heterogeneity of reported results did not have significant influence on the effect estimates for any PPIs. CONCLUSIONS: Several frequently used PPIs previously thought to be safe for concomitant use with clopidogrel were associated with greater risk of adverse cardiovascular events. Although the data are observational, they highlight the need for randomized controlled trials to evaluate the safety of concomitant PPI and clopidogrel use in patients with coronary artery disease. PMID- 26514162 TI - Interneuron Deficit Associates Attenuated Network Synchronization to Mismatch of Energy Supply and Demand in Aging Mouse Brains. AB - Higher cognitive functions depend critically on synchronized network activity in the gamma range (30-100 Hz), which results from activity of fast-spiking parvalbumin-positive (PV) interneurons. Here, we examined synaptic activity in the gamma band in relation to PV interneuron activity, stimulation-induced calcium activity in neurons and astrocytes, and cerebral blood flow and oxygen responses in the somatosensory cortex of young adult and old adult mice in vivo using electrical whisker pad stimulation. Gamma activity was reduced in old adult mice, and associated with reduced calcium activity of PV interneurons, whereas the overall responses of neurons and astrocytes were unchanged. Hemodynamic responses were highly correlated to the power of synaptic activity in both young adult and old adult mice, but the hemodynamic response amplitude attained was lower in old adult mice. In comparison, the work-dependent rise in O2 use, that is, the rise in the cerebral metabolic rate of oxygen (CMRO2) evoked by excitatory postsynaptic currents almost doubled in old adult mice. We conclude that PV interneuron function and gamma activity are particularly affected in old adult mice. Alterations in neurovascular coupling and CMRO2 responses may contribute to increased frailty and risk of cognitive decline in aged brains. PMID- 26514164 TI - Studying both sexes: a guiding principle for biomedicine. AB - In May 2014, the U.S. National Institutes of Health (NIH) announced that it will ensure that investigators account for sex as a biological variable (SABV) in NIH funded preclinical research as part of the agency's rigor and transparency initiative. Herein, I describe in more detail the rationale behind the SABV policy component and provide additional detail about policy goals. In short, studying both sexes is a guiding principle in biomedical research that will expand knowledge toward turning discovery into health. NIH expects that considering SABV in preclinical research will help to build a knowledge base that better informs the design of clinical research and trials in humans. Integrating the practice of studying both sexes in preclinical research will, over time, expand our currently incomplete knowledge base that plays a critical role in informing the development of sex- and gender-appropriate medical care for women and men. PMID- 26514165 TI - Multiple excitatory and inhibitory neural signals converge to fine-tune Caenorhabditis elegans feeding to food availability. AB - How an animal matches feeding to food availability is a key question for energy homeostasis. We addressed this in the nematode Caenorhabditis elegans, which couples feeding to the presence of its food (bacteria) by regulating pharyngeal activity (pumping). We scored pumping in the presence of food and over an extended time course of food deprivation in wild-type and mutant worms to determine the neural substrates of adaptive behavior. Removal of food initially suppressed pumping but after 2 h this was accompanied by intermittent periods of high activity. We show pumping is fine-tuned by context-specific neural mechanisms and highlight a key role for inhibitory glutamatergic and excitatory cholinergic/peptidergic drives in the absence of food. Additionally, the synaptic protein UNC-31 [calcium-activated protein for secretion (CAPS)] acts through an inhibitory pathway not explained by previously identified contributions of UNC 31/CAPS to neuropeptide or glutamate transmission. Pumping was unaffected by laser ablation of connectivity between the pharyngeal and central nervous system indicating signals are either humoral or intrinsic to the enteric system. This framework in which control is mediated through finely tuned excitatory and inhibitory drives resonates with mammalian hypothalamic control of feeding and suggests that fundamental regulation of this basic animal behavior may be conserved through evolution from nematode to human. PMID- 26514166 TI - Hepatocyte beta-Klotho regulates lipid homeostasis but not body weight in mice. AB - beta-Klotho (beta-Kl), a transmembrane protein expressed in the liver, pancreas, adipose tissues, and brain, is essential for feedback suppression of hepatic bile acid synthesis. Because bile acid is a key regulator of lipid and energy metabolism, we hypothesized potential and tissue-specific roles of beta-Kl in regulating plasma lipid levels and body weight. By crossing beta-kl(-/-) mice with newly developed hepatocyte-specific beta-kl transgenic (Tg) mice, we generated mice expressing beta-kl solely in hepatocytes (beta-kl(-/-)/Tg). Gene expression, metabolomic, and in vivo flux analyses consistently revealed that plasma level of cholesterol, which is over-excreted into feces as bile acids in beta-kl(-/-), is maintained in beta-kl(-/-) mice by enhanced de novo cholesterogenesis. No compensatory increase in lipogenesis was observed, despite markedly decreased plasma triglyceride. Along with enhanced bile acid synthesis, these lipid dysregulations in beta-kl(-/-) were completely reversed in beta-kl(-/ )/Tg mice. In contrast, reduced body weight and resistance to diet-induced obesity in beta-kl(-/-) mice were not reversed by hepatocyte-specific restoration of beta-Kl expression. We conclude that beta-Kl in hepatocytes is necessary and sufficient for lipid homeostasis, whereas nonhepatic beta-Kl regulates energy metabolism. We further demonstrate that in a condition with excessive cholesterol disposal, a robust compensatory mechanism maintains cholesterol levels but not triglyceride levels in mice. PMID- 26514167 TI - Intrauterine growth restriction in neonatal piglets affects small intestinal mucosal permeability and mRNA expression of redox-sensitive genes. AB - Neonates with intrauterine growth restriction (IUGR) show lower efficiency of nutrient utilization compared to normal birth weight (NBW) newborns. This study was conducted using neonatal piglets as a model to test the hypothesis that IUGR affects the intestinal barrier function, intestinal structure, and antioxidant system development during the suckling period. The small intestinal mucosae were obtained from IUGR and NBW littermates in the suckling period (d 0, 3, 8, and 19 postnatal). The epithelial barrier function was assessed by FITC-dextran 4 (FD4) and horseradish peroxidase (HRP) fluxes across the epithelium, histomorphologic measurements, and expression of tight-junction proteins. Redox status represented by the glutathione disulfide/glutathione ratio and malondialdehyde concentrations was determined, whereas mRNA expressions of some redox-sensitive proteins were quantified. Results showed that IUGR piglets exhibited a 2-fold higher intestinal permeability in the proximal small intestine on d 0 (P < 0.05), and this difference between IUGR and NBW piglets was widened to 3 and 4 times for FD4 and HRP, respectively (P < 0.05), on d 3. In accordance, expression of occludin was down-regulated at the transcriptional level in IUGR piglets at d 0 and 19 (P < 0.01). Furthermore, the transcription of heme oxygenase 1, catalase, and thioredoxin reductase genes was down-regulated in IUGR piglets, mainly on postnatal d 0 and 19 (P < 0.01). It appears that IUGR subjects have a lower capacity to mount an antioxidant response in the early postnatal period. Collectively, these results add to our understanding of the mechanisms responsible for intestinal dysfunction in IUGR neonates. PMID- 26514163 TI - A Computational Model of Major Depression: the Role of Glutamate Dysfunction on Cingulo-Frontal Network Dynamics. AB - Major depression disease (MDD) is associated with the dysfunction of multinode brain networks. However, converging evidence implicates the reciprocal interaction between midline limbic regions (typified by the ventral anterior cingulate cortex, vACC) and the dorso-lateral prefrontal cortex (dlPFC), reflecting interactions between emotions and cognition. Furthermore, growing evidence suggests a role for abnormal glutamate metabolism in the vACC, while serotonergic treatments (selective serotonin reuptake inhibitor, SSRI) effective for many patients implicate the serotonin system. Currently, no mechanistic framework describes how network dynamics, glutamate, and serotonin interact to explain MDD symptoms and treatments. Here, we built a biophysical computational model of 2 areas (vACC and dlPFC) that can switch between emotional and cognitive processing. MDD networks were simulated by slowing glutamate decay in vACC and demonstrated sustained vACC activation. This hyperactivity was not suppressed by concurrent dlPFC activation and interfered with expected dlPFC responses to cognitive signals, mimicking cognitive dysfunction seen in MDD. Simulation of clinical treatments (SSRI or deep brain stimulation) counteracted this aberrant vACC activity. Theta and beta/gamma oscillations correlated with network function, representing markers of switch-like operation in the network. The model shows how glutamate dysregulation can cause aberrant brain dynamics, respond to treatments, and be reflected in EEG rhythms as biomarkers of MDD. PMID- 26514168 TI - Mesolimbic dopamine and its neuromodulators in obesity and binge eating. AB - Obesity has reached epidemic prevalence, and much research has focused on homeostatic and nonhomeostatic mechanisms underlying overconsumption of food. Mesocorticolimbic circuitry, including dopamine neurons of the ventral tegmental area (VTA), is a key substrate for nonhomeostatic feeding. The goal of the present review is to compare changes in mesolimbic dopamine function in human obesity with diet-induced obesity in rodents. Additionally, we will review the literature to determine if dopamine signaling is altered with binge eating disorder in humans or binge eating modeled in rodents. Finally, we assess modulation of dopamine neurons by neuropeptides and peripheral peptidergic signals that occur with obesity or binge eating. We find that while decreased dopamine concentration is observed with obesity, there is inconsistency outside the human literature on the relationship between striatal D2 receptor expression and obesity. Finally, few studies have explored how orexigenic or anorexigenic peptides modulate dopamine neuronal activity or striatal dopamine in obese models. However, ghrelin modulation of dopamine neurons may be an important factor for driving binge feeding in rodents. PMID- 26514169 TI - Supersonically blown nylon-6 nanofibers entangled with graphene flakes for water purification. AB - Water purification membranes, capable of purifying a few to tens of milliliters of aqueous methylene blue solution in a minute, were produced by supersonically blowing graphene flakes with a nylon-6 polymeric solution. The solution-blown nylon-6 nanofibers became entangled with graphene flakes thereby locking the graphene flakes within the frame of the bendable two-dimensional film structure. This method, which yielded a 5 * 7 cm(2)-sized membrane in less than 10 seconds, is commercially viable owing to fast fabrication and scalability. We show that our water purification device allows a flow rate range of 0.3-4 L h(-1) with a membrane area of just 5 cm(2), under a pressure difference of 0.5-3.5 bar. If the membrane were scaled up to 0.5 m(2), it could provide 300-4000 L h(-1) flow rate, an ample supply for home use. PMID- 26514170 TI - Performance of the colorectal cancer screening marker Sept9 is influenced by age, diabetes and arthritis: a nested case-control study. AB - BACKGROUND: Annually, colorectal cancer (CRC) is diagnosed in >1.4 million subjects worldwide and incidence is increasing. Much effort has therefore been focused on screening, which has proven to reduce cancer-related mortality. The Sept9 DNA-methylation assay is among the most well studied blood-based screening markers. However, earlier reported performances may be misleading: the Sept9 test was recently examined in two screening based cohorts and yielded performances lower than expected. We hypothesize that comorbidities and/or demographic characteristics affect the results of the Sept9 test. METHODS: Using a retrospective nested case-control study design, we studied plasma from 150 cancer and 150 controls selected from a well-characterized cohort of 4698 subjects referred for diagnostic colonoscopy due to CRC-related symptoms. The cases and controls were matched on age and gender, and moreover cases were stratified on tumor-site and tumor-stage. The selected cohort included a wide range of comorbidities. Plasma Sept9 levels were assessed using a commercially available PCR based assay (Epi-proColon). RESULTS: Clinical sensitivity for CRC stages I-IV was 37 %, 91 %, 77 %, and 89 %, and the overall sensitivity 73 % (95 % CI, 64-80 %) and specificity 82 % (95 % CI, 75-88 %), respectively. Age >65 was associated with both increased false positive and false negative results (p < 0.05). Arthritis was associated with a higher false negative rate (p = 0.005) whereas Arteriosclerosis was associated with a higher false positive rate (p = 0.007). Diabetes was associated with Sept9 positivity with an OR of 5.2 (95 % CI 1.4 19.1). When the performance of Sept9 was adjusted for these parameters in a final multivariate regression model, the OR for a positive Sept9 test to be associated with CRC increased from 8.25 (95 % CI 4.83-14.09) to 29.46 (95 % CI 12.58-69.02). CONCLUSIONS: The results indicate that the performance of the Sept9 assay is negatively affected by several factors commonly associated with CRC screening populations: early-stage disease, age > 65 years, diabetes, arthritis, and arteriosclerosis. This should be taken into account if the Sept9 assay is used as a single marker for CRC screening, but may also have a wider impact, as it is likely that such factors may affect other blood based DNA markers as well. PMID- 26514171 TI - Can an 18F-ALF-NOTA-PRGD2 PET/CT Scan Predict Treatment Sensitivity to Concurrent Chemoradiotherapy in Patients with Newly Diagnosed Glioblastoma? AB - This study examined the value of a novel 1-step labeled integrin alpha(v)beta3 targeting (18)F-AlF-NOTA-PRGD2 (denoted as (18)F-RGD) scan in assessing sensitivity to concurrent chemoradiotherapy (CCRT) in patients with newly diagnosed glioblastoma multiforme (GBM). METHODS: Twenty-five patients with newly diagnosed GBM were enrolled in this study 3-5 wk after surgical resection. All participants were investigated with (18)F-RGD PET/CT on baseline (T1) and at the third week (T2) after the start of CCRT. Tumor volume, maximal and mean standardized uptake value of the tumor (SUVmax, SUVmean), and tumor-to-nontumor ratios of the tumor volume were obtained. The MRI treatment response was assessed at the 11th week (T3). The change in the lesion volume from T1 to T3 on MRI was used as an endpoint to evaluate the predictive ability of (18)F-RGD PET/CT. RESULTS: With (18)F-RGD PET/CT imaging, we successfully visualized the residual lesions of GBM. Twenty-five and 23 (18)F-RGD PET/CT scans at baseline and the third week, respectively, were available for analysis. We found that (18)F-RGD PET/CT parameters, both pretreatment SUVmax on baseline (P< 0.05) and intratreatment SUVmax at the third week (SUV(maxT2)) (P< 0.05) and tumor-to nontumor ratios at the third week (P< 0.05), were predictive of treatment sensitivity to CCRT. Additionally, the change of volume from T1 to T2 on MRI was also predictive (P< 0.05). According to receiver-operating-characteristic curve analysis, the most significant parameter was SUV(maxT2) (area under the curve, 0.846). The threshold of SUV(maxT2) was 1.35, and its sensitivity, specificity, and accuracy were 84.6%, 90.0% and 87.0%, respectively. CONCLUSION: (18)F-RGD PET/CT allows for the noninvasive visualization of GBM lesions and the prediction of sensitivity to CCRT as early as 3 wk after treatment initiation. PMID- 26514172 TI - Immuno-PET Imaging of CD30-Positive Lymphoma Using 89Zr-Desferrioxamine-Labeled CD30-Specific AC-10 Antibody. AB - The CD30-specific antibody-drug conjugate, brentuximab vedotin, is approved for the treatment of relapsed, refractory Hodgkin lymphomas and systemic anaplastic large T-cell lymphomas. Multiple ongoing clinical trials are investigating brentuximab vedotin efficacy in other CD30-positive hematologic malignancies. Because CD30 expression varies among different types of lymphoma and can also change during the course of treatment, companion diagnostic imaging of CD30 could be a valuable tool in optimizing patient-specific brentuximab vedotin treatment regimens. METHODS: The mouse antihuman CD30 antibody AC-10 was radiolabeled with the positron-emitting radionuclide (89)Zr. The stability and specificity of (89)Zr-desferrioxamine (DFO)-labeled CD30-specific AC-10 antibody ((89)Zr-DFO-AC 10) was evaluated in vitro. The pharmacokinetics of (89)Zr-DFO-AC-10 was studied in BALB/c nude mice bearing subcutaneous human Karpas 299 tumors (CD30-positive model) or A-431 tumors (CD30-negative model) using PET/CT imaging, biodistribution studies, and autoradiography. RESULTS: AC-10 was conjugated with a DFO B chelator and radiolabeled with (89)Zr to give formulated (89)Zr-DFO-AC-10 with a radiochemical yield of 80%, radiochemical purity greater than 99%, and specific activity of 111-148 MBq/mg. (89)Zr-DFO-AC-10 was stable in mouse and human sera and preserved the immunoreactivity toward CD30. Biodistribution data showed the highest tissue accumulation of (89)Zr-DFO-AC-10 in CD30-positive tumors, with 37.9% +/- 8.2% injected activity per gram of tissue at 72 h after injection, whereas uptake in CD30-negative tumors was 11.0% +/- 0.4%. The specificity of (89)Zr-DFO-AC-10 binding to CD30 in vivo was confirmed by blocking studies. Time-activity curves showed that between 24 and 144 h after injection, tumor-to-muscle ratios increased from 18.9 to 51.8 in the CD30-positive model and from 4.8 to 8.7 in the CD30-negative model. Tumor-to-blood ratios also increased, from 3.2 to 13.6 and from 1 to 2 in the CD30-positive and -negative models, respectively. CONCLUSION: Our results demonstrate that for measuring CD30 expression, (89)Zr-DFO-AC-10 is a sensitive PET agent with high tumor-to-normal tissue contrast. (89)Zr-DFO-AC-10 is a promising CD30-imaging radiotracer for clinical translation in patients with various lymphomas and other diseases. PMID- 26514173 TI - Evaluation of the Outcome of Lung Nodules Missed on 18F-FDG PET/MRI Compared with 18F-FDG PET/CT in Patients with Known Malignancies. AB - The lower detection rate of (18)F-FDG PET/MRI than (18)F-FDG PET/CT regarding small lung nodules should be considered in the staging of malignant tumors. The purpose of this study was to evaluate the outcome of these small lung nodules missed by (18)F-FDG PET/MRI. METHODS: Fifty-one oncologic patients (mean age +/- SD, 56.6 +/- 14.0 y; 29 women, 22 men; tumor stages, I [n = 7], II [n = 7], III [n = 9], IV [n = 28]) who underwent (18)F-FDG PET/CT and subsequent (18)F-FDG PET/MRI on the same day were retrospectively enrolled. Images were analyzed by 2 interpreters in random order and separate sessions with a minimum of 4 wk apart. A maximum of 10 lung nodules was identified for each patient on baseline imaging. The presence, size, and presence of focal tracer uptake was noted for each lung nodule detected on (18)F-FDG PET/CT and (18)F-FDG PET/MRI using a postcontrast T1 weighted 3-dimensional gradient echo volume-interpolated breath-hold examination sequence with fat suppression as morphologic dataset. Follow-up CT or (18)F-FDG PET/CT (mean time to follow-up, 11 mo; range, 3-35 mo) was used as a reference standard to define each missed nodule as benign or malignant based on changes in size and potential new tracer uptake. Nodule-to-nodule comparison between baseline and follow-up was performed using descriptive statistics. RESULTS: Out of 134 lung nodules found on (18)F-FDG PET/CT, (18)F-FDG PET/MRI detected 92 nodules. Accordingly, 42 lung nodules (average size +/- SD, 3.9 +/- 1.3 mm; range, 2-7 mm) were missed by (18)F-FDG PET/MRI. None of the missed lung nodules presented with focal tracer uptake on baseline imaging or follow-up (18)F-FDG PET/CT. Thirty-three out of 42 missed lung nodules (78.6%) in 26 patients were rated benign, whereas 9 nodules (21.4%) in 4 patients were rated malignant. As a result, 1 patient required upstaging from tumor stage I to IV. CONCLUSION: Although most small lung nodules missed on (18)F-FDG PET/MRI were found to be benign, there was a relevant number of undetected metastases. However, in patients with advanced tumor stages the clinical impact remains controversial as upstaging is usually more relevant in lower stages. PMID- 26514174 TI - Radioimmunotherapy: From Current Clinical Success to Future Industrial Breakthrough? PMID- 26514175 TI - Radiopeptides for Imaging and Therapy: A Radiant Future. AB - Radiopeptides are powerful tools for diagnostic imaging and radionuclide therapy of various diseases. Since the introduction of the first radiopeptide into the clinical setting to diagnose neuroendocrine tumors about 25 y ago, many advances have been made in the field. This short review highlights novel strategies to improve the application of radiopeptides for imaging and therapy. PMID- 26514176 TI - The PET Radioligand 18F-FIMX Images and Quantifies Metabotropic Glutamate Receptor 1 in Proportion to the Regional Density of Its Gene Transcript in Human Brain. AB - A recent study from our laboratory found that (18)F-FIMX is an excellent PET radioligand for quantifying metabotropic glutamate receptor 1 (mGluR1) in monkey brain. This study evaluated the ability of (18)F-FIMX to quantify mGluR1 in humans. A second goal was to use the relative density of mGluR1 gene transcripts in brain regions to estimate specific uptake and nondisplaceable uptake (VND) in each brain region. METHODS: After injection of 189 +/- 3 MBq of (18)F-FIMX, 12 healthy volunteers underwent a dynamic PET scan over 120 min. For 6 volunteers, images were acquired until 210 min. A metabolite-corrected arterial input function was measured from the radial artery. Four other subjects underwent whole body scanning to estimate radiation exposure. RESULTS: (18)F-FIMX uptake into the human brain was high (SUV = 4-6 in the cerebellum), peaked at about 10 min, and washed out rapidly. An unconstrained 2-tissue-compartment model fitted the data well, and distribution volume (VT) (mL?cm(-3)) values ranged from 1.5 in the caudate to 11 in the cerebellum. A 120-min scan provided stable VT values in all regions except the cerebellum, for which an acquisition time of at least 170 min was necessary. VT values in brain regions correlated well with mGluR1 transcript density, and the correlation suggested that VND of (18)F-FIMX was quite low (0.5 mL?cm(-3)). This measure of VND in humans was similar to that from a receptor blocking study in monkeys, after correcting for differences in plasma protein binding. Similar to other (18)F-labeled ligands, the effective dose was about 23 MUSv/MBq. CONCLUSION: (18)F-FIMX can quantify mGluR1 in the human brain with a 120- to 170-min scan. Correlation of brain uptake with the relative density of mGluR1 transcript allows specific receptor binding of a radioligand to be quantified without injecting pharmacologic doses of a blocking agent. PMID- 26514177 TI - Comparison of the Therapeutic Response to Treatment with a 177Lu-Labeled Somatostatin Receptor Agonist and Antagonist in Preclinical Models. AB - Peptide receptor scintigraphy and peptide receptor radionuclide therapy using radiolabeled somatostatin receptor (SSTR) agonists are successfully used in the clinic for imaging and treatment of neuroendocrine tumors. Contrary to the paradigm that internalization and the resulting accumulation of radiotracers in cells is necessary for efficient tumor targeting, recent studies have demonstrated the superiority of radiolabeled SSTR antagonists for imaging purposes, despite little to no internalization in cells. However, studies comparing the therapeutic antitumor effects of radiolabeled SSTR agonists versus antagonists are lacking. The aim of this study was to directly compare the therapeutic effect of (177)Lu-DOTA-octreotate, an SSTR agonist, and (177)Lu-DOTA JR11, an SSTR antagonist. METHODS: We analyzed radiotracer uptake (both membrane bound and internalized fractions) and the produced DNA double-strand breaks, by determining the number of p53 binding protein 1 foci, after incubating SSTR2 positive cells with (177)Lu-diethylene triamine pentaacetic acid, (177)Lu-DOTA octreotate, or (177)Lu-DOTA-JR11. Also, biodistribution studies were performed in tumor-xenografted mice to determine the optimal dose for therapy experiments. Afterward, in vivo therapy experiments comparing the effect of (177)Lu-DOTA octreotate and (177)Lu-DOTA-JR11 were performed in this same animal model. RESULTS: We found a 5-times-higher uptake of (177)Lu-DOTA-JR11 than of (177)Lu DOTA-octreotate. The major part (88% +/- 1%) of the antagonist uptake was membrane-bound, whereas 74% +/- 3% of the total receptor agonist uptake was internalized. Cells treated with (177)Lu-DOTA-JR11 showed 2 times more p53 binding protein 1 foci than cells treated with (177)Lu-DOTA-octreotate. Biodistribution studies with (177)Lu-DOTA-JR11 (0.5 MUg/30 MBq) resulted in the highest tumor radiation dose of 1.8 +/- 0.7 Gy/MBq, 4.4 times higher than the highest tumor radiation dose found for (177)Lu-DOTA-octreotate. In vivo therapy studies with (177)Lu-DOTA-octreotate and (177)Lu-DOTA-JR11 resulted in a tumor growth delay time of 18 +/- 5 and 26 +/- 7 d, respectively. Median survival rates were 43.5, 61, and 71 d for the control group, (177)Lu-DOTA-octreotate group, and the (177)Lu-DOTA-JR11-treated group, respectively. CONCLUSION: On the basis of these results, we concluded that the use of radiolabeled SSTR antagonists such as JR11 might enhance peptide receptor scintigraphy and peptide receptor radionuclide therapy of neuroendocrine tumors and provide successful imaging and therapeutic strategies for cancer types with relatively low SSTR expression. PMID- 26514178 TI - In Vivo Evaluation of 11C-DASB for Quantitative SERT Imaging in Rats and Mice. AB - Serotonin, or 5-hydroxytryptamine (5-HT), plays a key role in the central nervous system and is involved in many essential neurologic processes such as mood, social behavior, and sleep. The serotonin transporter ligand (11)C-3-amino-4(2 dimethylaminomethyl-phenylsufanyl)-benzonitrile ((11)C-DASB) has been used to determine nondisplaceable binding potential (BPND), which is defined as the quotient of the available receptor density (Bavail) and the apparent equilibrium dissociation rate constant (1/appKD) under in vivo conditions. Because of the increasing number of animal models of human diseases, there is a pressing need to evaluate the applicability of (11)C-DASB to rats and mice. Here, we assessed the feasibility of using (11)C-DASB for quantification of serotonin transporter (SERT) density and affinity in vivo in rats and mice. METHODS: Rats and mice underwent 4 PET scans with increasing doses of the unlabeled ligand to calculate Bavail and appKD using the multiple-ligand concentration transporter assay. An additional PET scan was performed to calculate test-retest reproducibility and reliability. BPND was calculated using the simplified reference tissue model, and the results for different reference regions were compared. RESULTS: Displaceable binding of (11)C-DASB was found in all brain regions of both rats and mice, with the highest binding being in the thalamus and the lowest in the cerebellum. In rats, displaceable binding was largely reduced in the cerebellar cortex, which in mice was spatially indistinguishable from cerebellar white matter. Use of the cerebellum with fully saturated binding sites as the reference region did not lead to reliable results. Test-retest reproducibility in the thalamus was more than 90% in both mice and rats. In rats, Bavail, appKD, and ED50 were 3.9 +/- 0.4 pmol/mL, 2.2 +/- 0.4 nM, and 12.0 +/- 2.6 nmol/kg, respectively, whereas analysis of the mouse measurements resulted in inaccurate fits due to the high injected tracer mass. CONCLUSION: Our data showed that in rats, (11)C-DASB can be used to quantify SERT density with good reproducibility. BPND agreed with the distribution of SERT in the rat brain. It remains difficult to estimate quantitative parameters accurately from mouse measurements because of the high injected tracer mass and underestimation of the binding parameters due to high displaceable binding in the reference region. PMID- 26514179 TI - A molecular off switch for transcriptional quiescence. PMID- 26514180 TI - Instructable Nanoparticles Using Dynamic Combinatorial Chemistry. AB - The application of nanoparticles to the multivalent recognition of biomacromolecules or programmed self-assembly requires control over the relative placement of chemical groups on their surface. We have developed a method to direct the functionalization of surfaces of aldehyde-equipped gold nanoparticles using a DNA template. An error-correction mechanism is built into the functionalization process thanks to the thermodynamic control enabled by the hydrazone exchange reaction. This reversible reaction can be conveniently switched off by removing the catalyst, preserving the functionalization. PMID- 26514181 TI - Reduced ratio of eicosapentaenoic acid and docosahexaenoic acid to arachidonic acid is associated with early onset of acute coronary syndrome. AB - BACKGROUND: The hospitalization rate for acute coronary syndrome (ACS) for people aged <=50 has remained stable over the past decade. Increased serum levels of n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with a decreased incidence of cardiovascular events and mortality in older patients; however, it is currently unknown whether reduced serum levels of n-3 PUFAs is also a risk factor for ACS in patients aged <=50 years. METHODS AND RESULTS: We retrospectively reviewed 102 (male/ female 73/29) Japanese ACS patients whose serum levels of EPA/arachidonic acid (AA) and DHA/AA were evaluated on admission. The EPA/AA ratio was the lowest in patients aged <=50 compared to patients aged 51-74 and >=75. Pearson correlation analysis showed that early ACS onset was associated with low EPA/AA and DHA/AA ratios, and multiple regression analysis determined that decreased ratios of EPA/AA and DHA/AA, and male sex, current smoker status, increased body mass index and triglyceride levels, independently correlated with early ACS onset. Conversely, low-density and high-density lipoproteins, glycated hemoglobin, and hypertension did not correlate with early ACS onset. Subgroup analyses of male patients revealed that decreased ratios of EPA/AA and DHA/AA independently correlated with early ACS onset. CONCLUSION: Decreased EPA/AA and DHA/AA ratios may be risk factors for early onset of ACS, suggesting that reduced EPA/AA and DHA/AA may represent targets for preventing ACS in Japanese young people. PMID- 26514182 TI - Antitumor activity of the multikinase inhibitor regorafenib in patient-derived xenograft models of gastric cancer. AB - BACKGROUND: Unresectable gastric cancer is associated with poor outcomes, with few treatment options available after failure of cytotoxic chemotherapy. Clinical trials of targeted therapies have generally shown no survival benefit in gastric cancer, with the exceptions of the antibodies ramucirumab (anti-VEGFR2) and trastuzumab (anti-HER2/neu). Given the efficacy of the multikinase inhibitor regorafenib in other gastrointestinal tumors, we investigated its potential in gastric cancer. METHODS: The antitumor activity of oral regorafenib was assessed in eight murine patient-derived gastric cancer xenograft models. Dose-response experiments assessed the efficacy and tolerability of oral regorafenib 5, 10, and 15 mg/kg/day in two models, with 10 mg/kg/day selected for further investigation in all eight models. Tumor weight and volume was monitored during treatment; tumor cell proliferation, angiogenesis, apoptosis, and intracellular signaling were assessed using immunohistochemistry and Western blotting of total tumor lysates at the end of treatment. RESULTS: Regorafenib showed dose-dependent inhibition of tumor growth and was well tolerated, with no significant decreases in bodyweight or evident toxicity. Regorafenib 10 mg/kg/day significantly inhibited tumor growth in all eight models (72 to 96 %; all p < 0.01), resulting in reduced tumor weight versus vehicle controls. Regorafenib reduced tumor angiogenesis 3- to 11-fold versus controls in all models (all p < 0.05), reduced tumor proliferation 2- to 5-fold in six of the eight models (all p < 0.05), and induced apoptosis in seven models. CONCLUSION: Regorafenib was effective in patient-derived models of gastric cancer of different histological subtypes, with inhibition of tumor growth, angiogenesis, and tumor-cell proliferation observed in almost all models. These findings are consistent with the observed activity of regorafenib in preclinical models of other gastrointestinal tumors, and support further clinical investigation in gastric cancer. PMID- 26514183 TI - Specific interactions of leucine with disaccharides by electrospray ionization mass spectrometry: application to rapid differentiation of disaccharide isomers in combination with statistical analysis. AB - The identification of carbohydrate isomers, including mono units, linkage positions and anomeric configurations, remains an arduous subject. In this study, the natural amino acid leucine (Leu) was found to specifically interact with cellobiose (Cello) to form a series of potassium adducts as [Cello + Leu + K](+), [Cello + 2Leu + K](+), and [2Cello + Leu + K](+) in the gas phase using mass spectrometry. By using CID-MS/MS, these complexes produced specific fragmentation patterns from the sugar backbone cleavage instead of non-covalent interactions. Moreover, their fragment distributions were dependent on the ratios of Cello-to Leu in the complexes and the fragmentation pathways of potassium-cationized disaccharides (Dis) were remarkably changed with leucine binding. It should be pointed out that the ternary complex [2Cello + AA + K](+) was unique for leucine among all the twenty natural amino acids. The [2Dis + Leu + K](+) complex produced the most informative fragments by tandem mass spectrometry, which was successfully applied for rapid and efficient discrimination of twelve glucose containing disaccharide isomers in combination with statistical analyses including PCA and OPLS-DA. The methodology developed here not only provides a novel analytical approach for the differentiation of disaccharide isomers, but also brings new sight towards the interactions of amino acids with disaccharides. PMID- 26514184 TI - Evaluation of fotonovela to increase human papillomavirus vaccine knowledge, attitudes, and intentions in a low-income Hispanic community. AB - BACKGROUND: It has nearly been a decade since the introduction of the vaccine against human papillomavirus (HPV), yet vaccination rates in the United States have remained suboptimal, particularly among Hispanics. Culturally and linguistically relevant health education tools targeting Hispanics are needed to increase the current rate of HPV vaccination. This article evaluates a theory informed, evidence-guided fotonovela (photographic short story) intervention to improve HPV vaccination knowledge, attitudes, and intention among young adults. METHODS: Young adults (N = 41, aged 18-26 years) in a low-income primary care clinic in Southern California were administered pre- and post-intervention surveys to measure changes in perceived susceptibility to HPV, perceived benefit of vaccination in committed relationship, intention to vaccinate, intention to encourage social networks to vaccinate, and attitude towards vaccination. Post intervention survey also examined attitudes towards fotonovela. Relationships between attitudes towards fotonovela and demographic characteristics were assessed with Fisher's exact test. Self-reported gains in knowledge were categorized and tabulated. Changes in perceptions and intentions were analyzed with the marginal homogeneity test. RESULTS: The majority of participants were female (78.0%), Latino/Hispanic (92.7%), single (70.7%), and had at least a college education (61.0%). The mean age was 21.9 years (SD 0.4). The fotonovela was viewed as entertaining (95.1%), educational (97.6%), and easy to read (100 %). Following the intervention, Hispanic participants improved in all five variables of interest measured in the survey, including perceived susceptibility (+10.5%, p = 0.03), benefit of vaccination (+7.8%, p = 0.25), intent to vaccinate (+18.4%, p = 0.06), intent to encourage others to vaccinate (+10.5%, p = 0.14) and attitude towards vaccination (+13.1%, p = 0.05). Improvements in perceived susceptibility and attitude towards vaccination reached statistical significance (p < 0.05). The most frequent gains in knowledge were the risk of HPV infection despite condom use (N = 16) and relationship status (N = 8), three-dose vaccine administration schedule (N = 13), and burden of HPV infection among males (N = 9). CONCLUSION: Results are promising because they demonstrate that health messages delivered through a narrative format can promote positive changes in knowledge, attitudes, and intentions. The fotonovela may be a powerful vehicle for HPV education, particularly among Hispanics. PMID- 26514185 TI - Association of Dietary Protein Consumption With Incident Silent Cerebral Infarcts and Stroke: The Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND AND PURPOSE: The effect of dietary protein on the risk of stroke has shown inconsistent results. We aimed to evaluate the relationship of dietary protein sources with the risk of stroke and silent cerebral infarcts in a large community-based cohort. METHODS: We studied 11601 adults (age, 45-64 years at baseline in 1987-1989) enrolled in the Atherosclerosis Risk in Communities (ARIC) Study, free of diabetes mellitus and cardiovascular disease. Dietary protein intake was assessed with validated food frequency questionnaires at baseline and after 6 years of follow-up. Incident stroke events were identified through hospital discharge codes and stroke deaths and physician-adjudicated through December 31, 2011. A subset of participants (n=653) underwent brain magnetic resonance imaging in 1993 to 1995 and in 2004 to 2006. Cox proportional hazard models and logistic regression were used for statistical analyses. RESULTS: During a median follow-up of 22.7 years, there were 699 stroke events. In multivariable analyses, total, animal, and vegetable protein consumption was not associated with risk of stroke. Red meat consumption was associated with increased stroke risk, particularly ischemic events. The hazard ratios (95% confidence interval) for risk of ischemic stroke across ascending quintiles of red meat consumption were 1 (ref), 1.13 (0.85-1.49), 1.44 (1.09-1.90), 1.33 (0.99 1.79), and 1.47 (1.06-2.05); Ptrend=0.01. No association of major dietary protein sources with silent cerebral infarcts was detected. CONCLUSIONS: This study supports the notion that consumption of red meat may increase the risk of ischemic stroke. No association between dietary protein intake and silent cerebral infarcts was found. PMID- 26514186 TI - Time-Dependent Computed Tomographic Perfusion Thresholds for Patients With Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Among patients with acute ischemic stroke, we determine computed tomographic perfusion (CTP) thresholds associated with follow-up infarction at different stroke onset-to-CTP and CTP-to-reperfusion times. METHODS: Acute ischemic stroke patients with occlusion on computed tomographic angiography were acutely imaged with CTP. Noncontrast computed tomography and magnectic resonance diffusion-weighted imaging between 24 and 48 hours were used to delineate follow-up infarction. Reperfusion was assessed on conventional angiogram or 4-hour repeat computed tomographic angiography. Tmax, cerebral blood flow, and cerebral blood volume derived from delay-insensitive CTP postprocessing were analyzed using receiver-operator characteristic curves to derive optimal thresholds for combined patient data (pooled analysis) and individual patients (patient-level analysis) based on time from stroke onset-to-CTP and CTP-to reperfusion. One-way ANOVA and locally weighted scatterplot smoothing regression was used to test whether the derived optimal CTP thresholds were different by time. RESULTS: One hundred and thirty-two patients were included. Tmax thresholds of >16.2 and >15.8 s and absolute cerebral blood flow thresholds of <8.9 and <7.4 mL.min(-1).100 g(-1) were associated with infarct if reperfused <90 min from CTP with onset <180 min. The discriminative ability of cerebral blood volume was modest. No statistically significant relationship was noted between stroke onset to-CTP time and the optimal CTP thresholds for all parameters based on discrete or continuous time analysis (P>0.05). A statistically significant relationship existed between CTP-to-reperfusion time and the optimal thresholds for cerebral blood flow (P<0.001; r=0.59 and 0.77 for gray and white matter, respectively) and Tmax (P<0.001; r=-0.68 and -0.60 for gray and white matter, respectively) parameters. CONCLUSIONS: Optimal CTP thresholds associated with follow-up infarction depend on time from imaging to reperfusion. PMID- 26514187 TI - Prediction of Early Reperfusion From Repeated Arterial Spin Labeling Perfusion Magnetic Resonance Imaging During Intravenous Thrombolysis. AB - BACKGROUND AND PURPOSE: There are few in vivo data on the pathophysiology of reperfusion during systemic thrombolysis. We monitored the time course of cerebral perfusion changes in patients during thrombolysis with repeated arterial spin labeling perfusion magnetic resonance imaging. METHODS: Ten patients with proximal arterial occlusion within 4.5 hours after symptom onset were prospectively enrolled. All patients received intravenous thrombolysis during the magnetic resonance imaging examination. Repeated arterial spin labeling perfusion images were acquired during the 60-minute therapy and at follow-up after 24 to 72 hours. Clinical data, magnetic resonance imaging features, and cerebral perfusion changes were analyzed. RESULTS: Before thrombolysis, arterial spin labeling hypoperfusion and fluid-attenuation inversion recovery vascular hyperintensity in the territory of the occluded arteries were observed in all patients. In 5 patients, extensive arterial transit artifacts (ATA) developed in the hypoperfused area. The ATA corresponded with fluid-attenuation inversion recovery vascular hyperintensities. All 5 patients who developed extensive ATA in the hypoperfused area had complete reperfusion after thrombolysis, whereas the 5 without extensive ATA showed no or only partial reperfusion (P<0.01). The development of ATA preceded the normalization of tissue perfusion. CONCLUSIONS: The development of ATA during thrombolysis is associated with early reperfusion after thrombolysis. arterial spin labeling assessment during intravenous thrombolysis has the potential to guide subsequent therapeutic strategies in patients with acute stroke. PMID- 26514188 TI - Incidence of Stroke or Systemic Embolism in Paroxysmal Versus Sustained Atrial Fibrillation: The Fushimi Atrial Fibrillation Registry. AB - BACKGROUND AND PURPOSE: There is controversy on the relationship of the type of atrial fibrillation (AF) to stroke. Although several studies show that patients with paroxysmal AF (PAF) have a stroke risk similar to those with persistent or permanent AF, recent studies suggest that PAF is associated with a lower rate of stroke. Limited data on stroke risk associated with PAF are evident in Asian populations. METHODS: The Registry Study of Atrial Fibrillation Patients in Fushimi-ku (Fushimi AF Registry) is a community-based survey of patients with AF in Fushimi-ku, Kyoto, Japan. Patients were categorized into 2 types of AF: PAF or sustained (persistent or permanent) AF. We compared clinical events between PAF (n=1588) and sustained AF (n=1716). RESULTS: Patients with PAF were younger, had less comorbidities, and received oral anticoagulants (OAC) less commonly. A lower risk of stroke/systemic embolism during follow-up period in the patients with PAF was consistently observed (non-OAC users: hazard ratio, 0.45; 95% confidence intervals, 0.27-0.75; P<0.01 and OAC users: hazard ratio, 0.59; 95% confidence interval, 0.35-0.93; P=0.03). The composite end point of stroke/systemic embolism/all-cause mortality was also lower in PAF, whether among OAC users (hazard ratio, 0.77; 95% confidence interval, 0.59-0.99; P=0.046) or non-OAC users (hazard ratio, 0.59; 95% confidence interval, 0.46-0.75; P<0.01). On multivariate analysis, PAF was an independent predictor of lower stroke/systemic embolism risk. CONCLUSIONS: In this large cohort of Japanese patients with AF, PAF was independently associated with lower incidence of stroke/systemic embolism than sustained AF. This may aid decision making for anticoagulation, especially in those patients with AF with few stroke risk factors. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000005834. PMID- 26514189 TI - Nontraditional Risk Factors for Ischemic Stroke: An Update. PMID- 26514190 TI - Coronary and Basilar Artery Ectasia Are Associated: Results From an Autopsy Case Control Study. AB - BACKGROUND AND PURPOSE: Intracranial artery dolichoectasia (IADE) and coronary artery ectasia have been associated with stroke and myocardial infarction, respectively. Only rarely have cases of coexisting IADE and coronary artery ectasia been reported. We investigated this association in a large consecutive autopsy series. METHODS: Sixteen stroke patients with IADE were identified among 381 stroke patients and were matched with 16 stroke patients without IADE. The heart and coronary arteries from all patients were examined after a prespecified protocol. RESULTS: Coronary artery ectasia was observed in 8 of the stroke patients with IADE, and in none of the stroke patients without IADE (P=0.008). The diameters of basilar and right coronary arteries were positively correlated (IADE patients, r=0.51; P=0.003 and coronary artery ectasia patients, P=0.006). CONCLUSIONS: This autopsy study examining the association of coronary artery ectasia and IADE in stroke patients suggests a common pathogenesis. PMID- 26514191 TI - Use of Antiplatelet Agents Is Associated With Intraplaque Hemorrhage on Carotid Magnetic Resonance Imaging: The Plaque at Risk Study. AB - BACKGROUND AND PURPOSE: Intraplaque hemorrhage (IPH), visualized by magnetic resonance imaging, has shown to be associated with the risk of stroke in patients with carotid artery stenosis. The mechanisms of IPH development are poorly understood. In this study, we investigated the association between clinical patient characteristics and carotid IPH on high-resolution magnetic resonance imaging. METHODS: Patients participate in the Plaque at Risk (PARISK) study. This prospective, multicenter cohort study included patients with recent amaurosis fugax, hemispheric transient ischemic attack, or nondisabling stroke in the internal carotid artery territory and an ipsilateral carotid stenosis of <70%, who were not scheduled for carotid revascularization procedure. One hundred patients, recruited between 2010 and 2012, underwent a 3-T high-resolution carotid magnetic resonance imaging. We documented clinical patient characteristics and performed multivariable logistic regression analysis to investigate their association with IPH. RESULTS: IPH was observed in 45 patients (45%) in 1 or both carotid arteries. Male sex and the use of antiplatelet agents before the index event were associated with IPH in univariable analysis. In a multivariable analysis, only previous use of antiplatelet agents was significantly associated with IPH (odds ratio, 2.71; 95% confidence interval, 1.12-6.61). Risk factors of atherosclerotic arterial disease, including a history of symptomatic arterial diseases, were not associated with IPH. CONCLUSIONS: In this cohort of 100 patients with recently symptomatic carotid stenosis, the previous use of antiplatelet agents is associated with carotid IPH on magnetic resonance imaging. Antiplatelet therapy may increase the risk of IPH, but our findings need to be confirmed in larger patient cohorts. The implications for risk stratification remain to be determined. PMID- 26514192 TI - Coagulation and Fibrinolytic Activity of Tenecteplase and Alteplase in Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: We compared the fibrinolytic activity of tenecteplase and alteplase in patients with acute ischemic stroke, and explored the association between hypofibrinogenaemia and intracerebral hemorrhage. METHODS: Venous blood samples from a subgroup of participants in the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST) study were obtained at pretreatment, 3 to 12 hours, and 24+/-3 hours post-intravenous thrombolysis for analyses of plasminogen, plasminogen activator inhibitor-1, d-dimer, factor V, fibrinogen, and fibrin(ogen) degradation products, in addition to routine coagulation assays. Related sample Wilcoxon signed-rank tests were used to test the within-group changes, and independent Mann-Whitney tests for between-group differences. RESULTS: Thirty patients were included (alteplase=14 and tenecteplase=16) with similar baseline demographics. Compared with baseline, alteplase caused significant hypofibrinogenaemia (P=0.002), prolonged prothrombin time (P=0.011), hypoplasminogenaemia (P=0.001), and lower factor V (P=0.002) at 3 to 12 hours after administration with persistent hypofibrinogenaemia at 24 hours (P=0.011), whereas only minor hypoplasminogenaemia (P=0.029) was seen in the tenecteplase group. Tenecteplase consumed less plasminogen (P<0.001) and fibrinogen (P=0.002) compared with alteplase. CONCLUSIONS: In patients with acute ischemic stroke, alteplase 0.9 mg/kg caused significant disruption of the fibrinolytic system, whereas tenecteplase 0.25 mg/kg did not, consistent with the trend toward lower intracerebral hemorrhage incidence with tenecteplase in the ATTEST study. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01472926. PMID- 26514193 TI - Predominance of Nonatherosclerotic Internal Elastic Lamina Calcification in the Intracranial Internal Carotid Artery. AB - BACKGROUND AND PURPOSE: Calcification of the intracranial internal carotid artery (iICA) is an independent risk factor for stroke. These calcifications are generally seen as manifestation of atherosclerosis, but histological investigations are limited. The aim of this study is to determine whether calcifications in the iICA are present in atherosclerotic plaques, or in other parts of the arterial wall. METHODS: Thirty-nine iICAs were histologically assessed, using digital microscopy to quantify the amount of calcification in the different layers of the arterial wall. RESULTS: Calcifications were found in the intima, around the internal elastic lamina and in the medial layer of the arterial wall. In 71% of the arteries, internal elastic lamina calcification contributed most to the total calcified cross-sectional surface area. Internal elastic lamina calcification was unrelated to the occurrence of atherosclerotic intimal lesions. Intimal calcifications were most often associated with atherosclerotic lesions, but also many noncalcified atherosclerotic lesions were found. CONCLUSIONS: In the iICA, calcifications are predominantly present around the internal elastic lamina, suggesting that this nonatherosclerotic type of calcification contributes to the previously observed increased risk of stroke in patients with iICA calcifications. PMID- 26514194 TI - Precision medicine for acute myeloid leukemia. AB - The goal of precision medicine is to personalize therapy based on individual patient variation, to correctly select the right treatment, for the right patient, at the right time. Acute myeloid leukemia (AML) is a heterogeneous collection of myeloid malignancies with diverse genetic etiology and the potential for intra-patient clonal evolution over time. We discuss here how the precision medicine paradigm might be applied to the care of AML patients by focusing on the potential roles of targeting therapy by patient-specific somatic mutations and aberrant pathways, ex-vivo drug sensitivity and resistance testing, high sensitivity measurements of residual disease burden and biology along with potential clinical trial and regulatory constraints. PMID- 26514195 TI - Nonclinical Tools to Assess Risk of Drug Hypersensitivity Reactions. AB - The term drug hypersensitivity refers to a category of adverse drug reactions mediated by various immunological and nonimmunological mechanisms. Small-molecule drugs and biotherapeutics have been associated with drug hypersensitivity reactions (DHRs), and the mechanisms driving the responses vary. Depending on the mechanism, some DHRs may be detected in nonclinical toxicology studies, and there may be tools and models in place that can be used as part of a risk assessment strategy. In contrast, for other mechanisms, particularly those that are not readily detected during nonclinical development, predictive tools and strategies for risk assessment are not well defined. This chapter provides an overview of the nonclinical tools currently available to assess the risk for developing DHRs. PMID- 26514196 TI - Toward a Better Understanding of the Complexity of Cancer Drug Resistance. AB - Resistance to anticancer drugs is a complex process that results from alterations in drug targets; development of alternative pathways for growth activation; changes in cellular pharmacology, including increased drug efflux; regulatory changes that alter differentiation pathways or pathways for response to environmental adversity; and/or changes in the local physiology of the cancer, such as blood supply, tissue hydrodynamics, behavior of neighboring cells, and immune system response. All of these specific mechanisms are facilitated by the intrinsic hallmarks of cancer, such as tumor cell heterogeneity, redundancy of growth-promoting pathways, increased mutation rate and/or epigenetic alterations, and the dynamic variation of tumor behavior in time and space. Understanding the relative contribution of each of these factors is further complicated by the lack of adequate in vitro models that mimic clinical cancers. Several strategies to use current knowledge of drug resistance to improve treatment of cancer are suggested. PMID- 26514197 TI - New Strategies in Cancer Nanomedicine. AB - We review recent progress in cancer nanomedicine, including stimulus-responsive drug delivery systems and nanoparticles responding to light for phototherapy or tumor imaging. In addition, several new strategies to improve the circulation of nanoparticles in vivo, tumor penetration, and tumor targeting are discussed. The application of nanomedicine in cancer immunology, a relatively new type of cancer therapy, is also highlighted. PMID- 26514198 TI - My Winding Road: From Microbiology to Toxicology and Environmental Health. PMID- 26514200 TI - Genome Integrity in Aging: Human Syndromes, Mouse Models, and Therapeutic Options. AB - Human syndromes and mouse mutants that exhibit accelerated but bona fide aging in multiple organs and tissues have been invaluable for the identification of nine denominators of aging: telomere attrition, genome instability, epigenetic alterations, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular communication, loss of proteostasis, cellular senescence and adult stem cell exhaustion. However, whether and how these instigators of aging interrelate or whether they have one root cause is currently largely unknown. Rare human progeroid syndromes and corresponding mouse mutants with resolved genetic defects highlight the dominant importance of genome maintenance for aging. A second class of aging-related disorders reveals a cross connection with metabolism. As genome maintenance and metabolism are closely interconnected, they may constitute the main underlying biology of aging. This review focuses on the role of genome stability in aging, its crosstalk with metabolism, and options for nutritional and/or pharmaceutical interventions that delay age-related pathology. PMID- 26514199 TI - Clinical Trials in a Dish: The Potential of Pluripotent Stem Cells to Develop Therapies for Neurodegenerative Diseases. AB - Neurodegenerative diseases are a leading cause of death. No disease-modifying therapies are available, and preclinical animal model data have routinely failed to translate into success for therapeutics. Induced pluripotent stem cell (iPSC) biology holds great promise for human in vitro disease modeling because these cells can give rise to any cell in the human brain and display phenotypes specific to neurodegenerative diseases previously identified in postmortem and clinical samples. Here, we explore the potential and caveats of iPSC technology as a platform for drug development and screening, and the future potential to use large cohorts of disease-bearing iPSCs to perform clinical trials in a dish. PMID- 26514201 TI - Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells. AB - RNA has become an increasingly important target for therapeutic interventions and for chemical probes that dissect and manipulate its cellular function. Emerging targets include human RNAs that have been shown to directly cause cancer, metabolic disorders, and genetic disease. In this review, we describe various routes to obtain bioactive compounds that target RNA, with a particular emphasis on the development of small molecules. We use these cases to describe approaches that are being developed for target validation, which include target-directed cleavage, classic pull-down experiments, and covalent cross-linking. Thus, tools are available to design small molecules to target RNA and to identify the cellular RNAs that are their targets. PMID- 26514202 TI - Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles. AB - It is now recognized that G protein-coupled receptors (GPCRs), once considered largely independent functional units, have a far more diverse molecular architecture. Receptor activity-modifying proteins (RAMPs) provide an important example of proteins that interact with GPCRs to modify their function. RAMPs are able to act as pharmacological switches and chaperones, and they can regulate signaling and/or trafficking in a receptor-dependent manner. This review covers recent discoveries in the RAMP field and summarizes the known GPCR partners and functions of RAMPs. We also discuss the first peptide-bound structures of RAMP GPCR complexes, which give insight into the molecular mechanisms that enable RAMPs to alter the pharmacology and signaling of GPCRs. PMID- 26514205 TI - Structure, Function, and Drug Interactions of Neurotransmitter Transporters in the Postgenomic Era. AB - Vesicular neurotransmitter transporters are responsible for the accumulation of neurotransmitters in secretory vesicles and play essential roles in chemical transmission. The SLC17 family contributes to sequestration of anionic neurotransmitters such as glutamate, aspartate, and nucleotides. Identification and subsequent cellular and molecular biological studies of SLC17 transporters unveiled the principles underlying the actions of these transporters. Recent progress in reconstitution methods in combination with postgenomic approaches has advanced studies on neurotransmitter transporters. This review summarizes the molecular properties of SLC17-type transporters and recent findings regarding the novel SLC18 transporter. PMID- 26514203 TI - G Protein-Coupled Receptor Heteromers. AB - G protein-coupled receptors (GPCRs) compose one of the largest families of membrane proteins involved in intracellular signaling. They are involved in numerous physiological and pathological processes and are prime candidates for drug development. Over the past decade, an increasing number of studies have reported heteromerization between GPCRs. Many investigations in heterologous systems have provided important indications of potential novel pharmacology; however, the physiological relevance of these findings has yet to be established with endogenous receptors in native tissues. In this review, we focus on family A GPCRs and describe the techniques and criteria to assess their heteromerization. We conclude that advances in approaches to study receptor complex functionality in heterologous systems, coupled with techniques that enable specific examination of native receptor heteromers in vivo, are likely to establish GPCR heteromers as novel therapeutic targets. PMID- 26514206 TI - Biobanking Comes of Age: The Transition to Biospecimen Science. AB - Biobanking involves the collection, processing, storage, and distribution of biological specimens and the policies and procedures necessary to accomplish those aims successfully. Although biobanking may also involve collections for environmental studies or museum archives, most efforts to standardize biobanking practices have been directed toward human biomedical research. Initially focused primarily on collecting samples for diagnostic purposes in pathology settings, biobanks have evolved into complex organizations engaged in advancing personalized (or precision) medicine and translational research. This evolution has involved the development of biobanking best practices and the transformation of a field driven by empirical approaches into the emerging area of biospecimen science. It has become increasingly important to develop evidence-based practices for collecting biospecimens and data that can be shared with confidence with international collaborators. Aside from these technical approaches, other factors play crucial roles, such as ethical and regulatory issues, business planning and sustainability, and approaches to data collection and sharing. PMID- 26514207 TI - Existing and Future Drugs for the Treatment of the Dark Side of Addiction. AB - The identification of a heuristic framework for the stages of the addiction cycle that are linked to neurocircuitry changes in pathophysiology includes the binge/intoxication stage, the withdrawal/negative affect stage, and the preoccupation/anticipation (craving) stage, which represent neuroadaptations in three neurocircuits (basal ganglia, extended amygdala, and frontal cortex, respectively). The identification of excellent and validated animal models, the development of human laboratory models, and an enormous surge in our understanding of neurocircuitry and neuropharmacological mechanisms have provided a revisionist view of addiction that emphasizes the loss of brain reward function and gain of stress function that drive negative reinforcement (the dark side of addiction) as a key to compulsive drug seeking. Reversing the dark side of addiction not only explains much of the existing successful pharmacotherapies for addiction but also points to vast new opportunities for future medications to alleviate this major source of human suffering. PMID- 26514204 TI - MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. AB - Melatonin, or 5-methoxy-N-acetyltryptamine, is synthesized and released by the pineal gland and locally in the retina following a circadian rhythm, with low levels during the day and elevated levels at night. Melatonin activates two high affinity G protein-coupled receptors, termed MT1 and MT2, to exert beneficial actions in sleep and circadian abnormality, mood disorders, learning and memory, neuroprotection, drug abuse, and cancer. Progress in understanding the role of melatonin receptors in the modulation of sleep and circadian rhythms has led to the discovery of a novel class of melatonin agonists for treating insomnia, circadian rhythms, mood disorders, and cancer. This review describes the pharmacological properties of a slow-release melatonin preparation (i.e., Circadin(r)) and synthetic ligands (i.e., agomelatine, ramelteon, tasimelteon), with emphasis on identifying specific therapeutic effects mediated through MT1 and MT2 receptor activation. Discovery of selective ligands targeting the MT1 or the MT2 melatonin receptors may promote the development of novel and more efficacious therapeutic agents. PMID- 26514208 TI - Can Humanized Mice Predict Drug "Behavior" in Humans? AB - Most of what we know about a drug prior to human clinical studies is derived from animal testing. Because animals and humans have substantial differences in their physiology and in their drug metabolism pathways, we do not know very much about the pharmacokinetic and pharmacodynamic behavior of a drug in humans until after it is administered to many people. Hence, drug-induced liver injury has become a significant public health problem, and we have a very inefficient drug development process with a high failure rate. Because the human liver is at the heart of these problems, chimeric mice with humanized livers could be used to address these issues. We examine recent evidence indicating that drug testing in chimeric mice could provide better information about a drug's metabolism, disposition, and toxicity (i.e., its "behavior") in humans and could aid in developing personalized medicine strategies, which would improve drug efficacy and safety. PMID- 26514210 TI - Effective rate constant for nanostructured heterogeneous catalysts. AB - There is a great deal of interest in the use of nanostructured heterogeneous catalysts, particularly those based on expensive precious metals, in order to maximise the surface to volume ratio of the catalyst, potentially reducing the cost without sacrificing performance. When there is an abundance of reactants available, the effective reactivity will depend on the surface density of the catalytically active sites. However, under diffusion-limited conditions, catalytically active sites may compete for reactants, potentially leading to diminishing returns from the use of nanostructures. In this paper we apply a mathematical homogenization approach to investigate the effect of scale and patterning on the effective activity of catalytic sites on a heterogeneous catalyst operating under diffusion-limited conditions. We test these theoretical results numerically using Monte Carlo simulations, and show that in the continuum limit the theory works well. In particular, in the limit where the mean free path is much less than the scale of patterning of catalytically active sites, the effective rate constant is found to be equal to the area-weighted harmonic mean of the rate constants on the surface. However, as the length scale of the patterns becomes comparable to the mean free path length, the simulations show that the effective activity of the system can exceed the theoretical limit suggested by the continuum theory. PMID- 26514209 TI - microRNA-145 promotes differentiation in human urothelial carcinoma through down regulation of syndecan-1. AB - BACKGROUND: A new molecular marker of carcinoma in the urinary bladder is needed as a diagnostic tool or as a therapeutic target. Potential markers include microRNAs (miRNAs), which are short, low molecular weight RNAs 19-24 nt long that regulate genes associated with cell proliferation, differentiation, and development in various cancers. In this study, we investigated the molecular mechanisms by which miR-145 promotes survival of urothelial carcinoma cells and differentiation into multiple lineages. We found miR-145 to regulate expression of syndecan-1, a heparin sulfate proteoglycan. METHODS: Cell proliferation in the human urothelial carcinoma cell lines T24 and KU7 was assessed by MTS assay. Cellular senescence and apoptosis were measured by senescence-associated beta galactosidase (SA-beta-gal) and TUNEL assay, respectively. Quantitative RT-PCR was used to measure mRNA expression of various genes, including syndecan-1, stem cell factors, and markers of differentiation into squamous, glandular, or neuroendocrine cells. RESULTS: Overexpression of miR-145 induced cell senescence, and thus significantly inhibited cell proliferation in T24 and KU7 cells. Syndecan-1 expression diminished, whereas stem cell markers such as SOX2, NANOG, OCT4, and E2F3 increased. miR-145 also up-regulated markers of differentiation into squamous (p63, TP63, and CK5), glandular (MUC-1, MUC-2, and MUC-5 AC), and neuroendocrine cells (NSE and UCHL-1). Finally, expression of miR-145 was down regulated in high-grade urothelial carcinomas, but not in low-grade tumors. CONCLUSIONS: Results indicate that miR-145 suppresses syndecan-1 and, by this mechanism, up-regulates stem cell factors and induces cell senescence and differentiation. We propose that miR-145 may confer stem cell-like properties on urothelial carcinoma cells and thus facilitate differentiation into multiple cell types. PMID- 26514211 TI - Individual differences in subjective circadian flexibility. AB - The aim of this study was to evaluate individual differences in the subjective flexibility of the circadian system in a community sample, with respect to age, gender, chronotype, and sleepiness perceptions. An online questionnaire containing the Circadian Type Inventory, the Composite Scale of Morningness, the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale was administered. In addition, participants performed a visuo-verbal judgment task to determine time-of-day variations in estimated sleepiness. We analyzed data of 752 participants, aged between 18 and 83 years, who reported good sleep quality, no sleep disturbances, no excessive daytime sleepiness, and no engagement in shiftwork. Our results suggest gender- and chronotype-related differences in the subjective flexibility of the circadian system. Subjective circadian flexibility was higher in men in comparison with women and was positively related to evening preference. Age was not associated with flexibility scores. Additionally, the subjective flexibility of the circadian system had an influence on estimated sleepiness profiles: individuals with a high flexibility displayed lower sleepiness estimations during the biological night in comparison to individuals with a low flexibility. These findings suggests that, next to known chronotype and other dispositional differences, subjective circadian flexibility should be taken into account when evaluating tolerance to activities associated with nighttime functioning (e.g. night shifts). PMID- 26514212 TI - Projected ozone trends and changes in the ozone-precursor relationship in the South Coast Air Basin in response to varying reductions of precursor emissions. AB - This study examined the effects of varying future reductions in emissions of oxides of nitrogen (NOx) and volatile organic compounds (VOC) on the location and magnitude of peak ozone levels within California's South Coast Air Basin (SoCAB or Basin). As ozone formation is currently VOC-limited in the Basin, model simulations with 2030 baseline emissions (-61% for NOx and -32% for VOC from 2008) predict 10-20% higher peak ozone levels (i.e., NOx disbenefit) in the western and central SoCAB compared with the 2008 base simulation. With additional NOx reductions of 50% beyond the 2030 baseline emissions (-81% from 2008), the predicted ozone levels are reduced by about 15% in the eastern SoCAB but remain comparable to 2008 levels in the western and central Basin. The Basin maximum ozone site shifts westward to more populated areas of the Basin and will result potentially in greater population-weighted exposure to ozone with even a relatively small shortfall in the required NOx reductions unless accompanied by additional VOC reductions beyond 2030 baseline levels. Once committed to a NOx focused control strategy, NOx reductions exceeding 90% from 2008 levels will be necessary to attain the ozone National Ambient Air Quality Standards (NAAQS). The findings from this study and other recent work that the current VOC emission estimates are underestimated by about 50% suggest that greater future VOC reductions will be necessary to reach the projected 2030 baseline emissions. Increasing the base year VOC emissions by a factor of 1.5 result in higher 2008 baseline ozone predictions, lower relative response factors, and about 20% lower projected design values. If correct, these findings have important implications for the total and optimum mix of VOC and NOx emission reductions that will be required to attain the ozone NAAQS in the SoCAB. IMPLICATIONS: Results of this study indicate that ozone levels in the western and central SoCAB would remain the same or increase with even a relatively small shortfall in the projected NOx reductions under planned NOx-focused controls. This possibility, therefore, warrants a rigorous analysis of the costs and effects of varying reductions of VOC and NOx on the formation and combined health impacts of ozone and secondary particles. Given the nonlinearity of ozone formation, such analyses should include the implications of gradually increasing global background ozone concentrations and the Basin's topography and meteorology on the practical limits of alternative emission control strategies. PMID- 26514214 TI - Do not treat the radiograph, treat the patient! PMID- 26514213 TI - Resistant starch and protein intake enhances fat oxidation and feelings of fullness in lean and overweight/obese women. AB - BACKGROUND: Diets high in either resistant starch or protein have been shown to aid in weight management. We examined the effects of meals high in non-resistant or resistant starch with and without elevated protein intake on substrate utilization, energy expenditure, and satiety in lean and overweight/obese women. METHODS: Women of varying levels of adiposity consumed one of four pancake test meals in a single-blind, randomized crossover design: 1) waxy maize (control) starch (WMS); 2) waxy maize starch and whey protein (WMS+WP); 3) resistant starch (RS); or 4) RS and whey protein (RS+WP). RESULTS: Total post-prandial energy expenditure did not differ following any of the four test meals (WMS = 197.9 +/- 8.9; WMS+WP = 188 +/- 8.1; RS = 191.9 +/- 8.9; RS+WP = 195.8 +/- 8.7, kcals/180 min), although the combination of RS+WP, but not either intervention alone, significantly increased (P <0.01) fat oxidation (WMS = 89.5 +/- 5.4; WMS+WP = 84.5 +/- 7.2; RS = 97.4 +/- 5.4; RS+WP = 107.8 +/- 5.4, kcals/180 min). Measures of fullness increased (125% vs. 45%) and hunger decreased (55% vs. 16%) following WP supplemented versus non-whey conditions (WMS+WP, RS+WP vs. WMS, RS), whereas circulating hunger and satiety factors were not different among any of the test meals. However, peptide YY (PYY) was significantly elevated at 180 min following RS+WP meal. CONCLUSIONS: The combined consumption of dietary resistant starch and protein increases fat oxidation, PYY, and enhances feelings of satiety and fullness to levels that may be clinically relevant if maintained under chronic conditions. This trial was registered at clinicaltrials.gov as NCT02418429. PMID- 26514215 TI - Intrapelvic acetabulum surgery: does the positioning of the plate fixation play a role in the stability of the osteosynthesis? AB - OBJECTIVES: This study aims to investigate whether positioning of the plate fixation plays a role in the stability of the osteosynthesis. MATERIALS AND METHODS: We used finite element modelling to model an anterior pillar fracture and a T-type fracture of the acetabulum. Fracture fixation was carried out in three different variations: cranially positioned plate, medially positioned plate, and a combination of the two methods. In all cases, 3-3 screws were inserted on both ends of the plate to fix the fracture. RESULTS: In both fractures, nearly the same amount of displacement was detected in the fracture gap using a cranially positioned or medially positioned plate, and the amount of displacement was not less when using both plates simultaneously. CONCLUSION: The position of the plate fixation does not affect the stability of the osteosynthesis and in cases of simple fracture patterns, fixation using two plates does not provide more stability than one plate alone. PMID- 26514216 TI - Biomechanical comparision of femoral intramedullary nails for interfragmentary rotational stability. AB - OBJECTIVES: This study aims to investigate which intramedullary nail is biomechanically better for establishing interfragmentary rotational stability. MATERIALS AND METHODS: Thirty composite femurs were utilized in this study. We analyzed interfragmentary rotational arc displacements between 10 Nm external-6 Nm internal torques and 6 Nm external-6 Nm internal torques which imitate rotation torques while walking on a flat surface and descending stairs by administering 10 interlocking nails, 10 compression nails, and 10 Mehmet anti rotation nails with tube compression. RESULTS: Maximum interfragmentary rotation arc displacement between 10 Nm external rotation and 6 Nm internal rotation torques was mean 1.64 mm in the Mehmet nail compressed by 7 Nm torque wrench. This value was lower by 309% (6.72 mm) from interlocking nail (p=0.000), 201% (5.42 mm) from compression nail compressed by 2.5 Nm torque wrench (p=0.000), and 26% (1.92 mm) from compression nail compressed by 7 Nm torque wrench (p>0.05). CONCLUSION: In axially stable transvers and short oblique femur fractures, Mehmet nail is superior to other intramedullary nails with limited movement between locking screw and hole, more interfragmentary compression without locking screw deformation, and no proximal nail migration. PMID- 26514217 TI - Positive effect of tadalafil, a phosphodiesterase-5 inhibitor, on fracture healing in rat femur. AB - OBJECTIVES: This study aims to investigate whether tadalafil accelerates fracture healing with an efficiency equal to that of sildenafil. MATERIALS AND METHODS: Fracture healing was studied using a rat closed femur fracture model. Forty-eight male Wistar albino rats (mean age 13 weeks; range 12 to 14 weeks) were divided into three groups: 16 received sildenafil (5 mg/kg/day per oral), 16 received tadalafil (1 mg/kg/day per oral), and 16 (control group) received saline daily. After two and five weeks, eight rats from each group were euthanized and bone healing was evaluated using radiographic, histologic, and histomorphometric analyses. RESULTS: At second week, radiologic score of tadalafil group was higher than the sildenafil treated groups and the sildenafil and tadalafil groups both had higher radiographic scores than the control group, all groups had similar scores at fifth week. The sildenafil and tadalafil treated group exhibited smaller callus diameter at the second week comparing to control group but the difference was not statistically significant, while callus diameter was significantly smaller in tadalafil group when compared to the control group in fifth week. Compared with the control group, cartilage percentage of the callus was lower in the sildenafil group at two weeks and lower in both the tadalafil and sildenafil groups at five weeks. There were no differences between the tadalafil and sildenafil groups regarding the radiographic scores, callus size, cartilage and osseous callus percentage, and the qualitative bridging scores at second or fifth week. CONCLUSION: This study demonstrated that tadalafil accelerates fracture healing by enhancing osseous tissue formation similar to sildenafil. PMID- 26514218 TI - Biomechanical comparison of three-point bending resistance of titanium and stainless steel locking screws in intramedullary nails. AB - OBJECTIVES: This study aims to investigate whether there is any significant difference in bending resistance between titanium and stainless steel locking screws of femur nails and to review deformation of locking screws which is a common problem in interlocking nailing. MATERIALS AND METHODS: In this study, a total of 60 pieces of 5 mm major diameter titanium and stainless steel locking screws were used as six groups in three different thread depth structures (high threaded, low threaded, and unthreaded). Three-point bending tests were conducted on steel screws placed inside stainless steel tube with 30 mm inner diameter, which imitated the level of lesser trochanter. We used an axial compression testing machine in order to determine the yield points that permanent deformation occurred in the locking screws. RESULTS: For low threaded locking screws, which are the most frequently used thread type for locking screws, the mean bending yield points were 1413 N on the titanium screws and this level was below 1922 N (2.8 BW) of level walking loading on femur for 70 kg person. On low threaded stainless screws, bending resistance was 2071 N, which was above the value of 1922 N. For high threaded locking screws, the mean bending yield points were 874 N on the titanium screws and 556 N on stainless screws. CONCLUSION: In comminuted femur shaft fractures (in full load bearing conditions), using stainless steel locking screws is better instead of titanium screws to avoid locking screw deformation since low threaded stainless steel screws were 46.5% more resistant to bending deformation than titanium ones. Stainless steel or titanium high threaded locking screws may only be carefully used in non-comminuted fractures. PMID- 26514219 TI - Flexion type supracondylar humerus fractures: 12 year experience of a pediatric orthopedics clinic. AB - OBJECTIVES: This study aims to review flexion type supracondylar humerus fractures in children and treatment options. PATIENTS AND METHODS: Forty-seven patients (26 males, 21 females; mean age 8.6+/-3.2 years; range 4 to 15 years) who admitted to and were hospitalized in a pediatric orthopedics clinic between January 2002 and January 2014 due to flexion type supracondylar humerus fracture were included in this retrospective study. Fractures were classified according to Wilkins modification of Gartland system. Closed reduction and percutaneous pinning (CRPP) were administered in all patients with type 2 and 3 fractures. An overhead traction or open reduction was applied when closed reduction could not be achieved with three manipulations. Patients were evaluated clinically and radiologically. The results were graded according to Flynn criteria. RESULTS: Four patients with type 1 fracture were treated conservatively. Of the remaining patients, we were able to perform CRPP successfully in 36 (83.7%). While six patients (14%) were treated with open reduction and internal fixation, one patient (2.1%) was treated with overhead traction. The results were excellent or good in 44 patients (93.7%). CONCLUSION: Compared with extension type fractures, these fractures are seen in older children and are rarer. One should be prepared to perform open reduction especially for type 3 fractures. In our study, results of patients with type 3 fractures treated with CRPP were superior. PMID- 26514220 TI - The efficacy of subcutaneous local analgesic infusion in the early postoperative period after bilateral total knee arthroplasty. AB - OBJECTIVES: This study aims to evaluate the analgesic and functional efficacy of subcutaneous local analgesic infusion (ScLAI) in the early postoperative period (especially on the second postoperative day) in patients undergoing simultaneous bilateral total knee arthroplasty with an intraoperative periarticular injection (PAI) of local analgesic cocktail. PATIENTS AND METHODS: Fifteen patients (1 male, 14 females; mean age 62 years; range 52 to 76 years) who underwent simultaneous bilateral total knee arthroplasty (30 knees) and who received the same pre- and intraoperative analgesic protocols were included in this randomized, double-blind, placebo-controlled study. By using a flexible catheter, bupivacaine was administered for ScLAI to either knee (ScLAI group) and placebo infusion was applied to the other one (control group). Postoperative visual analog scale (VAS) pain scores and knee functions were compared between bupivacain and placebo infused knees. RESULTS: In the ScLAI group, VAS pain scores were lower than the control group during knee flexion and straight leg raise activities (SLR) on the second postoperative day. ScLAI also prevented the rebound pain following intraoperative PAI of local analgesic cocktail and prolonged the analgesic efficacy period of the cocktail during both knee flexion and SLR. CONCLUSION: Subcutaneous infusion of bupivacaine in patients undergoing simultaneous bilateral total knee arthroplasty may prevent emergence of the rebound pain arising after application of intraoperative PAI of local analgesic cocktail and prolong the analgesic efficacy of the cocktail during both knee flexion and SLR activities on the second postoperative day. PMID- 26514221 TI - [Is intraarticular administration of tranexamic acid efficient and safe as systemic administration in total knee arthroplasty? Single center, randomized, controlled trial]. AB - OBJECTIVES: This study aims to compare the efficiency and safety of intraarticular and intravenous tranexamic acid administration in patients who were performed primary total knee arthroplasty. PATIENTS AND METHODS: This single center, randomized, controlled trial included 60 patients (8 males, 52 females; mean age 67.8 years; range 53 to 87 years) who were performed primary total knee arthroplasty by three surgeons due to a diagnosis of primary osteoarthritis between January 2015 and June 2015. Patients were separated into three groups. Patients in group 1 and group 2 were administered 2 g intravenous tranexamic acid and 2 g intraarticular tranexamic acid, respectively. Patients in group 3 were not administered tranexamic acid. Pre- and postoperative hemoglobin difference, volume of blood collected in drains, and transfusion rate were analyzed. RESULTS: Compared with the control group, there was no significant difference between group 1 and group 2 in terms of total blood loss from the drain, pre- and postoperative hemoglobin difference, and the need for blood transfusion. CONCLUSION: Both intraarticular and intravenous administrations reduce blood loss and need for transfusion and there is no significant difference between the two techniques in terms of safety. PMID- 26514222 TI - [Salter innominate osteotomy for the treatment of developmental dysplasia of the hip: 37 years of follow-up]. AB - In this article, we report the radiological and clinical status at postoperative 37th year of a 39-year-old male patient who was treated with bilateral Salter innominate osteotomy due to bilateral developmental dysplasia of the hip when he was two years old. The patient expressed that he had no complaint including pain or limitation in range of motion in both hip joints for 37 years. Pain started six months ago in right hip joint. Patient used cortisone for 12 months with a diagnosis of Henoch-Schonlein purpura five years ago. Radiologic imaging revealed findings of bilateral Salter innominate osteotomy and avascular osteonecrosis on the right femoral head. Kirschner wires which were used during operations 37 years ago remained buried in pelvic bone. Bilateral development of acetabulum and femoral head was very good. Anteroposterior and lateral radiographs of right hip joint revealed degenerative osteoarthritis secondary to avascular osteonecrosis on the right femoral head. Except for the last six months, patient has been living without pain or limitation in range of motion for postoperative 37 years. PMID- 26514223 TI - Elbow septic arthritis associated with pediatric acute leukemia: a case report and literature review. AB - Acute leukemia in children presents with various clinical manifestations that mimic orthopaedic conditions. The association of septic arthritis of the elbow with acute leukemia is very rare, and the correct diagnosis of acute leukemia is often established only after treatment of the septic arthritis. In this article, we present a three-year-old child patient with elbow septic arthritis related to acute leukemia, diagnosed promptly by bone marrow aspiration on the same day as emergency surgical debridement of the septic elbow joint due to the maintenance of a high index of suspicion, and treated with chemotherapy as soon as possible. The emergency physician and orthopaedist must recognize unusual patterns of presentation like this. Since delay in initiating treatment of septic arthritis may result in growth disturbance, elbow septic arthritis associated with pediatric acute leukemia must be treated promptly and appropriately. Early diagnosis is a good prognostic feature of childhood acute leukemia. PMID- 26514224 TI - One-stage surgical treatment of neglected simultaneous bilateral locked posterior dislocation of shoulder: a case report and literature review. AB - Simultaneous bilateral locked posterior dislocation of the shoulder is a rare injury. Herein, we present a 59-year-old male case with a three-month history of an irreducible locked bilateral posterior dislocation of the shoulders with an associated large impression fracture on the anteromedial aspect of both humeral heads after a grand mal type epileptic seizure. Plain X-ray and computed tomograph revealed a defect on the right side more than 40% of the articular surface, and on the left side, 30%. He was treated with a one-stage operation with a reconstruction of femoral head osteochondral allograft on the right side and transfer of the osteotomized tuberculum minus with its attached subscapularis tendon into the defect (modified McLaughlin technique) on the left side. At 14 months during follow-up, the patient was pain-free with stable shoulder joints and satisfactory functionality. PMID- 26514225 TI - Osteochondral mosaicplasty along with osteochondroplasty of the femoral head in femoroacetabular impingement: a case report. AB - Although femoroacetabular impingement (FAI) syndrome is included in the etiology of lesions involving the acetabular labrum and acetabular cartilage, it is one of many possible reasons behind osteochondral lesions in the femoral head. Herein, we present clinical findings and outcomes of two cases with osteochondral defects and cam type impingement of femoral head. Both cases underwent autologous osteochondral mosaicplasty along with femoral osteochondroplasty following controlled hip dislocation. Harris hip scores improved significantly postoperatively and magnetic resonance imaging showed an adequate graft union and formation of a healthy chondral surface at the final assessment. Autologous osteochondral mosaicplasty of parafoveal region defects and femoral neck osteochondroplasty combination may be an effective treatment method for young patients with FAI syndrome. In addition, we believe that cam type impingement may also have a role in the etiology of parafoveal osteochondral lesions. PMID- 26514227 TI - Treatment of Anxiety Disorders in a Psychology Clinic. AB - People with anxiety disorders demand psychological attention most often. Therefore, it seems important to identify both the characteristics of the patients who demand help and the clinical variables related to that demand and its treatment. A cohort of 292 patients who requested help at a university clinical facility was studied. The typical profile of the patient was: being female, young, unmarried, with some college education, and having previously received treatment, especially pharmacological one. The three most frequent diagnoses of anxiety, which include 50% of the cases, were: Anxiety Disorder not otherwise specified, Social Phobia, and Panic Disorder with Agoraphobia. Regarding the characteristics of the intervention, the average duration of the assessment was 3.5 sessions (SD = 1.2), and the duration of the treatment was 14 sessions (SD = 11.2). The percentage of discharges was 70.2%. The average cost of treatment was around ?840. The results are discussed, underlining the value of empirically supported treatments for anxiety disorders. PMID- 26514226 TI - HOXD9 promotes epithelial-mesenchymal transition and cancer metastasis by ZEB1 regulation in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a common malignant tumor that severely threatens human health. The poor prognosis of HCC is mainly attributed to intrahepatic and extrahepatic metastases. HOXD9 proteins belong to a superfamily that regulates the development and control of many cellular processes, including proliferation, apoptosis, cell shape, and cell migration. HOXD9 can also function as an oncogene in several cancer cells. However, its biological function in human HCC requires further investigation. In this study, HOXD9 exhibited high expression in invasive HCC cells. HOXD9 overexpression can significantly enhance HCC cell migration, invasion, and metastasis, whereas silencing HOXD9 inhibits these processes. HOXD9 also promotes the epithelial-mesenchymal transition (EMT) of HCC cells. Microarray analysis suggests that ZEB1 can function as a downstream factor of HOXD9. HOXD9 can interact with the promoter region of ZEB1 and promotes ZEB1 expression. ZEB1 knockdown inhibits HOXD9-induced migration and invasion, as well as EMT in HCC cells. This study helps elucidates the oncogenic functions of HOXD9 in HCC. PMID- 26514228 TI - A newly found manganese hyperaccumulator--Polygonum lapathifolium Linn. AB - In the present work, both field investigation and laboratory experiment were carried out to testify whether Polygonum lapathifolium L. is a potential manganese (Mn) hyperaccumulator. Results from field investigation showed that P. lapathifolium had great tolerance and accumulation to Mn. Mn concentrations in leaves were the highest, varied from 6889.2 mg kg-1 dry weight (DW) to 18841.7 mg kg(-1) DW with the average of 12180.6 mg kg(-1). The values of translocation factor (the concentrations of Mn in leaf to that in root) ranged from 5.72 to 9.53. Results from laboratory experiment illuminated that P. lapathifolium could grow well and show no toxic symptoms even under high Mn stress (16 mmol L(-1)). Although the changes of antioxidant enzymes activities were triggered under Mn stress, the alterations of pigments were not significant (P > 0.05) as compared with control. Total plant biomass and plant height increased with increasing Mn supply. Mn concentrations in leaves and stems were constantly greater than those in roots, the ratio of concentrations in leaves to that in roots were 2.58-6.72 and the corresponding values in stems to that in roots were 1.45-3.18. The results showed that P. lapathifolium is a Mn-hyperaccumulator. PMID- 26514230 TI - Detection of Right-to-Left Cardiac Shunt in the Absence of Transcranial Acoustic Bone. AB - PURPOSE: Paradoxical thrombotic embolism via right-to-left cardiac shunt (RLS) is a risk factor of cryptogenic ischemic stroke. Transtemporal Doppler (TTD) is a valid method used in the detection of patent foramen ovale (PFO). Temporal acoustic bone windows are missing with increasing age and in some younger subjects. We studied prospectively whether Doppler ultrasound of the cervical arteries (submandibular internal carotid artery [ICA] and vertebral artery [VA]) is an alternative, when compared to TTD, in the detection and quantification of PFO. MATERIAL AND METHODS: A total of 94 patients with sufficient temporal bone windows suffering from recent ischemic stroke underwent TTD and ICA (n = 51) or TTD and VA (n = 43). After injection of microbubbles, the numbers of artificial high-intensity signals (HITS) were recorded at rest and after Valsalva maneuver. RESULTS: For 47 patients in the ICA group, an RLS was found at rest in 23 patients and after Valsalva in 28 patients. At rest, sensitivity was 100%, specificity 96%, positive predictive value (ppv) 95.6%, and negative predictive value (npv) 100%. After Valsalva, sensitivity was 100%, specificity 95%, ppv 96.4%, npv 100%. For 43 patients in the VA group an RLS was found at rest in 14 patients and after Valsalva in 19 patients. At rest, sensitivity was 71.4%, specificity 100%, ppv 100%, and npv 87.8%. After Valsalva, 94.4%, 96%, 94.4%, and 96%, respectively. Pearson's correlations of the number of HITS between TTD and ICA and between TTD and VA were highly significant. CONCLUSIONS: When transcranial acoustic bone windows are missing, Doppler ultrasound of the cervical submandibular ICA and VAs are valid screening methods to detect RLS due to a PFO. PMID- 26514229 TI - Fluorinated porphyrinoids as efficient platforms for new photonic materials, sensors, and therapeutics. AB - Porphyrinoids are robust heterocyclic dyes studied extensively for their applications in medicine and as photonic materials because of their tunable photophysical properties, diverse means of modifying the periphery, and the ability to chelate most transition metals. Commercial applications include their use as phthalocyanine dyes in optical discs, porphyrins in photodynamic therapy, and as oxygen sensors. Most applications of these dyes require exocyclic moieties to improve solubility, target diseases, modulate photophysical properties, or direct the self-organization into architectures with desired photonic properties. The synthesis of the porphyrinoid depends on the desired application, but the de novo synthesis often involves several steps, is time consuming, and results in low isolated yields. Thus, the application of core porphyrinoid platforms that can be rapidly and efficiently modified to evaluate new molecular architectures allows researchers to focus on the design concepts rather than the synthesis methods, and opens porphyrinoid chemistry to a broader scientific community. We have focused on several widely available, commercially viable porphyrinoids as platforms: meso-perfluorophenylporphyrin, perfluorophthalocyanine, and meso perfluorophenylcorrole. The perfluorophenylporphyrin is readily converted to the chlorin, bacteriochlorin, and isobacteriochlorin. Derivatives of all six of these core platforms can be efficiently and controllably made via mild nucleophilic aromatic substitution reactions using primary S, N, and O nucleophiles bearing a wide variety of functional groups. The remaining fluoro groups enhance the photo and oxidative stability of the dyes and can serve as spectroscopic signatures to characterize the compounds or in imaging applications using (19)F NMR. This review provides an overview of the chemistry of fluorinated porphyrinoids that are being used as a platform to create libraries of photo-active compounds for applications in medicine and materials. PMID- 26514231 TI - Acutely administered grape-seed proanthocyanidin extract acts as a satiating agent. AB - Grape-seed proanthocyanidins' role as stimulators of active GLP-1 in rats suggests that they could be effective as satiating agents. Wistar rats were used to study the effects of proanthocyanidins on food intake with different doses, administration times and proanthocyanidin extract compositions. A dose of 423 mg of phenolics per kg body weight (BW) of grape-seed proanthocyanidin extract (GSPE) was necessary to decrease the 12-hour cumulative food intake by 18.7 +/- 3.4%. Proanthocyanidins were effective when delivered directly into the gastrointestinal tract one hour before, or simultaneously at the start of the feeding period. Proanthocyanidins without galloyl forms, such as those from cocoa extract, were not as effective as grape-seed derived forms. GSPE increased the portal levels of active GLP-1 and total ghrelin and decreased the CCK levels, simultaneously with a decrease in gastric emptying. In conclusion, grape-seed proanthocyanidins could be useful as a satiating agent under the conditions defined in this study. PMID- 26514232 TI - Covariability in three dimensions of teenage driving risk behavior: impaired driving, risky and unsafe driving behavior, and secondary task engagement. AB - OBJECTIVE: This research examined the extent to which teenagers who engaged in one form of risky driving also engaged in other forms and whether risky driving measures were reciprocally associated over time. METHODS: The data were from waves 1, 2, and 3 (W1, W2, and W3) of the NEXT Generation study, with longitudinal assessment of a nationally representative sample starting with 10th graders starting in 2009-2010. Three measures of risky driving were assessed in autoregressive and cross-lagged analyses: driving while alcohol/drug impaired (DWI), Checkpoints Risky Driving Scale (risky and unsafe driving), and secondary task engagement while driving. RESULTS: In adjusted autoregression models, the risk variables demonstrated high levels of stability, with significant associations observed across the 3 waves. However, associations between variables were inconsistent. DWI at W2 was associated with risky and unsafe driving at W3 (beta = 0.21, P < .01); risky and unsafe driving at W1 was associated with DWI at W2 (beta = 0.20, P < .01); and risky and unsafe driving at W2 is associated with secondary task engagement at W3 (beta = 0.19, P < .01). Over time, associations between DWI and secondary task engagement were not significant. CONCLUSIONS: Our findings provide modest evidence for the covariability of risky driving, with prospective associations between the Risky Driving Scale and the other measures and reciprocal associations between all 3 variables at some time points. Secondary task engagement, however, appears largely to be an independent measure of risky driving. The findings suggest the importance of implementing interventions that addresses each of these driving risks. PMID- 26514233 TI - Radiotherapy-related acute myeloid leukaemia with KMT2A amplification. PMID- 26514234 TI - Multiscale peak detection in wavelet space. AB - Accurate peak detection is essential for analyzing high-throughput datasets generated by analytical instruments. Derivatives with noise reduction and matched filtration are frequently used, but they are sensitive to baseline variations, random noise and deviations in the peak shape. A continuous wavelet transform (CWT)-based method is more practical and popular in this situation, which can increase the accuracy and reliability by identifying peaks across scales in wavelet space and implicitly removing noise as well as the baseline. However, its computational load is relatively high and the estimated features of peaks may not be accurate in the case of peaks that are overlapping, dense or weak. In this study, we present multi-scale peak detection (MSPD) by taking full advantage of additional information in wavelet space including ridges, valleys, and zero crossings. It can achieve a high accuracy by thresholding each detected peak with the maximum of its ridge. It has been comprehensively evaluated with MALDI-TOF spectra in proteomics, the CAMDA 2006 SELDI dataset as well as the Romanian database of Raman spectra, which is particularly suitable for detecting peaks in high-throughput analytical signals. Receiver operating characteristic (ROC) curves show that MSPD can detect more true peaks while keeping the false discovery rate lower than MassSpecWavelet and MALDIquant methods. Superior results in Raman spectra suggest that MSPD seems to be a more universal method for peak detection. MSPD has been designed and implemented efficiently in Python and Cython. It is available as an open source package at . PMID- 26514235 TI - The occurrence of visual and cognitive impairment, and eye diseases in the super elderly in Japan: a cross-sectional single-center study. AB - BACKGROUND: The current state of eye diseases and treatments in the elderly as well as the relationships between dementia and systemic diseases remain unclear. Therefore, this study evaluated the prevalence of eye diseases, visual impairment, cognitive impairment, and falls (which are an important health issue and are considered one of the Geriatric Giants) in super-elderly people in Japan. METHODS: The subjects were 31 elderly people (62 eyes; mean age: 84.6 +/- 8.8 years; age range 61-98 years) who were admitted to a geriatric health services facility. Eye treatment status, systemic diseases, dementia, and recent falls were investigated. Eye examinations including vision and intraocular pressure measurement, and slit-lamp biomicroscopy were conducted. RESULTS: Mean best corrected visual acuity (logMAR) was 0.51 +/- 0.56, and mean intraocular pressure was 13.7 +/- 3.5 mmHg. Approximately half of the subjects exhibited excavation of the optic nerve head including cataracts and glaucoma. Ten subjects had visual impairment (i.e., visual acuity of the eye with the better vision <20/40). The mean Hasegawa dementia scale scores between the visually impaired and non visually impaired groups were 10.2 +/- 6 and 16 +/- 8 points, respectively (p < 0.05). Furthermore, 70% of subjects with visual impairment experienced a fall in the past year compared to 48% of those without visual impairment, although the difference was not significant. Regarding systemic diseases, there were 6, 5, and 15 cases of diabetes, hyperlipidemia, and hypertension, respectively. There was no significant difference between these systemic diseases and visual function after adjusted for age and gender. CONCLUSIONS: The percentages of patients with age-related eye diseases and poor visual acuity in a geriatric health services facility were extremely high. Compared to those without visual impairment, those with visual impairment had lower dementia scores and a higher rate of falls. PMID- 26514236 TI - Posttraumatic Growth in Populations with Posttraumatic Stress Disorder-A Systematic Review on Growth-Related Psychological Constructs and Biological Variables. AB - : Posttraumatic growth (PTG) and Posttraumatic Stress Disorder (PTSD) are possible consequences of trauma. PTG is supposed to emerge from cognitive processes and can have functional and dysfunctional aspects. This systematic review aims to identify and evaluate publications assessing PTG in adults diagnosed with PTSD in order to analyse the relationship between both constructs, how PTG is related to specific psychological variables and if there are biological variables linked to PTG. This extended review evaluates the quality of measures applied and is the first to study PTG only in populations meeting full PTSD criteria. In addition, the relationship between PTG and other relevant constructs, such as openness, optimism and social support, is explored. Our systematic literature search identified 140 studies of which 19 fulfilled our inclusion criteria; most of them used the Post-Traumatic Growth Inventory. Results indicate that trauma survivors with PTSD exhibit more PTG than those without PTSD and that PTG can be intensified during the therapeutic process whereat it is unclear whether PTG is a desirable outcome of PTSD therapy. Positive correlations between PTG and PTSD are reported. For diagnosed populations, we could not find strong evidence of a quadratic relationship between PTG and PTSD, although some studies support this hypothesis. Findings regarding the association of PTG with psychological variables are heterogeneous. Only one study focused on PTG as well as on biological variables (salivary cortisol) but did not discuss possible links between these two so far unconnected research fields in PTSD. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Trauma survivors with PTSD develop more PTG than those without PTSD, it remains unclear whether PTSD and PTG are curvilinearly related. PTG can be enhanced through PTSD therapy, nevertheless one must not assume that PTG is a favorable treatment outcome since we do not know if the development of PTG during therapy promotes the reduction of PTSD symptoms. It is unclear whether PTG in PTSD sufferers is a constructive outcome of cognitive processes or a positive illusion in favor of avoidance and denial. Results regarding the association of personality factors, social support and PTG are inconsistent, studies on biological aspects of PTG are lacking. PMID- 26514237 TI - Obesity and risk of bleeding: the SMART study. AB - Essentials Whether obesity protects against clinically relevant bleeding is unclear. We investigated the risk of bleeding according to various measures of obesity in a cohort of 9736 patients. Obesity was not associated with a lower risk of bleeding. The procoagulant profile in obese subjects may not be enough to protect against clinically relevant bleeding. SUMMARY: Background Obesity is associated with increased levels of procoagulant factors and decreased fibrinolytic activity. Whether this hemostatic profile protects against clinically relevant bleeding has been scarcely investigated. Objectives To assess the impact of measures of obesity on the risk of bleeding in a large cohort of patients at increased atherothrombotic risk. Methods The Second Manifestation of ARTerial disease (SMART) study included 9736 patients aged 18-79 years, followed for a median of 5.9 years. Body mass index (BMI), waist circumference and hip circumference were measured at inclusion. All incident fatal or non-fatal hemorrhagic events were recorded. Results During follow-up, 359 first bleeding events occurred. In quintile-based analyses, the risk of bleeding was highest in the lowest quintile (Q) of BMI (age and sex-adjusted HR Q2 vs. Q1, 0.68; 95% CI, 0.50-0.94), but there was a threshold effect at low BMI levels (men, < 23.84 kg m(-2) ; women, < 22.49 kg m(-2) ), and the risk estimates for bleeding did not further change across the remaining quintiles (HR Q3 0.81 and Q5 0.75). For waist circumference the relationship appeared to be U-shaped, with the lowest risk of bleeding in quintile 3 (HR Q3 vs. Q1, 0.69; 95% CI, 0.46-1.04). Adjustments for hypertension, hemoglobin level, renal failure, diabetes and use of oral anticoagulants or platelet inhibitors did not affect the results. Conclusion Obesity was not associated with lower risk of bleeding. Our findings suggest that presumed protection against bleeding due to an apparently efficient hemostatic system may be counterbalanced by other factors in obese subjects. PMID- 26514238 TI - Phonon and magnetic structure in delta-plutonium from density-functional theory. AB - We present phonon properties of plutonium metal obtained from a combination of density-functional-theory (DFT) electronic structure and the recently developed compressive sensing lattice dynamics (CSLD). The CSLD model is here trained on DFT total energies of several hundreds of quasi-random atomic configurations for best possible accuracy of the phonon properties. The calculated phonon dispersions compare better with experiment than earlier results obtained from dynamical mean-field theory. The density-functional model of the electronic structure consists of disordered magnetic moments with all relativistic effects and explicit orbital-orbital correlations. The magnetic disorder is approximated in two ways: (i) a special quasi-random structure and (ii) the disordered-local moment method within the coherent potential approximation. Magnetism in plutonium has been debated intensely, but the present magnetic approach for plutonium is validated by the close agreement between the predicted magnetic form factor and that of recent neutron-scattering experiments. PMID- 26514239 TI - Identification of a novel HLA-C*03 variant allele, C*03:280 by sequence-based typing. AB - The new allele, HLA-C*03:280 differs from C*03:04:01 by one nucleotide substitution at codon 35 (CGG->CAG). PMID- 26514240 TI - Physico-chemical properties of Moringa oleifera seed oil enzymatically interesterified with palm stearin and palm kernel oil and its potential application in food. AB - BACKGROUND: High oleic acid Moringa oleifera seed oil (MoO) has been rarely applied in food products due to the low melting point and lack of plasticity. Enzymatic interesterification (EIE) of MoO with palm stearin (PS) and palm kernel oil (PKO) could yield harder fat stocks that may impart desirable nutritional and physical properties. RESULTS: Blends of MoO and PS or PKO were examined for triacylglycerol (TAG) composition, thermal properties and solid fat content (SFC). EIE caused rearrangement of TAGs, reduction of U3 and increase of U2 S in MoO/PS blends while reduction of U3 and S3 following increase of S2 U and U2 S in MoO/PKO blends (U, unsaturated and S, saturated fatty acids). SFC measurements revealed a wide range of plasticity, enhancements of spreadability, mouthfeel and cooling effect for interesterified MoO/PS, indicating the possible application of these blends in margarines. However, interesterified MoO/PKO was not suitable in margarine application, while ice-cream may be formulated from these blends. A soft margarine formulated from MoO/PS 70:30 revealed high oxidative stability during 8 weeks storage with no significant changes in peroxide and p-anisidine values. CONCLUSION: EIE of fats with MoO allowed nutritional and oxidative stable plastic fats to be obtained, suitable for possible use in industrial food applications. (c) 2015 Society of Chemical Industry. PMID- 26514241 TI - Novel functionalized 5-(phenoxymethyl)-1,3-dioxane analogs exhibiting cytochrome P450 inhibition: a patent evaluation WO2015048311 (A1). AB - Cytochrome P450's (CYP's) constitute a diverse group of over 500 monooxygenase hemoproteins, catalyzing transformations that involve xenobiotic metabolism, steroidogenesis and other metabolic processes. Over-production of the steroid hormone cortisol is implicated in the progression of diseases such as diabetes, heart failure and hypertension, stroke, Cushing's syndrome, obesity and renal failure, among others. The biosynthesis of cortisol involves a cascade of cholesterol metabolizing reactions regulated through three major CYP proteins: 17alpha-hydroxylase-C17/20-lyase (CYP17), 21-hydroxylase (CYP21), and 11beta hydroxylase (CYP11B1). Excess activities of these enzymes are linked to the progression of malignancies including prostate, breast, ovarian, and uterine cancers. A series of novel functionalized dioxane analogs have been developed and recently patented as CYP17, CYP21, and CYP11B1 inhibitors, which lead to the modulation of cortisol production as a method for treating, delaying, slowing, and inhibiting the implicated diseases. The findings disclosed in this patent have been analyzed and compared with the literature data on inhibitors of CYP17, CYP21, and CYP11B1. The compiled data provide insight into the novel functionality of the compounds described in the patent. In this regard, an objective opinion on the effectiveness and novel biochemistry of these compounds in comparison to current CYP inhibitors used in the treatment of cortisol-related diseases is presented in this paper. PMID- 26514242 TI - Ultrastructure of medial rectus muscles in patients with intermittent exotropia. AB - PURPOSE To study the ultrastructure of the medial rectus in patients with intermittent exotropia at different ages.PATIENTS AND METHODS The medial recti were harvested surgically from 20 patients with intermittent exotropia. Patients were divided into adolescent (age<18 years, n=10) and adult groups (age >18 years, n=10). The normal control group included five patients without strabismus and undergoing eye enucleation. Hematoxylin and eosin staining and transmission electron microscopy were used to visualize the medial recti. Western blot was used to determine the levels of myosin and actin.RESULTS Varying fiber thickness, atrophy, and misalignment of the medial recti were visualized under optical microscope in patients with exotropia. Electron microscopy revealed sarcomere destruction, myofilament disintegration, unclear dark and light bands, collagen proliferation, and fibrosis. The adolescent group manifested significantly higher levels of myosin and actin than the adult group (P<0.05).CONCLUSION Younger patients with intermittent exotropia show stronger contraction of the medial recti compared with older patients. Our findings suggest that childhood was the appropriate time for surgery as the benefit of the intervention was better than in adulthood. PMID- 26514243 TI - Photodynamic therapy and anti-vascular endothelial growth factor for acute central serous chorioretinopathy: a systematic review and meta-analysis. AB - This systematic review aims to update current evidence on the efficacy and safety of photodynamic therapy (PDT) and anti-vascular endothelial growth factor (anti VEGF) injections for acute central serous chorioretinopathy (CSC). A comprehensive literature search was conducted in PubMed, EMBASE, and Cochrane Library. Studies comparing (1) PDT versus placebo, (2) anti-VEGF versus placebo, and (3) PDT versus anti-VEGF were included and meta-analyzes were performed when appropriate. Ocular and systemic adverse effects were also summarized. Literature search yielded six comparative studies, among which five were included for this review. Meta-analysis with three studies indicated that eyes treated with PDT achieved better best-corrected visual acuity (BCVA) and central macular thickness (CMT) than the placebo group throughout a follow-up of 12 months. Meta-analysis with another two studies comparing anti-VEGF injections and placebo showed that BCVA at first month was better in anti-VEGF group than in placebo group, though the differences of BCVA and CMT no longer existed at 3 and 6 months after injection. There was no report directly comparing PDT and anti-VEGF for acute CSC. No severe complications was reported in included studies. In this review, current evidence suggested that early treatment of acute CSC by PDT is valuable in improving visual acuity, reducing subretinal fluid, and maintaining long term effectiveness. Anti-VEGF injection could shorten the duration of symptoms and accelerate visual improvement at early stage of disease. Direct comparison between these two treatment will be needed in the future. PMID- 26514244 TI - Aflibercept as primary treatment for myopic choroidal neovascularisation: a retrospective study. AB - AIM The aim of this study is to evaluate long-term efficacy of intravitreal injections of aflibercept as primary treatment for subfoveal/juxtafoveal myopic choroidal neovascularisation (CNV).METHODS Thirty-eight treatment-naive eyes of thirty-eight patients with subfoveal/juxtafoveal myopic CNV received initial intravitreal aflibercept injections and were followed for at least 18 months. Aflibercept was applied again for persistent or recurrent CNV, as required. Statistical analysis was carried out using SPSS.RESULTS Mean patient age was 45.8 years, and mean eye refractive error was -7.79 D. For the total patient group (n=38 eyes), mean logMAR best-corrected visual acuity (BCVA) significantly improved from 0.69 at baseline to 0.15 at 18 months (P<0.01). Over half of the treated eyes obtained resolution with one aflibercept injection. Patients were also grouped according to age, as <50 years (n=20 eyes) and >=50 years (n=18 eyes). Mean BCVA improvement was significantly greater in eyes of the younger myopic CNV group, compared with those of >=50 years (0.21 vs 0.35; P<0.05). The mean number of aflibercept injections was 1.8 for the <50 years myopic CNV group, and 3.6 for the >=50 years myopic CNV group (P<0.001). Correlation between spherical equivalent refraction and final visual acuity reached statistical significance only for the <50 years myopic CNV group (P<0.001; Levene's correlation).CONCLUSIONS Intravitreal aflibercept provides long-term visual acuity improvement in myopic CNV. The <50 years old myopic CNV group had significantly fewer injections, with greater visual acuity improvement. Intravitreal aflibercept in myopic CNV does not require the three-injection loading phase used for aflibercept treatment of neovascular age-related macular degeneration. PMID- 26514245 TI - Impact of telephone consent and potential for eye donation in the UK: the Newcastle Eye Centre study. AB - AIMS: To examine the impact of telephone consent introduced in 2007 on the eye donation rate and to report the changing trend and potential for improvement in eye donation in Newcastle upon Tyne, UK. METHODS: Relevant data were retrospectively collected from the local eye retrieval database for two separate years, namely, 2006 (before the introduction of telephone consent) and 2010. All the hospitals within Newcastle were included in the study. RESULTS: From 2006 to 2010, there was a 3.5-fold increase in eye donation from 32 (of 2479 deaths) to 111 donors per year (of 2213 deaths) in Newcastle (P<0.001). Consent was obtained via face-to-face interview in all 32 (100%) and 59 (53.2%) donors in 2006 and 2010, respectively. Introduction of telephone consent increased the donation rate by an additional 88.1% (from 59 to 111 donors) in 2010 (P<0.001). In addition, there was a significant increase in medical notes of the deceased being reviewed from 27.1% (671/2479 cases) in 2006 to 62.4% (1382/2213 cases) in 2010 (P<0.001). Acceptance rate of eye donation was 45.7% (32/70) in 2006 and 49.6% (111/224) in 2010 (P=0.575). Acceptance rate was positively associated with registration on organ donor register (P<0.001) and telephone consent (P<0.001), but not with age (P=0.883), gender (P=0.234), or location of death (P=0.984) of the potential donors. CONCLUSION: There has been a substantial improvement in eye donation rate in Newcastle over the recent years. Introduction of telephone consent and high quality eye donation service serve as effective measures for increasing eye donation. PMID- 26514246 TI - Comment on 'The Royal College of Ophthalmologists Guidelines on retinal vein occlusions: executive summary'. PMID- 26514247 TI - Comment on 'The Royal College of Ophthalmologists Guidelines on retinal vein occlusions'. PMID- 26514248 TI - Layer-by-Layer Assembled 2D Montmorillonite Dielectrics for Solution-Processed Electronics. AB - Layer-by-layer assembled 2D montmorillonite nanosheets are shown to be high performance, solution-processed dielectrics. These scalable and spatially uniform sub-10 nm thick dielectrics yield high areal capacitances of ~600 nF cm(-2) and low leakage currents down to 6 * 10(-9) A cm(-2) that enable low voltage operation of p-type semiconducting single-walled carbon nanotube and n-type indium gallium zinc oxide field-effect transistors. PMID- 26514249 TI - Hexaphyrin-Cyclodextrin Hybrids: A Nest for Switchable Aromaticity, Asymmetric Confinement, and Isomorphic Fluxionality. AB - Conformational control over the highly flexible pi-conjugated system of expanded porphyrins is a key step toward the fundamental understanding of aromaticity and for the development of molecular electronics. We have synthesized unprecedented hexaphyrin-cyclodextrin (HCD) capped hybrids in which the hexaphyrin part is constrained in a planar rectangular conformation in either a 26 or a 28 pi electron oxidation state ([26]/[28]HCD). These structures display strong aromaticity and antiaromaticity, respectively, exhibit markedly different chiroptical properties, and are interconvertible upon the addition of DDQ or NaBH(OAc)3, thus affording a rare switchable aromatic-antiaromatic system with a free-base expanded porphyrin. Conformational analysis revealed discrimination of the two coordination sites of the hexaphyrin, one of which was coupled to a confined asymmetric environment, and fluxional behavior consisting of apparent rotation of the hexaphyrin cap through a shape-shifting mechanism. PMID- 26514250 TI - Right-lateralized unconscious, but not conscious, processing of affective environmental sounds. AB - Much research on the laterality of affective auditory stimuli features emotional speech. However, environmental sounds can also carry affective information, but their lateralized processing for affect has been studied much less. We studied this in 2 experiments. In Experiment 1 we explored whether the detection of affective environmental sounds (from International Affective Digital Sounds) that appeared in auditory scenes was lateralized. While we found that negative targets were detected more rapidly, detection latencies were the same on the left and right. In Experiment 2 we examined whether conscious appraisal of the stimulus was needed for lateralization patterns to emerge, and asked participants to rate the stimuli's pleasantness in a dichotic listening test. This showed that when positive/negative environmental sounds were in the attended to-be-rated channel, ratings were the same regardless of laterality. However, when participants rated neutral stimuli and the unattended channel was positive/negative, the valence of the unattended channel affected the neutral ratings more strongly with left ear (right hemisphere, RH) processing of the affective sound. We link our findings to previous work that suggests that the RH may specialize in the unconscious processing of emotion via subcortical routes. PMID- 26514251 TI - An in vitro porcine model evaluating a novel stent retriever for thrombectomy of the common carotid artery. AB - OBJECTIVES: This study aimed to test the safety and efficiency of a novel stent retriever, RECO, in a swine model. BACKGROUND: The stent retrievers show great benefit for patients with acute ischemic stroke. METHODS: The framework of the stent was optimized. The proximal stent was closed; mechanical connection replaced the electrolysis connection and the push wire located on the longitudinal axis. After tests in vitro, the safety and thrombectomy efficiency of RECO device were evaluated by angiography and histological analysis in a swine model with placement of experimental soft or hard thrombi. RESULTS: No device related thrombi were observed on the perioperative term or 1 month later. The endothelial cells were intact and the smooth muscle cells did not migrate or proliferate. Device-related vasospasm was detected in 9% vessels undergoing the procedure and was alleviated after delivery of a dose of nitroglycerin. The RECO device demonstrated a high recanalization rate in the target vessels with a mean of 1.3 runs. No residual thrombi were observed under the DSA or microscope. CONCLUSIONS: Our data indicated that RECO device was a novel, safe and effective stent based clot retriever. A phase IIa clinical trial, RESTORE, is undergoing (NCT01983644). PMID- 26514252 TI - Caveat Emptor: Powdered Alcohol Products. PMID- 26514253 TI - Qualitative Systematic Review of Intimate Partner Violence among Native Americans. AB - The incidence of intimate partner violence (IPV) among Native Americans is high, and a full understanding of how to prevent it is unclear. Based on this qualitative systematic review of 13 research reports, a model of IPV among Native Americans was developed. IPV appears to be grounded within a history of upheaval and loss, and is entrenched and repressed within families. Victims are reluctant to seek assistance, and when they do, they often experience barriers within the service system. To prevent and resolve IPV, service providers are urged to establish trust with individuals who seek assistance and to leverage cultural strengths. They also are encouraged to adapt theoretical models to optimize care. PMID- 26514254 TI - Evaluating the Orbach Mikulincer Mental Pain Scale among Late Adolescent and Early Adult African Americans: A Rasch Analysis. AB - Although there are only a few psychometric investigations of mental pain measurement in the literature, there are no previous evaluations of mental pain scales among African Americans. The present study examined the Rasch measurement properties of the nine subscales contained in the Orbach-Mikulincer Mental Pain (OMMP) Scale among a sample of older adolescent and young adult African Americans. Results from the analyses suggest that three of the OMMP subscales meet the requirements of the Rasch model and hold promise for use in research and applied settings. Implications for further development and use of the remaining subscales are discussed. PMID- 26514255 TI - The Recovery-Based Interprofessional Distance Education (RIDE) Rotation: Content and Rationale. AB - A faculty team of two psychiatric nurse practitioners, an exercise physiologist, a registered dietician and a pharmacist developed the 8-week Recovery-Based Interprofessional Distance Education (RIDE) rotation for graduate students in the four disciplines. Organizing the RIDE rotation around the recovery model ensured an emphasis upon optimal health and quality of life. RIDE faculty engaged in project planning for several months before the RIDE rotation was offered to students. In this paper, we describe details of the 8-week program. Our next step will be to analyze student feedback and de-identified evaluation data from the first student cohort. PMID- 26514256 TI - Physical Health Risk Behaviours in Young People with Mental Illness. AB - Comorbid physical health conditions, commonly associated with mental illness, contribute to increased morbidity and reduced life expectancy. The trajectory to poorer health begins with the onset of mental illness. For young people with mental illness, health risk behaviours and poor physical health can progress to adulthood with long-term detrimental impacts. Using a cross-sectional survey design, self-reported health risk behaviours were gathered from 56 young (16-25 years) Australians who had been hospitalised for mental illness and taking psychotropic medication. Smoking, alcohol use, minimal physical activity, and lack of primary health care were evident. While these behaviours are typical of many young people, those with mental illness have substantially increased vulnerability to poor health and reduced life expectancy. Priority needs to be given to targeted health promotion strategies for young people with mental illness to modify their risky long-term health behaviours and improve morbidity and mortality outcomes. Nurses in mental health settings play a vital role in promoting young peoples' well-being and preventing poorer physical health outcomes. Implementation of a cardiometabolic health nurse role in inpatient settings for young people with mental illness could facilitate prevention and early intervention for health risk behaviours. PMID- 26514257 TI - Psychiatric Nursing in Integrated Wards Accommodating Both Female and Male Patients: A Historic Pioneering Reform Initiative Implemented by the Institute of Psychiatry, a Unit of the Federal University of Rio De Janeiro, Brazil. AB - The purpose of this research is to analyze aspects of the sexuality of people with mental disorders, an issue that influenced nursing care in the mixed nursing wards of the Institute of Psychiatry at the Federal University of Rio de Janeiro between 1996-2002. A qualitative Historical Social Study methodology used written and oral texts that were analyzed drawing on Michel Foucault's ideas about sexuality. Results of the study indicate that a rupture occurred in the distribution model according to gender at the Psychiatric Hospitalization Unit. This, in turn, influenced nursing care. From this study, we conclude that accommodating patients in mixed wards better facilitates the psychosocial rehabilitation process and changes nursing teams' conceptions about the sexuality of people with mental disorders. PMID- 26514258 TI - The Recovery Knowledge Inventory for Measurement of Nursing Student Views on Recovery-oriented Mental Health Services. AB - Recovery-oriented services are a goal for policy and practice in the Australian mental health service system. Evidence-based reform requires an instrument to measure knowledge of recovery concepts. The Recovery Knowledge Inventory (RKI) was designed for this purpose, however, its suitability and validity for student health professionals has not been evaluated. The purpose of the current article is to report the psychometric features of the RKI for measuring nursing students' views on recovery. The RKI, a self-report measure, consists of four scales: (I) Roles and Responsibilities, (II) Non-Linearity of the Recovery Process, (III) Roles of Self-Definition and Peers, and (IV) Expectations Regarding Recovery. Confirmatory and exploratory factor analyses of the baseline data (n = 167) were applied to assess validity and reliability. Exploratory factor analyses generally replicated the item structure suggested by the three main scales, however more stringent analyses (confirmatory factor analysis) did not provide strong support for convergent validity. A refined RKI with 16 items had internal reliabilities of alpha = .75 for Roles and Responsibilities, alpha = .49 for Roles of Self Definition and Peers, and alpha = .72, for Recovery as Non-Linear Process. If the RKI is to be applied to nursing student populations, the conceptual underpinning of the instrument needs to be reworked, and new items should be generated to evaluate and improve scale validity and reliability. PMID- 26514259 TI - Challenges Highlighted During Peer Supervision by Mental Health Nurses and Social Workers Recently Trained as Case Managers in Sweden. AB - This study looked at 13 mental health nurses and social workers who were recently trained as case managers (CMs) and the work-related challenges they faced in community mental health services. Data were collected during ten peer supervisions sessions. Participants expressed pride and enthusiasm about their new function as CMs, but they also acknowledged that their new position meant they had to confront existing systems and posed several challenges, including organizational hindrances, economic prerequisites, nominated administrators, role function, and model fidelity. We conclude that the existing organizations seemed to be unprepared to hold and facilitate more person-centered approaches, such as designating CMs. The model fidelity is important, but has to be flexible according to clients' daily state. PMID- 26514260 TI - Nursing Leadership, Missing Questions, and the Elephant(s) in the Room: Problematizing the Discourse on Nursing Leadership. AB - To expose inconsistencies and contradictions in the nurse leadership literature ("text"), this article adopts a deconstructive approach and draws upon the work of Derrida in examining the text or discourse. What is almost entirely missing in the literature are articles that ask difficult, searching questions that challenge some of the taken-for-granted truths or maxims about nursing leadership. The current examination of the literature, described in this article, shows: (a) a lack of convergence of the literature and health care/nursing organizations concerning leadership, (b) a conflation of nursing leadership with managerial or administrative positions, and PMID- 26514261 TI - The Use of Acceptance to Promote Positive Change by Decreasing Shame and Guilt: A Practice Exemplar. AB - The use of acceptance by mental health clinicians in the clinical setting is an effective method for providing a safe environment for clients to make positive changes. Acceptance means that mental health clinicians are non-judgmental and acknowledge the clients' situations as they are. When actively used by clinicians, acceptance decreases clients' anxiety and the intensity of their feelings of guilt and shame. Clients are then able to begin to accept themselves as they are. The purpose of this article is to discuss the ways in which mental health clinicians promote clients' acceptance of themselves using the tools of acceptance and commitment therapy and dialectical behavioral therapy. PMID- 26514262 TI - Societal, Individual, and Illness Uncertainty. PMID- 26514263 TI - A Psychiatric Mental Health Nurse Practitioner Program: Meeting the Needs of the Community and Veterans as Students as Well as Care Recipients. AB - The goal of excellence in nursing education has led to efforts to recruit students into baccalaureate and graduate programs. Additionally, a need exists to prepare practitioners to meet the mental health needs of health care recipients, including veterans. As a strategy for meeting these objectives, educators from an urban private college proposed a Psychiatric Mental Health Nurse Practitioner (PMHNP) program. This program was developed in response to an identified need in the community for improved mental health services. Although several groups in need would be served, attention was focused on veterans in need of care as well as those veteran students interested in Psychiatric Mental Health (PMH) nursing. Some factors that supported this thinking included the proximity of the campus to the Veterans Administration Medical Center and other veteran community services, the college's significant number of student veterans, and its distinction as among the most veteran friendly campuses in the nation. This article reviews the literature that supports the need for graduate education in this specialty and the value of providing educational opportunities for interested veterans. PMID- 26514266 TI - Erratum. PMID- 26514264 TI - Clinical Psychopharmacology Update: Additional Safety Concerns for Using Varenicline (Chantix) for Smoking Cessation Treatment. AB - Smoking cessation remains a positive therapeutic goal and should be encouraged for the millions of individuals who continue to smoke and struggle to quit. While psychiatric nurses should encourage patients to start or continue smoking cessation therapies, they must be aware of the additional safety concerns relating to the use of varenicline (Chantix). Research published subsequent to the last clinical update in this journal (Tobin, 2007 ) has prompted additional warnings from the Food and Drug Administration concerning varenicline for smoking cessation therapy. In particular, clinicians need to be aware of increased concerns about varenicline's association with neuropsychiatric side effects, seizures, and alcohol interactions. PMID- 26514268 TI - DHN melanin biosynthesis in the plant pathogenic fungus Botrytis cinerea is based on two developmentally regulated key enzyme (PKS)-encoding genes. AB - Botrytis cinerea is the causal agent of gray mold disease in various plant species and produces grayish macroconidia and/or black sclerotia at the end of the infection cycle. It has been suggested that the pigmentation is due to the accumulation of 1,8-dihydroxynaphthalene (DHN) melanin. To unravel its basis and regulation, the putative melanogenic and regulatory genes were identified and functionally characterized. Unlike other DHN melanin-producing fungi, B. cinerea and other Leotiomycetes contain two key enzyme (PKS)-encoding enzymes. Bcpks12 and bcpks13 are developmentally regulated and are required for melanogenesis in sclerotia and conidia respectively. BcYGH1 converts the BcPKS13 product and contributes thereby to conidial melanogenesis. In contrast, enzymes acting downstream in conversion of the PKS products (BcBRN2, BcSCD1 and BcBRN1) are required for both, sclerotial and conidial melanogenesis, suggesting that DHN melanogenesis in B. cinerea follows a non-linear pathway that is rather unusual for secondary metabolic pathways. Regulation of the melanogenic genes involves three pathway-specific transcription factors (TFs) that are clustered with bcpks12 or bcpks13 and other developmental regulators such as light-responsive TFs. Melanogenic genes are dispensable in vegetative mycelia for proper growth and virulence. However, DHN melanin is considered to contribute to the longevity of the reproduction structures. PMID- 26514267 TI - Protein interactome mining defines melatonin MT1 receptors as integral component of presynaptic protein complexes of neurons. AB - In mammals, the hormone melatonin is mainly produced by the pineal gland with nocturnal peak levels. Its peripheral and central actions rely either on its intrinsic antioxidant properties or on binding to melatonin MT1 and MT2 receptors, belonging to the G protein-coupled receptor (GPCR) super-family. Melatonin has been reported to be involved in many functions of the central nervous system such as circadian rhythm regulation, neurotransmission, synaptic plasticity, memory, sleep, and also in Alzheimer's disease and depression. However, little is known about the subcellular localization of melatonin receptors and the molecular aspects involved in neuronal functions of melatonin. Identification of protein complexes associated with GPCRs has been shown to be a valid approach to improve our understanding of their function. By combining proteomic and genomic approaches we built an interactome of MT1 and MT2 receptors, which comprises 378 individual proteins. Among the proteins interacting with MT1 , but not with MT2 , we identified several presynaptic proteins, suggesting a potential role of MT1 in neurotransmission. Presynaptic localization of MT1 receptors in the hypothalamus, striatum, and cortex was confirmed by subcellular fractionation experiments and immunofluorescence microscopy. MT1 physically interacts with the voltage-gated calcium channel Cav 2.2 and inhibits Cav 2.2-promoted Ca(2+) entry in an agonist-independent manner. In conclusion, we show that MT1 is part of the presynaptic protein network and negatively regulates Cav 2.2 activity, providing a first hint for potential synaptic functions of MT1. PMID- 26514269 TI - Neural cells play an inhibitory role in pancreatic differentiation of pluripotent stem cells. AB - Pancreatic endocrine beta-cells derived from embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have received attention as screening systems for therapeutic drugs and as the basis for cell-based therapies. Here, we used a 12-day beta-cell differentiation protocol for mouse ES cells and obtained several hit compounds that promoted beta-cell differentiation. One of these compounds, mycophenolic acid (MPA), effectively promoted ES cell differentiation with a concomitant reduction of neuronal cells. The existence of neural cell-derived inhibitory humoral factors for beta-cell differentiation was suggested using a co culture system. Based on gene array analysis, we focused on the Wnt/beta-catenin pathway and showed that the Wnt pathway inhibitor reversed MPA-induced beta-cell differentiation. Wnt pathway activation promoted beta-cell differentiation also in human iPS cells. Our results showed that Wnt signaling activation positively regulates beta-cell differentiation, and represent a downstream target of the neural inhibitory factor. PMID- 26514270 TI - Clinical parameters predicting development of pulmonary malignancies in patients treated for head and neck squamous cell carcinoma. AB - BACKGROUND: As the locoregional control rates in head and neck squamous cell carcinoma (HNSCC) have increased, these patients may suffer distant metastasis in a higher proportion of cases. Clinicopathological characteristics allowing prediction of high-risk profile would allow adapting posttreatment surveillance to individual risk. METHODS: A retrospective review of all patients with HNSCC treated at the Jewish General Hospital, McGill University, Montreal, Quebec, Canada, between 1999 and 2008 was conducted for this study. RESULTS: The study included 428 patients with a mean follow-up of 65 months (+/-SEM 1.7). Eighty patients (18.6%) developed pulmonary malignancy during follow-up. In multivariate Cox-regression analysis, locoregional failure and current smoking were associated with higher risk of pulmonary malignancy (p < .001 and p = .008, respectively). CONCLUSION: Locoregional failure and smoking persistence are predictors of pulmonary malignancy in patients with HNSCC. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1277-E1280, 2016. PMID- 26514272 TI - Hepatitis E-induced severe myositis. AB - INTRODUCTION: Hepatitis E virus (HEV) is endemic in Asian and African countries but is rarely reported in Western countries. Although there are some prominent neurological manifestations, HEV is rarely recognized by neurologists. METHODS: This is a case report of myositis induced by HEV. RESULTS: We report the life threatening case of a 57-year-old man with flaccid tetraparesis due to myositis, acute hepatitis, and renal failure caused by HEV infection. Muscle biopsy revealed scattered myofiber necrosis with a diffuse, mild lymphomonocytic infiltrate in the endomysium and perimysium. Because the patient suffered from an acute HEV infection with a rapidly progressive course of severe myopathy, we started ribavirin treatment. He recovered partially within 3 weeks and recovered fully within 6 months. CONCLUSION: This case highlights a neurological manifestation of endemic HEV infection with severe myositis in a patient with alcoholic chronic liver disease. Ribavirin treatment is effective in severe HEV infection and may also lead to rapid neurological recovery. PMID- 26514271 TI - Midgut of the non-hematophagous mosquito Toxorhynchites theobaldi (Diptera, Culicidae). AB - In most mosquito species, the females require a blood-feeding for complete egg development. However, in Toxorhynchites mosquitoes, the eggs develop without blood-feeding, and both females and males exclusively feed on sugary diets. The midgut is a well-understood organ in blood-feeding mosquitoes, but little is known about it in non-blood-feeding ones. In the present study, the detailed morphology of the midgut of Toxorhynchites theobaldi were investigated using histochemical and ultrastructural methods. The midgut of female and male T. theobaldi adults consists of a long, slender anterior midgut (AMG), and a short, dilated posterior midgut (PMG). The AMG is subdivided into AMG1 (short, with folds) and AMG2 (long, without folds). Nerve branches and enteroendocrine cells are present in AMG and PMG, respectively. Compared with the PMG of blood-feeding female mosquitoes, the PMG of T. theobaldi is smaller; however, in both mosquitoes, PMG seems be the main region of food digestion and absorption, and protein secretion. The epithelial folds present in the AMG of T. theobaldi have not been reported in other mosquitoes; however, the midgut muscle organization and endocrine control of the digestion process are conserved in both T. theobaldi and blood-feeding mosquitoes. PMID- 26514273 TI - Immobilization of ALA-Zn(II) Coordination Polymer Pro-photosensitizers on Magnetite Colloidal Supraparticles for Target Photodynamic Therapy of Bladder Cancer. AB - 5-Aminolevulinic acid (ALA) is a widely used photodynamic therapy (PDT) prodrug in the clinic. It can be metalized to the photosensitizer PpIX, which produces toxic singlet oxygen to kill cancer cells upon visible light irradiation. Herein, a core/shell-structured vehicle is designed to comprise magnetite colloidal supraparticles (MCSPs) as cores and ALA-Zn(II) coordination polymers as shells (Fe3O4@ALA-Zn(II) ) for target pro-photosensitizer delivery. The coordination polymers with 2D layered structures are locally deposited on the MCSPs by the complexation of the ALA and Zn(II) ions, and are readily controlled by varying the feed precursors and reaction temperatures. The maximum conjugated ALA amount is up to 17%. The Fe3O4@ALA-Zn(II) microspheres exhibit pH-sensitive release of ALA in acidic environment and rapid magnetic responsiveness. Cytotoxicity results demonstrate that Fe3O4@ALA-Zn(II) shows a significant inhibitory effect to T24 cells and is nontoxic to 293T normal cells as exposed to the 630 nm visible light for a very short time, which may due to the selective accumulation of ALA-induced PpIX in T24 cancer cells. Compared to the ALA used alone, the coordination polymer form is more efficient because of the bioactivity of incorporated Zn ions despite underlying the same apoptosis mechanism as ALA agent. PMID- 26514274 TI - Highly efficient organic light emitting diodes formed by solution processed red emitters with evaporated blue common layer structure. AB - We prepared highly-efficient solution-processed red phosphorescent organic light emitting diodes (PHOLEDs) with a blue common layer structure that can reasonably confine the triplet excitons inside of the red emission layer (EML) with the assistance of a bipolar exciton blocking layer. The red PHOLEDs containing EML with a 7 : 3 ratio of 11-(4,6-diphenyl-[1,3,5]triazin-2-yl)-12-phenyl-11,12 dihydro-11,12-diaza-indeno[2,1-a]fluorene (n-type host, NH) : 4-(3-(triphenylen-2 yl)phenyl)dibenzo[b,d]thiophene (p-type host, PH) doped with 5% Iridium(III) bis(2-(3,5-dimethylphenyl)quinolinato-N,C2')tetramethylheptadionate (Red Dopant, RD) produced the highest current and power efficiencies at 23.4 cd/A and 13.6 lm/W, with a 19% external quantum efficiency at 1000 cd/m(2). To the best of our knowledge, such efficiency was the best among those that have been obtained from solution-processed small molecular red PHOLEDs. In addition, the host molecules utilized in this study have no flexible spacers, such as an alkyl chain, which normally deteriorate the stability of the device. PMID- 26514275 TI - P73 and P63: The siblings that work together in neurodevelopment. PMID- 26514276 TI - Efficient Two-Photon Fluorescent Probe for Nitroreductase Detection and Hypoxia Imaging in Tumor Cells and Tissues. AB - Hypoxia plays an important role in tumor progression, and the development of efficient methods for monitoring hypoxic degree in living systems is of great biomedical importance. In the solid tumors, the nitroreductase level is directly corresponded with the hypoxic status. Many one-photon excited fluorescent probes have been developed for hypoxia imaging in tumor cells via the detection of nitroreductase level. However, two-photon excited probes are more suitable for bioimaging. In this work, a two-photon probe 1 for nitroreductase detection and hypoxic status monitoring in living tumor cells and tissues was reported for the first time. The detection is based on the fact that the nitro-group of probe 1 could be selectively reduced to an amino-group by nitroreductase in the presence of reduced NADH, following by a 1,6-rearrangement-elimination to release the fluorophore, resulting in the enhancement of fluorescence. The probe exhibited both one-photon and two-photon excited remarkable fluorescence enhancement (~70 fold) for nitroreductase, which afforded a high sensitivity for nitroreductase, with a detection limit of 20 ng/mL observed. Moreover, the applications of the probe for fluorescent bioimaging of hypoxia in living cells and two-photon bioimaging in tissues were carried out, with tissue-imaging depths of 70-160 MUm observed, which demonstrates its practical application in complex biosystems. PMID- 26514277 TI - Enhanced ethanol production via electrostatically accelerated fermentation of glucose using Saccharomyces cerevisiae. AB - The global demand for ethanol as an alternative fuel continues to rise. Advancement in all aspects of ethanol production is deemed beneficial to the ethanol industry. Traditional fermentation requires 50-70 hours to produce the maximum ethanol concentration of 7-8% (v/v). Here we demonstrate an electrostatic fermentation method that is capable of accelerating the fermentation of glucose using generic Saccharomyces cerevisiae as the fermenting microorganism to produce ethanol. The method, when applied to the batch fermentation of 1 liter fermenting mixture containing dry yeast without pre-culture, is able to achieve ethanol yield on the high gravity level (12.3% v/v) in 24 hours. The fermentation results in almost complete consumption of glucose. With pre-cultured yeast, ethanol yield can reach 14% v/v in 20 hours. The scale-up capability of the method is demonstrated with 2 liter fermenting mixture. The method does not consume external energy due to its electrostatic nature. Our results indicate the applicability of the fermentation technique to industry applications. PMID- 26514278 TI - Exploration of Quenching Pathways of Multiluminescent Acenes Using the GRRM Method with the SF-TDDFT Method. AB - The quenching pathways were investigated for three types of multiluminescent acene derivatives, which show environment-dependent fluorescence. Spin-flip time dependent density functional theory (SF-TDDFT) combined with the Global Reaction Route mapping (GRRM) strategy is employed to locate minimum-energy conical intersections (MECIs). The energies and geometries of the MECIs relative to the Franck-Condon (FC) state control the difference in fluorescence behavior among the three derivatives. For the molecule with a phenyamide moiety, a MECI with energy lower than the FC state with large geometrical change from V-type to flat structure provides an efficient internal conversion (quenching) pathway in solution. For the same molecule, in a solid, this large geometrical change is inhibited, and the second MECI, with an energy lower than FC but higher than the first MECI requiring only a small geometry change of CH out-of-plane bending, contributes to the quenching. The molecule with the napthaleneimide moiety has only one low-energy MECI that requires large geometrical change from the V-type to flat structure. Although this MECI provides the quenching pathway in solution, in the solid, this large motion is inhibited, and the molecule will stay in the excited state and emit. The molecule with an anthraceneimide moiety has no conical intersection lower than the FC state, and no quenching pathway is available in solution or solid. In addition, in this molecule, at the local minimum of the excited state, the dipole transition to the ground state is allowed, and this molecule prefers emission rather than internal conversion. PMID- 26514279 TI - Investigating the properties of PODIPYs (phosphorus-dipyrromethene) with ab initio tools. AB - We investigate with a hybrid SOS-CIS(D)/TD-DFT approach accounting for solvation effects, the structural, electronic and optical properties of recently-proposed PODIPY dyes. Being more soluble in water than the well-known BODIPYs, these new chromogens are particularly appealing, but their characterization remains very limited. It turns out that the selected theoretical protocol could reproduce the experimentally reported differences between PODIPY and BODIPY dyes. Based on this, we have investigated a large number of new PODIPY dyes and determined their theoretical 0-0 energies. PMID- 26514280 TI - Implementation of continuous-variable quantum key distribution with composable and one-sided-device-independent security against coherent attacks. AB - Secret communication over public channels is one of the central pillars of a modern information society. Using quantum key distribution this is achieved without relying on the hardness of mathematical problems, which might be compromised by improved algorithms or by future quantum computers. State-of-the art quantum key distribution requires composable security against coherent attacks for a finite number of distributed quantum states as well as robustness against implementation side channels. Here we present an implementation of continuous-variable quantum key distribution satisfying these requirements. Our implementation is based on the distribution of continuous-variable Einstein Podolsky-Rosen entangled light. It is one-sided device independent, which means the security of the generated key is independent of any memoryfree attacks on the remote detector. Since continuous-variable encoding is compatible with conventional optical communication technology, our work is a step towards practical implementations of quantum key distribution with state-of-the-art security based solely on telecom components. PMID- 26514281 TI - Fast-track video-assisted thoracoscopic surgery: future challenges. AB - OBJECTIVES: To provide a short overview of fast-track video-assisted thoracoscopic surgery (VATS) and to identify areas requiring further research. DESIGN: A literature search was made using key words including: fast-track, enhanced recovery, video-assisted thoracoscopic surgery, robot-assisted thoracoscopic surgery (RATS), robotic, thoracotomy, single-incision, uniportal, natural orifice transluminal endoscopic surgery (NOTES), chest tube, air-leak, digital drainage, pain management, analgesia, perioperative management, anaesthesia and non-intubated. References from articles were screened for further articles. Using abstracts, areas of interest for developing a fast-track protocol were selected. RESULTS: The minimally invasive approach can be divided into several surgical methods that need further research to establish superiority. The role of intubation has to be further examined as well as the role of chest drains. Multimodal analgesic treatment including preoperative methylprednisolone seems promising and requires further research. CONCLUSIONS: The fast-track data from other procedures may support future development and improvement of fast track VATS. PMID- 26514282 TI - Sexual and reproductive health in Greenland: evaluation of implementing sexual peer-to-peer education in Greenland (the SexInuk project). AB - BACKGROUND: For decades, the rates of sexually transmitted infections (STIs), such as gonorrhoea, chlamydia and syphilis, have increased in Greenland, especially within the young age groups (15-29 years). From 2006 to 2013, the number of abortions has been consistent with approximately 800-900 abortions per year in Greenland, which is nearly as high as the total number of births during the same period. Previous studies in Greenland have reported that knowledge about sexual health is important, both as prevention and as facilitator to stop the increasing rates of STIs. A peer-to-peer education programme about sexual health requires adaption to cultural values and acceptance among the population and government in order to be sustainable. OBJECTIVE: Formative evaluation of a voluntary project (SexInuk), in relation to peer-to-peer education with focus on sexual health. Two workshops were conducted in Nuuk, Greenland, to recruit Greenlandic students. DESIGN: Qualitative design with focus group interviews (FGIs) to collect qualitative feedback on feasibility and implementation of the project. Supplemented with a brief questionnaire regarding personal information (gender, age, education) and questions about the educational elements in the SexInuk project. Eight Greenlandic students, who had completed one or two workshops, were enrolled. RESULTS: The FGIs showed an overall consensus regarding the need for improving sexual health education in Greenland. The participants requested more voluntary educators, to secure sustainability. The articulation of taboo topics in the Greenlandic society appeared very important. The participants suggested more awareness by promoting the project. CONCLUSIONS: Cultural values and language directions were important elements in the FGIs. To our knowledge, voluntary work regarding peer-to-peer education and sexual health has not been structurally evaluated in Greenland before. To achieve sustainability, the project needs educators and financial support. Further research is needed to investigate how peer-to-peer education can improve sexual and reproductive health in Greenland. PMID- 26514283 TI - Surgery time interval and molecular subtype may influence Ki67 change after core needle biopsy in breast cancer patients. AB - BACKGROUND: To investigate the accuracy of core needle biopsy (CNB) in evaluating breast cancer estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 status and to identify factors which might be associated with Ki67 value change after CNB. METHODS: A retrospective study was carried out on 276 patients with paired CNB and surgically removed samples (SRS). Clinico-pathological factors as well as the surgery time interval (STI) between CNB and surgery were analyzed to determine whether there were factors associated with Ki67 value change after CNB. Five tumor subtypes were classified as follows: Luminal A, Luminal B-HER2-, Luminal B-HER2+, Triple Negative (TN), and HER2+. Ki67 value change was calculated as SRS minus CNB. RESULTS: Mean STI after CNB was 4.5 (1-37) days. Good agreement was achieved for ER, PR, and HER2 evaluation between CNB and SRS. However, Ki67 expression level was significantly higher in SRS compared with CNB samples: 29.1 % vs. 26.2 % (P < 0.001). Both univariate and multivariate analysis demonstrated that STI and molecular subtype were associated with a Ki67 change after CNB. Luminal A tumors experienced more Ki67 elevation than Luminal B-HER2- diseases (6.2 % vs -0.1 %, P = 0.014). Patients with longer STI after CNB had a higher Ki67 increase: -1.1 % within 1-2 days, 2.1 % with 3-4 days, and 5.6 % more than 4 days, respectively (P = 0.007). For TN and HER2+ tumors, the Ki67 change was apt to be 0 with STI <= 4 days, while a >7 % Ki67 increase was noticed in patients with STI >= 5 days. CONCLUSION: CNB was accurate in evaluating ER, PR, HER2, and molecular subtype status. Ki67 value significantly increased after CNB, which was associated with STI and molecular subtype. Further translational research needs to consider Ki67 changes following CNB among different breast cancer molecular subtypes. PMID- 26514284 TI - A Pilot Study of Seeking Safety in a Sample of German Women Outpatients with Substance Dependence and Posttraumatic Stress Disorder. AB - Seeking Safety is an integrated coping skills therapy for substance use disorder (SUD) and posttraumatic stress disorder (PTSD). Our aim was to examine the effects of Seeking Safety in a sample of female German outpatients with current SUD and PTSD. A total of 53 women were offered 12 weekly sessions of Seeking Safety, conducted in group modality. Women (N=33) who attended at least six sessions were considered minimum-dose completers and were in the analysis. We measured PTSD and substance use symptoms using the Posttraumatic Diagnostic Scale (PDS) and the Addiction Severity Index (ASI-Lite) at end-of-treatment and three month follow-up. Additional measures were the Brief Symptom Checklist (BSI) and the Inventory of Interpersonal Problems (IIP-25). Our sample reported chronic SUD, multiple prior detoxifications, and serious childhood trauma. We found medium to large effect sizes for improvements in PTSD symptoms, general psychopathology, and interpersonal problems at end-of-treatment, all of which were sustained at follow-up. Alcohol use improved significantly only at follow up. This study suggests that the model was associated with positive effects, at least in a subgroup of women attending a minimum of sessions. Limitations include the lack of a control condition as well as an intention-to-treat analysis. PMID- 26514286 TI - Splanchnic Hemodynamics and Intestinal Vascularity in Crohn's Disease: An In Vivo Evaluation Using Doppler and Contrast-Enhanced Ultrasound and Biochemical Parameters. AB - Crohn's disease (CD) is characterized by inflammation and angiogenesis of affected bowel. We evaluated the correlation among vascularity of intestinal wall in CD, splanchnic hemodynamics, clinical activity and biochemical parameters of inflammation and angiogenesis. Sixteen patients with ileal CD and 10 healthy controls were investigated by means of Doppler ultrasound of the superior mesenteric artery and color Doppler and contrast-enhanced ultrasound of the ileal wall. In parallel, serum levels of vascular endothelial growth factor, tumor necrosis factor-alpha (TNF-alpha) and nitric oxide, before and 30 min after a standard meal, were evaluated. In CD patients, there was a significant post prandial reduction in the resistance index and pulsatility index of the superior mesenteric artery, associated with increased levels of nitric oxide and decreased amounts of TNF-alpha. A correlation was observed between vascular endothelial growth factor and contrast-enhanced ultrasound parameters of intestinal wall vascularity (r = 0.63-0.71, p < 0.05) and between these parameters and superior mesenteric artery blood flow after fasting (resistance and pulsatility indexes: r = -0.64 and -0.72, p < 0.05). Our results revealed a post-prandial increase in nitric oxide and decrease in TNF-alpha in CD patients in vivo. They also confirm the role of vascular endothelial growth factor in angiogenesis and in pathologic vascular remodeling of CD and its effect on splanchnic blood flow. PMID- 26514287 TI - High and Low Trait Anger, Angry Thoughts, and the Recognition of Anger Problems. AB - This research had two goals: (1) it tested hypotheses of the State-Trait Model of anger, and (2) it explored characteristics that may distinguish individuals with high trait anger who recognize problems with their anger from those who do not recognize anger problems. Regarding the first goal, findings supported three hypotheses tested. In particular, compared to those low in trait anger, individuals with high trait anger reported: (a) more intense anger (intensity hypothesis), p < .001, effect size (eta(2)) = .109; (b) more thoughts involving pejorative labeling/denigration, p < .001, eta(2) = .280, thoughts of revenge, p < .001, eta(2) = .170, more outward, negative anger expression (anger-out), p < .001, eta(2) = .229, and more physically aggressive expression, p < .001, eta(2) = .046-.123, (aggression hypothesis); and (c) more anger suppression (anger-in), p < .001, eta(2) = .231, and fewer thoughts of self-control, p < .001, eta(2) = .088, and behavioral efforts to control angry feelings (anger control-in), p < .001, eta(2) = .116, and behavior (anger control-out), p < .001, eta(2) = .260 (reduced positive coping hypothesis). For the second goal we employed two types of individuals, both with high trait anger: those who identified anger as a personal problem and wanted help, and those who did not identify anger as a personal issue. As a result, compared to those who did not report anger problems, those who reported anger problems demonstrated a higher overall propensity to experience anger (i.e., higher trait anger), p < .01, eta(2) = .028, greater anger suppression and harboring grudges (anger-in), p < .001, eta(2) = .035, fewer thoughts of self-control, p < .05, eta(2) = .015, and attempts to control their angry feelings (anger-control-in), p < .05, eta(2) = .016, and behavior (anger-control-out), p < .001, eta(2) = .054. Gender was not associated with trait anger or anger problem recognition. Findings were discussed in terms of State-Trait Theory and implications for anger interventions. PMID- 26514285 TI - Coherent Raman Scattering Microscopy in Biology and Medicine. AB - Advancements in coherent Raman scattering (CRS) microscopy have enabled label free visualization and analysis of functional, endogenous biomolecules in living systems. When compared with spontaneous Raman microscopy, a key advantage of CRS microscopy is the dramatic improvement in imaging speed, which gives rise to real time vibrational imaging of live biological samples. Using molecular vibrational signatures, recently developed hyperspectral CRS microscopy has improved the readout of chemical information available from CRS images. In this article, we review recent achievements in CRS microscopy, focusing on the theory of the CRS signal-to-noise ratio, imaging speed, technical developments, and applications of CRS imaging in bioscience and clinical settings. In addition, we present possible future directions that the use of this technology may take. PMID- 26514288 TI - Arterial input function and gray matter cerebral blood volume measurements in children. AB - PURPOSE: To investigate how arterial input functions (AIFs) vary with age in children and compare the use of individual and population AIFs for calculating gray matter CBV values. Quantitative measures of cerebral blood volume (CBV) using dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) require measurement of an AIF. AIFs are affected by numerous factors including patient age. Few data presenting AIFs in the pediatric population exists. MATERIALS AND METHODS: Twenty-two previously treated pediatric brain tumor patients (mean age, 6.3 years; range, 2.0-15.3 years) underwent DSC-MRI scans on a 3T MRI scanner over 36 visits. AIFs were measured in the middle cerebral artery. A functional form of an adult population AIF was fitted to each AIF to obtain parameters reflecting AIF shape. The relationship between parameters and age was assessed. Correlations between gray matter CBV values calculated using the resulting population and individual patient AIFs were explored. RESULTS: There was a large variation in individual patient AIFs but correlations between AIF shape and age were observed. The center (r = 0.596, P < 0.001) and width of the first-pass peak (r = 0.441, P = 0.007) were found to correlate significantly with age. Intrapatient coefficients of variation were significantly lower than interpatient values for all parameters (P < 0.001). Differences in CBV values calculated with an overall population and age-specific population AIF compared to those calculated with individual AIFs were 31.3% and 31.0%, respectively. CONCLUSION: Parameters describing AIF shape correlate with patient age in line with expected changes in cardiac output. In pediatric DSC-MRI studies individual patient AIFs are recommended. PMID- 26514289 TI - Glycemic index and microstructure analysis of a newly developed fiber enriched cookie. AB - A diet with a high glycemic index (GI) is associated with an elevated risk for obesity or type 2 diabetes. We investigated the GI of a newly-developed fiber enriched cookie and characterized the microstructure of ingredients used. In a study with 26 non-diabetic healthy volunteers it was shown that the fiber enriched cookie has a GI of 58.9 in relation to white bread as reference. Using a conversion factor of 1.4, the GI of the fiber enriched cookie in relation to a glucose-solution is 42.0 and can be classified as a low-GI food. Postprandial insulin concentration was significantly lower after consumption of fiber enriched cookies compared to white bread. Glucose release after in vitro digestion was significantly lower from fiber enriched cookies compared to other cookies tested. In addition to its high percentage of fiber, the cookies' low GI can be attributed to the limited gelatinization potential of the starch granules found in the ingredients used. Using confocal laser scanning microscopy it is shown that starch granule surface area of whole grain barley flour, spelt flour and oat flakes bears cluster-shaped protein-NSPS complexes that preferentially absorb water in conditions of water shortage and thereby prevent starch gelatinization. PMID- 26514290 TI - Breaking-up sedentary time is associated with impairment in activities of daily living. PMID- 26514291 TI - Comparison of three remote radiolabelling methods for long-circulating liposomes. AB - Long-circulating liposomes (LCL) are often used as a drug carrier system to improve the therapeutic index of water-soluble drugs. To track these LCL in vivo, they can be radiolabelled with (111)In-oxine. For this labelling method, generally DTPA is encapsulated in the aqueous phase of LCL (DTPA-LCL). Alternatively, LCL can be labelled with (111)InCl3 after incorporation of DTPA conjugated DSPE in the lipid bilayer (DTPA-DSPE LCL). Here, we compared the in vitro properties of DTPA-DSPE LCL with those of DTPA LCL and empty LCL. Additionally, we compared the in vivo performance of DTPA-DSPE LCL with those of DTPA LCL in mice. DTPA LCL (88 nm) and empty LCL (84 nm) were labelled with (111)In-oxine, and DTPA-DSPE LCL (83 nm) were labelled with (111)InCl3. Labelling efficiency at increasing specific activity was determined. In vitro stability of (111)In-labelled LCL was determined in human serum at 37 degrees C. The in vivo properties of (111)In-labelled LCL were determined in mice with a Staphylococcus aureus infection in the thigh muscle. Image acquisition, blood sampling and biodistribution studies were performed 1, 4 (blood sampling only), 24, 48 and 72 h p.i. of (111)In-labelled LCL. DTPA-DSPE LCL could be labelled efficiently at a much higher specific activity compared to DTPA LCL and empty LCL: > 90% at 15 GBq/mmol, > 90% at 150 MBq/mmol and 60-65% at 150 MBq/mmol, respectively. (111)In labelled DTPA-DSPE LCL and DTPA LCL were stable in human serum, regarding label retention, for at least 48 h at 37 degrees C (> 98% retention of the radiolabel). In contrast, only 68% radiolabel was retained in empty LCL after 48 h. In vivo targeting of (111)In-DTPA-DSPE LCL to the abscess was comparable to targeting of (111)In-DTPA LCL (3.5 +/- 0.9%ID/g and 3.4 +/- 0.9%ID/g abscess uptake respectively, 48 h p.i.). In conclusion, labelling of DTPA-DSPE LCL with (111)InCl3 represents a robust, easy and fast procedure which is preferred over the more laborious conventional labelling of DTPA-LCL with (111)In-oxine. PMID- 26514292 TI - Enzyme-triggered, cell penetrating peptide-mediated delivery of anti-tumor agents. AB - Conventional chemotherapy has little or no specificity for cancer cells, normally resulting in low drug accumulation at the tumor region (inefficacy) and drug induced severe side effects (toxicity). Nowadays, new strategies have been developed to improve both the targeting ability and cellular drug uptake using active targeting ligands and drug internalization agents, which could recognize and interact with specific receptors overexpressed on tumor cells and then trigger a drug internalization process by transporting the cargos into cells. Among those strategies, enzyme-triggered cell penetrating peptide (CPP)-mediated systems seem to be a feasible approach. The expression level of specific enzymes like proteases, esterases or glycosidases is often higher in tumor cells than in normal tissues, and such concentration gradients can be exploited as a tool for targeted cancer therapy. CPPs are known to be effective in promoting membrane transportation of the drug cargos, rendering a deeper tumor permeation that could further enhance the therapeutic efficacy of the delivered drug. An enzyme triggered, CPP-mediated system would combine these advantages to yield a system with the enhanced tumor targeting ability and internalization efficiency and so far many systems have been successfully exploited and applied to cancer therapy. In this review, typical enzymes applied in cancer theranostic systems were firstly reviewed, followed by analyzing pros and cons of cell penetrating peptides. Most importantly, different types of applications of enzyme-triggered CPP-mediated systems in tumor imaging were illustrated. Finally, the drug loaded applications, i.e. enzyme-triggered CPP-mediated systems in drug delivery were reviewed. PMID- 26514293 TI - Rumination and Moderators of Multifinality: Predicting Internalizing Symptoms and Alcohol Use During Adolescence. AB - Rumination, a perseverative cognitive process that involves repetitively and passively focusing on negative emotions, is a transdiagnostic risk factor for the development of psychopathology. Although rumination has been linked to various forms of psychopathology including depression, anxiety, and alcohol misuse, little is known about the conditions that lead to multifinality. Here, we test putative moderators (Nolen-Hoeksema & Watkins, 2011) of the association between rumination and subsequent internalizing symptoms and frequency of alcohol use during adolescence. Participants included 388 youth (52% girls; 90% Caucasian) in a longitudinal birth cohort study who completed questionnaires in Grades 9 and 11. Brooding, a maladaptive form of rumination measured in Grade 9, was associated with greater internalizing symptoms in Grade 11 and greater perceived peer rejection in Grade 9 amplified this association. Brooding was also associated with greater frequency of alcohol use among adolescents who reported having more friends who use alcohol. Gender differences were also examined. Findings provide support for some of the predictions regarding moderators of multifinality made by Nolen-Hoeksema and Watkins. Implications of understanding divergent trajectories in the prevention of psychopathology are discussed. PMID- 26514294 TI - Stimulus-driven changes in the direction of neural priming during visual word recognition. AB - Visual object recognition is generally known to be facilitated when targets are preceded by the same or relevant stimuli. For written words, however, the beneficial effect of priming can be reversed when primes and targets share initial syllables (e.g., "boca" and "bono"). Using fMRI, the present study explored neuroanatomical correlates of this negative syllabic priming. In each trial, participants made semantic judgment about a centrally presented target, which was preceded by a masked prime flashed either to the left or right visual field. We observed that the inhibitory priming during reading was associated with a left-lateralized effect of repetition enhancement in the inferior frontal gyrus (IFG), rather than repetition suppression in the ventral visual region previously associated with facilitatory behavioral priming. We further performed a second fMRI experiment using a classical whole-word repetition priming paradigm with the same hemifield procedure and task instruction, and obtained well-known effects of repetition suppression in the left occipito-temporal cortex. These results therefore suggest that the left IFG constitutes a fast word processing system distinct from the posterior visual word-form system and that the directions of repetition effects can change with intrinsic properties of stimuli even when participants' cognitive and attentional states are kept constant. PMID- 26514295 TI - Neural substrates of shared attention as social memory: A hyperscanning functional magnetic resonance imaging study. AB - During a dyadic social interaction, two individuals can share visual attention through gaze, directed to each other (mutual gaze) or to a third person or an object (joint attention). Shared attention is fundamental to dyadic face-to-face interaction, but how attention is shared, retained, and neutrally represented in a pair-specific manner has not been well studied. Here, we conducted a two-day hyperscanning functional magnetic resonance imaging study in which pairs of participants performed a real-time mutual gaze task followed by a joint attention task on the first day, and mutual gaze tasks several days later. The joint attention task enhanced eye-blink synchronization, which is believed to be a behavioral index of shared attention. When the same participant pairs underwent mutual gaze without joint attention on the second day, enhanced eye-blink synchronization persisted, and this was positively correlated with inter individual neural synchronization within the right inferior frontal gyrus. Neural synchronization was also positively correlated with enhanced eye-blink synchronization during the previous joint attention task session. Consistent with the Hebbian association hypothesis, the right inferior frontal gyrus had been activated both by initiating and responding to joint attention. These results indicate that shared attention is represented and retained by pair-specific neural synchronization that cannot be reduced to the individual level. PMID- 26514296 TI - Effects of Neck-Specific Exercises Compared to Waiting List for Individuals With Chronic Whiplash-Associated Disorders: A Prospective, Randomized Controlled Study. AB - OBJECTIVE: To determine whether 3 months of neck-specific exercises (NSEs) could benefit individuals with chronic whiplash-associated disorder (WAD) who were on a waiting list (WL) for treatment. DESIGN: A prospective, randomized controlled study. SETTING: Primary health care. PARTICIPANTS: Individuals (N=41; 31 women, 10 men; mean age +/- SD, 38+/-11.2y) with chronic (6-36mo) WAD, grades 2 and 3, were analyzed. INTERVENTIONS: Patients were randomly assigned to NSEs or no treatment for 3 months. MAIN OUTCOME MEASURES: Neck-specific disability (Neck Disability Index [NDI]), neck pain (visual analog scale), general pain-related disability (Pain Disability Index [PDI]), self-perceived performance ability (Self-Efficacy Scale [SES]), and health-related quality of life (EuroQol 5 dimensions [EQ-5D]) were measured. RESULTS: NSEs significantly improved the NDI, SES, and EQ-5D compared with WL (P<.01). There was significant improvement (P<.0001) over time in all outcomes for NSEs, and apart from the PDI, significant worsening (P=.002-.0002) over time for the untreated group. CONCLUSIONS: NSEs were more beneficial than no intervention while on a WL for individuals with chronic WAD. PMID- 26514297 TI - Tricin, flavonoid from Njavara reduces inflammatory responses in hPBMCs by modulating the p38MAPK and PI3K/Akt pathways and prevents inflammation associated endothelial dysfunction in HUVECs. AB - Previous studies revealed the potent anti-inflammatory activity of tricin, the active component of Njavara rice bran. Here, we report the involvement of specific signaling pathways in the protective effect of tricin against LPS induced inflammation in hPBMCs and the role of tricin in modulating endothelial dysfunction in LPS induced HUVECs. Pretreatment with tricin (15MUM) significantly inhibited the release of TNF-alpha and was comparable to the specific pathway blockers like ERK inhibitor (PD98059), JNK inhibitor (SP600125) and p38 inhibitor (SB203580), whereas an increased release of TNF-alpha was observed in PI3K/Akt inhibitor (LY294002) treated cells. Tricin alone and combination treatment of tricin and SB203580 showed more significant inhibition of activation of COX-2 and TNF-alpha than that of SB203580 alone treated group. Combination treatment of tricin and LY294002 showed increased activation of COX-2 and TNF-alpha, proved that PI3K activation is essential for the anti-inflammatory effect of tricin. Studies conducted on HUVECs revealed the protective effect of tricin against endothelial dysfunction associated with LPS induced inflammation by inhibiting the activation of proinflammatory mediators like TNF-alpha, IFN-gamma, MCP 1 by modulating NF-kappaB and MAPK signaling pathways. ELISA and flow cytometric analysis again confirmed the protection of tricin against endothelial damage, especially from the decreased activation of cell adhesion molecules like ICAM-1, VCAM-1 and E-Selectin upon tricin treatment. This work establishes the mechanism behind the potent anti-inflammatory activity of the flavonoid tricin. PMID- 26514298 TI - NLRP12 is a neutrophil-specific, negative regulator of in vitro cell migration but does not modulate LPS- or infection-induced NF-kappaB or ERK signalling. AB - NOD-like receptors (NLR) are a family of cytosolic pattern recognition receptors that include many key drivers of innate immune responses. NLRP12 is an emerging member of the NLR family that is closely related to the well-known inflammasome scaffold, NLRP3. Since its discovery, various functions have been proposed for NLRP12, including the positive regulation of dendritic cell (DC) and neutrophil migration and the inhibition of NF-kappaB and ERK signalling in DC and macrophages. We show here that NLRP12 is poorly expressed in murine macrophages and DC, but is strongly expressed in neutrophils. Using myeloid cells from WT and Nlrp12(-/)(-) mice, we show that, contrary to previous reports, NLRP12 does not suppress LPS- or infection-induced NF-kappaB or ERK activation in myeloid cells, and is not required for DC migration in vitro. Surprisingly, we found that Nlrp12 deficiency caused increased rather than decreased neutrophil migration towards the chemokine CXCL1 and the neutrophil parasite Leishmania major, revealing NLRP12 as a negative regulator of directed neutrophil migration under these conditions. PMID- 26514300 TI - Oleanolic acid ameliorates dextran sodium sulfate-induced colitis in mice by restoring the balance of Th17/Treg cells and inhibiting NF-kappaB signaling pathway. AB - In a preliminary experiment, it was found that oleanolic acid (OA), which is widely distributed in food and medicinal plants, inhibited interleukin (IL) 6/tumor growth factor beta-induced differentiation of splenic T cells into Th17 cells. Moreover, OA induced the differentiation of splenic T cells into Treg cells. Therefore, we examined the anti-inflammatory effect of OA in mice with dextran sodium sulfate (DSS)-induced colitis. Oral administration of OA significantly inhibited DSS-induced colon shortening, macroscopic score, and myeloperoxidase activity. Treatment with OA inhibited DSS-induced differentiation to Th17 cells and downregulated the expression of RORgammat and IL-17 in the lamina propria of colon and Treg cell differentiation and Foxp3 and IL-10 expression were increased. OA treatment increased the DSS-suppressed expression of tight junction proteins such as ZO-1, occludin, and claudin-1 in the colon. Moreover, OA treatment inhibited DSS-induced expression of tumor necrosis factor alpha, interleukin (IL)-1beta, and IL-17, the activation of NF-kappaB and mitogen activated protein kinases, and increased IL-10 expression. OA also inhibited the activation of NF-kappaB and expression of proinflammatory cytokines in LPS stimulated peritoneal macrophages. These findings suggest that OA may ameliorate inflammatory diseases such as colitis by inhibiting Th17 cell differentiation and increasing Treg cell differentiation. PMID- 26514299 TI - Tracking the flow of hippocampal computation: Pattern separation, pattern completion, and attractor dynamics. AB - Classic computational theories of the mnemonic functions of the hippocampus ascribe the processes of pattern separation to the dentate gyrus (DG) and pattern completion to the CA3 region. Until the last decade, the large majority of single unit studies of the hippocampus in behaving animals were from the CA1 region. The lack of data from the DG, CA3, and the entorhinal inputs to the hippocampus severely hampered the ability to test these theories with neurophysiological techniques. The past ten years have seen a major increase in the recordings from the CA3 region and the medial entorhinal cortex (MEC), with an increasing (but still limited) number of experiments from the lateral entorhinal cortex (LEC) and DG. This paper reviews a series of studies in a local-global cue mismatch (double rotation) experiment in which recordings were made from cells in the anterior thalamus, MEC, LEC, DG, CA3, and CA1 regions. Compared to the standard cue environment, the change in the DG representation of the cue-mismatch environment was greater than the changes in its entorhinal inputs, providing support for the theory of pattern separation in the DG. In contrast, the change in the CA3 representation of the cue-mismatch environment was less than the changes in its entorhinal and DG inputs, providing support for a pattern completion/error correction function of CA3. The results are interpreted in terms of continuous attractor network models of the hippocampus and the relationship of these models to pattern separation and pattern completion theories. Whereas DG may perform an automatic pattern separation function, the attractor dynamics of CA3 allow it to perform a pattern separation or pattern completion function, depending on the nature of its inputs and the relative strength of the internal attractor dynamics. PMID- 26514301 TI - Impact of Free Thyroxine on the Outcomes of Left Atrial Ablation Procedures. AB - The prevalence of atrial fibrillation (AF) is increased in hyperthyroidism. The degree to which thyroid hormones affect the outcomes of left atrial (LA) ablation is still unclear. From September 2010 to September 2013, 1,095 patients who underwent LA ablation (59.7% paroxysmal AF, 32.3% persistent AF, and 8.0% LA tachycardia) had their serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels measured in the 48 hours before the procedure. Patients were followed until they presented the first AF relapse after a blanking period of 3 months. TSH and FT4 were assessed as predictors of arrhythmia relapse and were adjusted for possible confounders. During a mean follow-up of 12.5 +/- 7.9 months, 28.9% of patients presented an atrial arrhythmia relapse. TSH was not a predictor of relapse. In contrast, after adjustment, FT4 (median = 11.8 ng/L and interquartile range 10.6 to 14.6 ng/L) remained a predictor of relapse with 15% increase per quartile (hazard ratio 1.15, 95% confidence interval 1.03 to 1.29, p = 0.014). In conclusion, FT4 levels influence the success rate of LA ablation procedures, even when in the normal range. PMID- 26514302 TI - Influence of Gender on the Tolerability, Safety, and Efficacy of Quinidine Used for Treatment of Supraventricular and Ventricular Arrhythmias. AB - Quinidine, a class IA antiarrhythmic drug (AAD), has been used for the treatment of arrhythmias since the early 1900s. Use has decreased recently because of the availability of newer AADs and concerns about side effects and safety. Quinidine can cause QT prolongation, and women have longer QT intervals and are more susceptible to torsades de pointes (TdP) than are men. We sought to evaluate the influence of gender on quinidine tolerability, safety, and efficacy. We performed retrospective analyses of patients at our institution prescribed quinidine as an AAD between 2000 and 2012. Time to quinidine discontinuation and arrhythmia recurrence were evaluated using Cox proportional hazards models. In 179 patients, 23.5% were women and median age was 65.8 years. Quinidine indication was supraventricular arrhythmias in 68.7% and ventricular arrhythmias in 27.9% of patients. At 3 years after quinidine initiation, Kaplan-Meier probability of quinidine discontinuation was 65.7% for men and 82.4% for women (p = 0.015). Women were more likely than men to discontinue quinidine for QT prolongation (14.3 vs 4.4%, p = 0.036) and TdP (4.8 vs 0%, p = 0.054). After multivariate adjustment, female gender remained independently associated with quinidine discontinuation (adjusted hazard ratio 1.97, p = 0.014). Gender had no influence on arrhythmia recurrence: 1 year after quinidine initiation, Kaplan-Meier probability of freedom from recurrent arrhythmia was 62.4% in men and 57.9% in women (p = 0.33). Quinidine is highly effective in both genders. However, women are more likely than men to experience QT prolongation and TdP on quinidine and are more likely to discontinue quinidine independent of these side effects. PMID- 26514303 TI - Antihypertensive therapy increases natural immunity response in hypertensive patients. AB - AIMS: The aim of this work was to evaluate the effects of treatment of hypertension on the autoantibodies to apolipoprotein B-derived peptides (anti ApoB-D peptide Abs) response, inflammation markers and vascular function. MAIN METHODS: Eighty-eight patients with hypertension (stage 1 or 2) were recruited and advised to receive perindopril (4mg), hydrochlorothiazide (25mg), or indapamide (1.5mg) for 12weeks in a blinded fashion. Office and 24-h ambulatory blood pressure monitoring (24h ABPM), flow-mediated dilatation (FMD), nitrate induced dilatation (NID), titers of IgG and IgM anti-ApoB-D peptide Abs, hsCRP, and interleukins (IL-8 and IL-10) were evaluated at baseline and 12weeks after therapies. KEY FINDINGS: All treatments reduced office BP, and improved FMD (P<0.05 vs. baseline). The NID was improved only in the perindopril arm (P<0.05 vs. baseline). The 24h-ABPM was reduced with perindopril and hydrochlorothiazide therapies (P<0.05 vs. baseline), but not with indapamide, and this effect was followed by increase in titers of IgM Anti-ApoB-D peptide Abs (P<0.05 vs. baseline), without modifications in titers IgG Anti-ApoB-D peptide Abs and interleukins. Multivariable regression analysis has shown that change in the titers of IgM anti-ApoB-D peptide was associated with the changes in FMD (beta 0.347; P<0.05). SIGNIFICANCE: These findings shed light to a possible modulator effect of the antihypertensive therapy on the natural immunity responses and vascular function. PMID- 26514305 TI - Radiation-induced hyperproliferation of intestinal crypts results in elevated genome instability with inactive p53-related genomic surveillance. AB - AIMS: Radiation-induced hyperproliferation of intestinal crypts is well documented, but its potential tumorigenic effects remain elusive. Here we aim to determine the genomic surveillance process during crypt hyperproliferation, and its consequential outcome after ionizing radiation. MAIN METHODS: Crypt regeneration in the intestine was induced by a single dose of 12Gy abdominal irradiation. gamma-H2AX, 53BP1 and DNA-PKcs were used as DNA repair surrogates to investigate the inherent ability of intestinal crypt cells to recognize and repair double-strand breaks. Ki67 staining and the 5-bromo-2'-deoxyuridine incorporation assay were used to study patterns of cell proliferation in regenerating crypts. Staining for ATM, p53, Chk1 and Chk2 was performed to study checkpoint activation and release. Apoptosis was evaluated through H&E staining and terminal deoxynucleotidyl transferase (dUTP) nick-end labeling. KEY FINDINGS: The ATM-p53 pathway was immediately activated after irradiation. A second wave of DSBs in crypt cells was observed in regenerating crypts, accompanied with significantly increased chromosomal bridges. The p53-related genomic surveillance pathway was not active during the regeneration phase despite DSBs and chromosomal bridges in the cells of regenerating crypts. Non-homologous end joining (NHEJ) DSBs repair was involved in the DSBs repair process, as indicated by p-DNA-PKcs staining. SIGNIFICANCE: Intestinal crypt cells retained hyperproliferation with inactive p53-related genomic surveillance system. NHEJ was involved in the resultant genomic instability during hyperproliferation. PMID- 26514304 TI - Chaetocin inhibits RANKL-induced osteoclast differentiation through reduction of Blimp1 in Raw264.7 cells. AB - AIMS: Periodontitis is one of the most common bone-destructive diseases. Osteoclast is differentiated from hematopoietic macrophage-like cells through receptor activator of NFkappaB ligand (RANKL)-RANK signaling system, and the reduction in osteoclast formation may result in prevention of bone-resorptive diseases. Chaetocin is a compound isolated from fungal cultures and has been reported as a potent and selective inhibitor of suppressor of variegation 3-9 homolog 1 (Suv39h1), which catalyzes histone methylation on histone H3 lysine 9 (H3K9) residues. However, the effect of chaetocin on osteoclast differentiation is uncertain. In this study, we examine the effect of chaetocin on RANKL-induced osteoclast differentiation and cell growth. MAIN METHODS: Mouse macrophage-like Raw264.7 cells were treated with RANKL in the presence or absence of chaetocin, and tartrate-resistant acid phosphatase (TRAP) staining was performed. Cell growth was measured as the amount of DNA stained with SYTOX Green dye. Expression and production of osteoclast differentiation markers, anti-osteoclastogenic genes, B lymphocyte-induced maturation protein-1 (Blimp1), and cell growth suppressors were examined by qRT-PCR or/and Western blot analysis. KEY FINDINGS: Here we show that chaetocin dose-dependently reduced RANKL-induced osteoclast differentiation and cell growth via Blimp1 downregulation which results in the upregulation of osteoclast differentiation inhibitors and cell growth suppressors. These effects were not derived from the chaetocin's inhibitory effect of Suv39h1. SIGNIFICANCE: These results suggest that chaetocin suppresses RANKL-induced osteoclastogenesis and cell growth through blimp1 downregulation, followed by induction of anti-osteoclastogenic genes and cell growth suppressors, without inhibition of Suv39h1. Thus, chaetocin might be a drug candidate for the prevention of bone resorption in bone-destructive diseases. PMID- 26514306 TI - Commercial Airline In-Flight Emergency: Medical Student Response and Review of Medicolegal Issues. AB - BACKGROUND: As the prevalence of air travel increases, in-flight medical emergencies occur more frequently. A significant percentage of these emergencies occur when there is no certified physician, nurse, or paramedic onboard. During these situations, flight crews might enlist the help of noncertified passengers, such as medical students, dentists, or emergency medical technicians in training. Although Good Samaritan laws exist, many health care providers are unfamiliar with the limited legal protections and resources provided to them after responding to an in-flight emergency. CASE REPORT: A 78-year-old woman lost consciousness and became pulseless onboard a commercial aircraft. No physician was available. A medical student responded and coordinated care with the flight crew, ground support physician, and other passengers. After receiving a packet (4 g) of sublingual sucrose and 1 L i.v. crystalloid, the patient regained pulses and consciousness. The medical student made the decision not to divert the aircraft based on the patient's initial response to therapy and, 45 min later, the patient had normal vital signs. Upon landing, she was met and taken by paramedics to the nearest emergency department for evaluation of her collapse. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians are the most qualified to assist in-flight emergencies, but they might not be aware of the medicolegal risks involved with in-flight care, the resources available, and the role of the flight crew in liability and decision making. This case, which involved a medical student who was not given explicit protection under Good Samaritan laws, illustrates the authority of the flight crew during these events and highlights areas of uncertainty in the legislation for volunteer medical professionals. PMID- 26514307 TI - The Ethics of a Postmortem Testicular Harvest. AB - BACKGROUND: Faith and religion are topics that are not routinely discussed or of much significance in the emergency department (ED). However, there are certain cases when faith or religion can cause certain ethical dilemmas for the physician, patient, or hospital. Understanding patients' beliefs affects our own medical decision-making and the ability to treat certain illnesses. Hospital policy or religious views of the hospital can affect patient management. Spirituality or religion in the ED will not be an issue with every patient; however, there are times where religious beliefs will be at the very center of an ED visit, as shown by this case report. CASE REPORT: A 42-year-old man presented to the ED in cardiac arrest. Despite resuscitation and appropriate advanced cardiac life support, he was pronounced dead in the ED. The patient's wife stated they were trying to have a child and requested testicular harvest, planning for in vitro fertilization. Being at a Catholic institution, this raised important ethical questions. After the involvement of several disciplines, a resolution was reached that placated the patient's wife and the hospital. CONCLUSION: This report highlights the importance of understanding the ethical questions raised from faith-based issues in the ED to be able to provide the highest level of patient-centered care. PMID- 26514308 TI - Metformin-Associated Lactic Acidosis Presenting as Acute ST-Elevation Myocardial Infarction. AB - BACKGROUND: Metformin-associated lactic acidosis (MALA) is a rare but life threatening adverse drug reaction of metformin, the most frequently prescribed medication for patients with type 2 diabetes mellitus. The diagnosis of MALA is difficult to make because of diverse clinical presentations that can masquerade as other critical illnesses. CASE REPORT: A 52-year-old woman presented with altered mental status, hypoglycemia, and shock. A prehospital electrocardiogram showed findings consistent with posterolateral ST-elevation myocardial infarction, and the cardiac catheterization laboratory was activated before patient arrival. On arrival to the emergency department, she was found to have severe metabolic derangements and hypothermia, and the catheterization laboratory was canceled. Aggressive supportive measures and emergent hemodialysis were instituted. A metformin concentration was sent from the ED and returned at 51 MUg/mL (therapeutic range 1-2 MUg/mL), making MALA the most likely diagnosis. She recovered after prolonged critical illness and was discharged in good condition. No alternate diagnoses were found despite extensive work-up. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Metformin is the most prescribed antidiabetic drug in the world. Although MALA is a rare complication, it is important for emergency physicians to keep MALA on the differential for diabetic patients presenting with severe metabolic acidosis. PMID- 26514309 TI - An Unusual Treatment for Cardiac Ischemia. PMID- 26514310 TI - Synthetic Cannabinoids and Their Effects on the Cardiovascular System. AB - BACKGROUND: In the past couple of years, there has been an outbreak of synthetic cannabinoid (SC) use in major cities in the United States. Patients can present with various symptoms affecting the central nervous and cardiovascular systems. The effects of endocannabinoid on contractility and Ca(2+) signaling have been shown through both cannabinoid receptors and a direct effect on ion channels. These effects result in abnormalities in ionotropy, chronotropy, and conduction. CASE REPORT: Here we report on two cases of SC abuse and abnormalities in the cardiovascular system. These cases raise concerns about the adverse effects of SCs and the possibility of QTc prolongation and subsequent complications when using antipsychotic medication in the presence of SC abuse. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Given the rise in SC use and the potential effect on the cardiovascular system, physicians need to be mindful of potential cardiac complications, such as QTc prolongation and torsade de pointe, especially when administering medications that have the potential to cause QTc prolongation. PMID- 26514311 TI - Impact of intermittent aerations on leachate quality and greenhouse gas reduction in the aerobic-anaerobic landfill method. AB - The aerobic-anaerobic landfill method (AALM) is a novel approach in solid waste management that could shorten the landfill post-closure period and minimize the environmental loads. In this study, the aerobic-anaerobic landfill method was evaluated by using intermittent aeration. In addition, the nitrification denitrification process was assessed as a means of reducing the emission of greenhouse gases (GHGs) and improving the leachate quality during the degradation of the organic solid waste. The leachate quality and the gas composition in each of the reactors were measured during the experimental period (408days). The aeration process entailed the injection of air into plexiglass cylinders (200cm height*10 cm diameter), filled with fresh organic solid waste collected from a composting plant. Different aeration routines were applied, namely, continuous aeration (aerobic reactor A), aeration for three days/week (aerobic-anaerobic reactor B), aeration for 6h/day (aerobic-anaerobic reactor C), and no aeration (non-aerated reactor D). It was found that aerobic reactor A produced the best results in terms of reduction of GHGs and improvement of the leachate quality. The aerobic-anaerobic reactor C was found to be more effective than reactor B in respect of both the emission of GHGs and the leachate quality; moreover, compared with aerobic reactor A, energy costs were reduced by operating this reactor. The transition period phenomenon was investigated during an intensive seven-day experiment conducted on the discharged leachate obtained from aerobic-anaerobic reactors B and C. The experiment concerned the differences in the composition of the gas during the aeration and the non-aeration periods. It was found that the transition period between the aeration and non-aeration cycles, which followed the simultaneous nitrification-denitrification had a considerable effect on the leachate quality of both the reactors. The results indicated that AALM has the potential to reduce leachate pollutants and the emission of GHGs. Furthermore, the occurrence of simultaneous nitrification-denitrification presents the prospect that intermittent aeration could reduce landfill aftercare and energy costs. PMID- 26514312 TI - Economic analysis of waste-to-energy industry in China. AB - The generation of municipal solid waste is further increasing in China with urbanization and improvement of living standards. The "12th five-year plan" period (2011-2015) promotes waste-to-energy technologies for the harmless disposal and recycling of municipal solid waste. Waste-to-energy plant plays an important role for reaching China's energy conservation and emission reduction targets. Industrial policies and market prospect of waste-to-energy industry are described. Technology, cost and benefit of waste-to-energy plant are also discussed. Based on an economic analysis of a waste-to-energy project in China (Return on Investment, Net Present Value, Internal Rate of Return, and Sensitivity Analysis) the paper makes the conclusions. PMID- 26514313 TI - Detection of alpha human papillomaviruses in archival formalin-fixed, paraffin embedded (FFPE) tissue specimens. AB - Formalin-fixed, paraffin-embedded (FFPE) tissue specimens stored in pathology departments worldwide are an invaluable source for diagnostic purposes when fresh clinical material is unavailable as well as for retrospective molecular and epidemiological studies, especially when dealing with rare clinical conditions for which prospective collection is not feasible. Accurate detection of HPV infection in these specimens is particularly challenging because nucleic acids are often degraded and therefore, not suitable for amplification of larger fragments of the viral genome or viral gene transcripts. This review provides a brief summary of molecular methods for detecting alpha-HPV DNA/RNA in FFPE tissue specimens. We specifically address the key procedural and environmental factors that have the greatest impact on the quality of nucleic acids extracted from FFPE tissue specimens, and describe some solutions that can be used to increase their integrity and/or amplifiability. Moreover, commonly used methods for HPV DNA/RNA detection in FFPE tissue specimens are presented and discussed, focusing on studies using polymerase chain reaction as an HPV detection method and published after 1999. Finally, we briefly summarize our 22 years of experience with HPV detection in FFPE tissue specimens. PMID- 26514314 TI - Lipid-modifying Therapy: The Clinician's Perspective. PMID- 26514315 TI - Effects of Fostamatinib on the Pharmacokinetics of Digoxin (a P-Glycoprotein Substrate): Results From in Vitro and Phase I Clinical Studies. AB - PURPOSE: Fostamatinib, a spleen tyrosine kinase inhibitor and prodrug of the active metabolite R406, is being developed as an anti-inflammatory drug for several indications for which polypharmacy is likely. Digoxin, indicated for congestive cardiac failure, may be used for certain supraventricular dysrhythmias. The studies reported herein examined whether fostamatinib and R406 are inhibitors of P-glycoprotein (P-gp) in vitro and evaluated the effect of fostamatinib on the pharmacokinetic parameters of digoxin to understand drug-drug interaction (DDI) potential in the clinic. METHODS: Inhibition of P-gp-mediated digoxin transport by fostamatinib and R406 was determined across Caco-2 cell monolayers. Apparent permeability of digoxin was determined and used to calculate efflux ratios and percentage inhibition. Half maximal inhibitory concentrations (IC50) and theoretical gastrointestinal concentration [I2] (dose in moles per 250 mL) were calculated to gauge clinical DDI potential. In a subsequent Phase I study, the plasma concentration-time profiles and resulting pharmacokinetic parameters were examined across 2 treatment periods: (1) oral digoxin loading dose of 0.25 mg BID on day 1 and 0.25 mg once daily on days 2 to 8, and (2) oral digoxin 0.25 mg once daily and oral fostamatinib 100 mg BID on days 9 to 15. FINDINGS: Fostamatinib (but not R406) was determined to be a P-gp inhibitor in vitro (IC50 = 3.2 MUM). On the basis of a theoretical gastrointestinal concentration (I2)/IC50 ratio of 216 ([I2] = 691 MUM), predictions indicated the potential for absorption-based DDI in vivo through inhibition of intestinal P-gp. In the clinical study, when digoxin was co-administered with fostamatinib, digoxin levels were higher before dosing and throughout the dosing interval, and an increase in exposure to digoxin was observed. Co-administration led to a 1.70 fold increase in digoxin maximum plasma concentration at steady state (Cmax,ss) versus digoxin administration alone (2.18 vs 1.32 ng/mL). Median digoxin time of Cmax was earlier when digoxin was co-administered with fostamatinib (1.00 vs 1.48 hours). The digoxin AUC during the dosing interval at steady state was increased 1.37-fold with co-administration. No severe or serious adverse events or deaths were reported. IMPLICATIONS: Fostamatinib was confirmed to be a P-gp inhibitor in vitro and in vivo, and a DDI with digoxin was apparent. Co-administration of digoxin and fostamatinib was generally well tolerated. However, continued review of digoxin response and dose is advisable should these agents be prescribed concomitantly. ClinicalTrials.gov identifier: NCT01355354. PMID- 26514316 TI - Maleimide-assisted anti-Markovnikov Wacker-type oxidation of vinylarenes using molecular oxygen as a terminal oxidant. AB - Arylacetaldehydes were successfully synthesized by the anti-Markovnikov Wacker type oxidation of vinylarenes using 1 atm O2 as a terminal oxidant under mild conditions. Electron-deficient alkenes, such as maleic anhydride and maleimides, were effective additives and would operate as ligands to stabilize the Pd(0) species during the reaction. PMID- 26514317 TI - Minimal extrathyroid extension in papillary thyroid carcinoma does not result in increased rates of either cause-specific mortality or postoperative tumor recurrence. AB - BACKGROUND: This study assessed the influence of extrathyroid extension (EE) on cause-specific mortality (CSM) and tumor recurrence (TR) in patients treated for papillary thyroid carcinoma (PTC). METHODS: We studied outcome in 3,524 patients with PTC without distant metastases at diagnosis. CSM and TR were investigated in 422 patients with gross EE (GEE) or microscopic EE (MEE). RESULTS: The 30-year CSM rate for GEE of 25% was 12-fold greater (P < .001) than 2% seen with surgically intra-thyroid tumors (SIT); no patient who underwent MEE died of PTC. No difference (P = .36) existed in CSM rates between 127 MEE and 3,102 microscopically intra-thyroid tumors (MITs). The 20-year TR rate for GEE was 43% versus 12% with SIT (P < .001). Analyzing only 2,067 pN0 tumors, we found that GEE patients had greater TR rates (all sites), compared with SIT or MEE (P < .001). When 44 MEE were compared with 1,941 MIT cases, TR (all sites) rates were not different (P = .74). In patients aged >45 with tumors <41 mm, 20-year TR rates for MIT (stages I/II) and MEE (stage III) were not different at 4.7% and 3.8% (P = .71). CONCLUSION: MEE without concomitant GEE did not increase rates of either CSM or TR in PTC. Accordingly, these results raise concerns regarding current AJCC staging recommendations. PMID- 26514318 TI - Discussion. PMID- 26514319 TI - Numb chin syndrome as a manifestation of jaw metastasis diagnosed in a bone scan. AB - In many cases, numb chin syndrome (NCS) may represent a banal pathology. However, as it can be associated with malignant processes, its presence should alert the clinician of a possible occult disease. In patients already diagnosed with cancer, it often represents an ominous sign that indicates poor prognosis, due to the rapid progress of the disease. The case is presented of a 62-year-old man diagnosed with synchronous lung and bladder cancer, who suddenly complained of numbness in the chin. The bone scan confirmed the suspicion of metastastic bone disease, and the patient died two months after the appearance of this sign. PMID- 26514320 TI - Cardiac sympathetic innervation assessed with (123)I-MIBG retains prognostic utility in diabetic patients with severe left ventricular dysfunction evaluated for primary prevention implantable cardioverter-defibrillator. AB - BACKGROUND: Scintigraphy with iodine-123-metaiodobenzylguanidine ((123)I-MIBG) is a non-invasive tool for the assessment of cardiac sympathetic innervation (CSI) that has proven to be an independent predictor of survival. Recent studies have shown that diabetic patients with heart failure (HF) have a higher deterioration in CSI. It is unknown if (123)I-MIBG has the same predictive value for diabetic and non-diabetic patients with advanced HF. An analysis is performed to determine whether CSI with (123)I-MIBG retains prognostic utility in diabetic patients with HF, evaluated for a primary prevention implantable cardioverter-defibrillator (ICD). MATERIAL AND METHODS: Seventy-eight consecutive HF patients (48 diabetic) evaluated for primary prevention ICD implantation were prospectively enrolled and underwent (123)I-MIBG to assess CSI (heart-to-mediastinum ratio - HMR). A Cox proportional hazards multivariate analysis was used to determine the influence of (123)I-MIBG images for prediction of cardiac events in both diabetic and non diabetic patients. The primary end-point was a composite of arrhythmic event, cardiac death, or admission due to HF. RESULTS: During a mean follow-up of 19.5 [9.3-29.3] months, the primary end-point occurred in 24 (31%) patients. Late HMR was significantly lower in diabetic patients (1.30 vs. 1.41, p=0.014). Late HMR<=1.30 was an independent predictor of cardiac events in diabetic (hazard ratio 4.53; p=0.012) and non-diabetic patients (hazard ratio 12.31; p=0.023). CONCLUSIONS: Diabetic patients with HF evaluated for primary prevention ICD show a higher deterioration in CSI than non-diabetics; nevertheless (123)I-MIBG imaging retained prognostic utility for both diabetic and non-diabetic patients. PMID- 26514321 TI - Detection of bone metastases in breast cancer patients in the PET/CT era: Do we still need the bone scan? AB - AIM: To examine the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for the detection of bone metastasis in breast cancer patients and assess whether whole body bone scan (BS) with (99m)Tc-methylene diphosphonate provides any additional information. MATERIAL AND METHODS: Study group comprised 150 patients, mean age 52 years (range 27-85) with breast cancer, suspected of having bone metastases. All patients had undergone both FDG-PET/CT and BS with or without single photon emission tomography/computed tomography (SPECT/CT) within a period of 6 weeks. The final diagnosis of bone metastasis was established by histopathological findings, additional imaging, or clinical follow-up longer than 10 months. Cancer antigen 15-3 (CA15-3) and carcinoembryogenic antigen (CEA) were measured in all patients. RESULTS: Histologically 83%, 7% and 10% had infiltrating ductal, lobular and mixed carcinoma respectively. Confirmed bone metastases were present in 86 patients (57.3%) and absent in 64 (42.7%). Mean CA15-3 and CEA values in patients with bone metastases were 74.6ng/mL and 60.4U/mL respectively, compared to 21.3ng/mL and 3.2U/mL without metastases (p<0.001). The sensitivity of FDG-PET/CT for the detection of bone metastases was 97.6% compared to 89.5% with SPECT/CT. In 57 patients, FDG-PET/CT correctly identified additional pulmonary, hepatic, nodal and other soft tissue metastases, not detected by BS. CONCLUSION: Our findings suggest that FDG-PET/CT is superior to BS with or without SPECT/CT. PMID- 26514322 TI - Ratio between maximum standardized uptake value of N1 lymph nodes and tumor predicts N2 disease in patients with non-small cell lung cancer in 18F-FDG PET-CT scan. AB - OBJECTIVE: F-18 fluorodeoxyglucose integrated PET-CT scan is commonly used in the work-up of lung cancer to improve preoperative disease stage. The aim of the study was to analyze the ratio between SUVmax of N1 lymph nodes and primary lung cancer to establish prediction of mediastinal disease (N2) in patients operated on non-small cell lung cancer. MATERIAL AND METHOD: This is a retrospective study of a prospective database. Patients operated on non-small cell lung cancer (NSCLC) with N1 disease by PET-CT scan were included. None of them had previous induction treatment, but they underwent standard surgical resection plus systematic lymphadenectomy. RESULTS: There were 51 patients with FDG-PET-CT scan N1 disease. 44 (86.3%) patients were male with a mean age of 64.1+/-10.8 years. Type of resection: pneumonectomy=4 (7.9%), lobectomy/bilobectomy=44 (86.2%), segmentectomy=3 (5.9%). HISTOLOGY: adenocarcinoma=26 (51.0%), squamous=23 (45.1%), adenosquamous=2 (3.9%). Lymph nodes after surgical resection: N0=21 (41.2%), N1=12 (23.5%), N2=18 (35.3%). Mean ratio of the SUVmax of N1 lymph node to the SUVmax of the primary lung tumor (SUVmax N1/T ratio) was 0.60 (range 0.08 2.80). ROC curve analysis to obtain the optimal cut-off value of SUVmax N1/T ratio to predict N2 disease was performed. At multivariate analysis, we found that a ratio of 0.46 or greater was an independent predictor factor of N2 mediastinal lymph node metastases with a sensitivity and specificity of 77.8% and 69.7%, respectively. CONCLUSIONS: SUVmax N1/T ratio in NSCLC patients correlates with mediastinal lymph node metastasis (N2 disease) after surgical resection. When SUVmax N1/T ratio on integrated PET-CT scan is equal or superior to 0.46, special attention should be paid on higher probability of N2 disease. PMID- 26514323 TI - Infective endocarditis detected by (18)F-FDG PET-CT in a patient with gram positive bacteraemia of unknown origin. PMID- 26514324 TI - New technologies for DNA analysis--a review of the READNA Project. AB - The REvolutionary Approaches and Devices for Nucleic Acid analysis (READNA) project received funding from the European Commission for 41/2 years. The objectives of the project revolved around technological developments in nucleic acid analysis. The project partners have discovered, created and developed a huge body of insights into nucleic acid analysis, ranging from improvements and implementation of current technologies to the most promising sequencing technologies that constitute a 3(rd) and 4(th) generation of sequencing methods with nanopores and in situ sequencing, respectively. PMID- 26514325 TI - Safety of prasugrel in real-world patients with ST-segment elevation myocardial infarction: 1-year results from a prospective observational study (Bleeding and Myocardial Infarction Study). AB - BACKGROUND: Antiplatelet therapies, including prasugrel, are a cornerstone in the treatment of ST-segment elevation myocardial infarction (STEMI), but are associated with a bleeding risk. This risk has been evaluated in randomized trials, but few data on real-world patients are available. AIM: To evaluate prasugrel safety in real-world patients with STEMI. METHODS: Consecutive patients with STEMI were recruited over 1 year. Follow-up was done at 3 months and 1 year to evaluate prasugrel safety from hospital discharge to the STEMI anniversary date. The primary outcome was occurrence of any major bleeding according to the Bleeding Academic Research Consortium (BARC) 3 or 5 definitions, or minor bleeding according to the BARC 2 definition. RESULTS: Overall, 1083 patients were recruited. Compared to patients treated with aspirin+clopidogrel, patients treated with aspirin+prasugrel had fewer BARC 3 or 5 bleedings (two [0.4%] patients vs. nine [1.8%] patients; P=0.04), but more BARC 2 bleedings (45 [9.3%] patients vs. 20 [4.0%] patients; P<0.001). The baseline characteristics of prasugrel- and clopidogrel-treated patients differed because the former were carefully selected (younger, higher body mass index, less frequent history of stroke). In the overall population, rates of in-hospital and out-of-hospital major bleeding were 2.6% (n=28) and 1.3% (n=13), respectively. CONCLUSION: The rate of major bleeding, particularly out-of-hospital bleeding, in patients treated with prasugrel is low within 1 year after a STEMI. Accurate selection of patient candidates for prasugrel is likely to have reduced the risk of bleeding. PMID- 26514326 TI - Global longitudinal strain software upgrade: Implications for intervendor consistency and longitudinal imaging studies. AB - BACKGROUND: Speckle tracking can be used to measure left ventricular global longitudinal strain (GLS). AIMS: To study the effect of speckle tracking software product upgrades on GLS values and intervendor consistency. METHODS: Subjects (patients or healthy volunteers) underwent systematic echocardiography with equipment from Philips and GE, without a change in their position. Off-line post processing for GLS assessment was performed with the former and most recent upgrades from these two vendors (Philips QLAB 9.0 and 10.2; GE EchoPAC 12.1 and 13.1.1). GLS was obtained in three myocardial layers with EchoPAC 13.1.1. Intersoftware and intervendor consistency was assessed. Interobserver variability was tested in a subset of patients. RESULTS: Among 73 subjects (65 patients and 8 healthy volunteers), absolute values of GLS were higher with QLAB 10.2 compared with 9.0 (intraclass correlation coefficient [ICC]: 0.88; bias: 2.2%). Agreement between EchoPAC 13.1.1 and 12.1 varied by myocardial layer (13.1.1 only): midwall (ICC: 0.95; bias: -1.1%), endocardium (ICC: 0.93; bias: 1.6%) and epicardial (ICC: 0.80; bias: -3.3%). Although GLS was comparable for QLAB 9.0 versus EchoPAC 12.1 (ICC: 0.95; bias: 0.5%), the agreement was lower between QLAB 10.2 and EchoPAC 13.1.1 endocardial (ICC: 0.91; bias: 1.1%), midwall (ICC: 0.73; bias: 3.9%) and epicardial (ICC: 0.54; bias: 6.0%). Interobserver variability of all software products in a subset of 20 patients was excellent (ICC: 0.97-0.99; bias: -0.8 to 1.0%). CONCLUSION: Upgrades of speckle tracking software may be associated with significant changes in GLS values, which could affect intersoftware and intervendor consistency. This finding has important clinical implications for the longitudinal follow-up of patients with speckle tracking echocardiography. PMID- 26514327 TI - Congenital Retroperitoneal Teratoma in Neurofibromatosis Type 1. AB - Neurofibromatosis type 1 (NF1) is caused by mutations in the tumor suppressor gene NF1. The increased tumor risk in affected individuals is well established, caused by somatic biallelic inactivation of NF1 due to loss of heterozygosity. Pediatric teratoma has not been reported in individuals with NF1 previously. We report a case of congenital teratoma in an infant with a heterozygous maternally inherited pathogenic NF1 mutation (c.[1756_1759delACTA] and p.[Thr586Valfs*18]). We detected a "second hit" in the form of mosaic whole NF1 deletion in the tumor tissue using multiplex ligation-dependent probe amplification, as a proof to support the hypothesis of NF1 involvement in the pathogenesis of teratoma. PMID- 26514328 TI - Identification of a novel HLA-B*15 variant, B*15:367, using sequence-based typing in a Korean woman. AB - New allele, B*15:367, differs from B*15:11:01 by a single nucleotide exchange at codon 222 (GAG->AAG). PMID- 26514329 TI - Increased expression of transient receptor potential canonical 6 (TRPC6) in differentiating human megakaryocytes. AB - Members of the transient receptor potential (TRP) family of cation conducting channels are found in several tissues and cell types where they have different physiological functions. The canonical TRP channel 6 (TRPC6) is present on the platelet membrane and appears to participate in calcium influx during platelet activation. However, limited information is available on the importance of TRPC channels in megakaryocytes (MKs), the precursor cells of platelets. We determined the mRNA and protein expression of TRPC family members and investigated the role of TRPC6 for proliferation and differentiation of human MKs derived from CD34+ progenitor cells. TRPC6 transcripts were highly expressed during the differentiation of MKs and TRPC6 protein was detectable in MK cytoplasm by confocal staining. TRPC6 channel activity was modulated by pharmacological approaches using flufenamic acid (FFA) for activation and SKF96365 for inhibition. Upon FFA stimulation in MKs, an increase in intracellular calcium was observed, which was blocked by SKF96365 at 10 uM concentration. Incubation of MKs with SKF96365 resulted in a reduction in thrombopoietin-stimulated cell proliferation. Our results suggest a role of TRPC6 in calcium homeostasis during MK development, particularly for cell proliferation. PMID- 26514330 TI - Incidence and natural history of hen's egg allergy in the first 2 years of life the EuroPrevall birth cohort study. AB - BACKGROUND: Parents and health staff perceive hen's egg allergy (HEA) as a common food allergy in early childhood, but the true incidence is unclear because population-based studies with gold-standard diagnostic criteria are lacking. OBJECTIVE: To establish the incidence and course of challenge-confirmed HEA in children, from birth until the age of 24 months, in different European regions. METHODS: In the EuroPrevall birth cohort study, children with a suspected HEA and their age-matched controls were evaluated in 9 countries, using a standardized protocol including measurement of HE-specific immunoglobulin E-antibodies in serum, skin prick tests, and double-blind, placebo-controlled food challenges (DBPCFC). RESULTS: Across Europe, 12 049 newborns were enrolled, and 9336 (77.5%) were followed up to 2 years of age. In 298 children, HEA was suspected and DBPCFC was offered. HEA by age two was confirmed in 86 of 172 challenged children (mean raw incidence 0.84%, 95% confidence interval (95% CI) 0.67-1.03). Adjusted mean incidence of HEA was 1.23% (95% CI 0.98-1.51) considering possible cases among eligible children who were not challenged. Centre-specific incidence ranged from United Kingdom (2.18%, 95% CI 1.27-3.47) to Greece (0.07%). Half of the HE allergic children became tolerant to HE within 1 year after the initial diagnosis. CONCLUSIONS: The largest multinational European birth cohort study on food allergy with gold-standard diagnostic methods showed that the mean adjusted incidence of HEA was considerably lower than previously documented, although differences in incidence rates among countries were noted. Half of the children with documented HEA gained tolerance within 1 year postdiagnosis. PMID- 26514331 TI - Screen printed passive components for flexible power electronics. AB - Additive and low-temperature printing processes enable the integration of diverse electronic devices, both power-supplying and power-consuming, on flexible substrates at low cost. Production of a complete electronic system from these devices, however, often requires power electronics to convert between the various operating voltages of the devices. Passive components-inductors, capacitors, and resistors-perform functions such as filtering, short-term energy storage, and voltage measurement, which are vital in power electronics and many other applications. In this paper, we present screen-printed inductors, capacitors, resistors and an RLC circuit on flexible plastic substrates, and report on the design process for minimization of inductor series resistance that enables their use in power electronics. Printed inductors and resistors are then incorporated into a step-up voltage regulator circuit. Organic light-emitting diodes and a flexible lithium ion battery are fabricated and the voltage regulator is used to power the diodes from the battery, demonstrating the potential of printed passive components to replace conventional surface-mount components in a DC-DC converter application. PMID- 26514332 TI - A randomized two way cross over study for comparison of absorption of vitamin D3 buccal spray and soft gelatin capsule formulation in healthy subjects and in patients with intestinal malabsorption. AB - BACKGROUND: Vitamin D deficiency has been proposed to contribute to the development of malabsorption diseases. Despite this, the vitamin D status of these patients is often neglected. The objective of the present work was to compare the absorption of vitamin D3 through the oral route by comparing a 1000 IU soft gelatin capsule and a 500 IU buccal spray (delivering 1000 IU in two spray shots) in healthy subjects and in patients with malabsorption disease. METHODS: An open label, randomized, two-periods, two-way cross over study was conducted, first in healthy subjects (n = 20) and then in patients with malabsorption syndrome (n = 20). The study participants were equally divided and received either of the treatments (buccal spray, n = 7; soft gelatin capsule, n = 7; control, n = 6) in Period I for 30 days. After washout of another 30 days, the treatments were changed in crossover fashion in Period II. Fasting blood samples were collected to measure baseline 25-hydroxyvitamin D [25(OH)D] levels in all participants at day 0 (Screening visit), day 30 (completion of period I), day 60 (end of wash out and initiation of period II) and day 90 (completion of period II). Safety was evaluated by hematology and biochemistry analyses. Statistical analyses was performed using differences of mean and percentage change from baseline of 25(OH)D levels between two formulation by two tailed Paired t-test with 95% confidence interval. RESULTS: In healthy subjects, the mean increase in serum 25(OH)D concentration was 4.06 (95% CI 3.41, 4.71) ng/ml in soft gelatin capsule group and 8.0 (95% CI 6.86, 9.13) ng/ml in buccal spray group after 30 days treatment (p < 0.0001). In patients with malabsorption disease, the mean increase in serum 25(OH)D concentration was 3.96 (95% CI 2.37, 5.56) ng/ml in soft gelatin capsule group and 10.46 (95% CI 6.89, 14.03) ng/ml in buccal spray group (p < 0.0001). CONCLUSION: It can be concluded from the results that the buccal spray produced a significantly higher mean serum 25(OH)D concentration as compared to the soft gelatin capsule, in both healthy subjects as well as in patients with malabsorption syndrome over a period of 30 days administration in a two way cross over study. Treatments were well tolerated by both subject groups TRIAL REGISTRATION: CTRI/2013/06/003770. PMID- 26514333 TI - Vitamin E derivatives: a patent review (2010 - 2015). AB - INTRODUCTION: The vitamin E family consists of four tocopherols and four tocotrienols. alpha-Tocopherol is the most studied member of this family for its antioxidant and non-antioxidant properties, while tocotrienols have attracted recent research interest. The structural motifs of the vitamin E family and specifically the chroman moiety, are amenable to various modifications in order to improve their bioactivities towards numerous therapeutic targets. AREAS COVERED: This review includes the patent literature from 2010 - 2015 related to vitamin E derivatives and it is focused on 2-, 5- or 6-substituted chroman analogues. The patent search was performed using Reaxys(r) and esp@cenet. EXPERT OPINION: The chroman moiety of vitamin E is a privileged structure and an essential pharmacophore which inspired organic chemists to synthesize new analogues with improved bioactivities. Modifications at the 2- and 5- positions of the chroman ring resulted in very interesting active compounds in cellular and animal models of diseases related to oxidative stress. More recent publications and patents reported 6-substituted chromans as anticancer agents in vitro and in vivo. Additionally, an emerging interest is observed towards the use of vitamin E analogues incorporated in drug delivery systems and for medical imaging as contrast agents or fluorescent probes. PMID- 26514334 TI - The treatment of spleen injuries: a retrospective study. AB - BACKGROUND: Hemorrhage after blunt trauma is a major contributor to death after trauma. In the abdomen, an injured spleen is the most frequent cause of major bleeding. Splenectomy is historically the treatment of choice. In 2007, non operative management (NOM) with splenic artery embolization (SAE) was introduced in our institution. The indication for SAE is hemodynamically stable patients with extravasation of contrast, or grade 3-5 spleen injury according to the Abbreviated Organ Injury Scale 2005, Update 2008. We wanted to examine if the introduction of SAE increased the rate of salvaged spleens in our trauma center. METHOD: All patients discharged with the diagnosis of splenic injury in the period 01.01.2000 - 31.12.2013 from the University Hospital of North Norway Tromso were included in the study. Patients admitted for rehabilitation purposes or with an iatrogenic injury were excluded. RESULTS: A total of 109 patients were included in the study. In the period 2000-7, 20 of 52 patients were splenectomized. During 2007-13, there were 6 splenectomies and 24 SAE among 57 patients. The reduction in splenectomies is significant (p < 0.001). There is an increase in the rate of treated patients (splenectomy and SAE) from 38 to 53 % in the two time periods, but not significantly (p = 0.65). CONCLUSION: The rate of salvaged spleens has increased after the introduction of SAE in our center. TRIAL REGISTRATION: The study is registered at www.clinicaltrials.gov with the identification number NCT01965548. PMID- 26514335 TI - ToPASeq: an R package for topology-based pathway analysis of microarray and RNA Seq data. AB - BACKGROUND: Pathway analysis methods, in which differentially expressed genes are mapped to databases of reference pathways and relative enrichment is assessed, help investigators to propose biologically relevant hypotheses. The last generation of pathway analysis methods takes into account the topological structure of a pathway, which helps to increase both specificity and sensitivity of the findings. Simultaneously, the RNA-Seq technology is gaining popularity and becomes widely used for gene expression profiling. Unfortunately, majority of topological pathway analysis methods remains without implementation and if an implementation exists, it is limited in various factors. RESULTS: We developed a new R/Bioconductor package ToPASeq offering uniform interface to seven distinct topology-based pathway analysis methods, of which three we implemented de-novo and four were adjusted from existing implementations. Apart this, ToPASeq offers a set of tailored visualization functions and functions for importing and manipulating pathways and their topologies, facilitating the application of the methods on different species. The package can be used to compare the differential expression of pathways between two conditions on both gene expression microarray and RNA-Seq data. The package is written in R and is available from Bioconductor 3.2 using AGPL-3 license. CONCLUSION: ToPASeq is a novel package that offers seven distinct methods for topology-based pathway analysis, which are easily applicable on microarray as well as RNA-Seq data, both in human and other species. At the same time, it provides specific tools for visualization of the results. PMID- 26514336 TI - Actin Polymerization: An Event Regulated by Tyrosine Phosphorylation During Buffalo Sperm Capacitation. AB - In the female reproductive tract, the spermatozoa undergo a series of physiological and biochemical changes, prior to gaining the ability to fertilize, that result to capacitation. However, the actin polymerization and protein tyrosine phosphorylation are the two necessary steps for capacitation. In this study, we have demonstrated the actin polymerization and established the correlation between protein tyrosine phosphorylation and actin reorganization during in vitro capacitation in buffalo (Bubalus bubalis) spermatozoa. Indirect immunofluorescence and Western blot techniques were used to detect actin polymerization and tyrosine phosphorylation. The time-dependent fluorimetric studies revealed that the actin polymerization starts from the tail region and progressed towards the head region of spermatozoa during capacitation. The lysophosphatidyl choline (LPC)-induced acrosome reaction (AR) stimulated quick actin depolymerization. The inhibitor cytochalasin D (CD) blocked the in vitro capacitation by inhibiting the actin polymerization. In addition, we also performed different inhibitor (Genistein, H-89, PD9809 and GF-109) and enhancer (dbcAMP, H(2)O(2) and vanadate) studies on actin tyrosine phosphorylation and actin polymerization. The inhibitors of tyrosine phosphorylation inhibit actin tyrosine phosphorylation and polymerization, whereas enhancers of tyrosine phosphorylation stimulate F-actin formation and tyrosine phosphorylation. These observations suggest that the tyrosine phosphorylation regulates the actin polymerization, and both are coupled processes during capacitation of buffalo spermatozoa. PMID- 26514338 TI - Overcoming Statistical Complexity: Selective Coordination of Three Different Metal Ions to a Ligand with Three Different Coordination Sites. AB - In general, it is difficult to selectively introduce different metal ions at specific positions of a cluster-like structure. This is mainly due to statistical problems as well as the reversibility of the formation of coordination bonds. To overcome this statistical problem, we used a carefully designed ligand, H6 L, which can accommodate three different kinds of metal ions in three types of coordination sites. The complex [LNiZn2La](3+), which contains three different metals, was quantitatively obtained by a stepwise procedure, but different products were obtained when the metal ions were added in a different order. However, equilibration studies indicated that this complex was almost solely formed among 54 (=3*3*3H2) possible products upon heating; the formation efficiency (ca. 100%) was significantly higher than the statistical probability (2.47%). Such carefully designed ligands should be useful for the synthesis multimetallic systems, which are of interest because of the interplay between the different metals. PMID- 26514337 TI - Acromegaly presenting with low insulin-like growth factor-1 levels and diabetes: a case report. AB - INTRODUCTION: Acromegaly is an endocrine disorder arising from excessive serum growth hormone levels in adulthood and is characterized by progressive somatic enlargement. Biochemical confirmation is achieved by demonstration of elevated baseline serum growth hormone levels which are not suppressed during an oral glucose tolerance test, and by increased levels of serum insulin-like growth factor-1. The serum insulin-like growth factor-1 level provides an assessment of integrated growth hormone secretion and is recommended for diagnosis, monitoring, and screening of acromegaly. We report a case of a patient with acromegaly secondary to a pituitary microadenoma who presented with low insulin-like growth factor-1. CASE PRESENTATION: An 83-year-old Sinhalese woman presented to our hospital with an enlarging multinodular goiter. She was observed to have macroglossia, thickened coarse skin, acral enlargement, and newly detected, uncontrolled diabetes. A diagnosis of acromegaly was suspected. She did not complain of recent headaches, vomiting, visual difficulties, or galactorrhea and was clinically euthyroid. Her pulse rate was 84 beats/min, and her blood pressure was 150/90 mmHg. A visual field assessment did not reveal a defect. Her random growth hormone levels were 149 mU/L (<10 mU/L), and her oral glucose tolerance test was supportive of acromegaly with a paradoxical rise of growth hormone. Her serum age-specific insulin-like growth factor-1 level was below normal at 124.7 ng/ml (normal range 150-350 ng/ml). Her serum insulin-like growth factor-1 level, measured after glycemic control was achieved with metformin and insulin, was elevated, which is characteristic of acromegaly. Magnetic resonance imaging of her pituitary revealed a pituitary microadenoma. Acromegaly secondary to a growth hormone-secreting pituitary microadenoma was confirmed. CONCLUSIONS: Systemic illnesses, including catabolic states, hepatic or renal failure, malnutrition, and diabetes mellitus, are known to decrease insulin-like growth factor-1 levels and may result in false-negative values in patients with acromegaly A low insulin like growth factor-1 level does not exclude acromegaly in a patient with supportive clinical features and poorly controlled diabetes. PMID- 26514339 TI - Disrupted bonds - parental perceptions of regionalised transfer of very preterm infants: a small-scale study. AB - BACKGROUND: Routine regionalised transfer of preterm infants occurs throughout Westernised countries. Transfer to lower acuity units occurs once infants are ready for convalescence and signals an infant's improving health. However, many parents find transfer traumatic. AIMS: To investigate parents' perceptions of preterm infants' transfer; to provide neonatal clinicians with insights to facilitate optimal service provision. METHODS: Participants had experienced their baby born at less than 29 weeks gestation, and subsequent transfer. Six parents were interviewed. DESIGN: Data were analysed using a general inductive approach. FINDINGS: Three themes were interpreted through data analysis: NICU - incomparable haven; abandonment; and parental expertise side-lined. These themes represent a journey of interrupted identity that parents undergo when their baby is transferred to another unit. CONCLUSION: Despite studies recommending more family-centred transfer planning, gaps persist. Nursing care might be enhanced by incorporating insight into parental experiences and promotion of collaborative changes within and between units. PMID- 26514340 TI - Percutaneous aortic valve closure for patients with left ventricular assist device-associated aortic insufficiency. AB - The development of de novo aortic insufficiency (AI) is a significant complication of long-term LVAD support, which can lead to ineffective support, decreased device durability, end organ malperfusion, and increased mortality. Surgical aortic valve (AV) closure has been the standard treatment for symptomatic patients, but is associated with high mortality and recurrence of AI. Percutaneous AV closure using the Amplatzer cribriform device is a feasible and may be the preferable option to treat LVAD-associated severe AI in high-surgical risk patients. Certain technical issues with this procedure should be taken into consideration to achieve optimal results. (c) 2015 Wiley Periodicals, Inc. PMID- 26514341 TI - Delayed surgical management is not effective for severe Bell's palsy after two months of onset. AB - AIMS: To assess the effectiveness of delayed surgery and follow-up observation in managing severe Bell's palsy after two months of onset. METHODS: Forty-one Bell's palsy patients with severe facial paralysis were treated after two months of onset. Eighteen patients in group I underwent decompression operations between two and three months after onset, and eight patients in group II underwent surgery after three months of onset; 15 patients in group III were managed with follow-up observation. All patients were followed up at the end of 3rd, 6th and 12th months, and surgical outcomes were compared with follow-up observations using House-Brackmann score and Facial Clinimetric Evaluation (FaCE) scale. RESULTS: Between groups I and III, the difference in the proportion of the patients with fair or poor recoveries was statistically significant (p < 0.05) at the three-month follow-up visit. There was no significant difference in the distribution of complete, fair or poor recoveries at the 12-month follow-up visits among the three groups (p < 0.05). The total FaCE score and five individual domains were significantly improved at the end of the follow-up period in groups I and III (p < 0.05). However, in group I, the lacrimal control scores were significantly decreased at the end of the follow-up period compared to scores before surgery (p < 0.05). After surgery, four patients had sensorineural hearing loss, three patients had tinnitus and no patients had vertigo. CONCLUSION: Patients with severe Bell's palsy after two months of onset would not benefit from delayed decompression surgery. PMID- 26514342 TI - Melatonin set out to ER stress signaling thwarts epithelial mesenchymal transition and peritoneal dissemination via calpain-mediated C/EBPbeta and NFkappaB cleavage. AB - Peritoneal dissemination of tumor has high mortality and is associated with the loss of epithelial features, acquisition of motile mesenchymal morphology characteristics, and invasive properties by tumor cells. Melatonin is an endogenously produced molecule in all plant species that is known to exert antitumor activity, but to date, its underlying mechanisms and antiperitoneal metastasis efficacy is not well defined. This study determined the antiperitoneal dissemination potential of melatonin in vivo and assessed its association with the inhibition of epithelial-to-mesenchymal transition (EMT) signaling mechanism by endoplasmic reticulum (ER) stress, which may be a major molecular mechanism of melatonin against cancer. The results demonstrate that melatonin inhibited peritoneal metastasis in vivo and activated ER stress in Cignal ERSE Reporter Assay, organelle structure in transmission electron microscopy images, calpain activity, and protein biomarkers like p-elf2alpha. Moreover, the overexpression of transcription factor C/EBPbeta in gastric cancer interacted with NFkappaB and further regulates COX-2 expression. These were dissociated and downregulated by melatonin, as proven by immunofluorescence imaging, immunoprecipitation, EMSA, and ChIP assay. Melatonin or gene silencing of C/EBPbeta decreased the EMT protein markers (E-cadherin, Snail, and Slug) and Wnt/beta-catenin activity by Topflash activity, and increased ER stress markers. In an animal study, the results of melatonin therapy were consistent with those of in vitro findings and attenuated systemic proangiogenesis factor production. In conclusion, C/EBPbeta and NFkappaB inhibition by melatonin may impede both gastric tumor growth and peritoneal dissemination by inducing ER stress and inhibiting EMT. PMID- 26514343 TI - Transcriptome changes in STSV2-infected Sulfolobus islandicus REY15A undergoing continuous CRISPR spacer acquisition. AB - A transcriptome study was performed on Sulfolobus islandicus REY15A actively undergoing CRISPR spacer acquisition from the crenarchaeal monocaudavirus STSV2 in rich and basal media over a 6 day period. Spacer acquisition preceded strong host growth retardation, altered transcriptional activity of four different CRISPR-Cas modules and changes in viral copy numbers, and with significant differences in the two media. Transcript levels of proteins involved in the cell cycle were reduced, whereas those of DNA replication, DNA repair, transcriptional regulation and some antitoxin-toxin pairs and transposases were unchanged or enhanced. Antisense RNAs were implicated in the transcriptional regulation of adaptation and interference modules of the type I-A CRISPR-Cas system, and evidence was found for the occurrence of functional co-ordination between the single CRISPR-Cas adaptation module and the functionally diverse interference modules. PMID- 26514344 TI - Self-Advocacy as a Means to Positive Identities for People with Intellectual Disability: 'We Just Help Them, Be Them Really'. AB - BACKGROUND: Stigma attached to having an intellectual disability has negative implications for the social identities and inclusion of people with intellectual disability. AIM: The study explored the effects of membership of independent self advocacy groups on the social identity of people with intellectual disability. METHOD: Using a constructivist grounded theory methodology, semi-structured interviews were conducted with 25 members of six self-advocacy groups which varied in size, resources, location and policy context: two based in the Australian states of Victoria and Tasmania and four in the UK. RESULTS: Collegiality, ownership and control by members characterized groups. They gave members opportunities for paid or voluntary work, skill development and friendship which contributed to their confidence and engagement with life. Possibilities for new more positive identities such as being an expert, a business-like person, a self-advocate and an independent person were opened up. Self-advocacy is an important means of furthering social inclusion of people with intellectual disability. PMID- 26514345 TI - Metal release from stainless steel in biological environments: A review. AB - Due to its beneficial corrosion resistance, stainless steel is widely used in, e.g., biomedical applications, as surfaces in food contact, and for products intended to come into skin contact. Low levels of metals can be released from the stainless steel surface into solution, even for these highly corrosion resistant alloys. This needs to be considered in risk assessment and management. This review aims to compile the different metal release mechanisms that are relevant for stainless steel when used in different biological settings. These mechanisms include corrosion-induced metal release, dissolution of the surface oxide, friction-induced metal release, and their combinations. The influence of important physicochemical surface properties, different organic species and proteins in solution, and of biofilm formation on corrosion-induced metal release is discussed. Chemical and electrochemical dissolution mechanisms of the surface oxides of stainless steel are presented with a focus on protonation, complexation/ligand-induced dissolution, and reductive dissolution by applying a perspective on surface adsorption of complexing or reducing ligands and proteins. The influence of alloy composition, microstructure, route of manufacture, and surface finish on the metal release process is furthermore discussed as well as the chemical speciation of released metals. Typical metal release patterns are summarized. PMID- 26514346 TI - BUILDING A WORKFORCE COMPETENCY-BASED TRAINING PROGRAM IN INFANT/EARLY CHILDHOOD MENTAL HEALTH. AB - This article describes findings from a project conducted in Western Australia (Mental Health Commission WA, 2015) that investigated the education and training needs of the Infant/Early Childhood Mental Health (I/ECMH) workforce. We examined international training programs and models of delivery in infant mental health, including a review of the current training available in Australia. Data collected from over 60 interviews were analyzed, and a staged delivery model for I/ECMH training and supervision that aligned with the Michigan Association for Infant Mental Health (2014) Competency Guidelines was recommended. These findings led to the purchase of the Michigan Association for Infant Mental Health (2014) for use in Western Australia. In a very short time, use of the Michigan Competency Framework by the Australian Association for Infant Mental Health West Australian Branch Incorporated has begun to change the training and education opportunities for upskilling the infant and early childhood workforce in Western Australia. It has resulted in a map to guide and develop training in the I/ECMH field for individual practitioners and professionals as well as for workplaces that will ultimately benefit Western Australian infants, young children, and their families during the perinatal period and in the early years. PMID- 26514348 TI - Hepatic and intestinal glucuronidation of mono(2-ethylhexyl) phthalate, an active metabolite of di(2-ethylhexyl) phthalate, in humans, dogs, rats, and mice: an in vitro analysis using microsomal fractions. AB - Mono(2-ethylhexyl) phthalate (MEHP) is an active metabolite of di(2-ethylhexyl) phthalate (DEHP) and has endocrine-disrupting effects. MEHP is metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in mammals. In the present study, the hepatic and intestinal glucuronidation of MEHP in humans, dogs, rats, and mice was examined in an in vitro system using microsomal fractions. The kinetics of MEHP glucuronidation by liver microsomes followed the Michaelis-Menten model for humans and dogs, and the biphasic model for rats and mice. The K m and V max values of human liver microsomes were 110 uM and 5.8 nmol/min/mg protein, respectively. The kinetics of intestinal microsomes followed the biphasic model for humans, dogs, and mice, and the Michaelis-Menten model for rats. The K m and V max values of human intestinal microsomes were 5.6 uM and 0.40 nmol/min/mg protein, respectively, for the high-affinity phase, and 430 uM and 0.70 nmol/min/mg protein, respectively, for the low-affinity phase. The relative levels of V max estimated by Eadie-Hofstee plots were dogs (2.0) > mice (1.4) > rats (1.0) ~ humans (1.0) for liver microsomes, and mice (8.5) > dogs (4.1) > rats (3.1) > humans (1.0) for intestinal microsomes. The percentages of the V max values of intestinal microsomes to liver microsomes were mice (120 %) > rats (57 %) > dogs (39 %) > humans (19 %). These results suggest that the metabolic abilities of UGT enzymes expressed in the liver and intestine toward MEHP markedly differed among species, and imply that these species differences are strongly associated with the toxicity of DEHP. PMID- 26514347 TI - Littoral lichens as a novel source of potentially bioactive Actinobacteria. AB - Cultivable Actinobacteria are the largest source of microbially derived bioactive molecules. The high demand for novel antibiotics highlights the need for exploring novel sources of these bacteria. Microbial symbioses with sessile macro organisms, known to contain bioactive compounds likely of bacterial origin, represent an interesting and underexplored source of Actinobacteria. We studied the diversity and potential for bioactive-metabolite production of Actinobacteria associated with two marine lichens (Lichina confinis and L. pygmaea; from intertidal and subtidal zones) and one littoral lichen (Roccella fuciformis; from supratidal zone) from the Brittany coast (France), as well as the terrestrial lichen Collema auriforme (from a riparian zone, Austria). A total of 247 bacterial strains were isolated using two selective media. Isolates were identified and clustered into 101 OTUs (98% identity) including 51 actinobacterial OTUs. The actinobacterial families observed were: Brevibacteriaceae, Cellulomonadaceae, Gordoniaceae, Micrococcaceae, Mycobacteriaceae, Nocardioidaceae, Promicromonosporaceae, Pseudonocardiaceae, Sanguibacteraceae and Streptomycetaceae. Interestingly, the diversity was most influenced by the selective media rather than lichen species or the level of lichen thallus association. The potential for bioactive-metabolite biosynthesis of the isolates was confirmed by screening genes coding for polyketide synthases types I and II. These results show that littoral lichens are a source of diverse potentially bioactive Actinobacteria. PMID- 26514349 TI - Quantitative Analysis of Three-Dimensional Distribution and Clustering of Intramuscular Fat in Muscles of the Rotator Cuff. AB - The purpose of this study was to (1) develop and present a technique to quantitatively assess three-dimensional distribution and clustering of intramuscular fat and (2) use the technique to compare spatial characteristics of intramuscular fat in rotator cuff muscles of older adults with and without a supraspinatus tear. Moran's Index (I), an existing quantitative measure of clustering, was extended for use with MRI to allow comparisons across individuals with different size muscles. Sixteen older adults (>60 years) with (N = 6) and without (N = 10) a degenerative supraspinatus tear participated. Following 3D Dixon MRIs of the shoulder, which separates fat from water, rotator cuff muscles were segmented and sectioned and fat% and Moran's I were calculated to assess distribution and clustering, respectively. Moran's I ranged was 0.40-0.92 and 0.39-0.76 for the tear and control subjects, respectively. Compared to uninjured controls, tear subjects demonstrated increased fat distribution (p = 0.036) and clustering (p = 0.020) distally in the supraspinatus. Tear subjects had more pronounced distribution (p < 0.001) and clustering distally (p < 0.001) than proximally. Other rotator cuff muscles exhibited different patterns of fat clustering and distribution. This technique, which we applied to quantify spatial characteristics of intramuscular fat, can be applied to assess clustering of fat in other pathologies and tissues. PMID- 26514350 TI - Repetitive DNA in eukaryotic genomes. AB - Repetitive DNA--sequence motifs repeated hundreds or thousands of times in the genome--makes up the major proportion of all the nuclear DNA in most eukaryotic genomes. However, the significance of repetitive DNA in the genome is not completely understood, and it has been considered to have both structural and functional roles, or perhaps even no essential role. High-throughput DNA sequencing reveals huge numbers of repetitive sequences. Most bioinformatic studies focus on low-copy DNA including genes, and hence, the analyses collapse repeats in assemblies presenting only one or a few copies, often masking out and ignoring them in both DNA and RNA read data. Chromosomal studies are proving vital to examine the distribution and evolution of sequences because of the challenges of analysis of sequence data. Many questions are open about the origin, evolutionary mode and functions that repetitive sequences might have in the genome. Some, the satellite DNAs, are present in long arrays of similar motifs at a small number of sites, while others, particularly the transposable elements (DNA transposons and retrotranposons), are dispersed over regions of the genome; in both cases, sequence motifs may be located at relatively specific chromosome domains such as centromeres or subtelomeric regions. Here, we overview a range of works involving detailed characterization of the nature of all types of repetitive sequences, in particular their organization, abundance, chromosome localization, variation in sequence within and between chromosomes, and, importantly, the investigation of their transcription or expression activity. Comparison of the nature and locations of sequences between more, and less, related species is providing extensive information about their evolution and amplification. Some repetitive sequences are extremely well conserved between species, while others are among the most variable, defining differences between even closely relative species. These data suggest contrasting modes of evolution of repetitive DNA of different types, including selfish sequences that propagate themselves and may even be transferred horizontally between species rather than by descent, through to sequences that have a tendency to amplification because of their sequence motifs, to those that have structural significance because of their bulk rather than precise sequence. Functional consequences of repeats include generation of variability by movement and insertion in the genome (giving useful genetic markers), the definition of centromeres, expression under stress conditions and regulation of gene expression via RNA moieties. Molecular cytogenetics and bioinformatic studies in a comparative context are now enabling understanding of the nature and behaviour of this major genomic component. PMID- 26514351 TI - Chromosomes in the taiga. PMID- 26514352 TI - Rationale and design of the ODIn-AF Trial: randomized evaluation of the prevention of silent cerebral thromboembolism by oral anticoagulation with dabigatran after pulmonary vein isolation for atrial fibrillation. AB - Oral anticoagulation treatment following clinically successful catheter ablation of atrial fibrillation is controversial. Recent guidelines recommend continuation of oral anticoagulation in all patients with CHA2DS2VASc score >= 2 even if there is no evidence of recurrent atrial fibrillation. Due to lack of prospective data, the net clinical benefit of oral anticoagulation after successful ablation in these patients is unclear. As oral anticoagulation bears the risk of severe bleeding events, the ODIn-AF study aims to evaluate the effect of oral anticoagulation on the incidence of silent cerebral embolic events in patients with a high risk for embolic events, but free from symptomatic atrial fibrillation after successful pulmonary vein ablation. PMID- 26514353 TI - Safety of percutaneous coronary intervention in patients with acute ischemic stroke/transient ischemic attack and acute coronary syndrome. AB - BACKGROUND: Cardiac events in patients with acute stroke are frequent. Urgent PCI in myocardial infarction is crucial to improve outcome. However, the situation is complex as intracranial hemorrhage is a frequent complication of stroke but antithrombotic medication is indispensable during and after PCI. Therefore in this study, we aimed to investigate the safety of percutaneous coronary intervention (PCI) in patients hospitalized with acute ischemic stroke and concomitant acute coronary syndrome (ACS). METHODS AND RESULTS: In a single center, case-series study we investigated 80 patients hospitalized with acute stroke/transient ischemic attack (TIA) and concomitant ACS undergoing coronary angiography. Patients with subsequent PCI were compared to patients with medical treatment alone. The primary end point was the composite of death, recurrent MI, coronary re-intervention, recurrent stroke or bleeding during 1-year follow-up. The secondary end point consisted of the components of the primary end point. Age, gender and cardiovascular risk factors did not differ between groups. However, severity of initial stroke and coronary artery disease was higher in the PCI group. Accordingly, antiplatelet medication with aspirin and clopidogrel was prescribed more frequently in the PCI group. Nevertheless, during 1-year follow up, the primary end point did not differ between groups [38 vs. 50 %, odds ratio (OR) 1.7, CI 0.69-4.07, P = 0.23]. Intracranial hemorrhage was even numerically lower in patients undergoing PCI (5 vs. 3 %, OR 0.4, CI 0.04-5.6, P = 0.46). CONCLUSIONS: The primary and secondary end points were not enhanced in patients undergoing PCI. Therefore PCI is safe in patients with stroke/TIA and concomitant ACS. PMID- 26514354 TI - Case report: Cerebral stentretreiver thrombectomy of an embolized valve fragment after valve in valve TAVI. PMID- 26514355 TI - Effects of soil temperature and snow cover on the mortality of overwintering pupae of the cotton bollworm, Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae). AB - Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae) is one of the most damaging insect pests in the world. However, little is known about the effects of snow cover and soil temperature on the overwintering pupae of H. armigera. A field experiment was conducted from November 2, 2012 to April 24, 2013 at the agrometeorological experimental station in Wulanwusu, China. Overwintering pupae were embedded into the soil at depths of 5, 10, and 15 cm in the following four treatments: without snow cover, snow cover, and increased temperatures from 600 and 1200 W infrared lights. The results showed that snow cover and rising temperatures could all markedly increase soil temperatures, which was helpful in improving the survival of the overwintering pupae of H. armigera. The mortality of overwintering pupae (MOP) at a depth of 15 cm was the highest, and the MOP at a depth of 5 cm followed. The lower accumulated temperature (<=0 degrees C) (AT <= degrees C) led to the higher MOP, and the lower diurnal soil temperature range (DSTR) likely led to the lower MOP. After snowmelt, the MOPs at the depths of 5 and 10 cm increased as the soil temperature increased, especially in April. The AT of the soil (<=0 degrees C) was the factor with the strongest effect on MOP. The soil moisture content was not a major factor affecting the MOP in this semiarid region because precipitation was 45 mm over the entire experimental period. With climate warming, the MOP will likely decrease, and the overwintering boundary air temperatures of H. armigera should be expanded due to higher soil temperatures and increased snow cover. PMID- 26514356 TI - Erratum to: Preclinical Comparison of the Amyloid-beta Radioligands [(11)C]Pittsburgh compound B and [(18)F]florbetaben in Aged APPPS1-21 and BRI1-42 Mouse Models of Cerebral Amyloidosis. PMID- 26514357 TI - The Clinical and Histological Spectrum of Idiopathic Inflammatory Myopathies. AB - Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of myositis, characterised by chronic muscle weakness, cutaneous features, different extra muscular manifestations and circulating autoantibodies. IIMs included classical polymyositis (PM), dermatomyositis (DM) and other different types of myositis with a wide range of muscle involvement. A complete autoantibody profile and a muscle biopsy are mandatory to correctly diagnose different clinical entities and to define their different prognosis. Bohan and Peter's criteria included five items to diagnose adult onset PM and DM. The sensitivity was 74-100 %, while the specificity is low, due to a poor ability to differentiate PM from neuromuscular diseases. Other criteria included a more accurate histological definition of PM, DM or amyopathic DM, obtaining a higher specificity. Autoantibodies' association, interstitial lung disease and clinical cardiac involvement represent the main items that could define the prognosis of these patients. On the other hand, inclusion body myositis is a different myopathy characterised by a peculiar muscle mass involvement, muscle atrophy and progressive loss of function, due to complete failure to all immunosuppressive drugs used. Treatment of IIMs is based on corticosteroids (CS), which show rapid clinical response and functional improvement. Different immunosuppressant drugs are given to obtain a better control of the disease during CS tapering dose. No controlled double blind trials demonstrated the superiority of one immunesuppressant on another. The occurrence of interstitial lung involvement requires the immediate introduction of immunosuppressants in addiction to CS. Severe dysphagia seems to improve with intravenous immunoglobulins (Ig). Physical therapy could be started after the acute phase of diseases and seems to have a beneficial role in muscle strength recovery. PMID- 26514358 TI - Pediatric brain tumors in a low/middle income country: does it differ from that in developed world? AB - Central nervous system (CNS) tumors are the most frequent solid tumors in children and adolescents. The epidemiology of these tumors differs in areas of the world. However, very little data is available in the low/middle income countries (LMIC). The aim of this study is to describe the characteristics of primary childhood brain tumors treated at a leading LMIC pediatric cancer hospital and its difference from that in other countries. One thousand one hundred fourteen children and adolescent having CNS tumors were treated in the largest pediatric cancer hospital in the Middle East during a period of 51/2 years. They were diagnosed histopathologically in 80.2 %, through medical imaging in 19.4 % and via both tumor markers and imaging in the remaining 0.4 % of cases. Through epidemiological analysis was performed using all available patients' data revealed that 96 % of the patients had primary brain tumors, while only 4 % the primary lesion was in the spinal cord. The most common histological type was astrocytic tumor (30.0 %, pilocytic (GI) = 13.2 %, GII = 10.5 % and GIII + IV (high grade) = 6.3 %) followed by embryonal tumor (23.2 %, medulloblastoma = 18.7 %, PNET = 2.8 %, ATRT = 1.5 % and ependymoblastoma = 0.2 %) then ependymoma in 8.7 %, craniopharyngeoma in 5.3 %. The mean age at diagnosis was 7.1 +/- 4.2 years which did not differ significantly by gender nor residency but it differed by the pathological subtype. The frequency of each pathological type was different among different age groups. Though the present study was a hospital based analysis in a low/middle income country, yet it did not differ from the well-established population-based study reports in the high income countries. PMID- 26514359 TI - Somatic gain-of-function HIF2A mutations in sporadic central nervous system hemangioblastomas. AB - Central nervous system hemangioblastomas (CNS-HBs) occur sporadically or as a component of von Hippel-Lindau-VHL syndrome. CNS-HBs share some molecular similarities with pheochromocytomas/paragangliomas (PPGLs) and renal cell carcinomas (RCCs). Recently, hypoxia-inducible factors, particularly somatic HIF2A mutations, have been found to play an important role in the pathogenesis of PPGLs. Somatic mutations in HIF2A have been reported in PPGLs associated with polycythemia, which have been reported to also be present in patients with RCCs and HBs. However, whether CNS-HBs is associated with the presence of a HIF2A mutation is currently uknown. We analyzed somatic HIF2A and VHL mutations in a series of 28 sporadic CNS-HBs. We also investigated the expression of HIF target proteins and hypoxia-associated factor (HAF). Two sporadic CNS-HBs were found to have somatic HIF2A mutations. One tumor had 2 HIF2A missense mutations, one of which was previously described in a PPGL (c.1121 T>A, F374Y). The second patient had coexistence of somatic truncated mutations (c.1669 C>T, Q557*) in HIF2A together with a VHL mutation. Neither of the two patients had polycythemia at the time of diagnosis. We demonstrate that the novel truncated mutation in HIF2A (Q557*) affects HIF-2alpha prolyl hydroxylation with its reduced ubiquitination but intact transcriptional activity, resulting in an activating effect. Both CNS HB samples showed positive expression of VEGFR2/CA9/Glut1 and HAF. Our data support the unique central role of the VHL/HIF-2alpha signaling pathway in the molecular pathogenesis of CNS-HBs and show for the first time the presence of HIF2A mutations in sporadic HB. PMID- 26514360 TI - Pituitary metastasis: is there still a place for neurosurgical treatment? AB - Pituitary metastases are uncommon, ranging from 1 to 5 % of all metastases. Between 10 and 30 % of pituitary lesions are symptomatic responsible for diabetes insipidus, visual field defect or cranial nerve palsy. Primary sites are lung or breast in two-thirds of cases. There is no current reference concerning treatment of such lesions. Overall survival is poor and depends on primary site. Although the role of surgery is currently limited, discussion is warranted in several indications for diagnostic or symptomatic purposes. We report two cases of symptomatic pituitary metastases in a context of breast cancer and review the litterature concerning the role of surgery and other treatment modalities. PMID- 26514361 TI - Tryptophan PET predicts spatial and temporal patterns of post-treatment glioblastoma progression detected by contrast-enhanced MRI. AB - Amino acid PET is increasingly utilized for the detection of recurrent gliomas. Increased amino acid uptake is often observed outside the contrast-enhancing brain tumor mass. In this study, we evaluated if non-enhancing PET+ regions could predict spatial and temporal patterns of subsequent MRI progression in previously treated glioblastomas. Twelve patients with a contrast-enhancing area suspicious for glioblastoma recurrence on MRI underwent PET scanning with the amino acid radiotracer alpha-[(11)C]-methyl-L-tryptophan (AMT). Brain regions showing increased AMT uptake in and outside the contrast-enhancing volume were objectively delineated to include high uptake consistent with glioma (as defined by previous studies). Volume and tracer uptake of such non-enhancing PET+ regions were compared to spatial patterns and timing of subsequent progression of the contrast-enhancing lesion, as defined by serial surveillance MRI. Non-enhancing PET+ volumes varied widely across patients and extended up to 24 mm from the edge of MRI contrast enhancement. In ten patients with clear progression of the contrast-enhancing lesion, the non-enhancing PET+ volumes predicted the location of new enhancement, which extended beyond the PET+ brain tissue in six. In two patients, with no PET+ area beyond the initial contrast enhancement, MRI remained stable. There was a negative correlation between AMT uptake in non-enhancing brain and time to subsequent progression (r = -0.77, p = 0.003). Amino acid PET imaging could complement MRI not only for detecting glioma recurrence but also predicting the location and timing of subsequent tumor progression. This could support decisions for surgical intervention or other targeted therapies for recurrent gliomas. PMID- 26514362 TI - Review of seizure outcomes after surgical resection of dysembryoplastic neuroepithelial tumors. AB - Dysembryoplastic neuroepithelial tumors (DNETs) are rare tumors that present with seizures in the majority of cases. We report the results of a review of seizure freedom rates following resection of these benign lesions. We searched the English literature using PubMed for articles presenting seizure freedom rates for DNETs as a unique entity. Patient demographics, tumor characteristics, and operative variables were assessed across selected studies. Twenty-nine articles were included in the analysis. The mean age at surgery across studies was a median of 18 years (interquartile range 11-25 years). The mean duration of epilepsy pre-operatively was a median 7 years (interquartile range 3-11 years). Median reported gross-total resection rate across studies was 79% (interquartile range 62-92%). Authors variously chose lesionectomy or extended lesionectomy operations within and across studies. The median seizure freedom rate was 86% (interquartile range 77-93%) with only one study reporting fewer than 60% of patients seizure free. Seizure outcomes were either reported at 1 year of follow up or at last follow-up, which occurred at a median of 4 years (interquartile range 3-7 years). The number of seizure-free patients who discontinued anti epileptic drugs varied widely from zero to all patients. Greater extent of resection was associated with seizure freedom in four studies. PMID- 26514363 TI - Genetic variations in the homologous recombination repair pathway genes modify risk of glioma. AB - Accumulative epidemiological evidence suggests that single nucleotide polymorphisms (SNPs) in genes involved in homologous recombination (HR) DNA repair pathway play an important role in glioma susceptibility. However, the effects of such SNPs on glioma risk remain unclear. We used a used a candidate pathway-based approach to elucidate the relationship between glioma risk and 12 putative functional SNPs in genes involved in the HR pathway. Genotyping was conducted on 771 histologically-confirmed glioma patients and 752 cancer-free controls from the Chinese Han population. Odds ratios (OR) were calculated both for each SNP individually and for grouped analyses, examining the effects of the numbers of adverse alleles on glioma risk, and evaluated their potential gene gene interactions using the multifactor dimensionality reduction (MDR). In the single-locus analysis, two variants, the NBS1 rs1805794 (OR 1.42, 95% CI 1.15 1.76, P = 0.001), and RAD54L rs1048771 (OR 1.61, 95% CI 1.17-2.22, P = 0.002) were significantly associated with glioma risk. When we examined the joint effects of the risk-conferring alleles of these three SNPs, we found a significant trend indicating that the risk increases as the number of adverse alleles increase (P = 0.005). Moreover, the MDR analysis suggested a significant three-locus interaction model involving NBS1 rs1805794, MRE11 rs10831234, and ATM rs227062. These results suggested that these variants of the genes involved in the HR pathway may contribute to glioma susceptibility. PMID- 26514364 TI - Coexistence of Antiferromagnetism and Superconductivity in Heavy Fermion Cerium Compound Ce3PdIn11. AB - Many current research efforts in strongly correlated systems focus on the interplay between magnetism and superconductivity. Here we report on coexistence of both cooperative ordered states in recently discovered stoichiometric and fully inversion symmetric heavy fermion compound Ce3PdIn11 at ambient pressure. Thermodynamic and transport measurements reveal two successive magnetic transitions at T1 = 1.67 K and TN = 1.53 K into antiferromagnetic type of ordered states. Below Tc = 0.42 K the compound enters a superconducting state. The large initial slope of dBc2/dT ~ - 8.6 T/K indicates that heavy quasiparticles form the Cooper pairs. The origin of the two magnetic transitions and the coexistence of magnetism and superconductivity is briefly discussed in the context of the coexistence of the two inequivalent Ce-sublattices in the unit cell of Ce3PdIn11 with different Kondo couplings to the conduction electrons. PMID- 26514365 TI - Taxonomic Study of the Genus Apalacris Walker (Orthoptera: Catantopidae). AB - The research history of the genus Apalacris is reviewed; a key to all known species of the genus is given, and one new species, Apalacris eminifronta n. sp., and one new combination, Apalacris maculifemura (Lin & Zheng), are described. The new species is very closely related to Apalacris antennata Liang, but differs in the following characters: (1) tegmen longer, reaching apex of hind femur; (2) basal part of inner side of hind femur orange red; (3) frontal ridge more protruded, obviously depressed under median ocellus in lateral view; and (4) epiphallus bridge prominent, ancora shorter than anterior projection. PMID- 26514366 TI - Fluorescently-tagged anti-ganglioside antibody selectively identifies peripheral nerve in living animals. AB - Selective in vivo delivery of cargo to peripheral nervous system (PNS) has broad clinical and preclinical applications. An important applicability of this approach is systemic delivery of fluorescently conjugated ligands that selectively label PNS, which could allow visualization of peripheral nerves during any surgery. We examine the use of an anti-ganglioside monoclonal antibody (mAb) as selective neuronal delivery vector for surgical imaging of peripheral nerves. Systemic delivery of an anti-ganglioside mAb was used for selective intraneuronal/axonal delivery of fluorescent agents to visualize nerves by surgical imaging in living mice. In this study, we show that intact motor, sensory, and autonomic nerve fibers/paths are distinctly labeled following a single nanomolar systemic injection of fluorescently labeled anti-ganglioside mAb. Tissue biodistribution studies with radiolabeled mAb were used to validate neuronal uptake of fluorescently labeled mAb. Implications of this proof of concept study are that fluorescent conjugates of anti-ganglioside mAbs are valuable delivery vectors to visualize nerves during surgery to avoid nerve injury and monitor nerve degeneration and regeneration after injury. These findings support that antibodies, and their derivatives/fragments, can be used as selective neuronal delivery vector for transport of various cargos to PNS in preclinical and clinical settings. PMID- 26514367 TI - CXCR-4 Targeted, Short Wave Infrared (SWIR) Emitting Nanoprobes for Enhanced Deep Tissue Imaging and Micrometastatic Cancer Lesion Detection. AB - Realizing the promise of precision medicine in cancer therapy depends on identifying and tracking cancerous growths to maximize treatment options and improve patient outcomes. This goal of early detection remains unfulfilled by current clinical imaging techniques that fail to detect lesions due to their small size and suborgan localization. With proper probes, optical imaging techniques can overcome this by identifying the molecular phenotype of tumors at both macroscopic and microscopic scales. In this study, the first use of nanophotonic short wave infrared technology is proposed to molecularly phenotype small lesions for more sensitive detection. Here, human serum albumin encapsulated rare-earth nanoparticles (ReANCs) with ligands for targeted lesion imaging are designed. AMD3100, an antagonist to CXCR4 (a classic marker of cancer metastasis) is adsorbed onto ReANCs to form functionalized ReANCs (fReANCs). fReANCs are able to preferentially accumulate in receptor positive lesions when injected intraperitoneally in a subcutaneous tumor model. fReANCs can also target subtissue microlesions at a maximum depth of 10.5 mm in a lung metastatic model of breast cancer. Internal lesions identified with fReANCs are 2.25 times smaller than those detected with ReANCs. Thus, an integrated nanoprobe detection platform is presented, which allows target-specific identification of subtissue cancerous lesions. PMID- 26514368 TI - Copper(II) mediated phenol ring nitration by nitrogen dioxide. AB - Cu(II) complexes of N2O2 type ligands, L(1)H2 and L(2)H2 [L(1)H2 = 6,6' (((pyridin-2-ylmethyl)azanediyl)bis(methylene))bis(2,4-di-tert-butylphenol); L(2)H2 = 2,4-di-tert-butyl-6-(((3-(tert-butyl)-2-hydroxy-5-methylbenzyl)(pyridin 2-yl-methyl)amino)methyl)phenol], have been synthesized. Addition of nitrogen dioxide (NO2) in THF solutions of the complexes resulted in the nitration at the 4-position of a coordinated equatorial phenolate ring of the ligand frameworks. This nitration did not occur at the phenol ring which is axially coordinated to the metal center. Spectroscopic evidence suggests that the reaction proceeds through a phenoxyl radical complex formation. PMID- 26514369 TI - For which cancers might patients benefit most from expedited symptomatic diagnosis? Construction of a ranking order by a modified Delphi technique. AB - BACKGROUND: This study aimed to answer the question 'for which cancers, in a symptomatic patient, does expediting the diagnosis provide an improvement in mortality and/or morbidity?' METHODS: An initial ranking was constructed from previous work identifying 'avoidable deaths' for 21 common cancers in the UK. In a two-round modified Delphi exercise, 22 experts, all experienced across multiple cancers, used an evidence pack summarising recent relevant publications and their own experience to adjust this ranking. Participants also answered on a Likert scale whether they anticipated mortality or morbidity benefits for each cancer from expedited diagnosis. RESULTS: Substantial changes in ranking occurred in the Delphi exercise. Finally, expedited diagnosis was judged to provide the greatest mortality benefit in breast cancer, uterine cancer and melanoma, and least in brain and pancreatic cancers. Three cancers, prostate, brain and pancreas, attracted a median answer of 'disagree' to whether they expected mortality benefits from expedited diagnosis of symptomatic cancer. CONCLUSIONS: Our results can guide future research, with emphasis given to studying interventions to improve symptomatic diagnosis of those cancers ranked highly. In contrast, research efforts for cancers with the lowest rankings could be re-directed towards alternative avenues more likely to yield benefit, such as screening or treatment. PMID- 26514370 TI - Management of bone disease in women after breast cancer. AB - Breast cancer and osteoporosis are common conditions affecting women, particularly following menopause. With increasing breast cancer incidence, effects of therapies and decreasing mortality, issues relating to the preservation of bone health with breast cancer therapy have become a priority. Contributing factors to bone loss and fractures in women with breast cancer include tumor effects, estrogen deprivation secondary to breast cancer therapies (chemotherapy, ovarian ablation or aromatase inhibitors), natural menopause and secondary causes of bone loss, typically from concurrently prescribed medications. Management of osteoporosis and other survivorship care is complex, and a multi-disciplinary approach is recommended with assessment of risk factors for bone loss, optimization of bone health through lifestyle approaches and pharmacological interventions based on evidence-based algorithms. This review examines the pathophysiology of bone loss and gives guidelines for the management of bone disease in women with breast cancer. PMID- 26514371 TI - Parasediminibacterium paludis gen. nov., sp. nov., isolated from wetland. AB - A novel orange-pigmented bacterial strain, designated HME6815T, was isolated from wetland in Jeju Island, Republic of Korea. The cells were Gram stain-negative, non-motile, strictly aerobic and rod-shaped. Optimal growth occurred at 30 degrees C and pH 7.0 on R2A agar. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain HME6815T formed a distinct phyletic lineage within the family Chitinophagaceae and was most closely related to members of the genera Sediminibacterium, Vibrionimonas, Hydrobacter, Hydrotalea and Asinibacterium with 92.3-94.3 % 16S rRNA gene sequence similarity. The major cellular fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and iso-C13 : 0. The only respiratory quinone was MK-7. Polar lipid analysis revealed the presence of phosphatidylethanolamine, four unidentified aminolipids, one unidentified aminophospholipid and three unidentified polar lipids. The DNA G+C content was 38.4 mol%. On the basis of the evidence presented in this study, strain HME6815T represents a novel species of a new genus in the family Chitinophagaceae, for which the name Parasediminibacterium paludis gen. nov., sp. nov. is proposed. The type strain of the type species is HME6815T ( = KCTC 23736T = CECT 8010T). PMID- 26514372 TI - Ultra-high modulation depth exceeding 2,400% in optically controlled topological surface plasmons. AB - Modulating light via coherent charge oscillations in solids is the subject of intense research topics in opto-plasmonics. Although a variety of methods are proposed to increase such modulation efficiency, one central challenge is to achieve a high modulation depth (defined by a ratio of extinction with/without light) under small photon-flux injection, which becomes a fundamental trade-off issue both in metals and semiconductors. Here, by fabricating simple micro-ribbon arrays of topological insulator Bi2Se3, we report an unprecedentedly large modulation depth of 2,400% at 1.5 THz with very low optical fluence of 45 MUJ cm( 2). This was possible, first because the extinction spectrum is nearly zero due to the Fano-like plasmon-phonon-destructive interference, thereby contributing an extremely small denominator to the extinction ratio. Second, the numerator of the extinction ratio is markedly increased due to the photoinduced formation of massive two-dimensional electron gas below the topological surface states, which is another contributor to the ultra-high modulation depth. PMID- 26514373 TI - Pheromone-encoded mRNA transport in mating yeast. PMID- 26514374 TI - Exploring the communication of oncologists, patients and family members in cancer consultations: development and application of a coding system capturing family relevant behaviours (KINcode). AB - BACKGROUND: Family members (FMs) regularly attend oncology consultations. However, limited studies have assessed actual behaviours of oncologists, patients and FMs - particularly during decision-making. The current study aimed the following: (i) to rigorously develop a family (kin) interaction coding system (KINcode) capturing communication and decision-making behaviours of FMs and family-relevant behaviours of oncologists and patients and (ii) to apply KINcode to initial oncology consultations. METHODS: The 80-item KINcode system was developed and applied to 72 transcripts of audiotaped medical/radiation oncology consultations including an FM, collected as part of two previous studies. RESULTS: The role of the FM varied considerably within the one encounter, with 33% of FMs assuming three or more roles across the four consultation stages. Whilst most FMs asked treatment decision questions (71%), a minority engaged in other behaviours such as prompting patient questions (4%) or providing information relevant to the decision to the oncologist (18%). Although oncologists rarely initiated interaction with FMs such as in rapport building (18%) or asking FMs questions (25%), they were typically fully responsive to FM questions (90%). Many patients asked their FM a question (42%), but few elicited the FM's decision preferences (4%). CONCLUSIONS: This study provides novel insights into the complex nature of family involvement. The findings highlight potentially positive FM-focused consultation behaviours such as oncologist responsiveness to family questions and potential areas for improvement such as rapport building, invitation of questions and validation of the family's role. Family-specific communication skills training should be considered in medical student and professional education settings. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26514375 TI - Current preclinical small interfering RNA (siRNA)-based conjugate systems for RNA therapeutics. AB - Recent promising clinical results of RNA therapeutics have drawn big attention of academia and industries to RNA therapeutics and their carrier systems. To improve their feasibility in clinics, systemic evaluations of currently available carrier systems under clinical trials and preclinical studies are needed. In this review, we focus on recent noticeable preclinical studies and clinical results regarding siRNA-based conjugates for clinical translations. Advantages and drawbacks of siRNA-based conjugates are discussed, compared to particle-based delivery systems. Then, representative siRNA-based conjugates with aptamers, peptides, carbohydrates, lipids, polymers, and nanostructured materials are introduced. To improve feasibility of siRNA conjugates in preclinical studies, several considerations for the rational design of siRNA conjugates in terms of cleavability, immune responses, multivalent conjugations, and mechanism of action are also presented. Lastly, we discuss lessons from previous preclinical and clinical studies related to siRNA conjugates and perspectives of their clinical applications. PMID- 26514376 TI - Group Violence and Migration Experience among Latin American Youths in Justice Enforcement Centers (Madrid, Spain). AB - Group violence among Latin American immigrant youth has led to ongoing debates in political, legal, and media circles, yet none of those many perspectives has arrived at a solid, empirically supported definition for the phenomenon. This study aims to explore the relationship between the immigrant experience and violent group behavior in youths from Latin America serving prison sentences in Justice Enforcement Centers in the Community of Madrid. Semi-structured interviews were conducted with 19 juveniles, and content analysis was applied to the resulting transcripts, employing Grounded Theory to create an axial codification of intra- and inter-categorical contents, and Delphi panels for quality control. The research team delved into 62 topics, addressing participants' perceptions of the immigrant experience and its effects on five socialization settings (neighborhood, school, family, peer group, and significant other), and each one's relationship to violent behavior. The results led us to believe the young people's immigration experiences had been systematically examined. Their personal and social development was influenced by negative socioeconomic conditions, ineffective parental supervision, maladjustment and conflict at school, and experiences of marginalization and xenophobia. All those conditions favored affiliation with violent groups that provided them instrumental (economic and material), expressive, or affective support. PMID- 26514377 TI - Hippocampal-dependent neurocognitive impairment following cranial irradiation observed in pre-clinical models: current knowledge and possible future directions. AB - We reviewed the literature for studies pertaining to impaired adult neurogenesis leading to neurocognitive impairment following cranial irradiation in rodent models. This compendium was compared with respect to radiation dose, converted to equivalent dose in 2 Gy fractions (EQD2) to allow for direct comparison between studies. The effects of differences between animal species and the dependence on animal age as well as for time after irradiation were also considered. One of the major sites of de novo adult neurogenesis is the hippocampus, and as such, this review also focuses on assessing evidence related to the expression and potential effects of inflammatory cytokines on neural stem cells in the subgranular zone of the dentate gyrus and whether this correlates with neurocognitive impairment. This review also discusses potential strategies to mitigate the detrimental effects on neurogenesis and neurocognition resulting from cranial irradiation, and how the rationale for these strategies compares with the current outcome of pre-clinical studies. PMID- 26514379 TI - Diterpenoids of terrestrial origin. AB - Covering January to December 2014. Previous review, Nat. Prod. Rep., 2015, 32, 76 87 This review covers the isolation and chemistry of diterpenoids from terrestrial as opposed to marine sources and includes, labdanes, clerodanes, abietanes, pimaranes, kauranes, cembranes and their cyclization products. There are 200 references. PMID- 26514378 TI - Exploring Massachusetts Health Care Reform Impact on Fee-for-Service-Funded Substance Use Disorder Treatment Providers. AB - The Affordable Care Act (ACA) is forecast to increase the demand for and utilization of substance use disorder (SUD) treatment. Massachusetts implemented health reforms similar to the ACA in 2006-2007 that included expanding coverage for SUD treatment. This study explored the impact of Massachusetts health reforms from 2007 to 2010 on SUD treatment providers in Massachusetts, who relied on fee for-service billings for more than 50% of their revenue. The changes across treatment facilities located in Massachusetts were compared to changes in other similar fee-for-service-funded SUD treatment providers in Northeast states bordering Massachusetts and in all other states across the US. From 2007-2010, the percentage changes for Massachusetts based providers were significantly different from the changes among providers located in the rest of the US for admissions, outpatient census, average weeks of outpatient treatment, residential/in-patient census, detoxification census, length of average inpatient and outpatient stays, and provision of medication-assisted treatment. Contrary to previous studies of publicly funded treatment providers, the results of this exploratory study of providers dependent on fee-for-service revenues were consistent with some predictions for the overall effects of the ACA. PMID- 26514381 TI - [Pathophysiology of human mitochondrial diseases]. AB - Mitochondrial diseases, defined as the diseases due to oxidative phosphorylation defects, are the most frequent inborn errors of metabolism. Their clinical presentation is highly diverse. Their diagnosis is difficult. It relies on metabolic parameters, histological anomalies and enzymatic assays showing defective activity, all of which are both inconstant and relatively unspecific. Most mitochondrial diseases have a genetic origin. Candidate genes are very numerous, located either in the mitochondrial genome or the nuclear DNA. Pathophysiological mechanisms of mitochondrial diseases are still the matter of much debate. Those underlying the tissue-specificity of diseases due to the alterations of a ubiquitously expressed gene are discussed including (i) quantitative aspect of the expression of the causal gene or its partners when appropriate, (ii) quantitative aspects of the bioenergetic function in each tissue, and (iii) tissue distribution of heteroplasmic mitochondrial DNA alterations. PMID- 26514380 TI - Comparisons of the performance of different statistical tests for time-to-event analysis with confounding factors: practical illustrations in kidney transplantation. AB - Confounding factors are commonly encountered in observational studies. Several confounder-adjusted tests to compare survival between differently exposed subjects were proposed. However, only few studies have compared their performances regarding type I error rates, and no study exists evaluating their type II error rates. In this paper, we performed a comparative simulation study based on two different applications in kidney transplantation research. Our results showed that the propensity score-based inverse probability weighting (IPW) log-rank test proposed by Xie and Liu (2005) can be recommended as a first descriptive approach as it provides adjusted survival curves and has acceptable type I and II error rates. Even better performance was observed for the Wald test of the parameter corresponding to the exposure variable in a multivariable adjusted Cox model. This last result is of primary interest regarding the exponentially increasing use of propensity score-based methods in the literature. PMID- 26514382 TI - [Mechanisms of antiviral immunity, therapeutic challenges and development of anti AIDS vaccines]. PMID- 26514383 TI - [Plasmacytoid dendritic cells: the novel Eldorado for antiviral therapy?]. AB - Plasmacytoid dendritic cells (pDCs) represent the first line of host defense against viruses and are an essential link between innate and adaptive immunity. The antiviral factor IFN-alpha is massively produced by pDCs in response to HIV infection and induces the expression of cellular genes that interfere with viral replication (ISG). Indeed, type I IFN produced by pDCs has a direct anti-viral activity against HIV and has important adjuvant function on other immune cell types, such as T cells, macrophages and dendritic cells. However, the role of type I IFN in HIV disease is complex and may depend on the stage of the disease. The immunologic hallmark of HIV infection is a status of chronic and progressive immune activation, which drives the immune system to exhaustion and leads to severe immunodeficiency. There is now strong evidence that chronic activation of pDCs may promote HIV pathogenesis and have an impact on adaptive T-cell response. Thus, targeting pDCs and type I IFN may open new therapeutic strategies for chronically activated HIV patients. PMID- 26514384 TI - [Stimulating Type I interferon response with small molecules: revival of an old idea]. AB - Type I interferons play a central role in the establishment of an innate immune response against viral infections and tumor cells. Shortly after their discovery in 1957, several groups have looked for small molecules capable of inducing the expression of these cytokines with therapeutic applications in mind. A set of active compounds in mice were identified, but because of their relative inefficiency in humans for reasons not understood at the time, these studies fell into oblivion. In recent years, the characterization of pathogen recognition receptors and the signaling pathways they activate, together with the discovery of plasmacytoid dendritic cells, have revolutionized our understanding of innate immunity. These discoveries and the popularization of high-throughput screening technologies have renewed the interest for small molecules that can induce type I interferons. Proofs about their therapeutic potency in humans are expected very soon. PMID- 26514385 TI - [Towards a vaccine against HIV: antibodies raised by a gp41 peptide neutralize the virus and inhibit pathogenesis]. AB - In spite of numerous attempts, only one vaccine candidate showed a potentiality to prevent HIV infection. Such capacity, unfortunately partial, was due to the activity of specific antibodies, indicating the importance of humoral responses. However, the lack of a specific target did not allow to identify an epitope able to stimulate such a response. In addition, in view of a vaccine with preventive and therapeutic activities, it seems of interest to both be able to neutralize the virus and prevent its pathogenesis. We have identified a gp41 peptide inducing antibodies with such dual properties, therefore representing a future vaccine candidate to test functional capacities to fight HIV infection. PMID- 26514386 TI - [Ovocyte vitrification: a tool for the future]. AB - Ovocyte vitrification was finally authorized by the new law voted in July 2011 upon the revision of the French bioethics law. Expected for 30 years, cryopreservation of female gametes had a major impact on Assisted Reproductive Technologies (ART) practice worldwide and in our country. It brought tremendous changes in the field of reproductive biology, from intraconjugal infertility management to gamete donation, through autologous cryopreservation for fertility preservation. Although it appears to be "obvious", ovocyte vitrification seems to be barely used as a routine technique in French IVF laboratories. We will discuss the events that led to the present situation. We will also tackle the expected benefits of ovocyte vitrification especially as an alternative to embryo freezing. PMID- 26514387 TI - [Epigenetics and Nutrition: maternal nutrition impacts on placental development and health of offspring]. AB - The environment, defined broadly by all that is external to the individual, conditions the phenotype during development, particularly the susceptibility to develop non-communicable diseases. This notion, called Developmental Origins of Health and Disease (DOHaD), is based on numerous epidemiological studies as well as animal models. Thus, parental nutrition and obesity can predispose the offspring to develop metabolic and cardiovascular diseases in adulthood. The known underlying mechanisms include an altered development of tissues that adapt to maternal metabolic condition, and a placental dysfunction, which in turn impacts fetal growth and development. Epigenetic mechanisms modulate gene expression without affecting the DNA sequence itself. The main epigenetic marks are DNA methylation and histone post-translational modifications. These marks are erased and set-up during gametogenesis and development in order to ensure cellular identity. Therefore, they can lead to a memorisation of early environment and induce long-term alteration of cell and tissue functions, which will condition the susceptibility to non-communicable diseases. The placenta is a programming agent of adult disease. The environment, such as smoking or psychosocial stress, is able to modify epigenetic processes in placenta, such as small RNA expression and DNA methylation. We showed that placenta is sensitive to maternal obesity and maternal nutrition, in terms of histology, transcription and epigenetic marks. A clear sexual dimorphism is remarkable in the placental response to maternal environment. In adulthood, the phenotype is also different between males and females. Epigenetic mechanisms could underlie this differential response of males and females to the same environment. The DOHaD can no longer be ignored in Biology of Reproduction. The prevention of non-communicable diseases must take this new paradigm into account. Research will allow a better comprehension of the mechanisms of this early conditioning and the marked sexual dimorphism it is associated to. PMID- 26514388 TI - [Pierre Rayer and the creation of the Societe de Biologie]. PMID- 26514389 TI - Reversible switching of liquid crystal micro-particles in a nematic liquid crystal. AB - Liquid crystal micro-particles are functional materials possessing optical and dielectric anisotropies originating from the arrangement of rod-like molecules within the particles. Although they can be switched by an electric field, particles dispersed in isotropic hosts usually cannot return to their original state, because there is no restoration force acting on the particles. Here, we describe reversible switching of liquid crystal micro-particles by dispersing them in a nematic liquid crystal host. We fabricate square micro-particles with unidirectional molecular alignment and investigate their static and dynamic electro-optic properties by applying an in-plane electric field. The behavior of the micro-particles is well-described by the theoretical model we construct, making this study potentially useful for the development of liquid crystal-liquid crystal particle composites with engineered properties. PMID- 26514391 TI - A major failure of scientific governance. PMID- 26514390 TI - Fast reconstruction of highly undersampled MR images using one and two dimensional principal component analysis. AB - Recent compressed sensing techniques allow signal acquisition with less sampling than required by the Nyquist-Shannon theorem which reduces the data acquisition time in magnetic resonance imaging (MRI). However, prior knowledge becomes essential to reconstruct detailed features when the sampling rate is exceedingly low. In this work, one compressed sensing scheme developed in wireless sensing networks was adapted for the purpose of reconstructing magnetic resonance images by using one-dimensional principal component analysis (1D-PCA). Moreover, another related reconstruction method was proposed based on two-dimensional principal component analysis (2D-PCA). When comparing with one wavelet compressed sensing method, we demonstrate that these techniques are feasible and efficient at high undersampling rates. PMID- 26514392 TI - Defining postoperative stability in children with radial polydactyly. AB - There is little fundamental data on paediatric metacarpophalangeal joint instability in radial polydactyly following surgical reconstruction. We evaluated 27 thumbs in a healthy paediatric population (Group A: eight girls and 19 boys with a mean age of 9.7 years (range 2.7-14.2)) and 12 thumbs following Wassel-IV reconstruction (Group B: eight girls and four boys with a mean age at follow-up of 10.6 years (range 2.7-13.2)). Metacarpophalangeal joint radial deviation, ulnar deviation on stress testing, interphalangeal joint and metacarpophalangeal joint alignment on posterior-anterior radiographs were measured and scored according to parameters defining joint instability. The aim of our study was to provide fundamental data on thumb metacarpophalangeal joint mobility patterns and alignment for further postoperative evaluations in children. The average ulnar deviation and radial deviation on stress testing of the healthy (Group A) metacarpophalangeal joints was 25 degrees (10 degrees -45 degrees ) and 30 degrees (10 degrees -55 degrees ), respectively. In the operated (Group B) thumbs, the ulnar deviation and radial deviation was greater at 35 degrees (10 degrees -55 degrees ) and 30 degrees (10 degrees -70 degrees ). Ulnar deviation (UD) of the proximal phalanx at the metacarpophalangeal joint on posterior anterior radiographs was a mean of 10 degrees (range -10 degrees -30 degrees ) in Group B; this was significantly greater than in Group A at a mean of 5 degrees (range -5-20 degrees ) (p = 0.029). The mean radial alignment of the interphalangeal joint (distal phalanx relative to the proximal phalanx) was significantly higher in Group B (15 degrees ) than Group A (0 degrees ) (p = 0.221). In the literature on radial polydactyly, cut off values defining metacarpophalangeal joint instability in children range from 5 degrees to 20 degrees . According to our results, high but physiological metacarpophalangeal joint mobility of the thumb needs to be taken into consideration when evaluating children following reconstruction. Ulnar or radial deviation greater than 30 degrees , in combination with the lack of a definite end point on metacarpophalangeal joint stress testing, may be regarded as unstable. Based on our study on healthy paediatric and reconstructed thumbs, comparison of joint stability with the healthy contralateral hand is recommended in order to define pathological instability. LEVEL OF EVIDENCE: II. PMID- 26514393 TI - Dimensionality and Genetic Correlates of Problem Behavior in Low-Income African American Adolescents. AB - Researchers have long observed that problem behaviors tend to cluster together, particularly among adolescents. Epidemiological studies have suggested that this covariation is due, in part, to common genetic influences, and a number of plausible candidates have emerged as targets for investigation. To date, however, genetic association studies of these behaviors have focused mostly on unidimensional models of individual phenotypes within European American samples. Herein, we compared a series of confirmatory factor models to best characterize the structure of problem behavior (alcohol and marijuana use, sexual behavior, and disruptive behavior) within a representative community-based sample of 592 low-income African American adolescents (50.3% female), ages 13 to 18. We further explored the extent to which 3 genes previously implicated for their role in similar behavioral dimensions (CHRM2, GABRA2, and OPRM1) independently accounted for variance within factors specified in the best-fitting model. Supplementary analyses were conducted to derive comparative estimates for the predictive utility of these genes in more traditional unidimensional models. Findings provide initial evidence for a bifactor structure of problem behavior among African American adolescents and highlight novel genetic correlates of specific behavioral dimensions otherwise undetected in an orthogonal syndromal factor. Implications of this approach include increased precision in the assessment of problem behavior, with corresponding increases in the reliability and validity of identified genetic associations. As a corollary, the comparison of primary and supplementary association analyses illustrates the potential for overlooking and/or overinterpreting meaningful genetic effects when failing to adequately account for phenotypic complexity. PMID- 26514394 TI - Ambient air pollution and risk of tuberculosis: a cohort study. AB - OBJECTIVES: Several respirable hazards, including smoking and indoor air pollution from biomass, were suggested to increase the risk of tuberculosis. Few studies have been conducted on ambient air pollution and tuberculosis. We investigated the association between exposure to ambient air pollution and incidence of active tuberculosis. METHODS: We conducted a cohort study using 106,678 participants of a community-based screening service in Taiwan, 2005-2012. We estimated individual exposure to air pollution using data from the nearest air quality monitoring station and the road intensity within a 500 m buffer zone. The incidence of tuberculosis was ascertained from the national tuberculosis registry. RESULTS: After a median follow-up of 6.7 years, 418 cases of tuberculosis occurred. Exposure to fine particulate matter (PM2.5) was associated with increased risk of active tuberculosis (adjusted HR: 1.39/10 MUg/m3 (95% CI 0.95 to 2.03)). In addition, traffic-related air pollution including nitrogen dioxide (adjusted HR: 1.33/10 ppb; 95% CI 1.04 to 1.70), nitrogen oxides (adjusted HR: 1.21/10 ppb; 95% CI 1.04 to 1.41) and carbon monoxide (adjusted HR: 1.89/ppm; 95% CI 0.78 to 4.58) was associated with tuberculosis risk. There was a non-significant trend between the length of major roads in the neighbourhood and culture-confirmed tuberculosis (adjusted HR: 1.04/km; 95% CI 0.995 to 1.09). CONCLUSIONS: Our study revealed a possible link between ambient air pollution and risk of active tuberculosis. Since people from developing countries continue to be exposed to high levels of ambient air pollution and to experience high rates of tuberculosis, the impact of worsening air pollution on global tuberculosis control warrants further investigation. PMID- 26514395 TI - Graft Failure and Intraocular Pressure Control After Keratoplasty in Iridocorneal Endothelial Syndrome. PMID- 26514396 TI - Reply. PMID- 26514397 TI - Blood Trials: Transfusions, Injections, and Experiments in Africa, 1890-1920. AB - From about 1880 to 1920, a culture of medical experimentation promoted blood transfusion as a therapy for severe anemia in Europe, which was applied in German East Africa in 1892 for a case of blackwater fever, a complication of malaria afflicting mainly Europeans. This first case of blood transfusion in Africa, in which an African's blood was transfused into a German official, complicates the dominant narrative that blood transfusions in Africa came only after World War I. Medical researchers moreover experimented with blood serum therapies on human and animal subjects in Europe and Africa, injecting blood of different species, "races" and ethnicities into others to demonstrate parasite transmissibility and to discover vaccines for diseases such as malaria, sleeping sickness, and yellow fever. While research in German colonies is highlighted here, this was a transnational medical culture that crossed borders and oceans. This research is of interest as a possible early pathway for the epidemic spread of HIV and other zoonoses in Africa and the world, which biomedical researchers have identified as emerging in West-Central Africa sometime around the turn of the twentieth century. PMID- 26514398 TI - Differences in preductal and postductal arterial blood gas measurements in infants with severe congenital diaphragmatic hernia. AB - OBJECTIVE: To determine whether right-to-left shunting across the ductus arteriosus (DA) in patients with congenital diaphragmatic hernia (CDH) with suprasystemic pulmonary hypertension (PH) results in differences between preductal and postductal arterial blood gas (ABG) measurements. DESIGN: Demographics, baseline echocardiographic parameters and differences in simultaneous right upper extremity (preductal) and umbilical artery (postductal) ABG samples were determined in newborns with PH and CDH. SETTING: Newborn intensive care unit at Children's Hospital Colorado. PATIENTS: 30 newborns with CDH and systemic or suprasystemic PH. INTERVENTIONS: Simultaneous preductal and postductal ABGs were compared in 30 newborns with PH and CDH, and ventilator settings and fraction of inspired oxygen (FiO2) were adjusted based on preductal ABG samples. Differences in respiratory support before and after obtaining preductal ABG samples were compared. RESULTS: All patients had severe PH by echocardiogram with right-to-left DA shunting. However, only two newborns (6.6%) had right-to-left shunting across the foramen ovale. When compared with postductal ABG samples, preductal arterial pH was 7.35+/-0.02 vs 7.30+/-0.02, PaCO2 40.8+/-1.9 vs 48.3+/-1.9, PaO2 99.3+/-7.8 vs 46+/-3, oxygen saturation 95.6+/-1.2 vs 85.2+/-1.7 and oxygenation index 14.1+/-2.3 vs 30.1+/-5.1 (p<0.05 for all comparisons). Targeting preductal ABG measurements allowed for significant weaning of FiO2. CONCLUSIONS: Right-to-left DA shunting decreases postductal PaO2, oxygen saturation and pH, and increases PaCO2. Targeting preductal ABG measurements may allow for a more physiological approach to ventilator management, and potentially reduce lung injury. PMID- 26514399 TI - Does retrieval intentionality really matter? Similarities and differences between involuntary memories and directly and generatively retrieved voluntary memories. AB - Theories of autobiographical memory distinguish between involuntary and voluntary retrieval as a consequence of conscious intention (i.e., wanting to remember). Another distinction can be made between direct and generative retrieval, which reflects the effort involved (i.e., trying to remember). However, it is unclear how intention and effort interacts. For example, involuntary memories and directly retrieved memories have been used interchangeably in the literature to refer to the same phenomenon of effortless, non-strategic retrieval. More recent theoretical advances suggest that they are separate types of retrieval, one unintentional (involuntary), another intentional and effortless (direct voluntary retrieval), and a third intentional and effortful (generative voluntary retrieval). Whether this also entails differing phenomenological characteristics, such as vividness, rehearsal, or emotional valence, has not been previously investigated. In the current study, participants reported memories in an experimental paradigm designed to elicit voluntary and involuntary memories and rated them on a number of characteristics. If intention affects the retrieval process, then we should expect differences between the characteristics of involuntary and directly retrieved memories. The results imply that retrieval intention seems to differentiate how a memory appears in a person's mind. Furthermore, we argue that these differences in part could result from differences in encoding and consolidation. PMID- 26514400 TI - Is there a role for neurotrophic factors and their receptors in augmenting the neuroprotective effect of (-)-epigallocatechin-3-gallate treatment of sciatic nerve crush injury? AB - This study analyzed and compared the effects of EGCG treatment on the expression of NTFs and NTF receptors expression in the sciatic nerve and the L3-L6 spinal cord segments at the early phase of regeneration following sciatic nerve crush injury. Analysis of BDNF, GDNF and NT3 neurotropic factors and Trk-B, Trk-C and NGFR-p75 receptors in neurons in the spinal cord of CRUSH and CRUSH + EGGC rats showed significant (p < 0.0001) decrease compared to NAIVE and SHAM at day 1, 3, 7 and 14 after nerve injury. EGCG treatment significantly (p < 0.0001) increased the BDNF, GDN, NT3, Trk-B, Trk-C and NGFR-p75 immunostaining in the L3-L6 spinal cord compared to CRUSH animals. Also, EGCG treatment significantly increased the Trk-B protein concentration and Trk-B, NT3 and Trk-C gene expression in the spinal cords compared to CRUSH group. However, at day 1 and 3 post nerve injury, EGCG treatment significantly decreased the NGFR-p75 expression compared to CRUSH rats. In the sciatic nerve, EGCG treatment significantly (p < 0.01) increased the Trk-B and NGFR-p75 protein concentration in the controls. EGCG treatment significantly (p < 0.0001) increased the Trk-B, Trk-C and NGFR-p75 mRNA gene expressions in the sciatic nerves compared to CRUSH group. Only at day 1, CRUSH + EGCG animals displayed significant rise in the sciatic nerves NT3 gene expression compared to CRUSH group. Our data suggest that the EGCG neuroprotective effect on the spinal cord neurons may be mediated through the modulation of NTFs and NTF receptors following nerve crush injury in a rat model. PMID- 26514401 TI - Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons. AB - Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan, is elevated in the brain of patients with psychotic disorders. Therefore, lowering brain KYNA levels might be a novel approach in the treatment of psychotic disorders. The present in vivo electrophysiological study aimed to investigate the effect of an inhibitor of kynurenine aminotransferase (KAT) II, the primary enzyme for KYNA synthesis, on dopamine (DA) neurons in the ventral tegmental area (VTA). Acute administration of the KAT II inhibitor PF-04859989 (5 or 10 mg/kg) was associated with a short-onset, time-dependent decrease in firing rate and burst activity of DA neurons, both parameters reaching a 50% reduction within 45 min. Furthermore, PF-04859989 reduced the number of spontaneously active DA cells as measured 4-6 after administration. Pretreatment with d-cycloserine (30 mg/kg) or CGP-52432 (10 mg/kg) prevented the inhibitory action of PF-04859989 (5 mg/kg) on firing rate and burst firing activity. In contrast, pretreatment with methyllycaconitine (MLA, 4 mg/kg) did not change the response, whereas picrotoxin (4.5 mg/kg) partially prevented the inhibitory effects of PF-04859989 (5 mg/kg, i.v.). Our results show that a specific inhibition of KAT II is associated with a marked reduction in VTA DA firing activity. This effect appears to be specifically executed by NMDA-receptors and mediated indirectly via a GABA(B)-receptor-induced disinhibition of DA neurons. Our findings are in line with the view that endogenous KYNA, by modulation of the NMDA-receptor, exerts important physiological roles in the brain. PMID- 26514402 TI - Purinergic contribution to amyotrophic lateral sclerosis. AB - By signalling through purinergic receptors classified as ionotropic P2X (for ATP) and metabotropic P1 (for adenosine) and P2Y (mainly for ADP, UDP, UTP, ATP), the extracellular nucleotides and their metabolic derivatives originated by extracellular activity of several different ectonucleotidases, are involved in the functioning of the nervous system. Here they exert a central role during physiological processes, but also in the precarious balance between beneficial and noxious events. Indeed, in recent years, the dysregulation of extracellular purinergic homeostasis has been correlated to well-characterized acute and chronic neurodegenerative and neuroinflammatory diseases. Among these, we focus our attention on purinergic signalling occurring in amyotrophic lateral sclerosis (ALS), the most common late onset motoneuron disease, characterized by specific loss of motoneurons in brain stem and ventral horns of spinal cord. ALS is a progressive non-cell-autonomous and multifactorial neuroinflammatory disease, whose aetiology and pathological mechanisms are unidentified for most patients and initiate long before any sign or symptom becomes apparent. By combining purinergic with ALS knowledge, in this work we thus present and sustain a novel line of investigation on the purinergic contribution to ALS. In particular, here we recapitulate very early results about P2X4, P2X7 and P2Y6 receptor expression in tissues from ALS animal and cell models and patients, and more recent achievements about purinergic signalling mainly performed in vitro in microglia and lately in astrocytes and motoneurons. We finally highlight how purinergic signalling has progressively evolved up to preclinical trials, to the point of deserving now full consideration with reference to ALS. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID- 26514403 TI - From culturomics to taxonomogenomics: A need to change the taxonomy of prokaryotes in clinical microbiology. AB - By diversifying culture conditions, in a strategy named culturomics, we were able in a short time to grow 124 new bacterial species from human stools, including 39 strict anaerobes. To describe these microorganisms, we use genome sequencing and MALDI-TOF mass spectrometry. Both tools have been major breakthroughs in clinical microbiology over the past decade, have previously been used for taxonomic purposes, and have the advantage over chemotaxonomic methods and DNA-DNA hybridization, to exhibit an excellent intra- and inter-laboratory reproducibility. We developed a polyphasic taxonomic strategy including MALDI-TOF MS and genomic analyses to describe new bacterial species associated with human beings. This strategy, that we have named taxono-genomics, was used to propose the description of 48 new species, the names of 13 of which have officially been validated. In this manuscript, we briefly reviewed the pros and cons of the currently validated taxonomic tools and propose that genomic sequencing and MALDI TOF mass spectrometry may be incorporated in the taxonomic classification of prokaryotes. PMID- 26514404 TI - Enhancing the efficacy of cation-independent mannose 6-phosphate receptor inhibitors by intracellular delivery. AB - Intracellular delivery of M6P/IGFII receptor inhibitors exhibits better efficacy than extracellular inhibitors to regulate TGFbeta1 mediated upregulation of profibrotic marker, collagen I. PMID- 26514405 TI - Characterization of red-shifted phycobilisomes isolated from the chlorophyll f containing cyanobacterium Halomicronema hongdechloris. AB - Phycobilisomes are the main light-harvesting protein complexes in cyanobacteria and some algae. It is commonly accepted that these complexes only absorb green and orange light, complementing chlorophyll absorbance. Here, we present a new phycobilisome derived complex that consists only of allophycocyanin core subunits, having red-shifted absorption peaks of 653 and 712 nm. These red shifted phycobiliprotein complexes were isolated from the chlorophyll f containing cyanobacterium, Halomicronema hongdechloris, grown under monochromatic 730 nm-wavelength (far-red) light. The 3D model obtained from single particle analysis reveals a double disk assembly of 120-145 A with two alpha/beta allophycocyanin trimers fitting into the two separated disks. They are significantly smaller than typical phycobilisomes formed from allophycocyanin subunits and core-membrane linker proteins, which fit well with a reduced distance between thylakoid membranes observed from cells grown under far-red light. Spectral analysis of the dissociated and denatured phycobiliprotein complexes grown under both these light conditions shows that the same bilin chromophore, phycocyanobilin, is exclusively used. Our findings show that red shifted phycobilisomes are required for assisting efficient far-red light harvesting. Their discovery provides new insights into the molecular mechanisms of light harvesting under extreme conditions for photosynthesis, as well as the strategies involved in flexible chromatic acclimation to diverse light conditions. PMID- 26514406 TI - Evoked potentials as predictors of adverse outcomes after intracranial vascular procedures. PMID- 26514407 TI - Pulmonary cysts identified on chest CT: are they part of aging change or of clinical significance? AB - OBJECTIVE: To investigate the prevalence and natural course of pulmonary cysts in a population-based cohort and to describe the CT image characteristics in association with participant demographics and pulmonary functions. MATERIALS AND METHODS: Chest CT scans of 2633 participants (mean age 59.2 years; 50% female) of the Framingham Heart Study (FHS) were visually evaluated for the presence of pulmonary cysts and their image characteristics. These findings were correlated with participant demographics and results of pulmonary function tests as well as the presence of emphysema independently detected on CT. The interval change was investigated by comparison with previous CT scans (median interval 6.1 years). RESULTS: Pulmonary cysts were seen in 7.6% (95% CI 6.6% to 8.7%; 200/2633). They were not observed in participants younger than 40 years old, and the prevalence increased with age. Multiple cysts (at least five) were seen in 0.9% of all participants. Participants with pulmonary cysts showed significantly lower body mass index (BMI) (p<0.001). Pulmonary cysts were most likely to appear solitary in the peripheral area of the lower lobes and remain unchanged or slightly increase in size over time. Pulmonary cysts showed no significant influence on pulmonary functions (p=0.07-0.6) except for diffusing capacity of the lung for carbon monoxide (DLCO) (p=0.03) and no association with cigarette smoking (p=0.1 0.9) or emphysema (p=0.7). CONCLUSIONS: Pulmonary cysts identified on chest CT may be a part of the aging changes of the lungs, occurring in asymptomatic individuals older than 40 years, and are associated with decreased BMI and DLCO. Multiple pulmonary cysts may need to be evaluated for the possibility of cystic lung diseases. PMID- 26514408 TI - Handgrip weakness and mortality risk in COPD: a multicentre analysis. PMID- 26514409 TI - Saccharin Taste Conditions Flavor Preference in Weanling Rats. AB - Innate and learned taste/flavor preferences to chemical stimuli in weanling rats are not fully understood. Our previous study showed that weanling rats could establish conditioned flavor preferences when low, but not high, concentrations of sucrose solutions were used as associative rewarding stimuli. Here, we examined whether 3-week-old rats could acquire flavor learning when the rewarding stimulus was saccharin, a non-nutritive artificial sweetener. In the acquisition session, they consumed water with a flavor (cherry or grape) and 0.1% sodium saccharin with another flavor (grape or cherry) for 15 min daily on alternative days over 6 consecutive days. The subsequent test session revealed significant preferences for the flavor previously associated with saccharin. However, they failed to retain the preference when retested in adulthood at the age of 20 weeks. These behavioral results were similar to those previously demonstrated when 2% sucrose was used as an associative sweetener. Although these 2 solutions were equally preferred, the taste quality may not be the same because the weanling rats showed neophobia to 0.1% saccharin and a larger chorda tympani response than 2% sucrose. The present study showed that a conditioned flavor preference was established to saccharin in weanling rats on the basis of flavor taste association. PMID- 26514411 TI - Public health impact of disease-behavior dynamics: Comment on "Coupled disease behavior dynamics on complex networks: A review" by Z. Wang et al. PMID- 26514410 TI - Changes in Olfactory Sensory Neuron Physiology and Olfactory Perceptual Learning After Odorant Exposure in Adult Mice. AB - The adult olfactory system undergoes experience-dependent plasticity to adapt to the olfactory environment. This plasticity may be accompanied by perceptual changes, including improved olfactory discrimination. Here, we assessed experience-dependent changes in the perception of a homologous aldehyde pair by testing mice in a cross-habituation/dishabituation behavioral paradigm before and after a week-long ester-odorant exposure protocol. In a parallel experiment, we used optical neurophysiology to observe neurotransmitter release from olfactory sensory neuron (OSN) terminals in vivo, and thus compared primary sensory representations of the aldehydes before and after the week-long ester-odorant exposure in individual animals. Mice could not discriminate between the aldehydes during pre-exposure testing, but ester-exposed subjects spontaneously discriminated between the homologous pair after exposure, whereas home cage control mice cross-habituated. Ester exposure did not alter the spatial pattern, peak magnitude, or odorant-selectivity of aldehyde-evoked OSN input to olfactory bulb glomeruli, but did alter the temporal dynamics of that input to make the time course of OSN input more dissimilar between odorants. Together, these findings demonstrate that odor exposure can induce both physiological and perceptual changes in odor processing, and suggest that changes in the temporal patterns of OSN input to olfactory bulb glomeruli could induce differences in odor quality. PMID- 26514412 TI - Children's claims to knowledge regarding their mental health experiences and practitioners' negotiation of the problem. AB - OBJECTIVE: The objective was to identify how children's knowledge positions were negotiated in child mental health assessments and how this was managed by the different parties. METHODS: The child psychiatry data consisted of 28 video recorded assessments. A conversation analysis was undertaken to examine the interactional detail between the children, parents, and practitioners. RESULTS: The findings indicated that claims to knowledge were managed in three ways. First, practitioners positioned children as 'experts' on their own health and this was sometimes accepted. Second, some children resisted this epistemic position, claiming not to have the relevant knowledge. Third, some children's claims to knowledge were negotiated and sometimes contested by adult parties who questioned their competence to share relevant information about their lives in accordance with the assessment agenda. CONCLUSION: Through question design, the practitioner was able to position the child as holding relevant knowledge regarding their situation. The child was able to take up this position or resist it in various ways. PRACTICE IMPLICATIONS: This has important implications for debates regarding children's competence to contribute to mental health interventions. Children are often treated as agents with limited knowledge, yet in the mental health assessment they are directly questioned about their own lives. PMID- 26514414 TI - Aeromonas salmonicida infection levels in pre- and post-stocked cleaner fish assessed by culture and an amended qPCR assay. AB - Due to increasing resistance to chemical therapeutants, the use of 'cleaner fish' (primarily wrasse, Labridae, species) has become popular in European salmon farming for biocontrol of the salmon louse, Lepeophtheirus salmonis (Kroyer). While being efficient de-licers, cleaner fish mortality levels in salmon cages are commonly high, and systemic bacterial infections constitute a major problem. Atypical furunculosis, caused by Aeromonas salmonicida A-layer types V and VI, is among the most common diagnoses reached in clinical investigations. A previously described real-time PCR (qPCR), targeting the A. salmonicida A-layer gene (vapA), was modified and validated for specific and sensitive detection of all presently recognized A-layer types of this bacterium. Before stocking and during episodes of increased mortality in salmon cages, cleaner fish (primarily wild-caught wrasse) were sampled and screened for A. salmonicida by qPCR and culture. Culture indicated that systemic bacterial infections are mainly contracted after salmon farm stocking, and qPCR revealed A. salmonicida prevalences of approximately 4% and 68% in pre- and post-stocked cleaner fish, respectively. This underpins A. salmonicida's relevance as a contributing factor to cleaner fish mortality and emphasizes the need for implementation of preventive measures (e.g. vaccination) if current levels of cleaner fish use are to be continued or expanded. PMID- 26514413 TI - Effect of coagulation factor concentrate administration on ROTEM(r) parameters in major trauma. AB - BACKGROUND: Purified coagulation factor concentrates, such as fibrinogen concentrate (FC) and prothrombin complex concentrate (PCC) are increasingly used as haemostatic therapy for trauma-induced coagulopathy (TIC). The impact of FC and PCC administration on ROTEM parameters among patients with TIC has not been adequately investigated. METHODS: In this retrospective observational study, changes to ROTEM parameters, induced by three different therapeutic interventions, were investigated: patients receiving FC only (FC-group); patients treated with FC and PCC (FC + PCC-group) and patients treated with PCC only (PCC group). RESULTS: The study population comprised 96 patients who were predominately male (69 [71.9 %]), median age was 45.0 (26.3-60.0) years, and the median injury severity score was 34.0 (25.0-44.5). Administration of FC resulted in a significant reduction of the clotting time (CT) in both the EXTEM and FIBTEM assays but had no effect on INTEM CT. Clot amplitude (CA) increased significantly in the FIBTEM assay but remained unchanged in the EXTEM and INTEM assays. The combined administration of FC and PCC increased FIBTEM maximum clot firmness (MCF) and normalized EXTEM CT but did not change either INTEM or FIBTEM CT. Following PCC therapy, EXTEM and FIBTEM CT normalized; CA at 10 min after CT measurements decreased significantly in EXTEM, INTEM and FIBTEM. CONCLUSIONS: Administration of FC alone or in combination with PCC resulted in a significant improvement of fibrin polymerisation as measured by an increase in FIBTEM MCF. CT is dependent not only on thrombin generation but also on the availability of substrate (fibrinogen). Accelerated fibrin polymerisation rate results in earlier clot formation and consequently shorter CT. PCC administration normalised EXTEM CT below the upper threshold of 80 s. This study was performed at the AUVA Trauma Centre Salzburg, Salzburg, Austria. PMID- 26514415 TI - Utility of gamma-Glutamyl Transferase in Predicting Troponin Elevation in Emergency Departments. AB - Serum gamma-glutamyl transferase (GGT) activity is a risk predictor for the development of coronary artery disease and is related to cardiovascular morbidity and mortality. We evaluated the clinical utility of GGT activity in predicting high troponin levels in patients with acute coronary syndrome (ACS) admitted to the emergency department with chest pain. A total of 200 troponin-positive and 203 troponin-negative patients were classified into groups 1 and 2, respectively. gamma-Glutamyl transferase activity was significantly higher in group 1 (44 +/- 34 U/L) compared with group 2 (31 +/- 26 U/L, P = .001). A GGT activity cutoff >25.5 showed 62% sensitivity and 61% specificity in predicting troponin positivity. Logistic regression analysis demonstrated a significant predictive value of GGT for troponin positivity. Spearman rank correlation analysis showed a moderately strong relationship between GGT activity and troponin positivity. Considering the predictive value of high GGT activity for troponin positivity, GGT activity may complement other diagnostic biomarkers for predicting troponin positivity in patients having ACS admitted with chest pain. PMID- 26514416 TI - Predictors of Symptom Development in Intermediate Carotid Artery Stenosis: Mean Platelet Volume and Platelet Distribution Width. AB - Platelets play an important role in the pathogenesis of atherothrombosis. Platelet activation is associated with increased mean platelet volume (MPV) and platelet distribution width (PDW). In this study, we investigated the relation of MPV and PDW with the risk of stroke in patients with intermediate (50%-70%) carotid artery stenosis. A total of 254 patients (115 symptomatic and 139 asymptomatic) with intermediate carotid artery stenosis were enrolled in this study. Symptomatic and asymptomatic patients were compared in regard to MPV and PDW. Mean platelet volume was significantly greater in the symptomatic group compared with the asymptomatic group (11.1 and 9.4 fL, respectively; P < .001). Platelet distribution width was significantly greater in the symptomatic group compared with the asymptomatic group (15.0% and 11.9%, respectively; P < .001). Multivariate regression analysis showed that an MPV >=10.2 fL and a PDW >=14.3% were independent predictors of developing symptomatic carotid artery stenosis. Mean platelet volume and PDW are increased in the presence of symptomatic intermediate carotid artery stenosis. Increased MPV and PDW may be independent predictors of developing symptomatic carotid artery plaque. PMID- 26514417 TI - The Impact of Routine Angiographic Follow-Up in a Population of Patients Undergoing Percutaneous Coronary Intervention Within the Left Main Coronary Artery. AB - Prognostic value of angiographic follow-up in patients undergoing percutaneous coronary interventions (PCIs) of the left main coronary artery (LMCA) still remains uncertain. The aim of the study was to compare clinical characteristics, mortality, and major cardiovascular events in patients with versus without angiographic follow-up after PCI of the LMCA as well as to identify independent risk factors for death after PCI of the LMCA. Study population consisted of 217 patients of 290 consecutive participants who underwent PCI of the LMCA and subsequently were divided into 2 groups: angiographic follow-up group (angio FU group, n = 155) and clinical follow-up group (clinical FU group, n = 62). In angio FU group, significantly lower mortality (19.4% vs 32.3%, P < .05) and higher repeated revascularization rates (PCI: 46.5% vs 8.1%, P < .001 and coronary artery bypass grafting: 12.9% vs 1.6%, P < .05) were observed. Independent risk factors for death were as follows: metal stent implantation (hazard ratio [HR]: 2.753), no angiographic follow-up (HR: 1.959), and an increase in serum creatinine level of 1 MUmol/L (HR: 1.006). These preliminary data suggest that the lack of angiographic follow-up after PCI of the LMCA may result in higher long-term mortality. PMID- 26514418 TI - Initiation of recombination suppression and PAR formation during the early stages of neo-sex chromosome differentiation in the Okinawa spiny rat, Tokudaia muenninki. AB - BACKGROUND: Sex chromosomes of extant eutherian species are too ancient to reveal the process that initiated sex-chromosome differentiation. By contrast, the neo sex chromosomes generated by sex-autosome fusions of recent origin in Tokudaia muenninki are expected to be evolutionarily 'young', and therefore provide a good model in which to elucidate the early phases of eutherian sex chromosome evolution. Here we describe the genomic evolution of T. muenninki in neo-sex chromosome differentiation. RESULTS: FISH mapping of a T. muenninki male, using 50 BAC clones as probes, revealed no chromosomal rearrangements between the neo sex chromosomes. Substitution-direction analysis disclosed that sequence evolution toward GC-richness, which positively correlates with recombination activity, occurred in the peritelomeric regions, but not middle regions of the neo-sex chromosomes. In contrast, the sequence evolution toward AT-richness was observed in those pericentromeric regions. Furthermore, we showed genetic differentiation between the pericentromeric regions as well as an accelerated rate of evolution in the neo-Y region through the detection of male-specific substitutions by gene sequencing in multiple males and females, and each neo-sex derived BAC sequencing. CONCLUSIONS: Our results suggest that recombination has been suppressed in the pericentromeric region of neo-sex chromosomes without chromosome rearrangement, whereas high levels of recombination activity is limited in the peritelomeric region of almost undifferentiated neo-sex chromosomes. We conclude that PAR might have been formed on the peritelomeric region of sex chromosomes as an independent event from spread of recombination suppression during the early stages of sex chromosome differentiation. PMID- 26514419 TI - Combination recombinant simian or chimpanzee adenoviral vectors for vaccine development. AB - Recombinant adenoviral vector (rAd)-based vaccines are currently being developed for several infectious diseases and cancer therapy, but pre-existing seroprevalence to such vectors may prevent their use in broad human populations. In this study, we investigated the potential of low seroprevalence non-human primate rAd vectors to stimulate cellular and humoral responses using HIV/SIV Env glycoprotein (gp) as the representative antigen. Mice were immunized with novel simian or chimpanzee rAd (rSAV or rChAd) vectors encoding HIV gp or SIV gp by single immunization or in heterologous prime/boost combinations (DNA/rAd; rAd/rAd; rAd/NYVAC or rAd/rLCM), and adaptive immunity was assessed. Among the rSAV and rChAd tested, rSAV16 or rChAd3 vector alone generated the most potent immune responses. The DNA/rSAV regimen also generated immune responses similar to the DNA/rAd5 regimen. rChAd63/rChAd3 and rChAd3 /NYVAC induced similar or even higher levels of CD4+ and CD8+ T-cell and IgG responses as compared to rAd28/rAd5, one of the most potent combinations of human rAds. The optimized vaccine regimen stimulated improved cellular immune responses and neutralizing antibodies against HIV compared to the DNA/rAd5 regimen. Based on these results, this type of novel rAd vector and its prime/boost combination regimens represent promising candidates for vaccine development. PMID- 26514421 TI - Presentation of peptides from Bacillus anthracis protective antigen on Tobacco Mosaic Virus as an epitope targeted anthrax vaccine. AB - The current anthrax vaccine requires improvements for rapidly invoking longer lasting neutralizing antibody responses with fewer doses from a well-defined formulation. Designing antigens that target neutralizing antibody epitopes of anthrax protective antigen, a component of anthrax toxin, may offer a solution for achieving a vaccine that can induce strong and long lasting antibody responses with fewer boosters. Here we report implementation of a strategy for developing epitope focused virus nanoparticle vaccines against anthrax by using immunogenic virus particles to present peptides derived from anthrax toxin previously identified in (1) neutralizing antibody epitope mapping studies, (2) toxin crystal structure analyses to identify functional regions, and (3) toxin mutational analyses. We successfully expressed two of three peptide epitopes from anthrax toxin that, in previous reports, bound antibodies that were partially neutralizing against toxin activity, discovered cross-reactivity between vaccine constructs and toxin specific antibodies raised in goats against native toxin and showed that antibodies induced by our vaccine constructs also cross-react with native toxin. While protection against intoxication in cellular and animal studies were not as effective as in previous studies, partial toxin neutralization was observed in animals, demonstrating the feasibility of using plant-virus nanoparticles as a platform for epitope defined anthrax vaccines. PMID- 26514420 TI - Phase 1 testing of detoxified LPS/group B meningococcal outer membrane protein vaccine with and without synthetic CPG 7909 adjuvant for the prevention and treatment of sepsis. AB - BACKGROUND: Gram-negative bacteria (GNB) are a leading cause of nosocomial infection and sepsis. Increasing multi-antibiotic resistance has left clinicians with fewer therapeutic options. Antibodies to GNB lipopolysaccharide (LPS, or endotoxin) have reduced morbidity and mortality as a result of infection and are not subject to the resistance mechanisms deployed by bacteria against antibiotics. In this phase 1 study, we administered a vaccine that elicits antibodies against a highly conserved portion of LPS with and without a CpG oligodeoxynucleotide (ODN) TLR9 agonist as adjuvant. METHODS: A vaccine composed of the detoxified LPS (dLPS) from E. coli O111:B4 (J5 mutant) non-covalently complexed to group B meningococcal outer membrane protein (OMP). Twenty healthy adult subjects received three doses at 0, 29 and 59 days of antigen (10 MUg dLPS) with or without CPG 7909 (250 or 500 MUg). Subjects were evaluated for local and systemic adverse effects and laboratory findings. Anti-J5 LPS IgG and IgM antibody levels were measured by electrochemiluminesence. Due to premature study termination, not all subjects received all three doses. RESULTS: All vaccine formulations were well-tolerated with no local or systemic events of greater than moderate severity. The vaccine alone group achieved a >= 4-fold "responder" response in IgG and IgM antibody in only one of 6 subjects. In contrast, the vaccine plus CPG 7909 groups appeared to have earlier and more sustained (to 180 days) responses, greater mean-fold increases, and a higher proportion of "responders" achieving >= 4-fold increases over baseline. CONCLUSIONS: Although the study was halted before all enrolled subjects received all three doses, the J5dLPS/OMP vaccine, with or without CpG adjuvant, was safe and well-tolerated. The inclusion of CpG increased the number of subjects with a >= 4-fold antibody response, evident even after the second of three planned doses. A vaccine comprising J5dLPS/OMP antigen with CpG adjuvant merits further investigation. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01164514. PMID- 26514422 TI - Community awareness and predictors of uptake of pertussis booster vaccine in South Australian adults. AB - OBJECTIVE: Pertussis is a highly virulent vaccine preventable disease that remains a global challenge. This study aimed to assess community knowledge of pertussis infection as well as awareness and uptake of adult pertussis booster vaccine. METHODS: A cross-sectional survey was conducted of randomly selected households in South Australia by Computer Assisted Telephone Interviews in 2011. Survey data were weighted to the age, gender and geographical area profile of the population. RESULTS: From 3124 randomly sampled contactable households, 1967 interviews were conducted (participation rate 63%) with individuals aged 18-93 years, including 608 parents of children aged <18 years. The majority of respondents (97%) had heard of pertussis (whooping cough) and 18% reported that a household member had previously contracted whooping cough infection. Most respondents considered whooping cough to be highly contagious (73%) and severe for infants (89%). Over half (51%) of those surveyed were aware that family members commonly transmit pertussis to infants. Despite high knowledge, pertussis vaccine uptake was low, with only 10% of respondents reporting pertussis vaccination in the previous five years. Whilst 61% of respondents were aware of the availability of an adult pertussis booster vaccine, only 8% (n=154) reported their Family Physician had discussed it with them. If provided free, 77% agreed that they would be more likely to accept a booster pertussis vaccination. Independent predictors of recent pertussis vaccination included higher education, larger household size, perception of greater disease severity for infants and discussion with a Family Physician about pertussis vaccination. CONCLUSIONS: Whilst knowledge regarding transmission and severity of Bordetella pertussis was high, uptake of pertussis vaccination for adults is remarkably low amongst the South Australian community. Improved awareness regarding the availability of a booster pertussis vaccine through Family Physicians and/or provision of funded pertussis vaccination for adults has the potential to improve pertussis vaccine coverage. PMID- 26514423 TI - Partial protective immunity against toxoplasmosis in mice elicited by recombinant Toxoplasma gondii malate dehydrogenase. AB - Toxoplasma gondii can infect humans and wildlife, sometimes causing serious clinical presentations. Currently, no viable vaccine or effective drug strategies exist to prevent and control toxoplasmosis. T. gondii malate dehydrogenase (TgMDH) is a crucial enzyme in cellular redox reactions and has been shown to be an immunogenic compound that could be a potential vaccine candidate. Here, we investigate the protective efficacy of recombinant TgMDH (rTgMDH) against T. gondii infection in BALB/c mice. All mice were vaccinated via the nasal route. We determined the optimal vaccination dose by monitoring systemic and mucosal immune responses. The results showed that mice vaccinated with 30 MUg of rTgMDH produced the highest antibody titers in serum, a strong lymphoproliferative response, marked increases in their levels of IL-2 and IFN-gamma, and significantly greater levels of specific secretory IgA (sIgA) in mucosal washes. In addition, the vaccinated mice were orally challenged with tachyzoites of the virulent T. gondii RH strain 2 weeks after the final vaccination. Compared to the control group, we found that vaccination with rTgMDH increased the survival rate of infected mice by 47% and also significantly reduced the tachyzoite loads in their liver (by 58%) and brain (by 41%). Therefore, the rTgMDH protein triggers a strong systemic and mucosal immune response and provides partial protection against T. gondii infection. PMID- 26514424 TI - Vaccination coverage of patients with inborn errors of metabolism and the attitudes of their parents towards vaccines. AB - To evaluate vaccination coverage of children and adolescents with inborn errors of metabolism (IEMs) and the attitudes of their parents towards vaccination, the vaccination status of 128 patients with IEM and 128 age- and gender-matched healthy controls was established by consulting the official vaccination chart. In children with IEMs, compared with healthy controls, low vaccination rates and/or delays in administration were observed for pneumococcal conjugate, meningococcus C, measles, mumps, rubella, diphtheria-tetanus-pertussis-inactivated polio, Bacillus Calmette-Guerin, and influenza vaccines. Among the parents of IEM patients, vaccine schedule compliance was primarily driven by the doctors at the hospital's reference centres; among the parents of the healthy controls, compliance was driven by the primary care paediatricians. These results show that IEM patients demonstrate sub-optimal vaccination coverage. Further studies of the different vaccines in each IEM disorder and educational programmes aimed at physicians and parents to increase immunization coverage in these patients are urgently needed. PMID- 26514426 TI - Cilostazol inhibits interleukin-1-induced ADAM17 expression through cAMP independent signaling in vascular smooth muscle cells. AB - Increased A disintegrin and metalloprotease 17 (ADAM17) expression in vascular smooth muscle cells (VSMC) is implicated in the development of cardiovascular diseases including atherosclerosis and hypertension. Although cilostazol, type III phosphodiesterase (PDE III) inhibitor, has recently been found to inhibit VSMC proliferation, the mechanisms remain largely unclear. Here, we hypothesized that cilostazol regulates the ADAM17 expression in VSMC. In cultured VSMC, interleukin (IL)-1alpha and IL-1beta significantly increased ADAM17 expression. MEK inhibitor U0126, NF-kappaB inhibitor BAY-11-7085, and siRNA targeting p65/RelA significantly inhibited IL-1alpha or IL-beta-induced ADAM17 expression. Cilostazol significantly inhibited IL-1alpha or IL-1beta-induced extracellular signal-regulated kinase (ERK) phosphorylation and ADAM17 expression. Unexpectedly, cilostamide, dibutryl cAMP, and forskolin did not affect IL-1 induced ADAM17 expression. Our results clearly demonstrated that IL-1 induces ADAM17 expression through ERK/NF-kappaB activation in VSMCs. Moreover, the inhibitory effects of cilostazol on IL-1-induced ADAM17 expression may be independent of the cAMP signaling pathway in VSMC. These novel findings may provide important clues to understanding the expression mechanisms of ADAM17 and the inhibitory mechanisms of cilostazol in VSMC proliferation. PMID- 26514427 TI - DCIR negatively regulates CpG-ODN-induced IL-1beta and IL-6 production. AB - C-type lectin receptors (CLR) are a diverse family of proteins mainly expressed on antigen-presenting cells (APC). As antigen-uptake and signaling receptors, CLR modulate immune responses of APC. The dendritic cell immunoreceptor (DCIR) is a member of CLR and has an immunoreceptor tyrosine based inhibitory motif (ITIM) in cytoplasmic tail, which is believed to play a negative role in cellular responses after antigen exposure. In addition to pathogen recognition, DCIR has been shown to be pivotal in preventing autoimmune disease by controlling dendritic cell proliferation. However, much less is known about the role of DCIR in innate immunity and its crosstalk with the Toll like receptors (TLR) pathway. In this study, we demonstrate that CpG-ODN stimulation can promote DCIR expression in macrophages and DCIR triggering inhibits the production of CpG-ODN-induced proinflammatory cytokines. We further confirm that siRNA-mediated knockdown of DCIR expression enhances CpG-ODN-induced phosphorylation of Erk1/2, JNK1/2 and p38 in macrophages. Collectively, these results indicate that DCIR is a negatively regulator in TLR9-mediated innate immune response. PMID- 26514425 TI - Oral administration of a recombinant attenuated Yersinia pseudotuberculosis strain elicits protective immunity against plague. AB - A Yersinia pseudotuberculosis PB1+ (Yptb PB1+) mutant strain combined with chromosome insertion of the caf1R-caf1A-caf1M-caf1 operon and deletions of yopJ and yopK, chi10068 [pYV-omega2 (DeltayopJ315 DeltayopK108) DeltalacZ044::caf1R caf1M-caf1A-caf1] was constructed. Results indicated that gene insertion and deletion did not affect the growth rate of chi10068 compared to wild-type Yptb cultured at 26 degrees C. In addition, the F1 antigen in chi10068 was synthesized and secreted on the surface of bacteria at 37 degrees C (mammalian body temperature), not at ambient culture temperature (26 degrees C). Immunization with chi10068 primed antibody responses and specific T-cell responses to F1 and YpL (Y. pestis whole cell lysate). Oral immunization with a single dose of chi10068 provided 70% protection against a subcutaneous (s.c.) challenge with ~ 2.6 * 10(5) LD50 of Y. pestis KIM6+ (pCD1Ap) (KIM6+Ap) and 90% protection against an intranasal (i.n.) challenge with ~ 500 LD50 of KIM6+Ap in mice. Our results suggest that chi10068 can be used as an effective precursor to make a safe vaccine to prevent plague in humans and to eliminate plague circulation among humans and animals. PMID- 26514428 TI - A novel gain-of-function STAT1 mutation resulting in basal phosphorylation of STAT1 and increased distal IFN-gamma-mediated responses in chronic mucocutaneous candidiasis. AB - Gain-of-function STAT1 mutations have recently been associated with autosomal dominant chronic mucocutaneous candidiasis (CMC). The purpose of this study was to characterize the three members of a non-consanguineous family, the father and his two sons, who presented with recurrent oral thrush and ocular candidiasis since early childhood. The three patients had reduced levels of IL-17-producing T cells. This reduction affected specifically IL-17(+)IFN-gamma(-) T cells, because the levels of IL-17(+)IFN-gamma(+) T cells were similar to controls. We found that PBMC (peripheral blood mononuclear cells) from the patients did not respond to Candida albicans ex vivo. Moreover, after polyclonal activation, patients' PBMC produced lower levels of IL-17 and IL-6 and higher levels of IL-4 than healthy controls. Genetic analyses showed that the three patients were heterozygous for a new mutation in STAT1 (c.894A>C, p.K298N) that affects a highly conserved residue of the coiled-coil domain of STAT1. STAT1 phosphorylation levels were significantly higher in patients' cells than in healthy controls, both in basal conditions and after IFN-gamma stimulation, suggesting a permanent activation of STAT1. Cells from the patients also presented increased IFN-gamma-mediated responses measured as MIG and IP-10 production. In conclusion, we report a novel gain-of-function mutation in the coiled-coil domain of STAT1, which increases STAT1 phosphorylation and impairs IL 17-mediated immunity. The mutation is responsible for CMC in this family with autosomal dominant inheritance of the disease. PMID- 26514429 TI - High affinity IgM(+) memory B cells are generated through a germinal center dependent pathway. AB - During a T cell-dependent immune response, B cells undergo clonal expansion and selection and the induction of isotype switching and somatic hypermutation (SHM). Although somatically mutated IgM(+) memory B cells have been reported, it has not been established whether they are really high affinity B cells. We tracked (4 hydroxy-3-nitrophenyl) acetyl hapten-specific GC B cells from normal immunized mice based on affinity of their B cell receptor (BCR) and performed BCR sequence analysis. SHM was evident by day 7 postimmunization and increased with time, such that high affinity IgM(+) as well as IgG(+) memory B cells continued to be generated up to day 42. In contrast, class-switch recombination (CSR) was almost completed by day 7 and then the ratio of IgG1(+)/IgM(+) GC B cells remained unchanged. Together these findings suggest that IgM(+) B cells undergo SHM in the GC to generate high affinity IgM(+) memory cells and that this process continues even after CSR is accomplished. PMID- 26514430 TI - Superior ophthalmic vein thrombosis associated with severe facial trauma: a case report. AB - INTRODUCTION: Superior ophthalmic vein thrombosis is a rare entity, but is associated with significant morbidities. We describe a case in which superior ophthalmic vein thrombosis occurred shortly after severe facial trauma. CASE PRESENTATION: A 77-year-old Japanese man was transferred to our tertiary hospital after a motor vehicle accident. Le Fort III facial bone fractures and a minor cerebral contusion were detected. Follow-up computed tomography scans detected dilatation of his left superior ophthalmic vein on day 3 and thrombosis on day 12; however, no causative carotid cavernous fistula was observed. As he did not present with any symptoms other than slight conjunctival congestion, a conservative management strategy was adopted along with anticoagulant therapy against deep venous thrombosis. The superior ophthalmic vein thrombosis resolved spontaneously and the conjunctival congestion also improved. CONCLUSIONS: Superior ophthalmic vein thrombosis should be taken into consideration and managed properly after severe facial injuries, and further investigation of its cause is necessary to prevent morbidities. PMID- 26514431 TI - Methylation-dependent regulation of hypoxia inducible factor-1 alpha gene expression by the transcription factor Kaiso. AB - Low oxygen tension (hypoxia) is a common characteristic of solid tumors and strongly correlates with poor prognosis and resistance to treatment. In response to hypoxia, cells initiate a cascade of transcriptional events regulated by the hypoxia inducible factor-1 (HIF-1) heterodimer. Since the oxygen-sensitive HIF 1alpha subunit is stabilized during hypoxia, it functions as the regulatory subunit of the protein. To date, while the mechanisms governing HIF-1alpha protein stabilization and function have been well studied, those governing HIF1A gene expression are not fully understood. However, recent studies have suggested that methylation of a HIF-1 binding site in the HIF1A promoter prevents its autoregulation. Here we report that the POZ-ZF transcription factor Kaiso modulates HIF1A gene expression by binding to the methylated HIF1A promoter in a region proximal to the autoregulatory HIF-1 binding site. Interestingly, Kaiso's regulation of HIF1A occurs primarily during hypoxia, which is consistent with the finding that Kaiso protein levels peak after 4 h of hypoxic incubation and return to normoxic levels after 24 h. Our data thus support a role for Kaiso in fine tuning HIF1A gene expression after extended periods of hypoxia. PMID- 26514432 TI - From transcriptomic to protein level changes in TDP-43 and FUS loss-of-function cell models. AB - The full definition of the physiological RNA targets regulated by TDP-43 and FUS RNA-binding proteins (RBPs) represents an important issue in understanding the pathogenic mechanisms associated to these two proteins in amyotrophic lateral sclerosis and frontotemporal dementia. In the last few years several high throughput screenings have generated a plethora of data, which are difficult to compare due to the different experimental designs and models explored. In this study by using the Affymetrix Exon Arrays, we were able to assess and compare the effects of both TDP-43 and FUS loss-of-function on the whole transcriptome using the same human neuronal SK-N-BE cell model. We showed that TDP-43 and FUS depletion induces splicing and gene expression changes mainly distinct for the two RBPs, although they may regulate common pathways, including neuron differentiation and cytoskeleton organization as evidenced by functional annotation analysis. In particular, TDP-43 and FUS were found to regulate splicing and expression of genes related to neuronal (SEPT6, SULT4A1, TNIK) and RNA metabolism (DICER, ELAVL3/HuC, POLDIP3). Our extended analysis at protein level revealed that these changes have also impact on the protein isoform ratio and content, not always in a direct correlation with transcriptomic data. Contrarily to a loss-of-function mechanism, we showed that mutant TDP-43 proteins maintained their splicing activity in human ALS fibroblasts and experimental cell lines. Our findings further contribute to define the biological functions of these two RBPs in physiological and disease state, strongly encouraging the evaluation of the identified transcriptomic changes at protein level in neuronal experimental models. PMID- 26514433 TI - Overdiagnosis in Lung Cancer Screening can be Reduced to a Low, Manageable Level via a Multilayered Strategy Involving Perfecting Reporting Systems, Restricting Screening to High-Risk Groups, Developing Better Risk Stratification Models, and Improving Management Algorithms. PMID- 26514434 TI - Letter to the Editor in Response to a Recent Commentary, "Mammography Trials" by Drs. Saurabh Jha and Jeffrey B. Ware. PMID- 26514435 TI - Screening Mammography: More Than Just One Trial. PMID- 26514436 TI - Mammographic Breast Density Assessment Using Automated Volumetric Software and Breast Imaging Reporting and Data System (BIRADS) Categorization by Expert Radiologists. AB - RATIONALE AND OBJECTIVES: To investigate agreement on mammographic breast density (MD) assessment between automated volumetric software and Breast Imaging Reporting and Data System (BIRADS) categorization by expert radiologists. MATERIALS AND METHODS: Forty cases of left craniocaudal and mediolateral oblique mammograms from 20 women were used. All images had their volumetric density classified using Volpara density grade (VDG) and average volumetric breast density percentage. The same images were then classified into BIRADS categories (I-IV) by 20 American Board of Radiology examiners. RESULTS: The results demonstrated a moderate agreement (kappa = 0.537; 95% CI = 0.234-0.699) between VDG classification and radiologists' BIRADS density assessment. Interreader agreement using BIRADS also demonstrated moderate agreement (kappa = 0.565; 95% CI = 0.519-0.610) ranging from 0.328 to 0.669. Radiologists' average BIRADS was lower than average VDG scores by 0.33, with their mean being 2.13, whereas the mean VDG was 2.48 (U = -3.742; P < 0.001). VDG and BIRADS showed a very strong positive correlation (rho = 0.91; P < 0.001) as did BIRADS and average volumetric breast density percentage (rho = 0.94; P < 0.001). CONCLUSIONS: Automated volumetric breast density assessment shows moderate agreement and very strong correlation with BIRADS; interreader variations still exist within BIRADS. Because of the increasing importance of MD measurement in clinical management of patients, widely accepted, reproducible, and accurate measures of MD are required. PMID- 26514437 TI - Screening Mammography Would Have Been Initiated Regardless of the CNBSS. PMID- 26514438 TI - In Estimating Overdiagnosis, Details Matter. PMID- 26514440 TI - Effects of esculetin on lipopolysaccharide (LPS)-induced acute lung injury via regulation of RhoA/Rho Kinase/NF-kB pathways in vivo and in vitro. AB - The purpose of the present study was to investigate the protective effect of esculetin (ES) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the lung epithelial A549 cells. Mice were intragastrically administered with ES (20 and 40 mg/kg) 1 h prior to LPS challenge. ES pretreatment at doses of 20 and 40 mg/kg effectively attenuated LPS-induced lung histopathological change, myeloperoxidase or MPO activity, inflammatory cells infiltration, pulmonary wet to-dry weight ratio, and the generation of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) in vivo and in vitro. Furthermore, we demonstrated that ES blocked the activation of NF-kB and RhoA/Rho kinase pathways in LPS-induced mice and A549 cells. The results suggested that ES exhibited protective effect on ALI and might attribute partly to the inhibition of NF-kB and RhoA/Rho kinase pathways in vivo and in vitro. PMID- 26514439 TI - Comparing Mammography Abnormality Features to Genetic Variants in the Prediction of Breast Cancer in Women Recommended for Breast Biopsy. AB - RATIONALE AND OBJECTIVES: The discovery of germline genetic variants associated with breast cancer has engendered interest in risk stratification for improved, targeted detection and diagnosis. However, there has yet to be a comparison of the predictive ability of these genetic variants with mammography abnormality descriptors. MATERIALS AND METHODS: Our institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study utilized a personalized medicine registry in which participants consented to provide a DNA sample and to participate in longitudinal follow-up. In our retrospective, age matched, case-controlled study of 373 cases and 395 controls who underwent breast biopsy, we collected risk factors selected a priori based on the literature, including demographic variables based on the Gail model, common germline genetic variants, and diagnostic mammography findings according to Breast Imaging Reporting and Data System (BI-RADS). We developed predictive models using logistic regression to determine the predictive ability of (1) demographic variables, (2) 10 selected genetic variants, or (3) mammography BI-RADS features. We evaluated each model in turn by calculating a risk score for each patient using 10-fold cross-validation, used this risk estimate to construct Receiver Operator Characteristic Curve (ROC) curves, and compared the area under the ROC curve (AUC) of each using the DeLong method. RESULTS: The performance of the regression model using demographic risk factors was not statistically different from the model using genetic variants (P = 0.9). The model using mammography features (AUC = 0.689) was superior to both the demographic model (AUC = .598; P < 0.001) and the genetic model (AUC = .601; P < 0.001). CONCLUSIONS: BI-RADS features exceeded the ability of demographic and 10 selected germline genetic variants to predict breast cancer in women recommended for biopsy. PMID- 26514441 TI - Nonylphenol exposure is associated with oxidative and nitrative stress in pregnant women. AB - Animal studies have shown that exposure to nonylphenol (NP) increases oxidative/nitrative stress, but whether it does so in humans is unknown. This study examines prenatal exposure to NP and its effects on oxidatively/nitratively damaged DNA, lipid peroxidation, and the activities of antioxidants. A total of 146 urine and blood specimens were collected during gestational weeks 27-38 and hospital admission for delivery, respectively. Urinary NP was analyzed by high performance liquid chromatography (HPLC). Urinary biomarkers of oxidatively/nitratively damaged DNA and lipid peroxidation, including 8-oxo-7,8 dihydro-2'-deoxyguanosine (8-oxodG), 8-nitroguanine (8-NO(2)Gua), 8-iso prostaglandin F(2alpha) (8-isoPF(2alpha)) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), were simultaneously analyzed using isotope-dilution liquid chromatography/electron spray ionization tandem mass spectrometry. The activities of maternal plasma superoxide dismutase and glutathione peroxidase were analyzed by enzyme-linked immunosorbent assay. Urinary NP level was significantly associated with 8-oxodG and 8-NO(2)Gua levels in late pregnancy, suggesting that NP may enhance oxidatively and nitratively damaged DNA. The adjusted odds ratios for high 8-oxodG level exhibited a significantly dose-response relationship with NP levels, stratified into four quartiles. 8-oxodG appears to be a more sensitive and effective biomarker of NP exposure than 8-NO(2)Gua. These relationships suggest NP may play a role in the pregnancy complications. PMID- 26514442 TI - N-acetyl tryptophan glucopyranoside (NATG) provides radioprotection to murine macrophage J774A.1 cells. AB - Ionizing radiation induced perturbations in cellular redox homeostasis are manifested as cell cycle arrest, inflammatory response, and apoptosis. Present study was focused on determination of radioprotective efficacy of a secondary metabolite N-acetyl-l-tryptophan glucoside (NATG) isolated from radioresistant bacterium Bacillus sp. INM-1. Macrophage J774A.1 cells were treated with NATG (0.025-200 MUg/ml) before gamma-irradiation (10-50 Gy) and radioprotective efficacy in terms of cellular metabolic activity was assessed using MTT assay. Radiation-induced intracellular ROS generation and its inhibition by NATG (0.25 MUg/ml) pretreatment was evaluated using 2',7'-dichlorodihydrofluorescein diacetate (H(2)DCFDA) probe. Effects of NATG pretreatment with or without gamma irradiation (20 Gy) on cell cycle perturbations and apoptosis regulation was evaluated using flowcytometry. Results of the study displayed 0.25 and 50 MUg/ml as effective dose (ED) and lethal dose (LD(50)) dose of NATG. A significant (p < 0.05) decrease in DCFDA fluorescence corresponding to decreased ROS levels was observed in NATG pretreated irradiated cells as compared to irradiated alone cells. Cell cycle progression analysis demonstrated decrease (~10%) in G(1), G(2), and S phase cells at 24 h post-treatment time interval in NATG pretreated cells as compared to control group. However, radiation-induced or NATG-induced treatment did not cause any alterations in G(2)/M arrest. APO-BrDU analysis demonstrated significant (p < 0.05) reduction in apoptosis level at 24 h time interval in NATG pretreated irradiated cells as compared to alone irradiated cells. Conclusively, present study suggests that NATG offers radioprotection by apoptosis inhibition mechanism without altering cell-cycle progression in J774A.1 cells. Further studies to evaluate detailed molecular mechanisms of radioprotection offered by NATG are ongoing. PMID- 26514443 TI - HIV epidemic and human rights among men who have sex with men in sub-Saharan Africa: Implications for HIV prevention, care, and surveillance. AB - Recent research has presented evidence that men who have sex with men (MSM) bear a disproportionate burden of HIV and are at increased risk for HIV in sub-Saharan Africa (SSA). However, many countries in SSA have failed to address the needs of MSM in national HIV/AIDS programmes. Furthermore, many MSM face structural barriers to HIV prevention and care, the most significant of which include laws that criminalise male-to-male sexual contact and facilitate stigma and discrimination. This in turn increases the vulnerability of MSM to acquiring HIV and presents barriers to HIV prevention, care, and surveillance. This relationship illustrates the link between human rights, social justice, and health outcomes and presents considerable challenges to addressing the HIV epidemic among MSM in SSA. The response to the HIV epidemic in SSA requires a non discriminatory human rights approach to all at-risk groups, including MSM. Existing international human rights treaties, to which many SSA countries are signatories, and a 'health in all policies' approach provides a strong basis to reduce structural barriers to HIV prevention, care, surveillance, and research, and to ensure that all populations in SSA, including MSM, have access to the full range of rights that help ensure equal opportunities for health and wellness. PMID- 26514445 TI - Copper-Catalyzed Reaction of Trifluoromethylketones with Aldehydes via a Copper Difluoroenolate. AB - A copper-catalyzed reaction of easily accessible alpha,alpha,alpha trifluoromethylketones with various aldehydes affords difluoro-methylene compounds in the presence of diboron and NaOtBu. The key process of the reaction is the formation of a copper difluoroenolate by 1,2-addition of a borylcopper intermediate to alpha,alpha,alpha-trifluoromethylketones and subsequent beta fluoride elimination. Mechanistic studies including the isolation and characterization of a possible anionic copper alkoxide intermediate are also described. PMID- 26514444 TI - Dynamin-related protein 1 controls the migration and neuronal differentiation of subventricular zone-derived neural progenitor cells. AB - Mitochondria are important in many essential cellular functions, including energy production, calcium homeostasis, and apoptosis. The organelles are scattered throughout the cytoplasm, but their distribution can be altered in response to local energy demands, such as cell division and neuronal maturation. Mitochondrial distribution is closely associated with mitochondrial fission, and blocking the fission-promoting protein dynamin-related protein 1 (Drp1) activity often results in mitochondrial elongation and clustering. In this study, we observed that mitochondria were preferentially localized at the leading process of migratory adult neural stem cells (aNSCs), whereas neuronal differentiating cells transiently exhibited perinuclear condensation of mitochondria. Inhibiting Drp1 activity altered the typical migratory cell morphology into round shapes while the polarized mitochondrial distribution was maintained. With these changes, aNSCs failed to migrate, and neuronal differentiation was prevented. Because Drp1 blocking also impaired the mitochondrial membrane potential, we tested whether supplementing with L-carnitine, a compound that restores mitochondrial membrane potential and ATP synthesis, could revert the defects induced by Drp1 inhibition. Interestingly, L-carnitine fully restored the aNSC defects, including cell shrinkage, migration, and impaired neuronal differentiation. These results suggest that Drp1 is required for functionally active mitochondria, and supplementing with ATP can restore the defects induced by Drp1 suppression. PMID- 26514446 TI - Psychopathology among a sample of hearing impaired adolescents. AB - Hearing impairment is a recognized cause of emotional and psychological disturbances worldwide, however little is known about this condition in Nigeria. The aim of this study is to compare the prevalence of psychopathology between hearing impaired adolescents and healthy adolescents. Students attending two special schools for the hearing impaired were assessed for psychopathology with the help of a trained signer and their teacher, using the International Classification of Diseases Diagnostic Criteria (ICD 10). Fifty two hearing impaired students and 52 age and sex matched controls from the same school were also interviewed using the same instrument. The mean age of the hearing impaired students was 16 (sd=3.8), while for the controls the mean age was 16 (sd=2.5). Psychopathology was present in 10 (19%) of the hearing impaired adolescents compared to 2 (4%) among the control group, this difference was statistically significant (chi(2)=4.62 p=0.03). The most common diagnosis was generalized anxiety disorder 4 (8%), followed by depression 2 (4%). Years spent in school (t=4.81, p=0.001), primary guardian (chi(2)=18.3, p=0.001) and mean income of guardian (t=7.10, p=0.001) were all significantly different between the two groups. Psychopathology is relatively common in this population. Proper assessment and treatment should be made available for this population group. A limitation to this study is communication difficulty which made only a third party assessment possible; this may affect the generalizability of the findings. PMID- 26514447 TI - Comparison of efficacy, safety and brain derived neurotrophic factor (BDNF) levels in patients of major depressive disorder, treated with fluoxetine and desvenlafaxine. AB - This randomized, open label, prospective, observational study compared clinical efficacy, safety alongwith plasma BDNF levels in outpatients of depression treated with fluoxetine and desvenlafaxine. Patients (aged 18-60 years) with moderate to severe major depressive disorder (MDD) diagnosed by DSM-IV criteria, and Hamilton Rating Scale for Depression (HAM-D) score >=14, who were prescribed fluoxetine or desvenlafaxine were included (n=30 in each group). Patients were followed up for 12 weeks for evaluation of clinical efficacy, safety along with BDNF levels. In the fluoxetine group, HAM-D scores at the start of treatment was 19+/-4.09 which significantly (p<0.05) reduced to 9.24+/-3.98 at 12 weeks. In the desvenlafaxine group, HAM-D scores at the start of treatment was 18+/-3.75 which significantly (p<0.05) reduced to 10+/-3.75 at 12 weeks. The BDNF levels in the fluoxetine group were 775.32+/-30.38pg/ml at the start of treatment which significantly (p<0.05) increased to 850.3+/-24.92pg/ml at 12 weeks. The BDNF levels in the desvenlafaxine group were 760.5+/-28.53pg/ml at the start of treatment which significantly (p<0.05) increased to 845.8+/-32.82pg/ml at 12 weeks. Both the antidepressants were found to be safe and well tolerated. The efficacy and the safety profile of desvenlafaxine is comparable to fluoxetine in patients of MDD. BDNF levels were significantly increased post-treatment with both the antidepressive agents. Whether BDNF may have a prognostic value in predicting treatment response to antidepressant drugs needs to be investigated in a larger patient population. PMID- 26514448 TI - Group 1 CD1-restricted T cells and the pathophysiological implications of self lipid antigen recognition. AB - T cell responses are generally regarded as specific for protein-derived peptide antigens. This is based on the molecular paradigm dictated by the T cell receptor (TCR) recognition of peptide-major histocompatibility complexs, which provides the molecular bases of the specificity and restriction of the T cell responses. An increasing number of findings in the last 20 years have challenged this paradigm, by showing the existence of T cells specific for lipid antigens presented by CD1 molecules. CD1-restricted T cells have been proven to be frequent components of the immune system and to recognize exogenous lipids, derived from pathogenic bacteria, as well as cell-endogenous self-lipids. This represents a young and exciting area of research in immunology with intriguing biological bases and a potential direct impact on human health. PMID- 26514449 TI - Multimodality Treatment of Pediatric Esthesioneuroblastoma. AB - BACKGROUND: Esthesioneuroblastoma (ENB) is a rare cancer of the nasal cavity in children. Radical surgery followed by postoperative radiation is considered the standard of care in adults. A similar approach in children can lead to significant long-term morbidity. PROCEDURE: A retrospective multi-institutional review of patients less than 21 years of age diagnosed with ENB between 1990 and 2014 was performed. Clinical features, treatment, and outcome were obtained from the medical records. RESULTS: Twenty-four patients were identified with a median age of 14 years (range 0.6-20 years) at diagnosis. The majority (75%) were females. Headache was the most common presenting symptom, followed by nasal obstruction and epistaxis. Eight patients had Kadish stage B tumors and 16 had Kadish stage C tumors. Nine patients had metastatic disease. Gross total resection was achieved at diagnosis in eight patients and after neoadjuvant chemotherapy in four patients. Twenty-one patients received radiation therapy (45 68.4 Gy). Thirteen patients received neoadjuvant chemotherapy with 84% objective response rate. Seven patients experienced disease progression or relapse-five in central nervous system, one local, and one in cervical lymph node. Fifteen patients were alive at the last follow-up. The 5-year disease-free survival and overall survival were 74% and 73%, respectively. Late effects were observed in 78% of long-term survivors. Four patients developed subsequent malignant neoplasms. CONCLUSIONS: Pediatric ENB is a chemosensitive disease. Preoperative chemotherapy-based multimodal approach should be used in patients with advanced stage disease. Radiation therapy is effective for local control, but lower doses should be considered in children. PMID- 26514450 TI - Caveolin-1 in Breast Cancer: Single Molecule Regulation of Multiple Key Signaling Pathways. AB - Caveolin-1 is a 22-kD trans-membrane protein enriched in particular plasma membrane invaginations known as caveolae. Cav-1 expression is often dysregulated in human breast cancers, being commonly upregulated in cancer cells and downregulated in stromal cells. As an intracellular scaffolding protein, Cav-1, is involved in several vital biological regulations including endocytosis, transcytosis, vesicular transport, and signaling pathways. Several pathways are modulated by Cav-1 including estrogen receptor, EGFR, Her2/neu, TGFbeta, and mTOR and represent as major drivers in mammary carcinogenesis. Expression and role of Cav-1 in breast carcinogenesis is highly variable depending on the stage of tumor development as well as context of the cell. However, recent data have shown that downregulation of Cav-1 expression in stromal breast tumors is associated with frequent relapse, resistance to therapy, and poor outcome. Modification of Cav-1 expression for translational cancer therapy is particularly challenging since numerous signaling pathways might be affected. This review focuses on present understanding of Cav-1 in breast carcinogenesis and its potential role as a new biomarker for predicting therapeutic response and prognosis as well as new target for therapeutic manipulation. PMID- 26514451 TI - Overview of Transforming Growth Factor beta Superfamily Involvement in Glioblastoma Initiation and Progression. AB - Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive of human brain tumors and has a stunning progression with a mean survival of one year from the date of diagnosis. High cell proliferation, angiogenesis and/or necrosis are histopathological features of this cancer, which has no efficient curative therapy. This aggressiveness is associated with particular heterogeneity of the tumor featuring multiple genetic and epigenetic alterations, but also with implications of aberrant signaling driven by growth factors. The transforming growth factor beta (TGFbeta) superfamily is a large group of structurally related proteins including TGFbeta subfamily members Nodal, Activin, Lefty, bone morphogenetic proteins (BMPs) and growth and differentiation factor (GDF). It is involved in important biological functions including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. This superfamily is also considered to impact on cancer biology including that of GBM, with various effects depending on the member. The TGFbeta subfamily, in particular, is overexpressed in some GBM types which exhibit aggressive phenotypes. This subfamily impairs anti-cancer immune responses in several ways, including immune cells inhibition and major histocompatibility (MHC) class I and II abolishment. It promotes GBM angiogenesis by inducing angiogenic factors such as vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI-I) and insulin- like growth factor-binding protein 7 (IGFBP7), contributes to GBM progression by inducing metalloproteinases (MMPs), "pro-neoplastic" integrins (alphavbeta3, alpha5beta1) and GBM initiating cells (GICs) as well as inducing a GBM mesenchymal phenotype. Equally, Nodal promotes GICs, induces cancer metabolic switch and supports GBM cell proliferation, but is negatively regulated by Lefty. Activin promotes GBM cell proliferation while GDF yields immune-escape function. On the other hand, BMPs target GICS and induce differentiation and sensitivity to chemotherapy. This multifaceted involvement of this superfamily in GBM necessitates different strategies in anti-cancer therapy. While suppressing the TGFbeta subfamily yields advantageous results, enhancing BMPs production is also beneficial. PMID- 26514452 TI - Review and Current Status of Opisthorchis viverrini Infection at the Community Level in Thailand. AB - Opisthorchis viverrini is remains a public health problem in Thailand, particularly in the northeast and north regions which have the highest incidences of chonalgiocarcinoma (CCA). O. viverrini causes the disease opithorchiasis, and its has been classified as a group 1 biological carcinogen. Humans, dogs, and cats become infected with O. viverrini by ingesting raw or undercooked fish containing infective metacercariae. The first human cases of O. viverrini infection were reported in Thailand 100 years ago, and it's still a problem at the community level. Based on data for the year 2009, more than 6 million people were infected with O. viverrini. Associated medical care and loss of wages in Thailand costs about $120 million annually. This review highlights the current status of O. viverrini infection in communities of Thailand through active surveillance for the five years period from 2010 and 2015. A total of 17 community-based surveys were conducted, most in the northeast region. Some 7 surveys demonstrated a high prevalence over 20%, and the highest was 45.7%. Most commonly infection was found in age group of 35 years and older, males, and agricultural workers. Although, the national prevalence may be decreasing but the results show that the O. viverrini infection is still high in communities of the northeast region. Therefore, the focus in populations living in northeast Thailand should be screening of infection and changing their eating behavior. PMID- 26514453 TI - Enhancing Activity of Anticancer Drugs in Multidrug Resistant Tumors by Modulating P-Glycoprotein through Dietary Nutraceuticals. AB - Multidrug resistance is a principal mechanism by which tumors become resistant to structurally and functionally unrelated anticancer drugs. Resistance to chemotherapy has been correlated with overexpression of p-glycoprotein (p-gp), a member of the ATP-binding cassette (ABC) superfamily of membrane transporters. P gp mediates resistance to a broad-spectrum of anticancer drugs including doxorubicin, taxol, and vinca alkaloids by actively expelling the drugs from cells. Use of specific inhibitors/blocker of p-gp in combination with clinically important anticancer drugs has emerged as a new paradigm for overcoming multidrug resistance. The aim of this paper is to review p-gp regulation by dietary nutraceuticals and to correlate this dietary nutraceutical induced-modulation of p-gp with activity of anticancer drugs. PMID- 26514454 TI - Impact of Omega-3 Fatty Acid Supplements on Gastrointestinal Cancer Patients after Surgery: Beneficial or Useless? AB - Omega-3 polyunsaturated fatty acids (w-3 PUFAs) are essential nutrients for human beings and their potential roles against cancer development and progression have become of wide concern recently. Some studies have suggested that perioperative supplementation with omega-3 fatty acids may have beneficial effects in gastrointestinal cancer patients undergoing surgery, while other researchers reported contrary results. This paper reviews recent research to establish therapeutic effects as well as possible underlying mechanisms of ????PUFA actions, and to help explain possible reasons for inconsistent results from different institutions. PMID- 26514455 TI - Molecular Screening for P53 Mutations among Tobacco Smokers in a Survey of Awareness of Links between Tobacco, Alcohol Use and Cancer in Saudi Arabia. AB - BACKGROUND: Roles of tobacco and alcohol use in etiology of cancer are well established. Alterationin in P53 have essential roles neoplastic change by preventing genome mutation; the aim of this study was to assess the association between P53 mutation and tobacco and alcohol consumption, as well as to assess the epidemiology of tobacco and alcohol use as risk factors for cancer in the adult population of northern Saudi civilians. MATERIALS AND METHODS: A cross sectional survey from October 2014 to January 2015, covering 3,398 adults, was performed. P53 mutation molecular detection was performed for 100 tobacco and alcohol users, using DNA extracted from buccal cells. RESULTS: Of the 3,398 participants 3,253/3398(95.7%) responded, with a male female ratio of 1.10: 1.00. Out of these, 24.8% had smoked tobacco in their lifetime and 2.7% were consumers of alcoholic beverages. None was identified with any P53 mutation. CONCLUSIONS: The prevalence of tobacco smoking among the northern Saudi civilians was relatively high. Females' attitudes in tobacco and alcohol related issues were found to be affected by social stigma. Tobacco and alcohol use has no link to P53 gene mutations. PMID- 26514456 TI - Expression of Fatty Acid Synthase Negatively Correlates with PTEN and Predicts Peritoneal Dissemination of Human Gastric Cancer. AB - BACKGROUND: This study aimed to examine the clinical significance of fatty acid synthase (FASN) expression in gastric cancer (GC), and investigate any prognostic role. MATERIALS AND METHODS: FASN expression was assessed in gastric cancers by immunohistochemistry using 60 paraffin-embedded tissue specimens, and clinical data were collected by retrospective chart review. Moreover, FASN mRNA expression in 15 fresh resected specimens was evaluated by the reverse transcription polymerase chain reaction (RT-PCR). Immunohistochemical staining of PTEN was performed to assess the correlation of PTEN with FASN in gastric cancer. RESULTS: Increased expression of FASN was noted in gastric cancers. The frequency of FASN gene amplification was also significantly higher in gastric cancer than in adjacent normal tissue. FASN expression in human gastric cancer tissues was significantly correlated with patient TNM stage and peritoneal dissemination (p<0.05). Moreover, higher FASN expression significantly correlated with shorter overall survival (p<0.05). Here, upregulation of FASN negatively correlated with PTEN expression in gastric cancer. CONCLUSIONS: These findings indicate that FASN expression is upregulated in gastric cancer, and increased FASN may be critical to th peritoneal metastasis and survival. Our results suggest that FASN upregulation and PTEN downregualtion may be involved in peritoneal dissemination for gastric cancer progression. PMID- 26514457 TI - Cost-Effectiveness Analysis of Different Management Strategies for Detection CIN2+ of Women with Atypical Squamous Cells of Undetermined Significance (ASC-US) Pap Smear in Thailand. AB - BACKGROUND: To identify the optimal cost effective strategy for the management of women having ASC-US who attended at King Chulalongkorn Memorial Hospital (KMCH). DESIGN: An Economical Analysis based on a retrospective study. SUBJECT: The women who were referred to the gynecological department due to screening result of ASC US at King Chulalongkorn Memorial Hospital, a general and tertiary referral center in Bangkok Thailand, from Jan 2008 - Dec 2012. MATERIALS AND METHODS: A decision tree-based was constructed to evaluate the cost effectiveness of three follow up strategies in the management of ASC-US results: repeat cytology, triage with HPV testing and immediate colposcopy. Each ASC-US woman made the decision of each strategy after receiving all details about this algorithm, advantages and disadvantages of each strategy from a doctor. The model compared the incremental costs per case of high-grade cervical intraepithelial neoplasia (CIN2+) detected as measured by incremental cost-effectiveness ratio (ICER). RESULTS: From the provider's perspective, immediate colposcopy is the least costly strategy and also the most effective option among the three follow up strategies. Compared with HPV triage, repeat cytology triage is less costly than HPV triage, whereas the latter provides a more effective option at an incremental cost-effectiveness ratio (ICER) of 56,048 Baht per additional case of CIN 2+ detected. From the patient's perspective, the least costly and least effective is repeat cytology triage. Repeat colposcopy has an incremental cost-effectiveness (ICER) of 2,500 Baht per additional case of CIN2+ detected when compared to colposcopy. From the sensitivity analysis, immediate colposcopy triage is no longer cost effective when the cost exceeds 2,250 Baht or the cost of cytology is less than 50 Baht (1USD = 31.58 THB). CONCLUSIONS: In women with ASC-US cytology, colposcopy is more cost-effective than repeat cytology or triage with HPV testing for both provider and patient perspectives. PMID- 26514458 TI - Women's Knowledge, Attitudes, and Practices about Breast Cancer in a Rural District of Central India. AB - BACKGROUND: Breast cancer accounted for almost 25% of all cancers in women globally in 2012. Although breast cancer is the most prevalent cancer in India, there is no organised national breast cancer screening programme. Local studies on the burden of breast cancer are essential to develop effective context specific strategies for an early detection breast cancer programme, considering the cultural and ethnic heterogeneity in India. This study examined the knowledge, attitudes, and practices about breast cancer in rural women in Central India. MATERIALS AND METHODS: This community-based cross sectional study was conducted in Wardha district, located in Maharashtra state in Central India in 2013. The sample included 1000 women (609 rural, 391 urban) aged 13-50 years, selected as representative from each of the eight development blocks in the district, using stratified cluster sampling. Trained social workers interviewed women and collected demographic and socio-economic data. The instrument also assessed respondents' knowledge about breast cancer and its symptoms, risks, methods of screening, diagnosis and treatment, as well as their attitudes towards breast cancer and self- reported practices of breast cancer screening. Chi-square and t-test were applied to assess differences in the levels of knowledge, attitude, and practice (the outcome variables) between urban and rural respondents. Multivariable linear regression was conducted to analyse the relationship between socio-demographic factors and the outcome variables. RESULTS: While about two-thirds of rural and urban women were aware of breast cancer, less than 7% in rural and urban areas had heard about breast self examination. Knowledge about breast cancer, its symptoms, risk factors, diagnostic modalities, and treatment was similarly poor in both rural and urban women. Urban women demonstrated more positive attitudes towards breast cancer screening practices than their rural counterparts. Better knowledge of breast cancer symptoms, risk factors, diagnosis, and treatment correlated significantly with older age, higher levels of education, and being office workers or in business. CONCLUSIONS: Women in rural Central India have poor knowledge about breast cancer, its symptoms and risk factors. Breast self-examination is hardly practiced, though the willingness to learn is high. Positive attitudes towards screening provide an opportunity to promote breast self-examination. PMID- 26514459 TI - Meningeal Hemangiopericytomas and Meningomas: a Comparative Immunohistochemical and Genetic Study. AB - BACKGROUND: The meningeal hemangiopericytoma (MHPC) is a vascular tumor arising from pericytes. Most intracranial MHPCs resemble meningiomas (MNGs) in their clinical presentation and histological features and may therefore be misdiagnosed, despite important differences in prognosis. MATERIALS AND METHODS: We report 8 cases of MHPC and 5 cases of MNG collected from 2007 to 2011 from the Neuro-Surgery and Histopathology departments. All 13 samples were re reviewed by two independent pathologists and investigated by immunohistochemistry (IHC) using mesenchymal, epithelial and neuro-glial markers. Additionally, we screened all tumors for a large panel of chromosomal alterations using multiplex ligation probe amplification (MLPA). Presence of the NAB2-STAT6 fusion gene was inferred by immunohistochemical staining for STAT6. RESULTS: Compared with MNG, MHPCs showed strong VIM (100% of cases), CD99 (62%), bcl-2 (87%), and p16 (75%) staining but only focal positivity with EMA (33%) and NSE (37%). The p21 antibody was positive in 62% of MHPC and less than 1% in all MNGs. MLPA data did not distinguish HPC from MNG, with PTEN loss and ERBB2 gain found in both. By contrast, STAT6 nuclear staining was observed in 3 MHPC cases and was absent from MNG. CONCLUSIONS: MNG and MHPC comprise a spectrum of tumors that cannot be easily differentiated based on histopathology. The presence of STAT6 nuclear positivity may however be a useful diagnostic marker. PMID- 26514460 TI - Protective Role of Selenium and High Dose Vitamin E against Cisplatin - Induced Nephrotoxicty in Rats. AB - BACKGROUND: Cisplatin (CDDP) is one of the most active cytotoxic agents in the treatment of cancer. We investigated the effect of selenium (Se) with high dose vitamin E (VE) administration to prevent CDDP-induced nephrotoxicity in rats. MATERIALS AND METHODS: In this study, 40 female Wistar rats were randomly divided into five equal groups. The first group, which served as the control, was administered physiological saline (2.5 cc/day, 5 days) intraperitoneally (IP), while group A was administered cisplatin (6 mg/kg BW/ single dose) plus physiological saline IP. Groups B, C, D received IP five doses of Se (1.5 mg/kg BW), and a high dose of VE (1000 mg/kg BW) (Se-VE) in combination before, simultaneously, and after CDDP, respectively. The rats were sacrificed five days after CDDP administration. Plasma malondialdehide (MDA), glutathione peroxidase (GSH-Px), reduced glutathione (GSH), catalase, urea, creatinine levels, renal histopathological changes were measured. RESULTS: The histopathological injury score, plasma levels of MDA, urea, creatinine were found to increase in group A compared to the control (p<0.05), while plasma levels of GSH-Px, GSH and catalase decreased (p<0.05). In contrast, plasma levels of MDA decreased (p<0.05) in groups B, C, D, which were treated with Se- VE, whereas levels of GSH-Px, GSH were found to increase only for group D (p<0.05). Plasma urea, creatinine levels improved in the treatment groups compared to group A (p<0.001). Histopathological changes caused by CDDP were also significantly improved after Se-VE treatment (p<0.05). CONCLUSIONS: Oxidative stress increases with CDDP-induced nephrotoxicity in rats. Se-VE supplementation might thus play a role in the prevention of CDDP-induced nephrotoxicity in patients. PMID- 26514461 TI - A Cross Sectional Study of Kretek Smoking in Indonesia as a Major Risk to Public Health. AB - BACKGROUND: Tobacco smoking is a major cause of preventable disease and death worldwide. Kreteks are clove-flavored cigarettes made from a combination of tobacco and ground-clove mixed with a sauce, smoked widely in Indonesia. Because health and social consequences of kretek smoking are potentially as great as those of traditional cigarettes, this study examines the prevalence of kretek smoking in Indonesia and associated risk factors. MATERIALS AND METHODS: The study used nationally representative Indonesia Global Adult Tobacco Survey data. Multiple logistic regression analysis was employed to identify correlates of kretek smoking. RESULTS: One- third of Indonesian adults smoked tobacco of which about 90.0% smoked kreteks. Prevalence of kretek smoking among men (60.9%) was more than 25 times the rate among women (2.3%). Overall, the highest prevalence of kretek use was in the age group 45-54 years (36.5%), followed by 34-44 (35.1%), 25-34 (34.2 %), and 55-64 years (32.8%). By wealth index, prevalence of kreteks smoking among those in the middle index was almost 50% above the rate for the wealthiest group (36.4% vs 24.8% respectively). Logistic regression results showed that being male, being older, having less education, and being less wealthy were significant predictors of kretek smoking, while urban vs rural residence was not. CONCLUSIONS: Kretek smoking is common in Indonesia and is entrenched in the sociocultural fabric of the country. However, potential consequences of kretek smoking, particularly as risks for noncommunicable diseases, underscore the importance of a comprehensive approach to tobacco control as outlined in the World Health Organization's MPOWER strategies. PMID- 26514462 TI - Analysis of Relationships between Altitude and Distance from Volcano with Stomach Cancer Incidence Using a Geographic Information System. AB - Gastric cancer (GC) is the fifth most common cancer in the world, with a wide variation in incidence rates across different geographical areas. In Iran GC is the most common cancer in males and it is reported to be the third most prevalent after breast and colorectal in females. A geographical information system (GIS) allows investigation of the geographical distribution of diseases. The purpose of the present study was to explore the relationship between gastric cancer and effective climatic factors using GIS. The dispersion distribution and the relationship between environmental factors effective on cancer were measured using Arc GIS. Of all cases, 672 (73.8%) were in males with a sex ratio of 3 to 1. The highest incidence by cities was seen in Namin with 137.5 per 100,000. The results of this study showed that the distribution of GC around the Sabalan volcanic mountain was significantly higher than other places in the same province. These results can be considered as a window to future comprehensive research on gastric cancer. PMID- 26514463 TI - Patient-Centredness, Job Satisfaction and Psychological Distress: a Brief Survey Comparing Oncology Nurses and Doctors. AB - BACKGROUND: We aimed to explore whether levels of patient-centredness, job satisfaction and psychological distress varied between oncology nurses and doctors. MATERIALS AND METHODS: In a cross-sectional study using self administered questionnaires, a total of 24 nurses and 43 doctors were assessed for patient-centredness, psychological distress, and job satisfaction using the Patient-Practitioner Orientation Scale, Hospital Anxiety and Depression Scale, and Job Satisfaction Scale. Data were analysed using descriptive statistics, independent samples t-test and MANCOVA, with p<0.05 considered significant. RESULTS: Overall response rate was 95.6% (43/45) for physicians and 85.7% (24/28) for nurses. Even after adjusting for known covariates, our principal finding was that doctors reported greater psychological distress compared to nurses (p=0.009). Doctors also reported lower job satisfaction compared to nurses (p = 0.017), despite higher levels of patient-centredness found in nurses (p=0.001). Findings may be explained in part by differences in job characteristics and demands. CONCLUSIONS: Mental health is an important concern not just in cancer patients but among healthcare professionals in oncology. PMID- 26514464 TI - Incidences, Trends and Long Term Outcomes of Retinoblastoma in Three Cancer Registries, Thailand. AB - BACKGROUND: Retinoblastoma (RB) is rare, albeit the most common primary intraocular malignancy among children. To elucidate the true incidence, trend and survival, we studied incidences and trends of retinoblastoma in a large population with long-term follow-up using data from 3 population-based cancer registries. OBJECTIVE: To describe the incidence, trends and survival of RB between 1990 and 2009 in Khon Kaen, Songkhla and Chiang Mai, Thailand. MATERIALS AND METHODS: We sourced the data from the cancer registries in Khon Kaen, Songkhla and Chiang Mai on children with retinoblastoma, diagnosed between 1990 and 2009. Retinoblastoma was defined as per the International Classification of Disease for Oncology version 3 using the code 9510/3. Incidence was analyzed using the standard method with the criteria of the International Association of Cancer Registries. The Kaplan-Meier method was applied to calculate cumulative survival. Trends were calculated using the log rank test. RESULTS: We identified 75 cases of children between 0 and 15 years of age diagnosed with RB (Khon Kaen 31, Chiang Mai 20, Songkhla 24). Males and females were equally affected. The most common age group was 0-4 years. The morphological verification of the disease was 90.7%. The respective ASR in Khon Kaen, Chiang Mai and Songkhla was 4.4, 4.0 and 4.6 per million; for which the overall ASR for all 3 areas was 4.3 per million. The respective trend in incidence was 4, 2.8, 5.8 and 5.4 during 1990-4, 1995-9, 2000-4 and 2005-9. Overall, incidence trended gradually upward by 2% annually. The respective survival rate in Khon Kaen, Chiang Mai and Songkhla was 50, 40 and 75% (differences not significantly different at p=0.14) and the overall survival for all centers was 60%. CONCLUSIONS: Over the last two decades, the incidence and overall survival of retinoblastoma has increased. The ASRs and survival in Thailand were less than those in resource-rich countries. PMID- 26514465 TI - Burden of Cancers Related to Smoking among the Indonesian Population: Premature Mortality Costs and Years of Potential Life Lost. AB - BACKGROUND: As smoking is the leading preventable cause of multiple diseases and premature cancer deaths, estimating the burden of cancer attributable to smoking has become the standard in documenting the adverse impact of smoking. In Indonesia, there is a dearth of studies assessing the economic costs of cancers related to smoking. This study aimed to estimate indirect mortality costs of premature cancer deaths and years of potential life lost (YPLL) attributable to smoking among the Indonesian population. MATERIALS AND METHODS: A prevalence based method was employed. Using national data, we estimated smoking-attributable cancer mortality in 2013. Premature mortality costs and YPLL were estimated by calculating number of cancer deaths, life expectancy, annual income, and workforce participation rate. A human capital approach was used to calculate the present value of lifetime earnings (PVLE). A discount rate of 3% was applied. RESULTS: The study estimated that smoking attributable cancer mortality was 74,440 (30.6% of total cancer deaths), comprised of 95% deaths in men and 5% in women. Cancers attributed to smoking were responsible for 1,207,845 YPLL. Cancer mortality costs caused by smoking accounted for USD 1,309 million in 2013. Among all cancers, lung cancer is the leading cause of death and economic burden. CONCLUSIONS: Cancers related to smoking pose an enormous economic burden in Indonesia. Therefore, tobacco control efforts need to be prioritized in order to prevent more losses to the nation. The data of this study are important for advocating national tobacco control policy. PMID- 26514466 TI - Cervical Cancer Screening in an Early Diagnosis and Screening Center in Mersin, Turkey. AB - Cancer is a major public health problem due to the jeavy disease burden, fatality and tendency for increased incidence. Of all cancer types, cervical cancer is reported to be the fourth most common cancer in women, and the seventh overall, with an estimated 528,000 new cases worldwide in 2012. It features a long preclinical phase with slowly progressing precancerous lesions such as CIN 2 and 3 and adenocarcinoma in situ. Therefore, screening programs such as with Pap smear tests may play an important role in cervical cancer prevention. The purpose of this study was to present results of a Pap smear screening survey for cervical cancer targeting women living in an urban area in the province of Mersin, located in the Mediterranean region of Turkey. This community- based descriptive study included women living at Akdeniz county of Mersin province. A total of 1,032 screened women between 30 and 65 ages within the routine screening programme constituted the study population. The mean age of the participants was 43.8 +/- 8.6 (min. 30, max. 65) years. The percentage of the participants who had previously undergone smears was 40.6%. Epithelial cell changes were found in 26 (2.5%) participants, with ASC-US in 18 (1.7%), ASC-H in 2 (0.2%), LSIL in 5 (0.5%) and HSIL in 1 (0.1%). The most common clinical presentation together with epithelial changes was abnormal vaginal discharge. Taking into account the presence of women who had never undergone Pap test; it should be offered at primary level of health care in the form of a community-based service to achieve reduced morbidity and mortality rates. PMID- 26514467 TI - Quality of Life of Family Members Living with Cancer Patients. AB - BACKGROUND: Due to the rapid progress of industrialization, the expansion of the nuclear family, and an increase in women's social activities, the burden of care of cancer patients has increased, so that all family members are now involved in care. We compared the health-related quality of life (HRQOL) between members of families of cancer patients (hereafter, cancer families) and members of cancer free families (non-cancer families). MATERIALS AND METHODS: The data were from the Community Health Survey (2012). The study population included respondents at least 30 years of age. Data were adjusted for the following covariates: sex, age, education, marital status, household income, economic activity, household type, chronic disease, and perceived health status. Frequency analysis, analyses of variance, and multiple linear regression analysis were performed. RESULTS: Among 163,495 respondents, 3,406 (2.1%) were part of a cancer family and 160,089 (97.9%) were part of a non-cancer family. Cancer families had lower EQ-5D scores than non-cancer families. However, by subgroup, the scores had significant association between cancer and non-cancer families only for females and for those who worked. CONCLUSIONS: There was a significant relationship between HRQOL scores and being a family member of a cancer patient. This indicates that the responsibility for care has been extended to the entire family, not only the primary caregiver. PMID- 26514468 TI - Outcome of Palliative and Radical Radiotherapy in Patients with Oral Squamous Cell Carcinoma - a Retrospective Study. AB - BACKGROUND: The treatment selection for the oral squamous cell carcinoma remains controversial. Radiation therapy or surgical excision of the lesion can be applied as the sole treatment or it can be used in combination with other treatment modalities. Radiotherapy is considered to be the safest of all the treatment modalities and can be used in several situations for oral and oropharyngeal cancers. The aim of this study was to evaluate the survival outcome differences in patients treated with radical and palliative radiotherapy as the primary treatment modality. MATERIALS AND METHODS: The study included a total of 47 patients with oral cancer reporting to our hospital between years 2009 to 2010. The age group for the selected patients was more than 65 years, treated with radical and palliative radiotherapy with no prior surgical interventions. Patients were evaluated till Dec 2013 for overall survival time. RESULTS: Twenty nine patients were treated with radical radiotherapy as main stay of treatment, out of which 21 died during the follow up time with median survival of 352 +/- 281.7 days with 8 patients alive. All the 16 patients were dead who received palliative radiotherapy with a median survival time of 112 +/- 144.0 days. CONCLUSIONS: This retrospective study showed improved overall survival time, loco regional control rates and reduced morbidity in patients treated with radical radiotherapy when compared to patients treated with palliative radiotherapy. PMID- 26514469 TI - Circulating Levels of Adipocytokines as Potential Biomarkers for Early Detection of Colorectal Carcinoma in Egyptian Patients. AB - BACKGROUND: Early detection of various kinds of cancers nowadays is needed including colorectal cancer due to the highly significant effects in improving cancer treatment. The aim of this study was to evaluate the potential value of adiponectin, visfatin and resistin as early biomarkers for colorectal cancer patients. MATERIALS AND METHODS: Serum levels of adiponectin, visfatin and resistin were measured by a sandwich-enzyme-linked (ELISA) assay technique in 114 serum samples comprising 34 patients with colorectal cancer (CRC), 27 with colonic polyps (CP), 24 with inflammatory bowel disease (IBD) and 29 healthy controls .The diagnostic accuracy of each serum marker was evaluated using receiver-operating characteristic (ROC) curve analysis. RESULTS: The mean concentration of adiponectin was significantly higher in CRC and CP groups than IBD and control groups (P-value <0.05). Also the mean concentration of serum resistin was significantly elevated in the IBD and control groups compared to CRC and CP groups (P-value = 0.014). However, no significant difference was noted in patients of the CRC and CP groups. On the other hand, the mean concentration of visfatin was significantly elevated in CRC and control groups compared to CP and IBD groups (P-value = 0.03). ROC analysis curves for the studied markers revealed that between CRC and IBD groups serum level of adiponectin had a sensitivity of 76.7% and a specificity of 76% at a cut off value of 3940, +LR being 3.2 and -LR 0.31 with AUC 0.852, while serum level of adiponectin between CP and IBD had a sensitivity of 77.8% and a specificity of 75% at a cut off value of 3300, with +LR=3.11 and -LR = 0.3 with AUC 0.852. On the other hand the serum level of visfatin between CRC and CP groups had a sensitivity of 65.5% and a specificity of 66.7 at a cut off value of 2.4, +LR being 1.67 and -LR 0.52 with AUC 0.698. Also the serum level of resistin had a sensitivity of 62.5% and a specificity of 70.3% at a cut off value of 24500, with +LR=2.1 and -LR = 0.53 with AUC 0.685 between control and other groups. On the other hand by comparing control vs CP groups resistin had a sensitivity of 81.8% and a specificity of 70.8% at a cut off value of 17700, with +LR=2.8 and -LR = 0.26 with AUC 0.763 while visfatin had a sensitivity of 68.2% and a specificity of 70.8% at a cut off value of 2.7, with +LR=2.34 and -LR = 0.0.45 with AUC 0.812. CONCLUSIONS: These findings support potential roles of adiponectin, visfatin and resistin in early detection of CRC and discrimination of different groups of CRC, CP or IBD patients from normal healthy individuals. PMID- 26514470 TI - Real Life Treatment of Hepatocellular Carcinoma: Impact of Deviation from Guidelines for Recommended Therapy. AB - BACKGROUND: Real life management of hepatocellular carcinoma occasionally deviates from guidelines for recommended therapy. AIMS: To evaluate how frequent this deviation happens in our center and assess its impact on outcome. MATERIALS AND METHODS: The treatment of 770 patients (87% males, mean age 57.8 years) was analyzed and the effect of deviation on outcome over 36 months was examined. RESULTS: Of Barcelona Clinic liver cancer stages 0 and A patients, 65.8% received resection, ablation, liver transplantation or transarterial chemoembolisation for unresectable tumors more than 5 cm in diameter, and 34.2% received treatment recommended for later stages. Of stage B patients, 62.2% received recommended therapy, 34.3% of patients received supportive therapy or sorafenib and 3.5% received upward treatment stage migration. Among stage C patients, 7.6% received sorafenib, and most (79.2%) were given supportive care. Deviation from recommended therapy occurred in 34.2%, 37.7%, and 92.4% in stages 0-A, B and C. Survival of stage 0-A patients who received downwards treatment stage migration was lower than those who received recommended treatment (p <0.001). Upward treatment stage migration in stages B, C and D did not improve survival compared to those who received recommended treatment. CONCLUSIONS: Deviation from recommended therapy had a negative impact on survival in Barcelona Clinic liver cancer stage A patients. PMID- 26514471 TI - Prevalence of Abnormal Papanicolaou Test Results and Related Factors among Women Living in Zanjan, Iran. AB - BACKGROUND: Currently, a comprehensive program for screening and early detection of cervical cancer does not exist in Iran. This study aimed to determine the prevalence of abnormal Papanicolaou (Pap) smears and some related factors among women living in Zanjan, Iran. MATERIALS AND METHODS: This cross-sectional study was conducted in 2012 in Zanjan on 4274 married women aged 20-65 years. The study participants were selected through two-stage cluster sampling. After obtaining written consent, demographic and fertility questionnaires were completed. Samples from cervix were obtained through a standard method using the Rover Cervex- Brush. Evaluation and interpretation of the samples were reported using the Bethesda 2001 method. Data were statistically analyzed using chi-square and logistic regression models. RESULTS: Most inflammatory changes in the samples were mild (37.4%). Abnormal atypical changes in the epithelial cells were found in 4.04%. The highest percentage of abnormal changes in the epithelial cells was atypical squamous cells of undetermined significance (ASCUS) (1.9%). Abnormal results of Pap smear was significantly and independently associated with age, papillomavirus infection, and lack of awareness about Pap smear tests. CONCLUSIONS: Given the high prevalence of inflammatory and precancerous changes in this study, compared to other studies in Iran and other Muslim countries, and the effect of demographic variables and individual factors on abnormal results, increasing the awareness of women and their families regarding the risk factors for cervical cancer, preventive measures such as screening, and timely treatment seem necessary. PMID- 26514472 TI - Awareness and Attitude of Nurses in Regard to Providing Hospice Care. AB - BACKGROUND: Awareness and attitudes of nurses regarding end of life care are important factors in providing hospice care. In an extensive literature review, we found no related articles investigating Iranian nurses awareness and attitudes about providing such care. OBJECTIVES: The aims of this study were to investigate the awareness and attitudes of Iranian nurses in providing hospice care. MATERIALS AND METHODS: In this descriptive-correlational study, 240 nurses employed in six educational centers were selected by non-randomized stratified sampling. The data collection instruments included an awareness test and attitudes regarding providing end of life care in hospice questionnaire. The data were analyzed using descriptive statistics and independent sample t-tests, one way ANOVA, and Pearson correlation tests. RESULTS: The nurses' awareness score was 14.3 out of 29 and 55.7% of them stated that they had not received any education in providing end of life care. Also, by obtaining the score of 91.7 out of 120 the attitudes of participants in providing end of life care in hospices were positive. In addition, the highest attitudes score of nurses were in the dimensions of benefits of implementation and health care team. CONCLUSIONS: Considering low awareness of nurses about end of life care in hospices, continuing education should be provided for them in this regard. Especially, by considering the positive attitude of nurses, providing such programs could help develop hospice care in Iran. PMID- 26514473 TI - Hesa-A Down-Regulates erb/b2 Oncogene Expression and Improves Outcome of Oral Carcinoma in a Rat Model. AB - BACKGROUND: Oral carcinoma (OC) remains one of the most difficult malignancies to cure. Hesa-A is an Iranian herbal-marine compound that has shown promising anti tumor properties against various human tumors. However, its mechanism of action remains to be addressed. The present study was conducted to evaluate the effect of two doses of Hesa-A on mRNA expression of erb?b2 as a main prognosticator tumor marker for OC in an animal model. MATERIALS AND METHODS: A total of 60 rats were randomly divided into 5 groups of 12 animals each. Rats in carcinoma groups received 0, 250 and 500 mg/kg body weight doses of Hesa-A 3 times a day. The other two groups were considered as treated and untreated control groups. At the end of the experiment, animals were sacrificed and tongue tissues subjected to H and E staining and real time PCR. RESULTS: Our results showed that compared to the control group, erb? b2 was over-expressed ~ 30% in the carcinoma group. After treatment with 250 mg/kg and 500 mg/kg body weight of Hesa-A , erb?b2 levels dropped by 24.1% and 3.4 % respectively compared to the control carcinoma group (p<0.01, p<0.0001). Moreover, there was a significant relation between erb? b2 mRNA content and observed pathological changes in studied groups (p<0.05). CONCLUSIONS: These data provide insight into mechanism(s) by which Hesa-A may improve clinical outcome of oral carcinoma by affecting oncogene erb?b2 expression and suggest Hesa-A as an effective chemotherapeutic agent in treatment of HER+ tumors. PMID- 26514474 TI - Influence of the CYP1A1 T3801C Polymorphism on Tobacco and Alcohol-Associated Head and Neck Cancer Susceptibility in Northeast India. AB - BACKGROUND: Tobacco and alcohol contain or may generate carcinogenic compounds related to cancers. CYP1A1 enzymes act upon these carcinogens before elimination from the body. The aim of this study was to investigate whether CYP1A1 T3801C polymorphism modulates the relationship between tobacco and alcohol- associated head and neck cancer (HNC) susceptibility among the northeast Indian population. MATERIALS AND METHODS: One hundred and seventy histologically confirmed HNC cases and 230 controls were included within the study. The CYP1A1 T3801C polymorphism was determined using PCR-RFLP, and the results were confirmed by DNA sequencing. Logistic regression (LR) and multifactor dimensionality reduction (MDR) approaches were applied for statistical analysis. RESULTS: The CYP1A1 CC genotype was significantly associated with HNC risk (P=0.045). A significantly increased risk of HNC (OR=6.09; P<0.0001) was observed in individuals with combined habits of smoking, alcohol drinking and tobacco-betel quid chewing. Further, gene environment interactions revealed enhanced risks of HNC among smokers, alcohol drinkers and tobacco-betel quid chewers carrying CYP1A1 TC or CC genotypes. The highest risk of HNC was observed among smokers (OR=7.55; P=0.009) and chewers (OR=10.8; P<0.0001) carrying the CYP1A1 CC genotype. In MDR analysis, the best model for HNC risk was the three-factor model combination of smoking, tobacco betel quid chewing and the CYP1A1 variant genotype (CVC=99/100; TBA=0.605; P<0.0001); whereas interaction entropy graphs showed synergistic interaction between tobacco habits and CYP1A1. CONCLUSIONS: Our results confirm that the CYP1A1 T3801C polymorphism modifies the risk of HNC and further demonstrated importance of gene-environment interaction. PMID- 26514475 TI - Anti-Proliferative Effects of Hesa-A on Human Cancer Cells with Different Metastatic Potential. AB - BACKGROUND: During the past few years, Hesa-A, a herbal-marine mixture, has been used to treat cancer as an alternative medicine in Iran. Based on a series of studies, it is speculated that Hesa-A possesses special cytotoxic effects on invasive tumors. To test this hypothesis, we investigated the selective anticancer effects of Hesa-A on several cancer cell lines with different metastatic potential. MATERIALS AND METHODS: Hesa-A was prepared in normal saline as a stock solution of 10 mg/ml and further diluted to final concentrations of 100 MUg/ml, 200 MUg/ ml, 300 MUg/ml and 400 MUg/ml. MTT-based cytotoxicity assays were performed with A549 (lung non small cancer), MCF-7 (breast adenocarcinoma), SKOV3 (ovarian cancer), and PC-3 (prostate adenocarcinoma) cells. RESULTS: All treated cancer cells showed significant (P<0.01) or very significant (P<0.0001) differences in comparison to negative control at almost all of the tested doses (100-400 MUg/ml). At the lower dose (100 MUg/ml), Hesa-A reduced cell viability to 66%, 45.3%, 35.5%, 33.2% in SKOV3, A549, PC-3 and MCF-7 cells, respectively. Moreover, at the highest dose (400 MUg/ml), Hesa-A resulted in 88.5%, 86.6% , 84.9% and 79.3% growth inhibition in A549, MCF-7, PC-3 and SKOV3 cells, respectively. CONCLUSIONS: Hesa-A exert potent cytotoxic effects on different human cancer cells, especially those with a high metastatic potential. PMID- 26514476 TI - Tobacco Use Increases Oxidative DNA Damage in Sperm - Possible Etiology of Childhood Cancer. AB - BACKGROUND: Cigarette smoking and tobacco chewing are common modes of consuming tobacco all over the world. Parents need to be aware that germ cell integrity is vital for birth of healthy offspring as biological parenting begins much before birth of a child and even before conception. The present study was conducted to determine the etiology of non-familial sporadic heritable retinoblastoma (NFSHRb), by evaluating oxidative sperm DNA damage in fathers due to use of tobacco (smoking and chewing). MATERIALS AND METHODS: We recruited 145 fathers of NFSHRb children and 53 fathers of healthy children (controls) in the study. Tobacco history was obtained by personal interview. Seminal reactive oxygen species (ROS) in semen, sperm DNA fragmentation index (DFI) and 8 hydroxy 2' deoxyguanosine (8-OHdG) levels in sperm were evaluated. The RB1 gene was screened in genomic blood DNA of parents of children with NFSHRb and controls. Odds ratios (ORs) derived from conditional logistic regression models. RESULTS: There was significant difference in the levels of ROS (p<0.05), DFI (p<0.05) and 8-OHdG (p<0.05) between tobacco users and non-users. The OR of NFSHRb for smokers was 7.29 (95%CI 2.9-34.5, p<0.01), for tobacco chewers 4.75 (2.07-10.9, p<0.05) and for both 9.11 (3.79-39.2; p<0.01). CONCLUSIONS: This study emphasizes the adverse effect of tobacco on the paternal genome and how accumulation of oxidative damage in sperm DNA may contribute to the etiology of NFSHRb. In an ongoing parallel study in our laboratory, 11 of fathers who smoked underwent. Meditation and yoga interventions, showed significant decline in levels of highly mutagenic oxidised DNA adducts after 6 months. Thus our lifestyle and social habits impact sperm DNA integrity and simple interventions like yoga and meditation are therapeutic for oxidative damage to sperm DNA. PMID- 26514477 TI - Evaluation of Effects of Metformin in Primary Ovarian Cancer Cells. AB - BACKGROUND: Ovarian cancer is the third most common cause of cancer in Indian women. Despite an initial 70-80% response rate, most patients relapse within 1-2 years and develop chemoresistance. Hence, identification or repositioning of drugs to resensitise ovarian cancer cells to existing chemotherapy is needed. Traditionally immortalized cell lines have been used in research, but these may contain genetic aberrations and chromosomal abnormalities serving as poor indicators of normal cell phenotype and progression of early-stage disease. The use of primary cells, maintained for only short periods of time in vitro, may serve as the best representative for studying in vivo conditions of the tissues from which they are derived. In this study we have attempted to evaluate the effect of metformin (an antidiabetic drug) in primary ovarian cancer cells because of its promising effect in other solid tumours. MATERIALS AND METHODS: Primary cultures of epithelial ovarian cancer cells established from ascitic fluid of untreated ovarian cancer patients were used. The cells were treated with metformin at doses standardized by MTT assay and its ability to induce apoptosis was studied. The cells were analysed for apoptosis and apoptosis related proteins by flow cytometry and western blotting respectively. RESULTS: Metformin induced apoptosis in ovarian cancer cells, provoking cell cycle arrest in the G0/G1 and S phase. It induced apoptosis in ovarian cancer cells by, down-regulating Bcl-2 and up-regulating Bax expression. CONCLUSIONS: Metformin was able to induce apoptosis in primary ovarian cancer cells by modulating the expression of Bcl-2 family proteins. These data are relevant to ongoing translational research efforts exploring the chemotherapeutic potential of metformin. PMID- 26514478 TI - Comparison of Two Different Educational Methods for Teachers' Mammography Based on the Health Belief Model. AB - BACKGROUND: Breast cancer is the most common cancer in women. One way to decrease the burden of this cancer is early detection through mammography. This study compared the effectiveness of two different educational methods for teachers' uptake of mammography based on the Health Belief Model. MATERIALS AND METHODS: The current study was a randomised trial of 120 teachers over 40 years old in two groups receiving multimedia or group education, both based on the Health Belief Model. Participants completed questionnaires before, immediately and three months after educational intervention. Mammography was evaluated before and after educational intervention. RESULTS: The participants in the two groups were demographically similar. Comparison showed no difference noted in the scores of knowledge, perceived barriers, susceptibility, and severity constructs between two groups (p > 0.05). Health motivation and benefit were perceived to be higher in the group education compared to the multimedia group. There was a significant difference in mammography between two groups after the intervention (p= 0.003). CONCLUSIONS: Planning and implementation of educational program based on the Health Belief Model can raise knowledge and increase participation in mammography especially with group education. PMID- 26514479 TI - Evaluation of General Dentists' and Dental Specialists' Knowledge about Oral Cancer in South Khorasan-Iran 2014. AB - BACKGROUND: Oral cancer is one of the most prevalent cancers and one of the top ten causes of death in the whole world. Most oral cancers are diagnosed at late stages. Since dentists play a critical role in early detection of oral cancer, they should be knowledgeable and skillful in oral cancer diagnosis. The aim of this study was to survey dentist knowledge about oral cancer in Southern Khorasan Province. MATERIALS AND METHODS: This descriptive, cross-sectional study was conducted with dentists who participated in an in-service educational program at the Faculty of Dentistry of Birjand University of Medical Sciences in spring 2014. A questionnaire including demographic information with 11 questions regarding oral cancer was prepared. The participants were required to be complete the questionnaires within a specific time span. The data were analyzed using SPSS 15 software by t-test and one-way ANOVA at 0.05 confidence level. RESULTS: A total of 73 dentists out of 80 answered the questionnaires - 36 (49.3%) were females and 37 (50.7%) were males. Total mean score of knowledge was 7.91 +/- 1 of 11. Mean scores of knowledge of male and female participants were 7.70 +/- 1.83 and 8.13 +/- 1.94 respectively. Mean knowledge score of general dentists was 7.41 +/- 1.79 and of dental specialists was 9.44 +/- 1.0 In spite of higher knowledge score of women compared to men and general dentists compared to dental specialists, these differences were not statistically significant (p=0.09). Tukey testing showed a significant difference between groups with 1-4 years of experience (8.74) and over twenty years of experience (6.50) ( p=0.001). CONCLUSIONS: Considering the good knowledge level of young dentists and the specialists and the importance of early diagnosis of oral cancer, it seems necessary to pay more attention to academic education for dentistry students, as well as holding retraining courses for experienced dentists, so that their knowledge not be reduced over time. PMID- 26514480 TI - TRAIL in Combination with Subtoxic 5-FU Effectively Inhibit Cell Proliferation and Induce Apoptosis in Cholangiocarcinoma Cells. AB - In the past decade, the incidence and mortality rates of cholangiocarcinoma (CCA) have been increasing worldwide. The relatively low responsiveness of CCA to conventional chemotherapy leads to poor overall survival. Recently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) has emerged as the most promising anti-cancer therapeutic agent since it is able to selectively induce apoptosis of tumor cells but not normal cells. In this study, we aimed to investigate the therapeutic effect of TRAIL in CCA cell lines (M213, M214 and KKU100) compared with the immortal biliary cell line, MMNK1, either alone or in combination with a subtoxic dose of 5-fluorouracil (5-FU). We found that recombinant human TRAIL (rhTRAIL) was a potential agent which significantly inhibited cell proliferation and mediated caspase activities (caspases 8, 9 and 3/7) and apoptosis of CCA cells. The combined treatment of rhTRAIL and 5-FU effectively enhanced inhibition of CCA cell growth with a smaller effect on MMNK1. Our finding suggests TRAIL to be a novel anti-cancer therapeutic agent and advantage of its combination with a conventional chemotherapeutic drug for effective treatment of CCA. PMID- 26514481 TI - Ki-67/MIB-1 as a Prognostic Marker in Cervical Cancer - a Systematic Review with Meta-Analysis. AB - BACKGROUND: In cervical cancer patients it has been reported that there in a significant Ki-67/MIB-1 expression is correlated with survival in cervical cancer patients. However, the prognostic value is still not well understood. MATERIALS AND METHODS: In the present meta-analysis the prognostic value of Ki-67/MIB-1 with regard to overall survival (OS) and disease-free survival (DFS) in cervical cancer was investigated. The databases of PubMed, ISI Web of Science, Cochrane Central Register of Controlled Trials, EMBASE, Science Direct and Wiley Online Library were used to identify appropriate literature. RESULTS: In order to explore the relationship between Ki-67/ MIB-1 and cervical cancer, we have included 13 studies covering 894 patients in the current meta-analysis. The effect of Ki-67/MIB-1 on OS for pooled random effects HR estimate was 1.63 (95%confidence interval (CI) 1.09- 2.45; P<0.05). The pooled HR for DFS was 1.26 (95%CI 0.58-2.73; P>0.05) and the subgroup analysis indicated Ki-67/MIB1 was associated with DFS (HR=3.67, 95%CI 2.65-5.09) in Asians. CONCLUSIONS: According to this meta-analysis, Ki-67/MIB-1 has prognostic value for OS in patients suffering from cervical cancer. For better evaluation of the prognostic role of Ki-67/MIB-1 on DFS, studies with larger numbers of patients are needed to validate present findings in the future. PMID- 26514482 TI - BIAN N-Heterocyclic Gold Carbene Complexes induced cytotoxicity in human cancer cells via upregulating oxidative stress. AB - BACKGROUND: Nanoparticles of gold and silver are offering revolutionary changes in the field of cancer therapy. N-heterocyclic carbene (NHC) metal complexes possess diverse biological activities and are being investigated as potential chemotherapeutic agents. The purpose of this study was to examine the cytotoxicity and possible mechanisms of action of two types of newly synthesized nanofiber composites containing BIAN N-heterocyclic gold carbene complexes in two types of human cancer cells, namely breast cancer (MCF7) and liver cancer (HepG2) cells and also in normal human embryonic kidney cells (HEK 293). MATERIALS AND METHODS: Cytotoxicity was assessed by MTT cell viability assay and oxidative stress by checking the total glutathione level. RESULTS: Both compounds affected the cell survival of the tested cell lines at very low concentrations (IC50 values in the micro molar range) as compared to a well-known anti-cancer drug, 5 fluorouracil. A 60-80% depletion in total glutathione level was detected in treated cells. CONCLUSIONS: Reduction in total glutathione level is one of the biochemical pathways for the induction of oxidative stress which in turn could be a possible mechanism of action by which these compounds induce cytotoxicity in cancer cell lines. The in vitro toxicity towards cancer cells found here means that these molecules could be potential anticancer candidates. PMID- 26514483 TI - Sneak Peek into Tobacco Habits and Associated Insidious Oral Lesions in an Odisha Sample Population. AB - BACKGROUND: Tobacco use in various forms, including with Areca nut, causes several potentially malignant disorders. Many lesions may transform into oral squamous cell carcinoma. Although patients may be aware of the hazards of tobacco habits, the lesions by themselves are insidious in nature resulting in failure of patients to present to general dentists/specialists at early stages. Our aim was to study the types of habits prevalent in the region of Rourkela in Orissa and to assess the insidious nature of the lesions associated with these habits. Not many studies have been done from this part of India. MATERIALS AND METHODS: A camp was conducted for habitual users of tobacco and its products, Areca nut and other mixed habit users. A thorough history was taken of the type, duration and frequency of habits, symptoms of patients along with clinical examination by a single examiner. The data was entered in detail into an excel sheet and analysed. RESULTS: 54.7% had lesions and 60.9 % of them were asymptomatic and rest had mild burning sensation while eating. There was a very low awareness of the presence of lesions among the patients. CONCLUSIONS: There is a need to spread the awareness of the ill effects of the tobacco and other associated habits far and wide and more importantly educate the general public on the appearance of associated lesions as these are almost always insidious in nature. The patients can self examine, detect lesions early when present and approach the dentist at the earliest opportunity. PMID- 26514484 TI - Enhancing Knowledge, Beliefs, and Intention to Screen for Prostate Cancer via Different Health Educational Interventions: a Literature Review. AB - BACKGROUND: Prostate cancer is one of the most common cancers affecting men globally, constituting the sixth leading cause of cancer related death in males, and the eleventh leading cause of death from cancer in all age groups. In Jordan, prostate cancer is the third most common cancer in the male population, accounting for one third (6.2%) of cancer related deaths and in 2010 alone, 218 (9.4%) new cases were identified. OBJECTIVE: To assess the effectiveness of different health education interventions aimed at enhancing knowledge, beliefs and intention to screen for prostate cancer. MATERIALS AND METHODS: A literature search from January 2000 to April 2015 was conducted using the key words "prostate disease," "educational program," "knowledge," "prostate cancer," "demographic factors and prostate cancer," "knowledge and prostate cancer," "education for patients with prostate cancer," "factors that affect intention to screen," "knowledge, beliefs, and intention to screen for prostate cancer," "impact of prostate educational program on beliefs," and "impact of educational program on intention to screen." RESULTS: Majority of studies reviewed indicated that men had low levels of knowledge regarding prostate cancer, and mild to moderate beliefs with good intention to screen for prostate cancer. CONCLUSIONS: Most studies indicated that men's knowledge levels about prostate cancer were poor and they had mild to moderate beliefs and intentions to screen for prostate cancer. Therefore, development of an assessment strategy based on the Health Belief Model seems essential. An effectively designed and implemented educational program can help identify the needs and priorities of the target population. PMID- 26514485 TI - Extrapulmonary Small Cell Carcinoma - a Case Series of Oropharyngeal and Esophageal Primary Sites Treated with Chemo-Radiotherapy. AB - BACKGROUND: The optimal sequence and extent of multimodality therapy remains to be defined for extrapulmonary small cell carcinoma because of its rarity. The purpose of our study was to assess the response to neoadjuvant chemotherapy followed by chemoradiation/radiation in patients with extrapulmonary small cell carcinoma. MATERIALS AND METHODS: Four consecutively diagnosed patients were included in this study. The primary tumor site was oropharynx in three patients and esophagus in one. The patients with the limited disease were treated with chemotherapy followed by concurrent chemoradiation (n=2) or radiotherapy (n=1). The patient with the extensive disease with the primary site in vallecula was treated with chemotherapy and palliative radiotherapy to the metastatic site. RESULTS: The median follow-up was 22.5 months (range, 8-24 months). Three patients with the limited disease (base of tongue, n=2; esophagus, n=1) were in complete remission. The patient with the extensive disease died of loco-regional tumor progression at 8 months from the time of diagnosis. CONCLUSIONS: The combination of chemotherapy and radiotherapy is the preferred therapeutic approach for patients with extrapulmonary small cell carcinoma. Induction chemotherapy followed by concurrent chemoradiation or radiation provides a good loco-regional control in patients with limited disease. PMID- 26514486 TI - Modulation of L-Arginine-Arginase Metabolic Pathway Enzymes: Immunocytochemistry and mRNA Expression in Peripheral Blood and Tissue Levels in Head and Neck Squamous Cell Carcinomas in North East India. AB - BACKGROUND: Arginine may play important roles in tumor progression by providing ornithine for polyamine biosynthesis, required for cell growth. The aim of this work was to determine the expression of arginine metabolic pathway enzymes in head and neck squamous cell carcinoma (HNSCC) in northeast India. MATERIALS AND METHODS: The expressions of arginase isoforms (ARG1 and ARG2), ornithine aminotransferase (OAT) and ornithine decarboxylase (ODC) were examined in fifty paired HNSCC and adjacent non-tumor tissues by immunohistochemistry. Immunocytochemistry, semiquantitative reverse transcription sq-PCR and quantitative real-time qPCR were used to assess protein and mRNA expressions in peripheral blood of fifty HNSCC patients and hundred controls. RESULTS: ARG1 and ODC protein and mRNA were strongly expressed in peripheral blood from HNSCC patients. No ARG2 expression was observed. In vivo, expression of ARG1, ARG2 and ODC was significantly higher in tumor than in non-tumor tissues. Most tumors expressed low levels of OAT, with no difference in tissues or blood, compared to controls. The absolute extent of maximal ARG1 upregulation with qPCR showed 6.23 fold increase in HNSCC. CONCLUSIONS: These findings strongly suggest that in HNSCCs, the ARG1 pathway is stimulated leading to the formation of polyamines as indicated by higher ODC expression, which promote tumor growth. PMID- 26514488 TI - Can Head and Neck Cancers Be Detected with Mean Platelet Volume? AB - BACKGROUND: Mean platelet volume (MPV) is a marker which has been investigated in many cancers but data for head and neck lesions are limited. We aimed to study the MPV levels in head and neck cancers as a diagnostic marker. MATERIALS AND METHODS: A total of 96 head and neck cancer patients and 31 control patients who did not meet exclusion criteria were enrolled in the study. The cancer locations, the platelet and MPV levels at the first diagnosis time were collected. RESULTS: The head and neck cancer location distribution between these patients was 2 (2.1%) buccal, 9 (9.4%) tongue, 6 (6.3) lip, 1 (1%) gingiva, 1 (1%) hypopharynx, 1 (1%) ear, 58 (60.4%) larynx, 2 (2.1%) maxilla, 2 (2.1%) nasal, 1 (1%) nasopharynx, 2 (2.1%) palatal, 3 (3.1%) primary unknown, 1 (1%) retromolar, 1 (1%) thyroid, 2 (2.1%) tonsil, and 4 (4.2%) salivary gland. MPV levels were significantly different between cancer and control group (p=0.002). The cut-off point for MPV predicting head and neck cancer is >10 fL (sensitivity=55.21, specificity=87.10). CONCLUSIONS: MPV level increase, a readily assessable parameter which does not bring extra costs can warn us regarding head and neck cancer risk. PMID- 26514487 TI - S100A16 is a Prognostic Marker for Lung Adenocarcinomas. AB - BACKGROUND: Many functional molecules controlling diverse cellular function are included in low-molecular weight proteins and peptides. MATERIALS AND METHODS: To identify proteins controlling function in lung adenocarcinomas (AC), we performed two-dimensional gel electrophoresis employing tricine-SDS polyacrylamide in the second dimension (tricine 2-DE). This system was able to detect proteins under 1 kDa even with post- translational modifications. To confirm the utility of detected proteins as novel tumor markers for AC, we performed immunohistochemical analysis using 170 formalin-fixed and paraffin-embedded lung AC tissues. RESULTS: Tricine 2-DE revealed that five proteins including S100A16 were overexpressed in lung AC-derived cells compared with lung squamous cell carcinoma, small cell carcinoma, and large cell neuroendocrine carcinoma- derived cells. Immunohistochemically, S100A16 showed various subcellular localization in lung cancer tissues and a membranous staining status was correlated with the T-factor (P=0.0008), pathological stage (P=0.0015), differentiation extent (P=0.0001), lymphatic invasion (P=0.0007), vascular invasion (P=0.0001), pleural invasion (P=0.0087), and gender (P=0.039), but not with the age or smoking history. More importantly, membranous staining of S100A16 was significantly correlated with a poorer overall survival of either stage I (P=0.0088) or stage II / III (P=0.0003) lung AC patients, and multivariate analysis confirmed that membranous expression of S100A16 was an independent adverse prognostic indicator (P=0.0001). CONCLUSIONS: The present results suggest that S100A16 protein is a novel prognostic marker for lung AC. PMID- 26514489 TI - Genetic Polymorphism of MDM2 SNP309 in Patients with Helicobacter Pylori Associated Gastritis. AB - BACKGROUND: Helicobacter pylori plays an important role in gastric cancer, which has a relatively low inciduence in Thailand. MDM2 is a major negative regulator of p53, the key tumor suppressor involved in tumorigenesis of the majority of human cancers. Whether its expression might explain the relative lack of gastric cancer in Thailand was assessed here. MATERIALS AND METHODS: This single-center study was conducted in the northeast region of Thailand. Gastric mucosa from 100 patients with Helicobacter pylori associated gastritis was analyzed for MDM2 SNP309 using real-time PCR hybridization (light-cycler) probes. RESULTS: In the total 100 Helicobacter pylori associated gastritis cases the incidence of SNP 309 T/T homozygous was 78 % with SNP309 G/T heterozygous found in 19% and SNP309 G/G homozygous in 3%. The result show SNP 309 T/T and SNP 309 G/T to be rather common in the Thai population. CONCLUSIONS: Our study indicates that the MDM2 SNP309 G/G homozygous genotype might be a risk factor for gastric cancer in Thailand and the fact that it is infrequent could explain to some extent the low incidence of gastric cancer in the Thai population. PMID- 26514490 TI - In Vitro Antioxidant and Antiproliferative Activities of Novel Orange Peel Extract and It's Fractions on Leukemia HL-60 Cells. AB - In the present work, novel orange peel was extracted with 100%EtOH (ethanol) and fractionated into four fractions namely F1, F2, F3, F4 which were eluted from paper chromatographs using 100%EtOH, 80%EtOH, 50%EtOH and pure water respectively. The crude extract and its four fractions were evaluated for their total polyphenol content (TPC), total flavonoid content (TFC) and radical scavenging activity using DPPH (1,1-diphenyl-2-picrylhydrazyl) assay. Their cytotoxic activity using WST assay and DNA damage by agarose gel electrophoresis were also evaluated in a human leukemia HL-60 cell line. The findings revealed that F4 had the highest TPC followed by crude extract, F2, F3 and F1. However, the crude extract had the highest TFC followed by F4, F3, F2, and F1. Depending on the values of EC50 and trolox equivalent antioxidant capacity, F4 possessed the strongest antioxidant activity while F1 and F2 displayed weak antioxidant activity. Further, incubation HL-60 cells with extract/fractions for 24h caused an inhibition of cell viability in a concentration- dependent manner. F3 and F4 exhibited a high antiproliferative activity with a narrow range of IC50 values (45.9 - 48.9 MUg/ml). Crude extract exhibited the weakest antiproliferative activity with an IC50 value of 314.89 MUg/ml. Analysis of DNA fragmentation displayed DNA degradation in the form of a smear-type pattern upon agarose gel after incubation of HL-60 cells with F3 and F4 for 6 h. Overall, F3 and F4 appear to be good sources of phytochemicals with antioxidant and potential anticancer activities. PMID- 26514491 TI - Relationship of Amplification and Expression of the C-MYC Gene with Survival among Gastric Cancer Patients. AB - BACKGROUND: During the past decades, the incidence and mortality rate of stomach cancer has demonstrated a great decrease in the world, but it is still one of the most common and fatal cancers especially among men worldwide, including Iran. The MYC proto-oncogene, which is located at 8q24.1, regulates 15% of genes and is activated in 20% of all human tumors. MYC amplification and overexpression of its protein product has been reported in 15-30% of gastric neoplasias. The aim of this investigation was to find the relative efficacy of CISH (chromogenic in situ hybridization) or IHC (immunohistochemistry) in diagnosis and prognosis of gastric cancer, as well as the relationship of amplification and expression of C MYC gene with patient survival. MATERIALS AND METHODS: In this cross-sectional study, 102 samples of gastric cancer were collected from patients who had undergone primary surgical resection at the Cancer Institute Hospital, Tehran University of Medical Sciences, from July 2009 to March 2014. All samples were randomly selected from those who were diagnosed with gastric adenocarcinomas. CISH and IHC methods were performed on all of them. RESULTS: Patients were classified into two groups. The first consisted of stage I and II cases, and the second of stage III and IV. Survival tests for both groups was carried out with referrnce to CISH test reults. Group II (stage III and IV) with CISH+ featured lower survival than those with CISH- (p=0.233), but group I (stage I and II) patients demonstrated no significant variation with CISH+ or CISH- (p=0.630). Kaplan-Meier for both groups was carried out with IHC test findings and showed similar results. This data revealed that both diffuse and intestinal types of gastric cancer occurred significantly more in men than women. Our data also showed that CISH+ patients (43%) were more frequent in comparison with IHC+ patients (14.7%). CONCLUSIONS: For planning treatment of gastric cancer patients, by focusing on expanding tumors, which is the greatest concern of the surgeons and patients, CISH is a better and more feasible test than IHC, in regard to sensitivity and specificity. Therefore, CISH can be used as a feasible test for tumor growth and prognosis in stage III and IV lesions. This study also indicated that C-MYC amplification in gastric cancer is correlated with survival in advanced stages. PMID- 26514492 TI - Correlation between EGFR Gene Mutations and Lung Cancer: a Hospital-Based Study. AB - Epidermal growth factor receptor (EGFR) is one of the targeted molecular markers in many cancers including lung malignancies. Gefitinib and erlotinib are two available therapeutics that act as specific inhibitors of tyrosine kinase (TK) domains. We performed a case-control study with formalin-fixed paraffin-embedded tissue blocks (FFPE) from tissue biopsies of 167 non-small cell lung carcinoma (NSCLC) patients and 167 healthy controls. The tissue biopsies were studied for mutations in exons 18-21 of the EGFR gene. This study was performed using PCR followed by DNA sequencing. We identified 63 mutations in 33 men and 30 women. Mutations were detected in exon 19 (delE746-A750, delE746-T751, delL747-E749, delL747-P753, delL747-T751) in 32 patients, exon 20 (S786I, T790M) in 16, and exon 21 (L858R) in 15. No mutations were observed in exon 18. The 63 patients with EFGR mutations were considered for upfront therapy with oral tyrosine kinase inhibitor (TKI) drugs and have responded well to therapy over the last 15 months. The control patients had no mutations in any of the exons studied. The advent of EGFR TKI therapy has provided a powerful new treatment modality for patients diagnosed with NSCLC. The study emphasizes the frequency of EGFR mutations in NSCLC patients and its role as an important predictive marker for response to oral TKI in the south Indian population. PMID- 26514493 TI - Do Human Papilloma Viruses Play Any Role in Oral Squamous Cell Carcinoma in North Indians? AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy among males in India. While tobacco and alcohol are main aetiological factors, human papilloma virus (HPV) presence has surprisingly increased in head and neck Squamous Cell Carcinoma (HNSCC) in the past two decade but its frequency in OSCCS is still uncertain. We aim to explore the frequency of HPV and its major genotypes in North Indian patients and their association with clinicopathological and histopathological features and p16 expression pattern. MATERIALS AND METHODS: The study group comprised 250 histologically proven cases of OSCC. HPV was detected by real time PCR in tumor biopsy specimens and confirmed by conventional PCR with PGMY09/ PGMY11 primers. Genotyping for high-risk types 16/ 18 was conducted by type specific PCR. p16 expression was assessed by immunohistochemsitry. RESULTS: HPV presence was confirmed in 23/250 (9.2%) OSCC cases, of which 30.4% had HPV 16 infection, 17.4%were positive for HPV 18 and 26.1% had co-infections. HPV presence was significantly associated with male gender (p=0.02) and habit of pan masala chewing (p=0.01). HPV positive cases also had a history of tobacco consumption in 91.3% cases. p16 over expression was observed in 39.1% of HPV positive cases but this was not significantly different from negative cases (p=0.54). CONCLUSIONS: The frequency of HPV in OSCC is low in North-India and majority of cases are associated with a tobacco habit. It appears that tobacco shows a confounding effect in HPV positive cases and use of p16 protein as a reliable marker to assess the potential etiological role of HPV in OSCC in our population is not suggested. PMID- 26514494 TI - Human Kallikrein-2, Prostate Specific Antigen and Free- Prostate Specific Antigen in Combination to Discriminate Prostate Cancer from Benign Diseases in Syrian Patients. AB - BACKGROUND: The high incidence of prostate cancer as the most common malignancy in males in many countries raises the question of developing reliable detection tests. The prostate specific antigen (PSA) test is the most widely used for screening for prostate cancer; however, its low specificity elevates the number of unnecessarily biopsies. Serum human kallikrein-2 (hK2) is considered as a promising marker, and especially its ratio to fPSA, for predicting the presence of malignancy to select the best choice referring to biopsy or surveillance. In this study, we investigated the role of hK2 and its combinations with other markers to discriminate prostate cancer from benign diseases in Syrian patients. MATERIALS AND METHODS: In this prospective oriented cross-sectional cohort study, serum samples were collected from patients referred to many Hospitals in Damascus, Syria, between May 2011 and March 2012, and diagnosed with biopsy proven benign prostate hyperplasia (BPH) or prostate cancer (PCa). Serum was analyzed for hK2, PSA and fPSA, and the ratios of fPSA/PSA and hK2/fPSA were calculated. RESULTS: We found that mean hK2/fPSA ratios were significantly higher (P=0.01) in prostate cancer patients than in the BPH or control groups. Also the ratio hk2/fPSA gave the largest area under the curve (AUC:0.96) which was significantly larger than for fPSA/PSA (AUC:0.41) indicative of higher specificity. CONCLUSIONS: Our results demonstrate that the ratio of hK2/fPSA might be superior to the use of fPSA/PSA alone. The hK2 could be shown to enhance the early detection of prostate cancer; especially the ratio hK2/fPSA improves specificity and hence may reduce the number of negative biopsies. PMID- 26514495 TI - High Affinity Pharmacological Profiling of Dual Inhibitors Targeting RET and VEGFR2 in Inhibition of Kinase and Angiogeneis Events in Medullary Thyroid Carcinoma. AB - Clinical evidence shows that dual inhibition of kinases as well angiogenesis provides ideal therapeutic option in the treatment of medullary thyroid carcinoma (MTC) than inhibiting either of these with the events separately. Although treatment with dual inhibitors has shown good clinical responses in patients with MTC, it has been associated with serious side effects. Some inhibitors are active agents for both angiogenesis or kinase activity. Owing to narrow therapeutic window of established inhibitors, the present study aims to identify high affinity dual inhibitors targeting RET and VEGFR2 respectively for kinase and angiogenesis activity. Established inhibitors like Vandetanib, Cabozantinib, Motesanib, PP121, RAF265 and Sunitinib served as query parent compounds for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. All the parent inhibitors and respective similar compounds were docked against RET and VEGFR2 in order to retrieve high affinity compounds with these two proteins. AGN-PC-0CUK9P PubCID: 59320403 a compound related to PPI21 showed almost equal affinity for RET and VEGFR2 and unlike other screened compounds with no apparent bias for either of the receptors. Further, AGN- PC-0CUK9P demonstrated appreciable interaction with both RET and VEGFR2 and superior kinase activity in addition to showed optimal ADMET properties and pharmacophore features. From our in silico investigation we suggest AGN-PC-0CUK9P as a superior dual inhibitor targeting RET and VEGFR2 with high efficacy which should be proposed for pharmacodynamic and pharmacokinetic studies for improved treatment of MTC. PMID- 26514496 TI - Declining Incidence of Nasopharyngeal Carcinoma in Brunei Darussalam: a Three Decade Study (1986-2014). AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is linked to Epstein Barr virus infection and is particularly common in the Far East, particularly among some Chinese groups. Certain ethnicities have been reported to have low incidence of NPC. This study looked at NPC in Brunei Darussalam over a three decade period. MATERIALS AND METHODS: The cancer registry from 1986 to 2014 maintained by the State Laboratory was retrospectively reviewed. The age standardized rates (ASR) and the age specific incidence rates (ASIR) were calculated. Non NPC tumors were excluded from the study. RESULTS: Altogether, there were a total of 450 NPC cases diagnosed accounting for 4.4% of all total cancer cases over the study period, declining from 10.3% in 1986-1990 to 2.3% in 2011-2014. The most common tumor type was the undifferentiated carcinoma (96.4%). The case characteristics were mean age 50.4 +/- 14.4 years old, male 69%, and predominately Malays 74.4%, followed by Chinese 16.7%. The mean age of diagnosis increased over the study period from 45.6 +/- 17.1 years (1986-1989) to 54.1 +/- 12.5 years (ANOVA, p<0.01 for trend). There were no differences in the mean age of diagnosis between the ethnic groups or genders. The ASR showed a declining trend from 11.1 per 100,000 in 1986-1990 to 5.95 per 100,000 in 2011-2014, similar trends been observedfor both genders. Among the age groups, declining trends were seen in all the other age groups apart from the >70 years group. The overall ASRs for the Malays and Chinese were 7.92/100,000 and 8.83/100,000 respectively, both showing declining trends. CONCLUSIONS: The incidence of NPC in Brunei Darussalam is comparable to rates reported from Singapore and Malaysia, but higher than rates reported from the other Southeast Asian nations. Unlike higher rates reported for Chinese compared to the Malays in other countries, the rates between the Malays and Chinese in our study was comparable. Importantly, the ASR is declining overall and for both genders and ethnic groups. PMID- 26514498 TI - Association between p16 Promoter Methylation and Thyroid Cancer Risk: A Meta analysis. AB - BACKGROUND: The aim of the meta-analysis was to derive a more precise assessment of the association between p16 promoter methylation and thyroid cancer risk. MATERIALS AND METHODS: The PubMed, Web of Science databases and Chinese CNKI were searched for relevant articles. Ultimately, seventeen case-control studies were included with a total of 804 thyroid cancer cases and 487 controls analysis by R Software (R version 3.1.2) including meta. Crude odds ratios with 95% confidence intervals were calculated using the random-effects model which were used to assess the strength of relationship between p16 methylation and lung carcinogenesis. Funnel plots were carried out to evaluate publication bias. RESULTS: The meta-analysis results showed that the frequency of p16 promoter methylation in cancer tissue/blood was significantly higher than that normal tissue/ blood (OR=5.46, 95%CI 3.12-9.55, P<0.0001) by random effects model with small heterogeneity. CONCLUSIONS: Thus, p16 promoter methylation may be associated with thyroid cancer risk. PMID- 26514497 TI - Induction of P3NS1 Myeloma Cell Death and Cell Cycle Arrest by Simvastatin and/or gamma-Radiation. AB - The present study was conducted to investigate the effect of gamma-radiation alone or combined with a cytotoxic drug, simvastatin, on viability and cell cycling of a myeloma cell line. P3NS1 myeloma cells were treated with the selected dose of simvastatin (0.1 MUM/l) 24 hours prior to gamma-irradiation (0.25, 0.5 and 1 Gy). The cell viability, induction of apoptosis, cell death, cell cycling, generation of ROS, and expression of P53, Bax, Bcl2, caspase3, PARP1 and Fas genes were estimated. The results indicated that simvastatin (0.1 MUM/l) treatment for 24 hours prior to gamma- irradiation increased cell death to 37.5% as compared to 4.81% by radiation (0.5 Gy) alone. It was found that simvastatin treatment before irradiation caused arrest of cells in G0/G1 and G2/M phases as assessed using flow cytometry. Interestingly, simvastatin treatment of P3NS1 cells increased the intracellular ROS production and decreased antioxidant enzyme activity with increased P53, Bax and Caspase3 gene expression while that of Bcl2 was decreased. Consequently, our results indicated that pre-treatment with simvastatin increased radio sensitivity of myeloma tumor cells in addition to apoptotic effects through an intrinsic mitochondrial pathway. PMID- 26514499 TI - Effects of Home Nursing Intervention on the Quality of Life of Patients with Nasopharyngeal Carcinoma after Radiotherapy and Chemotherapy. AB - BACKGROUND: The effects of home nursing intervention on the quality of life in patients with nasopharyngeal carcinoma (NPC) after radiotherapy and chemotherapy are unclear. According to the characteristics of nursing home patients with nasopharyngeal carcinoma, we should continuously improve the nursing plan and improve the quality of life of patients at home. MATERIALS AND METHODS: We selected 180 patients at home with NPC after radiotherapy and chemotherapy. The patients were randomly divided into experimental and control groups (90 patients each). The experimental group featured intervention with an NPC home nursing plan, while the control group was given routine discharge and outpatient review. Nursing intervention for patients was mainly achieved by regular telephone follow up and home visits. We use the quality of life scale (QOL-C30), anxiety scale (SAS) and depression scale (SDS) to evaluate these patients before intervention, and during follow-up at 1 month and 3 months after the intervention. RESULTS: Overall health and quality of life were significantly different between the groups (p<0.05), Emotional function score was significantly higher after intervention (p<0.05), as were cognitive function and social function scores after 3 months of intervention (p<0.05). Scores of fatigue, nausea and vomiting, pain, appetite and constipation were also significantly different between the two groups (p<0.05). Rates of anxiety and depression after 3 months of intervention were 11.1%, 22.2% and 34.4%, 53.3%, the differences being significant (p<0.05). CONCLUSIONS: NPC home nursing plan could effectively improve overall quality of life, cognitive function, social function (after 3 months) of patients, but improvement regarding body function is not suggested. Fatigue, nausea and vomiting, pain, appetite, constipation were clearly improved. We should further pursue a personalized, comprehensive measurements for nursing interventions and try to improve the quality of life of NPC patients at home. PMID- 26514500 TI - Comparison of the Walz Nomogram and Presence of Secondary Circulating Prostate Cells for Predicting Early Biochemical Failure after Radical Prostatectomy for Prostate Cancer in Chilean Men. AB - PURPOSE: To determine the utility of secondary circulating prostate cells for predicting early biochemical failure after radical prostatectomy for prostate cancer and compare the results with the Walz nomagram. MATERIALS AND METHODS: A single centre, prospective study of men with prostate cancer treated with radical prostatectomy between 2004 and 2014 was conducted, with registration of clinical pathological details, total serum PSA pre-surgery, Gleason score, extracapsular extension, positive surgical margins, infiltration of lymph nodes, seminal vesicles and pathological stage. Secondary circulating prostate cells were obtained using differential gel centrifugation and assessed using standard immunocytochemistry with anti-PSA. Biochemical failure was defined as a PSA >0.2ng/ml, predictive values werecalculated using the Walz nomagram and CPC detection. RESULTS: A total of 326 men participated, with a median follow up of 5 years; 64 had biochemical failure within two years. Extracapsular extension, positive surgical margins, pathological stage, Gleason score >= 8, infiltration of seminal vesicles and lymph nodes were all associated with higher risk of biochemical failure. The discriminative value for the nomogram and circulating prostate cells was high (AUC >0.80), predictive values were higher for circulating prostate cell detection, with a negative predictive value of 99%, sensitivity of 96% and specificity of 75%. CONCLUSIONS: The nomagram had good predictive power to identify men with a high risk of biochemical failure within two years. The presence of circulating prostate cells had the same predictive power, with a higher sensitivity and negative predictive value. The presence of secondary circulating prostate cells identifies a group of men with a high risk of early biochemical failure. Those negative for secondary CPCs have a very low risk of early biochemical failure. PMID- 26514501 TI - Multi-Parameter Approach for Evaluation of Genomic Instability in the Polycystic Ovary Syndrome. AB - BACKGROUND: The polycystic ovary syndrome (PCOS), characterized by hyperandrogenism and chronic anovulation, is a common endocrine disorder in women. PCOS, which is associated with polycystic ovaries, hirsutism, obesity and insulin resistance, is a leading cause of female infertility. In this condition there is an imbalance in female sex hormones. All the sequelae symptoms of PCOS gradually lead to cancer in the course of time. It is heterogeneous disorder of unknown etiology so it is essential to find the exact cause. MATERIALS AND METHODS: In this study both invasive and non-invasive techniques were employed to establish the etiology. Diagnosis was based on Rotterdam criteria (hyperandrogenism, ovulatory dysfunction, PCOM) and multiparameters using buccal samples and dermatoglypic analysis and cytogenetic study for 10 cases and four age and sex matched controls. RESULTS: In clinical analysis we have observed the mean value of total testosterone level was 23.6nmol/L, total hirsutism score was from 12-24, facial acne was found in in 70% patients with 7-12 subcapsular follicular cysts, each measuring 2-8 mm in diameter. In dermatoglypic analysis we observed increases in mean value (45.9 degrees ) of ATD angle when compared with control group and also found increased frequency (38%) of Ulnar loops on both fingers (UU), (18%) whorls on the right finger and Ulnar loop on left finger (WU) and (16%) arches on right and left fingers (AA) were observed in PCOS patients when compared with control subjects. Features which could be applied as markers for PCOS patients are the presence of Ulnar loops in middle and little fingers of right and left hand. The buccal micronucleus cytome assay in exfoliated buccal cells, we found decrease in frequency of micronuclei and significant increases in frequency of karyolysed nuclei in polycystic ovarian syndrome patients. Chromosome aberration analysis revealed a significant increase in frequency of chromosome aberrations (CAs) in PCOS patients when compared with controls. CONCLUSIONS: From this present work it can be concluded that non-invasive technique like dermatoglypics analysis and buccal micronucleus cytome assays with exfoliated buccal cell can also be effective biomarkers for PCOS, along with increased CAs in lymphocytes as a sign of genetic instability. There is a hypothesis that micronuclei and chromosomal aberrations could have a predictive value for cancer. From this present work it can be concluded to some extent that non-invasive technique like dermatoglypics and buccal cell analysis can also be effective for diagnosis. PMID- 26514502 TI - Resistin and Insulin Resistance: A Link Between Inflammation and Hepatocarcinogenesis. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer related death overall. The role of insulin resistance in the development of HCC associated with chronic HCV infection has not been established. Resistin is a polypeptide hormone belonging to the adipokine family which could contribute to tumorigenesis and angiogenesis. Our aim was to study serum resistin and insulin resistance as risk factors for HCC in HCV cirrhotic patients. MATERIALS AND METHODS: This prospective case controlled study included 100 patients with HCV related liver cirrhosis and HCC, 100 patients with HCV related liver cirrhosis without HCC and 50 apparently healthy participants as controls. For all subjects, liver profile, serologic markers for viral hepatitis, lipid profile, alpha-fetoprotein level (AFP), homeostasis model assessment (HOMA) were examined along with resistin. RESULTS: HCC patients had higher mean values of HOMA-IR and resistin than cirrhotic patients and the control subjects (p<0.01). HOMA and resistin were considered independent risk factors in development of HCC, those patients with resistin > 12 ng/ml and HOMA >4 being 1.6 times more likely to have HCC. CONCLUSIONS: HOMA and serum resistin allow for early identification of patients with cirrhosis who are at substantially increased risk of HCC. RECOMMENDATION: HOMA and serum resistin could represent novel markers to identify HCV cirrhotic patients at greater risk of development of HCC. PMID- 26514503 TI - Gold Nanoparticles Enhance the Anticancer Activity of Gallic Acid against Cholangiocarcinoma Cell Lines. AB - Gold nanoparticles (GNPs) were conjugated with gallic acid (GA) at various concentrations between 30 and 150 MUM and characterized using transmission electron microscopy (TEM) and UV-Vis spectroscopy (UV-VIS). The anticancer activities of the gallic acid-stabilized gold nanoparticles against well differentiated (M213) and moderately differentiated (M214) adenocarcinomas were then determined using a neutral red assay. The GA mechanism of action was evaluated using Fourier transform infrared (FTIR) microspectroscopy. Distinctive features of the FTIR spectra between the control and GA-treated cells were confirmed by principal component analysis (PCA). The surface plasmon resonance spectra of the GNPs had a maximum absorption at 520 nm, whereas GNPs-GA shifted the maximum absorption values. In an in vitro study, the complexed GNPs-GA had an increased ability to inhibit the proliferation of cancer cells that was statistically significant (P<0.0001) in both M213 and M214 cells compared to GA alone, indicating that the anticancer activity of GA can be improved by conjugation with GNPs. Moreover, PCA revealed that exposure of the tested cells to GA resulted in significant changes in their cell membrane lipids and fatty acids, which may enhance the efficacy of this anticancer activity regarding apoptosis pathways. PMID- 26514504 TI - IL-17A Levels in the Sera of Patients with Gastric Cancer Show Limited Elevation. AB - BACKGROUND: Inflammation plays a major role in the development and progression of gastric and other gastrointestinal tumors. The IL-17 family of cytokines has been under investigation as targets of immunotherapy. MATERIALS AND METHODS: We investigated the levels of IL-17A inflammatory cytokine in the sera of 57 patients with gastric cancer (GC) and 90 healthy age/sex matched controls using ELISA methods. RESULTS: In only 5 (8.8%) of the patients' sera was IL-17A detectable. No IL-17A was apparent in the sera of healthy controls. The maximum concentration of IL-17A in patients was 7.004 pg/ml. Vascular and lymphatic invasions were only seen in one of the 5 positive cases. Although all of them were in the age group >60 years, no correlation was seen between age and IL-17A level. These results are somewhat different from our findings for colorectal cancer (CRC) in the same population. CONCLUSIONS: It is possible that the inflammopathology of CRC and GC are rather different, at least in Fars, a southern province of Iran. PMID- 26514505 TI - Cytotoxicity of Cratoxylum Formosum Subsp. Pruniflorum Gogel Extracts in Oral Cancer Cell Lines. AB - BACKGROUND: Oral cancer is a health problem in Thailand. Cratoxylum formosum subsp. pruniflorum Gogel (Teawdang), normally consumed in northeast Thailand, has proven cytotoxic to cervical cancer cell lines including HeLa, SiHa and C-33A. Recently, Asian oral cancer cell lines, ORL-48 and ORL-136, were established. Therefore, we aimed to study cytotoxicity of Teawdang in these. Total phenolic (TPC) and flavonoid content (TFC), and antioxidant activity of Teawdang were also determined. MATERIALS AND METHODS: Teawdang was purchased from Khon Kaen market during June-October 2013. Hexane (CHE), ethyl acetate (CEE) and methanol (CME) extracts of its edible part were analyzed for TPC by the folin-ciocalteau method and for TFC by an aluminium colorimetric method. Antioxidant activity and cytotoxicity in normal Vero cells and oral cancer cells were investigated. Cell viability was assessed using 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assays. RESULTS: CME and CEE had higher TPC and TFC and antioxidant activity than CHE. Both CME and CEE, at 200 MUg dry wt/mL, were cytotoxic to the studied oral cancer cell lines. However, CME was cytotoxic to Vero cells whereas CEE was not. Compared to Vero cells, CEE significantly inhibited ORL-48 and ORL 136 growth (p=0.03 and p=0.02, respectively). CONCLUSIONS: CEE exhibited cytotoxic effects on the studied oral cancer cell lines but not normal Vero cells. The bioactive compounds in CEE should be further purified and elucidated for their mechanisms of action for development as anticancer agents. PMID- 26514506 TI - p16 Expression as a Surrogate Marker for HPV Infection in Esophageal Squamous Cell Carcinoma can Predict Response to Neo-Adjuvant Chemotherapy. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a common cancer in the north east of India. The present study concerned the prevalence of human papilloma virus (HPV) in the ESCC in north eastern India and its impact on response to chemotherapy. MATERIALS AND METHODS: p16 expression, a surrogate marker for HPV infection was assessed in 101 pre-treatment biopsies of locally advanced ESCC, reported from a comprehensive cancer centre in north east India, using immunohistochemistry. All patients received neo-adjuvant chemotherapy. Response was assessed clinically and histopathologically with attention to p16 expression. RESULTS: p16 was expressed in 22% of ESCC (22 out of 101) and was more prevalent in patients who were more than 45 years of age (P=0.048). p16 positive tumors appeared more commonly in the upper 2/3 of the thoracic esophagus (18 in 22). Nine of the 22 (41%) p16 positive tumors achieved pathologic complete response following neo-adjuvant chemotherapy (P=0.008). There was a trend towards reduced mortality in this group (P=0.048). Some 9 of the 20 (45%) patients who achieved pathologic complete response were p16 positive. CONCLUSIONS: Expression of p16 in ESCC correlates with higher rate of pathologic complete remission in patients undergoing neo adjuvant chemotherapy and could be a predictive marker for response assessment. PMID- 26514507 TI - High Dose Rate Brachytherapy in Two 9 Gy Fractions in the Treatment of Locally Advanced Cervical Cancer - a South Indian Institutional Experience. AB - BACKGROUND: Although 3D image based brachytherapy is currently the standard of treatment in cervical cancer, most of the centres in developing countries still practice orthogonal intracavitary brachytherapy due to financial constraints. The quest for optimum dose and fractionation schedule in high dose rate (HDR) intracavitary brachytherapy (ICBT) is still ongoing. While the American Brachytherapy Society recommends four to eight fractions of each less than 7.5 Gy, there are some studies demonstrating similar efficacy and comparable toxicity with higher doses per fraction. OBJECTIVE: To assess the treatment efficacy and late complications of HDR ICBT with 9 Gy per fraction in two fractions. MATERIALS AND METHODS: This is a prospective institutional study in Southern India carried on from 1st June 2012 to 31st July 2014. In this period, 76 patients of cervical cancer satisfying our inclusion criteria were treated with concurrent chemo radiation following ICBT with 9 Gy per fraction in two fractions, five to seven days apart. RESULTS: The median follow-up period in the study was 24 months (range 10.6 - 31.2 months). The 2 year actuarial local control rate, disease-free survival and overall survival were 88.1%, 84.2% and 81.8% respectively. Although 38.2% patients suffered from late toxicity, only 3 patients had grade III late toxicity. CONCLUSIONS: In our experience, HDR brachytherapy with 9 Gy per fraction in two fractions is an effective dose fractionation for the treatment of cervical cancer with acceptable toxicity. PMID- 26514508 TI - Perspectives of Women during Reproductive Years for Cervical Cancer Scans and Influencing Factors. AB - BACKGROUND: This descriptive study was performed in order to assess health perspectives of women, who applied to Yildirim Beyazit University Ataturk Education and Research Hospital, Outpatient Clinic of Obstetrics and Gynecology for cervical cancer scans and were in the reproductive years. Factors influencing their perspectives were also assessed. MATERIALS AND METHODS: In this study, a simple random sampling formula was adopted to calculate the volume (300) of the targeted sample. Results of the research were obtained through individual diagnosis form and cervical cancer and the Pap smear test health belief model scale (HBMS). RESULTS: It was found that 75.0% of the women heard of the Pap smear test before, and 48.7% had undertaken one. Some 51.4% of the women who had Pap smear test expressed that they had the test at irregular periods. Most of the women stated that they heard about the smear test from the health staff (51.7%). Lack of any health complaints (28.3%) and not having adequate information about the test (21.0%) were among the reasons for not undergoing a Pap smear test. It was found that lower dimension average scores of the women obtained from the cervical cancer and Pap smear test HBMS varied from 7.7+/-2.3 to 33.5+/-9.3. When the lower dimension average scores of women from the HBMS were examined, the perception of usefulness was high but the susceptibility and health motivations were low. CONCLUSIONS: In this study, it was determined that the awareness of women about cervical cancer and the Pap smear test was insufficient, and susceptibility and motivation perception towards having a Pap smear test were low. PMID- 26514509 TI - Phytochemical Analysis and Anti-cancer Investigation of Boswellia serrata Bioactive Constituents In Vitro. AB - Cancer is a major health obstacle around the world, with hepatocellular carcinoma (HCC) and colorectal cancer (CRC) as major causes of morbidity and mortality. Nowadays, there isgrowing interest in the therapeutic use of natural products for HCC and CRC, owing to the anticancer activity of their bioactive constituents. Boswellia serrata oleo gum resin has long been used in Ayurvedic and traditional Chinese medicine to alleviate a variety of health problems such as inflammatory and arthritic diseases. The current study aimed to identify and explore the in vitro anticancer effect of B. Serrata bioactive constituents on HepG2 and HCT 116 cell lines. Phytochemical analysis of volatile oils of B. Serrata oleo gum resin was carried out using gas chromatography- mass spectrometry (GC/MS). Oleo-gum resin of B. Serrata was then successively extracted with petroleum ether (extract 1) and methanol (extract 2). Gas-liquid chromatography (GLC) analysis of the lipoidal matter was also performed. In addition, a methanol extract of B. Serrata oleo gum resin was phytochemically studied using column chromatography (CC) and thin layer chromatography (TLC) to obtain four fractions (I, II, III and IV). Sephadex columns were used to isolate beta-boswellic acid and identification of the pure compound was done using UV, mass spectra, 1H NMR and 13C NMR analysis. Total extracts, fractions and volatile oils of B. Serrata oleo-gum resin were subsequently applied to HCC cells (HepG2 cell line) and CRC cells (HCT 116 cell line) to assess their cytotoxic effects. GLC analysis of the lipoidal matter resulted in identification of tricosane (75.32%) as a major compound with the presence of cholesterol, stigmasterol and beta-sitosterol. Twenty two fatty acids were identified of which saturated fatty acids represented 25.6% and unsaturated fatty acids 74.4% of the total saponifiable fraction. GC/MS analysis of three chromatographic fractions (I,II and III) of B. Serrata oleo gum resin revealed the presence of pent-2-ene-1,4-dione, 2-methyl- levulinic acid methyl ester, 3,5- dimethyl- 1- hexane, methyl-1-methylpentadecanoate, 1,1- dimethoxy cyclohexane, 1 methoxy-4-(1-propenyl)benzene and 17a-hydroxy-17a-cyano, preg-4-en-3-one. GC/MS analysis of volatile oils of B. Serrata oleo gum resin revealed the presence of sabinene (19.11%), terpinen-4-ol (14.64%) and terpinyl acetate (13.01%) as major constituents. The anti-cancer effect of two extracts (1 and 2) and four fractions (I, II, III and IV) as well as volatile oils of B. Serrata oleo gum resin on HepG2 and HCT 116 cell lines was investigated using SRB assay. Regarding HepG2 cell line, extracts 1 and 2 elicited the most pronounced cytotoxic activity with IC50 values equal 1.58 and 5.82 MUg/mL at 48 h, respectively which were comparable to doxorubicin with an IC50 equal 4.68 MUg/mL at 48 h. With respect to HCT 116 cells, extracts 1 and 2 exhibited the most obvious cytotoxic effect; with IC50 values equal 0.12 and 6.59 MUg/mL at 48 h, respectively which were comparable to 5-fluorouracil with an IC50 equal 3.43 MUg/ mL at 48 h. In conclusion, total extracts, fractions and volatile oils of B. Serrata oleo gum resin proved their usefulness as cytotoxic mediators against HepG2 and HCT 116 cell lines with different potentiality (extracts > fractions > volatile oil). In the two studied cell lines the cytotoxic acivity of each of extract 1 and 2 was comparable to doxorubicin and 5-fluorouracil, respectively. Extensive in vivo research is warranted to explore the precise molecular mechanisms of these bioactive natural products in cytotoxicity against HCC and CRC cells. PMID- 26514510 TI - Incidence, Trends and Epidemiology of Cancers in North West of Iran. AB - BACKGROUND: Cancer is a leading cause of death throughout the world. Increasing life expectancy and aging population are important factors for increasing cancer incidences in developing countries. National programs are essential for prevention and control of cancer in any society. This study aimed to investigate cancer epidemiology and trends in the province of Hamadan, located in Northwest Iran. MATERIALS AND METHODS: This analytical study was carried out based on cancer registry data from 2004 to 2009 in the province of Hamadan, analyzed using STATA (version 12) software for descriptive tests and Join point 4.1.1.1 software for analytical tests. RESULTS: There were 7,767 registered cases of cancer during the 6 years studied. Of the total cases registered, 59.1% (4,592 cases) involved men and 40.9% (3,175 cases) occurred in women. Age-standardized incidence rates (ASR) increased from 72.9 to 132.0 in males and 48.2 to 115.0 in females during the 6 years of the study (p<0.001). The most common cancers were skin, stomach, breast, bladder, and leukemia. In women, teh most common were breast, skin, stomach, colorectal, and leukemia, in that order, and in men skin, stomach, bladder, leukemia, and prostate cancers. CONCLUSIONS: The cancer incidence is greater in men that women in this region but with increasing trends in both sexes. Planning regarding education in prevention of exposure to risk factors and control strategies is required to decrease the incident cases. Screening programs for common cancers in older age groups might be helpful to reduce the disease impact. PMID- 26514511 TI - Comparison of Clinical Characteristics between Occupational and Sporadic Young Onset Cholangiocarcinoma. AB - BACKGROUND: Since seventeen employees of an offset printing company in Osaka, Japan developed cholangiocarcinoma it has become recognized as an occupational cancer. This study investigated the differences of clinical features between occupational cholangiocarcinoma and sporadic young-onset cholangiocarcinoma. MATERIALS AND METHODS: Thirty-four young adults (<50 years old) with sporadic cholangiocarcinoma were extracted from the Rosai Hospital Group database (sporadic group) and their clinical features were compared with those of 17 patients with occupational cholangiocarcinoma (occupational group). RESULTS: The 34 patients in the sporadic group were treated for cholangiocarcinoma at 16 different Rosai hospitals. There were significant differences of age (p<0.01), gender (p<0.01), abnormal laboratory tests (p<0.01), and tumor location (p<0.01) between the two groups. The percentage of patients with abnormal laboratory tests was significantly higher in the occupational group than in the sporadic group (p<0.001). Regional dilation of bile ducts, which is a characteristic of occupational cholangiocarcinoma, was not observed in the sporadic group. CONCLUSIONS: No cluster of cholangiocarcinoma cases was identified in the Rosai Hospital database. There were differences of clinical features between occupational and sporadic cholangiocarcinoma, which might be helpful for diagnosing occupational cholangiocarcinoma in the future. PMID- 26514512 TI - Trans-arterial Chemo-Embolization in Treating Elderly Patients with Hepatocellular Carcinoma. AB - BACKGROUND: This analysis was conducted to evaluate the efficacy and safety of Trans-arterial Chemo- Embolization (TACE) in treating Elderly patients with Hepatocellular Carcinoma (EHPC). METHODS: Clinical studies evaluating the efficacy and safety of TACE on response and safety for patients with EHPC were identified by using a predefined search strategy. Pooled response rate of treatment were calculated. RESULTS: In TACE based regimen, clinical studies which including patients with EHPC were considered eligible for the evaluation of response. And, in these TACE based treatments, pooled analysis suggested that, in all 288 patients whose response could be assessed, the pooled reponse rate was 29.5%(85/288) in TACE based treatment. The most commonly encountered TACE-related morbidity was liver function impairment. No grade III or IV renal or liver toxicity were observed. No treatment related death occurred in EHPC patients with TACE based treatments. CONCLUSION: This evidence based analysis suggests that TACE based treatments are associated with mild response rate and accepted toxicities for treating patients with EHPC. PMID- 26514513 TI - Influence of Expression Plasmid of Connective Tissue Growth Factor and Tissue Inhibitor of Metalloproteinase-1 shRNA on Hepatic Precancerous Fibrosis in Rats. AB - BACKGROUND: In this study, influence caused by expression plasmids of connective tissue growth factor (CTGF) and tissue inhibitor of metalloproteinase-1 (TIMP-1) short hairpin RNA (shRNA) on mRNA expression of CTGF,TIMP-1,procol-alpha1 and PCIII in hepatic tissue with hepatic fibrosis, a precancerous condition, in rats is analyzed. MATERIALS AND METHODS: To screen and construct shRNA expression plasimid which effectively interferes RNA targets of CTGF and TIMP-1 in rats. 50 cleaning Wistar male rats are allocated randomly at 5 different groups after precancerous fibrosis models and then injection of shRNA expression plasimids. Plasmid psiRNA-GFP-Com (CTGF and TIMP-1 included), psiRNA-GFP-CTGF, psiRNA-GFP TIMP-1 and psiRNA- DUO-GFPzeo of blank plasmid are injected at group A, B, C and D, respectively, and as model control group that none plasimid is injected at group E. In 2 weeks after last injection, to hepatic tissue at different groups, protein expression of CTGF, TIMP-1, procol-alpha1and PC III is tested by immunohistochemical method and,mRNA expression of CTGF,TIMP-1,procol-alpha1 and PCIII is measured by real-time PCR. One-way ANOVA is used to comparison between groups. RESULTS: Compared with model group, there is no obvious difference of mRNA expression among CTGF,TIMP-1,procol-alpha1,PC III and of protein expression among CTGF, TIMP-1, procol-alpha1, PC III in hepatic tissue at group injected with blank plasmid. Expression quantity of mRNA of CTGF, TIMP-1, procol-alpha1 and PCIII at group A, B and C decreases, protein expression of CTGF, TIMP-1, procol-alpha1, PC III in hepatic tissue is lower, where the inhibition of combination RNA interference group (group A) on procol-alpha1 mRNA transcription and procol-alpha1 protein expression is superior to that of single interference group (group B and C) (P<0.01 or P<0.05). CONCLUSIONS: RNA interference on CTGF and/or TIMP-1 is obviously a inhibiting factor for mRNA and protein expression of CTGF, TIMP-1, procol-alpha1 and PCIII. Combination RNA interference on genes of CTGF and TIMP-1 is superior to that of single RNA interference, and this could be a contribution for prevention of precancerous condition. PMID- 26514514 TI - Diagnostic and Prognostic Roles of Serum Osteopontin and Osteopontin Promoter Polymorphisms in Hepatitis B-related Hepatocellular Carcinoma. AB - BACKGROUND: The aims of this study were to evaluate the diagnostic and prognostic roles of serum osteopontin (OPN) and single nucleotide polymorphisms (SNPs) in the OPN promoter in patients with hepatitis B-related hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Four groups were studied, which included 157 patients with HCC, 73 with liver cirrhosis (LC) and 97 with chronic hepatitis (CH), along with 80 healthy subjects. Serum OPN and alpha-fetoprotein (AFP) levels were measured. The SNPs -66 T/G, -156 G/deltaG and -433 C/T within the OPN promoter were determined by direct sequencing. RESULTS: Serum OPN levels were significantly higher in patients with HCC than in the other groups. Area under receiver operating characteristics curves in distinguishing HCC from chronic liver disease (CLD; CH and LC) were 0.782 (95% CI; 0.729-0.834) for OPN and 0.888 (95% CI; 0.850-0.927) for AFP. Using the optimal cut-off value (70 ng/mL), OPN had sensitivity and specificity of 72% and 71%, respectively. Serum OPN was superior to AFP in detecting early-stage HCC (68% vs. 46%). A combination of both markers yielded an improved sensitivity for detecting early HCC to 82%. A high OPN level was significantly correlated with advanced BCLC stage and was an independent prognostic factor for HCC. The SNPs -156 and -443 were associated with susceptibility to HCC, but were not related to overall survival. CONCLUSIONS: Serum OPN is a useful diagnostic and prognostic marker for HCC. The combined use of serum OPN and AFP improved the diagnosis of early HCC. Genetic variation in the OPN promoter is associated with the risk, but not the prognosis of HCC. PMID- 26514515 TI - Cytogenetic Profile of De Novo B lineage Acute Lymphoblastic Leukemia: Determination of Frequency, Distribution Pattern and Identification of Rare and Novel Chromosomal Aberrations in Indian Patients. AB - BACKGROUND: Chromosomal aberrations identified in acute lymphoblastic leukemia (ALL) have an important role in disease diagnosis, prognosis and management. Information on karyotype and associated clinical parameters are essential to physicians for planning cancer control interventions in different geographical regions. MATERIALS AND METHODS: In this study, we present the overall frequency and distribution patterns of chromosomal aberrations in both children and adult de novo B lineage ALL Indian patients using conventional cytogenetics, interphase FISH and multiplex RT-PCR. RESULTS: Among the 215 subjects, cytogenetic results were achieved in 172 (80%) patients; normal karyotype represented 37.2% and abnormal 62.8% with a distribution as follows: 15.3% hypodiploidy; 10.3% hyperdiploidy; 15.8% t(9;22); 9.8% t(1;19); 3.7% t(12;21); 2.8% t(4;11); 2.8% complex karyotypes. Apart from these, we observed several novel, rare and common chromosomal rearrangements. Also, FISH studies using LSI extra-signal dual-color probes revealed additional structural or numerical changes. CONCLUSIONS: These results demonstrate cytogenetic heterogeneity of ALL and confirm that the incidence of chromosomal abnormalities varies considerably. To the best of our knowledge, this is one of the largest reported series of cytogenetic investigations in Indian B-lineage ALL cases. In addition, ongoing cytogenetic studies are warranted in larger groups of B-lineage ALL cases to identify newly acquired chromosomal abnormalities that may contribute to disease diagnosis and management. PMID- 26514516 TI - Is Age an Independent Predictor of High-Grade Histopathology in Women Referred for Colposcopy after Abnormal Cervical Cytology? AB - This study was conducted to determine whether advancing age is an independent predictor of increased risk of high-grade pathologies among women referred for colposcopy after abnormal cervical cytology. Medical records were reviewed for women with abnormal cervical cytology who underwent colposcopy at Khon Kaen University Hospital. Logistic regression was used to determine the independent impact of age on the risk of high-grade pathologies. Mean age of the women was 42.8 years. Of 482 women, 97 (20.1%) were postmenopausal, and 92 (19.1%) were nulliparous. The rate of high-grade pathologies included cervical intraepithelial neoplasia 2-3, 99 (20.5%), adenocarcinoma in situ, 4 (0.8%), cervical cancer, 30 (6.2%), and endometrial cancer, 1 (0.2%). The prevalence of significant lesions was 26.9% (95% CI, 23.1%-31.2%). In total, 31 women had cancers (6.4%; 95% CI, 4.4%-9.0%). When controlling for smear types and parity, age was noted to be a significant independent predictor of high-grade histopathology. Women older than 35-40 years were approximately 2 times as likely to have severe histopathology as the younger women. This study illustrates the substantial risk of underlying significant lesions especially invasive cancer in Thai women with abnormal cervical cytology. Age was a significant independent factor predicting the risk of high-grade pathologies. PMID- 26514517 TI - Treatment Outcomes of Epithelial Ovarian Cancers Following Maximum Cytoreduction and Adjuvant Paclitaxel-Carboplatin Chemotherapy: Egyptian NCI Experience. AB - BACKGROUND: Epithelial ovarian cancer (EOC) is the commonest malignancy involving the ovaries. Maximum surgical cytoreduction (MCR) followed by adjuvant taxane platinum chemotherapy are the standard of care treatments. AIMS: To study treatment outcomes of EOC patients that were maximally cyto-reduced and received adjuvant paclitaxel-carboplatin (PC) chemotherapy. MATERIALS AND METHODS: This retrospective cohort study included 174 patients with EOC treated at the Egyptian National Cancer Institute between 2006 and 2010. For inclusion, they should have had undergone MCR with no-gross residual followed by adjuvant PC chemotherapy. MCR was total abdominal hysterectomy/bilateral salpingo-oophorectomy [TAH/BSO] or unilateral salpingo- oophorectomy [USO] plus comprehensive staging. RESULTS: The median age was 50 years. Most patients were married (97.1%), had offspring (92.5%), were postmenopausal (53.4%), presented with abdominal/pelvic pain and swelling (93.7%), had tumors involving both ovaries (45.4%) without extra-ovarian extension i.e. stage I (55.2%) of serous histology (79.9%) and grade II (87.4%). TAH/BSO was performed in 97.7% of cases. A total of 1,014 PC chemotherapy cycles were administered and were generally tolerable with 93.7% completing 6 cycles. Alopecia and numbness were the commonest adverse events. The median follow up period was 42 months. The 2-year rates for disease free survival (DFS) and overall survival (OS) were 70.7% and 94.8%, respectively. The respective 5-year rates were 52.6% and 81.3%. Advanced stage and high-grade were significantly associated with poor DFS and OS (p<0.001). Age >65 years was associated with poor OS (p =0.008). Using Cox-regression, stage was independent predictor of poor DFS and OS. Age was an independent predictor of poor OS. PMID- 26514518 TI - Association of the -2518 A/G Polymorphism of MCP-1 with Breast Cancer in Punjab, North-West India. AB - BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is a major chemokine thought to be responsible for monocyte and T-lymphocyte recruitment in acute inflammatory conditions and recruitment of macrophages in tumors. It is also implicated in cardiovascular disease, rheumatoid arthritis and chronic obstructive pulmonary disease. The aim of the present study was to investigate the correlation between MCP-1 -2518 A/G polymorphism and breast cancer risk in patients from Amritsar city of Punjab state in North-West India. MATERIALS AND METHODS: We screened DNA samples of 200 sporadic breast cancer patients and 200 age and gender matched unrelated healthy individuals for MCP-1 -2518 A/G polymorphism using the PCR-RFLP method. RESULTS: A significantly increased frequency of the GG genotype was observed in patients as compared to controls. Individuals carrying the MCP1 -2518GG genotype had a two fold risk for breast cancer (OR=2.06, 95%CI, 1.06-3.98; p=0.03). Genetic models analysis revealed a significant association between MCP-1 -2518 A/G polymorphism and cancer risk in homozygous co-dominant (OR=2.06, 95%CI, 1.06-3.98; p=0.03) and recessive (OR=1.97, 95%CI, 1.05-3.70; p=0.03) models. CONCLUSIONS: We conclude that the GG genotype of the MCP-1-2518 A/G polymorphism is associated with increased risk to breast cancer in Punjab, North-West India. PMID- 26514519 TI - Association between the CYP1A2 rs762551 Polymorphism and Bladder Cancer Susceptibility: a Meta-Analysis Based on Case-Control Studies. AB - BACKGROUND: Previous studies evaluated associations between the CYP1A2 rs762551 polymorphism and bladder cancer risk. However, the results were inconsistent. We therefore performed a meta-analysis of the published case-control studies to assess in detail the association between CYP1A2 rs762551 polymorphism and bladder cancer risk. MATERIALS AND METHODS: PubMed, Embase and Web of Science were searched to identify relevant studies and the pooled odds ratio (OR) and 95 % confidence interval (95%CI) were calculated. RESULTS: A total of seven articles including 3,013 cases and 2,771 controls were finally included. Overall, a significant association was found between the CYP1A2 rs762551 polymorphism and bladder cancer susceptibility for CC vs AA (OR=0.82, 95% CI=0.69~0.99), but no significant associations were found for the other three models (AC vs AA: OR=0.91, 95% CI=0.81~1.02; the dominant model: OR=0.90, 95% CI=0.80~1.00; the recessive model: OR=0.84, 95% CI =0.72~1.00). In the subgroup analysis by ethnicity, we detected significant associations between the CYP1A2 rs762551 polymorphism and bladder cancer susceptibility for GA vs GG (OR = 0.78, 95% CI =0.64~0.96) and for the recessive model (OR=0.80, 95% CI=0.66~0.96) in Caucasians, but not for Asians. CONCLUSIONS: The results from the meta-analysis suggested that the CYP1A2 rs762551 polymorphism is a protective factor for bladder cancer, especially in Caucasians. PMID- 26514520 TI - Clinicopathological Significance of DLC-1 Expression in Cancer: a Meta-Analysis. AB - BACKGROUND: Recent reports have shown that DLC-1 is widely expressed in normal tissues and is down- regulated in a wide range of human tumors, suggesting it may act as a tumor suppressor gene. We conducted a meta-analysis to determine the correlation between DLC-1 expression and clinicopathological characteristics in cancers. MATERIALS AND METHODS: A detailed literature search was made for relevant publications from PubMed, EMBASE, Cochrane library databases, Web of Science, CNKI. The methodological quality of the studies was also evaluated. Analyses of pooled data were performed and odds ratios (ORs) were calculated and summarized. RESULTS: Final analysis was performed of 1,815 cancer patients from 19 eligible studies. We observed that DLC- 1 expression was significantly lower in cancers than in normal tissues. DLC-1 expression was not found to be associated with tumor differentiation status. However, DLC-1 expression was obviously lower in advance stage than in early-stage cancers and was more down regulated in metastatic than non-metastatic cancers. CONCLUSIONS: The results of our meta-analysis suggested that DLC-1 expression is significantly lower in cancers than in normal tissues. Aberrant DLC-1 expression may play an important role in cancer genesis and metastasis. PMID- 26514521 TI - Shikonin Induced Necroptosis via Reactive Oxygen Species in the T-47D Breast Cancer Cell Line. AB - Breast cancer, the most common cancer in the women, is the leading cause of death. Necrotic signaling pathways will enable targeted therapeutic agents to eliminate apoptosis-resistant cancer cells. In the present study, the effect of shikonin on the induction of cell necroptosis or apoptosis was evaluated using the T-47D breast cancer cell line. The cell death modes, caspase-3 and 8 activities and the levels of reactive oxygen species (ROS) were assessed. Cell death mainly occurred through necroptosis. In the presence of Nec-1, caspase-3 mediated apoptosis was apparent in the shikonin treated cells. Shikonin stimulates ROS generation in the mitochondria of T-47D cells, which causes necroptosis or apoptosis. Induction of necroptosis, as a backup-programmed cell death pathway via ROS stimulation, offers a new strategy for the treatment of breast cancer. PMID- 26514522 TI - Prevalence of Cancers of Female Organs among Patients with Diabetes Type 2 in Kelantan, Malaysia: Observations over an 11 Year Period and Strategies to Reduce the Incidence. AB - INTRODUCTION: Kelantan is one of the states in Malaysia which has a high prevalence of type 2 diabetes (DM2). Other than with endometrial carcinoma, the association of DM2 with particular female cancers is not known. OBJECTIVE: To determine the proportion of breast, cervical, ovarian and endometrial cancers among females with DM2 diagnosed in Hospital Universiti Sains Malaysia (HUSM) over an 11 year period. MATERIALS AND METHODS: All histologically confirmed cases of breast, endometrial, cervical and ovarian carcinomas admitted to the Hospital were included in the study. The patient diabetic status was traced from the hospital medical records. RESULTS: There was a total of 860 cases of breast, cervical, ovarian and endometrial carcinomas over this period. Breast carcinoma was the commonest, accounting for 437/860 (50.8%) followed by cervix, 159/860 (18.5%), ovarian, 143/860 (16.6%) and endometrial carcinomas, 121/860 (14.1%). Out of these, 228/860 (26.5%) were confirmed diabetics. Endometrial carcinoma patients showed the highest proportion being diabetics, 42.1% (51/121), followed by ovarian cancer, 25.9% (37/143), breast carcinoma, 23.6% (103/437) and cervical cancer 23.3% (37/159). CONCLUSIONS: There is a significant proportion of DM2 among women with these four cancers, endometrial carcinoma being the highest followed by ovarian, breast and cervical carcinoma. The rising trend of these four cancers is in tandem with an increasing trend of DM2 in the community. In populations where diabetes is prevalent, screening for epithelial cancers should be rigourous. Diabetic clinics should include screening for these cancers among their female patients and gynecology clinics should screen the women they treat for their diabetes status. PMID- 26514523 TI - Histologic Outcomes in HPV-Positive and Cervical Cytology- Negative Women - Screening Results in Northern Thailand. AB - The objective of this study was to determine the prevalence of significant lesions defined as high grade squamous intraepithelial lesions (HSIL), adenocarcinoma in situ (AIS) and invasive carcinoma in women who had HPV-positive and cytology negative co-testing screening results. This retrospective study was conducted in Chiang Mai University Hospital between May, 2013 and August, 2014. Hybrid capture 2 (HC2) was used for HPV testing and conventional Pap smears for cytologic screening. A repeat liquid-based cytology (LBC) was performed in women with such co-testing results followed by colposcopy. Random biopsy was performed in cases of normal colposcopic findings. Further investigations were carried out according to the biopsy or the repeat LBC results. During the study period, 273 women met the criteria and participated in the study. The mean age of these women was 46.4 years with 30% of them reporting more than one partner. The median interval time to colposcopy was 165 days. About 40% showed an abnormality in the repeat cytology. Significant cervical lesions were found in 20 (7.3%) women, including 2 invasive cancers. Of interest was that only 2 of 20 significant lesions were diagnosed by colposcopic examination while the remainder were initially detected by cervical biopsy and abnormal repeat cytology. In conclusion, the prevalence of significant cervical lesions in HPV positive and cytology negative women in Northern Thailand was 7.3%. Further diagnostic work up with repeat cytology follow by colposcopy is recommended. Random biopsy should be performed even when the colposcopic findings are normal. PMID- 26514524 TI - AXIN2 Polymorphisms, the beta-Catenin Destruction Complex Expression Profile and Breast Cancer Susceptibility. AB - BACKGROUND: The Wnt/beta-catenin signaling pathway is an important regulator of cellular functions such as proliferation, survival and cell adhesion. Wnt/beta catenin signaling is associated with tumor initiation and progression; beta catenin mutations explain only 30% of aberrant signaling found in breast cancer, indicating that other components and/or regulation of the Wnt/beta-catenin pathway may be involved. OBJECTIVE: We evaluated AXIN2 rs2240308 and rs151279728 polymorphisms, and expression profiles of beta-catenin destruction complex genes in breast cancer patients. MATERIALS AND METHODS: We collected peripheral blood samples from 102 breast cancer and 102 healthy subjects. The identification of the genetic variation was performed using PCR-RFLPs and DNA sequencing. RT-qPCR was used to determine expression profiles. RESULTS: We found significant association of AXIN2 rs151279728 and rs2240308 polymorphisms with breast cancer risk. Significant increase was observed in AXIN2 level expression in breast cancer patients. Further analyses showed APC, beta-catenin, CK1alpha, GSK3beta and PP2A gene expression to be associated to clinic-pathological characteristics. CONCLUSIONS: The present study demonstrated, for the first time, that AXIN2 genetic defects and disturbance of beta-catenin destruction complex expression may be found in breast cancer patients, providing additional support for roles of Wnt/beta-catenin pathway dysfunction in breast cancer tumorigenesis. However, the functional consequences of the genetic alterations remain to be determined. PMID- 26514525 TI - Radiosensitization Effects of a Zataria multiflora Extract on Human Glioblastoma Cells. AB - BACKGROUND: Although radiotherapy is one of the most effective strategies in the treatment of cancers, it is associated with short and long term side effects on normal tissues. Zataria multiflora Boiss (Laminacea) (ZM) has several biological properties such as antioxidant and anti-inflammation activities.Here we investigated cell killing effects of a hydroalcoholic Zataria multiflora extract on cell death induced by ionizing radiation in a human glioblastoma cell line (A172) and human non-malignant fibroblasts (HFFF2) in vitro. MATERIALS AND METHODS: A172 and HFFF2 cells were treated with a hydroalcoholic extract of dried aerial parts of Zataria multiflora at different concentrations (25, 50, 100, 150 and 200 MUg/ml) and then exposed to ionizing radiation (IR). Cell proliferation and DNA fragmentation were evaluated. Thymol content in the extract was analyzed and quantified by HPLC methods. RESULTS: A172 cell proliferation was significantly inhibited by ZM. The percentage cell survival was 91.8 +/- 8.57 for cells treated with 200 MUg/ml of ZM extract alone while it was 76.0 +/- 4.27 and 66.2 +/- 8.42 for cells treated with ZM and exposed to IR at doses of 3 Gy and 6Gy, respectively. Radiation-induced apoptosis in A172 cells was significantly increased following treatment with ZM at doses of 200 MUg/ml. ZM extract did not exhibit any enhanced cell killing effects and apoptosis caused by IR on HFFF2 cells. CONCLUSIONS: These data show selective radiosensitization effects of ZM in A172 cells apparently due to increased radiation-induced apoptosis. PMID- 26514526 TI - Quantitative Analysis of Enlarged Cervical Lymph Nodes with Ultrasound Elastography. AB - PURPSOE: To investigate the diagnostic value of quantitative analysis of a tissue diffusion and virtual touch tissue imaging quantification (VTIQ) technique with acoustic radiation force impulse (ARFI) elastography for assessing enlarged cervical lymph nodes. MATERIALS AND METHODS: Fifty-six enlarged cervical lymph nodes confirmed by pathologic diagnoses were covered in the study. According to the results of pathologic diagnosis, patients were classified into benign and malignant groups. All the patients were examined by both conventional ultrasonography and elastography. AREA% and shear wave velocity (SWV) in ROI of different groups were calculated and compared using ROC curves. Cut-off points of AREA% and SWV were determined with receiver operating characteristic curves. RESULTS: Final histopathological results revealed 21 cases of benign and 35 cases of malignant lymph nodes. The mean values of AREA% and SWV in benign and malignant groups were 45.0 +/- 17.9% and 2.32 +/- 0.57 m/s, and 61.3 +/- 21.29% and 4.36 +/- 1.25)m/s, respectively. For the parameters of elastography, "AREA%"and SWV demonstrated significant differences between groups (p=0.002). AREA% was positively correlated with SWV with a correlation coefficient of 0.809 (P<0.001). CONCLUSIONS: Stiffness of different lymph node diseases in patients may differ. Elastography can evaluate changes sensitively and provide valuable information to doctors. The study proved that the VTIQ elastography technique can play an important role in differential diagnosis of lymph nodes. PMID- 26514527 TI - Lung Cancer in a Rural Area of China: Rapid Rise in Incidence and Poor Improvement in Survival. AB - BACKGROUND: Lung cancer has been a major health problem in developed countries for several decades, and has emerged recently as the leading cause of cancer death in many developing countries. The incidence of lung cancer appears to be increasing more rapidly in rural than in urban areas of China. This paper presents the trends of lung cancer incidence and survival derived from a 40-year population-based cancer monitoring program in a rural area, Qidong, China. MATERIALS AND METHODS: The Qidong cancer registration data of 1972- 2011 were used to calculate the crude rate, age-standardized rate by Chinese population (CASR) and by world population (WASR), birth cohort rates, and other descriptive features. Active and passive methods were used to construct the data set, with a deadline of the latest follow-up of April 30, 2012. RESULTS: The total number of lung cancer cases was 15,340, accounting for 16.5% of all sites combined. The crude incidence rate, CASR and WASR of this cancer were 34.1, 15.7 and 25.4 per 100,000, respectively. Males had higher crude rates than females (49.7 vs 19.0). Rapidly increasing trends were found in annual percent change resulting in lung cancer being a number one cancer site after year 2010 in Qidong. Birth cohort analysis showed incidence rates have increased for all age groups over 24 years old. The 5 year observed survival rates were 3.55% in 1973-1977, 3.92 in 1983 1987, 3.69% in 1993-1997, and 6.32% in 2003-2007. Males experienced poorer survival than did females. CONCLUSIONS: Lung cancer has become a major cancer related health problem in this rural area. The rapid increases in incidence likely result from an increased cigarette smoking rate and evolving environmental risk factors. Lung cancer survival, while showing some improvement in prognosis, still remains well below that observed in the developed areas of the world. PMID- 26514529 TI - Weekly Cisplatin-Based Concurrent Chemoradiotherapy for Treatment of Locally Advanced Head and Neck Cancer: a Single Institution Study. AB - BACKGROUND: The organ preservation approach of choice for the treatment of locally advanced head and neck cancers is concurrent chemoradiation with three weekly high doses of cisplatin. Although this is an efficacious treatment policy, it has high acute systemic and mucosal toxicities, which lead to frequent treatment breaks and increased overall treatment time. Hence, the current study was undertaken to evaluate the efficacy of concurrent chemoradiation using 40 mg/m2 weekly cisplatin. MATERIALS AND METHODS: This is a single institutional retrospective study including the data of 266 locally advanced head and neck cancer patients who were treated with concurrent chemoradiation using 40 mg/m2 weekly cisplatin from January 2012 to January 2014. A p-value of < 0.05 was taken to be significant statistically for all purposes in the study. RESULTS: The mean age of the study patients was 48.8 years. Some 36.1% of the patients had oral cavity primary tumors. The mean overall treatment time was 57.2 days. With a mean follow up of 15.2 months for all study patients and 17.5 months for survivors, 3 year local control, locoregional control and disease free survival were seen in 62.8%, 42.8% and 42.1% of the study patients. Primary tumor site, nodal stage of disease, AJCC stage of the disease and number of cycles of weekly cisplatin demonstrated statistically significant correlations with 3 year local control, locoregional control and disease free survival. CONCLUSIONS: Concurrent chemoradiotherapy with moderate dose weekly cisplatin is an efficacious treatment regime for locally advanced head and neck cancers with tolerable toxicity which can be used in developing countries with limited resources. PMID- 26514528 TI - Assessment of Relationship between Wilms' Tumor Gene (WT1) Expression in Peripheral Blood of Acute Leukemia Patients and Serum IL-12 and C3 Levels. AB - BACKGROUND: Leukemia is a common cancer among children and adolescents. Wilms' tumor gene (WT1) is highly expressed in patients with acute leukemia. It is found as a tumor associated antigen (TAA) in various types of hematopoietic malignancies and can be employed as a useful marker for targeted immunotherapy and monitoring of minimal residual disease (MRD). In this regard, WT1 is a transcription factor that promotes gene activation or repression depending on cellular and promoter context. The purpose of this study was assessment of WT1 gene expression in patients with acute leukemia, measurement of IL-12 and C3 levels in serum and evaluation of the relationship between them. MATERIALS AND METHODS: We evaluated the expression of WT1 mRNA using real-time quantitative RT PCR and serum levels of IL-12 and C3 using ELISA and nephelometry in peripheral blood of 12 newly diagnosed patients with acute leukemia and 12 controls. RESULTS: The results of our study showed that the average wT1 gene expression in patients was 7.7 times higher than in healthy controls (P <0.05). In addition, IL 12 (P = 0.003) and C3 (P <0.0001) were significantly decreased in the test group compared to controls. CONCLUSIONS: WT1 expression levels are significantly higher in patients compared with control subjects whereas serum levels of interleukin-12 and C3 are significantly lower in patients. Wt1 expression levels in patients are inversely related with serum levels of IL-12 and C3. PMID- 26514530 TI - Long Term Outcomes of Preoperative versus Postoperative Concurrent Chemoradiation for Locally Advanced Rectal Cancer: Experience from Ramathibodi Medical School in Thailand. AB - OBJECTIVES: The study analyzed and compared the long term outcome in locally advanced rectal cancer treated with preoperative and postoperative concurrent chemoradiation (CCRT). MATERIALS AND METHODS: A retrospective review of 105 patients with stage T3-T4 or regional lymph node positive adenocarcinoma of rectum treated with preoperative or postoperative CCRT at Ramathibodi Hospital during 2005 to 2010 was performed. The results of treatment were reported with 5 year overall survival (OS), 5- year locoregional recurrence free survival (LRFS), and toxicity according to preoperative versus postoperative concurrent chemoradiation (CCRT) groups. RESULTS: Among 105 patients, 34 (32%) were treated with preoperative CCRT and 71 (68%) with postoperative CCRT. At the median follow up time of 50.5 months (range 2-114 months), five-year OS and LRFS of all patients were 87% and 91.6%, respectively. The study found no difference in 5 year OS (81.7% vs 89.2 %) or LRFS (83.4% vs 95.1%) between preoperative versus postoperative CCRT. Seven cases of loco-regional recurrence were diagnosed, 4 (11.8%) after preoperative CCRT and 3 (4.2%) after postoperative CCRT. The recurrent sites were anastomosis in all patients. There was no significant factor associated with outcome after univariate and multivariate testing. Grade 3 or 4 acute and late complications were low in both preoperative and postoperative CCRT groups. CONCLUSIONS: Locally advanced rectum cancer patients experience good results with surgery and adjuvant concurrent chemoradiation. PMID- 26514531 TI - Relationship between Spiritual Health and Quality of Life in Patients with Cancer. AB - As the essence of health in humans, spiritual health is a fundamental concept for discussing chronic diseases such as cancer and a major approach for improving quality of life in patients is through creating meaningfulness and purpose. The present descriptive analytical study was conducted to assess the relationship between spiritual health and quality of life in 210 patients with cancer admitted to the Cancer Institute of Iran, selected through convenience sampling in 2014. Data were collected using Spiritual Health Questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ). Patients' performance was assessed through the Karnofsky Performance Status Indicator and their cognitive status through the Mini-Mental State Examination (MMSE). Data were analyzed in SPSS-16 using descriptive statistics and stepwise linear regression. The results obtained reported the mean and standard deviation of the patients' spiritual health scoreas 78.4+/-16.1and the mean and standard deviation of their quality of life score as 58.1+/-18.7. The stepwise linear regression analysis confirmed a positive and significant relationship between spiritual health and quality of life in patients with cancer (beta=0.688 and r=0.00). The results of the study show that spiritual health should be more emphasized and reinforced as a factor involved in improving quality of life in patients with cancer. Designing care therapies and spiritual interventions is a priority in the treatment of these patients. PMID- 26514532 TI - Acquired JAK-2 V617F Mutational Analysis in Pakistani Patients with Essential Thrombocythemia. AB - BACKGROUND: Essential thrombocythemia (ET) is a clonal hemopoietic stem cell myeloproliferative neoplasm characterized by persistent thrombocytosis along with megakaryocytic hyperplasia. In the last decade following the identification of an acquired JAK2 V617F mutation, there has been acceleration in our understanding of this disease. The rational of this study was to determine the mutational profile of JAK2 V617F in Pakistan patients with ET. MATERIALS AND METHODS: In this retrospective cross sectional study, 21 patients with ET were enrolled from January 2011 to December 2014. Patients were diagnosed based on WHO criteria for essential thrombocythemia. Complete blood count was done on an automated hematology analyzer, while JAK2 V617F expression was evaluated by polymerase chain reaction. RESULTS: The mean age was 56.7+/-19.0 years (range 18-87) and the male to female ratio was 1:1.1. The frequency of JAK2 V617F positivity in our ET patients was found to be 61.9%. The mean hemoglobin was 11.7+/-2.4 g/dl with a total leukocyte count of 13.3+/-8.1x109/l and a platelet count of 1188+/ 522x109/l. Positive correlations for JAK2 V617F mutation were established with high TLC count and raised LDH (P<0.05). No correlation of JAK2 V617F could be established with age and gender (P>0.05). CONCLUSIONS: JAK2 V617F mutation frequency in our ET patients was similar to those reported previously. Screening for the mutation in all suspected essential thrombocythemia cases could be beneficial in differentiating patients with reactive and clonal thrombocytosis. PMID- 26514533 TI - Concurrent Chemoradiation with Weekly Cisplatin for the Treatment of Head and Neck Cancers: an Institutional Study on Acute Toxicity and Response to Treatment. AB - BACKGROUND: Concurrent chemoradiation with three weekly high dose cisplatin is the non-surgical standard of care for the treatment of locally advanced head and neck cancers. Although this treatment regime is efficacious, it has high acute toxicity, which leads not only to increased treatment cost, but also to increased overall treatment time. Hence, the current study was undertaken to evaluate the acute toxicity and tumor response in head and neck cancer patients treated with concurrent chemoradiation using 40 mg/m2 weekly cisplatin, which has been our institutional practice. MATERIALS AND METHODS: This single institution retrospective study included data for 287 head and neck cancer patients treated with concurrent chemoradiation from 2012 to 2014. RESULTS: The mean age of the patients was 48.8 years. The most common site of involvement was oral cavity. Most of the study patients presented with advanced stage disease. The mean overall treatment time was 56.9 days. Some 67.2% had overall complete response to treatment as documented till 90 days from the start of treatment. According to the Radiation Therapy Oncology Group (RTOG) acute radiation morbidity scoring criteria, mucositis was seen in 95.1% of the patients. Dermatitis and emesis were observed in 81.9% and 98.6%, respectively. Regarding haematological toxicity, 48.8% and 29.6% suffered from anaemia and leukopenia, respectively, during treatment. Acute kidney injury was assessed using the Common Terminology Criteria for Adverse Events (CTCAE), and was found in 18.8% of the patients. CONCLUSIONS: Concurrent chemoradiotherapy with weekly cisplatin is an effective treatment regime for head and neck cancers with reasonable toxicity which can be used in developing countries, where cost of treatment is so important. PMID- 26514534 TI - Cytotoxic Effect and Constituent Profile of Alkaloid Fractions from Ethanolic Extract of Ficus septica Burm. f. Leaves on T47D Breast Cancer Cells. AB - The study aimed to investigate the profile of alkaloids in two ethyl acetate soluble fractions, namely fractions A and B from an ethanolic extract of Ficus septica leaves and cytotoxic effect on T47D breast cancer cells. Preparation of both fractions involved maceration of leaves with 70% (v/v) ethanol, filtration with Al2O3, precipitation with 0.1 N HCl, Mayer reagent, and 0.1 N NaOH, and also partition with ethyl acetate. Qualitative thin layer chromatography (TLC) was conducted to determine the profile of alkaloids in the two fractions, using alkaloid specific reagents such as Dragendorff, sodium nitrite, and Van Urk Salkowski. Cytotoxic effects of both fractions on T47D cells were evaluated using MTT assay with a concentration series of 1.56; 3.12; 6.25; 12.5; 25 and 50 MUg/mL. The TLC test showed that fractions A and B contained alkaloids with Rx values of 0.74 and 0.80 for fraction A and 0.74, 0.84, 0.92 for fraction B with regard to yohimbine using the mobile phase of n-buthanol:glacial acetic acid:distilled water (3:1:1 v/v/v). Moreover, an indole alkaloid was detected with Rx values of 0.80 and 0.84, respectively. Fractions A and B exhibited high cytotoxic effects on T47D cells with IC50 values of 2.57 and 2.73 MUg/mL, respectively. In conclusion, overall the results of this study showed that fractions of Ficus septica contain alkaloids including indole alkaloid or its derivatives and possess a cytotoxic effect on T47D cells. This research supports the idea that alkaloids in F. septica have anticancer activity. PMID- 26514535 TI - Importance of FISH combined with Morphology, Immunophenotype and Cytogenetic Analysis of Childhood/ Adult Acute Lymphoblastic Leukemia in Omani Patients. AB - Genetic changes associated with acute lymphoblastic leukemia (ALL) provide very important diagnostic and prognostic information with a direct impact on patient management. Detection of chromosome abnormalities by conventional cytogenetics combined with fluorescence in situ hybridization (FISH) play a very significant role in assessing risk stratification. Identification of specific chromosome abnormalities has led to the recognition of genetic subgroups based on reciprocal translocations, deletions and modal number in B or T-cell ALL. In the last twelve years 102 newly diagnosed childhood/adult ALL bone marrow samples were analysed for chromosomal abnormalities with conventional G-banding, and FISH (selected cases) using specific probes in our hospital. G-banded karyotype analysis found clonal numerical and/or structural chromosomal aberrations in 74.2% of cases. Patients with pseudodiploidy represented the most frequent group (38.7%) followed by high hyperdiploidy group (12.9%), low hyperdiploidy group (9.7%), hypodiploidy (<46) group (9.7%) and high hypertriploidy group (3.2%). The highest observed numerical chromosomal alteration was high hyperdiploidy (12.9%) with abnormal karyotypes while abnormal 12p (7.5%) was the highest observed structural abnormality followed by t(12;21)(p13.3;q22) resulting in ETV6/RUNX1 fusion (5.4%) and t(9;22)(q34.1;q11.2) resulting in BCR/ABL1 fusion (4.3%). Interestingly, we identified 16 cases with rare and complex structural aberrations. Application of the FISH technique produced major improvements in the sensitivity and accuracy of cytogenetic analysis with ALL patients. In conclusion it confirmed heterogeneity of ALL by identifying various recurrent chromosomal aberrations along with non specific rearrangements and their association with specific immunophenotypes. This study pool is representative of paediatric/adult ALL patients in Oman. PMID- 26514536 TI - Evaluation Frequency of Merkel Cell Polyoma, Epstein-Barr and Mouse Mammary Tumor Viruses in Patients with Breast Cancer in Kerman, Southeast of Iran. AB - Breast cancer is the most common cancer among women worldwide. Roles of the Epstein-Barr, Merkel cell polyoma and mouse mammary tumor viruses in breast carcinogenesis are still controversial although any relationship would clearly be important for breast cancer etiology, early detection and prevention. In the present study associations between EBV, MMTV and Merkel cell polyoma virus and breast cancer in 100 Iranian patients were evaluated using paraffin-embedded tissues. EBER RNA and expression of p53 and large T antigen were evaluated by real time PCR and CD34, p63, HER2, PR and ER markers were studied by immunohistochemistry. EBV was detected in 8/100 (8%), MMTV in 12/100 (12%), MPy in 3/100 (3%) and EBER RNA in 18/100 (18%) cases. None of the control samples demonstrated any of the viruses. p53 was suppressed in EBV, MPy and MMTV positive samples. The large T antigen rate was raised in MPy positive samples. Our results showed that EBV, MMTV and the Merkel cell polyoma virus are foundwith some proportion of breast cancers in our patients, suggesting that these viruses might have a significant role in breast cancer in Kerman, southeast of Iran. PMID- 26514537 TI - Application of a Non-Mixture Cure Rate Model for Analyzing Survival of Patients with Breast Cancer. AB - BACKGROUND: As a result of significant progress made in treatment of many types of cancers during the last few decades, there have been an increased number of patients who do not experience mortality. We refer to these observations as cure or immune and models for survival data which include cure fraction are known as cure rate models or long-term survival models. MATERIALS AND METHODS: In this study we used the data collected from 438 female patients with breast cancer registered in the Cancer Research Center in Shahid Beheshti University of Medical Sciences, Tehran, Iran. The patients had been diagnosed from 1992 to 2012 and were followed up until October 2014. We had to exclude some because of incomplete information. Phone calls were made to confirm whether the patients were still alive or not. Deaths due to breast cancer were regarded as failure. To identify clinical, pathological, and biological characteristics of patients that might have had an effect on survival of the patients we used a non-mixture cure rate model; in addition, a Weibull distribution was proposed for the survival time. Analyses were performed using STATA version 14. The significance level was set at P <= 0.05. RESULTS: A total of 75 patients (17.1%) died due to breast cancer during the study, up to the last follow-up. Numbers of metastatic lymph nodes and histologic grade were significant factors. The cure fraction was estimated to be 58%. CONCLUSIONS: When a cure fraction is not available, the analysis will be changed to standard approaches of survival analysis; however when the data indicate that the cure fraction is available, we suggest analysis of survival data via cure models. PMID- 26514538 TI - Incidence and Mortality of Bladder Cancer and their Relationship with Development in Asia. AB - BACKGROUND: Over the past decade, bladder cancer was associated with a significant increase. Given the importance of the impact of socioeconomic status on the distribution of cancer incidence and mortality, and the need to information on these parameters for prevention planning, the aim of this study was to evaluate data for bladder cancer and their relationship with human development index (HDI) and its components in Asia in 2012. MATERIALS AND METHODS: The study was conducted based on data from the world data of cancer and the World Bank (including the HDI and its components). The incidence and mortality rates were drawn for Asian countries. To analyze data, correlation tests between incidence and death rates, and HDI and its components were employed with a significance level of 0.05 using SPSS software. RESULTS: A total incidence of 696,231 cases (68.7% in males and 31.3% in females, sex ratio of 2.19:1) and 524,465 deaths (67.0% in men and 32.9% in women, sex ratio was 2.03:1) were recorded in Asian countries in 2012. Correlation between HDI and standardized incidence rate was 0.241 overall (p=0.106), 0.236 in men (p=0.114) and -0.250 in women (p=0.094). Also between HDI and standardized mortality rate 0.025 (p=0.871) in men 0.118 (p=0.903) and in women 0.014 (p=0.927). CONCLUSIONS: Bladder cancer incidence is higher in developed countries, but the rate is declining, and in less developed and developing countries it is growing. There was no statistically significant correlation between the standardized incidence rate of bladder cancer and the HDI and its dimensions in Asia, except for the level of education. PMID- 26514539 TI - Community Participation in Cholangiocarcinoma Prevention in Ubon Ratchathani, Thailand: Relations with Age and Health Behavior. AB - A high prevalence of Opisthorchis viverrini infection is usually found in wetland geographical areas of Thailand where people have traditional behavior of eating uncooked freshwater fish dishes which results in cholangiocarcinoma (CCA) development. There were several approaches for reducing opisthorchiasis-linked CCA, but the prevalence remains high. To develop community participation as a suitable model for CCA prevention is, firstly, to know what factors are related. We therefore aimed to investigate factors associated with the community participation in CCA prevention among rural residents in wetland areas of Ubon Ratchathani, Thailand. This was a cross-sectional analytic study. All participants were 30-69 years of age, and only one member per house was invited to participate. A total of 906 participants were interviewed and asked to complete questionnaires. Independent variables were socio-demographic parameters, knowledge, health belief and behavior to prevent CCA. The dependent variable was community participation for CCA prevention. Descriptive statistics were computed as number, percentage, mean and standard deviation. Associations were assessed using logistic regression analysis with a P-value <0.05 considered statistically significant. Of all the participants, more than 60% had regularly participated in activities to prevent CCA following health officials advice. Age and health behavior to prevent CCA were factors associated with community participation for CCA (p<0.001). Both factors will be taken into consideration for community participation approaches for CCA prevention through participatory action research (PAR) in future studies. PMID- 26514540 TI - Comparison of Efficacy in Abnormal Cervical Cell Detection between Liquid-based Cytology and Conventional Cytology. AB - This study was conducted to 1206 women who had cervical cancer screening at Chonburi Cancer Hospital. The spilt-sample study aimed to compare the efficacy of abnormal cervical cells detection between liquid-based cytology (LBC) and conventional cytology (CC). The collection of cervical cells was performed by broom and directly smeared on a glass slide for CC then the rest of specimen was prepared for LBC. All slides were evaluated and classified by The Bethesda System. The results of the two cytological tests were compared to the gold standard. The LBC smear significantly decreased inflammatory cell and thick smear on slides. These two techniques were not difference in detection rate of abnormal cytology and had high cytological diagnostic agreement of 95.7%. The histologic diagnosis of cervical tissue was used as the gold standard in 103 cases. Sensitivity, specificity, positive predictive value, negative predictive value, false positive, false negative and accuracy of LBC at ASC-US cut off were 81.4, 75.0, 70.0, 84.9, 25.0, 18.6 and 77.7%, respectively. CC had higher false positive and false negative than LBC. LBC had shown higher sensitivity, specificity, PPV, NPV and accuracy than CC but no statistical significance. In conclusion, LBC method can improve specimen quality, more sensitive, specific and accurate at ASC-US cut off and as effective as CC in detecting cervical epithelial cell abnormalities. PMID- 26514541 TI - Diagnostic Accuracy of Fine Needle Aspiration Cytology versus Concurrent Core Needle Biopsy in Evaluation of Intrathoracic Lesions: a Retrospective Comparative Study. AB - BACKGROUND: Transthoracic fine needle aspiration (FNA) cytology and core needle biopsy (CNB) are two commonly used approaches for the diagnosis of suspected neoplastic intrathoracic lesions. This study compared the diagnostic accuracy of FNA cytology and concurrent CNB in the evaluation of intrathoracic lesions. MATERIALS AND METHODS: We studied FNA cytology and concurrent CNB specimens of 127 patients retrospectively, using hematoxylin and eosin (H and E), immunohistochemistry, and, on certain occasions cytochemistry. Information regarding additional tissue tests was derived from the electronic archives of the Department of Pathology and Laboratory Medicine as well as patient records. Diagnostic accuracy was calculated for each test. RESULTS: Of 127 cases, 22 were inconclusive and excluded from the study. The remaining 105 were categorized into 73 (69.5%) malignant lesions and 32 (30.5%) benign lesions. FNA and CNB findings were in complete agreement in 63 cases (60%). The accuracy and confidence intervals (CIs) of FNA and CNB for malignant tumors were 86.3% (CI: 79.3-90.7) and 93.2% (CI: 87.3- 96.0 ) respectively. For epithelial malignant neoplasms, a definitive diagnosis was made in 44.8% of cases by FNA and 80.6% by CNB. The diagnostic accuracy of CNB for nonepithelial malignant neoplasms was 83.3% compared with 50% for FNA. Of the 32 benign cases, we made specific diagnoses in 16 with diagnostic accuracy of 81.3% and 6.3% for CNB and FNA, respectively. CONCLUSIONS: Our findings suggest that FNA is comparable to CNB in the diagnosis of malignant epithelial lesions whereas diagnostic accuracy of CNB for nonepithlial malignant neoplasms is superior to that for FNA. Further, for histological typing of tumors and examining tumor origin, immunohistochemical work up plays an important role. PMID- 26514542 TI - Colorectal Cancer Screening Program: a Needed Intervention in Saudi Arabia. PMID- 26514543 TI - Myopathy associated with neuromyelitis optica spectrum disorders. AB - Neuromyelitis optica spectrum disorders (NMOSD) were generally thought to affect only central nervous system and spare peripheral aquaporin-4 (AQP4)-expressing organs. In recent years, however, increasing evidence has shown that skeletal muscle is involved in NMOSD. We provided a comprehensive review of the relevant literature and summarized the clinical and pathological characteristics of myopathy associated with NMOSD. NMOSD-associated myopathy seems to be characterized by mild muscle symptoms with prominent hyperCKemia and minimal changes on conventional pathological staining. Loss of AQP4 and deposition of IgG and activated complement products on sarcolemma of type II fibers are diagnostic features on immunohistochemical examinations. Creatine kinase leakage as a result of AQP4-IgG-induced, complement-mediated sarcolemmal injury may be a potential mechanism for hyperCKemia. Myopathy should be considered a component of NMOSD unified by AQP4-IgG seropositivity. PMID- 26514545 TI - Retrograde transcatheter device closure of a complex paravalvular leak after bioprosthetic pulmonary valve replacement in a pediatric patient. AB - We report a case of retrograde transcatheter device closure of a complex paravalvular leak (PVL) after bioprosthetic pulmonary valve replacement (PVR) in a 13-year-old patient with congenital pulmonary valve stenosis. There are prior reports of pulmonary PVL closure after PVR in adults (Seery and Slack, Congenit Heart Dis 2014;9:E19-F22), but indications for and technical considerations in PVL closure after bioprosthetic PVR, particularly in children, are not well defined. (c) 2015 Wiley Periodicals, Inc. PMID- 26514544 TI - Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes. AB - Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53 and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53 VAF predicted for complex cytogenetics in both the training (P=0.001) and validation set (P<0.0001). MDS patients with a TP53 VAF > 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF <20% (hazard ratio (HR), 3.52; P=0.01) with validation in an independent cohort (HR, 4.94, P=0.01). TP53 VAF further stratified distinct prognostic groups independent of clinical prognostic scoring systems (P=0.0005). In multivariate analysis, only a TP53 VAF >40% was an independent covariate (HR, 1.61; P<0.0001). In addition, SRSF2 VAF predicted for monocytosis (P=0.003), RUNX1 VAF with thrombocytopenia (P=0.01) and SF3B1 with ringed sideroblasts (P=0.001). Together, our study indicates that VAF should be incorporated in patient management and risk stratification in MDS. PMID- 26514546 TI - Ex Vivo and In Situ Evaluation of 'Dispelling-Wind' Chinese Medicine Herb-Drugs on Intestinal Absorption of Chlorogenic Acid. AB - This study aims to investigate the additive or synergistic effects and mechanism of intestinal absorption of extracts from two commonly used 'dispelling-wind' TCM botanical drugs [roots of Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav. (RAD) and Saposhnikovia divaricata (Turcz.) Schischk. (RSD)] using chlorogenic acid as a marker substance. Ex vivo everted intestinal sac and in situ single pass perfusion methods using rats were employed to investigate the effects of two TCM botanical drugs extracts on the intestinal absorption of chlorogenic acid. Both the extracts of RAD and RSD showed synergistic properties on the intestinal absorption of chlorogenic acid. The verapamil (a P-gp inhibitor) and intestinal dysbacteriosis model induced by norfloxacin increased the P(app) and K(a) of intestinal absorption of chlorogenic acid. These synergistic effects on intestinal absorption in a rat model can be correlated with the inhibition of P-gp and regulation of gut microbiota. This experimental approach has helped to better understand changes in the absorption of chlorogenic acid under different conditions. PMID- 26514547 TI - Sentinel lymph node biopsy in cN0 squamous cell carcinoma of the lip: A retrospective study. AB - BACKGROUND: The purpose of this study was to assess the use of sentinel lymph node biopsy (SLNB) in clinically lymph node-negative (cN0) squamous cell carcinoma (SCC) of the lip deemed high risk for occult nodal metastasis. METHODS: Twenty-six patients with cT1 to T2 cN0 with SCC of the lip underwent SLNB at a tertiary referral center between January 2001 and March 2012. Initial staging methods were clinical examination only (65.4%), ultrasound (23.1%), or CT (11.5%). Operations were performed with the patients under local anesthesia with sedation (50%) or general anesthesia (50%). RESULTS: The mean follow-up time was 53 months. Three patients (11.5%) had a positive sentinel node and were upstaged. One SLNB-related complication was observed. Regional recurrence occurred in 2 patients (7.7%). The relationship between regional status and both tumor diameter and tumor thickness was statistically significant (p < .05). CONCLUSION: SLNB can be a viable staging technique in SCC of the lip. Tumor diameter of >= 20 mm and increasing tumor thickness seem to delineate higher risk for regional disease in our study. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1375-E1380, 2016. PMID- 26514548 TI - Absence of Sperm Factors as in the Parthenogenesis Does Not Interfere on Bovine Embryo Sensitiveness to Heat Shock at Pre-Implantation Stage. AB - Oocyte has been considered the major contributor for embryo thermo-tolerance. However, it was shown that sperm factors can be transferred to the oocyte during fertilization, raising the question of whether the absence of such factors could interfere on embryo thermo-tolerance. In this study, we used parthenogenesis to generate bovine embryos without spermatozoa in order to test whether the absence of sperm factors could influence their thermo-sensitiveness at early stages. In vitro fertilized (IVF) and parthenogenetic (PA) embryos at 44 h post insemination/chemical activation were exposed to 38.5 degrees C (control) or 41 degrees C (heat shock) for 12 h and then developed for 48 h and up to blastocyst stage. Apoptosis index and expression of PRDX1, GLUT1, GLUT5 and IGF1r genes in blastocysts derived from heat-shocked embryos were also evaluated. The heat shock decreased the blastocyst rate at day seven (p < 0.05) for IVF embryos and at day eight (p < 0.01) for both IVF and PA embryos. Total cell number was not affected by heat shock in IVF and PA blastocysts, but there was an increased proportion (p < 0.05) of apoptotic cells in heat-shocked embryos when compared to controls. There was no interaction (p > 0.05) between method of activation (IVF and PA) and temperature (38.5 degrees C or 41.5 degrees C) for all developmental parameters evaluated. Expression of GLUT1 gene was downregulated (p < 0.05) by heat shock in both IVF and PA blastocyst whereas expression of GLUT5 and IGF1r genes was downregulated (p < 0.05) by heat shock in PA blastocysts. Those data show that the heat shock affects negatively the embryo development towards blastocysts stage, increases the apoptotic index and disturbed the expression of some genes in both IVF and PA embryos, indicating that the presence or absence of sperm factors does not influence the sensitivity of the bovine embryo to heat shock. PMID- 26514549 TI - Employed Carers' Empathy Towards People with Intellectual Disabilities: The Development of a New Measure and Some Initial Theory. AB - BACKGROUND: This study aimed to develop a self-report measure of paid caregivers' empathy towards people with intellectual disabilities. MATERIALS AND METHODS: Following questionnaire develop-ment, 194 staff working in services for people with intellectual disabilities completed self-report questionnaires, including the new empathy measure. The measure's factor structure and psychometric properties were investigated. RESULTS: A three factor solution suggested two key processes in empathizing: experiencing commonality between one's own and people with intellectual disabilities' psychological experiences and efforts to attune to their internal worlds. The final factor represented whether carers find it challenging to empathize. Correlations with beliefs about the self and others in caregiving relationships provided initial evidence of validity, although further investigation is needed. CONCLUSIONS: The most salient processes in empathizing with people with intellectual disabilities may be different from empathy in other contexts. Establishing determinants of carer empathy may facilitate the development of psychological interventions to promote and enhance this important quality. PMID- 26514550 TI - Melatonin nephroprotective action in Zucker diabetic fatty rats involves its inhibitory effect on NADPH oxidase. AB - Excessive activity of NADPH oxidase (Nox) is considered to be of importance for the progress of diabetic nephropathy. The aim of the study was to elucidate the effect of melatonin, known for its nephroprotective properties, on Nox activity under diabetic conditions. The experiments were performed on three groups of animals: (i) untreated lean (?/+) Zucker diabetic fatty (ZDF) rats; (ii) untreated obese diabetic (fa/fa) ZDF rats; and (iii) ZDF fa/fa rats treated with melatonin (20 mg/L) in drinking water. Urinary albumin excretion was measured weekly. After 4 wk of the treatment, the following parameters were determined in kidney cortex: Nox activity, expression of subunits of the enzyme, their phosphorylation and subcellular distribution. Histological studies were also performed. Compared to ?/+ controls, ZDF fa/fa rats exhibited increased renal Nox activity, augmented expression of Nox4 and p47(phox) subunits, elevated level of p47(phox) phosphorylation, and enlarged phospho-p47(phox) and p67(phox) content in membrane. Melatonin administration to ZDF fa/fa rats resulted in the improvement of renal functions, as manifested by considerable attenuation of albuminuria and some amelioration of structural abnormalities. The treatment turned out to nearly normalize Nox activity, which was accompanied by considerably lowered expression and diminished membrane distribution of regulatory subunits, that is, phospho-p47(phox) and p67(phox) . Thus, it is concluded that: (i) melatonin beneficial action against diabetic nephropathy involves attenuation of the excessive activity of Nox; and (ii) the mechanism of melatonin inhibitory effect on Nox is based on the mitigation of expression and membrane translocation of its regulatory subunits. PMID- 26514551 TI - Retraction of "Efficient Reactivation of p53 in Cancer Cells by a Dual MdmX/Mdm2 Inhibitor". PMID- 26514552 TI - INFANT MENTAL HEALTH IN THE NEXT DECADE: A CALL FOR ACTION. PMID- 26514553 TI - Paeoniflorin exerts analgesic and hypnotic effects via adenosine A1 receptors in a mouse neuropathic pain model. AB - RATIONAL: Neuropathic pain is frequently comorbid with sleep disturbances. Paeoniflorin, a main active compound of total glucosides of paeony, has been well documented to exhibit neuroprotective bioactivity. OBJECTIVE: The present study evaluated effects of paeoniflorin on neuropathic pain and associated insomnia and the mechanisms involved. METHODS: The analgesic and hypnotic effects of paeoniflorin were measured by mechanical threshold and thermal latency, electroencephalogram (EEG) and electromyogram, and c-Fos expression in a neuropathic pain insomnia model. RESULTS: The data revealed that paeoniflorin (50 or 100 mg/kg, i.p.) significantly increased the mechanical threshold and prolonged the thermal latency in partial sciatic nerve ligation (PSNL) mice. Meanwhile, paeoniflorin increased non-rapid eye movement (NREM) sleep amount and concomitantly decreased wakefulness time. However, pretreatment with l,3-dimethy 8-cyclopenthylxanthine, an adenosine A1 receptor (R, A1R) antagonist, abolished the analgesic and hypnotic effects of paeoniflorin. Moreover, paeoniflorin at 100 mg/kg failed to change mechanical threshold and thermal latency and NREM sleep in A1R knockout PSNL mice. Immunohistochemical study showed that paeoniflorin inhibited c-Fos overexpression induced by PSNL in the anterior cingulate cortex and ventrolateral periaqueductal gray. CONCLUSIONS: The present findings indicated that paeoniflorin exerted analgesic and hypnotic effects via adenosine A1Rs and might be of potential use in the treatment of neuropathic pain and associated insomnia. PMID- 26514554 TI - Examination of clozapine and haloperidol in improving ketamine-induced deficits in an incremental repeated acquisition procedure in BALB/c mice. AB - RATIONALE: Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, causes locomotor hyperactivity, aberrant prepulse inhibition and impaired reversal learning among other deficits. There are numerous clinical and pre-clinically uses of NMDAR antagonists and a growing need to characterize their neurobehavioral effects. OBJECTIVES: The present study was designed to characterize 1) ketamine's effect on incremental repeated acquisition (IRA), a procedure that taps multiple neurobehavioral functions and has performance measures correlated with IQ in humans, and 2) the extent to which clozapine (CLZ) and haloperidol (HAL) block ketamine's detrimental effects. METHODS AND RESULTS: In experiment 1 (Exp. 1), BALB/c mice nose-poked under an IRA procedure for sucrose pellets. Systemic ketamine (1-30 mg/kg) dose-dependently decreased measures of cognitive and motor function. CLZ pretreatment (CLZ 0.1-4.0 mg/kg) dose-dependently attenuated ketamine-induced (30 mg/kg) deficits; the effective dose range of CLZ was 0.3-1.0 mg/kg. HAL pretreatment (0.01-0.1 mg/kg) did not attenuate any ketamine-induced deficits. In experiment 2 (Exp. 2), BALB/c mice lever-pressed under an IRA procedure for sweetened condensed milk. Ketamine (30 mg/kg) produced a global impairment in the IRA procedure and CLZ pretreatment (0.3-1.0 mg/kg) dose-dependently attenuated that impairment; motor-based performance recovered to a greater extent than cognitive performance. When tested alone, these doses of CLZ had little effect on IRA performance. CONCLUSIONS: These findings support the notion that CLZ is more effective than HAL at blocking ketamine-induced deficits. The IRA procedure may be beneficial for distinguishing the efficacy of drugs that seek to alleviate deficits in complex behavior that result from acute NMDAR antagonism. PMID- 26514555 TI - Regulation of glutamate transporter 1 via BDNF-TrkB signaling plays a role in the anti-apoptotic and antidepressant effects of ketamine in chronic unpredictable stress model of depression. AB - RATIONALE: Growing evidence suggests that downregulated clearance of glutamate and signaling pathways involving brain-derived neurotrophic factor (BDNF) and its receptor TrkB play a role in morphological changes in the hippocampus of depressed patients. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is the most attractive antidepressant, although precise mechanisms are unknown. OBJECTIVE: In this study, we examined whether hippocampal BDNF-TrkB signaling underlies the antidepressant effects of ketamine via upregulating glutamate transporter 1 (GLT-1) in rats, subjected to the chronic unpredictable stress (CUS) for 42 days. The rats received a single injection of ketamine (10 mg/kg, i.p.) and/or a TrkB inhibitor, K252a (1 MUl, 2 mM, intracerebroventicular (i.c.v.)) on day 43. Behavioral tests and brain sample collection were evaluated 24 h later. RESULTS: The CUS-exposed rats exhibited depression- and anxiety-like behaviors; decreased number of glial fibrillary acidic protein (GFAP)-positive (but not NeuN-positive) cells in the dentate gyrus (DG), CA1, and CA3 areas; increased number of cleaved caspase-3-positive astrocytes; reduced spine density; lower ratio of Bcl2 to Bax; and decreased levels of BDNF, phosphorylated cAMP response element binging protein (CREB), GLT-1, and postsynaptic density 95 (PSD95) proteins in the hippocampus. Ketamine alleviated the CUS-induced abnormalities. The effects of ketamine were antagonized by pretreatment with K252a. CONCLUSIONS: Our findings suggest that regulation of GLT-1 on astrocytes, responsible for 90 % of glutamate reuptake from the synapse, through BDNF-TrkB signaling is involved in mediation of the therapeutic effects of ketamine on behavioral abnormalities and morphological changes in the hippocampus of the CUS exposed rats. PMID- 26514556 TI - Alterations of naltrexone-induced conditioned place avoidance by pre-exposure to high fructose corn syrup or heroin in Sprague-Dawley rats. AB - RATIONALE: It has been suggested that withdrawal from sugar produces a set of symptoms that resemble those observed following withdrawal from opiate drugs. OBJECTIVES: This study explored naltrexone-induced withdrawal in animals pre exposed to acute, chronic, and intermittent high fructose corn syrup (HFCS) or acute and chronic heroin administration. METHODS: Experiment 1 examined conditioned place avoidance (CPA) induced by different doses of naltrexone (0.01 1 mg/kg) in naive male Sprague-Dawley rats. In experiment 2, rats received continuous or intermittent home cage HFCS access (0 or 50 %) prior to conditioning with 1 mg/kg naltrexone. In experiment 3, HFCS ingestion was increased by food restriction and rats were conditioned with 3 mg/kg naltrexone. In experiment 4, the timing and quantity of HFCS ingestion (0, 0.5, 1, 2 g/kg) was controlled by intragastric administration, and rats were conditioned with 1 mg/kg naltrexone. In experiment 5, rats received acute (2 mg/kg) or chronic heroin (3.5 mg/kg/day) prior to conditioning with 1 mg/kg naltrexone. RESULTS: Administration of naltrexone produced moderate conditioned place avoidance in naive rats. Importantly, acute, continuous, and intermittent HFCS pre-exposure did not significantly amplify this effect, but acute and chronic heroin pre exposure did. CONCLUSIONS: As assessed by CPA, these results in rats fail to support the hypothesis that an opioid antagonist can precipitate similar affective withdrawal states following pre-exposure to sugars and opiates. PMID- 26514558 TI - Necroptosis: a potential, promising target and switch in acute pancreatitis. AB - Pancreatic acinar cell death is the major pathophysiological change in early acute pancreatitis (AP), and the death modalities are important factors determining its progression and prognosis. During AP, acinar cells undergo two major modes of death, including necrosis and apoptosis. Acinar necrosis can lead to intensely local and systemic inflammatory responses, which both induce and aggravate the lesion. Necrosis has long been considered an unregulated, and passive cell death process. Since the effective interventions of necrosis are difficult to perform, its relevant studies have not received adequate attention. Necroptosis is a newly discovered cell death modality characterized by both necrosis and apoptosis, i.e., it is actively regulated by special genes, while has the typical morphological features of necrosis. Currently, necroptosis is gradually becoming an important topic in the fields of inflammatory diseases. The preliminary results from necroptosis in AP have confirmed the existence of acinar cell necroptosis, which may be a potential target for effectively regulating inflammatory injuries and improving its outcomes; however, the functional changes and mechanisms of necroptosis still require further investigation. This article reviewed the progress of necroptosis in AP to provide a reference for deeply understanding the pathogenic mechanisms of AP and identifying new therapeutic targets. PMID- 26514557 TI - Behavioral and neurochemical effects induced by reserpine in mice. AB - RATIONALE: Reserpine, a monoamine-depleting agent, which irreversibly and non selectively blocks the vesicular monoamine transporter, has been used as an animal model to study several neurological disorders, including tardive dyskinesia and Parkinson's disease. OBJECTIVE: The purpose of this study was to examine if motor deficits induced by reserpine in mice could be related to alterations in the expression of dopaminergic system proteins such as tyrosine hydroxylase (TH) and dopamine transporter (DAT) and in the activity of monoamine oxidase (MAO). METHODS: Mice received either vehicle or reserpine (0.1, 0.5, or 1 mg/kg, s.c.) for four consecutive days. Two, 20, or 60 days after reserpine withdrawal, behavioral, and neurochemical changes were evaluated. RESULTS: Reserpine at a dose of 0.5 and 1 mg/kg increased vacuous chewing movements (VCMs) and reduced locomotion. Behavioral changes were accompanied by reduction in TH immunoreactivity in the striatum evaluated on days 2 and 20 after the last injection of 1 mg/kg reserpine. Furthermore, negative correlations were found between VCM and MAO-A or MAO-B on day 2 and TH striatal immunoreactivity on day 20 after the last injection of 1 mg/kg reserpine. A positive correlation was observed between VCMs and DAT immunoreactivity in the substantia nigra on day 2 after the last injection of 0.5 mg/kg reserpine. CONCLUSIONS: These findings suggest that the pharmacological blockage of vesicular monoamine transporter (VMAT) by reserpine caused neurochemical and behavioral alterations in mice. PMID- 26514559 TI - Atmospheric ammonia and its impacts on regional air quality over the megacity of Shanghai, China. AB - Atmospheric ammonia (NH3) has great environmental implications due to its important role in ecosystem and global nitrogen cycle, as well as contribution to secondary particle formation. Here, we report long-term continuous measurements of NH3 at different locations (i.e. urban, industrial and rural) in Shanghai, China, which provide an unprecedented portrait of temporal and spatial characteristics of atmospheric NH3 in and around this megacity. In addition to point emission sources, air masses originated from or that have passed over ammonia rich areas, e.g. rural and industrial sites, increase the observed NH3 concentrations inside the urban area of Shanghai. Remarkable high-frequency NH3 variations were measured at the industrial site, indicating instantaneous nearby industrial emission peaks. Additionally, we observed strong positive exponential correlations between NH4(+)/(NH4(+)+NH3) and sulfate-nitrate-ammonium (SNA) aerosols, PM2.5 mass concentrations, implying a considerable contribution of gas to-particle conversion of ammonia to SNA aerosol formation. Lower temperature and higher humidity conditions were found to favor the conversion of gaseous ammonia to particle ammonium, particularly in autumn. Although NH3 is currently not included in China's emission control policies of air pollution precursors, our results highlight the urgency and importance of monitoring gaseous ammonia and improving its emission inventory in and around Shanghai. PMID- 26514560 TI - Social Phobia and Educational and Interpersonal Impairments in Adolescence: A Prospective Study. AB - We examined longitudinal associations between social phobia (SP) and educational and interpersonal impairments among Finnish adolescents. Participants were 3278 adolescents (9th grade; M age = 15.5 years) who completed measures of SP and depressive symptoms; 2070 participated in follow-up two years later. Indicators for educational and interpersonal functioning were assessed for each sex separately. Multivariate analyses, controlling for depression and relevant socioeconomic covariates, indicated that for boys, age 15 SP predicted slow academic progression, being without a close friend or not having a romantic relationship, and poor support from friends and significant others at age 17. However, for girls, age 15 SP only predicted not having been involved in a romantic relationship by age 17. In conclusion, we found striking sex differences for adolescent SP as a predictor for subsequent educational and interpersonal impairments in late adolescence. SP may have a more devastating effect on boys' social and academic functioning relative to that of girls. PMID- 26514561 TI - Adipose tissue metabolic and inflammatory responses to a mixed meal in lean, overweight and obese men. AB - PURPOSE: Most of what we know about adipose tissue is restricted to observations derived after an overnight fast. However, humans spend the majority of waking hours in a postprandial (fed) state, and it is unclear whether increasing adiposity impacts adipose tissue responses to feeding. The aim of this research was to investigate postprandial responses in adipose tissue across varying degrees of adiposity. METHODS: Thirty males aged 35-55 years with waist circumference 81-118 cm were divided equally into groups categorized as either lean, overweight or obese. Participants consumed a meal and insulinaemic, glycaemic and lipidaemic responses were monitored over 6 h. Subcutaneous adipose tissue samples were obtained at baseline and after 6 h to examine changes in gene expression and adipose tissue secretion of various adipokines. RESULTS: Following consumption of the meal, insulin and glucose responses were higher with increased adiposity (total AUC effects of group; p = 0.058 and p = 0.027, respectively). At 6 h, significant time effects reflected increases in IL-6 (F = 14.7, p = 0.001) and MCP-1 (F = 10.7, p = 0.003) and reduction in IRS2 adipose tissue gene expression (F = 24.6, p < 0.001), all independent of adiposity. Ex vivo adipokine secretion from adipose tissue explants remained largely unchanged after feeding. CONCLUSIONS: Increased systemic measures of postprandial metabolism with greater adiposity do not translate into increased inflammatory responses within adipose tissue. Instead, postprandial adipose tissue changes may represent a normal response to feeding or a (relatively) normalized response with increased adiposity due to either similar net exposure (i.e. per g of adipose) or reduced adipose tissue responsiveness. PMID- 26514562 TI - Vitamin B2, vitamin B12 and total homocysteine status in children and their associations with dietary intake of B-vitamins from different food groups: the Healthy Growth Study. AB - PURPOSE: To examine the associations between the dietary intakes of certain B vitamins from different food sources with the relevant plasma status indices in children. METHODS: A representative subsample of 600 children aged 9-13 years from the Healthy Growth Study was selected. Dietary intakes of vitamins B2, B12, B6 and folate derived from different food sources were estimated. Plasma levels of vitamin B2 (or riboflavin), methylmalonic acid (MMA) and total homocysteine (tHcy) were also measured. RESULTS: Plasma concentrations of vitamin B2 below 3 MUg/L were found in 22.8 % of the children. Children in the lower quartile of dietary vitamin B2 intake were found to have the lowest plasma vitamin B2 levels compared to children in the upper three quartiles (5.06 +/- 7.63 vs. 6.48 +/- 7.88, 6.34 +/- 7.63 and 6.05 +/- 4.94 MUg/L respectively; P = 0.003). Regarding vitamin B12 children in the lower quartile of dietary intake had higher mean plasma tHcy levels compared to children in the upper two quartiles, respectively (6.00 +/- 1.79 vs. 5.41 +/- 1.43 and 5.46 +/- 1.64 MUmol/L; P = 0.012). Positive linear associations were observed between plasma vitamin B2 levels and dietary vitamin B2 derived from milk and fruits (beta = 0.133; P = 0.001 and beta = 0.086; P = 0.037). Additionally, nonlinear associations were also observed between plasma vitamin B2 levels and vitamin B2 derived from red meat, as well as between tHcy levels and vitamins B12 and B6 derived from milk; vitamins B12, B6 and folate derived from cereal products and folate derived from fruits. CONCLUSION: A considerably high prevalence of poor plasma vitamin B2 status was observed in children. The intake of milk, fruits and cereals was associated with more favorable tHcy levels, while the intake of milk and fruits with more favorable plasma B2 levels. However, these findings need to be further confirmed from controlled dietary intervention studies examining the modulation of biomarkers of B-vitamins. PMID- 26514563 TI - Do-not-resuscitate orders and related factors among family surrogates of patients in the emergency department. AB - PURPOSE: The purpose of this study was to investigate the prevalence of do-not resuscitate (DNR) orders and to identify relevant factors influencing the DNR decision-making process by patients' surrogates in the emergency department (ED). METHODS: A prospective, descriptive, and correlational research design was adopted. A total of 200 surrogates of cancer or non-cancer terminal patients, regardless of whether they signed a DNR order, were recruited as subjects after physicians of the emergency department explained the patient's conditions, advised on withholding medical treatment, and provided information on palliative care to all surrogates. RESULTS: Of the 200 surrogates, 23 % signed a DNR order for the patients. The demographic characteristics of patients and surrogates, the level of understanding of DNR orders, and factors of the DNR decision had no significant influence on the DNR decision. However, greater severity of disease (odds ratio (OR) = 1.38; 95 % confidence interval (CI) = 0.95-1.74), physician's initiative in discussing with the families (OR = 1.42; 95 % CI = 1.21-1.84), and longer length of hospital stay (OR = 1.06; 95 % CI = 1.03-1.08) were contributing factors affecting patient surrogates' DNR decisions. CONCLUSIONS: The findings of this study indicated that surrogates of patients who were more severe in disease condition, whose physicians initiated the discussion of palliative care, and who stayed longer in hospital were important factors affecting the surrogates' DNR decision-making. Therefore, early initiation of DNR discussions is suggested to improve end-of-life care. PMID- 26514564 TI - Comparative histology of muscle in free ranging cetaceans: shallow versus deep diving species. AB - Different marine mammal species exhibit a wide range of diving behaviour based on their breath-hold diving capabilities. They are classically categorized as long duration, deep-diving and short duration, shallow-diving species. These abilities are likely to be related to the muscle characteristics of each species. Despite the increasing number of publications on muscle profile in different cetacean species, very little information is currently available concerning the characteristics of other muscle components in these species. In this study, we examined skeletal muscle fiber type, fiber size (cross sectional area and lesser diameter), intramuscular substrates, and perimysium-related structures, by retrospective study in 146 stranded cetaceans involving 15 different species. Additionally, we investigated diving profile-specific histological features. Our results suggest that deep diving species have higher amount of intramyocyte lipid droplets, and evidence higher percentage of intramuscular adipose tissue, and larger fibre sizes in this group of animals. PMID- 26514565 TI - A novel approach to enhance biological nutrient removal using a culture supernatant from Micrococcus luteus containing resuscitation-promoting factor (Rpf) in SBR process. AB - A culture supernatant from Micrococcus luteus containing resuscitation-promoting factor (SRpf) was used to enhance the biological nutrient removal of potentially functional bacteria. The obtained results suggest that SRpf accelerated the start up process and significantly enhanced the biological nutrient removal in sequencing batch reactor (SBR). PO4 (3-)-P removal efficiency increased by over 12 % and total nitrogen removal efficiency increased by over 8 % in treatment reactor acclimated by SRpf compared with those without SRpf addition. The Illumina high-throughput sequencing analysis showed that SRpf played an essential role in shifts in the composition and diversity of bacterial community. The phyla of Proteobacteria and Actinobacteria, which were closely related to biological nutrient removal, were greatly abundant after SRpf addition. This study demonstrates that SRpf acclimation or addition might hold great potential as an efficient and cost-effective alternative for wastewater treatment plants (WWTPs) to meet more stringent operation conditions and legislations. PMID- 26514566 TI - Impact of emission control on PM2.5 and the chemical composition change in Beijing-Tianjin-Hebei during the APEC summit 2014. AB - The success of the emission reduction measures undertaken by authorities in the Asia-Pacific Economic Cooperation summit 2014 demonstrated that the Beijing Tianjin-Hebei air quality can be improved by introducing integrated emission reduction measures. This paper combines observation data, emission reduction measures, and air quality simulations that were applied before, during, and after the emission control measure implement to analyze the chemical composition change and relationship between emissions and concentrations of pollutants in region. The 24-h PM2.5 samples were collected in the city Beijing, Shijiazhuang, and Tangshan during the period of 20 October to 25 November, 2014. The total PM2.5 mass was measured. PM2.5 samples were used for the analysis of inorganic elements, selected ions, and organic carbon (OC) and element carbon (EC). PM2.5 concentrations during the emission control period were decreased. Total PM2.5 concentrations were reduced by 54, 26, and 39 % when compared to non-emission control period in Beijing, Shijiazhuang, and Tangshan. The average element concentrations were reduced significantly by 75 % in Beijing, 37 % in Shijiazhuang, and 36 % in Tangshan. After the Asia-Pacific Economic Cooperation (APEC) conference, the average element concentration increased. At both cities, the concentration secondary water-soluble ions, primary carbon, and element carbon were reduced. However, the concentration of secondary carbon species increased in Beijing due to photochemical oxidants change. More stringent control of regional emissions will be needed for significant reductions of fine particulate pollution in the region to continue to improve air quality. PMID- 26514568 TI - Earthworms facilitate the stabilization of pelletized dewatered sludge through shaping microbial biomass and activity and community. AB - In this study, the effect of earthworms on microbial features during vermicomposting of pelletized dewatered sludge (PDS) was investigated through comparing two degradation systems with and without earthworm E isenia fetida involvement. After 60 days of experimentation, a relatively stable product with low organic matter and high nitrate and phosphorous was harvested when the earthworms were involved. During the process, earthworms could enhance microbial activity and biomass at the initial stage and thus accelerating the rapid decomposition of PDS. The end products of vermicomposting allowed the lower values of bacterial and eukaryotic densities comparison with those of no earthworm addition. In addition, the presence of earthworms modified the bacterial and fungal diversity, making the disappearances of some pathogens and specific decomposing bacteria of recalcitrant substrates in the vermicomposting process. This study evidences that earthworms can facilitate the stabilization of PDS through modifying microbial activity and number and community during vermicomposting. PMID- 26514567 TI - Dioxin risk assessment: mechanisms of action and possible toxicity in human health. AB - Dioxin-like compounds (DLCs) have been classified by the World Health Organization (WHO) as one of the most persistent toxic chemical substances in the environment, and they are associated with several occupational activities and industrial accidents around the world. Since the end of the 1970s, these toxic chemicals have been banned because of their human toxicity potential, long half life, wide dispersion, and they bioaccumulate in the food web. This review serves as a primer for environmental health professionals to provide guidance on short term risk assessment of dioxin and to identify key findings for health and exposure assessment based on policies of different agencies. It also presents possible health effects of dioxins, mechanisms of action, toxic equivalency factors (TEFs), and dose-response characterization. Key studies related to toxicity values of dioxin-like compounds and their possible human health risk were identified through PubMed and supplemented with relevant studies characterized by reviewing the reference lists in the review articles and primary literature. Existing data decreases the scope of analyses and models in relevant studies to a manageable size by focusing on the set of important studies related to the perspective of developing toxicity values of DLCs. PMID- 26514570 TI - Metallothionein gene expression in embryos of the terrestrial snail (Cantareus aspersus) exposed to cadmium and copper in the Bordeaux mixture. AB - The response specificity of three metallothionein (MT) genes (CdMT, CuMT and Cd/CuMT) was assessed after long-term exposure (20 days) of Cantareus aspersus eggs to cadmium (Cd) (2 to 6 mg/L) or to the fungicide Bordeaux mixture (BM) (2.5 and 7.5 g/L). MT gene expression measured by quantitative real-time PCR (qRT-PCR) revealed that in the unexposed embryos, the transcript levels of the three MT genes decreased significantly through embryonic development. However, the CdMT gene was strongly upregulated with increasing Cd exposure concentration, whereas the transcript levels of the other two genes increased less pronouncedly, but significantly above an exposure concentration of 4 mg Cd/L. Upon exposure to BM, all three MT genes were significantly upregulated above a BM concentration of 2.5 g/L. It is concluded that long-term Cd exposure in hatched snails induced patterns of MT gene expression that differed from those obtained after short-term exposure (24 h). PMID- 26514569 TI - Antioxidant defense gene analysis in Brassica oleracea and Trifolium repens exposed to Cd and/or Pb. AB - This study focused on the expression analysis of antioxidant defense genes in Brassica oleracea and in Trifolium repens. Plants were exposed for 3, 10, and 56 days in microcosms to a field-collected suburban soil spiked by low concentrations of cadmium and/or lead. In both species, metal accumulations and expression levels of genes encoding proteins involved and/or related to antioxidant defense systems (glutathione transferases, peroxidases, catalases, metallothioneins) were quantified in leaves in order to better understand the detoxification processes involved following exposure to metals. It appeared that strongest gene expression variations in T. repens were observed when plants are exposed to Cd (metallothionein and ascorbate peroxidase upregulations) whereas strongest variations in B. oleracea were observed in case of Cd/Pb co-exposures (metallothionein, glutathione transferase, and peroxidase upregulations). Results also suggest that there is a benefit to use complementary species in order to better apprehend the biological effects in ecotoxicology. PMID- 26514571 TI - Trace metals in surface sediments of the Taiwan Strait: geochemical characteristics and environmental indication. AB - The concentration and geochemical fractionation of six trace metals related with environmental quality assessment, namely Cd, Cr, Cu, Ni, Pb, and Zn, in 30 surface sediments from both inshore and offshore areas of the Taiwan Strait were measured to investigate their distribution characteristics, evaluate their potential mobility, and assess their pollution status. The geoaccumulation index results indicated that, on average, the studied metals presented an order of Cd > Pb > Ni > Zn > Cu > Cr and were practically in uncontaminated status except Cd. The results of the sequential extraction analysis indicated that, on average, the studied metals were mostly accumulated in residual fraction except Cd whose concentration was the highest in the acid soluble fraction presenting a high risk to the environment, and their mobility decreased in the sequence of Cd > Pb > Ni > Cu > Zn > Cr. Based on the mean probable effect level quotients, the combination of the studied metals had an 8 % probability of being toxic at two sampling sites and had a 21 % probability of being toxic at the rest of sites. The spatial distribution of the studied metals in total concentrations and different geochemical fractions corroborated the previous findings about the possible sediment transportation routes in and around the Taiwan Strait. PMID- 26514572 TI - Traffic aerosol lobar doses deposited in the human respiratory system. AB - Aerosol pollution in urban environments has been recognized to be responsible for important pathologies of the cardiovascular and respiratory systems. In this perspective, great attention has been addressed to Ultra Fine Particles (UFPs < 100 nm), because they efficiently penetrate into the respiratory system and are capable of translocating from the airways into the blood circulation. This paper describes the aerosol regional doses deposited in the human respiratory system in a high-traffic urban area. The aerosol measurements were carried out on a curbside in downtown Rome, on a street characterized by a high density of autovehicular traffic. Aerosol number-size distributions were measured by means of a Fast Mobility Particle Sizer in the range from 5.6 to 560 nm with a 1 s time resolution. Dosimetry estimates were performed with the Multiple-Path Particle Dosimetry model by means of the stochastic lung model. The exposure scenario close to traffic is represented by a sequence of short-term peak exposures: about 6.6 * 1010 particles are deposited hourly into the respiratory system. After 1 h of exposure in proximity of traffic, 1.29 * 1010, 1.88 * 1010, and 3.45 * 1010 particles are deposited in the head, tracheobronchial, and alveolar regions. More than 95 % of such doses are represented by UFPs. Finally, according to the greater dose estimated, the right lung lobes are expected to be more susceptible to respiratory pathologies than the left lobes. PMID- 26514573 TI - Purification of industrial phosphoric acid (54 %) using Fe-pillared bentonite. AB - The current problem of excess impurities in industrial phosphoric acid (IPA) 54 % P2O5 makes phosphates industries look toward low-cost but efficient adsorbents. In the present study, iron-oxide-modified bentonite (Fe-PILB) was prepared and investigated as a possible adsorbent for the removal of organic matter (OM) like humic acid (HA), chromium (Cr(III)), and zinc (Zn(II)) from IPA aqueous solutions. These adsorbents were characterized using XRD, TEM, and BET. The adsorption of impurities is well described by the pseudo-second-order model. The results indicate that Fe-PILB has a good ability to resist co-existing anions and the low-pH condition of IPA and owns a relatively high-removal capacity of 80.42 and 25 % for OM, Cr(III), and Zn(II). The mechanism of adsorption may be described by the ligand and ion exchange that happened on the active sites. The selected order of adsorption OM > Cr(3+) > Zn(2+) showed the importance of the competitive phenomenon onto bentonite materials' pore adsorption. For the adsorption of OM at the low pH of IPA, H-bond complexation was the dominant mechanism. From the adsorption of heavy metals and OM complex compounds contained in IPA 54 % on Fe-PILB, the bridging of humic acid between bentonite and heavy metals (Zn(II) or Cr(III)) is proposed as the dominant adsorption mechanism (bentonite-HA-Me). Overall, the results obtained in this study indicate Fe pillared bentonite possesses a potential for the practical application of impurity (OM, Zn(II), and Cr(III)) removal from IPA aqueous solutions. PMID- 26514575 TI - Microfluidic Assisted Synthesis of Multipurpose Polymer Nanoassembly Particles for Fluorescence, LSPR, and SERS Activities. AB - Potential biomedical applications such as controlled delivery with sustained drug release profile demand for multifunctional polymeric particles of precise chemical composition and with welldefined physicochemical properties. The real challenge is to obtain the reproducible and homogeneous nanoparticles in a minimum number of preparation steps. Here, single-step nanoarchitectures of soft surface layered copolymer nanoparticles with a regular tuning in the size via micro flow-through assisted synthesis are reported. Interfacial copolymerization induces the controlled compartmentalization where a hydrophobic core adopts spherical shape in order to minimize the surface energy and simultaneously shelter in the hydrophilic shelllike surface layer. Surface layer can swell in the aqueous medium and allow controlled entrapping of functional hydrophobic nanoparticles in the hydrophilic interior via electrostatic interaction which can be particularly interesting for combined fluorescence activity. Furthermore, the nanoarchitecture of size and concentration controlled polymer-metal nanoassembly particles can be implemented as an ideal surface-enhanced Raman scattering substrate for detection of the trace amounts of various analytes. PMID- 26514574 TI - Complex stability and dynamic subunit interchange modulates the disparate activities of the yeast moonlighting proteins Hal3 and Vhs3. AB - Saccharomyces cerevisiae Hal3 and Vhs3 are moonlighting proteins, acting both as inhibitors of the serine/threonine protein phosphatase Ppz1 and as subunits (together with Cab3) of the unique heterotrimeric phosphopantothenoylcysteine decarboxylase (PPCDC) enzyme of Hemiascomycetous yeast. Both these roles are essential: PPCDC catalyses the third step of coenzyme A biosynthesis, while Ppz1 inhibition is required for regulation of monovalent cation homeostasis. However, the mechanisms by which these proteins' disparate activities are regulated are not well understood. The PPCDC domains (PDs) of Hal3, Vhs3 and Cab3 constitute the minimum requirement for these proteins to show both PPCDC activity and, in the case of Hal3 and Vhs3, to bind to Ppz1. Using these PD proteins as a model system to study the possibility of dynamic interchange between these roles, we provide evidence that Hal3 binds Ppz1 as a monomer (1:1 stoichiometry), requiring it to de-oligomerize from its usual homo- and heterotrimeric states (the latter having PPCDC activity). This de-oligomerization is made possible by structural features that set Hal3 apart from Vhs3, increasing its ability to undergo monomer exchange. These findings suggest that oligomer interchange may be a significant factor in the functional regulation of these proteins and their various unrelated (moonlighting) functions. PMID- 26514576 TI - Serial imaging and outcome prediction. PMID- 26514577 TI - An effective approach for modifying carbonaceous materials with niobium single sites to improve their catalytic properties. AB - In this paper we show a very simple route for the incorporation of catalytically active niobium species on the surface of carbon materials, such as graphene oxide, carbon nanotubes and activated carbon. Some existing methods of incorporating a transition metal on a support have involved co-precipitation or wet impregnation, to obtain the corresponding oxides. These methods, however, cause reduction in the specific area of the support and can also form large metal oxide particles with loss of metal exposure. Therefore, here we present a novel way to add catalytically active species on the surfaces of different types of carbon through the formation of interaction complexes between the metal precursor and the functional groups of the carbon matrix. Because of the excellent catalytic properties exhibited by the niobium species we choose the NH4[NbO(C2O4)2(H2O)2].2H2O salt as the model precursor. The characterization by XPS reveals the presence of the niobium species indicated by the displacement of the peaks between 206-212 eV related to the oxalate species according to the spectrum from pure niobium oxalate. Images obtained by TEM and SEM show the typical morphologies of carbonaceous materials without the niobium oxide formation signal, which indicates the presence of niobium complexes as isolated sites on the carbon surfaces. This new class of materials exhibited excellent properties as catalysts for pollutant oxidation. The presence of Nb promotes the catalytic activation of H2O2 generating hydroxyl radicals in situ, which allows their use in the organic compound oxidation processes. Tests for DBT oxidation indicate that Nb significantly improves the removal of such pollutants in biphasic reactions with removal around 90% under the tested conditions. Theoretical calculations showed that the most favorable adsorption model is an ionic complex presenting a DeltaG = -108.7 kcal mol(-1) for the whole adsorption process. PMID- 26514578 TI - Treatment with QiBaoMeiRan, a Chinese herbal formula, prevents bone loss in ovariectomized rat. AB - OBJECTIVE: Hormone replacement therapy has been used as an effective treatment for the prevention of bone loss in postmenopausal women. In our previous study, QiBaoMeiRan formula (QBMR) had estrogenic activity and could relieve symptoms of hot flushes and body weight increase induced by estrogen decline. However, no evidence base links QBMR to preventing bone loss. The aim of this study is to investigate the effect of QBMR on bone loss. METHODS: The ovariectomized rat model was established, and ovariectomized rats were treated with QBMR at doses of 0.875, 1.75, and 3.5 g/kg per day for 8 weeks. Biochemical parameters, bone mineral density, structural morphometric traits and histological characteristics of trabecular bone were assessed. RESULTS: QBMR treatment significantly decreased the increase in serum alkaline phosphatase, bone Gla-protein and C-telopeptide fragments of type I collagen and decreased the decline of serum calcium and phosphorus in the circulation of ovariectomized rats. QBMR completely corrected the decrease in bone mineral density in lumbar vertebrae (L4-L6) comparable to the sham group. In addition, QBMR treatment also significantly ameliorated the decrease of structural parameters of femur trabecular bone, bone volume fraction, trabecular number, trabecular thickness and bone mineral density as well as the increase in trabecular separation by micro-computerized tomography scanning. These were also confirmed by bone histological results that showed its protective action. CONCLUSIONS: Our results indicated that QBMR had a definite anti-bone loss effect and will have potential to be used for the treatment of postmenopausal osteoporosis. PMID- 26514579 TI - Aerosolized Non-viral Nucleic Acid Delivery in the Vaginal Tract of Pigs. AB - PURPOSE: The human pathogen Chlamydia trachomatis is worldwide the leading cause of bacterial sexually transmitted disease. Nasal or vaginal nucleic acid vaccination is a promising strategy for controlling genital Chlamydia trachomatis infections. Since naked nucleic acids are generally not efficiently taken up by cells, they are often complexed with carriers that facilitate their intracellular delivery. METHODS: In the current study, we screened a variety of commonly used non-viral gene delivery carriers for their ability to transfect newborn pig tracheal cells. The effect of aerosolization on the physicochemical properties and transfection efficiency of the complexes was also evaluated in vitro. Subsequently, a pilot experiment was performed in which the selected complexes were aerosolized in the vaginal tract of pigs. RESULTS: Both mRNA and pDNA containing lipofectamine and ADM70 complexes showed promise for protein expression in vitro, before and after aerosolization. In vivo, only lipofectamine/pDNA complexes resulted in high protein expression levels 24 h following aerosolization. This correlates to the unexpected observation that the presence of vaginal mucus increases the efficiency of lipofectamine/pDNA complexes 3-fold, while the efficiency of lipofectamine/mRNA complexes and ADM70/mRNA and ADM70/pDNA complexes decreased. CONCLUSIONS: As aerosolization was an easy and effective method to deliver complexes to the vaginal tract of pigs, we believe this application technique has future potential for both vaginal and perhaps nasal vaccination using non-viral gene delivery vectors. PMID- 26514580 TI - Do, don't and don't know: guidelines for medical education with a difference. PMID- 26514581 TI - Brain Mapping-Based Model of Delta(9)-Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix. AB - Cannabinoids receive increasing interest as analgesic treatments. However, the clinical use of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) has progressed with justified caution, which also owes to the incomplete mechanistic understanding of its analgesic effects, in particular its interference with the processing of sensory or affective components of pain. The present placebo-controlled crossover study therefore focused on the effects of 20 mg oral THC on the connectivity between brain areas of the pain matrix following experimental stimulation of trigeminal nocisensors in 15 non-addicted healthy volunteers. A general linear model (GLM) analysis identified reduced activations in the hippocampus and the anterior insula following THC administration. However, assessment of psychophysiological interaction (PPI) revealed that the effects of THC first consisted in a weakening of the interaction between the thalamus and the secondary somatosensory cortex (S2). From there, dynamic causal modeling (DCM) was employed to infer that THC attenuated the connections to the hippocampus and to the anterior insula, suggesting that the reduced activations in these regions are secondary to a reduction of the connectivity from somatosensory regions by THC. These findings may have consequences for the way THC effects are currently interpreted: as cannabinoids are increasingly considered in pain treatment, present results provide relevant information about how THC interferes with the affective component of pain. Specifically, the present experiment suggests that THC does not selectively affect limbic regions, but rather interferes with sensory processing which in turn reduces sensory-limbic connectivity, leading to deactivation of affective regions. PMID- 26514582 TI - A Preliminary Prospective Study of an Escalation in 'Maximum Daily Drinks', Fronto-Parietal Circuitry and Impulsivity-Related Domains in Young Adult Drinkers. AB - Excessive alcohol use in young adults is associated with greater impulsivity and neurobiological alterations in executive control systems. The maximum number of drinks consumed during drinking occasions ('MaxDrinks') represents a phenotype linked to vulnerability of alcohol use disorders, and an increase, or 'escalation', in MaxDrinks may be indicative of greater risk for problematic drinking. Thirty-six young adult drinkers performed a Go/No-Go task during fMRI, completed impulsivity-related assessments, and provided monthly reports of alcohol use during a 12-month follow-up period. Participants were characterized by MaxDrinks at baseline and after follow-up, identifying 18 escalating drinkers and 18 constant drinkers. Independent component analysis was used to investigate functional brain networks associated with response inhibition, and relationships with principal component analysis derived impulsivity-related domains were examined. Greater baseline MaxDrinks was associated with an average reduction in the engagement of a right-lateralized fronto-parietal functional network, while an escalation in MaxDrinks was associated with a greater difference in fronto parietal engagement between successful inhibitions and error trials. Escalating drinkers displayed greater impulsivity/compulsivity-related domain scores that were positively associated with fronto-parietal network engagement and change in MaxDrinks during follow-up. In young adults, an escalating MaxDrinks trajectory was prospectively associated with altered fronto-parietal control mechanisms and greater impulsivity/compulsivity scores. Continued longitudinal studies of MaxDrinks trajectories, functional network activity, and impulsivity/compulsivity related features may lend further insight into an intermediate phenotype vulnerable for alcohol use and addictive disorders. PMID- 26514583 TI - Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids. AB - Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders. PMID- 26514585 TI - Rational design of therapeutic mAbs against aggregation through protein engineering and incorporation of glycosylation motifs applied to bevacizumab. AB - The aggregation of biotherapeutics is a major hindrance to the development of successful drug candidates; however, the propensity to aggregate is often identified too late in the development phase to permit modification to the protein's sequence. Incorporating rational design for the stability of proteins in early discovery has numerous benefits. We engineered out aggregation-prone regions on the Fab domain of a therapeutic monoclonal antibody, bevacizumab, to rationally design a biobetter drug candidate. With the purpose of stabilizing bevacizumab with respect to aggregation, 2 strategies were undertaken: single point mutations of aggregation-prone residues and engineering a glycosylation site near aggregation-prone residues to mask these residues with a carbohydrate moiety. Both of these approaches lead to comparable decreases in aggregation, with an up to 4-fold reduction in monomer loss. These single mutations and the new glycosylation pattern of the Fab domain do not modify binding to the target. Biobetters with increased stability against aggregation can therefore be generated in a rational manner, by either removing or masking the aggregation prone region or crowding out protein-protein interactions. PMID- 26514584 TI - Essential Contributions of Serotonin Transporter Inhibition to the Acute and Chronic Actions of Fluoxetine and Citalopram in the SERT Met172 Mouse. AB - Depression is a common mental illness and a leading cause of disability. The most widely prescribed antidepressant medications are serotonin (5-HT) selective reuptake inhibitors (SSRIs). Although there is much support for 5-HT transporter (SERT) antagonism as a basis of antidepressant efficacy, this evidence is indirect and other targets and mechanisms have been proposed. In order to distinguish SERT-dependent and -independent effects of SSRIs, we developed a knock-in mouse model whereby high-affinity interactions of many antidepressants at SERT have been ablated via knock-in substitution (SERT Met172) without disrupting 5-HT recognition or uptake. Here we utilize the C57BL/6J SERT Met172 model to evaluate SERT dependence for the actions of two widely prescribed SSRIs, fluoxetine and citalopram, in tests sensitive to acute and chronic actions of antidepressants. In the tail suspension and forced swim tests, fluoxetine and citalopram fail to reduce immobility in SERT Met172 mice. In addition, SERT Met172 mice are insensitive to chronic fluoxetine and citalopram administration in the novelty induced hypophagia test (NIH) and fail to exhibit enhanced proliferation or survival of hippocampal stem cells. In both acute and chronic studies, SERT Met172 mice maintained sensitivity to paroxetine, an antidepressant that is unaffected by the Met172 mutation. Together, these studies provide definitive support for an essential role of SERT antagonism in the acute and chronic actions of two commonly used SSRIs in these tests, and reinforce the utility of the SERT Met172 model for isolating SERT/5-HT contributions of drug actions in vivo. PMID- 26514586 TI - Downregulation of toll-like receptor 4 induces suppressive effects on hepatitis B virus-related hepatocellular carcinoma via ERK1/2 signaling. AB - BACKGROUND: Hepatitis B virus (HBV) infection is a major risk factor which can lead to development of hepatocellular carcinoma (HCC). In this study, we aimed to explore the effects of toll-like receptor 4 (TLR4) downregulation on the growth and survival of HBV-related HCC cells and to examine the molecular mechanisms been involved. METHODS: The expression levels of TLR4 were examined in a panel of HCC cell lines (HepG2, SMMC7721, Huh7, HepG2.2.15 and Hep3B). The effects of TLR4 downregulation on the proliferation, apoptosis, and tumorigenicity of HBV-related HepG2.2.15 cells were determined. The effects of TLR4 downregulation on multiple signaling pathways were also measured. Co-immunoprecipitation and immunofluoresence staining assays were performed to investigate the interaction between TLR4 and HBV X protein (HBx). RESULTS: The mRNA and protein levels of TLR4 were significantly increased in HepG2.2.15 cells than those in the other cells which have been studied. Downregulation of TLR4 significantly decreased the proliferation and induced G2/M cell cycle arrest and apoptosis in HepG2.2.15 cells. TLR4 depletion inhibited HepG2.2.15 cell colony formation and tumor growth in nude mice. TLR4 silencing decreased the phosphorylation of ERK1/2 but not JNK1/2, p38, or NF-kappaB. Chemical inhibition of ERK1/2 approximately phenocopied the growth-suppressive effect of TLR4 downregulation on HepG2.2.15 cells. In addition, TLR4 showed a physical interaction with HBx. CONCLUSIONS: Taken together, TLR4 plays a tumor-promoting role in HBV-related HCC cells, which is associated with regulation of ERK1/2 activation and interaction with HBx. Therefore, TLR4 may be a potential therapeutic target for HBV-related HCC. PMID- 26514587 TI - Patient's lung cancer diagnosis as a cue for relatives' smoking cessation: evaluating the constructs of the teachable moment. AB - BACKGROUND: To understand whether patient-reported experiences with lung cancer may create teachable moments (TM) for their relatives as evidenced by shifts in their risk perceptions, affective response, and self-image and in turn, motivation to quit smoking. METHODS: Patients at a comprehensive cancer center (n = 152) completed a survey within 6 months of lung cancer diagnosis to assess their cancer-related symptoms and openness and enumerated relatives who were smokers. Relative smokers (n = 218) then completed a survey assessing their risk perceptions, affective response, and self-image as a smoker related to the patient's diagnosis (TM mechanisms), and their motivation to quit smoking. Cross sectional mediation and moderation analyses were conducted to explore the links between patient-reported experiences, and relatives' TM mechanisms, and motivation to quit smoking. RESULTS: Relative-reported affect was a significant mediator of the association between patient-reported symptoms and relative smoker's desire to quit. Relatives' self-image was a significant moderator of the association between patient-reported symptoms and relative smoker's desire to quit, such that patients' reported symptoms were associated with relatives' desire to quit only when the relative smoker reported a generally positive self image as a smoker. No evidence was found for moderated mediation. However, the link between symptoms and negative affect was moderated by perceptions of risk. CONCLUSION: Whether smokers experience a family member's lung cancer as a TM is influenced by multiple interrelated cognitive and affective factors that warrant further exploration. Clearer understanding of these factors could inform how to re-invigorate and sustain this motivation to promote concrete actions toward smoking cessation. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26514588 TI - Enterovibrio pacificus sp. nov., isolated from seawater, and emended descriptions of Enterovibrio coralii and the genus Enterovibrio. AB - A Gram-stain-negative, elliptical and facultatively anaerobic strain, designated SW014T, motile by means of a single polar flagellum and positive for poly-beta hydroxybutyrate accumulation, was isolated from surface seawater of the South Pacific Gyre, during the Integrated Ocean Drilling Program Expedition 329. The strain was able to grow at 10-37 degrees C (optimum 28 degrees C). Growth was observed at NaCl concentrations (w/v) of 1-7 % (optimum 3-4 %). The pH range for growth was 7.0-9.0 (optimum pH 8.0). Phylogenetic analysis based on 16S rRNA gene sequences and multilocus sequence analysis indicated that strain SW014T belongs to the genus Enterovibrio within the family Vibrionaceae and is related most closely to Enterovibrio coralii LMG 22228T with 96.3, 83.7, 95.0, 77.1, 84.1 and 85.8 % sequence similarity based on 16S rRNA, recA, rpoA, rpoD, pyrH and ftsZ genes, respectively. The predominant cellular fatty acids were C16 : 1omega7c and/or C16 : 1omega6c, C16 : 0, and C18 : 1omega7c and/or C18 : 1omega6c. The respiratory quinone was ubiquinone-8 (Q-8). The polar lipids of strain SW014T comprised phosphatidylethanolamine, glycolipid, two unidentified aminolipids, two unidentified phospholipids and two unidentified polar lipids. The DNA G+C content was 44.8 mol%. Combining phylogenetic analysis, phenotypic characteristics and chemotaxonomic studies, strain SW014T represents a novel species of the genus Enterovibrio, for which the name Enterovibrio pacificus sp. nov. is proposed. The type strain is SW014T ( = KCTC 42425T = MCCC 1K00500T). Emended descriptions of Enterovibrio coralii and of the genus Enterovibrio are also provided. PMID- 26514589 TI - Ayahuasca Tourism: Participants in Shamanic Rituals and their Personality Styles, Motivation, Benefits and Risks. AB - Ayahuasca continues to attract tourists to South America, where there has been a growth in the number of centers offering hallucinogenic ayahuasca experiences. The aims of this study were to (1) discover the reasons foreigners seek this type of experience; (2) define what an ayahuasca experience entails; (3) discover subjective perceptions of ayahuasca's benefits and risks; and (4) describe personality styles of participants using the personality questionnaire (PSSI). Participants (N=77) were persons who had travelled to South America to use ayahuasca. Among the most frequent motivations were curiosity, desire to treat mental health problems, need for self-knowledge, interest in psychedelic medicine, spiritual development, and finding direction in life. Frequently mentioned benefits included self-knowledge, change in the way one relates to oneself, spiritual development, improved interpersonal relations, overcoming mental and physical problems, and gaining a new perspective on life. Stated potential risks included lack of trust in the shaman or organizer, inaccurate information provided by the shaman or organizer, and exposure to dangerous situations. PSSI results showed that people using ayahuasca scored significantly above the norm on the scales of intuition, optimism, ambition, charm, and helpfulness and significantly lower on the scales of distrust and quietness. PMID- 26514590 TI - Emergency abdominal MRI: current uses and trends. AB - When evaluating the abdomen in the emergency setting, CT and ultrasound are the imaging modalities of choice, mainly because of accessibility, speed and lower relative cost. CT has the added benefit of assessing the whole abdomen for a wide spectrum of gastrointestinal disease, whereas ultrasound has the benefit of avoiding ionizing radiation. MRI is another tool that has demonstrated increasing utility in the emergency setting and also avoids the use of ionizing radiation. MRI also has the additional advantage of excellent soft-tissue contrast. However, widespread use of MRI in the emergency setting is limited by availability and relative cost. Despite such limitations, advances in MRI technology, including improved pulse sequences and coil technology and increasing clinician awareness of MRI, have led to an increased demand in abdominal MRI in the emergency setting. This is particularly true in the evaluation of acute pancreatitis; choledocholithiasis with or without cholecystitis; acute appendicitis, particularly in pregnant patients; and, in some cases, Crohn's disease. In cases of pancreatitis and Crohn's disease, MRI also plays a role in subsequent follow up examinations. PMID- 26514591 TI - The potential link between sugar-sweetened beverage consumption and post-exercise airway narrowing across puberty: a longitudinal cohort study. AB - OBJECTIVE: The prevalence of asthma is rising, presenting serious public health challenges. Recent data suggest that sugar-sweetened beverage (SSB) consumption plays a role in asthma aetiology. The purpose of the present study was to determine whether SSB consumption is linked to post-exercise airway narrowing (predictor of asthma development) across puberty. DESIGN: Participants completed pulmonary function tests, physical activity and dietary habit questionnaires, and an exercise test to exhaustion. SETTING: Community in Manhattan, Kansas, USA. SUBJECTS: We recruited ten boys and ten girls from an original cohort of forty participants tested in our laboratory approximately 5 years prior. Participants were aged 9.7 (sd 0.9) years at baseline and 14.7 (sd 0.9) years at follow-up. RESULTS: Pre-puberty, boys consumed 6.8 (sd 4.8) servings/week and girls consumed 6.9 (sd 3.7) servings/week, while post-puberty boys consumed 11.5 (sd 5.3) servings/week and girls consumed 7.7 (sd 4.3) servings/week. Using Pearson correlation, SSB consumption was not significantly related to post-exercise airway narrowing at pre-puberty (r=-0.35, P=0.130). In linear regression analyses, SSB consumption was significantly related to post-exercise airway narrowing post-puberty before (standardized beta=-0.60, P=0.005) but not after (standardized beta=-0.33, P=0.211) adjustment for confounders. Change in SSB consumption from pre- to post-puberty was significantly associated with post exercise airway narrowing post-puberty (r=-0.61, P=0.010) and change in post exercise airway narrowing from pre- to post-puberty (r=-0.45, P=0.048) when assessed via Pearson correlations. CONCLUSIONS: These findings suggest a possible link between SSB consumption and asthma development during maturation. Reduced SSB intake may be a possible public health avenue for blunting rising asthma prevalence. PMID- 26514592 TI - Medications between psychiatric and addictive disorders. AB - INTRODUCTION: Many epidemiological studies have revealed a frequent co-occurrence of psychiatric and substance use disorders. The term used in the literature to refer to this co-occurrence is dual diagnosis. The high prevalence of dual diagnosis has led physicians to observe the effects of medication prescribed to treat psychiatric disorders on the co-occurring substance use disorder and vice versa. The concept of medications between psychiatric and addictive disorders stems from these clinical observations, alongside which, however, it has developed from the observation that both psychiatric and substance use disorders share common neurobiological pathways and trigger common cognitive disorders. This has led researchers to develop medications on the basis of neurobiological and cognitive rationales. MATERIAL AND METHOD: In our article, we review peculiar medications based on neurobiological and cognitive rationales and that have an impact in both psychiatric and addictive disorders. RESULTS: We highlight how interesting these new prescriptions are for clinical observation and for the treatment of patients suffering from dual diagnosis. CONCLUSION: We then go on to discuss the interest in them from the perspective of clinical practice and clinical research, in that the development of medications to treat dual diagnosis helps to further our knowledge of both psychiatric and substance use disorders. PMID- 26514593 TI - Routing of surface plasmons in silver nanowire networks controlled by polarization and coating. AB - Controllable propagation of electromagnetic energy in plasmonic nanowaveguides is of great importance for building nanophotonic circuits. Here, we studied the routing of surface plasmons in silver nanowire structures by combining experiments and electromagnetic simulations. The superposition of different plasmon modes results in the tunable near field patterns of surface plasmons on the nanowire. Using the quantum dot fluorescence imaging technique, we experimentally demonstrate that the near field distribution on the nanowire controls the surface plasmon transmission in the nanowire networks. By controlling the polarization of the input light or by controlling the dielectric coating on the nanowire to modulate the plasmon field distribution and guarantee the strong local field intensity at the connecting junction, the surface plasmons can be efficiently routed to the connected nanowires. Depositing a thin layer of Al2O3 film onto the nanowires can reverse the polarization dependence of the output intensity at the nanowire terminals. These results are instructive for designing functional plasmonic nanowire networks and metal-nanowire-based nanophotonic devices. PMID- 26514594 TI - A new species of Torrestrongylus (Trichostrongylidae, Anoplostrongylinae) from Macrotus waterhousii (Chiroptera: Phyllostomidae) in Central Mexico. AB - A new species of nematode, Torrestrongylus tetradorsalis n. sp., is described herein, based on specimens recovered from the small intestine of the leaf-nosed bat, Macrotus waterhousii, from the Biosphere Reserve "Sierra de Huautla" in the state of Morelos, Mexico. The new species is included in Torrestrongylus because it features a bursa of the type 3 - 2, a divided cephalic vesicle with an anterior half in the shape of an umbrella, and a posterior widened half. The new species can be distinguished from the only other congener T. torrei Perez Vigueras, 1935 by four key features: first, by the absence of cervical alae in both males and females; second, by the relatively longer second half of the cephalic cap; third, by the configuration of the dorsal ray, that does not have a medial terminal ray, and finally, by the structure of the spicules. This is the second species in the genus, previously known from bats of the families Phyllostomidae and Molossidae in Cuba, and now in Mexico. PMID- 26514595 TI - Fatal Toxoplasma gondii infection in the giant panda. AB - Toxoplasma gondii can infect nearly all warm-blooded animals. We report an acute fatal T. gondii infection in the endangered giant panda (Ailuropoda melanoleuca) in a zoo in China, characterized by acute gastroenteritis and respiratory symptoms. T. gondii infection was confirmed by immunological and molecular methods. Multilocus nested PCR-RFLP revealed clonal type I at the SAG1 and c29-2 loci, clonal type II at the SAG2, BTUB, GRA6, c22-8, and L358 loci, and clonal type III at the alternative SAG2 and SAG3 loci, thus, a potential new genotype of T. gondii in the giant panda. Other possible pathogens were not detected. To our knowledge, this is the first report of clinical toxoplasmosis in a giant panda. PMID- 26514596 TI - Joint modelling of longitudinal and survival data: incorporating delayed entry and an assessment of model misspecification. AB - A now common goal in medical research is to investigate the inter-relationships between a repeatedly measured biomarker, measured with error, and the time to an event of interest. This form of question can be tackled with a joint longitudinal survival model, with the most common approach combining a longitudinal mixed effects model with a proportional hazards survival model, where the models are linked through shared random effects. In this article, we look at incorporating delayed entry (left truncation), which has received relatively little attention. The extension to delayed entry requires a second set of numerical integration, beyond that required in a standard joint model. We therefore implement two sets of fully adaptive Gauss-Hermite quadrature with nested Gauss-Kronrod quadrature (to allow time-dependent association structures), conducted simultaneously, to evaluate the likelihood. We evaluate fully adaptive quadrature compared with previously proposed non-adaptive quadrature through a simulation study, showing substantial improvements, both in terms of minimising bias and reducing computation time. We further investigate, through simulation, the consequences of misspecifying the longitudinal trajectory and its impact on estimates of association. Our scenarios showed the current value association structure to be very robust, compared with the rate of change that we found to be highly sensitive showing that assuming a simpler trend when the truth is more complex can lead to substantial bias. With emphasis on flexible parametric approaches, we generalise previous models by proposing the use of polynomials or splines to capture the longitudinal trend and restricted cubic splines to model the baseline log hazard function. The methods are illustrated on a dataset of breast cancer patients, modelling mammographic density jointly with survival, where we show how to incorporate density measurements prior to the at-risk period, to make use of all the available information. User-friendly Stata software is provided. PMID- 26514597 TI - Putting RNA to work: Translating RNA fundamentals into biotechnological engineering practice. AB - Synthetic biology, in close concert with systems biology, is revolutionizing the field of metabolic engineering by providing novel tools and technologies to rationally, in a standardized way, reroute metabolism with a view to optimally converting renewable resources into a broad range of bio-products, bio-materials and bio-energy. Increasingly, these novel synthetic biology tools are exploiting the extensive programmable nature of RNA, vis-a-vis DNA- and protein-based devices, to rationally design standardized, composable, and orthogonal parts, which can be scaled and tuned promptly and at will. This review gives an extensive overview of the recently developed parts and tools for i) modulating gene expression ii) building genetic circuits iii) detecting molecules, iv) reporting cellular processes and v) building RNA nanostructures. These parts and tools are becoming necessary armamentarium for contemporary metabolic engineering. Furthermore, the design criteria, technological challenges, and recent metabolic engineering success stories of the use of RNA devices are highlighted. Finally, the future trends in transforming metabolism through RNA engineering are critically evaluated and summarized. PMID- 26514598 TI - Loneliness in Early Adolescence: Friendship Quantity, Friendship Quality, and Dyadic Processes. AB - Friendship quantity and quality are related to adolescent loneliness, but the exact link between these constructs is not well understood. The present study aimed to examine whether adolescents' perception of friendship quantity and quality, and the perceptions of their peers, were related to loneliness. We examined the relation between loneliness and the number of unilateral and reciprocal friendships and compared the views of best friendship quality. Overall, 1,172 Dutch adolescents (49.1% male, M age = 12.81, SD = .43) nominated their friends and rated their friendship quality. Friendship quantity was measured using sociometrics to distinguish reciprocated and unilateral (i.e., one sided) friendships. The analyses indicated that loneliness was related to fewer reciprocal and unilateral-received friendships (i.e., the adolescent received a friendship nomination but did not reciprocate that nomination) and a lower quality of best friendship. Actor-partner interdependence analyses revealed that adolescents' loneliness was related to a less positive evaluation of their friendship, as reported by adolescents themselves (i.e., a significant actor effect) but not by their friends (i.e., nonsignificant partner effect). These findings (a) indicate that loneliness is negatively related to the number of friends adolescents have, as perceived by themselves and their peers and (b) suggest that, once a friendship is established, lonely adolescents may interpret the friendship quality less positively compared to their friends. Implications of these findings for our current understanding of adolescent loneliness are discussed, and suggestions for future research are outlined. PMID- 26514599 TI - Retraction: Influence of maternal diet during lactation and use of formula feeds on development of atopic eczema in high risk infants. PMID- 26514600 TI - A history of the American Board of Surgery: vignettes from the certifying examination: The Edgar J. Poth Memorial Lecture. AB - The American Board of Surgery was established in 1937 to certify surgeons who through training, experience, and examination meet the highest standards of surgical care. This lecture was given as the Edgar Poth lecture at the April 2015 meeting of the Southwestern Surgical Congress. Dr Poth was a surgical educator from the University of Texas Medical Branch, Galveston who was President of the Southwestern in 1963. The paper presents the history of the founding of the American Board of Surgery, with particular emphasis on the certifying examination Part 2. Vignettes of occurrences associated with the "Oral" examination are given. The examination has changed substantially from a 2-day event involving an actual surgical procedure to the 90-minute quiz given today. The oral examinations remain an important part in the process of certification of surgeons of the highest quality. PMID- 26514601 TI - Discordance of histopathologic parameters in cutaneous melanoma: Clinical implications. AB - BACKGROUND: Histopathologic analysis remains the gold standard for the diagnosis of melanoma, however previous studies have shown a substantial rate of interobserver variability in the evaluation of melanocytic lesions. OBJECTIVE: We sought to evaluate discordance in the histopathological diagnosis and microstaging parameters of melanoma and subsequent impact on clinical management. METHODS: This was a retrospective review of 588 cases of cutaneous melanoma and melanoma in situ from January 2009 to December 2014 that were referred to Emory University Hospital, Atlanta, GA, for treatment. Per institutional policy, all outside melanoma biopsy specimens were reviewed internally. Outside and institutional reports were compared. RESULTS: Disagreement between outside and internal reports resulted in a change in American Joint Committee on Cancer pathologic stage in 114/588 (19%) cases, resulting in a change in management based on National Comprehensive Cancer Network guidelines in 105/588 (18%) cases. LIMITATIONS: Given the retrospective nature of data collection and the bias of a tertiary care referral center, cases in this study may not be representative of all melanoma diagnoses. CONCLUSION: These findings confirm consistent subjectivity in the histopathologic interpretation of melanoma. This study emphasizes that a review of the primary biopsy specimen may lead to significant changes in tumor classification, resulting in meaningful changes in clinical management. PMID- 26514602 TI - Branched phospholipids render lipid vesicles more susceptible to membrane-active peptides. AB - Iso- and anteiso-branched lipids are abundant in the cytoplasmic membranes of bacteria. Their function is assumed to be similar to that of unsaturated lipids in other organisms - to maintain the membrane in a fluid state. However, the presence of terminally branched membrane lipids is likely to impact other membrane properties as well. For instance, lipid acyl chain structure has been shown to influence the activity of antimicrobial peptides. Moreover, the development of resistance to antimicrobial agents in Staphylococcus aureus is accompanied by a shift in the fatty acid composition toward a higher fraction of anteiso-branched lipids. Little is known about how branched lipids and the location of the branch point affect the activity of membrane-active peptides. We hypothesized that bilayers containing lipids with low phase transition temperatures would tend to exclude peptides and be less susceptible to peptide induced perturbation than those made from higher temperature melting lipids. To test this hypothesis, we synthesized a series of asymmetric phospholipids that only differ in the type of fatty acid esterified at the sn-2 position of the lipid glycerol backbone. We tested the influence of acyl chain structure on peptide activity by measuring the kinetics of release from dye-encapsulated lipid vesicles made from these synthetic lipids. The results were compared to those obtained using vesicles made from S. aureus and Staphylococcus sciuri membrane lipid extracts. Anteiso-branched phospholipids, which melt at very low temperatures, produced lipid vesicles that were only slightly less susceptible to peptide-induced dye release than those made from the iso-branched isomer. However, liposomes made from bacterial phospholipid extracts were generally much more resistant to peptide-induced perturbation than those made from any of the synthetic lipids. The results suggest that the increase in the fraction of anteiso-branched fatty acids in antibiotic-resistant strains of S. aureus is unlikely to be the sole factor responsible for the observed increased antibiotic resistance. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. PMID- 26514603 TI - Molecular mechanisms of membrane targeting antibiotics. AB - The bacterial membrane provides a target for antimicrobial peptides. There are two groups of bacteria that have characteristically different surface membranes. One is the Gram-negative bacteria that have an outer membrane rich in lipopolysaccharide. Several antimicrobials have been found to inhibit the synthesis of this lipid, and it is expected that more will be developed. In addition, antimicrobial peptides can bind to the outer membrane of Gram-negative bacteria and block passage of solutes between the periplasm and the cell exterior, resulting in bacterial toxicity. In Gram-positive bacteria, the major bacterial lipid component, phosphatidylglycerol can be chemically modified by bacterial enzymes to convert the lipid from anionic to cationic or zwitterionic form. This process leads to increased levels of resistance of the bacteria against polycationic antimicrobial agents. Inhibitors of this enzyme would provide protection against the development of bacterial resistance. There are antimicrobial agents that directly target a component of bacterial cytoplasmic membranes that can act on both Gram-negative as well as Gram-positive bacteria. Many of these are cyclic peptides with a rigid binding site capable of binding a lipid component. This binding targets antimicrobial agents to bacteria, rather than being toxic to host cells. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. PMID- 26514604 TI - CNS myelin structural modification induced in vitro by phospholipases A2. AB - Myelin is the self-stacked membrane surrounding axons; it is also the target of several pathological and/or neurodegenerative processes like multiple sclerosis. These processes involve, among others, the hydrolytic attack by phospholipases. In this work we describe the changes in isolated myelin structure after treatment with several secreted PLA2 (sPLA2), by using small angle x-ray scattering (SAXS) measurements. It was observed that myelin treated with all the tested sPLA2s (from cobra and bee venoms and from pig pancreas) preserved the lamellar structure but displayed an enlarged separation between membranes in certain zones. Additionally, the peak due to membrane asymmetry was clearly enhanced. The coherence length was also lower than the non-treated myelin, indicating increased disorder. These SAXS results were complemented by Langmuir film experiments to follow myelin monolayer hydrolysis at the air/water interface by a decrease in electric surface potential at different surface pressures. All enzymes produced hydrolysis with no major qualitative difference between the isoforms tested. PMID- 26514605 TI - Retrospective Analysis of Delayed Intraparenchymal Hemorrhage after Flow-Diverter Treatment: Presentation of a Retrospective Multicenter Trial. AB - BACKGROUND AND PURPOSE: Intracranial aneurysm treatment with flow diverters has shown satisfying results in terms of aneurysm occlusion, and while some cases of delayed intraparenchymal hemorrhage have been described, no systematic analysis of the risk factors affecting its occurrence has been conducted in a large series of patients. This retrospective analysis of delayed intraparenchymal hemorrhage after flow-diverter treatment is a multicenter, retrospective study using a large series of treated patients to analyze factors affecting the occurrence of delayed intraparenchymal hemorrhage. MATERIALS AND METHODS: Patients treated with flow diverters and presenting with delayed intraparenchymal hemorrhage were included from December 2007 to December 2014 in 7 participating centers in France. Patient and aneurysm characteristics were recorded as were characteristics of bleeding (size, lateralization, and time to bleed), treatment, and clinical outcome after 1, 3, and 6 months. RESULTS: Delayed intraparenchymal hemorrhage occurred in 11 patients between 1 and 21 days after the procedure. In 10 of these patients, hemorrhages were ipsilateral to the treated aneurysms. Five of the 11 underwent surgery, and 9 of the 11 had good clinical outcomes at 6 months (mRS <=2). CONCLUSIONS: The pathogenesis of delayed intraparenchymal hemorrhage occurring after flow-diverter treatment remains unclear. The multidisciplinary management of delayed intraparenchymal hemorrhage yields a relatively low morbidity mortality rate compared with the initial clinical presentation. PMID- 26514606 TI - Prominence of Medullary Veins on Susceptibility-Weighted Images Provides Prognostic Information in Patients with Subacute Stroke. AB - BACKGROUND AND PURPOSE: The demonstration of prominent medullary veins in the deep white matter ipsilateral to acute ischemic stroke has been shown to predict poor clinical outcome. We have investigated the prognostic implications of prominent medullary veins in patients with subacute stroke who present outside the therapeutic window for revascularization therapy. MATERIALS AND METHODS: Forty-three consecutive patients with ischemic stroke in the middle cerebral artery territory presenting within 3-7 days of ictus were enrolled. The presence of prominent medullary veins in the periventricular white matter of the ipsilateral and contralateral medullary vein hemispheres was recorded. Perfusion weighted imaging was used to calculate differences in hemispheric CBF from corresponding areas. Clinical outcome was classified as good if the modified Rankin Scale score was <3. RESULTS: Prominent medullary veins were observed in 24/43 patients with 14 ipsilateral medullary veins and 10 contralateral medullary veins. The ipsilateral medullary vein was independently associated with poor outcome (odds ratio, 11.19; P = .046). The contralateral medullary vein was not independently predictive of outcome but was significantly more common in patients with good outcome (90.0% contralateral medullary veins). A mean 64.5% decrease and a 52.4% increase of differences in hemispheric CBF were found in ipsilateral medullary veins and contralateral medullary veins, respectively. CONCLUSIONS: The ipsilateral medullary vein was a significant predictive biomarker of poor clinical outcome after stroke and was associated with hypoperfusion. The contralateral medullary vein was associated with good clinical outcome, and we hypothesize that prominent contralateral medullary veins indirectly reflect increased CBF in the ipsilateral hemisphere due to spontaneous recanalization or collateral flow. PMID- 26514607 TI - Multimodal Imaging in Malignant Brain Tumors: Enhancing the Preoperative Risk Evaluation for Motor Deficits with a Combined Hybrid MRI-PET and Navigated Transcranial Magnetic Stimulation Approach. AB - BACKGROUND AND PURPOSE: Motor deficits in patients with brain tumors are caused mainly by irreversible infiltration of the motor network or by indirect mass effects; these deficits are potentially reversible on tumor removal. Here we used a novel multimodal imaging approach consisting of structural, functional, and metabolic neuroimaging to better distinguish these underlying causes in a preoperative setting and determine the predictive value of this approach. MATERIALS AND METHODS: Thirty patients with malignant brain tumors involving the central region underwent a hybrid O-(2-[(18)F]fluoroethyl)-L-tyrosine-PET-MR imaging and motor mapping by neuronavigated transcranial magnetic stimulation. The functional maps served as localizers for DTI tractography of the corticospinal tract. The spatial relationship between functional tissue (motor cortex and corticospinal tract) and lesion volumes as depicted by structural and metabolic imaging was analyzed. RESULTS: Motor impairment was found in nearly all patients in whom the contrast-enhanced T1WI or PET lesion overlapped functional tissue. All patients who functionally deteriorated after the operation showed such overlap on presurgical maps, while the absence of overlap predicted a favorable motor outcome. PET was superior to contrast-enhanced T1WI for revealing a motor deficit before the operation. However, the best correlation with clinical impairment was found for T2WI lesion overlap with functional tissue maps, but the prognostic value for motor recovery was not significant. CONCLUSIONS: Overlapping contrast-enhanced T1WI or PET-positive signals with motor functional tissue were highly indicative of motor impairment and predictive for surgery-associated functional outcome. Such a multimodal diagnostic approach may contribute to the risk evaluation of operation-associated motor deficits in patients with brain tumors. PMID- 26514608 TI - WEB Treatment of Intracranial Aneurysms: Clinical and Anatomic Results in the French Observatory. AB - BACKGROUND AND PURPOSE: Flow disruption with the WEB device is a new technique for the endovascular treatment of wide-neck bifurcation aneurysms. To obtain precise data regarding the safety and efficacy of this treatment with high quality methodology, the prospective French Observatory study was conducted. Analysis of these data is presented, including 1-year follow-up. MATERIALS AND METHODS: Patients with bifurcation aneurysms for which WEB treatment was indicated were included in this prospective, multicenter Good Clinical Practice study. Clinical data, including adverse events and clinical status at 1 month and 1 year, were collected and independently analyzed by a medical monitor. An independent core laboratory evaluated the anatomic results at 1 year following the procedure. RESULTS: Ten French neurointerventional centers included 62 patients (39 women), 33-74 years of age (mean, 56.6 +/- 9.80 years) with 63 aneurysms. Aneurysm locations were the middle cerebral artery in 32 aneurysms (50.8%), anterior communicating artery in 16 (25.4%), basilar artery in 9 (14.3%), and internal carotid artery terminus in 6 (9.5%). Morbidity and mortality at 1 month were, respectively, 3.2% (2/62 patients) and 0.0% (0/62). Morbidity and mortality (unrelated to the treatment) at 1 year were, respectively, 0.0% (0/59) and 3.4% (2/59 patients). At 1 year, complete occlusion was observed in 30/58 aneurysms (51.7%); neck remnant, in 16/58 aneurysms (27.6%); and aneurysm remnant, in 12/58 aneurysms (20.7%). CONCLUSIONS: This prospective French Observatory study showed very good safety of aneurysm treatment with the WEB, with a high rate of adequate aneurysm occlusion at 1 year (79.3%). PMID- 26514609 TI - 3D T2 MR Imaging-Based Measurements of the Posterior Cervical Thecal Sac in Flexion and Extension for Cervical Puncture. AB - BACKGROUND AND PURPOSE: The current standard technique for cervical puncture involves prone positioning with neck extension. The purpose of this study was to compare measurements of the posterior cervical thecal sac during neck flexion and extension in supine and prone positions by using high-resolution MR imaging to help determine the optimal positioning for cervical puncture. MATERIALS AND METHODS: High-resolution T2-weighted MR imaging was performed of the cervical spine in 10 adult volunteers 18 years of age and older. Exclusion criteria included the following: a history of cervical spine injury/surgery, neck pain, and degenerative spondylosis. Images of sagittal 3D sampling perfection with application-optimized contrasts by using different flip angle evolutions were obtained in the following neck positions: supine extension, supine flexion, prone extension, and prone flexion. The degree of neck flexion and extension and the distance from the posterior margin of the spinal cord to the posterior aspect of the C1-C2 thecal sac were measured in each position. RESULTS: The mean anteroposterior size of the posterior C1-C2 thecal sac was as follows: 4.76 mm for supine extension, 3.63 mm for supine flexion, 5.00 mm for prone extension, and 4.00 mm for prone flexion. Neck extension yielded a larger CSF space than flexion, independent of supine/prone positioning. There was no correlation with neck angle and thecal sac size. CONCLUSIONS: The posterior C1-C2 thecal sac is larger with neck extension than flexion, independent of prone or supine positioning. Given that this space is the target for cervical puncture, findings suggest that extension is the ideal position for performing the procedure, and the decision for prone-versus-supine positioning can be made on the basis of operator comfort and patient preference/ability. PMID- 26514610 TI - Variability of Forebrain Commissures in Callosal Agenesis: A Prenatal MR Imaging Study. AB - BACKGROUND AND PURPOSE: Agenesis of the corpus callosum, even when isolated, may be characterized by anatomic variability. The aim of this study was to describe the types of other forebrain commissures in a large cohort of randomly enrolled fetuses with apparently isolated agenesis of the corpus callosum at prenatal MR imaging. MATERIALS AND METHODS: All fetuses with apparent isolated agenesis of the corpus callosum undergoing prenatal MR imaging from 2004 to 2014, were evaluated for the presence of the anterior or a vestigial hippocampal commissure assessed in consensus by 2 pediatric neuroradiologists. RESULTS: Overall, 62 cases of agenesis of the corpus callosum were retrieved from our data base. In 3/62 fetuses (4.8%), no forebrain commissure was visible at prenatal MR imaging, 23/62 fetuses (37.1%) presented with only the anterior commissure, and 20/62 fetuses (32.3%) showed both the anterior commissure and a residual vestigial hippocampal commissure, whereas in the remaining 16/62 fetuses (25.8%), a hybrid structure merging a residual vestigial hippocampal commissure and a rudiment of the corpus callosum body was detectable. Postnatal MR imaging, when available, confirmed prenatal forebrain commissure findings. CONCLUSIONS: Most fetuses with apparent isolated agenesis of the corpus callosum showed at least 1 forebrain commissure at prenatal MR imaging, and approximately half of fetuses also had a second commissure: a vestigial hippocampal commissure or a hybrid made of a hippocampal commissure and a rudimentary corpus callosum body. Whether such variability is the result of different genotypes and whether it may have any impact on the long-term neurodevelopmental outcome remains to be assessed. PMID- 26514611 TI - Diagnostic Accuracy of Transcranial Doppler for Brain Death Confirmation: Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: Transcranial Doppler is a useful ancillary test for brain death confirmation because it is safe, noninvasive, and done at the bedside. Transcranial Doppler confirms brain death by evaluating cerebral circulatory arrest. Case series studies have generally reported good correlations between transcranial Doppler confirmation of cerebral circulatory arrest and clinical confirmation of brain death. The purpose of this study is to evaluate the utility of transcranial Doppler as an ancillary test in brain death confirmation. MATERIALS AND METHODS: We conducted a systematic review of the literature and a diagnostic test accuracy meta-analysis to compare the sensitivity and specificity of transcranial Doppler confirmation of cerebral circulatory arrest, by using clinical confirmation of brain death as the criterion standard. RESULTS: We identified 22 eligible studies (1671 patients total), dating from 1987 to 2014. Pooled sensitivity and specificity estimates from 12 study protocols that reported data for the calculation of both values were 0.90 (95% CI, 0.87-0.92) and 0.98 (95% CI, 0.96-0.99), respectively. Between-study differences in the diagnostic performance of transcranial Doppler were found for both sensitivity (I(2) = 76%; P < .001) and specificity (I(2) = 74.3%; P < .001). The threshold effect was not significant (Spearman r = -0.173; P = .612). The area under the curve with the corresponding standard error (SE) was 0.964 +/- 0.018, while index Q test +/- SE was estimated at 0.910 +/- 0.028. CONCLUSIONS: The results of this meta-analysis suggest that transcranial Doppler is a highly accurate ancillary test for brain death confirmation. However, transcranial Doppler evaluates cerebral circulatory arrest rather than brain stem function, and this limitation needs to be taken into account when interpreting the results of this meta analysis. PMID- 26514612 TI - Normal Development and Measurements of the Occipital Condyle-C1 Interval in Children and Young Adults. AB - BACKGROUND AND PURPOSE: Widening of the occipital condyle-C1 interval is the most specific and sensitive means of detecting atlanto-occipital dislocation. Recent studies attempting to define normal measurements of the condyle-C1 interval in children have varied substantially. This study was performed to test the null hypothesis that condyle-C1 interval morphology and joint measurements do not change as a function of age. MATERIALS AND METHODS: Imaging review of subjects undergoing CT of the upper cervical spine for reasons unrelated to trauma or developmental abnormality was performed. Four equidistant measurements were obtained for each bilateral condyle-C1 interval on sagittal and coronal images. The cohort was divided into 7 age groups to calculate the mean, SD, and 95% CIs for the average condyle-C1 interval in both planes. The prevalence of a medial occipital condyle notch was calculated. RESULTS: Two hundred forty-eight joints were measured in 124 subjects with an age range of 2 days to 22 years. The condyle-C1 interval varies substantially by age. Average coronal measurements are larger and more variable than sagittal measurements. The medial occipital condyle notch is most prevalent from 1 to 12 years and is uncommon in older adolescents and young adults. CONCLUSIONS: The condyle-C1 interval increases during the first several years of life, is largest in the 2- to 4-year age range, and then decreases through late childhood and adolescence. A single threshold value to detect atlanto-occipital dissociation may not be sensitive and specific for all age groups. Application of this normative data to documented cases of atlanto occipital injury is needed to determine clinical utility. PMID- 26514613 TI - Endovascular Treatment of Unruptured Paraclinoid Aneurysms: Single-Center Experience with 400 Cases and Literature Review. AB - BACKGROUND AND PURPOSE: Paraclinoid aneurysms have been increasingly treated endovascularly. The natural history of these aneurysms has gradually been elucidated. The purpose of this study was to assess the safety and efficacy of endovascular treatment for these aneurysms. MATERIALS AND METHODS: We performed a retrospective review of 377 patients with 400 paraclinoid aneurysms treated between January 2006 and December 2012. Their clinical records, endovascular reports, and radiologic and clinical outcomes were analyzed. Because aneurysms >=7 mm are at higher risk of rupture, we classified aneurysms as small (<7 mm) or large (>=7 mm). RESULTS: Overall, 115 of the 400 aneurysms (28.8%) were large (>=7 mm). Thromboembolic complications were found significantly more often with large aneurysms than with small ones (7.4% vs 1.0%, P = .001). Hemorrhagic complications were found only with small aneurysms (0.7%). The 6-month morbidity rates were similar for small (1.0%) and large (0.8%) aneurysms. Immediate angiographic outcomes were similar (P = .37), whereas recurrences and retreatment occurred more frequently with large aneurysms (P = .001 and P = .007, respectively). Multivariate analysis showed that aneurysm size was the only independent predictor for recurrence (P = .005). Most recurrences (81%) were detected by scheduled angiography at 6 months. CONCLUSIONS: Aneurysm size influenced the type of complication (thromboembolic or hemorrhagic) and the recurrence rate. Given the approximately 1% annual rupture rate for aneurysms >=7 mm, analysis of our data supports the rationale of using prophylactic endovascular treatment for unruptured paraclinoid aneurysms >=7 mm. PMID- 26514615 TI - Chemical processing of three-dimensional graphene networks on transparent conducting electrodes for depleted-heterojunction quantum dot solar cells. AB - We present a novel chemical procedure to prepare three-dimensional graphene networks (3DGNs) as a transparent conductive film to enhance the photovoltaic performance of PbS quantum-dot (QD) solar cells. It is shown that 3DGN electrodes enhance electron extraction, yielding a 30% improvement in performance compared with the conventional device. PMID- 26514614 TI - Social and behavioral predictors of insufficient sleep among African Americans and Caucasians. AB - BACKGROUND: Few studies have examined the social and behavioral predictors of insufficient sleep. OBJECTIVE: To assess the social and behavioral predictors of insufficient sleep in the U.S. METHODS: Data from the 2009 Behavioral Risk Factor Surveillance System (BRFSS) were analyzed. Telephone interviews were conducted in six representative states that completed the optional sleep module. A total of 31,059 respondents were included in the present analysis. BRFSS-provided weights were applied to analyses to adjust for the use of complex design. RESULTS: The mean age for the sample was 56 +/- 16 years, with 63% of the sample being female; 88% identified as non-Hispanic white and 12% identified as non-Hispanic black; 42% were not married and 8% did not have a high school degree. The prevalence of insufficient sleep (<7 hours) was 37%. Multivariate-adjusted logistic regression revealed associations of four important factors with insufficient sleep, which were: working more than 40 hours per week [OR = 1.65, p < 0.001, 95% CI = 1.65 1.66], black race/ethnicity [OR = 1.37, p < 0.001, 95% CI = 1.37-1.38], history of heart disease [OR = 1.26, p < 0.001, 95% CI = 1.25-1.28], care-giving to family/friends [OR = 1.50, p < 0.001, 95% CI = 1.49-1.51], and lack of social and emotional support [OR = 1.24, p < 0.001, 95% CI = 1. 23-1.25]. CONCLUSION: Social and behavioral predictors of health uniquely contribute to the report of insufficient sleep and should be considered when developing programs to increase awareness of the adverse effects of insufficient sleep. PMID- 26514617 TI - Perceived trustworthiness shapes neural empathic responses toward others' pain. AB - As might be expected, neural empathic responses toward someone in pain are shaped by the affective/social relationship between the observer and the suffering person. Brain activity associated with empathy is sensitive to previous knowledge on the other's social conduct, such that, for instance, an unfair person in pain elicits in the observer reduced activations of empathy-related brain regions compared to a fair person. We conjectured that even in the absence of information on the personality and social behavior of an individual, empathy might be modulated by the 'first impression' based on other's physical facial features, such that the other is perceived as trustworthy or untrustworthy. By means of event-related potentials technique, we monitored in two experiments the neural empathic responses associated with the pain of trustworthy and untrustworthy faces, either computerized and parametrically manipulated (Experiment 1) and real faces (Experiment 2) in a cue-based paradigm. We observed P3 empathic reactions towards individuals looking trustworthy whereas the reactions towards individuals looking untrustworthy were negligible, if not null. An additional experiment (Experiment 3) was conducted in order to substantiate our conclusions by demonstrating that the experimental paradigm we designed did very likely activate an empathic response. PMID- 26514616 TI - Conversion to stem-cell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells. AB - Cancer cells within a tumor are functionally heterogeneous and specific subpopulations, defined as cancer initiating cells (CICs), are endowed with higher tumor forming potential. The CIC state, however, is not hierarchically stable and conversion of non-CICs to CICs under microenvironment signals might represent a determinant of tumor aggressiveness. How plasticity is regulated at the cellular level is however poorly understood. To identify determinants of plasticity in lung cancer we exposed eight different cell lines to TGFbeta1 to induce EMT and stimulate modulation of CD133(+) CICs. We show that response to TGFbeta1 treatment is heterogeneous with some cells readily switching to stem cell state (1.5-2 fold CICs increase) and others being unresponsive to stimulation. This response is unrelated to original CICs content or extent of EMT engagement but is tightly dependent on balance between epithelial and mesenchymal features as measured by the ratio of expression of CDH1 (E-cadherin) to SNAI2. Epigenetic modulation of this balance can restore sensitivity of unresponsive models to microenvironmental stimuli, including those elicited by cancer associated fibroblasts both in vitro and in vivo. In particular, tumors with increased prevalence of cells with features of partial EMT (hybrid epithelial/mesenchymal phenotype) are endowed with the highest plasticity and specific patterns of expression of SNAI2 and CDH1 markers identify a subset of tumors with worse prognosis. In conclusion, here we describe a connection between a hybrid epithelial/mesenchymal phenotype and conversion to stem-cell state in response to external stimuli. These findings have implications for current endeavors to identify tumors with increased plasticity. PMID- 26514618 TI - Aberrant function of frontoamygdala circuits in adolescents with previous verbal abuse experiences. AB - Previous studies reported an association of depressive disorder and structural alteration of frontolimbic brain regions in subjects with emotional abuse experiences during childhood and adolescence. The results suggest that aberrant function of the frontolimbic circuit and its relation with psychiatric symptoms can be found in adolescents with preclinical status. We investigated functional changes of frontolimbic networks during implicit negative emotional face processing and their relationships with depressive symptoms in adolescents with previous verbal abuse experiences. We designed a gender discrimination task using emotional faces to induce an implicit level of emotional exposure, and was completed by 31 preclinical male adolescents during an fMRI scan. The right amygdala activity and its functional connectivity with the rostral anterior cingulate cortex (ACC) during implicit processing of negative emotional faces showed a significant relationship with previous verbal abuse experiences. The hierarchical regression analyses showed that their current depressive symptoms were associated with aberrant functional interaction between the right amygdala activity and right amygdala-rostral ACC connectivity. Our findings of verbal abuse-related functional changes in the right frontoamygdala circuit may be related to vulnerability to future mood disorder. PMID- 26514619 TI - Impact of 5-aminolevulinic acid with iron supplementation on exercise efficiency and home-based walking training achievement in older women. AB - A reduction in exercise efficiency with aging limits daily living activities. We examined whether 5-aminolevulinic acid (ALA) with sodium ferrous citrate (SFC) increased exercise efficiency and voluntary achievement of interval walking training (IWT) in older women. Ten women [65 +/- 3(SD) yr] who had performed IWT for >12 mo and were currently performing IWT participated in this study. The study was conducted in a placebo-controlled, double-blind crossover design. All subjects underwent two trials for 7 days each in which they performed IWT with ALA+SFC (100 and 115 mg/day, respectively) or placebo supplement intake (CNT), intermittently with a 2-wk washout period. Before and after each trial, subjects underwent a graded cycling test at 27.0 degrees C atmospheric temperature and 50% relative humidity, and oxygen consumption rate, carbon dioxide production rate, and lactate concentration in plasma were measured. Furthermore, for the first 6 days of each trial, exercise intensity for IWT was measured by accelerometry. We found that, in the ALA+SFC trial, oxygen consumption rate and carbon dioxide production rate during graded cycling decreased by 12% (P < 0.001) and 11% (P = 0.001) at every workload, respectively, accompanied by a 16% reduction in lactate concentration in plasma (P < 0.001), although all remained unchanged in the CNT trial (P > 0.2). All of the reductions were significantly greater in the ALA+SFC than the CNT trial (P < 0.05). Furthermore, the training days, impulse, and time at fast walking were 42% (P = 0.028), 102% (P = 0.027), and 69% (P = 0.039) higher during the ALA+SFC than the CNT intake period, respectively. Thus ALA+SFC supplementation augmented exercise efficiency and thereby improved IWT achievement in older women. PMID- 26514620 TI - p(70S6K1) in the TORC1 pathway is essential for the differentiation of Th17 Cells, but not Th1, Th2, or Treg cells in mice. AB - The TORC1 pathway is necessary for ribosomal biogenesis and initiation of protein translation. Furthermore, the differentiation of Th1 and Th17 cells requires TORC1 activity. To investigate the role of the TORC1 pathway in the differentiation of Th1 and/or Th17 cells in more detail, we compared the differentiation capacity of naive T cells from wild type and p70(S6K1) knockout mice. Expression of many of the genes associated with Th17-cell differentiation, such as IL17a, IL17f, and IL-23R, were reduced in p70(S6K1) knockout mice. In contrast, the development of Th1, Th2, and Treg cells was unaffected in the absence of p70(S6K1) . Furthermore, expression of the major transcription factor in Th17-cell differentiation, retinoic acid receptor-related orphan receptor gamma T, remained unchanged. However, the acetylation of histone 3 at the promoters of IL17a and IL17f was reduced in the absence of p70(S6K1) . In accordance with the in vitro data, the kinetics, but not the development, of EAE was affected with the loss of p70(S6K1) expression. Collectively, our findings suggested that both in vitro and in vivo differentiation of Th17 cells were positively regulated by p70(S6K1) . PMID- 26514622 TI - TRIM-NHL proteins in development and disease. AB - TRIM-NHL proteins are key regulators of developmental transitions, for example promoting differentiation, while inhibiting cell growth and proliferation, in stem and progenitor cells. Abnormalities in these proteins have been also associated with human diseases, particularly affecting muscular and neuronal functions, making them potential targets for therapeutic intervention. The purpose of this review is to provide a systematic and comprehensive summary on the most studied TRIM-NHL proteins, highlighting examples where connections were established between structural features, molecular functions and biological outcomes. PMID- 26514621 TI - Cell healing: Calcium, repair and regeneration. AB - Cell repair is attracting increasing attention due to its conservation, its importance to health, and its utility as a model for cell signaling and cell polarization. However, some of the most fundamental questions concerning cell repair have yet to be answered. Here we consider three such questions: (1) How are wound holes stopped? (2) How is cell regeneration achieved after wounding? (3) How is calcium inrush linked to wound stoppage and cell regeneration? PMID- 26514623 TI - A review on hydrothermal pre-treatment technologies and environmental profiles of algal biomass processing. AB - The need for efficient and clean biomass conversion technologies has propelled Hydrothermal (HT) processing as a promising treatment option for biofuel production. This manuscript discussed its application for pre-treatment of microalgae biomass to solid (biochar), liquid (biocrude and biodiesel) and gaseous (hydrogen and methane) products via Hydrothermal Carbonisation (HTC), Hydrothermal Liquefaction (HTL) and Supercritical Water Gasification (SCWG) as well as the utility of HT water as an extraction medium and HT Hydrotreatment (HDT) of algal biocrude. In addition, the Solar Energy Retained in Fuel (SERF) using HT technologies is calculated and compared with benchmark biofuel. Lastly, the Life Cycle Assessment (LCA) discusses the limitation of the current state of art as well as introduction to new potential input categories to obtain a detailed environmental profile. PMID- 26514624 TI - Dental Homes for Children With Autism: A Longitudinal Analysis of Iowa Medicaid's I-Smile Program. AB - INTRODUCTION: Medicaid-enrolled children with autism spectrum disorder (ASD) encounter significant barriers to dental care. Iowa's I-Smile Program was implemented in 2006 to improve dental use for all children in Medicaid. This study compared dental home and preventive dental utilization rates for Medicaid enrolled children by ASD status and within three time periods (pre implementation, initial implementation, maturation) and determined I-Smile's longitudinal influence on ASD-related dental use disparities. METHODS: Data from 2002-2011 were analyzed for newly Medicaid-enrolled children aged 3-17 years (N=30,059); identified each child's ASD status; and assessed whether the child had a dental home or utilized preventive dental care. Log-linear regression models were used to generate rate ratios. Analyses were conducted in 2015. RESULTS: In 2003-2011, 9.8% of children with ASD had dental homes compared with 8% of children without ASD; 36.3% of children with ASD utilized preventive care compared to 45.7% of children without ASD. There were no significant differences in dental home rates by ASD status during pre-implementation, initial implementation, or maturation. There were no significant differences in preventive dental utilization by ASD status during pre-implementation or initial implementation, but children with ASD were significantly less likely to utilize preventive care during maturation (rate ratio=0.79, p<0.001). Longitudinal trends in dental home and preventive dental utilization rates were not significant (p=0.54 and p=0.71, respectively). CONCLUSIONS: Among newly Medicaid-enrolled children in Iowa's I-Smile Program, those with ASDs were not less likely than those without ASD to have dental homes but were significantly less likely to utilize preventive dental care. PMID- 26514625 TI - Shoot-derived abscisic acid promotes root growth. AB - The phytohormone abscisic acid (ABA) plays a major role in regulating root growth. Most work to date has investigated the influence of root-sourced ABA on root growth during water stress. Here, we tested whether foliage-derived ABA could be transported to the roots, and whether this foliage-derived ABA had an influence on root growth under well-watered conditions. Using both application studies of deuterium-labelled ABA and reciprocal grafting between wild-type and ABA-biosynthetic mutant plants, we show that both ABA levels in the roots and root growth in representative angiosperms are controlled by ABA synthesized in the leaves rather than sourced from the roots. Foliage-derived ABA was found to promote root growth relative to shoot growth but to inhibit the development of lateral roots. Increased root auxin (IAA) levels in plants with ABA-deficient scions suggest that foliage-derived ABA inhibits root growth through the root growth-inhibitor IAA. These results highlight the physiological and morphological importance, beyond the control of stomata, of foliage-derived ABA. The use of foliar ABA as a signal for root growth has important implications for regulating root to shoot growth under normal conditions and suggests that leaf rather than root hydration is the main signal for regulating plant responses to moisture. PMID- 26514626 TI - Wide distribution and ancient evolutionary history of simian foamy viruses in New World primates. AB - BACKGROUND: Although simian foamy viruses (SFV) are the only exogenous retroviruses to infect New World monkeys (NWMs), little is known about their evolutionary history and epidemiology. Previous reports show distinct SFVs among NWMs but were limited to small numbers of captive or wild monkeys from five (Cebus, Saimiri, Ateles, Alouatta, and Callithrix) of the 15 NWM genera. Other studies also used only PCR testing or serological assays with limited validation and may have missed infection in some species. We developed and validated new serological and PCR assays to determine the prevalence of SFV in blood specimens from a large number of captive NWMs in the US (n = 274) and in captive and wild caught NWMs (n = 236) in Peruvian zoos, rescue centers, and illegal trade markets. Phylogenetic and co-speciation reconciliation analyses of new SFV polymerase (pol) and host mitochondrial cytochrome B sequences, were performed to infer SFV and host co-evolutionary histories. RESULTS: 124/274 (45.2 %) of NWMs captive in the US and 59/157 (37.5 %) of captive and wild-caught NWMs in Peru were SFV WB-positive representing 11 different genera (Alouatta, Aotus, Ateles, Cacajao, Callithrix, Cebus, Lagothrix, Leontopithecus, Pithecia, Saguinus and Saimiri). Seroprevalences were lower at rescue centers (10/53, 18.9 %) compared to zoos (46/97, 47.4 %) and illegal trade markets (3/7, 8/19, 42.9 %) in Peru. Analyses showed that the trees of NWM hosts and SFVs have remarkably similar topologies at the level of species and sub-populations suggestive of co speciation. Phylogenetic reconciliation confirmed 12 co-speciation events (p < 0.002) which was further supported by obtaining highly similar divergence dates for SFV and host genera and correlated SFV-host branch times. However, four ancient cross-genus transmission events were also inferred for Pitheciinae to Atelidae, Cacajao to ancestral Callithrix or Cebus monkeys, between Callithrix and Cebus monkeys, and Lagothrix to Alouatta. CONCLUSIONS: We demonstrate a broad distribution and stable co-speciation history of SFV in NWMs at the species level. Additional studies are necessary to further explore the epidemiology and natural history of SFV infection of NWMs and to determine the zoonotic potential for persons exposed to infected monkeys in captivity and in the wild. PMID- 26514627 TI - QbD-Based Development and Validation of a Stability-Indicating HPLC Method for Estimating Ketoprofen in Bulk Drug and Proniosomal Vesicular System. AB - The current studies entail systematic quality by design (QbD)-based development of simple, precise, cost-effective and stability-indicating high-performance liquid chromatography method for estimation of ketoprofen. Analytical target profile was defined and critical analytical attributes (CAAs) were selected. Chromatographic separation was accomplished with an isocratic, reversed-phase chromatography using C-18 column, pH 6.8, phosphate buffer-methanol (50 : 50v/v) as a mobile phase at a flow rate of 1.0 mL/min and UV detection at 258 nm. Systematic optimization of chromatographic method was performed using central composite design by evaluating theoretical plates and peak tailing as the CAAs. The method was validated as per International Conference on Harmonization guidelines with parameters such as high sensitivity, specificity of the method with linearity ranging between 0.05 and 250 ug/mL, detection limit of 0.025 ug/mL and quantification limit of 0.05 ug/mL. Precision was demonstrated using relative standard deviation of 1.21%. Stress degradation studies performed using acid, base, peroxide, thermal and photolytic methods helped in identifying the degradation products in the proniosome delivery systems. The results successfully demonstrated the utility of QbD for optimizing the chromatographic conditions for developing highly sensitive liquid chromatographic method for ketoprofen. PMID- 26514628 TI - Utility of QuantiFERON-TB Gold In-Tube Test in the Diagnosis of Latent TB in HIV Positive Patients in a Medium-TB Burden Country. AB - BACKGROUND: The authors aimed to compare TST with QuantiFERON-TB Gold In-Tube (QFT) for detecting latent tuberculosis infection (LTBI) in HIV-infected patients in Iran as a TB-medium endemic country. METHODS: In a cross-sectional design,130 HIV-positive patients in HIV clinic of Tehran University were studied. Patients screened for LTBI with QFT and TST simultaneously. Concordance between 2 tests results and variables associated with tests discordance were assessed. RESULTS: Positive results found in 24.6% for TST and 7.7% for QFT. Overall agreement between them was 73.85% (Kappa = 0.083). History of imprisonment was associated with more positive TST (P = 0.014) and QFT (P = 0.01). Patients with intravenous drug use (IDU) history had significant discordant results (0.018). CONCLUSION: The authors recommend QFT for all negative cases of TST in HIV-positive patients especially who had history of IDU. PMID- 26514629 TI - Severe, Disfiguring, Pityriasis Rubra Pilaris in a Woman in the Dominican Republic: Histopathologic Diagnosis and Response to Antiretroviral Therapy. AB - Pityriasis rubra pilaris (PRP) is a poorly understood dermatologic condition usually accompanied by keratoderma and intense erythroderma with islands of unaffected skin. The PRP categories include HIV-associated PRP VI. A 23-year-old HIV-infected, dark-skinned woman in the Dominican Republic developed an extremely severe, disfiguring process characterized first by a dry scaly rash involving her face, trunk, and extremities with hyperpigmentation and islands of spared skin and minimal erythroderma, followed by alopecia and development of a thick horny layer on the scalp and face. The condition, histologically proven to be PRP, was accompanied by fever, wasting, and decline in CD4 count. Initiation of combination antiretroviral therapy (cART) was followed by rapid and sustained resolution of PRP. Nine years after ART initiation, she remains well, with viral suppression and immune recovery, without PRP recurrence but with sparse hair regrowth and facial scarring. In some dark-skinned patients, severe PRP may not feature characteristic erythroderma but will respond to combination ART. PMID- 26514630 TI - Lipid Profile in HIV-Infected Patients Using First-Line Antiretroviral Drugs. AB - OBJECTIVE: To determine the prevalence of dyslipidemia in HIV-infected patients using the first-line antiretroviral (ARV) drugs triple regimen. METHODS: HIV infected patients aged >=15 years and attending Care and Treatment Clinic (CTC) at Muhimbili National Hospital, in Dar es Salaam, Tanzania, were recruited for the study. Blood samples from patients were collected during their regular visits at the CTC and assayed for determination of total cholesterol, triglycerides (TGs), high-density lipoprotein, low-density lipoprotein cholesterol, and CD4 counts. RESULTS: The median CD4 count was 346 cells/mm(3) (2-2600). Triple therapy combinations of ARV drugs used by patients included zidovudine (ZDV)/lamivudine (3TC)/efavirenz (EFV; 42.4%), ZDV/3TC/nevirapine (NVP; 33.8%), tenofovir (TDF)/emtricitabine/EFV (19.9%), and TDF/3TC/EFV (3.9%). The overall prevalence of dyslipidemia in patients was 77.5%. There were varied prevalence of derangement of individual lipids among patients. Age, body mass index, CD4 count, sex, and duration of ARV drug use were the predictors of poor lipid profiles. CONCLUSION: The findings of this study indicate the need for routine monitoring of lipids among HIV-infected patients. PMID- 26514631 TI - Width-Controlling Fixation of Symphyseal/Parasymphyseal Fractures Associated With Bilateral Condylar Fractures With 2 2.0-mm Miniplates: A Retrospective Investigation of 45 Cases. AB - PURPOSE: Symphyseal and parasymphyseal fractures and bilateral condylar fractures represent a pattern that is quite challenging to manage. This study evaluated the treatment outcomes of a group of patients who underwent surgery using miniplate fixation for anterior mandibular fractures. MATERIALS AND METHODS: This retrospective case series study reviewed patients with bilateral condylar fractures and noncomminuted symphyseal and parasymphyseal fractures. The patients were surgically treated from 2008 to 2014 in the department of oral surgery. Evaluation of facial width control was considered the primary outcome variable, which consisted of clinical assessment and measurement of the lingual gap using computed tomography. Medical information was collected before surgery. Temporomandibular joint function and postoperative complications also were evaluated during follow-up. A paired sample t test was used for statistical analysis. RESULTS: Forty-five patients (37 male, 8 female; mean age, 34.8 +/- 14.5 yr; range, 16 to 74 yr) were included in this study. Lingual gaps measured before surgery (3.38 +/- 0.61 mm) and after surgery (0.64 +/- 0.14 mm) were significantly different (P < .001). No patient was rated as "unsatisfactory" after esthetic evaluation of facial width. CONCLUSION: For noncomminuted symphyseal and parasymphyseal fractures associated with bilateral condylar fractures, 2 2.0-mm miniplates with monocortical screws are stable and efficacious in controlling mandibular width when bilateral condylar fractures are anatomically reduced and stably fixated. PMID- 26514632 TI - Treatment Algorithm for Intracranial Intrusion Injuries of the Mandibular Condyle. AB - PURPOSE: Traumatic injuries of the mandible resulting in intrusion of the condyle into the middle cranial fossa are rare and treatment is often based on anecdotal experience. The objective of this study was to develop an algorithm for the management of condylar intrusion injuries by identifying factors that influenced the treatment decision of closed versus open reduction of the condyle. MATERIALS AND METHODS: This study was a systematic review of the literature on intracranial intrusion injuries of the mandibular condyle. A thorough search of the PubMed and Cochrane databases and individual maxillofacial and craniofacial journal databases was conducted using the Medical Subject Heading terms condylar impaction, condylar dislocation, condylar intrusion, and middle cranial fossa and condyle without date and language restriction. Quantitative data on the patient's age, gender, etiology of injury, and time from injury to diagnosis were analyzed using descriptive statistics. The authors studied how the predictor variables of age, etiology, time from injury to diagnosis, and associated neurologic injuries influenced the outcome variable of closed versus open reduction of the condyle. RESULTS: Forty-eight of the 62 retrieved case reports, case series, and review articles were published in the English-language literature from 1963 to 2015. Data on 51 patients with these injuries showed that 38 (75%) were female and younger than 30 years. The most common etiology of injury was motor vehicular accidents, occurring in 25 of 51 patients (49%). The mean time from injury to diagnosis was 31.2 days (0 to 106.4 days). Forty of the 51 patients (78%) were diagnosed within the first 2 weeks of injury. A good proportion of patients underwent open reduction (63%) and 18 of the 51 of patients (35%) underwent closed reduction. CONCLUSIONS: Predictor variables that influenced the treatment decision of open versus closed reduction were age of the patient, etiology of injury, and time from injury to diagnosis. Based on the present results, younger patients (0 to 15 yr old), patients who sustain condylar intrusion injuries from bicycle accidents, and those diagnosed within the first 2 weeks of injury are more likely to benefit from closed reduction. The treatment algorithm emphasizes the importance of assessment of associated neurologic injuries and an interdisciplinary approach for the management of these injuries. PMID- 26514633 TI - Assessment of pain in a Norwegian Emergency Department. AB - BACKGROUND: Although pain management is a fundamental aspect of care in emergency departments (EDs), inadequate treatment of pain is unfortunately common. There are multiple local protocols for pain assessment in the ED. This study evaluated whether the initial assessment and treatment of pain in the ED are in accordance with the in-hospital protocol of the ED at a Norwegian University Hospital. MATERIALS AND METHODS: Prospective data on pain assessment and initial treatment in the ED were collected from nursing and physician documentation. The patients' perceptions of subjective pain were recorded using a numerical rating scale (NRS) that ranged from 0 to 10. RESULTS: Seventy-seven percent of the 764 enrolled patients were evaluated for pain at arrival. Female patients had a higher probability of not being asked about pain, but there was no difference in the percentage of patients asked about pain with respect to age. Additionally, patients with low oxygen saturation and systolic blood pressure were less likely to be asked about pain. Of those with moderate and severe pain (58 %), only 14 % received pain relief. DISCUSSION: Assessment and treatment of pain in the ED are inadequate and not in line with the local protocols. A focus on strategies to improve pain treatment in the ED is a necessary aspect of developing optimal acute patient care in Norway in the future. PMID- 26514634 TI - R/S Ratio Variability in Lead V1 Observed between Selected Four 1-Minute ECG Fragments of 24-Hour ECG as a Predictor of Incomplete Resynchronization during Full 24-Hour ECG: Pilot Study. AB - BACKGROUND: About 30% of patients do not have an effective cardiac resynchronization therapy (CRT). Routine assessment of CRT by devices interrogation (DI) is not entirely reliable. Additional information provide detailed QRS analysis in 24-hour ECG, however it is time-consuming. The aim of the study was the assessment of R/S ratio variability in lead V1 between selected fragments of 24-hour ECG as a predictor of incomplete biventricular pacing (BIVP) during full 24-hour ECG. METHODS: The 12-lead 24-hour ECGs of 43 patients with sinus rhythm were studied. During 24-hour ECG the 6-minute walk test (6MWT) was performed. The CRT was assessed by analyzing DI and full 24-hour ECG and four 1 minute fragments of these ECG recordings: during the minimum and the maximum heart rate and at the 1st and last minute of 6MWT. RESULTS: During DI the effective (>95%) BIVP was present in 36 patients (83.7%). Analysis of full 24 hour ECG confirmed appropriate BIVP in 31 patients (72%) and suspected incomplete BIVP (<=95%) in 12 patients (28%). In 9/12 patients the R/S ratio variability in lead V1 was visible between selected ECG fragments of 24-hour ECG. These results were not associated with the results of DI but were significantly associated with full 24-hour analysis of QRS. CONCLUSIONS: R/S variability in lead V1 between selected fragments of 24-hour ECG can be considered a predictor of potentially incomplete BIVP confirmed by further complete 24-hour ECG analysis in patients with appropriate pacing reported during DI. PMID- 26514635 TI - Intraoperative Hemorrhage in Ventriculoscopic Surgery: Experience of a Single Chinese Neurosurgery Center. AB - BACKGROUND: The ventriculoscopic approach has been considered to be more safe and effective in the treatment of hydrocephalus, arachnoid cysts and intraventricular lesions in neurosurgery. We found that intraoperative bleeding-related complications have the greatest impact on ventriculoscopic surgery. Until now, few studies fully discussed this complication. METHODS: Patients who underwent ventriculoscopic surgery between May 2011 and December 2012 at Beijing Tiantan Hospital were analyzed. RESULTS: A total of 126 patients were enrolled in the study. Intraoperative hemorrhage was observed in 75 cases (59.5%). Intraoperative hemorrhage classification of patients was as follows: stage I (n = 62); stage II (n = 11); stage III (n = 2). We found that there was no significant difference in complication rate and rate of symptom improvement between the patients who had hemorrhage and the patients who did not (P < 0.05). CONCLUSIONS: Intraoperative hemorrhage in ventriculoscopic surgery should be paid more attention. Generally, a skilled neurosurgeon can address hemorrhage with a low complication rate. Consequently, the ventriculoscopic approach is safe and effective in the treatment of specified brain ventricular disease. PMID- 26514636 TI - A Proposed Resident's Operative Case Tracking and Evaluation System. AB - OBJECTIVES: Neurosurgery program trainers are continuously searching for new methods to evaluate trainees' competency besides number of cases and training duration. Recently, efforts are made on the development of reliable methods to teach competency and valid methods to measure teaching efficacy. Herein, we propose the "Resident's Operative Case Tracking and Evaluation System" (ROCTES) for the assessment and monitoring of the resident's performance quality during each procedure. METHODS: We developed a data-based website and smartphone application for neurosurgical attending physicians, residents, and resident review committees in our accredited neurosurgical institutions. ROCTES runs through five steps: Login (Resident), Case Entry, Login (Attending Physician), Case Approval and Evaluation, and Report. The Resident enters each case record under "Case Entry" field and can "save," "edit," or "submit" the case data to the Attending Physician. The latter from the attending physician login profile will be able to "approve and evaluate" the resident's "knowledge," "skills," and "attitude" ranking from 1 to 15 for that particular case; add his comments and then "save," "edit," or "submit" the data, which can be viewed by users as a "report." Program Directors can also "login" to monitor the resident's progress. RESULTS: The implementation of this communication tool should enable the filtering and retrieval of information needed for the better assessment and monitoring of residents' exposure to variety of cases in each training center. CONCLUSIONS: This proposed evaluation system will provide a transparent assessment for residency training programs and should convert trainees into competent neurosurgeons. PMID- 26514637 TI - Adaptation of cortical activity to sustained pressure stimulation on the fingertip. AB - BACKGROUND: Tactile adaptation is a phenomenon of the sensory system that results in temporal desensitization after an exposure to sustained or repetitive tactile stimuli. Previous studies reported psychophysical and physiological adaptation where perceived intensity and mechanoreceptive afferent signals exponentially decreased during tactile adaptation. Along with these studies, we hypothesized that somatosensory cortical activity in the human brain also exponentially decreased during tactile adaptation. The present neuroimaging study specifically investigated temporal changes in the human cortical responses to sustained pressure stimuli mediated by slow-adapting type I afferents. METHODS: We applied pressure stimulation for up to 15 s to the right index fingertip in 21 healthy participants and acquired functional magnetic resonance imaging (fMRI) data using a 3T MRI system. We analyzed cortical responses in terms of the degrees of cortical activation and inter-regional connectivity during sustained pressure stimulation. RESULTS: Our results revealed that the degrees of activation in the contralateral primary and secondary somatosensory cortices exponentially decreased over time and that intra- and inter-hemispheric inter-regional functional connectivity over the regions associated with tactile perception also linearly decreased or increased over time, during pressure stimulation. CONCLUSION: These results indicate that cortical activity dynamically adapts to sustained pressure stimulation mediated by SA-I afferents, involving changes in the degrees of activation on the cortical regions for tactile perception as well as in inter-regional functional connectivity among them. We speculate that these adaptive cortical activity may represent an efficient cortical processing of tactile information. PMID- 26514638 TI - Tortuosity is the Significant Predictive Factor for Renal Branch Occlusion after Branched Endovascular Aortic Aneurysm Repair. AB - OBJECTIVE: After multi-branched endovascular aneurysm repair (mbEVAR), renal branch occlusion is the most frequent form of branch failure. Pre-operative renal angulation and post-operative morphology of the renal branch were quantified and their impact on occlusion was analyzed. METHODS: Patients who underwent mbEVAR between January 2010 and December 2013 were reviewed retrospectively. Only renal branches constructed with caudally directed cuffs were included. Patients without post-operative computed (CT) angiography were excluded. The main outcome was the primary patency of the renal branches. The renal angulation and the morphology of renal branch (bridging length, renal coverage length, tortuosity index, and angulation of distal renal artery) were quantified using CT. The impacts of morphology, implanted stents, and patient characteristics were investigated by time to event analyses. RESULTS: Ninety renal arteries in 49 patients were enrolled. Median follow up was 12 months (IQR 6-20 months). Balloon expandable stent grafts were used in 93% (84/90) of renal branches. Self expandable stent grafts were used in 12. Ninety-one percent (82/90) were lined with self expandable bare stents. Ten branches occluded after 8 months (median; IQR 1-14 months). Four of them underwent re-interventions, achieving secondary patency. The median renal angulation was -10 degrees (IQR -40 to 0). The median bridging length was 42 mm (IQR 39-46 mm) and renal coverage 17 mm (IQR 12-22 mm). Median tortuosity index was 1.11 (IQR 1.04-1.19). The angulation of the distal renal artery was 140.7 +/- 20.5 degrees . In multivariate analysis, a tortuosity index > 1.11 was identified as the only significant predictor for occlusion (hazard ratio: 4.94; 95% CI: 1.01-24.30, p = .04). CONCLUSIONS: High tortuosity was a significant predictor for the occlusion of renal branches, but renal angulation, bridging length, and the extent of renal coverage were not. By avoiding highly tortuous renal branch paths, good outcomes are expected even in upwardly directed renal arteries. Longer paths are acceptable. PMID- 26514639 TI - Death by sex in an Australian icon: a continent-wide survey reveals extensive hybridization between dingoes and domestic dogs. AB - Hybridization between domesticated animals and their wild counterparts can disrupt adaptive gene combinations, reduce genetic diversity, extinguish wild populations and change ecosystem function. The dingo is a free-ranging dog that is an iconic apex predator and distributed throughout most of mainland Australia. Dingoes readily hybridize with domestic dogs, and in many Australian jurisdictions, distinct management strategies are dictated by hybrid status. Yet, the magnitude and spatial extent of domestic dog-dingo hybridization is poorly characterized. To address this, we performed a continent-wide analysis of hybridization throughout Australia based on 24 locus microsatellite DNA genotypes from 3637 free-ranging dogs. Although 46% of all free-ranging dogs were classified as pure dingoes, all regions exhibited some hybridization, and the magnitude varied substantially. The southeast of Australia was highly admixed, with 99% of animals being hybrids or feral domestic dogs, whereas only 13% of the animals from remote central Australia were hybrids. Almost all free-ranging dogs had some dingo ancestry, indicating that domestic dogs could have poor survivorship in nonurban Australian environments. Overall, wild pure dingoes remain the dominant predator over most of Australia, but the speed and extent to which hybridization has occurred in the approximately 220 years since the first introduction of domestic dogs indicate that the process may soon threaten the persistence of pure dingoes. PMID- 26514640 TI - Selenoprotein P is not elevated in gestational diabetes mellitus. AB - Selenoprotein P concentrations have been found to be associated with insulin resistance and elevated in patients with type 2 diabetes mellitus (DM). The aim of the present study was to investigate circulating selenoprotein P level and its possible relationship with metabolic parameters in gestational diabetes mellitus (GDM). Plasma selenoprotein P concentrations were measured in 30 pregnant women with GDM, 35 pregnant women without GDM and 22 healthy nonpregnant women. No difference in selenoprotein P levels was observed among the groups [6.2 (4.5 8.2), 7.9 (4.5-10.7) and 6.7 (5.3-9.1) ng/ml, respectively, p = 0.69]. In pregnant women with and without GDM, selenoprotein P did not correlate with age, gestational age, prepregnancy body mass index (BMI), HbA1c, glucose concentrations at oral glucose tolerance test (OGTT), area under curve (AUC) glucose, total cholesterol, LDL cholesterol and triglycerides levels (p > 0.05). But, there were statistically significant correlations between selenoprotein P and current BMI (r = -0.28, p = 0.04) and HDL cholesterol levels (r = 0.43, p = 0.01). We found that selenoprotein P concentrations are not elevated in women with GDM but associated with BMI and HDL cholesterol. PMID- 26514642 TI - A Direct Comparison of Self-Injurious and Stereotyped Motor Behavior Between Preschool-Aged Children With and Without Developmental Delays. AB - OBJECTIVE: To compare the prevalence of self-injurious behavior (SIB) and stereotyped motor behavior (STY) of preschool-aged children with developmental delays (DD group) and their peers without developmental delays (TD group) using a standardized caregiver report scale. METHODS: The Repetitive Behavior Scale Revised was completed by caregivers of children with developmental delays and their peers without developmental delays. Frequency of occurrence and severity ratings for SIB and STY were compared between groups. RESULTS: SIB and STY were reported more often and at a greater level of severity in the DD group. Older chronological age was associated with more severe STY in the DD group but not the TD group. Gender was not related to STY or SIB for either group. CONCLUSIONS: Differences in STY and SIB were evident between preschoolers with and without DD. Findings are discussed from developmental and behavioral psychology perspectives regarding the expression of repetitive behavior in developmentally at-risk pediatric populations. PMID- 26514641 TI - The Association Between Motor Skills and Academic Achievement Among Pediatric Survivors of Acute Lymphoblastic Leukemia. AB - OBJECTIVE: Assess the association between fine motor (FM) and visual-motor integration (VMI) skills and academic achievement in pediatric acute lymphoblastic leukemia (ALL) survivors. METHODS: In this 28-site cross-sectional study of 256 children in first remission, a mean of 8.9 +/- 2.2 years after treatment for standard-risk precursor-B ALL, validated measures of FM, VMI, reading, math, and intelligence were administered at mean follow-up age of 12.8 +/- 2.5 years. RESULTS: VMI was significantly associated with written math calculation ability (p < .0069) after adjusting for intelligence (p < .0001). VMI was more strongly associated with math in those with lower intelligence (p = .0141). Word decoding was also significantly associated with VMI but with no effect modification by intelligence. FM skills were not associated with either reading or math achievement. CONCLUSION: These findings suggest that VMI is associated with aspects of math and reading achievement in leukemia survivors. These skills may be amenable to intervention. PMID- 26514643 TI - The Cost-Effectiveness of Intensive Interdisciplinary Pediatric Chronic Pain Rehabilitation. AB - OBJECTIVE: Examine the cost-effectiveness of a 3-week interdisciplinary pediatric chronic pain rehabilitation program. METHODS: Self-reported health care utilization and parent missed work of youth with chronic pain (n = 127) at admission and 1-year follow-up were compared. Financials were calculated from program revenue and established national costs for health care and wages. RESULTS: Data indicate significant reductions in days hospitalized, physician office visits, physical/occupational therapy services, psychotherapy visits, and parental missed work. Estimated health care expenses were $61,988 in the year before admission and $14,189 in the year after admission (-$58,839). Estimated cost of missed work was $12,229 in the year prior and $1,189 in the year after ( $11,039). CONCLUSIONS: Comparing estimated expenses before ($74,217) and after ($15,378) minus program costs ($31,720), yielded estimated savings of $27,119 per family in the year following admission. These findings extend the benefit of the program beyond clinical improvement, to outcomes important to both families and insurers. PMID- 26514644 TI - Intervention Component Analysis (ICA): a pragmatic approach for identifying the critical features of complex interventions. AB - BACKGROUND: In order to enable replication of effective complex interventions, systematic reviews need to provide evidence about their critical features and clear procedural details for their implementation. Currently, few systematic reviews provide sufficient guidance of this sort. METHODS: Through a worked example, this paper reports on a methodological approach, Intervention Component Analysis (ICA), specifically developed to bridge the gap between evidence of effectiveness and practical implementation of interventions. By (a) using an inductive approach to explore the nature of intervention features and (b) making use of trialists' informally reported experience-based evidence, the approach is designed to overcome the deficiencies of poor reporting which often hinders knowledge translation work whilst also avoiding the need to invest significant amounts of time and resources in following up details with authors. RESULTS: A key strength of the approach is its ability to reveal hidden or overlooked intervention features and barriers and facilitators only identified in practical application of interventions. It is thus especially useful where hypothesised mechanisms in an existing programme theory have failed. A further benefit of the approach is its ability to identify potentially new configurations of components that have not yet been evaluated. CONCLUSIONS: ICA is a formal and rigorous yet relatively streamlined approach to identify key intervention content and implementation processes. ICA addresses a critical need for knowledge translation around complex interventions to support policy decisions and evidence implementation. PMID- 26514645 TI - Four weeks of running sprint interval training improves cardiorespiratory fitness in young and middle-aged adults. AB - The purpose of this study was to determine the effectiveness of a 4-week running sprint interval training protocol to improve both aerobic and anaerobic fitness in middle-aged adults (40-50 years) as well as compare the adaptations to younger adults (20-30 years). Twenty-eight inactive participants - 14 young 20-30-year olds (n = 7 males) and 14 middle-aged 40-50-year-olds (n = 5 males) - completed 4 weeks of running sprint interval training (4 to 6, 30-s "all-out" sprints on a curved, self-propelled treadmill separated by 4 min active recovery performed 3 times per week). Before and after training, all participants were assessed for maximal oxygen consumption (VO2max), 2000 m time trial performance, and anaerobic performance on a single 30-s sprint. There were no interactions between group and time for any tested variable, although training improved relative VO2max (young = 3.9, middle-aged = 5.2%; P < 0.04), time trial performance (young = 5.9, middle aged = 8.2%; P < 0.001), peak sprint speed (young = 9.3, middle-aged = 2.2%; P < 0.001), and average sprint speed (young = 6.8, middle-aged = 11.6%; P < 0.001) in both young and middle-aged groups from pre- to post-training on the 30-s sprint test. The current study demonstrates that a 4-week running sprint interval training programme is equally effective at improving aerobic and anaerobic fitness in younger and middle-aged adults. PMID- 26514646 TI - Perfect spin filtering effect and negative differential behavior in phosphorus doped zigzag graphene nanoribbons. AB - On the basis of the density functional theory combined with the Keldysh nonequilibrium Green's function method, we investigate the spin-dependent transport properties of single-edge phosphorus-doped ZGNR systems with different widths. The results show a perfect spin filtering effect reaching 100% at a wide bias range in both parallel (P) and antiparallel (AP) spin configurations for all systems, especially for 6-ZGNR-P system. Instructively, for the AP spin configuration, the spin down current of the 4-ZGNR-P system exhibits a negative differential effect. By analyzing the transmission spectrum and the spin-resolved band structures of the electrodes, we elucidate the mechanism for these peculiar properties. Our findings provide a new way to produce multifunctional spintronic devices based on phosphorus-doped zigzag graphene nanoribbons. PMID- 26514647 TI - Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure-Activity Relationships. AB - The bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half-life in mice and antitumor efficacy in a melanoma mouse model. PMID- 26514648 TI - Primary-Care Weight-Management Strategies: Parental Priorities and Preferences. AB - OBJECTIVE: To examine parental perspectives/rankings of the most important weight management clinical practices and to determine whether preferences/rankings differ when parents disagree that their child is overweight. METHODS: We performed mixed-methods analysis of a 32-question survey of parents of 2- to 18 year-old overweight children assessing parental agreement that their child is overweight, the single most important thing providers can do to improve weight status, ranking American Academy of Pediatrics-recommended clinical practices, and preferred follow-up interval. Four independent reviewers analyzed open response data to identify qualitative themes/subthemes. Multivariable analyses examined parental rankings, preferred follow-up interval, and differences by agreement with their child's overweight assessment. RESULTS: Thirty-six percent of 219 children were overweight, 42% obese, and 22% severely obese; 16% of parents disagreed with their child's overweight assessment. Qualitative analysis of the most important practice to help overweight children yielded 10 themes; unique to parents disagreeing with their children's overweight assessments was "change weight-status assessments." After adjustment, the 3 highest-ranked clinical practices included, "check for weight-related problems," "review growth chart," and "recommend general dietary changes" (all P < .01); parents disagreeing with their children's overweight assessments ranked "review growth chart" as less important and ranked "reducing screen time" and "general activity changes" as more important. The mean preferred weight-management follow-up interval (10-12 weeks) did not differ by agreement with children's overweight assessments. CONCLUSIONS: Parents prefer weight-management strategies that prioritize evaluating weight-related problems, growth-chart review, and regular follow-up. Parents who disagree that their child is overweight want changes in how overweight is assessed. Using parent-preferred weight-management strategies may prove useful in improving child weight status. PMID- 26514649 TI - Beyond ADHD: How Well Are We Doing? AB - BACKGROUND AND OBJECTIVE: There has been increasing emphasis on the role of the pediatrician with respect to behavioral, learning, and mental health (MH) issues, and developmental behavioral rotations are now required in pediatric residency programs. We sought to examine whether this newer emphasis on MH is reflected in pediatricians' reports of their current practices. METHODS: Data from 2 periodic surveys conducted in 2004 and 2013 by the American Academy of Pediatrics were examined to see whether there were differences in self-reported behaviors of usually inquiring/screening, treating/managing/comanaging, or referring patients for attention-deficit/hyperactivity disorder (ADHD), anxiety, depression, behavioral problems, or learning problems. We examined patterns for all practicing members and for those who practiced general pediatrics exclusively. RESULTS: There were few changes over the decade in the percentage who inquired or screened among all clinicians; among those exclusively practicing general pediatrics, the percentage who inquired or screened increased about 10% for ADHD and depression. ADHD remained the only condition for which the majority of respondents treated/managed/comanaged (57%). While there was some increase in the percentages who treated other conditions, the other conditions were usually treated by <30% of respondents. A similar pattern of results was observed in analyses adjusted for physician, practice, and patient characteristics. CONCLUSIONS: Despite the changing nature of pediatric practice and increased efforts to emphasize the importance of behavior, learning, and MH, the pediatric community appears to be making little progress toward providing for the long-term behavioral, learning, and MH needs of children and adolescents in its care. PMID- 26514650 TI - Characterization of bovine MHC class II DRB3 diversity in South American Holstein cattle populations. AB - Holstein cattle dominate the global milk production industry because of their outstanding milk production, however, this breed is susceptible to tropical endemic pathogens and suffers from heat stress and thus fewer Holstein populations are raised in tropical areas. The bovine major histocompatibility complex (BoLA)-DRB3 class II gene is used as a marker for disease and immunological traits, and its polymorphism has been studied extensively in Holstein cattle from temperate and cold regions. We studied the genetic diversity of the BoLA-DRB3 gene in South American Holstein populations to determine whether tropical populations have diverged from those bred in temperate and cold regions by selection and/or crossbreeding with local native breeds. We specifically studied Exon 2 of this gene from 855 South American Holstein individuals by a polymerase chain reaction (PCR) sequence-based typing method. We found a high degree of gene diversity at the allelic (Na > 20 and He > 0.87) and molecular (pi > 0.080) levels, but a low degree of population structure (FST = 0.009215). A principal components analysis and tree showed that the Bolivian subtropical population had the largest genetic divergence compared with Holsteins bred in temperate or cold regions, and that this population was closely related to Bolivian Creole cattle. Our results suggest that Holstein genetic divergence can be explained by selection and/or gene introgression from local germplasms. This is the first examination of BoLA-DRB3 in Holsteins adapted to tropical environments, and contributes to an ongoing effort to catalog bovine MHC allele frequencies by breed and location. PMID- 26514651 TI - Differential Contribution of Endoplasmic Reticulum and Chloroplast omega-3 Fatty Acid Desaturase Genes to the Linolenic Acid Content of Olive (Olea europaea) Fruit. AB - Linolenic acid is a polyunsaturated fatty acid present in plant lipids, which plays key roles in plant metabolism as a structural component of storage and membrane lipids, and as a precursor of signaling molecules. The synthesis of linolenic acid is catalyzed by two different omega-3 fatty acid desaturases, which correspond to microsomal- (FAD3) and chloroplast- (FAD7 and FAD8) localized enzymes. We have investigated the specific contribution of each enzyme to the linolenic acid content in olive fruit. With that aim, we isolated two different cDNA clones encoding two omega-3 fatty acid desaturases from olive (Olea europaea cv. Picual). Sequence analysis indicates that they code for microsomal (OepFAD3B) and chloroplast (OepFAD7-2) omega-3 fatty acid desaturase enzymes, different from the previously characterized OekFAD3A and OekFAD7-1 genes. Functional expression in yeast of the corresponding OepFAD3A and OepFAD3B cDNAs confirmed that they encode microsomal omega-3 fatty acid desaturases. The linolenic acid content and transcript levels of olive FAD3 and FAD7 genes were measured in different tissues of Picual and Arbequina cultivars, including mesocarp and seed during development and ripening of olive fruit. Gene expression and lipid analysis indicate that FAD3A is the gene mainly responsible for the linolenic acid present in the seed, while FAD7-1 and FAD7-2 contribute mostly to the linolenic acid present in the mesocarp and, therefore, in the olive oil. These results also indicate the relevance of lipid trafficking between the endoplasmic reticulum and chloroplast in determining the linolenic acid content of membrane and storage lipids in oil accumulating photosynthetic tissues. PMID- 26514652 TI - Base to Tip and Long-Distance Transport of Sodium in the Root of Common Reed [Phragmites australis (Cav.) Trin. ex Steud.] at Steady State Under Constant High Salt Conditions. PMID- 26514653 TI - Immunogenic, cellular, and angiogenic drivers of tumor dormancy--a melanoma view. AB - In tumor cells, the ability to maintain viability over long time periods without proliferation is referred to as a state of dormancy. Maintenance of dormancy is controlled by numerous cellular and environmental factors, from immune surveillance and tumor-stroma interaction to intracellular signaling. Interference of dormancy (to an 'awaken' state) is associated with reduced response to therapy, resulting in relapse or in metastatic burst. Thus, maintaining a dormant state should prolong therapeutic responses and delay metastasis. Technical obstacles in studying tumor dormancy have limited our understanding of underlying mechanisms and hampered our ability to target dormant cells. In this review, we summarize the progress of research in the field of immunogenic, angiogenic, and cellular dormancy in diverse malignancies with particular attention to our current understanding in melanoma. PMID- 26514654 TI - Osteogenic potential and synergistic effects of growth factors delivered from a bionic composite system. AB - Previous research has raised substantial controversy over the synergistic effects of exogenous growth factors, BMP-2 and bFGF, when used together for the treatment of bony defects. Thus, this study evaluated the effects of BMP-2 and bFGF at specified dose ratio composited with n-HA/PU40, a porous scaffold material, for repairing femoral defect in rats. Four weeks after implantation of this composite system, tissue specimens were collected for histological, immunohistochemical examinations, and u-CT scanning. The results showed that the group DUAL/BMSCs with both the factors had better effect on repairing bone defects than the other four groups in terms of new bone formation and bone-scaffold bonding, suggesting crosstalk between these growth factors during early bone regeneration. This work demonstrates that provided that there is effective contact between cells and active proteins in the defect area, the controlled release of bFGF and BMP-2 have positive synergistic effects on early bone formation in the defect area. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 659-668, 2016. PMID- 26514655 TI - Hypothalamic abnormality in patients with inflammatory demyelinating disorders. AB - BACKGROUND: Hypothalamic lesions in neuromyelitis optica (NMO) patients might be more specific for NMO than multiple sclerosis (MS). However, this is controversial. OBJECTIVE: To characterize clinical features of patients with inflammatory demyelinating disorders (IDDs) with visible hypothalamic lesions using magnetic resonance imaging (MRI). METHODS: Patients with IDDs (n = 429) were recruited retrospectively. RESULTS: Of 52 patients with hypothalamic images enrolled, 42 were positive for aquaporin-4 (AQP4) antibodies, including 28 patients with NMO, 6 with recurrent transverse myelitis, 3 with recurrent optic neuritis, and 5 with brainstem and brain syndrome. The remaining 10 patients were anti-AQP4-negative, including 3 with MS, 3 with acute disseminated encephalomyelitis, and 4 with other disorders. In the AQP4-positive group, manifestations, including ataxia, intractable hiccup and nausea, syndrome of inappropriate antidiuretic hormone secretion and encephalopathy were more frequent in those with hypothalamic lesions than those without. Cell counts of cerebrospinal fluid in patients with hypothalamic lesions differed from patients without lesions. Brain MRI abnormalities were more frequent in brainstem and hemisphere of the hypothalamic lesion group. CONCLUSIONS: Hypothalamic lesions were observed frequently in patients with AQP4 antibodies. Clinical manifestations and paraclinical features in AQP4-positive patients with hypothalamic lesions differed from those without lesions. PMID- 26514656 TI - The Roles of Maternal Depression, Serotonin Reuptake Inhibitor Treatment, and Concomitant Benzodiazepine Use on Infant Neurobehavioral Functioning Over the First Postnatal Month. AB - OBJECTIVE: The purpose of this article was to systematically compare the developmental trajectory of neurobehavior over the first postnatal month for infants with prenatal exposure to pharmacologically untreated maternal depression, selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors (collectively: SSRIs), SSRIs with concomitant benzodiazepines (SSRI plus benzodiazepine), and no maternal depression or drug treatment (no exposure). METHOD: Women (N=184) were assessed at two prenatal time points to determine psychiatric diagnoses, symptom severity, and prenatal medication usage. Infants were examined with a structured neurobehavioral assessment (Neonatal Intensive Care Unit Network Neurobehavioral Scale) at multiple time points across the first postnatal month. SSRI exposure was confirmed in a subset of participants with plasma SSRI levels. General linear mixed models were used to examine group differences in neurobehavioral scores over time with adjustment for demographic variables and depression severity. RESULTS: Infants in the SSRI and SSRI plus benzodiazepine groups had lower motor scores and more CNS stress signs across the first postnatal month, as well as lower self-regulation and higher arousal at day 14. Infants in the depression group had low arousal throughout the newborn period. Infants in all three clinical groups had a widening gap in scores from the no-exposure group at day 30 in their response to visual and auditory stimuli while asleep and awake. Infants in the SSRI plus benzodiazepine group had the least favorable scores on the Neonatal Intensive Care Unit Network Neurobehavioral Scale. CONCLUSIONS: Neonatal adaptation syndrome was not limited to the first 2 weeks postbirth. The profile of neurobehavioral development was different for SSRI exposure than depression alone. Concomitant benzodiazepine use may exacerbate adverse behavioral effects. PMID- 26514657 TI - Risk of Postpartum Relapse in Bipolar Disorder and Postpartum Psychosis: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: Women with a history of bipolar disorder, postpartum psychosis, or both are at high risk for postpartum relapse. The aim of this meta-analysis was to estimate the risk of postpartum relapse in these three patient groups. METHOD: A systematic literature search was conducted in all public medical electronic databases, adhering to the PRISMA guidelines. Studies were included if they reported postpartum relapse in patients diagnosed with bipolar disorder and/or a history of postpartum psychosis or mania according to DSM or ICD criteria or the Research Diagnostic Criteria. RESULTS: Thirty-seven articles describing 5,700 deliveries in 4,023 patients were included in the quantitative analyses. The overall postpartum relapse risk was 35% (95% CI=29, 41). Patients with bipolar disorder were significantly less likely to experience severe episodes postpartum (17%, 95% CI=13, 21) than patients with a history of postpartum psychosis (29%, 95% CI=20, 41). Insufficient information was available to determine relapse rates for patients with bipolar disorder and a history of postpartum episodes. In women with bipolar disorder, postpartum relapse rates were significantly higher among those who were medication free during pregnancy (66%, 95% CI=57, 75) than those who used prophylactic medication (23%, 95% CI=14, 37). CONCLUSIONS: One-third of women at high risk experience a postpartum relapse. In women with bipolar disorder, continuation of prophylactic medication during pregnancy appears highly protective for maintaining mood stability postpartum. In women with a history of isolated postpartum psychosis, initiation of prophylaxis immediately after delivery offers the opportunity to minimize the risk of relapse while avoiding in utero medication exposure. PMID- 26514658 TI - Disruption of Fractalkine Signaling Leads to Microglial Activation and Neuronal Damage in the Diabetic Retina. AB - Fractalkine (CX3CL1 or FKN) is a membrane-bound chemokine expressed on neuronal membranes and is proteolytically cleaved to shed a soluble chemoattractant domain. FKN signals via its unique receptor CX3CR1 expressed on microglia and other peripheral leukocytes. The aim of this study is to determine the role of CX3CR1 in inflammatory-mediated damage to retinal neurons using a model of diabetic retinopathy. For this, we compared neuronal, microglial, and astroglial densities and inflammatory response in nondiabetic and diabetic (Ins2(Akita)) CX3CR1-wild-type and CX3CR1-deficient mice at 10 and 20 weeks of age. Our results show that Ins2(Akita) CX3CR1-knockout mice exhibited (a) decreased neuronal cell counts in the retinal ganglion cell layer, (b) increased microglial cell numbers, and (c) decreased astrocyte responses comparable with Ins2(Akita) CX3CR1-Wild type mice at 20 weeks of age. Analyses of the inflammatory response using PCR arrays showed several inflammatory genes differentially regulated in diabetic tissues. From those, the response in Ins2(Akita) CX3CR1-deficient mice at 10 weeks of age revealed a significant upregulation of IL-1beta at the transcript level that was confirmed by enzyme-linked immunosorbent assay in soluble retinal extracts. Overall, IL-1beta, VEGF, and nitrite levels as a read out of nitric oxide production were abundant in Ins2(Akita) CX3CR1-deficient retina. Notably, double immunofluorescence staining shows that astrocytes act as a source of IL 1beta in the Ins2(Akita) retina, and CX3CR1-deficient microglia potentiate the inflammatory response via IL-1beta release. Collectively, these data demonstrate that dysregulated microglial responses in absence of CX3CR1 contribute to inflammatory-mediated damage of neurons in the diabetic retina. PMID- 26514660 TI - Characterization of dendritic cells in lip and oral cavity squamous cell carcinoma. AB - BACKGROUND: There may be differences in the antitumor immunity induced by dendritic cells (DCs) during the development of squamous cell carcinoma (SCC) located in the lip rather than in the oral cavity. The aim of this study was to evaluate the number of immature and mature DCs in SCC and potentially malignant disorders of the oral cavity and lip. METHODS: Immunohistochemistry was used to identify the number (cells/mm(2) ) of immature (CD1a(+) ) or mature (CD83(+) ) DCs in samples of oral cavity SCC (OCSCC) (n = 39), lip SCC (LSCC) (n = 23), leukoplakia (LK) (n = 21), actinic cheilitis (AC) (n = 13), and normal mucosa of the oral cavity (OC control, n = 12) and the lip (lip control, n = 11). RESULTS: The number of CD1a(+) cells tended to be higher in the OC control samples compared with the LK (P = 0.04) and OCSCC (P = 0.21). Unlike, this cell population was lower in the lip control than in AC or LSCC (P < 0.05). The number of CD83(+) cells was increased in the LSCC samples compared with the AC and lip control (P = 0.0001) and in OCSCC compared with both the LK (P = 0.001) and OC control (P = 0.0001) samples. LSCC showed an elevated number of CD1a(+) and CD83(+) cells compared with OCSCC (P = 0.03). The population of mature DCs was lower than the population of immature DCs in all of the tested groups (P < 0.05). CONCLUSION: There were a greater number of both mature and immature DC populations in the LSCC samples than in the OCSCC, which could contribute to establishing a more effective immune antitumor response for this neoplasm. PMID- 26514659 TI - Ultrastructural Correlates of Enhanced Norepinephrine and Neuropeptide Y Cotransmission in the Spontaneously Hypertensive Rat Brain. AB - The spontaneously hypertensive rat (SHR) replicates many clinically relevant features of human essential hypertension and also exhibits behavioral symptoms of attention-deficit/hyperactivity disorder and dementia. The SHR phenotype is highly complex and cannot be explained by a single genetic or physiological mechanism. Nevertheless, numerous studies including our own work have revealed striking differences in central catecholaminergic transmission in SHR such as increased vesicular catecholamine content in the ventral brainstem. Here, we used immunolabeling followed by confocal microscopy and electron microscopy to quantify vesicle sizes and populations across three catecholaminergic brain areas nucleus tractus solitarius and rostral ventrolateral medulla, both key regions for cardiovascular control, and the locus coeruleus. We also studied colocalization of neuropeptide Y (NPY) in norepinephrine and epinephrine containing neurons as NPY is a common cotransmitter with central and peripheral catecholamines. We found significantly increased expression and coexpression of NPY in norepinephrine and epinephrine-positive neurons of locus coeruleus in SHR compared with Wistar rats. Ultrastructural analysis revealed immunolabeled vesicles of 150 to 650 nm in diameter (means ranging from 250 to 300 nm), which is much larger than previously reported. In locus coeruleus and rostral ventrolateral medulla, but not in nucleus tractus solitarius, of SHR, noradrenergic and adrenergic vesicles were significantly larger and showed increased NPY colocalization when compared with Wistar rats. Our morphological evidence underpins the hypothesis of hyperactivity of the noradrenergic and adrenergic system and increased norepinephrine and epinephrine and NPY cotransmission in specific brain areas in SHR. It further strengthens the argument for a prohypertensive role of C1 neurons in the rostral ventrolateral medulla as a potential causative factor for essential hypertension. PMID- 26514662 TI - Comparison of outcomes for open versus endoscopic approaches for olfactory neuroblastoma: A systematic review and individual participant data meta-analysis. AB - BACKGROUND: Endoscopic approaches have been adopted as an alternative to craniofacial resection in the surgical management of olfactory neuroblastoma. METHODS: We conducted a systematic review and meta-analysis using MEDLINE, EMBASE, Cochrane, and CINAHL (2000-2014) to compare outcomes for open versus endoscopic approaches. RESULTS: Thirty-six studies containing 609 patients were included. Meta-analysis of (a) all patients, (b) Kadish C/D only, and (c) Hyams III/IV only, failed to show a difference in locoregional control and metastasis free survival between approaches. However, endoscopic approaches were associated with improved overall survival (OS) for all 3 groups (p = .001, .04, and .001, respectively), and higher disease-specific survival (DSS) for all patients (p = .004) and Hyams III/IV only (p = .002). CONCLUSION: The current study suggests that endoscopic approaches have comparable control rates to open approaches for olfactory neuroblastoma. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E2306 E2316, 2016. PMID- 26514661 TI - High Blood Pressure and Related Factors Among Individuals at High Risk for HIV/Sexually Transmitted Infections. AB - Data from a social network-based human immunodeficiency virus (HIV)/sexually transmitted infection (STI) prevention study with a total of 330 men and women at high risk for HIV/STIs were used to examine the relationships between substance use, depressive symptoms, general health, cardiovascular disease risk factors, sociodemographic characteristics, and systolic/diastolic blood pressure (SBP/DBP). Approximately 60% of the participants had prehypertension to stage 2 hypertension. In the base model, older patients (P<.0001), men (P=.003), and patients with poorer self-reported health (P=.029) were significantly associated with high SBP, whereas older age (P<.001) and higher body mass index (P<.001) were significantly associated with higher DBP. After adjusting for the base model, high frequency of alcohol drinking and high frequency of binge drinking remained significant for high SBP and DBP. These data suggest that future cardiovascular disease programs should target moderate alcohol consumption to improve blood pressure among individuals at high risk for HIV/STIs. PMID- 26514663 TI - Hypercholesterolemia and Ecto-enzymes of Purinergic System: Effects of Paullinia cupana. AB - Hypercholesterolemia is a metabolic disorder characterized by high levels of low density lipoprotein and blood cholesterol, causing inflammatory lesion. Purinergic signaling modulates the inflammatory and immune responses through adenine nucleotides and nucleoside. Guarana has hypocholesterolemic and antiinflammatory properties. Considering that there are few studies demonstrating the effects of guarana powder on the metabolism of adenine nucleotides, we investigated its effects on the activity of ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and ecto-adenosine deaminase activity in lymphocytes of rats with diet-induced hypercholesterolemia. The rats were divided into hypercholesterolemic and normal diet groups. Each group was subdivided by treatment: saline, guarana powder 12.5, 25, or 50 mg/kg/day and caffeine concentration equivalent to highest dose of guarana, fed orally for 30 days. An increase in adenosine triphosphate hydrolysis was observed in the lymphocytes of rats with hypercholesterolemia and treated with 25 or 50 mg/kg/day when compared with the other groups. The hypercholesterolemic group treated with the highest concentration of guarana powder showed decreased ecto-adenosine deaminase activity compared with the normal diet groups. Guarana was able to reduce the total cholesterol and low-density lipoprotein cholesterol to basal levels in hypercholesterolemic rats. High concentrations of guarana associated with a hypercholesterolemic diet are likely to have contributed to the reduction of the inflammatory process. PMID- 26514664 TI - Luminescent Quadrupolar Borazine Oligomers: Synthesis, Photophysics, and Two Photon Absorption Properties. AB - A set of monodisperse bent donor-acceptor-donor-type conjugated borazine oligomers, BnNn+1 (n=1-4), incorporating electron-rich triarylamine donor and electron-deficient triarylborane acceptor units has been prepared through an iterative synthetic approach that takes advantage of highly selective silicon boron and tin-boron exchange reactions. The effect of chain elongation on the electrochemical, one- and two-photon properties and excited-state photodynamics has been investigated. Strong intramolecular charge transfer (ICT) from the arylamine donors to boryl-centered acceptor sites results in emissions with high quantum yields (Phifl >0.5) in the range of 400-500 nm. Solvatochromic effects lead to solvent shifts as large as ~70 nm for the shortest member (n=1) and gradually decrease with chain elongation. The oligomers exhibit strong two-photon absorption (2PA) in the visible spectral region with 2PA cross sections as large as 1410 GM (n=4), and broadband excited-state absorption (ESA) attributed to long lived singlet-singlet and radical cation/anion absorption. The excited-state dynamics also show sensitivity to the solvent environment. Electrochemical observations and DFT calculations (B3LYP/6-31G*) reveal spatially separated HOMO and LUMO levels resulting in highly fluorescent oligomers with strong ICT character. The BnNn+1 oligomers have been used to demonstrate the detection of cyanide anions with association constants of log K>7. PMID- 26514665 TI - Controlled attenuation parameter for the diagnosis of steatosis in non-alcoholic fatty liver disease. AB - BACKGROUND AND AIM: Controlled attenuation parameter (CAP) evaluated with transient elastography (FibroScan) is a recent method for non-invasive assessment of steatosis. Its usefulness in non-alcoholic fatty liver disease (NAFLD) is unknown. We prospectively investigated the performance of CAP for the diagnosis of steatosis in NAFLD, factors associated with discordances between CAP and steatosis grades, and relationships between CAP and clinical or biological parameters. METHODS: All CAP examinations performed in NAFLD patients with a liver biopsy performed within 1 week of CAP measurement were included. Liver biopsies were assessed for activity and fibrosis stage, NAFLD activity score, and steatosis graded as follows: S0, steatosis < 5%; S1, 5-33%; S2, 34-66%; S3, >66%. RESULTS: Two hundred sixty-one patients (59% male, age 56 years) from two ethnic groups were included. No patient had steatosis < 5%. The area under the receiver operating characteristics curve of CAP for steatosis >=S2 and S3 was 0.80 and 0.66, respectively. At a cut-off value of 310 dB/m, the sensitivity, specificity, and positive and negative predictive values for >=S2 steatosis were 79%, 71%, 86%, and 71%, respectively. Discordance of at least one grade between CAP and steatosis was observed in 81 patients. By multivariate analysis, only steatosis S2S3 was associated with no discordance. By multivariate analysis, only BMI >= 30 kg/m(2) was significantly associated with CAP > 310 dB/m. CONCLUSION: The association of CAP with steatosis, especially in patients with non-alcoholic steatohepatitis, and with elevated BMI could be useful for the diagnosis and follow-up of NAFLD patients. PMID- 26514666 TI - Evolutionary Design of Low Molecular Weight Organic Anolyte Materials for Applications in Nonaqueous Redox Flow Batteries. AB - The integration of renewable energy sources into the electric grid requires low cost energy storage systems that mediate the variable and intermittent flux of energy associated with most renewables. Nonaqueous redox-flow batteries have emerged as a promising technology for grid-scale energy storage applications. Because the cost of the system scales with mass, the electroactive materials must have a low equivalent weight (ideally 150 g/(mol.e(-)) or less), and must function with low molecular weight supporting electrolytes such as LiBF4. However, soluble anolyte materials that undergo reversible redox processes in the presence of Li-ion supports are rare. We report the evolutionary design of a series of pyridine-based anolyte materials that exhibit up to two reversible redox couples at low potentials in the presence of Li-ion supporting electrolytes. A combination of cyclic voltammetry of anolyte candidates and independent synthesis of their corresponding charged-states was performed to rapidly screen for the most promising candidates. Results of this workflow provided evidence for possible decomposition pathways of first-generation materials and guided synthetic modifications to improve the stability of anolyte materials under the targeted conditions. This iterative process led to the identification of a promising anolyte material, N-methyl 4-acetylpyridinium tetrafluoroborate. This compound is soluble in nonaqueous solvents, is prepared in a single synthetic step, has a low equivalent weight of 111 g/(mol.e(-)), and undergoes two reversible 1e(-) reductions in the presence of LiBF4 to form reduced products that are stable over days in solution. PMID- 26514667 TI - Optical forces in nanorod metamaterial. AB - Optomechanical manipulation of micro and nano-scale objects with laser beams finds use in a large span of multidisciplinary applications. Auxiliary nanostructuring could substantially improve performances of classical optical tweezers by means of spatial localization of objects and intensity required for trapping. Here we investigate a three-dimensional nanorod metamaterial platform, serving as an auxiliary tool for the optical manipulation, able to support and control near-field interactions and generate both steep and flat optical potential profiles. It was shown that the 'topological transition' from the elliptic to hyperbolic dispersion regime of the metamaterial, usually having a significant impact on various light-matter interaction processes, does not strongly affect the distribution of optical forces in the metamaterial. This effect is explained by the predominant near-fields contributions of the nanostructure to optomechanical interactions. Semi-analytical model, approximating the finite size nanoparticle by a point dipole and neglecting the mutual re-scattering between the particle and nanorod array, was found to be in a good agreement with full-wave numerical simulation. In-plane (perpendicular to the rods) trapping regime, saddle equilibrium points and optical puling forces (directed along the rods towards the light source), acting on a particle situated inside or at the nearby the metamaterial, were found. PMID- 26514668 TI - Two Quantum Protocols for Oblivious Set-member Decision Problem. AB - In this paper, we defined a new secure multi-party computation problem, called Oblivious Set-member Decision problem, which allows one party to decide whether a secret of another party belongs to his private set in an oblivious manner. There are lots of important applications of Oblivious Set-member Decision problem in fields of the multi-party collaborative computation of protecting the privacy of the users, such as private set intersection and union, anonymous authentication, electronic voting and electronic auction. Furthermore, we presented two quantum protocols to solve the Oblivious Set-member Decision problem. Protocol I takes advantage of powerful quantum oracle operations so that it needs lower costs in both communication and computation complexity; while Protocol II takes photons as quantum resources and only performs simple single-particle projective measurements, thus it is more feasible with the present technology. PMID- 26514669 TI - Comprehensive profiling and characterization of quassinoids from the seeds of Brucea javanica via segment and exposure strategy coupled with modified mass defect filter. AB - Quassinoids, the predominant constituents in the seeds of Brucea javanica (BJ), have gained an increasing interest over the past decades since the discovery of their extensive biological activities. In the present study, a method based on the segment and exposure strategy coupled with two mass spectrometer data acquisition techniques was firstly developed and validated for comprehensive profiling of quassinoids in the seeds of BJ via high-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (HPLC-QTOF/MS). The segment and exposure strategy could significantly improve the detection efficiency for trace quassinoids in the seeds of BJ. Furthermore, the five-point screening approach based on modified mass defect filter (MDF) and the visual isotopic ion technique could rapidly screen the precursor ions of interest. The fragmentation behavior of quassinoids was systematically investigated, and a total of 148 quassinoids including 86 potentially new ones were unambiguously or tentatively identified in the seeds of BJ. Collectively, our results demonstrate that the integrated strategy reported in this study has considerable potential for rapid screening of natural compounds especially for the trace ones in herbal medicines. PMID- 26514670 TI - A powerless on-the-spot detection protocol for transgenic crops within 30 min, from leaf sampling up to results. AB - The requirement of power-dependent instruments or excessive operation time usually restricts current nucleic acid amplification methods from being used for detection of transgenic crops in the field. In this paper, an easy and rapid detection method which requires no electricity supply has been developed. The time-consuming process of nucleic acid purification is omitted in this method. DNA solution obtained from leaves with 0.5 M sodium hydroxide (NaOH) can be used for loop-mediated isothermal amplification (LAMP) only after simple dilution. Traditional instruments like a polymerase chain reaction (PCR) amplifier and water bath used for DNA amplification are abandoned. Three kinds of dewar flasks were tested and it turned out that the common dewar flask was the best. Combined with visual detection of LAMP amplicons by phosphate (Pi)-induced coloration reaction, the whole process of detection of transgenic crops via genetically pure material (leaf material of one plant) could be accomplished within 30 min. The feasibility of this method was also verified by analysis of practical samples. PMID- 26514671 TI - Determination of urinary metabolites of XLR-11 by liquid chromatography quadrupole time-of-flight mass spectrometry. AB - Recently, use of novel synthetic cannabinoids has increased greatly despite worldwide efforts to regulate these drugs. XLR-11 ((1-[5'-fluoropentyl]indol-3 yl)-(2,2,3,3-tetramethylcyclopropyl)methanone), a fluorinated synthetic cannabinoid with a tetramethylcyclopropyl moiety, has been frequently abused since 2012. XLR-11 produces a number of metabolites in common with its non fluorinated parent analogue, UR-144 ((1-pentylindol-3-yl)-(2,2,3,3 tetramethylcyclopropyl)methanone). Therefore, it is essential to develop effective urinary markers to distinguish between these drugs. In this study, we investigated the metabolic profile of authentic human urine specimens from suspected users of XLR-11 using liquid chromatography-quadrupole time-of-flight mass spectrometry. Furthermore, we quantified four potential XLR-11 metabolites by using commercially available reference standards. In vitro metabolism of XLR 11 and UR-144 using human liver microsomes was also investigated to compare patterns of production of hydroxypentyl metabolites. Urine samples were prepared with and without enzymatic hydrolysis, and subjected to solid-phase extraction. We identified 19 metabolites generated by oxidative defluorination, hydroxylation, carboxylation, dehydrogenation, glucuronidation, and combinations of these reactions. Among the identified metabolites, 12 were generated from a cyclopropyl ring-opened XLR-11 degradation product formed during smoking. The XLR 11 metabolite with a hydroxylated 2,4-dimethylpent-1-ene moiety was detected in most specimens after hydrolysis and could be utilized as a specific marker for XLR-11 intake. Quantitative results showed that the concentration ratio of 5- and 4-hydroxypentyl metabolites should also be considered as a useful marker for differentiating between the abuse of XLR-11 and UR-144. PMID- 26514672 TI - Multi-mycotoxin stable isotope dilution LC-MS/MS method for Fusarium toxins in cereals. AB - A multi-mycotoxin stable isotope dilution LC-MS/MS method was developed for 14 Fusarium toxins including modified mycotoxins in cereals (deoxynivalenol, 3 acetyldeoxynivalenol, 15-acetyldeoxynivalenol, HT2-toxin, T2-toxin, enniatin B, enniatin B1, enniatin A1, enniatin A, beauvericin, fusarenone X, nivalenol, deoxynivalenol-3-glucoside, and zearalenone). The chromatographic separation of the toxins with particular focus on deoxynivalenol and deoxynivalenol-3-glucoside was achieved using a C18-hydrosphere column. An expedient sample preparation method was developed that uses solid-phase extraction for the purification of trichothecenes combined with zearalenone, enniatins, and beauvericin and provides excellent validation data. Linearity, intra-day precision, inter-day precision, and recoveries were >=0.9982, 1-6%, 5-12%, and 79-117%, respectively. Method accuracy was verified by analyzing certified reference materials for deoxynivalenol, HT2-toxin, and T2-toxin with deviations below 7%. The results of this method found barley malt samples from 2012, 2013, and 2014 frequently contaminated with high concentrations of enniatin B, deoxynivalenol, and its modified mycotoxin deoxynivalenol-3-glucoside. Samples from 2012 were especially contaminated. Fusarenone X was not detected in any of the analyzed samples. PMID- 26514673 TI - One-pot green hydrothermal synthesis of fluorescent nitrogen-doped carbon nanodots for in vivo bioimaging. AB - One-pot green synthesis of fluorescent nitrogen-doped carbon nanodots (CNDs) was developed by hydrothermal treatments of biocompatible polyvinylpyrrolidone (PVP) and glycine. The fluorescent nitrogen-doped CNDs exhibited excellent water solubility, low cytotoxicity, and good salt stability for biological imaging. UV vis spectroscopy, fluorescence spectroscopy, transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR) spectroscopy, and Raman spectroscopy were applied to confirm the optical and structural characteristics of the CNDs. Fluorescence of the CNDs was tunable from 417 to 450 nm adjusted by different excitation energy. Fluorescent quantum yield of the CNDs (21.43%) was significantly increased ~47.59% in comparison to that of the CNDs (14.52%) without nitrogen doping by glycine. In the in vivo imaging system (IVIS), fluorescence signal of the nitrogen-doped CNDs was obviously observed in the lungs at 12- and 24-h post-injection. Our work has shown the potential applications of the nitrogen-doped CNDs in fluorescence imaging in vivo. PMID- 26514674 TI - The quantum Ising model: finite sums and hyperbolic functions. AB - We derive exact closed-form expressions for several sums leading to hyperbolic functions and discuss their applicability for studies of finite-size Ising spin chains. We show how they immediately lead to closed-form expressions for both fidelity susceptibility characterizing the quantum critical point and the coefficients of the counterdiabatic Hamiltonian enabling arbitrarily quick adiabatic driving of the system. Our results generalize and extend the sums presented in the popular Gradshteyn and Ryzhik Table of Integrals, Series, and Products. PMID- 26514675 TI - Time Trends, Clinical Characteristics, and Risk Factors of Chronic Anal Fissure Among a National Cohort of Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Chronic anal fissure (CAF) is a common problem that causes significant morbidity. Little is known about the risk factors of CAF among patients with inflammatory bowel disease (IBD). AIM: To study the clinical characteristics and prevalence of CAF among a cohort of IBD patients. METHODS: We performed a population-based study on IBD patients from the National Veterans Affairs administrative datasets from 1998 to 2011. IBD and AF were identified by ICD-9 diagnosis codes. RESULTS: We identified 60,376 patients with IBD between the ages of 18-90 years, 94% males, 59% diagnosed with ulcerative colitis (UC), and 88% were Caucasians. The overall prevalence of CAF was 4% for both males and females. African Americans (AA) were two times more likely to have CAF compared to Caucasians (8 vs. 4%; OR 2.0, 95% CI 1.6-20.2, p = 0.0001) or Hispanics (8 vs. 4.8%; OR 2.1, 95% CI 1.4-25.2, p = 0.0001). The prevalence of CAF significantly dropped with age from 7% at age group 20-50 to 1.5% at 60-90 (p = 0.0001). CD patients were two times more likely to have CAF than UC patients (6 vs. 3%; OR 1.9, 95% CI 1.5-18.2, p = 0.0001). The initial diagnosis of CAF occurred within 14 years after the initial diagnosis of IBD in 74.5% patients. CONCLUSIONS: CAF is more prevalent among IBD than what is reported in the general population and diagnosed after the diagnosis of IBD. CAF is more prevalent among patients with CD, younger patients, and AA. The current results lay the groundwork for further outcome studies relate to anal fissure such as utilization, hospitalization, and cost. PMID- 26514676 TI - Keratinocyte Growth Factor Regulation of Aryl Hydrocarbon Receptor Activation in Colorectal Cancer Cells. AB - BACKGROUND: Keratinocyte growth factor (KGF) stimulates normal growth, development and intestinal epithelial cell proliferation. Cyclin D1 promotes the cell cycle by inhibiting retinoblastoma protein (RB1). The activated aryl hydrocarbon receptor (AhR) has an important influence on the development of tumors through its interactions with the cell cycle. AIM: The aim of the present study was to explore a new role for AhR in KGF-induced colon cancer cell growth. MATERIALS AND METHODS: Real-time PCR, western blot or immunofluorescence analysis were used to detect the expression of KGF, AhR, cyclin D1 and CYP1A1. Immunohistochemistry was used to observe the localization of AhR. MTT assay and flow cytometric analyses were performed to measure cell viability and the cell cycle. RESULTS: Real-time PCR analysis revealed that KGF, AhR, and CYP1A1 mRNAs were overexpressed in colorectal cancer tissues. Meanwhile, overexpression of AhR was primarily observed in epithelial cells. In in vitro assay, KGF promoted colon cancer cell growth, as well as up-regulated and activated AhR. At the same time, AhR-knockdown colon cancer cells were less responsive to KGF. Western blot analysis, real-time PCR, or immunofluorescence data indicated that cyclin D1 expression was up-regulated by KGF but this up-regulation was compromised when AhR was silenced, and the cell cycle was arrested in the G0/G1 stage in these cells. CONCLUSIONS: Our study suggests that KGF, AhR, and CYP1A1 are overexpressed in colorectal cancer tissues. Moreover, we reveal a new mechanism by which KGF promotes cell proliferation through the AhR-cyclin D1 pathway in colon cancer cells. PMID- 26514678 TI - Biliary Cystadenoma: A Suggested "Cystamatic" Approach? PMID- 26514679 TI - The paradigm shift in cervical cancer screening in Germany. AB - With the adoption of the Cancer Screening and Registration Law (KFRG, 2013) based on the National Cancer Plan, the so far opportunistic cervical cancer screening in Germany is to be converted to an organized screening program. This decision in Germany is consistent with the new EU Guidelines and, in anticipation of the upcoming German S3 guideline for cervical cancer screening. PMID- 26514680 TI - The sixth Italian Supplement. PMID- 26514677 TI - Association Between Long-Term Lipid Profiles and Disease Severity in a Large Cohort of Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) has been linked to an increased risk of coronary heart disease and stroke. Dyslipidemia is a well-established risk factor for cardiovascular disease. The aim of this study was to investigate the long-term lipid profiles in a large cohort of IBD patients. METHODS: Data of patients from an IBD registry who had more than one measurement of total cholesterol and triglyceride levels during the follow-up period were analyzed. The lipid profiles of IBD patients were compared to those of the general population according to National Health and Nutrition Examination Survey (2009 2012). Quartiles of cholesterol or triglyceride levels in relation to surrogate markers of disease severity were analyzed. RESULTS: Seven hundred and one IBD patients [54% Crohn's disease (CD), 46% ulcerative colitis (UC)] were included. IBD patients had less frequent high total cholesterol and high LDL cholesterol (6 vs. 13 and 5 vs. 10%) and more frequent low HDL and high triglycerides (24 vs. 17 and 33 vs. 25%) compared to the general population (all p < 0.001). Median total cholesterol levels were lower and median triglycerides higher in CD compared to UC (171 vs. 184; 123 vs. 100 mg/dL; both p < 0.001). In the multiple regression analysis, lipid profile was independently associated with hospitalizations (low cholesterol) and IBD surgeries (low cholesterol and high triglycerides). CONCLUSIONS: Low total cholesterol and high triglyceride levels are more frequent in IBD patients (in particular CD) compared to healthy controls and are independently associated with more severe disease. PMID- 26514681 TI - Mono- and di-bromo platinum(IV) prodrugs via oxidative bromination: synthesis, characterization, and cytotoxicity. AB - Platinum(IV)-based anticancer prodrugs have attracted much attention due to their relative inertness under physiological conditions, being activated inside cells, and their capacity for functionalization with a variety of small-molecule or macromolecule moieties. Novel asymmetric platinum(IV) compounds synthesized through expedient and unique methods are desired. Here we utilize N bromosuccinimide (NBS) and carry out oxidative bromination on platinum(II) drugs, namely cisplatin, carboplatin, and oxaliplatin, to obtain asymmetric and mono bromo platinum(IV) prodrugs. Different solvents are used to obtain various compounds, and the compounds are further functionalized. Di-bromo compounds are also obtained through NBS-directed oxidative bromination in ethanol. The crystal structures of representative compounds are discussed, and the reduction potentials of some compounds are examined. A cytotoxicity test shows that the mono- and di-bromo platinum(IV) compounds are active against human ovarian cancer cells. Our study enriches the family of asymmetric platinum(IV) prodrugs and provides with a convenient strategy to obtain brominated platinum(IV) complexes. PMID- 26514682 TI - L-Arginine Pathway in COPD Patients with Acute Exacerbation: A New Potential Biomarker. AB - BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remains a major cause of mortality. Clinical criteria of AECOPD are subjective. Biomarkers for AECOPD may aid in the initiation of early treatment. Increased production of asymmetric and symmetric dimethylarginine (ADMA, SDMA) is related to hypoxia. In COPD, a rise in ADMA results in a shift of L-arginine breakdown, contributing to airway obstruction. We aimed to compare serum levels of ADMA, SDMA and L-arginine in patients with and without AECOPD. METHODS: L-arginine metabolites quantified by high-performance liquid chromatography in venous blood samples and partial capillary oxygen pressure were prospectively investigated in 32 patients with COPD, 12 with AECOPD and 30 healthy subjects. RESULTS: Both ADMA and SDMA were significantly higher in AECOPD compared to stable COPD (p = 0.004 and p < 0.001, respectively). Oxygen content in capillaries correlated with serum ADMA concentration. However, the concentration of L-arginine was not different between AECOPD and stable COPD. Both ADMA and SDMA separated AECOPD with high sensitivity and specificity (AUC: 0.81, p = 0.001; AUC: 0.91, p < 0.001, respectively). A cut-off value >=0.57 for SDMA was an independent variable to confirm AECOPD in a regression model (OR: 1.632, p = 0.001). All markers were significantly higher in the sera of both patient groups compared to the controls (p < 0.05, respectively). CONCLUSIONS: COPD is associated with elevated L arginine, ADMA and SDMA serum levels. In patients with AECOPD, production of ADMA and SDMA are more pronounced presumably due to more severe hypoxic insult. Methylated arginine derivatives in the sera may help early recognition of AECOPD. PMID- 26514683 TI - An open tool for input function estimation and quantification of dynamic PET FDG brain scans. AB - PURPOSE: Positron emission tomography (PET) analysis of clinical studies is mostly restricted to qualitative evaluation. Quantitative analysis of PET studies is highly desirable to be able to compute an objective measurement of the process of interest in order to evaluate treatment response and/or compare patient data. But implementation of quantitative analysis generally requires the determination of the input function: the arterial blood or plasma activity which indicates how much tracer is available for uptake in the brain. The purpose of our work was to share with the community an open software tool that can assist in the estimation of this input function, and the derivation of a quantitative map from the dynamic PET study. METHODS: Arterial blood sampling during the PET study is the gold standard method to get the input function, but is uncomfortable and risky for the patient so it is rarely used in routine studies. To overcome the lack of a direct input function, different alternatives have been devised and are available in the literature. These alternatives derive the input function from the PET image itself (image-derived input function) or from data gathered from previous similar studies (population-based input function). In this article, we present ongoing work that includes the development of a software tool that integrates several methods with novel strategies for the segmentation of blood pools and parameter estimation. RESULTS: The tool is available as an extension to the 3D Slicer software. Tests on phantoms were conducted in order to validate the implemented methods. We evaluated the segmentation algorithms over a range of acquisition conditions and vasculature size. Input function estimation algorithms were evaluated against ground truth of the phantoms, as well as on their impact over the final quantification map. End-to-end use of the tool yields quantification maps with [Formula: see text] relative error in the estimated influx versus ground truth on phantoms. CONCLUSIONS: The main contribution of this article is the development of an open-source, free to use tool that encapsulates several well-known methods for the estimation of the input function and the quantification of dynamic PET FDG studies. Some alternative strategies are also proposed and implemented in the tool for the segmentation of blood pools and parameter estimation. The tool was tested on phantoms with encouraging results that suggest that even bloodless estimators could provide a viable alternative to blood sampling for quantification using graphical analysis. The open tool is a promising opportunity for collaboration among investigators and further validation on real studies. PMID- 26514684 TI - A general method for cupping artifact correction of cone-beam breast computed tomography images. AB - PURPOSE: Cone-beam breast computed tomography (CBBCT), a promising breast cancer diagnostic technique, has been under investigation for the past decade. However, owing to scattered radiation and beam hardening, CT numbers are not uniform on CBBCT images. This is known as cupping artifact, and it presents an obstacle for threshold-based volume segmentation. In this study, we proposed a general post reconstruction method for cupping artifact correction. METHODS: There were four steps in the proposed method. First, three types of local region histogram peaks were calculated: adipose peaks with low CT numbers, glandular peaks with high CT numbers, and unidentified peaks. Second, a linear discriminant analysis classifier, which was trained by identified adipose and glandular peaks, was employed to identify the unidentified peaks as adipose or glandular peaks. Third, adipose background signal profile was fitted according to the adipose peaks using the least squares method. Finally, the adipose background signal profile was subtracted from original image to obtain cupping corrected image RESULTS: In experimental study, standard deviation of adipose tissue CT numbers was obviously reduced and the CT numbers were more uniform after cupping correction by proposed method; in simulation study, root-mean-square errors were significantly reduced for both symmetric and asymmetric cupping artifacts, indicating that the proposed method was effective to both artifacts. CONCLUSIONS: A general method without a circularly symmetric assumption was proposed to correct cupping artifacts in CBBCT images for breast. It may be properly applied to images of real patient breasts with natural pendent geometry. PMID- 26514685 TI - Industry-academia collaborations for biomarkers. AB - Several types of collaboration are being pursued to identify, validate and apply new biomarkers. Here, we highlight examples of such initiatives and discuss the challenges, approaches to address these challenges and key factors for success. PMID- 26514686 TI - Evaluation of a glycoengineered monoclonal antibody via LC-MS analysis in combination with multiple enzymatic digestion. AB - Glycosylation affects the efficacy, safety and pharmacokinetics/pharmacodynamics properties of therapeutic monoclonal antibodies (mAbs), and glycoengineering is now being used to produce mAbs with improved efficacy. In this work, a glycoengineered version of rituximab was produced by chemoenzymatic modification to generate human-like N-glycosylation with alpha 2,6 linked sialic acid. This modified rituximab was comprehensively characterized by liquid chromatography mass spectrometry and compared to commercially available rituximab. As anticipated, the majority of N-glycans were converted to alpha 2,6 linked sialic acid, in contrast to CHO-produced rituximab, which only contains alpha 2,3 linked sialic acid. Typical posttranslational modifications, such as pyro-glutamic acid formation at the N-terminus, oxidation at methionine, deamidation at asparagine, and disulfide linkages were also characterized in both the commercial and glycoengineered mAbs using multiple enzymatic digestion and mass spectrometric analysis. The comparative study reveals that the glycoengineering approach does not cause any additional posttranslational modifications in the antibody except the specific transformation of the glycoforms, demonstrating the mildness and efficiency of the chemoenzymatic approach for glycoengineering of therapeutic antibodies. PMID- 26514687 TI - Successful treatment of an adult with symptomatic attention deficit, hyperactivity, and impulsivity after temporal lobe resection: case report. AB - Attention deficit hyperactivity disorder (ADHD) is defined by inattentiveness, impulsivity, and/or hyperactivity and mandatorily requires an onset in childhood. Structural or functional anatomical abnormalities have mostly been found in the prefrontal cortex, the corpus callosum, the striatum, and the cerebellum. We here present the case of an adult woman who developed severe symptoms analogous to ADHD after right temporal lobectomy. Surgery had been necessary because of a large temporobasal arterio-venous malformation (AVM). The patient's childhood and personal history before surgery had been without any indication of ADHD or any other mental disorder. Because of her distinct and impairing symptoms of ADHD, we initiated off-label methylphenidate treatment, achieving strong reduction in the symptoms. This proves further similarity of her symptomatic disorder to ADHD and supports a role of the right temporal lobe in ADHD. PMID- 26514688 TI - Hydrogen Bond and Ligand Dissociation Dynamics in Fluoride Sensing of Re(I) Polypyridyl Complex. AB - Hydrogen bonding interaction plays an essential role in the early phases of molecular recognition and colorimetric sensing of various anions in aprotic media. In this work, the host-guest interaction between fac-[Re(CO)3Cl(L)] with L = 4-([2,2'-bipyridin]-4-yl)phenol and fluoride ions is investigated for the hydrogen bond dynamics and the changing local coordination environment. The stoichiometric studies using (1)H NMR and ESI-MS spectroscopies have shown that proton transfer in the H-bonded phenol-fluoride complex activates the dissociation of the CO ligand in the Re(I) center. The phenol-to-phenolate conversion during formation of HF2(-) ion induces nucleophilic lability of the CO ligand which is probed by intraligand charge transfer (ILCT) and ligand-to-metal charge transfer (LMCT) transitions in transient absorption spectroscopy. After photoexcitation, phenol-phenoxide conversion rapidly equilibrates in 280 fs time scale and the ensuing excited state [Re(II)(bpy*(-)-phenolate-) (CO)3Cl]* undergoes CO dissociation in the ultrafast time scale of ~3 ps. A concerted mechanism of hydrogen cleavage and coordination change is established in anion sensing studies of the rhenium complex. PMID- 26514689 TI - The influence of 1.5 and 3 T magnetic resonance unit magnetic fields on the movement of steel-jacketed projectiles in ordnance gelatin. AB - PURPOSE: Ferromagnetic bullets can move in air or gelatin in magnetic resonance (MR) units. According to our experience, ferromagnetic bullets do not always present consistent movement. We examined factors affecting ferromagnetic projectile movement in a 1.5T and a 3T MR unit, focusing in this study on the steel-jacketed Swiss ordnance ammunition 7.5 mm GP11 Suisse. METHODS: Five 7.5 mm GP11 Suisse bullets were embedded horizontally and vertically in 10 % ordnance gelatin phantoms. Before and after exposing the bullets to 1.5T (Siemens) and 3T (Philips) MR units each bullet's position was documented by a CT scan. In a second phase, the magnetic polarization of the bullets in relation to the MR units was measured by a dry magnetic portable compass (Suunto). RESULTS: Our results showed that the displacement of the bullets increased when subjected to a stronger magnetic field (max. Movement 1.5T: 24.4 mm vs. 3T: 101.5 mm) and that the position, i.e. orientation of the bullet toward the gantry, strongly influenced its mobility (horizontally embedded projectiles showed poor movement, vertically placed ones strong movement). One of the bullets presented a 180 degrees rotation in the 3T MR unit. Magnetization and changing of the polarization of these ferromagnetic bullets is possible when subjected to MR units. CONCLUSION: In conclusion, the location of a bullet, and its orientation toward the gantry must be taken into account when assessing the risk of performing an MR examination on a gunshot victim in clinical and in forensic cases. PMID- 26514690 TI - Metamemory function in chemotherapy-treated patients with breast cancer: an explanation for the dissociation between subjective and objective memory measures? AB - BACKGROUND: The purpose of this study was to determine if a deficit in metamemory could account for the disparity between subjective and objective measures of memory function commonly observed in patients with breast cancer (BC). Metamemory refers to the awareness and management of one's own memory function. It is considered an aspect of executive functioning, one of the most common areas of cognitive compromise associated with BC and its treatment. METHODS: Fifty-four women with early stage BC who had recently completed chemotherapy were compared with 54 healthy women matched on age and education. Cognitive function was objectively assessed with a neuropsychological test battery and subjectively assessed with the Functional Assessment of Cancer Therapy Cognitive Scale. Metamemory was assessed with a Feeling of Knowing (FOK) paradigm. RESULTS: The patients with BC scored significantly lower than the controls on both the objective and subjective cognitive measures, as well as on free recall and recognition conditions of the FOK, suggesting some decline in primary memory functions such as working memory, encoding, and retrieval. The discrepancy between the objective and subjective measures was larger in the patients with BC than in the controls, but there was no difference between the groups on the FOK metamemory index. CONCLUSIONS: Discrepancy in objective and subjective measures of cognition in patients with BC cannot be accounted for in terms of a deficit in meta-cognition. Objective and subjective measures are complementary, and a comprehensive cognitive assessment in patients with BC requires both. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26514691 TI - Benzene Exposures and Risk Potential for Vehicle Mechanics from Gasoline and Petroleum-Derived Products. AB - Benzene exposures among vehicle mechanics in the United States and abroad were characterized using available data from published and unpublished studies. In the United States, the time-weighted-average (TWA) airborne concentration of benzene for vehicle mechanics averaged 0.01-0.05 ppm since at least the late 1970s, with maximal TWA concentrations ranging from 0.03 to 0.38 ppm. Benzene exposures were notably lower in the summer than winter and in the Southwest compared to other geographic regions, but significantly higher during known gasoline-related tasks such as draining a gas tank or changing a fuel pump or fuel filter. Measured airborne concentrations of benzene were also generally greater for vehicle mechanics in other countries, likely due to the higher benzene content of gasoline and other factors. Short-term airborne concentrations of benzene frequently exceeded 1 ppm during gasoline-related tasks, but remained below 0.2 ppm for tasks involving other petroleum-derived products such as carburetor and brake cleaner or parts washer solvent. Application of a two-zone mathematical model using reasonable input values from the literature yielded predicted task based benzene concentrations during gasoline and aerosol spray cleaner scenarios similar to those measured for vehicle mechanics during these types of tasks. When evaluated using appropriate biomarkers, dermal exposures were found to contribute little to total benzene exposures for this occupational group. Available data suggest that vehicle mechanics have not experienced significant exposures to benzene in the workplace, except perhaps during short-duration gasoline-related tasks, and full-shift benzene exposures have remained well below current and contemporaneous occupational exposure limits. These findings are consistent with epidemiology studies of vehicle mechanics, which have not demonstrated an increased risk of benzene-induced health effects in this cohort of workers. Data and information presented here may be used to assess past, current, or future exposures and risks to benzene for vehicle mechanics who may be exposed to gasoline or other petroleum-derived products. PMID- 26514692 TI - Formation of Nanoporous Gold Studied by Transmission Electron Backscatter Diffraction. AB - Transmission electron backscatter diffraction (t-EBSD) was used to investigate the effect of dealloying on the microstructure of 140-nm thin gold foils. Statistical and local comparisons of the microstructure between the nonetched and nanoporous gold foils were made. Analyses of crystallographic texture, misorientation distribution, and grain structure clearly prove that during the dealloying manufacturing process of nanoporous materials the crystallographic texture is enhanced significantly with a clear decrease of internal strain, whereas maintaining the grain structure. PMID- 26514693 TI - Marital stability, satisfaction and well-being in old age: variability and continuity in long-term continuously married older persons. AB - OBJECTIVES: Recent research shows that the well-documented positive effects of marital stability on well-being and health outcomes are conditional upon the quality of marriage. To date, few studies have explored the relationship between marital satisfaction, well-being and health among very long-term married individuals. This study aims at identifying groups of long-term married persons with respect to marital satisfaction and comparing them longitudinally concerning their well-being outcomes, marital stressors, personality and socio-demographic variables. METHOD: Data are derived from a survey (data collection 2012 and 2014) with 374 continuously married individuals at wave 1 (mean age: 74.2 years, length of marriage: 49.2 years) and 252 at wave 2. Cluster analyses were performed comparing the clusters with regard to various well-being outcomes. The predictive power of cluster affiliation and various predictors at wave 1 on well-being outcomes at wave 2 was tested using regression analyses. RESULTS: Two groups were identified, one happily the other unhappily married, with the happily married scoring higher on all well-being and health outcomes. Regression analyses revealed that group affiliation at wave 1 was not any longer predictive of health, emotional loneliness and hopelessness two years later, when taking into account socio-demographic variables, psychological resilience and marital strain, whereas it remained an important predictor of life satisfaction and social loneliness. CONCLUSION: Marital satisfaction is associated with health and well being in older couples over time, whereas psychological resilience and marital strain are major predictors explaining the variance of these outcomes. PMID- 26514694 TI - Facet-controlled facilitation of PbS nanoarchitectures by understanding nanocrystal growth. AB - Nanostructured lead sulphide is a significant component in a number of energy related sustainable applications such as photovoltaic cells and thermoelectric components. In many micro-packaging processes, dimensionality-controlled nano architectures as building blocks with unique properties are required. This study investigates different facet-merging growth behaviors through a wet-chemical synthetic strategy to produce high-quality controlled nanostructures of lead sulphide in various dimensionalities. It was found that 1D nanowires or 2D nanosheets can be obtained by the merging of reactive {111}- or {110}-facets, respectively, while promoting {100} facets in the early stages after nucleation leads to the growth of 0D nanocubes. The influence of temperature, capping ligands and co-solvent in facilitating the crystal facet growth of each intermediate seed is also demonstrated. The novelty of this work is characterized by the delicate manipulation of various PbS nanoarchitectures based on the comprehension of the facet-merging evolution. The synthesis of facet-controlled PbS nanostructures could provide novel building blocks with desired properties for use in many applications. PMID- 26514695 TI - A rare case of primary congenital glaucoma in combination with neurofibromatosis 1: a case report. AB - BACKGROUND: Neurofibromatosis 1 (NF1) is a common disease that mainly affects the skin and peripheral nervous system, and is characterized by bony dysplasia. Primary congenital glaucoma (PCG) is a sight-threatening disease that can manifest as a prodrome of NF1, especially in newborn babies. We report a case of PCG with NF 1. CASE PRESENTATION: A 1-month-old boy presented with an enlarged right eyeball. An increased IOP and typical glaucomatous optic neuropathy were found, on the initial physical examination, a clinical diagnosis of primary congenital glaucoma (PCG) was made and a trabeculectomy with mitomycin C (MMC) therapy was subsequently performed. Three year later, the boy again presented with an even larger right eye and a gradually expanding left one. In addition to typical glaucomatous optic neuropathy, the boy also had multiple cafe au lait patches all over his body, megacephaly (head circumference = 60 cm; body weight = 14 kg; height = 93 cm) and remarkable facial features included swollen, soft upper eyelids and a flat, broad nose sphenoid wing dysplasia, eyelid thickening, bony orbit enlargement were found. CONCLUSIONS: It is rare have both PCG and NF1, and PCG may be a prelude to NF1. Continuous follow-up should be advised and we should raise our awareness of the combined condition and to improve chances for an early diagnosis. PMID- 26514696 TI - Analysis of mycotoxins in coffee and risk assessment in Spanish adolescents and adults. AB - Mycotoxins are toxic compounds produced by fungal secondary metabolism that cause toxicological effects. Coffee is a highly popular beverage that is susceptible to contamination by mycotoxigenic fungi. The aim of the present study was to determine the presence of the following 21 mycotoxins in coffee using liquid chromatography tandem mass spectrometry (LC-MS/MS-IT): aflatoxin B1, B2, G1 and G2; ochratoxin A; nivalenol; deoxynivalenol; 3-acetyldeoxynivalenol; 15 acetyldeoxynivalenol; diacetoxyscirpenol; neosolaniol; T-2 and HT-2 toxin; sterigmatocystin; enniatin A, A1, B, and B1; beauvericin; and fumonisin B1 and B2. We aimed to determine differences by coffee process (coffee maker, electrical machine, soluble and traditional Turkish process) and to calculate the estimated daily intake (EDI) and risk assessment of mycotoxins from coffee consumption using deterministic approach at various scenarios of food consumption in Spanish adolescents and adults. The results demonstrate that all studied mycotoxins were detected in samples with mean concentrations ranging from 0.69 ug/kg to 282.89 ug/kg. Eleven percent of samples did not show contamination with legislated mycotoxins. Only 15-acetyldeoxynivalenol, deoxynivalenol, neosolaniol, fumonisin B1, and ochratoxin A exhibited significant differences between methods of coffee brewing. The results show that coffee intake does not represent a potential risk for consumers with respect to individual mycotoxin contamination. PMID- 26514697 TI - A dietary two-generation reproductive toxicity study of (2R,4R)-monatin salt in Crl:CD(SD) rats. AB - (2R,4R)-Monatin salt [sodium/potassium 2R,4R-2-amino-4-carboxy-4-hydroxy-5-(3 indolyl) pentanoate] was fed at 5000, 15,000, or 35,000 ppm to Crl:CD(SD) rats over two generations. Reduced body weights were observed at all dose levels. Sustained effect on body weight gain at 35,000 ppm in the F0 and F1 parental animals was associated with lower feed efficiency, soft stool, and slightly lower numbers of implantation sites. Lower numbers of pups born and live litter size at 35,000 ppm were considered secondary to slightly lower numbers of former implantation sites in the dams. Spermatogenic endpoints, estrous cyclicity, reproductive performance, mean gestation length, and parturition were unaffected in the F0 and F1 generations. There were no effects on F1 and F2 generation postnatal survival. Reduced pre-weaning pup body weights at 35,000 ppm resulted in lower F1 and F2 body weights at study termination. Slight delays in pubertal landmarks in the F1 offspring were considered secondary to the reduced pup body weights. The no-observed-adverse-effect level (NOAEL) was 15,000 ppm for systemic, reproductive, and neonatal effects based on test article-related effects on body weight and food efficiency, slight decrease in maternal implantation sites and corresponding reduction in live litter size, and reductions in pre-weaning pup body weights at 35,000 ppm. PMID- 26514698 TI - Vibrio galatheae sp. nov., a member of the family Vibrionaceae isolated from a mussel. AB - Based on genetic, chemotaxonomic and phenotypic characteristics, a novel species belonging to the genus Vibrio is described. The facultatively anaerobic strain S2757T was isolated from a mussel collected in the Solomon Sea (Solomon Islands). Phylogenetic analyses based on sequences of 16S rRNA and fur genes indicated affiliation of the strain to a novel species. This observation was supported by a multilocus sequence analysis including sequences of the housekeeping genes 16S rRNA, gyrB, pyrH, recA and topA. In silico DNA-DNA hybridization and average nucleotide identity values comparing the genomic sequence of strain S2757T with those of closely related type strains were lower than 23 and 82 %, respectively. The DNA G+C content of the strain was 45.3 mol%. Phenotypic and chemotaxonomic analyses clearly differentiated the strain from other Vibrio species. Hence, strain S2757T should be considered to represent a novel species of the genus Vibrio, for which the name Vibrio galatheae sp. nov. is proposed. The type strain is S2757T ( = DSM 100497T = LMG 28895T). PMID- 26514699 TI - Review and evaluation of penalised regression methods for risk prediction in low dimensional data with few events. AB - Risk prediction models are used to predict a clinical outcome for patients using a set of predictors. We focus on predicting low-dimensional binary outcomes typically arising in epidemiology, health services and public health research where logistic regression is commonly used. When the number of events is small compared with the number of regression coefficients, model overfitting can be a serious problem. An overfitted model tends to demonstrate poor predictive accuracy when applied to new data. We review frequentist and Bayesian shrinkage methods that may alleviate overfitting by shrinking the regression coefficients towards zero (some methods can also provide more parsimonious models by omitting some predictors). We evaluated their predictive performance in comparison with maximum likelihood estimation using real and simulated data. The simulation study showed that maximum likelihood estimation tends to produce overfitted models with poor predictive performance in scenarios with few events, and penalised methods can offer improvement. Ridge regression performed well, except in scenarios with many noise predictors. Lasso performed better than ridge in scenarios with many noise predictors and worse in the presence of correlated predictors. Elastic net, a hybrid of the two, performed well in all scenarios. Adaptive lasso and smoothly clipped absolute deviation performed best in scenarios with many noise predictors; in other scenarios, their performance was inferior to that of ridge and lasso. Bayesian approaches performed well when the hyperparameters for the priors were chosen carefully. Their use may aid variable selection, and they can be easily extended to clustered-data settings and to incorporate external information. PMID- 26514701 TI - Thriving as Healthy Perioperative Nurses. PMID- 26514700 TI - Puerarin attenuates severe burn-induced acute myocardial injury in rats. AB - BACKGROUND: Puerarin, the main isoflavone glycoside extracted from the root of Pueraria lobata, is widely prescribed for patients with cardiovascular disorders in China. This study investigates the effect of puerarin on severe burn-induced acute myocardial injury in rats and its underlying mechanisms. MATERIALS AND METHODS: Healthy adult Wistar rats were divided into three groups: (1) sham group, sham burn treatment; (2) burn group, third-degree burns over 30% of the total body surface area (TBSA) with lactated Ringer's solution for resuscitation; and (3) burn plus puerarin group, third-degree burns over 30% of TBSA with lactated Ringer's solution containing puerarin for resuscitation. The burned animals were sacrificed at 1, 3, 6, 12, and 24 h after burn injury. Myocardial injury was evaluated by analyzing serum creatine kinase MB fraction (CK-MB) activity and cardiac troponin T (cTNT) level. Changes in cardiomyocyte ultrastructure were also determined using a transmission electron microscope. Tumor necrosis factor (TNF)-alpha concentration in serum was measured by radioimmunoassay. Cardiac myeloperoxidase (MPO) activity and malondialdehyde (MDA) concentration were measured to determine neutrophil infiltration and oxidative stress in the heart, respectively. The expression of p38 mitogen activated protein (MAP) kinase in the heart was determined by Western blot analysis. RESULTS: After the 30% TBSA full-thickness burn injury, serum CK-MB activities and cTnT levels increased markedly, both of which were significantly decreased by the puerarin treatment. The level of serum TNF-alpha concentration in burn group at each time-point was obviously higher than those in sham group (1.09+/-0.09 ng/ml), and it reached the peak value at 12 h post burn. Burn trauma also resulted in worsen ultrastructural condition, elevated MPO activity and MDA content in heart tissue, and a significant activation of cardiac p38 MAP kinase. Administration of puerarin improved the ultrastructural changes in cardiomyocytes, decreased TNF-alpha concentration in serum as well as suppressed cardiac MPO activity and reduced MDA content, and abolished the activation of p38 MAP kinase in heart tissue after severe burn. CONCLUSIONS: These results suggest that puerarin attenuates inflammatory responses, reduces neutrophil infiltration and oxidative stress in the heart, and protects against acute myocardial injury induced by severe burn. PMID- 26514702 TI - The Benefits of Enhanced Recovery Pathways in Perioperative Care. PMID- 26514703 TI - A Few Minutes With Beverly Kirchner. PMID- 26514704 TI - Successful Implementation of an Enhanced Recovery Pathway: The Nurse's Role. AB - Enhanced recovery pathways (ERPs) are standardized, multidisciplinary approaches to caring for patients with a goal of decreasing length of stay and care costs without negatively affecting patient outcomes. One facility successfully implemented ERPs for patients undergoing abdominal surgery. For implementation to be successful, nurses were found to be key in providing education, perioperative care, and postoperative evaluation, as well as cost containment. The implementation team collaborated to define, design, implement, and audit an ERP for surgical services. Initial audits demonstrated an increase in compliance with order set use (61% to 93%) and use of ERPs more than standardized order sets (< 1% to 27%), as well as decreased use of daily laboratory orders (94% to 62%) and elimination of automatically ordered laboratory tests (38% to 0%). These results led to the conclusion that the nurse's role is essential for education and successful use of the pathways and that best practices for developing ERPs requires consistency across the care team, diligence to ensure compliance, and use of an audit tool for quality improvement. PMID- 26514705 TI - Enhanced Recovery in a Minimally Invasive Thoracic Surgery Program. AB - Enhanced Recovery After Surgery (ERAS(r)) is a strategy that seeks to reduce patients' perioperative stress response, thereby reducing potential complications, decreasing hospital length of stay, and enabling patients to return more quickly to their baseline functional status. The concept was introduced in the late 1990s and was first adopted for use with patients undergoing open colorectal surgery. Since that time, the concept of ERAS has spread to multiple surgical specialties. This article explores the changes in patient care using an ERAS framework in a minimally invasive thoracic surgery program, barriers to implementation, and patient outcomes. PMID- 26514706 TI - Use of Transversus Abdominis Plane (TAP) Blocks for Pain Management in Elderly Surgical Patients. AB - Elderly patients who require surgical interventions often have multiple comorbidities that complicate their intraoperative and postoperative care. Surgical team members should consider all potential problems that elderly patients may experience and base perioperative care on their assessment. This article discusses the use of the transversus abdominis plane (TAP) block in elderly patients undergoing surgical procedures to relieve pain and reduce the use of narcotics or sedatives during the immediate and extended postoperative recovery period. By reducing postoperative pain and the use of sedatives and narcotics, the TAP block improves pain management and helps reduce the incidence of postoperative delirium, pneumonia, urinary retention, and falls. PMID- 26514707 TI - The Hidden Costs of Reconciling Surgical Sponge Counts. AB - Retained surgical sponges are serious adverse events that can result in negative patient outcomes. The primary method of prevention is the sponge count. Searching for sponges to reconcile counts can result in inefficient use of OR time. The purpose of this descriptive study was to estimate the cost of nonproductive OR time (ie, time spent not moving forward with the surgical procedure) spent reconciling surgical sponge counts and the cost of using radiography to rule out the presence of retained sponges. We included 13,322 patient surgeries during a nine-month period. Perioperative personnel required from one to 90 minutes of additional time to reconcile each of 212 incorrect/unresolved counts. The total annualized cost of OR time spent searching for sponges and ruling out the presence of potentially retained sponges using radiography was $219,056. These costs should be included in comprehensive cost analyses when considering alternatives to supplement the surgical count. PMID- 26514708 TI - Back to Basics: Guideline Review and Commenting. AB - Professional guidelines are based on evidence. AORN develops the Guidelines for Perioperative Practice based on a review of pertinent evidence; however, perioperative nurses should participate in the review and public commenting process for these practice guidelines. This article explains how nurses can participate to strengthen the guidelines and help make them accurate and applicable to perioperative practice. PMID- 26514709 TI - Can Wireless Devices Improve Communication? PMID- 26514710 TI - Perioperative Policy: 2015 Legislation in Review. PMID- 26514711 TI - Moderate Sedation: A Primer for Perioperative Nurses. PMID- 26514712 TI - Clinical Issues-November 2015. AB - Unique device identifier Key words: unique device identifier, UDI, FDA UDI. Wearing a dosimeter Key words: dosimeter, radiation monitoring device. PMID- 26514713 TI - May I Have Another? - Medication Error. PMID- 26514714 TI - The Clinical Use of Intravenous Acetaminophen Postoperatively on Patients Who Have Undergone Bowel Surgery. AB - The purpose of this quality improvement project was to determine the effect of using IV acetaminophen postoperatively for 48 hours or until a return to a general diet in adult patients who have undergone bowel surgery at a Midwestern hospital. The sample included 50 adults who underwent bowel surgery and a comparison group of 50 adult patients of the same surgeons who received usual care before the intervention period. Outcome measures included the number of narcotic requests after surgery and the number of hours from the end surgical time to (1) first bowel movement, (2) return to a general diet, (3) first hallway ambulation, and (4) discharge. The data analysis revealed a significant improvement in the time to ambulation (acetaminophen group, 14.46 hours versus 30.51 hours; P = .036). The results of this project inform current postoperative care management at the Midwestern hospital in which the project was conducted. PMID- 26514715 TI - Standardizing the Handling of Surgical Specimens. AB - To standardize the handling of surgical specimens, the OR clinical educators in a community hospital setting devised a series of departmental changes as a quality improvement project. A newly created skill validation was reviewed in an hour long educational meeting with all OR staff members. In addition to creating a new annual skill validation, discussions about specimens were included in the hand over, the time out, and a newly instituted debriefing tool to be used toward the end of a procedure. This interdisciplinary group devised interventions to improve the process of handling specimens such as standardizing the labeling process and changing the transparency of the specimen container. The goal was to assure standardization of specimen handling, specifically to assist novice staff members, and to harmonize inconsistencies between specialties within the practice of existing staff members. These combined methods helped to ensure accurate communication and procurement of specimens for all procedures. PMID- 26514716 TI - Compassion in Health Care: An Empirical Model. AB - CONTEXT: Compassion is frequently referenced as a hallmark of quality care by patients, health care providers, health care administrators, and policy makers. Despite its putative centrality, including its institution in recent health care reform, an empirical understanding based on the perspectives of patients, the recipients of compassion, is lacking-making compassion one of the most referenced yet poorly understood elements of quality care. OBJECTIVES: The objective of this study was to investigate palliative cancer patients' understanding and experiences of compassion to provide a critical perspective on the nature and importance of compassion. METHODS: This grounded theory study used semi structured interviews to investigate how patients understand and experience compassion in clinical care. Using convenience and theoretical sampling, 53 advanced cancer inpatients were recruited over a seven-month period from a specialized palliative care unit and hospital-wide palliative care service within a Canadian urban setting. Data were analyzed by four members of the research team through the three stages of Straussian grounded theory. RESULTS: Qualitative analysis yielded seven categories, each containing distinct themes and subthemes. Together, they constitute components of the compassion model-the first empirically based clinical model of compassion. The model defines compassion as a virtuous response that seeks to address the suffering and needs of a person through relational understanding and action. CONCLUSION: The components of the compassion model provide insight into how patients understand and experience compassion, providing the necessary empirical foundation to develop future research, measures, training, and clinical care based on this vital feature of quality care. PMID- 26514717 TI - Does Increasing Home Care Nursing Reduce Emergency Department Visits at the End of Life? A Population-Based Cohort Study of Cancer Decedents. AB - CONTEXT: Despite being commonplace in health care systems, little research has described home care nursing's effectiveness to reduce acute care use at the end of life. OBJECTIVES: To examine the temporal association between home care nursing rate on emergency department (ED) visit rate in the subsequent week during the last six months of life. METHODS: We conducted a retrospective cohort study of end-of-life cancer decedents in Ontario, Canada, from 2004 to 2009 by linking administrative databases. We examined the association between home care nursing rate of one week with the ED rate in the subsequent week closer to death, controlling for covariates and repeated measures among decedents. Nursing was dichotomized into standard and end-of-life care intent. RESULTS: Our cohort included 54,576 decedents who used home care nursing services in the last six months before death, where 85% had an ED visit and 68% received end-of-life home care nursing. Patients receiving end-of-life nursing at any week had a significantly reduced ED rate in the subsequent week of 31% (relative rate [RR] 0.69; 95% confidence interval [CI] 0.68, 0.71) compared with standard nursing. In the last month of life, receiving end-of-life nursing and standard nursing rate of more than five hours/week was associated with a decreased ED rate of 41% (RR 0.59, 95% CI 0.58, 0.61) and 32% (RR 0.68, 95% CI 0.66, 0.70), respectively, compared with standard nursing of one hour/week. CONCLUSION: Our study showed a temporal association between receiving end-of-life nursing in a given week during the last six months of life, and of more standard nursing in the last month of life, with a reduced ED rate in the subsequent week. PMID- 26514718 TI - In a Serving Profession, Family Makes a Difference. PMID- 26514719 TI - SuperTracker Groups: Connecting Registered Dietitian Nutritionists with Clients. PMID- 26514720 TI - Position of the Academy of Nutrition and Dietetics: Health Implications of Dietary Fiber. AB - It is the position of the Academy of Nutrition and Dietetics that the public should consume adequate amounts of dietary fiber from a variety of plant foods. Dietary fiber is defined by the Institute of Medicine Food Nutrition Board as "nondigestible carbohydrates and lignin that are intrinsic and intact in plants." Populations that consume more dietary fiber have less chronic disease. Higher intakes of dietary fiber reduce the risk of developing several chronic diseases, including cardiovascular disease, type 2 diabetes, and some cancers, and have been associated with lower body weights. The Adequate Intake for fiber is 14 g total fiber per 1,000 kcal, or 25 g for adult women and 38 g for adult men, based on research demonstrating protection against coronary heart disease. Properties of dietary fiber, such as fermentability and viscosity, are thought to be important parameters influencing the risk of disease. Plant components associated with dietary fiber may also contribute to reduced disease risk. The mean intake of dietary fiber in the United States is 17 g/day with only 5% of the population meeting the Adequate Intake. Healthy adults and children can achieve adequate dietary fiber intakes by increasing their intake of plant foods while concurrently decreasing energy from foods high in added sugar and fat, and low in fiber. Dietary messages to increase consumption of whole grains, legumes, vegetables, fruits, and nuts should be broadly supported by food and nutrition practitioners. PMID- 26514721 TI - Trailblazer Lecture: Why Are Processed Foods So Controversial? PMID- 26514722 TI - Is Medical Nutrition Therapy Considered a Form of Preventive Care and Is It Reimbursable? PMID- 26514723 TI - [Women and acute coronary syndrome with ST elevation: Excess mortality related to longer delays and spontaneous coronary dissection]. AB - The outcome of patients with ST elevation acute coronary syndrome (ACS) has been increasingly improving in the general population over the past few decades. However, detailed analysis of the results show that the reduction in mortality rates is higher in males compared to their female counterparts. The excess mortality rate observed in women, though sometimes questioned, has been widely reported in the literature. The higher mortality rate observed in women with ST elevation ACS can be explained by the presence of aggravating clinical factors such as older age, a higher percentage of diabetics, and a higher frequency of cardiogenic shock. Other factors pertaining to patient management seem to negatively impact the outcome. These factors include a lower use of reperfusion strategies, longer time to treatment mainly as a result of diagnostic uncertainty with respect to a disease, which is believed to affect principally the male gender. The doubts that female patients themselves and their families have about the nature of their symptoms are also present in the medical environment but cease to exist in the catheterization laboratory. This is illustrated in the first clinical case that we present here. Coronary reperfusion is the cornerstone of the therapeutic management of MI. In this context, bleeding complications associated with the implemented treatments can also result in an increased mortality rate in this more vulnerable population. When all the factors likely to influence the prognosis are taken into account, excess mortality seems to persist in women, especially in younger patients. As described in the second clinical case, a distinct physio-pathological factor, more frequent in women, could account for this higher mortality rate. Indeed, spontaneous coronary dissection and intramural hematoma are not always easy to diagnose and may not be adequately managed by reperfusion treatments. In addition, these coronary reperfusion strategies are probably not adapted to this type of ACS. It is, therefore, very important to identify them by angiography coupled with intra-coronary imaging examination when necessary and to carry out further research to adjust our PCI techniques to this pathology. PMID- 26514724 TI - Dual mTORC1/2 inhibition by INK-128 results in antitumor activity in preclinical models of osteosarcoma. AB - Existing evidence has shown that mammalian target of rapamycin (mTOR) overactivation is an important contributor of osteosarcoma (OS) progression. Here, we studied the potential anti-OS activity of a potent mTOR kinase inhibitor: INK-128 (MLN0128). We demonstrated that INK-128 induced potent cytotoxic effects against several human OS cell lines (U2OS, MG-63 and SaOs-2), yet same INK-128 treatment was safe (non-cytotoxic) to OB-6 human osteoblastic cells and MLO-Y4 human osteocytic cells. INK-128 induced caspase-dependent apoptosis in OS cells, but not in MLO-Y4/OB-6 cells. The caspase-3 specific inhibitor (z-DVED-fmk) or the pan caspase inhibitor (z-VAD-fmk) dramatically attenuated INK-128-exerted cytotoxicity against OS cells. Molecularly, INK-128 inhibited activation of mTORC1 (S6K1 and S6 phosphorylations) and mTORC2 (AKT Ser 473 phosphorylation), without affecting AKT Thr-308 phosphorylation in U2OS cells. Significantly, AKT inhibition by MK-2206 (an AKT inhibitor), or AKT1/2 stable knockdown by targeted-shRNA, remarkably sensitized INK-128-induced activity in OS cells. In vivo, oral administration of INK-128 potently inhibited U2OS xenograft growth in severe combined immuno-deficient (SCID) mice. mTORC1/2 activation in xenograft tumors was also suppressed with INK-128 administration. In summary, we show that INK-128 exerts potent anti-OS activity in vitro and in vivo. INK-128 might be further investigated as a novel anti-OS agent. PMID- 26514725 TI - GIV/girdin binds exocyst subunit-Exo70 and regulates exocytosis of GLUT4 storage vesicles. AB - Insulin resistance (IR) is a metabolic disorder characterized by impaired glucose uptake in response to insulin. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the chief conduit for post-receptor signaling. We recently demonstrated that GIV, a Guanidine Exchange Factor (GEF) for the trimeric G protein, Galphai, is a major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind the InsR, IRS1 and PI3K, GIV enhances the InsR-IRS1 Akt-AS160 (RabGAP) signaling cascade and cellular glucose uptake via its GEF function. Phosphoinhibition of GIV-GEF by the fatty-acid/PKCtheta pathway inhibits the cascade and impairs glucose uptake. Here we show that GIV directly and constitutively binds the exocyst complex subunit Exo-70 and also associates with GLUT4-storage vesicles (GSVs) exclusively upon insulin stimulation. Without GIV or its GEF function, membrane association of Exo-70 as well as exocytosis of GSVs in response to insulin are impaired. Thus, GIV is an essential component within the insulin signaling cascade that couples upstream signal transducers within the InsR and G-Protein signaling cascade to downstream vesicular trafficking events within the exocytic pathway. These findings suggest a role of GIV in coordinating key signaling and trafficking events of metabolic insulin response. PMID- 26514726 TI - Regulation of Ripply1 expression in MDCK organoids. AB - Epithelial organs are made of a well-polarized monolayer of epithelial cells, and their morphology must be maintained for their proper function. To examine the genes that are specifically expressed in the late stages of cystogenesis and are involved in maintaining the morphology of the mature cysts, we performed a microarray analysis comparing the mRNA expression between the early and late stages of Madin-Darby Canine Kidney (MDCK) cystogenesis. We found that one of the gene candidates, Ripply1, was expressed higher in the late stages, and its expression was also transiently much higher in the early stages. Although the protein expression showed similar kinetics, depletion of Ripply1 had only a slight effect on organoid growth. Unexpectedly, we found that the Ripply1 protein is degraded by the proteasome system. Mutant analysis suggests that Ripply1 is not ubiquitinated directly, but rather is degraded only after binding to Transducin-like Enhancer of Split (TLE)1, a transcriptional repressor. Ripply1 is degraded in the nucleus, and this degradation is inhibited during the mitosis. These data indicate for the first time that Ripply1 expression is regulated at the protein level. PMID- 26514727 TI - Activation of the NLRP3 inflammasome induces vascular dysfunction in obese OLETF rats. AB - OBJECTIVE: Obesity-induced vascular dysfunction is related to chronic low-grade systemic inflammation. Recent studies indicate that NLRP3, a multiprotein complex formed by NOD-like receptor (NLR) family members, is a key component mediating internal sterile inflammation, but the role in obesity-related vascular dysfunction is largely unknown. In the present study, we investigate whether NLRP3 activation is involved in vascular inflammation in obese Otsuka Long-Evans Tokushima Fatty rats (OLETF). METHODS AND RESULTS: Male OLETF with their control Long-Evans Tokushima Otsuka rats (LETO) were studied at 3 and 12 months of age. Aortic relaxation in response to acetylcholine decreased gradually with age in both strains, with early and persistent endothelium dysfunction in obese OLETF compared with age-matched LETO controls. These changes are associated with parallel changes of aortic endothelial nitric oxide synthase (eNOS) content, macrophage accumulation and intimal thickening. NLRP3 increased in OLETF rats compared to LETO. Consistent with inflammasome activation, the conversion of procaspase-1 to cleaved and activated forms as well as IL-1beta markedly increased in OLETF rats. Additionally, we observed increased expression of dynamin-related protein-1 (Drp1) and decreased fusion-relative protein optic atropy-1(OPA1). Altered mitochondrial dynamics was associated with elevated oxidative stress level in OLETF aortas. CONCLUSIONS: These results demonstrate that obesity seems to accelerate endothelial dysfunction in OLETFs via the activation of NLRP3 and mitochondrial dysfunction. PMID- 26514728 TI - Epileptic patients with de novo STXBP1 mutations: Key clinical features based on 24 cases. AB - OBJECTIVE: Mutations in the syntaxin binding protein 1 gene (STXBP1) have been associated mostly with early onset epileptic encephalopathies (EOEEs) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography (EEG) features associated with STXBP1-related epilepsies to orient molecular screening. METHODS: We screened STXBP1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging (MRI) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP1 found using array comparative genomic hybridization (CGH). RESULTS: We found a mutation of STXBP1 in 22 patients and included 2 additional patients with a deletion including STXBP1. In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression-burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%. SIGNIFICANCE: Our data confirm that STXBP1 mutations are associated with neonatal-infantile epileptic encephalopathies. The initial key features highlighted in the cohort of early epileptic patients are motor seizures either focal or generalized, abnormal initial interictal EEG, and normal head growth. In addition, we constantly found an ongoing moderate to severe developmental delay with normal head growth. Patients often had ongoing ataxic gait with trembling gestures. Altogether these features should help the clinician to consider STXBP1 molecular screening. PMID- 26514729 TI - Linking DNA polymerase theta structure and function in health and disease. AB - DNA polymerase theta (Pol theta) is an error-prone A-family polymerase that is highly conserved among multicellular eukaryotes and plays multiple roles in DNA repair and the regulation of genome integrity. Studies conducted in several model organisms have shown that Pol theta can be utilized during DNA interstrand crosslink repair and during alternative end-joining repair of double-strand breaks. Recent genetic and biochemical studies have begun to elucidate the unique structural features of Pol theta that promote alternative end-joining repair. Importantly, Pol theta-dependent end joining appears to be important for overall genome stability, as it affects chromosome translocation formation in murine and human cell lines. Pol theta has also been suggested to act as a modifier of replication timing in human cells, though the mechanism of action remains unknown. Pol theta is highly upregulated in a number of human cancer types, which could indicate that mutagenic Pol theta-dependent end joining is used during cancer cell proliferation. Here, we review the various roles of Pol theta across species and discuss how these roles may be relevant to cancer therapy. PMID- 26514732 TI - Contextual factors related to physical activity during daily middle school physical education. AB - OBJECTIVES: Given the importance of optimizing physical activity in adolescents, the purpose of this study was to examine the effect of activity mode, environment, and semester on step counts/minute and MVPA during daily middle school physical education (PE). DESIGN: A prospective and observational research design. METHODS: Participants included 232 students (Mean age=13.3+/-0.4 years) recruited from the seventh and eighth grades from one public middle-school in the U.S. Activity modes were employed across the school year including motor skills, games, and fitness activities located in indoor and outdoor environments. Step counts/minute and MVPA were monitored across 132 PE lessons during Fall and Spring semesters using NL-1000 piezoelectric pedometers. A three-way Multivariate Analysis of Covariance (MANCOVA) was employed to examine the effect of activity mode (skill games vs. fitness), environment (indoors vs. outdoors), and semester (Fall vs. Spring) on student step counts/minute and MVPA. MANCOVA was followed by separate ANCOVA tests. RESULTS: MANCOVA yielded a statistically significant three way interaction (Wilks' Lambda=0.98 F(2, 1153)=8.9, P<0.001). Follow-up tests supported that physical activity was higher during outdoor fitness activities in the Fall compared to indoor motor skills in the Spring for step counts/minute (Mean difference=27.0 steps/minute, P<0.001, Cohen's d=1.6) and MVPA (Mean difference=7.8min, P<0.001, Cohen's d=2.0). CONCLUSIONS: Daily middle-school physical activity was the highest during outdoor fitness activities in the Fall and the lowest during indoor motor skill games in the Spring. PMID- 26514733 TI - Lung cancer care in UK is still unacceptably variable, says report. PMID- 26514734 TI - Hydrophobized plant polyphenols: self-assembly and promising antibacterial, adhesive, and anticorrosion coatings. AB - Hydrophobized plant polyphenols can be easily prepared by rational and controlled etherification of highly abundant aromatic hydroxyls with linear alkyl chains. The resultant organo-soluble polyphenols spontaneously formed fibrous structures and unravelled to be potential adhesive, anticorrosion, and antibacterial coatings. PMID- 26514730 TI - WNT-5A: signaling and functions in health and disease. AB - WNT-5A plays critical roles in a myriad of processes from embryonic morphogenesis to the maintenance of post-natal homeostasis. WNT-5A knock-out mice fail to survive and present extensive structural malformations. WNT-5A predominantly activates beta-catenin-independent WNT signaling cascade but can also activate beta-catenin signaling to relay its diverse cellular effects such as cell polarity, migration, proliferation, cell survival, and immunomodulation. Moreover, aberrant WNT-5A signaling is associated with several human pathologies such as cancer, fibrosis, and inflammation. Thus, owing to its diverse functions, WNT-5A is a crucial signaling molecule currently under intense investigation with efforts to not only delineate its signaling mechanisms and functions in physiological and pathological conditions, but also to develop strategies for its therapeutic targeting. PMID- 26514731 TI - Mechanisms of sodium channel clustering and its influence on axonal impulse conduction. AB - The efficient propagation of action potentials along nervous fibers is necessary for animals to interact with the environment with timeliness and precision. Myelination of axons is an essential step to ensure fast action potential propagation by saltatory conduction, a process that requires highly concentrated voltage-gated sodium channels at the nodes of Ranvier. Recent studies suggest that the clustering of sodium channels can influence axonal impulse conduction in both myelinated and unmyelinated fibers, which could have major implications in disease, particularly demyelinating pathology. This comprehensive review summarizes the mechanisms governing the clustering of sodium channels at the peripheral and central nervous system nodes and the specific roles of their clustering in influencing action potential conduction. We further highlight the classical biophysical parameters implicated in conduction timing, followed by a detailed discussion on how sodium channel clustering along unmyelinated axons can impact axonal impulse conduction in both physiological and pathological contexts. PMID- 26514735 TI - Cytokeratin 18-Aspartate396 apoptotic fragment for fibrosis detection in patients with non-alcoholic fatty liver disease and chronic viral hepatitis. AB - BACKGROUND: The combination of non-invasive markers for the detection of fibrosis in patients with chronic liver diseases is still a matter of debate. AIMS: To test the performance of cytokeratin18-Aspartate396 alone or in combination with transient elastography as a marker of fibrosis, compared to liver biopsy as gold standard. METHODS: In 259 prospectively enrolled patients with chronic liver diseases, clinical, biochemical, and histological features were assessed. Serum cytokeratin18-Aspartate396 and Fibroscan were performed within 6 months prior to liver biopsy. RESULTS: Cytokeratin18-Aspartate396 levels predicted both significant and advanced fibrosis in non-alcoholic fatty liver disease group, correctly identifying 83.7% and 80.8% of cases, respectively. Liver stiffness performed best in predicting severe fibrosis in patients with chronic viral infection, correctly identifying 78.7% of chronic hepatitis B and 88.6% of chronic hepatitis C subjects. The combination of cytokeratin18-Aspartate396 and liver stiffness improved their diagnostic performance for the detection of significant and advanced fibrosis in non-alcoholic fatty liver disease group, only (sensitivity=78.3%, specificity=90.7%; sensitivity=91.7%, specificity=71.6%, respectively). CONCLUSION: Cytokeratin18-Aspartate396 and liver stiffness can improve the non-invasive prediction of significant and advanced fibrosis in patients with non-alcoholic fatty liver disease, while in hepatitis B and C virus infected patients their combined use had no advantage over the diagnostic accuracy of transient elastography alone. PMID- 26514736 TI - Early changes in dynamic biomarkers of liver fibrosis in hepatitis C virus infected patients treated with sofosbuvir. AB - BACKGROUND: Chronic hepatitis C is a major cause of liver-associated mortality caused by decompensated cirrhosis and hepatocellular carcinoma. With the approval of sofosbuvir, therapeutic efficacy has markedly increased. Early changes in non invasive biomarkers of liver fibrosis under effective antiviral therapy are widely unknown. AIM: To evaluate early changes of fibrosis markers determined by enhanced liver fibrosis (ELF) scores and liver stiffness measurement (FibroScan((r))) in patients treated with sofosbuvir. METHODS: A total of 32 hepatitis C patients treated prospectively with sofosbuvir were included. The ELF panel and FibroScan measurements were performed at baseline, week 4, end-of treatment and 12 weeks thereafter. RESULTS: Antiviral therapy resulted in a biochemical and virological response within 4 weeks. Sustained virological response rate at 12-week follow-up (SVR12) was 93.8%; there was a significantly decrease from baseline to 12-week post-treatment follow-up in ELF (10.00 vs. 9.37; p=0.007) and FibroScan (8.0 vs. 6.8 kPa; p=0.016) measurements, indicating improvement of the dynamics of liver fibrosis. CONCLUSION: We observed a rapid decrease in non-invasive fibrosis markers measured by ELF-scores and FibroScan in hepatitis C-infected patients receiving sofosbuvir treatment. These initial results need to be histologically confirmed by liver biopsy in the future. PMID- 26514737 TI - Bowel ultrasound imaging in patients with cystic fibrosis: Relationship with clinical symptoms and CFTR genotype. AB - BACKGROUND: Ultrasound imaging is used to assess bowel abnormalities in gastrointestinal diseases. We aimed to assess the rate of predefined bowel ultrasound signs and their relationship with gastrointestinal symptoms and the cystic fibrosis transmembrane conductance regulator (CFTR) genotype in cystic fibrosis patients in regular follow-up. METHODS: Prospective study of 70 consecutive patients with cystic fibrosis and 45 controls who underwent abdominal ultrasound; pertinent findings were related to gastrointestinal symptoms and, in cystic fibrosis patients, to pancreatic status, malabsorption degree, lipase intake, CFTR genotype (classified as severe or mild against functional class of CFTR mutations). RESULTS: 96% patients showed at least one abnormal bowel ultrasound sign. Most frequent signs were lymph node enlargement (64%), bowel loop dilatation (55%), thick corpuscular intraluminal content (49%), bowel wall hypervascularization (26%), thickened bowel wall (22%) and intussusception (17%). Patients with recurrent abdominal pain showed more bowel wall hypervascularization than patients without recurrent pain (47% vs. 19%, respectively; p = 0.02) and intussusception (58% vs. 17%, respectively; p < 0.01). Genotype was not associated to specific bowel ultrasound signs. Patients with bowel loop intussusception showed greater lipase intake than those without intussusception (8.118 +/- 2.083 vs. 5.994 +/- 4.187, respectively; p < 0.01). CONCLUSION: Cystic fibrosis patients present a higher rate of bowel ultrasound abnormalities than controls. Bowel ultrasound abnormalities are associated with abdominal symptoms. PMID- 26514738 TI - Prevalence and clinical outcome of hepatic haemangioma with specific reference to the risk of rupture: A large retrospective cross-sectional study. AB - BACKGROUND: Prevalence and incidence of hepatic haemangioma are estimated from autopsy series only. Although benign and generally asymptomatic, hepatic haemangioma can cause serious complications. AIMS: The aim of the study was to assess the prevalence of hepatic haemangioma and to attempt to quantify the risk of major complications such as spontaneous rupture. METHODS: We retrospectively analyzed the radiology database of a Regional University Hospital over a 7-year period: the radiological records of 83,181 patients who had an abdominal computed tomography or magnetic resonance scan were reviewed. Diagnoses made at imaging were reviewed and related to clinical course. RESULTS: Hepatic haemangioma was diagnosed in 2071 patients (2.5% prevalence). In 226 patients (10.9%), haemangioma had diameter of 4 cm or more (giant haemangioma). The risk of bleeding was assessed on patients without concomitant malignancies. Spontaneous bleeding occurred in 5/1067 patients (0.47%). All 5 patients had giant haemangioma: 4 had exophytic lesions and presented with haemoperitoneum; 1 with centrally located tumour experienced intrahepatic bleeding. CONCLUSION: Giant haemangiomas have a low but relevant risk of rupture (3.2% in this series), particularly when peripherally located and exophytic. Surgery might be considered in these cases. PMID- 26514739 TI - Is capsule endoscopy appropriate for elderly patients? The influence of ageing on findings and diagnostic yield: An Italian retrospective study. AB - BACKGROUND: Few data are available on the use of capsule endoscopy in the elderly. METHODS: We performed a retrospective study on 1008 consecutive patients referred to our centre between December 1, 2002 and January 30, 2014 who underwent capsule endoscopy for various indications. Patients were enrolled and divided into 3 sub-groups according to their age (Group A: <50 years; Group B: 50 69 years; Group C: >70 years). The Pillcam diagnostic yield, clinically significant findings and post-treatment outcomes were compared between groups. RESULTS: Diagnostic yield was significantly higher in Group C vs. Groups A and B (65.2% vs. 42.3% and 47.5%, respectively; p<0.05). The most common diagnosis in the elderly was angiodysplasia (42.5%). In 84.5% of elderly patients (Group C) capsule endoscopy results modified patient management. CONCLUSIONS: Capsule endoscopy has a high diagnostic yield and positive impact on management in patients aged >70 years. PMID- 26514740 TI - Gypensapogenin H, a novel dammarane-type triterpene induces cell cycle arrest and apoptosis on prostate cancer cells. AB - Gypensapogenin H (GH) is a novel dammarane-type triterpenes obtained from hydrolyzate of total saponins from Gynostemma pentaphyllum and its anti-tumor activity has been studied in previous work. In this study, we report the effects of this compound on human prostate cancer cells (DU145 and 22RV-1). It significantly inhibited proliferation, decreased survival, led to G1 cell cycle arrest and induced apoptosis in both cell lines, while having lesser effect on the growth of normal human gastric mucosa cells (GES-1), embryonic kidney cells (HEK293) and lung fibroblast cells (MRC5). Consistent with these phenotypes, we observed decreased expression of the cell cycle-related proteins cyclinD1, and CDK4, and increased expression of p21 in GH-treated cells. Besides, the anti apoptotic Bcl-2 protein decreased in a dose-dependent manner, while Bax, cleaved caspase-3 and -9 increased upon GH treatment. Taken together, these results indicated GH exerted promising anticancer activity, and may represent a potential agent for the treatment of prostate cancer. PMID- 26514741 TI - Immunohistochemical expression of p16 in lipoblastomas. AB - Lipoblastoma (LB) is a rare benign adipocytic tumor of childhood occasionally showing histological similarities to myxoid liposarcoma (ML) or well differentiated liposarcoma (WDL). p16 immunohistochemistry has proved to be useful in distinguishing various types of liposarcomas, in particular WDL from lipoma, with higher sensitivity and specificity than MDM2 and CDK4 immunohistochemistry. In this study, we reported the histologic features of a series of 30 LB with emphasis on the potential diagnostic pitfalls and investigated the immunohistochemical expression of p16. Moreover, p16 immunostaining was performed in 16 liposarcomas (11 WDL and 5 ML), 16 lipomas, and 16 cases of liponecrosis in order to evaluate its usefulness in the differential diagnosis of challenging lesions occurring in older children. Overall, p16 immunostaining was positive in 3 LBs and in 12 out of 16 liposarcomas (10 WDL and 2 ML), with a sensitivity of 75%, a specificity of 90%, a positive predictive value of 80%, and a negative predictive value of 87%. All lipomas were p16 negative, whereas 5 liponecroses were positive. Accounting altogether the benign lesions versus liposarcomas, p16 showed a sensitivity of 75%, a specificity of 87%, a positive predictive value of 60%, and a negative predictive value of 93%. Our data suggest that a negative p16 immunostaining may be helpful in excluding a liposarcoma when occurring in unusual clinical contexts, such as in adolescence or late recurrence. However, such finding should be interpreted with caution since also some liposarcomas lack p16 and occasional LBs are positive. PMID- 26514742 TI - Alternatively spliced, spliceosomal twin introns in Helminthosporium solani. AB - Spliceosomal twin introns, "stwintrons", have been defined as complex intervening sequences that carry a second intron ("internal intron") interrupting one of the conserved sequence domains necessary for their correct splicing via consecutive excision events. Previously, we have described and experimentally verified stwintrons in species of Sordariomycetes, where an "internal intron" interrupted the donor sequence of an "external intron". Here we describe and experimentally verify two novel stwintrons of the potato pathogen Helminthosporium solani. One instance involves alternative splicing of an internal intron interrupting the donor domain of an external intron and a second one interrupting the acceptor domain of an overlapping external intron, both events leading to identical mature mRNAs. In the second case, an internal intron interrupts the donor domain of the external intron, while an alternatively spliced intron leads to an mRNA carrying a premature chain termination codon. We thus extend the stwintron concept to the acceptor domain and establish a link of the occurrence of stwintrons with that of alternative splicing. PMID- 26514743 TI - Aptamer selection for fishing of palladium ion using graphene oxide-adsorbed nanoparticles. AB - A new aptamer selection method using graphene oxide (GO)-adsorbed nanoparticles (GO-adsorbed NPs) was employed for specific fishing of palladium ion. High affinity ssDNA aptamers were isolated through 13 rounds of selection and the capacity of the selected DNA aptamers for palladium ion uptake was measured, clarifying that DNA01 exhibits the highest affinity to palladium ion with a dissociation constant (Kd) of 4.60+/-1.17 MUM. In addition, binding ability of DNA01 to palladium ion was verified against other metal ions, such as Li(+), Cs(+), Mg(2+), and Pt(2+). Results of the present study suggest that future modification of DNA01 may improve palladium ion-binding ability, leading to economic recovery of palladium from water solution. PMID- 26514744 TI - Synthesis of donepezil-based multifunctional agents for the treatment of Alzheimer's disease. AB - Amyloid beta (Abeta) and cholinesterase enzymes (AChE, BuChE) are important biological targets for the effective treatment of Alzheimer's disease. In this study, the aim was to synthesize new donepezil-like secondary amide compounds that display a potent inhibition of cholinesterases and Abeta with antioxidant and metal chelation abilities. All test compounds showed activities against both ChEs and beta1-42 inhibition. The most encouraging compound, 20, is an AChE inhibitor with high anti-aggregation activity (55.3%). Based on the results, compound 20 may be a promising structure in further research for new anti Alzheimer's agents. PMID- 26514745 TI - Chrysin-benzothiazole conjugates as antioxidant and anticancer agents. AB - 7-(4-Bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one, obtained from chrysin with 1,4-dibromobutane, was combined with a wide range of 6-substituted 2 aminobenzthiazoles, which had been prepared from the corresponding anilines with potassium thiocyanate. Free radical scavenging efficacies of newer analogues were measured using DPPH and ABTS assays, in addition to the assessment of their anticancer activity against cervical cancer cell lines (HeLa and CaSki) and ovarian cancer cell line (SK-OV-3) implementing the SRB assay. Cytotoxicity of titled compounds was checked using Madin-Darby canine kidney (MDCK) non-cancer cell line. Overall, 6a-r indicated remarkable antioxidant power as DPPH and ABTS(+) scavengers; particularly the presence of halogen(s) (6g, 6h, 6j-6l) was favourable with IC50 values comparable to the control ascorbic acid. Unsubstituted benzothiazole ring favored the activity of resultant compounds (6a and 6r) against HeLa cell line, whereas presence of chlorine (6g) or a di-fluoro group (6k) was a key to exert strong action against CaSki. Moreover, a mono fluoro (6j) and a ketonic functionality (6o) were beneficial to display anticipated anticancer effects against ovarian cancer cell line SK-OV-3. The structural assignments of the new products were done on the basis of IR, (1)H NMR, (13)C NMR spectroscopy and elemental analysis. PMID- 26514746 TI - Combined synthetic and recombinant techniques for the development of lipoprotein based, self-adjuvanting vaccines targeting human papillomavirus type-16 associated tumors. AB - Human papillomaviruses (HPVs) are associated with various cancers, with HPV16 linked to more than half of cervical cancer cases. Vaccines to prevent HPV infection and cancer development have proven effective, but are not useful in individuals with prior HPV exposure. Treatment vaccines to eradicate or control HPV-associated lesions are therefore desirable for these patients. Herein we describe the development of a process to enable the production of semisynthetic vaccines based on the site-specific attachment of synthetic bacterial lipid analogs (e.g., Pam2Cys) to a non-oncogenic mutant HPV16 E7 protein to generate molecularly defined vaccines. Many cytotoxic lymphocyte (CTL) epitopes from E7 are delivered by this approach; potentially ensuring that large numbers of immunized individuals can generate CTLs to clear HPV infected cells. Delivery of this construct reduced the growth of HPV16-associated tumors in a TC1 mouse model, the effects of which were better than the potent CTL epitope HPV16 E7(44 57) administered with Montanide ISA51 adjuvant. PMID- 26514747 TI - Ablation of Complex Fractionated Atrial Electrograms for Atrial Fibrillation Rhythm Control: A Systematic Review and Meta-analysis. AB - BACKGROUND: Pulmonary vein isolation (PVI) has become an increasingly important therapy in the management of atrial fibrillation (AF), however, the best procedural techniques to ensure success have not been determined. We assessed the incremental benefit of complex fractionated atrial electrograms (CFAEs) ablation for AF rhythm control. METHODS: PubMed, Embase, CENTRAL, and Clinicaltrials.gov databases were searched up until May 7, 2015. Included were randomized controlled trials that compared PVI with PVI and CFAEs ablation (PVI+) with a minimum of 3 months' follow-up. Statistical analysis was performed with Review Manager version 5.3 (Cochrane Collaboration, Oxford, United Kingdom). Categorical and continuous outcomes were reported as summary risk differences and mean differences (MDs), respectively. P < 0.05 was considered statistically significant for all analyses. RESULTS: Ten randomized controlled trials randomized patients to PVI+ (n = 635) and PVI (n = 427) with follow-up ranging from 3 to 23 months. There was no significant difference in freedom from atrial tachyarrhythmias without antiarrhythmic agents after a single ablation between PVI+ and PVI (313 of 635 vs 230 of 427; risk difference, 0.01 [95% confidence interval (CI)-0.08 to 0.10]; P = 0.78; I(2) = 52%). Findings were not different for any prespecified subgroup analyses, including paroxysmal vs nonparoxysmal AF, automated vs manual detection of CFAEs, and left atrial vs biatrial ablation. PVI+ led to significantly increased procedure time (MD, 49.81 minutes [95% CI 42.86-56.76]; P < 0.001), fluoroscopy time (MD, 11.55 minutes [95% CI 8.02-15.07]; P < 0.001), and radiofrequency energy application time (MD, 19.16 minutes [95% CI 6.61-31.70]; P = 0.003) compared with PVI. CONCLUSIONS: Ablation of CFAEs in addition to PVI did not increase freedom from atrial tachyarrhythmias but procedural times were increased. PMID- 26514748 TI - Usefulness of Clinical Data and Biomarkers for the Identification of Frailty After Acute Coronary Syndromes. AB - BACKGROUND: Frailty predicts mortality after acute coronary syndrome (ACS). The standard frailty scales, such as the Fried score, consist of a variety of questionnaires and physical tests. Our aim was to investigate easily available clinical data and blood markers to predict frailty at discharge, in elderly patients after ACS. METHODS: A total of 342 patients older than 65 years, survivors after ACS, were included. A high number of clinical variables were collected. In addition, blood markers potentially linked to frailty and related to the processes of inflammation, coagulation, hormonal dysregulation, nutrition, renal dysfunction, and heart dysfunction were determined. Frailty was evaluated using the Fried score at discharge. The main outcome was frailty defined by a Fried score >= 3 points. Secondary endpoints were mortality and myocardial infarction at 30-month median follow-up. RESULTS: A total of 116 patients were frail. Seven clinical variables or biomarkers predicted frailty: age >= 75 years, female, prior ischemic heart disease, admission heart failure, haemoglobin <= 12.5 g/dL, vitamin D <= 9 ng/mL, and cystatin-C >= 1.2 mg/L. This model based on clinical data and biomarkers showed an excellent discrimination accuracy for frailty (C-statistic = 0.818). During the follow-up, 105 patients died and 137 died or suffered myocardial infarction. The clinical data and biomarker model (C statistics = 0.730 and 0.691) performed better than the Fried score (C-statistics = 0.676 and 0.650) for death and death or myocardial infarction, respectively. CONCLUSIONS: Easy available clinical data and biomarkers can identify frail patients at discharge after ACS and predict outcomes better than the standard Fried's frailty scale. PMID- 26514750 TI - Very Late Stent Thrombosis: The Value of Optical Coherence Tomography in Defining Etiology and Guiding Treatment. PMID- 26514749 TI - Resistant and Refractory Hypertension: Antihypertensive Treatment Resistance vs Treatment Failure. AB - Resistant or difficult to treat hypertension is defined as high blood pressure that remains uncontrolled with 3 or more different antihypertensive medications, including a diuretic. Recent definitions also include controlled blood pressure with use of 4 or more medications as also being resistant to treatment. Recently, refractory hypertension, an extreme phenotype of antihypertensive treatment failure has been defined as hypertension uncontrolled with use of 5 or more antihypertensive agents, including a long-acting thiazide diuretic and a mineralocorticoid receptor antagonist. Patients with resistant vs refractory hypertension share similar characteristics and comorbidities, including obesity, African American race, female sex, diabetes, coronary heart disease, chronic kidney disease, and obstructive sleep apnea. Patients with refractory vs resistant hypertension tend to be younger and are more likely to have been diagnosed with congestive heart failure. Refractory hypertension might also differ from resistant hypertension in terms of underlying cause. Preliminary evidence suggests that refractory hypertension is more likely to be neurogenic in etiology (ie, heightened sympathetic tone), vs a volume-dependent hypertension that is more characteristic of resistant hypertension in general. PMID- 26514751 TI - A Crack in the Wall: Evolution of a Left Ventricular Apical Pseudoaneurysm. PMID- 26514752 TI - Primary Cardiac Angiosarcoma Treated With Positron Emission Tomography/Magnetic Resonance Imaging-Guided Adaptive Radiotherapy. AB - Radiotherapy (RT) for inoperable patients with primary cardiac sarcomas or residual tumor is often limited by the sensitivity of the heart and lung to radiation injury. We describe a novel treatment modality with adaptive radiotherapy (ART) using tumor volume tracking in a 37-year-old woman who presented with unresectable primary cardiac angiosarcoma. The patient was treated using positron emission tomography/magnetic resonance imaging-guided ART with 55.8 Gy concomitant with paclitaxel chemotherapy. In conclusion, the treatment was well tolerated, and a significant tumor volume reduction of ~ 57% was achieved during radiotherapy, suggesting the effectiveness and tolerability of ART in combination with paclitaxel-based chemotherapy. PMID- 26514753 TI - Population Data on Blood Pressure and Dietary Sodium and Potassium Do Not Support Public Health Strategy to Reduce Salt Intake in Canadians. PMID- 26514754 TI - Variation in circadian rhythms is maintained among and within populations in Boechera stricta. AB - Circadian clocks have evolved independently in all three domains of life, and fitness benefits of a functional clock have been demonstrated in experimental genotypes in controlled conditions. Still, little is known about genetic variation in the clock and its fitness consequences in natural populations from heterogeneous environments. Using Wyoming populations of the Arabidopsis relative Boechera stricta as our study system, we demonstrate that genetic variation in the clock can occur at multiple levels: means of circadian period among populations sampled at different elevations differed by less than 1 h, but means among families sampled within populations varied by as much as 3.5 h. Growth traits also varied among and within populations. Within the population with the most circadian variation, we observed evidence for a positive correlation between period and growth and a negative correlation between period and root-to-shoot ratio. We then tested whether performance tradeoffs existed among families of this population across simulated seasonal settings. Growth rankings of families were similar across seasonal environments, but for root-to-shoot ratio, genotype * environment interactions contributed significantly to total variation. Therefore, further experiments are needed to identify evolutionary mechanisms that preserve substantial quantitative genetic diversity in the clock in this and other species. PMID- 26514755 TI - Influence of Sampling Procedure on Codeine Concentrations in Oral Fluid. AB - For many drugs, there is a poor correlation between the plasma and oral fluid (OF) concentrations, due to differences in OF pH, oral contamination, stimulation of OF flow and variability of the volume of sample taken. The aim of this study was to evaluate the OF/plasma ratio and variability in drug concentration in OF sampled by two commercially available collection systems: Saliva Collection System (SCS) and Quantisal. Blood and OF samples were collected from 12 volunteers after intake of 19.5 mg codeine phosphate. Six persons were sampled by SCS first, followed by Quantisal; six other participants used Quantisal before SCS. The OF content of SCS tubes was measured spectrophotometrically. The Quantisal devices were weighed to correct for the effectively obtained OF volume. Codeine was measured by gas chromatography-mass spectrometry. The mean codeine concentration at 1 h was 29.8 +/- 18.8 MUg/L in plasma, 72.8 +/- 63.9 MUg/L in SCS OF and 85.3 +/- 72.6 MUg/L in Quantisal OF. The mean OF/plasma ratio was 2.30 +/- 0.77 (SCS) and 2.69 +/- 1.94 (Quantisal). Pearson's correlation coefficient between OF and plasma codeine concentrations was statistically significantly (P = 0.005) higher for SCS (R(2) = 0.745) than for Quantisal (R(2) = 0.403). The variability in ratios with Quantisal was markedly reduced when used after SCS. Codeine concentrations measured in OF taken with SCS correlate better with plasma concentrations than in OF obtained with Quantisal, particularly when Quantisal was used first. PMID- 26514756 TI - Prevalence of antibodies to canine parvovirus and reaction to vaccination in client-owned, healthy dogs. AB - The purpose of this population-based cohort study was to assess current prevalence of antibodies to canine parvovirus (CPV) in adult, healthy dogs, including risk factors associated with lack of antibodies, and reaction to revaccination with a modified live vaccine (MLV). One hundred dogs routinely presented for vaccination were included in the study and vaccinated with a single dose of a combined MLV. Information was collected on signalment, origin, environment, vaccination history and side effects. Prevaccination and postvaccination antibodies were detected by haemagglutination inhibition. Univariate analysis, followed by multivariate logistic regression, was used to investigate association between different variables and presence of antibodies as well as titre increase. Protective CPV antibodies were present in 86.0 per cent of dogs. Intervals of more than four years since the last vaccination and rare contacts with other dogs were determined as main risk factors for the absence of antibodies. An increase in titres only occurred in 17.0 per cent of dogs. Dogs without protective titres before vaccination or with bodyweight <10 kg were more likely to have an adequate titre increase. Based on these findings, antibody status should be determined instead of periodic vaccinations to ensure reliable protection without unnecessary vaccinations in adult dogs. PMID- 26514757 TI - Assessing youth-friendly-health-services and supporting planning in the Republic of Moldova. AB - INTRODUCTION: Several countries have set up youth-friendly-health-services. Relatively little is known about approaches to systematically assess their performance against set standards in terms of quality and coverage and define improvement activities based on the findings. The objective of this paper is to fill this gap and to describe the methods and findings of an external review of youth-friendly-health-services in Moldova and the use of the findings to support further planning. BACKGROUND: The Republic of Moldova scaled up youth-friendly health-services (YFHS) nationwide with the target of setting up at least one youth-friendly-health-centre (YFHC) in each of the 35 districts. METHODS: We carried out an external review of the YFHS in Moldova using a framework that examined the project's design, implementation and monitoring, outputs, outcomes and impact. We collected primary data - obtained from health worker and client exit interviews with semi-structured questionnaires, direct observation and focus group discussions - and used secondary data from progress reports, previous studies and surveys and national level data. RESULTS: While impressive progress with geographical scale up had taken place, services were not always provided to the required quality and comprehensively in the newly established YFHC, thereby diminishing chances of achieving the desired outcomes and impact. The causes of this were identified, and possible ways of addressing them were proposed. DISCUSSION: Designating health facilities to be made youth friendly and assigning health workers to manage them can be done fairly quickly, improving performance takes time and effort. Approaches that go beyond training such as collaborative learning and job shadowing may hold the best opportunity to improve the knowledge, understanding and motivation of health workers in the newly designated YFHC to address the problem of poor quality. CONCLUSIONS: The Healthy Generation project was well designed and energetically implemented in line with the plan. It has contributed to tangible improvements in the quality of health service provision, and to their uptake. While progress has been made, considerable work is needed, especially in the newer centres. If the efforts of the Healthy Generation project are stepped up, if weaknesses in its planning and implementation are addressed, if complementary activities to build knowledge, understanding, skills and an enabling environment are carried out, the project can be expected to improve the health and well- being of Moldova's young people. PMID- 26514758 TI - Current trends and challenges in proteomic identification of protease substrates. AB - Proteolytic cleavage is a ubiquitous, irreversible, posttranslational modification that changes protein structure and function and plays an important role in numerous physiological and pathological processes. Over the last decade, proteases have become increasingly important clinical targets because many of their inhibitors are already used in the clinic or in various stages of clinical testing. Therefore, a better understanding of protease action and their repertoires of physiological substrates can not only provide an important insight into their mechanisms of action but also open a path toward novel drug design. Historically, proteases and their substrates were mainly studied on a case-by case basis, but recent advancements in mass spectrometry-based proteomics have enabled proteolysis studies on a global scale. Because there are many different types of proteases that can operate in various cellular contexts, multiple experimental approaches for their degradomic characterization had to be developed. The present paper reviews the mass spectrometry-based approaches for determining the proteolytic events in complex biological samples. The methodologies for substrate identification and the determination of protease specificity are discussed, with a special focus on terminomic strategies, which combine peptide labeling and enrichment. PMID- 26514760 TI - Draft Genome Sequences of Two New Zealand Xanthomonas campestris pv. campestris Isolates, ICMP 4013 and ICMP 21080. AB - Xanthomonas campestris pv. campestris is a necrotrophic bacterial pathogen of crucifers. We report here the draft genome sequences of isolates ICMP 4013 and ICMP 21080 from New Zealand. These sequences will facilitate the identification of race-specific factors in X. campestris pv. campestris. PMID- 26514759 TI - Right Atrial Function in Pulmonary Arterial Hypertension. AB - BACKGROUND: Elevated right atrial (RA) pressure is an established prognostic measure in pulmonary arterial hypertension (PAH). However, little is known about perturbations in RA function in PAH. METHODS AND RESULTS: Reservoir (RA longitudinal strain [RA LS]), conduit (RA early LS rate), and active (RA late LS rate) phases were assessed by 2D speckle tracking in 65 patients with PAH, 6 minute walk distance <=450 m, and a pulmonary vascular resistance >800 dynes.s/cm(5), despite therapy with at least 2 PAH-specific medications enrolled in the Imatinib in Pulmonary Arterial Hypertension, a Randomized Efficacy Study (IMPRES) trial and were compared with 30 healthy controls of similar age and sex. We studied the association of RA functional measures with invasive pulmonary hemodynamics, cardiac structure and function, and N-terminal pro brain natriuretic peptide. RA LS and early LS rate were reduced in PAH patients compared with controls (27.1+/-11.6 versus 56.9+/-12.7, adjusted P<0.001 and 0.6+/-0.5 versus -1.5+/-0.5, adjusted P<0.001, respectively) even after adjusting for RA area and invasive RA pressure, whereas RA late LS rate was similar between groups (-1.4+/-0.7 versus -1.5+/-0.4, P=0.42). Among PAH patients, worse RA LS correlated with greater RA size (r=-0.50, P<0.0001) and pressure (r=-0.37, P=0.002), but not pulmonary artery pressure (r=-0.07, P=0.58). Worse RA LS was also associated with right ventricular enlargement and dysfunction and higher N terminal pro brain natriuretic peptide independent of RA size and pressure. CONCLUSIONS: RA reservoir and passive conduit functions are impaired in PAH, independent of RA size and pressure, and likely reflect right ventricular failure and overload. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00902174. PMID- 26514761 TI - Complete Genome Sequences of Grapevine Yellow Speckle Viroid 1 and Hop Stunt Viroid Assembled from the Transcriptome of Ixeridium dentatum Plants. AB - Here, we report complete genome sequences of grapevine yellow speckle viroid 1 (GYSVd1) and hop stunt viroid (HSVd), members of the family Pospiviroidae, assembled from the transcriptome data generated from Ixeridium dentatum plants. To our knowledge, this is the first report of GYSVd1 and HSVd in I. dentatum. PMID- 26514762 TI - First Complete Genome Sequences of Two Keystone Viruses from Florida. AB - We report here the first complete sequences of two Keystone virus (KEYV) genomes isolated from Florida in 2005, which include the first two publicly available complete large (L) gene sequences. The sequences of the KEYV L segments show 75.99 to 83.86% nucleotide similarity with those of other viruses in the California (CAL) serogroup of bunyaviruses. PMID- 26514763 TI - Genome Sequence of the Deep-Sea Bacterium Idiomarina abyssalis KMM 227T. AB - Idiomarina abyssalis KMM 227(T) is an aerobic flagellar gammaproteobacterium found at a depth of 4,000 to 5,000 m below sea level in the Pacific Ocean. This paper presents a draft genome sequence for I. abyssalis KMM 227(T), with a predicted composition of 2,684,812 bp (47.15% G+C content) and 2,611 genes, of which 2,508 were predicted coding sequences. PMID- 26514764 TI - Draft Whole-Genome Sequence of the Marine Bacterium Idiomarina zobellii KMM 231T. AB - Idiomarina zobellii was isolated from the northwest Pacific Ocean at a depth of 4,000 to 5,000 m in 1985. The draft whole-genome shotgun sequence of I. zobellii KMM 231(T) described in this paper has a predicted length of 2,602,160 bp, containing 2,570 total genes, 52 tRNAs, and a G+C content of 47.10%. PMID- 26514765 TI - Draft Genome Sequence of Pseudomonas aeruginosa ATCC 9027 (DSM 1128), an Important Rhamnolipid Surfactant Producer and Sterility Testing Strain. AB - Pseudomonas aeruginosa ATCC 9027 (DSM1128) is often used as a quality-control strain for sterility and microbial contamination testing and is an important biosurfactant producer. Here, we present the 6.4-Mb draft genome sequence and highlight some genomic differences to its closest relative, P. aeruginosa strain PA7. PMID- 26514766 TI - Complete Genome Sequence of Methicillin-Resistant Staphylococcus schleiferi Strain TSCC54 of Canine Origin. AB - We report a complete genome sequence of the methicillin-resistant Staphylococcus schleiferi strain TSCC54, isolated from the skin of a dog in Tokyo, Japan. PMID- 26514767 TI - Draft Genome Sequence of the Streptothricin-Producing Strain Streptomyces sp. fd2 tb. AB - Streptomyces sp. fd2-tb can produce streptothricin class antibiotics with broad antimicrobial spectra. To better understand the mechanism of streptothricin biosynthesis and to assess the capacity of this strain in secondary metabolism, we report the draft genome sequence of Streptomyces sp. strain fd2-tb. PMID- 26514768 TI - Draft Genome Sequence and Assembly of Photorhabdus heterorhabditis Strain VMG, a Bacterial Symbiont Associated with the Entomopathogenic Nematode Heterorhabditis zealandica. AB - Here, we report the draft genome sequence of Photorhabdus heterorhabditis strain VMG, a symbiont of the entomopathogenic nematode Heterorhabditis zealandica in South Africa. The draft genome sequence is 4,878,919 bp long and contains 4,023 protein-coding genes. The genome assembly contains 262 contigs with a G+C content of 42.22%. PMID- 26514769 TI - Full-Length Genome Characterization of Chinese Porcine Deltacoronavirus Strain CH/SXD1/2015. AB - A porcine deltacoronavirus (PDCoV) was identified in the Chinese mainland and found to be closely related to Hong Kong strain HKU15-155 but differed from PDCoV strains in the United States and South Korea. The complete genome of PDCoV strain CH/SXD1/201 was sequenced and analyzed to further characterize PDCoV in Chinese swine. PMID- 26514770 TI - Complete Genome Sequence of Herbaspirillum hiltneri N3 (DSM 17495), Isolated from Surface-Sterilized Wheat Roots. AB - We report the complete genome sequence of Herbaspirillum hiltneri N3 (DSM 17495), a member of the genus Herbaspirillum of the Betaproteobacteria. The genome is contained in a single chromosome, and analysis revealed that N3 lacks the whole nitrogen fixation (nif) gene cluster, confirming its inability to fix nitrogen. PMID- 26514771 TI - Interleukin-27: a novel biomarker in predicting bacterial infection among the critically ill. AB - INTRODUCTION: A continued need exists for effective diagnostic biomarkers in bacterial sepsis among critically ill patients, despite increasing use of available biomarkers such as procalcitonin (PCT). Interleukin-27 (IL-27) has shown early promise in a recent preliminary study, exhibiting high specificity and positive predictive values for bacterial infection in critically ill children. This validation study was performed to assess the value of IL-27 in predicting bacterial infection among patients admitted to the pediatric intensive care unit and to compare its performance with that of PCT. METHODS: A single center (n = 702) prospective study was performed comparing both IL-27 and PCT levels between bacterially infected and uninfected cohorts in the pediatric intensive care unit. Infected status was determined by a chart review by an intensivist blinded to biomarker results. Formal performance comparisons included calculations of receiver operating characteristic (ROC) curves for IL-27 and PCT individually in addition to a combination strategy using a decision tree generated by classification and regression tree (CART) methodology. Secondary analysis focusing on subjects with documented bloodstream infections was performed. RESULTS: The overall infection rate was 27 %. ROC curves for the primary analysis yielded areas under the curve (AUCs) of 0.64 (0.59 to 0.68) for IL-27 and 0.61 (0.56 to 0.65) for PCT. Secondary analysis defining infected status exclusively through positive blood cultures yielded AUCs of 0.75 (0.68 to 0.81) for IL-27 and 0.64 (0.57 to 0.71) for PCT, with a specificity of 95 % (92 % to 97 %) for the prior established IL-27 cut-point value of at least 5.0 ng/ml. Similar AUCs were found for the subset of immunocompromised patients. In a CART derived analysis taking immunocompromised status into consideration, a combination of IL-27 and PCT yielded an AUC of 0.81 (0.75 to 0.86), statistically improved from either IL-27 or PCT alone. CONCLUSIONS: Despite having a modest predictive value for infection independent of source, IL-27 may serve as a useful biomarker in estimating risk of bacterial infection among critically ill pediatric patients with bloodstream infections. In particular, among immunocompromised subjects, this diagnostic biomarker may be helpful either alone or using a combination strategy with other available biomarkers. PMID- 26514772 TI - Dialectical behaviour therapy in an inpatient unit for women with a learning disability: Service users' perspectives. AB - There is a general lack of self-report data from service users with an intellectual disability (ID) about their views of psychological interventions. This research explored the views and experiences of female inpatients, with a diagnosis of a personality disorder and an ID, about dialectical behaviour therapy (DBT). Semi-structured interviews were used with 10 women, recruited from two independent mental health hospitals. The interviews were analysed using interpretative phenomenological analysis. Participants showed varying levels of understanding of DBT. Findings highlight the need for a standardized approach with a suitably adapted structure and curriculum to meet the needs of inpatients with an ID. Factors such as the therapeutic relationship were identified as playing a role in participants' motivation, engagement and participation in DBT. PMID- 26514774 TI - Identification of alanyl aminopeptidase (CD13) as a surface marker for isolation of mature gastric zymogenic chief cells. AB - Injury and inflammation in the gastric epithelium can cause disruption of the pathways that guide the differentiation of cell lineages, which in turn can cause persistent alterations in differentiation patterns, known as metaplasia. Metaplasia that occurs in the stomach is associated with increased risk for cancer. Methods for isolating distinct gastric epithelial cell populations would facilitate dissection of the molecular and cellular pathways that guide normal and metaplastic differentiation. Here, we identify alanyl aminopeptidase (CD13) as a specific surface marker of zymogenic chief cells (ZCs) in the gastric epithelium. We show that 1) among gastric epithelial cells alanyl aminopeptidase expression is confined to mature ZCs, and 2) its expression is lost en route to metaplasia in both mouse and human stomachs. With this new marker coupled with new techniques that we introduce for dissociating gastric epithelial cells and overcoming their constitutive autofluorescence, we are able to reliably isolate enriched populations of ZCs for both molecular analysis and for the establishment of ZC-derived ex vivo gastroid cultures. PMID- 26514773 TI - Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis. AB - Recent studies have implicated a pathogenic role for matrix metalloproteinases 9 (MMP-9) in inflammatory bowel disease. Although loss of epithelial barrier function has been shown to be a key pathogenic factor for the development of intestinal inflammation, the role of MMP-9 in intestinal barrier function remains unclear. The aim of this study was to investigate the role of MMP-9 in intestinal barrier function and intestinal inflammation. Wild-type (WT) and MMP-9(-/-) mice were subjected to experimental dextran sodium sulfate (DSS) colitis by administration of 3% DSS in drinking water for 7 days. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon using fluorescently labeled dextran. The DSS-induced increase in the colonic permeability was accompanied by an increase in intestinal epithelial cell MMP-9 expression in WT mice. The DSS-induced increase in intestinal permeability and the severity of DSS colitis was found to be attenuated in MMP-9(-/-) mice. The colonic protein expression of myosin light chain kinase (MLCK) and phospho-MLC was found to be significantly increased after DSS administration in WT mice but not in MMP-9(-/-) mice. The DSS-induced increase in colonic permeability and colonic inflammation was attenuated in MLCK(-/-) mice and MLCK inhibitor ML-7 treated WT mice. The DSS-induced increase in colonic surface epithelial cell MLCK mRNA was abolished in MMP-9(-/-) mice. Lastly, increased MMP-9 protein expression was detected within the colonic surface epithelial cells in ulcerative colitis cases. These data suggest a role of MMP-9 in modulation of colonic epithelial permeability and inflammation via MLCK. PMID- 26514775 TI - Elevated IL-33 expression is associated with pediatric eosinophilic esophagitis, and exogenous IL-33 promotes eosinophilic esophagitis development in mice. AB - We tested whether the T helper (Th) type 2 (Th2) cell agonist and allergenic ligand IL-33 was associated with eosinophilic esophagitis (EoE) development in a pediatric cohort and whether IL-33 protein could induce disease symptoms in mice. Biopsies from EoE patients or controls were used to measure IL-33 mRNA and protein expression. Increased expression of IL-33 mRNA was found in the esophageal mucosa in EoE. IL-33 protein was detected in cells negative for CD45, mast cells, and epithelial cell markers near blood vessels. Circulating levels of IL-33 were not increased. The time course for IL-33 gene expression was quantified in an established Aspergillus fumigatus allergen mouse model of EoE. Because IL-33 induction was transient in this model and chronicity of IL-33 expression has been demonstrated in humans, naive mice were treated with recombinant IL-33 for 1 wk and esophageal pathology was evaluated. IL-33 application produced changes consistent with phenotypically early EoE, including transmural eosinophilia, mucosal hyperproliferation, and upregulation of eosinophilic genes and chemokines. Th2 cytokines, including IL-13, along with innate lymphoid cell group 2, Th1/17, and M2 macrophage marker genes, were increased after IL-33 application. IL-33-induced eosinophilia was ablated in IL 13 null mice. In addition, IL-33 induced a profound inhibition of the regulatory T cell gene signature. We conclude that IL-33 gene expression is associated with pediatric EoE development and that application of recombinant protein in mice phenocopies the early clinical phase of the human disease in an IL-13-dependent manner. IL-33 inhibition of esophageal regulatory T cell function may induce loss of antigenic tolerance, thereby providing a mechanistic rationale for EoE development. PMID- 26514776 TI - Proline affects the size of the root meristematic zone in Arabidopsis. AB - BACKGROUND: We reported previously that root elongation in Arabidopsis is promoted by exogenous proline, raising the possibility that this amino acid may modulate root growth. RESULTS: To evaluate this hypothesis we used a combination of genetic, pharmacological and molecular analyses, and showed that proline specifically affects root growth by modulating the size of the root meristem. The effects of proline on meristem size are parallel to, and independent from, hormonal pathways, and do not involve the expression of genes controlling cell differentiation at the transition zone. On the contrary, proline appears to control cell division in early stages of postembryonic root development, as shown by the expression of the G2/M-specific CYCLINB1;1 (CYCB1;1) gene. CONCLUSIONS: The overall data suggest that proline can modulate the size of root meristematic zone in Arabidopsis likely controlling cell division and, in turn, the ratio between cell division and cell differentiation. PMID- 26514777 TI - Anterior arthroscopic-assisted fixation of posterior cruciate ligament avulsion fractures. AB - BACKGROUND: Avulsion fractures of the tibial insertion of the posterior cruciate ligament (PCL) have always been regarded as rare injuries. The tibial attachment of the PCL is located in an area, which is difficult to access. HYPOTHESIS: To verify the effects of anterior arthroscopic fixation of PCL avulsion fractures. METHODS: 18 patients with PCL avulsion fracture were included. The inclusion criteria were: (1) the fracture fragment size was greater than 20 mm; (2) surgery in the acute phase of fractures (<3 weeks). The intervention was anterior arthroscopic fixation of fractures. Outcome variables included posterior laxity assessment with KT2000 arthrometer, posterior sag sign, the quadriceps activation test, the reverse Lachman, posterior stress X-rays, range of motion, and the IKDC form assessment. RESULTS: Complete osseous union showed in all cases during the follow-up (24-49 months). The posterior laxity assessment demonstrated slight posterior tibia translation (<5 mm) on the femur in 1 patient at 89 N and in 2 at maximal testing. All were stable on the posterior sag sign, the quadriceps activation test, the reverse Lachman and posterior stress X-rays. Two had loss of flexion of about 10 degrees (grade B). Others showed a full range of knee motion. According to the IKDC form assessment, 16 patients were classified as grade A and 2 were classified as grade B. 16 of 18 patients were absolutely pain free, and there was general satisfaction on pain questionnaire. All the patients returned to their pre-injury knee function. No revision surgery was performed. CONCLUSIONS: The anterior arthroscopic-assisted fixation guided with a tibial PCL guide is a simple and feasible alternative for treating PCL avulsion fractures when the fragment size is larger than 20 mm. PMID- 26514778 TI - A Case of Brugada Pattern Migrant from Right Precordial Leads to Peripheral Leads. AB - Since the first report in 1992, Brugada pattern (BP) diagnosis is mainly based on analysis of the precordial leads. In cases with no clear BP evidence in the conventional right precordial leads (4th intercostal space), limb leads analysis resulted helpful in suspecting BP. Fluctuations within right precordial leads between the diagnostic ECG pattern and nondiagnostic ECGs are well known. For the first time, in the patient herewith reported, the transformation of BP phenotype involves both precordial and peripheral leads, confirming that the analysis of all the 12 leads has a key role in BP diagnosis. PMID- 26514779 TI - Comparative toxicity and mutagenicity of soy-biodiesel and petroleum-diesel emissions: overview of studies from the U.S. EPA, Research Triangle Park, NC. AB - Biodiesel use as a fuel is increasing globally as an alternate to petroleum sources. To comprehensively assess the effects of the use of biodiesel as an energy source, end stage uses of biodiesel such as the effects of inhalation of combusted products on human health must be incorporated. To date, few reports concerning the toxicological effects of the emissions of combusted biodiesel or blends of biodiesel on surrogates of health effects have been published. The relative toxicity of the combusted biodiesel emissions compared to petroleum diesel emissions with short term exposures is also not well known. To address the paucity of findings on the toxicity of combusted biodiesel emissions, studies were undertaken at the U.S. Environmental Protection Agency laboratories in Research Triangle Park, North Carolina. The studies used a variety of approaches with nonhuman animal models to examine biological responses of the lung and cardiovascular systems induced by acute and repeated exposures to pure biodiesel and biodiesel blended with petroleum diesel. Effects of the emissions on induction of mutations in bacterial test strains and mammalian DNA adducts were also characterized and normalized to engine work load. The emissions were characterized as to the physicochemical composition in order to determine the magnitude of the differences among the emissions utilized in the studies. This article summarizes the major finding of these studies which are contained within this special issue of Inhalation Toxicology. The findings provided in these articles provide information about the toxicity of biodiesel emissions relative to petroleum diesel emissions and which can be utilized in a life cycle analyses of the effects of increased biodiesel usage. PMID- 26514780 TI - Generation and characterization of diesel engine combustion emissions from petroleum diesel and soybean biodiesel fuels and application for inhalation exposure studies. AB - Biodiesel made from the transesterification of plant- and animal-derived oils is an important alternative fuel source for diesel engines. Although numerous studies have reported health effects associated with petroleum diesel emissions, information on biodiesel emissions are more limited. To this end, a program at the U.S. EPA assessed health effects of biodiesel emissions in rodent inhalation models. Commercially obtained soybean biodiesel (B100) and a 20% blend with petroleum diesel (B20) were compared to pure petroleum diesel (B0). Rats and mice were exposed independently for 4 h/day, 5 days/week for up to 6 weeks. Exposures were controlled by dilution air to obtain low (50 ug/m(3)), medium (150 ug/m(3)) and high (500 ug/m(3)) diesel particulate mass (PM) concentrations, and compared to filtered air. This article provides details on facilities, fuels, operating conditions, emission factors and physico-chemical characteristics of the emissions used for inhalation exposures and in vitro studies. Initial engine exhaust PM concentrations for the B100 fuel (19.7 +/- 0.7 mg/m(3)) were 30% lower than those of the B0 fuel (28.0 +/- 1.5 mg/m(3)). When emissions were diluted with air to control equivalent PM mass concentrations, B0 exposures had higher CO and slightly lower NO concentrations than B100. Organic/elemental carbon ratios and oxygenated methyl esters and organic acids were higher for the B100 than B0. Both the B0 and B100 fuels produced unimodal-accumulation mode particle-size distributions, with B0 producing lower concentrations of slightly larger particles. Subsequent papers in this series will describe the effects of these atmospheres on cardiopulmonary responses and in vitro genotoxicity studies. PMID- 26514781 TI - Soy biodiesel emissions have reduced inflammatory effects compared to diesel emissions in healthy and allergic mice. AB - Toxicity of exhaust from combustion of petroleum diesel (B0), soy-based biodiesel (B100), or a 20% biodiesel/80% petrodiesel mix (B20) was compared in healthy and house dust mite (HDM)-allergic mice. Fuel emissions were diluted to target fine particulate matter (PM(2.5)) concentrations of 50, 150, or 500 MUg/m(3). Studies in healthy mice showed greater levels of neutrophils and MIP-2 in bronchoalveolar lavage (BAL) fluid 2 h after a single 4-h exposure to B0 compared with mice exposed to B20 or B100. No consistent differences in BAL cells and biochemistry, or hematological parameters, were observed after 5 d or 4 weeks of exposure to any of the emissions. Air-exposed HDM-allergic mice had significantly increased responsiveness to methacholine aerosol challenge compared with non-allergic mice. Exposure to any of the emissions for 4 weeks did not further increase responsiveness in either non-allergic or HDM-allergic mice, and few parameters of allergic inflammation in BAL fluid were altered. Lung and nasal pathology were not significantly different among B0-, B20-, or B100-exposed groups. In HDM allergic mice, exposure to B0, but not B20 or B100, significantly increased resting peribronchiolar lymph node cell proliferation and production of T(H)2 cytokines (IL-4, IL-5, and IL-13) and IL-17 in comparison with air-exposed allergic mice. These results suggest that diesel exhaust at a relatively high concentration (500 MUg/m(3)) can induce inflammation acutely in healthy mice and exacerbate some components of allergic responses, while comparable concentrations of B20 or B100 soy biodiesel fuels did not elicit responses different from those caused by air exposure alone. PMID- 26514782 TI - Comparative cardiopulmonary toxicity of exhausts from soy-based biofuels and diesel in healthy and hypertensive rats. AB - Increased use of renewable energy sources raise concerns about health effects of new emissions. We analyzed relative cardiopulmonary health effects of exhausts from (1) 100% soy biofuel (B100), (2) 20% soy biofuel + 80% low sulfur petroleum diesel (B20), and (3) 100% petroleum diesel (B0) in rats. Normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats were exposed to these three exhausts at 0, 50, 150 and 500 MUg/m(3), 4 h/day for 2 days or 4 weeks (5 days/week). In addition, WKY rats were exposed for 1 day and responses were analyzed 0 h, 1 day or 4 days later for time-course assessment. Hematological parameters, in vitro platelet aggregation, bronchoalveolar lavage fluid (BALF) markers of pulmonary injury and inflammation, ex vivo aortic ring constriction, heart and aorta mRNA markers of vasoconstriction, thrombosis and atherogenesis were analyzed. The presence of pigmented macrophages in the lung alveoli was clearly evident with all three exhausts without apparent pathology. Overall, exposure to all three exhausts produced only modest effects in most endpoints analyzed in both strains. BALF gamma-glutamyl transferase (GGT) activity was the most consistent marker and was increased in both strains, primarily with B0 (B0 > B100 > B20). This increase was associated with only modest increases in BALF neutrophils. Small and very acute increases occurred in aorta mRNA markers of vasoconstriction and thrombosis with B100 but not B0 in WKY rats. Our comparative evaluations show modest cardiovascular and pulmonary effects at low concentrations of all exhausts: B0 causing more pulmonary injury and B100 more acute vascular effects. BALF GGT activity could serve as a sensitive biomarker of inhaled pollutants. PMID- 26514783 TI - The effects of B0, B20, and B100 soy biodiesel exhaust on aconitine-induced cardiac arrhythmia in spontaneously hypertensive rats. AB - CONTEXT: Diesel exhaust (DE) has been shown to increase the risk of cardiac arrhythmias. Although biodiesel has been proposed as a "safer" alternative to diesel, it is still uncertain whether it actually poses less threat. OBJECTIVE: We hypothesized that exposure to pure or 20% soy biodiesel exhaust (BDE) would cause less sensitivity to aconitine-induced arrhythmia than DE in rats. METHODS: Spontaneously hypertensive (SH) rats implanted with radiotelemeters were exposed once or for 5 d (4 h) to either 50 mg/m(3) (low), 150 mg/m(3) (medium), or 500 mg/m(3) (high) of DE (B0), 20% (B20) or 100% (B100) soy biodiesel exhaust. Arrhythmogenesis was assessed 24 h later by continuous infusion of aconitine, an arrhythmogenic drug, while heart rate (HR), and electrocardiogram (ECG) were monitored. RESULTS: Rats exposed once or for 5 d to low, medium, or high B0 developed arrhythmia at significantly lower doses of aconitine than controls, whereas rats exposed to B20 were only consistently sensitive after 5 d of the high concentration. B100 caused mild arrhythmia sensitivity at the low concentration, only after 5 d of exposure at the medium concentration and after either a single or 5 d at the high concentration. DISCUSSION AND CONCLUSIONS: These data demonstrate that exposure to B20 causes less sensitivity to arrhythmia than B0 and B100. This diminished effect may be due to lower irritant components such as acrolein and nitrogen oxides. Thus, in terms of cardiac health, B20 may be a safer option than both of the pure forms. PMID- 26514784 TI - Comparative electrocardiographic, autonomic and systemic inflammatory responses to soy biodiesel and petroleum diesel emissions in rats. AB - CONTEXT: Biodiesel fuel represents an alternative to high particulate matter (PM) emitting petroleum-based diesel fuels, yet uncertainty remains regarding potential biodiesel combustion emission health impacts. OBJECTIVE: The purpose of this study was to compare cardiovascular responses to pure and blended biodiesel fuel emissions relative to petroleum diesel exhaust (DE). MATERIALS AND METHODS: Spontaneously hypertensive rats were exposed for 4 h per day for four days via whole body inhalation to combustion emissions (based on PM concentrations 50, 150 or 500 MUg/m(3) or filtered air) from pure (B100) or blended (B20) soy biodiesel, or to pure petroleum DE (B0). Electrocardiogram (ECG) and heart rate variability (HRV, an index of autonomic balance) were monitored before, during and after exposure while pulmonary and systemic inflammation were assessed one day after the final exposure. ECG and HRV data and inflammatory data were statistically analyzed using a linear mixed model for repeated measures and an analysis of variance, respectively. RESULTS: B100 and B0, but not B20, increased HRV during all exposure days at the highest concentration indicating increased parasympathetic tone. Electrocardiographic data were mixed. B100 and B0, but not B20, caused significant changes in one or more of the following: serum C-reactive protein, total protein, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, and blood urea nitrogen (BUN) and plasma angiotensin converting enzyme (ACE) and fibrinogen. DISCUSSION AND CONCLUSIONS: Although responses to emissions from all fuels were mixed and relatively mild, some findings point to a reduced cardiovascular impact of blended biodiesel fuel emissions. PMID- 26514785 TI - DNA adducts induced by in vitro activation of extracts of diesel and biodiesel exhaust particles. AB - CONTEXT: Biodiesel and biodiesel-blend fuels offer a renewable alternative to petroleum diesel, but few data are available concerning the carcinogenic potential of biodiesel exhausts. OBJECTIVES: We compared the formation of covalent DNA adducts by the in vitro metabolic activation of organic extracts of diesel-exhaust particles (DEP) from petroleum diesel and soy biodiesel and correlated DNA adduct levels and mutagenicity in Salmonella TA100. METHODS: We examined two different DEP from petroleum diesel (C-DEP and B0), one from soy bean oil biodiesel (B100) and one from combustion of a blend of 20% B100 and 80% B0 (B20) for in vitro DNA adduct-forming potential under oxidative or nitroreductive conditions in the presence of calf thymus DNA as well as in vivo in Salmonella TA100. The modified DNA was hydrolyzed and analyzed by (32)P postlabeling using either butanol extraction or nuclease P1 pre-enrichment. RESULTS: Multiple DNA adducts were produced with chromatographic mobilities consistent with PAH and nitro-PAH adducts. The types and quantities of DNA adducts produced by the two independent petroleum diesel DEP were similar, with both polycyclic aromatic hydrocarbon (PAH)- and nitro-PAH-derived adducts formed. Relative potencies for S9-mediated DNA adduct formation, either per mass of particulate or per MJ(th) energy consumed were B100 > B0 > B20. CONCLUSIONS: Soy biodiesel emissions induced DNA damage in the form of presumptive PAH and nitro PAH DNA adducts that correlated with mutagenicity in Salmonella. B20 is the soy biodiesel used most commonly in the US, and it produced the lowest DNA adduct emission factor, ~50% that of petroleum diesel. PMID- 26514786 TI - Health effects of soy-biodiesel emissions: mutagenicity-emission factors. AB - CONTEXT: Soy biodiesel is the predominant biodiesel fuel used in the USA, but only a few, frequently conflicting studies have examined the potential health effects of its emissions. OBJECTIVE: We combusted petroleum diesel (B0) and fuels with increasing percentages of soy methyl esters (B20, B50 and B100) and determined the mutagenicity-emission factors expressed as revertants/megajoule of thermal energy consumed (rev/MJ(th)). MATERIALS AND METHODS: We combusted each fuel in replicate in a small (4.3-kW) diesel engine without emission controls at a constant load, extracted organics from the particles with dichloromethane, determined the percentage of extractable organic material (EOM), and evaluated these extracts for mutagenicity in 16 strains/S9 combinations of Salmonella. RESULTS: Mutagenic potencies of the EOM did not differ significantly between replicate experiments for B0 and B100 but did for B20 and B50. B0 had the highest rev/MJ(th), and those of B20 and B100 were 50% and ~85% lower, respectively, in strains that detect mutagenicity due to polycyclic aromatic hydrocarbons (PAHs), nitroarenes, aromatic amines or oxidative mutagens. For all strains, the rev/MJ(th) decreased with increasing biodiesel in the fuel. The emission factor for the 16 EPA Priority PAHs correlated strongly (r(2 )= 0.69) with the mutagenicity-emission factor in strain TA100 + S9, which detects PAHs. CONCLUSIONS: Under a constant load, soy-biodiesel emissions were 50-85% less mutagenic than those of petroleum diesel. Without additional emission controls, petroleum and biodiesel fuels had mutagenicity-emission factors between those of large utility-scale combustors (e.g. natural gas, coal, or oil) and inefficient open-burning (e.g. residential wood fireplaces). PMID- 26514787 TI - Health effects of soy-biodiesel emissions: bioassay-directed fractionation for mutagenicity. AB - CONTEXT: Soy biodiesel is the predominant biodiesel in the USA, but there is little understanding of the classes of chemicals responsible for the mutagenicity of its emissions. OBJECTIVE: We determined some of the chemical classes responsible for the mutagenicity of the particulate matter (PM) of the emissions from petroleum diesel (B0) and biodiesel containing increasing concentrations of soy methyl esters (B20, B50, and B100). MATERIALS AND METHODS: We subjected organic extracts of the PM to bioassay-directed fractionation by sequential elution on silica gel with solvents of increasing polarity to produce four fractions per fuel. We injected these onto high performance liquid chromatography to produce 62 sub-fractions per fraction based on chemical polarity and evaluated all fractions and sub-fractions for mutagenicity in Salmonella. We correlated the results with the concentrations of 32 polycyclic aromatic hydrocarbons (PAHs) in the fractions. RESULTS: The mutagenicity-emission factors of the fractions generally decreased with increasing concentrations of soy in the fuel. Despite the different chemical compositions of the fuels, the extractable organics of all four emissions had similar features: ~60% of the mass was nonpolar, non-mutagenic compounds; most of the PAHs were polar; and most of the mutagenicity was due to weakly polar and polar compounds. Some of the mutagenicity of B20 was due to highly polar compounds. CONCLUSIONS: The PM from soy biodiesel emissions was less mutagenic than that from petroleum diesel, and this reduction was associated with reduced concentrations of various weakly polar, polar, and highly polar mutagens, including PAHs, aromatic amines, nitroarenes, and oxy-PAHs. PMID- 26514788 TI - Functional Outcomes and Unplanned Transfers of Pediatric Patients With Central Neurological Impairments Receiving Inpatient Rehabilitation Care With Cancer and Noncancer Diagnoses. AB - BACKGROUND: Functional impairments from central nervous system (CNS) dysfunction experienced by pediatric patients with cancer diagnoses are well documented. However, little is known of these patients' functional outcomes and potential complications while receiving inpatient rehabilitation services. OBJECTIVE: To compare functional outcomes and unplanned transfer rates of pediatric patients with impairments associated with CNS dysfunction between those with primary cancer diagnoses and noncancer diagnoses while receiving inpatient rehabilitation care. DESIGN: Retrospective comparison cohort study. SETTING: Inpatient rehabilitation unit within a regional tertiary care pediatric hospital. PARTICIPANTS: Patients with CNS-based functional impairments with primary cancer diagnoses (n = 107) and noncancer diagnoses (n = 480), admitted to the inpatient rehabilitation unit between January 1, 2005 and April 1, 2012, who were aged 1 to 20 years at time of admission. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Pediatric Functional Independence Measure (WeeFIM) reflecting functional status was collected at admission and discharge with change score and WeeFIM efficiency calculated. Length of stay on the rehabilitation unit and unplanned transfer rates were also collected. RESULTS: No significant difference in total WeeFIM scores at admission was found between cancer and noncancer groups. Both groups had significant increases in WeeFIM scores at discharge (P < .001). The noncancer group had significantly higher WeeFIM change in self-care (P = .001), mobility (P = .009), and total score (P = .004) and had a greater length of stay (P < .001). A comparison of WeeFIM efficiency in all domains revealed no significant difference between cancer and noncancer groups. There was also no significant between-group difference in unplanned transfer rates. CONCLUSIONS: Children with CNS-based functional impairments with cancer and noncancer diagnoses made functional gains with similar WeeFIM efficiencies after undergoing inpatient rehabilitation. However, patients with noncancer diagnoses made greater gains in self care, mobility, and total scores with longer stays on the rehabilitation service. No significant difference was found in unplanned transfer rates between cancer and noncancer groups for acute medical care. PMID- 26514789 TI - Mirror Movements After Stroke Suggest Facilitation From Nonprimary Motor Cortex: A Case Presentation. AB - When stroke occurs in adulthood, mirror movements (MMs; involuntary movements occurring in 1 hand when performing unilateral movements with the contralateral hand) in the paretic hand rarely occur. We present a case of an apparently healthy 54-year-old man presenting with MMs in his left (nondominant) hand. Further evaluation revealed diminished strength and dexterity in left hand, increased spinal excitability, decreased corticospinal excitability, occurrence of ipsilateral motor responses, enlarged cortical motor representation, and imaging findings consistent with a previously undiagnosed right-subcortical stroke. MMs and ipsilateral motor responses may reflect the increased spinal motor neurons' excitability sustained by the spared nonprimary ipsilesional motor areas. PMID- 26514790 TI - A Randomized Controlled Trial to Evaluate the Veterans' In-home Program for Military Veterans With Traumatic Brain Injury and Their Families: Report on Impact for Family Members. AB - BACKGROUND: Traumatic brain injury (TBI) creates many challenges for families as well as for patients. Few intervention studies have considered both the needs of the person with TBI and his or her family and included both in the intervention process. To address this gap, we designed an innovative intervention for veterans with TBI and families-the Veterans' In-home Program (VIP)-targeting veterans' environment, delivered in veterans' homes, and involving their families. OBJECTIVES: To determine whether the VIP is more effective than standard outpatient clinic care in improving family members' well-being in 3 domains (depressive symptoms, burden, and satisfaction) and to assess its acceptability to family members. DESIGN: In this randomized controlled trial, 81 dyads (veteran/family member) were randomly assigned to VIP or an enhanced usual care control condition. Randomization occurred after the baseline interview. Follow-up interviews occurred 3-4 months after baseline, and the interviewer was blinded to group assignment. SETTING: Interviews and intervention sessions were conducted in veterans' homes or by telephone. PARTICIPANTS: A total of 81 veterans with TBI recruited from a Veterans Affairs (VA) polytrauma program and a key family member for each participated. Of the 81 family members, 63 completed the follow-up interview. INTERVENTION: The VIP, guided by the person-environment fit model, consisted of 6 home visits and 2 telephone calls delivered by occupational therapists over a 3- to 4-month period. Family members were invited to participate in the 6 home sessions. MAIN OUTCOME MEASURES: Family member well being was operationally defined as depressive symptomatology, caregiver burden, and caregiver satisfaction 3-4 months after baseline. Acceptability was operationally defined through 3 indicators. RESULTS: Family members in the VIP showed significantly lower depressive symptom scores and lower burden scores when compared to controls at follow-up. Satisfaction with caregiving did not differ between groups. Family members' acceptance of the intervention was high. CONCLUSIONS: VIP represents the first evidence-based intervention that considers both the veteran with TBI and the family. VIP had a significant impact on family member well-being and thus addresses a large gap in previous research and services for families of veterans with TBI. PMID- 26514791 TI - Sensory properties of obsessive thoughts in OCD and the relationship to psychopathology. AB - For decades hallucinations and perception-laden thoughts were considered specific indicators of schizophrenia. This assumption has been revised over the years. Novel studies indicate that a subgroup of patients with obsessive-compulsive disorder (OCD), borderline disorder or depression display hallucinations and "loud"/perceptual thoughts. The present study examined the frequency of sensory laden obsessive thoughts and their relationship with the severity of obsessive compulsive, paranoid and depressive symptoms in a sample of 137 OCD patients who were recruited via the Internet. Participants were asked to fill out the Sensory Properties of Obsessions Questionnaire (SPOQ), the Obsessive-Compulsive Inventory Revised (OCI-R), the Paranoia Checklist and the Patient Health Questionnaire (PHQ9). In line with a prior study, a total of 72% displayed perceptual intrusions (i.e. vivid obsessions). Correlations emerged between perceptual thoughts and obsessive-compulsive, paranoid and depressive symptoms. Results further strengthen the assumption of a continuum ranging from "silent" thoughts to vivid intrusions and hallucinations. PMID- 26514792 TI - The West Coast Trail Rescue, and 6 Lessons to Pack With You. PMID- 26514793 TI - Anxiety in high-functioning autism: A pilot study of experience sampling using a mobile platform. AB - Anxiety and stress are everyday issues for many people with high-functioning autism, and while cognitive-behavioural therapy is the treatment of choice for the management of anxiety, there are challenges in using it with people with high functioning autism. This study used modified experience sampling techniques to examine everyday anxiety and stress in adults with high-functioning autism and to explore the feasibility of delivering real-time stress management techniques using a mobile platform. High levels of anxiety were found to be characterised by worry, confusing thoughts and being alone but was not associated with internal focus, imagery or rumination. Participants reported improved mood and less worry and anxious thinking in the active phase of the study. These results support previous studies indicating that people with high-functioning autism differ in their experience of anxiety and provided preliminary data on the feasibility of real-time stress management. The limitations of this approach are discussed together with considerations for future work in the area of developing clinical interventions on mobile platforms. PMID- 26514795 TI - Novel Epidermal Growth Factor Receptor Inhibitor Attenuates Angiotensin II Induced Kidney Fibrosis. AB - Chronic activation of renin-angiotensin system (RAS) greatly contributes to renal fibrosis and accelerates the progression of chronic kidney disease; however, the underlying molecular mechanism is poorly understood. Angiotensin II (Ang II), the central component of RAS, is a key regulator of renal fibrogenic destruction. Here we show that epidermal growth factor receptor (EGFR) plays an important role in Ang II-induced renal fibrosis. Inhibition of EGFR activation by novel small molecules or by short hairpin RNA knockdown in Ang II-treated SV40 mesangial cells in vitro suppresses protein kinase B and extracellular signal-related kinase signaling pathways and transforming growth factor-beta/Sma- and Mad related protein activation, and abolishes the accumulation of fibrotic markers such as connective tissue growth factor, collagen IV. The transactivation of EGFR by Ang II in SV40 cells depends on the phosphorylation of proto-oncogene tyrosine protein kinase Src (c-Src) kinase. Further validation in vivo demonstrates that EGFR small molecule inhibitor successfully attenuates renal fibrosis and kidney dysfunction in a mouse model induced by Ang II infusion. These findings indicate a crucial role of EGFR in Ang II-dependent renal deterioration, and reveal EGFR inhibition as a new therapeutic strategy for preventing progression of chronic renal diseases. PMID- 26514794 TI - Methylmercury-Dependent Increases in Fluo4 Fluorescence in Neonatal Rat Cerebellar Slices Depend on Granule Cell Migrational Stage and GABAA Receptor Modulation. AB - Methylmercury (MeHg) disrupts cerebellar function, especially during development. Cerebellar granule cells (CGC), which are particularly susceptible to MeHg by unknown mechanisms, migrate during this process. Transient changes in intracellular Ca(2+) (Ca(2+) i) are crucial to proper migration, and MeHg is well known to disrupt CGC Ca(2+) i regulation. Acutely prepared slices of neonatal rat cerebellum in conjunction with confocal microscopy and fluo4 epifluorescence were used to track changes induced by MeHg in CGC Ca(2+) i regulation in the external (EGL) and internal granule cell layers (IGL) as well as the molecular layer (ML). MeHg caused no cytotoxicity but did cause a time-dependent increase in fluo4 fluorescence that depended on the stage of CGC development. CGCs in the EGL were most susceptible to MeHg-induced increases in fluo4 fluorescence. MeHg increased fluorescence in CGC processes but only diffusely; Purkinje cells rarely fluoresced in these slices. Neither muscimol nor bicuculline alone altered baseline fluo4 fluorescence in any CGC layer, but each delayed the onset and reduced the magnitude of effect of MeHg on fluo4 fluorescence in the EGL and ML. In the IGL, both muscimol and bicuculline delayed the onset of MeHg-induced increases in fluo4 fluorescence but did not affect fluorescence magnitude. Thus, acute exposure to MeHg causes developmental stage-dependent increases in Ca(2+) i in CGCs. Effects are most prominent in CGCs during development or early stages of migration. GABAA receptors participate in an as yet unclear manner to MeHg induced Ca(2+) i dysregulation of CGCs. PMID- 26514796 TI - Fate of cadmium at the soil-solution interface: a thermodynamic study as influenced by varying pH at South 24 Parganas, West Bengal, India. AB - A study on the sorption kinetics of Cd from soil solution to soils was conducted to assess the persistence of Cd in soil solution as it is related to the leaching, bioavailability, and potential toxicity of Cd. The kinetics of Cd sorption on two non-contaminated alkaline soils from Canning (22 degrees 18' 48.02" N and 88 degrees 39' 29.0" E) and Lakshmikantapur (22 degrees 06' 16.61" N and 88 degrees 19' 08.66" E) of South 24 Parganas, West Bengal, India, were studied using conventional batch experiment. The variable soil suspension parameters were pH (4.00, 6.00, 8.18, and 9.00), temperatures (308, 318, and 328 K) and Cd concentrations (5-100 mg L(-1)). The average rate coefficient (kavg) and half-life (t1/2) values indicate that the persistence of Cd in soil solution is influenced by both temperature and soil suspension pH. The concentration of Cd in soil solution decreases with increase of temperature; therefore, Cd sorption on the soil-solution interface is an endothermic one. Higher pH decreases the t 1/2 of Cd in soil solution, indicating that higher pH (alkaline) is not a serious concern in Cd toxicity than lower pH (acidic). Based on the energy of activation (Ea) values, Cd sorption in acidic pH (14.76+/-0.29 to 64.45+/-4.50 kJ mol(-1)) is a surface control phenomenon and in alkaline pH (9.33+/-0.09 to 44.60+/-2.01 kJ mol(-1)) is a diffusion control phenomenon The enthalpy of activation (DeltaH?) values were found to be between 7.28 and 61.73 kJ mol(-1). Additionally, higher positive energy of activation (DeltaG?) values (46.82+/-2.01 to 94.47+/-2.36 kJ mol(-1)) suggested that there is an energy barrier for product formation. PMID- 26514797 TI - Effect of mesohabitats on responses of invertebrate community structure in streams under different land uses. AB - Riparian vegetation is one of the most important abiotic components determining the water flow pattern in lotic ecosystems, influencing the composition, richness, and diversity of invertebrates. We have identified whether differences in the structure of the assemblages of invertebrates between riffles and pools may influence the responses of fauna to the effects of land use. In addition, we investigated which fauna metrics are responsible for the differentiation between riffles and pools in streams subject to different land uses. During the dry season of 2012, the main substrates of riffles and pools were sampled (Surber collector) from nine streams within forest, pasture, and urban areas. Principal component analysis (PCA) and Permanova showed differences in the set of environmental variables between streams and mesohabitats. The first PCA axis distinguished the forest and pasture streams from the urban area streams and was related to variables indicative of nutrient enrichment and land use, while the second axis was formed by velocity flow and by the quantities of ultrafine and coarse sand, which distinguished the riffles and pools of the streams. The faunal composition distinguished the streams in pasture and forest areas from the urban streams. Riffles and pools were not concordant in the representation of the invertebrate fauna, indicating the importance of sampling both mesohabitats in the types of streams investigated. The richness, taxonomic composition, and relative abundance of families of Ephemeroptera, Plecoptera, and Trichoptera showed robust responses in riffles to the effects of environmental changes, while in pools, only the richness showed a significant response. It was possibly concluded that riffles were more sensitive in detecting the effects of land use. The information from this study help to understand how the community of invertebrates and the types of habitats in streams may be affected by anthropogenic impacts. PMID- 26514798 TI - Soil CO2 efflux among four coniferous forest types of Kashmir Himalaya, India. AB - Soil CO2 efflux was measured in four different coniferous forest types (Cedrus deodara (CD), Pinus wallichiana (PW), mixed coniferous (MC), and Abies pindrow (AP)) for a period of 2 years (April 2012 to December 2013). The monthly soil CO2 efflux ranged from 0.8 to 4.1 MUmoles CO2 m(-2) s(-1) in 2012 and 1.01 to 5.48 MUmoles CO2 m(-2) s(-1) in 2013. The soil CO2 efflux rate was highest in PW forest type in both the years, while it was lowest in MC and CD forest types during 2012 and 2013, respectively. Soil temperature (TS) at a depth of 10 cm ranged from 3.8 to 19.4 degrees C in 2012 and 3.5 to 19.1 degrees C in 2013 in all the four forest types. Soil moisture (MS) ranged from 19.8 to 58.6% in 2012 and 18.5 to 58.6% in 2013. Soil CO2 efflux rate was found to be significantly higher in summer than the other seasons and least during winter. Soil CO2 efflux showed a significant positive relationship with TS (R2=0.52 to 0.74), SOC% (R2=0.67), pH (R2=0.68), and shrub biomass (R2=0.51), whereas, only a weak positive relationship was found with soil moisture (R2=0.16 to 0.41), tree density (R2=0.25), tree basal area (R2=0.01), tree biomass (R2=0.07), herb biomass (R2=0.01), and forest floor litter (R2=0.02). Thus, the study indicates that soil CO2 efflux in high mountainous areas is greatly influenced by seasons, soil temperature, and other environmental factors. PMID- 26514799 TI - Effect of coated urea on cadmium accumulation in Oryza sativa L. grown in contaminated soil. AB - Experiments were conducted to determine the effects of three types of coated urea on the accumulation of cadmium (Cd) in rice (Oryza sativa L.) grown in contaminated soil. Pot-culture experiments were conducted in a greenhouse from July to November 2012 on the rice cultivar "Hua Hang Si Miao" in Guangzhou (China). The experimental design was completely randomized with four treatments and three replications. The treatments were control (CK) (N 0 mg/kg), prilled urea (PU) (N 200 mg/kg), polymer-coated urea (PCU) (N 200 mg/kg), and sulfur coated urea (SCU) (N 200 mg/kg). Our results indicated that applications of PCU and SCU slightly increased the dry weight of rice grains. The application of SCU significantly decreased the CaCl2 and toxicity characteristic leaching procedure (TCLP)-extractable Cd concentrations by 15.4 and 56.1%, respectively. Sequential extractions showed that PCU and SCU applications led to a significant decrease in Cd in the exchangeable fraction and an increase in the bound iron (Fe) and manganese (Mn) oxides fractions. Cd concentrations in grains treated with PCU were reduced by 11.7%, whereas SCU significantly reduced Cd concentrations by 29.1%. SCU reduced Cd transfer from the straws to the grain. Our results demonstrated that PCU and SCU may be effective in mitigating Cd accumulation in rice grown in acidic Cd-contaminated soil, especially in plants receiving SCU. PMID- 26514800 TI - Metal enrichment of soils following the April 2012-2013 eruptive activity of the Popocatepetl volcano, Puebla, Mexico. AB - We analyzed the total (Zn, Pb, Ni, Hg, Cr, Cd, Cu, As) and partially leachable metals (PLMs) in 25 ash and soil samples from recent (2012-2013) eruptions of the Popocatepetl Volcano in Central Mexico. More recent ash and soil samples from volcanic activity in 2012-2013 had higher metal concentrations than older samples from eruptions in 1997 suggesting that the naturally highly volatile and mobile metals leach into nearby fresh water sources. The higher proportions of As (74.72%), Zn (44.64%), Cu (42.50%), and Hg (32.86%) reflect not only their considerable mobility but also the fact that they are dissolved and accumulated quickly following an eruption. Comparison of our concentration patterns with sediment quality guidelines indicates that the Cu, Cd, Cr, Hg, Ni, and Pb concentrations are higher than permissible limits; this situation must be monitored closely as these concentrations may reach lethal levels in the future. PMID- 26514801 TI - Influencing factor analysis of phosphorus loads from non-point source: a case study in central China. AB - The influence factor analysis for non-point source (NPS) pollution is very important to taking effective water pollution control measures. In this study, the self-organizing map (SOM) and linear model analysis were used to analyze the relationships between total phosphorus (TP) loads and influencing factors, both qualitatively and quantitatively. The land-use type, topography, and vegetation coverage were the main factors influencing the export of TP loads in Tangxun watershed. Slope and normalized difference vegetation index (NDVI) were chosen as characteristic indices of topography and vegetation coverage, respectively. For the whole watershed, the high TP loads were mainly distributed in areas with high slope and low vegetation coverage for a specific land-use type. For different land types, the slope significantly influenced the export of TP loads in waste/bare land and forest/green land while NDVI influenced the export of TP loads in forest/green land and farmland. In terms of multi-factor analysis, the comprehensive influence of slope and NDVI on TP loads showed as waste/bare land>forest/green land>farmland>rural/urban construction land. PMID- 26514802 TI - Brominated flame retardants in food and environmental samples from a production area in China: concentrations and human exposure assessment. AB - Human exposure to brominated flame retardants (BFRs: decabromodiphenyl ether (BDE209), decabromodiphenyl ethane (DBDPE), hexabromobenzene (HBB), pentabromoethylbenzene (PBEB), pentabromotoluene (PBT), 1,2,3,4,5 pentabromobenzene (PBBz), and 2,3,5,6-tetrabromo-p-xylene (TBX)) in a brominated flame retardant production area (Weifang, Shandong Province, China) was estimated. Thirty food samples, 14 air samples, and 13 indoor dust samples were analyzed. BDE209 and DBDPE were the dominant BFRs in all samples. Higher alternative brominated flame retardant (including DBDPE, HBB, PBEB, PBT, PBBz, and TBX) concentrations were found in vegetables than in fish and meat; thus, plant-original foods might be important alternative BFR sources in the study area. The BDE209 and alternative BFR concentrations in air were 1.5*10(4) to 2.2*10(5) and 620 to 3.6*10(4) pg/m3, respectively. Mean total BFR exposures through the diet, inhalation, and indoor dust ingestion were 570, 3000, and 69 ng/d, respectively (16, 82, and 2% of total intake, respectively). Inhalation was the dominant BFR source except for DBDPE, for which diet dominated. BDE209 contributed 85% of the total BFR intake in the study area. PMID- 26514803 TI - Human adenovirus spread, rainfalls, and the occurrence of gastroenteritis cases in a Brazilian basin. AB - Climate variables may interfere with the environmental persistence and spread of pathogenic microorganisms. This study aimed to investigate the occurrence of human adenovirus (HAdV) and total and thermotolerant coliforms in treated and untreated water and report gastroenteritis cases in seven cities located in the hydrographic basin of the Sinos River (HBSR), Southern Brazil. The data on water quality from samples collected at catchment areas of HBSR from March to December 2011 were compared with precipitation records, virus detection rates and viral loads, and information on enteric diseases among residents of the region. There was a marked increase in precipitation intensity in April, July, and August and a decrease in May and November. The number of HAdV genome copies (gc) in untreated water ranged from 2.1*10(8) gc/L in June to 7.8*10(1) gc/L in December, and in treated water, from 6.3*10(4) gc/L in September to 4.1*10(1) gc/L in November. The most probable number (MPN) of total coliforms ranged from 5*10(1) MPN/100 mL in December to 2.4*10(5) MPN/100 mL in July, and thermotolerant coliforms ranged from 1*10(1) MPN/100 mL in August to 6.9*10(4) MPN/100 mL in July. A total of 79 hospital admissions due to gastroenteritis were registered in the cities studied. The results for coliforms in untreated water demonstrate deficits in sanitation and wastewater treatment. These findings also indicate a possible relationship between the occurrence of rainfalls after dry periods and an increase in the number of gastroenteritis cases and in HAdV load quantified in surface water collected for conventional potabilization. PMID- 26514804 TI - An assessment of water quality in the Coruh Basin (Turkey) using multivariate statistical techniques. AB - The purpose of this study was to assess the impact of 24 water parameters, measured semi-annually between 2011 and 2013 in Coruh Basin (Turkey), based on the quality of the water. The study utilised analysis of variance (ANOVA), principal component analysis (PCA) and factor analysis (FA) methods. The water quality data was obtained from a total of four sites by the 26th Regional Directorate of the State Hydraulic Works (DSI). ANOVA was carried out to identify the differences between the parameters at the different measuring sites. The variables were classified using factor analysis, and at the end of the ANOVA test, it was established that there was a statistically significant difference between the downstream and upstream waste waters released by the Black Sea copper companies and between the Murgul and Borcka Dams, in terms of water quality, while no statistically significant difference was observed between the Murgul and Borcka Dams. It was determined through factor analysis that five factors explained 81.3% of the total variance. It was concluded that domestic, industrial and agricultural activities, in combination with physicochemical properties, were factors affecting the quality of the water in the Coruh Basin. PMID- 26514805 TI - Analyzing nonlinear variations in terrestrial vegetation in China during 1982 2012. AB - Quantifying the long-term trends of changes in terrestrial vegetation on a large scale is an effective method for detecting the effects of global environmental change. In view of the trend towards overall restoration and local degradation of terrestrial vegetation in China, it is necessary to pay attention to the spatial processes of vegetative restoration or degradation, as well as to clarify the temporal and spatial characteristics of vegetative growth in greater geographical detail. However, traditional linear regression analysis has some drawbacks when describing ecological processes. Combining nonparametric linear regression analysis with high-order nonlinear fitting, the temporal and spatial characteristics of terrestrial vegetative growth in China during 1982-2012 were detected using the third generation of Global Inventory Modeling and Mapping Studies (GIMMS3g) dataset. The results showed that high-order curves could be effective. The region joining Ordos City and Shaanxi Gansu Ningxia on the Loess Plateau may have experienced restoration-degradation-restoration processes of vegetative growth. In the Daloushan Mountains, degradation-restoration processes of vegetative growth may have occurred, and the occurrence of several hidden vegetative growth processes was located in different regions of eastern China. Changes in cultivated vegetation were inconsistent with changes in other vegetation types. In southern China and some high-altitude areas, temperature was the primary driver of vegetative growth on an interannual scale, while in the north, the effect of rainfall was more significant. Nevertheless, the influence of climate on vegetation activity in large urban areas was weak. The trend types of degradation-restoration processes in several regions were inconsistent with the implements of regional land development and protection strategy. Thus, the role of human activity cannot be ignored. In future studies, it will be still necessary to quantify the effects of human management on spatial patterns, develop trend-fitting methods, and explore more refined methods of analyzing the driving forces affecting large-scale changes in vegetative growth. PMID- 26514807 TI - Identification of Aminoimidazole and Aminothiazole Derivatives as Src Family Kinase Inhibitors. AB - Src family kinases (SFKs) are a family of non-receptor tyrosine kinases (TKs) implicated in the regulation of many cellular processes. The aberrant activity of these TKs has been associated with the growth and progression of cancer. In particular, c-Src is overexpressed or hyperactivated in a variety of solid tumors and is most likely a strong promoting factor for the development of metastasis. Herein, the synthesis of new 4-aminoimidazole and 2-aminothiazole derivatives and their in vitro biological evaluation are described for their potential use as SFK inhibitors. Initially, 2-aminothiazole analogues of dasatinib and 4 aminoimidazole derivatives were synthesized and tested against the SFKs Src, Fyn, Lyn, and Yes. Five hits were identified as the most promising compounds, with Ki values in the range of 90-480 nm. A combination of molecular docking, homology modeling, and molecular dynamics were then used to investigate the possible binding mode of such compounds within the ATP binding site of the SFKs. Finally, the antiproliferative activities of the best candidates were evaluated against SH SY5Y and K562 cell lines. Compound 3 b [2-(4-{2-methyl-6-[(5-phenylthiazol-2 yl)amino]pyrimidin-4-yl}piperazin-1-yl)ethanol] was found to be the most active inhibitor. PMID- 26514806 TI - Overexpression of truncated AIF regulated by Egr1 promoter radiation-induced apoptosis on MCF-7 cells. AB - It has been demonstrated that gene-radiotherapy can improve the radiotherapy by selectively increasing cells' response to ionizing radiation. Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein, and its C-terminal domain is responsible for the proapoptotic activity. In the present study, we overexpressed truncated AIF on MCF-7 cells by transfection of pcDNA3.1-tAIF (pc-tAIF) and pcDNA3.1-Egr1-tAIF (pc-Egr1-tAIF) plasmids. After MCF-7-tAIF cells were exposed to X-rays, the AIF and tAIF expressions, cell proliferation, apoptosis, cell cycle invasion, cytochrome c (Cyt c) release and activation of caspase-9 were measured by using Western blot, MTT assay, flow cytometry and Matrigel transwell assay, respectively. Our results showed that tAIF expression increased on time- and dose-dependent manners. Both tAIF and radiation can synergistically enhance the apoptosis, cell proliferation inhibition, cell cycle arrest and cell-invasive inhibition. In addition, tAIF overexpression and irradiation increased Cyt c release. However, only irradiation increased caspase-9 activation. Our studies indicated that tAIF overexpression might enhance apoptosis induced by radiation in MCF-7 cells. PMID- 26514808 TI - An Intracellular Laccase Is Responsible for Epicatechin-Mediated Anthocyanin Degradation in Litchi Fruit Pericarp. AB - In contrast to the detailed molecular knowledge available on anthocyanin synthesis, little is known about its catabolism in plants. Litchi (Litchi chinensis) fruit lose their attractive red color soon after harvest. The mechanism leading to quick degradation of anthocyanins in the pericarp is not well understood. An anthocyanin degradation enzyme (ADE) was purified to homogeneity by sequential column chromatography, using partially purified anthocyanins from litchi pericarp as a substrate. The purified ADE, of 116 kD by urea SDS-PAGE, was identified as a laccase (ADE/LAC). The full-length complementary DNA encoding ADE/LAC was obtained, and a polyclonal antibody raised against a deduced peptide of the gene recognized the ADE protein. The anthocyanin degradation function of the gene was confirmed by its transient expression in tobacco (Nicotiana benthamiana) leaves. The highest ADE/LAC transcript abundance was in the pericarp in comparison with other tissues, and was about 1,000-fold higher than the polyphenol oxidase gene in the pericarp. Epicatechin was found to be the favorable substrate for the ADE/LAC. The dependence of anthocyanin degradation by the enzyme on the presence of epicatechin suggests an ADE/LAC epicatechin-coupled oxidation model. This model was supported by a dramatic decrease in epicatechin content in the pericarp parallel to anthocyanin degradation. Immunogold labeling transmission electron microscopy suggested that ADE/LAC is located mainly in the vacuole, with essential phenolic substances. ADE/LAC vacuolar localization, high expression levels in the pericarp, and high epicatechin-dependent anthocyanin degradation support its central role in pigment breakdown during pericarp browning. PMID- 26514809 TI - Differential neural activity patterns for spatial relations in humans: a MEG study. AB - Children learn the words for above-below relations earlier than for left-right relations, despite treating these equally well in a simple visual categorization task. Even as adults--conflicts in congruency, such as when a stimulus is depicted in a spatially incongruent manner with respect to salient global cues- can be challenging. Here we investigated the neural correlates of encoding and maintaining in working memory above-below and left-right relational planes in 12 adults using magnetoencephalography in order to discover whether above-below relations are represented by the brain differently than left-right relations. Adults performed perfectly on the task behaviorally, so any differences in neural activity were attributed to the stimuli's cognitive attributes. In comparing above-below to left-right relations during stimulus encoding, we found the greatest differences in neural activity in areas associated with space and movement. In comparing congruent to incongruent trials, we found the greatest differential activity in premotor areas. For both contrasts, brain areas involved in the encoding phase were also involved in the maintenance phase, which provides evidence that those brain areas are particularly important in representing the relational planes or congruency types throughout the trial. When comparing neural activity associated with the relational planes during working memory, additional right posterior areas were implicated, whereas the congruent-incongruent contrast implicated additional bilateral frontal and temporal areas. These findings are consistent with the hypothesis left-right relations are represented differently than above-below relations. PMID- 26514810 TI - A "one size fits all" approach to language fMRI: increasing specificity and applicability by adding a self-paced component. AB - We have previously established an fMRI task battery suitable for mapping the language processing network in children. Among the tasks used, the synonyms and the vowel identification task induced robust task-related activations in children with average language abilities; however, the fixed presentation time seems to be a drawback in participants with above- or below-average language abilities. This feasibility study in healthy adults (n = 20) was aimed at adapting these tasks to the individual level of each patient by implementing a self-paced stimulus presentation. The impact of using a block- versus an event-related statistical approach was also evaluated. The self-paced modification allowed our participants with above-average language abilities to process stimuli much faster than originally implemented, likely increasing task adherence. A higher specificity of the event-related analysis was confirmed by stronger left inferior frontal and crossed cerebellar activations. We suggest that self-paced paradigms and event related analyses may both increase specificity and applicability. PMID- 26514811 TI - The effect of dual-task difficulty on the inhibition of the motor cortex. AB - Dual-tasking is intrinsic to many daily activities, including walking and driving. However, the activity of the primary motor cortex (M1) in response to dual-tasks (DT) is still not well characterised. A recent meta-analysis (Corp in Neurosci Biobehav Rev 43:74-87, 2014) demonstrated a reduction in M1 inhibition during dual-tasking, yet responses were not consistent between studies. It was suggested that DT difficulty might account for some of this between-study variability. The aim of this study was to investigate whether corticospinal excitability and M1 inhibition differed between an easier and more difficult dual task. Transcranial magnetic stimulation (TMS) was applied to participants' abductor pollicis brevis muscle representation during a concurrent pincer grip task and stationary bike-riding. The margin of error in which to maintain pincer grip force was reduced to increase task difficulty. Compared to ST conditions, significantly increased M1 inhibition was demonstrated for the easier, but not more difficult, DT. However, there was no significant difference in M1 inhibition between easy and difficult DTs. The difference in difficulty between the two tasks may not have been wide enough to result in significant differences in M1 inhibition. Increased M1 inhibition for the easy DT condition was in opposition to the reduction in M1 inhibition found in our meta-analysis (Corp in Neurosci Biobehav Rev 43:74-87, 2014). We propose that this may be partially explained by differences in the timing of the TMS pulse between DT studies. PMID- 26514812 TI - Transcutaneous trigeminal nerve stimulation induces a long-term depression-like plasticity of the human blink reflex. AB - The beneficial effects of trigeminal nerve stimulation (TNS) on several neurological disorders are increasingly acknowledged. Hypothesized mechanisms include the modulation of excitability in networks involved by the disease, and its main site of action has been recently reported at brain stem level. Aim of this work was to test whether acute TNS modulates brain stem plasticity using the blink reflex (BR) as a model. The BR was recorded from 20 healthy volunteers before and after 20 min of cyclic transcutaneous TNS delivered bilaterally to the infraorbital nerve. Eleven subjects underwent sham-TNS administration and were compared to the real-TNS group. In 12 subjects, effects of unilateral TNS were tested. The areas of the R1 and R2 components of the BR were recorded before and after 0 (T0), 15 (T15), 30 (T30), and 45 (T45) min from TNS. In three subjects, T60 and T90 time points were also evaluated. Ipsi- and contralateral R2 areas were significantly suppressed after bilateral real-TNS at T15 (p = 0.013), T30 (p = 0.002), and T45 (p = 0.001), while R1 response appeared unaffected. The TNS induced inhibitory effect on R2 responses lasted up to 60 min. Real- and sham-TNS protocols produced significantly different effects (p = 0.005), with sham-TNS being ineffective at any time point tested. Bilateral TNS was more effective (p = 0.009) than unilateral TNS. Acute TNS induced a bilateral long-lasting inhibition of the R2 component of the BR, which resembles a long-term depression-like effect, providing evidence of brain stem plasticity produced by transcutaneous TNS. These findings add new insight into mechanisms of TNS neuromodulation and into physiopathology of those neurological disorders where clinical benefits of TNS are recognized. PMID- 26514813 TI - A pilot study to determine the optimal timing of the Physician Global Assessment (PGA) in patients with systemic lupus erythematosus. AB - The Physician Global Assessment (PGA) is an important and useful outcome measurement of lupus disease activity, but consensus on whether the PGA should be performed prior to or after the receipt of laboratory values is lacking. The objective of this study was to collect preliminary data on the optimal time to perform a PGA. In this pilot study, a PGA was performed by a single clinician upon completion of an outpatient clinical encounter and again after receipt of pertinent laboratory values. Laboratory values obtained at each clinical visit included a CBC, comprehensive chemistries, C3, C4, anti-dsDNA antibody levels, urinalysis and, if pertinent, a spot urinary protein/creatinine ratio. Disease activity was additionally determined by the SELENA-SLEDAI. Fifty-four patients, 3 males and 51 females with an average SLE disease duration of 12.3 (SD 10.5) years contributed 74 assessments to this study. The average SELENA-SLEDAI was 2.2. The average pre-laboratory PGA was 0.46, and the average post-laboratory PGA was 0.55 (p < 0.02 paired Student's t test). Among the 48 encounters with active disease and a mean SELENA-SLEDAI of 3.37, concordance of the pre-laboratory and post laboratory PGAs occurred in only third of the patient encounters. Both pre- and post-PGA correlated with the SELENA-SLEDAI. However, the correlation of the post PGA with the SELENA-SLEDAI was significantly greater than the correlation of the pre-PGA and SELENA-SLEDAI [r = 0.69 vs 0.79, respectively (p < 0.0179)]. In some lupus patients, the PGA determined prior to receipt of laboratory values may be the same as the PGA determined after laboratory values are received. However, in these preliminary data, there was a significant difference between pre-laboratory and post-laboratory PGA with a significantly greater correlation of the post laboratory PGA with the SELENA-SLEDAI. Further studies in a larger patient population with a greater range of disease activity are needed to confirm and extend these findings. PMID- 26514814 TI - Complementing the characterization of in vivo generated N-glucuronic acid conjugates of stanozolol by collision cross section computation and analysis. AB - Detailed structural information on metabolites serving as target analytes in clinical, forensic, and sports drug testing programmes is of paramount importance to ensure unequivocal test results. In the present study, the utility of collision cross section (CCS) analysis by travelling wave ion mobility measurements to support drug metabolite characterization efforts was tested concerning recently identified glucuronic acid conjugates of the anabolic androgenic steroid stanozolol. Employing travelling-wave ion mobility spectrometry/quadrupole-time-of-flight mass spectrometry, drift times of five synthetically derived and fully characterized steroid glucuronides were measured and subsequently correlated to respective CCSs as obtained in silico to form an analyte-tailored calibration curve. The CCSs were calculated by equilibrium structure minimization (density functional theory) using the programmes ORCA with the data set B3LYP/6-31G and MOBCAL utilizing the trajectory method (TM) with nitrogen as drift gas. Under identical experimental conditions, synthesized and/or urinary stanozolol-N and O-glucuronides were analyzed to provide complementary information on the location of glucuronidation. Finally, the obtained data were compared to CCS results generated by the system's internal algorithm based on a calibration employing a polyalanine analyte mixture. The CCSs OmegaN2 calculated for the five steroid glucuronide calibrants were found between 180 and 208 A(2) , thus largely covering the observed and computed CCSs for stanozolol-N1'-, stanozolol-N2'-, and stanozolol-O-glucuronide found at values between 195.1 and 212.4 A(2) . The obtained data corroborated the earlier suggested N- and O-glucuronidation of stanozolol, and demonstrate the exploit of ion mobility and CCS computation in structure characterization of phase-II metabolic products; however, despite reproducibly measurable differences in ion mobility of stanozolol-N1'-, N2'-, and O-glucuronides, the discriminatory power of the chosen CCS computation algorithm was found to be not appropriate to allow for accurate assignments of the two N-conjugated structures. Using polyalanine based calibrations, significantly different absolute values were obtained for all CCSs, but due to a constant offset of approximately 45 A(2) an excellent correlation (R(2) = 0.9997) between both approaches was observed. This suggests a substantially accelerated protocol when patterns of computed and polyalanine based experimental data can be used for structure elucidations instead of creating individual analyte-specific calibration curves. PMID- 26514815 TI - Nivolumab: a review in advanced squamous non-small cell lung cancer. AB - Nivolumab (Opdivo((r)); Nivolumab BMSTM) was the first programmed death (PD)-1 immune checkpoint inhibitor to be approved for use in advanced, squamous non small cell lung cancer (NSCLC) following prior chemotherapy. In the pivotal CheckMate 017 trial, intravenous nivolumab 3 mg/kg every 2 weeks was associated with significantly better overall survival and progression-free survival and a significantly higher overall response rate than intravenous docetaxel in the second-line treatment of advanced, squamous NSCLC. Nivolumab was also better tolerated than docetaxel in CheckMate 017, and its adverse event profile (which included immune-mediated adverse events) was manageable. In conclusion, nivolumab represents an important advance in previously-treated, advanced, squamous NSCLC. PMID- 26514816 TI - Devosia humi sp. nov., isolated from soil of a Korean pine (Pinus koraiensis) garden. AB - A bacterial isolate, designated strain THG-MM1T, was isolated from soil in Yongin region, Republic of Korea. Strain THG-MM1T was Gram-stain-negative, aerobic, non motile and rod-shaped. Based on 16S rRNA gene sequence comparisons, strain THG MM1T was most closely related to Devosia insulae DS-56T (96.5 % 16S rRNA gene sequence similarity), followed by Devosia yakushimensis Yak96BT (95.7 %) and Devosia albogilva IPL15T (95.2 %). The G+C content of the genomic DNA was 63.7 mol%. The major cellular fatty acids were C16 : 0, summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and C18 : 0. The predominant isoprenoid quinone was ubiquinone-10 (Q-10). The major polar lipids were phosphatidylglycerol and an unidentified lipid. The combined phenotypic, chemotaxonomic and phylogenetic data showed that strain THG-MM1T represents a novel species of the genus Devosia, for which the name Devosia humi sp. nov. is proposed, with strain THG-MM1T ( = KACC 18281T = CCTCC AB 2015121T) as the type strain. PMID- 26514818 TI - Erratum to: Effects of tolvaptan in the early postoperative stage after heart valve surgery: results of the STAR (Study of Tolvaptan for fluid retention AfteR valve surgery) trial. PMID- 26514819 TI - Modifying alginate with early embryonic extracellular matrix, laminin, and hyaluronic acid for adipose tissue engineering. AB - Extracellular matrix provides both mechanistic and chemical cues that can influence cellular behaviors such as adhesion, migration, proliferation, and differentiation. In this study, a new material, HA-L-Alg, was synthesized by linking developmentally essential ECM constituents hyaluronic acid (HA) and laminin(L) to alginate (Alg). The fabrication of HA-L-Alg was confirmed by FTIR spectroscopy, and it was used to form 3D cell-carrying beads. HA-L-Alg beads had a steady rate of degradation and retained 63.25% of mass after 9 weeks. HA-L-Alg beads showed biocompatibility comparable to beads formed by Alg-only with no obvious cytotoxic effect on the embedded 3T3-L1 preadipocytes. HA-L-Alg encapsulated 3T3-L1 cells were found to have a higher proliferation rate over those in Alg-only beads. These cells also showed better differentiation capacity after 2 weeks of adipogenic induction within HA-L-Alg beads. These results support that HA-L-Alg facilitated cell survival and proliferation, as well as stimulated and maintained cell differentiation. Our results suggest that HA-L-Alg has a great clinical potential to be used as stem cell carrier for adipose tissue engineering. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 669-677, 2016. PMID- 26514817 TI - DNA damage response and sphingolipid signaling in liver diseases. AB - Patients with unresectable hepatocellular carcinoma (HCC) cannot generally be cured by systemic chemotherapy or radiotherapy due to their poor response to conventional therapeutic agents. The development of novel and efficient targeted therapies to increase their treatment options depends on the elucidation of the molecular mechanisms that underlie the pathogenesis of HCC. The DNA damage response (DDR) is a network of cell-signaling events that are triggered by DNA damage. Its dysregulation is thought to be one of the key mechanisms underlying the generation of HCC. Sphingosine-1-phosphate (S1P), a lipid mediator, has emerged as an important signaling molecule that has been found to be involved in many cellular functions. In the liver, the alteration of S1P signaling potentially affects the DDR pathways. In this review, we explore the role of the DDR in hepatocarcinogenesis of various etiologies, including hepatitis B and C infection and non-alcoholic steatohepatitis. Furthermore, we discuss the metabolism and functions of S1P that may affect the hepatic DDR. The elucidation of the pathogenic role of S1P may create new avenues of research into therapeutic strategies for patients with HCC. PMID- 26514820 TI - Evaluation of a Porcine Gastric Mucin and RNase A Assay for the Discrimination of Infectious and Non-infectious GI.1 and GII.4 Norovirus Following Thermal, Ethanol, or Levulinic Acid Plus Sodium Dodecyl Sulfate Treatments. AB - Human noroviruses (NoVs) are a major source of foodborne illnesses worldwide. Since human NoVs cannot be cultured in vitro, methods that discriminate infectious from non-infectious NoVs are needed. The purpose of this study was to evaluate binding of NoV genotypes GI.1 and GII.4 to histo-blood group antigens expressed in porcine gastric mucin (PGM) as a surrogate for detecting infectious virus following thermal (99 degrees C/5 min), 70% ethanol or 0.5% levulinic acid (LV) plus 0.01 or 0.1% sodium dodecyl sulfate (SDS) sanitizer treatments and to determine the limit of detection of GI.1 and GII.4 binding to PGM. Treated and control virus samples were applied to 96-well plates coated with 1 ug/ml PGM followed by RNase A (5 ng/ul) treatment for degradation of exposed RNA. Average log genome copies per ml (gc/ml) reductions and relative differences (RD) in quantification cycle (Cq) values after thermal treatment were 1.77/5.62 and 1.71/7.25 (RNase A) and 1.73/5.50 and 1.56/6.58 (no RNase A) for GI.1 and GII.4, respectively. Treatment of NoVs with 70% EtOH resulted in 0.05/0.16 (GI.1) and 3.54/10.19 (GII.4) log reductions in gc/ml and average RD in Cq value, respectively. LV (0.5%) combined with 0.1 % SDS provided a greater decrease of GI.1 and GII.4 NoVs with 8.97 and 8.13 average RD in Cq values obtained, respectively than 0.5% LV/0.01 % SDS. Virus recovery after PGM binding was variable with GII.4 > GI.1. PGM binding is a promising surrogate for identifying infectious and non-infectious NoVs after capsid destruction, however, results vary depending on virus strain and inactivation method. PMID- 26514821 TI - [Decision conflicts with relatives in the intensive care unit]. AB - BACKGROUND: If medicine is coming close to its limits conflicts sometimes occur. Most conflicts in the intensive care unit (ICU) involve the medical team and patients' relatives. In particular decisions about withholding and withdrawing life-sustaining therapy lead to conflicts. Decisions about limiting life sustaining treatment are burdened by conflicts and put an enormous strain particularly on relatives. AIM: Illustration of currently available studies and existing recommendations on how to manage potentially conflict-laden decision finding discussions on the ICU are presented. MATERIAL AND METHODS: This article is based on a selective literature research in the PubMed database. RESULTS: Studies have been carried out to evaluate posttraumatic stress disorders in relatives who were involved in life-limiting treatment decisions. Conflicts on the ICU put an emotional strain on relatives. Evidence-based recommendations are available regarding physicians' attitudes during discussions about therapy decisions, communication style and other contextual factors. Study results show that the emotional stress level relatives have to endure can be reduced if conversations between patients' families and the clinical personnel were conducted according to these recommendations. The involvement of a clinical ethics committee can prevent conflicts and has been shown to have no impact on the mortality rate but does decrease the time life-sustaining measures were unsuccessfully pursued. CONCLUSION: To prevent conflicts between the medical personnel and patients' relatives on the ICU, a timely, congruent and empathic conversation style in an appropriate, quiet environment is essential. Consultation with clinical ethics committees is recommended to de-escalate disputes. PMID- 26514823 TI - Pityriasis rosea. PMID- 26514822 TI - A comparison of visual and quantitative methods to identify interstitial lung abnormalities. AB - BACKGROUND: Evidence suggests that individuals with interstitial lung abnormalities (ILA) on a chest computed tomogram (CT) may have an increased risk to develop a clinically significant interstitial lung disease (ILD). Although methods used to identify individuals with ILA on chest CT have included both automated quantitative and qualitative visual inspection methods, there has been not direct comparison between these two methods. To investigate this relationship, we created lung density metrics and compared these to visual assessments of ILA. METHODS: To provide a comparison between ILA detection methods based on visual assessment we generated measures of high attenuation areas (HAAs, defined by attenuation values between -600 and -250 Hounsfield Units) in >4500 participants from both the COPDGene and Framingham Heart studies (FHS). Linear and logistic regressions were used for analyses. RESULTS: Increased measures of HAAs (in >= 10 % of the lung) were significantly associated with ILA defined by visual inspection in both cohorts (P < 0.0001); however, the positive predictive values were not very high (19 % in COPDGene and 13 % in the FHS). In COPDGene, the association between HAAs and ILA defined by visual assessment were modified by the percentage of emphysema and body mass index. Although increased HAAs were associated with reductions in total lung capacity in both cohorts, there was no evidence for an association between measurement of HAAs and MUC5B promoter genotype in the FHS. CONCLUSION: Our findings demonstrate that increased measures of lung density may be helpful in determining the severity of lung volume reduction, but alone, are not strongly predictive of ILA defined by visual assessment. Moreover, HAAs were not associated with MUC5B promoter genotype. PMID- 26514825 TI - Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Ralpha2-positive Glioma. AB - Immunotherapy with T cells expressing chimeric antigen receptors (CARs) is an attractive approach to improve outcomes for patients with glioblastoma (GBM). IL13Ralpha2 is expressed at a high frequency in GBM but not in normal brain, making it a promising CAR T-cell therapy target. IL13Ralpha2-specific CARs generated up to date contain mutated forms of IL13 as an antigen-binding domain. While these CARs target IL13Ralpha2, they also recognize IL13Ralpha1, which is broadly expressed. To overcome this limitation, we constructed a panel of IL13Ralpha2-specific CARs that contain the IL13Ralpha2-specific single-chain variable fragment (scFv) 47 as an antigen binding domain, short or long spacer regions, a transmembrane domain, and endodomains derived from costimulatory molecules and CD3.zeta (IL13Ralpha2-CARs). IL13Ralpha2-CAR T cells recognized IL13Ralpha2-positive target cells in coculture and cytotoxicity assays with no cross-reactivity to IL13Ralpha1. However, only IL13Ralpha2-CAR T cells with a short spacer region produced IL2 in an antigen-dependent fashion. In vivo, T cells expressing IL13Ralpha2-CARs with short spacer regions and CD28.zeta, 41BB.zeta, and CD28.OX40.zeta endodomains had potent anti-glioma activity conferring a significant survival advantage in comparison to mice that received control T cells. Thus, IL13Ralpha2-CAR T cells hold the promise to improve current IL13Ralpha2-targeted immunotherapy approaches for GBM and other IL13Ralpha2-positive malignancies. PMID- 26514826 TI - Dengue virus infection alters post-transcriptional modification of microRNAs in the mosquito vector Aedes aegypti. AB - Recent discoveries regarding the importance of isomiRs have increased our understanding of the regulatory complexities of the miRNAome. Observed changes in the miRNA profiles in mosquitoes infected with flaviviruses have implicated small RNAs in the interactions between viruses and their vectors. Here we analysed the isomiR profiles of both uninfected and infected Aedes aegypti mosquitoes with the major human pathogen dengue virus (DENV). We found that several specific isomiRs were significantly altered in their abundance patterns in response to DENV infection potentially affecting their target repertoire. Notable among these were isomiR variants which displayed arm-switching. We also demonstrate that modifications to the 3p end of miRNAs are vastly more prevalent than those at the 5p ends. We also observed that in only 45% of Ae. aegypti miRNAs the most abundant read matches the exact sequence reported in miRBase. Further, we found positive correlations between the number of mature miRNA reads, pre-miRNA length, GC content and secondary structure minimum free energy with the number of isomiRs. The findings presented here provide some evidence that isomiR production is not a random phenomenon and may be important in DENV replication in its vector. PMID- 26514827 TI - Prevalence of antenatal depression and associated factors among pregnant women in Addis Ababa, Ethiopia: a cross-sectional study. AB - BACKGROUND: The World Health Organization identifies depressive disorders as the second leading cause of global disease burden by 2020. However, there is a paucity of studies which examined the associated factors of antenatal depression in low-income countries. This study aimed to determine the prevalence of antenatal depression and associated factors among pregnant women in Addis Ababa, Ethiopia. METHODS: A cross-sectional study was employed among 393 pregnant women attending antenatal care service in Addis Ababa public health centers, Ethiopia from April 12-26, 2012. The Edinburgh Postnatal Depression Scale (EPDS) was used to detect depressive symptoms. Descriptive statistics and logistic regression were used in the statistical analysis. RESULTS: Prevalence of antenatal depression was 24.9 % (95 % CI: 20.85-29.30 %). In the final multivariable model, those pregnant women who have previous history of depression were nearly three times at higher odds of having antenatal depression as compared to pregnant women who have no history of depression [AOR = 2.57(95 % CI: 1.48-4.48 )]. Those pregnant women having unplanned pregnancy were nearly three times at higher odds to develop depression as compared to pregnant women whose pregnancy was planned [AOR = 2.78(95 % CI: 1.59-4.85)]. The odd of developing antenatal depression was 89 % higher in those pregnant women who experienced lack of baby's father support [AOR = 1.89(95 % CI: 1.06-3.36)]. Education level, community's support, and partner's feeling on current pregnancy were not significantly associated factors with antenatal depression in the final multivariable model. CONCLUSION: Although clinical confirmation for antenatal depression is not conducted, one quarter of the pregnant women attending antenatal care were depressed in Addis Ababa based on EPDS. Unplanned pregnancy, experiencing lack of baby's father support and previous history of depression were factors independently associated with antenatal depression. Promotion of family planning and integration of mental health service with existing maternal health care as well as strengthening the referral system among public health centers were the recalled interventions to prevent antenatal depression in Addis Ababa Public Health Centers. PMID- 26514828 TI - Evolution of an archaeal virus nucleocapsid protein from the CRISPR-associated Cas4 nuclease. AB - Many proteins of viruses infecting hyperthermophilic Crenarchaeota have no detectable homologs in current databases, hampering our understanding of viral evolution. We used sensitive database search methods and structural modeling to show that a nucleocapsid protein (TP1) of Thermoproteus tenax virus 1 (TTV1) is a derivative of the Cas4 nuclease, a component of the CRISPR-Cas adaptive immunity system that is encoded also by several archaeal viruses. In TTV1, the Cas4 gene was split into two, with the N-terminal portion becoming TP1, and lost some of the catalytic amino acid residues, apparently resulting in the inactivation of the nuclease. To our knowledge, this is the first described case of exaptation of an enzyme for a virus capsid protein function. PMID- 26514824 TI - Enhanced Recovery After Surgery (ERAS) for gastrointestinal surgery, part 2: consensus statement for anaesthesia practice. AB - BACKGROUND: The present interdisciplinary consensus review proposes clinical considerations and recommendations for anaesthetic practice in patients undergoing gastrointestinal surgery with an Enhanced Recovery after Surgery (ERAS) programme. METHODS: Studies were selected with particular attention being paid to meta-analyses, randomized controlled trials and large prospective cohort studies. For each item of the perioperative treatment pathway, available English language literature was examined and reviewed. The group reached a consensus recommendation after critical appraisal of the literature. RESULTS: This consensus statement demonstrates that anaesthesiologists control several preoperative, intraoperative and postoperative ERAS elements. Further research is needed to verify the strength of these recommendations. CONCLUSIONS: Based on the evidence available for each element of perioperative care pathways, the Enhanced Recovery After Surgery (ERAS(r)) Society presents a comprehensive consensus review, clinical considerations and recommendations for anaesthesia care in patients undergoing gastrointestinal surgery within an ERAS programme. This unified protocol facilitates involvement of anaesthesiologists in the implementation of the ERAS programmes and allows for comparison between centres and it eventually might facilitate the design of multi-institutional prospective and adequately powered randomized trials. PMID- 26514830 TI - From filaments to function: The role of the plant actin cytoskeleton in pathogen perception, signaling and immunity. AB - The eukaryotic actin cytoskeleton is required for numerous cellular processes, including cell shape, development and movement, gene expression and signal transduction, and response to biotic and abiotic stress. In recent years, research in both plants and animal systems have described a function for actin as the ideal surveillance platform, linking the function and activity of primary physiological processes to the immune system. In this review, we will highlight recent advances that have defined the regulation and breadth of function of the actin cytoskeleton as a network required for defense signaling following pathogen infection. Coupled with an overview of recent work demonstrating specific targeting of the plant actin cytoskeleton by a diversity of pathogens, including bacteria, fungi and viruses, we will highlight the importance of actin as a key signaling hub in plants, one that mediates surveillance of cellular homeostasis and the activation of specific signaling responses following pathogen perception. Based on the studies highlighted herein, we propose a working model that posits changes in actin filament organization is in and of itself a highly specific signal, which induces, regulates and physically directs stimulus-specific signaling processes, most importantly, those associated with response to pathogens. PMID- 26514829 TI - Malpositioned olecranon fracture tension-band wiring results in proximal radioulnar synostosis. AB - BACKGROUND: Tension-band wiring (TBW) is a well-established fixation technique for two-part, transverse fracture types of the olecranon. However, complication rates up to 80 % are reported. By reporting on the enormous impact on the patient if failed the aim of the present report was to emphasize the importance of correct K wire positioning in TBW. CASE PRESENTATION: We present the case of a 49 year-old woman who suffered from a radioulnar synostosis of the forearm due to malpositioned K wires after TBW treatment. The patient was treated by heterotopic bone resection supported by ossification prophylaxis (radiotherapy and Indomethacin). At follow-up of 12 months after revision surgery, elbow motion was unrestricted with a strength grade 5/5. The patient was free of pain and reported no restrictions in daily as well as sporting activities. Radiologic assessment showed no recurrence of heterotopic bone tissue. CONCLUSION: Intraoperative radiographic and clinical examination of the elbow is highly recommended to identify incorrect hardware positioning and, therefore, to avoid serious postoperative complications in TBW. PMID- 26514831 TI - The role of central vision in posture: Postural sway adaptations in Stargardt patients. AB - The role of central and peripheral vision in the maintenance of upright stance is debated in literature. Stargardt disease causes visual deficits affecting the central field, but leaving unaltered a patient's peripheral vision. Hence, the study of this rare pathology gives the opportunity to selectively investigate the role of central vision in posture. Postural sway in quiet stance was analyzed in 10 Stargardt patients and 10 control subjects, in three different conditions: (1) eyes closed, (2) eyes open, gazing at a fixed target, and (3) eyes open, tracking a moving target. Stargardt patients outperformed controls in the condition with eyes closed, showing a reduced root mean square (RMS) of the medio-lateral COP displacement, while their performance was not significantly different from controls in the antero-posterior direction. There were no significant differences between patients and controls in open eyes conditions. These results suggest that Stargardt patients adapted to a different visual-somatosensory integration, relying less on vision, especially in the medio-lateral direction. Hence, the central vision seems to affect mostly the medio-lateral direction of postural sway. This finding supports the plausibility of the "functional sensitivity hypothesis", that assigns complementary roles to central and peripheral vision in the control of posture. PMID- 26514832 TI - Testing Postural Stability: Are the Star Excursion Balance Test and Biodex Balance System Limits of Stability Tests Consistent? AB - There are a variety of options to test postural stability; however many physical tests lack validity information. Two tests of postural stability - the Star Excursion Balance Test (SEBT) and Biodex Balance System Limits of Stability Test (LOS) - were examined to determine if similar components of balance were measured. Healthy adults (n=31) completed the LOS (levels 6 and 12) and SEBT (both legs). SEBT directions were offset by 180 degrees to approximate LOS direction. Correlations and partial correlations controlling for height were analyzed. Correlations were significant for SEBT 45 degrees and LOS back-left (6: r=-0.41; 12: r=-0.42; p<0.05), SEBT 90 degrees and LOS 6 left (r=-0.51, p<0.05), SEBT 135(o) and LOS 6 front-left (r=-0.53, p<0.05), SEBT overall and LOS 6 overall (r=-0.43, p<0.05). Partial correlations were significant for SEBT 90 degrees and LOS 6 left (rSEBT,LOS.H=-0.45, p<0.05) and SEBT 135 degrees and LOS 6 front-left (rSEBT,LOS.H=-0.51, p<0.05), and SEBT overall and LOS 6 overall (rSEBT,LOS.H=-0.37, p<0.05). These findings indicate the tests seem to assess different components of balance. Research is needed to determine and define what specific components of balance are being assessed. Care must be taken when choosing balance tests to best match the test to the purpose of testing (fall risk, athletic performance, etc.). PMID- 26514833 TI - Design, synthesis, and anti-HIV-1 activity of 1-substituted 3-(3,5 dimethylbenzyl)triazine derivatives. AB - BACKGROUND: The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is an attractive target for the development of drugs used in the treatment of HIV-1 infection and acquired immune deficiency syndrome (AIDS). We have continued the search for novel anti-HIV-1 agents using the structure activity relationships of the successful 1,3-disubstituted and 1,3,6 trisubstituted uracil-type HIV-1 RT inhibitors. METHODS: A series of new triazine analogs were synthesized using an established method. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells. The cytotoxicity of the compounds was evaluated by assessing the viability of mock-infected cells. RESULTS: Some of the compounds showed good-to-moderate activities against HIV-1, with half-maximal effective concentrations (EC50) in the submicromolar range. In particular, a dihydro-1-(4 aminobenzyl)triazine analog showed satisfactory anti-HIV-1 activity with an EC50 of 0.110 uM and a selectivity index (SI) of 909. Furthermore, molecular modeling analyses were performed to explore the major interactions between HIV-1 RT and potent inhibitors. These results may be important for further development of this class of compounds as anti-HIV-1 agents. CONCLUSION: The satisfactory anti-HIV-1 activity of triazine analogs may serve as the basis for further investigations of the behavior of this class of compounds against drug-resistant mutants. PMID- 26514834 TI - Low Contrast Dose Catheter-Directed CT Angiography (CCTA). AB - PURPOSE: Catheter-directed computed tomography angiography (CCTA) has been shown to reduce the contrast volumes required in conventional CTA, thus minimizing the risk of contrast-induced nephropathy (CIN). MATERIALS AND METHODS: A retrospective analysis was performed on cases where CCTA was used to assess access vessels prior to transfemoral aortic valve implantation (TAVI, n = 53), abdominal aortic aneurysm assessment for endovascular aneurysm repair (EVAR, n = 11), and peripheral vascular disease (PVD, n = 24). RESULTS: We show that CCTA can image vasculature with adequate diagnostic detail to allow assessment of lower extremity disease, anatomic suitability for EVAR, as well as potential contraindications to TAVI. Average contrast volumes for pre-TAVI, pre-EVAR, and PVD cases were 7, 11, and 28 mL, respectively. CONCLUSION: This study validates the use of CCTA in obtaining diagnostic images of the abdominal and pelvic vessels and in imaging lower extremity vasculature. PMID- 26514835 TI - Prognosis in multiple sclerosis and the unveiling of pathogenic clues. PMID- 26514836 TI - Association between antidepressants and falls in Parkinson's disease. AB - Parkinson's disease (PD) patients have an increased risk of falls resulting in important social and economical consequences. Risk factors for falls include the use of psychotropic drugs, which are used for the treatment of PD neuropsychiatric symptoms. We aimed to determine the association between psychotropic drug use and falls in a PD cohort. A cross-sectional study from the NPF QII study UF site was conducted. Subjects reported presence and frequency of falls in the prior year. Frequency was scored from 0 (no falls) to 4 (falling daily). Antidepressants, antipsychotics, cognitive enhancers/stimulants, and benzodiazepines were considered psychotropics. Forty percent of the 647 subjects included had a fall in the previous year. Fallers were found to have clinical signs of a more advanced disease. After adjusting for confounding variables, the regression analysis showed that use of antidepressants alone (adjusted OR 2.2, CI 95 % 1.3-3.8, p = 0.04), benzodiazepines alone (adjusted OR 2.0, CI 95 % 1.1-3.5, p = 0.02), and the combination of antidepressants with benzodiazepines (adjusted OR 4.1, CI 95 % 2.0-8.3, p < 0.0001) were independently associated with the presence of falls. When comparing to those not on psychotropics, subjects on antidepressants alone had a significantly higher mean frequency of falls score (1.07 vs. 0.44, p < 0.0001). The use of antidepressants was independently associated with falls in our PD cohort after considering for confounding variables such as age and measures of disease progression. Other factors related to disease progression should be considered before claiming the use of psychotropic drugs as causative. PMID- 26514837 TI - Leflunomide treatment in corticosteroid-dependent myasthenia gravis: an open label pilot study. AB - Leflunomide is an effective drug used in the treatment of rheumatoid arthritis. Here we report the findings of an open-label pilot study, which found that leflunomide is also an effective treatment for myasthenia gravis (MG). This study recruited 15 corticosteroid-dependent MG patients. For 6 months, leflunomide 20 mg was given to these patients daily along with prednisone. The quantitative myasthenia gravis (QMG) scores and MG activities of daily living (MG-ADL) profiles were measured in these MG patients. After 6 months of treatment, 9 of the 15 patients enrolled in this study showed improvements in both QMG and MG ADL. The mean QMG scores (13.4 to 8.5) and MG-ADL profiles (5.8 to 2.8) were significantly decreased (P = 0.01, 0.006 respectively). Furthermore, we found that the mean corticosteroid doses were reduced after treatment with leflunomide (24.3 to 12.3 mg per day). Leflunomide is a well-tolerated and efficacious treatment for corticosteroid-dependent MG, which may also enable lower doses of corticosteroids to be administered. PMID- 26514839 TI - Erratum to: Provider patient-sharing networks and multiple-provider prescribing of benzodiazepines. PMID- 26514838 TI - The neural correlates of motor intentional disorders in patients with subcortical vascular cognitive impairment. AB - Subcortical vascular cognitive impairment (SVCI) refers to cognitive impairment associated with small vessel disease. Motor intentional disorders (MID) have been reported in patients with SVCI. However, there are no studies exploring the neuroanatomical regions related to MID in SVCI patients. The aim of this study, therefore, was to investigate the neural correlates of MID in SVCI patients. Thirty-one patients with SVCI as well as 10 healthy match control participants were included. A "Pinch-Grip" apparatus was used to quantify the force control capabilities of the index finger in four different movement phases including initiation, development, maintenance, and termination. All participants underwent magnetic resonance imaging (MRI). Topographical cortical areas and white matter tracts correlated with the performances of the four different movement phases were assessed by the surface-based morphometry and tract-based spatial statistics analyses. Poorer performance in the maintenance task was related to cortical thinning in bilateral dorsolateral prefrontal, orbitofrontal and parietal cortices, while poorer performance in the termination task was associated with the disruption of fronto-parietal cortical areas as well as the white matter tracts including splenium and association fibers such as superior longitudinal fasciculus. Our study demonstrates that cortical areas and underlying white matter tracts associated with fronto-parietal attentional system play an important role in motor impersistence and perseveration in SVCI patients. PMID- 26514840 TI - Bone Matrix Composition Following PTH Treatment is Not Dependent on Sclerostin Status. AB - Sclerostin and parathyroid hormones are strong negative and positive regulators of bone formation, respectively. The anabolic response induced by intermittent (iPTH) treatment is sclerostin status-dependent. However, the interaction between sclerostin and iPTH at the matrix level is unknown. The goal of the current study was to determine if iPTH treatment affects matrix composition and, if so, whether these effects are dependent on sclerostin status. Humeral trabecular and cortical bone sites from 16 week old male wild-type (WT) and sclerostin knockout (KO) mice, which had been treated with vehicle or iPTH from age 10-16 weeks, were examined by micro-computed tomography (uCT) to measure bone volume, backscatter scanning electron microscopy (bSEM) to assess global mineralization, and Fourier transform infrared microspectroscopy (FTIRM) to examine matrix composition (mineral-to-matrix ratio, crystallinity, collagen cross-link ratio, and carbonate substitution). The FTIRM measurements were restricted to the tissue formed during the 6-week treatment period. iPTH treatment led to increased trabecular bone volume (p < 0.001) and this effect was much greater in KO mice than WT mice (interaction effect, p < 0.001). iPTH treatment led to reduced trabecular crystallinity (p = 0.047), increased cortical bone area (p < 0.001), decreased cortical bone crystallinity (p = 0.002) and increased cortical bone collagen cross-linking (p = 0.028) to similar degrees in both WT and KO mice. Compared to WT mice, sclerostin KO mice had higher trabecular and cortical bone mass (p < 0.001) and lower mineral-to-matrix ratio in the trabecular (p = 0.010) and cortical (p = 0.016) compartments. Thus, iPTH-induced changes in bone mass are dependent upon sclerostin status in the trabecular compartment, but not in the cortical compartment. In contrast, iPTH-induced changes in matrix composition are sclerostin-independent in both trabecular and cortical compartments. PMID- 26514841 TI - Professional judgement and decision-making in adventure sports coaching: the role of interaction. AB - This qualitative study presents the view that coaching practice places demands on the coach's adaptability and flexibility. These requirements for being adaptive and flexible are met through a careful process of professional judgement and decision-making based on context-appropriate bodies of knowledge. Adventure sports coaches were selected for study on the basis that adventure sports create a hyper-dynamic environment in which these features can be examined. Thematic analysis revealed that coaches were generally well informed and practised with respect to the technical aspects of their sporting disciplines. Less positively, however, they often relied on ad hoc contextualisation of generalised theories of coaching practice to respond to the hyper-dynamic environments encountered in adventure sports. We propose that coaching practice reflects the demands of the environment, individual learning needs of the students and the task at hand. Together, these factors outwardly resemble a constraints-led approach but, we suggest, actually reflect manipulation of these parameters from a cognitive rather than an ecological perspective. This process is facilitated by a refined judgement and decision-making process, sophisticated epistemology and an explicit interaction of coaching components. PMID- 26514843 TI - Differential effect of cholesterol on type I and II feline coronavirus infection. AB - Feline infectious peritonitis (FIP) is a fatal disease of domestic and wild felidae that is caused by feline coronavirus (FCoV). FCoV has been classified into types I and II. Since type I FCoV infection is dominant in the field, it is necessary to develop antiviral agents and vaccines against type I FCoV infection. However, few studies have been conducted on type I FCoV. Here, we compare the effects of cholesterol on types I and II FCoV infections. When cells were treated methyl-beta-cyclodextrin (MbetaCD) and inoculated with type I FCoV, the infection rate decreased significantly, and the addition of exogenous cholesterol to MbetaCD-treated cells resulted in the recovery of the infectivity of type I FCoV. Furthermore, exogenous cholesterol increased the infectivity of type I FCoV. In contrast, the addition of MbetaCD and exogenous cholesterol had little effect on the efficiency of type II FCoV infection. These results strongly suggest that the dependence of infection by types I and II FCoV on cholesterol differs. PMID- 26514842 TI - Detection and monitoring of early caries lesions: a review. AB - AIM: To review the current evidence base of detecting and monitoring early carious lesions in children and adolescents and a rationale proposed to ensure that such lesions are identified and appropriately managed. METHODS: The systematic literature search identified initially a review by Gomez and co workers from 2013 and this still represents the current state of the science in relation to caries detection and monitoring. The review described among others, visible detection systems, image-based detection systems and point-measurement approaches. RESULTS: The current evidence base suggests that while there are numerous devices or technology-enabled detection systems, the use of a careful, methodical visual inspection of clean, dry teeth, supplemented where indicated by radiographic views, remains the standard of care in caries detection and diagnostics. Further, it is possible by means of existing visible and radiographical systems to monitor lesions over time. Using low-cost intra-oral cameras facilitates the recording of lesion appearance in the patient record and may be of significant benefit in monitoring early lesions over time following their detection. This benefit extends to the clinician and the patient for whom it may be a useful educational and motivational tool. CONCLUSIONS: Recommendations are presented that can be adopted and adapted to local circumstances and that are both substantiated by evidence and promote a clear, simple and consistent approach to caries detection, diagnosis and monitoring in children and adolescents. The diagnoses (initial, active; moderate, active and extensive, active) are linked to appropriate management options within primary care. PMID- 26514844 TI - Opium poppy mosaic virus, a new umbravirus isolated from Papaver somniferum in New Zealand. AB - A novel virus, tentatively named "opium poppy mosaic virus" (OPMV), was isolated from Papaver somniferum (opium poppy) with leaf mosaic and mottling symptoms in Auckland, New Zealand, in 2006. The virus was mechanically transmitted to herbaceous plants of several species, in which it induced local and/or systemic symptoms. No virus particles were observed by electron microscopy in the diseased P. somniferum or any of the symptomatic herbaceous plants. The complete genomic sequence of 4230 nucleotides contains four open reading frames (ORF) and is most closely related (59.3 %) to tobacco bushy top virus, a member of the genus Umbravirus. These data suggest that OPMV is a new umbravirus. PMID- 26514845 TI - Papain-templated Cu nanoclusters: assaying and exhibiting dramatic antibacterial activity cooperating with H2O2. AB - Herein, papain-functionalized Cu nanoclusters (CuNCs@Papain) were originally synthesized in aqueous solution together with a quantum yield of 14.3%, and showed obviously red fluorescence at 620 nm. Meanwhile, their corresponding fluorescence mechanism was fully elucidated by fluorescence spectroscopy, HR-TEM, FTIR spectroscopy, and XPS. Subsequently, the as-prepared CuNCs were employed as probes for detecting H2O2. Using CuNCs as probes, H2O2 was determined in the range from 1 MUM to 50 MUM based on a linear decrease of fluorescence intensity as well as a detection limit of 0.2 MUM with a signal-to-noise ratio of 3. More significantly, it has been proved that CuNCs could convert H2O2 to OH, which exhibited dramatic antibacterial activity. Both in vitro and in vivo experiments were performed to validate their antibacterial activity against Gram positive/negative bacteria and actual wound infection, suggesting their potential for serving as one type of promising antibacterial material. PMID- 26514846 TI - Neuronal organization of the main olfactory bulb revisited. AB - The main olfactory bulb is now one of the most interesting parts of the brain; firstly as an excellent model for understanding the neural mechanisms of sensory information processing, and secondly as one of the most prominent sites whose interneurons are generated continuously in the postnatal and adult periods. The neuronal organization of the main olfactory bulb is fundamentally important as the basis of ongoing and future studies. In this review we focus on four issues, some of which appear not to have been recognized previously: (1) axons of periglomerular cells, (2) the heterogeneity and peculiarity of dopamine-GABAergic juxtaglomerular cells, (3) neurons participating in the interglomerular connections, and (4) newly found transglomerular cells. PMID- 26514847 TI - ISPOG European Consensus Statement - chronic pelvic pain in women (short version). AB - To date there is no international guideline on chronic pelvic pain available that focuses on medical, psychosomatic and psychological diagnostics and treatment of this complicated disease pattern. In this paper, a European working group, which was established in October 2010, aims to bridge this gap. The working group decided to use the current German guideline as source text and to transform it into a European consensus statement by deleting parts that apply only to the conditions of the German health system. The literature search included papers published up to and including December 2010, using Medline search and by adding some new search terms. This manuscript reports the essential facts of the above mentioned consensus statement. Within this article we use the term "psychosomatic" as the integrated concept of medical and psychosocial aspects of a disease. PMID- 26514849 TI - Is coracoclavicular stabilisation alone sufficient for the endoscopic treatment of severe acromioclavicular joint dislocation (Rockwood types III, IV, and V)? AB - BACKGROUND: The primary objective was to evaluate correlations linking anatomical to functional outcomes after endoscopically assisted repair of acute acromioclavicular joint dislocation (ACJD). HYPOTHESIS: Combined acromioclavicular and coracoclavicular stabilisation improves radiological outcomes compared to coracoclavicular stabilisation alone. MATERIAL AND METHODS: A prospective multicentre study was performed. Clinical outcome measures were pain intensity on a visual analogue scale (VAS), subjective functional impairment (QuickDASH score), and Constant's score. Anatomical outcomes were assessed on standard radiographs (anteroposterior view of the acromioclavicular girdle and bilateral axillary views) obtained preoperatively and postoperatively and on postoperative dynamic radiographs taken as described by Tauber et al. RESULTS: Of 116 patients with acute ACJD included in the study, 48% had type III, 30% type IV, and 22% type V ACJD according to the Rockwood classification. Coracoclavicular stabilisation was achieved using a double endobutton in 93% of patients, and concomitant acromioclavicular stabilisation was performed in 50% of patients. The objective functional outcome was good, with an unweighted Constant's score >= 85/100 and a subjective QuickDASH functional disability score <= 10 in 75% of patients. The radiographic analysis showed significant improvements from the preoperative to the 1-year postoperative values in the vertical plane (decrease in the coracoclavicular ratio from 214 to 128%, p=10( 6)) and in the horizontal plane (decrease in posterior displacement from 4 to 0mm, p=5*10(-5)). The anatomical outcome correlated significantly with the functional outcome (absolute R value=0.19 and p=0.045). We found no statistically significant differences across the various types of constructs used. Intra operative control of the acromioclavicular joint did not improve the result. Implantation of a biological graft significantly improved both the anatomical outcome in the vertical plane (p=0.04) and acromioclavicular stabilisation in the horizontal plane (p=0.02). The coracoclavicular ratio on the anteroposterior radiograph was adversely affected by a longer time from injury to surgery (p=0.02) and by a higher body mass index (BMI) (p=0.006). High BMI also had a negative effect on the difference in the distance separating the anterior edge of the acromion from the anterior edge of the clavicle between the injured and uninjured sides, as assessed on the axillary views (p=0.009). CONCLUSION: This study demonstrates that acute ACJD requires stabilisation in both planes, i.e., at the coracoclavicular junction and at the acromioclavicular joint. Coracoclavicular stabilisation alone is not sufficient, regardless of the type of implant used. Implantation of a biological graft should be considered when the time from injury to surgery is longer than 10days. The weight of the upper limb should be taken into account, with 6weeks of immobilisation to unload the construct in patients who have high BMI values. LEVEL OF EVIDENCE: II, prospective non-randomised comparative study. PMID- 26514850 TI - Sequential 3D analysis of patellofemoral kinematics from biplanar x-rays: In vitro validation protocol. AB - BACKGROUND: Developing criteria for assessing patellofemoral kinematics is crucial to understand, evaluate, and monitor patellofemoral function. The objective of this study was to assess a sequential 3D analysis method based on biplanar radiographs, using an in vitro protocol. HYPOTHESIS: Biplanar radiography combined with novel 3D reconstruction methods provides a reliable evaluation of patellofemoral function, without previous imaging. MATERIAL AND METHODS: Eight cadaver specimens were studied during knee flexion cycles from 0 degrees to 60 degrees induced by an in vitro simulator. The protocol was validated by investigating sequential and continuous motion using an optoelectronic system, evaluating measurement accuracy and reproducibility using metallic beads embedded in the patella, and comparing the 3D patellar geometry to computed tomography (CT) images. RESULTS: The differences in position between the sequential and continuous kinematic analyses were less than 1mm and 1 degrees . The protocol proved reliable for tracking several components of knee movements, including patellar translations, flexion, and tilt. In this analysis, uncertainty was less than 2 mm for translations and less than 3 degrees for rotations, except rotation in the coronal plane. For patellar tilt, uncertainty was 5 degrees . Mean difference in geometry was 0.49 mm. DISCUSSION: Sequential analysis results are consistent with continuous kinematics. This analysis method provides patellar position parameters without requiring previous CT or magnetic resonance imaging. A clinical study may deserve consideration to identify patellofemoral kinematic profiles and position criteria in vivo. LEVEL OF EVIDENCE: IV, experimental study. PMID- 26514851 TI - Exact matrix treatment of an osmotic ensemble model of adsorption and pressure induced structural transitions in metal organic frameworks. AB - Here we present an exactly treated quasi-one dimensional statistical mechanical osmotic ensemble model of pressure and adsorption induced breathing structural transformations of metal-organic frameworks (MOFs). The treatment uses a transfer matrix method. The model successfully reproduces the gas and pressure induced structural changes which are observed experimentally in MOFs. The model treatment presented here is a significant step towards analytical statistical mechanical treatments of flexible metal-organic frameworks. PMID- 26514852 TI - Do you want chips with that? PMID- 26514853 TI - Antibacterial antibodies gain traction. PMID- 26514857 TI - Trial watch: Telomerase inhibitor shows promise in myeloproliferative disorders. PMID- 26514858 TI - Husseini Manji. PMID- 26514859 TI - The psoriasis drugs market. PMID- 26514860 TI - Neurodegenerative disease: Targeting tau acetylation attenuates neurodegeneration. PMID- 26514861 TI - Cancer: Antitumour responses with more BiTE. PMID- 26514866 TI - Current Assessment of Reciprocation in Endodontic Preparation: A Comprehensive Review-Part I: Historic Perspectives and Current Applications. AB - INTRODUCTION: During the evolution of mechanical instrumentation in endodontics, an important role has been played by reciprocating stainless steel files using horizontal rotational, vertical translational, or combined movements. These kinds of systems are still in use mainly as an accessory to help in the first phases of the treatment. METHODS: The literature concerning these systems has been analyzed using selected criteria. RESULTS: The latest evolution of horizontal rotational reciprocating movement brought to the development of a different kind of movement in which the angles are asymmetrical and that appears to be ideal in conjunction with modern nickel-titanium (NiTi) files with a greater taper. Initially, this movement was limited to particular handpieces available on the market that was used with existing NiTi files to complete root canal instrumentation. Later on, specific files and proprietary motors were introduced into the market. The differences between reciprocating motion used for NiTi and stainless steel files are described and critically analyzed. CONCLUSIONS: A classification of the different mechanical reciprocating motions used is presented, thus enabling an easier understanding of these systems and anticipated future developments. PMID- 26514867 TI - Double Dens Invaginatus with Multiple Canals in a Maxillary Central Incisor: Retreatment and Managing Complications. AB - Dens invaginatus is a developmental anomaly that often presents a perplexing challenge to the endodontist. It involves the maxillary central incisor less commonly than the maxillary lateral incisor. Double dens invaginatus is even rarer. Herein a unique case of dens invaginatus in a maxillary central incisor is presented. The tooth had an inadequate previous root canal treatment. On retreatment, multiple canals and double dens invaginatus were found. The invaginations were Oehlers type 3b and type 2. The complex morphology was diagnosed and confirmed with cone-beam computed tomography imaging and managed with a combined surgical and orthograde approach. Four canals and a blind sac along with an open apex were found. There were many intercommunications between the canals. During the treatment, a complication of a separated instrument occurred, which was managed successfully. The 1-year follow-up shows successful outcome of the treatment. Dens invaginatus may be more complicated than it seems. It needs meticulous treatment by a specialist. Failure or a delay in referring the case to a specialty setting may further increase the complications. With the advancements in equipment and materials, it is possible to save even severe cases of dens invaginatus. PMID- 26514868 TI - Exquisite specificity of mitogenic lectin from Cephalosporium curvulum to core fucosylated N-glycans. AB - Lectins are carbohydrate binding proteins that are gaining attention as important tools for the identification of specific glycan markers expressed during different stages of the cancer. We earlier reported the purification of a mitogenic lectin from human pathogenic fungus Cephalosporium curvulum (CSL) that has complex sugar specificity when analysed by hapten inhibition assay. In the present study, we report the fine sugar specificity of CSL as determined by glycan array analysis. The results revealed that CSL has exquisite specificity towards core fucosylated N-glycans. Fucosylated trimannosyl core is the basic structure required for the binding of CSL. The presence of fucose in the side chain further enhances the avidity of CSL towards such glycans. The affinity of CSL is drastically reduced towards the non-core fucosylated glycans, in spite of their side chain fucosylation. CSL showed no binding to the tested O-glycans and monosaccharides. These observations suggest the unique specificity of CSL towards core fucosylated N-glycans, which was further validated by binding of CSL to human colon cancer epithelial and hepatocarcinoma cell lines namely HT29 and HepG2, respectively, that are known to express core fucosylated N-glycans, using AOL and LCA as positive controls. LCA and AOL are fucose specific lectins that are currently being used clinically for the diagnosis of hepatocellular carcinomas. Most of the gastrointestinal markers express core fucosylated N glycans. The high affinity and exclusive specificity of CSL towards alpha1-6 linkage of core fucosylated glycans compared to other fucose specific lectins, makes it a promising molecule that needs to be further explored for its application in the diagnosis of gastrointestinal cancer. PMID- 26514869 TI - Erratum to: expression of the Streptococcus pneumoniae yoeB Chromosomal toxin gene causes Cell Death in the model plant Arabidopsis thaliana. PMID- 26514870 TI - Diversity of key players in the microbial ecosystems of the human body. AB - Coexisting bacteria form various microbial communities in human body parts. In these ecosystems they interact in various ways and the properties of the interaction network can be related to the stability and functional diversity of the local bacterial community. In this study, we analyze the interaction network among bacterial OTUs in 11 locations of the human body. These belong to two major groups. One is the digestive system and the other is the female genital tract. In each local ecosystem we determine the key species, both the ones being in key positions in the interaction network and the ones that dominate by frequency. Beyond identifying the key players and discussing their biological relevance, we also quantify and compare the properties of the 11 networks. The interaction networks of the female genital system and the digestive system show totally different architecture. Both the topological properties and the identity of the key groups differ. Key groups represent four phyla of prokaryotes. Some groups appear in key positions in several locations, while others are assigned only to a single body part. The key groups of the digestive and the genital tracts are totally different. PMID- 26514872 TI - The geography of divergence with gene flow facilitates multitrait adaptation and the evolution of pollinator isolation in Mimulus aurantiacus. AB - Ecological adaptation is the driving force during divergence with gene flow and generates reproductive isolation early in speciation. Although gene flow opposes divergence, local adaptation can be facilitated by factors that prevent the breakup of favorable allelic combinations. We investigated how selection, genetic architecture, and geography have contributed to the maintenance of floral trait divergence and pollinator isolation between parapatric ecotypes of Mimulus aurantiacus. Combining greenhouse, field, and genomic studies, we show that sharp clines in floral traits are maintained by spatially varying selection. Although adaptation breaks down where the ecotypes co-occur, leading to the formation of a hybrid zone, the largely non-overlapping distributions of the ecotypes shield them from immigrant genes, facilitating divergence across most of the range. In contrast to the sharp genetic discontinuities observed across most hybrid zones, we observed a gradual cline in genome-wide divergence and a pattern of isolation by distance across the landscape. Thus, contrary to a long period of allopatry followed by recent re-contact, our data suggest that floral trait divergence in M. aurantiacus may have evolved with locally restricted, but ongoing gene flow. Therefore, our study reveals how the geographic distribution of an organism can contribute to the evolution of premating isolation in the early stages of divergence with gene flow. PMID- 26514873 TI - Seven days in medicine: 24-30 October. PMID- 26514871 TI - Radiometric assay of ghrelin hydrolase activity and 3H-ghrelin distribution into mouse tissues. AB - A high-throughput radiometric assay was developed to characterize enzymatic hydrolysis of ghrelin and to track the peptide's fate in vivo. The assay is based on solvent partitioning of [(3)H]-octanoic acid liberated from [(3)H]-octanoyl ghrelin during enzymatic hydrolysis. This simple and cost-effective method facilitates kinetic analysis of ghrelin hydrolase activity of native and mutated butyrylcholinesterases or carboxylesterases from multiple species. In addition, the assay's high sensitivity facilitates ready evaluation of ghrelin's pharmacokinetics and tissue distribution in mice after i.v. bolus administration of radiolabeled peptide. PMID- 26514875 TI - Antimicrobial Assessment of Resins from Calophyllum Antillanum and Calophyllum Inophyllum. AB - The Calophyllum genus is well-known for its antimicrobial and cytotoxic activities, and therefore, we analyzed these biological activities for resins of Calophyllum antillanum and Calophyllum inophyllum growing in Cuba. C. antillanum resins showed a potent activity against Plasmodium falciparum (IC50 = 0.3 +/- 0.1 ug/mL), while its cytotoxicity against MRC-5 cells was much lower (IC50 = 21.6 +/- 1.1 ug/mL). In contrary, the resin of C. inophyllum showed an unspecific activity. The presence of apetalic acid, isoapetalic acid, calolongic acid, pinetoric acid I, pinetoric acid II, isocalolongic acid, pinetoric acid III, and isopinetoric acid III in C. antillanum resins was also confirmed. These results demonstrated for the first time the potential activity of C. antillanum resins against P. falciparum. PMID- 26514874 TI - Effectiveness of implementation strategies for clinical guidelines to community pharmacy: a systematic review. AB - BACKGROUND: The clinical role of community pharmacists is expanding, as is the use of clinical guidelines in this setting. However, it is unclear which strategies are successful in implementing clinical guidelines and what outcomes can be achieved. The aim of this systematic review is to synthesise the literature on the implementation of clinical guidelines to community pharmacy. The objectives are to describe the implementation strategies used, describe the resulting outcomes and to assess the effectiveness of the strategies. METHODS: A systematic search was performed in six electronic databases (Medline, EMBASE, CINAHL, Web of Science, Informit, Cochrane Library) for relevant articles. Studies were included if they reported on clinical guidelines implementation strategies in the community pharmacy setting. Two researchers completed the full search strategy, data abstraction and quality assessments, independently. A third researcher acted as a moderator. Quality assessments were completed with three validated tools. A narrative synthesis was performed to analyse results. RESULTS: A total of 1937 articles were retrieved and the titles and abstracts were screened. Full-text screening was completed for 36 articles resulting in 19 articles (reporting on 22 studies) included for review. Implementation strategies were categorised according to a modified version of the EPOC taxonomy. Educational interventions were the most commonly utilised strategy (n = 20), and computerised decision support systems demonstrated the greatest effect (n = 4). Most studies were multifaceted and used more than one implementation strategy (n = 18). Overall outcomes were moderately positive (n = 17) but focused on process (n = 22) rather than patient (n = 3) or economic outcomes (n = 3). Most studies (n = 20) were rated as being of low methodological quality and having low or very low quality of evidence for outcomes. CONCLUSIONS: Studies in this review did not generally have a well thought-out rationale for the choice of implementation strategy. Most utilised educational strategies, but the greatest effect on outcomes was demonstrated using computerised clinical decision support systems. Poor methodology, in the majority of the research, provided insufficient evidence to be conclusive about the best implementation strategies or the benefit of clinical guidelines in this setting. However, the generally positive outcomes across studies and strategies indicate that implementing clinical guidelines to community pharmacy might be beneficial. Improved methodological rigour in future research is required to strengthen the evidence for this hypothesis. PROTOCOL REGISTRATION: PROSPERO 2012: CRD42012003019 . PMID- 26514876 TI - Negligible Pharmacokinetic Interaction of Red Ginseng and Losartan, an Antihypertensive Agent, in Sprague-Dawley Rats. AB - Red ginseng (RG) is one of the top selling herbal medicines in Korea, but is not recommended in hypertensive patients. In this study, the pharmacokinetic (PK) interaction between RG and losartan, an antihypertensive drug, was examined. RG was orally administered for 2 wk to male Sprague-Dawley (S-D) rats at either control (0), 0.5, 1, or 2 g/kg/d for 2 wk. After the last administration of RG and 30 min later, all animals were treated with 10 mg/kg losartan by oral route. In addition, some S-D rats were administered RG orally for 21 d at 2 g/kg followed by losartan intravenously (iv) at 10 mg/kg/d. Post losartan administration, plasma samples were collected at 5, 15, and 30 min and 1, 1.5, 2, 3, 6, 12, and 24 h. Plasma concentrations of losartan and E-3174, the active metabolite of losartan, were analyzed by a high-pressure liquid chromatography tandem mass spectrometer system (LC-MS/MS). Oral losartan administration showed dose-dependent pharmacokinetics (PK) increase with time to maximum plasma, but this was not significant between different groups. There was no significant change in tmax with E-3174 PK. With iv losartan, pharmacokinetics showed elevation of area under the plasma concentration-time curve from time zero extrapolated to infinitity. There was not a significant change in AUCinf with E 3174 PK. Therefore, RG appeared to interfere with biotransformation of losartan, as RG exerted no marked effect on E-3174 PK in S-D rats. Data demonstrated that oral or iv treatment with losartan in rats pretreated with RG for 2 wk showed that losartan PK was affected but E-3174 PK remained unchanged among different dose groups. These results suggested that RG induces negligible influence on losartan and E-3174 PK in rats. PMID- 26514877 TI - Developing clinical practice guidelines for epilepsy: A report from the ILAE Epilepsy Guidelines Working Group. AB - Clinical practice guidelines (CPGs) contain evidence-based recommendations to guide clinical care, policy development, and quality of care improvement. A recent systematic review of epilepsy guidelines identified considerable variability in the quality of available guidelines. Although excellent frameworks for CPG development exist, processes are not followed uniformly internationally, and resources to develop CPGs may be limited in certain settings. An International League Against Epilepsy (ILAE) working group was charged with proposing methodology to guide the development of future epilepsy-specific CPGs. A comprehensive literature search (1985-2014) identified articles related to CPG development and handbooks. Guideline handbooks were included if they were publicly available, and if their methodology had been used to develop CPGs. The working group's expertise also informed the creation of methodologies and processes to develop future CPGs for the ILAE. Five handbooks from North America (American Academy of Neurology), Europe (Scottish Intercollegiate Guidelines Network & National Institute for Health and Care Excellence), Australia (National Health and Medical Research Council), World Health Organization (WHO), and additional references were identified to produce evidence-based, consensus-driven methodology for development of epilepsy-specific CPGs. Key components of CPG development include the following: identifying the topic and defining the scope; establishing a working group; identifying and evaluating the evidence; formulating recommendations and determining strength of recommendations; obtaining peer reviews; dissemination, implementation, and auditing; and updating and retiring the CPG. A practical handbook and toolkit was developed. The resulting CPG development toolkit should facilitate the development of high quality ILAE CPGs to improve the care of persons with epilepsy. PMID- 26514878 TI - A triacontanuclear [Zn12Dy18] cluster: a ring of [Dy4] cubes. AB - The reaction between Dy(NO3)3.6H2O, Zn(OAc)2.4H2O, salicylaldehyde and 2-amino isobutyric acid, in MeOH in the presence of NEt3 under solvothermal conditions, led to the isolation of the triacontanuclear mixed-metal cluster [Zn(II)12Dy(III)18(OH)30(L)12(sal)6(OAc)6(NO3)3(H2O)6](NO3)3.12MeOH.5H2O (1.12MeOH.5H2O), which displays frequency- and temperature-dependent out-of-phase magnetic susceptibility signals. PMID- 26514879 TI - Prospective comparison of three risk scoring systems in non-variceal and variceal upper gastrointestinal bleeding. AB - BACKGROUND AND AIM: Data regarding the efficacy of the Glasgow Blatchford score (GBS), full Rockall score (FRS) and pre-endoscopic Rockall scores (PRS) in comparing non-variceal and variceal upper gastrointestinal bleeding (UGIB) are limited. Our aim was to determine the performance of these three risk scores in predicting the need for treatment, mortality, and re-bleeding among patients with non-variceal and variceal UGIB. METHODS: During January, 2010 and September, 2011, patients with UGIB from 11 hospitals were prospectively enrolled. The GBS, FRS, and PRS were calculated. Discriminative ability for each score was assessed using the receiver operated characteristics curve (ROC) analysis. RESULTS: A total of 981 patients presented with acute UGIB, 225 patients (22.9%) had variceal UGIB. The areas under the ROC (AUC) of the GBS, FRS, and PRS for predicting the need for treatment were 0.77, 0.69, and 0.61 in non-variceal versus 0.66, 0.66, and 0.59 in variceal UGIB. The AUC for predicting mortality and re-bleeding during admission were 0.66, 0.80, and 0.76 in non-variceal versus 0.63, 0.57, and 0.63 in variceal UGIB. AUC score was not statistically significant for predicting need for therapy and clinical outcome in variceal UGIB. The GBS <= 2 and FRS <= 1 identified low-risk non-variceal UGIB patients for death and re-bleeding during hospitalization. CONCLUSION: In contrast to non variceal UGIB, the GBS, FRS, and PRS were not precise scores for assessing the need for therapy, mortality, and re-bleeding during admission in variceal UGIB. PMID- 26514880 TI - Pharmacokinetic properties of IgG and various Fc fusion proteins in mice. AB - Fusion to an IgG Fc region is an established strategy to extend the half-life of therapeutic proteins. Most Fc fusion proteins, however, do not achieve the long half-life of IgGs. Based on findings that scFv-Fc fusion proteins exhibit a shorter half-life than the corresponding IgG molecules, we performed a comparative study of different antibody-derived Fc fusion proteins. We could confirm that fusion of single-chain Fv (scFv) and single-chain diabody (scDb) molecules to an Fc region yields in fusion proteins with substantially extended half-lives compared with the single-chain versions. However, even fusion proteins with a size similar to that of IgG, e.g., scDb-Fc, did not have a half-life as long as an IgG molecule. Binding to the neonatal Fc receptor (FcRn) under acidic and neutral conditions was similar for IgG and all Fc fusion proteins. However, we observed differences between IgG and the Fc fusion proteins for dissociation of FcRn-bound proteins induced by shifting from acidic to neutral pH, reflecting the physiological release mechanism, further supporting a contribution of the kinetics of pH-dependent release from FcRn to the pharmacokinetic properties of IgG and Fc fusion proteins. PMID- 26514881 TI - Taking a byte out of big data. PMID- 26514882 TI - The 'Busyness' Problem. PMID- 26514883 TI - Authors' response. PMID- 26514884 TI - Citing the literature. PMID- 26514885 TI - The effect of education debt on dentists' career decisions. AB - BACKGROUND: The purpose of the study was to determine whether there is an association between the amount of education debt on completing dental school (initial debt) and certain career decisions. METHODS: The authors surveyed 1,842 practicing dentists who completed dental school between 1996 and 2011 to ascertain their initial education debt, the balance on their debt in 2013, and a variety of specialization and practice decisions made during their careers. Data also included demographic characteristics and parental income and education levels. RESULTS: Dentists with higher initial debt were less likely to specialize and more likely to enter private practice, accept high-paying jobs on graduation, and work longer hours. Choice of employment setting, practice ownership, and whether to provide Medicaid and charity care were associated with dentists' sexes and races but not debt. CONCLUSIONS: High debt levels influenced some career decisions, but the magnitude of these effects was small compared with the effects of demographic characteristics, including race and sex, on career choices. PRACTICAL IMPLICATIONS: Policy makers concerned about the influence of student debt on the professional decisions of dental school graduates should recognize that students' demographic characteristics may be more powerful in driving career choices. PMID- 26514886 TI - Preoperative assessment of labial bone perforation for virtual immediate implant surgery in the maxillary esthetic zone: A computer simulation study. AB - BACKGROUND: In this computer simulation study, the authors investigated the frequency distribution of labial bone perforation (LBP) between various sagittal root position (SRP) classes with respect to the anterior maxillary osseous housing and evaluated the associated factors correlated with a higher risk of LBP when performing a virtual immediate implant surgery in the esthetic zone. METHODS: The authors analyzed cone-beam computed tomography (CBCT) images from 285 qualified study participants (1,449 teeth) to determine the probability of LBP when associated with selected variables, such as tooth type, SRP class, and morphologic parameters. The authors examined associated factors and analyzed the adjusted odds ratios by means of multiple logistic regression analysis. RESULTS: The overall probability of LBP was 81.7%, which presented statistically significant differences between each specific tooth type and SRP class (all P<.001). After adjusting for other factors, the authors found that the maxillary central incisor was 2.37 times more likely to have LBP than the canine. SRP class I was 4.9 times more likely to be associated with LBP when compared with SRP class IV. CONCLUSIONS: When a clinician performs an immediate implant in the anterior esthetic zone, he or she should be aware that the specific tooth type, SRP class, and morphologic features of fossa concavities are associated with a risk of experiencing LBP. PRACTICAL IMPLICATIONS: Presurgical cross-sectional images can be analyzed to identify anatomic features relative to LBP in the maxillary esthetic region, and this can avoid unpleasant complications, specifically when performing immediate implant procedures. PMID- 26514887 TI - Mandibular molar protraction as an alternative treatment for edentulous spaces: Focus on changes in root length and alveolar bone height. AB - BACKGROUND: The authors conducted a retrospective cohort study to investigate external apical root resorption (EARR) and alveolar bone loss (ABL) after protraction of the mandibular molars by using miniscrews. METHODS: The authors protracted 51 mandibular molars in 37 adults into an edentulous area by using sliding mechanics with a lever arm or a miniscrew-supported root spring. The authors measured root length and alveolar bone height on panoramic radiographs and corrected according to the crown length registration method. The authors measured the amounts of crown movement (CM) and root movement (RM) on the superimposed lateral cephalometric radiographs along the mandibular occlusal plane. The authors used a linear mixed model to determine the risk factors for EARR and ABL. RESULTS: All edentulous spaces closed successfully in an average of 31.7 months, and the average CM and RM were 4.97 and 8.64 millimeters, respectively, with an RM:CM ratio of 2.81. The root length decreased significantly by 0.80 mm (5.53%), but EARR of more than 2 mm occurred in only 4.0% of molars. The alveolar bone height was reduced significantly by 0.56 mm, but ABL of more than 2 mm occurred in only 2.0% of molars. Linear mixed model results revealed that EARR and ABL correlated only with RM and age, respectively. CONCLUSIONS: Protraction of the mandibular molars into an edentulous area by using miniscrews was effective and safe, especially in younger adults. PRACTICAL IMPLICATIONS: Protraction of the mandibular molars can be considered as an alternative treatment to conventional prosthetic treatment in the restoration of edentulous space, especially in young adults, if patients accept longer treatment duration. PMID- 26514888 TI - Cost-effectiveness of antibiotic prophylaxis for dental patients with prosthetic joints: Comparisons of antibiotic regimens for patients with total hip arthroplasty. AB - BACKGROUND: Clinician uncertainty concerning the need for antibiotic prophylaxis to prevent prosthetic joint infection (PJI) after undergoing dental procedures persists. Improved understanding of the potential clinical and economic risks and benefits of antibiotic prophylaxis will help inform the debate and facilitate the continuing evolution of clinical management guidelines for dental patients with prosthetic joints. METHODS: The authors developed a Markov decision model to compare the lifetime cost-effectiveness of alternative antibiotic prophylaxis strategies for dental patients aged 65 years who had undergone total hip arthroplasty (THA). On the basis of the authors' interpretation of previous recommendations from the American Dental Association and American Academy of Orthopaedic Surgeons, they compared the following strategies: no prophylaxis, prophylaxis for the first 2 years after arthroplasty, and lifetime prophylaxis. RESULTS: A strategy of foregoing antibiotic prophylaxis before dental visits was cost-effective and resulted in lower lifetime accumulated costs ($11,909) and higher accumulated quality-adjusted life years (QALYs) (12.375) when compared with alternative prophylaxis strategies. CONCLUSIONS: The results of Markov decision modeling indicated that a no-antibiotic prophylaxis strategy was cost effective for dental patients who had undergone THA. These results support the findings of case-control studies and the conclusions of an American Dental Association Council on Scientific Affairs report that questioned general recommendations for antibiotic prophylaxis before dental procedures. PRACTICAL IMPLICATIONS: The results of cost-effectiveness decision modeling support the contention that routine antibiotic prophylaxis for dental patients with total joint arthroplasty should be reconsidered. PMID- 26514889 TI - Recurrent pain and swelling associated with impacted maxillary third molar. THE DIAGNOSIS: Squamous cell carcinoma of the maxillary sinus. PMID- 26514890 TI - No sufficient evidence for or against providing preoperative analgesics for some dental procedures with local anesthetic in pediatric patients. PMID- 26514892 TI - What to consider before hiring an associate. PMID- 26514891 TI - Antiplatelet therapy and exodontia. AB - BACKGROUND: This is a review of the management considerations regarding exodontia for patients taking antithrombotic medications that affect platelet function or aggregation. METHODS: The authors reviewed the literature, focusing on the indications and mechanisms of antiplatelet therapy and the perioperative management of patients taking these agents who require exodontia or other dentoalveolar surgery. RESULTS: Dentists making management decisions regarding patients taking antiplatelet therapy should consider the patient's risk of experiencing perioperative hemorrhage against the risk of experiencing complications associated with thromboembolic events. The risk of perioperative bleeding complications is low for patients taking single or dual antiplatelet therapy. Intraoperative and postoperative bleeding can be controlled with local hemostatic measures. CONCLUSION: For patients taking antiplatelet medication, bleeding risk for exodontia is generally lower than the risk of experiencing thromboembolic events owing to cessation of therapy. PRACTICAL IMPLICATIONS: Dentists can safely complete exodontia in patients who continue taking antiplatelet therapy. The dentist should consult the patient's prescribing physician before considering altering the patient's antiplatelet therapy regimen. PMID- 26514893 TI - Googling a patient. PMID- 26514911 TI - Correlative Light-Electron Fractography of Interlaminar Fracture in a Carbon Epoxy Composite. AB - This work evaluates the use of light microscopes (LMs) as a tool for interlaminar fracture of polymer composite investigation with the aid of correlative fractography. Correlative fractography consists of an association of the extended depth of focus (EDF) method, based on reflected LM, with scanning electron microscopy (SEM) to evaluate interlaminar fractures. The use of these combined techniques is exemplified here for the mode I fracture of carbon-epoxy plain weave reinforced composite. The EDF-LM is a digital image-processing method that consists of the extraction of in-focus pixels for each x-y coordinate in an image from a stack of Z-ordered digital pictures from an LM, resulting in a fully focused picture and a height elevation map for each stack. SEM is the most used tool for the identification of fracture mechanisms in a qualitative approach, with the combined advantages of a large focus depth and fine lateral resolution. However, LMs, with EDF software, may bypass the restriction on focus depth and present enough lateral resolution at low magnification. Finally, correlative fractography can provide the general comprehension of fracture processes, with the benefits of the association of different resolution scales and contrast modes. PMID- 26514894 TI - Pulmonary Nodular Lymphoid Hyperplasia presenting cavitating pulmonary nodules. AB - Pulmonary Nodular Lymphoid Hyperplasia (PNLH) is a rare benign pulmonary disorder characterized by a localized, reactive polyclonal lymphoproliferation. Although the radiological features of this disease have not been clearly defined, they usually consist of a solitary non-cavitatory pulmonary nodule. In this report, we describe two cases of histologically confirmed PNLH presenting as multiple bilateral cavitatory lesions on CT Thorax. PMID- 26514912 TI - The Effect on Total Mortality of Adding Inhaled Corticosteroids to Long-Acting Bronchodilators for COPD: A Real Practice Analysis in Italy. AB - PURPOSE: Chronic therapy with long-acting bronchodilators (LB) is recommended to treat moderate-to-severe COPD. Although the benefits of adding inhaled corticosteroid (ICS) to LB are still unclear, patients who experience repeated exacerbations are suggested to add ICS to their LB treatment. The objective of this study is to analyze whether adding ICS to LB therapy reduces mortality. METHODS: We identified a cohort of patients discharged from hospital with COPD diagnosis between 2006 and 2009. The first prescription for LB or ICS following discharge was defined as the index prescription. Only new users were included (no use of any study drug in the 6 months before treatment). A 4-day time window was used to classify patients into "LB alone" or "LB plus ICS" initiators. We used propensity score to balance the study groups. Sensitivity analyses were performed in patients with recent out-of-hospital exacerbations. RESULTS: Among the 18615 adults enrolled, 12207 initiated "LB plus ICS" therapy and 6408 "LB alone." Crude mortality rates were 110 and 143 cases per 1000 person-years in the "LB plus ICS" and "LB alone" groups, respectively. The adjusted hazard ratio (HR) was 0.83 (95% CI: 0.72-0.97; p-value: 0.024). When analyzing patients with recent out-of hospital exacerbations, the benefit of the combination therapy was more pronounced, HR = 0.63 (95% CI: 0.44-0.90; p-value: 0.012). DISCUSSION: Our findings showed a beneficial effect on mortality of adding inhaled corticosteroids to long-acting bronchodilators. The advantage was much more pronounced in patients with frequent exacerbations. PMID- 26514913 TI - Macroscopic digestive tract anatomy of two small antelopes, the blackbuck (Antilope cervicapra) and the Arabian sand gazelle (Gazella subgutturosa marica). AB - The digestive tract anatomy of 14 blackbucks (Antilope cervicapra) and seven Arabian sand gazelles (Gazella subgutturosa marica) was quantified by dimensions, area and weight. Data from the two small-sized antilopinae were evaluated against a larger comparative data set from other ruminants classified as having either a 'cattle-type' or 'moose-type' digestive system. The digestive anatomy of the blackbuck resembled that of 'cattle-type' ruminants, which corresponds to their feeding ecology and previous studies of solute and particle retention time; however, a surprising exception was the remarkably small omasum in this species, which makes the blackbuck stand out from the general rule of a relatively large omasum in grazing ruminants. Sand gazelles had morphological features that corresponded more to the 'moose type' or an intermediate position, although previous studies of solute and particle retention time had led to the expectation of a more 'cattle-type' anatomy. The results show that outliers to general morphological trends exist, that findings on physiology and anatomy do not always match completely and that differences in the digestive morphology among ruminant species are more difficult to demonstrate at the lower end of the body mass range. PMID- 26514914 TI - Selective Probing of Gaseous Ammonia Using Red-Emitting Carbon Dots Based on an Interfacial Response Mechanism. AB - Solid-state fluorescence sensing is one of the most appealing detection techniques because of its simplicity and convenience in practical operation. Herein, we report the development of a red-emitting carbon dots (RCDs)-based material as a solid-state fluorescence sensor for the selective probing of gaseous ammonia. The RCDs were prepared by a low-cost, one-step carbonization method using sugar cane bagasse as the carbon precursor. The pristine RCDs were then directly coated on polyvinylidene fluoride membrane to produce a new fluorescence sensor capable of selectively distinguishing toxic gaseous ammonia from other analyte vapors through sensitive fluorescence quenching with a low detection limit. More importantly, the interfacial response mechanism occurring on the surface of the RCDs has been studied by X-ray photoelectron spectroscopy, Fourier-transform infrared spectroscopy, and Raman measurements. The results indicate that fluorescence quenching in the RCDs might result from ammonia induced Michael addition through insertion of N into the C=C group and deprotonation of the carboxyl group. To the best of our knowledge, this is the first report that provides clear insight into the mechanism of surface chemistry on CDs in the solid state. PMID- 26514915 TI - Structure and Hydrogen Bonding of Water in Polyacrylate Gels: Effects of Polymer Hydrophilicity and Water Concentration. AB - The ability to tune the hydrophilicity of polyacrylate copolymers by altering their composition makes these materials attractive candidates for membranes used to separate alcohol-water mixtures. The separation behavior of these polyacrylate membranes is governed by a complex interplay of factors such as water and alcohol concentrations, water structure in the membrane, polymer hydrophilicity, and temperature. We use molecular dynamics simulations to investigate the effect of polymer hydrophilicity and water concentration on the structure and dynamics of water molecules in the polymer matrix. Samples of poly(n-butyl acrylate) (PBA), poly(2-hydroxyethyl acrylate) (PHEA), and a 50/50 copolymer of BA and HEA were synthesized in laboratory, and their properties were measured. Model structures of these systems were validated by comparing the simulated values of their volumetric properties with the experimental values. Molecular simulations of polyacrylate gels swollen in water and ethanol mixtures showed that water exhibits very different affinities toward the different (carbonyl, alkoxy, and hydroxyl) functional groups of the polymers. Water molecules are well dispersed in the system at low concentrations and predominantly form hydrogen bonds with the polymer. However, water forms large clusters at high concentrations along with the predominant formation of water-water hydrogen bonds and the acceleration of hydrogen bond dynamics. PMID- 26514916 TI - Can the Number of Leads with fQRS Be Used as an Additional Tool to Detect Significant Coronary Artery Disease? PMID- 26514917 TI - Electronic Properties of Fluoride and Half-fluoride Superlattices KZnF3/KAgF3 and SrTiO3/KAgF3. AB - We present the formation of cupratelike electronic structures in KAgF3-related superlattices resulted from the confinement together with structural chemical modification by using the generalized gradient approximation augmented with maximally localized Wannier functions analysis. Strong antiferromagnetic coupling found in bulk KAgF3 is held in purely-fluoride KZnF3/KAgF3. Under 4% in-plane compression strain, its Fermi surface shape breaks away from the edge of electron pocket and resembles that of La2CuO4. While within half-fluoride SrTiO3/KAgF3, out-of-plane electronic reconstruction results in electron doping of AgF2 plane and antiferromagnetic state instability, and the Fermi surface shape presents considerable similarity to that in HgBaCuO4. These results shed light on two dimensional antiferromagnetic precursors of a new Ag(II) family of high temperature superconductors. PMID- 26514918 TI - DE-based tuning of PI(lambda)D(MU) controllers. AB - A new method that relies on evolutionary computation concepts is proposed in this paper to tune the parameters of fractional order PI(lambda)D(MU) controllers, in which the orders of the integral and derivative parts, lambda and MU, respectively, are fractional. The main advantage of the fractional order controllers is that the increase in the number of parameters in the controller allows an increase in the number of control specifications that can be met. A Differential Evolution (DE) algorithm is proposed to make the controlled system fulfill different design specifications in time and frequency domains. This method is based on the minimization of a fitness function. Experiments have been carried out in simulation and in a real DC motor platform. The results illustrate the effectiveness of this method. PMID- 26514919 TI - Protocol description and optimization scheduling for multi-fieldbus integration system. AB - Device integration technique is applied to integrate different fieldbus devices into one control system. At present mature integration techniques use appropriative software to support corresponding protocols. New software must be developed when a new fieldbus is integrated. In this research, a universal protocol description method is proposed. It focuses on the packets encapsulation description, and different protocol messages can be encapsulated and parsed by the interpreter in a unified way. Moreover, in order to ensure the communication efficiency and QoS of different kinds of messages, packets encapsulated via protocol description are optimized and scheduled before transmission inside the interpreter. The approaches have been applied in the prototype of a software product and verified in a power monitoring project. PMID- 26514921 TI - Applying Bifactor Statistical Indices in the Evaluation of Psychological Measures. AB - The purpose of this study was to apply a set of rarely reported psychometric indices that, nevertheless, are important to consider when evaluating psychological measures. All can be derived from a standardized loading matrix in a confirmatory bifactor model: omega reliability coefficients, factor determinacy, construct replicability, explained common variance, and percentage of uncontaminated correlations. We calculated these indices and extended the findings of 50 recent bifactor model estimation studies published in psychopathology, personality, and assessment journals. These bifactor derived indices (most not presented in the articles) provided a clearer and more complete picture of the psychometric properties of the assessment instruments. We reached 2 firm conclusions. First, although all measures had been tagged "multidimensional," unit-weighted total scores overwhelmingly reflected variance due to a single latent variable. Second, unit-weighted subscale scores often have ambiguous interpretations because their variance mostly reflects the general, not the specific, trait. Finally, we review the implications of our evaluations and consider the limits of inferences drawn from a bifactor modeling approach. PMID- 26514920 TI - The need to balance merits and limitations from different disciplines when considering the stepped wedge cluster randomized trial design. AB - BACKGROUND: Various papers have addressed pros and cons of the stepped wedge cluster randomized trial design (SWD). However, some issues have not or only limitedly been addressed. Our aim was to provide a comprehensive overview of all merits and limitations of the SWD to assist researchers, reviewers and medical ethics committees when deciding on the appropriateness of the SWD for a particular study. METHODS: We performed an initial search to identify articles with a methodological focus on the SWD, and categorized and discussed all reported advantages and disadvantages of the SWD. Additional aspects were identified during multidisciplinary meetings in which ethicists, biostatisticians, clinical epidemiologists and health economists participated. All aspects of the SWD were compared to the parallel group cluster randomized design. We categorized the merits and limitations of the SWD to distinct phases in the design and conduct of such studies, highlighting that their impact may vary depending on the context of the study or that benefits may be offset by drawbacks across study phases. Furthermore, a real-life illustration is provided. RESULTS: New aspects are identified within all disciplines. Examples of newly identified aspects of an SWD are: the possibility to measure a treatment effect in each cluster to examine the (in)consistency in effects across clusters, the detrimental effect of lower than expected inclusion rates, deviation from the ordinary informed consent process and the question whether studies using the SWD are likely to have sufficient social value. Discussions are provided on e.g. clinical equipoise, social value, health economical decision making, number of study arms, and interim analyses. CONCLUSIONS: Deciding on the use of the SWD involves aspects and considerations from different disciplines not all of which have been discussed before. Pros and cons of this design should be balanced in comparison to other feasible design options as to choose the optimal design for a particular intervention study. PMID- 26514922 TI - Reduced Fgf10/Fgfr2 and androgen receptor (AR) in anorectal malformations male rats induced by di-n-butyl phthalate (DBP): A study on the local and systemic toxicology of DBP. AB - Previous study have demonstrated that not only the anorectal development but also the general conditions of anorectal malformations (ARMs) male rats are severely affected by di-n-butyl phthalate (DBP) maternal exposure. However, the mechanisms underlying DBP-induced congenital defects remain elusive. Reportedly, Fgf10/Fgfr2 and androgen receptor (AR) are pivotal for the development of multiple organs. In this study, we therefore investigated the expression of Fgf10/Fgfr2 together with AR in the terminal rectum and multiple organs of ARM male rats induced by in utero exposure to DBP. DBP was administered to pregnant rats to establish the model and the incidence of ARMs in male offspring was 39.5%. On postnatal day(PND)1, the gross photograph and histopathological staining confirmed the abnormal manifestations in these organs of newborn ARMs. Decreased anogenital distance, body weight and serum testosterone level were observed in ARM male offspring. The reduced expression of Fgf10/Fgfr2 mRNA and protein was seen in terminal rectum and kidney, spleen, liver, heart in ARM male rats, whereas the reduced expression of AR was only observed in the kidney and terminal rectum. Our findings suggest the potential involvement of altered Fgf10/Fgfr2 signaling and AR in pathogenesis of local and systemic development defects in ARMs male rats induce by DBP. PMID- 26514923 TI - Cadmium induces matrix metalloproteinase-9 expression via ROS-dependent EGFR, NF kB, and AP-1 pathways in human endothelial cells. AB - Cadmium (Cd), a widespread cumulative pollutant, is a known human carcinogen, associated with inflammation and tumors. Matrix metalloproteinase-9 (MMP-9) plays a pivotal role in tumor metastasis; however, the mechanisms underlying the MMP-9 expression induced by Cd remain obscure in human endothelial cells. Here, Cd elevated MMP-9 expression in dose- and time-dependent manners in human endothelial cells. Cd increased ROS production and the ROS-producing NADPH oxidase. Cd translocates p47(phox), a key subunit of NADPH oxidase, to the cell membrane. Cd also activated the phosphorylation of EGFR, Akt, Erk1/2, and JNK1/2 in addition to promoting NF-kB and AP-1 binding activities. Specific inhibitor and mutagenesis studies showed that EGFR, Akt, Erk1/2, JNK1/2 and transcription factors NF-kappaB and AP-1 were related to Cd-induced MMP-9 expression in endothelial cells. Akt, Erk1/2, and JNK1/2 functioned as upstream signals in the activation of NF-kappaB and AP-1, respectively. In addition, N-acetyl-l-cystein (NAC), diphenyleneiodonium chloride (DPI) and apocynin (APO) inhibited the Cd induced activation of EGFR, Akt, Erk1/2, JNK1/2, and p38 MAPK, indicating that ROS production by NADPH oxidase is the furthest upstream signal in MMP-9 expression. At present, it states that Cd displayed marked invasiveness in ECV304 cells, which was partially abrogated by MMP-9 neutralizing antibodies. These results demonstrated that Cd induces MMP-9 expression via ROS-dependent EGFR >Erk1/2, JNK1/2->AP-1 and EGFR->Akt->NF-kappaB signaling pathways and, in turn, stimulates invasiveness in human endothelial cells. PMID- 26514924 TI - Chlorpyrifos promotes colorectal adenocarcinoma H508 cell growth through the activation of EGFR/ERK1/2 signaling pathway but not cholinergic pathway. AB - Aside from the effects on neuronal cholinergic system, epidemiological studies suggest an association between chlorpyrifos (CPF) exposure and cancer risk. This in vitro study examined the effects of CPF and its toxic metabolite, chlorpyrifos oxon (CPF-O), on the growth of human colorectal adenocarcinoma H508, colorectal adenocarcinoma HT-29, normal colon epithelial CCD841, liver hepatocellular carcinoma HepG2, and normal liver hepatocyte THLE-3 cells. The results showed that CPF (5-100 MUM) concentration-dependently increased viability of H508 and CCD841 cells in serum-free conditions. This increasing trend was not found in HT 29, HepG2 and THLE-3 cells. In contrast, CPF-O (50-100 MUM) reduced the viability of all cell lines. Cell cycle analysis showed the induction of cells in the S phase, and EdU incorporation assay revealed the induction of DNA synthesis in CPF treated H508 cells indicating that CPF promotes cell cycle progression. Despite the observation of acetylcholinesterase activity inhibition and reactive oxygen species (ROS) generation, atropine (a non-selective muscarinic acetylcholine receptor antagonist) and N-acetylcysteine (a potent antioxidant) failed to inhibit the growth-promoting effect of CPF. CPF increased the phosphorylation of epidermal growth factor receptor (EGFR) and its downstream effector, extracellular signal regulated kinase (ERK1/2), in H508 cells. AG-1478 (a specific EGFR tyrosine kinase inhibitor) and U0126 (a specific MEK inhibitor) completely mitigated the growth promoting effect of CPF. Altogether, these results suggest that EGFR/ERK1/2 signaling pathway but not cholinergic pathway involves in CPF-induced colorectal adenocarcinoma H508 cell growth. PMID- 26514925 TI - Joint Bayesian variable and graph selection for regression models with network structured predictors. AB - In this work, we develop a Bayesian approach to perform selection of predictors that are linked within a network. We achieve this by combining a sparse regression model relating the predictors to a response variable with a graphical model describing conditional dependencies among the predictors. The proposed method is well-suited for genomic applications because it allows the identification of pathways of functionally related genes or proteins that impact an outcome of interest. In contrast to previous approaches for network-guided variable selection, we infer the network among predictors using a Gaussian graphical model and do not assume that network information is available a priori. We demonstrate that our method outperforms existing methods in identifying network-structured predictors in simulation settings and illustrate our proposed model with an application to inference of proteins relevant to glioblastoma survival. PMID- 26514926 TI - Psychological detachment and savoring in adaptation to cancer caregiving. AB - BACKGROUND: Recovery experience including psychological detachment from caregiving and savoring positive moments in life could be complementary coping processes for cancer caregivers. This study aims to examine the nature of their associations with caregiving burden and anxiety and depressive symptoms among Chinese cancer caregivers in Hong Kong. METHODS: A total of 155 Chinese caregivers of recently diagnosed cancer patients (mean time since diagnosis = 42.57 days, SD = 39.25) were recruited from two major government-funded hospitals and administered a questionnaire assessing psychological detachment, savoring, caregiving burden, anxiety and depressive symptoms, and demographics. RESULTS: Controlling for demographic and medical covariates, structural equation modeling revealed significant associations of detachment, savoring, and their interaction term with caregiving burden and anxiety and depressive symptoms. Detachment and savoring were inversely associated with caregiving burden only when the other was at lower/medium levels. Detachment was inversely associated with anxiety and depressive symptoms at lower/medium levels of savoring, but savoring was inversely associated with anxiety and depressive symptoms across all levels of detachment. CONCLUSIONS: Detachment and savoring could overshadow the positive impact of the other on caregiving burden if either one is at higher levels, while they could demonstrate concurrent positive impact on burden when both are at lower/medium levels. Savoring could have a prioritized role in ameliorating caregivers' anxiety and depressive symptoms, supplemented by detachment. Copyright (c) 2015 John Wiley & Sons, Ltd. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26514927 TI - Astrovirus-induced "white chicks" condition - field observation, virus detection and preliminary characterization. AB - Chicken astrovirus (CAstV) was recently indicated as the factor of the "white chicks" condition associated not only with increased embryo/chick mortality but also with weakness and white plumage of hatched chicks. In February 2014, organ samples (livers and kidneys) from dead-in-shell embryos, as well as 1-day-old whitish and normal chicks, were delivered from one hatchery in Poland for disease diagnosis. The samples originated from the same 30-week-old breeder flock in which the only observed abnormal signs were 4-5% decrease in the number of hatched chickens and the presence (about 1%) of weaker chicks with characteristic whitish plumage among normal ones. CAstV was detected in submitted samples and was then isolated in 10-day-old embryonated specific pathogen free (SPF) chicken eggs. We also reproduced an infection model for the "white chicks" condition in SPF layer chickens using the isolated PL/G059/2014 strain as the infectious agent. Results of experimental reproduction of the "white chicks" condition were somewhat more serious than field observation. The administration of the CAstV material into the yolk sac of 8-day-old SPF chicken eggs caused delay and prolongation of hatching, as well as death of embryos/chicks, and also a change of plumage pigmentation. Only two chicks of a total of 10 inoculated SPF eggs survived and were observed for 2 months. A gradual elimination of the CAstV genome was noted in this period. Moreover, a few contact-naive SPF chicks, which had been placed in the same cage, were infected with CAstV. Molecular characterization of detected CAstV was performed by nucleotide sequencing of the full ORF2 region encoding the capsid precursor protein gene. Phylogenetic studies showed that the PL/G059/2014 isolate clustered in the subgroup Aiii of CAstV. In the light of the new classification rules, the Polish PL/G059/2014 CAstV isolate could be assigned to a new species of the Avastrovirus genus. PMID- 26514928 TI - Behavioral techniques to optimize success of in-office pediatric tympanostomy tube placement without sedation. AB - OBJECTIVE: Tympanostomy tube insertion is the most common pediatric surgery, but it typically requires general anesthesia. To facilitate in-office tube placement without general anesthesia, two complementary technologies have recently been developed comprising an iontophoresis system for delivering local anesthesia and an integrated tube delivery system. The purpose of this study was to evaluate behavioral support techniques used during a clinical study of the new technology for pediatric in-office tube placement without general anesthesia or physical restraints. METHODS: As part of an IRB-approved, prospective, nine-center clinical study, pediatric patients requiring tube insertion underwent in-office treatment using the new procedure. The behavior management techniques included preparation, distraction, coaching, and reinforcement for cooperation. The entire procedure was videotaped and two independent coders used the validated FLACC (Face, Legs, Activity, Cry, Consolability) scale to code behavioral distress across five procedural phases. RESULTS: Seventy pediatric patients aged 8 months to 17 years (M=7.0 years; 51% female) were enrolled in the study and 68 had video recordings available for analysis. Of the 68 recordings analyzed, 63 patients completed the procedure and had tubes placed without sedation. Mean FLACC scores ranged from 0.05 to 2.38 (M=1.25, SD=0.82) and median FLACC scores ranged from 0 to 1 (Mdn=0, IQR=0.05), which indicate "mild" distress. During iontophoresis, eardrum tap (anesthesia assessment), and tube delivery, older children displayed lower distress and girls had higher FLACC scores during the eardrum tap procedural phase. CONCLUSION: When combined with the evidence-based behavioral techniques, office-based local anesthesia and tube delivery resulted in minimal distress, suggesting that the new procedure may be a viable method of conducting tympanostomy tube placement in children without having to use general anesthesia. Clinicaltrials.gov identifier: NCT01496287. PMID- 26514929 TI - Ex vivo ovine model for pediatric flexible endoscopy training. AB - OBJECTIVES: Medical students and residents in training have limited opportunities to develop pediatric endoscopy skills and would benefit from a realistic simulation model. We sought to develop such a model for flexible endoscopy using fresh head and neck tissue from young sheep. METHODS: Tissue was collected from pre-pubescent sheep (n=5; mean age: 4 months; mean mass: 28kg) following humane euthanasia at the end of an in vivo protocol. No live animals were used in this study. The head and neck of the sheep were disarticulated 4-6cm above the sternal notch and stored at 5 degrees C for 1-5 days. With the preparation was supported in supine position, flexible nasopharyngolaryngoscopy and transnasal endoscopic intubation were performed with video recording. RESULTS: Five sheep were studied. Endoscopy was performed by a medical student under direct supervision by a pediatric otolaryngologist. Differences between ovine and human pediatric airway anatomy were defined. CONCLUSIONS: Despite variations in proportion and structure, the experience of passing a flexible nasopharyngoscope through a sheep's airway is remarkably similar to pediatric endoscopy. The nasal anatomy is elongated, but very much like a child's in terms of anatomy, color and texture. The tactile feedback is nearly identical. Annoying secretions and their associated "whiteout" phenomena nicely simulate these challenges in pediatric endoscopy. When performing transnasal intubation, navigating to the larynx and advancing an endotracheal tube under guidance have the look and feel of the pediatric procedure. Issues of cost, availability, risk of zoonotic infection, and ethics are discussed. PMID- 26514930 TI - Early identification: Language skills and social functioning in deaf and hard of hearing preschool children. AB - OBJECTIVE: Permanent childhood hearing impairment often results in speech and language problems that are already apparent in early childhood. Past studies show a clear link between language skills and the child's social-emotional functioning. The aim of this study was to examine the level of language and communication skills after the introduction of early identification services and their relation with social functioning and behavioral problems in deaf and hard of hearing children. STUDY DESIGN: Nationwide cross-sectional observation of a cohort of 85 early identified deaf and hard of hearing preschool children (aged 30-66 months). METHODS: Parents reported on their child's communicative abilities (MacArthur-Bates Communicative Development Inventory III), social functioning and appearance of behavioral problems (Strengths and Difficulties Questionnaire). Receptive and expressive language skills were measured using the Reynell Developmental Language Scale and the Schlichting Expressive Language Test, derived from the child's medical records. RESULTS: Language and communicative abilities of early identified deaf and hard of hearing children are not on a par with hearing peers. Compared to normative scores from hearing children, parents of deaf and hard of hearing children reported lower social functioning and more behavioral problems. Higher communicative abilities were related to better social functioning and less behavioral problems. No relation was found between the degree of hearing loss, age at amplification, uni- or bilateral amplification, mode of communication and social functioning and behavioral problems. CONCLUSION: These results suggest that improving the communicative abilities of deaf and hard of hearing children could improve their social-emotional functioning. PMID- 26514931 TI - Nasal saline irrigation with or without systemic antibiotics in treatment of children with acute rhinosinusitis. AB - OBJECTIVES: Acute rhinosinusitis (ARS) is a common pediatric problem. Our aim was to determine the efficacy of normal nasal saline irrigation (NSI) with or without amoxicillin in treatment of acute rhinosinusitis (ARS) in children. METHODS: It is a prospective randomized, blind placebo-controlled trial. Children with uncomplicated ARS were recruited. One group received (amoxacillin 100mg/kg/day) and 0.9% NSI. The second group received placebo and 0.9% NSI. The primary outcome was the effect of treatment on clinical response. Secondary outcomes included: Rating of Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ), middle meatus (MM) bacteriological and cytological cellular responses and adverse effects. RESULTS: Sixty two patients with ARS were eligible for the study. In amoxicillin group (31 patients); clinical cure was observed in 26 (83.9%) in comparison to 22 (71%) patients in NSI without antibiotics group (31 patients) (p=0.22). No differences between both groups in the reported nasal symptom scores and total symptoms scores improvements at day 7 (p=0.09 and 0.65) and day 14 (p=0.29 and 0.14), respectively. The mean total PRQLQ values had no differences between both groups after the 2 weeks of treatment (p=0.06). At day 7, MM neutrophils reduced significantly in amoxicillin group in comparison to placebo group (p=0.004). At day 14, the MM cytological content had no differences between both groups (p=0.07). Normal NSI with placebo has less reported adverse effects than amoxicillin and nasal saline irrigations (p=0.005). CONCLUSIONS: NSI can be used alone with the same clinical, bacteriological and cytological cellular changes efficacy and with higher safety profile than amoxicillin after 14 days of treatment in uncomplicated clinically diagnosed ARS in children. PMID- 26514932 TI - Ultrafast traveling wave dominates the electric organ discharge of Apteronotus leptorhynchus: an inverse modelling study. AB - Identifying and understanding the current sources that give rise to bioelectric fields is a fundamental problem in the biological sciences. It is very difficult, for example, to attribute the time-varying features of an electroencephalogram recorded from the head surface to the neural activity of specific brain areas; model systems can provide important insight into such problems. Some species of fish actively generate an oscillating (c. 1000 Hz) quasi-dipole electric field to communicate and sense their environment in the dark. A specialized electric organ comprises neuron-like cells whose collective signal underlies this electric field. As a step towards understanding the detailed biophysics of signal generation in these fish, we use an anatomically-detailed finite-element modelling approach to reverse-engineer the electric organ signal over one oscillation cycle. We find that the spatiotemporal profile of current along the electric organ constitutes a travelling wave that is well-described by two spatial Fourier components varying in time. The conduction velocity of this wave is faster than action potential conduction in any known neuronal axon (>200 m/s), suggesting that the spatiotemporal features of high-frequency electric organ discharges are not constrained by the conduction velocities of spinal neuron pathways. PMID- 26514933 TI - Endoplasmic reticulum stress as a novel cellular response to di (2-ethylhexyl) phthalate exposure. AB - Di (2-ethylhexyl) phthalate is a high-production chemical widely used as a plasticizer for polyvinyl chloride products. Due to its ubiquitous presence in environmental compartments and the constant exposure of the general population through ingestion, inhalation, and dermal absorption, this compound has been subjected to extensive in vivo and in vitro toxicological studies. Despite the available information, research on the cytotoxicity of di (2-ethylhexyl) phthalate in mammalian cells is relatively limited.In this paper, an in vitro multi-parametric approach was used to provide further mechanistic data on the toxic activity of this chemical in Vero and HaCaT cells. Our results reveal that a 24 h exposure to di (2-ethylhexyl) phthalate causes, in both cell lines, an inhibition of cell proliferation that was linked to cell cycle delay at the G1 phase. Concomitantly, the tested compound induces mild endoplasmic reticulum stress which leads to an adaptive rather than a pro-apoptotic response in mammalian cells. These findings demonstrate that there are multiple potential cellular targets of di (2-ethylhexyl) phthalate-induced toxicity and the need to develop further experimental studies for the risk assessment of this ubiquitous plasticizer. PMID- 26514934 TI - Viability, function and morphological integrity of precision-cut liver slices during prolonged incubation: Effects of culture medium. AB - Precision-cut liver slices (PCLS) are an ex vivo model for metabolism and toxicity studies. However, data on the maintenance of the morphological integrity of the various cell types in the slices during prolonged incubation are lacking. Therefore, our aims were to characterize morphological and functional changes in rat PCLS during five days of incubation in a rich medium, RegeneMed(r), and a standard medium, Williams' Medium E. Although cells of all types in the slices remain viable, profound changes in morphology were observed, which were more prominent in RegeneMed(r). Slices underwent notable fibrosis, bile duct proliferation and fat deposition. Slice thickness increased, resulting in necrotic areas, while slice diameter decreased, possibly indicating cell migration. An increased proliferation of parenchymal and non-parenchymal cells (NPCs) was observed. Glycogen, albumin and Cyp3a1 were maintained albeit to a different level in two media. In conclusion, both hepatocytes and NPCs remain viable and functional, enabling five-day toxicity studies. Tissue remodeling and formation of a new capsule-like cell lining around the slices are evident after 3 4 days. The differences in effects between media emphasize the importance of media selection and of the recognition of morphological changes in PCLS, when interpreting results from toxicological or pharmacological studies. PMID- 26514935 TI - MiR-122 partly mediates the ochratoxin A-induced GC-2 cell apoptosis. AB - Ochratoxin A (OTA) is a mycotoxin which has been shown to be nephrotoxic, hepatotoxic, and immunotoxic to animals, and mainly exists in the mildew grain. MicroRNAs (miRNAs) regulate a wide variety of cellular processes. However, the toxic effects of OTA on the germ cell and whether miRNAs mediate the effects of OTA-induced GC-2 cell apoptosis are still not clear. In the present study, OTA treatment resulted in a dose-dependent increase apoptosis in GC-2 cells. MiR-122 was increased in the OTA-treated GC-2 cells. It showed that Bcl-w was down regulated after OTA treatment, and caspase-3 was obviously activated. Cyclin G1 (CCNG1) was significantly decreased, and inversely the expression of p53 was increased. Inhibition of miR-122 partly relieved the OTA-induced GC-2 cell apoptosis. These results indicate that OTA induces GC-2 cell apoptosis by causing the increase of caspase-3 activity and that miR-122 partly mediates the OTA induced cell apoptosis. PMID- 26514936 TI - Cocoa Flavanol Cardiovascular Effects Beyond Blood Pressure Reduction. AB - The protective cardiovascular (CV) effect of cocoa flavanol has been a target of many recent clinical prospective and retrospective investigations. Epidemiological data in different patient cohorts revealed an association between higher intake of flavanol-rich foods and decreased incidence of CV events, especially stroke and myocardial infarction. Cocoa flavanol has been shown to reduce systolic (2.8 mm Hg) and diastolic (2.2 mm Hg) office blood pressure (BP). Greater BP reduction has been found in hypertensive patients and people younger than 50 years. Cocoa flavanol intake exerts beneficial effects on pathophysiologic mechanisms of hypertension-related organ damage, such as improved endothelial function, anti-inflammatory potency, inhibition of platelet activation, and increased vasodilatory capacity. Recent clinical trials have focused on establishing a potential link between epidemiology and pathophysiology of flavanol and identified possible mechanisms for prevention of end-organ damage in patients at CV risk. This review summarizes the available data on the antihypertensive effects of cocoa flavanol beyond BP-BP lowering lowering effects, accentuates subgroup-specific protective actions of cocoa according to patients' different CV risk profile, and outlines potential cocoa flavanol associated clinical implications. PMID- 26514937 TI - Flexible, Stretchable, and Rechargeable Fiber-Shaped Zinc-Air Battery Based on Cross-Stacked Carbon Nanotube Sheets. AB - The fabrication of flexible, stretchable and rechargeable devices with a high energy density is critical for next-generation electronics. Herein, fiber-shaped Zn-air batteries, are realized for the first time by designing aligned, cross stacked and porous carbon nanotube sheets simultaneously that behave as a gas diffusion layer, a catalyst layer, and a current collector. The combined remarkable electronic and mechanical properties of the aligned carbon nanotube sheets endow good electrochemical properties. They display excellent discharge and charge performances at a high current density of 2 A g(-1) . They are also flexible and stretchable, which is particularly promising to power portable and wearable electronic devices. PMID- 26514938 TI - 3D chemical imaging in the laboratory by hyperspectral X-ray computed tomography. AB - We report the development of laboratory based hyperspectral X-ray computed tomography which allows the internal elemental chemistry of an object to be reconstructed and visualised in three dimensions. The method employs a spectroscopic X-ray imaging detector with sufficient energy resolution to distinguish individual elemental absorption edges. Elemental distributions can then be made by K-edge subtraction, or alternatively by voxel-wise spectral fitting to give relative atomic concentrations. We demonstrate its application to two material systems: studying the distribution of catalyst material on porous substrates for industrial scale chemical processing; and mapping of minerals and inclusion phases inside a mineralised ore sample. The method makes use of a standard laboratory X-ray source with measurement times similar to that required for conventional computed tomography. PMID- 26514939 TI - Amino acid substitutions in GyrA affect quinolone susceptibility in Salmonella typhimurium. AB - The prevalence of quinolone-resistant Salmonella has become a public health concern. Amino acid substitutions have generally been found within the quinolone resistance-determining region in subunit A of DNA gyrase (GyrA) of Salmonella Typhimurium. However, direct evidence of the contribution of these substitutions to quinolone resistance remains to be shown. To investigate the significance of amino acid substitutions in S. Typhimurium GyrA to quinolone resistance, we expressed recombinant wild-type (WT) and five mutant DNA gyrases in Escherichia coli and characterized them in vitro. WT and mutant DNA gyrases were reconstituted in vitro by mixing recombinant subunits A and B of DNA gyrase. The correlation between the amino acid substitutions and resistance to quinolones ciprofloxacin, levofloxacin, nalidixic acid, and sitafloxacin was assessed by quinolone-inhibited supercoiling assays. All mutant DNA gyrases showed reduced susceptibility to all quinolones when compared with WT DNA gyrases. DNA gyrase with a double amino acid substitution in GyrA, serine to phenylalanine at codon 83 and aspartic acid to asparagine at 87 (GyrA-S83F-D87N), exhibited the lowest quinolone susceptibility amongst all mutant DNA gyrases. The effectiveness of sitafloxacin was shown by the low inhibitory concentration required for mutant DNA gyrases, including the DNA gyrase with GyrA-S83F-D87N. We suggest sitafloxacin as a candidate drug for the treatment of salmonellosis caused by ciprofloxacin-resistant S. Typhimurium. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26514940 TI - Influence of consciousness, muscle action and activity on medial condyle translation after Oxford unicompartmental knee replacement. AB - BACKGROUND: Quantification of the in vivo position of the medial condyle throughout flexion is important for knee replacement design, and understanding knee pathology. The influence of consciousness, muscle action, and activity type on condyle translation was examined in patients who had undergone medial unicompartmental knee replacement (UKR) using lateral video fluoroscopy. METHODS: The position of the centre of the femoral component relative to the tibial component was measured for nine patients under different conditions. The following activities were assessed; passive flexion and extension when anaesthetised, passive flexion and extension when conscious, and active flexion, extension and step-up. RESULTS: The position of the centre of the femoral component relative to the tibial component was highly patient dependent. The greatest average translation range (14.9 mm) was observed in anaesthetised patients, and the condyle was significantly more anterior near to extension. Furthermore, when conscious but being moved passively, the femoral condyle translated a greater range (8.9 mm) than when moving actively (5.2mm). When ascending stairs, the femoral condyle was more posterior at 20-30 degrees of flexion than during flexion/extension. CONCLUSIONS: The similarity between these results and published data suggest that knee kinematics following mobile-bearing UKR is relatively normal. The results show that in the normal knee and after UKR, knee kinematics is variable and is influenced by the patient, consciousness, muscle action, and activity type. CLINICAL RELEVANCE: It is therefore essential that all these factors are considered during knee replacement design, if the aim is to achieve more normal knee kinematics. PMID- 26514941 TI - Quantification and comparison of virulence and characteristics of different variants of carbapenemase-producing Klebsiella pneumoniae clinical isolates from Taiwan and the United States. AB - BACKGROUND/PURPOSE: The emergence of Klebsiella pneumoniae carbapenemase (KPC) producing strains is a challenge for clinicians. The characteristics and virulence of variants of KPC-producing K. pneumoniae isolates were evaluated. METHODS: Five clinical isolates-three KPC subtypes from Taiwan (KPC2-TW, KPC3-TW, and KPC17-TW) and two clinical strains from the United States (US; KPC2-US, KPC3 US)-were included. Virulent traits and capsular serotypes were analyzed by Polymerase Chain Reaction (PCR). Serum killing, neutrophil phagocytosis, and mice lethargy studies were performed to evaluate virulence. RESULTS: Multilocus sequence typing (MLST) demonstrated that KPC2-TW and KPC17-TW belonged to sequence type (ST)11, and KPC2-US, KPC3-US, and KPC3-TW to ST258. KPC3-TW expressed capsular serotype K1, whereas the others were non-K1/K2/K5 isolates. MLST analysis indicated that ST11 strains were serum resistant, whereas ST258 isolates were serum sensitive. ST11 isolates exhibited significantly higher 15 minute phagocytic rates than ST258 isolates (70.28 +/- 16.68% vs. 34.88 +/- 10.52%, p < 0.001). The capsular serotype K1 strain was more resistant to neutrophil phagocytosis than non-K1/K2/K5 isolates (27.1 +/- 10.23% vs. 54.46 +/- 20.94%, p = 0.050). All KPC-producing strain variants from Taiwan and the US demonstrated less virulence in a mouse lethality study, where the LD50 ranged from approximately 10(6) colony-forming units (CFU) to >10(7) CFU. Immunological responses were not significantly correlated with KPC subtype; however, responses were associated with MLST and capsular serotype. CONCLUSION: Production of KPC itself was not associated with increased virulence despite different variants of KPC. The ST11 KPC-producing strain was resistant to serum killing, whereas capsular ss K1 was associated with resistance to neutrophil phagocytosis. PMID- 26514942 TI - Kidney dysfunction associated with tenofovir exposure in human immunodeficiency virus-1-infected Taiwanese patients. AB - BACKGROUND/PURPOSE: Tenofovir disoproxil fumarate (TDF) is associated with kidney tubular dysfunction, for which the risk may vary among patients of different ethnicities. Data are limited, however, on the association between renal function changes and TDF exposure in human immunodeficiency virus (HIV)-infected Taiwanese patients. METHODS: Medical records of HIV-infected Taiwanese patients seeking HIV care at a university hospital from 2011 to 2014 were reviewed. The change of estimated glomerular filtration rate (eGFR) was compared between patients not receiving combination antiretroviral therapy (cART) and those starting cART with or without TDF. The determinants of annual eGFR changes and factors associated with greater annual eGFR decline in TDF-exposed patients were explored. RESULTS: A total of 775 patients were included: 140 were cART-naive, 393 received TDF containing cART, and 242 received cART without TDF. Compared with cART-naive patients, the annual eGFR decline was greater in TDF-exposed patients (0.57 +/- 8.6 mL/min/1.73 m2 and 2.7 +/- 8.9 mL/min/1.73 m2, p = 0.012). The annual eGFR decline between patients receiving cART with or without TDF was similar (2.7 +/- 8.9 mL/min/1.73 m2 and 1.8 +/- 8.3 mL/min/1.73 m2, p = 0.567). Diabetes was associated with worsening eGFR decline in all studied patients. TDF exposure correlated with an additional annual eGFR decline of 2.73 mL/min/1.73 m2 (95% confidence interval 0.139-5.326, p = 0.039) in patients with CD4 count < 350 cells/MUL. Among TDF-exposed patients, the factors associated with annual eGFR decline of > 3 mL/min/1.73 m2 were higher baseline eGFR and lower CD4 counts. CONCLUSION: Among HIV-infected Taiwanese patients, cART exposure correlated with the decline of renal function. However, TDF-exposed patients are more likely to have prominent eGFR decline, especially those with higher baseline eGFR, advanced HIV disease, and diabetes. PMID- 26514943 TI - The Radiologic Diagnosis and Treatment of Typical and Atypical Bone Hemangiomas: Current Status. PMID- 26514944 TI - Future-directed thinking in first-episode psychosis. AB - OBJECTIVES: This study employed the Future Thinking Task (MacLeod et al., 2005, Br. J. Clin. Psychol., 44, 495) to investigate whether future-directed thinking in first-episode psychosis is significantly different from that of matched controls, and to identify its correlates in this patient group. DESIGN: Cross sectional, mixed-model, case-control design. METHOD: Participants were 30 patients with first-episode psychosis and 27 matched controls. The Future Thinking Task was used to assess future-directed thinking in both groups. Anxiety and depression were also measured as well as self-report measures of hopelessness, suicide ideation and a measure of negative symptoms. RESULTS: Individuals with psychosis were impaired in future-directed thinking in both positive and negative domains, particularly with respect to the coming year. Increased self-reported hopelessness was associated with reduced positive future thinking and increased negative future thinking. Increased positive future thinking was also associated with reduced severity of negative symptoms, whilst negative future thinking was associated with suicide ideation. CONCLUSIONS: Individuals with first-episode psychosis show a reduction in positive future thinking in line with that seen in other clinical groups, but this is accompanied by an unexpected reduction in negative future thinking. The findings suggest a general disengagement with the future in this group that may affect recovery and functioning. PRACTITIONER POINTS: Individuals with first-episode psychosis may benefit from interventions to help them engage with their future, in particular in the mid-range, up to 1 year. The Future Thinking Task may be a helpful addition to the assessment of suicide risk in those with first-episode psychosis. Decreased positive future thinking was associated with increased severity of negative symptoms, indicating a potential new treatment angle for this resistant aspect of psychosis. The cross-sectional design of this study does not allow for conclusions about the causal relationship between psychosis and future-directed thinking. This study investigated future-directed thinking in individuals with a range of psychotic illnesses employing a trans-diagnostic approach; therefore, conclusions cannot be drawn about the nature of future-directed thinking in individual psychotic disorders. PMID- 26514945 TI - Sturgeon hatching enzyme and the mechanism of egg envelope digestion: Insight into changes in the mechanism of egg envelope digestion during the evolution of ray-finned fish. AB - We investigated the evolution of the hatching enzyme gene using bester sturgeon (hybrid of Acipencer ruthenus and Huso huso), a basal member of ray-finned fishes. We purified the bester hatching enzyme from hatching liquid, yielding a single band on SDS-PAGE, then isolated its cDNA from embryos by PCR. The sturgeon hatching enzyme consists of an astacin family protease domain and a CUB domain. The CUB domains are present in frog and bird hatching enzymes, but not in teleostei, suggesting that the domain structure of sturgeon hatching enzyme is the tetrapod type. The purified hatching enzyme swelled the egg envelope, and selectively cleaved one of five egg envelope proteins, ZPAX. Xenopus hatching enzyme preferentially digests ZPAX, thus, the egg envelope digestion process is conserved between amphibians and basal ray-finned fish. Teleostei hatching enzymes cleave the repeat sequences at the N-terminal region of ZPB and ZPC, suggesting that the targets of the teleostei hatching enzymes differ from those of amphibians and sturgeons. Such repeat sequences were not found in the N terminal region of ZPB and ZPC of amphibians and sturgeons. Our results suggest that the change in substrates of the hatching enzymes was accompanied by the mutation of the amino acid sequence of N-terminal regions of ZPB and ZPC. We conclude that the changes in the mechanism of egg envelope digestion, including the change in the domain structure of the hatching enzymes and the switch in substrate, occurred during the evolution of teleostei, likely triggered by the teleost-specific third whole genome duplication. J. Exp. Zool. (Mol. Dev. Evol.) 324B: 720-732, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26514946 TI - Clinico-microbiological study of Pseudomonas aeruginosa in wound infections and the detection of metallo-beta-lactamase production. AB - Pseudomonas aeruginosa is a common opportunistic pathogen of humans among the Gram-negative bacilli. Clinically, it is associated with nosocomial infections like burns and surgical-site wound infections and remains a major health concern, especially among critically ill and immunocompromised patients. This is a prospective laboratory-based 2 year study conducted to isolate P. aeruginosa from wound specimens and the antimicrobial susceptibility pattern with reference to metallo-beta-lactamase (MBL) production. Two hundred and twenty-four samples of P. aeruginosa isolated from wound specimens were included in the study. Antimicrobial susceptibility was done as per Clinical Laboratory Standard Institute (CLSI) guidelines. MBL-producing P. aeruginosa was detected using the EDTA disk diffusion synergy test. Statistical analysis was done using the SPSS 11 package (SPSS Inc., Chicago, IL). Out of the 224 P. aeruginosa isolates, 100% were susceptible to polymyxin B and colistin, 92.8% were sensitive to imipenem, 38% showed resistance to gentamicin followed by ceftazidime (31.69%) and meropenem (33.03). Sixteen (7.14%) isolates showed MBL production. Infection caused by drug-resistant P. aeruginosa is important to identify as it poses a therapeutic problem and is also a serious concern for infection control management. The acquired resistance genes can be horizontally transferred to other pathogens or commensals if aseptic procedures are not followed. PMID- 26514947 TI - Carcinogenicity of consumption of red and processed meat. PMID- 26514948 TI - The correlation of plasma omentin-1 with insulin resistance in non-obese polycystic ovary syndrome. AB - OBJECTIVES: Aberrant circulating adipokines are considered to be related to the pathological mechanism of polycystic ovary syndrome (PCOS). This study aims to evaluate the relationship between plasma omentin-1 levels, metabolic and hormonal parameters in the setting of non-obese Chinese women with PCOS. MATERIAL AND METHODS: This was a case-controlled, cross-sectional study of 153 non-obese (BMI<25kg/m(2)) PCOS and 114 age-matched healthy non-obese control individuals. Levels of plasma omentin-1, fasting blood glucose, insulin and sexual hormones and ovary volume were analyzed in all subjects. RESULTS: Plasma omentin-1 levels of non-obese PCOS individuals were significantly lower than in healthy non-obese controls. Body Mass Index (BMI), homeostasis model of assessment for insulin resistance index (HOMA-IR), levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), LH/FSH ratio and ovary volume (OV) were significantly higher in subjects with PCOS than controls. In the HOMA-IR stratified subgroups, PCOS individuals with insulin resistance had lower omentin 1 than those without insulin resistance after BMI adjustment. Omentin-1 was negatively correlated with BMI, HOMA-IR and fasting insulin. Multiple linear regressions revealed that BMI contributed to omentin-1 levels. Ovary volume was negatively correlated to HOMA-IR but had no correlation with omentin-1. CONCLUSIONS: Plasma omentin-1 concentrations were decreased in the non-obese PCOS group. Insulin resistance could further decrease plasma omentin-1 in non-obese individuals with PCOS independent of BMI status. PMID- 26514949 TI - Valuable predictive features of relapse of Graves' disease after antithyroid drug treatment. AB - PURPOSE: Antithyroid drug treatment (ATDT) effectively achieves euthyroidism in patients with Graves' disease (GD). However, apparently successful treatment may be followed by relapse. We investigated the outcome of ATDT in Chinese patients with GD to identify predictive features of relapse. METHODS: In total, 133 patients with mild to moderate goiter were included in this analysis. All patients received methimazole for 12 to 40 months and were subsequently followed up for at least 1 year. Lasting remission was defined as the presence of clinical and laboratory features of euthyroidism for >= 1 year after stopping methimazole. RESULTS: Most patients (118 of 133, 88.7%) remained in remission after the follow up period; 15 patients (11.3%) developed relapse. A history of GD, larger goiter at the time of drug withdrawal, a positive thyroid-stimulating antibody titer and restauration of low thyroid-stimulating hormone levels during the maintenance period were related to a subsequent risk of relapse according to stepwise logistic regression analysis results. However, other clinical and biological features (age, sex, initial goiter, ophthalmopathy, thyroxine and triiodothyronine levels and thyroglobulin antibody and thyroid microsomal antibody titers) did not reach statistical significance. CONCLUSION: Regular, individualized ATDT achieved an 88.7% remission rate in Chinese patients with GD. The features associated with probable relapse were a history of GD, larger goiter at the time of drug withdrawal, a positive thyroid-stimulating antibody titer at the time of drug withdrawal and redevelopment of low thyroid-stimulating hormone levels during the maintenance period. PMID- 26514950 TI - Hypophysitis in 2014. AB - Hypophysitis is a rare pathology. As clinical symptoms and radiologic signs are non-specific, the diagnostic is difficult. Hypophysitis's pathogenesis remains obscure but new histological and etiological variants have recently been reported. Primary hypophysitis is the main form. For the first time, hypophysitis in ANCA-associated vasculitides has been reported. An entity of immunoglobulin G4 related plasmatic hypophysitis has been described and well-defined diagnostic criteria are proven. Monoclonal antibodies directed against the cytotoxic T lymphocyte antigen-4 (CTLA-4), investigated in metastatic cancer, can induce hypophysitis. Hypophysitis's pathogenesis remains obscure but several candidate pituitary autoantigens have been described in the last decade, although none has proven useful as a diagnostic tool. PMID- 26514951 TI - Does DRD2 polymorphism influence the clinical characteristics of prolactinoma? AB - OBJECTIVES: Genetic alterations explaining the clinical variability of prolactinomas still could not be clarified and dopamine D2 receptor (DRD2) polymorphism is a putative candidate for the variable response to dopaminergic treatment. The present study was conducted to investigate the influence of DRD2 TaqI A polymorphism on initial and follow-up characteristics of prolactinoma. PATIENTS AND METHODS: Seventy-two patients with prolactinoma and 98 age and gender matched control subjects were recruited to the case-control study. Serum prolactin levels were assessed by enzyme-linked immunosorbent assay and DRD2 polymorphism was determined by polymerase chain reaction and restriction length polymorphism analysis. RESULTS: Decrease of prolactin levels and the tumor shrinkage after cabergoline treatment were 93.9+/-5.9% and 58.3+/-33.1% in microadenomas and 96.1+/-6.1% and 51.7+/-29.3 in macroadenomas (P=0.02 and P>0.05, respectively). We observed no significant difference for DRD2 genotypes and the alleles between the patients and healthy group (P>0.05). Prolactin levels before treatment were correlated with tumor diameter before and after treatment and the percentage of prolactin decrease with treatment (P<0.001 r=0.58, P<0.001 r=0.40 and P<0.001 r=0.47, respectively). Tumor diameter before the treatment was also correlated with the tumor diameter after the treatment (P<0.001 r=0.64) and the percentage of prolactin decrease (P=0.01 r=0.30). However, no significant association was found between characteristics of prolactinoma and DRD2 genotypes and alleles (P>0.05). CONCLUSION: This study revealed that DRD2 TaqI A receptor polymorphism was not associated with the development of prolactinoma and its clinical characteristics. Future studies are needed to clarify the clinical implications of genetic alterations in prolactinoma. PMID- 26514952 TI - Non-osteoporotic women with low-trauma fracture present altered birefringence in cortical bone. AB - Areal bone mineral density (BMD) by DXA, although an important index, does not accurately assess risk of fragility fracture. Another bone structural parameter, the orientation of type I collagen, is known to add to risk determination, independently of BMD. Accordingly, we investigated the Haversian systems of transiliac crest biopsies from non-osteoporotic women with low-trauma fractures, matched to healthy women without fracture by age and BMD. We employed circularly polarized light (CPL) microscopy because 1) each of the extinct and bright birefringent signals of CPL corresponds to a specific collagen arrangement; and 2) CPL can employ magnification suitable to provide data, of manageable size, from the whole cortical component of a section of biopsy. Under CPL, the coaxial layers of osteons, called lamellae, appear either birefringent extinct or bright. On a section transverse to the Haversian system, the extinct lamella comprises mainly collagen forming small angles, and the bright lamella comprises mainly collagen forming large angles, relative to the general orientation of the Haversian system. We performed semi-automatic morphometry for birefringent and structural parameters for which we computed intra- and inter-observer errors. The statistical analysis used a linear mixed model to compare fracturing and non fracturing groups while addressing pairing of fracturing and non-fracturing subjects, and linear regression to assess differences between matched subjects. We found significant reduction in 1) lamellar width and area for extinct lamella and bright lamella; 2) percentage of extinct birefringence in osteons, and 3) single osteon area; in the fracturing group; and in lamellar width in the fracturing subject of all pairs. Our results evidence the need to investigate, in a larger sample of subjects, the distribution of collagen orientation as a parameter diagnostic of increased fracture risk. PMID- 26514953 TI - Self-Reported Acute Health Effects and Exposure to Companion Animals. AB - To understand the etiological burden of disease associated with acute health symptoms [e.g. gastrointestinal (GI), respiratory, dermatological], it is important to understand how common exposures influence these symptoms. Exposures to familiar and unfamiliar animals can result in a variety of health symptoms related to infection, irritation and allergy; however, few studies have examined this association in a large-scale cohort setting. Cross-sectional data collected from 50 507 participants in the United States enrolled from 2003 to 2009 were used to examine associations between animal contact and acute health symptoms during a 10-12 day period. Fixed-effects multivariable logistic regression estimated adjusted odds ratios (AORs) and 95% confident intervals (CI) for associations between animal exposures and outcomes of GI illness, respiratory illness and skin/eye symptoms. Two-thirds of the study population (63.2%) reported direct contact with animals, of which 7.7% had contact with at least one unfamiliar animal. Participants exposed to unfamiliar animals had significantly higher odds of self-reporting all three acute health symptoms, when compared to non-animal-exposed participants (GI: AOR = 1.4, CI = 1.2-1.7; respiratory: AOR = 1.5, CI = 1.2-1.8; and skin/eye: AOR = 1.9, CI = 1.6-2.3), as well as when compared to participants who only had contact with familiar animals. Specific contact with dogs, cats or pet birds was also significantly associated with at least one acute health symptom; AORs ranged from 1.1 to 1.5, when compared to participants not exposed to each animal. These results indicate that contact with animals, especially unfamiliar animals, was significantly associated with GI, respiratory and skin/eye symptoms. Such associations could be attributable to zoonotic infections and allergic reactions. Etiological models for acute health symptoms should consider contact with companion animals, particularly exposure to unfamiliar animals. Prevention of pet-associated zoonotic diseases includes commonsense measures such as hand-washing, but are often overlooked by pet owners and non-pet owners alike. PMID- 26514954 TI - Pure-tone audiometry outside a sound booth using earphone attentuation, integrated noise monitoring, and automation. AB - OBJECTIVE: Accessibility of audiometry is hindered by the cost of sound booths and shortage of hearing health personnel. This study investigated the validity of an automated mobile diagnostic audiometer with increased attenuation and real time noise monitoring for clinical testing outside a sound booth. DESIGN: Attenuation characteristics and reference ambient noise levels for the computer based audiometer (KUDUwave) was evaluated alongside the validity of environmental noise monitoring. Clinical validity was determined by comparing air- and bone conduction thresholds obtained inside and outside the sound booth (23 subjects). STUDY SAMPLE: Twenty-three normal-hearing subjects (age range, 20-75 years; average age 35.5) and a sub group of 11 subjects to establish test-retest reliability. RESULTS: Improved passive attenuation and valid environmental noise monitoring was demonstrated. Clinically, air-conduction thresholds inside and outside the sound booth, corresponded within 5 dB or less > 90% of instances (mean absolute difference 3.3 +/- 3.2 SD). Bone conduction thresholds corresponded within 5 dB or less in 80% of comparisons between test environments, with a mean absolute difference of 4.6 dB (3.7 SD). Threshold differences were not statistically significant. Mean absolute test-retest differences outside the sound booth was similar to those in the booth. CONCLUSION: Diagnostic pure-tone audiometry outside a sound booth, using automated testing, improved passive attenuation, and real-time environmental noise monitoring demonstrated reliable hearing assessments. PMID- 26514955 TI - Evaluation of the toxicology and pharmacokinetics of recombinant factor VIII Fc fusion protein in animals. AB - INTRODUCTION: Recombinant factor VIII Fc fusion protein (rFVIIIFc) is a novel recombinant factor VIII with a prolonged half-life, developed for the treatment of hemophilia A. Studies that evaluated the toxicological effects of rFVIIIFc in 2 pharmacologically relevant species, cynomolgus monkeys and Sprague Dawley rats, are reported here. MATERIALS AND METHODS: In repeat-dose toxicology studies, rats and monkeys received 0, 50, 250, or 1000 IU/kg rFVIIIFc every other day for 4 weeks. In a high-dose tolerance study, monkeys received 1 rFVIIIFc dose of 3000, 10,000, or 20,000 IU/kg. Evaluations included in-life observations, laboratory and post-mortem evaluations, pharmacokinetics, and local tolerance. Allometric scaling, using data from 4 animal species and humans, was used to evaluate the relationship between animal and human pharmacokinetics. RESULTS: rFVIIIFc was well tolerated with no adverse toxicological findings directly attributable to rFVIIIFc. As expected, antibodies to this fully human protein developed in rats and monkeys in a time-dependent fashion following repeated dosing, leading to increased clearance in both species. There were no local reactions (infusion site) or evidence of thrombosis at high doses in rats and monkeys. Allometric scaling demonstrated more rapid clearance in small animals compared with humans and a volume of distribution (steady state) proportional to body weight across species, suggesting that animal pharmacokinetics are predictive of human pharmacokinetics. CONCLUSIONS: Repeated doses of rFVIIIFc in 2 relevant animal species and high doses of rFVIIIFc in monkeys were well tolerated. These results supported the clinical safety of rFVIIIFc observed in phase 1/2a and phase 3 clinical trials. PMID- 26514956 TI - The role of protein disulfide isomerase in the post-ligation phase of beta3 integrin-dependent cell adhesion. AB - INTRODUCTION: Protein disulfide isomerase (PDI) catalyzes disulfide bond exchange. It is crucial for integrin-mediated platelet adhesion and aggregation and disulfide bond exchange is necessary for alphaIIbbeta3 and alphavbeta3 activation. However, the role of disulfide bond exchange and PDI in the post ligation phase of alphaIIbbeta3 and alphavbeta3 mediated cell adhesion has yet to be determined. METHODS: To investigate a possible such role, we expressed wild type (WT) human alphaIIb and either WT human beta3, or beta3 harboring single or double cysteine to serine substitutions disrupting Cys473-Cys503 or Cys523-Cys544 bonds, in baby hamster kidney (BHK) cells, leading to expression of both human alphaIIbbeta3 and a chimeric hamster/human alphavbeta3. Adhesion to fibrinogen coated wells was studied in the presence or absence of bacitracin, a PDI inhibitor, with and without an alphavbeta3 blocker. RESULTS: Flow cytometry showed WT and mutant alphaIIbbeta3 expression in BHK cells and indicated that mutated alphaIIbbeta3 receptors were constitutively active while WT alphaIIbbeta3 was inactive. Both alphaIIbbeta3 and alphavbeta3 integrins, WT and mutants, mediated adhesion to fibrinogen as shown by reduced but still substantial adhesion following treatment with the alphavbeta3 blocker. Mutated alphaIIbbeta3 integrins disrupted in the Cys523-Cys544 bond still depended on PDI for adhesion as shown by the inhibitory effect of bacitracin in the presence of the alphavbeta3 blocker. Mutated integrins disrupted in the Cys473-Cys503 bond showed a similar trend. CONCLUSIONS: PDI-mediated disulfide bond exchange plays a pivotal role in the post-ligation phase of alphaIIbbeta3-mediated adhesion to fibrinogen, while this step in alphavbeta3-mediated adhesion is independent of disulfide exchange. PMID- 26514957 TI - A Randomized Controlled Trial to Compare Computer-assisted Motivational Intervention with Didactic Educational Counseling to Reduce Unprotected Sex in Female Adolescents. AB - STUDY OBJECTIVE: To examine a computer-assisted, counselor-guided motivational intervention (CAMI) aimed at reducing the risk of unprotected sexual intercourse. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We conducted a 9-month, longitudinal randomized controlled trial with a multisite recruitment strategy including clinic, university, and social referrals, and compared the CAMI with didactic educational counseling in 572 female adolescents with a mean age of 17 years (SD = 2.2 years; range = 13-21 years; 59% African American) who were at risk for pregnancy and sexually transmitted diseases. The primary outcome was the acceptability of the CAMI according to self-reported rating scales. The secondary outcome was the reduction of pregnancy and sexually transmitted disease risk using a 9-month, self-report timeline follow-back calendar of unprotected sex. RESULTS: The CAMI was rated easy to use. Compared with the didactic educational counseling, there was a significant effect of the intervention which suggested that the CAMI helped reduce unprotected sex among participants who completed the study. However, because of the high attrition rate, the intent to treat analysis did not demonstrate a significant effect of the CAMI on reducing the rate of unprotected sex. CONCLUSION: Among those who completed the intervention, the CAMI reduced unprotected sex among an at-risk, predominantly minority sample of female adolescents. Modification of the CAMI to address methodological issues that contributed to a high drop-out rate are needed to make the intervention more acceptable and feasible for use among sexually active predominantly minority, at-risk, female adolescents. PMID- 26514958 TI - [Chronic lateral epicondylitis : The Nirschl procedure]. AB - PURPOSE: Reduction of burden insufficiency. INDICATION: Chronic lateral epicondylitis. CONTRAINDICATIONS: Acute infection in the surgical area. C6/7 nerve root and plexus irritation. Frohse Arcade syndrome. Posterolateral rotatory instability. SURGICAL TECHNIQUE: Incision slightly cranial to the radial epicondyle. Identification of the extensor carpi radial brevis tendon (ERCB) and longus (ECRL). Mobilisation of the ECRL tendon, identification of degenerative tendons of the ECRB. Excision of degenerative tissue. Drill holes in the area of the smoothed radial epicondyle, thermal denervation. POSTOPERATIVE MANAGEMENT: Arm plaster splint for 14 days. Unrestricted activity after 4-6 weeks. Maximum loading after 6 months. RESULTS: Of the 24 consecutively operated patients, 83.3 % were included. High patient satisfaction. Nirschl tennis and elbow score improved from 35 to 75 points postoperatively. Pain levels decreased from 6.8 to 1.4 points postoperatively. PMID- 26514959 TI - Ventricular tachycardia in ischemic cardiomyopathy; a combined endo-epicardial ablation as the first procedure versus a stepwise approach (EPILOGUE) - study protocol for a randomized controlled trial. AB - BACKGROUND: The role of epicardial substrate ablation of ventricular tachycardia (VT) as a first-line approach in patients with ischemic heart disease is not clearly defined. Epicardial ablation as a first-line option is standard for patients with nonischemic dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Several nonrandomized studies, including studies on patients with ischemic heart disease, have shown that epicardial VT ablation improves outcome but this approach was often used after a failed endocardial approach. The aim of this study is to determine whether a combined endo epicardial scar homogenization as a first-line approach will improve the outcome of VT ablation. METHODS/DESIGN: The EPILOGUE study is a multicenter, two-armed, nonblinded, randomized controlled trial. Patients with ischemic heart disease who are referred for VT ablation will be randomly assigned to combined endo epicardial scar homogenization or endocardial scar homogenization only (control group). The primary outcome is recurrence of sustained VT during a 2-year follow up. Secondary outcomes include procedural success and safety. DISCUSSION: This study is the first randomized trial that evaluates the role of a combined endo epicardial scar homogenization versus endocardial scar homogenization for the treatment of ischemic scar-related VT. TRIAL REGISTRATION: NL4816807814v02. PMID- 26514960 TI - Synthesis of functional polyester for fabrication of nano-fibrous scaffolds and its effect on PC12 cells. AB - An ideal scaffold should mimic the advantageous characteristics of a natural extracellular matrix for cell attachment, proliferation, and differentiation. In this study, well-defined block copolymer with functional groups was synthesized. The structure of the block copolymer was characterized by nuclear magnetic resonance, gel permeation chromatography, and differential scanning calorimetry. Thermally induced phase separation was employed to fabricate nano-fibrous scaffolds based on the synthesized block copolymer. The scaffold, with fiber diameter ranging from 400 to 500 nm, was fabricated for in vitro culture of PC12 cells. The carboxyl groups on the side chain resulted in increased hydrophilicity of nano-fibrous scaffolds and enhanced cell proliferation. In addition, this scaffold structure was beneficial in directing the growth of regenerating axons in nerve tissue engineering. Results of 3-(4,5-dimethylthiazol-2yl)-2,5 diphenyltetrazolium bromide (MTT) assay and scanning electron microscopy confirmed that the nano-fibrous scaffolds with functional groups were suitable for PC12 cells growth. Moreover, the carboxyl groups were suitable for coupling with biological signals. Thus, the nano-fibrous scaffolds have potential applications in tissue engineering. PMID- 26514961 TI - Temporal lobe anatomy: eight imaging signs to facilitate interpretation of MRI. AB - PURPOSE: The temporal lobe is anatomically and functionally complex. However, relatively few radiologic signs are described to facilitate recognition of temporal lobe sulci and gyri in clinical practice. We devised and tested 8 radiologic signs of temporal lobe anatomy. METHODS: Images from volumetric magnetization-prepared rapid gradient-echo imaging were analyzed of 100 temporal lobes from 26 female and 24 male patients. Patient age ranged from 1 to 79 years (mean 19 years; standard deviation 16 years). Standardized axial, coronal, and sagittal planes were evaluated and cross-referenced. Eight signs to delineate the superior temporal gyrus, Heschl gyrus (HG), parahippocampal gyrus, rhinal sulcus, collateral sulcus proper, or the occipitotemporal sulcus, or a combination, were evaluated in the sagittal or axial plane. Two neuroradiologists independently evaluated each sign; the sign was considered present only with positive reader agreement. RESULTS: All 8 signs were present in most patients. The most frequent signs were the posterior insular corner to identify HG in the axial plane (100 %), pointed STG to identify STG in the axial plane (98 %), and parahippocampal Y to identify the posterior parahippocampal gyrus in the sagittal plane (98 %). The frequencies were similar between the right and left cerebral hemispheres. CONCLUSIONS: Temporal lobe gyri and sulci can be reliably identified in multiple planes using anatomic signs. PMID- 26514962 TI - What is the pelvic lymph node normal size? Determination from normal MRI examinations. AB - PURPOSE: There are few previous reports on maximal pelvic lymph node sizes and no data on normal mesorectal nodes. Therefore, the aim of the study was to estimate the normal size of pelvic lymph nodes and to determine the upper limits of the normal range. MATERIALS AND METHODS: Pelvic magnetic resonance imaging (MRI) examinations were prospectively carried out using a Intera 1.5 T magnet (Philips, the Netherlands), on 36 healthy volunteers (22 females, 14 males, mean age 25 years). A balanced fast field echo (b-FFE) sequence was used with the following parameters: 3-mm-thick contiguous slice, matrix 512 * 512. Short axis diameters of pelvic and inguinal lymph nodes were measured in each anatomic territory (internal iliac, external iliac, common iliac, mesorectum and inguinal). After normalization of the measurements, the influences of age, gender, laterality and territory were evaluated. Upper limits (95th percentile) were then calculated. RESULTS: A total of 1147 lymph nodes were measured. Age, gender and side (right/left) had no significant influence on size. The upper limits of the normal range were, respectively, 5.3, 4.4, 6.3 and 3.9 mm for the external and common iliac, internal iliac, inguinal and mesorectum nodes. CONCLUSION: This work presents maximal normal values for each pelvic area, and the values for mesorectum nodes are reported for the first time. ADVANCES IN KNOWLEDGE: The mesorectum nodes should be considered as abnormal when they are over 4 mm in short diameter. For the other node areas, the upper limits of the normal range were, respectively, 6, 6, 5, 7 mm for the external and common iliac, internal, iliac and inguinal nodes for the short axis. PMID- 26514964 TI - Ammonia-induced robust photocatalytic hydrogen evolution of graphitic carbon nitride. AB - We report a new and effective method to prepare high activity graphitic carbon nitride (g-C3N4) by a simple ammonia etching treatment. The obtained g-C3N4 displays a high BET surface area and enhanced electron/hole separation efficiency. The hydrogen evolution rates improved from 52 MUmol h(-1) to 316.7 MUmol h(-1) under visible light. PMID- 26514963 TI - The association between systemic oxidative stress and ocular blood flow in patients with normal-tension glaucoma. AB - PURPOSE: To evaluate the association between ocular blood flow and biomarkers of systemic oxidative stress, as well as the potential of these biomarkers to assess normal-tension glaucoma (NTG). METHODS: This study included 73 eyes of 73 patients with NTG. We assessed ocular blood flow by measuring mean blur rate (MBR) in the optic nerve head using laser speckle flowgraphy, both overall and separately in the vessel and tissue areas. We also measured urinary 8-hydroxy-2' deoxyguanosine (8-OHdG) and skin autofluorescence (SAF), and lastly, determined correlations between these measurements and with other clinical parameters. RESULTS: SAF was correlated with age, circumpapillary retinal nerve fiber layer thickness (cpRNFLT), mean deviation (MD), and overall MBR (P = 0.003, P = 0.013, P = 0.015 and P = 0.006, respectively). SAF and 8-OHdG were both correlated with tissue-area MBR (P = 0.006 and P = 0.010, respectively). Visual acuity, cpRNFLT, mean deviation and tissue-area MBR had a significant tendency to change with NTG severity (P = 0.014, P < 0.001, P < 0.001 and P = 0.006, respectively). Multiple regression analysis revealed that cpRNFLT and 8-OHdG were independent contributing factors to MD (P < 0.001 and P = 0.040, respectively), and that cpRNFLT and 8-OHdG were independent contributing factors to tissue-area MBR (P = 0.005 and P = 0.028, respectively). CONCLUSIONS: We found a close relationship between cpRNFLT, MD, tissue MBR, SAF and 8-OHdG, suggesting that systemic oxidative stress is associated with decreased ocular blood flow and may be involved in the pathogenesis of NTG. PMID- 26514965 TI - Sleep Quality in Family Caregivers of Individuals With Dementia: A Concept Analysis. AB - Poor sleep quality in family caregivers may impact their health status and cause quality of life to decline. Nurses are conducting an increasing number of studies that use sleep quality or related concepts as a main indicator to assess caregiver's sleep. Therefore, a clear understanding of sleep quality and how it is different from other relevant sleep domains is essential. This article aimed to analyze the concept of sleep quality using the steps outlined by Walker and Avant. Findings include (a) attributes of sleep quality including subjective perception of sleep, sleep hours, and evaluation of activity after awaking; (b) antecedents of sleep quality including the ability to get naturally into the sleep cycle and status of conscious state; and (c) consequences of sleep quality including bio-psycho-social and global dimensions of health. This article intends to help clinicians and researchers better understand and define sleep quality in dementia caregivers. PMID- 26514966 TI - Acute and sub-chronic toxicity of tetrandrine in intravenously exposed female BALB/c mice. AB - OBJECTIVE: To evaluate the acute and sub-chronic toxicity of intravenously administered tetrandrine (TET) in female BALB/c mice. METHODS: The median lethal dose (LD50) of intravenously administered TET was calculated in mice using Dixon's up-and-down method. In the acute toxicity study, mice were intravenously administered with TET at a single dose of 20, 100, 180, 260 and 340 mg/kg, respectively and were evaluated at 14 days after administration. In the sub-acute toxicity study, mice were intravenously administered various doses of TET (30, 90 and 150 mg/kg) each day for 14 consecutive days. Clinical symptoms, mortality, body weight, serum biochemistry, organ weight and histopathology were examined at the end of the experiment, as well as after a 1-week recovery period. RESULT: LD50 was found to be 444.67+/-35.76 mg/kg. In the acute toxicity study, no statistically signifificant differences in body weight, blood biochemistry, or organ histology were observed between the administration and control groups when mice were intravenously administered with single dose at 20, 100, 180, 260 and 340 mg/kg of TET (P >0.05). In the sub-acute toxicity study, no signifificant changes in body weight, biochemistry and organ histology were observed with up to 90 mg/kg of TET compared with the control group (P >0.05), however, in the 150 mg/kg administered group, TET induced transient toxicity to liver, lungs and kidneys, but withdrawal of TET can lead to reversal of the pathological conditions. CONCLUSIONS: The overall fifindings of this study indicate that TET is relatively non-toxic from a single dose of 20, 100, 180, 260 or 340 mg/kg, and that up to 90 mg/kg daily for 14 consecutive days can be considered a safe application dose. PMID- 26514967 TI - Influence of verapamil on the pharmacokinetics of oxcarbazepine and of the enantiomers of its 10-hydroxy metabolite in healthy volunteers. AB - PURPOSE: Oxcarbazepine (OXC), a second-generation antiepileptic, and its chiral metabolite 10-hydroxycarbazepine (MHD) are substrates of P-glycoprotein, which can be inhibited by verapamil. This study evaluated the influence of verapamil on the pharmacokinetics of OXC and MHD enantiomers in healthy volunteers. METHODS: Healthy volunteers (n = 12) on occasion O (OXC monotherapy) received 300 mg OXC/12 h for 5 days, and on the O + V occasion (treatment with OXC + verapamil), they received 300 mg OXC/12 h and 80 mg verapamil/8 h for 5 days. Blood samples were collected over a period of 12 h. Total and free plasma concentrations of OXC and the MHD enantiomers were evaluated by LC-MS/MS. Noncompartmental pharmacokinetic analysis was performed using the WinNonlin program. RESULTS: The kinetic disposition of MHD was enantioselective with plasma accumulation (AUC(0 12) S-(+)/R-(-) ratio of 4.38) and lower fraction unbound (0.37 vs 0.42) of the S (+)-MHD enantiomer. Treatment with verapamil reduced the OXC mean residence time (4.91 vs 4.20 h) and apparent volume of distribution (4.72 vs 3.15 L/kg). Verapamil also increased for both MHD enantiomers C max total [R-(-)-MHD: 2.65 vs 2.98 MUg/mL and S-(+)-MHD: 10.15 vs 11.60 MUg/mL], C average [R-(-)-MHD: 1.98 vs 2.18 MUg/mL and S-(+)-MHD: 8.10 vs 8.83 MUg/mL], and AUC(0-12) [R-(-)-MHD: 23.79 vs 26.19 MUg h/mL and S-(+)-MHD: 97.87 vs 108.35 MUg h/mL]. CONCLUSION: Verapamil increased the AUC values of both MDH enantiomers, which is probably related to the inhibition of intestinal P-glycoprotein. Considering that the exposure of both MHD enantiomers was increased in only 10 %, no OXC dose adjustment could be recommended in the situation of verapamil coadministration. PMID- 26514968 TI - Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol. AB - PURPOSE: Therapeutic drug monitoring (TDM) of antipsychotics can aid in therapy optimization, explaining adverse effects or non-response. One reason for therapeutic failure or adverse effects is caused by genetic variations in the cytochrome P450 drug-metabolizing genes. The aim of this study was to evaluate the impact of CYP2D6 polymorphisms on steady-state serum concentrations of antipsychotics metabolized by CYP2D6, taking into account the co-medication with CYP2D6 inhibitors. METHODS: Serum and EDTA samples were collected from 82 psychiatric patients. After a liquid-liquid extraction, serum samples were analyzed using an ultra-high performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method for quantification of the antipsychotics. CYP2D6 genotyping was performed using the Luminex xTAG(r) CYP2D6 Kit v3 (Luminex Corporation). Patients were divided into five phenotype subgroups by calculation of the activity score (AS): poor metabolizers (PM; AS 0), intermediate metabolizers (IM; AS 0.5-1), extensive metabolizers with slow activity (EM-s; AS 1-1.5), extensive metabolizers with fast activity (EM-f; AS 2), and ultra-rapid metabolizers (UM; AS >2). The influence of the phenotypes on the concentration-to dose and metabolite-to-parent ratios was evaluated. RESULTS: Overall, 6.1 % UM (n = 5), 25.6 % EM-f (n = 21), 46.3 % EM-s (n = 38), 1.2 % EM-s/EM-f (n = 1), 6.1 % IM (n = 5), and 14.6 % PM (n = 12) were found, taking co-administration of strong and moderate CYP2D6 inhibitors into account (phenoconversion). It was demonstrated that CYP2D6 polymorphisms affect the serum concentrations of aripiprazole (n = 18), haloperidol (n = 11), risperidone (n = 20), and zuclopenthixol (n = 6), while no influence was seen on the paliperidone serum concentrations (n = 31). CONCLUSIONS: Even with a small number of patients per antipsychotic, the importance of CYP2D6 genotyping was still clearly stated. This study illustrates the high potential of combining TDM and CYP2D6 genotyping in clinical practice. PMID- 26514970 TI - Effect of extremely low frequency electromagnetic fields on bacterial membrane. AB - PURPOSE: The effect of extremely low frequency electromagnetic fields (ELF-EMF) on bacteria has attracted attention due to its potential for beneficial uses. This research aimed to determine the effect of ELF-EMF on bacterial membrane namely the membrane potential, surface potential, hydrophobicity, respiratory activity and growth. MATERIALS AND METHODS: Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli were subjected to ELF-EMF, 50 Hz, 1 mT for 2 h. Membrane potential was determined by fluorescence spectroscopy with or without EDTA (Ethylenediaminetetraacetic acid) with DisC3(5) (3,3 dipropylthiacarbocyanine iodide), zeta potential measurements were performed by electrophoretic mobility, hydrophobicity of the membrane was measured with MATH (Microbial Adhesion to Hydrocarbons) test, respiratory activity was determined with CTC (5-Cyano-2,3-ditolyl tetrazolium chloride), colony forming unit (CFU) and DAPI (4',6-diamidino-2-phenylindole, dihydrochloride) was used for growth determinations. RESULTS: ELF-EMF caused changes in physicochemical properties of both Gram-positive and Gram-negative bacteria. Hyperpolarization was seen in S. aureus and EDTA-treated E. coli. Surface potential showed a positive shift in S. aureus contrariwise to the negative shift seen in EDTA-untreated E. coli. Respiratory activity increased in both bacteria. A slight decrease in growth was observed. CONCLUSION: These results show that ELF-EMF affects the crucial physicochemical processes in both Gram-positive and Gram-negative bacteria which need further research. PMID- 26514969 TI - Scutellarin Alleviates Behavioral Deficits in a Mouse Model of Multiple Sclerosis, Possibly Through Protecting Neural Stem Cells. AB - Scutellarin, a flavonoid extracted from an herbal medication (Erigeron breviscapus Hand-Mazz), has been shown to protect neurons against damage and to promote neurogenesis, and thus has therapeutic potential in the treatment of a variety of neurodegenerative diseases. Since neural stem cells (NSCs) could differentiate into myelin-producing oligodendrocytes, we speculate that scutellarin could also be used to treat multiple sclerosis (MS). In the current study, we examined potential effects of scutellarin using a mouse model of MS. Briefly, adult C57BL/6 mice exposed to cuprizone (8 mg/day through diet, for 6 consecutive weeks) randomly received scutellarin (50 mg/kg/day) or vehicle for 10 consecutive days. In the scutellarin-treated group, rotarod testing at the end of the treatment showed significant improvement of motor function (increased time to fall); myelin basic protein (MBP) staining of the corpus callosum revealed decreased demyelination; TUNEL staining followed by Nestin or Sox2 staining revealed increased number of NSCs and decreased rate of NSC apoptosis in the subventricular zone (SVZ) of the lateral ventricles (LV). In a series of experiments using cultured NSCs subjected to cuprizone injury, we confirmed the protective effects of scutellarin. At 30 MUM, scutellarin increased the commitment of NSCs to the oligodendrocyte and neuronal lineages, as evidenced by NG2 chondroitin sulfate proteoglycan (NG2) and doublecortin (DCX) staining. Differentiation into astrocytes (as revealed by glial fibrillary acidic protein (GFAP) staining) was decreased. Maturation of the NSCs committed to the oligodendrocyte lineage, as evidenced by oligodendrocyte marker O4 antibody (O4) staining and MBP staining, was also promoted by scutellarin. Further analysis revealed that scutellarin might suppress the phosphorylation of p38 in cuprizone induced NSCs. In summary, scutellarin could alleviate motor deficits in a mouse model for MS, possibly by inhibiting NSC apoptosis and promoting differentiation of NSCs to myelin-producing oligodendrocytes. PMID- 26514971 TI - Beral's 1974 paper: A step towards universal prevention of cervical cancer. AB - In 1974, Valerie Beral published a landmark paper on the sexually transmitted origin of cervical cancer (CC) using statistics routinely available in the United Kingdom (UK). Among women born between 1902 and 1947, CC mortality rates correlated remarkably well with the incidence rates of gonorrhoea when they were 20 years old and both were highest among women born after 1940. Hence, if CC prevention and treatment had remained unchanged, the youngest generations of women would have experienced a high risk of CC death as they grew older. Fortunately, progress in CC prevention has helped avoid this scenario. The adverse consequences of the "sexual revolution" were greatly mitigated in the UK and other high-resource countries by the implementation of high quality cytology based CC screening. An age-period-cohort analysis suggests that >30,000 cases or approximately 35% of expected CC cases may have been prevented by screening programmes in the UK between 1983 and 2007 and this percentage has been steadily increasing. In addition, the discovery of the causal role of HPV is reshaping primary and secondary prevention of CC. Cheaper HPV tests are becoming available and HPV-based primary screening may at last facilitate CC screening in low resource countries. In the long-term, however, HPV vaccination, which has already been adopted by many countries, represents the best hope for preventing CC and overcoming socio-economic differences in CC risk within and across countries. The additional elucidation of HPV cofactors to which Beral has greatly contributed may also help control HPV infection in unvaccinated women. PMID- 26514972 TI - Long-term dietary supplementation with cystathionine improves tissue glutathione in ageing rats. AB - BACKGROUND: Ageing is associated with decrease in tissue glutathione that can be reduced by food fortification with the amino acid cysteine. However, cysteine is not stable in solution and generates bad taste. Cystathionine, the direct precursor of cysteine, could be a valuable alternative. AIMS: This study aimed to determine whether long-term dietary supplementation with cystathionine induces an increase in glutathione pools. METHODS: Aged rats (20.5-month-old) were fed ad libitum during 29 weeks with either a cystathionine-supplemented diet (7.3 g/kg, n = 90 rats) or a control iso-nitrogenous alanine-supplemented diet (2.9 g/kg, n = 90 rats). RESULTS: Cystathionine was detected in the plasma of the cystathionine-supplemented rats but not in the control alanine-supplemented rats. Cystathionine increased glutathione concentrations in liver, small intestine and gastrocnemius muscle (P < 0.03). No adverse effect was observed. CONCLUSION: Cystathionine supplementation being able to increase moderately glutathione in healthy old rats could be considered as a candidate for nutritional supports aiming to revert the stronger glutathione depletions occurring in unhealthy elderly. PMID- 26514974 TI - Two water-bridged cobalt(II) chains with isomeric naphthoate spacers: from metamagnetic to single-chain magnetic behaviour. AB - The crystal structures and magnetic behaviours of two water-bridged one dimensional (1D) cobalt(II) chains with different isomeric naphthoate (na(-)) terminals, [Co(H2O)3(2-na)2]n (1) and {[Co(H2O)3(1-na)2].2H2O}n (2), were reported to investigate the effect of interchain distance on their magnetic properties. Complex 1 with trans-2-na(-) blocks and dense interchain separation exhibits a metamagnetic transition from antiferromagnetic ordering to a saturated paramagnetic phase. By contrast, complex 2 possessing cis-arranged 1-na(-) spacers and good interchain isolation shows unusual single-chain magnetic behavior under a zero dc field. Thus, completely different interchain packing by isomeric naphthoate ligands governs the ratio of intra- to inter-chain magnetic interactions and further results in different magnetic phenomena, which provide significant magnetostructural information on 1D magnetic systems. PMID- 26514973 TI - Serum concentration of 25-hydroxyvitamin D in autism spectrum disorder: a systematic review and meta-analysis. AB - Vitamin D may play an important role in the etiology of Autism Spectrum Disorders (ASD). Vitamin D is regarded as a neuroactive steroid affecting brain development and function. It plays an essential role in myelination, which is important for connectivity in the brain. Studies have shown that decreased vitamin D levels in patients, decreased maternal vitamin D levels during pregnancy, and decreased exposure to solar UVB might increase the risk for ASD. In addition, autism symptoms and global functioning may improve after vitamin D supplementation. Here, we sought to aggregate information from previous publications on vitamin D levels and ASD, in order to achieve a higher statistical power and thereby to determine the validity of vitamin D deficiency as a risk factor for ASD. For this meta-analysis, 11 studies met the inclusion and exclusion criteria, accounting for a total of 870 ASD patients and 782 healthy controls. Levels of serum 25(OH) D in participants with ASD were significantly lower than controls, suggesting that lower vitamin D level might be a risk factor for ASD. PMID- 26514975 TI - Complete Bladder Duplication by a Transversal Septum With Pelvic Ectopic Kidney: A Case Report. AB - Bladder duplication is an unusual and congenital abnormality that is usually associated with other abnormalities. We reported the first case in a 16-year-old child who has complete bladder duplication by a tranversal septum. No duplication of the urethra was noted. The pelvic ectopic right kidney was associated with this duplication. The treatment was a right nephroureterectomy with upper bladder bag resection. PMID- 26514976 TI - 11 Years Later-Isolated Testicular Relapse of ALL After Stem Cell Transplantation Treated With Surgery Only: A Case Report and Review of the Literature. AB - Despite advances in therapy for childhood acute lymphoblastic leukemia (ALL), relapses continue to occur and are associated with significant morbidity and mortality. Individuals who relapse after stem cell transplantation (SCT) have an especially poor prognosis and typically require intensive systemic therapy to provide any chance of cure. The majority of relapses occur within 2 years following SCT; relapses later than 4 years post SCT are rare. Here we describe an isolated testicular relapse of ALL 11 years after SCT, treated with local control measures only, and review the literature for other cases of very late ALL relapse following SCT. PMID- 26514977 TI - Comparison of Postoperative Complications and Mortality Between Laparoscopic and Percutaneous Local Tumor Ablation for T1a Renal Cell Carcinoma: A Population based Study. AB - OBJECTIVE: To evaluate potential differences in local tumor ablation (LTA) perioperative outcomes between the percutaneous LTA (pLTA) and the laparoscopic LTA (lapLTA) approaches. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare, we identified all patients diagnosed with T1a renal cell carcinoma (RCC) who underwent either pLTA or lapLTA between 2000 and 2009. Overall complications at 30 days and mortality at 90 days were examined for both groups. A multivariable logistic regression model was fitted to evaluate the effect of the approach on perioperative complications. A second model was fitted to test for associations between patient or tumor characteristics and type of LTA approach. RESULTS: Overall, 516 patients diagnosed with T1a RCC were identified. Of those, 289 (56%) were treated with pLTA and 227 (44%) were treated with lapLTA. LapLTA-treated patients were younger (median 76 vs 78, P < .001) and healthier (median Charlson comorbidity index 2.1 vs 2.7, P = .03) than their counterpart. After pLTA and lapLTA, overall complication rates were 21% and 25%, respectively (P = .3). Similarly, 90-day mortality rates did not differ between the two groups (P = 1). After adjusting for patient and tumor characteristics, LTA approach was not associated with perioperative complications (odds ratio: 1.38, P = .1). However, older and sicker patients were less likely to be treated with lapLTA (both <= 0.04). CONCLUSION: No differences in 30-day overall complications or 90-day mortality rates were detected between lapLTA and pLTA for T1a RCC. pLTA was more frequently used in older and sicker individuals. Further prospective studies comparing both procedures should be undertaken. PMID- 26514978 TI - Change in autoantibody and cytokine responses during the evolution of neuromyelitis optica in patients with systemic lupus erythematosus: A preliminary study. AB - BACKGROUND: Neuromyelitis optica (NMO)-systemic lupus erythematosus (SLE) association is a rare condition characterized by multiple autoantibodies. OBJECTIVE: To examine if, during the evolution of NMO, anti-AQP4 responses are part of polyclonal B cell activation, and if T cell responses contribute. METHODS: In 19 samples of six patients who developed NMO during SLE, we examined the correlation of AQP4-IgG1 and IgM with (i) anti-MOG IgG and IgM, (ii) anti nuclear, anti-nucleosome and anti-dsDNA IgG antibodies, (iii) cytokines and chemokines in the serum and (iv) longitudinal relation to NMO relapses/remission. RESULTS: AQP4-IgG1 was present 1-2-5 years before the first NMO relapse. During relapse, AQP4-IgG1, ANA, anti-dsDNA and anti-nucleosome antibodies were elevated. Anti-MOG IgG/IgM and AQP4-IgM antibodies were not detected. AQP4-IgG1 antibodies correlated with concentration of anti-nucleosome, IFN-gamma,interferon-gamma induced CCL10/IP-10 and CCL17/TARC (p<0.05, respectively). CCL17/TARC correlated with levels of anti-nucleosome and anti-dsDNA (p<0.05, respectively). Compared to healthy subjects, concentration of IFN-gamma and CCL17/TARC was higher in NMO/SLE (p<0.05). CONCLUSIONS: AQP4-IgG1 antibodies are present in the sera years before the first NMO attack in patients with SLE; elevation of anti-AQP4 is part of a polyclonal B cell response during NMO relapses; in spite of multiple autoantibodies in the serum, MOG antibodies were not present; Th1 responses accompany autoantibody responses in NMO/SLE. PMID- 26514979 TI - Alemtuzumab for multiple sclerosis: Long term follow-up in a multi-centre cohort. AB - BACKGROUND: Alemtuzumab has recently been approved for treatment of relapsing MS, but concerns remain about its use since long-term studies of adverse events remain limited. Furthermore, a clear understanding of its application and durability of effect in clinical practice has yet to evolve. OBJECTIVES: To investigate long-term efficacy and safety outcomes in a multicentre cohort of patients treated with alemtuzumab. METHODS: Patients treated from 2000 and followed-up at three regional centres were identified. Baseline and prospective data were obtained and validated by clinical record review. RESULTS: One hundred patients were identified with a mean follow-up of 6.1 years (range 1-13). Forty patients were retreated with at least one further treatment cycle. Annualized relapse rates fell from 2.1 to 0.2 (p<0.0001) post-treatment and were sustained for up to eight years of follow-up. Mean change in EDSS score was +0.14. Forty seven patients developed secondary autoimmunity. CONCLUSION: Observed reduction in relapse rates reflected those reported in clinical trials, but we were unable to corroborate previous observations of disability reversal. 40% of patients required additional treatment cycles. Autoimmune adverse events were common, occurring at a higher rate than previously reported, but were largely predictable, and could be managed effectively within a rigorous monitoring regime. PMID- 26514980 TI - Erratum to: Managing the challenging pediatric airway: Continuing Professional Development. AB - Erratum to: Can J Anesth/J Can Anesth (2015) 62:1000-1016 DOI 10.1007/s12630-015 0423-y. In the article entitled: "Managing the challenging pediatric airway: Continuing Professional Development" published in the September 2015 issue, Can J Anesth 2015; DOI: 10.1007/s12630-015-0423-y, the Electronic Supplementary Material (ESM) was incorrect. The ESM should be as follows: [see text]. The publisher apologizes most sincerely for this technical error. PMID- 26514981 TI - Fetal descending aortic flow and heart rate monitoring with transesophageal echocardiography during maternal cardiac surgery. PMID- 26514982 TI - Definitive airway management of patients presenting with a pre-hospital inserted King LT(S)-D laryngeal tube airway: a historical cohort study. AB - PURPOSE: The King LT(S)-D laryngeal tube (King LT) has gained popularity as a bridge airway for pre-hospital airway management. In this study, we retrospectively reviewed the use of the King LT and its associated airway outcomes at a single Level 1 trauma centre. METHODS: The data on all adult patients presenting to the Mayo Clinic in Rochester, Minnesota with a King LT in situ from July 1, 2007 to October 10, 2012 were retrospectively evaluated. Data collected and descriptively analyzed included patient demographics, comorbidities, etiology of respiratory failure, airway complications, subsequent definitive airway management technique, duration of mechanical ventilation, and status at discharge. RESULTS: Forty-eight adult patients met inclusion criteria. The most common etiology for respiratory failure requiring an artificial airway was cardiac arrest [28 (58%) patients] or trauma [9 (19%) patients]. Four of the nine trauma patients had facial trauma. Surgical tracheostomy was the definitive airway management technique in 14 (29%) patients. An airway exchange catheter, direct laryngoscopy, and video laryngoscopy were used in 11 (23%), ten (21%), and ten (21%) cases, respectively. Seven (78%) of the trauma patients underwent surgical tracheostomy compared with seven (18%) of the medical patients. Adverse events associated with King LT use occurred in 13 (27%) patients, with upper airway edema (i.e., tongue engorgement and glottic edema) being most common (19%). CONCLUSION: In this study of patients presenting to a hospital with a King LT, the majority of airway exchanges required an advanced airway management technique beyond direct laryngoscopy. Upper airway edema was the most common adverse observation associated with King LT use. PMID- 26514983 TI - A systematic review of transthoracic and transesophageal echocardiography in non cardiac surgery: implications for point-of-care ultrasound education in the operating room. AB - PURPOSE: Point-of-care ultrasound (POCU) is an evolving field in anesthesia. Therefore a systematic review of common diagnoses made by POCU during non-cardiac surgery was conducted. The information obtained from the review may be used to develop POCU curricula for the perioperative setting during non-cardiac surgery. SOURCE: A systematic review was conducted for perioperative use of transthoracic /transesophageal echocardiography (TTE/TEE) in high-risk patients or in other patients experiencing periods of hemodynamic instability. The diagnoses included segmental wall motion abnormalities (SWMAs), low left ventricular ejection fraction (LVEF), hypovolemia, air embolism, cardiac/aortic thrombus, pulmonary embolus (PE), aortic valve disease, mitral valve disease, tricuspid valve disease, right ventricular (RV) failure, pericardial disease, and patent foramen ovale. PRINCIPAL FINDINGS: Three hundred twenty-one studies were found using our search terms, and thirteen studies were retained that met our inclusion criteria for review. The studies included 968 patients analyzed as either preoperative exams in high-risk patients (n = 568) or intraoperative exams during times of hemodynamic compromise/cardiac arrest (n = 400). The most common diagnoses in the preoperative exam group were low ejection fraction (25.4%), aortic valve disease (24.4%), mitral valve disease (20.0%), RV failure (6.6%), and hypovolemia (6.3%). In the intraoperative exam group, the most common diagnoses were hypovolemia (33.2%), low ejection fraction (20.5%), RV failure (13.1%), SWMAs (10.1%), and PE (5.8%). CONCLUSION: In this systematic review examining the use of TTE or TEE in non-cardiac surgery, the most frequent diagnoses were valvulopathy, low LVEF, hypovolemia, PE, SWMAs, and RV failure. This information should be used to inform evidence-based curricula for POCU in anesthesiology. PMID- 26514985 TI - A simple dried blood spot method for clinical pharmacological analyses of etoposide in cancer patients using liquid chromatography and fluorescence detection. AB - BACKGROUND: Therapeutic drug monitoring of etoposide is not part of the routine clinical practice, however, measuring etoposide plasma concentration may be useful to prevent chemotherapy related adverse drug reactions. This paper describes the development and validation of a dried blood spot (DBS) assay for the determination of etoposide in blood samples of lung cancer patients. METHODS: The whole blood spot was cut out of the DBS card followed by sonication assisted liquid drug extraction. Extraction solution was evaporated and re-dissolved. A high-performance-liquid-chromatography method with fluorimetric detection ( lambdaex=230nm; lambdaem=330nm) was used. RESULTS: Method met the validation criteria in terms of selectivity, linearity (0.5-20.0MUg/mL), accuracy (>=96.1%), precision (<=10.1%) and stability (long term 4weeks at room temperature and 40 degrees C). Haematocrit did not influence DBS etoposide concentration. Good correlation between measured plasma and DBS concentrations was observed. The equation considering only haematocrit value was used for conversion of DBS to plasma concentration. CONCLUSIONS: DBS sampling method showed comparable results to plasma samples. Therefore, it can be concluded that the developed and validated DBS method, which is more patient-friendly and requires less sample handling, is a reliable alternative to conventional plasma methods for measuring etoposide concentration in clinical pharmacological analyses. PMID- 26514984 TI - Evidence for microRNA-31 dependent Bim-Bax interaction preceding mitochondrial Bax translocation during radiation-induced apoptosis. AB - Downregulation of microRNA-31 has been linked with enhanced stress resistance, while its overexpression leads to cell death. In this study, we found mediatory role of microRNA-31 in gamma-radiation-induced apoptosis in a model insect cell line Sf9 carrying well-conserved apoptotic machinery. Mature microRNA-31 is perfectly conserved amongst insects; hence we used biotinylated probes designed from Bombyx mori sequence for its successful detection in Sf9 cells. Target identification using Bombyx mori 3'UTRs predicted miR-31's potential role in Lepidopteran apoptosis, which prompted us to investigate alterations in its expression during radiation-induced cell death. We found significant overexpression of Sf-miR-31 following lethal dose (1,000Gy-3,000Gy) irradiation. Its mediatory role was finally confirmed as antisense-microRNA-31 could successfully inhibit radiation-induced cytochrome-c release, caspase-3 activation and apoptosis. While Bax/Bcl-2 expression remained unchanged, lethal radiation doses induced Bim overexpression and direct Bim-Bax interaction (co immunoprecipitation) which is not yet unequivocally demonstrated during apoptosis. Quite important, these events were found to be dependent on radiation induced miR-31 overexpression, as antisense-miR-31 inhibited both the responses and resulted in significant inhibition of cell death. Pro-apoptotic role of miR 31 was further confirmed when miR-31 mimic induced apoptosis involving similar Bim/Bax alterations. Therefore, our study reveals an important mediatory role of miR-31 in radiation-induced cell death. PMID- 26514986 TI - Protective role of carnosic acid against liver injury. PMID- 26514988 TI - Correction to "charge transfer excitons at van der Waals interfaces". PMID- 26514987 TI - Conservative and compensatory evolution in oxidative phosphorylation complexes of angiosperms with highly divergent rates of mitochondrial genome evolution. AB - Interactions between nuclear and mitochondrial gene products are critical for eukaryotic cell function. Nuclear genes encoding mitochondrial-targeted proteins (N-mt genes) experience elevated rates of evolution, which has often been interpreted as evidence of nuclear compensation in response to elevated mitochondrial mutation rates. However, N-mt genes may be under relaxed functional constraints, which could also explain observed increases in their evolutionary rate. To disentangle these hypotheses, we examined patterns of sequence and structural evolution in nuclear- and mitochondrial-encoded oxidative phosphorylation proteins from species in the angiosperm genus Silene with vastly different mitochondrial mutation rates. We found correlated increases in N-mt gene evolution in species with fast-evolving mitochondrial DNA. Structural modeling revealed an overrepresentation of N-mt substitutions at positions that directly contact mutated residues in mitochondrial-encoded proteins, despite overall patterns of conservative structural evolution. These findings support the hypothesis that selection for compensatory changes in response to mitochondrial mutations contributes to the elevated rate of evolution in N-mt genes. We discuss these results in light of theories implicating mitochondrial mutation rates and mitonuclear coevolution as drivers of speciation and suggest comparative and experimental approaches that could take advantage of heterogeneity in rates of mtDNA evolution across eukaryotes to evaluate such theories. PMID- 26514989 TI - Sox4 enhances chondrogenic differentiation and proliferation of human synovium derived stem cell via activation of long noncoding RNA DANCR. AB - Mesenchymal stem cells (MSCs) have several features that make them an attractive option for potentiating cartilage repair. Synovium-derived (SMSCs) have been recently recognized as an excellent source. SRY-related HMG-box (Sox) family plays an important role in the proliferation and differentiation of SMSCs. However, the role of Sox4 in human SMSCs remains elusive. In the present study, we investigated the role of Sox4 in SMSCs through gain-of-function studies and found that Sox4 promoted cell proliferation and chondrogenesis. Furthermore, Sox4 could directly bind to the promoter of long noncoding RNA DANCR and increased its expression. Finally, knockdown of DANCR could reverse the stimulative effect of Sox4 on the proliferation and chondrogenesis of SMSCs. Taken together, our data highlights the pivotal role of Sox4 in the proliferation and differentiation of SMSCs. PMID- 26514990 TI - A novel loss-of-function mutation of GATA3 (p.R299Q) in a Japanese family with Hypoparathyroidism, Deafness, and Renal Dysplasia (HDR) syndrome. AB - BACKGROUND: Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder caused by mutations in the zinc finger transcription factor gene, GATA3. GATA3 has 2 zinc finger domains, which play an important role in the increase in target gene transcription activity. CASE PRESENTATION: A 50-year-old woman and her 27-year-old daughter were followed up because of hypoparathyroidism. They had bilateral sensorineural deafness. Abdominal computed tomography scanning revealed renal dysplasia in the mother, but no renal anomaly in the daughter. Direct sequencing of GATA3 gene revealed a novel heterozygous missense mutation at codon 299 (p.R299Q) in exon 4. This mutation is located at the junction between the 2 zinc fingers. The structure prediction showed that it caused a conformation change in this junction area, affecting the spatial position of the zinc fingers. Additionally, a more marked conformation change was observed in the N-terminal zinc finger region compared to that in the C-terminal region. Functional analysis of this mutant protein using an in vitro luciferase reporter assay system confirmed that the mutation abolished the enhancing effects of wild-type GATA3 on the promoter activity of the consensus GATA responsive element and that of human PTH gene. CONCLUSION: We identified a novel R299Q mutation in GATA3 in a Japanese family with HDR syndrome. We confirmed that R299Q is a loss-of-function mutation, due to the extensive conformational change in the zinc fingers of GATA3. PMID- 26514991 TI - Regulatory T cells: getting to the heart of the matter. PMID- 26514992 TI - The Effect of Schizandrol A-Induced DNA Methylation on SH-SY5YAB 1-40 Altered Neuronal Cell Line: A Potential Use in Alzheimer's Disease. AB - Disturbances in DNA methylation are postulated to result in various central nervous system diseases including Alzheimer's disease (AD). The SH-SY5Y neuronal cell line treated with Abeta1-40 (5 MUmol/L) protein is considered to be a model of AD. Hence the aim of this study was to examine the influence of Schizandrol A, a plant extract, on DNA methylation in SH-SY5Y cells exposed to Abeta1-40. Abeta1 40 were incubated with varying concentrations of Sehizandrol A to a final concentration of 1 (low), 3 (intermediate) or 9 MUg/ml (high). Exposure of SH SY5Y with Abeta1-40 reduced viability, and altered cellular morphology and mRNA expression of DNA methyltransferase (DNMT3A) and DNMT3B. Treatment with 1 or 3 MUg/ml Sehizandrol A resulted in normal cell morphology as well as elevated cell number, enhanced viability, and increased mRNA expression of DNMT3A and DNMT3B compared to saline. However, an increase in Sehizandrol A to 9 MUg/ml produced a fall in cell viability, as well as a decrease in mRNA DNMT3A and DNMT3B expression to control levels. Data demonstrated that Schizandrol A at 1 or 3 MUg/ml improved cell morphological appearance and viability of Abeta1-40 injured SH-SY5Y cells by an enhanced DNA methylation pathway. PMID- 26514994 TI - Nanopatterning of a covalent organic framework host-guest system. AB - We have used a boroxine-based COF as a template for C60-fullerene self-assembly on graphite. Local removal of the COF by STM based nanomanipulation creates nanocorrals that may host other species. PMID- 26514993 TI - Evolution of temporal and spectral dynamics of pathologic high-frequency oscillations (pHFOs) during epileptogenesis. AB - OBJECTIVE: In temporal lobe epilepsy (TLE), pathologic high frequency oscillations (pHFOs, 200-600 Hz) are present in the hippocampus, especially the dentate gyrus (DG). The pHFOs emerge during a latent period prior to the onset of spontaneous generalized seizures. We used a unilateral suprahippocampal injection of kainic acid (KA) mouse model of TLE to characterize the properties of hippocampal pHFOs during epileptogenesis. METHODS: In awake head-fixed mice, 4-14 days after KA-induced status epilepticus (SE), we recorded local field potentials (LFPs) with 64-channel silicon probes spanning from CA1 alveus to the DG hilus, or with glass pipettes in the DC mode in the CA1 str radiatum. RESULTS: The pHFOs, are observed simultaneously in the CA1 and the DG, or in the DG alone, as early as 4 days post-SE. The pHFOs ride on top of DC deflections, occur during motionless periods, persist through the onset of TLE, and are generated in bursts. Burst parameters remain remarkably constant during epileptogenesis, with a random number of pHFOs generated per burst. In contrast, pHFO duration and spectral dynamics evolve from short events at 4 days post-SE to prolonged discharges with complex spectral characteristics by 14 days post-SE. Simultaneous dural EEG recordings were exceedingly unreliable for detecting hippocampal pHFOs; therefore, such recordings may deceptively indicate a "silent" period even when massive hippocampal activity is present. SIGNIFICANCE: Our results demonstrate that hippocampal pHFOs exhibit a dynamic evolution during the epileptogenic period following SE, consistent with their role in transitioning to the chronic stage of TLE. PMID- 26514995 TI - GM-CSF: a possible prognostic serum biomarker of vitiligo patients' considered for transplantation treatment with cultured autologous melanocytes: a pilot study. PMID- 26514997 TI - Unexpected rapid weight gain in a patient with HIV and anorexia. PMID- 26514996 TI - Molecular basis for the antagonistic activity of an anti-CXCR4 antibody. AB - Antagonistic antibodies targeting the G-protein C-X-C chemokine receptor 4 (CXCR4) hold promising therapeutic potential in various diseases. We report for the first time the detailed mechanism of action at a molecular level of a potent anti-CXCR4 antagonistic antibody (MEDI3185). We characterized the MEDI3185 paratope using alanine scanning on all 6 complementary-determining regions (CDRs). We also mapped its epitope using CXCR4 mutagenesis to assess the relative importance of the CXCR4 N-terminal peptide, extracellular loops (ECL) and ligand binding pocket. We show that the interaction between MEDI3185 and CXCR4 is mediated mostly by CDR3H in MEDI3185 and ECL2 in CXCR4. The MEDI3185 epitope comprises the entire ECL2 sequence, lacks any so-called 'hot-spot' and is remarkably resistant to mutations. The structure of MEDI3185 variable domains was modeled, and suggested a beta-strand/beta-strand interaction between MEDI3185 CDR3H and CXCR4 ECL2, resulting in direct steric hindrance with CXCR4 ligand SDF 1. These findings may have important implications for designing antibody therapies against CXCR4. PMID- 26514998 TI - Cost-effectiveness of treating chronic hepatitis C virus with direct-acting antivirals in people who inject drugs in Australia. AB - BACKGROUND AND AIM: Reducing the burden of hepatitis C virus (HCV) related liver disease will require treating people who inject drugs (PWID), the group at most risk of infection and transmission. We determine the cost-effectiveness of treating PWID with interferon-free direct-acting antiviral therapy in Australia. METHODS: Using a deterministic model of HCV treatment and liver disease progression, including a fixed rate of re-infection, the expected healthcare costs and quality-adjusted life years (QALYs) of a cohort of newly HCV-infected PWID were calculated for: no treatment; treatment after initial infection ("early treatment"); and treatment prior to developing compensated cirrhosis ("late treatment"). Incremental cost-effectiveness ratios (ICERs) were used to compare scenarios. RESULTS: Late-treatment was cost-effective compared to no treatment, with a discounted average gain of 2.98 (95%confidence interval 2.88-5.22) QALYs per person for an additional cost of $15,132 ($11,246-18,922), giving an ICER of $5078 ($2847-5295) per QALY gained. Compared to late-treatment, early-treatment gained a further discounted average of 2.27 (0.58-4.80) QALYs per person for $38,794 ($34,789-41,367), giving an ICER of $17,090 ($2847-63,282), which was cost-effective in approximately 90% of Monte-Carlo uncertainty simulations. For every 100 newly HCV-infected PWID, there were an estimated 40 (39-56) eventual liver-related deaths without treatment, compared to 7 (6-11) and 8 (7-13) with early-treatment and late-treatment available respectively. CONCLUSIONS: Treating HCV-infected PWID with new therapies is cost-effective and could prevent a significant number of liver-related deaths. Although late-treatment was the most cost-effective option, the cost per QALY gained for early-treatment compared to late-treatment is likely to be below unofficial Australian willingness to pay thresholds. PMID- 26514999 TI - Design of a dual aptamer-based recognition strategy for human matrix metalloproteinase 9 protein by piezoelectric biosensors. AB - MMP-9, human matrix metalloproteinase 9, belongs to the family of zinc-dependent peptide-bond hydrolases and is involved in the degradation of the extracellular matrix (ECM). In clinics, it is well known that elevated MMP-9 serum levels are associated with cardiovascular dysfunctions, several aspects of the physiology and pathology of the central nervous system, neuropsychiatric disorders and degenerative diseases related to brain tumors, and excitotoxic/neuroinflammatory processes. Due to the large interest of diagnostics in this protein, efforts to set up sensitive methods to detect MMP-9 for early diagnosis of a number of metabolic alterations are rapidly increasing. In this panorama, biosensors could play a key role; therefore we explored for the first time the development of an aptamer-based piezoelectric biosensor for a sensitive, label free, and real time detection of MMP-9. The detecting strategy involved two different aptamers in a sandwich-like approach able to detect down to 100 pg mL(-1) (1.2 pM) of MMP-9 as detection limit in standard solution. As proof of principle, commercial serum was investigated in terms of possible interferents, their identification and role in MMP-9 detection. The estimated detection limit for MMP-9 is about 560 pg mL(-1) (6.8 pM) in untreated serum. PMID- 26515000 TI - A regenerated electrochemical biosensor for label-free detection of glucose and urea based on conformational switch of i-motif oligonucleotide probe. AB - Improving the reproducibility of electrochemical signal remains a great challenge over the past decades. In this work, i-motif oligonucleotide probe-based electrochemical DNA (E-DNA) sensor is introduced for the first time as a regenerated sensing platform, which enhances the reproducibility of electrochemical signal, for label-free detection of glucose and urea. The addition of glucose or urea is able to activate glucose oxidase-catalyzed or urease-catalyzed reaction, inducing or destroying the formation of i-motif oligonucleotide probe. The conformational switch of oligonucleotide probe can be recorded by electrochemical impedance spectroscopy. Thus, the difference of electron transfer resistance is utilized for the quantitative determination of glucose and urea. We further demonstrate that the E-DNA sensor exhibits high selectivity, excellent stability, and remarkable regenerated ability. The human serum analysis indicates that this simple and regenerated strategy holds promising potential in future biosensing applications. PMID- 26515001 TI - Development of a versatile rotating ring-disc electrode for in situ pH measurements. AB - There are some electrocatalytic reactions in which the key parameter explaining their behavior is a local change in pH. Therefore, it is of utter importance to develop an electrode that could quantify this parameter in situ, but also be customizable to be used in different systems. The purpose of this work is to build a versatile rotating ring/disc electrode (RRDE) with IrOx deposited on a glass tube as a ring and any kind of material as disc. As the IrOx is sensitive to pH variation, the reactions promoted on the disc can trigger proportional pH shifts on the ring. In such assembly, the IrOx ring presents a fast response time even during the pH transients due to the small thickness of the ring (approximately 10 MUm), which enables the detection of interfacial pH changes. The ring electrode was tested toward the interfacial pH shift observed during the electrolytic reduction of water on the disc and also characterized by acid-base titration to determine the response time. As the main conclusions, fast response and durable RRDE were obtained, and this assembly could be used to revisit many electrocatalytic reactions in order to test the importance of local pH on the process. PMID- 26515002 TI - A method for measurement of free cadmium species in waters using diffusive gradients in thin films technique with an ion-imprinted sorbent. AB - A diffusive gradients in thin films (DGT) device for the analysis of free Cd(II) species, based on Cd(II) ion-imprinted sorbent (IIS) as the binding agents and commercial polyethersulfone membrane (PES) as diffusion layer, was developed (PES/IIS-DGT). DGT time-series experiments showed that the mass of free Cd(II) species accumulated by PES/IIS-DGT was linear vs. time (R(2) = 0.9953) and the concentration of free Cd(II) species by PES/IIS-DGT was in good agreement with the total dissolved concentrations of free Cd(II) species in simple synthetic solutions where free ionic species dominated. PES/IIS-DGT performance was independent in the range of pH 4.5-7.5 and ionic strength range from 1.0 * 10(-3) to 0.7 mol L(-1). The measurement of free Cd(II) species in synthetic solution containing different concentrations of ligands by PES/IIS-DGT showed an excellent agreement with the value measured by Cd(II) ion selective electrodes (Cd-ISE), indicating that PES/IIS-DGT method is more suitable than Cd-ISE for the measurement of low concentration of free Cd(II) species due to the enrichment of IIS for the analytes. PMID- 26515003 TI - The application of high-resolution mass spectrometry-based data-mining tools in tandem to metabolite profiling of a triple drug combination in humans. AB - Patients are usually exposed to multiple drugs, and metabolite profiling of each drug in complex biological matrices is a big challenge. This study presented a new application of an improved high resolution mass spectrometry (HRMS)-based data-mining tools in tandem to fast and comprehensive metabolite identification of combination drugs in human. The model drug combination was metronidazole pantoprazole-clarithromycin (MET-PAN-CLAR), which is widely used in clinic to treat ulcers caused by Helicobacter pylori. First, mass defect filter (MDF), as a targeted data processing tool, was able to recover all relevant metabolites of MET-PAN-CLAR in human plasma and urine from the full-scan MS dataset when appropriate MDF templates for each drug were defined. Second, the accurate mass based background subtraction (BS), as an untargeted data-mining tool, worked effectively except for several trace metabolites, which were buried in the remaining background signals. Third, an integrated strategy, i.e., untargeted BS followed by improved MDF, was effective for metabolite identification of MET-PAN CLAR. Most metabolites except for trace ones were found in the first step of BS processed datasets, and the results led to the setup of appropriate metabolite MDF template for the subsequent MDF data processing. Trace metabolites were further recovered by MDF, which used both common MDF templates and the novel metabolite-based MDF templates. As a result, a total of 44 metabolites or related components were found for MET-PAN-CLAR in human plasma and urine using the integrated strategy. New metabolic pathways such as N-glucuronidation of PAN and dehydrogenation of CLAR were found. This study demonstrated that the combination of accurate mass-based multiple data-mining techniques in tandem, i.e., untargeted background subtraction followed by targeted mass defect filtering, can be a valuable tool for rapid metabolite profiling of combination drugs in vivo. PMID- 26515004 TI - Enhancement of ionization efficiency of mass spectrometric analysis from non electrospray ionization friendly solvents with conventional and novel ionization techniques. AB - Electrospray ionization mass spectrometry (ESI-MS) has significantly impacted the analysis of complex biological and petroleum samples. However ESI-MS has limited ionization efficiency for samples in low dielectric and low polarity solvents. Addition of a make-up solvent through a T union or electrospray solvent through continuous flow extractive desorption electrospray ionization (CF-EDESI) enable ionization of analytes in non-ESI friendly solvents. A conventional make-up solvent addition setup was used and a CF-EDESI source was built for ionization of nitrogen-containing standards in hexane or hexane/isopropanol. Factors affecting the performance of both sources have been investigated and optimized. Both the make-up solvent addition and CF-EDESI improve the ionization efficiency for heteroatom compounds in non-ESI friendly solvents. Make-up solvent addition provides higher ionization efficiency than CF-EDESI. Neither the make-up solvent addition nor the CF-EDESI eliminates ionization suppression of nitrogen containing compounds caused by compounds of the same chemical class. PMID- 26515005 TI - Metabolism of human insulin after subcutaneous administration: A possible means to uncover insulin misuse. AB - The misuse of insulin for performance enhancement in sport or as toxic agent has frequently been reported in the past. In contrast to synthetic insulin analogues, the administration of recombinant human insulin is hardly recognized by mass spectrometry. The present study was designed to uncover the misuse of recombinant human insulin for doping control purposes as well as for forensic applications. It is hypothesized that an altered metabolite profile of circulating insulin prevails after subcutaneous administration due to exposure of insulin to epidermal proteases. In vitro experiments with skin tissue lysates (S9 fraction and microsomes), different biological fluids (urine, serum, plasma) and recombinant human insulin were performed and the deriving metabolites were characterized by liquid chromatography coupled to high resolution mass spectrometry (HRMS). Afterwards, authentic blood samples of patients suffering from diabetes mellitus and a control group of healthy humans were analysed. Therefore, a method using protein precipitation, ultrafiltration and antibody coated magnetic beads for purification with subsequent separation by nano-scale liquid chromatography coupled a Q Exactive mass spectrometer was applied. Several metabolites of insulin with C-terminally truncated sequences of the B-chain (and A-chain in minor extent) were identified within this study. Here, the DesB30 human insulin represents the major metabolite in all experiments. This metabolite is frequently found in urine samples due to degradation processes and, thus, disqualifies this matrix for the intended purposes. In contrast, blood samples do commonly not contain DesB30 insulin, which was corroborated by data obtained from the control group. In post-administration blood samples, minute but distinct amounts (approx. 50 pg mL(-1)) of DesB30 insulin were found and suggest the use of this analyte as potential marker for subcutaneous human insulin administration, supporting the attempts to uncover illicit recombinant human insulin administrations. PMID- 26515006 TI - Design and evaluation of a real-time activity probe for focal adhesion kinase. AB - Focal adhesion kinase (FAK) has been identified as a potential therapeutic target for the treatment of metastatic cancers. Herein we describe the design, synthesis and optimization of a direct activity sensor for FAK and its application to screening FAK inhibitors. We find that the position of the sensing moiety, a phosphorylation-sensitive sulfonamido-oxine fluorophore, can dramatically influence the performance of peptide sensors for FAK. Real-time fluorescence activity assays using an optimized sensor construct, termed FAKtide-S2, are highly reproducible (Z' = 0.91) and are capable of detecting as little as 1 nM recombinant FAK. Utilizing this robust assay format, we define conditions for the screening of FAK inhibitors and demonstrate the utility of this platform using a set of well-characterized small molecule kinase inhibitors. Additionally, we provide the selectivity profile of FAKtide-S2 among a panel of closely related enzymes, identifying conditions for selectively monitoring FAK activity in the presence of off-target enzymes. In the long term, the chemosensor platform described in this work can be used to identify novel FAK inhibitor scaffolds and potentially assess the efficacy of FAK inhibitors in disease models. PMID- 26515007 TI - Characterisation and deployment of an immobilised pH sensor spot towards surface ocean pH measurements. AB - The oceans are a major sink for anthropogenic atmospheric carbon dioxide, and the uptake causes changes to the marine carbonate system and has wide ranging effects on flora and fauna. It is crucial to develop analytical systems that allow us to follow the increase in oceanic pCO2 and corresponding reduction in pH. Miniaturised sensor systems using immobilised fluorescence indicator spots are attractive for this purpose because of their simple design and low power requirements. The technology is increasingly used for oceanic dissolved oxygen measurements. We present a detailed method on the use of immobilised fluorescence indicator spots to determine pH in ocean waters across the pH range 7.6-8.2. We characterised temperature (-0.046 pH/ degrees C from 5 to 25 degrees C) and salinity dependences (-0.01 pH/psu over 5-35), and performed a preliminary investigation into the influence of chlorophyll on the pH measurement. The apparent pKa of the sensor spots was 6.93 at 20 degrees C. A drift of 0.00014 R (ca. 0.0004 pH, at 25 degrees C, salinity 35) was observed over a 3 day period in a laboratory based drift experiment. We achieved a precision of 0.0074 pH units, and observed a drift of 0.06 pH units during a test deployment of 5 week duration in the Southern Ocean as an underway surface ocean sensor, which was corrected for using certified reference materials. The temperature and salinity dependences were accounted for with the algorithm, R=0.00034 0.17.pH+0.15.S(2)+0.0067.T-0.0084.S.1.075. This study provides a first step towards a pH optode system suitable for autonomous deployment. The use of a short duration low power illumination (LED current 0.2 mA, 5 MUs illumination time) improved the lifetime and precision of the spot. Further improvements to the pH indicator spot operations include regular application of certified reference materials for drift correction and cross-calibration against a spectrophotometric pH system. Desirable future developments should involve novel fluorescence spots with improved response time and apparent pKa values closer to the pH of surface ocean waters. PMID- 26515008 TI - Potassium polytitanate gas-sensor study by impedance spectroscopy. AB - Nanocrystalline potassium polytitanates K2O.nTiO2.mH2O represent a new type of semiconducting compounds which are characterized by a high specific surface that makes them promising for use in gas sensors. In this work, we have studied potassium polytitanate mesoporous nanoparticle agglomerates placed over a SiO2/Si substrate equipped with multiple coplanar electrodes to measure the electrical response to various organic vapors, 1000 ppm of concentration, mixed with air by impedance spectrometry in range of the 10(-2)-10(6) Hz. The recorded impedance data for each sensor segment are associated with RC components of an equivalent circuit which are applied to selectively recognize the test vapors exploiting a "multisensor array" approach. PMID- 26515009 TI - Thiourea-treated graphene aerogel as a highly selective gas sensor for sensing of trace level of ammonia. AB - As a result of this study, a new and simple method was proposed for the fabrication of an ultra sensitive, robust and reversible ammonia gas sensor. The sensing mechanism was based upon the change in electrical resistance of a graphene aerogel as a result of sensor exposing to ammonia. Three-dimensional graphene hydrogel was first synthesized via hydrothermal method in the absence or presence of various amounts of thiourea. The obtained material was heated to obtain aerogel and then it was used as ammonia gas sensor. The materials obtained were characterized using different techniques such as Fourier transform infra red spectroscopy (FT-IR), thermal gravimetric analysis (TGA), X-ray diffraction (XRD) and scanning electron microscopy (SEM). The thiourea-treated graphene aerogel was more porous (389 m(2) g(-1)) and thermally unstable and exhibited higher sensitivity, shorter response time and better selectivity toward ammonia gas, compared to the aerogel produced in the absence of thiourea. Thiourea amount, involved in the hydrogel synthesis step, was found to be highly effective factor in the sensing properties of finally obtained aerogel. The sensor response time to ammonia was short (100 s) and completely reversible (recovery time of about 500 s) in ambient temperature. The sensor response to ammonia was linear between 0.02 and 85 ppm and its detection limit was found to be 10 ppb (3S/N). PMID- 26515010 TI - Homogeneous single-label tyrosine kinase activity assay for high throughput screening. AB - Protein post-translational modifications (PTMs) are regulatory mechanisms carried out by different enzymes in a cell. Kinase catalyzed phosphorylation is one of the most important PTM affecting the protein activity and function. We have developed a single-label quenching resonance energy transfer (QRET) assay to monitor tyrosine phosphorylation in a homogeneous high throughput compatible format. Epidermal growth factor receptor (EGFR) induced phosphorylation was monitored using Eu(3+)-chelate labeled peptide and label-free phosphotyrosine specific antibody in presence of a soluble quencher molecule. In the QRET kinase assay, antibody binding to phosphorylated Eu(3+)-peptide protects the Eu(3+) chelate from luminescence quenching, monitoring high time-resolved luminescence (TRL) signals. In the presence of specific kinase inhibitor, antibody recognition and Eu(3+)-chelate protection is prevented, allowing an efficient luminescence quenching. The assay functionality was demonstrated with a panel of EGFR inhibitors (AG-1478, compound 56, erlotinib, PD174265, and staurosporine). The monitored IC50 values ranged from 0.08 to 155.3 nM and were comparable to those found in the literature. EGFR activity and inhibition assays were performed using low nanomolar enzyme and antibody concentration in a 384-well plate format, demonstrating its compatibility for high throughput screening (HTS). PMID- 26515011 TI - Rapidly responsive and highly selective fluorescent probe for sulfite detection in real samples and living cells. AB - Sulfites (HSO3(-) or SO3(-)) have very significant toxicity in the environment and in the system. However, developing specific identification of sulfite probes is still very important. In this paper, a highly selective colorimetric and fluorescent probe (HHC) was synthesized to detect HSO3(-) in real samples and living cells. Sensing performance and preponderance are listed as follows. First, probe HHC showed remarkable selectivity for HSO3(-) over varieties of other species, including cysteine, glutathione, S(2-), CN(-), and reactive oxygen species, mainly because of the introduction of the electron-poor C=C double bond for HSO3(-). Second, probe HHC has great molar absorptivity, allowing it to act as a visual detection of probe for HSO3(-). Third, the fluorescence intensities of HHC linearly correlate with the concentration of HSO3(-), with a detection limit of 6.8 nm. Finally, our proposed probe can be applied to the visually determination of trace HSO3(-) in real samples and living HeLa cells with high precision. We hope that our proposed probe will greatly benefit biological sciences when biological researchers survey the role of HSO3(-) in biological systems. PMID- 26515012 TI - A new specific polymeric material for mercury speciation: Application to environmental and food samples. AB - A new polymeric material (Patent: P201400535) highly specific for mercury is presented. Its great capability to pre-concentrate and selectively elute inorganic mercury and methylmercury are the main figures of merit. The polymer can be reused several times. To our knowledge, this is the only polymer proposed in the literature for direct inorganic mercury and methylmercury speciation without need of chromatography or quantification by difference. The polymer formation is based on the reaction of a vinyl derivative of 8-hydroxiquinoline as monomer, and 2-(Methacryloylamino) ethyl 2-Methyl Acrylate (NOBE) as co-monomer. Random radical polymerization by the precipitation method was carried out using Azobisisobutyronitrile (AIBN) as initiator. The polymer was characterized by SEM and FTIR. Adsorption binding isotherms were evaluated using Langmuir and Freundlich models, showing high adsorption capacity for both inorganic and organic mercury species. The polymer was employed to sequentially determine inorganic mercury and methylmercury, using a solid phase extraction (SPE) scheme. Cross reactivity of several ions, as well as matrix effects from a high saline matrix like seawater was irrelevant as the retained fractions mostly eluted during the washing step. The procedure was first validated by analyzing a certified reference material (BCR 464) and finally applied to commercial fish samples. The speciation proposed procedure is cheap, fast, and easy to use and minimizes reagents waste. PMID- 26515013 TI - Investigation of crimson-dyed fibres for a new approach on the characterization of cochineal and kermes dyes in historical textiles. AB - The colorant behaviour of cochineal and kermes insect dyes in 141 experimentally dyed and 28 artificially-aged samples of silk and wool was investigated using ultra-high performance liquid chromatography coupled to photodiode array detector (UHPLC-PDA), liquid chromatography electrospray ionisation mass spectrometry (LC ESI-MS) and image scanning electron microscopy - energy dispersive X-ray spectroscopy (SEM-EDX). Partial-least squares discriminant analysis (PLS-DA) was then used to model the acquired UHPLC-PDA data and assess the possibility of discriminating cochineal insect species, as well as their correspondent dyed and aged reference fibres. The resulting models helped to characterize a set of 117 red samples from 95 historical textiles, in which UHPLC-PDA analyses have reported the presence of cochineal and kermes insect dyes. Analytical investigation of the experimentally-dyed and artificially-aged fibres has demonstrated that the ratio of compounds in the insects dye composition can change, depending on the dyeing conditions applied and the type of fibres used. Similarities were observed when comparing the UHPLC-MS and SEM-EDX results from the dyed and aged references with the historical samples. This was verified with PLS-DA models of the chromatographic data, facilitating the classification of the cochineal species present in the historical samples. The majority of these samples were identified to contain American cochineal, which is in agreement with historical and dye identification literature that describe the impact of this dyestuff into European and Asian dyeing practices, after the Iberian Expansion in the 16th century. The analytical results emphasize the importance of using statistical data interpretation for the discrimination of cochineal dyes, besides qualitative and quantitative evaluation of chromatograms. Hence, the combination of UHPLC-PDA with a statistical classification method, such as PLS-DA, has been demonstrated to be an advisable approach in future investigations to assess closely related species of natural dyes in historical textile samples. This is particularly important when aiming to achieve more accurate interpretations about the history of works of art, or the application of natural dyes in old textile production. PMID- 26515014 TI - Erratum to: Expanded Quality Management Using Information Power (EQUIP): protocol for a quasi-experimental study to improve maternal and newborn health in Tanzania and Uganda. PMID- 26515015 TI - Aflibercept in exudative age related macular degeneration refractory to ranibizumab. AB - PURPOSE: The aim of this study is to determine the effectiveness, safety and cost of aflibercept in the treatment of wet age-related macular degeneration (ARMD) refractory to ranibizumab. METHODS: Retrospective observational study was conducted on patients diagnosed with wet ARMD, and previously treated with ranibizumab. Efficacy variables assessed were changes in visual acuity (BCVA) and anatomical improvements in the most affected eye. Factors associated with improvement of BCVA with aflibercept were also studied. Adverse events related to the aflibercept administration were recorded. Cost analysis data were collected from the hospital perspective, and only taking the direct medical costs into account. Cost-effectiveness analysis was calculated using the aflibercept treatment cost, and effectiveness calculated as BCVA gained. RESULTS: A total of 50 eyes corresponding to 46 patients were included. The median follow-up period was 4.6 months (range: 1.0-6.0). Improvement in visual acuity after the first 2 doses and at the end of the follow-up period was observed in 32.0 and 28.0% of treated eyes, respectively. None of the variables studied was associated with an improvement in the BCVA after treatment. No significant differences were found in the average monthly cost between treatments. CONCLUSIONS: Aflibercept is shown to be an effective treatment in a significant number of patients resistant to treatment with ranibizumab, presenting a cost similar to that generated during the final stages of treatment with ranibizumab. PMID- 26515016 TI - [Santa Rosa de Lima]. PMID- 26515017 TI - Endosomal integrin signals for survival. AB - The mechanisms underlying integrin-dependent signalling are a topic of continued study. Endocytosed integrins are now shown to drive assembly of signalling complexes on the cytoplasmic face of endocytic membranes to promote cancer cell survival and increase metastatic capacity following cell detachment. PMID- 26515018 TI - RNF138 joins the HR team. AB - Two studies show that the E3 ubiquitin ligase RNF138 is recruited to DNA double strand break sites, where it ubiquitylates key repair factors to promote DNA-end resection and homologous recombination. These findings add insights into the multilayered regulatory mechanisms underlying DNA double-strand break repair pathway choice in mammalian cells. PMID- 26515019 TI - Corrigendum: Complementary activities of TPX2 and chTOG constitute an efficient importin-regulated microtubule nucleation module. PMID- 26515020 TI - Advances in the molecular genetics of non-syndromic polydactyly. AB - Polydactyly is one of the most common inherited limb abnormalities, characterised by supernumerary fingers or toes. It results from disturbances in the normal programme of the anterior-posterior axis of the developing limb, with diverse aetiology and variable inter- and intra-familial clinical features. Polydactyly can occur as an isolated disorder (non-syndromic polydactyly) or as a part of an anomaly syndrome (syndromic polydactyly). On the basis of the anatomic location of the duplicated digits, non-syndromic polydactyly is divided into three kinds, including preaxial polydactyly, axial polydactyly and postaxial polydactyly. Non syndromic polydactyly frequently exhibits an autosomal dominant inheritance with variable penetrance. To date, in human, at least ten loci and four disease causing genes, including the GLI3 gene, the ZNF141 gene, the MIPOL1 gene and the PITX1 gene, have been identified. In this paper, we review clinical features of non-syndromic polydactyly and summarise the recent progress in the molecular genetics, including loci and genes that are responsible for the disorder, the signalling pathways that these genetic factors are involved in, as well as animal models of the disorder. These progresses will improve our understanding of the complex disorder and have implications on genetic counselling such as prenatal diagnosis. PMID- 26515021 TI - How the Size of Our Social Network Influences Our Semantic Skills. AB - People differ in the size of their social network, and thus in the properties of the linguistic input they receive. This article examines whether differences in social network size influence individuals' linguistic skills in their native language, focusing on global comprehension of evaluative language. Study 1 exploits the natural variation in social network size and shows that individuals with larger social networks are better at understanding the valence of restaurant reviews. Study 2 manipulated social network size by randomly assigning participants to learn novel evaluative words as used by two (small network) versus eight (large network) speakers. It replicated the finding from Study 1, showing that those exposed to a larger social network were better at comprehending the valence of product reviews containing the novel words that were written by novel speakers. Together, these studies show that the size of one's social network can influence success at language comprehension. They thus open the door to research on how individuals' lifestyle and the nature of their social interactions can influence linguistic skills. PMID- 26515022 TI - Adsorptive Separation of Acetylene from Light Hydrocarbons by Mesoporous Iron Trimesate MIL-100(Fe). AB - A reducible metal-organic framework (MOF), iron(III) trimesate, denoted as MIL 100(Fe), was investigated for the separation and purification of methane/ethane/ethylene/acetylene and an acetylene/CO2 mixtures by using sorption isotherms, breakthrough experiments, ideal adsorbed solution theory (IAST) calculations, and IR spectroscopic analysis. The MIL-100(Fe) showed high adsorption selectivity not only for acetylene and ethylene over methane and ethane, but also for acetylene over CO2 . The separation and purification of acetylene over ethylene was also possible for MIL-100(Fe) activated at 423 K. According to the data obtained from operando IR spectroscopy, the unsaturated Fe(III) sites and surface OH groups are mainly responsible for the successful separation of the acetylene/ethylene mixture, whereas the unsaturated Fe(II) sites have a detrimental effect on both separation and purification. The potential of MIL-100(Fe) for the separation of a mixture of C2 H2 /CO2 was also examined by using the IAST calculations and transient breakthrough simulations. Comparing the IAST selectivity calculations of C2 H2 /CO2 for four MOFs selected from the literature, the selectivity with MIL-100(Fe) was higher than those of CuBTC, ZJU-60a, and PCP-33, but lower than that of HOF-3. PMID- 26515023 TI - Quantum Chemical Studies on Stability and Chemical Activities in Calcium Ion Bound Calmodulin Loops. AB - Quantum chemical (QC) calculations for macromolecules require truncation of the molecule, highlighting the portion of interest due to heavy computation cost. As a result, an estimation of the effects of truncation is important to interpret the energy spectrum of such calculations. We perform density functional theory based QC calculations on calcium ion bound EF-hand loops of Calmodulin isolated from the crystal structure in an implicit solvent. We find that the terminal contributions of neutral capping are negligible across the entire ground-state energy spectrum. The coordination energy range and the nature of hybridization of the coordination state molecular orbitals remain qualitatively similar across these loops. While the HOMO and LUMO of loops in the N-terminal domain are dominated by the acidic aspartates, and the polar/hydrophobic residues, respectively, these levels of the C-terminal domain loops show strong localized electron density on the phenyl rings of the tyrosines. The Fukui index calculation identifies the hydroxyl oxygen in the phenyl ring of Y99 as a potent nucleophile. Our analysis indicates a general way of interpreting the electronic energy spectra to understand stability and functions of large biomolecules where the truncation of the molecule and, hence, the terminal capping effects are inevitable. PMID- 26515024 TI - Optimizing Multiple Analyte Injections in Surface Plasmon Resonance Biosensors with Analytes having Different Refractive Index Increments. AB - Surface plasmon resonance-based biosensors have been successfully applied to the study of the interactions between macromolecules and small molecular weight compounds. In an effort to increase the throughput of these SPR-based experiments, we have already proposed to inject multiple compounds simultaneously over the same surface. When specifically applied to small molecular weight compounds, such a strategy would however require prior knowledge of the refractive index increment of each compound in order to correctly interpret the recorded signal. An additional experiment is typically required to obtain this information. In this manuscript, we show that through the introduction of an additional global parameter corresponding to the ratio of the saturating signals associated with each molecule, the kinetic parameters could be identified with similar confidence intervals without any other experimentation. PMID- 26515025 TI - Nurse moral distress: A survey identifying predictors and potential interventions. AB - BACKGROUND: Ethical dilemmas and conflicts are inherent in today's health care organizations and may lead to moral distress, which is often associated with physical and psychological symptoms. Although the existence of moral distress has been observed by scholars for decades, most of the research has been descriptive and has examined what types of health care conflicts lead to distress. OBJECTIVE: This study tested a comprehensive model, underpinned by Social Cognitive Theory, that examined work environment and intrapersonal variables that may influence moral distress. DESIGN/SETTING/PARTICIPANTS: We surveyed nursing staff employed in a U.S. acute care hospital (response rate=45%; n=290). RESULTS: More than half of the respondents reported they experience ethical dilemmas and conflicts from several times a month to daily, and nearly half reported they experience moral distress at least several times a month. Structural equation modeling analysis simultaneously examined the effects of five independent variables on moral distress and moral voice: (a) frequency of ethical dilemmas and conflicts; (b) moral efficacy; (c) ethics communication; (d) ethical environment; and (e) organizational ethics support. Results revealed significant independent effects of the frequency of ethics issues and organizational ethics support on moral distress. Bootstrapping analysis indicated that voice fully mediated the relationship between moral efficacy and moral distress, and partially mediated the relationship between organizational ethics support and distress. Supplemental analysis revealed that organizational ethics support moderated the moral efficacy voice-moral distress relationship such that when organizational support was low, moral efficacy was negatively related to moral distress via voice. CONCLUSIONS: Although it may be impossible to eliminate all ethical dilemmas and conflicts, leaders and organizations may wish to help improve nurses' moral efficacy, which appears to give rise to voice, and reduced moral distress. Increasing organizational ethics support may be a key approach. PMID- 26515026 TI - Mostly Heterosexual and Lesbian/Gay Young Adults: Differences in Mental Health and Substance Use and the Role of Minority Stress. AB - Individuals mostly attracted to other-sex but also to same-sex partners are a distinct and common sexual orientation group with possibly increased levels of health problems. The current study examined whether mostly heterosexual individuals differed in mental health and substance use from lesbian/gay individuals and whether sexual minority risk and protective factors offer an explanation in a sample of 528 Dutch young adults (16 to 25 years old, M = 21.2 years). Mostly heterosexual participants reported higher levels of psychological distress, suicidality, drug use, and smoking than lesbian/gay participants and equal levels of binge drinking. They also reported higher levels of internalized negativity to same-sex attractions, less openness to family members and others, less community involvement, and lower numbers of lesbian/gay/bisexual friends. However, bootstrapped mediation analysis showed that the differences in minority stress risk and protective factors did not mediate most of the differences in mental health and substance use with one exception: higher levels of psychological distress were mediated by the higher levels of internalized negativity to same-sex attractions. The limited explanatory power of the minority stress factors combined with the elevated level of problems of mostly heterosexual individuals call for future studies examining other risk and protective factors. PMID- 26515027 TI - Re-evaluation of the bond length-bond strength rule: The stronger bond is not always the shorter bond. AB - A set of 42 molecules with N-F, O-F, N-Cl, P-F, and As-F bonds has been investigated in the search for potential bond anomalies, which lead to reverse bond length-bond strength (BLBS) relationships. The intrinsic strength of each bond investigated has been determined by the local stretching force constant obtained at the CCSD(T)/aug-cc-pVTZ level of theory. N-F or O-F bond anomalies were found for fluoro amine radicals, fluoro amines, and fluoro oxides, respectively. A rationale for the deviation from the normal Badger-type inverse BLBS relation is given and it is shown that electron withdrawal accompanied by strong orbital contraction and bond shortening is one of the prerequisites for a bond anomaly. In the case of short electron-rich bonds such as N-F or O-F, anomeric delocalization of lone pair electrons in connection with lone pair repulsion are decisive whether a bond anomaly can be observed. This is quantitatively assessed with the help of the CCSD(T) local stretching force constants, CCSD(T) charge distributions, and G4 bond dissociation energies. Bond anomalies are not found for fluoro phosphines and fluoro arsines because the bond weakening effects are no longer decisive. PMID- 26515028 TI - Three measures of physical rehabilitation effectiveness in elderly patients: a prospective, longitudinal, comparative analysis. AB - BACKGROUND: Rehabilitation success is measured by instruments that assess performance of activities of daily living. Guidelines on the use and choice of these instruments are lacking. The present study aimed to analyse prognostic indicators of physical rehabilitation effectiveness in elderly patients according to three rehabilitation impact indices. METHODS: Prospective, longitudinal study in a post-acute care unit. The study included rehabilitation-eligible deconditioned elderly in-patients prospectively admitted to post-acute care (n = 685, aged 83.2 +/- 8.3 years, mean length of stay 15 +/- 9.2 days). DATA COLLECTION: Premorbid health status variables (PHSV): age, sex, comorbidity (Charlson index), medical history (heart failure, pulmonary disease, cerebrovascular disease, dementia), previous living situation and pre-admission functional status (premorbid Lawton and Barthel indices). Admission health status variables (AHSV): main diagnoses, referral source, physical (Barthel-adm) and cognitive function (Pfeiffer test), undernutrition and dysphagia. OUTCOME MEASURES: Absolute functional gain (AFG, admission-to-discharge Barthel change), relative functional gain (RFG, achieved percentage of potential gain) and rehabilitation efficiency index (REI, AFG over length of stay). Univariate analysis considered these parameters, along with PHSV and AHSV. Multivariate logistic regression analysis was performed for AFG >=20, RFG >=35 % and REI >= 0.50. RESULTS: Greater AFG was associated with 14 variables, 8 PHSV (57.1 %) and 6 AHSV (42.8 %); greater RFG with 9 variables, 3 PHSV (33.3 %) and 6 AHSV (66.6 %); and REI with 9 variables, 4 PHSV (44.4 %) and 5 AHSV (55.5 %). Mean AFG value was 34.5 +/- 15.8 in patients who achieved complete recovery (RFG 100 %, n = 189, 27.5 %) and 35.3 +/- 15.0 (p = 0.593) in the remaining patients (n = 311, 45.4 %). In multivariate analysis, only Barthel-adm was related to all three rehabilitation impact indices. CONCLUSIONS: Both premorbid and acute-process variables have a greater impact on AFG and REI, compared to RFG. Although AFG gives information about the degree of reduction in dependence, it does not provide clinical information about post-rehabilitation functional status (mean AFG values did not differ between patients with and without complete recovery). A future implication for evaluating rehabilitation effectiveness in elderly patients is to recommend RFG corrected by premorbid Barthel score, which is less affected by previous health conditions, as the optimum method to assess the degree to which maximum potential improvement was achieved. PMID- 26515029 TI - K14 + compound niches are present on the mouse cornea early after birth and expand after debridement wounds. AB - BACKGROUND: We previously identified compound niches (CNs) at the limbal:corneal border of the mouse cornea that contain corneal epithelial progenitor cells, express Keratin 8 (K8), and goblet cell mucin Muc5AC. During re-epithelialization after 2.5 mm epithelial debridement wounds, CNs migrate onto the cornea and expand in number mimicking conjunctivalization. When CNs form during development and whether they express corneal epithelial progenitor cell enriched K14 was not known. RESULTS: To provide insight into corneal epithelial homeostasis, we quantify changes in expression of simple (K8, K18, K19) and stratified squamous epithelial keratins (K5, K12, K14, and K15) during postnatal development and in response to 2.5 mm wounds using quantitative polymerase chain reaction (Q-PCR), confocal imaging and immunoblots. K14 + CNs are present 7 days after birth. By 21 days, when the eyelids are open, K8, K19, and Muc5AC are also expressed in CNs. By 28 days after wounding, the corneal epithelium shows enhanced mRNA and protein expression for K14 and retains mRNA and protein for corneal epithelial specific K12. CONCLUSIONS: The keratin phenotype observed in corneal epithelial cells before eyelid opening is similar to that seen during wound healing. Data show K14 + corneal epithelial progenitor cells expand in number after 2.5 mm wounds. PMID- 26515030 TI - A working model for the type III secretion mechanism in Chlamydia. AB - It has been appreciated for almost 20 years that members of the Chlamydiales possess a virulence-associated type III secretion mechanism. Given the obligate intracellular nature of these bacteria, defining exactly how type III secretion functions to promote pathogenesis has been challenging. We present a working model herein that is based on current evidence. PMID- 26515031 TI - Age and sex or gender (sex/gender) and HIV vaccine preparedness. AB - An examination of age and sex or gender (sex/gender) in HIV vaccine preparedness studies can contribute to an understanding of these demographic variables in preparation for actual HIV vaccine trials. In this descriptive review, age and sex or gender (sex/gender) were examined in relation to willingness to participate (WTP) and retention in an HIV vaccine trial. Twenty-five articles were retrieved from the Organization for Economic Co-operation and Development (OECD) countries and 28 articles were retrieved from the non-OECD countries. In US studies that involved mainly white MSM, older men were more likely to be WTP in a hypothetical HIV vaccine trial and more likely to be retained than younger men. In most OECD studies, sex/gender was not associated with WTP in a hypothetical HIV vaccine trial, while females were more likely to be retained in most studies. Largely, age was not associated with WTP in the non-OECD countries, but the results on sex/gender were more variable. The relationship between adolescent or adult WTP in hypothetical HIV vaccine trials in South Africa did not appear to be modified by high school student status. In addition, more studies in discordant couples in the context of HIV vaccine preparedness could be conducted to examine gender roles and inequalities in preparation for HIV vaccine trials. PMID- 26515033 TI - Plant Species Rather Than Climate Greatly Alters the Temporal Pattern of Litter Chemical Composition During Long-Term Decomposition. AB - A feedback between decomposition and litter chemical composition occurs with decomposition altering composition that in turn influences the decomposition rate. Elucidating the temporal pattern of chemical composition is vital to understand this feedback, but the effects of plant species and climate on chemical changes remain poorly understood, especially over multiple years. In a 10-year decomposition experiment with litter of four species (Acer saccharum, Drypetes glauca, Pinus resinosa, and Thuja plicata) from four sites that range from the arctic to tropics, we determined the abundance of 11 litter chemical constituents that were grouped into waxes, carbohydrates, lignin/tannins, and proteins/peptides using advanced (13)C solid-state NMR techniques. Decomposition generally led to an enrichment of waxes and a depletion of carbohydrates, whereas the changes of other chemical constituents were inconsistent. Inconsistent convergence in chemical compositions during decomposition was observed among different litter species across a range of site conditions, whereas one litter species converged under different climate conditions. Our data clearly demonstrate that plant species rather than climate greatly alters the temporal pattern of litter chemical composition, suggesting the decomposition-chemistry feedback varies among different plant species. PMID- 26515034 TI - Global arginine bioavailability, a marker of nitric oxide synthetic capacity, is decreased in PTSD and correlated with symptom severity and markers of inflammation. AB - INTRODUCTION: Psychiatric, physical and biological aspects of posttraumatic stress disorder (PTSD) may be associated with dysfunctions in several cellular processes including nitric oxide (NO) production. NO is synthesized from arginine in a reaction carried out by NO synthase (NOS) enzymes. The recently introduced "global arginine bioavailability ratio" (GABR; ratio of arginine to [ornithine+citrulline]) has been proposed as a reliable approximation of NO synthetic capacity in vivo. The objectives of the present study were to test the hypotheses that (i) subjects with combat-related PTSD have lower GABR scores than combat controls, (ii) GABR score is inversely associated with the severity of psychopathological measures, (iii) GABR score is inversely associated with markers of inflammation. METHODS: Metabolic profiling for plasma samples (i.e. arginine, citrulline and ornithine) and inflammation markers (interleukin [IL]-6, IL-1beta, tumor necrosis factor [TNF]-alpha, interferon [IFN]-gamma and C reactive protein [CRP]) were assessed in 56 combat-exposed males with PTSD and 65 combat-exposed males without PTSD. We assessed severity of PTSD (Clinician Administered PTSD Scale [CAPS]) and depression (Beck Depression Inventory-II [BDI II]) as well as history of early life trauma (Early Trauma Inventory [ETI]) and affectivity (Positive and Negative Affect Schedule [PANAS]). RESULTS: The GABR value was (i) significantly lower in PTSD subjects compared to controls (p=0.001), (ii) significantly inversely correlated with markers of inflammation including IL6 (p=0.04) and TNFalpha (p=0.02), and (iii) significantly inversely correlated with CAPS current (p=0.001) and lifetime (p<0.001) subscales, ETI (p=0.045) and PANAS negative (p=0.006). Adding antidepressant use or MDD diagnosis as covariates led to similar results. Adding age and BMI as covariates also led to similar results, with the exception of IL6 and ETI losing their significant association with GABR. DISCUSSION: This study provides the first evidence that global arginine bioavailability, a marker of NO synthetic capacity in vivo, is lower in veterans with PTSD and is negatively associated with some markers of inflammation as well as with measures of PTSD symptom severity, negative affectivity and childhood adverse experiences. These findings add to the accumulating evidence that specific cellular dysfunction may be associated with the symptomatology of PTSD and may help to explain the higher burden of cardio metabolic disturbances seen in this disorder. PMID- 26515036 TI - Single Nanoparticle Voltammetry: Contact Modulation of the Mediated Current. AB - The cyclic voltammetric responses of individual palladium-coated carbon nanotubes are reported. Upon impact-from the solution phase-with the electrified interface, the nanoparticles act as individual nanoelectrodes catalyzing the hydrogen oxidation reaction. At high overpotentials the current is shown to reach a quasi steady-state diffusion limit, allowing determination of the tube length. The electrochemical response of the individual nanotubes also reveals the system to be modulated by the electrical contact between the electrode and carbon nanotube. This modulation presents itself as fluctuations in the recorded Faradaic current. PMID- 26515032 TI - Translational Significance of Heme Oxygenase in Obesity and Metabolic Syndrome. AB - The global epidemic of obesity continues unabated with sequelae of diabetes and metabolic syndrome. This review reflects the dramatic increase in research on the role of increased expression of heme oxygenase (HO)-1/HO-2, biliverdin reductase, and HO activity on vascular disease. The HO system engages with other systems to mitigate the deleterious effects of oxidative stress in obesity and cardiovascular disease (CVD). Recent reports indicate that HO-1/HO-2 protein expression and HO activity have several important roles in hemostasis and reactive oxygen species (ROS)-dependent perturbations associated with metabolic syndrome. HO-1 protects tissue during inflammatory stress in obesity through the degradation of pro-oxidant heme and the production of carbon monoxide (CO) and bilirubin, both of which have anti-inflammatory and anti-apoptotic properties. By contrast, repression of HO-1 is associated with increases of cellular heme and inflammatory conditions including hypertension, stroke, and atherosclerosis. HO-1 is a major focus in the development of potential therapeutic strategies to reverse the clinical complications of obesity and metabolic syndrome. PMID- 26515035 TI - Fatigue is associated with inflammation in patients with head and neck cancer before and after intensity-modulated radiation therapy. AB - Patients with head and neck cancer (HNC) receiving intensity-modulated radiation therapy (IMRT) have particularly high rates of fatigue, and pre- and post radiotherapy fatigue are prognostic factors for pathologic tumor responses and poor survival. Although inflammation has been proposed as one of the potential mechanisms of fatigue in cancer patients, findings have not been consistent, and there is a dearth of longitudinal studies. Accordingly, we conducted a prospective study in 46 HNC patients pre- and one-month post-IMRT. Fatigue was measured by the Multidimensional Fatigue Inventory (MFI)-20 at both time points along with the assessment of peripheral blood inflammatory markers including interleukin (IL)-6, soluble tumor necrosis factor receptor 2, and C-reactive protein (CRP) and gene expression. Generalized estimating equations were used to examine the association between inflammatory markers and fatigue. Gene enrichment analysis using MetaCore software was performed using up-regulated genes that were significantly associated with IMRT and fatigue. Significant associations between fatigue and IL-6 as well as CRP, which were independent of time, were observed. In addition the change in fatigue from pre- to post-IMRT was positively associated with the change in IL-6 and CRP. Analysis of up-regulated gene transcripts as a function of IMRT and fatigue revealed overrepresentation of transcripts related to the defense response and nuclear factor kappa B. In conclusion, our findings support the hypotheses that inflammation is associated with fatigue over time in HNC patients. Future studies on how inflammation contributes to fatigue as well as strategies targeting inflammation to reduce fatigue are warranted. PMID- 26515037 TI - Chemosensory proteins involved in host recognition in the stored-food mite Tyrophagus putrescentiae. AB - BACKGROUND: Chemosensory proteins (CSPs) have been proposed to transport a range of aliphatic compounds, esters and other long-chain compounds. A large number of CSPs from different gene subfamilies have been identified and annotated in arthropods; however, the CSP genes in mites remain unknown. Tyrophagus putrescentiae Schrank is an important stored-product and house-dust pest. RESULTS: By analysing the transcriptome, two putative CSPs were identified, namely TputCSP1 and TputCSP2 (14.9 kDa and 12.1 kDa respectively). The phylogenetic tree showed that the two TputCSPs shared most homology with CSPs in Ixodes scapularis and partially with Diptera, including Anopheles gambiae, Drosophila melanogaster, D. pseudoobscura, D. simulans, Delia antiqua and Culex quinquefasciatus. Additionally, they had similar secondary structure. The 3D models revealed that there are six alpha-helices enclosing the hydrophobic ligand binding pocket. Based on a docking study, we found that three ligands, (-) alloaromadendrene, 2-methylnaphthalene and cyclopentadecane, had high binding affinities for TputCSP1. Moreover, the TputCSP2 protein had a higher inhibition constant with different affinities to all test ligands from host volatile substances. CONCLUSION: The two CSPs have distinct physiological functions. TputCSP1 may mediate host recognition. (c) 2015 Society of Chemical Industry. PMID- 26515038 TI - Deletion of Cyclophilin D Impairs beta-Oxidation and Promotes Glucose Metabolism. AB - Cyclophilin D (CypD) is a mitochondrial matrix protein implicated in cell death, but a potential role in bioenergetics is not understood. Here, we show that loss or depletion of CypD in cell lines and mice induces defects in mitochondrial bioenergetics due to impaired fatty acid beta-oxidation. In turn, CypD loss triggers a global compensatory shift towards glycolysis, with transcriptional upregulation of effectors of glucose metabolism, increased glucose consumption and higher ATP production. In vivo, the glycolytic shift secondary to CypD deletion is associated with expansion of insulin-producing beta-cells, mild hyperinsulinemia, improved glucose tolerance, and resistance to high fat diet induced liver damage and weight gain. Therefore, CypD is a novel regulator of mitochondrial bioenergetics, and unexpectedly controls glucose homeostasis, in vivo. PMID- 26515039 TI - Synthesis and biological evaluation of new C-10 substituted dithranol pleiotropic hybrids. AB - Selective alkylation of the antipsoriatic drug dithranol (DTR) at C-10 with tert butyl bromoacetate, followed by acid-mediated deprotection, produced the corresponding carboxylic acid 4 which was coupled with selectively protected polyamines (PAs), such as putrescine (PUT), spermidine (SPD) and spermine (SPM), dopamine and aliphatic amines and substituted benzylamines producing a series of DTR-PA hybrids, after acid-mediated deprotection, as well as simple amides. The compounds were tested as antioxidants and inhibitors of lipoxygenase (LOX). The amides 4,4'-dimethoxybenzhydrylamide 13 (86% and 95%), 2,4-dimethoxybenzylamide 12 (87% and 81%) and dodecylamide 9 (98% and 74%), and the hybrid DTR-SPM (7) (93% and 87%), showed the highest antioxidant activity in the DPPH and AAPH assays, whereas the most potent inhibitors of LOX were amide 13 (IC50=7 MUM), the benzylamide 10 (IC50=7.9 MUM) and the butylamide 8 (IC50=10 MUM). Molecular binding studies showed that binding of these derivatives into the hydrophobic domain blocks approach of substrate to the active site, inhibiting soybean LOX. Amide 13 presented the highest anti-inflammatory activity (79.7%). The DTR moiety was absolutely necessary for securing high anti-inflammatory potency. Ethyl ester 3 (IC50=0.357 MUM) and the amides 9 (IC50=0.022 MUM) and 13 (IC50=0.56 MUM) exhibited higher antiproliferative activity than DTR (IC50=0.945 MUM) on HaCaT keratinocytes whereas amide 13 generally presented better cytocompatibility. Amide 13 is a very promising lead compound for further development as an anti inflammatory and antiproliferative agent. PMID- 26515040 TI - Fine tuning of agonistic/antagonistic activity for vitamin D receptor by 22-alkyl chain length of ligands: 22S-Hexyl compound unexpectedly restored agonistic activity. AB - 1alpha,25-Dihydroxyvitamin D3 exerts its actions by binding to vitamin D receptor (VDR). We are continuing the study related to the alteration of pocket structure of VDR by 22-alkyl substituent of ligands and the relationships between the alteration and agonistic/antagonistic activity. Previously we reported that compounds 2 (22-H), 3 (22S-Et), and 4 (22S-Bu) are VDR agonist, partial agonist and antagonist, respectively. Here, we describe the synthesis and biological evaluation of 22S-hexyl analog 5 (22S-Hex), which was designed to be a stronger VDR antagonist than 4. Unexpectedly, 5 showed partial agonistic but not antagonistic activity when bound to VDR, indicating that it is not necessarily true that the bulkier the side chain is, the stronger the antagonistic activity will be. X-ray crystallographic analysis of the VDR-ligand-binding domain (VDR LBD) accommodating compound 5 indicated that the partial agonist activity of 5 is dependent on the mixed population of the agonistic and antagonistic conformations. Binding of compound 5 may not bring the complex into the only antagonistic conformation due to the large conformational change of the VDR-LBD. From this study it was found that fine tuning of agonistic/antagonistic activity for VDR is possible by 22-alkyl chain length of ligands. PMID- 26515041 TI - Triazole linked mono carbonyl curcumin-isatin bifunctional hybrids as novel anti tubulin agents: Design, synthesis, biological evaluation and molecular modeling studies. AB - Keeping in view the limitations associated with currently available anticancer drugs, molecular hybrids of mono carbonyl curcumin and isatin tethered by triazole ring have been synthesized and evaluated for in vitro cytotoxicity against THP-1, COLO-205, HCT-116, A549, HeLa, CAKI-I, PC-3, MiaPaca-2 human cancer cell lines. The results revealed that the compounds SA-1 to SA-9, SB-2, SB 3, SB-4, SB-7 and SC-2 showed a good range of IC50 values against THP-1, COLO 205, HCT-116 and PC-3 cell lines, while the other four cell lines among these were found to be almost resistant. Structure activity relationship revealed that the nature of Ring X and substitution at position R influences the activity. Methoxy substituted phenyl ring as Ring X and H as R were found to be the ideal structural features. The most potent compounds (SA-2, SA-3, SA-4, SA-7) were further tested for tubulin inhibition. Compound SA-2 was found to significantly inhibit the tubulin polymerization (IC50=1.2 MUM against HCT-116). Compound SA-2, moreover, lead to the disruption of microtubules as confirmed by immunofluorescence technique. The significant cytotoxicity and tubulin inhibition by SA-2 was streamlined by molecular modeling studies where it was docked at the curcumin binding site of tubulin. PMID- 26515042 TI - [Consensus-based approach for severe paediatric asthma in routine clinical practice]. AB - INTRODUCTION: Accurate identification of paediatric patients with severe asthma is essential for an adequate management of the disease. However, criteria for defining severe asthma and recommendations for control vary among different guidelines. MATERIAL AND METHODS: An online survey was conducted to explore expert opinions about the definition and management of severe paediatric asthma. To reach a consensus agreement, a modified Delphi technique was used, and practice guidelines were prepared after the analysis of the results. RESULTS: Eleven paediatric chest disease physicians and allergy specialists with wide expertise in severe asthma responded to the survey. Consensus was reached in 50 out of 65 questions (76.92%). It was considered that a patient has severe asthma if during the previous year they have required 2 or more cycles of oral steroids, required daily treatment with medium doses of inhaled corticosteroids (with other controller medication) or high doses (with or without other controller medication), did not respond to optimised conventional treatment, or if the disease threatened the life of the patient or seriously impairs their quality of life. The definition of severe asthma may also include patients who justifiably use health resources on a regular basis, or have psychosocial or environmental factors impeding control. For monitoring, the use of questionnaires designed specifically for paediatric population, such as CAN or ACT, is recommended. As regards treatment, the use of omalizumab should be considered prior to the use of oral corticosteroids. CONCLUSIONS: This paper provides consensus recommendations that may be useful in the management of severe paediatric asthma. PMID- 26515043 TI - Clinical Results and Metal Ion Levels After Ceramic-on-Metal Total Hip Arthroplasty: A Mean 50-Month Prospective Single-Center Study. AB - BACKGROUND: The aim of our study was to investigate the clinical results and serum metal ion levels in a cohort of patients who received total hip arthroplasty (THA) with ceramic-on-metal (CoM) bearings. METHODS: From September 2009 to December 2011, 78 patients (89 hips) who underwent THA with CoM bearings were involved in this study. Harris Hip Score, Short-Form 12, and Western Ontario and McMaster Universities Osteoarthritis Index scores were measured and radiographs were taken for radiographic analysis. Serum metal ion levels of cobalt (Co), chromium (Cr), molybdenum (Mo), and titanium (Ti) were measured using high-resolution inductively coupled plasma-mass spectrometry. RESULTS: Severy-four patients (85 hips) were followed up at a mean of 50 months. At the end of follow-up, HSS, Short-Form 12, and Western Ontario and McMaster Universities Osteoarthritis Index scores were improved significantly compared with preoperative values. No intraoperative and postoperative complications occurred, and no radiolucency, osteolysis, and loosening was found from radiographic examination. Metal ion analysis showed that serum metal ions levels were significantly elevated compared with normal values. Spearman correlation analysis revealed that there was a correlation between 3 metal ion levels and body mass index(Co: r = 0.49, P < .01; Cr: r = 0.47, P < .01; Mo: r = 0.36, P = .04). No correlation was found between metal ion levels and age, cup abduction angle, cup anteversion angle, acetabular version, bilateral arthroplasty, cup screw used, hip stem implant type, or femoral head size. CONCLUSION: Our study concluded that the use of a CoM THA is effective clinically, but the systemic metal ion levels are significantly elevated at midterm follow-up. Whether the elevated metal ion levels will induce an adverse reaction is unknown and long term follow-up is need. PMID- 26515044 TI - The Cobalt-To-Chromium Ratio "May Be" a Key Marker for Adverse Local Tissue Reactions in Metal-On-Metal Hips. PMID- 26515046 TI - Iatrogenic pressure sores: primum non nocere. PMID- 26515045 TI - Mas receptor mediates cardioprotection of angiotensin-(1-7) against Angiotensin II-induced cardiomyocyte autophagy and cardiac remodelling through inhibition of oxidative stress. AB - Angiotensin II (Ang II) plays an important role in the onset and development of cardiac remodelling associated with changes of autophagy. Angiotensin1-7 [Ang-(1 7)] is a newly established bioactive peptide of renin-angiotensin system, which has been shown to counteract the deleterious effects of Ang II. However, the precise impact of Ang-(1-7) on Ang II-induced cardiomyocyte autophagy remained essentially elusive. The aim of the present study was to examine if Ang-(1-7) inhibits Ang II-induced autophagy and the underlying mechanism involved. Cultured neonatal rat cardiomyocytes were exposed to Ang II for 48 hrs while mice were infused with Ang II for 4 weeks to induce models of cardiac hypertrophy in vitro and in vivo. LC3b-II and p62, markers of autophagy, expression were significantly elevated in cardiomyocytes, suggesting the presence of autophagy accompanying cardiac hypertrophy in response to Ang II treatment. Besides, Ang II induced oxidative stress, manifesting as an increase in malondialdehyde production and a decrease in superoxide dismutase activity. Ang-(1-7) significantly retarded hypertrophy, autophagy and oxidative stress in the heart. Furthermore, a role of Mas receptor in Ang-(1-7)-mediated action was assessed using A779 peptide, a selective Mas receptor antagonist. The beneficial responses of Ang-(1-7) on cardiac remodelling, autophagy and oxidative stress were mitigated by A779. Taken together, these result indicated that Mas receptor mediates cardioprotection of angiotensin-(1-7) against Ang II-induced cardiomyocyte autophagy and cardiac remodelling through inhibition of oxidative stress. PMID- 26515047 TI - A Bradyzoite is a Bradyzoite is a Bradyzoite? AB - Bradyzoite forms of Toxoplasma gondii persist in tissue cysts for the lifetime of an infected host and can reactivate to cause clinical disease. It was thought that in vivo bradyzoites within tissue cysts are biologically inactive dormant forms that rarely replicate. Apparently, consensus was wrong. PMID- 26515048 TI - Meta-Analyses of Factors Associated with Leptospirosis in Domestic Dogs. AB - Factors related with leptospirosis in domestic dogs have been reported worldwide. The aims of this study were to identify factors associated with this disease described in different observational studies and to combine the coinciding factors in at least four studies using meta-analyses, to obtain a pooled odds ratio (OR) as measure of infection risk. A literature search was performed in electronic databases, electronic databases of specific journals and search engines to find studies published in English, Spanish and Portuguese available from January 1960 to January 2015. Two hundred and eighteen factors were identified in 31 publications including cross-sectional and case-control studies. Finally, independent meta-analyses were performed with six different variables, which included between 4 and 8 articles. The pooled OR indicated that the variables 'mixed-breed dogs', 'flooding occurrence in the habitat of the dog' and 'working dogs' were risk factors for leptospirosis, while 'being a dog less than 1 year old' was a protective factor; however, all these associations were not statistically significant. Otherwise, the variables 'male dog' and 'urban dog' were statistically significant risk factors for infection. This study highlights the need for more formal studies on the epidemiology of canine leptospirosis. Nevertheless, the study revealed that some risk factors for infection coincided in different observational studies. These factors could be considered to raise suspicion about the disease, especially when there is a history of exposure to the bacteria. PMID- 26515049 TI - Evaluation of less invasive methods to assess fatty acids from phospholipid fraction: cheek cell and capillary blood sampling. AB - Plasma is the most commonly employed matrix for analyzing fatty acids (FAs), but its extraction is not well accepted in the infant population. The objectives of this study were to evaluate cheek cells and capillary blood as alternatives to plasma sampling for FA analysis and to standardize the methodology. Samples were obtained from 20 children who underwent lipid extraction, phospholipid isolation by Solid Phase Extraction (SPE) in a 96-well plate, methylation, and analysis by fast gas chromatography (GC). A positive correlation was found for most of the FAs, especially long-chain polyunsaturated fatty acids (LC-PUFAs), in cheek cells and capillary blood versus plasma samples (r = 0.32-0.99). No differences were found in the levels of n-6: n-3 PUFA and n-6: n-3 LC-PUFA ratios between cheek cells and capillary blood. These two proposed samples can therefore be used as alternatives to plasma sampling for phospholipid FA analysis, especially LC PUFAs. PMID- 26515050 TI - Ultrastructural characterization of craniopharyngioma at the tumor boundary: A structural comparison with an experimental toxic model using "oil machinery" fluid, with emphasis on Rosenthal fibers. AB - Craniopharyngiomas (CPs) are cystic, encapsulated, slow-growing epithelial tumors. CPs can be aggressive forms invading and resorting surrounding structures of adjacent brain tissue, where Rosenthal fibers (RFs) are expressed. The aim of this study was to investigate the ultrastructure of these fibers in human biopsies and compare it with an experimental toxic model produced by the cortical infusion of the oil cyst fluid ("Oil machinery" fluid or OMF) from CPs to rats. For this purpose, the CPs from ten patients were examined by light and electron microscopy. OMF was administered to rats intracortically. Immunohistochemical detection of glial fibrillary acidic protein (GFAP) and vimentin was assessed. In both freshly obtained CPs and rat brain tissue, the presence of abundant cellular debris, lipid-laden macrophages, reactive gliosis, inflammation and extracellular matrix destruction were seen. Ultrastructural results suggest focal pathological disturbances and an altered microenvironment surrounding the tumor-brain junction, with an enhanced presence of RFs in human tumors. In contrast, in the rat brain different degrees of cellular disorganization with aberrant filament filament interactions and protein aggregation were seen, although RFs were absent. Our immunohistochemical findings in CPs also revealed an enhanced expression of GFAP and vimentin in RFs at the peripheral, but not at the central (body) level. Through these findings we hypothesize that the continuous OMF release at the CPs boundary may cause tissue alterations, including damaging of the extracellular matrix, and possibly contributing to RFs formation, a condition that was not possible to reproduce in the experimental model. The presence of RFs at the CPs boundary might be considered as a major criterion for the degree of CPs invasiveness to normal tissue. The lack of RFs reactivity in the experimental model reveals that the invasive component of CPs is not present in the OMF, although the fluid per se can exert tissue damage. PMID- 26515051 TI - [Violence by and against people with mental illnesses]. AB - There is robust evidence for an increased risk of violence through people with psychotic disorders. Until recently this was frequently denied to prevent stigmatization. Alcohol and drug abuse equally increases the risk, while appropriate treatment reduces it drastically. Staff in psychiatric hospitals is exposed to an elevated risk of aggressive assaults. A limited number of severely ill and socially disintegrated patients accounts for these incidents, which are often recurrent. Besides patient characteristics, factors such as ward climate, staffing levels, education and attitudes of staff, and physical environment play a major role in aggressive escalations. On the other hand, mentally ill people, particularly women, are themselves at a higher risk of becoming victims of violent and non-violent crime. This also applies after correction for variables such as social status and living environment. Additionally mentally ill people are confronted with violence in the form of coercive interventions legitimised by the state (involuntary admission, involuntary treatment, freedom-restrictive measures such as seclusion or manual/physical restraint). In contrast to other countries in Central and Western Europe, involuntary outpatient treatment has never been legalized in Germany. Efforts to reduce violence and coercion in psychiatric facilities by evidence-based interventions are widespread nowadays, treatment guidelines are available. PMID- 26515052 TI - Self-reported psychopathy in the Middle East: a cross-national comparison across Egypt, Saudi Arabia, and the United States. AB - BACKGROUND: The construct of psychopathy is sparsely researched in the non Western world, particularly in the Middle East. As such, the extent to which the psychopathy construct can be generalized to other cultures, including Middle Eastern Arab cultures, is largely unknown. METHODS: The present study investigated the cross-cultural/national comparability of self-reported psychopathy in the United States (N = 786), Egypt (N = 296), and Saudi Arabia (N = 341). RESULTS: A widely used psychopathy questionnaire demonstrated largely similar properties across the American and Middle Eastern samples and associations between Five Factor Model (FFM) personality and psychopathy were broadly consistent. Nevertheless, several notable cross-cultural differences emerged, particularly with regard to the internal consistencies of psychopathy dimensions and the correlates of Coldheartedness. Additionally, in contrast to most findings in Western cultures, associations between psychopathy and FFM personality varied consistently by gender in the Egyptian sample. CONCLUSIONS: These findings lend preliminary support to the construct validity of self reported psychopathy in Arabic-speaking cultures, providing provisional evidence for the cross-cultural generalizability of certain core characteristics of psychopathy. PMID- 26515053 TI - Remarkably low-energy one-dimensional fault line defects in single-layered phosphorene. AB - Systematic engineering of atomic-scale low-dimensional defects in two-dimensional nanomaterials is a promising method to modulate the electronic properties of these nanomaterials. Defects at interfaces such as grain boundaries and line defects can often be detrimental to technologically important nanodevice operations and thus a fundamental understanding of how such one-dimensional defects may have an influence on their physio-chemical properties is pivotal for optimizing their device performance. Of late, two-dimensional phosphorene has attracted much attention due to its high carrier mobility and good mechanical flexibility. In this study, using density-functional theory, we have investigated the temperature-dependent energetics and electronic structure of single-layered phosphorene with various fault line defects. We have generated different line defect models based on a fault method, rather than the conventional rotation method. This has allowed us to study and identify new low-energy line defects, and we show how these low-energy line defects could well modulate the electronic band gap energies of single-layered two-dimensional phosphorene - offering a range of metallic to semiconducting properties in these newly proposed low-energy line defects in phosphorene. PMID- 26515054 TI - Analysis of redox and apoptotic effects of anthracyclines to delineate a cardioprotective strategy. AB - PURPOSE: Cardiotoxic side effects of anthracyclines limit their use as effective chemotherapeutics. One mechanistic model of anthracycline-induced cardiotoxicity is attributed to the generation of intracellular reactive oxygen species (ROS). However, this theory has been questioned because several cardioprotective strategies have included the use of antioxidants without significant clinical benefit. We sought to determine whether measurement of intracellular reactive oxygen species after anthracycline exposure in vivo and in vitro could provide a means for designing more effective antioxidant-based cardioprotective schemes. METHODS: Intracellular levels of ROS were assessed in peripheral blood mononuclear cells from leukemia bearing mice exposed to anthracyclines and in patients receiving anthracyclines. Comparison of cell death induction and ROS levels were also conducted in vitro in cardiomyocyte and leukemia lines. ROS blockade using antioxidants was conducted, and effects on cell death were assessed. RESULTS: Elevated ROS in blood of mice and representative patient samples correlated with cardiomyocyte necrosis and decreased ejection fraction. In vitro, comparison of the cytotoxic effects of anthracyclines in acute leukemia cells and in cardiomyocytes revealed distinct kinetics of cell death induction and dependence upon oxidative stress. Although apoptotic cell death was observed in both acute leukemia cells and cardiomyocytes, the antioxidant N-acetylcysteine protected cardiomyocytes but not acute leukemia cells from anthracycline cytotoxicity. CONCLUSIONS: Our findings point toward revisiting the use of NAC as a cardioprotective agent since it does not appear to interfere with the cytotoxic action of anthracyclines. NAC has been evaluated clinically for cardioprotective activity but future trials must ensure that adequate dose, scheduling and incorporation of markers of oxidative stress are included. PMID- 26515055 TI - Hyaluronidase 2 (HYAL2) is expressed in endothelial cells, as well as some specialized epithelial cells, and is required for normal hyaluronan catabolism. AB - Hyaluronidase 2 (HYAL2) is a membrane-anchored protein that is proposed to initiate the degradation of hyaluronan (HA) in the extracellular matrix. The distribution of HYAL2 in tissues, and of HA in tissues lacking HYAL2, is largely unexplored despite the importance of HA metabolism in several disease processes. Herein, we use immunoblot and histochemical analyses to detect HYAL2 and HA in mouse tissues, as well as agarose gel electrophoresis to examine the size of HA. HYAL2 was detected in all tissues that were examined, including the brain. It was localized to the surface and cytoplasm of endothelial cells, as well as specialized epithelial cells in several tissues, including the skin. Accumulated HA, often of higher molecular mass than that in control tissues, was detected in tissues from Hyal2 (-/-) mice. The accumulating HA was located near to where HYAL2 is normally found, although in some tissues, it was distant from the site of HYAL2 localization. Overall, HYAL2 was highest in tissues that remove HA from the circulation (liver, lymph node and spleen), but the levels of HA accumulation in Hyal2 (-/-) mice were highest in tissues that catabolize locally synthesized HA. Our results support HYAL2's role as an extracellular enzyme that initiates HA breakdown in somatic tissues. However, our findings also suggest that HYAL2 contributes to HA degradation through other routes, perhaps as a soluble or secreted form. PMID- 26515057 TI - Systemic lupus erythematosus exacerbation following cessation of belimumab treatment. AB - OBJECTIVES: Belimumab has recently been approved for the treatment of systemic lupus erythematosus (SLE) refractory to standard therapy. Following one case of an SLE flare after cessation of belimumab, we hypothesized that this might lead to a rebound phenomenon and possible exacerbation of SLE. METHOD: Members of the Israeli Society of Rheumatology were contacted by e-mail and asked to report cases of an SLE flare following cessation of belimumab treatment. RESULTS: Three cases of SLE patients who experienced a severe SLE flare following cessation of belimumab therapy were reported. In all cases, belimumab was given as treatment for active mucocutaneous manifestations and/or polyarthritis with improvement in all three patients, one of whom achieved disease remission. In all three cases, patients experienced a severe flare in previously uninvolved major organ systems, including one case of class IV lupus nephritis accompanied by a new-onset severe headache with elevated cerebrospinal fluid (CSF) protein and white matter lesions on brain magnetic resonance imaging (MRI), one case of severe pneumonitis and haemolytic anaemia, and one case of a systemic flare, fatigue, arthritis, and severe abdominal pain. CONCLUSIONS: Belimumab therapy has been shown to be beneficial in the management of active SLE, mostly in patients with mucocutaneous and musculoskeletal manifestations. We suggest a possible rebound effect following cessation of belimumab that could be due to an increase in B-cell activating factor (BAFF) levels and lead to a disease flare. Future assessment of BAFF levels in patients stopping belimumab therapy and clinical correlation may support this hypothesis. Further studies are needed to confirm this observation. PMID- 26515056 TI - Immunolocalization of hyperpolarization-activated cationic HCN1 and HCN3 channels in the rat nephron: regulation of HCN3 by potassium diets. AB - Hyperpolarization-activated cationic and cyclic nucleotide-gated channels (HCN) comprise four homologous subunits (HCN1-HCN4). HCN channels are found in excitable and non-excitable tissues in mammals. We have previously shown that HCN2 may transport ammonium (NH4 (+)), besides sodium (Na(+)), in the rat distal nephron. In the present work, we identified HCN1 and HCN3 in the proximal tubule (PT) and HCN3 in the thick ascending limb of Henle (TALH) of the rat kidney. Immunoblot assays detected HCN1 (130 kDa) and HCN3 (90 KDa) and their truncated proteins C-terminal HCN1 (93 KDa) and N-terminal HCN3 (65 KDa) in enriched plasma membranes from cortex (CX) and outer medulla (OM), as well as in brush-border membrane vesicles. Immunofluorescence assays confirmed apical localization of HCN1 and HCN3 in the PT. HCN3 was also found at the basolateral membrane of TALH. We evaluated chronic changes in mineral dietary on HCN3 protein abundance. Animals were fed with three different diets: sodium-deficient (SD) diet, potassium-deficient (KD) diet, and high-potassium (HK) diet. Up-regulation of HCN3 was observed in OM by KD and in CX and OM by HK; the opposite effect occurred with the N-terminal truncated HCN3 in CX (KD) and OM (HK). SD diet did not produce any change. Since HCN channels activate with membrane hyperpolarization, our results suggest that HCN channels may play a role in the Na(+)-K(+)-ATPase activity, contributing to Na(+), K(+), and acid-base homeostasis in the rat kidney. PMID- 26515058 TI - Prevalence of infection with Rickettsia helvetica in Ixodes ricinus ticks feeding on non-rickettsiemic rodent hosts in sylvatic habitats of west-central Poland. AB - Ixodes ricinus is the most prevalent and widely distributed tick species in European countries and plays a principal role in transmission of a wide range of microbial pathogens. It is also a main vector and reservoir of Rickettsia spp. of the spotted fever group with the infection level ranging in Poland from 1.3% to 11.4%. Nevertheless, little research has been conducted so far to identify reservoir hosts for these pathogens. A survey was undertaken to investigate the presence of Rickettsia spp. in wild small rodents and detached I. ricinus. Rodents, Apodemus flavicollis mice and Myodes glareolus voles were captured in typically sylvatic habitats of west-central Poland. Blood samples and collected ticks were analyzed by conventional, semi-nested and nested PCRs. Rickettsial species were determined by sequence analysis of obtained fragments of gltA and 16S rRNA genes. A total of 2339 immature I. ricinus (mostly larvae) were collected from 158 animals. Proportion of hosts carrying ticks was 84%, being higher for A. flavicollis than for M. glareolus. Rickettsia helvetica, the only species identified, was detected in 8% of 12 nymphs and in at least 10.7% (MIR) of 804 larvae investigated. Prevalence of infected ticks on both rodent species was comparable (10.8 vs. 9%). None of blood samples tested was positive for Rickettsia spp. The results showed that in sylvatic habitats the level of infestation with larval I. ricinus was higher in A. flavicollis mice in comparison with M. glareolus voles. They show that R. helvetica frequently occurred in ticks feeding on rodents. Positive immature ticks were collected from non-rickettsiemic hosts what might suggest a vertical route of their infection (transovarial and/or transstadial) or a very short-lasting rickettsiemia in rodents. A natural vertebrate reservoir host for R. helvetica remains to be determined. PMID- 26515059 TI - Coxiella-like endosymbiont in argasid ticks (Ornithodoros muesebecki) from a Socotra Cormorant colony in Umm Al Quwain, United Arab Emirates. AB - Coxiella burnetii is a pathogen causing Q fever in domestic animals and humans. Seabirds have been implicated as possible reservoirs of this bacterium in the Arabian Gulf and in the Western Indian Ocean. Recently, Coxiella species closely related to C. burnetii was detected from ticks collected from oil rigs used as roosting areas by Socotra Cormorants (Phalacrocorax nigrogularis) in the western Arabian Gulf. We collected ticks from the largest breeding colony of Socotra Cormorants in the United Arab Emirates on the eastern extreme of the species' breeding range to determine the prevalence of C. burnetii and evaluate its role as a wild reservoir. All ticks were identified as Ornithodoros muesebecki and genomic DNA was extracted from larval and nymph/adult tick pools. Multiplex PCR tests were performed targeting three C. burnetii specific genes. C. burnetii was not detected although a Coxiella-like endosymbiont was identified that was closely related to Coxiella symbionts from Ornithodoros capensis ticks. Because domestic and wild ungulates are the primary source of C. burnetii, we suggest that the presence of free-ranging, native and non-native ungulates in some off shore islands in the Arabian Gulf could disseminate C. burnetii to seabirds. More comprehensive studies on seabird colonies are needed to better understand the diversity and prevalence of Coxiella symbionts and to establish if C. burnetii is endemic on some of these islands. PMID- 26515060 TI - Note on Ehrlichia chaffeensis, Ehrlichia ewingii, and "Borrelia lonestari" infection in lone star ticks (Acari: Ixodidae), Nebraska, USA. AB - The lone star tick, Amblyomma americanum (L.) (Acari: Ixodidae), is established in southeastern Nebraska yet the prevalence of tick-associated microorganisms is not known. An initial PCR-based analysis for Ehrlichia chaffeensis, Ehrlichia ewingii, and Borrelia infection in host-seeking adult ticks collected in southeast Nebraska was conducted. A total of 251 adult ticks collected in six sites in southeast Nebraska were tested. E. chaffeensis, E. ewingii, and Borrelia spp. were present, and the prevalence of each was approximately 1.6%. This study demonstrates that Ehrlichia spp. are present in Nebraska lone star tick populations. PMID- 26515062 TI - Proteolytic Cleavage Driven by Glycosylation. AB - Proteolytic processing of human host cell factor 1 (HCF-1) to its mature form was recently shown, unexpectedly, to occur in a UDP-GlcNAc-dependent fashion within the transferase active site of O-GlcNAc-transferase (OGT) (Lazarus, M. B., Jiang, J., Kapuria, V., Bhuiyan, T., Janetzko, J., Zandberg, W. F., Vocadlo, D. J., Herr, W., and Walker, S. (2013) Science 342, 1235-1239). An interesting mechanism involving formation and then intramolecular rearrangement of a covalent glycosyl ester adduct of the HCF-1 polypeptide was proposed to account for this unprecedented proteolytic activity. However, the key intermediate remained hypothetical. Here, using a model enzyme system for which the formation of a glycosyl ester within the enzyme active site has been shown unequivocally, we show that ester formation can indeed lead to proteolysis of the adjacent peptide bond, thereby providing substantive support for the mechanism of HCF-1 processing proposed. PMID- 26515061 TI - ATP-binding Cassette Subfamily C Member 5 (ABCC5) Functions as an Efflux Transporter of Glutamate Conjugates and Analogs. AB - The ubiquitous efflux transporter ABCC5 (ATP-binding cassette subfamily C member 5) is present at high levels in the blood-brain barrier, neurons, and glia, but its in vivo substrates and function are not known. Using untargeted metabolomic screens, we show that Abcc5(-/-) mice accumulate endogenous glutamate conjugates in several tissues, but brain in particular. The abundant neurotransmitter N acetylaspartylglutamate was 2.4-fold higher in Abcc5(-/-) brain. The metabolites that accumulated in Abcc5(-/-) tissues were depleted in cultured cells that overexpressed human ABCC5. In a vesicular membrane transport assay, ABCC5 also transported exogenous glutamate analogs, like the classic excitotoxic neurotoxins kainic acid, domoic acid, and NMDA; the therapeutic glutamate analog ZJ43; and, as previously shown, the anti-cancer drug methotrexate. Glutamate conjugates and analogs are of physiological relevance because they can affect the function of glutamate, the principal excitatory neurotransmitter in the brain. After CO2 asphyxiation, several immediate early genes were expressed at lower levels in Abcc5(-/-) brains than in wild type brains, suggesting altered glutamate signaling. Our results show that ABCC5 is a general glutamate conjugate and analog transporter that affects the disposition of endogenous metabolites, toxins, and drugs. PMID- 26515063 TI - Commensal Bacteria-induced Interleukin 1beta (IL-1beta) Secreted by Macrophages Up-regulates Hepcidin Expression in Hepatocytes by Activating the Bone Morphogenetic Protein Signaling Pathway. AB - The liver hormone hepcidin is the central regulator of systemic iron metabolism. Its increased expression in inflammatory states leads to hypoferremia and anemia. Elucidation of the mechanisms that up-regulate hepcidin during inflammation is essential for developing rational therapies for this anemia. Using mouse models of inflammatory bowel disease, we have shown previously that colitis-associated hepcidin induction is influenced by intestinal microbiota composition. Here we investigate how two commensal bacteria, Bifidobacterium longum and Bacteroides fragilis, representative members of the gut microbiota, affect hepcidin expression. We found that supernatants of a human macrophage cell line infected with either of the bacteria up-regulated hepcidin when added to a human hepatocyte cell line. This activity was abrogated by neutralization of IL-1beta. Moreover, purified IL-1beta increased hepcidin expression when added to the hepatocyte line or primary human hepatocytes and when injected into mice. IL 1beta activated the bone morphogenetic protein (BMP) signaling pathway in hepatocytes and in mouse liver, as indicated by increased phosphorylation of small mothers against decapentaplegic proteins. Activation of BMP signaling correlated with IL-1beta-induced expression of BMP2 in human hepatocytes and activin B in mouse liver. Treatment of hepatocytes with two different chemical inhibitors of BMP signaling or with a neutralizing antibody to BMP2 prevented IL 1beta-induced up-regulation of hepcidin. Our results clarify how commensal bacteria affect hepcidin expression and reveal a novel connection between IL 1beta and activation of BMP signaling. They also suggest that there may be differences between mice and humans with respect to the mechanism by which IL 1beta up-regulates hepcidin. PMID- 26515064 TI - A Combination of Structural and Empirical Analyses Delineates the Key Contacts Mediating Stability and Affinity Increases in an Optimized Biotherapeutic Single chain Fv (scFv). AB - Fully-human single-chain Fv (scFv) proteins are key potential building blocks of bispecific therapeutic antibodies, but they often suffer from manufacturability and clinical development limitations such as instability and aggregation. The causes of these scFv instability problems, in proteins that should be theoretically stable, remains poorly understood. To inform the future development of such molecules, we carried out a comprehensive structural analysis of the highly stabilized anti-CXCL13 scFv E10. E10 was derived from the parental 3B4 using complementarity-determining region (CDR)-restricted mutagenesis and tailored selection and screening strategies, and carries four mutations in VL CDR3. High-resolution crystal structures of parental 3B4 and optimized E10 scFvs were solved in the presence and absence of human CXCL13. In parallel, a series of scFv mutants was generated to interrogate the individual contribution of each of the four mutations to stability and affinity improvements. In combination, these analyses demonstrated that the optimization of E10 was primarily mediated by removing clashes between both the VL and the VH, and between the VL and CXCL13. Importantly, a single, germline-encoded VL-CDR3 residue mediated the key difference between the stable and unstable forms of the scFv. This work demonstrates that, aside from being the critical mediators of specificity and affinity, CDRs may also be the primary drivers of biotherapeutic developability. PMID- 26515065 TI - Muscle Wasting in Fasting Requires Activation of NF-kappaB and Inhibition of AKT/Mechanistic Target of Rapamycin (mTOR) by the Protein Acetylase, GCN5. AB - NF-kappaB is best known for its pro-inflammatory and anti-apoptotic actions, but in skeletal muscle, NF-kappaB activation is important for atrophy upon denervation or cancer. Here, we show that also upon fasting, NF-kappaB becomes activated in muscle and is critical for the subsequent atrophy. Following food deprivation, the expression and acetylation of the p65 of NF-kappaB on lysine 310 increase markedly in muscles. NF-kappaB inhibition in mouse muscles by overexpression of the IkappaBalpha superrepressor (IkappaBalpha-SR) or of p65 mutated at Lys-310 prevented atrophy. Knockdown of GCN5 with shRNA or a dominant negative GCN5 or overexpression of SIRT1 decreased p65K310 acetylation and muscle wasting upon starvation. In addition to reducing atrogene expression, surprisingly inhibiting NF-kappaB with IkappaBalpha-SR or by GCN5 knockdown in these muscles also enhanced AKT and mechanistic target of rapamycin (mTOR) activities, which also contributed to the reduction in atrophy. These new roles of NF-kappaB and GCN5 in regulating muscle proteolysis and AKT/mTOR signaling suggest novel approaches to combat muscle wasting. PMID- 26515066 TI - Conformational Changes in the Endosomal Sorting Complex Required for the Transport III Subunit Ist1 Lead to Distinct Modes of ATPase Vps4 Regulation. AB - Intralumenal vesicle formation of the multivesicular body is a critical step in the delivery of endocytic cargoes to the lysosome for degradation. Endosomal sorting complex required for transport III (ESCRT-III) subunits polymerize on endosomal membranes to facilitate membrane budding away from the cytoplasm to generate these intralumenal vesicles. The ATPase Vps4 remodels and disassembles ESCRT-III, but the manner in which Vps4 activity is coordinated with ESCRT-III function remains unclear. Ist1 is structurally homologous to ESCRT-III subunits and has been reported to inhibit Vps4 function despite the presence of a microtubule-interacting and trafficking domain-interacting motif (MIM) capable of stimulating Vps4 in the context of other ESCRT-III subunits. Here we report that Ist1 inhibition of Vps4 ATPase activity involves two elements in Ist1: the MIM itself and a surface containing a conserved ELYC sequence. In contrast, the MIM interaction, in concert with a more open conformation of the Ist1 core, resulted in stimulation of Vps4. Addition of the ESCRT-III subunit binding partner of Ist1, Did2, also converted Ist1 from an inhibitor to a stimulator of Vps4 ATPase activity. Finally, distinct regulation of Vps4 by Ist1 corresponded with altered ESCRT-III disassembly in vitro. Together, these data support a model in which Ist1-Did2 interactions during ESCRT-III polymerization coordinate Vps4 activity with the timing of ESCRT-III disassembly. PMID- 26515067 TI - The Crystal Structure of an Integral Membrane Fatty Acid alpha-Hydroxylase. AB - Neuronal electrical impulse propagation is facilitated by the myelin sheath, a compact membrane surrounding the axon. The myelin sheath is highly enriched in galactosylceramide (GalCer) and its sulfated derivative sulfatide. Over 50% of GalCer and sulfatide in myelin is hydroxylated by the integral membrane enzyme fatty acid 2-hydroxylase (FA2H). GalCer hydroxylation contributes to the compact nature of the myelin membrane, and mutations in FA2H result in debilitating leukodystrophies and spastic paraparesis. We report here the 2.6 A crystal structure of sphingolipid alpha-hydroxylase (Scs7p), a yeast homolog of FA2H. The Scs7p core is composed of a helical catalytic cap domain that sits atop four transmembrane helices that anchor the enzyme in the endoplasmic reticulum. The structure contains two zinc atoms coordinated by the side chains of 10 highly conserved histidines within a dimetal center located near the plane of the cytosolic membrane. We used a yeast genetic approach to confirm the important role of the dimetal-binding histidines in catalysis and identified Tyr-322 and Asp-323 as critical determinants involved in the hydroxylase reaction. Examination of the Scs7p structure, coupled with molecular dynamics simulations, allowed for the generation of a model of ceramide binding to Scs7p. Comparison of the Scs7p structure and substrate-binding model to the structure of steroyl-CoA desaturase revealed significant differences in the architecture of the catalytic cap domain and location of the dimetal centers with respect to the membrane. These observations provide insight into the different mechanisms of substrate binding and recognition of substrates by the hydroxylase and desaturase enzymes. PMID- 26515068 TI - Selective Activation of Nociceptor TRPV1 Channel and Reversal of Inflammatory Pain in Mice by a Novel Coumarin Derivative Muralatin L from Murraya alata. AB - Coumarin and its derivatives are fragrant natural compounds isolated from the genus Murraya that are flowering plants widely distributed in East Asia, Australia, and the Pacific Islands. Murraya plants have been widely used as medicinal herbs for relief of pain, such as headache, rheumatic pain, toothache, and snake bites. However, little is known about their analgesic components and the molecular mechanism underlying pain relief. Here, we report the bioassay guided fractionation and identification of a novel coumarin derivative, named muralatin L, that can specifically activate the nociceptor transient receptor potential vanilloid 1 (TRPV1) channel and reverse the inflammatory pain in mice through channel desensitization. Muralatin L was identified from the active extract of Murraya alata against TRPV1 transiently expressed in HEK-293T cells in fluorescent calcium FlexStation assay. Activation of TRPV1 current by muralatin L and its selectivity were further confirmed by whole-cell patch clamp recordings of TRPV1-expressing HEK-293T cells and dorsal root ganglion neurons isolated from mice. Furthermore, muralatin L could reverse inflammatory pain induced by formalin and acetic acid in mice but not in TRPV1 knock-out mice. Taken together, our findings show that muralatin L specifically activates TRPV1 and reverses inflammatory pain, thus highlighting the potential of coumarin derivatives from Murraya plants for pharmaceutical and medicinal applications such as pain therapy. PMID- 26515069 TI - Neutron Crystal Structure of RAS GTPase Puts in Question the Protonation State of the GTP gamma-Phosphate. AB - RAS GTPase is a prototype for nucleotide-binding proteins that function by cycling between GTP and GDP, with hydrogen atoms playing an important role in the GTP hydrolysis mechanism. It is one of the most well studied proteins in the superfamily of small GTPases, which has representatives in a wide range of cellular functions. These proteins share a GTP-binding pocket with highly conserved motifs that promote hydrolysis to GDP. The neutron crystal structure of RAS presented here strongly supports a protonated gamma-phosphate at physiological pH. This counters the notion that the phosphate groups of GTP are fully deprotonated at the start of the hydrolysis reaction, which has colored the interpretation of experimental and computational data in studies of the hydrolysis mechanism. The neutron crystal structure presented here puts in question our understanding of the pre-catalytic state associated with the hydrolysis reaction central to the function of RAS and other GTPases. PMID- 26515070 TI - Mechanisms of Calmodulin Regulation of Different Isoforms of Kv7.4 K+ Channels. AB - Calmodulin (CaM), a Ca(2+)-sensing protein, is constitutively bound to IQ domains of the C termini of human Kv7 (hKv7, KCNQ) channels to mediate Ca(2+)-dependent reduction of Kv7 currents. However, the mechanism remains unclear. We report that CaM binds to two isoforms of the hKv7.4 channel in a Ca(2+)-independent manner but that only the long isoform (hKv7.4a) is regulated by Ca(2+)/CaM. Ca(2+)/CaM mediate reduction of the hKv7.4a channel by decreasing the channel open probability and altering activation kinetics. We took advantage of a known missense mutation (G321S) that has been linked to progressive hearing loss to further examine the inhibitory effects of Ca(2+)/CaM on the Kv7.4 channel. Using multidisciplinary techniques, we demonstrate that the G321S mutation may destabilize CaM binding, leading to a decrease in the inhibitory effects of Ca(2+) on the channels. Our study utilizes an expression system to dissect the biophysical properties of the WT and mutant Kv7.4 channels. This report provides mechanistic insights into the critical roles of Ca(2+)/CaM regulation of the Kv7.4 channel under physiological and pathological conditions. PMID- 26515071 TI - Evaluation of the Conformational Stability of Recombinant Desulfurizing Enzymes from a Newly Isolated Rhodococcus sp. AB - Metabolic pathways of aerobic bacteria able to assimilate sulfur can provide biocatalysts for biodesulfurization of petroleum and of other sulfur-containing pollutants. Of major interest is the so-called "4S pathway," in that C-S bonds are specifically cleaved leaving the carbon skeleton of substrates intact. This pathway is carried out by four enzymes, named Dsz A, B, C, and D. In view of a possible application of recombinant Dsz enzymes in biodesulfurization treatments, we have investigated the structural features of enzymes cloned from a Rhodococcus strain isolated from polluted environmental samples and their resistance to temperature (20-95 degrees C) and to organic solvents (5, 10, and 20 % v/v methanol, acetonitrile, hexane, and toluene). Changes in protein structures were assessed by circular dichroism and intrinsic fluorescence spectroscopy. We found that all Dsz proteins are unfolded by temperatures in the range 45-60 degrees C and by all solvents tested, with the most dramatic effect being produced by toluene. These results suggest that stabilization of the biocatalysts by protein engineering will be necessary for developing biodesulfurization technologies based on Dsz enzymes. PMID- 26515072 TI - Outcomes of middle cerebral artery angioplasty and stenting with Wingspan at a high-volume center. AB - INTRODUCTION: This study was to investigate the periprocedural stroke rates, safety, and long-term effect of Wingspan stenting for symptomatic severe stenosis of the middle cerebral artery (MCA) at a high-volume center. METHODS: Between July 2007 and April 2013, 196 consecutive patients with severe MCA atherosclerotic stenosis (>=70%) who were treated with Wingspan stenting were retrospectively studied. All patients had arterial stenosis-related temporary ischemic attack or strokes. The demographic data, cerebral angiography, technical success rate, periprocedural complications, and clinical and imaging follow-up were analyzed. RESULTS: The successful stenting rate was 98.0%, and the stenosis rate was improved from pre-stenting (80.6 +/- 8.3 %) to post-stenting (15.5 +/- 6.8%). The 30-day periprocedural stroke or death rate was 7.1%, with a disabling or fatal rate of 2.6%. The perioprocedural stroke rate was significantly (P < 0.01) greater in the early learning stage (16.0%) than in the later technical maturation stage (4.1%). The total periprocedural ischemic and perforator stroke rates were greater in patients with the most stenosis in the distal MCA 1/3 segment (6.8 and 5.7%, respectively) than in the proximal and middle 2/3 segments (0.9 and 0%, respectively). The ipsilateral stroke or death rate beyond 30 days (6-69 months, mean 30 +/- 16) was 4.8%, with the 1- and 2-year cumulative stroke rates of 9.6 and 12.1%, respectively. Imaging follow-up 6-69 months (mean 10.9 +/ 8.5) revealed restenosis in 21 cases (20.4 %). CONCLUSION: Intracranial stenting of MCA stenoses may have the potential of better clinical outcomes if patients are properly selected and treated by an experienced operator at a high-volume center. PMID- 26515073 TI - On the Current Drive Capability of Low Dimensional Semiconductors: 1D versus 2D. AB - Low-dimensional electronic systems are at the heart of many scaling approaches currently pursuit for electronic applications. Here, we present a comparative study between an array of one-dimensional (1D) channels and its two-dimensional (2D) counterpart in terms of current drive capability. Our findings from analytical expressions derived in this article reveal that under certain conditions an array of 1D channels can outperform a 2D field-effect transistor because of the added degree of freedom to adjust the threshold voltage in an array of 1D devices. PMID- 26515074 TI - Capture Efficiency of Biocompatible Magnetic Nanoparticles in Arterial Flow: A Computer Simulation for Magnetic Drug Targeting. AB - The primary limitation of magnetic drug targeting (MDT) relates to the strength of an external magnetic field which decreases with increasing distance. Small nanoparticles (NPs) displaying superparamagnetic behaviour are also required in order to reduce embolization in the blood vessel. The small NPs, however, make it difficult to vector NPs and keep them in the desired location. The aims of this work were to investigate parameters influencing the capture efficiency of the drug carriers in mimicked arterial flow. In this work, we computationally modelled and evaluated capture efficiency in MDT with COMSOL Multiphysics 4.4. The studied parameters were (i) magnetic nanoparticle size, (ii) three classes of magnetic cores (Fe3O4, Fe2O3, and Fe), and (iii) the thickness of biocompatible coating materials (Au, SiO2, and PEG). It was found that the capture efficiency of small particles decreased with decreasing size and was less than 5 % for magnetic particles in the superparamagnetic regime. The thickness of non-magnetic coating materials did not significantly influence the capture efficiency of MDT. It was difficult to capture small drug carriers (D<200 nm) in the arterial flow. We suggest that the MDT with high-capture efficiency can be obtained in small vessels and low-blood velocities such as micro-capillary vessels. PMID- 26515075 TI - A crown-like heterometallic unit as the building block for a 3D In-Ge-S framework. AB - Supertetrahedral clusters are the most common building blocks in constructing Group 13/14/16 microporous metal chalcogenide materials while other types of clusters are yet scarcely explored. Herein, a new crown-like building unit [In3Ge3S16] has been obtained. The units assemble into a 3D framework [C6H14NO]4[In6Ge3S17].1.5H2O (1) via a dual-connection mode and a SrSi2 (srs) type topology could be achieved by treating each unit as a tri-connected node. PMID- 26515076 TI - 18F-FDG-PET/CT can identify histopathological non-responders to platinum-based neoadjuvant chemotherapy in advanced epithelial ovarian cancer. AB - OBJECTIVE: The aim of this study was to examine the relationship between the reduction of maximum standardized uptake values (SUVmax) in 18F-FDG-PET/CT to histopathological changes obtained with neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer (EOC). We wanted to evaluate whether 18F-FDG PET/CT is useful for identifying patients who will not respond to NACT and would therefore benefit from second-line chemotherapy instead of interval debulking surgery (IDS). METHODS: Twenty-six primarily inoperable EOC patients treated with NACT were enrolled in this study. 18F-FDG-PET/CT imaging was performed before diagnostic laparoscopy and after three to four NACT cycles. The relationship between the decrease in omental SUVmax from before to after NACT with omental histopathological response was examined in samples taken from the corresponding anatomical sites during IDS. Patients were divided into three groups according to chemotherapy-induced histopathological changes. Serum CA125 and HE4 halftimes during NACT as well as Ki-67 antigen expression in IDS samples were determined. RESULTS: The median omental SUVmax change during NACT was -64% (range-16% to 84%), and it was associated with histopathological response (p=0.004, OR 0.9, CI 0.84-0.97). A SUVmax decrease of less than 57% identified histopathological non responders. Progression-free survival (PFS) differed between the poor, moderate and good histopathological response groups (0.9 year vs. 1.2 years vs. 1.4 years, respectively, p=0.05). The SUVmax change was not associated with PFS. CONCLUSION: 18F-FDG-PET/CT was able to identify patients who would not respond to NACT. To obtain a histopathological response in EOC, a substantial metabolic response in 18F-FDG-PET/CT is necessary. PMID- 26515077 TI - T cell responses: A long-chain reaction. PMID- 26515078 TI - B cells: Resetting the scene. PMID- 26515079 TI - Tracking the T cell repertoire. PMID- 26515080 TI - Mucosal immunology: A smoke-induced microRNA fires up DCs. PMID- 26515081 TI - Contribution of Anthocyanin Composition to Total Antioxidant Capacity of Berries. AB - The present study aimed to evaluate the contribution of anthocyanin composition to the total antioxidant capacity (TAC) of berries having different anthocyanin composition; blackberry, black currant, and blueberry. Blackberry demonstrated the highest TAC, while it had the lowest total anthocyanin content among the three berries in both of the phenolic extract and anthocyanin fractions. On the other hand, black currant had the highest total anthocyanin content, but the lowest TAC. Cyanidin-3-O-glucoside (cya-3-glc) accounted for 94% of blackberry anthocyanins, and as one of the strongest antioxidants present in these three berries, it substantially contributed to the TAC of blackberry anthocyanin fraction (96.0%). Delphinidin-3-O-rutinoside and cyanidin-3-O-rutinoside in black currant had lower antioxidant capacities compared with delphinin-3-O-glucoside and cya-3-glc, resulting in its lowest TAC among berry anthocyanin fractions examined. Malvidin derivatives, major anthocyanins of blueberry, had considerably lower antioxidant capacity than other anthocyanidin derivatives, such as cyanidin or delphinidin, resulting in lower TAC of blueberry compared with blackberry. Our findings indicate that anthocyanin composition as well as the antioxidant capacity of individual anthocyanins contributes to the TAC of berries rich in distinct anthocyanins. PMID- 26515082 TI - Isolation, identification and screening of antimicrobial thermophilic Streptomyces sp. Al-Dhabi-1 isolated from Tharban hot spring, Saudi Arabia. AB - The strain Streptomyces sp. Al-Dhabi-1 was isolated from soil sediments collected from Tharban hot spring in the southern west of Saudi Arabia using actinomycetes isolation agar and starch casein agar at 55 degrees C. Identification of the isolate was done according to morphological, physiological and biochemical characteristics and 16S rRNA sequence similarity as well. 16S rRNA sequence and blast analyses confirmed that the isolate belonging to the genus Streptomyces. The sequence was submitted to GenBank with accession number (KF815080). Ethyl acetate extract of Streptomyces sp. Al-Dhabi-1 showed good antimicrobial activities against tested pathogenic microbes. Minimum inhibitory concentration results showed that the best values were observed against S. agalactiae (<0.039 mg/ml) and Klebsiella pneumonia (0.125 mg/ml). Minimum inhibitory concentration of Al-Dhabi-1 against fungi; Cryptococcus neoformans (0.078 mg/ml), C. albicans (0.156 mg/ml), A. niger (0.625 mg/ml), and T. mentagrophytes (0.156 mg/ml). GC-MS analysis was used for the chemical profile of ethyl acetate extract. Benzeneacetic acid (16.02 %) and acetic acid 2-phenylethyl ester (10.35 %) were the major compounds among 31 substances found the ethyl acetate extract. According to the results of antimicrobial activity against pathogenic microbes, it is clear that the actinomycetes from hot springs with extreme environments are promising source for antimicrobial compounds. PMID- 26515083 TI - Glue, Grease, and Container: A Simplified Take on Administrative Skills. PMID- 26515084 TI - Topological Superfluid and Majorana Zero Modes in Synthetic Dimension. AB - Recently it has been shown that multicomponent spin-orbit-coupled fermions in one dimensional optical lattices can be viewed as spinless fermions moving in two dimensional synthetic lattices with synthetic magnetic flux. The quantum Hall edge states in these systems have been observed in recent experiments. In this paper we study the effect of an attractive Hubbard interaction. Since the Hubbard interaction is long-range in the synthetic dimension, it is able to efficiently induce Cooper pairing between the counterpropagating chiral edge states. The topological class of the resultant one-dimensional superfluid is determined by the parity (even/odd) of the Chern number in the two-dimensional synthetic lattice. We also show the presence of a chiral symmetry in our model, which implies Z classification and the robustness of multiple zero modes when this symmetry is unbroken. PMID- 26515085 TI - The role of human kallikrein 6, clusterin and adiponectin as potential blood biomarkers of dementia. AB - OBJECTIVES: Progressive degenerative syndromes which affect brain, altering memory, behavior, cognition and emotion, are commonly defined as dementia. It was suggested that serum human kallikrein 6 (KLK6), clusterin (CLU) and adiponectin (ADPN) in combination with inflammation markers, neuroimaging and neuropsychological testing could assist in discriminating dementia patients from control individuals. Our aim was therefore to compare serum concentrations of KLK6, CLU and ADPN and inflammatory marker, interleukin-6 (IL-6), in patients suffering from Alzheimer's disease (AD), patients with vascular dementia (VAD), cognitively healthy participants (CHP) and those with mild cognitive impairment (MCI). DESIGN AND METHODS: Serum samples were collected from AD, VAD and MCI patients admitted to the University Department of Neurology (Zagreb, Croatia) for regular follow-up. All patients underwent standard neuroimaging procedures including brain CT, neurosonological assessment with intima-media thickness (IMT) and breath holding index (BHI) calculations. Cognitive abilities were tested using standard Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Concentrations of KLK6, CLU, ADPN and IL-6 were determined in all serum samples. RESULTS: We have recruited a total of 235 participants, divided in 4 groups: AD (N=70), VAD (N=67), MCI (N=48) and CHP (N=50). Serum concentrations of KLK6 (P=0.137), CLU (P=0.178) and ADPN (P=0.268) did not differ between AD, VAD, MCI and cognitively healthy control group of participants, whereas IL-6 was significantly higher in VAD patients than in AD, MCI and CHP individuals (P=0.014). There was no association between investigated biomarkers and clinical patient parameters. CONCLUSIONS: Serum concentrations of KLK6, CLU and ADPN do not differ between AD, VAD and controls with and without mild cognitive impairment. Higher IL-6 levels in VAD group point to the inflammatory component in the development of vascular dementia. Investigated biomarkers are not associated with neuroimaging findings and neuropsychological patient data. PMID- 26515086 TI - Molecular mechanisms of dominance evolution in Mullerian mimicry. AB - Natural selection acting on dominance between adaptive alleles at polymorphic loci can be sufficiently strong for dominance to evolve. However, the molecular mechanisms underlying such evolution are generally unknown. Here, using Mullerian mimicry as a case-study for adaptive morphological variation, we present a theoretical analysis of the invasion of dominance modifiers altering gene expression through different molecular mechanisms. Toxic species involved in Mullerian mimicry exhibit warning coloration, and converge morphologically with other toxic species of the local community, due to positive frequency-dependent selection acting on these colorations. Polymorphism in warning coloration may be maintained by migration-selection balance with fine scale spatial heterogeneity. We modeled a dominance modifier locus altering the expression of the warning coloration locus, targeting one or several alleles, acting in cis or trans, and either enhancing or repressing expression. We confirmed that dominance could evolve when balanced polymorphism was maintained at the color locus. Dominance evolution could result from modifiers enhancing one allele specifically, irrespective of their linkage with the targeted locus. Nonspecific enhancers could also persist in populations, at frequencies tightly depending on their linkage with the targeted locus. Altogether, our results identify which mechanisms of expression alteration could lead to dominance evolution in polymorphic mimicry. PMID- 26515088 TI - Does the scientific evidence support the advertising claims made for products containing Lactobacillus casei and Bifidobacterium lactis? A systematic review. AB - BACKGROUND: To analyse the scientific evidence that exists for the advertising claims made for two products containing Lactobacillus casei and Bifidobacterium lactis and to conduct a comparison between the published literature and what is presented in the corporate website. METHODS: Systematic review, using Medline through Pubmed and Embase. We included human clinical trials that exclusively measured the effect of Lactobacillus casei or Bifidobacterium lactis on a healthy population, and where the objective was related to the health claims made for certain products in advertising. We assessed the levels of evidence and the strength of the recommendation according to the classification criteria established by the Oxford Centre for Evidence Based Medicine (CEBM). We also assessed the outcomes of the studies published on the website that did not appear in the search. RESULTS: Of the 440 articles identified, 16 met the inclusion criteria. Only four (25%) of these presented a level of evidence of 1b and a recommendation grade of A, all corresponding to studies on product containing Bifidobacterium lactis, and only 12 of the 16 studies were published on the corporate website (47). CONCLUSIONS: There is insufficient scientific evidence to support the health claims made for these products, especially in the case of product containing Lactobacillus casei. PMID- 26515089 TI - The Role of Arginase 1 in Post-Stroke Immunosuppression and Ischemic Stroke Severity. AB - A balanced immune system response plays an important role in acute ischemic stroke (AIS) recovery. Our laboratory has previously identified several immune related genes, including arginase 1 (ARG1), with altered expression in human AIS patients. The neutrophil-lymphocyte ratio (NLR) may be a marker of the degree of immune dysregulation following AIS; however, the molecular mechanisms that may mediate the NLR are unknown. The purpose of this study was to (1) examine the relationship between ARG1, NLR, and AIS severity and (2) to utilize principal component analysis (PCA) to statistically model multiple gene expression changes following AIS. AIS patients and stroke-free control subjects were recruited, and blood samples were collected from AIS patients within 24 h of stroke symptom onset. White blood cell differentials were obtained at this time to calculate the NLR. Gene expression was measured using real-time PCR. PCA with varimax rotation was used to develop composite variables consisting of a five-gene profile. ARG1 was positively correlated with NLR (r = 0.57, p = 0.003), neutrophil count (r = 0.526, p = 0.007), NIHSS (r = 0.607, p = 0.001), and infarct volume (r = 0.27, p = 0.051). PCA identified three principal components that explain 84.4 % of variation in the original patient gene dataset comprised of ARG1, LY96, MMP9, s100a12, and PC1 was a significant explanatory variable for NIHSS (p < 0.001) and NLR (p = 0.005). Our study suggests a novel relationship between ARG1, NLR, and stroke severity, and the NLR is an underutilized clinically available biomarker to monitor the post-stroke immune response. PMID- 26515090 TI - Genetics of alcohol use disorders: Actin gets into the act. PMID- 26515091 TI - Reply to Keelan and Payne: Microbiota-related pathways for preterm birth. PMID- 26515092 TI - Vaginal microbiota during pregnancy: Pathways of risk of preterm delivery in the absence of intrauterine infection? PMID- 26515093 TI - Training refines brain representations for multitasking. PMID- 26515094 TI - Type I IFN induces protein ISGylation to enhance cytokine expression and augments colonic inflammation. AB - Type I IFNs have broad activity in tissue inflammation and malignant progression that depends on the expression of IFN-stimulated genes (ISGs). ISG15, one such ISG, can form covalent conjugates to many cellular proteins, a process termed "protein ISGylation." Although type I IFNs are involved in multiple inflammatory disorders, the role of protein ISGylation during inflammation has not been evaluated. Here we report that protein ISGylation exacerbates intestinal inflammation and colitis-associated colon cancer in mice. Mechanistically, we demonstrate that protein ISGylation negatively regulates the ubiquitin-proteasome system, leading to increased production of IFN-induced reactive oxygen species (ROS). The increased cellular ROS then enhances LPS-induced activation of p38 MAP kinase and the expression of inflammation-related cytokines in macrophages. Thus our studies reveal a regulatory role for protein ISGylation in colonic inflammation and its related malignant progression, indicating that targeting ubiquitin-activating enzyme E1 homolog has therapeutic potential in treating inflammatory diseases. PMID- 26515095 TI - Molecular pathways for defect annihilation in directed self-assembly. AB - Over the last few years, the directed self-assembly of block copolymers by surface patterns has transitioned from academic curiosity to viable contender for commercial fabrication of next-generation nanocircuits by lithography. Recently, it has become apparent that kinetics, and not only thermodynamics, plays a key role for the ability of a polymeric material to self-assemble into a perfect, defect-free ordered state. Perfection, in this context, implies not more than one defect, with characteristic dimensions on the order of 5 nm, over a sample area as large as 100 cm(2). In this work, we identify the key pathways and the corresponding free energy barriers for eliminating defects, and we demonstrate that an extraordinarily large thermodynamic driving force is not necessarily sufficient for their removal. By adopting a concerted computational and experimental approach, we explain the molecular origins of these barriers and how they depend on material characteristics, and we propose strategies designed to overcome them. The validity of our conclusions for industrially relevant patterning processes is established by relying on instruments and assembly lines that are only available at state-of-the-art fabrication facilities, and, through this confluence of fundamental and applied research, we are able to discern the evolution of morphology at the smallest relevant length scales-a handful of nanometers-and present a view of defect annihilation in directed self-assembly at an unprecedented level of detail. PMID- 26515096 TI - Ultrahigh electrical conductivity in solution-sheared polymeric transparent films. AB - With consumer electronics transitioning toward flexible products, there is a growing need for high-performance, mechanically robust, and inexpensive transparent conductors (TCs) for optoelectronic device integration. Herein, we report the scalable fabrication of highly conductive poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS) thin films via solution shearing. Specific control over deposition conditions allows for tunable phase separation and preferential PEDOT backbone alignment, resulting in record high electrical conductivities of 4,600 +/- 100 S/cm while maintaining high optical transparency. High-performance solution-sheared TC PEDOT:PSS films were used as patterned electrodes in capacitive touch sensors and organic photovoltaics to demonstrate practical viability in optoelectronic applications. PMID- 26515098 TI - Reply to Remans et al.: Strengthening markets is key to promote sustainable agricultural and food systems. PMID- 26515097 TI - Uncoupling binding of substrate CO from turnover by vanadium nitrogenase. AB - Biocatalysis by nitrogenase, particularly the reduction of N2 and CO by this enzyme, has tremendous significance in environment- and energy-related areas. Elucidation of the detailed mechanism of nitrogenase has been hampered by the inability to trap substrates or intermediates in a well-defined state. Here, we report the capture of substrate CO on the resting-state vanadium-nitrogenase in a catalytically competent conformation. The close resemblance of this active CO bound conformation to the recently described structure of CO-inhibited molybdenum nitrogenase points to the mechanistic relevance of sulfur displacement to the activation of iron sites in the cofactor for CO binding. Moreover, the ability of vanadium-nitrogenase to bind substrate in the resting-state uncouples substrate binding from subsequent turnover, providing a platform for generation of defined intermediate(s) of both CO and N2 reduction. PMID- 26515099 TI - Expanding the view on the production and dietary diversity link: Scale, function, and change over time. PMID- 26515100 TI - Reply to Purcell et al.: Fishers and science agree, rotational harvesting reduces risk and promotes efficiency. PMID- 26515101 TI - Rotational harvesting is a risky strategy for vulnerable marine animals. PMID- 26515103 TI - Brivaracetam augments short-term depression and slows vesicle recycling. AB - OBJECTIVE: Brivaracetam (BRV) decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle glycoprotein 2A (SV2A) with a higher affinity than the antiepileptic drug levetiracetam (LEV). Experiments were performed to determine if BRV acted similarly to LEV to induce or augment short term depression (STD) under high-frequency neuronal stimulation and slow synaptic vesicle recycling. METHODS: Electrophysiologic field excitatory postsynaptic potential (fEPSP) recordings were made from CA1 synapses in rat hippocampal slices loaded with BRV or LEV during intrinsic activity or with BRV actively loaded during hypertonic stimulation. STD was examined in response to 5 or 40 Hz stimulus trains. Presynaptic release of FM1-43 was visualized using two-photon microscopy to assess drug effects upon synaptic vesicle mobilization. RESULTS: When hippocampal slices were incubated in 0.1-30 MUm BRV or 30 MUm-1 mm LEV for 3 h, the relative CA1 field EPSPs decreased over the course of a high-frequency train of stimuli more than for control slices. This STD was frequency- and concentration-dependent, with BRV being 100-fold more potent than LEV. The extent of STD depended on the length of the incubation time for both drugs. Pretreatment with LEV occluded the effects of BRV. Repeated hypertonic sucrose treatments and train stimulation successfully unloaded BRV from recycling vesicles and reversed BRVs effects on STD, as previously reported for LEV. At their maximal concentrations, BRV slowed FM1-43 release to a greater extent than in slices loaded with LEV during prolonged stimulation. SIGNIFICANCE: BRV, similar to LEV, entered into recycling synaptic vesicles and produced a frequency-dependent decrement of synaptic transmission at 100-fold lower concentrations than LEV. In addition, BRV slowed synaptic vesicle mobilization more effectively than LEV, suggesting that these drugs may modify multiple functions of the synaptic vesicle protein SV2A to curb synaptic transmission and limit epileptic activity. PMID- 26515104 TI - Synthesis of linear [5]catenanes via olefin metathesis dimerization of pseudorotaxanes composed of a [2]catenane and a secondary ammonium salt. AB - [5]Catenanes were synthesized by olefin metathesis dimerization. The reaction of pseudorotaxanes, which were derived from a [2]catenane and one equivalent of an ammonium salt bearing two terminal olefins in dichloromethane, with a catalytic amount of Grubbs catalyst afforded linear [5]catenanes in 12% yield. Intermolecular and intramolecular olefin metathesis reactions were controlled by the length of the alkyl chain of the ammonium salts. PMID- 26515105 TI - At the Centennial of the Bacteriophage: Reviving the Overlooked Contribution of a Forgotten Pioneer, Richard Bruynoghe (1881-1957). AB - The year 2015 marks the 100th anniversary of a publication by William Twort, in which he first described lysis of bacterial cultures by a filterable, self replicating agent. In 1917, Felix d'Herelle, coined the name "bacteriophage" for the proposed agent. Two Belgian teams of microbiologists were among the few to critically examine the nature of the bacteriophage at that time. Although their experimental results agreed, their interpretations did not. Richard Bruynoghe (University of Louvain/Leuven) interpreted them as supportive of d'Herelle's notion of an ultramicroscopic microorganism. Jules Bordet (University of Brussels) found the proposal of a complex organism unnecessary and saw the bacteriophage as a simple endogenous bacterial enzyme endowed with capacity to induce its own secretion as well as ability to cause lysis of the bacteria. Two decades would elapse before bacteriophages were visualized and confirmed to be organized particles. However, by that time, Bruynoghe's work, that had only been published in short notes in society proceedings, was virtually forgotten. The present paper revives his original observations and arguments, while also recognizing that Bordet's alternative hypothesis had scientific merit. PMID- 26515106 TI - The role of strigolactones in root development. AB - Strigolactones (SLs) and their derivatives were recently defined as novel phytohormones that orchestrate shoot and root growth. Levels of SLs, which are produced mainly by plant roots, increase under low nitrogen and phosphate levels to regulate plant responses. Here, we summarize recent work on SL biology by describing their role in the regulation of root development and hormonal crosstalk during root deve-lopment. SLs promote the elongation of seminal/primary roots and adventitious roots (ARs) and they repress lateral root formation. In addition, auxin signaling acts downstream of SLs. AR formation is positively or negatively regulated by SLs depending largely on the plant species and experimental conditions. The relationship between SLs and auxin during AR formation appears to be complex. Most notably, this hormonal response is a key adaption that radically alters rice root architecture in response to nitrogen- and phosphate-deficient conditions. PMID- 26515107 TI - Structure and function of mitochondrial membrane protein complexes. AB - Biological energy conversion in mitochondria is carried out by the membrane protein complexes of the respiratory chain and the mitochondrial ATP synthase in the inner membrane cristae. Recent advances in electron cryomicroscopy have made possible new insights into the structural and functional arrangement of these complexes in the membrane, and how they change with age. This review places these advances in the context of what is already known, and discusses the fundamental questions that remain open but can now be approached. PMID- 26515108 TI - Rural-Urban Differences in Chronic Disease and Drug Utilization in Older Oregonians. AB - PURPOSE: To characterize disease burden and medication usage in rural and urban adults aged >=85 years. METHODS: This is a secondary analysis of 5 years of longitudinal data starting in the year 2000 from 3 brain-aging studies. Cohorts consisted of community-dwelling adults: 1 rural cohort, the Klamath Exceptional Aging Project (KEAP), was compared to 2 urban cohorts, the Oregon Brain Aging Study (OBAS) and the Dementia Prevention study (DPS). In this analysis, 121 participants were included from OBAS/DPS and 175 participants were included from KEAP. Eligibility was determined based on age >=85 years and having at least 2 follow-up visits after the year 2000. Disease burden was measured by the Modified Cumulative Illness Rating Scale (MCIRS), with higher values representing more disease. Medication usage was measured by the estimated mean number of medications used by each cohort. FINDINGS: Rural participants had significantly higher disease burden as measured by MCIRS, 23.0 (95% CI: 22.3-23.6), than urban participants, 21.0 (95% CI: 20.2-21.7), at baseline. The rate of disease accumulation was a 0.2 increase in MCIRS per year (95% CI: 0.05-0.34) in the rural population. Rural participants used a higher mean number of medications, 5.5 (95% CI: 4.8-6.1), than urban participants, 3.7 (95% CI: 3.1-4.2), at baseline (P < .0001). CONCLUSIONS: These data suggest that rural and urban Oregonians aged >=85 years may differ by disease burden and medication usage. Future research should identify opportunities to improve health care for older adults. PMID- 26515109 TI - What is new in acetabular fracture fixation? PMID- 26515110 TI - Resident c-kit(+) cells in the heart are not cardiac stem cells. AB - Identifying a bona fide population of cardiac stem cells (CSCs) is a critical step for developing cell-based therapies for heart failure patients. Previously, cardiac c-kit(+) cells were reported to be CSCs with a potential to become myocardial, endothelial and smooth muscle cells in vitro and after cardiac injury. Here we provide further insights into the nature of cardiac c-kit(+) cells. By targeting the c-kit locus with multiple reporter genes in mice, we find that c-kit expression rarely co-localizes with the expression of the cardiac progenitor and myogenic marker Nkx2.5, or that of the myocardial marker, cardiac troponin T (cTnT). Instead, c-kit predominantly labels a cardiac endothelial cell population in developing and adult hearts. After acute cardiac injury, c-kit(+) cells retain their endothelial identity and do not become myogenic progenitors or cardiomyocytes. Thus, our work strongly suggests that c-kit(+) cells in the murine heart are endothelial cells and not CSCs. PMID- 26515111 TI - Insufficient communication and anxiety in cancer-bereaved siblings: A nationwide long-term follow-up. AB - OBJECTIVE: The purpose of this study was to examine siblings' long-term psychological health in relation to their perception of communication with their family, friends, and healthcare professionals during a brother or sister's last month of life. METHOD: A nationwide questionnaire study was conducted during 2009 in Sweden of individuals who had lost a brother or sister to cancer within the previous two to nine years. Of the 240 siblings contacted, 174 (73%), participated. The Hospital Anxiety and Depression Scale (HADS) was employed to assess psychological health (anxiety). The data are presented as proportions (%) and relative risks (RR) with a 95% confidence interval (CI 95%). RESULTS: Siblings who were not satisfied with the amount they talked about their feelings with others during their brother or sister's last month of life were more likely to report anxiety (15/58, 26%) than those who were satisfied (13/115, 11%; RR = 2.3(1.2-4.5)). The same was true for those who had been unable to talk to their family after bereavement (RR = 2.5(1.3-4.8)). Avoiding healthcare professionals for fear of being in their way increased siblings' risk of reporting anxiety at follow-up (RR = 2.2(1.1-4.6)), especially avoidance in the hospital setting (RR = 6.7(2.5-18.2)). No such differences were seen when the ill brother or sister was cared for at home. SIGNIFICANCE OF RESULTS: Long-term anxiety in bereaved siblings might be due to insufficient communication. Avoiding healthcare professionals, especially when the brother or sister is cared for at the hospital, may also increase the risk of anxiety. PMID- 26515113 TI - Tuberculosis killed 1.5 million people in 2014. PMID- 26515112 TI - Stimulant-induced hyperthermia and ice-water submersion: Practical considerations. PMID- 26515114 TI - Kinetic Studies on the Palladium(II)-Catalyzed Oxidative Cross-Coupling of Thiophenes with Arylboron Compounds and Their Mechanistic Implications. AB - Reaction orders for the key components in the palladium(II)-catalyzed oxidative cross-coupling between phenylboronic acid and ethyl thiophen-3-yl acetate were obtained by the method of initial rates. It turned out that the reaction rate not only depended on the concentration of palladium trifluoroacetate (reaction order: 0.97) and phenylboronic acid (reaction order: 1.26), but also on the concentration of the thiophene (reaction order: 0.55) and silver oxide (reaction order: -1.27). NMR spectroscopy titration studies established the existence of 1:1 complexes between the silver salt and both phenylboronic acid and ethyl thiophen-3-yl acetate. A low inverse kinetic isotope effect (kH /kD =0.93) was determined upon employing the 4-deuterated isotopomer of ethyl thiophen-3-yl acetate and monitoring its reaction to the 4-phenyl-substituted product. A Hammett analysis performed with para-substituted 2-phenylthiophenes gave a negative rho value for oxidative cross-coupling with phenylboronic acid. Based on the kinetic data and additional evidence, a mechanism is suggested that invokes transfer of the phenyl group from phenylboronic acid to a 1:1 complex of palladium trifluoroacetate and thiophene as the rate-determining step. Proposals for the structure of relevant intermediates are made and discussed. PMID- 26515116 TI - The effects of freeze/thawing on the function and phenotype of CD4(+) lymphocyte subsets in normal individuals and patients with systemic lupus erythematosus. AB - Several studies report on lymphocyte phenotypic and functional abnormalities in Systemic Lupus Erythematosus (SLE). Freezing and thawing may alter functional and phenotypic properties of cells. We assessed the effect of the freezing/thawing process (F/T) on Th1 (CD3(+)CD4(+)CCR4(-)CXCR3(+)CCR5(+)), Th2 (CD3(+)CD4(+)CCR5( )CXCR3(-)CCR4(+)), Th17 (CD3(+)CD4(+)CCR6(+)CD161(+)), and Treg (CD3(+)CD4(+)CD25(high)CD127(-)) cell cultures in healthy controls and SLE patients. F/T was associated with decreased frequency of Th2 and Th17 cells in cultures from SLE patients but not from controls. F/T was also associated with increased frequency of apoptotic cells, as measured by annexin V labeling, in all T cell subtypes analyzed, as well as increased cell proliferation, as measured by Ki-67 labeling, in all cells except Th1 from SLE patients. Thus, F/T can have differentiated effects on T lymphocyte subtypes from SLE patients and controls, and can have significant effects on cell death and proliferation. These findings should be carefully considered when designing and interpreting studies on functional and phenotypic aspects of T lymphocytes in SLE. PMID- 26515115 TI - Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers. AB - Somatic mutations in the promoter of the gene for telomerase reverse transcriptase (TERT) are the most common noncoding mutations in cancer. They are thought to activate telomerase, contributing to proliferative immortality, but the molecular events driving TERT activation are largely unknown. We observed in multiple cancer cell lines that mutant TERT promoters exhibit the H3K4me2/3 mark of active chromatin and recruit the GABPA/B1 transcription factor, while the wild type allele retains the H3K27me3 mark of epigenetic silencing; only the mutant promoters are transcriptionally active. These results suggest how a single-base pair mutation can cause a dramatic epigenetic switch and monoallelic expression. PMID- 26515117 TI - Micro-Fresnel-Zone-Plate Array on Flexible Substrate for Large Field-of-View and Focus Scanning. AB - Field of view and accommodative focus are two fundamental attributes of many imaging systems, ranging from human eyes to microscopes. Here, we present arrays of Fresnel zone plates fabricated on a flexible substrate, which allows for the adjustment of both the field of view and optical focus. Such zone plates function as compact and lightweight microlenses and are fabricated using silicon nanowires. Inspired by compound eyes in nature, these microlenses are designed to point along various angles in order to capture images, offering an exceptionally wide field of view. Moreover, by flexing the substrate, the lens position can be adjusted, thus achieving axial focus scanning. An array of microlenses on a flexible substrate was incorporated into an optical system to demonstrate high resolution imaging of objects located at different axial and angular positions. These silicon based microlenses could be integrated with electronics and have a wide range of potential applications, from medical imaging to surveillance. PMID- 26515118 TI - Surgical approach to vesicourethral anastomotic stricture following radical prostatectomy. AB - INTRODUCTION: Vesicourethral anastomotic stricture following prostatectomy is uncommon but represents a challenge for reconstructive surgery and has a significant impact on quality of life. The aim of this study was to relate our experience in managing vesicourethral anastomotic strictures and present the treatment algorithm used in our institution. PATIENTS AND METHODS: We performed a descriptive, retrospective study in which we assessed the medical records of 45 patients with a diagnosis of vesicourethral anastomotic stricture following radical prostatectomy. The patients were treated in the same healthcare centre between January 2002 and March 2015. Six patients were excluded for meeting the exclusion criteria. The stricture was assessed using cystoscopy and urethrocystography. The patients with patent urethral lumens were initially treated with minimally invasive procedures. Open surgery was indicated for the presence of urethral lumen obliteration or when faced with failure of endoscopic treatment. Urinary continence following the prostatectomy was determinant in selecting the surgical approach (abdominal or perineal). RESULTS: Thirty-nine patients treated for vesicourethral anastomotic stricture were recorded. The mean age was 64.4 years, and the mean follow-up was 40.3 months. Thirty-three patients were initially treated endoscopically. Seventy-five percent progressed free of restenosis following 1 to 4 procedures. Twelve patients underwent open surgery, 6 initially due to obliterative stricture and 6 after endoscopic failure. All patients progressed favourable after a mean follow-up of 29.7 months. CONCLUSIONS: Endoscopic surgery is the initial treatment option for patients with vesicourethral anastomotic strictures with patent urethral lumens. Open reanastomosis is warranted when faced with recalcitrant or initially obliterative strictures and provides good results. PMID- 26515119 TI - Seminal epithelium in prostate biopsy can mimic malignant and premalignant prostatic lesions. AB - OBJECTIVES: In most prostate biopsies, the seminal epithelium is easily recognised because it meets characteristic histological criteria. However, some biopsies can mimic malignant or premalignant prostatic lesions. The aims of this study were to analyse the histological appearance of the biopsies that mimic adenocarcinomas or preneoplastic prostatic lesions, discuss the differential diagnosis and determine the frequency of seminal epithelia in prostate biopsies. METHODS: We consecutively reviewed 500 prostate puncture biopsies obtained using the sextant method and selected those cases in which we observed seminal vesicle or ejaculatory duct epithelium. In the biopsies in which the seminal epithelium resembled malignant or premalignant lesions, immunohistochemical studies were conducted that included prostate-specific antigen and MUC6. The most important clinical data were recorded. RESULTS: Thirty-six (7.2%) biopsies showed seminal epithelium, and 7 of them (1.4%) resembled various prostate lesions, including high-grade prostatic intraepithelial neoplasia, atypical acinar proliferations, adenocarcinomas with papillary patterns and poorly differentiated carcinoma. The seminal epithelium resembled prostate lesions when the lipofuscin deposit, the perinuclear vacuoles or the nuclear pseudoinclusions were inconspicuous or missing. Five of the 7 biopsies showed mild to moderate cellular atypia with small and hyperchromatic nuclei, and only 2 showed cellular pleomorphism. The patients were alive and asymptomatic after an average of 6 years of progression. CONCLUSIONS: The seminal epithelium resembles prostatic intraepithelial neoplasia, atypical acinar proliferations and various types of prostatic adenocarcinomas in approximately 1.4% of prostate biopsies. PMID- 26515120 TI - "Is That A Method of Birth Control?" A Qualitative Exploration of Young Women's Use of Withdrawal. AB - Despite its ubiquity, withdrawal is understudied as a family planning method. We investigated the context of and decision making around withdrawal use, drawing on in-depth, qualitative interviews with 38 Black and Latina women (ages 18 to 24). We examined contraceptive use histories to understand when and why participants used withdrawal. The majority of participants (n = 29; 76%) had used withdrawal in their lifetimes, though two-thirds of users mentioned withdrawal in their contraceptive histories only after interviewer prompts. Withdrawal was primarily used during transitions between contraceptive methods and when other methods were not desired. Relationship context was also an important factor, as many used withdrawal to increase intimacy with their partners; because they felt condoms were no longer necessary due to monogamy; or to fulfill their partners' preferences to increase sexual pleasure. Our findings indicate that decision making around withdrawal is embedded in situational and relational contexts. Future research should explore how health care providers and sex educators can engage young women in discussions of withdrawal's benefits and constraints. A harm reduction framework, which recognizes that optimal use of withdrawal is preferable to not using a pregnancy prevention method at all, may inform the ways that withdrawal can be addressed in clinical and educational settings. PMID- 26515121 TI - Long-term learning effect is essential. PMID- 26515122 TI - Surface chemistry of oxygen on aluminum--Performance of the density functionals: PBE, PBE0, M06, and M06-L. AB - We investigated the performance of the density functional theory (DFT) functionals PBE, PBE0, M06, and M06-L for describing the molecular and dissociative adsorption of O2 onto pure and doped Al(111) surfaces. Adsorption of O2 was studied at the perfect Al(111) surface and compared with the case where an additional Al atom was present as an adatom. Additionally, we studied how these functionals perform when different dopants are present at the Al(111) surface in two distinct geometries: as an adatom or as a substitutional atom replacing an Al atom. The performance of the different functionals is greatly affected by the surface geometry. The inclusion of Hartree-Fock exchange in the functional leads to slight differences in adsorption energies for molecular adsorption of O2 . These differences become very pronounced for dissociative adsorption, with the hybrids PBE0 and M06 predicting more exergonic adsorption than PBE and M06-L. Furthermore, PBE0 and M06 predicted trends in adsorption energies for defective and perfect surfaces which are in line with the experimental knowledge of the effects of surface defects in adsorption energies. The predictions of the non hybrids PBE and M06-L point in the opposite direction. The analysis of the contributions of the van der Waals (vdW) forces to the adsorption energies reveals that the PBE and PBE0 functionals have similar difficulties in describing vdW interactions for molecular adsorption of O2 while the M06 functional can give a description of these forces with an accuracy which is at least similar to that of the correction of the D3 type. PMID- 26515123 TI - Cardiomyocyte differentiation from mouse embryonic stem cells using a simple and defined protocol. AB - BACKGROUND: Embryonic stem (ES) cells are pluripotent cells with the ability to differentiate to any cell type of the resident organism. In recent years, significant advances have been made in using these cells to obtain large numbers of cardiomyocyte (CM)-like cells for scientific research and clinical application. A vast number of protocols have emerged describing differentiation methods without the use of animal serum or extracts restrictive for use in a human clinical setting. These techniques follow a complicated procedure, which although successful, show a relatively varied yield among cell batches. RESULTS: We have designed a three-step differentiation protocol using defined reagents and a monolayer culture without feeder cells, avoiding embryoid body formation and multiple trypsin treatment, in which beating foci appeared as early as day 6 in in vitro differentiating conditions. Our results show a high yield of CM reaching approximately 60% of the differentiated cells after 13 days in vitro. CONCLUSIONS: We provide a fast, simple, reliable and reproducible protocol for inducing murine ES cells toward a CM-like phenotype comparable to available high yield protocols, without the use of intermediate trypsinization/passage steps. PMID- 26515124 TI - Changes of Saccharomyces cerevisiae cell membrane components and promotion to ethanol tolerance during the bioethanol fermentation. AB - During bioethanol fermentation process, Saccharomyces cerevisiae cell membrane might provide main protection to tolerate accumulated ethanol, and S. cerevisiae cells might also remodel their membrane compositions or structure to try to adapt to or tolerate the ethanol stress. However, the exact changes and roles of S. cerevisiae cell membrane components during bioethanol fermentation still remains poorly understood. This study was performed to clarify changes and roles of S. cerevisiae cell membrane components during bioethanol fermentation. Both cell diameter and membrane integrity decreased as fermentation time lasting. Moreover, compared with cells at lag phase, cells at exponential and stationary phases had higher contents of ergosterol and oleic acid (C18:1) but lower levels of hexadecanoic (C16:0) and palmitelaidic (C16:1) acids. Contents of most detected phospholipids presented an increase tendency during fermentation process. Increased contents of oleic acid and phospholipids containing unsaturated fatty acids might indicate enhanced cell membrane fluidity. Compared with cells at lag phase, cells at exponential and stationary phases had higher expressions of ACC1 and HFA1. However, OLE1 expression underwent an evident increase at exponential phase but a decrease at following stationary phase. These results indicated that during bioethanol fermentation process, yeast cells remodeled membrane and more changeable cell membrane contributed to acquiring higher ethanol tolerance of S. cerevisiae cells. These results highlighted our knowledge about relationship between the variation of cell membrane structure and compositions and ethanol tolerance, and would contribute to a better understanding of bioethanol fermentation process and construction of industrial ethanologenic strains with higher ethanol tolerance. PMID- 26515125 TI - Exemestane metabolites suppress growth of estrogen receptor-positive breast cancer cells by inducing apoptosis and autophagy: A comparative study with Exemestane. AB - Around 60-80% of all breast tumors are estrogen receptor-positive. One of the several therapeutic approaches used for this type of cancers is the use of aromatase inhibitors. Exemestane is a third-generation steroidal aromatase inhibitor that undergoes a complex and extensive metabolism, being catalytically converted into chemically active metabolites. Recently, our group showed that the major exemestane metabolites, 17beta-hydroxy-6-methylenandrosta-1,4-dien-3-one and 6-(hydroxymethyl)androsta-1,4,6-triene-3,17-dione, as well as, the intermediary metabolite 6beta-Spirooxiranandrosta-1,4-diene-3,17-dione, are potent aromatase inhibitors in breast cancer cells. In this work, in order to better understand the biological mechanisms of exemestane in breast cancer and the effectiveness of its metabolites, it was investigated their effects in sensitive and acquired-resistant estrogen receptor-positive breast cancer cells. Our results indicate that metabolites induced, in sensitive breast cancer cells, cell cycle arrest and apoptosis via mitochondrial pathway, involving caspase-8 activation. Moreover, metabolites also induced autophagy as a promoter mechanism of apoptosis. In addition, it was demonstrated that metabolites can sensitize aromatase inhibitors-resistant cancer cells, by inducing apoptosis. Therefore, this study indicates that exemestane after metabolization originates active metabolites that suppress the growth of sensitive and resistant breast cancer cells. It was also concluded that, in both cell lines, the biological effects of metabolites are different from the ones of exemestane, which suggests that exemestane efficacy in breast cancer treatment may also be dependent on its metabolites. PMID- 26515126 TI - Default mode network connectivity is linked to cognitive functioning and CSF Abeta1-42 levels in Alzheimer's disease. AB - BACKGROUND: Changes in the default mode network (DMN) activity are early features of Alzheimer's disease (AD) and may be linked to AD-specific Abeta pathology. METHODS: Cognitive profiles; DMN connectivity alterations; and cerebrospinal fluid (CSF) amyloid beta (Abeta)1-42, total tau, phosphorylated tau 181, and alpha-synuclein levels were studied in 21 patients with AD and 10 controls. RESULTS: DMN activity is altered in AD. Posterior cingulate cortex (PCC) functional connectivity with other parts of DMN was related to cognitive function scores. The reduction of connectivity of the dorsal PCC with the retrosplenial cortex on the right side was closely related to decreased CSF Abeta1-42 levels in patients with AD. CONCLUSIONS: The dorsal PCC and retrosplenial cortex may have special importance in the pathogenesis and cognitive findings of AD. PMID- 26515127 TI - An NMR Study of Biomimetic Fluorapatite - Gelatine Mesocrystals. AB - The mesocrystal system fluoroapatite-gelatine grown by double-diffusion is characterized by hierarchical composite structure on a mesoscale. In the present work we apply solid state NMR to characterize its structure on the molecular level and provide a link between the structural organisation on the mesoscale and atomistic computer simulations. Thus, we find that the individual nanocrystals are composed of crystalline fluorapatite domains covered by a thin boundary apatite-like layer. The latter is in contact with an amorphous layer, which fills the interparticle space. The amorphous layer is comprised of the organic matrix impregnated by isolated phosphate groups, Ca3F motifs and water molecules. Our NMR data provide clear evidence for the existence of precursor complexes in the gelatine phase, which were not involved in the formation of apatite crystals, proving hence theoretical predictions on the structural pre-treatment of gelatine by ion impregnation. The interfacial interactions, which may be described as the glue holding the composite materials together, comprise hydrogen bond interactions with the apatite PO4(3-) groups. The reported results are in a good agreement with molecular dynamics simulations, which address the mechanisms of a growth control by collagen fibers, and with experimental observations of an amorphous cover layer in biominerals. PMID- 26515128 TI - Comprehensive analysis of chemokine-induced cAMP-inhibitory responses using a real-time luminescent biosensor. AB - Chemokine receptors are members of the G-protein-coupled receptor (GPCR) family coupled to members of the Gi class, whose primary function is to inhibit the cellular adenylate cyclase. We used a cAMP-related and PKA-based luminescent biosensor (GloSensorTM F-22) to monitor the real-time downstream response of chemokine receptors, especially CX3CR1 and CXCR4, after activation with their cognate ligands CX3CL1 and CXCL12. We found that the amplitudes and kinetic profiles of the chemokine responses were conserved in various cell types and were independent of the nature and concentration of the molecules used for cAMP prestimulation, including either the adenylate cyclase activator forskolin or ligands mediating Gs-mediated responses like prostaglandin E2 or beta-adrenergic agonist. We conclude that the cAMP chemokine response is robustly conserved in various inflammatory conditions. Moreover, the cAMP-related luminescent biosensor appears as a valuable tool to analyze the details of Gi-mediated cAMP-inhibitory cellular responses, even in native conditions and could help to decipher their precise role in cell function. PMID- 26515131 TI - BRI2 and BRI3 are functionally distinct phosphoproteins. AB - Three BRI protein family members have been identified. Among these are BRI3 and BRI2, the latter is associated with Familial Danish and Familial British dementias. 'In silico' sequence analysis identified putative PP1 binding sites in BRI2 and BRI3. This is singularly important, given that protein phosphorylation is a major mechanism regulating intracellular processes. Protein phosphatase 1 (PP1) interacting proteins (PIPs) are fundamental in determining substrate specificity and subcellular localization of this phosphatase. More than 200 PIPs have thus far been reported. Both BRI2 and BRI3 are type II transmembrane glycoproteins relevant in neuronal systems. Using Myc-BRI2 and Myc-BRI3, wild type and PP1 binding mutant constructs, it was possible to show, for the first time, that in fact BRI2 and BRI3 bind PP1. The complexes BRI2:PP1 and BRI3:PP1 were validated in vitro and in vivo. The subcellular distribution of BRI2 and BRI3 is similar; both localize to the perinuclear area and Golgi apparatus in non neuronal cells. However, in SH-SY5Y cells, BRI2 and BRI3 could also be detected in elongated cellular projections ('processes') and in rat cortical neurons both are broadly distributed throughout the cell body, neuritis and the nucleus. Consistently, co-localization of BRI2 and BRI3 with PP1 was evident. The functional significance of these complexes is apparent given that both BRI proteins are substrates of PP1, thus simultaneously this is the first report of BRI2 and BRI3 as phosphoproteins. Moreover, we show that when BRI2 is phosphorylated a significant increase in neuronal outgrowth and differentiation is evident. Interestingly, the Alzheimer's amyloid precursor protein (APP), forms a trimeric complex composed of PP1 and Fe65, with PP1 having the capacity to dephosphorylate APP at Thr668 residue. The emerging consensus appears to be that PP1 containing complexes are crucial in regulating signaling events underlying neuropathological conditions. PMID- 26515130 TI - CCN1/CYR61 overexpression in hepatic stellate cells induces ER stress-related apoptosis. AB - CCN1/CYR61 is a matricellular protein of the CCN family, comprising six secreted proteins specifically associated with the extracellular matrix (ECM). CCN1 acts as an enhancer of the cutaneous wound healing process by preventing hypertrophic scar formation through induction of myofibroblast senescence. In liver fibrosis, the senescent cells are primarily derived from activated hepatic stellate cells (HSC) that initially proliferate in response to liver damage and are the major source of ECM. We investigate here the possible use of CCN1 as a senescence inducer to attenuate liver fibrogenesis by means of adenoviral gene transfer in primary HSC, myofibroblasts (MFB) and immortalized HSC lines (i.e. LX-2, CFSC 2G). Infection with Ad5-CMV-CCN1 induced large amounts of CCN1 protein in all these cells, resulting in an overload of the endoplasmic reticulum (ER) and in a compensatory unfolded protein response (UPR). The UPR resulted in upregulation of ER chaperones including BIP/Grp78, Grp94 and led to an activation of IRE1alpha as evidenced by spliced XBP1 mRNA with IRE1alpha-induced JNK phosphorylation. The UPR arm PERK and eIF2a was phosphorylated, combined with significant CHOP upregulation. Ad5-CMV-CCN1 induced HSC apoptosis that was evident by proteolytic cleavage of caspase-12, caspase-9 and the executor caspase-3 and positive TUNEL stain. Remarkably, Ad5-CMV-CCN1 effectively reduced collagen type I mRNA expression and protein. We conclude that the matricellular protein CCN1 gene transfer induces HSC apoptosis through ER stress and UPR. PMID- 26515129 TI - Insulin promotes Rip11 accumulation at the plasma membrane by inhibiting a dynamin- and PI3-kinase-dependent, but Akt-independent, internalisation event. AB - Rip11 is a Rab11 effector protein that has been shown to be important in controlling the trafficking of several intracellular cargoes, including the fatty acid transporter FAT/CD36, V-ATPase and the glucose transporter GLUT4. We have previously demonstrated that Rip11 translocates to the plasma membrane in response to insulin and here we examine the basis of this regulated phenomenon in more detail. We show that Rip11 rapidly recycles between the cell interior and surface, and that the ability of insulin to increase the appearance of Rip11 at the cell surface involves an inhibition of Rip11 internalisation from the plasma membrane. By contrast the hormone has no effect on the rate of Rip11 translocation towards the plasma membrane. The ability of insulin to inhibit Rip11 internalisation requires dynamin and class I PI3-kinases, but is independent of the activation of the protein kinase Akt; characteristics which are very similar to the mechanism by which insulin inhibits GLUT4 endocytosis. PMID- 26515132 TI - Biochar, activated carbon, and carbon nanotubes have different effects on fate of (14)C-catechol and microbial community in soil. AB - This study investigated the effects of biochar, activated carbon (AC)-, and single-walled and multi-walled carbon nanotubes (SWCNTs and MWCNTs) in various concentrations (0, 0.2, 20, and 2,000 mg/kg dry soil) on the fate of (14)C catechol and microbial community in soil. The results showed that biochar had no effect on the mineralization of (14)C-catechol, whereas AC at all amendment rates and SWCNTs at 2,000 mg/kg significantly reduced mineralization. Particularly, MWCNTs at 0.2 mg/kg significantly stimulated mineralization compared with the control soil. The inhibitory effects of AC and SWCNTs on the mineralization were attributed to the inhibited soil microbial activities and the shifts in microbial communities, as suggested by the reduced microbial biomass C and the separated phylogenetic distance. In contrast, the stimulatory effects of MWCNTs on the mineralization were attributed to the selective stimulation of specific catechol degraders by MWCNTs at 0.2 mg/kg. Only MWCNTs amendments and AC at 2,000 mg/kg significantly changed the distribution of (14)C residues within the fractions of humic substances. Our findings suggest biochar, AC, SWCNTs and MWCNTs have different effects on the fate of (14)C-catechol and microbial community in soil. PMID- 26515133 TI - Mediterranean fruit fly on Mimusops zeyheri indigenous to South Africa: a threat to the horticulture industry. AB - BACKGROUND: Claims abound that the Transvaal red milkwood, Mimusops zeyheri, indigenous to areas with tropical and subtropical commercial fruit trees and fruiting vegetables in South Africa, is relatively pest free owing to its copious concentrations of latex in the above-ground organs. On account of observed fruit fly damage symptoms, a study was conducted to determine whether M. zeyheri was a host to the notorious quarantined Mediterranean fruit fly (Ceratitis capitata). RESULTS: Fruit samples were kept for 16-21 days in plastic pots containing moist steam-pasteurised growing medium with tops covered with a mesh sheath capable of retaining emerging flies. Microscopic diagnosis of the trapped flies suggested that the morphological characteristics were congruent with those of C. capitata, which was confirmed through cytochrome c oxidase I (COI) gene sequence alignment with a 100% bootstrap value and 99% confidence probability when compared with those from the National Centre for Biotechnology Information database. CONCLUSION: This study demonstrated that M. zeyheri is a host of C. capitata. Therefore, C. capitata from infestation reservoirs of M. zeyheri fruit trees could be a major threat to the tropical and subtropical fruit industries in South Africa owing to the fruit-bearing nature of the new host. (c) 2015 Society of Chemical Industry. PMID- 26515134 TI - Rates of pneumonia among children and adults with chronic medical conditions in Germany. AB - BACKGROUND: The objective of this study is to evaluate rates of all-cause pneumonia among "at-risk" and "high-risk" children and adults in Germany-in comparison with age-stratified healthy counterparts-during the period following the 2006 recommendation for universal immunization of infants with pneumococcal conjugate vaccine. METHODS: Retrospective cohort design and healthcare claims information for 3.4 M persons in Germany (2009-2012) were employed. Study population was stratified by age and risk profile (healthy, "at-risk" [with chronic medical conditions], and "high-risk" [immunocompromised]). At-risk and high-risk conditions, as well as episodes of all-cause pneumonia, were identified via diagnosis, procedure, and drug codes. RESULTS AND DISCUSSION: Rates of all cause pneumonia were 1.7 (95 % CI 1.7-1.8) to 2.5 (2.4-2.5) times higher among children and adults with at-risk conditions versus healthy counterparts, and 1.8 (1.8-1.9) to 4.1 (4.0-4.2) times higher among children and adults with high-risk conditions. Rates of all-cause pneumonia among at-risk persons increased in a graded and monotonic fashion with increasing numbers of conditions (i.e., risk stacking). CONCLUSIONS: An increased risk for all-cause pneumonia in German children and adults with a spectrum of medical conditions persists in the era of widespread pneumococcal vaccination, and pneumonia risk in persons with >=2 at risk conditions is comparable or higher than those with high-risk conditions. PMID- 26515135 TI - Reprint of Bioneutronics: Thermal scattering in organics tissues and its impact on BNCT dosimetry. AB - Neutron transport calculation is a key factor in BNCT numerical dosimetry assessments where thermal neutron flux is intimately related to the neutron dose, specially, the therapeutic boron dose. In this work, numerical calculations in phantoms were performed to determine the importance of utilizing the appropriate thermal scattering treatment for different organic tissues. Two thermal treatments for the neutron scattering were included in the simulations: hydrogen bounded in bulk water and hydrogen bounded in a lipid like carbon chain (polyethylene). The results showed difference between both thermal treatments that can reach several percent points depending on the type of source and irradiated geometry. PMID- 26515136 TI - Reprint of localized dose delivering by ion beam irradiation for experimental trial of establishing brain necrosis model. AB - Localized dose delivery techniques to establish a brain radiation necrosis model are described. An irradiation field was designed by using accelerated protons or helium ions with a spread-out Bragg peak. Measurement of the designed field confirmed that a high dose can be confined to a local volume of an animal brain. The irradiation techniques described here are very useful for establishing a necrosis model without existence of extraneous complications. PMID- 26515137 TI - Reprint of Application of BNCT to the treatment of HER2+ breast cancer recurrences: Research and developments in Argentina. AB - In the frame of the Argentine BNCT Project a new research line has been started to study the application of BNCT to the treatment of locoregional recurrences of HER2+ breast cancer subtype. Based on former studies, the strategy considers the use of immunoliposomes as boron carriers nanovehicles to target HER2 overexpressing cells. The essential concerns of the current stage of this proposal are the development of carriers that can improve the efficiency of delivery of boron compounds and the dosimetric assessment of treatment feasibility. For this purpose, an specific pool of clinical cases that can benefit from this application was determined. In this work, we present the proposal and the advances related to the different stages of current research. PMID- 26515138 TI - A modified technique for percutaneous dilatational tracheostomy: A retrospective review of 60 cases. AB - BACKGROUND: We describe a modified technique for percutaneous dilatational tracheostomy (PDT) using intermittent bronchoscopy and ultrasound (US). This method requires 1 single physician operator and no special airway adjuncts. Our aim is to reduce the complications associated with the current popular PDT technique, that is, accidental intraprocedural airway loss, intraprocedural bleeding, and hypoventilation associated with use of continuous bronchoscopy. STUDY DESIGN: This is a retrospective review of all PDTs performed on intensive care unit patients at a single nonacademic hospital by a pulmonologist using the modified PDT technique. RESULTS: Sixty consecutive PDT procedures were performed using the modified technique. Forty-five percent of the patients were considered high-risk individuals for PDT. There were no deaths from the modified PDT procedure. There were no major complications including accidental extubation, major bleeding, posterior tracheal wall laceration, pneumothorax, hemodynamic instability, severe hypoxemia, or infection. The failure rate of PDT was 1.6%. There was no puncture of the bronchoscope, endotracheal tube, or endotracheal tube balloon. All procedures were performed by 1 single physician operator. CONCLUSION: Our modified technique demonstrates a potential to reduce accidental intraprocedural airway loss and intraoperative bleeding associated with PDT while possibly improving gas exchange and saving procedural costs. This technique needs to be comparatively studied with current popular PDT technique in a prospective trial to firmly establish associated risks and benefits. PMID- 26515139 TI - miRNA-532-5p functions as an oncogenic microRNA in human gastric cancer by directly targeting RUNX3. AB - Accumulating data reveal that microRNAs are involved in gastric carcinogenesis. To date, no information was reported about the function and regulatory mechanism of miR-532-5p in human gastric cancer (GC). Thus, our study aims to determine the role and regulation of miR-532-5p in GC. Here, we found that transient and stable overexpression of miR-532-5p dramatically increased the potential of colony formation and migration of GC cells, decreased the percentage of cells in G1 phase and cell apoptosis in vitro, and increased the weight of mice lungs and number of lung xenografts in vivo. Gain-of-function, loss-of-function and luciferase activity assays demonstrated that miR-532-5p negatively regulated the expression of RUNX3 and its targets directly. We also found that miR-532-5p level was negatively correlated with RUNX3 gene expression in various GC cell lines. Our results indicate that miR-532-5p functions as an oncogenic miRNA by promoting cell growth, migration and invasion in human GC cells. PMID- 26515140 TI - Lysyl oxidase mediates hypoxia-induced radioresistance in non-small cell lung cancer A549 cells. AB - Hypoxia-induced radioresistance has been well known as the main obstacle in cancer radiotherapy. Lysyl oxidase (LOX) was previously demonstrated to play an important role in hypoxia-induced biological behaviors, such as metastasis and angiogenesis, through hypoxia-inducible factor-1alpha (HIF-1alpha), which is an important contributing factor to radioresistance in tumor cells. However, how LOX plays a role in hypoxia-induced radioresistance has yet to be determined. Here, we found that LOX expression was in accordance with HIF-1alpha expression, and LOX expression at the mRNA and protein level, and enzymatic activity were remarkably upregulated in the hypoxic A549 cells, compared with normoxic A549 cells. Inhibition of LOX resulted in the reduction of the ability to repair double-stranded breaks (DSBs), promotion of apoptosis, relief of G2/M cycle arrest, and eventually reduction of hypoxia-induced radioresistance in the hypoxic A549 cells. This suggests that LOX may play an important role in hypoxia induced radioresistance. Together, our results might suggest a novel potential therapeutic target in the management of non-small cell lung cancer (NSCLC). PMID- 26515141 TI - Female mice with loss-of-function ITCH display an altered reproductive phenotype. AB - Major progress in deciphering the role of the E3 ligase, ITCH, in animal physiology has come from the generation and identification of Itch loss-of function mutant mice (itchy). Mutant mice display an autoimmune-like phenotype characterized by chronic dermatitis, which has been attributed to increased levels of ITCH target proteins (e.g. transcription factors JUNB and CJUN) in T cells. Autoimmune disorders also exist in humans with Itch frameshift mutations resulting in loss of functional ITCH protein. Recent phenotypic analysis of male itchy mice revealed reduced sperm production, although cross breeding experiments showed no difference in litter size when male itchy mice were bred to wild type females. However, a reduction in litter sizes did occur when itchy females were bred to wild type males. Based on these results, characterization of female reproductive function in itchy mice was performed. Developmental analysis of fetuses at gestational day 18.5, cytological evaluation of estrous cyclicity, histopathological analysis of ovaries, and protein analysis were used to investigate the itchy reproductive phenotype. Gross skeletal and soft tissue analysis of gestational day 18.5 itchy fetuses indicated no gross developmental deformities. Itchy females had reduced implantation sites, decreased corpora lutea, and increased estrous cycle length due to increased number of days in estrus compared to controls. Alterations in the expression of prototypical ITCH targets in the ovaries were not indicated, suggesting that an alteration in an as yet defined ovary-specific ITCH substrate or interaction with the altered immune system likely accounts for the disruption of female reproduction. This report indicates the importance of the E3 ligase, ITCH, in female reproduction. PMID- 26515142 TI - Blockade of glucocorticoid receptors improves cutaneous wound healing in stressed mice. AB - Stress is an important condition of modern life. The successful wound healing requires the execution of three major overlapping phases: inflammation, proliferation, and remodeling, and stress can disturb this process. Chronic stress impairs wound healing through the activation of the hypothalamic-pituitary adrenal axis, and the glucocorticoids (GCs) hormones have been shown to delay wound closure. Therefore, the aim of this study was to investigate the effects of a GC receptor antagonist (RU486) treatment on cutaneous healing in chronically stressed mice. Male mice were submitted to rotational stress, whereas control animals were not subjected to stress. Stressed and control animals were treated with RU486. A full-thickness excisional lesion was generated, and seven days later, lesions were recovered. The RU486 treatment improves wound healing since contraction takes place earlier in RU486-treated in comparison to non-treated mice, and the RU486 treatment also improves the angiogenesis in Stress+RU486 mice when compared to stressed animals. The Stress+RU486 group showed a decrease in inflammatory cell infiltration and in hypoxia-inducible factor-1alpha and inducible nitric oxide synthase expression; meanwhile, there was an increase in myofibroblasts quantity. In conclusion, blockade of GC receptors with RU486 partially ameliorates stress-impaired wound healing, suggesting that stress inhibits healing through more than one functional pathway. PMID- 26515143 TI - The reduced soluble fibrinogen-like protein 2 and regulatory T cells in acute coronary syndrome. AB - Soluble fibrinogen-like protein 2, sfgl2, is the new effector of CD4(+)CD25(+)FOXP3(+) regulatory T cell (Treg) and exerts immunosuppressive activity. We design this study to investigate the possible role of sfgl2 in atherosclerosis. A total of 58 acute coronary syndrome (ACS) patients, together with 22 stable angina (SA) patients and 31 normal coronary artery (NCA) people were enrolled in our study. Serum level of sfgl2 and plasma level of Treg were respectively measured. In line with the change of Treg, serum level of sfgl2 in ACS (8.70 ng/mL) was significantly decreased (P = 0.003), compared with that in SA (11.86 ng/mL) and NCA (17.55 ng/mL). Both sfgl2 and Treg level were obviously decreased in ACS; Sfgl2 may play a protective role in atherosclerosis. PMID- 26515144 TI - Influence of doxazosin on biosynthesis of S100A6 and atrial natriuretic factor peptides in the heart of spontaneously hypertensive rats. AB - Hypertension frequently results in severe complications in cardiovascular system and histopathological changes in the heart. To better understand the cellular processes and signaling pathways responsible for the proper functioning of the heart, we decided to check whether doxazosin affects the density of structures containing S100A6 and atrial natriuretic factor in the heart of spontaneously hypertensive rats. The aim of this study is to find differences in the density of the structures containing S100A6 and atrial natriuretic factor in the heart of spontaneously hypertensive rats treated with doxazosin compared to untreated animals. Fragments of heart were collected from five spontaneously hypertensive rats and five spontaneously hypertensive rats receiving doxazosin for six weeks (dose 0.1 mg per 1 kg of body weight). On the paraffin sections S100A6 and atrial natriuretic factor peptides were localized in the heart using immunohistochemistry. Positive immunohistochemical reaction for S100A6 was observed in atrial and ventricular cardiomyocytes and in the coronary vasculature. In the heart of hypertensive rats treated with doxazosin the S100A6 immunoreactivity was significantly lower compared to untreated animals. Immunodetection of atrial natriuretic factor in the heart of rats confirmed presence of peptide in atrial myocardium. Delicate atrial natriuretic factor immunoreactivity was observed also in few ventricular cardiomyocytes. The atrial natriuretic factor-immunosignal was significantly weaker in hearts of hypertensive rats receiving doxazosin compared to spontaneously hypertensive rats untreated. Since we found that doxazosin reduces the levels of S100A6 and atrial natriuretic factor peptides in the heart of spontaneously hypertensive rats, it can be assumed that cardiovascular disorders that occur in hypertension may be associated with disturbances of cellular processes and signaling pathways. PMID- 26515145 TI - Hypoxia-inducible miR-152 suppresses the expression of WNT1 and ERBB3, and inhibits the proliferation of cervical cancer cells. AB - Hypoxia has been a research focus in cancer because of its important role in maintaining tumor microenvironments. Previous studies have demonstrated that the expression of several miRNAs was altered under hypoxic conditions, suggesting their crucial roles in the development of cancer. In the present study, the expression of 22 miRNAs reported to be significantly upregulated in cervical cancer tissues was examined. We found that four of these miRNAs were upregulated in response to hypoxia in HeLa cervical cancer cells. MiR-152 was upregulated to the greatest extent and was also found to be upregulated by hypoxia in C33A cells and tumor, but not in non-tumor cervical tissues. Moreover, we found that hypoxia inducible factor-1alpha regulated the expression of miR-152 in HeLa cells through a hypoxia-responsive element. A bioinformatic tool predicted that WNT1 and ERBB3 were target genes of miR-152. This was confirmed by dual luciferase assays and Western blots. Overexpression of miR-152 repressed WNT1 and ERBB3 expression and decreased proliferation of HeLa cells. Collectively, these data indicate an important role for miR-152 in regulating the hypoxic response of tumor cells. PMID- 26515146 TI - Attitudes of Slovene paediatricians to end-of-life care. AB - AIMS: The aims of this study were to assess the attitudes of Slovene paediatricians to aspects of end-of-life (EOL) care and compare these attitudes between paediatric intensivists, paediatric specialists and paediatric residents. METHODS: We performed a cross-sectional survey, using a specifically designed 43 item anonymous questionnaire. RESULTS: We included 323 out of 586 Slovene paediatricians and residents, while 46.7% (151 of 323) of them responded to our questionnaire. More than half of intensivists (54.2%) had sought counsel from the Committee for Medical Ethics in the past as compared with 12.0% and 12.1% of specialists and residents, respectively (P < 0.001). The decision to limit life sustaining treatment (LST) was found to be ethically acceptable in all groups of respondents. The highest level of agreement was found in residents (90.2%), followed by 83.3% among intensivists and 73.8% among specialists (P = not statistically significant (NS)). Disagreement with termination of hydration was highest among residents (85%) and intensivists (79.2%) while it was lower among specialists (66.7%) (P = NS). Patient's best interest, good clinical practice and patient's autonomous decision were graded as the top three aspects of the EOL care, while cost effectiveness and availability of patient's bed in intensive care were the least important. CONCLUSIONS: The decision to limit LST measures was found to be ethically acceptable for Slovene paediatricians. No major differences were found among paediatric intensivists, specialist paediatricians and paediatric residents in the attitudes towards the EOL care. PMID- 26515147 TI - Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval: a randomized controlled trial. AB - Clinical outcomes of IVF cycles using propofol or thiopental sodium as anaesthetic agents for oocyte retrieval were compared. The primary outcome measure was fertilization rate per patient. One hundred and eighty patients undergoing ovarian stimulation with gonadotrophins and gonadotrophin-releasing hormone antagonists for IVF were randomized to receive either propofol (n = 90) or thiopental sodium (n = 90). No significant differences in baseline characteristics were present between the two groups. Overall fertilization rates were similar between propofol and thiopental sodium groups, respectively: median (IQR): 54.8 (29.2) versus 54.6 (29.7); fertilization rates for intracytoplasmic sperm injection only: median (IQR): 70 (50) versus 75 (50), respectively. For secondary outcome measures, time under anaesthesia was significantly increased in the thiopental sodium group: median (IQR): 12(5) versus 10 (4.5) min, P = 0.019 compared with the propofol group. Number of cumulus oocyte complexes retrieved [median (IQR): 7.1 (6.3) versus 6.5 (5.6)] did not differ significantly between the two groups. A non-significant difference in live birth rates per randomized patient of +4.4% (95% CI: -5.7 to +14.6) in favour of propofol was observed. Use of propofol compared with thiopental sodium for general anaesthesia during oocyte retrieval results in similar fertilization rates and IVF outcomes. PMID- 26515148 TI - The effect of a high progesterone concentration before oocyte retrieval on the peri-implantation endometrium. AB - In this single-centre, prospective cohort study, the effect of high progesterone level before oocyte retrieval on endometrial morphology and uterine natural killer cell (uKN) count in the peri-implantation period was investigated. A total of 106 women undergoing IVF treatment who did not proceed to fresh embryo transfer were included. Endometrial samples were obtained 7 days after HCG administration. Multiple regression analysis was used to identify factors affecting the results of histological staging and uNK cell count. Progesterone level on the day after HCG administration was the only significant variable associated with the results of histological staging (P = 0.004). Endometrial development in women with high progesterone level was significantly (P < 0.001) more advanced than that of women with normal progesterone; progesterone level on the day of HCG administration was the only significant variable associated with uNK cell count. The median (range) of uNK cell count of 9.6% (2.3-21.6%) in women with high progesterone was significantly (P < 0.001) higher than the median (range) of uNK cell count of 5.7% (1.4-18.7%) in women with normal progesterone. High progesterone level before oocyte retrieval was correlated with advancement in endometrial development as well as increased uNK cell count. PMID- 26515150 TI - Ingress and egress motion strategies of elderly and young passengers for the rear seat of minivans with sliding doors. AB - This study investigates the motion strategies performed by elderly and young passengers while entering and exiting the rear seat of minivans with sliding doors. A minivan mock-up was constructed with four adjustable parameters to represent nine different conditions of vehicle geometry. Ten elderly male participants (66.8 +/- 3.8 years old) and ten young male participants (31.5 +/- 6.6 years old) were recruited. Each of them entered and exited the minivan mock up for five times under each condition, and the motion data were acquired by the optical motion capture system. Based on the criteria derived from previous studies, all motions were automatically categorized into seven ingress motion strategies and seven egress motion strategies. Further, the differences among motion strategies are discussed in terms of vehicle factors and passenger factors, which provide clues for future studies. PMID- 26515151 TI - A dyadic model of living with epilepsy based on the perspectives of adults with epilepsy and their support persons. AB - Epilepsy is a chronic condition that significantly affects the lives of individuals with epilepsy and their support persons, though few studies have examined the experiences of both. To examine these experiences and explore the interpersonal relationships between dyad members, we conducted in-depth interviews with 22 persons with epilepsy and 16 support persons. Data analysis was guided by a grounded theory perspective. We developed a model that shows how epilepsy impacts the lives of both persons with epilepsy and their support persons and how the experiences of persons with epilepsy and supporters influence one another. The core model elements were seizure and treatment factors, relationship characteristics, self-management, seizure control, support provided, illness intrusiveness, and quality of life. Persons with epilepsy moved through the model in five trajectories depending on seizure control, relationship type, and gender. Support providers followed four trajectories based on seizure control, perception of burden, and support for themselves. Persons with epilepsy and their primary support providers have varied experiences in how epilepsy affects their lives. This model could serve as a basis for future research and intervention efforts focused on ways to reduce illness intrusiveness and improve quality of life for persons with epilepsy and their supporters. PMID- 26515152 TI - Health-related quality of life and emotional well-being in parents of children with epilepsy referred for presurgical evaluation in Sweden. AB - PURPOSE: The purpose of this study was to assess and compare health-related quality of life (HRQoL) and emotional well-being in mothers and fathers of children with drug-resistant epilepsy, referred for presurgical evaluation in Sweden. METHODS: Mothers (n=117) and fathers (n=102) of 122 children (0-18 years) completed the generic 36-item Short Form Health Survey (SF-36) and the Hospital Anxiety and Depression Scale (HADS). Mothers' and fathers' SF-36 scores were compared with age-adjusted Swedish population values using the independent t tests. Differences in the proportions of mothers vs. fathers classified as 'noncases' or 'possible/probable' clinical cases of anxiety (HADS-A) and depression (HADS-D), respectively, were assessed with the chi-square test. Parents' HADS scores were also compared using independent t-tests. RESULTS: Mothers had significantly lower scores compared with norms on 6 of the 8 SF-36 domains (p<0.01), while fathers had significantly lower scores on 4 of the domains (p<0.01). Mothers had significantly lower scores than fathers on 4 of the SF-36 domains (p<0.05). Significantly more mothers than fathers scored below the population mean for the SF-36 Mental Component Summary score. A significantly larger proportion of mothers than fathers had 'possible/probable' anxiety (52% vs. 38%) but not depression (30% vs. 22%). Mothers had significantly worse scores than fathers on HADS-A (p<0.01) but not on HADS-D. CONCLUSION: Mothers and fathers of children with drug-resistant epilepsy have diminished HRQoL compared with population norms. Symptoms of anxiety appear to be more common than symptoms of depression. Mothers experienced higher levels of anxiety, but not depression, than fathers and scored lower than fathers on vitality, mental health, and Mental Component Summary of the SF-36. There is a need to identify contributory factors and interventions to ameliorate these difficulties. PMID- 26515153 TI - Reevaluating the prevalence and diagnostic subtypes of depressive disorders in epilepsy. AB - OBJECTIVE: Depressive disorders are common among patients with epilepsy (PWE). The aim of this study was to estimate the prevalence of different forms of depressive disorders among PWE treated in the outpatient setting. METHODS: A group of consecutive PWE that visited the epilepsy outpatient clinic was invited to participate in the study. Ninety-six patients met inclusion criteria and were examined by a trained psychiatrist using standardized measures. RESULTS: A diagnosis of a current major depression was established in 21 (22.3%) out of 96 participants. Furthermore, almost 20% of the study group fulfilled criteria for mood disorder categories other than MDD, adding up to over 40% of PWE suffering from any mood disorder category. Older age and later age at seizure onset, as well as unemployment, were associated with an increase in the odds of MDD diagnosis. STUDY LIMITATIONS: A number of limitations are to be considered: the sample size is relatively small, and the findings may not be representative of PWE in general because our population represents a sample coming from a single outpatient clinic with a higher ratio of drug-resistant epilepsy. CONCLUSIONS: Major depression as well as other forms of depressive disorders are common among PWE. Unemployment, age, and age at seizure onset are important factors associated with major depression among PWE. PMID- 26515154 TI - Theory of mind abilities in patients with psychogenic nonepileptic seizures. AB - BACKGROUND: Psychogenic nonepileptic seizures (PNES) have been frequently linked to deficits in affect regulation and altered processing of emotionally salient information. However, less is known about how patients suffering from PNES actually process and interpret affective social stimuli. Thus, the present study aimed to investigate basal facial affect recognition as well as mind-reading skills in a sample of patients with PNES and matched control subjects. METHODS: Patients with PNES (N=15) and healthy controls (N=15) completed self-report questionnaires that measured alexithymia and perceived stress vulnerability. Affect perception was tested using a series of computerized movies of models whose facial expressions slowly change from neutral to full-blown emotions (anger, fear, sadness, happiness, disgust, and surprise), allowing for a fine grained assessment of facial emotion recognition impairments. Further, all participants were presented with the Movie for the Assessment of Social Cognition, a well-validated video-based test for the evaluation of subtle mind reading deficits. RESULTS: Data analyses revealed increased alexithymic traits and, impaired mentalizing skills in individuals with PNES, while basal facial expression recognition was not compromised. DISCUSSION: The present findings are the first to demonstrate that patients with PNES exhibit several deficits in reasoning about their own and other people's mental states. Patients with PNES may benefit from psychotherapeutic interventions that focus on disturbed affect regulation and aim to enhance emotional awareness. PMID- 26515155 TI - Anxiety and depression in Saudi patients with epilepsy. PMID- 26515156 TI - The role of outpatient ambulatory electroencephalography in the diagnosis and management of adults with epilepsy or nonepileptic attack disorder: A systematic literature review. AB - Electroencephalography (EEG) is an established diagnostic tool with important implications for the clinical management of patients with epilepsy or nonepileptic attack disorder. Different types of long-term EEG recording strategies have been developed over the last decades, including the widespread use of ambulatory electroencephalography (AEEG), which holds great potential in terms of both clinical usefulness and cost-effectiveness. In this paper, we present the results of a systematic review of the scientific literature on the use of AEEG in the diagnosis of epilepsy and nonepileptic attacks in adult patients. Taken together, our findings confirmed that AEEG is a useful diagnostic tool in patients with equivocal findings on routine EEG studies and influences management decisions in the majority of studies. There is evidence that AEEG is also more likely to capture events than sleep-deprived EEG; however, there are currently insufficient data available to compare the diagnostic utility of modern AEEG technology with inpatient video-telemetry. Further research on the combined use of AEEG and home-video recording is, therefore, warranted. PMID- 26515157 TI - Long-term seizure and psychosocial outcomes of vagus nerve stimulation for intractable epilepsy. AB - Vagus nerve stimulation (VNS) is a widely used adjunctive treatment option for intractable epilepsy. Most studies have demonstrated short-term seizure outcomes, usually for up to 5 years, and thus far, none have reported psychosocial outcomes in adults. We aimed to assess long-term seizure and psychosocial outcomes in patients with intractable epilepsy on VNS therapy for more than 15 years. We identified patients who had VNS implantation for treatment of intractable epilepsy from 1997 to 2013 at our Comprehensive Epilepsy Program and gathered demographics including age at epilepsy onset and VNS implantation, epilepsy type, number of antiepilepsy drugs (AEDs) and seizure frequency before VNS implantation and at the last clinic visit, and the most recent stimulation parameters from electronic medical records (EMR). Phone surveys were conducted by research assistants from May to November 2014 to determine patients' current seizure frequency and psychosocial metrics, including driving, employment status, and use of antidepressants. Seizure outcomes were based on modified Engel classification (I: seizure-free/rare simple partial seizures; II: >90% seizure reduction (SR), III: 50-90% SR, IV: <50% SR; classes I to III (>50% SR)=favorable outcome). A total of 207 patients underwent VNS implantation, 15 of whom were deceased at the time of the phone survey, and 40 had incomplete data for medical abstraction. Of the remaining 152, 90 (59%) were contacted and completed the survey. Of these, 51% were male, with the mean age at epilepsy onset of 9.4 years (range: birth to 60 years). There were 35 (39%) patients with extratemporal epilepsy, 19 (21%) with temporal, 18 (20%) with symptomatic generalized, 5 (6%) with idiopathic generalized, and 13 (14%) with multiple types. Final VNS settings showed 16 (18%) patients with an output current >2 mA and 14 (16%) with rapid cycling. Of the 80 patients with seizure frequency information, 16 (20%) had a modified Engel class I outcome, 14 (18%) had class II, 24 (30%) had class III, and 26 (33%) had class IV. Eighty percent said having VNS was worthwhile. Among the 90 patients, 43 patients were >= 18 years old without developmental delay in whom psychosocial outcomes were further analyzed. There was a decrease in the number of patients driving (31% vs 14%, p=0.052) and working (44% vs 35%, p=0.285) and an increase in the number of patients using antidepressant medication (14% vs 28%, p=0.057) at the time of survey compared to before VNS. In this subset, patients with >50% SR (60%) were taking significantly fewer AEDs at the time of survey compared to patients with unfavorable outcomes (median: 3 vs 4, p=0.045). The associations of >50% SR with the psychosocial outcomes of driving, employment, and antidepressant use were not significant, although 77% of this subset said VNS was worthwhile. This is the first study that assesses both seizure and psychosocial outcomes, and demonstrates favorable seizure outcomes of >50% SR in 68% of patients and seizure freedom in 20% of patients. A large majority of patients (80%) considered VNS therapy worthwhile regardless of epilepsy type and psychosocial outcomes. PMID- 26515158 TI - Cuffing-based photoacoustic flowmetry in humans in the optical diffusive regime. AB - Measuring blood flow speed in the optical diffusive regime in humans has been a long standing challenge for photoacoustic tomography. In this work, we proposed a cuffing-based method to quantify blood flow speed in humans with a handheld photoacoustic probe. By cuffing and releasing the blood vessel, we can measure the blood flow speed downstream. In phantom experiments, we demonstrated that the minimum and maximum measurable flow speeds were 0.035 mm/s and 42 mm/s, respectively. In human experiments, flow speeds were measured in three different blood vessels: a radial artery in the right forearm, a radial artery in the index finger of the right hand, and a radial vein in the right forearm. Taking advantage of the handheld probe, our method can potentially be used to monitor blood flow speed in the clinic and at the bedside. PMID- 26515160 TI - DERM: Dermatologic Education Reinforced Mnemonically. PMID- 26515159 TI - Non-invasive assessment of intracranial pressure. AB - Monitoring of intracranial pressure (ICP) is invaluable in the management of neurosurgical and neurological critically ill patients. Invasive measurement of ventricular or parenchymal pressure is considered the gold standard for accurate measurement of ICP but is not always possible due to certain risks. Therefore, the availability of accurate methods to non-invasively estimate ICP has the potential to improve the management of these vulnerable patients. This review provides a comparative description of different methods for non-invasive ICP measurement. Current methods are based on changes associated with increased ICP, both morphological (assessed with magnetic resonance, computed tomography, ultrasound, and fundoscopy) and physiological (assessed with transcranial and ophthalmic Doppler, tympanometry, near-infrared spectroscopy, electroencephalography, visual-evoked potentials, and otoacoustic emissions assessment). At present, none of the non-invasive techniques alone seem suitable as a substitute for invasive monitoring. However, following the present analysis and considerations upon each technique, we propose a possible flowchart based on the combination of non-invasive techniques including those characterizing morphologic changes (e.g., repetitive US measurements of ONSD) and those characterizing physiological changes (e.g., continuous TCD). Such an integrated approach, which still needs to be validated in clinical practice, could aid in deciding whether to place an invasive monitor, or how to titrate therapy when invasive ICP measurement is contraindicated or unavailable. PMID- 26515163 TI - Characterization of the intravenous glucose tolerance test and the combined glucose-insulin test in donkeys. AB - Glucose-insulin dynamic challenges such as the intravenous glucose tolerance test (IVGTT) and combined glucose-insulin test (CGIT) have not been described in donkeys. The objectives of this study were (1) to characterize the IVGTT and CGIT in healthy adult donkeys, and (2) to establish normal glucose-insulin proxies. Sixteen donkeys were used and body morphometric variables obtained each. For the IVGTT, glucose (300 mg/kg) was given IV. For the CGIT, glucose (150 mg/kg) followed by recombinant insulin (0.1 IU/kg) were administered IV. Blood samples for glucose and insulin determinations were collected over 300 min. In the IVGTT the positive phase lasted 160.9 +/- 13.3 min, glucose concentration peaked at 323.1 +/- 9.2 mg/dL and declined at a rate of 1.28 +/- 0.15 mg/dL/min. The glucose area under the curve (AUC) was 21.4 +/- 1.9 * 10(3) mg/dL/min and the insulin AUC was 7.2 +/- 0.9 * 10(3) uIU/mL/min. The positive phase of the CGIT curve lasted 44 +/- 3 min, with a glucose clearance rate of 2.01 +/- 0.18 mg/dL/min. The negative phase lasted 255.9 +/- 3 min, decreasing glucose concentration at rate of -0.63 +/- 0.06 mg/dL/min, and reaching a nadir (33.1 +/- 3.6 mg/dL) at 118.3 +/- 6.3 min. The glucose and insulin AUC values were 15.2 +/- 0.9 * 10(3) mg/dL/min and 13.2 +/- 0.9 * 10(3) uIU/mL/min. This is the first study characterizing CGIT and IVGTT, and glucose-insulin proxies in healthy adult donkeys. Distinct glucose dynamics, when compared with horses, support the use of species-specific protocols to assess endocrine function. PMID- 26515162 TI - Aryl hydrocarbon receptor-dependent apoptotic cell death induced by the flavonoid chrysin in human colorectal cancer cells. AB - The polyphenolic flavone chrysin has been evaluated as a natural chemopreventive agent due to its anti-cancer effects in a variety of cancer cell lines. However, the mechanism of the chemopreventive effect has been not well established, especially in human colorectal cancer cells. We evaluated the chemopreventive effect of chrysin in three different human colorectal cancer cell lines. We found that chrysin treatment consequently reduced cell viability via induction of apoptosis. We identified that the involvement of up-regulation of pro-apoptotic cytokines tumor necrosis factor (Tnf) alpha and beta genes and consequent activation of the TNF-mediated transcriptional pathway in chrysin-induced apoptosis. Using our generated AHR siRNA expressing colorectal cancer cells, we demonstrated that the chrysin-induced up-regulation of Tnfalpha and beta gene expression was dependent on the aryl hydrocarbon receptor (AHR), which is a ligand-receptor for chrysin. Subsequently, we found that the AHR siRNA expressing colorectal cancer cells were resistant to chrysin-induced apoptosis. Therefore, we concluded that AHR is required for the chrysin-induced apoptosis and the up regulation of Tnfalpha and beta gene expression in human colorectal cancer cells. PMID- 26515164 TI - Equine recurrent uveitis: Lessons from and for autoimmune anterior uveitis in humans. PMID- 26515165 TI - Comprehensive analysis of translational osteochondral repair: Focus on the histological assessment. AB - Articular cartilage guarantees for an optimal functioning of diarthrodial joints by providing a gliding surface for smooth articulation, weight distribution, and shock absorbing while the subchondral bone plays a crucial role in its biomechanical and nutritive support. Both tissues together form the osteochondral unit. The structural assessment of the osteochondral unit is now considered the key standard procedure for evaluating articular cartilage repair in translational animal models. The aim of this review is to give a detailed overview of the different methods for a comprehensive evaluation of osteochondral repair. The main focus is on the histological assessment as the gold standard, together with immunohistochemistry, and polarized light microscopy. Additionally, standards of macroscopic, non-destructive imaging such as high resolution MRI and micro-CT, biochemical, and molecular biological evaluations are addressed. Potential pitfalls of analysis are outlined. A second focus is to suggest recommendations for osteochondral evaluation. PMID- 26515166 TI - Impact of Voltage Mapping to Guide Whether to Perform Ablation of the Posterior Wall in Patients With Persistent Atrial Fibrillation. AB - BACKGROUND: Fibrosis as a substrate for atrial fibrillation (AF) has been shown in numerous preclinical models. Voltage mapping enables in vivo assessment of scar in the left atrium (LA), which can be targeted with catheter ablation. OBJECTIVE: We hypothesized that using the presence or absence of low voltage to guide ablation beyond pulmonary vein antral isolation (PVAI) will improve atrial arrhythmia (AF/AT)-free survival in persistent AF. METHODS AND RESULTS: Single center retrospective analysis of 2 AF ablation strategies: (1) standard ablation (SA) versus (2) voltage-guided ablation (VGA). PVAI was performed in both groups. With SA, additional lesions beyond PVAI were performed at the discretion of the operator. With VGA, additional lesions to isolate the LA posterior wall were performed if voltage mapping of this region in sinus rhythm showed scar (LA voltage < 0.5 mV). AF-/AT-free endpoint was defined as no sustained AF/AT seen off antiarrhythmic medications after a 2-month postablation blanking period. Seventy-six patients underwent SA and 65 underwent VGA. Patients were well matched for comorbidities, LVEF, and left atrial size. Posterior wall ablation was performed in 57% of patient with SA compared to 42% with VGA. VGA ablation increased 1-year AF-/AT-free survival in patients when compared to SA (80% vs. 57%; P = 0.005). In a multivariate analysis, VGA was the only independent predictor of AF-/AT-free survival (hazard ratio of 0.30; P = 0.002). CONCLUSIONS: The presence of LA posterior wall scar may be an important ablation target in persistent AF. A prospective randomized trial is needed to confirm these data. PMID- 26515167 TI - An investigation of the mimetic enzyme activity of two-dimensional Pd-based nanostructures. AB - In this work, we investigated the mimetic enzyme activity of two-dimensional (2D) Pd-based nanostructures (e.g. Pd nanosheets, Pd@Au and Pd@Pt nanoplates) and found that they possess intrinsic peroxidase-, oxidase- and catalase-like activities. These nanostructures were able to activate hydrogen peroxide or dissolved oxygen for catalyzing the oxidation of organic substrates, and decompose hydrogen peroxide to generate oxygen. More systematic investigations revealed that the peroxidase-like activities of these Pd-based nanomaterials were highly structure- and composition-dependent. Among them, Pd@Pt nanoplates displayed the highest peroxidase-like activity. Based on these findings, Pd-based nanostructures were applied for the colorimetric detection of H2O2 and glucose, and also the electro-catalytic reduction of H2O2. This work offers a promising prospect for the application of 2D noble metal nanostructures in biocatalysis. PMID- 26515168 TI - [Pathological and metabolic bone diseases: Clinical importance for fracture treatment]. AB - Pathological and metabolic bone diseases are common and relevant occurrences in orthopedics and trauma surgery; however, fractures are often treated as being the illness itself and not seen as the symptom of an underlying bone disease. This is why further diagnostics and systemic treatment options are often insufficiently considered in the routine treatment of fractures. This review focuses on osteoporosis, osteopetrosis, hypophosphatasia and Paget's disease of bone.In patients with osteoporotic vertebral or proximal femur fractures, pharmaceutical treatment to prevent subsequent fractures is an integral part of fracture therapy together with surgical treatment. Osteopetrosis is caused by compromised osteoclastic bone resorption; therefore, even in the face of an elevated bone mass, vitamin D3 supplementation is crucial to avoid clinically relevant hypocalcemia. Unspecific symptoms of the musculoskeletal system, especially together with stress fractures, are typically found in patients suffering from hypophosphatasia. In these patients measurement of alkaline phosphatase shows reduced enzyme activity. Elevated levels of alkaline phosphatase are found in Paget's disease of bone where bisphosphonates are still the treatment of choice. PMID- 26515171 TI - Literature reviews. PMID- 26515170 TI - Outcome analysis of 215 patients with parotid gland tumors: a retrospective cohort analysis. AB - BACKGROUND: To identify prognostic factors in patients with parotid gland carcinomas who were treated at the Princess Margaret Hospital. METHODS: Clinical outcome of two hundred fifteen patients with malignancies of the parotid gland was evaluated over a 16-year period. RESULTS: Two-hundred-fifteen patients with adenoid cystic carcinoma (n = 20), adenocarcinoma (n = 19), acinic cell carcinoma (n = 62), basal cell adenocarcinoma (n = 7), carcinoma-ex-pleomorphic adenoma (n = 18), mucoepidermoid carcinoma (n = 70) and salivary duct carcinoma (n = 19) have been included. The 5- and 10-year overall and disease-free survivals were 80.62%/69.48% and 74.37%/62.42%, respectively. Multivariable analysis showed that age greater than 60 years, advanced pN classification, histopathological grade and the presence of lymphovascular invasion significantly worsened overall and disease-free survival. Univariable analysis revealed periparotid lymph node involvement was associated with decreased overall (p < 0.0001) and disease-free survival (p < 0.0001). CONCLUSIONS: In addition to age, pN classification, histopathological grade, perineural invasion, and lymphovascular involvement, periparotid lymph node metastasis appears to be an important prognosticator in parotid gland malignancy. PMID- 26515169 TI - Reference gene stability of a synanthropic fly, Chrysomya megacephala. AB - BACKGROUND: Stable reference genes are essential for accurate normalization in gene expression studies with reverse transcription quantitative polymerase chain reaction (qPCR). A synanthropic fly, Chrysomya megacephala, is a well known medical vector and forensic indicator. Unfortunately, previous studies did not look at the stability of reference genes used in C. megacephala. RESULTS: In this study, the expression level of Actin, ribosomal protein L8 (Rpl8), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), elongation factor 1alpha (EF1), alpha-tubulin (alpha-TUB), beta-tubulin (beta-TUB), TATA binding box (TBP), 18S rRNA (18S) and ribosomal protein S7 (Rps7) were evaluated for their stability using online software RefFinder, which combines the normal software of the DeltaCt method, BestKeeper, Normfinder, and geNorm. Moreover the number of suitable reference gene pairs was also suggested by Excel-based geNorm. The expression levels of these reference genes were evaluated under different experimental conditions with special perspectives of forensic applications: developmental stages (eggs, first, second and third instar larvae, pupae and adults); food sources of larvae (pork, fish and chicken); feeding larvae with drugs (untreated control, Estazolam and Marvelon); feeding larvae with heavy metals (untreated control, cadmium and zinc); tissues of adults (head, thorax, abdomen, legs and wings). According to RefFinder, EF1 was the most suitable reference gene of developmental stages, food and tissues; 18S and GAPDH were the most suitable reference genes for drugs and heavy metals, respectively, which could be widely used for quantification of target gene expression with qPCR in C. megacephala. Suitable reference gene pairs were also suggested by geNorm. CONCLUSION: This fundamental but vital work should facilitate the gene studies of related biological processes and deepen the understanding in physiology, toxicology, and especially medical and forensic entomology of C. megacephala. PMID- 26515172 TI - The deterministic SIS epidemic model in a Markovian random environment. AB - We consider the classical deterministic susceptible-infective-susceptible epidemic model, where the infection and recovery rates depend on a background environmental process that is modeled by a continuous time Markov chain. This framework is able to capture several important characteristics that appear in the evolution of real epidemics in large populations, such as seasonality effects and environmental influences. We propose computational approaches for the determination of various distributions that quantify the evolution of the number of infectives in the population. PMID- 26515173 TI - Effects of Melatonin on Morphological and Functional Parameters of the Pineal Gland and Organs of Immune System in Rats During Natural Light Cycle and Constant Illumination. AB - We studied the response of the pineal gland and organs of the immune system to melatonin treatment in Wistar rats kept under conditions of abnormal illumination regimen. The animals were kept under natural light regimen or continuous illumination for 14 days and then received daily injections of melatonin (once a day in the evening) for 7 days. Administration of melatonin to rats kept at natural light cycle was followed by a decrease in percent ratio of CD4+8+ splenocytes and CD4-8+ thymocytes. In 24-h light with the following melatonin injections were accompanied by an increase in percent rate and absolute amount of CD4+8+ cells in the spleen, and a decrease in percent rate of CD11b/c and CD4-8+ splenocytes. In the thymus amount of CD4-8+ cells increased, and absolute number of CD4+25+ cells reduced. Melatonin significantly decreased lipofuscin concentration in the pineal gland during continuous light. Direction and intensity of effects of melatonin on parameters of cell immunity and state of the pineal gland were different under normal and continuous light conditions. It should be taken into account during using of this hormone for correction of immune and endocrine impairments developing during change in light/dark rhythm. PMID- 26515174 TI - Erratum to: Suppression of ITGB4 Gene Expression in PC-3 Cells with Short Interfering RNA Induces Changes in the Expression of beta-Integrins Associated with RGD-Receptors. PMID- 26515175 TI - Responses of Spermatogenous Tissue and Mechanisms of Their Development Upon Cytostatic Exposure. AB - A decrease in the total number of sperm cells and reduction of spermatogonium population were observed upon cytostatic damage of spermatogenous tissue caused by single paclitaxel administration. It was established that the paclitaxel induced damage to the testicular tissue is underlain by reduction of its regenerative potential consisting in depletion of regional precursor pool. Changes in functional activity of progenitor cells were caused not only by direct action of paclitaxel, but also by suppression of the secretory function of the tissue microenvironment. PMID- 26515176 TI - Peptides Restore Functional State of the Kidneys During Cisplatin-Induced Acute Renal Failure. AB - The effects of polypeptide complex from the kidney and short peptides AED, EDL, and AEDG on renal functions were studied in rats with cisplatin-induced acute renal failure. AED peptide decreased protein excretion and electrolyte concentration in the urine. Polypeptide complex from the kidney and peptides EDL and AEDG normalized diuresis, creatinine concentration in the urine and its excretion, glomerular filtration rate, and absolute resorption of sodium ions and reduced protein concentration in the urine and its excretion, the concentrations of sodium and potassium ions in the urine, and other parameters. EDL peptide produced was potent nephroprotective effect. It is known that the polypeptide complex of the kidney and short peptides restore the expression of signal molecules (marker of functional state of the kidneys), so these peptide substances can have nephroprotective effect during various renal pathologies. PMID- 26515177 TI - Stable Lentiviral Vector Transfer into Mesenchymal Stem Cells In Vivo. AB - Green fluorescent protein (eGFP) gene was transferred into mouse mesenchymal stem cells in vivo using a lentiviral vector. In 2 months after injection of the lentivirus into the cavity of the femoral bone, up to 30% fibroblast CFU in the bone marrow of infected mice contained the alien gene. The transferred gene was found in more than 50% of adherent layers of longterm bone marrow cultures formed by mesenchymal stem cells from the infected mice bone marrow; 4% fibroblast CFU obtained from these layers were labeled. Ectopic hemopoiesis foci developed after transplantation of the bone marrow from infected mice under the renal capsule of syngeneic recipients contained bone tissue labeled with the alien gene in 57% cases and labeled fibroblast CFU in 11%. The data confirm the possibility of gene transfer with the lentiviral vectors into the mesenchymal stem cells in vivo. PMID- 26515178 TI - Activation of P-450-Dependent Monooxygenases Modulates the Diuretic Effect of Histochrome in Rats. AB - We studied the role of the liver monooxygenase system in pharmacological activity of histochrome, a pharmaceutical form of echinochrome A. In experiments on rats, benzonal, an inductor of the monooxygenase system of phenobarbytal type, significantly potentiated the diuretic effect of histochrome. Benzonal withdrawal was followed by a natriuretic reaction. In view of the known inverse relation between the biological effect of the drug and the rate of its metabolism, our findings suggest that the effects of echinochrome A on some kidney excretory function parameters are produced not by native agent, but one of its metabolites. PMID- 26515179 TI - Role of Interleukin-4, Interleukin-10, and Tumor Necrosis Factor-alpha Polymorphic Genes in the Pathogenesis of Occupational Allergic Dermatoses. AB - Study of polymorphic genes of pro- and anti-inflammatory cytokines (IL-4, IL-10, TNF-alpha) in patients with occupational allergic dermatoses showed significantly higher frequency of polymorphic variants of cytokine genes IL4 C589T, IL10 C819T, IL10 G1082A, IL10 C592A, and TNF G308A in comparison with the population control. The presence of homozygous variant IL10 G1082A--AA in 80% cases characterizes early disease development, i.e. within 3 years after the first exposure to the occupational factor. PMID- 26515180 TI - Sex-Related Differences in the Sensitivity to Carcinogenic Effect of Urethane on the Lungs in Mice Are Reversed after Neonatal Androgenization. AB - Experiments on male and female CC57BR/Mv mice differing by the sensitivity to carcinogenic effect of urethane on the lungs showed that castration 1 week before carcinogen challenge reduced the number of lung adenomas caused by it in males and somewhat increased the number of tumors in females. Exogenous testosterone after urethane injection caused virtually no changes in urethane effect in males and females. By contrast, elevation of testosterone concentrations in newborn male and female mice by injections or its decrease in feminized males receiving sodium glutamate during the neonatal period reduced the sensitivity to the carcinogenic effect of urethane in adult males and to its increase in females. PMID- 26515181 TI - Immunohistochemical Analysis of the Structure of Injured Peripheral Nerve Neuroma after Electrosurgical Welding Intervention. AB - Immunohistochemical analysis of changes in neuroma after surgical treatment of damaged peripheral nerve with the use of high frequency electrosurgical device for high frequency current welding of soft tissues was carried out. No adverse effects of this technology and the bipolar instrument on degeneration and regeneration of damaged nerve stem were detected. PMID- 26515182 TI - Parameters of Microcirculation in the Broad Ligament of the Uterus in Wistar Rats after Injection of Autologous Biomedical Cell Product. AB - We studied the effects of autologous biomedical cell product (bone marrow multipotent mesenchymal stromal cells and their conditioned media) on the parameters of the microcirculatory bed in the broad ligament of the uterus of normal Wistar rats were studied. The parameters of microcirculation and lymph drainage in the broad ligament changed in opposite directions in response to injection of autologous biomedical cell product via different routes. This fact should be taken into consideration when prescribing cell therapy for inflammatory degenerative processes in the pelvic organs. PMID- 26515183 TI - Stimulation of Cardiomyocyte Regeneratory Reactions under Conditions of Cytopathic Hypercholesterolemia. AB - The regeneratory reactions of cardiomyocytes in the heart under conditions of cytopathic exposure to hypercholesterolemia and during verapamil treatment were studied by immunohistochemical detection of proliferation marker Ki-67 and evaluation of cardiomyocyte count. A 30-day exposure of rats to atherogenic diet led to an increase of Ki-67+ cardiomyocytes by 14.5-16.7 times (p<0.05). The Ki 67 label index in cardiomyocytes remained higher than normally (8-9-fold; p<0.05) after 64 days. It remained elevated (8-11-fold; p<0.05) after verapamil treatment. Evaluation of cardiomyocyte count and of their nuclear status detected various regeneratory strategies: increase of the total cardiomyocyte count, with increase of the percentage of mononuclear cardiomyocytes (particularly in response to verapamil in group 1 rats); decrease of total cardiomyocyte count with increase of the percentage of multinuclear cardiomyocytes (particularly in group 2 rats in response to verapamil). PMID- 26515184 TI - Different work capacity impairments in patients with different work-anxieties. AB - PURPOSE: Persons with work-anxieties are especially endangered for work capacity impairment and sick leave. Work capacity impairment is not directly due to symptoms but due to illness-related capacity disorders. Work capacity impairments can be described on different dimensions (e.g., social interaction, decision making and judgment, endurance, mobility). Understanding the type of work capacity impairment is important for reintegration interventions. This is the first study to investigate work capacity impairment in risk patients with different work-anxieties. METHODS: Two hundred and forty-four patients in inpatient rehabilitation suffering from work-anxieties were investigated concerning degree of work capacity impairment. Capacity impairment was described on 13 capacity dimensions according to the internationally evaluated observer rating Mini-ICF-APP (impairment grades 0-4, grade 2 and higher indicating clinically relevant observable impairment). A physician's rating on global work ability prognosis was obtained along with sick leave duration during 6 months after assessment. Patients with different work-anxieties were compared concerning capacity impairments. RESULTS: Patients with different work-anxieties were impaired in different capacity dimensions: Work-related social anxiety went along with clinically relevant impairment in capacity of assertiveness (M = 2.40), anxiety of insufficiency went along with impaired capacity of endurance (M = 2.20), and work-related generalized worrying was accompanied by impairment in the capacity for decision making (M = 1.82). Specific capacity impairment dimensions were related to sick leave duration, while a global work ability prognosis was not. CONCLUSIONS: The capacity approach is useful to describe work impairment more precisely and beyond symptoms. On this basis, reintegration-focusing interventions such as capacity training (e.g., social interaction training) or work adjustment (e.g., reducing exposure with interactional work tasks) can be initiated. PMID- 26515185 TI - Experiences of work ability in young workers: an exploratory interview study. AB - PURPOSE: The aim of this study was to explore the experiences of and influences on work ability in young workers related to their work and life situation. METHODS: In a qualitative study of a strategic sample of 12 young female and 12 young male workers, aged 25-30 years, in work or recently left work, recruited from the 5-year follow-up of a Swedish cohort, semi-structured interviews were performed to explore the experiences of work ability in these young workers. Systematic text condensation inspired by phenomenology was used in the analysis. RESULTS: Work ability was experienced as complex, consisting of four themes, each with three subthemes. To be alert and have energy, to possess sufficient education, skills and working life experience and experience meaningfulness and engagement in work, were perceived to be fundamental for work ability and were seen as the worker's own responsibility. Moreover, work ability can be improved or reduced by the psychosocial work climate, the work organization and the private life. Optimal work ability was experienced when all themes integrated in a positive way. CONCLUSIONS: Work ability was experienced as the worker's own responsibility that could be influenced by work circumstances and private life. To promote good work ability among young workers, work ability has to be understood in its specific context. Whether the understanding of work ability found in this study is explicit for the group of young adults needs to be explored in a more general population in further research. PMID- 26515187 TI - Crystal structures and ligand binding of PurM proteins from Thermus thermophilus and Geobacillus kaustophilus. AB - Crystal structures of 5-aminoimidazole ribonucleotide (AIR) synthetase, also known as PurM, from Thermus thermophilus (Tt) and Geobacillus kaustophilus (Gk) were determined. For TtPurM, the maximum resolution was 2.2 A and the space group was P21212 with four dimers in an asymmetric unit. For GkPurM, the maximum resolution was 2.2 A and the space group was P21212 with one monomer in asymmetric unit. The biological unit is dimer for both TtPurM and GkPurM and the dimer structures were similar to previously determined structures of PurM in general. For TtPurM, ~50 residues at the amino terminal were disordered in the crystal structure whereas, for GkPurM, the corresponding region covered the ATP binding site forming an alpha helix in part, suggesting that the N-terminal region of PurM changes its conformation upon binding of ligands. FGAM binding site was predicted by the docking simulation followed by the MD simulation based on the SO4 (2-) binding site found in the crystal structure of TtPurM. PMID- 26515186 TI - Nitric Oxide Interacts with Caveolin-1 to Facilitate Autophagy-Lysosome-Mediated Claudin-5 Degradation in Oxygen-Glucose Deprivation-Treated Endothelial Cells. AB - Using in vitro oxygen-glucose deprivation (OGD) model, we have previously demonstrated that 2-h OGD induces rapid, caveolin-1-mediated dissociation of claudin-5 from the cellular cytoskeletal framework and quick endothelial barrier disruption. In this study, we further investigated the fate of translocated claudin-5 and the mechanisms by which OGD promotes caveolin-1 translocation. Exposure of bEND3 cells to 4-h OGD, but not 2-h OGD plus 2-h reoxygenation, resulted in claudin-5 degradation. Inhibition of autophagy or the fusion of autophagosome with lysosome, but not proteasome, blocked OGD-induced claudin-5 degradation. Moreover, knockdown of caveolin-1 with siRNA blocked OGD-induced claudin-5 degradation. Western blot analysis showed a transient colocalization of caveolin-1, claudin-5, and LC3B in autolysosome or lipid raft fractions at 2-h OGD. Of note, inhibiting autophagosome and lysosome fusion sustained the colocalization of caveolin-1, claudin-5, and LC3B throughout the 4-h OGD exposure. EPR spin trapping showed increased nitric oxide (NO) generation in 2-h OGD-treated cells, and inhibiting NO with its scavenger C-PTIO or inducible nitric oxide synthase (iNOS) inhibitor 1400W prevented OGD-induced caveolin-1 translocation and claudin-5 degradation. Taken together, our data provide a novel mechanism underlying endothelial barrier disruption under prolonged ischemic conditions, in which NO promotes caveolin-1-mediated delivery of claudin-5 to the autophagosome for autophagy-lysosome-dependent degradation. PMID- 26515189 TI - Facile electrochemical synthesis of CeO2@Ag@CdS nanotube arrays with enhanced photoelectrochemical water splitting performance. AB - In this work, for the first time, three-component CeO2@Ag@CdS heterostructured nanotube arrays with remarkable photoelectrochemical (PEC) performance have been synthesized by an electrodeposition method. In this configuration, the modification with Ag nanoparticles can significantly strengthen light absorption and provide an interior direct pathway to facilitate the separation and transport of photogenerated carriers. Therefore, the CeO2@Ag@CdS heterostructured nanotubes generate a remarkable photocurrent density of 2.14 mA cm(-2) at a potential of 0.2 V (vs. Ag/AgCl), which is 9.8 and 2.4 times higher than that of the two component CeO2@Ag system (0.218 mA cm(-2)) and the CeO2@CdS system (0.879 mA cm( 2)), respectively. It also gives efficiency as high as 69% around 360 nm in the incident photon to electron conversion efficiency (IPCE) spectrum. Moreover, the stability of the photoelectrode was tested over 16 min. Furthermore, these results provide a valuable insight for the further development of such materials for PEC water splitting. PMID- 26515191 TI - Erratum: Superconducting magnetoresistance in ferromagnet/superconductor/ferromagnet trilayers. PMID- 26515190 TI - Chronic ethanol exposure increases voluntary home cage intake in adult male, but not female, Long-Evans rats. AB - The current experiment examined the effects of 10 days of chronic intermittent ethanol (CIE) exposure on anxiety-like behavior and home cage ethanol intake using a 20% intermittent access (M, W, F) paradigm in male and female Long-Evans rats. Withdrawal from alcohol dependence contributes to relapse in humans and increases in anxiety-like behavior and voluntary ethanol consumption in preclinical models. Our laboratory has shown that 10 days of CIE exposure produces both behavioral and neurophysiological alterations associated with withdrawal in male rats; however, we have yet to examine the effects of this exposure regime on ethanol intake in females. During baseline, females consumed more ethanol than males but, unlike males, did not show escalations in intake. Rats were then exposed to CIE and were again given intermittent access to 20% ethanol. CIE males increased their intake compared to baseline, whereas air exposed males did not. Ethanol intake in females was unaffected by CIE exposure. Notably, both sexes expressed significantly elevated withdrawal-associated anxiety-like behavior in the plus maze. Finally, rats were injected with the cannabinoid CB1 receptor antagonist, SR141716A (0, 1, 3, 10mg/kg, i.p.) which reduced ethanol intake in both sexes. However, females appear to be more sensitive to lower doses of this CB1 receptor antagonist. Our results show that females consume more ethanol than males; however, they did not escalate their intake using the intermittent access paradigm. Unlike males, CIE exposure had no effect on drinking in females. It is possible that females may be less sensitive than males to ethanol-induced increases in drinking after a short CIE exposure. Lastly, our results demonstrate that males and females may have different pharmacological sensitivities to CB1 receptor blockade on ethanol intake, at least under the current conditions. PMID- 26515193 TI - Waste-Glycerol-Directed Synthesis of Mesoporous Silica and Carbon with Superior Performance in Room-Temperature Hydrogen Production from Formic Acid. AB - The development of easier, cheaper, and more ecofriendly synthetic methods for mesoporous materials remains a challenging topic to commercialize them, and the transformation of waste glycerol, as a biodiesel byproduct, into something useful and salable is one of the pending issues to be resolved. Here we first report that mesoporous silica (KIE-6) and carbon (KIE-7) can be simultaneously synthesized by using cheap and ecofriendly crude-waste-glycerol of biodiesel with or without glycerol purification, and we demonstrated the excellent performance of the mesoporous material as a catalyst support for formic acid decomposition. As a result, Pd-MnOx catalysts supported on NH2-functionalized KIE-6 showed the highest catalytic activity (TOF: 540.6 h(-1)) ever reported for room-temperature formic acid decomposition without additives. Moreover, we conducted life-cycle assessment (LCA) from biomass cultivation through biodiesel production to KIE-6 and KIE-7 preparation, and it was confirmed that CO2 emission during synthesis of KIE-6 and KIE-7 could be reduced by 87.1% and 85.7%, respectively. We believe that our study suggested more ecofriendly and industry-friendly approaches for preparation of mesoporous materials, and utilization of waste glycerol. PMID- 26515192 TI - An advanced white matter tract analysis in frontotemporal dementia and early onset Alzheimer's disease. AB - Cortical and subcortical nuclei degenerate in the dementias, but less is known about changes in the white matter tracts that connect them. To better understand white matter changes in behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer's disease (EOAD), we used a novel approach to extract full 3D profiles of fiber bundles from diffusion-weighted MRI (DWI) and map white matter abnormalities onto detailed models of each pathway. The result is a spatially complex picture of tract-by-tract microstructural changes. Our atlas of tracts for each disease consists of 21 anatomically clustered and recognizable white matter tracts generated from whole-brain tractography in 20 patients with bvFTD, 23 with age-matched EOAD, and 33 healthy elderly controls. To analyze the landscape of white matter abnormalities, we used a point-wise tract correspondence method along the 3D profiles of the tracts and quantified the pathway disruptions using common diffusion metrics - fractional anisotropy, mean, radial, and axial diffusivity. We tested the hypothesis that bvFTD and EOAD are associated with preferential degeneration in specific neural networks. We mapped axonal tract damage that was best detected with mean and radial diffusivity metrics, supporting our network hypothesis, highly statistically significant and more sensitive than widely studied fractional anisotropy reductions. From white matter diffusivity, we identified abnormalities in bvFTD in all 21 tracts of interest but especially in the bilateral uncinate fasciculus, frontal callosum, anterior thalamic radiations, cingulum bundles and left superior longitudinal fasciculus. This network of white matter alterations extends beyond the most commonly studied tracts, showing greater white matter abnormalities in bvFTD versus controls and EOAD patients. In EOAD, network alterations involved more posterior white matter - the parietal sector of the corpus callosum and parahipoccampal cingulum bilaterally. Widespread but distinctive white matter alterations are a key feature of the pathophysiology of these two forms of dementia. PMID- 26515194 TI - The safety of hormonal contraceptives for women living with HIV and their sexual partners. AB - BACKGROUND: Hormonal contraceptives are important for the health and well-being of some women living with HIV, so evaluation of evidence regarding their safety vis-a-vis HIV-related risks is important. METHODS: We updated two prior systematic reviews on the impact of hormonal contraception (HC) on HIV disease progression and female-to-male HIV transmission. RESULTS: One new study finds no increased risk for HIV disease progression or death associated with oral contraceptive use [adjusted (adj) hazard ratio (HR) 0.83, confidence interval [CI] 0.48-1.44] or injectables (adj HR 0.72, CI 0.53-0.98). Three new studies did not find significantly increased risks for measures of female-to-male HIV transmission with HC use. CONCLUSIONS: Hormonal contraceptive methods do not appear to accelerate HIV disease progression. More research is needed to clarify whether HC impacts HIV transmissibility. PMID- 26515195 TI - Projections and opinions from 100 experts in long-acting reversible contraception. AB - OBJECTIVE: This survey of published researchers of long-acting reversible contraceptives (LARCs) examines their opinions about important barriers to LARC use in the United States (US), projections for LARC use in the absence of barriers and attitudes toward incentives for clinicians to provide and women to use LARC methods. STUDY DESIGN: We identified 182 authors of 59 peer-reviewed papers on LARC use published since 2013. A total of 104 completed an internet survey. We used descriptive and multivariate analyses to assess LARC use barriers and respondent characteristics associated with LARC projections and opinions. RESULTS: The most commonly identified barrier was the cost of the device (63%), followed by women's knowledge of safety, method acceptability and expectations about use. A shortage of trained providers was a commonly cited barrier, primarily of primary care providers (49%). Median and modal projections of LARC use in the absence of these barriers were 25-29% of contracepting women. There was limited support for provider incentives and almost no support for incentives for women to use LARC methods, primarily out of concern about coercion. CONCLUSIONS: Clinical and social science LARC experts project at least a doubling of the current US rate of LARC use if barriers to method provision and adoption are removed. While LARC experts recognize the promise of LARC methods to better meet women's contraceptive needs, they anticipate that the majority of US women will not choose LARC methods. Reducing unintended pregnancy rates will depend on knowledge, availability and use of a wider range of methods of contraception to meet women's individual needs. IMPLICATIONS: Efforts to increase LARC use need to meet the dual goals of increasing access to LARC methods and protecting women's reproductive autonomy. To accomplish this, we need reasonable expectations for use, provider training, low-cost devices and noncoercive counseling, rather than incentives for provision or use. PMID- 26515196 TI - Improving protein-ligand docking with flexible interfacial water molecules using SWRosettaLigand. AB - Computational protein-ligand docking is of great importance in drug discovery and design. Conformational changes greatly affect the results of protein-ligand docking, especially when water molecules take part in mediating protein ligand interactions or when large conformational changes are observed in the receptor backbone interface. We have developed an improved protocol, SWRosettaLigand, based on the RosettaLigand protocol. This approach incorporates the flexibility of interfacial water molecules and modeling of the interface of the receptor into the original RosettaLigand. In a coarse sampling step, SWRosettaLigand pre optimizes the initial position of the water molecules, docks the ligand to the receptor with explicit water molecules, and minimizes the predicted structure with water molecules. The receptor backbone interface is treated as a loop and perturbed and refined by kinematic closure, or cyclic coordinate descent algorithm, with the presence of the ligand. In two cross-docking test sets, it was identified that for 8 out of 14, and 16 out of 22, test instances, the top ranked structures by SWRosettaLigand achieved better accuracy than other protocols. PMID- 26515198 TI - Patient-Centered Decision Support in Acute Ischemic Stroke: Qualitative Study of Patients' and Providers' Perspectives. AB - BACKGROUND: National guidelines endorse recombinant tissue-type plasminogen activator (r-tPA) in eligible patients with acute ischemic stroke to improve patients' functional recovery. However, 23% to 40% of ideal candidates with acute ischemic stroke for reperfusion are not treated, perhaps because of the difficulty in explaining the benefits and risks of r-tPA within the frenetic pace of emergency department care. To support better knowledge transfer and creation of a shared decision-making tool, we conducted qualitative interviews to define the information needs and preferred presentation format for stroke survivors, caregivers, and clinicians considering r-tPA treatment. METHODS AND RESULTS: A multidisciplinary team used qualitative research methods to identify informational needs and strategies for describing the benefits and risks of r-tPA in a clinical setting. Through focus groups (n=10) of stroke survivors (n=39) and caregivers (n=24) and individual interviews with emergency physicians (n=23) and advanced practice nurses (n=20), several themes emerged. Survivors and caregivers preferred a broader definition of a good outcome (independence, rather than no significant disability), simpler graphs as compared with detailed pictographs, and presentation of both population and individualized benefits (framed positively) and risk of receiving r-tPA. Some physicians expressed skepticism with the data and the ability to present risk/benefit information emergently, whereas other physicians and most advanced practice nurses thought such information would improve care. Physicians stressed the importance of presenting the risk of thrombolytic-related intracranial hemorrhage. CONCLUSIONS: This study suggests that a positively framed risk-benefit tool with graphical presentations of general and patient-specific risk estimates could support patients and providers in considering r-tPA for acute ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01864928. PMID- 26515197 TI - Mechanisms of long-term cognitive dysfunction of sepsis: from blood-borne leukocytes to glial cells. AB - Several mechanisms are associated with brain dysfunction during sepsis; one of the most important are activation of microglia and astrocytes. Activation of glial cells induces changes in permeability of the blood-brain barrier, secretion of inflammatory cytokines, and these alterations could induce neuronal dysfunction. Furthermore, blood-borne leukocytes can also reach the brain and participate in inflammatory response. Mechanisms involved in sepsis-associated brain dysfunction were revised here, focusing in neuroinflammation and involvement of blood-borne leukocytes and glial cells in this process. PMID- 26515199 TI - Quality of Care and Ischemic Stroke Risk After Hospitalization for Transient Ischemic Attack: Findings From Get With The Guidelines-Stroke. AB - BACKGROUND: Patients with transient ischemic attack (TIA) are at increased risk for ischemic stroke. We derived a prediction rule for 1-year ischemic stroke risk post-TIA, examining estimated risk, receipt of inpatient quality of care measures for TIA, and the presence or absence of stroke at 1 year post discharge. METHODS AND RESULTS: We linked 67 892 TIA Get With The Guidelines-Stroke patients >65 years (2003-2008) to Medicare inpatient claims to obtain longitudinal outcomes. Using Cox proportional hazards modeling in a split sample, we identified baseline demographics and clinical characteristics associated with ischemic stroke admission during the year post-TIA, and developed a Get With The Guidelines Ischemic Stroke after TIA Risk Score; performance was examined in the validation sample. Quality of care was estimated by a global defect-free care measure, and individual performance measures within estimated risk score quintiles. The overall hospital admission rate for ischemic stroke during the year post-TIA was 5.7%. Patients with ischemic stroke were more likely to be older, black, and have higher rates of smoking, previous stroke, diabetes mellitus, previous myocardial infarction, heart failure, and atrial fibrillation. The Risk Score showed moderate discriminative performance (c-statistic=0.606); highest quintile patients were less likely to receive statins, smoking cessation counseling, and defect-free care. Although not associated with 1-year ischemic stroke, DCF was associated with a significantly lower risk of all-cause mortality. CONCLUSIONS: TIA patients with high estimated ischemic stroke risk are less likely to receive defect-free care than low-risk patients. Standardized risk assessment and delivery of optimal inpatient care are needed to reduce this risk-treatment mismatch. PMID- 26515200 TI - Mobile Phone-Based Questionnaire for Assessing 3 Months Modified Rankin Score After Acute Stroke: A Pilot Study. AB - BACKGROUND: In many countries, a majority of stroke patients are not assessed for long-term functional outcome owing to limited resources and time. We investigated whether automatic assessment of the modified Rankin Scale (mRS) based on a mobile phone questionnaire may serve as an alternative to mRS assessments at clinical visits after stroke. METHODS AND RESULTS: We enrolled 62 acute stroke patients admitted to our stroke unit during March to May 2014. Forty-eight patients completed the study. During the stay, patients and/or caregivers were equipped with a mobile phone application in their personal mobile phones. The mobile phone application contained a set of 20 questions, based on the Rankin Focused Assessment, which we previously tested in a pilot study. Three months after inclusion, the mobile phone application automatically prompted the study participants to answer the mRS questionnaire in the mobile phones. Each question or a group of questions in the questionnaire corresponded to a certain mRS score. Using a predefined protocol, the highest mRS score question where the study participant had answered yes was deemed the final mobile mRS score. A few days later, a study personnel performed a clinical visit mRS assessment. The 2 assessments were compared using quadratic weighing kappa-statistics. Mean age was 67 years (38% females), and median baseline National Institutes of Health Stroke Scale (NIHSS) score was 5 (interquartile range 2-10.5, range 0-23). Median and mean clinical visit mRS at 3 months was 2 and 2.3, respectively. We found a 62.5% agreement between clinical visit and mobile mRS assessment, weighted kappa 0.89 (95% confidence interval 0.82-0.96), and unweighted kappa 0.53 (95% confidence interval 0.36-0.70). Dichotomized mRS outcome separating functionally independent (mRS score 0-2) from dependent (mRS score 3-5) showed 83% agreement and unweighted kappa of 0.66 (95% confidence interval 0.45-0.87). CONCLUSIONS: Mobile phone-based automatic assessments of mRS performed well in comparison with clinical visit mRS and could be used as an alternative in stroke follow-up. PMID- 26515201 TI - Care Trajectories of Veterans in the 12 Months After Hospitalization for Acute Ischemic Stroke. AB - BACKGROUND: Recovery after a stroke varies greatly between individuals and is reflected by wide variation in the use of institutional and home care services. This study sought to classify veterans according to their care trajectories in the 12 months after hospitalization for ischemic stroke. METHODS AND RESULTS: The sample consisted of 3811 veterans hospitalized for ischemic stroke in Veterans Health Administration facilities in 2007. Three outcomes--nursing home care, home care, and mortality--were modeled jointly >12 months using latent class growth analysis. Data on Veterans' care use and cost came from the Veterans Administration and Medicare. Covariates included stroke severity (National Institutes of Health Stroke Scale), functional status (functional independence measure score), age, marital status, chronic conditions, and prestroke ambulation. Five care trajectories were identified: 49% of Veterans had Rapid Recovery with little or no use of care; 15% had a Steady Recovery with initially high nursing home or home care that tapered off; 9% had Long-Term Home Care; 13% had Long-Term Nursing Home Care; and 14% had an Unstable trajectory with multiple transitions between long-term and acute care settings. Care use was greatest for individuals with more severe strokes, lower functioning at hospital discharge, and older age. Average annual costs were highest for individuals with the Long Term Nursing Home trajectory ($63,082), closely followed by individuals with the Unstable trajectory ($58,720). Individual with the Rapid Recovery trajectory had the lowest costs ($9271). CONCLUSIONS: Care trajectories after stroke were associated with stroke severity and functional dependency and they had a dramatic impact on subsequent costs. PMID- 26515202 TI - Does the Volume of Ischemic Stroke Admissions Relate to Clinical Outcomes in the Ontario Stroke System? AB - BACKGROUND: Better outcomes have been found among hospitals treating higher volumes of patients for specific surgical and medical conditions. We examined hospital ischemic stroke (IS) volume and 30-day mortality to inform regionalization planning. METHODS AND RESULTS: Using a population-based hospital discharge administrative database (2005/2006 to 2011/2012), average annual IS patient volumes were calculated for 162 Ontario acute hospitals. Hospitals were ranked and classified as small (<126), medium (126-202), and large (>202). Hierarchical multivariable logistic regression was used to estimate the odds of death within 7 and 30 days to account for the homogeneity in outcomes for patients treated at the same hospital. Overall, 73 368 patients were hospitalized for IS, and 30-day mortality was 15.3%. The mean (+/-SD) of annual hospitalizations for IS was 29 (31) for small-volume hospitals, 156 (20) for medium-volume hospitals, and 300 (78) for high-volume hospitals. High-volume hospitals admitted younger patients (mean [+/-SD] age, 73.0 [13.9] years) compared with medium- and small-volume hospitals (74.0 [13.2] and 75.5 [12.5] years, respectively; P<0.0001). Patients at small-volume hospitals were more likely than patients at high-volume hospitals to die at 30 days after an acute IS (adjusted odds ratio, 1.37; 95% confidence interval, 1.14-1.65). CONCLUSIONS: Hospital IS volume is associated with 30-day mortality in Ontario. Patients admitted to hospitals with annual IS volumes <126 annually are more likely to die within 30 days than patients admitted to hospitals that see on average 300 patients annually. This finding supports centralizing care in stroke-specialized hospitals. PMID- 26515203 TI - Academic-Community Hospital Comparison of Vulnerabilities in Door-to-Needle Process for Acute Ischemic Stroke. AB - BACKGROUND: Although best practices have been developed for achieving door-to needle (DTN) times <=60 minutes for stroke thrombolysis, critical DTN process failures persist. We sought to compare these failures in the Emergency Department at an academic medical center and a community hospital. METHODS AND RESULTS: Failure modes effects and criticality analysis was used to identify system and process failures. Multidisciplinary teams involved in DTN care participated in moderated sessions at each site. As a result, DTN process maps were created and potential failures and their causes, frequency, severity, and existing safeguards were identified. For each failure, a risk priority number and criticality score were calculated; failures were then ranked, with the highest scores representing the most critical failures and targets for intervention. We detected a total of 70 failures in 50 process steps and 76 failures in 42 process steps at the community hospital and academic medical center, respectively. At the community hospital, critical failures included (1) delay in registration because of Emergency Department overcrowding, (2) incorrect triage diagnosis among walk-in patients, and (3) delay in obtaining consent for thrombolytic treatment. At the academic medical center, critical failures included (1) incorrect triage diagnosis among walk-in patients, (2) delay in stroke team activation, and (3) delay in obtaining computed tomographic imaging. CONCLUSIONS: Although the identification of common critical failures suggests opportunities for a generalizable process redesign, differences in the criticality and nature of failures must be addressed at the individual hospital level, to develop robust and sustainable solutions to reduce DTN time. PMID- 26515204 TI - Changes in European Label and Guideline Adherence After Updated Recommendations for Stroke Thrombolysis: Results From the Safe Implementation of Treatments in Stroke Registry. AB - BACKGROUND: Intravenous thrombolysis (IVT) for acute ischemic stroke is subject to label and guideline contraindications. Updated European guidelines in 2008/2009 recommended IVT in selected patients aged >80 years and stroke onset-to treatment time 3 to 4.5 hours, which the label still prohibited. Our aim was to compare contraindication nonadherence before and after the guideline update. METHODS AND RESULTS: Data on IVT-treated patients with stroke at 232 European hospitals participating in the Safe Implementation of Treatments in Stroke registry during both periods 2006 to 2007 (n=6354) and 2010 to 2011 (n=12 046). After the 2008/2009 guideline update, the proportion of patients nonadherent to label increased from 23.6% to 51.1% (P<0.001). Specifically, nonadherence to onset-to-treatment time >3 hours increased from 8.2% to 27.9% and IVT in patients aged >80 years from 8.9% to 17.2% (both P<0.001). Nonadherence also increased to the contraindications severe stroke (National Institutes of Health Stroke Scale score >25), onset-to-treatment time >4.5 hours, blood pressure >185/110 mm Hg, and ongoing oral anticoagulation (all P<=0.001). Higher hospital IVT patient volumes were associated with higher nonadherence rates. CONCLUSIONS: After the European guideline update, new recommendations were promptly adopted and nonadherence to the unchanged label increased. Label contraindications should be updated. PMID- 26515205 TI - Chronic Stroke Outcome Measures for Motor Function Intervention Trials: Expert Panel Recommendations. AB - BACKGROUND: About half of survivors with stroke experience severe and significant long-term disability. The purpose of this article is to review the state of the science and to make recommendations for measuring patient-centric outcomes in interventions for motor improvement in the chronic stroke phase. METHODS AND RESULTS: A 9-member expert panel reviewed evidence to identify measures of upper and lower extremity function used to date as outcomes in trials with patients who experienced a stroke >=6 months before assessment. Outcome measures were screened using StrokEDGE consensus panel recommendations, and evaluated for availability of a published minimal clinically important difference. Measures meeting these criteria were further evaluated with regard to their level of measurement, psychometric properties, and ability of minimal clinically important difference to capture gains associated with improved function and clinical relevance to patients, to arrive at recommendations. A systematic literature review yielded 115 clinical trials of upper and lower extremity function in chronic stroke that used a total of 34 outcome measures. Seven of these had published minimal clinically important differences and were recommended or highly recommended by StrokEDGE. Those are the Fugl-Meyer Upper Extremity and Lower Extremity scales, Wolf Motor Function Test, Action Research Arm Test, Ten-Meter and Six-Minute Walk Tests, and the Stroke Impact Scale. All had evidence for their psychometric performance, although the strength of evidence for validity varied, especially in populations with chronic stroke Fugl-Meyer Upper and Lower Extremity scales showing the strongest evidence for validity. CONCLUSIONS: The panel recommends that the Fugl-Meyer Upper and Lower Extremity scales be used as primary outcomes in intervention trials targeting motor function in populations with chronic stroke. The other 6 measures are recommended as secondary outcomes. PMID- 26515206 TI - Patient Characteristics and Outcomes After Hemorrhagic Stroke in Pregnancy. AB - BACKGROUND: Hospitalizations for pregnancy-related stroke are rare but increasing. Hemorrhagic stroke (HS), ie, subarachnoid hemorrhage and intracerebral hemorrhage, is more common than ischemic stroke in pregnant versus nonpregnant women, reflecting different phenotypes or risk factors. We compared stroke risk factors and outcomes in pregnant versus nonpregnant HS in the Get With The Guidelines-Stroke Registry. METHODS AND RESULTS: Using medical history or International Classification of Diseases-Ninth Revision codes, we identified 330 pregnant and 10 562 nonpregnant female patients aged 18 to 44 years with HS in Get With The Guidelines-Stroke (2008-2014). Differences in patient and care characteristics were compared by chi(2) or Fisher exact test (categorical variables) or Wilcoxon rank-sum (continuous variables) tests. Conditional logistic regression assessed the association of pregnancy with outcomes conditional on categorical age and further adjusted for patient and hospital characteristics. Pregnant versus nonpregnant HS patients were younger with fewer pre-existing stroke risk factors and medications. Pregnant versus nonpregnant subarachnoid hemorrhage patients were less impaired at arrival, and less than half met blood pressure criteria for severe preeclampsia. In-hospital mortality was lower in pregnant versus nonpregnant HS patients: adjusted odds ratios (95% CI) for subarachnoid hemorrhage 0.17 (0.06-0.45) and intracerebral hemorrhage 0.57 (0.34-0.94). Pregnant subarachnoid hemorrhage patients also had a higher likelihood of home discharge (2.60 [1.67-4.06]) and independent ambulation at discharge (2.40 [1.56-3.70]). CONCLUSIONS: Pregnant HS patients are younger and have fewer risk factors than their nonpregnant counterparts, and risk-adjusted in hospital mortality is lower. Our findings suggest possible differences in underlying disease pathophysiology and challenges to identifying at-risk patients. PMID- 26515207 TI - Electronic Stroke CarePath: Integrated Approach to Stroke Care. AB - We describe the development, implementation, and outcomes of the first 2 years of the Electronic Stroke CarePath, an initiative developed for management of ischemic stroke patients in an effort to improve efficiency and quality of care for patients. The CarePath consists of care pathways for ischemic stroke that are integrated within the electronic health record. Patient-reported outcomes are collected using an external software platform. Documentation tools, order sets, and clinical decision support were designed to improve efficiency, optimize process measure adherence, and produce clinical data as a byproduct of care that are available for future analyses. Inpatient mortality and length of stay were compared before and after CarePath implementation in ischemic stroke patients after adjustment for case-mix. Postdischarge functional outcomes of patients with ischemic stroke were compared between the first 3 months of rollout and remainder of the study period. From January 2011 to December 2012, there were 1106 patients with ischemic stroke on the CarePath. There was a decline in inpatient mortality in patients with ischemic stroke, but not in control patients with intracerebral or subarachnoid hemorrhage. Completion rate of patient-reported questionnaires at postdischarge stroke follow-up was 72.9%. There was a trend toward improved functional outcomes at follow-up with CarePath implementation. Implementation of the Electronic Stroke CarePath is feasible and may be associated with a benefit in multiple different outcomes after ischemic stroke. This approach may be an important strategy for optimizing stroke care in the future. PMID- 26515208 TI - Transitions of Care for Stroke Patients: Opportunities to Improve Outcomes. PMID- 26515209 TI - Mapping Primary and Comprehensive Stroke Centers by Certification Organization. PMID- 26515210 TI - Stroke Issue 2015. PMID- 26515211 TI - Future of Quality and Outcomes Research in Stroke. PMID- 26515212 TI - Acute Stroke: Shifting From Informed Consent to Informed Refusal of Intravenous Tissue-Type Plasminogen Activator. PMID- 26515213 TI - Smoking Paradox in Patients Hospitalized With Coronary Artery Disease or Acute Ischemic Stroke: Findings From Get With The Guidelines. AB - BACKGROUND: Smoking is a potent risk factor for coronary artery disease (CAD) and acute ischemic stroke (AIS), but there are numerous reports of lower in-hospital mortality among smokers versus nonsmokers hospitalized for these events. METHODS AND RESULTS: We analyzed all consecutive patients hospitalized with a first index CAD (n=158 054) or AIS (n=899 295) event in Get With The Guidelines from 2002 to 2012; 20.4% of AIS and 30.4% of patients with CAD were past-year smokers. Multivariable models and age-stratified analyses were used to estimate the adjusted odds ratio of in-hospital mortality in smokers versus nonsmokers. Smokers were younger, more often male, with fewer vascular risk factors, and were more likely to be admitted to hospitals that were large, academic, or in the South. In-hospital mortality was significantly lower among smokers in both CAD (2.7% versus 5.2%; P<0.0001) and AIS (3.5% versus 5.8%; P<0.0001). The difference between unadjusted and adjusted odds ratios for smoking (0.57 versus 0.86 in CAD; 0.56 versus 0.86 in AIS) indicates the presence of substantial confounding by age and other covariates, but a significant association of past-year smoking remained. CONCLUSIONS: Among patients hospitalized with CAD and AIS, smoking is a risk factor for early age of onset, even among those with few vascular risk factors. The persistent association with lower in-hospital mortality after adjusted and stratified analyses probably represents residual unmeasured confounding, although a biological effect of smoking cannot be excluded. Further clinical and prospective population-based studies are needed to explore variables that contribute to outcomes in these patients. PMID- 26515214 TI - Relationship Between Physician and Hospital Procedure Volume and Mortality After Carotid Artery Stenting Among Medicare Beneficiaries. AB - BACKGROUND: Clinical trials demonstrated the efficacy of carotid artery stenting (CAS) relative to carotid endarterectomy when performed by physicians with demonstrated proficiency. It is unclear how CAS performance may be influenced by the diversity in CAS and non-CAS provider volumes in routine clinical practice. METHODS AND RESULTS: We linked Medicare claims to the Centers for Medicare and Medicaid Services' CAS Database (2005-2009). We assessed the association between 30-day mortality and past-year physician (0, 1-4, 5-9, 10-19, >=20) and hospital (<10, 10-19, 20-39, >=40) CAS volumes and past-year hospital coronary and peripheral stenting volumes (<200, 200-399, 400-849, >=850) among beneficiaries at least 66 years of age. Unadjusted 30-day mortality risk was 1.8% (95% confidence interval [CI], 1.6-2.0) for 19 724 patients undergoing CAS by 2045 physicians in 729 hospitals. Median past-year CAS volume was 9 (interquartile range, 4-19) for physicians and 23 (interquartile range, 12-41) for hospitals. Compared to physicians performing >=20 CAS in the past year, lower CAS volumes were associated with higher adjusted risks of 30-day morality (P value for trend < 0.05): 1.4 (95% CI, 0.9-2.3) for 0 past-year CAS, 1.3 (95% CI, 0.9-1.8) for 1 to 4, 1.1 (95% CI, 0.8-1.6) for 5 to 9, and 0.9 (95% CI, 0.7-1.4) for 10 to 19. An inverse relationship between 30-day mortality and past-year CAS hospital volume as well as past-year hospital non-CAS volume, past-year hospital non-CAS volume, and 30-day mortality was also noted. CONCLUSIONS: Among Medicare patients, an inverse relationship exists between physician and hospital CAS volumes and hospital non-CAS stenting volume and 30-day mortality, even after adjusting for all pertinent patient- and hospital-level factors. PMID- 26515215 TI - Variation and Trends in the Documentation of National Institutes of Health Stroke Scale in GWTG-Stroke Hospitals. AB - BACKGROUND: Although National Institutes of Health Stroke Scale (NIHSS) is an important prognostic variable, it is often incompletely documented in clinical registries, such as Get With The Guidelines (GWTG)-Stroke. We describe trends in NIHSS documentation by GWTG-Stroke hospitals, identify patient-level and hospital level factors associated with documentation, and determine the degree to which the reporting of NIHSS is potentially biased. METHODS AND RESULTS: We analyzed NIHSS documentation in 1 184 288 patients with acute ischemic stroke admitted to 1704 GWTG-Stroke hospitals between 2003 and 2012. We used multivariable logistic regression models to identify hospital-level and patient-level predictors of NIHSS documentation. We examined the relationship between hospital-level NIHSS documentation rates and observed NIHSS scores to determine whether the reporting of NIHSS data was subject to selection bias. The overall NIHSS documentation rate was 56.1%; the median NIHSS was 4 (interquartile range, 2-9). Between 2003 and 2012, mean hospital-level NIHSS documentation increased dramatically from 27% to 70% (P<0.0001). Documentation was higher in patients who arrived by ambulance, who arrived soon after onset, and were treated at larger, primary stroke centers. Hospital-level NIHSS documentation rates and NIHSS scores were modestly inversely correlated (r=-0.207; P<0.0001), suggesting that NIHSS data from hospitals with low documentation were shifted toward higher values. In sensitivity analysis, the degree of bias in NIHSS reporting was reduced in more recent years (2011-2012) when NIHSS documentation was noticeably better. CONCLUSIONS: Documentation of NIHSS is higher in patients who are thrombolysis candidates. Evidence of modest bias in NIHSS scores was observed but this has lessened as the documentation of NIHSS has improved in recent years. PMID- 26515216 TI - Meta-Analysis of Randomized Controlled Trials Comparing the Long-Term Outcomes of Carotid Artery Stenting Versus Endarterectomy. AB - BACKGROUND: Stenting is an endovascular alternative to endarterectomy for the management of carotid stenosis, but its long-term safety and efficacy relative to endarterectomy remain unclear. Our objective was to compare the safety and efficacy of stenting with those of endarterectomy, with a particular focus on long-term outcomes, via meta-analysis of randomized controlled trials (RCTs). METHODS AND RESULTS: We systematically searched PubMed, EMBASE, MEDLINE, and the Cochrane Library for RCTs with >=50 patients that compared stenting with endarterectomy in patients with carotid stenosis. Periprocedural and long-term outcomes were assessed, with data pooled across RCTs using random-effects models. Eight RCTs were included in our meta-analysis (n=7091), with follow-up ranging from 2.0 to 10.0 years. When compared with endarterectomy, stenting was associated with an increased risk of periprocedural stroke (relative risk, 1.49, 95% confidence interval [CI], 1.11 to 2.01; risk difference, 1.7%; 95% CI, 0.3 to 3.0) but a decreased risk of periprocedural myocardial infarction (relative risk, 0.47; 95% CI, 0.29 to 0.78; risk difference, -0.4%; 95% CI, -0.8% to 0.1%). During long-term follow-up, stenting was associated with an increased risk of stroke (relative risk, 1.36; 95% CI, 1.16 to 1.61) and a composite end point of ipsilateral stroke, periprocedural stroke, or periprocedural death (relative risk, 1.45; 95% CI, 1.20 to 1.75). CONCLUSIONS: Although stenting has more favorable periprocedural outcomes with respect to myocardial infarction, the observed increased risk of stroke and death throughout follow-up with stenting suggests that endarterectomy remains the treatment of choice for carotid stenosis. PMID- 26515217 TI - A randomised trial in carotid surgery: great evidence, and the next steps forward. PMID- 26515218 TI - Exercise rehabilitation for peripheral artery disease: An exercise physiology perspective with special emphasis on the emerging trend of home-based exercise. AB - Peripheral artery disease (PAD) is a significant medical concern that is highly prevalent, costly, and deadly. Additionally, patients with PAD have significant impairments in functional independence and health-related quality of life due to leg symptoms and ambulatory dysfunction. Exercise therapy is a primary treatment for patients with PAD, as ambulatory outcome measures improve following a program of exercise rehabilitation. This review describes the outcomes that improve with exercise, the potential mechanisms for improved leg symptoms, key exercise program considerations for training patients with PAD with walking-based exercise, other exercise modalities that have been utilised, the use of on-site supervised exercise programs, and a major focus on historical and contemporary trials on conducting home-based, minimally supervised exercise program to treat PAD. The review concludes with recommendations for future exercise trials, with particular emphasis on reported greater details of the exercise prescription to more accurately quantify the total exercise dose of the program. PMID- 26515219 TI - Vascular compression syndromes. AB - Dealing with vascular compression syndromes is one of the most challenging tasks in Vascular Medicine practice. This heterogeneous group of disorders is characterised by external compression of primarily healthy arteries and/or veins as well as accompanying nerval structures, carrying the risk of subsequent structural vessel wall and nerve damage. Vascular compression syndromes may severely impair health-related quality of life in affected individuals who are typically young and otherwise healthy. The diagnostic approach has not been standardised for any of the vascular compression syndromes. Moreover, some degree of positional external compression of blood vessels such as the subclavian and popliteal vessels or the celiac trunk can be found in a significant proportion of healthy individuals. This implies important difficulties in differentiating physiological from pathological findings of clinical examination and diagnostic imaging with provocative manoeuvres. The level of evidence on which treatment decisions regarding surgical decompression with or without revascularisation can be relied on is generally poor, mostly coming from retrospective single centre studies. Proper patient selection is critical in order to avoid overtreatment in patients without a clear association between vascular compression and clinical symptoms. With a focus on the thoracic outlet-syndrome, the median arcuate ligament syndrome and the popliteal entrapment syndrome, the present article gives a selective literature review on compression syndromes from an interdisciplinary vascular point of view. PMID- 26515220 TI - Low serum testosterone and increased diastolic ocular perfusion pressure: a risk for retinal microvasculature. AB - BACKGROUND: Low levels of testosterone in men and changes in retinal microvascular calibre are both associated with hypertension and cardiovascular disease risk. Sex hormones are also associated with blood flow in microvascular beds which might be a key intermediate mechanism in the development of hypertension. Whether a direct association between endogenous testosterone and retinal microvascular calibre exists is currently unknown. We aimed to determine whether testosterone is independently associated with ocular perfusion via a possible association with retinal vascular calibre or whether it plays only a secondary role via its effect on blood pressure in a bi-ethnic male cohort. PROBANDS AND METHODS: A total of 72 black and 81 white men (28-68 years of age) from the follow-up phase of the Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study were included in this sub-study. Ambulatory pulse pressure and intraocular perfusion pressures were obtained, while metabolic variables and testosterone were measured from fasting venous blood samples. Retinal vascular calibre was quantified from digital photographs using standardised protocols. RESULTS: The black men revealed a poorer cardiometabolic profile and higher pulsatile pressure (>50 mm Hg), intraocular pressure and diastolic ocular perfusion pressure than the white men (p<=0.05). Only in the white men was free testosterone positively associated with retinal calibre, i.e. arterio-venular ratio and central retinal arterial calibre and inversely with central retinal venular calibre. These associations were not found in the black men, independent of whether pulse pressure and ocular perfusion pressure were part of the model. CONCLUSIONS: These results suggest an independent, protective effect of testosterone on the retinal vasculature where an apparent vasodilatory response in the retinal resistance microvessels was observed in white men. PMID- 26515221 TI - Normal values for intima-media thickness of the common carotid artery--an update following a novel risk factor profiling. AB - BACKGROUND: There is a widely approved influence of novel risk factors like the body fat distribution and the associated metabolic syndrome, subclinical inflammation, insulin resistance and prediabetic disturbances in glucose metabolism on the progression of atherosclerosis. Former studies examining normal values for intima-media thickness (IMT) did not consider all of these new study results in detail. We therefore aimed to assess an update on age- and gender specific normal values for IMT accounting for these novel risk factors. PATIENTS AND METHODS: We evaluated IMT by high-resolution ultrasound (13 MHz) on the far wall of the common carotid artery in 801 subjects without cardiovascular disease (428 women aged 46.2+/-12.9 years; 373 men aged 47.3+/-13.3 years). After precise evaluation and exclusion of 14 cardiovascular risk factors, 90% limits of IMT were determined by parametric statistics. RESULTS: The reference limits of IMT according to the age classes 18-29, 30-39, 40-49 and 50-59 years were estimated as 0.47, 0.59, 0.67 and 0.70 mm in women and 0.47, 0.62, 0.72 and 0.80 mm in men. CONCLUSIONS: Age and gender-specific normal values for IMT are lower than reported in former studies after additionally accounting for novel cardiovascular risk factors. The still widely regarded upper IMT limit of 1 mm must be strictly regarded as obsolete. PMID- 26515222 TI - Absorbable suture material in carotid surgery. AB - BACKGROUND: Absorbable sutures are not generally accepted by most vascular surgeons for the fear of breakage of the suture line and the risk of aneurysmal formation, except in cases of paediatric surgery or in case of infections. Aim of this study is to provide evidence of safety and efficacy of the use of absorbable suture materials in carotid surgery. PATIENTS AND METHODS: In an 11 year period, 1126 patients (659 male [58.5%], 467 female [41.5%], median age 72) underwent carotid endarterectomy for carotid stenosis by either conventional with primary closure (cCEA) or eversion (eCEA) techniques. Patients were randomised into two groups according to the type of suture material used. In Group A, absorbable suture material (polyglycolic acid) was used and in Group B non-absorbable suture material (polypropylene) was used. Primary end-point was to compare severe restenosis and aneurysmal formation rates between the two groups of patients. For statistical analysis only cases with a minimum period of follow-up of 12 months were considered. RESULTS: A total of 868 surgical procedures were considered for data analysis. Median follow-up was 6 years (range 1-10 years). The rate of postoperative complications was better for group A for both cCEA and eCEA procedures: 3.5% and 2.0% for group A, respectively, and 11.8% and 12.9% for group B, respectively. CONCLUSIONS: In carotid surgery, the use of absorbable suture material seems to be safe and effective and with a general lower complications rate compared to the use of non-absorbable materials. PMID- 26515223 TI - Regional differences of vasodilatation and vasomotion response to local heating in human cutaneous microcirculation. AB - BACKGROUND: The aim of this study was to evaluate the vasodilatation and vasomotion response to local heating in the cutaneous microcirculation of the ankle, dorsum of foot and forearm. Recently, it has been suggested that this response differs between the forearm and the leg. PROBANDS AND METHODS: Twenty nine young healthy adults were recruited. They underwent measurement by laser Doppler flowmetry (LDF) in three sites of the body (ankle, dorsum of foot, forearm). Percentage change of the median flow of the skin before and after provocation and normalised perfusion flow to maximal dilation (cutaneous vascular conductance--CVC % Max) during short provocation test were monitored. Spectral analysis of laser Doppler flowmetry signals was performed using the fast Fourier transform algorithm. RESULTS: Significant differences were found in CVC % Max between ankle/dorsum (45.18+/-6.38% Max vs. 51.24+/-6.87% Max, respectively; p<0.05) and between ankle/forearm (45.18+/-6.38% Max vs. 54.49+/-5.37% Max, respectively; p<0.05). Percentage change of flux after provocation has revealed significant differences between ankle/dorsum (394.1+/-204.5% vs. 577.4+/-273.5%, respectively; p<0.05) and ankle/forearm (394.1+/-204.5% vs. 637.1+/-324.7%, respectively; p<0.05). Total spectral activity of vasomotion has differed between ankle/dorsum and ankle/forearm: 69.59 [49.58-96.04] vs. 93.01 [73.15-121.8] (p<0.05) and 69.59 [49.58-96.04] vs. 107.5 [80.55-155.8] (p<0.05), respectively. CONCLUSIONS: Cutaneous microcirculation exhibits regional differences. Significant variability of function between ankle and dorsum of foot suggests that leg microcirculation is not uniform. PMID- 26515224 TI - Endovascular stent-graft treatment for graft-vein anastomotic stenosis in haemodialysis patients with arteriovenous grafts. AB - BACKGROUND: In this study, we investigated the patency of endovascular stent grafts in haemodialysis patients with arteriovenous grafts, the modes of patency loss, and the risk factors for re-intervention. PATIENTS AND METHODS: Haemodialysis patients with graft-vein anastomotic stenosis of their arteriovenous grafts who were treated with endovascular stent-grafts between 2008 and 2013 were entered into this retrospective study. Primary and secondary patency, modes of patency loss, and risk factors for intervention were recorded. RESULTS: Cumulative circuit primary patency rates decreased from 40.0% at 6 months to 7.3% at 24 months. Cumulative target lesion primary patency rates decreased from 72.1% at 6 months to 22.0% at 24 months. Cumulative secondary patency rates decreased from 81.3% at 12 months to 31.6% at 36 months. Patients with a history of cerebrovascular accident had a significantly higher risk of secondary patency loss, and graft puncture site stenosis jeopardised the results of stent-graft treatment. CONCLUSIONS: Our data can help to improve outcomes in haemodialysis patients treated with stent-grafts for venous anastomosis of an arteriovenous graft. PMID- 26515225 TI - Nitrous oxide/oxygen inhalation provides effective analgesia during the administration of tumescent local anaesthesia for endovenous laser ablation. AB - BACKGROUND: Tumescent anaesthesia (TA) is an important but sometimes very painful step during endovenous thermal ablation of incompetent veins. The aim of this study was to examine whether the use of fixed 50% nitrous oxide/oxygen mixture (N2O/O2), also called equimolar mixture of oxygen and nitrous oxide, reduces pain during the application of TA. PATIENTS AND METHODS: Patients undergoing endovenous laser ablation (EVLA) of incompetent saphenous veins were included. Thirty consecutive patients inhaled N2O/O2 during the application of TA. Thirty consecutive patients received TA alone (controls). Patients were asked to complete a questionnaire immediately after the intervention to assess satisfaction with the intervention and pain-levels during the different steps of the intervention (0=not at all, 10=very much). Adverse events during the treatment were monitored. RESULTS: 30 patients (14 men, mean age of 44 years) were included in the N2O/O2 group and 30 patients (9 men, mean age 48 years) were included in the control group. In the N2O/O2 group a significantly lower pain score was noted (mean 2.45 points, range 0-6) compared to the controls (mean 4.3 points, range 1-9, p<0.001). Overall, 64.5% of the patients were perfectly satisfied with the N2O/O2-Inhalation. Only 4 patients receiving N2O/O2 complained of adverse effects such as unpleasant loss of control (2 patients), headache (1 patient) and dizziness (1 patient). CONCLUSIONS: N2O/O2 is a safe and effective method to reduce pain during the application of tumescent anaesthesia for EVLA. PMID- 26515226 TI - Infective aortic aneurysm caused by Leclercia adecarboxylata. PMID- 26515227 TI - Childhood tobacco smoke exposure - A silent risk fur atherosclerosis plaque in adulthood. PMID- 26515228 TI - Thermoregulatory effects of swaddling in Mongolia: a randomised controlled study. AB - OBJECTIVE: To investigate thermal balance of infants in a Mongolian winter, and compare the effects of traditional swaddling with an infant sleeping-bag in apartments or traditional tents (Gers). DESIGN: A substudy within a randomised controlled trial. SETTING: Community in Ulaanbaatar, Mongolia. SUBJECTS: A stratified randomly selected sample of 40 swaddled and 40 non-swaddled infants recruited within 48 h of birth. INTERVENTION: Sleeping-bags and baby outfits of total thermal resistance equivalent to that of swaddled babies. OUTCOME MEASURE: Digital recordings of infants' core, peripheral, environmental and microenvironmental temperatures at 30-s intervals over 24 h at ages 1 month and 3 months. RESULTS: In Gers, indoor temperatures varied greatly (<0->25 degrees C), but remained between 20 degrees C and 22 degrees C, in apartments. Despite this, heavy wrapping, bed sharing and partial head covering, infant core and peripheral temperatures were similar and no infants showed evidence of significant heat or cold stress whether they were swaddled or in sleeping-bags. At 3 months, infants in sleeping-bags showed the 'mature' diurnal pattern of a fall in core temperature after sleep onset, accompanied by a rise in peripheral temperature, with a reverse pattern later in the night, just before awakening. This pattern was not related to room temperature, and was absent in the swaddled infants, suggesting that the mature diurnal pattern may develop later in them. CONCLUSIONS: No evidence of cold stress was found. Swaddling had no identifiable thermal advantages over sleeping-bags during the coldest times, and in centrally heated apartments could contribute to the risk of overheating during the daytime. TRIAL REGISTRATION NUMBER: ISRTN01992617. PMID- 26515229 TI - A case-control study of the health and well-being benefits of allotment gardening. AB - BACKGROUND: Allotments in the UK are popular and waiting lists long. There is, however, little evidence on the health benefits of allotment gardening. The aims of this study were to determine the impacts of a session of allotment gardening on self-esteem and mood and to compare the mental well-being of allotment gardeners with non-gardeners. METHODS: Self-esteem, mood and general health were measured in 136 allotment gardeners pre- and post- an allotment session, and 133 non-gardener controls. Allotment gardeners also detailed the time spent on their allotment in the current session and previous 7 days, and their length of tenure. RESULTS: Paired t-tests revealed a significant improvement in self-esteem (P < 0.05) and mood (P < 0.001) as a result of one allotment session. Linear regression revealed that neither the time spent on the allotment in the current session, the previous 7 days or the length of tenure affected the impacts on self esteem and mood (P > 0.05). One-way ANCOVA revealed that allotment gardeners had a significantly better self-esteem, total mood disturbance and general health (P < 0.001), experiencing less depression and fatigue and more vigour (P < 0.0083). CONCLUSIONS: Allotment gardening can play a key role in promoting mental well being and could be used as a preventive health measure. PMID- 26515230 TI - Design and synthesis of a new chromophore, 2-(4-nitrophenyl)benzofuran, for two photon uncaging using near-IR light. AB - A new chromophore, 2-(4-nitrophenyl)benzofuran (NPBF), was designed for two photon (TP) uncaging using near-IR light. The TP absorption (TPA) cross-sections of the newly designed NPBF chromophore were determined to be 18 GM at 720 nm and 54 GM at 740 nm in DMSO. The TP uncaging reaction of a caged benzoate with the NPBF chromophore quantitatively produced benzoic acid with an efficiency (deltau) of ~5.0 GM at 740 nm. The TP fragmentation of an EGTA unit was observed with deltau = 16 GM. This behavior makes the new chromophore a promising TP photoremovable protecting group for physiological studies. PMID- 26515231 TI - A rare RECQL4 indel mutation in a Chinese patient with Rothmund-Thomson syndrome. PMID- 26515232 TI - Autophagy in sexual plant reproduction as an emerging field. AB - Autophagy is an evolutionary conserved system for clearing and recycling cellular components. Critical roles of autophagy in the responses of plant to different environmental stresses have been revealed during past decades. However, little is known about the role of autophagy in plant developmental processes, especially in the processes of sexual plant reproduction. Here, we briefly discuss recent advances in the emerging field and wish to bring some potential research directions into attention. Possible divergence of molecular mechanism of autophagy in respect to the current debatable view is also discussed. PMID- 26515233 TI - Parkinson's Disease and Pesticides Exposure: New Findings From a Comprehensive Study in Nebraska, USA. AB - BACKGROUND: The association between exposure to agricultural pesticides and Parkinson's Disease (PD) has long been a topic of study in the field of environmental health. This research takes advantage of the unique Nebraska PD registry and state-level crop classification data to investigate the PD pesticides exposure relationship. METHODS: First, Geographic Information System and satellite remote sensing data were adopted to calculate exposure to different pesticides for Nebraska residents. An integrated spatial exploratory framework was then adopted to explore the association between PD incidence and exposure to specific pesticide ingredients at the county level. RESULTS: Our results reveal similarities in geographic patterns of pesticide exposure and PD incidence. The regression analyses indicate that, for most Nebraska counties, PD incidence was significantly associated with exposure to certain pesticide ingredients such as alachlor and broxomy. However, the results also suggest that factors other than pesticide exposure may help further explain the risk of PD at the county level. CONCLUSIONS: We found significant associations between PD incidence and exposure to different pesticide ingredients. These results have useful implications for PD prevention in Nebraska and other agricultural states in the United States. PMID- 26515234 TI - Immunohistochemical expression of matrix metalloproteinase-1, matrix metalloproteinase-2 and matrix metalloproteinase-9, myofibroblasts and Ki-67 in actinic cheilitis and lip squamous cell carcinoma. AB - Matrix metalloproteinases (MMPs), myofibroblasts (MFs) and epithelial proliferation have key roles in neoplastic progression. In this study immunoexpression of MMP-1, MMP-2 and MMP-9, presence of MFs and the epithelial proliferation index were investigated in actinic cheilitis (AC), lip squamous cell carcinoma (LSCC) and mucocele (MUC). Thirty cases of AC, thirty cases of LSCC and twenty cases of MUC were selected for immunohistochemical investigation of the proteins MMP-1, MMP-2, MMP-9, alpha-smooth muscle actin (alpha-SMA) and Ki 67. The MMP-1 expression in the epithelial component was higher in the AC than the MUC and LSCC. In the connective tissue, the expression was higher in the LSCC. MMP-2 showed lower epithelial and stromal immunostaining in the LSCC when compared to the AC and MUC. The epithelial staining for MMP-9 was higher in the AC when compared to the LSCC. However, in the connective tissue, the expression was lower in the AC compared to other lesions. The cell proliferation rate was increased in proportion to the severity of dysplasia in the AC, while in the LSCC it was higher in well-differentiated lesions compared to moderately differentiated. There were no statistically significant differences in number of MFs present in the lesions studied. The results suggest that MMPs could affect the biological behaviour of ACs and LSCCs inasmuch as they could participate in the development and progression from premalignant lesions to malignant lesions. PMID- 26515235 TI - Dyslipidemia and its association with meibomian gland dysfunction. AB - Abnormal serum lipid levels significantly increase the risk for cardiovascular disease. Furthermore, abnormal compositions of cholesterol in glandular secretions have been hypothesized as an etiology for meibomian gland dysfunction, yet this relationship has not been well studied in clinical settings. The primary purpose of this study was to determine if there is an association between dyslipidemia and meibomian gland dysfunction (MGD). The secondary purpose was to identify the factors, if any, that play a role in this association. A case control study was performed between October 2013 and February 2015 which recruited 109 patients with MGD and 115 control patients without MGD. All participants were of Indian descent and had no history of dyslipidemia. Basic demographic information was collected as well as fasting levels of serum glucose, creatinine, triglycerides, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). To calculate differences between groups, Z test or Student t test were used. A stepwise logistic regression model was used to calculate the estimates of odds ratios (ORs), where MGD was the dependent variable, making the independent variables consist of sex, age, body mass index (BMI), triglycerides >=150 mg/dL, total cholesterol >=200 mg/dL, LDL >=130 mg/dL, or HDL <=40 mg/dL, serum glucose, and serum creatinine. Dyslipidemia, defined by either a fasting total cholesterol level of >= 200 mg/dL, triglycerides >=150 mg/dL, LDL >=130 mg/dL, or HDL <=40 mg/dL, was detected in 70 cases (64 %) and 21 controls (18 %), P < 0.001. Mean levels of triglycerides, total cholesterol, LDL, and HDL were 98.5 +/- 42.1, 203.1 +/- 13.2, 126.1 +/- 10.2, and 53.3 +/- 4.2 mg/dL, respectively, in cases and 82.3 +/- 36.5, 156.6 +/- 14.5, 92.2 +/- 12.4, 45.8 +/- 2.6 mg/dL, respectively, in controls. All differences were statistically significant (P < 0.05). MGD was significantly associated with age >65 years (OR 2.1; 95 % CI 1.2-3.2, P = 0.04), serum triglyceride concentration >=150 mg/dL (OR 3.2; 95 % CI 1.9-4.4; P = 0.03), total cholesterol >=200 mg/dL (OR 14.3; 95 % CI 8.2-20.7, P < 0.01), and LDL >=130 mg/dL (OR 9.1; 95 % CI 6.6-13.2, P < 0.01). Adults from northern rural India with MGD are more likely to have abnormal serum lipid levels compared to age- and sex-matched adults without MGD. Eye care providers may have a role in discovering undiagnosed dyslipidemia, an important risk factor for cardiovascular illness. PMID- 26515237 TI - The effects of a novel synthetic emulsifier product on growth performance of chickens for fattening and weaned piglets. AB - Two experiments were conducted to evaluate the effects of a novel synthetic emulsifier product (AVI-MUL TOP) on the growth performance of chickens for fattening and weaned piglets. The emulsifier product consists of 50% vegetal bi distillated oleic acid emulsified with 50% glyceryl polyethyleneglycol ricinoleate. In experiment 1, 480 1-day-old female Cobb500 chickens for fattening were assigned to two treatments: (1) a control diet (CTR); and (2) the control diet+the emulsifier (AMT, 1 g/kg from day 0 to day 10, 0.75 g/kg from day 10 to day 20 and 0.5 g/kg from day 20 to day 34 of the trial). AMT supplementation increased BW on days 20 and 34 (P<0.01). Dietary AMT increased the average daily gain and average daily feed intake (ADFI) from day 10 to day 20, from day 20 to day 34 and from day 0 to day 34 (P<0.01). A reduced feed conversion ratio was observed in the AMT group from day 10 to day 20 (P<0.01). In experiment 2, 96 Stambo HBI*Dalland piglets were weaned at 24 days and assigned to two treatments (the basal diet without the product (CTR) or with 2 g/kg emulsifier from day 0 to day 14 and 1.5 g/kg from day 14 to day 42 (AMT)). There was an increase in the ADFI associated with AMT supplementation from day 14 to day 42 (P=0.04). These results indicated that supplementation with the synthetic emulsifier may significantly improve the growth performance of chickens for fattening and numerically improve that of weaned piglets. PMID- 26515236 TI - A CpG-methylation-based assay to predict survival in clear cell renal cell carcinoma. AB - Clear cell renal cell carcinomas (ccRCCs) display divergent clinical behaviours. Molecular markers might improve risk stratification of ccRCC. Here we use, based on genome-wide CpG methylation profiling, a LASSO model to develop a five-CpG based assay for ccRCC prognosis that can be used with formalin-fixed paraffin embedded specimens. The five-CpG-based classifier was validated in three independent sets from China, United States and the Cancer Genome Atlas data set. The classifier predicts the overall survival of ccRCC patients (hazard ratio=2.96 4.82; P=3.9 * 10(-6)-2.2 * 10(-9)), independent of standard clinical prognostic factors. The five-CpG-based classifier successfully categorizes patients into high-risk and low-risk groups, with significant differences of clinical outcome in respective clinical stages and individual 'stage, size, grade and necrosis' scores. Moreover, methylation at the five CpGs correlates with expression of five genes: PITX1, FOXE3, TWF2, EHBP1L1 and RIN1. Our five-CpG-based classifier is a practical and reliable prognostic tool for ccRCC that can add prognostic value to the staging system. PMID- 26515239 TI - Visualized intravesical floating hydrogel encapsulating vaporized perfluoropentane for controlled drug release. AB - Intravesical drug delivery is the main strategy for the treatment of bladder disorders. To reduce the relief arising from frequent intravesical instillation, mucoadhesive hydrogel was used for the controlled release of the drug. However, the viscosity of mucoadhesive gel might cause severe urinary obstruction and bladder irritation. To solve all these problems, a floating hydrogel delivery system was developed using perfluoropentane (PFP) as the floating agent. After intravesical instillation of the floating hydrogel, the increased temperature in bladder vaporized PFP, resulting in the generation of microbubbles in the hydrogel. Then, it can float in urine to avoid the urinary obstruction and bladder irritation. In this study, systematic experiments were conducted to investigate the influences of PFP vaporization on the morphology and floating ability of hydrogels. The floating process is much milder and safer than other floating methods published before. In addition, PFP had been used as contrast agent, which affiliated the monitoring of gels during the operation. Therefore, this new drug delivery system addresses the problems of conventional intravesical instillation and is promising for clinic use. PMID- 26515240 TI - Real Time Metastatic Route Tracking of Orthotopic PC-3-GFP Human Prostate Cancer Using Intravital Imaging. AB - The cellular basis of metastasis is poorly understood. An important step to understanding this process is to be able to visualize the routes by which cancer cells migrate from the primary tumor to various distant sites to eventually form metastasis. Our laboratory previously developed single-cell in vivo imaging using fluorescent proteins to label cancer cells. In the present study, using PC-3 human prostate cancer cells labeled with green fluorescent protein (GFP) and orthotopic tumor transplantation, we have imaged in live mice various highly diverse routes by which PC-3 cells metastasize superiorly and inferiorly to distant sites, including in the portal area, stomach area, and urogenital system. Imaging began at day 9, at which time distant metastasis had already occurred, and increased at each imaging point at days 10, 13, 14, and 16. Metastatic cells were observed migrating superiorly and inferiorly from the primary tumor as well as in lymphatic channels and trafficking in various organ systems demonstrating that PC-3 has multiple metastatic routes similar to hormone-independent advanced stage prostate cancer in the clinic. PMID- 26515241 TI - Microwave-Assisted Organocatalyzed Rearrangement of Propargyl Vinyl Ethers to Salicylaldehyde Derivatives: An Experimental and Theoretical Study. AB - The microwave-assisted imidazole-catalyzed transformation of propargyl vinyl ethers (PVEs) into multisubstituted salicylaldehydes is described. The reaction is instrumentally simple, scalable, and tolerates a diverse degree of substitution at the propargylic position of the starting PVE. The generated salicylaldehyde motifs incorporate a broad range of topologies, spanning from simple aromatic monocycles to complex fused polycyclic systems. The reaction is highly regioselective and takes place under symmetry-breaking conditions. The preparative power of this reaction was demonstrated in the first total synthesis of morintrifolin B, a benzophenone metabolite isolated from the small tree Morinda citrifolia L. A DFT study of the reaction was performed with full agreement between calculated values and experimental results. The theoretically calculated values support a domino mechanism comprising a propargyl Claisen rearrangement, a [1,3]-H shift, a [1,7]-H shift (enolization), a 6pi electrocyclization, and an aromatization reaction. PMID- 26515238 TI - Reproductive factors and risk of mortality in the European Prospective Investigation into Cancer and Nutrition; a cohort study. AB - BACKGROUND: Reproductive events are associated with important physiologic changes, yet little is known about how reproductive factors influence long-term health in women. Our objective was to assess the relation of reproductive characteristics with all-cause and cause-specific mortality risk. METHODS: The analysis was performed within the European Investigation into Cancer and Nutrition prospective cohort study, which enrolled >500,000 women and men from 1992 to 2000, who were residing in a given town/geographic area in 10 European countries. The current analysis included 322,972 eligible women aged 25-70 years with 99 % complete follow-up for vital status. We assessed reproductive characteristics reported at the study baseline including parity, age at the first birth, breastfeeding, infertility, oral contraceptive use, age at menarche and menopause, total ovulatory years, and history of oophorectomy/hysterectomy. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for mortality were determined using Cox proportional hazards regression models adjusted for menopausal status, body mass index, physical activity, education level, and smoking status/intensity and duration. RESULTS: During a mean follow-up of 12.9 years, 14,383 deaths occurred. The HR (95 % CI) for risk of all-cause mortality was lower in parous versus nulliparous women (0.80; 0.76-0.84), in women who had ever versus never breastfed (0.92; 0.87-0.97), in ever versus never users of oral contraceptives (among non-smokers; 0.90; 0.86-0.95), and in women reporting a later age at menarche (>=15 years versus <12; 0.90; 0.85-0.96; P for trend = 0.038). CONCLUSIONS: Childbirth, breastfeeding, oral contraceptive use, and a later age at menarche were associated with better health outcomes. These findings may contribute to the development of improved strategies to promote better long term health in women. PMID- 26515242 TI - Risk assessment and decision-making for patients undergoing orthopedic surgery. AB - PURPOSE: Physical and operative severity score for the enumeration of mortality and morbidity (POSSUM) scoring system was designed to predict the postoperative morbidity and mortality mainly in general surgery. The purpose of this study was to assess the value of POSSUM scoring system in predicting outcomes of patients undergoing orthopedic surgery, and to do some modifications to make the system more accurate in predicting postoperative complication rates. METHODS: This is a retrospective clinical study involving 779 patients between April 1, 2009 and September 1, 2010. The postoperative complication rates were predicted by POSSUM, and then compared with the actual morbidity. Logistic regression was taken to improve the POSSUM equation. RESULTS: In the 779 cases, the predicted morbidity was 27.2% (212 cases) by POSSUM, while the actual morbidity is 8.3% (65 cases). CONCLUSION: POSSUM excessively predicted the morbidity of patients undergoing orthopedic surgery, and it could be more accurate with appropriate modification. Of all risk factors, echocardiography ejection fraction showed a close relationship with postoperative complications. PMID- 26515243 TI - Indian health ministry refutes UK journal editor's criticism of health sector. PMID- 26515244 TI - Plant-microbe rhizosphere interactions mediated by Rehmannia glutinosa root exudates under consecutive monoculture. AB - Under consecutive monoculture, the biomass and quality of Rehmannia glutinosa declines significantly. Consecutive monoculture of R. glutinosa in a four-year field trial led to significant growth inhibition. Most phenolic acids in root exudates had cumulative effects over time under sterile conditions, but these effects were not observed in the rhizosphere under monoculture conditions. It suggested soil microbes might be involved in the degradation and conversion of phenolic acids from the monocultured plants. T-RFLP and qPCR analysis demonstrated differences in both soil bacterial and fungal communities during monoculture. Prolonged monoculture significantly increased levels of Fusarium oxysporum, but decreased levels of Pseudomonas spp. Abundance of beneficial Pseudomonas spp. with antagonistic activity against F. oxysporum was lower in extended monoculture soils. Phenolic acid mixture at a ratio similar to that found in the rhizosphere could promote mycelial growth, sporulation, and toxin (3 Acetyldeoxynivalenol, 15-O-Acetyl-4-deoxynivalenol) production of pathogenic F. oxysporum while inhibiting growth of the beneficial Pseudomonas sp. W12. This study demonstrates that extended monoculture can alter the microbial community of the rhizosphere, leading to relatively fewer beneficial microorganisms and relatively more pathogenic and toxin-producing microorganisms, which is mediated by the root exudates. PMID- 26515245 TI - The many ways adherent cells respond to applied stretch. AB - Cells in various tissues are subjected to mechanical stress and strain that have profound effects on cell architecture and function. The specific response of the cell to applied strain depends on multiple factors, including cell contractility, spatial and temporal strain pattern, and substrate dimensionality and rigidity. Recent work has demonstrated that the cell response to applied strain depends on a complex combination of these factors, but the way these factors interact to elicit a specific response is not intuitive. We submit that an understanding of the integrated response of a cell to these factors will provide new insight into mechanobiology and contribute to the effective design of deformable engineered scaffolds meant to provide appropriate mechanical cues to the resident cells. PMID- 26515246 TI - Reliability of gait variability assessment in older individuals during a six minute walk test. AB - Gait variability is an important indicator of gait performance. However, the reliability of the parameters used for its quantification, obtained from trunk linear accelerations, has still not been thoroughly investigated. The aim of this study is to assess the reliability of gait variability assessment in healthy older individuals based on lower trunk accelerations during a six-minute walk test and to examine the reliability of the data acquired in shorter periods. Twenty-nine subjects (84+/-5 years) performed the test while wearing one inertial sensor on the lower trunk. Gait variability parameters (standard deviation and coefficient of variation of the stride duration, and correlation coefficients of accelerations between neighbouring strides) were calculated from the accelerations over 35 rectilinear strides observed during six series of one minute intervals extracted from the original signal. The reliability of these parameters was assessed using intraclass correlation coefficients (ICC). Results showed no significant changes across the six series for any of the parameters, with very high ICC values (0.93-0.95), indicating a strong reliability of the observed quantities. Therefore, gait variability analysis based on lower trunk acceleration data is a reliable and informative quantity in gait performance assessment in older individuals, and 1min interval is sufficient to ensure reliable results. PMID- 26515247 TI - [Quality of life in people with diabetes]. PMID- 26515248 TI - [Shades and shadows in the application of the long-term care law]. AB - The aim of this study was to provide a brief overview of the most controversial aspects of the Spanish Act of Promotion of Personal Autonomy and Long-Term Care 39/2006, which, in the last few years, has led to heated debates between the state and the autonomous regions. Because of the funding problems due to initial poor planning, the decline of contributions from the Spanish Government in the last few years, including the suppression of the agreed level, and low cash collection from the user through copayment, the autonomous regions have had to provide significant economic resources to maintain this social policy in an environment characterised by a lack of transparency of the system. In addition, the regulatory reforms of mid-2012 to ease the burden on state and autonomous budgets have represented a clear setback to the spirit of the act and a loss of welfare to dependent individuals and their families. All these circumstances have contributed to a widely heterogeneous picture in the territorial implementation of the act, with clear differences in waiting lists, abuse in the granting of cash benefits in some regions, and differences in the number of applications for benefits and services. PMID- 26515249 TI - [A strategy for institutionalisation of health impact assessment in Andalusia (Spain)]. AB - Health impact assessment (HIA) aims to incorporate people's health and wellbeing as a key feature in policy-making. Many authors believe that HIA might be systematically integrated into all decision-making processes as a way to achieve that goal. To that end, there is need to overcome a number of challenges, including the fact that Andalusia (Spain) has made HIA compulsory by law, the need for awareness of all public sectors whose decisions might have substantial impacts on health and for a methodology that would enable a comprehensive approach to health determinants and inequalities, and the training of both the public health staff and professional sectors responsible for its application. In Andalusia, a law provides mandatory and binding health impact reports for most authorisation procedures in different areas: from sectoral plans to urban planning schemes, and especially projects subject to environmental assessment. Implementation of this law has required its integration into authorisation procedures, the training of interdisciplinary working groups in public health, the preparation of technical guidelines, and the organisation of dissemination and training seminars for developers. PMID- 26515250 TI - Fetal brain-sparing after laser surgery for twin-twin transfusion syndrome appears associated with two-year neurodevelopmental outcomes. AB - OBJECTIVE: The cerebroplacental ratio (CPR) is a semi-quantitative marker for fetal brain-sparing. Our purpose was to measure the CPR at the time of treatment with selective laser photocoagulation of communicating vessels in gestations with twin-twin transfusion syndrome (TTTS) to test its association with neurological outcomes at approximately 2 years. METHODS: One-hundred children treated for TTTS with laser surgery underwent neurodevelopmental assessment at age 2 years (within 6 weeks) via the Battelle Developmental Inventory 2nd Edition (BDI-2). The CPR was obtained 24 h before and after laser surgery. An abnormal CPR was categorically defined at <1.0. Multilevel linear regression was used to evaluate associations between CPR and neurodevelopment as assessed by the BDI-2. RESULTS: Ninety-nine children had data available for analysis: 55 (56%) had normal CPR prior to laser surgery, and 62 (63%) had normal CPR following surgery. Post-laser CPR <1.0 was a risk factor for lower BDI-2 scores at age 2 years [98.1 (SD 11.5) vs 103.4 (SD 12.3) vs beta = -0.23, p = 0.01]; this relationship remained significant after controlling for pre-surgical CPR and Quintero stage (adjusted beta = -0.25, p = 0.01). CONCLUSIONS: In this population, an abnormal CPR was associated with poorer 2-year neurodevelopmental outcomes. (c) 2015 John Wiley & Sons, Ltd. PMID- 26515251 TI - Effects of Er,Cr:YSGG laser parameters on dentin bond strength and interface morphology. AB - Previous studies have shown the effects of Er,Cr:YSGG laser irradiation on the dentin bond strength; but there are few reports that show the significance of the irradiation with different laser parameters on dentin bond strength and interface morphology. This in-vitro study attempted to evaluate the microtensile bond strength (MUTBS) and interface morphology of resin-dentin interfaces, either followed by treatment with Er,Cr:YSGG laser irradiation with different parameters or not. The flattened dentin samples of 35 bovine teeth were embedded into acrylic blocks and randomly divided into seven groups according to surface treatments using Er,Cr:YSGG lasers with different parameters: 3 W/20 Hz, 3 W/35 Hz, 3 W/50 Hz, 1.5 W/20 Hz, 1.5 W/35 Hz, 1.5 W/50 Hz, or no laser treatment (n = 5). Composite buildups were done over bonded surfaces and stored in water (24 hours at 37 degrees C). Specimens were sectioned into sticks that were subjected to MUTBS testing and observed under FE-SEM. Control groups (27.70 +/- 7.0) showed statistically higher values than laser-irradiated groups. There were no significant differences among laser groups. Despite that, increasing the pulse frequency yielded slightly higher bond strength. Depending on laser settings, Er,Cr:YSGG laser irradiation caused interfacial gaps and resin tags with wings morphology. With the parameters used in this study, Er,Cr:YSGG laser irradiation promoted morphological changes within resin-dentin interfaces and negatively influenced the bond strength of adhesive systems. PMID- 26515252 TI - Lipid metabolism in mycobacteria--Insights using mass spectrometry-based lipidomics. AB - Diseases including tuberculosis and leprosy are caused by species of the Mycobacterium genus and are a huge burden on global health, aggravated by the emergence of drug resistant strains. Mycobacteria have a high lipid content and complex lipid profile including several unique classes of lipid. Recent years have seen a growth in research focused on lipid structures, metabolism and biological functions driven by advances in mass spectrometry techniques and instrumentation, particularly the use of electrospray ionization. Here we review the contributions of lipidomics towards the advancement of our knowledge of lipid metabolism in mycobacterial species. PMID- 26515253 TI - Culturing of HepG2 cells with human serum improve their functionality and suitability in studies of lipid metabolism. AB - Primary human hepatocytes are considered to be the "gold standard" in studies of lipid metabolism despite a number of disadvantages like large inter-donor differences and inability to proliferate. Human hepatoma HepG2 cells retain many hepatocyte-specific functions but do also exhibit disadvantages like secretion of lipoproteins and bile acids that do not emulate human hepatocytes in vivo. The aim of this study was to investigate whether supplementation of the culturing media with human serum could improve the functionality of HepG2 cells and thereby make them more apposite in studies of lipid metabolism. The cells were cultured with human sera (2%) from three healthy individuals or with fetal bovine serum (10%). Lipoprotein, apolipoprotein, bile acid, albumin, and proprotein subtilisin/kexin type 9 (Pcsk9) concentrations in the cell media, as well as gene and protein expressions were then measured. We found apoB-containing LDL-sized but also apoA1-containing HDL-sized particles, increased bile acid and Pcsk9 concentrations in the cell media, as well as increased expression of genes involved in lipid metabolism and differentiation in HepG2 cells cultured with human sera. Thus, supplementation of the culturing media with human serum improves the functionality of HepG2 cells and makes them more apposite in studies of lipid metabolism. PMID- 26515254 TI - Which microbial factors really are important in Pseudomonas aeruginosa infections? AB - Over the last two decades, tens of millions of dollars have been invested in understanding virulence in the human pathogen, Pseudomonas aeruginosa. However, the top 'hits' obtained in a recent TnSeq analysis aimed at identifying those genes that are conditionally essential for infection did not include most of the known virulence factors identified in these earlier studies. Instead, it seems that P. aeruginosa faces metabolic challenges in vivo, and unless it can overcome these, it fails to thrive and is cleared from the host. In this review, we look at the kinds of metabolic pathways that the pathogen seems to find essential, and comment on how this knowledge might be therapeutically exploited. PMID- 26515255 TI - The effects of parasympatholytic and sympatheticomimetic nebulization therapy in gradient increase in the left ventricular outflow tract: Do they have the same influence? PMID- 26515256 TI - Griffiths phase behaviour in a frustrated antiferromagnetic intermetallic compound. AB - The rare coexistence of a Griffiths phase (GP) and a geometrically frustrated antiferromagnetism in the non-stoichiometric intermetallic compound GdFe0.17Sn2 (the paramagnetic Weiss temperature thetap ~ -59 K) is reported in this work. The compound forms in the Cmcm space group with large structural anisotropy (b/c ~ 4). Interestingly, all the atoms in the unit cell possess the same point group symmetry (Wycoff position 4c), which is rather rare. The frustration parameter, f = |thetap|/TN has been established as 3.6, with the Neel temperature TN and Griffiths temperature TG being 16.5 and 32 K, respectively. The TG has been determined from the heat capacity measurement and also from the magnetocaloric effect (MCE). It is also shown that substantial difference in GP region may exist between zero field and field cooled measurements - a fact hitherto not emphasized so far. PMID- 26515257 TI - Estimating the Years Lived With and Without Age-Related Sensory Impairment. AB - BACKGROUND: The aim of this study was to estimate the expected years lived with hearing impairment, vision impairment, and dual sensory impairment among older adults. METHODS: A total of 4,160 adults (45.1% men) from two Australian community based studies were followed for up to 16 years (average 8.9 years). Hearing impairment was defined by a pure-tone average (500-4000 Hz) greater than 25 dB in the better ear. Vision impairment was defined by presenting distance visual acuity worse than 6/12 (20/40). Postliminary analyses were also conducted for moderate levels of sensory impairment. Dual sensory impairment was defined by concurrent hearing and vision impairment. Multistate Markov models were used to calculate sensory life expectancies based on transition probabilities between health states (no sensory impairment, sensory impairment, and death). RESULTS: Based on thresholds for mild impairment, men aged 65 had a total life expectancy of 19.4 years, and were estimated to live for 10.4 years (95% confidence interval [CI]: 9.1, 11.7) with hearing impairment, 2.8 years (95% CI: 2.4, 3.2) with vision impairment, and 2.2 years (95% CI: 1.8, 2.6) with dual sensory impairment. Women aged 65 had a total life expectancy of 23.2 years, and were estimated to live for 12.9 years (95% CI: 11.9, 13.9) with hearing impairment, 3.9 years (95% CI: 3.4, 4.4) with vision impairment, and 3.2 years (95% CI: 2.7, 3.7) with dual sensory impairment. CONCLUSIONS: In addition to being highly prevalent, hearing and vision impairment affect older adults for substantial periods of their remaining life. Given their broad ranging impacts on health and well-being, sensory impairments are ideal targets for strategies to compress morbidity in late life. PMID- 26515258 TI - Analysis and Interpretation of Accelerometry Data in Older Adults: The LIFE Study. AB - BACKGROUND: Accelerometry has become the gold standard for evaluating physical activity in the health sciences. An important feature of using this technology is the cutpoint for determining moderate to vigorous physical activity (MVPA) because this is a key component of exercise prescription. This article focused on evaluating what cutpoint is appropriate for use with older adults 70-89 years who are physically compromised. METHODS: The analyses are based on data collected from the Lifestyle Interventions and Independence for Elders (LIFE) study. Accelerometry data were collected during a 40-minute, overground, walking exercise session in a subset of participants at four sites; we also used 1-week baseline and 6-month accelerometry data collected in the main trial. RESULTS: There was extreme variability in median counts per minute (CPM) achieved during a controlled bout of exercise (n = 140; median = 1,220 CPM (25th, 75th percentile = 715, 1,930 CPM). An equation combining age, age(2), and 400 m gait speed explained 61% of the variance in CPM achieved during this session. When applied to the LIFE accelerometry data (n = 1,448), the use of an individually tailored cutpoint based on this equation resulted in markedly different patterns of MVPA as compared with using standard fixed cutpoints. CONCLUSIONS: The findings of this study have important implications for the use and interpretations of accelerometry data and in the design/delivery of physical activity interventions with older adults. PMID- 26515259 TI - A strategy for oral chemotherapy via dual pH-sensitive polyelectrolyte complex nanoparticles to achieve gastric survivability, intestinal permeability, hemodynamic stability and intracellular activity. AB - Efficient oral administration of anticancer agents requires a nanocarrier to long survive in the stomach, effectively penetrate across the small intestine, tightly retain the drug during bloodstream and quickly release drug in tumor cells. Herein a kind of dual pH-sensitive polyelectrolyte complex nanoparticles (CNPs) was developed by employing electrostatic interaction between positively charged chitosan (CS) and negative poly (L-glutamic acid) grafted polyethylene glycol doxorubicin conjugate nanoparticles (PG-g-PEG-hyd-DOX NPs) with acid-labile hydrazone linkages. The obtained NPs and CNPs were characterized for their morphology, particle size, zeta-potential, pH-sensitivity under the simulated physiological conditions, drug release, as well as in vivo antitumor activity and biodistribution. The results indicated that CNPs can remain intact structure in pH range from 3.0 to 6.5. After detaching CS layer due to the pH-induced deprotonation with increasing pH to 7.4 in the mucus layer of the small intestine, the inner NPs would be released and effectively absorbed into blood circulation via opening the tight junctions by CS. PG-g-PEG-hyd-DOX NPs with demonstrated long-circulating properties can be accumulated in the tumor via EPR effect and dump the drug within tumor cells by acid-cleavage of hydrazone bonds between PG-g-PEG and DOX, achieving high therapeutic efficacy and low systemic toxicity. These results suggest that the design presented here, combining the functions of the gastrointestinal pH-sensitive electrostatic complex and intracellular acid-sensitive macromolecular prodrugs NPs, can sequentially overcome the biological barriers of oral anticancer drug delivery, which thus provides a promising nanomedicine platform for oral chemotherapy. PMID- 26515260 TI - Nanoparticle therapeutics: Technologies and methods for overcoming cancer. AB - It is anticipated that by 2030 approximately 13 million people will die of cancer. Common cancer therapy often fails due to the development of multidrug resistance (MDR), resulting in high morbidity and poor patient prognosis. Nanotechnology seeks to use drug delivery vehicles of 1-100 nm in diameter, made up of several different materials to deliver anti-cancer drugs selectively to cancer cells and potentially overcome MDR. Several technologies exist for manufacturing and functionalizing nanoparticles. When functionalized appropriately, nanoparticles have been shown to overcome several mechanisms of MDR in vivo and in vitro, reduce drug side effects and represent a promising new area of anti-cancer therapy. This review discusses the fundamental concepts of enhanced permeability and retention (EPR) effect and explores the mechanisms proposed to enhance preferential "retention" in the tumour. The overall objective of this review was to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancer. PMID- 26515261 TI - A new biorelevant dissolution method for orodispersible films. AB - Specific knowledge about the dissolution behavior under biorelevant conditions is of high interest for the rational development of orodispersible films (ODFs). As the conditions in the oral cavity strongly differ from those in the gastrointestinal tract and from those performed with the pharmacopoeial test setups, a biorelevant dissolution setup was developed in this work, considering the mechanical force of the tongue, the saliva flow, the small fluid volume and the saliva composition. Especially in the initial phase, dissolution profiles of KTP (ketoprofen) ODFs observed by the new method showed a slower drug release than obtained with setups based on conventional dissolution methods. 27.47% KTP release after 100s was detected using the new method, compared to 59.29-82.55% detected without considering the in vivo conditions. Furthermore, an influence of the simulated in vivo conditions on the dissolution profile was observed. By simulating either saliva flow or mechanical force, the KTP release after 100s was two to three times higher (18.78% and 14.18%) compared to the profiles, measured without considering one of the parameters (6.76%). Further studies have to show, whether obtained data are comparable to in vivo data to predict drug release profiles of ODFs in the oral cavity. PMID- 26515262 TI - A combined MR and CT study for precise quantitative analysis of the avian brain. AB - Brain size is widely used as a measure of behavioural complexity and sensory locomotive capacity in avians but has largely relied upon laborious dissections, endoneurocranial tissue displacement, and physical measurement to derive comparative volumes. As an alternative, we present a new precise calculation method based upon coupled magnetic resonance (MR) imaging and computed tomography (CT). Our approach utilizes a novel interactive Fakir probe cross-referenced with an automated CT protocol to efficiently generate total volumes and surface areas of the brain tissue and endoneurocranial space, as well as the discrete cephalic compartments. We also complemented our procedures by using sodium polytungstate (SPT) as a contrast agent. This greatly enhanced CT applications but did not degrade MR quality and is therefore practical for virtual brain tissue reconstructions employing multiple imaging modalities. To demonstrate our technique, we visualized sex-based brain size differentiation in a sample set of Ring-necked pheasants (Phasianus colchicus). This revealed no significant variance in relative volume or surface areas of the primary brain regions. Rather, a trend towards isometric enlargement of the total brain and endoneurocranial space was evidenced in males versus females, thus advocating a non-differential sexually dimorphic pattern of brain size increase amongst these facultatively flying birds. PMID- 26515263 TI - Role of Physical Therapists in the Management of Individuals at Risk for or Diagnosed With Venous Thromboembolism: Evidence-Based Clinical Practice Guideline. AB - The American Physical Therapy Association (APTA), in conjunction with the Cardiovascular & Pulmonary and Acute Care sections of APTA, have developed this clinical practice guideline to assist physical therapists in their decision making process when treating patients at risk for venous thromboembolism (VTE) or diagnosed with a lower extremity deep vein thrombosis (LE DVT). No matter the practice setting, physical therapists work with patients who are at risk for or have a history of VTE. This document will guide physical therapist practice in the prevention of, screening for, and treatment of patients at risk for or diagnosed with LE DVT. Through a systematic review of published studies and a structured appraisal process, key action statements were written to guide the physical therapist. The evidence supporting each action was rated, and the strength of statement was determined. Clinical practice algorithms, based on the key action statements, were developed that can assist with clinical decision making. Physical therapists, along with other members of the health care team, should work to implement these key action statements to decrease the incidence of VTE, improve the diagnosis and acute management of LE DVT, and reduce the long term complications of LE DVT. PMID- 26515264 TI - Evaluation of 5-year-old children with complete cleft lip and palate: Multicenter study. Part 1: Lip and nose aesthetic results. AB - BACKGROUND AND PURPOSE: Cleft surgery is marked by all the controversies and the multiplication of protocols, as it has been shown by the Eurocleft study. The objective of this pilot study is to start a comparison and analyzing procedure between primary surgical protocols in French centers. METHODS: Four French centers with different primary surgical protocols for cleft lip and palate repair, have accepted to be involved in this retrospective study. In each center, 20 consecutive patients with complete cleft lip and palate (10 UCLP and 10 BCLP per center), non syndromic, have been evaluated at a mean age of 5 [4,6]. In this first part, the aesthetic results of nose and lip repair were assessed based on the scale established by Mortier et al. (1997). RESULTS: Considering nose outcome, primary cleft repair surgery including a nasal dissection gives a statistically significant benefit in terms of septum deviation. Considering lip result, muscular dehiscence rate is significantly higher in BCLP patients with a two-stage lip closure. The centers using Millard one-stage lip closure do not have uniform results. For UCLP patients, the quality of scar is not statistically different between Skoog and Millard techniques. CONCLUSIONS: Primary results based on a simple, reproducible evaluation protocol. Extension to other centers required. LEVEL OF EVIDENCE: Therapeutic study. Level III/retrospective multicenter comparative study. PMID- 26515265 TI - Occurrence of cervical lymph node metastasis of maxillary squamous cell carcinoma - A monocentric study of 171 patients. AB - INTRODUCTION: Fewer than 5% of oral squamous cell carcinomas (SCC) are presented in the maxilla. The absence of cervical lymph node metastasis (LNM) is one of the main positive prognostic factors. This single-centre study analysed the cervical lymph node metastasis behaviour in patients with oral SCC of the upper jaw and serves as a basis for a cervical lymph node treatment suggestion. MATERIAL AND METHODS: The retrospective study includes 171 patients with isolated SCC of the maxilla. In addition to tumour resection, 83% of the patients underwent a selective neck dissection (ND). The data of cervical metastasis, TNM-status, tumour grade, tumour location as well as nicotine and alcohol behaviour were statistically analysed. RESULTS: The average rate of cervical metastasis was 44% in total. Tumour stage significantly affected risk for cervical metastasis (T1 = 6%, T2 = 41%, T3 = 60% and T4 = 60%) (p < 0.01). Development of cervical LNM was seemingly influenced by male gender. DISCUSSION: This study postulates a high rate of cervical metastasis of maxillary SCC. Risk for metastasis is mainly determined by the tumour stage. Alcohol and nicotine abuse have a negative impact on cervical LNM. CONCLUSION: Reviewing recent literature underlined by the illustrated data, we put up for discussion the treatment of SCC of the maxilla as similar to therapy protocols for SCC of the oral cavity. This would include an ipsilateral ND even in low tumour stage and in T4 staged tumours on both sides. However, prospective multicentre studies are needed to verify and recommend these therapy assumptions. PMID- 26515266 TI - Systematic reviews and meta-analysis. AB - Systematic reviews and meta-analyses are at the top of the 'evidence hierarchy' when assessing the effectiveness of health interventions. As such, they are important sources of synthesized information for decision-makers including consumers, clinicians, funders, payers, regulators, and researchers. The main reasons for undertaking systematic reviews and meta-analyses are to minimize bias and to maximize data by collating all the relevant, available evidence on a particular topic. In order to correctly inform decision-makers, but not mislead them, a number of key methodological conditions need to be met when undertaking these types of analysis. In this article we first review the history of systematic reviews and meta-analyses and then outline those conditions that may lead to the correct, or incorrect, use of these types of study. Also, new variations on standard systematic review methods are explored, with the pros and cons of each outlined. PMID- 26515267 TI - Human haematopoietic stem/progenitor cells express several functional sex hormone receptors. AB - Evidence has accumulated that murine haematopoietic stem/progenitor cells (HSPCs) share several markers with the germline, a connection supported by recent reports that pituitary and gonadal sex hormones (SexHs) regulate development of murine HSPCs. It has also been reported that human HSPCs, like their murine counterparts, respond to certain SexHs (e.g. androgens). However, to better address the effects of SexHs, particularly pituitary SexHs, on human haematopoiesis, we tested for expression of receptors for pituitary SexHs, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL), as well as the receptors for gonadal SexHs, including progesterone, oestrogens, and androgen, on HSPCs purified from human umbilical cord blood (UCB) and peripheral blood (PB). We then tested the functionality of these receptors in ex vivo signal transduction studies and in vitro clonogenic assays. In parallel, we tested the effect of SexHs on human mesenchymal stromal cells (MSCs). Finally, based on our observation that at least some of the UCB derived, CD45(-) very small embryonic-like stem cells (VSELs) become specified into CD45(+) HSPCs, we also evaluated the expression of pituitary and gonadal SexH receptors on these cells. We report for the first time that human HSPCs and VSELs, like their murine counterparts, express pituitary and gonadal SexH receptors at the mRNA and protein levels. Most importantly, SexH if added to suboptimal doses of haematopoietic cytokines and growth factors enhance clonogenic growth of human HSPCs as well as directly stimulate proliferation of MSCs. PMID- 26515268 TI - Clinical and radiographic differentiation of lung nodules caused by mycobacteria and lung cancer: a case-control study. AB - BACKGROUND: Lung nodules caused by mycobacteria can resemble lung cancer on chest imaging. The advent of lung cancer screening with low-dose Computed Tomography is accompanied by high false-positive rates, making it necessary to establish criteria to differentiate malignant from benign nodules. METHODS: We conducted a retrospective case-control study of 52 patients with mycobacterial lung nodules and 139 patients with lung cancer, diagnosed between 2010 and 2012. We compared clinical and radiographic characteristics to identify predictors of disease by univariate and multivariate analysis. The discriminatory power of maximum Standardized Uptake Values from Positron-Emission-Tomography was also evaluated. RESULTS: Several variables were correlated with a diagnosis of mycobacterial infection or lung cancer on univariate analysis. Such variable include smoking status and history, lesion size and imaging evidence of tree-in-bud opacities, lymphadenopathy or emphysema on computed tomography. Upon author consensus, the most clinically-relevant variables were selected to undergo multivariate analysis. A history of current or former smoking [OR 4.4 (95 % CI 1.2-15.6) and 2.7 (95 % CI 1.1-6.8), respectively P = 0.04] was correlated with diagnoses of lung cancer. Contrarily, the presence of tree-in-bud opacities was less likely to be correlated with a diagnosis of malignancy [OR 0.04 (95 % CI 0.0-1.0), P = 0.05]. Additionally, higher maximum standardized uptake values from positron emission tomography were associated with malignancy on multivariate analysis [OR 1.1 (95 % CI 1.0-1.2), P = 0.04]; but the accuracy of the values in differentiating between diseases was only 0.67 as measured by the area under the curve. Lesion size was not independently associated with diagnosis [OR 0.5 (95 % CI 0.2-1.2), (P = 0.12)]. CONCLUSIONS: Establishing the likelihood of malignancy for lung nodules based on isolated clinical or radiographic criteria is difficult. Using the variables found in this study may allow clinicians to stratify patients into groups of high and low risk for malignancy, and therefore establish efficient diagnostic strategies. PMID- 26515269 TI - Melatonin versus midazolam premedication in children undergoing surgery: A pilot study. AB - AIM: Melatonin has been proposed as a premedication alternative to midazolam, preceding anaesthesia induction. However, to our knowledge, data concerning interaction between melatonin and intravenous anaesthetic drugs in children are not available. The aim of this prospective, randomized, double-blind pilot study was to investigate the possible effect of melatonin premedication, in comparison to midazolam, on the required infusion of propofol in children undergoing surgery. As a secondary outcome, the effect of oral melatonin on the preoperative sedation level and on the post anaesthesia recovery score was evaluated. METHODS: Children between the age of 5 and 14 years, scheduled for elective surgery, were prospectively enrolled between January 2012 and December 2013, and randomly assigned to two groups based on whether they received oral melatonin (0.5 mg/kg) or oral midazolam (0.5 mg/kg) premedication before induction of anaesthesia with propofol. Degree of sedation before and after anaesthesia was also evaluated. RESULTS: Ninety-two patients were studied, 46 for each group. We found that oral administration of melatonin significantly reduced doses of propofol required for induction of anaesthesia in paediatric patients, more than midazolam (P < 0.001). No statistically significant differences were found in the pre- and post anaesthesia sedation score (P = 0.387 and P = 0.525, respectively) between the two groups. CONCLUSIONS: The present study demonstrates that melatonin enhances the potency of propofol also in paediatric patients. Moreover, considering the paediatric level of sedation, melatonin was equally as effective as midazolam. These data support the use of melatonin as a premedicant in paediatric surgical patients. PMID- 26515270 TI - Interferon gamma release assays for monitoring the response to treatment for tuberculosis: A systematic review. AB - INTRODUCTION: The ability to monitor the response to therapy for tuberculosis (TB) and confirm adequate treatment would be a major advance. The utility of interferon gamma assays (IGRA) for this purpose remains uncertain. METHODS: A systematic search of all studies investigating commercial IGRA to monitor anti tuberculous treatment was done. Studies were included if they included an IGRA before the start of, and at least once during, treatment for active or latent TB. RESULTS: We identified 30 studies, of which 24 used QuantiFERON-TB (QFT), three used T-SPOT.TB and three used both QFT and T-SPOT.TB. Most studies were done in low TB incidence countries. No uniform pattern was seen in IGRA conversion and reversion rates at the end of treatment for active or latent TB. In most studies, the majority of IGRA results remained positive at the end of treatment. In many studies, the quantitative levels of IFN-gamma decreased during treatment, particularly in active TB. There was significant heterogeneity in the included studies. CONCLUSION: While quantitative IGRA responses generally fall during treatment for TB, the large degree of variation in results between participants in each study means that IGRAs are unlikely to be useful for monitoring anti tuberculous treatment in clinical practice for any individual patient. PMID- 26515271 TI - Lessons from the History of Ivermectin and Other Antiparasitic Agents. AB - The twentieth century's arsenal of chemical anthelmintics brought manifold improvement in human health and, more abundantly, in animal health. The benefits were not only in health per se but also in agricultural economics, livestock management, and the overall production of food and fiber to support expanding human populations. Nevertheless, there remains (due in large part to drug resistance and paucity of available vaccines) a great need for new means of controlling disease caused by parasitic worms. Prudence should persuade us to look to our past for lessons that might help in our quest for new drugs. The lessons suggested here derive from the history of ivermectin and other anthelmintics. They deal with the means of finding substances with useful antiparasitic activity and with alternative approaches to drug discovery. PMID- 26515272 TI - Molecular Basis for Adaptation of Oysters to Stressful Marine Intertidal Environments. AB - Oysters that occupy estuarine and intertidal habitats have well-developed stress tolerance mechanisms to tolerate harsh and dynamically changing environments. In this review, we summarize common pathways and genomic features in oyster that are responsive to environmental stressors such as temperature, salinity, hypoxia, air exposure, pathogens, and anthropogenic pollutions. We first introduce the key genes involved in several pathways, which constitute the molecular basis for adaptation to stress. We use genome analysis to highlight the strong cellular homeostasis system, a unique adaptive characteristic of oysters. Next, we provide a global view of features of the oyster genome that contribute to stress adaptation, including oyster-specific gene expansion, highly inducible expression, and functional divergence. Finally, we review the consequences of interactions between oysters and the environment from ecological and evolutionary perspectives by discussing mass mortality and adaptive divergence among populations and related species of the genus Crassostrea. We conclude with prospects for future study. PMID- 26515274 TI - Astroglia dynamics in ageing and Alzheimer's disease. AB - Ageing of the brain is the major risk factor for neurodegenerative disorders that result in cognitive decline and senile dementia. Ageing astrocytes undergo complex and region specific remodelling which can reflect life-long adaptive plasticity. In neurodegeneration, astroglial cells are similarly a subject for morpho-functional changes hampering the homoeostasis, defence and regeneration of the central nervous system. Region-specific astroglial atrophy with the loss of function and astroglial reactivity have been reported in virtually all forms of neurodegenerative pathologies. Modulating these astroglia changes may represent a fertile ground for novel therapeutic intervention strategies to prevent, delay progression and/or ameliorate pathology. While at present this bodacious goal represents a wishful thinking, further understanding of astroglial role in ageing and neurodegeneration could bring us closer to laying the foundations for such cell-specific therapeutic approaches. PMID- 26515275 TI - Effects of Water on the Copper-Catalyzed Conversion of Hydroxymethylfurfural in Tetrahydrofuran. AB - Reaction kinetics were studied to quantify the effects of water on the conversion of hydroxymethylfurfural (HMF) in THF over Cu/gamma-Al2 O3 at 448 K using molecular H2 as the hydrogen source. We show that low concentrations of water (5 wt %) in the THF solvent significantly alter reaction rates and selectivities for the formation of reaction products by hydrogenation and hydrogenolysis processes. In the absence of water, HMF was converted primarily to hydrogenolysis products 2 methyl-5-hydroxymethylfuran (MHMF) and 2,5-dimethylfuran (DMF), whereas reactions carried out in THF-H2 O mixtures (THF/H2 O=95:5 w/w) led to the selective production of the hydrogenation product 2,5-bis(hydroxymethyl)furan (BHMF) and inhibition of HMF hydrogenolysis. PMID- 26515273 TI - Pharmacological modulation of astrocytes and the role of cell type-specific histone modifications for the treatment of mood disorders. AB - Astrocytes orchestrate arrangement and functions of neuronal circuits and of the blood-brain barrier. Dysfunctional astrocytes characterize mood disorders, here showcased by deregulation of the astrocyte end-feet protein Aquaporin-4 around blood vessels and, hypothetically, of the astrocyte-specific phagocytic protein MEGF10 to shape synapses. Development of mood disorders is often a result of 'gene * environment' interactions, regulated among others by histone modifications and related modulator enzymes, which rapidly promote adaptive responses. Thus, they represent ideal targets of drugs aimed at inducing stable effects with quick onsets. One of the prevalent features of histone modifications and their modulators is their cell-type specificity. Investigating cell type specific epigenetic modulations upon drug administration might therefore help to implement therapeutic treatments. PMID- 26515277 TI - The Long View of Long-Term Care: Our Personal Take on Progress, Pitfalls, and Possibilities. PMID- 26515276 TI - Cluster Randomized Trial of a Church-Based Peer Counselor and Tailored Newsletter Intervention to Promote Colorectal Cancer Screening and Physical Activity Among Older African Americans. AB - Action Through Churches in Time to Save Lives (ACTS) of Wellness was a cluster randomized controlled trial developed to promote colorectal cancer screening and physical activity (PA) within urban African American churches. Churches were recruited from North Carolina (n = 12) and Michigan (n = 7) and were randomized to intervention (n = 10) or comparison (n = 9). Intervention participants received three mailed tailored newsletters addressing colorectal cancer screening and PA behaviors over approximately 6 months. Individuals who were not up-to-date for screening at baseline could also receive motivational calls from a peer counselor. The main outcomes were up-to-date colorectal cancer screening and Metabolic Equivalency Task (MET)-hours/week of moderate-vigorous PA. Multivariate analyses examined changes in the main outcomes controlling for church cluster, gender, marital status, weight, and baseline values. Baseline screening was high in both intervention (75.9%, n = 374) and comparison groups (73.7%, n = 338). Screening increased at follow-up: +6.4 and +4.7 percentage points for intervention and comparison, respectively (p = .25). Baseline MET-hours/week of PA was 7.8 (95% confidence interval [6.8, 8.7]) for intervention and 8.7 (95% confidence interval [7.6, 9.8]) for the comparison group. There were no significant changes (p = .15) in PA for intervention (-0.30 MET-hours/week) compared with the comparison (-0.05 MET-hours/week). Among intervention participants, PA increased more for those who participated in church exercise programs, and screening improved more for those who spoke with a peer counselor or recalled the newsletters. Overall, the intervention did not improve PA or screening in an urban church population. These findings support previous research indicating that structured PA opportunities are necessary to promote change in PA and churches need more support to initiate effective peer counselor programs. PMID- 26515278 TI - Can we predict the need for pharmacological treatment according to demographic and clinical characteristics in gestational diabetes? AB - OBJECTIVE: To determine the ability to predict the need for pharmacological treatment in gestational diabetes mellitus (GDM). METHOD: A retrospective cohort study. Data were collected from medical records of 1324 GDM patients including demographic data, family history of diabetes, obstetrical history, laboratory results, treatment modality and level of glycemic control. Patients who were identified as pre-gestational diabetes were excluded. RESULTS: Overall, 143 (10.8%) GDM patients required pharmacological therapy. Of women who had GDM in their previous pregnancy; only 11.65% achieved desired glycemic control solely by diet treatment. Moreover, 62.5% of patients requiring pharmacological therapy in their previous pregnancy achieved desired level of glycemic control only by diet. Of patients who achieved desired level of glycemic control on diet until the second antenatal visit, 95% continued to maintain desired level glycemic control throughout pregnancy. Pre-pregnancy BMI >30, fasting plasma glucose >95 mg/dL and maternal age above 30 were associated with increase need for pharmacological treatment. One abnormal value in the OGTT and GCT result >2 mg/dL did not predict the need for pharmacological therapy. Primigravida and family history of GDM were not found to be predictors for treatment modality. CONCLUSION: Using clinical and demographical data can predict the need for pharmacological treatment for GDM. PMID- 26515279 TI - Low-power broadband homonuclear dipolar recoupling in MAS NMR by two-fold symmetry pulse schemes for magnetization transfers and double-quantum excitation. AB - We provide an experimental, numerical, and high-order average Hamiltonian evaluation of an open-ended series of homonuclear dipolar recoupling sequences, SR [Formula: see text] with p=1,2,3,.... While operating at a very low radio frequency (rf) power, corresponding to a nutation frequency of 1/2 of the magic angle spinning (MAS) rate (omeganut=omegar/2), these recursively generated double quantum (2Q) dipolar recoupling schemes offer a progressively improved compensation to resonance offsets and rf inhomogeneity for increasing pulse sequence order p. The excellent recoupling robustness to these experimental obstacles, as well as to CSA, is demonstrated for 2Q filtering (2QF) experiments and for driving magnetization transfers in 2D NMR correlation spectroscopy, where the sequences may provide either double or zero quantum dipolar Hamiltonians during mixing. Experimental and numerical demonstrations, which mostly target conditions of "ultra-fast" MAS (?50kHz) and high magnetic fields, are provided for recoupling of (13)C across a wide range of isotropic and anisotropic chemical shifts, as well as dipolar coupling constants, encompassing [2,3-(13)C2]alanine, [1,3-(13)C2]alanine, diammonium [1,4-(13)C2]fumarate, and [U-(13)C]tyrosine. When compared at equal power levels, a superior performance is observed for the SR [Formula: see text] sequences with p?3 relative to existing and well-established 2Q recoupling techniques. At ultra-fast MAS, proton decoupling is redundant during the homonuclear dipolar recoupling of dilute spins in organic solids, which renders the family of SR [Formula: see text] schemes the first efficient 2Q recoupling option for general applications, such as 2Q-1Q correlation NMR and high-order multiple-quantum excitation, under truly low-power rf conditions. PMID- 26515280 TI - Application of transcriptomic analyses to reproductive studies in contemporary commercial sows. AB - Genetic selection in sows has substantially increased the total number of pigs born, but there has been an associated decrease in litter birth weight. Furthermore, irrespective of the total number of pigs born, a repeatable low litter birth weight phenotype has evolved in a subpopulation of mature sows, in which a high ovulation rate drives extremes of intrauterine crowding in early gestation and limits placental development: placental development continues to be compromised in later gestation and is associated with intrauterine growth restriction and a low litter birth weight. Furthermore, although contemporary commercial sows are increasingly resilient to the challenges of lactational catabolism in terms of the traditional measures of reproductive performance, gender-specific effects on early embryonic development of the subsequent litter are apparent and are likely linked to effects of sow catabolism on folliculogenesis and oocyte maturation. Recent transcriptomic studies that have helped elucidate some of the regulatory mechanisms mediating the evolving changes in the reproductive biology of contemporary commercial sows are summarized in the present review. However, the lack of clearly differentiated reproductive phenotypes among commercial sow populations is a problem for ongoing studies. Access to an unselected "wild-type" population with which to make comparisons, or the application of more standardized experimental approaches to mechanistic studies, may help advance the field of sow reproductive biology. PMID- 26515281 TI - Analysis of sterigmatocystin in cereals, animal feed, seeds, beer and cheese by immunoaffinity column clean-up and HPLC and LC-MS/MS quantification. AB - A method is reported for the analysis of sterigmatocystin in various food and feed matrices using a commercial sterigmatocystin immunoaffinity column (IAC) for sample clean-up prior to HPLC analysis by UV with mass spectrometric detection (LC-MS/MS). Cereals (wheat, oats, rye, maize and rice), sunflower seeds and animal feed were spiked with sterigmatocystin at levels from 0.75 to 50 ug kg(-1) to establish method performance. Using acetonitrile/water extraction followed by IAC clean-up, and analysis by HPLC with detection at 325 nm, recoveries ranged from 68% to 106%, with repeatability from 4.2% to 17.5%. The limit of quantification with UV detection in these matrices was 1.5 ug kg(-1). For the analysis of beer and cheese the sample preparation prior to IAC clean-up was changed to accommodate the different properties of the matrix, prior to analysis by LC-MS/MS. For beer and cheese spiked at 5.0 ug kg(-1) the recoveries were 94% and 104%, and precision (RSDs) were 1.9% and 2.9% respectively. The limits of quantification by LC-MS/MS in beer and cheese were 0.02 and 0.6 ug kg(-1) respectively. The sterigmatocystin IAC was demonstrated to provide an efficient clean-up of various matrices to enable this mycotoxin to be determined by either HPLC with UV detection or LC-MS/MS. PMID- 26515282 TI - Oxidation-resistant hybrid metal oxides/metal nanodots/silver nanowires for high performance flexible transparent heaters. AB - Despite its excellent optical, electrical, mechanical, and thermal performances, a silver nanowire (AgNW)-based transparent conducting heater (TCH) still demonstrates several drawbacks such as facile nanowire breakdown on application of a high DC voltage, easy oxidation when exposed to harsh environments, leading to increased surface resistivity, and high resistance among wire junctions causing nonhomogeneous temperature profiles. To overcome these issues, the AgNW was hybridized with other transparent heating materials made of fluorine-doped tin oxide (FTO) thin films and NiCr nanodots (FTO/NiCr/AgNW). The dispersed NiCr nanodots (~50 nm) and FTO thin films (~20 nm) electrically bridge the nanowire junctions leading to a decreased sheet resistance and uniform temperature profiles. The hybrid transparent heater shows excellent optical transmittance (>90%) and high saturation temperature (162 degrees C) at low applied DC voltage (6 V). Moreover, the FTO/NiCr/AgNW heater exhibits a stable sheet resistance in a hostile environment, hence highlighting the excellent oxidation-resistance of the heating materials. These results indicate that the proposed hybrid transparent heaters could be a promising approach to combat the inherent problems associated with AgNW-based transparent heaters for various functional applications. PMID- 26515283 TI - Quantitative cancer risk assessment for occupational exposures to asphalt fumes during built-up roofing asphalt (BURA) operations. AB - The International Agency for Research on Cancer qualitatively characterized occupational exposure to oxidized bitumen emissions during roofing as probably carcinogenic to humans (Group 2A). We examine chemistry, exposure, epidemiology and animal toxicity data to explore quantitative risks for roofing workers applying built-up roofing asphalt (BURA). Epidemiology studies do not consistently report elevated risks, and generally do not have sufficient exposure information or adequately control for confounders, precluding their use for dose response analysis. Dermal carcinogenicity bioassays using mice report increased tumor incidence with single high doses. In order to quantify potential cancer risks, we develop time-to-tumor model methods [consistent with U.S. Environmental Protection Agency (EPA) dose-response analysis and mixtures guidelines] using the dose-time-response shape of concurrent exposures to benzo[a]pyrene (B[a]P) as concurrent controls (which had several exposure levels) to infer presumed parallel dose-time-response curves for BURA-fume condensate. We compare EPA relative potency factor approaches, based on observed relative potency of BURA to B[a]P in similar experiments, and direct observation of the inferred BURA dose time-response (scaled to humans) as means for characterizing a dermal unit risk factor. We apply similar approaches to limited data on asphalt-fume inhalation and respiratory cancers in rats. We also develop a method for adjusting potency estimates for asphalts that vary in composition using measured fluorescence. Overall, the various methods indicate that cancer risks to roofers from both dermal and inhalation exposure to BURA are within a range typically deemed acceptable within regulatory frameworks. The approaches developed may be useful in assessing carcinogenic potency of other complex mixtures of polycyclic aromatic compounds. PMID- 26515284 TI - [Multifocal tumors in a 56-year-old male patient]. PMID- 26515285 TI - [MR imaging of the prostate]. AB - CLINICAL ISSUE: Prostate cancer is the most common form of cancer in men in Germany; however, there is a distinct difference between incidence and mortality. STANDARD TREATMENT: The detection of prostate cancer is based on clinical and laboratory testing using serum prostate-specific antigen (PSA) levels and transrectal ultrasound with randomized biopsy. DIAGNOSTIC WORK-UP: Multiparametric MR imaging of the prostate can provide valuable diagnostic information for detection of prostate cancer, especially after negative results of a biopsy prior to repeat biopsy. PERFORMANCE: In addition the use of MR ultrasound fusion-guided biopsy has gained in diagnostic importance and has increased the prostate cancer detection rate. ACHIEVEMENTS AND PRACTICAL RECOMMENDATIONS: The prostate imaging reporting and data system (PI-RADS) classification has standardized the reporting of prostate MRI which has positively influenced the acceptance by urologists. PMID- 26515286 TI - Erratum to: Molecular characterization and classification of Trypanosoma spp. Venezuelan isolates based on microsatellite markers and kinetoplast maxicircle genes. AB - Unfortunately, the original version of this article [1] contained an error. Figure 1 in the original article, corresponded to the first coinertia analysis that was carried out with no data on the procyclin PE repeats for the T. brucei brucei strains. After including these data, the coinertia analysis was modified both in the directionality of the arrows in the Y Hyperspace and in the biplot generated by the interaction of the two coinertia axes. The modified coinertia analysis is included in Fig. 1. PMID- 26515288 TI - Monomeric siliconthiodichloride trapped by a Lewis base. AB - Thiophosgene (CSCl2), a chemical reagent used in numerous organic syntheses, exists in the monomeric form while its heavier silicon analogue [siliconthiodichloride (SiSCl2)] has been isolated so far as a dimer at room temperature and as a tetramer at 180 degrees C. Herein, we report on the first synthesis, isolation, and characterization of cyclic alkyl(amino) carbene (cAAC) stabilized siliconthiodichloride (cAAC)SiSCl2 (3) in the neutral monomeric form. 3 is synthesized via reaction of (cAAC)2Si2Cl4 (1) or (cAAC)2Si2Cl2 (2) with S8 in the temperature range of -78 to 20 degrees C. An NHC [NHC = N-heterocyclic carbene] analogue of 3 is not isolated when (NHC)SiCl2 is reacted with S8. The bright yellow colored compound 3 is soluble in polar organic solvents. It is stable at room temperature for a month under an inert atmosphere. 3 decomposes above 160 degrees C. The monomeric molecular structure of 3 has been unambiguously confirmed by X-ray single crystal diffraction. 3 is also characterized by NMR, UV-vis, and IR spectroscopy. The bonding and electron density distributions of 3 have been further studied by theoretical calculations. PMID- 26515287 TI - miR-205 promotes proliferation and invasion of laryngeal squamous cell carcinoma by suppressing CDK2AP1 expression. AB - BACKGROUND: The aberrant expression of microRNAs (miRNAs) has been found in various types of cancer. miR-205 was reported to be upregulated in laryngeal squamous cell carcinoma (LSCC) tissues, however, the mechanisms by which miR-205 functions as a regulator of LSCC are largely unknown. RESULTS: In this study, Real-time qPCR and Western blot assay showed that expression of miR-205 was upregulated and expression of cyclin-dependent kinase 2-associated protein 1 (CDK2AP1) was downregulated in LSCC tissues. The expression levels of miR-205 were negatively related to those of CDK2AP1 in LSCC tissues and cell lines. Moreover, we found that miR-205 was the upstream regulator of CDK2AP1 and could suppress the CDK2AP1 expression in LSCC cells. 3-(4,5-dimethylthiazal-2-yl)-2,5 diphenyl-tetrazolium bromide assays and transwell invasion assay were performed to test the proliferation and invasion of LSCC cells. Gelatin zymography was used to detect the activity of MMP2 and MMP9. CDK2AP1, c-Myc and CyclinD1 expression in cells was assessed with Western blotting. We found that miR-205 was the upstream regulator of CDK2AP1 and could suppress the expression of CDK2AP1 in LSCC cells. In addition, miR-205 significantly induced cell proliferation and invasion by suppressing CDK2AP1 expression. Consistent with miR-205 inhibitors, overexpressed CDK2AP1 suppressed the activity of MMP2 and MMP9 and c-Myc and CyclinD1 expression in LSCC cells. CONCLUSION: These findings help us to better elucidate the molecular mechanisms of LSCC progression and provide a new theoretical basis to further investigate miR-205 as a potential biomarker and a promising approach for LSCC treatment. PMID- 26515289 TI - Neurodegeneration in multiple sclerosis is a process separate from inflammation: Yes. PMID- 26515290 TI - Neurodegeneration in multiple sclerosis is a process separate from inflammation: No. PMID- 26515291 TI - Smoking cessation among U.S. Hispanic/Latino adults: Findings from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). AB - This paper examines patterns of smoking cessation among Hispanics/Latinos with particular attention to gender, acculturation, and national background. Data are from the Hispanic Community Health Study/Study of Latinos, a population-based study of 16,415 non-institutionalized Hispanics/Latinos ages 18-74 from a stratified random sample of households in Chicago, Miami, the Bronx, and San Diego. Face-to-face interviews, in English or Spanish, were conducted from 2008 to 2011. Findings are based on 6398 participants who reported smoking at least 100 cigarettes in their lifetime. Associations with smoking cessation outcomes were assessed in bivariate and multivariable analyses. Findings indicate that approximately equal proportions of men and women were former smokers. There was little difference by gender in socioeconomic characteristics associated with smoking cessation. Both men and women who lived in households with smokers were less likely to be abstinent. Multivariable analysis indicated that the likelihood of quitting varied by national background primarily among men, however, Puerto Rican and Cuban smokers of both genders were the least likely to successfully quit smoking. Among women, but not men, younger and more socially acculturated individuals had lower odds of sustaining cessation. Over 90% of female and male former smokers reported quitting on their own without cessation aids or therapy. The results suggest that many Hispanics/Latinos are self-motivated to quit and are able to do so without clinical assistance. Heterogeneity in smoking behaviors among Hispanics/Latinos should be taken into account when developing and delivering smoking cessation interventions and public health campaigns. PMID- 26515293 TI - Synergistic effect of copper and low temperature over Listeria monocytogenes. AB - The capacity to grow at low temperatures has allowed Listeria monocytogenes to become one of the primary food pathogens to date, representing a major public health problem worldwide. Several works have described the homeostatic response of L. monocytogenes under different copper (Cu) treatments growing at mild temperature (30 degrees C). The aims of this report were to evaluate if changes in the external concentration of Cu affected viability and Cu homeostasis of L. monocytogenes growing at low temperature. Ours results showed that L. monocytogenes growing at 8 degrees C had a reduced viability relative to 30 degrees C when exposed to Cu treatments. This decrease was correlated with an increase in the internal concentration of Cu, probably linked to the transcriptional down-regulation of mechanisms involved in Cu homeostasis. This combined effect of Cu and low temperature showed a synergistic impact over the viability and homeostasis of L. monocytogenes, where low temperature exacerbated the toxic effect of Cu. These results can be useful in terms of the use of Cu as an antibacterial agent. PMID- 26515292 TI - Mycobacterium-Infected Dendritic Cells Disseminate Granulomatous Inflammation. AB - The disappearance and reformation of granulomas during tuberculosis has been described using PET/CT/X-ray in both human clinical settings and animal models, but the mechanisms of granuloma reformation during active disease remains unclear. Granulomas can recruit inflammatory dendritic cells (iDCs) that can regulate local T-cell responses and can carry bacteria into the lymph nodes, which is crucial for generating systemic T-cell responses against mycobacteria. Here, we report that a subset of mycobacterium-infected iDCs are associated with bacteria-specific T-cells in infected tissue, outside the granuloma, and that this results in the formation of new and/or larger multi-focal lesions. Mycobacterium-infected iDCs express less CCR7 and migrate less efficiently compared to the non-infected iDCs, which may support T-cell capture in granulomatous tissue. Capture may reduce antigen availability in the lymph node, thereby decreasing systemic priming, resulting in a possible regulatory loop between systemic T-cell responses and granuloma reformation. T-cell/infected iDCs clusters outside the granuloma can be detected during the acute and chronic phase of BCG and Mtb infection. Our studies suggest a direct role for inflammatory dendritic cells in the dissemination of granulomatous inflammation. PMID- 26515294 TI - An inability to distinguish edematous swelling from true hypertrophy still prevents a completely accurate interpretation of the time course of muscle hypertrophy. PMID- 26515295 TI - Sirenomelia: Expansion of the Phenotype. PMID- 26515296 TI - Nanorod Surface Plasmon Enhancement of Laser-Induced Ultrafast Demagnetization. AB - Ultrafast laser-induced magnetization dynamics in ferromagnetic thin films were measured using a femtosecond Ti:sapphire laser in a pump-probe magneto-optic Kerr effect setup. The effect of plasmon resonance on the transient magnetization was investigated by drop-coating the ferromagnetic films with dimensionally-tuned gold nanorods supporting longitudinal surface plasmon resonance near the central wavelength of the pump laser. With ~4% nanorod areal coverage, we observe a >50% increase in demagnetization signal in nanorod-coated samples at pump fluences on the order of 0.1 mJ/cm(2) due to surface plasmon-mediated localized electric field enhancement, an effect which becomes more significant at higher laser fluences. We were able to qualitatively reproduce the experimental observations using finite-difference time-domain simulations and mean-field theory. This dramatic enhancement of ultrafast laser-induced demagnetization points to possible applications of nanorod-coated thin films in heat-assisted magnetic recording. PMID- 26515297 TI - Acute effects of whole-body cryotherapy on sit-and-reach amplitude in women and men. AB - Flexibility is an intrinsic property of body tissues, which among other factors determines the range of motion (ROM). A decrease in neural activation of the muscle has been linked with greater ROM. Cryotherapy is an effective technique to reduces neural activation. Hence, the aim of the present study was to evaluate if a single session of whole-body cryotherapy (WBC) affects ROM. 60 women and 60 men were divided into two groups (control and experimental). After the initial sit and-reach test, experimental group performed a 150 s session of WBC, whereas the control group stayed in thermo-neutral environment. Immediately after, both groups performed another sit-and-reach test. A 3-way analysis of variance revealed statistically significant time*group and time * gender interaction. Experimental groups improved sit-and-reach amplitude to a greater extend than the control group. Our results support the hypothesis that ROM is increased immediately after a single session of WBC. PMID- 26515298 TI - Measurements of Coronary Artery Aneurysms Due to Kawasaki Disease by Dual-Source Computed Tomography (DSCT). AB - Diameters of coronary artery aneurysms (CAAs) complicating acute phase KD can strongly predict the long-term prognosis of coronary artery lesions (CAL). Recently, computed tomographic angiography (CTA) has been used to detect CAL, and the purpose of this study was to determine whether coronary artery diameters measurements by CTA using dual-source computed tomography (DSCT) can be used instead of coronary angiogram (CAG) measurements. Twenty-five patients (22 males and three females) with CAL due to KD, who had undergone both CTA and CAG within one year, were retrospectively evaluated between 2007 and 2013. A prospective electrocardiogram-triggered CTA was performed on a DSCT (SOMATOM((r)) Definition, Siemens Healthcare, Germany). Two pediatric cardiologists independently measured the diameters of CAAs twice in each maximum intensity projection (MIP), curved multiplaner reconstruction (MPR) and CAG. We measured 161 segments in total (segment 1-3, 5-7, 11, 13). Diagnostic accuracy was expressed as kappa coefficient. A Bland-Altman analysis was also used to assess the intra-observer, inter-observer and inter-modality agreement. The diagnostic quality of CTA was excellent (kappa = 0.93). Excellent inter-observer agreement for the diameters of CAAs was obtained for MIP, MPR and CAG and for the intra-observer agreement. The inter-modality agreement was also excellent in measurements of CAA (MPR-CAG: y = 0.9x + 0.40, r = 0.97, p < 0.0001 MIP-CAG: y = x + 0.1, r = 0.94, p < 0.0001). These values in normal coronary arteries were also obtained. We found a significant correlation between CTA and CAG in measuring the coronary arteries. We conclude that measuring coronary artery diameters by CTA is reliable and useful. PMID- 26515299 TI - What does the lay public know about heart failure? Findings from the Heart Failure Awareness Day Initiative. AB - AIM & METHODS: One critical factor enhancing the implementation of successful diagnostic and therapeutic strategies into clinical practice is awareness among the lay public. We describe awareness in a contemporary, multinational convenience sample of subjects attending the Heart Failure Awareness (HFA) Day Initiatives in 2013. RESULTS: We analysed 2,438 subjects (Germany 33%, Lithuania 42%, Romania 8%, Slovenia 17%) : 53% were female, 58% were aged >60 years, 11% (had) worked in the medical sector, 82% heard about HF before. Shortness of breath and tiredness were correctly identified as symptoms of heart failure in 71% and 61%, but only 52% recognized swelling of feet and legs as a clinical sign; 31% considered heart failure a normal symptom of old age, and only 38% realized the particularly poor prognosis after a heart failure related hospitalization. Subjects who had heard about heart failure before had a lower prevalence of common misbeliefs about HF. CONCLUSION: In subjects participating in the HFA Day initiative 2013, the level of awareness was unsatisfactory, and important misconceptions remain. The educational and awareness activities for both the population at large and also for decision makers should be broadened and intensified. PMID- 26515300 TI - Hempseed Products Fed to Hens Effectively Increased n-3 Polyunsaturated Fatty Acids in Total Lipids, Triacylglycerol and Phospholipid of Egg Yolk. AB - Hempseed products represent potential alternative feed ingredients for poultry. However, their usage is not currently approved due to a lack of data to support their safety and efficacy. In this regard, the current study was conducted to assess the impact of dietary concentration of hempseed (HS) products and duration of their feeding to hens on the polyunsaturated fatty acid (PUFA) composition of egg yolk lipids. In the current study, 48 Lohmann LSL-Classic hens were individually housed in metabolism cages, in a completely randomized design, and provided one of six diets (wheat-barley-soybean-based) containing either HS (10, 20 and 30 %), hempseed oil (HO; 4.5 and 9.0 %) or no hempseed product (control) over 12 weeks. Increasing alpha-linolenic acid (ALA) intake via increasing dietary hempseed product inclusion, significantly (p < 0.0001) increased the n-3 PUFA contents of yolk total lipid. The values of ALA increased by 12-fold (152 +/ 3.56 and 156 +/- 2.42 mg/yolk) and docosahexaenoic acid (DHA) by twofold to threefold (41.3 +/- 1.57 and 43.6 +/- 1.61 mg/yolk) over the control, for the highest levels of HS and HO inclusion, respectively. Increasing levels of hemp products in laying hen diets proved effective in manipulating the fatty acid profile of the total lipid, triacylglycerol (TAG) and total phospholipid (PL) fractions of yolks, enhancing the n-3 fatty acids and reducing the n-6/n-3 ratio. The latter benefit was achieved within 4 weeks of feeding hens either HS- or HO containing diets. PMID- 26515301 TI - Terthiophene-based D-A polymer with an asymmetric arrangement of alkyl chains that enables efficient polymer solar cells. AB - We report a series of difluorobenzothiadizole (ffBT) and oligothiophene-based polymers with the oligothiophene unit being quaterthiophene (T4), terthiophene (T3), and bithiophene (T2). We demonstrate that a polymer based on ffBT and T3 with an asymmetric arrangement of alkyl chains enables the fabrication of 10.7% efficiency thick-film polymer solar cells (PSCs) without using any processing additives. By decreasing the number of thiophene rings per repeating unit and thus increasing the effective density of the ffBT unit in the polymer backbone, the HOMO and LUMO levels of the T3 polymers are significantly deeper than those of the T4 polymers, and the absorption onset of the T3 polymers is also slightly red-shifted. For the three T3 polymers obtained, the positions and size of the alkyl chains play a critical role in achieving the best PSC performances. The T3 polymer with a commonly known arrangement of alkyl chains (alkyl chains sitting on the first and third thiophenes in a mirror symmetric manner) yields poor morphology and PSC efficiencies. Surprisingly, a T3 polymer with an asymmetric arrangement of alkyl chains (which is later described as having an "asymmetric bi repeating unit") enables the best-performing PSCs. Morphological studies show that the optimized ffBT-T3 polymer forms a polymer:fullerene morphology that differs significantly from that obtained with T4-based polymers. The morphological changes include a reduced domain size and a reduced extent of polymer crystallinity. The change from T4 to T3 comonomer units and the novel arrangement of alkyl chains in our study provide an important tool to tune the energy levels and morphological properties of donor polymers, which has an overall beneficial effect and leads to enhanced PSC performance. PMID- 26515302 TI - Findings from frozen sections of spinal subependymomas: Is it possible to differentiate this diagnosis from other common spinal tumors? AB - Subependymomas are slow-growing, benign neoplasms that are rarely found in the spinal cord. Because of the differences in the treatment plans, it might be very helpful for neurosurgeons to intraoperatively establish a diagnosis of spinal subependymoma, differentiated from other spinal intramedullary tumors. In this study, we analyzed frozen sections of spinal subependymomas to identify potential histological clues of spinal subependymomas to differentiate them from tumors that mimic spinal subependymoma. We reviewed the frozen sections and the corresponding permanent slides for 7 cases of spinal subependymoma. The spinal subependymomas showed several characteristic patterns, including, most importantly, an eccentric or both central and eccentric location in the axial plane. Histologically, they showed a (1) well-demarcated and multinodular mass with (2) low or moderate cellularity, (3) a microlobular pattern, and (4) small clusters of neoplastic cells. These features appear to be very specific to spinal subependymomas and could help differentiate them from ependymomas or astrocytomas. Although we might not be able to provide an exact diagnosis of all spinal subependymomas using these histological features, we hope that they help neuropathologists and neurosurgeons to adequately diagnose and treat spinal subependymomas. PMID- 26515303 TI - Targeting redox balance to deprogramme obesity: are we starting early enough? PMID- 26515304 TI - Nature versus exposure: matched exposure to circulatory stressors of different natures elicits adaptive remodelling. PMID- 26515305 TI - Mechanisms of protein synthesis activation following exercise: new pieces to the increasingly complex puzzle. PMID- 26515306 TI - Temperature in the hot spot: oesophageal temperature and whole body thermal status in patent foramen ovale. PMID- 26515307 TI - Fishy Hearing: A Short Biography of Arthur N. Popper, PhD. AB - Biologist Dr. Arthur Popper's career spans decades, from his early work on comparative inner ear morphology in fishes to his recent interest in how underwater noise impacts aquatic vertebrates. Along the way Dr. Popper's research subjects span at least 19 vertebrate taxa, from lamprey to lungfish to humans, and he's had a profound influence in the field of fish bioacoustics. This brief biography describes some of Dr. Popper's many contributions to fish hearing research and highlights both some of his major discoveries and some of the biological mysteries he has yet to solve. PMID- 26515308 TI - A Most Interesting Man of Science: The Life and Research of Richard Rozzell Fay. AB - On May 25, 2013, a special symposium was held at the Mote Marine Laboratory in Sarasota, FL to honor the outstanding careers of Drs. Richard R. Fay and Arthur N. Popper, a "dynamic duo" of scientists who were pioneers in the field of contemporary fish hearing and bioacoustics. The present article details the research, academic life, and "other side" of Richard Rozzell Fay, a most interesting man of science who is known to all as a kind, gentle, wise, and introspective scientist. PMID- 26515309 TI - It Started in Hawai'i Kai: Reminiscences of 43 Years (and Counting) of Collaboration and Friendship. AB - This paper discusses the 43+ year collaboration of Arthur Popper and Richard Fay. Over these years, we have co-authored over 30 papers and 55 books. The collaboration benefits from a strong friendship that includes our spouses and children. By any measure, our collaboration must be seen as being successful. The basis for this success is, we think, twofold. First, we have very complementary and overlapping research interests. This has enabled us to tackle issues, whether in research or in planning meetings or books, from different perspectives. Second, a hallmark of our successful collaboration has been our deep and close friendship and the extension of that friendship to our spouses and children. In this paper, we discuss some of the events that have shaped our collaboration, and some of the people who have impacted our lives. PMID- 26515311 TI - Acoustic Communication in Butterflyfishes: Anatomical Novelties, Physiology, Evolution, and Behavioral Ecology. AB - Coral reef fishes live in noisy environments that may challenge their capacity for acoustic communication. Butterflyfishes (Family Chaetodontidae) are prominent and ecologically diverse members of coral reef communities worldwide. The discovery of a novel association of anterior swim bladder horns with the lateral line canal system in the genus Chaetodon (the laterophysic connection) revealed a putative adaptation for enhancement of sound reception by the lateral line system and/or the ear. Behavioral studies show that acoustic communication is an important component of butterflyfish social behavior. All bannerfish (Forcipiger, Heniochus, and Hemitaurichthys) and Chaetodon species studied thus far produce several sound types at frequencies of <1 to >1000 Hz. Ancestral character state analyses predict the existence of both shared (head bob) and divergent (tail slap) acoustic behaviors in these two clades. Experimental auditory physiology shows that butterflyfishes are primarily sensitive to stimuli associated with hydrodynamic particle accelerations of <=500 Hz. In addition, the gas-filled swim bladder horns in Chaetodon are stimulated by sound pressure, which enhances and extends their auditory sensitivity to 1700-2000 Hz. The broadband spectrum of ambient noise present on coral reefs overlaps with the frequency characteristics of their sounds, thus both the close social affiliations common among butterflyfishes and the evolution of the swim bladder horns in Chaetodon facilitate their short-range acoustic communication. Butterflyfishes provide a unique and unexpected opportunity to carry out studies of fish bioacoustics in the lab and the field that integrate the study of sensory anatomy, physiology, evolution, and behavioral ecology. PMID- 26515312 TI - Convergent Aspects of Acoustic Communication in Darters, Sculpins, and Gobies. AB - Darters (Perciformes, Percidae), sculpins (Perciformes, Cottidae), and gobioids (Gobiiformes, Gobioidei) exhibit convergent life history traits, including a benthic lifestyle and a cavity nesting spawning mode. Soniferous species within these taxa produce pulsed and/or tonal sounds with peak frequencies below 200 Hz (with some exceptions), primarily in agonistic and/or reproductive contexts. The reduced or absent swim bladders found in these taxa limit or prevent both hearing enhancement via pressure sensitivity and acoustic amplification of the contracting sonic muscles, which are associated with the skull and pectoral girdle. While such anatomies constrain communication to low frequency channels, optimization of the S/N (signal-to-noise) ratio in low frequency channels is evident for some gobies, as measured by habitat soundscape frequency windows, nest cavity sound amplification, and audiograms. Similar S/N considerations are applicable to many darter and sculpin systems. This chapter reviews the currently documented diversity of sound production in darters, sculpins, and gobioids within a phylogenetic context, examines the efficacy of signal transmission from senders to receivers (sound production mechanisms, audiograms, and masking challenges), and evaluates the potential functional significance of sound attributes in relation to territorial and reproductive behaviours. PMID- 26515313 TI - Directional Hearing and Sound Source Localization in Fishes. AB - Evidence suggests that the capacity for sound source localization is common to mammals, birds, reptiles, and amphibians, but surprisingly it is not known whether fish locate sound sources in the same manner (e.g., combining binaural and monaural cues) or what computational strategies they use for successful source localization. Directional hearing and sound source localization in fishes continues to be important topics in neuroethology and in the hearing sciences, but the empirical and theoretical work on these topics have been contradictory and obscure for decades. This chapter reviews the previous behavioral work on directional hearing and sound source localization in fishes including the most recent experiments on sound source localization by the plainfin midshipman fish (Porichthys notatus), which has proven to be an exceptional species for fish studies of sound localization. In addition, the theoretical models of directional hearing and sound source localization for fishes are reviewed including a new model that uses a time-averaged intensity approach for source localization that has wide applicability with regard to source type, acoustic environment, and time waveform. PMID- 26515314 TI - Revisiting Psychoacoustic Methods for the Assessment of Fish Hearing. AB - Behavioral methods have been critical in the study of auditory perception and discrimination in fishes. In this chapter, we review some of the common methods used in fish psychoacoustics. We discuss associative methods, such as operant, avoidance, and classical conditioning, and their use in constructing audiograms, measuring frequency selectivity, and auditory stream segregation. We also discuss the measurement of innate behavioral responses, such as the acoustic startle response (ASR), prepulse inhibition (PPI), and phonotaxis, and their use in the assessment of fish hearing to determine auditory thresholds and in the testing of mechanisms for sound source localization. For each psychoacoustic method, we provide examples of their use and discuss the parameters and situations where such methods can be best utilized. In the case of the ASR, we show how this method can be used to construct and compare audiograms between two species of larval fishes, the three-spined stickleback (Gasterosteus aculeatus) and the zebrafish (Danio rerio). We also discuss considerations for experimental design with respect to stimulus presentation and threshold criteria and how these techniques can be used in future studies to investigate auditory perception in fishes. PMID- 26515315 TI - Hearing in Cavefishes. AB - Caves and associated subterranean habitats represent some of the harshest environments on Earth, yet many organisms, including fishes, have colonized and thrive in these habitats despite the complete absence of light, and other abiotic and biotic constraints. Over 170 species of fishes are considered obligate subterranean inhabitants (stygobionts) that exhibit some degree of troglomorphy, including degeneration of eyes and reduction in pigmentation. To compensate for lack of vision, many species have evolved constructive changes to non-visual sensory modalities. In this chapter we review hearing in cavefishes, with particular emphasize on our own studies on amblyopsid cavefishes. Hearing in cavefishes has not been well studied to date, as hearing ability has only been examined in four species. Two species show no differences in hearing ability relative to their surface relatives, while the other two species (family Amblyopsidae) exhibit regression in the form of reduced hearing range and reduction in hair cell densities on sensory epithelia. In addition to reviewing our current knowledge on cavefish hearing, we offer suggestions for future avenues of research on cavefish hearing and discuss the influence of Popper and Fay on the field of cavefish bioacoustics. PMID- 26515316 TI - What the Toadfish Ear Tells the Toadfish Brain About Sound. AB - Of the three, paired otolithic endorgans in the ear of teleost fishes, the saccule is the one most often demonstrated to have a major role in encoding frequencies of biologically relevant sounds. The toadfish saccule also encodes sound level and sound source direction in the phase-locked activity conveyed via auditory afferents to nuclei of the ipsilateral octaval column in the medulla. Although paired auditory receptors are present in teleost fishes, binaural processes were believed to be unimportant due to the speed of sound in water and the acoustic transparency of the tissues in water. In contrast, there are behavioral and anatomical data that support binaural processing in fishes. Studies in the toadfish combined anatomical tract-tracing and physiological recordings from identified sites along the ascending auditory pathway to document response characteristics at each level. Binaural computations in the medulla and midbrain sharpen the directional information provided by the saccule. Furthermore, physiological studies in the central nervous system indicated that encoding frequency, sound level, temporal pattern, and sound source direction are important components of what the toadfish ear tells the toadfish brain about sound. PMID- 26515317 TI - Comparison of Electrophysiological Auditory Measures in Fishes. AB - Sounds provide fishes with important information used to mediate behaviors such as predator avoidance, prey detection, and social communication. How we measure auditory capabilities in fishes, therefore, has crucial implications for interpreting how individual species use acoustic information in their natural habitat. Recent analyses have highlighted differences between behavioral and electrophysiologically determined hearing thresholds, but less is known about how physiological measures at different auditory processing levels compare within a single species. Here we provide one of the first comparisons of auditory threshold curves determined by different recording methods in a single fish species, the soniferous Hawaiian sergeant fish Abudefduf abdominalis, and review past studies on representative fish species with tuning curves determined by different methods. The Hawaiian sergeant is a colonial benthic-spawning damselfish (Pomacentridae) that produces low-frequency, low-intensity sounds associated with reproductive and agonistic behaviors. We compared saccular potentials, auditory evoked potentials (AEP), and single neuron recordings from acoustic nuclei of the hindbrain and midbrain torus semicircularis. We found that hearing thresholds were lowest at low frequencies (~75-300 Hz) for all methods, which matches the spectral components of sounds produced by this species. However, thresholds at best frequency determined via single cell recordings were ~15-25 dB lower than those measured by AEP and saccular potential techniques. While none of these physiological techniques gives us a true measure of the auditory "perceptual" abilities of a naturally behaving fish, this study highlights that different methodologies can reveal similar detectable range of frequencies for a given species, but absolute hearing sensitivity may vary considerably. PMID- 26515318 TI - The Potential Overlapping Roles of the Ear and Lateral Line in Driving "Acoustic" Responses. AB - Examination of fish responses to sound stimuli has a rich and varied history but it is not always clear when responses are true measures of hearing or the lateral line. The central innervation of auditory and lateral-line sensory afferents lie in close proximity in the brainstem and both sets of receptors are, at heart, hair cell-based particle motion detectors. While it is possible to separately measure physiological activity of these two receptor subtypes, many studies of fish "hearing" use whole brain potentials or behavioural assays in complex sound fields where it is not possible to distinguish inputs. We argue here that, as often measured, what is thought of as fish "hearing" is often a multisensory response of both auditory and lateral line receptors. We also argue that in many situations where fish use sound stimuli, the behaviour is also an integrative response of both systems, due to the often close proximity of fish during sound communication. We end with a set of recommendations for better understanding the separate and combined roles of ear and lateral-line hair cells as well as an acknowledgment of the seminal and continuing contributions of Arthur N. Popper and Richard R. Fay to this field. PMID- 26515319 TI - Multimodal Sensory Input in the Utricle and Lateral Line of the Toadfish, Opsanus tau. AB - The utricular otolith and the mechanosensory lateral line of the toadfish, Opsanus tau, were investigated for sensitivity to multimodal sensory input by recording neural activity from free swimming fish. The utricle was sensitive to horizontal body movement, and displayed broad sensitivity to low frequency (80 200 Hz) sound. The lateral line was sensitive to water currents, swimming, prey movements, and sound with maximal sensitivity at 100 Hz. Both systems showed directional sensitivity to pure tones and toadfish vocalizations, indicating potential for sound localization. Thus, toadfish possess two hair cell based sensory systems that integrate information from disparate sources. However, swimming movements or predation strikes can saturate each system and it is unclear the effect that self-generated movement has on sensitivity. It is hypothesized that the toadfish's strategy of short distance swim movements allows it to sample the acoustical environment while static. Further study is needed to determine the integration of the two systems and if they are able to segregate and/or integrate multimodal sensory input. PMID- 26515320 TI - Development of Structure and Sensitivity of the Fish Inner Ear. AB - Fish represent the largest group of vertebrates and display the greatest diversity of auditory structures. However, studies addressing how the form and function of the auditory system change during development to enhance perception of the acoustic environment are rather sparse in this taxon compared to other vertebrate groups. An ontogenetic perspective of the auditory system in fishes provides a readily testable framework for understanding structure-function relationships. Additionally, studying ancestral models such as fish can convey valuable comparable information across vertebrates, as early developmental events are often evolutionary conserved. This chapter reviews the literature on the morphological development of the fish auditory system, with particular focus on the inner ear structures that evolve from an otic placode during early embryonic development and then continue to undergo differentiation and maturation in the postembryonic phase. Moreover, the chapter provides a systematic overview of how auditory sensitivity develops during ontogeny. Although most studies indicate a developmental improvement in auditory sensitivity, there is considerably species specific variation. Lastly, the paucity of information and literature concerning the development of auditory capabilities for social communication in fishes is also discussed. Further investigation on the development of structure and function of the fish auditory system is recommended in order to obtain a deeper understanding of how ontogenetic morphological changes in the auditory pathway relate to modifications in acoustic reception, auditory processing, and the capacity to communicate acoustically. PMID- 26515321 TI - Peripheral Hearing Structures in Fishes: Diversity and Sensitivity of Catfishes and Cichlids. AB - Fishes have evolved an astonishing diversity of peripheral (accessory/ancillary) auditory structures to improve hearing based on their ability to transmit oscillations of gas bladder walls to the inner ears. So far it is unclear to what degree the size of the bladder and the linkage to the ear affect hearing in fishes. An interfamilial study in catfishes revealed that families which possess large, single swim bladders and one to four Weberian ossicles were more sensitive at higher frequencies (>=1 kHz) than families which have small, paired, and encapsulated bladders and one to two ossicles. An intrafamilial investigation in thorny catfishes (family Doradidae) revealed that small differences in bladder morphology did not affect hearing similarly. Members of the cichlid family possess an even larger variation in peripheral auditory structures than catfishes. The linkage between the swim bladder and ear can either be present via anterior extensions of the bladder or be completely absent (in contrast to catfishes). Representatives having large bladders with extensions had the best sensitivities. Cichlids lacking extensions had lower sensitivities above 0.3 kHz. Species with a vestigial swim bladder exhibited a smaller hearing bandwidth than those with larger swim bladder (maximum frequency: 0.7 kHz vs. 3 kHz). Catfishes and cichlids reveal that larger gas bladders and more pronounced connections between the swim bladder and the inner ear result in improved hearing at higher frequencies. The lack of a connection between a large bladder and the inner ear does not necessarily result in a smaller detectable frequency range. PMID- 26515322 TI - Diversity of Inner Ears in Fishes: Possible Contribution Towards Hearing Improvements and Evolutionary Considerations. AB - Fishes have evolved the largest diversity of inner ears among vertebrates. While G. Retzius introduced us to the diversity of the gross morphology of fish ears in the late nineteenth century, it was A. N. Popper who unraveled the large variety of the fine structure during the last four decades. Modifications of the basic inner ear structure-consisting of three semicircular canals and their sensory epithelia, the cristae and three otolithic end organs (utricle, saccule, lagena) including the maculae-mainly relate to the saccule and lagena and the respective sensory epithelia, the macula sacculi and macula lagenae. Despite the profound morphological knowledge of inner ears and the morphological variability, the functional significance of this diversity is still largely unknown. The aims of this review are therefore twofold. First it provides an update of the state of the art of inner ear diversity in bony fishes. Second it summarizes and discusses hypotheses on the evolution of this diversity as well as formulates open questions and promising approaches to tackle these issues. PMID- 26515323 TI - Causes and Consequences of Sensory Hair Cell Damage and Recovery in Fishes. AB - Sensory hair cells are the mechanotransductive receptors that detect gravity, sound, and vibration in all vertebrates. Damage to these sensitive receptors often results in deficits in vestibular function and hearing. There are currently two main reasons for studying the process of hair cell loss in fishes. First, fishes, like other non-mammalian vertebrates, have the ability to regenerate hair cells that have been damaged or lost via exposure to ototoxic chemicals or acoustic overstimulation. Thus, they are used as a biomedical model to understand the process of hair cell death and regeneration and find therapeutics that treat or prevent human hearing loss. Secondly, scientists and governmental natural resource managers are concerned about the potential effects of intense anthropogenic sounds on aquatic organisms, including fishes. Dr. Arthur N. Popper and his students, postdocs and research associates have performed pioneering experiments in both of these lines of fish hearing research. This review will discuss the current knowledge regarding the causes and consequences of both lateral line and inner ear hair cell damage in teleost fishes. PMID- 26515324 TI - Chemical Ototoxicity of the Fish Inner Ear and Lateral Line. AB - Hair cell-driven mechanosensory systems are crucial for successful execution of a number of behaviors in fishes, and have emerged as good models for exploring questions relevant to human hearing. This review focuses on ototoxic effects in the inner ear and lateral line system of fishes. We specifically examine studies where chemical ototoxins such as aminoglycoside antibiotics have been employed as tools to disable the lateral line. Lateral line ablation results in alterations to feeding behavior and orientation to water current in a variety of species. However, neither behavior is abolished in the presence of additional sensory cues, supporting the hypothesis that many fish behaviors are driven by multisensory integration. Within biomedical research, the larval zebrafish lateral line has become an important model system for understanding signaling mechanisms that contribute to hair cell death and for developing novel pharmacological therapies that protect hair cells from ototoxic damage. Furthermore, given that fishes robustly regenerate damaged hair cells, ototoxin studies in fishes have broadened our understanding of the molecular and genetic events in an innately regenerative system, offering potential targets for mammalian hair cell regeneration. Collectively, studies of fish mechanosensory systems have yielded insight into fish behavior and in mechanisms of hair cell death, protection, and regeneration. PMID- 26515325 TI - Neuroanatomical Evidence for Catecholamines as Modulators of Audition and Acoustic Behavior in a Vocal Teleost. AB - The plainfin midshipman fish (Porichthys notatus) is a well-studied model to understand the neural and endocrine mechanisms underlying vocal-acoustic communication across vertebrates. It is well established that steroid hormones such as estrogen drive seasonal peripheral auditory plasticity in female Porichthys in order to better encode the male's advertisement call. However, little is known of the neural substrates that underlie the motivation and coordinated behavioral response to auditory social signals. Catecholamines, which include dopamine and noradrenaline, are good candidates for this function, as they are thought to modulate the salience of and reinforce appropriate behavior to socially relevant stimuli. This chapter summarizes our recent studies which aimed to characterize catecholamine innervation in the central and peripheral auditory system of Porichthys as well as test the hypotheses that innervation of the auditory system is seasonally plastic and catecholaminergic neurons are activated in response to conspecific vocalizations. Of particular significance is the discovery of direct dopaminergic innervation of the saccule, the main hearing end organ, by neurons in the diencephalon, which also robustly innervate the cholinergic auditory efferent nucleus in the hindbrain. Seasonal changes in dopamine innervation in both these areas appear dependent on reproductive state in females and may ultimately function to modulate the sensitivity of the peripheral auditory system as an adaptation to the seasonally changing soundscape. Diencephalic dopaminergic neurons are indeed active in response to exposure to midshipman vocalizations and are in a perfect position to integrate the detection and appropriate motor response to conspecific acoustic signals for successful reproduction. PMID- 26515326 TI - The Role of Trait Emotional Intelligence in Academic Performance: Theoretical Overview and Empirical Update. AB - Considerable debate still exists among scholars over the role of trait emotional intelligence (TEI) in academic performance. The dominant theoretical position is that TEI should be orthogonal or only weakly related to achievement; yet, there are strong theoretical reasons to believe that TEI plays a key role in performance. The purpose of the current article is to provide (a) an overview of the possible theoretical mechanisms linking TEI with achievement and (b) an update on empirical research examining this relationship. To elucidate these theoretical mechanisms, the overview draws on multiple theories of emotion and regulation, including TEI theory, social-functional accounts of emotion, and expectancy-value and psychobiological model of emotion and regulation. Although these theoretical accounts variously emphasize different variables as focal constructs, when taken together, they provide a comprehensive picture of the possible mechanisms linking TEI with achievement. In this regard, the article redresses the problem of vaguely specified theoretical links currently hampering progress in the field. The article closes with a consideration of directions for future research. PMID- 26515327 TI - A sustainable protocol for the facile synthesis of zinc-glutamate MOF: an efficient catalyst for room temperature CO2 fixation reactions under wet conditions. AB - A water stable zinc-MOF (ZnGlu) catalyst was facilely prepared from the proteinogenic amino acid, l-glutamic acid at room temperature in aqueous medium. CO2 fixations were promoted by the ZnGlu catalyst's inherently coordinated water and externally added water in yielding cyclic carbonate and cyclic urethane at room temperature. This eliminates the need for catalyst activation, making ZnGlu a ready-to-use catalyst. The enhanced CO2 cycloaddition with added water hints at the application of ZnGlu in wet flue gas conversions. This is the first reported attempt for the use of an MOF in the cycloaddition of aziridine and CO2. PMID- 26515329 TI - Penile 'tuberculid': could it be sexually acquired primary inoculation tuberculosis? PMID- 26515328 TI - Differential Role of G Protein-Coupled Receptor Kinase 5 in Physiological Versus Pathological Cardiac Hypertrophy. AB - RATIONALE: G protein-coupled receptor kinases (GRKs) are dynamic regulators of cellular signaling. GRK5 is highly expressed within myocardium and is upregulated in heart failure. Although GRK5 is a critical regulator of cardiac G protein coupled receptor signaling, recent data has uncovered noncanonical activity of GRK5 within nuclei that plays a key role in pathological hypertrophy. Targeted cardiac elevation of GRK5 in mice leads to exaggerated hypertrophy and early heart failure after transverse aortic constriction (TAC) because of GRK5 nuclear accumulation. OBJECTIVE: In this study, we investigated the role of GRK5 in physiological, swimming-induced hypertrophy (SIH). METHODS AND RESULTS: Cardiac specific GRK5 transgenic mice and nontransgenic littermate control mice were subjected to a 21-day high-intensity swim protocol (or no swim sham controls). SIH and specific molecular and genetic indices of physiological hypertrophy were assessed, including nuclear localization of GRK5, and compared with TAC. Unlike after TAC, swim-trained transgenic GRK5 and nontransgenic littermate control mice exhibited similar increases in cardiac growth. Mechanistically, SIH did not lead to GRK5 nuclear accumulation, which was confirmed in vitro as insulin-like growth factor-1, a known mediator of physiological hypertrophy, was unable to induce GRK5 nuclear translocation in myocytes. We found specific patterns of altered gene expression between TAC and SIH with GRK5 overexpression. Further, SIH in post-TAC transgenic GRK5 mice was able to preserve cardiac function. CONCLUSIONS: These data suggest that although nuclear-localized GRK5 is a pathological mediator after stress, this noncanonical nuclear activity of GRK5 is not induced during physiological hypertrophy. PMID- 26515330 TI - Long-distance transport of endogenous gibberellins in Arabidopsis. AB - Gibberellins (GAs) are phytohormones controlling major aspects of plant growth and development. Although previous studies suggested the existence of a transport of GAs in plants, the nature and properties associated with this transport were unknown. We recently showed through micrografting and biochemical approaches that the GA12 precursor is the chemical form of GA undergoing long-distance transport across plant organs in Arabidopsis. Endogenous GA12 moves through the plant vascular system from production sites to recipient tissues, in which GA12 can be converted to bioactive forms to support growth via the activation of GA-dependent processes. GAs are also essential to promote seed germination; hence GA biosynthesis mutants do not germinate without exogenous GA treatment. Our results suggest that endogenous GAs are not (or not sufficiently) transmitted to the offspring to successfully complete the germination under permissive conditions. PMID- 26515331 TI - Rural-Urban Differences in Alzheimer's Disease and Related Disorders Diagnostic Prevalence in Kentucky and West Virginia. AB - PURPOSE: Older adults living in rural areas may face barriers to obtaining a diagnosis of Alzheimer's disease and related disorders (ADRD). We sought to examine rural-urban differences in prevalence of ADRD among Medicare beneficiaries in Kentucky and West Virginia, 2 contiguous, geographically similar states with large rural areas and aged populations. METHODS: We used Centers for Medicare and Medicaid Services Public Use Files data from 2007 to 2013 to assess prevalence of ADRD at the county level among all Medicare beneficiaries in each state. Rural-Urban Continuum Codes were used to classify counties as rural or urban. We used Poisson regression to estimate unadjusted and adjusted prevalence ratios. Primary analyses focused on 2013 data and were repeated for 2007 to 2012. This study was completely ecologic. FINDINGS: After adjusting for state, average beneficiary age, percent of female beneficiaries, percent of beneficiaries eligible for Medicaid in each county, Central Appalachian county, percent of age eligible residents enrolled in Medicare, and percent of residents under age 65 enrolled in Medicare in our adjusted models, we found that 2013 ADRD diagnostic prevalence was 11% lower in rural counties (95% CI: 9%-13%). CONCLUSIONS: Medicare beneficiaries in rural counties in Kentucky and West Virginia may be underdiagnosed with respect to ADRD. However, due to the ecologic design, and evidence of a younger, more heavily male beneficiary population in some rural areas, further studies using individual-level data are needed to confirm the results. PMID- 26515332 TI - KRAS polymorphisms are associated with survival of CRC in Chinese population. AB - rs12245, rs12587, rs9266, rs1137282, rs61764370, and rs712 of KRAS oncogene are characterized in the 3'UTR. The study highlights the important role of these polymorphisms playing in the susceptibility, oxaliplatin-based chemotherapy sensitivity, progression, and prognosis of CRC. Improved multiplex ligation detection reaction (iMLDR) technique is used for genotyping. An unconditional logistic regression model was used to estimate the association of certain polymorphism and CRC risk. The Kaplan-Meier method, log-rank test, and Cox regression model were used to evaluate the effects of polymorphisms on survival analysis. Results demonstrated that TT genotype and T allele of rs712 were associated with the increased risk of CRC; the patients with GG genotype and G allele of rs61764370 had a shorter survival and a higher risk of relapse or metastasis of CRC. Our studies supported the conclusions that rs61764370 and rs712 polymorphisms of the KRAS are functional and it may play an important role in the development of CRC and oxaliplatin-based chemotherapy efficiency and prognosis of CRC. PMID- 26515333 TI - Does the elevation of serum carbohydrate antigen 19-9 level predict poor overall survival in patients with hepatocellular carcinoma? PMID- 26515334 TI - Letter regarding "CD95 rs1800682 polymorphism and cervical cancer risk: evidence from a meta-analysis" by Zhang et al. PMID- 26515335 TI - CIZ1 is upregulated in hepatocellular carcinoma and promotes the growth and migration of the cancer cells. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, and the prognosis for the HCC remains very poor. Although dys-regulation of CIZ1 (Cip1 interacting zinc finger protein 1) has been observed in various cancer types, its expression and functions in HCC remain unknown. In this study, the mRNA level of CIZ1 in the HCC tissues were examined using real-time polymerase chain reaction, and the effects of CIZ1 on the growth, migration, and metastasis of HCC cells were examined by crystal violet assay, Boyden chamber assay, and in vivo image system, respectively. In addition, the molecular mechanisms were investigated by luciferase assay. Upregulation of CIZ1 in the clinical HCC samples was observed. Forced expression of CIZ1 promoted the growth and migration of HCC cells, while knocking down the expression of CIZ1 inhibited the growth, migration, and metastasis of HCC cells. Molecular mechanism studies revealed that CIZ1 activated YAP/TAZ signaling in HCC cells. Taken together, our study demonstrated the oncogenic roles of CIZ1 in HCC cells and CIZ1 might be a promising therapeutic target for HCC. PMID- 26515336 TI - Regulatory T cells in the immunotherapy of melanoma. AB - Patients with melanoma are supposed to develop spontaneous immune responses against specific tumor antigens. However, several mechanisms contribute to the failure of tumor antigen-specific T cell responses, inducing immune escape. Importantly, immunosuppression mediated by regulatory T cells (Tregs) in tumor lesions is a dominant mechanism of tumor immune evasion. Based on this information, several therapies targeting Tregs such as cyclophosphamide, IL-2 based therapies, and antibodies against the surface molecular of Tregs have been developed. However, only some of these strategies showed clinical efficacy in patients with melanoma in spite of their success in shifting immune systems to antitumor responses in animal models. In the future, strategies specifically depleting local Tregs, inhibiting Treg migration to the tumor lesion, and Treg depletion in combination with other chemotherapies or immune modulation will hopefully bring benefits to melanoma patients. PMID- 26515337 TI - SIRT1 induces tumor invasion by targeting epithelial mesenchymal transition related pathway and is a prognostic marker in triple negative breast cancer. AB - Absence of therapeutic targets poses a critical hurdle in improving prognosis for patients with triple negative breast cancer (TNBC). We evaluated interaction between SIRT1 and epithelial mesenchymal transition (EMT)-associated proteins as well as the role of combined protein expression as a predictor of lymph node metastasis and clinical outcome in TNBC through in vivo and vitro studies. Three hundred nineteen patients diagnosed with TNBC were chosen, immunohistochemical staining for SIRT1 and EMT-related markers' expression was performed on tissue microarrays, and in vitro experiments with each of the three human TNBC cell lines were carried out. The cohort was reclassified according to the use of adjuvant chemotherapy, tumor size, and AJCC stage to analyze the prognostic role of SIRT1 and EMT-related proteins' expression considering different therapeutic modalities and AJCC stages. Combination of four proteins including SIRT1 and three EMT-related proteins was revealed to be a statistically significant independent predictor of lymph node metastasis in the tumor size cohort as well as in the total patient population. Upon Cox regression analysis, increased expression level of the combined proteins correlated with decreased disease-free survival in the total patients as well as those who received adjuvant chemotherapy and those who had early stage breast cancer. In additional in vitro experiments, inhibition of SIRT1 expression with small interfering RNA (siRNA) suppressed tumor invasion in three different TNBC cell lines, and altered expression levels of EMT-related proteins following SIRT1 gene inhibition were identified on western blotting and fluorescence activated cell sorting (FACS) analysis; on the other hand, no change in expression levels of the cell cycle related factors was observed. Our analysis showed the potential role of SIRT1 in association with EMT-related factors on tumor invasion, metastasis, and disease free survival in TNBC, SIRT1, and associated EMT-related markers may offer a new prognostic indicator as well as a novel therapeutic candidate. PMID- 26515340 TI - Extensive portal venous gas in a post-operative patient with no identifiable cause. AB - Gas within the portal venous system is often considered a pre-morbid radiological sign. We present a case of extensive portal venous gas (PVG) identified in a patient 6 days following emergency Hartmann's procedure for large bowel obstruction. The patient underwent re-laparotomy on the basis of these radiological findings, but no clear cause was identified. She went on to have an uneventful recovery. Of interest is the discrepancy between the extent of PVG on the preoperative imaging in comparison with the lack of positive findings on direct visualization at laparotomy. We discuss the causes of PVG, its clinical significance, strategies for its management and, in particular, whether surgical management is always indicated in such patients. PMID- 26515339 TI - Grape juice concentrate (G8000((r)) ) intake mitigates testicular morphological and ultrastructural damage following cadmium intoxication. AB - Cadmium is a well-known testicular toxicant, and parts of the world population are exposed chronically by inhalation or by food and water intake. Grape products have been highlighted as important sources of bioactive compounds, having anti inflammatory, anti-oxidant and metal chelating properties. Since maintenance of tissue morphology is essential for testicular sperm development and hence male fertility, we analysed the protective effect of grape juice concentrate (GJC) (G8000((r)) ) consumption on testicular morphology in rats exposed to cadmium. Thus, four groups of male Wistar rats (n = 6 per group), 50 days old, ingested either water or G8000((r)) (2 g/kg/day) until they had completed one spermatogenic cycle in adult life (136 days old). Cadmium (1.2 mg / kg) was injected intraperitoneally when the animals were 80 days old into one of the water and one of the G8000 groups; intraperitoneal saline was used as a control in the other two groups. Animals anaesthetised and exsanguinated at 136 days and then perfused with Karnovsky's fixative and then the testes were collected for morphological analysis. We describe evident disruption of testicular morphology by cadmium, with alteration in tissue component proportions, reduced Leydig cells volume and initial signs of an inflammatory process. Ultrastructural analysis showed greater damage, suggesting spermatogenesis disruption. G8000((r)) ingestion allowed tissue architecture to be re-established, as was corroborated by our stereological and morphometric findings. Animals from the group where G8000((r)) had been administered together with cadmium revealed a significant reduction in macrophages and blood vessel volume, suggesting diminished inflammation, when compared to animals that received only cadmium. Moreover, smaller number of ultrastructural alterations was noted, revealing fewer areas of degeneration and disorganized interstitium. In conclusion, our results demonstrate that GJC consumption prevented the spermatogenic disruption promoted by cadmium, and thus could be a promising form of therapy against male infertility. PMID- 26515338 TI - Secretome of human bone marrow mesenchymal stem cells: an emerging player in lung cancer progression and mechanisms of translation initiation. AB - Non-small cell lung cancer (NSCLC) remains the most common cause of cancer related death worldwide. Patients presenting with advanced-stage NSCLC have poor prognosis, while metastatic spread accounts for >70 % of patient's deaths. The major advances in the treatment of lung cancer have brought only minor improvements in survival; therefore, novel strategic treatment approaches are urgently needed. Accumulating data allocate a central role for the cancer microenvironment including mesenchymal stem cells (MSCs) in acquisition of drug resistance and disease relapse. Furthermore, studies indicate that translation initiation factors are over expressed in NSCLC and negatively impact its prognosis. Importantly, translation initiation is highly modulated by microenvironmental cues. Therefore, we decided to examine the effect of bone marrow MSCs (BM-MSCs) from normal donors on NSCLC cell lines with special emphasis on translation initiation mechanism in the crosstalk. We cultured NSCLC cell lines with BM-MSC conditioned media (i.e., secretome) and showed deleterious effects on the cells' proliferation, viability, death, and migration. We also demonstrated reduced levels of translation initiation factors implicated in cancer progression [eukaryotic translation initiation factor 4E (eIF4E) and eukaryotic translation initiation factor 4GI (eIF4GI)], their targets, and regulators. Finally, we outlined a mechanism by which BM-MSCs' secretome affected NSCLC's mitogen-activated protein kinase (MAPK) signaling pathway, downregulated the cell migration, and diminished translation initiation factors' levels. Taken together, our study demonstrates that there is direct dialogue between the BM MSCs' secretome and NSCLC cells that manipulates translation initiation and critically affects cell fate. We suggest that therapeutic approach that will sabotage this dialogue, especially in the BM microenvironment, may diminish lung cancer metastatic spread and morbidity and improve the patient's life quality. PMID- 26515341 TI - BVA briefing for parliamentarians. PMID- 26515342 TI - Compulsory microchipping of dogs in Wales to begin next year. PMID- 26515343 TI - ASRU's annual report and advice notes. PMID- 26515344 TI - Number of scientific procedures on animals falls in 2014. PMID- 26515345 TI - Royal support for collaboration and research in the Scottish food industry. PMID- 26515346 TI - Equine obesity levels continue to rise. PMID- 26515347 TI - Showcasing the skills of VNs. PMID- 26515348 TI - Vet struck off for unprofessional behaviour. PMID- 26515349 TI - UK veterinary surgeon elected to the US National Academy of Medicine. PMID- 26515350 TI - Erythropoietic protoporphyria in Limousin calves. PMID- 26515351 TI - Reducing error and improving patient safety. PMID- 26515352 TI - Mycobacterium microti detection in French wildlife. PMID- 26515353 TI - Shortage of experienced vets. PMID- 26515354 TI - Shortage of experienced vets. PMID- 26515355 TI - Profession's approach to pet insurance. PMID- 26515356 TI - Use of plasma preparations to provide passive immunity in calves. PMID- 26515357 TI - Reporting suspected adverse events to feed additives. PMID- 26515358 TI - Using the VMD's product information database. PMID- 26515359 TI - PRRS vaccines for gilts, sows and piglets. PMID- 26515360 TI - Shelf life of cattle parasiticide extended. PMID- 26515361 TI - New indication for NSAID. PMID- 26515362 TI - Determining the best diets for allergic dogs and cats. PMID- 26515363 TI - Paperless ordering for laboratory tests. PMID- 26515364 TI - Veterinary app now on Android. PMID- 26515365 TI - Distribution deal signed. PMID- 26515366 TI - Building a career. PMID- 26515367 TI - Ten-minute chat. PMID- 26515368 TI - Learning from Listening: Helping Healthcare Students to Understand Spiritual Assessment in Clinical Practice. AB - We aim to evaluate the perceptions of healthcare students while taking a spiritual history (SH). Fifty students were trained on how to take a SH, interviewed inpatients and answered a questionnaire concerning their perceptions. A total of 362 patients were interviewed: 60.1% of students felt comfortable taking a SH, 85.1% believed the patient liked the approach, and 72.1% believed more benefits could come with a follow-up. When students felt more comfortable, they tended to believe the patient: liked the approach (p < 0.01), felt better (p < 0.01) and more motivated (p < 0.01). Spirituality/health educational strategies may be a valid strategy to prepare future health professionals to face spiritual issues in health scenarios. PMID- 26515369 TI - Protein kinase B is required for follicle-stimulating hormone mediated beta catenin accumulation and estradiol production in granulosa cells of cattle. AB - Follicle-stimulating hormone regulation of ovarian estradiol (E2) production requires involvement of beta-catenin (CTNNB1), a transcriptional co-factor. In cultured granulosa cells (GC) of cattle, FSH treatment increased protein abundance of CTNNB1 as well as protein kinase B (AKT), a molecule known to regulate components of the CTNNB1 degradation complex. However, whether FSH induction of CTNNB1 is through direct modulation of AKT remains to be determined. To investigate specific contributions of AKT to CTNNB1 accumulation, GC were treated with insulin-like growth factor-I (IGF-I), a well-established AKT activator, in the presence or absence of FSH. Granulosa cells treated with FSH, IGF-I, and IGF-I plus FSH had increased CTNNB1 accumulation compared with controls (P <= 0.02; n=6). E2 medium concentrations were greater (P=0.09; n=4) in FSH treated cells compared to controls (166 and 100 +/- 28 pg/mL, respectively). Treatment with IGF-I and IGF-I plus FSH increased (P<0.01) E2 to comparable concentrations. Subsequently, GC treated with lithium chloride (LiCl), a pharmacological activator of AKT, provided a response consistent with IGF-I treated cells, as LiCl, FSH, and FSH plus LiCl increased CTNNB1 accumulation compared with non-treated controls (P <= 0.03; n=3). In contrast, inhibition of AKT signaling with LY294002 suppressed the ability of FSH and IGF-I to regulate CTNNB1. Additionally, LY294002 treatment reduced FSH and IGF-I mediated E2 medium concentrations (P <= 0.004). These results demonstrate that activation of AKT is required for gonadotropin regulation of CTNNB1 accumulation and subsequent ovarian E2 production. PMID- 26515370 TI - Butylated hydroxytoluene can reduce oxidative stress and improve quality of frozen-thawed bull semen processed in lecithin and egg yolk based extenders. AB - The aims of this study were to evaluate the effects of anti-oxidant butylated hydroxytoluene (BHT), when added at different concentrations into lecithin-based Bioxcell((r)) (BX) and two egg-yolk-based; Tris (TY) and citrate (CE) semen extenders, on post-thaw bull sperm quality and oxidative stress. A total of 30 ejaculates from three bulls were collected using an electro ejaculator. Ejaculates were extended with one of the BX, TY and CE extenders, which contained different concentrations (0.0 - control, 0.5, 1.0, 1.5, 2.0 and 3.0mM/ml) of BHT. The extended semen samples were chilled to 4 degrees C, and then frozen slowly to -196 degrees C in 0.25 ml straws before being stored in liquid nitrogen for 2 weeks. Results showed that supplementation of BHT improved (P<0.05) general motility, progressive motility, morphology, acrosome integrity, DNA integrity and malondialdehyde of sperm at 0.5mM/ml for BX and at 1-1.5mM/ml of BHT for TY and CE when compared with the control. However, greater concentrations of 2.0 and 3.0mM/ml of BHT had a detrimental (P<0.05) effect compared with the control with all extenders evaluated. In conclusion, BHT supplementation at lesser concentrations (0.5-1.5mM/ml) could improve frozen-thawed bull sperm quality by reducing oxidative stress produced during the freezing-thawing procedures in either lecithin or egg-yolk based extenders. PMID- 26515371 TI - Genetic pathways for differentiation of the peripheral nervous system in ascidians. AB - Ascidians belong to tunicates, the sister group of vertebrates. Peripheral nervous systems (PNSs) including epidermal sensory neurons (ESNs) in the trunk and dorsal tail regions of ascidian larvae are derived from cells adjacent to the neural plate, as in vertebrates. On the other hand, peripheral ESNs in the ventral tail region are derived from the ventral ectoderm under the control of BMP signalling, reminiscent of sensory neurons of amphioxus and protostomes. In this study, we show that two distinct mechanisms activate a common gene circuit consisting of Msx, Ascl.b, Tox, Delta.b and Pou4 in the dorsal and ventral regions to differentiate ESNs. Our results suggest that ventral ESNs of the ascidian larva are not directly homologous to vertebrate PNSs. The dorsal ESNs might have arisen via co-option of the original PNS gene circuit to the neural plate border in an ancestral chordate. PMID- 26515372 TI - Low prevalence rates of common mental disorders in Japan: does it still hold true? PMID- 26515373 TI - Diagnostic Differences and Demographic Predictors of Respondents Adjudicated Civilly Incompetent Versus Competent. AB - The purpose of this study was to determine if diagnostic and demographic variables predict civil competency adjudications, a topic that has received scant research attention. Respondents (i.e., individuals alleged to be incompetent) were evaluated by a licensed psychologist to assist the court in civil competency and possible guardianship determination. Prior research using some of the same participants demonstrated select differences on activities of daily living between these groups (Quickel & Demakis, ), but the current set of analyses was not conducted. The current study included 107 competency evaluations in Mecklenburg County North Carolina and, at conclusion of the case, the public record of the adjudication was obtained. Based on prior legal theorizing in related criminal areas--focused on discrimination of individuals with mental illness--we predicted that cases involving respondents with psychiatric diagnoses would be likely to be overrepresented in those referred for evaluation as well as those subsequently adjudicated incompetent. A series of analyses indicated no statistical differences between competency groups (psychiatric/substance abuse, neurological, both psychiatric and neurological, and intellectually disabled). In a series of exploratory logistic regression analyses, we found that respondents who were single versus in a relationship and those not living at home versus living at home were significantly more likely to be adjudicated incompetent, even after controlling for difference in activities of daily living. There were no differences in incompetency adjudication by age, education, gender, race, or relationship status. Results are discussed in terms of implications for individuals with mental illness in incompetency hearings, as well as specific issues for psychologists evaluating a broad range of respondents. PMID- 26515374 TI - In vivo study of the early bone-bonding ability of Ti meshes formed with calcium titanate via chemical treatments. AB - Alkali and heat (AH) treatment forming sodium titanate has been shown to connect bioinert Ti metal and bone tissue. Artificial joints treated with this method have achieved extensive clinical application. Recently a new chemical treatment of Alkali-Calcium-Heat-Water (ACaHW) treatment forming calcium titanate was proposed. Notably, the apatite-forming ability of this treatment is greater than that of AH treatment, as verified in vitro. However, the early bone-bonding abilities of the two treatments have not been compared in vivo. To simulate clinical application, we treated a commercially pure Ti (Cp-Ti) mesh implant with AH or ACaHW. Then, using mechanical and histological methods, we compared the bone-bonding abilities of the two treatments early during the implantation process (2-4 weeks); untreated Cp-Ti mesh was used as a control. Because the mesh structure might influence bone-bonding ability, we compared these bonding abilities with values obtained at 4 and 8 weeks using a Cp-Ti implant with a plate structure. In the mesh group, histological comparisons at 2 and 3 weeks indicated that ACaHW treatment resulted in a bone-bonding ability similar to that of AH treatment; ACaHW exhibited a greater bonding ability than AH at 4 weeks. However, in tests of the plate group at later time points, such differences were not apparent. The results obtained here indicate that during the early stage of embedment, ACaHW treatment of Cp-Ti mesh implants yields a higher bone-bonding ability than AH treatment, thus providing a positive reference for future clinical applications. PMID- 26515375 TI - Mesoporous Carbon Nanofibers Embedded with MoS2 Nanocrystals for Extraordinary Li Ion Storage. AB - MoS2 nanocrystals embedded in mesoporous carbon nanofibers are synthesized through an electrospinning process followed by calcination. The resultant nanofibers are 100-150 nm in diameter and constructed from MoS2 nanocrystals with a lateral diameter of around 7 nm with specific surface areas of 135.9 m(2) g( 1) . The MoS2 @C nanofibers are treated at 450 degrees C in H2 and comparison samples annealed at 800 degrees C in N2 . The heat treatments are designed to achieve good crystallinity and desired mesoporous microstructure, resulting in enhanced electrochemical performance. The small amount of oxygen in the nanofibers annealed in H2 contributes to obtaining a lower internal resistance, and thus, improving the conductivity. The results show that the nanofibers obtained at 450 degrees C in H2 deliver an extraordinary capacity of 1022 mA h g(-1) and improved cyclic stability, with only 2.3 % capacity loss after 165 cycles at a current density of 100 mA g(-1) , as well as an outstanding rate capability. The greatly improved kinetics and cycling stability of the mesoporous MoS2 @C nanofibers can be attributed to the crosslinked conductive carbon nanofibers, the large specific surface area, the good crystallinity of MoS2 , and the robust mesoporous microstructure. The resulting nanofiber electrodes, with short mass- and charge-transport pathways, improved electrical conductivity, and large contact area exposed to electrolyte, permitting fast diffusional flux of Li ions, explains the improved kinetics of the interfacial charge-transfer reaction and the diffusivity of the MoS2 @C mesoporous nanofibers. It is believed that the integration of MoS2 nanocrystals and mesoporous carbon nanofibers may have a synergistic effect, giving a promising anode, and widening the applicability range into high performance and mass production in the Li-ion battery market. PMID- 26515376 TI - Changes in sperm methylation profile: a potential cause of infertility and a handle to monitor improvements in genetic and lifestyle interactions. PMID- 26515377 TI - Assisted reproductive technology use, embryo transfer practices, and birth outcomes after infertility insurance mandates: New Jersey and Connecticut. AB - OBJECTIVE: To explore whether recently enacted infertility mandates including coverage for assisted reproductive technology (ART) treatment in New Jersey (2001) and Connecticut (2005) increased ART use, improved embryo transfer practices, and decreased multiple birth rates. DESIGN: Retrospective cohort study using data from the National ART Surveillance System. We explored trends in ART use, embryo transfer practices and birth outcomes, and compared changes in practices and outcomes during a 2-year period before and after passing the mandate between mandate and non-mandate states. SETTING: Not applicable. PATIENT(S): Cycles of ART performed in the United States between 1996 and 2013. INTERVENTION(S): Infertility insurance mandates including coverage for ART treatment passed in New Jersey (2001) and Connecticut (2005). MAIN OUTCOME MEASURES(S): Number of ART cycles performed, number of embryos transferred, multiple live birth rates. RESULT(S): Both New Jersey and Connecticut experienced an increase in ART use greater than the non-mandate states. The mean number of embryos transferred decreased significantly in New Jersey and Connecticut; however, the magnitudes were not significantly different from non-mandate states. There was no significant change in ART birth outcomes in either mandate state except for an increase in live births in Connecticut; the magnitude was not different from non-mandate states. CONCLUSION(S): The infertility insurance mandates passed in New Jersey and Connecticut were associated with increased ART treatment use but not a decrease in the number of embryos transferred or the rate of multiples; however, applicability of the mandates was limited. PMID- 26515379 TI - Role of spermatozoa in the etiology of miscarriage. PMID- 26515378 TI - Cryopreservation and recovery of human endometrial epithelial cells with high viability, purity, and functional fidelity. AB - OBJECTIVE: To develop a protocol for cryopreservation and recovery of human endometrial epithelial cells (eECs) retaining molecular and functional characteristics of endometrial epithelium in vivo. DESIGN: In vitro study using human endometrial cells. SETTING: University research laboratory. PATIENT(S): Endometrial biopsies were obtained from premenopausal women undergoing benign gynecologic procedures. INTERVENTION(S): Primary eECs were cryopreserved in 1% fetal bovine serum/10% dimethylsulfoxide in Defined Keratinocyte Serum-Free Medium (KSFM). Recovered cells were observed for endometrial stromal fibroblast (eSF) contamination and subsequently evaluated for morphology, gene expression, and functional characteristics of freshly cultured eECs and in vivo endometrial epithelium. MAIN OUTCOME MEASURE(S): Analysis of eEC morphology and the absence of eSF contamination; evaluation of epithelial-specific gene and protein expression; assessment of epithelial polarity. RESULT(S): Endometrial epithelial cells recovered after cryopreservation (n = 5) displayed epithelial morphology and expressed E-cadherin (CDH1), occludin (OCLN), claudin1 (CLDN1), and keratin18 (KRT18). Compared with eSF, recovered eECs displayed increased (P<.05) expression of epithelial-specific genes AREG, CDH1, DEFB4A, MMP7, and WNT7A, while exhibiting low-to-undetectable (P<.05) stromal-specific genes COL6A3, HOXA11, MMP2, PDGFRB, and WNT5A. Recovered eECs secreted levels of cytokines and growth factors similarly to freshly cultured eECs. Recovered eECs could form a polarized monolayer with high transepithelial electrical resistance (TER) and impermeability to small molecules, and expressed apical/basolateral localization of CDH1 and apical localization of OCLN. CONCLUSION(S): We have developed a protocol for cryopreservation of eECs in which recovered cells after thawing demonstrate morphologic, transcriptomic, and functional characteristics of human endometrial epithelium in vivo. PMID- 26515380 TI - Prognostic indicators of assisted reproduction technology outcomes of cycles with ultralow serum antimullerian hormone: a multivariate analysis of over 5,000 autologous cycles from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database for 2012-2013. AB - OBJECTIVE: To assess cycle outcomes when antimullerian hormone (AMH) is ultralow (<=0.16 ng/mL) and to determine which parameters contribute to the probability of cycle cancellation and/or outcome. DESIGN: Retrospective analysis. SETTING: Not applicable. PATIENT(S): 5,087 (7.3%) fresh and 243 (1.5%) thawed cycles with ultralow AMH values. INTERVENTION(S): Linear and logistic regression, comparison with age-matched cycles with normal AMH concentrations. MAIN OUTCOME MEASURE(S): Cancellation rate; number of retrieved oocytes, embryos, transferred embryos, and cryopreserved embryos; clinical pregnancy, live-birth, and multiple birth rates. RESULT(S): The total cancellation rate per cycle start for fresh cycles was 54%. Of these, 38.6% of the cycles were canceled before retrieval, and 3.3% of cycles obtained no oocytes at time of retrieval. Of all retrieval attempts, 50.7% had three oocytes or fewer retrieved, and 25.1% had no embryo transfer. The live birth rates were 9.5% per cycle start. Cycles with ultralow AMH levels compared with age-matched normal AMH cycles demonstrated more than a fivefold greater pre retrieval cancellation rate, a twofold less live-birth rate per cycle and a 4.5 fold less embryo cryopreservation rate. CONCLUSION(S): Refusing treatment solely on the basis of ultralow AMH levels is not advisable, but patients should be counseled appropriately about the prognostic factors for cancellation and outcomes. PMID- 26515381 TI - Introduction: Microbiome in human reproduction. AB - The human microbiome has been termed the "second human genome" and data that has come about of late certainly makes it appear every bit as complex. The human body contains 10-fold more microbial cells than the human cells and accounts for 1%-3% of our total body mass. As we learn more about this symbiotic relationship, it appears this complex interaction occurs in nearly every part of the body, even those areas at one time considered to be sterile. Indeed, the microbiome in human reproduction has been investigated in terms of both the lower and upper reproductive tract and includes interactions even at the point of gametogenesis. What is all the more fascinating is that we have known about the importance of microbes for over 150 years, even before they existed in name. And now, with the assistance of an exciting technologic revolution which has pushed forward our understanding of the microbiome, we appear to stand on the precipice of a higher level of understanding of microbes, the biofilms they create, and their impact of health and disease in human reproduction. PMID- 26515382 TI - Wide expression of ZEB1 in sarcomatous component of spindle cell carcinoma of the esophagus. AB - The pathogenesis of sarcomatous component in spindle cell carcinoma (SpCC) of the esophagus is unclear. To investigate the involvement of epithelial-mesenchymal transition (EMT) in sarcomatous differentiation, we performed immunohistochemistry for Slug, Twist, ZEB1, and ZEB2, transcription factors associated with EMT and E-cadherin, in 14 cases of SpCC of the esophagus. In order to verify the neoplastic nature of sarcomatous components, TP53 mutation status and protein expression were examined in each case. Nuclear ZEB1 expression was extensive in the sarcomatous component, greater than invasive front of carcinoma components (P < 0.0001). Membranous E-cadherin expression was mostly lost in sarcomatous cells in all cases (P < 0.0001). The p53 expression pattern was almost concordant between the two areas in all cases. TP53 mutation analysis revealed that seven cases harbored identical mutations in both components. One case had mutations only in the sarcomatous component. It is noteworthy that none of them harbored mutation in exon 5, unlike conventional esophageal squamous cell carcinoma. These findings show that ZEB1 are widely expressed in the sarcomatous area of SpCC of the esophagus, suggesting the involvement of EMT. The avoidance of exon 5 in terms of TP53 mutation may also be a feature of the tumor. PMID- 26515383 TI - Randomized controlled trial of the effects of high intensity and low-to-moderate intensity exercise on physical fitness and fatigue in cancer survivors: results of the Resistance and Endurance exercise After ChemoTherapy (REACT) study. AB - BACKGROUND: International evidence-based guidelines recommend physical exercise to form part of standard care for all cancer survivors. However, at present, the optimum exercise intensity is unclear. Therefore, we aimed to evaluate the effectiveness of a high intensity (HI) and low-to-moderate intensity (LMI) resistance and endurance exercise program compared with a wait list control (WLC) group on physical fitness and fatigue in a mixed group of cancer survivors who completed primary cancer treatment, including chemotherapy. METHODS: Overall, 277 cancer survivors were randomized to 12 weeks of HI exercise (n = 91), LMI exercise (n = 95), or WLC (n = 91). Both interventions were identical with respect to exercise type, duration and frequency, and only differed in intensity. Measurements were performed at baseline (4-6 weeks after primary treatment) and post-intervention. The primary outcomes were cardiorespiratory fitness (peakVO2), muscle strength (grip strength and 30-second chair-stand test), and self-reported fatigue (Multidimensional Fatigue Inventory; MFI). Secondary outcomes included health-related quality of life, physical activity, daily functioning, body composition, mood, and sleep disturbances. Multilevel linear regression analyses were performed to estimate intervention effects using an intention-to-treat principle. RESULTS: In the HI and LMI groups, 74 % and 70 % of the participants attended more than 80 % of the prescribed exercise sessions, respectively (P = 0.53). HI (beta = 2.2; 95 % CI, 1.2-3.1) and LMI (beta = 1.3; 95 % CI, 0.3-2.3) exercise showed significantly larger improvements in peakVO2 compared to WLC. Improvements in peakVO2 were larger for HI than LMI exercise (beta = 0.9; 95 % CI, -0.1 to 1.9), but the difference was not statistically significant (P = 0.08). No intervention effects were found for grip strength and the 30-second chair-stand test. HI and LMI exercise significantly reduced general and physical fatigue and reduced activity (MFI subscales) compared to WLC, with no significant differences between both interventions. Finally, compared to WLC, we found benefits in global quality of life and anxiety after HI exercise, improved physical functioning after HI and LMI exercise, and less problems at work after LMI exercise. CONCLUSIONS: Shortly after completion of cancer treatment, both HI and LMI exercise were safe and effective. There may be a dose-response relationship between exercise intensity and peakVO2, favoring HI exercise. HI and LMI exercise were equally effective in reducing general and physical fatigue. TRIAL REGISTRATION: This study was registered at the Netherlands Trial Register [ NTR2153 ] on the 5th of January 2010. PMID- 26515384 TI - Chemometrics-enhanced high performance liquid chromatography-ultraviolet detection of bioactive metabolites from phytochemically unknown plants. AB - This work describes the use of Colubrina greggii as a model to investigate the use of chemometric analysis combined with data from a leishmanicidal bioassay, using Principal Component Analysis (PCA) and Orthogonal Projections to Latent Structures (O-PLS), to detect biologically active natural products in crude extracts from plants having little or no phytochemical information. A first analysis of the HPLC-UV profiles of the extract and its semi-purified fractions using both Principal Component Analysis (PCA) and Orthogonal Partial Least Squares (O-PLS) indicated that the components at tR 48.2, 48.7, 51.8min correlated with the variation in bioactivity. However, a further O-PLS analysis of the HPLC-UV profiles of fractions obtained through a final semi-preparative HPLC purification showed two components at tR 48.7 and 49.5min which correlated with the variation of the bioactivity in a high performance predictive model, with high determination coefficient, high correlation coefficient values (R(2) and Q(2)=0.99) and a low root mean square error (RMSE=0.018). This study demonstrates that the association of chemometric analysis with bioassay results can be an excellent strategy for the detection and isolation of bioactive metabolites from phytochemically unknown plant crude extracts. PMID- 26515385 TI - Hyphenation of a Deoxyribonuclease I immobilized enzyme reactor with liquid chromatography for the online stability evaluation of oligonucleotides. AB - The stability of antisense oligonucleotides (ONs) toward nucleases is a key aspect for their possible implementation as therapeutic agents. Typically, ON stability studies are performed off-line, where the ONs are incubated with nucleases in solution, followed by their analysis. The problematics of off-line processing render the detailed comparison of relative ON stability quite challenging. Therefore, the development of an online platform based on an immobilized enzyme reactor (IMER) coupled to liquid chromatography (LC) was developed as an alternative for improved ON stability testing. More in detail, Deoxyribonuclease I (DNase I) was immobilized on epoxy-silica particles of different pore sizes and packed into a column for the construction of an IMER. Subsequently, the hyphenation of the IMER with ion-pair chromatography (IPC) and ion-exchange chromatography (IEC) was evaluated, leading to the successful development of two online methodologies: IMER-IPC and IMER-IEC. More specifically, natural and modified DNA and RNA oligonucleotides were used for testing the performance of the methodologies. Both methodologies proved to be simple, automatable, fast and highly reproducible for the quantitative and qualitative evaluation of ON degradation. In addition, the extended IMER life time in combination with a more straightforward control of the reaction kinetics substantiate the applicability of the IMER-LC platform for ON stability tests and its implementation in routine and research laboratories. PMID- 26515386 TI - Associations between occupation exposure to Formaldehyde and semen quality, a primary study. AB - Formaldehyde (FA), a ubiquitous environmental pollutant, has long been suspected of having male reproductive toxicity. However, FA male reproductive toxicity was inconclusive due to dearth of human studies. Therefore, we sought to investigate whether occupational exposure to FA affects semen quality. Semen quality including five conventional parameters and seven kinematics parameters were compared between 114 male workers occupationally exposed to FA and 76 referents. FA exposure index (FEI) was measured and calculated. Our results showed that sperm progressive motility, total sperm motility, VCL, VSL and VAP were statistically significant decreased in FA exposure workers compared with the referents. Moreover, FEI was significantly negative associated with sperm progressive motility (beta = -0.19, P = 0.01) and total sperm motility (beta = 0.23, P = 0.004). In addition, a significant elevated risk of abnormal sperm progressive motility were observed in both low- (OR = 2.58; 95% CI: 1.11-5.97) and high-FA-exposed group (OR = 3.41; 95% CI: 1.45-7.92) respectively. Furthermore, a significant increased risk was also estimated for abnormal total sperm motility in both low- (OR = 3.21; 95% CI: 1.24-8.28) and high-FA-exposed group (OR = 4.84; 95% CI: 1.83-12.81) respectively. In conclusion, our study revealed the adverse effects of FA occupation exposure on semen quality, especially on sperm motion parameters. PMID- 26515387 TI - Radical surgical resection of advanced thymoma and thymic carcinoma infiltrating the heart or great vessels with cardiopulmonary bypass support. AB - BACKGROUND: Radical surgical resection of advanced thymic tumors invading either the heart or great vessels facing towards the heart is uncommonly performed because of the potential morbidity and mortality. To achieve a complete tumor resection, the use of cardiolpulmonary bypass (CPB) support might be necessary. METHODS: Retrospective analysis of the results in six patients, who underwent radical tumor resection with CBP support. RESULTS: Mean age was 46 years (27 to 66 years) and five patients were male. Tumor infiltration of the heart or the great vessels was evident in all patients. Five patients underwent induction therapy. Two patients were operated in complete cardioplegic arrest (antegrade cerebral perfusion: n = 1). Arterial cannulation of the ascending aorta (n = 5) or the femoral artery (n = 1) and venous cannulation of the right atrium (n = 4) or the femoral vein (n = 2) were performed. Resection of the left brachiocephalic vein (n = 6), resection of the superior caval vein (n = 2), the ascending aorta (n = 1) and the complete aortic arch with outgoing branches (n = 1) were performed. A macroscopic complete resection (R0/R1) was achieved in five patients, whereas one patient was resected incompletely (R2). In-hospital mortality was 0 %. Three (50 %) patients needed operative revision (hematothorax: n = 2, chylothorax: n = 1). All patients had a complicated postoperative course and developed respiratory insufficiency. CONCLUSIONS: Locally advanced thymoma/thymic carcinoma invading the heart or great vessels can be treated with radical surgical resection alongside with increased perioperative morbidity. The usage of CBP improves the chance of complete tumor resection in selected patients and might lead to a prolonged survival. PMID- 26515388 TI - [Abnormal kidneys]. PMID- 26515389 TI - Hunt pledges that no junior doctor working within legal hours will face pay cut. PMID- 26515390 TI - In vitro anticancer properties and biological evaluation of novel natural alkaloid jerantinine B. AB - Natural products play a pivotal role in medicine especially in the cancer arena. Many drugs that are currently used in cancer chemotherapy originated from or were inspired by nature. Jerantinine B (JB) is one of seven novel Aspidosperma indole alkaloids isolated from the leaf extract of Tabernaemontana corymbosa. Preliminary antiproliferative assays revealed that JB and JB acetate significantly inhibited growth and colony formation, accompanied by time- and dose-dependent apoptosis induction in human cancer cell lines. JB significantly arrested cells at the G2/M cell cycle phase, potently inhibiting tubulin polymerisation. Polo-like kinase 1 (PLK1; an early trigger for the G2/M transition) was also dose-dependently inhibited by JB (IC50 1.5 uM). Furthermore, JB provoked significant increases in reactive oxygen species (ROS). Annexin V+ cell populations, dose-dependent accumulation of cleaved-PARP and caspase 3/7 activation, and reduced Bcl-2 and Mcl-1 expression confirm apoptosis induction. Preclinical in silico biopharmaceutical assessment of JB calculated rapid absorption and bioavailability >70%. Doses of 8-16 mg/kg JB were predicted to maintain unbound plasma concentrations >GI50 values in mice during efficacy studies. These findings advocate continued development of JB as a potential chemotherapeutic agent. PMID- 26515392 TI - Intraoperative reduction does not result in better outcomes in low-grade lumbar spondylolisthesis with neurogenic symptoms after minimally invasive transforaminal lumbar interbody fusion-a 5-year follow-up study. AB - BACKGROUND CONTEXT: Intraoperative reduction of low-grade lumbar spondylolisthesis (LGLS) remains disputed. There is currently no published data comparing midterm outcomes of reduction versus in situ fusion. PURPOSE: This study aimed to compare mid-term clinical, radiological, and perioperative outcomes for reduction versus in situ fusion in LGLS with neurogenic symptoms. STUDY DESIGN/SETTING: A retrospective review of prospectively collected spine registry data in a single institution was carried out. PATIENT SAMPLE: All patients who underwent minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) for LGLS with neurogenic symptoms with a minimum 5-year follow-up comprised the patient sample. OUTCOME MEASURES: Self-reported measures were Oswestry Disability Index, North American Spine Society Neurogenic Symptom Score, Health Outcomes Survey Short Form-36 score, and Numerical Pain Rating Scale (back and leg pain). Radiological outcomes were fusion grading, adjacent segment degeneration (ASD), and implant failure or loosening. Perioperative outcomes were fluoroscopic time, operative time, intraoperative blood loss, opioid analgesia usage, time to ambulation, duration of hospitalization, and complication rate. Functional outcomes were patient satisfaction rate and rate of return to full function. METHODS: A retrospective review was performed on prospectively collected registry data of patients undergoing MIS TLIF for LGLS with neurogenic symptoms, from 2004 to 2009. The operative technique and postoperative protocol were standardized. Two groups were formed based on complete reduction of the spondylolisthesis (reduction group [RG]) or the lack thereof (non-reduction group [NRG]) in the immediate postoperative radiograph. Outcomes at baseline, 6 months, 2 years, and 5 years postsurgery were compared. RESULTS: There were 56 patients included (RG=30, NRG=26). The two groups had comparable baseline characteristics: demographics, body mass index, spondylolisthesis etiology, spinal level involved, bone graft and bone morphogenetic protein used, and all self-reported outcome measures. Perioperative outcomes were not significantly different. The early complication rate (RG=3.3%, NRG=19.2%, p=.086) and late complication rate (RG=10%, NRG=23.1%, p=.184) were similar. All patients achieved Bridwell grade 1 fusion from 2 years onward. Adjacent segment degeneration rate at 5 years was similar (RG=10%, NRG=0%, p=NS). Both groups showed significant postoperative improvement in all self-reported measures with no significant differences between the two groups at all follow-up points. Functional outcomes were equivalent. CONCLUSIONS: Intraoperative reduction does not improve outcomes in LGLS with neurogenic symptoms after MIS TLIF. Adequate decompression and solid fusion are likely the keys to good mid-term outcomes. PMID- 26515391 TI - Blocking TNF-alpha inhibits angiogenesis and growth of IFIT2-depleted metastatic oral squamous cell carcinoma cells. AB - Our previous study demonstrated that the depletion of interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) promoted metastasis and was associated with a poor prognosis in patients with oral squamous cell carcinoma (OSCC). Our current study explores the major downstream signaling involved in IFIT2 depletion induced OSCC metastasis. To this end, we used two cell lines (designated sh control-xeno and sh-IFIT2-xeno) derived from human OSCC xenografts expressing sh control and sh-IFIT2, respectively, and one metastatic OSCC subline (sh-IFIT2 meta) from an IFIT2-depleted metastatic tumor. We found that the sh-IFIT2-meta cells proliferated more slowly than the sh-control-xeno cells but exhibited higher migration and chemoresistance. Using microarray technology and Ingenuity Pathway Analysis, we found that TNF-alpha was one of the major downstream targets in IFIT2-depleted OSCC cells. Quantitative real-time PCR, western blotting, and ELISA results confirmed that TNF-alpha was upregulated in the sh-IFIT2-meta cells. Blocking TNF-alpha abolished the angiogenic activity induced by the sh IFIT2-meta cells. Furthermore, the human-specific TNF-alpha antibody golimumab significantly inhibited in vivo angiogenesis, tumor growth and metastasis of sh IFIT2-meta cells. These results demonstrate that IFIT2 depletion results in TNF alpha upregulation, leading to angiogenesis and metastasis of OSCC cells. PMID- 26515394 TI - A rare presentation in a girl with occult spinal bifida. PMID- 26515393 TI - Giant pelvic chondrosarcoma with vertebral column invasion. PMID- 26515395 TI - Change in spinal height following correction of adolescent idiopathic scoliosis. AB - BACKGROUND CONTEXT: Corrective surgery for adolescent idiopathic scoliosis (AIS) leads to vertical growth arrest of the instrumented spine. This might be offset by the immediate gain in spinal height (SH) as a result of correction of the curvature. PURPOSE: This study aimed to identify predictors of gain in SH following corrective surgery for AIS. We present a unique model to predict postoperative height prior to intervention, which could contribute to the preoperative counseling and consenting process. STUDY DESIGN: This was a retrospective case series. All surgeries were performed by one of four substantive pediatric spinal surgeons within a single regional center over a 3.5 year period. PATIENT SAMPLE: There were 104 patients who had instrumented posterior spinal fusion for AIS included. There were 93 females, and the age range was from 11 to 17 years. All patients had posterior instrumented fusion using rods and anchors (pedicle screws+/-hooks). OUTCOME MEASURES: Postoperative SH was the primary outcome measure. The SH (C7-L5) and Cobb angles were measured from a pre- and postoperative standing X-ray of each patient. METHODS: Variables associated with patients (demographic and radiological) and the surgical constructs were analyzed for predictability of height gain. A model was derived including only significant predictors of substantive importance using hierarchical regression methods. Cross-validation procedures verified the adequacy of the model fit. Analysis was performed using IBM SPSS Statistics for Windows version 20.0 (IBM Corp. Armonk, NY, USA). RESULTS: The major curve was thoracic in 90% of cases. The number of vertebrae fused ranged from 5 to 15. The average preoperative Cobb angle was 66 degrees , with an average correction of 45 degrees . The average change in SH was 4.66 cm (SD 2.13 cm). The model presented included preoperative height, preoperative Cobb angle, and number of vertebrae within the construct, with coefficients of 1.00 (95% CI: 0.90, 1.09), 0.067 (95% CI: 0.039, 0.095), and 0.26 (95% CI: 0.11, 0.41), respectively. This model had an adjusted-R(2) value of 0.83 and a R(2) for prediction of 0.79, and can be shown to have similar predictive capability as a model comprising a wider range of predictors. CONCLUSION: The greatest postoperative height values following posterior spinal fusion for AIS could be expected from a patient with greater preoperative height and Cobb angle, and whose construct spans a large number of vertebrae. PMID- 26515396 TI - "Snake eyes" sign confined to thoracic spinal cord caused by infarction. PMID- 26515397 TI - Gibbus deformity. PMID- 26515398 TI - Radiographic progression of vertebral fractures in patients with multiple myeloma. AB - BACKGROUND CONTEXT: Nearly 70% of patients with multiple myeloma (MM) experience vertebral fracture. As a consequence, these patients suffer significantly poorer quality of life. However, no studies have characterized the natural progression of these fractures. PURPOSE: The purpose of this study was to characterize the progression of MM-associated vertebral fractures. STUDY DESIGN/SETTING: A consecutive retrospective chart review at a single tertiary-care center was carried out. PATIENT SAMPLE: Patients with MM and pathologic vertebral fracture with at least one follow-up between January 2007 and December 2013 were included. Radiographic measurements were recorded until last follow-up (LFU) or until surgical intervention or patient death. Patients with a history of vertebral fracture not associated with MM were excluded. OUTCOME MEASURES: The primary outcome measure was change in height of the fractured vertebrae. Fractures were characterized by Genant grade and morphology. METHODS: At baseline and each follow-up, anterior, middle, and posterior vertebral body heights were measured from midline sagittal T1-weighted magnetic resonance imaging. Student t tests and Fisher exact tests were performed to identify variables associated with fracture progression. RESULTS: Among 33 patients, 67 fractures were followed. Sixty-four percent of patients were female, with a mean age of 66. Baseline mean anterior, middle, and posterior vertebral body height losses were 30%, 36%, and 15%, respectively. Forty-three percent of fractures were Genant grade 3, and 57% were biconcave. Mean time to LFU was 40 months. At LFU, mean anterior, middle, and posterior vertebral body height losses increased to 47% (p<.01), 49% (p<.01), and 28% (p<.01), respectively. More fractures became Genant grade 3 (75%, p<.01) and wedge (54%, p=.03). On average, patients lost 0.83% in vertebral body height per month, with initial Genant grade 1 fractures progressing most rapidly (1.69%/month, p<.01). Patients treated with bisphosphonates suffered less additional height loss compared with untreated patients (14% vs. 24%, p=.07). CONCLUSIONS: We observed significant fracture progression despite high utilization of bisphosphonates. Patients lost nearly 1% of additional vertebral body height per month, with the least severe presenting fractures progressing most rapidly, highlighting the necessity for early referral to spine specialists and evidence-based guidelines for surveillance and treatment in the myeloma population. PMID- 26515399 TI - Spinal subdural hematoma presenting as paraplegia. PMID- 26515400 TI - Life-threatening retropharyngeal fluid collection after whiplash-type injury of the cervical spine. PMID- 26515401 TI - Adjacent segment degeneration and disease following cervical arthroplasty: a systematic review and meta-analysis. AB - BACKGROUND CONTEXT: Cervical arthroplasty is an increasingly popular alternative for the treatment of cervical radiculopathy and myelopathy. This technique preserves motion at the index and adjacent disc levels, avoiding the restraints of fusion and potentially minimizing adjacent segment pathology onset during the postoperative period. PURPOSE: This study aimed to identify all prospective studies reporting adjacent segment pathology rates for cervical arthroplasty. STUDY DESIGN/SETTING: Systematic review and meta-analysis were carried out. PATIENT SAMPLE: Studies reporting adjacent segment degeneration (ASDegeneration) and adjacent segment disease (ASDisease) rates in patients who underwent cervical arthroplasty comprised the patient sample. OUTCOME MEASURES: Outcomes of interest included reported ASDegeneration and ASDisease events after cervical arthroplasty. METHODS: We conducted a MEDLINE, SCOPUS, and Web of Science search for studies reporting ASDegeneration or ASDisease following cervical arthroplasty. A meta-analysis was performed to calculate effect summary values, 95% confidence intervals (CIs), Q values, and I(2) values. Forest plots were constructed for each analysis group. RESULTS: Of the 1,891 retrieved articles, 32 met inclusion criteria. The patient incidence of ASDegeneration and ASDisease was 8.3% (95% CI 3.8%-12.7%) and 0.9% (95% CI 0.1%-1.7%), respectively. The rate of ASDegeneration and ASDisease at individual levels was 10.5% (95% CI 6.1%-14.9%) and 0.2% (95% CI -0.1% to 0.5%), respectively. Studies following patients for 12 24 months reported a 5.1% (95% CI 2.1%-8.1%) incidence of ASDegeneration and 0.2% (95% CI 0.1%-0.2%) incidence of ASDisease. Conversely, studies following patients for greater than 24 months reported a 16.6% (5.8%-27.4%) incidence of ASDegeneration and 2.6% (95% CI 1.0%-4.2%) of ASDisease. This identified a statistically significant increase in ASDisease diagnosis with lengthier follow up. Additionally, 1- and 2-level procedures resulted in a 7.4% (95% CI 3.3% 11.4%) and15.6% (95 CI-9.2% to 40.4%) incidence of ASDegeneration, respectively. Although there was an 8.2% increase in ASDegeneration following 2-level operations (relative to 1-level), it did not reach statistical significance. We were unable to analyze ASDisease incidence following 2-level arthroplasty (too few cases), but 1-level operations resulted in an ASDisease incidence of 0.8% (95% CI 0.1%-1.5%). CONCLUSIONS: This review represents a comprehensive estimation of the actual incidence of ASDegeneration and ASDisease across a heterogeneous group of surgeons, patients, and arthroplasty techniques. Our investigation should serve as a framework for individual surgeons to understand the impact of various cervical arthroplasty techniques, follow-up duration, and surgical levels on the incidence of ASDegeneration and ASDisease during the postoperative period. PMID- 26515402 TI - Hemodynamic studies of isolated absent ductus venosus. AB - OBJECTIVE: The objective of this article is to evaluate hemodynamic changes among fetuses with isolated absent ductus venosus (IADV) diagnosed by prenatal ultrasonography. PATIENTS AND METHODS: Fetuses with prenatal diagnosis of IADV were recruited and followed. Hemodynamic assessment was performed in all cases, including measurement of cardiac dimensions, shortening fraction, myocardial performance index, preload index in the inferior vena cava and the presence of venous pulsations in the umbilical vein (UV). RESULTS: Nine fetuses of IADV were assessed, including six cases with extra-hepatic UV drainage and three with intra hepatic drainage. All fetuses with extra-hepatic UV drainage showed an elevated preload index in the inferior vena cava, venous pulsations in the UV and cardiomegaly. Of them, four had hydrops, two showed poor cardiac function and three resulted in perinatal mortality. Three cases with intra-hepatic drainage had continuous flow in the UV, normal in all hemodynamic parameters and all survived. CONCLUSION: Hemodynamic assessment of fetuses with IADV was helpful in predicting the development of hydrops and perinatal mortality. The poor prognostic factors included cardiac overload, cardiomegaly, poor myocardial performance, increased preload, the presence of venous pulsations and extra hepatic UV drainage. (c) 2015 John Wiley & Sons, Ltd. PMID- 26515405 TI - Impact of body mass index on posttransplant outcomes reexamined. PMID- 26515403 TI - ArnT proteins that catalyze the glycosylation of lipopolysaccharide share common features with bacterial N-oligosaccharyltransferases. AB - ArnT is a glycosyltransferase that catalyzes the addition of 4-amino-4-deoxy-l arabinose (l-Ara4N) to the lipid A moiety of the lipopolysaccharide. This is a critical modification enabling bacteria to resist killing by antimicrobial peptides. ArnT is an integral inner membrane protein consisting of 13 predicted transmembrane helices and a large periplasmic C-terminal domain. We report here the identification of a functional motif with a canonical consensus sequence DEXRYAX(5)MX(3)GXWX(9)YFEKPX(4)W spanning the first periplasmic loop, which is highly conserved in all ArnT proteins examined. Site-directed mutagenesis demonstrated the contribution of this motif in ArnT function, suggesting that these proteins have a common mechanism. We also demonstrate that the Burkholderia cenocepacia and Salmonella enterica serovar Typhimurium ArnT C-terminal domain is required for polymyxin B resistance in vivo. Deletion of the C-terminal domain in B. cenocepacia ArnT resulted in a protein with significantly reduced in vitro binding to a lipid A fluorescent substrate and unable to catalyze lipid A modification with l-Ara4N. An in silico predicted structural model of ArnT strongly resembled the tertiary structure of Campylobacter lari PglB, a bacterial oligosaccharyltransferase involved in protein N-glycosylation. Therefore, distantly related oligosaccharyltransferases from ArnT and PglB families operating on lipid and polypeptide substrates, respectively, share unexpected structural similarity that could not be predicted from direct amino acid sequence comparisons. We propose that lipid A and protein glycosylation enzymes share a conserved catalytic mechanism despite their evolutionary divergence. PMID- 26515406 TI - Optical Surface Transformation: Changing the optical surface by homogeneous optic null medium at will. AB - A new theory on designing electromagnetic/optical devices is proposed, namely, an optical surface transformation (OST). One arbitrary surface can establish the corresponding relationship with another surface entirely optically with an optic null medium (ONM), (i.e. the electromagnetic wave propagates from one surface to its equivalent surface without any phase delay). Many novel optical devices can be designed by an OST with the help of an ONM. Compared with traditional devices designed by Transformation Optics, our optical surface-reshaping devices have two main advantages. Firstly, the design process is very simple (i.e. we do not need to consider any mathematics on how to make a coordinate transformation, and what we need to do is simply to design the shapes of the input and the output surfaces of the devices). Secondly, we only need one homogeneous anisotropic medium to realize all devices designed by this method. Our method will explore a new way to design novel optical devices without considering any coordinate transformations. PMID- 26515404 TI - Dental enamel cells express functional SOCE channels. AB - Dental enamel formation requires large quantities of Ca(2+) yet the mechanisms mediating Ca(2+) dynamics in enamel cells are unclear. Store-operated Ca(2+) entry (SOCE) channels are important Ca(2+) influx mechanisms in many cells. SOCE involves release of Ca(2+) from intracellular pools followed by Ca(2+) entry. The best-characterized SOCE channels are the Ca(2+) release-activated Ca(2+) (CRAC) channels. As patients with mutations in the CRAC channel genes STIM1 and ORAI1 show abnormal enamel mineralization, we hypothesized that CRAC channels might be an important Ca(2+) uptake mechanism in enamel cells. Investigating primary murine enamel cells, we found that key components of CRAC channels (ORAI1, ORAI2, ORAI3, STIM1, STIM2) were expressed and most abundant during the maturation stage of enamel development. Furthermore, inositol 1,4,5-trisphosphate receptor (IP3R) but not ryanodine receptor (RyR) expression was high in enamel cells suggesting that IP3Rs are the main ER Ca(2+) release mechanism. Passive depletion of ER Ca(2+) stores with thapsigargin resulted in a significant raise in [Ca(2+)]i consistent with SOCE. In cells pre-treated with the CRAC channel blocker Synta-66 Ca(2+) entry was significantly inhibited. These data demonstrate that enamel cells have SOCE mediated by CRAC channels and implicate them as a mechanism for Ca(2+) uptake in enamel formation. PMID- 26515407 TI - Preferred natural food of breeding Kakapo is a high value source of calcium and vitamin D. AB - : The Kakapo, a large NZ native parrot, is under severe threat of extinction. Kakapo breed only in years when the local podocarps, including rimu (Dacrydium cupressinum), are fruiting heavily, and the fruit are the preferred food both in the diet of breeding females and for provisioning chicks. Attempts to provide a supplementary food during years of poor fruit supply have failed to encourage breeding. Nutrient analysis of rimu berries reveals high calcium content (8.4mg/g dry matter) which would be essential for both egg shell production and the growing skeleton of the chick. Vitamin D is also critical for these processes and for the maintenance of calcium homeostasis, but the source of vitamin D for these nocturnal, ground-dwelling vegetarians is unknown. OBJECTIVE: To examine the vitamin D status of adult Kakapo, and to investigate the possibility that rimu berries provide vitamin D as well as calcium, thus differentiating them from the supplementary foods provided to date. METHOD: Previously collected and frozen serum from 10 adult birds (6 females, 4 males) was assayed for 25(OH)D3 and D2. Two batches of previously frozen rimu berries were analysed for vitamin D3 and D2. RESULTS: Vitamin D status of the 10 adult birds was very low; mean 4.9nmol/l, range 1-14nmol/l 25(OH)D3. No 25(OH)D2 was detected in any of the birds. High levels of D2 and moderate levels of D3 were found in the rimu berries. CONCLUSION: Traditionally it has been considered that the D3 isoform of this endogenously produced secosteroid is produced only in animals. However, D3 has been reported in the leaves of plants of the Solanacae family (tomato, potato, capsicum). The avian vitamin D receptor (VDR) is thought to have a much greater affinity for the D3 form. Therefore if rimu fruit are able to provide breeding Kakapo with D3, and are a plentiful source of calcium, they could be the perfect food package for breeding and nesting birds. Of wider importance, this finding challenges conventional understanding that D3 production is exclusive to animals, and that there are no high concentration food sources of vitamin D. PMID- 26515408 TI - Bacterial biofilm on successful and failed orthodontic mini-implants--a scanning electron microscopy study. AB - Mini-implants have been extensively used in Orthodontics as temporary bone anchorage devices. However, early failure of mini-implants due to mobility might occur and the colonization of their surfaces by pathogenic bacteria has been referred to as one of the contributing factors. In this study, scanning electron microscopy (SEM) was used to assess the presence of microorganisms adhered to the surface of mini-implants that failed due to loss of stability. Twelve self drilling titanium mini-implants (1.6 mm diameter * 9.0 mm long) were collected from 12 patients undergoing orthodontic treatment-7 successful and 5 failed mini implants. The mean time of permanence in the mouth was 15.8 and 2.4 months for successful and failed mini-implants, respectively. The devices were placed in the maxilla and/or mandible and removed by the same surgeon and were processed for SEM analysis of the presence of microorganisms on their surfaces (head, transmucosal profile, and body). Extensive bacterial colonization on mini-implant head and transmucosal profile was observed in all successful and failed mini implants. None of the failed mini-implants exhibited bacteria on its body and only one mini-implant belonging to the successful (stable) group exhibited bacteria on its body. The results did not suggest a relationship between failure and presence of bacterial colonies on mini-implant surfaces. PMID- 26515409 TI - Development of a rapid recombinase polymerase amplification assay for the detection of Streptococcus pneumoniae in whole blood. AB - BACKGROUND: Streptococcus pneumoniae is an important cause of microbial disease in humans. The introduction of multivalent vaccines has coincided with a dramatic decrease in the number of pneumococcal-related deaths. In spite of this, at a global level, pneumococcal infection remains an important cause of death among children under 5 years of age and in adults 65 years of age or older. In order to properly manage patients and control the spread of infection, a rapid and highly sensitive diagnostic method is needed for routine implementation, especially in resource-limited regions where pneumococcal disease is most prevalent. METHODS: Using the gene encoding leader peptidase A as a molecular diagnostics target, a real-time RPA assay was designed and optimised for the detection of S. pneumoniae in whole blood. The performance of the assay was compared to real-time PCR in terms of its analytical limit of detection and specificity. The inhibitory effect of human genomic DNA on amplification was investigated. The potential clinical utility of the assay was investigated using a small number of clinical samples. RESULTS: The RPA assay has a limit of detection equivalent to PCR (4.0 and 5.1 genome equivalents per reaction, respectively) and was capable of detecting the equivalent of <1 colony forming unit of S. pneumoniae when spiked into human whole blood. The RPA assay was 100 % inclusive (38/38 laboratory reference strains and 19/19 invasive clinical isolates) and 100 % exclusive; differentiating strains of S. pneumoniae species from other viridans group streptococci, including S. pseudopneumoniae. When applied to the analysis of a small number (n = 11) of clinical samples (blood culture positive for S. pneumoniae), the RPA assay was demonstrated to be both rapid and sensitive. CONCLUSIONS: The RPA assay developed in this work is shown to be as sensitive and as specific as PCR. In terms of reaction kinetics, the RPA assay is shown to exceed those of the PCR, with the RPA running to completion in 20 minutes and capable generating a positive signal in as little as 6 minutes. This work represents a potentially suitable assay for application in point-of-care settings. PMID- 26515410 TI - Incidence and treatment patterns of complicated bone metastases in a population based radiotherapy program. AB - INTRODUCTION: There is abundant evidence in support of single fraction (SF) radiation therapy (RT) for uncomplicated bone metastases (BoM). We sought to determine the proportion of BoM that is complicated in a population-based RT program in order to act as a potential guide for assessing SFRT utilization rates. MATERIALS AND METHODS: A total of 3200 RT courses were prescribed to 1880 consecutive patients diagnosed with BoM in 2013. Associations between choice of RT fractionation and BoM characterization, whether complicated or not, were assessed with logistic regression. RESULTS: The incidence of complicated BoM was 34.4%, resulting most often from adverse features of actual pathological fracture (42.1%), and neurological compromise (36.3%). Complicated BoM were most common in lung cancers (24.2%) and in the spine (68.5%), followed by extremity (15.2%) and pelvis (14.4%). SFRT was prescribed less commonly in complicated versus un complicated BoM (39.4% vs. 70.4%; p<0.001), which was confirmed on multivariable analysis (OR 0.32; 95% CI 0.28-0.61; p<0.001). CONCLUSIONS: This study found that 34.4% of BoM are complicated by fracture, or neurological compromise (i.e. 65.6% were un-complicated), and that they were less likely to receive SFRT. A reasonable benchmark for SFRT utilization should be at least 60%. PMID- 26515411 TI - Predictive model for survival in patients having repeat radiation treatment for painful bone metastases. AB - PURPOSE: To establish a survival prediction model in the setting of a randomized trial of re-irradiation for painful bone metastases. METHODS: Data were randomly divided into training and testing sets with an approximately 3:2 ratio. Baseline factors of gender, primary cancer site, KPS, worst-pain score and age were included with backward variable selection to derive a model using the training set. A partial score was assigned by dividing the value of each statistically significant regression coefficient by the smallest statistically significant regression coefficient. The survival prediction score (SPS) was obtained by adding together partial scores for the variables that were statistically significant. Three risk groups were modelled. RESULTS: The training set included 460 patients and the testing set 351 patients. Only KPS and primary cancer site reached the 5%-significance level. Summing up the partial scores assigned to KPS (90-100, 0; 70-80, 1; 50-60, 2) and primary cancer site (breast, 0; prostate, 1.3; other, 2.6; lung, 3) totalled the SPS. The 1/3 and 2/3 percentiles of the SPS were 2 and 3.6. For the testing set, the median survival of the 3 groups was not reached, 11.3 (95% C.I. 8.5 - not reached) and 5.2 months (95% C.I. 3.7-6.5). The 3, 6 and 12 month survival rates for the worst group were 64.4% (95% C.I. 55.3-72.1%), 43.0% (95% C.I. 34.0-51.8%) and 19.7% (95% C.I. 12.4-28.1%) respectively, similar to that in the training set. CONCLUSION: This survival prediction model will assist in choosing dose fractionation. We recommend a single 8 Gy in the worst group identified. PMID- 26515412 TI - Unraveling the Determinants of Fear of Crime Among Men and Women in Istanbul: Examining the Impact of Perceived Risk and Fear of Sexual Assault. AB - Studies have examined university students' fear of crime focusing on the relationship between the fear of sexual assault and fear of other crimes, termed the shadow of sexual assault hypothesis; however, no study to date has examined the shadow thesis in a Turkish context. Drawing on the shadow thesis, using a sample of 723 university students in Istanbul, this study focuses on the effect of fear of sexual assault and perceived risk of crime to general fear of crime among university students in Istanbul. Also, the predictors of fear of crime are explored to examine the relationship between lifestyle characteristics, constrained behaviors, and fear. The findings of the study supported the shadow thesis, indicating that fear of sexual assault shaped the nonsexual crimes, especially crimes involving face-to-face confrontations between the victim and offender. Furthermore, lifestyle characteristics are correlated with the men's fear of nonsexual crimes, particularly fear of robbery, aggravated assault, and burglary home. PMID- 26515413 TI - Nursing handover from ICU to cardiac ward: Standardised tools to reduce safety risks. AB - BACKGROUND: Standardising handover processes and content, and using context specific checklists are proposed as solutions to mitigate risks for preventable errors and patient harm associated with clinical handovers. OBJECTIVES: Adapt existing tools to standardise nursing handover from the intensive care unit (ICU) to the cardiac ward and assess patient safety risks before and after pilot implementation. METHODS: A three-stage, pre-post interrupted time-series design was used. Data were collected using naturalistic observations and audio-recording of 40 handovers and focus groups with 11 nurses. In Stage 1, examination of existing practice using observation of 20 handovers and a focus group interview provided baseline data. In Stage 2, existing tools for high-risk handovers were adapted to create tools specific to ICU-to-ward handovers. The adapted tools were introduced to staff using principles from evidence-based frameworks for practice change. In Stage 3, observation of 20 handovers and a focus group with five nurses were used to verify the design of tools to standardise handover by ICU nurses transferring care of cardiac surgical patients to ward nurses. RESULTS: Stage 1 data revealed variable and unsafe ICU-to-ward handover practices: incomplete ward preparation; failure to check patient identity; handover located away from patients; and information gaps. Analyses informed adaptation of process, content and checklist tools to standardise handover in Stage 2. Compared with baseline data, Stage 3 observations revealed nurses used the tools consistently, ward readiness to receive patients (10% vs 95%), checking patient identity (0% vs 100%), delivery of handover at the bedside (25% vs 100%) and communication of complete information (40% vs 100%) improved. CONCLUSION: Clinician adoption of tools to standardise ICU-to-ward handover of cardiac surgical patients reduced handover variability and patient safety risks. The study outcomes provide context-specific tools to guide handover processes and delivery of verbal content, a safety checklist, and a risk recognition matrix. PMID- 26515414 TI - IL-37 Is a Novel Proangiogenic Factor of Developmental and Pathological Angiogenesis. AB - OBJECTIVE: Angiogenesis is tightly controlled by growth factors and cytokines in pathophysiological settings. Interleukin 37 (IL-37) is a newly identified cytokine of the IL-1 family, some members of which are important in inflammation and angiogenesis. However, the function of IL-37 in angiogenesis remains unknown. We aimed to explore the regulatory role of IL-37 in pathological and physiological angiogenesis. APPROACH AND RESULTS: We found that IL-37 was expressed and secreted in endothelial cells and upregulated under hypoxic conditions. IL-37 enhanced endothelial cell proliferation, capillary formation, migration, and vessel sprouting from aortic rings with potency comparable with that of vascular endothelial growth factor. IL-37 activates survival signals including extracellular signal-regulated kinase 1/2 and AKT in endothelial cells. IL-37 promoted vessel growth in implanted Matrigel plug in vivo in a dose dependent manner with potency comparable with that of basic fibroblast growth factor. In the mouse model of retinal vascular development, neonatal mice administrated with IL-37 displayed increased neovascularization. We demonstrated further that IL-37 promoted pathological angiogenesis in the mouse model of oxygen-induced retinopathy. CONCLUSIONS: Our findings suggest that IL-37 is a novel and potent proangiogenic cytokine with essential role in pathophy siological settings. PMID- 26515415 TI - S100A12 and the S100/Calgranulins: Emerging Biomarkers for Atherosclerosis and Possibly Therapeutic Targets. AB - Atherosclerosis is mediated by local and systematic inflammation. The multiligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell-targeted expression of S100A12 demonstrate increased coronary and aortic calcification, as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis-susceptible apolipoprotein E null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 apolipoprotein E null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis, and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis. PMID- 26515416 TI - HMGB1-Driven Inflammation and Intimal Hyperplasia After Arterial Injury Involves Cell-Specific Actions Mediated by TLR4. AB - OBJECTIVE: Endoluminal vascular interventions such as angioplasty initiate a sterile inflammatory response resulting from local tissue damage. This response drives the development of intimal hyperplasia (IH) that, in turn, can lead to arterial occlusion. We hypothesized that the ubiquitous nuclear protein and damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1), is one of the endogenous mediators that activates processes leading to IH after endoluminal injury to the arterial wall. The aim of this study is to investigate whether approaches that reduce the levels of HMGB1 or inhibit its activity suppresses IH after arterial injury. APPROACH AND RESULTS: Here, we show that HMGB1 regulates IH in a mouse carotid wire injury model. Induced genetic deletion or neutralization of HMGB1 prevents IH, monocyte recruitment, and smooth muscle cell growth factor production after endoluminal carotid artery injury. A specific inhibitor of HMGB1 myeloid differentiation factor 2-toll-like receptor 4 (TLR4) interaction, P5779, also significantly inhibits IH. HMGB1 deletion is mimicked in this model by global deletion of TLR4 and partially replicated by myeloid specific deletion of TLR4 but not TLR2 or receptor for advanced glycation endproducts deletion. The specific HMGB1 isoform known to activate TLR4 signaling (disulfide HMGB1) stimulates smooth muscle cell to migrate and produce monocyte chemotactic protein 1/CCL2) via TLR4. Macrophages produce smooth muscle cell mitogens in response to disulfide HMGB1 also in a TLR4/myeloid differentiation primary response gene (88)/Trif-dependent manner. CONCLUSIONS: These findings place HMGB1 and its receptor, TLR4 as critical regulators of the events that drive the inflammation leading to IH after endoluminal arterial injury and identify this pathway as a possible therapeutic target to limit IH to attenuate damage-associated molecular pattern molecule-mediated vascular inflammatory responses. PMID- 26515417 TI - Platelet P2Y12 Inhibitors Reduce Systemic Inflammation and Its Prothrombotic Effects in an Experimental Human Model. AB - OBJECTIVE: Clinical studies suggest that platelet P2Y12 inhibitors reduce mortality from sepsis, although the underlying mechanisms have not been clearly defined in vivo. We hypothesized that P2Y12 inhibitors may improve survival from sepsis by suppressing systemic inflammation and its prothrombotic effects. We therefore determined whether clopidogrel and the novel, more potent P2Y12 inhibitor, ticagrelor, modify these responses in an experimental human model. APPROACH AND RESULTS: We randomized 30 healthy volunteers to ticagrelor (n=10), clopidogrel (n=10), or no antiplatelet medication (controls; n=10). We examined the effect of P2Y12 inhibition on systemic inflammation, which was induced by intravenous injection of Escherichia coli endotoxin. Both P2Y12 inhibitors significantly reduced platelet-monocyte aggregate formation and peak levels of major proinflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, and chemokine (C-C motif) ligand 2. In contrast to clopidogrel, ticagrelor also significantly reduced peak levels of IL-8 and growth colony stimulating factor and increased peak levels of the anti-inflammatory cytokine IL 10. In addition, ticagrelor altered leukocyte trafficking. Both P2Y12 inhibitors suppressed D-dimer generation and scanning electron microscopy revealed that ticagrelor also suppressed prothrombotic changes in fibrin clot ultrastructure. CONCLUSIONS: Potent inhibition of multiple inflammatory and prothrombotic mechanisms by P2Y12 inhibitors demonstrates critical importance of platelets as central orchestrators of systemic inflammation induced by bacterial endotoxin. This provides novel mechanistic insight into the lower mortality associated with P2Y12 inhibitors in patients with sepsis in clinical studies. PMID- 26515419 TI - Effects of extended-release niacin on the postprandial metabolism of Lp(a) and ApoB-100-containing lipoproteins in statin-treated men with type 2 diabetes mellitus. AB - OBJECTIVE: The effects of extended-release niacin (ERN; 1-2 g/d) on the metabolism of lipoprotein(a) (Lp(a)) and apolipoprotein (apo) B-100-containing lipoproteins were investigated in 11 statin-treated white men with type 2 diabetes mellitus in a randomized, crossover trial of 12-weeks duration. APPROACH AND RESULTS: The kinetics of Lp(a) and very low-density lipoprotein (VLDL), intermediate-density lipoprotein, and low-density lipoprotein (LDL) apoB-100 were determined following a standardized oral fat load (87% fat) using intravenous administration of D3-leucine, gas chromatography-mass spectrometry, and compartmental modeling. ERN significantly decreased fasting plasma total cholesterol, LDL cholesterol, and triglyceride concentrations. These effects were achieved without significant changes in body weight or insulin resistance. ERN significantly decreased plasma Lp(a) concentration (-26.5%) and the production rates of apo(a) (-41.5%) and Lp(a)-apoB-100 (-32.1%); the effect was greater in individuals with elevated Lp(a) concentration. ERN significantly decreased VLDL ( 58.7%), intermediate-density lipoprotein (-33.6%), and LDL (-18.3%) apoB-100 concentrations and the corresponding production rates (VLDL, -49.8%; intermediate density lipoprotein, -44.7%; LDL, -46.1%). The number of VLDL apoB-100 particles secreted increased in response to the oral fat load. Despite this, total VLDL apoB-100 production over the 10-hour postprandial period was significantly decreased with ERN (-21.9%). CONCLUSIONS: In statin-treated men with type 2 diabetes mellitus, ERN decreased plasma Lp(a) concentrations by decreasing the production of apo(a) and Lp(a)-apoB-100. ERN also decreased the concentrations of apoB-100-containing lipoproteins by decreasing VLDL production and the transport of these particles down the VLDL to LDL cascade. Our study provides further mechanistic insights into the lipid-regulating effects of ERN. PMID- 26515418 TI - IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model: Role of Both IL-1alpha and IL-1beta. AB - OBJECTIVE: Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease among US children. We have previously shown that both TLR2/MyD88 and interleukin (IL)-1beta signaling are required for the Lactobacillus casei cell wall extract-induced KD vasculitis mouse model. The objectives of this study were to investigate the cellular origins of IL-1 production, the role of CD11c(+) dendritic cells and macrophages, and the relative contribution of hematopoietic and stromal cells for IL-1 responsive cells, as well the MyD88 signaling, in Lactobacillus casei cell wall extract induced KD mouse model of vasculitis. APPROACH AND RESULTS: Using mouse knockout models and antibody depletion, we found that both IL-1alpha and IL-1beta were required for Lactobacillus casei cell wall extract-induced KD. Both dendritic cells and macrophages were necessary, and we found that MyD88 signaling was required in both hematopoietic and stromal cells. However, IL-1 response and signaling were critically required in nonendothelial stromal cells, but not in hematopoietic cells. CONCLUSIONS: Our results suggest that IL-1alpha and IL 1beta, as well as CD11c(+) dendritic cells and macrophages, are essential for the development of KD vasculitis and coronary arteritis in this mouse model. Bone marrow chimera experiments suggest that MyD88 signaling is important in both hematopoietic and stromal cells, whereas IL-1 signaling and response are required only in stromal cells, but not in endothelial cells. Determining the role of IL 1alpha and IL-1beta and of specific cell types in the KD vasculitis mouse model may have important implications for the design of more targeted therapies and understanding of the molecular mechanisms of KD immunopathologies. PMID- 26515420 TI - Iatrogenic embolization and transcatheter retrieval of a ventricular septal defect occluder in a dog. AB - A 7-month-old Irish Setter underwent transcatheter therapy of a muscular ventricular septal defect (VSD) and pulmonary valve stenosis. Standard devices for muscular VSD closure could not span the interventricular septum due to right ventricular hypertrophy, and an Amplatzer post-infarction muscular VSD occluder with a wider waist was successfully implanted. Following VSD closure, inflation of the balloon dilation catheter during balloon pulmonary valvuloplasty resulted in iatrogenic embolization of the VSD occluder to the left ventricular outflow tract. Retrieval and reimplantation of the device was achieved using a snare catheter. This report describes a potential complication and management during intracardiac device implantation in a dog. Additionally, the case illustrates that the Amplatzer post-infarction muscular VSD occluder holds potential value in animals with a hypertrophied interventricular septum that cannot be spanned using a conventional device. PMID- 26515421 TI - Is urate crystal precipitation a predictor of cardiovascular risk in hyperuricemic patients? A Danish cohort study. AB - INTRODUCTION: There is increasing evidence that both hyperuricemia and gout increase the risk of cardiovascular morbidity and mortality. Whether urate crystal precipitation confers a particular risk above what is already inherent in having hyperuricemia is not well established. We conducted this cohort study to establish whether the presence of monosodium urate crystal precipitation per se is associated with increased risk of cardiovascular diseases among hyperuricemic patients. METHODS: We identified hyperuricemic individuals who had joint fluid examinations for urate crystals. Individuals with intra-articular urate crystals were matched by propensity score to individuals without crystals and compared with respect to a composite cardiovascular endpoint. Included in the propensity score model were potential confounders retrieved from four different health care registries. RESULTS: We identified 862 hyperuricemic patients having urate crystal examination. After propensity score matching, we could include 317 patients with urate crystals matched 1:1 to patients without urate crystals. We found no difference between the two groups with respect to cardiovascular outcomes (hazard ratios = 0.86; 95 % confidence interval (CI) 0.52 - 1.43) or death (hazard ratio 0.74; CI 0.45 - 1.21). CONCLUSION: The presence of urate crystal precipitations does not seem to confer a particular cardiovascular risk in hyperuricemic patients. PMID- 26515422 TI - Discrete associations of the GCKR variant with metabolic risk in a Chinese population: longitudinal change analysis. AB - AIMS/HYPOTHESIS: Glucokinase regulatory protein gene (GCKR) variant rs780092 is a novel genetic variant associated with serum triacylglycerol (TG) identified in a genome-wide association study in East Asians. We aimed to investigate associations of rs780092 with incident type 2 diabetes and dyslipidaemia, and the longitudinal changes in glucose and lipid levels. METHODS: A community-based prospective cohort study was conducted at baseline in 2008, including 5,613 non diabetic participants (37% male, mean age 57.6 years) with 5 years of follow-up. Blood glucose and lipid was measured at baseline and follow-up. RESULTS: Each rs780092 T-allele was associated with a 17% lower risk of incident type 2 diabetes (HR 0.83 [95% CI 0.73, 0.95]) and 36% higher risk of incident hypertriacylglycerolaemia (OR 1.36 [95% CI 1.08, 1.72]), after adjustment for baseline fasting glucose and TG and other confounders. The T-allele was associated with a 5 year increasing level of log10 TG (beta +/- SE, 0.01 +/- 0.004, p = 0.005). Mediation analysis showed that both baseline TG and the 5 year increase in log10 TG were significant mediators in the associations of rs780092 with risk of diabetes. The risk of incident type 2 diabetes associated with 1 SD increase in total and LDL-cholesterol was 35% and 22% lower in TT carriers compared with CC carriers, respectively (both p for interaction <= 0.04). CONCLUSIONS/INTERPRETATION: The GCKR rs780092 variant showed opposite-directional associations with type 2 diabetes and hypertriacylglycerolaemia in a Chinese population. Both baseline level and 5 year change in serum TG were mediators of the association between the genetic variant and type 2 diabetes. PMID- 26515424 TI - Biosynthesis of the Peptide Antibiotic Feglymycin by a Linear Nonribosomal Peptide Synthetase Mechanism. AB - Feglymycin, a peptide antibiotic produced by Streptomyces sp. DSM 11171, consists mostly of nonproteinogenic phenylglycine-type amino acids. It possesses antibacterial activity against methicillin-resistant Staphylococcus aureus strains and antiviral activity against HIV. Inhibition of the early steps of bacterial peptidoglycan synthesis indicated a mode of action different from those of other peptide antibiotics. Here we describe the identification and assignment of the feglymycin (feg) biosynthesis gene cluster, which codes for a 13-module nonribosomal peptide synthetase (NRPS) system. Inactivation of an NRPS gene and supplementation of a hydroxymandelate oxidase mutant with the amino acid l-Hpg proved the identity of the feg cluster. Feeding of Hpg-related unnatural amino acids was not successful. This characterization of the feg cluster is an important step to understanding the biosynthesis of this potent antibacterial peptide. PMID- 26515423 TI - JAK2 promotes brown adipose tissue function and is required for diet- and cold induced thermogenesis in mice. AB - AIMS/HYPOTHESIS: Non-shivering thermogenesis in adipose tissue can be activated by excessive energy intake or following cold exposure. The molecular mechanisms regulating this activation have not been fully elucidated. The Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway mediates the signal transduction of numerous hormones and growth factors that regulate adipose tissue development and function, and may play a role in adaptive thermogenesis. METHODS: We analysed mRNA and protein levels of uncoupling protein 1 (UCP1) and JAK2 in different adipose depots in response to metabolic and thermal stress. The in vivo role of JAK2 in adaptive thermogenesis was examined using mice with adipocyte-specific Jak2 deficiency (A-Jak2 KO). RESULTS: We show in murine brown adipose tissue (BAT) that JAK2 is upregulated together with UCP1 in response to high-fat diet (HFD) feeding and cold exposure. In contrast to white adipose tissue, where JAK2 was dispensable for UCP1 induction, we identified an essential role for BAT JAK2 in diet- and cold-induced thermogenesis via mediating the thermogenic response to beta-adrenergic stimulation. Accordingly, A-Jak2 KO mice were unable to upregulate BAT UCP1 following a HFD or after cold exposure. Therefore, A-Jak2 KO mice were cold intolerant and susceptible to HFD-induced obesity and diabetes. CONCLUSIONS/INTERPRETATION: Taken together, our results suggest that JAK2 plays a critical role in BAT function and adaptive thermogenesis. Targeting the JAK-STAT pathway may be a novel therapeutic approach for the treatment of obesity and related metabolic disorders. PMID- 26515426 TI - Use of textile waste water along with liquid NPK fertilizer for production of wheat on saline sodic soils. AB - A field experiment in collaboration with a private textile industry (Noor Fatima Fabrics Private (Ltd.), Faisalabad) was conducted to evaluate the effect of disposed water from bleaching unit, printing unit and end drain for improving growth and yield of wheat under saline sodic soil. Textile waste water along with canal water (control) was applied with and without liquid NPK fertilizer. The application of liquid NPK fertilizer with end drain waste water increased plant height, spike length, flag leaf length, root length, number of tillers (m(-2)), number of fertile tillers (m(-2)), 1000 grain weight, grain yield, straw yield and biological yield up to 21, 20, 20, 44, 17, 20, 14, 44, 40 and 41%, respectively compared to canal water (control). Similarly, the NPK uptake in grain was increased up to 15, 30 and 28%, respectively by liquid fertilizer treated end drain water as compare to canal water with liquid fertilizer. Moreover, concentration of different heavy metals particularly Cu, Cr, Pb and Cd was decreased in grains by application of waste water along with liquid NPK. The result may imply that waste water application along with liquid-NPK could be a novel approach for improving growth and yield of wheat in saline sodic soils. PMID- 26515425 TI - Amniotic mesenchymal cells from pre-eclamptic placentae maintain immunomodulatory features as healthy controls. AB - Pre-eclampsia (PE) is one of the most severe syndromes in human pregnancy, and the underlying mechanisms of PE have yet to be determined. Pre-eclampsia is characterized by the alteration of the immune system's activation status, an increase in inflammatory Th1/Th17/APC cells, and a decrease in Th2/Treg subsets/cytokines. Moreover, inflammatory infiltrates have been detected in the amniotic membranes of pre-eclamptic placentae, and to this date limited data are available regarding the role of amniotic membrane cells in PE. Interestingly, we and others have previously shown that human amniotic mesenchymal stromal cells (hAMSC) possess anti-inflammatory properties towards almost all immune cells described to be altered in PE. In this study we investigated whether the immunomodulatory properties of hAMSC were altered in PE. We performed a comprehensive study of cell phenotype and investigated the in vitro immunomodulatory properties of hAMSC isolated from pre-eclamptic pregnancies (PE hAMSC), comparing them to hAMSC from normal pregnancies (N-hAMSC). We demonstrate that PE-hAMSC inhibit CD4/CD8 T-cell proliferation, suppress Th1/Th2/Th17 polarization, induce Treg and block dendritic cells and M1 differentiation switching them to M2 cells. Notably, PE-hAMSC generated a more prominent induction of Treg and higher suppression of interferon-gamma when compared to N hAMSC, and this was associated with higher transforming growth factor-beta1 secretion and PD-L2/PD-L1 expression in PE-hAMSC. In conclusion, for the first time we demonstrate that there is no intrinsic impairment of the immunomodulatory features of PE-hAMSC. Our results suggest that amniotic mesenchymal stromal cells do not contribute to the disease, but conversely, could participate in offsetting the inflammatory environment which characterizes PE. PMID- 26515427 TI - The use of sonographic cervical length assessment for the prediction of time from induction to delivery. AB - OBJECTIVE: The objective of this study is to investigate the role of trans vaginal cervical length measurement in the prediction of the interval to successful vaginal delivery after induction of labor with balloon catheter. METHODS: In this prospective study of cervical length measurement before induction of labor, singleton pregnancies that underwent induction of labor between 37 and 42 weeks of gestation were included. The data collected included trans-vaginal sonographic cervical measurements followed by digital cervical assessment. Bishop score was used to quantify digital assessment (before induction of labor). RESULTS: During the study period, 71 patients were included in the study. A statistically significant linear correlation was found between sonographic cervical length prior to induction of labor and the time of delivery (Pearson correlation 0.335; p values 0.005). Of the 57 vaginal deliveries, 27 patients had a cervical length of less than 28 mm. Patients with a cervical length of less than 28 mm had a significantly shorter time to delivery compared to patients with more than 28 mm length (20.4 versus 28.7, respectively; p value = 0.019). Cervical length of 28 mm remained significantly correlated even after performing several logistic regression models in order to control for confounders such as parity and age. In addition, a correlation was found between Bishop scores of above 7 to the time to delivery. CONCLUSIONS: Cervical length is correlated linearly to the time interval between induction of labor and delivery. A cervical length of less than 28 mm was found to be statistically significant in predicting a shorter time to delivery. PMID- 26515428 TI - A Pilot Study Assessing ECG versus ECHO Ventriculoventricular Optimization in Pediatric Resynchronization Patients. AB - INTRODUCTION: Cardiac resynchronization therapy indications and management are well described in adults. Echocardiography (ECHO) has been used to optimize mechanical synchrony in these patients; however, there are issues with reproducibility and time intensity. Pediatric patients add challenges, with diverse substrates and limited capacity for cooperation. Electrocardiographic (ECG) methods to assess electrical synchrony are expeditious but have not been extensively studied in children. We sought to compare ECHO and ECG CRT optimization in children. METHODS: Prospective, pediatric, single-center cross over trial comparing ECHO and ECG optimization with CRT. Patients were assigned to undergo either ECHO or ECG optimization, followed for 6 months, and crossed over to the other assignment for another 6 months. ECHO pulsed-wave tissue Doppler and 12-lead ECG were obtained for 5 VV delays. ECG optimization was defined as the shortest QRSD and ECHO optimization as the lowest dyssynchrony index. ECHOs/ECGs were interpreted by readers blinded to optimization technique. After each 6 month period, these data were collected: ejection fraction, velocimetry-derived cardiac index, quality of life, ECHO-derived stroke distance, M-mode dyssynchrony, study cost, and time. Outcomes for each optimization method were compared. RESULTS: From June 2012 to December 2013, 19 patients enrolled. Mean age was 9.1 +/- 4.3 years; 14 (74%) had structural heart disease. The mean time for optimization was shorter using ECG than ECHO (9 +/- 1 min vs. 68 +/- 13 min, P < 0.01). Mean cost for charges was $4,400 +/- 700 less for ECG. No other outcome differed between groups. CONCLUSION: ECHO optimization of synchrony was not superior to ECG optimization in this pilot study. ECG optimization required less time and cost than ECHO optimization. PMID- 26515430 TI - Reaction of an allylstannylene with adamantyl phosphaalkyne. AB - The reaction of a terphenyl tin(ii) compound bearing an eta(3) coordinating allyl ligand with adamantyl phosphaalkyne is reported. The quantitative stochiometric reaction towards one product involves an addition of one Sn-Ar bond across the C[triple bond, length as m-dash]P triple bond and formation of a phosphadistannacyclobutene ring. This kinetically favoured product can be isolated in the solid state, however, in solution, it shows rearrangement towards a new tin-phosphorus molecule over a period of five days. PMID- 26515429 TI - Evaluation of the experimental basis for assessment factors to protect individuals with asthma from health effects during short-term exposure to airborne chemicals. AB - BACKGROUND: Asthmatic individuals constitute a large sub-population that is often considered particularly susceptible to the deleterious effects of inhalation of airborne chemicals. However, for most such chemicals information on asthmatics is lacking and inter-individual assessment factors (AFs) of 3-25 have been proposed for use in the derivation of health-based guideline values. OBJECTIVE: To evaluate available information in attempt to determine whether a general difference in airway response during short-term exposure between healthy and asthmatic individuals can be identified, and whether current AFs for inter individual variability provide sufficient protection for asthmatics. METHODS: After performing systematic review of relevant documents and the scientific literature estimated differential response factors (EDRF) were derived as the ratio between the lowest observed adverse effect levels for healthy and asthmatic subjects based on studies in which both groups were tested under the same conditions. Thereafter, the concentration-response relationships for healthy and asthmatic subjects exposed separately to four extensively tested chemicals (nitrogen dioxide, ozone, sulfuric acid, sulfur dioxide) were compared on the basis of combined data. Finally, a Benchmark Concentration (BMC) analysis was performed for sulfur dioxide. RESULTS: We found evidence of higher sensitivity among asthmatics (EDRF > 1) to 8 of 19 tested chemicals, and to 3 of 11 mixtures. Thereafter, we confirmed the higher sensitivity of asthmatics to sulfuric acid and sulfur dioxide. No difference was observed in the case of ozone and nitrogen dioxide. Finally, our BMC analysis of sulfur dioxide indicated a ninefold higher sensitivity among asthmatics. CONCLUSION: Although experimental data are often inconclusive, our analyses suggest that an AF of 10 is adequate to protect asthmatics from the deleterious respiratory effects of airborne chemicals. PMID- 26515431 TI - Psychosocial characteristics and predictors of health-care use in families of young children with cystic fibrosis in Western Australia. AB - OBJECTIVE: Early childhood psychosocial experiences determine future health and health-care use. Identifying psychosocial predictors in cystic fibrosis may inform intervention strategies that can reduce health-care utilization. DESIGN: The study was designed as a prospective cohort study. SETTING: The study was set in the only cystic fibrosis clinic in Western Australia. PATIENTS: The patients were children up to 6 years diagnosed with cystic fibrosis in Western Australia between 2005 and 2011. MAIN OUTCOME MEASURES: Psychosocial data collected for each year of life were compared with Australian population data and analysed as predictors of annual hospital, emergency and outpatient visits. RESULTS: Compared with the Australian population, cystic fibrosis families demonstrated lower socio economic status and labour supply (P < 0.001), increased residential mobility (P < 0.001) and trends towards increased rates of parental separation (P = 0.066). Marital discord and maternal and child psychological stress significantly predicted increased hospital admissions, emergency and outpatient visits. CONCLUSIONS: Social gradients may exist for families of young children with cystic fibrosis in Western Australia with potential implications for child health. Family psychological and relationship stress predicted increased child cystic fibrosis-related health-care use. PMID- 26515432 TI - Enumeration of residual white blood cells in leukoreduced blood products: Comparing flow cytometry with a portable microscopic cell counter. AB - Transfusion of blood components is potentially associated to the risk of cell mediated adverse events and current guidelines require a reduction of residual white blood cells (rWBC) below 1 * 10(6) WBC/unit. The reference method to enumerate rare events is the flow cytometry (FCM). The ADAM-rWBC microscopic cell counter has been proposed as an alternative: it measures leukocytes after their staining with propidium iodide. We have tested the Adam-rWBC for the ability to enumerate rWBC in red blood cells and concentrates. We have validated the flow cytometry (FCM) for linearity, precision accuracy and robustness and then the ADAM-rWBC results have been compared with the FCM. Our data confirm the linearity, accuracy, precision and robustness of the FCM. The ADAM-rWBC has revealed an adequate precision and accuracy. Even if the Bland-Altman analysis of the paired data has indicated that the two systems are comparable, it should be noted that the rWBC values obtained by the ADAM-rWBC were significantly higher compared to FCM. In conclusion, the Adam-rWBC cell counter could represent an alternative where FCM technology expertise is not available, even if the risk that borderline products could be misclassified exists. PMID- 26515433 TI - Folate, vitamin B6, vitamin B12 and methionine intakes and risk for nasopharyngeal carcinoma in Chinese adults: a matched case-control study. AB - Many studies have suggested that folate-related one-carbon metabolism-related nutrients may play a role in certain cancer risks, but few studies have assessed their associations with the risk for nasopharyngeal carcinoma (NPC). In this study, we investigated the association between four folate-related one-carbon metabolism-related nutrients (folate, vitamin B6, vitamin B12 and methionine) and NPC risk in Chinese adults. A total of 600 patients newly diagnosed (within 3 months) with NPC were individually matched with 600 hospital-based controls by age, sex and household type (urban v. rural). Folate, vitamin B6, vitamin B12 and methionine intakes were measured using a validated seventy-eight-item FFQ. A higher dietary folate or vitamin B6 intake was associated with a lower NPC risk after adjusting for potential confounders. The adjusted OR of NPC for quartiles 2 4 (v. 1) were 0.66 (95% CI 0.48, 0.91), 0.52 (95% CI 0.37, 0.74) and 0.34 (95% CI 0.23, 0.50) (P(trend)<0.001) for folate and 0.72 (95% CI 0.52, 1.00), 0.55 (95% CI 0.39, 0.78) and 0.44 (95% CI 0.30, 0.63) (P(trend)<0.001) for vitamin B6. No significant association with NPC risk was observed for dietary vitamin B12 or methionine intake. The risk for NPC with dietary folate intake was more evident in the participants who were not exposed to toxic substances than in those who were exposed (P(interaction)=0.014). This study suggests that dietary folate and vitamin B6 may be protective for NPC in a high-risk population. PMID- 26515434 TI - Fast synthesis of platinum nanopetals and nanospheres for highly-sensitive non enzymatic detection of glucose and selective sensing of ions. AB - Novel methods to obtain Pt nanostructured electrodes have raised particular interest due to their high performance in electrochemistry. Several nanostructuration methods proposed in the literature use costly and bulky equipment or are time-consuming due to the numerous steps they involve. Here, Pt nanostructures were produced for the first time by one-step template-free electrodeposition on Pt bare electrodes. The change in size and shape of the nanostructures is proven to be dependent on the deposition parameters and on the ratio between sulphuric acid and chloride-complexes (i.e., hexachloroplatinate or tetrachloroplatinate). To further improve the electrochemical properties of electrodes, depositions of Pt nanostructures on previously synthesised Pt nanostructures are also performed. The electroactive surface areas exhibit a two order of magnitude improvement when Pt nanostructures with the smallest size are used. All the biosensors based on Pt nanostructures and immobilised glucose oxidase display higher sensitivity as compared to bare Pt electrodes. Pt nanostructures retained an excellent electrocatalytic activity towards the direct oxidation of glucose. Finally, the nanodeposits were proven to be an excellent solid contact for ion measurements, significantly improving the time-stability of the potential. The use of these new nanostructured coatings in electrochemical sensors opens new perspectives for multipanel monitoring of human metabolism. PMID- 26515435 TI - Assessment of the interest of the geriatric oncology consultation among French general practitioners. AB - OBJECTIVE: We assessed the interest of the geriatric oncology (GO) consultation (GOC) among general practitioners (GPs). MATERIALS AND METHODS: We conducted a survey among GPs whose patients had had a GOC in 2012. A questionnaire was sent to GPs. The 1st part collected GPs' characteristics including medical education in geriatrics and GO, and knowledge of GOC. The following parts concerned the GOC and included the cancer type, GOC report and care plan. RESULTS: One-hundred twenty-six questionnaires corresponding to 94 GPs were collected. Concerning the GPs' characteristics, age range 50-59 (44.7%), men (62.8%) and urban practice (79.8%) were the most represented, 80.8% had no expertise in geriatrics, 60.6% knew of the existence of GOCs, and 14.9% had received medical education in GO. The most frequent cancer location was gynecological (40.7%) (82.6% were breast cancers). Of the GPs, 69.8% had received a GOC report and 92% were (very) satisfied with the delivery time. A care plan was proposed after the GOC in 83% of cases. It was satisfactory in 96.4% of cases, and applied by 74.7% of GPs. Sixteen percent of GPs were called by the GO team. The less the GP was satisfied with the GOC, the more he or she wanted phone contact (p=0.02); 94% of GPs considered the GOC (very) satisfactory. Sixty-seven percent of GPs wanted to be trained in GO. CONCLUSION: Very few GPs had been trained in geriatrics and/or GO. They were mostly satisfied with GOC and expressed a wish to be trained in GO. PMID- 26515436 TI - Optical field terahertz amplitude modulation by graphene nanoribbons. AB - In this study, first-principles time-dependent density functional theory calculations were used to demonstrate the possibility to modulate the amplitude of the optical electric field (E-field) near a semiconducting graphene nanoribbon. A significant enhancement of the optical E-field was observed 3.34 A above the graphene nanoribbon sheet, with an amplitude modulation of approximately 100 fs, which corresponds to a frequency of 10 THz. In general, a six-fold E-field enhancement could be obtained, which means that the power of the obtained THz is about 36 times that of incident UV light. We suggest the use of semiconducting graphene nanoribbons for converting visible and UV light into a THz signal. PMID- 26515437 TI - Levels of platinum group elements and rare-earth elements in wild mushroom species growing in Poland. AB - Due to limited data-describing abilities of mushrooms to accumulate platinum group elements (PGEs) and rare-earth elements (REEs), the aim of this study was to determine, by inductively coupled plasma optical emission spectrometry followed by microwave-assisted sample digestion by nitric acid, the content of these elements in 20 mushroom species (10 above ground and 10 growing on wood), mostly edible, collected near a busy trunk road. The highest content of PGEs in above-ground mushroom species was observed in Lepista gilva and Suillus bovinus fruit bodies (0.38 +/- 0.05 and 0.37 +/- 0.03 mg kg(-1) DW, respectively), while in mushrooms growing on wood, the highest content was observed in Pleurotus ostreatus (0.35 +/- 0.04 mg kg(-1) DW). The mean content of PGEs for both these groups was 0.23 +/- 0.08 and 0.26 +/- 0.07 mg kg(-1) DW, respectively. The highest content of REEs in Suillus luteus and Tricholoma equestra was 5.03 +/- 0.50 and 2.18 +/- 0.56 mg kg(-1) DW, respectively, but within mushrooms growing on wood in Ganoderma applanatum fruiting bodies it was 4.19 +/- 0.78 mg kg(-1) DW. Mean contents of REEs were 1.39 +/- 1.21 and 1.61 +/- 0.97 mg kg(-1) DW in above-ground species and species growing on wood, respectively. Generally, the group of mushroom species growing on wood was capable of slightly higher accumulation of both REEs and PGEs. No limits have been established for both the groups until now. PMID- 26515438 TI - Partial and No Recovery from Delirium in Older Hospitalized Adults: Frequency and Baseline Risk Factors. AB - OBJECTIVES: To determine the frequency and baseline risk factors for partial and no recovery from delirium in older hospitalized adults. DESIGN: Cohort study with assessment of recovery status approximately 1 and 3 months after enrollment. SETTING: University-affiliated, primary, acute-care hospital. PARTICIPANTS: Medical or surgical inpatients aged 65 and older with delirium (N = 278). MEASUREMENTS: The Mini-Mental State Examination (MMSE), Confusion Assessment Method (CAM), Delirium Index (DI), and activities of daily living (ADLs) were completed at enrollment and each follow-up. Primary outcome categories were full recovery (absence of CAM core symptoms of delirium), partial recovery (presence of >=1 CAM core symptoms but not meeting criteria for delirium), no recovery (met CAM criteria for delirium), or death. Secondary outcomes were changes in MMSE, DI, and ADL scores between the baseline and last assessment. Potential risk factors included many clinical and laboratory variables. RESULTS: In participants with dementia, frequencies of full, partial, and no recovery and death at first follow-up were 6.3%, 11.3%, 74.6%, and 7.7%, respectively; in participants without dementia, frequencies were 14.3%, 17%, 50.9%, and 17.9%, respectively. In participants with dementia, frequencies at the second follow-up were 7.9%, 15.1%, 57.6%, and 19.4%, respectively; in participants without dementia, frequencies were 19.2%, 20.2%, 31.7%, and 28.8%, respectively. Frequencies were similar in participants with prevalent and incident delirium and in medical and surgical participants. The DI, MMSE, and ADL scores of many participants with partial and no recovery improved. Independent baseline risk factors for delirium persistence were chart diagnosis of dementia (odds ratio (OR) = 2.51, 95% confidence interval (CI) =1.38, 4.56), presence of any malignancy (OR = 5.79, 95% CI = 1.51, 22.19), and greater severity of delirium (OR =9.39, 95% CI = 3.95, 22.35). CONCLUSION: Delirium in many older hospitalized adults appears to be much more protracted than previously thought, especially in those with dementia, although delirium symptoms, cognition, and function improved in many participants with partial and no recovery. It may be important to monitor the longer-term course of delirium in older hospitalized adults and develop strategies to ensure full recovery. PMID- 26515439 TI - Dynamic Regulation of Delta-Opioid Receptor in Rat Trigeminal Ganglion Neurons by Lipopolysaccharide-induced Acute Pulpitis. AB - INTRODUCTION: Delta-opioid receptor (DOR) and its endogenous ligands distribute in trigeminal system and play a very important role in modulating peripheral inflammatory pain. DOR activation can trigger p44/42 mitogen-activated protein kinase (ERK1/2) and Akt signaling pathways, which participate in anti inflammatory and neuroprotective effects. In this study, our purpose was to determine the dynamic changes of DOR in trigeminal ganglion (TG) neurons during the process of acute dental pulp inflammation and elucidate its possible mechanism. METHODS: Forty rats were used to generate lipopolysaccharide-induced acute pulpitis animal models at 6, 12, and 24 hours and sham-operated groups. Acute pulpitis was confirmed by hematoxylin-eosin staining, and TG neuron activation was determined by anti-c-Fos immunohistochemistry. DOR protein and gene expression in TG was investigated by immunohistochemistry, Western blotting, and real-time polymerase chain reaction, and DOR expression in trigeminal nerves and dental pulp was also determined by immunohistochemistry. To further investigate the mechanism of DOR modulating acute inflammation, the change of pErk1/2 and pAkt in TG was examined by immunohistochemistry. RESULTS: Lipopolysaccharide could successfully induce acute pulpitis and activated TG neurons. Acute pulpitis could dynamically increase DOR protein and gene expression at 6, 12, and 24 hours in TG, and DOR dimerization was significantly increased at 12 and 24 hours. Acute pulpitis also induced the dynamic change of DOR protein in trigeminal nerve and dental pulp. Furthermore, ERK1/2 and Akt signaling pathways were inhibited in TG after acute pulpitis. CONCLUSIONS: Increased DOR expression and dimerization may play important roles in peripheral acute inflammatory pain. PMID- 26515440 TI - Immunosensor based on nanocomposite of nanostructured zirconium oxide and gelatin A. AB - We have reported the studies related to the fabrication of a nanocomposite, comprising of sol-gel derived inorganic zirconium oxide nanoparticles (ZrO2 NPs) and organic biopolymer gelatin-A (GA), deposited on indium-tin-oxide (ITO) coated glass substrate by drop casting method. The GA-ZrO2/ITO electrode was used for immobilization of monoclonal antibodies (Ab) specific to antigen Vibrio cholerae (Vc) followed by bovine serum albumin (BSA) for antigen Vc detection using electrochemical techniques. The structural and morphological behaviour of these ZrO2 NPs, GA-ZrO2/ITO electrode and BSA/Ab/GA-ZrO2/ITO immunosensor was characterized by scanning electron microscopy and Fourier transform infrared spectroscopy techniques. The transmission electron microscopy study exhibited a spherical shape ZrO2 NPs. The average crystalline size of ZrO2 NPs was obtained as 10.3 +/- 1 nm from X-ray diffraction measurement and 72 nm hydrodynamic radius measured by dynamic light scattering. GA-ZrO2 nanocomposite provides a porous structure which assists to higher loading of Ab on the matrix surface that improved the biosensing properties. The electrochemical response studies of the fabricated BSA/Ab/GA-ZrO2/ITO immunosensor exhibited good linearity in the range of 50-400 ng mL(-1), low limit of detection of 0.74 ng/mL, sensitivity as 0.03 Omega ng(-1)mL(-1)cm(-2) and reproducibility more than 10 times. PMID- 26515441 TI - Emerging interactions between matrix components during biofilm development. AB - Bacterial cells are most often found in the form of multicellular aggregates commonly referred to as biofilms. Biofilms offer their member cells several benefits, such as resistance to killing by antimicrobials and predation. During biofilm formation there is a production of extracellular substances that, upon assembly, constitute an extracellular matrix. The ability to generate a matrix encasing the microbial cells is a common feature of biofilms, but there is diversity in matrix composition and in interaction between matrix components. The different components of bacterial biofilm extracellular matrixes, known as matrix interactions, and resulting implications are discussed in this review. PMID- 26515442 TI - Dual Tuning of Biomass-Derived Hierarchical Carbon Nanostructures for Supercapacitors: the Role of Balanced Meso/Microporosity and Graphene. AB - Rational design of advanced carbon nanomaterials with a balanced mesoporosity to microporosity is highly desirable for achieving high energy/power density for supercapacitors because the mesopore can allow better transport pathways for the solvated ions of larger than 1 nm. Inspired by the inherent meso/macroporous architecture and huge absorption ability to aqueous solution of auricularia biomass, we demonstrate a new biomass-derived synthesis process for the three dimensional (3D) few-layered graphene nanosheets incorporated hierarchical porous carbon (GHPC) nanohybrids. The as-prepared GHPC nanohybrids possess a balanced mesoporosity to microporosity with much improved conductivity, which is highly desirable for achieving high energy/power density for supercapacitors. As we predicted, they delivered a high specific capacitance of 256 F g(-1) at 1 A g(-1) with excellent rate capability (120 F g(-1) at 50 A g(-1)) and long cycle life (92% capacity retention after 10000 cycles) for symmetric supercapacitors in 1 M H2SO4. Based on the as-obtained carbon materials, a flexible and all-solid-state supercapacitor was also assembled, which can be fully recharged within 10 s and able to light an LED even under bended state. Such excellent performance is at least comparable to the best reports in the literature for two-electrode configuration under aqueous systems. PMID- 26515443 TI - Response to letter from Youngson et al. PMID- 26515444 TI - Computerised prescribing for safer medication ordering: still a work in progress. PMID- 26515445 TI - Response to: 'Lack of standardisation between specialties for human factors content in postgraduate surgical training: an analysis of specialty curricula in the UK' by Greig et al. PMID- 26515446 TI - Fucosterol, a sterol extracted from Sargassum fusiforme, shows antidepressant and anticonvulsant effects. AB - We previously showed that extracts of Sargassum fusiforme significantly reduce immobility time in the forced swim test and tail suspension test, suggesting that these extracts possess antidepressant-like effects. Here, fucosterol extracted from S. fusiforme was evaluated for antidepressant and anticonvulsant activities in mice. Fucosterol (10, 20, 30 and 40mg/kg) significantly shortened immobility time in the forced swim test and tail suspension test for30min after treatment but had no effect on locomotor activity in the open field test. Fucosterol significantly increased serotonin, norepinephrine and the metabolite 5 hydroxyindoleacetic acid in mouse brain, suggesting that the effects of fucosterol may be mediated through these neurotransmitters. As assessed using maximal electroshock, fucosterol (20, 40, 100mg/kg) possessed anticonvulsant activity, whereas rotarod toxicity test results indicated that fucosterol did not induce neurotoxicity at the same dose levels in mice. Thus, fucosterol may be a useful antidepressant adjunct candidate for treating depression in patients with epilepsy. A significant increase in hippocampal brain-derived neurotrophic factor (BDNF) levels was found in the fucosterol 20mg/kg group (P<0.05). Our findings suggested that fucosterol may possess an antidepressant-like effect, which may be mediated by increasing central BDNF levels. PMID- 26515447 TI - Physiological threat responses predict number processing. AB - Being able to adequately process numbers is a key competency in everyday life. Yet, self-reported negative affective responses towards numbers are known to deteriorate numerical performance. Here, we investigated how physiological threat responses predict numerical performance. Physiological responses reflect whether individuals evaluate a task as exceeding or matching their resources and in turn experience either threat or challenge, which influences subsequent performance. We hypothesized that, the more individuals respond to a numerical task with physiological threat, the worse they would perform. Results of an experiment with cardiovascular indicators of threat/challenge corroborated this expectation. The findings thereby contribute to our understanding of the physiological mechanism underlying the influence of negative affective responses towards numbers on numerical performance. PMID- 26515448 TI - Development of bilateral coronary artery aneurysms in a child with Noonan syndrome. AB - Noonan syndrome is a constellation of congenital malformations including heart defects, facial anomalies and short stature. The cardiovascular defects are variable and extensive, with the most common being pulmonary stenosis and hypertrophic cardiomyopathy. Coronary artery anomalies have only been reported in a few cases. We report a child with Noonan syndrome status post pulmonary stenosis and atrial septal defect repair, who developed bilateral coronary artery aneurysms. The aneurysms were diagnosed with both cardiac magnetic resonance imaging and coronary computed tomography angiography. There had been no evidence of them on a cardiac MR exam 5 years previously. PMID- 26515449 TI - Allergic Fungal Rhinosinusitis and the Unified Airway: the Role of Antifungal Therapy in AFRS. AB - Allergic fungal sinusitis (AFS) or rhinosinusitis (AFRS) is a form of polypoid chronic rhinosinusitis that is believed to be due to hypersensitivity to fungal antigens. The disease is characterized by type 1 hypersensitivity to fungal allergens, dramatically elevated total serum IgE, accumulation of thick eosinophil-laden mucin with non-invasive fungal hyphae within the paranasal sinuses, nasal polyposis, and sinus bony remodeling. Because of many clinicopathologic similarities to allergic bronchopulmonary aspergillosis (ABPA), these conditions can be considered analogous examples of disease in the unified airway. However, these conditions rarely occur together and their treatment differs. The treatment of AFRS relies upon surgical removal of fungal hyphae in eosinophilic mucin, while antifungal therapy is used to clear fungi from the airways in ABPA. Several uncontrolled studies suggest there may be some benefit to antifungal agents in AFRS, but randomized trials of topical and systemic antifungal therapies have not shown beneficial results in chronic rhinosinusitis (CRS). Antifungal treatment within the sinonasal cavities does not appear to be an effective approach for most chronic sinusitis, and antifungal therapy for AFRS is unproven. PMID- 26515450 TI - The value of 18F-FDG PET in pediatric patients with post-transplant lymphoproliferative disorder at initial diagnosis. AB - PTLD is a serious complication of both solid organ and BMT. This study assessed whether (18) F-FDG PET, when added to CT scan, had additional value in the initial evaluation of PTLD in pediatric patients and whether PET/CT at baseline can reliably guide biopsy. This retrospective study evaluated 34 consecutive pediatric patients (14 female), aged 3.5-17.0 yr (mean age: 9.9 yr, s.d.: 4.9 yr), who had undergone (18) F-FDG PET/CT from May 2007 to December 2014 at initial diagnosis of PTLD following heart (n = 13), lung (n = 8), kidney (n = 4), liver (n = 3), liver and bowel (n = 3), and bone marrow (n = 3) transplantation. PTLD was diagnosed histopathologically in 33 patients and was based on clinical findings, elevated EBV, and imaging and follow-up results in one patient. On lesion-based analysis, (18) F-FDG PET showed more lesions than conventional CT scan (168 vs. 134), but CT revealed 22 lesions negative on PET. On per patient analysis, PET detected more lesions in 13 patients, CT identified more abnormalities in seven, and both showed the same number of lesions in 14. Adding (18) F-FDG PET to CT scans upstaged the disease in seven patients (20.5%). A combination of (18) F-FDG PET and CT was also useful in guiding biopsy, being positive in 36 of 39 samples (92.3%). These findings indicated that (18) F-FDG PET and CT are complementary at initial staging of pediatric PTLD and that (18) F FDG PET/CT scanning can guide biopsies. PMID- 26515451 TI - Does affective information influence domestic dogs' (Canis lupus familiaris) point-following behavior? AB - Several studies have examined dogs' (Canis lupus familiaris) comprehension and use of human communicative cues. Relatively few studies have, however, examined the effects of human affective behavior (i.e., facial and vocal expressions) on dogs' exploratory and point-following behavior. In two experiments, we examined dogs' frequency of following an adult's pointing gesture in locating a hidden reward or treat when it occurred silently, or when it was paired with a positive or negative facial and vocal affective expression. Like prior studies, the current results demonstrate that dogs reliably follow human pointing cues. Unlike prior studies, the current results also demonstrate that the addition of a positive affective facial and vocal expression, when paired with a pointing gesture, did not reliably increase dogs' frequency of locating a hidden piece of food compared to pointing alone. In addition, and within the negative facial and vocal affect conditions of Experiment 1 and 2, dogs were delayed in their exploration, or approach, toward a baited or sham-baited bowl. However, in Experiment 2, dogs continued to follow an adult's pointing gesture, even when paired with a negative expression, as long as the attention-directing gesture referenced a baited bowl. Together these results suggest that the addition of affective information does not significantly increase or decrease dogs' point following behavior. Rather these results demonstrate that the presence or absence of affective expressions influences a dogs' exploratory behavior and the presence or absence of reward affects whether they will follow an unfamiliar adult's attention-directing gesture. PMID- 26515452 TI - Rural Kentucky High School Students' Exposure to All-Terrain Vehicle Riding and Injuries. AB - From 1982 to 2007, Kentucky had 459 deaths related to all-terrain vehicles (ATVs), fifth highest among US states. By 2012, Kentucky ranked fourth highest, with 578 ATV-related deaths. Following the sentinel event of an ATV-related traumatic brain injury to an unhelmeted high school student, the authors developed a 19-item survey that collected data regarding rural Kentucky high school students' years of ATV driving, second-rider frequency, typical duration of riding events, estimated weekly number of riding events, and frequency of helmet use. Of the 159 students involved, males scored significantly higher on each of these items, except frequency of any ATV driving and frequency of helmet use, which showed no gender differences. Overall, 9.3% of students reported always wearing a helmet when driving and/or riding; 61.2% reported never wearing a helmet; 132 (83.0%) reported that they either drove ATVs or rode as a second rider, and 72 of these (57.1%) reported having had an ATV incident, 33 (45.8%) of which resulted in an injury. Twenty-one of these were serious injuries, including concussions; unconsciousness; fractures to skull, nose, collarbones, arms, ribs, and legs; elbow and hip dislocations; lacerations to head, eyes, arms, legs, and back; and multiple contusions and sprains. Findings have implications for the design of responsibility to protect (R2P) interventions that will reduce exposure and prevent ATV injury and fatality. A method that leverages the relevance of a sentinel event as a community public-health surveillance opportunity is described. Study surveillance data showed higher exposure to ATV hazards than previously reported. PMID- 26515453 TI - Erratum to: Resolving Heterogeneity: Fluorescence-Activated Cell Sorting of Dynamic Cell Populations from Feeder-Free Mouse Embryonic Stem Cell Culture. PMID- 26515454 TI - Highly efficient and color tunable thermally activated delayed fluorescent emitters using a "twin emitter" molecular design. AB - High efficiency and color tuning of thermally activated delayed fluorescent emitters were achieved at the same time by designing emitters with a twin emitter molecular design. The control of the interconnect position between two emitters could manage the emission spectrum of the thermally activated delayed fluorescent emitters without affecting the quantum efficiency. PMID- 26515455 TI - Overexpression of FAB1A-GFP recruits SNX2b on the endosome membrane in snx1-1 mutant in Arabidopsis. AB - Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is one of the phosphoinositides that controls endosomal trafficking events in eukaryotes. PtdIns(3,5)P2 is produced from PI(3)P by phosphatidylinositol 3-phosphate 5-kinase FAB1/PIKfyve. Recently, we reported that FAB1 predominantly localizes on the SNX1-residing late endosomes and a loss-of FAB1 function causes the release of late endosomal effector proteins, ARA7/RABF2b and SORTING NEXIN 1 from the endosome membrane, indicating that FAB1 or its product PtdIns(3,5)P2 mediates the maturation process of the late endosomes. Intriguingly, the ectopic expression of FAB1A could complement the sucrose-dependent seedling growth phenotype of snx1-1 mutant. Here, we demonstrated that the depletion of SNX1 causes the release of SNX2b-mRFP from the endosomal membrane. However, overexpression of FAB1A-GFP reassembles SNX2b-mRFP on the endosomal membrane despite the absence of SNX1. From these results, we proposed that SNX2b homodimer or SNX2a/SNX2b heterodimer might function as functional Sorting Nexin complex instead of SNX1 to attach the endosomal membrane by binding of overproduced PI(3,5)P2 in Arabidopsis. PMID- 26515456 TI - Increasing the Rural Physician Workforce: A Potential Role for Small Rural Medical School Campuses. AB - PURPOSE: To address the issue of physician maldistribution, some medical schools have rural-focused efforts, and many more are in the planning or early implementation stage. The best duration and structure of the rural immersion experience are unclear, and the relative effects of rural upbringing and rural training on subsequent rural practice choice are often difficult to determine. METHODS: To determine the effect of adding a rural clinical campus to our school, we analyzed the variables of rural upbringing, demographics, family medicine residency choice, and campus participation using a multivariate model for association with rural practice choice. We included graduates from the classes of 2001-2008 from both campuses (urban and rural) in the analysis. FINDINGS: We found similar associations to those reported previously of rural upbringing (OR = 2.67 [1.58-4.52]) and family medicine residency (OR = 5.08 [2.88-8.98]) with rural practice choice. Even controlling for these 2 variables, participation in the full 2 years at the rural clinical campus showed the strongest association (OR = 5.46 [2.61-11.42]). All 3 associations were significant at P < .001, and no other variables were significant. CONCLUSIONS: We conclude that the investment of resources in our rural campus may add an increment to rural practice choice beyond the established associations with rural upbringing and family medicine residency. The decision of practice site choice is complex, and collaborative studies that include data from several schools with differently structured rural exposures, including those with rural clinical campuses, are needed. PMID- 26515457 TI - Clinical Characteristics of Patients Responding to Once-Daily Basal Insulin Therapy in Korean Subjects with Type 2 Diabetes. AB - INTRODUCTION: A1chieve(r) (ClinicalTrials.gov identifier NCT00869908) was a 24 week observational study evaluating certain insulin analogs and not insulin analogs in general in 66,726 people with type 2 diabetes (T2D) in routine clinical care in 28 non-Western countries. This study demonstrated that insulin analogs improved self-management and metabolic control in patients with T2D. We investigated the effectiveness and clinical characteristics of patients with T2D showing better response to basal insulin (BI) (detemir), using data from the A1chieve study performed in Korea. METHODS: Subjects were classified into two groups according to the achievement of target glycated hemoglobin (A1c) level of <7.5%. Multivariate logistic regression analysis was performed to determine the variables independently associated with the achievement of target A1c level. RESULTS: Baseline A1c, postprandial glucose (PPG), difference between PPG and fasting plasma glucose, and duration of diabetes were independently associated with better response to BI after adjusting for other risk factors. Compared to patients with BI use at evening, those who took BI in the morning demonstrated a larger reduction in A1c level. CONCLUSION: Once-daily BI therapy appears to be effective in Korean subjects with type 2 diabetes who had a shorter duration of diabetes and a smaller postprandial glucose excursion. FUNDING: Novo Nordisk Pharma Korea and Novo Nordisk International Operations. PMID- 26515458 TI - Changes in calsequestrin, TNF-alpha, TGF-beta and MyoD levels during the progression of skeletal muscle dystrophy in mdx mice: a comparative analysis of the quadriceps, diaphragm and intrinsic laryngeal muscles. AB - In Duchenne muscular dystrophy (DMD), the search for new biomarkers to follow the evolution of the disease is of fundamental importance in the light of the evolving gene and pharmacological therapies. In addition to the lack of dystrophin, secondary events including changes in calcium levels, inflammation and fibrosis greatly contribute to DMD progression and the molecules involved in these events may represent potential biomarkers. In this study, we performed a comparative evaluation of the progression of dystrophy within muscles that are differently affected by dystrophy (diaphragm; DIA and quadriceps; QDR) or spared (intrinsic laryngeal muscles) using the mdx mice model of DMD. We assessed muscle levels of calsequestrin (calcium-related protein), tumour necrosis factor (TNF alpha; pro-inflammatory cytokine), tumour growth factor (TGF-beta; pro-fibrotic factor) and MyoD (muscle proliferation) vs. histopathology at early (1 and 4 months of age) and late (9 months of age) stages of dystrophy. Fibrosis was the primary feature in the DIA of mdx mice (9 months: 32% fibrosis), which was greater than in the QDR (9 months: 0.6% fibrosis). Muscle regeneration was the primary feature in the QDR (9 months: 90% of centrally nucleated fibres areas vs. 33% in the DIA). The QDR expressed higher levels of calsequestrin than the DIA. Laryngeal muscles showed normal levels of TNF-alpha, TGF-beta and MyoD. A positive correlation between histopathology and cytokine levels was observed only in the diaphragm, suggesting that TNF-alpha and TGF-beta serve as markers of dystrophy primarily for the diaphragm. PMID- 26515459 TI - More Than Just Oligomannose: An N-glycomic Comparison of Penicillium Species. AB - N-glycosylation is an essential set of post-translational modifications of proteins; in the case of filamentous fungi, N-glycans are present on a range of secreted and cell wall proteins. In this study, we have compared the glycans released by peptide/N-glycosidase F from proteolysed cell pellets of three Penicillium species (P. dierckxii, P. nordicum and P. verrucosum that all belong to the Eurotiomycetes). Although the major structures are all within the range Hex(5-11)HexNAc(2) as shown by mass spectrometry, variations in reversed-phase chromatograms and MS/MS fragmentation patterns are indicative of differences in the actual structure. Hydrofluoric acid and mannosidase treatments revealed that the oligomannosidic glycans were not only in part modified with phosphoethanolamine residues and outer chain och1-dependent mannosylation, but that bisecting galactofuranose was present in a species-dependent manner. These data are the first to specifically show the modification of N-glycans in fungi with zwitterionic moieties. Furthermore, our results indicate that mere mass spectrometric screening is insufficient to reveal the subtly complex nature of N glycosylation even within a single fungal genus. PMID- 26515460 TI - Effects of curcumin in pediatric epithelial liver tumors: inhibition of tumor growth and alpha-fetoprotein in vitro and in vivo involving the NFkappaB- and the beta-catenin pathways. AB - In children with hepatocellular carcinoma (pHCC) the 5-year overall survival rate is poor. Effects of cytostatic therapies such as cisplatin and doxorubicin are limited due to chemoresistance and tumor relapse. In adult HCC, several antitumor properties are described for the use of curcumin. Curcumin is one of the best investigated phytochemicals in complementary oncology without relevant side effects. Its use is limited by low bioavailability. Little is known about the influence of curcumin on pediatric epithelial hepatic malignancies. We investigated the effects of curcumin in combination with cisplatin on two pediatric epithelial liver tumor cell lines. As mechanisms of action inhibition of NFkappaB, beta-catenin, and decrease of cyclin D were identified. Using a mouse xenograft model we could show a significant decrease of alpha-fetoprotein after combination therapy of oral micellar curcumin and cisplatin. Significant concentrations of curcuminoids were found in blood samples, organ lysates, and tumor tissue after oral micellar curcumin administration. Micellar curcumin in combination with cisplatin can be a promising strategy for treatment of pediatric HCC. PMID- 26515461 TI - BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo. AB - BRCA1 mutation is associated with carcinogenesis, especially of breast tissue. Telomere maintenance is crucial for malignant transformation. Being a part of the DNA repair machinery, BRCA1 may be implicated in telomere biology. We explored the role of BRCA1 in telomere maintenance in lymphocytes of BRCA1/2 mutation carriers and in in vitro system by knocking down its expression in non-malignant breast epithelial cells.The results in both systems were similar. BRCA1/2 mutation caused perturbation of telomere homeostasis, shortening of the single stranded telomere overhang and increased the intercellular telomere length variability as well as the number of telomere free chromosomal ends and telomeric circles. These changes resulted in an increased DNA damage status. Telomerase activity, inducibility and expression remained unchanged. BRCA1 mutation resulted also in changes in the binding of shelterin proteins to telomeres. DNMT-1 levels were markedly reduced both in the carriers and in in vitro system. The methylation pattern of the sub-telomeric regions in carriers suggested hypomethylation in chromosome 10. The expression of a distinct set of genes was also changed, some of which may relate to pre-disposition to malignancy.These results show that BRCA gene products have a role in telomere length homeostasis. It is plausible that these perturbations contribute to malignant transformation in BRCA mutants. PMID- 26515462 TI - Etoposide enhances antitumor efficacy of MDR1-driven oncolytic adenovirus through autoupregulation of the MDR1 promoter activity. AB - Conditionally replicating adenoviruses (CRAds), or oncolytic adenoviruses, such as E1B55K-deleted adenovirus, are attractive anticancer agents. However, the therapeutic efficacy of E1B55K-deleted adenovirus for refractory solid tumors has been limited. Environmental stress conditions may induce nuclear accumulation of YB-1, which occurs in multidrug-resistant and adenovirus-infected cancer cells. Overexpression and nuclear localization of YB-1 are associated with poor prognosis and tumor recurrence in various cancers. Nuclear YB-1 transactivates the multidrug resistance 1 (MDR1) genes through the Y-box. Here, we developed a novel E1B55K-deleted adenovirus driven by the MDR1 promoter, designed Ad5GS3. We tested the feasibility of using YB-1 to transcriptionally regulate Ad5GS3 replication in cancer cells and thereby to enhance antitumor efficacy. We evaluated synergistic antitumor effects of oncolytic virotherapy in combination with chemotherapy. Our results show that adenovirus E1A induced E2F-1 activity to augment YB-1 expression, which shut down host protein synthesis in cancer cells during adenovirus replication. In cancer cells infected with Ad5WS1, an E1B55K deleted adenovirus driven by the E1 promoter, E1A enhanced YB-1 expression, and then further phosphorylated Akt, which, in turn, triggered nuclear translocation of YB-1. Ad5GS3 in combination with chemotherapeutic agents facilitated nuclear localization of YB-1 and, in turn, upregulated the MDR1 promoter activity and enhanced Ad5GS3 replication in cancer cells. Thus, E1A, YB-1, and the MDR1 promoter form a positive feedback loop to promote Ad5GS3 replication in cancer cells, and this regulation can be further augmented when chemotherapeutic agents are added. In the in vivo study, Ad5GS3 in combination with etoposide synergistically suppressed tumor growth and prolonged survival in NOD/SCID mice bearing human lung tumor xenografts. More importantly, Ad5GS3 exerted potent oncolytic activity against clinical advanced lung adenocarcinoma, which was associated with elevated levels of nuclear YB-1 and cytoplasmic MDR1 expression in the advanced tumors. Therefore, Ad5GS3 may have therapeutic potential for cancer treatment, especially in combination with chemotherapy. Because YB-1 is expressed in a broad spectrum of cancers, this oncolytic adenovirus may be broadly applicable. PMID- 26515463 TI - A-803467, a tetrodotoxin-resistant sodium channel blocker, modulates ABCG2 mediated MDR in vitro and in vivo. AB - ATP-binding cassette subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which has been implicated in the development of multidrug resistance (MDR) in cancer, apart from its physiological role to remove toxic substances out of the cells. The diverse range of substrates of ABCG2 includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been reported to be significantly increased in some solid tumors and hematologic malignancies, correlated to poor clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter facilitates resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the effect of a tetrodotoxin-resistant sodium channel blocker, A-803467 on ABCG2 overexpressing drug selected and transfected cell lines. We found that at non toxic concentrations, A-803467 could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies demonstrated that A-803467 (7.5 MUM) significantly increased the intracellular accumulation of [(3)H] mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression levels. In addition, A-803467 stimulated the ATPase activity in membranes overexpressed with ABCG2. In a murine model system, combination treatment of A-803467 (35 mg/kg) and topotecan (3 mg/kg) significantly inhibited the tumor growth in mice xenografted with ABCG2-overexpressing cancer cells. Our findings indicate that a combination of A-803467 and ABCG2 substrates may potentially be a novel therapeutic treatment in ABCG2-positive drug resistant cancers. PMID- 26515466 TI - Palliative care in dementia: Does it work? PMID- 26515465 TI - Gut mucosal microbiome across stages of colorectal carcinogenesis. AB - Gut microbial dysbiosis contributes to the development of colorectal cancer (CRC). Here we catalogue the microbial communities in human gut mucosae at different stages of colorectal tumorigenesis. We analyse the gut mucosal microbiome of 47 paired samples of adenoma and adenoma-adjacent mucosae, 52 paired samples of carcinoma and carcinoma-adjacent mucosae and 61 healthy controls. Probabilistic partitioning of relative abundance profiles reveals that a metacommunity predominated by members of the oral microbiome is primarily associated with CRC. Analysis of paired samples shows differences in community configurations between lesions and the adjacent mucosae. Correlations of bacterial taxa indicate early signs of dysbiosis in adenoma, and co-exclusive relationships are subsequently more common in cancer. We validate these alterations in CRC-associated microbiome by comparison with two previously published data sets. Our results suggest that a taxonomically defined microbial consortium is implicated in the development of CRC. PMID- 26515464 TI - In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer. AB - EGFR mutated lung cancer accounts for a significant subgroup of non-small-cell lung cancer (NSCLC). Over the last decade, multiple EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed to target mutated EGFR. However, there is little information regarding mutation specific potency of EGFR-TKIs against various types of EGFR mutations. The purpose of this study is to establish an in vitro model to determine the "therapeutic window" of EGFR-TKIs against various types of EGFR mutations, including EGFR exon 20 insertion mutations. The potency of 1st (erlotinib), 2nd (afatinib) and 3rd (osimertinib and rociletinib) generation EGFR-TKIs was compared in vitro for human lung cancer cell lines and Ba/F3 cells, which exogenously express mutated or wild type EGFR. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR. The in vitro model identified a wide therapeutic window of afatinib for exon 19 deletions and L858R and of osimertinib and rociletinib for T790M positive mutations. The results obtained with our models matched well with previously reported preclinical and clinical data. Interestingly, for EGFR exon 20 insertion mutations, most of which are known to be resistant to 1st and 2nd generation EGFR-TKIS, osimertinib was potent and presented a wide therapeutic window. To our knowledge, this is the first report that has identified the therapeutic window of osimertinib for EGFR exon 20 insertion mutations. In conclusion, this model will provide a preclinical rationale for proper selection of EGFR-TKIs against clinically-relevant EGFR mutations. PMID- 26515467 TI - Obesity, Physical Activity and Sedentary Behaviors in Children with an Autism Spectrum Disorder. AB - BACKGROUND AND OBJECTIVES: Previous literature using small sample sizes and limited geographic areas report that overweight/obesity and physical inactivity occur at higher rates among children with autism spectrum disorder (ASD) compared to typically developing peers. The purpose of this study was to examine obesity, overweight, physical activity, and sedentary behavior among children and youth with and without ASD using nationally representative data and controlling for secondary conditions, including intellectual and learning disabilities, ADHD, developmental delay, and other mental, physical, and medical conditions, as well as medication use. METHODS: Data were collected from the 2011-2012 National Survey of Children's Health, a cross-sectional survey of 65,680 (weighted N = 49,586,134) children aged 6-17 (1385 with ASD, weighted N = 986,352). Logistic regression was used to estimate odds ratios, adjusting for demographics and possible secondary conditions. RESULTS: Having a diagnosis of ASD was associated with higher odds of obesity (OR 1.76, CI 1.27-2.43; p = <0.001). However, after additional adjustment for possible secondary conditions, ASD diagnosis was no longer associated with obesity. Those with moderate ASD (OR 0.58, CI 0.36-0.93; p = <0.05) reported lower odds of sedentary behavior, but this association failed to achieve significance after adjustment for secondary conditions and medication use. No significant associations between ASD and overweight or physical activity were found. CONCLUSIONS: These findings suggest that ASD diagnosis is not significantly associated with obesity status after adjustment for possible secondary conditions and medication use. Decision makers, clinicians, and researchers developing interventions for children with ASDs should consider how secondary conditions may impact obesity and related activities. PMID- 26515468 TI - Predictive Models for Characterizing Disparities in Exclusive Breastfeeding Performance in a Multi-ethnic Population in the US. AB - OBJECTIVES: Maternal lactation performance varies across populations, yet the relative impact of maternal sociodemographics, perinatal factors, and birth outcomes on disparities in exclusive breastfeeding (XBR) outcomes is not well known. We aimed to develop predictive models and compare the relative contribution of predictors for XBR initiation and XBR >= 6 months. METHODS: Infant feeding data were obtained from women with children aged 0-6 years (n = 1471) in a multi-ethnic cross-sectional study in the US (2011-2012). We compared discriminant ability of predictors for ever XBR and XBR >= 6 months using discriminant function analysis, respectively. We also calculated adjusted ORs for factors associated with XBR outcomes and breast-bottle feeding (BrBot) subgroups. RESULTS: Maternal sociodemographics (education level, marital status, nativity, and age at childbirth) had greater discriminating abilities in predicting ever XBR and XBR >= 6 months than birth outcomes and perinatal factors. Foreign-born women were two-fold more likely to initiate XBR but not necessarily continue to 6 months compared to their US-born counterparts. Factors associated with BrBot subgroups differed from those associated with XBR outcomes, whereas maternal age was the only predictor consistently associated with ever XBR, XBR >= 6 months, and BrBot subgroups. The areas under the receiver operating characteristic curves for models predicting ever XBR and XBR >= 6 months were 0.88 (95 % CI 0.85, 0.91) and 0.90 (95 % CI 0.88, 0.93), respectively. CONCLUSIONS: Findings underscore the importance of educational, clinical, and social support to promote XBR in mothers with sociodemographic factors predictive of none or poor XBR outcomes. PMID- 26515469 TI - The Impact of Prior Poor Birth Outcomes on Smoking Behavior on Subsequent Pregnancies: Analysis of the National PRAMS Data. AB - OBJECTIVES: The link between cigarette smoking and poor birth outcomes has been well established. However, there is paucity of research investigating the effect of previous history of poor birth outcomes on smoking behavior during subsequent pregnancies. The present study seeks to determine whether a previous preterm or low birth weight delivery impacts maternal smoking during the subsequent pregnancy. METHODS: Data from the National Pregnancy Risk Assessment Monitoring System (PRAMS) was analyzed. Multiparous women who currently had singleton birth were included in the analysis (N = 137,297). Previous poor birth outcome and smoking were defined based on the PRAMS question that asked women whether their immediate previous baby was born preterm or low birth weight and if they smoked during the index pregnancy. RESULTS: Approximately 16.3 % of the women who reported previous poor birth outcome also reported smoking during the subsequent pregnancy. Multiple logistic regression analysis revealed that women who had previous poor birth outcome had 22 % higher odds of smoking during the subsequent pregnancy. Similarly, the odds of smoking during pregnancy were 30 and 13 % higher among women who had previous low birth weight and preterm birth, respectively. CONCLUSIONS: Women who experienced previous preterm or low birth weight baby had higher prevalence of smoking during the subsequent pregnancy. The occurrence of a preterm/low birth weight may present a critical intervention point for providers to educate women on the risks of repeated poor birth outcomes and provide intervention programs to address high-risk behaviors. PMID- 26515470 TI - Low-Level Symptoms of Depression in Mothers of Young Children are Associated with Behavior Problems in Middle Childhood. AB - OBJECTIVES: Examine the association between mothers' low- and high-level depressive symptoms in early childhood and children's behavior problems in middle childhood. METHODS: We used data from 1844 families in a multi-site, longitudinal study beginning when children were 14 months and continuing to age 11 years. Children's internalizing and externalizing behavior problems at age 11 were assessed using the child behavior checklist for ages 6-18. Mothers' scores on the Center for Epidemiological Studies-Depression Scale when children were 14 months were used to classify them into three groups: 'no depressive symptoms', 'low level depressive symptoms (below the clinical cut-off)' and 'clinically significant depressive symptoms (above the clinical cut-off).' RESULTS: Mothers were racially/ethnically diverse, including Caucasian (38.9 %), African-American (34.4 %), Hispanic (21.6 %), or other (5.1 %). More than one-third (39.2 %) were teenaged mothers, and 46.0 % did not complete high school. Of the 1844 families, 1172 had age 11 child outcome data. Logistic regression analyses controlling for family demographics revealed a significant association between early maternal depressive symptoms and later child behavioral outcomes. Both low level and clinically significant symptoms were associated with internalizing and externalizing behavior problems. For example, children whose mothers had low level depressive symptoms were twice as likely to have clinically elevated internalizing problems compared with children whose mothers never had symptoms of depression. CONCLUSIONS: Children whose mothers experience low-level depressive symptoms early in their development have increased risk for later behavioral problems, suggesting a possible need for new screening and intervention strategies for mothers with lower than clinically elevated symptoms. PMID- 26515471 TI - Obese Mothers have Lower Odds of Experiencing Pro-breastfeeding Hospital Practices than Mothers of Normal Weight: CDC Pregnancy Risk Assessment Monitoring System (PRAMS), 2004-2008. AB - OBJECTIVES: This study examines the extent to which a mother's pre-pregnancy body mass index (BMI) category is associated with her exposure to pro-breastfeeding hospital practices. METHODS: Data from the 2004-2008 CDC PRAMS were analyzed for three states (Illinois, Maine, and Vermont) that had administered an optional survey question about hospital pro-breastfeeding practices. RESULTS: Of 19,145 mothers surveyed, 19 % were obese (pre-pregnancy BMI >= 30). Obese mothers had lower odds than mothers of normal weight of initiating breastfeeding [70 vs. 79 % (unweighted), p < 0.0001]. Compared with women of normal weight, obese mothers had lower odds of being exposed to pro-breastfeeding hospital practices during the birth hospitalization. Specifically, obese mothers had higher odds of using a pacifier in the hospital [odds ratio (OR) 1.31, 95 % confidence interval (CI) (1.17-1.48), p < 0.0001] and lower odds of: a staff member providing them with information about breastfeeding [OR 0.71, 95 % CI (0.57-0.89), p = 0.002], a staff member helping them breastfeed [OR 0.69, 95 % CI (0.61-0.78), p < 0.0001], breastfeeding in the first hour after delivery [OR 0.55, 95 % CI (0.49-0.62), p < 0.0001], being given a telephone number for breastfeeding help [OR 0.65, 95 % CI (0.57-0.74), p < 0.0001], rooming in [OR 0.84, 95 % CI (0.73-0.97), p = 0.02], and being instructed to breastfeed on demand [OR 0.66, 95 % CI (0.58-0.75), p < 0.0001]. Adjusting for multiple covariates, all associations except rooming in remained significant. CONCLUSIONS: Obesity stigma may be a determinant of breastfeeding outcomes for obese mothers. Breastfeeding support should be improved for this at-risk population. PMID- 26515472 TI - Prepregnancy Obesity and Birth Outcomes. AB - OBJECTIVE: To investigate the association between prepregnancy obesity and birth outcomes using fixed effect models comparing siblings from the same mother. METHODS: A total of 7496 births to 3990 mothers from the National Longitudinal Survey of Youth 1979 survey are examined. Outcomes include macrosomia, gestational length, incidence of low birthweight, preterm birth, large and small for gestational age (LGA, SGA), c-section, infant doctor visits, mother's and infant's days in hospital post-partum, whether the mother breastfed, and duration of breastfeeding. Association of outcomes with maternal pre-pregnancy obesity was examined using Ordinary Least Squares (OLS) regression to compare across mothers and fixed effects to compare within families. RESULTS: In fixed effect models we find no statistically significant association between most outcomes and prepregnancy obesity with the exception of LGA, SGA, low birth weight, and preterm birth. We find that prepregnancy obesity is associated with a with lower risk of low birthweight, SGA, and preterm birth but controlling for prepregnancy obesity, increases in GWG lead to increased risk of LGA. CONCLUSIONS: Contrary to previous studies, which have found that maternal obesity increases the risk of c section, macrosomia, and LGA, while decreasing the probability of breastfeeding, our sibling comparison models reveal no such association. In fact, our results suggest a protective effect of obesity in that women who are obese prepregnancy have longer gestation lengths, and are less likely to give birth to a preterm or low birthweight infant. PMID- 26515473 TI - Particles in the oceans: Implication for a safe marine environment. AB - Strategies and technologies for the ecosafety assessment and design of engineered particles entering the marine environment are urgently needed. As the application of nanoparticles in science and technology grows, the need to understand their impact on the marine environment becomes increasingly important. This Editorial introduces a Special Issue on the topic of a sustainable and safety use of nanoparticles for protecting, recovering and supporting the oceans' environment and consequently human health. The issue focus on the impact of micro/nano plastics and metallic nanoparticles on marine organisms, as well as some methodological aspects associated to the eco/toxicity and analytical approaches for in deep physico-chemical characterization of nanoparticles in marine waters and sediment media. Important and urgent topics are addressed in the field of nano-ecosafety in order to assess more precisely both exposure routes and environmental hazards of nanoparticles in the ocean. Ecotoxicological and toxicological data, obtained using a wide variety of organisms representative of different trophic levels and biological organization, from whole animals to macromolecules, will be useful for a better definition of cleaner and safer nanoparticles. Efforts in developing a broad understanding of target species, expected results, benchmarks and timelines, will be of primary importance. PMID- 26515474 TI - The persisting burden of psychiatric disorder. PMID- 26515475 TI - In memoriam: Cyril B. Frank, MD (1949-2015). PMID- 26515476 TI - In memoriam: Victor M. Goldberg, MD (1939-2015). PMID- 26515478 TI - Autologous and allogeneic hematopoietic stem cell transplantation in follicular lymphoma. AB - INTRODUCTION: High-dose chemotherapy and autologous stem cell transplantation (ASCT) improve survival in follicular lymphoma; however, relapse remains the most common cause of death. The lower risk of relapse with allogeneic SCT (alloSCT) is offset by a high transplant-related mortality (TRM). AREAS COVERED: English articles indexed in the MEDLINE database were reviewed to discuss the role of graft purging, rituximab maintenance after ASCT, reduced-intensity conditioning (RIC) alloSCT, T-cell depletion, donor lymphocyte infusion (DLI) and alternate donor sources. EXPERT OPINION: Optimal salvage consolidation strategy may utilize ASCT following non-total body irradiation-based conditioning regimen in second remission. Rituximab maintenance after ASCT may improve molecular remission but is not yet shown to improve overall survival. RIC alloSCT permits its use in older and less-fit patients. Studies with T-cell depleted graft failed to reduce TRM despite a decline in graft-versus-host disease; however, these studies did demonstrate a therapeutic role of DLI in post-transplant relapses. In recent years, haploidentical and umbilical cord blood donors have emerged as alternative donor sources, with outcomes comparable to matched unrelated donor SCT. In the future, incorporation of novel therapeutic agents, improved risk-adapted treatment strategies, and advancement of transplant techniques may provide a better chance of survival. PMID- 26515479 TI - Activation of C?H Bonds through Oxidant-Free Photoredox Catalysis: Cross-Coupling Hydrogen-Evolution Transformation of Isochromans and beta-Keto Esters. AB - The direct and controlled activation of a C(sp(3) )?H bond adjacent to an O atom is of particular synthetic value for the conventional derivatization of ethers or alcohols. In general, stoichiometric amounts of an oxidant are required to remove an electron and a hydrogen atom of the ether for subsequent transformations. Herein, we demonstrate that the activation of a C?H bond next to an O atom could be achieved under oxidant-free conditions through photoredox-neutral catalysis. By using a commercial dyad photosensitizer (Acr(+) -Mes ClO4 (-) , 9-mesityl-10 methylacridinium perchlorate) and an easily available cobaloxime complex (Co(dmgBF2 )2 ?2 MeCN, dmg=dimethylglyoxime), the nucleophilic addition of beta keto esters to oxonium species, which is rarely observed in photocatalysis, leads to the corresponding coupling products and H2 in moderate to good yields under visible-light irradiation. Mechanistic studies suggest that both isochroman and the cobaloxime complex quench the electron-transfer state of this dyad photosensitizer and that benzylic C?H bond cleavage is probably the rate determining step of this cross-coupling hydrogen-evolution transformation. PMID- 26515480 TI - Response to the Letter to the Editor "the bioenergetics of hepatic mitochondria isolated from avocado oil-treated rats". PMID- 26515481 TI - Letter to the Editor: The bioenergetics of hepatic mitochondria isolated from avocado oil-treated rats: typical experimental errors in the study of the bioenergetics of isolated mitochondria. PMID- 26515483 TI - Reply: To PMID 26116807. PMID- 26515482 TI - Robust and efficient parameter estimation in dynamic models of biological systems. AB - BACKGROUND: Dynamic modelling provides a systematic framework to understand function in biological systems. Parameter estimation in nonlinear dynamic models remains a very challenging inverse problem due to its nonconvexity and ill conditioning. Associated issues like overfitting and local solutions are usually not properly addressed in the systems biology literature despite their importance. Here we present a method for robust and efficient parameter estimation which uses two main strategies to surmount the aforementioned difficulties: (i) efficient global optimization to deal with nonconvexity, and (ii) proper regularization methods to handle ill-conditioning. In the case of regularization, we present a detailed critical comparison of methods and guidelines for properly tuning them. Further, we show how regularized estimations ensure the best trade-offs between bias and variance, reducing overfitting, and allowing the incorporation of prior knowledge in a systematic way. RESULTS: We illustrate the performance of the presented method with seven case studies of different nature and increasing complexity, considering several scenarios of data availability, measurement noise and prior knowledge. We show how our method ensures improved estimations with faster and more stable convergence. We also show how the calibrated models are more generalizable. Finally, we give a set of simple guidelines to apply this strategy to a wide variety of calibration problems. CONCLUSIONS: Here we provide a parameter estimation strategy which combines efficient global optimization with a regularization scheme. This method is able to calibrate dynamic models in an efficient and robust way, effectively fighting overfitting and allowing the incorporation of prior information. PMID- 26515484 TI - Ask Before Shooting. PMID- 26515485 TI - Fecal Infliximab Loss. PMID- 26515486 TI - An Unusual Cause of Acute Abdominal Pain. PMID- 26515487 TI - Practical Teaching Cases for GI Trainees: A Wealth of Educational Data. PMID- 26515488 TI - Reply: To PMID 25865049. PMID- 26515489 TI - A Child With a Pancreatic Mass. PMID- 26515490 TI - Low Carbohydrate Rather Than Low Fat Is More Important in Dietary Management of Nonalcoholic Steatohepatitis. PMID- 26515491 TI - Reply: To PMID 25917786. PMID- 26515492 TI - Individual response technology to promote active learning within the caring sciences: An experimental research study. AB - BACKGROUND: One major challenge in delivering lectures to large and diverse classes is the maintenance of a high standard of lecturing in order to engage students and increase their participation and involvement. The lecturer's assignment is to arrange and prepare the lecture before teaching, hence enabling students' enhanced learning. Individual response technology could encourage students' active learning and activate higher cognitive levels. OBJECTIVES: The aim of this study was to evaluate individual response technology as a complement during lectures for students in higher education, in terms of the students' experiences of participation, engagement, and active learning. Also of interest was whether this technology can be considered a supportive technical system. DESIGN: Data were collected through a questionnaire where levels of each condition were reported on a numeric rating scale (0-10) at baseline and after the introduction of individual response technology. To get a broader perspective, two types of lectures (pediatric and statistical) were included, giving a total of four assessment times. PARTICIPANTS: The participants comprised 59 students in Bachelor of Nursing program at a Swedish metropolitan university. RESULTS: Overall, when individual response technology was used, students reported increased experience of engagement (n=82, mean 6.1 vs. n=65, mean 7.3, p<0.001), participation (n=92, mean 6.1 vs. n=79, mean 7.7, p<0.001), and active learning (n=92, mean 7.3 vs. n=79, mean 8.2 p<0.001). Additionally, the students experienced this technology as a supportive technical system during lectures (mean 6.6 vs. mean 8.1, p<0.001). CONCLUSIONS: The use of individual response technology during teaching is one way to enhance students' experiences of engagement, participation, and learning within the caring sciences. PMID- 26515493 TI - Rare genetic disease in China: a call to improve clinical services. PMID- 26515494 TI - A Novel Bioavailable BH3 Mimetic Efficiently Inhibits Colon Cancer via Cascade Effects of Mitochondria. AB - PURPOSE: Gossypol and its analogs, through their ability to bind to and inactivate BH3 domain-containing antiapoptotic proteins, have been shown to inhibit the growth of various human cancer cells in culture and xenograft models. Here, we evaluated the antitumor efficacy of a novel gossypol derivative and BH3 mimetic ch282-5 (2-aminoethanesulfonic acid sodium-gossypolone) in colon cancer models. Several innovative combination strategies were also explored and elaborated. EXPERIMENTAL DESIGN: Ch282-5 was synthesized by modifying the active aldehyde groups and R groups of gossypol according to a computer-aided drug design program. The stability of ch282-5 was examined by high-performance liquid chromatography, and cytotoxic effects of ch282-5 on colon cancer cells were assessed by MTS assay. Activation of mitochondrial apoptotic pathway by ch282-5 was evidenced with a series of molecular biology techniques. In vivo antitumor activity of ch282-5 and its combination with chloroquine, rapamycin, oxaliplatin, and ABT-263 was also evaluated in colon cancer xenograft models and experimental liver metastasis models. RESULTS: Ch282-5 showed antiproliferative and pro-cell death activity against colon cancer cells both in vitro and in vivo, and the response to the drug correlated with inhibition of antiapoptotic Bcl-2 proteins, induction of mitochondria-dependent apoptotic pathway, and disruption of mitophagy and mTOR pathway. Ch282-5 also suppressed liver metastasis produced by intrasplenic injection of colon cancer cells. Furthermore, ch282-5 could potentiate the effectiveness of oxaliplatin and rescue ABT-263 efficacy by downregulation of Mcl-1 and elevation of platelet number. CONCLUSIONS: These findings provide a rational basis for clinical investigation of this highly promising BH3 mimetic in colon cancer. PMID- 26515495 TI - Cancer Neoantigens and Applications for Immunotherapy. AB - Recent advances in immune checkpoint blockade therapy have revolutionized the treatment of cancer. Tumor-specific antigens that are generated by somatic mutation, neoantigens, can influence patient response to immunotherapy and contribute to tumor shrinkage. Recent evidence demonstrating the success of checkpoint blockade immunotherapy in boosting T-cell reactivity against patient specific neoantigens constitutes a strong rationale for the development of personalized vaccines against these nonself peptides. With the decreasing cost of next-generation sequencing, peptide manufacturing, and improvement of in silico prediction of peptide immunogenicity, it is increasingly important to evaluate the potential use of neoantigens in both diagnosis and treatment. Specifically, these neoantigens could be useful both as predictors of immune checkpoint blockade therapy response and/or incorporated in therapeutic vaccination strategies. PMID- 26515497 TI - Abnormal DNA methylation in the lumbar spinal cord following chronic constriction injury in rats. AB - Pathogenesis of neuropathic pain is complex and not clearly understood. Glutamate decarboxylase 67 (GAD 67) is a key synthetic enzyme for the main inhibitory transmitter gamma-aminobutyric acid (GABA), and diminishes in the spinal dorsal horn in rats following chronic constriction injury (CCI). GAD 67 is coded by gene GAD 1. DNA methylation can regulate the expression of GAD 67 by regulating the methylation of GAD 1 promoter in the psychotic brain. DNA methylation is primarily mediated by DNA methyltransferases (DNMTs) and methyl-DNA binding domain proteins (MBDs). In this study, in order to discover whether DNA methylation regulates GAD 67 expression in the spinal cord in CCI rats and is involved in neuropathic pain, we examined mRNA levels of DNMTs, MBDs and GAD 67 with real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), and methylation of GAD 1 promoter with Pyromark CpG Assays in the lumbar spinal cord in CCI rats on day 14 after surgery. Our results showed that DNMT3a, DNMT3b and methyl-CpG binding protein 2 (MeCP2) expression increased, MBD2 expression decreased, and DNMT1, MBD1 and MBD3 expression hardly changed in the lumbar spinal cord in CCI rats on day 14 after surgery. GAD 67 expression decreased, and methylation of GAD 1 promoter increased in the lumbar spinal cord in CCI rats on day 14 after surgery. These results indicate that decreased GAD 67 may be associated with increased GAD 1 promoter methylation, which may be mediated by DNMT3a, DNMT3b, MeCP2 and MBD2 in CCI rats. These indicate that abnormal DNA methylation may be highly involved in CCI-induced neuropathic pain. PMID- 26515498 TI - Effects of captopril, telmisartan and bardoxolone methyl (CDDO-Me) in ischemia reperfusion-induced acute kidney injury in rats: an experimental comparative study. AB - Renal ischemia-reperfusion (IR) injury is one of the most common causes of acute kidney injury. This study investigated the effects of captopril (CAP), telmisartan (TEL) and bardoxolone methyl (BM) in animals with renal IR injury. Adult male Wistar-Albino rats were divided into six groups: control, vehicle, IR, IR with CAP, IR with TEL and IR with BM. Before IR was induced, drugs were administered by oral gavage. After a 60-min ischemia and a 120-min reperfusion period, bilateral nephrectomies were performed. Serum urea, creatinine, neutrophil gelatinase-associated lipocalin (NGAL) levels, tissue total oxidant status (TOS), total antioxidant status (TAS), total thiol (TT), asymmetric dimethylarginine (ADMA) levels, superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-Px) activity were measured. Tissue mRNA expression levels of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB) were analyzed. In addition, renal tissues were evaluated histopathologically and immunohistochemically. All tested drugs reduced renal damage, apoptosis, urea, creatinine, NGAL, TOS, nitric oxide (NO) and ADMA levels, NF-kappaB, inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1) expressions (P < 0.001). All tested drugs increased SOD activity, GSH-Px activity, TAS levels, TT levels, endothelial nitric oxide synthase (eNOS) expression, dimethylarginine dimethylaminohydrolases (DDAHs) expression, Nrf2 expression and PPAR-gamma expression (P < 0.001, P < 0.003). These results suggest that CAP, TEL and BM pretreatment could reduce renal IR injury via anti-inflammatory, antioxidant and anti-apoptotic effects. PMID- 26515496 TI - RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors. AB - PURPOSE: Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking. EXPERIMENTAL DESIGN: We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1-targeted immunotherapy in mouse models of breast cancer. RESULTS: Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras-MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer. CONCLUSIONS: These data suggest the possibility that Ras-MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1-targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. PMID- 26515500 TI - Practical applications for natural language processing in clinical research: The 2014 i2b2/UTHealth shared tasks. PMID- 26515499 TI - The Akt-mTOR axis is a pivotal regulator of eccentric hypertrophy during volume overload. AB - The heart has two major modalities of hypertrophy in response to hemodynamic loads: concentric and eccentric hypertrophy caused by pressure and volume overload (VO), respectively. However, the molecular mechanism of eccentric hypertrophy remains poorly understood. Here we demonstrate that the Akt-mammalian target of rapamycin (mTOR) axis is a pivotal regulator of eccentric hypertrophy during VO. While mTOR in the heart was activated in a left ventricular end diastolic pressure (LVEDP)-dependent manner, mTOR inhibition suppressed eccentric hypertrophy and induced cardiac atrophy even under VO. Notably, Akt was ubiquitinated and phosphorylated in response to VO, and blocking the recruitment of Akt to the membrane completely abolished mTOR activation. Various growth factors were upregulated during VO, suggesting that these might be involved in Akt-mTOR activation. Furthermore, the rate of eccentric hypertrophy progression was proportional to mTOR activity, which allowed accurate estimation of eccentric hypertrophy by time-integration of mTOR activity. These results suggested that the Akt-mTOR axis plays a pivotal role in eccentric hypertrophy, and mTOR activity quantitatively determines the rate of eccentric hypertrophy progression. As eccentric hypertrophy is an inherent system of the heart for regulating cardiac output and LVEDP, our findings provide a new mechanistic insight into the adaptive mechanism of the heart. PMID- 26515501 TI - Semantic processing of EHR data for clinical research. AB - There is a growing need to semantically process and integrate clinical data from different sources for clinical research. This paper presents an approach to integrate EHRs from heterogeneous resources and generate integrated data in different data formats or semantics to support various clinical research applications. The proposed approach builds semantic data virtualization layers on top of data sources, which generate data in the requested semantics or formats on demand. This approach avoids upfront dumping to and synchronizing of the data with various representations. Data from different EHR systems are first mapped to RDF data with source semantics, and then converted to representations with harmonized domain semantics where domain ontologies and terminologies are used to improve reusability. It is also possible to further convert data to application semantics and store the converted results in clinical research databases, e.g. i2b2, OMOP, to support different clinical research settings. Semantic conversions between different representations are explicitly expressed using N3 rules and executed by an N3 Reasoner (EYE), which can also generate proofs of the conversion processes. The solution presented in this paper has been applied to real-world applications that process large scale EHR data. PMID- 26515502 TI - Extracellular biosynthesis of anti-Candida silver nanoparticles using Monascus purpureus. AB - An eco-friendly process for the silver nanoparticles (Ag-NPs) biosynthesis was investigated using the fungus Monascus purpureus as a safe and commercially used microorganism. M. purpureus growth filtrate was used for the reduction of the aqueous silver nitrate into Ag-NPs with almost 100% size range of 1-7 nm, which was considered as one of the smallest microbial biosynthesized Ag-NPs. The biosynthesized Ag-NPs were structurally characterized using UV, FTIR, DLS, TEM, and XRD. The biosynthesized Ag-NPs were stable after 3 months with no alteration in shape or size. M. purpureus showed no nitrate reductase activity, whereas its pigments reducing power was decreased after nanoparticles formation indicating its role in the Ag-NPs biosynthesis. The synthesized Ag-NPs exhibited strong antimicrobial activity against different bacteria and yeasts species. The anti Candida activity of M. purpureus culture filtrate was enhanced in the presence of Ag-NPs; the maximum increase in microbial inhibition was observed against Candida albicans with 1.73 increased folds of inhibition zones, followed by their activity against C. tropicalis and C. glabrata with 0.919- and 0.694-folds of increase, respectively. The obtained results suggest that the biosynthesized Ag NPs offers a promising cost-effective, eco-friendly, and an alternative way to the conventional method of synthesis that could have wide applications in medicine. PMID- 26515503 TI - Facile Synthesis of Defective TiO2-x Nanocrystals with High Surface Area and Tailoring Bandgap for Visible-light Photocatalysis. AB - A facile hydrothermal approach has been developed to prepare defective TiO2-x nanocrystals using Ti(III)-salt as a precursor and L-ascorbic acid as reductant and structure direction agent. The prepared TiO2-x nanocrystals are composed of a highly crystallized TiO2 core and a disordered TiO2-x outer layer, possessing high surface area, controlled oxygen vacancy concentration and tunable bandgap via simply adjusting the amount of added L-ascorbic acid. The defective TiO2-x shows high photocatalytic efficiency in methylene blue and phenol degradation as well as in hydrogen evolution under visible light, underlining the significance of the present strategy for structural and bandgap manipulation in TiO2-based photocatalysis. PMID- 26515504 TI - Cancer outcomes will not improve without more funding, say GPs. PMID- 26515505 TI - Multishock Compression Properties of Warm Dense Argon. AB - Warm dense argon was generated by a shock reverberation technique. The diagnostics of warm dense argon were performed by a multichannel optical pyrometer and a velocity interferometer system. The equations of state in the pressure-density range of 20-150 GPa and 1.9-5.3 g/cm(3) from the first- to fourth-shock compression were presented. The single-shock temperatures in the range of 17.2-23.4 kK were obtained from the spectral radiance. Experimental results indicates that multiple shock-compression ratio (etai = rhoi/rho0) is greatly enhanced from 3.3 to 8.8, where rho0 is the initial density of argon and rhoi (i = 1, 2, 3, 4) is the compressed density from first to fourth shock, respectively. For the relative compression ratio (etai' = rhoi/rhoi-1), an interesting finding is that a turning point occurs at the second shocked states under the conditions of different experiments, and etai' increases with pressure in lower density regime and reversely decreases with pressure in higher density regime. The evolution of the compression ratio is controlled by the excitation of internal degrees of freedom, which increase the compression, and by the interaction effects between particles that reduce it. A temperature-density plot shows that current multishock compression states of argon have distributed into warm dense regime. PMID- 26515506 TI - Hemophilia B acquired through liver transplantation. PMID- 26515508 TI - Ultrastructure of bovine sperm chromatin. AB - Mammalian semen chromatin comprises DNA, protamine, and, at lower levels, other proteins. This constitution confers intense compaction to the chromatin, helping to protect the DNA and causing the head of the sperm to be very small, facilitating the safe transport of its genetic contents. It is known that changes in the sperm chromatin compaction lead to fertility problems in bulls, justifying studies of this structure. Although there are theoretical models of sperm chromatin because of its high compaction, there is no morphological evidence of such models. The aim of this study was to demonstrate the ultrastructure of bovine sperm chromatin in an attempt to corroborate the theoretical chromatin models existing today. The isolated bull sperm heads had their chromatin partially unpacked by chemical treatment using sodium dodecyl sulfate (SDS) and dithiothreitol (DTT) and were then embedded in Epon resin. Using an ultramicrotome, ultrathin sections were obtained, which were contrasted with uranyl acetate and lead citrate, and then viewed under transmission electron microscopy. The methodology used allowed the visualization of toroidal structures interconnected by a filamentous nuclear matrix, which is entirely consistent with the most current theoretical models. PMID- 26515507 TI - Identification of a novel 11beta-HSD1 inhibitor from a high-throughput screen of natural product extracts. AB - Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) have considerable potential as a treatment for metabolic syndrome including type 2 diabetes mellitus and obesity. To identify 11beta-HSD1 inhibitors, we conducted high-throughput screening (HTS) of active natural product extracts from the Korea Chemical Bank, including Tanshinone I, Tanshinone IIA, and flavanone derivatives, and 2- and 3-phenyl-4H-chromen-4-one. Then Tanshinone IIA and its derivatives were targeted for the development of a lead compound according to the HTS results. However, the mechanism for anti-adipogenic effect through 11beta-HSD1 enzyme inhibition by Tanshinone IIA is not clear. Tanshinone IIA (2a) concentration-dependently inhibited 11beta-HSD1 activity in human and mouse 11beta-HSD1 overexpressed cells and 3T3-L1 adipocytes. Tanshinone IIA (2a) also inhibited 11beta-HSD1 enzyme activities in murine liver and fats. Furthermore, Tanshinone IIA (2a)-suppressed adipocyte differentiation of cortisone-induced adipogenesis in 3T3-L1 cells was associated with the suppression of the cortisone induced adipogenesis-specific markers mRNA and protein expression. In 3T3-L1 preadipocytes, Tanshinone IIA (2a)-inhibited cortisone induced reactive oxygen species formation in a concentration-dependent manner. Thus, these results support the therapeutic potential of Tanshinone IIA (2a) as a 11beta-HSD1 inhibitor in metabolic syndrome patients. PMID- 26515509 TI - Bacterial munch for infants: potential pediatric therapeutic interventions of probiotics. AB - Probiotics are viable microorganisms with the capacity to alter the gastrointestinal microbiota of the host. The recent scientific advancements and development of probiotic formulations have rekindled the importance of these clinical interpretations, underlining the starring role of the gut flora in host metabolism, defense and immune regulation. Despite encouraging preliminary results from randomized clinical trials of probiotics for various clinical conditions including irritable bowel syndrome, necrotizing enterocolitis, gastroenteritis, antibiotic-associated diarrhea, infantile colic, and improvement of digestion and immune function, further evidence is needed to determine the reproducibility of the findings and elucidate the underlying mechanisms. In this review, we have considered the postnatal development of gut flora and appraised the role of probiotics in health and disease condition among infants. PMID- 26515510 TI - Regression models for analyzing radiological visual grading studies--an empirical comparison. AB - BACKGROUND: For optimizing and evaluating image quality in medical imaging, one can use visual grading experiments, where observers rate some aspect of image quality on an ordinal scale. To analyze the grading data, several regression methods are available, and this study aimed at empirically comparing such techniques, in particular when including random effects in the models, which is appropriate for observers and patients. METHODS: Data were taken from a previous study where 6 observers graded or ranked in 40 patients the image quality of four imaging protocols, differing in radiation dose and image reconstruction method. The models tested included linear regression, the proportional odds model for ordinal logistic regression, the partial proportional odds model, the stereotype logistic regression model and rank-order logistic regression (for ranking data). In the first two models, random effects as well as fixed effects could be included; in the remaining three, only fixed effects. RESULTS: In general, the goodness of fit (AIC and McFadden's Pseudo R (2)) showed small differences between the models with fixed effects only. For the mixed-effects models, higher AIC and lower Pseudo R (2) was obtained, which may be related to the different number of parameters in these models. The estimated potential for dose reduction by new image reconstruction methods varied only slightly between models. CONCLUSIONS: The authors suggest that the most suitable approach may be to use ordinal logistic regression, which can handle ordinal data and random effects appropriately. PMID- 26515511 TI - Internalization and Accumulation in Dendritic Cells of a Small pH-Activatable Glycomimetic Fluorescent Probe as Revealed by Spectral Detection. AB - DC-SIGN, an antigen-uptake receptor in dendritic cells (DCs), has a clear role in the immune response but, conversely, can also facilitate infection by providing entry of pathogens into DCs. The key action in both processes is internalization into acidic endosomes and lysosomes. Molecular probes that bind to DC-SIGN could thus provide a useful tool to study internalization and constitute potential antagonists against pathogens. So far, only large molecules have been used to directly observe DC-SIGN-mediated internalization into DCs by fluorescence visualization. We designed and synthesized an appropriate small glycomimetic probe. Two particular properties of the probe were exploited: activation in a low pH environment and an aggregation-induced spectral shift. Our results indicate that small glycomimetic molecules could compete with antigen/pathogen for binding not only outside but also inside the DC, thus preventing the harmful action of pathogens that are able to intrude into DCs, for example, HIV-1. PMID- 26515513 TI - Neural hypernetwork approach for pulmonary embolism diagnosis. AB - BACKGROUND: Hypernetworks are based on topological simplicial complexes and generalize the concept of two-body relation to many-body relation. Furthermore, Hypernetworks provide a significant generalization of network theory, enabling the integration of relational structure, logic and analytic dynamics. A pulmonary embolism is a blockage of the main artery of the lung or one of its branches, frequently fatal. RESULTS: Our study uses data on 28 diagnostic features of 1427 people considered to be at risk of pulmonary embolism enrolled in the Department of Internal and Subintensive Medicine of an Italian National Hospital "Ospedali Riuniti di Ancona". Patients arrived in the department after a first screening executed by the emergency room. The resulting neural hypernetwork correctly recognized 94% of those developing pulmonary embolism. This is better than previous results obtained with other methods (statistical selection of features, partial least squares regression, topological data analysis in a metric space). CONCLUSION: In this work we successfully derived a new integrative approach for the analysis of partial and incomplete datasets that is based on Q-analysis with machine learning. The new approach, called Neural Hypernetwork, has been applied to a case study of pulmonary embolism diagnosis. The novelty of this method is that it does not use clinical parameters extracted by imaging analysis. PMID- 26515514 TI - Naturally occurring phenanthrene degrading bacteria associated with seeds of various plant species. AB - Seeds of 11 of 19 plant species tested yielded naturally occurring phenanthrene degrading bacteria when placed on phenanthrene impression plates. Seed associated phenanthrene degrading bacteria were mostly detected on caragana, Canada thistle, creeping red fescue, western wheatgrass, and tall wheat grass. Based on 16S rRNA analysis the most common bacteria isolated from these seeds were strains belonging to the genera Enterobacteria, Erwinia, Burkholderia, Pantoea, Pseudomonas, and Sphingomonas. These plants may provide an excellent source of pre-adapted bacterial-plant associations highly suitable for use in remediation of contaminated soil environments. PMID- 26515512 TI - Apigenin, a potent suppressor of dendritic cell maturation and migration, protects against collagen-induced arthritis. AB - This study aimed to investigate whether apigenin (API) suppresses arthritis development through the modulation of dendritic cell functions. Bone marrow derived dendritic cells (BMDCs) were stimulated in vitro with lipopolysaccharide (LPS) and treated with API for 24 hrs; DC functions, including phenotype expressions, cytokine secretion, phagocytosis and chemotaxis, were then investigated. The effects of API on collagen-induced arthritis (CIA) were examined in vivo, and purified DCs from the lymph nodes (LNs) of API-treated CIA mice were analysed for phenotypes and subsets. In in vitro, API efficiently restrained the phenotypic and functional maturation of LPS-stimulated BMDCs while maintaining phagocytotic capabilities. Moreover, API inhibited the chemotactic responses of LPS-stimulated BMDCs, which may be related to the depressive effect on chemokine receptor 4 (CXCR4). In in vivo, API treatment delayed the onset and reduced the severity of arthritis in CIA mice, and diminished secretion of pro inflammatory cytokines in the serum and supernatants from the LN cells of the CIA mice. Similar to the in vitro findings, the API-treated mice exhibited reduced expression of co-stimulatory molecules and major histocompatibility complex II on DCs. Furthermore, API treatment strongly down-regulated the number of Langerhans cells, but not plasmacytoid DCs (pDCs) in LNs, which may be related to the depressive effect of API on the expression of CXCR4 on DCs of peripheral blood. These data provide new insight into the mechanism of action of API on arthritis and indicate that the inhibition of maturation and migration of DCs by API may contribute to its immunosuppressive effects. PMID- 26515515 TI - A cross-over study of continuous tracheal cuff pressure monitoring in critically ill children. PMID- 26515516 TI - Protein expression in the brain of rat offspring in relation to prenatal caloric restriction. AB - OBJECTIVE: Intrauterine growth restriction (IUGR) has been associated with decreased supply of crucial substrates to the fetus and affects its growth and development by temporarily or permanently modifying gene expression and function. However, not all neonates born by calorie restricted mothers are IUGR and there are no reports regarding their brain protein expression vis-a-vis that of their IUGR siblings. Here, we investigated the expression of key proteins that regulate growth and development of the brain in non-IUGR newborn pups versus IUGR siblings and control pups. METHODS: Rat brain proteins were isolated from each group upon delivery and separated by two-dimensional gel electrophoresis (2-DE). RESULTS: 14 3-3 Protein, calreticulin, elongation factor, alpha-enolase, fascin, heat-shock protein HSP90 and pyruvate kinase isozymes were significantly increased (p < 0.05) in samples obtained from IUGR newborn pups compared to non-IUGR. Conversely, collapsin response mediator proteins, heat-shock70 and peroxiredoxin2 were decreased in IUGR group compared to non-IUGR. CONCLUSIONS: In our experimental study, IUGR pups showed an altered proteomic profile compared to their non-IUGR siblings and non-IUGR controls. Thus, not all offspring of calorie restricted mothers become IUGR with the accompanying alterations in the expression of proteins. The differentially expressed proteins could modulate alterations in the energy balance, plasticity and maturation of the brain. PMID- 26515517 TI - Analysis of genetic variation in sorghum (Sorghum bicolor (L.) Moench) genotypes with various agronomical traits using SPAR methods. AB - Genetic variation among 45 genotypes of sorghum (Sorghum bicolor L.) representing seven subpopulations was assessed using three single primer amplification reaction (SPAR) methods viz., inter-simple sequence repeat (ISSR), random amplified polymorphic DNA (RAPD) and directed amplification of minisatellite region DNA (DAMD). Totally 15 ISSR, 8 RAPD and 7 DAMD primers generated 263 amplification products, accounting for 84.6% polymorphism across all the genotypes. The Mantel's test of correlation revealed the best correlation between ISSR and cumulative data with a correlation coefficient (r) of 0.84. Assessment of population diversity indicated that the maximum intra population genetic diversity was recorded among high FeZn lines (HFL) having maximum values of Nei's genetic diversity (h) (0.244), Shannon information index (I) (0.368) and the percentage of polymorphic loci (Pp) (72.65%) while the corresponding lowest values of 0.074, 0.109 and 17.95% respectively were observed among the members of MDT subpopulation. The mean coefficient of gene differentiation (GST) and the gene flow (Nm) between populations were observed to be 0.396 and 0.7680 respectively. The analysis of molecular variance (AMOVA) suggested that maximum genetic variation exists within populations (95%) than among populations (5%). Thus the information obtained from this study could be utilized in sorghum breeding programmes for the development of varieties with improved nutrition and agronomic values in future. PMID- 26515518 TI - The complete mitogenomes of Calameuta filiformis (Eversmann, 1847) and Calameuta idolon (Rossi, 1794) (Hymenoptera: Cephidae): The remarkable features of the elongated A+T rich region in Cephini. AB - Two complete mitogenomes of the stem borers, Calameuta filiformis and Calameuta idolon, and the complete A+T-rich region of Trachelus iudaicus (Hymenoptera: Cephidae), are reported. The mitogenomes of these species are the longest reported from hymenopterans to date. A remarkable increase in length of the A+T rich region, the longest for Hymenoptera, was found and compared across the tribe Cephini. The presence of the tRNA- and rRNA-like sequences were reported in the A+T-rich region of sawflies and they were suggested to play a role in replication and/or transcription. The long and short tandem repeats were orderly located in both sides of the A+T-rich region producing stable secondary structures. We suggest that the short tandem repeats are likely to function as a replication fork barrier. PMID- 26515519 TI - Change of Heart: Altered Atrial Activation Following an Atrial Extrastimulus. PMID- 26515520 TI - An association of AKT1 gene polymorphism with antidepressant treatment response. AB - OBJECTIVES: Nowadays it is considered that protein kinase Akt1 could be involved in pathogenesis of affective disorders. We have examined whether AKT1 gene polymorphisms are associated with antidepressant treatment response. METHODS: The study included 106 Caucasian patients with depressive disorders from Siberia and 103 healthy control donors. The frequencies of single nucleotide polymorphisms rs1130214 and rs3730358 of AKT1 gene were examined. RESULTS: A comparison of genotypic or allelic frequencies between the groups of healthy donors and depressive patients showed no statistically significant difference. No association between the polymorphisms under study and the scores according to Hamilton Depression Rating Scale 17 was found. However, an association between treatment response assessed by the Clinical Global Impression - Improvement scale and rs1130214 polymorphism was observed. CONCLUSIONS: AKT1 gene polymorphism rs1130214 is associated with antidepressant treatment response in patients with depressive disorders. PMID- 26515521 TI - Unidirectional thermal expansion in KZnB3O6: role of alkali metals. AB - The driving force of the unidirectional thermal expansion in KZnB3O6 has been studied experimentally and theoretically. Our results show that the low-energy vibrational modes of alkali metals play a crucial role in this unusual thermal behavior. PMID- 26515522 TI - Intestinal perforation in premature neonates: The need for subsequent laparotomy after placement of peritoneal drains. AB - AIM: In view of recent studies questioning the usefulness of peritoneal drainage (PD) in premature neonates with pneumoperitoneum, suggesting approximately 75% of those treated with PD needed delayed laparotomy, we reviewed the requirement for laparotomy after initial PD at our institution. METHODS: Retrospective cohort of all premature infants with a diagnosis of intestinal perforation (ICD Code P78.0) from 1995 to 2012. Inclusion criteria were pneumoperitoneum on x-ray (isolated perforation or necrotising enterocolitis), birthweight <1800 g and gestational age <33 weeks. RESULTS: Fifty patients met the criteria (38 PD, 12 primary laparotomy). Thirty-two per cent (95% CI 18-49%) received secondary laparotomy after initial PD. There was no significant difference when stratified according to isolated perforation (24%) versus necrotising enterocolitis (56%, P = 0.11). There was no significant difference between PD and primary laparotomy for time to full enteral nutrition, hazard ratio (HR) 0.99 (95% CI 0.48-2.04) or mortality, HR 2.15 (95% CI 0.48-9.63). The HR for mortality was partly confounded by birthweight, birthweight-adjusted HR 1.52 (95% CI 0.32-7.23). CONCLUSIONS: Thirty two per cent of neonates treated with primary PD received secondary laparotomy, with no significant difference in key outcomes. Primary PD still appears to be of benefit for those without features of necrotising enterocolitis. PMID- 26515524 TI - Typing of Neisseria meningitidis by whole-genome analysis. PMID- 26515523 TI - Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort study. AB - BACKGROUND: Invasive meningococcal disease (IMD) is a worldwide health issue that is potentially preventable with vaccination. In view of its sporadic nature and the high diversity of Neisseria meningitidis, epidemiological surveillance incorporating detailed isolate characterisation is crucial for effective control and understanding the evolving epidemiology of IMD. The Meningitis Research Foundation Meningococcus Genome Library (MRF-MGL) exploits whole-genome sequencing (WGS) for this purpose and presents data on a comprehensive and coherent IMD isolate collection from England and Wales via the internet. We assessed the contribution of these data to investigating IMD epidemiology. METHODS: WGS data were obtained for all 899 IMD isolates available for England and Wales in epidemiological years 2010-11 and 2011-12. The data had been annotated at 1720 loci, analysed, and disseminated online. Information was also available on meningococcal population structure and vaccine (Bexsero, GlaxoSmithKline, Brentford, Middlesex, UK) antigen variants, which enabled the investigation of IMD-associated genotypes over time and by patients' age groups. Population genomic analyses were done with a hierarchical gene-by-gene approach. FINDINGS: The methods used by MRF-MGL efficiently characterised IMD isolates and information was provided in plain language. At least 20 meningococcal lineages were identified, three of which (hyperinvasive clonal complexes 41/44 [lineage 3], 269 [lineage 2], and 23 [lineage 23]) were responsible for 528 (59%) of IMD isolates. Lineages were highly diverse and showed evidence of extensive recombination. Specific lineages were associated with IMD in particular age groups, with notable diversity in the youngest and oldest individuals. The increased incidence of IMD from 1984 to 2010 in England and Wales was due to successive and concurrent epidemics of different lineages. Genetically, 74% of isolates were characterised as encoding group B capsules: 16% group Y, 6% group W, and 3% group C. Exact peptide matches for individual Bexsero vaccine antigens were present in up to 26% of isolates. INTERPRETATION: The MRF-MGL represents an effective, broadly applicable model for the storage, analysis, and dissemination of WGS data that can facilitate real-time genomic pathogen surveillance. The data revealed information crucial to effective deployment and assessment of vaccines against N meningitidis. FUNDING: Meningitis Research Foundation, Wellcome Trust, Public Health England, European Union. PMID- 26515525 TI - Benefits of combined preventive therapy with co-trimoxazole and isoniazid in adults living with HIV: time to consider a fixed-dose, single tablet coformulation. AB - Antiretroviral therapy (ART) is the main intervention needed to reduce morbidity and mortality and to prevent tuberculosis in adults living with HIV. However, in most resource-limited countries, especially in sub-Saharan Africa, ART is started too late to have an effect with substantial early morbidity and mortality, and in high tuberculosis burden settings ART does not reduce the tuberculosis risk to that reported in individuals not infected with HIV. Co-trimoxazole preventive therapy started before or with ART, irrespective of CD4 cell count, reduces morbidity and mortality with benefits that continue indefinitely. Isoniazid preventive therapy as an adjunct to ART prevents tuberculosis in high-exposure settings, with long-term treatment likely to be needed to sustain this benefit. Unfortunately, both preventive therapies are underused in low-income and high burden settings. ART development has benefited from patient-centred simplification with several effective regimens now available as a one per day pill. We argue that co-trimoxazole and isoniazid should also be combined into a single fixed-dose pill, along with pyridoxine (vitamin B6), that would be taken once per day to help with individual uptake and national scale-up of therapies. PMID- 26515526 TI - Effects of azelastine nasal spray on nasal and nasopharyngeal microflora. AB - OBJECTIVE: Azelastine nasal spray is a topical antihistaminic drug for the symptomatic treatment of allergic rhinitis. This study aimed to investigate the effects of azelastine on nasal and nasopharyngeal microflora. METHODS: Swab samples from 25 patients prescribed azelastine nasal spray monotherapy were collected just before treatment and after 1 month of treatment. After incubation of inoculates, the number of bacteria present in cultures was measured (in colony forming units per millilitre). RESULTS: Evaluation of the number of microflora revealed increased bacterial reproduction after treatment, but this difference was not statistically significant. The use of azelastine nasal spray decreased the reproduction of three potentially pathogenic bacteria; however, it did not affect the reproduction of other potentially pathogenic bacteria. CONCLUSION: The use of azelastine nasal spray for one month did not have a statistically significant effect on the numbers of nasal and nasopharyngeal microflora; it is therefore safe from a microbiological viewpoint. PMID- 26515527 TI - Comorbid insomnia and cognitive behavior therapy. AB - Insomnia most commonly presents comorbidly in association with medical and psychiatric disorders. Comorbid insomnia, however, remains under treated in the majority of patients. Concerns about drug interactions, adverse events, and dependence as well as the assumption that treating the insomnia as a secondary presentation that will resolve when the primary condition improves are all factors that contribute to the under treatment of comorbid insomnia. This article presents the growing research evidence that highlights the benefits and importance of targeting the insomnia that presents comorbidly with medical and psychiatric conditions utilizing the nonpharmacological and effective treatment of cognitive behavior therapy. PMID- 26515528 TI - High serum sodium level in affective episode associated with coronary heart disease in old adults with bipolar disorder. AB - OBJECTIVE: Coronary heart disease (CHD) remains the principal cause of excessive natural deaths in bipolar patients; however, electrocardiogram analyses and clinical features predicting CHDs in elderly bipolar patients remain limited. We sought to examine the relationship between CHDs, as determined by electrocardiogram, and clinical characteristics. METHODS: We recruited bipolar I outpatients Diagnostic Statistical Manual of Mental Health (DSM-IV) who were more than 60 years old and had at least one psychiatric admission. Subjects were divided into two groups based on the presence or absence of CHD diagnosed by electrocardiogram analysis at entry of study. Clinical data were obtained by a combination of interviewing patients and family members and retrospectively reviewing medical records of the most recent acute psychiatric hospitalization. RESULTS: Eighty patients with bipolar disorder were enrolled. A total of 20 (25%) in the study had CHDs. The mean age at the time of entry into study was 67.6 +/- 5.5 years old in group with CHD and 66.8 +/- 6.8 years old in that without CHD. Among the clinical characteristics examined, higher mean levels of serum sodium and thyroxine during the acute affective phase as well as more first-degree family history with bipolar disorder were related to having CHD, particularly the serum sodium level. CONCLUSIONS: About one fourth of old bipolar patients have CHDs in both Asian and Western populations. Aging patients with bipolar disorder may have unique clinical factors (e.g., hypernatremia or elevated thyroxine) related CHDs that could warrant special attention in their psychiatric and medical care to minimize cardiovascular disease and mortality. PMID- 26515529 TI - Social redistribution of pain and money. AB - People show empathic responses to others' pain, yet how they choose to apportion pain between themselves and others is not well understood. To address this question, we observed choices to reapportion social allocations of painful stimuli and, for comparison, also elicited equivalent choices with money. On average people sought to equalize allocations of both pain and money, in a manner which indicated that inequality carried an increasing marginal cost. Preferences for pain were more altruistic than for money, with several participants assigning more than half the pain to themselves. Our data indicate that, given concern for others, the fundamental principle of diminishing marginal utility motivates spreading costs across individuals. A model incorporating this assumption outperformed existing models of social utility in explaining the data. By implementing selected allocations for real, we also found that while inequality per se did not influence pain perception, altruistic behavior had an intrinsic analgesic effect for the recipient. PMID- 26515530 TI - Fibula free flap in the treatment of mandibular osteoradionecrosis. AB - INTRODUCTION: Mandibular osteoradionecrosis (mORN) is one of the major complications of radiation therapy in head and neck cancer. It is responsible for intractable pain and functional problems. Radical treatment, required in case of failure of conservative management, consists in wide resection of the necrotic tissue followed by reconstruction, notably by free flaps. The present study assessed the efficacy of reconstructive surgery by fibula free flap (FFF) in terms of pain, suppuration and functional results. MATERIAL AND METHODS: A retrospective study recruited 5 cases of mORN treated surgically with FFF reconstruction between 2005 and 2012. For each patient, pain, resolution of suppuration, articulation, mastication and swallowing functions and recovery of oral feeding were assessed. RESULTS: The flaps had good vitality in 4 of the 5 patients. Infection and pain resolved in all patients. Functional results were satisfactory in 4 of the 5 cases (80%). There was no recurrence of mORN. CONCLUSIONS: Micro-anastomosed FFF seems to be the method of choice for mandibular reconstruction in advanced mORN. Delayed treatment, however, seems to reduce the chances of good functional results. The precise indications for radical surgery and its timing remain to be defined, but it appears wise to decide on ever earlier radical surgery in the hope of obtaining better functional results. PMID- 26515531 TI - Computational resources and strategies to construct single-molecule metabolic models of microbial cells. AB - Recent computational methodologies, such as individual-based modelling, pave the way to the search for explanatory insight into the collective behaviour of molecules. Many reviews offer an up-to-date perspective about such methodologies, but little is discussed about the practical information requirements involved. The biological information used as input should be easily and routinely determined in the laboratory, publicly available and, preferably, organized in programmatically accessible databases. This review is the first to provide a systematic and comprehensive overview of available resources for the modelling of metabolic events at the molecular scale. The glycolysis pathway of Escherichia coli, which is one of the most studied pathways in Microbiology, serves as case study. This curation addressed structural information about E. coli (i.e. defining the simulation environment), the reactions forming the glycolysis pathway including the enzymes and the metabolites (i.e. the molecules to be represented), the kinetics of each reaction (i.e. behavioural logic of the molecules) and diffusion parameters for all enzymes and metabolites (i.e. molecule movement in the environment). Furthermore, the interpretation of relevant biological features, such as molecular diffusion and enzyme kinetics, and the connection of experimental determination and simulation validation are detailed. Notably, the information from classical theories, such as enzymatic rates and diffusion coefficients, is translated to simulation parameters, such as collision efficiency and particle velocity. PMID- 26515532 TI - An evaluation of methods to test predefined genomic regions for differential methylation in bisulfite sequencing data. AB - In the biology of tissue development and diseases, DNA methylation plays an important role. For a deeper understanding, it is crucial to accurately compare DNA methylation patterns between groups of samples representing different conditions. A widely used method to investigate DNA methylation in the CpG context is bisulfite sequencing, which produces data on the single-nucleotide scale. While there are benefits to analyzing CpG sites on a basepair level, there are both biological and statistical reasons to test entire genomic regions for differential methylation. However, the analysis of DNA methylation is hampered by the lack of best practice standards. Here, we compared multiple approaches for testing predefined genomic regions for differential DNA methylation in bisulfite sequencing data. Nine methods were evaluated: BiSeq, COHCAP, Goeman's Global Test, Limma, methylKit/eDMR, RADMeth and three log-linear regression approaches with different distribution assumptions. We applied these methods to simulated data and determined their sensitivity and specificity. This revealed performance differences, which were also seen when applied to real data. Methods that first test single CpG sites and then test regions based on transformed CpG-wise P values performed better than methods that summarize methylation levels or raw reads. Interestingly, smoothing of methylation levels had a negligible impact. In particular, Global Test, BiSeq and RADMeth/z-test outperformed the other methods we evaluated, providing valuable guidance for more accurate analysis of DNA methylation. PMID- 26515533 TI - Design of magnetic molecularly imprinted polymer nanoparticles for controlled release of doxorubicin under an alternative magnetic field in athermal conditions. AB - An innovative magnetic delivery nanomaterial for triggered cancer therapy showing active control over drug release by using an alternative magnetic field is proposed. In vitro and In vivo release of doxorubicin (DOX) were investigated and showed a massive DOX release under an alternative magnetic field without temperature elevation of the medium. PMID- 26515534 TI - Cooking rice in excess water reduces both arsenic and enriched vitamins in the cooked grain. AB - This paper reports the effects of rinsing rice and cooking it in variable amounts of water on total arsenic, inorganic arsenic, iron, cadmium, manganese, folate, thiamin and niacin in the cooked grain. We prepared multiple rice varietals both rinsed and unrinsed and with varying amounts of cooking water. Rinsing rice before cooking has a minimal effect on the arsenic (As) content of the cooked grain, but washes enriched iron, folate, thiamin and niacin from polished and parboiled rice. Cooking rice in excess water efficiently reduces the amount of As in the cooked grain. Excess water cooking reduces average inorganic As by 40% from long grain polished, 60% from parboiled and 50% from brown rice. Iron, folate, niacin and thiamin are reduced by 50-70% for enriched polished and parboiled rice, but significantly less so for brown rice, which is not enriched. PMID- 26515535 TI - Are Health-Related Tweets Evidence Based? Review and Analysis of Health-Related Tweets on Twitter. AB - BACKGROUND: Health care professionals are utilizing Twitter to communicate, develop disease surveillance systems, and mine health-related information. The immediate users of this health information is the general public, including patients. This necessitates the validation of health-related tweets by health care professionals to ensure they are evidence based and to avoid the use of noncredible information as a basis for critical decisions. OBJECTIVE: The aim of this study was to evaluate health-related tweets on Twitter for validity (evidence based) and to create awareness in the community regarding the importance of evidence-based health-related tweets. METHODS: All tweets containing health-related information in the Arabic language posted April 1-5, 2015, were mined from Twitter. The tweets were classified based on popularity, activity, interaction, and frequency to obtain 25 Twitter accounts (8 physician accounts, 10 nonofficial health institute accounts, 4 dietitian accounts, and 3 government institute accounts) and 625 tweets. These tweets were evaluated by 3 American Board-certified medical consultants and a score was generated (true/false) and interobserver agreement was calculated. RESULTS: A total of 625 health-related Arabic-language tweets were identified from 8 physician accounts, 10 nonofficial health institute accounts, 4 dietician accounts, and 3 government institute accounts. The reviewers labeled 320 (51.2%) tweets as false and 305 (48.8%) tweets as true. Comparative analysis of tweets by account type showed 60 of 75 (80%) tweets by government institutes, 124 of 201 (61.7%) tweets by physicians, and 42 of 101 (41.6%) tweets by dieticians were true. The interobserver agreement was moderate (range 0.78-0.22). More than half of the health-related tweets (169/248, 68.1%) from nonofficial health institutes and dietician accounts (59/101, 58.4%) were false. Tweets by the physicians were more likely to be rated "true" compared to other groups (P<.001). CONCLUSIONS: Approximately half of the medical tweets from professional accounts on Twitter were found to be false based on expert review. Furthermore, most of the evidence based health-related tweets are posted by government institutes and physicians. PMID- 26515536 TI - Paradoxical embolus following percutaneous thrombectomy of hemodialysis reliable outflow graft. AB - Percutaneous interventions to maintain or re-establish patent vascular access are common and often necessary for patients on hemodialysis. This case illustrates an extremely rare but potentially devastating complication of one of these procedures: cerebrovascular insult due to paradoxical embolism in the setting of a patent foramen ovale. PMID- 26515539 TI - Antiquity and diversity of aboriginal Australian Y-chromosomes. AB - OBJECTIVE: Understanding the origins of Aboriginal Australians is crucial in reconstructing the evolution and spread of Homo sapiens as evidence suggests they represent the descendants of the earliest group to leave Africa. This study analyzed a large sample of Y-chromosomes to answer questions relating to the migration routes of their ancestors, the age of Y-haplogroups, date of colonization, as well as the extent of male-specific variation. METHODS: Knowledge of Y-chromosome variation among Aboriginal Australians is extremely limited. This study examined Y-SNP and Y-STR variation among 657 self-declared Aboriginal males from locations across the continent. 17 Y-STR loci and 47 Y-SNPs spanning the Y-chromosome phylogeny were typed in total. RESULTS: The proportion of non-indigenous Y-chromosomes of assumed Eurasian origin was high, at 56%. Y lineages of indigenous Sahul origin belonged to haplogroups C M130*(xM8,M38,M217,M347) (1%), C-M347 (19%), K M526*(xM147,P308,P79,P261,P256,M231,M175,M45,P202) (12%), S-P308 (12%), and M M186 (0.9%). Haplogroups C-M347, K-M526*, and S-P308 are Aboriginal Australian specific. Dating of C-M347, K-M526*, and S-P308 indicates that all are at least 40,000 years old, confirming their long-term presence in Australia. Haplogroup C M347 comprised at least three sub-haplogroups: C-DYS390.1del, C-M210, and the unresolved paragroup C-M347*(xDYS390.1del,M210). CONCLUSIONS: There was some geographic structure to the Y-haplogroup variation, but most haplogroups were present throughout Australia. The age of the Australian-specific Y-haplogroups suggests New Guineans and Aboriginal Australians have been isolated for over 30,000 years, supporting findings based on mitochondrial DNA data. Our data support the hypothesis of more than one route (via New Guinea) for males entering Sahul some 50,000 years ago and give no support for colonization events during the Holocene, from either India or elsewhere. PMID- 26515540 TI - Anopheles gambiae hemocytes exhibit transient states of activation. AB - Hemocytes are crucial players of the mosquito immune system and critically affect transmission of pathogens including malaria parasites. We and others discovered previously that a blood meal is a major immune stimulus for mosquito hemocytes. To determine whether these blood meal-induced hemocyte changes in Anopheles gambiae constitute steps in cell differentiation or demonstrate transient cell activation, we analyzed the temporal pattern of these changes over the first three days post blood meal (dpbm). Flow cytometry and immunofluorescence analyses revealed a global shift of the entire hemocyte population, peaking at 1 dpbm. All hemocyte activation markers returned to pre-blood meal baseline levels within the following 24-48 h. Our observations are consistant with An. gambiae hemocytes undergoing transient activation rather than terminal differentiation upon blood feeding. Interestingly, the temporal pattern followed the gonotrophic cycle of the mosquito, strongly suggesting hormonal control of mosquito hemocyte activation and deactivation. PMID- 26515541 TI - Chemical, mechanical and biological properties of contemporary composite surface sealers. AB - OBJECTIVES: To evaluate the chemical, mechanical, and biological properties of modern composite surface sealers (CSS) having different compositions. METHODS: The CSS products tested were Biscover LV (BC), Durafinish (DF), G-Coat Plus (GC), and Permaseal (PS). The tests performed were: (A): degree of conversion (DC%) by ATR-FTIR spectroscopy; (B): thickness of O2-inhibition layer by transmission optical microscopy; (C): surface hardness, 10 min after irradiation and following 1 week water storage, employing a Vickers indenter (VHN); (D): color (DeltaE*) and gloss changes (DeltaGU) after toothbrush abrasion, using L*a*b* colorimetry and glossimetry; (E): accelerated wear (GC,PS only) by an OHSU wear simulator plus 3D profilometric analysis, and (F): cytotoxicity testing of aqueous CSS eluents on human gingival fibroblast cultures employing the methyl-(3)H thymidine DNA labeling method. Statistical analyses included 1-way (A, B, DeltaE*, DeltaGU) and 2-way (C, F) ANOVAs, plus Tukey post hoc tests. Student's t-test was used to evaluate the results of the accelerated wear test (alpha=0.05 for all). RESULTS: The rankings of the statistical significant differences were: (A) PS (64.9)>DF,BC,GC (56.1-53.9) DC%; (B) DF,PS (12.3,9.8)>GC,BC (5.2,4.8) MUm; (C): GC (37.6)>BC,DF (32.6,31.1)>PS (26.6) VHN (10 min/dry) and BC,DF (29.3,28.7)>GC(26.5)>PS(21.6) VHN (1w/water), with no significant material/storage condition interaction; (D): no differences were found among GC,DF,BC,PS (0.67-1.11) DeltaE*, with all values within the visually acceptable range and PS,BC (32.8,29.4)>GC,DF (19.4,12.9) DeltaGU; (E): no differences were found between GC and PS in volume loss (0.10,0.11 mm(3)), maximum (113.9,130.5 MUm) and mean wear depths (30.3,27.5 MUm); (F): at 1% v/v concentration, DF showed toxicity (23% vital cells vs 95-102% for others). However, at 5% v/v concentration DF (0%) and BC (9%) were the most toxic, whereas GC (58%) and PS (56%) showed moderate toxicity. SIGNIFICANCE: Important chemical, mechanical, and biological properties exist among the CSS tested, which may affect their clinical performance. PMID- 26515542 TI - A 50-year-old woman with a recurrent oesophageal stricture. PMID- 26515543 TI - Faecal haemoglobin concentration influences risk prediction of interval cancers resulting from inadequate colonoscopy quality: analysis of the Taiwanese Nationwide Colorectal Cancer Screening Program. AB - OBJECTIVES: Interval colorectal cancer (CRC) after colonoscopy may affect effectiveness and cost-effectiveness of screening programmes. We aimed to investigate whether and how faecal haemoglobin concentration (FHbC) of faecal immunochemical testing (FIT) affected the risk prediction of interval cancer (IC) caused by inadequate colonoscopy quality in a FIT-based population screening programme. DESIGN: From 2004 to 2009, 29 969 subjects underwent complete colonoscopy after positive FIT in the Taiwanese Nationwide CRC Screening Program. The IC rate was traced until the end of 2012. The incidence of IC was calculated in relation to patient characteristics, endoscopy-related factors (such adenoma detection rate (ADR)) and FHbC. Poisson regression analysis was performed to assess the potential risk factors for colonoscopy IC. RESULTS: One hundred and sixty-two ICs developed after an index colonoscopy and the estimated incidence was 1.14 per 1000 person-years of observation for the entire cohort. Increased risk of IC was most remarkable in the uptake of colonoscopy in settings with ADR lower than 15% (adjusted relative risk (aRR)=3.09, 95% CI 1.55 to 6.18) and then higher FHbC (MUg Hb/g faeces) (100-149: aRR=2.55, 95% CI 1.52 to 4.29, >=150: aRR=2.74, 95% CI 1.84 to 4.09) with adjustment for older age and colorectal neoplasm detected at baseline colonoscopy. Similar findings were observed for subjects with negative index colonoscopy. CONCLUSIONS: Colonoscopy ICs arising from FIT-based population screening programmes were mainly influenced by inadequate colonoscopy quality and independently predicted by FHbC that is associated with a priori chance of advanced neoplasm. This finding is helpful for future modification of screening logistics based on FHbC. PMID- 26515545 TI - Non-contrast-enhanced MR angiography using time-spin labelling inversion pulse technique for detecting crossing renal vessels in children with symptomatic ureteropelvic junction obstruction: comparison with surgical findings. AB - OBJECTIVES: Investigate the feasibility and evaluate the accuracy of non-contrast enhanced MR angiography (NC-MRA) using time-spin labelling inversion pulse (time SLIP)to identify crossing renal vessels (CRVs) in children requiring surgical treatment of ureteropelvic junction (UPJ) obstructionand compare to laparoscopic findings. MATERIALS AND METHODS: Nineteen children ranging from 6 to 16 years of age underwent NC-MRA using the time-SLIP technique before surgery. Two independent readers analysed the MRA images. Number of renal arteries and presence or absence of CRVs were identified and compared with surgicalfindings. Image quality was assessed, as well as the presence of CRVs and measurement of renal pelvis diameter. Intra and inter-reader agreement was calculated using Cohen's kappa coefficient and Bland-Altman plots. RESULTS: The overall image quality was fair or good in 88% of cases. NC-MRA demonstrated CRVs at the level of the obstruction in 10 children and no CRV in 9 children. All were confirmed intra-operatively except in one of the nine children. Sensitivity, specificity, NPV, PPV for predicting CRVs were 92%, 100%, 100% and 87.5%, respectively, for both readers. CONCLUSION: NC-MRA is a good alternative to contrast-enhanced MRA and CT scanning for identifying CRVs in children with symptomatic UPJ. KEY POINTS: * Time-SLIP technique offers acceptable imaging quality for identifying crossing renal vessel. * Time-SLIP technique is easy to apply to the renal MRA examination. * Time-SLIP technique is an alternative to contrast-enhanced MRA and CT scanning. PMID- 26515544 TI - Phosphorylation of NR2B NMDA subunits by protein kinase C in arcuate nucleus contributes to inflammatory pain in rats. AB - The arcuate nucleus (ARC) of the hypothalamus plays a key role in pain processing. Although it is well known that inhibition of NMDA receptor (NMDAR) in ARC attenuates hyperalgesia induced by peripheral inflammation, the underlying mechanism of NMDAR activation in ARC remains unclear. Protein kinase C (PKC) is involved in several signalling cascades activated in physiological and pathological conditions. Therefore, we hypothesised that upregulation of PKC activates NMDARs in the ARC, thus contributing to inflammatory hyperalgesia. Intra-ARC injection of chelerythrine (CC), a specific PKC inhibitor, attenuated complete Freund's adjuvant (CFA) induced thermal and mechanical hyperalgesia in a dose-dependent manner. In vivo extracellular recordings showed that microelectrophoresis of CC or MK-801 (a NMDAR antagonist) significantly reduced the enhancement of spontaneous discharges and pain-evoked discharges of ARC neurons. In addition, CFA injection greatly enhanced the expression of total and phosphorylated PKCgamma in the ARC. Interestingly, CFA injection also remarkably elevated the level of phosphorylated NR2B (Tyr1472) without affecting the expression of total NR2B. Importantly, intra-ARC injection of CC reversed the upregulation of phosphorylated NR2B subunits in the ARC. Taken together, peripheral inflammation leads to an activation of NMDARs mediated by PKC activation in the ARC, thus producing thermal and mechanical hyperalgesia. PMID- 26515546 TI - Neurite orientation dispersion and density imaging in the substantia nigra in idiopathic Parkinson disease. AB - OBJECTIVES: We used neurite orientation dispersion and density imaging (NODDI) to quantify changes in the substantia nigra pars compacta (SNpc) and striatum in Parkinson disease (PD). METHODS: Diffusion-weighted magnetic resonance images were acquired from 58 PD patients and 36 age- and sex-matched controls. The intracellular volume fraction (Vic), orientation dispersion index (OD), and isotropic volume fraction (Viso) of the basal ganglia were compared between groups. Multivariate logistic regression analysis determined which diffusion parameters were independent predictors of PD. Receiver operating characteristic (ROC) analysis compared the diagnostic accuracies of the evaluated indices. Pearson coefficient analysis correlated each diffusional parameter with disease severity. RESULTS: Vic in the contralateral SNpc and putamen were significantly lower in PD patients than in healthy controls (P < 0.00058). Vic and OD in the SNpc and putamen showed significant negative correlations (P < 0.05) with disease severity. Multivariate logistic analysis revealed that Vic (P = 0.0000046) and mean diffusivity (P = 0.019) in the contralateral SNpc were the independent predictors of PD. In the ROC analysis, Vic in the contralateral SNpc showed the best diagnostic performance (mean cutoff, 0.62; sensitivity, 0.88; specificity, 0.83). CONCLUSION: NODDI is likely to be useful for diagnosing PD and assessing its progression. KEY POINTS: * Neurite orientation dispersion and density imaging (NODDI) is a new diffusion MRI technique * NODDI estimates neurite microstructure more specifically than diffusion tensor imaging * By using NODDI, nigrostriatal alterations in PD can be evaluated in vivo * NOODI is useful for diagnosing PD and assessing its disease progression. PMID- 26515547 TI - Optimal threshold of subtraction method for quantification of air-trapping on coregistered CT in COPD patients. AB - OBJECTIVES: To investigate the optimal threshold of subtraction method for quantification of air trapping on co-registered CT in COPD patients in correlation with pulmonary function parameters. METHODS: From June 2005 to October 2010, 174 patients were included in our study. Inspiration and expiration CT were performed followed by non-rigid registration using in-house software. The subtraction value per voxel between inspiration and registered expiration CT was obtained, and volume fraction of air trapping (air trapping index, ATI), using variable thresholds was calculated. ATI, expiration/inspiration ratio of mean lung density (E/I MLD) and the percentage of lung voxels below -856 HU on expiration CT (Exp-856) were correlated with FEF25-75% and RV/TLC. RESULTS: The highest correlation coefficient with FEF25-75% was -0.656, using the threshold of 80 HU. As for RV/TLC, the highest correlation coefficient was 0.664, using the threshold of 30 HU. When plotting the relationship between subtraction thresholds and FEF25-75% and RV/TLC, the threshold of 60 HU was most suitable (r = -0.649 and 0.651). Those correlation coefficients were comparable to the results with E/I MLD (r = -0.670 and 0.657) and Exp-856 (r = -0.604 and 0.565). CONCLUSIONS: The optimal threshold for quantification of air trapping was 60 HU and showed comparable correlations with pulmonary function parameters. KEY POINTS: * The optimal CT threshold of subtraction method for air trapping was 60 HU. * ATI with 60 HU threshold was comparable to E/I MLD and Exp -856 . * Emphysema may substantially contribute to air trapping with statistical significance (P < 0.001). PMID- 26515548 TI - Non-enhanced, ECG-gated MR angiography of the pedal vasculature: comparison with contrast-enhanced MR angiography and digital subtraction angiography in peripheral arterial occlusive disease. AB - OBJECTIVES: This study was conducted in order to compare a high resolution, non contrast-enhanced MRA (NATIVE SPACE, NE-MRA) of the pedal vasculature with contrast-enhanced MRA (CE-MRA) and digital subtraction angiography (DSA) in patients with peripheral arterial occlusive disease (PAOD). METHODS: The prospective study consists of 20 PAOD patients. All patients underwent percutaneous transluminal angioplasty or stenting and received MR angiographies the following day. RESULTS: With CE-MRA, 75.7 % of vessel segments showed good, 16.4 % suboptimal and 7.9 % not usable image quality. With NE-MRA, 64.6 % showed good, 18.6 % suboptimal and 16.8 % not usable image quality. CE-MRA showed a sensitivity and negative predictive value of 90 %/95 % regarding significant stenosis (greater than 50 %), and specificity and positive predictive value were 88 %/77 %. Accordingly, sensitivity and negative predictive value for the NE-MRA were 96 %/97 % and specificity and positive predictive value were 80 %/69 % for stenoses greater than 50 %. CONCLUSIONS: The applied NE-MRA technique achieves high diagnostic accuracy even in very small distal arteries of the foot. However, the rate of non-diagnostic vessel segments is considerably higher for NE-MRA than for CE-MRA. NE-MRA is a valuable alternative to CE-MRA in selected patients. KEY POINTS: * Comparison of non-enhanced MRA with contrast-enhanced MRA and DSA as gold standard. * High resolution MRA at 3 T for the depiction of small pedal vessels. * Evaluation of high resolution non-enhanced MRA in PAOD patients. PMID- 26515549 TI - Prognostic value of dipyridamole stress cardiac magnetic resonance in patients with known or suspected coronary artery disease: a mid-term follow-up study. AB - OBJECTIVES: Dipyridamole stress cardiac magnetic resonance (CMR) evaluates the key phases (perfusion and wall motion) of the ischemic cascade. We sought to determine the prognostic value of dipyridamole stress-CMR in consecutive patients symptomatic for chest pain. METHODS: Seven hundred and ninety-three consecutive patients symptomatic for chest pain underwent dipyridamole stress-CMR and were followed up for 810 +/- 665 days. Patients were classified in group 1 (no- reversible ischemia), group 2 (stress perfusion defect alone), and group 3 [stress perfusion defect plus abnormal wall motion (AWM)]. End points were "all cardiac events" (myocardial infarction, cardiac death and revascularization) and "hard cardiac events" (all cardiac events excluding revascularization). RESULTS: One hundred and ninety-five (24 %) all cardiac events and 53 (7 %) hard cardiac events were observed. All and hard cardiac event rates in groups 1, 2, and 3 were 11 %, 49 %, 69 % and 4 %, 8 %, 21 %, respectively, with a higher rate in group 2 vs. group 1 (p<0.01) and group 3 vs. groups 1 and 2 (p<0.01). Multivariate analysis showed the presence of late gadolinium enhancement and stress perfusion defect plus AWM as independent predictors of all and hard cardiac events. CONCLUSIONS: Dipyridamole stress-CMR improves prognostic stratification of patients through differentiation between the different components of the ischemic cascade. KEY POINTS: * Dipyridamole stress cardiac magnetic resonance helps to assess coronary artery disease. * Novel technique to study the key phases of myocardial ischemia. * Combined assessment of perfusion and motion defects. * Dipyridamole stress imaging has additional value for predicting cardiac events. PMID- 26515550 TI - MDCT Linear and Volumetric Analysis of Adrenal Glands: Normative Data and Multiparametric Assessment. AB - OBJECTIVES: To study linear and volumetric adrenal measurements, their reproducibility, and correlations between total adrenal volume (TAV) and adrenal micronodularity, age, gender, body mass index (BMI), visceral (VAAT) and subcutaneous adipose tissue volume (SAAT), presence of diabetes, chronic alcoholic abuse and chronic inflammatory disease (CID). METHODS: We included 154 patients (M/F, 65/89; mean age, 57 years) undergoing abdominal multidetector row computed tomography (MDCT). Two radiologists prospectively independently performed adrenal linear and volumetric measurements with semi-automatic software. Inter-observer reliability was studied using inter-observer correlation coefficient (ICC). Relationships between TAV and associated factors were studied using bivariate and multivariable analysis. RESULTS: Mean TAV was 8.4 +/- 2.7 cm(3) (3.3-18.7 cm(3)). ICC was excellent for TAV (0.97; 95 % CI: 0.96-0.98) and moderate to good for linear measurements. TAV was significantly greater in men (p < 0.0001), alcoholics (p = 0.04), diabetics (p = 0.0003) and those with micronodular glands (p = 0.001). TAV was lower in CID patients (p = 0.0001). TAV correlated positively with VAAT (r = 0.53, p < 0.0001), BMI (r = 0.42, p < 0.0001), SAAT (r = 0.29, p = 0.0003) and age (r = 0.23, p = 0.005). Multivariable analysis revealed gender, micronodularity, diabetes, age and BMI as independent factors influencing TAV. CONCLUSIONS: Adrenal gland MDCT-based volumetric measurements are more reproducible than linear measurements. Gender, micronodularity, age, BMI and diabetes independently influence TAV. KEY POINTS: * Volumetric measurements are more reproducible than linear measurements for adrenal glands. * Inter-observer reproducibility of adrenal gland volume is excellent using semiautomatic software. * Gender, age, BMI, and diabetes independently influence total adrenal gland volume. * Adrenal micronodularity is associated with increased total adrenal gland volume. PMID- 26515552 TI - Lipid droplet dynamics in skeletal muscle. AB - The skeletal muscle is subjected to high mechanical and energetic demands. Lipid droplets are an important source of energy substrates for the working muscle. Muscle cells contain a variety of lipid droplets, which are fundamentally smaller than those found in adipocytes. This translates into a greater lipid droplet surface area serving as the interface for intracellular lipid metabolism. The skeletal muscle has a high plasticity, it is subjected to major remodeling following training and detraining. This coincides with adaptations in lipid droplet characteristics and dynamics. The majority of lipid droplets in skeletal muscle are located in the subsarcolemmal region or in-between the myofibrils, in close vicinity to mitochondria. The vastly organized nature of skeletal muscle fibers limits organelle mobility. The high metabolic rate and substrate turnover in skeletal muscle demands a strict coordination of intramyocellular lipid metabolism and LD dynamics, in which lipid droplet coat proteins play an important role. This review provides insights into the characteristics, diversity and dynamics of skeletal muscle lipid droplets. PMID- 26515551 TI - Lipid droplets in leukocytes: Organelles linked to inflammatory responses. AB - Studies on lipid droplets (LDs) in leukocytes have attracted attention due to their association with human diseases. In these cells, LDs are rapidly formed in response to inflammatory stimuli or allergic/inflammatory diseases including infections with parasites and bacteria. Leukocyte LDs are linked to the regulation of immune responses by compartmentalization of several proteins and lipids involved in the control and biosynthesis of inflammatory mediators (eicosanoids). In this mini review, we summarize current knowledge on the composition, structure and function of leukocyte LDs, organelles now considered as structural markers of inflammation. PMID- 26515553 TI - Mechanosensitivity of integrin adhesion complexes: role of the consensus adhesome. AB - Cell and tissue stiffness have been known to contribute to both developmental and pathological signalling for some time, but the underlying mechanisms remain elusive. Integrins and their associated adhesion signalling complexes (IACs), which form a nexus between the cell cytoskeleton and the extracellular matrix, act as a key force sensing and transducing unit in cells. Accordingly, there has been much interest in obtaining a systems-level understanding of IAC composition. Proteomic approaches have revealed the complexity of IACs and identified a large number of components that are regulated by cytoskeletal force. Here we review the function of the consensus adhesome, an assembly of core IAC proteins that emerged from a meta-analysis of multiple proteomic datasets, in the context of mechanosensing. As IAC components have been linked to a variety of diseases involved with rigidity sensing, the field is now in a position to define the mechanosensing function of individual IAC proteins and elucidate their mechanisms of action. PMID- 26515555 TI - Proteomic investigation of embryonic rat heart-derived H9c2 cell line sheds new light on the molecular phenotype of the popular cell model. AB - Due to their cardiac origin, H9c2 cells rank among the most popular cell lines in current cardiovascular research, yet molecular phenotype remains elusive. Hence, in this study we used proteomic approach to describe molecular phenotype of H9c2 cells in their undifferentiated (i.e., most frequently used) state, and its functional response to cardiotoxic drug doxorubicin. Of 1671 proteins identified by iTRAQ IEF/LC-MSMS analysis, only 12 proteins were characteristic for striated muscle cells and none was cardiac phenotype-specific. Targeted LC-SRM and western blot analyses confirmed that undifferentiated H9c2 cells are phenotypically considerably different to both primary neonatal cardiomyocytes and adult myocardium. These cells lack proteins essential for formation of striated muscle myofibrils or they express only minor amounts thereof. They also fail to express many proteins important for metabolism of muscle cells. The challenge with clinically relevant concentrations of doxorubicin did not induce a proteomic signature that has been previously noted in primary cardiomyocytes or adult hearts. Instead, several alterations previously described in other cells of mesodermal origin, such as fibroblasts, were observed (e.g., severe down regulation of collagen synthesis pathway). In conclusion, the molecular phenotype of H9c2 cells resembles very immature myogenic cells with skeletal muscle commitment upon differentiation and thus, translatability of findings obtained in these cells deserves caution. PMID- 26515554 TI - Pathophysiology of lipid droplet proteins in liver diseases. AB - Cytosolic lipid droplets (LDs) are present in most cell types, and consist of a core comprising neutral lipids, mainly triglycerides and sterol esters, surrounded by a monolayer of phospholipids. LDs are heterogeneous in their structure, chemical composition, and tissue distribution. LDs are coated by several proteins, including perilipins and other structural proteins, lipogenic enzymes, lipases and membrane-trafficking proteins. Five proteins of the perilipin (PLIN) family (PLIN1 (perilipin), PLIN2 (adipose differentiation related protein), PLIN3 (tail-interacting protein of 47kDa), PLIN4 (S3-12), and PLIN5 (myocardial lipid droplet protein)), are associated with LD formation. More recently, the CIDE family of proteins, hypoxia-inducible protein 2 (HIG2), and patanin-like phospholipase domain-containing 3 (PNPLA3) have also gained attention in hepatic LD biology. Evidence suggests that LD proteins are involved in the pathophysiology of fatty liver diseases characterized by excessive lipid accumulation in hepatocytes. This review article will focus on how hepatic LDs and their associated proteins are involved in the pathogenesis of three chronic liver conditions: hepatitis C virus infection, non-alcoholic fatty liver disease, and alcoholic liver disease. PMID- 26515556 TI - Synthesis and biological evaluation of novel fluorine-containing stilbene derivatives as fungicidal agents against phytopathogenic fungi. AB - The rising development of resistance to conventional fungicides is driving the search for new alternative candidates to control plant diseases. In this study, a series of new fluorine-containing stilbene derivatives was synthesized on the basis of our previous quantitative structure-activity relationship analysis results. Bioassays in vivo revealed that the title compounds exhibited potent fungicidal activities against phytopathogenic fungi (Colletotrichum lagenarium and Pseudoperonospora cubensis) from cucumber plants. In comparison to the previous results, the introduction of a fluorine moiety showed improved activities of some compounds against those fungi. Notably, compound 9 exhibited a control efficacy against C. lagenarium (83.4 +/- 1.3%) comparable to that of commercial fungicide (82.7 +/- 1.7%). For further understanding the possible mode of action of the stilbene against C. lagenarium, the effects on hyphal morphology, electrolyte leakage, and respiration of mycelial cell suspension were studied. Microscopic observation showed considerably deformed mycelial morphology. The conductivity of mycelial suspension increased in the presence of compound 9, whereas no significantly inhibitory effect on respiration was observed. Taken together, the fungicidal mechanism of this stilbene is associated with its membrane disruption effect, resulting in increased membrane permeability. These results provide important clues for mechanistic study and derivatization of stilbenes as alternative sources of fungicidal agents for plant disease control. PMID- 26515557 TI - Dimethylarginine dimethylaminohydrolase 2 promotes tumor angiogenesis in lung adenocarcinoma. AB - Although embryonal proteins have been used as tumor marker, most are not useful for detection of early malignancy. In the present study, we developed mouse monoclonal antibodies against fetal lung of miniature swine, and screened them to find an embryonal protein that is produced at the early stage of malignancy, focusing on lung adenocarcinoma. We found an antibody clone that specifically stained stroma of lung adenocarcinoma. LC-MS/MS identified the protein recognized by this clone as dimethylarginine dimethylaminohydrolase 2 (DDAH2), an enzyme known for antiatherosclerotic activity. DDAH2 was found to be expressed in fibroblasts of stroma of malignancies, with higher expression in minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma than in adenocarcinoma in situ (AIS). Moreover, tumors with high stromal expression of DDAH2 had a poorer prognosis than those without. In vitro analysis showed that DDAH2 increases expression of endothelial nitric oxide synthase (eNOS), inducing proliferation and capillary-like tube formation of vascular endothelial cells. In resected human tissues, eNOS also showed higher expression in invasive adenocarcinoma than in AIS and normal lung, similarly to DDAH2. Our data indicate that expression of DDAH2 is associated with invasiveness of lung adenocarcinoma via tumor angiogenesis. DDAH2 expression might be a prognostic factor in lung adenocarcinoma. PMID- 26515558 TI - Confinement of Ionic Liquids in Nanocages: Tailoring the Molecular Sieving Properties of ZIF-8 for Membrane-Based CO2 Capture. AB - Fine-tuning of effective pore size of microporous materials is necessary to achieve precise molecular sieving properties. Herein, we demonstrate that room temperature ionic liquids can be used as cavity occupants for modification of the microenvironment of MOF nanocages. Targeting CO2 capture applications, we tailored the effective cage size of ZIF-8 to be between CO2 and N2 by confining an imidazolium-based ionic liquid [bmim][Tf2 N] into ZIF-8's SOD cages by in-situ ionothermal synthesis. Mixed matrix membranes derived from ionic liquid-modified ZIF-8 exhibited remarkable combinations of permeability and selectivity that transcend the upper bound of polymer membranes for CO2 /N2 and CO2 /CH4 separation. We observed an unusual response of the membranes to varying pressure, that is, an increase in the CO2 /CH4 separation factor with pressure, which is highly desirable for practical applications in natural gas upgrading. PMID- 26515560 TI - EEG Correlates of Relative Motion Encoding. AB - A large portion of the visual cortex is organized retinotopically, but perception is usually non-retinotopic. For example, a reflector on the spoke of a bicycle wheel appears to move on a circular or prolate cycloidal orbit as the bicycle moves forward, while in fact it traces out a curtate cycloidal trajectory. The moving bicycle serves as a non-retinotopic reference system to which the motion of the reflector is anchored. To study the neural correlates of non-retinotopic motion processing, we used the Ternus-Pikler display, where retinotopic processing in a stationary reference system is contrasted against non-retinotopic processing in a moving one. Using high-density EEG, we found similar brain responses for both retinotopic and non-retinotopic rotational apparent motion from the earliest evoked peak (around 120 ms) and throughout the rest of the visual processing, but only minor correlates of the motion of the reference system itself (mainly around 100-120 ms). We suggest that the visual system efficiently discounts the motion of the reference system from early on, allowing a largely reference system independent encoding of the motion of object parts. PMID- 26515559 TI - HSP25 down-regulation enhanced p53 acetylation by dissociation of SIRT1 from p53 in doxorubicin-induced H9c2 cell apoptosis. AB - Heat shock proteins (HSPs) play important roles in cellular stress resistance. Previous reports had already suggested that HSP27 played multiple roles in preventing doxorubicin-induced cardiotoxicity. Although HSP25 might have biological functions similar to its human homolog HSP27, the mechanism of HSP25 is still unclear in doxorubicin-induced cardiomyocyte apoptosis. To investigate HSP25 biological function on doxorubicin-induced apoptosis, flow cytometry was employed to analyze cell apoptosis in over-expressing HSP25 H9c2 cells in presence of doxorubicin. Unexpectedly, the H9c2 cells of over-expressing HSP25 have no protective effect on doxorubicin-induced apoptosis. Moreover, no detectable interactions were detected by coimmunoprecipitation between HSP25 and cytochrome c, and HSP25 over-expression failed in preventing cytochrome c release induced by doxorubicin. However, down-regulation of endogenous HSP25 by a specific small hairpin RNA aggravates apoptosis in H9c2 cells. Subsequent studies found that HSP25, but not HSP90, HSP70, and HSP20, interacted with SIRT1. Knockdown of HSP25 decreased the interaction between SIRT1 and p53, leading to increased p53 acetylation on K379, up-regulated pro-apoptotic Bax protein expression, induced cytochrome c release, and triggered caspase-3 and caspase-9 activation. These findings indicated a novel mechanism by which HSP25 regulated p53 acetylation through dissociation of SIRT1 from p53 in doxorubicin-induced H9c2 cell apoptosis. PMID- 26515561 TI - Biogas process parameters--energetics and kinetics of secondary fermentations in methanogenic biomass degradation. AB - Pool sizes of short-chain fatty acids (formate, acetate, propionate, and butyrate), hydrogen, and carbon monoxide were assayed in digesting sludge from four different methanogenic reactors degrading either sewage sludge or agricultural products and wastes at pH 8.0 and 40 or 47 degrees C. Free reaction energies were calculated for the respective degradation reactions involved, indicating that acetate, propionate, and butyrate degradation all supplied sufficient energy (-10 to -30 kJ per mol reaction) to sustain the microbial communities involved in the respective processes. Pools of formate and hydrogen were energetically equivalent as electron carriers. In the sewage sludge reactor, homoacetogenic acetate formation from H2 and CO2 was energetically feasible whereas syntrophic acetate oxidation appeared to be possible in two biogas reactors, one operating at enhanced ammonia content (4.5 g NH4 (+)-N per l) and the other one at enhanced temperature (47 degrees C). Maximum capacities for production of methanogenic substrates did not exceed the consumption capacities by hydrogenotrophic and aceticlastic methanogens. Nonetheless, the capacity for acetate degradation appeared to be a limiting factor especially in the reactor operating at enhanced ammonia concentration. PMID- 26515562 TI - Biotransformations of bisphenols mediated by a novel Arthrobacter sp. strain YC RL1. AB - Arthrobacter sp. strain YC-RL1, capable of utilizing bisphenol A (BPA) as sole carbon source for growth, was isolated from petroleum contaminated soil. YC-RL1 could rapidly degrade BPA in a wide range of pH (5.0-9.0) and temperature (20-40 degrees C). Substrate analysis found that YC-RL1 could also degrade bisphenol F (BPF) and tetrabromobisphenol A (TBBPA). The maximum and minimum concentrations of BPA (0.2-600 mg/L), BPF (0.2-600 mg/L), and TBBPA (0.2-300 mg/L) for efficient biodegradation were detected. The released bromide ion and metabolic intermediates of BPF and BPA/TBBPA were detected, as well as the degradation pathways for BPF and BPA/TBBPA were deduced tentatively. The present study provides important information for the investigation of BPs degrading mechanism and the application of microbial remediation in BP-contaminated environment. This study is the first report about a genus Arthrobacter bacterium which could simultaneously degrade BPA, BPF, and TBBPA. PMID- 26515563 TI - Nitrite-dependent anaerobic methane oxidizing bacteria along the water level fluctuation zone of the Three Gorges Reservoir. AB - The nitrite-dependent anaerobic methane oxidation (n-damo) mediated by "Candidatus Methylomirabilis oxyfera" connects the biogeochemical carbon and nitrogen cycles in a novel way. Many environments have been reported to harbor such organism being slow-growing and oxygen-sensitive anaerobes. Here, we focused on the population of n-damo bacteria in a fluctuating habitat being the wetland in the water level fluctuation zone (WLFZ) of the Three Gorges Reservoir (TGR) in China. A molecular approach demonstrated positive amplifications when targeting the functional pmoA gene only in the lower sites which endured longer flooding time in an elevation gradient. Only 1 operational taxonomic unit (OTU) in the lower elevation zone targeting the 16S ribosomal RNA (rRNA) gene was clustering into the NC-10 group a, which is presumed to be the true n-damo group. Moreover, a relatively low level of diversity was observed in this study. The abundances were as low as 4.7 * 10(2) to 1.5 * 10(3) copies g(-1) dry soil (ds) in the initial stage, which were almost the lowest reported. However, an increase was observed (3.2 * 10(3) to 5.3 * 10(4) copies g(-1) ds) after nearly 6 months of flooding. Intriguingly, the abundance of n-damo bacteria correlated positively with the accumulated flooding time (AFT). The current study revealed that n-damo bacteria can be detected in a fluctuating environment and the sites with longer flooding time seem to be preferred habitats. The water flooding may be the principal factor in this ecosystem by creating anoxic condition. The wide range of such habitats suggests a high potential of n-damo bacteria to play a key role in natural CH4 consumption. PMID- 26515564 TI - The Places We Can Go! PMID- 26515565 TI - Letters to the Editor. PMID- 26515567 TI - Diabetes Education and Support: A Must for Students With Diabetes. AB - Ongoing diabetes self-management education and support is critical to helping youth with diabetes and their families learn about the disease, make and sustain behavioral changes, and cope with the reality of a chronic illness. Diabetes self management education and support is best provided by a multidisciplinary team. School nurses are an important part of the student's diabetes health care team. This article highlights information and resources that school nurses can use to help support students with diabetes, their families, and other school personnel. PMID- 26515566 TI - Asthma Management in Educational Settings: Implementing Guideline-Based Care in Washington State Schools. AB - Managing asthma in the schools is complex and requires careful planning. This article highlights key steps in implementing guideline-based care for children with asthma in Washington State schools: assessing students, establishing acuity, communicating with parents, and training staff. Advance planning can improve outcomes for students, parents, and school staff in managing this complex and prevalent disease. NASN recently developed asthma management guidelines. Developing state-specific guidelines provides an opportunity to speak specifically to state laws and nurse practice acts while also reinforcing the importance of specialized practice to school nurses, school administrators and teachers, parents, and students. PMID- 26515568 TI - Childhood Obesity and Sleep Disturbances. AB - Childhood obesity has been linked with many comorbidities, including sleep disturbances and daytime sleepiness. This article will specifically discuss the association between obesity and obstructive sleep apnea and excessive daytime sleepiness. Signs and symptoms, risk factors, and treatment options will also be addressed. School nurses are in a prime position to help identify children who have the daytime cognitive and behavioral effects of obstructive sleep apnea. PMID- 26515569 TI - Step Up and Be Counted! PMID- 26515570 TI - The 2015 NASN School Nurse Survey: Developing and Providing Leadership to Advance School Nursing Practice. AB - This article summarizes the results of the 2015 NASN School Nurse Survey, identifies similarities and differences between this survey and the 2013 NASN School Nurse Survey, and evaluates the possible impacts of this data on the organization. PMID- 26515571 TI - Culturally Competent School Nurse Practice. AB - School nurses are among the professional specialty disciplines in the school environment that have the unique opportunity of exploring and building upon effective practices when working and providing service to diverse populations. As such, school nurses must not only acquire the skills to survive in the culture of education; they must also develop cultural competence by engaging in self identity and reflection, understanding cultural differences, being culturally responsive, identifying social injustices, and engaging in life-long learning experiences. PMID- 26515572 TI - School Nurse Cultural Competence Needs Assessment: Results and Response. AB - NASN conducted a needs assessment to learn about the cultural competence skills needed by school nurses. The purpose of this article is to describe the results of the needs assessment and describe actions taken to address cultural competency needs for the U.S. school nurse workforce. PMID- 26515573 TI - Grief Across Cultures: Awareness for Schools. PMID- 26515574 TI - Immune-Mediated Necrotizing Myopathy: Update on Diagnosis and Management. AB - The idiopathic inflammatory myopathies (IIMs) comprise a group of autoimmune disorders that target skeletal muscle. They are characterized by typical laboratory and clinical features including muscle weakness, elevated muscle enzymes, characteristic histopathology of muscle biopsies, as well as electromyography abnormalities. The IIMs are divided into polymyositis, dermatomyositis, inclusion body myositis, nonspecific myositis, and immune mediated necrotizing myopathy (IMNM). IMNM is distinguished by the absence of primary inflammation on muscle biopsy. IMNM may be associated with myositis specific autoantibodies (i.e., anti-SRP and anti-HMGCR) and malignancy, in association with viral infections (HIV or hepatitis C), or in relation to other connective tissue diseases (i.e., scleroderma). Typical clinical findings such as severe muscle weakness, highly elevated creatine kinase (CK) levels, as well as resistance to conventional immunosuppressive therapy are associated with this subtype of IIM. This review provides an overview of this disease entity and focuses on its diagnosis and treatment. PMID- 26515576 TI - Calretinin Variant in Hirschsprung Disease: Pretransitional Sign and Surgical Planning. AB - Objectives Calretinin immunohistochemistry (IHC) with slight submucosal positivity (variant) has been reported in short forms of Hirschsprung disease (HD). The first aim of our study was to confirm this variant being a pretransitional sign. The second was to evaluate if its presence on suction rectal biopsy was reliable enough for surgical planning. Methods We performed a monocentric retrospective study of all rectosigmoid HD between 2009 and 2014. Suction rectal biopsy defined two groups of calretinin results: P- group with no staining and P+ group with slight positivity. P- group final resection specimen was retrospectively reanalyzed looking for the variant to appear within the aganglionic bowel. P+ group surgical management was analyzed in terms of initial symptoms, radiological results, type of surgery and outcome, before and after formal identification of the variant by our pathologists (2011). Results Overall, 54 patients with rectosigmoid HD were included from 2009 to 2014. In the P- group (48.2%), the variant pattern finally appeared on all surgical resection specimens, 1 cm before the transitional zone (minimum-maximum: 0-5 cm). In the P+ group, 46% of these patients had peroperative biopsies before the transanal pull through before 2011 against 10% after 2011, with 100% of ganglionic coloanal anastomosis and similar outcome. Conclusion We confirmed our hypothesis of this varied pattern of calretinin being a pretransitional sign only visible on rectal suction biopsies in short segment HD and reliable enough to plan direct transanal pull through. PMID- 26515577 TI - Laparoscopy in Pediatric Abdominal Trauma: A 13-Year Experience. AB - Introduction Abdominal injuries are common, costly, deadly, and a source of considerable uncertainty in pediatric trauma. In some circumstances, laparoscopy offers a diagnostic and therapeutic alternative with less morbidity than standard exploration, and more certainty than most imaging. In this study, we review our experience with laparoscopic exploration for trauma. We hypothesized that laparoscopy could be employed effectively in stable blunt or penetrating trauma patients in whom diagnostic uncertainty was unresolved by imaging. Patients and Methods A retrospective review of the trauma database identified all children admitted to our Level I pediatric trauma center between January 1, 2000, and December 31, 2012, requiring surgical abdominal exploration. The utilization of laparoscopy and laparotomy was charted over the 13-year period. Negative laparoscopies and laparotomies and nontherapeutic laparoscopies and laparotomies were examined to investigate clinical scenarios in which laparotomy might have been avoided. Statistical analyses were performed using descriptive statistics, simple linear regression analysis, and Mann-Whitney U test (p < 0.05). Results Over the 13-year study period, there were 16,321 trauma admissions. Of these, 119 patients (0.7%) required surgical abdominal exploration: 81 patients underwent laparotomy and 38 patients underwent laparoscopy. In 13 patients (34.2%), laparoscopic exploration ruled out injuries. In nine patients (23.7%), laparoscopy identified an injury for which no surgical intervention was necessary. In nine patients (23.7%), an injury was repaired laparoscopically. In seven cases (18.4%), the identified injury required conversion to laparotomy. There were no missed injuries. In the laparotomy group, a less invasive approach could have yielded the same information in 8.7% of patients. Laparoscopy was more likely to be used after a qualitative change in institutional minimally invasive surgical capability. Conclusion Laparoscopy reliably resolves diagnostic uncertainty in selected cases of pediatric abdominal blunt and penetrating trauma. In a hemodynamically stable patient with a concerning exam and inconclusive imaging, laparoscopy provides sensitive diagnostic capability and opportunity for definitive repair with diminished surgical morbidity. PMID- 26515578 TI - Microbial diversity on intravascular catheters from paediatric patients. AB - Microorganisms play important roles in intravascular catheter (IVC)-related infections, which are the most serious complications in children with IVCs, leading to increased hospitalisation, intensive care admissions, extensive antibiotic treatment and mortality. A greater understanding of bacterial communities is needed in order to improve the management of infections. We describe here the systematic culture-independent evaluation of IVC bacteriology in IVC biofilms. Twenty-four IVC samples (six peripherally inserted central catheters, eight central venous catheters and ten arterial catheters) were collected from 24 paediatric patients aged 0 to 14 years old. Barcoded amplicon libraries produced from genes coding 16S rRNA and roll-plate culture methods were used to determine the microbial composition of these samples. From a total of 1,043,406 high-quality sequence reads, eight microbial phyla and 136 diverse microbial genera were detected, separated into 12,224 operational taxonomic units (OTUs). Three phyla (Actinobacteria, Firmicutes and Proteobacteria) predominate the microorganism on the IVC surfaces, with Firmicutes representing nearly half of the OTUs found. Among the Firmicutes, Staphylococcus (15.0% of 16S rRNA reads), Streptococcus (9.6%) and Bacillus (6.1%) were the most common. Community composition did not appear to be affected by patients' age, gender, antibiotic treatment or IVC type. Differences in IVC microbiota were more likely associated with events arising from catheter dwell time, rather than the type of IVC used. PMID- 26515580 TI - Conjugated porous polymers as precursors for electrocatalysts and storage electrode materials. AB - Conjugated porous polymers were used as precursors to prepare nitrogen and sulphur doped carbon atoms, which were then used for oxygen reduction and energy storage. PMID- 26515579 TI - Dynamics of nasal carriage of methicillin-resistant Staphylococcus aureus among healthcare workers in a tertiary-care hospital in Peru. AB - The study aims were to describe the frequency and dynamics of methicillin resistant Staphylococcus aureus (MRSA) carriage among healthcare workers (HCWs), and to compare the molecular epidemiology of MRSA isolates from HCWs with those from patients with bacteremia. HCWs were interviewed and three nasal swabs were collected in a hospital in Lima, Peru, during 2009-2010. Consecutive S. aureus blood culture isolates from patients with bacteremia in the same hospital were also collected. SCCmec, multilocus sequence typing (MLST), and spa typing were performed. Persistent carriage was defined if having at least two consecutive cultures grown with S. aureus harboring an identical spa type. Among 172 HCWs included, the proportions of S. aureus and MRSA nasal carriage during first sampling were 22.7 % and 8.7 %, respectively. From 160 HCWs who were sampled three times, 12.5 % (20/160) were persistent S. aureus carriers and 26.9 % (43/160) were intermittent carriers. MRSA carriage among persistent and intermittent S. aureus carriers was 45.0 % (9/20) and 37.2 % (16/43), respectively. Fifty-six S. aureus blood culture isolates were analyzed, and 50 % (n = 28) were MRSA. Multidrug resistant ST5-spa t149-SCCmec I and ST72-spa t148 SCCmec non-typeable were the two most frequent genotypes detected among HCWs (91.7 %, i.e., 22/24 HCW in whom MRSA was isolated in at least one sample) and patients (24/28, 85.7 %). In conclusion, we found high proportions of MRSA among persistent and intermittent S. aureus nasal carriers among HCWs in a hospital in Lima. They belonged to similar genetic lineages as those recovered from patients with bacteremia. PMID- 26515581 TI - Three orphans one should know: red scalp, red ear and red scrotum syndrome. PMID- 26515582 TI - Cap-dependent translation is mediated by 'RNA looping' rather than 'ribosome scanning'. AB - The 40S ribosomal subunit cannot directly recognize the start codon of eukaryotic mRNAs. Instead, it recognizes the start codon after its association with the 5' cap structure via translation initiation factors. Base-by-base inspection of the 5'UTR by a scanning ribosome is the generally accepted hypothesis of start codon selection. As part of an effort to confirm the underlying mechanism of start codon selection by the 40S ribosome, we investigated the role of eIF4G, which participates in the recruitment of 40S ribosomes to various translation enhancers, such as 5'-cap structure, poly(A) tail, and several internal ribosome entry sites. We found that an artificial translation factor composed of recombinant eIF4G fused with MS2 greatly enhanced translation of an upstream reporter gene when it was tethered to the 3'UTR. These data suggest that the 40S ribosome recruited to a translation enhancer can find the start codon by looping of the intervening RNA segment. The 'RNA-looping' hypothesis of translation start codon recognition was further supported by an analysis of the effect of 5'UTR length on translation efficiency and the mathematically predicted probability of RNA-loop-mediated interactions between the start codon and the 40S ribosome associated at the 5'-end. PMID- 26515583 TI - Disparities in Alcohol, Drug Use, and Mental Health Condition Prevalence and Access to Care in Rural, Isolated, and Reservation Areas: Findings From the South Dakota Health Survey. AB - PURPOSE: Research on urban/rural disparities in alcohol, drug use, and mental health (ADM) conditions is inconsistent. This study describes ADM condition prevalence and access to care across diverse geographies in a predominantly rural state. METHODS: Multimodal cross-sectional survey in South Dakota from November 2013 to October 2014, with oversampling in rural areas and American Indian reservations. Measures assessed demographic characteristics, ADM condition prevalence using clinical screenings and participant self-report, perceived need for treatment, health service usage, and barriers to obtaining care. We tested for differences among urban, rural, isolated, and reservation geographic areas, controlling for participant age and gender. FINDINGS: We analyzed 7,675 surveys (48% response rate). Generally, ADM condition prevalence rates were not significantly different across geographies. However, respondents in isolated and reservation areas were significantly less likely to have access to primary care. Knowledge of treatment options was significantly lower in isolated regions and individuals in reservation areas had significantly lower odds of reporting receipt of all needed care. Across the sample there was substantial discordance between ADM clinical screenings and participant self-reported need; 98.1% of respondents who screened positive for alcohol or drug misuse and 63.8% of respondents who screened positive for a mental health condition did not perceive a need for care. CONCLUSION: In a predominantly rural state, geographic disparities in ADM conditions are related to differences in access as opposed to prevalence, particularly for individuals in isolated and reservation areas. Educational interventions about ADM condition characteristics may be as important as improving access to care. PMID- 26515584 TI - Altered expression of CKs 14/20 is an early event in a rat model of multistep bladder carcinogenesis. AB - Cytokeratins (CKs) 14 and 20 are promising markers for diagnosing urothelial lesions and for studying their prognosis and histogenesis. This work aimed to study the immunohistochemical staining patterns of CK14/20 during multistep carcinogenesis leading to papillary bladder cancer in a rat model. Thirty female Fischer 344 rats were divided into three groups: group 1 (control); group 2, which received N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 20 weeks plus 1 week without treatment; and group 3, which received BBN for 20 weeks plus 8 weeks without treatment. Bladder lesions were classified histologically. CK14 and CK20 immunostaining was assessed according to its distribution and intensity. In control animals, 0-25% of basal cells and umbrella cells stained positive for CK14 and CK20 respectively. On groups 2 and 3, nodular hyperplastic lesions showed normal CK20 and moderately increased CK14 staining (26-50% of cells). Dysplasia, squamous metaplasia, papilloma, papillary tumours of low malignant potential and low- and high-grade papillary carcinomas showed increased CK14 and CK20 immunostaining in all epithelial layers. Altered CK14 and CK20 expression is an early event in urothelial carcinogenesis and is present in a wide spectrum of urothelial superficial neoplastic and preneoplastic lesions. PMID- 26515585 TI - Erratum to: Sequence Elucidation of an Unknown Cyclic Peptide of High Doping Potential by ETD and CID Tandem Mass Spectrometry. PMID- 26515586 TI - Experimental quantum fingerprinting with weak coherent pulses. AB - Quantum communication holds the promise of creating disruptive technologies that will play an essential role in future communication networks. For example, the study of quantum communication complexity has shown that quantum communication allows exponential reductions in the information that must be transmitted to solve distributed computational tasks. Recently, protocols that realize this advantage using optical implementations have been proposed. Here we report a proof-of-concept experimental demonstration of a quantum fingerprinting system that is capable of transmitting less information than the best-known classical protocol. Our implementation is based on a modified version of a commercial quantum key distribution system using off-the-shelf optical components over telecom wavelengths, and is practical for messages as large as 100 Mbits, even in the presence of experimental imperfections. Our results provide a first step in the development of experimental quantum communication complexity. PMID- 26515587 TI - A phase I clinical trial utilizing autologous tumor-infiltrating lymphocytes in patients with primary hepatocellular carcinoma. AB - This report describes an ongoing Phase I clinical trial testing the safety of adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) in patients with primary hepatocellular carcinoma (HCC). Fifteen HCC patients were treated with their activated and expanded TILs following tumor resection. From a total of 17 patients with HCC, TIL were successfully expanded from 15 patients (88%), whereas two patients showed minimal or no expansion of TIL. Transient increase in the frequency of T cells was observed after adoptive transfer who was found only associated with grade I flu-like symptoms and malaise. After a median follow-up of 14 months, 15 patients (100%) were alive; and 12 patients (80%) showed no evidence of disease, 3 patients (patient 1,11,12) had tumor recurrence. The time to the diagnosis of tumor recurrence following therapy ranged from 105 to 261 days. These results indicate that immunotherapy with activated and expanded autologous TIL could be successfully performed with low toxicity, thus would serve as a novel treatment modality for patients with HCC. PMID- 26515588 TI - Mitochondrial oncobioenergetic index: A potential biomarker to predict progression from indolent to aggressive prostate cancer. AB - Mitochondrial function is influenced by alterations in oncogenes and tumor suppressor genes and changes in the microenvironment occurring during tumorigenesis. Therefore, we hypothesized that mitochondrial function will be stably and dynamically altered at each stage of the prostate tumor development. We tested this hypothesis in RWPE-1 cells and its tumorigenic clones with progressive malignant characteristics (RWPE-1 < WPE-NA22 < WPE-NB14 < WPE-NB11 < WPE-NB26) using high-throughput respirometry. Our studies demonstrate that mitochondrial content do not change with increasing malignancy. In premalignant cells (WPE-NA22 and WPE-NB14), OXPHOS is elevated in presence of glucose or glutamine alone or in combination compared to RWPE-1 cells and decreases with increasing malignancy. Glutamine maintained higher OXPHOS than glucose and suggests that it may be an important substrate for the growth and proliferation of prostate epithelial cells. Glycolysis significantly increases with malignancy and follow a classical Warburg phenomenon. Fatty acid oxidation (FAO) is significantly lower in tumorigenic clones and invasive WPE-NB26 does not utilize FAO at all. In this paper, we introduce for the first time the mitochondrial oncobioenergetic index (MOBI), a mathematical representation of oncobioenergetic profile of a cancer cell, which increases significantly upon transformation into localized premalignant form and rapidly falls below the normal as they become aggressive in prostate tumorigenesis. We have validated this in five prostate cancer cell lines and MOBI appears to be not related to androgen dependence or mitochondrial content, but rather dependent on the stage of the cancer. Altogether, we propose that MOBI could be a potential biomarker to distinguish aggressive cancer from that of indolent disease. PMID- 26515589 TI - Genes with stable DNA methylation levels show higher evolutionary conservation than genes with fluctuant DNA methylation levels. AB - Different human genes often exhibit different degrees of stability in their DNA methylation levels between tissues, samples or cell types. This may be related to the evolution of human genome. Thus, we compared the evolutionary conservation between two types of genes: genes with stable DNA methylation levels (SM genes) and genes with fluctuant DNA methylation levels (FM genes). For long-term evolutionary characteristics between species, we compared the percentage of the orthologous genes, evolutionary rate dn/ds and protein sequence identity. We found that the SM genes had greater percentages of the orthologous genes, lower dn/ds, and higher protein sequence identities in all the 21 species. These results indicated that the SM genes were more evolutionarily conserved than the FM genes. For short-term evolutionary characteristics among human populations, we compared the single nucleotide polymorphism (SNP) density, and the linkage disequilibrium (LD) degree in HapMap populations and 1000 genomes project populations. We observed that the SM genes had lower SNP densities, and higher degrees of LD in all the 11 HapMap populations and 13 1000 genomes project populations. These results mean that the SM genes had more stable chromosome genetic structures, and were more conserved than the FM genes. PMID- 26515590 TI - Expressions of glia maturation factor-beta by tumor cells and endothelia correlate with neovascularization and poor prognosis in human glioma. AB - Glia maturation factor-beta (GMF-beta) has been reported to promote glial differentiation, and act as a negative prognostic indicator in certain cancers. However, its roles in glioma progression remain unclear. Since neurogenesis and vasculogenesis were proved to share some common regulators during gliomagenesis, we aim to explore the potential impact of GMF-beta on tumor neovascularization and patient survival in glioma. In this study, we first detected GMF-beta expression not only in tumor cells but also in microvascular endothelia by double immunohistochemical staining. Both tumoral and endothelial GMF-beta expression levels were positively correlated with tumor grade and microvessel density (MVD), while negatively associated with poor prognoses of the patients. Interestingly, multivariate analysis demonstrated that endothelial GMF-beta expression level was the only independent predictor of progression-free and overall survival of glioma patients. The results of in vitro angiogenesis assay showed that GMF-beta knockdown significantly inhibited tubulogenesis of human U87 glioblastoma cells. Furthermore, GMF-beta knockdown suppressed tumor growth and the formation of human-CD31 positive (glioma cell-derived) microvessels in a mouse orthotopic U87 glioma model. Our results demonstrated that GMF-beta is an important player in glioma progression via promoting neovascularization. GMF-beta may therefore be a novel prognostic marker as well as a potential therapeutic target for glioma. PMID- 26515591 TI - A novel prognostic biomarker SPC24 up-regulated in hepatocellular carcinoma. AB - SPC24 is an important component of the nuclear division cycle 80 (Ndc80) kinetochore complex, which plays an essential role in the coupling of kinetochore to spindle microtubules (MTs) and the accurate segregation of chromosomes during mitosis. However, the functional role of SPC24 in hepatocellular carcinoma (HCC) remains unknown. Here, we detected the expression of SPC24 in HCC and analyzed its association with clinicopathologic features and prognosis of HCC patients. The expression of SPC24 mRNA was investigated in 212 cases of paired HCC and adjacent liver tissues by quantitative real-time PCR (qRT-PCR) and in the tissues of 20 HCC patients by semi-quantitative RT-PCR. Additionally, the expression of SPC24 protein was detected in 69 cases of HCC by immunohistochemistry (IHC) or in 2 cases of HCC tissues by Western-blotting. Furthermore, small interfering RNA (siRNA)-mediated silencing of SPC24 was employed in SMMC7721 and HepG2 human HCC cells to investigate cell proliferation, invasion and apoptosis. Survival curves were plotted using the Kaplan-Meier method, and differences in survival probability were obtained using the log-rank test. Independent predictors associated with disease-free survival (DFS) and overall survival (OS) were analyzed using the Cox proportional-hazards regression model. In this study, we showed that SPC24 was noticeably increased in HCC tissues compared to normal adjacent noncancerous tissues, at both mRNA and protein levels. High expression of SPC24 was significantly correlated with alpha-fetoprotein (AFP) (p = 0.044), median size (p = 0.030), tumor number (p = 0.019), and Barcelona-Clinic Liver Cancer (BCLC) stage (p = 0.015). Kaplan-Meier analysis showed that the DFS and OS of high SPC24 expression group was significantly shorter than that of low SPC24 expression group (p < 0.001; p = 0.001; respectively). The prognostic impact of SPC24 was further confirmed by stratified survival analysis. Importantly, multivariate analysis identified SPC24 upregualtion (p = 0.001), PVTT (p = 0.007), size of tumor > 5 cm (p < 0.001) as independent risk factors of DFS after resection, and SPC24 upregualtion (p < 0.001), PVTT (p = 0.029), size of tumor > 5 cm (p = 0.002), recurrence (p < 0.001) as independent prognostic factors for the OS of HCC patients. Additionally, siRNA-mediated silencing of SPC24 dramatically suppressed cell growth, adhesion, invasion and increased apoptosis in HCC cells. In conclusion, these results showed for the first time that SPC24 expression was significantly up-regulated in HCC, which may act as a novel prognostic biomarker for patients suffering from this deadly disease. Additionally, silence of SPC24 inhibiting HCC cell growth indicated that SPC24 may be a promising molecular target for HCC therapy. PMID- 26515592 TI - Inhibition of the Tcf/beta-catenin complex increases apoptosis and impairs adrenocortical tumor cell proliferation and adrenal steroidogenesis. AB - BACKGROUND: To date, there is no effective therapy for patients with advanced/metastatic adrenocortical cancer (ACC). The activation of the Wnt/beta catenin signaling is frequent in ACC and this pathway is a promising therapeutic target. AIM: To investigate the effects of the inhibition of the Wnt/beta-catenin in ACC cells. METHODS: Adrenal (NCI-H295 and Y1) and non-adrenal (HeLa) cell lines were treated with PNU-74654 (5-200 MUM) for 24-96 h to assess cell viability (MTS-based assay), apoptosis (Annexin V), expression/localization of beta-catenin (qPCR, immunofluorescence, immunocytochemistry and western blot), expression of beta-catenin target genes (qPCR and western blot), and adrenal steroidogenesis (radioimmunoassay, qPCR and western blot). RESULTS: In NCI-H295 cells, PNU-74654 significantly decreased cell proliferation 96 h after treatment, increased early and late apoptosis, decreased nuclear beta-catenin accumulation, impaired CTNNB1/beta-catenin expression and increased beta-catenin target genes 48 h after treatment. No effects were observed on HeLa cells. In NCI-H295 cells, PNU-74654 decreased cortisol, testosterone and androstenedione secretion 24 and 48 h after treatment. Additionally, in NCI-H295 cells, PNU-74654 decreased SF1 and CYP21A2 mRNA expression as well as the protein levels of STAR and aldosterone synthase 48 h after treatment. In Y1 cells, PNU-74654 impaired corticosterone secretion 24 h after treatment but did not decrease cell viability. CONCLUSIONS: Blocking the Tcf/beta-catenin complex inhibits the Wnt/beta-catenin signaling in adrenocortical tumor cells triggering increased apoptosis, decreased cell viability and impairment of adrenal steroidogenesis. These promising findings pave the way for further experiments inhibiting the Wnt/beta-catenin pathway in pre-clinical models of ACC. The inhibition of this pathway may become a promising adjuvant therapy for patients with ACC. PMID- 26515593 TI - Hepatitis B virus (HBV) receptors: Deficiency in tumor results in scant HBV infection and overexpression in peritumor leads to higher recurrence risk. AB - Hepatitis B virus (HBV) infection is a risk factor for hepatocarcinogenesis and recurrence. Here, we sought to characterize intratumoral and peritumoral expression of HBsAg and its specific receptors in HBsAg-positive hepatocellular carcinoma (HCC) patients and further examined their correlation with the recurrence-free survival (RFS). HCC tissue and adjacent normal tissue specimens were acquired from HBsAg-positive patients. The presence of HBsAg and receptors, as well as hepatic progenitor cells (HPCs) were detected by tissue microassay and immunohistochemistry. Necroinflammatory activity was evaluated by HE staining. The mean IOD of HBsAg and HBV DNA in the intratumoral tissues was markedly lower than that in the peritumoral tissues (P < 0.001). Pearson correlation analysis further showed a significant correlation between the expression of HBsAg and NTCP (r = 0.461, P < 0.001) or ASGPR (r = 0.506, P < 0.001) in peritumoral tissues. And the peritumoral HBsAg and receptors presented a positive association with necroinflammatory activity (P < 0.05). Inflammation induced by HBV infection presented a positive association with HPCs activation (P < 0.05). Additionally, due to lack of HBV receptors, HPCs was not preferentially infected with HBV, but activated HPCs had a significant correlation with HBsAg expression in peritumoral tissues, and the peritumoral HPCs activation was associated with RFS of HCC patients, therefore, the overexpression of HBsAg and receptors in peritumor were also with higher recurrence risk (P < 0.05). In conclusion, lack of HBV receptors resulted in scant HBV infection in tumor cells, and overexpression of HBsAg and receptors in peritumor was strongly associated with higher recurrence risk in HCC patients. PMID- 26515595 TI - Dietary fat and fatty acid intake and epithelial ovarian cancer risk: evidence from epidemiological studies. AB - The associations between dietary fat and fatty acid (FA) intakes and epithelial ovarian cancer (EOC) risk have been inconsistent in previous studies. We conducted a meta-analysis of epidemiological studies to evaluate these associations. We identified relevant studies by searching PubMed, EMBASE, and Web of Science databases. We used random-effects models to estimate summary relative risks (RRs) and 95% confidence intervals (CIs). Overall, the search yielded 20 studies (1 pooled analysis of 12 cohort studies, 5 cohorts, and 14 case-control studies). The summary RR for EOC for the highest versus lowest categories of total dietary fat intake was 1.12 (95%CI= 0.95-1.33; I2 = 77.4%; n = 14). The RRs were not significant when fats were divided into plant-based fats (RR = 0.93, 95%CI = 0.77-1.13; n = 6), animal-based fats (RR = 1.15, 95%CI = 0.95-1.39; n = 8), dairy-based fats (RR = 1.02, 95%CI = 0.88-1.18; n = 3), saturated FAs (RR = 1.04, 95%CI = 0.93-1.17; n = 12), monounsaturated FAs (RR = 0.98, 95%CI = 0.84 1.13; n = 10), polyunsaturated FAs (RR = 0.96, 95%CI = 0.81-1.12; n = 10), and trans-unsaturated FAs (RR = 1.15, 95%CI = 0.98-1.36; n = 3). Similar non significant results were also observed in most of the subgroup and sensitivity analyses. The findings of this meta-analysis suggest a lack of evidence for associations between dietary fat and FA intakes and EOC risk. Further analyses should be conducted to assess the associations with other types of fat, and the results should be stratified by tumor invasiveness and EOC histology. PMID- 26515594 TI - Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer. AB - In metastatic breast cancers, the acquisition of metastatic ability, which leads to clinically incurable disease and poor survival, has been associated with acquisition of epithelial-mesenchymal transition (EMT) program and self-renewing trait (CSCs) via activation of PI3K/AKT and IL6/JAK2/STAT3 signaling pathways. We found that TrkB is a key regulator of PI3K/AKT and JAK/STAT signal pathway mediated tumor metastasis and EMT program. Here, we demonstrated that TrkB activates AKT by directly binding to c-Src, leading to increased proliferation. Also, TrkB increases Twist-1 and Twist-2 expression through activation of JAK2/STAT3 by inducing c-Src-JAK2 complex formation. Furthermore, TrkB in the absence of c-Src binds directly to JAK2 and inhibits SOCS3-mediated JAK2 degradation, resulting in increased total JAK2 and STAT3 levels, which subsequently leads to JAK2/STAT3 activation and Twist-1 upregulation. Additionally, activation of the JAK2/STAT3 pathway via induction of IL-6 secretion by TrkB enables induction of activation of the EMT program via induction of STAT3 nuclear translocation. These observations suggest that TrkB is a promising target for future intervention strategies to prevent tumor metastasis, EMT program and self-renewing trait in breast cancer. PMID- 26515596 TI - Elucidating drivers of oral epithelial dysplasia formation and malignant transformation to cancer using RNAseq. AB - Oral squamous cell carcinoma (OSCC) is a prevalent cancer with poor prognosis. Most OSCC progresses via a non-malignant stage called dysplasia. Effective treatment of dysplasia prior to potential malignant transformation is an unmet clinical need. To identify markers of early disease, we performed RNA sequencing of 19 matched HPV negative patient trios: normal oral mucosa, dysplasia and associated OSCC. We performed differential gene expression, principal component and correlated gene network analysis using these data. We found differences in the immune cell signatures present at different disease stages and were able to distinguish early events in pathogenesis, such as upregulation of many HOX genes, from later events, such as down-regulation of adherens junctions. We herein highlight novel coding and non-coding candidates for involvement in oral dysplasia development and malignant transformation, and speculate on how our findings may guide further translational research into the treatment of oral dysplasia. PMID- 26515598 TI - Targeting the ROR1 and ROR2 receptors in epithelial ovarian cancer inhibits cell migration and invasion. AB - AIM: In recent years, the Wnt signalling pathway has been implicated in epithelial ovarian cancer and its members have potential as diagnostic, prognostic and therapeutic targets. Here we investigated the role of two Wnt receptor tyrosine kinases (RTKs), ROR1 and ROR2, and their putative ligand, Wnt5a, in ovarian cancer. METHODS: Immunohistochemistry for ROR2 was performed in a large patient cohort, including benign controls, borderline tumours and epithelial ovarian cancer. In addition, siRNA was used to silence ROR1, ROR2 and Wnt5a individually, and together, in two ovarian cancer cell lines, and the effects on cell proliferation, adhesion, migration and invasion were measured. RESULTS: ROR2 expression is significantly increased in ovarian cancer patients compared to patients with benign disease. In vitro assays showed that silencing either receptor inhibits ovarian cancer cell migration and invasion, and concurrently silencing both receptors has an even stronger inhibitory effect on proliferation, migration and invasion. CONCLUSIONS: ROR2 expression is increased in epithelial ovarian cancer, and silencing ROR2 and its sister receptor ROR1 has a strong inhibitory effect on the ability of ovarian cancer cells to proliferate, migrate and invade through an extracellular matrix. PMID- 26515597 TI - Genome-wide association study identifies two new susceptibility loci for colorectal cancer at 5q23.3 and 17q12 in Han Chinese. AB - Genome-wide association studies (GWAS) have reported a number of loci harboring common variants that influence risk of colorectal cancer (CRC) in European descent. But all the SNPs identified explained a small fraction of total heritability. To identify more genetic factors that modify the risk of CRC, especially Chinese Han specific, we conducted a three-stage GWAS including a screening stage (932 CRC cases and 966 controls) and two independent validations (Stage 2: 1,759 CRC cases and 1,875 controls; Stage 3: 943 CRC cases and 1,838 controls). In the combined analyses, we discovered two novel loci associated with CRC: rs12522693 at 5q23.3 (CDC42SE2-CHSY3, OR = 1.31, P = 2.08 * 10-8) and rs17836917 at 17q12 (ASIC2-CCL2, OR = 0.75, P = 4.55 * 10-8). Additionally, we confirmed two previously reported risk loci, rs6983267 at 8q24.21 (OR = 1.17, P = 7.17 * 10-7) and rs10795668 at 10p14 (OR = 0.86, P = 2.96 * 10-6) in our cohorts. These results bring further insights into the CRC susceptibility and advance our understanding on etiology of CRC. PMID- 26515599 TI - Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues. AB - Until recently, few molecular signatures of drug resistance identified in drug induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5 fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens. PMID- 26515600 TI - Serum levels of soluble programmed death ligand 1 predict treatment response and progression free survival in multiple myeloma. AB - Immune checkpoint signaling plays an important role in immunosuppression in multiple myeloma (MM). Blood levels of soluble programmed death-ligand 1 (sPD L1), a checkpoint-relevant protein, might predict treatment response and survival outcomes in MM patients. We used an enzyme-linked immunosorbent assay to measure serum sPD-L1 levels in 81 newly diagnosed MM patients. We found that myeloma patients had higher sPD-L1 concentrations than healthy controls. The best sPD-L1 cutoff value for predicting disease progression risk was 2.783 ng/mL. The overall response rate to treatment was higher in low sPD-L1 patients than in high sPD-L1 patients. The 3-year progression free survival (PFS) and overall survival (OS) rates for all patients were 16% and 64%, respectively. Multivariate survival analysis including Eastern Cooperative Oncology Group performance status score, treatment response, and sPD-L1 level showed that a less than partial treatment response (PR) and higher sPD-L1 levels (>2.783 ng/ml) were independent prognostic factors for shorter PFS; neither factor was predictive of OS. The serum sPD-L1 level is a valuable biomarker for predicting treatment response and an independent prognostic factor for PFS. PD-1/ PD-L1 blockade may be a promising novel immune-based therapeutic strategy in MM. PMID- 26515601 TI - Novel C6-substituted 1,3,4-oxadiazinones as potential anti-cancer agents. AB - The insulin-like growth factor 1 receptor (IGF-1R) is a membrane receptor tyrosine kinase over-expressed in a number of tumors. However, combating resistance is one of the main challenges in the currently available IGF-1R inhibitor-based cancer therapies. Increased Src activation has been reported to confer resistance to anti-IGF-1R therapeutics in various tumor cells. An urgent unmet need for IGF-1R inhibitors is to suppress Src rephosphorylation induced by current anti-IGF-1R regimens. In efforts to develop effective anticancer agents targeting the IGF-1R signaling pathway, we explored 2-aryl-1,3,4-oxadiazin-5-ones as a novel scaffold that is structurally unrelated to current tyrosine kinase inhibitors (TKIs). The compound, LL-2003, exhibited promising antitumor effects in vitro and in vivo; it effectively suppressed IGF-1R and Src and induced apoptosis in various non-small cell lung cancer cells. Further optimizations for enhanced potency in cellular assays need to be followed, but our strategy to identify novel IGF-1R/Src inhibitors may open a new avenue to develop more efficient anticancer agents. PMID- 26515602 TI - The prognostic value of age for invasive lobular breast cancer depending on estrogen receptor and progesterone receptor-defined subtypes: A NCDB analysis. AB - PURPOSE: We aimed to assess the effect of age on survival according to estrogen receptor (ER) and progesterone receptor (PR)-defined lobular breast cancer subtype in a wide age range. METHODS: 43,230 invasive lobular breast cancer women without comorbidities diagnosed between 2004 and 2011 in the National Cancer Database (NCDB) were analyzed. The effects of age on overall survival (OS) among different age groups were evaluated by log-rank test and Cox proportional model. RESULTS: Multivariate analysis showed that patients diagnosed at both young (< 35 years) and old (>= 70 years) ages had worse prognosis compared with those in the middle ages. We further analyzed the interaction between age and molecular subtype for predicting OS: in ER+PR+ subtype, the HR of OS declined with age from 1.55 (95% CI, 1.08-2.22; P = 0.019) in the group younger than 35 years to 1.38 (1.02-1.86; P = 0.036) in the 35-39 group, but increased with age to 10.1 (8.49 11.94; P < 0.001) in the group older than 79. While in ER+PR- and ER-PR- subtypes, the HRs showed no statistical differences among women diagnosed before 60 (P > 0.1); and in ER-PR+ subgroup, the HRs were similar in patients younger than 70 (P > 0.1); thus, the plots of HRs in these three subtypes remained steady until the age of 60 or 70. CONCLUSIONS: Our findings identified that the effect of age on OS in lobular breast cancer varied with ER/PR-defined subtypes. Personalized treatment strategies should be developed to improve outcomes of breast cancer patients with different ages and ER/PR statuses. PMID- 26515603 TI - Local 3D matrix confinement determines division axis through cell shape. AB - How the division axis is determined in mammalian cells embedded in three dimensional (3D) matrices remains elusive, despite that many types of cells divide in 3D environments. Cells on two-dimensional (2D) substrates typically round up completely to divide. Here, we show that in 3D collagen matrices, mammalian cells such as HT1080 human fibrosarcoma and MDA-MB-231 breast cancer cells exhibit division modes distinct from their Counterparts on 2D substrates, with a markedly higher fraction of cells remaining highly elongated through mitosis in 3D matrices. The long axis of elongated mitotic cells accurately predicts the division axis, independently of matrix density and cell-matrix interactions. This 3D-specific elongated division mode is determined by the local confinement produced by the matrix and the ability of cells to protrude and locally remodel the matrix via beta1 integrin. Elongated division is readily recapitulated using collagen-coated microfabricated channels. Cells depleted of beta1 integrin still divide in the elongated mode in microchannels, suggesting that 3D confinement is sufficient to induce the elongated cell-division phenotype. PMID- 26515604 TI - Neoadjuvant chemotherapy (NCT) plus targeted agents versus NCT alone in colorectal liver metastases patients: A systematic review and meta-analysis. AB - PURPOSE: To assess the efficacy of neoadjuvant chemotherapy (NCT) plus targeted agents versus NCT alone for the treatment of colorectal liver metastases (CRLM) patients. METHODS: Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). All clinical studies were independently identified by two authors for inclusion. Demographic data, treatment regimens, objective response rate (ORR), hepatic resection and R0 hepatic resection rate were extracted and analyzed using Comprehensive MetaAnalysis software (Version 2.0). RESULTS: A total of 40 cohorts with 2099 CRLM patients were included: 962 patients were treated with NCT alone, 602 with NCT plus anti-epidermal growth-factor receptor (EGFR)-monoclonal antibodies (MoAbs) and 535 with NCT plus bevacizumab. Pooled ORR was significantly higher for NCT plus bevacizumab or anti-EGFR-MoAbs than NCT alone [relative risk (RR) 1.53, 95% CI 1.30-1.80; p < 0.001; RR 1.53, 95% CI: 1.27 1.83, p < 0.001; respectively]. NCT plus bevacizumab significantly improved R0 hepatic resection rate (RR 1.61, 95% CI: 1.27-2.04, p < 0.001), but not for overall hepatic resection rate (RR 1.26, 95% CI: 0.81-1.94, p = 0.30). While hepatic resection and R0 hepatic resection rate was comparable between NCT plus anti-EGFR-MoAbs and NCT alone (p = 0.42 and p = 0.37, respectively). CONCLUSIONS: In comparison with NCT alone, NCT plus bevacizumab significantly improve ORR and R0 hepatic resection rate but not for hepatic resection rate. Our findings support the need to compare NCT plus bevacizumab with NCT alone in the neoadjuvant setting in large prospective trials due to its higher hepatic resection rate and R0 hepatic resection rate in CRLM patients. PMID- 26515605 TI - Mitochondrial DNA copy number in peripheral blood leukocytes and the aggressiveness of localized prostate cancer. AB - We investigated whether low mitochondrial DNA copy number (mtDNAcn) in peripheral blood leukocytes at diagnosis was associated with an increased risk of the aggressive form of the tumor and disease progression among localized prostate cancer (PCa) patients. We recruited 1,751 non-Hispanic white men with previously untreated PCa from The University of Texas MD Anderson Cancer Center. mtDNAcn was categorized into three groups according to tertiles. We used multivariate logistic regression to estimate the odds ratios (ORs) and 95 percent confidence intervals (95% CIs) for the association of mtDNAcn with the risk of having aggressive PCa at diagnosis. We used Cox proportional hazards model to estimate hazard ratios (HRs) and 95% CIs for disease progression. We observed an inverse association between aggressiveness of PCa and mtDNAcn (P < 0.001). In multivariate analysis, compared to patients in the highest tertile of mtDNAcn, those in the second and lowest tertiles had significantly increased risks of presenting with the high-risk form of PCa, as defined by the D'Amico criteria, with ORs of 1.33 (95% CI, 0.89-1.98; P = 0.17) and 1.53 (95% CI, 1.02-2.30; P = 0.04), respectively. Furthermore, PCa patients in the lowest and second tertiles combined relative to those in the highest tertile had a 56% increased risk of disease progression (HR, 1.56; 95% CI, 0.96-2.54; P = 0.07). In summary, our results suggested that low mtDNAcn in peripheral blood leukocytes was associated with aggressive PCa at diagnosis and might further predict poor progression-free survival among localized PCa patients. PMID- 26515607 TI - Comparative effectiveness of long-acting antipsychotics: issues and challenges from a pragmatic randomised study. AB - Although long-acting antipsychotics are widely used in individuals with psychotic disorders, it is unclear which long-acting preparation should be considered as first-line treatment in clinical practice. In this commentary, the main strengths and weaknesses of a recently published pragmatic randomised study comparing long acting paliperidone palmitate v. long-acting haloperidol decanoate are briefly analysed. PMID- 26515606 TI - NDRG4 stratifies the prognostic value of body mass index in colorectal cancer. AB - NDRG4 is a novel candidate tumor suppressor and can inhibit PI3K/AKT signal which is related with energy balance and related carcinogenesis. In the present study, we investigated whether NDRG4 status could modify the association of obesity with clinical outcome of colorectal cancer. For this purpose, a hospital-based prospective study cohort of 226 colorectal cancer patients was involved. NDRG4 mRNA levels were determined by real-time PCR. Association of NDRG4 mRNA expression with disease-free and overall survival was studied first. Then, the association of obesity with clinical outcome was determined according to NDRG4 level. Multivariate Cox proportional hazards model was used to compute hazard ratio, adjusting for covariates including microsatellite instability, KRAS, BRAF and PIK3CA mutation. Results showed that NDRG4 mRNA expression was decreased in tumor specimens and significantly correlated with tumor differentiation, invasion and metastasis. Patients with tumor of reduced NDRG4 mRNA level had unfavorable disease-free and overall survival. Obesity was found to be adversely associated with disease-free and overall survival in tumors with reduced NDRG4 level, not in preserved NDRG4 level group, in both univariate and multivariate analysis. These data provided the first evidence that NDRG4 level in colorectal cancer could effectively stratify the prognostic value of obesity, which would better the understanding of the prognostic role of obesity in colorectal cancer. Our results also support the notion that the host-tumor interactions in colorectal cancer might influence tumor aggressiveness. PMID- 26515608 TI - Redirected T cells in cancer therapy. AB - Genetic engineering of T lymphocytes is an appealing strategy to confer and enhance new antitumor specificities to generate effective anticancer cell products for adoptive immunotherapy. The two main approaches are based either on transgenic tumor-antigen specific T cell receptors (TCR) or chimeric antigen receptors (CAR). Initial clinical trials reported important results against selected diseases, along with relevant warnings. Ongoing research challenges are directed toward a widespread application of this approach enhancing the range of possible target antigens, antitumor activity and safety, but also addressing logistic issues regarding cost/effectiveness, up-scaled/automated production and compliance with regulations. PMID- 26515612 TI - Indium Tribromide Catalyzed Coupling Reaction of Enol Ethers with Silyl Ketene Imines toward the Synthesis of beta,gamma-Unsaturated Nitriles. AB - Herein, a coupling reaction of enol ethers with silyl ketene imines in the presence of catalytic amounts of InBr3 and Me3 SiBr is described. Kinetic studies have revealed that an indium catalyst and Me3 SiBr accelerated the coupling process and the regeneration of the catalyst, respectively. Various types of enol ethers and silyl ketene imines are applicable. In addition, a formal synthesis of verapamil was achieved by using this novel coupling reaction. PMID- 26515613 TI - Extreme Neonatal Hyperbilirubinemia: A View from Down Under. PMID- 26515609 TI - Multiple SNP Set Analysis for Genome-Wide Association Studies Through Bayesian Latent Variable Selection. AB - The power of genome-wide association studies (GWAS) for mapping complex traits with single-SNP analysis (where SNP is single-nucleotide polymorphism) may be undermined by modest SNP effect sizes, unobserved causal SNPs, correlation among adjacent SNPs, and SNP-SNP interactions. Alternative approaches for testing the association between a single SNP set and individual phenotypes have been shown to be promising for improving the power of GWAS. We propose a Bayesian latent variable selection (BLVS) method to simultaneously model the joint association mapping between a large number of SNP sets and complex traits. Compared with single SNP set analysis, such joint association mapping not only accounts for the correlation among SNP sets but also is capable of detecting causal SNP sets that are marginally uncorrelated with traits. The spike-and-slab prior assigned to the effects of SNP sets can greatly reduce the dimension of effective SNP sets, while speeding up computation. An efficient Markov chain Monte Carlo algorithm is developed. Simulations demonstrate that BLVS outperforms several competing variable selection methods in some important scenarios. PMID- 26515614 TI - Target Prolactin Range in Treatment of Tetrahydrobiopterin Deficiency. AB - The introduction of dopamine agonists for treating tetrahydrobiopterin deficiency imposes the evaluation of peripheral prolactin as the sole reliable biochemical marker of dopaminergic homeostasis. Here we provide the clinical interpretation of the previously described short prolactin profile, based on the longitudinal monitoring of 8 patients with tetrahydrobiopterin deficiency. PMID- 26515615 TI - Late Onset Hypomorphic RAG2 Deficiency Presentation with Fatal Vaccine-Strain VZV Infection. AB - PURPOSE: Hypomorphic mutations in RAG1 and RAG2 are associated with significant clinical heterogeneity and symptoms of immunodeficiency or autoimmunity may be late in appearance. As a result, immunosuppressive medications may be introduced that can have life-threatening consequences. We describe a previously healthy 13 month-old girl presenting with rash and autoimmune hemolytic anemia, while highlighting the importance of vigilance and consideration of an underlying severe immunodeficiency disease prior to instituting immunosuppressive therapy. METHODS: Given clinical deterioration of the patient and a temporal association with recently administered vaccinations, virus genotyping was carried out via 4 real-time Forster Resonance Energy Transfer PCR protocols targeting vaccine associated single nucleotide polymorphisms. Genomic DNA was extracted from whole blood and analyzed via the next-generation sequencing method of sequencing-by synthesis. Immune function studies included immunophenotyping of peripheral blood lymphocytes, mitogen-induced proliferation and TLR ligand-induced production of TNFalpha. Analysis of recombination activity of wild-type and mutant RAG2 constructs was performed. RESULTS: Virus genotyping revealed vaccine-strain VZV, mumps, and rubella. Next-generation sequencing identified heterozygosity for RAG2 R73H and P180H mutations. Profound lymphopenia was associated with intense corticosteroid therapy, with some recovery after steroid reduction. Residual, albeit low, RAG2 protein activity was demonstrated. CONCLUSIONS: Because of the association of RAG deficiency with late-onset presentation and autoimmunity, live virus vaccination and immunosuppressive therapies are often initiated and can result in negative consequences. Here, hypomorphic RAG2 mutations were linked to disseminated vaccine-strain virus infections following institution of corticosteroid therapy for autoimmune hemolytic anemia. PMID- 26515616 TI - Genome-wide identification and evaluation of constitutive promoters in streptomycetes. AB - BACKGROUND: Streptomycetes attract a lot of attention in metabolic engineering and synthetic biology because of their well-known ability to produce secondary metabolites. However, the available constitutive promoters are rather limited in this genus. RESULTS: In this work, constitutive promoters were selected from a pool of promoters whose downstream genes maintained constant expression profiles in various conditions. A total of 941 qualified genes were selected based on systematic analysis of five sets of time-series transcriptome microarray data of Streptomyces coelicolor M145 cultivated under different conditions. Then, 166 putative constitutive promoters were selected by following a rational selection workflow containing disturbance analysis, function analysis, genetic loci analysis, and transcript abundance analysis. Further, eight promoters with different strengths were chosen and subjected to experimental validation by green fluorescent protein reporter and real-time reverse-transcription quantitative polymerase chain reaction in S. coelicolor, Streptomyces venezuelae and Streptomyces albus. The eight promoters drove the stable expression of downstream genes in different conditions, implying that the 166 promoters that we identified might be constitutive under the genus Streptomyces. Four promoters were used in a plug-and-play platform to control the expression of the cryptic cluster of jadomycin B in S. venezuelae ISP5230 and resulted in different levels of the production of jadomycin B that corresponded to promoter strength. CONCLUSIONS: This work identified and evaluated a set of constitutive promoters with different strengths in streptomycetes, and it enriched the presently available promoter toolkit in this genus. These promoters should be valuable in current platforms of metabolic engineering and synthetic biology for the activation of cryptic biosynthetic clusters and the optimization of pathways for the biosynthesis of important natural products in Streptomyces species. PMID- 26515617 TI - Amyotrophic Lateral Sclerosis: A Historical Perspective. AB - This article looks back in time to see where the foundational basis for the understanding of amyotrophic lateral sclerosis originated. This foundation was created primarily in France by Jean-Martin Charcot and his fellow countrymen and disciples, along with key contributions from early clinicians in England and Germany. The early work on amyotrophic lateral sclerosis provides a useful foundation for today's clinicians with respect to tying together genetic and biologic aspects of the disorder that have been discovered over the past few decades. PMID- 26515618 TI - Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis. AB - When approaching a patient with suspected motor neuron disease (MND), the pattern of weakness on examination helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing. MNDs exist on a spectrum, from a pure lower motor neuron to mixed upper and lower motor neuron to a pure upper motor neuron variant. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic, which is invariably fatal. This article describes a pattern approach to identifying MND and clinical features of sporadic ALS. PMID- 26515620 TI - Progressive Muscular Atrophy. AB - Progressive muscular atrophy (PMA) is a rare, sporadic, adult-onset motor neuron disease, clinically characterized by isolated lower motor neuron features; however, clinically evident upper motor neuron signs may emerge in some patients. Subclinical upper motor neuron involvement is identified pathologically, radiologically, and neurophysiologically in a substantial number of patients with PMA. Patients with subclinical upper motor neuron involvement do not fulfill the revised El Escorial criteria to participate in amyotrophic lateral sclerosis clinical trials. Intravenous immunoglobulin therapy is only marginally beneficial in a small subgroup of patients with lower motor neuron syndrome without conduction block. PMID- 26515619 TI - Primary Lateral Sclerosis. AB - Primary lateral sclerosis is characterized by insidious onset of progressive upper motor neuron dysfunction in the absence of clinical signs of lower motor neuron involvement. Patients experience stiffness; decreased balance and coordination; mild weakness; and, if the bulbar region is affected, difficulty speaking and swallowing, and emotional lability. The diagnosis is made based on clinical history, typical examination findings, and diagnostic testing negative for other causes of upper motor neuron dysfunction. Electromyogram is normal, or only shows mild neurogenic findings in a few muscles, not meeting El Escorial criteria. Treatment is largely supportive. PMID- 26515621 TI - Amyotrophic Lateral Sclerosis Regional Variants (Brachial Amyotrophic Diplegia, Leg Amyotrophic Diplegia, and Isolated Bulbar Amyotrophic Lateral Sclerosis). AB - Amyotrophic lateral sclerosis (ALS), a rapidly progressive, invariably fatal disease, involves mixed upper and lower motor neurons in different spinal cord regions. Patients with bulbar onset progress more rapidly than patients with limb onset or with a lower motor neuron presentation. Recent descriptions of regional variants suggest some patients have ALS isolated to a single spinal region for many years, including brachial amyotrophic diplegia, leg amyotrophic diplegia, and isolated bulbar palsy. Clearer definitions of regional variants will have implications for prognosis, understanding the pathophysiology of ALS, identifying genetic factors related to slower disease progression, and future planning of clinical trials. PMID- 26515622 TI - Frontotemporal Dysfunction and Dementia in Amyotrophic Lateral Sclerosis. AB - Although amyotrophic lateral sclerosis (ALS) is classically considered a disorder exclusively affecting motor neurons, there is substantial clinical, neuroimaging, and neuropathologic evidence that more than half of patients have an associated syndrome of frontotemporal dysfunction. These syndromes range from frontotemporal dementia to behavioral or cognitive syndromes. Neuroimaging and neuropathologic findings are consistent with frontotemporal lobar degeneration that underpins alterations in network connectivity. Future clinical trials need to be stratified based on the presence or absence of frontotemporal dysfunction on the disease course of ALS. PMID- 26515624 TI - Spinal Muscular Atrophy. AB - Spinal muscular atrophy is an autosomal-recessive disorder characterized by degeneration of motor neurons in the spinal cord and caused by mutations in the survival motor neuron 1 gene, SMN1. The severity of SMA is variable. The SMN2 gene produces a fraction of the SMN messenger RNA (mRNA) transcript produced by the SMN1 gene. There is an inverse correlation between SMN2 gene copy number and clinical severity. Clinical management focuses on multidisciplinary care. Preclinical models of SMA have led to an explosion of SMA clinical trials that hold great promise of effective therapy in the future. PMID- 26515623 TI - Familial Amyotrophic Lateral Sclerosis. AB - Genes linked to amyotrophic lateral sclerosis (ALS) susceptibility are being identified at an increasing rate owing to advances in molecular genetic technology. Genetic mechanisms in ALS pathogenesis seem to exert major effects in about 10% of patients, but genetic factors at some level may be important components of disease risk in most patients with ALS. Identification of gene variants associated with ALS has informed concepts of the pathogenesis of ALS, aided the identification of therapeutic targets, facilitated research to develop new ALS biomarkers, and supported the establishment of clinical diagnostic tests for ALS-linked genes. PMID- 26515625 TI - Spinal and Bulbar Muscular Atrophy. AB - Spinal and bulbar muscular atrophy, or Kennedy disease, is a slowly progressive X linked neuromuscular disease caused by a trinucleotide (CAG) repeat expansion in the androgen receptor gene. Affected males typically develop weakness in their mid-40s as well as evidence of androgen insensitivity with reduced fertility and gynecomastia. Diagnosis is often delayed because of decreased awareness of the disease, although genetic testing allows for direct diagnosis. Therapeutic strategies to block the toxicity of the mutant androgen receptor have been unsuccessful thus far, and evaluation of additional candidate therapies is underway. PMID- 26515627 TI - Potential Environmental Factors in Amyotrophic Lateral Sclerosis. AB - The causes of amyotrophic lateral sclerosis (ALS) are largely unknown, and may always be multiple, including environmental factors. Monogenetic determinants of ALS are involved in roughly 20% of all cases (including 10% familial cases). Less well understood multigenetic causes may contribute to another 20% to 80%. Environmental factors likely play a role in the development of ALS in susceptible individuals, but proved causation remains elusive. This article discusses the possible factors of male gender (males are selectively exposed to different influences, or genetically predisposed to be susceptible), smoking, military service, exercise, electrical exposure, heavy metals, agricultural chemicals, and geographic clusters. PMID- 26515626 TI - Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants. AB - The neuropathologic molecular signature common to almost all sporadic amyotrophic lateral sclerosis (ALS) and most familial ALS is TDP-43 immunoreactive neuronal cytoplasmic inclusions. The neuropathologic and molecular neuropathologic features of ALS variants, primarily lateral sclerosis and progressive muscular atrophy, are less certain but also seem to share the primary features of ALS. Genetic causes, including mutations in SOD1, TDP-43, FUS, and C9orf72, all have distinctive molecular neuropathologic signatures. Neuropathology will continue to play an increasingly key role in solving the puzzle of ALS pathogenesis. PMID- 26515628 TI - Symptom Management and End-of-Life Care in Amyotrophic Lateral Sclerosis. AB - The number of available symptomatic treatments has markedly enhanced the care of patients with amyotrophic lateral sclerosis (ALS). Once thought to be untreatable, patients with ALS today clearly benefit from multidisciplinary care. The impact of such care on the disease course, including rate of progression and mortality, has surpassed the treatment effects commonly sought in clinical drug trials. Unfortunately, there are few randomized controlled trials of medications or interventions addressing symptom management. In this review, the authors provide the level of evidence, when available, for each intervention that is currently considered standard of care by consensus opinion. PMID- 26515630 TI - The Dilemma of the Clinical Trialist in Amyotrophic Lateral Sclerosis: The Hurdles to Finding a Cure. AB - Amyotrophic lateral sclerosis can be described as a disease with a poorly understood pathophysiologic mechanism and no treatment that dramatically impacts the course of the disease. Clinical trialists are faced with finding small treatment effects against a background of multiple potential treatments, a past history of failed trials, and heterogenous clinical outcomes. This article summarizes this environment and provides a rationale for drug development going forward. PMID- 26515631 TI - Motor Neuron Disease. PMID- 26515632 TI - Modelling the association between weight status and social deprivation in English school children: Can physical activity and fitness affect the relationship? AB - BACKGROUND: The association between being overweight/obese and deprivation is a serious concern in English schoolchildren. AIM: To model this association incorporating known confounders and to discover whether physical fitness and physical activity may reduce or eliminate this association. SUBJECTS AND METHODS: Cross-sectional data were collected between 2007-2009, from 8053 10-16 year old children from the East-of-England Healthy Heart Study. Weight status was assessed using waist circumference (cm) and body mass (kg). Deprivation was measured using the Index of Multiple Deprivation (IMD). Confounding variables used in the proportional, allometric models were hip circumference, stature, age and sex. Children's fitness levels were assessed using predicted VO2 max (20-metre shuttle run test) and physical activity was estimated using the Physical Activity Questionnaire for Adolescents or Children. RESULTS: A strong association was found between both waist circumference and body mass and the IMD. These associations persisted after controlling for all confounding variables. When the children's physical activity and fitness levels were added to the models, the association was either greatly reduced or, in the case of body mass, absent. CONCLUSIONS: To reduce deprivation inequalities in children's weight-status, health practitioners should focus on increasing physical fitness via physical activity in areas of greater deprivation. PMID- 26515629 TI - Complementary and Alternative Therapies in Amyotrophic Lateral Sclerosis. AB - Given the severity of their illness and lack of effective disease-modifying agents, it is not surprising that most patients with amyotrophic lateral sclerosis (ALS) consider trying complementary and alternative therapies. Some of the most commonly considered alternative therapies include special diets, nutritional supplements, cannabis, acupuncture, chelation, and energy healing. This article reviews these in detail. The authors also describe 3 models by which physicians may frame discussions about alternative therapies: paternalism, autonomy, and shared decision making. Finally, the authors review a program called ALSUntangled, which uses shared decision making to review alternative therapies for ALS. PMID- 26515633 TI - Crystallin biochemistry in health and disease. PMID- 26515635 TI - Sustained increase in platelet aggregation after the cessation of clopidogrel. AB - This study shows that the abrupt cessation of one-year clopidogrel treatment was not associated with thrombotic events in a prospective, multicentre study that enrolled 200 patients subjected to coronary stent implantation and treated with aspirin + clopidogrel 1 year after the stent placement. The aim of the study was to investigate the causes of a sustained increase of platelet aggregability, considering that the values of platelet aggregation stimulated with ADP + PGE1 (ADPHS values) significantly increased 10-90 days after the cessation of clopidogrel. Values of platelet aggregation induced by thrombin receptor activating peptide (TRAP values) and arachidonic acid (ASPI values) were divided into quartiles on the basis of ADPHS values 10 days after stopping clopidogrel (ADPHS10 ). There was a significant difference between TRAP values divided into quartiles according to ADPHS10 , 10, 45 and 90 days after stopping clopidogrel (P < 0.001, all), and ASPI values across the same quartiles 10 and 45 days after the cessation of clopidogrel (P = 0.028 and 0.003). The results of the study indicate that patients with early pronounced rebound phenomena to clopidogrel termination have a long-term (at least 90 days) increased platelet aggregation to other agonists such as thrombin-related activated protein and arachidonic acid, suggesting the complex mutual relationship of various factors/agonists influencing the function of platelets. PMID- 26515634 TI - Protein conformational perturbations in hereditary amyloidosis: Differential impact of single point mutations in ApoAI amyloidogenic variants. AB - Amyloidoses are devastating diseases characterized by accumulation of misfolded proteins which aggregate in fibrils. Specific gene mutations in Apolipoprotein A I (ApoAI) are associated with systemic amyloidoses. Little is known on the effect of mutations on ApoAI structure and amyloid properties. Here we performed a physico-chemical characterization of L75P- and L174S-amyloidogenic ApoAI (AApoAI) variants to shed light on the effects of two single point mutations on protein stability, proteolytic susceptibility and aggregation propensity. Both variants are destabilized in their N-terminal region and generate fibrils with different morphological features. L75P-AApoAI is significantly altered in its conformation and compactness, whereas a more flexible and pronounced aggregation-competent state is associated to L174S-AApoAI. These observations point out how single point mutations in ApoAI gene evocate differences in the physico-chemical and conformational behavior of the corresponding protein variants, with the common feature of diverting ApoAI from its natural role towards a pathogenic pathway. PMID- 26515636 TI - Immunoproteasome subunit LMP7 Deficiency Improves Obesity and Metabolic Disorders. AB - Inflammation plays an important role in the development of obesity and metabolic disorders; however, it has not been fully understood how inflammation occurs and is regulated in their pathogenesis. Low-molecular mass protein-7 (LMP7) is a proteolytic subunit of the immunoproteasome that shapes the repertoire of antigenic peptides on major histocompatibility complex class I molecule. In this study, we investigated the role of LMP7 in the development of obesity and metabolic disorders using LMP7-deficient mice. LMP7 deficiency conveyed resistant to obesity, and improved glucose intolerance and insulin sensitivity in mice fed with high-fat diet (HFD). LMP7 deficiency decreased pancreatic lipase expression, increased fecal lipid contents, and inhibited the increase of plasma triglyceride levels upon oral oil administration or HFD feeding. Using bone marrow-transferred chimeric mice, we found that LMP7 in both bone marrow- and non-bone marrow derived cells contributes to the development of HFD-induced obesity. LMP7 deficiency decreased inflammatory responses such as macrophage infiltration and chemokine expression while it increased serum adiponection levels. These findings demonstrate a novel role for LMP7 and provide new insights into the mechanisms underlying inflammation in the pathophysiology of obesity and metabolic disorders. PMID- 26515638 TI - Treatment of Alcohol Use Disorders: Benchmarking Houston, Texas, and Philadelphia, Pennsylvania. PMID- 26515637 TI - A Model Based on Pathologic Features of Superficial Esophageal Adenocarcinoma Complements Clinical Node Staging in Determining Risk of Metastasis to Lymph Nodes. AB - BACKGROUND & AIMS: It is important to identify superficial (T1) gastroesophageal adenocarcinomas (EAC) that are most or least likely to metastasize to lymph nodes, to select appropriate therapy. We aimed to develop a risk stratification model for metastasis of superficial EAC to lymph nodes using pathologic features of the primary tumor. METHODS: We collected pathology data from 210 patients with T1 EAC who underwent esophagectomy from 1996 through 2012 on factors associated with metastasis to lymph nodes (tumor size, grade, angiolymphatic invasion, and submucosal invasion). Using these variables, we developed a multivariable logistic model to generate 4 categories for estimated risk of metastasis (<5% risk, 5%-10% risk, 15%-20% risk, or >20% risk). The model was validated in a separate cohort of 39 patients who underwent endoscopic resection of superficial EAC and subsequent esophagectomy, with node stage analysis. RESULTS: We developed a model based on 4 pathologic factors that determined risk of metastasis to range from 2.9% to 60% for patients in the first cohort. In the endoscopic resection validation cohort, higher risk scores were associated with increased detection of lymph node metastases at esophagectomy (P = .021). Among patients in the first cohort who did not have lymph node metastases detected before surgery (cN0), those with high risk scores (>20% risk) had 11-fold greater odds for having lymph node metastases at esophagectomy compared with patients with low risk scores (95% confidence interval, 2.3-52 fold). Increasing risk scores were associated with reduced patient survival time (P < .001) and shorter time to tumor recurrence (P < .001). Patients without lymph node metastases (pT1N0) but high risk scores had reduced times of survival (P < .001) and time to tumor recurrence (P = .001) after esophagectomy than patients with pT1N0 tumors and lower risk scores. CONCLUSIONS: Pathologic features of primary superficial EACs can be used, along with the conventional node staging system, to identify patients at low risk for metastasis, who can undergo endoscopic resection, or at high risk, who may benefit from induction or adjuvant therapy. PMID- 26515639 TI - The versatile low-molecular-weight thiols: Beyond cell protection. AB - Low-molecular-weight (LMW) thiols are extensively involved in the maintenance of cellular redox potentials and the protection of cells from a variety of reactive chemical and electrophilic species. However, we recently found that the metabolic coupling of two LMW thiols - mycothiol (MSH) and ergothioneine (EGT) - programs the biosynthesis of the anti-infective agent lincomycin A. Remarkably, such a constructive role of the thiols in the biosynthesis of natural products has so far received relatively little attention. We speculate that the unusual thiol EGT might function as a chiral thiolation carrier (for modification) and a novel activator (for glycosylation) of sugar. Additionally, we examine recent evidence for LMW thiols (MSH and others) as sulfur donors of sulfur-containing natural products. Clearly, the LMW thiols have more diverse activities beyond cell protection, and more attention should be paid to the correlation of their functions with thiol-dependent enzymes. PMID- 26515640 TI - Amiodarone as an autophagy promoter reduces liver injury and enhances liver regeneration and survival in mice after partial hepatectomy. AB - The deregulation of autophagy is involved in liver regeneration. Here, we investigated the role of autophagy in the regulation of liver regeneration after partial hepatectomy (PHx) and the development of pharmacological interventions for improved liver regeneration after PHx. We show that autophagy was activated in the early stages of liver regeneration following 70% PHx in vivo. Moreover, amiodarone was associated with a significant enhancement of autophagy, liver growth, and hepatocyte proliferation, along with reduced liver injury and the termination of liver regeneration due to decreased transforming growth factor beta1 expression after 70% PHx. The promotion of autophagy appeared to selectively increase the removal of damaged mitochondria. We also found that Atg7 knockdown or pretreatment with chloroquine aggravated the liver injury associated with 70% PHx and reduced liver growth and hepatocyte proliferation. Finally, amiodarone improved liver regeneration, survival, and liver injury after 90% PHx. In conclusion, our results indicate that autophagy plays an important role in mouse liver regeneration and that modulating autophagy with amiodarone may be an effective method of improving liver regeneration, increasing survival, and ameliorating liver injury following PHx. PMID- 26515641 TI - Mouse polyQ database: a new online resource for research using mouse models of neurodegenerative diseases. AB - BACKGROUND: The polyglutamine (polyQ) family of disorders comprises 9 genetic diseases, including several types of ataxia and Huntington disease. Approximately two decades of investigation and the creation of more than 130 mouse models of polyQ disorders have revealed many similarities between these diseases. The disorders share common mutation types, neurological characteristics and certain aspects of pathogenesis, including morphological and physiological neuronal alterations. All of the diseases still remain incurable. DESCRIPTION: The large volume of information collected as a result of the investigation of polyQ models currently represents a great potential for searching, comparing and translating pathogenesis and therapeutic information between diseases. Therefore, we generated a public database comprising the polyQ mouse models, phenotypes and therapeutic interventions tested in vivo. The database is available at http://conyza.man.poznan.pl/ . CONCLUSION: The use of the database in the field of polyQ diseases may accelerate research on these and other neurodegenerative diseases and provide new perspectives for future investigation. PMID- 26515642 TI - A patient with novel mutations causing MEN1 and hereditary multiple osteochondroma. AB - We report of a male patient aged 32 years who presented with primary hyperparathyroidism. Three parathyroid glands were resected. At the age of 46 years, nervus facialis irritation was noted, and an MRI scan incidentally revealed a non-functioning pituitary adenoma with affection of the chiasma opticum. The patient underwent transsphenoidal operation resulting in pituitary insufficiency postoperatively. At the same time, primary hyperparathyroidism reoccurred and a parathyroid adenoma located at the thymus was resected. The mother of the patient died early due to multiple tumors. The patient was suspected to have multiple endocrine neoplasia type 1 (MEN1) and genetic analysis was performed. In addition, on clinical examination, multiple exostoses were noticed and an additional genetic analysis was performed. His father was reported to have multiple osteochondromas too. MEN1 was diagnosed in the patient showing a novel heterozygote mutation c.2T>A in exon 2, codon 1 (start codon ATG>AAG;p.Met1?) of the MEN1 gene. In genetic mutational analysis of the EXT1 gene, another not yet known mutation c.1418-2A>C was found in intron 5 of the EXT1 gene (heterozygotic). In conclusion, we report novel mutations of the EXT1 and the MEN1 genes causing hereditary multiple osteochondromas and MEN1 in one patient. LEARNING POINTS: It is important to ask for the patient's family history in detail.Patients with MEN1 are characterized by the occurrence of tumors in multiple endocrine tissues and nonendocrine tissues, most frequently parathyroid (95%), enteropancreatic neuroendocrine (50%), and anterior pituitary (40%) tissues.Familiar MEN1 has a high degree of penetrance (80-95%) by the age over 50; however, combinations of the tumors may be different in members of the same family.Patients with EXT1 gene mutations should be monitored for possible transformation of bone lesions into osteochondrosarcoma. PMID- 26515643 TI - Efficacy and cost-effectiveness of voriconazole prophylaxis for prevention of invasive aspergillosis in high-risk liver transplant recipients. AB - Aspergillus infection remains a significant and deadly complication after liver transplantation (LT). We sought to determine whether the antifungal prophylactic use of voriconazole reduces the incidence of invasive aspergillosis (IA) in high risk LT recipients without prohibitively increasing cost. During the study era (April 2008 to April 2014), 339 deceased donor LTs were performed. Of those patients, 174 high-risk recipients were administered antifungal prophylaxis with voriconazole. The median biological Model for End-Stage Liver Disease score at the time of LT was 33 (range, 18-49) with 56% requiring continuous renal replacement therapy and 50% requiring ventilatory support immediately before transplantation. Diagnosis of IA was stratified as proven, probable, or possible according to previously published definitions. No IA was documented in patients receiving voriconazole prophylaxis. At 90 days after LT, the institutional cost of prophylaxis was $5324 or 5.6% of the predicted cost associated with post-LT aspergillosis. There was no documentation of resistant strains isolated from any recipient who received voriconazole. In conclusion, these data suggest that voriconazole prophylaxis is safe, clinically effective, and cost-effective in high-risk LT recipients. PMID- 26515644 TI - Surface plasmon resonance imaging (SPRi) for analysis of DNA aptamer:beta conglutin interactions. AB - Surface plasmon resonance imaging (SPRi) is a label-free detection method that offers a suitable and reliable platform for the real time monitoring of biomolecular interactions. In the work reported here, SPRi was used to evaluate the affinity and specificity of three different aptamers selected against the Lup an 1 anaphylactic allergen beta-conglutin (beta-conglutin binding aptamers I and II (beta-CBA I and beta-CBA II)), as well as an 11-mer truncated version of beta CBA I. Thiol modified aptamers were immobilised on a gold substrate through a self-assembling process and the use of different blocking strategies to prevent non-specific binding were evaluated. Dissociation constants of 20, 13 and 1 nM were determined for beta-CBA I, beta-CBA II and the 11-mer truncated aptamer, respectively. The three aptamers were then studied in various different sandwich formats and the beta-CBA I/11-mer and beta-CBA II were observed to bind to different aptatopes on the target protein. Each of the aptamers were then used either as surface immobilised aptamer, or as reporter aptamer, and added with the protein target beta-conglutin in either a sequential of simultaneous manner, and the changes in SPR signal monitored. The preferred approach for formation of a sandwich aptacomplex was with immobilised beta-CBA II, followed by addition of pre-incubated beta-conglutin and 11-mer, whilst addition of the 11-mer following addition of the beta-conglutin, resulted in displacement of the bound target. The ability to provide parallel qualitative and quantitative detection establishes SPRi as a powerful tool for the study of immobilised aptamer-target interactions. PMID- 26515645 TI - Generation of polyhormonal and multipotent pancreatic progenitor lineages from human pluripotent stem cells. AB - Generation of pancreatic beta-cells from human pluripotent stem cells (hPSCs) has enormous importance in type 1 diabetes (T1D), as it is fundamental to a treatment strategy based on cellular therapeutics. Being able to generate beta-cells, as well as other mature pancreatic cells, from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) will also enable the development of platforms that can be used for disease modeling and drug testing for a variety of pancreas-associated diseases, including cystic fibrosis. For this to occur, it is crucial to develop differentiation strategies that are robust and reproducible across cell lines and laboratories. In this article we describe two serum-free differentiation protocols designed to generate specific pancreatic lineages from hPSCs. Our approach employs a variety of cytokines and small molecules to mimic developmental pathways active during pancreatic organogenesis and allows for the in vitro generation of distinct pancreatic populations. The first protocol is designed to give rise to polyhormonal cells that have the potential to differentiate into glucagon-producing cells. The second protocol is geared to generate multipotent pancreatic progenitor cells, which harbor the potential to generate all pancreatic lineages including: monohormonal endocrine cells, acinar, and ductal cells. PMID- 26515646 TI - Real-time in vivo confocal laser scanning microscopy of melanin-containing cells: A promising diagnostic intervention. AB - The use of noninvasive imaging techniques to evaluate different types of skin lesions is increasing popular. In vivo confocal laser scanning microscopy (CLSM) is a new method for high resolution non-invasive imaging of intact skin in situ and in vivo. Although many studies have investigated melanin-containing cells in lesions by in vivo CLSM, few studies have systematically characterized melanin containing cells based on their morphology, size, arrangement, density, borders, and brightness. In this study, the characteristics of melanin-containing cells were further investigated by in vivo CLSM. A total of 130 lesions, including common nevi, giant congenital pigmented nevi, vitiligo, melasma, melanoma, and chronic eczema, were imaged by in vivo CLSM. This research helps dermatologists understand the characteristics of melanin-containing cells and facilitate the clinical application of melanin-containing cells in the investigation of dermatological disease. In summary, melanin-containing cells include keratinocytes, melanocytes, macrophages, and melanocytic skin tumor cells. Our study presents the CLSM characteristics of melanin-containing cells to potentially facilitate in vivo diagnosis based on shape, size, arrangement, density, borders, and brightness. PMID- 26515647 TI - Ethnic differences in ischemic stroke subtypes in young-onset stroke: the Stroke Prevention in Young Adults Study. AB - BACKGROUND: Prior studies indicate that young African-Americans (AA) have a greater frequency of ischemic stroke than similarly aged European-Americans (EA). We hypothesized that differences in stroke subtype frequency mediated through sex and differing risk factor profiles may play a role in ethnicity-specific stroke. Utilizing our biracial young-onset stroke population, we explored these relationships. METHODS: Fifty nine hospitals in the Baltimore-Washington area participated in a population-based study of young-onset stroke in men (218-AA, 291-EA) and women (219-AA, 222-EA) aged 16-49. Data on age, sex, ethnicity and stroke risk factors (hypertension (HTN) and smoking) were gathered through standardized interview. A pair of vascular neurologists adjudicated each case to determine TOAST subtype. Logistic regression analyses evaluating for differences in stroke risk factors by TOAST subtype were performed. RESULTS: Analyses controlling for age and sex demonstrated that AA were more likely to have a lacunar stroke than EA (OR = 1.61; 95% CI = 1.12-2.32; p = 0.011) when utilizing the other TOAST subtypes as the reference group. This effect was mediated by HTN, which increases the risk of lacunar stroke (OR = 2.03; 95% CI = 1.38-2.98; p = 0.0003) and large artery stroke (OR = 1.70; 95% CI = 1.01-2.88; p = 0.048) when controlling for sex, ethnicity, and age. Cases below age 40 were more likely to have a cardioembolic stroke than those above age 40 (OR = 1.62; 95% CI = 1.15 2.27; p = 0.006), controlling for sex and ethnicity. Lastly, current smokers were more likely to have a large artery stroke than non-smokers (OR = 1.79; 95% CI = 1.08-2.98; p = 0.024). CONCLUSIONS: Our population-based data demonstrate ethnic differences in ischemic stroke subtypes. These findings may help clarify mechanisms of stroke in young adults which may in part be driven by ethnic specific differences in early-onset traditional risk factors, thereby indicating differing emphasis on workup and prevention. PMID- 26515648 TI - Epileptic Ictal Hyperperfusion on Arterial Spin Labeling Perfusion and Diffusion Weighted Magnetic Resonance Images in Posterior Reversible Encephalopathy Syndrome. AB - BACKGROUND: The hemodynamic state of the posterior dominant vasogenic edema in posterior reversible encephalopathy syndrome (PRES) is controversial. The aim of this retrospective study was to examine the contribution of epileptic ictal hyperperfusion in patients with PRES using combined magnetic resonance perfusion imaging with arterial spin labeling (ASL) and diffusion-weighted magnetic resonance imaging (MRI). METHODS: A detailed review of chronological MRI findings in 2 patients, including diffusion-weighted imaging (DWI) and ASL, with special reference to clinical and electroencephalographic findings, was performed. At the onset of PRES, both patients developed secondary generalized seizures. RESULTS: At the first PRES episode in Case 1, ASL and DWI clearly depicted "ictal hyperperfusion" and prolonged epilepsy-induced cytotoxic edema in the left parieto-occipital lobe cortex, located around the vasogenic edema of the PRES lesion in the left occipital lobe (hypoperfused area). At the second and third episodes (2 and 7 months after the first episode, respectively), although recurrent PRES was ruled out, ASL and DWI clearly demonstrated ictal hyperperfusion in the left posterior temporal and parieto-occipital lobes associated with partial nonconvulsive status epilepticus, which developed around the PRES-related old hematoma lesion. In Case 2, peri-ictal MRI findings of ictal ASL hyperperfusion and cortical hyperintensity on DWI were also noted in the left parieto-occipital lobe, but were mild compared with Case 1. CONCLUSIONS: Combined use of DWI and ASL can provide information on hemodynamic state associated with epileptic ictal hyperperfusion in the various phases of PRES. PMID- 26515649 TI - Optimal Blood Pressure in Patients after Stroke in Rural Areas of China. AB - BACKGROUND: The purpose of this study was to investigate the impact of different blood pressure (BP) categories on risk of developing cardiovascular disease (CVD) events and mortality, and to evaluate the optimal range of BP in patients after stroke in rural areas of China. METHODS: We performed a post hoc analysis of 1058 patients with a history of stroke or transient ischemic attack from the Northeast China Rural Cardiovascular Health Study. The average follow-up systolic blood pressure (SBP) and diastolic blood pressure (DBP) were categorized into 10-mm Hg increments. The primary outcome was a composite of death due to any cause, nonfatal coronary heart disease, and nonfatal stroke. The secondary outcomes were recurrent stroke, CVD events, CVD mortality, and all-cause mortality. RESULTS: The relationship between BP (systolic and diastolic) followed a J- or U-shaped curve with primary and secondary outcomes, with increased event rates at low and high BP values, both unadjusted variables and after adjustment for baseline confounding variables. The event rates were lowest in the SBP of 110-119 and DBP of 80-89 mm Hg. Patients with a BP lower than 110/70 or 140/90 mm Hg or higher had a significantly increased risk of worse outcomes. CONCLUSIONS: For stroke survivors, a J- or U-shaped curve association exists between BP and the risk of future CVD events and mortality, with the lowest event rates in the BP range of 110-119 systolic and 80-89 diastolic. SBPs of 110-139 and DBPs of 70-89 are the appropriate range for patients after stroke in rural areas of China. PMID- 26515651 TI - Single-tube PCR coupled with mini-sequencing assay for the detection of cyp51A and cyp51B polymorphisms in Aspergillus fumigatus. AB - AIM: Triazole resistance in Aspergillus fumigatus is associated with mutations in cyp51 genes, therefore, a single-tube multiplex PCR was proposed for rapid detection of such mutations. METHODS: Relevant markers (n = 21) located in cyp51A and cyp51B were amplified in a multiplex reaction and subsequently analyzed by mini-sequencing. RESULTS: A set of nonresistant A. fumigatus were tested. The markers F46, G89, M172, D255, L358, E427 and C454 located in cyp51A, as well as P394 and S35 from cyp51B, were found to be modified. CONCLUSIONS: A. fumigatus triazole resistance in Portugal is rare, nevertheless, some isolates showed alterations in the cyp51 genes. Multicenter studies with more isolates should better evaluate and validate the potential use of this method in clinical laboratories. The new methodology allows the addition of extra markers if described as relevant for A. fumigatus susceptibility to triazoles. PMID- 26515650 TI - Proteomics studies of the interactome of RNA polymerase II C-terminal repeated domain. AB - BACKGROUND: Eukaryotic RNA polymerase II contains a C-terminal repeated domain (CTD) consisting of 52 consensus heptad repeats of Y1S2P3T4S5P6S7 that mediate interactions with many cellular proteins to regulate transcription elongation, RNA processing and chromatin structure. A number of CTD-binding proteins have been identified and the crystal structures of several protein-CTD complexes have demonstrated considerable conformational flexibility of the heptad repeats in those interactions. Furthermore, phosphorylation of the CTD at tyrosine, serine and threonine residues can regulate the CTD-protein interactions. Although the interactions of CTD with specific proteins have been elucidated at the atomic level, the capacity and specificity of the CTD-interactome in mammalian cells is not yet determined. RESULTS: A proteomic study was conducted to examine the mammalian CTD-interactome. We utilized six synthetic peptides each consisting of four consensus CTD-repeats with different combinations of serine and tyrosine phosphorylation as affinity-probes to pull-down nuclear proteins from HeLa cells. The pull-down fractions were then analyzed by MUDPIT mass spectrometry, which identified 100 proteins with the majority from the phospho-CTD pull-downs. Proteins pulled-down by serine-phosphorylated CTD-peptides included those containing the previously defined CTD-interacting domain (CID). Using SILAC mass spectrometry, we showed that the in vivo interaction of RNA polymerase II with the mammalian CID-containing RPRD1B is disrupted by CID mutation. We also showed that the CID from four mammalian proteins interacted with pS2-phosphorylated but not pY1pS2-doubly phosphorylated CTD-peptides. However, we also found proteins that were preferentially pulled-down by pY1pS2- or pY1pS5-doubly phosphorylated CTD-peptides. We prepared an antibody against tyrosine phosphorylated CTD and showed that ionizing radiation (IR) induced a transient increase in CTD tyrosine phosphorylation by immunoblotting. Combining SILAC and IMAC purification of phospho-peptides, we found that IR regulated the phosphorylation at four CTD tyrosine sites in different ways. CONCLUSION: Upon phosphorylation, the 52 repeats of the CTD have the capacity to generate a large number of binding sites for cellular proteins. This study confirms previous findings that serine phosphorylation stimulates whereas tyrosine phosphorylation inhibits the protein binding activity of the CTD. However, tyrosine phosphorylation of the CTD can also stimulate other CTD-protein interactions. The CTD-peptide affinity pull-down method described here can be adopted to survey the mammalian CTD-interactome in various cell types and under different biological conditions. PMID- 26515652 TI - Antibacterial effect of N-acetylcysteine and taurolidine on planktonic and biofilm forms of Enterococcus faecalis. AB - AIM: This study investigated the antimicrobial activity of taurolidine and N acetylcysteine (NAC) on planktonic and biofilm Enterococcus faecalis phenotypes. MATERIALS AND METHODS: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of NAC and taurolidine were determined using broth microdilution, utilizing calcium hydroxide (CH), sodium hypochlorite, and chlorhexidine for comparisons. Thereafter, the ability of dentin powder to neutralize the antibacterial activity of NAC and taurolidine was studied. The efficacy of both antimicrobial agents on E. faecalis biofilms was examined quantitatively by exposure of 21-day-old E. faecalis biofilms on dentin disks. The cytotoxicity of human dental pulp fibroblast cells in contact with the extracts was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The MIC and MBC of NAC, taurolidine, and CH were not affected by pre-incubation in dentin powder. As verified by qualitative assay of E. faecalis biofilms, CH was the strongest bactericidal agent at all test dilutions, regardless of the presence of dentin powder. The antibacterial effect of NAC and taurolidine was significantly lower than that of CH at all test dilutions. At 48 h, all test agents showed similar, but high levels of cytotoxicity. CONCLUSION: NAC and taurolidine were effective against E. faecalis in planktonic state, at the expense of demonstrating cytotoxic effects. For both planktonic and biofilm forms of E. faecalis, neither NAC nor taurolidine offered any advantage over CH. PMID- 26515654 TI - X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities. AB - Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/beta-galactosidase (beta-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, beta-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using beta-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group. PMID- 26515655 TI - Oxygen administration at birth in preterm infants: a retrospective analysis. AB - OBJECTIVE: The aim of the study was to retrospectively investigate the association between initial oxygen concentration in delivery room and short-term outcomes in preterm infants. METHODS: Data from infants needing neonatal resuscitation, born at our department between January 2008 and December 2011, were analyzed. Patients were divided into three groups based on gestational age: between 32 and 36 weeks, between 31 and 28 weeks, and below 28 weeks. RESULTS: The administration of each additional unit of oxygen up to 50% showed an association with a 5% increased need for mechanical ventilation (MV) in the neonatal intensive care unit in infants between 32 and 36 weeks [adjusted odds ratio 1.1, 95% confidence interval (CI) 1.04-1.1] and infants between 28 and 31 weeks (adjusted odds ratio 1.12, 95% CI 1.08-1.44). On the contrary, in infants below 28 weeks, increasing initial concentration of supplementary oxygen did not show any association with MV. CONCLUSIONS: Initial oxygen concentration seems to be associated with increased MV in the NICU. Our observations further stress the need for randomized controlled studies in order to obtain definitive recommendations for the optimal initial oxygen concentration during neonatal resuscitation of preterm infants. PMID- 26515656 TI - Relating DSM-5 section III personality traits to section II personality disorder diagnoses. AB - BACKGROUND: The DSM-5 Personality and Personality Disorders Work Group formulated a hybrid dimensional/categorical model that represented personality disorders as combinations of core impairments in personality functioning with specific configurations of problematic personality traits. Specific clusters of traits were selected to serve as indicators for six DSM categorical diagnoses to be retained in this system - antisocial, avoidant, borderline, narcissistic, obsessive-compulsive and schizotypal personality disorders. The goal of the current study was to describe the empirical relationships between the DSM-5 section III pathological traits and DSM-IV/DSM-5 section II personality disorder diagnoses. METHOD: Data were obtained from a sample of 337 clinicians, each of whom rated one of his or her patients on all aspects of the DSM-IV and DSM-5 proposed alternative model. Regression models were constructed to examine trait disorder relationships, and the incremental validity of core personality dysfunctions (i.e. criterion A features for each disorder) was examined in combination with the specified trait clusters. RESULTS: Findings suggested that the trait assignments specified by the Work Group tended to be substantially associated with corresponding DSM-IV concepts, and the criterion A features provided additional diagnostic information in all but one instance. CONCLUSIONS: Although the DSM-5 section III alternative model provided a substantially different taxonomic structure for personality disorders, the associations between this new approach and the traditional personality disorder concepts in DSM-5 section II make it possible to render traditional personality disorder concepts using alternative model traits in combination with core impairments in personality functioning. PMID- 26515653 TI - Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction. AB - Up to 80% of individuals with myotonic dystrophy type 1 (DM1) will develop cardiac abnormalities at some point during the progression of their disease, the most common of which is heart blockage of varying degrees. Such blockage is characterized by conduction defects and supraventricular and ventricular tachycardia, and carries a high risk of sudden cardiac death. Despite its importance, very few animal model studies have focused on the heart dysfunction in DM1. Here, we describe the characterization of the heart phenotype in a Drosophila model expressing pure expanded CUG repeats under the control of the cardiomyocyte-specific driver GMH5-Gal4. Morphologically, expression of 250 CUG repeats caused abnormalities in the parallel alignment of the spiral myofibrils in dissected fly hearts, as revealed by phalloidin staining. Moreover, combined immunofluorescence and in situ hybridization of Muscleblind and CUG repeats, respectively, confirmed detectable ribonuclear foci and Muscleblind sequestration, characteristic features of DM1, exclusively in flies expressing the expanded CTG repeats. Similarly to what has been reported in humans with DM1, heart-specific expression of toxic RNA resulted in reduced survival, increased arrhythmia, altered diastolic and systolic function, reduced heart tube diameters and reduced contractility in the model flies. As a proof of concept that the fly heart model can be used for in vivo testing of promising therapeutic compounds, we fed flies with pentamidine, a compound previously described to improve DM1 phenotypes. Pentamidine not only released Muscleblind from the CUG RNA repeats and reduced ribonuclear formation in the Drosophila heart, but also rescued heart arrhythmicity and contractility, and improved fly survival in animals expressing 250 CUG repeats. PMID- 26515657 TI - Impact of Periprocedural Colchicine on Postprocedural Management in Patients Undergoing a Left Atrial Appendage Ligation Using LARIAT. AB - INTRODUCTION: Left atrial appendage (LAA) can be effectively and safely excluded using a novel percutaneous LARIAT ligation system. However, due to pericardial catheter manipulation and LAA ligation and subsequent necrosis, postprocedural course is complicated by pericarditis. We intended to evaluate the preprocedural use of colchicine on the incidence of postprocedural pericardial complications. METHODS AND RESULTS: In this multicenter observational study, we included all consecutive patients who underwent LARIAT procedure at the participating centers. Many patients received periprocedural colchicine at the discretion of the physician. We compared the postprocedural outcomes of patients who received prophylactic periprocedural colchicine (colchicine group) with those who did not receive colchicine (standard group). A total of 344 consecutive patients, 243 in the "colchicine group" and 101 in the "standard group," were included. The mean age, median CHADS2VASc score, and HASBLED scores were 70 +/- 11 years, 3 +/- 1.7, and 3 +/- 1.1, respectively. There were no significant differences in major baseline characteristics between the two groups. Severe pericarditis was significantly lower in the "colchicine group" compared to the "standard group" (10 [4%] vs. 16 [16%] P<0.0001). The colchicine group, compared to the standard group, had lesser pericardial drain output (186 +/- 84 mL vs. 351 +/- 83, P<0.001), shorter pericardial drain duration (16 +/- 4 vs. 23 +/- 19 hours, P<0.04), and similar incidence of delayed pericardial effusion (4 [1.6%] to 3 [3%], P = 0.42) when compared to the standard group. CONCLUSION: Use of colchicine periprocedurally was associated with significant reduction in postprocedural pericarditis and associated complications. PMID- 26515658 TI - [Aristolochic acid nephropathy ("Chinese herb nephropathy")]. AB - Aristolochic acid nephropathy is a renal disease of toxic origin characterized by a progressive interstitial fibrosis and frequently associated with urinary tract cancer. It was initially reported in Belgium after the intake of slimming pills containing root extracts of a Chinese herb, Aristolochia fangchi. In the following decades, numerous cases have been reported worldwide, particularly in Asian countries. Several experimental models of aristolochic acid nephropathy (AAN) have been designed. They confirm the causal link between AA exposure and the onset of acute and chronic renal toxicity, as well as urinary tract cancer. These experimental models offer the opportunity to study the mechanisms of renal interstitial fibrosis and carcinogenesis. In terms of public health, the history of this nephropathy demonstrates that it is mandatory to submit all "natural medicinal products" to the same controls of efficacy, toxicity and conformity applied to the classical drugs derived from the pharmaceutical producers. Any unusual observation of renal failure and/or cancer of the urinary tract should lead to a questioning about any prior exposure to AA. The confirmation of the ingestion of AA containing compounds by phytochemical analysis is not always feasible. However, the renal biopsy remains a crucial diagnostic point through the demonstration of a hypocellular interstitial fibrosis with a decreasing corticomedullary gradient, mostly in advanced cases of kidney disease. Moreover, the detection of AA-related DNA adducts within a renal or urothelial tissue sample could confirm the prior AA exposure. The persistence of these specific DNA adducts in renal tissue is very long (up to 20 years). Finally, considering the highly carcinogenic properties of AA, a systematic endo-urological screening is absolutely necessary. PMID- 26515659 TI - Long-term effects of Alzheimer's disease treatment. PMID- 26515661 TI - Age-dependent and -independent changes in attention-deficit/hyperactivity disorder (ADHD) during spatial working memory performance. AB - OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) has been associated with spatial working memory as well as frontostriatal core deficits. However, it is still unclear how the link between these frontostriatal deficits and working memory function in ADHD differs in children and adults. This study examined spatial working memory in adults and children with ADHD, focussing on identifying regions demonstrating age-invariant or age-dependent abnormalities. METHODS: We used functional magnetic resonance imaging to examine a group of 26 children and 35 adults to study load manipulated spatial working memory in patients and controls. RESULTS: In comparison to healthy controls, patients demonstrated reduced positive parietal and frontostriatal load effects, i.e., less increase in brain activity from low to high load, despite similar task performance. In addition, younger patients showed negative load effects, i.e., a decrease in brain activity from low to high load, in medial prefrontal regions. Load effect differences between ADHD and controls that differed between age groups were found predominantly in prefrontal regions. Age-invariant load effect differences occurred predominantly in frontostriatal regions. CONCLUSIONS: The age-dependent deviations support the role of prefrontal maturation and compensation in ADHD, while the age-invariant alterations observed in frontostriatal regions provide further evidence that these regions reflect a core pathophysiology in ADHD. PMID- 26515660 TI - Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses. AB - BACKGROUND: Findings from observational studies have suggested a delay in nursing home placement with dementia drug treatment, but findings from a previous randomised trial of patients with mild-to-moderate Alzheimer's disease showed no effect. We investigated the effects of continuation or discontinuation of donepezil and starting of memantine on subsequent nursing home placement in patients with moderate-to-severe Alzheimer's disease. METHODS: In the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial, community-living patients with moderate-to severe Alzheimer's disease (who had been prescribed donepezil continuously for at least 3 months at a dose of 10 mg for at least the previous 6 weeks and had a score of between 5 and 13 on the Standardised Mini-Mental State Examination) were recruited from 15 secondary care memory centres in England and Scotland and randomly allocated to continue donepezil 10 mg per day without memantine, discontinue donepezil without memantine, discontinue donepezil and start memantine 20 mg per day, or continue donepezil 10 mg per day and start memantine 20 mg per day, for 52 weeks. After 52 weeks, choice of treatment was left to participants and their physicians. Place of residence was recorded during the first 52 weeks of the trial and then every 26 weeks for a further 3 years. A secondary outcome of the trial, reported in this study, was nursing home placement: an irreversible move from independent accommodation to a residential caring facility. Analyses restricted to risk of placement in the first year of follow-up after the patients had completed the double-blind phase of the trial were post-hoc. The DOMINO-AD trial is registered with the ISRCTN Registry, number ISRCTN49545035. FINDINGS: Between Feb 11, 2008, and March 5, 2010, 73 (25%) patients were randomly assigned to continue donepezil without memantine, 73 (25%) to discontinue donepezil without memantine, 76 (26%) to discontinue donepezil and start memantine, and 73 (25%) to continue donepezil and start memantine. 162 (55%) patients underwent nursing home placement within 4 years of randomisation, with similar numbers for all groups (36 [49%] in patients who continued donepezil without memantine, 42 [58%] who discontinued donepezil without memantine, 41 [54%] who discontinued donepezil and started memantine, and 43 [59%] who continued donepezil and started memantine). We noted significant (p=0.010) heterogeneity of treatment effect over time, with significantly more nursing home placements in the combined donepezil discontinuation groups during the first year (hazard ratio 2.09 [95% CI 1.29-3.39]) than in the combined donepezil continuation groups, and no difference during the next 3 years (0.89 [0.58 1.35]). We noted no effect of patients starting memantine compared with not starting memantine during the first year (0.92 [0.58-1.45]) or the next 3 years (1.23 [0.81-1.87]). INTERPRETATION: Withdrawal of donepezil in patients with moderate-to-severe Alzheimer's disease increased the risk of nursing home placement during 12 months of treatment, but made no difference during the following 3 years of follow-up. Decisions to stop or continue donepezil treatment should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear. FUNDING: Medical Research Council and UK Alzheimer's Society. PMID- 26515662 TI - Heavy metal uptake capacity of fresh water algae (Oedogonium westti) from aqueous solution: A mesocosm research. AB - The green macroalgae present in freshwater ecosystems have attracted a great attention of the world scientists for removal of heavy metals from wastewater. In this mesocosm study, the uptake rates of heavy metals such as cadmium (Cd), nickel (Ni), chromium (Cr), and lead (Pb) by Oedogonium westi (O. westti) were measured. The equilibrium adsorption capabilities of O. westti were different for Cd, Ni, Cr, and Pb (0.974, 0.418, 0.620, and 0.261 mgg(-1), respectively) at 18 degrees C and pH 5.0. Furthermore, the removal efficiencies for Cd, Cr, Ni and Pb were observed from 55-95%, 61-93%, 59-89%, and 61-96%, respectively. The highest removal efficiency was observed for Cd and Cr from aqueous solution at acidic pH and low initial metal concentrations. However, the removal efficiencies of Ni and Pb were higher at high pH and high concentrations of metals in aqueous solution. The results summarized that O. westti is a suitable candidate for removal of selected toxic heavy metals from the aqueous solutions. PMID- 26515663 TI - Modeling longitudinal changes in hypertensive and waist phenotype: The oporto growth, health, and performance study. AB - OBJECTIVES: This study aimed to: (1) model changes in the hypertensive and waist phenotype (HWP) in youth, and (2) investigate the effects of sex, biological maturation, total physical activity (TPA), and physical fitness (PF) in HWP trajectories. METHODS: Data were obtained annually for 3 years from the Oporto Growth, Health, and Performance Study, and comprised 5,549 adolescents (2,732 girls) divided into four age cohorts (10, 12, 14, and 16 years). The HWP was computed as the sum of the standardized score of waist circumference and mean arterial pressure. Biological maturation was indirectly assessed by the maturity offset procedure; TPA was estimated with the Baecke questionnaire; PF measures included 1-mile run/walk, 50-yard dash (50YD), standing long jump (SLJ), handgrip strength (HGr), and agility shuttle run. Longitudinal changes in HWP were analyzed using multilevel modelling. RESULTS: HWP increased across time with a nonlinear trend in girls and boys. However, when adjusted for a set of predictors, the trend was reversed: girls and boys had a significant annual decrease on HWP of -0.202 +/- 0.032 and -0.147 +/- 0.032, respectively. Maturity offset was positively associated with HWP changes (beta = 0.913 +/- 0.023); TPA had a negative association (beta = -0.027 +/- 0.011); and improved PF tests were associated with a significant reduction in HWP across time (beta1mile = -0.081 +/- 0.009; betaSLJ = -0.003 +/- 0.00; beta50YD =0.106 +/- 0.020; and betaHGr = 3.335 +/- 0.196). CONCLUSIONS: Boys showed higher HWP values compared to girls from 10 to 18 years of age. Adolescents who were more biologically mature had a more adverse HWP. Longitudinal increases in TPA and PF predicted annual decreases in HWP across the adolescence years.Am. J. Hum. Biol. 28:387-393, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26515664 TI - Fabrication of nanocomposites composed of silver cyanamide and titania for improved photocatalytic hydrogen generation. AB - Highly efficient composite photocatalysts composed of silver cyanamide (Ag2NCN) and anatase titania (TiO2) were fabricated through a chemical precipitation process of silver nitrate and cyanamide in TiO2 suspensions. The TiO2 nanoparticles around 15 nm were immobilized on the surface of rectangular Ag2NCN particles to form a hetero-structure, and the contents of TiO2 were varied to tune the structure and the photocatalytic performances. In comparison with single TiO2 or Ag2NCN, the TiO2/Ag2NCN nanocomposites exhibited a prominent improved photocatalytic activity in the hydrogen generation, and the hydrogen evolution rate (1494.0 MUmol (g h)(-1)) was higher than most of the reported TiO2-composite photocatalysts. Based on the structure investigation, the photocatalytic mechanism of these TiO2/Ag2NCN nanocomposites was proposed. The enhanced photocatalytic activity was attributed to three points: the matched energy level between TiO2 and Ag2NCN promoted the electron-hole transfer and thus inhibited the recombination of photogenerated electrons and holes; the great electron storage capacity of metallic silver produced in the photocatalytic process also facilitated the charge separation; in addition, the expanded absorption spectrum because of the composite structure enhanced the UV and visible light response ability. These TiO2/Ag2NCN nanocomposites also presented good photocatalytic stability in the typical cycle tests. This work provided new insights into fabricating highly efficient composite photocatalysts containing silver and TiO2 for hydrogen generation. PMID- 26515665 TI - Objective assessment of low contrast detectability in computed tomography with Channelized Hotelling Observer. AB - PURPOSE: Iterative algorithms introduce new challenges in the field of image quality assessment. The purpose of this study is to use a mathematical model to evaluate objectively the low contrast detectability in CT. MATERIALS AND METHODS: A QRM 401 phantom containing 5 and 8 mm diameter spheres with a contrast level of 10 and 20 HU was used. The images were acquired at 120 kV with CTDIvol equal to 5, 10, 15, 20 mGy and reconstructed using the filtered back-projection (FBP), adaptive statistical iterative reconstruction 50% (ASIR 50%) and model-based iterative reconstruction (MBIR) algorithms. The model observer used is the Channelized Hotelling Observer (CHO). The channels are dense difference of Gaussian channels (D-DOG). The CHO performances were compared to the outcomes of six human observers having performed four alternative forced choice (4-AFC) tests. RESULTS: For the same CTDIvol level and according to CHO model, the MBIR algorithm gives the higher detectability index. The outcomes of human observers and results of CHO are highly correlated whatever the dose levels, the signals considered and the algorithms used when some noise is added to the CHO model. The Pearson coefficient between the human observers and the CHO is 0.93 for FBP and 0.98 for MBIR. CONCLUSION: The human observers' performances can be predicted by the CHO model. This opens the way for proposing, in parallel to the standard dose report, the level of low contrast detectability expected. The introduction of iterative reconstruction requires such an approach to ensure that dose reduction does not impair diagnostics. PMID- 26515666 TI - Graphene quantum dots for the inhibition of beta amyloid aggregation. AB - The aggregation of Abeta peptides is a crucial factor leading to Alzheimer's disease (AD). Inhibiting the Abeta peptide aggregation has become one of the most essential strategies to treat AD. In this work, efficient and low-cytotoxicity inhibitors, graphene quantum dots (GQDs) are reported for their application in inhibiting the aggregation of Abeta peptides. Compared to other carbon materials, the low cytotoxicity and great biocompatibility of GQDs give an advantage to the clinical research for AD. In addition, the GQDs may cross the blood-brain barrier (BBB) because of the small size. It is believed that GQDs may be therapeutic agents against AD. This work provides a novel insight into the development of Alzheimer's drugs. PMID- 26515667 TI - Studies of levels of biogenic amines in meat samples in relation to the content of additives. AB - The impact of meat additives on the concentration of biogenic amines and the quality of meat was studied. Fresh white and red meat samples were fortified with the following food additives: citric and lactic acids, disodium diphosphate, sodium nitrite, sodium metabisulphite, potassium sorbate, sodium chloride, ascorbic acid, alpha-tocopherol, propyl 3,4,5-trihydroxybenzoate (propyl gallate) and butylated hydroxyanisole. The content of spermine, spermidine, putrescine, cadaverine, histamine, tyramine, tryptamine and 2-phenylethylamine was determined by capillary isotachophoretic methods in meat samples (fresh and fortified) during four days of storage at 4 degrees C. The results were applied to estimate the impact of the tested additives on the formation of biogenic amines in white and red meat. For all tested meats, sodium nitrite, sodium chloride and disodium diphosphate showed the best inhibition. However, cadaverine and putrescine were characterised by the biggest changes in concentration during the storage time of all the additives. Based on the presented data for the content of biogenic amines in meat samples analysed as a function of storage time and additives, we suggest that cadaverine and putrescine have a significant impact on meat quality. PMID- 26515668 TI - Changes in Physical Activity and Psychological Variables Following a Web-Based Motivational Interviewing Intervention: Pilot Study. AB - BACKGROUND: Web-based interventions for enhancing physical activity participation are in demand for application in health care settings. Recent research suggests Web-based interventions that are based on motivational interviewing are effective to increase physical activity. It is unclear whether motivational interviewing can influence targeted psychological variables such as perceived readiness, willingness, and ability to participate in physical activity. OBJECTIVE: The aims of this study were to determine whether there were changes in physical activity and psychological variables associated with readiness, willingness, and perceived ability to participate in physical activity following completion of a novel Web based intervention. The goal of the motivational interviewing-based intervention was to increase physical activity. METHODS: Twenty-three underactive or inactive urban dwelling adults were recruited at a medical office for participation in a 4 session Web-based intervention lasting approximately 15 minutes per week. Sessions were based on principles of motivational interviewing. Assessment of physical activity was conducted using pedometers immediately prior to intervention participation (pre) and immediately post intervention (post1). Self report assessments of physical activity and psychological variables were conducted using online surveys at pre, post1, and again at one month following intervention participation (post2). RESULTS: Comparisons of pre and post1 pedometer recordings revealed significant increases in steps per day (t22=2.09, P=.049). There were also significant changes in total physical activity energy expenditure per week (chi(2) 2=8.4, P=.02) and in moderate intensity physical activity energy expenditure per week (chi(2) 2=13.9, P<.001) over time following participation in the Web-based intervention. Significant changes in psychological variables following participation in the Web-based intervention included: (1) change in stage classification over time (chi(2) 2=21.5, P<.001), where the percentage of participants classified in the action or maintenance stages of change in physical activity increased over time (pre=25% [6/24], post1=71% [17/24], post2=68% [15/22]); (2) decreases in self-reported decisional balance cons (F2,42=12.76, P<.001); (3) increases in self-reported decisional balance pros (F2,42=16.19, P<.001); (4) increases in physical activity enjoyment (F2,20=3.85, P=.04); and (5) increases in self-efficacy (F2,42=3.30, P=.047). CONCLUSIONS: The Web-based intervention piloted in this study shows preliminary promise as a tool to promote physical activity in health care settings. Additional research is needed to test the effectiveness of motivational interviewing compared to a control condition and to refine content by considering mediation by psychological variables in a larger sample. PMID- 26515669 TI - Environmental and individual determinants of parasite richness across seasons in a free-ranging population of Mandrills (Mandrillus sphinx). AB - OBJECTIVES: Parasites are ubiquitous and evolve fast. Therefore, they represent major selective forces acting on their hosts by influencing many aspects of their biology. Humans are no exception, as they share many parasites with animals and some of the most important outbreaks come from primates. While it appears important to understand the factors involved in parasite dynamics, we still lack a clear understanding of the determinants underlying parasitism. In this 2-year study, we identified several factors that influence parasite patterns in a wild population of free-ranging mandrills (Mandrillus sphinx). METHODS: We explored the potential impact of seasonal factors-rainfall and temperature-and host characteristics, including sex, age, rank, and reproductive status, on parasite richness. We analyzed 12 parasite taxa found in 870 fecal samples collected from 63 individuals. Because nematodes and protozoa have different life-cycles, we analyzed these two types of parasites separately. RESULTS: Contrary to other studies where humid conditions seem favorable to parasite development, we report here that rainfall and high temperatures were associated with lower nematode richness and were not associated with lower protozoa richness. In contrast, female reproductive status seemed to reflect the seasonal patterns found for protozoa richness, as early gestating females harbored more protozoa than other females. Sex and dominance rank had no impact on overall parasite richness. However, age was associated with a specific decrease in nematode richness. CONCLUSION: Our study emphasizes the need to consider the ecological context, such as climatic conditions and habitat type, as well as the biology of both parasite and host when analyzing determinants of parasite richness. PMID- 26515670 TI - Large Scale Laser Crystallization of Solution-based Alumina-doped Zinc Oxide (AZO) Nanoinks for Highly Transparent Conductive Electrode. AB - A new method combining aqueous solution printing with UV Laser crystallization (UVLC) and post annealing is developed to deposit highly transparent and conductive Aluminum doped Zinc Oxide (AZO) films. This technique is able to rapidly produce large area AZO films with better structural and optoelectronic properties than most high vacuum deposition, suggesting a potential large-scale manufacturing technique. The optoelectronic performance improvement attributes to UVLC and forming gas annealing (FMG) induced grain boundary density decrease and electron traps passivation at grain boundaries. The physical model and computational simulation developed in this work could be applied to thermal treatment of many other metal oxide films. PMID- 26515671 TI - Seated postural hypotension. AB - Most studies of postural hypotension (PH) have focused on standing PH. Less is known about PH after transition from a supine to sitting position. Moreover, seated PH has not been previously reviewed in the English literature. The aim of this review was to provide current information regarding seating-induced PH. Seventeen studies were reviewed regarding prevalence, methods of evaluation, manifestations, predisposing factors, prognosis, and management of seated PH. Prevalence ranged from 8% among community-dwelling persons to 56% in elderly hospitalized patients. Dizziness and palpitations were the most frequent symptoms. Of a variety of factors that have been identified as predisposing and contributing to seated PH, aging, bed rest, and hypertension were most important. Because seated PH is a common, easily diagnosable and frequently symptomatic condition, especially in elderly inpatients, this disorder warrants attention. Moreover, seating-induced falls in blood pressure and the associated symptoms, may be largely prevented by nonpharmacologic interventions. PMID- 26515673 TI - Effect of tenofovir disoproxil fumarate on drug-resistant HBV clones. AB - BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) has been approved for chronic hepatitis B treatment, and favorable susceptibility of hepatitis B virus (HBV) has been indicated. However, differences in TDF susceptibility among HBV genotypes and drug-resistant strains are unclear. In this study, TDF susceptibilities between genotypes A and C were evaluated in vitro and in vivo using several drug-resistant HBV clones. METHODS: HBV expression plasmids were constructed from sera of HBV carriers, and drug-resistant substitutions were introduced by site-directed mutagenesis. TDF susceptibility was evaluated by changes of core-associated HBV replication intermediates in vitro or by change of serum HBV DNA in human hepatocyte chimeric mice carrying each HBV clone in vivo. RESULTS: TDF susceptibilities of lamivudine-resistant clones (rtL180M/M204V) and lamivudine plus entecavir-resistant clones (rtL180M/S202G/M204V) were similar to wild type clones in vitro. However, lamivudine plus adefovir-resistant clones (rtA181T/N236T) acquired tolerance to TDF, and the rtN236T mutation was considered to be a causal substitution for TDF resistance. Furthermore, genotypic differences in TDF susceptibility were also observed between genotypes A and C in vitro, and the differences could be confirmed in vivo (p = 0.023). CONCLUSIONS: The present study indicates that TDF susceptibility varies among HBV genotypes and drug-resistant HBV clones. PMID- 26515674 TI - Harvard launches new global health centre in Dubai. PMID- 26515675 TI - Turning off the tap: stopping tuberculosis transmission through active case finding and prompt effective treatment. AB - To halt the global tuberculosis epidemic, transmission must be stopped to prevent new infections and new cases. Identification of individuals with tuberculosis and prompt initiation of effective treatment to rapidly render them non-infectious is crucial to this task. However, in settings of high tuberculosis burden, active case-finding is often not implemented, resulting in long delays in diagnosis and treatment. A range of strategies to find cases and ensure prompt and correct treatment have been shown to be effective in high tuberculosis-burden settings. The population-level effect of targeted active case-finding on reducing tuberculosis incidence has been shown by studies and projected by mathematical modelling. The inclusion of targeted active case-finding in a comprehensive epidemic-control strategy for tuberculosis should contribute substantially to a decrease in tuberculosis incidence. PMID- 26515677 TI - Tuberculosis--getting to zero. PMID- 26515676 TI - Data for action: collection and use of local data to end tuberculosis. AB - Accelerating progress in the fight against tuberculosis will require a drastic shift from a strategy focused on control to one focused on elimination. Successful disease elimination campaigns are characterised by locally tailored responses that are informed by appropriate data. To develop such a response to tuberculosis, we suggest a three-step process that includes improved collection and use of existing programmatic data, collection of additional data (eg, geographic information, drug resistance, and risk factors) to inform tailored responses, and targeted collection of novel data (eg, sequencing data, targeted surveys, and contact investigations) to improve understanding of tuberculosis transmission dynamics. Development of a locally targeted response for tuberculosis will require substantial investment to reconfigure existing systems, coupled with additional empirical data to evaluate the effectiveness of specific approaches. Without adoption of an elimination strategy that uses local data to target hotspots of transmission, ambitious targets to end tuberculosis will almost certainly remain unmet. PMID- 26515678 TI - Stopping tuberculosis: a biosocial model for sustainable development. AB - Tuberculosis transmission and progression are largely driven by social factors such as poor living conditions and poor nutrition. Increased standards of living and social approaches helped to decrease the burden of tuberculosis before the introduction of chemotherapy in the 1940s. Since then, management of tuberculosis has been largely biomedical. More funding for tuberculosis since 2000, coinciding with the Millennium Development Goals, has yielded progress in tuberculosis mortality but smaller reductions in incidence, which continues to pose a risk to sustainable development, especially in poor and susceptible populations. These at risk populations need accelerated progress to end tuberculosis as resolved by the World Health Assembly in 2015. Effectively addressing the worldwide tuberculosis burden will need not only enhancement of biomedical approaches but also rebuilding of the social approaches of the past. To combine a biosocial approach, underpinned by social, economic, and environmental actions, with new treatments, new diagnostics, and universal health coverage, will need multisectoral coordination and action involving the health and other governmental sectors, as well as participation of the civil society, and especially the poor and susceptible populations. A biosocial approach to stopping tuberculosis will not only target morbidity and mortality from disease but would also contribute substantially to poverty alleviation and sustainable development that promises to meet the needs of the present, especially the poor, and provide them and subsequent generations an opportunity for a better future. PMID- 26515680 TI - Stopping the body count: a comprehensive approach to move towards zero tuberculosis deaths. PMID- 26515679 TI - Controlling the seedbeds of tuberculosis: diagnosis and treatment of tuberculosis infection. AB - The billions of people with latent tuberculosis infection serve as the seedbeds for future cases of active tuberculosis. Virtually all episodes of tuberculosis disease are preceded by a period of asymptomatic Mycobacterium tuberculosis infection; therefore, identifying infected individuals most likely to progress to disease and treating such subclinical infections to prevent future disease provides a crucial opportunity to interrupt tuberculosis transmission and reduce the global burden of tuberculosis disease. Programmes focusing on single strategies rather than comprehensive programmes that deliver an integrated arsenal for tuberculosis control might continue to struggle. Tuberculosis preventive therapy is a poorly used method that is essential for controlling the reservoirs of disease that drive the epidemic. Comprehensive control strategies that combine preventive therapy for the most high-risk populations and communities with improved case-finding and treatment, control of transmission, and health systems strengthening could ultimately lead to worldwide tuberculosis elimination. In this Series paper we outline challenges to implementation of preventive therapy and provide pragmatic suggestions for overcoming them. We further advocate for tuberculosis preventive therapy as the core of a renewed worldwide focus to implement a comprehensive epidemic control strategy that would reduce new tuberculosis cases to elimination targets. This strategy would be underpinned by accelerated research to further understand the biology of subclinical tuberculosis infections, develop novel diagnostics and drug regimens specifically for subclinical tuberculosis infection, strengthen health systems and community engagement, and enhance sustainable large scale implementation of preventive therapy programmes. PMID- 26515681 TI - Salmaan Keshavjee: tackling tuberculosis (without rocket science). PMID- 26515682 TI - No one with HIV should die from tuberculosis. PMID- 26515683 TI - CFTR-regulated MAPK/NF-kappaB signaling in pulmonary inflammation in thermal inhalation injury. AB - The mechanism underlying pulmonary inflammation in thermal inhalation injury remains elusive. Cystic fibrosis, also hallmarked with pulmonary inflammation, is caused by mutations in CFTR, the expression of which is temperature-sensitive. We investigated whether CFTR is involved in heat-induced pulmonary inflammation. We applied heat-treatment in 16HBE14o- cells with CFTR knockdown or overexpression and heat-inhalation in rats in vivo. Heat-treatment caused significant reduction in CFTR and, reciprocally, increase in COX-2 at early stages both in vitro and in vivo. Activation of ERK/JNK, NF-kappaB and COX-2/PGE2 were detected in heat treated cells, which were mimicked by knockdown, and reversed by overexpression of CFTR or VX-809, a reported CFTR mutation corrector. JNK/ERK inhibition reversed heat-/CFTR-knockdown-induced NF-kappaB activation, whereas NF-kappaB inhibitor showed no effect on JNK/ERK. IL-8 was augmented by heat-treatment or CFTR-knockdown, which was abolished by inhibition of NF-kappaB, JNK/ERK or COX-2. Moreover, in vitro or in vivo treatment with curcumin, a natural phenolic compound, significantly enhanced CFTR expression and reversed the heat-induced increases in COX-2/PGE2/IL-8, neutrophil infiltration and tissue damage in the airway. These results have revealed a CFTR-regulated MAPK/NF-kappaB pathway leading to COX-2/PGE2/IL-8 activation in thermal inhalation injury, and demonstrated therapeutic potential of curcumin for alleviating heat-induced pulmonary inflammation. PMID- 26515684 TI - Association of rule of law and health outcomes: an ecological study. AB - OBJECTIVES: To explore whether the rule of law is a foundational determinant of health that underlies other socioeconomic, political and cultural factors that have been associated with health outcomes. SETTING: Global project. PARTICIPANTS: Data set of 96 countries, comprising 91% of the global population. PRIMARY AND SECONDARY OUTCOME MEASURES: The following health indicators, infant mortality rate, maternal mortality rate, life expectancy, and cardiovascular disease and diabetes mortality rate, were included to explore their association with the rule of law. We used a novel Rule of Law Index, gathered from survey sources, in a cross-sectional and ecological design. The Index is based on eight subindices: (1) Constraints on Government Powers; (2) Absence of Corruption; (3) Order and Security; (4) Fundamental Rights; (5) Open Government; (6) Regulatory Enforcement, (7) Civil Justice; and (8) Criminal Justice. RESULTS: The rule of law showed an independent association with infant mortality rate, maternal mortality rate, life expectancy, and cardiovascular disease and diabetes mortality rate, after adjusting for the countries' level of per capita income, their expenditures in health, their level of political and civil freedom, their Gini measure of inequality and women's status (p<0.05). Rule of law remained significant in all the multivariate models, and the following adjustment for potential confounders remained robust for at least one or more of the health outcomes across all eight subindices of the rule of law. Findings show that the higher the country's level of adherence to the rule of law, the better the health of the population. CONCLUSIONS: It is necessary to start considering the country's adherence to the rule of law as a foundational determinant of health. Health advocates should consider the improvement of rule of law as a tool to improve population health. Conversely, lack of progress in rule of law may constitute a structural barrier to health improvement. PMID- 26515685 TI - Incidence of ventilator-associated pneumonia in Australasian intensive care units: use of a consensus-developed clinical surveillance checklist in a multisite prospective audit. AB - OBJECTIVES: With disagreements on diagnostic criteria for ventilator-associated pneumonia (VAP) hampering efforts to monitor incidence and implement preventative strategies, the study objectives were to develop a checklist for clinical surveillance of VAP, and conduct an audit in Australian/New Zealand intensive care units (ICUs) using the checklist. SETTING: Online survey software was used for checklist development. The prospective audit using the checklist was conducted in 10 ICUs in Australia and New Zealand. PARTICIPANTS: Checklist development was conducted with members of a bi-national professional society for critical care physicians using a modified Delphi technique and survey. A 30-day audit of adult patients mechanically ventilated for >72 h. PRIMARY AND SECONDARY OUTCOME MEASURES: Presence of items on the screening checklist; physician diagnosis of VAP, clinical characteristics, investigations, treatments and patient outcome. RESULTS: A VAP checklist was developed with five items: decreasing gas exchange, sputum changes, chest X-ray infiltrates, inflammatory response, microbial growth. Of the 169 participants, 17% (n=29) demonstrated characteristics of VAP using the checklist. A similar proportion had an independent physician diagnosis (n=30), but in a different patient subset (only 17% of cases were identified by both methods). The VAP rate per 1000 mechanical ventilator days for the checklist and clinician diagnosis was 25.9 and 26.7, respectively. The item 'inflammatory response' was most associated with the first episode of physician-diagnosed VAP. CONCLUSIONS: VAP rates using the checklist and physician diagnosis were similar to ranges reported internationally and in Australia. Of note, different patients were identified with VAP by the checklist and physicians. While the checklist items may assist in identifying patients at risk of developing VAP, and demonstrates synergy with the recently developed Centers for Disease Control (CDC) guidelines, decision-making processes by physicians when diagnosing VAP requires further exploration. PMID- 26515687 TI - Non-dental primary care providers' views on challenges in providing oral health services and strategies to improve oral health in Australian rural and remote communities: a qualitative study. AB - OBJECTIVES: To investigate the challenges of providing oral health advice/treatment as experienced by non-dental primary care providers in rural and remote areas with no resident dentist, and their views on ways in which oral health and oral health services could be improved for their communities. DESIGN: Qualitative study with semistructured interviews and thematic analysis. SETTING: Four remote communities in outback Queensland, Australia. PARTICIPANTS: 35 primary care providers who had experience in providing oral health advice to patients and four dental care providers who had provided oral health services to patients from the four communities. RESULTS: In the absence of a resident dentist, rural and remote residents did present to non-dental primary care providers with oral health problems such as toothache, abscess, oral/gum infection and sore mouth for treatment and advice. Themes emerged from the interview data around communication challenges and strategies to improve oral health. Although, non-dental care providers commonly advised patients to see a dentist, they rarely communicated with the dentist in the nearest regional town. Participants proposed that oral health could be improved by: enabling access to dental practitioners, educating communities on preventive oral healthcare, and building the skills and knowledge base of non-dental primary care providers in the field of oral health. CONCLUSIONS: Prevention is a cornerstone to better oral health in rural and remote communities as well as in more urbanised communities. Strategies to improve the provision of dental services by either visiting or resident dental practitioners should include scope to provide community-based oral health promotion activities, and to engage more closely with other primary care service providers in these small communities. PMID- 26515686 TI - Design of the DRAGET Study: a multicentre controlled diagnostic study to assess the detection of acute rejection in patients with heart transplant by means of T2 quantification with MRI in comparison to myocardial biopsies. AB - INTRODUCTION: Patients with heart transplant are screened for silent graft rejection by recurrent endomyocardial biopsies. MRI can detect the presence of oedema non-invasively by quantitatively measuring changes of the transverse relaxation time T2 in the myocardium. Several monocentric studies have shown that T2 quantification could help detect graft rejection in a less invasive way. DRAGET is a national multicentre diagnostic study designed to prove that T2 quantification by MRI can detect graft rejection. METHODS AND ANALYSIS: 190 patients from 10 centres will undergo T2 quantification and endomyocardial biopsy, within 24 h, 4 to 6 times during the first year after transplantation. T2 will be computed by analysing a sequence of 10 images obtained from a short-axis slice. Specific phantoms will be used to calibrate the T2 quantification on each MR scanner to cope with the different equipment (different vendors, magnetic field strength, etc). Specific pads with known T2 will also be used during each examination and provide a quality check to cope with the different experimental conditions (temperature, etc). All MRI and biopsy data will be reinterpreted in our centre and reproducibility will be assessed. The primary outcome will be sensitivity and specificity of MRI. The secondary outcomes will be (1) prognostic values of T2, (2) reproducibility of each techniques, (3) number of adverse events during each procedures and (4) confidence of the physicians in T2. ETHICS AND DISSEMINATION: Ethics approval has been obtained. The new MRI method will be disseminated at a national level and its practical usefulness will be assessed in centres not familiar with MRI T2 quantification. The ultimate aim of the DRAGET project is to replace a strategy based solely on biopsy with one based on a first line MRI (with biopsy only when needed) for a more efficient and less invasive detection of rejection. TRIAL REGISTRATION NUMBERS: ANSM 2014-A00848-39, NCT02261870. PMID- 26515688 TI - JNK-mediated activation of ATF2 contributes to dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease. AB - The c-Jun N-terminal kinase (JNK)/c-Jun pathway is a known critical regulator of dopaminergic neuronal death in Parkinson's disease (PD) and is considered a potential target for neuroprotective therapy. However, whether JNK is activated within dopaminergic neurons remains controversial, and whether JNK acts through downstream effectors other than c-Jun to promote dopaminergic neuronal death remains unclear. In this study, we confirm that JNK but not p38 is activated in dopaminergic neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. Furthermore, within the dopaminergic neurons of the substantia nigra in MPTP-treated mice, JNK2/3 phosphorylates threonine 69 (Thr69) of Activating transcription factor-2 (ATF2), a transcription factor of the ATF/CREB family, whereas the phosphorylation of Thr71 is constitutive and remains unchanged. The increased phosphorylation of ATF2 on Thr69 by JNK in the MPTP mouse model suggests a functional relationship between the transcriptional activation of ATF2 and dopaminergic neuron death. By using dopaminergic neuron specific conditional ATF2 mutant mice, we found that either partial or complete deletion of the ATF2 DNA-binding domain in dopaminergic neurons markedly alleviates the MPTP-induced dopaminergic neurodegeneration, indicating that the activation of ATF2 plays a detrimental role in neuropathogenesis in PD. Taken together, our findings demonstrate that JNK-mediated ATF2 activation contributes to dopaminergic neuronal death in an MPTP model of PD. PMID- 26515689 TI - Amyloid-beta suppresses AMP-activated protein kinase (AMPK) signaling and contributes to alpha-synuclein-induced cytotoxicity. AB - Dementia with Lewy bodies (DLB) is a neurodegenerative disorder caused by abnormal accumulation of Lewy bodies, which are intracellular deposits composed primarily of aggregated alpha-synuclein (alphaSyn). Although alphaSyn has been strongly implicated to induce neurotoxicity, overexpression of wild-type alphaSyn is shown to be insufficient to trigger formation of protein aggregates by itself. Therefore, investigating the possible mechanism underlying alphaSyn aggregation is essential to understand the pathogenesis of DLB. Previous studies have demonstrated that amyloid beta (Abeta), the primary cause of Alzheimer's disease (AD), may promote the formation of alphaSyn inclusion bodies. However, it remains unclear how Abeta contributes to the deposition and neurotoxicity of alphaSyn. In the present study, we investigated the cytotoxic effects of Abeta in alphaSyn overexpressed neuronal cells. Our results showed that Abeta inhibits autophagy and enhances alphaSyn aggregation in alphaSyn-overexpressed cells. Moreover, Abeta also reduced sirtuin 1 (Sirt1) and its downstream signaling, resulting in increased intracellular ROS accumulation and mitochondrial dysfunction. Our in vitro and in vivo studies support that Abeta-inhibition of AMP-activated protein kinase (AMPK) signaling is involved in the neurotoxic effects of alphaSyn. Taken together, our findings suggest that Abeta plays a synergistic role in alphaSyn aggregation and cytotoxicity, which may provide a novel understanding for exploring the underlying molecular mechanism of DLB. PMID- 26515690 TI - The molecular physiology of the axo-myelinic synapse. AB - Myelinated axons efficiently transmit information over long distances. The apposed myelin sheath confers favorable electrical properties, but restricts access of the axon to its extracellular milieu. Therefore, axonal metabolic support may require specific axo-myelinic communication. Here we explored activity-dependent glutamate-mediated signaling from axon to myelin. 2-Photon microscopy was used to image Ca(2+) changes in myelin in response to electrical stimulation of optic nerve axons ex vivo. We show that optic nerve myelin responds to axonal action potentials by a rise in Ca(2+) levels mediated by GluN2D and GluN3A-containing NMDA receptors. Glutamate is released from axons in a vesicular manner that is tetanus toxin-sensitive. The Ca(2+) source for vesicular fusion is provided by ryanodine receptors on axonal Ca(2+) stores, controlled by L-type Ca(2+) channels that sense depolarization of the internodal axolemma. Genetic ablation of GluN2D and GluN3A subunits results in greater lability of the compact myelin. Our results support the existence of a novel synapse between the axon and its myelin, suggesting a means by which traversing action potentials can signal the overlying myelin sheath. This may be an important physiological mechanism by which an axon can signal companion glia for metabolic support or adjust properties of its myelin in a dynamic manner. The axo myelinic synapse may contribute to learning, while its disturbances may play a role in the pathophysiology of central nervous system disorders such as schizophrenia, where subtle abnormalities of myelinated white matter tracts have been shown in the human, or to frank demyelinating disorders such as multiple sclerosis. PMID- 26515691 TI - Co-transplantation of syngeneic mesenchymal stem cells improves survival of allogeneic glial-restricted precursors in mouse brain. AB - Loss of functional cells from immunorejection during the early post transplantation period is an important factor that reduces the efficacy of stem cell-based therapies. Recent studies have shown that transplanted mesenchymal stem cells (MSCs) can exert therapeutic effects by secreting anti-inflammatory and pro-survival trophic factors. We investigated whether co-transplantation of MSCs could improve the survival of other transplanted therapeutic cells. Allogeneic glial-restricted precursors (GRPs) were isolated from the brain of a firefly luciferase transgenic FVB mouse (at E13.5 stage) and intracerebrally transplanted, either alone, or together with syngeneic MSCs in immunocompetent BALB/c mice (n=20) or immunodeficient Rag2(-/-) mice as survival control (n=8). No immunosuppressive drug was given to any animal. Using bioluminescence imaging (BLI) as a non-invasive readout of cell survival, we found that co transplantation of MSCs significantly improved (p<0.05) engrafted GRP survival. No significant change in signal intensities was observed in immunodeficient Rag2( /-) mice, with transplanted cells surviving in both the GRP only and the GRP+MSC group. In contrast, on day 21 post-transplantation, we observed a 94.2% decrease in BLI signal intensity in immunocompetent mice transplanted with GRPs alone versus 68.1% in immunocompetent mice co-transplanted with MSCs and GRPs (p<0.05). Immunohistochemical analysis demonstrated a lower number of infiltrating CD45, CD11b(+) and CD8(+) cells, reduced astrogliosis, and a higher number of FoxP3(+) cells at the site of transplantation for the immunocompetent mice receiving MSCs. The present study demonstrates that co-transplantation of MSCs can be used to create a microenvironment that is more conducive to the survival of allogeneic GRPs. PMID- 26515692 TI - Phosphodiesterase-5 inhibition promotes remyelination by MCP-1/CCR-2 and MMP-9 regulation in a cuprizone-induced demyelination model. AB - While it has recently been shown that sildenafil (Viagra(r)) has a protective effect on myelination/remyelination, the mechanism of this protection is still unknown. In general, cytokines, chemokines and metalloproteinases have a pro inflammatory action, but can also exert a role in modulating glial cell activation, contributing to the balance of cell response. Investigating these molecules can contribute to clarifying the mechanisms of sildenafil neuroprotection. In addition, it is not known whether sildenafil is able to restore an already installed neurodegenerative process or if the treatment period is critical for its action. The aim of the present study was to evaluate, in a cuprizone (CPZ)-induced demyelination model, the effects and mechanisms of time dependent treatment with sildenafil (beginning 15 days after neurodegeneration and continuing for 15 days, or starting concomitantly with neurodegeneration and continuing for 30 days) on neuroinflammation and remyelination. Neuroinflammation and demyelination induced by CPZ in rodents has been widely used as a model of multiple sclerosis (MS). In the present study, five male C57BL/6 mice aged 7-10 weeks were used per group. For four weeks, the groups received either cuprizone (CPZ) 0.2% mixed in feed or CPZ combined with the administration of sildenafil (Viagra(r), Pfizer, 25 mg/kg) orally in drinking water, starting concurrently with (sild-T0) or 15 days (sild-T15) after the start of CPZ treatment. Control animals received pure food and water. The cerebella were dissected and processed for immunohistochemistry, immunofluorescence (frozen), Western blotting, Luxol fast blue staining and transmission electron microscopy. Magnetic resonance was performed for live animals, after the same treatment, using CPZ 0.3%. CPZ induced an increase in the expression of IL-1beta and a decrease in MCP-1, CCR-2, MBP and GST-pi, as well as promoting damage in the structure and ultra-structure of the myelin sheath. Interestingly, the administering of sild-T0 promoted a further increase of MMP-9, MCP-1, and CCR-2, possibly contributing to changes in the microglia phenotype, which becomes more phagocytic, cleaning myelin debris. It was also observed that, after sild-T0 treatment, the expression of GST-pi and MBP increased and the myelin structure was improved. However, sild-T15 was not efficient in all aspects, probably due to the short treatment period and to starting after the installation of the degenerative process. Therefore, the present study shows that sildenafil modulates inflammation, with the involvement of MMP-9, MCP-1, and CCR-2, and also contributes to myelin repair. These protective effects were dependent on the therapeutic strategy used. This clarification can strengthen research proposals into the mechanism of action of sildenafil and contribute to the control of neurodegenerative diseases such as MS. PMID- 26515693 TI - Targeting vulnerable households in urban Burkina Faso: effectiveness of geographical criteria but not of proxy-means testing. AB - The 2007/2008 food prices hike has increased the interest in social safety nets programmes to fight food insecurity. Targeting the most in need is central to achieve effectiveness of such interventions. In 2009 in Ouagadougou, Burkina Faso, a food voucher (FV) programme targeted the 25 000 most vulnerable households (8.3% of the population). Targeting used a two-stage process: first geographical selection of poorest districts (~90 000 households); then, in those districts, identification of the most vulnerable households according to a proxy means test (PMT). Targeted households were entitled to receive FV for 1 year. A first survey was conducted at the beginning of the FV distribution on a representative sample of 2273 households drawn from the poorest districts. One year later a second survey, conducted on a subsample of same households (n = 901), identified those who actually received FV (beneficiary). The performance of the whole process was assessed against household food expenditure, used as the reference measure for vulnerability with a cut-off point of 1513 FCFA (corresponding to the 8.3th percentile of the distribution of expenditure). The 'normalized share of transfers going to vulnerable households' (NSTVH), i.e. proportion of FVs allocated to households below the cut-point, was the main criteria of judgement. Almost twice as many FV were allocated to vulnerable households as compared with a theoretical random distribution all over Ouagadougou (NSTVH = 1.85). When considering the sole targeted districts the NSTVH was only 0.84 (i.e. no more effective than a random distribution), meaning that the geographical stage was effective to select vulnerable districts while the PMT did not perform well to identify the most vulnerable households in those districts. Results could have been improved if only targeted households had received FV (NSTVH = 2.61 and 1.18 for the whole Ouagadougou and targeted districts, respectively). Improved targeting procedures or alternate targeting instruments are needed. PMID- 26515694 TI - Detecting Cytosolic Peptide Delivery with the GFP Complementation Assay in the Low Micromolar Range. AB - Transfection of cells with a plasmid encoding for the first ten strands of the GFP protein (GFP1-10) provides the means to detect cytosolic peptide import at low micromolar concentrations. Cytosolic import of the eleventh strand of the GFP protein either by electroporation or by cell-penetrating peptide-mediated import leads to formation of the full-length GFP protein and fluorescence. An increase in sensitivity is achieved through structural modifications of the peptide and the expression of GFP1-10 as a fusion protein with mCherry. PMID- 26515695 TI - Identification of putative SNPs in progressive retinal atrophy affected Canis lupus familiaris using exome sequencing. AB - Progressive retinal atrophy (PRA) is one of the major causes of retinal photoreceptor cell degeneration in canines. The inheritance pattern of PRA is autosomal recessive and genetically heterogeneous. Here, using targeted sequencing technology, we have performed exome sequencing of 10 PRA-affected (Spitz=7, Cocker Spaniel=1, Lhasa Aphso=1 and Spitz-Labrador cross breed=1) and 6 normal (Spitz=5, Cocker Spaniel=1) dogs. The high-throughput sequencing using 454 Roche Titanium sequencer generated about 2.16 Giga bases of raw data. Initially, we have successfully identified 25,619 single nucleotide polymorphisms (SNPs) that passed the stringent SNP calling parameters. Further, we performed association study on the cohort, and the highly significant (0.001) associations were short-listed and investigated in-depth. Out of the 171 significant SNPs, 113 were previously unreported. Interestingly, six among them were non-synonymous coding (NSC) SNPs, which includes CPPED1 A>G (p.M307V), PITRM1 T>G (p.S715A), APP G>A (p.T266M), RNF213 A>G (p.V1482A), C>A (p.V1456L), and SLC46A3 G>A (p.R168Q). On the other hand, 35 out of 113 unreported SNPs were falling in regulatory regions such as 3'-UTR, 5'-UTR, etc. In-depth bioinformatics analysis revealed that majority of NSC SNPs have damaging effect and alter protein stability. This study highlighted the genetic markers associated with PRA, which will help to develop genetic assay-based screening in effective breeding. PMID- 26515696 TI - MicroRNA-206 functions as a tumor suppressor in colorectal cancer by targeting FMNL2. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers in the world. MicroRNAs play important roles in the progression of CRC. This study aimed to investigate the role of miR-206 and its novel mechanism in the invasion and metastasis of CRC. METHODOLOGY: Real-time RT-PCR or Western blotting was used to detect the expressions of miR-206, FMNL2 and c-MET in CRC cell lines and tissues. Luciferase reporter assays were conducted to detect the associations between miR 206 and 3'UTRs of FMNL2 and c-MET. A series of loss-of-function and gain-of function assays were performed to evaluate the effect of miR-206 on the proliferation, invasion and metastasis of CRC cells. RESULTS: miR-206 was significantly down-regulated in CRC tissues and correlated closely with differentiation, lymphatic metastasis and serosal invasion. miR-206 suppressed CRC cell proliferation by arresting CRC cells in the G1/G0 phase and accelerating apoptosis. miR-206 also inhibited cell invasion and lung metastasis in CRC cells. Mechanically, FMNL2 and c-MET were identified as direct targets of miR-206. And FMNL2 rescued the suppression of miR-206 in the proliferation and invasion of CRC cells. CONCLUSIONS: This study revealed functional and mechanistic links between miR-206 and oncogene FMNL2 and c-MET in the progression of CRC. miR-206 functioned as a tumor suppressor in the progression of CRC by targeting FMNL2 and c-MET. Restoration of miR-206 expression may represent a promising therapeutic approach for targeting malignant CRC. PMID- 26515698 TI - Acute stroke from tumor embolus in a patient with cardiac sarcoma: Aspiration thrombectomy with Penumbra catheter. AB - The most common primary malignant cardiac tumor is the cardiac sarcoma, which is mesenchymal in origin. This case report describes a patient with hyperacute stroke caused by cardiac sarcoma who underwent rapid recanalization through mechanical aspiration thrombectomy with Penumbra catheter. PMID- 26515699 TI - Amplatzer vascular plug for rapid vessel occlusion in interventional neuroradiology. AB - The purpose of this paper is to report different uses of endovascular Amplatzer vascular plug (AVP) treatment for rapid vessel occlusion in the field of interventional neuroradiology. We retrospectively reviewed our interventional neuroradiology database from November 2010 to July 2015 and found nine patients who were treated with endovascular AVP. AVP was used for rapid vessel occlusion of common carotid artery (1 patient), internal carotid artery (5 patients), vertebral artery (2 patients), and internal jugular vein (1 patient). A median of three AVPs were used with almost immediate occlusion and no thromboembolic complications. Use of AVP is feasible, safe, rapid, and potentially cost effective method for rapid occlusion of larger size vessels in the head and neck region for different indications. PMID- 26515697 TI - In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia. AB - KEY POINTS: The mechanism of therapeutic efficacy of flecainide for catecholaminergic polymorphic ventricular tachycardia (CPVT) is unclear. Model predictions suggest that Na(+) channel effects are insufficient to explain flecainide efficacy in CPVT. This study represents a first step toward predicting therapeutic mechanisms of drug efficacy in the setting of CPVT and then using these mechanisms to guide modelling and simulation to predict alternative drug therapies. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by fatal ventricular arrhythmias in structurally normal hearts during beta-adrenergic stimulation. Current treatment strategies include beta-blockade, flecainide and ICD implementation--none of which is fully effective and each comes with associated risk. Recently, flecainide has gained considerable interest in CPVT treatment, but its mechanism of action for therapeutic efficacy is unclear. In this study, we performed in silico mutagenesis to construct a CPVT model and then used a computational modelling and simulation approach to make predictions of drug mechanisms and efficacy in the setting of CPVT. Experiments were carried out to validate model results. Our simulations revealed that Na(+) channel effects are insufficient to explain flecainide efficacy in CPVT. The pure Na(+) channel blocker lidocaine and the antianginal ranolazine were additionally tested and also found to be ineffective. When we tested lower dose combination therapy with flecainide, beta blockade and CaMKII inhibition, our model predicted superior therapeutic efficacy than with flecainide monotherapy. Simulations indicate a polytherapeutic approach may mitigate side-effects and proarrhythmic potential plaguing CPVT pharmacological management today. Importantly, our prediction of a novel polytherapy for CPVT was confirmed experimentally. Our simulations suggest that flecainide therapeutic efficacy in CPVT is unlikely to derive from primary interactions with the Na(+) channel, and benefit may be gained from an alternative multi-drug regimen. PMID- 26515703 TI - [In Process Citation]. PMID- 26515701 TI - Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins. AB - The Wnt-inhibitor dickkopf-1 (DKK-1) promotes cancer-induced osteolytic bone lesions by direct inhibition of osteoblast differentiation and indirect activation of osteoclasts. DKK-1 is highly expressed in human breast cancer cells and can be suppressed by inhibitors of the mevalonate pathway such as statins and amino-bisphosphonates. However, supraphysiological concentrations are required to suppress DKK-1. We show that a sequential mevalonate pathway blockade using statins and amino-bisphosphonates suppresses DKK-1 more significantly than the individual agents alone. Thus, the reduction of the DKK-1 expression and secretion in the human osteotropic tumor cell lines MDA-MB-231, MDA-MET, and MDA BONE by zoledronic acid was potentiated by the combination with low concentrations of statins (atorvastatin, simvastatin, and rosuvastatin) by up to 75% (p < 0.05). The specific rescue of prenylation using farnesyl pyrophosphate or geranylgeranyl pyrophosphate revealed that these effects were mediated by suppressed geranylgeranylation rather than by suppressed farnesylation. Moreover, combining low concentrations of statins (1 uM atorvastatin or 0.25 uM simvastatin) and zoledronic acid at low concentrations resulted in an at least 50% reversal of breast cancer-derived DKK-1-mediated inhibition of osteogenic markers in C2C12 cells (p < 0.05). Finally, the intratumoral injection of atorvastatin and zoledronic acid in as subcutaneous MDA-MB-231 mouse model reduced the serum level of human DKK-1 by 25% compared to untreated mice. Hence our study reveals that a sequential mevalonate pathway blockade allows for the combined use of low concentration of statins and amino-bisphosphonates. This combination still significantly suppresses breast cancer-derived DKK-1 to levels where it can no longer inhibit Wnt-mediated osteoblast differentiation. PMID- 26515700 TI - Flow-diverting stents allow efficient treatment of unruptured, intradural dissecting aneurysms of the vertebral artery: An explanatory approach using in vivo flow analysis. AB - OBJECT: Our study aimed to evaluate the efficiency of flow-diverting stents (FDS) in treating unruptured, intradural dissecting aneurysms of the vertebral artery (VADAs). Additionally, the effect of FDS on the aneurysmal flow pattern was investigated by performing in vivo flow analysis using parametric color coding (PCC). METHODS: We evaluated 11 patients with unruptured, intradural VADAs, treated with FDS. Pre- and postinterventional DSA-series were postprocessed by PCC, and time-density curves were calculated. The parameters aneurysmal inflow velocity, outflow-velocity and relative time-to-peak (rTTP) were calculated. Pre- and postinterventional values were compared and correlated with the occlusion rate after six months. RESULTS: Follow-up DSA detected 10 aneurysms occluded, meaning an occlusion rate of 91%. No procedure-related morbidity and mortality was found. Flow analyses revealed a significant reduction of aneurysmal inflow- velocity and prolongation of rTTP after FDS deployment. Concerning aneurysm occlusion, the postinterventional outflow-velocity turned out to be a marginally statistically significant predictor. A definite threshold value (-0.7 density change/s) could be determined for the outflow-velocity that allows prediction of complete aneurysm occlusion with high sensitivity and specificity (100%). CONCLUSIONS: Using FDS can be considered an efficient and safe therapy option in treating unruptured, intradural VADA. From in vivo flow analyses the postinterventional aneurysmal outflow-velocity turned out to be a potential predictor for later complete aneurysm occlusion. Here, it might be possible to determine a threshold value that allows prediction of aneurysm occlusion with high specificity and sensitivity. As fast, applicable and easy-to-handle tool, PCC could be used for procedural monitoring and might contribute to further treatment optimization. PMID- 26515704 TI - [In Process Citation]. PMID- 26515705 TI - [Vector-Borne Diseases]. PMID- 26515706 TI - [In Process Citation]. PMID- 26515707 TI - [Influence of Nonverbal Intelligence and Migration Background on Language Abilities]. AB - AIM OF THE STUDY: The aim of this study was to investigate the importance of nonverbal intelligence for child language skills. METHODS: 414 children aged between 4 and 5 years were examined regarding their lexical-grammatical skills, their emotion recognition and empathic skill as a basic competence of their pragmatic as well as nonverbal intelligence. Correlations and regression analyses were performed to determine whether the nonverbal IQ contributes to variance explanation in each language area. Additionally, maternal educational level and the migration background were taken into account. RESULTS: Nonverbal intelligence contributed to variance explanation, but to a low degree. A relatively high proportion of variance for the lexical-grammatical skills could be explained by the migration background; contact time with the German language played an essential role here. CONCLUSIONS: The models for lexical-grammatical skills prediction indicate the importance of migration background in relation to the contact time with the German language and nonverbal intelligence. The migration background does not seem to influence emotion recognition competence and empathic skills; nonverbal intelligence represents the only relevant factor. PMID- 26515708 TI - [The Impact of Visual Perceptual Abilities on the Performance on the Wechsler Nonverbal Scale of Ability (WNV)]. AB - BACKGROUND: The use of psychometric tests in with children and adolescents is especially important in psychological diagnostics. Nonverbal intelligence tests are very often used to diagnose psychological abnormalities and generate developmental prognosis independent of the child's verbal abilities. METHODS: The correlation of the German version of the Developmental Test of Visual Perception Adolescents and Adults (DTVP-A) with the Wechsler Nonverbal Scala of Abilities (WNV) was calculated based on the results of 172 children, adolescents and young adults aged 9-21 years. Furthermore, it was examined if individuals with poor visual perceptual abilities scored lower on the WNV than healthy subjects. RESULTS: The correlations of the results scored on DTVP-A and WNV ranged from moderate to strong. The group with poor visual perceptual abilities scored significantly lower on the WNV than the control group. CONCLUSIONS: Nonverbal intelligence tests like the WNV are not reliable for estimating the intelligence of individuals with low visual perceptual abilities. Therefore, the intelligence of these subjects should be tested with a test that also contains verbal subtests. If poor visual perceptual abilities are suspected, then they should be tested. The DTVP-A seems to be the right instrument for achieving this goal. PMID- 26515709 TI - [Language Competence and Behavioural Problems in Preschool]. AB - AIM OF THE STUDY: Children with language disorders are at increased risk of developing behavioural and emotional problems. The analysis focused on the question whether behavioural problems differ depending on the type of language deficit. The present study examines the behaviour of preschool children with different language impairments. METHOD: The results of N=540 children aged between 4;0 and 5;11 years were analyzed. Language impairments were classified into phonetics/phonology (n=44), vocabulary (n=44), grammar (n=58), pragmatics (n=26) and multiple language impairments (n=171). In addition, a distinction was made between deficits in language production and comprehension. The children were compared with an unimpaired control group (n=197). The extent of emotional and behavioural problems were analyzed. RESULTS: The results indicate that emotional and behavioural problems differ depending on the type of language deficit already in preschoolers. Especially deficits in language comprehension, pragmatic impairments and multiple language impairments increase the risk of behavioural and emotional problems and hyperactivity. CONCLUSIONS: The relationship between language skills and emotional and behavioural problems should be emphasized in the developmental observation and documentation in preschool. In particular, the distinction between deficits in pragmatics and behavioural problems requires a differentiated examination to ensure an optimal intervention. PMID- 26515710 TI - [Relationship between Intelligence and Executive Function]. AB - AIM OF THE STUDY: In this study the correlation between executive functions and intelligence as assessed by the BRIEF-P and WNV, respectively will be examined. METHODS: A sample of 447 children at the 4;0-5;11 year age group was assessed with the WNV. Additionally, parents answered a questionnaire on executive functions (BRIEF-P) and a second questionnaire concerning family background. Partial correlations were calculated on the subtest and scale level and linear regression models were tested. RESULTS: The primary scale Working Memory (BRIEF P) contributes to an explanation of cognitive functions (WNV), as does the maternal educational level. WM an the Emergent Metacognition Index, which is incorporated the WM scale, shows significant correlation with subtests and with both of the higher order IQ scales of the WNV. CONCLUSION: Already at the preschool age, executive functions play an important role in intelligence. Deficits in EF are related to ADHD and to negative school careers. Early programs for prevention or intervention should be implemented to improve conditions for academic learning. PMID- 26515711 TI - [Relationship Between General Cognitive Abilities and School Achievement: The Mediation Role of Learning Behavior]. AB - BACKGROUND: General cognitive abilities are still considered as the most important predictor of school achievement and success. Whether the high correlation (r=0.50) can be explained by other variables has not yet been studied. Learning behavior can be discussed as one factor that influences the relationship between general cognitive abilities and school achievement. METHODS: This study examined the relationship between intelligence, school achievement and learning behavior. Mediator analyses were conducted to check whether learning behavior would mediate the relationship between general cognitive abilities and school grades in mathematics and German. RESULTS: Statistical analyses confirmed that the relationship between general cognitive abilities and school achievement was fully mediated by learning behavior for German, whereas intelligence seemed to be the only predictor for achievement in mathematics. These results could be confirmed by non-parametric bootstrapping procedures. CONCLUSION: RESULTS indicate that special training of learning behavior may have a positive impact on school success, even for children and adolescents with low IQ. PMID- 26515713 TI - An off-the-shelf, authentic, and versatile undergraduate molecular biology practical course. AB - We provide a prepackaged molecular biology course, which has a broad context and is scalable to large numbers of students. It is provided complete with technical setup guidance, a reliable assessment regime, and can be readily implemented without any development necessary. Framed as a forensic examination of blue/white cloning plasmids, the course is a versatile workbench, adaptable to different degree subjects, and can be easily modified to undertake novel research as part of its teaching activities. Course activities include DNA extraction, RFLP, PCR, DNA sequencing, gel electrophoresis, and transformation, alongside a range of basic microbiology techniques. Students particularly appreciated the relevance of the practical to professional practice and the authenticity of the experimental work. PMID- 26515712 TI - Treatment Engagement: Female Survivors of Intimate Partner Violence in Treatment for PTSD and Alcohol Use Disorder. AB - OBJECTIVE: Treatment engagement rates are low for individuals with comorbid posttraumatic stress disorder (PTSD) and alcohol use disorders across available interventions and treatment modalities. A better understanding of who does and does not engage in treatment can help improve retention, completion, and subsequent treatment outcomes. METHODS: Forty female survivors of intimate partner violence with PTSD and alcohol use disorder participated in a randomized controlled trial comparing twenty-five 90-minute sessions of either modified Seeking Safety or Facilitated Twelve-Step in a community-based outpatient clinic. This study examined differences in demographics and pre-treatment PTSD symptoms and alcohol use between participants who engaged in treatment (attended >= 6 sessions, n = 18) and those who dropped out (n = 22). RESULTS: There were no significant differences in PTSD or alcohol use disorder symptoms between treatment conditions. Women who engaged in therapy versus those who did not were significantly older (M = 46.2, SD = 9.14 vs. M = 38.95, SD = 10.49, respectively; p =.027), and had fewer dependents (M =.17, SD =.38, range = 0-1 vs. M =.95, SD = 1.66, range = 1-7, respectively; p =.046). Greater avoidance/numbing PTSD symptoms (OR = 1.13, p =.028, 95% CI [1.02-1.25]) and more years of heavy drinking (OR = 1.04, p =.03, 95% CI [1.00-1.07]) were also significantly associated with treatment engagement. CONCLUSIONS: This study replicates previous findings suggesting a need for additional retention strategies for younger women with dependents in comorbid PTSD and alcohol use disorder treatment. This is an analysis of data collected as part of a clinical trial registered as NCT00607412, at www.clinicaltrials.gov. PMID- 26515714 TI - Svetlana Miceva Ristevska--an obituary. PMID- 26515715 TI - The impact of acquisition time of planar cardiac (123)I-MIBG imaging on the late heart to mediastinum ratio. AB - PURPOSE: The aim of this study was to investigate whether performing the late cardiac (123)I-metaiodobenzylguanidine (MIBG) scan earlier than 4 h post injection (p.i.) has relevant impact on the late heart to mediastinum ratio (H/M ratio) in patients with heart failure (HF). METHODS: Forty-nine patients with HF (median left ventricular ejection fraction of 31 %, 51 % ischaemic HF) referred for cardiac (123)I-MIBG scintigraphy were scanned at 15 min (early) p.i. and at 1, 2, 3 and 4 h (late) p.i. of (123)I-MIBG. Late H/M ratios were calculated and evaluated using a linear mixed model with the mean late H/M ratio at 4 h p.i. as a reference. A difference in late H/M ratios of more than 0.10 between the different acquisition times in comparison with the late H/M ratio at 4 h p.i. was considered as clinically relevant. RESULTS: Statistically significant mean differences were observed between the late H/M ratios at 1, 2 and 3 h p.i. compared with the late H/M ratio at 4 h p.i. (0.09, 0.05 and 0.02, respectively). However, the mean differences did not exceed the cut-off value of 0.10. On an individual patient level, compared to the late H/M ratio at 4 h p.i., the late H/M ratios at 1, 2 and 3 h p.i. differed more than 0.10 in 24 (50 %), 9 (19 %) and 2 (4 %) patients, respectively. CONCLUSION: Variation in acquisition time of (123)I-MIBG between 2 and 4 h p.i. does not lead to a clinically significant change in the late H/M ratio. An earlier acquisition time seems to be justified and may warrant a more time-efficient cardiac (123)I-MIBG imaging protocol. PMID- 26515716 TI - A planarized 9-phenylanthracene: a simple electron-donating building block for fluorescent materials. AB - A 9-phenylanthracene, constrained in a coplanar fashion by two methylene tethers, was synthesized and its optoelectronic properties were investigated. The rigid planarization increased its electron-donating character and induced a bathochromic shift of its absorption, as well as an increased molar absorption coefficient and intense fluorescence. These properties render this compound a promising building block for fluorescent materials. PMID- 26515717 TI - Crystalline cast nephropathy in a patient with IgD lambda myeloma. PMID- 26515718 TI - African Cattle do not Carry Unique Mutations on the Exon 9 of the ARHGAP15 Gene. AB - A panel of 81 Asian, African and European cattle (Bos taurus and B. indicus) was sequenced for the exon 9 of the ARHGAP15, a strong candidate for cattle trypanotolerance on BTA2. The analyses provided five different haplotypes defined by four (two nonsynonymous) mutations. Neutrality tests suggest a recent sweep in the studied bovine sequences. The two most frequent haplotypes (H1 and H3) gathered 88% of the chromosomes analyzed and were present in all the cattle groups analyzed, including Asian zebu and European cattle. The current results question the sole association of the polymorphism identified, including mutation c.53317501A > C, with the trypanotolerant response in West African cattle. PMID- 26515719 TI - A simple method to overcome the inhibitory effect of heparin on DNA amplification. AB - BACKGROUND: Genetic material from large patient cohorts is increasingly central to translational genetic research. However, patient blood samples are a finite resource and their supply and storage are often dictated by clinical and not research protocols. Our experience supports difficulty in amplifying DNA from blood stored in herparin; a scenario that other researchers may have or will encounter. This technical note describes a number of simple steps that enable successful PCR amplification. METHODS: DNA was extracted using the Illustra Nucleon Genomic DNA Extraction Kit. PCR amplification was attempted using a number of commercially available PCR mastermixes. RESULTS: PCR DNA amplification failed using ReddyMixTM PCR Master Mix, Thermo-Start(r) (Thermo Scientific Inc. US) and ZymoTaqTM (Zymo research, US) PCR mastermixes, as demonstrated absence of products on gel electrophoresis. However, using the InvitrogenTM (Thermo Scientific Inc., US) Platinum(r) Taq DNA Polymerase, PCR products were identified on a 1% agarose gel for all samples. PCR products were cleaned with ExoSAP-IT(r) (Affymetrix Inc., US) and a sequencing reaction undertaken using a standard Big Dye protocol. Subsequent genotyping was successful for all samples for alleles at the CDH1 locus. CONCLUSION: From our experience a standard phenol/chloroform purification and using the InvitrogenTM Platinum(r) Taq has enabled the amplification of whole blood samples taken into lithium heparin and stored frozen for up to a month. This simple method may enable investigators to utilise blood taken in lithium heparin for DNA extraction and amplification. PMID- 26515721 TI - Do Rural Patients in Canada Underutilize Preventive Care for Myocardial Infarction? AB - PURPOSE: The objective of this study was to explore Canadian rural-urban differences in the use of primary and secondary preventive diagnostic services for acute myocardial infarction (AMI)-a condition that is amenable to primary health care prevention efforts. METHODS: We examined primary and secondary preventive care services utilized 2 years prior to a patient's first AMI in a cohort of 30,491 patients in Ontario, Canada, from 2010 to 2012. Using logistic regression, rural-urban differences in lipid testing, glucose testing, stress testing, electrocardiograms, and echocardiograms in middle-age and senior patients were examined. FINDINGS: The odds of rural patients receiving care for primary preventive screening were more than 50% lower than the odds for urban patients, with rural seniors being the most affected. Lipid testing: middle-age OR 0.519 (95% CI, 0.469-0.574), senior OR 0.422 (0.386-0.460); glucose testing: middle-age OR 0.471 (0.426-0.521), senior OR 0.359 (0.328-0.394). The odds of rural patients receiving secondary preventive diagnostic care were also lower than the odds for urban patients, but differences between the age groups were not as apparent. Stress testing: middle-age OR 0.745 (95%CI, 0.642-0.866), senior OR 0.726 (0.643-0.820); electrocardiogram: middle-age OR 0.815 (0.737-0.901), senior OR 0.724 (0.659-0.795); echocardiogram: middle-age OR 0.755 (0.655-0.869), senior OR 0.746 (0.681-0.818). CONCLUSIONS: Study results support ongoing concerns related to health care for rural Canadians by demonstrating underutilization of AMI preventive diagnostic care among rural patients. Rural seniors are most at risk. These results have implications for rural health care as well as seniors' health policy in Canada. PMID- 26515723 TI - MRI and MRS findings in fucosidosis; a rare lysosomal storage disease. AB - Fucosidosis is a rare lysosomal storage disorder caused by deficient activity of the enzyme l-fucosidase in all tissues. We presented magnetic resonance imaging [MRI] and MR spectroscopy [MRS] findings of a 4-year-old boy with genetically proven fucosidosis. He had a history and clinical findings of recurrent sinopulmonary infections, hypertonicity on lower extremities, gingival hypertrophy, bilateral ptosis, angiokeratoma corporis diffusum, and dysostosis multiplex. He had no organomegaly and urine glycosaminoglycan analysis were normal. MRI revealed abnormalities within the globus pallidus and periventricular and subcortical white matter. MRS showed a peak at the 3.8-3.9 ppm as a result of accumulating carbohydrate containing macromolecules and another peak at 1.2 which was doublet and inverted on TE 135, suggesting fructose peak. A final diagnosis of fucosidosis was proved by mutational analysis of FUCA1 gene which is responsible for the Fucosidosis phenotype. Two recent reports of MRS of two patients demonstrated that MRS is specific for fucosidosis. In this case, we aim to discuss fucosidosis with MRI and MRS findings accompanied by the literature. PMID- 26515720 TI - Allelic variation contributes to bacterial host specificity. AB - Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population and functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. Together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts. PMID- 26515722 TI - Effects of the association of diabetes and pulmonary emphysema on cardiac structure and function in rats. AB - Chronic obstructive pulmonary disease is often associated with chronic comorbid conditions of cardiovascular disease, diabetes mellitus and hypertension. This study aimed to investigate the effects of the association of diabetes and pulmonary emphysema on cardiac structure and function in rats. Wistar rats were divided into control non-diabetic instilled with saline (CS) or elastase (CE), diabetic instilled with saline (DS) or elastase (DE), DE treated with insulin (DEI) groups and echocardiographic measurements, morphometric analyses of the heart and lungs, and survival analysis conducted 50 days after instillation. Diabetes mellitus was induced [alloxan, 42 mg/kg, intravenously (iv)] 10 days before the induction of emphysema (elastase, 0.25 IU/100 g). Rats were treated with NPH insulin (4 IU before elastase plus 2 IU/day, 50 days). Both CE and DE exhibited similar increases in mean alveolar diameter, which are positively correlated with increases in right ventricular (RV) wall thickness (P = 0.0022), cavity area (P = 0.0001) and cardiomyocyte thickness (P = 0.0001). Diabetic saline group demonstrated a reduction in left ventricular (LV) wall, interventricular (IV) septum, cardiomyocyte thickness and an increase in cavity area, associated with a reduction in LV fractional shortening (P < 0.05), and an increase in LViv relaxation time (P < 0.05). Survival rate decreased from 80% in DS group to 40% in DE group. In conclusion, alloxan diabetes did not affect RV hypertrophy secondary to chronic emphysema, even in the presence of insulin. Diabetes per se induced left ventricular dysfunction, which was less evident in the presence of RV hypertrophy. Survival rate was substantially reduced as a consequence, at least in part, of the coexistence of RV hypertrophy and diabetic cardiomyopathy. PMID- 26515724 TI - Activity-dependent synaptic plasticity modulates the critical phase of brain development. AB - Plasticity or neuronal plasticity is a unique and adaptive feature of nervous system which allows neurons to reorganize their interactions in response to an intrinsic or extrinsic stimulation and shapes the formation and maintenance of a functional neuronal circuit. Synaptic plasticity is the most important form of neural plasticity and plays critical role during the development allowing the formation of precise neural connectivity via the process of pruning. In the sensory systems-auditory and visual, this process is heavily dependent on the external cues perceived during the development. Environmental enrichment paradigms in an activity-dependent manner result in early maturation of the synapses and more efficient trans-synaptic signaling or communication flow. This has been extensively observed in the avian auditory system. On the other hand, stimuli results in negative effect can cause alterations in the synaptic connectivity and strength resulting in various developmental brain disorders including autism, fragile X syndrome and rett syndrome. In this review we discuss the role of different forms of activity (spontaneous or environmental) during the development of the nervous system in modifying synaptic plasticity necessary for shaping the adult brain. Also, we try to explore various factors (molecular, genetic and epigenetic) involved in altering the synaptic plasticity in positive and negative way. PMID- 26515726 TI - Cancer metastasis and EGFR signaling is suppressed by amiodarone-induced versican V2. AB - Extracellular matrix components play an active role in cancer progression and prognosis. Versican, a large extracellular matrix proteoglycan, can promote cancer metastasis through facilitating cell proliferation, adhesion, migration and angiogenesis. We had previously demonstrated that amiodarone caused ectopic overexpression of similar to versican b (s-vcanb), inhibited EGFR/GSK3beta/Snail signaling, and enhanced Cdh5 at the heart field of zebrafish, indicating interference with epithelial-mesenchymal transition (EMT). Since S-vcanb is homologous to mammalian versican V2 isoform, we examined the effects of amiodarone on mammalian tumor proliferation, migration, invasion and metastasis in vitro and in vivo and on EMT signaling pathways. Monolayer wound assays and extracellular matrix transwell invasion assays showed reduced migration and invasion by 15 MUM amiodarone treated B16OVA, JC, 4T-1, MDA-MB-231 and MCF-7 tumor cell lines. All cancer cell lines showed reduced metastatic capabilities in vivo after treatment with amiodarone in experimental animals. Western blots revealed that EMT-related transcription factors Snail and Twist were reduced and E-cadherin was enhanced in amiodarone treated cells through an EGFR/ERK/GSK3beta dependent pathway. Immunohistochemistry showed amiodarone lead to increased expression of versican V2 isoform concomitant with reduced versican V1. Our study illustrated the role of versican v2 in EMT modulation and cancer suppression by amiodarone treatment. PMID- 26515727 TI - Stromal cells promote anti-estrogen resistance of breast cancer cells through an insulin-like growth factor binding protein 5 (IGFBP5)/B-cell leukemia/lymphoma 3 (Bcl-3) axis. AB - There is strong evidence that stromal cells promote drug resistance of cancer. Here, we show that mesenchymal stem cells (MSCs) and carcinoma-associated fibroblasts (CAFs) desensitize ERalpha-positive breast cancer cells to the anti estrogen fulvestrant. In search for the mechanism, we found that MSCs and CAFs similarly increased the activity of the PI3K/AKT and the JAK/STAT3 pathways and upregulated the expression of integrin beta1, IGF1R, HIF1alpha, CAIX and Bcl-3 in MCF-7 cells. Further analyses revealed that MSCs and CAFs coordinately induce these changes by triggering the downregulation of IGFBP5. Loss of IGFBP5 in MCF-7 cells was an early and long-lasting event in response to MSCs and CAFs and was accompanied by growth stimulation both in the absence and presence of fulvestrant. The growth-stimulatory effect in the absence of fulvestrant could be attributed to PI3K/AKT pathway activation and could be mimicked by insulin. The growth-promoting effect in the presence of fulvestrant depended upon the upregulation of Bcl-3. By cRNA microarray analysis we identified additional IGFBP5 targets, of which two (KLHL4 and SEPP1) were inversely regulated by IGFBP5 and Bcl-3. BT474 cells also responded to stromal cells by downregulating IGFBP5 and upregulating the P-AKT, Bcl-3 and IGF1R levels, whereas T47D cells did not show any of these responses. In conclusion, our data suggest that, by targeting IGFBP5 expression in ERalpha-positive breast cancer cells, such as MCF-7 cells, MSCs and CAFs are able to orchestrate a variety of events, particularly activation of the PI3K/AKT pathway, upregulation of Bcl-3 expression and desensitization to anti-estrogen. PMID- 26515728 TI - TGF-beta blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner. AB - Our neoadjuvant clinical trial of a GM-CSF secreting allogeneic pancreas tumor vaccine (GVAX) revealed the development of tertiary lymphoid aggregates (TLAs) within the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment 2 weeks after GVAX treatment. Microarray studies revealed that multiple components of the TGF-beta pathway were suppressed in TLAs from patients who survived greater than 3 years and who demonstrated vaccine-enhanced mesothelin-specific T cell responses. We tested the hypothesis that combining GVAX with TGF-beta inhibitors will improve the anti-tumor immune response of vaccine therapy. In a metastatic murine model of pancreatic cancer, combination therapy with GVAX vaccine and a TGF-beta blocking antibody improved the cure rate of PDA-bearing mice. TGF-beta blockade in combination with GVAX significantly increased the infiltration of effector CD8+ T lymphocytes, specifically anti-tumor-specific IFN-g producing CD8+ T cells, when compared to monotherapy controls (all p < 0.05). TGF-beta blockade alone did not deplete T regulatory cells (Tregs), but when give in combination with GVAX, GVAX induced intratumoral Tregs were depleted. Therefore, our PDA preclinical model demonstrates a survival advantage in mice treated with an anti-TGF-beta antibody combined with GVAX therapy and provides strong rational for testing this combinational therapy in clinical trials. PMID- 26515729 TI - Polarized cell migration induces cancer type-specific CD133/integrin/Src/Akt/GSK3beta/beta-catenin signaling required for maintenance of cancer stem cell properties. AB - CD133 is widely used as a surface marker to isolate cancer stem cells (CSCs). Here we show that in CSCs CD133 contributes to beta-catenin-mediated transcriptional activation and to the self-renewal capacity of sphere-forming and side-population (SP) cells in cell lines from brain, colon and lung cancers, but not gastric or breast cancers. In chromatin immunoprecipitation assays, beta catenin binding to the proximal promoter regions of ITGA2-4 and ITGA10-11 in brain, colon and lung cancer cell lines could be triggered by CD133, and beta catenin also bound to the proximal promoter regions of ITGB6 and ITGB8 in cell lines from gastric and breast cancers. CD133 thus induces beta-catenin binding and transcriptional activation of diverse targets that are cancer type-specific. Cell migration triggered by wounding CD133+ cells cultured on ECM-coated dishes can induce polarity and lipid raft coalescence, enhancing CD133/integrin signaling and asymmetric cell division. In response to directional cues, integrins, Src and the Par complex were enriched in lipid rafts, and the assembly and activation of an integrated CD133-integrin-Par signaling complex was followed by Src/Akt/GSK3beta signaling. The subsequent increase and nuclear translocation of beta-catenin may be a regulatory switch to increase drug resistance and stemness properties. Collectively, these findings 1) indicate that a polarized cell migration-induced CD133/integrin/Src/Akt/GSK3beta/beta-catenin axis is required for maintenance of CSC properties, 2) establish a function for CD133 and 3) support the rationale for targeting CD133 in cancer treatment. PMID- 26515731 TI - Strain Analysis by Tissue Doppler Imaging: Comparison of Conventional Manual Measurement with a Semiautomated Approach. AB - PURPOSE: Myocardial strain and strain rate (SR) can be derived from either tissue Doppler (TDI) information or two-dimensional speckle tracking. As conventional TDI analysis (TDI-manual) is time-consuming with poor reproducibility, we developed a faster semiautomated approach (TDI-ST). We aimed to study the comparability of TDI-ST with TDI-manual, an established method for measuring strain and SR. METHODS: Forty healthy subjects (mean age 38.3 +/- 12.8 years) and 16 patients with FHL-1 cardiomyopathy (CMP) (36.8 +/- 14.2 years) were analyzed with TDI-manual and TDI-ST. TDI-ST was performed with commercial software, using speckle tracking for myocardial tracking and TDI information to derive longitudinal strain and SR from high frame rate TDI recordings. Measurements of longitudinal systolic strain (S) and global S (GLS) made with the two methods were compared with Bland-Altman plots and Deming regression. Receiver operating characteristics (ROC) curves were used to compare discrimination between healthy individuals and patients. RESULTS: Mean S was -20.11 +/- 4.85% (healthy) and 16.12 +/- 4.44% (CMP) with TDI-ST and -21.15 +/- 5.68% (healthy) and -16.27 +/- 6.44 (CMP) with TDI-manual. Using all measured segments, the mean bias was 0.78% strain toward less negative S with TDI-ST; the Deming regression slope was 0.7 for S and 0.9 for GLS. Intra- and inter-observer CVs were 5.4% and 7.0%, respectively. ROC curves showed no significant differences between the methods. CONCLUSION: The described S and SR measurements with TDI-ST are comparable to conventional manual analysis. Thus, using TDI-ST, it is possible to quickly and easily extract high-resolution deformation data. PMID- 26515732 TI - Regioselective Synthesis of Polyheterohalogenated Naphthalenes via the Benzannulation of Haloalkynes. AB - Independent control of halide substitution at six of the seven naphthalene positions of 2-arylnaphthalenes is achieved through the regioselective benzannulation of chloro-, bromo-, and iodoalkynes. The modularity of this approach is demonstrated through the preparation of 44 polyheterohalogenated naphthalene products, most of which are difficult to access through known naphthalene syntheses. The outstanding regioselectivity of the reaction is both predictable and proven unambiguously by single-crystal X-ray diffraction for many examples. This synthetic method enables the rapid preparation of complex aromatic systems poised for further derivatization using established cross-coupling methods. The power and versatility of this approach makes substituted naphthalenes highly attractive building blocks for new organic materials and diversity-oriented synthesis. PMID- 26515730 TI - CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia. AB - We investigated cell cycle regulation in acute myeloid leukemia cells expressing the FLT3-ITD mutated tyrosine kinase receptor, an underexplored field in this disease. Upon FLT3 inhibition, CDC25A mRNA and protein were rapidly down regulated, while levels of other cell cycle proteins remained unchanged. This regulation was dependent on STAT5, arguing for FLT3-ITD-dependent transcriptional regulation of CDC25A. CDC25 inhibitors triggered proliferation arrest and cell death of FLT3-ITD as well as FLT3-ITD/TKD AC-220 resistant cells, but not of FLT3 wt cells. Consistently, RNA interference-mediated knock-down of CDC25A reduced the proliferation of FLT3-ITD cell lines. Finally, the clonogenic capacity of primary FLT3-ITD AML cells was reduced by the CDC25 inhibitor IRC-083864, while FLT3-wt AML and normal CD34+ myeloid cells were unaffected. In good agreement, in a cohort of 100 samples from AML patients with intermediate-risk cytogenetics, high levels of CDC25A mRNA were predictive of higher clonogenic potential in FLT3 ITD+ samples, not in FLT3-wt ones.Importantly, pharmacological inhibition as well as RNA interference-mediated knock-down of CDC25A also induced monocytic differentiation of FLT3-ITD positive cells, as judged by cell surface markers expression, morphological modifications, and C/EBPalpha phosphorylation. CDC25 inhibition also re-induced monocytic differentiation in primary AML blasts carrying the FLT3-ITD mutation, but not in blasts expressing wild type FLT3. Altogether, these data identify CDC25A as an early cell cycle transducer of FLT3 ITD oncogenic signaling, and as a promising target to inhibit proliferation and re-induce differentiation of FLT3-ITD AML cells. PMID- 26515733 TI - Serum N-Glycome Characterization in Patients with Resectable Periampullary Adenocarcinoma. AB - Serum N-glycans are promising biomarkers for systemic disease states. Better understanding of the serum N-glycome of patients with resectable periampullary adenocarcinoma may identify novel prognostic markers for this disease. Serum N glycans in 70 patients with resectable periampullary adenocarcinoma, 15 patients with benign periampullary tumor, and 129 healthy individuals were quantified using ultra performance liquid chromatography. High-sensitivity C-reactive protein (hsCRP) was analyzed for all samples using an immunoturbidimetric method. The N-glycome was compared to clinical and histopathological data, and to the acute phase response as measured by hsCRP. Whole-genome tumor tissue mRNA expression data were used for correlation and enrichment analysis to investigate underlying biological processes giving rise to changes in the serum N-glycome. Significant changes were found in the serum N-glycome of patients with periampullary adenocarcinoma (n = 70) compared to healthy individuals (n = 129). No significant differences were found between patients with benign (n = 15) and malignant periampullary tumors (n = 70). Many alterations in the N-glycome correlated with systemic acute phase response as measured by hsCRP. Enrichment analysis indicated that immunologic pathways of the cancer microenvironment correlate with specific features of the serum N-glycome. Certain glycans were associated with poor overall and disease free survival in patients with pancreatobiliary type of periampullary adenocarcinoma. Our study supports the hypothesis that certain factors secreted by the tumor affect liver and plasma cells to orchestrate the changes in the serum N-glycome observed. The serum N glycome could potentially reflect modified phenotypes of the host and/or tumor microenvironment. The prognostic impact of the serum N-glycome should be evaluated in larger, prospective studies. PMID- 26515734 TI - Standards for QUality Improvement Reporting Excellence 2.0: revised publication guidelines from a detailed consensus process. AB - Since the publication of Standards for QUality Improvement Reporting Excellence (SQUIRE 1.0) guidelines in 2008, the science of the field has advanced considerably. In this article, we describe the development of SQUIRE 2.0 and its key components. We undertook the revision between 2012 and 2015 using (1) semistructured interviews and focus groups to evaluate SQUIRE 1.0 plus feedback from an international steering group, (2) two face-to-face consensus meetings to develop interim drafts, and (3) pilot testing with authors and a public comment period. SQUIRE 2.0 emphasizes the reporting of three key components of systematic efforts to improve the quality, value, and safety of health care: the use of formal and informal theory in planning, implementing, and evaluating improvement work; the context in which the work is done; and the study of the intervention(s). SQUIRE 2.0 is intended for reporting the range of methods used to improve health care, recognizing that they can be complex and multidimensional. It provides common ground to share these discoveries in the scholarly literature (www.squire-statement.org). PMID- 26515735 TI - Management of Medication-Related Osteonecrosis of the Jaw. AB - Medication-related osteonecrosis of the jaw (MRONJ) primarily involves patients receiving intravenous bisphosphonates for treatment of skeletal-related malignancies, oral bisphosphonates, and denosumab. There is no consensus regarding the clinical management of MRONJ. Successful treatment may be that which results in a cure, with complete mucosal coverage and elimination of disease, or that which improves the quality of life without a cure (palliation). Helping patients to understand the chronicity and potential progression of the disease is essential to a satisfactory outcome. This review aims to share our treatment approach to patients with MRONJ. Treatment can be divided into medical and surgical therapies. PMID- 26515736 TI - The Role of Antiangiogenic Therapy in the Development of Osteonecrosis of the Jaw. AB - There is an increasing use of established and newer medications that have antiangiogenic properties. Inhibition of angiogenesis likely has either a primary or secondary role in the development of osteonecrosis of the jaw (ONJ). These medications are being used in the treatment of various cancers and in the treatment of several non-oncologic conditions. Antiangiogenic medications when used in combination with antiresorptive medications, such as nitrogen-containing bisphosphonates or denosumab, seem to increase the likelihood of osteonecrosis of the jaw. This review highlights the role of inhibitors of angiogenesis and their role in the development of osteonecrosis of the jaws. PMID- 26515737 TI - Antiresorptive Therapies for the Treatment of Malignant Osteolytic Bone Disease. AB - Osteolytic bone disease contributes to morbidity and mortality. Antiresorptive therapies reduce the morbidity of metastatic bone disease and alter the natural progression of malignant bone pathophysiology. Several trials showed improvement in quality of life, delay of skeletal-related events, and improvement in bone pain with these agents. Evolving data suggest a role of improvement in morbidity related to other cancer therapies that have potential side effects. Early indication shows they may alter survival in a subset of patients. This article reviews data confirming the efficacy of antiresorptive agents and discusses preliminary data on preventative therapy. PMID- 26515740 TI - Pulling habits out of rats: adenosine 2A receptor antagonism in dorsomedial striatum rescues meth-amphetamine-induced deficits in goal-directed action. AB - Addiction is characterized by a persistent loss of behavioral control resulting in insensitivity to negative feedback and abnormal decision-making. Here, we investigated the influence of methamphetamine (METH)-paired contextual cues on decision-making in rats. Choice between goal-directed actions was sensitive to outcome devaluation in a saline-paired context but was impaired in the METH paired context, a deficit that was also found when negative feedback was provided. Reductions in c-Fos-related immunoreactivity were found in dorsomedial striatum (DMS) but not dorsolateral striatum after exposure to the METH context suggesting this effect reflected a loss specifically in goal-directed control in the METH context. This reduction in c-Fos was localized to non-enkephalin expressing neurons in the DMS, likely dopamine D1-expressing direct pathway neurons, suggesting a relative change in control by the D1-direct versus D2 indirect pathways originating in the DMS may have been induced by METH-context exposure. To test this suggestion, we infused the adenosine 2A receptor antagonist ZM241385 into the DMS prior to test to reduce activity in D2 neurons relative to D1 neurons in the hope of reducing the inhibitory output from this region of the striatum. We found that this treatment fully restored sensitivity to negative feedback in a test conducted in the METH-paired context. These results suggest that drug exposure alters decision-making by downregulation of the circuitry mediating goal-directed action, an effect that can be ameliorated by acute A2A receptor inhibition in this circuit. PMID- 26515741 TI - A combination of experimental and finite element analyses of needle-tissue interaction to compute the stresses and deformations during injection at different angles. AB - One of the main clinical applications of the needles is its practical usage in the femoral vein catheterization. Annually more than two million peoples in the United States are exposed to femoral vein catheterization. How to use the input needles into the femoral vein has a key role in the sense of pain in post injection and possible injuries, such as tissue damage and bleeding. It has been shown that there might be a correlation between the stresses and deformations due to femoral injection to the tissue and the sense of pain and, consequently, injuries caused by needles. In this study, the stresses and deformations induced by the needle to the femoral tissue were experimentally and numerically investigated in response to an input needle at four different angles, i.e., 30 degrees , 45 degrees , 60 degrees , and 90 degrees , via finite element method. In addition, a set of experimental injections at different angles were carried out to compare the numerical results with that of the experimental ones, namely pain score. The results revealed that by increasing the angle of injection up to 60 degrees , the strain at the interaction site of the needle-tissue is increased accordingly while a significant falling is observed at the angle of 90 degrees . In contrast, the stress due to injection was decreased at the region of needle tissue interaction with showing the lowest one at the angle of 90 degrees . Experimental results were also well confirmed the numerical observations since the lowest pain score was seen at the angle of 90 degrees . The results suggest that the most effective angle of injection would be 90 degrees due to a lower amount of stresses and deformations compared to the other angles of injection. These findings may have implications not only for understating the stresses and deformations induced during injection around the needle-tissue interaction, but also to give an outlook to the doctors to implement the most suitable angle of injection in order to reduce the pain as well as post injury of the patients. PMID- 26515742 TI - Utility of the bispectral index for assessing natural physiological sleep stages in children and young adults. AB - Polysomnography (PSG) is the gold standard for the analysis of sleep architecture but is not always available in routine practice, as it is time consuming and cumbersome for patients. Bispectral index (BIS), developed to quantify the deepness of general anesthesia, may be used as a simplified tool to evaluate natural sleep depth. We objectively recorded sleep architecture in young patients using the latest BIS Vista monitor and correlated BIS values with PSG sleep stages in order to determine BIS thresholds. Patients, referred for the screening of sleep apnea/hypopnea syndrome or differential diagnosis of hypersomnia were recruited. Overnight PSG and BIS were performed simultaneously. BIS values were averaged for each sleep stage. Pre-sleep wakefulness (W) and wake after sleep onset (WASO) were also differentiated. BIS values were discarded for a signal quality index <90 %. ROC curves were plotted to discriminate sleep stages from each other. Twelve patients (5.7-29.3 years old) were included. Mean BIS values were 83 +/- 8, 76 +/- 12, 77 +/- 11, 70 +/- 10, 43 +/- 10, and 75 +/- 10 for W, WASO, N1, N2, N3 and R (REM) stages, respectively. BIS failed to distinguish W, WASO, N1 and R stages. BIS threshold that identified stage N2 was <73 (AUC = 0.784, p < 0.001) with low sensitivity (75 %) and poor specificity (64 %). BIS threshold that identified stage N3 was <55 (AUC = 0.964, p < 0.001) with an 87 % sensitivity and a 93 %-specificity. BIS identified stage N3 with satisfactory sensitivity and specificity but is limited by its inability to distinguish REM sleep from wake. Further studies combining BIS with chin electromyogram and/or electrooculogram could be of interest. PMID- 26515743 TI - Midwifery competence: Content in midwifery students' daily written reflections on clinical practice. AB - OBJECTIVE: to examine the content in midwifery students' written daily reflections and in their supervisors' written feedback during clinical practice at birth units. METHOD: a total of 388 reflections written by a cohort of 18 midwifery students and written feedback provided by their supervisors have been analysed using content analysis. FINDINGS: one main category, transition to midwifery competence emerged and was interpreted as a process of development in midwifery skills over time. This main category encompasses five categories: evaluations, own actions, communication, own emotions and insights comprising fourteen subcategories. As the education programme progressed there was evidence of development from fragmented reflections about care and learning to holistic reflections on learning. Comments from the clinical supervisors contained acknowledgement of the students' reflections or comments with a didactic content. CONCLUSIONS: daily written reflections on practice may be a useful pedagogical tool as reflective writing helps students to be active in transition to midwifery competence. Professional development may be facilitated by insights generated by reflection. Amount and content of feedback varied between supervisors which can result in a discrepancy in pedagogical value for individual students. PMID- 26515744 TI - Symptoms in women with Peripartum Cardiomyopathy: A mixed method study. AB - OBJECTIVE: Peripartum Cardiomyopathy is a form of cardiac disease often associated with cardiac failure, occurring in late pregnancy or after childbirth. The anatomical and physiological changes in the mother associated with normal pregnancy are profound, and this may result in symptoms and signs that overlap with Peripartum Cardiomyopathy, leading to missed or delayed diagnosis. Women's experiences of Peripartum Cardiomyopathy symptoms remain poorly studied. The aim of this study was to explore and describe women's experiences of symptoms in Peripartum Cardiomyopathy. DESIGN: A triangulation of methods with individual interviews and data from medical records. SETTING: Mothers with Peripartum Cardiomyopathy diagnosis were recruited from Western Sweden as a part of research project. PARTICIPANTS: 19 women were interviewed and medical records were reviewed by authors. DATA ANALYSIS: All interview transcripts were analysed using qualitative inductive content analysis to identify key themes. RESULTS: The main theme, meaning of onset and occurrence of symptoms is captured in the metaphor: being caught in a spider web, comprising subthemes, invasion of the body by experienced symptoms and feeling of helplessness. Symptoms related to Peripartum Cardiomyopathy started for 17 women during pregnancy and in two post partum and time from symptoms to diagnosis varied between three and 190 days (median 40). The physical symptoms were:shortness of breath, excessive fatigue and swelling, bloatedness, nausea, palpitation, coughing, chest tightness, bodily pain, headache, fever, tremor, dizziness, syncope, restless and tingly body and reduced urine output. Emotional symptoms were: fear, anxiety, feelings of panic, and thoughts of impending death. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Symptoms of Peripartum Cardiomyopathy were debilitating, exhausting and frightening for the women interviewed in this study. Health care professionals responsible for the antenatal care, especially midwives, need skills to identify initial symptoms of Peripartum Cardiomyopathy for early referral and treatment by a specialist. In order to give optimal care more research is needed to show how to improve midwives' knowledge of Peripartum Cardiomyopathy. PMID- 26515745 TI - Sexual stature dimorphism as an indicator of living standards? AB - BACKGROUND: A group of researchers has argued that sexual stature dimorphism (SSD) can serve as an indicator of living standards. This argument is based on evidence that boys' physical growth is more sensitive to environmental conditions than girls' physical growth. Because Korea's economic growth in the second half of the 20th century was unprecedentedly rapid, according to their logic, it is likely to see an increasing trend in SSD. AIM: We aimed to determine whether SSD can serve as an accurate indicator of living standards for a population that would exhibit a pronounced trend in SSD, providing that the logic for use of SSD is correct. SUBJECTS AND METHODS: We employed nationally representative Korean men born in 1941-1990 (n = 17 268) and women born in 1941-1991 (n = 22 543) and estimated mean heights by sex and birth years. We then calculated SSD values and charted the trend. RESULTS: Although male height increased faster than female height, the SSD trend was flat for the pooled observations and for sub-groups by socioeconomic status. CONCLUSION: These results cast doubt on the argument for using SSD as an indicator of living standards. PMID- 26515746 TI - The role of different strain backgrounds in bacterial endotoxin-mediated sensitization to neonatal hypoxic-ischemic brain damage. AB - Genetic background is known to influence the outcome in mouse models of human disease, and previous experimental studies have shown strain variability in the neonatal mouse model of hypoxia-ischemia. To further map out this variability, we compared five commonly used mouse strains: C57BL/6, 129SVJ, BALB/c, CD1 and FVB in a pure hypoxic-ischemic setup and following pre-sensitization with lipopolysaccharide (LPS). Postnatal day 7 pups were subjected to unilateral carotid artery occlusion followed by continuous 30 min 8% oxygen exposure at 36 degrees C. Twelve hours prior, a third of the pups received a single intraperitoneal LPS (0.6 MUg/g) or a saline (vehicle) administration, respectively; a further third underwent hypoxia-ischemia alone without preceding injection. Both C57BL/6 and 129SVJ strains showed minimal response to 30min hypoxia-ischemia alone, BALB/c demonstrated a moderate response, and both CD1 and FVB revealed the highest brain damage. LPS pre-sensitization led to substantial increase in overall brain infarction, microglial and astrocyte response and cell death in four of the five strains, with exception of BALB/c that only showed a significant effect with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Saline administration prior to hypoxia-ischemia resulted in an increase in inflammatory-associated markers, particularly in the astroglial activation of C57BL/6 mice, and in combined microglial activation and neuronal cell loss in FVB mice. Finally, two of the four strongly affected strains- C57BL/6 and CD1--revealed pronounced contralateral astrogliosis with a neuroanatomical localization similar to that observed on the occluded hemisphere. Overall, the current findings demonstrate strain differences in response to hypoxia-ischemia alone, to stress associated with vehicle injection, and to LPS mediated pre-sensitization, which partially explains the high variability seen in the neonatal mouse models of hypoxia-ischemia. These results can be useful in future studies of fetal/neonatal response to inflammation and reduced oxygen blood supply. PMID- 26515747 TI - Neuronal expression of CB2 cannabinoid receptor mRNAs in the mouse hippocampus. AB - In the brain, CB1 cannabinoid receptors primarily mediate the effects of cannabinoids, but CB2 cannabinoid receptors (CB2Rs) have recently been discovered in the nervous system and also implicated in neuromodulatory roles. To understand the mechanisms of CB2R functions in the brain, it is essential to localize CB2Rs, but the types of cells expressing CB2Rs have been controversial. Unequivocal localization of CB2Rs in the brain has been impeded in part by the low expression levels of CB2Rs and poor specificity of detection methods. Here, we used an ultrasensitive and specific in situ hybridization method called the RNAscope to determine the spatial pattern of CB2R mRNA expression in the mouse hippocampus. CB2R mRNAs were mostly expressed in a subset of excitatory and inhibitory neurons in the CA1, CA3 and dentate gyrus areas, but rarely in microglia. CB2R knock-out mice were used as a negative control. Using the quantitative real-time polymerase chain reaction, we also found that the temporal pattern of CB2R mRNA expression was stable during postnatal development. Consistent with previous reports, the immunological detection of CB2Rs was not reliable, implying extremely low levels of the protein expression and/or insufficient specificity of the current anti CB2R antibodies. Our findings of the expression patterns of CB2R mRNAs may help determine the cell types involved in, and hence the mechanisms of, the CB2R mediated neuromodulation. PMID- 26515748 TI - Accuracy of CT angiography in detection of blood supply dominance of posterior cerebral artery in patients with posterior communicating artery aneurysm. AB - BACKGROUND AND PURPOSE: The use of computed tomography angiography (CTA) as the sole vascular imaging study for preoperative planning for clipping of aneurysms is well described in the literature. CTA is widely available, provides quick acquisition, has low morbidity, and low cost. In this study, we describe the accuracy of CTA in determining the blood supply dominance in comparison to standard digital subtraction angiography. MATERIALS AND METHODS: Sixty-six patients, with both CTAs and angiograms, were reviewed by two independent neuroradiologists. The posterior cerebral artery was determined to have dominant supply from the posterior communicating artery if it was of similar size to the P2 segment and the P1 segment was smaller by approximately 50%. If the posterior communicating artery and P1 segment were the same size, it was considered to have a dual supply. If P1 and P2 segments were the same caliber and the posterior communicating artery was smaller by 50%, it was deemed to have posterior circulation dominance. RESULTS: Based on the findings of our reviewers, CTA had a sensitivity and specificity of 69% and 96%, respectively, in predicting the presence of a fetal PCA. The positive predictive value was found to be 82% while a negative predictive value was estimated as 93%. A small-caliber P1 segment and large-caliber posterior communicating artery led to inaccurate interpretations of the CTAs. CONCLUSION: This study shows that one cannot accurately predict blood supply dominance of the posterior cerebral artery. Knowledge of the blood flow dominance is essential when clipping a posterior communicating artery aneurysm to avoid compromise in posterior circulation. PMID- 26515749 TI - Childhood posterior reversible encephalopathy syndrome: Magnetic resonance imaging findings with emphasis on increased leptomeningeal FLAIR signal. AB - PURPOSE: Posterior reversible encephalopathy syndrome (PRES) is a clinico radiologic syndrome characterized clinically by headache, seizures, and altered sensorium and radiological changes which are usually reversible. The purpose of this study was to describe the spectrum of magnetic resonance imaging (MRI) findings in childhood PRES, to determine the common etiologies for childhood PRES, and to have an insight into the pathophysiology of PRES. METHODS: The MRI results of 20 clinically diagnosed cases of PRES between July 2011 and June 2013 were reviewed. The final diagnosis of PRES was based on the clinical presentation and the MRI features at the time of presentation, which resolved on the follow-up imaging. The medical records of the patients were reviewed to determine the underlying medical disease. RESULTS: Eight out of the 20 patients included in the study were on cyclosporine or tacrolimus based immunosuppressant therapy for kidney transplant. Four patients had severe hypertension at presentation. The most common MRI finding was high T2-fluid-attenuated inversion recovery (FLAIR) signal in the cortex and subcortical white matter of both cerebral hemispheres, particularly in the parietal and occipital lobes (n=16). The second most common MRI finding was increased leptomeningeal FLAIR signal (n=7). Out of seven patients with leptomeningeal signal, five demonstrated leptomeningeal enhancement as well. Four out of these seven patients had no other parenchymal findings. CONCLUSION: Childhood PRES is commonly seen in the setting of immunosuppressant therapy for kidney transplant, severe hypertension and cancer treatment. There was high incidence of increased leptomeningeal FLAIR signal and leptomeningeal enhancement in our study. It supports the current theory of endothelial injury with increased microvascular permeability as the potential pathophysiology of PRES. Also, absence of elevated blood pressure in majority of the patients in our study supports the theory of direct endothelial injury by some agents leading to vasogenic edema. PMID- 26515750 TI - Brainstem variant of posterior reversible encephalopathy syndrome: A case report. AB - Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological condition, generally observed in conjunction with severe and acute hypertension, that involves mainly the posterior head areas (occipital and temporal lobes) and anterior "watershed" areas. In this syndrome it is rare to observe a predominant involvement of the brainstem. We describe the clinical and radiological findings in a patient with brainstem involvement, discussing its pathophysiological features and possible differential diagnosis. PMID- 26515751 TI - Curcumin alleviates glucocorticoid-induced osteoporosis by protecting osteoblasts from apoptosis in vivo and in vitro. AB - Curcumin, an active component of the rhizomes of Curcumin longa L., possesses broad anti-inflammation and anti-cancer properties. Curcumin was previously reported to be capable of protecting ovariectomized rats against osteoporosis. However, the effect of curcumin on glucocorticoid-induced osteoporosis (GIO) is not yet clear. The present study investigated the effects of curcumin on dexamethasone (Dex)-induced osteoporosis in vivo and Dex-induced osteoblast apoptosis in vivo and in vitro. The GIO rat model was induced by subcutaneous injection of Dex for 60 days and verified to be successful as evidenced by the significantly decreased bone mineral density (BMD) determined using dual X-ray absorptiometry. Subsequently, curcumin administration (100 mg/kg) for 60 days obviously increased BMD and bone-alkaline phosphatase, decreased carboxy-terminal collagen cross links, enhanced bone mechanical strength, and improved trabecular microstructure, thereby alleviating Dex-induced osteoporosis. Mechanically, curcumin remarkably reversed Dex-induced femoral osteoblast apoptosis in vivo. In cultured primary osteoblasts, pretreatment with curcumin concentration dependently decreased the number of Dex-induced apoptotic osteoblasts by down regulating the ratio of Bax/Bcl-2 as well as the levels of cleaved caspase-3 and cleaved poly ADP-ribose polymerase (PARP). Moreover, curcumin pretreatment activated extracellular signal regulated kinase (ERK) signalling in Dex-induced osteoblasts by up-regulating the expression level of p-ERK1/2. Taken together, our study demonstrated that curcumin could ameliorate GIO by protecting osteoblasts from apoptosis, which was possibly related to the activation of the ERK pathway. The results suggest that curcumin may be a promising drug for prevention and treatment of GIO. PMID- 26515752 TI - Anti-malarial effect of semi-synthetic drug amitozyn. AB - BACKGROUND: Malaria caused by Plasmodium falciparum is the most virulent form of malaria, leading to approximately a half million deaths per year. Chemotherapy continues to be a key approach in malaria prevention and treatment. Due to widespread parasite drug resistance, identification and development of new anti malarial compounds remains an important task of malarial parasitology. The semi synthetic drug amitozyn, obtained through alkylation of major celandine (Chelidonium majus) alkaloids with N,N'N'-triethylenethiophosphoramide (ThioTEPA), is a widely used Eastern European folk medicine for the treatment of various tumours. However, its anti-malarial effect has never been studied. METHODS: The anti-malarial effects of amitozyn alone and in combination with chloroquine, pyrimethamine and artemisinin on the blood stages of P. falciparum were analysed. The cytostatic effects of amitozyn on parasites and various cancerous and non-cancerous human cells were compared and their toxic effects on unparasitized human red blood cells were analysed. RESULTS: Obtained results demonstrate that amitozyn effectively inhibits the growth of blood-stage parasites with IC50 9.6 +/- 2, 11.3 +/- 2.8 and 10.8 +/- 1.8 MUg/mL using CS2, 3G8 and NF54 parasite lines, respectively. The median IC50 for 14 tested human cell lines was 33-152 MUg/mL. Treatment of uninfected red blood cells with a high dose of amitozyn (500 MUg/mL) did not change cell morphology, demonstrating its non-toxicity for erythrocytes. The synergistic impact of the amitozyn/chloroquine combination was observed at growth inhibition levels of 10-80 %, while demonstrating a nearly additive effect at a growth inhibition level of 90 %. The combination of amitozyn with pyrimethamine has a synergistic effect at growth inhibition levels of 10-70 % and a nearly additive effect at a growth inhibition level of 90 %. The synergistic anti-malarial effect of the amitozyn/artemisinin combination was observed at growth inhibition levels of 10-40 % and a nearly additive effect at growth inhibition levels of 50-90 %. CONCLUSIONS: These in vitro results suggest that the semi-synthetic drug amitozyn, typically used for the treatment of tumours, is a potential anti-malarial candidate and warrants more detailed laboratory and pre-clinical investigations. PMID- 26515753 TI - The C-terminal region of the non-structural protein 2B from Hepatitis A Virus demonstrates lipid-specific viroporin-like activity. AB - Viroporins are virally encoded, membrane-active proteins, which enhance viral replication and assist in egress of viruses from host cells. The 2B proteins in the picornaviridae family are known to have viroporin-like properties, and play critical roles during virus replication. The 2B protein of Hepatitis A Virus (2B), an unusual picornavirus, is somewhat dissimilar from its analogues in several respects. HAV 2B is approximately 2.5 times the length of other 2B proteins, and does not disrupt calcium homeostasis or glycoprotein trafficking. Additionally, its membrane penetrating properties are not yet clearly established. Here we show that the membrane interacting activity of HAV 2B is localized in its C-terminal region, which contains an alpha-helical hairpin motif. We show that this region is capable of forming small pores in membranes and demonstrates lipid specific activity, which partially rationalizes the intracellular localization of full-length 2B. Using a combination of biochemical assays and molecular dynamics simulation studies, we also show that HAV 2B demonstrates a marked propensity to dimerize in a crowded environment, and probably interacts with membranes in a multimeric form, a hallmark of other picornavirus viroporins. In sum, our study clearly establishes HAV 2B as a bona fide viroporin in the picornaviridae family. PMID- 26515755 TI - Zinc oxide nanoparticle suspensions and layer-by-layer coatings inhibit staphylococcal growth. AB - Despite a decade of engineering and process improvements, bacterial infection remains the primary threat to implanted medical devices. Zinc oxide nanoparticles (ZnO-NPs) have demonstrated antimicrobial properties. Their microbial selectivity, stability, ease of production, and low cost make them attractive alternatives to silver NPs or antimicrobial peptides. Here we sought to (1) determine the relative efficacy of ZnO-NPs on planktonic growth of medically relevant pathogens; (2) establish the role of bacterial surface chemistry on ZnO NP effectiveness; (3) evaluate NP shape as a factor in the dose-response; and (4) evaluate layer-by-layer (LBL) ZnO-NP surface coatings on biofilm growth. ZnO-NPs inhibited bacterial growth in a shape-dependent manner not previously seen or predicted. Pyramid shaped particles were the most effective and contrary to previous work, larger particles were more effective than smaller particles. Differential susceptibility of pathogens may be related to their surface hydrophobicity. LBL ZnO-NO coatings reduced staphylococcal biofilm burden by >95%. From the Clinical Editor: The use of medical implants is widespread. However, bacterial colonization remains a major concern. In this article, the authors investigated the use of zinc oxide nanoparticles (ZnO-NPs) to prevent bacterial infection. They showed in their experiments that ZnO-NPs significantly inhibited bacterial growth. This work may present a new alternative in using ZnO NPs in medical devices. PMID- 26515754 TI - Dual-therapy with alphavbeta3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model. AB - Fumagillin, an unstable anti-angiogenesis mycotoxin, was synthesized into a stable lipase-labile prodrug and incorporated into integrin-targeted lipid encapsulated nanoparticles (alphavbeta3-Fum-PD NP). Dual anti-angiogenic therapy combining alphavbeta3-Fum-PD NP with zoledronic acid (ZA), a long-acting osteoclast inhibitor with proposed anti-angiogenic effects, was evaluated. In vitro, alphavbeta3-Fum-PD NP reduced (P<0.05) endothelial cell viability without impacting macrophage viability. ZA suppressed (P<0.05) macrophage viability at high dosages but not endothelial cell proliferation. 3D MR neovascular imaging of rabbit Vx2 tumors showed no effect with ZA, whereas alphavbeta3-Fum-PD NP alone and with ZA decreased angiogenesis (P<0.05). Immunohistochemistry revealed decreased (P<0.05) microvascularity with alphavbeta3-Fum-PD NP and ZA and further microvascular reduction (P<0.05) with dual-therapy. In vivo, ZA did not decrease tumor macrophage numbers nor cancer cell proliferation, whereas alphavbeta3-Fum PD-NPs reduced both measures. Dual-therapy with ZA and alphavbeta3-Fum-PD-NP may provide enhanced neo-adjuvant utility if macrophage ZA uptake is increased. From the Clinical Editor: Although anti-angiogenesis is one of the treatment modalities in the fight against cancer, many cancers become resistant to VEGF pathway inhibitors. In this article, the authors investigated the use of dual therapy using fumagillin, integrin-targeted lipid-encapsulated nanoparticles (alphavbeta3- Fum-PD NP) and zoledronic acid (ZA), in both in-vitro and in-vivo experiments. This combination approach may provide an insight to the design of future drugs against cancers. PMID- 26515756 TI - Detection of genetic variants affecting cattle behaviour and their impact on milk production: a genome-wide association study. AB - Behaviour traits of cattle have been reported to affect important production traits, such as meat quality and milk performance as well as reproduction and health. Genetic predisposition is, together with environmental stimuli, undoubtedly involved in the development of behaviour phenotypes. Underlying molecular mechanisms affecting behaviour in general and behaviour and productions traits in particular still have to be studied in detail. Therefore, we performed a genome-wide association study in an F2 Charolais * German Holstein cross-breed population to identify genetic variants that affect behaviour-related traits assessed in an open-field and novel-object test and analysed their putative impact on milk performance. Of 37,201 tested single nucleotide polymorphism (SNPs), four showed a genome-wide and 37 a chromosome-wide significant association with behaviour traits assessed in both tests. Nine of the SNPs that were associated with behaviour traits likewise showed a nominal significant association with milk performance traits. On chromosomes 14 and 29, six SNPs were identified to be associated with exploratory behaviour and inactivity during the novel-object test as well as with milk yield traits. Least squares means for behaviour and milk performance traits for these SNPs revealed that genotypes associated with higher inactivity and less exploratory behaviour promote higher milk yields. Whether these results are due to molecular mechanisms simultaneously affecting behaviour and milk performance or due to a behaviour predisposition, which causes indirect effects on milk performance by influencing individual reactivity, needs further investigation. PMID- 26515757 TI - Treatment of rheumatoid arthritis: Unraveling the conundrum. AB - Rheumatoid arthritis (RA) is a heterogeneous disease with a complex and yet not fully understood pathophysiology, where numerous different cell-types contribute to a destructive process of the joints. This complexity results into a considerable interpatient variability in clinical course and severity, which may additionally involve genetics and/or environmental factors. After three decades of focused efforts scientists have now achieved to apply in clinical practice, for patients with RA, the "treat to target" approach with initiation of aggressive therapy soon after diagnosis and escalation of the therapy in pursuit of clinical remission. In addition to the conventional synthetic disease modifying anti-rheumatic drugs, biologics have greatly improved the management of RA, demonstrating efficacy and safety in alleviating symptoms, inhibiting bone erosion, and preventing loss of function. Nonetheless, despite the plethora of therapeutic options and their combinations, unmet therapeutic needs in RA remain, as current therapies sometimes fail or produce only partial responses and/or develop unwanted side-effects. Unfortunately the mechanisms of 'nonresponse' remain unknown and most probable lie in the unrevealed heterogeneity of the RA pathophysiology. In this review, through the effort of unraveling the complex pathophysiological pathways, we will depict drugs used throughout the years for the treatment of RA, the current and future biological therapies and their molecular or cellular targets and finally will suggest therapeutic algorithms for RA management. With multiple biologic options, there is still a need for strong predictive biomarkers to determine which drug is most likely to be effective, safe, and durable in a given individual. The fact that available biologics are not effective in all patients attests to the heterogeneity of RA, yet over the long term, as research and treatment become more aggressive, efficacy, toxicity, and costs must be balanced within the therapeutic equation to enhance the quality of life in patients with RA. PMID- 26515758 TI - Beneficial effects of low dose radiation in response to the oncogenic KRAS induced cellular transformation. AB - Recently low dose irradiation has gained attention in the field of radiotherapy. For lack of understanding of the molecular consequences of low dose irradiation, there is much doubt concerning its risks on human beings. In this article, we report that low dose irradiation is capable of blocking the oncogenic KRAS induced malignant transformation. To address this hypothesis, we showed that low dose irradiation, at doses of 0.1 Gray (Gy); predominantly provide defensive response against oncogenic KRAS -induced malignant transformation in human cells through the induction of antioxidants without causing cell death and acts as a critical regulator for the attenuation of reactive oxygen species (ROS). Importantly, we elucidated that knockdown of antioxidants significantly enhanced ROS generation, invasive and migratory properties and abnormal acini formation in KRAS transformed normal as well as cancer cells. Taken together, this study demonstrates that low dose irradiation reduces the KRAS induced malignant cellular transformation through diminution of ROS. This interesting phenomenon illuminates the beneficial effects of low dose irradiation, suggesting one of contributory mechanisms for reducing the oncogene induced carcinogenesis that intensify the potential use of low dose irradiation as a standard regimen. PMID- 26515760 TI - Super-resolution optical microscopy based on scannable cantilever-combined microsphere. AB - We report an ingenious method of super-resolution optical microscopy utilizing scannable cantilever-combined microsphere. By scanning the microsphere over the sample surface in a cantilever-combined microsphere-sample contact state, super resolution images can be acquired at arbitrary sample regions through near-field information collection by the microsphere. In addition, such a state can effectively reduce the possibility of breaking the cantilever and damaging the microsphere or sample surface. This work has developed a new method and technique of sub-diffraction-limit optical microscopy, and can be practically applied in various fields of micro/nanoscopy. PMID- 26515759 TI - Establishment and characterization of a novel MYC/BCL2 "double-hit" diffuse large B cell lymphoma cell line, RC. AB - BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoid malignancy worldwide. Approximately 5 % of cases of DLBCL are so-called double-hit lymphomas (DHL), defined by a chromosomal translocation or rearrangement involving MYC/8q24.2 in combination with another recurrent breakpoint, usually BCL2/18q21.3. Patients with MYC/BCL2 DHL are resistant to standard front-line therapy, and currently, there is no consensus for a therapeutic strategy to treat these patients. Lack of clinically relevant or validated human experimental DHL models of any type that would improve our understanding of the biologic basis of MYC/BCL2 DHL pathophysiology continues to hamper identification of valid therapeutic targets. We describe a unique MYC/BCL2 DHL cell line with morphologic features of DLBCL that we have established, designated as RC. METHODS: We used tissue culture techniques to establish the RC cell line from primary DLBCL cells. We also utilized molecular and cellular biological techniques including flow cytometry, polymerase chain reaction (PCR), DNA fingerprinting, reverse-phase protein array, conventional cytogenetics, and fluorescence in situ hybridization (FISH) analysis to characterize the RC cell line. NSG-severe combined immunodeficiency (SCID) mice were utilized as a model for xeno-transplantation of RC cells. RESULTS: RC cells had the following immunophenotype: positive for CD10, CD19, CD20, CD22, CD38, CD43, CD44, and CD79b and negative for CD3, CD4, CD5, CD8, CD11c, CD14, CD30, CD56, and CD200, which was identical to the primary tumor cells. Conventional cytogenetic analysis showed a t(2;8)(p12;q24.2) and t(14;18)(q32;q21.3), corresponding to MYC and BCL2 gene rearrangements, respectively. DNA fingerprinting authenticated the RC cell line to be of the same clone as the primary tumor cells. In addition, RC cells were established in SCID mice as an in vivo model for translational therapeutics studies. Proteomic analysis showed activation of the mTOR signaling pathway in RC cells that can be targeted with an mTOR inhibitor. CONCLUSION: The data presented confirm the validity of the RC cell line as a representative model of MYC/BCL2 DHL that will be useful for both in vitro and in vivo studies of DHL pathogenesis and therapeutics. PMID- 26515761 TI - The molecular structure of the silk fibers from Hymenoptera aculeata (bees, wasps, ants). AB - Silks from the Hymenoptera aculeata (bees, wasps, ants) contain ropes with four alpha-helical strands, rather than the more usual two strands found, for example, in alpha-keratin and myosin molecules. Extensive studies of the chemical structure of the silks have shown that each of the four chains in the molecule contains a central coiled-coil rod domain. However, little progress has been made in modeling the three-dimensional structure. X-ray diffraction data on honeybee silk (Apis mellifera), recorded by Rudall and coworkers, has been re-examined in detail and possible structures developed for the various types of filament seen in the silk glands, and for the packing arrangement in the spun fibers. The original X-ray data were re-collected by scanning figures in the original publications, de-screening and averaging perpendicular to the direction of interest, thereby reducing the graininess of the original images. Sufficient numbers of equatorial and meridional reflections were collected to define the axial projection of the base of the unit cell in fibers drawn from the contents of the silk glands, and to suggest that the axial period is different from that suggested by Rudall and coworkers. Models for two types of filament of increasing diameter are developed based on the node-internode packing scheme observed in protein crystals containing four-strand alpha-helical ropes. The central domains of the four component chains in the molecule are enclosed by N- and C-terminal domains with widely different lengths and compositions. The fibers thus have a composite filament-matrix texture, and possible locations for the matrix are discussed. PMID- 26515762 TI - Establishing the "meaning" of microbleeds: Clinical context or lobar microbleed burden? PMID- 26515763 TI - Adverse pregnancy outcomes in rural Uganda (1996-2013): trends and associated factors from serial cross sectional surveys. AB - OBJECTIVE: Community based evidence on pregnancy outcomes in rural Africa is lacking yet it is needed to guide maternal and child health interventions. We estimated and compared adverse pregnancy outcomes and associated factors in rural south-western Uganda using two survey methods. METHODS: Within a general population cohort, between 1996 and 2013, women aged 15-49 years were interviewed on their pregnancy outcome in the past 12 months (method 1). During 2012-13, women in the same cohort were interviewed on their lifetime experience of pregnancy outcomes (method 2). Adverse pregnancy outcome was defined as abortions or stillbirths. We used random effects logistic regression for method 1 and negative binomial regression with robust clustered standard errors for method 2 to explore factors associated with adverse outcome. RESULTS: One third of women reported an adverse pregnancy outcome; 10.8% (abortion = 8.4%, stillbirth = 2.4%) by method 1 and 8.5% (abortion = 7.2%, stillbirth = 1.3%) by method 2. Abortion rates were similar (10.8 vs 10.5) per 1000 women and stillbirth rates differed (26.2 vs 13.8) per 1000 births by methods 1 and 2 respectively. Abortion risk increased with age of mother, non-attendance of antenatal care and proximity to the road. Lifetime stillbirth risk increased with age. Abortion and stillbirth risk reduced with increasing parity. DISCUSSION: Both methods had a high level of agreement in estimating abortion rate but were markedly below national estimates. Stillbirth rate estimated by method 1 was double that estimated by method 2 but method 1 estimate was more consistent with the national estimates. CONCLUSION: Strategies to improve prospective community level data collection to reduce reporting biases are needed to guide maternal health interventions. PMID- 26515764 TI - Duodenal perforations after endoscopic retrograde cholangiopancreatography. PMID- 26515766 TI - Incidence rates of chronic lymphocytic leukemia in US states are associated with residential radon levels. AB - AIM: Environmental risk factors for chronic lymphocytic leukemia (CLL) have not been consistently identified. An etiologic role for ionizing radiation in CLL is controversial. Because most of the ionizing radiation to which individuals are exposed comes from radon at home, we examined CLL incidence rates in relation to residential radon levels. METHODS: We used population-based rates for CLL for US states from 2007 to 2011 and measurements of residential radon made by the US Environmental Protection Agency. RESULTS: Incidence rates for CLL were significantly correlated with residential radon levels among whites (both genders together and each gender separately; p < 0.005) and among blacks (p < 0.05). CONCLUSION: We speculate that radon increases CLL risk and that the mechanisms may be similar to those by which radon causes lung cancer. PMID- 26515767 TI - Unexpected Findings in the Left Atrium of a Patient With a Paravalvular Mitral Leak. PMID- 26515768 TI - Electrocardiographic Changes Caused by Severe Accidental Hypothermia. PMID- 26515769 TI - Prevalence and factors associated with VIA positive result among clients screened at Family Guidance Association of Ethiopia, south west area office, Jimma model clinic, Jimma, Ethiopia 2013: a cross-sectional study. AB - BACKGROUND: Cervical cancer is the 2nd most frequent and top killer cancer among women in Ethiopia. Prevalence and factors associated with visual inspection with acetic acid (VIA) positive result is not studied yet at the study area. METHODS: A cross-sectional study was conducted at Jimma model clinic of Family Guidance Association of Ethiopia, from September 11, 2013 to October 11, 2013. Pertinent data of 334 screened clients were transferred to Epidata version3.1 using checklist, double data entry verification done and exported to SPSS version16.0. After cleaning the data, descriptive analysis was done and logistic regression model employed to identify predictors of VIA positive result. Statistical significance was declared at P < 0.05. RESULTS: Out of 334 screened clients, 43 (12.9%) had VIA positive result. Initiation of sexual intercourse earlier than 16 years was found to be an independent predictor increasing the risk of VIA positive by 2.2 times as compared to clients who started at the age of 16 or more years (AOR [95% CI] = 2.2 [1.1, 4.3]). CONCLUSIONS: Early initiation of sexual intercourse was an independent predictor of VIA positive result in this study. Thus, any cervical cancer prevention and control effort at the study area should address the problem of early initiation of sexual intercourse. PMID- 26515770 TI - Validation de l'outil d'evaluation de l'aptitude (OEA): Une etude Delphi. AB - Western societies currently face the aging of their populations. New challenges are experienced by health professionals who are involved in competency assessment that may necessitate a public guardianship. This assessment is complex and its consequences are significant. The Competency Assessment Tool (CAT) can be used to provide a rigorous, objective and ethical evaluation by an interdisciplinary team. The purpose of this study was to validate the CAT. To do this, a Delphi study was conducted among 33 experts from five professions (social worker, occupational therapist, physician, neuropsychologist and nurse), working in seven administrative regions of Quebec. An expert consensus on the content of the CAT was obtained in the first round of consultation. Thus, this study has validated an assessment and decision-making process (CAT) designed for health and social professionals. This decision model can guide the competency assessment of the ability of persons with cognitive impairment to take care of themselves and to manage their finances. Further studies will be necessary to support use of the CAT in practice. PMID- 26515765 TI - Decoding the non-coding genome: elucidating genetic risk outside the coding genome. AB - Current evidence emerging from genome-wide association studies indicates that the genetic underpinnings of complex traits are likely attributable to genetic variation that changes gene expression, rather than (or in combination with) variation that changes protein-coding sequences. This is particularly compelling with respect to psychiatric disorders, as genetic changes in regulatory regions may result in differential transcriptional responses to developmental cues and environmental/psychosocial stressors. Until recently, however, the link between transcriptional regulation and psychiatric genetic risk has been understudied. Multiple obstacles have contributed to the paucity of research in this area, including challenges in identifying the positions of remote (distal from the promoter) regulatory elements (e.g. enhancers) and their target genes and the underrepresentation of neural cell types and brain tissues in epigenome projects the availability of high-quality brain tissues for epigenetic and transcriptome profiling, particularly for the adolescent and developing brain, has been limited. Further challenges have arisen in the prediction and testing of the functional impact of DNA variation with respect to multiple aspects of transcriptional control, including regulatory-element interaction (e.g. between enhancers and promoters), transcription factor binding and DNA methylation. Further, the brain has uncommon DNA-methylation marks with unique genomic distributions not found in other tissues - current evidence suggests the involvement of non-CG methylation and 5-hydroxymethylation in neurodevelopmental processes but much remains unknown. We review here knowledge gaps as well as both technological and resource obstacles that will need to be overcome in order to elucidate the involvement of brain-relevant gene-regulatory variants in genetic risk for psychiatric disorders. PMID- 26515771 TI - Anxiety and depressive disorders in elderly with chronic dizziness of vestibular origin. AB - INTRODUCTION: Dizziness is one of the most prevalent symptoms in the elderly. Anxiety and depression are common in dizzy adult patients, but there is scarce information about comorbidity between vestibular disturbances and psychiatric disorders in the aged. OBJECTIVE: To assess the prevalence of anxiety and depression disorders in elderly with chronic dizziness of vestibular origin. METHODS: Transversal study that used the Brazilian version of the Composite International Diagnostic Interview 2.1 to assess anxiety and depressive disorders in elderly patients (>= 60 years old) with chronic dizziness. RESULTS: Most of the 44 patients included in the study were female (88.6%) with a mean age of 71 years (+/- 7.5), 68.1% had experienced dizziness for 1 year or more. The most prevalent diagnosis was benign paroxysmal positional vertigo (52.3%). The prevalence of generalized anxiety disorder and specific phobias during life were 29.5% and 22.7%, respectively, and, in the last 12 months, 18.2% and 15.9%. There was no patient with panic disorder, agoraphobia or social phobia. The prevalence of depressive disorder during life was 45.4%, and, in the last 12 months, were 11.3%. CONCLUSION: Aged patients with chronic dizziness had high prevalence of some mental disorders. PMID- 26515772 TI - Value of stress ultrasound for the diagnosis of chronic ankle instability compared to manual anterior drawer test, stress radiography, magnetic resonance imaging, and arthroscopy. AB - PURPOSE: Clinicians frequently diagnose chronic ankle instability using the manual anterior drawer test and stress radiography. However, both examinations can yield incorrect results and do not reveal the extent of ankle instability. Stress ultrasound has been reported to be a new diagnostic tool for the diagnosis of chronic ankle instability. The purpose of this study was to assess the diagnostic value of stress ultrasound for chronic ankle instability compared to the manual anterior drawer test, stress radiography, magnetic resonance imaging (MRI), and arthroscopy. METHODS: Twenty-eight consecutive patients who underwent ankle arthroscopy and subsequent modified Brostrom repair for treatment of chronic ankle instability were included. The arthroscopic findings were used as the reference standard. A standardized physical examination (manual anterior drawer test), stress radiography, MRI, and stress ultrasound were performed to assess the anterior talofibular ligament (ATFL) prior to operation. Ultrasound images were taken in the resting position and the maximal anterior drawer position. RESULTS: Grade 3 lateral instability was verified arthroscopically in all 28 cases with a clinical diagnosis (100%). Twenty-two cases showed grade III instability on the manual anterior drawer test (78.6%). Twenty-four cases displayed anterior translation exceeding 5 mm on stress radiography (86%), and talar tilt angle exceeded 15 degrees in three cases (11 %). Nineteen cases displayed a partial chronic tear (change in thickness or signal intensity), and nine cases displayed complete tear on MRI (100%). Lax and wavy ATFL was evident on stress ultrasound in all cases (100 %). The mean value of the ATFL length was 2.8 +/- 0.3 cm for the stressed condition and 2.1 +/- 0.2 cm for the resting condition (p < 0.001). CONCLUSION: Stress ultrasound may be useful for the diagnosis of chronic ankle instability in addition to the manual anterior drawer test and stress radiography. LEVEL OF EVIDENCE: III. PMID- 26515773 TI - Attachment area of fibres from the horns of lateral meniscus: anatomic study with special reference to the positional relationship of anterior cruciate ligament. AB - PURPOSE: Although studies support the clinical importance of the fibres from the horns of lateral meniscus (LM), few studies have investigated the detailed anatomy. This anatomic study was conducted to analyse the structural details of LM with special reference to (1) the attachment area of the fibres from the anterior and posterior horns and (2) the positional relationship between these fibres and the anterior cruciate ligament (ACL). METHODS: A total of 24 cadaveric knees were used in the macroscopic investigation, and six knees were used in the histological investigation. Micro-computed tomography analysis was also performed to assess the anatomy of the posteriormost fibre from the posterior horn of LM. RESULTS: Based on the macroscopic investigations, the outer fibres from the anterior horn of LM extended to ACL and seemed to intermingle with ACL fibres. However, the histological investigations showed a distinct border between the fibres and ACL. The inner fibres from the anterior horn of LM attached to the lateral intercondylar tubercle serving as a lateral margin of ACL attachment. Fibres from the posterior horn of LM were separated into anterolateral and posteromedial crura which attached to the posterior aspect of the lateral and medial intercondylar tubercles, respectively. These two crura formed the posterior margin of the ACL attachment, except for the central part of ACL. CONCLUSION: The outer fibres from the anterior horn of LM adjoined ACL. The inner fibres from the anterior horn of LM and two crura from the posterior horn of LM formed the border of the attachment area of ACL. The distinctive fibre anatomy from LM could provide a surgical landmark during arthroscopic surgery. PMID- 26515774 TI - Aspirin mono-therapy continuation does not result in more bleeding after knee arthroplasty. AB - PURPOSE: Current clinical practice guidelines sometimes still recommend stopping aspirin five to seven days before knee arthroplasty surgery. Literature regarding multimodal blood management and continuation of anti-platelet therapy in this type of surgery is scant. The study hypothesis was that knee arthroplasty under low-dose aspirin mono-therapy continuation does not cause more total blood loss than knee arthroplasty performed without aspirin. Blood loss would be measured by haemoglobin (Hb) and haematocrit (HTC) levels drop at day 2 or day 4 for patients who benefit from multimodal bleeding control measures. METHODS: A database of all patients undergoing knee arthroplasty between 2006 and 2014 was analysed. Demographic, surgical and complete blood workup data were collected. A retrospective comparison study analysed both groups in terms of blood loss, by mean calculated blood loss as haemoglobin or haematocrit drop between the preoperative Nadir value and the postoperative day 2 and 4 value. A group of 198 (44 UKA and 154 TKA) patients underwent surgery without interrupting their aspirin therapy for cardiovascular prevention. Mean (SD) age was 71 (8) and the mean (SD) BMI was 29 (5.5) kg/m2. The control group consisted of 403 (102 UKA and 301 TKA) patients who were not under aspirin, or any other anti-platelet agent. Mean (SD) age was 65 (10) (p < 0.05) and the mean (SD) BMI was 29 (5.0) kg/m2 (n.s.). All patients in the control group were randomly selected. RESULTS: There were no differences in terms of visible (early) or hidden (late) blood loss as measured by Hb drop in between both groups. There is no difference in transfusion rates. CONCLUSIONS: Modern multimodal blood management provides sufficient blood loss prevention during and after knee arthroplasty to allow physicians to continue low-dose aspirin mono-therapy for cardiovascular prevention. LEVEL OF EVIDENCE: III. PMID- 26515775 TI - A third of midwives who have experienced traumatic perinatal events have symptoms of post-traumatic stress disorder. PMID- 26515776 TI - TIP hypospadias repair: A pediatric urology indicator operation. AB - OBJECTIVE: We review development and evolution of TIP hypospadias repair, including technical changes made to improve its results. We also discuss general risk factors for hypospadias surgical complications. METHODS: We describe use of a database with prospective data entry to first identify our most common complications and their frequency, and then to monitor results of technical modifications made to reduce their occurrence. Multiple logistic regression of various factors recorded in the database was done to identify those predicting increased risk for urethroplasty complications. RESULTS: Fistula and glans dehiscence are the two most common complications we encountered after TIP repair. Changes in urethral plate tubularization and barrier layers covering the neourethra resulted in a significant reduction in fistulas after proximal TIP. Changes in glansplasty sutures and use of preoperative testosterone to increase glans size did not reduce likelihood for dehiscence, whereas increasing the extent of glans wings dissection did. Logistic regression analysis confirmed proximal meatal location and reoperation predicted increased complications, but also identified glans width <= 14 mm as an independent risk factor for hypospadias urethroplasty complications. CONCLUSIONS: Systematic, prospective data collection facilitated identification of complications and their risk factors, and provided a means to assess results of modifications made to address them. Limiting the algorithm used for hypospadias repair increases expertise in those techniques used. Reported low surgical volumes for proximal hypospadias repair suggest subspecialization of these cases be carried out so that designated surgeons can achieve sufficient volume to analyze their results and make improvements. PMID- 26515777 TI - Histone H3 lysine 27 trimethylation acts as an epigenetic barrier in porcine nuclear reprogramming. AB - Aberrant epigenetic reprogramming is the main obstacle to the development of somatic cell nuclear transfer (SCNT) embryos and the generation of induced pluripotent stem (iPS) cells, which results in the low reprogramming efficiencies of SCNT and iPS. Histone H3 lysine 27 trimethylation (H3K27me3), as a repressive epigenetic mark, plays important roles in mammalian development and iPS induction. However, the reprogramming of H3K27me3 in pig remains elusive. In this study, we showed that H3K27me3 levels in porcine early cloned embryos were higher than that in IVF embryos. Then GSK126 and GSK-J4, two small molecule inhibitors of H3K27me3 methylase (EZH2) and demethylases (UTX/JMJD3), were used to regulate the H3K27me3 level. The results showed that H3K27me3 level was reduced in cloned embryos after treatment of PEF with 0.75 MUM GSK126 for 48 h, incubation of one cell reconstructed oocytes with 0.1 MUM GSK126 and injection of antibody for EZH2 into oocyte. Meanwhile, the development of the cloned embryos was significantly improved after these treatments. On the contrary, GSK-J4 treatment increased the H3K27me3 level in cloned embryos and decreased the cloned embryonic development. Furthermore, iPS efficiency was both increased after reducing the H3K27me3 level in donor cells and in early reprogramming phase. In summary, our results suggest that H3K27me3 acts as an epigenetic barrier in SCNT and iPS reprogramming, and reduction of H3K27me3 level in donor cells and in early reprogramming phase can enhance both porcine SCNT and iPS efficiency. PMID- 26515778 TI - NUP50 is necessary for the survival of primordial germ cells in mouse embryos. AB - Nucleoporin 50 kDa (NUP50), a component of the nuclear pore complex, is highly expressed in male germ cells, but its role in germ cells is largely unknown. In this study, we analyzed the expression and function of NUP50 during the embryonic development of germ cells using NUP50-deficient mice. NUP50 was expressed in germ cells of both sexes at embryonic day 15.5 (E15.5), E13.5, and E12.5. In addition, NUP50 expression was also detected in primordial germ cells (PGCs) migrating into the genital ridges at E9.5. The gonads of Nup50-/- embryos of both sexes contained few PGCs at both E11.5 and E12.5 and no developing germ cells at E15.5. The migratory PGCs in Nup50-/- embryos at E9.5 showed increased apoptosis but a normal rate of proliferation, resulting in the progressive loss of germ cells at later stages. Taken together, these results suggest that NUP50 plays an essential role in the survival of PGCs during embryonic development. PMID- 26515779 TI - Compound amino acids added in media improved Solanum nigrum L. phytoremediating CD-PAHS contaminated soil. AB - Cd hyperaccumulator Solanum nigrum L. was a promising plant used to simultaneously remediate Cd-PAHs combined pollution soil through its extra accumulation capacity and rhizosphere degradation. This article compared the strengthening remediation role of cysteine (Cys), glycine (Gly) and glutamic acid (Glu) with EDTA and TW80. The results showed that the addition of 0.03 mmol L(-1) Cys, Gly, and Glu didn't significantly impact (p < 0.05) shoot biomass of S. nigrum, but obviously increased Cd concentration. Therefore, Cd capacity (ug pot( 1)) in shoots of S. nigrum was significantly increased (p < 0.05) by 37.7% compared to the control without reagent added. At the meantime, the PAHs degradation ratio in rhizoshpere was increased by 34.5%. Basically, the improving role of Cys, Gly, and Glu was higher than EDTA and TW80. The main reasons of enhanced the accumulation of S. nigrum to Cd might lie in the addition of Cys, Gly, and Glu which reduced pH and increased extractable Cd concentration in rhizosphere and phytochelatines (PCs) concentration in leaves. As for the degradation of PAHs in rhizosphere, increased microorganism number might be play important role. PMID- 26515781 TI - Effects of atmospheric deposition nitrogen flux and its composition on soil solution chemistry from a red soil farmland, southeast China. AB - A detailed study on the solution chemistry of red soil in South China is presented. Data are collected from two simulated column-leaching experiments with an improved setup to evaluate the effects of atmospheric N deposition (ADN) composition and ADN flux on agricultural soil acidification using a (15)N tracer technique and an in situ soil solution sampler. The results show that solution pH values decline regardless of the increase of the NH4(+)/NO3(-) ratio in the ADN composition or ADN flux, while exchangeable Al(3+), Ca(2+), Mg(2+), and K(+) concentrations increase at different soil depths (20, 40, and 60 cm). Compared with the control, ADN (60 kg per ha per year N, NH4(+)/NO3(-) ratio of 2 : 1) decreases solution pH values, increases solution concentrations of NO3(-)-N, Al(3+), Ca(2+) and Mg(2+) at the middle and lower soil depths, and promotes their removal. NH4(+)-N was not detected in red soil solutions of all the three soil layers, which might be attributed to effects of nitrification, absorption and fixation in farmland red soil. Some of the NO3(-)-N concentrations at 40-60 cm soil depth exceed the safe drinking level of 10 mg L(-1), especially when the ADN flux is beyond 60 kg ha(-1) N. These features are critical for understanding the ADN agro-ecological effects, and for future assessment of ecological critical loads of ADN in red soil farmlands. PMID- 26515780 TI - Ethnic differences in the consistency and accuracy of perceived exertion. AB - OBJECTIVES: This study investigated the effect of weight loss and weight regain on accuracy of perceived exertion (APE) in previously overweight African American (AA) and European American (EA) women. METHODS: Formerly overweight women (n = 102, age 20-44 years) completed a weight loss program to achieve BMI < 25 kg/m(2) . Physiological variable of exertion and rating of perceived exertion (RPE, Borg's 6-20 Scale) were recorded during submaximal aerobic exercise prior to, immediately following, and approximately 1 year after weight loss. APE was defined as the composite score of physiological variables (heart rate, ventilation rate, and respiratory exchange ratio) minus RPE. RESULTS: APE was significantly different from the composite score of physiological variables at baseline and at 1-year follow-up for EA women (0.347 +/- 0.88 P < 0.05 and 0.53 +/- 0.92, P < 0.01, respectively) and at 1-year follow-up for AA (-0.37 +/- 1.1, P < 0.01). EA women had lower physiological effort at baseline and 1-year follow up states (-0.24 +/- 0.66 P < 0.05; and, -0.27 +/- 0.84 P < 0.05, respectively). AA women had higher physiological effort, at 1-year follow-up state (0.21 +/- 0.61, P < 0.01). CONCLUSIONS: Physiologic effort and perceived exertion contributed independently to the racial differences in APE, and APE may be an important trait to evaluate before planning an exercise intervention. Am. J. Hum. Biol. 28:398-404, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26515782 TI - Pesticide residues and estrogenic activity in fruit and vegetables sampled from major fresh produce markets in South Africa. AB - Food is likely to be one of the major pathways through which people are exposed to endocrine-disrupting chemicals. With the exception of residual effects, there are concerns that a number of naturally occurring and synthetic chemicals exert adverse effects upon endocrine systems in wildlife and humans. The current study reports selected pesticide concentrations and the total estrogenic activity of fruit and vegetables using the recombinant yeast oestrogen screen (YES) and T47D KBluc reporter gene assays. A total of 53 food samples (27 fruit and 26 vegetables) from Johannesburg and Tshwane fresh produce markets (in South Africa) were analysed. Of these, 17 contained one to three different pesticide residues with concentrations ranging between 0.01 and 0.68 mg kg(-1), whereas in the rest of the samples no residues were detected. All pesticides detected except in one sample were below the maximum residue level (MRL), but others were unauthorised for use in specified fruit and vegetables. Estrogenic activity was detected in 26.4% (14 samples) of the samples tested, and the estradiol equivalents ranged from 0.007 to 2 pg g(-1). Although the estrogenic activity was low, it may contribute to adverse health effects. Continuous monitoring for pesticides in fruit and vegetables is important in view of the unauthorised pesticides detected in produce from South Africa and the endocrine-disrupting chemical activity found. PMID- 26515783 TI - [Cryptococcosis during HIV infection]. AB - Cryptococcosis is a cosmopolitan fungal serious condition due to an encapsulated yeast Cryptococcus neoformans. This is the systemic fungal infection the most common in HIV infection. This yeast is present in the environment and its main entrance in the body is the respiratory tract. Its gravity is linked to its tropism for the central nervous system. It generally affects subjects with severe deficit of cellular immunity and in particular, patients living with HIV. The diagnosis of neuromeningeal cryptococcosis is based on the detection of encapsulated yeasts at microscopic examination of cerebrospinal fluid, the detection of capsular polysaccharide antigen in serum or cerebrospinal fluid, but especially on the culture. A staging is always essential. The prognosis is severe. The control of intracranial hypertension is a major element of prognosis. PMID- 26515784 TI - Template-free synthesis of hierarchical ZnFe2O4 yolk-shell microspheres for high sensitivity acetone sensors. AB - Metal oxides with hierarchical microstructures have attracted tremendous attention with respect to their enhanced gas sensing properties. Herein, we reported the facile synthesis of hierarchical ZnFe2O4 yolk-shell microspheres via a template-free solvothermal strategy and the subsequent annealing and chemical etching process. Electron microscopy images undoubtedly demonstrated that the novel ZnFe2O4 architecture was constructed of a large number of nanosheet subunits with a thickness around 20 nm. As a proof-of-concept demonstration of the function, when evaluated as gas sensing materials, the as-prepared ZnFe2O4 yolk-shell microspheres manifested an extremely high response and a low detection limit to acetone at the operating temperature of 200 degrees C. Significantly, the response to 20 ppm acetone was retained well even after 200 cycles and continuous measurement for 30 days, indicating superior cyclability and long-term stability. PMID- 26515785 TI - Antenatal psychosocial assessment and depression screening in a private hospital. AB - BACKGROUND: It has been recommended that psychosocial assessment (including depression screening) be integrated into routine antenatal care across Australia, but implementation in the private sector has lagged. AIMS: This study aimed to report preliminary outcomes associated with an antenatal psychosocial assessment and depression screening program implemented at an Australian private obstetric hospital setting and to report characteristics and correlates of elevated depression symptoms in this sample. MATERIALS AND METHODS: A total of 993 pregnant women (mean +/- SD gestational age 27.9 +/- 6.7 weeks) participated in a structured psychosocial assessment interview and completed the Edinburgh Postnatal Depression Scale (EPDS). RESULTS: Six per cent of participants scored >=13 on the EPDS. Psychosocial correlates of antenatal depressive symptoms included low income, history of pregnancy termination, poor practical support, lack of confidence and history of depression. Almost 1 in 10 of the total sample was referred for further assessment and clinical support. CONCLUSIONS: The prevalence of clinically significant antenatal depressive symptoms in this sample highlights the importance of antenatal depression screening for all women, including those who choose to access private obstetric care. PMID- 26515786 TI - Cholinergic circuitry functioning in patients with vascular cognitive impairment- no dementia. AB - BACKGROUND: An impairment of central cholinergic activity, as evaluated non invasively by the short-latency afferent inhibition (SAI) of motor responses evoked by transcranial magnetic stimulation (TMS), was observed in patients with Alzheimer's disease (AD) and amnestic Mild Cognitive Impairment. Conversely, the involvement of central cholinergic neurotransmission in vascular dementia (VaD) is still under debate and data on Vascular Cognitive Impairment--No Dementia (VCI ND) at risk for future VaD are lacking. OBJECTIVE: To test for the first time SAI in patients with VCI-ND. METHODS: Single-pulse TMS measures of cortical excitability and SAI were evaluated in 25 VCI-ND patients with subcortical ischemic lesions and 20 age-matched healthy controls. Functional status, neuropsychological tests evaluating frontal lobe abilities, and white matter lesions (WMLs) load were assessed. RESULTS: A significant difference was found between patients and controls for the mean SAI, although this result did not resist after the Bonferroni correction. In the whole group of patients and controls, SAI showed a correlation with worse scores at the Montreal Cognitive Assessment (r = 0.376, p < 0.01). SAI also positively correlated with the total vascular burden (r = 0.345, p < 0.05) but not with the WML severity. CONCLUSIONS: Central cholinergic pathway does not seem to be involved in VCI-ND, and the current results differ from those reported in primary cholinergic forms of dementia, such as AD. SAI might represent a valuable additional tool in the differential diagnosis of the dementing processes and in identifying potential responders to cholinergic agents. PMID- 26515787 TI - Living in a risky world: the onset and ontogeny of an integrated antipredator phenotype in a coral reef fish. AB - Prey individuals with complex life-histories often cannot predict the type of risk environment to which they will be exposed at each of their life stages. Because the level of investment in defences should match local risk conditions, we predict that these individuals should have the ability to modulate the expression of an integrated defensive phenotype, but this switch in expression should occur at key life-history transitions. We manipulated background level of risk in juvenile damselfish for four days following settlement (a key life history transition) or 10 days post-settlement, and measured a suite of physiological and behavioural variables over 2 weeks. We found that settlement stage fish exposed to high-risk conditions displayed behavioural and physiological alterations consistent with high-risk phenotypes, which gave them a survival advantage when exposed to predators. These changes were maintained for at least 2 weeks. The same exposure in post-settlement fish failed to elicit a change in some traits, while the expression of other traits disappeared within a week. Our results are consistent with those expected from phenotypic resonance. Expression of antipredator traits may be masked if individuals are not exposed to certain conditions at key ontogenetic stages. PMID- 26515788 TI - Identification of novel anti-hepatitis C virus agents by a quantitative high throughput screen in a cell-based infection assay. AB - Hepatitis C virus (HCV) poses a major health threat to the world. The recent development of direct-acting antivirals (DAAs) against HCV has markedly improved the response rate of HCV and reduced the side effects in comparison to the interferon-based therapy. Despite this therapeutic advance, there is still a need to develop new inhibitors that target different stages of the HCV life cycle because of various limitations of the current regimens. In this study, we performed a quantitative high throughput screening of the Molecular Libraries Small Molecule Repository (MLSMR) of ~350,000 chemicals for novel HCV inhibitors using our previously developed cell-based HCV infection assay. Following confirmation and structural clustering analysis, we narrowed down to 158 compounds from the initial ~3000 molecules that showed inhibitory activity for further structural and functional analyses. We were able to assign the majority of these compounds to specific stage(s) in the HCV life cycle. Three of them are direct inhibitors of NS3/4A protease. Most of the compounds appear to act on novel targets in HCV life cycle. Four compounds with novel structure and excellent drug-like properties, three targeting HCV entry and one targeting HCV assembly/secretion, were advanced for further development as lead hits. These compounds represent diverse chemotypes that are potential lead compounds for further optimization and may offer promising candidates for the development of novel therapeutics against HCV infection. In addition, they represent novel molecular probes to explore the complex interactions between HCV and the cells. PMID- 26515790 TI - A New Strategy of Lithography Based on Phase Separation of Polymer Blends. AB - Herein, we propose a new strategy of maskless lithographic approach to fabricate micro/nano-porous structures by phase separation of polystyrene (PS)/Polyethylene glycol (PEG) immiscible polymer blend. Its simple process only involves a spin coating of polymer blend followed by a development with deionized water rinse to remove PEG moiety, which provides an extremely facile, low-cost, easily accessible nanofabrication method to obtain the porous structures with wafer scale. By controlling the weight ratio of PS/PEG polymer blend, its concentration and the spin-coating speed, the structural parameters of the porous nanostructure could be effectively tuned. These micro/nano porous structures could be converted into versatile functional nanostructures in combination with follow-up conventional chemical and physical nanofabrication techniques. As demonstrations of perceived potential applications using our developed phase separation lithography, we fabricate wafer-scale pure dielectric (silicon)-based two dimensional nanostructures with high broadband absorption on silicon wafers due to their great light trapping ability, which could be expected for promising applications in the fields of photovoltaic devices and thermal emitters with very good performances, and Ag nanodot arrays which possess a surface enhanced Raman scattering (SERS) enhancement factor up to 1.64 * 10(8) with high uniformity across over an entire wafer. PMID- 26515789 TI - Enterovirus 71 induces autophagy by regulating has-miR-30a expression to promote viral replication. AB - Enterovirus 71 (EV71), the etiological agent of hand-foot-and-mouth disease, has increasingly become a public health challenge around the world. Previous studies reported that EV71 infection can induce autophagic machinery to enhance viral replication in vitro and in vivo, but did not address the underlying mechanisms. Increasing evidence suggests that autophagy, in a virus-specific manner, may function to degrade viruses or facilitate viral replication. In this study, we reported that EV71 infection of human epidermoid carcinoma (Hep2) and African green monkey kidney cells (Vero) induced autophagy, which is beneficial for viral replication. Our investigation of the mechanisms revealed that EV71 infection resulted in the reduction of cellular miR-30a, which led to the inhibition of Beclin-1, a key autophagy-promoting gene that plays important roles at the early phase of autophagosome formation. We provided further evidence that by modulating cellular miR-30a level through either overexpression or inhibition, one can inhibit or promote EV71 replication, respectively, through regulating autophagic activity. PMID- 26515791 TI - Personal Perspectives on Mentoring. PMID- 26515792 TI - Extending the Family of V(4+) S=(1/2) Kagome Antiferromagnets. AB - The ionothermal synthesis, structure, and magnetic susceptibility of a novel inorganic-organic hybrid material, imidazolium vanadium(III,IV) oxyfluoride [C3 H5 N2 ][V9 O6 F24 (H2 O)2 ] (ImVOF) are presented. The structure consists of inorganic vanadium oxyfluoride slabs with kagome layers of V(4+) S=${{ 1/2 }}$ ions separated by a mixed valence layer. These inorganic slabs are intercalated with imidazolium cations. Quinuclidinium (Q) and pyrazinium (Pyz) cations can also be incorporated into the hybrid structure type to give QVOF and PyzVOF analogues, respectively. The highly frustrated topology of the inorganic slabs, along with the quantum nature of the magnetism associated with V(4+) , means that these materials are excellent candidates to host exotic magnetic ground states, such as the highly sought quantum spin liquid. Magnetic susceptibility measurements of all samples suggest an absence of conventional long-range magnetic order down to 2 K despite considerable antiferromagnetic exchange. PMID- 26515793 TI - Impact of registration on clinical trials on infection risk in pediatric acute myeloid leukemia. AB - Little is known about the impact of enrollment on therapeutic clinical trials on adverse event rates. Primary objective was to describe the impact of clinical trial registration on sterile site microbiologically documented infection for children with newly diagnosed acute myeloid leukemia (AML). We conducted a multicenter cohort study that included children aged <=18 years with de novo AML. Primary outcome was microbiologically documented sterile site infection. Infection rates were compared between those registered and not registered on clinical trials. Five hundred seventy-four children with AML were included of which 198 (34.5%) were registered on a therapeutic clinical trial. Overall, 400 (69.7%) had at least one sterile site microbiologically documented infection. In multiple regression, registration on clinical trials was independently associated with a higher risk of microbiologically documented sterile site infection [adjusted odds ratio (OR) 1.24, 95% confidence interval (CI) 1.01-1.53; p = 0.040] and viridans group streptococcal infection (OR 1.46, 95% CI 1.08-1.98; p = 0.015). Registration on trials was not associated with Gram-negative or invasive fungal infections. Children with newly diagnosed AML enrolled on clinical trials have a higher risk of microbiologically documented sterile site infection. This information may impact on supportive care practices in pediatric AML. PMID- 26515794 TI - Human eukaryotic elongation factor 1A forms oligomers through specific cysteine residues. AB - Eukaryotic elongation factor 1A (eEF1A) is a multifunctional protein involved in bundling actin, severing microtubule, activating the phosphoinositol-4 kinase, and recruiting aminoacyl-tRNAs to ribosomes during protein biosynthesis. Although evidence has shown the presence of the isoform eEF1A1 oligomers, the substantial mechanism of the self-association remains unclear. Herein, we found that human eEF1A1 could spontaneously form oligomers. Specifically, mutagenesis screen on cysteine residues demonstrated that Cys(234) was essential for eEF1A1 oligomerization. In addition, we also found that hydrogen peroxide treatment could induce the formation of eEF1A oligomers in cells. By cysteine replacement, eEF1A2 isoform displayed the ability to oligomerize in cells under the oxidative environment. In summary, in this study we characterized eEF1A1 oligomerization and demonstrated that specific cysteine residues are required for this oligomerization activity. PMID- 26515795 TI - Effect of modulation of unfolded protein response pathway on dengue virus infection. AB - The unfolded protein response (UPR) is a cascade of events that helps restoring cellular homeostasis under stressful conditions. It is activated when there is an imbalance in the protein load and protein folding capacity of the endoplasmic reticulum (ER) as a result of an increase in the naive, unfolded, or misfolded protein content of the cell. Dengue virus (DENV) utilizes the host machinery to synthesize viral proteins and replicates in the cell. During DENV infection, up regulation of viral proteins increases the protein pool of the cell, resulting in the induction of UPR pathway. In this study, we have tried to understand the consequence of UPR induction during DENV infection in human monocytic cells. To fulfill this objective, we have used VER-155008 (VER), a known inhibitor of the 78 kDa glucose-regulated protein (GRP78), which is the master regulator of the UPR pathway. After VER treatment, cells were infected with DENV, and the induction of the UPR elements and their downstream activation was studied by western blotting and RT-PCR analysis. Interestingly, inhibition of GRP78 via VER treatment led to the decreased expression of DENV envelope protein through the activation of the UPR elements, protein kinase-like ER resident kinase, activating transcription factor 6, and inositol-requiring enzyme 1 (IRE1), and then led to the activation of innate immune factors such as double-stranded RNA activated protein kinase (PKR), interferon regulated factor 3 (IRF3), nuclear factor-kappaB (NF-kappaB) and interleukin 1beta (IL-1beta). This strategy may be used to decrease viral infection transiently. Thus UPR elements could be important therapeutic targets for decreasing DENV multiplication. PMID- 26515796 TI - De novo assembly and characterization of the Welsh onion (Allium fistulosum L.) transcriptome using Illumina technology. AB - Welsh onion (Allium fistulosum L.) has long been cultivated as a vegetable and spice for its flavor and aroma. However, transcriptomic and genomic data for A. fistulosum remain scarce. The goal of this study was to generate transcript sequences for functional genomic analyses, and identify genes potentially involved in sulfur, selenium, and vitamin metabolism. In total, 53,378,674 high quality reads were generated, and de novo assembly resulted in 103,286 contigs and 53,837 unigenes. The average unigene length was 619 bp with an N50 of 832 bp. Similarity searches revealed that 36,155 sequences were similar to those of known proteins in public databases. Of these, 35,250 unigenes sequences were significantly similar to sequences in the NCBI non-redundant protein database and 22,804 were annotated in the Swiss-Prot database. Additionally, 13,125 and 26,660 unigenes were annotated in the Cluster of Orthologous Group and Gene Ontology databases, respectively. A total of 20,680 unigenes were classified into 128 pathways via functional annotation against the Kyoto Encyclopedia of Genes and Genomes pathway database. Key enzymes involved in sulfur and selenium metabolism were also identified. Additionally, our transcriptome revealed a number of unigenes encoding important enzymes involved in vitamin metabolism. We also identified 2014 simple sequence repeats in 1892 unigenes. This transcriptome analysis provides valuable information to further our understanding of the molecular mechanisms regulating the biosynthesis of organic sulfur compounds. The detected simple sequence repeats may facilitate marker-assisted selection in Welsh onion breeding experiments. PMID- 26515797 TI - Developing an App for College Women in Abusive Same-Sex Relationships and Their Friends. AB - Young women experiencing dating violence in same-sex relationships face significant barriers to help for safety planning. Therefore, our team developed a tailored smartphone safety decision aid app for dating violence survivors and their peers. College women survivors of same-sex dating violence, peers, and college staff reviewed the app, identifying users' barriers to information, resources, and services and key strategies for dissemination, inclusiveness, and safety for the app. Findings support the use of the app to assist college women experiencing same-sex dating violence and peers to connect with resources and develop tailored safety plans to reduce violence and increase their safety. PMID- 26515799 TI - An end-to-end urethral anastomosis after inguinal tunnelization: a new technique in a dog. AB - An 8-year-old male dog was presented with a peri-urethral intrapelvic mass with the characteristics of a sarcoma on computed tomography and cytology evaluation. A two-step procedure leading to a permanent urinary diversion was performed. During the same procedure, the caudal pelvic urethra and mass were resected and an extrapelvic anastomosis of the pelvic portion of the urethra to its penile portion was performed after passage of the pelvic urethra through the inguinal canal. The procedure successfully produced a tension-free end-to-end urethral anastomosis and no complications were observed during the postoperative period. Histologically, the lesion was reported as a narrowly excised liposarcoma. A 4 week course of curative intent of radiotherapy was initiated 2 weeks after surgery. Eight months later, the dog was free of clinical signs. PMID- 26515798 TI - Design of an Inflammation-Sensitive Polyelectrolyte-Based Topical Drug Delivery System for Arthritis. AB - The most successful treatment strategy for arthritis is intra-articular injections that are costly and have reduced patient compliance. The purpose of the current study was to develop an inflammation-sensitive system for topical drug administration. Multi-macromolecular alginate-hyaluronic acid-chitosan (A-H C) polyelectrolyte complex nanoparticles, loaded with indomethacin were developed employing pre-gel and post-gel techniques in the presence of dodecyl-L pyroglutamate (DLP). In addition to in vitro studies, in silico simulations were performed to affirm and associate the molecular interactions inherent to the formulation of core all-natural multi-component biopolymeric architectures composed of an anionic (alginate), a cationic (chitosan), and an amphi-ionic polyelectrolytic (hyaluronic acid) macromolecule. The results demonstrated that DLP significantly influenced the size of the synthesized nanoparticles. Drug content analysis revealed higher encapsulation efficiency (77.3%) in the presence of DLP, irrespective of the techniques used. Moreover, in vitro drug release studies showed that indomethacin release from the nanosystem was significantly improved (98%) in Fenton's reagent. Drug permeation across a cellulose membrane using a Franz diffusion cell system showed an initial surge flux (0.125 mg/cm( 2)/h), followed by sustained release of indomethacin for the post-gel nanoparticles revealing its effective skin permeation efficiency. In conclusion, the study presents novel nanoparticles which could effectively encapsulate and deliver hydrophobic drugs to the target site, particularly for arthritis. PMID- 26515800 TI - Quantitative Assessment of Free Flap Viability with CEUS Using an Integrated Perfusion Software. AB - PURPOSE: New treatment strategies in oncology and trauma surgery lead to an increasing demand for soft tissue reconstruction with free tissue transfer. In previous studies, CEUS was proven to detect early flap failure. The aim of this study was to detect and quantify vascular disturbances after free flap transplantation using a fast integrated perfusion software tool. MATERIAL AND METHODS: From 2011 to 2013, 33 patients were examined by one experienced radiologist using CEUS after a bolus injection of 1-2.4 ml of SonoVue((r)). Flap perfusion was analysed qualitatively regarding contrast defects or delayed wash in. Additionally, an integrated semi-quantitative analysis using time-intensity curve analysis (TIC) was performed. TIC analysis of the transplant was conducted on a centimetre-by-centimetre basis up to a penetration depth of 4 cm. The 2 perfusion parameters "Time to PEAK" and "Area under the Curve" were compared in patients without complications vs. patients with minor complications or complete flap loss to figure out significant differences. TtoPk is given in seconds (s) and Area is given in relative units (rU) Results: A regular postoperative process was observed in 26 (79%) patients. In contrast, 5 (15%) patients with partial superficial flap necrosis, 1 patient (3%) with complete flap loss and 1 patient (3%) with haematoma were observed. TtoPk revealed no significant differences, whereas Area revealed significantly lower perfusion values in the corresponding areas in patients with complications. The critical threshold for sufficient flap perfusion was set below 150 rU. CONCLUSION: In conclusion, CEUS is a mobile and cost-effective opportunity to quantify tissue perfusion and can even be used almost without any restrictions in multi-morbid patients with renal and hepatic failure. PMID- 26515801 TI - [In Vitro and In Vivo Biocompatibility of a Novel, 3-Dimensional Cellulose Matrix Structure]. AB - BACKGROUND: Biological and physical characteristics of matrices are one essential factor in creating bioartificial tissue. In this study, a new 3-dimensional cellulose matrix (Xellulin((r))) was tested in terms of biocompatibility and applicability for tissue engineering in vitro and in vivo. MATERIALS AND METHODS: The tested matrix Xellulin((r)) is a natural hydrological gel-matrix containing bacterial cellulose and water. To evaluate the cell biocompatibilty, cell adherence and proliferation characteristics in vitro, the matrix was cultured with human fibroblasts. Further in vivo studies were carried out by transplanting preadipocytes of 4- to 6-week-old Wistar rats with 3 different conditions: a) Xellulin((r)) including 500 000 preadipocytes subcutaneous, b) Xellulin((r)) including 500 000 preadipocytes within an in vivo bioreactor chamber, c) Xellulin((r)) without cells subcutaneous as control. After explantation on day 14 histomorphological and immunohistochemical evaluations were performed. RESULTS: In vitro study revealed an excellent biocompatibility with good cell adherence of the fibroblasts on the matrix and evidence of cell proliferation and creation of a 3-dimensional cell network. In vivo neocapillarisation could be shown in all groups with evidence of erythrocytes (H/E staining) and endothelial vascular cells (RECA-1-staining). A significantly higher vascular density was shown in vascularised bioreactor group (18.4 vessels/100 000 um(2) (group b) vs. 8.1 (group a), p<0.05). Cell density was the highest in the vascularised group, but without significant values. No immunogenic reaction to the matrix was noticed. DISCUSSION: The promising in vitro results concerning cell adherence and proliferation on the tested matrix could be confirmed in vivo with an evidence of 3-dimensional neocapillarisation. Cell survival was higher in the vascularised group, but without significance. Long-term tests (28-42 days) need to be carried out to evaluate long-term cell survival and the matrix stability. Furthermore, studies concerning the implementation of the matrix within anatomic structures as well as long-term biocompatibility are needed. PMID- 26515802 TI - [Evaluation of Cutaneous Microcirculation at the Dorsum of the Hand within Different Age Groups - Implications for Wound Healing in Hand Surgery?]. AB - BACKGROUND: Cutaneous microcirculation has shown to play a key role in wound healing. Although healing disorders are still one of the most common complications in hand surgery, there still exists a lack of scientific research on possible age-related changes in cutaneous microcirculation at the dorsum of hand. HYPOTHESIS: Cutaneous microcirculation at the dorsum of the hand differs significantly between different age groups. METHODS: 53 healthy subjects were divided into 2 groups by age (Group A:<40 years, n=31 vs. Group B>=40 years, n=22). All subjects underwent measurement of the microcirculation at the dorsum of the hand with combined laser-Doppler and photo spectrometry. RESULTS: Cutaneous oxygen saturation was significantly higher in Group A than in Group B (A: 64.7+/-9.9% vs. B: 58.3+/-12.6%; p=0,044). In contrast, blood flow velocity was significantly higher in Group B (A: 43+/-19.6 AU vs. B: 56.7+/-21.1 AU; p=0.019). CONCLUSION: The hypothesis of this study was confirmed. This is the first study to show significant differences of cutaneous microcirculation at the dorsum of the hand within different age groups. Further clinical trials are needed in order to examine if delayed wound healing can be correlated to impaired cutaneous microcirculation at the dorsum of the hand. PMID- 26515803 TI - [What is allowed? - Aesthetic Surgery in Children and Adolescents]. AB - More and more children, and even more so adolescents, undergo procedures pertaining to the category of aesthetic surgery and mainly aiming to improve the patient's physical appearance. There is a broad spectrum of possible operations ranging from purely cosmetic procedures to operations with a medical indication. PMID- 26515804 TI - Nanoarchitectures for Mesoporous Metals. AB - The field of mesoporous metal nanoarchitectonics offers several advantages which cannot be found elsewhere. These materials have been showcasing impressive enhancements of their electrochemical properties for further implementation, compared to their micro- and macroporous counterparts. Since the last few decades, various methods have been developed to achieve narrow pore size distribution with a tunable porosity and particle morphology. While hard templates offer a reliable and intuitive approach to synthesize mesoporous metals, the complexity of the technique and the use of harmful chemicals pushed several research groups to focus in other directions. For example, soft templates (e.g., lyotropic crystals, micelles assemblies) and solution phase methods (requiring to control reduction reactions) offer more and more possibilities in terms of available compositions and morphologies. Indeed, various metal (Pt, Pd, Au, Ru, etc.) can now be synthesized as dendritic, core@shell, hollow or polyhedral nanoparticles, with single- or multicomponents, alloyed or not, with unprecedented electrochemical activity. PMID- 26515805 TI - Do intravascular hypo- and hypervolaemia result in changes in central blood volumes? AB - BACKGROUND: Hypovolaemia is generally believed to induce centralization of blood volume. Therefore, we evaluated whether induced hypo- and hypervolaemia result in changes in central blood volumes (pulmonary blood volume (PBV), intrathoracic blood volume (ITBV)) and we explored the effects on the distribution between these central blood volumes and circulating blood volume (Vd circ). METHODS: Six anaesthetized, spontaneously breathing Foxhound dogs underwent random blood volume alterations in steps of 150 ml (mild) to 450 ml (moderate), either by haemorrhage, retransfusion of blood, or colloid infusion. PBV, ITBV and Vd circ were measured using (transpulmonary) dye dilution. The PBV/Vd circ ratio and the ITBV/Vd circ ratio were used as an assessment of blood volume distribution. RESULTS: 68 blood volume alterations resulted in changes in Vdcirc ranging from 33 to +31%. PBV and ITBV decreased during mild and moderate haemorrhage, while during retransfusion, PBV and ITBV increased during moderate hypervolaemia only. The PBV/Vd circ ratio remained constant during all stages of hypo- and hypervolaemia (mean values between 0.20-0.22). This was also true for the ITBV/Vd circ ratio, which remained between 0.31 and 0.32, except for moderate hypervolaemia, where it increased slightly to 0.33 (0.02), P<0.05. CONCLUSIONS: Mild to moderate blood volume alterations result in changes of Vd circ, PBV and ITBV. The ratio between the central blood volumes and Vd circ generally remained unaltered. Therefore, it could be suggested that in anaesthetized spontaneously breathing dogs, the cardiovascular system maintains the distribution of blood between central and circulating blood volume. PMID- 26515806 TI - Disagreement between cardiac output measurement devices: which device is the gold standard? PMID- 26515807 TI - Hetero-bimetallic metal-organic polyhedra. AB - Porous metal-organic polyhedra (MOPs), constructed from heterometallic Pd(II) M(II) (M = Cu, Ni, Zn) paddlewheel nodes and 5-tert-butyl-1,3 benzenedicarboxylate organic links, were prepared in which the Pd(II) ions preferentially line the inner surface of the cage molecules. Careful activation produces co-ordinatively unsaturated 3d transition metal sites on the external MOP surfaces giving rise to H2 adsorption enthalpies in excess of -12 kJ mol(-1). PMID- 26515808 TI - Acceptance of clickers in a large multimodal biochemistry class as determined by student evaluations of teaching: Are they just an annoying distraction for distance students? AB - A student response system (clickers) was introduced into a second year introductory biochemistry class to improve student engagement and performance. The class was delivered in both internal and distance education (DE) modes, with the DE students receiving recordings of the lectures (including clicker activities). However, there was concern over the use of clickers in internal classes as it may be alienating or distracting to DE students while reviewing the recordings of these lectures. In order to examine students' attitudes toward clickers, closed- and open-ended questions were examined in the student evaluations of teaching (SET). Understanding attitudes of internal and DE students is especially important as differences may exist between these groups due to the different learning environments they experience. Approximately 45% of students completed the surveys, of which 88%-91% provided written comments. Of the written comments, 18% of DE students and 22% of internal students provided unsolicited comments about clickers. Interestingly, no difference was observed in the themes identified in the comments between cohorts. The key themes included 1) clickers were beneficial for learning (and increased knowledge), 2) clickers were engaging/fun, and 3) clickers could have been used more widely. Overall, based on this study, it was believed that clicker usage was not seen as negative activity by DE students and it was worth continuing to use clickers in teaching the large multimodal class studied here. However, there is a need to investigate the potential of new and emerging technologies to provide more interactive experiences for DE students. PMID- 26515809 TI - The Thermodynamics of Marine Biogeochemical Cycles: Lotka Revisited. AB - Nearly 100 years ago, Alfred Lotka published two short but insightful papers describing how ecosystems may organize. Principally, Lotka argued that ecosystems will grow in size and that their cycles will spin faster via predation and nutrient recycling so as to capture all available energy, and that evolution and natural selection are the mechanisms by which this occurs and progresses. Lotka's ideas have often been associated with the maximum power principle, but they are more consistent with recent developments in nonequilibrium thermodynamics, which assert that complex systems will organize toward maximum entropy production (MEP). In this review, we explore Lotka's hypothesis within the context of the MEP principle, as well as how this principle can be used to improve marine biogeochemistry models. We need to develop the equivalent of a climate model, as opposed to a weather model, to understand marine biogeochemistry on longer timescales, and adoption of the MEP principle can help create such models. PMID- 26515810 TI - Ecological Insights from Pelagic Habitats Acquired Using Active Acoustic Techniques. AB - Marine pelagic ecosystems present fascinating opportunities for ecological investigation but pose important methodological challenges for sampling. Active acoustic techniques involve producing sound and receiving signals from organisms and other water column sources, offering the benefit of high spatial and temporal resolution and, via integration into different platforms, the ability to make measurements spanning a range of spatial and temporal scales. As a consequence, a variety of questions concerning the ecology of pelagic systems lend themselves to active acoustics, ranging from organism-level investigations and physiological responses to the environment to ecosystem-level studies and climate. As technologies and data analysis methods have matured, the use of acoustics in ecological studies has grown rapidly. We explore the continued role of active acoustics in addressing questions concerning life in the ocean, highlight creative applications to key ecological themes ranging from physiology and behavior to biogeography and climate, and discuss emerging avenues where acoustics can help determine how pelagic ecosystems function. PMID- 26515811 TI - Changes in Ocean Heat, Carbon Content, and Ventilation: A Review of the First Decade of GO-SHIP Global Repeat Hydrography. AB - Global ship-based programs, with highly accurate, full water column physical and biogeochemical observations repeated decadally since the 1970s, provide a crucial resource for documenting ocean change. The ocean, a central component of Earth's climate system, is taking up most of Earth's excess anthropogenic heat, with about 19% of this excess in the abyssal ocean beneath 2,000 m, dominated by Southern Ocean warming. The ocean also has taken up about 27% of anthropogenic carbon, resulting in acidification of the upper ocean. Increased stratification has resulted in a decline in oxygen and increase in nutrients in the Northern Hemisphere thermocline and an expansion of tropical oxygen minimum zones. Southern Hemisphere thermocline oxygen increased in the 2000s owing to stronger wind forcing and ventilation. The most recent decade of global hydrography has mapped dissolved organic carbon, a large, bioactive reservoir, for the first time and quantified its contribution to export production (~20%) and deep-ocean oxygen utilization. Ship-based measurements also show that vertical diffusivity increases from a minimum in the thermocline to a maximum within the bottom 1,500 m, shifting our physical paradigm of the ocean's overturning circulation. PMID- 26515812 TI - Measurement of geometric dephasing using a superconducting qubit. AB - A quantum system interacting with its environment is subject to dephasing, which ultimately destroys the information it holds. Here we use a superconducting qubit to experimentally show that this dephasing has both dynamic and geometric origins. It is found that geometric dephasing, which is present even in the adiabatic limit and when no geometric phase is acquired, can either reduce or restore coherence depending on the orientation of the path the qubit traces out in its projective Hilbert space. It accompanies the evolution of any system in Hilbert space subjected to noise. PMID- 26515813 TI - Overexpression of miR-664 is associated with enhanced osteosarcoma cell migration and invasion ability via targeting SOX7. AB - Osteosarcoma (OS) is one of the most common types of primary sarcoma of bone in children and young adults, and the long-term prognosis for OS patients still remains dismal due to the lack of effective early diagnostic biomarkers. Identifying sensitive and specific biomarkers in carcinogenesis may improve diagnostic and therapeutic strategies for this malignancy. The expression of miR 664 in osteosarcoma cell lines and osteosarcoma tissues was examined using real time PCR. The effects of miR-664 on osteosarcoma cell migration and invasion were evaluated by cell invasion assays, migration assays, and three-dimension spheroid invasion assay. The effect of miR-664 on SOX7 was determined by luciferase assays and Western blot assay. The clinical association between miR-664 and SOX7 was analyzed by real-time PCR and Western blot assay. Expression of miR-664 was found to be upregulated in OS cell lines and tissues. Overexpression of miR-664 was associated with increased migration and invasive abilities of OS cells in vitro, whereas downregulation of miR-664 appeared to inhibit their migration and invasive potential. Furthermore, using biological approaches, we showed that miR 664 directly targeted and suppressed expression of the tumor suppressor SOX7. Additionally, the expression of miR-664 was negatively correlated with SOX7 expression in OS clinical tissues. Our findings suggest that miR-664 functions as an oncogene miRNA and has an important role in promoting human OS cell invasion and migration by suppressing SOX7 expression. Consequently, miR-664 may have potential as a novel diagnostic and therapeutic target of osteosarcoma. PMID- 26515814 TI - Reasons for continuous sedation until death in cancer patients: a qualitative interview study. AB - End-of-life sedation, though increasingly prevalent and widespread, remains a highly debated medical practice in the context of palliative medicine. This qualitative study aims to look more specifically at how health care workers justify their use of continuous sedation until death and which factors they report as playing a part in the decision-making process. In-depth interviews were held with 28 physicians and 22 nurses of 27 cancer patients in Belgium who had received continuous sedation until death in hospitals, palliative care units or at home. Our findings indicate that medical decision-making for continuous sedation is not only based on clinical indications but also related to morally complex issues such as the social context and the personal characteristics and preferences of individual patient and their relatives. The complex role of non clinical factors in palliative sedation decision-making needs to be further studied to assess which medically or ethically relevant arguments are underlying daily clinical practice. Finally, our findings suggest that in some cases continuous sedation was resorted to as an alternative option at the end of life when euthanasia, a legally regulated option in Belgium, was no longer practically possible. PMID- 26515815 TI - Time and chronic illness: a narrative review. AB - PURPOSE: This narrative review is concerned with the ways in which the relationships between time and chronic illnesses have been chartered in recent literature. It aims to identify types of time (referred to here as temporal structures) most commonly reported in chronic illness literature and to assess their bearing on people's lived experiences. METHODS: Literature searches of three electronic databases (Google Scholar, MEDLINE, and PubMed) were carried out in November 2014 of articles published between 1970 and 2013 using the following search terms (and derivatives): chronic illness AND time AND (patient OR carer). The review followed four procedural steps: (a) comprehensive search, (b) temporal structure appraisal, (c) synthesis of findings, and (d) critical appraisal. RESULTS: Forty studies met the inclusion criteria and were included for review. Four types of called temporal structures had a strong presence in the literature: calendar and clocked time, biographical time, past-present-future time, and inner time and rhythms. The first three temporal structures are largely understood socially, and the fourth is predominantly understood in and through the body. Several studies reported more than one temporal structure as informing people's chronic illness experiences. A wide array of chronic illnesses were represented in these studies. Few studies reported on the experiences of people with multi morbid chronic illnesses. CONCLUSION: Chronic illness induces new relationships to time. Drawing on Hyden (Sociol Health Illn 19(1):48-69, 1997), it is suggested that "narrative" storytelling--as a temporally informed analytic device---might prove effective for reconciling the tensions emergent from new and multiple relationships to time that chronic and multiple illnesses create. Opportunities exist for healthcare practitioners and health services to offer patients illness support that is cognisant of their relationships to time. PMID- 26515816 TI - The upper-hemifield advantage for masked face processing: Not just an attentional bias. AB - Recent evidence suggests that face processing may be more robust in the upper visual field (UVF) than in the lower visual field (LVF). We asked whether this UVF advantage is due to an upward bias in participants' visuospatial attention. Participants classified the sex of a UVF or LVF target face that was preceded by a congruent or incongruent masked prime face. We manipulated spatial attention within subjects by varying the predictability of target location across sessions (UVF:LVF ratio of 50:50 on Day 1 and 20:80 on Day 2). When target location was unpredictable, priming emerged earlier in the UVF (~165 ms) than the LVF (~195 ms). This UVF advantage was reversed when targets were more likely to be presented in the LVF. Here priming arose earlier for LVF targets (~53 ms) than UVF targets (~165 ms). Critically, however, UVF primes were processed to the same degree regardless of whether spatial attention was diffuse (Day 1) or deployed elsewhere (Day 2). We conclude that, while voluntarily directed spatial attention is sufficient to modulate the processing of masked faces in the LVF, it is not sufficient to explain the UVF advantage for masked face processing. PMID- 26515817 TI - Spatial priming in ecologically relevant reference frames. AB - In recent years, researchers have observed many phenomena demonstrating how the visual system exploits spatial regularities in the environment in order to benefit behavior. In this paper, we question whether spatial priming can be considered one such phenomenon. Spatial priming is defined as a response time facilitation to a visual search target when its spatial position has been repeated in recent trials (Maljkovic & Nakayama, 1996, Perception & Psychophysics, 58, 977-991). Does this priming serve a behaviorally adaptive role or is it merely a byproduct of ongoing visual processing? Critically, an adaptive priming mechanism must actively transform visual inputs from native retinotopic (eye-centered) coordinates into ecologically relevant coordinates, e.g., spatiotopic (world-centered) and/or object-centered. In Experiment 1, we tested this hypothesis by having participants move their eyes between trials, which dissociated retinotopic and spatiotopic frames of reference. Results showed only weak retinotopic priming, but robust spatiotopic priming. The second experiment again had participants move their eyes between trials but also manipulated the placement of a grouped array of display objects from trial to trial. This allowed us to measure not just retinotopic and spatiotopic priming, but object-centered priming as well. Results from this experiment did not yield retinotopic priming but showed robust spatiotopic and object-centered priming. These findings demonstrate that spatial priming operates within ecologically relevant coordinate systems, and the findings support the notion that spatial priming serves an adaptive role in human behavior. PMID- 26515818 TI - EMDomics: a robust and powerful method for the identification of genes differentially expressed between heterogeneous classes. AB - MOTIVATION: A major goal of biomedical research is to identify molecular features associated with a biological or clinical class of interest. Differential expression analysis has long been used for this purpose; however, conventional methods perform poorly when applied to data with high within class heterogeneity. RESULTS: To address this challenge, we developed EMDomics, a new method that uses the Earth mover's distance to measure the overall difference between the distributions of a gene's expression in two classes of samples and uses permutations to obtain q-values for each gene. We applied EMDomics to the challenging problem of identifying genes associated with drug resistance in ovarian cancer. We also used simulated data to evaluate the performance of EMDomics, in terms of sensitivity and specificity for identifying differentially expressed gene in classes with high within class heterogeneity. In both the simulated and real biological data, EMDomics outperformed competing approaches for the identification of differentially expressed genes, and EMDomics was significantly more powerful than conventional methods for the identification of drug resistance-associated gene sets. EMDomics represents a new approach for the identification of genes differentially expressed between heterogeneous classes and has utility in a wide range of complex biomedical conditions in which sample classes show within class heterogeneity. AVAILABILITY AND IMPLEMENTATION: The R package is available at http://www.bioconductor.org/packages/release/bioc/html/EMDomics.html. PMID- 26515819 TI - Gapped sequence alignment using artificial neural networks: application to the MHC class I system. AB - MOTIVATION: Many biological processes are guided by receptor interactions with linear ligands of variable length. One such receptor is the MHC class I molecule. The length preferences vary depending on the MHC allele, but are generally limited to peptides of length 8-11 amino acids. On this relatively simple system, we developed a sequence alignment method based on artificial neural networks that allows insertions and deletions in the alignment. RESULTS: We show that prediction methods based on alignments that include insertions and deletions have significantly higher performance than methods trained on peptides of single lengths. Also, we illustrate how the location of deletions can aid the interpretation of the modes of binding of the peptide-MHC, as in the case of long peptides bulging out of the MHC groove or protruding at either terminus. Finally, we demonstrate that the method can learn the length profile of different MHC molecules, and quantified the reduction of the experimental effort required to identify potential epitopes using our prediction algorithm. AVAILABILITY AND IMPLEMENTATION: The NetMHC-4.0 method for the prediction of peptide-MHC class I binding affinity using gapped sequence alignment is publicly available at: http://www.cbs.dtu.dk/services/NetMHC-4.0. PMID- 26515820 TI - MaxBin 2.0: an automated binning algorithm to recover genomes from multiple metagenomic datasets. AB - The recovery of genomes from metagenomic datasets is a critical step to defining the functional roles of the underlying uncultivated populations. We previously developed MaxBin, an automated binning approach for high-throughput recovery of microbial genomes from metagenomes. Here we present an expanded binning algorithm, MaxBin 2.0, which recovers genomes from co-assembly of a collection of metagenomic datasets. Tests on simulated datasets revealed that MaxBin 2.0 is highly accurate in recovering individual genomes, and the application of MaxBin 2.0 to several metagenomes from environmental samples demonstrated that it could achieve two complementary goals: recovering more bacterial genomes compared to binning a single sample as well as comparing the microbial community composition between different sampling environments. AVAILABILITY AND IMPLEMENTATION: MaxBin 2.0 is freely available at http://sourceforge.net/projects/maxbin/ under BSD license. PMID- 26515821 TI - tcsBU: a tool to extend TCS network layout and visualization. AB - MOTIVATION: TCS is a widely used haplotype network reconstruction software, but lacks the capability of overlapping genetic with geographic structure, which is often a first step in phylogeographic analysis. RESULTS: tcsBU is a web-based program that extends the capabilities of TCS, by implementing haplotype classification into an arbitrary user-defined scheme, which is displayed as pie chart like graphs embedded into the network. Taking advantage of modern graphic libraries, tcsBU also improves the speed at which the final network layout is reached. Networks can be saved as a Scalable Vector Graphics format. AVAILABILITY AND IMPLEMENTATION: tcsBU is available on-line at http://cibio.up.pt/software/tcsBU/. The source code is freely available from https://github.com/sairum/tcsbu/ under a standard MIT license. PMID- 26515822 TI - PRIMUS: improving pedigree reconstruction using mitochondrial and Y haplotypes. AB - PRIMUS is a pedigree reconstruction algorithm that uses estimates of genome-wide identity by descent to reconstruct pedigrees consistent with observed genetic data. However, when genetic data for individuals within a pedigree are missing, often multiple pedigrees can be reconstructed that fit the data. We report a major expansion of PRIMUS that uses mitochondrial (mtDNA) and non-recombining Y chromosome (NRY) haplotypes to eliminate many pedigree structures that are inconsistent with the genetic data. We demonstrate that discordances in mtDNA and NRY haplotypes substantially reduce the number of potential pedigrees, and often lead to the identification of the correct pedigree. AVAILABILITY AND IMPLEMENTATION: We have implemented PRIMUS updates in PERL and it is available at primus.gs.washington.edu. PMID- 26515823 TI - SylvX: a viewer for phylogenetic tree reconciliations. AB - MOTIVATION: Reconciliation methods aim at recovering the evolutionary processes that shaped the history of a given gene family including events such as duplications, transfers and losses by comparing the discrepancies between the topologies of the associated gene and species trees. These methods are also used in the framework of host/parasite studies to recover co-diversification scenarios including co-speciation events, host-switches and extinctions. These evolutionary processes can be graphically represented as nested trees. These interconnected graphs can be visually messy and hard to interpret, and despite the fact that reconciliations are increasingly used, there is a shortage of tools dedicated to their graphical management. Here we present SylvX, a reconciliation viewer which implements classical phylogenetic graphic operators (swapping, highlighting, etc.) and new methods to ease interpretation and comparison of reconciliations (multiple maps, moving, shrinking sub-reconciliations). AVAILABILITY AND IMPLEMENTATION: SylvX is an open source, cross-platform, standalone editor available for Windows and Unix-like systems including OSX. It is publicly available at www.sylvx.org. PMID- 26515824 TI - SeqSIMLA2_exact: simulate multiple disease sites in large pedigrees with given disease status for diseases with low prevalence. AB - It is difficult for current simulation tools to simulate sequence data in a pre specified pedigree structure and pre-specified affection status. Previously, we developed a flexible tool, SeqSIMLA2, for simulating sequence data in either unrelated case-control or family samples with different disease and quantitative trait models. Here we extended the tool to efficiently simulate sequences with multiple disease sites in large pedigrees with a given disease status for each pedigree member, assuming that the disease prevalence is low. AVAILABILITY AND IMPLEMENTATION: SeqSIMLA2_exact is implemented with C++ and is available at http://seqsimla.sourceforge.net. PMID- 26515825 TI - DelPhiPKa web server: predicting pKa of proteins, RNAs and DNAs. AB - A new pKa prediction web server is released, which implements DelPhi Gaussian dielectric function to calculate electrostatic potentials generated by charges of biomolecules. Topology parameters are extended to include atomic information of nucleotides of RNA and DNA, which extends the capability of pKa calculations beyond proteins. The web server allows the end-user to protonate the biomolecule at particular pH based on calculated pKa values and provides the downloadable file in PQR format. Several tests are performed to benchmark the accuracy and speed of the protocol. IMPLEMENTATION: The web server follows a client-server architecture built on PHP and HTML and utilizes DelPhiPKa program. The computation is performed on the Palmetto supercomputer cluster and results/download links are given back to the end-user via http protocol. The web server takes advantage of MPI parallel implementation in DelPhiPKa and can run a single job on up to 24 CPUs. AVAILABILITY AND IMPLEMENTATION: The DelPhiPKa web server is available at http://compbio.clemson.edu/pka_webserver. PMID- 26515826 TI - Protael: protein data visualization library for the web. AB - Protael is a JavaScript library for creating interactive visualizations of biological sequences and various associated data. It allows users to generate high-quality vector graphics (SVG) and integrate it into web pages. AVAILABILITY AND IMPLEMENTATION: Protael distribution, documentation and examples are freely available at http://protael.org; source code is hosted at https://github.com/sanshu/protaeljs. PMID- 26515827 TI - ERRATUM. PMID- 26515829 TI - Immune-mediated statin myopathy. AB - Statin-induced necrotizing autoimmune myopathy (SINAM) is associated with a unique clinical 5 phenotype of severe proximal muscle weakness during or after exposure to statins in patients with high creatine kinase (CK) levels. Electromyography (EMG) and muscle biopsy reveal features of a necrotizing myopathy and the anti-HMGCR autoantibody is frequently detected. Treatment requires a combination of statin discontinuation as well as immunomodulatory or immunosuppressive therapy. HLA typing (HLADRB1*1101) is strongly associated with anti-10 HMGCR autoantibody positivity in statin-exposed patients. It is well documented that statin triggers autoimmune disease in those with a genetic susceptibility. With the commercial availability of an accurate ELISA test, the natural history of the disease and its phenotypic features are becoming increasingly understood. PMID- 26515831 TI - Avoidance of Left Atrial Wall Puncture with Marked Atrial Septal Tenting during Attempted Septal Puncture for the Pulmonary Vein Cryoballoon Ablation Procedure. PMID- 26515832 TI - Guidelines for bath PUVA, bathing suit PUVA and soak PUVA. AB - BACKGROUND: The aim of these guidelines is to encourage dermatologists to use bath psoralen plus ultraviolet A (PUVA), bathing suit PUVA and soak PUVA in the treatment of psoriasis vulgaris and other conditions. METHODS: Evidence was collected using searches of the PubMed, MEDLINE and COCHRANE databases using the keywords "bath PUVA," "soak PUVA," "bathing suit PUVA" and "turban PUVA." Only publications in English were reviewed. RESULTS: One hundred and thirty-eight studies were evaluated, 57 of which fulfilled the criteria for inclusion. CONCLUSIONS: Both bath PUVA and bathing suit PUVA are very effective and safe treatments for generalized stable plaque psoriasis (strength of recommendation, A). Soak PUVA is very effective in the treatment of both palmoplantar psoriasis and chronic palmoplantar eczema (strength of recommendation, A). PMID- 26515833 TI - Sun-related behaviors among individuals previously diagnosed with non-melanoma skin cancer. AB - Compared to the general population, the risk of developing non-melanoma skin cancer is considerably higher among individuals with a previous history of this condition. Protection from ultraviolet (UV) radiation is the primary evidence based approach for minimizing this risk. This review was aimed to assess the prevalence of sun-safe behaviors in non-melanoma skin cancer survivors. Searches were conducted in six electronic databases including PubMed, Psyclnfo, CINAHL, EMBASE, ERIC and Science Direct. A narrative approach was adopted to synthesize the data. The findings demonstrated that respondents do not protect themselves optimally from UV radiation exposure. Low levels of perceived skin cancer risk, a lack of knowledge about effective sun protection strategies and the inconvenience associated with sun-safe behaviors appear to explain this finding. A note of caution is required here, as there is a potential for publication bias. Moreover, the results of this study cannot be generalized to all non-melanoma skin cancer patients. Skin cancer survivors must be educated about their increased risk of future skin cancers. Behavioral interventions must be developed to increase the adoption of skin protective behaviors in this high-risk population group. PMID- 26515834 TI - Idiopathic eruptive macular pigmentation: A critical review of published literature and suggestions for revision of criteria for diagnosis. PMID- 26515835 TI - Understanding macular pigmentation of uncertain aetiology. PMID- 26515836 TI - Narrow band ultraviolet-B versus Goeckerman therapy for psoriasis with and without acitretin: A retrospective study. AB - BACKGROUND: Narrow band ultraviolet-B (NB-UVB) is now one of the most widely used modalities in the treatment of psoriasis. However, despite its high efficacy, conventional Goeckerman treatment has fallen out of favor in recent years and some institutions are now using NBUVB with coal tar as their regimen. OBJECTIVE: To evaluate the efficacy of NB-UVB, Goeckerman therapy and the effect of addition of retinoid to the treatment regimen in the treatment of psoriasis,. PATIENTS AND METHODS: A retrospective analysis of 65 patients who underwent 81 courses of treatment in our department was undertaken. The efficacy of NB-UVB and Goeckerman therapy individually, and in combination with acitretin was assessed. Data were analysed to evaluate the contribution of acitretin to these modalities. RESULTS: PASI-75 responses in the NB-UVB, retinoid+NB-UVB (re-NB), Goeckerman and retinoid+Goeckerman (re-Goeckerman) groups were achieved for 12 of 31 patients (39%), 13 of 21 patients (62%), 15 of 17 patients (88%) and 10 of 12 patients, respectively. The addition of acitretin to both modalities reduced both the number of sessions and the cumulative ultraviolet-B dose delivered. LIMITATIONS: This is a retrospective study, the patients were not randomized and the number of patients in the treatment groups were dissimilar. CONCLUSION: Goeckerman therapy is more effective than NB-UVB phototherapy. Although the addition of acitretin to both NB-UVB and Goeckerman therapy did not contribute to treatment outcomes in terms of PASI-75 responses, it enabled a reduction in UV exposures and enhanced efficacy. PMID- 26515837 TI - A morphometric and immunohistochemical study of melanocytes in periorbital hyperpigmentation. AB - BACKGROUND: An increase in number of melanocytes in the basal cell layer of the epidermis is an important feature in many disorders of hyperpigmentation. In this study, we attempted an objective evaluation of the linear density of melanocytes and keratinocytes, along with other epidermal characteristics, in periorbital hyperpigmentation using immunohistochemistry and morphometric techniques. METHODS: Melanocytes and epidermal parameters were assessed by digital morphometry in 30 newly diagnosed cases of periorbital hyperpigmentation and 14 controls from the post-auricular region. Melanocytes were labelled with the immunohistochemical stains, Melan-A and tyrosinase. We studied the linear keratinocyte density, mean linear melanocyte density, ratio of melanocytes to keratinocytes, the ratio between inner and outer epidermal length, maximum epidermal thickness and minimum epidermal thickness. RESULTS: Melan-A expression of melanocytes showed strong positive correlation (r=0.883) with the tyrosinase expression. Mean linear melanocyte density was 24/mm (range: 13-30/mm) in cases and 17/mm (13-21/mm) in controls and this difference was statistically significant (P<0.001). The mean ratio of melanocyte to keratinocyte was 0.22 (0.12-0.29) in cases and 0.16 (0.12-0.21) in controls; again, this difference was statistically significant (P<0.001). There was a mild negative correlation with linear keratinocyte density (r=-0.302) and the ratio between inner and outer epidermal length (r=-0.456). However, there were no differences in epidermal thicknesses. LIMITATIONS: There were fewer control biopsies than optimal, and they were not taken from the uninvolved periorbital region. CONCLUSION: Mean linear melanocyte density and the ratio of melanocytes to keratinocytes is increased in cases with periorbital hyperpigmentation. It is, therefore, likely that increased melanocyte density may be the key factor in the pathogenesis of periorbital hyperpigmentation. PMID- 26515838 TI - Differential expression of solute carrier family 11a member 1 and inducible nitric oxide synthase 2 in skin biopsies from leprosy patients. AB - BACKGROUND: Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae, an intracellular parasite that resides within macrophages and cannot be eliminated effectively. Solute carrier family 11a member 1 (Slc11a1) and inducible nitric oxide synthase (iNOS), both expressed in macrophages, play major roles in host defense against several intracellular pathogens. However, the roles of these molecules in natural infection with M. leprae remain unknown. OBJECTIVE: We aimed to investigate the expression of Slc11a1 and iNOS in macrophages (CD68+ cells) infiltrating skin lesions in leprosy. METHODS: Skin biopsies from 48 Mexican patients of leprosy [(33 lepromatous (LL), 15 tuberculoid (TT)] and from 10 healthy controls, were subjected to immunohistochemistry to determine expression of CD68, Slc11a1 and iNOS. RESULTS: We found a high expression of Slc11a1 and iNOS in most lepromatous leprosy samples. In tuberculoid leprosy samples, Slc11a1 expression was moderate or low, and that of iNOS was almost always low. In addition, Slc11a1 and iNOS expression levels were positively associated with bacillary loads in lepromatous leprosy lesions (P=0.05). CONCLUSIONS: These observations suggest that M. leprae infection promotes the expression of Slc11a1 and iNOS in macrophages and that lepromatous leprosy can occur despite this response. PMID- 26515839 TI - Targeted ultraviolet B phototherapy in vitiligo: A comparison between once-weekly and twice-weekly treatment regimens. AB - BACKGROUND: Targeted ultraviolet B (T-UVB) phototherapy in vitiligo is usually administered twice or thrice a week on non-consecutive days. It is difficult for many patients to adhere to this regimen, forcing them to discontinue treatment. AIM: The study aimed to compare the efficacy of twice-weekly and once-weekly targeted ultraviolet B phototherapy regimens in vitiligo. METHODS: Sixty patients with non-segmental vitiligo on the face, neck or trunk were divided into two groups of 30 patients each. The patients in group A received targeted ultraviolet B twice weekly, while those in group B received targeted ultraviolet B once weekly. Repigmentation was monitored and graded as excellent (>=75% repigmentation), good (50-74% repigmentation) and poor (<50% repigmentation). The extent of repigmentation at each body site (primary outcome measure), the number of doses required for initiation of pigmentation, and the cumulative dose of targeted ultraviolet B administered was calculated and compared between both groups. RESULTS: A total of 90 lesions (48 in the twice weeklygroup and 42 in the once weekly group) were treated on the face, neck and trunk. Excellent results were obtained in 62.5% (30/48) of lesions treated twice weekly, and 64.3% (27/42) in lesions treated once weekly. The mean number of doses required for initiation of pigmentation was 4.69 in the twice weekly group, and 4.35 in the once weekly group. The patients in the twice weekly group received a mean cumulative dose of 8.26 J/cm 2, while the once weekly group received 7.69 J/cm2. No statistically significant differences were observed between the two groups with respect to the outcome, with respect to the total repigmentation, the number of doses till onset of pigmentation, as well as the cumulative dose of targeted UVB. CONCLUSION: Once weekly targeted ultraviolet B phototherapy appears to be as efficacious as the twice-weekly regimen in vitiligo. PMID- 26515840 TI - Pseudocyst of the auricle. PMID- 26515841 TI - Dermoscopy of aggressive basal cell carcinomas. PMID- 26515842 TI - Valacyclovir-induced urticaria without acyclovir hypersensitivity. PMID- 26515843 TI - Mixed primary infection by herpes simplex virus 1 and 2 in a 5-month-old infant with no evidence of sexual abuse. PMID- 26515844 TI - Phakomatosis pigmentovascularis Type IIb, Sturge-Weber syndrome and cone shaped tongue: An unusual association. PMID- 26515845 TI - Entomophthoromycosis (basidiobolomycosis) presenting with "saxophone" penis and responding to potassium iodide. PMID- 26515846 TI - Pityriasis rubra pilaris occurring after vaccination with diphtheria-pertussis tetanus and oral poliovirus vaccines. PMID- 26515847 TI - Crusted scabies diagnosed by reflectance confocal microscopy. PMID- 26515848 TI - Ochronosis with subtle histological findings. PMID- 26515849 TI - Bullous pemphigoid with malignant melanoma. PMID- 26515850 TI - Dowling-Degos disease and malignant melanoma: Association or mere coincidence? PMID- 26515851 TI - Ankyloblepharon-ectodermal dysplasia-clefting syndrome. PMID- 26515852 TI - Systemic T cell lymphoma presenting as cutis verticis gyrata. PMID- 26515853 TI - Easy bruising due to giant platelet (possibly MYH9-related/Sebastian) syndrome. PMID- 26515854 TI - Infantile dermatofibrosarcoma protuberans: An underrecognized diagnosis? PMID- 26515855 TI - Anti-BP180-type oral mucous membrane pemphigoid reactive to both NC16a and C terminal domains. PMID- 26515856 TI - Sulfasalazine and pentoxifylline, a new adjuvant in young pemphigus patients: A pilot study. PMID- 26515857 TI - Tacrolimus for treatment of toxic epidermal necrolysis. PMID- 26515858 TI - Successful treatment of cutaneous leishmaniasis with nitazoxanide. PMID- 26515859 TI - Keratosis follicularis spinulosa decalvans showing excellent response to isotretinoin. PMID- 26515860 TI - Permanent treatment of aquagenic syringeal acrokeratoderma with endoscopic thoracic sympathectomy. PMID- 26515861 TI - Blepharochalasis with double lip: A case of Ascher syndrome. PMID- 26515862 TI - A fleshy protuberant growth on the leg. Diagnosis: Eccrine poroma. PMID- 26515863 TI - Vesicular lesions in lichen amyloidosis. PMID- 26515864 TI - Self-perceived emotional side effects of systemic corticosteroid therapy in dermatology patients. PMID- 26515865 TI - Pemphigus vegetans associated with Gitelman syndrome. PMID- 26515866 TI - Streptococcal vulvovaginitis in adults: Not a rare entity. PMID- 26515867 TI - Benign penile melanosis: A linear variant. PMID- 26515868 TI - Superficial epidermolytic ichthyosis. PMID- 26515869 TI - The cardiac surgeon as electrophysiologist. PMID- 26515870 TI - The Single Ventricle Reconstruction trial: The gift that keeps on giving. PMID- 26515871 TI - A possible strike on postoperative atrial fibrillation with the bullet amiodarone. PMID- 26515872 TI - Copy number variants in congenital heart disease: A new risk factor impacting outcomes? PMID- 26515873 TI - Increased cyclic guanosine monophosphate levels and continuous-flow left ventricular assist devices: Implications for gastrointestinal bleeding. AB - OBJECTIVES: We examine the hypothesis that cyclic guanosine monophosphate (cGMP) levels are elevated in recipients of continuous-flow left ventricular assist devices (CF-LVADs) and that elevated cGMP levels are associated with a risk of gastrointestinal (GI) bleeding events. METHODS: The levels of cGMP, nitric oxide, platelet activation markers, platelet-derived growth factors (PDGF) AB/BB and AA, and the inflammatory mediator C-reactive protein (CRP) were examined in 19 CF LVAD recipients, 21 patients who had heart failure, and 19 healthy control-group participants. RESULTS: The median level of cGMP was significantly higher in CF LVAD recipients, compared with healthy participants (6.6 vs 2.1 pmol/mL, u = 62.5; P = .001; r = -0.55). Median cGMP levels in the heart failure group (12.5 pmol/L) were higher, compared with both CF-LVAD recipients (u = 75.0; P = .001; r = -0.53) and healthy participants (u = 4.0; P < .001; r = -0.83). Compared with the healthy group, median CRP levels were significantly higher in CF-LVAD recipients (2.9 vs 8.0 mg/L; u = 58.0; P < .001; r = -0.63) and heart failure patients (2.9 vs 7.0 mg/L; u = 59.0; P < .001; r = -0.65). In the subgroup of patients supported with the HeartMate II (Thoratec Corporation, Pleasanton, Calif), pulsatility index was significantly negatively correlated with cGMP levels (r = -0.73; P < .05), indicating that low pulsatility index is associated with higher cGMP levels. High cGMP levels were significantly associated with GI bleeding events, but not with bleeding events in general. CONCLUSIONS: The primary finding of this study is that GI bleeding in CF-LVAD recipients is associated with significantly elevated cGMP levels, despite high levels of CRP, which interfere with cGMP production. Further studies are required to determine whether elevated cGMP levels can be used as a clinical marker for increased risk of GI bleeding in CF-LVAD recipients. PMID- 26515874 TI - Hepatic stiffness in the bidirectional cavopulmonary circulation: The Liver Adult Pediatric-Congenital-Heart-Disease Dysfunction Study group. AB - OBJECTIVES: We hypothesized that hepatic injury in single-ventricle CHD has origins that predate the Fontan operation. We aimed to measure hepatic stiffness using ultrasound and shear wave elastography (SWE) in a bidirectional cavopulmonary connection (BCPC) cohort. METHODS: Subjects were prospectively recruited for real-time, hepatic, ultrasound-SWE for hepatic stiffness (kPa) and echocardiography. Doppler velocities, a velocity-time integral, flow volume, and resistive index, pulsatility index, and acceleration index were measured in celiac and superior mesenteric arteries, and in the main portal vein (MPV). Comparisons were made among subjects who had BCPC, subjects who were healthy, and a cohort of patients who had undergone the Fontan procedure. RESULTS: Forty subjects (20 patients who had BCPC; 20 age- and gender-matched control subjects) were studied. The hepatic stiffness in BCPC was elevated, compared with that in control subjects (7.2 vs 5.7 kPa; P = .039). Patients who had BCPC had significantly higher celiac artery resistive index (0.9 vs 0.8; P = .002); pulsatility index (2.2 vs 1.7; P = .002); and systolic-diastolic flow ratio (10.1 vs 5.9; P = .002), whereas the superior mesenteric artery acceleration index (796 vs 1419 mL/min in control subjects; P = .04) was lower. An elevated resistive index (0.42 vs 0.29; P = .002) and pulsatility index (0.55 vs 0.35; P = .001) were seen in MPV, whereas MPV flow was reduced (137.3 vs 215.7 mL/min in control subjects; P = .036). A significant correlation was found for hepatic stiffness with right atrial pressure obtained at catheterization (P = .002). Comparison with patients who underwent the Fontan procedure showed patients who had BCPC had lower hepatic stiffness (7.2 vs 15.6 kPa; P < .001). CONCLUSIONS: Hepatic stiffness is increased with BCPC physiology, and this finding raises concerns that hepatopathology in palliated, single-ventricle CHD is not exclusively attributable to Fontan physiology. Hepatic stiffness measurements using SWE are feasible in this young population, and the technique shows promise as a means for monitoring disease progression. PMID- 26515875 TI - High-mobility group box-1 protein induces osteogenic phenotype changes in aortic valve interstitial cells. AB - OBJECTIVES: Calcific aortic valve (AV) disease is known to be an inflammation related process. High-mobility group box-1 (HMGB1) protein and Toll-like receptor 4 (TLR4) have been reported to participate in several inflammatory diseases. The purpose of the present study was to determine whether the HMGB1-TLR4 axis is involved in calcific AV disease, and to evaluate the effect of HMGB1, and its potential mechanisms, on the pro-osteogenic phenotype change of valvular interstitial cells (VICs). METHODS: Expression of HMGB1 and TLR4 in human calcific AVs was evaluated using immunohistochemical staining and immunoblotting. Cultured VICs were used as an in vitro model. The VICs were stimulated with HMGB1 for analysis, with versus without TLR4 small interfering ribonucleic acid (siRNA), c-Jun N-terminal kinase mitogen-activated protein kinase (JNK MAPK), and nuclear factor kappa-B (NF-kappaB) inhibitors. RESULTS: Enhanced accumulation of HMGB1 and TLR4 was observed in calcific valves. Moreover, we found that HMGB1 induced high levels of pro-inflammatory cytokine production and promoted the osteoblastic differentiation and calcification of VICs. In addition, HMGB1 induced phosphorylation of JNK MAPK and NF-kappaB. However, these effects were markedly suppressed by siRNA silencing of TLR4. In addition, blockade of JNK MAPK and NF-kappaB phosphorylation prohibited HMGB1-induced production of pro osteogenic factors, and mineralization of VICs. CONCLUSIONS: The HMGB1 protein may promote osteoblastic differentiation and calcification of VICs, through the TLR4-JNK-NF-kappaB signaling pathway. PMID- 26515876 TI - Postoperative tricuspid regurgitation after adult congenital heart surgery is associated with adverse clinical outcomes. AB - OBJECTIVE: Many patients with adult congenital heart disease will require cardiac surgery during their lifetime, and some will have concomitant tricuspid regurgitation. However, the optimal management of significant tricuspid regurgitation at the time of cardiac surgery remains unclear. We assessed the determinants of adverse outcomes in patients with adult congenital heart disease and moderate or greater tricuspid regurgitation undergoing cardiac surgery for non-tricuspid regurgitation-related indications. METHODS: All adult patients with congenital heart disease and greater than moderate tricuspid regurgitation who underwent cardiac surgery for non-tricuspid regurgitation-related indications were included in a retrospective study at the Schneeweiss Adult Congenital Heart Center. Cohorts were defined by the type of tricuspid valve intervention at the time of surgery. The primary end point of interest was a composite of death, heart transplantation, and reoperation on the tricuspid valve. RESULTS: A total of 107 patients met inclusion criteria, and 17 patients (17%) reached the primary end point. A total of 68 patients (64%) underwent tricuspid valve repair, 8 patients (7%) underwent tricuspid valve replacement, and 31 patients (29%) did not have a tricuspid valve intervention. By multivariate analysis, moderate or greater postoperative tricuspid regurgitation was associated with a hazard ratio of 6.12 (1.84-20.3) for the primary end point (P = .003). In addition, failure to perform a tricuspid valve intervention at the time of surgery was associated with an odds ratio of 4.17 (1.26-14.3) for moderate or greater postoperative tricuspid regurgitation (P = .02). CONCLUSIONS: Moderate or greater postoperative tricuspid regurgitation was associated with an increased risk of death, transplant, or reoperation in adult patients with congenital heart disease undergoing cardiac surgery for non-tricuspid regurgitation-related indications. Concomitant tricuspid valve intervention at the time of cardiac surgery should be considered in patients with adult congenital heart disease with moderate or greater preoperative tricuspid regurgitation. PMID- 26515877 TI - Do we need a bibliometrician to know which way the wind is blowing? PMID- 26515878 TI - Transaortic, video-assisted removal of a mobile left ventricular apical thrombus in a patient with aortic stenosis and severe left ventricular dysfunction. PMID- 26515879 TI - Direct Carboxylation of Aryl Tosylates by CO2 Catalyzed by In situ-Generated Ni(0). AB - A novel Ni(0) -catalyzed carboxylation of aryl tosylates with carbon dioxide has been achieved under moderate temperatures and atmospheric pressure. In this procedure, the active Ni(0) species is generated in situ by simply mixing the Ni(0) precatalyst [NiBr2 (bipy)] with an excess of manganese metal. This approach requires neither a glove-box nor the tedious preparation of sophisticated intermediate organometallic derivatives. This mild, convenient, and user-friendly process is successfully applied to the valorization of carbon dioxide and the synthesis of versatile reactants with broad tolerance of substituents. PMID- 26515880 TI - Clarification of the History and Use of the STAR ProsthesisTM. PMID- 26515881 TI - Selection and Publication Bias Color Interpretation. PMID- 26515882 TI - Limitations Based on Registry Data Used. PMID- 26515883 TI - The Importance of Biomechanics. PMID- 26515884 TI - Quantification of alcohol drinking patterns in mice. AB - The use of mice in alcohol research provides an excellent model system for a better understanding of the genetics and neurobiology of alcohol addiction. Almost 60 years ago, alcohol researchers began to test strains of mice for alcohol preference and intake. In particular, various voluntary alcohol drinking paradigms in the home cage were developed. In mouse models of voluntary oral alcohol consumption, animals have concurrent access to water and either one or several concentrated alcohol solutions in their home cages. Although these models have high face validity, many experimental conditions require a more precise monitoring of alcohol consumption in mice in order to capture the role of specific strains or genes, or any other manipulation on alcohol drinking behavior. Therefore, we have developed a fully automated, highly precise monitoring system for alcohol drinking in mice in the home cage. This system is now commercially available. We show that this drinkometer system allows for detecting differences in drinking behavior (i) in transgenic mice, (ii) following alcohol deprivation, and (iii) following stress applications that are usually not detected by classical home-cage drinking paradigms. In conclusion, our drinkometer system allows disturbance-free and high resolution monitoring of alcohol drinking behavior. In particular, micro-drinking and circadian drinking patterns can be monitored in genetically modified and inbred strains of mice after environmental and pharmacological manipulation, and therefore this system represents an improvement in measuring behavioral features that are of relevance for the development of alcohol use disorders. PMID- 26515885 TI - Bifidobacterium myosotis sp. nov., Bifidobacterium tissieri sp. nov. and Bifidobacterium hapali sp. nov., isolated from faeces of baby common marmosets (Callithrix jacchus L.). AB - In a previous study on bifidobacterial distribution in New World monkeys, six strains belonging to the Bifidobacteriaceae were isolated from faecal samples of baby common marmosets (Callithrix jacchus L.). All the isolates were Gram positive-staining, anaerobic, asporogenous and fructose-6-phosphate phosphoketolase-positive. Comparative analysis of 16S rRNA gene sequences revealed relatively low levels of similarity (maximum identity 96 %) to members of the genus Bifidobacterium, and placed the isolates in three independent clusters: strains of cluster I (MRM_5.9T and MRM_5.10) and cluster III (MRM_5.18T and MRM_9.02) respectively showed 96.4 and 96.7 % 16S rRNA gene sequence similarity to Bifidobacterium callitrichos DSM 23973T, while strains of cluster II (MRM_8.14T and MRM_9.14) showed 95.4 % similarity to Bifidobacterium stellenboschense DSM 23968T. Phylogenetic analysis of partial hsp60 and clpC gene sequences supported an independent phylogenetic position of each cluster from each other and from the related type strains B. callitrichos DSM 23973T and B. stellenboschense DSM 23968T. Clusters I, II and III respectively showed DNA G+C contents of 64.9-65.1, 56.4-56.7 and 63.1-63.7 mol%. The major cellular fatty acids of MRM_5.9T were C14 : 0, C16 : 0 and C18 : 1omega9c dimethylacetal, while C16 : 0 was prominent in strains MRM_5.18T and MRM_8.14T, followed by C18 : 1omega9c and C14 : 0. Biochemical profiles and growth parameters were recorded for all the isolates. Based on the data provided, the clusters represent three novel species, for which the names Bifidobacterium myosotis sp. nov. (type strain MRM_5.9T = DSM 100196T = JCM 30796T), Bifidobacterium hapali sp. nov. (type strain MRM_8.14T = DSM 100202T = JCM 30799T) and Bifidobacterium tissieri sp. nov. (type strain MRM_5.18T = DSM 100201T = JCM 30798T) are proposed. PMID- 26515886 TI - Three-dimensional hip and knee kinematics during walking, running, and single limb drop landing in females with and without genu valgum. AB - BACKGROUND: Dynamic knee valgus in females has been associated with various knee pathologies. Abnormal 3D hip and knee kinematics contribute prominently to this presentation, and these may become more aberrant with more demanding tasks. Underlying genu valgus may also accentuate such kinematics, but this effect has never been tested. Therefore, the purpose of this study was to compare 3D hip and knee kinematics during walking, running, and single-limb drop landing in females with and without genu valgus malalignment. We expected abnormal kinematics to become more evident in the valgus subjects as task demands increased. METHODS: Eighteen healthy females with genu valgum and 18 female controls with normal alignment underwent 3D motion analysis while performing walking, running, and single-limb drop-landing trials. Sagittal, frontal, and transverse plane hip and knee kinematics were compared between groups across tasks using analyses of variance and between-group effect sizes. FINDINGS: Group differences did not generally increase with higher forces. The valgus females demonstrated decreased hip flexion (ES=0.72-0.88) and increased knee abduction (ES=0.87-1.47) across the tasks. During running and single-limb drop landing, they showed increased knee external rotation (ES=0.69-0.73). Finally, during walking, the valgus females showed increased hip adduction (ES=0.69). INTERPRETATION: These results suggest that females with genu valgus alignment utilize aberrant hip and knee mechanics previously associated with dynamic valgus in the literature, but that these pathomechanics do not generally worsen with rising task demands. Healthy females that present with genu valgus may be natively at elevated risk for knee pathology. PMID- 26515887 TI - Interleukin-17A rs2275913, Interleukin-17F rs763780 and rs2397084 gene polymorphisms as possible risk factors in Juvenile lupus and lupus related nephritis. AB - There are no reports about the association of interleukin (IL)-17A and IL-17F gene polymorphism and susceptibility to pediatric systemic lupus erythematosus (pSLE). OBJECTIVE: To examine the possible role of IL-17A rs2275913, IL-17F rs763780 and rs2397084 polymorphisms as risk factors for pSLE in a cohort of Egyptian children and to investigate their association with the clinico pathological features including lupus nephritis (LN). METHODS: Typing of IL-17A and IL-17F polymorphisms was done using restriction fragment length polymorphism for 115 children with SLE and 259 age- and sex-matched healthy controls. RESULTS: No significant differences were found between pSLE patients and healthy controls for the allele and genotype frequencies of IL-17A rs2275913, IL-17F rs763780 and rs2397084 (p > 0.05). However, the combined genotype GGAGAA and the haplotype GGA had significant association with pSLE (pc = 0.042 and <0.001, respectively). The AA genotype of IL-17F rs763780 is more frequent in female patients (p = 0.002) and the AA genotype of IL-17F rs2397084 is more associated with positivity of ds DNA (p = 0.007). No more associations were found for the demographic and clinical data of pSLE patients including risk of LN development, risk of non-remission, overall survival, activity and chronicity indices. CONCLUSION: The GGAGAA combined genotype and the GGA haplotype of IL-17A rs2275913, IL-17F rs763780 and rs2397084 can be considered risk factors for the development of SLE in Egyptian children. IL-17A rs2275913, IL-17F rs763780 and rs2397084 are not related to the LN development, SLE disease activity or overall survival. PMID- 26515889 TI - Behavioral assessment of combinatorial semantics in baboons (Papio papio). AB - Combinatorial semantics is a core property of human language whose mechanisms remain poorly known. This study used computerized tasks with touch screens to investigate whether baboons (Papio papio) can understand the combination of shape and color labels in order to designate their corresponding colored shape. The baboons were trained either directly with label-pairs (Experiment 1) or with individual shape and color labels (Experiment 2), before being tested with novel compound labels from which they had to identify the referent. Compound labels understanding was found in one out of seven baboons tested in Experiment 1. Quite surprisingly, none of the 11 baboons showed this capacity in Experiment 2. We discuss several aspects of our protocols which could explain this difference between our two experiments, as well as the significance of our findings for language studies in animals and children. PMID- 26515890 TI - Proteomic Analysis of Silkworm Antennae. AB - The silkworm Bombyx mori is an oligophagous insect that feeds mainly on mulberry leaves. The olfactory system of silkworm is a good model to study olfaction in Lepidoptera. Here, we carried out shotgun proteomic analysis and MS sequencing of the silkmoth antennae. A total of 364 proteins were detected, 77 were female specific, 143 were male specific, and 144 were expressed in both male and female antennae. Five odorant-binding proteins, two chemosensory proteins, and one olfactory receptor were identified. They may play a major role in the perception of odorants. An esterase and an aldehyde dehydrogenase were found only in male antennae. Glutathione S-transferases (GSTs) and cytochrome P450s, also found in silkworm antennae, may be involved in the degradation of xenobiotics. Additionally, antioxidation proteins and immunity proteins were identified. Juvenile hormone binding proteins (JHBP), juvenile hormone resistance protein II, and juvenile hormone episode hydrolase (JHEH) were found in the proteomic analysis, which suggests that the antennae are a target for juvenile hormone in the silkworm. Our results provide insight into the expression of proteins in the antennae of silkworm and will facilitate the future functional analysis of silkworm antennae. PMID- 26515891 TI - Social Support in Children With ADHD: An Exploration of Resilience. AB - OBJECTIVE: This study investigated the role of perceived social support in promoting emotional well-being among children with ADHD. Specifically, it examined how children with ADHD perceive support from key individuals in their lives and the relationships between this support and aspects of emotional well being. Main versus buffering models of social support in the context of social preference status were also explored. METHOD: Participants were 55 school-age children with ADHD-combined or hyperactive/impulsive (ADHD-C/HI). Parent and child ratings evaluated source-specific social support, social status, and aspects of self-concept, anxiety, and depression. RESULTS: Children with ADHD reported lower social support than normative samples. Social support had moderate positive associations with self-concept, with source-specific differences, but was not associated with internalizing symptoms. Regression models with social preference status supported a main effect model of perceived social support. CONCLUSION: Social support may provide a target for resilience-based interventions among children with ADHD in promoting their self-concept and well being. PMID- 26515892 TI - Functional Imaging Changes in the Medial Prefrontal Cortex in Adult ADHD. AB - OBJECTIVE: Functional imaging studies have found reduced frontal activity, mainly in dorso/ventro-lateral regions and reduced task-related de-activation of the default mode network in childhood ADHD. Adult studies are fewer and inconclusive. We aimed to investigate the potential neural bases of executive function in ADHD adults, examining brain activity during N-back task performance, and to explore the potential corrective effects of long-term methylphenidate treatment. METHOD: We recruited a large adult ADHD-combined sample and a matched control group and obtained functional magnetic resonance imaging (fMRI) images during task. ADHD participants were subdivided in a group under long-term treatment with methylphenidate (washed out for the scan) and a treatment-naive group. RESULTS: ADHD participants showed deficient de-activation of the medial prefrontal cortex during 2-back task, implying default mode network dysfunction. We found no relationship between blunted de-activation and treatment history. CONCLUSION: As de-activation failure in the medial frontal cortex is linked to lapses of attention, findings suggest a potential link to ADHD symptomatology. PMID- 26515893 TI - The Burden of ADHD in Older Adults: A Qualitative Study. AB - OBJECTIVE: To explore how ADHD may have affected the lives of older adults who meet the diagnostic criteria of ADHD, but are unaware of their diagnosis. Our second aim was to examine whether the reported symptoms change over the life span. METHOD: A qualitative study was conducted. Seventeen Dutch older people (>65 years) diagnosed in this study with ADHD participated in in-depth interviews. Data were analyzed according to techniques of thematic approach. RESULTS: Seven themes emerged from the analyses. Four themes correspond to ADHD symptoms: "being active," "being impulsive," "attention problems," and "mental restlessness." In addition, the themes "low self-esteem," "overstepping boundaries," and "feeling misunderstood" emerged. The impact of ADHD symptoms seems to have declined with age. CONCLUSION: ADHD has a negative impact on late life, and older adults with the disorder may benefit from treatment. Moreover, this study's findings call for early detection and treatment of ADHD in children and adults. PMID- 26515894 TI - Cross-Cultural and Gender Differences in ADHD Among Young Adults. AB - OBJECTIVE: This study explored the effect of cultural and gender differences in ADHD among Spanish, African American, Hispanic American, and European American young adults. METHOD: Structural equivalence between the four groups was examined by Tucker's phi coefficient. A MANCOVA was carried out with cultural groups and gender as factors and age as covariate. RESULTS: Structural equivalence was observed across all groups, and no differential item functioning was found. No significant effect was found for gender, although, with the exception of the Hispanic group, males scored higher than females. Furthermore, small, though significant, cultural differences were found. The lowest levels of ADHD were observed in the European American group and the highest in the Hispanic American group. ADHD symptoms, notably inattention, showed some decline with age. CONCLUSION: Findings extend existing data and suggest a relationship between culture and the development of ADHD, which might be mediated by parenting style. PMID- 26515895 TI - The evolution of tumor metastasis during clonal expansion with alterations in metastasis driver genes. AB - Metastasis is a leading cause of cancer-related deaths. Carcinoma generally initiates at a specific organ as a primary tumor, but eventually metastasizes and forms tumor sites in other organs. In this report, we developed a mathematical model of cancer progression with alterations in metastasis-related genes. In cases in which tumor cells acquire metastatic ability through two steps of genetic alterations, we derive formulas for the probability, the expected number, and the distribution of the number of metastases. Moreover, we investigate practical pancreatic cancer disease progression in cases in which both one and two steps of genetic alterations are responsible for metastatic formation. Importantly, we derive a mathematical formula for the survival outcome validated using clinical data as well as direct simulations. Our model provides theoretical insights into how invisible metastases distribute upon diagnosis with respect to growth rates, (epi)genetic alteration rates, metastatic rate, and detection size. Prediction of survival outcome using the formula is of clinical importance in terms of determining therapeutic strategies. PMID- 26515896 TI - Retrospective Cohort Study to Assess Outcomes, Cost-Effectiveness, and Patient Satisfaction in Primary Vaginal Ovarian Cystectomy versus the Laparoscopic Approach. AB - STUDY OBJECTIVE: To compare surgical outcomes, cost-effectiveness, and patient satisfaction in women undergoing primary vaginal or laparoscopic ovarian cystectomy for benign ovarian cysts. DESIGN: Retrospective cohort control study (Canadian Task Force classification II-3). SETTING: Gynecologic unit at a university-affiliated hospital. PATIENTS: Fifty patients who underwent primary ovarian cystectomy either through the vaginal route via posterior colpotomy (n = 29) or laparoscopic route (n = 21). INTERVENTIONS: Nonmalignant ovarian cysts were initially determined by transvaginal ultrasonography and serum tumor markers. The index group of women (n = 29) underwent vaginal ovarian cystectomy via a posterior colpotomy incision, whereas the control group (n = 21) comprised women who had laparoscopic ovarian cystectomy using the traditional "grasp and peel" technique. The following outcomes were evaluated: duration of surgery, intraoperative complications, estimated blood loss, length of inpatient stay, and postoperative pain (visual analogue scale). The average cost of both surgical methods was calculated by factoring in theater time, equipment required, and the length of hospital stay. Patients were then surveyed to compare postoperative pain and satisfaction scores as well as the time taken to return to work (in days). MEASUREMENTS AND MAIN RESULTS: The 2 groups had similar mean ages (35.79 vs 36.72 years) and cyst diameter (6.8 vs 6.6 cm) (p > .05 in both cases). Vaginal ovarian cystectomy took a mean of 13.7 minutes longer (91.7 vs 78.0 minutes, p < .001) to perform and resulted in a greater mean estimated blood loss (116.1 vs 95 mL, p < .001). The spillage rate in the index group was 6-fold less compared with control cases (6% +/- 2.4% vs 35% +/- 4.6, p < .01). Although patients from the index group spent a mean of 2 hours longer as inpatients (10.9 vs 8.9 hours, p < .001), they reported a lower mean visual analogue pain score (2.01/10 vs 3.95/10, p < .05) and higher patient satisfaction scores (8.2/10 vs 6.5/10, p < .001). Mean perioperative cost of women who underwent vaginal ovarian cystectomy was lower (L1690.13 vs 1761.67) and they returned to work quicker compared with the laparoscopic group (13.6 vs 39.2 days, p < .001). CONCLUSION: Vaginal ovarian cystectomies took longer to perform and led to longer inpatient stay. However, these women had less postoperative pain and reported higher satisfaction scores compared with laparoscopic ovarian cystectomy, with a quicker return to work. The vaginal approach is a viable and cost-effective alternative to the laparoscopic approach in carefully selected patients. PMID- 26515897 TI - Systematic review: predicting and optimising response to anti-TNF therapy in Crohn's disease - algorithm for practical management. AB - BACKGROUND: Nonresponse and loss of response to anti-TNF therapies in Crohn's disease represent significant clinical problems for which clear management guidelines are lacking. AIM: To review the incidence, mechanisms and predictors of primary nonresponse and secondary loss of response to formulate practical clinical algorithms to guide management. METHODS: Through a systematic literature review, 503 articles were identified which fit the inclusion criteria. RESULTS: Primary nonresponse to anti-TNF treatment affects 13-40% of patients. Secondary loss of response to anti-TNF occurs in 23-46% of patients when determined according to dose intensification, and 5-13% of patients when gauged by drug discontinuation rates. Recent evidence suggests that the mechanisms underlying primary nonresponse and secondary loss of response are multifactorial and include disease characteristics (phenotype, location, severity); drug (pharmacokinetic, pharmacodynamic or immunogenicity) and treatment strategy (dosing regimen) related factors. Clinical algorithms that employ therapeutic drug monitoring (using anti-TNF tough levels and anti-drug antibody levels) may be used to determine the underlying cause of primary nonresponse and secondary loss of response respectively and guide clinicians as to which patients are most likely to respond to anti-TNF therapy and help optimise drug therapy for those who are losing response to anti-TNF therapy. CONCLUSIONS: Nonresponse or loss of response to anti-TNF occurs commonly in Crohn's disease. Clinical algorithms utilising therapeutic drug monitoring may establish the mechanisms for treatment failure and help guide the subsequent therapeutic approach. PMID- 26515899 TI - Carbohydrates for people with diabetes is not cautious. PMID- 26515898 TI - Modeling the effect of comprehensive interventions on Ebola virus transmission. AB - Since the re-emergence of Ebola in West Africa in 2014, comprehensive and stringent interventions have been implemented to decelerate the spread of the disease. The effectiveness of interventions still remains unclear. In this paper, we develop an epidemiological model that includes various controlling measures to systematically evaluate their effects on the disease transmission dynamics. By fitting the model to reported cumulative cases and deaths in Guinea, Sierra Leone and Liberia until March 22, 2015, we estimate the basic reproduction number in these countries as 1.2552, 1.6093 and 1.7994, respectively. Model analysis shows that there exists a threshold of the effectiveness of isolation, below which increasing the fraction of latent individuals diagnosed prior to symptoms onset or shortening the duration between symptoms onset and isolation may lead to more Ebola infection. This challenges an existing view. Media coverage plays a substantial role in reducing the final epidemic size. The response to reported cumulative infected cases and deaths may have a different effect on the epidemic spread in different countries. Among all the interventions, we find that shortening the duration between death and burial and improving the effectiveness of isolation are two effective interventions for controlling the outbreak of Ebola virus infection. PMID- 26515900 TI - Thiamine responsive acute life threatening metabolic acidosis in exclusively breast-fed infants. AB - BACKGROUND: Acute life threatening metabolic acidosis in exclusively breast fed infants due to thiamine deficiency is not described. Kashmir valley, a north Indian state has a population that largely consumes polished rice. METHODS: A six months prospective descriptive study of infants who presented with acute life threatening metabolic acidosis (Blood pH <= 7.0) due to thiamine deficiency. RESULTS: Twenty three infants (Eleven male; Twelve female) in the age range of 32 days to 4 months had a pH of <=7 at admission. Onset of moaning was immediate (2 24 hours). Blood lactate levels were more than 15mmol/L. Blood thiamine levels of six infants in whom it was done ranged from 11-69 nmol/L (control 78-185 nmol/L). All infants were exclusively breast fed. Maternal staple diet consisted of polished rice. All mothers consumed rice after washing it thrice. Twelve lactating mothers were on customary dietary restrictions. Practice of straining rice after cooking was observed in thirteen. The commonest symptoms were irritability (82%) and reflux (56%). Commonest signs were tachycardia (100%) and moaning (73%). At presentation 52% were in cardiogenic shock. Response to thiamine was dramatic with moaning and irritability subsiding in two hours and tachycardia in four hours. Adequate perfusion was achieved in one hour. Eighteen patients seen at six months follow up had normal neurodevelopment. CONCLUSIONS: Thiamine deficiency in an infant can present as sudden onset metabolic acidosis. If treated early, metabolic acidosis due to thiamine deficiency is associated with good immediate and long term prognosis even if pH is less than 7 at presentation. PMID- 26515901 TI - Simplifications of the mini nutritional assessment short-form are predictive of mortality among hospitalized young and middle-aged adults. AB - OBJECTIVE: Measuring malnutrition in hospitalized patients is difficult in all settings. I evaluated associations of items in the mini nutritional assessment short-form (MNA-sf), a nutritional-risk screening tool previously validated in the elderly, with malnutrition among hospitalized patients in Uganda. I used results to construct two simplifications of this tool that may be applicable to young and middle-aged adults. METHODS: I assessed the association of each MNA-sf item with the mid-upper arm circumference (MUAC), a specific measure of malnutrition at appropriate cut-offs. I incorporated only malnutrition-specific items into the proposed simplifications scoring each item according to its association with malnutrition. I assessed numbers classified to different score levels by the simplifications and, via proportional hazards regression, how the simplifications predicted in-hospital mortality. RESULTS: I analyzed 318 patients (median age 37, interquartile range 27 to 56). Variables making it into the simplifications were: reduced food intake, weight loss, mobility, and either BMI in kg/m(2) (categorized as <16, 16 to 16.9, and >=17) or MUAC in centimeters (categorized as <16 or <17, 16 to 18.9 or 17 to 19.9, and >=19 or >=20 for females and males respectively). Compared to the traditional MNA-sf, the simplifications classified fewer patients as malnourished, yet remained strongly predictive of in-hospital mortality. In the MUAC-incorporating simplification, malnourished patients had 3.8-fold (95% CI 1.9 to 7.8) higher risk of in-hospital death than those not malnourished; adjusting for age, sex, and HIV status. CONCLUSION: The MNA-sf simplifications described may provide an improved measure of malnutrition in hospitalized young and middle-aged adults. PMID- 26515902 TI - A cross-modal, cross-species comparison of connectivity measures in the primate brain. AB - In systems neuroscience, the term "connectivity" has been defined in numerous ways, according to the particular empirical modality from which it is derived. Due to large differences in the phenomena measured by these modalities, the assumptions necessary to make inferences about axonal connections, and the limitations accompanying each, brain connectivity remains an elusive concept. Despite this, only a handful of studies have directly compared connectivity as inferred from multiple modalities, and there remains much ambiguity over what the term is actually referring to as a biological construct. Here, we perform a direct comparison based on the high-resolution and high-contrast Enhanced Nathan Klein Institute (NKI) Rockland Sample neuroimaging data set, and the CoCoMac database of tract tracing studies. We compare four types of commonly-used primate connectivity analyses: tract tracing experiments, compiled in CoCoMac; group-wise correlation of cortical thickness; tractographic networks computed from diffusion weighted MRI (DWI); and correlational networks obtained from resting-state BOLD (fMRI). We find generally poor correspondence between all four modalities, in terms of correlated edge weights, binarized comparisons of thresholded networks, and clustering patterns. fMRI and DWI had the best agreement, followed by DWI and CoCoMac, while other comparisons showed striking divergence. Networks had the best correspondence for local ipsilateral and homotopic contralateral connections, and the worst correspondence for long-range and heterotopic contralateral connections. k-Means clustering highlighted the lowest cross-modal and cross-species consensus in lateral and medial temporal lobes, anterior cingulate, and the temporoparietal junction. Comparing the NKI results to those of the lower resolution/contrast International Consortium for Brain Imaging (ICBM) dataset, we find that the relative pattern of intermodal relationships is preserved, but the correspondence between human imaging connectomes is substantially better for NKI. These findings caution against using "connectivity" as an umbrella term for results derived from single empirical modalities, and suggest that any interpretation of these results should account for (and ideally help explain) the lack of multimodal correspondence. PMID- 26515903 TI - STEAM - Statistical Template Estimation for Abnormality Mapping: A personalized DTI analysis technique with applications to the screening of preterm infants. AB - We introduce the STEAM DTI analysis engine: a whole brain voxel-based analysis technique for the examination of diffusion tensor images (DTIs). Our STEAM analysis technique consists of two parts. First, we introduce a collection of statistical templates that represent the distribution of DTIs for a normative population. These templates include various diffusion measures from the full tensor, to fractional anisotropy, to 12 other tensor features. Second, we propose a voxel-based analysis (VBA) pipeline that is reliable enough to identify areas in individual DTI scans that differ significantly from the normative group represented in the STEAM statistical templates. We identify and justify choices in the VBA pipeline relating to multiple comparison correction, image smoothing, and dealing with non-normally distributed data. Finally, we provide a proof of concept for the utility of STEAM on a cohort of 134 very preterm infants. We generated templates from scans of 55 very preterm infants whose T1 MRI scans show no abnormalities and who have normal neurodevelopmental outcome. The remaining 79 infants were then compared to the templates using our VBA technique. We show: (a) that our statistical templates display the white matter development expected over the modeled time period, and (b) that our VBA results detect abnormalities in the diffusion measurements that relate significantly with both the presence of white matter lesions and with neurodevelopmental outcomes at 18months. Most notably, we show that STEAM produces personalized results while also being able to highlight abnormalities across the whole brain and at the scale of individual voxels. While we show the value of STEAM on DTI scans from a preterm infant cohort, STEAM can be equally applied to other cohorts as well. To facilitate this whole-brain personalized DTI analysis, we made STEAM publicly available at http://www.sfu.ca/bgb2/steam. PMID- 26515904 TI - Integrating longitudinal information in hippocampal volume measurements for the early detection of Alzheimer's disease. AB - BACKGROUND: Structural MRI measures for monitoring Alzheimer's Disease (AD) progression are becoming instrumental in the clinical practice, and more so in the context of longitudinal studies. This investigation addresses the impact of four image analysis approaches on the longitudinal performance of the hippocampal volume. METHODS: We present a hippocampal segmentation algorithm and validate it on a gold-standard manual tracing database. We segmented 460 subjects from ADNI, each subject having been scanned twice at baseline, 12-month and 24month follow up scan (1.5T, T1 MRI). We used the bilateral hippocampal volume v and its variation, measured as the annualized volume change Lambda=deltav/year(mm(3)/y). Four processing approaches with different complexity are compared to maximize the longitudinal information, and they are tested for cohort discrimination ability. Reference cohorts are Controls vs. Alzheimer's Disease (CTRL/AD) and CTRL vs. Mild Cognitive Impairment who subsequently progressed to AD dementia (CTRL/MCI co). We discuss the conditions on v and the added value of Lambda in discriminating subjects. RESULTS: The age-corrected bilateral annualized atrophy rate (%/year) were: -1.6 (0.6) for CTRL, -2.2 (1.0) for MCI-nc, -3.2 (1.2) for MCI-co and -4.0 (1.5) for AD. Combined (v, Lambda) discrimination ability gave an Area under the ROC curve (auc)=0.93 for CTRL vs AD and auc=0.88 for CTRL vs MCI co. CONCLUSIONS: Longitudinal volume measurements can provide meaningful clinical insight and added value with respect to the baseline provided the analysis procedure embeds the longitudinal information. PMID- 26515906 TI - Motion parallax links visual motion areas and scene regions. AB - When we move, the retinal velocities of objects in our surrounding differ according to their relative distances and give rise to a powerful three dimensional visual cue referred to as motion parallax. Motion parallax allows us to infer our surrounding's 3D structure as well as self-motion based on 2D retinal information. However, the neural substrates mediating the link between visual motion and scene processing are largely unexplored. We used fMRI in human observers to study motion parallax by means of an ecologically relevant yet highly controlled stimulus that mimicked the observer's lateral motion past a depth-layered scene. We found parallax selective responses in parietal regions IPS3 and IPS4, and in a region lateral to scene selective occipital place area (OPA). The traditionally defined scene responsive regions OPA, the para hippocampal place area (PPA) and the retrosplenial cortex (RSC) did not respond to parallax. During parallax processing, the occipital parallax selective region entertained highly specific functional connectivity with IPS3 and with scene selective PPA. These results establish a network linking dorsal motion and ventral scene processing regions specifically during parallax processing, which may underlie the brain's ability to derive 3D scene information from motion parallax. PMID- 26515907 TI - Cryo-scanning electron microscopy investigation of the Octopus Vulgaris arm structures for the design of an octopus-like arm artefact. AB - Octopus vulgaris is a cephalopod of the Octopodidae family. It has four pairs of arms and two rows of suckers which perform many functions, including bending and elongation. For this reason the octopus was chosen as model to develop a new generation of soft-body robots. In order to explain some of the fine structures of the octopus arm in relation to its specific ability, we examined the external and internal structures of O. vulgaris arms in a frozen-hydrated state using cryo scanning electron microscopy. The arms showed skin with a very complex design that is useful to elongation, and a pore pattern distribution on their surface which is functional to cutaneous oxygen uptake. The analysis of freeze-fractured frozen-hydrated arm samples allowed us to describe the developmental differences in the relative proportion of the areas of axial nerve cord, intrinsic and extrinsic musculature, in relation to the growth of the arms and of the increase in functional capability. In the suckers, we analyzed the shedding mechanisms in the outer part of the infundibulum and described the outer and inner characteristics of the denticles, showing in detail their pore system, which is fundamental for their ability to explore the environment. These results are discussed by considering their possible application in the design of new octopus like artefacts, which will be able to take advantage of some of these ultrastructure characteristics and achieve advanced bioinspired functionalities. PMID- 26515905 TI - The quest for the best: The impact of different EPI sequences on the sensitivity of random effect fMRI group analyses. AB - We compared the sensitivity of standard single-shot 2D echo planar imaging (EPI) to three advanced EPI sequences, i.e., 2D multi-echo EPI, 3D high resolution EPI and 3D dual-echo fast EPI in fixed effect and random effects group level fMRI analyses at 3T. The study focused on how well the variance reduction in fixed effect analyses achieved by advanced EPI sequences translates into increased sensitivity in the random effects group level analysis. The sensitivity was estimated in a functional MRI experiment of an emotional learning and a reward based learning tasks in a group of 24 volunteers. Each experiment was acquired with the four different sequences. The task-related response amplitude, contrast level and respective t-value were proxies for the functional sensitivity across the brain. All three advanced EPI methods increased the sensitivity in the fixed effects analyses, but standard single-shot 2D EPI provided a comparable performance in random effects group analysis when whole brain coverage and moderate resolution are required. In this experiment inter-subject variability determined the sensitivity of the random effects analysis for most brain regions, making the impact of EPI pulse sequence improvements less relevant or even negligible for random effects analyses. An exception concerns the optimization of EPI reducing susceptibility-related signal loss that translates into an enhanced sensitivity e.g. in the orbitofrontal cortex for multi-echo EPI. Thus, future optimization strategies may best aim at reducing inter-subject variability for higher sensitivity in standard fMRI group studies at moderate spatial resolution. PMID- 26515908 TI - Localization of dipeptidyl peptidase-4 (CD26) to human pancreatic ducts and islet alpha cells. AB - AIM: DPP-4/CD26 degrades the incretins GLP-1 and GIP. The localization of DPP-4 within the human pancreas is not well documented but is likely to be relevant for understanding incretin function. We aimed to define the cellular localization of DPP-4 in the human pancreas from cadaveric organ donors with and without diabetes. METHODS: Pancreas was snap-frozen and immunoreactive DPP-4 detected in cryosections using the APAAP technique. For co-localization studies, pancreas sections were double-stained for DPP-4 and proinsulin or glucagon and scanned by confocal microscopy. Pancreata were digested and cells in islets and in islet depleted, duct-enriched digests analyzed for expression of DPP-4 and other markers by flow cytometry. RESULTS: DPP-4 was expressed by pancreatic duct and islet cells. In pancreata from donors without diabetes or with type 2 diabetes, DPP-4-positive cells in islets had the same location and morphology as glucagon positive cells, and the expression of DPP-4 and glucagon overlapped. In donors with type 1 diabetes, the majority of residual cells in islets were DPP-4 positive. CONCLUSION: In the human pancreas, DPP-4 expression is localized to duct and alpha cells. This finding is consistent with the view that DPP-4 regulates exposure to incretins of duct cells directly and of beta cells indirectly in a paracrine manner. PMID- 26515909 TI - Validation and psychometric properties of the 8-item Morisky Medication Adherence Scale (MMAS-8) in Type 2 diabetes patients in sub-Saharan Africa. AB - OBJECTIVES: Research in the field of adherence to medications has not been explored in sub-Saharan Africa. The goal of this manuscript is to (1) validate the use of an adherence tool: a translated 8-item Morisky Medication Adherence Scale (MMAS-8) for Type 2 diabetes and (2) assess association between levels of adherence and psychometric properties. METHODS: 154 Type 2 diabetic patients being chronically treated were surveyed from Togolese Diabetes Association using a demographic survey, 4-item Morisky Medication Adherence Scale (MMAS-4) and MMAS 8 from January to March 2012. RESULTS: Internal reliability for the 8-item scale showed the Cronbach alpha being 0.47. The MMAS-8 and MMAS-4 showed a Pearson's correlation of 0.6851. For known groups validity, the chi-square (chi(2)) tests of proportions showed a significant relationship between blood glucose control and MMAS-8 (chi(2)=12.17; p=0.002). The sensitivity, specificity, positive predictive value and negative predictive value were 75%, 48.39%, 56.76%, and 68.18% respectively. CONCLUSIONS: Psychometric analyses showed that the MMAS-8 was a suitable way of measuring medication adherence in the study population given its low cost, ease of use, and the low income status of the country. PMID- 26515910 TI - Risk of type 2 diabetes mellitus in female breast cancer patients treated with morphine: A retrospective population-based time-dependent cohort study. AB - AIMS: We aimed to examine whether morphine treatment is associated with type 2 diabetes mellitus (T2DM) in female breast cancer patients. METHODS: We conducted a retrospective cohort analysis of the Longitudinal Health Insurance Database for Catastrophic Illness Patients in Taiwan. A total of 31,112 women with breast cancer without T2DM history during the period 2000-2005 were identified, divided into morphine and non-morphine users (8071 and 23,041 patients, respectively), and the hazard ratios of newly diagnosed T2DM during the period 2005-2010 were calculated. We used a Cox proportional hazard model with time-dependent exposure covariates to estimate the risk of T2DM. The dosage of morphine was counted as defined daily dose and its effect was assessed by multivariable Cox proportional hazard regression controlling age, Charlson comorbidity index, outpatient department visits, antipsychotics, and breast cancer drugs. RESULTS: Morphine users were 1.24 times more likely to suffer from T2DM than non-morphine users (95% CI=1.04-1.49). Risk increased slightly with the morphine dosage, in patients aged 35-49 years, and with tamoxifen, aromatase inhibitors, and antipsychotics treatment. CONCLUSIONS: The incidence of T2DM is associated with morphine treatment in female breast cancer patients. A higher risk was observed in patients aged 35-49 years using higher dose of morphine, and may be increased by tamoxifen and aromatase inhibitors. PMID- 26515911 TI - Increased healing in diabetic toe ulcers in a multidisciplinary foot clinic-An observational cohort study. AB - AIM: To study toe ulcer healing in patients with diabetic foot ulcers attending a multidisciplinary foot clinic over a 10 years period. METHODS: The study was retrospective, consecutive and observational during 2001 through 2011. The patients were treated according to the International Consensus on the Diabetic Foot. During the period the chiropodist staffing in the foot clinic was doubled; new offloading material and orthopedic foot corrections for recalcitrant ulcers were introduced. Healing was investigated in toe ulcers in Cox regression models. RESULTS: 2634 patients developed foot ulcers, of which 1461 developed toe ulcers; in 790 patients these were neuropathic, in 551 they were neuro-ischemic and in 120 they were critically ischemic. One-year healing rates increased in the period 2001-2011 from 75% to 91% for neuropathic toe ulcers and from 72% to 80% for neuro-ischemic toe ulcers, while no changes was observed for ischemic toe ulcers. Adjusted for changes in the patient population, the overall rate of healing for neuropathic and neuro-ischemic toe ulcers almost doubled (HR=1.95 [95% CI: 1.36 2.80]). CONCLUSION: The results show that the healing of toe ulcers improved. This outcome could not be explained by changes in the patient characteristics, but coincided with a number of improvements in organization and therapy. PMID- 26515912 TI - Severe hypoglycaemia during treatment with sulphonylureas in patients with type 2 diabetes in the Capital Region of Denmark. AB - AIMS: Sulphonylureas (SU) are currently recommended as a well-established second line treatment in guidelines for type 2 diabetes (T2DM). In the Capital Region of Denmark 16,865 patients were given SU as part of their treatment of T2DM in 2010 2011. To what extent SU are associated with hospitalizations due to severe hypoglycaemic episodes, defined as episodes with a need for external assistance, was investigated. The prevalence and characteristics of these patients and potential risk factors were studied. METHODS: ICD-10 diagnosis codes were used to identify patients hospitalized due to hypoglycaemia and T2DM for a period of 2 years (2010-2011). Inclusion criteria were T2DM, hospitalization due to hypoglycaemia and treatment with SU as monotherapy or in combination with other glucose-lowering drugs except insulin treatment. RESULTS: We identified 161 patients fulfilling the inclusion criteria. Their mean age was 76 (53-97) years and 54% were males. Sixty percent of the patients had diabetic complications, including 19% with diabetic nephropathy. The major reason for severe hypoglycaemia was an unchanged dose of SU despite of a significant decline in food intake (45%). In 22% of the patients more than one reason was listed, most commonly a concomitant infection associated with decreased food intake and unchanged dose of SU. CONCLUSION: The incidence of hospital admission-requiring severe hypoglycaemia in patients treated with SU was 0.48 episodes per 100 patient-years of SU-treated patients. It was mainly older patients with diminished food intake, excessive alcohol use or other medications, concomitant infection, and with diabetic complications. PMID- 26515913 TI - Osteoprotegerin and zoledronate bone effects during orthodontic tooth movement. AB - OBJECTIVES: To assess the effects of local delivery of recombinant fusion protein osteoprotegerin (OPG-Fc) and bisphosphonate zoledronate on bone and periodontal ligament in a rat tooth movement model. MATERIALS AND METHODS: Maxillary first molars of 36 male Sprague-Dawley rats were displaced mesially using a calibrated spring connected to an anterior mini-screw. Two different drugs were used: a single dose of Zoledronate (16 MUg) and a twice-weekly dose of OPG-Fc (5.0 mg/kg) were injected. Tooth movement was measured on scanned plaster casts. Structural and immunohistochemical analysis of the orthodontic-induced changes in bone included receptor activator of nuclear factor K (RANK), Runx, type 1 collagen, matrix metalloproteinases (MMPs) 2 and 9, tissue inhibitors of metalloproteinases (TIMPs) 1 and 2, and vimentin. RESULTS: Both groups showed a reduction in mesial molar displacement. Animals receiving OPG-Fc demonstrated only 52%, 31%, and 21% of the total mesial molar displacement compared to control rats at 7, 14, and 21 days, respectively (*p < 0.001). For rats receiving zoledronate tooth displacement decreased significantly with 52%, 46% and 30%, respectively (*p < 0.001). At 14 and 21 days, OPG-Fc group showed significantly less molar displacement than the zoledronate group (*p < 0.001). RANK, Runx, vimentin, MMP-9 and tissues-inhibitor metalloproteinase 1 immunoreactivity were reduced in zoledronate treated animals and even more in OPG treated animals. CONCLUSION: Local delivery of OPG-Fc or zoledronate inhibits bone resorption and therefore tooth movement. OPG-Fc was more effective than zoledronate in blocking the action of osteoclasts. PMID- 26515914 TI - Injury mechanisms in fatal Australian quad bike incidents. AB - OBJECTIVES: The ability to determine risk management controls for quad bike use is confounded by limitations in crash and injury information. The aim of this article is to identify the injury mechanisms, crash characteristics, and contributing factors in fatal quad bike incidents in Australia by activity (recreation and work). METHODS: An in-depth case series study was undertaken of 106 Australian quad bike fatalities that had occurred between 2000 and 2013. All case material held by Australian coroners was obtained and reviewed. RESULTS: One hundred and six cases were categorized as occurring during recreation (53) and work (53). Fifty-two of the work cases occurred during farmwork. The mean age for those killed during a work activity was 56 years compared to 27 years for recreational riders. Two children under 16 years died while performing farmwork and 13 children under 16 years during recreational activities. The analyses show a very clear pattern for farmwork-related deaths: quad bike rolls or pitches over (farmworker, 85%; recreational rider, 55%), rider becomes pinned under quad bike (farmworker, 68%; recreational rider, 30%), and death by asphyxia (farmworker, 42%; recreational rider, 11%). In contrast, recreational riders suffered complex impact injuries to the head and chest that occurred when the rider was traveling at speed, lost control, was ejected, and collided with an object in the environment and/or interacted with the moving quad bike. CONCLUSIONS: The analyses support the need to improve safe quad bike operation through consideration of the age of the rider, training, helmet use, reducing the propensity of quad bikes to roll, and improving handling so that loss of control events are reduced and to prevent crushing and pinning by the vehicle during and after a rollover crash. PMID- 26515915 TI - Challenges facing the drug discovery pipeline for non-tuberculous mycobacteria. AB - Non-tuberculous mycobacteria (NTM) infections are increasingly being reported worldwide. They are a major concern for healthcare professionals for multiple reasons, ranging from the intrinsic resistance of NTM to most conventionally utilized antimicrobials to inharmonious diagnostic criteria utilized for evaluation of NTM-infected patients, leading to high morbidity. In this review, we highlight the paucity of drugs having potent anti-NTM activity amongst the new antimicrobials currently under various stages of development for anti-tubercular activity and issue a call for the establishment of a concerted dedicated drug discovery pipeline targeting NTM. PMID- 26515916 TI - Associations between gestational anthropometry, maternal HIV, and fetal and early infancy growth in a prospective rural/semi-rural Tanzanian cohort, 2012-13. AB - BACKGROUND: Healthcare access and resources differ considerably between urban and rural settings making cross-setting generalizations difficult. In resource restricted rural/semi-rural environments, identification of feasible screening tools is a priority. The objective of this study was to evaluate gestational anthropometry in relation to birth and infant growth in a rural/semi-rural Tanzanian prospective cohort of mothers and their infants. METHODS: Mothers (n = 114: 44 HIV-positive) attending antenatal clinic visits were recruited in their second or third trimester between March and November, 2012, and followed with their infants through 6-months post-partum. Demographic, clinical, and infant feeding data were obtained using questionnaires administered by a Swahili speaking research nurse on demographic, socioeconomic, clinical, and infant feeding practices. Second or third trimester anthropometry (mid-upper arm circumference [MUAC], triceps skinfold thickness, weight, height), pregnancy outcomes, birth (weight, length, head circumference) and infant anthropometry (weight-for-age z-score [WAZ], length-for-age z-score [LAZ]) were obtained. Linear regression and mixed effect modeling were used to evaluate gestational factors in relation to pregnancy and infant outcomes. RESULTS AND DISCUSSION: Gestational MUAC and maternal HIV status (HIV-positive mothers = 39%) were associated with infant WAZ and LAZ from birth to 6-months in multivariate models, even after adjustment for infant feeding practices. The lowest gestational MUAC tertile was associated with lower WAZ throughout early infancy, as well as lower LAZ at 3 and 6-months. In linear mixed effects models through 6-months, each 1 cm increase in gestational MUAC was associated with a 0.11 increase in both WAZ (P < 0.001) and LAZ (P = 0.001). Infant HIV-exposure was negatively associated with WAZ (beta = -0.65, P < 0.001) and LAZ (beta = -0.49, P < 0.012) from birth to 6 months. CONCLUSIONS: Lower gestational MUAC, evaluated using only a tape measure and minimal training that is feasible in non-urban clinic and community settings, was associated with lower infant anthropometric measurements. In this rural and semi-rural setting, HIV-exposure was associated with poorer anthropometry through 6-months despite maternal antiretroviral access. Routine assessment of MUAC has the potential to identify at-risk women in need of additional health interventions designed to optimize pregnancy outcomes and infant growth. Further research is needed to establish gestational MUAC reference ranges and to define interventions that successfully improve MUAC during pregnancy. PMID- 26515917 TI - The burden of early-onset sepsis in Emilia-Romagna (Italy): a 4-year, population based study. AB - OBJECTIVE: To provide the first Italian data on pathogens causing early-onset sepsis (EOS) and their antimicrobial susceptibility, after the successfully prevention of Group B streptococcus (GBS) EOS. METHODS: Retrospective area-based cohort study from Emilia-Romagna (Italy). Cases of EOS registered (from 2009 to 2012) in all gestational age neonates were reviewed. RESULTS: Live births (LB) numbered 146 682. Ninety neonates had EOS and 12 died (incidence rates of 0.61 and 0.08/1000 LB, respectively). EOS and mortality were the highest among neonates with a birth weight <1000 g (20.37/1000 LB and 8.49/1000 LB, respectively). The most common pathogens were GBS (n = 27, 0.18/1000 LB) and Escherichia coli (n = 19, 0.13/1000 LB). Most infants affected by E. coli EOS were born preterm (n = 13), had complications (n = 4) or died (n = 7). Among 90 isolates tested, only 3 were resistant to both first line empirical antibiotics. Multivariate logistic regression analysis showed that low gestational age, caesarean section and low platelet count at presentation were significantly associated with death or brain lesions (area under ROC curve = 0.939, H-L = 0.944, sensitivity 76.0%, specificity 90.7%). CONCLUSIONS: GBS slightly exceeds E. coli as a cause of EOS. However, E. coli is the prominent cause of death, complications and in most cases affects preterm neonates. Empirical antimicrobial therapy of EOS seems appropriate. PMID- 26515918 TI - Hepatitis B e antigen-positive and high levels of alanine aminotransferase are associated with prevalence of metabolic syndrome in chronic HBV patients. AB - OBJECTIVE: The interactions between hepatitis B virus (HBV) infection and metabolic syndrome (MS) have not been elucidated. This study was aimed to investigate the relationship between metabolic profile and HBV infection. METHODS: A retrospective cross-sectional study including patients infected by HBV (HBV group, n=121) and healthy volunteers (control group, n=263) was conducted, serum HBV viral load and markers, serum alanine aminotransferase (ALT) levels and MS were analyzed. Factors associated with prevalence of MS were explored with multivariate adjusted logistic regression analyses. RESULTS: The prevalence of MS was 9.9% in HBV infected patients and 19.4% in controls (p=0.011). Factors associated with the prevalence of MS were (odds ratio, 95% confidence interval, p value): hepatitis B e antigen (HBeAg) positive (0.368, 0.107-0.653, 0.008) and high levels of ALT (0.183, 0.120-0.268, <0.001) in HBV patients. But clinical and virological factors (including age, HBV DNA level, male gender, BMI, and fatty liver) were not found to be associated with prevalence of MS in HBV patients who were HBeAg positive with high levels of ALT. CONCLUSION: These findings suggest that HBeAg positive and high levels of ALT are independently associated with lower prevalence of MS in HBV patients. But HBV DNA may not have impact on the lipid metabolism. HBV-related immune reactions may play a certain role in the mechanism of MS. PMID- 26515919 TI - Clinical interpretation of cardiopulmonary exercise testing in cystic fibrosis and implications for exercise counselling. AB - The measurement of exercise capacity in persons with cystic fibrosis by Cardiopulmonary Exercise Testing (CPET) offers a functional assessment of lung performance and efficiency in a dynamic setting. Exercise performance can measured against predicted values and the mechanism by which exercise limitation occurs can be identified. In healthy subjects, exercise is limited by cardiac output, such that a significant breathing reserve exists at the end of exercise. However, other mechanisms of exercise limitation which may be identified in CF subjects include ventilatory limitation, and/or limitation due to physical deconditioning. A detailed understanding of exercise capacity and the mechanism for exercise limitation may enable health professionals to tailor an individualised exercise programme for each CF patient. PMID- 26515920 TI - Negotiating Diet in Networks: A Cross-European Study of the Experiences of Managing Type 2 Diabetes. AB - Food and diet are central aspects of diabetes self-management but the relevance of social networks for the way people are supported in their management of type 2 diabetes is often under-acknowledged. In this article, we aimed to explore the coalescences between these two phenomena among people with type 2 diabetes to increase knowledge of interactions within social network related to daily diet. The article is based on 125 qualitative interviews with individuals with type 2 diabetes from five European countries. Based on assumptions that people with chronic illnesses reshape relationships through negotiation, we analyzed negotiations of food at different levels of network. The respondents' reflections indicate that there are complex negotiations that influence self-management and food, including support, knowledge, and relationships within families; attention and openness in social situations; and the premises and norms of society. PMID- 26515921 TI - Shared Illness and Social Support Within Two HIV-Affected African American Communities. AB - A key source of resiliency within HIV-affected African American communities is informal social support. Data from dyadic conversations and focus groups were used to address the following research question: What are HIV-positive African Americans' social support experiences within their informal social networks in response to HIV-related problems? Circumstances that exacerbated HIV-related problems included others' fear of contagion, reticence to be involved, judgment and rejection, and disregard for privacy Support from HIV-negative others buffered the impact of problems when others communicate interest, take the initiative to help, or make a long-term investment in their success. Support from other HIV-positive persons was helpful given the shared connection because of HIV, the opportunity to commiserate about what is mutually understood, and the fight for mutual survival Based on these findings, we offer suggestions for future research and social network interventions aimed at bolstering connections between HIV-positive peers, reducing stigma, and improving family support. PMID- 26515922 TI - Negotiating Violence in the Context of Transphobia and Criminalization: The Experiences of Trans Sex Workers in Vancouver, Canada. AB - A growing body of international evidence suggests that sex workers face a disproportionate burden of violence, with significant variations across social, cultural, and economic contexts. Research on trans sex workers has documented high incidents of violence; however, investigations into the relationships between violence and social-structural contexts are limited. Therefore, the objective of this study was to qualitatively examine how social-structural contexts shape trans sex workers' experiences of violence. In-depth semistructured interviews were conducted with 33 trans sex workers in Vancouver, Canada, between June 2012 and May 2013. Three themes emerged that illustrated how social-structural contexts of transphobia and criminalization shaped violent experiences: (a) transphobic violence, (b) clients' discovery of participants' gender identity, and (c) negative police responses to experiences of violence. The findings demonstrate the need for shifts in sex work laws and culturally relevant antistigma programs and policies to address transphobia. PMID- 26515923 TI - Exploring the Photodeactivation Pathways of Pt[O^N^C^N] Complexes: A Theoretical Perspective. AB - In this article, the influence of the tert-butyl unit on the photodeactivation pathways of Pt[O^N^C^N] (O^N^C^N=2-(4-(3,5-di-tert-butylphenyl)-6-(3-(pyridin-2 l)phenyl) pyridin-2-yl)phenolate) is investigated by DFT/TDDFT calculations. To further explore the factors that determine the radiative processes, the transition dipole moments of the singlet excited states, spin-orbit coupling (SOC) matrix elements, and energy gaps between the lowest triplet excited states and singlet excited states are calculated. As demonstrated by the results, compared with Pt-3, Pt-1 and Pt-2 have larger SOC matrix elements between the lowest triplet excited states and singlet excited states, an indicator that they have faster radiative decay processes. In addition, the SOC matrix elements between the lowest triplet excited states and ground states are also computed to elucidate the temperature-independent non-radiative decay processes. Moreover, the temperature-dependent non-radiative decay mechanisms are also explored via the potential energy profiles. PMID- 26515924 TI - Remediation of lead and cadmium-contaminated soils. AB - The research was designated to study the ability of plants to bio-accumulate, translocate and remove the heavy metals, lead and cadmium from contaminated soil. The herbal plant ryegrass, Lolium multiflorum was investigated as a bio accumulator plant for these metals. The translocation of these heavy metals in the herbal plant was compared considering root to shoot transport and redistribution of metals in the root and shoot system. The trace metal contents from root and shoot parts were determined using atomic absorption spectrometer. The results showed that the percent of lead and cadmium transferred to ryegrass plant were averaged as 51.39, and 74.57%, respectively, while those remained in the soil were averaged as 48.61 and 25.43% following 60 days of treatment. The soil-plant transfer index in root and shoot system of ryegrass was found to be 0.32 and 0.20 for lead, and 0.50 and 0.25 for cadmium. These findings indicated that the herbal plant ryegrass, Lolium multiflorum is a good accumulator for cadmium than lead. The soil-plant transfer factor (the conc. of heavy metal in plant to the conc. in soil) indicated that the mechanism of soil remedy using the investigated plant is phytoextraction where the amounts of heavy metals transferred by plant roots into the above ground portions were higher than that remained in the soil. The method offers green technology solution for the contamination problem since it is effective technology with minimal impact on the environment and can be easily used for soil remedy. PMID- 26515925 TI - An assessment of the herd-level impact of the Theileria orientalis (Ikeda) epidemic of cattle in New Zealand, 2012-2013: a mixed methods approach. AB - AIM: To estimate incidence risk, cumulative mortality and case fatality rate within herds affected by bovine anaemia associated with Theileria orientalis infection (TABA), in New Zealand during the early phase of the epidemic (August 2012-September 2013). METHODS: A mixed methods approach was utilised to integrate data from various sources, including a detailed questionnaire carried out on 18 dairy farms which had experienced cases of TABA; a brief telephone survey of an additional 139 case farms; and data extracted from a Ministry for Primary Industries database for a further 42 case farms. The subsequent analysis determined incidence risk, cumulative mortality and case fatality rates for beef and dairy herds. RESULTS: Data were analysed from 196/263 (74%) known case farms at the date of closing the questionnaires. These farms contained 99,505 cattle; 2,847 animals were reported with clinical disease, and a further 590 animals were recorded as having died from TABA. The within-herd incidence risk, cumulative mortality and case fatality rate were consistent between the three data sources, did not differ between beef and dairy herds, and were estimated to be 0.97 (inter quartile range (IQR) 0.36-2.07)%, 0.23 (IQR 0.00-0.66)% and 16.67 (IQR 0.00 33.33)%, respectively. There was substantial variability in the level of impact, with 22 farms severely affected (incidence risk >5% and cumulative mortality >5%). CONCLUSIONS: The mixed methods approach was effective in dealing with the disparate data sources. The inclusion of the majority of farms known to be affected at the time the questionnaires were performed implies that the information is likely to be representative. The collective outputs of the analyses represent the best estimate available of within-herd measures of disease frequency in the early phase of the epidemic in New Zealand. The limitations of the data imply that their primary application may be to inform the design of subsequent structured observational field studies. CLINICAL RELEVANCE: The results of this study provide information on the impact of TABA on cattle farms during the emergence and early spread of the disease, as well as for generating hypotheses on causal mechanisms and risk factors that may influence the course of disease. PMID- 26515926 TI - Biosocial correlates and spatial distribution of consanguinity in South America. AB - OBJECTIVE: To analyze potential biosocial factors in consanguineous unions according to the level of consanguinity and its spatial distribution in South America. METHODS: The data used came from the Latin American Collaborative Study of Congenital Malformations. Information on 126,213 nonmalformed newborns out of 6,014,749 births was used. This information was collected between 1967 and 2011 at 204 hospitals in 116 cities in 10 South American countries. The spatial scan statistic was performed under a model of nonhierarchical k-means segmentation, based on statistically significant clusters, areas with levels of high, medium, and low consanguinity were determined. RESULTS: Consanguinity in South America is heterogeneously distributed, with two groups of high consanguinity, in northwestern Venezuela and southeast of Brazil, and two clusters of low consanguinity located in the south of the continent, mainly Argentina. The socio demographic factors associated with consanguinity influence the population structure in areas of high consanguinity. CONCLUSIONS: This study demonstrates that consanguinity in the South American continent is strongly associated with a greater magnitude of poverty in the area of high consanguinity. Am. J. Hum. Biol. 28:405-411, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26515927 TI - Transcriptomic and epigenomic landscapes during cell fusion in BeWo trophoblast cells. AB - INTRODUCTION: Syncytialization is a process essential to the genesis and vitality of the decisive maternal-fetal interface, the syncytiotrophoblast. While the role of specific genes important in syncytial fusion is appreciated, an integrated global analysis of syncytialization is absent. METHODS: We leveraged a variety of approaches (RNA-seq, genome-scale DNA methylation and ChIP-seq) to assemble a genome-wide transcriptomic and epigenomic view of syncytialization in BeWo cells. RESULTS: RNA-seq analysis of expression profiles revealed alterations in ~3000 genes over the 3 day time-course of forskolin, including identification of several previously unrecognized genes to be involved in syncytialization. These genes were enriched for cell differentiation, morphogenesis, blood vessel and placental labyrinth development and steroid hormone response. Genome-scale DNA methylation via reduced representation bisulfite sequencing (RRBS) showed altered methylation of a number of CpGs associated with cell differentiation and commitment. Finally, genome-wide localization of seven key histone marks encompassing permissive (H3K4me3, H3K9ac, H3K27ac), enhancer (H3K4me1), elongation (H3K36me3) and repressive (H3K27me3, H3K9me3) states was performed via ChiP-seq. These analyses clearly revealed that syncytialization was associated with a gain in transcriptionally permissive/active marks (H3K4me3, K9ac, K27ac and K36me3) among genes that are either constitutive or upregulated in syncytialization. DISCUSSION: Overall, these results provide a novel resource to elucidate the underlying epigenetic mechanisms coordinating transcriptional changes associated with syncytialization in BeWo cells. PMID- 26515928 TI - IL-1 beta but not the NALP3 inflammasome is an important determinant of endothelial cell responses to necrotic/dangerous trophoblastic debris. AB - INTRODUCTION: Necrotic but not apoptotic trophoblastic debris can induce endothelial cell activation but the mechanism by which endothelial cells distinguish apoptotic from necrotic debris is unclear. The NALP3 inflammasome is a pattern recognition receptor that macrophages employ to recognise "danger signals" in necrotic cell corpses. In this study, we hypothesized that endothelial cells can identify and respond to necrotic trophoblastic debris via the NALP3 inflammasome. METHODS: The effect of trophoblastic debris on endothelial expression of NALP3 inflammasome components was investigated using qRT-PCR, immunoassays and fluorescent caspase 1 activity assay. IL-1beta in was quantified by ELISA. Endothelial cell activation was measured by cell surface ICAM expression and monocytes adhesion assay. RESULTS: The NALP3 inflammasome was expressed in resting vascular endothelial cells and is involved in endothelial response to danger signals. However, exposure to necrotic trophoblastic debris did not significantly alter the expression of any of the three components of the NALP3 inflammasome at the mRNA level, nor was caspase-1 activation increased. Conditioned media from endothelial cells exposed to necrotic trophoblastic debris contained elevated levels of IL-1beta which was derived from the necrotic debris and which contributed to endothelial cell activation. DISCUSSION: Necrotic trophoblastic debris induced endothelial cell activation through the IL-1beta/IL 1R pathway. However, the NALP3 inflammasome in endothelial cells was not involved in this process. PMID- 26515930 TI - Supramolecular photochemistry applied to artificial photosynthesis and molecular logic devices. AB - Supramolecular photochemical systems consist of photochemically active components such as chromophores, electron donors or electron acceptors that are associated via non-covalent or covalent interactions and that interact in some functional way. Examples of interactions are singlet-singlet energy transfer, triplet triplet energy transfer, photoinduced electron transfer, quantum coherence and spin-spin magnetic interactions. Supramolecular photochemical "devices" may have applications in areas such as solar energy conversion, molecular logic, computation and data storage, biomedicine, sensing, imaging, and displays. This short review illustrates supramolecular photochemistry with examples drawn from artificial photosynthesis, molecular logic, analog photochemical devices and models for avian magnetic orientation. PMID- 26515929 TI - Circadian clock-related genetic risk scores and risk of placental abruption. AB - INTRODUCTION: The circadian clock plays an important role in several aspects of female reproductive biology. Evidence linking circadian clock-related genes to pregnancy outcomes has been inconsistent. We sought to examine whether variations in single nucleotide polymorphisms (SNPs) of circadian clock genes are associated with PA risk. METHODS: Maternal blood samples were collected from 470 PA case and 473 controls. Genotyping was performed using the Illumina Cardio-MetaboChip platform. We examined 119 SNPs in 13 candidate genes known to control circadian rhythms (e.g., CRY2, ARNTL, and RORA). Univariate and penalized logistic regression models were fit to estimate odds ratios (ORs); and the combined effect of multiple SNPs on PA risk was estimated using a weighted genetic risk score (wGRS). RESULTS: A common SNP in the RORA gene (rs2899663) was associated with a 21% reduced odds of PA (P < 0.05). The odds of PA increased with increasing wGRS (Ptrend < 0.001). The corresponding ORs were 1.00, 1.83, 2.81 and 5.13 across wGRS quartiles. Participants in the highest wGRS quartile had a 5.13-fold (95% confidence interval: 3.21-8.21) higher odds of PA compared to those in the lowest quartile. Although the test for interaction was not significant, the odds of PA was substantially elevated for preeclamptics with the highest wGRS quartile (OR = 14.44, 95%CI: 6.62-31.53) compared to normotensive women in the lowest wGRS quartile. DISCUSSION: Genetic variants in circadian rhythm genes may be associated with PA risk. Larger studies are needed to corroborate these findings and to further elucidate the pathogenesis of this important obstetrical complication. PMID- 26515931 TI - Role of the dorsal diencephalic conduction system in the brain reward circuitry. AB - Previous work with psychophysically based studies suggests that electrolytic lesion of the habenula, which lies in the dorsal diencephalic conduction system (DDC), degrades the intracranial self-stimulation (ICSS). This experiment was aimed at studying the importance of the DDC in brain stimulation reward, and its connections with other areas that support operant responding for brain stimulation. For this purpose, rats were implanted with stimulating electrodes at the dorsal raphe (DR) and lateral hypothalamus (LH), and lesioning electrodes in the medial forebrain bundle (MFB) and the DDC. Rats were trained to self administer the stimulation at three different current intensities and were tested daily for changes in reward thresholds, defined as the pulse frequency required for half-maximal responding. The lesions were done at the DDC and the MFB, and were separated by two weeks interval during which the rats were tested for self stimulation. At the end of the experiment, rats were transcardially perfused and their brains collected to determine the extent of the lesions and the locations of the stimulation sites. Results show that lesions at both the DDC and MFB produce larger and longer-lasting increases in the reward thresholds (upto 0.40 log10 units) than lesions at either pathway alone (upto 0.25 log10 units), and were more effective in attenuating the reward induced by the LH stimulation. These results suggest that there exist two parallel pathways, the MFB and the DDC, which could constitute a viable route for the reward signal triggered by ICSS. PMID- 26515933 TI - Spontaneous pneumomediastinum in pregnancy: A case report. PMID- 26515932 TI - Brain functional connectivity patterns for emotional state classification in Parkinson's disease patients without dementia. AB - Successful emotional communication is crucial for social interactions and social relationships. Parkinson's Disease (PD) patients have shown deficits in emotional recognition abilities although the research findings are inconclusive. This paper presents an investigation of six emotions (happiness, sadness, fear, anger, surprise, and disgust) of twenty non-demented (Mini-Mental State Examination score >24) PD patients and twenty Healthy Controls (HCs) using Electroencephalogram (EEG)-based Brain Functional Connectivity (BFC) patterns. The functional connectivity index feature in EEG signals is computed using three different methods: Correlation (COR), Coherence (COH), and Phase Synchronization Index (PSI). Further, a new functional connectivity index feature is proposed using bispectral analysis. The experimental results indicate that the BFC change is significantly different among emotional states of PD patients compared with HC. Also, the emotional connectivity pattern classified using Support Vector Machine (SVM) classifier yielded the highest accuracy for the new bispectral functional connectivity index. The PD patients showed emotional impairments as demonstrated by a poor classification performance. This finding suggests that decrease in the functional connectivity indices during emotional stimulation in PD, indicating functional disconnections between cortical areas. PMID- 26515934 TI - Bronchial artery embolisation in management of hemoptysis--A retrospective analysis in a tertiary university hospital. AB - BACKGROUND: Bronchial artery embolisation (BAE) becomes a mainstay in the treatment of hemoptysis. OBJECTIVE: To characterise patients with hemoptysis undergoing bronchial artery angiography (BAA) for embolisation, evaluating outcomes. METHODS: We retrospectively evaluated patients with acute severe or chronic recurrent hemoptysis admitted to the Pulmonology department and submitted to BAA for purpose of embolisation. RESULTS: A total of 88 patients were submitted to BAA, 47 (53.4%) were male, with a mean age of 61.4 +/- 15.8 years. In 64 (72.7%) patients, hemoptysis presented as chronic recurrent episodes. Hemoptysis was considered severe in 40 (45.5%) patients. Bronchiectasis (other than cystic fibrosis) (n=35; 38.0%) and tuberculosis sequelae (n=31; 35.2) were the major aetiology for hemoptysis. The main angiographic abnormality was hypertrophy and tortuosity (n=68; 77.3%). BAE was performed in 67 (76.1%) of the 88 patients submitted to BAA. Immediate success was achieved in 66 (98.5%) patients. Recurrence of hemoptysis occurred in 25 (37.3%) patients, and was related to presence of shunting (p=0.049). The procedure-related complications were self-limited. CONCLUSION: Our results suggest that BAE is a safe and effective treatment for acute severe and chronic recurrent hemoptysis, supporting the current literature. Besides this, bleeding recurrence was relatively high, and correlated with presence of systemic pulmonary shunting. PMID- 26515935 TI - Social profile of the highest tuberculosis incidence areas in Portugal. PMID- 26515936 TI - Association of uterine wall thickness with pregnancy outcome following uterine sparing surgery for diffuse uterine adenomyosis. AB - BACKGROUND: The risk of uterine rupture is a major concern for women who become pregnant after undergoing an adenomyomectomy. AIMS: The aim of this study was to investigate the association of uterine wall thickness with pregnancy outcome. MATERIALS AND METHODS: Uterine wall thickness was measured using sonography and/or magnetic resonance imaging in 23 pregnant women who underwent uterine sparing surgery for diffuse uterine adenomyosis prior to conception. RESULTS: Of the 23 women, 10 (43.5%) had an early miscarriage and 13 (56.5%) proceeded to delivery. Of the ten early miscarriage cases, two had a uterine rupture caused by excision of the uterine wall to within 7 mm. CONCLUSIONS: Wall thickness of the excised uterus was highly associated with uterine rupture. We concluded that optimum wall thickness for conception and preventing uterine rupture during pregnancy may range from 9 to 15 mm. PMID- 26515937 TI - Corrigendum: Formation and reshuffling of disulfide bonds in bovine serum albumin demonstrated using tandem mass spectrometry with collision-induced and electron transfer dissociation. PMID- 26515938 TI - Use of hydrodynamic cavitation in (waste)water treatment. AB - The use of acoustic cavitation for water and wastewater treatment (cleaning) is a well known procedure. Yet, the use of hydrodynamic cavitation as a sole technique or in combination with other techniques such as ultrasound has only recently been suggested and employed. In the first part of this paper a general overview of techniques that employ hydrodynamic cavitation for cleaning of water and wastewater is presented. In the second part of the paper the focus is on our own most recent work using hydrodynamic cavitation for removal of pharmaceuticals (clofibric acid, ibuprofen, ketoprofen, naproxen, diclofenac, carbamazepine), toxic cyanobacteria (Microcystis aeruginosa), green microalgae (Chlorella vulgaris), bacteria (Legionella pneumophila) and viruses (Rotavirus) from water and wastewater. As will be shown, hydrodynamic cavitation, like acoustic, can manifest itself in many different forms each having its own distinctive properties and mechanisms. This was until now neglected, which eventually led to poor performance of the technique. We will show that a different type of hydrodynamic cavitation (different removal mechanism) is required for successful removal of different pollutants. The path to use hydrodynamic cavitation as a routine water cleaning method is still long, but recent results have already shown great potential for optimisation, which could lead to a low energy tool for water and wastewater cleaning. PMID- 26515939 TI - Cardiovascular Complications Following Thoracic Surgery. AB - Cardiovascular events after thoracic surgery can result in increased morbidity, mortality, length of stay, and increased overall cost. The prevention of postoperative cardiovascular complications is an area of intense study, and the body of evidence guiding clinicians continues to grow. Early diagnosis and management of cardiovascular events can minimize the consequences of these complications. PMID- 26515940 TI - Pain Management Following Thoracic Surgery. AB - Postoperative pain following thoracic surgery presents a significant challenge, and multiple factors complicate recovery and pain management for this population. Considerable comorbidities often exist in thoracic surgical patients, further limiting therapeutic options. Elements of nociceptive and neuropathic pain may contribute greatly to patient discomfort. There is no single pharmaceutical agent or route of administration that addresses every individual contributor to pain, and thus treatment regimens should be multimodal and tailored to the patient and procedure. This article outlines systemic agents, regional techniques and attendant complications, etiologies of pain following thoracic procedures, and the development and treatment of chronic pain. PMID- 26515941 TI - The Prevention and Management of Air Leaks Following Pulmonary Resection. AB - Alveolar air leaks are a common problem in the daily practice of thoracic surgeons. Prolonged air leak following pulmonary resection is associated with increased morbidity, increased length of hospital stay, and increased costs. This article reviews the evidence for the various intraoperative and postoperative options to prevent and manage postoperative air leak. PMID- 26515942 TI - Bronchopleural Fistula and Empyema After Anatomic Lung Resection. AB - Empyema after anatomic lung resection is rare but causes serious morbidity, particularly if associated with a bronchopleural fistula. Careful assessment of preoperative risk factors and proper surgical technique can minimize risks. Empyema after segmentectomy or lobectomy may respond to simple drainage and antibiotics, or may require decortication with or without muscle transposition. After pneumonectomy, treatment principles include initial drainage of the intrathoracic space, closure of the fistula if present, and creation of an open thoracostomy, which is packed and later closed. Success rates can exceed 80%. PMID- 26515943 TI - Management of Postoperative Respiratory Failure. AB - Despite best efforts, postoperative complications such as postoperative respiratory failure may occur and prompt recognition of the process and management is required. Postoperative respiratory failure, such as postoperative pneumonia, postpneumonectomy pulmonary edema, acute respiratory distress-like syndromes, and pulmonary embolism, are associated with high morbidity and mortality. The causes of these complications are multifactorial and depend on preoperative, intraoperative, and postoperative factors, some of which are modifiable. The article identifies some of the risk factors, causes, and treatment strategies for successful management of the patient with postoperative respiratory failure. PMID- 26515944 TI - Complications Following Carinal Resections and Sleeve Resections. AB - Pulmonary resections with concomitant circumferential airway resection and resection and reconstruction of carina and main stem bronchi remain challenging operations in thoracic surgery. Anastomotic complications range from mucosal sloughing and formation of granulation tissue, anastomotic ischemia promoting scar formation and stricture, to anastomotic breakdown leading to bronchopleural or bronchovascular fistulae or complete dehiscence. Careful attention to patient selection and technical detail results in acceptable morbidity and mortality as well as good long-term survival. In this article, we focus on the technical details of the procedures, how to avoid complications and most importantly how to manage complications when they occur. PMID- 26515945 TI - Anastomotic Leakage Following Esophagectomy. AB - Anastomotic leaks remain a significant clinical challenge following esophagectomy with foregut reconstruction. Despite an increasing understanding of the multiple contributing factors, advancements in perioperative optimization of modifiable risks, and improvements in surgical, endoscopic, and percutaneous management techniques, leaks remain a source of major morbidity associated with esophageal resection. The surgeon should be well versed in the principles underlying the cause of leaks, and strategies to minimize their occurrence. Appropriately diagnosed and managed, most anastomotic leaks following esophagectomy can be brought to a successful resolution. PMID- 26515946 TI - Management of Conduit Necrosis Following Esophagectomy. AB - The management of conduit necrosis during or after esophagectomy requires the assembly of a multidisciplinary team to manage nutrition, sepsis, intravenous access, reconstruction, and recovery. Reconstruction is most often performed as a staged procedure. The initial surgery is likely to involve esophageal diversion onto the chest where possible, making an effort to preserve esophageal length. Optimization of patients before reconstruction enhances outcomes following reconstruction with either jejunum or colon after gastric conduit failure. Maintaining enteral access for feeding at all times is imperative. Management of patients should be performed at high-volume esophageal centers performing regular reconstructions. PMID- 26515947 TI - Functional Conduit Disorder Complicating Esophagectomy. AB - Esophagectomy remains a key component of treatment for esophageal cancer and is also required in certain benign conditions. The functional sequelae of esophageal resection and reconstruction have taken on increasing importance due to the impact on long-term patient quality of life. Surgeons should be committed to a meticulous approach to conduit construction, avoid anastomoses in the mid and lower chest, and should also commit to careful long-term functional follow-up in their postesophagectomy patient population. Operative strategies to minimize functional disorders have been developed and all surgeons should have a structured approach to dealing with functional issues when they occur. PMID- 26515948 TI - Complications Following Surgery for Gastroesophageal Reflux Disease and Achalasia. AB - Surgical procedures to treat reflux disease are common, but good outcomes rely on both a thorough preoperative workup and careful surgical techniques. Although complications are uncommon, surgeons should recognize these and possess the skills to overcome them in clinical practice. PMID- 26515949 TI - Prevention and Management of Complications Following Tracheal Resection. AB - Careful patient selection and preparation are paramount to optimize outcomes following tracheal resection. Risk factors for postoperative anastomotic complications include age less than 17 years, reoperation, laryngeal involvement, diabetes, increased length of resection, and need for preoperative tracheostomy. Major complications involve the anastomosis and are associated with an increased risk of mortality. Complications range from granulation tissue formation to stricture to separation, and successful management typically requires reoperation, T-tube stenting, or tracheostomy. Other complications to consider include vocal cord edema, recurrent laryngeal nerve injury, esophageal injury, wound infection, swallowing dysfunction, aspiration pneumonia, and fistula to the esophagus or innominate artery. PMID- 26515950 TI - Prevention and Management of Nerve Injuries in Thoracic Surgery. AB - Nerve injuries can cause substantial morbidity after thoracic surgical procedures. These injuries are preventable, provided that the surgeon has a thorough understanding of the anatomy and follows important surgical principles. When nerve injuries occur, it is important to recognize the options available in the immediate and postoperative settings, including expectant management, immediate nerve reconstruction, or auxiliary procedures. This article covers the basic anatomy and physiology of nerves and nerve injuries, an overview of techniques in nerve reconstruction, and a guide to the nerves most commonly involved in thoracic operative procedures. PMID- 26515951 TI - Chest Wall Resection and Reconstruction: Management of Complications. AB - The main indications for chest wall resection continue to be tumors, infection, and radiation injury. Complications surrounding chest wall resection procedures include respiratory failure, wound complications, and prosthetic complications. The main risk factors for complications are size of defect, age, and concomitant lung resection. Most complications related to either the wound or the prosthesis are late postoperative events. The identification of complications related to chest wall reconstruction requires clinical examination and the use of detailed imaging studies. The management of both prosthetic and wound complications often requires reoperation and removal of the prosthesis combined with soft tissue wound management. PMID- 26515952 TI - Postoperative Chylothorax. AB - Chylothorax is an unusual but serious complication of thoracic surgical procedures, and may carry considerable morbidity if not addressed in a timely fashion. Thoracic surgeons should be able to promptly diagnose this complication, and understand the implications of prolonged chyle loss to the patient. Conservative measures are often successful; direct intervention with percutaneous embolization of the cisterna chyli or thoracoscopic ligation is reserved for refractory cases. Some controversy exists regarding the timing of reintervention to limit the accumulated chyle loss. Prophylactic thoracic duct ligation has been examined but to date does not seem to reduce the incidence of chylothorax. PMID- 26515953 TI - Reducing the Footprint of Postoperative Complications. PMID- 26515954 TI - Light-intensity grazing improves alpine meadow productivity and adaption to climate change on the Tibetan Plateau. AB - To explore grazing effects on carbon fluxes in alpine meadow ecosystems, we used a paired eddy-covariance (EC) system to measure carbon fluxes in adjacent fenced (FM) and grazed (GM) meadows on the Tibetan plateau. Gross primary productivity (GPP) and ecosystem respiration (Re) were greater at GM than FM for the first two years of fencing. In the third year, the productivity at FM increased to a level similar to the GM site. The higher productivity at GM was mainly caused by its higher photosynthetic capacity. Grazing exclusion did not increase carbon sequestration capacity for this alpine grassland system. The higher optimal photosynthetic temperature and the weakened ecosystem response to climatic factors at GM may help to facilitate the adaption of alpine meadow ecosystems to changing climate. PMID- 26515955 TI - Risk stratification in acute upper GI bleeding: comparison of the AIMS65 score with the Glasgow-Blatchford and Rockall scoring systems. AB - BACKGROUND AND AIMS: The American College of Gastroenterology recommends early risk stratification in patients presenting with upper GI bleeding (UGIB). The AIMS65 score is a risk stratification score previously validated to predict inpatient mortality. The aim of this study was to validate the AIMS65 score as a predictor of inpatient mortality in patients with acute UGIB and to compare it with established pre- and postendoscopy risk scores. METHODS: ICD-10 (International Classification of Diseases, Tenth Revision) codes identified patients presenting with UGIB requiring endoscopy. All patients were risk stratified by using the AIMS65, Glasgow-Blatchford score (GBS), pre-endoscopy Rockall, and full Rockall scores. The primary outcome was inpatient mortality. Secondary outcomes were a composite endpoint of inpatient mortality, rebleeding, and endoscopic, radiologic, or surgical intervention; blood transfusion requirement; intensive care unit (ICU) admission; rebleeding; and hospital length of stay. The area under the receiver-operating characteristic curve (AUROC) was calculated for each score. RESULTS: Of the 424 study patients, 18 (4.2%) died and 69 (16%) achieved the composite endpoint. The AIMS65 score was superior to both the GBS (AUROC, 0.80 vs 0.76, P < .027) and the pre-endoscopy Rockall score (0.74, P = .001) and equivalent to the full Rockall score (0.78, P = .18) in predicting inpatient mortality. The AIMS65 score was superior to all other scores in predicting the need for ICU admission and length of hospital stay. AIMS65, GBS, and full Rockall scores were equivalent (AUROCs, 0.63 vs 0.62 vs 0.63, respectively) and superior to pre-endoscopy Rockall (AUROC, 0.55) in predicting the composite endpoint. GBS was superior to all other scores for predicting blood transfusion. CONCLUSION: The AIMS65 score is a simple risk stratification score for UGIB with accuracy superior to that of GBS and pre-endoscopy Rockall scores in predicting in-hospital mortality and the need for ICU admission. PMID- 26515956 TI - EUS-guided drainage of peripancreatic fluid collections and necrosis by using a novel lumen-apposing stent: a large retrospective, multicenter U.S. experience (with videos). AB - BACKGROUND AND AIMS: EUS-guided drainage of peripancreatic fluid collection (PFC) (pancreatic pseudocyst [PP] or walled-off necrosis [WON]) by using a novel lumen apposing, fully covered, self-expandable metal stent (LAMS) has been promising, but few of these data are from the United States. The aim of this study was to evaluate clinical outcomes and safety of EUS-guided drainage of pancreatic pseudocysts and WON by using the LAMS. METHODS: We conducted a multicenter, retrospective study on 82 patients with symptomatic PFC who underwent EUS-guided drainage by using the LAMS at 4 U.S. tertiary care centers. Outcomes evaluated included successful placement of the LAMS, the number of patients in whom complete resolution of PPs or WON was achieved, the number of procedures performed per patient to achieve PFC resolution, and adverse events. RESULTS: The mean size of the PFC was 11.8 cm. LAMSs were successfully placed in 80 patients (97.5%). Twelve patients had PP and 68 had WON. The median stent in-dwelling time was 2 months (range 1-3 months). Endoscopic debridement with the LAMS in WON was performed in 54 patients. The patency of the stent was maintained in 98.7% of the patients (77/78). There was spontaneous dislodgment of 2 LAMSs. Successful endoscopic therapy by using the LAMS was successful in 12 of 12 patients (100%) with PP compared with 60 of 68 patients (88.2%) with WON. All stents were endoscopically removed from all patients after peripancreatic fluid collection (PFC) resolution. There was 1 PFC recurrence during the 3-month median follow-up period. Procedure-related adverse events occurred in 8 patients (9.8%), and included stent maldeployment (n = 2), and self-limited bleeding (n = 6). In 1 patient with stent maldeployment gastric perforation developed, and the patient underwent surgical repair. CONCLUSION: EUS-guided drainage of PFCs by using the novel LAMS has high technical and long-term success rates. Due to its ease of use, the LAMSs may simplify and streamline EUS-guided management of PFCs, particularly for the endoscopic debridement of WON, and may help in its widespread adoption as an alternative to surgery. PMID- 26515957 TI - Variation in learning curves and competence for ERCP among advanced endoscopy trainees by using cumulative sum analysis. AB - BACKGROUND AND AIMS: There are limited data on learning curves and competence in ERCP. By using a standardized data collection tool, we aimed to prospectively define learning curves and measure competence among advanced endoscopy trainees (AETs) by using cumulative sum (CUSUM) analysis. METHODS: AETs were evaluated by attending endoscopists starting with the 26th hands-on ERCP examination and then every ERCP examination during the 12-month training period. A standardized ERCP competency assessment tool (using a 4-point scoring system) was used to grade the examination. CUSUM analysis was applied to produce learning curves for individual technical and cognitive components of ERCP performance (success defined as a score of 1, acceptable and unacceptable failures [p1] of 10% and 20%, respectively). Sensitivity analyses varying p1 and by using a less-stringent definition of success were performed. RESULTS: Five AETs were included with a total of 1049 graded ERCPs (mean +/- SD, 209.8 +/- 91.6/AET). The majority of cases were performed for a biliary indication (80%). The overall and native papilla allowed cannulation times were 3.1 +/- 3.6 and 5.7 +/- 4, respectively. Overall learning curves demonstrated substantial variability for individual technical and cognitive endpoints. Although nearly all AETs achieved competence in overall cannulation, none achieved competence for cannulation in cases with a native papilla. Sensitivity analyses increased the proportion of AETs who achieved competence. CONCLUSION: This study demonstrates that there is substantial variability in ERCP learning curves among AETs. A specific case volume does not ensure competence, especially for native papilla cannulation. PMID- 26515958 TI - Divergent C-H Insertion-Cyclization Cascades of N-Allyl Ynamides. AB - Gold carbene reactivity patterns were accessed by ynamide insertion into a C(sp(3) )?H bond. A substantial increase in molecular complexity occurred through the cascade polycyclization of N-allyl ynamides to form fused nitrogen heterocycle scaffolds. Exquisite selectivity was observed despite several competing pathways in an efficient gold-catalyzed synthesis of densely functionalized C(sp(3) )-rich polycycles and a copper-catalyzed synthesis of fused pyridine derivatives. The respective gold-keteniminium and ketenimine activation pathways have been explored through a structure-reactivity study, and isotopic labeling identified turnover-limiting C?H bond-cleavage in both processes. PMID- 26515961 TI - Introduction to the Special Issue: Social Work Takes a Leading Role in Affordable Care Act Initiatives at The Mount Sinai Hospital. PMID- 26515959 TI - ROUTINE-a prospective, multicentre, non-interventional, observational study to evaluate the safety and effectiveness of intravenous tocilizumab for the treatment of active rheumatoid arthritis in daily practice in Germany. AB - OBJECTIVE: To evaluate the tolerability, effectiveness and utilization of tocilizumab for the treatment of RA in a usual care setting. METHODS: ROUTINE was a prospective, non-interventional, observational 52-week study performed at 174 sites throughout Germany. RA patients were selected and treated according to label. Study objectives included the targeted documentation of infections, other adverse events, and various effectiveness outcomes (e.g. DAS28, clinical disease activity). Statistical analyses were performed primarily based on the data as observed. RESULTS: A total of 850 patients (75% women, mean age: 56 +/- 13 years, mean RA duration: 10.3 +/- 8.6 years) were enrolled. Most patients (79%) were pretreated with TNF-inhibitors, whereas 21% were pretreated with conventional DMARDs only. Most common DMARD pretreatments were MTX (79%), LEF (68%), adalimumab (53%) and etanercept (50%). At baseline, 60.5% of patients received tocilizumab in combination with any other RA drugs, while 39.5% were treated in monotherapy. Mean baseline DAS28 was 5.5 +/- 1.3, and this decreased to 2.6 +/- 1.6 at week 52. At week 52, good EULAR response was achieved in 62.3%, low disease activity state in 66.4%, and DAS28 remission in 55.1% of patients (adjusted relative frequencies). 35.3% of patients discontinued the study prematurely; common reasons were lack of effectiveness (10.5%) and intolerability (7.3%). Any infections and severe infections occurred in 37.6% and 7.2% of patients, respectively (N = 836); serious infections were seen in 5.3% (N = 850). Event rates of any, severe and serious infections were 70.3, 9.8 and 4.4 events/100 patient-years, respectively. CONCLUSION: Tocilizumab administered in a real-life setting showed clinically meaningful improvements and a safety profile that was consistent with data reported from pre-approval Phase III studies. PMID- 26515960 TI - Motivational interviewing: relevance in the treatment of rheumatoid arthritis? AB - Advances in pharmacological treatment options in RA have led to a dramatic potential for improvement in patients' physical and psychological status. Despite advances, poor outcomes, including fatigue, pain, reduced physical activity and quality of life, are still observed. Reasons include non-adherence to medication, insufficient knowledge about the disease and lack of support in coping and effectively self-managing their condition. Motivational interviewing (MI) is a person-centred approach that relies on collaboration and empathy aiming to elicit a person's own motivation for behaviour change. It has been implemented in a variety of long-term conditions, addressing issues such as lifestyle changes with beneficial effects, but it is yet to be widely recognized and adopted in the field of rheumatology. This review will explain the techniques underpinning MI and the rationale for adopting this approach in rheumatology with the aim to increase medication adherence and physical activity and improve patients' coping strategies for pain and fatigue. PMID- 26515962 TI - Differential controls by climate and physiology over the emission rates of biogenic volatile organic compounds from mature trees in a semi-arid pine forest. AB - Drought has the potential to influence the emission of biogenic volatile organic compounds (BVOCs) from forests and thus affect the oxidative capacity of the atmosphere. Our understanding of these influences is limited, in part, by a lack of field observations on mature trees and the small number of BVOCs monitored. We studied 50- to 60-year-old Pinus ponderosa trees in a semi-arid forest that experience early summer drought followed by late-summer monsoon rains, and observed emissions for five BVOCs-monoterpenes, methylbutenol, methanol, acetaldehyde and acetone. We also constructed a throughfall-interception experiment to create "wetter" and "drier" plots. Generally, trees in drier plots exhibited reduced sap flow, photosynthesis, and stomatal conductances, while BVOC emission rates were unaffected by the artificial drought treatments. During the natural, early summer drought, a physiological threshold appeared to be crossed when photosynthesis ?2 MUmol m(-2) s(-1) and conductance ?0.02 mol m(-2) s(-1). Below this threshold, BVOC emissions are correlated with leaf physiology (photosynthesis and conductance) while BVOC emissions are not correlated with other physicochemical factors (e.g., compound volatility and tissue BVOC concentration) that have been shown in past studies to influence emissions. The proportional loss of C to BVOC emission was highest during the drought primarily due to reduced CO2 assimilation. It appears that seasonal drought changes the relations among BVOC emissions, photosynthesis and conductance. When drought is relaxed, BVOC emission rates are explained mostly by seasonal temperature, but when seasonal drought is maximal, photosynthesis and conductance-the physiological processes which best explain BVOC emission rates-decline, possibly indicating a more direct role of physiology in controlling BVOC emission. PMID- 26515963 TI - Identification and characterisation of hemocyanin of the fish louse Argulus (Crustacea: Branchiura). AB - Hemocyanin transports oxygen in the hemolymph of many arthropod species. Within the crustaceans, this copper-containing protein was thought to be restricted to Malacostraca, while other crustacean classes were assumed to employ hemoglobin or lack any respiratory protein. Only recently it has become evident that hemocyanins also occur in Remipedia and Ostracoda. Here we report for the first time the identification and characterisation of hemocyanin in the fish louse Argulus, which belongs to the class of Branchiura. This finding indicates that hemocyanin was the principal oxygen carrier in the stem lineage of the pancrustaceans, but has been lost independently multiple times in crustacean taxa. We obtained the full-length cDNA sequences of two hemocyanin subunits of Argulus foliaceus by a combination of RT-PCR, RACE and Illumina sequencing of the transcriptome. In addition, one full-length and one partial cDNA sequence were derived from the transcriptome data of Argulus siamensis. Western blot analysis confirmed the presence of at least two hemocyanin subunits in A. foliaceus, which are expressed at the mRNA level at a 1:3.5 ratio. The addition to the branchiuran hemocyanin subunits to a multiple sequence alignment of arthropod, hemocyanins improved the phylogenetic resolution within the pancrustacean hemocyanins. Malacostracan, ostracod and branchiuran hemocyanins are distinct from the hexapod and remipede hemocyanins, reinforcing the hypothesis of a close relationship of Remipedia and Hexapoda. Notably, the ostracod hemocyanins are paraphyletic with respect to the branchiuran hemocyanins, indicating ancient divergence and differential loss of distinct subunit types. PMID- 26515964 TI - Coronary calcium scans and radiation exposure in the multi-ethnic study of atherosclerosis. AB - With the increasing use of coronary artery calcium (CAC) scoring to risk stratify asymptomatic patients for future cardiovascular events, there have been concerns raised regarding the theoretical risk of radiation exposure to this potentially large patient population. Newer CT protocols have sought to reduce radiation exposure without compromising image quality, but the reported radiation exposures in the literature remains widely variable (0.7-10.5 mSv). In this study, we report the radiation exposure of calcium scoring from our MESA cohort across several modern CT scanners with the aim of clarifying the radiation exposure of this imaging modality. To evaluate the mean effective doses of radiation, using dose length product, utilized for coronary artery calcium scoring in the MESA cohort, in an effort to understand estimated population quantity effective dose using individual measurements of scanner radiation output using current CT scanners. We reviewed effective dose in milliSieverts (mSv) for 3442 participants from the MESA cohort undergoing coronary artery calcium scoring, divided over six sites with four different modern CT scanners (Siemens64, Siemens Somatom Definition, GE64, and Toshiba 320). For effective dose calculation (milliSieverts, mSv), we multiplied the dose length product by conversion factor k (0.014). The mean effective dose amongst all participants was 1.05 mSv, a median dose of 0.95 mSV. The mean effective dose ranged from 0.74 to 1.26 across the six centers involved with the MESA cohort. The Siemens Somatom Definition scanner had effective dose of 0.53 (n = 123), Siemens 64 with 0.97 (n = 1684), GE 64 with 1.16 (n = 1219), and Toshiba 320 with 1.26 mSv (n = 416). Subgroup analysis by BMI, age, and gender showed no variability between scanners, gender, ages 45-74 years old, or BMI less than 30 kg/m(2). Subjects over age 75 yo had a mean effective dose of 1.29 +/- 0.31 mSv, while the <75 yo subgroup was 0.78 +/- 0.09 mSv (p < 0.05). Effective doses in subjects with BMI > 40 kg/m(2) was significantly greater than other subgroups, with mean dose of 1.47 +/- 0.51 mSv (p < 0.01). Using contemporary CT scanners and protocols, the effective dose for coronary artery calcium is approximately 1 mSv, an estimate which is consistently lower than previously reported for CAC scanning, regardless of age, gender, and body mass index. PMID- 26515965 TI - EFSUMB Guidelines on Interventional Ultrasound (INVUS), Part VI - Ultrasound Guided Vascular Interventions. AB - The sixth part of the Guidelines on Interventional Ultrasound produced under the auspices of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) assesses the evidence for ultrasound guidance and assistance in vascular interventions. Based on convincing data, real-time sonographic guidance for central venous access is strongly recommended as a key safety measure. Systematic analysis of scientific literature shows that in difficult situations and special circumstances US guidance may also improve the efficacy and safety of peripheral venous and arterial access and endovascular interventions. Moreover, the recommendations of this guideline endorse the use of ultrasound to detect complications of vascular access and US-guided interventional treatment of arterial pseudoaneurysms. PMID- 26515966 TI - EFSUMB Guidelines on Interventional Ultrasound (INVUS), Part IV - EUS-guided Interventions: General aspects and EUS-guided sampling (Long Version). AB - The fourth part of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) Guidelines on Interventional Ultrasound describes general aspects of endoscopic ultrasound-guided diagnostic and therapeutic interventions and assesses the evidence for endoscopic ultrasound-guided sampling. Endoscopic ultrasound combines the most advanced high-resolution ultrasound imaging of lesions within the wall and in the vicinity of the gastrointestinal tract and safe and effective fine needle based tissue acquisition from these lesions. The guideline addresses the indications, contraindications, techniques, adverse events, training and clinical impact of EUS-guided sampling. Advantages and drawbacks are weighed in comparison with image-guided percutaneous biopsy. Based on the most current evidence, clinical practice recommendations are given for crucial preconditions and steps of EUS guided sampling as well as for safe performance. Additionally, the guideline deals with the principles and reliability of cytopathological reporting in endoscopic ultrasound-guided sampling (long version). PMID- 26515967 TI - Differential effects of sodium channel blockers on in vitro induced epileptiform activities. AB - Antiepileptic drugs act on voltage gated sodium channels in many different ways: rufinamide is thought to influence the fast inactivation, so its anticonvulsant action could be similar to carbamazepine, whereas lacosamide enhances the slow inactivation; however some antidepressants were also described to act in the same way. Rufinamide, lacosamide, carbamazepine, fluoxetine and imipramine were tested using in vitro models of epileptiform activities. Extracellular local field potentials were recorded using hippocampal slices from immature rats and the pattern of epileptiform activities was analyzed. Seizure-like events (SLE), but not interictal bursts were sensitive to AEDs' action. Rufinamide increased interictal periods by prolonging preictal phase and reducing SLE duration, and was the only tested AED which reduced SLE frequency. Lacosamide's effect resembled that of fluoxetine in the low-Mg2+ model: both drugs reduced markedly the SLE duration, but increased their frequency. Imipramine and fluoxetine irreversibly suppressed SLE in all slices. Some proconvulsive type of action on SLEs such as increasing preictal neuronal activity by rufinamide and increasing SLE frequency by lacosamide, fluoxetine and carbamazepine, were also observed. Newer drugs were more efficient than carbamazepine, and the anticonvulsant action of antidepressants on in vitro epileptiform activities may seem somewhat surprising. PMID- 26515968 TI - Great science inspires us to tackle the issue of data reproducibility. PMID- 26515969 TI - Advice to a young scientist (by someone who doesn't know how to give it). AB - While trying to extract original and general advice from the details of my career, I realized this might not be possible. My path, like those of so many others, had too many idiosyncratic twists and turns that had to work out just the way they did to be mined for generally useful strategies. So I abandon the conceit of advice and simply give you my story. There are many like it, but this one is mine. Take what you wish from it. PMID- 26515970 TI - What does it take to get the job done? AB - I am extremely honored to be the recipient of the 2015 Women in Cell Biology Junior Award. When I reflect on my journey in science, many great people and memorable experiences come to mind. Some of these encounters were truly career defining moments. Others provided priceless lessons. In this essay, I recount some of the moments and experiences that influenced my scientific trajectory with the hope that they may inspire others. PMID- 26515971 TI - How nontraditional model systems can save us. AB - In this essay I would like to highlight how work in nontraditional model systems is an imperative for our society to prepare for problems we do not even know exist. I present examples of how discovery in nontraditional systems has been critical for fundamental advancement in cell biology. I also discuss how as a collective we might harvest both new questions and new solutions to old problems from the underexplored reservoir of diversity in the biosphere. With advancements in genomics, proteomics, and genome editing, it is now technically feasible for even a single research group to introduce a new model system. I aim here to inspire people to think beyond their familiar model systems and to press funding agencies to support the establishment of new model systems. PMID- 26515972 TI - A case for more curiosity-driven basic research. AB - Having been selected to be among the exquisitely talented scientists who won the Sandra K. Masur Senior Leadership Award is a tremendous honor. I would like to take this opportunity to make the case for a conviction of mine that I think many will consider outdated. I am convinced that we need more curiosity-driven basic research aimed at understanding the principles governing life. The reasons are simple: 1) we need to learn more about the world around us; and 2) a robust and diverse basic research enterprise will bring ideas and approaches essential for developing new medicines and improving the lives of humankind. PMID- 26515973 TI - Surviving as an underrepresented minority scientist in a majority environment. AB - I believe the evidence will show that the science we conduct and discoveries we make are influenced by our cultural experience, whether they be positive, negative, or neutral. I grew up as a person of color in the United States of America, faced with challenges that many had as members of an underrepresented minority group. I write here about some of the lessons I have learned that have allowed me to survive as an underrepresented minority -scientist in a majority environment. PMID- 26515974 TI - An unconventional route to becoming a cell biologist. AB - I am honored to be the E. B. Wilson Award recipient for 2015. As we know, it was E. B. Wilson who popularized the concept of a "stem cell" in his book The Cell in Development and Inheritance (1896, London: Macmillan & Co.). Given that stem cell research is my field and that E. B. Wilson is so revered within the cell biology community, I am a bit humbled by how long it took me to truly grasp his vision and imaginative thinking. I appreciate it deeply now, and on this meaningful occasion, I will sketch my rather circuitous road to cell biology. PMID- 26515975 TI - Get that next job-how to break out of the postdoc trap. AB - In the past, the majority of graduate students and postdoctoral researchers were focused on careers in academia. Times have changed, and many are now considering careers outside of academia and are aware of numerous exciting career opportunities in industry and nonprofit and government organizations. However, although it is easy to find resources about academic careers, the same cannot be said for positions outside the ivory tower. Here, on the basis of my experience as a scientist and as someone who works with graduate students and postdocs to help them enter nonacademic career paths, I provide a perspective on career development and how to find a job. PMID- 26515976 TI - Flexible and Foldable Li-O2 Battery Based on Paper-Ink Cathode. AB - A flexible freestanding air cathode inspired by traditional Chinese calligraphy art is built. When this novel electrode is employed as both a new concept cathode and current collector, to replace conventional rigid and bulky counterparts, a highly flexible and foldable Li-O2 battery with excellent mechanical strength and superior electrochemical performance is obtained. PMID- 26515977 TI - Optical meta-atom for localization of light with quantized energy. AB - The capacity to confine light into a small region of space is of paramount importance in many areas of modern science. Here we suggest a mechanism to store a quantized 'bit' of light--with a very precise amount of energy--in an open core shell plasmonic structure ('meta-atom') with a nonlinear optical response. Notwithstanding the trapped light state is embedded in the radiation continuum, its lifetime is not limited by the radiation loss. Interestingly, it is shown that the interplay between the nonlinear response and volume plasmons enables breaking fundamental reciprocity restrictions, and coupling very efficiently an external light source to the meta-atom. The collision of an incident optical pulse with the meta-atom may be used to release the trapped light 'bit'. PMID- 26515978 TI - Stability and activity of MCSP-specific chimeric antigen receptors (CARs) depend on the scFv antigen-binding domain and the protein backbone. AB - Chimeric antigen receptor (CAR)-modified T cells emerged as effective tools in the immunotherapy of cancer but can produce severe on-target off-tissue toxicities. This risk can conceivably be overcome, at least partially, by transient transfection. The design of CARs, however, has so far not been optimized for use in non-permanent T cell modification. Here we compared the performance of T cells modified with three different first- and second-generation CARs, each specific for MCSP (HMW-MAA) which is commonly expressed by melanoma cells. Upon RNA transfer, the expression of all receptors was limited in time. The second-generation CARs, which combined CD28-CD3zeta signaling, were expressed at higher levels and more prolonged than first-generation CARs with CD3zeta only. The CD28 domain increased the cytokine production, but had only an indirect effect on the lytic capacity, by prolonging the CAR expression. Especially for the second-generation CARs, the scFv clearly impacted the level and duration of CAR expression and the T cell performance. Thus, we identified a CAR high in both expression and anti-tumor cell reactivity. T cells transfected with this CAR increased the mean survival time of mice after challenge with melanoma cells. To facilitate clinical application, this CAR was used to redirect T cells from late stage melanoma patients by RNA transfection. These T cells mediated effective antigen-specific tumor cell lysis and release of pro-inflammatory cytokines, even after cryoconservation of the transfected T cells. Taken together, the analysis identified a CAR with superior anti-melanoma performance after RNA transfer which is a promising candidate for clinical exploration. PMID- 26515979 TI - Rational Substitution of Surface Acidic Residues for Enhancing the Thermostability of Thermolysin. AB - Solvent-exposed acidic/amide residue (Asp/Glu or Asn/Gln) exerts great effects on the thermostability of protein; however, experimental attempts appear to be time consuming, so a more scientific, simple, and effective rational strategy is necessary. In this study, molecular dynamic (MD) simulation was performed to analyze two surface acidic residues (Asp37 and Glu119) of thermolysin (TLN) in mediating its thermostability. Root-mean-square-deviation (RMSD) was calculated to evaluate the thermosensitivity effect by acidic/amide substitutions. The wild type TLN and three mutants (TLM1, TLM2, and TLM) presented significantly different thermostability effect. Four profiles of RMSD values demonstrated that the thermal insensitivity of variants were TLM2 > TLM > TLN > TLM1. As expected, the thermostability and half-life (at 60 degrees C) behavior of enzyme variants showed the same trends with the computational predictions, and it was worth noting that the half-life of TLM2 showed 3.1-fold longer than that of wild-type. The T m and T 50 of TLM2 were 9 and 7 degrees C higher, respectively, than that of wild-type enzyme. Rational substitution of acidic/amide residue in regulation of thermostability using MD simulation would be an efficient approach for instructional design to improve the thermostability. PMID- 26515980 TI - Pedagogical view of model metabolic cycles. AB - The main purpose of this study was to present a simplified view of model metabolic cycles. Although the models have been elaborated with the Mathematica Program, and using a system of differential equations, the main conclusions were presented in a rather intuitive way, easily understandable by students of general courses of Biochemistry, and without any need of mathematical support. A change in any kinetic constant (Km or Vmax) of only one enzyme affected the metabolic profile of all the substrates of the cycle. In addition, it is shown how an increase in the Km or a decrease in the Vmax values of any particular enzyme promoted an increase of its substrate; the contrary occurred decreasing the Km or increasing the Vmax values. PMID- 26515981 TI - Advancing cell wall inhibitors towards clinical applications. AB - Natural products represent a major source of approved drugs and still play an important role in supplying chemical diversity. Consistently, 2014 has seen new, natural product-derived antibiotics approved for human use by the US Food and Drug Administration. One of the recently approved second-generation glycopeptides is dalbavancin, a semi-synthetic derivative of the natural product A40,926. This compound inhibits bacterial growth by binding to lipid intermediate II (Lipid II), a key intermediate in peptidoglycan biosynthesis. Like other recently approved antibiotics, dalbavancin has a complex history of preclinical and clinical development, with several companies contributing to different steps in different years. While our work on dalbavancin development stopped at the previous company, intriguingly our current pipeline includes two more Lipid II binding natural products or derivatives thereof. In particular, we will focus on the properties of NAI-107 and related lantibiotics, which originated from recent screening and characterization efforts. PMID- 26515982 TI - Molecular Profiles of Prostate Cancer: To Treat or Not to Treat. AB - A major dilemma in the selection of treatment for men with prostate cancer is the difficulty in accurately characterizing the risk posed by the cancer. This uncertainty has led physicians to recommend aggressive therapy for most men diagnosed with prostate cancer and has led to concerns about the benefits of screening and the adverse consequences of excessive treatment. Genomic analyses of prostate cancer reveal distinct patterns of alterations in the genomic landscape of the disease that show promise for improved prediction of prognosis and better medical decision making. Several molecular profiles are now commercially available and are being used to inform medical decisions. This article describes the clinical tests available for distinguishing aggressive from nonaggressive prostate cancer, reviews the new genomic tests, and discusses their advantages and limitations and the evidence for their utility in various clinical settings. PMID- 26515983 TI - Vaccination Against Dengue: Challenges and Current Developments. AB - Dengue is a growing threat worldwide, and the development of a vaccine is a public health priority. The completion of the active phase of two pivotal efficacy studies conducted in Asia and Latin America by Sanofi Pasteur has constituted an important step. Several other approaches are under development, and whichever technology is used, vaccine developers face several challenges linked to the particular nature and etiology of dengue disease. We start our review by defining questions and potential issues linked to dengue pathology and presenting the main types of vaccine approaches that have explored these questions; some of these candidates are in a late stage of clinical development. In the second part of the review, we focus on the Sanofi Pasteur dengue vaccine candidate, describing the steps from research to phase III efficacy studies. Finally, we discuss what could be the next steps, before and after vaccine introduction, to ensure that the vaccine will provide the best benefit with an acceptable safety profile to the identified target populations. PMID- 26515985 TI - Identification and re-addressing of a transcriptionally permissive locus in the porcine genome. AB - Recently, we established the Sleeping Beauty transposon system for germ line competent transgenesis in the pig. Here, we extend this approach to re-target a transposon-tagged locus for a site-specific gene knock-in, and generated a syngeneic cohort of piglets carrying either the original transposon or the re targeted event. A Cre-loxP-mediated cassette exchange of the tagging transposon with a different reporter gene was performed, followed by flow cytometric sorting and somatic cell nuclear transfer of recombined cells. In parallel, the original cells were employed in somatic cell nuclear transfer to generate clone siblings, thereby resulting in a clone cohort of piglets carrying different reporter transposons at an identical chromosomal location. Importantly, this strategy supersedes the need for an antibiotic selection marker. This approach expands the arsenal of genome engineering technologies in domestic animals, and will facilitate the development of large animal models for human diseases. Potentially, the syngeneic cohort of pigs will be instrumental for vital tracking of transplanted cells in pre-clinical assessments of novel cell therapies. PMID- 26515984 TI - Marijuana Legalization: Impact on Physicians and Public Health. AB - Marijuana is becoming legal in an increasing number of states for both medical and recreational use. Considerable controversy exists regarding the public health impact of these changes. The evidence for the legitimate medical use of marijuana or cannabinoids is limited to a few indications, notably HIV/AIDS cachexia, nausea/vomiting related to chemotherapy, neuropathic pain, and spasticity in multiple sclerosis. Although cannabinoids show therapeutic promise in other areas, robust clinical evidence is still lacking. The relationship between legalization and prevalence is still unknown. Although states where marijuana use is legal have higher rates of use than nonlegal states, these higher rates were generally found even prior to legalization. As states continue to proceed with legalization for both medical and recreational use, certain public health issues have become increasingly relevant, including the effects of acute marijuana intoxication on driving abilities, unintentional ingestion of marijuana products by children, the relationship between marijuana and opioid use, and whether there will be an increase in health problems related to marijuana use, such as dependence/addiction, psychosis, and pulmonary disorders. In light of this rapidly shifting legal landscape, more research is urgently needed to better understand the impact of legalization on public health. PMID- 26515986 TI - Age-related differences in sequential modulations of problem-size and rule violation effects during arithmetic problem verification tasks. AB - Young and older adults were asked to verify true (e.g., 5 * 61 = 305) and false (5 * 61 = 315) arithmetic problems. Half the problems were small (e.g., 5 * 17 = 85) and half were large problems (e.g., 5 * 93 = 465). Half the false problems respected the five rule (i.e., the product of an operand multiplied by five ends with either 5 or 0), and half violated this rule (e.g., 21 * 5 = 115 vs. 21 * 5 = 113). Both young and older adults showed problem-size effects (i.e., they verified small problems more quickly than large problems) and five-rule violation effects (i.e., they verified problem violating five rule more quickly than problems respecting five rule). Moreover, we found sequential modulations of these problem-size and five-rule effects. Problem-size effects were larger on current problems following large problems than after small problems, and five rule violation effects were larger after problems violating the five rule than after no-rule violation problems. Finally, sequential modulations of problem-size effects were larger in older adults than in young adults, and there were no age related differences in sequential modulations of five-rule violation effects. These findings speak to the determiners of arithmetic performance, as to how well arithmetic calculation and non-calculation strategies are executed and selected on current problems depends on strategies used with preceding problems. PMID- 26515987 TI - Fathers' intelligence measured at age 18-20 years is associated with offspring smoking: linking the Swedish 1969 conscription cohort to the Swedish Survey of Living Conditions. AB - BACKGROUND: An association between lower IQ of parents, measured early in life, and smoking among their offspring has been reported. The extent to which other background factors account for this association is unknown. METHODS: Data on IQ, smoking, mental health, social class, parental divorce and social problems in a cohort of men born during 1949-1951 and conscripted for military service in 1969 were linked to smoking data on 682 offspring interviewed in the Swedish Surveys of Living Conditions 1984-2009. RESULTS: In an age-adjusted model, a one-step decrease on a stanine scale was associated with an OR of 1.19 (95% CI 1.04 to 1.35) for offspring smoking. Adjusting for father's socioeconomic background and smoking, mental illness and social problems in youth only marginally lowered the OR's. CONCLUSIONS: Lower IQ among fathers measured at ages 18-20 years was associated with smoking in their offspring. The association was not explained by father's social class in childhood or a higher prevalence of mental illness, social problems or smoking measured among the fathers in their late adolescence. PMID- 26515988 TI - Erratum. PMID- 26515989 TI - Adjustment to cancer: exploring patients' experiences of participating in a psychodramatic group intervention. AB - The main purpose of the present study was to understand the subjective experience of patients adjusting to cancer by focusing on how that experience might be affected by participating in a psychodramatic group intervention. In-depth interviews using an interpretative-phenomenological approach were conducted with eight cancer patients involved in a psychodrama group. Four key themes were identified: (1) outside and inside relationships; (2) identities: nurturing other selves; (3) a feelings' gym: performing the internal world; and (4) many ends: mourning death and dying. Participation in cancer group using a psychodramatic approach provided positive results. In detail, the group setting: (1) favoured relationships in which it was possible to freely express oneself and (2) empowered patients in their feelings of being able to give and receive help; the psychodramatic approach: (1) supported the physical mobilisation of sense of agency and (2) permitted to deal with the grieving process. Cancer healthcare pathways would benefit from psychotherapeutic programmes using a similar approach, since psychodrama by actively involving body seems to works on areas that are often underwhelmed by other approaches, such as (i.e., physical mobilisation, body engagement, grieving adjustment). Psychodrama supports patients to achieve insights into their own possibilities to actively participate in their own life situations despite having cancer and undergoing treatment for it. PMID- 26515990 TI - Persistent gammadelta T large granular lymphocytosis in a patient with refractory pure red cell aplasia, celiac disease, and chronic hepatitis B infection. AB - The disorders of large granular lymphocytes include reactive proliferation as well as indolent or aggressive neoplasms of cytotoxic T cells, gammadelta T cells, and natural killer (NK) cells. They are associated with autoimmune and infectious disorders and have varied immunophenotypic features. We report a case, which highlights this complex association of autoimmune and infectious diseases with large granular lymphocytosis, the overlapping spectrum of large granular lymphocyte leukemias, and gammadelta T cell lymphomas as well as the difficulties in the diagnosis and management of these indolent T cell lymphomas in the usual clinical settings. PMID- 26515991 TI - Collection of NMR Scalar and Residual Dipolar Couplings Using a Single Experiment. AB - A new DMSO-compatible aligning gel based on cross-linked poly(2-hydroxylethyl methacrylate) (poly-HEMA) has been developed. Due to a significant difference in bulk magnetic susceptibility between the DMSO inside and outside the gel, it is possible to simultaneously collect isotropic and anisotropic NMR data, such as residual dipolar couplings (RDC), in the same NMR tube. RDC-assisted structural analysis of menthol and the alkaloid retrorsine is reported as proof of concept. PMID- 26515992 TI - Tumor necrosis at FDG-PET is an independent predictor of outcome in diffuse large B-cell lymphoma. AB - PURPOSE: To determine the prognostic performance of tumor necrosis at FDG-PET in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who are treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. MATERIALS AND METHODS: 108 patients with newly diagnosed DLBCL who underwent FDG-PET before R-CHOP therapy were retrospectively included. Lymphomatous sites at FDG-PET were assessed for the presence of a photopenic area, in keeping with tumor necrosis. Univariate and multivariate Cox regression analyses were performed to determine the associations of tumor necrosis and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) with progression-free survival (PFS) and overall survival (OS). RESULTS: On univariate Cox regression analysis, both tumor necrosis and higher NCCN-IPI risk groups were significantly associated with PFS (P=0.024 and P<0.001, respectively) and OS (P=0.034 and P<0.001, respectively). On multivariate Cox regression analysis, both tumor necrosis and the NCCN-IPI were independent significant predictors for PFS (P=0.007, hazard ratio: 2.723 [95% confidence interval: 1.324-5.597] and P<0.001, hazard ratio: 2.952 [95% confidence interval: 1.876-4.646], respectively) and OS (P=0.009, hazard ratio: 2.794 [95% confidence interval: 1.305-5.985] and P<0.001, hazard ratio: 2.813 [95% confidence interval: 1.724-4.587], respectively). CONCLUSION: Tumor necrosis at FDG-PET is an NCCN-IPI independent predictor of outcome in DLBCL. PMID- 26515993 TI - Laboratory tests for the phytoextraction of heavy metals from polluted harbor sediments using aquatic plants. AB - The aim of this study was to investigate the concentrations and pollution levels of heavy metals, organochlorine pesticides, and polycyclic aromatic hydrocarbons in marine sediments from the Leghorn Harbor (Italy) on the Mediterranean Sea. The phytoextraction capacity of three aquatic plants Salvinia natans, Vallisneria spiralis, and Cabomba aquatica was also tested in the removal of lead and copper, present in high concentration in these sediments. The average detectable concentrations of metals accumulated by the plants in the studied area were as follows: >3.328 +/- 0.032 mg/kg dry weight (DW) of Pb and 2.641 +/- 0.014 mg/kg DW of Cu for S. natans, >3.107 +/- 0.034 g/kg DW for V. spiralis, and >2.400 +/- 0.029 mg/kg DW for C. aquatica. The occurrence of pesticides was also analyzed in the sediment sample by gas chromatography coupled with mass spectrometry (GC/MS). Due to its metal and organic compound accumulation patterns, S. natans is a potential candidate in phytoextraction strategies. PMID- 26515994 TI - Beach debris in the Azores (NE Atlantic): Faial Island as a first case study. AB - Marine debris is widely recognised as a global environmental problem. This study assesses density, type, and temporal trends of marine debris in two sandy beaches of Faial Island (Azores, NE-Atlantic). During seven months (six days per month) the beaches were surveyed by performing 10 random transects at each site. Recorded items within the range 2-30 cm were organised into seven categories. Densities of total debris varied from 0 to 1.940 items m(-2), with plastics dominating both areas. Both beaches, presented the highest debris abundance in February, most probably related to prevailing winds and swell. Location and/or time of year also seemed to influence the type of debris present. These findings provide new insights into debris accumulation rates in the Azores, where no previous studies were made. It also confirms the global trend of increased plastics accumulation on shorelines, highlighting the need for further research in remote islands. PMID- 26515995 TI - Effect of heavy metals on the carbon and nitrogen ratio in Avicennia marina from polluted and unpolluted regions. AB - The accumulation of heavy metals and its impact on the C/N ratio of Avicennia marina of the Patalganga and Amba estuaries were studied. Vadinar was selected as a relatively uncontaminated location for comparison. Cd was accumulated in leaves of the Patalganga and Amba estuarine mangroves; however, at Vadinar it was accumulated and arrested only in roots and stems. Negative correlation of Cr, Cd, Pb and Zn with C in the mangroves suggested that their accumulation may lead to lowered C content in the mangroves. The average C/N ratios in mangroves of the inner Patalganga estuary, Patalganga mouth, and Amba estuary were found to be 80.1 +/- 7.3, 105.8 +/- 12.5 and 52.4 +/- 3.4 respectively, whereas at Vadinar it was well within the expected range (26.4 +/- 2.8). The results of the present study suggest: (i) metal accumulation, leading to less carbon content in plants; (ii) heavy metal enrichment in the root zone sediment, affecting the uptake of nitrogen by plants and resulting in altered C/N ratio. PMID- 26515996 TI - Sex Differences in Cardiac Risk Factors, Perceived Risk, and Health Care Provider Discussion of Risk and Risk Modification Among Young Patients With Acute Myocardial Infarction: The VIRGO Study. AB - BACKGROUND: Differences between sexes in cardiac risk factors, perceptions of cardiac risk, and health care provider discussions about risk among young patients with acute myocardial infarction (AMI) are not well studied. OBJECTIVES: This study compared cardiac risk factor prevalence, risk perceptions, and health care provider feedback on heart disease and risk modification between young women and men hospitalized with AMI. METHODS: We studied 3,501 AMI patients age 18 to 55 years enrolled in the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) study in U.S. and Spanish hospitals between August 2008 and January 2012, comparing the prevalence of 5 cardiac risk factors by sex. Modified Poisson regression was used to assess sex differences in self-perceived heart disease risk and self-reported provider discussions of risk and modification. RESULTS: Nearly all patients (98%) had >=1 risk factor, and 64% had >=3. Only 53% of patients considered themselves at risk for heart disease, and even fewer reported being told they were at risk (46%) or that their health care provider had discussed heart disease and risk modification (49%). Women were less likely than men to be told they were at risk (relative risk: 0.89; 95% confidence interval: 0.84 to 0.96) or to have a provider discuss risk modification (relative risk: 0.84; 95% confidence interval: 0.79 to 0.89). There was no difference between women and men for self-perceived risk. CONCLUSIONS: Despite having significant cardiac risk factors, only one-half of young AMI patients believed they were at risk for heart disease before their event. Even fewer discussed their risks or risk modification with their health care providers; this issue was more pronounced among women. PMID- 26515997 TI - Gender, Cardiovascular Disease, and the Sexism of Obesity. PMID- 26515998 TI - Temporal Trends and Sex Differences in Revascularization and Outcomes of ST Segment Elevation Myocardial Infarction in Younger Adults in the United States. AB - BACKGROUND: Older women presenting with ST-segment elevation myocardial infarction (STEMI) are less likely to receive revascularization and have worse outcomes relative to their male counterparts. OBJECTIVES: This study sought to determine temporal trends and sex differences in revascularization and in hospital outcomes of younger patients with STEMI. METHODS: We used the 2004 to 2011 Nationwide Inpatient Sample databases to identify all patients age 18 to 59 years hospitalized with STEMI. Temporal trends and sex differences in revascularization strategies, in-hospital mortality, and length of stay were analyzed. RESULTS: From 2004 to 2011, of 1,363,492 younger adults (age <60 years) with acute myocardial infarction, 632,930 (46.4%) had STEMI. Younger women with acute myocardial infarction were less likely than men to present with STEMI (adjusted odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.73 to 0.75). Younger women with STEMI were less likely to receive reperfusion as compared with younger men (percutaneous coronary intervention adjusted OR: 0.74; 95% CI: 0.73 to 0.75) (coronary artery bypass grafting adjusted OR: 0.61; 95% CI: 0.60 to 0.62) (thrombolysis adjusted OR: 0.80; 95% CI: 0.78 to 0.82). From 2004 to 2011, use of percutaneous coronary intervention for STEMI increased in both younger men (63.9% to 84.8%; ptrend < 0.001) and women (53.6% to 77.7%; ptrend < 0.001). In hospital mortality was significantly higher in younger women compared with men (4.5% vs. 3.0%; adjusted OR: 1.11; 95% CI: 1.07 to 1.15). There was an increasing trend in risk-adjusted in-hospital mortality in both younger men and women during the study period. Length of stay decreased in both younger men and women (ptrend < 0.001). CONCLUSIONS: Younger women are less likely to receive revascularization for STEMI and have higher in-hospital mortality as compared with younger men. Use of percutaneous coronary intervention for STEMI and in-hospital mortality have increased, whereas length of stay has decreased in both sexes over the past several years. PMID- 26515999 TI - Publicly Available Data: Crowd Sourcing to Identify and Reduce Disparities. PMID- 26516000 TI - Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome. AB - BACKGROUND: The right ventricular outflow tract (RVOT) is acknowledged to be responsible for arrhythmogenesis in Brugada syndrome (BrS), but the pathophysiology remains controversial. OBJECTIVES: This study assessed the substrate underlying BrS at post-mortem and in vivo, and the role for open thoracotomy ablation. METHODS: Six whole hearts from male post-mortem cases of unexplained sudden death (mean age 23.2 years) with negative specialist cardiac autopsy and familial BrS were used and matched to 6 homograft control hearts by sex and age (within 3 years) by random risk set sampling. Cardiac autopsy sections from cases and control hearts were stained with picrosirius red for collagen. The RVOT was evaluated in detail, including immunofluorescent stain for connexin-43 (Cx43). Collagen and Cx43 were quantified digitally and compared. An in vivo study was undertaken on 6 consecutive BrS patients (mean age 39.8 years, all men) during epicardial RVOT ablation for arrhythmia via thoracotomy. Abnormal late and fractionated potentials indicative of slowed conduction were identified, and biopsies were taken before ablation. RESULTS: Collagen was increased in BrS autopsy cases compared with control hearts (odds ratio [OR]: 1.42; p = 0.026). Fibrosis was greatest in the RVOT (OR: 1.98; p = 0.003) and the epicardium (OR: 2.00; p = 0.001). The Cx43 signal was reduced in BrS RVOT (OR: 0.59; p = 0.001). Autopsy and in vivo RVOT samples identified epicardial and interstitial fibrosis. This was collocated with abnormal potentials in vivo that, when ablated, abolished the type 1 Brugada electrocardiogram without ventricular arrhythmia over 24.6 +/- 9.7 months. CONCLUSIONS: BrS is associated with epicardial surface and interstitial fibrosis and reduced gap junction expression in the RVOT. This collocates to abnormal potentials, and their ablation abolishes the BrS phenotype and life-threatening arrhythmias. BrS is also associated with increased collagen throughout the heart. Abnormal myocardial structure and conduction are therefore responsible for BrS. PMID- 26516001 TI - Age, Genetics, and Fibrosis in the Brugada Syndrome. PMID- 26516003 TI - Cell Therapy Needs Rigorous Translational Studies in Large Animal Models. PMID- 26516002 TI - Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy. AB - BACKGROUND: Both bone marrow-derived mesenchymal stem cells (MSCs) and c-kit(+) cardiac stem cells (CSCs) improve left ventricular remodeling in porcine models and clinical trials. Using xenogeneic (human) cells in immunosuppressed animals with acute ischemic heart disease, we previously showed that these 2 cell types act synergistically. OBJECTIVES: To more accurately model clinical applications for heart failure, this study tested whether the combination of autologous MSCs and CSCs produce greater improvement in cardiac performance than MSCs alone in a nonimmunosuppressed porcine model of chronic ischemic cardiomyopathy. METHODS: Three months after ischemia/reperfusion injury, Gottingen swine received transendocardial injections with MSCs alone (n = 6) or in combination with cardiac-derived CSCs (n = 8), or placebo (vehicle; n = 6). Cardiac functional and anatomic parameters were assessed using cardiac magnetic resonance at baseline and before and after therapy. RESULTS: Both groups of cell-treated animals exhibited significantly reduced scar size (MSCs -44.1 +/- 6.8%; CSC/MSC -37.2 +/- 5.4%; placebo -12.9 +/- 4.2%; p < 0.0001), increased viable tissue, and improved wall motion relative to placebo 3 months post-injection. Ejection fraction (EF) improved (MSCs 2.9 +/- 1.6 EF units; CSC/MSC 6.9 +/- 2.8 EF units; placebo 2.5 +/ 1.6 EF units; p = 0.0009), as did stroke volume, cardiac output, and diastolic strain only in the combination-treated animals, which also exhibited increased cardiomyocyte mitotic activity. CONCLUSIONS: These findings illustrate that interactions between MSCs and CSCs enhance cardiac performance more than MSCs alone, establish the safety of autologous cell combination strategies, and support the development of second-generation cell therapeutic products. PMID- 26516004 TI - Development of Long Noncoding RNA-Based Strategies to Modulate Tissue Vascularization. AB - BACKGROUND: Long noncoding ribonucleic acids (lncRNAs) are a subclass of regulatory noncoding ribonucleic acids for which expression and function in human endothelial cells and angiogenic processes is not well studied. OBJECTIVES: The authors discovered hypoxia-sensitive human lncRNAs via next-generation ribonucleic acid sequencing and microarray approaches. To address their functional importance in angiogenic processes, several endothelial lncRNAs were characterized for their angiogenic characteristics in vitro and ex vivo. METHODS: Ribonucleic acid sequencing and microarray-derived data showed specific endothelial lncRNA expression changes after hypoxia. Validation experiments confirmed strong hypoxia-dependent activation of 2 intergenic lncRNAs: LINC00323 and MIR503HG. RESULTS: Silencing of these lncRNA transcripts led to angiogenic defects, including repression of growth factor signaling and/or the key endothelial transcription factor GATA2. Endothelial loss of these hypoxia-driven lncRNAs impaired cell-cycle control and inhibited capillary formation. The potential clinical importance of these endothelial lncRNAs to vascular structural integrity was demonstrated in an ex vivo model of human induced pluripotent stem cell-based engineered heart tissue. CONCLUSIONS: The authors report an expression atlas of human hypoxia-sensitive lncRNAs and identified 2 lncRNAs with important functions to sustain endothelial cell biology. LncRNAs hold great promise to serve as important future therapeutic targets of cardiovascular disease. PMID- 26516005 TI - Longing for Naiades in Heart Failure. PMID- 26516006 TI - Transcatheter Valve-in-Valve and Valve-in-Ring for Treating Aortic and Mitral Surgical Prosthetic Dysfunction. AB - Bioprosthetic valve use has increased significantly. Considering their limited durability, there will remain an ongoing clinical need for repairing or replacing these prostheses in the future. The current standard of care for treating bioprosthetic valve degeneration involves redo open-heart surgery. However, repeat cardiac surgery may be associated with significant morbidity and mortality. With the rapid evolution of transcatheter heart valve therapies, the feasibility and safety of implanting a transcatheter heart valve within a failed tissue valve has been established. We review the historical perspective of transcatheter valve-in-valve therapy, as well as the main procedural challenges and clinical outcomes associated with this new less invasive treatment option. PMID- 26516007 TI - Mechanisms Contributing to the Progression of Ischemic and Nonischemic Dilated Cardiomyopathy: Possible Modulating Effects of Paracrine Activities of Stem Cells. AB - Over the past 1.5 decades, numerous stem cell trials have been performed in patients with cardiovascular disease. Although encouraging outcome signals have been reported, these have been small, leading to uncertainty as to whether they will translate into significantly improved outcomes. A reassessment of the rationale for the use of stem cells in cardiovascular disease is therefore timely. Such a rationale should include analyses of why previous trials have not produced significant benefit and address whether mechanisms contributing to disease progression might benefit from known activities of stem cells. The present paper provides such a reassessment, focusing on patients with left ventricular systolic dysfunction, either nonischemic or ischemic. We conclude that many mechanisms contributing to progressive left ventricular dysfunction are matched by stem cell activities that could attenuate the myocardial effect of such mechanisms. This suggests that stem cell strategies may improve patient outcomes and justifies further testing. PMID- 26516008 TI - The Physical Examination and the Fifth Maneuver. PMID- 26516009 TI - Characteristics and Prognosis of Ischemic Stroke in Young Cannabis Users Compared With Non-Cannabis Users. PMID- 26516010 TI - Association of APOC3 Loss-of-Function Mutations With Plasma Lipids and Subclinical Atherosclerosis: The Multi-Ethnic BioImage Study. PMID- 26516011 TI - Analysis of Dual Antiplatelet Therapy. PMID- 26516012 TI - Reply: Analysis of Dual Antiplatelet Therapy. PMID- 26516013 TI - Left Atrial Appendage Occlusion Devices Versus Pharmacological Agents for Stroke Prevention in Atrial Fibrillation. PMID- 26516014 TI - Reply: Left Atrial Appendage Occlusion Devices Versus Pharmacological Agents for Stroke Prevention in Atrial Fibrillation. PMID- 26516016 TI - Development of a Cost-Effective Educational Tool to Promote Acceptance of the HPV Vaccination by Hispanic Mothers. AB - Although vaccination against the Human Papilloma Virus (HPV) reduces the risk of related morbidities, the vaccine uptake remains low in adolescents. This has been attributed to limited parental knowledge and misconceptions. In this cross sectional study, we assessed the (1) clarity of educational material informing Hispanic mothers about HPV, cervical cancer and the HPV vaccine, (2) determined vaccination acceptability and (3) identified predictors of vaccine acceptance in an underserved health setting. 418 Hispanic mothers received the educational material and completed an anonymous survey. 91 % of participants understood most or all of the information provided. 77 % of participants reported vaccine acceptance for their children; this increased to 84 % when only those with children eligible to receive vaccination were included. Significant positive predictors of maternal acceptance of the HPV vaccine for their children were understanding most or all of the provided information, older age and acceptance of the HPV vaccine for themselves. Concerns about safety and general dislike of vaccines were negatively associated with HPV vaccine acceptance. Prior knowledge, level of education, previous relevant gynecologic history, general willingness to vaccinate and other general beliefs about vaccines were not significantly associated with HPV vaccine acceptance. The majority of participants reported understanding of the provided educational material. Vaccine acceptability was fairly high, but was even higher among those who understood the information. This study documents a cost-effective way to provide Hispanic mothers with easy-to understand HPV-related information that could increase parental vaccine acceptability and future vaccine uptake among their children. PMID- 26516017 TI - Social and Environmental Determinants of Child Physical Activity in a Rural Mexican-Origin Community. AB - California's rural agricultural communities face an increased burden of obesity and metabolic disease. The present objective is to define the social and environmental influences to child obesity and physical activity within Mexican origin communities in California's Central Valley. A range of data (anthropometric, socioeconomic, demographic, cultural and environmental) were collected on more than 650 children enrolled in Ninos Sanos, Familia Sana. Physical activity data were gathered from a subsample of children 4-7 years of age (n = 148) via accelerometer. Cross sectional analyses explored the relationship between BMI and physical activity and the influence of numerous social and environmental variables. In this sample 45 % of children were determined to be overweight or obese. Boys had a higher daily average moderate-to vigorous physical activity than girls (p = 0.008). Chi square analyses showed weight status was associated with activity level in girls (p = 0.03) but not boys. Multivariate regression revealed several social and environmental indicators influenced BMI and physical activity (p = 0.004). In this population of school-age children of Mexican-origin, girls may benefit more from targeted efforts to increase MVPA. Family and community support systems may also boost child participation in physical activities. PMID- 26516018 TI - College Students Opinions on Gun Violence. AB - Gun violence and control issues have become serious public health problems. This study gathered the opinions from 419 college students from a Midwestern University. Participants were asked about beliefs about purchasing assault weapons, beliefs about bringing handguns to college campuses and beliefs about contributing factors that lead to gun violence. Participants completed surveys online. The findings showed that overall 54 % of respondents believed that military assault weapons should be banned and 53 % agree that teachers should be allowed to carry a registered handgun on campus. There were statistically significant differences between males and females on these issues. For instance, females believed military assault weapons and high capacity magazines should be banned more than 1.9 times (p = .004) p < .05 compared to male students. On the other hand, female students were more likely to believe that school teachers should be allowed to carry registered handguns on school campuses more than 1.55 times (p = .046) p < .05 compared to their male student counterparts. There were no statistically significant differences between ethnic groups. The top four contributing factors that students believed led to gun violence were decline in parenting and family values (17 %), gang involvement (14 %), bullying (13.8 %) and guns being easy to obtain (13.8 %). Limitations and implications for policy work are discussed. PMID- 26516019 TI - Rural Area Deprivation and Hospitalizations Among Children for Ambulatory Care Sensitive Conditions. AB - This study examined the intersection of rurality and community area deprivation using a nine-state sample of inpatient hospitalizations among children (<18 years of age) from 2011. One state from each of the nine US census regions with substantial rural representation and varying degrees of community vulnerability was selected. An area deprivation index was constructed and used in conjunction with rurality to examine differences in the rate of ACSC hospitalizations among children in the sample states. A mixed model with both fixed and random effects was used to test influence of rurality and area deprivation on the odds of a pediatric hospitalization due to an ACSC within the sample. Of primary interest was the interaction of rurality and area deprivation. The study found rural counties are disproportionality represented among the most deprived. Within the least deprived counties, the likelihood of an ACSC hospitalization was significantly lower in rural than among their urban counterparts. However, this rural advantage declines as the level of deprivation increases, suggesting the effect of rurality becomes more important as social and economic advantage deteriorates. We also found ACSC hospitalization to be much higher among racial/ethnic minority children and those with Medicaid or self-pay as an anticipated source of payment. These findings further contribute to the existing body of evidence documenting racial/ethnic disparities in important health related outcomes. PMID- 26516020 TI - Microbial diversity in support of anaerobic biomass valorization. AB - Microbial diversity provides an immense reservoir of functions and supports key steps in maintaining ecosystem balance through matter decomposition processes and nutrient recycling. The use of microorganisms for biomolecule production is now common, but often involves single-strain cultures. In this review, we highlight the significance of using ecosystem-derived microbial diversity for biotechnological researches. In the context of organic matter mineralization, diversity of microorganisms is essential and enhances the degradation processes. We focus on anaerobic production of biomolecules of interest from discarded biomass, which is an important issue in the context of organic waste valorization and processing. Organic waste represents an important and renewable raw material but remains underused. It is commonly accepted that anaerobic mineralization of organic waste allows the production of diverse interesting molecules within several fields of application. We provide evidence that complex and diversified microbial communities isolated from ecosystems, i.e. microbial consortia, offer considerable advantages in degrading complex organic waste, to yield biomolecules of interest. We defend our opinion that this approach is more efficient and offers enhanced potential compared to the approaches that use single strain cultures. PMID- 26516021 TI - Does evidence-based practice improve patient outcomes? An analysis of a natural experiment in a Spanish hospital. AB - RATIONALE, AIMS AND OBJECTIVES: Evidence-based practice (EBP) is widely promoted, but does EBP produce better patient outcomes? We report a natural experiment when part of the internal medicine service in a hospital was reorganized in 2003 to form an EBP unit, the rest of the service remaining unchanged. The units attended similar patients until 2012 permitting comparisons of outcomes and activity. METHODS: We used routinely collected statistics (2004-11) to compare the two different methods of practice and test whether patients being seen by the EBP unit differed from standard practice (SP) patients. Data were available by doctor and year. To check for differences between the EBP and SP doctors prior to reorganization, we used statistics from 2000 to 2003. We looked for changes in patient outcomes or activity following reorganization and whether the EBP unit was achieving significantly different results from SP. Data across the periods were combined and tested using Mann-Whitney test. RESULTS: No statistically significant differences in outcomes were detected between the EBP and the SP doctors prior to reorganization. Following the unit's establishment, the mortality of patients being treated by EBP doctors compared with their previous performance dropped from 7.4% to 6.3% (P < 0.02) and length of stay from 9.15 to 6.01 days (P = 0.002). No statistically significant improvements were seen in SP physicians' performance. No differences in the proportion of patients admitted or their complexity between the services were detected. Despite this, EBP patients had a clinically significantly lower risk of death 6.27% versus 7.75% (P < 0.001) and a shorter length of stay 6.01 versus 8.46 days (P < 0.001) than SP patients. Readmission rates were similar: 14.4% (EBP); 14.5% (SP). EBP doctors attended twice as many patients/doctor as SP doctors. CONCLUSION: The EBP unit was associated with better patient outcomes and more efficient performance than achieved by the same physicians previously or by SP concurrently. PMID- 26516023 TI - Ferulic acid decreases cell viability and colony formation while inhibiting migration of MIA PaCa-2 human pancreatic cancer cells in vitro. AB - Novel and combinatorial treatment methods are becoming sought after entities in cancer treatment and these treatments are even more valuable for pancreatic cancer. The scientists are always on the lookout for new chemicals to help them in their fight against cancer. In this study, we examine the effects of ferulic acid (FA), a phenolic compound, on gene expression, viability, colony formation and migration/invasion in the cultured MIA PaCa-2 human pancreatic cancer cell. Cytotoxic effects of FA were determined by using trypan blue dye exclusion test and Cell TiterGlo (CTG) assay. IC50 dose in MIA PaCa-2 cells was detected as 500MUM/ml at the 72nd hour. Expression profiles of certain cell cycle and apoptosis genes such as CCND1 (cyclin D1),CDK4, CDK6, RB, p21, p16, p53, caspase 3, caspase-9, caspase-8, caspase-10, Bcl-2, BCL-XL,BID, DR4,DR5,FADD,TRADD,PARP, APAF, Bax, Akt, PTEN, PUMA, NOXA, MMP2, MMP9, TIMP1 and TIMP2 were determined by real-time PCR. The effect of FA on cell viability was determined by CellTiter Glo(r) Luminescent Cell Viability Assay. Additionally, effects of FA on colony formation and invasion were also investigated. It was observed that FA caused a significant decrease in the expression of CCND1, CDK 4/6, Bcl2 and caspase 8 and 10 in the MIA PaCa-2 cells while causing an increase in the expression of p53, Bax, PTEN caspase 3 and 9. FA was observed to decrease colony formation while inhibiting cell invasion and migration as observed by the BioCoat Matrigel Invasion Chamber guide and colony formation assays. In conclusion, FA is thought to behave as an anti-cancer agent by affecting cell cycle, apoptotic, invasion and colony formation behavior of MIA PaCa-2 cells. Therefore, FA is placed as a strong candidate for further studies aimed at finding a better, more effective treatment approach for pancreatic cancer. PMID- 26516022 TI - Arabidopsis PARG1 is the key factor promoting cell survival among the enzymes regulating post-translational poly(ADP-ribosyl)ation. AB - Poly(ADP-ribosyl)ation is a reversible post-translational modification of proteins, characterized by the addition of poly(ADP-ribose) (PAR) to proteins by poly(ADP-ribose) polymerase (PARP), and removal of PAR by poly(ADP-ribose) glycohydrolase (PARG). Three PARPs and two PARGs have been found in Arabidopsis, but their respective roles are not fully understood. In this study, the functions of each PARP and PARG in DNA repair were analyzed based on their mutant phenotypes under genotoxic stresses. Double or triple mutant analysis revealed that PARP1 and PARP2, but not PARP3, play a similar but not critical role in DNA repair in Arabidopsis seedlings. PARG1 and PARG2 play an essential and a minor role, respectively under the same conditions. Mutation of PARG1 results in increased DNA damage level and enhanced cell death in plants after bleomycin treatment. PARG1 expression is induced primarily in root and shoot meristems by bleomycin and induction of PARG1 is dependent on ATM and ATR kinases. PARG1 also antagonistically modulates the DNA repair process by preventing the over induction of DNA repair genes. Our study determined the contribution of each PARP and PARG member in DNA repair and indicated that PARG1 plays a critical role in this process. PMID- 26516025 TI - Helicobacter pylori outer membrane protein Q allele distribution is associated with distinct pathologies in Pakistan. AB - Helicobacter pylori (H. pylori) strains expressing outer membrane protein Q (HopQ) promote adherence to the gastric epithelial cell. We characterized HopQ alleles in relation to H. pylori-related disease, histology and virulence markers. Gastric biopsies were obtained at esophagogastroduodenoscopy from patients with upper gastrointestinal symptoms. H. pylori culture, histology and polymerase chain reaction (PCR) for HopQ types, cagA, cagA-promoter and vacA alleles were performed. DNA extracted was used for PCR. Sequencing of PCR products of HopQ types 1 and 2 was followed by BLAST query. We examined 241 H. pylori isolates. HopQ type 1 was positive in 70 (29%) isolates, type 2 in 60 (25%) isolates, while both type 1 and type 2 in 111 (46%) H. pylori isolates, respectively. Nonulcer dyspepsia (NUD) was associated with HopQ type 2 in 48 (41%) isolates, while gastric carcinoma (GC) in 37 (53%) (P<0.001) with type 1 isolates. Gastric ulcers (GU) were 39 (46%) (P<0.001) in H. pylori infection with multiple HopQ alleles compared to 6 (23%) in HopQ type 1. Multivariate analysis demonstrated that multiple HopQ alleles were associated with GU OR 2.9 (1.07-7.8) (P=0.03). HopQ type 1 was associated with cagA 58 (84%) (P<0.001) and cagA promoter 58 (83%) (P<0.001) compared to 14 (23%) and 17 (28%) respectively, in type 2. VacAs1a was associated with HopQ type 1 in 59 (84%) isolates compared to HopQ type 2 in 35 (58%) (P=0.002) isolates. VacAm1 was associated with HopQ type 1 in 53 (76%) isolates compared to HopQ type 2 in 32 (53%) (P=0.004) isolates. H. pylori infection with multiple HopQ alleles was predominant. H. pylori infection with single HopQ type 1 was associated with GC in the presence of other H. pylori virulence markers. PMID- 26516026 TI - Formation of charged ferroelectric domain walls with controlled periodicity. AB - Charged domain walls in proper ferroelectrics were shown recently to possess metallic-like conductivity. Unlike conventional heterointerfaces, these walls can be displaced inside a dielectric by an electric field, which is of interest for future electronic circuitry. In addition, theory predicts that charged domain walls may influence the electromechanical response of ferroelectrics, with strong enhancement upon increased charged domain wall density. The existence of charged domain walls in proper ferroelectrics is disfavoured by their high formation energy and methods of their preparation in predefined patterns are unknown. Here we develop the theoretical background for the formation of charged domain walls in proper ferroelectrics using energy considerations and outline favourable conditions for their engineering. We experimentally demonstrate, in BaTiO3 single crystals the controlled build-up of high density charged domain wall patterns, down to a spacing of 7 MUm with a predominant mixed electronic and ionic screening scenario, hinting to a possible exploitation of charged domain walls in agile electronics and sensing devices. PMID- 26516027 TI - Mitoxantrone as a contributing factor in medication-related osteonecrosis of the jaws. AB - Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is usually initiated by dental surgery, but is occasionally exacerbated by other antiresorptive (denosumab) and anti-angiogenic therapies, and in such cases is currently termed medication-related osteonecrosis of the jaws (MRONJ). The case of a 58-year-old female with breast cancer who developed multiple and ultimately fatal metastases despite 3 years of treatment with chemotherapeutic drugs and intravenous bisphosphonates, is presented herein. Her malignant disease worsened and she was started on mitoxantrone. She developed a severe adverse reaction to this drug soon after starting treatment. As well as diarrhoea and vomiting, she had a very aggressive gingival inflammation with multiple ulcerations in both jaws and wide areas of necrotic bone, affecting the attached gingiva, and seemingly unrelated to dental plaque. These ulcerations and the exposed necrotic bone persisted for more that 6 months, until her death. This report describes a case in which severe gingival ulcerations that occurred after mitoxantrone treatment for metastatic breast cancer were a local factor that initiated MRONJ. PMID- 26516028 TI - Evaluating the anatomical location of the posterior superior alveolar artery in cone beam computed tomography images. AB - The purpose of this study was to examine the diameter, location, and frequency of the appearance of the posterior superior alveolar artery (PSAA) in preoperative cone beam computed tomography (CBCT) scans. Two hundred and eleven pre-implant CBCT scans were reviewed. The following criteria were considered in all subjects: (1) the location of the artery: intra-sinus or below the membrane (type I), intraosseous (type II), or superficial (type III); (2) the distance between the lower border of the artery and the alveolar crest; (3) the bone height measured from the floor of the sinus to the crest of the ridge; (4) the distance from the lateral wall of the artery to the medial wall of the maxillary sinus; and (5) the diameter of the artery (in millimetres). The distance between the artery and the medial sinus wall, as well as the diameter of the artery, were greater in patients with an alveolar bone height <=10mm than in those with a bone height >10mm. The distance from the artery to the medial sinus wall and the diameter of the artery were positively correlated with the number of missing teeth. It was also found that the diameter of the PSAA increased with increasing age. PMID- 26516029 TI - Molecular phylogeny of the highly diversified catfish subfamily Loricariinae (Siluriformes, Loricariidae) reveals incongruences with morphological classification. AB - The Loricariinae belong to the Neotropical mailed catfish family Loricariidae, the most species-rich catfish family. Among loricariids, members of the Loricariinae are united by a long and flattened caudal peduncle and the absence of an adipose fin. Despite numerous studies of the Loricariidae, there is no comprehensive phylogeny of this morphologically highly diversified subfamily. To fill this gap, we present a molecular phylogeny of this group, including 350 representatives, based on the analysis of mitochondrial and nuclear genes (8426 positions). The resulting phylogeny indicates that Loricariinae are distributed into two sister tribes: Harttiini and Loricariini. The Harttiini tribe, as classically defined, constitutes a paraphyletic assemblage and is here restricted to the three genera Harttia, Cteniloricaria, and Harttiella. Two subtribes are distinguished within Loricariini: Farlowellina and Loricariina. Within Farlowellina, the nominal genus formed a paraphyletic group, as did Sturisoma and Sturisomatichthys. Within Loricariina, Loricaria, Crossoloricaria, and Apistoloricaria are also paraphyletic. To solve these issues, and given the lack of clear morphological diagnostic features, we propose here to synonymize several genera (Quiritixys with Harttia; East Andean members of Crossoloricaria, and Apistoloricaria with Rhadinoloricaria; Ixinandria, Hemiloricaria, Fonchiiichthys, and Leliella with Rineloricaria), to restrict others (Crossoloricaria, and Sturisomatichthys to the West Andean members, and Sturisoma to the East Andean species), and to revalidate the genus Proloricaria. PMID- 26516030 TI - Coordinated ultrastructural and phylogenomic analyses shed light on the hidden phycobiont diversity of Trebouxia microalgae in Ramalina fraxinea. AB - The precise boundary delineations between taxa in symbiotic associations are very important for evolutionary and ecophysiological studies. Growing evidence indicates that in many cases, the use of either morphological characters or molecular markers results in diversity underestimation. In lichen symbioses, Trebouxia is the most common genus of lichen phycobionts, however, the diversity within this genus has been poorly studied and as such there is no clear species concept. This study constitutes a multifaceted approach incorporating aspects of ultrastructural characterization by TEM and phylogenomics to evaluate the morphological and genetic diversity of phycobionts within the sexually reproducing lichen Ramalina fraxinea in the context of Mediterranean and temperate populations. Results reveal an association with at least seven different Trebouxia lineages belonging to at least two species, T. decolorans and T. jamesii, and diverse combinations of such lineages coexisting within the same thallus depending on the analyzed sample. Some of these lineages are shared by several other non-related lichen taxa. Our findings indicate the existence of a highly diverse assemblage of Trebouxia algae associating with R. fraxinea and suggest a possible incipient speciation within T. decolorans rendering a number of lineages or even actual species. This study stresses the importance of coordinated ultrastructural and molecular analyses to improve estimates of diversity and reveal the coexistence of more than one Trebouxia species within the same thallus. It is also necessary to have clearer species delimitation criteria within the genus Trebouxia and microalgae in general. PMID- 26516031 TI - Quetol 651: Not just a low viscosity resin. AB - Quetol 651, a low viscosity epoxy resin, is miscible with alcohols, acetone, and water. It is versatile and can be used as a single epoxide or mixed with other epoxides and anhydrides. The most important characteristic is that the addition of Quetol 651 to a formulation results in a lower viscosity embedding medium and allows for good detection of antigenic activity. Properly formulated and mixed resins containing Quetol 651 have excellent sectioning properties and good beam stability. The decrease in viscosity lends to lower specific gravity of the embedding medium and less interfering electron density between specimen elements resulting in better spatial resolution. New formulations and viscosity data are presented and compared to long used, embedding formulations and the extensive uses of Quetol 651 are reviewed. PMID- 26516032 TI - EASL Clinical Practice Guidelines: Vascular diseases of the liver. PMID- 26516033 TI - Natural Sunflower Pollen as a Drug Delivery Vehicle. AB - In nature, pollen grains play a vital role for encapsulation. Many pollen species exist which are often used as human food supplements. Dynamic image particle analysis, scanning electron microscopy, and confocal microscopy analysis confirmed the size, structural uniformity, and macromolecular encapsulation in sunflower pollen, paving the way to explore natural pollen grains for the encapsulation of therapeutic molecules. PMID- 26516034 TI - Seat strength in rear body block tests. AB - PURPOSE: This study collected and analyzed available testing of motor vehicle seat strength in rearward loading by a body block simulating the torso of an occupant. The data were grouped by single recliner, dual recliner, and all belts to seat (ABTS) seats. METHODS: The strength of seats to rearward loading has been evaluated with body block testing from 1964 to 2008. The database of available tests includes 217 single recliner, 65 dual recliner, and 18 ABTS seats. The trends in seat strength were determined by linear regression and differences between seat types were evaluated by Student's t-test. The average peak moment and force supported by the seat was determined by decade of vehicle model year (MY). RESULTS: Single recliner seats were used in motor vehicles in the 1960s to 1970s. The average strength was 918 +/- 224 Nm (n = 26) in the 1960s and 1,069 +/ 293 Nm (n = 65) in the 1980s. There has been a gradual increase in strength over time. Dual recliner seats started to phase into vehicles in the late 1980s. By the 2000s, the average strength of single recliner seats increased to 1,501 +/- 335 Nm (n = 14) and dual recliner seats to 2,302 +/- 699 Nm (n = 26). Dual recliner seats are significantly stronger than single recliner seats for each decade of comparison (P < .001). The average strength of ABTS seats was 4,395 +/- 1,185 in-lb for 1989-2004 MY seats (n = 18). ABTS seats are significantly stronger than single or dual recliner seats (P < .001). The trend in ABTS strength is decreasing with time and converging toward that of dual recliner seats. CONCLUSIONS: Body block testing is an quantitative means of evaluating the strength of seats for occupant loading in rear impacts. There has been an increase in conventional seat strength over the past 50 years. By the 2000s, most seats are 1,700-3,400 Nm moment strength. However, the safety of a seat is more complex than its strength and depends on many other factors. PMID- 26516035 TI - Prostanoids in patients with peripheral arterial disease: A meta-analysis of placebo-controlled randomized clinical trials. AB - AIMS: Prostanoids are indicated in the treatment of peripheral arterial disease (PAD). Available trials suggest that these compounds could reduce the symptoms of intermittent claudication, even though the quality of studies is poor. The present meta-analysis is aimed at verifying the effects of prostanoids on amputation rate and ulcer healing in patients with lower limb PAD. MATERIALS AND METHODS: The review protocol was published on http://www.crd.york.ac.uk/prospero (CRD42015020258). A comprehensive search for published and unpublished trials comparing iloprost, alprostadil, prostaglandin-E1, epoprostenol, or taprostene with placebo/no therapy on amputation rate in patients with PAD and ulcer healing rate in patients with concomitant foot ulcers. Mantel-Haenzel odds ratio (MH-OR) was calculated with random effect models for the chosen endpoints. RESULTS: A total of 18 trials, enrolling 3,077 and 2,763 patients in the prostanoid and comparator groups, respectively were included in the analysis. Only 11 and 10 of those trials reported data on total and major amputations, respectively. Prostanoids were associated with a significantly lower risk of major (MH-OR [95% confidence interval] was 0.77 [0.63; 0.93], p=0.007), but not total, amputations. Healing rate (available only in 7 trials) was not significantly augmented by prostanoid treatment. CONCLUSIONS: Available data are not sufficient to support an extensive use of prostanoids in patients with critical limb ischemia, as an adjunct to revascularization or as an alternative to major amputation in cases which cannot undergo revascularization. PMID- 26516036 TI - Maternal perceptions of breastfeeding difficulty after caesarean section with regional anaesthesia: A qualitative study. AB - BACKGROUND: Caesarean delivery rates have increased in Australia over the last decade creating new challenges for breastfeeding mothers and caregivers. The advantages of breastfeeding are well recognised, however breastfeeding problems are common. Review of the literature revealed limited qualitative research relating to the experience of women having difficulties breastfeeding after caesarean section under regional anaesthesia. This study aimed to fill that gap in the literature. METHODS: Participants were women referred to the hospital Breastfeeding Support Centre with difficulty initiating and establishing breastfeeding. The methodology employed was interpretive phenomenology and purposeful sampling. Data was analysed using van Manen's hermeneutical circular process. RESULTS: Themes identified included Unnatural birth, Natural instincts compromised, Helping mothers to mother and Sabotage and defeat. These themes elicited ten subthemes which were interpreted and reflected upon to reveal key findings. These findings included the emotional and physical effects of the delivery and anaesthetic, the lack of true skin to skin contact, separation of mother and baby, inconsistent information, inadequate support, unnecessary formula supplementation and feelings of failure. CONCLUSION: Key recommendations included increasing skin to skin contact after caesarean section to support the natural instincts of mother and baby, increasing education on possible effects of surgical delivery on breastfeeding and increasing postnatal breastfeeding support for this group of women. Broader issues of inadequate staffing and a changing postnatal dynamic reflecting increased post-surgical care need further exploration. PMID- 26516037 TI - beta-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta Analysis. AB - The normal physiologic stress mechanism, mediated by the sympathetic nervous system, causes a release of the neurotransmitters epinephrine and norepinephrine. Preclinical data have demonstrated an effect on tumor progression and metastasis via the sympathetic nervous system mediated primarily through the beta-adrenergic receptor (beta-AR) pathway. In vitro data have shown an increase in tumor growth, migration, tumor angiogenesis, and metastatic spread in breast cancer through activation of the beta-AR. Retrospective cohort studies on the clinical outcomes of beta-blockers in breast cancer outcomes showed no clear consensus. The purpose of this study was to perform a systematic review and meta-analysis of the effect of beta-blockers on breast cancer outcomes. A systematic review was performed using the Cochrane library and PubMed. Publications between the dates of January 2010 and December 2013 were identified. Available hazard ratios (HRs) were extracted for breast cancer recurrence, breast cancer death, and all-cause mortality and pooled using a random effects meta-analysis. A total of 7 studies contained results for at least 1 of the outcomes of breast cancer recurrence, breast cancer death, or all-cause mortality in breast cancer patients receiving beta-blockers. In the 5 studies that contained results for breast cancer recurrence, there was no statistically significant risk reduction (HR, 0.67; 95% confidence interval [CI], 0.39-1.13). Breast cancer death results were contained in 4 studies, which also suggested a significant reduction in risk (HR, 0.50; 95% CI, 0.32-0.80). Among the 4 studies that reported all-cause mortality, there was no significant effect of beta-blockers on risk (HR, 1.02; 95% CI, 0.75-1.37). Results of this systematic review and meta-analysis suggest that the use of beta blockers significantly reduced risk of breast cancer death among women with breast cancer. PMID- 26516038 TI - The Impact of Duration of Atrial Fibrillation Recurrences on Measures of Health Related Quality of Life and Symptoms. AB - BACKGROUND: Little is known about the relationship between daily atrial fibrillation (AF) burden and quality of life (QOL). We sought to determine the influence of atrial tachycardia (AT) or AF burden on measures of QOL and symptoms. METHODS AND RESULTS: We retrospectively analyzed patients with dual chamber pacemakers from the Atrial Septal Pacing Efficacy Clinical Trial (ASPECT), Atrial Therapy Efficacy and Safety Trial (ATTEST), and aTRial arrhythmias dEtected by implaNted Device diagnostics Study (TRENDS) trials. All patients underwent at least one QOL evaluation. We predefined four AF burden groups: no AT/AF (group 1), <=30 minutes (group 2), 30 minutes-2 hours (group 3), and >2 hours (group 4) per day. We compared QOL measures using the 12-item Short Form Health Survey (SF-12; standard 4 week recall) and the AF Symptom Checklist (SC) severity and frequency between groups 2-4 to those in group 1. A total of 798 patients were analyzed (age 72 +/- 11 years, 447 male [56%]). SC frequency and severity and SF-12 physical and mental scores worsened significantly when patients in group 4 were compared to patients with no AF. There were no statistically significant differences for any of the measures when comparing group 2 or 3 patients to group 1. By linear regression, only the 2-hour-cutoff had a significant impact on QOL as measured by SC frequency (+3.15, P < 0.001), severity (+3.23, P < 0.001), SF-12 physical score (-2.42, P = 0.013), and SF-12 mental score (-2.11, P = 0.021). CONCLUSION: A daily AT/AF burden of more than 2 hours had significant impact on QOL. This might influence the choice of appropriate cut-off points to determine the success of an AF treatment. PMID- 26516039 TI - Single fluorophore melting curve analysis for detection of hypervirulent Clostridium difficile. AB - This study demonstrates a novel detection assay able to identify and subtype strains of Clostridium difficile. Primers carefully designed for melting curve analysis amplify DNA from three C. difficile genes, tcdB, tcdC and cdtB, during quantitative (q)PCR. The tcdB gene allows for confirmation of organism presence, whilst the tcdC and cdtB genes allow for differentiation of virulence status, as deletions in the tcdC gene and the concurrent presence of the cdtB gene, which produces binary toxin, are associated with hypervirulence. Following qPCR, subtyping is then achieved by automated, inline melting curve analysis using only a single intercalating dye and verified by microchip electrophoresis. This assay represents a novel means of distinguishing between toxigenic and hypervirulent C. difficile strains NAP1/027/BI and 078 ribotype, which are highly prevalent hypervirulent strains in humans. This methodology can help rapidly detect and identify C. difficile strains that impose a significant health and economic burden in hospitals and other healthcare settings. PMID- 26516040 TI - The Royal Australian and New Zealand College of Ophthalmologists 47th Annual Scientific Congress 31 October - 4 November 2015 Shed 6, TSB Bank Arena and InterContinental Hotel, Wellington. PMID- 26516041 TI - Past Lecturers and Briefs for the Named Lectures: RANZCO Annual Scientific Congress. PMID- 26516042 TI - Scientific Program. PMID- 26516044 TI - Sunday 1 November. PMID- 26516043 TI - Invited Speakers. PMID- 26516045 TI - Monday 2 November. PMID- 26516046 TI - Tuesday 3 November. PMID- 26516047 TI - Wednesday 4 November. PMID- 26516053 TI - Interpersonal violence against children in sport in the Netherlands and Belgium. AB - The current article reports on the first large-scale prevalence study on interpersonal violence against children in sport in the Netherlands and Belgium. Using a dedicated online questionnaire, over 4,000 adults prescreened on having participated in organized sport before the age of 18 were surveyed with respect to their experiences with childhood psychological, physical, and sexual violence while playing sports. Being the first of its kind in the Netherlands and Belgium, our study has a sufficiently large sample taken from the general population, with a balanced gender ratio and wide variety in socio-demographic characteristics. The survey showed that 38% of all respondents reported experiences with psychological violence, 11% with physical violence, and 14% with sexual violence. Ethnic minority, lesbian/gay/bisexual (LGB) and disabled athletes, and those competing at the international level report significantly more experiences of interpersonal violence in sport. The results are consistent with rates obtained outside sport, underscoring the need for more research on interventions and systematic follow-ups, to minimize these negative experiences in youth sport. PMID- 26516054 TI - Whirlin increases TRPV1 channel expression and cellular stability. AB - The expression and function of TRPV1 are influenced by its interaction with cellular proteins. Here, we identify Whirlin, a cytoskeletal PDZ-scaffold protein implicated in hearing, vision and mechanosensory transduction, as an interacting partner of TRPV1. Whirlin associates with TRPV1 in cell lines and in primary cultures of rat nociceptors. Whirlin is expressed in 55% of mouse sensory C fibers, including peptidergic and non-peptidergic nociceptors, and co-localizes with TRPV1 in 70% of them. Heterologous expression of Whirlin increased TRPV1 protein expression and trafficking to the plasma membrane, and promoted receptor clustering. Silencing Whirlin expression with siRNA or blocking protein translation resulted in a concomitant degradation of TRPV1 that could be prevented by inhibiting the proteasome. The degradation kinetics of TRPV1 upon arresting protein translation mirrored that of Whirlin in cells co-expressing both proteins, suggesting a parallel degradation mechanism. Noteworthy, Whirlin expression significantly reduced TRPV1 degradation induced by prolonged exposure to capsaicin. Thus, our findings indicate that Whirlin and TRPV1 are associated in a subset of nociceptors and that TRPV1 protein stability is increased through the interaction with the cytoskeletal scaffold protein. Our results suggest that the Whirlin-TRPV1 complex may represent a novel molecular target and its pharmacological disruption might be a therapeutic strategy for the treatment of peripheral TRPV1-mediated disorders. PMID- 26516055 TI - The hypertrabeculated (noncompacted) left ventricle is different from the ventricle of embryos and ectothermic vertebrates. AB - Ventricular hypertrabeculation (noncompaction) is a poorly characterized condition associated with heart failure. The condition is widely assumed to be the retention of the trabeculated ventricular design of the embryo and ectothermic (cold-blooded) vertebrates. This assumption appears simplistic and counterfactual. Here, we measured a set of anatomical parameters in hypertrabeculation in man and in the ventricles of embryos and animals. We compared humans with left ventricular hypertrabeculation (N=21) with humans with structurally normal left ventricles (N=54). We measured ejection fraction and ventricular trabeculation using cardiovascular MRI. Ventricular trabeculation was further measured in series of embryonic human and 9 animal species, and in hearts of 15 adult animal species using MRI, CT, or histology. In human, hypertrabeculated left ventricles were significantly different from structurally normal left ventricles by all structural measures and ejection fraction. They were far less trabeculated than human embryonic hearts (15-40% trabeculated volume versus 55-80%). Early in development all vertebrate embryos acquired a ventricle with approximately 80% trabeculations, but only ectotherms retained the 80% trabeculation throughout development. Endothermic (warm-blooded) animals including human slowly matured in fetal and postnatal stages towards ventricles with little trabeculations, generally less than 30%. Further, the trabeculations of all embryos and adult ectotherms were very thin, less than 50 MUm wide, whereas the trabeculations in adult endotherms and in the setting of hypertrabeculation were wider by orders of magnitude. It is concluded in contrast to a prevailing assumption, the hypertrabeculated left ventricle is not like the ventricle of the embryo or of adult ectotherms. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26516056 TI - Stress exposure results in increased peroxisomal levels of yeast Pnc1 and Gpd1, which are imported via a piggy-backing mechanism. AB - Saccharomyces cerevisiae glycerol phosphate dehydrogenase 1 (Gpd1) and nicotinamidase (Pnc1) are two stress-induced enzymes. Both enzymes are predominantly localised to peroxisomes at normal growth conditions, but were reported to localise to the cytosol and nucleus upon exposure of cells to stress. Import of both proteins into peroxisomes depends on the peroxisomal targeting signal 2 (PTS2) receptor Pex7. Gpd1 contains a PTS2, however, Pnc1 lacks this sequence. Here we show that Pnc1 physically interacts with Gpd1, which is required for piggy-back import of Pnc1 into peroxisomes. Quantitative fluorescence microscopy analyses revealed that the levels of both proteins increased in peroxisomes and in the cytosol upon exposure of cells to stress. However, upon exposure of cells to stress we also observed enhanced cytosolic levels of the control PTS2 protein thiolase, when produced under control of the GPD1 promoter. This suggests that these conditions cause a partial defect in PTS2 protein import, probably because the PTS2 import pathway is easily saturated. PMID- 26516057 TI - Small for Size and Flow (SFSF) syndrome: An alternative description for posthepatectomy liver failure. AB - Small for Size Syndrome (SFSS) syndrome is a recognizable clinical syndrome occurring in the presence of a reduced mass of liver, which is insufficient to maintain normal liver function. A definition has yet to be fully clarified, but it is a common clinical syndrome following partial liver transplantation and extended hepatectomy, which is characterized by postoperative liver dysfunction with prolonged cholestasis and coagulopathy, portal hypertension, and ascites. So far, this syndrome has been discussed with focus on the remnant size of the liver after partial liver transplantation or extended hepatectomy. However, the current viewpoints believe that the excessive flow of portal vein for the volume of the liver parenchyma leads to over-pressure, sinusoidal endothelial damages and haemorrhage. The new hypothesis declares that in both extended hepatectomy and partial liver transplantation, progression of Small for Size Syndrome is not determined only by the "size" of the liver graft or remnant, but by the hemodynamic parameters of the hepatic circulation, especially portal vein flow. Therefore, we suggest the term "Small for Size and Flow (SFSF)" for this syndrome. We believe that it is important for liver surgeons to know the pathogenesis and manifestation of this syndrome to react early enough preventing non-reversible tissue damages. PMID- 26516058 TI - Prognostic value of MAGE-A9 expression in patients with colorectal cancer. AB - MAGE-A9 is a novel member of the melanoma-associated antigen (MAGE) family and is expressed in testicular cancer. The present study investigated MAGE-A9 expression as a potential biomarker in colorectal cancer (CRC). Immunohistochemical analysis was used to determine the expression of MAGE-A9 in 201 cases CRC tissues. We used quantitative real-time polymerase chain reaction (RT-PCR) and western blot analysis to further verify the results. The correlation between MAGE-A9 expression, clinicopathological features and prognosis of CRC patients was analyzed. The results showed that MAGE-A9 was predominantly localized in the cytoplasm of cancer cells and stromal cells. Compared to normal adjacent tissues, the high expression rate of MAGE-A9 in CRC tissues was significantly increased (P<0.001). High MAGE-A9 expression was significantly associated with venous invasion (P=0.008) and lymph node metastasis (P<0.001). The survival rate of the CRC patients who were positive for MAGE-A9 expression was significantly lower than that of CRC patients with negative MAGE-A9 expression. Moreover, univariate and multivariate analyses showed that high MAGE-A9 expression was a poor prognostic factor for CRC patients. Hence, MAGE-A9 is expected to become a new target for CRC treatment. PMID- 26516059 TI - Predicting the behavior of microfluidic circuits made from discrete elements. AB - Microfluidic devices can be used to execute a variety of continuous flow analytical and synthetic chemistry protocols with a great degree of precision. The growing availability of additive manufacturing has enabled the design of microfluidic devices with new functionality and complexity. However, these devices are prone to larger manufacturing variation than is typical of those made with micromachining or soft lithography. In this report, we demonstrate a design for-manufacturing workflow that addresses performance variation at the microfluidic element and circuit level, in context of mass-manufacturing and additive manufacturing. Our approach relies on discrete microfluidic elements that are characterized by their terminal hydraulic resistance and associated tolerance. Network analysis is employed to construct simple analytical design rules for model microfluidic circuits. Monte Carlo analysis is employed at both the individual element and circuit level to establish expected performance metrics for several specific circuit configurations. A protocol based on osmometry is used to experimentally probe mixing behavior in circuits in order to validate these approaches. The overall workflow is applied to two application circuits with immediate use at on the bench-top: series and parallel mixing circuits that are modularly programmable, virtually predictable, highly precise, and operable by hand. PMID- 26516060 TI - Parkinson's and Alzheimer's diseases: Focus on mild cognitive impairment. AB - The mild cognitive impairment (MCI) concept was developed to identify the earliest stages of cognitive impairment. MCI and, more specifically, amnestic MCI were initially proposed as transitional states that ultimately progress to full blown Alzheimer's disease (AD). However, MCI subjects do not uniformly progress to dementia (either AD or another) and may revert back to normal cognitive state. The MCI as concept has been borrowed from AD to other neurodegenerative diseases, particularly Parkinson's disease (PD). However the operational definition of MCI may not adequately convey the intended concept. Additional modifications to the concept and its operationalization are needed in order to better identify patients with incipient cognitive impairment and to guide clinical and research practices. Patients with PD have a very high likelihood of developing dementia, insidiously over many years. Cognitive impairment may start even before other symptoms. No constellation of cognitive symptoms in an otherwise healthy individual will herald development of AD or indeed will progress to dementia, including PD-dementia, in high likelihood. At present, identification of subtle cognitive dysfunction even in a person with diagnosed PD does not benefit the patient and should be avoided, except for research purposes. PMID- 26516061 TI - Adrenergic DNA damage of embryonic pluripotent cells via beta2 receptor signalling. AB - Embryonic pluripotent cells are sensitive to genotoxicity though they need more stringent genome integrity to avoid compromising multiple cell lineages and subsequent generations. However it remains unknown whether the cells are susceptible to adrenergic stress which can induce somatic cell genome lesion. We have revealed that adrenergic stress mediators cause DNA damage of the cells through the beta2 adrenergic receptor/adenylate cyclase/cAMP/PKA signalling pathway involving an induction of intracellular reactive oxygen species (ROS) accumulation. The adrenergic stress agonists adrenaline, noradrenaline, and isoprenaline caused DNA damage and apoptosis of embryonic stem (ES) cells and embryonal carcinoma stem cells. The effects were mimicked by beta2 receptor coupled signalling molecules and abrogated by selective blockade of beta2 receptors and inhibition of the receptor signalling pathway. RNA interference targeting beta2 receptors of ES cells conferred the cells the ability to resist the DNA damage and apoptosis. In addition, adrenergic stimulation caused a consistent accumulation of ROS in the cells and the effect was abrogated by beta2 receptor blockade; quenching of ROS reversed the induced DNA damage. This finding will improve the understanding of the stem cell regulatory physiology/pathophysiology in an adrenergic receptor subtype signalling mechanism. PMID- 26516063 TI - Synthesis of a Neutral Mixed-Valence Diferrocenyl Carborane for Molecular Quantum Dot Cellular Automata Applications. AB - The preparation of 7-Fc(+) -8-Fc-7,8-nido-[C2 B9 H10 ](-) (Fc(+) FcC2 B9 (-) ) demonstrates the successful incorporation of a carborane cage as an internal counteranion bridging between ferrocene and ferrocenium units. This neutral mixed valence Fe(II) /Fe(III) complex overcomes the proximal electronic bias imposed by external counterions, a practical limitation in the use of molecular switches. A combination of UV/Vis-NIR spectroscopic and TD-DFT computational studies indicate that electron transfer within Fc(+) FcC2 B9 (-) is achieved through a bridge mediated mechanism. This electronic framework therefore provides the possibility of an all-neutral null state, a key requirement for the implementation of quantum dot cellular automata (QCA) molecular computing. The adhesion, ordering, and characterization of Fc(+) FcC2 B9 (-) on Au(111) has been observed by scanning tunneling microscopy. PMID- 26516062 TI - A novel approach to measuring cell-mediated lympholysis using quantitative flow and imaging cytometry. AB - In this study, we established a novel isotope-free approach for the detection of cell-mediated lympholysis (CML) in MHC defined peripheral blood mononuclear cells (PBMCs) using multiparameter flow and imaging cytometry. CML is an established in vitro assay to detect the presence of cytotoxic effector T-lymphocytes precursors (CTLp). Current methods employed in the identification of CTLp in the context of transplantation are based upon the quantification of chromium ((51)Cr) released from target cells. In order to adapt the assay to flow cytometry, primary porcine PBMC targets were labeled with eFluor670 and incubated with major histocompatibility complex (MHC) mismatched effector cytotoxic lymphocytes (CTLs). With this method, we were able to detect target-specific lysis that was comparable to that observed with the (51)Cr-based assay. In addition, the use of quantitative cell imaging demonstrates the presence of accessory cells involved in the cytotoxic pathway. This innovative technique improves upon the standard (51)Cr release assay by eliminating the need for radioisotopes and provides enhanced characterization of the interactions between effector and target cells. This technique has wide applicability to numerous experimental and clinical models involved with effector-cell interactions. PMID- 26516064 TI - Is PD-L1 Expression a Biomarker of Response? AB - Drugs that target the programmed cell death-1 (PD-1) receptor have shown promising antitumor activity in clinical trials, but it is not clear whether expression of the ligand PD-L1 is a biomarker for response. Increasingly, researchers say that PD-L1 expression is just one of many variables that may affect response to PD-1 blockade. PMID- 26516071 TI - Time Interval between Trauma and Arthroscopic Meniscal Repair Has No Influence on Clinical Survival. AB - Arthroscopic meniscal repair is the gold standard for longitudinal peripheral meniscal tears. The time interval between trauma and meniscal repair remains controversial. The aim of this study was to evaluate failure rates and clinical outcome of arthroscopic meniscal repair in relation to chronicity of injury. A total of 238 meniscal repairs were performed in 234 patients. Anterior cruciate ligament (ACL) was reconstructed in almost all ACL-deficient knees (130 out of 133). Time interval between injury and repair was divided into acute (< 2 weeks), subacute (> 2 to < 12 weeks), and chronic (> 12 weeks). Patients completed postal questionnaires to evaluate clinical outcome and failure rates. Study instruments included Lysholm, Knee injury and Osteoarthritis Outcome Score (KOOS), and Tegner scoring systems. At a median follow-up of 41 months (interquartile range [IQR], 34-53 months) 55 medial and 10 lateral meniscal repairs failed (overall failure rate, 27%). There was a significant higher failure rate for medial meniscal repair (p < 0.05) and ACL-deficient knees without ACL reconstruction. Functional outcome scores showed only significant differences on the KOOS subscale "function in daily living" (95% confidence interval, 1.05-15.27, p < 0.05). No significant difference was found for any interval between trauma and repair. The interval between trauma and arthroscopic meniscal repair has no influence on the failure rate. Differences in survival rate of meniscal repair are more dependent on location of the lesion and ACL status, rather than chronicity of injury. PMID- 26516072 TI - Indications for Medial Patellofemoral Ligament Reconstruction: A Systematic Review. AB - The medial patellofemoral ligament (MPFL) plays a key role in lateral patellofemoral stability, and there has been significant clinical and research interest in MPFL reconstruction (MPFLR) in recent years. The primary objective of this systematic review of clinical studies is to investigate the reported indications for an isolated MPFLR and secondarily to examine some of the reasons reported for not performing an isolated MPFLR. A comprehensive search of the MEDLINE, EMBASE, PUBMED, and Cochrane databases was conducted to identify surgical studies investigating MPFLR. Study information including author, publication date, sample size, patient age, follow-up period, procedure performed, surgical indications and contraindications, and study design were extracted. The most common indication for isolated MPFLR was recurrent patellofemoral instability (82.1%). Common reasons given for not performing an isolated MPFLR included bony malalignment (51.8%), trochlear dysplasia (30.4%), and patella alta (23.2%). This systematic review identified recurrent patellofemoral instability as the primary indication for an isolated MPFLR; however, a large number of the studies did not provide clear criteria for when an isolated MPFLR should be performed. Similarly, there was significant variability in the reasons given for not performing an isolated MPFLR. PMID- 26516065 TI - Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. AB - The CD19 antigen, expressed on most B-cell acute lymphoblastic leukemias (B-ALL), can be targeted with chimeric antigen receptor-armed T cells (CART-19), but relapses with epitope loss occur in 10% to 20% of pediatric responders. We detected hemizygous deletions spanning the CD19 locus and de novo frameshift and missense mutations in exon 2 of CD19 in some relapse samples. However, we also discovered alternatively spliced CD19 mRNA species, including one lacking exon 2. Pull-down/siRNA experiments identified SRSF3 as a splicing factor involved in exon 2 retention, and its levels were lower in relapsed B-ALL. Using genome editing, we demonstrated that exon 2 skipping bypasses exon 2 mutations in B-ALL cells and allows expression of the N-terminally truncated CD19 variant, which fails to trigger killing by CART-19 but partly rescues defects associated with CD19 loss. Thus, this mechanism of resistance is based on a combination of deleterious mutations and ensuing selection for alternatively spliced RNA isoforms. SIGNIFICANCE: CART-19 yield 70% response rates in patients with B-ALL, but also produce escape variants. We discovered that the underlying mechanism is the selection for preexisting alternatively spliced CD19 isoforms with the compromised CART-19 epitope. This mechanism suggests a possibility of targeting alternative CD19 ectodomains, which could improve survival of patients with B cell neoplasms. PMID- 26516073 TI - Anisotropic Thermal Conductivity of Exfoliated Black Phosphorus. AB - The anisotropic thermal conductivity of passivated black phosphorus (BP), a reactive two-dimensional material with strong in-plane anisotropy, is ascertained. The room-temperature thermal conductivity for three crystalline axes of exfoliated BP is measured by time-domain thermo-reflectance. The thermal conductivity along the zigzag direction is ~2.5 times higher than that of the armchair direction. PMID- 26516074 TI - Intestinal microbiota in neonates requiring urgent surgery: assessing the role of probiotics using fecal DNA sequencing. AB - PURPOSE: To assess the impact of urgent surgery on neonates and the value of an orally administered probiotic preparation of Bifidobacterium animalis subsp. lactis LKM512 (LKM) using fecal DNA sequencing to analyze intestinal microbiota. METHODS: Subjects for this study were 13 neonates born at our institution. Surgical cases required surgery within 3 days of birth. Groups studied were surgical cases administered LKM (n = 4; LKM+), surgical cases not administered have surgery and were not administered LKM (n = 2; CS), and normal healthy neonates (n = 3; CN). Stool specimens (20 mg) were collected five times (after birth, and on days 3, 7, 10, and 14 after surgery in surgical cases, and after birth, and on days 4, 8, 11, and 15 of life in controls). RESULTS: Clinical data were similar for LKM+ and LKM-. Enterobacteriaceae, Streptococcaceae, Staphylococcaceae and Bifidobacteriaceae were identified in the descending order of abundance in CS stool. Streptococcaceae, Staphylococcaceae, Enterococcaceae and Bifidobacteriaceae were identified in the descending order of abundance in LKM+ stool. Bifidobacteriaceae, Enterobacteriaceae, Staphylococcaceae and Streptococcaceae were identified in the descending order of abundance in LKM- stool. Unexpectedly, Bifidobacteriaceae was significantly more abundant in LKM- than LKM+ (p < 0.05). CONCLUSION: Surgical stress appears to affect intestinal microbiota considerably. Probiotic administration in neonates requires clarification. PMID- 26516075 TI - A New Accurate 3D Measurement Tool to Assess the Range of Motion of the Tongue in Oral Cancer Patients: A Standardized Model. AB - In oral cancer treatment, function loss such as speech and swallowing deterioration can be severe, mostly due to reduced lingual mobility. Until now, there is no standardized measurement tool for tongue mobility and pre-operative prediction of function loss is based on expert opinion instead of evidence based insight. The purpose of this study was to assess the reliability of a triple camera setup for the measurement of tongue range of motion (ROM) in healthy adults and its feasibility in patients with partial glossectomy. A triple-camera setup was used, and 3D coordinates of the tongue in five standardized tongue positions were achieved in 15 healthy volunteers. Maximum distances between the tip of the tongue and the maxillary midline were calculated. Each participant was recorded twice, and each movie was analysed three times by two separate raters. Intrarater, interrater and test-retest reliability were the main outcome measures. Secondly, feasibility of the method was tested in ten patients treated for oral tongue carcinoma. Intrarater, interrater and test-retest reliability all showed high correlation coefficients of >0.9 in both study groups. All healthy subjects showed perfect symmetrical tongue ROM. In patients, significant differences in lateral tongue movements were found, due to restricted tongue mobility after surgery. This triple-camera setup is a reliable measurement tool to assess three-dimensional information of tongue ROM. It constitutes an accurate tool for objective grading of reduced tongue mobility after partial glossectomy. PMID- 26516077 TI - Novel retinoid ester in combination with salicylic acid for the treatment of acne. AB - BACKGROUND: Retinoids (RC), alpha-hydroxy acids (AHA), and salicylic acid (BHA) treat acne through differing mechanisms of action. It is theorized that optimal improvement can be achieved by combining the RC-induced normalization of cellular differentiation, AHA-induced exfoliation in hydrophilic areas, and BHA-induced exfoliation in lipophilic areas. AHA and RC have been combined in a bioengineered molecule (AHA retinoid conjugate, or AHA-RC) delivering both lactic acid (AHA) and RC in a manner reducing retinoid-associated irritation. OBJECTIVES: To evaluate efficacy and tolerability of a twice-daily, three-product skincare regimen using AHA-RC in combination with BHA for patients with acne. METHODS: A total of 27 women (age range 20-58 years, mean 37.81 +/- 10.04 years) with mild to-moderate acne used a 3-product regimen consisting of a twice-daily cleanser and topical serum (0.1% AHA-RC, 2% salicylic acid, and 10.4% l-lactic acid), with broad-spectrum SPF 50+ sunscreen as needed, over an 8-week period. Counts were made at baseline, week 4, and week 8 of total inflammatory (papules, pustules) and noninflammatory (open comedones, closed comedones) lesions. Dryness, stinging, and other secondary endpoints were rated on a 0-5 scale. RESULTS: Statistically significant reduction in inflammatory and noninflammatory lesion counts (P = 0.006 and P = 0.015, respectively) was noted at 4 weeks. Improvement continued into week 8 with highly significant (P < 0.001) reductions in both lesion counts. CONCLUSIONS: The topical combination of lactic acid, SA, and AHA RC produced acne improvement after 4 weeks with continuing cumulative improvement at 8 weeks. AHA-RC represents a new molecule combining several mechanisms of action to achieve acne improvement. PMID- 26516078 TI - Rice arbuscular mycorrhiza as a tool to study the molecular mechanisms of fungal symbiosis and a potential target to increase productivity. AB - Rice (Oryza sativa L.) is a monocot model crop for cereal molecular biology. Following the emergence of molecular genetics of arbuscular mycorrhizal (AM) symbiosis in model legumes in the 1990s, studies on rice genetic resources have considerably contributed to our understanding of the molecular mechanisms and evolution of root intracellular symbioses.In this review, we trace the history of these studies and suggest the potential utility of AM symbiosis for improvement in rice productivity. PMID- 26516079 TI - Growth Factor Release from Lyophilized Porcine Platelet-Rich Plasma: Quantitative Analysis and Implications for Clinical Applications. AB - BACKGROUND: Freeze-dried platelet-rich plasma (FD PRP) is of potential value for clinical applications. However, growth factors released from FD PRP have not been well studied. Our study investigates growth factor release from FD PRP preparations, compared with other PRP samples, to further facilitate such clinical use. METHODS: We used four experimental groups: (1) Fresh porcine PRP (PRP), (2) PRP activated by calcium chloride (CaCl2) (Ca PRP), (3) PRP activated by CaCl2, followed by freeze drying (Ca-FD PRP), and (4) PRP freeze-dried first, then activated by CaCl2 (FD-Ca PRP). All FD PRP samples were kept for up to 4 weeks at room temperature (22 degrees C) and reconstituted prior to analysis. Transforming growth factor-beta1 (TGF-beta1), platelet-derived growth factor AB (PDGF-AB), and vascular endothelial growth factor (VEGF) were quantitated by ELISA at 15 min and 1 h incubation times. RESULTS: The concentrations of all growth factors in Ca PRP, measured at 1 h, were significantly higher than those in PRP (p < 0.05). PDGF-AB concentrations in FD-Ca PRP were not significantly different than in Ca PRP (p > 0.05). Levels of VEGF in Ca-FD PRP were not significantly different than in Ca PRP (p > 0.05). However, TGF-beta1 concentrations in Ca-FD PRP, measured at 15 min, were higher than those in Ca PRP (p < 0.05). CONCLUSIONS: PRP was activated efficiently by calcium chloride. Freeze-dried PRP remained rich in growth factors after storage for 4 weeks at room temperature, indicating its ease of use and wider possibilities for clinical applications. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26516080 TI - Selenium and Preeclampsia: a Systematic Review and Meta-analysis. AB - Conflicting results exist between selenium concentration and preeclampsia. The role of selenium in the development of preeclampsia is unclear. We conducted a meta-analysis to compare the blood selenium level in patients with preeclampsia and healthy pregnant women, and to determine the effectiveness of selenium supplementation in preventing preeclampsia. We searched PubMed, ScienceDirect, the Cochrane Library, and relevant references for English language literature up to November 25, 2014. Mean difference from observational studies and relative risk from randomized controlled trials were meta-analyzed by a random-effect model. Thirteen observational studies with 1515 participants and 3 randomized controlled trials with 439 participants were included in the meta-analysis. Using a random-effect model, a statistically significant difference in blood selenium concentration of -6.47 MUg/l (95 % confidence interval (CI) -11.24 to -1.7, p = 0.008) was seen after comparing the mean difference of observational studies. In randomized controlled trials, using a random-effect model, the relative risk for preeclampsia was 0.28 (0.09 to 0.84) for selenium supplementation (p = 0.02). Evidence from observational studies indicates an inverse association of blood selenium level and the risk of preeclampsia. Supplementation with selenium significantly reduces the incidence of preeclampsia. However, more prospective clinical trials are required to assess the association between selenium supplementation and preeclampsia and to determine the dose, beginning time, and duration of selenium supplementation. PMID- 26516081 TI - Service user involvement in preregistration general nurse education: a systematic review. AB - AIMS AND OBJECTIVES: A systematic review of published studies on service user involvement in undergraduate, preregistration general nursing education (excluding mental health-specific programmes). The objective is to examine how students are exposed to engagement with service users. BACKGROUND: The requirement of service user involvement in all nurse education is policy expectation of health professional education providers, in response to the increased public and political expectations. Previous literature reviews have focused solely on mental health. DESIGN: Systematic review using the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines; timeframe 1997-2014; published in English. METHODS: Search of CINAHL, Cochrane Review, Education Research Complete, Internurse, MEDLINE, PsychINFO, Scopus, SocINDEX and Web of Science yielded 229 citations; 11 studies met the review eligibility criteria. RESULTS: Seven studies used qualitative methodology, two quantitative and two mixed methods. Studies from the United Kingdom dominated (n = 9), the remainder from South Africa and Turkey. The results are described using four themes: benefits and limitations of service user involvement; nursing student selection; education delivery; practice-based learning and assessment. Most studies were small scale; nine had less than 30 participants. Overall the evidence suggests that student, lecturers and service users valued service user involvement in nurse education, to provide an authentic insight into the illness experience. Logistical considerations around support and student cohort size emerged. CONCLUSIONS: This is the first systematic review to focus on service user involvement in general nurse education. It reveals that service user involvement commenced later and is more limited in general programmes as compared to equivalent mental health education provision. Most of the evidence focuses on perceptions of the value of involvement. Further research is required to more clearly establish impact on learning and clinical practice. RELEVANCE TO CLINICAL PRACTICE: Service user involvement in nurse education is valued by stakeholders but preparation and support for those involved, including mentors is underestimated. PMID- 26516076 TI - Tumor cell survival pathways activated by photodynamic therapy: a molecular basis for pharmacological inhibition strategies. AB - Photodynamic therapy (PDT) has emerged as a promising alternative to conventional cancer therapies such as surgery, chemotherapy, and radiotherapy. PDT comprises the administration of a photosensitizer, its accumulation in tumor tissue, and subsequent irradiation of the photosensitizer-loaded tumor, leading to the localized photoproduction of reactive oxygen species (ROS). The resulting oxidative damage ultimately culminates in tumor cell death, vascular shutdown, induction of an antitumor immune response, and the consequent destruction of the tumor. However, the ROS produced by PDT also triggers a stress response that, as part of a cell survival mechanism, helps cancer cells to cope with the PDT induced oxidative stress and cell damage. These survival pathways are mediated by the transcription factors activator protein 1 (AP-1), nuclear factor E2-related factor 2 (NRF2), hypoxia-inducible factor 1 (HIF-1), nuclear factor kappaB (NF kappaB), and those that mediate the proteotoxic stress response. The survival pathways are believed to render some types of cancer recalcitrant to PDT and alter the tumor microenvironment in favor of tumor survival. In this review, the molecular mechanisms are elucidated that occur post-PDT to mediate cancer cell survival, on the basis of which pharmacological interventions are proposed. Specifically, pharmaceutical inhibitors of the molecular regulators of each survival pathway are addressed. The ultimate aim is to facilitate the development of adjuvant intervention strategies to improve PDT efficacy in recalcitrant solid tumors. PMID- 26516082 TI - A semi-automated "blanket" method for renal segmentation from non-contrast T1 weighted MR images. AB - OBJECTIVE: To investigate the precision and accuracy of a new semi-automated method for kidney segmentation from single-breath-hold non-contrast MRI. MATERIALS AND METHODS: The user draws approximate kidney contours on every tenth slice, focusing on separating adjacent organs from the kidney. The program then performs a sequence of fully automatic steps: contour filling, interpolation, non uniformity correction, sampling of representative parenchyma signal, and 3D binary morphology. Three independent observers applied the method to images of 40 kidneys ranging in volume from 94.6 to 254.5 cm(3). Manually constructed reference masks were used to assess accuracy. RESULTS: The volume errors for the three readers were: 4.4% +/- 3.0%, 2.9% +/- 2.3%, and 3.1% +/- 2.7%. The relative discrepancy across readers was 2.5% +/- 2.1%. The interactive processing time on average was 1.5 min per kidney. CONCLUSIONS: Pending further validation, the semi automated method could be applied for monitoring of renal status using non contrast MRI. PMID- 26516083 TI - Properties of short double-stranded RNAs carrying randomized base pairs: toward better controls for RNAi experiments. AB - Short interfering RNAs (siRNAs) are mediators of RNA interference (RNAi), a commonly used technique for selective down-regulation of target gene expression. Using an equimolar mixture of A, G, C, and U phosphoramidites during solid-phase synthesis, we introduced degenerate positions into RNA guide and passenger strands so that, when annealed, a large pool of distinct siRNA duplexes with randomized base pairs at defined sites was created. We assessed the randomization efficiency by deep sequencing one of the RNAs. All possible individual sequences were present in the pool with generally an excellent distribution of bases. Melting temperature analyses suggested that pools of randomized guide and passenger strands RNAs with up to eight degenerate positions annealed so that mismatched base-pairing was minimized. Transfections of randomized siRNAs (rnd siRNAs) into cells led to inhibition of luciferase reporters by a miRNA-like mechanism when the seed regions of rnd-siRNA guide strands were devoid of degenerate positions. Furthermore, the mRNA levels of a select set of genes associated with siRNA off-target effects were measured and indicated that rnd siRNAs with degenerate positions in the seed likely show typical non-sequence specific effects, but not miRNA-like off-target effects. In the wake of recent reports showing the preponderance of miRNA-like off-target effects of siRNAs, our findings are of value for the design of a novel class of easily prepared and universally applicable negative siRNA controls. PMID- 26516085 TI - Relayed Regioselective Alkynylation/Olefination of Unsymmetrical Cyclic Diaryliodonium Species Catalyzed by Cu and Pd: Affording Fluorescent Cytotoxic Benzoxazoles. AB - Although cyclic diaryliodonium species have the potential to act as valuable synthons for cascade transformations, they still remain largely unexplored. The regioselectivity associated with unsymmetrical cyclic diaryliodonium species has previously been known to pose a challenge. A regioselective relayed alkynylation and olefination of unsymmetrical cyclic diaryliodonium species has been achieved by installation of a directing amido group. These relayed transformations were delayed until an oxazole ring had formed, delivering a series of unique fluorescent benzoxazoles. Moreover, some of these synthetic benzoxazoles showed apparent inhibitory activity against malignant cancer cells. Further confocal visualization revealed that benzoxazoles targeted cell nuclei. These findings might provide a novel structural scaffold to develop desirable anticancer agents. PMID- 26516084 TI - An extensive allelic series of Drosophila kae1 mutants reveals diverse and tissue specific requirements for t6A biogenesis. AB - N(6)-threonylcarbamoyl-adenosine (t6A) is one of the few RNA modifications that is universally present in life. This modification occurs at high frequency at position 37 of most tRNAs that decode ANN codons, and stabilizes cognate anticodon-codon interactions. Nearly all genetic studies of the t6A pathway have focused on single-celled organisms. In this study, we report the isolation of an extensive allelic series in the Drosophila ortholog of the core t6A biosynthesis factor Kae1. kae1 hemizygous larvae exhibit decreases in t6A that correlate with allele strength; however, we still detect substantial t6A-modified tRNAs even during the extended larval phase of null alleles. Nevertheless, complementation of Drosophila Kae1 and other t6A factors in corresponding yeast null mutants demonstrates that these metazoan genes execute t6A synthesis. Turning to the biological consequences of t6A loss, we characterize prominent kae1 melanotic masses and show that they are associated with lymph gland overgrowth and ectopic generation of lamellocytes. On the other hand, kae1 mutants exhibit other phenotypes that reflect insufficient tissue growth. Interestingly, whole-tissue and clonal analyses show that strongly mitotic tissues such as imaginal discs are exquisitely sensitive to loss of kae1, whereas nonproliferating tissues are less affected. Indeed, despite overt requirements of t6A for growth of many tissues, certain strong kae1 alleles achieve and sustain enlarged body size during their extended larval phase. Our studies highlight tissue-specific requirements of the t6A pathway in a metazoan context and provide insights into the diverse biological roles of this fundamental RNA modification during animal development and disease. PMID- 26516086 TI - Prevalence of contagious caprine pleuro-pneumonia in pastoral flocks of goats in the Rift Valley region of Kenya. AB - A cross-sectional survey was conducted between the months of March 2014 and March 2015 to determine the prevalence of contagious caprine pleuropneumonia in goat populations in pastoral flocks in three sub-counties of the Rift Valley region. A total of 432 serum samples were collected from goats from 54 flocks and tested for the presence of antibodies against mycoplasma capricolum subspecies capripneumoniae (mccp) using monoclonal antibody-based competitive enzyme-linked immuno-sorbent assay. Sero-prevalence recorded for Turkana West was 63.9%, Kajiado Central was 48.6%, while Pokot East was 29.2% which was statistically significant (chi2 = 34.997; P = 0.000) in the study sites. The results of this study confirmed that CCPP is widespread and endemic in the pastoral production systems studied in the Rift Valley region. The results confirmed that regions sharing international boundaries are at a higher risk of CCPP hence the need for a unified cross-border approach to disease control measures in the border areas. PMID- 26516087 TI - Effect of in situ acids removal on mixed glucose and xylose fermentation by Clostridium tyrobutyricum. AB - In the present study, the effect of potassium ions and increasing concentrations of glucose and xylose on the growth of a strain of Clostridium tyrobutyricum, adapted to wheat straw hydrolysate, was investigated. Application of continuous fermentation of a mixture of glucose and xylose and in situ acid removal by reverse electro enhanced dialysis (REED) was investigated as a method to alleviate potassium and end-product inhibition and consequently enhance the sugar consumption rates and butyric acid productivity. It was found that glucose and xylose were not inhibitory up to a concentration of 50 and 37 g L(-1) respectively, and that they were consumed at comparable rates when fermented alone. However, continuous fermentation of a mixture of glucose and xylose resulted in a significantly decreased xylose consumption rate compared to that of glucose alone, supporting the conclusion that C. tyrobutyricum has a lower affinity for xylose than for glucose. Potassium ions negatively affected the effective maximum growth rate of C. tyrobutyricum at concentrations higher than 5 g L(-1) exhibiting a non-competitive type of inhibition. Continuous fermentation of a glucose and xylose mixture with simultaneous acid removal by REED resulted in a two to threefold increase of the glucose consumption rate, while the xylose consumption rate was enhanced sixfold compared to continuous fermentation without in situ acid removal. Similarly, butyric acid productivity was enhanced by a factor of 2-3, while the yield remained unaffected. PMID- 26516088 TI - Reclassification of Serpens flexibilis Hespell 1977 as Pseudomonas flexibilis comb. nov., with Pseudomonas tuomuerensis Xin et al. 2009 as a later heterotypic synonym. AB - Serpens flexibilis was proposed in 1977 and approved in 1980 without the 16S rRNA gene sequence information. The sequence of S. flexibilis became available in 2010, after the publication of Pseudomonas tuomuerensis in 2009. Our preliminary phylogenetic analyses indicated that these two strains share high sequence similarity and therefore showed strong potential to be united into a single species. To clarify the taxonomic status of the two species, a polyphasic taxonomy study was conducted including whole genome sequencing. The value of average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) between the genome sequences of S. flexibilis ATCC 29606(T) and P. tuomuerensis JCM 14085(T) were 98.1% and 89.0%, respectively. The phenotypic and chemotaxonomic properties including enzymatic activities, substrate utilization profiles, and fatty acids, supported that the two taxa have no pronounced difference and should thus constitute a single species. Therefore, we propose to transfer Serpens flexibilis Hespell 1977 to the genus Pseudomonas as Pseudomonas flexibilis comb. nov. (type strain=ATCC 29606(T)), with Pseudomonas tuomuerensis Xin et al. 2009 as a later heterotypic synonym of Pseudomonas flexibilis. PMID- 26516089 TI - High diversity and distinctive community structure of bacteria on glaciers in China revealed by 454 pyrosequencing. AB - The bacterial diversity, community structure and preliminary microbial biogeographic pattern were assessed on glacier surfaces, including three northern glaciers (cold glaciers) and three southern glaciers (temperate glaciers) in China that experienced distinct climatic conditions. Pyrosequencing revealed that bacterial diversities were surprisingly high. With respect to operational taxonomic units (OTUs), Proteobacteria was the most dominant phylum on the glacier surfaces, especially Betaproteobacteria. Significant differences of the bacterial communities were observed between northern and southern glacier surfaces. The rare and abundant populations showed similar clustering patterns to the whole community. The analysis of the culturable bacterial compositions from four glaciers supported this conclusion. Redundancy analysis (RDA) and partial Mantel tests indicated that annual mean temperature, as well as geographical distance, was significantly correlated with the bacterial communities on the glaciers. It was inferred that bacterial communities on northern and southern glacier surfaces experienced different climate, water and nutrient patterns, and consequently evolved different lifestyles. PMID- 26516090 TI - Uptake of Neonicotinoid Insecticides by Water-Foraging Honey Bees (Hymenoptera: Apidae) Through Guttation Fluid of Winter Oilseed Rape. AB - The water-foraging activity of honey bees (Apis mellifera L.) on guttation fluid of seed-coated crops, such as winter oilseed rape (WOR; Brassica napus L.), has not yet been evaluated. We analyzed the uptake of active substances (a.s.) in guttation fluid by evaluating residues of honey-sac contents. In autumn, insecticide residues of up to 130 ug a.s. per liter were released in WOR guttation fluid; this concentration is noticeably lower than levels reported in guttation fluid of seed-coated maize. Until winter dormancy, the concentrations declined to <30 ug a.s. per liter. In spring, residues were linked to prewintered plants and declined steadily until flowering. The maximum release of residues in guttation fluid of seed-coated WOR occurs on the first leaves in autumn when the colonies' water demand decreases. For the first time, proof for the uptake of guttation fluid from seed-coated WOR by honey bees was provided by measuring residues in individual honey-sac contents. In total, 38 out of 204 samples (19%) showed residues of thiamethoxam at concentrations ranging from 0.3 to 0.95 ug per liter while the corresponding concentrations in guttation fluid of WOR varied between 3.6 to 12.9 ug thiamethoxam per liter. The amounts of thiamethoxam we found in the honey sacs of water-foraging honey bees were therefore below the thresholds in nectar and pollen that are considered to have negative effects on honey bees after chronic exposure. PMID- 26516091 TI - Planting Date and Variety Selection for Management of Viruses Transmitted by the Wheat Curl Mite (Acari: Eriophyidae). AB - Wheat is an important food grain worldwide, and it is the primary dryland crop in the western Great Plains. A complex of three viruses (Wheat streak mosaic, Wheat mosaic, and Triticum mosaic viruses) is a common cause of loss in winter wheat production in the Great Plains. All these viruses are transmitted by the wheat curl mite (Aceria tosichella Keifer). Once these viruses are established, there are no curative actions; therefore, prevention is the key to successful management. A study was designed to evaluate preventative management tactics (planting date, resistant varieties) for reducing the impact from this virus complex. The main plot treatments were three planting dates, and split-plot treatments were three wheat varieties. Varieties were planted at three different times during the fall to simulate early, recommended, and late planting dates. The varieties evaluated in this study were Mace (virus resistant), Millennium (mild tolerance), and Tomahawk (susceptible). Measurements of virus symptomology and yield were used to determine virus impact. Results consistently showed that the resistant Mace yielded more than Millennium or Tomahawk under virus pressure. In some years, delayed planting improved the yields for all varieties, regardless of their background; however, under the most severe virus pressure the combination of both management strategies was not sufficient to provide practical control of this complex. These results illustrate the importance of using a combination of management tactics for this complex, but also reinforce the importance for producers to use additional management strategies (e.g., control preharvest volunteer wheat) to manage this complex. PMID- 26516093 TI - Gal3 Binds Gal80 Tighter than Gal1 Indicating Adaptive Protein Changes Following Duplication. AB - Derived from the yeast whole-genome duplication, Saccharomyces cerevisiae GAL1 and GAL3 encode the catabolic enzyme galactokinase (Gal1) and its transcriptional coinducer (Gal3), whereas the ancestral, preduplicated GAL1 gene performed both functions. Previous studies indicated that divergence was primarily driven by changes in upstream promoter elements, and changes in GAL3's coding region are assumed to be the result of drift. We show that replacement of GAL3's open reading-frame with GAL1's results in an extended lag phase upon switching to growth on galactose with up to 2.5-fold differences in the initial cell masses. Accordingly, the binding affinity of Gal3 to Gal80 was found to be greater than 10-folds higher than that of Gal1, with both a higher association rate (ka) and lower dissociation (kd) rate. Thus, while changes in the noncoding, regulatory regions were the initial driving force for GAL3's subfunctionalization as a coinducer, adaptive changes in the protein sequence seem to have followed. PMID- 26516092 TI - The Landscape of Realized Homologous Recombination in Pathogenic Bacteria. AB - Recombination enhances the adaptive potential of organisms by allowing genetic variants to be tested on multiple genomic backgrounds. Its distribution in the genome can provide insight into the evolutionary forces that underlie traits, such as the emergence of pathogenicity. Here, we examined landscapes of realized homologous recombination of 500 genomes from ten bacterial species and found all species have "hot" regions with elevated rates relative to the genome average. We examined the size, gene content, and chromosomal features associated with these regions and the correlations between closely related species. The recombination landscape is variable and evolves rapidly. For example in Salmonella, only short regions of around 1 kb in length are hot whereas in the closely related species Escherichia coli, some hot regions exceed 100 kb, spanning many genes. Only Streptococcus pyogenes shows evidence for the positive correlation between GC content and recombination that has been reported for several eukaryotes. Genes with function related to the cell surface/membrane are often found in recombination hot regions but E. coli is the only species where genes annotated as "virulence associated" are consistently hotter. There is also evidence that some genes with "housekeeping" functions tend to be overrepresented in cold regions. For example, ribosomal proteins showed low recombination in all of the species. Among specific genes, transferrin-binding proteins are recombination hot in all three of the species in which they were found, and are subject to interspecies recombination. PMID- 26516095 TI - The neural correlates of risky decision making across short and long runs. AB - People frequently change their preferences for options of gambles which they play once compared to those they play multiple times. In general, preferences for repeated play gambles are more consistent with the expected values of the options. According to the one-process view, the change in preference is due to a change in the structure of the gamble that is relevant to decision making. According to the two-process view, the change is attributable to a shift in the decision making strategy that is used. To adjudicate between these two theories, we asked participants to choose between gambles played once or 100 times, and to choose between them based on their expected value. Consistent with the two process theory, we found a set of brain regions that were sensitive to the extent of behavioral change between single and aggregated play and also showed significant (de)activation in the expected value choice task. These results support the view that people change their decision making strategies for risky choice considered once or multiple times. PMID- 26516094 TI - Resolution of Brassicaceae Phylogeny Using Nuclear Genes Uncovers Nested Radiations and Supports Convergent Morphological Evolution. AB - Brassicaceae is one of the most diverse and economically valuable angiosperm families with widely cultivated vegetable crops and scientifically important model plants, such as Arabidopsis thaliana. The evolutionary history, ecological, morphological, and genetic diversity, and abundant resources and knowledge of Brassicaceae make it an excellent model family for evolutionary studies. Recent phylogenetic analyses of the family revealed three major lineages (I, II, and III), but relationships among and within these lineages remain largely unclear. Here, we present a highly supported phylogeny with six major clades using nuclear markers from newly sequenced transcriptomes of 32 Brassicaceae species and large data sets from additional taxa for a total of 55 species spanning 29 out of 51 tribes. Clade A consisting of Lineage I and Macropodium nivale is sister to combined Clade B (with Lineage II and others) and a new Clade C. The ABC clade is sister to Clade D with species previously weakly associated with Lineage II and Clade E (Lineage III) is sister to the ABCD clade. Clade F (the tribe Aethionemeae) is sister to the remainder of the entire family. Molecular clock estimation reveals an early radiation of major clades near or shortly after the Eocene-Oligocene boundary and subsequent nested divergences of several tribes of the previously polytomous Expanded Lineage II. Reconstruction of ancestral morphological states during the Brassicaceae evolution indicates prevalent parallel (convergent) evolution of several traits over deep times across the entire family. These results form a foundation for future evolutionary analyses of structures and functions across Brassicaceae. PMID- 26516096 TI - Cross-laboratory analytical validation of the cardiac biomarker NT-proANP in rat. AB - INTRODUCTION: Natriuretic peptides, including N-terminal-proatrial natriuretic peptide (NT-proANP) are cardiac hormones that are produced in response to myocardial stretch and have been used in rats and humans as blood based functional cardiac biomarkers. There are limited validation data of these assays in rats and therefore the Predictive Safety Testing Consortium, Cardiac Hypertrophy Working Group (PSTC-CHWG) performed a cross-laboratory (5 laboratories) analytical evaluation of a commercially available NT-proANP ELISA for use with rat samples. METHODS: Serum samples were collected from normal Sprague Dawley (SD) rats and were spiked with kit calibrator material or rat heart tissue extracts to provide specimens for the validation. In addition, the cardiotoxicant, isoproterenol, was used to induce elevated endogenous NT-proANP levels in a subgroup of rats for additional validation specimens. The BiomedicaTM (BI-20892, Vienna, Austria) proANP (1-98) enzyme-linked immunoabsorbent assay (ELISA) kit was used to measure NT-proANP. Intra-assay and inter-assay precisions, accuracy, sample linearity, recovery, limit of detection, upper and lower limits of quantitation (ULOQ and LLOQ, respectively), sample-freeze/thaw stability and stored sample stability were assessed and compared to pre determined acceptance criteria. RESULTS: The majority of the experimental assessments met the established validation criteria, however there were individual results that did not meet these standards. Overall, acceptable intra- and inter-assay precisions and accuracies as well as inter-laboratory precision and accuracy were demonstrated. Linearity and recovery values fell within the pre determined acceptance criteria, samples remained stable for up to three freeze thaw cycles and frozen samples were stable at ~-70 degrees C for 12 months. The limit of detection (LOD) and LLOQ and ULOQ were similar to those specified by the manufacturer. DISCUSSION: Overall, the assay was demonstrated to be technically adequate for the detection of NT-proANP serum levels in SD rats. PMID- 26516097 TI - Violence, health, and South-North collaboration: Interdisciplinary research in light of the 2030 Agenda. PMID- 26516099 TI - Au@SiO2 core-shell structure involved with methotrexate: Fabrication, biodegradation process and bioassay explore. AB - A new strategy is proposed to synthesize a kind of Au@SiO2 core-shell structure with methotrexate (MTX) loaded within it. Firstly, MTX molecules are attracted to the surface and vicinity of Au nanoparticles (NPs). Then the enriched MTX molecules on the surface of Au NPs have a good chance to be wrapped into the core shell structure when SiO2 is uniformly deposited on the Au core. Secondly, the effect of Au amount and MTX content on the drug-loading capacity is emphatically studied and the result shows that core-shell structure plays a vital role in drug loading. In addition, the biodegradation process is also examined in phosphate buffer solution (PBS) at 37 degrees C. The results show that the biodegradation of Au-MTX@SiO2 core-shell structure can be divided into two stages: the release of drug together with the fragmentation of core-shell structure and the subsequent dissolution of SiO2 layers. Lastly, in vitro bioassay tests give the evidence that obvious tumor inhibition can be achieved in presence of Au-MTX@SiO2 NPs even at low concentration and the efficacy can be greatly enhanced by the photothermal therapy on Au cores. PMID- 26516098 TI - A DNA Mini-Barcoding System for Authentication of Processed Fish Products. AB - Species substitution is a form of seafood fraud for the purpose of economic gain. DNA barcoding utilizes species-specific DNA sequence information for specimen identification. Previous work has established the usability of short DNA sequences-mini-barcodes-for identification of specimens harboring degraded DNA. This study aims at establishing a DNA mini-barcoding system for all fish species commonly used in processed fish products in North America. Six mini-barcode primer pairs targeting short (127-314 bp) fragments of the cytochrome c oxidase I (CO1) DNA barcode region were developed by examining over 8,000 DNA barcodes from species in the U.S. Food and Drug Administration (FDA) Seafood List. The mini barcode primer pairs were then tested against 44 processed fish products representing a range of species and product types. Of the 44 products, 41 (93.2%) could be identified at the species or genus level. The greatest mini-barcoding success rate found with an individual primer pair was 88.6% compared to 20.5% success rate achieved by the full-length DNA barcode primers. Overall, this study presents a mini-barcoding system that can be used to identify a wide range of fish species in commercial products and may be utilized in high throughput DNA sequencing for authentication of heavily processed fish products. PMID- 26516100 TI - Delivery of drugs to intracellular organelles using drug delivery systems: Analysis of research trends and targeting efficiencies. AB - Targeting of drug delivery systems (DDSs) to specific intracellular organelles (i.e., subcellular targeting) has been investigated in numerous publications, but targeting efficiency of these systems is seldom reported. We searched scientific publications in the subcellular DDS targeting field and analyzed targeting efficiency and major formulation parameters that affect it. We identified 77 scientific publications that matched the search criteria. In the majority of these studies nanoparticle-based DDSs were applied, while liposomes, quantum dots and conjugates were used less frequently. The nucleus was the most common intracellular target, followed by mitochondrion, endoplasmic reticulum and Golgi apparatus. In 65% of the publications, DDSs surface was decorated with specific targeting residues, but the efficiency of this surface decoration was not analyzed in predominant majority of the studies. Moreover, only 23% of the analyzed publications contained quantitative data on DDSs subcellular targeting efficiency, while the majority of publications reported qualitative results only. From the analysis of publications in the subcellular targeting field, it appears that insufficient efforts are devoted to quantitative analysis of the major formulation parameters and of the DDSs' intracellular fate. Based on these findings, we provide recommendations for future studies in the field of organelle specific drug delivery and targeting. PMID- 26516102 TI - Adverse events and treatment failure leading to discontinuation of recently approved antipsychotic drugs in schizophrenia: A network meta-analysis. AB - Objective:We aimed to gather evidence of the discontinuation rates owing to adverse events or treatment failure for four recently approved antipsychotics (asenapine, blonanserin, iloperidone, and lurasidone).Methods: A systematic review followed by pairwise meta-analysis and mixed treatment comparison meta analysis(MTC) was performed, including randomized controlled trials (RCTs) that compared the use of the above-mentioned drugs versus placebo in patients with schizophrenia. An electronic search was conducted in PubMed, Scopus, Science Direct, Scielo, the Cochrane Library, and International Pharmaceutical Abstracts(January 2015). The included trials were at least single blinded. The main outcome measures extracted were discontinuation owing to adverse events and discontinuation owing to treatment failure.Results: Fifteen RCTs were identified (n = 5400 participants) and 13 of them were amenable for use in our meta analyses. No significant differences were observed between any of the four drugs and placebo as regards discontinuation owing to adverse events, whether in pairwise meta-analysis or in MTC. All drugs presented a better profile than placebo on discontinuation owing to treatment failure, both in pairwise meta analysis and MTC. Asenapine was found to be the best therapy in terms of tolerability owing to failure,while lurasidone was the worst treatment in terms of adverse events. The evidence around blonanserin is weak.Conclusion: MTCs allowed the creation of two different rank orders of these four antipsychotic drugs in two outcome measures. This evidence-generating method allows direct and indirect comparisons, supporting approval and pricing decisions when lacking sufficient, direct, head-to-head trials. PMID- 26516101 TI - Serum level of venlafaxine is associated with better memory in psychotic disorders. AB - Cognitive impairment is a core feature of psychosis spectrum disorders. Antipsychotics have at best small positive effects on cognitive performance. There is a lack of knowledge regarding the effects of antidepressants on cognitive functioning in these disorders. In the present study cognitive performance was investigated in relation to serum levels of antidepressants in persons with bipolar disorder and schizophrenia. Serum concentrations of escitalopram, citalopram and venlafaxine plus O-desmethylvenlafaxine were measured in a total of 187 participants with bipolar disorder (N=74) or schizophrenia spectrum disorders (N=113), and analyzed in relation to neuropsychological tests performance of verbal learning, verbal memory, attention, working memory, executive functioning and processing speed. Analyses were performed using linear regression adjusting for a range of confounders. There was a significant positive association between the serum level of venlafaxine plus O-desmethylvenlafaxine and verbal memory (immediate recall: Logical Memory Test immediate recall [p=0.015], and long term delayed recall: Logical Memory Test delayed recall [p=0.011]). No significant associations were seen between citalopram or escitalopram and verbal memory. There were no significant associations between the tested antidepressants and verbal learning, attention, working memory, executive functioning, or processing speed. Venlafaxine seem to be associated with better verbal memory in bipolar disorder and schizophrenia. This suggests a possible beneficial role of certain antidepressants on cognitive dysfunction, which may have clinical implications and provide insight into underlying pathophysiology. However, the current findings should be replicated in independent samples. PMID- 26516103 TI - Phenomenology and neurobiology of self disorder in schizophrenia: Primary factors. AB - Schizophrenia is a heterogeneous syndrome, varying between persons and over course of illness. In this and a companion article, we argue that comprehension of this condition or set of conditions may require combining a phenomenological perspective emphasizing disorders of basic-self experience ("ipseity disturbance") with a multidimensional appreciation of possible neurobiological correlates--both primary and secondary. Previous attempts to link phenomenology and neurobiology generally focus on a single neurocognitive factor. We consider diverse aspects of schizophrenia in light of a diverse, albeit interacting, set of neurocognitive abnormalities, examining both synchronic (structural) interdependence and diachronic (temporal) succession. In this article we focus on the primary or foundational role of early perceptual and motoric disturbances that affect perceptual organization and especially intermodal or multisensory perceptual integration ("perceptual dys-integration"). These disturbances are discussed in terms of their implications for three interconnected aspects of selfhood in schizophrenia, primary forms of: disrupted "hold" or "grip" on the world, hyperreflexivity, diminished self-presence (self-affection). Disturbances of organization or integration imply forms of perceptual incoherence or diminished cognitive coordination. The effect is to disrupt one's ability to apprehend the world in holistic, vital, or contextually grounded fashion, or to fully identify with or experience the unity of one's own body or thinking- thereby generating an early and profound (albeit often subtle) disruption or diminishment of basic or core self and of the sense of existing in a coherent world. We discuss interrelationships or possible complementarities between these three aspects, and consider their relevance for a neurodevelopmental account of schizophrenia. PMID- 26516105 TI - Differences in mitochondrial function in homogenated samples from healthy and epileptic specific brain tissues revealed by high-resolution respirometry. AB - Mitochondrial dysfunction and oxidative stress are strongly implicated in neurodegenerative diseases and epilepsy. Strikingly, neurodegenerative diseases show regional specificity in vulnerability and follow distinct patterns of neuronal loss. A challenge is to understand, why mitochondria fail in particular brain regions under specific pathological conditions. A potential explanation could be provided by regional or cellular specificity of mitochondrial function. We applied high-resolution respirometry to analyze the integrated Complex I- and II (CI and CII)-linked respiration, the activity of Complex IV, and the combined CI&II-linked oxidative phosphorylation (OXPHOS)- and electron-transfer system (ETS)-capacity in microsamples obtained from distinct regions of the mouse brain. We compared different approaches to assess mitochondrial density and suggest flux control ratios as a valid method to normalize respiration to mitochondrial density. This approach revealed significant differences of CI- and CII-linked OXPHOS capacity and coupling control between motor cortex, striatum, hippocampus and pons of naive mice. CI-linked respiration was highest in motor cortex, while CII-linked respiration predominated in the striatum. To investigate if this method could also determine differences in normal and disease states within the same brain region, we compared hippocampal homogenates in a chronic epilepsy model. Three weeks after stereotaxic injection of kainate, there was a down regulation of CI- and upregulation of CII-linked respiration in the resulting epileptic ipsilateral hippocampus compared to the contralateral one. In summary, respirometric OXPHOS analysis provides a very sensitive diagnostic approach using small amounts of distinct brain tissues. In a single assay, information is obtained on numerous OXPHOS parameters as indicators of tissue-specific mitochondrial performance. PMID- 26516106 TI - Evolution of Management of Intracranial Aneurysms in Children: A Systematic Review of the Modern Literature. AB - Pediatric intracranial aneurysms are rare. Management of their more common adult counterparts was profoundly influenced by recent high-quality clinical studies. The aim of this review was to aggregate the modern pediatric data published in the wake of these studies and to analyze their impact on management of aneurysms in children. A systematic PubMed search identified 135 publications published between 2000 and 2015, accounting for 573 children and 656 aneurysms. Descriptive statistical analyses revealed differences between children and adults concerning demographics and aneurysm characteristics. A significant proportion of patients were treated endovascularly, suggesting endovascular treatment has been established in the therapeutic armamentarium for pediatric aneurysms. However, these data highlight the unique nature of pediatric aneurysms, and neither this review nor generalization from adult data can replace high-quality clinical research. Multicenter registries and controlled trials are required to establish the natural history and evidence-based treatment of pediatric aneurysms. PMID- 26516104 TI - Systematic review with meta-analysis: direct comparisons of biomarkers for the diagnosis of fibrosis in chronic hepatitis C and B. AB - BACKGROUND: Blood tests and transient elastography (TE), proposed as alternatives to biopsy for identifying advanced fibrosis (METAVIR-stage-F2 or greater) or cirrhosis, have never been compared using an intention to diagnose approach, with direct comparisons only, and Bayesian approach. AIM: To permit more appropriate comparisons. METHODS: From an overview of articles (2002-2014), we selected studies that directly compared the diagnostic accuracy of FibroTest, aspartate aminotransferase-platelet ratio index (APRI), FIB4 or TE, with biopsy as a reference, in patients with chronic hepatitis C (CHC) or B (CHB). Investigators abstracted and checked study details and quality by using pre-defined criteria. Bayesian method in intention to diagnose was the primary outcome. RESULTS: Of 1321 articles identified, 71 studies including 77 groups according to aetiology (All-CB) were eligible: 37 Only-C, 28 Only-B and 12 Mixed-C-B. There were 185 direct comparisons between the area under the ROC curves (AUROCs), 99 for the diagnosis of advanced fibrosis and 86 for cirrhosis. In All-CB, Bayesian analyses revealed significant AUROCs differences in identifying advanced fibrosis in favour of FibroTest vs. TE [credibility interval: 0.06(0.02-0.09)], FibroTest vs. APRI [0.05 (0.03-0.07)] and for identifying cirrhosis TE vs. APRI [0.07 (0.02 0.13)] and FIB4 vs. APRI [0.04(0.02-0.05)]. No differences were observed between TE and FibroTest, for identifying cirrhosis in All-CB, and in sub-groups (Only-C, Only-B, Mixed-CB) for both cirrhosis and fibrosis. CONCLUSIONS: In CHC and CHB, APRI had lower performances than FIB-4, TE and FibroTest. TE had lower performance than FibroTest for identifying advanced fibrosis in All-CB, without significant difference for identifying cirrhosis in all groups. PMID- 26516107 TI - Mortality and cardiovascular disease outcomes among 740 patients with new-onset Type 2 diabetes detected by screening or clinically diagnosed in general practice. AB - AIM: Screening for Type 2 diabetes among people at high risk is recommended by many organizations. The aim of this study was to analyse all-cause mortality and cardiovascular disease (CVD) outcomes in patients with Type 2 diabetes detected by screening or diagnosed clinically. METHODS: A diabetes register was established at the primary healthcare centre in Laxa, Sweden beginning in 1972. The register was based on data from clinical records with information on medical treatment and laboratory data, as well as all-cause mortality, CVD, myocardial infarction and stroke events from national registers until 31 December 2013. A total of 740 patients with new-onset Type 2 diabetes were registered between 1972 and 2001. In addition, an opportunistic diabetes-screening programme involving people aged 35-79 years started in 1983 and was repeated onwards in 5-year cycles. RESULTS: Baseline characteristics showed a significantly higher CVD risk, mainly depending on more prevalent CVD events in the screened compared with the clinically detected group (propensity score 0.59 vs. 0.46, P < 0.0001). After mean follow-up periods of 12.9 and 13.6 years for screening detected vs. clinically detected patients, respectively, hazard ratios were as follows: all cause mortality, 0.99 (P = 0.89); CVD, 1.17 (P = 0.10); myocardial infarction, 1.08 (P = 0.49); and stroke, 1.03 (P = 0.83). CONCLUSIONS: No reduction in total mortality or CVD outcomes was found in patients with Type 2 diabetes that was detected by screening compared with those diagnosed clinically. PMID- 26516109 TI - A rapid molecular diagnosis of cutaneous leishmaniasis by colorimetric malachite green-loop-mediated isothermal amplification (LAMP) combined with an FTA card as a direct sampling tool. AB - Leishmaniasis remains one of the world's most neglected diseases, and early detection of the infectious agent, especially in developing countries, will require a simple and rapid test. In this study, we established a quick, one-step, single-tube, highly sensitive loop-mediated isothermal amplification (LAMP) assay for rapid detection of Leishmania DNA from tissue materials spotted on an FTA card. An FTA-LAMP with pre-added malachite green was performed at 64 degrees C for 60min using a heating block and/or water bath and DNA amplification was detected immediately after incubation. The LAMP assay had high detection sensitivity down to a level of 0.01 parasites per MUl. The field- and clinic applicability of the colorimetric FTA-LAMP assay was demonstrated with 122 clinical samples collected from patients suspected of having cutaneous leishmaniasis in Peru, from which 71 positives were detected. The LAMP assay in combination with an FTA card described here is rapid and sensitive, as well as simple to perform, and has great potential usefulness for diagnosis and surveillance of leishmaniasis in endemic areas. PMID- 26516108 TI - Tissue factor-positive tumor microvesicles activate platelets and enhance thrombosis in mice. AB - ESSENTIALS: Cancer patients have a high rate of venous thrombosis (VT) but the underlying mechanisms are unknown. Tumor-derived, tissue factor-positive microvesicles in platelet activation in vitro and in vivo were studied. Tumor derived, tissue factor-positive microvesicles enhanced VT in mice. Platelets may contribute to VT in some cancer patients, and this could be prevented with antiplatelet drugs. BACKGROUND: Cancer patients have an approximately 4-fold increased risk of venous thromboembolism (VTE) compared with the general population, and cancer patients with VTE have reduced survival. Tumor cells constitutively release small membrane vesicles called microvesicles (MVs) that may contribute to thrombosis in cancer patients. Clinical studies have shown that levels of circulating tumor-derived, tissue factor-positive (TF(+) ) MVs in pancreatic cancer patients are associated with VTE. Objectives We tested the hypothesis that TF(+) tumor-derived MVs (TMVs) activate platelets in vitro and in mice. MATERIALS AND METHODS: We selected two human pancreatic adenocarcinoma cell lines expressing high (BxPc-3) and low (L3.6pl) levels of TF as models to study the effect of TF(+) TMVs on platelets and thrombosis. RESULTS AND CONCLUSIONS: We found that both types of TF(+) TMVs activated human platelets and induced aggregation in vitro in a TF and thrombin-dependent manner. Further, injection of BxPc-3 TF(+) TMVs triggered platelet activation in vivo and enhanced thrombosis in two mouse models of venous thrombosis in a TF-dependent manner. Importantly, BxPc-3 TF(+) TMV-enhanced thrombosis was reduced in Par4-deficient mice and in wild-type mice treated with clopidogrel, suggesting that platelet activation was required for enhanced thrombosis. These studies suggest that TF(+) TMV-induced platelet activation contributes to thrombosis in cancer patients. PMID- 26516110 TI - Using an admittance algorithm for bone drilling procedures. AB - Bone drilling is a common procedure in many types of surgeries, including orthopedic, neurological and otologic surgeries. Several technologies and control algorithms have been developed to help the surgeon automatically stop the drill before it goes through the boundary of the tissue being drilled. However, most of them rely on thrust force and cutting torque to detect bone layer transitions which has many drawbacks that affect the reliability of the process. This paper describes in detail a bone-drilling algorithm based only on the position control of the drill bit that overcomes such problems and presents additional advantages. The implication of each component of the algorithm in the drilling procedure is analyzed and the efficacy of the algorithm is experimentally validated with two types of bones. PMID- 26516111 TI - Protective effect of ellagic acid on oxidative stress and antioxidant status in Cyprinus carpio during malathion exposure. AB - This study aims to determine protective efficiency of ellagic acid (EA) on malathion toxicity in carp. The fish were exposed to two sublethal concentrations of malathion (0.5 and 1 mg/L), and EA (100 mg per kg of fish weight) was simultaneously administered for 14 days. Malondialdehyde (MDA) level and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH—Px), and glutathione—S—transferase (GST) activities were evaluated in liver, kidney and gills, which were collected at the end of the experiment. In conclusion, the findings of this study demonstrated that malathion caused oxidative stress and negative alterations on the antioxidant enzyme activities of the fish. However, this toxic effect was neutralised by the administration of EA. Thus, the present results suggest that simultaneous treatment with EA (100 mg per kg of fish weight) may alleviate malathion—induced oxidative stress. PMID- 26516112 TI - Guaiasistanol: A new guaiane sesquiterpenoid from Teucrium persicum Boiss. AB - In this study, a new guaiane type skeleton sesquiterpenoid named guaiasistanol (6alpha, 10alpha-epoxy-4alpha-hydroxyguaiane) was isolated from chloroform part of the Teucrium persicum extract, also chrysothol. Spectroscopic means explained the structures. This compound was evaluated for inhibitory activity against acetylcholinesterase and it showed a moderate activity with 28% inhibition. PMID- 26516113 TI - Low expression of microRNA-21 contributes to LPS-induced osteoblast cell apoptosis through up-regulation of OAS1. AB - Lipopolysaccharide (LPS) is a critical component of the outer membrane of Gram—negative bacteria. Many cellular signals that are activated by Gram—negative bacteria are initiated by LPS. LPS triggers not only inflammatory responses, but also activates pro—apoptotic signals in a series of human cell types. However, there is relatively minimal data on the microRNA—dependent mechanism(s) of LPS—induced functional activity in osteoblast cells. CCK—8 assay and flow cytometry were used to measure cell viability and apoptosis, respectively. RT—PCR and western blot were performed to determine the mRNA and protein expression in osteoblast cells. In this study, we found that LPS triggered apoptosis in osteoblastic hFOB1.19 cells and induced a low expression of the miRNA—21. Furthermore, through the gene microarray technique, OAS1 was screened and later confirmed to be the target gene which was up—regulated in response to the low expression of miRNA—21. Knockdown of OAS1 by specific siRNAs significantly rescued the LPS—induced hFOB1.19 cell apoptosis. Our data suggest that LPS induces low expression of miRNA—21which consequently causes the up—regulation of the downstream gene OAS1 and eventually triggers apoptosis in hFOB1.19 cells. Knockdown of OAS1 rescues LPS—induced cell death and thus may be a promising therapeutic strategy for orthopedic diseases. PMID- 26516114 TI - A Short Review: Research progress of bovine stem cells. AB - All bodies rely on stem cells to grow from a single cell into an adult. Stem cells allow our bodies to build new tissue, such as new muscle when we exercise. Domestic livestock stem cells offer a unique opportunity to study developmental biology, serve as a resource to screen for harmful toxins or lifesaving drugs or even regenerative therapies for a number of diseases. This review provides information on bovine stem cells, emphasizing different sources of stem cells and current methods for isolation and culture of pluripotent stem cells from cattle. We also review the application of bovine stem cell in future. PMID- 26516115 TI - Effects of gamma irradiation on chickpea seeds vis-a-vis total seed storage proteins, antioxidant activity and protein profiling. AB - The present work describes radiation—induced effects on seed composition vis—a—vis total seed proteins, antioxidant levels and protein profiling employing two dimensional gel electrophoresis (2D—GE) in kabuli and desi chickpea varities. Seeds were exposed to the radiation doses of 1,2,3,4 and 5 kGy. The total protein concentrations decreased and antioxidant levels were increased with increasing dose compared to control seed samples. Radiation induced effects were dose dependent to these seed parameters while it showed tolerance to 1 kGy dose. Increase in the dose was complimented with increase in antioxidant levels, like 5 kGy enhanced % scavenging activities in all the seed extracts. Precisely, the investigations reflected that the dose range from 2 to 5 kGy was effective for total seed storage proteins, as depicted quantitatively and qualitative 2D—GE means enhance antioxidant activities in vitro. PMID- 26516116 TI - DNA polymorphisms in chickpea accessions as revealed by PCR-based markers. AB - Chickpea is a food legume which is alleged to be a preferred source of protein next only to milk. Germplasm of cultivated chickpea available is deficient in desired genetic variation. Genetic manipulations therefore, necessitate the genetic exploitation of its related annual and wild species. 42 RAPD and 41 ISSR markers were employed to ascertain polymorphism across 20 genotypes which were collected from 10 different geographical areas of the world. RAPD marker detected 51% genetic polymorphisms while ISSR marker detected 54 %. With an average of 6.5 each RAPD primer amplified 5—8 bands. Similarly with an average of 7.9 each ISSR primer amplified 4—12 bands. The cluster dendrogram demonstrated a similarity coefficient range from 0.80 to 0.92 due to RAPD markers, whereas with ISSR primers the cluster dendrogram showed similarity coefficient of 0.60 to 1.00. Accessions from same geographical area seem to be genetically similar than those from geographically distant and isolated ones. When however compared, interestingly the ISSR dendrogram showed more correlation with pedigree data than the RAPD dendrogram. The variability index worked out in the present study ranges from 0.79 to 0.96. Since the ultimate reason for such studies is selection of diverse genetic accessions for their recommendation to breeding programmers, the accessions like ICC6263, ICC6306 and ICC17160 can be recommended as parents. Further breeding programmes can therefore be planned to procure additional variation complexes in chickpea genetic stocks. PMID- 26516118 TI - Enhanced incorporation yield of cysteine for glutathione overproduction by fed batch fermentation of Saccharomyces cerevisiae. AB - In the following work a high cell density fed-batch process with Saccharomyces cerevisiae coupled with a high efficient incorporation of cysteine for glutathione (GSH) overproduction was developed. Therefore, a feeding strategy based on the respiratory quotient (RQ) was applied to ensure high biomass (96.1g/l). Furthermore, the optimal cysteine concentration and time of cysteine addition were investigated. Low concentrations of cysteine at late fermentation phases resulted in relatively high incorporation yields of about 0.40mol/mol and maintained the physiology of cultivated yeast. By changing the cysteine feeding from standard single shot to continuous addition, an often observed cell specific toxicity, triggered by high cysteine concentrations, could be prevented and the cysteine incorporation yield (0.54+/-0.01mol/mol) and GSH content (1650.7+/ 42.8mg/l; 1.76+/-0.08%) were maximized, respectively. The developed process was transferred from laboratory into pilot plant scale. Further, the reduced cell specific toxicity enabled the development of a repeated fed-batch procedure with a suitable performance concerning cysteine incorporation yield (0.40+/ 0.1mol/mol), biomass (84.2+/-1.2g/l) and GSH content (1304.7+/-61.4mg/l). PMID- 26516119 TI - Complete genome sequence of Kibdelosporangium phytohabitans KLBMP 1111(T), a plant growth promoting endophytic actinomycete isolated from oil-seed plant Jatropha curcas L. AB - Kibdelosporangium phytohabitans KLBMP 1111(T) is a plant growth promoting endophytic actinomycete isolated from the oil-seed plant Jatropha curcas L. collected from dry-hot valley, in Sichuan, China. The complete genome sequence of this actinomycete consists of one chromosome (11,759,770bp) with no plasmid. From the genome, we identified gene clusters responsible for polyketide and nonribosomal peptide synthesis of natural products, and genes related to the plant growth promoting, such as zeatin, 1-aminocyclopropane-1-carboxylate deaminase (ACCD) and siderophore. The complete genome information may be useful to understand the beneficial interactions between K. phytohabitans KLBMP 1111(T) and host plants. PMID- 26516120 TI - Myostatin inhibition for treatment of sarcopenia. PMID- 26516122 TI - Identification of Immunoreactive Luteinizing Hormone Receptors in the Adrenal Cortex of the Female Rhesus Macaque. AB - Female laboratory macaques were studied under a variety of treatment protocols to determine if immunoreactive luteinizing hormone/gonadal chorionic gonadotropin (LH/CG) receptors were present in the adrenal cortex. All adrenal tissues revealed an absence of immunoreactivity in the in the medulla while staining was present in all three outer zones of the cortex. Increased staining was observed in the zonae reticularis with least staining in the zonae glomerulosa. Moderate and variable staining was found in the zonae fasciculata. These results demonstrate that LH/CG receptors in the adrenal cortex may be more common in higher primates than previously recognized and help explain some aspects of the endocrine changes observed in mid-aged women during the menopausal transition when circulating LH concentrations are rising. PMID- 26516121 TI - Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial. AB - BACKGROUND: Myostatin inhibits skeletal muscle growth. The humanised monoclonal antibody LY2495655 (LY) binds and neutralises myostatin. We aimed to test whether LY increases appendicular lean body mass (aLBM) and improves physical performance in older individuals who have had recent falls and low muscle strength and power. METHODS: In this proof-of-concept, randomised, placebo-controlled, double-blind, parallel, multicentre, phase 2 study, we recruited patients aged 75 years or older who had fallen in the past year from 21 investigator sites across Argentina, Australia, France, Germany, Sweden, and the USA. Eligible patients had low performance on hand grip strength and chair rise tests, tested with the procedure described by Guralnik and colleagues. Participants were stratified by country, age, hand grip strength, and performance on the chair rise test, and were randomly assigned (1:1) by a computer-generated random sequence to receive subcutaneous injections of placebo or 315 mg LY at weeks 0 (randomisation visit), 4, 8, 12, 16, and 20, followed by 16 weeks observation. The primary outcome was change in aLBM from baseline to 24 weeks. We measured physical performance as secondary outcomes (four-step stair climbing time, usual gait speed, and time to rise five times from a chair without arms, or with arms for participants unable to do it without arms) and exploratory outcomes (12-step stair climbing test, 6 min walking distance, fast gait speed, hand grip strength, and isometric leg extension strength). Efficacy analyses included all randomly assigned patients who received at least one dose and had a baseline and at least one subsequent measure. The primary analysis and all other tests of treatment effect (except physical performance tests) were done at a two-sided alpha level of 0.05. Tests of treatment effect on physical performance tests were done at a pre-specified two-sided alpha level of 0.1. This trial is registered with ClinicalTrials.gov, number NCT01604408. FINDINGS: Between June 19, 2012, and Dec 12, 2013, we screened 365 patients. 99 were randomly assigned to receive placebo and 102 to receive LY. Treatment was completed in 85 (86%) of patients given placebo and in 82 (80%) given LY. At 24 weeks, the least-squares mean change in aLBM was -0.123 kg (95% CI -0.287 to 0.040) in the placebo group and 0.303 kg (0.135 to 0.470) in the LY group, a difference of 0.43 kg (95% CI 0.192 to 0.660; p<0.0001). Stair climbing time (four-step and 12-step tests), chair rise with arms, and fast gait speed improved significantly from baseline to week 24 with differences between LY and placebo of respectively -0.46 s (p=0.093), -1.28 s (p=0.011), -4.15 s (p=0.054), and 0.05 m/s (p=0.088). No effect was detected for other performance based measures. Injection site reactions were recorded in nine (9%) patients given placebo and in 31 (30%) patients given LY (p<0.0001), and were generally mild, and led to treatment discontinuation in two patients given LY. INTERPRETATION: Our findings show LY treatment increases lean mass and might improve functional measures of muscle power. Although additional studies are needed to confirm these results, our data suggest LY should be tested for its potential ability to reduce the risk of falls or physical dependency in older weak fallers. FUNDING: Eli Lilly and Company. PMID- 26516117 TI - Genes and environment in neonatal intraventricular hemorrhage. AB - Emerging data suggest intraventricular hemorrhage (IVH) of the preterm neonate is a complex disorder with contributions from both the environment and the genome. Environmental analyses suggest factors mediating both cerebral blood flow and angiogenesis contribute to IVH, while candidate gene studies report variants in angiogenesis, inflammation, and vascular pathways. Gene-by-environment interactions demonstrate the interaction between the environment and the genome, and a non-replicated genome-wide association study suggests that both environmental and genetic factors contribute to the risk for severe IVH in very low-birth weight preterm neonates. PMID- 26516124 TI - Outcomes of endothelial keratoplasty in pseudophakic corneal oedema: with or without Descemet's membrane stripping. AB - AIMS: To evaluate and compare outcomes of Descemet's stripping endothelial keratoplasty (DSEK) with non-DSEK (nDSEK) in pseudophakic corneal oedema (PCE). METHODS: The study was a prospective, non-consecutive, comparative, interventional case series. Twenty-six patients with PCE were randomised into two groups. Group 1 comprised of those cases that had undergone conventional DSEK, and group 2 consisted of those that had nDSEK for PCE between 2010 and 2012. The data on demographics and clinical characteristics were collected from all patients. Any intraoperative and early and late postoperative complications were also noted. The primary outcome measure was postoperative functional success. Graft survival and complications were analysed as secondary outcomes. RESULTS: The median best-corrected visual acuities at 6 months postoperatively in groups 1 and 2 were 0.18 (IQR 0.10-0.30) and 0.44 (IQR 0.18-0.51), respectively (p=0.11). Corneal oedema cleared in all patients. During the early postoperative period, a patient in group 2 had lenticule detachment managed by rebubbling. CONCLUSIONS: nDSEK has outcomes similar to DSEK in PCE with advantages of decreased surgical time and avoidance of inadvertent pull on the posterior stromal fibres that may occur during Descemet's stripping. PMID- 26516123 TI - Endometriosis Located Proximal to or Remote From the Uterus Differentially Affects Uterine Gene Expression. AB - The mechanisms that lead to the altered uterine gene expression in women with endometriosis are poorly understood. Are these changes in gene expression mediated by proximity to endometriotic lesions or is endometriosis a systemic disease where the effect is independent of proximity to the uterus? To answer this question, we created endometriosis in a murine model either in the peritoneal cavity (proximal) or at a subcutaneous remote site (distal). The expression of several genes that are involved in endometrial receptivity (homeobox A10 [Hoxa10], homeobox A11 [Hoxa11], insulin-like growth factor binding protein 1 [Igfbp1], Kruppel-like factor 9 [Klf9], and progesterone receptor [Pgr]) was measured in the eutopic endometrium of mice transplanted with either proximal or distal endometriosis lesions. Decreased expression of Hoxa10, Igfbp1, Klf9, and total Pgr genes was observed in the eutopic endometrium of mice with peritoneal endometriosis. In the mice with distal lesions, overall expression of these genes was not as severely affected, however, Igfbp1 expression was similarly decreased and the effect on Pgr was more pronounced. Endometriosis does have a systemic effect that varies with distance to the end organ. However, even remote disease selectively and profoundly alters the expression of genes such as Pgr. This is the first controlled experiment demonstrating that endometriosis is not simply a local peritoneal disease. Selective alteration of genes critical for endometrial receptivity and endometriosis propagation may be systemic. Similarly, systemic effects of endometriosis on other organs may also be responsible for the widespread manifestations of the disease. PMID- 26516125 TI - A systematic review of as needed versus treat and extend ranibizumab or bevacizumab treatment regimens for neovascular age-related macular degeneration. AB - PURPOSE: To evaluate the relative efficacy of as needed versus treat and extend regimen for the treatment of neovascular age-related macular degeneration (AMD). METHODS: We conducted a systematic review of studies that evaluated the efficacy of as needed or treat and extend regimen for neovascular AMD by searching multiple databases up to December 2013. Included studies were selected based on study duration of no less than 12 months, availability of outcome data, treatment protocol for as needed groups or pro re nata (PRN) receiving bevacizumab or ranibizumab, and all studies with treat extend protocols following the 'inject and extend' regimen. The outcome data were pooled and analysed. RESULTS: 1046 peer reviewed articles meeting our initial search criteria were returned. After further review by two independent reviewers, 8 studies meeting treat and extend protocol and 62 studies meeting PRN protocol were included. The mean improvement in visual acuity in the PRN group was 5.4 ETDRS letters compared with 10.4 ETDRS letters in the treat and extend group. The PRN group received an average of 5.60 injections at 1 year compared with 8.09 in the treat and extend group. Central retinal thickness improved on average by 100.32 u in the PRN group compared with 87.7 u in the treat and extend group. CONCLUSIONS: Though our study suggests superiority of the treat and extend regimen to PRN treatment in a 12-month period, this review demonstrates the need for randomised clinical trials to confirm our findings and to evaluate long-term efficacy outcomes with these regimens compared with monthly therapy. PMID- 26516127 TI - MutS HOMOLOG1 silencing mediates ORF220 substoichiometric shifting and causes male sterility in Brassica juncea. AB - Cytoplasmic male sterility (CMS) has consistently been associated with the expression of mitochondrial open reading frames (ORFs) that arise from genomic rearrangements. Spontaneous fertility reversion in CMS has been observed in several cases, but a clear understanding of fertility reversion controlled by nuclear genetic influences has been lacking. Here, we identified spontaneous fertile revertant lines for Brassica juncea CMS cytoplasm in which the mitochondrial genome has undergone substoichiometric shifting (SSS) to suppress ORF220 copy number. We placed ORF220, with or without a mitochondrial targeting presequence, under the control of the CaMV35S and AP3 promoters in Arabidopsis to confirm that ORF220 causes male sterility when mitochondrially localized. We found that copy number of the ORF220 gene was altered under conditions that suppress MSH1, a nuclear gene that controls illegitimate recombination in plant mitochondria. MSH1-RNAi lines with increased ORF220 copy number were male sterile compared with wild type. We found that a wide range of genes involved in anther development were up- and down-regulated in revertant and MSH1-RNAi lines, respectively. The system that we have developed offers valuable future insight into the interplay of MSH1 and SSS in CMS induction and fertility reversion as a mediator of nuclear-mitochondrial crosstalk. PMID- 26516126 TI - Modulation of copper deficiency responses by diurnal and circadian rhythms in Arabidopsis thaliana. AB - Copper homeostasis under deficiency is regulated by the SQUAMOSA PROMOTER BINDING PROTEIN-LIKE7 (SPL7) transcription factor. The daily oscillating expression of two SPL7-dependent copper deficiency markers, COPPER TRANSPORTER (COPT2) and IRON SUPEROXIDE DISMUTASE (FSD1), has been followed by quantitative PCR and in promoter:LUCIFERASE transgenic plants. Both genes showed circadian and diurnal regulation. Under copper deficiency, their expression decreased drastically in continuous darkness. Accordingly, total copper content was slightly reduced in etiolated seedlings under copper deficiency. The expression of SPL7 and its targets COPT2 and FSD1 was differently regulated in various light signalling mutants. On the other hand, increased copper levels reduced the amplitude of nuclear circadian clock components, such as GIGANTEA (GI). The alteration of copper homeostasis in the COPT1 overexpression line and spl7 mutants also modified the amplitude of a classical clock output, namely the circadian oscillation of cotyledon movements. In the spl7 mutant, the period of the oscillation remained constant. These results suggest a feedback of copper transport on the circadian clock and the integration of rhythmic copper homeostasis into the central oscillator of plants. PMID- 26516128 TI - The Role of Wnt Signaling in Squamous Cell Carcinoma. AB - Aberrant Wnt signaling pathway is a common feature of tumors and also plays important roles in tumor progression and metastasis of many cancer types. Various lines of evidence suggest that genetic defects affect Wnt pathway components, as well as epigenetic mechanisms that modulate the suppressors of Wnt pathway in oral squamous cell carcinoma. Recently, the newly discovered microRNAs are important molecular regulators in gene expression through transcription and translation repression. They play fundamental roles in a wide spectrum of biological functions, including cancer. In this review, we aim to accumulate recent research findings on the roles of Wnt/beta-catenin signaling and discuss how microRNAs affect Wnt/beta-catenin signaling in oral squamous cell carcinoma tumorigenesis. Apparently, investigations into the role of microRNAs with regard to the Wnt pathway in oral squamous cell carcinoma may help in the development of better strategies for tumor treatment. PMID- 26516129 TI - RADIATION PROTECTION CABIN FOR CATHETER-DIRECTED LIVER INTERVENTIONS: OPERATOR DOSE ASSESSMENT. AB - The number and complexity of interventional radiological procedures and in particular catheter-directed liver interventions have increased substantially. The current study investigates the reduction of personal doses when using a dedicated radiation protection cabin (RPC) for these procedures. Operator and assistant doses were assessed for 3 series of 20 chemoinfusion/chemoembolisation interventions, including an equal number of procedures with and without RPC. Whole body doses, finger doses and doses at the level of knees and eyes were evaluated with different types of TLD-100 Harshaw dosemeters. Dosemeters were also attached on the three walls of the RPC. The operator doses were significantly reduced by the RPC, but also without RPC, the doses appear to be limited as a result of thorough optimisation with existing radiation protection tools. The added value of the RPC should thus be determined by the outcome of balancing dose reduction and other aspects such as ergonomic benefits. PMID- 26516130 TI - NEURAL NETWORK MODELLING OF CARDIAC DOSE CONVERSION COEFFICIENT FOR ARBITRARY X RAY SPECTRA. AB - In this article, an approach to compute the dose conversion coefficients (DCCs) is described for the computational voxel phantom 'High-Definition Reference Korean-Man' (HDRK-Man) using artificial neural networks (ANN). For this purpose, the voxel phantom was implemented into the Monte Carlo (MC) transport toolkit GEANT4, and the DCCs for more than 30 tissues and organs, due to a broad parallel beam of monoenergetic photons with energy ranging from 15 to 150 keV by a step of 5 keV, were calculated. To study the influence of patient size on DCC values, DCC calculation was performed, for a representative body size population, using five different sizes covering the range of 80-120 % magnification of the original HDRK Man. The focus of the present study was on the computation of DCC for the human heart. ANN calculation and MC simulation results were compared, and good agreement was observed showing that ANNs can be used as an efficient tool for modelling DCCs for the computational voxel phantom. ANN approach appears to be a significant advance over the time-consuming MC methods for DCC calculation. PMID- 26516131 TI - INTEGRATED CIRCUITS FROM MOBILE PHONES AS POSSIBLE EMERGENCY OSL/TL DOSIMETERS. AB - In this article, optically stimulated luminescence (OSL) data are presented from integrated circuits (ICs) extracted from mobile phones. The purpose is to evaluate the potential of using OSL from components in personal electronic devices such as smart phones as a means of emergency dosimetry in the event of a large-scale radiological incident. ICs were extracted from five different makes and models of mobile phone. Sample preparation procedures are described, and OSL from the IC samples following irradiation using a (90)Sr/(90)Y source is presented. Repeatability, sensitivity, dose responses, minimum measureable doses, stability and fading data were examined and are described. A protocol for measuring absorbed dose is presented, and it was concluded that OSL from these components is a viable method for assessing dose in the days following a radiological incident. PMID- 26516132 TI - Acquired epidermodysplasia verruciformis in an HIV-positive patient. AB - Epidermodysplasia verruciformis (EV) is a rare dermatological manifestation of the human papillomavirus (HPV) infection, which causes distinctive skin lesions in sun-exposed areas. Both inherited and acquired forms exist. Immunocompromised individuals, such as HIV patients, are at risk of acquired EV. EV poses challenges in its management and variable responses are seen in different individuals. In addition, EV carries a significant risk of skin malignancy with certain HPV types that require skin surveillance. A case of acquired EV in a HIV positive patient is presented in this report. PMID- 26516133 TI - Improving National Trauma Data Bank(r) coding data reliability for traumatic injury using a prospective systems approach. AB - Trauma centers manage an active Trauma Registry from which research, quality improvement, and epidemiologic information are extracted to ensure optimal care of the trauma patient. We evaluated coding procedures using the Relational Trauma Scoring SystemTM to determine the relative accuracy of the Relational Trauma Scoring System for coding diagnoses in comparison to the standard retrospective chart-based format. Charts from 150 patients admitted to a level I trauma service were abstracted using standard methods. These charts were then randomized and abstracted by trauma nurse clinicians with coding software aide. For charts scored pre-training, percent correct for the trauma nurse clinicians ranged from 52 to 64 percent, while the registrars scored 51 percent correct. After training, percentage correct for the trauma nurse clinicians increased to a range of 80-86 percent. Our research has demonstrated implementable changes that can significantly increase the accuracy of data from trauma centers. PMID- 26516134 TI - PM2.5 and ash residue from combustion of moxa floss. AB - BACKGROUND: Moxibustion, a Traditional Chinese Medicine technique, involves burning moxa floss to apply heat to certain points or areas of the body surface to treat disease. Moxibustion releases a considerable amount of smoke into the environment. There remains controversy over the safety of moxa smoke and its potential effects on human health. METHODS: We measured the PM2.5 (particulate matter with aerodynamic diameter <2.5 MUm) mass concentration in moxa smoke and the oxidative capacity of PM2.5 and moxa ash (using a plasmid scission assay in whole and water-soluble fractions) in the by-products of moxibustion produced from burning moxa floss of different ratios (3:1 or 15:1) and duration of storage (3 or 10 years) in three simulated moxibustion clinics. RESULTS: PM2.5 mass concentration was 224.28, 226.39 and 210.56 MUg/m(3) for samples A (3 years and 3:1 ratio), B (3 years and 15:1 ratio), and C (10 years and 3:1 ratio), respectively. Average D500 oxidative damage of PM2.5 was 29.42%, 29.16% and 27.01% and that of moxa ash was 22.78%, 20.60% and 21.42% for samples A, B and C, respectively. PM2.5 demonstrated a significantly greater oxidative capacity than moxa ash (p<0.05). CONCLUSIONS: The oxidative DNA damage induced by individual PM2.5 following moxibustion was lower than that reported in other environments. However, PM2.5 mass concentration after moxibustion is still relatively high. We would recommend ensuring adequate ventilation during moxibustion to reduce any possible risks. Further studies are needed to better define the potential impact of particles in moxibustion by-products on human health. PMID- 26516135 TI - A cadaveric study of needle insertion at LI11. PMID- 26516136 TI - Effects of acupuncture on preeclampsia in Chinese women: a pilot prospective cohort study. AB - OBJECTIVE: To investigate the acceptability and feasibility of acupuncture treatment as an adjunct to usual care in Chinese women with preeclampsia. METHODS: This was a pilot prospective cohort study. Pregnant women with a diagnosis of preeclampsia were offered acupuncture and allocated into groups based on their choice: the acupuncture group (n=11) comprised women electing to receive treatment (up to 10 sessions over 2 weeks). The control group (n=11) was made up of women who declined and was matched for age, gestation at diagnosis, and parity. All women received usual care and underwent measurement of blood pressure (BP) at four time points: at baseline, at the end of the intervention, immediately before delivery, and postpartum (within 24 h). RESULTS: Patients in the acupuncture group had significantly lower BP at time of delivery, and postpartum, than patients in the control group (p<0.05). The individual change in BP between baseline and the end of treatment was significantly greater in the acupuncture group versus the control group for both systolic BP (median (IQR) -8 (-3 to -14) vs +1 (-7 to +9) mm Hg, p=0.007) and diastolic BP (-3 (-1 to -3) vs +2 (-2 to +7) mm Hg, p=0.013). There were no significant differences between the groups in perinatal outcomes and no adverse effects of treatment. CONCLUSIONS: Acupuncture plus usual care was associated with a greater reduction in BP than usual care alone. Further studies are needed to clarify the role of acupuncture in the treatment of preeclampsia. PMID- 26516137 TI - Epstein-Barr Virus-Associated Atraumatic Spleen Laceration Presenting with Neck and Shoulder Pain. AB - BACKGROUND: Infectious mononucleosis, caused by the Epstein-Barr virus (EBV), is a common infection with worldwide distribution; more than 90% of people have been infected by adulthood. One of the most feared, albeit rare, complications, occurring in less than 0.5% of those infected, is splenic injury or rupture. CASE REPORT: A febrile 15-year-old male presented to the emergency department with the chief compliant of headache, neck pain, and upper shoulder pain. He did not recall any specific traumatic injury. His abdomen was soft, nondistended, and was tender in the right and left lower quadrants. Right lower quadrant ultrasound demonstrated non-visualization of the appendix, moderate right lower quadrant free fluid, and positive McBurney's sign. CT of the abdomen and pelvis was ordered, which demonstrated moderate splenomegaly, with findings compatible with laceration through the anterior aspect of the spleen, with moderate hemoperitoneum. Monospot was negative and EBV panel demonstrated IGG negative, IGM positive, and, IGG negative. The patient was transferred to interventional radiology for a splenic angiogram and proximal splenic artery embolization. The angiogram demonstrated grade 3 laceration with moderate hemoperitoneum and no active extravasation or evidence of pseudoaneurysm. The patient was admitted and made a prompt recovery without any other sequelae. CONCLUSIONS: The presentation of splenic injury or rupture can vary; the patient may complain of abdominal pain or left upper quadrant pain, may exhibit referred left shoulder pain when the LUQ is palpated (Kehr's Sign), or may exhibit hemodynamic instability. Given the spectrum of non-specific symptoms, diagnosing EBV-induced splenic laceration can be difficult. PMID- 26516138 TI - Influence of MiR-451 on Drug Resistances of Paclitaxel-Resistant Breast Cancer Cell Line. AB - BACKGROUND: This study aimed to investigate the potential influence of microRNA 451 (miR-451) in drug resistances of the Paclitaxel-resistant breast cancer cell line by transfecting miR-451 mimics and miR-451 inhibitors to MCE-7, MCF-7/EPI, and MCF-7/DOC. MATERIAL AND METHODS: Real-time quantitative PCR (qRT-PCR) was performed for detecting whether transfected miR-451 mimics and miR-451 inhibitors could regulate the expression of miR-451 effectively. The apoptosis of the 3 cell lines was measured by applying Annexin V-APC/PI staining. Western blot was used for the detection of the protein expression of Bcl-2 and Caspase 3 after the transfection of miR-451 mimics /inhibitors. Bioinformatics analysis demonstrated that Bcl-2 protein is a potential target gene for miR-451. RESULTS: In comparison to the control group, after transfection with miR-451 mimics, there was a significant increase in miR-451 expression in MCF-7, MCF-7/EPI, and MCF-7/DOC. Cells in the three cell lines had increased apoptosis, Bcl-2 protein expression decreased significantly, and Caspase protein expression increased obviously. After the transfection with miR-451 inhibitors, miR-451 expression was significantly decreased and apoptosis in the 3 cell lines had no significant decrease compared with the control group. CONCLUSIONS: Increased miR-451 expression may negatively regulate Bcl-2 mRNA and protein expression, followed by affecting the protein expression of caspase 3, and accelerate the apoptosis in breast cancer, indicating that miR-451 might influence the drug resistances of the Paclitaxel-resistant breast cancer cell line. PMID- 26516139 TI - Adenovirus-delivered wwox inhibited lung cancer growth in vivo in a mouse model. AB - Lung cancer is the most prevalent and deadly malignancy worldwide. This study investigated the possibility of inhibiting lung cancer in vivo with adenovirus delivered WW domain-containing oxidoreductase (wwox). The lung cancer model was established by inoculating A549 lung cancer cells into the pleural space of nude mice. The control or wwox adenovirus was injected into the pleural space 7 days after cell inoculation and 14 days after first injection. The tumor number and burdens were measured 2 weeks after second virus injection. The carcinoembryonic antigen (CEA) and alpha-feto protein (AFP) levels in pleural effusion were analyzed by enzyme-linked immunosorbent assay. Apoptosis, proliferation and angiogenesis of tumor cells were assessed by terminal deoxinucleotidyl transferase-mediated dUTP-fluorescein nick end labeling assay, proliferating cell nuclear antigen (PCNA) and CD31 staining, respectively. Ectopic wwox significantly reduced both the number and size of lung tumors accompanied by substantially lower CEA and AFP levels in pleural effusion. The expression levels of Bcl2, Bcl-xL, vascular endothelial growth factor, PCNA-positive and CD31 positive cells in the tumors were significantly decreased, whereas levels of p21 and p73 and apoptotic cells markedly increased in mice receiving the wwox virus. These data demonstrated that wwox delivered by adenovirus was able to inhibit the growth of lung cancer in vivo, indicating the potential of using wwox as a gene therapy agent for lung cancer. PMID- 26516140 TI - Influenza Vaccination of Patients Receiving Statins: Where Do We Go From Here? PMID- 26516141 TI - Impact of Statins on Influenza Vaccine Effectiveness Against Medically Attended Acute Respiratory Illness. AB - BACKGROUND: Statins have antiinflammatory effects that may impact vaccine-induced immune responses. We investigated the impact of statin therapy on influenza vaccine effectiveness (VE) against medically attended acute respiratory illness (MAARI). METHODS: We conducted a retrospective cohort study over nine influenza seasons using research databases of a large managed care organization in the United States. Influenza vaccination and statin prescription statuses of cohort members and MAARI cases were ascertained on a per-season basis. Incidence rate ratios (IRRs) of MAARI were estimated using Poisson regression and stratified by statin use. Using a ratio of ratios approach, we compared IRRs from periods during to IRRs from periods before influenza circulation and then used relative IRRs to compute VE. RESULTS: After adjustment for multiple prespecified covariates, the influenza VE against MAARI was lower among statin users than nonusers during periods of local (14.1% vs 22.9%; mean difference, 11.4%; 95% confidence interval [CI], -1.7% to 26.1%) and widespread (12.6% vs 26.2%; mean difference, 18.4%; 95% CI, 2.9%-36.2%) influenza circulation. CONCLUSIONS: In this study, statin therapy was associated with reduced influenza VE against MAARI. Since many cases of MAARI are not caused by influenza, studies of the impact of statins on influenza VE against laboratory-confirmed influenza are needed. PMID- 26516142 TI - Influence of Statins on Influenza Vaccine Response in Elderly Individuals. AB - Influenza vaccination strategies have targeted elderly individuals because they are at high risk of disease complications and mortality. Statins are a class of drugs used to treat hypercholesterolemia and are frequently used in the elderly population to reduce the risk of cardiovascular disease. However, statins are also known to have immunomodulatory effects that could impact influenza vaccine response. In a post hoc analysis, we performed a cross-sectional observational study nested within a comparative immunogenicity clinical trial of adjuvanted versus unadjuvanted influenza vaccine in elderly persons to evaluate the influence of statin therapy on the immune response to vaccination. Overall, data on >5000 trial participants were available for analysis. Comparison of hemagglutination-inhibiting geometric mean titers to influenza A(H1N1), A(H3N2), and B strains revealed that titers were 38% (95% confidence interval [CI], 27% 50%), 67% (95% CI, 54%-80%), and 38% (95% CI, 28%-29%) lower, respectively, in subjects receiving chronic statin therapy, compared with those not receiving chronic statin therapy. This apparent immunosuppressive effect of statins on the vaccine immune response was most dramatic in individuals receiving synthetic statins. These effects were seen in both the adjuvanted and unadjuvanted vaccine groups in the clinical trial. These results, if confirmed, could have implications both for future clinical trials design, as well as for vaccine use recommendations for elderly individuals. PMID- 26516143 TI - Genome-scale detection of hypermethylated CpG islands in circulating cell-free DNA of hepatocellular carcinoma patients. AB - Despite advances in DNA methylome analyses of cells and tissues, current techniques for genome-scale profiling of DNA methylation in circulating cell-free DNA (ccfDNA) remain limited. Here we describe a methylated CpG tandems amplification and sequencing (MCTA-Seq) method that can detect thousands of hypermethylated CpG islands simultaneously in ccfDNA. This highly sensitive technique can work with genomic DNA as little as 7.5 pg, which is equivalent to 2.5 copies of the haploid genome. We have analyzed a cohort of tissue and plasma samples (n = 151) of hepatocellular carcinoma (HCC) patients and control subjects, identifying dozens of high-performance markers in blood for detecting small HCC (<= 3 cm). Among these markers, 4 (RGS10, ST8SIA6, RUNX2 and VIM) are mostly specific for cancer detection, while the other 15, classified as a novel set, are already hypermethylated in the normal liver tissues. Two corresponding classifiers have been established, combination of which achieves a sensitivity of 94% with a specificity of 89% for the plasma samples from HCC patients (n = 36) and control subjects including cirrhosis patients (n = 17) and normal individuals (n = 38). Notably, all 15 alpha-fetoprotein-negative HCC patients were successfully identified. Comparison between matched plasma and tissue samples indicates that both the cancer and noncancerous tissues contribute to elevation of the methylation markers in plasma. MCTA-Seq will facilitate the development of ccfDNA methylation biomarkers and contribute to the improvement of cancer detection in a clinical setting. PMID- 26516144 TI - aBETting therapeutic resistance by Wnt signaling. AB - BET inhibition has emerged as a promising epigenetic therapy for malignancies in the last five years, but little consensus has developed regarding what may mediate the axis between sensitivity and resistance. Two recent papers published in Nature attempt to address this question in acute myeloid leukemia (AML) and independently identify the Wnt signaling pathway as a driver and biomarker of therapeutic resistance. PMID- 26516145 TI - Policy analysis--important for improving iCCM implementation; essential for success of global health efforts. PMID- 26516146 TI - Epistemic communities in global health and the development of child survival policy: a case study of iCCM. AB - Nearly all African countries have recently implemented some form of integrated community case management of childhood illness (iCCM), a strategy aimed at reducing child mortality by providing curative care for common yet fatal childhood illnesses. This case study describes the evolution of iCCM at the global level using the theory of epistemic communities first outlined by Haas, which explains how international policy coordination on technical issues takes place via transnational expert networks. We draw from in-depth interviews with global policy-makers (n = 25), a document review (n = 72) and co-authorship network analysis of scientific articles on iCCM. We find that members of the iCCM epistemic community were mainly mid- to upper-level technical officers working in the headquarters of large norm-setting bodies, implementing partners, funders and academic/research groups in global health. Already linked by pre-existing relationships, the epistemic community was consolidated as conflicts were overcome through structural changes in the network (including or excluding some members), changes in the state of technology or scientific evidence, shifting funding considerations, and the development of consensus through argument, legitimation and other means. Next, the epistemic community positioned iCCM as a preferred solution via three causal dynamics outlined by Haas: (1) responding to decision-makers' uncertainty about how to reduce child mortality after previous policies proved insufficient, (2) using sophisticated analytic tools to link the problem of child mortality to iCCM as a solution and (3) gaining buy-in from major norm-setting bodies and financial and institutional support from large implementing agencies. Applying the epistemic communities framework to the iCCM case study reveals the strengths and weaknesses of a focused policy enterprise with highly specialized and homogenous disciplinary origins, allowing for efficient sharing of complex, high-level scientific information, but possibly excluding voices with relevant methodological, operational or country-level perspectives. PMID- 26516147 TI - Altogether now... understanding the role of international organizations in iCCM policy transfer. AB - INTRODUCTION: Policy transfer theories explain how policy ideas move across time and geography and offer an approach to understanding waves of policy change, a common phenomenon in global health. Four primary mechanisms for the transfer of policies from global to national levels are posited: learning, coercion, socialization and competition. METHODS: We used six concurrent country case studies of policy change for child survival followed by a global study to analyse (1) mechanisms for policy transfer and (2) the roles of international organizations in promoting policy transfer. Our six country cases drew upon early adopters of integrated Community Case Management of Childhood Illness policy (Malawi, Niger), as well as countries that were slower to adopt due either to practical implementation challenges (Mozambique, Mali) and/or policy resistance (Burkina Faso, Kenya). In total, 145 semi-structured interviews and 283 document reviews were conducted across the six country cases, and 25 semi-structured interviews and 72 document reviews for the global study. RESULTS: Three of the four diffusion mechanisms (learning, coercion and socialization) were important in these cases, but not competition. Multiple strategies were employed by multilateral organizations to support policy transfer, such as regional meetings or academic publications, frequently serving multiple diffusion mechanisms simultaneously (e.g. both learning and socialization). In just one country case, funding conditionalities were used to press for policy change. The emphasis of policy transfer mechanisms varied between early and later adopters. Early adopters, for example, were more likely to engage in learning. International multilateral organizations were active policy transfer agents, and national policy-makers perception of them as "trusted partners" made them well suited for this role. However, on occasion their role became more that of advocates than neutral facilitators. CONCLUSIONS: International actors use multiple synergistic channels to promote uptake of global health policies in low- and middle-income countries, and tailor strategies employed to country contexts. PMID- 26516148 TI - iCCM policy analysis: strategic contributions to understanding its character, design and scale up in sub-Saharan Africa. AB - Pneumonia, diarrhoea and malaria remain leading causes of death for children under 5 years of age and access to effective and appropriate treatment for sick children is extremely low where it is needed most. Integrated community case management (iCCM) enables community health workers to provide basic lifesaving treatment for sick children living in remote communities for these diseases. While many governments in sub-Saharan Africa recently changed policies to support iCCM, large variations in implementation remain. As a result, the collaboration represented in this supplement examined the policy processes underpinning iCCM through qualitative case study research in six purposively identified countries (Niger, Burkina Faso, Mali, Kenya, Malawi and Mozambique) and the global context. We introduce the supplement, by reviewing how policy analysis can inform: (a) how we frame iCCM and negotiate its boundaries, (b) how we tailor iCCM for national health systems and (c) how we foster accountability and learning for iCCM. In terms of framing, iCCM boundaries reflect how an array of actors use evidence to prioritize particular aspects of child mortality (lack of access to treatment), and how this underpins the ability to reach consensus and legitimate specific policy enterprises. When promoted at national level, contextual health system factors, such as the profile of CHWs and the history of primary health care, cannot be ignored. Adaptation to these contextual realities may lead to unintended consequences not forseen by technical or managerial expertize alone. Further scaling up of iCCM requires understanding of the political accountabilities involved, how ownership can be fostered and learning for improved policies and programs sustained. Collectively these articles demonstrate that iCCM, although often compartmentalized as a technical intervention, also reflects the larger and messier real world of health politics, policy and practice, for which policy analysis is vital, as an integral component of public health programming. PMID- 26516149 TI - Evidence-informed policymaking in practice: country-level examples of use of evidence for iCCM policy. AB - Integrated Community Case Management of Childhood Illness (iCCM) is a policy for providing treatment for malaria, diarrhoea and pneumonia for children below 5 years at the community level, which is generating increasing evidence and support at the global level. As countries move to adopt iCCM, it becomes important to understand how this growing evidence base is viewed and used by national stakeholders. This article explores whether, how and why evidence influenced policy formulation for iCCM in Niger, Kenya and Mozambique, and uses Carol Weiss' models of research utilization to further explain the use of evidence in these contexts. A documentary review and in-depth stakeholder interviews were conducted as part of retrospective case studies in each study country. Findings indicate that all three countries used national monitoring data to identify the issue of children dying in the community prior to reaching health facilities, whereas international research evidence was used to identify policy options. Nevertheless, policymakers greatly valued local evidence and pilot projects proved critical in advancing iCCM. World Health Organization and United Nations Children's Fund (UNICEF) functioned as knowledge brokers, bringing research evidence and experiences from other countries to the attention of local policymakers as well as sponsoring site visits and meetings. In terms of country specific findings, Niger demonstrated both Interactive and Political models of research utilization by using iCCM to capitalize on the existing health infrastructure. Both Mozambique and Kenya exhibit Problem-Solving research utilization with different outcomes. Furthermore, the persistent quest for additional evidence suggests a Tactical use of research in Kenya. Results presented here indicate that while evidence from research studies and other contexts can be critical to policy development, local evidence is often needed to answer key policymaker questions. In the end, evidence may not be enough to overcome resistance if the policy is viewed as incompatible with national goals. PMID- 26516150 TI - Policy entrepreneurs and structural influence in integrated community case management policymaking in Burkina Faso. AB - Policy entrepreneurs are individuals who attempt to influence the policy process and its outcomes through their opportunistic or incremental actions. Their success in the policy-making process has been associated with the convergence of four factors: behavioural traits; institutional factors; network position and political capital. Policy entrepreneurs have received little study in low- and middle-income country policy research despite observations of individualized decision-making, informal institutions and the unequal distribution and exercise of power in policymaking. This article aims to identify whether policy entrepreneurs were present in the policy process around integrated community case management (iCCM) in Burkina Faso, whether they were successful in achieving policy change, and whether success or failure can be explained using existing policy entrepreneur frameworks from high-income polities. This mixed methods policy study collected data from in-depth qualitative interviews and social network surveys of actors involved in iCCM policymaking [known locally as C integrated management of childhood illness (IMCI)]; data were analysed based on the framework categories. Interview data pointed to one key individual who played a significant role in the inclusion of pneumonia treatment into the country's iCCM policy, an issue that had been a point of contention between government policy elites and development partners. Social network data confirmed that this actor was strategically located in the policy network to be able to reach the most other actors and to be able to control the flow of information. Although some development partner actors were as strategically located, none had the same level of authority or trust as was imbued by being a member of the government civil service. The entrepreneur's mid-level rank in the health ministry may have encouraged him/her to invest political capital and take risks that would not have been feasible or attractive to a more senior actor. This study highlights the convergence of factors needed to be an entrepreneur, as well as the role of development partner actors in creating a facilitating environment. PMID- 26516151 TI - Relaunch of the official community health worker programme in Mozambique: is there a sustainable basis for iCCM policy? AB - BACKGROUND: In Mozambique, integrated community case management (iCCM) of diarrhoea, malaria and pneumonia is embedded in the national community health worker (CHW) programme, mainstreaming it into government policy and service delivery. Since its inception in 1978, the CHW programme has functioned unevenly, was suspended in 1989, but relaunched in 2010. To assess the long-term success of iCCM in Mozambique, this article addresses whether the current CHW programme exhibits characteristics that facilitate or impede its sustainability. METHODOLOGY: We undertook a qualitative case study based on document review (n = 54) and key informant interviews (n = 21) with respondents from the Ministry of Health (MOH), multilateral and bilateral agencies and non-governmental organizations (NGOs) in Maputo in 2012. Interviews were mostly undertaken in Portuguese and all were coded using NVivo. A sustainability framework guided thematic analysis according to nine domains: strategic planning, organizational capacity, programme adaptation, programme monitoring and evaluation, communications, funding stability, political support, partnerships and public health impact. RESULTS: Government commitment was high, with the MOH leading a consultative process in Maputo and facilitating successful technical coordination. The MOH made strategic decisions to pay CHWs, authorize their prescribing abilities, foster guidance development, support operational planning and incorporate previously excluded 'old' CHWs. Nonetheless, policy negotiations excluded certain key actors and uncertainty remains about CHW integration into the civil service and their long-term retention. In addition, reliance on NGOs and donor funding has led to geographic distortions in scaling up, alongside challenges in harmonization. Finally, dependence on external funding, when both external and government funding are declining, may hamper sustainability. CONCLUSIONS: Our analysis represents a nuanced assessment of the various domains that influence CHW programme sustainability, highlighting strategic areas such as CHW payment and programme financing. These organizational and contextual determinants of sustainability are central to CHW programme strengthening and iCCM policy support. PMID- 26516152 TI - Integrated community case management for childhood illnesses: explaining policy resistance in Kenya. AB - BACKGROUND: There has been a re-emphasis recently on community health workers to provide child health care services including integrated community case management for childhood illness (iCCM). This research analysed iCCM policy development in Kenya and in particular the types of decision-making criteria used by Kenyan policy-makers in considering whether to advance iCCM policy. METHOD: Data were collected through document reviews (n = 41) and semi-structured interviews (n = 19) with key stakeholders in iCCM policy including government officials, development partners, bilateral donors, and civil society organizations. Initial analysis was guided by the policy triangle with further analysis of factors affecting policy decision-making drawing upon a simple framework developed by Grindle and Thomas (Policy makers, policy choices and policy outcomes: the political economy of reform in developing countries. 1989; Policy Sci 22: :213 48.). FINDINGS: Policy development for iCCM has been slow in Kenya, compared with other Sub-Saharan African countries. At the time of the study, the Government had just completed the Community Health Training Manual which incorporated iCCM as a module, but this was the only formal expression of iCCM in Kenya. We found technical considerations, notably concerns about community health workers dispensing antibiotics to be a key factor slowing iCCM policy development, but this also overlapped with bureaucratic considerations, such as how the development of community health worker cadres may affect clinicians, as well as initial concerns about how an integrated approach might affect vertically oriented programs. International actors through agreements such as the Millennium Development Goals helped to get child survival onto the national policy agenda and such actors were active promoters of iCCM policy change. However international funders had not committed funding to scale-up iCCM policy, and this probably constrained their influence over iCCM policy debate. CONCLUSION: Kenyan actors' concerns about iCCM underline the importance of adapting global policies to local conditions, and also generating local evidence to inform decision making. PMID- 26516153 TI - Integrated community case management in Malawi: an analysis of innovation and institutional characteristics for policy adoption. AB - In 2007, Malawi became an early adopter of integrated community case management for childhood illnesses (iCCM), a policy aimed at community-level treatment for malaria, diarrhoea and pneumonia for children below 5 years. Through a retrospective case study, this article explores critical issues in implementation that arose during policy formulation through the lens of the innovation (i.e. iCCM) and of the institutions involved in the policy process. Data analysis is founded on a documentary review and 21 in-depth stakeholder interviews across institutions in Malawi. Findings indicate that the characteristics of iCCM made it a suitable policy to address persistent challenges in child mortality, namely that ill children were not interacting with health workers on a timely basis and consequently were dying in their communities. Further, iCCM was compatible with the Malawian health system due to the ability to build on an existing community health worker cadre of health surveillance assistants (HSAs) and previous experiences with treatment provision at the community level. In terms of institutions, the Ministry of Health (MoH) demonstrated leadership in the overall policy process despite early challenges of co-ordination within the MoH. WHO, United Nations Children's Fund (UNICEF) and implementing organizations played a supportive role in their position as knowledge brokers. Greater challenges were faced in the organizational capacity of the MoH. Regulatory issues around HSA training as well as concerns around supervision and overburdening of HSAs were discussed, though not fully addressed during policy development. Similarly, the financial sustainability of iCCM, including the mechanisms for channelling funding flows, also remains an unresolved issue. This analysis highlights the role of implementation questions during policy development. Despite several outstanding concerns, the compatibility between iCCM as a policy alternative and the local context laid the foundation for Malawi's road to early adoption of iCCM. PMID- 26516154 TI - Power and pro-poor policies: the case of iCCM in Niger. AB - Analyses of health policy in low- and middle-income countries frequently mention but rarely adequately explore power dynamics, whether or not the policy in question targets the poor. We present a case study in Niger of integrated community case management (iCCM), a policy to provide basic care for poor rural children sick with malaria, diarrhoea and pneumonia, which has contributed to measurable reductions in child mortality. We focus on the three dimensions of power in policymaking: political authority, financial resources and technical expertise. Data collection took place March to August 2012 and included semi structured interviews with policy actors (N = 32), a document review (N = 103) and contextual analysis. Preliminary data analysis relied on process tracing methodology to examine why iCCM was prioritized and identify dimensions of power most relevant to the Nigerien case; we then applied theoretical categories deductively to our data. We find that political authorities, namely President Mamadou Tandja, created the underlying health infrastructure for the policy ('health huts') as a way to distribute rents from development aid through client networks while claiming the mantle of political legitimacy. Conditional influxes of financial resources created an incentive to declare fee exemptions for children below 5 years, a key condition for the policy's success. Technical expertise was concentrated among international actors from multi-lateral and bilateral agencies who packaged and delivered scientific arguments in support of iCCM to Nigerien policymakers, whose input was limited mainly to operational decisions. The Nigerien case sheds light on the dimensions of power in health policymaking, particularly in neo-patrimonial African regimes, and provides insights on how external actors can work within these contexts to promote pro poor policies. PMID- 26516155 TI - Severely Impaired and Dysregulated Cytochrome P450 Expression and Activities in Hepatocellular Carcinoma: Implications for Personalized Treatment in Patients. AB - This study aims to systematically determine the activities and expressions of cytochrome P450s (CYP) in hepatocellular carcinoma (HCC) patients to support their optimal use in personalized treatment of HCC. Activities of seven major drug-metabolizing CYP enzymes (CYP1A2, 2A6, 2C8, 2C9, 2D6, 2E1, and 3A4) were determined in tumors and pericarcinomatous tissues harvested from 26 patients with hepatitis B virus-positive HCC using probe substrates. Protein and mRNA levels of these CYPs were also measured using isotope label-free LC/MS-MS method and real-time PCR, respectively. Maximal metabolic velocity (Vmax) of CYP probe substrates was decreased by 2.5- to 30-fold in tumor microsomes, accompanied by a corresponding decrease in their protein and mRNA expression levels. However, Km values and turnover numbers of substrates in tumor microsomes were not changed. High correlations between activities and CYP protein levels were also observed, but the correlation between activities and mRNA levels was often poor. There was a major decrease in the degree of correlation in CYP expression in tumor tissues, suggesting that CYP expression levels are greatly disrupted by the tumorigenic process. Our unprecedented systemic study of the effects of HCC on CYPs demonstrated that activities of CYPs were seriously impaired and their expression patterns were severely altered by HCC. We proposed that determination of the CYP protein expression profile by LC/MS-MS in each patient is a promising approach that can be clinically used for individualized treatment of HCC. PMID- 26516156 TI - Aurora A Is Critical for Survival in HPV-Transformed Cervical Cancer. AB - Human papillomavirus (HPV) is the causative agent in cervical cancer. HPV oncogenes are major drivers of the transformed phenotype, and the cancers remain addicted to these oncogenes. A screen of the human kinome has identified inhibition of Aurora kinase A (AURKA) as being synthetically lethal on the background of HPV E7 expression. The investigational AURKA inhibitor MLN8237/Alisertib selectively promoted apoptosis in the HPV cancers. The apoptosis was driven by an extended mitotic delay in the Alisertib-treated HPV E7 expressing cells. This had the effect of reducing Mcl-1 levels, which is destabilized in mitosis, and increasing BIM levels, normally destabilized by Aurora A in mitosis. Overexpression of Mcl-1 reduced sensitivity to the drug. The level of HPV E7 expression influenced the extent of Alisertib-induced mitotic delay and Mcl-1 reduction. Xenograft experiments with three cervical cancer cell lines showed Alisertib inhibited growth of HPV and non-HPV xenografts during treatment. Growth of non-HPV tumors was delayed, but in two separate HPV cancer cell lines, regression with no resumption of growth was detected, even at 50 days after treatment. A transgenic model of premalignant disease driven solely by HPV E7 also demonstrated sensitivity to drug treatment. Here, we show for the first time that targeting of the Aurora A kinase in mice using drugs such as Alisertib results in a curative sterilizing therapy that may be useful in treating HPV driven cancers. PMID- 26516157 TI - Dual Agonist Surrobody Simultaneously Activates Death Receptors DR4 and DR5 to Induce Cancer Cell Death. AB - Death receptors of the TNF family are found on the surface of most cancer cells and their activation typically kills cancer cells through the stimulation of the extrinsic apoptotic pathway. The endogenous ligand for death receptors 4 and 5 (DR4 and DR5) is TNF-related apoptosis-inducing ligand, TRAIL (Apo2L). As most untransformed cells are not susceptible to TRAIL-induced apoptosis, death receptor activators have emerged as promising cancer therapeutic agents. One strategy to stimulate death receptors in cancer patients is to use soluble human recombinant TRAIL protein, but this agent has limitations of a short half-life and decoy receptor sequestration. Another strategy that attempted to evade decoy receptor sequestration and to provide improved pharmacokinetic properties was to generate DR4 or DR5 agonist antibodies. The resulting monoclonal agonist antibodies overcame the limitations of short half-life and avoided decoy receptor sequestration, but are limited by activating only one of the two death receptors. Here, we describe a DR4 and DR5 dual agonist produced using Surrobody technology that activates both DR4 and DR5 to induce apoptotic death of cancer cells in vitro and in vivo and also avoids decoy receptor sequestration. This fully human anti-DR4/DR5 Surrobody displays superior potency to DR4- and DR5-specific antibodies, even when combined with TRAIL-sensitizing proapoptotic agents. Moreover, cancer cells were less likely to acquire resistance to Surrobody than either anti-DR4 or anti-DR5 monospecific antibodies. Taken together, Surrobody shows promising preclinical proapoptotic activity against cancer cells, meriting further exploration of its potential as a novel cancer therapeutic agent. PMID- 26516158 TI - Tumor-Priming Smoothened Inhibitor Enhances Deposition and Efficacy of Cytotoxic Nanoparticles in a Pancreatic Cancer Model. AB - Most pancreatic adenocarcinoma patients present with unresectable disease and benefit little from chemotherapy. Poor tumor perfusion and vascular permeability limit drug deposition. Previous work showed that Smoothened inhibitors of hedgehog signaling (sHHI) promote neovascularization in spontaneous mouse models of pancreatic cancer (PaCA) and enhance tumor permeability to low-molecular weight compounds. Here, we tested the hypothesis that sHHI can enhance tumor deposition and efficacy of drug-containing nanoparticles consisting of 80 to 100 nm sterically-stabilized liposomes (SSL) containing doxorubicin (SSL-DXR). SCID mice bearing low-passage patient-derived PaCA xenografts (PDX) were pretreated p.o. for 10 days with 40 mg/kg/d NVP-LDE225 (erismodegib), followed by i.v. SSL DXR. Microvessel density, permeability, perfusion, and morphology were compared with untreated controls, as was SSL deposition and therapeutic efficacy. The sHHI alone affected tumor growth minimally, but markedly increased extravasation of nanoparticles into adenocarcinoma cell-enriched regions of the tumor. Immunostaining showed that sHHI treatment decreased pericyte coverage (alpha SMA(+)) of CD31(+) vascular endothelium structures, and increased the abundance of endothelium-poor (CD31(-)) basement membrane structures (collagen IV(+)), suggesting increased immature microvessels. SSL-DXR (15 mg/kg) administered after sHHI pretreatment arrested tumor volume progression and decreased tumor perfusion/permeability, suggesting an initial vascular pruning response. Compared with controls, one cycle of 10-day sHHI pretreatment followed by 6 mg/kg SSL-DXR doubled median tumor progression time. Three cycles of treatment with sHHI and SSL-DXR, with a 10-day between-cycle drug holiday, nearly tripled median tumor progression time. Based upon these data, short-term sHHI treatment sequenced with nanoparticulate drug carriers constitutes a potential strategy to enhance efficacy of pancreatic cancer therapy. PMID- 26516159 TI - Dual Metronomic Chemotherapy with Nab-Paclitaxel and Topotecan Has Potent Antiangiogenic Activity in Ovarian Cancer. AB - There is growing recognition of the important role of metronomic chemotherapy in cancer treatment. On the basis of their unique antiangiogenic effects, we tested the efficacy of nab-paclitaxel, which stimulates thrombospondin-1, and topotecan, which inhibits hypoxia-inducible factor 1-alpha, at metronomic dosing for the treatment of ovarian carcinoma. In vitro and in vivo SKOV3ip1, HeyA8, and HeyA8 MDR (taxane-resistant) orthotopic models were used to examine the effects of metronomic nab-paclitaxel and metronomic topotecan. We examined cell proliferation (Ki-67), apoptosis (cleaved caspase-3), and angiogenesis (microvessel density, MVD) in tumors obtained at necropsy. In vivo therapy experiments demonstrated treatment with metronomic nab-paclitaxel alone and in combination with metronomic topotecan resulted in significant reductions in tumor weight (62% in the SKOV3ip1 model, P < 0.01 and 96% in the HeyA8 model, P < 0.03) compared with vehicle (P < 0.01). In the HeyA8-MDR model, metronomic monotherapy with either cytotoxic agent had modest effects on tumor growth, but combination therapy decreased tumor burden by 61% compared with vehicle (P < 0.03). The greatest reduction in MVD (P < 0.05) and proliferation was seen in combination metronomic therapy groups. Combination metronomic therapy resulted in prolonged overall survival in vivo compared with other groups (P < 0.001). Tube formation was significantly inhibited in RF-24 endothelial cells exposed to media conditioned with metronomic nab-paclitaxel alone and media conditioned with combination metronomic nab-paclitaxel and metronomic topotecan. The combination of metronomic nab-paclitaxel and metronomic topotecan offers a novel, highly effective therapeutic approach for ovarian carcinoma that merits further clinical development. PMID- 26516161 TI - Targeting the Neurokinin-1 Receptor Compromises Canonical Wnt Signaling in Hepatoblastoma. AB - The substance P (SP)/NK-1 receptor (NK1R) complex represents an intriguing anticancer target for a variety of tumors, including hepatoblastoma (HB). Therefore, NK1R antagonists, such as the clinical drug aprepitant, recently have been proposed as potent anticancer agents. However, very little is known regarding the molecular basis of NK1R inhibition in cancer. Using reverse phase protein array, Western blot, Super TOP/FOP, confocal microscopy, and sphere formation ability (SFA) assays, we identified the AKT and Wnt signaling pathways as the key targets of aprepitant in three human HB cell lines (HepT1, HepG2, and HuH6). Following NK1R blockage, we observed decreased phosphorylation of p70S6K and 4E-BP1/2 and inhibition of the canonical Wnt pathway with subsequent decrease of HB cell growth. This effect was dependent of high baseline Wnt activity either by mutational status of beta-catenin or extrinsic Wnt activation. Wnt inhibition seemed to be strengthened by disruption of the FOXM1-beta-catenin complex. Furthermore, treatment of HB cells with aprepitant led to reduced expression of (liver) stemness markers (AFP, CD13, SOX2, NANOG, and OCT4) and SFA when grown under cancer stem cell conditions. Taken together, we show for the first time that targeting the SP/NK1R signaling cascade inhibits canonical Wnt signaling in HB cells. These findings reveal important insight into the molecular mechanisms of the SP/NK1R complex as a critical component in a model of pediatric liver cancer and may support the development of novel therapeutic interventions for HB and other Wnt-activated cancers. PMID- 26516160 TI - Silibinin Preferentially Radiosensitizes Prostate Cancer by Inhibiting DNA Repair Signaling. AB - Radiotherapy, a frequent mode of cancer treatment, is often restricted by dose related toxicity and development of therapeutic resistance. To develop a novel and selective radiosensitizer, we studied the radiosensitizing effects and associated mechanisms of silibinin in prostate cancer. The radiosensitizing effect of silibinin with ionizing radiation (IR) was assessed on radioresistant prostate cancer cell lines by clonogenic, cell cycle, cell death, and DNA repair assays. Tumor xenograft growth, immunohistochemical (IHC) analysis of tumor tissues, and toxicity-related parameters were measured in vivo. Silibinin (25 MUmol/L) enhanced IR (2.5-10 Gy)-caused inhibition (up to 96%, P < 0.001) of colony formation selectively in prostate cancer cells, and prolonged and enhanced IR-caused G2-M arrest, apoptosis, and ROS production. Mechanistically, silibinin inhibited IR-induced DNA repair (ATM and Chk1/2) and EGFR signaling and attenuated the levels of antiapoptotic proteins. Specifically, silibinin suppressed IR-induced nuclear translocation of EGFR and DNA-PK, an important mediator of DSB repair, leading to an increased number of gamma-H2AX (ser139) foci suggesting lesser DNA repair. In vivo, silibinin strongly radiosensitized DU145 tumor xenograft inhibition (84%, P < 0.01) with higher apoptotic response (10-fold, P < 0.01) and reduced repair of DNA damage, and rescued the mice from IR-induced toxicity and hematopoietic injury. Overall, silibinin enhanced the radiotherapeutic response via suppressing IR-induced prosurvival signaling and DSB repair by inhibiting nuclear translocation of EGFR and DNA-PK. Because silibinin is already in phase II clinical trial for prostate cancer patients, the present finding has translational relevance for radioresistant prostate cancer. PMID- 26516162 TI - The Syrian Golden Hamster Estrous Cycle: Unique Characteristics, Visual Guide to Staging, and Comparison with the Rat. AB - The Syrian hamster, Mesocricetus auratus, is a suitable rodent species for standard regulatory toxicity studies. However, little is published about the female Syrian hamster reproductive system. It has unique anatomic features that differ from the other rodent species. In the hamster, the upper cervix is composed of 2 canals and the vagina shows 2 lateral pouches where keratin debris accumulates. These pouches must be distinguished from the vagina in order to stage the estrous cycle properly. The microscopic changes occurring during all the estrous cycle stages show some differences with the other rodents, the lower cervix and upper vagina presenting the more dramatic changes. The aim of this work was to produce a practical guide to staging the cycle and to highlight some of the differences between the rat and hamster reproductive system. PMID- 26516163 TI - FcRn Expression on Placenta and Fetal Jejunum during Early, Mid-, and Late Gestation in Minipigs. AB - Developmental toxicity testing of therapeutic antibodies is most often conducted in nonhuman primates owing to lack of cross-reactivity in other species. Minipigs may show cross-reactivity for some humanized antibodies but have not been used for developmental toxicity testing due to an assumed lack of embryo-fetal exposure. Unlike in humans, maternal IgGs do not cross the porcine placenta to reach the fetus. Some humanized IgGs, however, have a higher affinity for the neonatal Fc receptor (FcRn) and are more likely than endogenous antibodies to cross the placenta of animals. The major site of prenatal IgG transfer is the placenta, though FcRn in fetal intestine could also uptake maternal IgGs from swallowed amniotic fluid. Using immunohistochemistry andin situhybridization in this experiment, FcRn was found in minipig placenta and fetal intestine during early, mid-, and late gestation. To date, however, fetal exposure to maternally administered IgGs has never been demonstrated in the minipig. PMID- 26516164 TI - Hepatic Phospholipidosis Is Associated with Altered Hepatobiliary Function as Assessed by Gadoxetate Dynamic Contrast-enhanced Magnetic Resonance Imaging. AB - To determine if amiodarone induces hepatic phospholipidosis (PLD) sufficient to detect changes in hepatobiliary transporter function as assessed by gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), rats were orally dosed with vehicle (1% methyl cellulose) or amiodarone (300 mg/kg/day) for 7 consecutive days. Gadoxetate DCE-MRI occurred at baseline, day 7, and following a 2-week washout of amiodarone. At day 7, the gadoxetate washout rate was significantly decreased compared to the vehicle group. Blood chemistry analysis revealed no significant changes in liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]/alkaline phosphatase [ALP]), bilirubin, or bile acids between vehicle or amiodarone groups. Hepatic PLD was confirmed in all rats treated with amiodarone at day 7 by transmission electron microscopy. Following the 2-week washout, there was no ultrastructural evidence of hepatic PLD in rats and the gadoxetate washout rate returned to baseline levels. This is the first study to show the application of gadoxetate DCE-MRI to detect hepatobiliary functional changes associated with PLD and offer a potential new technique with clinical utility in patients suspected of having PLD. These results also suggest PLD itself has functional consequences on hepatobiliary function in the absence of biomarkers of toxicity, given the cause/effect relationship between PLD and function has not been fully established. PMID- 26516165 TI - Meganucleases Revolutionize the Production of Genetically Engineered Pigs for the Study of Human Diseases. AB - Animal models of human diseases are critically necessary for developing an in depth knowledge of disease development and progression. In addition, animal models are vital to the development of potential treatments or even cures for human diseases. Pigs are exceptional models as their size, physiology, and genetics are closer to that of humans than rodents. In this review, we discuss the use of pigs in human translational research and the evolving technology that has increased the efficiency of genetically engineering pigs. With the emergence of the clustered, regularly interspaced, short palindromic repeat (CRISPR)/CRISPR associated (Cas) protein 9 system technology, the cost and time it takes to genetically engineer pigs has markedly decreased. We will also discuss the use of another meganuclease, the transcription activator-like effector nucleases , to produce pigs with severe combined immunodeficiency by developing targeted modifications of the recombination activating gene 2 (RAG2).RAG2mutant pigs may become excellent animals to facilitate the development of xenotransplantation, regenerative medicine, and tumor biology. The use of pig biomedical models is vital for furthering the knowledge of, and for treating human, diseases. PMID- 26516166 TI - Rapid identification of Helicoverpa armigera and Helicoverpa zea (Lepidoptera: Noctuidae) using ribosomal RNA internal transcribed spacer 1. AB - Rapid identification of invasive species is crucial for deploying management strategies to prevent establishment. Recent Helicoverpa armigera (Hubner) invasions and subsequent establishment in South America has increased the risk of this species invading North America. Morphological similarities make differentiation of H. armigera from the native Helicoverpa zea (Boddie) difficult. Characteristics of adult male genitalia and nucleotide sequence differences in mitochondrial DNA are two of the currently available methods to differentiate these two species. However, current methods are likely too slow to be employed as rapid detection methods. In this study, conserved differences in the internal transcribed spacer 1 (ITS1) of the ribosomal RNA genes were used to develop species-specific oligonucleotide primers that amplified ITS1 fragments of 147 and 334 bp from H. armigera and H. zea, respectively. An amplicon (83 bp) from a conserved region of 18S ribosomal RNA subunit served as a positive control. Melting temperature differences in ITS1 amplicons yielded species specific dissociation curves that could be used in high resolution melt analysis to differentiate the two Helicoverpa species. In addition, a rapid and inexpensive procedure for obtaining amplifiable genomic DNA from a small amount of tissue was identified. Under optimal conditions, the process was able to detect DNA from one H. armigera leg in a pool of 25 legs. The high resolution melt analysis combined with rapid DNA extraction could be used as an inexpensive method to genetically differentiate large numbers of H. armigera and H. zea using readily available reagents. PMID- 26516167 TI - New gall wasp species attacking chestnut trees: Dryocosmus zhuili n. sp. (Hymenoptera: Cynipidae) on Castanea henryi from southeastern China. AB - A new gall wasp species, Dryocosmus zhuili Liu et Zhu, is herein described from the southeastern Fujian province of China. The new species induces galls on trees of Henry's chestnut, Castanea henryi, which is also a native host for the notorious Oriental chestnut gall wasp (OCGW, Dryocosmus kuriphilus Yasumatsu). D. zhuili overlaps with OCGW in emergence time and induces galls morphologically similar to that of OCGW on similar plant parts. In a previous study, we reported considerable divergence between mtDNA CO1 (mitochondrial DNA Cytochrome c oxidase subunit I) sequences of these wasps and the true OCGW wasps and suggested the existence of a cryptic species. Herein, we confirm the identity of the new species based on morphological and biological differences and provide a formal description. Although the new species is relatively easily separated from OCGW on basis of morphology, field identification involving the two species can still be problematic because of their small body size, highly similar gall morphology, and other life history traits. We further discussed the potential of the new species to be a pest for the chestnut industry and the consequences of accidental introduction of this species into nonnative areas, especially with regard to the bisexual reproduction mode of the new species in contrast to the parthenogenetic reproduction mode of OCGW. PMID- 26516168 TI - Identification of a new DPY19L2 mutation and a better definition of DPY19L2 deletion breakpoints leading to globozoospermia. AB - STUDY HYPOTHESIS: The purpose of this study was to analyze DPY19L2 sequence variants to investigate the mechanism leading to the entire DPY19L2 deletion in a large cohort of infertile globozoospermic patients. STUDY FINDING: An improved analysis of the DPY19L2 deletion breakpoints (BPs) allowed us to identify two BPs located in a small 1 kb region and to more precisely localize the BPs reported previously. WHAT IS KNOWN ALREADY: Three genes [spermatogenesis associated 16 (SPATA16), protein interacting with PRKCA (PICK1) and DPY19L2] were previously correlated with globozoospermia, but a homozygous deletion of the entire DPY19L2 was identified as the most frequent alteration causing this phenotype. In addition, several point mutations in this gene were reported. In previous work, we have identified nine BPs for the DPY19L2 deletion clustered in two hotspot regions, while others reported a total of five BPs. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: We screened for the DPY19L2 deletion and for mutations in the DPY19L2, SPATA16 and PICK1 genes in a cohort of 21 Tunisian globozoospermic patients. In order to characterize the DPY19L2 deletion BPs, we sequenced a 2 kb fragment on low copy repeat (LCR) 1 and LCR2 in Tunisian fertile controls to distinguish between single-nucleotide polymorphisms (SNPs) and LCR specific markers. MAIN RESULTS AND THE ROLE OF CHANCE: Molecular analyses performed on 18 genetically independent individuals showed that 11 (61.1%) were homozygous for the DPY19L2 deletion, 2 (11.1%) were homozygous for the non synonymous mutation (p.R298C) in exon 8, 1 patient (5.6%) was homozygous for a new splice-site mutation at the junction exon-intron 16 [c.1579_1580+4delAGGTAAinsTCAT] and no DPY19L2, SPATA16 or PICK1 mutations were identified for 4 patients (22.2%). By defining 15 specific LCR markers, we characterized 2 BPs for the DPY19L2 deletion in 11 patients showing the homozygous deletion. Using 20 non-LCR-specific SNPs, we identified 8 distinct haplotypes. LIMITATIONS, REASONS FOR CAUTION: A limitation of this study is the small number of patients owing to the rarity of this form of male infertility. WIDER IMPLICATIONS OF THE FINDINGS: Our data showed that some nucleotides, described by others as LCR-specific markers and used to limit their BPs, were in fact SNPs demonstrating the difficulty in precisely determining the localization of BPs. LARGE SCALE DATA: Not applicable. STUDY FUNDING AND COMPETING INTERESTS: This work was supported by the French Centre National de la Recherche Scientifique (CNRS), Institut National de la Sante et de la Recherche Medicale (INSERM), the Ministere de l'Education Nationale et de l'Enseignement Superieur et de la Recherche, the University of Strasbourg, the University Hospital of Strasbourg, the Agence Nationale pour la Recherche, the Agence de la BioMedecine and l'Agence Universitaire de la Francophonie (AUF). There are no conflicts of interest to declare. PMID- 26516169 TI - Social hierarchy modulates neural responses of empathy for pain. AB - Recent evidence indicates that empathic responses to others' pain are modulated by various situational and individual factors. However, few studies have examined how empathy and underlying brain functions are modulated by social hierarchies, which permeate human society with an enormous impact on social behavior and cognition. In this study, social hierarchies were established based on incidental skill in a perceptual task in which all participants were mediumly ranked. Afterwards, participants were scanned with functional magnetic resonance imaging while watching inferior-status or superior-status targets receiving painful or non-painful stimulation. The results revealed that painful stimulation applied to inferior-status targets induced higher activations in the anterior insula (AI) and anterior medial cingulate cortex (aMCC), whereas these empathic brain activations were significantly attenuated in response to superior-status targets' pain. Further, this neural empathic bias to inferior-status targets was accompanied by stronger functional couplings of AI with brain regions important in emotional processing (i.e. thalamus) and cognitive control (i.e. middle frontal gyrus). Our findings indicate that emotional sharing with others' pain is shaped by relative positions in a social hierarchy such that underlying empathic neural responses are biased toward inferior-status compared with superior-status individuals. PMID- 26516170 TI - When your friends make you cringe: social closeness modulates vicarious embarrassment-related neural activity. AB - Social closeness is a potent moderator of vicarious affect and specifically vicarious embarrassment. The neural pathways of how social closeness to another person affects our experience of vicarious embarrassment for the other's public flaws, failures and norm violations are yet unknown. To bridge this gap, we examined the neural response of participants while witnessing threats to either a friend's or a stranger's social integrity. The results show consistent responses of the anterior insula (AI) and anterior cingulate cortex (ACC), shared circuits of the aversive quality of affect, as well as the medial prefrontal cortex and temporal pole, central structures of the mentalizing network. However, the ACC/AI network activation was increased during vicarious embarrassment in response to a friend's failures. At the same time, the precuneus, a brain region associated with self-related thoughts, showed a specific activation and an increase in functional connectivity with the shared circuits in the frontal lobe while observing friends. This might indicate a neural systems mechanism for greater affective sharing and self-involvement while people interact with close others that are relevant to oneself. PMID- 26516171 TI - Functional neural correlates of social approval in schizophrenia. AB - Social approval is a reward that uses abstract social reinforcers to guide interpersonal interactions. Few studies have specifically explored social reward processing and its related neural substrates in schizophrenia. Fifteen patients with schizophrenia and fifteen healthy controls participated in a two-part study to explore the functional neural correlates of social approval. In the first session, participants were led to believe their personality would be assessed based on their results from various questionnaires and an interview. Participants were then presented with the results of their supposed evaluation in the scanner, while engaging in a relevant fMRI social approval task. Subjects provided subjective reports of pleasure associated with receiving self-directed positive or negative feedback. Higher activation of the right parietal lobe was found in controls compared with individuals with schizophrenia. Both groups rated traits from the high social reward condition as more pleasurable than the low social reward condition, while intergroup differences emerged in the low social reward condition. Positive correlations were found in patients only between subjective ratings of positive feedback and right insula activation, and a relevant behavioural measure. Evidence suggests potential neural substrates underlying the cognitive representation of social reputation in schizophrenia. PMID- 26516172 TI - Improved outcome with repeated intracoronary injection of bone marrow-derived cells within a registry: rationale for the randomized outcome trial REPEAT. AB - AIMS: Regenerative therapies have evolved as a promising new option in the treatment of post-infarction heart failure. A major limitation of intracoronary application of autologous bone marrow-derived mononuclear cells (BM-MNCs) is that homing of the applied cells is profoundly reduced in patients with post infarction heart failure compared with patients with acute myocardial infarction. However, early pilot and also randomized controlled trials have demonstrated significant improvements in overall cardiac function. The aim of the present analysis was to quantify a potential mortality risk reduction and reduced hospitalization in order to provide data for a prospective outcome trial. METHODS AND RESULTS: The results of an ongoing single-centre registry including 297 post infarction heart failure patients suggest that repeated intracoronary application of autologous bone marrow-derived cells is associated with a significant better 2 year survival compared with a single BM-MNC application (2-year survival 93.6 vs. 84.0%, P = 0.03). Likewise, mortality is significantly lower at 2-year follow-up compared with the mortality estimated by the use of the Seattle Heart Failure Model (SHFM) in patients receiving repeated BM-MNC application (observed mortality 6.4%, predicted mortality 16.2%, P = 0.02). Although the trend persisted at 3-year follow-up, the mortality reduction was no longer statistically significant between single and repeated treatment (mortality 21.9 vs. 13.7%, P = 0.06). CONCLUSION: Repeated intracoronary administration of BM-MNC appears to be associated with improved clinical outcome compared with single treatment at 2 years. This registry provides the rationale for the design of the multicentre randomized, controlled, open-label REPEAT trial, which prospectively compares the effects of single vs. repeated intracoronary application of autologous BM-MNC on total and SHFM-predicted mortality in patients with chronic post-infarction heart failure. PMID- 26516173 TI - Assessing generalizability of trial results in general practice. PMID- 26516174 TI - Inhibition of the platelet P2Y12 receptor for adenosine diphosphate does not impair the capacity of platelet to synthesize thromboxane A2. AB - AIMS: Patients with acute coronary syndromes (ACSs) are treated with acetylsalicylic acid (ASA) and antagonists of the P2Y12 receptor (P2Y12R) for adenosine diphosphate (ADP). Based on the demonstration that P2Y12R antagonists inhibit thromboxane A2 (TxA2) production (target of ASA), it was surmised that ACS patients might be treated with P2Y12R antagonists only. However, this demonstration contrasts with the results of previous studies. The aim of this study was to test whether P2Y12R antagonists have off-target/indirect inhibitory effects on platelet TxA2 production. METHODS AND RESULTS: We studied 3 patients with inherited P2Y12R deficiency and 33 healthy subjects. Serum TxB2 (TxA2 metabolite) levels were similar in P2Y12R-deficient patients and healthy subjects and were not decreased by P2Y12R antagonists in vitro. Serum TxB2 levels did not decrease in 20 patients treated with prasugrel (10 mg q.i.d.) or placebo for 14 days. Arachidonic acid- and collagen-induced platelet aggregation (PA) and TxB2 production in platelet-rich plasma (PRP) of healthy subjects were inhibited in vitro by P2Y12R antagonists. However, P2Y12R antagonists did not inhibit TxB2 production when PA was prevented by avoiding the stirring of PRP in the aggregometer. The P2Y1 ADP-receptor antagonist MRS2500 had similar effects on PA and TxB2 production as P2Y12R antagonists. Acetylsalicylic acid inhibited TxB2 production more effectively than a P2Y12R antagonist; only the combination of ASA and a P2Y12R antagonist inhibited PA induced by high concentration of collagen. CONCLUSION: Inherited deficiency or pharmacological inhibition of P2Y12R does not affect the platelet capacity to synthesize TxA2. There is no pharmacological evidence that ACS patients may be safely treated with P2Y12R antagonists without ASA. PMID- 26516175 TI - Heme oxygenase-1 suppresses a pro-inflammatory phenotype in monocytes and determines endothelial function and arterial hypertension in mice and humans. AB - AIMS: Heme oxygenase-1 (HO-1) confers protection to the vasculature and suppresses inflammatory properties of monocytes and macrophages. It is unclear how HO-1 determines the extent of vascular dysfunction in mice and humans. METHODS AND RESULTS: Decreased HO-1 activity and expression was paralleled by increased aortic expression and activity of the nicotinamide dinucleotide phosphate oxidase Nox2 in HO-1 deficient Hmox1-/- and Hmox1(+/-) compared with Hmox1+/+ mice. When subjected to angiotensin II-infusion, streptozotocin-induced diabetes mellitus and aging, HO-1 deficient mice showed increased vascular dysfunction inversely correlated with HO activity. In a primary prevention population-based cohort, we assessed length polymorphisms of the HMOX1 promoter region and established a bipolar frequency pattern of allele length (long vs. short repeats) in 4937 individuals. Monocytic HMOX1 mRNA expression was positively correlated with flow-mediated dilation and inversely with CD14 mRNA expression indicating pro-inflammatory monocytes in 733 hypertensive individuals of this cohort. Hmox1-/- mice showed drastically increased expression of the chemokine receptor CCR2 in monocytes and the aorta. Angiotensin II-infused Hmox1 /- mice had amplified endothelial inflammation in vivo, significantly increased aortic infiltration of pro-inflammatory CD11b+ Ly6C(hi) monocytes and Ly6G+ neutrophils and were marked by Ly6C(hi) monocytosis in the circulation and an increased blood pressure response. Finally, individuals with unfavourable HMOX1 gene promoter length had increased prevalence of arterial hypertension and reduced cumulative survival after a median follow-up of 7.23 years. CONCLUSIONS: Heme oxygenase-1 is a regulator of vascular function in hypertension via determining the phenotype of inflammatory circulating and infiltrating monocytes with possible implications for all-cause mortality. PMID- 26516178 TI - Prediction of outcome after out-of-hospital cardiac arrest already on hospital admission-not reliable enough to be true! PMID- 26516176 TI - Haematological determinants of cardiac involvement in adults with sickle cell disease. AB - AIMS: Cardiac involvement is common in sickle cell disease (SCD). Studies are needed to establish haematological determinants of this involvement and prognostic markers. The aim of the study was to identify haematological factors associated with cardiac involvement in SCD and their impact on prognosis. METHODS AND RESULTS: This longitudinal observational study was performed on 1780 SCD patients with SS or S-beta(0)-thalassemia referred to our centre. Six hundred fifty-six met our inclusion criteria (availability of a blood-workup and echocardiogram obtained <1 year apart, no heart valve surgery and no current pregnancy). Median age was 31 (interquartile range, 25-40) years, and median haemoglobin (Hb) was 87 (80-95)g/L. Left ventricular (LV) dilation, left atrial dilation, cardiac index (CI) >4 L/min/m(2), LV ejection fraction <55%, and tricuspid regurgitant velocity (TRV) >=2.5 m/s were found in 35, 78, 23, 8.5, and 17% of patients, respectively. Compared with other patients, those in the fourth quartiles (Q4) of LV end-diastolic dimension index (LVEDDind) and left atrial dimension index (LADind) and those with high CI had significantly lower Hb, % foetal Hb (HbF), and red blood cell (RBC) counts; and significantly higher lactate dehydrogenase, bilirubin, and %dense RBCs. Independent haematologic determinants of Q4 LVEDDind and LADind were low RBC count and %HbF; high %dense RBCs were associated with LADind. Low %HbF and RBC count were associated with high CI. High %dense RBCs or no alpha-thalassemia gene deletion was associated with greater severity of anaemia and cardiac dilation and with higher CI. During the median follow-up of 48 (32-59) months, 50 (7.6%) patients died. Tricuspid regurgitant velocity >= 2.5 m/s was a predictor of mortality. The risk of death increased four-fold when left ventricular ejection fraction <55% was present also (P = 0.0001). CONCLUSION: Cardiac dilation and CI elevation in patients with SCD are associated with haematologic variables reflecting haemolysis, RBC rigidity, and blood viscosity. Tricuspid regurgitant velocity >= 2.5 and LV dysfunction (even mild) predict mortality. PMID- 26516179 TI - Perceptions of Incapacitated Heterosexual Sexual Assault: Influences of Relationship Status, Perpetrator Intoxication, and Post-Assault Sleeping Arrangements. AB - This investigation explored college students' victim-blaming behaviors in perceptions of incapacitated rape. Participants received a vignette about a man who had sexual intercourse with a woman who had lost consciousness due to alcohol, with the conditions varied across the vignettes: the relationship between the parties, the alcohol use of the man, and the post-assault sleeping arrangements. Results revealed that when the man was a stranger, participants attributed less responsibility for the incident to him, but were more likely to label the incident as "rape." Neither the alcohol use of the man nor the post assault sleeping arrangements significantly influenced participants' perceptions. PMID- 26516180 TI - Why informally employed Chinese women do not go to the doctor. AB - Informal employment, in which workers have no security of employment and receive few or no health insurance benefits, has risen sharply in urban China in the last decade. The percentage of women in informal employment in China is higher than in the formal employment sector; 'feminization' has thus become a key feature of informal employment in China. A feminized informal labor sector has far-reaching effects on the status of women's health and on women's health-seeking behavior. To better understand this behavior, especially barriers to health seeking, we conducted 34 interviews informally employed women in Guangzhou, China. For comparative purposes, we also interviewed 22 men in the informal labor sector. Findings reveal that compared with men, women have more serious health problems but report seeking medical attention less frequently. Financial constraints, distrust of doctors and medical expenses, unfriendly treatment environments and traditional attitudes about health and illness among women were the main barriers to health seeking. Implications for health promotion are discussed. PMID- 26516181 TI - Identifying Twitter influencer profiles for health promotion in Saudi Arabia. AB - New media platforms, such as Twitter, provide the ideal opportunity to positively influence the health of large audiences. Saudi Arabia has one of the highest number of Twitter users of any country, some of whom are very influential in setting agendas and contributing to the dissemination of ideas. Those opinion leaders, both individuals and organizations, influential in the new media environment have the potential to raise awareness of health issues, advocate for health and potentially instigate change at a social level. To realize the potential of the new media platforms for public health, the function of opinion leaders is key. This study aims to identify and profile the most influential Twitter accounts in Saudi Arabia. Multiple measures, including: number of followers and four influence scores, were used to evaluate Twitter accounts. The data were then filtered and analysed using ratio and percentage calculations to identify the most influential users. In total, 99 Saudi Twitter accounts were classified, resulting in the identification of 25 religious men/women, 16 traditional media, 14 sports related, 10 new media, 6 political, 6 company and 4 health accounts. The methods used to identify the key influential Saudi accounts can be applied to inform profile development of Twitter users in other countries. PMID- 26516182 TI - Cellular and molecular basis of RV hypertrophy in congenital heart disease. AB - RV hypertrophy (RVH) is one of the triggers of RV failure in congenital heart disease (CHD). Therefore, improving our understanding of the cellular and molecular basis of this pathology will help in developing strategic therapeutic interventions to enhance patient benefit in the future. This review describes the potential mechanisms that underlie the transition from RVH to RV failure. In particular, it addresses structural and functional remodelling that encompass contractile dysfunction, metabolic changes, shifts in gene expression and extracellular matrix remodelling. Both ischaemic stress and reactive oxygen species production are implicated in triggering these changes and will be discussed. Finally, RV remodelling in response to various CHDs as well as the potential role of biomarkers will be addressed. PMID- 26516183 TI - Rat bone marrow-derived dendritic cells generated with GM-CSF/IL-4 or FLT3L exhibit distinct phenotypical and functional characteristics. AB - Dendritic cells are professional APCs that play a central role in the initiation of immune responses. The limited ex vivo availability of dendritic cells inspires the widespread use of bone marrow-derived dendritic cells as an alternative in research. However, the functional characteristics of bone marrow-derived dendritic cells are incompletely understood. Therefore, we compared functional and phenotypic characteristics of rat bone marrow-derived dendritic cells generated with GM-CSF/IL-4 or FLT3 ligand bone marrow-derived dendritic cells. A comparison of surface markers revealed that FLT3 ligand-bone marrow-derived dendritic cells expressed signal regulatory protein alpha, CD103, and CD4 and baseline levels of MHC class II, CD40, and CD86, which were highly up-regulated upon stimulation. Conversely, GM-CSF/IL-4-bone marrow-derived dendritic cells constitutively expressed signal regulatory protein alpha, CD11c, and CD11b but only mildly up-regulated MHC class II, CD40, or CD86 following stimulation. Expression of dendritic cell-associated core transcripts was restricted to FLT3 ligand-bone marrow-derived dendritic cells . GM-CSF/IL-4-bone marrow-derived dendritic cells were superior at phagocytosis but were outperformed by FLT3 ligand-bone marrow-derived dendritic cells at antigen presentation and T cell stimulation in vitro. Stimulated GM-CSF/IL-4-bone marrow-derived dendritic cells secreted more TNF, CCL5, CCL20, and NO, whereas FLT3 ligand-bone marrow-derived dendritic cells secreted more IL-6 and IL-12. Finally, whereas GM-CSF/IL-4-bone marrow-derived dendritic cell culture supernatants added to resting T cell cultures promoted forkhead box p3(+) regulatory T cell populations, FLT3 ligand bone marrow-derived dendritic cell culture supernatants drove Th17 differentiation. We conclude that rat GM-CSF/IL-4-bone marrow-derived dendritic cells and FLT3 ligand-bone marrow-derived dendritic cells are functionally distinct. Our data support the current rationale that FLT3 ligand-bone marrow derived dendritic cells mostly resemble classic dendritic cells but comprise additional minor subpopulations, whereas GM-CSF/IL-4-bone marrow-derived dendritic cells resemble monocyte-derived inflammatory dendritic cells (iNOS positive monocyte-derived cells). PMID- 26516184 TI - The inflammasome NLRP3 plays a protective role against a viral immunopathological lesion. AB - Herpes simplex 1 infection of the eye can cause blindness with lesions in the corneal stroma largely attributable to inflammatory events that include components of both adaptive and innate immunity. Several innate immune responses are triggered by herpes simplex 1, but it is unclear how such innate events relate to the subsequent development of stromal keratitis. In this study, we compared the outcome of herpes simplex 1 ocular infection in mice unable to express NLRP3 because of gene knockout (NLRP3(-/-)) to that of wild-type mice. The NLRP3(-/-) mice developed more-severe and earlier stromal keratitis lesions and had higher angiogenesis scores than did infected wild-type animals. In addition, NLRP3(-/-) mice generated an increased early immune response with heightened chemokines and cytokines, including interleukin-1beta and interleukin 18, and elevated recruitment of neutrophils. Increased numbers of CD4(+) T cells were seen at later stages of the disease in NLRP3(-/-) animals. Reduction in neutrophils prevented early onset of the disease in NLRP3(-/-) animals and lowered levels of bioactive interleukin-1beta but did not lower bioactive interleukin-18. In conclusion, our results indicate that NLRP3 has a regulatory and beneficial role in herpetic stromal keratitis pathogenesis. PMID- 26516185 TI - Recruited monocytes modulate malaria-induced lung injury through CD36-mediated clearance of sequestered infected erythrocytes. AB - Pulmonary complications occur in a significant percentage of adults and children during the course of severe malaria. The cellular and molecular innate immune mechanisms that limit the extent of pulmonary inflammation and preserve lung function during severe Plasmodium infections remain unclear. In particular, the contributions to pulmonary complications by parasitized erythrocyte sequestration and subsequent clearance from the lung microvasculature by immune cells have not been clearly defined. We used the Plasmodium berghei ANKA-C57BL/6 mouse model of severe malaria to investigate the mechanisms governing the nature and extent of malaria-associated lung injury. We have demonstrated that sequestration of infected erythrocytes on postcapillary endothelial surfaces results in acute lung injury and the rapid recruitment of CCR2(+)CD11b(+)Ly6C(hi) monocytes from the circulation. These recruited cells remain in the lungs as monocyte-derived macrophages and are instrumental in the phagocytic clearance of adherent Plasmodium berghei-infected erythrocytes. In contrast, alveolar macrophages do not play a significant role in the clearance of malaria-infected cells. Furthermore, the results obtained from Ccr2(-/-), Cd36(-/-), and CD36 bone marrow chimeric mice showed that sequestration in the absence of CD36-mediated phagocytic clearance by monocytes leads to exaggerated lung pathologic features. In summary, our data indicate that the intensity of malaria-induced lung pathologic features is proportional to the steady-state levels of Plasmodium infected erythrocytes adhering to the pulmonary vasculature. Moreover, the present work has defined a major role of recruited monocytes in clearing infected erythrocytes from the pulmonary interstitium, thus minimizing lung damage. PMID- 26516186 TI - NCG 5.0: updates of a manually curated repository of cancer genes and associated properties from cancer mutational screenings. AB - The Network of Cancer Genes (NCG, http://ncg.kcl.ac.uk/) is a manually curated repository of cancer genes derived from the scientific literature. Due to the increasing amount of cancer genomic data, we have introduced a more robust procedure to extract cancer genes from published cancer mutational screenings and two curators independently reviewed each publication. NCG release 5.0 (August 2015) collects 1571 cancer genes from 175 published studies that describe 188 mutational screenings of 13 315 cancer samples from 49 cancer types and 24 primary sites. In addition to collecting cancer genes, NCG also provides information on the experimental validation that supports the role of these genes in cancer and annotates their properties (duplicability, evolutionary origin, expression profile, function and interactions with proteins and miRNAs). PMID- 26516187 TI - SynLethDB: synthetic lethality database toward discovery of selective and sensitive anticancer drug targets. AB - Synthetic lethality (SL) is a type of genetic interaction between two genes such that simultaneous perturbations of the two genes result in cell death or a dramatic decrease of cell viability, while a perturbation of either gene alone is not lethal. SL reflects the biologically endogenous difference between cancer cells and normal cells, and thus the inhibition of SL partners of genes with cancer-specific mutations could selectively kill cancer cells but spare normal cells. Therefore, SL is emerging as a promising anticancer strategy that could potentially overcome the drawbacks of traditional chemotherapies by reducing severe side effects. Researchers have developed experimental technologies and computational prediction methods to identify SL gene pairs on human and a few model species. However, there has not been a comprehensive database dedicated to collecting SL pairs and related knowledge. In this paper, we propose a comprehensive database, SynLethDB (http://histone.sce.ntu.edu.sg/SynLethDB/), which contains SL pairs collected from biochemical assays, other related databases, computational predictions and text mining results on human and four model species, i.e. mouse, fruit fly, worm and yeast. For each SL pair, a confidence score was calculated by integrating individual scores derived from different evidence sources. We also developed a statistical analysis module to estimate the druggability and sensitivity of cancer cells upon drug treatments targeting human SL partners, based on large-scale genomic data, gene expression profiles and drug sensitivity profiles on more than 1000 cancer cell lines. To help users access and mine the wealth of the data, we developed other practical functionalities, such as search and filtering, orthology search, gene set enrichment analysis. Furthermore, a user-friendly web interface has been implemented to facilitate data analysis and interpretation. With the integrated data sets and analytics functionalities, SynLethDB would be a useful resource for biomedical research community and pharmaceutical industry. PMID- 26516188 TI - Integrated interactions database: tissue-specific view of the human and model organism interactomes. AB - IID (Integrated Interactions Database) is the first database providing tissue specific protein-protein interactions (PPIs) for model organisms and human. IID covers six species (S. cerevisiae (yeast), C. elegans (worm), D. melonogaster (fly), R. norvegicus (rat), M. musculus (mouse) and H. sapiens (human)) and up to 30 tissues per species. Users query IID by providing a set of proteins or PPIs from any of these organisms, and specifying species and tissues where IID should search for interactions. If query proteins are not from the selected species, IID enables searches across species and tissues automatically by using their orthologs; for example, retrieving interactions in a given tissue, conserved in human and mouse. Interaction data in IID comprises three types of PPI networks: experimentally detected PPIs from major databases, orthologous PPIs and high confidence computationally predicted PPIs. Interactions are assigned to tissues where their proteins pairs or encoding genes are expressed. IID is a major replacement of the I2D interaction database, with larger PPI networks (a total of 1,566,043 PPIs among 68,831 proteins), tissue annotations for interactions, and new query, analysis and data visualization capabilities. IID is available at http://ophid.utoronto.ca/iid. PMID- 26516189 TI - Folliculin, a tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation. AB - TDP-43 was identified as the major component of ubiquitin and autophagosome positive cytoplasmic inclusions in neurons in the large majority of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) patients. It has been shown that a loss of nuclear TDP-43 in combination with enhanced cytoplasmic mislocalization of TDP-43, which is associated with accumulation of TDP-43 aggregates in the cytosol, is an early and key event in TDP-43-mediated neurodegeneration. However, the mechanism underlying TDP-43 nucleocytoplasmic shuttling is still not clear. Here, we show that the tumor suppressor folliculin (FLCN) is a novel positive regulator of TDP-43 cytoplasmic translocation. FLCN directly interacts with TDP-43. The amino acids 202-299 of FLCN and RNA recognition motif domains of TDP-43 are necessary for their interaction. In addition, both exogenous and endogenous FLCNs are required for TDP-43 cytoplasmic accumulation, protein aggregation and stress granule formation. Overall, our study suggests that FLCN may play an important role in the regulation of TDP-43 nucleocytoplasmic shuttling and TDP-43-mediated proteinopathy. PMID- 26516190 TI - Multisite Lymphaticovenular Anastomosis Using Vein Graft for Uterine Cancer Related Lymphedema After Pelvic Lymphadenectomy. AB - BACKGROUND: Lymphaticovenular anastomosis (LVA) is becoming a treatment option for lymphedema. It is challenging to perform LVA when a lymphatic vessel is too far from a vein to anastomose directly. METHODS: We applied vein grafting for simultaneous multisite LVA (SM-LVA), when there was a considerable distance between a lymphatic vessel and a vein. Five patients with lower extremity lymphedema (LEL) who underwent SM-LVA were included in this study. Feasibility and treatment effect of the method were evaluated. RESULTS: Simultaneous multisite LVA resulted in 35 anastomoses. Vein grafting was performed in 5 of 35 anastomoses with 100% technical success. All LVAs showed good intraoperative anastomosis patency. At 6 months postoperatively, LEL index was significantly lower than preoperative LEL index (251.0 +/- 33.0 vs 271.0 +/- 38.5, P < .001). CONCLUSION: In SM-LVA surgery, a vein can be harvested from another surgical field without additional invasiveness and is useful for bridging a lymphatic vessel and a distant vein. PMID- 26516191 TI - Lack of Iliac Engagement Correlates With Iliac Limb Complications Following Standard EVAR. AB - OBJECTIVE: An adequate distal sealing zone is a prerequisite for successful endovascular aneurysm repair (EVAR). Poor engagement of iliac limbs within the common iliac artery potentially increases the risk of limb-related complications. The aim of this study was to investigate the proportion of common iliac artery used for distal sealing as a predictor of iliac limb complications following standard EVAR. METHODS: This was a retrospective case controlled study where an iliac complication group was compared to a larger control group from the unit database. Core analysis of postoperative computed tomography scans was used to ascertain the percentage engagement of the iliac limb of the stent graft within the native iliac artery in both groups. RESULTS: There were 240 limbs in the control group and 33 limbs in the complications group. Complications included 10 endoleaks, 1 iliac limb dislocation, 2 insufficient engagement, 4 occlusions, and 16 kinks. The proportion of common iliac artery engagement was significantly higher in the control group compared with the complications group (75.3:68.6%, P = .003). CONCLUSIONS: Increased engagement in the common iliac artery following standard EVAR reduces the risks of limb complications. A clinical guide utilization of more than 70% of the total length of common iliac artery could be used as this was associated with a significantly lower rate of iliac limb complications following standard EVAR. PMID- 26516192 TI - Simulium (Gomphostilbia) merapiense sp. nov. (Diptera: Simuliidae) from Java, Indonesia. AB - Simulium (Gomphostilbia) merapiense sp. nov. is described based on females, males, pupae, and mature larvae from Yagyakarta, Java, Indonesia. This new species is placed in the Simulium epistum species-group, and is characterized by the pupal gill with eight short filaments all arising at the same level from a short stalk, somewhat enlarged basal fenestra, entirely bare pupal head and thoracic integument, and small and short larval postgenal cleft. These characters rarely are found in the subgenus. Taxonomic notes are given to separate this new species from related species of the S. epistum species-group. PMID- 26516193 TI - Sutureless, rapid deployment valves and stented bioprosthesis in aortic valve replacement: recommendations of an International Expert Consensus Panel. AB - OBJECTIVES: After a panel process, recommendations on the use of sutureless and rapid deployment valves in aortic valve replacement were given with special respect as an alternative to stented valves. METHODS: Thirty-one international experts in both sutureless, rapid deployment valves and stented bioprostheses constituted the panel. After a thorough literature review, evidence-based recommendations were rated in a three-step modified Delphi approach by the experts. RESULTS: Literature research could identify 67 clinical trials, 4 guidelines and 10 systematic reviews for detailed text analysis to obtain a total of 28 recommendations. After rating by the experts, 12 recommendations were identified and degree of consensus for each was determined. Proctoring and education are necessary for the introduction of sutureless valves on an institutional basis as well as for the individual training of surgeons. Sutureless and rapid deployment should be considered as the valve prosthesis of first choice for isolated procedures in patients with comorbidities, old age, delicate aortic wall conditions such as calcified root, porcelain aorta or prior implantation of aortic homograft and stentless valves as well as for concomitant procedures and small aortic roots to reduce cross-clamp time. Intraoperative transoesophageal echocardiography is highly recommended, and in case of right anterior thoracotomy, preoperative computer tomography is strongly recommended. Suitable annular sizes are 19-27 mm. There is a contraindication for bicuspid valves only for Type 0 and for annular abscess or destruction due to infective endocarditis. Careful but complete decalcification of the aortic root is recommended to avoid paravalvular leakage; extensive decalcification should be avoided not to create annular defects. Proximal anastomoses of concomitant coronary artery bypass grafting should be placed during a single aortic cross clamp period or alternatively with careful side clamping. Available evidence suggests that the use of sutureless and rapid deployment valve is associated with (can translate into) reduced early complications such as prolonged ventilation, blood transfusion, atrial fibrillation, pleural effusions and renal replacement therapy, respectively, and may result in reduced intensive care unit and hospital stay in comparison with traditional valves. CONCLUSION: The international experts recommend various benefits of sutureless and rapid deployment technology, which may represent a helpful tool in aortic valve replacement for patients requiring a biological valve. However, further evidence will be needed to reaffirm the benefit of sutureless and rapid deployment valves. PMID- 26516194 TI - Outcome of patients with reduced ankle brachial index undergoing open heart surgery with cardiopulmonary bypass. AB - OBJECTIVES: In open heart surgery using cardiopulmonary bypass, perfusion of the lower extremities is markedly reduced which may induce critical ischaemia in patients with pre-existing peripheral artery disease. Whether these patients have an increased risk for amputation and should better undergo peripheral revascularization prior to surgery remains unclear. METHODS: From 1 January 2009 to 31 December 2010, 785 consecutive patients undergoing open heart surgery were retrospectively included. In 443 of these patients, preoperative ankle brachial index (ABI) measurements were available. The cohort was divided into four groups: (i) ABI < 0.5, (ii) ABI 0.5-0.69, (iii) ABI 0.7-0.89 or (iv) ABI >= 0.9. Follow up data of 413 (93.2%) patients were analysed with regard to mortality and amputations. RESULTS: The groups differed significantly in terms of age, cardiac risk factors, performed cardiac surgery and renal function. Postoperative delayed wound healing was significantly associated with lower ABI (25.9, 15.2, 27.0 and 9.6% in Groups I-IV, respectively, P = 0.003), whereas 30-day mortality was not significantly higher in patients with lower ABI (0, 4.3, 8.1 and 3.9%, respectively, P = 0.4). Kaplan-Meier models showed a significantly lower long term survival over 4 years in patients with reduced ABI (P = 0.001, long-rank test) while amputations occurred rarely with only one minor amputation in Group II (P = 0.023). CONCLUSIONS: Patients with reduced ABIs undergoing heart surgery showed more wound-healing disturbances, and higher long-term mortality compared with those with normal ABIs. However, no perioperative ischaemia requiring amputation occurred. Thus, reduced ABIs were not associated with increased peripheral risks in open heart surgery but ABI may be helpful in selecting the site for saphenectomy to potentially avoid delayed healing of related wounds in legs with severely impaired arterial perfusion. PMID- 26516195 TI - Immunotherapy for non-small cell lung cancer: current concepts and clinical trials. AB - Recent successes in immunotherapeutic strategies are being investigated to combat cancers that have less than ideal responses to standard of care treatment, such as non-small-cell lung cancer. In this paper, we summarize concepts and the current status of immunotherapy for non-small cell lung cancer, including salient features of the major categories of immunotherapy-monoclonal antibody therapy, immune checkpoint blockade, immunotoxins, anticancer vaccines, and adoptive cell therapy. PMID- 26516196 TI - Hemiarch replacement with concomitant antegrade stent grafting of the descending thoracic aorta versus total arch replacement for treatment of acute DeBakey I aortic dissection with arch tear?. AB - OBJECTIVES: For acute DeBakey I aortic dissection with arch tear, conventional distal reconstruction entails total arch replacement (TAR). Some surgeons at our institution have utilized an alternative reconstructive strategy-primary arch tear repair and transverse hemiarch reconstruction (THR) with concomitant antegrade thoracic endovascular aortic repair (TEVAR). We assessed early and mid term outcomes comparing these two surgical strategies for arch tear management. METHODS: A retrospective review of a prospectively maintained institutional aortic dissection database was carried out to compare early and mid-term outcomes for patients undergoing intervention for DeBakey I aortic dissection with arch tear. Hemiarch reconstruction with concomitant antegrade TEVAR was compared against conventional TAR. Arch tear at the origin of great vessels or greater curve was primarily repaired with interrupted sutures in TEVAR patients. RESULTS: From 2006 to 2013, 61 of 284 DeBakey I aortic dissection patients undergoing intervention for arch tear were retrospectively reviewed. Thirty-one patients had TAR (TAR group) and 30 patients had hemiarch + TEVAR (TEVAR group). Demographics and clinical presentation were similar. TEVAR group had more patients presenting in cardiogenic shock [3% (n = 1) vs 13% (n = 4), P = 0.2] and tamponade [10% (n = 3) vs 23% (n = 7), P = 0.2]. Intraoperatively, TEVAR group had lower cardiopulmonary bypass (239 +/- 34 vs 313 +/- 80 min, p0.001) and circulatory arrest (60 +/- 15 vs 78 +/- 45 min, P = 0.04) times. TAR group had higher in hospital/30-day mortality [26% (n = 8) vs 13% (n = 4), P = 0.3], but stroke rates were similar [6% (n = 2) vs 7% (n = 2), P = 1]. One-year (80 +/- 7.3 vs 71 +/- 8.3%), 3-year (73 +/- 8.3 vs 67 +/- 8.6%) and 5-year (73 +/- 8.3 vs 67 +/- 8.6%) actuarial survival were improved in TEVAR group, although not significantly (log rank, P = 0.56). TEVAR promoted increased false lumen thrombosis (43 vs 85%, P = 0.002). CONCLUSION: In treating DeBakey I aortic dissection with arch tear, hemiarch replacement with primary tear repair and concomitant TEVAR is a safe alternative to conventional TAR, with improved distal aortic remodelling. PMID- 26516197 TI - Slow adaptation in the face of rapid warming leads to collapse of the Gulf of Maine cod fishery. AB - Several studies have documented fish populations changing in response to long term warming. Over the past decade, sea surface temperatures in the Gulf of Maine increased faster than 99% of the global ocean. The warming, which was related to a northward shift in the Gulf Stream and to changes in the Atlantic Multidecadal Oscillation and Pacific Decadal Oscillation, led to reduced recruitment and increased mortality in the region's Atlantic cod (Gadus morhua) stock. Failure to recognize the impact of warming on cod contributed to overfishing. Recovery of this fishery depends on sound management, but the size of the stock depends on future temperature conditions. The experience in the Gulf of Maine highlights the need to incorporate environmental factors into resource management. PMID- 26516198 TI - Efficient and stable large-area perovskite solar cells with inorganic charge extraction layers. AB - The recent dramatic rise in power conversion efficiencies (PCEs) of perovskite solar cells (PSCs) has triggered intense research worldwide. However, high PCE values have often been reached with poor stability at an illuminated area of typically less than 0.1 square centimeter. We used heavily doped inorganic charge extraction layers in planar PSCs to achieve very rapid carrier extraction, even with 10- to 20-nanometer-thick layers, avoiding pinholes and eliminating local structural defects over large areas. The robust inorganic nature of the layers allowed for the fabrication of PSCs with an aperture area >1 square centimeter that have a PCE >15%, as certified by an accredited photovoltaic calibration laboratory. Hysteresis in the current-voltage characteristics was eliminated; the PSCs were stable, with >90% of the initial PCE remaining after 1000 hours of light soaking. PMID- 26516199 TI - Transcription factor trapping by RNA in gene regulatory elements. AB - Transcription factors (TFs) bind specific sequences in promoter-proximal and distal DNA elements to regulate gene transcription. RNA is transcribed from both of these DNA elements, and some DNA binding TFs bind RNA. Hence, RNA transcribed from regulatory elements may contribute to stable TF occupancy at these sites. We show that the ubiquitously expressed TF Yin-Yang 1 (YY1) binds to both gene regulatory elements and their associated RNA species across the entire genome. Reduced transcription of regulatory elements diminishes YY1 occupancy, whereas artificial tethering of RNA enhances YY1 occupancy at these elements. We propose that RNA makes a modest but important contribution to the maintenance of certain TFs at gene regulatory elements and suggest that transcription of regulatory elements produces a positive-feedback loop that contributes to the stability of gene expression programs. PMID- 26516200 TI - Immunogenicity of somatic mutations in human gastrointestinal cancers. AB - It is unknown whether the human immune system frequently mounts a T cell response against mutations expressed by common epithelial cancers. Using a next-generation sequencing approach combined with high-throughput immunologic screening, we demonstrated that tumor-infiltrating lymphocytes (TILs) from 9 out of 10 patients with metastatic gastrointestinal cancers contained CD4(+) and/or CD8(+) T cells that recognized one to three neo-epitopes derived from somatic mutations expressed by the patient's own tumor. There were no immunogenic epitopes shared between these patients. However, we identified in one patient a human leukocyte antigen-C*08:02-restricted T cell receptor from CD8(+) TILs that targeted the KRAS(G12D) hotspot driver mutation found in many human cancers. Thus, a high frequency of patients with common gastrointestinal cancers harbor immunogenic mutations that can potentially be exploited for the development of highly personalized immunotherapies. PMID- 26516202 TI - The PediGFR consortium: studying the genetics of complex kidney traits in children. PMID- 26516203 TI - The role of adipose tissue asymmetric dimethylarginine/dimethylarginine dimethylaminohydrolase pathway in adipose tissue phenotype and metabolic abnormalities in subtotally nephrectomized rats. AB - BACKGROUND: The lipodystrophy-like phenotype has been suggested in early chronic kidney disease (CKD). It includes adipose tissue atrophy, systemic insulin resistance (IR), dyslipidemia and ectopic lipid accumulation. To elucidate its pathogenesis, we investigated the role of two uremic toxins that affect insulin sensitivity: an endogenous nitric oxide synthase inhibitor, and asymmetric dimethylarginine (ADMA) and indoxyl sulfate (IS). METHODS: Six-week-old Sprague Dawley rats were rendered CKD by subtotal nephrectomy (Nx) and compared with sham operated rats. Cultured 3T3-L1 fibroblasts were differentiated into mature adipocytes with or without ADMA. Transgenic (Tg) mice overexpressing each isoform of ADMA degrading enzyme, dimethylarginine dimethylaminohydrolase 1 (DDAH1) and DDAH2 were subject to Nx and their phenotypes were investigated. RESULTS: In Nx rats, IR was evident and insulin stimulation failed to activate insulin signaling in adipose tissues. Adipose tissue weight, adipocyte size and adipocyte differentiation marker expressions decreased as a consequence of IR in Nx. Tissue lipid content in the liver and muscle increased in Nx rats. Tissue levels of ADMA, IS and oxidative stress increased in the adipose tissue of Nx rats. Both DDAH1 and DDAH2 expressions decreased, and a putative IS receptor, aryl hydrocarbon receptor, expression increased in the adipose tissue of Nx rats. ADMA inhibited adipocyte differentiation, triglyceride accumulation and insulin signaling, which were reversed by pretreatment with cGMP. In each type of Tg mice overexpressing DDAH1 or DDAH2, all lipodystrophy-like phenotypes induced by Nx were reversed. CONCLUSIONS: In mild CKD, dysregulation of the ADMA/DDAH pathway in adipose tissue triggers lipodystrophy-like phenotype changes, including ectopic fat depositions. PMID- 26516204 TI - The Nordic Health Registries: an important part of modern medical research. PMID- 26516201 TI - Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1. AB - Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer. We identified a loss-of function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1(-/-) mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses. PMID- 26516205 TI - Mental health and developmental outcomes for children born after ART: a comparative prospective study on child gender and treatment type. AB - STUDY QUESTION: Do children born after assisted reproductive techniques (ART; IVF/ICSI) display more mental health issues or social and cognitive developmental problems at 7-8 years than naturally conceived (NC) controls, and does child gender play a role? SUMMARY ANSWER: ART children do not differ with regard to mental health or social and cognitive developmental problems when compared with controls, but some gender-specific differences do exist. WHAT IS KNOWN ALREADY: Systematic reviews have not found any evidence of delays in neurocognitive or sensorimotor development in ART children. However findings on the effect of the type of ART treatment (IVF versus ICSI) on the offspring's physical and mental development have not been uniform. Knowledge of the role of child gender in ART research is scarce. STUDY DESIGN, SIZE, DURATION: This prospective follow-up study compares mental health and social and cognitive developmental problems between 7-8-year-old ART and NC children, controlling for the father's age, length of the parents' partnership, mother's parity, child's gestational age, and the need of neonatal intensive care unit (NICU). Further, within the ART group, we analysed whether the treatment type (IVF versus ICSI) and the child's gender are associated with the mental health and developmental outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: In this study, 255 singleton ART children (IVF and ICSI) were compared with 278 NC children on parent-reported internalizing and externalizing symptoms, and social (social skills and peer relations) and cognitive development (executive functioning, perception, memory, and language). Within the ART group, 164 IVF and 76 ICSI children were compared on the same outcomes. Statistics included analyses of covariates (ANCOVA) with group main effects, group and gender interaction effects, and Bonferroni post hoc tests. MAIN RESULTS AND THE ROLE OF CHANCE: ART and NC children did not differ generally in terms of their internalizing and externalizing symptoms or in the number of social and cognitive developmental problems (Group main effects, P > 0.05), but gender-specific group differences existed. The ART boys showed lower levels of cognitive problems than the NC boys, whereas ART girls showed higher levels of cognitive problems than the NC girls (Group * Gender-interaction effects with Bonferroni post hoc tests on mother-reports, P < 0.01). Further, unlike in the NC group, where boys showed more externalizing symptoms and social and cognitive developmental problems than girls (Group * Gender-interaction effects with Bonferroni post hoc tests for both parents' reports, P < 0.05), gender differences were not found in the ART group. Within the ART group, IVF and ICSI children did not differ in terms of mental health or developmental outcomes, and no significant gender differences emerged. LIMITATIONS, REASONS FOR CAUTION: The information on children's mental health and development was based on parental reports only. The dropout rate between the child's first year and the school age assessments was very high for fathers (57.4%) and substantial for mothers (30.1%), and the participating group was biased for older age of both parents and for better education of the fathers. WIDER IMPLICATIONS OF THE FINDINGS: The findings indicate the importance of considering child gender in learning about multiple developmental outcomes among children born after ART. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Academy of Finland (#11232276), the Emil Aaltonen Foundation, The Family Federation of Finland, Helsinki University Central Hospital Research Funds, and the National Graduate School of Psychology. None of authors has any competing interests to declare. PMID- 26516206 TI - Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnea: a randomized placebo-controlled trial. PMID- 26516207 TI - Amniotic Fluid Stem Cells within Chimeric Kidney Rudiments Differentiate to Functional Podocytes after Transplantation into Mature Rat Kidneys. PMID- 26516208 TI - Functional Human Podocytes Generated in Organoids from Amniotic Fluid Stem Cells. AB - Generating kidney organoids using human stem cells could offer promising prospects for research and therapeutic purposes. However, no cell-based strategy has generated nephrons displaying an intact three-dimensional epithelial filtering barrier. Here, we generated organoids using murine embryonic kidney cells, and documented that these tissues recapitulated the complex three dimensional filtering structure of glomerular slits in vivo and accomplished selective glomerular filtration and tubular reabsorption. Exploiting this technology, we mixed human amniotic fluid stem cells with mouse embryonic kidney cells to establish three-dimensional chimeric organoids that engrafted in vivo and grew to form vascularized glomeruli and tubular structures. Human cells contributed to the formation of glomerular structures, differentiated into podocytes with slit diaphragms, and internalized exogenously infused BSA, thus attaining in vivo degrees of specialization and function unprecedented for donor stem cells. In conclusion, human amniotic fluid stem cell chimeric organoids may offer new paths for studying renal development and human podocyte disease, and for facilitating drug discovery and translational research. PMID- 26516209 TI - ESRD due to Multiple Myeloma in the United States, 2001-2010. AB - Although management of multiple myeloma has changed substantially in the last decade, it is unknown whether the burden of ESRD due to multiple myeloma has changed, or whether survival of patients with multiple myeloma on RRT has improved. Regarding ESRD due to multiple myeloma necessitating RRT in the United States, we evaluated temporal trends between 2001 and 2010 for demography adjusted incidence ratios, relative to rates in 2001-2002, and mortality hazards from RRT initiation, relative to hazards in 2001-2002. In this retrospective cohort study, we used the US Renal Data System database (n=1,069,343), 2001-2010, to identify patients with ESRD due to multiple myeloma treated with RRT (n=12,703). Demography-adjusted incidence ratios of ESRD from multiple myeloma decreased between 2001-2002 and 2009-2010 in the overall population (demography adjusted incidence ratio 0.82; 95% confidence interval, 0.79 to 0.86) and in most demographic subgroups examined. Mortality rates were 86.7, 41.4, and 34.4 per 100 person-years in the first 3 years of RRT, respectively, compared with 32.3, 20.6, and 21.3 in matched controls without multiple myeloma. Unadjusted mortality hazards ratios declined monotonically after 2004 to a value of 0.72; 95% confidence interval, 0.67 to 0.77 in 2009-2010, and declines between 2001-2002 and 2008-2009 were observed (P<0.05) in most demographic subgroups examined. Findings were similar when adjustment was made for demographic characteristics, comorbidity markers, and laboratory test values. These data suggest the incidence of RRT from multiple myeloma in the United States has decreased in the last decade, and clinically meaningful increases in survival have occurred for these patients. PMID- 26516211 TI - NeuroD1 reprograms chromatin and transcription factor landscapes to induce the neuronal program. AB - Cell fate specification relies on the action of critical transcription factors that become available at distinct stages of embryonic development. One such factor is NeuroD1, which is essential for eliciting the neuronal development program and possesses the ability to reprogram other cell types into neurons. Given this capacity, it is important to understand its targets and the mechanism underlying neuronal specification. Here, we show that NeuroD1 directly binds regulatory elements of neuronal genes that are developmentally silenced by epigenetic mechanisms. This targeting is sufficient to initiate events that confer transcriptional competence, including reprogramming of transcription factor landscape, conversion of heterochromatin to euchromatin, and increased chromatin accessibility, indicating potential pioneer factor ability of NeuroD1. The transcriptional induction of neuronal fate genes is maintained via epigenetic memory despite a transient NeuroD1 induction during neurogenesis. NeuroD1 also induces genes involved in the epithelial-to-mesenchymal transition, thereby promoting neuronal migration. Our study not only reveals the NeuroD1-dependent gene regulatory program driving neurogenesis but also increases our understanding of how cell fate specification during development involves a concerted action of transcription factors and epigenetic mechanisms. PMID- 26516210 TI - Long non-coding RNAs in corticogenesis: deciphering the non-coding code of the brain. AB - Evidence on the role of long non-coding (lnc) RNAs has been accumulating over decades, but it has been only recently that advances in sequencing technologies have allowed the field to fully appreciate their abundance and diversity. Despite this, only a handful of lncRNAs have been phenotypically or mechanistically studied. Moreover, novel lncRNAs and new classes of RNAs are being discovered at growing pace, suggesting that this class of molecules may have functions as diverse as protein-coding genes. Interestingly, the brain is the organ where lncRNAs have the most peculiar features including the highest number of lncRNAs that are expressed, proportion of tissue-specific lncRNAs and highest signals of evolutionary conservation. In this work, we critically review the current knowledge about the steps that have led to the identification of the non-coding transcriptome including the general features of lncRNAs in different contexts in terms of both their genomic organisation, evolutionary origin, patterns of expression, and function in the developing and adult mammalian brain. PMID- 26516213 TI - aPTT in children receiving UFH: time for a change? PMID- 26516212 TI - Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson's disease patients. AB - The epigenomic landscape of Parkinson's disease (PD) remains unknown. We performed a genomewide DNA methylation and a transcriptome studies in induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) generated by cell reprogramming of somatic skin cells from patients with monogenic LRRK2-associated PD (L2PD) or sporadic PD (sPD), and healthy subjects. We observed extensive DNA methylation changes in PD DAn, and of RNA expression, which were common in L2PD and sPD. No significant methylation differences were present in parental skin cells, undifferentiated iPSCs nor iPSC-derived neural cultures not-enriched-in DAn. These findings suggest the presence of molecular defects in PD somatic cells which manifest only upon differentiation into the DAn cells targeted in PD. The methylation profile from PD DAn, but not from controls, resembled that of neural cultures not-enriched-in-DAn indicating a failure to fully acquire the epigenetic identity own to healthy DAn in PD. The PD-associated hypermethylation was prominent in gene regulatory regions such as enhancers and was related to the RNA and/or protein downregulation of a network of transcription factors relevant to PD (FOXA1, NR3C1, HNF4A, and FOSL2). Using a patient-specific iPSC-based DAn model, our study provides the first evidence that epigenetic deregulation is associated with monogenic and sporadic PD. PMID- 26516214 TI - FOXP1 inhibits plasma cell differentiation. PMID- 26516215 TI - Mutational landscape and complexity in CLL. PMID- 26516216 TI - Oral NETs: the deadly kiss. PMID- 26516217 TI - Expanding the binding model of DITP. PMID- 26516218 TI - Granulocyte transfusion: questions remain. PMID- 26516219 TI - Infection control in implantation of cardiac implantable electronic devices: current evidence, controversial points, and unresolved issues. AB - A significant increase in the implantation of cardiac implantable electronic devices (CIEDs) is evident over the past years, while there is evidence for a disproportionate increase in CIED-related infections. The cumulative probability of device infection seems to be higher in implantable cardioverter defibrillator and in cardiac resynchronization therapy patients compared with permanent pacemaker patients. Given that more than a half of CIED infections are possibly related to the operative procedure, there is a need for effective periprocedural infection control. However, many of the current recommendations are empirical and not evidence-based, while questions, unresolved issues, and conflicting evidence arise. The perioperative systemic use of antibiotics confers significant benefit in prevention of CIED infections. However, there are no conclusive data regarding the specific value of each agent in different clinical settings, the value of post-operative antibiotic treatment as well as the optimal duration of therapy. The merit of local pocket irrigation with antibiotic and/or antiseptic agents remains unproved. Of note, recent evidence indicates that the application of antibacterial envelopes into the device pocket markedly decreases the infection risk. In addition, limited reports on strict integrated infection control protocols show a dramatic reduction in infection rates in this setting and therefore deserve further attention. Finally, the relative impact of particular factors on the infection risk, including the type of the CIED, patients' individual characteristics and comorbidities, should be further examined since it may facilitate the development of tailored prophylactic interventions for each patient. PMID- 26516220 TI - Introduction. PMID- 26516222 TI - Dedication: Andrew T. Parsa. PMID- 26516221 TI - Vaccination strategies for neuro-oncology. AB - Vaccination against cancer-associated antigens has long held the promise of inducting potent antitumor immunity, targeted cytotoxicity while sparing normal tissues, and long-lasting immunologic memory that can provide surveillance against tumor recurrence. Evaluation of vaccination strategies in preclinical brain tumor models has borne out the capacity for the immune system to effectively and safely eradicate established tumors within the central nervous system. Early phase clinical trials have established the feasibility, safety, and immunogenicity of several vaccine platforms, predominantly in patients with glioblastoma. Definitive demonstration of clinical benefit awaits further study, but initial results have been encouraging. With increased understanding of the stimulatory and regulatory pathways that govern immunologic responses and the enhanced capacity to identify novel antigenic targets using genomic interrogation of tumor cells, vaccination platforms for patients with malignant brain tumors are advancing with increasing personalized complexity and integration into combinatorial treatment paradigms. PMID- 26516223 TI - Immunomodulation: checkpoint blockade etc. AB - The immune microenvironment is considered a major obstacle to generating an effective antitumor immune response. Checkpoint inhibitors manipulate the co stimulatory response between antigen-presenting cells and immune cells-or between the tumor and immune cells-to elicit an antitumor immune response that would have otherwise been suppressed. Checkpoint inhibitors have shown great promise in the clinics, and some inhibitors such as anti-CTLA-4 antibodies and anti-PD-1 antibodies have gained FDA approval for certain tumors. Here we will discuss the current state of checkpoint inhibitors, biomarker strategies, and management of associated toxicities in glioblastoma. PMID- 26516224 TI - Principles of immunology and its nuances in the central nervous system. AB - Cancer immunotherapy represents the biggest change in the cancer treatment landscape in the last several years. Indeed, the clinical successes in several cancer types have generated widespread enthusiasm that immune-based treatments may influence the management of patients with malignant brain tumors as well. A number of promising clinical trials in this area are currently ongoing in neuro oncology, and a wave of additional efforts are sure to follow. However, the basic immunology underlying immunotherapy-and the nuances unique to the immunobiology in the central nervous system-is often not in the daily lexicon of the practicing neuro-oncologist and neurosurgeon. To this end, here we provide a timely and working overview of key principles of fundamental immunology as a pragmatic context for understanding where therapeutic efforts may act in the cellular dynamics of the immune response. Moreover, we review the issues of lymphatic drainage, antigen presentation, and the blood-brain barrier as considerations that are germane to thinking about immunity to tumors arising in the brain. Together, these topics will provide a foundation for the exciting efforts in immune-based treatments that will hopefully provide real benefit to brain tumor patients. PMID- 26516226 TI - Immunosuppressive mechanisms in glioblastoma. AB - Despite maximal surgical and medical therapy, the treatment of glioblastoma remains a seriously vexing problem, with median survival well under 2 years and few long-term survivors. Targeted therapy has yet to produce significant advances in treatment of these lesions in spite of advanced molecular characterization of glioblastoma and glioblastoma cancer stem cells. Recently, immunotherapy has emerged as a promising mode for some of the hardest to treat tumors, including metastatic melanoma. Although immunotherapy has been evaluated in glioblastoma in the past with limited success, better understanding of the failures of these therapies could lead to more successful treatments in the future. Furthermore, there is a persistent challenge for the use of immune therapy to treat glioblastoma secondary to the existence of redundant mechanisms of tumor-mediated immune suppression. Here we will address these mechanisms of immunosuppression in glioblastoma and therapeutic approaches. PMID- 26516225 TI - Immunotherapy for neuro-oncology: the critical rationale for combinatorial therapy. AB - A successful therapeutic paradigm established historically in oncology involves combining agents with potentially complementary mechanisms of antitumor activity into rationally designed regimens. For example, cocktails of cytotoxic agents, which were carefully designed based on mechanisms of action, dose, and scheduling considerations, have led to dramatic improvements in survival including cures for childhood leukemia, Hodgkin's lymphoma, and several other complex cancers. Outcome for glioblastoma, the most common primary malignant CNS cancer, has been more modest, but nonetheless our current standard of care derives from confirmation that combination therapy surpasses single modality therapy. Immunotherapy has recently come of age for medical oncology with exciting therapeutic benefits achieved by several types of agents including vaccines, adoptive T cells, and immune checkpoint inhibitors against several types of cancers. Nonetheless, most benefits are relatively short, while others are durable but are limited to a minority of treated patients. Critical factors limiting efficacy of immunotherapeutics include insufficient immunogenicity and/or inadequate ability to overcome immunosuppressive factors exploited by tumors. The paradigm of rationally designed combinatorial regimens, originally established by cytotoxic therapy for oncology, may also prove relevant for immunotherapy. Realization of the true therapeutic potential of immunotherapy for medical oncology and neuro-oncology patients may require development of combinatorial regimens that optimize immunogenicity and target tumor adaptive immunosuppressive factors. PMID- 26516233 TI - A woman with pelvic pain. PMID- 26516227 TI - Anti-miR-148a regulates platelet FcgammaRIIA signaling and decreases thrombosis in vivo in mice. AB - Fc receptor for IgG IIA (FcgammaRIIA)-mediated platelet activation is essential in heparin-induced thrombocytopenia (HIT) and other immune-mediated thrombocytopenia and thrombosis disorders. There is considerable interindividual variation in platelet FcgammaRIIA activation, the reasons for which remain unclear. We hypothesized that genetic variations between FcgammaRIIA hyper- and hyporesponders regulate FcgammaRIIA-mediated platelet reactivity and influence HIT susceptibility. Using unbiased genome-wide expression profiling, we observed that human hyporesponders to FcgammaRIIA activation showed higher platelet T-cell ubiquitin ligand-2 (TULA-2) mRNA expression than hyperresponders. Silent interfering RNA-mediated knockdown of TULA-2 resulted in hyperphosphorylation of spleen tyrosine kinase following FcgammaRIIA activation in HEL cells. Significantly, we found miR-148a-3p targeted and inhibited both human and mouse TULA-2 mRNA. Inhibition of miR-148a in FcgammaRIIA transgenic mice upregulated the TULA-2 level and reduced FcgammaRIIA- and glycoprotein VI-mediated platelet alphaIIbbeta3 activation and calcium mobilization. Anti-miR-148a also reduced thrombus formation following intravascular platelet activation via FcgammaRIIA. These results show that TULA-2 is a target of miR-148a-3p, and TULA-2 serves as a negative regulator of FcgammaRIIA-mediated platelet activation. This is also the first study to show the effects of in vivo miRNA inhibition on platelet reactivity. Our work suggests that modulating miR-148a expression is a potential therapeutic approach for thrombosis. PMID- 26516234 TI - Differences in cancer dynamics may explain why prostate screening has cut metastatic disease while breast screening has not. PMID- 26516228 TI - Understanding the role of hyperdiploidy in myeloma prognosis: which trisomies really matter? AB - The prognosis of multiple myeloma is mainly dependent upon chromosomal changes. The 2 major abnormalities driving poor outcome are del(17p) and t(4;14). However, the outcome of these high-risk patients is not absolutely uniform, with some patients presenting long survival. We hypothesized that these better outcomes might be related to concomitant "good-risk" chromosomal changes exploring hyperdiploidy. We analyzed a large series of 965 myeloma patients, including 168 patients with t(4;14) and 126 patients with del(17p), using high-throughput single-nucleotide polymorphism arrays after plasma cell sorting. As expected, trisomic chromosomes were highly associated. Using the LASSO model, we found that only chromosome 3, when trisomic, was associated with a longer progression-free survival and that 3 trisomies modulated overall survival (OS) in myeloma patients: trisomies 3 and 5 significantly improved OS, whereas trisomy 21 worsened OS. In patients with t(4;14), trisomies 3 and/or 5 seemed to overcome the poor prognosis. For the first time, using a specific modeling approach, we show that not all trisomies display the same prognostic impact. This finding could be important for routine assessment of prognosis in myeloma, and some high risk patients with a traditional evaluation could in fact be standard-risk patients. PMID- 26516241 TI - Being married is linked to better outcomes from cardiac surgery. PMID- 26516242 TI - A case of presumed post-traumatic pneumocephalus. PMID- 26516243 TI - Anti-interleukin 6 receptor therapy for hyper-IgD syndrome. AB - Hyper-IgD syndrome (HIDS) is a rare, severe hereditary autoinflammatory disease characterised by periodic fevers, elevated serum IgD levels and a wide range of symptoms. Although a few randomised controlled trials have been performed in this disorder, there are no straightforward treatment protocols and none of the potential therapies are registered for this indication. We report a case of a young woman with severe HIDS who failed numerous therapies. Eventually, rational treatment with a monoclonal anti-interleukin 6 receptor antibody was initiated. This therapy resulted in an impressive clinical improvement and reduction in the number of hospital admissions per year. This case report underlines the difficulty of finding a suitable treatment for rare, severe inflammatory diseases. Furthermore, we show that treating patients with targeted therapies may result in clinical benefit for the patient, as well as simultaneously teach us more about the pathophysiology of these rare, relatively understudied diseases. PMID- 26516244 TI - Surviving stroke in an Ebola Treatment Centre. AB - A middle aged woman presented to an Ebola Treatment Centre in West Africa with a 4-day history of fever, fatigue, joint pain and vomiting. She tested positive for Ebola virus disease (EVD) and a standard treatment platform of care was started. On day 3 of her admission, she was found to have suffered a left-sided CVA of unknown aetiology. Treatment was largely supportive within a resource-constrained environment and the added layer of providing care with extensive personal protective equipment, and human resource and safety constraints. The patient was able to clear the EVD and did regain some functional use of her arm and leg. She was discharged on day 15 of her stay, as a survivor of both stroke and Ebola. PMID- 26516245 TI - Iatrogenic Cushing's syndrome and osteoporosis due to an interaction between fluticasone and ritonavir. AB - The advent of highly active antiretroviral therapy for HIV infection dramatically changed the landscape of the disease. Ritonavir, a protease inhibitor (PI) frequently used in low doses to 'boost' the concentrations of other PIs, inhibits the cytochrome P450 3A4 isoenzyme, a common metabolic pathway to multiple drugs, so the potential for drug interactions is not negligible. A 39-year-old man with HIV-1 infection, treated with a ritonavir-boosted PI, was started on fluticasone/salmeterol inhaler and intranasal fluticasone, in 2009, in the setting of asthma and allergic rhinitis. In 2013, he presented with 1-year evolution of symptoms suggesting Cushing's syndrome, and was experiencing recurrent falls. A spine CT showed a vertical L3 fracture and thoracolumbar erosions; a bone density scan revealed severe osteoporosis. Hormonal assays were compatible with hypothalamic-pituitary-adrenal axis suppression, and iatrogenic Cushing's syndrome due to ritonavir-fluticasone interaction was considered. Fluticasone was suspended and oral corticosteroid replacement initiated, with a favourable outcome. PMID- 26516246 TI - Successful use of pregabalin by the rectal route to treat chronic neuropathic pain in a patient with complete intestinal failure. AB - Pregabalin is widely used for treatment of neuropathic pain and is only approved for oral use. This is the first reported case of using pregabalin by the rectal route for treatment in a 70-year-old patient with chronic neuropathic pain and complete intestinal failure. Therapies used in an attempt to manage his chronic pain have included a variety of doses and strengths of opioid preparations and cannabinoids, plus topical and alternative therapies. These were not effective, so it was decided to start a trial of pregabalin administered by the rectal route. Serum levels were measured to assess absorption. Within a few weeks of starting the treatment, the patient had improved pain control and appeared more comfortable and calm. PMID- 26516247 TI - Exploring the possibilities: airspace disease in the postallogeneic haematopoietic stem cell transplant period. AB - A 50-year-old man with a history of myelodysplastic syndrome status postallogeneic haematopoietic stem cell transplantation (HSCT) in July 2013 presented in January 2014 with a 6-week history of worsening shortness of breath and dry cough. Chest imaging revealed scattered groundglass opacities in the upper lobes bilaterally and two areas of focal consolidation on the left side. Bronchoscopy with bronchoalveolar lavage grew methicillin-resistant Staphylococcus aureus and the patient was treated with a prolonged course of vancomycin without improvement in symptoms or oxygenation. Image-guided core biopsy of an area of consolidation revealed histological findings of acute fibrinous and organising pneumonia. The patient was diagnosed with what appeared to be a manifestation of chronic graft-versus-host disease of the lung and started on high-dose corticosteroids with resultant improvement in symptoms. The response was short-lived and the patient expired 2 months later. PMID- 26516248 TI - Open removal of a retained retrohepatic inferior vena cava filter with a residual primary neuroectodermal renal tumoral thrombus. AB - Primary neuroectodermal renal tumours (PNET) are rare and aggressive neoplasms; thrombosis of the inferior vena cava (IVC) is associated with this entity. We report here the case of a 19-year-old man who experienced a new onset of abdominal pain. A CT scan revealed a large left renal mass, perirenal haematoma and IVC thrombosis. Owing to an acute drop in haemoglobin and subsegmentary pulmonary embolism, he underwent emergency selective renal artery angiography and embolisation of bleeding vessels and IVC filter (IVCF) placement. Once stable, he underwent a left radical nephrectomy and IVC thrombectomy; the pathology report confirmed PNET. 6 months later, imaging revealed a residual tumoral thrombus in the IVCF located in the retrohepatic IVC. The patient underwent removal of this device and the thrombus via a right thoracoabdominal approach. He recovered well and at 4 months, he continues his chemotherapy cycles. PMID- 26516249 TI - Anterior and posterior fixation for delayed treatment of posterior atlantoaxial dislocation without fracture. AB - Posterior atlantoaxial dislocation (PAAD) without fracture of the odontoid process is a rare injury. Authors have variously reported closed or open reduction, followed by either anterior or posterior fixation, but there is no consensus on best treatment. We present a particularly unstable case of PAAD. Open reduction through a retropharyngeal approach with odontoidectomy was required for reduction. Anterior fixation with transarticular lag screws was required prior to posterior fixation with pedicle screws. Despite non-compliance with postoperative immobilisation, imaging at 20-month follow-up confirmed solid fusion. The patient is pain-free with a good range of movement of the neck and has returned to a manual job. Our case had a greater degree of instability than was previously reported, which necessitated 360 degrees fixation. This is the first reported case of this treatment strategy, which provided a very stable fixation allowing fusion despite early movement and without causing undue stiffness. PMID- 26516250 TI - A rare case of classical Hodgkin's lymphoma in the setting of a newly diagnosed left atrial myxoma. AB - We report a rare case of left atrial myxoma with concomitant classical Hodgkin's lymphoma in a 36-year-old woman with a non-significant medical history and 4 months of progressively worsening palpitations, dyspnoea on exertion, chest discomfort and fatigue. Outpatient echocardiography revealed functional mitral valve stenosis as a result of a large left atrial cardiac mass. Preoperative thoracic imaging revealed an anterior mediastinal mass with associated lymphadenopathy. The patient underwent successful resection of the anterior mediastinal mass and left atrial mass. Surgical pathology revealed myxoma in the left atrium and classical Hodgkin's lymphoma in the anterior mediastinum. Thus the patient was diagnosed with early-stage classical Hodgkin's lymphoma. This clinical vignette emphasises the importance of a comprehensive diagnostic evaluation in the setting of a newly discovered atrial tumour. PMID- 26516251 TI - Orbital emphysema: nose blowing leading to a blown orbit. AB - A 32-year-old woman with a painful swelling around the right eye few hours after blowing her nose, presented to the accident and emergency department. There was no associated history of facial trauma. Examination revealed a grossly swollen right eye and palpable subcutaneous emphysema. The patient's visual acuity and eye movements were normal. A CT scan of the orbit confirmed orbital emphysema secondary to a fracture of the floor of the orbit into the maxillary sinus, as a result of increased intranasal pressure during nose blowing. The patient was admitted and managed conservatively with antibiotics. She made a full recovery with complete resolution of all her symptoms. A nasal bone fracture was also seen on CT scan and even though the patient could not recall any history of facial trauma, it was an incidental finding. PMID- 26516252 TI - Embolisation of an iatrogenic pulmonary artery pseudoaneurysm. AB - A 62-year-old woman with idiopathic cardiomyopathy and class IIIB/stage C heart failure sustained right pulmonary artery injury from a Swan-Ganz catheter during a pretransplant work up. Postprocedure, it was noted that the patient's segmental pulmonary artery catheter was wedged for an unclear period of time. The patient developed a small volume of blood-tinged sputum and a chest CT revealed a 1.3 cm pseudoaneurysm in the right middle lobe medial segment pulmonary artery and a small area of haemorrhage. The patient underwent pulmonary artery preserving coil embolisation of the pseudoaneurysm to prevent further right heart strain, given an ejection fraction of 20%, which resolved haemoptysis. Imaging studies showed preserved distal outflow and no evidence of residual pseudoaneurysm filling. PMID- 26516253 TI - Macular congenital hypertrophy of retinal pigment epithelium (CHRPE) in a patient with best vitelliform dystrophy (BVD). PMID- 26516254 TI - Patellar tendon enthesitis as initial manifestation of ankylosing spondylitis: an atypical presentation. PMID- 26516255 TI - Rheumatoid lung nodule. PMID- 26516256 TI - Zero tolerance. Period. PMID- 26516258 TI - PLANETARY SCIENCE. Europe's Mars rover to target ancient wetland. PMID- 26516259 TI - NEUROSCIENCE. Lifelong memories may reside in nets around brain cells. PMID- 26516260 TI - PALEONTOLOGY. How some of the world's biggest dinosaurs got that way. PMID- 26516261 TI - BIG DATA. Proposed study would closely track 10,000 New Yorkers. PMID- 26516262 TI - POLAR SCIENCE. Mysterious Antarctic lake will remain out of reach. PMID- 26516263 TI - Q&A. Crisis manager with 194 bosses. PMID- 26516264 TI - Cradle of life. PMID- 26516265 TI - GEOPHYSICS. Pinched topography initiates the critical zone. PMID- 26516266 TI - SUPERCONDUCTIVITY. Randomness rules. PMID- 26516267 TI - DEVELOPMENTAL NEUROSCIENCE. Neurotransmitter-tailored dendritic trees. PMID- 26516268 TI - VIROLOGY. Visualizing trans-infection. PMID- 26516269 TI - ECONOMICS. From the lab to the real world. PMID- 26516270 TI - IMMUNOLOGY. Synthetic immunobiology boosts the IQ of T cells. PMID- 26516271 TI - EVOLUTION. A window into ape evolution. PMID- 26516272 TI - RETROSPECTIVE. Eric Davidson (1937-2015). PMID- 26516273 TI - Hunted carnivores at outsized risk. PMID- 26516274 TI - Repainting citizen science. PMID- 26516275 TI - Policies undermine Brazil's GHG goals. PMID- 26516276 TI - Comment on "Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism". AB - Li et al. (Reports, 30 January, p. 555) reported on a crystal structure for a translocator protein (TSPO) from Rhodobacter sphaeroides in which some of the electron density is modeled as a porphyrin. The analysis of the x-ray data discussed here suggests that this assignment is incorrect. PMID- 26516277 TI - Response to Comment on "Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism". AB - Wang comments that the diffraction data for the structure of the A139T mutant of translocator protein TSPO from Rhodobacter sphaeroides should be used to 1.65 instead of 1.8 angstroms and that the density interpreted as porphyrin and monoolein is better fitted as polyethylene glycol. Although different practices of data processing exist, in this case they do not substantially influence the final map. Additional data are presented supporting the fit of a porphyrin and monooleins. PMID- 26516278 TI - Cycling Li-O2 batteries via LiOH formation and decomposition. AB - The rechargeable aprotic lithium-air (Li-O2) battery is a promising potential technology for next-generation energy storage, but its practical realization still faces many challenges. In contrast to the standard Li-O2 cells, which cycle via the formation of Li2O2, we used a reduced graphene oxide electrode, the additive LiI, and the solvent dimethoxyethane to reversibly form and remove crystalline LiOH with particle sizes larger than 15 micrometers during discharge and charge. This leads to high specific capacities, excellent energy efficiency (93.2%) with a voltage gap of only 0.2 volt, and impressive rechargeability. The cells tolerate high concentrations of water, water being the dominant proton source for the LiOH; together with LiI, it has a decisive impact on the chemical nature of the discharge product and on battery performance. PMID- 26516279 TI - Geophysical imaging reveals topographic stress control of bedrock weathering. AB - Bedrock fracture systems facilitate weathering, allowing fresh mineral surfaces to interact with corrosive waters and biota from Earth's surface, while simultaneously promoting drainage of chemically equilibrated fluids. We show that topographic perturbations to regional stress fields explain bedrock fracture distributions, as revealed by seismic velocity and electrical resistivity surveys from three landscapes. The base of the fracture-rich zone mirrors surface topography where the ratio of horizontal compressive tectonic stresses to near surface gravitational stresses is relatively large, and it parallels the surface topography where the ratio is relatively small. Three-dimensional stress calculations predict these results, suggesting that tectonic stresses interact with topography to influence bedrock disaggregation, groundwater flow, chemical weathering, and the depth of the "critical zone" in which many biogeochemical processes occur. PMID- 26516280 TI - Mobile metallic domain walls in an all-in-all-out magnetic insulator. AB - Magnetic domain walls are boundaries between regions with different configurations of the same magnetic order. In a magnetic insulator, where the magnetic order is tied to its bulk insulating property, it has been postulated that electrical properties are drastically different along the domain walls, where the order is inevitably disturbed. Here we report the discovery of highly conductive magnetic domain walls in a magnetic insulator, Nd2Ir2O7, that has an unusual all-in-all-out magnetic order, via transport and spatially resolved microwave impedance microscopy. The domain walls have a virtually temperature independent sheet resistance of ~1 kilohm per square, show smooth morphology with no preferred orientation, are free from pinning by disorders, and have strong thermal and magnetic field responses that agree with expectations for all-in-all out magnetic order. PMID- 26516281 TI - Peer effects on worker output in the laboratory generalize to the field. AB - We compare estimates of peer effects on worker output in laboratory experiments and field studies from naturally occurring environments. The mean study-level estimate of a change in a worker's productivity in response to an increase in a co-worker's productivity (gamma) is gamma = 0.12 (SE = 0.03, n(studies) = 34), with a between-study standard deviation tau = 0.16. The mean estimated gamma values are close between laboratory and field studies (gamma(lab) - gamma(field) = 0.04, P = 0.55, n(lab) = 11, n(field) = 23), as are estimates of between-study variance tau(2) (tau(lab)(2) - tau(field)(2) = -0.003, P = 0.89). The small mean difference between laboratory and field estimates holds even after controlling for sample characteristics such as incentive schemes and work complexity (gamma(lab) - gamma(field) = 0.03, P = 0.62, n(samples) = 46). Laboratory experiments generalize quantitatively in that they provide an accurate description of the mean and variance of productivity spillovers. PMID- 26516282 TI - Gate control of mechanical itch by a subpopulation of spinal cord interneurons. AB - Light mechanical stimulation of hairy skin can induce a form of itch known as mechanical itch. This itch sensation is normally suppressed by inputs from mechanoreceptors; however, in many forms of chronic itch, including alloknesis, this gating mechanism is lost. Here we demonstrate that a population of spinal inhibitory interneurons that are defined by the expression of neuropeptide Y::Cre (NPY::Cre) act to gate mechanical itch. Mice in which dorsal NPY::Cre-derived neurons are selectively ablated or silenced develop mechanical itch without an increase in sensitivity to chemical itch or pain. This chronic itch state is histamine-independent and is transmitted independently of neurons that express the gastrin-releasing peptide receptor. Thus, our studies reveal a dedicated spinal cord inhibitory pathway that gates the transmission of mechanical itch. PMID- 26516284 TI - Going where the science matters. PMID- 26516283 TI - Disease tolerance mediated by microbiome E. coli involves inflammasome and IGF-1 signaling. AB - Infections and inflammation can lead to cachexia and wasting of skeletal muscle and fat tissue by as yet poorly understood mechanisms. We observed that gut colonization of mice by a strain of Escherichia coli prevents wasting triggered by infections or physical damage to the intestine. During intestinal infection with the pathogen Salmonella Typhimurium or pneumonic infection with Burkholderia thailandensis, the presence of this E. coli did not alter changes in host metabolism, caloric uptake, or inflammation but instead sustained signaling of the insulin-like growth factor 1/phosphatidylinositol 3-kinase/AKT pathway in skeletal muscle, which is required for prevention of muscle wasting. This effect was dependent on engagement of the NLRC4 inflammasome. Therefore, this commensal promotes tolerance to diverse diseases. PMID- 26516285 TI - Miocene small-bodied ape from Eurasia sheds light on hominoid evolution. AB - Miocene small-bodied anthropoid primates from Africa and Eurasia are generally considered to precede the divergence between the two groups of extant catarrhines hominoids (apes and humans) and Old World monkeys-and are thus viewed as more primitive than the stem ape Proconsul. Here we describe Pliobates cataloniae gen. et sp. nov., a small-bodied (4 to 5 kilograms) primate from the Iberian Miocene (11.6 million years ago) that displays a mosaic of primitive characteristics coupled with multiple cranial and postcranial shared derived features of extant hominoids. Our cladistic analyses show that Pliobates is a stem hominoid that is more derived than previously described small catarrhines and Proconsul. This forces us to reevaluate the role played by small-bodied catarrhines in ape evolution and provides key insight into the last common ancestor of hylobatids (gibbons) and hominids (great apes and humans). PMID- 26516286 TI - The realities of risk-cost-benefit analysis. AB - Formal analyses can be valuable aids to decision-making if their limits are understood. Those limits arise from the two forms of subjectivity found in all analyses: ethical judgments, made when setting the terms of an analysis, and scientific judgments, made when conducting it. As formal analysis has assumed a larger role in policy decisions, awareness of those judgments has grown, as have methods for making them. The present review traces these developments, using examples that illustrate the issues that arise when designing, executing, and interpreting analyses. It concludes with lessons learned from the science and practice of analysis. One common thread in these lessons is the importance of collaborative processes, whereby analysts and decision-makers educate one another about their respective needs and capabilities. PMID- 26516287 TI - Erratum for the Report "Base triplet stepping by the Rad51/RecA family of recombinases" by J. Y. Lee, T. Terakawa, Z. Qi, J. B. Steinfeld, S. Redding, Y. Kwon, W. A. Gaines, W. Zhao, P. Sung, E. C. Greene. PMID- 26516288 TI - Breast parenchymal signal enhancement ratio at preoperative magnetic resonance imaging: association with early recurrence in triple-negative breast cancer patients. AB - BACKGROUND: The signal enhancement ratio (SER) of surrounding non-tumor parenchyma at breast magnetic resonance imaging (MRI) can be helpful in breast cancer patients, but has not been investigated in patients with triple negative breast cancer (TNBC). PURPOSE: To investigate the association between background parenchymal SER around the tumor on preoperative dynamic contrast-enhanced MRI with recurrence-free survival in patients with TNBC. MATERIAL AND METHODS: Between April 2012 and May 2013, 71 TNBC patients who underwent preoperative MRI were included. SER values were calculated from regions of interest placed in the breast parenchyma around the tumor. Cox proportional hazards models were used to determine associations between MRI variables, clinical-pathologic variables, and recurrence-free survival. RESULTS: Recurrence occurred in 8.5% (6/71) of patients. At univariate analysis, a higher SER around the tumor, larger tumor size, lymphovascular invasion, lymph node metastasis, receipt of neoadjuvant chemotherapy, receipt of total mastectomy, and not receiving adjuvant chemotherapy were associated with worse recurrence-free survival. At multivariate analysis of preoperative variables, a higher SER around the tumor was independently associated with worse recurrence-free survival (hazard ratio [HR] = 7.072, P = 0.003 for SER1; HR = 6.268, P = 0.006 for SER2; HR = 3.004, P = 0.039 for SER3). CONCLUSION: Higher SER around the tumor at preoperative dynamic contrast-enhanced MRI is an independent predictor for recurrence in TNBC patients. PMID- 26516289 TI - Strategy improvement for concurrent reachability and turn-based stochastic safety games. AB - We consider concurrent games played on graphs. At every round of a game, each player simultaneously and independently selects a move; the moves jointly determine the transition to a successor state. Two basic objectives are the safety objective to stay forever in a given set of states, and its dual, the reachability objective to reach a given set of states. First, we present a simple proof of the fact that in concurrent reachability games, for all [Formula: see text], memoryless epsilon-optimal strategies exist. A memoryless strategy is independent of the history of plays, and an epsilon-optimal strategy achieves the objective with probability within epsilon of the value of the game. In contrast to previous proofs of this fact, our proof is more elementary and more combinatorial. Second, we present a strategy-improvement (a.k.a. policy iteration) algorithm for concurrent games with reachability objectives. Finally, we present a strategy-improvement algorithm for turn-based stochastic games (where each player selects moves in turns) with safety objectives. Our algorithms yield sequences of player-1 strategies which ensure probabilities of winning that converge monotonically (from below) to the value of the game. PMID- 26516290 TI - Rigorously modeling self-stabilizing fault-tolerant circuits: An ultra-robust clocking scheme for systems-on-chip. AB - We present the first implementation of a distributed clock generation scheme for Systems-on-Chip that recovers from an unbounded number of arbitrary transient faults despite a large number of arbitrary permanent faults. We devise self stabilizing hardware building blocks and a hybrid synchronous/asynchronous state machine enabling metastability-free transitions of the algorithm's states. We provide a comprehensive modeling approach that permits to prove, given correctness of the constructed low-level building blocks, the high-level properties of the synchronization algorithm (which have been established in a more abstract model). We believe this approach to be of interest in its own right, since this is the first technique permitting to mathematically verify, at manageable complexity, high-level properties of a fault-prone system in terms of its very basic components. We evaluate a prototype implementation, which has been designed in VHDL, using the Petrify tool in conjunction with some extensions, and synthesized for an Altera Cyclone FPGA. PMID- 26516291 TI - A Practical, Multi-gram Synthesis of (+/-)-Herbindole A, (+/-)-Herbindole B, and (+/-)-Herbindole C from a Common Intermediate via 6,7-Indole Aryne Cycloaddition and Pd(0)-Catalyzed Cross-Coupling Reactions. AB - A practical, multi-gram 10-step synthesis of racemic herbindole A, B, and C from a common intermediate is described. The key step features a remarkably regioselective C-7 metal-halogen exchange and elimination from a Bartoli generated N-t-butyldimethylsilyl-4,6,7-tribromo-5-methylindole scaffold to afford the 6,7-indole aryne. Cycloaddition with cyclopentadiene, oxidative cleavage, and Fujimoto reduction gave a common intermediate from which all three herbindoles were readily derived. A final Pd(0)-catalyzed Negishi and Stille cross-coupling reaction at the C-4 bromide afforded each of the herbindoles on a multigram scale. PMID- 26516292 TI - Imidoyl dichlorides as new reagents for the rapid formation of 2 aminobenzimidazoles and related azoles. AB - The development of a reagent for the efficient synthesis of 5- and 6-membered azoles at room temperature is proposed. A variety of substituted 2 aminobenzimidazoles are synthesized in good to excellent yields. The ability to incorporate various protecting groups makes the imidoyl dichloride reagent amenable to a large number of syntheses. The reagent is applied to the total synthesis of the 2-aminobenzimidazole containing carcinogen, 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (PhIP), from 2-chloro-3-nitropyridine in >60 % yield in 6 steps. PMID- 26516293 TI - Analysis of a Study of Lead Wheel Weight Deposition and Abrasion in New Jersey. AB - This paper analyzes the implications for children's health of shortcomings in the methods and results of a study of lead in the environment, "Quantity of Lead Released to the Environment in New Jersey in the Form of Motor Vehicle Wheel Weights," by the New Jersey Department of Environmental Protection (Aucott and Caldarelli, Water, Air, & Soil Pollution, 223, 1743-1752, 2012). The study significantly understates the amount of lead deposited in New Jersey streets as 12 metric tons per year and incorrectly concludes that only 40 kg per year of the lead from wheel weights is abraded into small particles. The 2012 New Jersey Department of Environmental Protection (NJDEP) study misleads regulators and the public into believing that little toxic particulate lead from abraded wheel weights occurs on the streets of New Jersey and by implication that little occurs elsewhere in the United States, thus minimizing the potential health risk that lead wheel weights may have to our nation's children and indeed all of us. PMID- 26516294 TI - Snezna jama (Slovenia): Interdisciplinary dating of cave sediments and implication for landscape evolution. AB - Caves are important markers of surface evolution, since they are, as a general rule, linked with ancient valley bottoms by their springs. However, caves can only be dated indirectly by means of the sediments they contain. If the sediment is older than common dating methods, one has to use multiple dating approaches in order to get meaningful results. U/Th dating, palaeomagnetic analysis of flowstone and sediment profiles, cosmogenic dating of quartz pebbles, and mammalian dating allowed a robust estimate of speleogenesis, sediment deposition, climatic change at the surface, and uplift history on the Periadriatic fault line during the Plio-Pleistocene. Our dates indicate that Snezna jama was formed in the (Upper) Miocene, received its sedimentary deposits during the Pliocene in a rather low-lying, hilly landscape, and became inactive due to uplift along the Periadriatic and Sava faults and climatic changes at the beginning of the Quaternary. Although it is only a single cave, the information contained within it makes it an important site of the Southern Alps. PMID- 26516295 TI - Continuous, real-time bioimaging of chemical bioavailability and toxicology using autonomously bioluminescent human cell lines. AB - Bioluminescent imaging is an emerging biomedical surveillance strategy that uses external cameras to detect in vivo light generated in small animal models of human physiology or in vitro light generated in tissue culture or tissue scaffold mimics of human anatomy. The most widely utilized of reporters is the firefly luciferase (luc) gene; however, it generates light only upon addition of a chemical substrate, thus only generating intermittent single time point data snapshots. To overcome this disadvantage, we have demonstrated substrate independent bioluminescent imaging using an optimized bacterial bioluminescence (lux) system. The lux reporter produces bioluminescence autonomously using components found naturally within the cell, thereby allowing imaging to occur continuously and in real-time over the lifetime of the host. We have validated this technology in human cells with demonstrated chemical toxicological profiling against exotoxin exposures at signal strengths comparable to existing luc systems (~1.33 * 107 photons/second). As a proof-in-principle demonstration, we have engineered breast carcinoma cells to express bioluminescence for real-time screening of endocrine disrupting chemicals and validated detection of 17beta estradiol (EC50 = ~ 10 pM). These and other applications of this new reporter technology will be discussed as potential new pathways towards improved models of target chemical bioavailability, toxicology, efficacy, and human safety. PMID- 26516296 TI - Rapid modulation of spoken word recognition by visual primes. AB - In a masked cross-modal priming experiment with ERP recordings, spoken Japanese words were primed with words written in one of the two syllabary scripts of Japanese. An early priming effect, peaking at around 200ms after onset of the spoken word target, was seen in left lateral electrode sites for Katakana primes, and later effects were seen for both Hiragana and Katakana primes on the N400 ERP component. The early effect is thought to reflect the efficiency with which words in Katakana script make contact with sublexical phonological representations involved in spoken language comprehension, due to the particular way this script is used by Japanese readers. This demonstrates fast-acting influences of visual primes on the processing of auditory target words, and suggests that briefly presented visual primes can influence sublexical processing of auditory target words. The later N400 priming effects, on the other hand, most likely reflect cross-modal influences on activity at the level of whole-word phonology and semantics. PMID- 26516297 TI - Perception of chemesthetic stimuli in groups who differ by food involvement and culinary experience. AB - In the English language, there is generally a limited lexicon when referring to the sensations elicited by chemesthetic stimuli like capsaicin, allyl isothiocyanate, and eugenol, the orally irritating compounds found in chiles, wasabi, and cloves, respectively. Elsewhere, experts and novices have been shown to use language differently, with experts using more precise language. Here, we compare perceptual maps and word usage across three cohorts: experts with formal culinary education, naive individuals with high Food Involvement Scale (FIS) scores, and naive individuals with low FIS scores. We hypothesized that increased experience with foods, whether through informal experiential learning or formal culinary education, would have a significant influence on the perceptual maps generated from a sorting task conducted with chemesthetic stimuli, as well as on language use in a descriptive follow-up task to this sorting task. The low- and highFIS non-expert cohorts generated significantly similar maps, though in other respects the highFIS cohort was an intermediate between the lowFIS and expert cohorts. The highFIS and expert cohorts generated more attributes but used language more idiosyncratically than the lowFIS group. Overall, the results from the expert group with formal culinary education differed from the two naive cohorts both in the perceptual map generated using MDS as well as the mean number of attributes generated. Present data suggest that both formal education and informal experiential learning result in lexical development, but the level and type of learning can have a significant influence on language use and the approach to a sorting task. PMID- 26516298 TI - 'A virtue beyond all medicine': The Hanged Man's Hand, Gallows Tradition and Healing in Eighteenth- and Nineteenth-century England. AB - From the eighteenth century through to the abolition of public executions in England in 1868, the touch of a freshly hanged man's hand was sought after to cure a variety of swellings, wens in particular. While the healing properties of corpse hands in general were acknowledged and experimented with in early modern medicine, the gallows cure achieved prominence during the second half of the eighteenth century. What was it about the hanged man's hand (and it always was a male appendage) that gave it such potency? While frequently denounced as a disgusting 'superstition' in the press, this popular medical practice was inadvertently legitimised and institutionalised by the authorities through changes in execution procedure. PMID- 26516299 TI - 'The bones tell a story the child is too young or too frightened to tell': The Battered Child Syndrome in Post-war Britain and America. AB - This article traces the emergence of child abuse as a medical concern in post-war Britain and America. In the early 1960s American paediatricians and radiologists defined the 'battered child syndrome' to characterise infants subjected to serious physical abuse. In the British context, paediatricians and radiologists, but also dermatologists and ophthalmologists, drew upon this work and sought to identify clear diagnostic signs of child maltreatment. For a time, the x-ray seemed to provide a reliable and objective visualisation of child maltreatment. By 1970, however, medical professionals began to invite social workers and policy makers to aid them in the diagnosis and management of child abuse. Discourse around the 'battered child syndrome', specifically, faded away, whilst concerns around child abuse grew. The battered child syndrome was a brief phenomenon of the 1960s, examination of which can inform the histories of medical authority, radiology and secrecy and privacy in the post-war period. PMID- 26516300 TI - An Analytical Approach towards Passive Ferromagnetic Shimming Design for a High Resolution NMR Magnet. AB - This paper presents a warm bore ferromagnetic shimming design for a high resolution NMR magnet based on spherical harmonic coefficient reduction techniques. The passive ferromagnetic shimming along with the active shimming is a critically important step to improve magnetic field homogeneity for an NMR Magnet. Here, the technique is applied to an NMR magnet already designed and built at the MIT's Francis Bitter Magnet Lab. Based on the actual magnetic field measurement data, a total of twenty-two low order spherical harmonic coefficients is derived. Another set of spherical harmonic coefficients was calculated for iron pieces attached to a 54 mm diameter and 72 mm high tube. To improve the homogeneity of the magnet, a multiple objective linear programming method was applied to minimize unwanted spherical harmonic coefficients. A ferromagnetic shimming set with seventy-four iron pieces was presented. Analytical comparisons are made for the expected magnetic field after Ferromagnetic shimming. The theoretically reconstructed magnetic field plot after ferromagnetic shimming has shown that the magnetic field homogeneity was significantly improved. PMID- 26516301 TI - Mining the Breast Cancer Proteome for Predictors of Drug Sensitivity. AB - Approximately 20 drugs have been approved by the FDA for breast cancer treatment, yet predictive biomarkers are known for only a few of these. The identification of additional biomarkers would be useful both for drugs currently approved for breast cancer treatment and for new drug development. Using glycoprotein expression data collected via mass spectrometry, in conjunction with statistical models constructed by elastic net or lasso regression, we modeled quantitatively the responses of breast cancer cell lines to ~90 drugs. Lasso and elastic net regression identified HER2 as a predictor protein for lapatinib, afatinib, gefitinib and erlotinib, which target HER2 or the EGF receptor, thus providing an internal control for the approach. Two additional protein datasets and two RNA datasets were also tested as sources of predictor proteins for modeling drug sensitivity. Protein expression measured by mass spectrometry gave models with higher coefficients of determination than did reverse phase protein array (RPPA) predictor data. Further, cross validation of the elastic net models shows that, for many drugs, the prediction error is lower when the predictor data is from proteins, rather than mRNA expression measured on microarrays. Drugs that could be modeled effectively include PI3K inhibitors, Akt inhibitors, paclitaxel and docetaxel, rapamycin, everolimus and temsirolimus, gemcitabine and vinorelbine. Strikingly, this modeling approach with protein predictors often succeeds for drugs that are targeted agents, even when the nominal target is not in the dataset. PMID- 26516302 TI - Baryon chiral perturbation theory extended beyond the low-energy region. AB - We consider an extension of the one-nucleon sector of baryon chiral perturbation theory beyond the low-energy region. The applicability of this approach for higher energies is restricted to small scattering angles, i.e. the kinematical region, where the quark structure of hadrons cannot be resolved. The main idea is to re-arrange the low-energy effective Lagrangian according to a new power counting and to exploit the freedom of the choice of the renormalization condition for loop diagrams. We generalize the extended on-mass-shell scheme for the one-nucleon sector of baryon chiral perturbation theory by choosing a sliding scale, that is, we expand the physical amplitudes around kinematical points beyond the threshold. This requires the introduction of complex-valued renormalized coupling constants, which can be either extracted from experimental data, or calculated using the renormalization group evolution of coupling constants fixed in threshold region. PMID- 26516303 TI - Notch as a Possible Cell Differentiation Factor in Pleomorphic Adenomas. AB - The expression of Notch in 30 cases of pleomorphic adenoma was examined by immunohistochemistry. Comparing the results of our study with previous literatures, from the partial CK7 expression and substantial Notch expression in ductal epithelial cells as well as the Notch expression in solid tumor nests, it can be inferred that Notch is involved in cell differentiation. CK13 expression was observed in cells undergoing squamous metaplasia and Notch expression was seen in the nucleus of basal and squamous cells. The intense Notch expression in basal cells and weak expression in squamous cells suggests that Notch is involved in the differentiation from basal to squamous cell. Moreover, the loss of nuclear expression on the inner layer would signify that differentiation is about to end or has been terminated. Notch was expressed in the cytoplasm of cartilage cells and in the cell membrane of mucous cells but not in the nucleus indicating that differentiation has been concluded. Notch involvement is suspected in cell differentiation in areas showing ductal structures and squamous metaplasia. In summary, Notch is involved in cell differentiation of ductal cells in PA. Nuclear expression was shown in tumor cells in solid nests and surrounding structures. Moreover, Notch is expressed by basal cells undergoing squamous metaplasia suggesting the participation of Notch in cell differentiation in PA. PMID- 26516304 TI - Serum Immune Proteins in Moderate and Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. AB - Immunological dysregulation is present in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), with recent studies also highlighting the importance of examining symptom severity. This research addressed this relationship between CFS/ME severity subgroups, assessing serum immunoglobulins and serum cytokines in severe and moderate CFS/ME patients. Participants included healthy controls (n= 22), moderately (n = 22) and severely (n=19) affected CFS/ME patients. The 1994 Fukuda Criteria defined CFS/ME and severity scales confirmed mobile and housebound CFS/ME patients as moderate and severe respectively. IL-1beta was significantly reduced in severe compared with moderate CFS/ME patients. IL-6 was significantly decreased in moderate CFS/ME patients compared with healthy controls and severe CFS/ME patients. RANTES was significantly increased in moderate CFS/ME patients compared to severe CFS/ME patients. Serum IL-7 and IL-8 were significantly higher in the severe CFS/ME group compared with healthy controls and moderate CFS/ME patients. IFN-gamma was significantly increased in severe CFS/ME patients compared with moderately affected patients. This was the first study to show cytokine variation in moderate and severe CFS/ME patients, with significant differences shown between CFS/ME symptom severity groups. This research suggests that distinguishing severity subgroups in CFS/ME research settings may allow for a more stringent analysis of the heterogeneous and otherwise inconsistent illness. PMID- 26516305 TI - Progesterone Inhibits Leptin-Induced Invasiveness of BeWo Cells. AB - BACKGROUND: This study investigated the roles of progesterone and leptin in placenta invasion, which is closely related to pregnancy prognosis. We examined the effects of leptin and progesterone on the invasion of BeWo cells, a human trophoblastic cell line, and the effect of concurrent treatment. METHODS: Cells were treated with leptin (0, 5, 50, or 500 ng/mL) or progesterone (0, 2, 20, or 200 uM) and cultured in an invasion assay. Cells treated with 500 ng/mL leptin were also treated with progesterone (0, 2, 20, or 200 uM) in the invasion assay for 48 h. The number of cells that invaded the lower surface was counted in five randomly chosen fields using a light microscope with a 200* objective. The mRNA expression levels of MMP-9, TIMP1, TIMP2, and E-cadherin were detected by semi quantitative PCR. RESULTS: Invasion of BeWo cells was promoted by leptin and influenced by both leptin concentration and treatment duration. Invasion was most effective at 500 ng/mL leptin and 48 h culture. Leptin-induced invasiveness was suppressed by progesterone in a dose-dependent manner. Leptin significantly decreased the expression levels of TIMP1 and E-cadherin, whereas progesterone significantly decreased expression of MMP-9 and significantly increased levels of TIMP1, TIMP2, and E-cadherin. CONCLUSIONS: Leptin promotes invasion of BeWo cells, and progesterone suppresses leptin-induced invasion by regulating the expressions of MMP-9, TIMP1, TIMP2, and E-cadherin. The balance between leptin and progesterone may play an important role in human placenta formation during early pregnancy. PMID- 26516306 TI - Current Status of the Application of Intracranial Venous Sinus Stenting. AB - The intracranial venous sinus is an important component of vascular disease. Many diseases involve the venous sinus and are accompanied by venous sinus stenosis (VSS), which leads to increased venous pressure and high intracranial pressure. Recent research has focused on stenting as a treatment for VSS related to these diseases. However, a systematic understanding of venous sinus stenting (VS Stenting) is lacking. Herein, the literature on idiopathic intracranial hypertension (IIH), venous pulsatile tinnitus, sinus thrombosis, high draining venous pressure in dural arteriovenous fistula (AVF) and arteriovenous malformation (AVM), and tumor-caused VSS was reviewed and analyzed to summarize experiences with VS-Stenting as a treatment. The literature review showed that satisfactory therapeutic effects can be achieved through stent angioplasty. Thus, the present study suggests that selective stent release in the venous sinus can effectively treat these diseases and provide new possibilities for treating intracranial vascular disease. PMID- 26516307 TI - Single Nucleotide Polymorphisms in IL-10, IL-12p40, and IL-13 Genes and Susceptibility to Glioma. AB - Glioma is one of the most aggressive and most common tumors of the central nervous system (CNS) in humans. The exact causes of glioma are not well known, but evidence suggests the involvement of genetic factors in addition to environmental risk factors. The present study aimed to determine whether polymorphisms in IL-10-1082A/G, IL-12p40 1188C/A, and IL-13+2044G/A (rs20541) are associated with the incidence of glioma in Iraqi patients. Ninety-six patients with different grades of glioma and 40 apparently healthy individuals were recruited. A blood sample and genomic DNA were collected from all subjects. The amplification refractory mutation system and sequence-specific primer polymerase chain reaction (PCR) were used for genotyping of IL-10-1082A/G and IL-12p40 1188C/A, respectively; whereas, the IL-13+2044G/A was detected by DNA sequencing after amplification of the genes by PCR. All SNPs were within Hardy-Weinberg equilibrium and each appeared in three genotypes in patients and controls. In IL 10-1082A/G, these genotypes frequencies were AA (75%), AG (22.93%) and GG (2.07%) in patients as compared to similar frequencies (62.5%), (27.5%) and (10%) respectively, in controls. The variant IL-12p40 1188C/A genotype was AA (72.92%), AC (23.96%), and CC (3.13%%) in patients as compared to 65%, 30%, and 5%, respectively, in controls. The frequencies of IL-13+2044G/A genotypes (GG, GA, and AA) were 89.58%, 9.37%, and 1.04% among patients versus 47.5%, 32.5% and 20%, respectively, among controls. These results suggest a protective role of mutant alleles G and A in IL-10-1082A/G and IL-13+2044G/A against gliomas. Further studies with more rigorous parameter designs will be needed to confirm the current findings. PMID- 26516308 TI - A Randomized, Double-blind, Non-inferiority Trial of Magnesium Sulphate versus Dexamethasone for Prevention of Postoperative Sore Throat after Lumbar Spinal Surgery in the Prone Position. AB - BACKGROUND: Postoperative sore throat (POST) is a frequent complication of tracheal intubation, particularly after surgery in the prone position. We designed this study to validate the non-inferiority of magnesium sulphate against dexamethasone for prevention of POST after lumbar spinal surgery. METHODS: One hundred and forty-six patients were randomly allocated to receive either magnesium or dexamethasone. Before anesthetic induction, the magnesium group (n = 73) received magnesium sulphate 30 mg/kg followed by 10 mg/kg/h by continuous infusion until the end of surgery. The dexamethasone group (n = 73) received dexamethasone 8 mg. The primary endpoint was the overall incidence of POST, which was assessed serially over 48 hr postoperatively. The predefined margin of non inferiority for magnesium against dexamethasone was 15%. RESULTS: Overall incidences of POST at rest (50.7% versus 49.3% in the magnesium and dexamethasone group, respectively, p = 0.869) and swallowing (65.8% versus 61.6% in the magnesium and dexamethasone group, respectively, p = 0.606) were not different between the groups. The upper limit of the 90% confidence interval, which must be lower than the predefined margin of non-inferiority to prove the non-inferiority of magnesium sulphate against dexamethasone, for at rest and swallowing were 14.97% (p = 0.0496) and 17.19% (p = 0.0854), respectively. The incidences and severities of POST and hoarseness were also not different between the groups throughout the study period. CONCLUSIONS: Prophylactic magnesium sulphate appears to be non-inferior to dexamethasone for the prevention of POST at rest in patients undergoing lumbar spinal surgery in the prone position. PMID- 26516309 TI - Lithium Chloride Promotes Apoptosis in Human Leukemia NB4 Cells by Inhibiting Glycogen Synthase Kinase-3 Beta. AB - Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML). With the application of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), APL becomes one of best prognosis of leukemia. However, ATRA and ATO are not effective against all APLs. Therefore, a new strategy for APL treatment is necessary. Here, we investigated whether lithium chloride (LiCl), a drug used for the treatment of mental illness, could promote apoptosis in human leukemia NB4 cells. We observed that treatment with LiCl significantly accelerated apoptosis in NB4 cells and led to cell cycle arrest at G2/M phase. Moreover, LiCl significantly increased the level of Ser9-phosphorylated glycogen synthase kinase 3beta(p-GSK-3beta), and decreased the level of Akt1 protein in a dose-dependent manner. In addition, LiCl inhibition of c-Myc also enhanced cell death with a concomitant increase in beta-catnin. Taken together, these findings demonstrated that LiCl promoted apoptosis in NB4 cells through the Akt signaling pathway and that G2/M phase arrest was induced by increase of p-GSK-3beta(S9). PMID- 26516311 TI - Efficacy of a Novel Fenugreek Seed Extract (Trigonella foenum-graecum, Furocyst) in Polycystic Ovary Syndrome (PCOS). AB - Polycystic ovary syndrome (PCOS) is one of the most prevalent hormonal disorders among women of reproductive age causing irregular menstrual cycles, excessive body or facial hair, miscarriage and infertility. The latter being a most common PCOS symptoms. Because the symptoms are seemingly unrelated to one another, PCOS is often overlooked and undiagnosed. The present study is an open label, one-arm, non-randomized, post-marketing surveillance study in 50 premenopausal women (18 45 years, BMI<42) diagnosed with PCOS using a novel Trigonella foenum-graecum seed extract (fenugreek seed extract, Furocyst, 2 capsules of 500 mg each/day) extract, enriched in approximately 40% furostanolic saponins, over a period of 90 consecutive days. The study was conducted to determine its efficacy on the reduction of ovarian volume and the number of ovarian cysts. Ethical committee approval was obtained for this study. Furocyst treatment caused significant reduction in ovary volume. Approximately 46% of study population showed reduction in cyst size, while 36% of subjects showed complete dissolution of cyst. It is important to mention that 71% of subjects reported the return of regular menstrual cycle on completion of the treatment and 12% of subjects subsequently became pregnant. Overall, 94% of patients benefitted from the regimen. Significant increases in luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels were observed compared to the baseline values. Extensive blood chemistry, hematological and biochemical assays demonstrated the broad spectrum safety. Furocyst caused significant decrease in both ovarian volume and the number of ovarian cysts. Serum ALT, BUN and CK were assessed to demonstrate the broad-spectrum safety of Furocyst. No significant adverse effects were observed. In summary, Furocyst was efficacious in ameliorating the symptoms of PCOS. PMID- 26516312 TI - Assessment of Psychopatologic Traits in a Group of Patients with Adult Chronic Periodontitis: Study on 108 Cases and Analysis of Compliance during and after Periodontal Treatment. AB - OBJECTIVES: Although there is nowadays wide agreement on bacteria being the main etiologic agents of periodontal disease, their sole presence cannot damage periodontal tissues in all subjects. This suggests that an individual response and an adaptation to a certain quantity of bacterial biofilm can occur without the disease progressing and vice versa. Depression, stress and anxiety have not been confirmed yet as risk conditions but, in some observational studies, they have been identified as potential risk factors of periodontal disease. The current study aims at investigating the role which these psychological disorder have in the onset and progression of advanced stage periodontitis. MATERIALS AND METHODS: The case selection was carried out by means of clinical and radiological periodontal assessment involving a total of 108 subjects, both male and female, aged between 24 and 67. Patients were then divided in two groups of 54 patients each: the first group included patients with severe periodontal disease, the second group was formed by periodontally healthy subjects. Clinical assessment was performed by a sole examiner who selected and divided periodontopathic patients from non-periodontopathic ones. From the current study were excluded: patients with systemic pathologies; smokers; patients taking antidepressant drugs; pregnant women. RESULTS: For what concerns depression, in the group of periodontopathic patients it was found that the 62.5% of them were depressed, against the 38.86% in the group of periodontally healthy subjects. For the other two psychological conditions taken into consideration, anxiety and stress, it emerged a different percentage of subjects with anxiety in the periodontal group (31.48%) against healthy controls (20.37%). CONCLUSIONS: For each of the psychological variables considered (depression, anxiety, stress), a significant correlation could be observed with periodontal disease, it can be therefore be suggested that the importance these disturbs have in the onset and progress of the dental disease which supports the existing available data in literature. The innovative aspect of this research was the focus on the assessment of compliance, monitoring the ability of periodontal patients to follow oral hygiene instructions aiming at the improving and keeping their own periodontal condition, even though this takes more time than the control group. PMID- 26516310 TI - Salivary Secretory Disorders, Inducing Drugs, and Clinical Management. AB - BACKGROUND: Salivary secretory disorders can be the result of a wide range of factors. Their prevalence and negative effects on the patient's quality of life oblige the clinician to confront the issue. AIM: To review the salivary secretory disorders, inducing drugs and their clinical management. METHODS: In this article, a literature search of these dysfunctions was conducted with the assistance of a research librarian in the MEDLINE/PubMed Database. RESULTS: Xerostomia, or dry mouth syndrome, can be caused by medication, systemic diseases such as Sjogren's Syndrome, glandular pathologies, and radiotherapy of the head and neck. Treatment of dry mouth is aimed at both minimizing its symptoms and preventing oral complications with the employment of sialogogues and topical acting substances. Sialorrhea and drooling, are mainly due to medication or neurological systemic disease. There are various therapeutic, pharmacologic, and surgical alternatives for its management. The pharmacology of most of the substances employed for the treatment of salivary disorders is well-known. Nevertheless, in some cases a significant improvement in salivary function has not been observed after their administration. CONCLUSION: At present, there are numerous frequently prescribed drugs whose unwanted effects include some kind of salivary disorder. In addition, the differing pathologic mechanisms, and the great variety of existing treatments hinder the clinical management of these patients. The authors have designed an algorithm to facilitate the decision making process when physicians, oral surgeons, or dentists face these salivary dysfunctions. PMID- 26516313 TI - MicroRNA-7: a promising new target in cancer therapy. AB - The incidence of tumors with life-threatening effects has increased gradually over time; however, the mechanisms involved in tumor development have not been fully elucidated. Recent studies have shown that microRNA-7 (miR-7), which is endogenous non-coding RNA molecules of approximately 23 nucleotides, plays an important role in the occurrence and development of tumors as a key tumor suppressor. Mechanistic evidence showed that miR-7 is closely related to the growth, metastasis, and prognosis of various malignant tumors through regulating different target molecules, which suggest that miR-7 may be a new target for the clinical diagnosis and treatment of various tumors. In this review, we summarize current knowledge of the relationship between miR-7 and tumor development, diagnosis, and treatment. PMID- 26516314 TI - Dimethylsulfoxide excerbates cisplatin-induced cytotoxicity in Ehrlich ascites carcinoma cells. AB - BACKGROUND: Cisplatin (CIS) is a potent antineoplastic agent with high therapeutic efficacy against many kinds of tumors. Its use is limited by its nephrotoxicity. The aim of this work was to minimize cisplatin effective dose and the possible reduction of its severe side effects. The present study was designed to assess the role of sulfur containing agent dimethyl sulfoxide (DMSO) on sensitization of mammary carcinoma, Ehrlich ascites carcinoma (EAC), to the action of cisplatin and at the same time the possible protective effect against cisplatin induced nephrotoxicity in experimental animals. METHODS: To evaluate these effects we have explored the cisplatin effect on the survival time of tumor bearing animals, tumor weight, cisplatin cellular uptake, apoptosis induction and cell cycle distribution and renal function in presence and absence of DMSO. RESULTS: Cisplatin at dose of 4.5 mg/kg increased the mean survival time of tumor bearing mice to 37 days compared with tumor bearing control mice. Pretreatment of tumor bearing mice with DMSO 50 % (2 ml/kg equal to 1 gm/kg) 2 h. before cisplatin showed a significant increase in their mean survival time 43 days compared to cisplatin treated animals. DMSO pretreatment retained rat's serum urea and creatinine levels to normal compared to animals treated with cisplatin alone. CONCLUSION: DMSO pretreatment enhanced the cytotoxic activity of cisplatin against the growth of EAC in vivo and showed protective effects against cisplatin induce nephrotoxicity. PMID- 26516315 TI - The role of host soluble inflammatory mediators induced by the BCG vaccine for the initiation of in vitro monocyte apoptosis in healthy Brazilian volunteers. AB - BACKGROUND: Tuberculosis (TB) is the second greatest killer worldwide that is caused by a single infectious agent. For its control, studies of TB vaccines are needed. Since Bacillus Calmette-Guerin (BCG) is the only vaccine against TB currently in use, studies addressing the protective role of BCG in the context of inducible inflammatory mediators are urgently required. METHODS: In this study, groups of HIV-negative adult healthy donors (HD; n = 42) and neonates (UV; n = 18) have been voluntarily enrolled, and BCG Moreau strain was used for the in vitro mononuclear cell infections for an initial period of 48 h. Subsequently, harvested conditioned medium (CM) was added to autologous resting cells for an additional 24, 48, and 120 h, and Annexin V, in conjunction with a vital dye, was then used for apoptosis detection. CM was also assayed for nitric oxide (NO), prostaglandin E2 (PGE2), leukotriene B4 (LTB4), interferon (IFN)-beta, and transforming growth factor (TGF)-beta1 levels. The p values were set up for any differences between two groups of individuals using Student's t-test and considered significant when <= 0.05. RESULTS: At 120 h, CM induced the highest apoptosis levels in both group studied, but necrosis was high in UV group only (p value < 0.05). NO was released equally during BCG infection in both groups, but higher levels were found in HD when compared with UV group (p-value < 0.05). Overall, BCG Moreau triggered high PGE2, LTB4 and IFN-beta productions in macrophages from the UV group (p-value <= 0.05), whereas the prostanoid PGE2 and TGF-beta1 had an opposite pattern in the HD group. CONCLUSIONS: This study uncovers critical roles for endogenous compounds in the instruction of host macrophage cell death patterns. Understanding the regulation of human immune responses is critical for vaccine development and the treatment of infectious diseases. These findings shed new light on the potential condition for a booster immunization in individuals already vaccinated with BCG for TB protection, and further studies are warranted. PMID- 26516316 TI - A High-Throughput Assay for Screening of Natural Products that Enhanced Tumoricidal Activity of NK Cells. AB - BACKGROUND: Recently, immunotherapy has shown a lot of promise in cancer treatment and different immune cell types are involved in this endeavor. Among different immune cell populations, NK cells are also an important component in unleashing the therapeutic activity of immune cells. Therefore, in order to enhance the tumoricidal activity of NK cells, identification of new small molecule natural products is important. Despite the availability of different screening methods for identification of natural products, a simple, economic and high-throughput method is lacking. Hence, in this study, we have developed a high throughput assay for screening and indentifying natural products that can enhance NK cell-mediated killing of cancer cells. RESULTS: We expanded human NK cell population from human peripheral blood mononuclear cells (PBMCs) by culturing these PBMCs with membrane-bound IL-21 and CD137L engineered K562 cells. Next, expanded NK cells were co-cultured with non-small cell lung cancer (NSCLC) cells with or without natural products and after 24 h of co-culturing, harvested supernatants were analyzed for IFN-gamma secretions by ELISA method. We screened 502 natural products and identified that 28 candidates has the potential to induce IFN-gamma secretion by NK cells to varying degrees. Among the 28 natural product candidates, we further confirmed and analyzed the potential of one molecule, andrographolide. It actually increased IFN-gamma secretion by NK cells and enhanced NK cell-mediated killing of NSCLC cells. CONCLUSIONS: Our results demonstrated that this IFN-gamma based high-throughput assay for screening of natural products for NK cell tumoricidal activity is a simple, economic and reliable method. PMID- 26516317 TI - Detection, Assessment, and Management of Schizophrenia in an Andean Population of South America: Parkinsonism Testing and Transcranial Ultrasound as Preventive Tools. AB - Schizophrenia is a debilitating psychiatric illness that is among the world's top 10 causes of long-term disability, affecting people who are just entering the peak of social, economic, and intellectual productivity. Such functional loss is particularly relevant in indigenous communities, which rely on change in functional status (rather than on the presence of symptoms) to identify mental illness. Particularly among the indigenous communities of Latin America, the gap between mental health need and availability of resources to reduce the burden has been judged "a case of outrageous exclusion." For more than a decade, as part of the Investigation of Movement Abnormalities and Genetic of Schizophrenia study, the authors have been studying vulnerability markers (genetic, motor, imaging, and neuropsychological differences) for schizophrenia in a remote, indigenous population in rural northern Argentina. In this article, the authors discuss the implementation of a task-shifting paradigm resulting in more proficient identification and referral of individuals with untreated psychosis and a severalfold reduction in the duration of untreated psychosis, with very high retention rates (70%) and treatment adherence during a decade in a rural environment. The authors also propose to use transcranial ultrasound screening and testing for parkinsonism at illness onset before introduction of neuroleptics as potentially useful markers in determining illness severity, negative symptomatology, and tolerance to antipsychotic treatment/refractoriness. PMID- 26516318 TI - Polarizable molecular dynamics in a polarizable continuum solvent. AB - We present, for the first time, scalable polarizable molecular dynamics (MD) simulations within a polarizable continuum solvent with molecular shape cavities and exact solution of the mutual polarization. The key ingredients are a very efficient algorithm for solving the equations associated with the polarizable continuum, in particular, the domain decomposition Conductor-like Screening Model (ddCOSMO), which involves a rigorous coupling of the continuum with the polarizable force field achieved through a robust variational formulation and an effective strategy to solve the coupled equations. The coupling of ddCOSMO with nonvariational force fields, including AMOEBA, is also addressed. The MD simulations are feasible, for real-life systems, on standard cluster nodes; a scalable parallel implementation allows for further acceleration in the context of a newly developed module in Tinker, named Tinker-HP. NVE simulations are stable, and long-term energy conservation can be achieved. This paper is focused on the methodological developments, the analysis of the algorithm, and the stability of the simulations; a proof-of-concept application is also presented to attest to the possibilities of this newly developed technique. PMID- 26516319 TI - Comparison of Prostatic Tissue Processed by Microwave and Conventional Technique Using Morphometry. AB - BACKGROUND AND OBJECTIVES: Rapid processing of histopathological specimens and decreased turnaround time is important to fulfill the needs of clinicians treating sick patients, so the present study was conducted to compare the time taken and quality of sections in processing of prostatic tissue by rapid microwave and conventional techniques using morphometry. METHODS: Four to five mm thick paired prostate tissue pieces of fifty cases of prostatectomy specimens were taken. One tissue piece of the pair was processed routinely overnight by conventional tissue processing and the other by microwave processing. Time taken for processing by both conventional technique and microwave technique was noted and compared. Then, both were stained with conventional method of hematoxylin and eosin staining and examined for histological typing and grading. Morphometric study was done on slides of prostatic tissue processed by both conventional and microwave technique. RESULT: The prostatectomy specimens included both benign (86%) and malignant (14%) prostatic lesions in the age range of 46-85 years. The time taken for steps of dehydration, clearing and impregnation in microwave technique was significantly less as compared to histoprocessing done by conventional technique. Morphology, staining patterns of prostatic tissue processed within minutes by microwave technique, whether benign or malignant, were comparable to those sections which were processed in days using standard technique. CONCLUSION: Domestic microwave oven can be used for histoprocessing to accelerate the processing with preservation of morphology and is cheaper than commercially available microwave ovens and processing time was considerably reduced from days to minutes. PMID- 26516320 TI - Liver Damage and Mortality in a Male Lewis Rat of Experimental Autoimmune Encephalomyelitis. AB - BACKGROUND AND OBJECTIVES: Multiple sclerosis is an inflammatory disease of the central nervous system. This is due to migration of peripherally activated lymphocytes to central nervous system leading to inflammatory lesions. However, liver has an anti-inflammatory microenvironment. Myelin expression in the liver of transgenic mice suppresses inflammatory lesions within central nervous system. Considering the notion that the inflammatory events originate from periphery, we investigated if the liver was affected in an animal model for multiple sclerosis. METHODS: Experimental autoimmune encephalomyelitis was induced in male Lewis rats using guinea pig spinal cord and complete Freund's adjuvant. Weight, clinical score, and survival rate were evaluated for 14 days post immunization. Liver sections were taken and stained with Hematoxylin and Eosin and examined with an Olympus microscope. RESULTS: Mortality was accompanied by liver damage. Sinusoidal congestion, pycnotic nuclei within hepatocytes, hepatocyte necrosis, and severe widespread congestion along with fat accumulation within hepatocytes (fatty degeneration) were observed in liver tissue sections. CONCLUSION: Liver damage occurs in experimental autoimmune encephalomyelitis. The perpetuation of self antigen leading to continuous migration of extrahepatically activated T cells makes an inflammatory milieu in the liver. It follows migration and development of more inflammatory cells and may paralyses tolerance inducing mechanisms. Apart from central nervous system lesion, liver injury may act as synergistic factor for debilitation and mortality. PMID- 26516321 TI - Evaluation of Clinico-Radio-Pathological Features of Tubular Adenoma of Breast: a Study of Ten Cases with Histopathological Differential Diagnosis. AB - BACKGROUND & OBJECTIVES: Tubular adenomas are rare benign epithelial tumours of breast affecting predominantly females of child bearing age group. Till now, very small number of cases have been reported in the literature. Present study was carried out to evaluate the clinico-pathological features of tubular adenoma cases diagnosed during three years study period along with discussion of possible differential diagnoses. METHODS: Overall, 346 female breast biopsies were diagnosed as benign lesions in three years (2010-2012), of which 10 cases of tubular adenomas were identified. Available clinical, radiological and cytological data of these cases were analysed retrospectively in detail. RESULT: Tubular adenomas were identified from 16 to 48 years of age with a predilection to younger age group (60% within 30 years). Most of the tubular adenomas were small and circumscribed mimicking fibroadenoma in almost all the cases. Diagnosis of tubular adenoma in each case was possible only after histological examination. Pre-operative diagnosis of tubular adenoma was not established by cytological and radiological evaluation in any case. CONCLUSION: Tubular adenomas are clinically indistinguishable from other benign breast neoplasms and it should be considered as potential differential diagnosis during histopathological evaluation of breast biopsies. PMID- 26516322 TI - Correlation of Hormone Receptor Expression with Histologic Parameters in Benign and Malignant Breast Tumors. AB - BACKGROUND AND OBJECTIVE: Breast cancer is the commonest cancer of Indian women. Estrogen and Progesterone expression is seen in benign breast lesions and in breast carcinoma associated with good prognostic parameters and it correlates well with response to hormone therapy. Although a lot of studies have been conducted in the past on hormone receptor expression in breast cancer and few have correlated them with other prognostic parameters of breast cancer, the present study was intended to document the prevalence of hormone receptor positive breast carcinomas in our population; their importance in benign breast diseases; to document a reliable scoring system of hormone receptors expression by Quick scoring; to correlate them with most of the proven prognostic parameters of breast carcinoma. METHODS: Tissue specimens from 25 patients with benign breast disease and 50 patients with breast carcinoma were assayed for estrogen (ER) and progesterone (PR) receptors using Quick scoring. ER/PR expression in breast carcinomas was correlated with various prognostic parameters including patients' age, menopausal status, tumor size, type, MBR grade, NPI, lymphatic vessel invasion, lymph node stage, lymphomononuclear invasion, elastosis and HER2/neu status. RESULT: Scoring of steroid receptors paralleled intensity of hyperplasia in benign breast diseases but in breast carcinoma, it was inversely correlated with grade of tumor, NPI, HER2/neu status, tumor necrosis, lymphomononuclear infiltrate and elastosis. We found no relationship with tumor size, lymph node status or age. CONCLUSION: Assessment of hormone receptors for clinical management of breast cancer patients is strongly advocated to provide prognostic information and best therapeutic options. PMID- 26516323 TI - The Value of Bronchoalveolar Lavage in the Diagnosis of Sputum Smear NegativePulmonary Tuberculosis. AB - BACKGROUND AND OBJECTIVES: Sputum smear staining for acid-fast bacilli is initial approach to the diagnosis of pulmonary tuberculosis (PTB) but more than 50% of cases are sputum smear-negative. This study was aimed to investigate the diagnostic value of fiberoptic bronchoscopy (FOB) guided bronchoalveolar lavage (BAL) in patients suspected to have tuberculosis. METHODS: This prospective cross sectional study was carried out on 290 sputum smear-negative patients who were clinically suspicious for PTB in 2006-12. All patients were subjected to FOB andBAL, then BAL specimens stained and cultured. RESULTS: Of the 290 patients, 173 cases (59.7%) were men and 117 cases (40.3%) were women with the age of 52.6+/-19.1 years (ranged 20-76 years). Of the total 290 BAL specimens, 110 specimens (38%) were positive for acid-fast bacilli. Sensitivity, specificity, PPV and NPV was 60%, 91%, 89% and 64%, respectively. Also, LR (+) and LR (-) was 64.6% and 0.44%, respectively. CONCLUSION: FOB guided BAL is a reliable, rapid and useful method for establishing the diagnosis of smear negative PTB with minimal complications. PMID- 26516324 TI - Assessment of the Association between Human Papillomavirus Infection and Breast Carcinoma. AB - BACKGROUND AND OBJECTIVES: Breast cancer is the most common malignancy in women throughout the world. There are controversial reports on the role of human papillomavirus (HPV) infection in breast carcinogenesis. The aim of this study was to assess the presence of HPV-DNA in invasive breast carcinoma to determine the association between HPV infection and breast carcinoma. METHODS: The study included formalin-fixed paraffin-embedded tissue samples of 100 cases with invasive ductal carcinoma of breast and 50 control tissues of mammoplasty specimens. HPV-DNA was purified and amplified through GP5+/GP6+ and MY09/MY11 primers. RESULTS: All tested carcinomas as well as normal tissues were negative for all types of HPV in PCR assay. CONCLUSION: Our results do not support the association between HPV infection and breast carcinoma. Further studies involving larger number of cases are required to elucidate the role of HPV infection in breast carcinogenesis. PMID- 26516325 TI - Fine Needle Aspiration Cytology versus Fine Needle Capillary Sampling in Cytological Diagnosis of Thyroid Lesions. AB - BACKGROUND AND OBJECTIVES: Fine needle aspiration cytology (FNAC) is an established out- patient procedure used in primary diagnosis of palpable thyroid lesions. A modified technique fine needle capillary sampling (FNCS) obviates the need of suction, is less painful, patient friendly and reported to overcome the problem of inadequate and bloody specimens. The aim of our study was to compare the efficacy and quality of FNCS with that of conventional FNAC in the lesions of thyroid. METHODS: One hundred patients, presenting between January 2011 to December 2012 at Cytopathology Department of M M Institute of Medical Sciences and Research, Mullana, with diffuse and nodular thyroid lesions were enrolled with both the techniques being executed on the patients, beginning with FNA followed by FNCS. The smears were scored using five objective parameters i.e. background blood, cellular material, cellular degeneration, cellular trauma, and retention of appropriate architecture, in a single blind setting by a cyto pathologist. The results were analyzed using Student's test for paired data and chi- square analysis. RESULTS: A highly significant differences (P<0.001) in favor of FNCS was observed for the background blood, cellular material and retention of architecture while total score favored FNA for cellular degeneration and degree of cellular trauma. Total scores and average score per case for FNCS was significantly better (P<0.001) than FNA. FNCS technique yielded more diagnostically superior and lesser number of unsatisfactory smears whereas greater number of diagnostically adequate samples was obtained by FNA technique. CONCLUSION: FNCS offers more number of diagnostically better quality smears. Both techniques could be supplementary on many occasions and substitutive on a few. Combination of the two techniques could offer better diagnostic accuracy. PMID- 26516326 TI - Microbial Etiology and Antimicrobial Susceptibility of Bactria Implicated in Urinary Tract Infection in Tehran, Iran. AB - BACKGROUND AND OBJECTIVES: Urinary tract infections (UTI) are one of the most common infectious diseases with different microbial agent and antimicrobial resistant pattern in hospitalized patients and outpatients. In order to assess the adequacy of therapy, knowledge of prevalence and resistance pattern of the bacteria is necessary. The main aim of this study was to evaluate the prevalence and the antimicrobial resistance pattern of main bacterial responsible for UTI in order to establish an appropriate empirical therapy. METHODS: All urine samples were referred to Imam Hospital Laboratory, Tehran, Iran during 2011-2012, urine culture isolated and bacteria were identified and the profile of antibiotic susceptibility was characterized. RESULT: From 1851 urine cultures, UTI was more frequent in woman (68%) E. coli was as usual the most common pathogen implicated in UTI. Most susceptibility was to imipenem (98.9%). nitroforantoin (96%) and amikacin (94.1%) and increased resistance to penicillin (66.6%), nalidixic acid (62.1%) ampicilin (60.1%) and cotrimoxazole 54.3%. DISCUSSION: The most common isolated pathogen was E. coli . According to antibiogram susceptibility, the recommended antimicrobial drugs are nitroforantoin and imipenem. nalidixic acid and cotrimoxazole are not recommended because drug resistance is high. PMID- 26516327 TI - Recurrence of Non-Syndromic Sex Cord Stromal Tumor with Annular Tubules of Ovary: Case Report. AB - One of the unusual variant of ovarian tumor is sex cord stromal tumor with annular tubules (SCTAT). The recurrence in case of malignant ovarian SCTAT ranges from 3mo to 20yr. This report describes the case of recurrence of SCTAT in a 35yr old woman after 4yr of hysterectomy with bilateral salphingo-Oopherectomy. Microscopic examination revealed features of SCTAT. Because of its unusual behavior evidenced by delayed recurrence in spite of bland cellular features, proper long term follow-up is essential. PMID- 26516328 TI - Eccrine Porocarcinoma of Scalp: a Rare Case Report. AB - Eccrine porocarcinoma is a rare malignant adnexal tumor of ductal portion of eccrine sweat gland. It occurs commonly in the lower extremities and rarely in scalp, face, ear, trunk and upper extremities. This survey presents a classic case of eccrine porocarcinoma of scalp in a 58 yr old male patient, presenting as cauliflower like growth over parietal aspect of scalp. PMID- 26516329 TI - Primary Cutaneous Leiomyosarcoma in a Young Patient Previously Misdiagnosed as Pleomorphic Fibroma. AB - Cutaneous leiomyosarcoma is a relatively rare tumor accounts for about 2-3% of superficial soft tissue sarcomas. It occurs more frequently in males in fifth and sixth decades with a predilection for extremities. We report a 27 years old male with cutaneous leiomyosarcoma of thigh, previously diagnosed as pleomorphicfibroma. The tumor composed of pleomorphic spindle shaped cells with blunt ended nuclei and high mitotic activity. Smooth muscle actin was positive. In this case, the young age of the patient and previous misdiagnosis of the tumor are interesting. Subtle histologic features of low grade leiomyosarcoma can be a pitfall in diagnosis and so affects the optimal management of the patient as it occurred in previous sample of this case. PMID- 26516330 TI - Intrathoracic Malignant Peripheral Nerve Sheath Tumor: Histopathological and Immunohistochemical Features. AB - Malignant peripheral nerve sheath tumor (MPNST) is a rare nerve sheath tumor derived from Schwann cells or pleuripotent cells of neural crest. Neurogenic tumors make about 10-20% of all mediastinal tumors. Incidence of MPNST is 0.001% in general population and 0.16% in patients with neurofibromatosis I (NF I). We report a case of 60 year female presenting with progressive cough and breathlessness for 2 years. The CECT revealed multiple focal enhancing lesions along inferior mediastinal pleural surface and along lateral pleural surface. A thoracotomy and tumor excision was done and MPNST was diagnosed on microscopy and immunohistochemistry. This case highlights that this unusual tumor may involve lung parenchyma. So this possibility should be kept in mind in patients with intrathoracic mass. PMID- 26516331 TI - Cecal Giant Lipoma Mimicking Malignancy. PMID- 26516332 TI - Red Palm Oil Attenuates Lead Acetate Induced Testicular Damage in Adult Male Sprague-Dawley Rats. AB - To study the protective effect of Red Palm Oil (RPO) on testicular damage induced by administration of lead acetate on male Sprague-Dawley rats, 28 rats divided into four groups of 7 animals each were used. They were administered orally with RPO (1 mL and 2 mL) and lead acetate (i.p.) 6 mg/kg body weight/day, respectively. Treatment was conducted for 8 weeks, and 24 hrs after the last treatment the rats were sacrificed using cervical dislocation. Sperms collected from epididymis were used for seminal fluid analyses; while the testes sample was used for ROS and oxidative enzyme activities assessment. Statistical analysis was carried out using GraphPad Prism 5.02 statistical analysis package. Administration of lead acetate increased generation of reactive oxygen species (ROS) significantly (p < 0.05) as evidenced by the elevated value of H2O2 and LPO and decreased GSH level. Also there was reduced epididymal sperm count, poor grade of sperm motility, and lower percentage of normal sperm morphology significantly. Coadministration with RPO, however, has a protective effect against lead toxicity by decreasing H2O2 production, increased GSH level, and increased sperm qualities especially. This shows that RPO has a potential to attenuate the toxic effect of lead on testicular cells preventing possible resultant male infertility. PMID- 26516333 TI - Short-Term Effect of Laser Acupuncture on Lower Back Pain: A Randomized, Placebo Controlled, Double-Blind Trial. AB - Purpose. This trial was performed to investigate the efficacy of laser acupuncture for the alleviation of lower back pain. Methods. This was a randomized, placebo-controlled, double-blind trial. Fifty-six participants were randomly assigned to either the laser acupuncture group (n = 28) or the sham laser acupuncture group (n = 28). Participants in both groups received three treatment sessions over the course of one week. Thirteen acupuncture points were selected. The visual analogue scale for pain, pressure pain threshold, Patient Global Impression of Change, and Euro-Quality-of-Life Five Dimensions questionnaire (Korean version) were used to evaluate the effect of laser acupuncture treatment on lower back pain. Results. There were no significant differences in any outcome between the two groups, although the participants in both groups showed a significant improvement in each assessed parameter relative to the baseline values. Conclusion. Although there was no significant difference in outcomes between the two groups, the results suggest that laser acupuncture can provide effective pain alleviation and can be considered an option for relief from lower back pain. Further studies using long-term intervention, a larger sample size, and rigorous methodology are required to clarify the effect of laser acupuncture on lower back pain. PMID- 26516334 TI - Decline of FOXN1 gene expression in human thymus correlates with age: possible epigenetic regulation. AB - BACKGROUND: Thymic involution is thought to be an important factor of age related immunodeficiency. Understanding the molecular mechanisms of human thymic senescence may lead to the discovery of novel therapeutic approaches aimed at the reestablishment of central and peripheral T cell repertoire. RESULTS: As an initial approach, here we report that the decline of human thymic FOXN1 transcription correlates with age, while other genes, DLL1, DLL4 and WNT4, essential for thymopoiesis, are constitutively transcribed. Using a human thymic epithelial cell line (hTEC), we show that FOXN1 expression is refractory to signals that induce FOXN1 transcription in primary 3D culture conditions and by stimulation of the canonical WNT signaling pathway. Blockage of FOXN1 induceability in the hTEC line may be mediated by an epigenetic mechanism, the CpG methylation of the FOXN1 gene. CONCLUSION: We showed a suppression of FOXN1 transcription both in cultured human thymic epithelial cells and in the aging thymus. We hypothesize that the underlying mechanism may be associated with changes of the DNA methylation state of the FOXN1 gene. PMID- 26516335 TI - Mandible evolution in the Scarabaeinae (Coleoptera: Scarabaeidae) and adaptations to coprophagous habits. AB - INTRODUCTION: The astonishing spectrum of scarabaeine lifestyles makes them an attractive group for studies in entomology and evolutionary biology. As a result of adaptions to specific food substrates and textures, the mouthparts of dung beetles, particularly the mandible, have undergone considerable evolutionary changes and differ distinctly from the presumptive ancestral conditions of the Coleoptera and Polyphaga. The possible functions of dung beetle mouthparts and the evolution of dung feeding have been controversial for decades. RESULTS: In this study, 187 scarabs representing all tribes of the Scarabaeinae and the major lineages within the Scarabaeoidea, along with three major feeding types within the Scarabaeoidea (omnivory, phytophagy and coprophagy), were studied. Based on geometric morphometric and three-dimensional (3D) reconstruction approaches, morphological differences in mandibles among the three feeding types were identified. The ancestral forms of the mandible within the Scarabaeinae were reconstructed and compared with those of modern species. The most recent common ancestor of the Scarabaeinae fed on soft materials, and the ancestor of the Scarabaeinae and the Aphodiinae was in an evolutionary transition between processing more solid and softer substrates. CONCLUSIONS: Coprophagy originated from omnivorous ancestors that were very likely saprophagous. Furthermore, phytophagy may also have originated from omnivory. In addition, our study addresses the integration and modularity of geometric morphometric data in a phylogenetic context. PMID- 26516336 TI - Low-calcium diet prevents fructose-induced hyperinsulinemia and ameliorates the response to glucose load in rats. AB - BACKGROUND: Consuming a fructose-rich diet leads to hyperinsulinemia, impaired glucose tolerance, and insulin resistance. In humans, the consumption of high levels of refined sugars often coincides with a diet containing suboptimal levels of calcium. Calcium and carbohydrate metabolism interact, so there is potential for fructose to have different health outcomes depending on whether the diet is calcium-rich or calcium-poor. METHODS: We evaluated the metabolic effects of feeding fructose to rats that were maintained on either a calcium-replete diet or a low-calcium diet. Growing male Sprague Dawley rats were fed diets based on the AIN-93G formulation, with the main source of carbohydrate derived either from a mixture of cornstarch and sucrose or from fructose. Half the rats given each carbohydrate source were fed calcium at recommended levels (125 mmol/kg Ca(2+)); the others were fed a diet low in calcium (25 mmol/kg Ca(2+)). At various times, glucose and insulin tolerance tests were conducted to assess glucose metabolism. RESULTS: Rats fed low-calcium diet had lower fasting insulin levels irrespective of the carbohydrate source they ate. They had a normal glycemic response to a glucose load and did not develop hyperinsulinemia under conditions of fructose feeding. The drop in blood glucose levels in response to insulin injection was larger in rats fed low-calcium diet than in those fed calcium-replete diet. CONCLUSIONS: Low-calcium diet prevented fructose-induced hyperinsulinemia and improved glucose handling under conditions of fructose feeding. Potential mechanisms underlying these effects of the low-calcium diet remain to be determined, but possibilities include impairment of insulin release from the pancreas and improved peripheral insulin sensitivity. PMID- 26516337 TI - Anxiety and depression among Greek men with primary erectile dysfunction and premature ejaculation. AB - BACKGROUND: Erectile dysfunction (ED) and premature ejaculation (PE) are the two most prevalent sexual disorders among males associated with significant distress and impairment in quality of life. The aim of this study was to investigate the prevalence of anxiety and depression symptoms among patients with primary ED and PE. METHODS: A sample of 57 men (ED = 31; PE = 26) were compared to 25 male outpatients with anxiety disorder (AD) and 25 healthy controls. Principal assessment measures included the State-Trait Anxiety Inventory (STAI) and the Beck Depression Inventory (BDI). RESULTS: Greater levels of STAI state anxiety were reported among the ED, PE, and AD groups as compared to healthy controls. In contrast ED and AD groups scored higher than controls on the STAI trait anxiety and BDI, but PE scores were not different from healthy controls in both measures. CONCLUSIONS: The study findings suggest that both primary ED and PE are conditions associated with significant state anxiety; however, PE appears to be less associated with trait anxiety and depression compared to ED, a finding that corroborates the recent acknowledgement of PE as a more biologically based condition. Limitations and potential clinical implications are also discussed. PMID- 26516338 TI - Smoking bans in mental health hospitals in Japan: barriers to implementation. AB - BACKGROUND: A number of studies have reported that smoking rates are higher and smoking cessation rates are lower in patients with mental disorders than in the general population. Despite the harmful effects of smoking, implementing total smoking bans in mental health hospitals is difficult. We investigate the status of smoking bans and the barriers to the implementation of total smoking bans in Japanese mental health hospitals. METHODS: A questionnaire survey was administered to the directors of 1242 Japanese mental health hospitals in March 2013. RESULTS: Forty-nine percent (n = 612) of the hospital directors responded. Of these, 24 % implemented total smoking bans and 14 % limited the bans to hospital buildings. In 66 and 68 % of the remaining hospitals, smoking rooms were located in open and closed wards, respectively, and completely separate from nonsmoking areas. Hospitals that had not implemented total smoking bans were concerned that introducing a total ban would exacerbate patients' psychiatric symptoms (46 %) or increase the incidence of surreptitious smoking (65 %). However, of the hospitals that had implemented total smoking bans, only 2 and 30 % identified "aggravation of psychiatric symptoms" and "increased surreptitious smoking" as disadvantages, respectively. The other concerns regarding the implementation of total smoking bans were staff opposition (21 %) and incidence of smoking around hospital grounds (46 %). These concerns were overcome by educating staff about smoking and cleaning the area around the hospital. CONCLUSIONS: There are some barriers to implementing total smoking bans in Japanese mental health hospitals. However, our study indicates that implementation of total smoking bans in mental health hospitals was minimally problematic and that barriers to the implementation of smoking bans could be overcome. As the current number of hospitals that have implemented total smoking bans is low in Japan, more hospitals should introduce total smoking bans. PMID- 26516339 TI - Chronic low back pain among French healthcare workers and prognostic factors of return to work (RTW): a non-randomized controlled trial. AB - BACKGROUND: Many factors influence the return to work of workers with chronic low back pain (CLBP). They have been said to vary according to socio-professional group. This study first aimed to compare prognostic factors influencing the return to work of CLBP healthcare workers (HCWs) and other workers (non-HCWs) after rehabilitation coupled with an occupational intervention. The second objective was to improve the evolution of indicators such as clinical examination, psychosocial impact and pain impact. METHODS: Between 2007 and 2012, a cohort of 217 CLBP workers (54.8 %-women; mean age = 41.3 +/- 9.5 years, 118 non-HCWs; 99 HCWs mainly from the public sector) was included in an ambulatory rehabilitation program (standard physiotherapy or intensive network physiotherapy) coupled with an occupational intervention. Workers completed a questionnaire and had a clinical examination at baseline and after 24 months' follow up. Physical, social and occupational data was collected at the same time. Statistical analyses were performed to evaluate prognostic factors for return to work and compare the two worker populations. RESULTS: There was no difference between groups for the rate of OP (occupational physician) intervention or type of physiotherapy. 77.3 % of workers returned to work after 2 years following inclusion. To be an HCW (OR 0.1; 95 % CI [0.03-0.34]), to have less than 112 sick leave days (OR 1.00; 95 % CI [0.93-1.00]), a small fingertip-floor distance (OR 0.96; 95 % CI [0.93-0.99]), a low anxiety/depression score (OR 0.97; 95 % CI [0.95-1.00]), a low impact of CLBP on daily life (OR 0.96; 95 % CI [0.93-1.00]), and on quality of life (OR 0.98; 95 % CI [0.95-1.00]) at baseline were statistically associated with return to work after 2 years of follow up. Only the profession (workplace) was statistically associated with return to work after 2 years of follow up using multivariate analysis. CONCLUSION: To our knowledge, this is the first cohort study concerning predictive factors of RTW among CLBP workers after 2 years of follow up. Interventions in the work environment did not seem to predict job retention significantly. But only 50 % of the employees in both groups (HCW and non-HCW) had one intervention at their workplace after 2 years. This study underlined the fact that the type of physiotherapy with a well trained physiotherapist used to take care of CLBP could not impact on the RTW forecast. To develop these initial results, it might be interesting to study the comparison between private and public sectors and to randomize the physiotherapeutic intervention. PMID- 26516340 TI - Postpartum women's use of medicines and breastfeeding practices: a systematic review. AB - The objectives of this article are to systematically review i) the extent of medicine use in postpartum women, and ii) the impact of maternal medicine use (excluding contraceptives and galactogogues) on breastfeeding outcomes (initiation and/or duration). PubMed, Medline (Ovid), Scopus (Elsevier), Cinahl (EBSCO), PsycINFO (Ovid), Embase (Ovid) and Web of Science (ISI) databases were searched to find original studies on medicine use in women after the birth. Additional studies were identified by searching Google Scholar, Wiley Online Library, Springer Link, selected journals and from the reference list of retrieved articles. Observational studies with information about postpartum women's use of any type of medicine either for chronic or acute illnesses with or without breastfeeding information were included. The majority of relevant studies suggest that more than 50 % of postpartum women (breastfeeding or not) required at least one medicine. Due to the lack of uniform medication use reporting system and differences in study designs, settings and samples, the proportion of medicine use by postpartum women varies widely, from 34 to 100 %. Regarding the impact of postpartum women's medicine use on breastfeeding, a few studies suggest that women's use of certain medicines (e.g. antiepileptics, propylthiouracil, antibiotics) during lactation can reduce initiation and/ or duration of breastfeeding. These studies are limited by small sample size, and with one exception, all were conducted in Canada more than a decade ago. Large scale studies are required to establish the relationship between maternal medicine use and breastfeeding, considering type of illness, period of use and total duration of medicine use. PMID- 26516341 TI - Protocol: an improved and universal procedure for whole-mount immunolocalization in plants. AB - Rapid advances in microscopy have boosted research on cell biology. However sample preparation enabling excellent reproducible tissue preservation and cell labeling for in depth microscopic analysis of inner cell layers, tissues and organs still represents a major challenge for immunolocalization studies. Here we describe a protocol for whole-mount immunolocalization of proteins which is applicable to a wide range of plant species. The protocol is improved and robust for optimal sample fixation, tissue clearing and multi-protein staining procedures and can be used in combination with simultaneous detection of specific sequences of nucleic acids. In addition, cell wall and nucleus labelling can be implemented in the protocol, thereby allowing a detailed analysis of morphology and gene expression patterns with single-cell resolution. Besides enabling accurate, high resolution and reproducible protein detection in expression and localization studies, the procedure takes a single working day to complete without the need for robotic equipment. PMID- 26516342 TI - Transcatheter thrombolysis combined with damage control surgery for treatment of acute mesenteric venous thrombosis associated with bowel necrosis: a retrospective study. AB - OBJECTIVE: This study aims to evaluate the clinical outcomes of transcatheter thrombolysis in acute superior mesenteric venous thrombosis (ASMVT) associated with bowel necrosis. METHODS: A retrospective study of six patients with ASMVT treated with catheter-directed thrombectomy/thrombolysis and damage control surgery at Jinling Hospital (Nanjing, China) between 2010 and 2013 was conducted. Demographics, past medical history, risk factors, therapeutic methods and effects, mortality, and follow-up of the study population were assessed. RESULTS: Five of six patients underwent arteriovenous combined thrombolysis, while one patient underwent arterial thrombolysis. All patients required damage control surgery, and four of these patients underwent temporary abdominal closure. All patients survived and were free of recurrence. CONCLUSIONS: Transcatheter thrombectomy/thrombolysis and damage control surgery could help avoid extensive bowel resection, prevent short bowel syndrome and reduce mortality for critically ill patients with acute mesenteric venous thrombosis associated with bowel necrosis. PMID- 26516343 TI - SEED: the six excesses (Liu Yin) evaluation and diagnosis scale. AB - BACKGROUND: Infections such as common colds, influenza, acute upper respiratory infections, bacterial gastroenteritis, and urinary tract infections are usually diagnosed according to patients' signs and symptoms. This study aims to develop a scale for the diagnosis of infectious diseases based on the six excesses (Liu Yin) etiological theory of Chinese medicine (CM) by the Delphi method. METHODS: A total of 200 CM-guided diagnostic items measuring signs and symptoms for infectious diseases were compiled from CM literature archives from the Han to Ming dynasties, CM textbooks in both China and Taiwan, and journal articles from the China Knowledge Resource Integrated Database. The items were based on infections and the six excesses (Liu Yin) etiological theory, i.e., Feng Xie (wind excess), Han Xie (coldness excess), Shu Xie (summer heat excess), Shi Xie (dampness excess), Zao Xie (dryness excess), and Huo Xie (fire excess). The items were further classified into the six excess syndromes and reviewed via a Delphi process to reach consensus among CM experts. RESULTS: In total, 178 items with a mean or median rating of 7 or above on a scale of 1-9 from a panel of 32 experts were retained. The numbers of diagnostic items in the categories of Feng (wind), Han (coldness), Shu (summer heat), Shi (dampness), Zao (dryness), and Huo (fire) syndromes were 15, 22, 25, 37, 17, and 62, respectively. CONCLUSIONS: A CM-based six excesses (Liu Yin) evaluation and diagnosis (SEED) scale was developed for the evaluation and diagnosis of infectious diseases based only on signs and symptoms. PMID- 26516344 TI - Most common robotic bariatric procedures: review and technical aspects. AB - Since its appear in the year 1997, when Drs. Cadiere and Himpens did the first robotic cholecystectomy in Brussels, not long after the first cholecystectomy, they performed the first robotic bariatric procedure. It is believed that robotically-assisted surgery's most notable contributions are reflected in its ability to extend the benefits of minimally invasive surgery to procedures not routinely performed using minimal access techniques. We describe the 3 most common bariatric procedures done by robot. The main advantages of the robotic system applied to the gastric bypass appear to be better control of stoma size, avoidance of stapler costs, elimination of the potential for oropharyngeal and esophageal trauma, and a potential decrease in wound infection. While in the sleeve gastrectomy and adjustable gastric banding its utility is more debatable, giving a bigger advantage during surgery on patients with a very large BMI or revisional cases. PMID- 26516345 TI - The effects of long-term medication on growth in children and adolescents with ADHD: an observational study of a large cohort of real-life patients. AB - BACKGROUND: Children and adolescents with ADHD treated with central stimulants (CS) often have growth deficits, but the implications of such treatment for final height and stature remain unclear. METHODS: Weight and height were assessed multiple times in 410 children and adolescents during long-term treatment with CS, which lasted between 0.9 and 16.1 years. Weight and height measures were converted to z-scores based on age- and sex-adjusted population tables. RESULTS: CS treatment was associated with (1) a relative reduction in body weight and a temporary halt in growth, (2) a weight and height lag after 72 months compared with relative baseline values. No relation to early start of medication (<6 years), gender, comorbid ODD/CD or emotional disorders was observed. CONCLUSIONS: Treatment with central stimulants for ADHD impacts growth in children and adolescents, and growth should be continuously monitored in patients on chronic treatment with these medications. PMID- 26516346 TI - Techno-economic analysis of the deacetylation and disk refining process: characterizing the effect of refining energy and enzyme usage on minimum sugar selling price and minimum ethanol selling price. AB - BACKGROUND: A novel, highly efficient deacetylation and disk refining (DDR) process to liberate fermentable sugars from biomass was recently developed at the National Renewable Energy Laboratory (NREL). The DDR process consists of a mild, dilute alkaline deacetylation step followed by low-energy-consumption disk refining. The DDR corn stover substrates achieved high process sugar conversion yields, at low to modest enzyme loadings, and also produced high sugar concentration syrups at high initial insoluble solid loadings. The sugar syrups derived from corn stover are highly fermentable due to low concentrations of fermentation inhibitors. The objective of this work is to evaluate the economic feasibility of the DDR process through a techno-economic analysis (TEA). RESULTS: A large array of experiments designed using a response surface methodology was carried out to investigate the two major cost-driven operational parameters of the novel DDR process: refining energy and enzyme loadings. The boundary conditions for refining energy (128-468 kWh/ODMT), cellulase (Novozyme's CTec3) loading (11.6-28.4 mg total protein/g of cellulose), and hemicellulase (Novozyme's HTec3) loading (0-5 mg total protein/g of cellulose) were chosen to cover the most commercially practical operating conditions. The sugar and ethanol yields were modeled with good adequacy, showing a positive linear correlation between those yields and refining energy and enzyme loadings. The ethanol yields ranged from 77 to 89 gallons/ODMT of corn stover. The minimum sugar selling price (MSSP) ranged from $0.191 to $0.212 per lb of 50 % concentrated monomeric sugars, while the minimum ethanol selling price (MESP) ranged from $2.24 to $2.54 per gallon of ethanol. CONCLUSIONS: The DDR process concept is evaluated for economic feasibility through TEA. The MSSP and MESP of the DDR process falls within a range similar to that found with the deacetylation/dilute acid pretreatment process modeled in NREL's 2011 design report. The DDR process is a much simpler process that requires less capital and maintenance costs when compared to conventional chemical pretreatments with pressure vessels. As a result, we feel the DDR process should be considered as an option for future biorefineries with great potential to be more cost-effective. PMID- 26516347 TI - Ethylenediamine pretreatment changes cellulose allomorph and lignin structure of lignocellulose at ambient pressure. AB - BACKGROUND: Pretreatment of lignocellulosic biomass is essential to increase the cellulase accessibility for bioconversion of lignocelluloses by breaking down the biomass recalcitrance. In this work, a novel pretreatment method using ethylenediamine (EDA) was presented as a simple process to achieve high enzymatic digestibility of corn stover (CS) by heating the biomass-EDA mixture with high solid-to-liquid ratio at ambient pressure. The effect of EDA pretreatment on lignocellulose was further studied. RESULTS: High enzymatic digestibility of CS was achieved at broad pretreatment temperature range (40-180 degrees C) during EDA pretreatment. Herein, X-ray diffractogram analysis indicated that cellulose I changed to cellulose III and amorphous cellulose after EDA pretreatment, and cellulose III content increased along with the decrease of drying temperature and the increase of EDA loading. Lignin degradation was also affected by drying temperature and EDA loading. Images from scanning electron microscope and transmission electron microscope indicated that lignin coalesced and deposited on the biomass surface during EDA pretreatment, which led to the delamination of cell wall. HSQC NMR analysis showed that ester bonds of p-coumarate and ferulate units in lignin were partially ammonolyzed and ether bonds linking the phenolic monomers were broken during pretreatment. In addition, EDA-pretreated CS exhibited good fermentability for simultaneous saccharification and co fermentation process. CONCLUSIONS: EDA pretreatment improves the enzymatic digestibility of lignocellulosic biomass significantly, and the improvement was caused by the transformation of cellulose allomorph, lignin degradation and relocalization in EDA pretreatment. PMID- 26516348 TI - A photorespiratory bypass increases plant growth and seed yield in biofuel crop Camelina sativa. AB - BACKGROUND: Camelina sativa is an oilseed crop with great potential for biofuel production on marginal land. The seed oil from camelina has been converted to jet fuel and improved fuel efficiency in commercial and military test flights. Hydrogenation-derived renewable diesel from camelina is environmentally superior to that from canola due to lower agricultural inputs, and the seed meal is FDA approved for animal consumption. However, relatively low yield makes its farming less profitable. Our study is aimed at increasing camelina seed yield by reducing carbon loss from photorespiration via a photorespiratory bypass. Genes encoding three enzymes of the Escherichia coli glycolate catabolic pathway were introduced: glycolate dehydrogenase (GDH), glyoxylate carboxyligase (GCL) and tartronic semialdehyde reductase (TSR). These enzymes compete for the photorespiratory substrate, glycolate, convert it to glycerate within the chloroplasts, and reduce photorespiration. As a by-product of the reaction, CO2 is released in the chloroplast, which increases photosynthesis. Camelina plants were transformed with either partial bypass (GDH), or full bypass (GDH, GCL and TSR) genes. Transgenic plants were evaluated for physiological and metabolic traits. RESULTS: Expressing the photorespiratory bypass genes in camelina reduced photorespiration and increased photosynthesis in both partial and full bypass expressing lines. Expression of partial bypass increased seed yield by 50-57 %, while expression of full bypass increased seed yield by 57-73 %, with no loss in seed quality. The transgenic plants also showed increased vegetative biomass and faster development; they flowered, set seed and reached seed maturity about 1 week earlier than WT. At the transcriptional level, transgenic plants showed differential expression in categories such as respiration, amino acid biosynthesis and fatty acid metabolism. The increased growth of the bypass transgenics compared to WT was only observed in ambient or low CO2 conditions, but not in elevated CO2 conditions. CONCLUSIONS: The photorespiratory bypass is an effective approach to increase photosynthetic productivity in camelina. By reducing photorespiratory losses and increasing photosynthetic CO2 fixation rates, transgenic plants show dramatic increases in seed yield. Because photorespiration causes losses in productivity of most C3 plants, the bypass approach may have significant impact on increasing agricultural productivity for C3 crops. PMID- 26516349 TI - BioDB extractor: customized data extraction system for commonly used bioinformatics databases. AB - BACKGROUND: Diverse types of biological data, primary as well as derived, are available in various formats and are stored in heterogeneous resources. Database specific as well as integrated search engines are available for carrying out efficient searches of databases. These search engines however, do not support extraction of subsets of data with the same level of granularity that exists in typical database entries. In order to extract fine grained subsets of data, users are required to download complete or partial database entries and write scripts for parsing and extraction. RESULTS: BioDBExtractor (BDE) has been developed to provide 26 customized data extraction utilities for some of the commonly used databases such as ENA (EMBL-Bank), UniprotKB, PDB, and KEGG. BDE eliminates the need for downloading entries and writing scripts. BDE has a simple web interface that enables input of query in the form of accession numbers/ID codes, choice of utilities and selection of fields/subfields of data by the users. CONCLUSIONS: BDE thus provides a common data extraction platform for multiple databases and is useful to both, novice and expert users. BDE, however, is not a substitute to basic keyword-based database searches. Desired subsets of data, compiled using BDE can be subsequently used for downstream processing, analyses and knowledge discovery. AVAILABILITY: BDE can be accessed from http://bioinfo.net.in/BioDB/Home.html. PMID- 26516350 TI - Integration and comparison of different genomic data for outcome prediction in cancer. AB - BACKGROUND: In cancer, large-scale technologies such as next-generation sequencing and microarrays have produced a wide number of genomic features such as DNA copy number alterations (CNA), mRNA expression (EXPR), microRNA expression (MIRNA), and DNA somatic mutations (MUT), among others. Several analyses of a specific type of these genomic data have generated many prognostic biomarkers in cancer. However, it is uncertain which of these data is more powerful and whether the best data-type is cancer-type dependent. Therefore, our purpose is to characterize the prognostic power of models obtained from different genomic data types, cancer types, and algorithms. For this, we compared the prognostic power using the concordance and prognostic index of models obtained from EXPR, MIRNA, CNA, MUT data and their integration for ovarian serous cystadenocarcinoma (OV), multiform glioblastoma (GBM), lung adenocarcinoma (LUAD), and breast cancer (BRCA) datasets from The Cancer Genome Atlas repository. We used three different algorithms for prognostic model selection based on constrained particle swarm optimization (CPSO), network feature selection (NFS), and least absolute shrinkage and selection operator (LASSO). RESULTS: The integration of the four genomic data produced models having slightly higher performance than any single genomic data. From the genomic data types, we observed better prediction using EXPR closely followed by MIRNA and CNA depending on the cancer type and method. We observed higher concordance index in BRCA, followed by LUAD, OV, and GBM. We observed very similar results between LASSO and CPSO but smaller values in NFS. Importantly, we observed that model predictions highly concur between algorithms but are highly discordant between data types, which seems to be dependent on the censoring rate of the dataset. CONCLUSIONS: Gene expression (mRNA) generated higher performances, which is marginally improved when other type of genomic data is considered. The level of concordance in prognosis generated from different genomic data types seems to be dependent on censoring rate. PMID- 26516351 TI - Pedobarographic and kinematic analysis in the functional evaluation of two post operative forefoot offloading shoes. AB - BACKGROUND: Forefoot offloading shoes are special orthopaedic footwear designed to protect and unload the injured part of the foot after surgery and for conservative treatments. The offloading action is often achieved by transferring plantar load to the rearfoot via rocker shoes with reduced contact area between shoe and ground. While these shoes are intended to be worn only for short periods, a compromise must be found between functionality and the risk of alterations in gait patterns at the lower limb joints. In this study, the pedobarographic, kinematic and kinetic effects of a traditional half-shoe and a double-rocker full-outsole shoe were compared to those of a comfortable shoe (control). METHODS: Ten healthy female participants (28.2 +/- 10.0 years) were asked to walk in three different footwear conditions for the left/right foot: control/half-shoe, control/full-outsole, and control/control. Full gait analysis was obtained in three walking trials for each participant in each condition. Simultaneously a sensor insole system recorded plantar pressure in different foot regions. Normalized root-mean-square error, coefficient of determination, and frame-by-frame statistical analysis were used to assess differences in time histories of kinematic and kinetic parameters between shoes. RESULTS: The half shoe group showed the slowest walking speed and the shortest stride length. Forefoot plantar load was significantly reduced in the half-shoe (maximum force as % of Body Weight: half-shoe = 62.1; full-outsole = 86.9; control = 93.5; p < 0.001). At the rearfoot, mean pressure was the highest in the full-outsole shoe. At the ankle, sagittal-plane kinematics in the full-outsole shoe had a pattern more similar to control. CONCLUSIONS: The half-shoe appears significantly more effective in reducing plantar load at the forefoot than a double-rocker full outsole shoe, which is designed to reduce forefoot loading by using an insole with a thicker profile anteriorly as to maintain the foot in slight dorsiflexion. However, the half-shoe is also associated with altered gait spatio-temporal parameters, more kinematic modifications at the proximal lower limb joints and reduced propulsion in late stance. PMID- 26516352 TI - Metabolic syndrome and benign prostatic hyperplasia: association or coincidence? AB - BACKGROUND: It has been suggested that individuals with metabolic syndrome (MetS) may be prone to developing benign prostatic hyperplasia (BPH), but the direction of causality remains uncertain. The objective of this cross-sectional study was to evaluate the association between BPH and MetS in men who were referred to surgery for BPH. We were interested in identifying the anthropometric, metabolic, and hormonal factors that potentially influence the risk of both conditions. METHODS: The study was conducted on 128 males with BPH and 141 without BPH (the control group). Fasting glucose, insulin, lipid profiles, total and free testosterone, estradiol, sex-hormone binding protein (SHBG), dehydroepiandrosterone sulfate (DHEA-S), homeostasis model assessment (HOMA-IR) index, and lipid accumulation product (LAP) were all evaluated. RESULTS: The prevalence of MetS was higher in patients with BPH than in the controls (58 vs. 41 %; P = 0.007). In comparison to the controls, patients with BPH had higher levels of cholesterol, low density lipoproteins, DHEA-S, insulin, and HOMA-IR, but lower levels of high-density lipoproteins (HDL), estradiol, and SHBG. The significant predictors of BPH were MetS (OR = 1.961), age (OR = 0.11), HDL (OR = 0.91), insulin (OR = 1.224), SHBG (OR = 0.98), and estradiol (OR = 0.978). Waist circumference and LAP inversely correlated with total and free testosterone and SHBG. CONCLUSIONS: Our study confirmed the frequent coexistence of MetS and BPH. This association seems to be a consequence of the MetS-related metabolic derangements, changes in the sex-hormone milieu, and lowered SHBG levels. PMID- 26516353 TI - Nucleocytoplasmic Translocation of UBXN2A Is Required for Apoptosis during DNA Damage Stresses in Colon Cancer Cells. AB - The subcellular localization, expression level, and activity of anti-cancer proteins alter in response to intrinsic and extrinsic cellular stresses to reverse tumor progression. The purpose of this study is to determine whether UBXN2A, an activator of the p53 tumor suppressor protein, has different subcellular compartmentalization in response to the stress of DNA damage. We measured trafficking of the UBXN2A protein in response to two different DNA damage stresses, UVB irradiation and the genotoxic agent Etoposide, in colon cancer cell lines. Using a cytosol-nuclear fractionation technique followed by western blot and immunofluorescence staining, we monitored and quantitated UBXN2A and p53 proteins as well as p53's downstream apoptotic pathway. We showed that the anti-cancer protein UBXN2A acts in the early phase of cell response to two different DNA damage stresses, being induced to translocate into the cytoplasm in a dose- and time-dependent manner. UVB-induced cytoplasmic UBXN2A binds to mortalin-2 (mot-2), a known oncoprotein in colon tumors. UVB-dependent upregulation of UBXN2A in the cytoplasm decreases p53 binding to mot-2 and activates apoptotic events in colon cancer cells. In contrast, the shRNA-mediated depletion of UBXN2A leads to significant reduction in apoptosis in colon cancer cells exposed to UVB and Etoposide. Leptomycin B (LMB), which was able to block UBXN2A nuclear export following Etoposide treatment, sustained p53-mot-2 interaction and had partially antagonistic effects with Etoposide on cell apoptosis. The present study shows that nucleocytoplasmic translocation of UBXN2A in response to stresses is necessary for its anti-cancer function in the cytoplasm. In addition, LMB-dependent suppression of UBXN2A's translocation to the cytoplasm upon stress allows the presence of an active mot-2 oncoprotein in the cytoplasm, resulting in p53 sequestration as well as activation of other mot 2-dependent growth promoting pathways. PMID- 26516354 TI - ABC-Transporter Expression Does Not Correlate with Response to Irinotecan in Patients with Metastatic Colorectal Cancer. AB - BACKGROUND: Active efflux of irinotecan by ATP-binding cassette (ABC) transporters, in particular ABCB1 and ABCG2, is a well-established drug resistance mechanism in vitro and in pre-clinical mouse models, but its relevance in colorectal cancer (CRC) patients is unknown. Therefore, we assessed the association between ABC-transporter expression and tumour response to irinotecan in patients with metastatic CRC. METHODS: Tissue microarrays of a large cohort of metastatic CRC patients treated with irinotecan in a prospective study (CAIRO study; n=566) were analysed for expression of ABCB1 and ABCG2 by immunohistochemistry. Kaplan-Meier and Cox proportional hazard regression analyses were performed to assess the association of ABC transporter expression with irinotecan response. Gene expression profiles of 17 paired tumours were used to assess the concordance of ABCB1/ABCG2 expression in primary CRC and corresponding metastases. RESULTS: The response to irinotecan was not significantly different between primary tumours with positive versus negative expression of ABCB1 (5.8 vs 5.7 months, p=0.696) or ABCG2 (5.7 vs 6.1 months, p=0.811). Multivariate analysis showed neither ABCB1 nor ABCG2 were independent predictors for progression free survival. There was a mediocre to poor concordance between ABC-transporter expression in paired tumours. CONCLUSION: In metastatic CRC, ABC-transporter expression in the primary tumour does not predict irinotecan response. PMID- 26516355 TI - Parity Correlates with the Timing of Developing Endometrial Cancer, But Not Subtype of Endometrial Cancer. AB - Parity is one of well-known risk factors of endometrial cancer, but it is less clear whether parity is associated with the timing of developing endometrial cancer, and with the incidence of subtype of endometrial cancer. Data on 902 patients including age at diagnosis, age at menarche and menopause, parity and age at last birth from two obstetrics and gynaecology hospitals in China was analysed. 5.6% patients were nulliparous, 53.4% patients had one live birth, 27.7% patients had two live births and 13.3% patients had three or more live births. Patients at diagnosis who had three or more live births were significantly older than patients who were nulliparous or had one or two live births with the median age at diagnosis of 63 versus 51 or 52 or 59 years respectively. The percentage of patients with three or more live births at diagnosis before menopause was significantly lower than patients who were nulliparous, had one live birth or had two live births (10% versus 52%, or 51.9% or 22.4%). Furthermore, time from last birth to endometrial cancer was significantly longer in patients who had three or more live births than patients who had two live births or had one live birth (35 versus 31, or 24 years). However, there was no difference in the incidence of subtypes of endometrial cancer according to parity. Our data suggests parity is negatively correlated with the time onset of endometrial cancer and not associated with the incidence of endometrial cancer subtypes. PMID- 26516356 TI - Receptor for Hyaluronic Acid-Mediated Motility is Associated with Poor Survival in Pancreatic Ductal Adenocarcinoma. AB - Receptor for hyaluronic acid (HA)-mediated motility (RHAMM) is a nonintegral cell surface receptor involved in the aggressive phenotype in a wide spectrum of human malignancies, but the significance of RHAMM in pancreatic ductal adenocarcinoma (PDAC) remains unknown. In this study, we investigated the expression of RHAMM and its clinical relevance in PDAC. RHAMM mRNA expression was examined in 8 PDAC cell lines and in primary pancreatic cancer and adjacent non-tumor tissues from 14 patients using real-time RT-PCR. Western blotting was carried out to analyze the expression of RHAMM protein in PDAC cell lines. We also investigated the expression patterns of RHAMM protein in tissue samples from 70 PDAC patients using immunohistochemistry. The RHAMM mRNA expression was increased in some PDAC cell lines as compared to a non-tumorous pancreatic epithelial cell line HPDE. The RHAMM mRNA expression was significantly higher in PDAC tissues as compared to corresponding non-tumorous pancreatic tissues (P < 0.0001). The RHAMM protein expression was higher in the vast majority of PDAC cell lines relative to the expression in HPDE. The immunohistochemical analysis revealed strong expression of RHAMM in 52 (74%) PDAC tissues. Strong expression of RHAMM was significantly associated with a shorter survival time (P = 0.038). In multivariate analysis, tumor stage (P = 0.039), residual tumor (P = 0.015), and strong RHAMM expression (P = 0.034) were independent factors predicting poor survival. Strong expression of RHAMM may predict poor survival in PDAC patients and may provide prognostic and, possibly, therapeutic value. PMID- 26516357 TI - Stereotactic Body Radiotherapy (SBRT) for Intrahepatic and Hilar Cholangiocarcinoma. AB - BACKGROUND: Unresectable intrahepatic and hilar cholangiocarcinomas carry a dismal prognosis. Systemic chemotherapy and conventional external beam radiation and brachytherapy have been used with limited success. We explored the use of stereotactic body radiotherapy (SBRT) for these patients. METHODS: Patients with unresectable intrahepatic or hilar cholangiocarcinoma or those with positive margins were included in this study. Systemic therapy was used at the discretion of the medical oncologist. The Cyberknife(TM) stereotactic body radiotherapy system used to treat these patients. Patients were treated with three daily fractions. Clinical and radiological follow-up were performed every three months. RESULTS: 34 patients (16 male and 18 female) with 42 lesions were included in this study. There were 32 unresectable tumors and two patients with resected tumors with positive margins. The median SBRT dose was 30Gy in three fractions. The median follow-up was 38 months (range 8-71 months). The actuarial local control rate was 79%. The median overall survival was 17 months and the median progression free survival was ten months. There were four Grade III toxicities (12%), including duodenal ulceration, cholangitis and liver abscess. CONCLUSIONS: SBRT is an effective and reasonably safe local therapy option for unresectable intrahepatic or hilar cholangiocarcinoma. PMID- 26516358 TI - Potential Approaches and Recent Advances in Biomarker Discovery in Clear-Cell Renal Cell Carcinoma. AB - The early diagnosis and monitoring of clear-cell Renal Cell Carcinoma (ccRCC), which is the most common renal malignancy, remains challenging. The late diagnosis and lack of tools that can be used to assess the progression of the disease and metastasis significantly influence the chance of survival of ccRCC patients. Molecular biomarkers have been shown to aid the diagnosis and disease monitoring for other cancers, but such markers are not currently available for ccRCC. Recently, plasma and serum circulating nucleic acids, nucleic acids present in urine, and plasma and urine proteins gained interest in the field of cancer biomarker discovery. Here, we describe the applicability of plasma and urine nucleic acids as cancer biomarkers with a particular focus on DNA, small RNA, and protein markers for ccRCC. PMID- 26516359 TI - CDKN2 Gene Deletion as Poor Prognosis Predictor Involved in the Progression of Adult B-Lineage Acute Lymphoblastic Leukemia Patients. AB - Deletion of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is well known in many hematologic malignancies, but only few reports have investigated this deletion effect on clinical prognosis. This study performed analysis of the CDKN2 deletion in 215 adult B- lineage acute lymphoblastic leukemia (B-ALL) patients, and related cytogenetic prognostic factors (BCR/ABL; E2A/PBXl; TEL/AML1; Mixed Lineage Leukemia (MLL) rearrangement; MYC, Immunoglobulin heavy locus (IGH) translocation). The prevalence of CDKN2 deletions in all study populations was 28.4%. There is no difference between patients with CDKN2 deletion and wild-type patients in sex, age, white blood cells (WBC) count, BM blast percentage, extra infiltration and induction complete remission (CR) rate. Analysis in relapse patients revealed that the distribution of CDKN2 deletion is higher in relapse patients (44.6%) than all patients (28.4%, P=0.006). Deletion of CDKN2 was significantly associated with poor outcomes including decreased overall survival (OS) (P<0.001), lower disease free-survival (DFS) (P<0.001), and increased cumulative incidence of relapse (P=0.002); Also, CDKN2 deletion was strongly associated with IGH translocation (P=0.021); and had an adverse effect on patients with BCR-ABL fusion gene or with MLL rearrangement. Patients with CDKN2 gene deletion benefited from allogenic hematopoietic stem cell transplantation (Allo-HSCT). Deletion of CDKN2 gene was commonly observed through leukemia progression and was poor prognostic marker in long-term outcomes. PMID- 26516360 TI - Chemotherapeutic Response and Prognosis among Lung Cancer Patients with and without Depression. AB - PURPOSE: The current study examined quality of life, progression of disease, and survival rate during chemotherapy in newly diagnosed non-small cell lung cancer (NSCLC) patients with depression (n=48) and without depression (n=78). Further, the study explored the hypothesis that the survival benefit resulted from the chemotherapy of docetaxel and cisplatin (the DC regimen). PATIENTS AND METHODS: In total, 126 patients with newly diagnosed NSCLC participated in a cross sectional study of DC chemotherapy integrated with standard oncology care in depression and non-depression groups. The health-related quality of life (HR-QOL) was assessed using the quality of life questionnaire for Chinese cancer patients receiving chemobiotherapy (QLQ-CCC). Depression was self-rated using the Zung Self-Rating Depression Scale (Z-SDS). Both HR-QOL and Z-SDS were completed before the first and after the last cycle of chemotherapy. Association between depression and quality of life, treatment responses, adverse effects and survival rate was considered positive at the significance level of p<0.05. Pearson and Spearman correlation coefficient, t-test and other statistical analysis were performed using the SPSS software version 13.0 for Windows. RESULTS: In total, 126 lung cancer patients were evaluated, 38% had a diagnosis of depression. The presence of depression was associated with reduced quality of life, increased progression of disease, nausea and fatigue and reduced survival rate by nearly 90 days on follow-up. Therefore, depression significantly predicted worse survival (P=0.009).In addition, the chemotherapy DC regimen did not appear to improve the quality of life in depressed patients (SDS 94.96+/-18.14 before chemotherapy vs. SDS 100.04+/-16.61 after therapy, P=0.155). In a secondary analysis, there was a positive relationship between depression and nausea and fatigue but there was no significant difference in hematologic toxicities between the depression and non depression groups. CONCLUSION: Depression was associated with worse survival in patients with newly diagnosed NSCLC. Also, the chemotherapy DC regimen did not improve quality of life in depressed patients and the data do not support the hypothesis that treatment responses of NSCLC patients with depression mediated the observed survival benefit from the DC regimen. There were more cases of progressed disease in the depressed group. Findings suggest that NSCLC patients with depression are at increased risk for decline in HR-QOL and survival rate during chemotherapy than patients without depression. PMID- 26516361 TI - High Expression of Pyruvate Kinase M2 is Associated with Chemosensitivity to Epirubicin and 5-Fluorouracil in Breast Cancer. AB - BACKGROUND: Pyruvate kinase M2 (PKM2) is the key enzyme in the Warburg effect, and it was recently reported to be involved in the metabolic pathways of chemotherapeutic drugs. However, the role of PKM2 in breast cancer and its influence in the sensitivity to front-line anticancer drugs remains unclear. METHODS: In this study, we examined the correlation between the expression of PKM2 and the sensitivity of primary breast cancer cells to anticancer drugs. PKM2 expression was studied by immunohistochemistry using biopsy samples of 296 patients diagnosed with invasive breast carcinoma, and the collagen gel droplet embedded culture-drug sensitivity tests (CD-DST) was conducted to all the patients to detect in vitro chemosensitivity after surgery. RESULTS: We found high PKM2 expression was significantly associated with in vitro chemosensitivity to epirubicin (EPI) (P=0.019) and 5-fluorouracil (5-Fu) (P=0.009) in breast cancer patients. Then we used a small group of neoadjuvant chemotherapy cases to confirm that the higher PKM2 expression, the better pathological response to therapy was obtained in patients treated with EPI-based or EPI plus 5-Fu chemotherapy regimens. Although univariate and multivariate analysis indicated that high PKM2 was a poor independent predictor of progression free survival (PFS) and overall survival (OS) in breast cancer, patients with PKM2 high expression who received EPI-based or EPI plus 5-Fu chemotherapy were found to have a longer PFS (P=0.003, P=0.013) and OS (P=0.003, P=0.004) than patients treated with non-EPI/5-Fu-based regimens, respectively. CONCLUSIONS: Our findings confirmed the poor prognosis of high PKM2 expression in breast cancer patients and revealed the predictive value of high PKM2 in the therapeutic response to EPI and 5-Fu. Moreover, our results provide the guidance of individual treatment for breast cancer patients who are foreboded a poor prognosis by the presence of high PKM2 status. PMID- 26516362 TI - Risk of Cancer in Patients with Insomnia, Parasomnia, and Obstructive Sleep Apnea: A Nationwide Nested Case-Control Study. AB - PURPOSE: Insomnia, parasomnia, and obstructive sleep apnea have been associated with a number of disease pathologies, but little is known about the relationship of these sleep disorders and cancer. The study explored the risk of sleep disorder (SD)-induced cancer using nationwide population data. Two million data from the National Health Insurance system of Taiwan was used to assess for the relationship. PATIENTS AND METHODS: Patients with cancer as our cases and patients without cancer as our control group in 2001-20011. The study patients were traced back to seek the exposure risk factor of sleep disorders, which was divided into three categories: insomnia, obstructive sleep apnea (OSA) and parasomnia. Patients were selected excluding patients who had cancer prior to presenting with the sleep disorder and the person-year is less than 2 years. Each case was randomly matched with two cases with the same age, gender, and index year. RESULTS: There were significantly increased risks of breast cancer in the patients with insomnia (AHR=1.73; 95% CI: 1.57-1.90), patients with parasomnia (AHR=2.76; 95% CI: 1.53-5.00), and patients with OSA (AHR=2.10; 95% CI: 1.16 3.80). Moreover, patients with parasomnia had significantly higher risk of developing oral cancer (AHR=2.71; 95% CI: 1.02-7.24) compared with patients without parasomnia. The risk of suffering from nasal cancer (AHR=5.96, 95% CI: 2.96-11.99) and prostate cancer (AHR=3.69, 95% CI: 1.98- 6.89) in patients with OSA was significantly higher than that of patients without OSA. CONCLUSIONS: Our findings provided the evidence that people diagnosed with insomnia, parasomnia and OSA are at a higher risk of developing cancers to remind people to improve sleep quality. PMID- 26516363 TI - Second-Line Therapy of Small-Cell Lung Cancer: Topotecan Compared to a Combination Treatment with Adriamycin, Cyclophosphamide And Vincristine (ACO) - a Single Center Experience. AB - BACKGROUND: Randomized trials established topotecan and the combination of adriamycin, cyclophosphamide and vincristine (ACO) as second-line therapy options for small-cell lung cancer. We retrospectively evaluated the outcome of SCLC patients undergoing second-line chemotherapy. PATIENTS AND METHODS: 92 consecutive patients with a diagnosis of SCLC between 2000 and 2010 were analyzed. RESULTS: 86 patients (93.5%) were evaluable for outcome analysis. All patients diagnosed with limited disease (LD) SCLC received platinum-based chemotherapy as first-line treatment. 69 patients (98.6%) diagnosed with extensive disease (ED) SCLC received first-line palliative chemotherapy. In the total cohort, the median overall survival (OS) was 10.3 months (19.2 months and 9.2 months for LD-SCLC and ED-SCLC, respectively). 42 patients received second line therapy (ACO in 47.6% and topotecan in 31.0% of patients, respectively). Eight patients (19.0%) were re-challenged with platinum/etoposide. Neither the overall response rate (52.9% vs. 22.2%; p=0.128) nor progression-free survival (2.4 vs. 2.4 months; p=0.794) or OS (5.5 vs. 5.0 months; p=0.997) were significantly different between ACO and topotecan. ACO-treated patients showed a trend towards a longer duration of inpatient care. CONCLUSION: We showed similar outcomes as reported in clinical trials. Second-line combination chemotherapy with ACO did not show superiority to intravenous topotecan, but was associated with a clinically relevant longer hospitalization time. PMID- 26516364 TI - CD20 Over-Expression in Hodgkin-Reed-Sternberg Cells of Classical Hodgkin Lymphoma: the Neglected Quest. AB - We have scrutinized a previously analyzed cohort of classical Hodgkin lymphoma patients for evidence of a CD20 over-expression. This was pursued in order to determine whether all the 24 (12.6%) CD20+++ patients had clinical and/or biological profiles which would warrant a separate consideration and treatment or would carry a different outcome from our 166 CD20 (-) classical Hodgkin lymphoma patients. Except for an older age and a significantly lower expression of non sialyl-CD15 antigen, both previously described in classical Hodgkin lymphoma, no justification to exclude these CD20+++ patients from the cohort at large is apparent. We suggest that the generally accepted view to the contrary be revised. In addition, we propose alternative interpretations for the low expression of CD20 found in a majority of Hodgkin-Reed-Sternberg cells in classical Hodgkin lymphoma. PMID- 26516365 TI - Identification and Validation of a Five MicroRNA Signature Predictive of Prostate Cancer Recurrence and Metastasis: A Cohort Study. AB - BACKGROUND: MicroRNA (miRNA) have been shown to be important in regulating gene expression in prostate cancer. We used next generation miRNA sequencing to conduct a whole miRNome analysis to identify miRNAs associated with prostate cancer metastasis. METHODS: We conducted discovery and validation analyses of miRNAs among a total of 546 men who underwent surgery for prostate cancer using the development of metastasis as an endpoint. Genome wide analysis was conducted among the discovery group (n=31) to identify new miRNAs associated with prostate cancer metastasis. Selected miRNAs were then analyzed using qPCR on prostatectomy specimens from an independent cohort (n=515) to determine whether their expression could predict the development of metastasis after surgery. To examine the biology underlying these associations, we created prostate cancer cell lines which overexpressed miR-301a for in vitro and in vivo functional assays. RESULTS: We identified 33 miRNAs associated with prostate cancer metastasis and selected a panel comprising miRs-301a, 652, 454, 223 and 139 which strongly predicted metastasis (AUC=95.3%, 95%C.I.:84%-99%). Among the validation cohort, the 15-year metastasis-free survival was 77.5% (95% C.I.:63.9%-86.4%) for patients with a high miRNA panel score and 98.8% (95% C.I.:94.9%-99.7%, p<0.0001 for difference) for those with a low score. After adjusting for grade, stage, and PSA, the hazard ratio for metastasis was 4.3 (95% C.I.: 1.7-11.1, p=0.002) for patients with a high miRNA panel score, compared to those with a low score. Prostate cancer cell lines overexpressing miR-301a had in significantly higher tumor growth and metastasis in a xenograft mouse model. CONCLUSIONS: A panel of miRNAs is associated with prostate cancer metastasis. These could be used as potential new prognostic factors in the surgical management of prostate cancer. PMID- 26516366 TI - Analysis of Clinical and Dosimetric Factors Influencing Radiation-Induced Lung Injury in Patients with Lung Cancer. AB - PURPOSE: Dose escalation of thoracic radiation can improve the local tumor control and surivival, and is in the meantime limited by the occurrence of radiation-induced lung injury (RILI). This study investigated the clinical and dosimetric factors influencing RILI in lung-cancer patients receiving chemoradiotherapy for better radiation planning. METHODS AND MATERIALS: A retrospective analysis was carried out on 161 patients with non-small-cell or small-cell lung cancer (NSCLC and SCLC, respectively), who underwent chemoradiotherapy between April 2010 and May 2011 with a median follow-up time of 545 days (range: 39-1453). Chemotherapy regimens were based on the histological type (squamous cell carcinoma, adenocarcinoma, or SCLC), and radiotherapy was delivered in 1.8-3.0 Gy (median, 2.0 Gy) fractions, once daily, to a total of 39 66 Gy (median, 60 Gy). Univariate analysis was performed to analyze clinical and dosimetric factors associated with RILI. Multivariate analysis using logistic regression identified independent risk factors correlated to RILI. RESULTS: The incidence of symptomatic RILI (>=grade 2) was 31.7%. Univariate analysis showed that V5, V20, and mean lung dose (MLD) were significantly associated with RILI incidence (P=0.029, 0.048, and 0.041, respectively). The association was not statistically significant for histological type (NSCLC vs. SCLC, P = 0.092) or radiation technology (IMRT vs. 3D-CRT, P = 0.095). Multivariate analysis identified MLD as an independent risk factor for symptomatic RILI (OR=1.249, 95%CI=1.055-1.48, P= 0.01). The incidence of bilateral RILI in cases where the tumor was located unilaterally was 22.7% (32/141) and all dosimetric-parameter values were not significantly different (P>0.05) for bilateral versus ipsilateral injury, except grade-1 (low) RILI (P < 0.05). The RILI grade was higher in cases of ipsilateral lung injury than in bilateral cases (Mann-Whitney U test, z=8.216, P< 0.001). CONCLUSION: The dosimetric parameter, MLD, was found to be an independent predictive factor for RILI. Additional contralateral injury does not seem to be correlated with increased RILI grade under the condition of conventional radiotherapy treatment planning. PMID- 26516367 TI - Predicting the Response of Neoadjuvant Therapy for Patients with Esophageal Carcinoma: an In-depth Literature Review. AB - Currently, the most promising strategy to improve the prognosis of advanced esophageal cancer is neoadjuvant chemoradiation (CRT) followed by surgery. However, patients who achieved pathological complete response can experience more survival benefit. Therefore, it is critical to identify the responders early in the course of treatment. Published data demonstrate that clinic-histopathological factors, molecular biomarkers, and functional imaging are predictive of neoadjuvant therapy. The existing biomarkers, including epidermal growth factor receptors, angiogenetic factors, transcription factors, tumor suppressor genes, cell cycle regulators, nucleotide excision repair pathway, cytokines, and chemotherapy associated genes, need to be validated and novel biomarkers warrant further exploration. Positron emission tomography (PET) is useful for differentiating the responders of neoadjuvant CRT. The most valuable parameters and the time point of performing PET in the course of treatment remains to be elucidated. Furthermore, predictive models incorporating the multiple categories of factors need to be established with a large, prospective, and homogeneous patient cohort in the future. Standardization of staging, biomarker detection method, and image acquisition protocol will be critical for the generalization of this model. Prospective, multi-center controlled trials, which stratified patients according to these predictive factors, will help guide individualized treatment strategies for patients with esophageal cancer. PMID- 26516368 TI - Silencing of Survivin Expression Leads to Reduced Proliferation and Cell Cycle Arrest in Cancer Cells. AB - Survivin is an anti-apoptotic gene that is overexpressed in most human tumors. RNA interference using short interfering RNA (siRNA) can be used to specifically inhibit survivin expression. Tumor cells were treated with a newly designed survivin siRNA, which was modified with 2'-OMe. Cellular survivin mRNA and protein levels were determined by real-time qRT-PCR and Western blot, respectively. Cell cycle and apoptosis were determined by flow cytometry. Cell proliferation was measured by MTT assay. Our data showed that the novel survivin targeted siRNA could efficiently knockdown the expression of survivin and inhibit cell proliferation. Survivin mRNA was reduced by 95% after 48h treatment with 20nM siRNA. In addition, the siRNA could markedly arrest the cell cycle at the G2/M checkpoint and induce cellular apoptosis in a dose-dependent manner. The percentage of apoptotic cells reached 50% when treated with 40nM siRNA. In conclusion, we have identified a novel chemically modified siRNA against survivin that is highly efficient and delineated its mechanism of action, thus demonstrating a potential therapeutic role for this molecule in cancer. Further evaluation of this siRNA for therapeutic activity is warranted. PMID- 26516369 TI - First-in-human uPAR PET: Imaging of Cancer Aggressiveness. AB - A first-in-human clinical trial with Positron Emission Tomography (PET) imaging of the urokinase-type plasminogen activator receptor (uPAR) in patients with breast, prostate and bladder cancer, is described. uPAR is expressed in many types of human cancers and the expression is predictive of invasion, metastasis and indicates poor prognosis. uPAR PET imaging therefore holds promise to be a new and innovative method for improved cancer diagnosis, staging and individual risk stratification. The uPAR specific peptide AE105 was conjugated to the macrocyclic chelator DOTA and labeled with (64)Cu for targeted molecular imaging with PET. The safety, pharmacokinetic, biodistribution profile and radiation dosimetry after a single intravenous dose of (64)Cu-DOTA-AE105 were assessed by serial PET and computed tomography (CT) in 4 prostate, 3 breast and 3 bladder cancer patients. Safety assessment with laboratory blood screening tests was performed before and after PET ligand injection. In a subgroup of the patients, the in vivo stability of our targeted PET ligand was determined in collected blood and urine. No adverse or clinically detectable side effects in any of the 10 patients were found. The ligand exhibited good in vivo stability and fast clearance from plasma and tissue compartments by renal excretion. In addition, high uptake in both primary tumor lesions and lymph node metastases was seen and paralleled high uPAR expression in excised tumor tissue. Overall, this first-in human study therefore provides promising evidence for safe use of (64)Cu-DOTA AE105 for uPAR PET imaging in cancer patients. PMID- 26516370 TI - Blood Accessibility to Fibrin in Venous Thrombosis is Thrombus Age-Dependent and Predicts Fibrinolytic Efficacy: An In Vivo Fibrin Molecular Imaging Study. AB - Fibrinolytic therapy of venous thromboembolism (VTE) is increasingly utilized, yet limited knowledge is available regarding in vivo mechanisms that govern fibrinolytic efficacy. In particular, it is unknown how age-dependent thrombus organization limits direct blood contact with fibrin, the target of blood-based fibrinolytic agents. Utilizing high-resolution in vivo optical molecular imaging with FTP11, a near-infrared fluorescence (NIRF) fibrin-specific reporter, here we investigated the in vivo interrelationships of blood accessibility to fibrin, thrombus age, thrombus neoendothelialization, and fibrinolysis in murine venous thrombosis (VT). In both stasis VT and non-stasis VT, NIRF microscopy showed that FTP11 fibrin binding was thrombus age-dependent. FTP11 localized to the luminal surface of early-stage VT, but only minimally to subacute VT (p<0.001). Transmission electron microscopy of early stage VT revealed direct blood cell contact with luminal fibrin-rich surfaces. In contrast, subacute VT exhibited an encasing CD31+ neoendothelial layer that limited blood cell contact with thrombus fibrin in both VT models. Next we developed a theranostic strategy to predict fibrinolytic efficacy based on the in vivo fibrin accessibility to blood NIRF signal. Mice with variably aged VT underwent FTP11 injection and intravital microscopy (IVM), followed by tissue plasminogen activator infusion to induce VT fibrinolysis. Fibrin molecular IVM revealed that early stage VT, but not subacute VT, bound FTP11 (p<0.05), and experienced higher rates of fibrinolysis and total fibrinolysis (p<0.05 vs. subacute VT). Before fibrinolysis, the baseline FTP11 NIRF signal predicted the net fibrinolysis at 60 minutes (p<0.001). Taken together, these data provide novel insights into the temporal evolution of VT and its susceptibility to therapeutic fibrinolysis. Fibrin molecular imaging may provide a theranostic strategy to identify venous thrombi amenable to fibrinolytic therapies. PMID- 26516371 TI - Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1beta. AB - Although strains of attenuated Salmonella typhimurium and wild-type Escherichia coli show similar tumor-targeting capacities, only S. typhimurium significantly suppresses tumor growth in mice. The aim of the present study was to examine bacteria-mediated immune responses by conducting comparative analyses of the cytokine profiles and immune cell populations within tumor tissues colonized by E. coli or attenuated Salmonellae. CT26 tumor-bearing mice were treated with two different bacterial strains: S. typhimurium defective in ppGpp synthesis (DeltappGpp Salmonellae) or wild-type E. coli MG1655. Cytokine profiles and immune cell populations in tumor tissue colonized by these two bacterial strains were examined at two time points based on the pattern of tumor growth after DeltappGpp Salmonellae treatment: 1) when tumor growth was suppressed ('suppression stage') and 2) when they began to re-grow ('re-growing stage'). The levels of IL-1beta and TNF-alpha were markedly increased in tumors colonized by DeltappGpp Salmonellae. This increase was associated with tumor regression; the levels of both IL-1beta and TNF-alpha returned to normal level when the tumors started to re-grow. To identify the immune cells primarily responsible for Salmonellae-mediated tumor suppression, we examined the major cell types that produce IL-1beta and TNF-alpha. We found that macrophages and dendritic cells were the main producers of TNF-alpha and IL-1beta. Inhibiting IL-1beta production in Salmonellae-treated mice restored tumor growth, whereas tumor growth was suppressed for longer by local administration of recombinant IL-1beta or TNF alpha in conjunction with Salmonella therapy. These findings suggested that IL 1beta and TNF-alpha play important roles in Salmonella-mediated cancer therapy. A better understanding of host immune responses in Salmonella therapy may increase the success of a given drug, particularly when various strategies are combined with bacteriotherapy. PMID- 26516372 TI - Blockade of Interplay between IL-17A and Endoplasmic Reticulum Stress Attenuates LPS-Induced Lung Injury. AB - IL-17 is a cytokine mainly from IL-17-producing T cells, which are one of subsets of CD4+ T cells and play a role in adaptive immune system. Recent studies have demonstrated that IL-17A can act rapidly as an innate immune responder during infection before the onset of its classic adaptive immune response. This role of IL-17A in innate immune response is implicated in lipopolysaccharide (LPS) induced lung inflammation. Very recently, we have reported that endoplasmic reticulum (ER) stress is involved in LPS-induced lung inflammation in vivo and in vitro. This study aimed to elucidate the role of IL-17A in LPS-induced lung injury, focusing on the link with ER stress. We treated a murine model of LPS induced lung injury with IL-17A neutralizing antibody and 4-phenylbutyrate (4 PBA), a representative ER stress inhibitor. In addition, we evaluated the effects of IL-17A on ER stress in LPS-stimulated bronchial epithelial cells. Our results showed that inhibition of IL-17A decreased LPS-induced pulmonary neutrophilia, vascular leakage, nuclear translocation of nuclear factor-kappaB (NF-kappaB), infiltration of dendritic cells, increased expression of Toll-like receptor 4 (TLR4), activation of NLRP3 inflammasome, and increased ER stress in the lung. 4 PBA or TAK-242, a TLR4 inhibitor attenuated expression of IL-17A thereby improving LPS-induced lung inflammation. Intriguingly, we observed that stimulation with LPS increased expression of IL-17A in airway epithelial cells and co-stimulation with IL-17A further increased ER stress and NF-kappaB activation. This study indicates that the interrelationship between IL-17A and ER stress plays an important role in LPS-induced injury showing a positive feedback in airway epithelial cells and suggests that targeting their interaction can be a potential therapeutic approach to overcome one of severe refractory pulmonary disorders. PMID- 26516373 TI - Interplay of Oxidative Stress and Autophagy in PAMAM Dendrimers-Induced Neuronal Cell Death. AB - Poly-amidoamine (PAMAM) dendrimers are proposed to be one of the most promising drug-delivery nanomaterials. However, the toxicity of PAMAM dendrimers on the central nervous system seriously hinders their medical applications. The relationship between oxidative stress and autophagy induced by PAMAM dendrimers, and its underlying mechanism remain confusing. In this study, we reported that PAMAM dendrimers induced both reactive oxygen species and autophagy flux in neuronal cells. Interestingly, autophagy might be triggered by the formation of reactive oxygen species induced by PAMAM dendrimers. Suppression of reactive oxygen species could not only impair PAMAM dendrimers-induced autophagic effects, but also reduce PAMAM dendrimers-induced neuronal cell death. Moreover, inhibition of autophagy could protect against PAMAM dendrimers-induced neuronal cell death. These findings systematically elucidated the interplay between oxidative stress and autophagy in the neurotoxicity of PAMAM dendrimers, which might encourage the application of antioxidants and autophagy inhibitors to ameliorate the neurotoxicity of PAMAM dendrimers in clinic. PMID- 26516374 TI - Draft Genome Sequences of Two Species of "Difficult-to-Identify" Human-Pathogenic Corynebacteria: Implications for Better Identification Tests. AB - Non-diphtheriae Corynebacterium species have been increasingly recognized as the causative agents of infections in humans. Differential identification of these bacteria in the clinical microbiology laboratory by the most commonly used biochemical tests is challenging, and normally requires additional molecular methods. Herein, we present the annotated draft genome sequences of two isolates of "difficult-to-identify" human-pathogenic corynebacterial species: C. xerosis and C. minutissimum. The genome sequences of ca. 2.7 Mbp, with a mean number of 2,580 protein encoding genes, were also compared with the publicly available genome sequences of strains of C. amycolatum and C. striatum. These results will aid the exploration of novel biochemical reactions to improve existing identification tests as well as the development of more accurate molecular identification methods through detection of species-specific target genes for isolate's identification or drug susceptibility profiling. PMID- 26516375 TI - Whole Genome Sequence of the Soybean Aphid Endosymbiont Buchnera aphidicola and Genetic Differentiation among Biotype-Specific Strains. AB - Endosymbiosis with microorganisms is common in insects, with more than 10% of species requiring the metabolic capabilities of intracellular bacteria for their nutrient acquisition. Aphids harbor an obligate mutualism with the vertically transferred endosymbiont, Buchnera aphidicola, which produces key nutrients lacking in the aphid's phloem-based diet that are necessary for normal development and reproduction. It is thought that, in some groups of insects, bacterial symbionts may play key roles in biotype evolution against host-plant resistance. The genome of Buchnera has been sequenced in several aphid strains but little genomic data is currently available for the soybean aphid (Aphis glycines), one of the most important pests of soybean in North America. In this study, DNA sequencing was used to assemble and annotate the genome sequence of the Buchnera A. glycines strain and to reconstruct phylogenetic relationships among different strains. In addition, we identified several fixed Buchnera SNPs between Aphis glycines biotypes that were avirulent or virulent to a soybean aphid resistance gene (Rag1). The results of this study describe the genetic and evolutionary relationships of the Buchnera A. glycines strain, and begin to define the roles of an aphid symbiont in host-plant resistance. PMID- 26516376 TI - Promoter methylation status and expression of PPAR-gamma gene are associated with prognosis of acute-on-chronic hepatitis B liver failure. AB - BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been demonstrated to be involved in anti-inflammatory reactions, but its role in acute-on-chronic hepatitis B liver failure (ACHBLF) is unclear. Therefore, DNA methylation patterns and expression level of PPAR-gamma gene were detected in peripheral blood mononuclear cells (PBMCs) from 81 patients with ACHBLF, 50 patients with chronic hepatitis B (CHB), and 30 healthy controls, and the possible role of PPAR-gamma in ACHBLF was analyzed. RESULTS: We found that aberrant PPAR-gamma promoter methylation was attenuated in ACHBLF patients compared with CHB patients and was responsible for the elevated PPAR-gamma expression level, which was negatively correlated with total bilirubin and international normalized ratio. Plasma level of TNF-alpha and IL-6 in ACHBLF patients were higher than CHB patients and healthy controls and significantly reduced in unmethylated group. ACHBLF patients with PPAR-gamma promoter methylation had poorer outcomes than those without. Correspondingly, PPAR-gamma messenger RNA (mRNA) level was higher in survivors than non-survivors and gradually increased in survivors with time, while remained low level in non survivors. CONCLUSIONS: Aberrant promoter methylation decline and PPAR-gamma expression rebound occurred in ACHBLF compared with CHB and could improve prognosis of ACHBLF by negatively regulating cytokines. PMID- 26516377 TI - Clinical features of gastroenteropancreatic tumours. AB - Gastroenteropancreatic (GEP) endocrine tumours (carcinoids and pancreatic islet cell tumours) are composed of multipotent neuroendocrine cells that exhibit a unique ability to produce, store, and secrete biologically active substances and cause distinct clinical syndromes. The classification of GEP tumours as functioning or non-functioning is based on the presence of symptoms that accompany these syndromes secondary to the secretion of hormones, neuropeptides and/or neurotransmitters (functioning tumours). Non-functioning tumours are considered to be neoplasms of neuroendocrine differentiation that are not associated with obvious symptoms attributed to the hypersecretion of metabolically active substances. However, a number of these tumours are either capable of producing low levels of such substances, which can be detected by immunohistochemistry but are insufficient to cause symptoms related to a clinical syndrome, or alternatively, they may secrete substances that are either metabolically inactive or inappropriately processed. In some cases, GEP tumours are not associated with the production of any hormone or neurotransmitter. Both functioning and non-functioning tumours can also produce symptoms due to mass effects compressing vital surrounding structures. Gastroenteropancreatic tumours are usually classified further according to the anatomic site of origin: foregut (including respiratory tract, thymus, stomach, duodenum, and pancreas), midgut (including small intestine, appendix, and right colon), and hindgut (including transverse colon, sigmoid, and rectum). Within these subgroups the biological and clinical characteristics of the tumours vary considerably, but this classification is still in use because a significant number of previous studies, mainly observational, have used it extensively. PMID- 26516378 TI - The role of dietary fibre in inflammatory bowel disease. AB - The aetiology of inflammatory bowel diseases (IBD), which are primarily Crohn's disease and ulcerative colitis, still remains unclear, while the incidence of IBD is constantly increasing, especially in the industrialised countries. Among genetic, environmental, and immunological factors, changes in the composition of the intestinal microflora and diet are indicated as very important in initiating and sustaining inflammation in patients with IBD. Above all nutrients dietary fibre is an especially important component of diet in the context of IBD. A potentially protective effect of high-fibre diet on intestinal disorders was described as early as in 1973. Several trials performed in animal models of IBD and human studies have reported that supplementation of some types of dietary fibre can prolong remission and reduce lesions of the intestinal mucosa during the course of the disease. This paper presents the current state of knowledge on the effects of dietary fibre in IBD. PMID- 26516379 TI - Sorafenib for the treatment of hepatocellular carcinoma with portal vein tumour thrombosis: a systematic review of comparative studies. AB - Sorafenib is the first-line treatment of choice for advanced hepatocellular carcinoma (HCC). However, the benefits of sorafenib in HCC patients with portal vein tumour thrombosis (PVTT) remain uncertain. Until now, a total of eight comparative studies have been identified for this systematic review. Four retrospective studies showed that hepatic arterial infusion chemotherapy, hepatic resection, and three-dimensional conformal radiotherapy might be superior to sorafenib in improving the overall survival. Two ongoing randomised controlled trials (RCTs) will compare the outcomes of transarterial chemoembolisation or radioembolisation with those of sorafenib for the treatment of HCC with PVTT. In addition, two completed RCTs found that additional use of cryotherapy or radiofrequency ablation could prolong the survival of patients receiving sorafenib. In conclusion, the clinical efficacy of sorafenib in HCC patients with PVTT has been widely challenged by other interventions. However, further well designed RCTs are necessary to confirm the findings of retrospective analyses. Cryotherapy or radiofrequency ablation may be considered as an adjunctive therapy in such patients, if sorafenib is prescribed. PMID- 26516380 TI - A meta-analysis of ursodeoxycholic acid therapy versus combination therapy with corticosteroids for PBC-AIH-overlap syndrome: evidence from 97 monotherapy and 117 combinations. AB - In this study, a meta-analysis of randomised controlled trials that compared ursodeoxycholic acid (UDCA) monotherapy with therapies combining UDCA and corticosteroids was performed. We found that combination therapy with UDCA and corticosteroids was more effective than UDCA monotherapy for primary biliary cirrhosis-autoimmune hepatitis-overlap syndrome. PMID- 26516381 TI - The role of mean platelet volume in patients with non-specific abdominal pain in an emergency department. AB - INTRODUCTION: Platelets play an important role in inflammation. Mean platelet volume (MPV) may be a useful parameter for inflammatory conditions, in differentiating between non-specific abdominal pain (NSAP) and conditions requiring surgery, or early diagnosis of abdominal pain as a serious problem for emergency services. AIM: To investigate the role of MPV on NSAP admittance to the emergency department. MATERIAL AND METHODS: The study consisted of 330 patients (186 female and 144 male, with mean age 49 +/-20 years) with NSAP and 249 patients with abdominal pain (144 female and 105 male, with mean age 49 +/-19 years) applied to our emergency service and enrolled to our study. Medical history, physical examination, complete blood count (CBC), and biochemical parameters were evaluated. Haematological parameters were measured by Beckman Coulter LH 780 instrument. Data were compared using Student's t test, and p < 0.05 was accepted as statistically significant. RESULTS: The MPV were significantly lower in patients with NSAP than in others (p = 0.025). There was no significant difference between both sexes with regard to MPV (p > 0.05). Moreover, the other haematological parameters (haemoglobin, platelet, or WBC counts) were not statistically different between both groups (p > 0.05). CONCLUSIONS: The MPV may be a useful, simple, and inexpensive parameter to diagnose or differentiate between NSAP and other conditions. PMID- 26516382 TI - The prevalence of Helicobacter pylori infection in patients with gastric and duodenal ulcers - a 10-year, single-centre experience. AB - INTRODUCTION: Helicobacter pylori (H. pylori) occurs throughout the world and causes gastroduodenal diseases. There is data indicating a change in the prevalence of H. pylori infection worldwide. The prevalence of H. pylori is 80% in Turkey, while it is higher in many developing countries, and the rate of infection varies throughout the world. In many developing countries, the prevalence of infection exceeds 90% by adulthood. AIM: To determine the change in the rate of H. pylori infection in gastric ulcers and duodenal ulcers for a 10 year period in a single centre. MATERIAL AND METHODS: The study population included 550 patients (342 in 2004, 208 in 1994) with gastric and duodenal ulcers. RESULTS: In 2004 there were 125 (36.5%) patients with gastric ulcer and 217 patients with duodenal ulcer (64.5%). CLO test positivity was 39.2% in patients with gastric ulcers and 60% in patients with duodenal ulcers. In 1994 there were 208 patients (159 duodenal ulcers, 49 gastric ulcers). Urease test was positive in 74.2% of patients with duodenal ulcer and in 65.2% of patients with gastric ulcer. The decrease in the rate of urease positivity in patients with gastric ulcer was statistically significant (p = 0.01) during this 10-year period. CONCLUSIONS: In the present study we found that the urease positivity decreased significantly in patients with gastric ulcer between 1994 and 2004. PMID- 26516383 TI - Safety profile of biologic therapy in Polish paediatric patients with Crohn's disease. AB - INTRODUCTION: In recent years, monoclonal antibodies against tumor necrosis factor alpha (TNF-alpha), infliximab (IFX), and adalimumab (ADA) have gained increasing popularity in Crohn's disease (CD) management. Many clinical trials have shown that biologics are a generally well-tolerated and safe treatment. However, the follow-up time with regards to safety is too short, and data on that issue are still limited. AIM: To report the cumulative safety profile of biologic therapy with IFX and/or ADA, up to 8 years, in Polish children with moderately to severely active CD. MATERIAL AND METHODS: We performed a retrospective analysis of 110 children, aged 13.0 +/-9.3 years, diagnosed with CD, and treated with IFX and/or ADA, within a period of 8 years between 2005 and 2013. Safety data for all treated patients were collected throughout the entire treatment period and were included in the safety analyses. RESULTS: The cumulative rates of treatment related adverse events (AE) (TRAEs) in all patients were 67 events - 43 (64.17%) events for IFX and 24 (35.83%) for ADA, respectively. The majority of TEAEs were mild-to-moderate in intensity. The most frequently reported ones were: anaemia in 17 (20.23%) IFX patients and 9 (23.08%) ADA patients, and mild infections in 9 (10.7%) IFX patients and 5 (12.8%) ADA patients, respectively. We did not report any serious AE (sAE). CONCLUSIONS: Biologic therapy with infliximab and/or adalimumab is generally well tolerated and safe, and does not cause any sAEs. PMID- 26516384 TI - Delta hepatitis-related thyroid disease: a unique phenomenon. AB - INTRODUCTION: Hepatitis delta virus (HDV) infection is a serious health problem worldwide. Thyroid disturbances represent a major limitation to the efficacy of interferon treatment targeting chronic HDV (C-HDV) infection. Moreover, pre treatment thyroid diseases may be influenced by interferon therapy. Despite this, the characteristic features of the thyroid diseases in C-HDV patients remain poorly characterised. AIM: To determine the prevalence of thyroid diseases and evaluate the impact of delta hepatitis on thyroid function tests. MATERIAL AND METHODS: We retrospectively reviewed the charts of 127 hepatitis C virus (HCV) negative adults, treatment-naive outpatients with C-HDV, between July 2013 and July 2014. Thyroid-stimulating hormone (TSH) and thyroid antibodies (TAbs) including anti-thyroid peroxidase antibodies (anti-TPO), liver transaminases, and other routine laboratory tests were conducted during the study period. RESULTS: A total of 127 C-HDV patients (female 52.9%, mean age 54.5 +/-8.01 years) were enrolled. The rate of hypothyroidism, defined as a TSH level above 10 IU/l, was 4.7%. No patient had hyperthyroidism. Both elevated levels of liver transaminases and HDV ribonucleic acid (HDV-RNA) were positively correlated with high levels of thyroid autoantibodies. CONCLUSIONS: The rate of hypothyroidism is higher than the rate of hyperthyroidism at baseline. Most remarkably, for the first time we discovered a correlation between disturbed thyroid autoantibodies and elevated liver transaminases as well as high HDV-RNA levels even in euthyroid delta hepatitis patients. But in order to have an adequate understanding of such correlations, further studies are needed. PMID- 26516386 TI - Massive gastrointestinal bleeding caused by a gastrointestinal stromal tumour of the third part of the duodenum treated by means of emergency partial duodenal resection. PMID- 26516385 TI - The burden of different pathogens in acute diarrhoeal episodes among a cohort of Egyptian children less than five years old. AB - INTRODUCTION: Diarrhoea continues to cause significant morbidity in Egypt. AIM: To determine the frequency and distribution of different enteropathogens in acute diarrhoeal episodes, utilising an expanded testing regimen, and to correlate clinical signs and symptoms associated with the detected pathogens. MATERIAL AND METHODS: The case-control study enrolled 356 patients < 5 years old with acute diarrhoea and 356 age and sex-matched healthy controls. Both cases and controls underwent a full history and physical examination, and provided two rectal swab specimens and a stool sample. Laboratory analysis included stool culture, microscopy, and indirect methods. RESULTS: Rotavirus was detected in 11% of patients. Enterotoxigenic Escherichia coli (ETEC), Campylobacter, Shigella, and Salmonella were detected in 7%, 3.7%, 1.1%, and 1.4% of patients, respectively; and in 11.1%, 3.1%, 0.6%, and 0.6% of controls, respectively, with no significant statistical difference. Cryptosporidium was detected in 3.9% of cases. Mixed infection was detected in 5.9% of cases and 0.9% of controls, with a significant difference (p < 0.001). No pathogen was detected in 66.3% of cases and in 83.5% of controls. Rotavirus infection was associated with recurrent vomiting, dehydration, and hospitalisation. Bacterial diarrhoea was associated with vomiting (52%) in ETEC infections, fever (80%) in Salmonella infections, mucus (100%) and blood (50%) in stools of Shigella infections, and convulsions (15%) in Campylobacter infections. CONCLUSIONS: Rotavirus is a prominent cause of diarrhoea among Egyptian children. Despite utilising an expanded testing regimen, more work is still needed for identification of other enteropathogens that constitute other causative agents of diarrhoea. PMID- 26516387 TI - Renal cell carcinoma metastases to the pancreas and the thyroid gland 19 years after the primary tumour. PMID- 26516388 TI - Aneurysm of Mid and Apical Interventricular Cardiac Septum Dissecting Along the Basal Part - An Uncommon Entity Diagnosed with CT Angiography. AB - BACKGROUND: Aneurysm of the muscular interventricular septum is a rare entity as compared to the membranous part. Only a few cases of dissecting septal aneurysm have been reported in literature. Two-dimensional echocardiography is the initial diagnostic modality with ECG-gated CT and MRI being non-invasive imaging modalities for comprehensive evaluation. The complications can arise from chronic pressure erosion of the intervening septal myocardium, leading to left-to-right shunting in the form of ventricular septal defect and paradoxical thromboembolism. Radiologists should be aware of imaging findings of interventricular septal aneurysm, because of its rarity of occurrence and complications. CASE REPORT: A 48-year-old male patient presented to a cardiology department with complaints of intermittent chest pain, palpitations and exertional dyspnoea. CT angiography revealed a wide-mouth large aneurysm arising from the mid and apical portion of the interventricular septum dissecting into the basal part. There was associated significant bowing (>15 mm) of the septum and mild obliteration of the right ventricular cavity. Myocardium surrounding the aneurysm was identified with no associated ventricular septal defect (VSD). No evidence of intraventricular clot was found. Catheter angiography confirmed the CT angiographic findings. CONCLUSIONS: Radiologists should be aware of imaging findings of interventricular septal aneurysm, because of its rarity of occurrence, complication in the form of thromboembolism, dissection and intracardiac shunting and mass effect over adjacent cardiovascular structures. Careful scrutiny is essential to avoid labelling of these cases as cardiac masses. PMID- 26516389 TI - Evaluation of the Degradation of the Selected Projectile, Commissural and Association White Matter Tracts Within Normal Appearing White Matter in Patients with Multiple Sclerosis Using Diffusion Tensor MR Imaging - a Preliminary Study. AB - BACKROUND: The aim of the study was to assess the impairment of the selected white matter tracts within normal appearing white matter (NAWM) in multiple sclerosis (MS) patients using diffusion tensor imaging (DTI). MATERIAL/METHODS: Thirty-six patients (mean age 33.4 yrs) with clinically definite, relapsing remitting MS and mild disability (EDSS - Expanded Disability Status Scale 1-3.5) and 16 control subjects (mean age 34.4 yrs) were enrolled in the study. DTI examinations were performed on a 1.5T MR scanner. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained with a small ROI method in several white matter tracts within NAWM including: the middle cerebellar peduncles (MCP), the inferior longitudinal fasciculi (ILF), inferior frontooccipital fasciculi (IFOF), genu (GCC) and splenium of the corpus callosum (SCC), posterior limbs of the internal capsules (PLIC), superior longitudinal fasciculi (SLF) and posterior cingula (CG). There were no demyelinative lesions within the ROIs in any of the patients. RESULTS: A significant decrease in FA was found in MS patients in both the ILFs and IFOFs (p<0.001) and in the left MCP and right SLF (p<0.05), compared to the normal subjects. There were no significant differences in FA values in the remaining evaluated ROIs, between MS patients and the control group. A significant increase in ADC (p<0.05) was found only in the right PLIC and the right SLF in MS subjects, compared to the control group. CONCLUSIONS: The FA values could be a noninvasive neuroimaging biomarker for assessing the microstructural changes within NAWM tracts in MS patients. PMID- 26516390 TI - Horseshoe Lung Associated with Left Lung Hypoplasia: Case Report and Systematic Review of the Literature. AB - Horseshoe lung (HL) is often associated with cardiovascular malformations such as scimitar syndrome and unilateral lung hypoplasia. In patients with HL, the hypoplastic lung is almost always located on the right side. Cases of HL with a hypoplastic left lung are extremely rare. In this paper, we describe a case of a one-day-old boy with HL involving left lung hypoplasia and perform a systematic review of the literature on HL with left lung hypoplasia. Only 10 cases of HL involving left lung hypoplasia have been reported in the literature. Most of those cases also exhibited cardiovascular malformations and pulmonary hypertension. There have not been any reported cases of HL involving left lung hypoplasia associated with scimitar syndrome. HL involving left lung hypoplasia is rare and tends to be associated with pulmonary hypertension. PMID- 26516391 TI - Metacognition in animals. AB - Metacognition is thinking about thinking. There is considerable interest in developing animal models of metacognition to provide insight about the evolution of mind and a basis for investigating neurobiological mechanisms of cognitive impairments in people. Formal modeling of low-level (i.e., alternative) mechanisms has recently demonstrated that prevailing standards for documenting metacognition are inadequate. Indeed, low-level mechanisms are sufficient to explain data from existing methods. Consequently, an assessment of what is 'lost' (in terms of existing methods and data) necessitates the development of new, innovative methods for metacognition. Development of new methods may prompt the establishment of new standards for documenting metacognition. PMID- 26516393 TI - [Fibromyxoid sarcoma of unusual location]. PMID- 26516392 TI - [Foreign bodies in ENT: ten-year experience]. PMID- 26516394 TI - Desmoid tumors: clinical features and treatment options: a case report and a review of literature. AB - Desmoid tumors are a rare group of locally aggressive, non malignant tumors of fibroblastic origin that can lead to significant morbidity due to local invasion and may even result in a fatal outcome when located around vital organs. Their clinical presentation, biological behavior and natural history can be quite varied and is incompletely understood at the present time. The optimal therapeutic approach depends on various factors, and a multidisciplinary approach is necessary to achieve local control with acceptable morbidity. Despite progress in the understanding of these tumors and the treatment options, local recurrence remains a major problem. PMID- 26516395 TI - Usefulness of routine preoperative testing in a developing country: a prospective study. AB - INTRODUCTION: The assessment of anesthetic risks is an essential component of preoperative evaluation. In developing world, preanesthesia evaluation may be challenging because patient's medical history and records are scare, and language barrier limits physical examination. Our objective was to evaluate the impact of routine preoperative testing in a low-resources setting. METHODS: Prospective observational study performed in a French forward surgical unit in Abidjan, Ivory Coast. 201 patients who were scheduled for non urgent surgery were screened with routine laboratory exams during preoperative evaluation. Changes in surgery were assessed (delayed or scheduled). RESULTS: Abnormal hemoglobin findings were reported in 35% of patients, abnormal WBC count in 11,1% of patients, abnormal platelets in 15,3% of patients. Positive HIV results were found in 8,3% of cases. Routine tests represented 43,6% of changes causes. CONCLUSION: Our study showed that in a developing country, routine preoperative tests showed abnormal results up to 35% of cases, and represented 43,5% of delayed surgery causes. The rate of tests leading to management changes varied widely, from 0% to 8,3%. These results suggested that selected tests would be useful to diagnose diseases that required treatment before non urgent surgery. However, larger studies are needeed to evaluate the cost/benefit ratio and the clinical impact of such a strategy. PMID- 26516396 TI - [Lung co-infection by Pneumocystis jirovecii and Pseudomonas aeruginosa in AIDS: report of two cases]. PMID- 26516398 TI - [Recurrent pericarditis indicative of a cardiac angiosarcoma]. PMID- 26516397 TI - A giant right atrial myxoma with pulmonary arterial hypertension. AB - Here we report a case of a right atrial mass that morphology mimicking myxoma, in a young patient with no past medical history. The mass was pathologically confirmed to be symptomatic and surgical removal was successfully done. PMID- 26516399 TI - [Malignant historical schwannoma of the forearm]. PMID- 26516400 TI - [Evaluation of the use of the partograph in a maternity of a university hospital]. PMID- 26516401 TI - [Atypical form of Lyme disease]. PMID- 26516403 TI - [Lacunar skull revealing a sinus pericranii]. PMID- 26516402 TI - Dynamic of plasmodium falciparum chloroquine resistance transporter gene Pfcrt K76T mutation five years after withdrawal of chloroquine in Burkina Faso. AB - We investigated the evolution of Pfcrt K76T mutation five years after the withdrawal of chloroquine in Burkina Faso. A total of 675 clinical isolates collected from October 2010 to September 2012 were successfully genotyped. Single nucleotide polymorphism in Pfcrt (codon 76) gene was analyzed. The prevalence of resistant Pfcrt 76T allele was 20.55%. There was a progressive decrease of the proportion of mutant type pfcrt T76 from 2010 to 2012 (X2=5.508 p=0.0189). Our results suggest a progressive return of the wild type Pfcrt K76 in Burkina Faso but the prevalence of the mutants Pfcrt T76 still remains high. PMID- 26516404 TI - Genomic information of the arsenic-resistant bacterium Lysobacter arseniciresistens type strain ZS79(T) and comparison of Lysobacter draft genomes. AB - Lysobacter arseniciresistens ZS79(T) is a highly arsenic-resistant,rod-shaped, motile, non-spore-forming, aerobic, Gram-negative bacterium. In this study, four Lysobacter type strains were sequenced and the genomic information of L. arseniciresistens ZS79(T) and the comparative genomics results of the Lysobacter strains were described. The draft genome sequence of the strain ZS79(T) consists of 3,086,721 bp and is distributed in 109 contigs. It has a G+C content of 69.5 % and contains 2,363 protein-coding genes including eight arsenic resistant genes. PMID- 26516405 TI - High quality draft genomes of the Mycoplasma mycoides subsp. mycoides challenge strains Afade and B237. AB - Members of the Mycoplasma mycoides cluster' represent important livestock pathogens worldwide. Mycoplasma mycoides subsp. mycoides is the etiologic agent of contagious bovine pleuropneumonia (CBPP), which is still endemic in many parts of Africa. We report the genome sequences and annotation of two frequently used challenge strains of Mycoplasma mycoides subsp. mycoides, Afade and B237. The information provided will enable downstream 'omics' applications such as proteomics, transcriptomics and reverse vaccinology approaches. Despite the absence of Mycoplasma pneumoniae like cyto-adhesion encoding genes, the two strains showed the presence of protrusions. This phenotype is likely encoded by another set of genes. PMID- 26516406 TI - Draft genome sequence of a nitrate-reducing, o-phthalate degrading bacterium, Azoarcus sp. strain PA01(T). AB - Azoarcus sp. strain PA01(T) belongs to the genus Azoarcus, of the family Rhodocyclaceae within the class Betaproteobacteria. It is a facultatively anaerobic, mesophilic, non-motile, Gram-stain negative, non-spore-forming, short rod-shaped bacterium that was isolated from a wastewater treatment plant in Constance, Germany. It is of interest because of its ability to degrade o phthalate and a wide variety of aromatic compounds with nitrate as an electron acceptor. Elucidation of the o-phthalate degradation pathway may help to improve the treatment of phthalate-containing wastes in the future. Here, we describe the features of this organism, together with the draft genome sequence information and annotation. The draft genome consists of 4 contigs with 3,908,301 bp and an overall G + C content of 66.08 %. Out of 3,712 total genes predicted, 3,625 genes code for proteins and 87 genes for RNAs. The majority of the protein-encoding genes (83.51 %) were assigned a putative function while those remaining were annotated as hypothetical proteins. PMID- 26516407 TI - Understanding leukemic hematopoiesis as a complex adaptive system. AB - Normal and abnormal hematopoiesis is working as a complex adaptive system. From this perspective, the development and the behavior of hematopoietic cell lineages appear as a balance between normal and abnormal hematopoiesis in the setting of a functioning or malfunctioning microenvironment under the control of the immune system and the influence of hereditary and environmental events. PMID- 26516409 TI - Therapies targeting cancer stem cells: Current trends and future challenges. AB - Traditional therapies against cancer, chemo- and radiotherapy, have multiple limitations that lead to treatment failure and cancer recurrence. These limitations are related to systemic and local toxicity, while treatment failure and cancer relapse are due to drug resistance and self-renewal, properties of a small population of tumor cells called cancer stem cells (CSCs). These cells are involved in cancer initiation, maintenance, metastasis and recurrence. Therefore, in order to develop efficient treatments that can induce a long-lasting clinical response preventing tumor relapse it is important to develop drugs that can specifically target and eliminate CSCs. Recent identification of surface markers and understanding of molecular feature associated with CSC phenotype helped with the design of effective treatments. In this review we discuss targeting surface biomarkers, signaling pathways that regulate CSCs self-renewal and differentiation, drug-efflux pumps involved in apoptosis resistance, microenvironmental signals that sustain CSCs growth, manipulation of miRNA expression, and induction of CSCs apoptosis and differentiation, with specific aim to hamper CSCs regeneration and cancer relapse. Some of these agents are under evaluation in preclinical and clinical studies, most of them for using in combination with traditional therapies. The combined therapy using conventional anticancer drugs with CSCs-targeting agents, may offer a promising strategy for management and eradication of different types of cancers. PMID- 26516412 TI - Intimal pericytes as the second line of immune defence in atherosclerosis. AB - Inflammation plays an essential role in the development of atherosclerosis. The initiation and growth of atherosclerotic plaques is accompanied by recruitment of inflammatory and precursor cells from the bloodstream and their differentiation towards pro-inflammatory phenotypes. This process is orchestrated by the production of a number of pro-inflammatory cytokines and chemokines. Human arterial intima consists of structurally distinct leaflets, with a proteoglycan rich layer lying immediately below the endothelial lining. Recent studies reveal the important role of stellate pericyte-like cells (intimal pericytes) populating the proteoglycan-rich layer in the development of atherosclerosis. During the pathologic process, intimal pericytes may participate in the recruitment of inflammatory cells by producing signalling molecules and play a role in the antigen presentation. Intimal pericytes are also involved in lipid accumulation and the formation of foam cells. This review focuses on the role of pericyte-like cells in the development of atherosclerotic lesions. PMID- 26516413 TI - Cost-effectiveness modelling of percutaneous coronary interventions in stable coronary artery disease. AB - The objective of this study is to develop a cost-effectiveness model comparing drug eluting stents (DES) vs bare metal stent (BMS) in patients suffering of stable coronary artery disease. Using a 2-years time horizon, two simulation models have been developed: BMS first line strategy and DES first line strategy. Direct medical costs were estimated considering ambulatory and hospital costs. The effectiveness endpoint was defined as treatment success, which is the absence of major adverse cardiac events. Probabilistic sensitivity analyses were carried out using 10000 Monte-Carlo simulations. DES appeared slightly more efficacious over 2 years (60% of success) when compared to BMS (58% of success). Total costs over 2 years were estimated at 9303 ? for the DES and at 8926 ? for bare metal stent. Hence, corresponding mean cost-effectiveness ratios showed slightly lower costs (P < 0.05) per success for the BMS strategy (15520 ?/success), as compared to the DES strategy (15588 ?/success). Incremental cost-effectiveness ratio is 18850 ? for one additional percent of success. The sequential strategy including BMS as the first option appears to be slightly less efficacious but more cost effective compared to the strategy including DES as first option. Future modelling approaches should confirm these results as further comparative data in stable coronary artery disease and long-term evidence become available. PMID- 26516408 TI - Common stemness regulators of embryonic and cancer stem cells. AB - Pluripotency of embryonic stem cells (ESCs) and induced pluripotent stem cells is regulated by a well characterized gene transcription circuitry. The circuitry is assembled by ESC specific transcription factors, signal transducing molecules and epigenetic regulators. Growing understanding of stem-like cells, albeit of more complex phenotypes, present in tumors (cancer stem cells), provides a common conceptual and research framework for basic and applied stem cell biology. In this review, we highlight current results on biomarkers, gene signatures, signaling pathways and epigenetic regulators that are common in embryonic and cancer stem cells. We discuss their role in determining the cell phenotype and finally, their potential use to design next generation biological and pharmaceutical approaches for regenerative medicine and cancer therapies. PMID- 26516411 TI - Whey protein: The "whey" forward for treatment of type 2 diabetes? AB - A cost-effective nutritional approach to improve postprandial glycaemia is attractive considering the rising burden of diabetes throughout the world. Whey protein, a by-product of the cheese-making process, can be used to manipulate gut function in order to slow gastric emptying and stimulate incretin hormone secretion, thereby attenuating postprandial glycaemic excursions. The function of the gastrointestinal tract plays a pivotal role in glucose homeostasis, particularly during the postprandial period, and this review will discuss the mechanisms by which whey protein slows gastric emptying and stimulates release of gut peptides, including the incretins. Whey protein is also a rich source of amino acids, and these can directly stimulate beta cells to secrete insulin, which contributes to the reduction in postprandial glycaemia. Appetite is suppressed with consumption of whey, due to its effects on the gut-brain axis and the hypothalamus. These properties of whey protein suggest its potential in the management of type 2 diabetes. However, the optimal dose and timing of whey protein ingestion are yet to be defined, and studies are required to examine the long-term benefits of whey consumption for overall glycaemic control. PMID- 26516410 TI - Erythropoietin and diabetes mellitus. AB - Erythropoietin (EPO) is a 30.4 kDa growth factor and cytokine that governs cell proliferation, immune modulation, metabolic homeostasis, vascular function, and cytoprotection. EPO is under investigation for the treatment of variety of diseases, but appears especially suited for the treatment of disorders of metabolism that include diabetes mellitus (DM). DM and the complications of this disease impact a significant portion of the global population leading to disability and death with currently limited therapeutic options. In addition to its utility for the treatment of anemia, EPO can improve cardiac function, reduce fatigue, and improve cognition in patients with DM as well as regulate cellular energy metabolism, obesity, tissue repair and regeneration, apoptosis, and autophagy in experimental models of DM. Yet, EPO can have adverse effects that involve the vasculature system and unchecked cellular proliferation. Critical to the cytoprotective capacity and the potential for a positive clinical outcome with EPO are the control of signal transduction pathways that include protein kinase B, the mechanistic target of rapamycin, Wnt signaling, mammalian forkhead transcription factors of the O class, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), and AMP activated protein kinase. Therapeutic strategies that can specifically target and control EPO and its signaling pathways hold great promise for the development of new and effective clinical treatments for DM and the complications of this disorder. PMID- 26516414 TI - "Obesity paradox" in coronary artery disease. AB - Obesity used to be among the more neglected public health problems, but has unfolded as a growing medical and socioeconomic burden of epidemic proportions. Morbid obesity is linked to traditional cardiovascular risk factors like, hypertension, hyperlipidemia and diabetes, and suspected to incur increased morbidity and mortality in the Western and even third world populations. This patient cohort is also at greater risk to develop coronary artery disease. Recent population-based registries revealed that 43% and 24% of all cases of coronary revascularization were carried out in overweight and obese patients, respectively. However, despite evidence of a positive correlation between obesity and increased cardiovascular morbidity, some authors have described a better clinical outcome in overweight and obese patients, a phenomenon they coined "obesity paradoxon". Thus, there is an ongoing debate in light of conflicting data and the possibility of confounding bias causing misconception and challenging the "obesity paradox". In this review article we present the current evidence and throughly discuss the validity of the "obesity paradoxon" in a variety of clinical settings. PMID- 26516415 TI - Lipoprotein-associated phospholipase A2 prognostic role in atherosclerotic complications. AB - Atherosclerosis manifests itself clinically at advanced stages when plaques undergo hemorrhage and/or rupture with superimposed thrombosis, thus abruptly stopping blood supply. Identification of markers of plaque destabilization at a pre-clinical stage is, therefore, a major goal of cardiovascular research. Promising results along this line were provided by studies investigating the lipoprotein-associated phospholipase A2 (Lp-PLA2), a member of phospholipase A2 proteins family that plays a key role in the metabolism of pro-inflammatory phospholipids, as oxidized low-density lipoproteins, and in the generation of pro atherogenic metabolites, including lysophosphatidylcholine and oxidized free fatty acids. We herein review the experimental and clinical studies supporting use of Lp-PLA2 activity for predicting cardiovascular events. To his end we considered not only Lp-PLA2 activity and mass, but also Lp-PLA2 gene variations and their association with incident coronary artery disease, stroke, and cardiovascular mortality. Based on these evidences the major scientific societies have included in their guidelines the measurement of Lp-PLA2 activity among the biomarkers that are useful in risk stratification of adult asymptomatic patients at intermediate cardiovascular risk. The results of two recently published major clinical trials with the Lp-PLA2 inhibitor darapladib, which seem to challenge the pathogenic role of Lp-PLA2, will also be discussed. PMID- 26516416 TI - Cardioprotection by remote ischemic conditioning: Mechanisms and clinical evidences. AB - In remote ischemic conditioning (RIC), several cycles of ischemia and reperfusion render distant organ and tissues more resistant to the ischemia-reperfusion injury. The intermittent ischemia can be applied before the ischemic insult in the target site (remote ischemic preconditioning), during the ischemic insult (remote ischemic perconditioning) or at the onset of reperfusion (remote ischemic postconditioning). The mechanisms of RIC have not been completely defined yet; however, these mechanisms must be represented by the release of humoral mediators and/or the activation of a neural reflex. RIC has been discovered in the heart, and has been arising great enthusiasm in the cardiovascular field. Its efficacy has been evaluated in many clinical trials, which provided controversial results. Our incomplete comprehension of the mechanisms underlying the RIC could be impairing the design of clinical trials and the interpretation of their results. In the present review we summarize current knowledge about RIC pathophysiology and the data about its cardioprotective efficacy. PMID- 26516417 TI - Cardiovascular disease in human immunodeficiency virus infected patients: A true or perceived risk? AB - After the successful introduction of highly active antiretroviral agents the survival of patients infected with the human immunodeficiency virus (HIV) in developed countries has increased substantially. This has allowed the surfacing of several chronic diseases among which cardiovascular disease (CVD) is prominent. The pathogenesis of CVD in HIV is complex and involves a combination of traditional and HIV related factors. An accurate assessment of risk of CVD in these patients is still elusive and as a consequence the most appropriate preventive and therapeutic interventions remain controversial. PMID- 26516418 TI - Concepts of hypoxic NO signaling in remote ischemic preconditioning. AB - Acute coronary syndromes remain a leading single cause of death worldwide. Therapeutic strategies to treat cardiomyocyte threatening ischemia/reperfusion injury are urgently needed. Remote ischemic preconditioning (rIPC) applied by brief ischemic episodes to heart-distant organs has been tested in several clinical studies, and the major body of evidence points to beneficial effects of rIPC for patients. The underlying signaling, however, remains incompletely understood. This relates particularly to the mechanism by which the protective signal is transferred from the remote site to the target organ. Many pathways have been forwarded but none can explain the protective effects completely. In light of recent experimental studies, we here outline the current knowledge relating to the generation of the protective signal in the remote organ, the signal transfer to the target organ and the transduction of the transferred signal into cardioprotection. The majority of studies favors a humoral factor that activates cardiomyocyte downstream signaling - receptor-dependent and independently. Cellular targets include deleterious calcium (Ca(2+)) signaling, reactive oxygen species, mitochondrial function and structure, and cellular apoptosis and necrosis. Following an outline of the existing evidence, we will furthermore characterize the existing knowledge and discuss future perspectives with particular emphasis on the interaction between the recently discovered hypoxic nitrite-nitric oxide signaling in rIPC. This refers to the protective role of nitrite, which can be activated endogenously using rIPC and which then contributes to cardioprotection by rIPC. PMID- 26516419 TI - Potential of dietary nitrate in angiogenesis. AB - Endothelial dysfunction with impaired bioavailability of nitric oxide (NO) is the hallmark in the development of cardiovascular disease. Endothelial dysfunction leads to atherosclerosis, characterized by chronic inflammation of the arterial wall and stepwise narrowing of the vessel lumen. Atherosclerosis causes deprivation of adequate tissue blood flow with compromised oxygen supply. To overcome this undersupply, remodeling of the vascular network is necessary to reconstitute and sustain tissue viability. This physiological response is often not sufficient and therapeutic angiogenesis remains an unmet medical need in critical limb ischemia or coronary artery disease. Feasible approaches to promote blood vessel formation are sparse. Administration of pro-angiogenic factors, gene therapy, or targeting of microRNAs has not yet entered the daily practice. Nitric oxide is an important mediator of angiogenesis that becomes limited under ischemic conditions and the maintenance of NO availability might constitute an attractive therapeutic target. Until recently it was unknown how the organism provides NO under ischemia. In recent years it could be demonstrated that NO can be formed independently of its enzymatic synthesis in the endothelium by reduction of inorganic nitrite under hypoxic conditions. Circulating nitrite derives from oxidation of NO or reduction of inorganic nitrate by commensal bacteria in the oral cavity. Intriguingly, nitrate is a common constituent of our everyday diet and particularly high concentrations are found in leafy green vegetables such as spinach, lettuce, or beetroot. Evidence suggests that dietary nitrate supplementation increases the regenerative capacity of ischemic tissue and that this effect may offer an attractive nutrition-based strategy to improve ischemia-induced revascularization. We here summarize and discuss the regenerative capacity of dietary nitrate on the vascular system. PMID- 26516420 TI - Is there a rationale for short cardioplegia re-dosing intervals? AB - While cardioplegia has been used on millions of patients during the last decades, the debate over the best technique is still going on. Cardioplegia is not only meant to provide a non-contracting heart and a field without blood, thus avoiding the risk of gas emboli, but also used for myocardial protection. Its electromechanical effect is easily confirmed through direct vision of the heart and continuous electrocardiogram monitoring, but there is no consensus on the best way to assess the quality of myocardial protection. The optimal approach is thus far from clear and the considerable amount of literature on the subject fails to provide a definite answer. Cardioplegia composition (crystalloid vs blood, with or without various substrate enhancement), temperature and site(s) of injection have been extensively researched. While less frequently studied, re dosing interval is also an important factor. A common and intuitive idea is that shorter re-dosing intervals lead to improved myocardial protection. A vast majority of surgeons use re-dosing intervals of 20-30 min, or even less, during coronary artery bypass graft and multidose cardioplegia has been the "gold standard" for decades. However, one-shot cardioplegia is becoming more commonly used and is likely to be a valuable alternative. Some surgeons prefer the comfort of single-shot cardioplegia while others feel more confident with shorter re dosing intervals. There is no guarantee that a single strategy can be safely applied to all patients, irrespective of their age, comorbidities or cardiopathy. The goal of this review is to discuss the rationale for short re-dosing intervals. PMID- 26516421 TI - Role of platelet-rich plasma in ischemic heart disease: An update on the latest evidence. AB - Myocardial infarction is the most common cause of congestive heart failure. Novel strategies such as directly reprogramming cardiac fibroblasts into cardiomyocytes are an exciting area of investigation for repair of injured myocardial tissue. The ultimate goal is to rebuild functional myocardium by transplanting exogenous stem cells or by activating native stem cells to induce endogenous repair. Cell based myocardial restoration, however, has not penetrated broad clinical practice yet. Platelet-rich plasma, an autologous fractionation of whole blood containing high concentrations of growth factors, has been shown to safely and effectively enhance healing and angiogenesis primarily by reparative cell signaling. In this review, we collected all recent advances in novel therapies as well as experimental evidence demonstrating the role of platelet-rich plasma in ischemic heart disease, focusing on aspects that might be important for future successful clinical application. PMID- 26516422 TI - Enhanced caveolin-1 expression in smooth muscle cells: Possible prelude to neointima formation. AB - AIM: To study the genesis of neointima formation in pulmonary hypertension (PH), we investigated the role of caveolin-1 and related proteins. METHODS: Male Sprague Dawley rats were given monocrotaline (M, 40 mg/kg) or subjected to hypobaric hypoxia (H) to induce PH. Another group was given M and subjected to H to accelerate the disease process (M + H). Right ventricular systolic pressure, right ventricular hypertrophy, lung histology for medial hypertrophy and the presence of neointimal lesions were examined at 2 and 4 wk. The expression of caveolin-1 and its regulatory protein peroxisome proliferator-activated receptor (PPAR) gamma, caveolin-2, proliferative and anti-apoptotic factors (PY-STAT3, p Erk, Bcl-xL), endothelial nitric oxide synthase (eNOS) and heat shock protein (HSP) 90 in the lungs were analyzed, and the results from M + H group were compared with the controls, M and H groups. Double immunofluorescence technique was used to identify the localization of caveolin-1 in pulmonary arteries in rat lungs and in human PH lung tissue. RESULTS: In the M + H group, PH was more severe compared with M or H group. In the 4 wk M+H group, several arteries with reduced caveolin-1 expression in endothelial layer coupled with an increased expression in smooth muscle cells (SMC), exhibited neointimal lesions. Neointima was present only in the arteries exhibiting enhanced caveolin-1 expression in SMC. Lung tissue obtained from patients with PH also revealed neointimal lesions only in the arteries exhibiting endothelial caveolin-1 loss accompanied by an increased caveolin-1 expression in SMC. Reduction in eNOS and HSP90 expression was present in the M groups (2 and 4 wk), but not in the M + H groups. In both M groups and in the M + H group at 2 wk, endothelial caveolin-1 loss was accompanied by an increase in PPARgamma expression. In the M + H group at 4 wk, increase in caveolin-1 expression was accompanied by a reduction in the PPARgamma expression. In the H group, there was neither a loss of endothelial caveolin-1, eNOS or HSP90, nor an increase in SMC caveolin-1 expression; or any alteration in PPARgamma expression. Proliferative pathways were activated in all experimental groups. CONCLUSION: Enhanced caveolin-1 expression in SMC follows extensive endothelial caveolin-1 loss with subsequent neointima formation. Increased caveolin-1 expression in SMC, thus, may be a prelude to neointima formation. PMID- 26516424 TI - Percutaneous pulmonary valve implantation in a single artery branch: A preliminary experience. AB - To describe preliminary experience of percutaneous pulmonary valve implantation, in a single pulmonary branch position. Two procedures in 2 patients from a single center are described, where implantation of percutaneous valves within a single pulmonary artery branch was technically successful. The procedural indication was pulmonary valve regurgitation and/or residual stenosis. The 2 patients were symptomatic. An Edwards SapienTM valve (Patient 1), and a Medtronic MelodyTM valve (Patient 2) were implanted. Both pts were discharged with an excellent valve function. In this report it is underlined that this modality is technically feasible and may be considered an option in patients with congenital heart defect under special circumstances. PMID- 26516423 TI - Renal function assessment in atrial fibrillation: Usefulness of chronic kidney disease epidemiology collaboration vs re-expressed 4 variable modification of diet in renal disease. AB - AIM: To compare the performance of the re-expressed Modification of Diet in Renal Disease equation vs the new Chronic Kidney Disease Epidemiology Collaboration equation in patients with non-valvular atrial fibrillation. METHODS: We studied 911 consecutive patients with non-valvular atrial fibrillation on vitamin-K antagonist. The performance of the re-expressed Modification of Diet in Renal Disease equation vs the new Chronic Kidney Disease Epidemiology Collaboration equation in patients with non-valvular atrial fibrillation with respect to either a composite endpoint of major bleeding, thromboembolic events and all-cause mortality or each individual component of the composite endpoint was assessed using continuous and categorical >= 60, 59-30, and < 30 mL/min per 1.73 m(2) estimated glomerular filtration rate. RESULTS: During 10 +/- 3 mo, the composite endpoint occurred in 98 (10.8%) patients: 30 patients developed major bleeding, 18 had thromboembolic events, and 60 died. The new equation provided lower prevalence of renal dysfunction < 60 mL/min per 1.73 m(2) (32.9%), compared with the re-expressed equation (34.1%). Estimated glomerular filtration rate from both equations was independent predictor of composite endpoint (HR = 0.98 and 0.97 for the re-expressed and the new equation, respectively; P < 0.0001) and all-cause mortality (HR = 0.98 for both equations, P < 0.01). Strong association with thromboembolic events was observed only when estimated glomerular filtration rate was < 30 mL/min per 1.73 m(2): HR is 5.1 for the re-expressed equation, and HR = 5.0 for the new equation. No significant association with major bleeding was observed for both equations. CONCLUSION: The new equation reduced the prevalence of renal dysfunction. Both equations performed similarly in predicting major adverse outcomes. PMID- 26516425 TI - Intra-His bundle block in 2:1 atrioventricular block. AB - Intra-hisian atrioventricular (AV) block is not a common phenomenon, but it is important for the development of advanced or complete AV block. We observed a 77 year-old female patient with the 2:1 AV block due to an intra-hisian block. In this case we tried to detect the block site, but an alternating pattern of the AH conduction was noted on the His-electrogram in the electrophysiological study (EPS). The cause of the confusing finding might have been the instability of the catheter to record a His potential. We could detect a splitting of the His electrogram with an intra-hisian block after minimal manipulation of the catheter. The authors' observations suggest that catheter stability is important for a precise recording in the EPS and radiofrequency catheter ablation procedure. PMID- 26516426 TI - Late endocarditis of Amplatzer atrial septal occluder device in a child. AB - Bacterial endocarditis following atrial septal defect closure using Amplatzer device in a child is extremely rare. We report a 10-year-old girl who developed late bacterial endocarditis, 6 years after placement of an Amplatzer atrial septal occluder device. Successful explantation of the device and repair of the resultant septal defect was carried out using a homograft patch. The rare occurrence of this entity prompted us to highlight the importance of long-term follow up, review the management and explore preventive strategies for similar patients who have multiple co-morbidities and a cardiac device. A high index of suspicion is warranted particularly in pediatric patients. PMID- 26516427 TI - Locoregional treatment for hepatocellular carcinoma: The best is yet to come. AB - Hepatocellular carcinoma (HCC) is the sixth-most common type of cancer worldwide. The only definitive treatment modalities capable of achieving a cure are hepatic resection and hepatic transplantation. However, most patients are not candidates for these therapies. Overall, treatment options are driven by the stage of HCC. Early-stage disease is treated with ablative therapies, with radiofrequency ablation the ablative therapy of choice. Microwave ablation and irreversible electroporation are the other upcoming alternatives. Intermediate-stage disease is managed with transarterial chemoembolization (TACE), while advanced-stage disease is managed by sorafenib, with TACE and radioembolization as other alternatives. PMID- 26516428 TI - Diffusion-weighted imaging of pancreatic cancer. AB - Magnetic resonance imaging (MRI) is a reliable and accurate imaging method for the evaluation of patients with pancreatic ductal adenocarcinoma (PDAC). Diffusion-weighted imaging (DWI) is a relatively recent technological improvement that expanded MRI capabilities, having brought functional aspects into conventional morphologic MRI evaluation. DWI can depict the random diffusion of water molecules within tissues (the so-called Brownian motions). Modifications of water diffusion induced by different factors acting on the extracellular and intracellular spaces, as increased cell density, edema, fibrosis, or altered functionality of cell membranes, can be detected using this MR sequence. The intravoxel incoherent motion (IVIM) model is an advanced DWI technique that consent a separate quantitative evaluation of all the microscopic random motions that contribute to DWI, which are essentially represented by molecular diffusion and blood microcirculation (perfusion). Technological improvements have made possible the routine use of DWI during abdominal MRI study. Several authors have reported that the addition of DWI sequence can be of value for the evaluation of patients with PDAC, especially improving the staging; nevertheless, it is still unclear whether and how DWI could be helpful for identification, characterization, prognostic stratification and follow-up during treatment. The aim of this paper is to review up-to-date literature data regarding the applications of DWI and IVIM to PDACs. PMID- 26516429 TI - Malformations of cortical development: 3T magnetic resonance imaging features. AB - Malformation of cortical development (MCD) is a term representing an inhomogeneous group of central nervous system abnormalities, referring particularly to embriyological aspect as a consequence of any of the three developmental stages, i.e., cell proliferation, cell migration and cortical organization. These include cotical dysgenesis, microcephaly, polymicrogyria, schizencephaly, lissencephaly, hemimegalencephaly, heterotopia and focal cortical dysplasia. Since magnetic resonance imaging is the modality of choice that best identifies the structural anomalies of the brain cortex, we aimed to provide a mini review of MCD by using 3T magnetic resonance scanner images. PMID- 26516430 TI - Evaluation of primary adrenal insufficiency secondary to tuberculous adrenalitis with computed tomography and magnetic resonance imaging: Current status. AB - As one kind of infectious diseases of adrenal gland, adrenal tuberculosis can result in a life-threatening disorder which is called primary adrenal insufficiency (PAI) due to the destruction of adrenal cortex. Computed tomography (CT) and magnetic resonance imaging (MRI) play significant roles in the diagnosis of this etiology of PAI based on the CT and MRI appearances of the adrenal lesions. In this mini-review, we intend to study the CT and MRI features of adrenal tuberculosis, which could be helpful to both endocrinologist and radiologist to establish a definitive diagnosis for adrenal tuberculosis resulting in PAI. PMID- 26516431 TI - Functional assessment of transplanted kidneys with magnetic resonance imaging. AB - Kidney transplantation has emerged as the treatment of choice for many patients with end-stage renal disease, which is a significant cause of morbidity and mortality. Given the shortage of clinically available donor kidneys and the significant incidence of allograft dysfunction, a noninvasive and accurate assessment of the allograft renal function is critical for postoperative management. Prompt diagnosis of graft dysfunction facilitates clinical intervention of kidneys with salvageable function. New advances in magnetic resonance imaging (MRI) technology have enabled the calculation of various renal parameters that were previously not feasible to measure noninvasively. Diffusion weighted imaging provides information on renal diffusion and perfusion simultaneously, with quantification by the apparent diffusion coefficient, the decrease of which reflects renal function impairment. Diffusion-tensor imaging accounts for the directionality of molecular motion and measures fractional anisotropy of the kidneys. Blood oxygen level-dependent MR evaluates intrarenal oxygen bioavailability, generating the parameter of R2* (reflecting the concentration of deoxyhemoglobin). A decrease in R2* could happen during acute rejection. MR nephro-urography/renography demonstrates structural data depicting urinary tract obstructions and functional data regarding the glomerular filtration and blood flow. MR angiography details the transplant vasculature and is particularly suitable for detecting vascular complications, with good correlation with digital subtraction angiography. Other functional MRI technologies, such as arterial spin labeling and MR spectroscopy, are showing additional promise. This review highlights MRI as a comprehensive modality to diagnose a variety of etiologies of graft dysfunction, including prerenal (e.g., renal vasculature), renal (intrinsic causes) and postrenal (e.g., obstruction of the collecting system) etiologies. PMID- 26516432 TI - Relevant incidental findings at abdominal multi-detector contrast-enhanced computed tomography: A collateral screening? AB - AIM: To investigate the prevalence of relevant incidental findings (RIFs) detected during routine abdominal contrast-enhanced computed tomography (CeCT). METHODS: We retrospectively evaluated the reports of a consecutive series of abdominal CeCT studies performed between January and May 2013. For each report, patients' age and sex, admission as inpatient or outpatient, clinical suspicion as indicated by the requesting physician, availability of a previous abdominal examination, and name of the reporting radiologist were recorded. Based on the clinical suspicion, the presence and features of any RIFs (if needing additional workup) was noted. RESULTS: One thousand forty abdominal CeCT were performed in 949 patients (528 males, mean age 66 +/- 14 years). No significant difference was found between inpatients and outpatients age and sex distribution (P > 0.472). RIFs were found in 195/1040 (18.8%) CeCT [inpatients = 108/470 (23.0%); outpatients = 87/570 (15.2%); P = 0.002]. RIFs were found in 30/440 (6.8%) CeCT with a previous exam and in 165/600 (27.5%) without a previous exam (P < 0.001). Radiologists' distribution between inpatients or outpatients was significantly different (P < 0.001). RIFs prevalence increased with aging, except for a peak in 40-49 year group. Most involved organs were kidneys, gallbladder, and lungs. CONCLUSION: A RIF is detected in 1/5 patients undergoing abdominal CeCT. Risk of overdiagnosis should be taken into account. PMID- 26516433 TI - Delayed diagnosis of isolated alar ligament rupture: A case report. AB - Ligament disruptions at the craniovertebral junction are typically associated with atlantoaxial rotatory dislocation during upper cervical spine injuries and require external orthoses or surgical stabilization. Only in few patients isolated ruptures of the alar ligament have been reported. Here we present a further case, in which the diagnosis was initially obscured by a misleading clinical symptomatology but finally established six month following the trauma, demonstrating the value of contrast-enhanced high resolution 3 Tesla magnetic resonance imaging in identifying this particular lesion. PMID- 26516434 TI - Comparative Study of Vaginal versus Intramuscular Progesterone in the Prevention of Preterm Delivery: A Randomized Clinical Trial. AB - BACKGROUND: Preterm birth is a worldwide health concern due to its various negative consequences. Therefore, the prevention of preterm birth is a top priority for healthcare systems in all countries. OBJECTIVE: To compare the effectiveness of vaginal versus intramuscular progesterone in the prevention of preterm delivery. METHODS: This randomized clinical trial was conducted at Shahid Sadoughi Hospital in Yazd, Iran, from November 21, 2012 to January 20, 2015. Seventy-eight pregnant women with singleton pregnancy and one risk factor of preterm delivery were included in the study. The subjects were assigned randomly to two groups, with group one receiving Cyclogest and group two receiving 17 alpha hydroxyprogesterone caproate. Subsequently, we analyzed drug complications during pregnancy, delivery time, neonatal outcomes, and patients' satisfaction among the two groups. The data were analyzed using SPSS version 16. We used descriptive statistics, chi-squared, t-test, and ANOVA for the analyses of primary and secondary outcomes. RESULTS: Among the 39 births in group one, 33.3% occurred preterm, and, among the 39 births in group two, 30.7% occurred preterm (< 37 weeks). The mean gestational ages at delivery in groups 1 and 2 were 37.07 +/- 2.23 and 36.81 +/- 2.77 weeks, respectively (p = 0.765). Other variables were not significantly different between the two groups, including birth weight (p = 0.745), Apgar scores for the first and fifth minutes (p = 0.574, 0.630), length of stay in the neonatal intensive care unit (NICU) when the newborns needed hospitalization (p = 0.358), and the patients' satisfaction with the drugs that were used (p = 0.615). CONCLUSIONS: In this study, vaginal progesterone and intramuscular progesterone had the same levels of effectiveness, safety and acceptance by patients in the prevention of preterm delivery. Therefore, both can be used for this purpose in clinical practices, but more studies are needed. PMID- 26516435 TI - Comparing the Therapeutic Effectiveness of N-acetylcysteine with the Combination of N-acetyl Cysteine and Cimetidine in Acute Acetaminophen Toxicity: A Double Blinded Clinical Trial. AB - BACKGROUND: N-acetylcysteine (NAC) has been used as a classic treatment for hepatotoxicity induced by N-acetyl-p-benzoquinone imine (NAPQI) as a metabolite of acetaminophen. However, cimetidine theoretically can reduce the production of toxic metabolites through the inhibition of cytochrome p450, and it recently was proposed as a complementary treatment for acetaminophen toxicity. OBJECTIVE: The aim of this study was to compare the effects of treating acute acetaminophen toxicity with NAC alone and with a combination of NAC and cimetidine. METHODS: From October 2013 to March 2014, 105 patients suspected of acetaminophen toxicity who had paraclinical confirmation of toxicity requiring medical treatment (based on the risk assessment nomogram of acetaminophen serum level) were enrolled in this double-blind, randomized, controlled trial at Imam Reza Hospital in Mashhad, Iran. The patients were divided into two groups, i.e., 1) patients who were treated with NAC alone (group A) and 2) patients who were treated with a combination of NAC and cimetidine (group B). The primary outcomes were 1) the serum level of acetaminophen and 2) the serum level of aminotransferases at the time of admission and 4, 12, 24, and 48 hours after admission. Exclusion criteria included multiple toxicities, concurrent diseases that could affect liver enzymes, the use of other drugs, and dissatisfaction with the project. For measuring quantitative data, SPSS version 16 was used for t-test analysis and for analyzing the qualitative data with chi-squared analysis. RESULTS: Sixty patients (32 females and 28 males) with a mean age of 25.2 +/- 7.3 years were classified in two groups of 30.. There was no difference between the groups in terms of their admission information. The average levels of acetaminophen in both groups at admission, 12, 24, and 48 hours after hospitalization were not significantly different from each other. Twelve hours after hospitalization, the aspartate aminotransferase (AST) level in the group treated with NAC was significantly higher than in the group treated with the combination of NAC and cimetidine (IU/L30.1 +/- 110.0 versus IU/L26.38 +/- 94.93, p = 0.044). At the other times that the level of liver enzymes was assessed, the serum levels of urea and creatinine were not significantly different in the two groups (p > 0.05). CONCLUSION: The intravenous administration of 300 mg of cimetidine every six hours with NAC did not improve the level of hepatoprotective action significantly compared with the NAC treatment protocol alone. PMID- 26516436 TI - Comparing Motivational Interviewing-Based Treatment and its combination with Nicotine Replacement Therapy on smoking cessation in prisoners: a randomized controlled clinical trial. AB - BACKGROUND: The prevalence of smoking is much higher in prisoners than it is in the general population. Prisoners who smoke cause many health problems for themselves and other prisoners. Therefore, we should help them stop smoking. OBJECTIVE: To compare the effects of motivational interviewing-based (MI-based) treatment and its combination with nicotine replacement therapy (NRT) on smoking cessation in prisoners at Mashhad Central Prison. METHODS: The study was designed as a double-blind, randomized, controlled clinical trial, and it began in February 2013 and ended in February 2014. Two hundred and thirteen prisoners met the inclusion criteria and were enrolled in the study. They were divided randomly into three groups, i.e., MI-based treatment, MI with NRT, and the control group, which didn't receive any therapy. The outcome measures were reported after intervention and at a 90-day follow-up, and changes in the CO levels in expired air and nicotine dependency were measured. RESULTS: The average age of the subjects was 37.59 +/- 8.76, and their mean duration of imprisonment was 3.3 +/- 1.90 years. They smoked an average of 21.84 +/- 8.72 cigarettes per day. Analysis of the concentration of CO in expired air in the pre-test, post-test, and at the follow-up for the three groups showed that the variations in the mean CO concentrations in the MI group and the MI with NRT group at the pre-test and at the post-test were statistically significant (p < 0.001), but no significant changes occurred between the post-test and the follow-up (p > 0.050). In addition, the results indicated that CO concentration in expired air in the MI with NRT group was statistically significant, with better efficacy of smoking cessation, compared with control group and the MI group after the follow-up (p = 0.02). CONCLUSIONS: Motivational interviewing combined with NRT for smoking cessation is more effective than MI alone, and it resulted in a significant decrease in the CO concentration in expired air at the 90-day follow-up. PMID- 26516437 TI - The comparison of Neoprene palumbo and Genu direxa stable orthosis effects on pain and activity of daily living in patients with patellofemoral syndrome: a randomized blinded clinical trial. AB - BACKGROUND: Patellofemoral pain syndrome (PFPS) is one of the most common disorders of the knee. Conservative approaches, as well as surgery, can decrease pain and the syndrome's progress effectively. OBJECTIVE: The aim of this study was to determine the effectiveness of neoprene palumbo orthosis (NPO) and Genu direxa stable orthosis (GDSO) on pain and the activities of daily living (ADL). METHODS: Thirty patients (males, ages 18 to 40) participated in this randomized blinded clinical trial. All of them were diagnosed with patella femoral pain syndrome. The participants were divided randomly into two groups of 15, with one group using neoprene palumbo (intervention group) and the other group using Genu direxa stable orthoses (control group). Using the Visual Analogue Scale (VAS) and the Knee injury and Osteoarthritis Outcome Score (KOOS), pain intensity and activities of daily living (ADL) and joint stiffness were analyzed before treatment and after three weeks of treatment. Data were analyzed using paired samples t-test and independent samples t-test. RESULTS: Both orthoses reduced the patients' pain. Both group showed meaningful improvement in pain reduction and ADL increase after using orthosis in each group. In comparing the variables, no significant differences were found between pain severity and ADL (p = 0.592, p = 0.887). In both groups, the mean of pain severity was different before, during, and after using orthosis (p < 0.05). CONCLUSION: The results of this study indicated that Neoprene palumbo and genudirexa stable orthoses improved the signs of patello femoral pain syndrome, including pain intensity and ADL. PMID- 26516438 TI - Biochemical progression-free survival in localized prostate cancer patients treated with definitive external beam radiotherapy. AB - INTRODUCTION: Prostate cancer is now the third most frequent noncutaneous malignancy in Iranian men and the fifth most common cancer worldwide. Measurement of total serum prostate specific antigens (PSAs) has been one of the strongest predictors of biochemical progression and overall survival in determining the efficacy of definitive external beam radiation therapy in patients with localized prostate cancer. The aim of this research was to identify the 5-year biochemical progression-free survival (BFS) and related prognostic and predictive factors of localized prostate cancer patients who were treated with definitive external beam radiotherapy. METHODS: This study analyzed 192 localized prostate cancer patients from stage T1aN0M0 to stage T3N0M0; they were treated with definitive radiation therapy and followed up in the radiation-oncology ward of Shohada-e-Tajrish Hospital in Tehran (Iran) between 2006 and 2013. The 5-year BFS was analyzed using the Kaplan-Meier estimate. For multivariate analysis, the Cox proportional hazards model was used to assess the strengths of various factors for 5-year BFS. RESULTS: The follow-up period was between 14-81 months, with a median of 31 months. The median cumulative prostate dose in our series was 64 Gray (Gy) (range 62 to 78 Gy). The 5-year BFS for all patients was 65.1%, and 5-year BFS in low risk, intermediate-risk and high-risk groups were 100%, 86.5%, and 54.9% respectively. Multivariate analysis found statistically significant relation between 5-year BFS and initial PSA>20, Gleason score 8-10, high risk group, TNM stage>=T2cN0M0, radiotherapy dose<70 Gy, radiotherapy with 2D technique and hormonal therapy in high-risk group (p=0.003, p=0.032, p=0.014, p=0.001, p=0.035, p=0.035, p=0.022 respectively). CONCLUSION: Our seven years' experience of follow up with PSA showed that PSA was the strongest predictor of biochemical progression survival in patients with prostate cancer who were treated with definitive external beam radiation therapy. PMID- 26516439 TI - Predictors of In-Hospital Mortality in patients with hepatocellular carcinoma and Acute Variceal bleeding. AB - INTRODUCTION: Detection of hepatocellular carcinoma (HCC) in cirrhotic patients remains a serious, unsolved problem, and the risk factors for acute variceal bleeding (AVB) in HCC patients remain unclear. This study aimed to determine the in-hospital mortality (IHM) and factors influencing the clinical outcomes of AVB in patients with liver cirrhosis and HCC. METHODS: This was a retrospective, non randomized, clinical study that was conducted in 2014. The study was conducted on 70 patients with liver cirrhosis and HCC presenting by acute upper gastrointestinal bleeding (AUGIH). All patients were examined endoscopically within 24 hours from presentation and bleeding varices accounted for AUGIH. Full medical history, clinical examination, and laboratory and radiologic data were collected from admission charts, and hospital medical records were statistically analyzed with SSPS version 22. RESULTS: Thirty-two patients (45.7%) survived and 38 died (54.3%). Survivors are more likely to be Child-Pugh class A or B, and the non-survivors were class C. The Model for End-Stage Liver Disease (MELD) was highly predictive of IHM at an optimized cut-off value of >= 12.9. Higher esophageal varices grades and presence of active bleeding on index endoscopy were significant (p < 0.01) in the non-survivors compared to survivors. Complications of liver cirrhosis and associated major comorbidity were significantly higher (p < 0.01) in the non-survivors than the survivors. Univariate logistic regression analysis identified higher Grade Esophageal Varices and number of transfused packed red blood cells units as two independent predictors of IHM. CONCLUSIONS: IHM was particularly high (54.3%) among HCC patients with AVB who had MELD score > 12.9, higher grade Esophageal Varices, active bleeding on index endoscopy, more increased needs for blood transfusion, longer hospital stay, decompensated liver disease with major comorbidity. PMID- 26516440 TI - Effectiveness of Vitamin B2 versus Sodium Valproate in Migraine Prophylaxis: a randomized clinical trial. AB - BACKGROUND: Migraine headache is a prevalent periodical and neurological impairment that is associated with functional disorders. Regarding the side effects of available medications, research is continuing in an effort to identify new, effective pharmaceutical regimens with limited side effects. OBJECTIVE: The aim of this study was to compare the effectiveness of vitamin B2 versus sodium valproate in migraine prophylaxis. METHODS: This was a single-blind clinical trial conducted on 90 migraine patients in two parallel groups. The first group underwent vitamin B2 treatment (400 mg/day) for three months, and the second group was treated with sodium valproate (500 mg/day). The patients were examined at the beginning of the study and 4, 8, and 12 weeks later. After the administration of the drugs in both groups, we recorded the duration of migraine pain, the frequency of migraine episodes, and the severity of the headaches. Potential complications of this study that were measured were weight gain, dizziness, and gastrointestinal problems. RESULTS: The findings showed that the frequency, median duration per month, and severity of the headaches decreased in both groups, but the difference between them was not significant (p > 0.05). However, there were significantly fewer side effects in vitamin B2 group (p = 0.005). CONCLUSION: Sodium valproate and vitamin B2 have similar effects on the reduction of migraine attacks, but vitamin B2 had fewer complications and fewer adverse effects; therefore, vitamin B2 can be administered to patients who are prohibited from taking sodium valproate or who have adverse side effects when they take it. PMID- 26516441 TI - Impact of hyponatremia on frequency of complications in patients with decompensated liver cirrhosis. AB - INTRODUCTION: Hyponatremia is common in cirrhosis. The relationship between hyponatremia and severity of cirrhosis is evidenced by its close association with the occurrence of complications, the prevalence of hepatic encephalopathy, hepatorenal syndrome, spontaneous bacterial peritonitis, refectory ascites, and hepatic hydrothorax. The aim of this study was assess the impact of hyponatremia on the occurrence of both liver-related complications and the hemodynamic cardiovascular dysfunction. METHODS: This prospective study was conducted in 2015 on 74 patients with liver cirrhosis. The patients were from the Gastroenterology and Hepatology Department of Theodor Bilharz Research Institute in Giza, Egypt. The patients were divided into three groups according to their serum level of sodium. Group 1 included 30 patients with serum sodium >135 meq/L, group 2 included 24 patients with serum sodium between135 and 125 meq/L, and group 3 included 20 patients with serum sodium <125 meq/L. For each of the patients, we conducted aclinical examination, laboratory investigations, chest X-ray, ECG, abdominal sonar, and echocardiography. RESULTS: Hyponatremia was found in 59.46% of our cirrhotic patients, and they showed significantly increased Model for End Stage Liver Disease (MELD) score, MELD-Na score, QTc interval, Pulmonary vascular resistance (PVR) and inferior vena cava (IVC) collapsibility, and decreased SVR and IVC diameter. Also hepatic encephalopathy, ascites, renal failure, infectious complications, and pleural effusion were significantly more common in hyponatremic cirrhotic patients. CONCLUSION: In cirrhosis, hyponatremia is more common in severe cardiovascular dysfunction and associated with increased risk of hepatic encephalopathy, ascites, illness severity scores, renal failure, infectious complications, and pleural effusion. We recommend selective oral administration of vasopressin V2-receptor antagonist, tolvaptan, which acts to increase the excretion of free water, thereby resolving hypervolemic hyponatremia and may have the potential to improve outcomes in these patients. PMID- 26516442 TI - Assessment of the level of health literacy among fertile Iranian women with breast cancer. AB - INTRODUCTION: Health literacy is one of the main determinants of health promotion. Regarding the influential role of the women in a society, enhancing their critical health literacy would be a prerequisite for the promotion of public health. The aims of this study were to determine the level of health literacy among fertile Iranian women with breast cancer and to determine the relationship between the health literacy level and socio demographic factors, such as age, educational level, occupation, age of marriage, duration of marriage, and several clinical factors, including taking psychiatric medication and the type of breast surgery among breast cancer patients. METHODS: This cross sectional study was conducted on 260 fertile patients with breast cancer from screening and monitoring centers and breast cancer clinics in Tehran from August 2014 to August 2015. Data were collected using socio demographic and clinical questionnaires developed by the researchers and the questionnaire for health literacy for Iranian adults (HELIA).The results were analyzed using SPSS-IBM version 20 and the Pearson product-moment correlation coefficient, along with Kido's correlation test. RESULTS: The mean age of the participants was 43.32. Most of the participants (68.5%) had high school diplomas or lower school degrees (based on educational system in Iran). The mean score of health literacy was 75.73. The levels of health literacy among the different groups of participants were as follows: insufficient health literacy (6.9% of patients), barely enough health literacy (18.8% of patients), enough health literacy (38.8% of patients) and excellent health literacy (35.1% of patients). Also, significant relationships were found between the level of health literacy and the participants' age of marriage, duration of marriage, educational level, and occupation (p < 0.05). CONCLUSION: This study showed that the level of health literacy was high among women with breast cancer. This indicates that their high level of health literacy might be used as a contributor to the promotion of the public health in terms of awareness about breast cancer. PMID- 26516443 TI - Effects of box size, frequency of lifting, and height of lift on maximum acceptable weight of lift and heart rate for male university students in Iran. AB - INTRODUCTION: In spite of the widespread use of automation in industry, manual material handling (MMH) is still performed in many occupational settings. The emphasis on ergonomics in MMH tasks is due to the potential risks of workplace accidents and injuries. This study aimed to assess the effect of box size, frequency of lift, and height of lift on maximum acceptable weight of lift (MAWL) on the heart rates of male university students in Iran. METHODS: This experimental study was conducted in 2015 with 15 male students recruited from Tehran University of Medical Sciences. Each participant performed 18 different lifting tasks that involved three lifting frequencies (1lift/min, 4.3 lifts/min and 6.67 lifts/min), three lifting heights (floor to knuckle, knuckle to shoulder, and shoulder to arm reach), and two box sizes. Each set of experiments was conducted during the 20 min work period using the free-style lifting technique. The working heart rates (WHR) were recorded for the entire duration. In this study, we used SPSS version 18 software and descriptive statistical methods, analysis of variance (ANOVA), and the t-test for data analysis. RESULTS: The results of the ANOVA showed that there was a significant difference between the mean of MAWL in terms of frequencies of lifts (p = 0.02). Tukey's post hoc test indicated that there was a significant difference between the frequencies of 1 lift/minute and 6.67 lifts/minute (p = 0. 01). There was a significant difference between the mean heart rates in terms of frequencies of lifts (p = 0.006), and Tukey's post hoc test indicated a significant difference between the frequencies of 1 lift/minute and 6.67 lifts/minute (p = 0.004). But, there was no significant difference between the mean of MAWL and the mean heart rate in terms of lifting heights (p > 0.05). The results of the t-test showed that there was a significant difference between the mean of MAWL and the mean heart rate in terms of the sizes of the two boxes (p = 0.000). CONCLUSION: Based on the results of this study, it was concluded that MAWL and heart rate are influenced by the variables of lifting frequency and the size of the boxes. PMID- 26516445 TI - The effects of different levels of peppermint alcoholic extract on body-weight gain and blood biochemical parameters of adult male Wistar rats. AB - INTRODUCTION: Peppermint is an efficient medicinal plant for the treatment of diseases, and it also can be used to produce raw materials in the pharmaceutical industry. The purpose of the current study was to evaluate the effects of various levels of peppermint alcoholic extract on body-weight gain and blood biochemical parameters in adult male Wistar rats. METHODS: This experiment was conducted using a completely randomized design (CRD). Fifty adult, healthy, male Wistar rats (ages of 2.5-3 months; weights of 190-210 g) were allocated randomly into five groups. T1 was the control group in which the rats received 0.3 ml of distilled water). Groups T2, T3, T4, and T5 received 75, 150, 300, and 600 mg/kg of peppermint extract, respectively. The rats received daily pretreatment by oral gavages for 21 days. We recorded body weights at the beginning and at the end of the study to determine the changes in the body weights. Blood samples were collected for the measurement of glucose, cholesterol, triglycerides, HDL, LDL, albumin, globulin, and total protein. Statistical analysis of the data was done by SAS software. The data statistically analyzed using one-way analysis of variance (ANOVA), which was conducted through Dennett's multiple comparison post test. RESULTS: The results indicated that the rats treated with peppermint gained more weight (p < 0.05) and also decreased the serum concentrations of triglycerides, total cholesterol, LDL, and glucose in T3, T4 and T5 than the other groups (p < 0.05). CONCLUSION: Peppermint extract had a positive effect on body-weight gain and some blood parameters in adult male Wistar rats. The findings showed that peppermint is a crucial substance at high temperature, and future research should be focused on determining the details of the mechanisms involved in producing the observed effects of peppermint extract. PMID- 26516444 TI - Effects of a single rectal dose of Misoprostol prior to abdominal hysterectomy in women with symptomatic leiomyoma: a randomized double blind clinical trial. AB - BACKGROUND: Fibroma, the most common benign pelvic tumor in women, affects 25 to 30% of women of reproductive age. Primary treatment for patients with symptomatic or large fibroma is surgery. OBJECTIVE: The purpose of this study was to investigate the effect of a single rectal dose of Misoprostol on bleeding during abdominal hysterectomy. METHODS: This double blind randomized clinical trial was conducted with 80 candidates for abdominal hysterectomy, due to uterine myoma, in the Shahid Sadoughi hospital of Yazd in 2012. The aim of this study was to assess the effect of single rectal dose of Misoprostol on peri-operational abdominal hysterectomy bleeding. Following administration of 400 micrograms of Misoprostol in the case group (n=40), predetermined criteria were compared with control group (n=40). RESULTS: Volume of bleeding during the operation was significantly lower in cases where Misoprostol was used. (268.71 +/- 156.85 vs. 350.38 +/- 152.61 cc in the case and control groups, respectively). Our findings also showed that Hemoglobin (Hb) levels before, 8, and 30 hours following the operation differed significantly (p=0.001), but these changes were similar in both groups. Pre operative Hb levels were 11.90 +/- 1.7 and 11.90 +/- 2.0 in the case and control groups, respectively. CONCLUSION: A single rectal dose of Misoprostol has positive effect on reducing peri-operational bleeding in women undergoing abdominal hysterectomy due to symptomatic leiomyoma. PMID- 26516446 TI - Genetic characterization of the wboA gene from the predominant biovars of Brucella isolates in Iran. AB - INTRODUCTION: Brucella spp. are gram-negative, facultative intracellular bacteria pathogens responsible for brucellosis, a zoonotic disease that can cause abortion, fetal death, and genital infections in animals and undulant fever in humans. Lipopolysaccharide (LPS) is known as a major virulence factor of Brucella spp. The wboA gene is capable of encoding a glycosyltransferase that appears to play a major role in LPS biosynthesis. Hence, the characterization of this gene can help in the clarification of the pathogenicity of Brucella spp. METHODS: This study was carried out at Razi Vaccine and Serum Research Institute in 2011. Briefly, the wboA gene in B. abortus biovar 3 and B. melitensis biovar 1, the predominant biovars in Iran, were amplified by using two pairs of specific primers. Polymerase chain reaction (PCR) products were cloned into a thymine adenine (TA) cloning vector and transformed into an E. coli DH5alpha before being sequenced. Multiple alignments of identified sequences were performed, with all wboA sequences deposited in the GenBank sequence database. RESULTS: This study showed that a mismatch has occurred in B. melitensis biovar 1; this biovar is predominant in Iran. In contrast, the wboA gene from B. abortus biovar 3 was similar to that of other B. abortus variations. CONCLUSION: The comparison and alignment of the wboA gene of native Brucella strains in Iran to all wboA sequences deposited in GenBank revealed that the wboA gene has changed in the long term; hence, because of its unique nucleotide pattern, the gene can be used for specific diagnosis of B. abortus and B. canis. PMID- 26516447 TI - Prevalence of hypocalcemia after phototherapy among neonates who underwent phototherapy in Koodakan Hospital in Bandar Abbas in 2013. AB - INTRODUCTION: Hyperbilirubinemia is one of the most common problems in newborns, and it is reported in about 60% of infants. Phototherapy is used extensively to treat these patients, and hypocalcemia is one important side effect of the phototherapy. The aim of this study was to determine the prevalence of hypocalcemia after phototherapy in full-term newborns that underwent phototherapy in Koodakan Hospital in Bandar Abbas in 2013. METHODS: This cross-sectional study was conducted on 100 neonates admitted to Koodakan Hospital in Bandar Abbas. All of the newborns were full-term, healthy, weighed more than 2,500 g, and were candidates for phototherapy. The newborns were divided into two groups, i.e., 1) those who were more than three days old and 2) those who were less than three days old. Serum bilirubin and calcium levels were measured for each newborn before phototherapy and 48 hours after phototherapy, and the before and after levels were compared. The data were analyzed using IBM SPSS 21.0 statistical software. The Fisher Exact test, the independent samples t-test, and the paired t test were used to test the research hypothesis. RESULTS: Among the 100 newborns studied, 54% had decreased calcium levels after phototherapy. The prevalence of hypocalcemia was 9% in this study, and the prevalence was not significantly different in the two age groups (P = 0.217). CONCLUSION: Phototherapy does not increase the risk of hypocalcemia in healthy, full-term neonates. Therefore, prophylactic calcium is not recommended for healthy, full-term neonates who have undergone phototherapy. PMID- 26516448 TI - Congenital Cutis Laxa Type 2 Associated With Recurrent Aspiration Pneumonia and Growth Delay: Case Report. AB - Cutis laxa is a connective tissue disorder caused by deficiency of fibro elastic plexus, which can involve multiple organs. It is inherited in autosomal dominant, autosomal recessive, and X-linked. Autosomal recessive cutis laxa type 2, which appears to compromise a spectrum of disorders, starts with severe wrinkly skin syndrome and leads to more severe diseases related to growth and developmental delays and skeletal anomalies. The clinical manifestations in some of cases of Cutis laxa consist of redundant loose skin, pre-and post-natal growth deficiency, mental retardation, large fontanels, and dislocation of the hips. The authors present the case of a female patient with involved internal organ disorder and delay in growth in addition to skin laxity in which gene sequence analysis of PYCR1 indicated C.797G>A mutation. PMID- 26516449 TI - Correlation between apical protrusion in the Scheimflug imaging and Corneal Hysteresis and Corneal Resistance factor by Ocular Response Analyzer, among refractive non-keratoconic Egyptian patients. AB - INTRODUCTION: Apical protrusion in the central 4-mm ring in the Scheimflug imaging (Pentacam), both for the anterior and posterior floats as well as Corneal Hysteresis and Corneal Resistance Factor by Ocular Response Analyzer (ORA), generally are considered important predictors for post-Lasik ectasia. The aim of this work was to find out if there is a statistically significant correlation between these different predictors and their correlation with the central corneal thickness for refractive non-keratoconic Egyptian patients trying to achieve a better decision and avoiding ectasia. METHODS: This case-control study involved 142 eyes (of 77 patients with various refractive errors) arriving at the refractive surgery unit in the Research Institute of Ophthalmology in Giza (Egypt) in 2014-2015 seeking excimer laser ablation. The flattest, steepest keratometry readings, central corneal thickness as well as the apical protrusion in the central 4-mm ring, both for the anterior and posterior floats, in microns were measured by Scheimflug imaging. The Corneal Hysteresis and Corneal Resistance Factor were measured by the ocular response analyzer. Statistical analysis was performed by SPSS, using the Pearson correlation test. RESULTS: The spherical refractive error ranged from +7.00 to -13.00 diopters (-3.80 +/- 2.89). The central pachymetry ranged from 494 to 634 MUm (550.35 +/- 32.13). For the central 4-mm ring, the apical protrusion ranged from 0 to +15 MU (6.93 +/- 2.99) for the anterior float and from -3 to +20 MU (9.33 +/- 4.55) for the posterior float. The Corneal Hysterisis (CH) ranged from 7 to 14.8 mmHg (10.18+/-1.44), while the Corneal Resistance Factor (CRF) ranged from 7.5 to 14.9 mmHg (10.58 +/- 1.67). There was a strong positive correlation between the central corneal thickness and both Corneal Hysteresis (CH: r = 0.56, P <= 0.01) and Corneal Resistance Factor (r = 0.46, P <= 0.01). A significant correlation (P < 0.05, r = 0.15) existed between apical protrusion in the posterior float and the central corneal thickness. Also, significant negative correlation (P < 0.05, r = -0.12) existed between apical protrusion in the anterior float by pentacam and the Corneal Resistance Factor by ocular response analyzer. CONCLUSIONS: Our finding of a strong positive correlation between both Corneal Hysteresis and Corneal Resistance Factor and the Central corneal thickness being important for biomechanical corneal stability. The findings of this study also support using both machines preoperatively to decrease the risk of post-Lasik ectasia. PMID- 26516450 TI - The Clinicopathologic Characteristics and 5-year Survival Rate of Epithelial Ovarian Cancer in Yazd, Iran. AB - INTRODUCTION: Ovarian cancer is the second most common malignancy in women, the most common cause of gynecologic cancer deaths, and most patients have advanced stage disease at the time of diagnosis. The purpose of this study was to estimate the 5-year survival of patients with epithelial ovarian cancer based on age, tumor histology, stage of disease, and type of treatment. METHODS: This study was conducted on 120 patients with epithelial ovarian cancer referred to Shahid Sadoughi hospital and Shah Vali oncology clinic of Yazd from 2006 to 2012. Demographic data and patient records were studied to evaluate the treatment outcome, pathology of the tumor, and stage of disease. Finally, the overall survival rate and tumor-free survival of patients was assessed. RESULTS: The mean patient age was 53.87+/- 14.11 years. Most participants had stage I (36.7%) or stage II (35%) disease. Serous adenocarcinoma (57.6%) was the most common pathology found in patients with epithelial ovarian cancer. The overall survival of patients in this study was significantly associated with the histological tumor type (p = 0.000) and disease stage (p = 0.0377). Stage I (84.18%) and serous adenocarcinoma (72.81%) demonstrated the best survival. The tumor-free survival rates were not associated with histology types (p = 0.079), surgical procedure (p = 0.18), or chemotherapy (p = 0.18). CONCLUSION: The survival of patients with epithelial ovarian cancer was significantly associated with disease stage. Serous adenocarcinoma also had the best prognosis among the pathologies studied. Therefore, early detection of ovarian cancer can substantially increase the survival rate. PMID- 26516451 TI - The Assessment of Inequality in the Geographical Distribution of Burn Beds in Iran. AB - INTRODUCTION: In recent years, the World Health Organization (WHO) has emphasized the importance of determining the equality of the distribution of healthcare resources. Inequalities in the healthcare system are one of the world's most important developmental challenges, and the inefficiencies that exist in healthcare systems are the most important reason for these challenges. Thermal burns are one of the common injuries worldwide, and their effects are a significant reason for the mortality and morbidity rates throughout the world. Considering the importance of burns as one of the 30 leading causes of death in Iran, this study was aimed to compare the distribution of burn beds with its disability-adjusted life years (DALY) in Iran. METHODS: This applied analytic descriptive study was conducted in order to determine the distribution of burn beds in Iran using the Lorenz curve. In this way, the distribution of burn beds was analyzed in relation to the population of each province and lost DALY caused by burns in Iran. For each province, the number of burn beds in 2012 was collected from credible and authoritative sources at the Ministry of Health, and the population of each province was obtained using data from the National Center of Statistics. The data were analyzed and presented using Microsoft Office Excel. RESULTS: Isfahan and Khorasan Razavi Provinces had approximately 11 and 10.4% of the country's burn beds, respectively. The Provinces that had the most DALY were Sistan Baluchestan, Fars, and Kerman with 10.75%, 10.34%, and 9.54%, respectively. The Gini coefficients of burn beds in relation to population and DALY were calculated as 0.09 and 0.16, respectively. CONCLUSION: The Gini coefficients in relation to population and DALY were less than 0.2. Although the Gini coefficient of the burn beds in relation to DALY was more than that for the population, the difference was not significant, and the distributions of beds regarding the two calculated coefficients were equal. It is recommended that healthcare policymakers distribute burn beds in proportion to the populations of the provinces. PMID- 26516452 TI - The protective effect of lemon fruit extract on histopathological changes induced in small intestines and pancreas of male mice by cyclophosphamide. AB - INTRODUCTION: Cyclophosphamide (CP) is alkylating agent and the most commonly used chemotherapeutic drug for various types of cancer; it causes severe toxicity. The aim of the research was to assess the protective effect of lemon fruit extract (LFE) against the side effects of the anti-cancer drug "cyclophosphamide" (CP). METHODS: This experimental study was conducted in 2015. Thirty male mice were divided into six groups: group A (control): intraperitoneal injection of saline, group B: oral LFE (10ml/kg), group C: intraperitoneal injection of CP (10 mg/kg), group D: intraperitoneal injection of CP (20 mg/kg), group E: intraperitoneal injection of CP (10 mg/kg) and oral LFE (10 ml/kg), and group F: intraperitoneal injection of CP (20 mg/kg) and oral LFE (10 ml/kg). All groups were treated daily for five consecutive days. RESULTS: The results of the group treated with the drug C and D was that, in their intestines, the effect was uneven between a severe to a sharp effect, and there was a lack of dense connective tissue and its collagen fibers and fat cells, the intestinal glands or crypt of Lieberkuhn appeared few in number and distorted in composition when compared with control A, as the pancreas appeared divided into several lobes containing small numbers of pancreatic Acini, padded with secretory pyramid shaped cells, although some of them appeared exaggerated. While treatment in group E and F resulted in the intestines and pancreas appearing to be semi normal; regarding the pancreas, it showed an observed improvement more than the response of the intestines. CONCLUSION: The results support the protective effect of lemon fruit extract against CP-induced intestinal and pancreatic injury. PMID- 26516453 TI - Modified Technique for Nonvital Tooth Bleaching: A Case Report. AB - The aim of this study is to report a case of a nonvital, discolored, maxillary central incisor bleached by 35% hydrogen peroxide gel with the use of glass ionomer cement as a mechanical barrier in an attempt to minimize the undesirable side effects of intracoronal bleaching. The patient was a 13-year-old boy complaining of a discolored nonvital upper-right central incisor and was selected for this study from the pedodontic clinic in the Shibin Elkom teaching hospital in June 2013. After successful endodontic treatment, the tooth was bleached by 35% hydrogen peroxide gel (Opalescence Xtra), activated by a standard curing light unit, and evaluated for any periapical changes by a periapical radiograph for a nine-months follow-up period. Radiographically, there was no evidence of cervical or apical resorption during the study period. PMID- 26516455 TI - The first six years of surveillance in pediatric and neonatal intensive care units in Turkey. AB - BACKGROUND: Patients in resourced-limited neonatal and pediatric intensive care units (NICU and PICU) are vulnerable to healthcare associated infections (HAI). We report the incidence of HAI, multidrug resistant microorganisms (MDROs) and the pattern of antibiotic usage in the first six years of a surveillance program in a teaching hospital in Turkey. METHODS: Between 2007 and 2012 surveillance data for HAI, MDROs and antibiotic usage were collected from the infection control department, pathology, hospital admissions and pharmacy. In 2009 hand hygiene auditing was introduced. Hand sanitizer usage was expressed as liters per 1000 patient-days. Antibiotic usage was presented as defined daily doses (DDD). Evidence of change in the incidence of HAI was tested using Poison regression modeling. RESULTS: The rate of gram negative MDRO in PICU increased significant between 2007 and 2012 (IRR 1.5, P = 0.033) but remained unchanged in NICU (P = 0.824). By 2012 ceftriaxone prescribing in PICU had decreased while carbapenem prescribing increased by 80 %. In NICU carbapenem decreased by 42 % and betalactam decreased by 29 %. Hand hygiene compliance significantly improved in PICU (IRR 1.9, p < 0.001) and NICU (IRR 2.2, p < 0.001) but compliance remained modest after three years with inconsistent levels across the 5 moments. CONCLUSION: The early years of our infection control program highlights the endemicity of HAI and MDROs in our NICU and PICU. The consistent pattern of antibiotic usage, endemic MROs in PICU and modest hand hygiene clearly provide strategic focuses for intervention. PMID- 26516454 TI - Regulatory functions and pathological relevance of the MECP2 3'UTR in the central nervous system. AB - Methyl-CpG-binding protein 2 (MeCP2), encoded by the gene MECP2, is a transcriptional regulator and chromatin-remodeling protein, which is ubiquitously expressed and plays an essential role in the development and maintenance of the central nervous system (CNS). Highly enriched in post-migratory neurons, MeCP2 is needed for neuronal maturation, including dendritic arborization and the development of synapses. Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a debilitating neurodevelopmental disorder characterized by a phase of normal development, followed by the progressive loss of milestones and cognitive disability. While a great deal has been discovered about the structure, function, and regulation of MeCP2 in the time since its discovery as the genetic cause of RTT, including its involvement in a number of RTT-related syndromes that have come to be known as MeCP2-spectrum disorders, much about this multifunctional protein remains enigmatic. One unequivocal fact that has become apparent is the importance of maintaining MeCP2 protein levels within a narrow range, the limits of which may depend upon the cell type and developmental time point. As such, MeCP2 is amenable to complex, multifactorial regulation. Here, we summarize the role of the MECP2 3' untranslated region (UTR) in the regulation of MeCP2 protein levels and how mutations in this region contribute to autism and other non-RTT neuropsychiatric disorders. PMID- 26516457 TI - Editorial. PMID- 26516458 TI - Guest Editorial. PMID- 26516456 TI - Prevalence and factors associated with stunting and thinness among adolescent students in Northern Ethiopia: a comparison to World Health Organization standards. AB - BACKGROUND: Adolescence is last chance for curbing the consequences of malnutrition and breaking the intergenerational cycle of malnutrition and poor health. This study aimed to assess the prevalence and the factors associated with stunting and thinness among in-school adolescents in northern Ethiopia using the 2006 World Health Organization (WHO) standards. METHODS: In-school adolescents (n = 348, 10-19 years old) were randomly selected to participate in this cross sectional study. Anthropometric measurements were carried out to determine the proportion of adolescents who were stunted (height-for-age < -2 Standard Deviation (SD)) and thin (body-mass-index-for-age < -2 SD). T-test was employed to evaluate mean weight and height differences between groups. Pearson chi square, chi-square trend and Fisher's exact tests were used to explore the crude association of categorical outcome variables and associated factors. Crude and adjusted associations between the outcome variables (stunting and thinness) and independent variables (socio-demographic, eating behavior and sanitation) were also determined using logistic regression. Stata version 11.1 was used to analyze the data. RESULTS: The height of the adolescents was 147.6 +/- 11.2 cm (mean +/- SD) and weight was37.2 +/- 9.5 kg. The mean Z-scores of height-for-age and body mass-index (BMI)-for-age of adolescents were -1.49 and -1.29, respectively. The prevalence of stunting and thinness among adolescents was 28.5 % (boys = 37.7 %; girls = 21.2 %; P = 0.001) and 26.1 % (boys = 32.4; girls = 21.6 %; p = 0.017), respectively. Adolescents in 13-15 year old age group (Adjusted Odds ratio (AOR) = 2.23; 95 % CI: 1.22, 4.08), boys (AOR = 2.53; 95 % CI: 1.52, 4.21) and rural residents (AOR = 2.15; 95 % CI: 1.20, 3.86) had significantly higher odds of being stunted compared to their counterparts. Furthermore, boys had higher (AOR = 1.97; 95 % CI: 1.19, 3.25) odds of being thin compared to girls. Compared to those 10 to 12 years of age, adolescents in 16 to 19 years of age were 53 % (AOR = 0.47; 95 % CI: 0.23, 0.95) less likely to be thin. CONCLUSIONS: Undernutrition is widely prevalent among adolescents in northern Ethiopia. Sex, age and area of residence significantly associated with adolescent undernutrition. The study underlines the need for nutrition interventions targeting rural and boy adolescents. PMID- 26516460 TI - Opioids for persistent pain: summary of guidance on good practice from the British Pain Society. PMID- 26516459 TI - Opioid prescribing in the UK: can we avert a public health disaster? PMID- 26516461 TI - Basic opioid pharmacology: an update. AB - Opioids are a group of analgesic agents commonly used in clinical practice. There are three classical opioid receptors (DOP, KOP and MOP), while the novel NOP receptor is considered to be a non-opioid branch of the opioid receptor family. Opioids can act at these receptors as agonists, antagonists or partial agonists. Opioid agonists bind to G-protein coupled receptors to cause cellular hyperpolarisation. Most clinically relevant opioid analgesics bind to MOP receptors in the central and peripheral nervous system in an agonist manner to elicit analgesia. Opioids may also be classified according to their mode of synthesis into alkaloids, semi-synthetic and synthetic compounds. PMID- 26516462 TI - Opioids and endocrine dysfunction. AB - The endocrine effects of opioids used for the management of persistent pain are poorly understood by clinicians and patients, and hormone levels are rarely measured. It is recognized that opioids exert this effect via the hypothalamic pituitary-gonadal axis. Additional effects on adrenal hormones, weight, blood pressure and bone density may also occur. Symptoms and signs of sex hormone deficiency occur in both men and women but are under-reported and are often clinically unrecognized. The potential effects of long term opioid therapy on the endocrine system should be explained to patients before opioid therapy is commenced. Monitoring of sex hormones is recommended; if there are deficiencies opioids should be tapered and withdrawn, if this is clinically acceptable. If opioid therapy has to continue, hormone replacement therapy should be initiated and monitored by an endocrinologist. PMID- 26516463 TI - Neuraxial (epidural and intrathecal) opioids for intractable pain. AB - 1. Neuraxial opioids are considered for use in patients who have resistant intractable pain that fails to respond to other treatment options or pain that responds to analgesia but for which the doses required result in unacceptable side-effects. 2. Neuraxial opiods can be considered for both chronic non malignant pain and chronic cancer-related pain. 3. Effectiveness in chronic non malignant pain and cancer pain is exerted through the use of either single-agent drugs (opioids) or a combination of drugs: opioids, local anaesthetics and other drugs such as clonodine and ziconotide. 4. Complications of long-term continuous infusion therapy are related to the insertion process (haematoma), the mechanical device (both pump and catheter) and the long-term effects of the drugs. 5. Patients will require ongoing ambulatory monitoring and supportive care. PMID- 26516464 TI - Opioids, pain and addiction - practical strategies. AB - 1. Addiction can occur with the repeated exposure of a biogenetically predisposed person to an addictive substance or behaviour. 2. In the patient with pain on opioid therapy, use the '4 Cs' to diagnose addiction. 3. Screening and risk stratification of all patients considered for opioid therapy is a key element of 'universal precautions' in pain management. 4. There are a number of established and new screening tools including the CAGE, Opioid Risk Tool and Screener and Opioid Assessment for Patients with Pain, which can be utilized in the office setting. 5. There are a number of potential ambiguous drug-related behaviours that should trigger a re-evaluation by the clinician. 6. Treating the higher-risk patient with opioids requires more assessment, more structure and more monitoring. Written opioid prescribing agreements and urine drug testing can be helpful strategies. 7. Essential documentation includes the '6As': Analgesia, Activity, Adverse effects, Ambiguous drug behaviours, Affect and Adequate prescription information. PMID- 26516465 TI - Equianalgesic doses of opioids - their use in clinical practice. PMID- 26516467 TI - Editorial. PMID- 26516468 TI - 'Education . . . Education . . . Education'. PMID- 26516469 TI - Education as part of wider health policy and improvement strategies. AB - 1. The majority of people living with persistent pain will receive treatment for the pain from non-specialists in pain management who may not have received the necessary training to deliver high-quality care. 2. There is now a wide range of learning platforms and packages available, but these may struggle to reach beyond those with a specialist interest. Addressing this will require action at both local and national levels to prioritise training in pain management. 3. Although education may improve knowledge, changing behaviour will require a wider change in clinical culture, including changing public and clinical attitudes and ensuring that the NHS recognises, prioritises and rewards high-quality pain management. PMID- 26516470 TI - Interprofessional pain education: definitions, exemplars and future directions. AB - 1. The management of pain frequently requires healthcare professionals (HCPs) to work together; thus, educational preparation should afford them opportunities to learn about the management of pain together. 2. Survey data suggest that most HCPs' curricula do not provide opportunities for learners to come together to learn about pain and understand their professional roles. 3. Despite the growth of published evaluations of interprofessional education (IPE) and pain, the ability to draw firm conclusions has been hampered by the lack of methodological heterogeneity across studies. 4. New directions in IPE and pain include innovative pedagogical approaches, web-based learning, standardised patients and simulated learning. 5. Harnessing the political agenda can offer a valuable opportunity to raise the profile and prominence of pain education for HCPs. PMID- 26516471 TI - Interprofessional pain learning and working: different perspectives. PMID- 26516472 TI - Reducing the distance: providing challenging and engaging online postgraduate education in pain management. AB - 1. Health professionals need access to flexible, high-quality, advanced education in pain management. 2. There are multiple pedagogical distances to be negotiated in the delivery of effective postgraduate education. 3. A critical consideration in the design and delivery of effective online learning for postgraduate education in pain management is how to: actively engage students in the learning process; and encourage students to become lifelong learners. 4. Conceptual frameworks for encouraging student interaction online provide a useful tool in the design of postgraduate online learning activities. PMID- 26516473 TI - Trust me, I'm a patient: pain education for professionals from a lay perspective. PMID- 26516474 TI - A decade of improvement in pain education and clinical practice in developing countries: IASP initiatives. AB - 1. Epidemiological studies, in the late 1990s and early 2000s, on the extent of pain in the community of western countries revealed a prevalence of around 18%, with significant effects on work and social activities despite 30 years of pain education programmes. 2. A survey by the International Association for the Study of Pain (IASP) Developing Countries on the extent of pain education and clinical training, and the barriers to them, was published as report in 2007 and confirmed significant deficiencies and problems in all areas. 3. An IASP Developing Countries Taskforce was established in 2002 to facilitate improvements in pain education and management in developing countries through a grants support programme for bottom-up projects from developing country members. 4. Clinical training posts in centres in Thailand, South America and South Africa have been established to improve the clinical training of pain clinicians and, through them, to develop pain services in their countries of origin in which services are poorly developed or absent. 5. There has been a major surge in the demand for and development of programmes and clinical training in developing countries since 2002, reflected in greatly increased local activity in various regions of the world. 6. Based on the ethical/moral belief that pain treatment is a human right, the IASP has recently increased its levels of advocacy to support this belief. PMID- 26516476 TI - Letter to the Editor. PMID- 26516475 TI - Evaluating the impact of pain education: how do we know we have made a difference? AB - 1. Education is a core activity for most healthcare professionals working in pain management and an effective evaluation strategy should assess its impact. 2. Evaluation may have one or more purposes: accountability, development or knowledge generation. Other key principles include making evaluation integral to the education process, reflecting with learners on progress, self-evaluation by the pain educator and involving all the key stakeholders. 3. A wide variety of methods are available, but the choice will be influenced by the nature and amount of the pain education, number of learners, purpose of the evaluation and time and resources available. 4. Patient education can be evaluated through knowledge and attitude questionnaires, concordance with the treatment plan, satisfaction and pain- and disability-related measures. 5. Further research is needed to explore the specific strategies or combination of techniques that are effective for different groups, and build on the theoretical base underpinning effective pain education and evaluation for patients and professionals. 6. The importance of education for the public has also been recently recognised, but this wider educational initiative should also be fully evaluated to assess whether this initiative is making a difference. PMID- 26516477 TI - Response to Letter to the Editor. PMID- 26516479 TI - Editorial. PMID- 26516480 TI - Guest Editorial. PMID- 26516481 TI - The International Headache Society's Core Curriculum on Headache for Neurologists. PMID- 26516484 TI - Editorial. PMID- 26516483 TI - Headache disorders: differentiating and managing the common subtypes. AB - Headache is an extremely common symptom and collectively headache disorders are among the most common of the nervous system disorders, with a prevalence of 48.9% in the general population.(1) Headache affects people of all ages, races and socioeconomic status and is more common in women. Some headaches are extremely debilitating and have significant impact on an individual's quality of life, imposing huge costs to healthcare and indirectly to the economy in general. Only a small proportion of headache disorders require specialist input. The vast majority can be effectively treated by a primary care physician or generalist with correct clinical diagnosis that requires no special investigation. Primary headache disorders - migraine, tension headache and cluster headache - constitute nearly 98% of all headaches; however, secondary headaches are important to recognise as they are serious and may be life threatening. This article provides an overview of the most common headache disorders and discusses the red flag symptoms that help identify serious causes that merit urgent specialist referral. The current pathway of headache care in the UK is discussed with a view to proposing a model that might fit well in the financially constrained National Health Service (NHS) and with new NHS reforms. The role of the national society, the British Association for the Study of Headache, and the patient organisations such as Migraine Trust in headache education to the professionals and the general public in shaping headache care in the UK is described. The article concludes by summarising evidence-based management of common headache diagnoses. PMID- 26516482 TI - Trigeminal autonomic cephalgias. AB - 1. Trigeminal autonomic cephalgias (TACs) are headaches/facial pains classified together based on:a suspected common pathophysiology involving the trigeminovascular system, the trigeminoparasympathetic reflex and centres controlling circadian rhythms;a similar clinical presentation of trigeminal pain, and autonomic activation. 2. There is much overlap in the diagnostic features of individual TACs. 3. In contrast, treatment response is relatively specific and aids in establishing a definitive diagnosis. 4. TACs are often presentations of underlying pathology; all patients should be imaged. 5. The aim of the article is to provide the reader with a broad introduction to, and an overview of, TACs. The reading list is extensive for the interested reader. PMID- 26516485 TI - Failed back surgery syndrome: are our patients getting a fair deal? PMID- 26516486 TI - Diagnosis and treatment of failed back surgery syndrome in the UK: mapping of practice using a cross-sectional survey. AB - BACKGROUND: Chronic back pain is a serious public health issue, associated with poor quality of life and disability. There is a specific group of chronic back pain sufferers whose pain persists despite their having undergone anatomically successful lumbosacral spine surgery. These patients are known as having failed back surgery syndrome (FBSS) and are frequently seen in pain clinics. It is currently unclear what constitutes routine practice in terms of diagnosis and treatment of FBSS in the UK. AIM: To map the diagnosis of and provision of care for patients with FBSS. METHODS: A cross-sectional survey of specialist pain clinics in the UK. RESULTS: This first attempt to survey 241 pain clinics in the UK achieved a response rate of 52%. The results of this survey suggest that patients at UK pain clinics were often diagnosed with FBSS between 6 and 12 months after surgery. Treatment is often initiated when patients report a level of pain between 3 and 5 cm (on a 10-cm visual analogue scale) and a range of therapeutic options are pursued in the hope of addressing the range of presenting symptoms. CONCLUSIONS: It is evident from the findings of this survey that, though there is some variation, pain specialists in the UK identify and handle patients with FBSS as a separate clinical entity. Direct, randomised comparisons of interventions should be the focus of research into appropriate treatment regimens going forward. Also, evidence of clinical effectiveness will need to incorporate elements of patient acceptance of interventions. PMID- 26516487 TI - Failed back surgery syndrome: a suggested algorithm of care. AB - Failed back surgery syndrome (FBSS) is a complex condition which can be very difficult to treat. In this article, we propose a pragmatic algorithm for the management of the syndrome. The management of this condition should include a comprehensive initial assessment to rule out treatable cause, pharmacological optimisation, psychological techniques and neuromodulation. There is good evidence to support early application of conventional spinal cord stimulation for FBSS patients suffering from predominant buttock and leg pain. Emerging techniques in neuromodulation such as high-frequency spinal cord stimulation, peripheral nerve field stimulation and dorsal root ganglion stimulation hold promise for the future, but long-term outcome regarding efficacy and safety is not yet established. Intrathecal drug delivery systems should also be considered in those who are unsuitable or unresponsive to neuromodulation and still warrant further treatment. However, the long-term outcome may not be as good as with other treatments mentioned above. PMID- 26516488 TI - Failed back surgery syndrome: whose failure? Time to discard a redundant term. AB - Failed back surgery syndrome or "failed back syndrome" refers to persistent pain after spinal surgery. This opinion piece will discuss the back ground and scale of failed back surgery syndrome. There will be a description of the medical and psychological factors that have been reported as predictors of poor outcome from spinal surgery. The management of failed back surgery syndrome will be discussed with a personal viewpoint based on working with this patient group for fifteen years. It will be argued that failed back surgery syndrome and failed back syndrome are now redundant terms and are not useful for either patient or healthcare provider, and so should be discarded.Key words Failed back surgery syndrome, failed back syndrome. PMID- 26516489 TI - The evidence base for managing older persons with low back pain. AB - It has been suggested that older persons are less likely to receive optimal care for pain, and a recent population study suggested that management of low back pain (LBP) in primary care differed with older age. Low back pain is the most commonly reported regional pain syndrome, and the objective of the current review was to determine the evidence base for managing LBP in older persons; specifically, to ascertain if randomized controlled trials provide information on the effectiveness of two common non-pharmacological treatments (manual therapy, physical activity/exercise) for LBP amongst older patients. We examine data from trials which contributed to the United Kingdom National Institute for Health and Clinical Excellence (NICE) guidelines on the management of LBP and determine whether the trials had upper age restrictions, their justification and whether any age-specific analyses had been conducted. The present survey included 21 studies of manual therapy and 71 of physical activity/exercise. Many studies had an upper age limit of <= 60 years (24% manual therapy, 44% physical activity/exercise) or 61-70 years (33%, 41%) but few gave a rationale for imposing an upper age limit in the trial eligibility criteria (2 out of 17 studies of manual therapy, 4 out of 68 studies of physical activity/exercise). Only 14% of studies of manual therapy and 1% of physical activity/exercise studies provided an age-specific analysis. Upper age limits in back pain trials of manual therapy and physical activity/exercise are common but a justification for these is rarely given. Almost no studies have reported whether effectiveness differs by age. PMID- 26516491 TI - Editorial. PMID- 26516490 TI - The economic impact of failed back surgery syndrome. AB - Failed back surgery syndrome (FBSS) is a generalised disorder that is characterised by chronic pain in the lower back and/or legs that persists or recurs following anatomically successful spinal surgery. This paper aims to (1) assess the burden of failed back surgery in terms of its epidemiology, impact on health outcomes and costs and (2) summarise the evidence base for the cost effectiveness of interventions for the management of FBSS. A narrative review based on a search of MEDLINE (PubMed) up to August 2012 was undertaken. Despite advances in technology and surgical techniques and increasing rates of spine surgery, a proportion of individuals continue to suffer from FBSS. Estimates from randomised controlled trials indicate that 5-50% of patients may have an unsuccessful outcome following lumbar spinal surgery. The understanding of the epidemiology and burden of FBSS remains poor and further research is needed in this area. The impact of FBSS on an individual's health-related quality of life and its economic cost to society are considerable and more disabling than other common chronic pain and chronic medical conditions, such as heart failure and motor neuron disease. There is a substantive body of evidence in FBSS patients showing spinal cord stimulation (SCS) to be cost-effective ( 1) were observed in the intervention groups as compared with the control groups. Improvements were noted in sleep latency, sleep efficiency and wake after sleep onset times. Although improvements were noted in pain experienced by the participants, this was not a significant finding. CONCLUSIONS: These clinical trials demonstrate that cognitive behavioural therapy for insomnia is effective as an intervention for insomnia in individuals suffering from chronic non malignant pain. Although pain and disturbed sleep are linked, cognitive behavioural therapy for insomnia alone may not be an effective solution for addressing chronic non-malignant pain. Trials of cognitive behavioural therapy for insomnia on a variety of chronic pain patients with disturbed sleep and with long-term follow-up are required to ascertain whether cognitive behavioural therapy for insomnia is an effective intervention to reduce pain and to add to increasing evidence that it is an effective intervention for insomnia in the chronic pain population. PMID- 26516516 TI - Evidence-based clinical practice guidelines on the management of pain in older people: executive summary. PMID- 26516517 TI - Editorial. PMID- 26516518 TI - Guest Editorial. PMID- 26516519 TI - Letter to the Editor. PMID- 26516520 TI - Obesity and pain. AB - Recent reports suggest that almost half of the UK population is expected to be obese by 2030. A number of associations between obesity and chronic pain have been displayed in previous studies, and therefore it can be expected that the presentation of obese patients with chronic pain will rise in accordance with the prevalence of obesity. No single causative relationship between the two can be suggested, so the link between them is believed to be multifactorial. Despite this, little work has been done to draw together the many associations between obesity and pain. A better understanding of their connection, then, is required to appropriately manage this patient group that is increasing in numbers. This article aims to draw together existing evidence on the associations between obesity and pain to create a model of their multifactorial relationship. The article will systematically address each of the current theories in order to gradually build a diagrammatic representation of the relationship, which shall conclude the article. PMID- 26516521 TI - Human pain and genetics: some basics. AB - Human pain causes untold misery and suffering, with major impact on functioning and resources. Recent advances in genetics have revealed that subtle changes in DNA could partly explain the variation in individual differences in pain. Various genes encoding for receptors are now known to play a major role in the sensitivity, perception and expression of pain. The fields of epigenetics and proteomics hold promises in the way pain could be treated and managed in future. PMID- 26516522 TI - Venom: the sharp end of pain therapeutics. AB - Adequate pain control is still a significant challenge and largely unmet medical need in the 21st century. With many small molecules failing to reach required levels of potency and selectivity, drug discovery is once again turning to nature to replenish pain therapeutic pipelines. Venomous animals are frequently stereotyped as inflictors of pain and distress and have historically been vilified by mankind. Yet, ironically, the very venoms that cause pain when directly injected by the host animal may actually turn out to contain the next generation of analgesics when injected by the clinician. The last 12 months have seen dramatic discoveries of analgesic tools within venoms. Spiders, snakes and even centipedes are yielding peptides with immense therapeutic potential. Significant advances are also taking place in delivery methods that can improve bioavailability and pharmacokinetics of these exciting natural resources. Turning proteinaceous venom into pharmaceutical liquid gold is the goal of venomics and the focus of this article. PMID- 26516526 TI - Guest Editorial. PMID- 26516525 TI - Editorial. PMID- 26516524 TI - Chronic pain epidemiology - where do lifestyle factors fit in? AB - Chronic pain is common and complex and has a large impact on individuals and society. Good epidemiological pain data provide key information on the use of resources (both in general practice and in specialist clinics), insight into factors that lead to or favour chronicity and the design of interventions aimed at reducing or preventing the effects of chronic pain. This review aims to highlight the important factors associated with chronic pain, including those factors which are amenable to lifestyle intervention. PMID- 26516527 TI - Letter to the Editor. PMID- 26516528 TI - Letter to the Editor. PMID- 26516529 TI - Problematic pain - redefining how we view pain? AB - The term 'problematic pain' is relatively new and has been the recent source of much debate, especially among primary and community care pain clinicians. In this article, we review the concept of problematic pain, highlighting how it fits in the context of acute, sub-acute and chronic pain. We also examine how risk for the development of chronicity can be assessed using current data and screening tools. The use of ultra-short screening tools for other conditions has previously been evaluated in the literature, and we propose a new tool, to open discussion for the assessment of problematic pain. This is especially relevant in the short consultation where it can be difficult to capture meaningful information quickly. Finally, we focus upon new initiatives currently in progress in the arena of problematic pain in the United Kingdom. PMID- 26516523 TI - Pharmacogenetics of analgesic drugs. AB - * Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined. * Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications. * While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype-phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the u-opioid receptor). * Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future. * This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors' views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain. PMID- 26516530 TI - Part-time, e-learning interprofessional pain management education for the primary and community care setting. AB - Chronic pain is a long-term condition, which has a major impact on patients, carers and the health service. Despite the Chief Medical Officer setting chronic pain and its management as a national priority in 2008, the utilisation of health services by patients with long-term conditions is increasing, people with pain related problems are not seen early enough and pain-related attendances to accident and emergency departments is increasing. Early assessment with appropriate evidence-based intervention and early recognition of when to refer to specialist and specialised services is key to addressing the growing numbers suffering with chronic pain. Pain education is recommended in many guidelines, as part of the process to address pain in these issues. Cardiff University validated an e-learning, master's level pain management module for healthcare professionals working in primary and community care. The learning outcomes revolve around robust early assessment and management of chronic pain in primary and community care and the knowledge when to refer on. The module focuses on the biopsychosocial aspects of pain and its management, using a blog as an online case study assessment for learners to demonstrate their knowledge, understanding and application to practice. The module has resulted in learners developing evidence-based recommendations, for pain management in clinical practice. PMID- 26516531 TI - Using health trainers to promote self-management of chronic pain: can it work? AB - BACKGROUND: In 2011, the Sheffield Primary Care Trust piloted a Health Trainer (HT) programme targeted specifically to people with chronic pain. The programme aimed to determine whether patients presenting to primary care with chronic pain would benefit from self-management support, thereby reducing the burden on primary care and secondary care services. METHODS: We conducted a formative mixed methods evaluation of the pilot programme, focusing on four aspects of implementation: general practitioner (GP) referral to the programme, HT's ability to use cognitive behavioural (CB) approaches, short-term outcomes for clients and adequacy of resources. Qualitative data were collected via interviews with GPs, HTs and the chronic pain team; supervision sessions with HTs; and client case studies. Quantitative data were collected on satisfaction with training, HT's self-reported confidence to implement CB and clients' self-rated well-being before and after participation. RESULTS: A total of 143 clients with pain for 1 year or more were referred, exceeding the projected 90 referrals by over 50%. A total of 70% of the clients came from the most deprived areas of Sheffield, 40% were listed as permanently sick/disabled and only 20% were working. Qualitative analysis indicated that the CB training was delivered as intended. Clients reported that 75% of their goals were either achieved or partly achieved, and at follow-up 43% of them reported maintaining strategies for self-management. Financial resources were supplemented by indirect resources, including GP 'champions' with a special interest in pain, and a multidisciplinary chronic pain team. The prior history of working with community organizations was critical in ensuring credibility in client communities and addressing client needs. CONCLUSION: A HT programme promoting self-management of chronic pain can be successfully implemented when supported by community organisations. Preliminary data indicate that the programme can be instrumental in helping clients to actively participate in identifying their own problems, set achievable goals for self-management and successfully manage the challenges of everyday life. SUMMARY POINTS: Community-based Health Trainer programmes can be successfully established to promote self-management of chronic pain among clients in the deprived areas using multidisciplinary pain management teams. Utilising a community organization infrastructure that has experience of delivering successful programmes was instrumental in ensuring credibility of the initiative and access for clients. Health trainers can integrate cognitive behavioral training with their existing skills to work with clients who have chronic pain. PMID- 26516532 TI - New approaches towards chronic pain: patient experiences of a solution-focused pain management programme. AB - Research has suggested that Solution-Focused Brief Therapy (SFBT) may be effective in facilitating meaningful change for those living with chronic pain. This study aimed to further this understanding through exploring the experiences of people living with chronic pain, who had attended an 8-week solution-focused pain management programme. The design of this study was conducted in consultation with a service-user advisory group, and employed a qualitative and interpretative design rooted in critical community psychology, participatory research frameworks and emancipatory disability research. Five participants opted-in to the study following an opportunity sampling method of persons who had attended a programme in the last 18 months. Interviews were transcribed verbatim and analysed using inductive thematic analysis. Five main themes were identified: 'Accessing the pain management programme', 'A solution-focused group', 'The solution-focused clinician', 'Solutions and changes' and 'Challenges and improvements'. Clinical and research implications of the findings are discussed. SUMMARY POINTS: There has been an international proliferation of pain management programmes (PMPs) aimed at helping those with chronic pain to live well, despite an unremitting condition.Arguably, the most popular psychological approaches used within PMPs are informed by cognitive behavioural therapy (CBT).Despite a supportive evidence base for psychological approaches in pain management, there is a recognised need for further research into alternative approaches and their effectiveness.Emerging research and policy recommendations are beginning to value the expertise of those living with chronic conditions, particularly how these perspectives can be used to develop effective treatments and services.SFBT is an approach aimed at achieving a patient's goals or 'preferred future' through identifying and utilising their expertise. SFBT may have significant efficacy in helping those with chronic conditions to live improved, meaningful lives. PMID- 26516533 TI - Sheffield spinal pathway audit cycle - pathways, mountains and the view from the top. AB - There is good evidence to suggest that a proactive stratified approach to management of spinal pain, taking into account psychosocial as well as biological factors, can realise significant savings for health-care systems and perhaps more importantly, health benefits for society at large. This audit cycle report captures data on quality of care and patient flows before and after the mandating of changes to the referral pathways in primary care. These included the introduction of a simple one-sided referral proforma, bounce back of inappropriate referrals from secondary care to physiotherapy lead teams and implementation of the STarT tool, as a decision aid in primary care. PMID- 26516536 TI - Editorial. PMID- 26516534 TI - A community pain service solution-focused pain management programme: delivery and preliminary outcome data. AB - 1. This article introduces a rationale for a solution-focused approach to a community-based pain management programme (PMP), describing delivery and preliminary outcome data. 2. It suggests PMPs can be feasibly run in the community without necessity for hospital care setting. 3. A community setting is also advantageous in that it allows maintenance of social networks and close third-sector links to support long-term, sustained mental well-being. 4. Solution focused psychological approaches help the clinician tap into patient expertise and develop rich descriptions of the patient's preferred future, enhancing self efficacy and empowerment. 5. Evaluation found significant statistical and clinical improvements in pre-post pain self-efficacy, mental well-being and function (but findings were limited by internal and external validity and no significant effect was found on pain levels). 6. Statistically significant change was maintained at 10 weeks for self-efficacy and function (and for the latter, clinically significant change was also maintained); improvements in mental well being showed maintenance at all measured time points (up to 12 months) in terms of both statistical and clinical significant changes. PMID- 26516537 TI - A psychological flexibility conceptualisation of the experience of injustice among individuals with chronic pain. AB - Accumulating evidence suggests that the experience of injustice in patients with chronic pain is associated with poorer pain-related outcomes. Despite this evidence, a theoretical framework to understand this relationship is presently lacking. This review is the first to propose that the psychological flexibility model underlying Acceptance and Commitment Therapy (ACT) may provide a clinically useful conceptual framework to understand the association between the experience of injustice and chronic pain outcomes. A literature review was conducted to identify research and theory on the injustice experience in chronic pain, chronic pain acceptance, and ACT. Research relating injustice to chronic pain outcomes is summarised, the relevance of psychological flexibility to the injustice experience is discussed, and the subprocesses of psychological flexibility are proposed as potential mediating factors in the relationship between injustice and pain outcomes. Application of the psychological flexibility model to the experience of pain-related injustice may provide new avenues for future research and clinical interventions for patients with pain. SUMMARY POINTS: * Emerging research links the experience of pain-related injustice to problematic pain outcomes. * A clinically relevant theoretical framework is currently lacking to guide future research and intervention on pain-related injustice. * The psychological flexibility model would suggest that the overarching process of psychological inflexibility mediates between the experience of injustice and adverse chronic pain outcomes. * Insofar as the processes of psychological inflexibility account for the association between injustice experiences and pain outcomes, methods of Acceptance and Commitment Therapy (ACT) may reduce the impact of injustice of pain outcomes. * Future research is needed to empirically test the proposed associations between the experience of pain-related injustice, psychological flexibility and pain outcomes, and whether ACT interventions mitigate the impact of pain-related injustice on pain outcomes. PMID- 26516538 TI - Howling at the moon? The effect of lunar phases on post-surgical pain outcome. AB - OBJECTIVE: Many people are convinced that lunar phases influence their lives - despite the fact that a lot of studies have shown that this belief is wrong. In this article, we investigate the effect of lunar phases on acute post-surgical pain and on treatment-related side effects. We hypothesize that there is no influence. METHODS: The data for the study were collected in 2010 and 2011 in 10 international hospitals participating in the research project PAIN OUT. Hospitalized patients were asked for their pain after surgery and pain treatment side effects using numerical ratings scales from 0 to 10. We applied Kurskal Wallis H-tests to find out if the four moon phases show significant differences in 14 outcome variables. Afterwards, we adjusted for age, gender and three tracer surgeries. RESULTS: A total of 12,224 patient data sets were assessed. For most variables and sub-groups, there is no lunar effect on the observed outcome variables. The only items that show statistically significant differences are pain interference with sleep (p = 0.01) and drowsiness (p = 0.01). The only sub groups that show statistically significant connections to lunar phases in some variables are men (7 out of 14 variables significant) and elderly people (4 out of 14 variables significant). DISCUSSION: Even in the statistically significant sub-groups, the differences are small and only show up in some variables. We conclude that lunar phases have no effect on post-surgical pain or its side effects. The hypothesis holds. Thus, there is no reason for patients to postpone surgeries or to fear surgeries on any given date. PMID- 26516539 TI - A prospective audit project into the adequacy of pain assessment in the medical and surgical wards in a North London District General Hospital. AB - BACKGROUND: Accurate assessment of pain is associated with improved pain management, which can lead to better patient outcomes. It has been recommended that all patients have their pain assessed and the scores documented as the 'fifth vital sign'. METHOD: All inpatients in the medical and surgical wards in our hospital were asked directly to score their pain according to the hospital wide scoring system. Their observation charts and drug charts were then reviewed in order to determine the accuracy of documented pain assessments and the subsequent analgesic management. RESULTS: Of the 208 patients reviewed, 20 (15%) patients on medical wards and 26 (38%) patients on surgical wards were in moderate to severe pain. Documentation of pain scores was not universal, with 29 (14%) patients having no score documented with their last set of observations. Of those with a score recorded, it was not found to correlate with the scores reported on direct questioning in 41% of medical patients and 71% of surgical patients. Provision of analgesia was also found to differ between medical and surgical wards. DISCUSSION: The care of pain in the wards falls below the standards set by the Royal College of Anaesthetists. It is necessary to undertake a programme of education to increase awareness of the problem and to improve assessment and management to enhance the patient experience. PMID- 26516540 TI - Editorial. PMID- 26516541 TI - From traditional cognitive-behavioural therapy to acceptance and commitment therapy for chronic pain: a mixed-methods study of staff experiences of change. AB - Health care organizations, both large and small, frequently undergo processes of change. In fact, if health care organizations are to improve over time, they must change; this includes pain services. The purpose of the present study was to examine a process of change in treatment model within a specialty interdisciplinary pain service in the UK. This change entailed a switch from traditional cognitive-behavioural therapy to a form of cognitive-behavioural therapy called acceptance and commitment therapy. An anonymous online survey, including qualitative and quantitative components, was carried out approximately 15 months after the initial introduction of the new treatment model and methods. Fourteen out of 16 current clinical staff responded to the survey. Three themes emerged in qualitative analyses: positive engagement in change; uncertainty and discomfort; and group cohesion versus discord. Quantitative results from closed questions showed a pattern of uncertainty about the superiority of one model over the other, combined with more positive views on progress reflected, and the experience of personal benefits, from adopting the new model. The psychological flexibility model, the model behind acceptance and commitment therapy, may clarify both processes in patient behaviour and processes of staff experience and skilful treatment delivery. This integration of processes on both sides of treatment delivery may be a strength of acceptance and commitment therapy. PMID- 26516542 TI - Weighing the balance: how analgesics used in chronic pain influence sleep? AB - Pain and sleep share a bidirectional relationship, with each influencing the other. Several excellent reviews have explored this relationship. In this article, we revisit the evidence and explore existing research on this complex inter-relationship. The primary focus of the article is on the pharmacological treatment of chronic non-malignant pain and the main purpose is to review the effect of various pharmacological agents used in the management of chronic pain on sleep. This has not been comprehensively done before. We explore the clinical use of these agents, their impact on sleep architecture and sleep physiology, the mechanism of action on sleep parameters and sleep disorders associated with these agents. Pharmacological classes reviewed include antidepressants, opioid analgesics, anti-epileptics, cannabinoids and non-steroidal anti-inflammatory agents, drugs most commonly used to manage chronic pain. The objective is to help health professionals gain better insight into the complex effect that commonly used analgesics have on an individual's sleep and how this could impact on the effectiveness of the drug as an analgesic. We conclude that antidepressants have both positive and negative effects on sleep, so do opioids, but in the latter case the evidence shifts towards the counterproductive side. Some anticonvulsants are sleep sparing and non-steroidal anti-inflammatory drugs (NSAIDs) are sleep neutral. Cannabinoids remain an underexplored and researched group. PMID- 26516543 TI - Pain reporting in older adults: the influence of cognitive impairment - results from the Cambridge City >75 Cohort study. AB - OBJECTIVES: Evidence suggests that while disabling back pain (BP), and rheumatic diseases associated with pain, continues to increase with age, the prevalence of non-disabling BP reaches a plateau, or even decreases, in the oldest old. This study aimed to determine whether this age-related pattern of non-disabling BP is a function of increasing cognitive impairment. METHODS: Cross-sectional study of adults aged >77 years. Participants answered interviewer-administered questions on BP and cognitive function, assessed using the Mini-Mental State Examination, categorised into normal versus mild, moderate or severe impairment. The relationship between cognitive function and BP was examined using multinomial logistic regression, adjusted for age, sex and residence. RESULTS: Of 1174 participants with BP data, 1126 (96%) completed cognitive assessments. The relationship between cognitive function and BP differed for disabling and non disabling BP. Across categories of cognitive impairment, increasingly higher prevalence of disabling BP was reported, compared to those with normal cognition, although this was not statistically significant (odds ratio (OR) = 1.7; 95% confidence interval (CI) = 0.7-4.6). No association was found between cognitive function and non-disabling BP (OR = 0.8; 95% CI = 0.4-1.6). CONCLUSION: This study found no association between the reporting of BP and level of cognitive impairment, suggesting that increasing cognitive impairment is an inadequate explanation for age-related decline in self-reported non-disabling BP. Future research should determine the reasons for the decline in non-disabling pain in older adults, although, meanwhile, it is important to ensure that this group receive appropriate pain assessment and pain management. KEY POINTS: Prevalence of non-disabling back pain decreases in the oldest old.Some have proposed that this may be a function of cognitive impairment in older age, and an increasing inability to adequately report pain.Our findings do not support this hypothesis. PMID- 26516544 TI - Guest Editorial. PMID- 26516545 TI - Editorial. PMID- 26516546 TI - Cancer pain for the 21st century: stepping off the ladder, stepping up to new challenges. PMID- 26516547 TI - Splice variation of the mu-opioid receptor and its effect on the action of opioids. AB - An individual's response to opioids is influenced by a complex combination of genetic, molecular and phenotypic factors.Intra- and inter-individual variations in response to mu opioids have led to the suggestion that mu-opioid receptor subtypes exist.Scientists have now proven that mu-opioid receptor subtypes exist and that they occur through a mechanism promoting protein diversity, called alternative splicing.The ability of mu opioids to differentially activate splice variants may explain some of the clinical differences observed between mu opioids.This article examines how differential activation of splice variants by mu opioids occurs through alternative mu-opioid receptor binding, through differential receptor activation, and as a result of the distinct distribution of variants located regionally and at the cellular level. PMID- 26516549 TI - Cancer pain physiology. AB - Mechanisms of inflammatory and neuropathic pains have been elucidated and translated to patient care by the use of animal models of these pain states. Cancer pain has lagged behind since early animal models of cancer-induced bone pain were based on the systemic injection of carcinoma cells. This precluded systematic investigation of specific neuronal and pharmacological alterations that occur in cancer-induced bone pain. In 1999, Schwei et al. described a murine model of cancer-induced bone pain that paralleled the clinical condition in terms of pain development and bone destruction, confined to the mouse femur. This model prompted related approaches, and we can now state that cancer pain may include elements of inflammatory and neuropathic pains but also unique changes in sensory processing. Cancer-induced bone pain results in progressive bone destruction, elevated osteoclast activity and distinctive nocifensive behaviours (indicating the triad of ongoing, spontaneous and movement-induced hyperalgesia). In addition, cancer cells induce an inflammatory infiltrate and release growth factors, cytokines, interleukins, chemokines, prostanoids and endothelins, resulting in a reduction of pH to below 5 and direct deformation of primary afferents within bone. These peripheral changes, in turn, drive hypersensitivity of spinal cord sensory neurons, many of which project to the parts of the brain involved in the emotional response to pain. Within the spinal cord, a unique neuronal function reorganization within segments of the dorsal horn of the spinal cord receiving nociceptive input from the bone are discussed. Changes in certain neurotransmitters implicated in brain modulation of spinal function are also altered with implications for the affective components of cancer pain. Treatments are described in terms of mechanistic insights and in the case of opioids, which modulate pain transmission at spinal and supraspinal sites, their use can be compromised by opioid-induced hyperalgesia. We discuss evidence for how this comes about and how it may be treated. PMID- 26516548 TI - Pain in cancer survivors. AB - Cancer and its treatment exert a heavy psychological and physical toll. Of the myriad symptoms which result, pain is common, encountered in between 30% and 60% of cancer survivors. Pain in cancer survivors is a major and growing problem, impeding the recovery and rehabilitation of patients who have beaten cancer and negatively impacting on cancer patients' quality of life, work prospects and mental health. Persistent pain in cancer survivors remains challenging to treat successfully. Pain can arise both due to the underlying disease and the various treatments the patient has been subjected to. Chemotherapy causes painful chemotherapy-induced peripheral neuropathy (CIPN), radiotherapy can produce late effect radiation toxicity and surgery may lead to the development of persistent post-surgical pain syndromes. This review explores a selection of the common causes of persistent pain in cancer survivors, detailing our current understanding of the pathophysiology and outlining both the clinical manifestations of individual pain states and the treatment options available. PMID- 26516551 TI - 'Not everything that can be counted counts and not everything that counts can be counted' (attributed to Albert Einstein). PMID- 26516550 TI - Pain services and palliative medicine - an integrated approach to pain management in the cancer patient. AB - The vast majority of cancer patients will experience pain during the course of their illness. Thankfully, in most instances, the consistent application of analgesic guidelines, tailored to the unique needs of each individual patient, will deliver a satisfactory outcome. These guidelines recommend the skilled use of analgesic medications, often in conjunction with a range of adjuvant therapies as may be required. Despite the consistent and rational application of such strategies, it is recognised that a small but significant proportion of cancer patients continue to experience more refractory pain. In addition, these patients may experience a plethora of unwanted dose-limiting side effects associated with their analgesic medication, sometimes even at low dose. All such patients with more complex and refractory pain syndromes require a more comprehensive review and many will require interventional therapy and/or adjuvant approaches. Unfortunately, the availability and accessibility of such services are variable. Even in circumstances in which palliative medicine and pain services co-exist in the same region, there may be poor integration between the two services. Each specialty area holds a unique set of skills and competencies, yet there is considerable overlap. Patient care and outcomes will be enhanced by establishing more formal relationships between these two specialty areas. PMID- 26516552 TI - Editorial. PMID- 26516553 TI - Using qualitative methods to access the pain experience. AB - Qualitative methods provide us with techniques to access the pain experience of patients in ways that provide explanation for apparent contradictions and idiosyncrasies that are difficult to access. In this article, I review three such strategies and the application of qualitative research to practice: (1) the analysis of the ways participants speak about agonizing pain using narrative inquiry, (2) comparisons of childbirth pain in two cultural groups using ethnography and (3) present a qualitative theory, the Praxis Theory of Suffering. This theory provides a theoretical explanation for behaviours that presently confound the understanding of distress using the Distress Thermometer. An alternative approach, 'reading' patients' behavioural manifestations of distress, is recommended. PMID- 26516554 TI - Ethnographies of pain: culture, context and complexity. AB - This article briefly introduces and discusses the value of ethnographic research, particularly research hailing from the discipline of social and cultural anthropology. After an introduction to ethnography in general, key ethnographic studies of pain are described. These show that ethnography provides a set of techniques for data collection and analysis, as well as a way of thinking about pain as socially and culturally embedded. Modern ethnographic writing is far removed from the literature of the past that sometimes described stereotypes rather than process and complexity. Ethnography provides the chance to describe the complexity and nuance of culture, which serves to counter stereotypes. The article concludes with an example from pain research conducted in a clinical setting. Through the use of ethnographic techniques, the research study provided greater insight than other methods alone might have achieved. The article includes references for further reading should readers be interested in developing their engagement with ethnographic method and interpretation. PMID- 26516555 TI - Qualitative systematic reviews: their importance for our understanding of research relevant to pain. AB - This article outlines what a qualitative systematic review is and explores what it can contribute to our understanding of pain. Many of us use evidence of effectiveness for various interventions when working with people in pain. A good systematic review can be invaluable in bringing together research evidence to help inform our practice and help us understand what works. In addition to evidence of effectiveness, understanding how people with pain experience both their pain and their care can help us when we are working with them to provide care that meets their needs. A rigorous qualitative systematic review can also uncover new understandings, often helping illuminate 'why' and can help build theory. Such a review can answer the question 'What is it like to have chronic pain?' This article presents the different stages of meta-ethnography, which is the most common methodology used for qualitative systematic reviews. It presents evidence from four meta-ethnographies relevant to pain to illustrate the types of findings that can emerge from this approach. It shows how new understandings may emerge and gives an example of chronic musculoskeletal pain being experienced as 'an adversarial struggle' across many aspects of the person's life. This article concludes that evidence from qualitative systematic reviews has its place alongside or integrated with evidence from more quantitative approaches. PMID- 26516556 TI - Interpretative phenomenological analysis as a useful methodology for research on the lived experience of pain. AB - Interpretative phenomenological analysis (IPA) is a qualitative approach which aims to provide detailed examinations of personal lived experience. It produces an account of lived experience in its own terms rather than one prescribed by pre existing theoretical preconceptions and it recognises that this is an interpretative endeavour as humans are sense-making organisms. It is explicitly idiographic in its commitment to examining the detailed experience of each case in turn, prior to the move to more general claims. IPA is a particularly useful methodology for examining topics which are complex, ambiguous and emotionally laden. Pain is a prime exemplar of such a phenomenon: elusive, involving complex psycho-somatic interactions and difficult to articulate. In addition to the 1998 article, published in this Special Issue, two further papers are suggested that the interested reader might wish to look out for. PMID- 26516557 TI - The role of the Internet for people with chronic pain: examples from the DIPEx International Project. AB - In this article we consider how people with chronic illness are using the internet, drawing on examples from published qualitative interview studies of experiences of chronic pain in the UK, Germany and Israel. Extracts from the interviews can be seen on the websites from the www.dipexinternational.org collaboration which publishes analyses and many thousands of video and audio interview clips on country specific web platforms. The UK branch of the collaboration has been operating for over a decade and currently includes broad based samples of qualitative interviews with patients about their experiences of over 80 health problems. The research has demonstrated that people living with chronic pain are increasingly using the web to find information, support and practical advice for self-management and also for reassurance, encouragement, to compare experiences of treatment and to offer advice and support to others. The internet is changing the way that people are experiencing illness, although access to relevant and reliable online material is not equally distributed. Those who do not speak one of the handful of dominant languages are less likely to find online experiences that resonate with their own. PMID- 26516558 TI - 'It makes you think' - exploring the impact of qualitative films on pain clinicians. AB - BACKGROUND: Researchers need to consider the impact and utility of their findings. Film is an accessible medium for qualitative research findings and can facilitate learning through emotional engagement. AIM: We aimed to explore the usefulness of a short film presenting findings from a published qualitative synthesis of adults' experience of chronic musculoskeletal pain for pain education. In particular, we were interested in the impact of the film on clinician's understanding of patients' experience of chronic pain and how this knowledge might be used for improved healthcare for people with pain. METHODS: Focus groups with healthcare professionals enrolled in a pain management foundation course explored healthcare professionals' experience of watching the film. A constructivist grounded theory approach was adopted by the researchers. FINDINGS: This article presents one thematic exemplar from a wider study. Participants reflected upon the pitfalls of judging by appearances and the value of seeing the person beneath his or her performance. CONCLUSION: There is a danger that the impact of qualitative findings is under-valued in clinical education. We present one exemplar from a study exploring knowledge mobilisation, which demonstrates that qualitative research, specifically qualitative films, can make us think about the care that we provide to people with chronic pain. PMID- 26516559 TI - How can qualitative research be utilised in the NHS when re-designing and commissioning services? AB - Patient experience is acknowledged as a key quality metric of healthcare quality and can be used to identify problems with healthcare delivery, to drive quality improvements and to inform commissioning of services that promote patient choice. In this article, the contribution of qualitative research studies to inform the redesign and patient-focussed commissioning of services is considered, illustrated with particular reference to elective orthopaedic surgical services. To fully embrace the concept of patient and public involvement (PPI) and to embed it in service delivery, health service design and informing commissioners to purchase healthcare that truly meets patient need and expectations, qualitative research has an increasingly important role to play. Through well-conducted qualitative research exploring patients' experiences, their knowledge and experiences of conditions can be utilised for the benefit of others and the impact of the patient voice truly heard when designing and commissioning healthcare services. PMID- 26516561 TI - Editorial. PMID- 26516562 TI - Epidural analgesia provides effective pain relief in patients undergoing open liver surgery. AB - BACKGROUND: Epidural analgesia has been the reference standard for the provision of post-operative pain relief in patients recovering from major upper abdominal operations, including liver resections. However, a failure rate of 20-32% has been reported. AIM: The aim of the study was to analyse the success rates of epidural analgesia and the outcome in patients who underwent liver surgery. METHODS: We collected data from a prospectively maintained database of 70 patients who underwent open liver surgery by a bilateral subcostal incision during a period of 20 months (February 2009 to September 2010). Anaesthetic consultants with expertise in anaesthesia for liver surgery performed the epidural catheter placement. A dedicated pain team assessed the post-operative pain scores on moving or coughing using the Verbal Descriptor Scale. The outcome was measured in terms of epidural success rates, pain scores, post-operative chest infection and length of hospital stay. RESULTS: The study group included 43 males and 27 females. The indication for resection was liver secondaries (70%), primary tumours (19%) and benign disease (11%). While major (>=3 segments) and minor resections (<= 2 segments) were performed in 44% and 47% respectively, 9% of patients were inoperable. Epidural analgesia was successful in 64 patients (91%). Bacterial colonisation of epidural tip was noticed in two patients. However, no neurological complications were encountered. Five patients (7%) had radiologically confirmed chest infection. Four patients (6%) developed wound infection. One patient died due to liver failure following extended right hepatectomy and cholecystectomy for gall bladder cancer. The median length of stay was 6 days (3-27 days). The extent of liver resection (p = 0.026) and post operative chest infection (p = 0.012) had a significant influence on the length of stay. CONCLUSION: Our experience shows that epidural analgesia is safe and effective in providing adequate pain relief following open liver surgery. PMID- 26516563 TI - The epidemiology of regional and widespread musculoskeletal pain in rural versus urban settings in those >=55 years. AB - OBJECTIVES: To examine whether the prevalence of regional and chronic widespread pain (CWP) varies with rurality and to determine the characteristics of persons in rural locations in whom pain is found to be in excess. METHODS: Participants, aged >=55 years, from participating general practices in seven different geographical locations in Scotland were sent a postal questionnaire. The 1-month prevalence of 10 regional pain conditions plus CWP was identified using body manikins. Differences in the prevalence of pain with differing rurality were examined using Chi(2) test for trend. Thereafter, among the rural population, the relationships between pain and putative risk factors were examined using Poisson regression. Thus, results are described as risk ratios. RESULTS: There was some evidence to suggest that the prevalence of CWP increased with increasing rurality, although the magnitude of this was slight. No large or significant differences were observed with any regional pain conditions. Factors associated with the reporting of CWP included poor general health, feeling downhearted most of the time and selected measures of social contact. Factors independently associated with CWP included female gender (risk ratio: 1.24; 95% confidence interval (CI): 0.997-1.55), poor self-rated health (risk ratio: 3.50; 95% CI: 1.92-6.39) and low mood (risk ratio: 1.54; 95% CI: 1.07-2.20). Also, having fewer than 10 people to turn to in a crisis was associated with a decrease in the risk of CWP - risk ratio: 0.68 (95% CI: 0.50-0.93) and 0.78 (95% CI: 0.60-1.02) for those with 5-10 and <5 people, respectively. CONCLUSIONS: This study provides no evidence that the prevalence of regional musculoskeletal pain is increased in rural settings, although there is some evidence of a modest increase in CWP. Risk factors for CWP are similar to those seen in the urban setting, including markers of general health, mental health and also aspects of social contact. It may be, however, that social networks are more difficult to maintain in rural settings, and clinicians should be aware of the negative effect of perceived social isolation on pain in rural areas. PMID- 26516564 TI - Prevalence of chronic non-cancer pain in a UK prison environment. AB - Chronic non-cancer pain (CNCP) is significant global health issue, accounting for a substantial increase in prescription analgesics worldwide, in recent decades. This clinical burden is evident in the UK prison population, where the prevalence of CNCP has never previously been determined. This study, conducted in June/July 2013, used prescribing data and a systematic review of clinical records from two UK prison establishments to derive a figure for point-prevalence of CNCP. Results showed that 20% of the total aggregated prisoner rolls (N = 1944) described CNCP and had been in receipt of treatment with daily analgesia, for a period of at least 3 months prior to observation date. This prevalence of CNCP was related to increasing age group (Spearman's rank correlation 0.94). Of those on continuous analgesic therapy (CAT), 44% were taking continuous opioid therapy (COT) of any sort. Prisoners with a diagnosis of opioid-type drug dependence (OTDD) were more than twice as likely to complain of CNCP and be on continuous medication for it (odds ratio 2.3). The issues relating to CNCP in prisons are discussed. Further research is recommended, identifying factors influencing CNCP prevalence in prisons, and enabling comparisons to CNCP prevalence in the UK general population. PMID- 26516565 TI - Medically Unexplained Symptoms: an acceptable term? AB - BACKGROUND: The term 'Medically Unexplained Symptoms' (MUS) is used by health professionals and researchers to refer to persistent bodily complaints, including pain and discomfort. AIMS: This study explores the views held by a lay sample on the clinical terminology used to describe 'MUS', to ascertain reasons for particular preferences and whether preferences differ between individuals who experience more somatic symptoms. DESIGN AND METHODS: A sample (n = 844) of healthy adults completed an online survey, which included a questionnaire measuring somatic symptoms (Patient Health Questionnaire-15 (PHQ-15)) and a question about their preferences for terminology used to describe MUS. RESULTS: Of 844 participants, 698 offered their preferences for terminology. The most popular terms were 'Persistent Physical Symptoms' (20%) and 'Functional Symptoms' (17%). 'MUS' (15%), 'Body Distress Disorder' (13%) and 'Complex Physical Symptoms' (5%) were less popular. And 24% indicated no preference, but high PHQ 15 scorers were more likely to express preferences than low scorers. CONCLUSION: Persistent Physical Symptoms and Functional Symptoms are more acceptable to this sample of healthy adults than the more commonly used term 'MUS'. PMID- 26516566 TI - Is intramuscular morphine satisfying frontline medical personnels' requirement for battlefield analgesia in Helmand Province, Afghanistan? A questionnaire study. AB - BACKGROUND: All deployed British Army personnel carry intramuscular (IM) morphine auto-injectors to treat battlefield casualties. No other nation supplies parenteral opiate analgesia on individual issue. Studies highlight this agent's inefficacy and safety issues, but are limited by a relative lack of inclusion of frontline personnel. We aimed to determine the opinions of frontline medical personnel on current battlefield analgesia. METHODS: We surveyed 88 British Army frontline medical personnel (medical officers (n = 12), nurses (n = 7), combat medical technicians (CMTs) (n = 67), paramedics (n = 1) and health-care assistants (n = 1)) upon completion of a six-month deployment (September 2011 to April 2012) to Helmand Province, Afghanistan, using Likert scale questions on the efficacy of battlefield analgesia, complications of IM morphine, safety of morphine auto-injectors and its suitability for treating child casualties. RESULTS: A total of 88/88 questionnaires were returned. Of these, 61/88 had treated casualties on the battlefield, 26/86 agreed that current battlefield analgesia is effective, 80/87 agreed that a more potent analgesic with a faster onset than IM morphine is desirable in the first hour following injury, 47/65 CMTs agreed that they can manage complications of current battlefield analgesia and 53/86 respondents correctly disagreed that current battlefield analgesia is suitable for child casualties. The potential for accidental self-injection was reported. CONCLUSIONS: A more potent, faster onset analgesic than IM morphine is desirable in the first hour following injury. Pre-deployment training should emphasise management of complications of opiate analgesics and treatment of child casualties. Oral transmucosal fentanyl citrate is now being issued to all frontline medical personnel. IM morphine will remain on individual issue to all deployed soldiers for environments where an oral agent is not suitable, for example, chemical, biological, radiological and nuclear warfare. SUMMARY POINTS: Frontline medical personnel agree that a more potent, faster onset analgesic than IM morphine is desirable in the first hour following injury.The two most desirable features of the ideal analgesic were ranked as rapid onset of action, and when fully onset produces a high degree of pain relief.Oral transmucosal fentanyl citrate (OTFC) has now been issued to all frontline medical personnel as an adjunct to IM morphine.IM morphine will remain on individual issue for situations where parenteral analgesia is required.Consideration should be given to individual issue of OTFC to all deployed personnel in the future.Pre deployment training should emphasise management of complications of opiate analgesics and treatment of child casualties. PMID- 26516568 TI - Editorial. PMID- 26516567 TI - Establishing the characteristics for patients with chronic Complex Regional Pain Syndrome: the value of the CRPS-UK Registry. AB - OBJECTIVE: The long-term prognosis of patients with Complex Regional Pain Syndrome (CRPS) is unknown with no reported prospective studies from the United Kingdom longer than 18 months. The CRPS-UK Network aims to study this by use of a Registry. The aims of this article are, to outline the CRPS-UK Registry, assess the validity of the data and to describe the characteristics of a sample of the UK CRPS population. METHODS: A web-based CRPS-UK Registry was developed and made accessible to centres experienced in diagnosing and managing patients with CRPS. Pragmatic annual follow-up questions were agreed. RESULTS: Up until July 2013, the Registry has recruited 240 patients. A blinded, validation study of 20 consecutive patients from two centres (10 each) demonstrated 95.6% completion and 99.4% accuracy of a random sample of the recorded data. These patients had chronic disease (median duration: 29 months); 72.5% were female (2.6:1), with a mean age at symptoms onset of 43 years, and were left-handed more than expected (21.8% versus 10% in the general population). Patients reported a delayed diagnosis, with the median time between symptom onset and diagnosis of 6 months. In all, 30 patients (12.5%) had multiple limb involvement and (83.3%) had a contiguous spread of CRPS. CONCLUSION: CRPS-UK Registry is a validated method for actively recruiting well-characterised patients with CRPS to provide further information on the long-term outcome. PMID- 26516569 TI - The re-evaluation of the measurement of pain in population-based epidemiological studies: The SHAMA study. AB - BACKGROUND: While many pain patients rely on pain-relieving treatments to manage their pain, pain-related research commonly quantifies pain status using validated questionnaires without taking into account that information. This will lead to an underestimate of the burden of pain in the community. To ensure a more accurate assessment of the prevalence and severity of pain, this study aimed to develop a pain management questionnaire and to assess how much population-based pain estimates change when pain management is considered. METHODS: This study was a cross-sectional population-based study in Grampian, north-east Scotland. A total of 4600 people, aged 25 years and over, were randomly selected from a population sample frame and sent a questionnaire on pain and pain management. Population estimates of pain were determined twice: with the use of standard pain status questionnaires ('current pain') and with the use of a newly developed enhanced pain status questionnaire to determine patients' estimated pain without pain management ('all pain'). RESULTS: The prevalence of current pain was 50.5% (95% CI = 48.0, 52.9). Of those who reported no current pain, 11.6% (95% CI = 9.4, 13.8) reported that they would have had pain had they not managed their pain. Thus, the all pain prevalence was 56.2% (95% CI = 53.7, 58.7). This difference in prevalence rates was statistically significant (difference = 5.7%; 95% CI = 2.2, 9.2). Likewise, participants' pain severity significantly increased when they estimated their pain without pain management (p < 0.001, Wilcoxon-signed rank test). CONCLUSIONS: Failure to assess pain management information results in an underestimation of pain prevalence and severity. This should be considered in future epidemiological studies. SUMMARY POINTS: Pain management information is currently not considered for the assessment of pain in epidemiological population based studies.Since pain management can affect people's pain status drastically, it is likely that we currently underestimate the true burden of pain in studies assessing pain.Incorporating self-reported pain management information in an epidemiological study of pain led to significantly increased estimates of both pain prevalence and pain severity.It is therefore crucial to collect and take into account people's pain management information in future studies for a more accurate measurement of pain. PMID- 26516570 TI - Temporary sympathectomy in chronic refractory angina: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Temporary sympathectomy by injection of bupivacaine at the site of the left stellate ganglion is used in the management of refractory angina at several UK centres. Although patients frequently report significant reduction in symptoms, efficacy has not been established by double-blind, randomised placebo controlled trial (RCT). OBJECTIVE: To investigate the efficacy of the procedure for the first time by a double-blind RCT. METHODS: Consecutive patients referred to the authors' National Health Service (NHS) angina centre who were candidates for temporary sympathectomy were invited to participate in a trial. A total of 65 patients were randomised to receive either bupivacaine or saline injections. Identical syringes were prepared remotely, blinding patients and staff from randomisation. Cardiac autonomic function was measured 3 hours pre- and post injection using new heart rate variability (HRV) analyses. Angina episodes were recorded contemporaneously by patients in study diaries in the 7-day periods pre- and post-injection. RESULTS: In 51 patients suitable for analysis, no significant differences between the active and placebo groups were found in patient-recorded frequency or intensity of angina episodes pre- and post-injection. However, across both groups combined, a significant difference was found in the frequency of angina episodes pre- and post-injection. CONCLUSION: The reduction in frequency of angina episodes produced by this procedure may not be due to drug pharmacology. It may be a placebo response or due to the mechanical effects of the injection of fluid. There is a need for further work using a larger patient cohort considering both mechanical and psychological factors. PMID- 26516571 TI - Comparison of the effects of intra-articular sole ropivacaine and combined ketorolac and ropivacaine for pain control after knee arthroscopy surgery. AB - INTRODUCTION: Effective pain relief is important after arthroscopic knee surgery to permit initiation of daily activities of life. This study is performed in order to investigate the effect of multi-model therapy for pain control after surgery. This clinical, randomized and double-blind trial is conducted on patients who get knee arthroscopy surgery. METHODS: Of these patients, 40 were divided into two groups by Block Randomization method: 1 - sole ropivacaine group (150 mg); 2 - combined ketorolac (30 mg); and ropivacain (150 mg) group. These drugs were injected intra-articularly at the end of knee arthroscopic surgery. The first consequence including measurement of pain severity after entrance to recovery room and 2, 4, 8, 12, 18 and 24 hours after surgery were evaluated according to the visual analogue pain score. The second consequence, including nausea, vomiting and sedation, was assessed by expert nurses in the recovery room and surgery part according to nausea and vomiting scale and Ramsay sedation scale, respectively. RESULTS: All groups had excellent analgesia at 0 and 4 hours, postoperatively. Group-combined ketorolac and ropivacaine had significantly lower visual analogue pain score as well as higher sedative scale at 8, 12, 18 and 24 hours after surgery at rest and during movement compared with the other group (p < 0.05). Moreover, there was no statistical difference between groups in regard of nausea and vomiting. CONCLUSION: Addition of ketolorac to ropivacaine intra-articularly in arthroscopic knee surgery enhances analgesic efficacy of local anaesthetics and cause more sedation after surgery. PMID- 26516572 TI - How do people with chronically painful joint hypermobility syndrome make decisions about activity? AB - BACKGROUND: The model of activity avoidance prompted by fear of increased pain and/or harm dominates understanding and research into activity limitation in chronic pain. Yet, the accounts of people with chronic pain on decisions about activity limitation are rarely heard beyond the confines of fear and avoidance questionnaires. METHODS: We used semi-structured interviews to explore the decisions of 11 women attending a pain management clinic with chronically painful Joint Hypermobility Syndrome (JHS). RESULTS: Six themes emerged from Interpretative Phenomenological Analysis: the overall aim of keeping pain to a manageable level, considering whether the planned activity was worth it and, running through all judgements, the influence of pain intensity. The decision was tipped towards avoidance by unpredictability of pain and by high emotional cost and towards going ahead with the activity by the wish to exert control and by low emotional cost. Many accounts described a specifiable cost-benefit analysis of individual decisions, weighing the importance of each activity against its potential aversive consequences, which only in a minority of cases was dominated by fear of pain or injury. CONCLUSION: Assumptions of fear as the basis of activity avoidance should not be used uncritically in clinical settings. Decisions about activity should explore beyond pain expectancy, incorporating goals, values, and decision processes. SUMMARY POINTS: The model of fear of pain or re/injury and associated avoidance, an important insight that has generated effective therapeutic interventions, risks being over-applied and assumed rather than demonstrated. Patients' own accounts, using qualitative analysis of interview in 11 women with long term chronic pain associated with joint hypermobility, give a more nuanced description of complex decision-making around activity. While a few activities were unquestionably avoided because of such fears, others were undertaken when benefits (according to personal values, such as children's needs) outweighed costs in pain and distress. We suggest that activity needs to be discussed with patients beyond asking about avoidance and in the context of their lifestyle choices. PMID- 26516573 TI - Influence of ethnicity on the perception and treatment of early post-operative pain. AB - BACKGROUND: Previous studies indicated that patients from Black, Asian and minority ethnic (BAME) groups tend to receive less analgesics compared to Caucasian (White) patients after similar surgical procedures. Most such data originated from North America and suggested that health-care professionals may perceive the expression of excessive pain by BAME patient groups as an exaggerated response to pain, rather than sub-optimal treatment. There are limited data comparing acute pain management between South Asian and White British patients. OBJECTIVE: We aimed to investigate correlation between patients' ethnicity and disparities of early post-operative pain perception/management, in an ethnically diverse population. METHODS: We conducted a retrospective case note review of acute post-operative pain after total abdominal hysterectomy (TAH) in 60 South Asian and 60 age-matched White British females. Data for 140 variables (pre-, intra- and post-operative) for each patient were recorded. We used propensity score matching to produce 30 closely matched patients in each group minimizing effects of recorded co-variates. Data were analysed with and without propensity score matching. RESULTS: There were no significant differences in acute post-operative pain scores, morphine requirements, pain management, adverse effects or duration of post-operative care unit stay between South Asian and White British patients. The median duration of hospital stay of South Asian patients was longer (4.5 days versus 3.0 days, p < 0.001). CONCLUSION: We conclude that in an institution where both patients and health-care professionals are from an ethnically diverse population, neither post operative pain nor pain management are influenced significantly by South Asian ethnicity. PMID- 26516574 TI - Can pictorial images communicate the quality of pain successfully? AB - Chronic pain is common and difficult for patients to communicate to health professionals. It may include neuropathic elements which require specialised treatment. A little used approach to communicating the quality of pain is through the use of images. This study aimed to test the ability of a set of 12 images depicting different sensory pain qualities to successfully communicate those qualities. Images were presented to 25 student nurses and 38 design students. Students were asked to write down words or phrases describing the quality of pain they felt was being communicated by each image. They were asked to provide as many or as few as occurred to them. The images were extremely heterogeneous in their ability to convey qualities of pain accurately. Only 2 of the 12 images were correctly interpreted by more than 70% of the sample. There was a significant difference between the two student groups, with nurses being significantly better at interpreting the images than the design students. Clearly, attention needs to be given not only to the content of images designed to depict the sensory qualities of pain but also to the differing audiences who may use them. Education, verbal ability, ethnicity and a multiplicity of other factors may influence the understanding and use of such images. Considerable work is needed to develop a set of images which is sufficiently culturally appropriate and effective for general use. PMID- 26516575 TI - An exploration of opioid medication management for non-malignant pain in primary care. AB - The present study aimed to explore how prescription of opioid medication for chronic non-malignant pain (CNMP) is managed in primary care. We used audit as a research tool, and one general practitioner (GP) practice in West London acted as an exemplar. Of the practice population with CNMP, 1% had repeat prescription of at least 12 months duration for opioid analgesics at the time of data collection. These 1% are on highly controlled opioids. Our study showed the following: (1) long-term opioid prescription appears to follow a fluctuating course as opposed to staying the same; (2) we found that medication reviews were done in most cases (85.7%), but the quality of the process is difficult to assess and ascertain; and (3) we identified two incidences where opioid contract was implemented. In both cases, contracts were used as a last chance warning for patients who were already problematic, suggesting that opioid contracts served as a disciplinary tool rather than a preventative measure. Our findings highlight a need for a more structured and specific review of analgesic medication, and a need for a simple and effective way to identify patients at high risk of developing problematic use, to ensure better monitoring and early presentations. PMID- 26516576 TI - Inhibition of hERG potassium channel by the antiarrhythmic agent mexiletine and its metabolite m-hydroxymexiletine. AB - Mexiletine is a sodium channel blocker, primarily used in the treatment of ventricular arrhythmias. Moreover, recent studies have demonstrated its therapeutic value to treat myotonic syndromes and to relieve neuropathic pain. The present study aims at investigating the direct blockade of hERG potassium channel by mexiletine and its metabolite m-hydroxymexiletine (MHM). Our data show that mexiletine inhibits hERG in a time- and voltage-dependent manner, with an IC50 of 3.7 +/- 0.7 MUmol/L. Analysis of the initial onset of current inhibition during a depolarizing test pulse indicates mexiletine binds preferentially to the open state of the hERG channel. Looking for a possible mexiletine alternative, we show that m-hydroxymexiletine (MHM), a minor mexiletine metabolite recently reported to be as active as the parent compound in an arrhythmia animal model, is a weaker hERG channel blocker, compared to mexiletine (IC50 = 22.4 +/- 1.2 MUmol/L). The hERG aromatic residues located in the S6 helix (Tyr652 and Phe656) are crucial in the binding of mexiletine and the different affinities of mexiletine and MHM with hERG channel are interpreted by modeling their corresponding binding interactions through ab initio calculations. The simulations demonstrate that the introduction of a hydroxyl group on the meta position of the aromatic portion of mexiletine weakens the interaction of the drug xylyloxy moiety with Tyr652. These results provide further insights into the molecular basis of drug/hERG interactions and, in agreement with previously reported results on clofilium and ibutilide analogs, support the possibility of reducing hERG potency and related toxicity by modifying the aromatic pattern of substitution of clinically relevant compounds. PMID- 26516577 TI - Applicability of second-generation upcyte(r) human hepatocytes for use in CYP inhibition and induction studies. AB - Human upcyte(r) hepatocytes are proliferating hepatocytes that retain many characteristics of primary human hepatocytes. We conducted a comprehensive evaluation of the application of second-generation upcyte(r) hepatocytes from four donors for inhibition and induction assays using a selection of reference inhibitors and inducers. CYP1A2, CYP2B6, CYP2C9, and CYP3A4 were reproducibly inhibited in a concentration-dependent manner and the calculated IC50 values for each compound correctly classified them as potent inhibitors. Upcyte(r) hepatocytes were responsive to prototypical CYP1A2, CYP2B6, CYP2C9, and CYP3A4 inducers, confirming that they have functional AhR-, CAR-, and PXR-mediated CYP regulation. A panel of 11 inducers classified as potent, moderate or noninducers of CYP3A4 and CYP2B6 were tested. There was a good fit of data from upcyte(r) hepatocytes to three different predictive models for CYP3A4 induction, namely the Relative Induction Score (RIS), AUCu/F2, and C max,u/Ind50. In addition, PXR (rifampicin) and CAR-selective (carbamazepine and phenytoin) inducers of CYP3A4 and CYP2B6 induction, respectively, were demonstrated. In conclusion, these data support the use of second-generation upcyte(r) hepatocytes for CYP inhibition and induction assays. Under the culture conditions used, these cells expressed CYP activities that were equivalent to or higher than those measured in primary human hepatocyte cultures, which could be inhibited or induced by prototypical CYP inhibitors and inducers, respectively. Moreover, they can be used to predict in vivo CYP3A4 induction potential using three prediction models. Bulk availability of cells from multiple donors makes upcyte(r) hepatocytes suitable for DDI screening, as well as more in-depth mechanistic investigations. PMID- 26516578 TI - Intestinal, portal, and peripheral profiles of daikenchuto (TU-100)'s active ingredients after oral administration. AB - A pharmaceutical grade Japanese traditional medicine, daikenchuto (TU-100), consisting of Japanese pepper, processed ginger, and ginseng, has been widely used for various intestinal disorders in Japan and now under development as a new therapeutic drug in the US. It is suggested that TU-100 ingredients exert pharmacological effects on intestines via two routes, from the luminal side before absorption and the peripheral blood stream after absorption. Therefore, in order to fully understand the pharmacological actions of TU-100, it is critically important to know the intraluminal amounts and forms of ingested TU-100 ingredients. In the present study, after administrating TU-100 to rats, the concentrations of TU-100 ingredients and their conjugates in the peripheral and portal blood and ileal contents were determined by LC-MS/MS. Next, TU-100 was administered to patients with ileostomy bags, but whose small intestines are diagnosed as healthy, and the ingredients/conjugates in the ileal effluent were analyzed. The results suggest that: (1) Pepper ingredients hydroxysanshools are rapidly absorbed and enter systemic circulation, (2) Ginseng ingredients ginsenosides are transported to the colon with the least absorption, (3) Ginger ingredients gingerols are absorbed and some conjugated in the small intestine and transported via the portal vein. While only a small amount of gingerols/gingerol conjugates enter systemic circulation, considerable amounts reappear in the small intestine. Thus, the effect of TU-100 on the intestines is believed to be a composite of multiple actions by multiple compounds supplied via multiple routes. PMID- 26516579 TI - Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H1 receptor and interleukin-4 genes. AB - Kujin contains antiallergic compounds that inhibit upregulation of histamine H1 receptor (H1R) and interleukin (IL)-4 gene expression. However, the underlying mechanism remains unknown. We sought to identify a Kujin-derived antiallergic compound and investigate its mechanism of action. The H1R and IL-4 mRNA levels were determined by real-time quantitative RT-PCR. To investigate the effects of maackiain in vivo, toluene-2,4-diisocyanate (TDI)-sensitized rats were used as a nasal hypersensitivity animal model. We identified (-)-maackiain as the responsible component. Synthetic maackiain showed stereoselectivity for the suppression of IL-4 gene expression but not for H1R gene expression, suggesting distinct target proteins for transcriptional signaling. (-)-Maackiain inhibited of PKCdelta translocation to the Golgi and phosphorylation of Tyr(311) on PKCdelta, which led to the suppression of H1R gene transcription. However, (-) maackiain did not show any antioxidant activity or inhibition of PKCdelta enzymatic activity per se. Pretreatment with maackiain alleviated nasal symptoms and suppressed TDI-induced upregulations of H1R and IL-4 gene expressions in TDI sensitized rats. These data suggest that (-)-maackiain is a novel antiallergic compound that alleviates nasal symptoms in TDI-sensitized allergy model rats through the inhibition of H1R and IL-4 gene expression. The molecular mechanism underlying its suppressive effect for H1R gene expression is mediated by the inhibition of PKCdelta activation. PMID- 26516580 TI - beta 1 Adrenoceptor antagonistic effects of the supposedly selective beta 2 adrenoceptor antagonist ICI 118,551 on the positive inotropic effect of adrenaline in murine hearts. AB - Studies on the relative contribution of beta 1- and beta 2-adrenoceptors (AR) generally employ selective beta 1- and beta 2-AR antagonists such as CGP 20712A and ICI 118,551, respectively, and assume that antagonism by one of these compounds indicates mediation by the respective AR subtype. Here, we evaluated the beta 2-AR-selectivity of ICI 118,551 in ventricular muscle strips of transgenic mice lacking beta 1-AR (beta 1-KO), beta 2-AR (beta 2-KO), or both (beta 1/beta 2-KO). Strips were electrically driven and force development was measured. In wild type (WT), ICI 118,551 (100 nmol/L) shifted the concentration response curve (CRC) for adrenaline by about 0.5 log units to the right, corresponding to the known affinity of ICI 118,551 to beta 1-AR but not to beta 2 AR. Conversely, the phosphodiesterase inhibitor rolipram (10 MUmol/L) shifted the CRC to the left, but did not enlarge the ICI 118,551 shift, indicating exclusive beta 1-AR mediation even when PDE4 is inactive. In line with this, rolipram and ICI 118,551 had similar effects in beta 2-KO than in WT. In contrast, beta 1-KO did not show any inotropic reaction to adrenaline (+/- rolipram). In WT, the beta 1-AR selective antagonist CGP 20712A (100 nmol/L) shifted the CRC for isoprenaline by 2.1 log units, corresponding to the affinity of CGP 20712A to beta 1-AR. Rolipram increased the sensitivity to adrenaline independently of the presence of CGP 20712A. We conclude that effects sensitive to the beta 2-AR antagonist ICI 118,551 are not necessarily beta 2-AR-mediated and CGP 20712A resistant effects cannot be simply interpreted as beta 2-AR-mediated. Catecholamine effects in murine ventricles strictly depend on beta 1-AR, even if PDE 4 is blocked. PMID- 26516581 TI - Modeling effects of dexamethasone on disease progression of bone mineral density in collagen-induced arthritic rats. AB - A mechanism-based model was developed to characterize the crosstalk between proinflammatory cytokines, bone remodeling biomarkers, and bone mineral density (BMD) in collagen-induced arthritic (CIA) rats. Male Lewis rats were divided into five groups: healthy control, CIA control, CIA receiving single 0.225 mg kg(-1) subcutaneous (SC) dexamethasone (DEX), CIA receiving single 2.25 mg kg(-1) SC DEX, and CIA receiving chronic 0.225 mg kg(-1) SC DEX. The CIA rats underwent collagen induction at day 0 and DEX was injected at day 21 post-induction. Disease activity was monitored throughout the study and rats were sacrificed at different time points for blood and paw collection. Protein concentrations of interleukin (IL)-1beta, IL-6, receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), and tartrate-resistant acid phosphatase 5b (TRACP 5b) in paws were measured by enzyme-linked immunosorbent assays (ELISA). Disease progression and DEX pharmacodynamic profiles of IL-1beta, IL-6, RANKL, and OPG were fitted simultaneously and parameters were sequentially applied to fit the TRACP-5b and BMD data. The model was built according to the mechanisms reported in the literature and modeling was performed using ADAPT 5 software with naive pooling. Time profiles of IL-1beta and IL-6 protein concentrations correlated with their mRNAs. The RANKL and OPG profiles matched previous findings in CIA rats. DEX inhibited the expressions of IL-1beta, IL-6, and RANKL, but did not alter OPG. TRACP-5b was also inhibited by DEX. Model predictions suggested that anti-IL-1beta therapy and anti-RANKL therapy would result in similar efficacy for prevention of bone loss among the cytokine antagonists. PMID- 26516582 TI - In silico identified targeted inhibitors of P-glycoprotein overcome multidrug resistance in human cancer cells in culture. AB - Failure of cancer chemotherapies is often linked to the over expression of ABC efflux transporters like the multidrug resistance P-glycoprotein (P-gp). P-gp expression in cells leads to the elimination of a variety of chemically unrelated, mostly cytotoxic compounds. Administration of chemotherapeutics during therapy frequently selects for cells that over express P-gp and are therefore capable of robustly exporting diverse compounds, including chemotherapeutics, from the cells. P-gp thus confers multidrug resistance to a majority of drugs currently available for the treatment of cancers and diseases like HIV/AIDS. The search for P-gp inhibitors for use as co-therapeutics to combat multidrug resistances has had little success to date. In a previous study (Brewer et al., Mol Pharmacol 86: 716-726, 2014), we described how ultrahigh throughput computational searches led to the identification of four drug-like molecules that specifically interfere with the energy harvesting steps of substrate transport and inhibit P-gp catalyzed ATP hydrolysis in vitro. In the present study, we demonstrate that three of these compounds reversed P-gp-mediated multidrug resistance of cultured prostate cancer cells to restore sensitivity comparable to naive prostate cancer cells to the chemotherapeutic drug, paclitaxel. Potentiation concentrations of the inhibitors were <3 MUmol/L. The inhibitors did not exhibit significant toxicity to noncancerous cells at concentrations where they reversed multidrug resistance in cancerous cells. Our results indicate that these compounds with novel mechanisms of P-gp inhibition are excellent leads for the development of co-therapeutics for the treatment of multidrug resistances. PMID- 26516583 TI - FTY720 (Fingolimod) sensitizes hepatocellular carcinoma cells to sorafenib mediated cytotoxicity. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The multityrosine kinase inhibitor sorafenib is used in the therapy of advanced disease. However, the effects of sorafenib are limited, and combination treatments aiming at improved survival are encouraged. The sphingosine analog FTY720 (Fingolimod), which is approved for treatment of multiple sclerosis, has shown tumor suppressive effects in cell lines and animal models of HCC. In the present study, we combined sorafenib with FTY720 in order to sensitize the HCC cell lines Huh7 and HepG2 to sorafenib treatment. Using the XTT assay we show that noncytotoxic doses of FTY720 synergistically enhanced the decrease in viability caused by treatment of both cell lines with increasing doses of sorafenib. Further studies in Huh7 revealed that combined treatment with FTY720 and sorafenib resulted in G1 arrest and enhanced cell death measured using flow cytometry analysis of cells labeled with propidium iodide (PI)/Annexin-V and PI and 4',6-diamidino-2-phenylindole-staining of nuclei. In addition, signs of both caspase-dependent and - independent apoptosis were observed, as cotreatment with FTY720 and sorafenib caused cytochrome c release and poly-ADP ribose polymerase-cleavage as well as translocation of Apoptosis-inducing factor into the cytosol. We also detected features of autophagy blockage, as the protein levels of LC3-II and p62 were affected by combined treatment with FTY720 and sorafenib. Together, our results suggest that FTY720 sensitizes HCC cells to cytotoxic effects induced by treatment with sorafenib alone. These findings warrant further investigations of combined treatment with sorafenib and FTY720 in vivo in order to develop more effective treatment of HCC. PMID- 26516584 TI - Randomized pharmacokinetic and drug-drug interaction studies of ceftazidime, avibactam, and metronidazole in healthy subjects. AB - We assessed pharmacokinetic and safety profiles of ceftazidime-avibactam administered +/- metronidazole, and whether drug-drug interactions exist between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole. The first study (NCT01430910) involved two cohorts of healthy subjects. Cohort 1 received ceftazidime-avibactam (2000-500 mg) as a single infusion or as multiple intravenous infusions over 11 days to evaluate ceftazidime-avibactam pharmacokinetics. Cohort 2 received ceftazidime, avibactam, or ceftazidime avibactam over 4 days to assess drug-drug interaction between ceftazidime and avibactam. The second study (NCT01534247) assessed interaction between ceftazidime-avibactam and metronidazole in subjects receiving ceftazidime avibactam (2000-500 mg), metronidazole (500 mg), or metronidazole followed by ceftazidime-avibactam over 4 days. In all studies, subjects received a single dose on the first and final days, and multiple-doses every 8 h on intervening days. Concentration-time profiles for ceftazidime and avibactam administered as single- or multiple-doses separately or together with/without metronidazole were similar. There was no evidence of time-dependent pharmacokinetics or accumulation. In both interaction studies, 90% confidence intervals for geometric least squares mean ratios of area under the curve and maximum plasma concentrations for each drug were within the predefined interval (80-125%) indicating no drug-drug interaction between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole. There were no safety concerns. In conclusion, pharmacokinetic parameters and safety of ceftazidime, avibactam, and metronidazole were similar after single and multiple doses with no observed drug drug interaction between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole. PMID- 26516585 TI - Interrogating the relationship between rat in vivo tissue distribution and drug property data for >200 structurally unrelated molecules. AB - The ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, in vivo distribution was most influenced by ionization state and lipophilicity which in turn affected phospholipid and plasma protein binding. Basic and neutral molecules were generally better distributed than acidic counterparts demonstrating weaker plasma protein and stronger phospholipid binding. The influence of phospholipid binding was particularly evident in tissues with high phospholipid content like spleen and lung. Conversely, poorer distribution of acidic drugs was associated with stronger plasma protein and weaker phospholipid binding. The distribution of a proportion of acidic drugs was enhanced, however, in tissues known to express anionic uptake transporters such as the liver and kidney. Greatest distribution was observed into melanin containing tissues of the eye, most likely due to melanin binding. Basic molecules were consistently better distributed into parts of the eye and skin containing melanin than those without. The data, therefore, suggest that drug binding to macromolecules strongly influences the distribution of total drug for a large proportion of molecules in most tissues. Reducing lipophilicity, a strategy often used in discovery to optimize pharmacokinetic properties such as absorption and clearance, also decreased the influence of nonspecific binding on drug distribution. PMID- 26516586 TI - Influence of sesamin on CYP2C-mediated diclofenac metabolism: in vitro and in vivo analysis. AB - Our previous studies revealed that sesamin caused a mechanism-based inhibition (MBI) of CYP2C9 in human liver microsomes. Additionally, we observed a similar MBI of CYP2C by sesamin in the rat liver microsomes. Sesamin-induced difference spectra of rat or human liver microsomes in the presence of NADPH showed a peak at 459 nm, suggesting the formation of a metabolic-intermediate (MI) complex of cytochrome P450 and the methylenedioxyphenyl group of sesamin. However, the peak disappeared in both liver microsomes within 30 min after the termination of the metabolism. These results suggest that the MI complex of cytochrome P450 and sesamin is unstable, and the effects of sesamin on human CYP2C9- or rat CYP2C mediated drug metabolism may be small. To confirm this, in vivo studies using rats were performed. The pharmacokinetics of diclofenac, which is mainly metabolized by CYP2C11 in male rats, were investigated after a 3-days administration of sesamin (0, 10, and 100 mg/kg bw). No significant differences were observed among the three groups in the pharmacokinetic parameters, C max, T max, and AUC. Furthermore, administration of sesamin to rats for 7 days had no significant effects on diclofenac hydroxylation activity in rat liver microsomes. These results demonstrate that no significant interaction occurs between diclofenac and sesamin in rats. Moreover, the results of these in vitro and in vivo studies suggest that no significant interaction may occur between sesamin and diclofenac when sesamin is administered to humans as a supplement, since the standard sesamin dose in humans is much lower than that administered to rats in this study. PMID- 26516587 TI - In vitro pharmacological profiling of R406 identifies molecular targets underlying the clinical effects of fostamatinib. AB - Off-target pharmacology may contribute to both adverse and beneficial effects of a new drug. In vitro pharmacological profiling is often applied early in drug discovery; there are fewer reports addressing the relevance of broad profiles to clinical adverse effects. Here, we have characterized the pharmacological profile of the active metabolite of fostamatinib, R406, linking an understanding of drug selectivity to the increase in blood pressure observed in clinical studies. R406 was profiled in a broad range of in vitro assays to generate a comprehensive pharmacological profile and key targets were further investigated using functional and cellular assay systems. A combination of traditional literature searches and text-mining approaches established potential mechanistic links between the profile of R406 and clinical side effects. R406 was selective outside the kinase domain, with only antagonist activity at the adenosine A3 receptor in the range relevant to clinical effects. R406 was less selective in the kinase domain, having activity at many protein kinases at therapeutically relevant concentrations when tested in multiple in vitro systems. Systematic literature analyses identified KDR as the probable target underlying the blood pressure increase observed in patients. While the in vitro pharmacological profile of R406 suggests a lack of selectivity among kinases, a combination of classical searching and text-mining approaches rationalized the complex profile establishing linkage between off-target pharmacology and clinically observed effects. These results demonstrate the utility of in vitro pharmacological profiling for a compound in late-stage clinical development. PMID- 26516588 TI - Prevention of fostamatinib-induced blood pressure elevation by antihypertensive agents. AB - Fostamatinib is a tyrosine kinase inhibitor with activity against spleen tyrosine kinase which has completed clinical trials for patients with rheumatoid arthritis. In clinical studies fostamatinib treatment was associated with a small elevation of systemic arterial blood pressure (BP), a similar finding to that seen with other kinase inhibitors, especially those that inhibit VEGFR2 signaling. We have investigated the link between fostamatinib-induced blood pressure elevation and plasma levels of the fostamatinib-active metabolite R940406 in conscious rats and found the time course of the BP effect correlated closely with changes in R940406 plasma concentration, indicating a direct pharmacological relationship. Free plasma levels of R940406 produced in these studies (up to 346 nmol/L) span the clinically observed mean peak free plasma concentration of 49 nmol/L. We have demonstrated that the blood pressure elevation induced by fostamatinib dosing can be successfully controlled by a variety of methods, notably simple drug withdrawal or codosing with a range of standard antihypertensive agents such as atenolol, captopril, and nifedipine. These findings support potential methods of maintaining patient safety while on fostamatinib therapy. Furthermore, we have demonstrated, using nifedipine as an example agent, that this blood pressure control was not achieved by reduction in plasma exposure of R940406, suggesting that potential benefits from the pharmacology of the investigational drug can be maintained while blood pressure control is managed by use of standard comedications. PMID- 26516589 TI - Clearance of systemic hematologic tumors by venetoclax (Abt-199) and navitoclax. AB - The Bcl-2 family inhibitors venetoclax and navitoclax demonstrated potent antitumor activity in chronic lymphocytic leukemia patients, notably in reducing marrow load and adenopathy. Subsequent trials with venetoclax have been initiated in non-Hodgkin's lymphoma and multiple myeloma patients. Traditional preclinical models fall short either in faithfully recapitulating disease progression within such compartments or in allowing the direct longitudinal analysis of systemic disease. We show that intravenous inoculation of engineered RS4;11 (acute lymphoblastic leukemia) and Granta 519 (mantle cell lymphoma) bioluminescent reporter cell lines result in tumor engraftment of bone marrow, with additional invasion of the central nervous system in the case of Granta 519. Importantly, apoptosis induction and response of these systemically engrafted tumors to Bcl-2 family inhibitors alone or in combination with standard-of-care agents could be monitored longitudinally with optical imaging, and was more accurately reflective of the observed clinical response. PMID- 26516590 TI - Evacetrapib: in vitro and clinical disposition, metabolism, excretion, and assessment of drug interaction potential with strong CYP3A and CYP2C8 inhibitors. AB - Evacetrapib is an investigational cholesteryl ester transfer protein inhibitor (CETPi) for reduction of risk of major adverse cardiovascular events in patients with high-risk vascular disease. Understanding evacetrapib disposition, metabolism, and the potential for drug-drug interactions (DDI) may help guide prescribing recommendations. In vitro, evacetrapib metabolism was investigated with a panel of human recombinant cytochromes P450 (CYP). The disposition, metabolism, and excretion of evacetrapib following a single 100-mg oral dose of (14)C-evacetrapib were determined in healthy subjects, and the pharmacokinetics of evacetrapib were evaluated in the presence of strong CYP3A or CYP2C8 inhibitors. In vitro, CYP3A was responsible for about 90% of evacetrapib's CYP associated clearance, while CYP2C8 accounted for about 10%. In the clinical disposition study, only evacetrapib and two minor metabolites circulated in plasma. Evacetrapib metabolism was extensive. A mean of 93.1% and 2.30% of the dose was excreted in feces and urine, respectively. In clinical DDI studies, the ratios of geometric least squares means for evacetrapib with/without the CYP3A inhibitor ketoconazole were 2.37 for area under the curve (AUC)(0-infinity) and 1.94 for C max. There was no significant difference in evacetrapib AUC(0-tau) or C max with/without the CYP2C8 inhibitor gemfibrozil, with ratios of 0.996 and 1.02, respectively. Although in vitro results indicated that both CYP3A and CYP2C8 metabolized evacetrapib, clinical studies confirmed that evacetrapib is primarily metabolized by CYP3A. However, given the modest increase in evacetrapib exposure and robust clinical safety profile to date, there is a low likelihood of clinically relevant DDI with concomitant use of strong CYP3A or CYP2C8 inhibitors. PMID- 26516592 TI - Microparticle of drug and nanoparticle: a biosynthetic route. AB - Microparticles (MPs) have great potentiality in material science- based applications. Their use in biology is however limited to clinics and has rarely been exploited in the pharmaceutical context. Unlike nanoparticles (NPs), they are amenable to routine detection by flow cytometry and confocal microscopy. Though MPs can constitute a wide variety of materials, including ceramics, glass, polymers, and metals and can be synthesized by chemical process but wet processes for the preparation of microparticles have rarely been attemped. In this paper, a thrombotic route is shown to successfully generate biocompatible MP of a model anticancer drug (doxorubicin hydrochloride). Synthesis of MPs from platelets and drug loading in to these MPs was confirmed by flow cytometry and confocal microscopy. Human cervical cancer cell line (HeLa) was treated with these drug loaded MPs to investigate whether the loaded MPs have the capacity to deliver drug to the cancer cells. In addition, Magnetic force microscopy was used to detect the preparation of MPs loaded with magnetic NPs. The efficiency of the drug-loaded MPs in inducing cytotoxicity in cancer cell line, shown to be significantly higher than the free drug itself. The drug-loaded MP is shown to have a much higher cytotoxic propensity than the free drug applied at comparable doses. The thrombotic approach can also be applied to synthesize MP containing NPs which in turn can lead to generate a wide variety of new biocompatible materials. PMID- 26516591 TI - Pharmacological implications of the Ca(2+)/cAMP signaling interaction: from risk for antihypertensive therapy to potential beneficial for neurological and psychiatric disorders. AB - In this review, we discussed pharmacological implications of the Ca(2+)/cAMP signaling interaction in the antihypertensive and neurological/psychiatric disorders therapies. Since 1975, several clinical studies have reported that acute and chronic administration of L-type voltage-activated Ca(2+) channels (VACCs) blockers, such as nifedipine, produces reduction in peripheral vascular resistance and arterial pressure associated with an increase in plasma noradrenaline levels and heart rate, typical of sympathetic hyperactivity. Despite this sympathetic hyperactivity has been initially attributed to adjust reflex of arterial pressure, the cellular and molecular mechanisms involved in this apparent sympathomimetic effect of the L-type VACCs blockers remained unclear for decades. In addition, experimental studies using isolated tissues richly innervated by sympathetic nerves (to exclude the influence of adjusting reflex) showed that neurogenic responses were completely inhibited by L-type VACCs blockers in concentrations above 1 MUmol/L, but paradoxically potentiated in concentrations below 1 MUmol/L. During almost four decades, these enigmatic phenomena remained unclear. In 2013, we discovered that this paradoxical increase in sympathetic activity produced by L-type VACCs blocker is due to interaction of the Ca(2+)/cAMP signaling pathways. Then, the pharmacological manipulation of the Ca(2+)/cAMP interaction produced by combination of the L-type VACCs blockers used in the antihypertensive therapy, and cAMP accumulating compounds used in the antidepressive therapy, could represent a potential cardiovascular risk for hypertensive patients due to increase in sympathetic hyperactivity. In contrast, this pharmacological manipulation could be a new therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases. PMID- 26516593 TI - Flexible ureterorenoscopy results: Analysis of 279 cases. AB - OBJECTIVE: In this study, the outcomes of 279 cases in whom we performed retrograde intrarenal surgery (RIRS) were evaluated retrospectively. MATERIAL AND METHODS: RIRS was performed on 279 cases with the aid of access sheath of guidewire between March 2011 and February 2015. All patients were operated in the standard lithotomy position. A hydrophilic guidewire was inserted with the aid of rigid ureterorenoscopy and we checked whether there were any residual ureteral stones and other pathologies. Fluoroscopy was used routinely in all cases. Stone fragments smaller than 3 mm were left off but those bigger than 3 mm were removed by grasper after stone fragmentation. Controls of the patients were assessed by plain films (KUB), urinary tract ultrasonography (US) and/or computed tomography (CT) 1 month after the operation. Success rate of the procedure was defined as the stone-free status or presence of residual fragments less than 3 mm. RESULTS: 152 of the patients were male and 127 were female. The median ages of the male and female patients were 47.7 (1-86) ve 45.9 (3-79) years respectively. The median stone size was 13.5 mm (8-25). Preoperatively 34 (12.1%) patients had double-J ureteral stent. 19 (6.8%) patients were operated while they were still receiving antithrombotic and antiplatelet therapy Solitary kidney was present in 24 patients while the remaining patients had kyphoscoliosis (n=3), rotation anomaly (n=6), pelvic kidney (n=2), double collecting system (n=3), and horseshoe kidney (n=6). In 264 patients access sheath was used, in 15 patients operation was performed with the help of the guidewire. Double-J stents were inserted to 14 patients because of ureteral stricture and they underwent operation after 2 weeks later. Renal stones of 219 patients among all cases were fragmented completely and the patients were discharged as stone free (SF). Our success rate (SF or presence of clinically insignificant residual [CIRF]) was 78.4%. Stone size (p=0.029), stone number (p=0.01), stone location (p=0.023) had significant influence on the stone-free rate after RIRS The mean operation and floroscopy time was 62.5 min. (40-180) and 29.8 sec (4-96), respectively. The mean hospitalization time was 26.4 hours (12-72). Double J stents were placed to 253 patients for more stone burden and ureteral edema. Any complication was not observed for all cases except perioperative developed infection for two patients. CONCLUSION: With advances in laser technology and flexible ureterorenoscopy, kidney stones can be treated with lower morbidity and high success rates. PMID- 26516594 TI - Use of a microdebrider for corporeal excavation and penile prosthesis implantation in men with severely fibrosed corpora cavernosa: a new minimal invasive surgical technique. AB - OBJECTIVE: To propose a new minimal invasive surgical technique using a microdebrider (shaver) to excavate the fibrosed corpora cavernosa for penile prosthesis implantation in patients with severe fibrosis. MATERIAL AND METHODS: Two patients with severe corporeal fibrosis were implanted with a penile prosthesis using this technique. In the first patient, fibrosis was due to neglected idiopathic ischemic priapism and the second patient had his prosthesis extruded because of erosion in another center. Both patients were counseled about the procedure and the possible complications related to the experimental nature of the technique. A written informed consent was obtained from both patients. Excavation of the corpora was performed using microdebrider in both patients. RESULTS: Both operations were performed successfully without any intraoperative complications, including urethral injury or perforation of the tunica. The mean operation time was 57 min. The postoperative period was uneventful without any infection, migration, erosion, or mechanical failure. The penile length was increased nearly 2 cm in both patients, and the penile girth was increased around 30% in the patient who underwent inflatable penile prosthesis implantation. CONCLUSION: The microdebrider potentially provides an important advance in patients with severe corporeal fibrosis to excavate the fibrosed corpora cavernosa for penile prosthesis implantation. The main advantages include fast, safe, and effective excavation of fibrous corpora cavernosa adequate for a satisfactory penile prosthesis implantation. PMID- 26516595 TI - Metabolic syndrome does not impair the response to alfuzosin treatment in men with lower urinary tract symptoms: a double-blind, randomized, placebo-controlled study. AB - OBJECTIVE: This study is a placebo-controlled comparison of the response to alfuzosin treatment for lower urinary tract symptoms (LUTS) in patients with and without metabolic syndrome (MetS). MATERIAL AND METHODS: A total of 80 men with LUTS were included in the study. Patients had a maximum flow rate of <15 mL/sec, prostate volume of >20 mL, and International Prostate Symptom Score (IPSS) of >8. All eligible men (n=68) for evaluation were initially divided into two groups as MetS (n=34) and non-MetS (n=34) groups. Patients were further randomized to receive alfuzosin (10 mg/day) or placebo (n=17/group; a total of four groups). The outcome was measured at 12(th) week according to the changes from baseline in IPSS, quality of life (QoL) scores, maximum flow rate (Qmax), and postmictional residue. RESULTS: Alfuzosin significantly improved LUTS in men with and without MetS compared with patients receiving placebo (p<0.05). Mean IPSS scores in treatment groups decreased significantly, whereas patients receiving placebo had no statistically significant difference (p>0.05). Similarly, alfuzosin treatment resulted in a significant increase in Qmax in patients with LUTS/benign prostatic enlargement when compared with patients in placebo group (p<0.05). Mean QoL scores measured by IPSS-QoL and QoL questionnaires also improved significantly in patients receiving alfuzosin for 3 months regardless of the presence of MetS (p<0.05). CONCLUSION: Our results revealed that the presence of MetS in patients with LUTS did not impair the response to alfuzosin treatment. PMID- 26516596 TI - Analysis of the learning curve for transurethral resection of the prostate. Is there any influence of musical instrument and video game skills on surgical performance? AB - OBJECTIVE: To evaluate the learning curve for transurethral resection of the prostate (TURP) among urology residents and study the impact of video game and musical instrument playing abilities on its performance. MATERIAL AND METHODS: A prospective study was performed from July 2009 to January 2013 with patients submitted to TURP for benign prostatic hyperplasia. Fourteen residents operated on 324 patients. The following parameters were analyzed: age, prostate-specific antigen levels, prostate weight on ultrasound, pre- and postoperative serum sodium and hemoglobin levels, weight of resected tissue, operation time, speed of resection, and incidence of capsular lesions. Gender, handedness, and prior musical instrument and video game playing experience were recorded using survey responses. RESULTS: The mean resection speed in the first 10 procedures was 0.36 g/min and reached a mean of 0.51 g/min after the 20(th) procedure. The incidence of capsular lesions decreased progressively. The operation time decreased progressively for each subgroup regardless of the difference in the weight of tissue resected. Those experienced in playing video games presented superior resection speed (0.45 g/min) when compared with the novice (0.35 g/min) and intermediate (0.38 g/min) groups (p=0.112). Musical instrument playing abilities did not affect the surgical performance. CONCLUSION: Speed of resection, weight of resected tissue, and percentage of resected tissue improve significantly and the incidence of capsular lesions reduces after the performance of 10 TURP procedures. Experience in playing video games or musical instruments does not have a significant effect on outcomes. PMID- 26516597 TI - The case study in the applicability of the improvements in the treatment of urinary system stone diseases in Anatolia: the last ten years with the sample of Western Black Sea region. AB - OBJECTIVE: The prevalence of stone diseases is high in Turkey. Thanks to the technological improvements and to the increase in the number of qualified and experienced specialists in the last thirty years, there has been an increase in the application of minimally invasive methods in the stone disease surgery. This study, with a sample survey of Western Black Sea region, aims at revealing the changes and improvements in the treatment of stone diseases in different centers in Anatolia within the last ten years. MATERIAL AND METHODS: Six centers in 4 of the provinces of the Western Black Sea Region were selected and the patients' files were retrospectively analyzed. The treatment methods that were recommended for and/or applied to the patients diagnosed with urinary stone diseases were recorded by years. The urinary stone diseases were divided into three separate groups; kidney, ureters and bladder. Treatment options were recorded into categories as open surgery, percutaneous nephrolithotripsy, retrograde intrarenal surgery, semirigid ureterorenoscopy, flexible ureterorenoscopy, and ESWL. RESULTS: A total of 26044 patients with stone diseases have been treated in the above-mentioned centers for the last 10 years. The distributions of the stone diseases in relation to their localization were as follows: - kidney stones: 9040 (34.7%), ureter stones: 15264 (58.6%), and bladder stones: 1740 (6.7%). As for the distribution of the treatment in relation to the treatment methods, it was seen that open surgery for 1032 (4%) patients, endoscopic surgery for 15038 (58%) patients, and ESWL for 9974 (38%) patients had been applied. While URS and PCNL are currently the commonly used treatment methods in the Western Black Sea Region, RIRS has begun to be used in a limited number of patients for the last 3 years. CONCLUSION: Though being a little late, the advances in endrourology offer practical applications in the Western Black Sea region as well. Although this study suggests implications for the evaluating of the periphery outcomes of the improvements in stone disease treatments, for the planning of training schemes, and for equipment planning, further research based on more data from more centers is needed to have a nation-wide perspective. PMID- 26516598 TI - Comparison of one-year results of transobturator tape method in the stress incontinence treatment according to body mass index. AB - OBJECTIVE: The purpose of this study was to compare the 1-year results of patients on whom we used the transobturator tape method for the stress incontinence treatment according to body mass index (BMI). MATERIAL AND METHODS: Patients diagnosed with stress incontinence and treated with the transobturator tape method were divided into three groups according to BMI. We recorded the results of preoperative urodynamic studies; durations of operation, catheterization, and hospitalization; and complications of patients. Patients were evaluated 1 year after the operation with respect to the objective/subjective success rates of the operation, patient satisfaction rates, and possible late complications. RESULTS: The obese group was observed to have a significantly higher duration of operation than the normal and overweight groups (p<0.001). The objective and subjective success rates were not significantly different between the groups (p=0.567 and p=0.245, respectively). There was no statistical difference between the groups with respect to the satisfaction rates (p=0.245). There was no significant difference between all three groups with respect to both preoperative and postoperative complication rates (p=0.096). CONCLUSION: The transobturator tape method for stress incontinence treatment has similar objective and subjective success rates, independent of BMI. In the obese patients, the operation time is longer than the others, but there is no difference with respect to the complication rates. PMID- 26516599 TI - Prostatic adenocarcinoma with initial metastatic spread to the mandible. AB - Prostate cancer is one of the commonest types of malignancy in males. Although prostate cancer has a propensity to metastasize to the bone, metastasis to the mandible is rare. Because of their uncommon incidence, the diagnosis of mandibular metastasis, especially those originating from the prostate, may represent a challenge both for urologists and dentists. Here we present a case of prostatic adenocarcinoma with initial metastatic spread to the mandible. PMID- 26516600 TI - A large and metastatic primitive neuroectodermal tumor of the kidney. AB - Primitive neuroectodermal tumor (PNET) of the kidney is rare. Mostly patients with renal PNET are young adults and the survival rates are poor. Although radiological and pathological investigations, differential diagnosis from other kidney tumours is very difficult. The treatment is often delayed because of difficulties with diagnosis. In most cases of renal PNET, as in this case, prognosis is poor. Particularly, in young adults with large renal masses, it must be diagnosed and treatment should be started immediately. PMID- 26516601 TI - Giant kidney stone: multi-session percutaneous nephrolithotomy with 12 accesses. AB - We report a case of a 37-year-old man with a body mass index of 28 kg/m(2) who presented to our outpatient clinic with intermittent left flank pain. Non contrast abdominopelvic computed tomography revealed a giant coralliform calculus in the left kidney. This giant kidney stone was successfully treated with 3 sessions of percutaneous nephrolithotomy (PNL) with a total 12 accesses. There was no significant reduction in the split function of the kidney after PNL. PMID- 26516602 TI - Robotic sequential right adrenalectomy and zero ischemia left partial nephrectomy in a patient with synchronous pheochromocytoma and renal cell carcinoma. AB - Currently, most renal masses are detected incidentally while still small in size because of the widespread use of radiological imaging, and most pheochromocytomas are localized in the adrenal glands as unilateral lesions. A 5 * 4-cm right adrenal mass and a 19 * 13-mm exophytic left renal mass were synchronously detected by contrast enhancement on computed tomography and magnetic resonance imaging in a 47-year-old male with hypertension. The patient's preoperative serum and 24-h urine catecholamine levels were elevated. Initially, robotic transperitoneal right adrenalectomy was performed, and histopathology confirmed a 4 cm pheochromocytoma. After 3 months, transperitoneal zero ischemia robotic left partial nephrectomy was performed, and histopathology demonstrated clear cell renal cell carcinoma, Fuhrman grade II, 17 mm in size with clear surgical margins. This case indicates that sequential robotic surgery is feasible and safe as a minimally invasive approach to remove bilateral renal and adrenal masses. Zero ischemia robotic partial nephrectomy is also feasible and safe for selected small renal masses. PMID- 26516603 TI - Meetings & Congresses. PMID- 26516604 TI - Levodopa-responsive Holmes' Tremor Caused by a Single Inflammatory Demyelinating Lesion. AB - BACKGROUND: Holmes' tremor is characterized by a combination of rest, postural, and kinetic tremor that is presumably caused by interruption of cerebello-thalamo cortical and nigrostriatal pathways. Medical treatment remains unsatisfactory. CASE REPORT: A 16-year-old girl presented with Holmes' tremor caused by a transient midbrain abnormality on magnetic resonance imaging (MRI). To explore the discrepancy between persistent tremor and resolved MRI changes, we performed dopamine transporter single-photon emission computed tomography (DaT-SPECT) with a 123I-ioflupane that revealed nearly absent DaT binding in the right striatum. Levodopa dramatically improved the tremor. DISCUSSION: This is only the second report of a transient midbrain MRI abnormality disrupting nigrostriatal pathways. The case highlights the sometimes limited sensitivity of morphologic imaging for identifying the functional consequences of tissue damage and confirms that DaT imaging may serve as a predictor for levodopa responsiveness in Holmes' tremor. PMID- 26516605 TI - Delineation of somatosensory finger areas using vibrotactile stimulation, an ECoG study. AB - BACKGROUND: In surgical planning for epileptic focus resection, functional mapping of eloquent cortex is attained through direct electrical stimulation of the brain. This procedure is uncomfortable, can trigger seizures or nausea, and relies on subjective evaluation. We hypothesize that a method combining vibrotactile stimulation and statistical clustering may provide improved somatosensory mapping. METHODS: Seven pediatric candidates for surgical resection underwent a task in which their fingers were independently stimulated using a custom designed finger pad, during electrocorticographic monitoring. A cluster based statistical analysis was then performed to localize the elicited activity on the recording grids. RESULTS: Mid-Gamma clusters (65-115 Hz) arose in areas consistent with anatomical predictions as well as clinical findings, with five subjects presenting a somatotopic organization of the fingers. This process allowed us to delineate finger representation even in patients who were sleeping, with strong interictal activity, or when electrical stimulation did not successfully locate eloquent areas. CONCLUSIONS: We suggest that this scheme, relying on the endogenous neural response rather than exogenous electrical activation, could eventually be extended to map other sensory areas and provide a faster and more objective map to better anticipate outcomes of surgical resection. PMID- 26516606 TI - The complexity of the relationship between neuropsychological deficits and impairment in everyday tasks after stroke. AB - BACKGROUND AND PURPOSE: A large body of research reports that stroke patients are debilitated in terms of daily independence after dismissal from the hospital unit. Patients struggle with the use of daily objects or performing complex actions. Differences between individual deficits of patients are often associated with the site of the brain damage. However, clinical studies suggest that patients exhibit varied constellations of action-associated difficulties and neuropsychological deficits. There is a lack of conclusive evidence indicating how different neuropsychological symptoms link to the impaired ability to perform activities of daily living (ADL). MATERIALS AND METHODS: To further address this matter, in this study we compared the behavior of patients with left brain damage (LBD) and right brain damage (RBD) following stroke in two naturalistic task scenarios (tea making and document filing), and compared the committed action errors to the neuropsychological screening results. RESULTS: We observed mild to severe impairments in both the LBD and RBD groups amounting to 37-55% of failure rate in attainment of action goal. Interestingly, the performance on both tasks was not correlated to each other, suggesting that the tasks involved a different set of higher cognitive functions. Despite similar behavioral manifestations, in the LBD group poor task performance was related to deficits in praxis performance and unilateral tactile and visual extinction. The presence of aphasia did not correlate with task performance, except for a link between low scores in Aachen aphasia test scales and misestimation error in the tea making task. In the RBD group, difficulties with performance were primarily linked to deficit in praxis and unilateral visual extinction. CONCLUSIONS: Despite similar behavior, the underlying mechanisms of the deficits after stroke might be different (in patients with LBD and RBD) and reveal complex interlinks of cognitive networks involved in the ability to carry on everyday tasks. PMID- 26516607 TI - Synaptic input changes to spinal cord motoneurons correlate with motor control impairments in a type 1 diabetes mellitus model. AB - INTRODUCTION: Hyperglycemia is the main cause of diabetic complications, contributing to a widespread degeneration of the nervous system. Nevertheless, the main focus has been the sensory neurons because of neuropathic pain, while the impairments associated with the spinal cord and motor deficits, mostly of those initiated at early stages of the disease, have been poorly investigated. In this way, the present study used the nonobese diabetic mouse model to evaluate the microenvironment around motoneurons at ventral horn of the spinal cord, following prolonged hyperglycemia. METHODS: Adult female mice were divided into two groups: spontaneously diabetic (n = 33) and nondiabetic (n = 26). Mice were considered hyperglycemic when blood glucose surpassed 400 mg/dL. Following 2 weeks from that stage, part of the animals was euthanized and the lumbar intumescences were obtained and processed for immunohistochemistry and transmission electron microscopy. For immunohistochemistry, the antibodies used for integrated density of pixels quantification were anti-synaptophysin, anti GFAP, and anti-Iba1. The functional analysis was monitored with the walking track test (CatWalk system) during 4 weeks. RESULTS: The results revealed significant motor impairment in diabetic animals in comparison to the control group. Such loss of motor control correlated with a significant reduction in presynaptic terminals apposed to the motoneurons. Nevertheless, there were no significant changes in glial reaction in the spinal cord. CONCLUSION: Overall, the results herein revealed central nervous system changes at early stages of the disease that may in turn contribute to the motor deficit. Such changes open a new window of investigation in early stages of diabetes to better comprehend motor impairment as a long-term complication of the disease. PMID- 26516608 TI - Selective serotonin reuptake inhibitors to improve outcome in acute ischemic stroke: possible mechanisms and clinical evidence. AB - BACKGROUND: Several clinical studies have indicated that selective serotonin reuptake inhibitors (SSRIs) administered in patients after acute ischemic stroke can improve clinical recovery independently of depression. Due to small sample sizes and heterogeneous study designs interpretability was limited in these studies. The mechanisms of action whereby SSRI might improve recovery from acute ischemic stroke are not fully elucidated. METHODS: We searched MEDLINE using the PubMed interface to identify evidence of SSRI mediated improvement of recovery from acute ischemic stroke and reviewed the literature on the potential underlying mechanisms of action. RESULTS: Among identified clinical studies, a well-designed randomized, double-blind, and placebo-controlled study (FLAME - fluoxetine for motor recovery after acute ischemic stroke) demonstrated improved recovery of motor function in stroke patients receiving fluoxetine. The positive effects of SSRIs on stroke recovery were further supported by a meta-analysis of 52 trials in a total of 4060 participants published by the Cochrane collaboration. Based on animal models, the mechanisms whereby SSRIs might ameliorate functional and structural ischemic-brain damage were suggested to include stimulation of neurogenesis with migration of newly generated cells toward ischemic-brain regions, anti-inflammatory neuroprotection, improved regulation of cerebral blood flow, and modulation of the adrenergic neurohormonal system. However, to date, it remains speculative if and to what degree these mechanisms convert into humans and randomized controlled trials in large populations of stroke patients comparing different SSRIs are still lacking. CONCLUSION: In addition to the need of comprehensive-clinical evidence, further elucidation of the beneficial mechanisms whereby SSRIs may improve structural and functional recovery from ischemic-brain damage is needed to form a basis for translation into clinical practice. PMID- 26516609 TI - Practice changes beta power at rest and its modulation during movement in healthy subjects but not in patients with Parkinson's disease. AB - BACKGROUND: PD (Parkinson's disease) is characterized by impairments in cortical plasticity, in beta frequency at rest and in beta power modulation during movement (i.e., event-related ERS [synchronization] and ERD [desynchronization]). Recent results with experimental protocols inducing long-term potentiation in healthy subjects suggest that cortical plasticity phenomena might be reflected by changes of beta power recorded with EEG during rest. Here, we determined whether motor practice produces changes in beta power at rest and during movements in both healthy subjects and patients with PD. We hypothesized that such changes would be reduced in PD. METHODS: We thus recorded EEG in patients with PD and age matched controls before, during and after a 40-minute reaching task. We determined posttask changes of beta power at rest and assessed the progressive changes of beta ERD and ERS during the task over frontal and sensorimotor regions. RESULTS: We found that beta ERS and ERD changed significantly with practice in controls but not in PD. In PD compared to controls, beta power at rest was greater over frontal sensors but posttask changes, like those during movements, were far less evident. In both groups, kinematic characteristics improved with practice; however, there was no correlation between such improvements and the changes in beta power. CONCLUSIONS: We conclude that prolonged practice in a motor task produces use-dependent modifications that are reflected in changes of beta power at rest and during movement. In PD, such changes are significantly reduced; such a reduction might represent, at least partially, impairment of cortical plasticity. PMID- 26516610 TI - White matter microstructure between the pre-SMA and the cingulum bundle is related to response conflict in healthy subjects. AB - INTRODUCTION: Response conflict involves selectively attending to relevant information and suppressing distracting, irrelevant information. The medial frontal cortex (MFC) is considered to be involved in response conflict. However, it remains unclear which white matter connectivity is associated with response conflict. This study aimed to delineate the neural connectivity of response conflict in healthy subjects and investigate the association between white matter microstructure and performance of a response conflict task. METHOD: Twenty-eight healthy subjects underwent functional magnetic resonance imaging (fMRI) during the Flanker task and diffusion MRI. We identified the presupplementary motor area (pre-SMA) using fMRI. Furthermore, we delineated the white matter connectivity between the pre-SMA and the cingulum bundle (CB), which is located in the MFC, using probabilistic tractography. We calculated the mean diffusivity (MD), index of white matter microstructure, of this tract and evaluate the association between MD and performance of the Flanker task. RESULT: The mean MD of this tract was significantly and positively associated with performance of the Flanker task. CONCLUSION: The present study suggests the white matter connectivity between the pre-SMA and the CB is related to the response conflict in healthy subjects and finer white matter microstructure is associated with smaller response conflict. PMID- 26516611 TI - Common variants in the ARC gene are not associated with cognitive abilities. AB - INTRODUCTION: The Activity-Regulated Cytoskeleton-associated (ARC) gene encodes a protein that is critical for the consolidation of synaptic plasticity and long term memory formation. Given ARC's key role in synaptic plasticity, we hypothesized that genetic variations in ARC may contribute to interindividual variability in human cognitive abilities or to attention-deficit hyperactivity disorder (ADHD) susceptibility, where cognitive impairment often accompanies the disorder. METHODS: We tested whether ARC variants are associated with six measures of cognitive functioning in 670 healthy subjects in the Norwegian Cognitive NeuroGenetics (NCNG) by extracting data from its Genome-Wide Association Study (GWAS). In addition, the Swedish Betula sample of 1800 healthy subjects who underwent similar cognitive testing was also tested for association with 19 tag SNPs. RESULTS: No ARC variants show association at the study-wide level, but several markers show a trend toward association with human cognitive functions. We also tested for association between ARC SNPs and ADHD in a Norwegian sample of cases and controls, but found no significant associations. CONCLUSION: This study suggests that common genetic variants located in ARC do not account for variance in human cognitive abilities, though small effects cannot be ruled out. PMID- 26516612 TI - Dynamic disconnection of the supplementary motor area after processing of dismissive biographic narratives. AB - INTRODUCTION: To understand the interplay between affective social information processing and its influence on mental states we investigated changes in functional connectivity (FC) patterns after audio exposure to emotional biographic narratives. METHODS: While lying in the 7T MR scanner, 23 male participants listened to narratives of early childhood experiences of three persons, each having either a secure, dismissing, or preoccupied attachment representation. Directly after having listened to each of the prototypical narratives, participants underwent a 10-minute resting-state fMRI scan. To study changes in FC patterns between experimental conditions, three post-task conditions were compared to a baseline condition. Specific local alterations, as well as differences in connectivity patterns between distributed brain regions, were quantified using Network-based statistics (NBS) and graph metrics. RESULTS: Using NBS, a nine-region subnetwork showing reduced FC after having listened to the dismissing narrative was identified. Of this subnetwork, only the left Supplementary Motor Area (SMA) exhibited a decrease in the nodal graph metrics degree and strength exclusively after listening to the dismissing narrative. No other region showed post-task changes in nodal metrics. A post hoc analysis of dynamic characteristics of FC of the left SMA showed a significant decrease in the dismissing condition when compared with the other conditions in the first three minutes of the scan, but faded away in the two subsequent intervals the differences. CONCLUSIONS: Nodal metrics and NBS converge on reduced connectivity measures exclusively in left SMA in the dismissing condition, which may specifically reflect ongoing network changes underlying prolonged emotional reactivity to attachment-related processing. PMID- 26516613 TI - Selective inhibition of dopamine-beta-hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex. AB - INTRODUCTION: Disulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release. METHODS: Noradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by alpha2-adrenoceptors. RESULTS: Fifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine combination, while it was ineffective in denervated rats. CONCLUSIONS: This research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The results indicate that nepicastat enhances DA release from noradrenergic terminals supposedly by removing NA from alpha2-autoreceptors. In addition to the inhibition of DA uptake, the latter mechanism may explain the synergistic effect of cocaine on nepicastat-induced DA release. PMID- 26516614 TI - Speech intelligibility in Parkinson's disease patients with zona incerta deep brain stimulation. AB - OBJECTIVES: To investigate the effects of l-dopa (Levodopa) and cZi-DBS (deep brain stimulation in caudal zona incerta) on spontaneous speech intelligibility in patients with PD (Parkinson's disease). MATERIALS AND METHODS: Spontaneous utterances were extracted from anechoic recordings from 11 patients with PD preoperatively (off and on l-dopa medication) and 6 and 12 months post bilateral cZi-DBS operation (off and on stimulation, with simultaneous l-dopa medication). Background noise with an amplitude corresponding to a clinical setting was added to the recordings. Intelligibility was assessed through a transcription task performed by 41 listeners in a randomized and blinded procedure. RESULTS: A group level worsening in spontaneous speech intelligibility was observed on cZi stimulation compared to off 6 months postoperatively (8 adverse, 1 positive, 2 no change). Twelve months postoperatively, adverse effects of cZi-DBS were not frequently observed (2 positive, 3 adverse, 6 no change). l-dopa administered preoperatively as part of the evaluation for DBS operation provided the overall best treatment outcome (1 adverse, 4 positive, 6 no change). CONCLUSIONS: cZi-DBS was shown to have smaller negative effects when evaluated from spontaneous speech compared to speech effects reported previously. The previously reported reduction in word-level intelligibility 12 months postoperatively was not transferred to spontaneous speech for most patients. Reduced intelligibility due to cZi stimulation was much more prominent 6 months postoperatively than at 12 months. PMID- 26516615 TI - Nonmelanoma skin cancer risk awareness in azathioprine-treated myasthenia gravis patients. AB - OBJECTIVES: Increased rates of NMSC (nonmelanoma skin cancer) have recently been reported in people with MG (myasthenia gravis) receiving azathioprine treatment. Guidelines on azathioprine for patients with dermatological and gastrointestinal disorders stress the importance of NMSC risk awareness and prevention. The aim of this study is to assess whether MG patients are being informed of this risk. METHODS: Clinical records of patients with MG attending a university hospital neurology clinic were reviewed. Data on patient demographics, clinical presentation, diagnostic tests, azathioprine treatment, development of NMSC, and counseling regarding NMSC risk were recorded. RESULTS: Sixty-nine MG cases were identified, median age 58 years (range 20-90). Forty-two (60.9%) had received azathioprine at some point with a mean cumulative dose of 235.5 g (range 9.1 972.8 g). Skin cancer risk and prevention advice provision was documented in 3 (7.1%) azathioprine-treated patients. Five patients developed histologically confirmed NMSC of whom all were treated with azathioprine (incidence rate of 24.9 per 1000, 16 times higher than expected). Documented advice on other safety issues such as regular blood test monitoring was found in 33 (78.8%) azathioprine treated cases. CONCLUSIONS: Preventative measures such as daily sunscreen use have been shown to reduce the incidence of NMSC in the general population. The results of this study demonstrate a very low rate of advice provision about NMSC risk in azathioprine-treated MG patients and the need for increased awareness among treating neurologists and patients. PMID- 26516616 TI - Effectiveness of regionalized systems for stroke and myocardial infarction. AB - BACKGROUND: Acute ischemic stroke (AIS) and ST-segment elevation myocardial infarction (STEMI) are ischemic emergencies. Guidelines recommend care delivery within formally regionalized systems of care at designated centers, with bypass of nearby centers of lesser or no designation. We review the evidence of the effectiveness of regionalized systems in AIS and STEMI. METHODS: Literature was searched using terms corresponding to designation of AIS and STEMI systems and from 2010 to the present. Inclusion criteria included report of an outcome on any dependent variable mentioned in the rationale for regionalization in the guidelines and an independent variable comparing care to a non- or pre regionalized system. Designation was defined in the AIS case as certification by the Joint Commission as either a primary (PSC) or comprehensive (CSC) stroke center. In the STEMI case, the search was conducted linking "regionalization" and "myocardial infarction" or citation as a model system by any American Heart Association statement. RESULTS: For AIS, 17 publications met these criteria and were selected for review. In the STEMI case, four publications met these criteria; the search was therefore expanded by relaxing the criteria to include any historical or anecdotal comparison to a pre- or nonregionalized state. The final yield was nine papers from six systems. CONCLUSION: Although regionalized care results in enhanced process and reduced unadjusted rates of disparity in access and adverse outcomes, these differences tend to become nonsignificant when adjusted for delayed presentation and hospital arrival by means other than emergency medical services. The benefits of regionalized care occur along with a temporal trend of improvement due to uptake of quality initiatives and guideline recommendations by all systems regardless of designation. Further research is justified with a randomized registry or cluster randomized design to support or refute recommendations that regionalization should be the standard of care. PMID- 26516617 TI - Use of T1-weighted/T2-weighted magnetic resonance ratio images to elucidate changes in the schizophrenic brain. AB - INTRODUCTION: One leading hypothesis suggests that schizophrenia (SZ) is a neurodevelopmental disorder caused by genetic defects in association with environmental risk factors that affect synapse and myelin formation. Recent magnetic resonance imaging (MRI) studies of SZ brain showed both gray matter (GM) reduction and white matter (WM) fractional anisotropy reduction. In this study, we used T1-weighted (T1w)/T2-weighted (T2w) MRI ratio images, which increase myelin-related signal contrast and reduce receiver-coil bias. METHODS: We measured T1w/T2w ratio image signal intensity in 29 patients with SZ and 33 healthy controls (HCs), and then compared them against bias-corrected T1w images. RESULTS: Mean T1w/T2w ratio signal intensity values across all SZ GM and WM voxels were significantly lower than those for the HC values (analysis of covariance with age, gender, handedness, and premorbid intelligence quotient as nuisance covariates). SZ mean WM T1w/T2w ratio values were related to Global Assessment of Functioning (GAF) scores and were inversely related to the positive psychotic symptoms of the Positive and Negative Syndrome Scale. Voxel-based analysis revealed significantly lower T1w/T2w ratio image signal intensity values in the right ventral putamen in SZ GM. T1w image intensities did not differ between the SZ and HC groups. CONCLUSIONS: T1-weighted/T2-weighted ratio imaging increased the detectability of SZ pathological changes. Reduced SZ brain signal intensity is likely due to diminished myelin content; therefore, mapping myelin related SZ brain changes using T1w/T2w ratio images may be useful for studies of SZ brain abnormalities. PMID- 26516618 TI - Persistent astrocyte activation in the fragile X mouse cerebellum. AB - BACKGROUND: Fragile X Syndrome, the most common single gene cause of autism, results from loss of the RNA-binding protein FMRP. Although FMRP is highly expressed in neurons, it has also recently been identified in glia. It has been postulated that in the absence of FMRP, abnormal function of non-neuronal cells may contribute to the pathogenesis of the disorder. We previously demonstrated reduced numbers of oligodendrocyte precursor cells and delayed myelination in the cerebellum of fragile X (Fmr1) knockout mice. METHODS: We used quantitative western blotting and immunocytochemistry to examine the status of astrocytes and microglia in the cerebellum of Fmr1 mice during development and in adulthood. RESULTS: We report increased expression of the astrocyte marker GFAP in the cerebellum of Fmr1 mice starting in the second postnatal week and persisting in to adulthood. At 2 weeks postnatal, expression of Tumor Necrosis Factor Receptor 2 (TNFR2) and Leukemia Inhibitory Factor (LIF) were elevated in the Fmr1 KO cerebellum. In adults, expression of TNFR2 and the glial marker S100beta were also elevated in Fmr1 knockouts, but LIF expression was not different from wild type mice. We found no evidence of microglial activation or neuroinflammation at any age examined. CONCLUSIONS: These findings demonstrate an atypical pattern of astrogliosis in the absence of microglial activation in Fmr1 knockout mouse cerebellum. Enhanced TNFR2 and LIF expression in young mice suggests that changes in the expression of astrocytic proteins may be an attempt to compensate for delayed myelination in the developing cerebellum of Fmr1 mice. PMID- 26516619 TI - The Relationship Between School Climate and Mental and Emotional Wellbeing Over the Transition from Primary to Secondary School. AB - BACKGROUND: School climate has often been described as the "quality and character of school life", including both social and physical aspects of the school, that can positively promote behaviour, school achievement, and the social and emotional development of students. METHODS: The current study examined the relationship between students' mental and emotional wellbeing and factors pertaining to school climate, focussing on the domains of safety, social relationships and school connectedness, during the last year of their primary schooling (age 11-12 years) and their first 2 years of secondary school. Data was collected using a self-completion questionnaire, four times over 3 years from 1800 students' aged 11-14 years. Multilevel modelling was used to determine the strongest school climate predictor of students' mental and emotional wellbeing at each time point. RESULTS: In the last year of primary school, peer support was the strongest protective predictor of wellbeing, while feeling less connected and less safe at school predicted mental wellbeing. Feeling safe at school was the strongest protective factor for student wellbeing in the first year of secondary school. In the second year of secondary school, peer support was the strongest protective factor for mental wellbeing, while feeling safe at school, feeling connected to school and having support from peers were predictive of emotional wellbeing. CONCLUSIONS: School climate factors of feeling safe at school, feeling connected to school, and peer support are all protective of mental and emotional wellbeing over the transition period while connectedness to teachers is protective of emotional wellbeing. Primary school appears to be an important time to establish quality connections to peers who have a powerful role in providing support for one another before the transition to secondary school. However, school policies and practices promoting safety and encouraging and enabling connectedness are important during the first years of secondary school. Recommendations for effective school policy and practice in both primary and secondary schools to help enhance the mental and emotional wellbeing of adolescents are discussed. PMID- 26516620 TI - Examination of community and consumer nutrition, tobacco and physical activity environments at food and tobacco retail stores in three diverse North Carolina communities. PMID- 26516621 TI - Engaging teenagers productively in service design. AB - Engaging young people in participatory design can be challenging, particularly in health-related projects. In a study co-designing diabetes support and information services with teenagers, we found framing activities using popular culture was a useful strategy. Various cultural references helped us stage activities that were productive for the design process, and were engaging for our young participants (e.g. exploring practical implications through discussions in a 'Dragons' Den'). Some activities were more effective than others and the idea of language-games, which has been widely explored in participatory design, explains why our strategy was successful when there was a clear 'family resemblance' between the popular cultural references and certain essential stages of designing. However, attention is required in selecting appropriate cultural references if this strategy is adopted elsewhere, and design facilitators should focus first on devising accessible language-games, rather than expecting popular cultural references to provide complete solutions to the challenge of staging participatory design. PMID- 26516622 TI - Burden of disease caused by local transport in Warsaw, Poland. AB - Transport is a major source of air pollution, noise, injuries and physical activity in the urban environment. The quantification of the health risks and benefits arising from these factors would provide useful information for the planning of cost-effective mitigation actions. In this study we quantified the burden of disease caused by local transport in the city of Warsaw, Poland. The disability-adjusted life-years (DALYs) were estimated for transport related air pollution (particulate matter (PM), nitrogen oxides (NO x ), sulfur dioxide (SO2), benzo[a]pyrene (BaP), cadmium, lead and nickel), noise, injuries and physical activity. Exposure to these factors was based on local and international data, and the exposure-response functions (ERFs) were based on published reviews and recommendations. The uncertainties were quantified and propagated with the Monte Carlo method. Local transport generated air pollution, noise and injuries were estimated to cause approximately 58,000 DALYs in the study area. From this burden 44% was due to air pollution and 46% due to noise. Transport related physical activity was estimated to cause a health benefit of 17,000 DALYs. Main quantified uncertainties were related to disability weight for the annoyance (due to noise) and to the ERFs for fine particulate matter (PM2.5) air pollution and walking. The results indicate that the health burden of transport could be mitigated by reducing motorized transport, which causes air pollution and noise, and by encouraging walking and cycling in the study area. PMID- 26516623 TI - Integrated Evaluation of Urban Water Bodies for Pollution Abatement Based on Fuzzy Multicriteria Decision Approach. AB - Today's ecology is erected with miscellaneous framework. However, numerous sources deteriorate it, such as urban rivers that directly cause the environmental pollution. For chemical pollution abatement from urban water bodies, many techniques were introduced to rehabilitate the water quality of these water bodies. In this research, Bacterial Technology (BT) was applied to urban rivers escalating the necessity to control the water pollution in different places (Xuxi River (XXU); Gankeng River (GKS); Xia Zhang River (XZY); Fenghu and Song Yang Rivers (FSR); Jiu Haogang River (JHH)) in China. For data analysis, the physiochemical parameters such as temperature, chemical oxygen demand (COD), dissolved oxygen (DO), total phosphorus (TP), and ammonia nitrogen (NH3N) were determined before and after the treatment. Multicriteria Decision Making (MCDM) method was used for relative significance of different water quality on each station, based on fuzzy analytical hierarchy process (FAHP). The overall results revealed that the pollution is exceeding at "JHH" due to the limit of "COD" as critical water quality parameter and after treatment, an abrupt recovery of the rivers compared with the average improved efficiency of nutrients was 79%, 74%, 68%, and 70% of COD, DO, TP, and NH3N, respectively. The color of the river's water changed to its original form and aquatic living organism appeared with clear effluents from them. PMID- 26516625 TI - Modeling the Effects of Multiple Intervention Strategies on Controlling Foot-and Mouth Disease. AB - Foot-and-mouth disease (FMD) is a threat to economic security and infrastructure as well as animal health, in both developed and developing countries. We propose and analyze an optimal control problem where the control system is a mathematical model for FMD that incorporates vaccination and culling of infectious animals. The control functions represent the fraction of animals that are vaccinated during an outbreak, infectious symptomatic animals that are detected and culled, and infectious nonsymptomatic animals that are detected and culled. Our aim was to study how these control measures should be implemented for a certain time period, in order to reduce or eliminate FMD in the community, while minimizing the interventions implementation costs. A cost-effectiveness analysis is carried out, to compare the application of each one of the control measures, separately or in combination. PMID- 26516626 TI - A Novel and Alternative Treatment Method for Diabetic Heel Ulceration Exposing the Calcaneus Which Is Not Suitable for Flap Surgery: Vacuum Assisted Sandwich Dermal Matrix. AB - BACKGROUND: Currently, free flaps and pedicled flaps are the first treatment choices for large heel ulcer reconstruction. However, flap reconstruction of heel ulcerations cannot be performed in all diabetics especially with concurrent severe peripheral vascular disease because of higher flap failure rate. In recent years, the use of acellular dermal matrix (ADM) has emerged as an alternative treatment option for extremity ulcers. METHODS: We present 13 diabetic patients with a large heel ulceration exposing the calcaneus, who were not eligible for flap surgery due to the presence of only one patent artery of trifurcation. These cases were treated with the vacuum assisted sandwich dermal matrix (VASDEM) method. RESULTS: None of the patients required amputation. Skin grafting was successful in ten patients. Although partial losses were observed in three patients, they were healed spontaneously without surgical interventions. During the follow-up period none of the patients developed ulceration on the treatment area. All patients maintained their preoperative ambulatory ability. CONCLUSION: VASDEM is a novel method offering opportunity for treatment before proceeding to amputation in diabetic heel ulceration exposing the calcaneus which is not suitable for flap surgery. It also has the potential to close wounds of all sizes independent of the vessel status and wound size in selected diabetic patients. PMID- 26516624 TI - How to Use SNP_TATA_Comparator to Find a Significant Change in Gene Expression Caused by the Regulatory SNP of This Gene's Promoter via a Change in Affinity of the TATA-Binding Protein for This Promoter. AB - The use of biomedical SNP markers of diseases can improve effectiveness of treatment. Genotyping of patients with subsequent searching for SNPs more frequent than in norm is the only commonly accepted method for identification of SNP markers within the framework of translational research. The bioinformatics applications aimed at millions of unannotated SNPs of the "1000 Genomes" can make this search for SNP markers more focused and less expensive. We used our Web service involving Fisher's Z-score for candidate SNP markers to find a significant change in a gene's expression. Here we analyzed the change caused by SNPs in the gene's promoter via a change in affinity of the TATA-binding protein for this promoter. We provide examples and discuss how to use this bioinformatics application in the course of practical analysis of unannotated SNPs from the "1000 Genomes" project. Using known biomedical SNP markers, we identified 17 novel candidate SNP markers nearby: rs549858786 (rheumatoid arthritis); rs72661131 (cardiovascular events in rheumatoid arthritis); rs562962093 (stroke); rs563558831 (cyclophosphamide bioactivation); rs55878706 (malaria resistance, leukopenia), rs572527200 (asthma, systemic sclerosis, and psoriasis), rs371045754 (hemophilia B), rs587745372 (cardiovascular events); rs372329931, rs200209906, rs367732974, and rs549591993 (all four: cancer); rs17231520 and rs569033466 (both: atherosclerosis); rs63750953, rs281864525, and rs34166473 (all three: malaria resistance, thalassemia). PMID- 26516628 TI - Antibodies to MOG in adults with inflammatory demyelinating disease of the CNS. AB - OBJECTIVE: To evaluate the clinical relevance of myelin oligodendrocyte glycoprotein antibody (MOG-Ab) in a cohort of adults with inflammatory demyelinating disease (IDD) of the CNS. METHODS: Live cell-based assays for MOG Ab (IgG1 subset) and antibody to aquaporin-4 (AQP4-Ab) were performed in a cohort of 270 adult patients with IDD and 72 controls. Patients were first grouped by positive antibody result as MOG-Ab or AQP4-Ab, and the remainder were grouped by published diagnostic criteria. RESULTS: Seventeen patients with IDD (6.3%) had MOG-Abs and 49 patients (18.1%) had AQP4-Abs; none had both antibodies. The MOG Ab patients predominantly manifested with isolated symptoms of optic neuritis (83%). One-third of these patients experienced relapses, which involved only the optic nerve, and all relapsed within 1 year of disease onset. At onset, MRI in the MOG-Ab group uniquely demonstrated perineural enhancement, extending to the soft tissues around the optic nerves (33%). Although about 30% of MOG-Ab patients had brain MRI lesions, they had fewer periventricular lesions than the 26 patients with relapsing-remitting multiple sclerosis (MS); none of these lesions were ovoid or perpendicular to the ventricle. Moreover, MOG-Ab patients did not meet the diagnostic criteria for definite neuromyelitis optica (NMO) and had less spinal cord involvement than the AQP4-Ab group. Four patients (23.5%) had poor visual outcomes (<0.2) or paraplegia. CONCLUSIONS: MOG-Abs may be a disease specific biomarker in adult patients with IDD who have a disease distinct from NMO or MS. The radiologic as well as clinical manifestations of MOG-Ab patients can be useful in their differential diagnosis. PMID- 26516627 TI - Evaluating more naturalistic outcome measures: A 1-year smartphone study in multiple sclerosis. AB - OBJECTIVE: In this cohort of individuals with and without multiple sclerosis (MS), we illustrate some of the novel approaches that smartphones provide to monitor patients with chronic neurologic disorders in their natural setting. METHODS: Thirty-eight participant pairs (MS and cohabitant) aged 18-55 years participated in the study. Each participant received an Android HTC Sensation 4G smartphone containing a custom application suite of 19 tests capturing participant performance and patient-reported outcomes (PROs). Over 1 year, participants were prompted daily to complete one assigned test. RESULTS: A total of 22 patients with MS and 17 cohabitants completed the entire study. Among patients with MS, low scores on PROs relating to mental and visual function were associated with dropout (p < 0.05). We illustrate several novel features of a smartphone platform. First, fluctuations in MS outcomes (e.g., fatigue) were assessed against an individual's ambient environment by linking responses to meteorological data. Second, both response accuracy and speed for the Ishihara color vision test were captured, highlighting the benefits of both active and passive data collection. Third, a new trait, a person-specific learning curve in neuropsychological testing, was identified using spline analysis. Finally, averaging repeated measures over the study yielded the most robust correlation matrix of the different outcome measures. CONCLUSIONS: We report the feasibility of, and barriers to, deploying a smartphone platform to gather useful passive and active performance data at high frequency in an unstructured manner in the field. A smartphone platform may therefore enable large-scale naturalistic studies of patients with MS or other neurologic diseases. PMID- 26516629 TI - Leptomeningeal contrast enhancement and blood-CSF barrier dysfunction in aseptic meningitis. AB - OBJECTIVE: To investigate the blood-CSF barrier (BCSFB) dysfunction in aseptic meningitis. METHODS: In our case series of 14 patients with acute aseptic meningitis, we compared MRI characteristics with CSF findings. RESULTS: Contrast enhancement in the sulcal space in a leptomeningeal pattern was visualized in 7 patients with BCSFB dysfunction categorized as moderate to severe as evidenced by the CSF/serum albumin ratio (Qalb) but was not present in those with mild or no barrier disturbance (p = 0.001). The Qalb as a marker for the leakiness of the BCSFB and, more indirectly, of the blood-brain barrier (BBB) was positively correlated with the incidence of leptomeningeal contrast enhancement seen on postcontrast fluid-attenuated inversion recovery (FLAIR) MRI (p = 0.003). Patients with a more pronounced brain barrier dysfunction recovered more slowly and stayed longer in the hospital. CONCLUSIONS: The severity of meningeal BBB disturbance can be estimated on postcontrast FLAIR MRI, which may be of diagnostic value in patients with aseptic meningitis. PMID- 26516630 TI - Reduction of microbleeds by immunosuppression in a patient with Abeta-related vascular inflammation. AB - OBJECTIVE: To investigate whether the occurrence or clearance of microhemorrhages in cerebral amyloid angiopathy (CAA)-related vascular inflammation can be modified by immunosuppressive treatment. METHODS: Clinical and radiologic follow up for more than 5 years of a patient with histopathologically confirmed CAA related vascular inflammation treated with a prolonged and tapered regimen of IV cyclophosphamide and oral steroids. RESULTS: Under long-term immunosuppressive treatment, a reduced number of cortical micobleeds was observed on repeat MRIs because of both the prevention of new microbleeds and the clearance of those existing at baseline. CONCLUSIONS: Sustained immunosuppression should be considered and systematically investigated as a treatment option for cortical microbleeds in CAA and related inflammatory phenotypes. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence. This is a single observational study without controls. PMID- 26516631 TI - The cognitive neuroscience of visual short-term memory. AB - Our understanding of the neural bases of visual short-term memory (STM), the ability to mentally retain information over short periods of time, is being reshaped by two important developments: the application of methods from statistical machine learning, often a variant of multivariate pattern analysis (MVPA), to functional magnetic resonance imaging (fMRI) and electroencephalographic (EEG) data sets; and advances in our understanding of the physiology and functions of neuronal oscillations. One consequence is that many commonly observed physiological "signatures" that have previously been interpreted as directly related to the retention of information in visual STM may require reinterpretation as more general, state-related changes that can accompany cognitive-task performance. Another is important refinements of theoretical models of visual STM. PMID- 26516632 TI - Social media interventions to prevent HIV: A review of interventions and methodological considerations. AB - Persistent new HIV infections and risky behaviors underscore the need for enhanced HIV prevention. Social media interventions may promote safe sexual behaviors, increase HIV testing uptake, and promote safe injection behaviors. This review discusses how social media interventions tap into the wisdom of crowds through crowdsourcing, build peer-mentored communities, and deliver interventions through social networks. Social media HIV prevention interventions are constrained by ethical issues, low social media usage among some key populations, and implementation issues. Comprehensive measurement of social media interventions to prevent HIV is necessary, but requires further development of metrics. PMID- 26516634 TI - Multicriteria Personnel Selection by the Modified Fuzzy VIKOR Method. AB - Personnel evaluation is an important process in human resource management. The multicriteria nature and the presence of both qualitative and quantitative factors make it considerably more complex. In this study, a fuzzy hybrid multicriteria decision-making (MCDM) model is proposed to personnel evaluation. This model solves personnel evaluation problem in a fuzzy environment where both criteria and weights could be fuzzy sets. The triangular fuzzy numbers are used to evaluate the suitability of personnel and the approximate reasoning of linguistic values. For evaluation, we have selected five information culture criteria. The weights of the criteria were calculated using worst-case method. After that, modified fuzzy VIKOR is proposed to rank the alternatives. The outcome of this research is ranking and selecting best alternative with the help of fuzzy VIKOR and modified fuzzy VIKOR techniques. A comparative analysis of results by fuzzy VIKOR and modified fuzzy VIKOR methods is presented. Experiments showed that the proposed modified fuzzy VIKOR method has some advantages over fuzzy VIKOR method. Firstly, from a computational complexity point of view, the presented model is effective. Secondly, compared to fuzzy VIKOR method, it has high acceptable advantage compared to fuzzy VIKOR method. PMID- 26516633 TI - SOX15 governs transcription in human stratified epithelia and a subset of esophageal adenocarcinomas. AB - BACKGROUND & AIMS: Intestinal metaplasia (Barrett's esophagus, BE) is the principal risk factor for esophageal adenocarcinoma (EAC). Study of the basis for BE has centered on intestinal factors, but loss of esophageal identity likely also reflects absence of key squamous-cell factors. As few determinants of stratified epithelial cell-specific gene expression are characterized, it is important to identify the necessary transcription factors. METHODS: We tested regional expression of mRNAs for all putative DNA-binding proteins in the mouse digestive tract and verified esophagus-specific factors in human tissues and cell lines. Integration of diverse data defined a human squamous esophagus-specific transcriptome. We used chromatin immunoprecipitation (ChIP-seq) to locate transcription factor binding sites, computational approaches to profile transcripts in cancer datasets, and immunohistochemistry to reveal protein expression. RESULTS: The transcription factor SOX15 is restricted to esophageal and other murine and human stratified epithelia. SOX15 mRNA levels are attenuated in BE and its depletion in human esophageal cells reduced esophageal transcripts significantly and specifically. SOX15 binding is highly enriched near esophagus expressed genes, indicating direct transcriptional control. SOX15 and hundreds of genes co-expressed in squamous cells are reactivated in up to 30% of EAC specimens. Genes normally confined to the esophagus or intestine appear in different cells within the same malignant glands. CONCLUSIONS: These data identify a novel transcriptional regulator of stratified epithelial cells and a subtype of EAC with bi-lineage gene expression. Broad activation of squamous-cell genes may shed light on whether EACs arise in the native stratified epithelium or in ectopic columnar cells. PMID- 26516635 TI - Differential Evolution Algorithm with Diversified Vicinity Operator for Optimal Routing and Clustering of Energy Efficient Wireless Sensor Networks. AB - Due to large dimension of clusters and increasing size of sensor nodes, finding the optimal route and cluster for large wireless sensor networks (WSN) seems to be highly complex and cumbersome. This paper proposes a new method to determine a reasonably better solution of the clustering and routing problem with the highest concern of efficient energy consumption of the sensor nodes for extending network life time. The proposed method is based on the Differential Evolution (DE) algorithm with an improvised search operator called Diversified Vicinity Procedure (DVP), which models a trade-off between energy consumption of the cluster heads and delay in forwarding the data packets. The obtained route using the proposed method from all the gateways to the base station is comparatively lesser in overall distance with less number of data forwards. Extensive numerical experiments demonstrate the superiority of the proposed method in managing energy consumption of the WSN and the results are compared with the other algorithms reported in the literature. PMID- 26516636 TI - Differential Evolution Based IDWNN Controller for Fault Ride-Through of Grid Connected Doubly Fed Induction Wind Generators. AB - The key objective of wind turbine development is to ensure that output power is continuously increased. It is authenticated that wind turbines (WTs) supply the necessary reactive power to the grid at the time of fault and after fault to aid the flowing grid voltage. At this juncture, this paper introduces a novel heuristic based controller module employing differential evolution and neural network architecture to improve the low-voltage ride-through rate of grid connected wind turbines, which are connected along with doubly fed induction generators (DFIGs). The traditional crowbar-based systems were basically applied to secure the rotor-side converter during the occurrence of grid faults. This traditional controller is found not to satisfy the desired requirement, since DFIG during the connection of crowbar acts like a squirrel cage module and absorbs the reactive power from the grid. This limitation is taken care of in this paper by introducing heuristic controllers that remove the usage of crowbar and ensure that wind turbines supply necessary reactive power to the grid during faults. The controller is designed in this paper to enhance the DFIG converter during the grid fault and this controller takes care of the ride-through fault without employing any other hardware modules. The paper introduces a double wavelet neural network controller which is appropriately tuned employing differential evolution. To validate the proposed controller module, a case study of wind farm with 1.5 MW wind turbines connected to a 25 kV distribution system exporting power to a 120 kV grid through a 30 km 25 kV feeder is carried out by simulation. PMID- 26516637 TI - Learning to live with landscape fires. AB - Catastrophic wildfires have become more frequent in the last few decades. The standard depiction in the media of fires as a disaster that has to be avoided and stopped at all cost fails to do justice to a more complex ecological balance of destruction and new growth. The emerging discipline of pyrogeography aims to gain a holistic understanding of the role that fire plays in nature and the ways in which we can manage it sustainably. Michael Gross reports. PMID- 26516638 TI - David Haig. PMID- 26516639 TI - Introduction to the SCiP special issue. PMID- 26516640 TI - Networking: Hello, stranger. PMID- 26516641 TI - Liraglutide in Weight Management. PMID- 26516642 TI - Retraction notice to "A novel modified electrode as GC/PPy-AuNPs- rGO/L Cys/Ag@MUA nanostructure configuration for determination of CCP and C RP antibodies in human blood serum samples" [Biosens. Bioelectron. 63(2015)490-498]. PMID- 26516643 TI - Case study. Warm and dead? Commentary. PMID- 26516644 TI - Case study. Warm and dead? Commentary. PMID- 26516646 TI - Molecular imaging: the ultimate success story of a 'golden' career? PMID- 26516647 TI - 4th European Live summit on retrograde chronic total occlusion revascularization. PMID- 26516648 TI - Alfredo Ruggero Galassi MD and the EuroCTO Club. PMID- 26516649 TI - Obituary - Judson G. Randolph M.D., 1932-2013. PMID- 26516650 TI - Quantifying and Reducing Uncertainty in Estimated Microcystin Concentrations from the ELISA Method. AB - We discuss the uncertainty associated with a commonly used method for measuring the concentration of microcystin, a group of toxins associated with cyanobacterial blooms. Such uncertainty is rarely reported and accounted for in important drinking water management decisions. Using monitoring data from Ohio Environmental Protection Agency and from City of Toledo, we document the sources of measurement uncertainty and recommend a Bayesian hierarchical modeling approach for reducing the measurement uncertainty. Our analysis suggests that (1) much of the uncertainty is a result of the highly uncertain "standard curve" developed during each test and (2) the uncertainty can be reduced by pooling raw test data from multiple tests. Based on these results, we suggest that estimation uncertainty can be effectively reduced through the effort of either (1) regional regulatory agencies by sharing and combining raw test data from regularly scheduled microcystin monitoring program or (2) the manufacturer of the testing kit by conducting additional tests as part of an effort to improve the testing kit. PMID- 26516651 TI - The continuum of high ovarian response: a rational approach to the management of high responder patient subgroups. AB - Ovarian follicular responsiveness to controlled ovarian hyperstimulation (COH) with gonadotropins is extremely variable between individual patients, and even from cycle to cycle for the same patient. High responder patients are characterized by an exaggerated response to gonadotropin administration, accompanied by a higher risk for ovarian hyperstimulation syndrome (OHSS). In spite of its importance, the literature regarding high responders is characterized by heterogeneous classification methodologies. A clear separation should be drawn between risk factors for a high ovarian response and the actual response exhibited by a patient to stimulation. Similarly, it is important to distinguish between high ovarian response and development of clinically significant OHSS. In this article we: (1) review recent publications pertaining to the identification and clinical management of high responders, (2) propose an integrated clinical model to differentiate sub-groups within this population based on this review, and (3) suggest specific protocols for each sub-group. The model is based on a chronological patient assessment in an effort to target treatment based on the specific clinical circumstances. It is our hope that the algorithm we have developed will assist clinicians to supply targeted and precise treatments in order to achieve a favorable reproductive outcome with minimum complications for each patient. PMID- 26516652 TI - Biomimetic Mineralization of Recombinamer-Based Hydrogels toward Controlled Morphologies and High Mineral Density. AB - The use of insoluble organic matrices as a structural template for the bottom-up fabrication of organic-inorganic nanocomposites is a powerful way to build a variety of advanced materials with defined and controlled morphologies and superior mechanical properties. Calcium phosphate mineralization in polymeric hydrogels is receiving significant attention in terms of obtaining biomimetic hierarchical structures with unique mechanical properties and understanding the mechanisms of the biomineralization process. However, integration of organic matrices with hydroxyapatite nanocrystals, different in morphology and composition, has not been well-achieved yet at nanoscale. In this study, we synthesized thermoresponsive hydrogels, composed of elastin-like recombinamers (ELRs), to template mineralization of hydroxyapatite nanocrystals using a biomimetic polymer-induced liquid-precursor (PILP) mineralization process. Different from conventional mineralization where minerals were deposited on the surface of organic matrices, they were infiltrated into the frameworks of ELR matrices, preserving their microporous structure. After 14 days of mineralization, an average of 78 MUm mineralization depth was achieved. Mineral density up to 1.9 g/cm(3) was found after 28 days of mineralization, which is comparable to natural bone and dentin. In the dry state, the elastic modulus and hardness of the mineralized hydrogels were 20.3 +/- 1.7 and 0.93 +/- 0.07 GPa, respectively. After hydration, they were reduced to 4.50 +/- 0.55 and 0.10 +/- 0.03 GPa, respectively. These values were lower but still on the same order of magnitude as those of natural hard tissues. The results indicated that inorganic organic hybrid biomaterials with controlled morphologies can be achieved using organic templates of ELRs. Notably, the chemical and physical properties of ELRs can be tuned, which might help elucidate the mechanisms by which living organisms regulate the mineralization process. PMID- 26516653 TI - Oxidative Difunctionalization of Alkynoates through Alkylation and Migration Decarboxylative Arylation. AB - A cascade oxidative difunctionalization reaction of alkynoates for the construction of trisubstituted olefins has been developed. The process undergoes alkylation of a C-C triple bond, 1,4-aryl migration, and decarboxylation, which demonstrates a multistep radical cascade reaction for the difunctionalization of alkynoates and also represents a strategy of direct decarboxylation of esters. PMID- 26516654 TI - Neutrophil-Mediated Delivery of Therapeutic Nanoparticles across Blood Vessel Barrier for Treatment of Inflammation and Infection. AB - Endothelial cells form a monolayer in lumen of blood vessels presenting a great barrier for delivery of therapeutic nanoparticles (NPs) into extravascular tissues where most diseases occur, such as inflammation disorders and infection. Here, we report a strategy for delivering therapeutic NPs across this blood vessel barrier by nanoparticle in situ hitchhiking activated neutrophils. Using intravital microscopy of TNF-alpha-induced inflammation of mouse cremaster venules and a mouse model of acute lung inflammation, we demonstrated that intravenously (iv) infused NPs made from denatured bovine serum albumin (BSA) were specifically internalized by activated neutrophils, and subsequently, the neutrophils containing NPs migrated across blood vessels into inflammatory tissues. When neutrophils were depleted using anti-Gr-1 in a mouse, the transport of albumin NPs across blood vessel walls was robustly abolished. Furthermore, it was found that albumin nanoparticle internalization did not affect neutrophil mobility and functions. Administration of drug-loaded albumin NPs markedly mitigated the lung inflammation induced by LPS (lipopolysaccharide) or infection by Pseudomonas aeruginosa. These results demonstrate the use of an albumin nanoparticle platform for in situ targeting of activated neutrophils for delivery of therapeutics across the blood vessel barriers into diseased sites. This study demonstrates our ability to hijack neutrophils to deliver nanoparticles to targeted diseased sites. PMID- 26516655 TI - Effect of simulated climate warming on the morphological and physiological traits of Elsholtzia haichowensis in copper contaminated soil. AB - The aim of this study was to investigate the effects of temperature and Cu on the morphological and physiological traits of Elsholtzia haichowensis grown in soils amended with four Cu concentrations (0, 50, 500, and 1000 mg kg(-1)) under ambient temperature and slight warming. At the same Cu concentration, the height, shoot dry weight, total plant dry weight, and root morphological parameters such as length, surface area and tip number of E. haichowensis increased due to the slight warming. The net photosynthetic rate, stomatal conductance, transpiration, light use efficiency were also higher under the slight warming than under ambient temperature. The increased Cu concentrations, total Cu uptake, bioaccumulation factors and tolerance indexes of shoots and roots were also observed at the slight warming. The shoot dry weight, root dry weight, total plant dry weight and the bioaccumulation factors of shoots and roots at 50 mg Cu kg(-1) were significantly higher than those at 500 and 1000 mg Cu kg(-1) under the slight warming. Therefore, the climate warming may improve the ability of E. haichowensis to phytoremediate Cu-contaminated soil, and the ability improvement greatly depended on the Cu concentrations in soils. PMID- 26516657 TI - Rate of establishing the gut microbiota in infancy has consequences for future health. AB - The gut of the human neonate is colonized rapidly after birth from an early sparse and highly distinct microbiota to a more adult-like and convergent state, within 1 to 3 years. The progression of colonizing bacterial species is non random. During the first months of life several shifts commonly occur in the species prevalent in our guts. Although the sequential progression of these species is remarkably consistent across individuals and geographies, there is inter-individual variation in the rate of progression. Our study and others suggest that the rate is influenced by environmental factors, and influences our future health. In this article, we review our recent contribution to cataloging the developing infant gut microbiota alongside other important recent studies. We suggest testable hypotheses that arise from this synthesis. PMID- 26516658 TI - Gut mycobiota and adenomas. AB - Fungal microbiota (mycobiota) is potentially involved in the intestinal illness. The characterization of the mycobiota in patients with adenomas is essential for understanding the etiology of the pre-cancerous lesion since the mycobiota is potentially associated with the presents of adenomas. The recovery of the mycobiome may also help to identify the potential biomarkers which may closely relate to different stages of adenoma. PMID- 26516656 TI - Reporter systems for in vivo tracking of lactic acid bacteria in animal model studies. AB - Bioluminescence (BLI) and fluorescence imaging (FI) allow for non-invasive detection of viable microorganisms from within living tissue and are thus ideally suited for in vivo probiotic studies. Highly sensitive optical imaging techniques detect signals from the excitation of fluorescent proteins, or luciferase catalyzed oxidation reactions. The excellent relation between microbial numbers and photon emission allow for quantification of tagged bacteria in vivo with extreme accuracy. More information is gained over a shorter period compared to traditional pre-clinical animal studies. The review summarizes the latest advances in in vivo bioluminescence and fluorescence imaging and points out the advantages and limitations of different techniques. The practical application of BLI and FI in the tracking of lactic acid bacteria in animal models is addressed. PMID- 26516659 TI - Alteration in systemic markers of oxidative and antioxidative status in Tunisian patients with asthma: relationships with clinical severity and airflow limitation. AB - OBJECTIVE: This study aims to determine the systemic oxidant-antioxidant status in Tunisian patients with asthma. METHODS: We evaluated the levels of malondialdehyde (MDA) as thiobarbituric acid complexes, total protein carbonyls (PCs) and advanced oxidation protein products (AOPP). The levels of total thiols, protein sulfhydryls, glutathione (GSH), together with hydrogen peroxide, ascorbic acid, iron and total antioxidant status (TAS) were colorimetrically estimated. Glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) activities were assessed in plasma and erythrocytes by spectrophotometry. We also determined the levels of nitric oxide (NO) and peroxynitrite in plasma from asthmatic patients and healthy controls. The volume of fractionated exhaled NO (FeNO) was evaluated by the Medisoft HypAir method. Estimation of DNA damage was determined using the comet assay. RESULTS: Asthmatic patients showed increased levels of MDA in comparison to healthy controls (p < 0.001), while no significant difference was found in protein carbonyls (p = 0.79) and AOPP (p = 0.98). Patients with asthma also had significantly lower levels of total thiols (355.9 +/- 15.72 versus 667.9 +/- 22.65, p < 0.001), protein sulfhydryls (333.99 +/- 16.41 versus 591.95 +/- 24.28, p < 0.001) and glutathione (p < 0.001). They also showed decreased GSH-Px activity (p < 0.001), whereas no significant differences in measurements of catalase and SOD enzyme activities were observed between the two groups (respectively, p = 0.06 and p = 0.55). In addition, ascorbic acid and nitric oxide levels were decreased in asthmatics in comparison to controls (p < 0.01). CONCLUSIONS: Our findings highlight that oxidative stress and defective anti-oxidative status are major alterations in Tunisian patients with asthma. PMID- 26516660 TI - Ligand Field Affected Single-Molecule Magnet Behavior of Lanthanide(III) Dinuclear Complexes with an 8-Hydroxyquinoline Schiff Base Derivative as Bridging Ligand. AB - New dinuclear lanthanide(III) complexes based on an 8-hydroxyquinoline Schiff base derivative and beta-diketonate ligands, [Ln2(hfac)4(L)2] (Ln(III) = Gd (1), Tb (2), Dy (3), Ho (4), Er (5)), [Ln2(tfac)4(L)2] (Ln(III) = Gd (6), Tb (7), Dy (8), Ho (9)), and [Dy(bfac)4(L)2.C7H16] (10) (L = 2-[[(4-fluorophenyl)imino] methyl]-8-hydroxyquinoline, hfac = hexafluoroacetylacetonate, tfac = trifluoroacetylacetonate, and bfac = benzoyltrifluoroacetone), have been synthesized. The single-crystal X-ray diffraction data show that complexes 1-10 are phenoxo-O-bridged dinuclear complexes; each eight-coordinated center Ln(III) ion is in a slightly distorted dodecahedral geometry with two bidentate beta diketonate coligands and two MU2-O bridging 8-hydroxyquinoline Schiff base derivative ligands. The magnetic study reveals that 1 and 6 display cryogenic magnetic refrigeration properties, whereas complexes 3, 8, and 10 show different SMM behaviors with energy barriers of 6.77 K for 3, 19.83 K for 8, and 25.65 K for 10. Meanwhile, slow magnetic relaxation was observed in 7, while no out-of phase alternating-current signals were found for 2. The different dynamic magnetic behaviors of two Tb2 complexes and the three Dy2 complexes mainly derive from the tiny crystal structure changes around the Ln(III) ions. It is also proved that the beta-diketonate coligands can play an important role in modulating magnetic dynamics of the lanthanide 8-hydroxyquinoline Schiff base derivative system. PMID- 26516661 TI - Properties of convective delivery in spinal cord gray matter: laboratory investigation and computational simulations. AB - OBJECT Convection-enhanced delivery (CED) is a method for distributing small and large molecules locally into the interstitial space of the spinal cord. Delivering these molecules to the spinal cord is otherwise difficult due to the blood-spinal cord barrier. Previous research has proven the efficacy of CED for delivering molecules over long distances along the white matter tracts in the spinal cord. Conversely, the characteristics of CED for delivering molecules to the gray matter of the spinal cord remain unknown. The purpose of this study was to reveal regional distribution of macromolecules in the gray and white matter of the spinal cord with special attention to the differences between the gray and white matter. METHODS Sixteen rats (F344) underwent Evans blue dye CED to either the white matter (dorsal column, 8 rats) or the gray matter (ventral horn, 8 rats) of the spinal cord. The rates and total volumes of infusion were 0.2 MUl/min and 2.0 MUl, respectively. The infused volume of distribution was visualized and quantified histologically. Computational models of the rat spinal cord were also obtained to perform CED simulations in the white and gray matter. RESULTS The ratio of the volume of distribution to the volume of infusion in the gray matter of the spinal cord was 3.60 +/- 0.69, which was comparable to that of the white matter (3.05 +/- 0.88). When molecules were injected into the white matter, drugs remained in the white matter tract and rarely infused into the adjacent gray matter. Conversely, when drugs were injected into the gray matter, they infiltrated laterally into the white matter tract and traveled longitudinally and preferably along the white matter. In the infusion center, the areas were larger in the gray matter CED than in the white matter (Mann-Whitney U test, p < 0.01). In computational simulations, the aforementioned characteristics of CED to the gray and white matter were reaffirmed. CONCLUSIONS In the spinal cord, the gray and white matter have distinct characteristics of drug distribution by CED. These differences between the gray and white matter should be taken into account when considering drug delivery to the spinal cord. Computational simulation is a useful tool for predicting drug distributions in the normal spinal cord. PMID- 26516662 TI - Conservative surgery in the treatment of giant cell tumor of the sacrum: 35 years' experience. AB - OBJECT There is no consensus regarding the appropriate treatment of sacral giant cell tumor (GCT). There are 3 main management problems: tumor control, neurological loss, and pelvic instability. The objective of this study was to examine oncological, neurological, and structural outcomes of sacral GCT after intralesional excision and local intraoperative adjunctive treatment. METHODS The authors retrospectively reviewed the records of 24 patients with sacral GCT who underwent conservative surgery (intralesional resection/curettage) at Memorial Sloan Kettering Cancer Center from 1973 through 2012. They analyzed patient demographic data, tumor characteristics, and operative techniques, and examined possible correlations with postoperative functional outcomes, complications, recurrence, and mortality. RESULTS There were 7 local recurrences (30%) and 3 distant recurrences (13%). Three of 24 patients (12.5%) had significant neurological loss after treatment-specifically, severe bowel and/or bladder dysfunction, but all regained function within 1-4 years. Larger tumor size (> 320 cm3) was associated with greater postoperative neurological loss. Radiation therapy and preoperative embolization were associated with prolonged disease-free survival. There were no local recurrences among the 11 patients who were treated with both modalities. Based on radiographic and clinical assessment, spinopelvic stability was present in 23 of 24 patients at final follow-up. CONCLUSIONS High local and distant recurrence rates associated with sacral GCT suggest the need for careful local and systemic follow-up in managing these patients. Intraoperative preservation of sacral roots was associated with better pain relief, improvement in ambulatory function, and retention of bowel/bladder function in most patients. Fusion and instrumentation of the sacroiliac joint successfully achieved spinopelvic stability in cases deemed clinically unstable. Despite improvement in the management of sacral GCT over 35 years, a need for novel therapies remains. The strategy of combining radiotherapy and embolization merits further study. PMID- 26516663 TI - Targeted epidural catheter injection of polyethylene glycol hydrogel for repair of a spontaneous dural tear: a novel case report. AB - The authors describe the novel approach of using a blunt-tipped catheter to repair a spontaneous dural tear. This case shows an effective percutaneous method of delivering dural sealant through an easily positioned catheter for the treatment of intracranial hypotension due to spontaneous CSF leakage. PMID- 26516664 TI - Isadore Max Tarlov (1905-1977) and the controversial Tarlov cyst: historical perspective. AB - Isadore Max Tarlov, an early neurosurgeon, made several important contributions to the field of spine surgery. He described sacral perineural cysts, now known as Tarlov cysts. Dr. Tarlov also introduced the knee-chest patient position to facilitate exposure and hemostasis in lumbar surgery. In addition, he developed the use of fibrin glue in nerve repair. His book on mechanisms of spinal compression was published in 1957. He published a book of essays titled Principles of Parsimony in Medical Practice that remains highly relevant in today's medical world. PMID- 26516665 TI - "Dinosaur spine" in ankylosing spondylitis: case illustration. PMID- 26516666 TI - Stereotactic radiosurgery for metastasis to the craniovertebral junction preserves spine stability and offers symptomatic relief. AB - OBJECT Metastatic disease to the craniovertebral junction (CVJ) is rare but presents unique management challenges. To date, studies on using stereotactic radiosurgery (SRS) for CVJ metastases have been limited to case reports and small case series. The aim of this analysis was to evaluate the utility of SRS in the management of these secondary lesions. METHODS Clinical and radiological information from the charts of 25 patients with metastatic disease of the CVJ who were treated with SRS between 2005 and 2013 at the Stanford CyberKnife Center were retrospectively reviewed. RESULTS Seven male and 18 female patients with a median age of 58 years (range 34-94 years) were identified. The most common primary tumors were breast cancer (n = 5) and non-small cell lung cancer (n = 5), and the most frequent symptom was neck pain (n = 17). The average tumor volume treated was 15.9 cm3 (range 0.16-54.1 cm3), with a mean marginal radiation dose of 20.3 Gy (range 15-25.5 Gy). The median follow-up was 18 months (range 1-81 months), though 1 patient was lost to follow-up. SRS provided radiographic tumor stability in over 80% of patients, offered pain alleviation in nearly two-thirds of patients, and produced no serious complications. Moreover, SRS preserved spinal stability in all but 1 patient, in whom pre-SRS stability was established. There was no evidence of radiation toxicity in the patient population. Median survival was 28 months (range 2-81 months), with survival of 13.3% at 5 years. CONCLUSIONS In the absence of unstable pathological fracture and spinal cord compression, metastatic tumors of the CVJ can be safely and effectively treated with SRS. This treatment option offers palliative pain relief and can halt tumor progression with only a low risk of complications or spinal instability. PMID- 26516667 TI - Treatment of isolated cervical facet fractures: a systematic review. AB - OBJECT In this clinically based systematic review of cervical facet fractures, the authors' aim was to determine the optimal clinical care for patients with isolated fractures of the cervical facets through a systematic review. METHODS A systematic review of nonoperative and operative treatment methods of cervical facet fractures was performed. Reduction and stabilization treatments were compared, and analysis of postoperative outcomes was performed. MEDLINE and Scopus databases were used. This work was supported through support received from the Association for Collaborative Spine Research and AOSpine North America. RESULTS Eleven studies with 368 patients met the inclusion criteria. Forty-six patients had bilateral isolated cervical facet fractures and 322 had unilateral isolated cervical facet fractures. Closed reduction was successful in 56.4% (39 patients) and 63.8% (94 patients) of patients using a halo vest and Gardner-Wells tongs, respectively. Comparatively, open reduction was successful in 94.9% of patients (successful reduction of open to closed reduction OR 12.8 [95% CI 6.1 26.9], p < 0.0001); 183 patients underwent internal fixation, with an 87.2% success rate in maintaining anatomical alignment. When comparing the success of patients who underwent anterior versus posterior procedures, anterior approaches showed a 90.5% rate of maintenance of reduction, compared with a 75.6% rate for the posterior approach (anterior vs posterior OR 3.1 [95% CI 1.0-9.4], p = 0.05). CONCLUSIONS In comparison with nonoperative treatments, operative treatments provided a more successful outcome in terms of failure of treatment to maintain reduction for patients with cervical facet fractures. Operative treatment appears to provide superior results to the nonoperative treatments assessed. PMID- 26516668 TI - Unilateral C-1 posterior arch screws and C-2 laminar screws combined with a 1 side C1-2 pedicle screw system as salvage fixation for atlantoaxial instability. AB - OBJECT Atlantoaxial instability often requires surgery, and the current methods for fixation pose some risk to vascular and neurological tissues. Thus, new effective and safer methods are needed for salvage operations. This study sought to assess unilateral C-1 posterior arch screws (PASs) and C-2 laminar screws (LSs) combined with 1-side C1-2 pedicle screws (PSs) for posterior C1-2 fixation using biomechanical testing with bilateral C1-2 PSs in a cadaveric model. METHODS Six fresh ligamentous human cervical spines were evaluated for their biomechanics. The cadaveric specimens were tested in their intact condition, stabilization after injury, and after injury at 1.5 Nm of pure moment in 6 directions. The 3 groups tested were bilateral C1-2 PSs (Group A); left side C1-2 PSs with an ipsilateral C-1 PAS + C-2 laminar screw (Group B); and left side C1-2 PSs with a contralateral C-1 PAS + C-2 LS (Group C). During the testing, angular motion was measured using a motion capture platform. Data were recorded, and statistical analyses were performed. RESULTS Biomechanical testing showed that there was no significant difference among the stabilities of these fixation systems in flexion-extension and rotation control. In left lateral bending, the bilateral C1-2 PS group decreased flexibility by 71.9% compared with the intact condition, the unilateral C1-2 PS and ipsilateral PAS+LS group decreased flexibility by 77.6%, and the unilateral C1-2 PS and contralateral PAS+LS group by 70.0%. Each method significantly decreased C1-2 movements in right lateral bending compared with the intact condition, and the bilateral C1-2 PS system was more stable than the C1-2 PS and contralateral PAS+LS system (p = 0.036). CONCLUSIONS A unilateral C-1 PAS + C-2 LS combined with 1-side C-1 PSs provided the same acute stability as the PS, and no statistically significant difference in acute stability was found between the 2 screw techniques. These methods may constitute an alternative method for posterior atlantoaxial fixation. PMID- 26516669 TI - Changing Patterns of Organ Donation: Brain Dead Donors Are Not Being Lost by Donation After Circulatory Death. AB - The clinical characteristics of all New England Organ Bank (NEOB) donors after circulatory death (DCD) donors were analyzed between July 1, 2009, and June 30, 2014. During that 5-year period, there were 494 authorized medically suitable potential DCDs that the NEOB evaluated, constituting more than 30% of deceased donors coordinated annually by the NEOB. From the cohort of 494 authorized potential DCDs, 331 (67%) became actual DCD, 82 (17%) were attempted as a DCD but did not progress to donation, and 81 (16%) transitioned to an actual donor after brain death (DBD). Two hundred seventy-six organs were transplanted from the 81 donors that transitioned from DCD to actual DBD, including 24 heart, 70 liver, 12 single and 14 bilateral lung, and 12 pancreas transplants. When patients with devastating brain injury admitted to the intensive care units are registered donors, the Organ Procurement Organization staff should share the patient's donation decision with the health care team and the patient's family, as early as possible after the comfort measures only discussion has been initiated. The experience of the NEOB becomes an important reference of the successful implementation of DCD that enables an expansion of deceased donation (inclusive of DBD). PMID- 26516670 TI - Promoting Organ Donor Registries Through Public Education: What Is the Cost of Securing Organ Donors? AB - BACKGROUND: Transplant medicine's impact on America's public health is seriously limited by acute shortage of transplantable organs. Consequently, the United Sates has witnessed considerable investment in the promotion of organ donor registries. Although there is no evidence to support that donor registry promotion alleviates organ shortage, this belief continues to drive investments into registry promotion. In this study, return on investment in donor registry promotion was examined using cost-outcomes analysis. METHODS: Cost of promoting the donor registry was estimated in US dollars whereas the outcome was measured as the number of individuals who join the registry (registrants) and their value in terms of organ donors. The study was conducted from the perspective of a regional Organ Procurement Organization (OPO). Costs were directly obtained from the OPO. The number of new registrants was obtained from the OPO and the departments of motor vehicles that maintain the donor registry. The value of registrants in terms of organ donors was computed based on a registrant's age dependent risk of dying and age-dependent probability of becoming an organ donor. RESULTS: Six thousand seven hundred eight individuals joined the organ donor registry (95% confidence interval [95% CI], 5429-7956) at a cost of $455 per registrant (95% CI, US $383-US $562). These individuals result in 4.2 present-day donors (95% CI, 2.5-6.6) at a cost of US $726 000 (95% CI, US $462000-US $1.2 million). CONCLUSIONS: Because the cost per registrant and cost per donor is less than society's willingness to pay, donor registry promotion offers positive return on investment. Investment in registry promotion should at the minimum be maintained at current levels. PMID- 26516671 TI - Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Human C1q Deficiency: The Karolinska Experience. AB - BACKGROUND: Human C1q deficiency is associated with systemic lupus erythematosus (SLE) and increased susceptibility to severe bacterial infections. These patients require extensive medical therapy and some develop treatment-resistant disease. Because C1q is produced by monocytes, it has been speculated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) may cure this disorder. METHODS: We have so far treated 5 patients with C1q deficiency. In 3 cases, SLE symptoms remained relatively mild after the start of medical therapy, but 2 patients developed treatment-resistant SLE, and we decided to pursue treatment with allo-HSCT. For this purpose, we chose a conditioning regimen composed of treosulfan (14 g/m) and fludarabine (30 mg/m) started on day -6 and given for 3 and 5 consecutive days, respectively. Thymoglobulin was given at a cumulative dose of 8 mg/kg, and graft-versus-host disease prophylaxis was composed of cyclosporine and methotrexate. RESULTS: A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms. The boy developed posttransplant lymphoproliferative disease, which resolved after treatment with rituximab and donor lymphocyte infusion. Unfortunately, donor lymphocyte infusion induced severe cortisone-resistant gastrointestinal graft-versus-host disease, and the patient died from multiple organ failure 4 months after transplantation. The girl is doing well 33 months after transplantation, and clinically, all signs of SLE have resolved. CONCLUSIONS: Allo-HSCT can cure SLE in human C1q deficiency and should be considered early in subjects resistant to medical therapy. PMID- 26516672 TI - Risky Business-Is the RoCKeT Ready to fly? PMID- 26516673 TI - A High Comorbidity Score Should Not be a Contraindication for Kidney Transplantation. AB - BACKGROUND: Currently, potential kidney transplant patients more often suffer from comorbidities. The Charlson Comorbidity Index (CCI) was developed in 1987 and is the most used comorbidity score. We questioned to what extent number and severity of comorbidities interfere with graft and patient survival. Besides, we wondered whether the CCI was best to study the influence of comorbidity in kidney transplant patients. METHODS: In our center, 1728 transplants were performed between 2000 and 2013. There were 0.8% cases with missing values. Nine pretransplant comorbidity covariates were defined: cardiovascular disease, cerebrovascular accident, peripheral vascular disease, diabetes mellitus, liver disease, lung disease, malignancy, other organ transplantation, and human immunodeficiency virus positivity. The CCI used was unadjusted for recipient age. The Rotterdam Comorbidity in Kidney Transplantation score was developed, and its influence was compared to the CCI. Kaplan-Meier analysis and multivariable Cox proportional hazards analysis, corrected for variables with a known significant influence, were performed. RESULTS: We noted 325 graft failures and 215 deaths. The only comorbidity covariate that significantly influenced graft failure censored for death was peripheral vascular disease. Patient death was significantly influenced by cardiovascular disease, other organ transplantation, and the total comorbidity scores. Model fit was best with the Rotterdam Comorbidity in Kidney Transplantation score compared to separate comorbidity covariates and the CCI. In the population with the highest comorbidity score, 50% survived more than 10 years. CONCLUSIONS: Despite the negative influence of comorbidity, patient survival after transplantation is remarkably good. This means that even patients with extensive comorbidity should be considered for transplantation. PMID- 26516674 TI - Is Donor Service Area Market Competition Associated With Organ Procurement Organization Performance? AB - BACKGROUND: Organ procurement organizations (OPOs) are currently evaluated on donation rates and number of organs per donor. However, there is significant variability in market characteristics which affect transplant programs' donor organ acceptance practices and OPOs' ability to successfully place higher risk organs. The impact of transplant market characteristics on OPO performance metrics has not been evaluated. METHODS: The OPO performance measures were correlated annually with the Herfindahl Hirschman Index, a standard measure of market competition for centers within the OPO donor service areas from 2003 to 2011. RESULTS: More competitive donor service areas were associated with increased number of donors (P = 0.01) and eligible deaths (P < 0.001). Market competition was associated with increased use of high Donor Risk Index for kidney (P = 0.03) and liver (P = 0.01) allografts. The OPOs with increased competition in liver transplant also were noted to have a higher donor conversion rate (P < 0.001), more donors per million population (P < 0.001), and a higher utilization rate for liver allografts (P = 0.007). CONCLUSIONS: These data suggest that proposals to increase district size to increase competition among transplant programs could result in improved organ utilization over time by incentivizing the use of marginal donor organs and increasing access to transplantation. PMID- 26516675 TI - Frailty and Its Impact on Posttransplant Outcomes: Quantification of the "Eyeball Test". PMID- 26516676 TI - The Prevalence and Prognostic Significance of Frailty in Patients With Advanced Heart Failure Referred for Heart Transplantation. AB - BACKGROUND: Frailty is a clinically recognized syndrome of decreased physiological reserve. The heightened state of vulnerability in these patients confers a greater risk of adverse outcomes after even minor stressors. Our aim was to assess the prevalence and prognostic significance of the frailty phenotype in patients referred for heart transplantation. METHODS: Consecutive patients referred or on the waiting list for heart transplantation from March 2013 underwent frailty assessment. Frailty was defined as a positive response to 3 or more of the following 5 components: weak grip strength, slowed walking speed, poor appetite, physical inactivity, and exhaustion. In addition, markers of disease severity were obtained, and all patients underwent cognitive (Montreal Cognitive Assessment) and depression (Depression in Medical Illness-10) screening. RESULTS: One hundred twenty patients (83 men:37 women; age, 53 +/- 12 years, range, 16-73 years; left ventricular ejection fraction, 27 +/- 14%) underwent frailty assessment. Thirty-nine of 120 patients (33%) were assessed as frail. Frailty was associated with New York Heart Association class IV heart failure, lower body mass index, elevated intracardiac filling pressures, lower cardiac index, anemia, hypoalbuminemia, hyperbilirubinemia, cognitive impairment, and depression (all rho < 0.05). Frailty was independent of age, sex, heart failure duration, left ventricular ejection fraction, or renal function. Frailty was an independent predictor of increased all-cause mortality: 1 year actuarial survival was 79 +/- 5% in the nonfrail group compared with only 54 +/- 9% for the frail group (P < 0.005). CONCLUSIONS: Frailty is prevalent among patients with advanced symptomatic heart failure referred for heart transplantation and is associated with increased mortality. PMID- 26516677 TI - The N- and C-Terminal Domains Differentially Contribute to the Structure and Function of Dystrophin and Utrophin Tandem Calponin-Homology Domains. AB - Dystrophin and utrophin are two muscle proteins involved in Duchenne/Becker muscular dystrophy. Both proteins use tandem calponin-homology (CH) domains to bind to F-actin. We probed the role of N-terminal CH1 and C-terminal CH2 domains in the structure and function of dystrophin tandem CH domain and compared with our earlier results on utrophin to understand the unifying principles of how tandem CH domains work. Actin cosedimentation assays indicate that the isolated CH2 domain of dystrophin weakly binds to F-actin compared to the full-length tandem CH domain. In contrast, the isolated CH1 domain binds to F-actin with an affinity similar to that of the full-length tandem CH domain. Thus, the obvious question is why the dystrophin tandem CH domain requires CH2, when its actin binding is determined primarily by CH1. To answer, we probed the structural stabilities of CH domains. The isolated CH1 domain is very unstable and is prone to serious aggregation. The isolated CH2 domain is very stable, similar to the full-length tandem CH domain. These results indicate that the main role of CH2 is to stabilize the tandem CH domain structure. These conclusions from dystrophin agree with our earlier results on utrophin, indicating that this phenomenon of differential contribution of CH domains to the structure and function of tandem CH domains may be quite general. The N-terminal CH1 domains primarily determine the actin binding function whereas the C-terminal CH2 domains primarily determine the structural stability of tandem CH domains, and the extent of stabilization depends on the strength of inter-CH domain interactions. PMID- 26516678 TI - Development of Immunochromatographic Assay for Identification of Organophosphate Pesticides in Environmental Samples. AB - Microtiter plate enzyme linked immunoassay (ELISA) experiments in competitive format were performed utilizing polyclonal antibody for establishing a detection system for organophosphate pesticides. IC50 value of and limit of detection (LOD) value was determined by standard inhibition curve and value obtained were 0.05 MUgmL(-1) and 0.001 MUgmL(-1), respectively. Specificity of antibody was investigated with different organophosphate pesticides. Immunochromatographic assay (ICA) experiments were also designed in competitive format by making use of immunochromatographic strip which was assembly of three main components: conjugate pad, membrane and adsorbent pad. Membrane was coated with hapten-OVA conjugate (test line) and antirabbit IgG (control line). ICA experiments were performed by employing gold-labeled antibody as a detector reagent which was applied over conjugate pad. Visual detection limit obtained from ICA was 0.5 MUgmL(-1). Major advantage of strip assay was rapid result, i.e., less than 10 min. which makes it suitable for onsite applications. PMID- 26516679 TI - Overcoming drug resistance for tuberculosis. AB - Despite enormous progress, tuberculosis (TB) is still a major global health problem. Poor patients' adherence to the current treatment leads to the emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) strains. While increased numbers of MDR-TB cases can be ascribed to difficulties in treating TB HIV coinfected patients, many studies demonstrated that the emergence of drug resistant TB is clearly linked to misdiagnosis and mismanagement of drug susceptible TB. Therefore, rapid detection and proper treatment are needed globally to both cure TB patients and prevent wide spreading of the disease. This paper provides a survey of the major strategies that have been explored for overcoming drug resistance in TB. PMID- 26516680 TI - Iodide surface decoration: a facile and efficacious approach to modulating the band energy level of semiconductors for high-performance visible-light photocatalysis. AB - We herein report a facile and general approach to modulating the band energy level of semiconductors for visible-light photocatalysis via iodide surface decoration. This strategy enables the wide-band-gap Bi2O2CO3 to possess a continuously tunable band gap and profoundly boosted visible-light photocatalytic performance for dye degradation and NO removal. PMID- 26516681 TI - Photoluminescence quenching of [Ru(bpy)2(atatp)](2+) bound to a condensed DNA matrix. AB - A novel [Ru(bpy)2(atatp)](2+) (bpy=2,2'-bipyridine and atatp=acenaphtheno[1,2-b] 1,4,8,9-tetraazatriphenylene) can induce the condensation of herring sperm DNA to form an orange-red cast film via intercalation and electrostatic attraction. The thus-prepared cast film shows microsecond emission lifetimes and reversible luminescence tuning characteristics by oxygen and nitrogen with an on-off emission intensity ratio of 4.3. The photoluminescence of [Ru(bpy)2(atatp)](2+) bound to a DNA condensed matrix can be quenched by water, dissolved oxygen, copper(II) and ferrocyanide ions. The DNA binding is found to hardly alter the dynamic quenching of [Ru(bpy)2(atatp)](2+) by oxygen at a low DNA-to-Ru(II) molar ratio (r=0.83), allowing [Ru(bpy)2(atatp)](2+) to keep a basically unchanged oxygen quenching constant, as well as endow the photo-induced electron transfer between [Ru(bpy)2(atatp)](2+) and copper(II) cations, and weaken the electrostatic attraction of [Ru(bpy)2(atatp)](2+) with ferrocyanide anions. In addition, the DNA condensation induced by [Ru(bpy)2(atatp)](2+) can protect the DNA oxidative damage against superoxide anion and hydroxyl radical toxicity. The present results could provide a versatile platform for better fabrication of optoelectronic devices. PMID- 26516682 TI - Retroactive modulation of spike timing-dependent plasticity by dopamine. AB - Most reinforcement learning models assume that the reward signal arrives after the activity that led to the reward, placing constraints on the possible underlying cellular mechanisms. Here we show that dopamine, a positive reinforcement signal, can retroactively convert hippocampal timing-dependent synaptic depression into potentiation. This effect requires functional NMDA receptors and is mediated in part through the activation of the cAMP/PKA cascade. Collectively, our results support the idea that reward-related signaling can act on a pre-established synaptic eligibility trace, thereby associating specific experiences with behaviorally distant, rewarding outcomes. This finding identifies a biologically plausible mechanism for solving the 'distal reward problem'. PMID- 26516683 TI - Total colectomy in a gangrenous large bowel due to a rare double closed loop obstruction. AB - INTRODUCTION: Closed loop obstruction is commonly encountered in sigmoid volvulus. When such obstruction becomes fulminant, it is called acute necrotizing colitis. Gangrene of the entire large bowel from the caecum till the distal end of the sigmoid is a rare entity. PRESENTATION OF THE CASE: We present here one such case of necrotizing colitis in a 27 years old gentleman who presented with large bowel obstruction and septic shock. Computed tomography (CT) revealed sigmoid volvulus with ischaemic changes. The rest of the colon was dilated. On laparotomy, a gangrenous sigmoid due to the volvulus was found along with complete gangrene of the proximal bowel from the ileocaecal junction till the volvulus. This was probably due to a double closed loop obstruction, one at the sigmoid volvulus and the second being between a probable competent ileocaecal valve and the proximal end of the volvulus. A total colectomy with an end ileostomy was performed. DISCUSSION: Necrotising colitis involving the entire colon is seldom seen. Large bowel obstruction is a known surgical emergency due to a probable closed loop obstruction due to a competent ileocaecal valve. CONCLUSION: To our knowledge, such gangrene of the entire large bowel due to a sigmoid volvulus and a competent ileocaecal valve has not been reported in literature so far. We also highlight here, the rapid ischaemic changes that follow a closed loop obstruction. In our case the CT has shown ischaemic changes only in the sigmoid. Hence, timely diagnosis and intervention is imperative. PMID- 26516684 TI - Electrochemiluminescence on digital microfluidics for microRNA analysis. AB - Electrochemiluminescence (ECL) is a sensitive analytical technique with great promise for biological applications, especially when combined with microfluidics. Here, we report the first integration of ECL with digital microfluidics (DMF). ECL detectors were fabricated into the ITO-coated top plates of DMF devices, allowing for the generation of light from electrically excited luminophores in sample droplets. The new system was characterized by making electrochemical and ECL measurements of soluble mixtures of tris(phenanthroline)ruthenium(II) and tripropylamine (TPA) solutions. The system was then validated by application to an oligonucleotide hybridization assay, using magnetic particles bearing 21-mer, deoxyribose analogues of the complement to microRNA-143 (miRNA-143). The system detects single nucleotide mismatches with high specificity, and has a limit of detection of 1.5 femtomoles. The system is capable of detecting miRNA-143 in cancer cell lysates, allowing for the discrimination between the MCF-7 (less aggressive) and MDA-MB-231 (more aggressive) cell lines. We propose that DMF-ECL represents a valuable new tool in the microfluidics toolbox for a wide variety of applications. PMID- 26516685 TI - A switched catalysis qualified sealers capped one-step synthesis biocompatibility bimetallic scaffold film for Neu5Acalpha(2-6)Gal beta MP Glycoside specific detection. AB - In this work, a novel label-free biosensor was designed for the sensitive and selective determination of Neu5Acalpha(2-6)Gal beta MP Glycoside using AuPt PPy(polypyrrole) conductive nanocomposite film as the sensor platform. The introduced AuPt-PPy nanocomposite provided a large surface area for the immobilization of Sambucus nigra agglutinis (SNA) through a coupling agent for specifically recognizing analytes and exhibited high electrocatalytic activity toward the reduction of hydrogen peroxide (H2O2) as an analytical signal. Subsequently, to block the non-specific sites of the modified electrode, GOx was employed instead of the usual sealers. Most importantly, in the presence of glucose, these localized GOx further enhanced the electrochemical signal, which was achieved by the efficient catalysis of glucose. This study is the first that demonstrates the specific detection of Neu5Acalpha(2-6)Gal beta MP Glycoside using AuPt-PPy as the electrocatalytic. Under optimal conditions, the electrochemical biosensor exhibited a wide linear range of 0.01 pgmL(-1)-800 ngmL(-1) with a low detection limit of 0.003 pgmL(-1) (S/N=3), due to the affinity between SNA and Neu5Acalpha(2-6)Gal beta MP Glycoside. Therefore, the co catalysis signal amplification approach has considerable potential in clinical applications and is suitable for the quantification of other biomarkers. PMID- 26516686 TI - Nitrated carbon nanoblisters for high-performance glucose dehydrogenase bioanodes. AB - Recently, many strategies are being explored for efficiently wiring glucose dehydrogenase (GDh) enzymes capable of glucose (fuel) oxidation. For instance, the use of GDh NAD(+)-dependent for glucose oxidation is of great interest in biofuel cell technology because the enzyme are unaffected by the presence of molecular oxygen commonly present in electrolyte. Here we present the fabrication of flexible carbon fibers modified with nitrated carbon nanoblisters and their application as high-performance GDh bioanodes. These bioelectrodes could electro oxidize glucose at -360 mV (vs. Ag/AgClsat) in the presence of a molecular oxygen saturated electrolyte with current densities higher than 1.0 mAcm(-2) at 0.0 V. It is corroborated by open circuit potential, where a potential stabilization occurs at -150 mV in a long term stability current-transient experiment. This value is in agreement with the quasi-steady current obtained at very low scan rate (0.1 mVs(-1)), where the onset potential for glucose oxidation is -180 mV. X ray photoelectron spectroscopy and scanning electron microscopy revealed that the nitrated blisters and edge-like carbon structures, enabling highly efficient enzyme immobilization and low overpotential for electron transfer, allowing for glucose oxidation with potential values close to the thermodynamic cofactor. PMID- 26516687 TI - Novel fabrication of immunochromatographic assay based on up conversion phosphors for sensitive detection of clenbuterol. AB - A novel and ultra sensitive immunochromatographic assay sensor (ICA) based on up conversion phosphor (UCP) for quantitative detection of clenbuterol (CL) was developed. Monoclonal antibody against CL was labeled with UCP beads. The detection strategy is based on competitive immunoreaction between CL antibodies conjugated to UCP beads and CL or CL antigen on the UCP-ICA sensor. It enables ultra sensitive detection of CL in one single test without complicated sample preparation. Sensing results can be obtained within 10 min. Under optimized conditions, visual limit of detection (vLOD) of UCP-ICA for CL was 0.1 ng/mL. Calculated LOD (cLOD) for CL, as low as 0.01 ng/mL, could be achieved with the UCP-ICA sensor. Recoveries of CL in various sample matrixes ranged from 73.0% to 92.2% and relative standard deviations (RSD) were below 12%. The assay was evaluated with spiked and real samples and the results were compared with liquid chromatography-tandem mass. The developed novel assay method based on UCP could be a potential alternative format for on site and rapid detection of CL as well as other illegal drugs. PMID- 26516688 TI - Luminescent silica nanoparticles for sensing acetylcholinesterase-catalyzed hydrolysis of acetylcholine. AB - This work highlights the H-function of Tb(III)-doped silica nanoparticles in aqueous solutions of acetic acid as a route to sense acetylcholinesterase catalyzed hydrolysis of acetylcholine (ACh). The H-function results from H(+) induced quenching of Tb(III)-centered luminescence due to protonation of Tb(III) complexes located close to silica/water interface. The H-function can be turned on/switched off by the concentration of complexes within core or nanoparticle shell zones, by the silica surface decoration and adsorption of both organic and inorganic cations on silica surface. Results indicate the optimal synthetic procedure for making nanoparticles capable of sensing acetic acid produced by enzymatic hydrolysis of acetylcholine. The H-function of nanoparticles was determined at various concentrations of ACh and AChE. The measurements show experimental conditions for fitting the H-function to Michaelis-Menten kinetics. Results confirm that reliable fluorescent monitoring AChE-catalyzed hydrolysis of ACh is possible through the H-function properties of Tb(III)-doped silica nanoparticles. PMID- 26516689 TI - Self-Assembled Infrapatellar Fat-Pad Progenitor Cells on a Poly-epsilon Caprolactone Film For Cartilage Regeneration. AB - Cartilage defects resulting from osteoarthritis (OA) or physical injury can severely reduce the quality of life for sufferers. Current treatment options are costly and not always effective in producing stable hyaline cartilage. Here we investigated a new treatment option that could potentially repair and regenerate damaged cartilage tissue. This novel approach involves the application of infrapatellar fat-pad derived chondroprogenitor cells onto a mechanically stable biodegradable polymer film that can be easily implanted into a defect site. Poly epsilon-caprolactone (PCL) films were fabricated via solvent casting in either acetone or chloroform. The hydrophobicity, mechanical properties, and surface morphology of the films were examined. Progenitor cells from infrapatellar fat pad were isolated, expanded, and then seeded onto the films. The cells were allowed to self-assemble on films, and these were then cultured in a chemically defined chondrogenic media for 28 days. The self-assembled tissue was characterized via histological staining, gene expression analysis, immunohistochemistry, and biochemical analysis. Chondrogenic differentiation was induced to generate a cartilaginous matrix upon the films. Despite differences between in the appearance, surface morphology, and mechanical properties of the films cast in chloroform or acetone, both methods produced tissues rich in sulfated glycosaminoglycan and collagen, although the extracellular matrix produced on chloroform-cast films appeared to contain more collagen type II and less collagen type I than acetone-cast films. These self-assembled constructs have the potential to be implanted into defect sites as a potential treatment for cartilage defect regeneration. PMID- 26516690 TI - Hyaluronic Acid Gel Re-Injection for Enophthalmos Correction in Silent Sinus Syndrome. AB - A 43-year-old female with residual enophthalmos following functional endoscopic surgery (FESS) due to silent sinus syndrome (SSS) was initially successfully treated with a 2-ml intraorbital injection of hyaluronic acid gel (HAG). The enophthalmos partially recurred 22 months after the injection. HAG was re injected with good functional and cosmetic results. Functional (kinetic) computed tomography was performed to visualize HAG distribution in the orbit. PMID- 26516691 TI - Differentiating Sitting and Lying Using a Thigh-Worn Accelerometer. AB - A triaxial accelerometer worn on the thigh can provide information on the angle of rotation of the thigh. These data may be used to estimate periods of lying versus sitting. PURPOSE: To develop and test a classification algorithm to identify sedentary events as either lying or sitting events using a thigh-worn, triaxial accelerometer. METHODS: Seven-day free-living activity from 14 sedentary workers was recorded using the activPAL3TM monitor. Participants recorded when they went to bed and when they got up in a diary. All "in-bed" sedentary events were assumed to be lying and all "not-in-bed" sedentary events as sitting. An algorithm computed the angle of rotation of the y-axis, which was used to detect orientation of the thigh. Crossing a rotational threshold in the transverse plane of +/-65 degrees was used to classify a sedentary event as lying. The classification accuracy of the algorithm was compared with self-reported classification from the diary. RESULTS: The algorithm classified 96.7% of the sedentary time "in bed" (sensitivity) as lying and 92.9% of the time "not in bed" as not lying (specificity). CONCLUSIONS: Triaxial accelerometer data recorded from a single site on the thigh can be used to classify sedentary events as sitting and lying. The automated method developed in this study will allow objective measurement of diurnal lying time and that while sleeping without relying on self-report. This will help advance the understanding of the impact of different types of sedentary behaviors on various health outcomes. PMID- 26516692 TI - Computed tomography parameters can be used as predictive markers for the improvement of renal function in patients with retroperitoneal fibrosis. AB - OBJECTIVES: To discover the relationship between computed tomography (CT) parameters of retroperitoneal soft tissue of untreated retroperitoneal fibrosis patients and the variation of renal function after treatment. METHODS: Data were collected retrospectively from 42 patients with established diagnosis of retroperitoneal fibrosis, at the Department of Rheumatology in Peking University First Hospital from May 2009 to April 2015. The demographic information, clinical characteristics, laboratory data, treatment and general therapeutic response were collected. The CT parameters such as radial lines, Hounsfield unit values, radiographic classification at baseline before the initiation of therapy were measured. Then the correlations between baseline CT parameters and clinical data were analysed. RESULTS: The Hounsfield unit values of venous phase and delayed phase at baseline were negatively correlated with the change of estimated glomerular filtration rate (eGFR) at the 12th month after the initiation of medications. The baseline transverse diameters of the retroperitoneal soft tissue were larger in the group of eGFR <60 ml/min/1.73 m2 compared with the group of eGFR >= 60 ml/min/1.73 m2 at the 12th month, while the vertical diameters and maximum cross-section thickness were not. The baseline transverse diameters were also significantly correlated with the duration of intubation. CONCLUSIONS: The baseline Hounsfield unit values and baseline transverse diameters of soft tissue of untreated retroperitoneal fibrosis patients may be used to predict the renal function after 12 months of therapy. PMID- 26516694 TI - Prevalence of diabetes and impaired fasting glucose in Costa Rica: Costa Rican National Cardiovascular Risk Factors Survey, 2010. AB - BACKGROUND: The projected rising prevalence of diabetes and impaired fasting glucose (IFG) in developing countries warrants careful monitoring. The aim of this study was to present the results of the Costa Rican National Cardiovascular Risk Factors Surveillance System, which provides the first national estimates of diabetes and IFG prevalence among adults in Costa Rica. METHODS: A cross sectional survey of 3653 non-institutionalized adults aged >=20 years (87.8% response rate) following the World Health Organization STEPwise approach was built on a probabilistic sample of the non-institutionalized population during 2010. Known diabetes was defined as self-reported diagnosis, the use of insulin, or hypoglycemic oral treatment as consequence of diabetes during at least the previous 2 weeks before the survey. Unknown diabetes was defined no self-reported diabetes but with venous blood concentrations of fasting glucose >125 mg/dL determined by laboratory testing. Impaired fasting glucose was defined as fasting glucose between 100 and 125 mg/dL among those without diabetes. The prevalence of diabetes and IFG prevalence was estimated according gender, body mass index (BMI), waist circumference (WC), educational level, and physical activity level. RESULTS: Overall diabetes prevalence was 10.8% (9.5% known and 1.3% unknown diabetes) and IFG prevalence was 16.5%. The prevalence of known diabetes was higher among women >65 years compared with men of the same age group. Both known and unknown diabetes were significantly associated with higher BMI, increased WC, and low education level (P = 0.01). CONCLUSIONS: The prevalence of diabetes and IFG in Costa Rica is comparable to that in developed countries and indicates an urgent need for effective preventive interventions. PMID- 26516695 TI - CKMT1 and NCOA1 expression as a predictor of clinical outcome in patients with advanced-stage head and neck squamous cell carcinoma. AB - BACKGROUND: We studied the association between the expression of a subset of previously identified genes and clinical outcome in patients with head and neck cancer. METHODS: We analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) the expression of 89 genes in tumor biopsies from stage III to IVa/b chemotherapy treated patients (n = 46). Two additional cohorts analyzed by RNAseq (The Cancer Genome Atlas [TCGA] project; n = 371) or immunohistochemistry (IHC; n = 73) were used to validate results. RESULTS: Thirty genes were associated with local-recurrence or progression-free survival. The best multi-gene decision-tree model to predict local recurrence included nuclear receptor coactivator 1 (NCOA1) and serum-amyloid A2 (SAA2) expression, whereas the best model to predict disease recurrence included creatine kinase mitochondrial 1 (CKMT1) and metal-regulatory transcription factor 1 (MTF1). Both models were associated with cancer-specific survival. Results were confirmed analyzing the RNAseq data included in the TCGA project. CKMT1 and NCOA1 were identified as independent risk factors for survival in an independent cohort analyzed by immunohistochemistry. CONCLUSION: CKMT1 and NCOA1 expression has prognostic significance in advanced-stage head and neck carcinoma. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1392-E1403, 2016. PMID- 26516696 TI - Ex Vivo Assay of Electrical Stimulation to Rat Sciatic Nerves: Cell Behaviors and Growth Factor Expression. AB - Neurite outgrowth and axon regeneration are known to benefit from electrical stimulation. However, how neuritis and their surroundings react to electrical field is difficult to replicate by monolayer cell culture. In this work freshly harvested rat sciatic nerves were cultured and exposed to two types of electrical field, after which time the nerve tissues were immunohistologically stained and the expression of neurotrophic factors and cytokines were evaluated. ELISA assay was used to confirm the production of specific proteins. All cell populations survived the 48 h culture with little necrosis. Electrical stimulation was found to accelerate Wallerian degeneration and help Schwann cells to switch into migratory phenotype. Inductive electrical stimulation was shown to upregulate the secretion of multiple neurotrophic factors. Cellular distribution in nerve tissue was altered upon the application of an electrical field. This work thus presents an ex vivo model to study denervated axon in well controlled electrical field, bridging monolayer cell culture and animal experiment. It also demonstrated the critical role of electrical field distribution in regulating cellular activities. PMID- 26516697 TI - Inflammatory hepatocellular adenomas developed in the setting of chronic liver disease and cirrhosis. AB - Hepatocellular adenoma is considered to occur exclusively in non-fibrotic livers. It is a heterogeneous entity and a molecular classification is now widely accepted. The most frequent hepatocellular adenoma subtype, namely inflammatory adenoma, harbor somatic activating mutations of genes involved in the interleukin 6 pathway that lead to high C-reactive protein and serum amyloid A expression. The aim of our study was to investigate a series of benign hepatocellular neoplasms developed on cirrhotic livers and characterized by an unequivocal histological diagnosis. We performed a clinical, pathological, and molecular study of 10 benign hepatocellular neoplasms developed in three patients with cirrhosis. Markers allowing hepatocellular adenoma classification were assessed by quantitative real-time PCR and immunohistochemistry. Samples were sequenced for CTNNB1, HNF1A, IL6ST, GNAS, STAT3, and TERT (promoter) mutations. A control series of 32 classical macronodules developed in cirrhosis related to various etiologies was screened by immunohistochemistry and gene sequencing. The three patients had cirrhosis related to metabolic syndrome and/or alcohol intake; two had a single tumor, while the third developed more than 30 lesions. Microscopic examination showed well-differentiated neoplasms sharing features with inflammatory adenoma including inflammatory infiltrates, sinusoidal dilatation, and dystrophic vessels. Sequencing revealed classical hotspot somatic mutations (IL6ST, n=8; STAT3, n=1; and GNAS, n=1) known to be responsible for IL-6/JAK/STAT pathway activation. Two classical high-grade macronodules demonstrated high serum amyloid A and/or C-reactive protein expression, without gene mutations. Altogether, our findings support the existence of rare inflammatory adenoma developed in cirrhosis. PMID- 26516698 TI - Loss of histone H3 lysine 36 trimethylation is associated with an increased risk of renal cell carcinoma-specific death. AB - Sequencing of clear cell renal cell carcinomas identified loss-of-function mutations of SETD2, a gene that encodes a nonredundant methytransferase responsible for histone H3 lysine 36 trimethylation (H3K36me3), and H3K36me3 is progressively deregulated in metastases. However, few data exist regarding the impact of loss of H3K36me3 on outcomes. We assessed the association of SETD2 DNA alterations and mRNA expression with overall survival using The Cancer Genome Atlas clear cell renal carcinoma data (N=411). Additionally, we assessed the association of H3K36 loss of methylation with renal cell carcinoma-specific survival and progression-free survival using an independent cohort at Mayo Clinic (N=1454). Overall survival, renal cell carcinoma-specific survival and progression-free survival were estimated using Kaplan-Meier method, and differences in survival across groups was compared using Cox regression models, adjusted for age and the Mayo SSIGN (stage, size, grade, and necrosis) score. In The Cancer Genome Atlas cohort, SETD2 DNA alterations or mRNA expression was not associated with overall survival (P>0.05). In the Mayo cohort, patients with H3K36me3-negative tumors were two times more likely to experience renal cell carcinoma-specific death than patients with H3K36me3-positive tumors (hazard ratio, 2.23; 95% confidence interval, 1.77-2.81); P<0.0001. After stratifying for the SSIGN score, H3K36me3-negative tumors in the low-risk SSIGN group had a worse renal cell carcinoma-specific survival (hazard ratio, 2.18; 95% confidence interval, 1.09-4.36); P=0.03. Although SETD2 DNA and mRNA alterations are not associated with overall survival, we provide evidence that deregulation of the H3K36me3 axis is associated with a higher risk of renal cell carcinoma-specific death. This association remains significant after stratifying for the SSIGN score, particularly among those patients with low-risk tumors. PMID- 26516699 TI - Changes in microRNA (miRNA) expression during pancreatic cancer development and progression in a genetically engineered KrasG12D;Pdx1-Cre mouse (KC) model. AB - Differential expression of microRNAs (miRNAs) has been demonstrated in various cancers, including pancreatic cancer (PC). Due to the lack of tissue samples from early-stages of PC, the stage-specific alteration of miRNAs during PC initiation and progression is largely unknown. In this study, we investigated the global miRNA expression profile and their processing machinery during PC progression using the KrasG12D;Pdx1-Cre (KC) mouse model. At 25 weeks, the miRNA microarray analysis revealed significant downregulation of miR-150, miR-494, miR-138, miR 148a, miR-216a, and miR-217 and upregulation of miR-146b, miR-205, miR-31, miR 192, and miR-21 in KC mice compared to controls. Further, expression of miRNA biosynthetic machinery including Dicer, Exportin-5, TRKRA, and TARBP2 were downregulated, while DGCR8 and Ago2 were upregulated in KC mice. In addition, from 10 to 50 weeks of age, stage-specific expression profiling of miRNA in KC mice revealed downregulation of miR-216, miR-217, miR-100, miR-345, miR-141, miR 483-3p, miR-26b, miR-150, miR-195, Let-7b and Let-96 and upregulation of miR-21, miR-205, miR-146b, miR-34c, miR-1273, miR-223 and miR-195 compared to control mice. Interestingly, the differential expression of miRNA in mice also corroborated with the miRNA expression in human PC cell lines and tissue samples; ectopic expression of Let-7b in CD18/HPAF and Capan1 cells resulted in the downregulation of KRAS and MSST1 expression. Overall, the present study aids an understanding of miRNA expression patterns during PC pathogenesis and helps to facilitate the identification of promising and novel early diagnostic/prognostic markers and therapeutic targets. PMID- 26516700 TI - Chemical probing of HER2-amplified cancer cells identifies TORC2 as a particularly effective secondary target for combination with lapatinib. AB - The clinical impact of HER2 inhibitors in the treatment of HER2-amplified breast cancers has been largely confined to chemotherapy combination regimens, since HER2 inhibitors appear to have very modest efficacies by themselves. This is due to the resilient nature of the functionally relevant HER2-HER3 tumor driver, bidirectionally linked with downstream PI3K/Akt pathway signaling, which can break through the inhibitory effects of most current HER2 or HER3 targeting therapies. A vertical combination approach targeting HER2 and a downstream pathway is a highly rational strategy for much more effective targeted therapy of this disease. However the importance of these downstream pathways in many human tissues and cells significant limits their usefulness as secondary targets by narrowing the therapeutic index of such combination therapies. The secondary target that can afford the highest potential for clinical translation is the one with the highest synergy against tumor cells in combination with HER2-inhibition, allowing the widest therapeutic index for clinical translation. We conducted a comparative analysis of such secondary targets in combination with the HER2 inhibitor lapatinib and find that the inhibition of mTor affords the highest degree of synergy. In further dissecting the individual roles of TORC1 and TORC2 complexes using pharmacologic and genetic tools, we find that it is specifically the inactivation of TORC2 that most synergistically enhances the efficacy of lapatinib. Although inhibitors that selectively target TORC2 are not currently available, these data make a compelling case for their development. PMID- 26516701 TI - Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis. AB - Grifolin, a secondary metabolite isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens, has been reported by us and others to display potent antitumor effects. However, the molecular target of grifolin has not been identified and the underlying mechanism of action is not fully understood. Here, we report that the ERK1/2 protein kinases are direct molecular targets of grifolin. Molecular modeling, affinity chromatography and fluorescence quenching analyses showed that grifolin directly binds to ERK1/2. And in vitro and ex vivo kinase assay data further demonstrated that grifolin inhibited the kinase activities of ERK1/2. We found that grifolin suppressed adhesion, migration and invasion of high-metastatic cancer cells. The inhibitory effect of grifolin against tumor metastasis was further confirmed in a metastatic mouse model. We found that grifolin decreased phosphorylation of Elk1 at Ser383, and the protein as well as the mRNA level of DNMT1 was also down-regulated. By luciferase reporter and ChIP assay analyses, we confirmed that grifolin inhibited the transcription activity of Elk1 as well as its binding to the dnmt1 promoter region. Moreover, we report that significant increases in the mRNA levels of Timp2 and pten were induced by grifolin. Thus, our data suggest that grifolin exerts its anti-tumor activity by epigenetic reactivation of metastasis inhibitory-related genes through ERK1/2-Elk1-DNMT1 signaling. Grifolin may represent a promising therapeutic lead compound for intervention of cancer metastasis, and it may also be useful as an ERK1/2 kinase inhibitor as well as an epigenetic agent to further our understanding of DNMT1 function. PMID- 26516702 TI - MicroRNA-15a/16-1 cluster located at chromosome 13q14 is down-regulated but displays different expression pattern and prognostic significance in multiple myeloma. AB - MiRNA-15a/16-1 cluster located at chromosome 13q14 has been confirmed to regulate critical genes associated with cell proliferation, apoptosis and drug resistance in multiple myeloma (MM). However, little is known about their expression pattern and prognostic value in MM patients. In this study, we have analyzed the expression levels of miR-15a/16-1 in 117 MM patients (90 newly diagnosed, 11 relapsed and 16 remission patients) and 19 health donors (HDs) by quantitative real-time PCR. Our results indicated that the expression levels of miR-15a and 16 1 were down-regulated in newly diagnosed MM patients as compared to HDs (P = 0.025; P < 0.001) and independent of del(13q14). Downregulation of miR-15a was significantly associated with disease progression and poor prognosis while miR-16 1 seemed to be a good diagnostic marker to distinguish MM from HDs with area under the curve (AUC) of 0.864, sensitivity of 100% and specificity of 73%. Furthermore, patients with miR-15a < 2.35 (low expression group) had significantly shorter PFS (P < 0.001) and OS (P < 0.001). After adjustment of the established prognostic variables including del(13q), del(17p), amp(1q21) and high risk genetic abnormality, low miR-15a expression (<2.35) was still a powerful independent predictor for PFS (P = 0.008) and OS (P = 0.038). In addition, miR 15a combined with high beta2-MG and high risk genetic abnormality can further identify the high-risk subpopulations. Therefore, our data suggest that the expression patterns of miR-15a/16-1 are different in MM patients, and miR-15a seems to be linked with disease progression and prognosis while miR-16-1 acts as a valuable diagnostic marker. PMID- 26516704 TI - Free factor XIII activation peptide (fAP-FXIII) is a regulator of factor XIII activity via factor XIII-B. AB - In a factor XIIIa (FXIIIa) generation assay with recombinant FXIII-A2 (rFXIII-A2 ) free FXIII activation peptide (fAP-FXII) prolonged the time to peak (TTP) but did not affect the area under the curve (AUC) or concentration at peak (CP). Addition of recombinant factorXIII-B2 (rFXIII-B2 ) restored the characteristics of the FXIIIa generation parameters (AUC, TTP and CP) to those observed for plasma FXIII (FXIII-A2 B2 ). FXIII-A2 B2 reconstituted from rFXIII-A2 and rFXIII B2 showed a similar effect on AUC, TTP and CP in the presence of fAP-FXII as observed for plasma FXIII-A2 B2 , indicating a role for FXIII-B in this observation. An effect of fAP-FXIII on thrombin, the proteolytic activator of FXIII, was excluded by thrombin generation assays and clotting experiments. In a purified system, fAP-FXIII did not interfere with the FXIIIa activity development of thrombin-cleaved rFXIII-A2 (rFXIII-A2 ') also excluding direct inhibition of FXIIIa. However, FXIIIa activity development of FXIII-A2 'B2 was inhibited in a concentration-dependent manner by fAP-FXIII, indicating that an interaction between AP-FXIII and FXIII-B2 contributes to the overall stability of FXIII-A2 'B2 . In addition to its well-known role, FXIII-B also contributes to FXIII-A2 B2 stability or dissociation depending on fAP-FXIII and calcium concentrations. PMID- 26516705 TI - Establishing clinically meaningful severity levels for the Tampa Scale for Kinesiophobia (TSK-13). AB - BACKGROUND: Kinesiophobia is an excessive, irrational and debilitating fear of physical movement and activity resulting from a feeling of vulnerability to painful injury or re-injury. The Tampa Scale for kinesiophobia (TSK) is a patient reported outcome (PRO) measure designed to help identify kinesiophobia. The original version of the TSK had 17 items. A 13-item version was later found to have better psychometric properties and was used in the present study. Although the TSK-13 has been widely studied, one shortcoming is the lack of clinically meaningful score categories. The objective of the present study was to develop severity levels to help aid clinical interpretation of TSK-13 scores. METHODS: After creating four proposed TSK-13 severity ranges, a sample of chronic musculoskeletal pain disorder (CMPD) patients (N = 912) was grouped by TSK-13 scores into: Subclinical (score = 13-22, n = 100; 11%), mild (23-32, n = 271; 30%), moderate (33-42, n = 385; 42%) and severe (43-52, n = 156; 17%) levels of kinesiophobia. These severity groups were then validated by their associations with objective lifting performance (presumed to be highly related to one's level of kinesiophobia) and other PRO questionnaires, assessing depressive symptoms, pain intensity, pain-related anxiety and perceived disability, which all have been shown in previous research to be associated with TSK scores. RESULTS: The TSK-13 severity level groups were significantly associated with all lifting performance and PRO variables (p < 0.001). As TSK-13 severity levels increased, lifting performance decreased, while pain intensity, depressive symptoms, pain related anxiety and perceived disability increased. CONCLUSIONS: TSK-13 severity levels were strongly associated with objective lifting performance variables and psychosocial PRO measures, providing support for these severity levels as a guideline for healthcare providers and researchers in interpreting TSK-13 scores. PMID- 26516703 TI - IL-32theta gene expression in acute myeloid leukemia suppresses TNF-alpha production. AB - The proinflammatory cytokine TNF-alpha is highly expressed in patients with acute myeloid leukemia (AML) and has been demonstrated to induce rapid proliferation of leukemic blasts. Thus suppressing the production of TNF-alpha is important because TNF-alpha can auto-regulate own expression through activation of NF kappaB and p38 mitogen-activated protein kinase (MAPK). In this study, we focused on the inhibitory effect of IL-32theta on TNF-alpha production in acute myeloid leukemia. Approximately 38% of patients with AML express endogenous IL-32theta, which is not expressed in healthy individuals. Furthermore, plasma samples were classified into groups with or without IL-32theta; then, we measured proinflammatory cytokine TNF-alpha, IL-1beta, and IL-6 levels. TNF-alpha production was not increased in patients with IL-32theta expression than that in the no-IL-32theta group. Using an IL-32theta stable expression system in leukemia cell lines, we found that IL-32theta attenuated phorbol 12-myristate 13-acetate (PMA)-induced TNF-alpha production. IL-32theta inhibited phosphorylation of p38 MAPK, inhibitor of kappaB (IkappaB), and nuclear factor kappaB (NF-kappaB), which are key positive regulators of TNF-alpha expression, and inhibited nuclear translocation of NF-kappaB. Moreover, the presence of IL-32theta attenuated TNF alpha promoter activity and the binding of NF-kappaB with the TNF-alpha promoter. In addition, IL-32gamma-induced TNF-alpha production has no correlation with inhibition of TNF-alpha via IL-32theta expression. Thus, IL-32theta may serve as a potent inhibitor of TNF-alpha in patients with AML. PMID- 26516706 TI - Kinetic isotope effect of proton-coupled electron transfer in a hydrogen bonded phenol-pyrrolidino[60]fullerene. AB - Proton-coupled electron transfer (PCET) plays a central role in photosynthesis and potentially in solar-to-fuel systems. We report a spectroscopy study on a phenol-pyrrolidino[60]fullerene. Quenching of the singlet excited state from 1 ns to 250 ps is assigned to PCET. A H/D exchange study reveals a kinetic isotope effect (KIE) of 3.0, consistent with a concerted PCET mechanism. PMID- 26516707 TI - Highly Enantioselective Aza-Michael Reaction between Alkyl Amines and beta Trifluoromethyl beta-Aryl Nitroolefins. AB - The aza-Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N-heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza-Michael reaction between primary alkyl amines and beta-trifluoromethyl beta-aryl nitroolefins. In contrast to classical conjugate-addition reactions, a strategy of HOMO-raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee). PMID- 26516708 TI - Effects of variable attachment shapes and aligner material on aligner retention. AB - OBJECTIVE: To evaluate the retention of four types of aligners on a dental arch with various attachments. MATERIALS AND METHODS: For this study, three casts were manufactured, two of which contained attachments (ellipsoid and beveled), and one without any attachments to serve as a control. Four types of aligners were thermoformed: Clear-Aligner (CA)-soft, CA-medium, and CA-hard, with various thicknesses, and Essix ACE. Measurements of vertical displacement force during aligner removal were performed with the Gabo Qualimeter Eplexor. Means and standard deviations were next compared between different aligner thicknesses and attachment shapes. RESULTS: CA-soft, CA-medium, and CA-hard did not present a significant increase in retention, except when used in the presence of attachments. Additionally, CA-medium and CA-hard required significantly more force for removal. Essix ACE demonstrated a significant decrease in retention when used with ellipsoid attachments. The force value for Essix ACE removal from the cast with beveled attachments was comparable to that of CA-medium. Forces for aligner removal from the model without attachments showed a linear trend. Essix ACE did not show a continuous increase in retention for each model. Overall, ellipsoid attachments did not present a significant change in retention. In contrast, beveled attachments improved retention. CONCLUSIONS: Ellipsoid attachments had no significant influence on the force required for aligner removal and hence on aligner retention. Essix ACE showed significantly less retention than CA-hard on the models with attachments. Furthermore, beveled attachments were observed to increase retention significantly, compared with ellipsoid attachments and when using no attachments. PMID- 26516709 TI - Airway compartments volume and oxygen saturation changes after rapid maxillary expansion: a longitudinal correlation study. AB - OBJECTIVE: To evaluate changes in airway volumes and respiratory performance in patients undergoing rapid maxillary expansion and determine whether any correlations exist between the morphological and respiratory functional modifications induced by rapid maxillary expansion and pretreatment airway stenosis. MATERIALS AND METHODS: Fifteen patients (11 females and 4 males; mean age, 7.5 +/- 0.3 years) were enrolled in the study. Each patient underwent cone beam computed tomography and polysomnography examination before rapid maxillary expansion and after the removal of the maxillary expander 12 months later. The airway regions were segmented and the volumes were computed. RESULTS: The upper, middle, and lower airway volumes were significantly increased 2305 mm(3), 1144 mm(3), and 1915 mm(3), respectively. Similarly, oxygen saturation was increased (+5.3%) and the apnea/hypopnea index was improved (-4.2 events). All the observed modifications were statistically significant (P < .05). Baseline middle and lower airway volume showed a significant negative correlation with the oxygen saturation modification. CONCLUSIONS: The results of this study showed that when rapid maxillary expansion is performed in subjects having posterior crossbite, oxygen saturation is improved. The improvement is greater in subjects having more reduced middle and lower airway volumes. PMID- 26516710 TI - Dental and skeletal changes in mild to moderate Class II malocclusions treated by either a Twin-block or Xbow appliance followed by full fixed orthodontic treatment. AB - OBJECTIVE: To compare the short-term skeletal and dental effects of two-phase orthodontic treatment including either a Twin-block or an XBow appliance. MATERIALS AND METHODS: This was a retrospective clinical trial of 50 consecutive Class II cases treated in a private practice with either a Twin-block (25) or XBow (25) appliance followed by full fixed orthodontic treatment. To factor out growth, an untreated Class II control group (25) was considered. RESULTS: A MANOVA of treatment/observation changes followed by univariate pairwise comparisons showed that the maxilla moved forward less in the treatment groups than in the control group. As for mandibular changes, the corpus length increase was larger in the Twin-block group by 3.9 mm. Dentally, mesial movement of mandibular molars was greater in both treatment groups. Although no distalization of maxillary molars was found in either treatment group, restriction of mesial movement of these teeth was seen in both treatment groups. Both treatment groups demonstrated increased mandibular incisor proclination with larger increases for the XBow group by 3.3 degrees . The Wits value was decreased by 1.6 mm more in the Twin-block group. No sex-related differences were observed. CONCLUSIONS: Class II correction using an XBow or Twin-block followed by fixed appliances occurs through a relatively similar combination of dental and skeletal effects. An increase in mandibular incisor inclination for the XBow group and an increased corpus length for the Twin-block group were notable exceptions. No overall treatment length differences were seen. PMID- 26516711 TI - Pain experience during initial alignment with three types of nickel-titanium archwires: a prospective clinical trial. AB - OBJECTIVE: To clinically evaluate the pain intensity during the week following initial placement of three different orthodontic aligning archwires. MATERIALS AND METHODS: A consecutive sample of 75 patients requiring upper and lower fixed orthodontic appliances were alternately allocated into three different archwires (0.014-inch superelastic NiTi, 0.014-inch thermoelastic NiTi or 0.014-inch conventional NiTi). Assessments of pain/discomfort were made on a daily basis over the first 7-day period after bonding by means of visual analog scale and consumption of analgesics. The maximum pain score was recorded. The possible associations between age, gender, degree of crowding, and teeth irregularity and the pain intensity were also examined. Demographic and clinical differences between the three groups were compared with chi-square test or analysis of variance (ANOVA) test. RESULTS: No statistically significant differences were found in the pain intensity when the three aligning NiTi archwires were compared (P = .63). No significant differences in pain perception were found in terms of gender, age, lower arch crowding, and incisor irregularity. The intake of analgesics was the least in the superelastic NiTi group. CONCLUSION: The three forms of NiTi wires were similar in terms of pain intensity during the initial aligning stage of orthodontic fixed appliance therapy. Gender, age, and the degree of crowding have no effect on the perceived discomfort experienced by patients undergoing fixed orthodontic treatment. PMID- 26516712 TI - Impact of malocclusion and dentofacial anomalies on the prevalence and severity of dental caries among adolescents. AB - OBJECTIVES: To investigate the association between malocclusion/dentofacial anomalies and dental caries among adolescents. MATERIALS AND METHODS: A cross sectional study was conducted with 509 adolescents aged 11 to 14 years enrolled at public schools in the city of Osorio in southern Brazil. Parents/caregivers answered a structured questionnaire on demographic and socioeconomic variables. A trained examiner recorded the presence of malocclusion (Dental Aesthetic Index [DAI]), traumatic dental injury, and dental caries. Data analysis involved the chi-square, Mann-Whitney, and Kruskal-Wallis tests. Poisson regression with robust variance was used for the multivariable analysis. RESULTS: A total of 44.8% of the adolescents had dental caries (mean DFMT = 1.33 +/- 1.84). The DAI index ranged from 15 to 77 (mean = 29.0 +/- 7.9); 43.6% of the sample had severe malocclusion and 11.6% had traumatic dental injury. The prevalence and severity of dental caries were significantly greater among adolescents with severe malocclusion. The multivariate analysis demonstrated that adolescents with severe or handicapping malocclusion had a 31% greater probability of having dental caries (prevalence ratio: 1.31; 95% CI: 1.02-1.67), independently of demographic, socioeconomic, or clinical aspects. The orthodontic characteristics associated with the occurrence and severity of caries were maxillary irregularity >=3 mm (P = .021) and abnormal molar relationship (P = .021). CONCLUSIONS: Handicapping malocclusion, maxillary irregularity, and abnormal molar relationship were associated with the occurrence and severity of dental caries. The findings suggest that the prevention and treatment of these conditions can contribute to a reduction in dental caries among adolescents. PMID- 26516713 TI - Rapid maxillary expansion effects in Class II malocclusion: a systematic review. AB - OBJECTIVE: To evaluate the effectiveness of rapid maxillary expansion (RME) on the sagittal dental or skeletal parameters of growing children with Class II malocclusion. MATERIALS AND METHODS: A systematic review intended to identify relevant literature was conducted. The search was performed on Medline, Embase, Cochrane Library, and Scopus databases. Reference lists of the included articles were also screened for relevant documents. The qualitative assessment was performed according to the Methodological Index for Non-Randomized Studies (MINORS) tool, and the resultant data were grouped and analyzed concerning dental and skeletal sagittal effects of RME. RESULTS: Of 25 screened studies, seven articles met eligibility criteria and were included. Study samples were observed during mixed dentition stage and characterized as having either Class II dental malocclusion or skeletal discrepancy. None of the included studies was a randomized clinical trial. Included controlled studies presented several inadequacies related to control group or lacked appropriate comparative statistical analysis. Besides being frequently based on deficient methodology, dental and skeletal sagittal effects of RME were either controversial or lacked clinical relevance. CONCLUSION: The effect of RME on the sagittal dimension of Class II malocclusions has not been proved yet. Future randomized controlled clinical trials are still needed to definitely address this question. PMID- 26516714 TI - Will I ever be a good teacher? PMID- 26516715 TI - Re: Chamberland S, Proffit WR, Chamberland PE. Functional Genioplasty in growing patients. Angle Orthod. 2015;85:360-373. PMID- 26516716 TI - Re: response to: functional genioplasty in growing patients by Chamberland S, Proffit WR, Chamberland PE. Angle Orthod. 2015; 85:360-373. PMID- 26516717 TI - Re: bone marrow mesenchymal stem cells enhance bone formation in orthodontically expanded maxillae in rats. Abdullah Ekizer, Mehmet Emir Yalvac, Tancan Uysal, Mehmet Fatih Sonmez, Fikrettin Sahin. The Angle Orthodontist. Online Early. PMID- 26516718 TI - Re: response to: bone marrow mesenchymal stem cells enhance bone formation in orthodontically expanded maxillae in rats. Abdullah Ekizer, Mehmet Emir Yalvac, Tancan Uysal, Mehmet Fatih Sonmez, Fikrettin Sahin. The Angle Orthodontist. Online Early. PMID- 26516722 TI - Linking T cells to Alzheimer's disease: from neurodegeneration to neurorepair. AB - The overly-simplistic view that inflammatory and anti-inflammatory influences in the brain were respectively detrimental and advantageous in Alzheimer's disease (AD) is being challenged by advances in methodologies, and a debate relating to immune surveillance mechanisms in the brain. In contrast with previous findings, increasing interleukin (IL)-4 and IL-10 in brain by a recently-developed adenoviral delivery method, had detrimental effects in an animal model of AD, and the ability to isolate the choroid plexus has opened the debate on the role of this specialized tissue in immune surveillance. Delivery of polarized T cells to animal models of AD by different routes has yielded contrasting results; analysis of these diverse responses is vital to understand the role of T cells in the brain in AD, first reported over 25 years ago. PMID- 26516725 TI - [CHIP Germany: Impact of a Lifestyle Coaching Intervention on Nutritional Behaviour Change in Primary and Secondary Prevention of Type 2 Diabetes and the Importance of Social-Cognitive Variables]. AB - Background: A high fibre and moderate fat diet can reduce the metabolic risk in diabetics. This study is the first one to test which social-cognitive variables affect nutritional behaviour changes in an educational lifestyle intervention. Patients and Methods: Subjects with diabetes or at high risk (intervention: N=43; control: N=40) joined an initial and a final individual health-coaching, an 8 week comprehensive lifestyle programme und a 10-month follow-up-period. Beside anthropometric, vital und clinical parameters (e. g., weight, HbA1c, FINDRISK), behavioural stages (preintenders, intenders, actors), outcome-expectancies, action planning and self-efficacy were evaluated for a healthy diet in both groups. Results: Weight, nutritional behaviour, self-efficacy, action planning, and outcome expectancies improved in the intervention group. Improved self efficacy after the lifestyle programme was linked to weight reduction. Discussion: The metabolic risk profile was reduced by the educational lifestyle programme. A highly developed self-efficacy seems to help to change nutritional behaviour and therefore prevent and deal with diabetes. Conclusion: Behavioural lifestyle-coachings should focus on the volitional phase and implicitly improve self-efficacy. PMID- 26516723 TI - Bile salt export pump-reactive antibodies form a polyclonal, multi-inhibitory response in antibody-induced bile salt export pump deficiency. AB - Progressive familial intrahepatic cholestasis type 2 (PFIC-2) is caused by mutations in ABCB11, encoding the bile salt export pump (BSEP). In 2009, we described a child with PFIC-2 who developed PFIC-like symptoms after orthotopic liver transplantation (OLT). BSEP-reactive antibodies were demonstrated to account for disease recurrence. Here, we characterize the nature of this antibody response in 7 more patients with antibody-induced BSEP deficiency (AIBD). Gene sequencing and immunostaining of native liver biopsies indicated absent or strongly reduced BSEP expression in all 7 PFIC-2 patients who suffered from phenotypic disease recurrence post-OLT. Immunofluorescence, western blotting analysis, and transepithelial transport assays demonstrated immunoglobulin (Ig) G class BSEP-reactive antibodies in these patients. In all cases, the N-terminal half of BSEP was recognized, with reaction against its first extracellular loop (ECL1) in six sera. In five, antibodies reactive against the C-terminal half also were found. Only the sera recognizing ECL1 showed inhibition of transepithelial taurocholate transport. In a vesicle-based functional assay, transport inhibition by anti-BSEP antibodies binding from the cytosolic side was functionally proven as well. Within 2 hours of perfusion with antibodies purified from 1 patient, rat liver showed canalicular IgG staining that was absent after perfusion with control IgG. CONCLUSIONS: PFIC-2 patients carrying severe BSEP mutations are at risk of developing BSEP antibodies post-OLT. The antibody response is polyclonal, targeting both extra- and intracellular BSEP domains. ECL1, a unique domain of BSEP, likely is a critical target involved in transport inhibition as demonstrated in several patients with AIBD manifest as cholestasis. PMID- 26516724 TI - A Preference Study of Two Placebo Dry Powder Inhalers in Adults with COPD: ELLIPTA(r) Dry Powder Inhaler (DPI) versus DISKUS(r) DPI. AB - Patients' preference is an important factor in selecting an inhaler treatment for COPD. The DISKUS(r) dry powder inhaler (DPI), which has been available to deliver several COPD medications for a decade, and the ELLIPTA(r) DPI, developed for the delivery of newer once-daily medications for patients with COPD, were studied in terms of patient preference and inhaler-specific attributes. We conducted a randomized, open-label, crossover study in patients with COPD. Patients used placebo ELLIPTA DPI once daily and placebo DISKUS DPI twice daily, for ~1 week each, while continuing their COPD medications. Endpoints were: inhaler preference based on size of the numbers on the dose-counter (primary); the number of steps needed and inhaler size (secondary); and based on comfort of the mouthpiece, ease of opening, overall preference, and dosing regimen preference ('other'). Safety assessments included adverse events (AEs). A total of 287 patients were randomized. A significantly (p < 0.001) larger proportion of patients preferred the ELLIPTA DPI over DISKUS DPI for each of the tested attributes and overall, and preferred once-daily over twice-daily dosing. AEs were reported for 36 patients (13%); one (dry mouth) was considered to be related to the placebo containing DISKUS DPI. Three patients had five non-fatal serious AEs, none were deemed inhaler-related. This study demonstrated that more patients with COPD preferred five specific inhaler attributes of the ELLIPTA DPI over DISKUS DPI and overall, and preferred once-daily versus twice-daily dosing. Safety profiles were consistent with those expected for COPD. PMID- 26516727 TI - The Effect of Spinal Cord Stimulation on Epileptic Seizures. AB - OBJECTIVE: Spinal cord stimulation (SCS) has been applied to relieve chronic pain for decades. Recent studies suggested that SCS also might alleviate epileptic seizures, but the most effective stimulation parameters are not known. The objective of this work was to investigate the role of SCS frequency in alleviating spike-and-wave (SW) discharges induced in rats by pentylenetetrazole (PTZ) infusion. MATERIALS AND METHODS: The SW discharges were induced in nine rats. An epidural electrode was placed in the spinal canal at the cervical level. SCS was delivered at four frequencies (30, 80, 130 and 180 Hz) and compared with control intervals without stimulation. The effect was evaluated by analyzing electrocorticographic and intracortical (IC) signals. The means of normalized SW spike power (mSP) and frequency (mSF) were derived from the IC recordings and used to estimate the seizure severity. RESULTS: Compared with the control intervals, SCS conducted at 30 Hz significantly increased the mSP and mSF indicating an increase of the SW spiking activity; 80 Hz did not induce significant changes of the features. In contrast, 130- and 180-Hz SCS reduced both mSP and mSF significantly indicating a reduction of the SW spiking activity. CONCLUSIONS: The present results showed that 130-Hz and 180-Hz SCS reduced the SWs power and frequency which may indicate an anticonvulsive effect of these SCS frequencies, whereas 30-Hz SCS induced the opposite effects and, therefore, may be proconvulsive. PMID- 26516728 TI - Understanding Fracture Healing Biomechanics Based on the "Strain" Concept and its Clinical Applications. PMID- 26516729 TI - Total En Bloc Spondylectomy of C3: A New Surgical Technique and Literature Review. AB - PURPOSE OF THE STUDY: Radical resection of a vertebra is reserved only for specific tumors that invade the surrounding tissues and recur when not removed completely. The vertebra may be removed using a piecemeal technique or en bloc, using only two (in thoracolumbar spine) or more osteotomies (in cervical spine). We present our technique of en bloc resection of subaxial cervical vertebra for Ewing's sarcoma of C3, with preservation of all nerve roots and both vertebral arteries. To our knowledge, this surgical technique has not been reported in the English literature. The aim of this study is to describe the new technique of radical resection of subaxial cervical vertebra. MATERIAL AND METHODS: A transoral biopsy of tumor tissue anterior to C2-C3 was performed in 8-year old boy, revealing a diagnosis of Ewing's sarcoma. The patient was started on neoadjuvant chemotherapy. After 6 chemotherapy cycles with the VIDE regimen, the soft-tissue component completely regressed, with the only a residual deposit in C3 vertebral body. Based on further multidisciplinary meeting, an en bloc spondylectomy of C3 was recommended, preferably with preservation of nerve roots and vertebral arteries. In August 2014, prior to the planned surgery, we performed another thorough examination of the patient using plain films, CT and MRI. Neither angiography nor embolization was performed. DESCRIPTION OF SURGICAL TECHNIQUE: The first stage of the operation consisted of resection of the posterior structures. We exposed the posterior elements of C2 to C4 by the mid line incision. The C3 arch was without pathological changes. After partial resection of the C2 inferior and C4 superior articular processes we performed bilateral osteotomy in the region of the pedicle adjacent to the arch with a chisel and removed the whole of the C3 posterior arch. Subsequently we perforated the transverse foramina close to the pedicle, using fine Kerrison rongeurs. The lateral parts around vertebral arteries were left in situ. In the next step we used instrumentation with polyaxial screws to stabilize the C2-C4 section. After 19 days we performed the second stage surgery from an anterior approach with the removal of the anterior and lateral parts of the vertebra. We made a transverse incision anterior to the sternocleidomastoid between the internal carotid artery and the trachea on the right side at the level of C3 to expose the spine. We resected C2-C3 and C3-C4 intervertebral discs and then performed osteotomy with fine Kerrison rongeurs on both sides, again, close to the vertebral body. Subsequently, the vertebral body was released and extracted en bloc. In the next step, both vertebral arteries were mobilized and shifted medially and the lateral portions of the transverse processes were released and removed en bloc. The empty space was filled with solid allograft and the C2-C4 levels were bridged by the cervical plate in 2+1+2 configuration. RESULTS: There were no complications during both surgeries. The follow-up CT examination 4 months after the operation revealed a clear bone fusion of C2-C4, both anteriorly between vertebral bodies and posteriorly between the arches. Clinically the patient has reached 8 month follow up and had no complaints, both he and his parents were satisfied. Physiotherapy is proceeding according to plan. The patient remains under supervision at our centre. DISCUSSION: Total en bloc resection of a subaxial cervical vertebra with preservation of neural and vascular structures has been described in the English literature only once. In 2007 was published a total en bloc resection of C5 for chordoma, preserving the above mentioned structures. Authors removed the lamina en bloc after bilateral osteotomy. Transverse foramina were perforated by the Gigli saw and removed in piecemeal fashion, including the posterior tubercle. In the next step, they removed the vertebral body and the anterior tubercle from the anterior approach. However, their treatment differs from the technique described here and does not correspond fully to the principle of en bloc resection. Our surgical technique is based on a similar principle of performing several osteotomies without the use of high speed burr, while preserving all neural and vascular structures. The difference can be particularly seen in the approach to remove lateral parts of the transverse foramen, which are surrounding the vertebral arteries. We consider it as ideal to split the cervical vertebra by smooth cuts into four parts and remove them en bloc. CONCLUSION: Total en bloc spondylectomy of a subaxial cervical vertebra with preservation of vertebral arteries and nerve roots is a radical surgery that should be used to treat only the most serious conditions. The risk of neurological deficit is outweighed by the benefits of oncological radicality. This new surgical technique has not yet been described and it is clear, that a larger cohort of patients is necessary to assess and potentially modify this technique so that it can be used more frequently in the future. PMID- 26516730 TI - Delayed Fracture Healing in Diabetics with Distal Radius Fractures. AB - PURPOSE OF THE STUDY: Diabetics may have an increased fracture risk, depending on disease duration, quality of metabolic adjustment and extent of comorbidities, and on an increased tendency to fall. The aim of this retrospective one-centre study consisted in detecting differences in fracture healing between patients with and without diabetes mellitus. Data of patients with the most common fracture among older patients were analyzed. MATERIAL AND METHODS: Classification of distal radius fractures was established according to the AO classification. Inital assessment and follow-up were made by conventional X-rays with radiological default settings. To evaluate fracture healing, formation of callus and sclerotic border, assessment of the fracture gap, and evidence of consolidation signs were used. RESULTS: The authors demonstrated that fracture morphology does not influence fracture healing regarding time span, neither concerning consolidation signs nor in fracture gap behaviour. However, tendency for bone remodeling is around 70% lower in investigated diabetics than in non diabetics, while probability for a successful fracture consolidation is 60% lower. CONCLUSIONS: To corroborate the authors hypothesis of delayed fracture healing in patients with diabetes mellitus, prospective studies incorporating influencing factors like duration of metabolic disease, quality of diabetes control, medical diabetes treatment, comorbidities and secondary diseases, like chronic nephropathy and osteoporosis, have to be carried out. PMID- 26516731 TI - Open versus Percutaneous Stabilization of Thoracolumbar Spine Fractures: A Short Term Functional and Radiological Follow-up. AB - PURPOSE OF THE STUDY: A prospective cohort study evaluates the functional and radiological outcome of thoracolumbar spine fractures treated either with open or percutaneous dorsal instrumentation. In recent years, several studies advocate percutaneous stabilization of spinal fractures in patients without neurological deficits. However, it is still debated whether percutaneous stabilization is superior to open dorsal instrumentation in spinal trauma. MATERIAL AND METHODS: This study was performed between 2010 and 2012 at a Level 1 trauma center. Patients treated either with an open or a percutaneous dorsal instrumentation for traumatic fractures of the thoracolumbar spine (T11 to L2) were included. Fracture morphology, screw positioning and clinical parameters were analyzed. Standardized questionnaires (VAS-spine-score; Oswestry-disability-score; SF-36) and follow up radiographs were performed. RESULTS: Overall 72 patients (29 percutaneous; 43 open) could be included. The surgical and the early postsurgical course were similar between both groups. Furthermore the operative approach had no influence on the functional and radiological outcome one year after surgery, but the questionnaires showed moderate impairments within both groups. Also both groups showed a significant loss of reduction after the first postoperative month (p < 0.01). Within the open group a significantly higher amount of fracture reduction (p < 0.01) and a significantly reduced intraoperative radiation exposure was seen (open 105.9 sec.; percutaneous 143.1 sec; p < 0.05); whereas the percutaneous approach was associated with significantly reduced intraoperative blood loss (open 2.2 g/dl; percutaneous 1.2 g/dl; p < 0.001). CONCLUSION: The functional and the radiological outcome of both groups was comparable one year after trauma. Minor advantages of the percutaneous system was less blood loss, whereas the open approach was associated with a significantly higher amount of initial reduction and significantly less intraoperative radiation exposure. Independent from the type of posterior fixation loss of reduction was already significant in the early postoperative course. PMID- 26516732 TI - [Fracture Type and Injury-to-Surgery Interval as Risk Factors for Avascular Necrosis of the Femoral Head after Internal Fixation of Intracapsular Femoral Neck Fracture]. AB - PURPOSE OF THE STUDY: The aim of the study was to investigate the occurrence of avascular necrosis (AVN) of the femoral head following the osteosynthesis of intracapsular fracture of the femoral neck in relation to the time interval between injury and surgery and the type of fracture. MATERIAL AND METHODS: The data of patients with intracapsular fractures of the femoral neck surgically treated in the period from 2001 to 2011 were reviewed. Of 1555 patients treated for this fracture, 125 (7%) underwent osteosynthesis. The evaluated group included 115 patients who came for examination at one-year follow-up. There were 59 (52%) women and 56 (48%) men. Dynamic hip screw (DHS) osteosynthesis with an anti-rotation screw was performed in 103 patients and lag-screw osteosynthesis involving three parallel cannulated cancellous screws was employed in 12 patients. The patients were allocated to groups according to the injury-to surgery interval and to sub-groups on the basis of the Garden classification of femoral fracture stage. RESULTS: In the group of 58 patients treated within 6 h of injury, AVN developed in 10 (17%). When the type of fracture was considered, 4% of the non-displaced fractures and 30% of the displaced fractures developed AVN. The patients with Garden stage I and II (non-displaced) fractures treated within 6 h of injury had a significantly lower risk of AVN development than those with Garden stage III or IV (displaced) fractures. The group treated between 6 and 24 post-injury hours comprised 21 patients, of whom four (19%) had AVN. In non-displaced and displaced fracture sub-groups, 25% of the patients in the former and 16% in the latter had AVN. The stage of displacement had no effect on AVN development. The two groups together (patients treated by 24 h) had a significantly lower AVN incidence than the patients treated after 24 h (p = 0.0025). In this group of 36 patients, 16 had AVN (44%) and the fracture stage made no significant difference (p = 0.6985; nondisplacement sub-group, 41%; displacement sub-group, 55%). CONCLUSIONS: The study showed a significantly lower AVN occurrence in the patients surgically treated within 24 h of injury. In the patients treated within 6 h of injury, AVN incidence was significantly lower in the patients with non-displaced fractures, as compared with those who had displaced fractures. This was not true for the two patient groups treated later (6-24 and later than 24 h) in which the differences between AVN development after non-displaced fractures and that after displaced fractures were similar. PMID- 26516734 TI - Reduction of Total Antioxidant Capacity after Femoral Fracture. AB - PURPOSE OF THE STUDY: The aim of this study was to determine the changes in total antioxidant capacity (TAC) during the fracture healing process. MATERIAL AND METHODS: Twenty patients with isolated closed femoral fracture, between the ages 18 and 60 years, were included in the study. The control group was formed with healthy volunteers. Venous blood was drawn from the healthy volunteers once, and from the patients five times during 14 days after fracture. TAC was measured in the sera of these samples. RESULTS: In the patient group, the serum TAC was the highest in the first 6 hours, whereas there was a decreasing trend on the 3rd, 7th and 14th days, and an increasing trend on the 5th day. The mean serum TAC in all measurements of the patient group were lower than those in the control group. CONCLUSION: The present study suggests that TAC may be decreased in considerable amounts during the first 2 weeks of fracture healing. PMID- 26516733 TI - [Does an Independent Predictor of In-Hospital Mortality Exist for Patients with Isolated Proximal Femoral Fracture? A Retrospective Two-Year Observational Study]. AB - PURPOSE OF THE STUDY: The primary objective of the study was to find out in hospital mortality in patients undergoing surgery for proximal femoral fracture. The secondary objective was to identify independent predictors of in-hospital mortality. MATERIAL AND METHODS: A retrospective single-centre observational study PROXIMORT of patients operated on for isolated proximal femoral fracture at the University Hospital (FN) Brno in the years 2011 and 2012. The 30-day and overall one-year mortality in the study group and the impact of observed parameters on mortality were also assessed. The observed parameters were: patient age and sex, ASA score, time from injury to surgery (hr), daily (7-20 hr) or night (20-7 hr) time of surgery, type of anaesthesia (general vs spinal), initial haemoglobin and haematocrit levels, intra-operative administration of blood products and vasopressors, and erudition of the anaesthesiologist and surgeon. To evaluate the relationship of in-hospital mortality to the observed characteristics, we used univariate logistic regression modelling and odds ratio, using SPSS 22 software (IBM, USA). RESULTS: Data were obtained from 414 patients and 369 patients were included (male, n = 91; female, n = 278). Due to exclusion criteria, 45 patients were excluded (not an isolated injury). In-hospital mortality was 6.5% (n = 24), 30-day mortality was 8.4% (n = 31) and total mortality of the study group was 35.8% (n = 132). Statistically significant effects on in-hospital mortality included: older age of the patient (p = 0.013), ASA score of 3 or more (p = 0.002) and general anaesthesia administration (p = 0.043). For 30-day mortality, this was older age (p = 0.012), ASA score of 3 and more (p < 0.001), general anaesthesia administration (p < 0.001), lower weight (p = 0.028), lower BMI (p = 0.006) and intra-operative administration of vasopressors (p = 0.023). The influence of other observed parameters on post operative mortality was not statistically significant. DISCUSSION: In-hospital mortality in the PROXIMORT study was 6.5% (95% confidence interval (CI) 4.2 to 9.5%), which was significantly higher than in-hospital mortality in unselected surgically treated patients in the Czech Republic, as reported in the EuSOS study (2.3% with 95% CI 0.9 to 3.7%). Administration of general anaesthesia was determined as an independent predictor of in-hospital and 30-day mortality, which was concordant with the results of meta-analysis published by Rodgers et al. and Barbosa et al in 2013. Postponing surgery for perioperative optimisation had no effect on mortality according to the PROXIMORT study. Patorn et al. have supported this conclusion by the results of a selected group of patients with surgery delayed for more than 24 hours; the patients mortality, regardless of anaesthesia, was up to 2.5%. CONCLUSIONS: The PROXIMORT study identified the higher patient age, ASA score of 3 and more and general anaesthesia administration as independent predictors of in-hospital mortality. PMID- 26516735 TI - [Augmentation of the Anterior Cruciate Ligament in Patients with Symptomatic Isolated Tear of Anteromedial or Posterolateral Bundle: Evaluation of Two-Year Clinical Results]. AB - PURPOSE OF THE STUDY: We present the results of a prospective study of patients with symptomatic partial ACL tears comparing the pre-operative findings with the clinical results at two years after anterior cruciate ligament (ACL) augmentation. MATERIAL AND METHODS: A total of 29 patients (7 women, 22 men; average age, 27.8 years) who were diagnosed with an isolated tear of the posterolateral (PL) bundle (18 patients) or the anteromedial (AM) bundle (11 patients) at 9 to 24 weeks after injury, and underwent ACL augmentation by isolated PL or AM bundle replacement, were evaluated. The characteristics assessed before surgery and at two years after it included the Lysholm and subjective IKDC scores and knee laxity measurement with a GNRB arthrometer (at 134 N and 250 N) and its assessment by the Lachman, anterior drawer and pivot shift tests. In addition, the presence of cyclop syndrome, graft failure and post operative complications were evaluated. RESULTS: The patients with isolated reconstruction of the PL bundle showed post-operatively statistically significant improvement in the degree of rotational knee laxity (p < 0.05) and the ventral knee laxity assessed by the Lachman test (p < 0.05). Postoperative improvement in the anterior drawer test results was not statistically significant (p = 0.07). The median value of side-to-side difference in knee laxity measured with the GNRB arthrometer decreased at 134 N from 1.7 mm pre-operatively to 0.8 mm at two years post-operatively (p < 0.05) and, at 250 N, from 2.8 mm to 1.5 mm (p < 0.05). The median Lysholm score increased from 74 to 91 points at two post-operative years and the median IKDC score improved from 76 to 92 points (p < 0.05). Graft failure was reported in one patient (5.6%) and 14 subjects (77.8%) reported return to pre injury sports activities. The patients undergoing isolated reconstruction of the AM bundle achieved, at two years after surgery, a statistically significant decrease in positivity of the Lachman and anterior drawer tests (p < 0.05), while the results of the pivot shift test did not improve significantly (p = 0.09). The decrease in median values of side-to-side difference in knee laxity measured with the GNRB arthrometer was from pre-operative 3.1 mm to 1.2 mm at 134 N (p < 0.05) and from 6.2 mm to 1.9 mm at 250N (p < 0.05). The median Lysholm and IKDC scores increased from 68 to 92 points and from 70 to 94 points, respectively (p < 0.05). Nine patients (81.9%) reported return to pre-injury participation in sports. Apart from early wound bleeding in one patient, no complications were recorded. DISCUSSION: By permitting maintenance of a healthy bundle and replacement of only a torn one, ACL augmentation provides several benefits. It allows for accelerated revascularization and re-innervation of the graft through mechanoreceptors of the healthy portion; it enables the surgeon to get a good anatomical orientation and achieve precise tunnel reaming; in addition the healthy bundle provides protection for the graft in the early post-operative period. Thus rehabilitation can be faster and also return to sports activities. CONCLUSIONS: Our results show that ACL augmentation using isolated replacement of either the AM or the PL bundle brings about statistically significant improvement of all subjective and most of the objective criteria by two years after surgery. PMID- 26516737 TI - [Bone and Joint Involvement in Celiac Disease]. AB - Celiac disease (gluten-sensitive enteropathy) is currently regarded as a multisystem autoimmune disorder; its clinical signs and symptoms do not involve merely the gastrointestinal tract but are associated with several other medical specialties, including orthopaedics and traumatology. In orthopaedic and trauma patients, celiac disease should be suspected in the following diagnoses: osteomalacia, premenopausal osteoporosis, post-menopausal osteoporosis more severe than expected and refractory to medication, osteoporosis in men under 55 years of age, recurrent bone fractures in the limbs, large joint arthralgia or arthritis of unclear aetiology, erosive spondyloarthropathy particularly in patients with the history of chronic diarrhoea, anaemia or associated autoimmune disorders (type 1 diabetes mellitus or autoimmune thyreopathy), and in women with secondary amenorrhea or early menopause. The orthopaedist or trauma surgeon should be aware of suspected celiac disease in patients who do not respond adequately to the standard treatment of pain related to the musculoskeletal system, in patients with recurrent fractures of the limb bones and in young patients with suspected secondary osteoporosis. With the use of appropriate screening methods, celiac disease as-yet undiagnosed can be revealed. A long-life gluten-free diet in these patients results in the alleviation of metabolic osteopathy and joint and muscle problems, in reduced requirements of analgesic and antiphlogistic drugs as well as in reduced risks of fracture. PMID- 26516736 TI - [Surgical Stabilisation of Flail Chest Injury: Indications, Technique and Results]. AB - PURPOSE OF THE STUDY: Multiple rib fractures with segmental chest wall instability are caused by high-energy chest trauma and are associated with significant morbidity and mortality. Flail chest injuries are mostly combined with lung injury (contusion, rupture, laceration) and subsequent pneumothorax or haemothorax. Early mechanical ventilation with internal pneumatic splinting is a conservative treatment for flail chest in patients with respiratory insufficiency. The surgical stabilisation of a flail chest is an effective method of treatment and is beneficial for selected patients. It shortens the duration of mechanical ventilation and thus reduces morbidity associated with prolonged ventilatory support. In addition, it decreases long-term pain and the inability of a flail chest to heal due to malunion, non-union or progressive collapse of the flail segment. Surgical stabilisation of a flail chest is indicated when the clinical examination shows progressive respiratory dysfunction confirmed by the results of multiple detector computer tomography (MDCT) of the thorax. MATERIAL AND METHODS: Thirty-three consecutive patients who underwent surgical stabilisation of a flail chest at the Trauma Centre between 2010 and 2014 were retrospectively evaluated. This included patient demographics, chest injury extent, results of pre-operative chest imaging (MDCT), surgical stabilisation technique and post-operative outcome. In addition to providing a radiographic finding of respiratory failure, the result of MDCT chest examination was considered an important criterion for surgical intervention. Surgical stabilisation of the chest wall was performed at an interval ranging from 2 hours to 11 days after injury. Intra-thoracic procedures were indicated in patients with lung injury (pulmonary laceration). The surgical procedure was completed by chest tube placement. RESULTS: Surgical stabilisation was carried out using 3 to 8 plates for flail segment fixation involving 3 to 4 ribs. The duration of post- operative mechanical ventilation was 5 days on the average. It was longer in patients with associated injuries such as craniocerebral trauma or severe pulmonary contusion. Tracheostomy was performed in seven patients requiring prolonged mechanical ventilation. Two patients had superficial surgical site infection. No death was recorded in the follow-up period. CONCLUSIONS: Surgical stabilisation of the flail chest segment is considered an effective procedure in selected patients, leading to improvement of respiratory function. By allowing for a shorter period of time on mechanical ventilation, it reduces the occurrence of complications due to ventilatory support. The result of MDCT chest examination in patients with fail chest is an important indication criterion for surgical fixation. PMID- 26516738 TI - Integrity and ethics in research and scientific communication: issues for Nursing considerations. PMID- 26516739 TI - [Implementation methodology of practices based on scientific evidence for assistance in natural delivery: a pilot study]. AB - OBJECTIVE: Presenting methodology for transferring knowledge to improve maternal outcomes in natural delivery based on scientific evidence. METHOD: An intervention study conducted in the maternity hospital of Itapecerica da Serra, SP, with 50 puerperal women and 102 medical records from July to November 2014. The PACES tool from Joanna Briggs Institute, consisting of pre-clinical audit (phase 1), implementation of best practice (phase 2) and Follow-up Clinical Audit (phase 3) was used. Data were analyzed by comparing results of phases 1 and 3 with Fisher's exact test and a significance level of 5%. RESULTS: The vertical position was adopted by the majority of puerperal women with statistical difference between phases 1 and 3. A significant increase in bathing/showering, walking and massages for pain relief was found from the medical records. No statistical difference was found in other practices and outcomes. Barriers and difficulties in the implementation of evidence-based practices have been identified. Variables were refined, techniques and data collection instruments were verified, and an intervention proposal was made. CONCLUSION: The study found possibilities for implementing a methodology of practices based on scientific evidence for assistance in natural delivery. PMID- 26516740 TI - [Primary Health Care from the perception of women living in a rural area]. AB - OBJECTIVE: Understanding the perception of women living in a rural area about the actions and services of Primary Health Care (PHC) in a municipality of southern Brazil, which is the only one regarded as predominantly rural. METHOD: A descriptive study of qualitative approach, carried out with women who lived in the countryside and required health services in the 15 days prior to collection. RESULTS: The results registered low fidelity to PHC attributes, focusing its functional axis on sickness, transforming the unit into small points of emergency care and a bureaucratic place where patients are referred to other types of services. The quality of service offered is compromised to offering quick, fragmented and unequal treatment in the rural context. CONCLUSION: The findings of this study highlight the need for greater efforts in order to adequate the new care model in the development of appropriate actions as designated by PHC in the rural context studied. PMID- 26516741 TI - [Child care and health rights: perspectives of adolescent mothers]. AB - OBJECTIVE: To analyze child health care and the defense of their rights from the perspective of adolescent mothers. METHODS: An exploratory study with qualitative thematic analysis of data, based on conceptual aspects of care and the right to health, from semi-structured interviews with 20 adolescent mothers ascribed by Family Health teams. RESULTS: Maternal reports indicate that child health care requires responsibility and protection, with health practices that promote child advocacy. Gaps in assistance which preclude the full guarantee of the right to child health care were also highlighted. CONCLUSION: The right to health care assumed different meanings, and the forms to guarantee them were linked to individual behavior in detriment to broader actions that consider health as a social product, connected to the guarantee of other fundamental rights. PMID- 26516742 TI - [Adolescent support networks in a health care context: the interface between health, family and education]. AB - OBJECTIVE: Analyze adolescents' perceptions about support networks and their health needs. METHOD: Analytical and interpretive study using focus groups conducted in municipal state schools in Fortaleza, in the State of Ceara during the first semester of 2012. The sample comprised 36 male and female adolescents aged between 13 and 16 years attending the ninth grade of the second phase of elementary school. RESULTS: Thematic analysis revealed that the health care support network and interaction between health professionals, education professionals and family members was insufficient, constituting a lack of an integrated network to enable and provide support for health promotion. CONCLUSION: Coordination between education, health and family services has the potential to act as a support network to help meet adolescents' healthcare needs and demands. PMID- 26516743 TI - [Map of homicides by firearms: profile of the victims and the assaults]. AB - OBJECTIVE: Describing the profile of victims and assaults by gunshot, where the outcome was death. METHOD: An ecological study conducted in the city of Maceio/AL, in 2012. Data were collected from the death statements. The variables studied were: the death circumstances, gender, age, marital status, place, date, time, month and proportion according to the occurring neighborhood. RESULTS: The homicide mortality rate was 65.2 per 100,000 inhabitants, with 130.6 per 100,000 men and 7.8 per 100,000 women. Of the total number of homicides, 93.6% of the victims were men. The age group between 15 and 29 years of age was the most affected, with 68.8%. In 97.6% of cases the death occurred at the site of aggression, 74.1% in the streets. In relation to the date, 54.2% of cases occurred between Friday and Sunday. 59.7% of the homicides were concentrated in seven neighborhoods. CONCLUSION: The map of violence presented shows heterogeneous areas for the occurrence of assaults with firearms, characterizing the existing urban inequality in violence distribution. PMID- 26516744 TI - [Functional independence measure in patients with intermittent claudication]. AB - OBJECTIVE: Of this study were to evaluate the functional independence of patients with intermittent claudication and to verify its association with sociodemographic and clinical variables, walking ability and physical activity level. METHOD: This was a descriptive, exploratory, cross-sectional study with a quantitative approach. Fifty participants (66.4 years; 68% male) were recruited from Claudication Unit of a tertiary hospital. Functional Independence Measure were used to evaluate functional incapacity; the Baltimore Activity Scale, to estimate the physical activity level and the Walking Impairement Questionnaire, the walking ability. RESULTS: Participants had complete functional independence (124.8 + 2.0), low levels of physical activity (4.2 + 2.0), and impairment of walking ability; the worst performance was found in walking velocity domain (21.2 + 16.4). The functional independence score was associated with physical activity (r=0,402) and walking ability scores (distance, r=0,485; speed, r=0,463; stairs, r=0,337). CONCLUSION: In conclusion, the level of functionality is associated with functional capacity in these patients. PMID- 26516746 TI - [Evaluation of adherence to measures for the prevention of surgical site infections by the surgical team]. AB - OBJECTIVE: Evaluate pre- and intraoperative practices adopted by medical and nursing teams for the prevention of surgical infections. METHOD: A prospective study carried out in the period of April to May 2013, in a surgical center of a university hospital in Belo Horizonte, Minas Gerais. RESULTS: 18 surgeries were followed and 214 surgical gloves were analyzed, of which 23 (10.7%) had postoperative glove perforation detected, with 52.2% being perceived by users. Hair removal was performed on 27.7% of patients in the operating room, with the use of blades in 80% of the cases. Antibiotic prophylaxis was administered to 81.8% of patients up to 60 minutes prior to surgical incision. An average of nine professionals were present during surgery and the surgery room door remained open in 94.4% of the procedures. CONCLUSION: Partial adhesion to the recommended measures was identified, reaffirming a need for greater attention to these critical steps/actions in order to prevent surgical site infection. PMID- 26516745 TI - [Advantages of a cohort study on cardiac arrest conducted by nurses]. AB - OBJECTIVE: Identifying factors associated to survival after cardiac arrest. METHOD: An experience report of a cohort study conducted in a university hospital, with a consecutive sample comprised of 285 patients. Data were collected for a year by trained nurses. The training strategy was conducted through an expository dialogue lecture. Collection monitoring was carried out by nurses via telephone calls, visits to the emergency room and by medical record searches. The neurological status of survivors was evaluated at discharge, after six months and one year. RESULTS: Of the 285 patients, 16 survived until hospital discharge, and 13 remained alive after one year, making possible to identify factors associated with survival. There were no losses in the process. CONCLUSION: Cohort studies help identify risks and disease outcomes. Considering cardiac arrest, they can subsidize public policies, encourage future studies and training programs for CPR, thereby improving the prognosis of patients. PMID- 26516747 TI - [Patient safety and the prevention of skin and mucosal lesions associated with airway invasive devices]. AB - OBJECTIVE: To analyze the care implemented by the nursing team to promote the safety of adult patients and prevention of skin and mucosal lesions associated with the presence of lower airways invasive devices. METHOD: Study with qualitative and quantitative approach, descriptive and exploratory type, whose investigative scenarios were adult inpatient units of a hospital in the West Frontier of Rio Grande do Sul. The study subjects consisted of nurses, nursing technicians and nursing assistants. RESULTS: A total of 118 professionals were interviewed. We highlight the observed specific care with endotracheal tube and tracheostomy, management and assessment of the cuff and the criteria used to secretion aspiration. CONCLUSION: There is a superficial nursing work in the patient direct care and a differentiation in relation to the perception of nurse technicians, especially those working in the intensive care unit, who presented major property and view of the patient's clinical status. PMID- 26516748 TI - [Triage at the Emergency Department: association between triage levels and patient outcome]. AB - OBJECTIVE: Identify association between sociodemographic, clinical and triage categories with protocol outcomes developed at Hospital Sao Paulo (HSP). METHODS: Retrospective cohort study conducted with patients older than 18 years submitted to the triage protocol in August 2012. Logistic regression was used to associate the risk categories to outcomes (p-value <=0,05). RESULTS: Men with older age and those treated in clinical specialties had higher rates of hospitalization and death. Patients in the high-priority group had hospitalization and mortality rates five and 10.6 times, respectively (p < 0.0001). CONCLUSION: The high priority group experienced higher hospitalization and mortality rates. The protocol was able to detect patients with more urgent conditions and to identify risk factors for hospitalization and death. PMID- 26516749 TI - [Heart failure as a predictor of functional dependence in hospitalized elderly]. AB - OBJECTIVE: Identify whether Heart Failure (HF) is a predictor of functional dependence for Basic Activities of Daily Living (BADL) in hospitalized elderly. METHODS: We investigated medical records and assessed dependence to BADL (by the Katz Index) of 100 elderly admitted to a geriatric ward of a university hospital. In order to verify if HF is a predictor of functional dependence, linear regression analyzes were performed. RESULTS: The prevalence of HF was 21%; 95% of them were dependent for BADLs. Bathing was the most committed ADL. HF is a predictor of dependence in hospitalized elderlies, increasing the chance of functional decline by 5 times (95% CI, 0.94-94.48), the chance of functional deterioration by 3.5 times (95% CI, 1.28-11.66; p <0.02) and reducing 0.79 points in the Katz Index score (p <0.05). CONCLUSION: HF is a dependency predictor of ADL in hospitalized elderly, who tend to be more dependent, especially for bathing. PMID- 26516750 TI - [Perceived stress in elderly stroke survivors after hospital discharge to home]. AB - OBJECTIVE: To evaluate the relationship between perceived stress and comorbidities, neurological deficit, functional independence and depressive symptoms of stroke survivors after hospital discharge. METHOD: Cross-sectional study with 90 elderly stroke survivors. The National Institutes of Health Stroke Scale instrument, the Functional Independence Measure instrument, the Geriatric Depression Scale and the Perceived Stress Scale were used. Bivariate Pearson correlation, independent t test and multiple regression analysis were used to evaluate the relationship between perceived stress and other variables. RESULTS: The final regression model showed that higher perceived stress was related to less functional independence (p= 0.022) and more depressive symptoms (p <0.001). CONCLUSION: At hospital discharge, interventions should be planned for the treatment of depressive symptoms and to create adaptation strategies to the reduction of functional independence, in order to reduce the stress of the survivors. PMID- 26516751 TI - [Pain intensity among institutionalized elderly: a comparison between numerical scales and verbal descriptors]. AB - OBJECTIVE: Correlating two unidimensional scales for measurement of self-reported pain intensity for elderly and identifying a preference for one of the scales. METHOD: A study conducted with 101 elderly people living in Nursing Home who reported any pain and reached ( 13 the scores on the Mini-Mental State Examination. A Numeric Rating Scale - (NRS) of 11 points and a Verbal Descriptor Scale (VDS) of five points were compared in three evaluations: overall, at rest and during movement. RESULTS: Women were more representative (61.4%) and the average age was 77.0+/-9.1 years. NRS was completed by 94.8% of the elderly while VDS by 100%. The association between the mean scores of NRS with the categories of VDS was significant, indicating convergent validity and a similar metric between the scales. CONCLUSION: Pain measurements among institutionalized elderly can be made by NRS and VDS; however, the preferred scale for the elderly was the VDS, regardless of gender. PMID- 26516752 TI - [Nursing beliefs and actions in exercising patient advocacy in a hospital context]. AB - OBJECTIVE: Analyzing beliefs and actions of nurses in exercising patient advocacy in a hospital context. METHOD: A quantitative cross-sectional exploratory and descriptive study, conducted with 153 nurses from two hospitals in southern Brazil, one public and one philanthropic, by applying Protective Nursing Advocacy Scale - Brazilian version. Data were analyzed using descriptive statistics and analysis of variance. RESULTS: Nurses believe they are advocating for patients in their workplaces, and agree that they should advocate, especially when vulnerable patients need their protection. Personal values and professional skills have been identified as major sources of support for the practice of advocacy. CONCLUSION: Nurses do not disagree nor agree that advocating for patients in their working environments can bring them negative consequences. It is necessary to recognize how the characteristics of public and private institutions have helped or not helped in exercising patient advocacy by nurses. PMID- 26516753 TI - Toward validating the Italian version of the "Spanish Burnout Inventory": a preliminary study. AB - OBJECTIVE: The aim of this study was to develop the Italian version of the Spanish Burnout Inventory (SBI) and to examine its psychometric properties within a sample of nursing staff. METHOD: The study was cross-sectional and not randomized. The data were gathered using an anonymous, self-report questionnaire. The sample consisted of 391 staff nurses employed in three hospitals in the Northern Region of Italy To evaluate burnout, the SBI and the Maslach Burnout Inventory were administered. RESULTS: An Exploratory Factor Analysis showed a four-factor structure close to the expected one. All Cronbach's alpha values were satisfactory. Furthermore, correlations support the concurrent validity. CONCLUSION: Overall, the results of this study provided evidence that the SBI is an adequate instrument to study burnout in the Italian nursing sample and indicated the feeling of guilt as an important dimension to gauge the structure of this phenomenon. PMID- 26516754 TI - [Laser therapy in pressure ulcers: evaluation by the Pressure Ulcer Scale for Healing and Nursing Outcomes Classification]. AB - OBJECTIVE: To describe the pressure ulcer healing process in critically ill patients treated with conventional dressing therapy plus low-intensity laser therapy evaluated by the Pressure Ulcer Scale for Healing (PUSH) and the result of Wound Healing: Secondary Intention, according to the Nursing Outcomes Classification (NOC). METHOD: Case report study according to nursing process conducted with an Intensive Care Unit patient. Data were collected with an instrument containing the PUSH and the result of the NOC. In the analysis we used descriptive statistics, considering the scores obtained on the instrument. RESULTS: A reduction in the size of lesions of 7cm to 1.5cm of length and 6cm to 1.1cm width, in addition to the increase of epithelial tissue and granulation, decreased secretion and odor. CONCLUSION: There was improvement in the healing process of the lesion treated with adjuvant therapy and the use of NOC allowed a more detailed and accurate assessment than the PUSH. PMID- 26516755 TI - [Participation of nurses in the execution of clinical research protocol about technological innovation]. AB - OBJECTIVE: To report the nurse's experience of inclusion in interdisciplinary clinical study about technological innovation, involving people with spinal cord injury. METHOD: Descriptive experience report. The empirical support was based on notes about perspectives and practice of clinical research, with a multi professional nursing, physical education, physiotherapy and engineering staff. RESULT: The qualification includes the elaboration of the document for the Ethics Committee, familiarization among the members of staff and with the studied topic, and also an immersion into English. The nurse's knowledge gave support to the uptake of participants and time adequacy for data collection, preparation and assistance of the participants during the intervention and after collection. Nursing theories and processes have contributed to reveal risky diagnoses and the plan of care. It was the nurse's role to monitor the risk of overlapping methodological strictness to the human aspect. The skills for the clinical research must be the object of learning, including students in multidisciplinary researches. CONCLUSION: To qualify the nurse for clinical research and to potentialize its caregiver essence, some changes are needed in the educational system, professional behavior, attitude and educational assistance. PMID- 26516756 TI - [The influence of quality of life in treatment adherence of diabetic patients: a systematic review]. AB - OBJECTIVE: To verify the influence of quality of life in treatment adherence of patients with diabetes mellitus. METHOD: Systematic review of the literature using the databases MEDLINE, CINAHL, Scopus, LILACS, SciELO and Web of Science with studies published between 2003 and 2014 in English, Portuguese or Spanish. RESULTS: Six studies were included in the review, three were identified as having better quality of life scores, being related to better adherence to diabetes treatment measured by glycated hemoglobin or characteristics related to diet, exercise, use of medication and foot care. No association was found between quality of life and adherence in two investigations and a study found a negative association between these variables. CONCLUSION: There is causal relationship between quality of life and adherence with diabetes treatment. It is suggested that psychosocial aspects of patients should be considered by health professionals in the search for better clinical outcomes in diabetes care. PMID- 26516757 TI - Dysfunctional psychological responses among Intensive Care Unit nurses: a systematic review of the literature. AB - OBJECTIVE: To systematically review evidence on dysfunctional psychological responses of Intensive Care Units nurses (ICUNs), with focus on anxiety and depressive symptoms and related factors. METHOD: A literature search was performed in CINAHL, PubMed and Scopus databases, from 1999 to present, along with a critical appraisal and synthesis of all relevant data. The following key words, separately and in combination, were used: "mental status" "depressive symptoms" "anxiety" "ICU nurses" "PTSD" "burnout" "compassion fatigue" "psychological distress". RESULTS: Thirteen quantitative studies in English and Greek were included. The results suggested increased psychological burden in ICUNs compared to other nursing specialties, as well as to the general population. CONCLUSIONS: Studies investigating psychological responses of ICUNs are limited, internationally. Future longitudinal and intervention studies will contribute to a better understanding of the phenomenon. PMID- 26516758 TI - [Controlling wound odor with metronidazole: a systematic review]. AB - OBJECTIVE: Verifying the evidence of therapeutic efficacy in the topical application of metronidazole for controlling wound odor. METHODS: A systematic literature review, according to the Cochrane Collaboration recommendations. RESULTS: 329 articles were identified in the Cochrane, LILACS, SciELO, CINAHL and PubMed databases, with 14 of them being included in the final sample. Two of the studies were double-blind randomized clinical trial studies. CONCLUSION: The actual effectiveness of metronidazole in controlling wound odor cannot yet be evidenced due to the absence of strong evidence from studies on the subject, despite clinical practice recommending its benefits. PMID- 26516759 TI - Retraction: 'Amelioration of Osteoporosis and Hypovitaminosis D by Sunlight Exposure in Hospitalized Elderly Women With Alzheimer's Disease: A Randomized Controlled Trial'. PMID- 26516760 TI - Construction of Commercial Sweet Cherry Linkage Maps and QTL Analysis for Trunk Diameter. AB - A cross between the sweet cherry (Prunus avium) cultivars 'Wanhongzhu' and 'Lapins' was performed to create a mapping population suitable for the construction of a linkage map. The specific-locus amplified fragment (SLAF) sequencing technique used as a single nucleotide polymorphism (SNP) discovery platform and generated 701 informative genotypic assays; these, along with 16 microsatellites (SSRs) and the incompatibility (S) gene, were used to build a map which comprised 8 linkage groups (LGs) and covered a genetic distance of 849.0 cM. The mean inter-marker distance was 1.18 cM and there were few gaps > 5 cM in length. Marker collinearity was maintained with the established peach genomic sequence. The map was used to show that trunk diameter (TD) is under the control of 4 loci, mapping to 3 different LGs. Different locus influenced TD at a varying stage of the tree's development. The high density 'W*L' genetic linkage map has the potential to enable high-resolution identification of QTLs of agronomically relevant traits, and accelerate sweet cherry breeding. PMID- 26516763 TI - Developmental Characterization of Tail Movements in the Appendicularian Urochordate Oikopleura dioica. AB - Using high-speed video cinematography, we characterized kinematically the spontaneous tail movements made by the appendicularian urochordate Oikopleura dioica. Videos of young adult (1-day-old) animals discriminated 4 cardinal movement types: bending, nodding, swimming and filtering, each of which had a characteristic signature including cyclicity, event or cycle duration, cycle frequency, cycle frequency variation, laterality, tail muscle segment coordination and episode duration. Bending exhibited a more common, unilateral form (single bending) and a rarer, bilateral form (alternating bending). Videos of developing animals showed that bending and swimming appeared in rudimentary form starting just after hatching and exhibited developmental changes in movement excursion, duration and frequency, whereas nodding and filtering appeared in the fully mature form in young adults at the time of first house production. More complex behaviors were associated with inflating, entering and exiting the house. We also assessed the influence of descending inputs by separating the tail (which contains all muscles and most likely the neural circuits that generate most motor outputs) from the head. Isolated tails spontaneously generated either bending or swimming movements in abnormally protracted episodes. This together with other observations of interactions between bending and swimming behaviors indicates the presence of several types of descending inputs that regulate the activity of the pattern generating circuitry in the tail nervous system. PMID- 26516762 TI - Suppression of Rat Oral Carcinogenesis by Agonists of Peroxisome Proliferator Activated Receptor gamma. AB - Peroxisome-proliferator-activated receptor gamma (PPARgamma) is a ligand activated transcription factor that regulates cell proliferation, differentiation, and apoptosis. In vivo studies were performed to evaluate the activities of two thiazolidinedione PPARgamma agonists, rosiglitazone and pioglitazone, as inhibitors of oral carcinogenesis in rats. Oral squamous cell carcinomas (OSCC) were induced in male F344 rats by 4-nitroquinoline-1-oxide (NQO; 20 ppm in the drinking water for 10 weeks). In each study, groups of 30 NQO treated rats were exposed to a PPARgamma agonist beginning at week 10 (one day after completion of NQO administration) or at week 17 (7 weeks post-NQO); chemopreventive agent exposure was continued until study termination at week 22 (rosiglitazone study) or week 24 (pioglitazone study). Administration of rosiglitazone (800 mg/kg diet) beginning at week 10 increased survival, reduced oral cancer incidence, and reduced oral cancer invasion score in comparison to dietary controls; however, chemopreventive activity was largely lost when rosiglitazone administration was delayed until week 17. Administration of pioglitazone (500 mg/kg diet beginning at week 10 or 1000 mg/kg diet beginning at week 17) induced significant reductions in oral cancer incidence without significant effects on OSCC invasion scores. Transcript levels of PPARgamma and its three transcriptional variants (PPARgammav1, PPARgammav2, and PPARgammav3) were not significantly different in OSCC versus age- and site-matched phenotypically normal oral tissues from rats treated with NQO. These data suggest that PPARgamma provides a useful molecular target for oral cancer chemoprevention, and that overexpression of PPARgamma at the transcriptional level in neoplastic lesions is not essential for chemopreventive efficacy. PMID- 26516764 TI - Impact of an Ivermectin Mass Drug Administration on Scabies Prevalence in a Remote Australian Aboriginal Community. AB - BACKGROUND: Scabies is endemic in many Aboriginal and Torres Strait Islander communities, with 69% of infants infected in the first year of life. We report the outcomes against scabies of two oral ivermectin mass drug administrations (MDAs) delivered 12 months apart in a remote Australian Aboriginal community. METHODS: Utilizing a before and after study design, we measured scabies prevalence through population census with sequential MDAs at baseline and month 12. Surveys at months 6 and 18 determined disease acquisition and treatment failures. Scabies infestations were diagnosed clinically with additional laboratory investigations for crusted scabies. Non-pregnant participants weighing >=15 kg were administered a single 200 MUg/kg ivermectin dose, repeated after 2-3 weeks if scabies was diagnosed, others followed a standard alternative algorithm. PRINCIPAL FINDINGS: We saw >1000 participants at each population census. Scabies prevalence fell from 4% at baseline to 1% at month 6. Prevalence rose to 9% at month 12 amongst the baseline cohort in association with an identified exposure to a presumptive crusted scabies case with a higher prevalence of 14% amongst new entries to the cohort. At month 18, scabies prevalence fell to 2%. Scabies acquisitions six months after each MDA were 1% and 2% whilst treatment failures were 6% and 5% respectively. CONCLUSION: Scabies prevalence reduced in the six months after each MDA with a low risk of acquisition (1-2%). However, in a setting where living conditions are conducive to high scabies transmissibility, exposure to presumptive crusted scabies and population mobility, a sustained reduction in prevalence was not achieved. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trial Register (ACTRN-12609000654257). PMID- 26516765 TI - The Impact of Sex Work on Women's Personal Romantic Relationships and the Mental Separation of Their Work and Personal Lives: A Mixed-Methods Study. AB - BACKGROUND: Very limited research has been undertaken on sex workers' personal romantic relationships and the impact the nature of their work has on their relationships. This exploratory study aimed to explore the impact sex work has on women's personal romantic relationships and the use of mental separation as a coping mechanism to balance the two aspects of their lives. METHODS: Fifty-five women working in the indoor sex industry in Melbourne, Australia, were recruited to complete a self-report questionnaire about various aspects of their work, including the impact of sex work on their personal relationships. Questionnaires were completed anonymously and included both closed and open-ended questions. A further six women were interviewed to 'member check' the accuracy of the questionnaire findings. RESULTS: Most women (78%) reported that, overall, sex work affected their personal romantic relationships in predominantly negative ways, mainly relating to issues stemming from lying, trust, guilt and jealousy. A small number of women reported positive impacts from sex work including improved sexual self-esteem and confidence. Just under half of women were in a relationship at the time of the study and, of these, 51% reported their partner was aware of the nature of their work. Seventy-seven percent of single women chose to remain single due to the nature of their work. Many women used mental separation as a coping mechanism to manage the tensions between sex work and their personal relationships. Member checking validated the accuracy of the questionnaire data. CONCLUSION: This exploratory study identified a number of ways in which sex work impacts negatively on women's personal romantic relationships. The findings of this study support the need for further studies to be undertaken to determine if the findings are reflected in a larger, more representative sample of Australian sex workers and should be considered in the context of any future intervention and support programs aimed at addressing the tensions sex workers experience between their work and personal relationships. Greater public awareness and education programs aimed at addressing the negative stigma associated with the sex industry may go some way towards easing the issues faced by women in their personal relationships. PMID- 26516761 TI - Human immunodeficiency virus infection does not worsen prognosis of liver transplantation for hepatocellular carcinoma. AB - The impact of human immunodeficiency virus (HIV) infection on patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) is uncertain. This study aimed to assess the outcome of a prospective Spanish nationwide cohort of HIV-infected patients undergoing LT for HCC (2002-2014). These patients were matched (age, gender, year of LT, center, and hepatitis C virus (HCV) or hepatitis B virus infection) with non-HIV-infected controls (1:3 ratio). Patients with incidental HCC were excluded. Seventy-four HIV-infected patients and 222 non HIV-infected patients were included. All patients had cirrhosis, mostly due to HCV infection (92%). HIV-infected patients were younger (47 versus 51 years) and had undetectable HCV RNA at LT (19% versus 9%) more frequently than non-HIV infected patients. No significant differences were detected between HIV-infected and non-HIV-infected recipients in the radiological characteristics of HCC at enlisting or in the histopathological findings for HCC in the explanted liver. Survival at 1, 3, and 5 years for HIV-infected versus non-HIV-infected patients was 88% versus 90%, 78% versus 78%, and 67% versus 73% (P = 0.779), respectively. HCV infection (hazard ratio = 7.90, 95% confidence interval 1.07-56.82) and maximum nodule diameter >3 cm in the explanted liver (hazard ratio = 1.72, 95% confidence interval 1.02-2.89) were independently associated with mortality in the whole series. HCC recurred in 12 HIV-infected patients (16%) and 32 non-HIV infected patients (14%), with a probability of 4% versus 5% at 1 year, 18% versus 12% at 3 years, and 20% versus 19% at 5 years (P = 0.904). Microscopic vascular invasion (hazard ratio = 3.40, 95% confidence interval 1.34-8.64) was the only factor independently associated with HCC recurrence. CONCLUSIONS: HIV infection had no impact on recurrence of HCC or survival after LT. Our results support the indication of LT in HIV-infected patients with HCC. PMID- 26516766 TI - Novel Insights into the Proteus mirabilis Crystalline Biofilm Using Real-Time Imaging. AB - The long-term use of indwelling catheters results in a high risk from urinary tract infections (UTI) and blockage. Blockages often occur from crystalline deposits, formed as the pH rises due to the action of urease-producing bacteria; the most commonly found species being Proteus mirabilis. These crystalline biofilms have been found to develop on all catheter materials with P. mirabilis attaching to all surfaces and forming encrustations. Previous studies have mainly relied on electron microscopy to describe this process but there remains a lack of understanding into the stages of biofilm formation. Using an advanced light microscopy technique, episcopic differential interference contrast (EDIC) microscopy combined with epifluorescence (EF), we describe a non-destructive, non contact, real-time imaging method used to track all stages of biofilm development from initial single cell attachment to complex crystalline biofilm formation. Using a simple six-well plate system, attachment of P. mirabilis (in artificial urine) to sections of silicone and hydrogel latex catheters was tracked over time (up to 24 days). Using EDIC and EF we show how initial attachment occurred in less than 1 h following exposure to P. mirabilis. This was rapidly followed by an accumulation of an additional material (indicated to be carbohydrate based using lectin staining) and the presence of highly elongated, motile cells. After 24 h exposure, a layer developed above this conditioning film and within 4 days the entire surface (of both catheter materials) was covered with diffuse crystalline deposits with defined crystals embedded. Using three-dimensional image reconstruction software, cells of P. mirabilis were seen covering the crystal surfaces. EDIC microscopy could resolve these four components of the complex crystalline biofilm and the close relationship between P. mirabilis and the crystals. This real-time imaging technique permits study of this complex biofilm development with no risk of artefacts due to sample manipulation. A full understanding of the stages and components involved in crystalline encrustation formation will aid in the development of new protocols to manage and ultimately prevent catheter blockage. PMID- 26516767 TI - Segmentation of Uterus Using Laparoscopic Ultrasound by an Image-Based Active Contour Approach for Guiding Gynecological Diagnosis and Surgery. AB - In laparoscopic gynecologic surgery, ultrasound has been typically implemented to diagnose urological and gynecological conditions. We applied laparoscopic ultrasonography (using Esaote 7.5~10MHz laparoscopic transducer) on the retrospective analyses of 42 women subjects during laparoscopic extirpation and excision of gynecological tumors in our hospital from August 2011 to August 2013. The objective of our research is to develop robust segmentation technique for isolation and identification of the uterus from the ultrasound images, so as to assess, locate and guide in removing the lesions during laparoscopic operations. Our method enables segmentation of the uterus by the active contour algorithm. We evaluated 42 in-vivo laparoscopic images acquired from the 42 patients (age 39.1 +/- 7.2 years old) and selected images pertaining to 4 cases of congenital uterine malformations and 2 cases of pelvic adhesions masses. These cases (n = 6) were used for our uterus segmentation experiments. Based on them, the active contour method was compared with the manual segmentation method by a medical expert using linear regression and the Bland-Altman analysis (used to measure the correlation and the agreement). Then, the Dice and Jaccard indices are computed for measuring the similarity of uterus segmented between computational and manual methods. Good correlation was achieved whereby 84%-92% results fall within the 95% confidence interval in the Student t-test) and we demonstrate that the proposed segmentation method of uterus using laparoscopic images is effective. PMID- 26516768 TI - A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo. AB - The CD4 binding site (CD4bs) on the envelope glycoprotein is a major site of vulnerability that is conserved among different HIV-1 isolates. Many broadly neutralizing antibodies (bNAbs) to the CD4bs belong to the VRC01 class, sharing highly restricted origins, recognition mechanisms and viral escape pathways. We sought to isolate new anti-CD4bs bNAbs with different origins and mechanisms of action. Using a gp120 2CC core as bait, we isolated antibodies encoded by IGVH3 21 and IGVL3-1 genes with long CDRH3s that depend on the presence of the N-linked glycan at position-276 for activity. This binding mode is similar to the previously identified antibody HJ16, however the new antibodies identified herein are more potent and broad. The most potent variant, 179NC75, had a geometric mean IC80 value of 0.42 MUg/ml against 120 Tier-2 HIV-1 pseudoviruses in the TZM.bl assay. Although this group of CD4bs glycan-dependent antibodies can be broadly and potently neutralizing in vitro, their in vivo activity has not been tested to date. Here, we report that 179NC75 is highly active when administered to HIV-1 infected humanized mice, where it selects for escape variants that lack a glycan site at position-276. The same glycan was absent from the virus isolated from the 179NC75 donor, implying that the antibody also exerts selection pressure in humans. PMID- 26516770 TI - Correction: Paracoccidoides brasiliensis 30 kDa Adhesin: Identification as a 14-3 3 Protein, Cloning and Subcellular Localization in Infection Models. PMID- 26516769 TI - Receptor, Ligand and Transducer Contributions to Dopamine D2 Receptor Functional Selectivity. AB - Functional selectivity (or biased agonism) is a property exhibited by some G protein-coupled receptor (GPCR) ligands, which results in the modulation of a subset of a receptor's signaling capabilities and more precise control over complex biological processes. The dopamine D2 receptor (D2R) exhibits pleiotropic responses to the biogenic amine dopamine (DA) to mediate complex central nervous system functions through activation of G proteins and beta-arrestins. D2R is a prominent therapeutic target for psychological and neurological disorders in which DA biology is dysregulated and targeting D2R with functionally selective drugs could provide a means by which pharmacotherapies could be developed. However, factors that determine GPCR functional selectivity in vivo may be multiple with receptors, ligands and transducers contributing to the process. We have recently described a mutagenesis approach to engineer biased D2R mutants in which G protein-dependent ([Gprot]D2R) and beta-arrestin-dependent signaling ([betaarr]D2R) were successfully separated (Peterson, et al. PNAS, 2015). Here, permutations of these mutants were used to identify critical determinants of the D2R signaling complex that impart signaling bias in response to the natural or synthetic ligands. Critical residues identified in generating [Gprot]D2R and [betaarr]D2R conferred control of partial agonism at G protein and/or beta arrestin activity. Another set of mutations that result in G protein bias was identified that demonstrated that full agonists can impart unique activation patterns, and provided further credence to the concept of ligand texture. Finally, the contributions and interplay between different transducers indicated that G proteins are not aberrantly activated, and that receptor kinase and beta arrestin activities are inextricably linked. These data provide a thorough elucidation of the feasibility and malleability of D2R functional selectivity and point to means by which novel in vivo therapies could be modeled. PMID- 26516772 TI - Don't Be Afraid of the Skeleton: It Is Your Patient's Best Friend! PMID- 26516771 TI - Epitope-Specific Anti-hCG Vaccines on a Virus Like Particle Platform. AB - The possibility of a contraceptive vaccine targeting human chorionic gonadotropin has long been recognized, but never fully realized. Here we describe an epitope specific approach based on immunogenic display of hCG-derived peptides on virus like particles of RNA bacteriophage. A number of recombinant VLPs were constructed, each displaying a different hCG-derived peptide. Some were taken from the disordered C-terminal tail of the hormone, another came from an internal loop, and yet another was an epitope mimic produced by affinity-selection on an hCG-neutralizing antibody target. Immunization of mice with some VLPs yielded antisera that bound the hormone and neutralized hCG biological activity. PMID- 26516773 TI - Evaluation of Fibroblast Growth Factor Receptor 2 Expression, Heterogeneity and Clinical Significance in Gastric Cancer. AB - BACKGROUND: We aimed to evaluate the protein and mRNA expression of fibroblast growth factor receptor 2 (FGFR2) by immunohistochemistry (IHC) and mRNA in situ hybridization (ISH), respectively, and to assess the heterogeneity of FGFR2 expression in gastric cancer (GC). METHODS: A tissue microarray containing 362 surgically resected GC tissues and 135 matched metastatic lymph nodes was evaluated using FGFR2b IHC and FGFR2 ISH. FGFR2 fluorescence ISH was also performed in 188 cases. RESULTS: All FGFR2-amplified cases (5 of 188) showed FGFR2b protein and FGFR2 mRNA overexpression (p < 0.001), and FGFR2 amplification was not identified in FGFR2b IHC- and FGFR2 mRNA ISH-negative cases. Kaplan-Meier survival analysis revealed that FGFR2b protein and FGFR2 mRNA overexpression was significantly associated with a poor overall survival (p < 0.001 and p = 0.012, respectively), and multivariate analyses showed that FGFR2 mRNA overexpression was an independent biomarker of a poor overall survival. Intratumoral heterogeneity of FGFR2b protein and FGFR2 mRNA overexpression was observed in 5 of 9 (55.5%) and 18 of 21 (85.7%) cases, respectively. Discordant FGFR2b and FGFR2 expression results between primary and matched metastatic lymph nodes were observed in 5 of 9 (55.5%) and 4 of 14 (28.6%) cases, respectively. CONCLUSIONS: Intratumoral heterogeneity and discordant FGFR2b expression in primary tumors and metastatic lymph nodes are common in GC. PMID- 26516774 TI - Hypoxia Induces a Prothrombotic State Independently of the Physical Activity. AB - Hypoxia (oxygen deprivation) is known to be associated with deep vein thrombosis and venous thromboembolism. We attempted to get a better comprehension of its mechanism by going to high altitude, thereby including the potential contributing role of physical activity. Two groups of 15 healthy individuals were exposed to hypoxia by going to an altitude of 3900 meters, either by climbing actively (active group) or transported passively by cable car (passive group). Both groups were tested for plasma fibrinogen, von Willebrand factor and factor VIII levels, fibrinolysis, thrombin generating capacity, heart rate, oxygen saturation levels and blood pressure. As a control for the passive group, 7 healthy volunteers stayed immobile in bed for 7 days at normoxic conditions. The heart rate increased and oxygen saturation levels decreased with increasing altitude. Fibrinolysis and fibrinogen levels were not affected. Factor VIII and von Willebrand factor levels levels increased significantly in the active group, but not in the passive group. Plasma thrombin generation remained unchanged in both the active and passive group with increasing altitude and during 7 days of immobility in healthy subjects. However, by applying whole blood thrombin generation, we found an increased peak height and endogenous thrombin potential, and a decreased lagtime and time-to-peak with increasing levels of hypoxia in both groups. In conclusion, by applying whole blood thrombin generation we demonstrated that hypoxia causes a prothrombotic state. As thrombin generation in plasma did not increase, our results suggest that the cellular part of the blood is involved in the prothrombotic phenotype induced by hypoxia. PMID- 26516775 TI - Emergence of Shared Intentionality Is Coupled to the Advance of Cumulative Culture. AB - There is evidence that the sharing of intentions was an important factor in the evolution of humans' unique cognitive abilities. Here, for the first time, we formally model the coevolution of jointly intentional behavior and cumulative culture, showing that rapid techno-cultural advance goes hand in hand with the emergence of the ability to participate in jointly intentional behavior. Conversely, in the absence of opportunities for significant techno-cultural improvement, the ability to undertake jointly intentional behavior is selected against. Thus, we provide a unified mechanism for the suppression or emergence of shared intentions and collaborative behavior in humans, as well as a potential cause of inter-species diversity in the prevalence of such behavior. PMID- 26516776 TI - Correction: A New Large Hyainailourine from the Bartonian of Europe and Its Bearings on the Evolution and Ecology of Massive Hyaenodonts (Mammalia). PMID- 26516777 TI - Urinary Retention, Incontinence, and Dysregulation of Muscarinic Receptors in Male Mice Lacking Mras. AB - Here we show that male, but not female mice lacking expression of the GTPase M Ras developed urinary retention with distention of the bladder that exacerbated with age but occurred in the absence of obvious anatomical outlet obstruction. There were changes in detrusor morphology in Mras-/- males: Smooth muscle tissue, which exhibited a compact organization in WT mice, appeared disorganized and became increasingly 'layered' with age in Mras-/- males, but was not fibrotic. Bladder tissue near the apex of bladders of Mras-/- males exhibited hypercontractility in response to the cholinergic agonist carbachol in in vitro, while responses in Mras-/- females were normal. In addition, spontaneous phasic contractions of detrusors from Mras-/- males were increased, and Mras-/- males exhibited urinary incontinence. We found that expression of the muscarinic M2 and M3 receptors that mediate the cholinergic contractile stimuli of the detrusor muscle was dysregulated in both Mras-/- males and females, although only males exhibited a urinary phenotype. Elevated expression of M2R in young males lacking M-Ras and failure to upregulate M3R with age resulted in significantly lower ratios of M3R/M2R expression that correlated with the bladder abnormalities. Our data suggests that M-Ras and M3R are functionally linked and that M-Ras is an important regulator of male bladder control in mice. Our observations also support the notion that bladder control is sexually dimorphic and is regulated through mechanisms that are largely independent of acetylcholine signaling in female mice. PMID- 26516779 TI - Antioxidant, Antimicrobial Activity and Medicinal Properties of Grewia asiatica L. AB - Since ancient time, India is a well known subcontinent for medicinal plants where diversity of plants is known for the treatment of many human disorders. Grewia asiatica is a dicot shrub belonging to the Grewioideae family and well known for its medicinally important fruit commonly called Falsa. G. asiatica, a seasonal summer plant is distributed in the forest of central India, south India, also available in northern plains and western Himalaya up to the height of 3000 ft. Fruits of G. asiatica are traditionally used as a cooling agent, refreshing drink, anti-inflammatory agent and for the treatment of some urological disorders. Recent advancement of Falsa researches concluded its antimicrobial and anti-diabetic activity. Since ancient time medicinal plants are traditionally used for the treatment of different diseases G. asiatica fruit is the edible and tasty part of the plant, now considered as a valuable source of unique natural product for the development of medicines which are used in different disease conditions like anti-diabetic, anti-inflammatory, anti-cancerous and antimicrobial. Now a days, G. asiatica is being used in different Ayurvedic formulation for the cure of different types of diseases. Different pharmacological investigations reveal the presence of phenols, saponnins, flavonoids and tannins compound in the fruits. Present review highlights the phytopharmacological and different traditional use of G. asiatica which is mentioned in ancient Ayurvedic texts. This review stimulates the researchers and scientists for further research on G. asiatica. PMID- 26516781 TI - Characterization of Pores in Dense Nanopapers and Nanofibrillated Cellulose Membranes: A Critical Assessment of Established Methods. AB - Nanofibrillated cellulose (NFC) is a natural fibrous material that can be readily processed into membranes. NFC membranes for fluid separation work in aqueous medium, thus in their swollen state. The present study is devoted to a critical investigation of porosity, pore volume, specific surface area, and pore size distribution of dry and wet NFC nanopapers, also known as membranes, with various established techniques, such as electron microscopy, helium pycnometry, mercury intrusion, gas adsorption (N2 and Kr), and thermoporometry. Although these techniques can be successfully applied to inorganic materials (e.g., mesoporous silica), it is necessary to appraise them for organic and hydrophilic products such as NFC membranes. This is due to different phenomena occurring at the materials interfaces with the probing fluids. Mercury intrusion and gas adsorption are often used for the characterization of porosity-related properties; nevertheless, both techniques characterize materials in the dry state. In parallel, thermoporometry was employed to monitor the structure changes upon swelling, and a water permeance test was run to show the accessibility of the membranes to fluids. For the first time, the methods were systematically screened, and we highlighted the need of uniform sample treatments prior to the measurements (i.e., sample cutting and outgassing protocols) in order to harmonize results from the literature. The need for revising the applicability range of mercury intrusion and the inappropriateness of nitrogen adsorption were pointed out. We finally present a table for selecting the most appropriate method to determine a desired property and propose guidelines for results interpretation from which future users could profit. PMID- 26516780 TI - Peer Support Workers in Health: A Qualitative Metasynthesis of Their Experiences. AB - OBJECTIVE: Peer support models, where an individual has a specific illness or lifestyle experience and supports others experiencing similar challenges, have frequently been used in different fields of healthcare to successfully engage hard-to-reach groups. Despite recognition of their value, the impact of these roles on the peer has not been systematically assessed. By synthesising the qualitative literature we sought to review such an impact, providing a foundation for designing future clinical peer models. METHODS: Systematic review and qualitative metasynthesis of studies found in Medline, CINAHL or Scopus documenting peer worker experiences. RESULTS: 1,528 papers were found, with 34 meeting the criteria of this study. Findings were synthesised to reveal core constructs of reframing identity through reciprocal relations and the therapeutic use of self, enhancing responsibility. CONCLUSIONS: The ability of the Peer Support Worker to actively engage with other marginalised or excluded individuals based on their unique insight into their own experience supports a therapeutic model of care based on appropriately sharing their story. Our findings have key implications for maximising the effectiveness of Peer Support Workers and in contributing their perspective to the development of a therapeutic model of care. PMID- 26516778 TI - Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. AB - BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0*10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction >= 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD. PMID- 26516782 TI - Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold. AB - G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., 1-3). Herein, we present the first structure-activity relationship study for the 2 arylindole antagonist 3, comprising the design, synthesis, and pharmacological evaluation of a focused library of 3-substituted 2-arylindoles. In a FRET-based inositol monophosphate (IP1) assay we identified compounds 7, 13e, and 34b as antagonists at the GPRC6A receptor in the low micromolar range and show that 7 and 34b display >9-fold selectivity for the GPRC6A receptor over related GPCRs, making 7 and 34b the most potent and selective antagonists for the GPRC6A receptor reported to date. PMID- 26516783 TI - One-Dimensional [P15](-) Tubes in Layered Semiconducting AgP15. AB - AgP15 was synthesized from the elements via a short-way transport reaction following the mineralizer concept. The needle-shaped crystals were characterized by single-crystal and powder X-ray diffraction. It crystallizes triclinically in space group P1 with cell parameters of a = 6.937(1) A, b = 9.000(1) A, c = 11.103(2) A, alpha = 99.95(1) degrees , beta = 99.61(1) degrees , and gamma = 105.980(9) degrees . AgP15 exhibits a tubular phosphorus substructure related but neither isotypic nor isostructural to the alkaline phosphides MP15 (M = Li-Rb). The thermal properties, electronic structure, and experimental band gap of this new semiconductor have been determined. Finally, Raman spectra of AgP15 and selected alkaline-metal polyphosphides MP15 have been measured and interpreted. AgP15 represents the first transition-metal representative of this class of materials. PMID- 26516784 TI - Low-Temperature Atomic Layer Deposition of Crystalline and Photoactive Ultrathin Hematite Films for Solar Water Splitting. AB - We developed a low-temperature atomic layer deposition route to deposit phase pure and crystalline hematite (alpha-Fe2O3) films at 230 degrees C without the need for postannealing. Homogenous and conformal deposition with good aspect ratio coverage was demonstrated on a nanostructured substrate and analyzed by transmission electron microscopy. These as-deposited alpha-Fe2O3 films were investigated as photoanodes for photoelectrochemical water oxidation and found to be highly photoactive. Combined with a TiO2 underlayer and a low-cost Ni(OH)2 catalyst, hematite films of less than 10 nm in thickness reached photocurrent densities of 0.3 mA cm(-2) at 1.23 V vs RHE and a photocurrent onset potential of less than 0.9 V vs RHE, previously unseen for films this thin and without high temperature annealing. In a thickness-dependent photoelectrochemical analysis, we identified a hematite thickness of only 10 nm to yield the highest internal quantum efficiency when using a suitable underlayer such as TiO2 that induces doping of the hematite film and reduces electron/hole recombination at the back contact. We find that, at high bias potentials, photocurrent density and quantum efficiency proportionally increase with light absorption in films thinner than 10 nm and are limited by the space charge layer width in thicker films. Thus, we propose to apply hematite films of 10 nm in thickness for future developments on suitable nanostructured conductive scaffolds that can now be extended to organic scaffolds due to our low-temperature process. PMID- 26516785 TI - Linking in Vitro Effects and Detected Organic Micropollutants in Surface Water Using Mixture-Toxicity Modeling. AB - Surface water can contain countless organic micropollutants, and targeted chemical analysis alone may only detect a small fraction of the chemicals present. Consequently, bioanalytical tools can be applied complementary to chemical analysis to detect the effects of complex chemical mixtures. In this study, bioassays indicative of activation of the aryl hydrocarbon receptor (AhR), activation of the pregnane X receptor (PXR), activation of the estrogen receptor (ER), adaptive stress responses to oxidative stress (Nrf2), genotoxicity (p53) and inflammation (NF-kappaB) and the fish embryo toxicity test were applied along with chemical analysis to water extracts from the Danube River. Mixture-toxicity modeling was applied to determine the contribution of detected chemicals to the biological effect. Effect concentrations for between 0 to 13 detected chemicals could be found in the literature for the different bioassays. Detected chemicals explained less than 0.2% of the biological effect in the PXR activation, adaptive stress response, and fish embryo toxicity assays, while five chemicals explained up to 80% of ER activation, and three chemicals explained up to 71% of AhR activation. This study highlights the importance of fingerprinting the effects of detected chemicals. PMID- 26516786 TI - Voltammetric pH Nanosensor. AB - Nanoscale pH evaluation is a prerequisite for understanding the processes and phenomena occurring at solid-liquid, liquid-liquid, and liquid-gas interfaces, e.g., heterogeneous catalysis, extraction, partitioning, and corrosion. Research on the homogeneous processes within small volumes such as intracellular fluids, microdroplets, and microfluidic chips also requires nanometer scale pH assessment. Due to the opacity of numerous systems, optical methods are useless and, if applicable, require addition of a pH-sensitive dye. Potentiometric probes suffer from many drawbacks such as potential drift and lack of selectivity. Here, we present a voltammetric nanosensor for reliable pH assessment between pH 2 and 12 with high spatial resolution. It consists of a pyrolytic carbon nanoelectrode obtained by chemical vapor deposition (CVD) inside a quartz nanopipette. The carbon is modified by adsorption of syringaldazine from its ethanolic solution. It exhibits a stable quasi-reversible cyclic voltammogram with nearly Nernstian dependency of midpeak potentials (-54 mV/pH). This sensor was applied as a probe for scanning electrochemical microscopy (SECM) in order to map pH over a platinum ultramicroelectrode (UME), generating hydroxide ions (OH(-)) by the oxygen reduction reaction (ORR) at a diffusion-controlled rate in aerated phosphate buffered saline (PBS). The results reveal the alkalization of the electrolyte close to the oxygen reducing electrode, showing the insufficient buffer capacity of PBS to maintain a stable pH at the given conditions. PMID- 26516787 TI - Enantioselective Synthesis of N-PMP-1,2-dihydropyridines via Formal [4 + 2] Cycloaddition between Aqueous Glutaraldehyde and Imines. AB - A simple and highly practical one-pot formal [4 + 2] cycloaddition approach for the enantioselective synthesis of N-PMP-1,2-dihydropyridines (DHPs) is described. This chemistry involves an amino-catalytic direct Mannich reaction/cyclization followed by IBX-mediated chemo- and regioselective oxidation sequence between readily available aqueous glutaraldehyde and imines under very mild conditions. A series of N-PMP-1,2-DHPs have been prepared in high yields and excellent enantioselectivity. This method also gives access to both enantiomers of 1,2-DHPs in surplus amount by shifting the catalyst configuration. PMID- 26516788 TI - Isocyanate-Free Routes to Polyurethanes and Poly(hydroxy Urethane)s. PMID- 26516789 TI - High utilization of inpatient detoxification: predictors among US veterans. AB - BACKGROUND: Readmissions are among the most problematic and expensive problems in the treatment of substance use disorders. OBJECTIVE: To evaluate the characteristics associated with four or more inpatient medically managed detoxification admissions in FY 2012, when all had post-discharge appointments within 7 days. METHODS: A retrospective case control study. A total of 38 (6.0%) of 623 unique veterans had four or more detoxification admissions (high utilizers). A random sample of 42 was selected from the remaining 585 people (comparison group). In all, 264 detoxification and 70 hospital admissions for other reasons were reviewed. RESULTS: The high utilizers had more alcohol use disorder (AUD, 82% versus 59%, p = 0.03) of significantly longer duration (mean 28.9 years [SD = 17] vs. 19.6 [SD = 13.4], p = 0.01). AUD increased the odds of being a high utilizer three-fold [OR = 3.0, 95% CI 1.1, 8.4], and every additional year of AUD, increased the number of admissions 1.3%, p = 0.0006. The high utilizers did not differ from the comparison group with regards to either number of hospitalizations for other reasons (mean 1.2 [SD = 1.9] vs. 0.57 [SD = 0.8], p = 0.06) or rate of 7 day post discharge appointments kept (46.9% vs. 49.3%, p = 0.82). CONCLUSIONS: High utilizers were a small percentage of patients (6.0%) who accounted for a disproportionate number (23%) of 977 detoxification admissions. They had greater disease severity as manifest by more years of AUD. They were not more likely to have hospitalizations for other reasons or less likely to keep post discharge appointments. These patients may warrant different services tailored to prevent hospital readmissions for detoxification. PMID- 26516790 TI - Understanding the structural mechanisms of antibiotic resistance sets the platform for new discovery. AB - Understanding the structural basis of antibacterial resistance may enable rational design principles that avoid and subvert that resistance, thus leading to the discovery of more effective antibiotics. In this review, we explore the use of crystal structures to guide new discovery of antibiotics that are effective against resistant organisms. Structures of efflux pumps bound to substrates and inhibitors have aided the design of compounds with lower affinity for the pump or inhibitors that more effectively block the pump. Structures of beta-lactamase enzymes have revealed the mechanisms of action toward key carbapenems and structures of gyrase have aided the design of compounds that are less susceptible to point mutations. PMID- 26516791 TI - Marking 20 years of aging and mental health. PMID- 26516792 TI - Regulation of RIPK1's cell death function by phosphorylation. PMID- 26516793 TI - Neuroprotective properties of the PrP-like Shadoo glycoprotein assessed in the middle cerebral artery occlusion model of ischemia. AB - Biochemical similarities have been noted between the natively unstructured region of the cellular prion protein, PrP(C), and a GPI-linked glycoprotein called Shadoo (Sho); these proteins are encoded by the Prnp and Sprn genes, respectively. Both proteins are expressed in the adult central nervous system and they share overlapping partners, including each other, in interactome studies. As prior studies have ascribed neuroprotective properties to the N-terminal region of PrP(C), specifically the octarepeat region, we investigated Sho's neuroprotective properties. To this end we assessed Sho-null (Sprn(0/0)) and hemizygous (Sprn(0/+)) mice in the middle cerebral artery occlusion (MCAO) model versus wild type mice and also vs. transgene-rescued Sprn(0/0)-TgSprn mice. Sprn(0/0) mice had a tendency to greater fragility in reaching endpoint and deficits in parameters including infarct volume and neurogenesis, with a reciprocal trend noted in transgene-rescued mice; however these effects did not reach significance. Loss of both PrP(C) and Sho immunostaining occurred in parallel to neuronal loss on the ipsilateral side of MCAO-lesioned animals; while focal elevations in immunostaining in the penumbra region were sometimes evident for PrP(C), they were not noted for Sho. Our studies argue against discernible neuroprotective action of Sho in the genetic backgrounds used for this MCAO paradigm. Whether or not the positively charged N-terminal regions in Sho and PrP(C) fulfil different roles in vivo remains to be determined. PMID- 26516795 TI - Effusive-constrictive pericarditis successfully treated with anakinra. PMID- 26516794 TI - Predictors of urine drug testing for patients with chronic pain: Results from a national cohort of U.S. veterans. AB - BACKGROUND: Urine drug testing (UDT) is recommended for all patients who initiate chronic opioid therapy (COT) for the treatment of chronic pain; however, it is infrequently utilized. Some prior research has identified factors that may predict UDT, but studies have been limited. The purpose of this study is to examine the rate and predictors of UDT among a national sample of patients with chronic pain who had new initiations of COT. METHODS: Administrative data were examined for all veterans receiving medical care at Department of Veterans Affairs medical facilities who had new initiations of chronic opioid therapy (COT) during fiscal year 2011. RESULTS: Nineteen percent of patients who had new initiations of COT for chronic noncancer pain received UDT within 90 days of starting opioids. In adjusted analyses, patient-level factors that predicted increased likelihood of UDT included male gender (risk ratio [RR] = 1.23, 95% confidence interval [CI] = 1.02-1.49), Black race (RR = 1.20, 95% CI = 1.06 1.37), divorced/separated marital status (RR = 1.13, 95% CI = 1.02-1.25), higher pain intensity (RR = 1.03, 95% CI = 1.01-1.05), comorbid substance use disorder (RR = 1.42, 95% CI = 1.27-1.60), posttraumatic stress disorder (PTSD) (RR = 1.14, 95% CI = 1.01-1.29), bipolar disorder or schizophrenia (RR = 1.29, 95% CI = 1.08 1.53), having received UDT prior to initiating opioid therapy (RR = 1.43, 95% CI = 1.26-1.62), and a higher baseline opioid dose (RR = 1.38-1.81, 95% CIs = 1.20 1.58, 1.57-2.09). Age was also associated with UDT, in a nonlinear manner. Several factors were associated with lower likelihood of UDT, including living in a highly rural setting (RR = 0.62, 95% CI = 0.29-0.99), having a VA service connected disability (RR = 0.85-0.89, 95% CIs = 0.75-0.97, 0.79-0.99), and having a nurse practitioner or physician assistant as one's primary care clinician (RR = 0.72, 95% CI = 0.61-0.85). CONCLUSIONS: Urine drug testing was conducted with 19% of patients who had new initiations of COT. Factors that predicted UDT were multifaceted and included patient and clinician variables. Multidimensional system-level interventions may be needed to facilitate widespread implementation of UDT. PMID- 26516796 TI - Primitive Myxoid Mesenchymal Tumor of Infancy Involving Chest Wall in an Infant: A Case Report and Clinicopathologic Correlation. AB - Primitive myxoid mesenchymal tumor of infancy (PMMTI) is a rare mesenchymal tumor of early childhood characterized by aggressive local infiltration of surrounding structures, rare metastases, and poor response to chemotherapy. Surgery alone appears to be the most effective treatment given the lack of predilection for metastasis and poor response to traditional chemotherapy. Below we report a patient with PMMTI successfully managed with surgery and observation and summarize the existing literature on histopathologic features and treatment of this lesion. PMID- 26516797 TI - Methicillin-resistant Staphylococcus aureus in Ohio EMS Providers: A Statewide Cross-sectional Study. AB - The objective was to determine the nasal carriage prevalence of methicillin resistant Staphylococcus aureus (MRSA) among emergency medical service (EMS) personnel and the associated risk factors. A cross-sectional study was conducted among Ohio EMS personnel randomly sampled from 84 urban and rural agencies. Surveys assessing demographics, occupational history, health, cohabitation status, and hygiene practice were collected with nasal swabs from those who enrolled. Survey weight adjusted analysis was performed (1) to estimate MRSA nasal carriage prevalence of Ohio EMS providers, and (2) to identify variables associated with MRSA. MRSA was detected in 4.6% (13/280) EMS personnel sampled. After employing a survey-weighted analysis the following risk factors associated with MRSA carriage were identified: those who did not practice frequent hand hygiene after glove use (OR, 10.51; 95% CI, 2.54-43.45; P = 0.0012), living with someone with a recent staphylococcal infection (OR, 9.02; 95% CI, 1.03-78.98; P = 0.0470), and individuals with low frequency of hand washing (< 8 times per shift) (OR, 4.20; 95% CI 1.02-17.27; P = 0.0468). An additional risk factor identified through the logistic regression analysis on the study population was EMS workers with an open wound or skin infection (OR, 6.75; 95% CI, 1.25-36.36; P = 0.0262). However, this was not significant in the survey-weighted analysis. The high prevalence of MRSA in Ohio EMS personnel is both an occupational hazard and patient safety concern. Implementing methods to reinforce CDC guidelines for proper hygiene could decrease MRSA found in the EMS setting. Previous literature suggests that a reduction in MRSA colonization can lead to decreases in transmission and improved health for both patients and personnel. PMID- 26516798 TI - Target-Controlled Infusion: A Mature Technology. AB - Target-controlled infusions (TCIs) have been used in research and clinical practice for >2 decades. Nonapproved TCI software systems have been used during the conduct of almost 600 peer-reviewed published studies involving large numbers of patients. The first-generation pumps were first approved in 1996, and since then an estimated 25,000 units have been sold and used. Second-generation pumps were first approved in 2003. During 2004 to 2013, >36,000 units were sold. Currently, TCI systems are approved or available in at least 96 countries. TCI systems are used to administer propofol and opioids for IV sedation and general anesthesia for millions of patients every year. In countries where TCI systems are approved, nonapproved software is still commonly used in studies of the pharmacology of hypnotics and opioids, because research software offers greater flexibility than approved TCI systems. Research software is also readily integrated into data management modules. Although TCI is a part of established practice around the world, TCI devices have not received regulatory approval in the United States. In the United States, TCI administration of propofol and opioids for sedation and anesthesia is only possible using research software in IRB-approved research studies. PMID- 26516799 TI - Nitrite Reduces Ischemia-Induced Ventricular Arrhythmias by Attenuating Connexin 43 Dephosphorylation in Rats. AB - BACKGROUND: Ventricular arrhythmias induced by ischemic heart disease are the main cause of sudden cardiac death. Ischemia can cause life-threatening arrhythmias by modulating connexin 43 (Cx43), a principal cardiac gap junction channel protein. The present study investigates whether nitrite can attenuate ischemia-induced ventricular arrhythmias and dephosphorylation of Cx43 in a rat model. METHODS: Rats were medicated with normal saline (control, n = 10), nitrite (0.015, 0.15, and 1.5 mg/kg, n = 9 or 10 each), and 0.15 mg/kg nitrite with either the nitric oxide scavenger 2-(4-carboxyphenyl)-4, 4, 5, 5 tetramethylimidazoline-1-oxyl-3-oxide, sodium salt (cPTIO; n = 9) or allopurinol (xanthine oxidoreductase inhibitor, n = 9). We determined the severity of ventricular arrhythmias based on arrhythmia scores and levels of phosphorylated Cx43. RESULTS: The median arrhythmia score may have been lower in the group given 0.15 mg/kg nitrite (4 [interquartile range {IQR}, 4-5]) than that in the control group (7.5 [IQR, 5.25-8]; P = 0.013). There was no difference among the control, the given 0.015 mg/kg nitrite (7 [IQR, 5-8]), and 1.5 mg/kg nitrite (7 [IQR, 5.5 7.75]; P = 0.95). The arrhythmia scores in the cPTIO (6 [IQR, 5-8]; P = 0.030) and allopurinol (7 [IQR, 5-8]; P = 0.005) groups may have been higher than that in 0.15 mg/kg nitrite group. Immunoblotting revealed that the level of phosphorylated Cx43 in the group given 0.15 mg/kg nitrite, but not in the other treated groups, was significantly higher compared with the control group (P = 0.007). CONCLUSIONS: Nitrite may have attenuated acute ischemia-induced ventricular arrhythmias and Cx43 dephosphorylation in rats. Nitric oxide, which might be generated by xanthine oxidoreductase via nitrite reduction, appears to play a crucial role in this antiarrhythmic effect. PMID- 26516800 TI - Target-Controlled Infusions: Paths to Approval. AB - Target-controlled infusion of IV anesthetic drugs is approved worldwide with the exception of the United States. The purpose of this special article is to review regulatory pathways that could lead to target-controlled infusion (TCI) clearance or approval in the United States. PMID- 26516802 TI - The Effectiveness of Midazolam for Preventing Postoperative Nausea and Vomiting: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Previous randomized controlled trials regarding the effectiveness of perioperative midazolam in preventing postoperative nausea and vomiting (PONV) have produced conflicting results. Consequently, the present systematic review was performed to assess the effect of perioperative administration of midazolam on PONV. METHODS: The MEDLINE(r), Embase, and Cochrane Central Register of Controlled Trials databases were searched to identify all randomized controlled trials that investigated the effectiveness of midazolam under general anesthesia. The primary end points were defined as postoperative nausea (PON), postoperative vomiting (POV), and PONV. RESULTS: From 16 studies, 1433 patients were included in the final analysis. Compared with the control group, patients who received midazolam showed a lower overall incidence of PON (risk ratio [RR], 0.51; 95% confidence interval [CI], 0.40-0.65; I = 35%; number needed to treat [NNT] = 6; number of included studies [n] = 11), POV (RR, 0.46; 95% CI, 0.33-0.65; I = 0%; NNT = 8; n = 10), and PONV (RR, 0.45; 95% CI, 0.36-0.57; I = 31%; NNT = 3; n = 7). CONCLUSIONS: Perioperative administration of midazolam was effective in preventing PON, POV, and PONV. PMID- 26516801 TI - The Safety of Target-Controlled Infusions. AB - Target-controlled infusion (TCI) technology has been available in most countries worldwide for clinical use in anesthesia for approximately 2 decades. This infusion mode uses pharmacokinetic models to calculate infusion rates necessary to reach and maintain the desired drug concentration. TCI is computationally more complex than traditional modes of drug administration. The primary difference between TCI and conventional infusions is that TCI decreases the infusion rate at regular intervals to account for the uptake of drug into saturable compartments. Although the calculated infusion rates are consistent with manually controlled infusion rates, there are concerns that TCI administration of IV anesthetics could introduce unique safety concerns. After approximately 2 decades of clinical use, it is appropriate to assess the safety of TCI. Our aim in this article was to describe safety-relevant issues related to TCI, which should have emerged after its use in millions of patients. We collected information from published medical literature, TCI manufacturers, and publicly available governmental Web sites to find evidence of safety issues with the clinical use of TCI. Although many case reports emphasize that IV anesthesia is technically more demanding than inhaled anesthesia, including human errors associated with setting up IV infusions, no data suggest that a TCI mode of drug delivery introduces unique safety issues other than selecting the wrong pharmacokinetic model. This is analogous to the risk of selecting the wrong drug with current infusion pumps. We found no evidence that TCI is not at least as safe as anesthetic administration using constant rate infusions. PMID- 26516803 TI - Ultrasound-Guided Single-Injection Infraclavicular Block Versus Ultrasound-Guided Double-Injection Axillary Block: A Noninferiority Randomized Controlled Trial. AB - BACKGROUND: Single-injection ultrasound-guided infraclavicular block is a simple, reliable, and effective technique. A simplified double-injection ultrasound guided axillary block technique with a high success rate recently has been described. It has the advantage of being performed in a superficial and compressible location, with a potentially improved safety profile. However, its effectiveness in comparison with single-injection infraclavicular block has not been established. We hypothesized that the double-injection ultrasound-guided axillary block would show rates of complete sensory block at 30 minutes noninferior to the single-injection ultrasound-guided infraclavicular block. METHODS: After approval by our research ethics committee and written informed consent, adults undergoing distal upper arm surgery were randomized to either group I, ultrasound-guided single-injection infraclavicular block, or group A, ultrasound-guided double-injection axillary block. In group I, 30 mL of 1.5% mepivacaine was injected posterior to the axillary artery. In group A, 25 mL of 1.5% mepivacaine was injected posteromedial to the axillary artery, after which 5 mL was injected around the musculocutaneous nerve. Primary outcome was the rate of complete sensory block at 30 minutes. Secondary outcomes were the onset of sensory and motor blocks, surgical success rates, performance times, and incidence of complications. All outcomes were assessed by a blinded investigator. The noninferiority of the double-injection ultrasound-guided axillary block was considered if the limits of the 90% confidence intervals (CIs) were within a 10% margin of the rate of complete sensory block of the infraclavicular block. RESULTS: At 30 minutes, the rate of complete sensory block was 79% in group A (90% CI, 71%-85%) compared with 91% in group I (90% CI, 85%-95%); the upper limit of CI of group A is thus included in the established noninferiority margin of 10%. The rate of complete sensory block was lower in group A (proportion difference of 12% [95% CI, 2-22]; P = 0.0091), as was surgical success rate (82% [95% CI, 74%-89%] vs 93% [95% CI, 86%-97%]; proportion difference of 11% [95% CI 1-20]; P = 0.0153). Sensory block onset also was slower in group A (log rank test P = 0.0020). Performance times were faster in group I (231 seconds [95% CI, 213 250]) than in group A (358 seconds [95% CI, 332-387]; P < 0.0001). No statistically significant difference was observed for vascular puncture, paresthesia during block performance, or procedure-related pain. No neurologic complication was noted at follow-up. CONCLUSIONS: We failed to demonstrate that the rate of complete sensory block of the double-injection axillary block is noninferior to the single-injection infraclavicular block. However, the rate of complete sensory block at 30 minutes is statistically significantly lower with the axillary block. The ultrasound-guided single-injection infraclavicular block thus seems to be the preferred technique over the axillary for upper arm anesthesia. PMID- 26516804 TI - The History of Target-Controlled Infusion. AB - Target-controlled infusion (TCI) is a technique of infusing IV drugs to achieve a user-defined predicted ("target") drug concentration in a specific body compartment or tissue of interest. In this review, we describe the pharmacokinetic principles of TCI, the development of TCI systems, and technical and regulatory issues addressed in prototype development. We also describe the launch of the current clinically available systems. PMID- 26516805 TI - Transcranial Motor-Evoked Potentials Are More Readily Acquired Than Somatosensory Evoked Potentials in Children Younger Than 6 Years. AB - BACKGROUND: There is a general belief that somatosensory-evoked potentials (SSEPs) are more easily obtained than transcranial motor-evoked potentials (TcMEPs) in children younger than 6 years. We tested this assumption and the assumption that motor-evoked potentials are rarely obtained in children younger than 2 years. METHODS: The records of all patients who were monitored during surgical procedures between April 1, 2010, and June 30, 2013, were reviewed and those who were younger than 72 months at the time of surgery were identified and analyzed for the rate of obtaining clinically useful SSEPs and motor-evoked potentials. Subgroup analysis was performed by age. RESULTS: A total of 146 patients were identified, 9 had SSEPs without TcMEPs monitored, 117 had both TcMEPs and SSEPs monitored, and the remainder had only electromyographic monitoring. All patients who were to have TcMEPs recorded received a total IV anesthetic. Among the 117 patients who had both SSEPs and TcMEPs monitored, clinically relevant TcMEPs were obtained more frequently than SSEPs (110/117 vs 89/117; chi = 14.82; P = 0.00012). There were significant differences between the rates of obtaining SSEPs and TcMEPs in the 0- to 23-month (P = 0.0038) and 24- to 47-month (P = 0.0056) age groups. Utilization of a double-train stimulation technique facilitated obtaining TcMEPs in the youngest patients. CONCLUSIONS: TcMEPs can be obtained more easily than SSEPs in patients younger than 72 months if a permissive anesthetic technique is used. The success rate for obtaining TcMEPs can be further enhanced by the use of a temporal facilitation (double train) stimulation technique. PMID- 26516806 TI - Differences in Patterns of Preoperative Assessment Between High, Intermediate, and Low Volume Surgeons When Performing Hysterectomy for Uterovaginal Prolapse. AB - OBJECTIVE: The aim of the study was to determine whether surgeon case volume is associated with preoperative evaluation of pelvic organ prolapse before a hysterectomy for uterovaginal prolapse including a complete objective evaluation of prolapse (Baden-Walker or Pelvic Organ Prolapse Quantification), an offer of nonsurgical options for therapy (pessary), and a preoperative assessment of urinary incontinence METHODS: We performed a multicenter retrospective review of hysterectomies done for uterovaginal prolapse at 4 hospital systems between January 1, 2008 and December 31, 2011. The number of hysterectomies per surgeon for 4 years was evaluated to establish low-volume (<=10 cases), intermediate volume (11-49 cases), and high-volume (>=50 cases) groups. Rates of preoperative standardized prolapse evaluations, offer of pessary, and evaluation of stress urinary incontinence were determined by chart review of 15% of the hysterectomy cases. Adjustment was made in a logistic regression model for age, race, insurance status, and prolapse size. RESULTS: Three hundred one surgeons performed 4238 hysterectomies for prolapse during the study period. Rates of preoperative assessment by standardized pelvic examination differed between high , intermediate-, and low-volume surgeons (91.2% vs. 61.3% vs. 48.8%, respectively), as did offer of a pessary (86.5% vs. 71.9% vs. 69.9%, respectively) and preoperative stress test for urinary incontinence (93.5% vs. 72.8% vs. 63.5%, respectively). Regression analysis revealed that high-volume surgeons were more likely than intermediate- or low-volume surgeons to perform a standardized pelvic examination, offer a pessary, or perform preoperative evaluation for urinary incontinence. CONCLUSIONS: High-volume surgeons were more likely than low-volume surgeons to perform a standardized preoperative pelvic examination, offer a pessary, and evaluate stress urinary incontinence. PMID- 26516807 TI - Predictors of Manuscript Publication: A Review of Obstetrics and Gynecology Society Meeting Abstracts. AB - OBJECTIVE: The authors attempted to understand the manuscript publication rate and predictors of publication of abstracts presented at obstetrical and gynecologic society meetings. METHODS: In 2013, the authors obtained the text of all 2005 abstracts presented at a major generalist- and fellowship-associated society meetings. In this cross-sectional study, a search was completed for publication and identified possible predictors. RESULTS: The authors examined 1405 abstracts; the overall full-text publication rate was 54% (755/1405 publications) and the mean (SD) time to publication was 25.6 (20.8) months. Variables associated with publication in multivariable analysis included number of abstract authors (odds ratio [OR], 1.7; confidence interval [CI], 1.0-1.2), first authorship in American Congress of Obstetricians and Gynecologists district IV (OR, 1.7; CI, 0.9-3.1), prospective design (OR, 1.7; CI, 0.9-3.1), multicenter design (OR, 2.5; CI, 1.3-4.9), and oral presentation (OR, 3.2; CI, 1.4-7.3). Abstracts from specialty meetings were more likely to have these characteristics and, thus, higher publication rates. CONCLUSIONS: This study can guide project development for young researchers by informing them of key study design features associated with manuscript publication. PMID- 26516808 TI - Safe Simultaneous Use of Sacral Neuromodulation and Vagal Nerve Stimulation. AB - INTRODUCTION: The potential for costimulation with competitive effects between implanted electronic devices remains speculative both at the level at the implanted device and with active programming but also at the retrograde site of action. We present a patient with an implanted vagal nerve stimulator for refractory epilepsy who underwent successful staged sacral neuromodulation (SNS) and benefits from both technologies. CASE: This is a case report of a 42-year-old female patient with a history notable for medically intractable epilepsy, temporal lobectomy, and vagal nerve stimulation who subsequently underwent staged SNS for refractory overactive bladder syndrome. The patient continues to benefit from sustained reduction in her bladder issues and without dimunition of her seizure threshold at 6-month follow-up. DISCUSSION: Different action sites for SNS as well as vagal nerve stimulation are possible. The role of the thalamus in continence and seizure activity is reviewed. There does not seem to be an interactive effect during the simultaneous use of these 2 modalities. PMID- 26516809 TI - Bladder Symptoms and Attitudes in an Ethnically Diverse Population. AB - OBJECTIVE: The aim of the study was to assess pelvic floor symptoms and attitudes in an ethnically diverse population. METHODS: We conducted a cross-sectional survey of women presenting to 2 community-based, ethnically diverse gynecology clinics. Before being seen by a provider, participants were asked to complete a questionnaire. RESULTS: A total of 312 women were included: 32.7% white, 50.3% African American, and 17.0% Hispanic. Other racial/ethnic groups were excluded secondary to small samples size. The median (interquartile range) age was 34.0 (27.0-44.0) years. The groups differed with respect to most demographic characteristics, such as income, education, and nation of origin. Nocturia and urinary frequency were the most commonly reported symptoms. African American respondents were more likely to report nocturia than white respondents (odds ratio, 2.4; 95% confidence interval, 1.2-4.8). Respondents' views of normal urinary function generally did not vary by race/ethnicity. However, Hispanic respondents were less likely than white respondents to agree that it is normal to leak urine after having children (odds ratio, 0.28; 95% confidence interval, 0.11 0.68). Among women who reported at least 1 symptom, 46.7% reported that at least 1 symptom bothered them, and this did not differ with respect to race/ethnicity (P >= 0.59). African American respondents were more likely than whites to report their urinary leakage to their doctors (P = 0.006). CONCLUSIONS: Our study demonstrates that with few exceptions, bladder symptoms and attitudes are similar among reproductive-age women of various racial/ethnic groups in a community setting. PMID- 26516811 TI - Laparoscopic Repair of Enterocervical Fistula After Mesh Erosion Into the Sigmoid Colon and Cervix After Robotic Supracervical Hysterectomy and Sacrocervicopexy. AB - OBJECTIVES: To discuss risk factors and describe laparoscopic management of an unusual late complication of sacrocolpopexy mesh erosion resulting in enterocervical fistula after supracervical hysterectomy and robotic sacrocervicopopexy. CASE: We report on a unique case of a long-term mesh complication after robotic supracervical hysterectomy and polypropylene mesh sacrocervicopexy. Four years after the procedure, the patient was found to have mesh extrusion through the cervical os as well as mesh erosion into the sigmoid colon with a connecting enterocervical fistula. CONCLUSIONS: A laparoscopic approach was used successfully to address the complications. The case is unique because of the success of minimally invasive surgery in its management and multiple sites of erosion with a connecting fistula. PMID- 26516810 TI - Adherence to Oral Therapy for Urgency Urinary Incontinence: Results from the Anticholinergic Versus Botox Comparison (ABC) Trial. AB - OBJECTIVES: Medication adherence with urgency urinary incontinence (UUI) treatment is challenging and the best assessment methodology is uncertain. We sought to describe adherence with anticholinergic (AC) versus placebo (P) by comparing pill counts and MEMSCAP event data and to identify factors associated with adherence. METHODS: The randomized controlled AC versus Botox Comparison trial of women with moderate to severe idiopathic UUI included 126 participants initiating AC plus P bladder injection and 121 receiving P pills plus Botox injection. Adherence data on 243 participants (124 AC and 119 P) were calculated by pill count and MEMSCAP data for each 2-month interval during the 6-month study that allowed for dose escalation/drug change. Overall composite adherence estimates were calculated using the average of both methods and weighted by the duration of each 2-month interval. RESULTS: Treatment groups had no significant differences in dosing duration (P = 0.76) or mean adherence (AC, 83.3% [16.8] vs. P, 84.8% [13.8]). Only 53% of women met the dichotomous outcome of more than 80% adherence during all intervals. Correlation between adherence by pill counts versus MEMSCAP decreased over time with pill counts demonstrating higher adherence than MEMSCAP (r = 0.53, 0.50, and 0.36 for each 2-month interval). Lower adherence was associated with higher baseline incontinence severity and better UUI quality of life for the AC group and with current smoking status in both groups. CONCLUSIONS: Adherence using pill counts and MEMSCAP was reasonably correlated and similar in both the AC and P groups. In the AC group, higher baseline incontinence severity and better UUI Quality of Life were associated with decreased adherence. Smokers were less adherent. PMID- 26516812 TI - Analysis of High-, Intermediate-, and Low-Volume Surgeons When Performing Hysterectomy for Uterovaginal Prolapse. AB - OBJECTIVES: To determine if surgeon volume is associated with differences in the use of apical colpopexy and cystoscopy and in the rate of intraoperative complications during hysterectomy for prolapse. METHODS: We performed a multicenter retrospective review of hysterectomies done for uterovaginal prolapse at 4 hospital systems between January 1, 2008, and December 31, 2011. Low (<=10 cases)-, intermediate (11-49 cases)-, and high (>=50 cases)-volume surgeon groups for the 4-year period were established a priori. Rates of concomitant colpopexy, cystoscopy, and intraoperative complications were determined by chart review for 15% of the cases. Multivariate logistic regression models adjusted for site and other clinical and patient variables were used to estimate associations between surgeon case volume and the use of apical colpopexy and cystoscopy and the rate of intraoperative complications. RESULTS: Three hundred one surgeons performed 4238 hysterectomies for prolapse during the study period. Six hundred thirty eight patients were selected for chart review. The rates among high-, intermediate-, and low-volume surgeons for performing colpopexy were 85.2% versus 77.8% versus 61.1% (P < 0.001) and for cystoscopy were 96.8% versus 78.3% versus 74.7% (P < 0.001), respectively. Rates of intraoperative complications among the 3 groups were 4.4%, 11.6%, and 6.3% (P = 0.011), respectively. With adjustment, high-volume surgeons were more likely to do a colpopexy than low-volume surgeons (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.1); however, the likelihood of colpopexy did not differ between high- and intermediate-volume surgeons (OR, 1.9; 95% CI, 0.84-4.3) or between intermediate- and low-volume surgeons (OR, 0.99; 95% CI, 0.50-2.0). High-volume surgeons were more likely than intermediate-volume (OR, 4.4; 95% CI, 1.7-11.0) and low-volume (OR, 4.5; 95% CI, 2.6-8.0) surgeons to do a cystoscopy. High-volume (OR, 0.42; 95% CI, 0.30-0.61) and low-volume (OR, 0.32; 95% CI, 0.15-0.66) surgeons were less likely than intermediate-volume surgeons to have intraoperative complications. The difference between high- and low-volume surgeons was not statistically significant (OR, 0.77; 95% CI, 0.5-1.2). CONCLUSIONS: Practice patterns with respect to hysterectomy for prolapse are complex when the use of colpopexy and cystoscopy and rates of intraoperative complications are analyzed by surgeon volume. The finding that intermediate-volume surgeons have the highest rates of intraoperative complications suggests a nonlinear relationship between surgeon volume and avoidance of injury. PMID- 26516814 TI - The Location and Distribution of Transurethral Bulking Agent: 3-Dimensional Ultrasound Study. AB - OBJECTIVES: To use 3-dimensional endovaginal ultrasound to describe the location and distribution of bulking agent after an uncomplicated transurethral injection. METHODS: Endovaginal ultrasound was performed in 24 treatment-naive patients immediately after bulking agent was injected. The distance between the center of the hyperechoic density of bulking agent and the urethrovesical junction (UVJ) was measured in the sagittal and axial views. This was calculated in percentile length of urethra. Also, the pattern of tracking of bulking agent was assessed if it is presented. RESULTS: After the 2 subjects were excluded because of the poor quality of images, 22 patients were included in this study. Eighteen (82%) subjects showed 2 sites of bulking agents, and mostly, they were located around 3 and 9-o'clock positions. The average distance of bulking agent from left UVJ was at 16.9% of the length of the urethra (6.2 mm; range, 0.5-17 mm) and at 25.5% of the length of the urethra (8.9 mm; range, 0-24.8 mm) in the right side. The average length of urethra was 36.7 mm. Eleven of the 22 subjects (50%) had both sides within upper one third of urethra. The difference in distance between the 2 sides was less than 10 mm in 12 of 22 patients (54%). Nine of the 22 patients (41%) had a significant spread of bulking agent mostly either into the bladder neck or toward the distal urethra. CONCLUSIONS: Although the bulking agent is most often found at 3- and 9-o'clock positions as intended, the distance from the UVJ is highly variable after an uncomplicated office-based transurethral injection. The bulking material does not form the characteristic spheres in 41% of cases and tracks toward the bladder neck or the distal urethra. PMID- 26516813 TI - Sacral Osteomyelitis After Robotic Sacrocolpopexy. AB - BACKGROUND: Robotic-assisted abdominal sacrocolpopexy (RASC) is an effective procedure for the surgical treatment of vaginal vault prolapse associated with a rare, but serious, risk of sacral osteomyelitis. CASE: We report a case of Bacteroides fragilis sacral osteomyelitis after RASC that presented only as back pain. Treatment included intravenous antibiotics and abdominal exploration with removal of sacral mesh. CONCLUSIONS: Sacral osteomyelitis is a rare complication following RASC and may present only as back pain without constitutional symptoms. Intravenous antibiotics and surgical excision of sacral mesh are routinely performed, but preservation of vaginal mesh is a viable option. The clinician should have a high index of suspicion for osteomyelitis in any patient who presents with back pain after RASC, regardless of absence of other presenting symptoms. PMID- 26516815 TI - Vaginal Apical Pain After Sacrocolpopexy in Absence of Vaginal Mesh Erosion: A Case Series. AB - INTRODUCTION: Sacrocolpopexy is one of the most effective surgeries to correct pelvic organ prolapse. Previous studies have described complications, such as mesh erosion and dyspareunia. However, there are few studies on the development of pelvic pain in the absence of mesh erosion in patients who have undergone sacrocolpopexy. CASE REPORTS: We describe 3 patients who presented with apical vaginal pain in the absence of mesh erosion remote from sacrocolpopexy. All patients were refractory to conservative therapies and underwent abdominal excision of mesh with improvement of symptoms postoperatively. CONCLUSIONS: The development of de novo pain in the absence of mesh erosion after sacrocolpopexy is an uncommon event but in our cases required complete excision for relief of symptoms. Further research will be needed to understand if surgical technique or materials may be related to the development of symptoms. PMID- 26516816 TI - Total Laparoscopic Colocolpopoiesis in a Kidney Transplant Recipient With Frasier Syndrome. AB - BACKGROUND: The absence of a normal functioning vagina can have a profound impact on women's quality of life and psychological well being. Frasier syndrome is a rare autosomal recessive disorder which presents with male pseudohermaphroditism with gonadal dysgenesis, renal failure in early adulthood and increased risk of developing gonadoblastoma. Kidney transplant recipients are reported to have a high complication rate after colorectal surgery, most probably resulting from immunosuppressive therapy. CASE: A 25-year-old female kidney transplant recipient with Frasier syndrome consulted our department to discuss the possibilities of surgically constructing a functional vagina. She successfully underwent a total laparoscopic colocolpopoiesis without any complications. A sigmoid segment of 16 cm long was isolated laparoscopically and transferred caudally in a dissected pouch between bladder and rectum on its vascular pedicle. There was no short-term morbidity and no complications up to 3 years postoperatively. She experienced no neovaginal symptoms and was able to engage in neovaginal penetration by means of vibrator or neovaginal dilatator. CONCLUSIONS: The positive results in this patient lead us to recommend laparoscopic colocolpopoiesis in kidney transplant patients who are seeking vaginoplasty. We advocate considering a total laparoscopic approach whenever rectosigmoid colocolpopoiesis is indicated, even after a kidney transplantation. PMID- 26516817 TI - Management of Urinary and Fecal Incontinence in Patients With Complex Regional Pain Syndrome. AB - BACKGROUND: Urinary voiding dysfunction is reported in many patients with complex regional pain syndrome (CRPS). However, there is a gap in the literature for treating patients with CRPS who develop incontinence symptoms. CASE: We report a case describing the use of sacral neuromodulation therapy in a patient with urgency urinary and fecal incontinence who had a previously implanted spinal cord stimulator for type 1 CRPS, formerly known as reflex sympathetic dystrophy. Despite initial hesitation and treatment delay, sacral neuromodulation therapy was successful and effective in controlling both fecal and urgency urinary incontinence symptoms for the patient. This intervention continues to provide her with an improved quality of life 10 months after her procedure. CONCLUSIONS: In this case, there was significant hesitation from the provider and patient to use invasive treatments for incontinence symptoms when the patient's pain symptoms have been well controlled with an existing spinal device. However, in this patient with type 1 CRPS, even in the setting of an existing spinal cord stimulator, sacral neuromodulation therapy was an effective treatment. PMID- 26516818 TI - Uterine Conservation During Prolapse Repair: 9-Year Experience at a Single Institution. AB - OBJECTIVES: The primary aim is to compare safety and long-term outcomes between uterine-sparing prolapse procedures performed using 4 different surgical routes over a 9-year period. METHODS: This is a retrospective cohort study of women who underwent uterine-sparing prolapse procedures performed by 10 female pelvic medicine and reconstructive surgeons between January 2003 and December 2011. Demographic information, operative characteristics, complications (intraoperative and postoperative), and prolapse recurrence were obtained by chart review. Additional information collected included subsequent uterine or cervical pathology, procedures, and pregnancies. RESULTS: Two hundred forty uterine sparing prolapse procedures were performed in the 9-year period. One hundred two patients (42.5%) underwent a vaginal procedure, 95 patients (39.6%) underwent a conventional laparoscopic procedure, 28 patients (11.7%) underwent a robotic assisted laparoscopic procedure, and 15 patients (6.3%) underwent an abdominal procedure. Median follow-up time and interquartile range for abdominal, vaginal, laparoscopic, and robotic surgical routes were 16.4 (3.9-23.9), 14 (3.3-36.4), 22.6 (2.9-64.5), and 6.1 (3-24.4) months, respectively. Prolapse recurrence rates were similar for all groups (abdominal 13.3%, vaginal 14.7%, laparoscopic 11.6%, robotic 3.6%; P = 0.39). Intraoperative, postoperative, and long-term complications rates were similar between all groups (P = 0.63, P = 0.43, P = 0.10). The rate of benign gynecologic conditions encountered after surgery was similar among all groups, with an overall rate of abnormal uterine bleeding/postmenopausal bleeding of 5.4% and overall rate of cervical dysplasia of 0.8%. Two pregnancies were reported, both undergoing cesarean delivery at term. CONCLUSIONS: Uterine-sparing prolapse procedures appear to have good long term safety and a low risk of future gynecologic pathology. PMID- 26516819 TI - Association of Hemodynamic Factors With Intracranial Aneurysm Formation and Rupture: Systematic Review and Meta-analysis. AB - BACKGROUND: Recent evidence suggests a link between the magnitude and distribution of hemodynamic factors and the formation and rupture of intracranial aneurysms. However, there are many conflicting results. OBJECTIVE: To quantify the effect of hemodynamic factors on aneurysm formation and their association with ruptured aneurysms. METHODS: We performed a systematic review and meta analysis through October 2014. Analysis of the effects of hemodynamic factors on aneurysm formation was performed by pooling the results of studies that compared geometrical models of intracranial aneurysms and "preaneurysm" models where the aneurysm was artificially removed. Furthermore, we calculated pooled standardized mean differences between ruptured and unruptured aneurysms to quantify the association of hemodynamic factors with ruptured aneurysms. Standard PRISMA guidelines were followed. RESULTS: The hemodynamic factors that showed high positive correlations with location of aneurysm formation were high wall shear stress (WSS) and high gradient oscillatory number, with pooled proportions of 78.8% and 85.7%, respectively. Positive correlations were largely seen in bifurcation aneurysms, whereas negative correlations were seen in sidewall aneurysms. Mean and normalized WSS were significantly lower and low shear area significantly higher in ruptured aneurysms. CONCLUSION: Pooled analyses of computational fluid dynamics models suggest that an increase in WSS and gradient oscillatory number may contribute to aneurysm formation, whereas low WSS is associated with ruptured aneurysms. The location of the aneurysm at the bifurcation or sidewall may influence the correlation of these hemodynamic factors. PMID- 26516820 TI - Transarterial Regional Brain Hypothermia Inhibits Acute Aquaporin-4 Surge and Sequential Microvascular Events in Ischemia/Reperfusion Injury. AB - BACKGROUND: Although transarterial regional hypothermia is an attractive alternative to general hypothermia, its efficacy and underlying mechanisms remain unclear. OBJECTIVE: To confirm transarterial regional hypothermia therapeutic effects on ischemia/reperfusion (I/R) injury and to elucidate the mechanisms responsible. METHODS: The therapeutic effects of transarterial regional hypothermia were initially investigated in 2-hour middle cerebral artery occlusion rats regionally infused with 10 degrees C saline (cold saline group) or 37 degrees C saline (warm saline group) and untreated rats (control group) just before the onset of 24 hours of reperfusion. The time course of infarct and edema progression, inflammatory reactions, microvascular morphological changes, and aquaporin-4 (AQP4) expression was analyzed after 0, 2, 6, and 24 hours of reperfusion. RESULTS: Cold saline infusion only lowered brain temperatures for 30 minutes but mediated strong neuroprotective effects with infarct volume reductions of less than one-third. The time-course analysis revealed the following sequence of ischemia/reperfusion injury-related events in the control group: upregulated expression of AQP4 (2 hours); microvascular narrowing resulting from swollen astrocytic end-feet (2-6 hours); infarct and edema progression, blood-brain barrier disruption, and upregulated expression of intracellular adhesion molecule-1 (6-24 hours); and the activation of other inflammatory reactions (24 hours). These sequential events were inhibited in the cold saline group. CONCLUSION: Transarterial regional hypothermia initially inhibited the acute AQP4 surge and then attenuated microvascular narrowing, blood brain barrier disruption, and activation of other inflammatory reactions, leading to strong neuroprotective effects. More direct and intensive cooling of the endothelium and its surroundings may contribute to these effects. ABBREVIATIONS: AQP4, aquaporin-4BBB, blood-brain barrierIba1, ionized calcium-binding adapter molecule 1ICA, internal carotid arteryICAM-1, intracellular adhesion molecule 1I/R, ischemia/reperfusionMCAO, middle cerebral artery occlusionMMP-9, matrix metalloproteinase-9. PMID- 26516821 TI - Depression and Anxiety in Traumatic Brachial Plexus Injury Patients Are Associated With Reduced Motor Outcome After Surgical Intervention for Restoration of Elbow Flexion. AB - BACKGROUND: Depression has been associated with poor outcomes in neurosurgical patients, including increased pain, poorer functional recovery, delayed return to work, and decreased patient satisfaction. No reports exist regarding an association of psychiatric diagnoses with outcomes after brachial plexus reconstruction. As outcomes and patient satisfaction become increasingly important to payers and physician reimbursement, assessing modifiable preoperative risk factors for their association with poor outcome and patient satisfaction is imperative. OBJECTIVE: To analyze patients undergoing brachial plexus reconstruction to assess the relationship of depression/anxiety with functional outcome. METHODS: Data were collected retrospectively on all patients who underwent brachial plexus reconstruction to restore elbow flexion between 2005 and 2013. Elbow flexion, graded via the Medical Research Council scale, was assessed at latest follow-up. Multiple variables, including the presence of Axis I psychiatric diagnoses, were assessed for their association with the dichotomous outcome of Medical Research Council scale score >=3 (antigravity) vs <3 elbow flexion. Standard statistical methods were used. RESULTS: Thirty-seven patients met inclusion criteria. The median postsurgical follow-up time was 21 months. Operations included neurolysis (n = 3), nerve graft repair (n = 6), and nerve transfer (n = 28). Depression was present in 10 of 37 patients (27%). Of variables tested, only depression was associated with poor elbow flexion outcome (odds ratio: 6.038; P = .04). CONCLUSION: Preoperative depression is common after brachial plexus injury. The presence of depression is associated with reduced elbow flexion recovery after reconstruction. Our data suggest assessment and treatment of preoperative mental health is important in designing a comprehensive postoperative management plan to optimize outcomes and patient satisfaction. ABBREVIATIONS: MRC, Medical Research CouncilTBI, traumatic brain injury. PMID- 26516823 TI - Comparison of Outcome Between Surgical and Conservative Management of Symptomatic Spinal Cord Cavernous Malformations. AB - BACKGROUND: Intramedullary cavernous malformations (CMs) are rare lesions with unclear natural history. OBJECTIVE: To compare the functional outcomes of spinal CMs managed surgically and conservatively. METHODS: We performed a retrospective study of patients diagnosed with intramedullary CMs seen at our institution from 2006 to 2013. Functional outcomes of patients were assessed by treatment modality with the Modified McCormick Scale and Karnofsky Performance Status. RESULTS: We identified a total of 85 study-eligible patients; 51 (60.0%) were male. Mean age of patients was 40.5 years. Fifty-eight patients underwent microsurgical removal, and 27 patients underwent conservative management. All patients except 1 harbored a single symptomatic intramedullary CM. Mean follow-up time was 42.8 months. For the surgical group (n = 58), 51 CMs were completely resected. During the follow up period, 40 patients (69.0%) within the surgical group had improvement in neurological state, 16 patients (27.6%) remained unchanged, and 2 patients (3.4%) experienced deteriorated functional status. In the conservative group, 4 patients (14.8%) had improvement of their symptoms, 19 patients (70.4%) remained in baseline, and 4 patients (14.8%) deteriorated. No significant statistical difference was observed in follow-up Karnofsky Performance Status assessment (odds ratio = 0.89; 95% confidence interval = 0.73-1.08; P = .15) or Modified McCormick Scale assessment (odds ratio = 0.90; 95% confidence interval = 0.74 1.10; P = .30) after adjustment for preoperative lesion size and location. Annual hemorrhagic risk was 3.9% in conservatively managed patients. In contrast, no patients experienced subsequent hemorrhages after surgical resection. CONCLUSION: Surgical resection of intramedullary CMs eliminates the risk of subsequent hemorrhagic and may achieve satisfactory outcome when patients are carefully selected. Although conservative management is recommended in patients at high surgical risk, they should be closely monitored because of persistent hemorrhagic risk. PMID- 26516822 TI - Low-grade Glioma Surgery in Intraoperative Magnetic Resonance Imaging: Results of a Multicenter Retrospective Assessment of the German Study Group for Intraoperative Magnetic Resonance Imaging. AB - BACKGROUND: The ideal treatment strategy for low-grade gliomas (LGGs) is a controversial topic. Additionally, only smaller single-center series dealing with the concept of intraoperative magnetic resonance imaging (iMRI) have been published. OBJECTIVE: To investigate determinants for patient outcome and progression-free-survival (PFS) after iMRI-guided surgery for LGGs in a multicenter retrospective study initiated by the German Study Group for Intraoperative Magnetic Resonance Imaging. METHODS: A retrospective consecutive assessment of patients treated for LGGs (World Health Organization grade II) with iMRI-guided resection at 6 neurosurgical centers was performed. Eloquent location, extent of resection, first-line adjuvant treatment, neurophysiological monitoring, awake brain surgery, intraoperative ultrasound, and field-strength of iMRI were analyzed, as well as progression-free survival (PFS), new permanent neurological deficits, and complications. Multivariate binary logistic and Cox regression models were calculated to evaluate determinants of PFS, gross total resection (GTR), and adjuvant treatment. RESULTS: A total of 288 patients met the inclusion criteria. On multivariate analysis, GTR significantly increased PFS (hazard ratio, 0.44; P < .01), whereas "failed" GTR did not differ significantly from intended subtotal-resection. Combined radiochemotherapy as adjuvant therapy was a negative prognostic factor (hazard ratio: 2.84, P < .01). Field strength of iMRI was not associated with PFS. In the binary logistic regression model, use of high-field iMRI (odds ratio: 0.51, P < .01) was positively and eloquent location (odds ratio: 1.99, P < .01) was negatively associated with GTR. GTR was not associated with increased rates of new permanent neurological deficits. CONCLUSION: GTR was an independent positive prognostic factor for PFS in LGG surgery. Patients with accidentally left tumor remnants showed a similar prognosis compared with patients harboring only partially resectable tumors. Use of high-field iMRI was significantly associated with GTR. However, the field strength of iMRI did not affect PFS. ABBREVIATIONS: EoR, extent of resectionFLAIR, fluid-attenuated inversion recoveryGTR, gross total resectionIDH1, isocitrate dehydrogenase 1iMRI, intraoperative magnetic resonance imagingLGG, low-grade gliomaMGMT, methylguanine-deoxyribonucleic acid methyltransferasenPND, new permanent neurological deficitOS, overall survivalPFS, progression-free survivalSTR, subtotal resectionWHO, World Health Organization. PMID- 26516824 TI - Posterior Cervical Fusion Using Cervical Interfacet Spacers in Patients With Symptomatic Cervical Pseudarthrosis. AB - BACKGROUND: Posterior cervical fusion with cervical interfacet spacer (CIS) is a novel allograft technology offering the potential to provide indirect neuroforaminal decompression while simultaneously enhancing fusion by placing the allograft in compression. OBJECTIVE: To analyze the clinical and radiological outcomes after posterior cervical fusion with CIS in patients with symptomatic anterior cervical pseudarthroses. METHODS: Medical records of patients who underwent posterior cervical fusion with CIS for symptomatic pseudarthrosis after anterior cervical diskectomy and fusion were reviewed. Standardized outcome measures such as visual analog scale (VAS) score for neck and arm pain, Neck Disability Index (NDI), and upright lateral cervical radiographs were reviewed. RESULTS: There were 19 patients with symptomatic cervical pseudarthrosis. Preoperative symptoms included refractory neck or arm pain. The average follow-up was 20 months (range, 12-56 months). There was improvement in VAS score for neck pain (P < .004), radicular arm pain (P < .007), and NDI score (P < .06) after surgery, with 83%, 72%, and 67% of patients showing improvement in their VAS neck pain, VAS arm pain, and NDI scores, respectively. Fusion rate was high, with fusion occurring at all levels treated for pseudarthrosis. There was a small improvement in cervical lordosis (mean difference, 2 +/- 5.17 degrees ; P = .09) and slight worsening of C2-7 sagittal vertical axis after surgery (mean difference, 1.89 +/- 7.87 mm; P = .43). CONCLUSION: CIS provides an important fusion technique, allowing placement of an allograft in compression for posterior cervical fusion in patients with anterior cervical pseudarthroses. Although there was improvement in clinical outcome measures after surgery, placement of CIS had no clinically significant impact on cervical lordosis and C2-7 sagittal vertical axis. PMID- 26516825 TI - Letter: Simple Intraoperative Technique for Hemostasis of Cervical Venous Bleeding. PMID- 26516826 TI - Commentary: Endoscopic Third Ventriculostomy in 250 Adults With Hydrocephalus: Patient Selection, Outcomes, and Complications. PMID- 26516827 TI - In Reply: Simple Intraoperative Technique for Hemostasis of Cervical Venous Bleeding. PMID- 26516828 TI - Antioxidants of Edible Mushrooms. AB - Oxidative stress caused by an imbalanced metabolism and an excess of reactive oxygen species (ROS) lead to a range of health disorders in humans. Our endogenous antioxidant defense mechanisms and our dietary intake of antioxidants potentially regulate our oxidative homeostasis. Numerous synthetic antioxidants can effectively improve defense mechanisms, but because of their adverse toxic effects under certain conditions, preference is given to natural compounds. Consequently, the requirements for natural, alternative sources of antioxidant foods identified in edible mushrooms, as well as the mechanistic action involved in their antioxidant properties, have increased rapidly. Chemical composition and antioxidant potential of mushrooms have been intensively studied. Edible mushrooms might be used directly in enhancement of antioxidant defenses through dietary supplementation to reduce the level of oxidative stress. Wild or cultivated, they have been related to significant antioxidant properties due to their bioactive compounds, such as polyphenols, polysaccharides, vitamins, carotenoids and minerals. Antioxidant and health benefits, observed in edible mushrooms, seem an additional reason for their traditional use as a popular delicacy food. This review discusses the consumption of edible mushrooms as a powerful instrument in maintaining health, longevity and life quality. PMID- 26516829 TI - Fluorescence and Docking Studies of the Interaction between Human Serum Albumin and Pheophytin. AB - In the North of Brazil (Para and Amazonas states) the leaves of the plant Talinum triangulare (popular: cariru) replace spinach as food. From a phytochemical point of view, they are rich in compounds of the group of pheophytins. These substances, related to chlorophyll, have photophysical properties that give them potential application in photodynamic therapy. Human serum albumin (HSA) is one of the main endogenous vehicles for biodistribution of molecules by blood plasma. Association constants and thermodynamic parameters for the interaction of HSA with pheophytin from Talinum triangulare were studied by UV-Vis absorption, fluorescence techniques, and molecular modeling (docking). Fluorescence quenching of the HSA's internal fluorophore (tryptophan) at temperatures 296 K, 303 K, and 310 K, resulted in values for the association constants of the order of 104 L?mol(-1), indicating a moderate interaction between the compound and the albumin. The negative values of DeltaG degrees indicate a spontaneous process; DeltaH degrees = 15.5 kJ?mol(-1) indicates an endothermic process of association and DeltaS degrees = 0.145 kJ?mol(-1)?K(-1) shows that the interaction between HSA and pheophytin occurs mainly by hydrophobic factors. The observed Trp fluorescence quenching is static: there is initial non-fluorescent association, in the ground state, HSA:Pheophytin. Possible solution obtained by a molecular docking study suggests that pheophytin is able to interact with HSA by means of hydrogen bonds with three lysine and one arginine residues, whereas the phytyl group is inserted in a hydrophobic pocket, close to Trp-214. PMID- 26516830 TI - Unique Reactivity of Transition Metal Atoms Embedded in Graphene to CO, NO, O2 and O Adsorption: A First-Principles Investigation. AB - Taking the adsorption of CO, NO, O2 and O as probes, we investigated the electronic structure of transition metal atoms (TM, TM = Fe, Co, Ni, Cu and Zn) embedded in graphene by first-principles-based calculations. We showed that these TM atoms can be effectively stabilized on monovacancy defects on graphene by forming plausible interactions with the C atoms associated with dangling bonds. These interactions not only give rise to high energy barriers for the diffusion and aggregation of the embedded TM atoms to withstand the interference of reaction environments, but also shift the energy levels of TM-d states and regulate the reactivity of the embedded TM atoms. The adsorption of CO, NO, O2 and O correlates well with the weight averaged energy level of TM-d states, showing the crucial role of interfacial TM-C interactions on manipulating the reactivity of embedded TM atoms. These findings pave the way for the developments of effective monodispersed atomic TM composites with high stability and desired performance for gas sensing and catalytic applications. PMID- 26516831 TI - Starch Modification by Organic Acids and Their Derivatives: A Review. AB - Starch has been an inexhaustible subject of research for many decades. It is an inexpensive, readily-available material with extensive application in the food and processing industry. Researchers are continually trying to improve its properties by different modification procedures and expand its application. What is mostly applied in this view are their chemical modifications, among which organic acids have recently drawn the greatest attention, particularly with respect to the application of starch in the food industry. Namely, organic acids naturally occur in many edible plants and many of them are generally recognized as safe (GRAS), which make them ideal modification agents for starch intended for the food industry. The aim of this review is to give a short literature overview of the progress made in the research of starch esterification, etherification, cross-linking, and dual modification with organic acids and their derivatives. PMID- 26516832 TI - Multivariate Quantification of the Solid State Phase Composition of Co-Amorphous Naproxen-Indomethacin. AB - To benefit from the optimized dissolution properties of active pharmaceutical ingredients in their amorphous forms, co-amorphisation as a viable tool to stabilize these amorphous phases is of both academic and industrial interest. Reports dealing with the physical stability and recrystallization behavior of co amorphous systems are however limited to qualitative evaluations based on the corresponding X-ray powder diffractograms. Therefore, the objective of the study was to develop a quantification model based on X-ray powder diffractometry (XRPD), followed by a multivariate partial least squares regression approach that enables the simultaneous determination of up to four solid state fractions: crystalline naproxen, gamma-indomethacin, alpha-indomethacin as well as co amorphous naproxen-indomethacin. For this purpose, a calibration set that covers the whole range of possible combinations of the four components was prepared and analyzed by XRPD. In order to test the model performances, leave-one-out cross validation was performed and revealed root mean square errors of validation between 3.11% and 3.45% for the crystalline molar fractions and 5.57% for the co amorphous molar fraction. In summary, even four solid state phases, involving one co-amorphous phase, can be quantified with this XRPD data-based approach. PMID- 26516833 TI - Elevated Expression and Pro-Inflammatory Activity of IL-36 in Patients with Systemic Lupus Erythematosus. AB - We investigated the expression and proinflammatory activity of interleukin (IL) 36 in patients with systemic lupus erythematosus (SLE). The expression level of IL-36, its putative receptors and the frequency of CD19+CD24(high)CD27+ regulatory B (Breg) lymphocytes of peripheral blood from 43 SLE patients and 16 normal control (NC) subjects were studied using ELISA and flow cytometry. Plasma cytokines/chemokines and ex vivo productions of cytokine/chemokine from peripheral blood mononuclear cells (PBMC) stimulated with recombinant IL-36 were determined by Luminex multiplex assay. Plasma concentrations of IL-36alpha, IL 36gamma and the proportions of circulating IL-36R-positive CD19+ B lymphocytes in total B lymphocytes and PBMC were significantly increased in active SLE patients compared with NC (all p < 0.05). Plasma IL-36alpha and IL-36gamma correlated positively with SLE disease activity and elevated plasma IL-10 concentration (all p < 0.05). The frequencies of circulating Breg lymphocytes in total B lymphocytes and PBMC were significantly decreased in both inactive and active SLE patients compared with NC (all p < 0.01). The frequency of Breg lymphocytes in total B lymphocytes correlated negatively with the proportion of IL-36R-positive B lymphocytes (p < 0.05). IL-36alpha exerted substantial proinflammatory effect in PBMC from SLE patients by inducing the production of IL-6 and CXCL8. Upon stimulation with IL-36alpha and IL-36gamma, ex vivo productions of IL-6 and CXCL8 were significantly increased in SLE patients compared with NC (all p < 0.05). This cross-sectional study demonstrated that over expression of circulating IL 36alpha may exert a proinflammatory effect as observed in human SLE. PMID- 26516834 TI - A Simple, Effective, Green Method for the Regioselective 3-Acylation of Unprotected Indoles. AB - A fast and green method is developed for regioselective acylation of indoles in the 3-position without the need for protection of the NH position. The method is based on Friedel-Crafts acylation using acid anhydrides. The method has been optimized, and Y(OTf)3 in catalytic amounts is found to be the best catalyst together with the commercially available ionic liquid [BMI]BF4 (1-butyl-3 methylimidazolium tetrafluoro-borate) as solvent. The reaction is completed in a very short time using monomode microwave irradiation. The catalyst can be reused up to four times without significant loss of activity. A range of substituted indoles are investigated as substrates, and thirteen new compounds have been synthesized. PMID- 26516835 TI - Supramolecular Complexation of Carbohydrates for the Bioavailability Enhancement of Poorly Soluble Drugs. AB - In this review, a comprehensive overview of advances in the supramolecular complexes of carbohydrates and poorly soluble drugs is presented. Through the complexation process, poorly soluble drugs could be efficiently delivered to their desired destinations. Carbohydrates, the most abundant biomolecules, have diverse physicochemical properties owing to their inherent three-dimensional structures, hydrogen bonding, and molecular recognition abilities. In this regard, oligosaccharides and their derivatives have been utilized for the bioavailability enhancement of hydrophobic drugs via increasing the solubility or stability. By extension, polysaccharides and their derivatives can form self assembled architectures with poorly soluble drugs and have shown increased bioavailability in terms of the sustained or controlled drug release. These supramolecular systems using carbohydrate will be developed consistently in the field of pharmaceutical and medical application. PMID- 26516836 TI - Novel Electrokinetic Microfluidic Detector for Evaluating Effectiveness of Microalgae Disinfection in Ship Ballast Water. AB - Ship ballast water treatment methods face many technical challenges. The effectiveness of every treatment method usually is evaluated by using large scale equipment and a large volume of samples, which involves time-consuming, laborious, and complex operations. This paper reports the development of a novel, simple and fast platform of methodology in evaluating the efficiency and the best parameters for ballast water treatment systems, particularly in chemical disinfection. In this study, a microfluidic chip with six sample wells and a waste well was designed, where sample transportation was controlled by electrokinetic flow. The performance of this microfluidic platform was evaluated by detecting the disinfection of Dunaliella salina (D. salina) algae in ballast water treated by sodium hypochlorite (NaClO) solution. Light-induced chlorophyll fluorescence (LICF) intensity was used to determine the viability of microalgae cells in the system, which can be operated automatically with the dimension of the detector as small as 50 mm * 24 mm * 5 mm. The 40 uL volume of sample solution was used for each treatment condition test and the validity of detection can be accomplished within about five min. The results show that the viability of microalgae cells under different treatment conditions can be determined accurately and further optimal treatment conditions including concentrations of NaClO and treatment time can also be obtained. These results can provide accurate evaluation and optimal parameters for ballast water treatment methods. PMID- 26516837 TI - The Role of Plant-Microbe Interactions and Their Exploitation for Phytoremediation of Air Pollutants. AB - Since air pollution has been linked to a plethora of human health problems, strategies to improve air quality are indispensable. Despite the complexity in composition of air pollution, phytoremediation was shown to be effective in cleaning air. Plants are known to scavenge significant amounts of air pollutants on their aboveground plant parts. Leaf fall and runoff lead to transfer of (part of) the adsorbed pollutants to the soil and rhizosphere below. After uptake in the roots and leaves, plants can metabolize, sequestrate and/or excrete air pollutants. In addition, plant-associated microorganisms play an important role by degrading, detoxifying or sequestrating the pollutants and by promoting plant growth. In this review, an overview of the available knowledge about the role and potential of plant-microbe interactions to improve indoor and outdoor air quality is provided. Most importantly, common air pollutants (particulate matter, volatile organic compounds and inorganic air pollutants) and their toxicity are described. For each of these pollutant types, a concise overview of the specific contributions of the plant and its microbiome is presented. To conclude, the state of the art and its related future challenges are presented. PMID- 26516839 TI - Theoretical Mechanistic and Kinetic Studies on Homogeneous Gas-Phase Formation of Polychlorinated Naphthalene from 2-Chlorophenol as Forerunner. AB - Polychlorinated naphthalenes (PCNs) are dioxins-like compounds and are formed along with polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in thermal and combustion procedures. Chlorophenols (CPs) are the most important forerunners of PCNs. A comprehensive comprehension of PCN formation procedure from CPs is a precondition for reducing the discharge of PCNs. Experiments on the formation of PCNs from CPs have been hindered by PCN toxicity and short of precise detection methods for active intermediate radicals. In this work, PCN formation mechanism in gas-phase condition from 2-chlorophenol (2-CP) as forerunner was studied by quantum chemistry calculations. Numbers of energetically advantaged formation routes were proposed. The rate constants of key elementary steps were calculated over 600-1200 K using canonical variational transition-state theory (CVT) with small curvature tunneling contribution (SCT) method. This study illustrates formation of PCNs with one chlorine atom loss from 2-CP is preferred over that without chlorine atom loss. In comparison with formation of PCDFs from 2-CP, PCN products are less chlorinated and have lower formation potential. PMID- 26516840 TI - De Novo Sequencing and Analysis of the Safflower Transcriptome to Discover Putative Genes Associated with Safflor Yellow in Carthamus tinctorius L. AB - Safflower (Carthamus tinctorius L.), an important traditional Chinese medicine, is cultured widely for its pharmacological effects, but little is known regarding the genes related to the metabolic regulation of the safflower's yellow pigment. To investigate genes related to safflor yellow biosynthesis, 454 pyrosequencing of flower RNA at different developmental stages was performed, generating large databases.In this study, we analyzed 454 sequencing data from different flowering stages in safflower. In total, 1,151,324 raw reads and 1,140,594 clean reads were produced, which were assembled into 51,591 unigenes with an average length of 679 bp and a maximum length of 5109 bp. Among the unigenes, 40,139 were in the early group, 39,768 were obtained from the full group and 28,316 were detected in both samples. With the threshold of "log2 ratio >= 1", there were 34,464 differentially expressed genes, of which 18,043 were up-regulated and 16,421 were down-regulated in the early flower library. Based on the annotations of the unigenes, 281 pathways were predicted. We selected 12 putative genes and analyzed their expression levels using quantitative real time-PCR. The results were consistent with the 454 sequencing results. In addition, the expression of chalcone synthase, chalcone isomerase and anthocyanidin synthase, which are involved in safflor yellow biosynthesis and safflower yellow pigment (SYP) content, were analyzed in different flowering periods, indicating that their expression levels were related to SYP synthesis. Moreover, to further confirm the results of the 454 pyrosequencing, full-length cDNA of chalcone isomerase (CHI) and anthocyanidin synthase (ANS) were cloned from safflower petal by RACE (Rapid amplification of cDNA ends) method according to fragment of the transcriptome. PMID- 26516838 TI - Perturbation of Brain Oscillations after Ischemic Stroke: A Potential Biomarker for Post-Stroke Function and Therapy. AB - Brain waves resonate from the generators of electrical current and propagate across brain regions with oscillation frequencies ranging from 0.05 to 500 Hz. The commonly observed oscillatory waves recorded by an electroencephalogram (EEG) in normal adult humans can be grouped into five main categories according to the frequency and amplitude, namely delta (1-4 Hz, 20-200 MUV), theta (4-8 Hz, 10 MUV), alpha (8-12 Hz, 20-200 MUV), beta (12-30 Hz, 5-10 MUV), and gamma (30-80 Hz, low amplitude). Emerging evidence from experimental and human studies suggests that groups of function and behavior seem to be specifically associated with the presence of each oscillation band, although the complex relationship between oscillation frequency and function, as well as the interaction between brain oscillations, are far from clear. Changes of brain oscillation patterns have long been implicated in the diseases of the central nervous system including ischemic stroke, in which the reduction of cerebral blood flow as well as the progression of tissue damage have direct spatiotemporal effects on the power of several oscillatory bands and their interactions. This review summarizes the current knowledge in behavior and function associated with each brain oscillation, and also in the specific changes in brain electrical activities that correspond to the molecular events and functional alterations observed after experimental and human stroke. We provide the basis of the generations of brain oscillations and potential cellular and molecular mechanisms underlying stroke induced perturbation. We will also discuss the implications of using brain oscillation patterns as biomarkers for the prediction of stroke outcome and therapeutic efficacy. PMID- 26516841 TI - The Effect of Interferon-gamma and Zoledronate Treatment on Alpha-Tricalcium Phosphate/Collagen Sponge-Mediated Bone-Tissue Engineering. AB - Inflammatory responses are frequently associated with the expression of inflammatory cytokines and severe osteoclastogenesis, which significantly affect the efficacy of biomaterials. Recent findings have suggested that interferon (IFN)-gamma and zoledronate (Zol) are effective inhibitors of osteoclastogenesis. However, little is known regarding the utility of IFN-gamma and Zol in bone tissue engineering. In this study, we generated rat models by generating critically sized defects in calvarias implanted with an alpha-tricalcium phosphate/collagen sponge (alpha-TCP/CS). At four weeks post-implantation, the rats were divided into IFN-gamma, Zol, and control (no treatment) groups. Compared with the control group, the IFN-gamma and Zol groups showed remarkable attenuation of severe osteoclastogenesis, leading to a significant enhancement in bone mass. Histomorphometric data and mRNA expression patterns in IFN-gamma and Zol-injected rats reflected high bone-turnover with increased bone formation, a reduction in osteoclast numbers, and tumor necrosis factor-alpha expression. Our results demonstrated that the administration of IFN-gamma and Zol enhanced bone regeneration of alpha-TCP/CS implants by enhancing bone formation, while hampering excess bone resorption. PMID- 26516842 TI - ClRTL1 Encodes a Chinese Fir RNase III-Like Protein Involved in Regulating Shoot Branching. AB - Identification of genes controlling shoot branching is crucial for improving plant architecture and increasing crop yield or biomass. A branching mutant of Chinese fir named "Dugansha" (Cunninghamia lanceolata var. dugan.) has been isolated in our laboratory. We chose the cDNA-AFLP technique and an effective strategy to screen genes that potentially regulate shoot branching in Chinese fir using this mutant. An RNase III-like1 cDNA fragment named ClRTL1 was identified as a potential positive regulator. To investigate the function of ClRTL1 in regulating shoot branching, we cloned the full-length cDNA sequence from C. lanceolata (Lamb.) Hook, deduced its secondary structure and function, and overexpressed the coding sequence in Arabidopsis. The ClRTL1 cDNA is 1045 bp and comprises an open reading frame of 705 bp. It encodes a protein of 235 amino acids. The deduced secondary structure of the ClRTL1 indicates that it is a mini RNase III-like protein. The expression analysis and phenotypes of 35S: ClRTL1 in A. thaliana implies that ClRTL1 plays a role in promoting shoot branching in Chinese fir. PMID- 26516844 TI - JNK-Bcl-2/Bcl-xL-Bax/Bak Pathway Mediates the Crosstalk between Matrine-Induced Autophagy and Apoptosis via Interplay with Beclin 1. AB - Autophagy is associated with drug resistance which has been a threat in chemotherapy of hepatocellular carcinoma (HCC). The interconnected molecular regulators between autophagy and apoptosis serve as switching points critical to the ultimate outcome of the cell. Our study was performed to investigate the crosstalk between autophagy and apoptosis in HCC after the treatment of matrine. Flow cytometry and TUNEL (terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling) assay were used to detect apoptosis in vitro and in vivo, respectively. Bax oligomerization and Cytochrome c release assay were performed. Immunoprecipitation and siRNA transfection were used to detect the interplay between Bcl-2/Bcl-xL,Bax, and Beclin 1. Our results showed that: (1) matrine not only activated caspase and PARP (poly ADP-ribose polymerase) cleavage, but also triggered autophagy as shown by the increased levels of LC3II, Beclin 1, and PI3KC3, and the decreased level of p62; (2) matrine treatment promoted the JNK Bcl-2/ Bcl-xL-Bax/Bak pathway; (3) Bax was oligomerized, the mitochondrial membrane potential altered, and Cytochrome c was released subsequently; (4) Bax interacts with Beclin 1 and inhibits autophagy, which may be a new crosstalk point; and (5) finally, we showed that matrine suppressed the growth of a MHCC97L xenograft in vivo for the first time. In conclusion, the JNK-Bcl-2/Bcl-xL-Bax/Bak pathway mediates the crosstalk between matrine-induced autophagy and apoptosis via interplay with Beclin 1. PMID- 26516845 TI - Identification and Analysis of Regulatory Elements in Porcine Bone Morphogenetic Protein 15 Gene Promoter. AB - Bone morphogenetic protein 15 (BMP15) is secreted by the mammalian oocytes and is indispensable for ovarian follicular development, ovulation, and fertility. To determine the regulation mechanism of BMP15 gene, the regulatory sequence of porcine BMP15 was investigated in this study. The cloned BMP15 promoter retains the cell-type specificity, and is activated in cells derived from ovarian tissue. The luciferase assays in combination with a series of deletion of BMP15 promoter sequence show that the -427 to -376 bp region of BMP15 promoter is the primary regulatory element, in which there are a number of transcription factor binding sites, including LIM homeobox 8 (LHX8), newborn ovary homeobox gene (NOBOX), and paired-like homeodomain transcription factor 1 (PITX1). Determination of tissue specific expression reveals that LHX8, but not PITX1 and NOBOX, is exclusively expressed in pig ovary tissue and is translocated into the cell nuclei. Overexpression of LHX8 in Chinese hamster ovary (CHO) cells could significantly promote BMP15 promoter activation. This study confirms a key regulatory element that is located in the proximal region of BMP15 promoter and is regulated by the LHX8 factor. PMID- 26516843 TI - Epidemiology of Hepatitis E Virus in European Countries. AB - Over the last decade the seroprevalence of immunoglobulin (IgG) anti hepatitis E virus (HEV) has been increasing in European countries and shows significant variability among different geographical areas. In this review, we describe the serological data concerning the general population and risk groups in different European countries. Anti-HEV antibody prevalence ranged from 1.3% (blood donors in Italy) to 52% (blood donors in France). Various studies performed on risk groups in Denmark, Moldova and Sweden revealed that swine farmers have a high seroprevalence of HEV IgG (range 13%-51.1%), confirming that pigs represent an important risk factor in HEV infection in humans. Subtypes 3e,f are the main genotypes detected in the European population. Sporadic cases of autochthonous genotype 4 have been described in Spain, France, and Italy. Although most HEV infections are subclinical, in immune-suppressed and transplant patients they could provoke chronic infection. Fulminant hepatitis has rarely been observed and it was related to genotype 3. Interferon and ribavirin treatment was seen to represent the most promising therapy. PMID- 26516846 TI - Rare Titin (TTN) Variants in Diseases Associated with Sudden Cardiac Death. AB - A leading cause of death in western countries is sudden cardiac death, and can be associated with genetic disease. Next-generation sequencing has allowed thorough analysis of genes associated with this entity, including, most recently, titin. We aimed to identify potentially pathogenic genetic variants in titin. A total of 1126 samples were analyzed using a custom sequencing panel including major genes related to sudden cardiac death. Our cohort was divided into three groups: 432 cases from patients with cardiomyopathies, 130 cases from patients with channelopathies, and 564 post-mortem samples from individuals showing anatomical healthy hearts and non-conclusive causes of death after comprehensive autopsy. None of the patients included had definite pathogenic variants in the genes analyzed by our custom cardio-panel. Retrospective analysis comparing the in house database and available public databases also was performed. We identified 554 rare variants in titin, 282 of which were novel. Seven were previously reported as pathogenic. Of these 554 variants, 493 were missense variants, 233 of which were novel. Of all variants identified, 399 were unique and 155 were identified at least twice. No definite pathogenic variants were identified in any of genes analyzed. We identified rare, mostly novel, titin variants that seem to play a potentially pathogenic role in sudden cardiac death. Additional studies should be performed to clarify the role of these variants in sudden cardiac death. PMID- 26516847 TI - Hormonal Regulation of Response to Oxidative Stress in Insects-An Update. AB - Insects, like other organisms, must deal with a wide variety of potentially challenging environmental factors during the course of their life. An important example of such a challenge is the phenomenon of oxidative stress. This review summarizes the current knowledge on the role of adipokinetic hormones (AKH) as principal stress responsive hormones in insects involved in activation of anti oxidative stress response pathways. Emphasis is placed on an analysis of oxidative stress experimentally induced by various stressors and monitored by suitable biomarkers, and on detailed characterization of AKH's role in the anti stress reactions. These reactions are characterized by a significant increase of AKH levels in the insect body, and by effective reversal of the markers-disturbed by the stressors-after co-application of the stressor with AKH. A plausible mechanism of AKH action in the anti-oxidative stress response is discussed as well: this probably involves simultaneous employment of both protein kinase C and cyclic adenosine 3',5'-monophosphate pathways in the presence of extra and intra cellular Ca(2+) stores, with the possible involvement of the FoxO transcription factors. The role of other insect hormones in the anti-oxidative defense reactions is also discussed. PMID- 26516848 TI - Interleukins 6 and 15 Levels Are Higher in Subcutaneous Adipose Tissue, but Obesity Is Associated with Their Increased Content in Visceral Fat Depots. AB - Excess adiposity is associated with chronic inflammation, which takes part in the development of obesity-related complications. The aim of this study was to establish whether subcutaneous (SAT) or visceral (VAT) adipose tissue plays a major role in synthesis of pro-inflammatory cytokines. Concentrations of interleukins (IL): 1beta, 6, 8 and 15 were measured at the protein level by an ELISA-based method and on the mRNA level by real-time PCR in VAT and SAT samples obtained from 49 obese (BMI > 40 kg/m2) and 16 normal-weight (BMI 20-24.9 kg/m2) controls. IL-6 and IL-15 protein concentrations were higher in SAT than in VAT for both obese (p = 0.003 and p < 0.0001, respectively) and control individuals (p = 0.004 and p = 0.001, respectively), while for IL-1beta this was observed only in obese subjects (p = 0.047). What characterized obese individuals was the higher expression of IL-6 and IL-15 at the protein level in VAT compared to normal-weight controls (p = 0.047 and p = 0.016, respectively). Additionally, obese individuals with metabolic syndrome had higher IL-1beta levels in VAT than did obese individuals without this syndrome (p = 0.003). In conclusion, concentrations of some pro-inflammatory cytokines were higher in SAT than in VAT, but it was the increased pro-inflammatory activity of VAT that was associated with obesity and metabolic syndrome. PMID- 26516849 TI - Site-Specific PEGylation of Therapeutic Proteins. AB - The use of proteins as therapeutics has a long history and is becoming ever more common in modern medicine. While the number of protein-based drugs is growing every year, significant problems still remain with their use. Among these problems are rapid degradation and excretion from patients, thus requiring frequent dosing, which in turn increases the chances for an immunological response as well as increasing the cost of therapy. One of the main strategies to alleviate these problems is to link a polyethylene glycol (PEG) group to the protein of interest. This process, called PEGylation, has grown dramatically in recent years resulting in several approved drugs. Installing a single PEG chain at a defined site in a protein is challenging. Recently, there is has been considerable research into various methods for the site-specific PEGylation of proteins. This review seeks to summarize that work and provide background and context for how site-specific PEGylation is performed. After introducing the topic of site-specific PEGylation, recent developments using chemical methods are described. That is followed by a more extensive discussion of bioorthogonal reactions and enzymatic labeling. PMID- 26516850 TI - Aminolevulinic Acid-Based Tumor Detection and Therapy: Molecular Mechanisms and Strategies for Enhancement. AB - Aminolevulinic acid (ALA) is the first metabolite in the heme biosynthesis pathway in humans. In addition to the end product heme, this pathway also produces other porphyrin metabolites. Protoporphyrin (PpIX) is one heme precursor porphyrin with good fluorescence and photosensitizing activity. Because tumors and other proliferating cells tend to exhibit a higher level of PpIX than normal cells after ALA incubation, ALA has been used as a prodrug to enable PpIX fluorescence detection and photodynamic therapy (PDT) of lesion tissues. Extensive studies have been carried out in the past twenty years to explore why some tumors exhibit elevated ALA-mediated PpIX and how to enhance PpIX levels to achieve better tumor detection and treatment. Here we would like to summarize previous research in order to stimulate future studies on these important topics. In this review, we focus on summarizing tumor-associated alterations in heme biosynthesis enzymes, mitochondrial functions and porphyrin transporters that contribute to ALA-PpIX increase in tumors. Mechanism-based therapeutic strategies for enhancing ALA-based modalities including iron chelators, differentiation agents and PpIX transporter inhibitors are also discussed. PMID- 26516851 TI - Heat Killed Lactobacillus reuteri GMNL-263 Reduces Fibrosis Effects on the Liver and Heart in High Fat Diet-Hamsters via TGF-beta Suppression. AB - Obesity is one of the major risk factors for nonalcoholic fatty liver disease (NAFLD), and NAFLD is highly associated with an increased risk of cardiovascular disease (CVD). Scholars have suggested that certain probiotics may significantly impact cardiovascular health, particularly certain Lactobacillus species, such as Lactobacillus reuteri GMNL-263 (Lr263) probiotics, which have been shown to reduce obesity and arteriosclerosis in vivo. In the present study, we examined the potential of heat-killed bacteria to attenuate high fat diet (HFD)-induced hepatic and cardiac damages and the possible underlying mechanism of the positive effects of heat-killed Lr263 oral supplements. Heat-killed Lr263 treatments (625 and 3125 mg/kg-hamster/day) were provided as a daily supplement by oral gavage to HFD-fed hamsters for eight weeks. The results show that heat-killed Lr263 treatments reduce fatty liver syndrome. Moreover, heat-killed Lactobacillus reuteri GMNL-263 supplementation in HFD hamsters also reduced fibrosis in the liver and heart by reducing transforming growth factor beta (TGF-beta) expression levels. In conclusion, heat-killed Lr263 can reduce lipid metabolic stress in HFD hamsters and decrease the risk of fatty liver and cardiovascular disease. PMID- 26516852 TI - Identification of Molecular Fingerprints in Human Heat Pain Thresholds by Use of an Interactive Mixture Model R Toolbox (AdaptGauss). AB - Biomedical data obtained during cell experiments, laboratory animal research, or human studies often display a complex distribution. Statistical identification of subgroups in research data poses an analytical challenge. Here were introduce an interactive R-based bioinformatics tool, called "AdaptGauss". It enables a valid identification of a biologically-meaningful multimodal structure in the data by fitting a Gaussian mixture model (GMM) to the data. The interface allows a supervised selection of the number of subgroups. This enables the expectation maximization (EM) algorithm to adapt more complex GMM than usually observed with a noninteractive approach. Interactively fitting a GMM to heat pain threshold data acquired from human volunteers revealed a distribution pattern with four Gaussian modes located at temperatures of 32.3, 37.2, 41.4, and 45.4 degrees C. Noninteractive fitting was unable to identify a meaningful data structure. Obtained results are compatible with known activity temperatures of different TRP ion channels suggesting the mechanistic contribution of different heat sensors to the perception of thermal pain. Thus, sophisticated analysis of the modal structure of biomedical data provides a basis for the mechanistic interpretation of the observations. As it may reflect the involvement of different TRP thermosensory ion channels, the analysis provides a starting point for hypothesis driven laboratory experiments. PMID- 26516855 TI - Vehicle Classification Using the Discrete Fourier Transform with Traffic Inductive Sensors. AB - Inductive Loop Detectors (ILDs) are the most commonly used sensors in traffic management systems. This paper shows that some spectral features extracted from the Fourier Transform (FT) of inductive signatures do not depend on the vehicle speed. Such a property is used to propose a novel method for vehicle classification based on only one signature acquired from a sensor single-loop, in contrast to standard methods using two sensor loops. Our proposal will be evaluated by means of real inductive signatures captured with our hardware prototype. PMID- 26516854 TI - Dynamic Strain Measurements on Automotive and Aeronautic Composite Components by Means of Embedded Fiber Bragg Grating Sensors. AB - The measurement of the internal deformations occurring in real-life composite components is a very challenging task, especially for those components that are rather difficult to access. Optical fiber sensors can overcome such a problem, since they can be embedded in the composite materials and serve as in situ sensors. In this article, embedded optical fiber Bragg grating (FBG) sensors are used to analyze the vibration characteristics of two real-life composite components. The first component is a carbon fiber-reinforced polymer automotive control arm; the second is a glass fiber-reinforced polymer aeronautic hinge arm. The modal parameters of both components were estimated by processing the FBG signals with two interrogation techniques: the maximum detection and fast phase correlation algorithms were employed for the demodulation of the FBG signals; the Peak-Picking and PolyMax techniques were instead used for the parameter estimation. To validate the FBG outcomes, reference measurements were performed by means of a laser Doppler vibrometer. Sensors 2015, 15 27175 The analysis of the results showed that the FBG sensing capabilities were enhanced when the recently-introduced fast phase correlation algorithm was combined with the state of-the-art PolyMax estimator curve fitting method. In this case, the FBGs provided the most accurate results, i.e. it was possible to fully characterize the vibration behavior of both composite components. When using more traditional interrogation algorithms (maximum detection) and modal parameter estimation techniques (Peak-Picking), some of the modes were not successfully identified. PMID- 26516856 TI - Robust Analysis of Network-Based Real-Time Kinematic for GNSS-Derived Heights. AB - New guidelines and procedures for real-time (RT) network-based solutions are required in order to support Global Navigation Satellite System (GNSS) derived heights. Two kinds of experiments were carried out to analyze the performance of the network-based real-time kinematic (RTK) solutions. New test marks were installed in different surrounding environments, and the existing GPS benchmarks were used for analyzing the effect of different factors, such as baseline lengths, antenna types, on the final accuracy and reliability of the height estimation. The RT solutions are categorized into three groups: single-base RTK, multiple-epoch network RTK (mRTN), and single-epoch network RTK (sRTN). The RTK solution can be biased up to 9 mm depending on the surrounding environment, but there was no notable bias for a longer reference base station (about 30 km) In addition, the occupation time for the network RTK was investigated in various cases. There is no explicit bias in the solution for different durations, but smoother results were obtained for longer durations. Further investigation is needed into the effect of changing the occupation time between solutions and into the possibility of using single-epoch solutions in precise determination of heights by GNSS. PMID- 26516853 TI - Combined Treatments with Photodynamic Therapy for Non-Melanoma Skin Cancer. AB - Non-melanoma skin cancer (NMSC) is the most common form of cancer in the Caucasian population. Among NMSC types, basal cell carcinoma (BCC) has the highest incidence and squamous cell carcinoma (SCC) is less common although it can metastasize, accounting for the majority of NMSC-related deaths. Treatment options for NMSC include both surgical and non-surgical modalities. Even though surgical approaches are most commonly used to treat these lesions, Photodynamic Therapy (PDT) has the advantage of being a non-invasive option, and capable of field treatment, providing optimum cosmetic outcomes. Numerous clinical research studies have shown the efficacy of PDT for treating pre-malignant and malignant NMSC. However, resistant or recurrent tumors appear and sometimes become more aggressive. In this sense, the enhancement of PDT effectiveness by combining it with other therapeutic modalities has become an interesting field in NMSC research. Depending on the characteristics and the type of tumor, PDT can be applied in combination with immunomodulatory (Imiquimod) and chemotherapeutic (5 fluorouracil, methotrexate, diclofenac, or ingenol mebutate) agents, inhibitors of some molecules implicated in the carcinogenic process (COX2 or MAPK), surgical techniques, or even radiotherapy. These new strategies open the way to a wider improvement of the prevention and eradication of skin cancer. PMID- 26516857 TI - Step Detection Robust against the Dynamics of Smartphones. AB - A novel algorithm is proposed for robust step detection irrespective of step mode and device pose in smartphone usage environments. The dynamics of smartphones are decoupled into a peak-valley relationship with adaptive magnitude and temporal thresholds. For extracted peaks and valleys in the magnitude of acceleration, a step is defined as consisting of a peak and its adjacent valley. Adaptive magnitude thresholds consisting of step average and step deviation are applied to suppress pseudo peaks or valleys that mostly occur during the transition among step modes or device poses. Adaptive temporal thresholds are applied to time intervals between peaks or valleys to consider the time-varying pace of human walking or running for the correct selection of peaks or valleys. From the experimental results, it can be seen that the proposed step detection algorithm shows more than 98.6% average accuracy for any combination of step mode and device pose and outperforms state-of-the-art algorithms. PMID- 26516858 TI - APFiLoc: An Infrastructure-Free Indoor Localization Method Fusing Smartphone Inertial Sensors, Landmarks and Map Information. AB - The utility and adoption of indoor localization applications have been limited due to the complex nature of the physical environment combined with an increasing requirement for more robust localization performance. Existing solutions to this problem are either too expensive or too dependent on infrastructure such as Wi-Fi access points. To address this problem, we propose APFiLoc-a low cost, smartphone based framework for indoor localization. The key idea behind this framework is to obtain landmarks within the environment and to use the augmented particle filter to fuse them with measurements from smartphone sensors and map information. A clustering method based on distance constraints is developed to detect organic landmarks in an unsupervised way, and the least square support vector machine is used to classify seed landmarks. A series of real-world experiments were conducted in complex environments including multiple floors and the results show APFiLoc can achieve 80% accuracy (phone in the hand) and around 70% accuracy (phone in the pocket) of the error less than 2 m error without the assistance of infrastructure like Wi-Fi access points. PMID- 26516859 TI - In-Line Measurement of Water Contents in Ethanol Using a Zeolite-Coated Quartz Crystal Microbalance. AB - A quartz crystal microbalance (QCM) was utilized to measure the water content in ethanol. For the improvement of measurement sensitivity, the QCM was modified by applying zeolite particles on the surface with poly(methyl methacrylate) (PMMA) binder. The measurement performance was examined with ethanol of 1% to 5% water content in circulation. The experimental results showed that the frequency drop of the QCM was related with the water content though there was some deviation. The sensitivity of the zeolite-coated QCM was sufficient to be implemented in water content determination, and a higher ratio of silicon to aluminum in the molecular structure of the zeolite gave better performance. The coated surface was inspected by microscopy to show the distribution of zeolite particles and PMMA spread. PMID- 26516860 TI - Quantification Method for Electrolytic Sensors in Long-Term Monitoring of Ambient Air Quality. AB - Traditional air quality monitoring relies on point measurements from a small number of high-end devices. The recent growth in low-cost air sensing technology stands to revolutionize the way in which air quality data are collected and utilized. While several technologies have emerged in the field of low-cost monitoring, all suffer from similar challenges in data quality. One technology that shows particular promise is that of electrolytic (also known as amperometric) sensors. These sensors produce an electric current in response to target pollutants. This work addresses the development of practical models for understanding and quantifying the signal response of electrolytic sensors. Such models compensate for confounding effects on the sensor response, such as ambient temperature and humidity, and address other issues that affect the usability of low-cost sensors, such as sensor drift and inter-sensor variability. PMID- 26516861 TI - Toward a Smartphone Application for Estimation of Pulse Transit Time. AB - Pulse transit time (PTT) is an important physiological parameter that directly correlates with the elasticity and compliance of vascular walls and variations in blood pressure. This paper presents a PTT estimation method based on photoplethysmographic imaging (PPGi). The method utilizes two opposing cameras for simultaneous acquisition of PPGi waveform signals from the index fingertip and the forehead temple. An algorithm for the detection of maxima and minima in PPGi signals was developed, which includes technology for interpolation of the real positions of these points. We compared our PTT measurements with those obtained from the current methodological standards. Statistical results indicate that the PTT measured by our proposed method exhibits a good correlation with the established method. The proposed method is especially suitable for implementation in dual-camera-smartphones, which could facilitate PTT measurement among populations affected by cardiac complications. PMID- 26516862 TI - RF-Based Location Using Interpolation Functions to Reduce Fingerprint Mapping. AB - Indoor RF-based localization using fingerprint mapping requires an initial training step, which represents a time consuming process. This location methodology needs a database conformed with RSSI (Radio Signal Strength Indicator) measures from the communication transceivers taken at specific locations within the localization area. But, the real world localization environment is dynamic and it is necessary to rebuild the fingerprint database when some environmental changes are made. This paper explores the use of different interpolation functions to complete the fingerprint mapping needed to achieve the sought accuracy, thereby reducing the effort in the training step. Also, different distributions of test maps and reference points have been evaluated, showing the validity of this proposal and necessary trade-offs. Results reported show that the same or similar localization accuracy can be achieved even when only 50% of the initial fingerprint reference points are taken. PMID- 26516863 TI - Evaluation of Sensor Configurations for Robotic Surgical Instruments. AB - Designing surgical instruments for robotic-assisted minimally-invasive surgery (RAMIS) is challenging due to constraints on the number and type of sensors imposed by considerations such as space or the need for sterilization. A new method for evaluating the usability of virtual teleoperated surgical instruments based on virtual sensors is presented. This method uses virtual prototyping of the surgical instrument with a dual physical interaction, which allows testing of different sensor configurations in a real environment. Moreover, the proposed approach has been applied to the evaluation of prototypes of a two-finger grasper for lump detection by remote pinching. In this example, the usability of a set of five different sensor configurations, with a different number of force sensors, is evaluated in terms of quantitative and qualitative measures in clinical experiments with 23 volunteers. As a result, the smallest number of force sensors needed in the surgical instrument that ensures the usability of the device can be determined. The details of the experimental setup are also included. PMID- 26516864 TI - A Monolithic CMOS Magnetic Hall Sensor with High Sensitivity and Linearity Characteristics. AB - This paper presents a fully integrated linear Hall sensor by means of 0.8 MUm high voltage complementary metal-oxide semiconductor (CMOS) technology. This monolithic Hall sensor chip features a highly sensitive horizontal switched Hall plate and an efficient signal conditioner using dynamic offset cancellation technique. An improved cross-like Hall plate achieves high magnetic sensitivity and low offset. A new spinning current modulator stabilizes the quiescent output voltage and improves the reliability of the signal conditioner. The tested results show that at the 5 V supply voltage, the maximum Hall output voltage of the monolithic Hall sensor microsystem, is up to +/-2.1 V and the linearity of Hall output voltage is higher than 99% in the magnetic flux density range from +/ 5 mT to +/-175 mT. The output equivalent residual offset is 0.48 mT and the static power consumption is 20 mW. PMID- 26516865 TI - A Low-Cost Modular Platform for Heterogeneous Data Acquisition with Accurate Interchannel Synchronization. AB - Most experimental fields of science and engineering require the use of data acquisition systems (DAQ), devices in charge of sampling and converting electrical signals into digital data and, typically, performing all of the required signal preconditioning. Since commercial DAQ systems are normally focused on specific types of sensors and actuators, systems engineers may need to employ mutually-incompatible hardware from different manufacturers in applications demanding heterogeneous inputs and outputs, such as small-signal analog inputs, differential quadrature rotatory encoders or variable current outputs. A common undesirable side effect of heterogeneous DAQ hardware is the lack of an accurate synchronization between samples captured by each device. To solve such a problem with low-cost hardware, we present a novel modular DAQ architecture comprising a base board and a set of interchangeable modules. Our main design goal is the ability to sample all sources at predictable, fixed sampling frequencies, with a reduced synchronization mismatch (<1 us) between heterogeneous signal sources. We present experiments in the field of mechanical engineering, illustrating vibration spectrum analyses from piezoelectric accelerometers and, as a novelty in these kinds of experiments, the spectrum of quadrature encoder signals. Part of the design and software will be publicly released online. PMID- 26516867 TI - Purification and Characterization of Cathepsin B from the Muscle of Horse Mackerel Trachurus japonicus. AB - An endogenous protease in fish muscle, cathepsin B, was partially purified and characterized from horse mackerel meat. On SDS-PAGE of the purified enzyme under reducing conditions, main protein bands were detected at 28 and 6 kDa and their respective N-terminal sequences showed high homology to heavy and light chains of cathepsin B from other species. This suggested that horse mackerel cathepsin B formed two-chain forms, similar to mammalian cathepsin Bs. Optimum pH and temperature of the enzyme were 5.0 and 50 degrees C, respectively. A partial cDNA encoding the amino acid sequence of 215 residues for horse mackerel cathepsin B was obtained by RT-PCR and cloned. The deduced amino acid sequence contains a part of light and heavy chains of cathepsin B. The active sites and an N-glycosylation site were conserved across species. We also confirmed that the modori phenomenon was avoided by CA-074, a specific inhibitor for cathepsin B. Therefore, our results suggest that natural cysteine protease inhibitor(s), such as oryzacystatin derived from rice, can apply to thermal-gel processing of horse mackerel to avoid the modori phenomenon. Meanwhile, this endogenous protease may be used for food processing, such as weaning meal and food for the elderly. PMID- 26516866 TI - Membrane Potential and Calcium Dynamics in Beta Cells from Mouse Pancreas Tissue Slices: Theory, Experimentation, and Analysis. AB - Beta cells in the pancreatic islets of Langerhans are precise biological sensors for glucose and play a central role in balancing the organism between catabolic and anabolic needs. A hallmark of the beta cell response to glucose are oscillatory changes of membrane potential that are tightly coupled with oscillatory changes in intracellular calcium concentration which, in turn, elicit oscillations of insulin secretion. Both membrane potential and calcium changes spread from one beta cell to the other in a wave-like manner. In order to assess the properties of the abovementioned responses to physiological and pathological stimuli, the main challenge remains how to effectively measure membrane potential and calcium changes at the same time with high spatial and temporal resolution, and also in as many cells as possible. To date, the most wide-spread approach has employed the electrophysiological patch-clamp method to monitor membrane potential changes. Inherently, this technique has many advantages, such as a direct contact with the cell and a high temporal resolution. However, it allows one to assess information from a single cell only. In some instances, this technique has been used in conjunction with CCD camera-based imaging, offering the opportunity to simultaneously monitor membrane potential and calcium changes, but not in the same cells and not with a reliable cellular or subcellular spatial resolution. Recently, a novel family of highly-sensitive membrane potential reporter dyes in combination with high temporal and spatial confocal calcium imaging allows for simultaneously detecting membrane potential and calcium changes in many cells at a time. Since the signals yielded from both types of reporter dyes are inherently noisy, we have developed complex methods of data denoising that permit for visualization and pixel-wise analysis of signals. Combining the experimental approach of high-resolution imaging with the advanced analysis of noisy data enables novel physiological insights and reassessment of current concepts in unprecedented detail. PMID- 26516868 TI - Chitosanases from Family 46 of Glycoside Hydrolases: From Proteins to Phenotypes. AB - Chitosanases, enzymes that catalyze the endo-hydrolysis of glycolytic links in chitosan, are the subject of numerous studies as biotechnological tools to generate low molecular weight chitosan (LMWC) or chitosan oligosaccharides (CHOS) from native, high molecular weight chitosan. Glycoside hydrolases belonging to family GH46 are among the best-studied chitosanases, with four crystallography derived structures available and more than forty enzymes studied at the biochemical level. They were also subjected to numerous site-directed mutagenesis studies, unraveling the molecular mechanisms of hydrolysis. This review is focused on the taxonomic distribution of GH46 proteins, their multi-modular character, the structure-function relationships and their biological functions in the host organisms. PMID- 26516869 TI - Heparanase and Syndecan-4 Are Involved in Low Molecular Weight Fucoidan-Induced Angiogenesis. AB - Induction of angiogenesis is a potential treatment for chronic ischemia. Low molecular weight fucoidan (LMWF), the sulfated polysaccharide from brown seaweeds, has been shown to promote revascularization in a rat limb ischemia, increasing angiogenesis in vivo. We investigated the potential role of two heparan sulfate (HS) metabolism enzymes, exostosin-2 (EXT2) and heparanase (HPSE), and of two HS-membrane proteoglycans, syndecan-1 and -4 (SDC-1 and SDC 4), in LMWF induced angiogenesis. Our results showed that LMWF increases human vascular endothelial cell (HUVEC) migration and angiogenesis in vitro. We report that the expression and activity of the HS-degrading HPSE was increased after LMWF treatment. The phenotypic tests of LMWF-treated and EXT2- or HPSE-siRNA transfected cells indicated that EXT2 or HPSE expression significantly affect the proangiogenic potential of LMWF. In addition, LMWF increased SDC-1, but decreased SDC-4 expressions. The effect of LMWF depends on SDC-4 expression. Silencing EXT2 or HPSE leads to an increased expression of SDC-4, providing the evidence that EXT2 and HPSE regulate the SDC-4 expression. Altogether, these data indicate that EXT2, HPSE, and SDC-4 are involved in the proangiogenic effects of LMWF, suggesting that the HS metabolism changes linked to LMWF-induced angiogenesis offer the opportunity for new therapeutic strategies of ischemic diseases. PMID- 26516870 TI - Bioactive Hydantoin Alkaloids from the Red Sea Marine Sponge Hemimycale arabica. AB - In the course of our continuing efforts to identify bioactive secondary metabolites from Red Sea marine invertebrates, we have investigated the sponge Hemimycale arabica. The antimicrobial fraction of an organic extract of the sponge afforded two new hydantoin alkaloids, hemimycalins A and B (2 and 3), together with the previously reported compound (Z)-5-(4 hydroxybenzylidene)imidazolidine-2,4-dione (1). The structures of the compounds were determined by extensive 1D and 2D NMR (COSY, HSQC and HMBC) studies and high resolution mass spectral determinations. Hemimycalins A (2) and B (3) represent the first examples of the natural N-alkylated hydantoins from the sponge Hemimycale arabica. Compounds 1-3 displayed variable antimicrobial activities against E. coli, S. aureus, and C. albicans. In addition, compound 1 displayed moderate antiproliferative activity against the human cervical carcinoma (HeLa) cell line. These findings provide further insight into the chemical diversity as well as the biological activity of this class of compounds. PMID- 26516871 TI - Isolation and Analysis of the Cppsy Gene and Promoter from Chlorella protothecoides CS-41. AB - Phytoene synthase (PSY) catalyzes the condensation of two molecules of geranylgeranyl pyrophosphate to form phytoene, the first colorless carotene in the carotenoid biosynthesis pathway. So it is regarded as the crucial enzyme for carotenoid production, and has unsurprisingly been involved in genetic engineering studies of carotenoid production. In this study, the psy gene from Chlorella protothecoides CS-41, designated Cppsy, was cloned using rapid amplification of cDNA ends. The full-length DNA was 2488 bp, and the corresponding cDNA was 1143 bp, which encoded 380 amino acids. Computational analysis suggested that this protein belongs to the Isoprenoid_Biosyn_C1 superfamily. It contained the consensus sequence, including three predicted substrate-Mg(2+) binding sites. The Cppsy gene promoter was also cloned and characterized. Analysis revealed several candidate motifs for the promoter, which exhibited light- and methyl jasmonate (MeJA)-responsive characteristics, as well as some typical domains universally discovered in promoter sequences, such as the TATA-box and CAAT-box. Light- and MeJA treatment showed that the Cppsy expression level was significantly enhanced by light and MeJA. These results provide a basis for genetically modifying the carotenoid biosynthesis pathway in C. protothecoides. PMID- 26516872 TI - Grouping and Read-Across Approaches for Risk Assessment of Nanomaterials. AB - Physicochemical properties of chemicals affect their exposure, toxicokinetics/fate and hazard, and for nanomaterials, the variation of these properties results in a wide variety of materials with potentially different risks. To limit the amount of testing for risk assessment, the information gathering process for nanomaterials needs to be efficient. At the same time, sufficient information to assess the safety of human health and the environment should be available for each nanomaterial. Grouping and read-across approaches can be utilised to meet these goals. This article presents different possible applications of grouping and read-across for nanomaterials within the broader perspective of the MARINA Risk Assessment Strategy (RAS), as developed in the EU FP7 project MARINA. Firstly, nanomaterials can be grouped based on limited variation in physicochemical properties to subsequently design an efficient testing strategy that covers the entire group. Secondly, knowledge about exposure, toxicokinetics/fate or hazard, for example via properties such as dissolution rate, aspect ratio, chemical (non-)activity, can be used to organise similar materials in generic groups to frame issues that need further attention, or potentially to read-across. Thirdly, when data related to specific endpoints is required, read-across can be considered, using data from a source material for the target nanomaterial. Read-across could be based on a scientifically sound justification that exposure, distribution to the target (fate/toxicokinetics) and hazard of the target material are similar to, or less than, the source material. These grouping and read-across approaches pave the way for better use of available information on nanomaterials and are flexible enough to allow future adaptations related to scientific developments. PMID- 26516873 TI - Threshold Dose of Three Types of Quantum Dots (QDs) Induces Oxidative Stress Triggers DNA Damage and Apoptosis in Mouse Fibroblast L929 Cells. AB - Although it has been reported that fluorescent quantum dots (QDs) have obvious acute toxic effects in vitro, their toxic effects at low doses or threshold doses are still unknown. Therefore, we evaluated the biological histocompatibility and in vitro toxicity of three types of QDs at threshold doses. Also, we compared the toxic effects of QDs with different raw chemical compositions and sizes. The results showed that low concentrations of QDs (<=7 MUg/mL) had no obvious effect on cell viability and cell membrane damage, oxidative damage, cell apoptosis or DNA damage. However, QD exposure led to a significant cytotoxicity at higher doses (>=14 MUg/mL) and induced abnormal cellular morphology. In addition, when comparing the three types of QDs, 2.2 nm CdTe QDs exposure showed a significantly increased proportion of apoptotic cells and significant DNA damage, suggesting that size and composition contribute to the toxic effects of QDs. Based on these discussions, it was concluded that the concentration (7 MUg/mL) may serve as a threshold level for these three types of QDs only in L929 fibroblasts, whereas high concentrations (above 14 MUg/mL) may be toxic, resulting in inhibition of proliferation, induction of apoptosis and DNA damage in L929 fibroblasts. PMID- 26516874 TI - Prevalence and Risk Factors Associated with Dyslipidemia in Chongqing, China. AB - The increasing prevalence of dyslipidemia has become a worldwide public health problem, and the prevalence varies widely according to socioeconomic, cultural and ethnic characteristics. Chongqing has experienced rapid economic development and is now the economic center of Southwestern China. There are scant data on serum lipid profile of residents in Chongqing, the largest municipality directly under the Central Government in China. We conducted a cross-sectional study in a representative sample of 5375 residents of Chongqing, aged >=18 years, and estimated the prevalence of dyslipidemia and its associated risk factors. According to the National Cholesterol Education Program-Adult Treatment Panel III criteria, the age-standardized prevalence of dyslipidemia was 35.5% (34.4% among men and 37.6% among women). Among the 2009 patients with dyslipidemia, 44.2% had isolated hypertriglyceridemia, 14.7% had isolated hypercholesterolemia, 13.2% had mixed hyperlipidemia, and 28.0% had isolated low high-density lipoprotein cholesterol. The peak prevalence of dyslipidemia in men was between 30 and 39 years (48.2%), and then declined gradually; in women, the prevalence of dyslipidemia increased with age, with the peak prevalence occurring after age 60 (46.3%). Multivariable logistic regression analysis revealed that dyslipidemia was associated with age, education level, physical activity, obesity and central obesity for both men and women. In conclusion, the results indicated dyslipidemia, particularly hypertriglyceridemia and low high-density lipoprotein cholesterol, are very common in Chongqing. To prevent dyslipidemia, it is essential to conduct appropriate intervention programs aimed at risk factor reduction and implement routine screening programs for blood lipid levels in Chongqing, China. PMID- 26516875 TI - Association of Roadway Proximity with Indoor Air Pollution in a Peri-Urban Community in Lima, Peru. AB - The influence of traffic-related air pollution on indoor residential exposure is not well characterized in homes with high natural ventilation in low-income countries. Additionally, domestic allergen exposure is unknown in such populations. We conducted a pilot study of 25 homes in peri-urban Lima, Peru to estimate the effects of roadway proximity and season on residential concentrations. Indoor and outdoor concentrations of particulate matter (PM2.5), nitrogen dioxide (NO2), and black carbon (BC) were measured during two seasons, and allergens were measured in bedroom dust. Allergen levels were highest for dust mite and mouse allergens, with concentrations above clinically relevant thresholds in over a quarter and half of all homes, respectively. Mean indoor and outdoor pollutant concentrations were similar (PM2.5: 20.0 vs. 16.9 MUg/m3, BC: 7.6 vs. 8.1 MUg/m3, NO2: 7.3 vs. 7.5 ppb), and tended to be higher in the summer compared to the winter. Road proximity was significantly correlated with overall concentrations of outdoor PM2.5 (rs = -0.42, p = 0.01) and NO2 (rs = -0.36, p = 0.03), and outdoor BC concentrations in the winter (rs = -0.51, p = 0.03). Our results suggest that outdoor-sourced pollutants significantly influence indoor air quality in peri-urban Peruvian communities, and homes closer to roadways are particularly vulnerable. PMID- 26516876 TI - Biomonitoring of Lead, Cadmium, Total Mercury, and Methylmercury Levels in Maternal Blood and in Umbilical Cord Blood at Birth in South Korea. AB - With rising concerns of heavy metal exposure in pregnancy and early childhood, this study was conducted to assess the relationship between the lead, cadmium, mercury, and methylmercury blood levels in pregnancy and neonatal period. The study population included 104 mothers and their children pairs who completed both baseline maternal blood sampling at the second trimester and umbilical cord blood sampling at birth. The geometric mean maternal blood levels of lead, cadmium, total mercury, and methylmercury at the second trimester were 1.02 +/- 1.39 ug/dL, 0.61 +/- 1.51 ug/L, 2.97 +/- 1.45 ug/L, and 2.39 +/- 1.45 ug/L, respectively, and in the newborns, these levels at birth were 0.71 +/- 1.42 ug/dL, 0.01 +/- 5.31 ug/L, 4.44 +/- 1.49 ug/L, and 3.67 +/- 1.51 ug/L, respectively. The mean ratios of lead, cadmium, total mercury, and methylmercury levels in the newborns to those in the mothers were 0.72, 0.04, 1.76, and 1.81, respectively. The levels of most heavy metals in pregnant women and infants were higher in this study than in studies from industrialized western countries. The placenta appears to protect fetuses from cadmium; however, total mercury and methylmercury were able to cross the placenta and accumulate in fetuses. PMID- 26516877 TI - Probable Post Traumatic Stress Disorder in Kenya and Its Associated Risk Factors: A Cross-Sectional Household Survey. AB - This study aimed to assess the prevalence of probable post-traumatic stress disorder (PTSD), and its associated risk factors in a general household population in Kenya. Data were drawn from a cross-sectional household survey of mental disorders and their associated risk factors. The participants received a structured epidemiological assessment of common mental disorders, and symptoms of PTSD, accompanied by additional sections on socio-demographic data, life events, social networks, social supports, disability/activities of daily living, quality of life, use of health services, and service use. The study found that 48% had experienced a severe trauma, and an overall prevalence rate of 10.6% of probable PTSD, defined as a score of six or more on the trauma screening questionnaire (TSQ). The conditional probability of PTSD was 0.26. Risk factors include being female, single, self-employed, having experienced recent life events, having a common mental disorder (CMD)and living in an institution before age 16. The study indicates that probable PTSD is prevalent in this rural area of Kenya. The findings are relevant for the training of front line health workers, their support and supervision, for health management information systems, and for mental health promotion in state boarding schools. PMID- 26516878 TI - Biodegradation of di-n-Butyl Phthalate by Achromobacter sp. Isolated from Rural Domestic Wastewater. AB - A bacterial strain W-1, isolated from rural domestic wastewater, can utilize the environmental hormone di-n-butyl phthalate (DBP) as the sole carbon and energy source. The isolated bacterium species was confirmed to belong to the genus Achromobacter based on its 16S rRNA gene sequence. The results of substrate utilization tests showed that the strain W-1 could utilize other common phthalates and phenol. High-performance liquid chromatography analysis revealed that the optimal conditions for DBP degradation were pH 7.0, 35 degrees C, and an agitation rate of 175 rpm. Under these conditions, 500 mg/L of DBP was completely degraded within 30 h. The effects of heavy metals (50 mg/L Cu(2+) and 500 mg/L Pb(2+)) and surfactants (100 mg/L SDS and 500 mg/L Tween 20) on DBP degradation were investigated. The results demonstrated that Cu(2+) and SDS severely inhibited DBP degradation and Pb(2+) weakly inhibited DBP degradation, while Tween 20 greatly enhanced DBP degradation. Furthermore, phthalate degradation genes were found to be located on a plasmid present in Achromobacter sp. W-1. PMID- 26516879 TI - Enhanced Arsenate Removal Performance in Aqueous Solution by Yttrium-Based Adsorbents. AB - Arsenic contamination in drinking water has become an increasingly important issue due to its high toxicity to humans. The present study focuses on the development of the yttrium-based adsorbents, with basic yttrium carbonate (BYC), Ti-loaded basic yttrium carbonate (Ti-loaded BYC) and yttrium hydroxide prepared using a co-precipitation method. The Langmuir isotherm results confirmed the maximum adsorption capacity of Ti-loaded BYC (348.5 mg/g) was 25% higher than either BYC (289.6 mg/g) or yttrium hydroxide (206.5 mg/g) due to its increased specific surface area (82 m2/g) and surface charge (PZC: 8.4). Pseudo first- and second-order kinetic models further confirmed that the arsenate removal rate of Ti-loaded BYC was faster than for BYC and yttrium hydroxide. It was subsequently posited that the dominant removal mechanism of BYC and Ti-loaded BYC was the carbonate-arsenate ion exchange process, whereas yttrium hydroxide was regarded to be a co-precipitation process. The Ti-loaded BYC also displayed the highest adsorption affinity for a wide pH range (3-11) and in the presence of coexisting anionic species such as phosphate, silicate, and bicarbonate. Therefore, it is expected that Ti-loaded BYC can be used as an effective and practical adsorbent for arsenate remediation in drinking water. PMID- 26516880 TI - Altered Hippocampal Lipid Profile Following Acute Postnatal Exposure to Di(2 Ethylhexyl) Phthalate in Rats. AB - Slight changes in the abundance of certain lipid species in the brain may drastically alter normal neurodevelopment via membrane stability, cell signalling, and cell survival. Previous findings have demonstrated that postnatal exposure to di (2-ethylhexyl) phthalate (DEHP) disrupts normal axonal and neural development in the hippocampus. The goal of the current study was to determine whether postnatal exposure to DEHP alters the lipid profile in the hippocampus during postnatal development. Systemic treatment with 10 mg/kg DEHP during postnatal development led to elevated levels of phosphatidylcholine and sphingomyelin in the hippocampus of female rats. There was no effect of DEHP exposure on the overall abundance of phosphatidylcholine or sphingomyelin in male rats or of lysophosphatidylcholine in male or female rats. Individual analyses of each identified lipid species revealed 10 phosphatidylcholine and six sphingomyelin lipids in DEHP-treated females and a single lysophosphatidylcholine in DEHP-treated males with a two-fold or higher increase in relative abundance. Our results are congruent with previous work that found that postnatal exposure to DEHP had a near-selective detrimental effect on hippocampal development in males but not females. Together, results suggest a neuroprotective effect of these elevated lipid species in females. PMID- 26516881 TI - Thermal Adaptation Methods of Urban Plaza Users in Asia's Hot-Humid Regions: A Taiwan Case Study. AB - Thermal adaptation studies provide researchers great insight to help understand how people respond to thermal discomfort. This research aims to assess outdoor urban plaza conditions in hot and humid regions of Asia by conducting an evaluation of thermal adaptation. We also propose that questionnaire items are appropriate for determining thermal adaptation strategies adopted by urban plaza users. A literature review was conducted and first hand data collected by field observations and interviews used to collect information on thermal adaptation strategies. Item analysis--Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA)--were applied to refine the questionnaire items and determine the reliability of the questionnaire evaluation procedure. The reliability and validity of items and constructing process were also analyzed. Then, researchers facilitated an evaluation procedure for assessing the thermal adaptation strategies of urban plaza users in hot and humid regions of Asia and formulated a questionnaire survey that was distributed in Taichung's Municipal Plaza in Taiwan. Results showed that most users responded with behavioral adaptation when experiencing thermal discomfort. However, if the thermal discomfort could not be alleviated, they then adopted psychological strategies. In conclusion, the evaluation procedure for assessing thermal adaptation strategies and the questionnaire developed in this study can be applied to future research on thermal adaptation strategies adopted by urban plaza users in hot and humid regions of Asia. PMID- 26516882 TI - Spatial Associations Between Contaminated Land and Socio Demographics in Ghana. AB - Associations between contaminated land and socio demographics are well documented in high-income countries. In low- and middle-income countries, however, little is known about the extent of contaminated land and possible demographic correlations. This is an important yet sparsely researched topic with potentially significant public health implications as exposure to pollution remains a leading source of morbidity and mortality in low-income countries. In this study, we review the associations between several socio demographic factors (population, population density, unemployment, education, and literacy) and contaminated sites in Ghana. Within this context, both correlation and association intend to show the relationship between two variables, namely contaminated sites and socio demographics. Aggregated district level 2010 census data from Ghana Statistical Service and contaminated site location data from Pure Earth's Toxic Sites Identification Program (TSIP) were spatially evaluated using the number of sites per kilometer squared within districts as the unit of measurement. We found a low to medium positive correlation (rho range: 0.285 to 0.478) between contaminated sites and the following socio demographics: higher population density, higher unemployment, greater education, and higher literacy rate. These results support previous studies and suggest that several socio demographic factors may be reasonably accurate predictors of contaminated site locations. More research and targeted data collection is needed to better understand these associations with the ultimate goal of developing a predictive model. PMID- 26516883 TI - Evaluation of Membrane Ultrafiltration and Residual Chlorination as a Decentralized Water Treatment Strategy for Ten Rural Healthcare Facilities in Rwanda. AB - There is a critical need for safe water in healthcare facilities (HCF) in low income countries. HCF rely on water supplies that may require additional on-site treatment, and need sustainable technologies that can deliver sufficient quantities of water. Water treatment systems (WTS) that utilize ultrafiltration membranes for water treatment can be a useful technology in low-income countries, but studies have not systematically examined the feasibility of this technology in low-income settings. We monitored 22 months of operation of 10 WTS, including pre-filtration, membrane ultrafiltration, and chlorine residual disinfection that were donated to and operated by rural HCF in Rwanda. The systems were fully operational for 74% of the observation period. The most frequent reasons for interruption were water shortage (8%) and failure of the chlorination mechanism (7%). When systems were operational, 98% of water samples collected from the HCF taps met World Health Organization (WHO) guidelines for microbiological water quality. Water quality deteriorated during treatment interruptions and when water was stored in containers. Sustained performance of the systems depended primarily on organizational factors: the ability of the HCF technician to perform routine servicing and repairs, and environmental factors: water and power availability and procurement of materials, including chlorine and replacement parts in Rwanda. PMID- 26516885 TI - Indoor Heating Drives Water Bacterial Growth and Community Metabolic Profile Changes in Building Tap Pipes during the Winter Season. AB - The growth of the bacterial community harbored in indoor drinking water taps is regulated by external environmental factors, such as indoor temperature. However, the effect of indoor heating on bacterial regrowth associated with indoor drinking water taps is poorly understood. In the present work, flow cytometry and community-level sole-carbon-source utilization techniques were combined to explore the effects of indoor heating on water bacterial cell concentrations and community carbon metabolic profiles in building tap pipes during the winter season. The results showed that the temperature of water stagnated overnight ("before") in the indoor water pipes was 15-17 degrees C, and the water temperature decreased to 4-6 degrees C after flushing for 10 min ("flushed"). The highest bacterial cell number was observed in water stagnated overnight, and was 5-11 times higher than that of flushed water. Meanwhile, a significantly higher bacterial community metabolic activity (AWCD590nm) was also found in overnight stagnation water samples. The significant "flushed" and "taps" values indicated that the AWCD590nm, and bacterial cell number varied among the taps within the flushed group (p < 0.01). Heatmap fingerprints and principle component analyses (PCA) revealed a significant discrimination bacterial community functional metabolic profiles in the water stagnated overnight and flushed water. Serine, threonine, glucose-phosphate, ketobutyric acid, phenylethylamine, glycerol, putrescine were significantly used by "before" water samples. The results suggested that water stagnated at higher temperature should be treated before drinking because of bacterial regrowth. The data from this work provides useful information on reasonable utilization of drinking water after stagnation in indoor pipes during indoor heating periods. PMID- 26516884 TI - Immigrant Mental Health, A Public Health Issue: Looking Back and Moving Forward. AB - The Mental Health Commission of Canada's (MHCC) strategy calls for promoting the health and wellbeing of all Canadians and to improve mental health outcomes. Each year, one in every five Canadians experiences one or more mental health problems, creating a significant cost to the health system. Mental health is pivotal to holistic health and wellbeing. This paper presents the key findings of a comprehensive literature review of Canadian research on the relationship between settlement experiences and the mental health and well-being of immigrants and refugees. A scoping review was conducted following a framework provided by Arskey and O'Malley (Int J Soc Res Methodol 8:19-32, 2005). Over two decades of relevant literature on immigrants' health in Canada was searched. These included English language peer-reviewed publications from relevant online databases Medline, Embase, PsycInfo, Healthstar, ERIC and CINAHL between 1990 and 2015. The findings revealed three important ways in which settlement affects the mental health of immigrants and refugees: through acculturation related stressors, economic uncertainty and ethnic discrimination. The recommendations for public health practice and policy are discussed. PMID- 26516886 TI - Prevalence and Determinants of Metabolic Health in Subjects with Obesity in Chinese Population. AB - BACKGROUND: The study was to investigate the prevalence of metabolic health in subjects with obesity in the Chinese population and to identify the determinants related to metabolic abnormality in obese individuals. METHODS: 5013 subjects were recruited from seven provincial capitals in China. The obesity and metabolic status were classified based on body mass index (BMI) and the number of abnormalities in common components of metabolic syndrome. RESULTS: 27.9% of individuals with obesity were metabolically healthy. The prevalence of the metabolically healthy obese (MHO) phenotype was significantly decreased with age in women (p trend < 0.001), but not significantly in men (p trend = 0.349). Central obesity (odds ratio [OR] = 4.07, 95% confidence interval [CI] = 1.93 8.59), longer sedentary time (OR = 1.97, 95%CI = 1.27-3.06), and with a family history of obesity related diseases (hypertension, diabetes, dyslipidemia) (OR = 1.85, 95%CI = 1.26-2.71) were significantly associated with having metabolic abnormality in obese individuals. Higher levels of physical activity and more fruit/vegetable intake had decreased ORs of 0.67 (95%CI = 0.45-0.98) and 0.44 (95%CI = 0.28-0.70), respectively. CONCLUSION: 27.9% of obese participants are in metabolic health. Central obesity, physical activity, sedentary time, fruits/vegetables intake and family history of diseases are the determinants associated with metabolic status in obesity. PMID- 26516888 TI - In Utero Exposure to Diethylhexyl Phthalate Affects Rat Brain Development: A Behavioral and Genomic Approach. AB - Diethylhexyl phthalate (DEHP) is one of the most widely utilized phthalate plasticizers. Previous studies have demonstrated that gestational or postnatal DEHP exposure induced adverse effects on rat brain development and function. In this study, we investigated the effects of gestational DEHP exposure on gene expression profiling in neonatal rat brain and cognitive function change at adulthood. Adult Sprague Dawley dams were orally treated with 10 or 750 mg/kg DEHP from gestational day 12 to 21. Some male pups were euthanized at postnatal day 1 for gene expression profiling, and the rest males were retained for water maze testing on postnatal day (PND) 56. DEHP showed dose-dependent impairment of learning and spatial memory from PND 56 to 63. Genome-wide microarray analysis showed that 10 and 750 mg/kg DEHP altered the gene expression in the neonatal rat brain. Ccnd1 and Cdc2, two critical genes for neuron proliferation, were significantly down-regulated by DEHP. Interestingly, 750 mg/kg DEHP significantly increased Pmch level. Our study demonstrated the changed gene expression patterns after in utero DEHP exposure might partially contribute to the deficit of cognitive function at adulthood. PMID- 26516887 TI - A Novel High-Throughput Approach to Measure Hydroxyl Radicals Induced by Airborne Particulate Matter. AB - Oxidative stress is one of the key mechanisms linking ambient particulate matter (PM) exposure with various adverse health effects. The oxidative potential of PM has been used to characterize the ability of PM induced oxidative stress. Hydroxyl radical (*OH) is the most destructive radical produced by PM. However, there is currently no high-throughput approach which can rapidly measure PM induced *OH for a large number of samples with an automated system. This study evaluated four existing molecular probes (disodium terephthalate, 3'-p (aminophenyl)fluorescein, coumarin-3-carboxylic acid, and sodium benzoate) for their applicability to measure *OH induced by PM in a high-throughput cell-free system using fluorescence techniques, based on both our experiments and on an assessment of the physicochemical properties of the probes reported in the literature. Disodium terephthalate (TPT) was the most applicable molecular probe to measure *OH induced by PM, due to its high solubility, high stability of the corresponding fluorescent product (i.e., 2-hydroxyterephthalic acid), high yield compared with the other molecular probes, and stable fluorescence intensity in a wide range of pH environments. TPT was applied in a high-throughput format to measure PM (NIST 1648a)-induced *OH, in phosphate buffered saline. The formed fluorescent product was measured at designated time points up to 2 h. The fluorescent product of TPT had a detection limit of 17.59 nM. The soluble fraction of PM contributed approximately 76.9% of the *OH induced by total PM, and the soluble metal ions of PM contributed 57.4% of the overall *OH formation. This study provides a promising cost-effective high-throughput method to measure *OH induced by PM on a routine basis. PMID- 26516889 TI - Growth Trajectories of Health Behaviors from Adolescence through Young Adulthood. AB - Based on nine waves of data collected during a period of 17 years (1990-2007), the present study explored different developmental trajectories of the following unhealthy behaviors: regular smoking, lack of regular exercise, lack of daily fruit intake, and drunkenness. A baseline sample of 1195 13-year-old pupils was from 22 randomly selected schools in the Hordaland County in western Norway. Latent class growth analysis revealed three developmental trajectories. The first trajectory was a conventional trajectory, comprising 36.3% of participants, who showed changes in smoking, physical exercise, fruit intake, and drunkenness consistent with the prevailing age specific norms of these behaviors in the Norwegian society at the time. The second trajectory was a passive trajectory, comprising 25.5% of participants, who reported low levels of both healthy and unhealthy behaviors during the 17-year period. The third trajectory was an unhealthy trajectory, comprising 38.2% of participants, who had high levels of unhealthy behaviors over time. Several covariates were examined, but only sex and mother's and father's educational levels were found to be significantly associated with the identified trajectories. While these findings need to be replicated in future studies, the identification of the different trajectories suggests the need to tailor intervention according to specific needs. PMID- 26516890 TI - Non-Seasonal Variation of Airborne Aspergillus Spore Concentration in a Hospital Building. AB - Nosocomial fungal infections are gaining increased attention from infectiologists. An adequate investigation into the levels of airborne Aspergillus and other fungal spores in hospital settings, under normal conditions, is largely unknown. We monitored airborne spore contamination in a Swiss hospital building in order to establish a seasonally-dependent base-line level. Air was sampled using an impaction technique, twice weekly, at six different locations over one year. Specimens were seeded in duplicate on Sabouraud agar plates. Grown colonies were identified to genus levels. The airborne Aspergillus spore concentration was constantly low throughout the whole year, at a median level of 2 spores/m3 (inter-quartile range = IQR 1-4), and displayed no seasonal dependency. The median concentration of other fungal spores was higher and showed a distinct seasonal variability with the ambient temperature change during the different seasons: 82 spores/m3 (IQR 26-126) in summer and 9 spores/m3 (IQR 6-15) in winter. The spore concentration varied considerably between the six sampling sites in the building (10 to 26 spores/m3). This variability may explain the variability of study results in the literature. PMID- 26516891 TI - Arsenic in Drinking Water, Transition Cell Cancer and Chronic Cystitis in Rural Bangladesh. AB - In earlier analyses, we demonstrated dose-response relationships between renal and lung cancer and local arsenic concentrations in wells used by Bangladeshi villagers. We used the same case-referent approach to examine the relation of arsenic to biopsy confirmed transition cell cancer (TCC) of the ureter, bladder or urethra in these villagers. As the International Agency for Research on Cancer (IARC) has conclude that arsenic in drinking water causes bladder cancer, we expected to find higher risk with increasing arsenic concentration. We used histology/cytology results from biopsies carried out at a single clinic in Dhaka, Bangladesh from January 2008 to October 2011. We classified these into four groups, TCC (n = 1466), other malignancies (n = 145), chronic cystitis (CC) (n = 844) and other benign (n = 194). Arsenic concentration was estimated from British Geological Survey reports. Odds ratios were calculated by multilevel logistic regression adjusted for confounding and allowing for geographic clustering. We found no consistent trend for TCC with increasing arsenic concentration but the likelihood of a patient with benign disease having CC was significantly increased at arsenic concentrations >100 ug/L. We conclude that the expected relationship of TCC to arsenic was masked by over-matching that resulted from the previously unreported relationship between arsenic and CC. We hypothesize that CC may be a precursor of TCC in high arsenic areas. PMID- 26516892 TI - Combined Effects of Soy Isoflavones and beta-Carotene on Osteoblast Differentiation. AB - Soy isoflavones, genistein, daidzein and its metabolite equol, as well as beta carotene have been reported to be effective for maintaining bone health. However, it remains to be elucidated whether combining soy isoflavones with beta-carotene is beneficial to bone formation. This study investigated the combined effect of soy isoflavones and beta-carotene on the differentiation of MC3T3-E1 preosteoblastic cells. Daidzein and genistein alone did not affect cell growth but increased alkaline phosphatase (ALP) activity. Beta-carotene alone inhibited cell growth and markedly enhanced ALP activity. Soy isoflavones combined with beta-carotene resulted in higher ALP activity than treatment with isoflavones or beta-carotene alone. We observed significant main effects of beta-carotene on the enhanced expression of Runx2, ALP, and ostepontin mRNA, whereas there was a significant main effect of soy isoflavones on the expression of osterix mRNA. To investigate how beta-carotene affected osteoblast differentiation, MC3T3-E1 cells were treated with retinoic acid receptor (RAR) pan-antagonist combined with beta carotene. Osteopontin and ALP mRNA expression levels, which were increased following treatment with beta-carotene, were significantly suppressed by the RAR pan-antagonist. This suggests treatment with beta-carotene enhanced early osteoblastic differentiation, at least in part via RAR signaling. These results indicate that a combination of isoflavones and beta-carotene may be useful for maintaining a positive balance of bone turnover by inducing osteoblast differentiation. PMID- 26516893 TI - Treatment of Actual Chemical Wastewater by a Heterogeneous Fenton Process Using Natural Pyrite. AB - Wastewater from chemical plants has remarkable antibiotic effects on the microorganisms in traditional biological treatment processes. An enhanced Fenton system catalyzed by natural pyrite was developed to degrade this kind of wastewater. Approximately 30% chemical oxygen demand (COD) was removed within 120 min when 50 mmol/L H2O2 and 10 g/L natural pyrite were used at initial pH from 1.8 to 7. A BOD5/COD enhancement efficiency of 210% and an acute biotoxicity removal efficiency of 84% were achieved. The COD removal efficiency was less sensitive to initial pH than was the classic Fenton process. Excessive amounts of pyrite and H2O2 did not negatively affect the pyrite Fenton system. The amount of aniline generated indicated that nitrobenzene reduction by pyrite was promoted using a low initial concentration of H2O2 (<5 mmol/L). Fluorescence excitation emission matrix analyses illustrated that H2O2 facilitated the reduction by natural pyrite of organic molecules containing an electron-withdrawing group to electron-donating group. Thus, the Fenton-like process catalyzed by pyrite can remediate wastewater containing organic pollutants under mild reaction conditions and provide an alternative environmentally friendly method by which to reuse natural pyrite. PMID- 26516895 TI - Understanding Walking Behavior among University Students Using Theory of Planned Behavior. AB - Walking has been shown to improve physical and mental well-being, yet insufficient walking among university students has been increasingly reported. This study aimed to understand walking behavior of university students using theory of planned behavior (TPB). We recruited 169 undergraduate students by university mass email of the Chinese University of Hong Kong, and first administered a salient belief elicitation survey, which was used to design the TPB questionnaire, to a subset of the study sample. Secondly, all participants completed the TPB questionnaire and walking-oriented diary in a two-day period in December 2012. We mapped the walking behavior data obtained from the diary using geographic information system, and examined the extent to which TPB constructs explained walking intentions and walking behavior using Structural equation model (SEM). We found perceived behavioral control to be the key determinant of walking intention. Shaped by participants' perceived behavioral control, attitude toward walking and subjective norms, and behavioral intention, in turn had a moderate explanatory effect on their walking behavior. In summary, our findings suggest that walking behavior among university students can be understood within the TPB framework, and could inform walking promotion interventions on the university campuses. PMID- 26516894 TI - Commercial Honeybush (Cyclopia spp.) Tea Extract Inhibits Osteoclast Formation and Bone Resorption in RAW264.7 Murine Macrophages-An in vitro Study. AB - Honeybush tea, a sweet tasting caffeine-free tea that is indigenous to South Africa, is rich in bioactive compounds that may have beneficial health effects. Bone remodeling is a physiological process that involves the synthesis of bone matrix by osteoblasts and resorption of bone by osteoclasts. When resorption exceeds formation, bone remodeling can be disrupted resulting in bone diseases such as osteoporosis. Osteoclasts are multinucleated cells derived from hematopoietic precursors of monocytic lineage. These precursors fuse and differentiate into mature osteoclasts in the presence of receptor activator of NF kB ligand (RANKL), produced by osteoblasts. In this study, the in vitro effects of an aqueous extract of fermented honeybush tea were examined on osteoclast formation and bone resorption in RAW264.7 murine macrophages. We found that commercial honeybush tea extract inhibited osteoclast formation and TRAP activity which was accompanied by reduced bone resorption and disruption of characteristic cytoskeletal elements of mature osteoclasts without cytotoxicity. Furthermore, honeybush tea extract decreased expression of key osteoclast specific genes, matrix metalloproteinase-9 (MMP-9), tartrate resistant acid phosphatase (TRAP) and cathepsin K. This study demonstrates for the first time that honeybush tea may have potential anti-osteoclastogenic effects and therefore should be further explored for its beneficial effects on bone. PMID- 26516896 TI - Impact of Fatigue in Rheumatic Diseases in the Work Environment: A Qualitative Study. AB - Fatigue is a symptom of arthritis that causes difficulty at work. An improved understanding of this symptom could assist its management in the work environment. The aim of this study was to explore people with rheumatic diseases' experiences of fatigue in work. A qualitative descriptive design was used with semi-structured interviews and a constant comparative method of data analysis. There were 18 participants, the majority of them female with Rheumatoid Arthritis (RA) and working full-time. Three themes were identified: "Impact of fatigue on work performance" with cognition, mood and physical abilities being the main difficulties reported. In the second theme "Disclosure at Work" participants discussed disclosing their disease to employers but reported a lack of understanding of fatigue from colleagues. The final theme "work-based fatigue management strategies" included cognitive strategies and energy management techniques, which were mainly self-taught. In this study, fatigue was reported to impact on many areas of work performance with limited understanding from colleagues and employers. Interventions from health professionals to assist with development of work-related self-management skills are required to assist with symptom management in the work place. Such interventions should include education to employers and colleagues on the nature of fatigue in Rheumatic diseases. PMID- 26516897 TI - Improving Management of Green Retrofits from a Stakeholder Perspective: A Case Study in China. AB - Green retrofits, which improve the environment and energy efficiency of buildings, are considered a potential solution for reducing energy consumption as well as improving human health and productivity. They represent some of the riskiest, most complex, and most uncertain projects to manage. As the foundation of project management, critical success factors (CSFs) have been emphasized by previous research. However, most studies identified and prioritized CSFs independently of stakeholders. This differs from the reality, where the success of green retrofits is tightly interrelated to the stakeholders of projects. To improve the analysis from a stakeholder perspective, the present study proposed an innovative method based on a two-mode social network analysis to integrate CSF analysis with stakeholders. The results of this method can provide further understanding of the interactions between stakeholders and CSFs, and the underlying relationship among CSFs through stakeholders. A pilot study was conducted to apply the proposed method and assess the CSFs for green retrofits in China. The five most significant CSFs are identified in the management of green retrofit. Furthermore, the interrelations between stakeholders and CSFs, coefficient and clusters of CSFs are likewise discussed. PMID- 26516898 TI - Vector-Enabled Metagenomic (VEM) Surveys Using Whiteflies (Aleyrodidae) Reveal Novel Begomovirus Species in the New and Old Worlds. AB - Whitefly-transmitted viruses belonging to the genus Begomovirus (family Geminiviridae) represent a substantial threat to agricultural food production. The rapid evolutionary potential of these single-stranded DNA viruses combined with the polyphagous feeding behavior of their whitefly vector (Bemisia tabaci) can lead to the emergence of damaging viral strains. Therefore, it is crucial to characterize begomoviruses circulating in different regions and crops globally. This study utilized vector-enabled metagenomics (VEM) coupled with high throughput sequencing to survey begomoviruses directly from whiteflies collected in various locations (California (USA), Guatemala, Israel, Puerto Rico, and Spain). Begomoviruses were detected in all locations, with the highest diversity identified in Guatemala where up to seven different species were identified in a single field. Both bipartite and monopartite viruses were detected, including seven new begomovirus species from Guatemala, Puerto Rico, and Spain. This begomovirus survey extends the known diversity of these highly damaging plant viruses. However, the new genomes described here and in the recent literature appear to reflect the outcome of interactions between closely-related species, often resulting from recombination, instead of unique, highly divergent species. PMID- 26516899 TI - Nucleobase but not Sugar Fidelity is Maintained in the Sabin I RNA-Dependent RNA Polymerase. AB - The Sabin I poliovirus live, attenuated vaccine strain encodes for four amino acid changes (i.e., D53N, Y73H, K250E, and T362I) in the RNA-dependent RNA polymerase (RdRp). We have previously shown that the T362I substitution leads to a lower fidelity RdRp, and viruses encoding this variant are attenuated in a mouse model of poliovirus. Given these results, it was surprising that the nucleotide incorporation rate and nucleobase fidelity of the Sabin I RdRp is similar to that of wild-type enzyme, although the Sabin I RdRp is less selective against nucleotides with modified sugar groups. We suggest that the other Sabin amino acid changes (i.e., D53N, Y73H, K250E) help to re-establish nucleotide incorporation rates and nucleotide discrimination near wild-type levels, which may be a requirement for the propagation of the virus and its efficacy as a vaccine strain. These results also suggest that the nucleobase fidelity of the Sabin I RdRp likely does not contribute to viral attenuation. PMID- 26516900 TI - Requirements within the Ebola Viral Glycoprotein for Tetherin Antagonism. AB - Tetherin is an interferon-induced, intrinsic cellular response factor that blocks release of numerous viruses, including Ebola virus, from infected cells. As with many viruses targeted by host factors, Ebola virus employs a tetherin antagonist, the viral glycoprotein (EboGP), to counteract restriction and promote virus release. Unlike other tetherin antagonists such as HIV-1 Vpu or KSHV K5, the features within EboGP needed to overcome tetherin are not well characterized. Here, we describe sequences within the EboGP ectodomain and membrane spanning domain (msd) as necessary to relieve tetherin restriction of viral particle budding. Fusing the EboGP msd to a normally secreted form of the glycoprotein effectively promotes Ebola virus particle release. Cellular protein or lipid anchors could not substitute for the EboGP msd. The requirement for the EboGP msd was not specific for filovirus budding, as similar results were seen with HIV particles. Furthermore trafficking of chimeric proteins to budding sites did not correlate with an ability to counter tetherin. Additionally, we find that a glycoprotein construct, which mimics the cathepsin-activated species by proteolytic removal of the EboGP glycan cap and mucin domains, is unable to counteract tetherin. Combining these results suggests an important role for the EboGP glycan cap and msd in tetherin antagonism. PMID- 26516901 TI - Entry of Oncolytic Herpes Simplex Virus into Human Squamous Cell Carcinoma Cells by Ultrasound. AB - Low-intensity ultrasound is a useful method to introduce materials into cells due to the transient formation of micropores, called sonoporations, on the cell membrane. Whether oncolytic herpes simplex virus type 1 (HSV-1) can be introduced into oral squamous cell carcinoma (SCC) cells through membrane pores remains undetermined. Human SCC cell line SAS and oncolytic HSV-1 RH2, which was deficient in the 134.5 gene and fusogenic, were used. Cells were exposed to ultrasound in the presence or absence of microbubbles. The increase of virus entry was estimated by plaque numbers. Viral infection was hardly established without the adsorption step, but plaque number was increased by the exposure of HSV-1-inoculated cells to ultrasound. Plaque number was also increased even if SAS cells were exposed to ultrasound and inoculated with RH2 without the adsorption step. This effect was abolished when the interval from ultrasound exposure to virus inoculation was prolonged. Scanning electron microscopy revealed depressed spots on the cell surface after exposure to ultrasound. These results suggest that oncolytic HSV-1 RH2 can be introduced into SAS cells through ultrasound-mediated pores of the cell membrane that are resealed after an interval. PMID- 26516902 TI - Exposure to West Nile Virus Increases Bacterial Diversity and Immune Gene Expression in Culex pipiens. AB - Complex interactions between microbial residents of mosquitoes and arboviruses are likely to influence many aspects of vectorial capacity and could potentially have profound effects on patterns of arbovirus transmission. Such interactions have not been well studied for West Nile virus (WNV; Flaviviridae, Flavivirus) and Culex spp. mosquitoes. We utilized next-generation sequencing of 16S ribosomal RNA bacterial genes derived from Culex pipiens Linnaeus following WNV exposure and/or infection and compared bacterial populations and broad immune responses to unexposed mosquitoes. Our results demonstrate that WNV infection increases the diversity of bacterial populations and is associated with up regulation of classical invertebrate immune pathways including RNA interference (RNAi), Toll, and Jak-STAT (Janus kinase-Signal Transducer and Activator of Transcription). In addition, WNV exposure alone, without the establishment of infection, results in similar alterations to microbial and immune signatures, although to a lesser extent. Multiple bacterial genera were found in greater abundance inWNV-exposed and/or infected mosquitoes, yet the most consistent and notable was the genus Serratia. PMID- 26516903 TI - Identification and Application of Neutralizing Epitopes of Human Adenovirus Type 55 Hexon Protein. AB - Human adenovirus type 55 (HAdV55) is a newly identified re-emergent acute respiratory disease (ARD) pathogen with a proposed recombination of hexon gene between HAdV11 and HAdV14 strains. The identification of the neutralizing epitopes is important for the surveillance and vaccine development against HAdV55 infection. In this study, four type-specific epitope peptides of HAdV55 hexon protein, A55R1 (residues 138 to 152), A55R2 (residues 179 to 187), A55R4 (residues 247 to 259) and A55R7 (residues 429 to 443), were predicted by multiple sequence alignment and homology modeling methods, and then confirmed with synthetic peptides by enzyme-linked immunosorbent assay (ELISA) and neutralization tests (NT). Finally, the A55R2 was incorporated into human adenoviruses 3 (HAdV3) and a chimeric adenovirus rAd3A55R2 was successfully obtained. The chimeric rAd3A55R2 could induce neutralizing antibodies against both HAdV3 and HAdV55. This current study will contribute to the development of novel adenovirus vaccine candidate and adenovirus structural analysis. PMID- 26516904 TI - Low Proviral Load is Associated with Indeterminate Western Blot Patterns in Human T-Cell Lymphotropic Virus Type 1 Infected Individuals: Could Punctual Mutations be Related? AB - BACKGROUND: indeterminate Western blot (WB) patterns are a major concern for diagnosis of human T-cell lymphotropic virus type 1 (HTLV-1) infection, even in non-endemic areas. OBJECTIVES: (a) to define the prevalence of indeterminate WB among different populations from Argentina; (b) to evaluate if low proviral load (PVL) is associated with indeterminate WB profiles; and (c) to describe mutations in LTR and tax sequence of these cases. RESULTS: Among 2031 samples, 294 were reactive by screening. Of them, 48 (16.3%) were WB indeterminate and of those 15 (31.3%) were PCR+. Quantitative real-time PCR (qPCR) was performed to 52 HTLV-1+ samples, classified as Group 1 (G1): 25 WB+ samples from individuals with pathologies; Group 2 (G2): 18 WB+ samples from asymptomatic carriers (AC); and Group 3 (G3): 9 seroindeterminate samples from AC. Median PVL was 4.78, 2.38, and 0.15 HTLV-1 copies/100 PBMCs, respectively; a significant difference (p=0.003) was observed. Age and sex were associated with PVL in G1 and G2, respectively. Mutations in the distal and central regions of Tax Responsive Elements (TRE) 1 and 2 of G3 were observed, though not associated with PVL.The 8403A>G mutation of the distal region, previously related to high PVL, was absent in G3 but present in 50% of WB+ samples (p = 0.03). CONCLUSIONS: indeterminate WB results confirmed later as HTLV-1 positive may be associated with low PVL levels. Mutations in LTR and tax are described; their functional relevance remains to be determined. PMID- 26516905 TI - Antioxidant and Anti-Fatigue Constituents of Okra. AB - Okra (Abelmoschus esculentus (L.) Moench), a healthy vegetable, is widely spread in tropical and subtropical areas. Previous studies have proven that okra pods possess anti-fatigue activity, and the aim of this research is to clarify the anti-fatigue constituents. To achieve this, we divided okra pods (OPD) into seeds (OSD) and skins (OSK), and compared the contents of total polysaccharides, total polyphenols, total flavonoids, isoquercitrin, and quercetin-3-O-gentiobiose and the antioxidant activity in vitro and anti-fatigue activity in vivo between OSD and OSK. The contents of total polyphenols and total polysaccharides were 29.5% and 14.8% in OSD and 1.25% and 43.1% in OSK, respectively. Total flavonoids, isoquercitrin and quercetin-3-O-gentiobiose (5.35%, 2.067% and 2.741%, respectively) were only detected in OSD. Antioxidant assays, including 1-diphenyl 2-picrylhydrazyl (DPPH) scavenging, ferric reducing antioxidant power (FRAP) and reducing power test, and weight-loaded swimming test showed OSD possessed significant antioxidant and anti-fatigue effects. Moreover, biochemical determination revealed that that anti-fatigue activity of OSD is caused by reducing the levels of blood lactic acid (BLA) and urea nitrogen (BUN), enhancing hepatic glycogen storage and promoting antioxidant ability by lowering malondialdehyde (MDA) level and increasing superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) levels. These results proved okra seeds were the anti-fatigue part of okra pods and polyphenols and flavonoids were active constituents. PMID- 26516906 TI - Association of Dietary Proportions of Macronutrients with Visceral Adiposity Index: Non-Substitution and Iso-Energetic Substitution Models in a Prospective Study. AB - We aimed to investigate associations between dietary macronutrient proportions and prospective visceral adiposity index changes (DeltaVAI). The study included 1254 adults (18-74 years), from the Tehran Lipid and Glucose Study (TLGS), who were followed for three years. Dietary intakes were assessed twice using food frequency questionnaires. Associations of dietary macronutrient with DeltaVAI and risk of visceral adiposity dysfunction (VAD) after three years were investigated. The percentage of energy intake from protein in the total population, and from fat in women, were associated with higher increases in VAI. A 5% higher energy intake from protein substituted for carbohydrate, monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) was associated with higher DeltaVAI. Higher energy intake from animal protein substituted for PUFAs was positively associated with DeltaVAI. Substituting protein and PUFAs with MUFAs were related to higher DeltaVAI. The associations were similar in men and women, but reached significance mostly among women. Risk of VAD was increased when 1% of energy from protein was replaced with MUFAs. Substituting protein for carbohydrate and fat, and fat for carbohydrate, resulted in increased risk of VAD in women. Higher dietary proportions of protein and animal-derived MUFA may be positively associated with DeltaVAI and risk of VAD. PMID- 26516907 TI - Real Time Monitoring of Inhibition of Adipogenesis and Angiogenesis by (-) Epigallocatechin-3-Gallate in 3T3-L1 Adipocytes and Human Umbilical Vein Endothelial Cells. AB - Little is known about the effect of (-)-epigallocatechin-3-gallate (EGCG) on angiogenesis in adipocytes. We aimed to test the effect of EGCG on the expression of vascular endothelial growth factor (VEGF) in adipocytes. The levels of VEGF secretion, the expression of VEGF message ribonucleic acid (mRNA) and VEGF protein in 3T3-L1 cells were measured by enzyme linked immunosorbent assay (ELISA), real time polymerase chain reaction (PCR), and immunofluorescence staining, respectively. The xCELLigence real time cell analysis system was used to study the growth and differentiation of 3T3-L1 preadipocytes. A coculture system was used to test the effects of 3T3-L1 cells on proliferation of human umbilical vein endothelial cells (HUVECs). The conditioned media derived from 3T3 L1 cells treated with or without EGCG was used to culture the HUVECs for a tube formation assay. Peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein alpha (C/EBPalpha), two transcription factors related to both adipogenesis and angiogenesis, were examined to explore the potential mechanism. We found that all the three measurements of VEGF expression in adipocytes (mRNA, protein and secretion in media) were reduced after EGCG treatment. The growth of HUVECs co-cultured with 3T3-L1 cells was significantly increased and the conditioned media from EGCG treated 3T3-L1 adipocytes inhibited tube formation in HUVECs. Both PPARgamma and C/EBPalpha expression in adipocytes were decreased with EGCG treatment. In conclusion, findings from this study suggest that EGCG may inhibit angiogenesis by regulating VEGF expression and secretion in adipocytes. PMID- 26516908 TI - An Investigation of the Acute Effects of Oligofructose-Enriched Inulin on Subjective Wellbeing, Mood and Cognitive Performance. AB - Inulin is a natural food component found in many plants that are part of the human diet (e.g., leeks, onions, wheat, garlic, chicory and artichokes). It is added to many foods and is used to increase dietary fibre, replace fats or carbohydrates, and as a prebiotic (a stimulant of beneficial bacteria in the colon). Oligofructose, which is also present in these foods, produces similar effects and most research has used a combination of these products. A previous study (Smith, 2005) investigated the effects of regular consumption of oligofructose-enriched inulin on wellbeing, mood, and cognitive performance in humans. The results showed that oligofructose-enriched inulin had no negative effects but that it did not improve wellbeing, mood, or performance. The aim of the present study was to examine the acute effects of oligofructose-enriched inulin (5 g) over a 4 h period during which the participants remained in the laboratory. A double blind placebo (maltodextrin) controlled study (N = 47) was carried out with the order of conditions being counterbalanced and the two sessions a week apart. On each test day mood and cognitive performance were assessed at baseline (at 8:00) and then following inulin or placebo (at 11:00). Prior to the second test session (at 10:30) participants completed a questionnaire assessing their physical symptoms and mental health during the test morning. The inulin and placebo were provided in powder form in 5 g sachets. Volunteers consumed one sachet in decaffeinated tea or decaffeinated coffee with breakfast (9:00). Questionnaire results showed that on the day that the inulin was consumed, participants felt happier, had less indigestion and were less hungry than when they consumed the placebo. As for performance and mood tasks, the most consistent effects were on the episodic memory tasks where consumption of inulin was associated with greater accuracy on a recognition memory task, and improved recall performance (immediate and delayed). Further research is required to identify the mechanisms that underlie this effect with glucose metabolism being one candidate. PMID- 26516909 TI - Association between Dietary Vitamin A Intake and the Risk of Glioma: Evidence from a Meta-analysis. AB - The results from epidemiological studies between dietary vitamin A intake and glioma risk is not consistent. Thus, a meta-analysis was conducted to confirm the exact relationship between them. PubMed and Web of Knowledge were used to search the relevant articles up to May 2015. Pooled relative risk (RR) with 95% confidence interval (CI)was calculated using random-effect model. Egger's test was used to assess the small-study effect. At the end, seven articles with eight case-control studies involving 1841 glioma cases and 4123 participants were included. Our study indicated that highest category of dietary vitamin A intake was significantly associated with reduced risk of glioma (RR = 0.80, 95% CI = 0.62-0.98, p = 0.014, I2 = 54.9%). Egger's test did not find any publication bias. In conclusion, our study indicated that higher category of dietary vitamin A intake could reduce the glioma risk. However, we could not do a dose-response analysis for vitamin A intake with glioma risk due to the limited data in each reported individual article. Due to this limitation, further studies with detailed dose, cases and person-years for each category is wanted to assess this dose-response association. PMID- 26516910 TI - Menaquinone-7 Supplementation to Reduce Vascular Calcification in Patients with Coronary Artery Disease: Rationale and Study Protocol (VitaK-CAC Trial). AB - Coronary artery calcification (CAC) develops early in the pathogenesis of atherosclerosis and is a strong and independent predictor of cardiovascular disease (CVD). Arterial calcification is caused by an imbalance in calcification regulatory mechanisms. An important inhibitor of calcification is vitamin K dependent matrix Gla protein (MGP). Both preclinical and clinical studies have shown that inhibition of the vitamin K-cycle by vitamin K antagonists (VKA) results in elevated uncarboxylated MGP (ucMGP) and subsequently in extensive arterial calcification. This led us to hypothesize that vitamin K supplementation may slow down the progression of calcification. To test this, we designed the VitaK-CAC trial which analyses effects of menaquinone-7 (MK-7) supplementation on progression of CAC. The trial is a double-blind, randomized, placebo-controlled trial including patients with coronary artery disease (CAD). Patients with a baseline Agatston CAC-score between 50 and 400 will be randomized to an intervention-group (360 microgram MK-7) or a placebo group. Treatment duration will be 24 months. The primary endpoint is the difference in CAC-score progression between both groups. Secondary endpoints include changes in arterial structure and function, and associations with biomarkers. We hypothesize that treatment with MK-7 will slow down or arrest the progression of CAC and that this trial may lead to a treatment option for vascular calcification and subsequent CVD. PMID- 26516911 TI - Quantification of in Vivo Colonic Short Chain Fatty Acid Production from Inulin. AB - Short chain fatty acids (SCFA), including acetate, propionate, and butyrate, are produced during bacterial fermentation of undigested carbohydrates in the human colon. In this study, we applied a stable-isotope dilution method to quantify the in vivo colonic production of SCFA in healthy humans after consumption of inulin. Twelve healthy subjects performed a test day during which a primed continuous intravenous infusion with [1-(13)C]acetate, [1-(13)C]propionate and [1 (13)C]butyrate (12, 1.2 and 0.6 MUmol.kg(-1).min(-1), respectively) was applied. They consumed 15 g of inulin with a standard breakfast. Breath and blood samples were collected at regular times during the day over a 12 h period. The endogenous rate of appearance of acetate, propionate, and butyrate was 13.3 +/- 4.8, 0.27 +/ 0.09, and 0.28 +/- 0.12 MUmol.kg(-1).min(-1), respectively. Colonic inulin fermentation was estimated to be 137 +/- 75 mmol acetate, 11 +/- 9 mmol propionate, and 20 +/- 17 mmol butyrate over 12 h, assuming that 40%, 10%, and 5% of colonic derived acetate, propionate, and butyrate enter the systemic circulation. In conclusion, inulin is mainly fermented into acetate and, to lesser extents, into butyrate and propionate. Stable isotope technology allows quantifying the production of the three main SCFA in vivo and proved to be a practical tool to investigate the extent and pattern of SCFA production. PMID- 26516912 TI - Balancing Sodium and Potassium: Estimates of Intake in a New Zealand Adult Population Sample. AB - Dietary intakes of sodium and potassium are important determinants of blood pressure. We assessed sodium and potassium intake in a cross-sectional survey which included a random sample of New Zealand Adults aged 18 to 64 years from two New Zealand cities: Dunedin and Wellington. Participants completed a short questionnaire, had height, weight and blood pressure measured, and collected a 24 h urine sample. Mean 24 h sodium excretion was 3386 mg/day (95% CI 3221, 3551): 3865 mg/day for men and for 2934 mg/day women. Mean 24 h potassium excretion was 2738 mg/day (95% CI 2623, 2855): 3031 mg/day for men and 2436 mg/day for women. Mean sodium:potassium ratio was 1.32 (95% CI 1.26, 1.39); 1.39 for men and 1.26 for women. Sodium intake was higher among younger people, men, those with a higher BMI and higher potassium excretion. Potassium excretion was higher among older people, men and those with a higher sodium excretion. New Zealand adults have high sodium intakes and low potassium intakes compared to recommended levels. This is likely to adversely affect population blood pressure levels as well as incidence of cardiovascular disease. A comprehensive public health programme to reduce dietary sodium intake and increase intake of fruit and vegetables is warranted. PMID- 26516913 TI - Differential Adsorption of Ochratoxin A and Anthocyanins by Inactivated Yeasts and Yeast Cell Walls during Simulation of Wine Aging. AB - The adsorption of ochratoxin A (OTA) by yeasts is a promising approach for the decontamination of musts and wines, but some potential competitive or interactive phenomena between mycotoxin, yeast cells, and anthocyanins might modify the intensity of the phenomenon. The aim of this study was to examine OTA adsorption by two strains of Saccharomyces cerevisiae (the wild strain W13, and the commercial isolate BM45), previously inactivated by heat, and a yeast cell wall preparation. Experiments were conducted using Nero di Troia red wine contaminated with 2 MUg/L OTA and supplemented with yeast biomass (20 g/L). The samples were analyzed periodically to assess mycotoxin concentration, chromatic characteristics, and total anthocyanins over 84 days of aging. Yeast cell walls revealed the highest OTA-adsorption in comparison to thermally-inactivated cells (50% vs. 43% toxin reduction), whilst no significant differences were found for the amount of adsorbed anthocyanins in OTA-contaminated and control wines. OTA and anthocyanins adsorption were not competitive phenomena. Unfortunately, the addition of yeast cells to wine could cause color loss; therefore, yeast selection should also focus on this trait to select the best strain. PMID- 26516914 TI - The Cystine Knot Is Responsible for the Exceptional Stability of the Insecticidal Spider Toxin omega-Hexatoxin-Hv1a. AB - The inhibitor cystine knot (ICK) is an unusual three-disulfide architecture in which one of the disulfide bonds bisects a loop formed by the two other disulfide bridges and the intervening sections of the protein backbone. Peptides containing an ICK motif are frequently considered to have high levels of thermal, chemical and enzymatic stability due to cross-bracing provided by the disulfide bonds. Experimental studies supporting this contention are rare, in particular for spider-venom toxins, which represent the largest diversity of ICK peptides. We used omega-hexatoxin-Hv1a (Hv1a), an insecticidal toxin from the deadly Australian funnel-web spider, as a model system to examine the contribution of the cystine knot to the stability of ICK peptides. We show that Hv1a is highly stable when subjected to temperatures up to 75 degrees C, pH values as low as 1, and various organic solvents. Moreover, Hv1a was highly resistant to digestion by proteinase K and when incubated in insect hemolymph and human plasma. We demonstrate that the ICK motif is essential for the remarkable stability of Hv1a, with the peptide's stability being dramatically reduced when the disulfide bonds are eliminated. Thus, this study demonstrates that the ICK motif significantly enhances the chemical and thermal stability of spider-venom peptides and provides them with a high level of protease resistance. This study also provides guidance to the conditions under which Hv1a could be stored and deployed as a bioinsecticide. PMID- 26516915 TI - Quantitative Detection of Shiga Toxins Directly from Stool Specimens of Patients Associated with an Outbreak of Enterohemorrhagic Escherichia coli in Japan- Quantitative Shiga toxin detection from stool during EHEC outbreak. AB - Detection of Shiga toxins (Stx) is important for accurate diagnosis of Enterohemorrhagic Escherichia coli infection. In this study, we quantitatively analyzed Stx protein in nine patients' stool during an outbreak that occurred in Japan. Highly sensitive immunoassay (bead enzyme-linked immunosorbent assay (bead ELISA)) revealed that the concentrations of toxins in stool of patients ranged from 0.71 to 10.44 ng/mL for Stx1 and 2.75 to 51.61 ng/mL for Stx2. To our knowledge, this is the first report that reveals the range of Stx protein concentrations in human stools. PMID- 26516916 TI - Indolic uremic solutes enhance procoagulant activity of red blood cells through phosphatidylserine exposure and microparticle release. AB - Increased accumulation of indolic uremic solutes in the blood of uremic patients contributes to the risk of thrombotic events. Red blood cells (RBCs), the most abundant blood cells in circulation, may be a privileged target of these solutes. However, the effect of uremic solutes indoxyl sulfate (IS) and indole-3-acetic acid (IAA) on procoagulant activity (PCA) of erythrocyte is unclear. Here, RBCs from healthy adults were treated with IS and IAA (mean and maximal concentrations reported in uremic patients). Phosphatidylserine (PS) exposure of RBCs and their microparticles (MPs) release were labeled with Alexa Fluor 488-lactadherin and detected by flow cytometer. Cytosolic Ca(2+) ([Ca(2+)]) with Fluo 3/AM was analyzed by flow cytometer. PCA was assessed by clotting time and purified coagulation complex assays. We found that PS exposure, MPs generation, and consequent PCA of RBCs at mean concentrations of IS and IAA enhanced and peaked in maximal uremic concentrations. Moreover, 128 nM lactadherin, a PS inhibitor, inhibited over 90% PCA of RBCs and RMPs. Eryptosis or damage, by indolic uremic solutes was due to, at least partially, the increase of cytosolic [Ca(2+)]. Our results suggest that RBC eryptosis in uremic solutes IS and IAA plays an important role in thrombus formation through releasing RMPs and exposing PS. Lactadherin acts as an efficient anticoagulant in this process. PMID- 26516917 TI - The Interactions of Obesity, Inflammation and Insulin Resistance in Breast Cancer. AB - Obese postmenopausal women have an increased breast cancer risk, the principal mechanism for which is elevated estrogen production by adipose tissue; also, regardless of menstrual status and tumor estrogen dependence, obesity is associated with biologically aggressive breast cancers. Type 2 diabetes has a complex relationship with breast cancer risk and outcome; coexisting obesity may be a major factor, but insulin itself induces adipose aromatase activity and estrogen production and also directly stimulates breast cancer cell growth and invasion. Adipose tissue inflammation occurs frequently in obesity and type 2 diabetes, and proinflammatory cytokines and prostaglandin E2 produced by cyclooxygenase-2 in the associated infiltrating macrophages also induce elevated aromatase expression. In animal models, the same proinflammatory mediators, and the chemokine monocyte chemoattractant protein-1, also stimulate tumor cell proliferation and invasion directly and promote tumor-related angiogenesis. We postulate that chronic adipose tissue inflammation, rather than body mass index defined obesity per se, is associated with an increased risk of type 2 diabetes and postmenopausal estrogen-dependent breast cancer. Also, notably before the menopause, obesity and type 2 diabetes, or perhaps the associated inflammation, promote estrogen-independent, notably triple-negative, breast cancer development, invasion and metastasis by mechanisms that may involve macrophage-secreted cytokines, adipokines and insulin. PMID- 26516918 TI - The Clinical Relevance of Long Non-Coding RNAs in Cancer. AB - Non-coding RNAs have long been associated with cancer development and progression, and since their earliest discovery, their clinical potential in identifying and characterizing the disease has been pursued. Long non-coding (lncRNAs), a diverse class of RNA transcripts >200 nucleotides in length with limited protein coding potential, has been only modestly studied relative to other categories of non-coding RNAs. However, recent data suggests they too may be important players in cancer. In this article, we consider the value of lncRNAs in the clinical setting, and in particular their potential roles as diagnostic and prognostic markers in cancer. Furthermore, we summarize the most significant studies linking lncRNA expression in human biological samples to cancer outcomes. The diagnostic sensitivity, specificity and validity of these non-coding RNA transcripts is compared in the various biological compartments in which they have been detected including tumor tissue, whole body fluids and exosomes. PMID- 26516919 TI - Hydrocarbon Patterns and Mating Behaviour in Populations of Drosophila yakuba. AB - Drosophila yakuba is widespread in Africa. Here we compare the cuticular hydrocarbon (CHC) profiles and mating behavior of mainland (Kounden, Cameroon) and island (Mayotte, Sao-Tome, Bioko) populations. The strains each had different CHC profiles: Bioko and Kounden were the most similar, while Mayotte and Sao-Tome contained significant amounts of 7-heptacosene. The CHC profile of the Sao-Tome population differed the most, with half the 7-tricosene of the other populations and more 7-heptacosene and 7-nonacosene. We also studied the characteristics of the mating behavior of the four strains: copulation duration was similar but latency times were higher in Mayotte and Sao-Tome populations. We found partial reproductive isolation between populations, especially in male-choice experiments with Sao-Tome females. PMID- 26516920 TI - Age-Related Response Bias in the Decoding of Sad Facial Expressions. AB - Recent studies have found that age is negatively associated with the accuracy of decoding emotional facial expressions; this effect of age was found for actors as well as for raters. Given that motivational differences and stereotypes may bias the attribution of emotion, the aim of the present study was to explore whether these age effects are due to response bias, that is, the unbalanced use of response categories. Thirty younger raters (19-30 years) and thirty older raters (65-81 years) viewed video clips of younger and older actors representing the same age ranges, and decoded their facial expressions. We computed both raw hit rates and bias-corrected hit rates to assess the influence of potential age related response bias on decoding accuracy. Whereas raw hit rates indicated significant effects of both the actors' and the raters' ages on decoding accuracy for sadness, these age effects were no longer significant when response bias was corrected. Our results suggest that age effects on the accuracy of decoding facial expressions may be due, at least in part, to age-related response bias. PMID- 26516921 TI - Biocompatible Hydrogels for Microarray Cell Printing and Encapsulation. AB - Conventional drug screening processes are a time-consuming and expensive endeavor, but highly rewarding when they are successful. To identify promising lead compounds, millions of compounds are traditionally screened against therapeutic targets on human cells grown on the surface of 96-wells. These two dimensional (2D) cell monolayers are physiologically irrelevant, thus, often providing false-positive or false-negative results, when compared to cells grown in three-dimensional (3D) structures such as hydrogel droplets. However, 3D cell culture systems are not easily amenable to high-throughput screening (HTS), thus inherently low throughput, and requiring relatively large volume for cell-based assays. In addition, it is difficult to control cellular microenvironments and hard to obtain reliable cell images due to focus position and transparency issues. To overcome these problems, miniaturized 3D cell cultures in hydrogels were developed via cell printing techniques where cell spots in hydrogels can be arrayed on the surface of glass slides or plastic chips by microarray spotters and cultured in growth media to form cells encapsulated 3D droplets for various cell-based assays. These approaches can dramatically reduce assay volume, provide accurate control over cellular microenvironments, and allow us to obtain clear 3D cell images for high-content imaging (HCI). In this review, several hydrogels that are compatible to microarray printing robots are discussed for miniaturized 3D cell cultures. PMID- 26516922 TI - Sensing of p53 and EGFR Biomarkers Using High Efficiency SERS Substrates. AB - In this paper we describe a method for the determination of protein concentration using Surface Enhanced Raman Resonance Scattering (SERRS) immunoassays. We use two different Raman active linkers, 4-aminothiophenol and 6-mercaptopurine, to bind to a high sensitivity SERS substrate and investigate the influence of varying concentrations of p53 and EGFR on the Raman spectra. Perturbations in the spectra are due to the influence of protein-antibody binding on Raman linker molecules and are attributed to small changes in localised mechanical stress, which are enhanced by SERRS. These influences are greatest for peaks due to the C S functional group and the Full Width Half Maximum (FWHM) was found to be inversely proportional to protein concentration. PMID- 26516923 TI - Advances in Metabolic Engineering of Cyanobacteria for Photosynthetic Biochemical Production. AB - Engineering cyanobacteria into photosynthetic microbial cell factories for the production of biochemicals and biofuels is a promising approach toward sustainability. Cyanobacteria naturally grow on light and carbon dioxide, bypassing the need of fermentable plant biomass and arable land. By tapping into the central metabolism and rerouting carbon flux towards desirable compound production, cyanobacteria are engineered to directly convert CO2 into various chemicals. This review discusses the diversity of bioproducts synthesized by engineered cyanobacteria, the metabolic pathways used, and the current engineering strategies used for increasing their titers. PMID- 26516924 TI - Modeling and Simulation of Optimal Resource Management during the Diurnal Cycle in Emiliania huxleyi by Genome-Scale Reconstruction and an Extended Flux Balance Analysis Approach. AB - The coccolithophorid unicellular alga Emiliania huxleyi is known to form large blooms, which have a strong effect on the marine carbon cycle. As a photosynthetic organism, it is subjected to a circadian rhythm due to the changing light conditions throughout the day. For a better understanding of the metabolic processes under these periodically-changing environmental conditions, a genome-scale model based on a genome reconstruction of the E. huxleyi strain CCMP 1516 was created. It comprises 410 reactions and 363 metabolites. Biomass composition is variable based on the differentiation into functional biomass components and storage metabolites. The model is analyzed with a flux balance analysis approach called diurnal flux balance analysis (diuFBA) that was designed for organisms with a circadian rhythm. It allows storage metabolites to accumulate or be consumed over the diurnal cycle, while keeping the structure of a classical FBA problem. A feature of this approach is that the production and consumption of storage metabolites is not defined externally via the biomass composition, but the result of optimal resource management adapted to the diurnally-changing environmental conditions. The model in combination with this approach is able to simulate the variable biomass composition during the diurnal cycle in proximity to literature data. PMID- 26516925 TI - Gold(i)-catalyzed highly stereoselective synthesis of polycyclic indolines: the construction of four contiguous stereocenters. AB - A convenient and efficient synthetic method has been developed to construct highly functionalized polycyclic indoline skeletons with four contiguous stereocenters, which are of great importance in biological and pharmaceutical chemistry. The selective formation of either the oxabridged-ring or ring-opening polycyclic indoline derivatives can be controlled by using different gold catalytic systems. A variety of polycyclic indoline derivatives were obtained in moderate to good yields under mild conditions with moderate to excellent enantioselectivity. PMID- 26516926 TI - PTTG regulates the metabolic switch of ovarian cancer cells via the c-myc pathway. AB - Human pituitary tumor-transforming gene (PTTG) is a proto-oncogene involved in the development, invasion, and metastasis of many types of cancer, including ovarian cancer. However, little is known about the role of PTTG in the metabolic shift of ovarian cancer cells. In our study, we show that PTTG expression was positively correlated with the differentiation degree of ovarian cancer tissue. In addition, PTTG suppression by specific shRNA could inhibit the proliferation of ovarian cancer cells A2780 and SKOV-3. Furthermore, aerobic glycolysis was suppressed and oxidative phosphorylation was increased in ovarian cancer cells after PTTG suppression. We further found that the expression of c-myc and several crucial enzymes involved in aerobic glycolysis (e.g., PKM2, LDHA, and glucose transporter 1 (GLUT-1)) were downregulated by PTTG knockwown. Overexpression of c myc could prevent the metabolic shift induced by PTTG knockwown. Together, our findings suggest that the oncogene PTTG promotes the progression of ovarian cancer cells, and its loss resists tumor development, in part, by regulating cellular metabolic reprogramming that supports cell growth and proliferation via c-myc pathway. PMID- 26516927 TI - LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer. AB - The Polycomb protein enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in advanced human prostate cancer (PCa), especially in lethal castration-resistant prostate cancer (CRPC). However, the signaling pathways that regulate EZH2 functions in PCa remain incompletely defined. Using EZH2 antibody based RNA immunoprecipitation-coupled high throughput sequencing (RIP-seq), we demonstrated that EZH2 binds to MALAT1, a long non-coding RNA (lncRNA) that is overexpressed during PCa progression. GST pull-down and RIP assays demonstrated that the 3' end of MALAT1 interacts with the N-terminal of EZH2. Knockdown of MALAT1 impaired EZH2 recruitment to its target loci and upregulated expression of EZH2 repressed genes. Further studies indicated that MALAT1 plays a vital role in EZH2-enhanced migration and invasion in CRPC cell lines. Meta-analysis and RT qPCR of patient specimens demonstrated a positive correlation between MALAT1 and EZH2 expression in human CRPC tissues. Finally, we showed that MALAT1 enhances expression of PRC2-independent target genes of EZH2 in CRPC cells in culture and patient-derived xenografts. Together, these data indicate that MALAT1 may be a crucial RNA cofactor of EZH2 and that the EZH2-MALAT1 association may provide a new avenue for development new strategies for treatment of CRPC. PMID- 26516928 TI - Inhibition of Eph receptor A4 by 2,5-dimethylpyrrolyl benzoic acid suppresses human pancreatic cancer growing orthotopically in nude mice. AB - Ephrin receptor A4 (EphA4) is overexpressed in human pancreatic adenocarcinoma (PDAC) and activate cell growth. Recent studies have identified small molecules that block EphA4. In this study, we investigated the correlation between EphA4 expression and the prognosis of patients with PDAC. We also examined the cytostatic efficacy of 2,5-dimethylpyrrolyl benzoic acid (compound 1), a small molecule that blocks EphA4, in PDAC cells. Overall survival of patients with EphA4 positivity was significantly shorter than that of patients with EphA4 negativity (P = 0.029). In addition, multivariate analysis revealed that EphA4 expression was an independent prognostic factor in PDAC patients (P = 0.039). Compound 1 showed a cytostatic efficacy in PDAC cells expressing EphA4 in vitro and in vivo. Our study indicated that compound 1 suppressed both EphA4 and Akt phosphorylations, and induced apoptosis in PDAC cells expressing EphA4. In conclusion, compound 1 has a high potential as a therapeutic agent for patients with PDAC. PMID- 26516930 TI - Whole transcriptome sequencing identifies BCOR internal tandem duplication as a common feature of clear cell sarcoma of the kidney. AB - PURPOSE: Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor that is frequently difficult to distinguish among other childhood renal tumors due to its histological heterogeneity. This work evaluates genetic abnormalities carried by a series of CCSK samples by whole transcriptome sequencing (WTS), to identify molecular biomarkers that could improve the diagnostic process. METHODS: WTS was performed on tumor RNA from 8 patients with CCSK. Bioinformatic analysis, with implementation of a pipeline for detection of intragenic rearrangements, was executed. Sanger sequencing and gene expression were evaluated to validate BCOR internal tandem duplication (ITD). RESULTS: WTS did not identify any shared SNVs, Ins/Del or fusion event. Conversely, analysis of intragenic rearrangements enabled the detection of a breakpoint within BCOR transcript recurrent in all samples. Three different in-frame ITD in exon15 of BCOR, were detected. The presence of the ITD was confirmed on tumor DNA and cDNA, and resulted in overexpression of BCOR. CONCLUSIONS: WTS coupled with specific bioinformatic analysis is able to detect rare genetic events, as intragenic rearrangements. ITD in the last exon of BCOR is recurrent in all CCSK samples analyzed, representing a valuable molecular marker to improve diagnosis of this rare childhood renal tumor. PMID- 26516932 TI - A simple clot based assay for detection of procoagulant cell-derived microparticles. AB - BACKGROUND: Cell-derived microparticles (MPs) are important biomarkers in many facets of medicine. However, the MP detection methods used till date are costly and time consuming. The main aim of this study was to standardize an in-house clot based screening method for MP detection which would not only be specific and sensitive, but also inexpensive. METHODS: Four different methods of MP assessment were performed and the results correlated. Using the flow cytometry technique as the gold standard, 25 samples with normal phosphatidylserine (PS) expressing MP levels and 25 samples with elevated levels were selected, which was cross checked by the commercial STA Procoag PPL clotting time (CT) assay. A simple recalcification time and an in-house clot assay were the remaining two tests. The in-house test measures the CT after the addition of calcium chloride to MP rich plasma, following incubation with Russell viper venom and phospholipid free plasma. RESULTS: The CT obtained by the in-house assay significantly correlated with the results obtained by flow cytometry (R2=0.87, p<0.01). CONCLUSIONS: Though preliminary, the in-house assay seems to be efficient, inexpensive and promising. It could definitely be utilized routinely for procoagulant MP assessment in various clinical settings. PMID- 26516929 TI - Regulation of aldo-keto-reductase family 1 B10 by 14-3-3epsilon and their prognostic impact of hepatocellular carcinoma. AB - 14-3-3epsilon is overexpressed in hepatocellular carcinoma (HCC) and its expression significantly associates with a poor prognostic outcome. To uncover how 14-3-3epsilon contributes to the tumor progression of HCC, we investigated the potential downstream targets regulated by 14-3-3epsilon. We found that 14-3 3epsilon increases expression and nuclear translocation of beta-catenin and that 14-3-3epsilon-induced cell proliferation is attenuated by beta-catenin silencing in HCC cells. Moreover, 14-3-3epsilon induces aldo-keto reductase family 1 member B10 (AKR1B10) expression through the activation of beta-catenin signaling. Knockdown of AKR1B10 by siRNAs abolished 14-3-3epsilon-induced in vitro cell proliferation, anchorage-independent growth as well as in vivo tumor growth. Furthermore, AKR1B10 silencing increased retinoic acid (RA) levels in the serum of tumor-bearing mice and RA treatment attenuated 14-3-3epsilon-induced HCC cell proliferation. We further examined 14-3-3epsilon and AKR1B10 expression and clinicopathological characteristics of HCC tumors. Although the expression of AKR1B10 was significantly correlated with 14-3-3epsilon, an increase of AKR1B10 expression in 14-3-3epsilon positive patients paradoxically had better overall survival and disease-free survival rates as well as lower metastatic incidence than those without an AKR1B10 increase. Finally, we found a loss of AKR1B10 expression in cells exhibiting a high capacity of invasiveness. Silencing of AKR1B10 resulted in inducing snail and vimentin expression in HCC cells. These results indicate that AKR1B10 may play a dual role during HCC tumor progression. Our results also indicate that 14-3-3epsilon regulates AKR1B10 expression by activating beta-catenin signaling. A combination of 14-3-3epsilon with AKR1B10 is a potential therapeutic target and novel prognostic biomarker of HCC. PMID- 26516931 TI - Relay proton transfer triggered twisted intramolecular charge transfer. AB - The mechanism for the dual emission of 2-(4'-N,N-dimethylaminophenyl)imidazo[4,5 c]pyridine (DMAPIP-c) in protic solvents was investigated by synthesizing and studying its analogues. Theoretical calculations were carried out to corroborate the experimental findings. The deprotonation studies suggest that the enhancement in the TICT emission of anionic forms of DMAPIP-c is limited to a protic environment. The spectral characteristics of DMAPIP-c were also studied in a methanol-acetonitrile binary solvent mixture. Unlike DMAPIP-c, the methyl derivatives do not emit dual fluorescence in protic solvents. The relative intensity of the TICT emission (with respect to that of normal emission) rises with the methanol amount in the acetonitrile-methanol binary solvent mixture. The studies also show that a 1:3 hydrogen bonded complex is formed between DMAPIP-c and methanol and it is responsible for the TICT emission. Based on the results a relay proton transfer tiggered TICT emission is proposed. TDDFT calculations were performed to predict the emission energies. PMID- 26516933 TI - The study of markers of endothelial dysfunction in metabolic syndrome. AB - BACKGROUND: Metabolic syndrome (MetS) consists of a constellation of metabolic abnormalities that confer increased risk of cardiovascular disease (CVD) and diabetes mellitus (DM). Endothelial dysfunction is one of the key components of MetS which is caused by imbalance between vasodilatory substances like nitric oxide (NO) and vaso-constrictive substances like endothelin and prothrombotic factors like plasminogen activator inhibitor-1 (PAI-1). OBJECTIVE: To study the markers of endothelial dysfunction (NO and endothelin) and prothrombotic markers (PAI-1) among the study subjects. MATERIALS AND METHODS: We enrolled 50 diagnosed cases of MetS as per International Diabetes Federation (IDF) criteria and 50 healthy volunteers as controls. Clinical evaluation included anthropometric, routine biochemical, hematological, serum insulin, NO, endothelin and PAI-1 measurements. RESULTS: Subjects with MetS had higher insulin, endothelin and PAI 1 levels and low NO levels as compared to controls and the difference was found to be significant. The serum insulin levels were positively correlated with PAI-1 and endothelin, and negatively correlated with NO. CONCLUSION: Endothelial functional status as reflected by decreased NO and increased serum endothelin levels along with insulin resistance is seen in MetS. Moreover, higher serum level of PAI-1 also tilts towards a more prothrombotic milieu in the vascular endothelium. Hence endothelial dysfunction and prothrombotic markers may be used to guide for early diagnosis of cardiovascular disease and type 2 diabetes in patients with MetS. PMID- 26516934 TI - A New Immunotherapy Drug Creates a Watershed for the Surgical Pathologist's Role in Patient Care. PMID- 26516935 TI - Considerations for Conducting Meta-analysis in Diagnostic Pathology. PMID- 26516936 TI - Emerging Concepts in Head and Neck Squamous Cell Carcinoma. PMID- 26516937 TI - Honeycomb Lung: Time for a Change. AB - The recent introduction of new US Food and Drug Administration-approved medications for the treatment of idiopathic pulmonary fibrosis/usual interstitial pneumonia raises important concerns about the accuracy of diagnosis. The term honeycomb lung, used widely by radiologists and pathologists in the diagnosis of usual interstitial pneumonia, represents a late stage of the disease and conveys no biological information. A new conception of end-stage lung disease in usual interstitial pneumonia, based on the dying back of the pulmonary acinus, is proposed, which may improve the sensitivity and specificity of the diagnosis and provide an understanding of its pathogenesis. PMID- 26516938 TI - Standards for Clinical Grade Genomic Databases. AB - CONTEXT: Next-generation sequencing performed in a clinical environment must meet clinical standards, which requires reproducibility of all aspects of the testing. Clinical-grade genomic databases (CGGDs) are required to classify a variant and to assist in the professional interpretation of clinical next-generation sequencing. Applying quality laboratory standards to the reference databases used for sequence-variant interpretation presents a new challenge for validation and curation. OBJECTIVES: To define CGGD and the categories of information contained in CGGDs and to frame recommendations for the structure and use of these databases in clinical patient care. DESIGN: Members of the College of American Pathologists Personalized Health Care Committee reviewed the literature and existing state of genomic databases and developed a framework for guiding CGGD development in the future. RESULTS: Clinical-grade genomic databases may provide different types of information. This work group defined 3 layers of information in CGGDs: clinical genomic variant repositories, genomic medical data repositories, and genomic medicine evidence databases. The layers are differentiated by the types of genomic and medical information contained and the utility in assisting with clinical interpretation of genomic variants. Clinical grade genomic databases must meet specific standards regarding submission, curation, and retrieval of data, as well as the maintenance of privacy and security. CONCLUSION: These organizing principles for CGGDs should serve as a foundation for future development of specific standards that support the use of such databases for patient care. PMID- 26516939 TI - The Pathologist Workforce in the United States: II. An Interactive Modeling Tool for Analyzing Future Qualitative and Quantitative Staffing Demands for Services. AB - CONTEXT: Pathologists are physicians who make diagnoses based on interpretation of tissue and cellular specimens (surgical/cytopathology, molecular/genomic pathology, autopsy), provide medical leadership and consultation for laboratory medicine, and are integral members of their institutions' interdisciplinary patient care teams. OBJECTIVE: To develop a dynamic modeling tool to examine how individual factors and practice variables can forecast demand for pathologist services. DESIGN: Build and test a computer-based software model populated with data from surveys and best estimates about current and new pathologist efforts. RESULTS: Most pathologists' efforts focus on anatomic (52%), laboratory (14%), and other direct services (8%) for individual patients. Population-focused services (12%) (eg, laboratory medical direction) and other professional responsibilities (14%) (eg, teaching, research, and hospital committees) consume the rest of their time. Modeling scenarios were used to assess the need to increase or decrease efforts related globally to the Affordable Care Act, and specifically, to genomic medicine, laboratory consolidation, laboratory medical direction, and new areas where pathologists' expertise can add value. CONCLUSIONS: Our modeling tool allows pathologists, educators, and policy experts to assess how various factors may affect demand for pathologists' services. These factors include an aging population, advances in biomedical technology, and changing roles in capitated, value-based, and team-based medical care systems. In the future, pathologists will likely have to assume new roles, develop new expertise, and become more efficient in practicing medicine to accommodate new value-based delivery models. PMID- 26516940 TI - The Role of High-Risk Human Papilloma Virus Testing in the Surveillance of Cervical Cancer After Treatment. AB - CONTEXT: Cervical cancer affects 12 000 women in the United States annually. However, despite its prevalence, there remains no good methodology to detect its recurrence. OBJECTIVE: To identify the role of cervicovaginal high-risk human papilloma virus (hr-HPV) testing in predicting cervical cancer recurrence. DESIGN: This is a retrospective study of patients who underwent hr-HPV testing as part of their routine surveillance for cervical cancer. Standard statistical analyses, including chi2 test and multivariable logistic regression, were performed with IBM SPSS 19.0. RESULTS: A total of 133 patients were identified, of whom 107 (80%) had squamous cell carcinoma. Ninety patients (68%) had bulky disease and were treated primarily with chemoradiation and brachytherapy. Of patients whose disease recurred, 5 patients (42%) had tested positive for hr-HPV during their surveillance period, compared to 13 patients (11%) for whom disease did not recur (relative risk: 3.88, P = .002). On multivariate logistic regression, hr-HPV status remained significantly predictive of disease recurrence (odds ratio: 12.3, P = .02, 95% confidence interval: 1.5-99.6). Using 2 * 2 table analysis, we found that while cervicovaginal cytology has limited specificity (5.7%) in predicting recurrence, the combination of cytology with hr-HPV testing increases the specificity of testing to 89.3%. CONCLUSIONS: Persistence of hr-HPV is a risk factor for disease recurrence. High-risk-HPV testing is not routinely used during surveillance for cervical cancer, but this study suggests that large, prospective trials investigating the role of hr-HPV testing in cervical cancer surveillance are needed. PMID- 26516941 TI - Sensitivity and Specificity of Community Fecal Immunotesting Screening for Colorectal Carcinoma in a High-Risk Canadian Population. AB - CONTEXT: Community-based programs are a common way of promoting colorectal cancer screening by primary care physicians. Fecal immunochemical testing (FIT) is a screening method commonly used in such programs. Fecal immunochemical testing has advantages to the patient as well as to clinical laboratories. OBJECTIVE: To assess the operational test characteristics of a FIT pilot program in Calgary, Alberta, Canada, between April 2011 and May 2012. DESIGN: Four hundred fifty seven high-risk patients undergoing both FIT and colonoscopy were included. Areas under the curve and positive predictive values were derived for FIT values and biopsy-proven neoplasia. Subgroup analysis was also performed on men and women and for ages older and younger than the mean age of 62 years. RESULTS: For colorectal carcinoma and colonic adenomas the areas under the curve were 0.79 (95% confidence interval 0.71-0.87) and 0.60 (95% confidence interval 0.54-0.65), respectively. The positive predictive value of a positive FIT result for any neoplasia was 53%. The overall performance of the test for all neoplasia was better for men and better for older individuals. CONCLUSIONS: The performance of FIT in this clinical setting was very good for detecting carcinoma, but marginal for detection of colonic adenomas. PMID- 26516942 TI - Examination of Surgical Specimens of the Esophagus. AB - CONTEXT: Esophageal cancer continues to be one of the most lethal of all gastrointestinal malignancies. Its prognostic parameters are based on the gross and histopathologic examination of resected specimens by pathologists. OBJECTIVE: To describe the implications of appropriate handling and examination of endomucosal resection and esophagectomy specimens from patients with esophageal carcinoma while considering the implications of the surgical techniques used to obtain such specimens. Parameters include histopathologic findings necessary for accurate staging, differences in the assessment of margins, residual malignancy, and criteria to evaluate for tumor regression after chemoradiation therapy as well as the role of immunohistochemistry and the judicious use of frozen sections. DATA SOURCES: Sources were a review of the literature and the authors' experience handling these types of specimens. CONCLUSIONS: Examining surgical specimens of the esophagus is critical in the management of patients with esophageal carcinoma, and it requires careful consideration of the diagnostic pitfalls, staging-related parameters, and results of molecular tests. PMID- 26516943 TI - Autoimmune Hemolytic Anemia and Red Blood Cell Autoantibodies. AB - Autoimmune hemolytic anemia is a rare disorder caused by autoreactive red blood cell (RBC) antibodies that destroy RBCs. Although autoimmune hemolytic anemia is rare, RBC autoantibodies are encountered frequently and can complicate transfusion workups, impede RBC alloantibody identification, delay distribution of compatible units, have variable clinical significance that ranges from benign to life-threatening, and may signal an underlying disease or disorder. In this review, we discuss the common presenting features of RBC autoantibodies, laboratory findings, ancillary studies that help the pathologist investigate the clinical significance of autoantibodies, and how to provide appropriate patient care and consultation for clinical colleagues. Pathologists must be mindful of, and knowledgeable about, this entity because it not only allows for direct clinical management but also can afford an opportunity to preemptively treat an otherwise silent malignancy or disorder. PMID- 26516944 TI - Alveolar Soft Part Sarcoma. AB - Alveolar soft part sarcoma is a rare neoplasm usually arising in the soft tissues of the lower limbs in adults and in the head and neck region in children. It presents primarily as a slowly growing mass or as metastatic disease. It is characterized by a specific chromosomal alteration, der(17)t(X:17)(p11:q25), resulting in fusion of the transcription factor E3 (TFE3) with alveolar soft part sarcoma critical region 1 (ASPSCR1) at 17q25. This translocation is diagnostically useful because the tumor nuclei are positive for TFE3 by immunohistochemistry. Real-time polymerase chain reaction to detect the ASPSCR1 TFE3 fusion transcript on paraffin-embedded tissue blocks has been shown to be more sensitive and specific than detection of TFE3 by immunohistochemical stain. Cathepsin K is a relatively recent immunohistochemical stain that can aid in the diagnosis. The recent discovery of the role of the ASPSCR1-TFE3 fusion protein in the MET proto-oncogene signaling pathway promoting angiogenesis and cell proliferation offers a promising targeted molecular therapy. PMID- 26516945 TI - The biological effects of vanadyl curcumin and vanadyl diacetylcurcumin complexes: the effect on structure, function and oxidative stability of the peroxidase enzyme, antibacterial activity and cytotoxic effect. AB - Curcumin has multiple pharmacological effects, but it has poor stability. Complexation of curcumin with metals improves its stability. Here, the effects of vanadyl curcumin and vanadyl diacetylcurcumin on the function and structure of horseradish peroxidase enzyme were evaluated by spectroscopic techniques. Cytotoxic effect of the complexes was also assessed on MCF-7 breast cancer, bladder and LNCaP prostate carcinoma cell line. The results showed that the complexes improve catalytic activity of HRP, and also increase its tolerance against the oxidative condition. The result also indicated that the affinity of HRP for hydrogen peroxide substrate decreases, while the affinity increases for phenol substrate. Circular dichroism and fluorescence spectroscopies showed that compactness of the enzyme structure around the catalytic heme group and the distance between the heme group and tryptophan residue decreases after the binding. The antibacterial and cytotoxic results indicated that the complexes have anticancer potential, but they have no considerable antibacterial activity. PMID- 26516946 TI - Biological Variations of Lupus Anticoagulant, Antithrombin, Protein C, Protein S, and von Willebrand Factor Assays. AB - The results of lupus anticoagulant (LA), antithrombin (AT), protein C (PC), and protein S (PS) testing, and the values of von Willebrand factor antigen (VWF:Ag) are important in diagnosis and therapeutic monitoring of thrombosis and hemostasis diseases. Till now, no published study has focused on the biological variations in LA testing, and only a few studies have examined the biological variations of AT, PC, PS, and VWF:Ag. With the latest fully automated instruments and improved reagents, the analytical, within-subject, and between-subject biological variations were estimated for these five coagulant parameters in a cohort of 25 apparently healthy subjects. Blood specimens were collected at 8:00 am, 12:00 pm, and 4:00 pm on days 1, 3, and 5. The analytical biological variation (CV(A)) values of all the parameters were less than 3%. The within subject biological variation (CV(W)) and between-subject biological variation (CV(G)) values of the LA normalized ratio were 4.64 and 6.83%, respectively. No significant differences were observed in the intraday and interday biological variations of LA tests, or in AT, PC, PS, and VWF:Ag values. Additionally, the utility of the conventional population-based reference intervals of the five coagulation parameters was evaluated by the index of individuality, and data on CV(W) and CV(A) were used to calculate the reference change value to identify the significance of changes in serial results from the same individual. PMID- 26516947 TI - Preface. PMID- 26516948 TI - C-Reactive Protein in Orthopaedic Surgery. AB - C-reactive protein (CRP) is a common laboratory infection marker in blood-serum of patients. In all diverse medical departments CRP is often used, and also in orthopaedics CRP is proved to be very helpful in diagnosis and monitor of infections. CRP in most fields is superior to conventional and newer infection parameter and is a basic parameter for inflammation. Especially for detection of an early postoperative infection CRP can be very helpful as an objective parameter easy to obtain. In uneventful operative treatment a similar evolution in CRP concentrations was found: the peak level occurred on the second or third postoperative day and reflected the extent of surgical trauma. A second rise of CRP in the postoperative course indicates a complication. Highest levels are reached in bacterial infection after the forth postoperative day with a cut-off level about 10 mg/dl. CRP can also be used as a preoperative marker for risk stratification and newer times CRP is reported as an independent fracture-risk factor. In general CRP is the basic inflammatory parameter in orthopaedic surgery and is more significant and common than WBC or ESR. But CRP is only a laboratory parameter and must always be correlated with clinical signs of infection. PMID- 26516949 TI - Is Whole-Body Computed Tomography the Standard Work-up for Severely-Injured Children? Results of a Survey among German Trauma Centers. AB - PURPOSE OF THE STUDY: Whole-body computed tomography is accepted as the standard procedure in the primary diagnostic of polytraumatised adults in the emergency room. Up to now there is still controversial discussion about the same algorithm in the primary diagnostic of children. The aim of this study was to survey the participation of German trauma-centres in the care of polytraumatised children and the hospital dependant use of whole-body computed tomography for initial patient work-up. MATERIAL AND METHODS: A questionnaire was mailed to every Department of Traumatology registered in the DGU (German Trauma Society) databank. RESULTS: We received 60,32% of the initially sent questionnaires and after applying exclusion criteria 269 (53,91%) were applicable to statistical analysis. In the three-tiered German hospital system no statistical difference was seen in the general participation of children polytrauma care between hospitals of different tiers (p = 0.315). Even at the lowest hospital level 69,47% of hospitals stated to participate in polytrauma care for children, at the intermediate and highest level hospitals 91,89% and 95,24% stated to be involved in children polytrauma care, respectively. Children suspicious of multiple injuries or polytrauma received significantly fewer primary whole-body CTs in lowest level compared to intermediate level hospitals (36,07% vs. 56,57%; p = 0.015) and lowest level compared to highest level hospitals (36,07% vs. 68,42%; p = 0.001). Comparing the use of whole-body CT in intermediate to highest level hospitals a not significant increase in its use could be seen in highest level hospitals (56,57% vs. 68,42%; p = 0.174). CONCLUSION: According to our survey, taking care of polytraumatised children in Germany is not limited to specialised hospitals or a defined hospital level-of-care. Additionally, there is no established radiologic standard in work-up of the polytraumatised child. However, in higher hospital care -levels a higher percentage of hospitals employs whole body CTs for primary radiologic diagnostics in polytraumatised children. PMID- 26516950 TI - Minimal Invasive Dorsal Plate Osteosynthesis of the Tibia--Are Nerves and Vessels at Risk? An Anatomical Study. AB - PURPOSE OF THE STUDY: Purpose of this anatomic study was to develop a new and safe technique of minimal invasive dorsal plate osteosynthesis for tibia shaft fractures. MATERIAL AND METHODS: Sixteen paired adult lower limbs of eight different cadaveric specimens were examined. Anatomical prebending for each plate was done. Plates were inserted percutaneously, following plate fixation the neurovascular bundle was dissected out. The distance between the neurovascular bundle (posterior tibial nerve, posterior tibial artery) and the plate was measured at two different positions. The distance to the origin of the flexor digitorum longus muscle and the arch of the soleus muscle was measured. RESULTS: The mean distance between the neurovascular bundle and the plate amounted 1.4 cm (+/-0,2 cm; 1.0-1.7 cm) at hole number six and 1.1 cm (+/-0.4 cm; 0.6-2.0 cm) at hole number ten. The nerve was never directly in contact with the plate. The flexor digitorum longus muscle had its origin along the plate and was between the plate and the neurovascular bundle in all cases. CONCLUSIONS: Dorsal percutaneous plate insertion is a safe and easy method for osteosyntesis of tiba shaft fractures. Especially in case of poor skin and soft tissue conditions this technique offers a good alternative. PMID- 26516951 TI - [Impaired Healing after Surgery for Femoral Fractures]. AB - PURPOSE OF THE STUDY: The aim of the study was to analyse causes of impaired bone healing in femoral fractures and to present options of their management. MATERIAL AND METHODS: This is a retrospective study of the data on complications prospectively collected between 2008 and 2013. The patients admitted for primary treatment at the Trauma Centre of the Faculty of Medicine in Hradec Kralove from January 2008 to December 2013 included 1186 patients with injury severity scores (ISS) > 15 and 1340 patients with new injury severity scores (NISS) >15, all older than 16 years. With the exception of two patients, the primary treatment involved the application of an external fixator as part of damage control surgery. Definitive surgery, regardless of the site of fracture, was performed using unreamed femoral nails (UFN) in 51, distal femoral nails (DFN) in 33, plates in 26, long proximal femoral nail antirotation (PFNA-long) in 14 and nails combined with dynamic hip screw (DHS) plates in five fractures. The analysis revealed both mechanical and biological causes of poor bone healing. RESULTS: Of the 124 patients whose multiple injuries included a fracture of the femur, 11 died within 24 hours in spite of intensive resuscitation. In the remaining 113 patients there were 16 bilateral fractures, 20 fractures of the proximal femur (extraarticular), 72 diaphyseal femur fractures and 26 distal femur fractures. Nine patients sustained segmental femoral shaft fractures. Ten diaphyseal and 14 distal femur injuries were open fractures (13.5% and 54%, respectively). Pseudarthrosis developed in a total of 12 fractures (9.3%); six (7.2%) were diaphyseal fractures, of which three were initially open fractures, and six (21.4%) were distal femur fractures with two initially open injuries. All proximal femur fractures healed completely. DISCUSSION: The frequency of non union femoral diaphyseal fractures in our patients treated by unreamed intra medullary nailing is in agreement with the literature data. The frequency of non union distal femur fractures in our group was slightly higher than is published in the literature. This can be accounted for by the characteristics of our group consisting of patients with multiple severe injuries in whom fractures are due to high-energy trauma; the overall severity of injuries negatively affects the biological potential of a human organism for bone healing. CONCLUSIONS: A successful outcome of femoral fracture repair is based on an understanding of the biomechanical principle, i.e., correct fracture reduction and stable osteosynthesis fitting the morphology of the fracture. Comminuted femoral fractures heal well with the use of a narrow long nail whose working length allows for even distribution of movement at a fracture line amongst the fragments and thus fracture motion load does not exceed 20%. On the other hand, short oblique and transverse fractures are examples of problematic fractures which require maximum possible stability provided by a thick nail with a short working length; this is achieved by reaming the medullary cavity or adding lag screws. In our group of patients these fractures were also the most problematic ones. Generally, nailing remains the golden standard in the management of femoral fractures. PMID- 26516952 TI - [Determination of a Friction Coefficient for THA Bearing Couples]. AB - PURPOSE OF THE STUDY: The wear of articular surfaces is considered one of the most important factors limiting the life of total hip arthroplasty (THA). It is assumed that the particles released from the surface of a softer material induce a complex inflammatory response, which will eventually result in osteolysis and aseptic loosening. Implant wear is related to a friction coefficient which depends on combination of the materials used, roughness of the articulating surfaces, internal clearance, and dimensions of the prosthesis. MATERIAL AND METHODS: The selected parameters of the bearing couples tested were studied using an experimental device based on the principle of a pendulum. Bovine serum was used as a lubricant and the load corresponded to a human body mass of 75 kg. The friction coefficient was derived from a curve of slowdown of pendulum oscillations. Roughness was measured with a device working on the principle of interferometry. Clearance was assessed by measuring diameters of the acetabular and femoral heads with a 3D optical scanner. The specimens tested included unused metal-on-highly cross-linked polyethylene, ceramic-on-highly cross-linked polyethylene and ceramic-on-ceramic bearing couples with the diameters of 28 mm and 36 mm. For each measured parameter, an arithmetic mean was calculated from 10 measurements. RESULTS: 1) The roughness of polyethylene surfaces was higher by about one order of magnitude than the roughness of metal and ceramic components. The Protasul metal head had the least rough surface (0.003 MUm). 2) The ceramic on-ceramic couples had the lowest clearance. Bearing couples with polyethylene acetabular liners had markedly higher clearances ranging from 150 MUm to 545 MUm. A clearance increased with large femoral heads (up to 4-fold in one of the couple tested). 3) The friction coefficient was related to the combination of materials; it was lowest in ceramic-on-ceramic surfaces (0.11 to 0.12) and then in ceramic on-polyethylene implants (0.13 to 0.14). The friction coefficient is supposed to increase with a decreasing femoral head diameter. However, in the bearing couples with polyethylene liners manufactured by one company, paradoxically, the friction coefficient slightly increased with an increase in femoral head size from 28 mm to 36 mm. 4) The lowest friction moment (< 3.5 Nm) was found for ceramic-on ceramic implants 28 mm in diameter; the highest values were recorded in metal-on polyethylene bearing couples 36 mm in diameter (> 7 Nm). DISCUSSION: Although our study confirmed that the bearing couples produced by different manufacturers varied to some extent in the parameters studied, in our opinion, this variability was not significant because it was not within an order of magnitude in any of the tests. CONCLUSIONS: The study showed that both the friction coefficient and the friction moment are affected more by the combination of materials than by the diameter of a femoral head. The best results were achieved in ceramic-on-ceramic implants. PMID- 26516953 TI - [Vertical Talus: Mid-Term Results of Surgical Therapy]. AB - PURPOSE OF THE STUDY: The aim of the study was to clinically and radiographically evaluate the results of a two-stage surgical technique used in our department to treat congenital vertical talus. MATERIAL AND METHODS: In the years 1990-2010 we treated eight patients (nine feet). We used a two-stage surgical technique, with lengthening of the dorsiflexor muscles of the leg and the tibialis anterior muscle at the first stage. This was followed by cast fixation with the ankle in plantar flexion for 6 weeks. At the second stage, through a Cincinnati approach, the talonavicular and calcaneocuboid joints were reduced and the Achilles tendon and peroneal tendons were elongated. Two patients underwent the Grice extra articular subtalar arthrodesis at the third stage. The post-operative outcomes were assessed based on radiographic findings of dorsoplantar views of the talocalcaneal angle (TC AP) and talar axis-first metatarsal base angle (TAMBA AP), lateral views of the weight-bearing talocalcaneal angle (TC LAT), talar axis first metatarsal base angle (TAMBA LAT) and talotibial angle (TT). In all patients but one who was lost to follow-up, the radiographic and objective findings were evaluated with the 10-point scale described by Adelaar et al. RESULTS: The average follow-up was 8 years and 9 months. All radiographic findings showed improvement in all angles measured. The pre-operative values decreased in TC AP from 64.2 degrees to 27.6 degrees ; in TC LAT from 48.8 degrees to 30.4 degrees ; in TT from 158 degrees to 109.3 degrees ; in TAMBA AP from 54.7 degrees to 17.4 degrees ; in TAMBA LAT from 57.3 degrees to 5.7 degrees . The Adelaar scoring system was employed in seven patients of whom three had excellent, three good and one fair results. Two patients required additional surgery due to recurrence of the deformity DISCUSSION: Studies in recent years have shown a gradual diversion from extensive surgical procedures and a trend toward techniques like manipulation, serial casting application and minimal surgical intervention with talonavicular reduction and fixation. The Dobbs technique has so far shown good results but no long-term results have yet been available and therefore the number of recurrent cases is not known. CONCLUSIONS: The two-stage surgical technique used in our department proved to be very successful in a long-term follow-up, but the group of patients was too small to provide conclusive evidence. However, benefits of this technique are clearly apparent from the post-operative radiographic and objective findings assessed as very good. PMID- 26516954 TI - [Long-Term Outcomes of Surgical Management of Symptomatic Fibular Discoid Meniscus in Childhood]. AB - PURPOSE OF THE STUDY: The aim of the study was to evaluate the outcomes of treatment in patients operated on in childhood for discoid meniscus, and to compare the results with those published in the relevant international literature. MATERIAL AND METHODS: The group evaluated consisted of 15 patients, 10 girls and five boys, who underwent surgery for symptomatic discoid meniscus in the period from 2000 to 2010. The average age at the time of surgery was 9 years and 2 months. The diagnosis was based on the patient's history of complaints, physical examination, X-rays of the knee joint taken in two planes, and ultrasonographic and magnetic resonance imaging of the knee. Arthroscopic verification of the diagnosis was done in all patients. They all had fibular discoid meniscus classified as type 1 in six and type 2 in nine patients according to the Watanabe classification system. Type 3 (Wrisberg variant) discoid meniscus was not recorded in this group. In six (40%) patients, the discoid meniscus had a tear in it. The patients were followed up on average for 8 years and 4 months. In addition to subjective evaluation by patients, the treatment outcome was assessed using the Ikeuchi and Lysholm scoring systems. RESULTS: Arthroscopic partial meniscectomy was performed in 10 patients. In five patients conversion to open surgery was necessary and partial or subtotal fibular meniscectomy was carried out by minimally invasive arthrotomy from the lateral approach. Total meniscectomy was not required in any of our patients. The average value for treatment evaluation by the patients was 2.25 on a 1-to-5 scale. The average Lysholm pre-operative score of 80.8 points increased to 95.4 points after surgery. The long-term results assessed by the Ikeuchi system were excellent in nine, good in four and satisfactory in two patients. None of the patients showed poor results and no intraoperative or post-operative complications were recorded. DISCUSSION: Discoid meniscus is a painful condition affecting the knee, particularly when a tear is also present. Meniscal lesions are found intra operatively in many symptomatic patients. The majority of international authors prefer arthroscopic management of discoid meniscus. The team of our department also support this procedure unanimously. Arthroscopy is used as the primary method with the aim of preserving the largest possible margin of the meniscus. Some literature data suggest that there are no statistically significant differences between an open and an arthroscopic procedure. Accordingly, in our patients no differences in the evaluation of treatment results were recorded. However, the advantages of minimally invasive arthroscopy for the management for discoid meniscus are beyond any doubt. CONCLUSIONS: The long-term results of discoid meniscus management reported in the international literature are very good. The results of long-term follow-up in our group give support to active surgical treatment. We take care to avoid total meniscectomy which often results in early development of secondary gonarthrosis. PMID- 26516955 TI - [Dynamic Hip Screw Osteosynthesis for Proximal Femoral Fractures in Patients with Coxarthrosis]. AB - PURPOSE OF THE STUDY: Evaluation of a group of patients with coxarthrosis who sustained fractures of the proximal femur and were treated by dynamic hip screw (DHS) osteosynthesis. MATERIAL AND METHODS: The group comprised 23 DHS osteosyntheses in 22 patients treated between the years 1997 and 2012. The indication to osteosynthesis in all 23 cases was a stable pertrochanteric fracture of the femur; all patients had grade III or grade IV coxarthrosis (assessed on the Kellgren & Lawrence scale) and their physical health was classified as ASA 3 or 4. Preventive antibiotic therapy was administered within 48 hours of surgery. The evaluated factors included operative time, blood loss, specific complications such as infection, osteosynthetic material fractiure or osteosynthesis failure, requirement of revision surgery, post-operative mobility and patient survival. The follow-up was 2 years. RESULTS: The operative time was 35 min to 85 min (average, 49 min); blood losses ranged from 50 ml to 450 ml (average, 189 ml). Of the 23 hips, infectious complication was found in one (4.3%) and osteosynthetic material fractiure also in one (4.3%). There was no necessity of revision surgery due to osteosynthesis failure, nor any conversion to total hip arthroplasty. Postoperative mobility (with use of walking aids or forearm crutches) was achieved in 17 (77.3%) patients. The average survival of the patients was 6.3 months, the range from 7 days to 3 years. DISCUSSION: DHS osteosynthesis is a reliable method for the treatment of proximal femoral fractures due to osteoporosis. These fractures in patients with coxarthosis are primarily indicated to total hip arthroplasty. However, this is questionable in polymorbid elderly patients in whom hip replacement carries high risk. In such patients DHS osteosynthesis is preferred as a less risky procedure. CONCLUSIONS: DHS osteosynthesis is indicated for stable pertrochanteric fractures of the femur in a limited number of patients with advanced coxarthrosis in whom total hip replacement would be associated with an undue risk. The majority of patients after surgery became mobile, but with short-term survival. PMID- 26516956 TI - [Plate Osteosynthesis of Distal Ulna Fractures with Associated Distal Radius Fractures Treated by Open Reduction and Internal Fixation. Short-Term Functional and Radiographic Results]. AB - PURPOSE OF THE STUDY: The aim of the study was to describe the indication criteria and operative technique and to present the first conclusions of a prospective study dealing with an assessment of functional and radiographic findings in patients with concurrent fractures of the distal ulna and distal radius; the former was treated by osteosynthesis using an LCP Distal Ulna Plate (De Puy Synthes, USA) and the latter by plate osteosynthesis. MATERIAL AND METHODS: Between August 2013 and September 2014, 18 patients (3 men and 15 women; average age, 58 years; range, 25-74 years) with a fracture of the distal ulna and a concurrent distal radius fracture were treated by plate osteosynthesis. The indications for surgery included displaced ulnar styloid base fractures in 10 patients, displaced comminuted fractures of the ulnar head in seven patients and a subcapital fracture of the ulna in one patient. The average follow-up was 9 months, with 13 (72%) patients being followed up for 6 months at least. The outcome of surgery was evaluated on the basis of X-ray views and multiplanar reconstruction of CT scans. Functional results were based on measuring the range of motion at wrist and forearm and hand grip strength and on the scores obtained from the Mayo Wrist Score System and Quick DASH Questionnaire. RESULTS: The average values for wrist and forearm range of motion were as follows: 68 degrees in flexion (60-80 degrees ), 71 degrees in extension (40- 90 degrees ), 87 degrees in pronation (70-90 degrees ), 81 degrees in supination (50-90 degrees ). This corresponded to a 92% (74-100%) range of motion at the contralateral wrist and forearm. The average hand grip strength measured with a dynamometer was 80.6% (53-100%) of the gripping force exerted by the unaffected extremity. Post operative X-ray and CT findings showed good reduction of both distal radius and distal ulna fractures as well as good fragment retention by means of LCP implants. During follow-up complete bone union and full stability of the radioulnar joint were achieved in all patients. The functional outcome of treatment was shown by the average Mayo wrist score and Quick DASH score of 84 (55-100) and 7.4 (0-47.7) points, respectively. DISCUSSION: The functional outcome of treatment in our patients corresponded to the severity of their distal forearm fractures. The patients with more serious distal radius fractures, frequently associated with ulnar head fractures, had poorer functional results than the patients with less serious fractures. According to the AO classification, in the distal radius fractures, prevailing fracture types were 23 C3 (78%) and 23-C2 (16%). In relation to the distal ulna fracture type, the patients with ulnar styloid base fractures had better functional results than the patients with ulnar head fractures, because a fracture of the styloid process does not affect the congruency of the distal radioulnar joint (DRUJ). Fractures of the ulnar styloid process base, following distal radius fracture osteosynthesis, were invariably associated with DRUJ instability. This fracture type is always accompanied by injury to the distal radioulnar ligament of the triangular fibrocartilage complex (TFCC) and, in case of a displaced fracture, surgical management is indicated. In agreement with the results of other authors it was found in our study that, when the anatomical position of the distal radioulnar joint had been achieved, both the functional and the radiographic findings were post-operatively very good. The final average values for the range of wrist and forearm motion, hand grip strength and hand and arm function were assessed as very good. CONCLUSIONS The assessment of our results and their comparison with the literature data showed that osteosynthesis of distal ulna fractures with concurrent distal radius fractures managed by open reduction and internal fixation are indicated in displaced fractures of the ulnar styloid process base, displaced comminuted fractures of the ulnar head where fragments interfere with DRUJ congruency, and unstable displaced subcapital fractures of the ulna. The early results of this study provide evidence for the efficiency of plate osteosynthesis in the treatment of distal ulna fractures. PMID- 26516957 TI - Short-course isoniazid plus rifapentine therapy for latent tuberculosis in Brazil. PMID- 26516958 TI - Rifapentine for latent tuberculosis infection treatment in the general population and human immunodeficiency virus-positive patients: summary of evidence. AB - Latent tuberculosis infection (LTBI) and human immunodeficiency virus (HIV) coinfection are challenges in the control of tuberculosis transmission. We aimed to assess and summarize evidence available in the literature regarding the treatment of LTBI in both the general and HIV-positive population, in order to support decision making by the Brazilian Tuberculosis Control Program for LTBI chemoprophylaxis. We searched MEDLINE, Cochrane Library, Centre for Reviews and Dissemination, Embase, LILACS, SciELO, Trip database, National Guideline Clearinghouse, and the Brazilian Theses Repository to identify systematic reviews, randomized clinical trials, clinical guidelines, evidence-based synopses, reports of health technology assessment agencies, and theses that investigated rifapentine and isoniazid combination compared to isoniazid monotherapy. We assessed the quality of evidence from randomized clinical trials using the Jadad Scale and recommendations from other evidence sources using the Grading of Recommendations, Assessment, Development, and Evaluations approach. The available evidence suggests that there are no differences between rifapentine + isoniazid short-course treatment and the standard 6-month isoniazid therapy in reducing active tuberculosis incidence or death. Adherence was better with directly observed rifapentine therapy compared to self-administered isoniazid. The quality of evidence obtained was moderate, and on the basis of this evidence, rifapentine is recommended by one guideline. Available evidence assessment considering the perspective of higher adherence rates, lower costs, and local peculiarity context might support rifapentine use for LTBI in the general or HIV positive populations. Since novel trials are ongoing, further studies should include patients on antiretroviral therapy. PMID- 26516959 TI - Comparative study of lymphocytes from individuals that were vaccinated and unvaccinated against the pandemic 2009-2011 H1N1 influenza virus in Southern Brazil. AB - INTRODUCTION: While no single factor is sufficient to guarantee the success of influenza vaccine programs, knowledge of the levels of immunity in local populations is critical. Here, we analyzed influenza immunity in a population from Southern Brazil, a region with weather conditions that are distinct from those in the rest of country, where influenza infections are endemic, and where greater than 50% of the population is vaccinated annually. METHODS: Peripheral blood mononuclear cells were isolated from 40 individuals. Of these, 20 had received the H1N1 vaccine, while the remaining 20 were unvaccinated against the disease. Cells were stimulated in vitro with the trivalent post-pandemic influenza vaccine or with conserved major histocompatibility complex I (MHC I) peptides derived from hemagglutinin and neuraminidase. Cell viability was then analyzed by [3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide)] based colorimetric assay (MTT), and culture supernatants were assayed for helper T type 1 (Th1) and Th2-specific cytokine levels. RESULTS: Peripheral blood lymphocytes from vaccinated, but not unvaccinated, individuals exhibited significant proliferation in vitro in the presence of a cognate influenza antigen. After culturing with vaccine antigens, cells from vaccinated individuals produced similar levels of interleukin (IL)-10 and interferon (IFN)-gamma, while those from unvaccinated individuals produced higher levels of IFN-gamma than of IL-10. CONCLUSIONS: Our data indicate that peripheral blood lymphocytes from vaccinated individuals are stimulated upon encountering a cognate antigen, but did not support the hypothesis that cross-reactive responses related to previous infections can ameliorate the immune response. Moreover, monitoring IL-10 production in vaccinated individuals could comprise a valuable tool for predicting disease evolution. PMID- 26516960 TI - Clinical and epidemiological profile of female blood donors with positive serology for viral hepatitis B. AB - INTRODUCTION: Since women are frequently the minority among blood donors worldwide, studies evaluating this population usually reflect male features. We assessed the features of female blood donors with positive serology for HBV and compared them with those of men.METHODS The study comprised consecutive blood donors referred to a specialized liver disease center to be evaluated due to HBsAg- and/or anti-HBc-positive tests. RESULTS: The study encompassed 1,273 individuals, 219 (17.2%) of whom were referred due to positive HBsAg test and 1,054 (82.8%) due to reactive anti-HBc test. Subjects' mean age was 36.8+/-10.9 years, and 28.7% were women. Female blood donors referred for positive HBsAg screening tests demonstrated higher prevalence of healthcare workers (9.3% vs 2.5%) and lower prevalence of sexual risk behaviors (15.1% vs 41.1%) and alcohol abuse (1.9% vs 19.8%) compared to men. Women had lower ALT (0.6 vs 0.8*ULN), AST (0.6 vs 0.8*ULN), direct bilirubin (0.2 vs 0.3mg/dL), and alkaline phosphatase (0.5 vs 0.6*ULN) levels and higher platelet count (223,380+/-50,293 vs 195,020+/ 53,060/mm3). Women also had a higher prevalence of false-positive results (29.6% vs 17.0%). No differences were observed with respect to liver biopsies. Female blood donors referenced for reactive anti-HBc screening tests presented similar clinical, epidemiological, and biochemical characteristics to those reported for positive HBsAg screening tests and similarly had a higher prevalence of false reactive results. CONCLUSIONS: Compared to men, female blood donors with positive HBsAg and/or anti-HBc screening tests demonstrated higher prevalence of professional risk and false-positive results and reduced alteration of liver chemistry. PMID- 26516961 TI - Triatominae (Hemiptera, Reduviidae) in the Pantanal region: association with Trypanosoma cruzi, different habitats and vertebrate hosts. AB - INTRODUCTION: The transmission cycle of Trypanosoma cruzi in the Brazilian Pantanal region has been studied during the last decade. Although considerable knowledge is available regarding the mammalian hosts infected by T. cruzi in this wetland, no studies have investigated its vectors in this region. This study aimed to investigate the presence of sylvatic triatomine species in different habitats of the Brazilian Pantanal region and to correlate their presence with the occurrences of vertebrate hosts and T. cruzi infection. METHODS: The fieldwork involved passive search by using light traps and Noireau traps and active search by visual inspection. The light traps were placed at five selected points along forested areas for seven nights during each of the nine excursions. At each point where a light trap was set, eight Noireau traps were placed in palm trees and bromeliads. RESULTS: In all, 88 triatomine bugs were collected: two and one individuals from light traps and Noireau traps, respectively; three from peridomestic areas; 23 in coati nests; and 59 in thornbird nests. In this study, active search in microhabitats showed higher efficiency than passive search, since 95% of the triatomine bugs were caught in nests. Further, triatomine bugs were only found to be infected by T. cruzi in coati nests. CONCLUSIONS: Coati nests might act as a point of convergence and dispersion for triatomine bugs and mammal hosts infected by T. cruzi, thereby playing an important role in the sylvatic cycle of T. cruziin the Pantanal region. PMID- 26516962 TI - Pharmacokinetic/pharmacodynamic target attainment of intravenous beta-lactam regimens against Gram-negative bacteria isolated in a Brazilian teaching hospital. AB - INTRODUCTION: Monte Carlo simulations have been used for selecting optimal antibiotic regimens for treatment of bacterial infections. The aim of this study was to assess the pharmacokinetic and pharmacodynamic target attainment of intravenous beta-lactam regimens commonly used to treat bloodstream infections (BSIs) caused by Gram-negative rod-shaped organisms in a Brazilian teaching hospital. METHODS: In total, 5,000 patients were included in the Monte Carlo simulations of distinct antimicrobial regimens to estimate the likelihood of achieving free drug concentrations above the minimum inhibitory concentration (MIC; fT > MIC) for the requisite periods to clear distinct target organisms. Microbiological data were obtained from blood culture isolates harvested in our hospital from 2008 to 2010. RESULTS: In total, 614 bacterial isolates, including Escherichia coli, Enterobacterspp., Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, were analyzed Piperacillin/tazobactam failed to achieve a cumulative fraction of response (CFR) > 90% for any of the isolates. While standard dosing (short infusion) of beta-lactams achieved target attainment for BSIs caused by E. coliand Enterobacterspp., pharmacodynamic target attainment against K. pneumoniaeisolates was only achieved with ceftazidime and meropenem (prolonged infusion). Lastly, only prolonged infusion of high-dose meropenem approached an ideal CFR against P. aeruginosa; however, no antimicrobial regimen achieved an ideal CFR against A. baumannii. CONCLUSIONS: These data reinforce the use of prolonged infusions of high-dose beta-lactam antimicrobials as a reasonable strategy for the treatment of BSIs caused by multidrug resistant Gram-negative bacteria in Brazil. PMID- 26516963 TI - Aerobic bacterial profile and antibiotic resistance in patients with diabetic foot infections. AB - INTRODUCTION: This study aimed to determine the frequencies of bacterial isolates cultured from diabetic foot infections and assess their resistance and susceptibility to commonly used antibiotics. METHODS: This prospective study included 41 patients with diabetic foot lesions. Bacteria were isolated from foot lesions, and their antibiotic susceptibility pattern was determined using the Kirby-Bauer disk diffusion method and/or broth method [minimum inhibitory concentration (MIC)]. RESULTS: The most common location of ulceration was the toe (54%), followed by the plantar surface (27%) and dorsal portion (19%). A total of 89 bacterial isolates were obtained from 30 patients. The infections were predominantly due to Gram-positive bacteria and polymicrobial bacteremia. The most commonly isolated Gram-positive bacteria were Staphylococcus aureus, followed by Staphylococcus saprophyticus, Staphylococcus epidermidis, Streptococcus agalactiae, and Streptococcus pneumoniae. The most commonly isolated Gram-negative bacteria were Proteus spp. and Enterobacterspp., followed by Escherichia coli, Pseudomonasspp., and Citrobacterspp. Nine cases of methicillin-resistant Staphylococcus aureus (MRSA) had cefoxitin resistance, and among these MRSA isolates, 3 were resistant to vancomycin with the MIC technique. The antibiotic imipenem was the most effective against both Gram-positive and Gram-negative bacteria, and gentamicin was effective against Gram-negative bacteria. CONCLUSIONS: The present study confirmed the high prevalence of multidrug-resistant pathogens in diabetic foot ulcers. It is necessary to evaluate the different microorganisms infecting the wound and to know the antibiotic susceptibility patterns of the isolates from the infected wound. This knowledge is crucial for planning treatment with the appropriate antibiotics, reducing resistance patterns, and minimizing healthcare costs. PMID- 26516964 TI - Polymerase chain reaction-based method for the identification of Leishmania (Viannia) braziliensis and Leishmania (Viannia) guyanensis in mucosal tissues conserved in paraffin. AB - INTRODUCTION: In the Americas, mucosal leishmaniasis is primarily associated with infection by Leishmania (Viannia) braziliensis. However, Leishmania (Viannia) guyanensis is another important cause of this disease in the Brazilian Amazon. In this study, we aimed at detecting Leishmaniadeoxyribonucleic acid (DNA) within paraffin-embedded fragments of mucosal tissues, and characterizing the infecting parasite species. METHODS: We evaluated samples collected from 114 patients treated at a reference center in the Brazilian Amazon by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses. RESULTS: Direct examination of biopsy imprints detected parasites in 10 of the 114 samples, while evaluation of hematoxylin and eosin-stained slides detected amastigotes in an additional 17 samples. Meanwhile, 31/114 samples (27.2%) were positive for Leishmania spp. kinetoplast deoxyribonucleic acid (kDNA) by PCR analysis. Of these, 17 (54.8%) yielded amplification of the mini-exon PCR target, thereby allowing for PCR-RFLP-based identification. Six of the samples were identified as L. (V.) braziliensis, while the remaining 11 were identified as L. (V.) guyanensis. CONCLUSIONS: The results of this study demonstrate the feasibility of applying molecular techniques for the diagnosis of human parasites within paraffin-embedded tissues. Moreover, our findings confirm that L. (V.) guyanensisis a relevant causative agent of mucosal leishmaniasis in the Brazilian Amazon. PMID- 26516965 TI - Expression of annexin A1 in Leishmania-infected skin and its correlation with histopathological features. AB - INTRODUCTION: The aim of this study was quantify annexin A1 expression in macrophages and cluster of differentiation 4 (CD4) + and cluster of differentiation 8 (CD8)+ T cells from the skin of patients with cutaneous leishmaniasis (n=55) and correlate with histopathological aspects. METHODS: Infecting species were identified by polymerase chain reaction-restriction fragment length polymorphism, and expression of annexin A1 was analyzed by immunofluorescence. RESULTS: All patients (n = 55) were infected with Leishmania braziliensis . Annexin A1 was expressed more abundantly in CD163 + macrophages in infected skin (p < 0.0001) than in uninfected skin. In addition, macrophages in necrotic exudative reaction lesions expressed annexin A1 at higher levels than those observed in granulomatous (p < 0.01) and cellular lesions p < 0.05). This difference might be due to the need to clear both parasites and necrotic tissue from necrotic lesions. CD4 + cells in cellular lesions expressed annexin A1 more abundantly than did those in necrotic (p < 0.05) and granulomatous lesions (p < 0.01). Expression in CD8 + T cells followed the same trend. These differences might be due to the pervasiveness of lymphohistiocytic and plasmacytic infiltrate in cellular lesions. CONCLUSIONS: Annexin A1 is differentially expressed in CD163 + macrophages and T cells depending on the histopathological features of Leishmania -infected skin, which might affect cell activation. PMID- 26516966 TI - Neospora caninum and Toxoplasma gondii serodiagnosis in human immunodeficiency virus carriers. AB - INTRODUCTION: Neospora caninum and Toxoplasma gondii belong to the Sarcocystidae family, and both have one definitive and various intermediary hosts. Owing to their weak immune systems, immunocompromised persons might be prone to opportunistic infections. The aim of this study was to investigate the presence of anti- N. caninum and anti- T. gondii antibodies in immunocompromised individuals. METHODS: This cross-sectional study investigated the rates of N. caninum and T. gondii , as assessed using immunofluorescent antibody reaction (IFAT) with 1:50 and 1:16 dilution, respectively, in patients with human immunodeficiency virus (HIV). RESULTS: The seropositivity for N. caninum was 26.1% (81/310) in Mato Grosso do Sul and 31.2% (10/32) in Parana and for T. gondii was 76.8% (238/310) in Mato Grosso do Sul and 68.7% (22/32) in Parana. CONCLUSIONS: There is evidence of anti- N caninum and anti- T. gondii antibodies in patients with HIV. Other aspects of T. gondii , which is a zoonosis, and N. caninum , which might affect immunodeficient individuals, need to be evaluated and reported. PMID- 26516967 TI - Basic sanitation, socioeconomic conditions, and degree of risk for the presence and maintenance of malaria in a low-transmission area in the Brazilian Amazon. AB - INTRODUCTION: This study aimed to evaluate basic sanitation and socioeconomic indicators, reported cases of malaria, and risk of contracting malaria in the Ananindeua municipality, State of Para. METHODS: Data on basic sanitation and socioeconomic dimensions were taken from the Brazilian Institute of Geography and Statistics [ Instituto Brasileiro de Geografia e Estatistica (IBGE)] 2010 census. Epidemiological malaria information was taken from the Epidemiological Malaria Surveillance Information System [ Sistema de Informacao de Vigilancia Epidemiologica de Malaria (SIVEP/Malaria)], between 2003 and 2013 of the Ministry of Health and from the SIVEP/Malaria forms of the municipality's Endemic Diseases Unit for 2,013 cases. RESULTS: Our data do not confirm the correlation among indicators of basic sanitation, socioeconomic conditions, and water supply with malaria cases. Of the 1,557 cases evaluated, most were caused by Plasmodium vivax , with rare cases of Plasmodium falciparum and mixed infections. There were 756 notifications in 2003. The number of reported cases was sharply reduced between 2006 and 2012, but a 142-case outbreak occurred in 2013. Ananindeua municipality's Annual Parasite Index indicated low risk in 2003 and no risk in other years, and the 2,013 cases were predominantly male individuals aged >=40 years. CONCLUSIONS: Our data confirm the non-endemicity of malaria in the Ananindeua municipality, as the Annual Parasite Indices described for the years 2004-2013 classify it as a risk-free area. However, the 2013 outbreak indicates the need to strengthen prevention, surveillance, and control activities to reduce the risk of new outbreaks and consequent economic and social impacts on the population. PMID- 26516968 TI - Cryptococcosis in Atlantico, Colombia: an approximation of the prevalence of this mycosis and the distribution of the etiological agent in the environment. AB - INTRODUCTION: Cryptococcosis is an invasive disease acquired by inhalation of infectious propagules from the environment. Currently, compulsory notification of the spread of this disease is not required in Colombia. However, reporting of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome cases to the National Surveillance System has suggested that there is a growing population at risk of contracting cryptococcosis. Few studies have described the occurrence of cryptococcosis in Colombia. Therefore, in this study, we examined the pathology of this disease in Atlantico, Colombia and determined the distributions of Cryptococcus neoformans and Cryptococcus gattii in the environment. METHODS: Clinical samples/isolates were gathered from cases of cryptococcosis previously diagnosed at health institutions in Atlantico, and surveys were completed by clinicians. The environmental study considered 32 sampling points and three tree species, i.e., Quickstick ( Gliricidia sepium ), Almond ( Terminalia catappa ), and Pink trumpet ( Tabebuia rosea ). Environmental and clinical samples/isolates were analyzed for phenotypic and genotypic confirmation. RESULTS: From 1997-2014, 41 cases of cryptococcosis were reported. The mean patient age was 40.5 years (range: 18-63 years); 76% were men, and 78% were HIV positive. Isolation was possible in 38 cases ( C. neoformans , molecular type VNI in 37 cases and C. gattii , molecular type VGI in one case). In 2012-2014, 2,068 environmental samples were analyzed with a positivity of 0.4% ( C. neoformans , molecular type VNI) in Almond and Pink trumpet trees. CONCLUSIONS: Cryptococcus neoformans , molecular type VNI had a higher prevalence than C. gattii and was associated with human exposure and the pathogenesis of cryptococcosis in this geographical region. PMID- 26516969 TI - Clinical and serological outcomes with different surgical approaches for human hepatic hydatidosis. AB - INTRODUCTION: Hydatidosis is the result of infection with the larval stages of some species of the genus Echinococcus. Treatment approaches for hydatid cysts include the use of albendazole, surgery, and/or medico-surgical procedures. The choice of the therapeutic surgical approach depends on the cyst number and localization, surgeon expertise, and presence of complications. The present study aimed to compare the outcomes of the following therapeutic approaches for the treatment of hepatic hydatid cysts: pericystectomy; the puncture, aspiration, injection, and reaspiration (PAIR) technique; and the PAIR technique followed by deroofing, evacuation of cysts, and omentoplasty. METHODS: The 54 patients were divided into 3 groups: Group I (14 patients) who underwent pericystectomy, Group II (23 patients) who underwent the PAIR technique, and Group III (17 patients) who underwent the PAIR technique followed by deroofing and omentoplasty. The diagnosis of hydatid cysts was based on serological testing using enzyme-linked immunosorbent assay, abdominal ultrasound, and parasitological examination of the cyst contents. Morbidity, mortality, length of hospital stay, recurrence, and postoperative complications were evaluated. RESULTS: Postoperative bleeding, infection, and recurrence were reported in Groups I and II; Group III did not experience postoperative infection and had shorter hospital stays. Recurrence and postoperative complications did not occur in Group III. CONCLUSIONS: The partial surgical procedure with deroofing, evacuation of the cysts, and omentoplasty, as performed in the present study, is recommended as a safe and effective method for elimination of the entire parasite with minimal possibility for intra-peritoneal spillage. PMID- 26516970 TI - Hydatid cysts in muscles: clinical manifestations, diagnosis, and management of this atypical presentation. AB - INTRODUCTION: Hydatid cysts are rarely detected in muscle tissue (0.7-0.9%), even in endemic countries. The aim of this study was to present information regarding the clinical manifestations, diagnosis, and management of muscle echinococcosis. METHODS: Twenty-two patients with hydatid cysts in the muscle were followed from January 2006 through December 2014. RESULTS: Twenty-four sites of muscle involvement were observed in the 22 patients. Fifteen (68%) of our patients were women, while seven (32%) were men. The mean age was 28.1 +/- 15.4 (6-61) years. The most frequent locations were the thigh (27.2%) and the paravertebral region (13.6%). Most patients reported a painless slow-growing mass with normal overlying skin. Most (90.2%) cases were treated by surgical excision and fine needle aspiration. CONCLUSIONS: Primary muscle hydatid cyst should be considered in the differential diagnosis in cystic masses of the muscular system without pain and localized enlargement of soft tissue, especially in endemic areas. Hydatid cyst should be investigated using serological tests and imaging modalities. If possible, total surgical excision of hydatid cyst in the muscle should be performed. PMID- 26516971 TI - Molecular characterization of group A rotavirus before and after the introduction of vaccines in Brazil. AB - INTRODUCTION: In this study, the molecular characteristics of group A rotavirus (RVA) were compared in samples obtained before and after RVA vaccine-introduction in Brazil. METHODS: Eighty samples were screened for the presence of RVA. Positive samples were molecularly analyzed. RESULTS: RVA positivity was 16.9%, with a predominance of G2P[4]. Periods: pre-vaccination: predominance of IId (G1), IId (G2) lineages, and I1 and E1 genotypes; post-vaccination: predominance of Ib (G1), IIa, and IIc (G2) lineages and I2 and E2 genotypes. CONCLUSIONS: Although changes in RVA-circulation pattern were observed in the post-vaccination period, it could not be attributed to vaccination process. PMID- 26516972 TI - Hepatitis B and C in a Brazilian deaf community. AB - INTRODUCTION: Although deaf people are exposed to hepatitis B and C risk factors, epidemiological studies regarding these diseases in deaf people are lacking. METHODS: After watching an explanatory digital versatile disc (DVD) in Brazilian Sign Language, 88 deaf people were interviewed and tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), and hepatitis C virus antibody (anti-HCV). RESULTS: The prevalence of hepatitis B markers was 8%; they were associated with incarceration and being born outside the State of Sao Paulo. No cases of hepatitis C were identified. CONCLUSIONS: Participants showed a substantial lack of knowledge regarding viral hepatitis, indicating a need for public policies that consider linguistic and cultural profiles. PMID- 26516973 TI - Phenotypic and genotypic profile of pyrethroid resistance in populations of the mosquito Aedes aegypti from Goiania, Central West Brazil. AB - INTRODUCTION: The mosquito Aedes aegypti has evolved resistance to pyrethroid insecticides. The present study evaluated Ae. aegypti from Goiania for the resistant phenotype and for mutations associated with resistance. METHODS: Insecticide dose-response bioassays were conducted on mosquitoes descended from field-collected eggs, and polymerase chain reaction (PCR) was used to genotype 90 individuals at sites implicated in pyrethroid resistance. RESULTS: All mosquito populations displayed high levels of resistance to deltamethrin, as well as high frequencies of the 1016Ile kdr and 1534Cys kdrmutations. CONCLUSIONS: Aedes aegypti populations in the Goiania area are highly resistant to deltamethrin, presumably due to high frequencies of kdr(knockdown-resistance) mutations. PMID- 26516974 TI - Larvicidal activity of oils, fatty acids, and methyl esters from ripe and unripe fruit of Solanum lycocarpum (Solanaceae) against the vector Culex quinquefasciatus (Diptera: Culicidae). AB - INTRODUCTION: The larvicidal activity of oils, fatty acids, and methyl esters of Solanum lycocarpum fruit against Culex quinquefasciatus is unknown. METHODS: The larvicidal activity of samples of ripe and unripe fruit from S. lycocarpum was evaluated against third and fourth instar larvae of C. quinquefasciatus . RESULTS: The oils, fatty acids, and methyl esters of S. lycocarpum showed the greatest larvicidal effect (57.1-95.0%) at a concentration of 100mg/L (LC 50values between 0.70 and 27.54mg/L). CONCLUSIONS: Solanum lycocarpum fruit may be a good source of new natural products with larvicidal activity. PMID- 26516975 TI - The nares as a CA-MRSA reservoir in the healthy elderly. AB - INTRODUCTION: The frequency of methicillin-resistant Staphylococcus aureus (MRSA) has increased in the community. This study evaluated the prevalence of MRSA and community-acquired (CA)-MRSA in 120 healthy elderly. METHODS: The MRSA were evaluated for the presence of the IS256, mecA, agr, icaA, icaD, fnbB , and pvl genes with PCR. RESULTS: Frequency of S. aureus and MRSA colonization was 17.8% and 19%, respectively. CA-MRSA isolate showed SCC mec IV, fnbB+ , and icaD+ . CONCLUSIONS: CA-MRSA was detected, with genotype determined as SCC mec type IV/IS256/ fnbB+ / icaA / icaD+ / bbp-/agr2 / bap / pvl, characterizing this population as a possible reservoir of this organism in the community. PMID- 26516976 TI - Influence of a subinhibitory concentration of vancomycin on the in vitro expression of virulence-related genes in the vancomycin-resistant Enterococcus faecalis. AB - INTRODUCTION: Exposure to subinhibitory concentrations (SICs) of antimicrobials may alter the bacterial transcriptome. METHODS: Here, we evaluated the expression of nine virulence-related genes in vancomycin-resistant enterococci (VRE) urinary tract infection isolates grown at SICs of vancomycin. RESULTS: A Subinhibitory concentrations of vancomycin interferes with gene modulation, but does not affect the phenotype of a VRE strain in vitro . CONCLUSIONS: Subinhibitory concentrations of vancomycin may regulate the expression of virulence factors in vivo or contribute to the selection of vancomycin-resistant strains. PMID- 26516977 TI - Presence of anti-Leishmania (Viannia) braziliensis antibodies in blood donors in the West-Central region of the State of Parana, Brazil. AB - INTRODUCTION: Serological screening in blood banks does not include all transmittable diseases. American cutaneous leishmaniasis (ACL) has a high detection rate in the municipalities of the State of Parana. METHODS: This study analyzed the presence of anti- Leishmania braziliensisantibodies in 176 blood donors who live in these endemic areas. The variables were analyzed with the chi2 test and Stata 9.1 software. RESULTS: Twenty (11.4%) samples were positive for the presence of anti- L. braziliensisantibodies. CONCLUSIONS: The high percentage of donors with anti- Leishmania spp. antibodies indicates the need to study the risk of ACL transmission through blood donors. PMID- 26516979 TI - Long-term follow-up of a patient since the acute phase of Chagas disease (South American trypanosomiasis): further treatment and cure of the infection. AB - A woman had been followed since 1957 for acute phase Chagas disease. Parasitological and serological tests were positive, and treatment included benznidazole in 1974. Following treatment, parasitological test results were negative and conventional serology remained positive until 1994, with subsequent discordant results (1995-1997). The results became consistently negative since 1999. She had an indeterminate chronic form until 1974. Only two minor and transitory nonspecific alterations on electrocardiogram were noted, with the last nine records normal until June 2014. This case confirms the possibility of curing chronic disease and suggests the benefit of specific treatments for preventing long-term morbidity. PMID- 26516978 TI - Detection of Leishmania (Viannia) DNA in leucocytes from the blood of patients with cutaneous leishmaniasis. AB - INTRODUCTION: Cutaneous leishmaniasis (CL) is a serious and global public health issue, with the potential of developing a mucosal form, occurring as subclinical cases, and showing recurrence despite previous treatment. METHODS: Polymorphonuclear and mononuclear DNA obtained from 49 patients was subjected to polymerase chain reaction for detection of Leishmania (Viannia). RESULTS: DNA was detected in mononuclear cells from two patients with active primary lesions positive for CL, with infection periods of 3 and 6 months, respectively. CONCLUSIONS: The DNA of Leishmania (Viannia) indicates probable parasite dissemination possibly explaining subclinical case emergence, lesion recurrence, and mucosal lesion appearance. PMID- 26516980 TI - First report of hepatic hematoma after presumed Bothrops envenomation. AB - In Latin America, Bothrops envenomation is responsible for the majority of accidents caused by venomous snakes. Patients usually present local edema, bleeding and coagulopathy. Visceral hemorrhage is extremely rare and considered a challenge for diagnosis and management. We report the first case of hepatic hematoma owing to the bothropic envenomation in a 66-year-old man who was bitten in the left leg. He presented local edema, coagulopathy, and acute kidney injury. Radiological findings suggested hepatic hematoma, with a volume of almost 3 liters. The hepatic hematoma was gradually absorbed without the need for surgical intervention with complete resolution in 8 months. PMID- 26516981 TI - A snakebite caused by a bushmaster (Lachesis muta): report of a confirmed case in State of Pernambuco, Brazil. AB - We report a case of envenomation caused by a bushmaster ( Lachesis muta) in a male child in State of Pernambuco, Brazil. The victim showed discrete local manifestations, but presented altered blood coagulation 2 hours after the bite. Ten ampoules of bothropic-lachetic antivenom therapy were administered, and 48 hours later, the patient showed discrete edema, pain, and ecchymosis around the bite and normal blood coagulation. The patient was discharged 5 days after the envenomation. The prompt administration of specific treatment was important for the favorable outcomes observed. PMID- 26516982 TI - Noncontiguous multiple-level brucellar spondylodiscitis with an epidural abscess. PMID- 26516983 TI - The indirect impact of antiretroviral therapy: Mortality risk, mental health, and HIV-negative labor supply. AB - To reduce the burden of the HIV/AIDS epidemic, international donors recently began providing free antiretroviral therapy (ART) in parts of Sub-Saharan Africa. ART dramatically prolongs life and reduces infectiousness for people with HIV. This paper shows that ART availability increases work time for HIV-negative people without caretaker obligations, who do not directly benefit from the medicine. A difference-in-difference design compares people living near and far from ART, before and after treatment becomes available. Next we explore the possible reasons for this pattern. Although we cannot pinpoint the mechanism, we find that ART availability substantially reduces subjective mortality risk and improves mental health. These results show an undocumented economic consequence of the HIV/AIDS epidemic and an important externality of medical innovation. They also provide the first evidence of a link between the disease environment and mental health. PMID- 26516984 TI - Long-term trajectories of cognitive deficits in schizophrenia: A critical overview. AB - BACKGROUND: Cognitive disturbances are widely pronounced in schizophrenia and schizophrenia spectrum disorders. Whilst cognitive deficits are well established in the prodromal phase and are known to deteriorate at the onset of schizophrenia, there is a certain discrepancy of findings regarding the cognitive alterations over the course of the illness. METHODS: We bring together the results of the longitudinal studies identified through PubMed which have covered more than 3 years follow-up and to reflect on the potential factors, such as sample characteristics and stage of the illness which may contribute to the various trajectories of cognitive changes. RESULTS: A summary of recent findings comprising the changes of the cognitive functioning in schizophrenia patients along the longitudinal course of the illness is provided. The potential approaches for addressing cognition in the course of schizophrenia are discussed. CONCLUSIONS: Given the existing controversies on the course of cognitive changes in schizophrenia, differentiated approaches specifically focusing on the peculiarities of the clinical features and changes in specific cognitive domains could shed light on the trajectories of cognitive deficits in schizophrenia and spectrum disorders. PMID- 26516985 TI - Knockdown of the coenzyme Q synthesis gene Smed-dlp1 affects planarian regeneration and tissue homeostasis. AB - The freshwater planarian is a model organism used to study tissue regeneration that occupies an important position among multicellular organisms. Planarian genomic databases have led to the identification of genes that are required for regeneration, with implications for their roles in its underlying mechanism. Coenzyme Q (CoQ) is a fundamental lipophilic molecule that is synthesized and expressed in every cell of every organism. Furthermore, CoQ levels affect development, life span, disease and aging in nematodes and mice. Because CoQ can be ingested in food, it has been used in preventive nutrition. In this study, we investigated the role of CoQ in planarian regeneration. Planarians synthesize both CoQ9 and rhodoquinone 9 (RQ9). Knockdown of Smed-dlp1, a trans prenyltransferase gene that encodes an enzyme that synthesizes the CoQ side chain, led to a decrease in CoQ9 and RQ9 levels. However, ATP levels did not consistently decrease in these animals. Knockdown animals exhibited tissue regression and curling. The number of mitotic cells decreased in Smed-dlp1 (RNAi) animals. These results suggested a failure in physiological cell turnover and stem cell function. Accordingly, regenerating planarians died from lysis or exhibited delayed regeneration. Interestingly, the observed phenotypes were partially rescued by ingesting food supplemented with alpha-tocopherol. Taken together, our results suggest that oxidative stress induced by reduced CoQ9 levels affects planarian regeneration and tissue homeostasis. PMID- 26516987 TI - Probing Photoexcited Carriers in a Few-Layer MoS2 Laminate by Time-Resolved Optical Pump-Terahertz Probe Spectroscopy. AB - We report the dynamics of photoinduced carriers in a free-standing MoS2 laminate consisting of a few layers (1-6 layers) using time-resolved optical pump terahertz probe spectroscopy. Upon photoexcitation with the 800 nm pump pulse, the terahertz conductivity increases due to absorption by the photoinduced charge carriers. The relaxation of the non-equilibrium carriers shows fast as well as slow decay channels, analyzed using a rate equation model incorporating defect assisted Auger scattering of photoexcited electrons, holes, and excitons. The fast relaxation time occurs due to the capture of electrons and holes by defects via Auger processes, resulting in nonradiative recombination. The slower relaxation arises since the excitons are bound to the defects, preventing the defect-assisted Auger recombination of the electrons and the holes. Our results provide a comprehensive understanding of the non-equilibrium carrier kinetics in a system of unscreened Coulomb interactions, where defect-assisted Auger processes dominate and should be applicable to other 2D systems. PMID- 26516988 TI - Validation of energy-weighted algorithm for radiation portal monitor using plastic scintillator. AB - To prevent illicit tracking of radionuclides, radiation portal monitor (RPM) systems employing plastic scintillators have been used in ports and airports. However, their poor energy resolution makes the discrimination of radioactive material inaccurate. In this study, an energy weight algorithm was validated to determine (133)Ba, (22)Na, (137)Cs, and (60)Co by using a plastic scintillator. The Compton edges of energy spectra were converted to peaks based on the algorithm. The peaks have a maximum error of 6% towards the theoretical Compton edge. PMID- 26516989 TI - Validation of the Serpent 2 code on TRIGA Mark II benchmark experiments. AB - The main aim of this paper is the development and validation of a 3D computational model of TRIGA research reactor using Serpent 2 code. The calculated parameters were compared to the experimental results and to calculations performed with the MCNP code. The results show that the calculated normalized reaction rates and flux distribution within the core are in good agreement with MCNP and experiment, while in the reflector the flux distribution differ up to 3% from the measurements. PMID- 26516986 TI - Complex I and complex III inhibition specifically increase cytosolic hydrogen peroxide levels without inducing oxidative stress in HEK293 cells. AB - Inhibitor studies with isolated mitochondria demonstrated that complex I (CI) and III (CIII) of the electron transport chain (ETC) can act as relevant sources of mitochondrial reactive oxygen species (ROS). Here we studied ROS generation and oxidative stress induction during chronic (24h) inhibition of CI and CIII using rotenone (ROT) and antimycin A (AA), respectively, in intact HEK293 cells. Both inhibitors stimulated oxidation of the ROS sensor hydroethidine (HEt) and increased mitochondrial NAD(P)H levels without major effects on cell viability. Integrated analysis of cells stably expressing cytosolic- or mitochondria targeted variants of the reporter molecules HyPer (H2O2-sensitive and pH sensitive) and SypHer (H2O2-insensitive and pH-sensitive), revealed that CI- and CIII inhibition increased cytosolic but not mitochondrial H2O2 levels. Total and mitochondria-specific lipid peroxidation was not increased in the inhibited cells as reported by the C11-BODIPY(581/591) and MitoPerOx biosensors. Also expression of the superoxide-detoxifying enzymes CuZnSOD (cytosolic) and MnSOD (mitochondrial) was not affected. Oxyblot analysis revealed that protein carbonylation was not stimulated by CI and CIII inhibition. Our findings suggest that chronic inhibition of CI and CIII: (i) increases the levels of HEt-oxidizing ROS and (ii) specifically elevates cytosolic but not mitochondrial H2O2 levels, (iii) does not induce oxidative stress or substantial cell death. We conclude that the increased ROS levels are below the stress-inducing level and might play a role in redox signaling. PMID- 26516990 TI - ETHERNES: A new design of radionuclide source-based thermal neutron facility with large homogeneity area. AB - A new thermal neutron irradiation facility based on an (241)Am-Be source embedded in a polyethylene moderator has been designed, and is called ETHERNES (Extended THERmal NEutron Source). The facility shows a large irradiation cavity (45 cm * 45 cm square section, 63 cm in height), which is separated from the source by means of a polyethylene sphere acting as shadowing object. Taking advantage of multiple scattering of neutrons with the walls of this cavity, the moderation process is especially effective and allows obtaining useful thermal fluence rates from 550 to 800 cm(-2) s(-1) with a source having nominal emission rate 5.7*10(6) s(-1). Irradiation planes parallel to the cavity bottom have been identified. The fluence rate across a given plane is as uniform as 3% (or better) in a disk with 30 cm (or higher) diameter. In practice, the value of thermal fluence rate simply depends on the height from the cavity bottom. The thermal neutron spectral fraction ranges from 77% up to 89%, depending on the irradiation plane. The angular distribution of thermal neutrons is roughly isotropic, with a slight prevalence of directions from bottom to top of the cavity. The mentioned characteristics are expected to be attractive for the scientific community involved in neutron metrology, neutron dosimetry and neutron detector testing. PMID- 26516991 TI - Far field 3D localization of radioactive hot spots using a coded aperture camera. AB - This paper presents a coded aperture method to remotely estimate the radioactivity of a source. The activity is estimated from the detected counts and the estimated source location, which is extracted by factoring the effect of aperture magnification. A 6mm thick tungsten-copper alloy coded aperture mask is used to modulate the incoming gamma-rays. The location of point and line sources in all three dimensions was estimated with an accuracy of less than 10% when the source-camera distance was about 4 m. The estimated activities were 17.6% smaller and 50.4% larger than the actual activities for the point and line sources, respectively. PMID- 26516992 TI - Rapid alpha spectrometry from liquids doped with 209Po and 241Am using simplified sample processing. AB - Rapid detection of alpha-particle emitting radionuclides from liquids doped with (209)Po and (241)Am was investigated. These nuclides may mimic or be among those that could be used as threat agents in malevolent actions such as deliberate poisoning of refreshments. The liquids investigated here by using a semiconductor alpha detector in vacuum were coffee, beer and apple juice. Methods for the sample processing were rapid evaporation of the liquids and filtration. Both methods produced samples, which gave alpha spectra that could be readily analyzed by an unfolding program. The doped radionuclides were easily identified from the spectra, but the samples were too thick for reliable activity determination. Determination of the activity ratios is possible if the peak shapes are equal. However, radionuclides may behave differently during the sample preparation, which must be accounted for in the activity ratio determination. PMID- 26516993 TI - 39Ar/Ar measurements using ultra-low background proportional counters. AB - Age-dating groundwater and seawater using the (39)Ar/Ar ratio is an important tool to understand water mass-flow rates and mean residence time. Low-background proportional counters developed at Pacific Northwest National Laboratory use mixtures of argon and methane as counting gas. We demonstrate sensitivity to (39)Ar by comparing geological (ancient) argon recovered from a carbon dioxide gas well and commercial argon. The demonstrated sensitivity to the (39)Ar/Ar ratio is sufficient to date water masses as old as 1000 years. PMID- 26516994 TI - Cytotoxic Clerodane Diterpenoids from the Leaves of Casearia grewiifolia. AB - Two new clerodane diterpenoids (1 and 2) and the known compound caseanigrescen D (3) were isolated from the leaves of Casearia grewiifolia by bioassay-guided fractionation. Their structures were determined by analyses of MS and 2D NMR data. The absolute configurations of 1 and 3 were established by analysis of X ray diffraction data. Compounds 1-3 were evaluated for their cytotoxicity against four cancer cell lines, KB (mouth epidermal carcinoma cells), HepG-2 (human liver hepatocellular carcinoma cells), LU-1 (human lung adenocarcinoma cells), and MCF 7 (human breast cancer cells). Caseagrewifolin B (2) had inhibitory activity against KB and HepG-2 cell lines with IC50 values of 6.2 to 7.0 MUM, respectively. When tested against the normal cells (NIH/3T3), caseagrewifolin B (2) exhibited a significant selective inhibition against cancer cells in comparison with the normal cells. Caseanigrescen D (3) was cytotoxic against four cancer cell lines; however it had no selective inhibition compared with normal cells. PMID- 26516995 TI - Shoulder Range of Motion and Strength in Professional Ice Hockey Players. AB - Ice hockey is a fast paced sport with unique injury potential. There are no studies in the literature that examine the shoulder strength and range of motion in this population. Players on a single professional ice hockey team underwent a comprehensive examination of shoulder motion and strength. Shoulder motion and strength between right and left extremities were compared within athletes. Comparisons were made between right and left handed players, players that shoot right versus left handed, and by position. Within individual athletes, there was no difference in motion or strength between right and left shoulders. There was no difference in motion or strength between the dominant and non-dominant shoulder and players that shoot right versus left handed. Defensemen had a statistically significant increase in external rotation with the arm at the side for the left shoulder (66 degrees versus 55 degrees , p = 0.02) and a trend towards increased external rotation with the arm at the side for the right shoulder (65 degrees versus 56 degrees , p = 0.07). In professional ice hockey players, there is no difference in shoulder motion and strength between the right and left upper extremity. Ice hockey defensemen may have more external rotation with the arm at the side than forward. PMID- 26516996 TI - The Importance of Tear Edge Fixation in Modified Transosseous-Equivalent Rotator Cuff Repair: A Biomechanical Study. AB - PURPOSE: The purpose of this study was to evaluate the impact of dog ear fixation with peripheral sutures on the biomechanical properties of transosseous equivalent rotator cuff repair. METHODS: Eight matched-pairs of fresh-frozen cadaveric shoulders were dissected to create an isolated, full thickness supraspinatus tear. One shoulder in each matched pair was randomly selected for repair with a standard transosseous-equivalent suture-bridge technique (TOE), and the contralateral shoulder underwent TOE repair with additional tear edge fixation (TEF). Unidirectional tensile testing was conducted to determine cyclic displacement, linear stiffness, yield load, ultimate load, and mode of failure for each specimen. RESULTS: The ultimate load and yield load were significantly higher for the TEF group (460 +/- 104 N and 455 +/- 97 N) than the TOE group (409 +/- 111 N and 356 +/- 143 N) (p = 0.020, p = 0.019, respectively). No statistical difference was noted in stiffness or displacement. Seven of eight TOE specimens versus two of eight TEF specimens failed by medial row tendon rupture, while one of eight TOE specimens versus five of eight TEF specimens failed by lateral row anchor pullout. CONCLUSIONS: The addition of peripheral tear edge fixation to transosseous-equivalent rotator cuff repair improves the initial load to failure properties of the construct. However, dog ear fixation has no significant impact on cyclical displacement or stiffness. CLINICAL RELEVANCE: Tear edge fixation with peripheral sutures should be considered to increase the initial strength of transosseous-equivalent rotator cuff repair while restoring the anatomic footprint. The addition of dog ear fixation may promote healing and minimize the risk of construct failure during the immediate postoperative period. PMID- 26516997 TI - The Effect of Adductor-Canal-Blockade on Outcome after Medial Unicondylar Knee Arthroplasty: A Preliminary Study. AB - INTRODUCTION: Unicondylar knee arthroplasty (UKA) offers decreased morbidity, faster recovery, better functional outcomes, and equivalent survivorship compared to TKA for certain patients. To fully capture these benefits, regional anesthesia techniques must facilitate rather than compromise patients ability for early postoperative mobilization and safe discharge following UKA. The purpose of this study was to determine whether the predominantly sensory adductor canal blockade (ACB) shortens hospital stay after medial UKA (mUKA). Secondary endpoints were narcotic consumption, steps walked during PT sessions, and total PT sessions required prior to discharge. METHODS: Twelve patients scheduled for elective mUKA received spinal anesthesia and single-shot ACB. ACB patients were matched by age, gender, body mass index (BMI), and Charlson Comorbidity Index in a 1:2 ratio to 24 lumbar plexus block (LPB) patients. Time to hospital discharge, number of physical therapy (PT) sessions required for safe discharge, and steps taken during PT sessions were retrospectively abstracted from each patient's medical record. RESULTS: Patients who received ACB had a significantly shorter hospital stay (27.8 +/- 3.9 hours) compared with patients who received LPB (39.7 +/-18.5 hours, p = 0.025). Patients treated with ACB required significantly fewer PT sessions (1.3 +/- 0.6 sessions) compared to patients who received LPB (2.4 +/- 1.5 sessions, p = 0.007). Patients treated with ACB walked significantly more steps during their first PT session (225.0 +/- 156.6 steps) compared with patients treated with LPB (107.4 +/- 170.0, p = 0.045). There was a trend towards decreased narcotic requirements in the ACB group. DISCUSSION AND CONCLUSIONS: Data from our study suggests that ACB may permit earlier hospital discharge and better participation in PT without compromising the quality of perioperative analgesia. Thus, ACB may represent a promising option for patients undergoing mUKA in terms of improved clinical outcomes, decreased postoperative morbidity, and cost-effectiveness. PMID- 26516998 TI - Intraoperative Spinal Cord and Nerve Root Monitoring: A Hospital Survey and Review. AB - Intraoperative monitoring (IOM) of spinal cord and nerve root injury through somatosensory evoked potentials (SSEP), transcranial motor evoked potentials (TcMEP), spontaneous electromyography (sEMG), and triggered electromyography (tEMG) modalities is vital during spinal surgery. However, there are currently no practice guidelines or practice patterns for the utilization of unimodal and multimodal IOM for specific surgeries. This study reviews IOM modalities and documents practice patterns of spine surgeons at our single-center tertiary hospital about their use of various IOM modalities on 23 spinal procedures. As different intraoperative monitoring modalities have shown to have different sensitivities and specificities, devising practice guidelines for IOM utilization in specific spinal procedures should be considered. PMID- 26516999 TI - The Impact of Popliteal Block on Postoperative Medication Administration and Time to Discharge from the Post-Anesthesia Care Unit. AB - BACKGROUND: Previous studies have demonstrated the efficacy of popliteal block anesthesia in decreasing post - operative narcotic administration, nausea, and length of stay in patients undergoing foot and ankle surgeries. The purpose of this study was to compare the amount of narcotic medication administered, the need for anti-emetic medication, PACU length of stay, and discharge status in patients treated surgically for ankle fractures who received popliteal blocks with those who received general anesthesia alone. METHODS: All patients being treated with open reduction and internal fixation for ankle fractures were randomized to receive either general anesthesia (GETA) or popliteal block. Postoperatively, data was collected on the duration of time in the PACU before discharge to home or to a hospital floor. Additional information was collection on the amount of anti-emetic and pain medication in the PACU. RESULTS: Fifty-one patients agreed to participate in the study. There was no significant difference between the two groups with regards to the need for anti-emetic medication, the amount of pain medication received in the PACU, or amount of time spent in the PACU. Patients who received a popliteal block were no more likely to be discharged to home from the PACU than those who received general anesthesia. DISCUSSION: While previous studies have demonstrated the efficacy of popliteal block in decreasing anti-emetic and pain medication administration in the PACU, we found no difference in the amount of medication administered. We found that popliteal block patients were no more likely to be discharged to home than those who received general anesthesia. PMID- 26517000 TI - Ceramic-Ceramic Hip Arthroplasty for Osteonecrosis: Average 5-year Follow-up in Patients Less Than 50 Years of Age. AB - INTRODUCTION: The optimal bearing surface for the young, active patient undergoing total hip arthroplasty (THA) is unknown. We sought to examine the clinical results of ceramic-on-ceramic (CoC) THA in patients under 50 years of age with a diagnosis of osteonecrosis. MATERIALS AND METHODS: Fifty-three hips underwent cementless THA with a CoC articulation. Clinical and functional outcomes, including preoperative and postoperative WOMAC and UCLA scores, were recorded. Serial radiographs were studied for component loosening or evidence of osteolysis. Revision surgery for any reason was the primary clinical endpoint. RESULTS: The average age at time of THA was 31.03 years (range: 15 to 50 years). Average follow-up was 64 months (range: 24 to 112 months). Average preoperative BMI was 25.3 (range: 20.1 to 39.4). WOMAC scores increased from a preoperative average of 37.1 (range: 3.9 to 70.2) to 89 (range: 11.7 to 100) at latest follow up (p less than 0.05). UCLA scores improved from a preoperative average of 2.39 (range: 1 to 4) to 6.72 (range: 1 to 10) postoperatively (p less than 0.05). Forty-five percent of patients were highly active with UCLA scores between 8 and 10. There were no dislocations, deep infections, or ceramic component failures. One patient was revised for chronic pain at another institution, and one patient underwent revision for femoral component loosening. Three patients experienced squeaking, which did not affect quality of life. CONCLUSION: At mid-term follow up, THA with CoC bearings affords high activity level with excellent clinical outcomes and component longevity in young, active patients with osteonecrosis. PMID- 26517001 TI - Can We Improve Workflows in the OR? A Comparison of Quality Perceptions and Preoperative Efficiency across Institutions in Spine Surgery. AB - INTRODUCTION: Cost containment and surgical inefficiencies are major concerns for hospitals in this era of declining resources. The primary aim of this investigation was to understand subjective perceptions of perioperative spine surgical quality across three practice settings and to identify potential factors contributing to these perceptions. Subsequently, we objectively evaluated factors that influence the duration of time in which the patient is in the operating room (OR) prior to the surgical incision and assessed the influence of fluoroscopy technician expertise on radiation dose and imaging efficiency. METHODS: One hundred and eight medical device representatives with at least 1 year of OR experience were surveyed at a national conference. Three distinct healthcare facilities were identified: university, small volume, and large volume private hospitals. Respondents rated facilities on a five-point scale for staff quality; size and consistency of surgical teams; and overall likelihood of recommending the facility. Separately, 140 posterior lumbar procedures from two institutions were retrospectively reviewed. Two time periods were quantified for each surgical case: patient arrival in the OR to induction of anesthesia (T1) and induction to surgical incision (T2). T1 and T2 were compared between university and large private hospital settings using t tests and multivariate analysis. For 44 separate lumbar spine surgical procedures, practice setting, patient BMI, number of vertebral levels requiring imaging, number of localizing fluoroscopy images taken, total fluoroscopy time, total radiation dose, fluoroscopy machine, and whether the fluoroscopist could correctly state his or her role, which was to obtain a lateral lumbar localizing image, were recorded. T-tests were used to compare cases in which the fluoroscopist could and could not correctly state the task. RESULTS: Survey ratings for surgeons were not significantly different across university, large private, and small private hospitals. Fewer circulating nurses were rated as excellent or good in university versus private hospitals (p < 0.001). Small volume private hospital surgical teams were more likely to have worked together before than university teams (p < 0.05), and university teams were larger (p < 0.05). Respondents were more likely to recommend a university or large private hospital for complex instrumentation cases (p < 0.001). On objective measures, university patients were older, less obese, and had higher mean ASA scores (2.5 versus 2.2, p < 0.001). Compared to the university setting, private hospital cases had significantly shorter Time 1 (8 versus 37 min, p < 0.001) and Time 2 (23 versus 30 min, p < 0.001), even after adjusting for ASA score, BMI, and age. Cases in which the fluoroscopist knew the imaging purpose were associated with significantly fewer images (mean 1.8 versus 3.4 images, p < 0.0001) and shorter total exposure times (2.3 versus 4.0 sec, p < 0.001). Operations performed in the university setting were associated with significantly more images (2.7 versus 1.8 images, p < 0.001), longer total exposure times (3.2 versus 2.3 sec, p = 0.0027), and total radiation dose (27.8 versus 53.3 rad, p < 0.001) when compared with those performed in the private setting. The university practice setting was associated with significantly more images (2.7 versus 1.8 images, p < 0.001), longer total exposure times (3.2 versus 2.3 sec, p = 0.003), and total radiation dose (27.8 versus 53.3 rad, p < 0.001) when compared with non university settings. CONCLUSION: Large private and university hospitals had higher surgeon ratings. The university setting was associated with larger and less consistent surgical teams and lower nurse ratings. Surgical staff awareness of the procedure and attention to preoperative tasks specific to the procedure reduced pre-operative time spent in the OR as well as fluoroscopy radiation. These data suggest that nurses and support staff make substantial contributions to overall quality of care, and that leadership and interpersonal coordination are especially important within large teams at teaching hospitals. PMID- 26517002 TI - Fatigue Failure of Newer Generation Modular Revision Femoral Stem Following Fracture Healing: A Case Report. AB - Mechanical failure of the femoral component following total hip arthroplasty is a relatively uncommon complication that has been previously well-described in the literature. Modular, cementless implants have become a popular option in revision total hip arthroplasty. They offer the distinct advantage of optimizing joint kinematics through varying the degree of version, offset, and leg length. We report the case of early fatigue fracture of the Restoration (Stryker, Mahwah, NJ) femoral prosthesis. The following is a detailed description of this case. This report details the events sur - rounding stem failure, and the technique of reconstruction used to deal with this failure. PMID- 26517003 TI - Atraumatic Myositis Ossificans of Iliopsoas Excised through an ASIS Osteotomy: Case Report and Description of a Novel Technique. AB - With a well-established incidence of 15% to 20% following a spinal injury, the occurrence of neurogenic myositis ossificans of the hip is quite rare. The most widely accepted theory supporting its occurrence is the repeated microtrauma by forceful passive mobilization during rehabilitation. An extensive involvement around the hip is quite disabling to the patient. We present the case of a 41 year-old man with an extensive involvement of the right iliopsoas following an incident of head injury with no primary injury to the hip, with a disabling restriction of movement. Computed tomography images and its 3D reconstruction were used to define the exact extent of involvement. The mass was excised piece meal using the iliofemoral approach with an osteotomy of the anterior superior iliac spine, which allowed us to have a better visualization to the extensive mass. Postoperatively the patient regained a good range of motion. In addition to adding a rare case of atraumatic myositis ossificans of the iliopsoas to literature, this reports describes a novel approach for its excision. PMID- 26517004 TI - Inverted Cyclops Lesion without Extension Block: A Case Report and Literature Review. AB - Cyclops lesion was previously described as a fibrous lesion with a granulation tissue core originating from the tibial insertion of the anterior cruciate ligament (ACL) graft. Recently, two case reports described inverted cyclops lesions, which originated from the femoral aspect of the ACL. Both cyclops and inverted cyclops lesions are usually associated with a block to knee extension. Here we present a case of an 18-year-old female who developed a painful inverted cyclops lesion originating from the femoral notch above hamstring autograft without restriction to knee range of motion 20 months after arthroscopically assisted ACL reconstruction. The case is followed by literature review on presentation, diagnosis, and treatment of cyclops and inverted cyclops lesions. PMID- 26517005 TI - Enhancing the Directed Self-assembly Kinetics of Block Copolymers Using Binary Solvent Mixtures. AB - The rapid pattern formation of well-ordered block copolymer (BCP) nanostructures is practical for next-generation nanolithography applications. However, there remain critical hurdles to achieve the rapid self-assembly of BCPs with a high Flory-Huggins interaction parameter (chi), owing to their slow kinetics. In this article, we report that a binary solvent vapor annealing methodology can significantly accelerate the self-assembly kinetics of poly(dimethylsiloxane-b styrene) (PDMS-b-PS) BCPs with a high-chi. In particular, we systemically analyzed the effects of the mixing ratio of a binary solvent composed of a PDMS selective solvent (heptane) and a PS-selective solvent (toluene), showing an ultrafast self-assembly time (<=1 min) to obtain a well-ordered nanostructure. Moreover, we successfully accomplished extremely fast generation of sub-20 nm dot patterns within an annealing time of 10 s in a 300 nm-wide trench by means of binary solvent annealing. We believe that these results are also applicable to other solvent-based annealing systems of BCPs and that they will contribute to the realization of next-generation ultrafine lithography applications. PMID- 26517007 TI - Can membrane progesterone receptor alpha on T regulatory cells explain the ensuing human labour? AB - Progesterone acts as an immunosteroid by contributing to the establishment of a pregnancy-protective milieu. It seems that it is the responsibility of progesterone to evade the inflammatory events that lead to parturition. T regulatory lymphocytes (Treg cells) could further explain the inhibition of the inflammatory mechanisms that lead to labour through the rapid action of progesterone on this cell subset. We investigated Treg cells and the membrane progesterone receptor alpha (mPRalpha) in these immune cells with in relationship to human parturition. This pilot cohort study was conducted in a single-centre tertiary obstetrical unit with 20 normal pregnant women. Variation in the absolute and relative frequency of CD4(+) T cells, Treg cells, and of mPR(alpha+) Treg cells was calculated by flow cytometry on three occasions (second and third trimesters; delivery day). Our results show that during normal pregnancy there is a generalised increase in Treg cells and mPR(alpha+) Treg cells, from the second to the third trimesters (23.4% vs. 52.3% and 4.3% vs. 8.3%, respectively). On the contrary, on delivery day, compared with the values in the third trimester, there is a sudden decrease in both Treg cells (52.3% vs. 17.4%) and mPR(alpha+) Treg cells (8.3% vs. 6.1%). Our findings suggest that human labour may develop as a consequence of a decline in mPR(alpha+) Treg cells, which reduces progesterone anti-inflammatory action through Treg cells. PMID- 26517006 TI - sHLA-G and sHLA-I levels in follicular fluid are not associated with successful implantation. AB - In the field of in vitro fertilization (IVF), useful markers for the prediction of successful implantation for oocyte or embryo selection are essential. It has been reported that sHLA-G (sHLA-G1/HLA-G5) could be detected in the supernatant of the fertilized embryo and in follicular fluid samples (FFs), and that the presence of sHLA-G was related to successful implantation. If sHLA-G could be used as a marker of oocyte selection from multiple FFs, oocytes could be selected without physical contact, thus reducing the likelihood of damage. To investigate the potential for sHLA-G as a marker of oocyte selection from multiple FFs in one patient, protein levels of total protein, sHLA-G, and sHLA-I (sHLA-A, B, and C) were examined in FFs. The variation among multiple FFs in total protein level and sHLA-G level was not related to successful pregnancy. The average sHLA-I levels did not differ in the successful implantation and unsuccessful implantation groups, indicating that sHLA-I levels were not related to successful pregnancy. Furthermore, sHLA-G in FFs was not detected by western blotting, despite being detected by ELISA, while sHLA-I was detected by both ELISA and western blot. These data suggest that sHLA-G in FF might not be a useful marker for oocyte selection as measurements of sHLA-G were inconsistent and there was no association with successful pregnancy. Further, more rigorously tested ELISA systems for detecting sHLA-G in body fluids are necessary before the utility of sHLA-G for diagnosis can be established. PMID- 26517008 TI - Spectroscopic Characterization of a Monomeric, Cyclopentadienyl-Based Rhenium(V) Dioxo Complex. AB - Mononuclear, coordinatively unsaturated rhenium(V) dioxo species of the type XReO2 (X = Me, substituted cyclopentadienyl) have long been postulated as intermediates in rhenium-catalyzed deoxydehydration, but their characterization was precluded because of aggregation into dimeric or oligomeric structures. Using the bulky 1,2,4-tri-tert-butylcyclopentadienyl (Cp(ttt)) ligand, the rhenium(V) dioxo species (Cp(ttt))ReO2 could now be observed, in equilibrium with the dimeric form [(Cp(ttt))Re(O)MU-O]2, and characterized by NMR, IR, and UV-vis spectroscopies, as well as electrospray ionization mass spectrometry. (Cp(ttt))ReO2 is shown to be the primary product of reduction of the rhenium(VII) complex (Cp(ttt))ReO3 with PPh3 and demonstrated to react with ethylene glycol significantly faster than its dimeric counterpart, supporting its role as an intermediate in rhenium-catalyzed deoxydehydration reactions. PMID- 26517009 TI - Development of a Tissue-Engineered Lymphatic Graft Using Nanocomposite Polymer for the Treatment of Secondary Lymphedema. AB - Damage of the lymphatic vessels, commonly due to surgical resection for cancer treatment, leads to secondary lymphedema. Tissue engineering approach offers a possible solution to reconstruct this damage with the use of lymphatic graft to re-establish the lymphatic flow, hence preventing lymphedema. The aim of this study is to develop a tissue-engineered lymphatic graft using nanocomposite polymer and human dermal lymphatic endothelial cells (HDLECs). A nanocomposite polymer, the polyhedral oligomeric silsequioxane-poly(carbonate-urea)urethane (POSS-PCU), which has enhanced mechanical, chemical, and physical characteristics, was used to develop the lymphatic graft. POSS-PCU has been used clinically for the world's first synthetic trachea, lacrimal duct, and is currently undergoing clinical trial for coronary artery bypass graft. Two designs and fabrication methods were used to manufacture the conduits. The fabrication method, the mechanical and physical properties, as well as the hydraulic conductivity were tested. This is followed by in vitro cell culture analysis to test the cytocompatibility of HDLEC with the polymer surface. Using the casted extrusion method, the nanocomposite lymphatic graft demonstrates desirable mechanical property and hydraulic conductivity to re-establish the lymphatic flow. The conduit has high tensile strength (casted: 74.86 +/- 5.74 MPa vs. coagulated: 31.33 +/- 3.71 MPa; P < 0.001), favorable kink resistance, and excellent suture retention property (casted vs. coagulated, P < 0.05). Cytocompatibility study showed that the POSS-PCU scaffold supports the attachment and growth of HDLECs. This study demonstrates the feasibility of developing a tissue-engineered lymphatic graft using the nanocomposite polymer. It displays excellent mechanical property and cytocompatibility to HDLECs, offering much promise for clinical applications and as a new treatment option for secondary lymphedema. PMID- 26517010 TI - Controlled Growth of Ferrihydrite Branched Nanosheet Arrays and Their Transformation to Hematite Nanosheet Arrays for Photoelectrochemical Water Splitting. AB - The morphology engineering represents an alternative route toward efficient hematite photoanodes for photoelectrochemical (PEC) water splitting without changing the chemical composition. In this work, a facile and mild solvothermal synthesis of unique ferrihydrite branched nanosheet arrays vertically aligned on FTO substrate was achieved at around 100 degrees C. The hierarchical branched ferrihydrite nanosheet arrays consisted of tiny branches up to 40 nm in length grown almost vertically on stem nanosheets ~10 nm in thickness. Moreover, the variation of the morphology of the ferrihydrite nanostructures from bare nanosheet arrays through branched nanosheet arrays to dense branched structures can be readily achieved through the regulation of the reaction time and temperature. The obtained ferrihydrite branched nanosheet arrays can be in situ transformed into alpha-Fe2O3 nanosheet arrays with small surface protrusions upon annealing at 550 degrees C. After a simple postgrowth Ti-doping process, the resulting Ti-doped alpha-Fe2O3 nanosheet arrays showed a good PEC performance for water splitting with a photocurrent density of 1.79 mA/cm(2) at 1.6 V vs RHE under AM 1.5G illumination (100 mW/cm(2)). In contrast, the Ti-doped irregular aggregates of the alpha-Fe2O3 nanograins transformed from dense ferrihydrite branched structures exhibited a much lower photocurrent density (0.41 mA/cm(2) at 1.6 V vs RHE), demonstrating the important influence of the morphology of alpha Fe2O3 photoanodes on the PEC performance. PMID- 26517011 TI - Tailoring sub-micron PLGA particle release profiles via centrifugal fractioning. AB - Poly(D,L-lactic-co -glycolic) acid (PLGA)-based sub-micron particles are uniquely posed to overcome limitations of conventional drug delivery systems. However, tailoring cargo/payload release profiles from PLGA micro/nanoparticles typically requires optimization of the multi-parameter formulation, where small changes may cause drastic shifts in the resulting release profiles. In this study, we aimed to establish whether refining the average diameter of sub-micron particle populations after formulation alters protein release profiles. PLGA particles were first produced via double emulsion-solvent evaporation method to encapsulate bovine serum albumin. Particles were then subjected to centrifugal fractioning protocols varying in both spin time and force to determine encapsulation efficiency and release profile of differently sized populations that originated from a single batch. We found the average particle diameter was related to marked alterations in encapsulation efficiencies (range: 36.4-49.4%), burst release (range: 15.8-49.1%), and time for total cargo release (range: 38-78 days). Our data corroborate previous reports relating PLGA particle size with such release characteristics, however, this is the first study, to our knowledge, to directly compare particle population size while holding all formulation parameters constant. In summary, centrifugal fractioning to selectively control the population distribution of sub-micron PLGA particles represents a feasible tool to tailor release characteristics. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A 104A: 688-696, 2016. PMID- 26517012 TI - Effects of Sleep Deprivation on Mice Bone Marrow and Spleen B Lymphopoiesis. AB - B lymphocytes are immune cells crucial for the maintenance and viability of the humoral response. Sleep is an essential event for the maintenance and integrity of all systems, including the immune system (IS). Thus, sleep deprivation (SD) causes problems in metabolism and homeostasis in many cell systems, including the IS. In this study, our goal was to determine changes in B lymphocytes from the bone marrow (BM) and spleen after SD. Three-month-old male Swiss mice were used. These mice were sleep deprived through the modified multiple platform method for different periods (24, 48, and 72 h), whereas another group was allowed to sleep for 24 h after 72 h of SD (rebound group) and a third group was allowed to sleep normally during the entire experiment. After this, the spleen and BM were collected, and cell analyses were performed. The numbers of B lymphocytes in the BM and spleen were reduced by SD. Additionally, reductions in the percentage of lymphocyte progenitors and their ability to form colonies were observed. Moreover, an increase in the death of B lymphocytes from the BM and spleen was associated with an increase in oxidative stress indicators, such as DCFH-DA, CAT, and mitochondrial SOD. Rebound was not able to reverse most of the alterations elicited by SD. The reduction in B lymphocytes and their progenitors by cell death, with a concomitant increase in oxidative stress, showed that SD promoted a failure in B lymphopoiesis. PMID- 26517013 TI - Direct-to-consumer genetic testing: Perspectives on its value in healthcare. AB - The direct-to-consumer genetic testing debate reached a fever pitch in November 2013 when the US Food and Drug Administration (FDA) instructed 23andMe to discontinue marketing and sale of their Personal Genome Service. In 2015, 23andMe emerged with FDA approval to market a carrier test for Bloom syndrome only, and plans to release additional reports. The dust has settled and it is time to ask: What have we learned, and where do we go from here? PMID- 26517014 TI - Acute pain Factors predictive of post-operative pain and opioid requirement in multimodal analgesia following knee replacement. AB - BACKGROUND: Despite the development of multimodal analgesia for postoperative pain management, opioids are still required for effective pain relief after knee arthroplasty. We aimed to identify the determinants of post-operative pain intensity and post-operative opioid requirement in this context. METHODS: In this observational prospective study, we recorded patient characteristics, pre operative pain intensity, anxiety and depression levels, sensitivity and pain thresholds in response to an electrical stimulus, and mu-opioid receptor (OPRM1) and catechol-O-methyltransferase (COMT) single-nucleotide polymorphisms. Multivariate linear regression models were used to identify predictors of post operative pain at rest and opioid requirement. RESULTS: We included 109 patients. Pre-operative pain at rest (p = 0.047), anxiety level (p = 0.001) and neuropathic pain symptoms (p = 0.030) were independently and positively associated with mean post-operative pain intensity adjusted for mean post-operative morphine equivalent dose (MED). Mean post-operative pain intensity at rest was lower (p = 0.006) in patients receiving celecoxib and pregabalin in the post-operative period, with all other variables constant. Mean post-operative MED over 5 days was low, but highly variable (78.2 +/- 32.1 mg, from 9.9 to 170 mg). Following adjustment for mean post-operative pain intensity, it was independently negatively correlated with age (p = 0.004), and positively correlated with associated paracetamol treatment (p = 0.031). No genetic effect was detected in our sample. CONCLUSIONS: Our findings suggest that clinicians could use the pre operative pain profile, in terms of anxiety levels, neuropathic pain symptoms, and chronic pre-operative pain intensity, to improve the efficacy of pain management after knee surgery. PMID- 26517015 TI - Mass Spectrometric Analysis of Glyoxal and Methylglyoxal-Induced Modifications in Human Hemoglobin from Poorly Controlled Type 2 Diabetes Mellitus Patients. AB - Glyoxal and methylglyoxal are oxoaldehydes derived from the degradation of glucose-protein conjugates and from lipid peroxidation, and they are also present in the environment. This study investigated the site-specific reaction of glyoxal and methylglyoxal with the amino acid residues on human hemoglobin using a shot gun proteomic approach with nanoflow liquid chromatography/nanospray ionization tandem mass spectrometry (nanoLC-NSI/MS/MS). In human hemoglobin incubated with glyoxal, modification on 8 different sites, including lysine residues at alpha Lys-11, alpha-Lys-16, alpha-Lys-56, beta-Lys-17, beta-Lys-66, beta-Lys-144, and arginine residues at alpha-Arg-92 and beta-Arg-30, was observed using a data dependent scan. In methylglyoxal-treated hemoglobin, there were specific residues, namely, alpha-Arg-92, beta-Lys-66, beta-Arg-30, and beta-Lys-144, forming carboxyethylation as well as the dehydrated product hydroimidazolone at alpha-Arg-92 and beta-Arg-30. These lysine and arginine modifications were confirmed by accurate mass measurement and the MS(2) and MS(3) spectra. The most intensive signal of each modified peptide was used as the precursor ion to perform the product ion scan. The relative extent of modifications was semiquantified simultaneously relative to the native reference peptide by nanoLC NSI/MS/MS under the selected reaction monitoring (SRM) mode. The extent of these modifications increased dose-dependently with increasing concentrations of glyoxal or methylglyoxal. Six out of the eight modifications induced by glyoxal and three out of the six modifications induced by methylglyoxal were detected in hemoglobin freshly isolated from human blood samples. The relative extent of modification of these post-translational modifications was quantified in poorly controlled type 2 diabetes mellitus patients (n = 20) and in nondiabetic control subjects (n = 21). The results show that the carboxymethylated peptides at alpha Lys-16, alpha-Arg-92, beta-Lys-17, beta-Lys-66, and the peptide at alpha-Arg-92 with methylglyoxal-derived hydroimidazolone are significantly higher in diabetic patients than in normal individuals (p value <0.05). This report identified and quantified glyoxal- and methylglyoxal-modified hemoglobin peptides in humans and revealed the association of the extent of modifications at specific sites with T2DM. Only one drop (10 MUL) of fresh blood is needed for this assay, and only an equivalent of 1 MUg of hemoglobin was analyzed by the nanoLC-NSI/MS/MS-SRM system. These results suggest the potential use of these specific post translational modifications in hemoglobin as feasible biomarker candidates to assess protein damage induced by glyoxal and methylglyoxal. PMID- 26517017 TI - Reply. PMID- 26517016 TI - DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection. AB - Chronic hepatitis C virus (HCV) infection may progress to cirrhosis and hepatocellular carcinoma (HCC). Recently, two genetic variants, DEPDC5 rs1012068 and MICA rs2596542, were associated with the onset of HCC in Asian subjects with chronic HCV infection. The aim of the present study was to analyze whether DEPDC5 and MICA genetic variants were associated with liver disease progression in European subjects with chronic HCV infection. In a Northern Italian discovery cohort (n = 477), neither DEPDC5 rs1012068 nor MICA rs2596542 were associated with HCC (n = 150). However, DEPDC5 rs1012068 was independently associated with cirrhosis (n = 300; P = 0.049). The association of rs1012068 with moderate to severe fibrosis was confirmed in an independent cross-sectional German cohort (n = 415; P = 0.006). Furthermore, DEPDC5 rs1012068 predicted faster fibrosis progression in a prospective cohort (n = 247; P = 0.027). Next, we examined the distribution of nonsynonymous DEPDC5 variants in the overall cross-sectional cohort (n = 912). The presence of at least one variant increased the risk of moderate/severe fibrosis by 54% (P = 0.040). To understand the molecular mechanism underlying the genetic association of DEPDC5 variants with fibrosis progression, we performed in vitro studies on immortalized hepatic stellate cells (LX-2). In these cells, down-regulation of DEPDC5 resulted in increased expression of beta-catenin and production of its target matrix metallopeptidase 2 (MMP2), a secreted enzyme involved in fibrosis progression. CONCLUSION: DEPDC5 variants increase fibrosis progression in European subjects with chronic HCV infection. Our findings suggest that DEPDC5 down-regulation may contribute to HCV related fibrosis by increasing MMP2 synthesis through the beta-catenin pathway. PMID- 26517018 TI - Reactions of 1,3-Diketones with a Dipeptide Isothiazolidin-3-one: Toward Agents That Covalently Capture Oxidized Protein Tyrosine Phosphatase 1B. AB - Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for the treatment of type 2 diabetes; however, the enzyme has been classified by some as an "undruggable target". Here we describe studies directed toward the development of agents that covalently capture the sulfenyl amide "oxoform" of PTP1B generated during insulin signaling events. The sulfenyl amide residue found in oxidized PTP1B presents a unique electrophilic sulfur center that may be exploited in drug and probe design. Covalent capture of oxidized PTP1B could permanently disable the intracellular pool of enzyme involved in regulation of insulin signaling. Here, we employed a dipeptide model of oxidized PTP1B to investigate the nucleophilic capture of the sulfenyl amide residue by structurally diverse 1,3 diketones. All of the 1,3-diketones examined here reacted readily with the electrophilic sulfur center in the sulfenyl amide residue to generate stable covalent attachments. Several different types of products were observed, depending upon the substituents present on the 1,3-diketone. The results provide a chemical foundation for the development of agents that covalently capture the oxidized form of PTP1B generated in cells during insulin signaling events. PMID- 26517019 TI - Synthesis and Biological Evaluation of Chlorinated Analogs of Leukotoxin Diol. AB - This study documents that chlorinated analogs of leukotoxin diol 1, in which the vic-diol has been replaced with vic-chlorides (2), induce caspase 3 activity and apoptosis on HepG2 cells in a dose-dependent manner in analogy to the parent diol. This suggests that chlorides may substitute for hydroxyls in certain lipids as bioisosteres in defined biological settings. PMID- 26517021 TI - Session 1 - joint opening session. PMID- 26517020 TI - The Impact of Peripheral Nerve Stimulation on Disability and Depression. AB - BACKGROUND: Peripheral nerve stimulation (PNS) of the named nerves of the head has been shown to be effective in reducing pain levels in patients with chronic pain refractory to other treatments. However, the impact of cranial PNS on depression and disability has not been well documented. OBJECTIVES: We prospectively examine the impact of PNS on quality of life via validated survey scores which assess symptoms of depression and daily functional capacities within patients. METHODS: Patients who underwent permanent PNS implantation completed five validated questionnaires: Oswestry Disability Index (ODI), the Beck's Depression Inventory (BDI), the Pain Catastrophizing Scale (PCS), McGill Pain Questionnaire (MPQ), and the visual analog scale (VAS) score. These were completed at baseline, six months, and one year to assess changes in functioning levels. Results were analyzed via repeated measures ANOVA and bivariate analysis. RESULTS: Compared with baseline, at six months patients showed significantly less depression on BDI (F = 7.9, p = 0.021), and at one year, a significant decrease in disability was observed on the ODI (F = 6.1, p = 0.036). At both six months and one year, patients showed a significant decrease in pain on VAS (F = 16.5, p = 0.012). We noted a trend for ODI to correlate with BDI at six months (R = 0.616, p = 0.077). DISCUSSION: Our prospective data show PNS to be an effective modality in improving overall life quality by limiting depression and disability as well as pain. PMID- 26517022 TI - Theme 1 Clinical Management. PMID- 26517023 TI - Theme 2 ALS Heterogeneity and Disease Progression. PMID- 26517024 TI - Theme 3 Biomarkers and Outcome Measures. PMID- 26517025 TI - Theme 4 Imaging and Electrophysiology. PMID- 26517026 TI - Theme 5 Cognitive Change. PMID- 26517027 TI - Theme 6 Respiratory and Nutritional Management. PMID- 26517028 TI - Theme 7 Quality of Life and Palliative Care. PMID- 26517029 TI - Theme 8 Epidemiology. PMID- 26517030 TI - Theme 9 Genetics. PMID- 26517031 TI - Theme 10 Molecular Cell Biology. PMID- 26517032 TI - Theme 11 ALS Pathogenesis and Neurotoxicity. PMID- 26517033 TI - Theme 12 In vitro Experimental Models. PMID- 26517034 TI - Theme 13 In vivo Experimental Models. PMID- 26517035 TI - Theme 14 Therapeutic Strategies. PMID- 26517038 TI - Corrigendum: Total Synthesis of Antitumor Antibiotic Derhodinosylurdamycin A. PMID- 26517040 TI - Efficient Automated Solid-Phase Synthesis of DNA and RNA 5'-Triphosphates. AB - A fast, high-yielding and reliable method for the synthesis of DNA- and RNA 5' triphosphates is reported. After synthesizing DNA or RNA oligonucleotides by automated oligonucleotide synthesis, 5-chloro-saligenyl-N,N diisopropylphosphoramidite was coupled to the 5'-end. Oxidation of the formed 5' phosphite using the same oxidizing reagent used in standard oligonucleotide synthesis led to 5'-cycloSal-oligonucleotides. Reaction of the support-bonded 5' cycloSal-oligonucleotide with pyrophosphate yielded the corresponding 5' triphosphates. The 5'-triphosphorylated DNA and RNA oligonucleotides were obtained after cleavage from the support in high purity and excellent yields. The whole reaction sequence was adapted to be used on a standard oligonucleotide synthesizer. PMID- 26517043 TI - Molecular typing of Mycoplasma pneumoniae: where do we stand? PMID- 26517044 TI - Importance of Endogenous Atrial and Brain Natriuretic Peptides in Murine Embryonic Vascular and Organ Development. AB - Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) bind to the receptor guanylyl cyclase (GC)-A, leading to diuresis, natriuresis, and blood vessel dilation. In addition, ANP and BNP have various angiogenic properties in ischemic tissue. When breeding mice devoid of GC-A, we noted significant skewing of the Mendelian ratio in the offspring, suggesting embryonic lethality due to knockout of GC-A. Consequently, we here investigated the roles of endogenous ANP and BNP in embryonic neovascularization and organ morphogenesis. Embryos resulting from GC-A(-/-) * GC-A(+/-) crosses developed hydrops fetalis (HF) beginning at embryonic day (E)14.5. All embryos with HF had the genotype GC-A(-/ ). At E17.5, 33.3% (12 of 36) of GC-A(-/-) embryos had HF, and all GC-A(-/-) embryos with HF were dead. Beginning at E16.0, HF-GC-A(-/-) embryos demonstrated poorly developed superficial vascular vessels and sc hemorrhage, the fetal side of the placenta appeared ischemic, and vitelline vessels on the yolk sac were poorly developed. Furthermore, HF-GC-A(-/-) embryos also showed abnormal constriction of umbilical cord vascular vessels, few cardiac trabeculae and a thin compact zone, hepatic hemorrhage, and poor bone development. Electron microscopy of E16.5 HF-GC-A(-/-) embryos revealed severe vacuolar degeneration in endothelial cells, and the expected 3-layer structure of the smooth muscle wall of the umbilical artery was indistinct. These data demonstrate the importance of the endogenous ANP/BNP-GC-A system not only in the neovascularization of ischemic tissues but also in embryonic vascular development and organ morphogenesis. PMID- 26517045 TI - beta1-Adrenergic and M2 Muscarinic Autoantibodies and Thyroid Hormone Facilitate Induction of Atrial Fibrillation in Male Rabbits. AB - Activating autoantibodies to the beta1-adrenergic and M2 muscarinic receptors are present in a very high percentage of patients with Graves' disease and atrial fibrillation (AF). The objective of this study was to develop a reproducible animal model and thereby to examine the impact of these endocrine-like autoantibodies alone and with thyroid hormone on induction of thyroid-associated atrial tachyarrhythmias. Five New Zealand white rabbits were coimmunized with peptides from the second extracellular loops of the beta1-adrenergic and M2 muscarinic receptors to produce both sympathomimetic and parasympathomimetic antibodies. A catheter-based electrophysiological study was performed on anesthetized rabbits before and after immunization and subsequent treatment with thyroid hormone. Antibody expression facilitated the induction of sustained sinus, junctional and atrial tachycardias, but not AF. Addition of excessive thyroid hormone resulted in induced sustained AF in all animals. AF induction was blocked acutely by the neutralization of these antibodies with immunogenic peptides despite continued hyperthyroidism. The measured atrial effective refractory period as one parameter of AF propensity shortened significantly after immunization and was acutely reversed by peptide neutralization. No further decrease in the effective refractory period was observed after the addition of thyroid hormone, suggesting other cardiac effects of thyroid hormone may contribute to its role in AF induction. This study demonstrates autonomic autoantibodies and thyroid hormone potentiate the vulnerability of the heart to AF, which can be reversed by decoy peptide therapy. These data help fulfill Witebsky's postulates for an increased autoimmune/endocrine basis for Graves' hyperthyroidism and AF. PMID- 26517046 TI - Beneficial effect of D-allose for isolated islet culture prior to islet transplantation. AB - BACKGROUND: Pretransplant restoration of islets damaged during isolation remains to be solved. In this study, we examined the effect of D-allose on islets isolated from rat pancreata prior to islet transplantation. METHODS: Rat islets isolated from fresh pancreata were cultured overnight in Roswell Park Memorial Institute 1640 solution in the absence (group 1) or presence (group 2) of D allose. Then we assessed stimulation index of insulin, and cure rate after islet transplantation to diabetic nude mice. We also measured malondialdehyde level and caspase 3 activity of islets after the overnight culture for assessment of the oxidative stress and the apoptosis. RESULTS: D-allose significantly improved insulin secretion of islets. The stimulation index in group 2 was significantly higher than in group 1. Cure rate after transplantation in group 2 was higher than in group 1 especially in the first week. The malondialdehyde level in group 2 was significantly lower than in group 1. But the caspase 3 activities in both groups did not differ. CONCLUSIONS: D-allose treatment of isolated islet culture prior to transplantation restored islet function and increased successful transplant rate. The results of this study suggested that D-allose improved function of damaged islets through its anti-oxidative activity. PMID- 26517047 TI - Handwriting as a marker for PD progression: a shift in paradigm. PMID- 26517048 TI - Counteracting PINK/Parkin Deficiency in the Activation of Mitophagy: A Potential Therapeutic Intervention for Parkinson's Disease. AB - Parkinson's Disease (PD) related genes PINK1, a protein kinase [1], and Parkin, an E3 ubiquitin ligase [2], operate within the same pathway [3-5], which controls, via specific elimination of dysfunctional mitochondria, the quality of the organelle network [6]. Parkin translocates to impaired mitochondria and drives their elimination via autophagy, a process known as mitophagy [6]. PINK1 regulates Parkin translocation through a not yet completely understood mechanism [7, 8]. Mitochondrial outer membrane proteins Mitofusin (MFN), VDAC, Fis1 and TOM20 were found to be targets for Parkin mediated ubiquitination [9-11]. By adding ubiquitin molecules to its targets expressed on mitochondria, Parkin tags and selects dysfunctional mitochondria for clearance, contributing to maintain a functional and healthy mitochondrial network. Abnormal accumulation of misfolded proteins and unfunctional mitochondria is a characteristic hallmark of PD pathology. Therefore a therapeutic approach to enhance clearance of misfolded proteins and potentiate the ubiquitin-proteosome system (UPS) could be instrumental to ameliorate the progression of the disease. Recently, much effort has been put to identify specific de-ubiquitinating enzymes (DUBs) that oppose Parkin in the ubiquitination of its targets. Similar to other post-translational modifications, such as phosphorylation and acetylation, ubiquitination is also a reversible modification, mediated by a large family of DUBs [12]. DUBs inhibitors or activators can affect cellular response to stimuli that induce mitophagy via ubiquitination of mitochondrial outer membrane proteins MFN, VDAC, Fis1 and TOM20. In this respect, the identification of a Parkin-opposing DUB in the regulation of mitophagy, might be instrumental to develop specific isopeptidase inhibitors or activators that can modulate the fundamental biological process of mitochondria clearance and impact on cell survival. PMID- 26517049 TI - Modulating the Amyloidogenesis of alpha-Synuclein. AB - Alpha-Synuclein is found in the neuronal cells but its native function is not well known. While alpha -synuclein is an intrinsically disordered protein that adopts a helical conformation upon membrane binding, numerous studies have shown that oligomeric beta-forms of this protein are cytotoxic. This response to misfolded species contributes to Parkinson's Disease etiology and symptoms. The resulting amyloid fibrils are an established diagnostic in Parkinson's Disease. In this review, we focus on strategies that have been used to inhibit the amyloidogenesis of alpha -synuclein either by stabilizing the native state, or by redirecting the pathway to less toxic aggregates. Small molecules such as polyphenols, peptides as well as large proteins have proven effective at protecting cells against the cytotoxicity of alpha-synuclein. These strategies may lead to the development of therapeutic agents that could prove useful in combating this disease. PMID- 26517050 TI - Targeting the Autophagy/Lysosomal Degradation Pathway in Parkinson's Disease. AB - Autophagy is a cellular quality control mechanism crucial for neuronal homeostasis. Defects in autophagy are critically associated with mechanisms underlying Parkinson's disease (PD), a common and debilitating neurodegenerative disorder. Autophagic dysfunction in PD can occur at several stages of the autophagy/lysosomal degradative machinery, contributing to the formation of intracellular protein aggregates and eventual neuronal cell death. Therefore, autophagy inducers may comprise a promising new therapeutic approach to combat neurodegeneration in PD. Several currently available FDA-approved drugs have been shown to enhance autophagy, which may allow for their repurposing for use in novel clinical conditions including PD. This review summarizes our current knowledge of deficits in the autophagy/lysosomal degradation pathways associated with PD, and highlight current approaches which target this pathway as possible means towards novel therapeutic strategies. PMID- 26517051 TI - LRRK2 Kinase Inhibition as a Therapeutic Strategy for Parkinson's Disease, Where Do We Stand? AB - One of the most promising therapeutic targets for potential disease-modifying treatment of Parkinson's disease (PD) is leucine-rich repeat kinase 2 (LRRK2). Specifically, targeting LRRK2's kinase function has generated a lot of interest from both industry and academia. This work has yielded several published studies showing the feasibility of developing potent, selective and brain permeable LRRK2 kinase inhibitors. The availability of these experimental drugs is contributing to filling in the gaps in our knowledge on the safety and efficacy of LRRK2 kinase inhibition. Recent studies of LRRK2 kinase inhibition in preclinical models point to potential undesired effects in peripheral tissues such as lung and kidney. Also, while strategies are now emerging to measure target engagement of LRRK2 inhibitors, there remains an important need to expand efficacy studies in preclinical models of progressive PD. Future work in the LRRK2 inhibition field must therefore be directed towards developing molecules and treatment regimens which demonstrate efficacy in mammalian models of disease in conditions where safety liabilities are reduced to a minimum. PMID- 26517053 TI - C. elegans and Arabidopsis thaliana show similar behavior: ROS induce escape tropisms both in illuminated nematodes and roots. PMID- 26517054 TI - GIP/MZT1 proteins: Key players in centromere regulation. PMID- 26517052 TI - Anti-Oxidants in Parkinson's Disease Therapy: A Critical Point of View. AB - Parkinson's disease (PD) is a degenerative neurological syndrome, which is characterized by the preferential death of dopaminergic (DAergic) neurons in the Substantia Nigra. The pathogenesis of this disorder remains poorly understood and PD is still incurable. Current drug treatments are aimed primarily for the treatment of symptoms to improve the quality of life. Therefore, there is a need to find out new therapeutic strategies that not only provide symptomatic relief but also halt or reverse the neuronal damage hampering PD progression. Oxidative stress has been identified as one of the major contributors for the nigral loss in both sporadic and genetic forms of PD. In this review we first evaluate the current literature that links oxidative stress and mitochondrial dysfunction to PD. We then consider the results obtained through the treatment of animal models or PD patients with molecules that prevent oxidative stress or reduce mitochondrial dysfunction. PMID- 26517055 TI - Temporal change in prevalence and complications of uveitis associated with juvenile idiopathic arthritis:data from a cross-sectional analysis of a prospective nationwide study. AB - OBJECTIVES: To analyse the nationwide prevalence of uveitis in JIA and its complications over a whole decade. METHODS: We conducted a prospective, observational and cross-sectional study including all JIA patients from a National Paediatric Rheumatological Database (NPRD) with a uveitis add-on module in Germany (2002-2013). Temporal changes in uveitis prevalence, related secondary complications and anti-inflammatory medication were evaluated. RESULTS: A total of 60 centres including 18,555 JIA patients (mean 3,863 patients/year, SD=837) were documented in the NPRD between 2002 and 2013. The mean age of the patients was 11.4 +/- 4.6 years, their mean disease duration 4.4 +/- 3.7 years. Among them, 66.9% were female and 51.7% ANA positive. Patients' mean age at arthritis onset was 6.9 +/- 4.5 years. Treatment rates with synthetic and biological DMARDs increased during the observation period (sDMARD: 39.8% to 47.2%, bDMARD: 3.3% to 21.8%). Uveitis prevalence decreased significantly from 2002 to 2013 (13.0% to 11.6%, OR = 0.98, p=0.015). The prevalence of secondary uveitis complications also decreased significantly between 2002 and 2013 (33.6% to 23.9%, OR=0.94, p<0.001). Among the complications, the most common ones were posterior synechiae, cataract and band keratopathy. A significant increase in achieving uveitis inactivity was observed at 30.6% in 2002 and 65.3% in 2013 (OR=1.15, p<0.001). CONCLUSIONS: Uveitis prevalence and complications significantly decreased between 2002 and 2013. This may be associated with a more frequent use of DMARDs. PMID- 26517056 TI - Intraoperative neurophysiological monitoring during endoscopic endonasal surgery for pediatric skull base tumors. AB - OBJECT The aim of this study was to evaluate the value of intraoperative neurophysiological monitoring (IONM) using electromyography (EMG), brainstem auditory evoked potentials (BAEPs), and somatosensory evoked potentials (SSEPs) to predict and/or prevent postoperative neurological deficits in pediatric patients undergoing endoscopic endonasal surgery (EES) for skull base tumors. METHODS All consecutive pediatric patients with skull base tumors who underwent EES with at least 1 modality of IONM (BAEP, SSEP, and/or EMG) at our institution between 1999 and 2013 were retrospectively reviewed. Staged procedures and repeat procedures were identified and analyzed separately. To evaluate the diagnostic accuracy of significant free-run EMG activity, the prevalence of cranial nerve (CN) deficits and the sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS A total of 129 patients underwent 159 procedures; 6 patients had a total of 9 CN deficits. The incidences of CN deficits based on the total number of nerves monitored in the groups with and without significant free-run EMG activity were 9% and 1.5%, respectively. The incidences of CN deficits in the groups with 1 staged and more than 1 staged EES were 1.5% and 29%, respectively. The sensitivity, specificity, and negative predictive values (with 95% confidence intervals) of significant EMG to detect CN deficits in repeat procedures were 0.55 (0.22-0.84), 0.86 (0.79-0.9), and 0.97 (0.92-0.99), respectively. Two patients had significant changes in their BAEPs that were reversible with an increase in mean arterial pressure. CONCLUSIONS IONM can be applied effectively and reliably during EES in children. EMG monitoring is specific for detecting CN deficits and can be an effective guide for dissecting these procedures. Triggered EMG should be elicited intraoperatively to check the integrity of the CNs during and after tumor resection. Given the anatomical complexity of pediatric EES and the unique challenges encountered, multimodal IONM can be a valuable adjunct to these procedures. PMID- 26517057 TI - Endoscopic third ventriculostomy and choroid plexus cauterization with a rigid neuroendoscope in infants with hydrocephalus. AB - OBJECT Combining endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) has been shown to improve the success rate compared with ETV alone in infants (less than 24 months) with hydrocephalus who were treated in developing countries. The authors sought to evaluate the safety and efficacy of this procedure, using a rigid neuroendoscope, in a single North American center, and to assess whether the ETV success score (ETVSS), the CURE Children's Hospital of Uganda ETVSS (CCHU ETVSS), and other pre- and intraoperative variables could predict success. METHODS The authors performed a retrospective review of consecutive ETV/CPC procedures performed using a rigid neuroendoscope to treat infantile hydrocephalus. The infants underwent the procedure at Miami Children's Hospital between January 2007 and 2014, with at least one postoperative follow up. Duration of follow-up or time to failure of ETV/CPC, the primary outcome measure, was documented. A repeat CSF diversion procedure or death was considered as a failure of ETV/CPC. The time to event was measured using a Kaplan-Meier analysis. The authors analyzed ETVSS, CCHU ETVSS, and pre- and intraoperative variables to determine their suitability to predict success. RESULTS Eighty-five patients (45 boys) with a mean age of 4.3 months (range 1 day to 20 months) underwent ETV/CPC. Etiology included intraventricular hemorrhage of prematurity in 44 patients (51.7%), myelomeningocele (MMC) in 7 (8.2%), congenital aqueductal stenosis in 12 (14.1%), congenital communicating hydrocephalus in 6 (7.1%), Dandy Walker complex in 6 (7.1%), postinfectious hydrocephalus in 5 (5.8%), and other cause in 5 (5.8%). Six procedure-related complications occurred in 5 (5.8%) patients, including 2 hygromas, 1 CSF leak, and 3 infections. There were 3 mortalities in this cohort. ETV/CPC was successful in 42.1%, 37.7%, and 36.8% of patients at 6, 12, and 24 months follow-up, respectively. The median (95% CI) time to ETV/CPC failure was 4.0 months (0.9-7.1 months). In univariate analyses, both the ETVSS (hazard ratio [HR] 1.03; 95% CI 1.01-1.05; p = 0.004) and CCHU ETVSS (HR 1.48; 95% CI 1.04-2.09; p = .028) were predictive of outcome following ETV/CPC. In multivariate analysis, the presence of prepontine scarring was associated with ETV/CPC failure (HR 0.34; 95% CI 0.19-0.63; p < 0.001). Other variables, such as radiological criteria (prepontine interval, prepontine space, aqueductal stenosis, Third Ventricular Morphology Index) and intraoperative findings (ventriculostomy pulsations, extent of CPC), did not predict outcome. CONCLUSIONS ETV/CPC is a feasible alternative to ETV and ventriculoperitoneal shunt in infants with hydrocephalus. Both the ETVSS and CCHU ETVSS predicted success following ETV/CPC in this single-center North American cohort of patients. PMID- 26517058 TI - Postoperative imaging for detection of recurrent arteriovenous malformations in children. AB - OBJECT The optimal method for detecting recurrent arteriovenous malformations (AVMs) in children is unknown. An inherent preference exists for MR angiography (MRA) surveillance rather than arteriography. The validity of this strategy is uncertain. METHODS A retrospective chart review was performed on pediatric patients treated for cerebral AVMs at a single institution from 1998 to 2012. Patients with complete obliteration of the AVM nidus after treatment and more than 12 months of follow-up were included in the analysis. Data collection focused on recurrence rates, associated risk factors, and surveillance methods. RESULTS A total of 45 patients with a mean age of 11.7 years (range 0.5-18 years) were treated for AVMs via surgical, endovascular, radiosurgical, or combined approaches. Total AVM obliteration on posttreatment digital subtraction angiography (DSA) was confirmed in 27 patients, of whom the 20 with more than 12 months of follow-up were included in subsequent analysis. The mean follow-up duration in this cohort was 5.75 years (median 5.53 years, range 1.11-10.64 years). Recurrence occurred in 3 of 20 patients (15%). Two recurrences were detected by surveillance DSA and 1 at the time of rehemorrhage. No recurrences were detected by MRA. Median time to recurrence was 33.6 months (range 19-71 months). Two patients (10%) underwent follow-up DSA, 5 (25%) had DSA and MRI/MRA, 9 (45%) had MRI/MRA only, 1 (5%) had CT angiography only, and 3 (15%) had no imaging within the first 3 years of follow-up. After 5 years posttreatment, 2 patients (10%) were followed with MRI/MRA only, 2 (10%) with DSA only, and 10 (50%) with continued DSA and MRI/MRA. CONCLUSIONS AVM recurrence in children occurred at a median of 33.6 months, when MRA was more commonly used for surveillance, but failed to detect any recurrences. A recurrence rate of 15% may be an underestimate given the reliance on surveillance MRA over angiography. A new surveillance strategy is proposed, taking into account exposure to diagnostic radiation and the potential for catastrophic rehemorrhage. PMID- 26517059 TI - Improvement of syrinx resolution after tonsillar cautery in pediatric patients with Chiari Type I malformation. AB - OBJECT Chiari Type I malformation involves caudal displacement of the cerebellar tonsils below the foramen magnum, which obstructs normal cerebrospinal fluid flow and increases intracranial pressure. Certain aspects of its surgical treatment remain controversial. A retrospective study was conducted to assess the efficacy of tonsillar cautery on syrinx resolution among pediatric Chiari patients undergoing cervicomedullary decompression. METHODS A retrospective cohort study was performed for patients 0-18 years of age who underwent surgical correction for Chiari Type I malformation with syrinx between 1995 and 2013. Basic demographic information was collected as well as data for preoperative symptoms, prior surgical history, perioperative characteristics, and postsurgical outcomes. Descriptive statistics were performed in addition to bivariate analyses. Candidate predictor variables were identified based on an association with tonsillar cautery with p < 0.10. Forward stepwise likelihood ratio was used to select candidate predictors in a binary logistic regression model (Pin = 0.05, Pout = 0.10) most strongly associated with the outcome. RESULTS A total of 171 patients with Chiari Type I malformation with syrinx were identified, and 43 underwent tonsillar cautery. Patients who underwent tonsillar cautery had 6.11 times greater odds of improvement in their syrinx (95% CI 2.57-14.49, p < 0.001). There was no effect of tonsillar cautery on increased perioperative complications as well as the need for repeat decompressions. CONCLUSIONS Tonsillar cautery is safe and effective in the treatment of Chiari Type I malformation with syrinx and may decrease time to syrinx resolution after cervicomedullary decompression. Tonsillar cautery does not increase postoperative complications in pediatric Chiari Type I malformation patients. PMID- 26517060 TI - Use of subtransverse process polyester bands in pediatric spine surgery: a case series of 4 patients with a minimum of 12 months' follow-up. AB - OBJECT In a previous study, the authors reported on their experience with the use of sublaminar polyester bands as part of segmental spinal constructs. However, the risk of neurological complications with sublaminar passage of instrumentation, such as spinal cord injury, limits the use of this technique. The present study reports the novel use of subtransverse process polyester bands in posterior instrumented spinal fusions of the thoracic and lumbar spines and sacrum or ilium in 4 patients. METHODS The authors retrospectively reviewed the demographic and procedural data of patients who had undergone posterior instrumented fusion using subtransverse process polyester bands. RESULTS Four patients, ranging in age from 11 to 22 years, underwent posterior instrumented fusion for neuromuscular scoliosis (3 patients) and thoracic hyperkyphosis (1 patient). There were 3 instances of transverse process fracture, with application and tensioning of the polyester band in 1 patient. Importantly, there was no instance of spinal cord injury with subtransverse process passage of the polyester band. The lessons learned from this technique are discussed. CONCLUSIONS This study has shown the "Eleghia" technique of passing subtransverse process bands to be a technically straightforward and neurologically safe method of spinal fixation. Pedicle screws, laminar/pedicle/transverse process hooks, and sublaminar metal wires/bands have been incorporated into posterior spinal constructs; they have been widely reported and used in the thoracic and lumbar spines and sacrum or ilium with varying success. This report demonstrates the promising results of hybrid posterior spinal constructs that include the Eleghia technique of passing subtransverse process polyester bands. This technique incorporates technical ease with minimal risk of neurological injury and biomechanical stability. PMID- 26517061 TI - Intrathecal baclofen trials: complications and positive yield in a pediatric cohort. AB - OBJECT Intrathecal baclofen (ITB) is an effective management option for childhood hypertonia. Given the potential complications of implanted ITB pumps, trials of ITB are usually performed as part of the workup for ITB pumps. Two methods are used for ITB trials, lumbar puncture (LP) and catheter insertion into the intrathecal space. Little has been written to date on the number of positive trials and complications in trials. This study aimed to report the outcomes and complications in ITB trials for childhood hypertonia (dystonia, spastic, or mixed). METHODS A retrospective case notes review was conducted of all patients who underwent ITB trials at the Evelina London Children's Hospital between 2005 and 2012 (inclusive). Positive trials were defined as a reduction in Modified Ashworth Scale by a minimum of 1 point in at least 2 muscle groups and improvement reported by the caregivers in the areas of goals agreed upon between professionals and the families. RESULTS Our patient group comprised children with dystonia (n = 7), mixed spasticity/dystonia (n = 29), spasticity (n = 4), and pain (n = 1). A total of 47 trials were attempted in 41 children. Forty trials were successfully completed, with 39 being positive. Thirty-three were catheter trials, and 14 were LPs. The overall complication rate in the 47 attempted trials was 53%: 61% in catheter trials, and 36% in LP trials. This difference was not statistically significant. The most common complications were vomiting (n = 9) and CSF leak (n = 4). The most serious complication was meningitis (n = 1) in a catheter trial. No patients experienced a permanent injury. CONCLUSIONS There is a high risk of minor self-limiting complications with ITB trials, which needs to be factored into the decision process of progression to trials. The rate of positive trials in this study was 98%, of which 21% did not progress to pump implantation. While the authors would still advocate for ITB trials prior to ITB pump insertion to aid parental decision-making, this figure suggests that with good patient selection, ITB pumps could be placed without a preceding trial. PMID- 26517062 TI - Utilizing Geographic Information Systems to Identify Clusters of Severe Sepsis Patients Presenting in the Out-of-Hospital Environment. AB - Understanding the geographic distribution of critical illness within a community may provide public health stakeholders with information that can be used to expedite access to specialized care. We hypothesized that severe sepsis patients transported by emergency medical services (EMS) exhibit geospatial clustering and that prehospital providers would recognize sepsis more frequently in patients transported from sepsis clusters. Retrospective review of a prospective, observational study of patients with severe sepsis transported to the emergency department (ED) by EMS and treated with early goal-directed therapy (EGDT). INCLUSION CRITERIA: suspected infection, 2 or more criteria for systemic inflammation, and either systolic blood pressure <90 mmHg after a fluid bolus or lactate >4 mmol/liter. EXCLUSION CRITERIA: age <18 or need for immediate surgery. Patient location at the time of EMS activation was recorded. Analysis of the addresses identified clusters, defined as a location in which EMS transported more than one patient experiencing the above associated signs and symptoms of septic shock. Other data collected included self-reported patient location as private residence or chronic care facility. One hundred sixty severe sepsis patients transported by EMS were eligible for analysis, presenting from 125 locations. Ninety-one patients (57%) presented from a private residence and 69 (37%) from a chronic care facility. Fifty (31%) patients were transported from 15 locations, with 25 of those transported from just 4 locations. Cluster patients tended to be older, come from medical facilities, and were more likely to have sepsis recognized by prehospital providers. Results from this study demonstrate low pre-hospital recognition of sepsis, as well as geospatially clustered presentations, most notably from skilled nursing facilities. Community education, public health initiatives, and EMS interventions could be targeted in such clusters of cases in order to both improve sepsis recognition and potentially expedite time-sensitive interventions. PMID- 26517063 TI - Noncoding Control Region Pattern of BK polyomavirus in Kidney Transplant Patients With Nephropathy. AB - OBJECTIVES: Adaptation of BK polyomavirus with infected host cells may cause rearrangement of the noncoding control region of viral genomic DNA. Archetype, the prearranged transmissible form of the virus, actively replicates in the tubular epithelial cells, whereas isolates with rearranged noncoding control region sequences are found in other parts of the kidney. Clinical observations highlighted the importance of the noncoding control region rearrangements in BK virus-associated nephropathy. Therefore, we evaluated the sequence pattern of the noncoding control region in kidney transplant patients suspected of having BK virus-associated nephropathy. MATERIALS AND METHODS: In this single-center, cross sectional study, 129 kidney transplant patients suspected of having BK virus associated nephropathy and who were admitted to Namazi Hospital were enrolled for analysis between years 2010 and 2013. Blood samples were collected from each patient. The BK polyomavirus infection was diagnosed using quantitative real-time polymerase chain reaction. The BK polyomavirus-infected patient plasma samples were amplified using in-house nested polymerase chain reaction and sequenced. The contiguous alignment noncoding control region sequences were analyzed with software. RESULTS: The BK polyomavirus infection was observed in plasma samples of 11 of 129 (8.5%) patients after kidney transplant. Sequence alignments showed that BK polyomavirus noncoding control region sequences in all viral infected patients with BK virus-associated nephropathy showed a complete rearranged algorithm compared with the archetype sequences. The most prevalent noncoding control region sequences were registered in a genetic sequence database (National Institutes of Health). No association was observed between risk factors and BK polyomavirus infection. There were 3 BK polyomavirus-infected patients who simultaneously had active cytomegalovirus infection. CONCLUSIONS: Determination of the rearranged pattern of the noncoding control region sequences in BK polyomavirus isolates from plasma samples may help improve the diagnostic and therapeutic protocols against this viral infection in patients with BK virus associated nephropathy. PMID- 26517064 TI - Challenges of the management of severe hemophilia A with inhibitors: two case reports emphasizing the potential interest of a high-purity human Factor VIII/von Willebrand factor concentrate and individually tailored prophylaxis guided by thrombin-generation test. AB - Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI. PMID- 26517065 TI - Factor VII Tokushima: the first case of factor VII Cys22Gly with the development of myocardial infarction in the proband receiving recombinant factor VIIa replacement therapy. AB - An 81-year-old man was referred to our department because of suspected factor VII (FVII) deficiency. His FVII activity was under 1%, whereas the FVII activity levels of his son and granddaughter were 65 and 109%, respectively. The nucleotide at position 3886 of his FVII gene was homozygous for G. A single T to G substitution results in the replacement of wild-type Cys at residue 22 by Gly. His son was heterozygous for G and T at position 3886, whereas his granddaughter was homozygous for wild-type T. These results suggest that he was homozygous for FVII Cys22Gly. He underwent radiofrequency ablation (RFA) for hepatocellular carcinoma, receiving 20 MUg/kg of recombinant FVIIa prior to RFA and 10 MUg/kg of recombinant FVIIa twice after RFA. He showed no bleeding tendency; however, a myocardial infarction was diagnosed and percutaneous coronary intervention was performed. PMID- 26517066 TI - Acquired factor VIII inhibitor and subsequent development of non-Hodgkin's lymphoma: a case report and review of the literature. AB - Acquired hemophilia A (AHA) is a rare disorder caused by the development of factor VIII autoantibodies. It can induce acute and major hemorrhages in patients with negative personal and family history of bleeding. AHA is frequently associated with hematologic malignancies. This study describes the first case of AHA in a patient who developed a mantle cell lymphoma after a year and half of complete remission. It also provides an example of an initial wrong approach in terms of diagnosis and treatment, as well as of a very long course of the disease. Further, a review of AHA-associated lymphomas from 1974 to 2014 is also presented.Clinical and laboratory staff should be alert to the possibility of such an event when the medical history of patients is enriched with new symptoms or signs. A follow-up of at least 2 years might therefore be required. PMID- 26517067 TI - Severe female hemophilia A patient caused by a nonsense mutation (p.Gln1686X) of F8 gene combined with skewed X-chromosome inactivation. PMID- 26517069 TI - Combined fuzzy logic and random walker algorithm for PET image tumor delineation. AB - PURPOSE: The random walk (RW) technique serves as a powerful tool for PET tumor delineation, which typically involves significant noise and/or blurring. One challenging step is hard decision-making in pixel labeling. Fuzzy logic techniques have achieved increasing application in edge detection. We aimed to combine the advantages of fuzzy edge detection with the RW technique to improve PET tumor delineation. METHODS: A fuzzy inference system was designed for tumor edge detection from RW probabilities. Three clinical PET/computed tomography datasets containing 12 liver, 13 lung, and 18 abdomen tumors were analyzed, with manual expert tumor contouring as ground truth. The standard RW and proposed combined method were compared quantitatively using the dice similarity coefficient, the Hausdorff distance, and the mean standard uptake value. RESULTS: The dice similarity coefficient of the proposed method versus standard RW showed significant mean improvements of 21.0+/-7.2, 12.3+/-5.8, and 18.4%+/-6.1% for liver, lung, and abdominal tumors, respectively, whereas the mean improvements in the Hausdorff distance were 3.6+/-1.4, 1.3+/-0.4, 1.8+/-0.8 mm, and the mean improvements in SUVmean error were 15.5+/-6.3, 11.7+/-8.6, and 14.1+/-6.8% (all P's<0.001). For all tumor sizes, the proposed method outperformed the RW algorithm. Furthermore, tumor edge analysis demonstrated further enhancement of the performance of the algorithm, relative to the RW method, with decreasing edge gradients. CONCLUSION: The proposed technique improves PET lesion delineation at different tumor sites. It depicts greater effectiveness in tumors with smaller size and/or low edge gradients, wherein most PET segmentation algorithms encounter serious challenges. Favorable execution time and accurate performance of the algorithm make it a great tool for clinical applications. PMID- 26517068 TI - Analysis of Different Impression Techniques and Materials on Multiple Implants Through 3-Dimensional Laser Scanner. AB - OBJECTIVE: The aim of this study was to evaluate the accuracy of 7 different implant impression techniques for full-arch prostheses. MATERIALS AND METHODS: A master cast simulating an edentulous arch with 4 implants was used. Seven impression techniques were tested: open tray with polyether Impregum (OTI); open tray with splint-polyether Impregum (OTSI); closed tray with polyether Impregum; open tray with polyether Ramitec; open tray with splint-polyether Ramitec; closed tray with polyether Ramitec (CTR); open tray with impression plaster (OTP). Five impressions of the master cast were taken for each technique using an impression simulator device. Casts were realized based on those impressions (n = 35). Median values of deviation from the master cast were recorded for each cast through a 3 dimensional laser scanner. RESULTS: Only OTI (P = 0.028) and OTSI (P < 0.001) presented a statistically significant difference compared to the master cast. OTP (P = 0.99) and CTR (P = 0.10) showed median values of deviation close to zero ( 0.001 and -0.003 mm, respectively). CONCLUSION: Stiff impression materials (such as plaster or rigid polyether) guarantee greater accuracy in cases of multiple implant impressions of patients with full-arch rehabilitations. Splinting of impression copings with acrylic resin did not improve accuracy. PMID- 26517070 TI - The Good News--Simulations Work, So Now What? PMID- 26517071 TI - Validity and Reliability Evidence for a New Measure: The Evidence-Based Practice Knowledge Assessment in Nursing. AB - BACKGROUND: Studies of evidence-based practice (EBP) among nurses often focus on attitudes and beliefs about EBP and self-reported EBP knowledge. Because knowledge self-assessments can be highly inaccurate, the authors developed and tested a new objective measure of EBP knowledge--the Evidence-Based Practice Knowledge Assessment in Nursing (EKAN). METHOD: Seven subject matter experts reviewed candidate items, resulting in a scale content validity index of 0.94. Rasch modeling was used to evaluate item-person performance on the proposed unidimensional trait of EBP knowledge. The candidate item pool was then tested among 200 undergraduate nursing students. RESULTS: Strong evidence of unidimensionality was confirmed by narrow item infit statistics centering on 1.0. The item separation index was 7.05, and the person separation index was 1.66. Item reliability was 0.98, and person reliability was 0.66. CONCLUSION: The 20 item EKAN showed strong psychometric properties for an instrument developed under the Rasch model and is available for use in research and educational contexts. PMID- 26517072 TI - Promoting Differentiated Competencies Among RN-to-Bachelor of Science in Nursing Program Graduates. AB - BACKGROUND: Bolstered by the Institute of Medicine's employment goal of 80% of baccalaureate (BSN)-prepared RNs by 2020, the number of RN-to-BSN programs has grown dramatically. This rapid growth has led to concerns about lack of standardization and significant variability in requirements related to content and expected competencies. METHOD: The Differentiated Essential Competencies (DECs) of Graduates of Texas Nursing Programs was reviewed to tease out the concepts, content, and competencies that are BSN-level specific and thereby appropriate for RN-to-BSN programs. RESULTS: The current review was a compilation of differentiated competencies based on education level. In this article, numerous examples are drawn from the DECs and are organized by the major content areas common to RN-to-BSN programs. CONCLUSION: Faculty should examine the DECs to consider how they may be used to enhance RN-to-BSN programs, to evaluate their congruence with traditional BSN programs, and to ensure that program graduates are educationally prepared for practice in today's complex health care system. PMID- 26517073 TI - ERRATUM for Evolving the PICOT Method for the Digital Age: The PICOT-D. PMID- 26517074 TI - From a Medical Problem to a Health Experience: How Nursing Students Think in Clinical Situations. AB - BACKGROUND: Nursing clinical judgment (NCJ) is a core competency that must be developed in nursing education. The objective of this study is to explore the development of NCJ among undergraduate nursing students, according to teachers and preceptors. METHOD: The collaborative group, composed of three educators, three nurse preceptors, and one researcher, analyzed six situations in which students in the program were assessed for NCJ. RESULTS: Key learnings and development indicators were identified for each of the three levels of NCJ development. Reasoning process, type of relationships with patients and their families, perception of the nursing role, and reflection are parameters of NCJ that exert a mutual influence and evolve from one level to the next. CONCLUSION: Knowing this evolution can help educators to plan the curriculum, select effective teaching methods, and provide feedback that will support NCJ development. For students, these developmental markers support self-evaluation with a view to self-regulation. PMID- 26517075 TI - Effectiveness of a Case-Based Computer Program on Students' Ethical Decision Making. AB - BACKGROUND: The aim of this study was to test the effectiveness of a case-based computer program, using an integrative ethical decision-making model, on the ethical decision-making competency of nursing students in South Korea. METHOD: This study used a pre- and posttest comparison design. Students in the intervention group used a computer program for case analysis assignments, whereas students in the standard group used a traditional paper assignment for case analysis. RESULT: The findings showed that using the case-based computer program as a complementary tool for the ethics courses offered at the university enhanced students' ethical preparedness and satisfaction with the course. CONCLUSION: On the basis of the findings, it is recommended that nurse educators use a case based computer program as a complementary self-study tool in ethics courses to supplement student learning without an increase in course hours, particularly in terms of analyzing ethics cases with dilemma scenarios and exercising ethical decision making. PMID- 26517076 TI - Exploring Unplanned Curriculum Drift. AB - BACKGROUND: This study explored the opportunities for quality enhancement in teaching and learning by examining unplanned curriculum drift in an undergraduate nursing course. Curriculum drift is defined here as a process whereby the learning experiences associated with a curriculum do not match the specific syllabus, vision, or intentions associated with attaining desired outcomes for nursing students. METHOD: Staff involved in the implementation of a new innovative Bachelor of Nursing curriculum at an Australian regional university were surveyed to explore their perceptions and knowledge of key philosophical and pedagogical concepts associated with a planned curriculum. A constructivist case study approach was used to explore curriculum drift. RESULTS: Survey responses revealed that staff actions were inconsistent with their interpretations of concepts underlying the proposed curriculum. CONCLUSION: It is proposed that the discrepancy is a contributing factor in curricular drift, where the potential to achieve desired learning outcomes associated with innovative curricula is compromised by a drift to preinnovative or unplanned states. PMID- 26517077 TI - Integrating Mental Health Concepts in the Care of Adults With Chronic Illnesses: A Curricular Enhancement. AB - BACKGROUND: In the United States, inadequate attention has been given to the mental health needs of chronically ill adults, and the attempts to integrate mental health in primary care have fallen short. METHOD: This article describes the beginning efforts of the faculty at Duke University School of Nursing to integrate mental health concepts into its adult-gerontological nurse practitioner and family nurse practitioner curricula. RESULTS: Competency and course content mapping activities revealed opportunities for mental health enhancement. Five mental health concepts were identified for module development: spectrum of emotions, validation skills, self-management, resilience, and diversity. Mental health modules will be integrated in the nurse practitioner Physical Assessment and Diagnostic Reasoning course, as well as in various clinical courses. CONCLUSION: Challenges and lessons learned, including efforts to foster active interprofessional learning among medical, physician assistant, and nurse practitioner students, are described. PMID- 26517078 TI - Building a Community of Scholars: One Cohort's Experience in an Online and Distance Education Doctor of Philosophy Program. AB - BACKGROUND: Online and distance education is becoming increasingly common in higher education. As students explore graduate programs, they are often overwhelmed with the variety of program delivery options available. For graduate students pursuing a Doctor of Philosophy (PhD), a particular concern relates to building a community of scholars and how to do so through an online and distance learning program. METHOD: Through a review of literature and personal stories, this article will highlight innovative strategies utilized by a cohort of PhD students related to online and distance learning and developing a community of scholars. RESULTS: PhD students developed a community of scholars using innovative strategies to communicate and collaborate. CONCLUSION: Building a community of scholars is possible through online and distance education using simple forms of technology to connect and collaborate. PMID- 26517079 TI - Connecting Theory to Practice: Using Guided Questions to Standardize Clinical Postconference. AB - BACKGROUND: Assisting nursing students with the integration of theoretical knowledge in the practice setting can be a challenge for clinical instructors. Clinical instructors using planned questions to guide discussion among students during postconference is one method that can be used to achieve this goal. Open ended guided questions that deliberately address and synthesize classroom knowledge during postconference discussions are advantageous to both students and clinical instructors. METHOD: The purpose of this article is to describe the process of standardizing the weekly postconference by deliberately integrating questions within a second-year nursing clinical course at a Canadian university. RESULTS: In this course, the guided questions provided clinical instructors who facilitated the postconferences with an opportunity to enhance their own level of comprehension and currency in various subject areas, as well as evaluate students' critical thinking and knowledge gaps. CONCLUSION: Understanding the nursing curriculum and providing clinical instructors with the appropriate skills to facilitate postconference discussions were paramount to the success of these standardized postconferences. PMID- 26517080 TI - Adapting and Integrating Photovoice in a Baccalaureate Community Course to Enhance Clinical Experiential Learning. AB - BACKGROUND: The adaptation and incorporation of photovoice--a qualitative research method--into the Community Health Nursing clinical course to foster students' clinical reasoning in a community setting is presented. METHOD: Photovoice was used as a teaching strategy in the windshield survey and key informant interview activities that are part of the community health clinical experience. Students were provided with disposable cameras and were instructed to take photographs of the community. RESULTS: Students shared the photographs with faculty and community members and explored ways of developing sustainable community-based interventions that promote and protect health. CONCLUSION: Photovoice can be used as a teaching strategy tool in any clinical course to foster experiential learning. PMID- 26517081 TI - Pseudostandardized Patients in Undergraduate Nursing Health Assessment. PMID- 26517082 TI - Incidence of Deep Sternal Wound Infection in Diabetic Patients Undergoing Off Pump Skeletonized Internal Thoracic Artery Grafting. AB - OBJECTIVES: To evaluate the impact of skeletonized bilateral or single internal thoracic artery (ITA) grafting on the risk of deep sternal wound infection (DSWI) in diabetic patients undergoing off-pump coronary artery bypass grafting (OPCAB). MATERIALS AND METHODS: A total of 803 diabetic patients undergoing OPCAB surgery from January 2010 to December 2014 were enrolled into this study and assigned to the pSITA group (patients undergoing pedicled single ITA grafting, n = 362), the sSITA group (skeletonized single ITA grafting, n = 295), or the sBITA group (skeletonized bilateral ITA grafting, n = 146). The primary end point was the diagnosis of a DSWI. RESULTS: Eighteen patients developed postoperative DSWI, with an incidence of 2.2%. Patients in the sSITA group had a significantly lower incidence of DSWI than those in the pSITA group (1.0 vs. 3.6%, p = 0.0408). In multivariate logistic regression analysis, the risk of DSWI in the sSITA group was 0.41 times that in the pSITA group. CONCLUSIONS: sSITA grafting lowered the risk of DSWI in diabetic patients undergoing OPCAB surgery compared to pSITA grafting. Multicenter clinical trials involving larger sample sizes are needed to determine the merit of pSITA grafting in reducing the risk of DSWI following OPCAB surgery. PMID- 26517083 TI - Albuminuria is Associated With Subendocardial Viability Ratio in Chronic Kidney Disease Patients. AB - BACKGROUND/AIMS: Albuminuria is a well-established marker of subclinical organ damage. Pulse-wave analysis (PWA) employs the technique of applanation tonometry to obtain a peripheral pulse pressure waveform, from which central hemodynamic data are derived by application of the transfer function. Using PWA we can measure the subendocardial viability ratio (SEVR) and ejection duration (ED). SEVR or the Buckberg index is a non-invasive estimate of myocardial workload, oxygen supply and perfusion and a measure of the ability of the arterial system to meet the heart's energy requirements. ED is the duration of ventricular ejection. The objective of this study was to evaluate the relationship between albuminuria and PWA parameters in chronic kidney disease (CKD) patients. METHODS: We studied 86 CKD patients aged 59.8+/-13.5 years, 56 (65.1%) were male. PWA analysis and 24-hour ambulatory blood pressure (24hABP) monitoring were performed. The following parameters were calculated: (1) aortic augmentation index with and without correction for a heart rate of 75 (Aix and AIx@ HR75), (2) SEVR, calculated as the ratio of the diastolic pressure time index and the systolic pressure time index, (3) ED, (4) estimated central aortic systolic and diastolic pressure and (5) central aortic pulse pressure calculated as the difference between estimated aortic systolic and diastolic BP. Blood samples and urine albumin-to-creatinine ratio (UACR) were analyzed; UACR values were natural log transformed (lnUACR). RESULTS: Using CKD-EPI creatinine-cystatin C formula the eGFR in patients was 7-130 ml/min/1.73 m2 (mean 32.6; SD+/-24.6). We found statistically significant correlation between lnUACR and cystatin C (r=0.308; P=0.004), eGFR (r=-0.219; P=0.04), hemoglobin (r=-0.255; P=0.02), phosphorus (r=0.222; P=0.04), iPTH (r=0.268; P=0.01), SEVR (r=-0.254; P=0.02) and ED (r=0.315; P=0.003). No statistically significant correlations between lnUACR and cardiac biomarkers TnI, NT-proBNP, central aortic BP and 24h ABP values were found. Using multiple regression analysis statistically significant association was found between SEVR as dependent variable and lnUACR (beta=-0.223, P=0.039), sex (beta=-0.216, P=0.035), and diabetes (beta=0.332, P=0.001). Multiple regression analysis with ED as dependent variable has shown statistically significant association with lnUACR (beta=0.242, P=0.031) and diabetes (beta= 0.275, P=0.01). Patients were stratified into tertiles according to the lnUACR. Statistically significant differences in serum creatinine (P=0.001), cystatin C (P=0.012), hemoglobin (P=0.03), calcium (P=0.036), iPTH (P=0.008), SEVR (P=0.007) and ED (P=0.004) were found between tertiles. In post hoc analysis we found statistically significant differences between first and third tertile in SEVR (P=0.002; 95% CI:10.5-45) and in ED (P=0.001; 95% CI:-6.89-(-1.87)). CONCLUSIONS: Nondialysis CKD patients with higher levels of albuminuria have lower SEVR and higher ED and our results have shown the importance of central hemodynamic parameters like are SEVR and ED as a better or earlier noninvasive hemodynamic indexes in these patients. PMID- 26517084 TI - Laparoscopy Reveals a Diversity of Peritoneal Change in Patients with Long-Term Vintage of Peritoneal Dialysis. AB - BACKGROUND: Although laparoscopy may provide more detailed morphological and histological information about peritoneal damage, its significance in patients with long vintage of peritoneal dialysis (PD) is not elucidated. METHODS: Findings in 12 patients with PD vintage of 7.3 (5.0-8.4) years who had undergone laparoscopy between 2007 and 2011 were reviewed. Macroscopic (peritoneal change, hypervascular change, adhesion, encapsulation) and histopathological peritoneal findings (interstitial fibrosis, microvascular change, fibrin deposition, inflammatory cell infiltration) were scored and summed as Macro-total score (Macro-TS) and Micro-total score (Micro-TS), respectively. Factors associated with these scores and the relationship between these scores were investigated. RESULTS: Neither Macro-TS nor Micro-TS were related to PD vintage (p = 0.069 and p = 0.769, respectively); moreover, Macro-TS varied from patient to patient regardless of similar PD vintage. However, Macro-TS showed a significant association with duration of acidic dialysate (p = 0.003). CONCLUSION: Macroscopic and microscopic findings via laparoscopy may help the assessment of peritoneal damage in patients with long PD vintage. PMID- 26517085 TI - Stenting the Left Secondary Carina: 'A Fork in the Road'. PMID- 26517086 TI - Self-Assembled Cubic Liquid Crystalline Nanoparticles for Transdermal Delivery of Paeonol. AB - BACKGROUND: The aim of this study was to optimize the preparation method for self assembled glyceryl monoolein-based cubosomes containing paeonol and to characterize the properties of this transdermal delivery system to improve the drug penetration ability in the skin. MATERIAL AND METHODS: In this study, the cubic liquid crystalline nanoparticles loaded with paeonol were prepared by fragmentation of glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel by high pressure homogenization. We evaluated the Zeta potential of these promising skin targeting drug-delivery systems using the Malvern Zeta sizer examination, and various microscopies and differential scanning calorimetry were also used for property investigation. Stimulating studies were evaluated based on the skin irritation reaction score standard and the skin stimulus intensity evaluation standard for paeonol cubosomes when compared with commercial paeonol ointment. In vitro tests were performed on excised rat skins in an improved Franz diffusion apparatus. The amount of paeonol over time in the in vitro penetration and retention experiments both was determined quantitatively by HPLC. RESULTS: Stimulating studies were compared with the commercial ointment which indicated that the paeonol cubic liquid crystalline nanoparticles could reduce the irritation in the skin stimulating test. Thus, based on the attractive characteristics of the cubic crystal system of paeonol, we will further exploit the cosmetic features in the future studies. CONCLUSIONS: The transdermal delivery system of paeonol with low-irritation based on the self-assembled cubic liquid crystalline nanoparticles prepared in this study might be a promising system of good tropical preparation for skin application. PMID- 26517087 TI - The Janus-faced roles of Kruppel-like factor 4 in oral squamous cell carcinoma cells. AB - Kruppel-like factor 4 (KLF4) is a zinc-finger transcription factor that regulates many essential processes, including development and cell differentiation, proliferation, and apoptosis. Along with these roles in normal cells and tissues, KLF4 has important tumor suppressive and oncogenic functions in some malignancies. However, the roles of KLF4 in oral squamous cell carcinoma remain unclear. This study investigated the epigenetic alterations and possible roles of KLF4 in oral cancer carcinogenesis. Notably, KLF4 expression was significantly decreased in human oral cancer tissues compared with healthy controls, and KLF4 promoter hypermethylation contributed to the suppression of KLF4 expression. KLF4 expression was associated with tumor grade. Its expression was much lower in poorly differentiated oral cancers than in well-differentiated cancer cells. KLF4 exerted its antitumor activity in vitro and/or in vivo by inhibiting cell proliferation, cell cycle progression, cell colony formation and by inducing apoptosis. In addition, KLF4 over-expression promoted oral cancer cell migration and invasion in vitro. Knockdown of KLF4 promoted oral cancer cells growth and colony formation, and simultaneously inhibited cell migration and invasion. Mechanistic studies revealed that MMP-9 might contribute to KLF4-mediated cell migration and invasion. These results provide evidence that KLF4 might play Janus faced roles in oral cancer carcinogenesis, acting both as a tumor suppressor and as an oncogene. PMID- 26517088 TI - beta-Lactoglobulin nanofibrils can be assembled into nanotapes via site-specific interactions with pectin. AB - Controlling the self-assembly of individual supramolecular entities, such as amyloid fibrils, into hierarchical architectures enables the 'bottom-up' fabrication of useful bionanomaterials. Here, we present the hierarchical assembly of beta-lactoglobulin nanofibrils into the form of 'nanotapes' in the presence of a specific pectin with a high degree of methylesterification. The nanotapes produced were highly ordered, and had an average width of 180 nm at pH 3. Increasing the ionic strength or the pH of the medium led to the disassembly of nanotapes, indicating that electrostatic interactions stabilised the nanotape architecture. Small-angle X-ray scattering experiments conducted on the nanotapes showed that adequate space is available between adjacent nanofibrils to accommodate pectin molecules. To locate the interaction sites on the pectin molecule, it was subjected to endopolygalacturonase digestion, and the resulting products were analysed using capillary electrophoresis and size-exclusion chromatography for their charge and molecular weight, respectively. Results suggested that the functional pectin molecules carry short (<10 residues) enzyme susceptible blocks of negatively charged, non-methylesterified galacturonic acid residues in the middle of their homogalacturonan backbones (and possibly near their ends), that specifically bind to sites on the nanofibrils. Blocking the interaction sites on the nanofibril surface using small oligomers of non methylesterified galacturonic acid residues similar in size to the interaction sites of the pectin molecule decreased the nanotape formation, indicating that site-specific electrostatic interactions are vital for the cross-linking of nanofibrils. We propose a structural model for the pectin-cross-linked beta lactoglobulin nanotapes, the elements of which will inform the future design of bionanomaterials. PMID- 26517089 TI - Aberrantly upregulated TRAP1 is required for tumorigenesis of breast cancer. AB - Tumor necrosis factor receptor-associated protein 1 (TRAP1) is abnormally expressed in many cancers. In this study, we showed that TRAP1 is aberrantly upregulated in breast tumors compared to control tissues. TRAP1 knockdown downregulates mitochondrial aerobic respiratory, sensitizes cells to lethal stimuli, and inhibited tumor growth in MDA-MB-231 and MCF-7 breast cancer cells in vivo. TRAP1 overexpression, however, enhances the capacity to cope with stress conditions. These evidences suggested that TRAP1 is required for tumorigenesis. We also found that TRAP1 regulates the mitochondrial morphology. Relatively lower TRAP1 levels are associated with the rod-shaped mitochondrial phenotype in invasive and metastatic MDA-MB-231 breast cancer cells; on the contrary, higher TRAP1 levels are associated with the tubular network-shaped mitochondrial phenotype in non-invasive MCF-7 cells. Interestingly, the expression of TRAP1 in human breast cancer specimens inversely correlates with tumor grade. Overexpression of TRAP1 in MDA-MB-231 cells causes mitochondrial fusion, triggers mitochondria to form tubular networks, and suppresses cell migration and invasion in vitro and in vivo. These data link TRAP1-regulated mitochondrial dynamics and function with tumorigenesis of breast cancer and suggested that TRAP1 may therefore be a potential target for breast cancer drug development. PMID- 26517090 TI - Deregulation of the miR-222-ABCG2 regulatory module in tongue squamous cell carcinoma contributes to chemoresistance and enhanced migratory/invasive potential. AB - Chemoresistance is often associated with other clinical characteristics such as enhanced migratory/invasive potential. However, the correlation and underlying molecular mechanisms remain unclear. The aim of this study was to elucidate the function of the miR-222-ABCG2 pathway in the correlation between cisplatin (DDP) resistance and enhanced cell migration/invasion in tongue squamous cell carcinoma (TSCC). Using TSCC cell lines and primary cultures from TSCC cases, we first confirmed the correlation among DDP resistance (measured by IC50 values and ABCG2/ERCC1 expression), migratory/invasive potential (assessed by migration/invasion assays) and miR-222 expression. In TSCC cells, siRNA-mediated ABCG2 knockdown led to enhanced DDP responsiveness and reduced migratory/invasive potential, whereas ABCG2 overexpression induced DDP resistance and enhanced cell migration/invasion. Luciferase assays revealed that ABCG2 is a direct target of miR-222. In addition to reducing cell migration/invasion, functional analyses in TSCC cells indicated that miR-222 can reduce expression of the ABCG2 gene and enhance DDP responsiveness. However, co-transfection with ABCG2 cDNA restored both DDP resistance and migration/invasion. Moreover, miR-222 mimics and ABCG2 siRNA inhibited tumor growth and lung metastasis in vivo. Thus, our results verified that DDP resistance is correlated with enhanced migratory/invasive potential in TSCC. ABCG2 is a direct target of miR-222,and deregulation of the miR-222-ABCG2 regulatory module in TSCC contributes to both DDP resistance and enhanced migratory/invasive potential. PMID- 26517091 TI - Olfactory bulb proteome dynamics during the progression of sporadic Alzheimer's disease: identification of common and distinct olfactory targets across Alzheimer related co-pathologies. AB - Olfactory dysfunction is present in up to 90% of Alzheimer's disease (AD) patients. Although deposition of hyperphosphorylated tau and beta-amyloid substrates are present in olfactory areas, the molecular mechanisms associated with decreased smell function are not completely understood. We have applied mass spectrometry-based quantitative proteomics to probe additional molecular disturbances in postmortem olfactory bulbs (OB) dissected from AD cases respect to neurologically intact controls (n=20, mean age 82.1 years). Relative proteome abundance measurements have revealed protein interaction networks progressively disturbed across AD stages suggesting an early imbalance in splicing factors, subsequent interrupted cycling of neurotransmitters, alteration in toxic and protective mechanisms of beta-amyloid, and finally, a mitochondrial dysfunction together with disturbance in neuron-neuron adhesion. We also present novel molecular findings in the OB in an autopsy cohort composed by Lewy body disease (LBD), frontotemporal lobar degeneration (FTLD), mixed dementia, and progressive supranuclear palsy (PSP) cases (n = 41, mean age 79.7 years). Olfactory mediators deregulated during the progression of AD such as Visinin-like protein 1, RUFY3 protein, and Copine 6 were also differentially modulated in the OB in LBD, FTLD, and mixed dementia. Only Dipeptidyl aminopeptidase-like protein 6 showed a specific down-regulation in AD. However, no differences were observed in the olfactory expression of this protein panel in PSP subjects. This study demonstrates an olfactory progressive proteome modulation in AD, unveiling cross disease similarities and differences especially for specific proteins involved in dendritic and axonic distributions that occur in the OB during the neurodegenerative process. PMID- 26517094 TI - Bedside matters - putting the patient at the centre of teaching and learning. PMID- 26517092 TI - Sense-antisense gene-pairs in breast cancer and associated pathological pathways. AB - More than 30% of human protein-coding genes form hereditary complex genome architectures composed of sense-antisense (SA) gene pairs (SAGPs) transcribing their RNAs from both strands of a given locus. Such architectures represent important novel components of genome complexity contributing to gene expression deregulation in cancer cells. Therefore, the architectures might be involved in cancer pathways and, in turn, be used for novel drug targets discovery. However, the global roles of SAGPs in cancer pathways has not been studied. Here we investigated SAGPs associated with breast cancer (BC)-related pathways using systems biology, prognostic survival and experimental methods. Gene expression analysis identified 73 BC-relevant SAGPs that are highly correlated in BC. Survival modelling and metadata analysis of the 1161 BC patients allowed us to develop a novel patient prognostic grouping method selecting the 12 survival significant SAGPs. The qRT-PCR-validated 12-SAGP prognostic signature reproducibly stratified BC patients into low- and high-risk prognostic subgroups. The 1381 SAGP-defined differentially expressed genes common across three studied cohorts were identified. The functional enrichment analysis of these genes revealed the GABPA gene network, including BC-relevant SAGPs, specific gene sets involved in cell cycle, spliceosomal and proteasomal pathways. The co-regulatory function of GABPA in BC cells was supported using siRNA knockdown studies. Thus, we demonstrated SAGPs as the synergistically functional genome architectures interconnected with cancer-related pathways and associated with BC patient clinical outcomes. Taken together, SAGPs represent an important component of genome complexity which can be used to identify novel aspects of coordinated pathological gene networks in cancers. PMID- 26517093 TI - The miR-24-Bim pathway promotes tumor growth and angiogenesis in pancreatic carcinoma. AB - miRNAs are a group of small RNAs that have been reported to play a key role at each stage of tumorigenesis and are believed to have future practical value. We now demonstrate that Bim, which stimulates cell apoptosis, is obviously down regulated in pancreatic cancer (PaC) tissues and cell lines. And Bim-related miR 24 is significantly up-regulated in PaC. The repressed expression of Bim is proved to be a result of miR-24, thus promoting cell growth of both cancer and vascular cells, and accelerating vascular ring formation. By using mouse tumor model, we clearly showed that miR-24 promotes tumor growth and angiogenesis by suppressing Bim expression in vivo. Therefore, a new pathway comprising miR-24 and Bim can be used in the exploration of drug-target therapy of PaC. PMID- 26517095 TI - The Medical Consultation Letters of Dr William Cullen: the launch of a digital edition. PMID- 26517096 TI - Pre-hospital notification is associated with improved stroke thrombolysis timing. AB - Intravenous thrombolysis increases disability-free survival after acute ischaemic stroke in a time-dependent fashion. We aimed to determine whether pre-hospital notification, introduction of a CT scanner near to assessment site and introduction of out-of-hours thrombolysis services affect thrombolysis timing. Methods Timings related to thrombolysis were collected between May 2012 and June 2014 at a single hospital site; these included time to stroke physician assessment, time to cranial CT imaging and door to needle time. All thrombolysed ischaemic stroke patients admitted via the emergency department were included. Ambulance services were asked to pre-notify the emergency department of any suspected stroke patient during this period. Results We studied 182 patients (48% female; mean age 74 years; 59% pre-notified). Pre-hospital notification was associated with a significantly higher rate of CT scanning within 25 minutes (60% vs 24%, odds ratio [OR] 4.7, 95% confidence interval [CI] 2.4-9.0; p<0.001), earlier stroke physician assessment (median 6 vs 32 minutes; p<0.001) and receiving thrombolysis within 60 minutes (89% vs 49%, OR 8.0, 95% CI 3.8-16.9; p<0.001). Being treated outside normal working hours did not alter thrombolysis timing. Logistic regression identified the introduction of a near-site CT scanner (OR 4.6 [95% CI 1.7-12.5]) and pre-hospital notification (OR 4.7, [95% CI 2.3 9.6]) as independent predictors of door to CT time less than or equal to 25 minutes, and pre-hospital notification (OR 11.6, [95% CI 4.9-30.3]) and stroke severity (OR 1.15 per point of NIHSS scale, [95% CI 1.08-1.23]) as predictors of door to thrombolysis time less than or equal to 60 minutes. The most common perceived timing delays were radiology-related (33%), the need to acutely lower blood pressure (15%) and obtaining consent (12%). Conclusion Pre-hospital notification is associated with earlier stroke physician review, CT imaging and delivery of thrombolysis. Referral to an out of hours thrombolysis service was not associated with additional delay. PMID- 26517097 TI - Distribution and presentation of Lyme borreliosis in Scotland - analysis of data from a national testing laboratory. AB - This study examines the distribution of laboratory-confirmed cases of Lyme borreliosis in Scotland and the clinical spectrum of presentations within NHS Highland. Methods General demographic data (age/sex/referring Health Board) from all cases of Lyme borreliosis serologically confirmed by the National Lyme Borreliosis Testing Laboratory from 1 January 2008 to 31 December 2013 were analysed. Clinical features of confirmed cases were ascertained from questionnaires sent to referring clinicians within NHS Highland during the study period. Results The number of laboratory-confirmed cases of Lyme borreliosis in Scotland peaked at 440 in 2010. From 2008 to 2013 the estimated average annual incidence was 6.8 per 100,000 (44.1 per 100,000 in NHS Highland). Of 594 questionnaires from NHS Highland patients: 76% had clinically confirmed Lyme borreliosis; 48% erythema migrans; 17% rash, 25% joint, 15% neurological and 1% cardiac symptoms. Only 61% could recall a tick bite. Conclusion The incidence of Lyme borreliosis may be stabilising in Scotland but NHS Highland remains an area of high incidence. Lyme borreliosis should be considered in symptomatic patients that have had exposure to ticks and not just those with a definite tick bite. PMID- 26517098 TI - Qualitative research in healthcare: an introduction to grounded theory using thematic analysis. AB - In today's NHS, qualitative research is increasingly important as a method of assessing and improving quality of care. Grounded theory has developed as an analytical approach to qualitative data over the last 40 years. It is primarily an inductive process whereby theoretical insights are generated from data, in contrast to deductive research where theoretical hypotheses are tested via data collection. Grounded theory has been one of the main contributors to the acceptance of qualitative methods in a wide range of applied social sciences. The influence of grounded theory as an approach is, in part, based on its provision of an explicit framework for analysis and theory generation. Furthermore the stress upon grounding research in the reality of participants has also given it credence in healthcare research. As with all analytical approaches, grounded theory has drawbacks and limitations. It is important to have an understanding of these in order to assess the applicability of this approach to healthcare research. In this review we outline the principles of grounded theory, and focus on thematic analysis as the analytical approach used most frequently in grounded theory studies, with the aim of providing clinicians with the skills to critically review studies using this methodology. PMID- 26517099 TI - Utility and prevalence of imaging for underlying cancer in unprovoked pulmonary embolism. AB - Current guidelines state that patients over 40 years of age with a first unprovoked pulmonary embolism should be offered limited screening for possible cancer and considered for intensive screening (abdomino-pelvic computed tomography and mammography), despite no evidence for the latter. The aim of this study was to evaluate the clinical utility and cost of intensive screening in routine clinical practice. Methods All patients diagnosed with a first unprovoked pulmonary embolism between January 2014 and June 2014 in a single large UK teaching hospital were included. The information management department searched for patients with an International Classification of Diseases 10 discharge diagnosis of pulmonary embolism and limited to 'acute pulmonary embolism with/without cor pulmonale'. Only patients with unprovoked pulmonary embolism were included. Patients with chronic medical conditions predisposing to pulmonary embolism were excluded. NHS costs were obtained from the Trust Finance Department. These costs were used to generate the costs of limited versus intensive screening, and then scaled up using adult population census information and assuming the same incidence of idiopathic pulmonary embolism to estimate the annual NHS cost of intensive screening. Results Ninety-two patients were diagnosed with pulmonary embolism, and 25 met the inclusion criteria. Clinical examination was often incomplete (84%). Limited screening was often missed (urinalysis 100%, serum calcium 64%). Intensive screening was performed in the majority of cases (68%, all abdomino-pelvic computed tomography with no cancer detected) with an L88 excess cost per patient. Conclusion Intensive screening in first unprovoked pulmonary embolism has a low yield, is costly and should not replace thorough clinical examination and basic screening. PMID- 26517100 TI - Rapid cognitive decline: not always Creutzfeldt-Jakob disease. AB - A patient with rapidly progressive cognitive decline over an approximately four month period was suspected to have sporadic Creutzfeldt-Jakob disease. Features thought to support this diagnosis included psychiatric symptoms (anxiety and depression), visual hallucinations and a visual field defect. However, the finding of papilloedema broadened the differential diagnosis. Although standard brain imaging and electroencephalography had shown only non-specific abnormalities, subsequent cerebral angiography disclosed an intracranial dural arteriovenous fistula. Following embolisation, the patient made a good functional recovery. Intracranial dural arteriovenous fistula merits consideration in any patient with subacute cognitive decline, and should be included in the differential diagnosis of sporadic Creutzfeldt-Jakob disease. PMID- 26517101 TI - Organising pneumonia due to dronedarone. AB - Organising pneumonia is one of the responses of the lung to injury and can mimic bacterial pneumonia but importantly it does not respond to antibiotic therapy. We present the case of a 67-year-old male who was diagnosed with organising pneumonia secondary to dronedarone. Drug reactions are a common cause and early identification of the culprit is mandatory to prevent further morbidity and ensure a favourable outcome. On chest radiography there may be fleeting peripheral consolidation, while computed tomography can show a range of stereotyped patterns including perilobular consolidation. Bronchoscopic biopsy may not always be possible but response to steroids is often rapid following removal of the culprit drug. Dronedarone should be included in the list of possible drugs and the Pneumotox database remains a useful resource for the clinician when acute drug-related pneumotoxicity is suspected. PMID- 26517102 TI - Has IMPROVE-IT improved cardiovascular outcome? PMID- 26517103 TI - The diagnostic criteria of pityriasis rosea and Gianotti-Crosti syndrome - a protocol to establish diagnostic criteria of skin diseases. AB - We established and validated diagnostic criteria for pityriasis rosea and Gianotti-Crosti syndrome. In this paper, we compare and contrast both diagnostic criteria to formulate a protocol in establishing diagnostic criteria for other dermatological diseases. The diagnostic criteria are similar in employing clear dividing lines and conjunctions ('and/or') to assure high reliability. Both sets of criteria should be applicable for all ethnic groups. Spontaneous remission is not included, so diagnosis is not delayed while waiting for disease remission. Laboratory investigations are not enlisted, so that the criteria can be used in medical care systems in different parts of the world. The diagnostic criteria are different in that pathognomonic clinical manifestations exist for pityriasis rosea, such as the herald patch and the orientation of lesions along the lines of skin cleavages. These features, however, score low for sensitivity. These specific manifestations are not seen in Gianotti-Crosti syndrome. Such differences led to different categorisation of clinical features. Atypical variants are more common for pityriasis rosea. The diagnostic criteria for pityriasis rosea therefore do not include a list of differential diagnoses, while diagnostic criteria for Gianotti-Crosti syndrome do. Using this comparison, we constructed a protocol to establish diagnostic criteria for other skin diseases. We advocate the need to justify the establishment of diagnostic criteria, that multiple diagnostic criteria for the same disease should be avoided, that diagnostic criteria should be compatible with the disease classification if applicable, and that the scope should be well-delineated with regard to clinical variants. We outline the need for validation studies to assess the criteria related validity, test-retest intra-clinician reliability, and inter-clinician reliability. We emphasise that the establishment of diagnostic criteria should not be a generic process. We also highlight limitations of diagnostic criteria, and emphasise that no diagnostic criteria can replace the bedside experience of clinicians. PMID- 26517104 TI - The invention of gonioscopy by Alexios Trantas and his contribution to ophthalmology. AB - Gonioscopy is a technique used to examine structures in the anterior chamber angle (the fluid filled space inside the eye between the iris and the innermost layer of the cornea, the endothelium). It is an essential tool in ophthalmic practice, particularly in the diagnosis of glaucoma. In 1899, the Greek ophthalmologist Alexios Trantas was the first to visualise the angle in vivo and coined the term 'gonioscopy'. He made a number of other important contributions to ophthalmology. PMID- 26517105 TI - The 13th Stationary/83rd (Dublin) General Hospital, Boulogne, 1914-1919. AB - Casualties from the Western Front during the First World War were often evacuated to base hospitals on the northern coast of France for more advanced and specialist care. These temporary base hospitals frequently had more than 1,000 beds and were typically staffed by older, more senior doctors than were present nearer the front line. The 13th Stationary Hospital opened in October 1914 on the Boulogne docks and became the main specialist unit for the treatment of eye, face and jaw injuries. In May 1917 it was renamed the 83rd (Dublin) Hospital when the staff was augmented by volunteer staff from Irish hospitals. The hospital subsequently housed an innovative 'physical medicine' or rehabilitation unit. The hospital remained open for the duration of the War, moving to Langenfeld in the Ruhr following the Armistice. PMID- 26517106 TI - A Dickensian origin for Sherrington's enchanted loom? AB - Sherrington's image of the mind-brain as an 'enchanted loom' has intrigued scientists for decades. Its origin, however, has been unclear. Here, we make a new suggestion as to where it may have come from. The article sheds light on the connections between literary and scientific similes and metaphors. PMID- 26517107 TI - The history of stress hyperglycaemia. AB - Stress hyperglycaemia, is a common phenomenon, frequently associated with adverse outcomes in a number of prevalent conditions including myocardial infarction and stroke. Knowledge on stress hyperglycaemia evolved in tandem with knowledge relating to homeostasis, stress and disease and involved some of the world's most eminent thinkers. Despite this, it still remains under-recognised. This paper illustrates significant points in the history of stress hyperglycaemia, from antiquity through to the present day, as well as the challenges faced in translating research into clinical benefit for patients. Profiles of significant protagonists including Claude Bernard, Walter Cannon and Hans Seyle are presented, as well their roles in the emergence of modern-day terminology and pathophysiological models. Major themes such as 'fight or flight' and homeostasis are central to this discussion. Closer to the present day, the role of stress hyperglycaemia in a number of common medical conditions is explored in more detail. Contention around evidence for treatment and the future risk of diabetes mellitus are also discussed. PMID- 26517108 TI - Agricola's De re metallica 1556. Part 2. PMID- 26517109 TI - Clinical trial design for rare cancers: why a less conventional route may be required. AB - Major recent advances in the diagnosis, treatment, prevention and screening of cancer have led to improvements in survival and other outcomes for cancer patients. When the 198 identified rare cancers are taken in aggregate, rare cancers account for 22% of all cancer diagnoses, higher than any single common cancer. Yet median survival for patients with rare cancer patients remains poor as clinical trial and treatment advancements trail those achieved for common cancer. Overcoming the challenges inherent in the study of rare diseases is critical to achieve improvements in outcomes for patients. Combining a redesign of clinical trial protocols with the new paradigm for the treatment of all cancers, may lead to improvements in survival benefits for rare cancers in line with those achieved in the treatment of more common types. PMID- 26517110 TI - Crofelemer for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on anti-retroviral therapy. AB - Chronic diarrhea remains a common condition that affects people infected with human immunodeficiency virus (HIV) despite the widespread use of potent antiretroviral therapy. It is important that providers control this condition, as the persistence of diarrhea affects the quality of life of patients and may contribute to decreased adherence to antiretroviral therapy. Strategies to control diarrhea in patients with HIV infection include switching to a new antiretroviral regimen and/or the use of specific medications to control the diarrhea. This review aims to provide a concise evaluation of a newly approved medication (crofelemer) that has a novel mechanism of action and has received approval for the symptomatic relief of non-infectious diarrhea in adult patients with HIV on anti-retroviral therapy. PMID- 26517111 TI - Dutrebis (lamivudine and raltegravir) for use in combination with other antiretroviral products for the treatment of HIV-1 infection. AB - Raltegravir and lamivudine have been part of highly active therapy regimens throughout the past years of antiretroviral therapy. A fixed-dose, single-tablet regimen comprising a non-poloxamer formulation of the integrase inhibitor raltegravir and the transcriptase inhibitor lamivudine (raltegravir/lamivudine; Dutrebis((r))) has been recently licensed for the treatment of HIV-1 infection. In several Phase I pharmacokinetic studies, one Dutrebis (150 mg lamivudine/300 mg raltegravir) fixed-dose combination tablet showed a higher bioavailability but comparable lamivudine and 400 mg raltegravir poloxamer exposures. Thus, the co administration of raltegravir together with lamivudine created a potent, effective, well-tolerated antiretroviral combination, which could be more convenient for the patient. However, the disadvantage of twice a day administration, and the existence of other fixed-dose combinations limit its widespread clinical use. This article reviews pharmacokinetics data and appraises their potential use in current and future HIV therapy. PMID- 26517112 TI - Editor's Commentary. PMID- 26517113 TI - Ethical Dilemmas at the Bedside: How Do We Decide? PMID- 26517114 TI - Patients under Psychiatric Medication Undergoing Cardiac Surgery Have a Higher Risk for Adverse Events. AB - Objective The percentage of patients undergoing cardiac surgery under some sort of psychiatric medication (PM) is not negligible. Thus, this study aimed to evaluate a possible impact of preoperative PM on the outcome after cardiac surgery. Methods A matched case-control study was conducted by including all patients who underwent myocardial revascularization and/or surgical valve operation in our institution from December 2008 till February 2011 by chart review and institutional quality assurance database (QS) analysis. Results Out of 1,949 patients included, 184 patients (9%) were identified with PM medication (group A). A control group matched for logistic EuroSCORE II, ejection fraction and age was generated (group C). Patients with PM were in mean significantly longer on the intensive care unit (A: 4.94 days; 95% confidence interval (CI), 3.9-5.9 days vs. C: 3.24 days; CI, 2.84-3.64 days; p = 0.003), had longer mechanical ventilation times (A: 36.70 hours; CI, 19.81-53.59 hours vs. C: 20.14 hours; CI, 14.61-25.68 hours; p = 0.258), and significantly more episodes of respiratory insufficiencies (A: 31 episodes [17%] vs. C: 17 episodes [9%]; p = 0.002). Regression analysis revealed preoperative PM as a significant risk factor for respiratory insufficiency (odds ratio: 1.99, CI: 1.0-3.74; p = 0.04). Chest tube drainage (A: 690 mL, CI: 571-808 mL vs. C: 690 mL; CI: 496-884 mL, p = 0.53) and the total amount of red blood cell transfusion units were similar (A: 1.69 units; CI: 1.21-2.18 units vs. C: 1.50 units; CI: 1.04-1.96 units; p = 0.37). Sternal dehiscence requiring sternal refixation was significantly more frequent in A (12 patients [7%] vs. C: 2 patients [1%]; odds ratio: 6.3, CI: 1.4-28.7; p = 0.01). The 30-day mortality was similar in both groups (A: 6 patients [3%] vs. C: 4 patients [2%]; odds ratio: 1.5; CI: 0.4-5.4; p = 0.5); however, the 100-day mortality was near significantly higher in group A (A: 14 patients (8%) vs. C: 6 patients (3%); odds ratio: 2.4, CI: 0.9-6.5, p = 0.057). Conclusion Patients with preoperative PM developed complications more frequently compared with a matched control group. The underlying multifactorial mechanisms remain unclear. Patients under PM need to be identified and particular care including optimal pre- and postoperative psychiatric assistance is recommended. PMID- 26517115 TI - The Unplanned Postoperative Coronary Angiogram after CABG: Identifying the Patients at Risk. AB - Objectives Coronary artery bypass grafting (CABG) is the "gold standard" for patients with multiple vessel coronary artery disease (CAD). However, there is no "gold standard" to control bypass patency immediately postoperatively. "Post completion" control angiogram (CA) is not routinely performed. We retrospectively analyzed the data of all patients undergoing urgent coronary angiogram post-CABG at our center. Methods Between January 2005 and June 2011, a total of 6,025 patients underwent CABG (isolated or combined) for CAD in our hospital. In patients who underwent urgent postoperative CA, high serum cardiac enzymes (>100 CK-MB), severe new ECG changes, or unexpected low left ventricular function were present. Results A total of 106 patients (1.8%) underwent post-CABG urgent coronary angiogram. Overall 30-day mortality in this cohort was 8.5%. The average time between the cardiac operation and the coronary angiogram in these patients was 3.41 +/- 5.68 days. The rates for an urgent coronary angiogram were 1.3% (n = 25), 2% (n = 65), and 1.8% (n = 16) for total arterial, combined arterial, and venous and solely venous CABG, respectively. Twenty-four percent of patients underwent CABG bypass revision, while 32% of the patients underwent PTCA, stenting, or both. Younger patients, female patients, smaller patients, and patients receiving a combined arterial and venous revascularization were at a higher risk for an unplanned postoperative CA in the multivariate risk analysis. Conclusion This study shows that the necessity for urgent post-CABG coronary angiogram is low (1.8%). However, more than half of the patients undergoing postoperative coronary angiogram needed reintervention, and, in spite of it, had high mortality. "Completion" control angiogram is not always feasible, patients at higher risk (e.g., female patients) should be identified and post-CABG coronary angiogram performed as soon as possible without undue delay, or a primary hybrid approach with an intraoperative CA should be applied. PMID- 26517116 TI - Fine Mapping of the Interaction between C4b-Binding Protein and Outer Membrane Proteins LigA and LigB of Pathogenic Leptospira interrogans. AB - The complement system consists of more than 40 proteins that participate in the inflammatory response and in pathogen killing. Complement inhibitors are necessary to avoid the excessive consumption and activation of this system on host cells. Leptospirosis is a worldwide zoonosis caused by spirochetes from the genus Leptospira. Pathogenic leptospires are able to escape from complement activation by binding to host complement inhibitors Factor H [FH] and C4b-binding protein (C4BP) while non-pathogenic leptospires are rapidly killed in the presence of fresh serum. In this study, we demonstrate that complement control protein domains (CCP) 7 and 8 of C4BP alpha-chain interact with the outer membrane proteins LcpA, LigA and LigB from the pathogenic leptospire L. interrogans. The interaction between C4BP and LcpA, LigA and LigB is sensitive to ionic strength and inhibited by heparin. We fine mapped the LigA and LigB domains involved in its binding to C4BP and heparin and found that both interactions are mediated through the bacterial immunoglobulin-like (Big) domains 7 and 8 (LigA7-8 and LigB7-8) of both LigA and LigB and also through LigB9-10. Therefore, C4BP and heparin may share the same binding sites on Lig proteins. PMID- 26517118 TI - Correction: Binaural Fusion and Listening Effort in Children Who Use Bilateral Cochlear Implants: A Psychoacoustic and Pupillometric Study. PMID- 26517117 TI - Antroquinonol Targets FAK-Signaling Pathway Suppressed Cell Migration, Invasion, and Tumor Growth of C6 Glioma. AB - Focal adhesion kinase (FAK) is a non-receptor protein tyrosine that is overexpressed in many types of tumors and plays a pivotal role in multiple cell signaling pathways involved in cell survival, migration, and proliferation. This study attempts to determine the effect of synthesized antroquinonol on the modulation of FAK signaling pathways and explore their underlying mechanisms. Antroquinonol significantly inhibits cell viability with an MTT assay in both N18 neuroblastoma and C6 glioma cell lines, which exhibits sub G1 phase cell cycle, and further induction of apoptosis is confirmed by a TUNEL assay. Antroquinonol decreases anti-apoptotic proteins, whereas it increases p53 and pro-apoptotic proteins. Alterations of cell morphology are observed after treatment by atomic force microscopy. Molecular docking results reveal that antroquinonol has an H bond with the Arg 86 residue of FAK. The protein levels of Src, pSrc, FAK, pFAK, Rac1, and cdc42 are decreased after antroquinonol treatment. Additionally, antroquinonol also regulates the expression of epithelial to mesenchymal transition (EMT) proteins. Furthermore, antroquinonol suppresses the C6 glioma growth in xenograft studies. Together, these results suggest that antroquinonol is a potential anti-tumorigenesis and anti-metastasis inhibitor of FAK. PMID- 26517119 TI - Community-Weighted Mean Plant Traits Predict Small Scale Distribution of Insect Root Herbivore Abundance. AB - Small scale distribution of insect root herbivores may promote plant species diversity by creating patches of different herbivore pressure. However, determinants of small scale distribution of insect root herbivores, and impact of land use intensity on their small scale distribution are largely unknown. We sampled insect root herbivores and measured vegetation parameters and soil water content along transects in grasslands of different management intensity in three regions in Germany. We calculated community-weighted mean plant traits to test whether the functional plant community composition determines the small scale distribution of insect root herbivores. To analyze spatial patterns in plant species and trait composition and insect root herbivore abundance we computed Mantel correlograms. Insect root herbivores mainly comprised click beetle (Coleoptera, Elateridae) larvae (43%) in the investigated grasslands. Total insect root herbivore numbers were positively related to community-weighted mean traits indicating high plant growth rates and biomass (specific leaf area, reproductive- and vegetative plant height), and negatively related to plant traits indicating poor tissue quality (leaf C/N ratio). Generalist Elaterid larvae, when analyzed independently, were also positively related to high plant growth rates and furthermore to root dry mass, but were not related to tissue quality. Insect root herbivore numbers were not related to plant cover, plant species richness and soil water content. Plant species composition and to a lesser extent plant trait composition displayed spatial autocorrelation, which was not influenced by land use intensity. Insect root herbivore abundance was not spatially autocorrelated. We conclude that in semi-natural grasslands with a high share of generalist insect root herbivores, insect root herbivores affiliate with large, fast growing plants, presumably because of availability of high quantities of food. Affiliation of insect root herbivores with large, fast growing plants may counteract dominance of those species, thus promoting plant diversity. PMID- 26517120 TI - Quantifying Preferences and Responsiveness of Marine Zooplankton to Changing Environmental Conditions using Microfluidics. AB - Global environmental change significantly affects marine species composition. However, analyzing the impact of these changes on marine zooplankton communities was so far mostly limited to assessing lethal doses through mortality assays and hence did not allow a direct assessment of the preferred conditions, or preferendum. Here, we use a microfluidic device to characterize individual behavior of actively swimming zooplankton, and to quantitatively determine their ecological preferendum. For the annelid zooplankton model Platynereis dumerilii we observe a broader pH preferendum than for the copepod Euterpina acutifrons, and reveal previously unrecognized sub-populations with different pH preferenda. For Platynereis, the minimum concentration difference required to elicit a response (responsiveness) is ~1 MUM for H+ and ~13.7 mM for NaCl. Furthermore, using laser ablations we show that olfactomedin-expressing sensory cells mediate chemical responsiveness in the Platynereis foregut. Taken together, our microfluidic approach allows precise assessment and functional understanding of environmental perception on planktonic behaviour. PMID- 26517121 TI - Social Crowding during Development Causes Changes in GnRH1 DNA Methylation. AB - Gestational and developmental cues have important consequences for long-term health, behavior and adaptation to the environment. In addition, social stressors cause plastic molecular changes in the brain that underlie unique behavioral phenotypes that also modulate fitness. In the adult African cichlid, Astatotilapia burtoni, growth and social status of males are both directly regulated by social interactions in a dynamic social environment, which causes a suite of plastic changes in circuits, cells and gene transcription in the brain. We hypothesized that a possible mechanism underlying some molecular changes might be DNA methylation, a reversible modification made to cytosine nucleotides that is known to regulate gene function. Here we asked whether changes in DNA methylation of the GnRH1 gene, the central regulator of the reproductive axis, were altered during development of A. burtoni. We measured changes in methylation state of the GnRH1 gene during normal development and following the gestational and developmental stress of social crowding. We found differential DNA methylation within developing juveniles between 14-, 28- and 42-day-old. Following gestational crowding of mouth brooding mothers, we saw differential methylation and transcription of GnRH1 in their offspring. Taken together, our data provides evidence for social control of GnRH1 developmental responses to gestational cues through DNA methylation. PMID- 26517122 TI - Prognostic Factors in Amyotrophic Lateral Sclerosis: A Population-Based Study. AB - OBJECTIVE: To determine the prognostic factors associated with survival in amyotrophic lateral sclerosis at diagnosis. METHODS: This retrospective population-based study evaluated 218 patients treated with riluzole between 2005 and 2014 and described their clinical and demographic profiles after the analysis of clinical data and records from the mortality information system in the Federal District, Brazil. Cox multivariate regression analysis was conducted for the parameters found. RESULTS: The study sample consisted of 132 men and 86 women with a mean age at disease onset of 57.2+/-12.3 years; 77.6% of them were Caucasian. The mean periods between disease onset and diagnosis were 22.7 months among men and 23.5 months among women, and the mean survival periods were 45.7+/ 47.0 months among men and 39.3+/-29.8 months among women. In addition, 80.3% patients presented non-bulbar-onset amyotrophic lateral sclerosis, and 19.7% presented bulbar-onset. Cox regression analysis indicated worse prognosis for body mass index (BMI) <25 kg/m2 (relative risk [RR]: 3.56, 95% confidence interval [CI]: 1.44-8.86), age >75 years (RR: 12.47, 95% CI: 3.51-44.26), and bulbar-onset (RR: 4.56, 95% CI: 2.06-10.12). Electromyography did not confirm the diagnosis in 55.6% of the suspected cases and in 27.9% of the bulbar-onset cases. CONCLUSIONS: The factors associated with lower survival in amyotrophic lateral sclerosis were age >75 years, BMI <25 kg/m2, and bulbar-onset. PMID- 26517123 TI - The Effects of Intravenous Immunoglobulins in Women with Recurrent Miscarriages: A Systematic Review of Randomised Trials with Meta-Analyses and Trial Sequential Analyses Including Individual Patient Data. AB - BACKGROUND: Immunological disturbances are hypothesised to play a role in recurrent miscarriage (RM) and therefore intravenous immunoglubulins (IVIg) have been tested in RM patients. OBJECTIVES: The objectives were to investigate the benefits and harms of IVIg versus placebo, no intervention, or treatment as usual in women with RM. SEARCH STRATEGY: We searched the published literature in all relevant databases. SELECTION CRITERIA: Randomised trials investigating IVIg versus placebo, no intervention, or treatment as usual in women with RM. DATA COLLECTION AND ANALYSIS: We undertook meta-analyses of aggregated data and individual patient data using a two-step approach, and we conducted bias domain assessments and trial sequential analyses to assess the risks of systematic and random errors. MAIN RESULTS: We identified 11 randomised clinical trials. No significant difference in the frequency of no live birth was found when IVIg was compared with placebo or treatment as usual (RR 0.92, 95% CI 0.75-1.12, p = 0.42). Trial sequential analysis showed that the required information size of 1,008 participants was not obtained. IVIg compared with placebo seems to increase the risk of adverse events. Subgroup analysis suggests that women with RM after a birth (secondary RM) seemed most likely to obtain a potential beneficial effect of IVIg (RR for no live birth 0.77, 95%CI 0.58-1.02, p = 0.06), however, trial sequential analysis showed that insufficient information is presently accrued. CONCLUSION: We cannot recommend or refute IVIg in women with RM. IVIg should therefore be assessed in further randomised clinical trials with positive outcomes before any clinical use is considered. PMID- 26517124 TI - Preclinical TSPO Ligand PET to Visualize Human Glioma Xenotransplants: A Preliminary Study. AB - Current positron emission tomography (PET) imaging biomarkers for detection of infiltrating gliomas are limited. Translocator protein (TSPO) is a novel and promising biomarker for glioma PET imaging. To validate TSPO as a potential target for molecular imaging of glioma, TSPO expression was assayed in a tumor microarray containing 37 high-grade (III, IV) gliomas. TSPO staining was detected in all tumor specimens. Subsequently, PET imaging was performed with an aryloxyanilide-based TSPO ligand, [18F]PBR06, in primary orthotopic xenograft models of WHO grade III and IV gliomas. Selective uptake of [18F]PBR06 in engrafted tumor was measured. Furthermore, PET imaging with [18F]PBR06 demonstrated infiltrative glioma growth that was undetectable by traditional magnetic resonance imaging (MRI). Preliminary PET with [18F]PBR06 demonstrated a preferential tumor-to-normal background ratio in comparison to 2-deoxy-2 [18F]fluoro-D-glucose ([18F]FDG). These results suggest that TSPO PET imaging with such high-affinity radiotracers may represent a novel strategy to characterize distinct molecular features of glioma growth, as well as better define the extent of glioma infiltration for therapeutic purposes. PMID- 26517125 TI - The Interaction between Root Herbivory and Competitive Ability of Native and Invasive-Range Populations of Brassica nigra. AB - The evolution of increased competitive ability (EICA) hypothesis predicts that escape from intense herbivore damage may enable invasive plants to evolve higher competitive ability in the invasive range. Below-ground root herbivory can have a strong impact on plant performance, and invasive plants often compete with multiple species simultaneously, but experimental approaches in which EICA predictions are tested with root herbivores and in a community setting are rare. Here, we used Brassica nigra plants from eight invasive- and seven native-range populations to test whether the invasive-range plants have evolved increased competitive ability when competing with Achillea millefolium and with a community (both with and without A. millefolium). Further, we tested whether competitive interactions depend on root herbivory on B. nigra by the specialist Delia radicum. Without the community, competition with A. millefolium reduced biomass of invasive- but not of native-range B. nigra. With the community, invasive-range B. nigra suffered less than native-range B. nigra. Although the overall effect of root herbivory was not significant, it reduced the negative effect of the presence of the community. The community produced significantly less biomass when competing with B. nigra, irrespective of the range of origin, and independent of the presence of A. millefolium. Taken together, these results offer no clear support for the EICA hypothesis. While native-range B. nigra plants appear to be better in dealing with a single competitor, the invasive-range plants appear to be better in dealing with a more realistic multi-species community. Possibly, this ability of tolerating multiple competitors simultaneously has contributed to the invasion success of B. nigra in North America. PMID- 26517127 TI - Allelic Variation of Cytochrome P450s Drives Resistance to Bednet Insecticides in a Major Malaria Vector. AB - Scale up of Long Lasting Insecticide Nets (LLINs) has massively contributed to reduce malaria mortality across Africa. However, resistance to pyrethroid insecticides in malaria vectors threatens its continued effectiveness. Deciphering the detailed molecular basis of such resistance and designing diagnostic tools is critical to implement suitable resistance management strategies. Here, we demonstrated that allelic variation in two cytochrome P450 genes is the most important driver of pyrethroid resistance in the major African malaria vector Anopheles funestus and detected key mutations controlling this resistance. An Africa-wide polymorphism analysis of the duplicated genes CYP6P9a and CYP6P9b revealed that both genes are directionally selected with alleles segregating according to resistance phenotypes. Modelling and docking simulations predicted that resistant alleles were better metabolizers of pyrethroids than susceptible alleles. Metabolism assays performed with recombinant enzymes of various alleles confirmed that alleles from resistant mosquitoes had significantly higher activities toward pyrethroids. Additionally, transgenic expression in Drosophila showed that flies expressing resistant alleles of both genes were significantly more resistant to pyrethroids compared with those expressing the susceptible alleles, indicating that allelic variation is the key resistance mechanism. Furthermore, site-directed mutagenesis and functional analyses demonstrated that three amino acid changes (Val109Ile, Asp335Glu and Asn384Ser) from the resistant allele of CYP6P9b were key pyrethroid resistance mutations inducing high metabolic efficiency. The detection of these first DNA markers of metabolic resistance to pyrethroids allows the design of DNA-based diagnostic tools to detect and track resistance associated with bednets scale up, which will improve the design of evidence-based resistance management strategies. PMID- 26517126 TI - Frataxin Is Localized to Both the Chloroplast and Mitochondrion and Is Involved in Chloroplast Fe-S Protein Function in Arabidopsis. AB - Frataxin plays a key role in eukaryotic cellular iron metabolism, particularly in mitochondrial heme and iron-sulfur (Fe-S) cluster biosynthesis. However, its precise role has yet to be elucidated. In this work, we studied the subcellular localization of Arabidopsis frataxin, AtFH, using confocal microscopy, and found a novel dual localization for this protein. We demonstrate that plant frataxin is targeted to both the mitochondria and the chloroplast, where it may play a role in Fe-S cluster metabolism as suggested by functional studies on nitrite reductase (NIR) and ferredoxin (Fd), two Fe-S containing chloroplast proteins, in AtFH deficient plants. Our results indicate that frataxin deficiency alters the normal functioning of chloroplasts by affecting the levels of Fe, chlorophyll, and the photosynthetic electron transport chain in this organelle. PMID- 26517128 TI - Alteration of Brain Functional Networks in Early-Stage Parkinson's Disease: A Resting-State fMRI Study. AB - Although alterations of topological organization have previously been reported in the brain functional network of Parkinson's disease (PD) patients, the topological properties of the brain network in early-stage PD patients who received antiparkinson treatment are largely unknown. This study sought to determine the topological characteristics of the large-scale functional network in early-stage PD patients. First, 26early-stage PD patients (Hoehn and Yahr stage:1-2) and 30 age-matched normal controls were scanned using resting-state functional MRI. Subsequently, graph theoretical analysis was employed to investigate the abnormal topological configuration of the brain network in early stage PD patients. We found that both the PD patient and control groups showed small-world properties in their functional brain networks. However, compared with the controls, the early-stage PD patients exhibited abnormal global properties, characterized by lower global efficiency. Moreover, the modular structure and the hub distribution were markedly altered in early-stage PD patients. Furthermore, PD patients exhibited increased nodal centrality, primarily in the bilateral pallidum, the inferior parietal lobule, and the medial superior frontal gyrus, and decreased nodal centrality in the caudate nucleus, the supplementary motor areas, the precentral gyrus, and the middle frontal gyrus. There were significant negative correlations between the Unified Parkinson Disease Rating Scale motor scores and nodal centralities of superior parietal gyrus. These results suggest that the topological organization of the brain functional network was altered in early-stage PD patients who received antiparkinson treatment, and we speculated that the antiparkinson treatment may affect the efficiency of the brain network to effectively relieve clinical symptoms of PD. PMID- 26517130 TI - Correction: Withania somnifera Root Extract Has Potent Cytotoxic Effect against Human Malignant Melanoma Cells. PMID- 26517129 TI - NSAIDs Alter Phosphorylated Forms of AQP2 in the Inner Medullary Tip. AB - Vasopressin increases urine concentration through activation of aquaporin-2 (AQP2) in the collecting duct. Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin E2 synthesis, and may suppress AQP2 producing a urine concentrating defect. There are four serines in AQP2 that are phosphorylated by vasopressin. To determine if chronic use of NSAIDs changes AQP2's phosphorylation at any of these residues, the effects of a non-selective NSAID, ibuprofen, and a COX-2-selective NSAID, meloxicam, were investigated. Daily ibuprofen or meloxicam increased the urine output and decreased the urine osmolality significantly by days 7 through 14. Concomitantly, meloxicam significantly reduced total AQP2 protein abundance in inner medulla (IM) tip to 64% of control and base to 63%, respectively. Ibuprofen significantly decreased total AQP2 in IM tip to 70% of control, with no change in base. Meloxicam significantly increased the ratios of p256-AQP2 and p261-AQP2 to total AQP2 in IM tip (to 44% and 40%, respectively). Ibuprofen increased the ratio of p256-AQP2 to total AQP2 in IM tip but did not affect p261-AQP2/total AQP2 in tip or base. Both ibuprofen and meloxicam increased p264-AQP2 and p269-AQP2 ratios in both tip and base. Ibuprofen increased UT-A1 levels in IM tip, but not in base. We conclude that NSAIDs reduce AQP2 abundance, contributing to decreased urine concentrating ability. They also increase some phosphorylated forms of AQP2. These changes may partially compensate for the decrease in AQP2 abundance, thereby lessening the decrease in urine osmolality. PMID- 26517131 TI - Enhancement of Skin Penetration of Hydrophilic and Lipophilic Compounds by pH sensitive Liposomes. AB - PURPOSE: Enhance skin penetration of hydrophilic and lipophilic compounds using liposomes that are responsible to the pH of the skin surface. METHODS: pH sensitive liposomes were prepared by a thin layer and freeze-thaw method with dioleoyl phosphatidyl ethanolamine and cholesteryl hemisuccinate. Liposomal fusion with stratum corneum lipid liposomes was measured using fluorescence resonance energy transfer. Particle diameter and zeta potential of the liposomes after fusion were measured by dynamic light scattering and electrophoresis. RESULTS: Under neutral pH conditions, the diameter of the pH-sensitive liposomes was 130 nm and their zeta potential was -70 mV. In weakly acidic conditions, the diameter was larger than 3,000 nm and the zeta potential was -50 mV. In contrast, the particle diameter and the zeta potential of the non-pH-sensitive liposomes remained constant under various pH conditions. A skin penetration study was performed on hairless mice skin using vertical diffusion cells, showing that the fusion ability of pH-sensitive liposomes was higher than that of non-pH-sensitive liposomes. In the skin penetration study was carried out using hydrophilic (calcein) and lipophilic (N-(7-nitrobenz- 2-oxa-1,3-diazol-4yl)-PE) (NBD-PE) model compounds which were applied to the skin with pH-sensitive liposomes as carrier. The fluorescent compounds contained within the pH-sensitive liposomes permeated the skin more effectively than those within non-pH-sensitive liposomes, and this ability was further enhanced with the lipophilic compound. CONCLUSION: These studies suggest that pH-sensitive liposomes have potential as an important tool for delivery of compounds into the skin. PMID- 26517132 TI - First Analysis of the Association Between CYP3A4/5, ABCB1 Genetic Polymorphisms and Oxcarbazepine Metabolism and Transport in Chinese Epileptic Patients with Oxcarbazepine Monotherapy and Bitherapy. AB - PURPOSE: Oxcarbazepine (OXC) is widely used in anti-epileptic treatment. Cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5(CYP3A5), and ATP-binding cassette sub-family B member 1 (ABCB1) are potential genes involved in OXC metabolisms and transport in vivo. This study aims to examine the genetic effects of CYP3A4, CYP3A5, and ABCB1 on OXC metabolism and transport in Chinese epileptic patients using OXC as monotherapy and bitherapy with lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA). METHODS: Sixty-six Chinese epileptic patients were recruited from Xiangya Hospital Central South University, of whom 40 patients were receiving OXC monotherapy, 11 patients were placed in the OXC bitherapy group combined with one enzyme-inducing anti-epileptic drugs (LTG or LEV), and 15 patients were placed in the OXC bitherapy group combined with VPA. Oxcarbazepine and its main metabolite 10-hydrocarbazepine (MHD) plasma concentrations were measured using high performance liquid chromatography (HPLC) UV method. In addition, eight single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, ABCB1 gene were genotyped by polymerase chain reaction-improved multiple ligase detection reaction (PCR-iMLDR). RESULTS: In the OXC+VPA group, ABCB1 rs2032582 and rs2032582-rs10234411-rs1045642 TAG haplotype were associated with MHD and MHD+OXC plasma concentration before permutation test. In OXC monotherapy and OXC+ LTG/LEV groups, no significant association between genetic polymorphisms in CYP3A4/5, ABCB1 gene and OXC plasma concentration parameters were observed. CONCLUSION: CYP3A4/5 and ABCB1 genetic variants might not take part in the metabolism and transport of MHD and OXC among epileptic patients using OXC monotherapy and bitherapy in combination with LEV, LTG or VPA. PMID- 26517133 TI - Statins Reduce Mortality After Non-severe but Not After Severe Pneumonia: A Systematic Review and Meta-Analysis. AB - PURPOSE: The objective of this study was to perform a systematic review and meta analysis of the effects of statins on mortality for patients with non-severe pneumonia or severe pneumonia. METHODS: PubMed, EMBASE, Cochrane Database of Systematic Reviews, Cochrane central register of controlled trials and Clinicaltrials.gov were searched for the association between statins and non severe/severe pneumonia. Eligible articles were analyzed in Stata 12.0. RESULTS: The database search yielded a total of 566 potential publications, 24 studies involving 312,309 patients met the eligibility criteria. Pooled unadjusted data showed that statin use was associated with lower mortality after non-severe pneumonia (odds ratio [OR] 0.70, 95% confidence interval [CI], 0.66-0.73), but not severe pneumonia (OR 1.05; 95% CI, 0.86-1.28). However, this protective effect of statins was weakened using adjusted estimates (OR 0.78, 95% CI, 0.75 0.82). Besides, protective effect of statins was attenuated by confounders in a subgroup analysis, especially when accounting for pneumonia severity indicators (OR 0.88; 95% CI, 0.80-0.96). CONCLUSIONS: Statin use was associated with reduced mortality after non-severe pneumonia but not severe pneumonia and this protective effect was weakened in subgroups. PMID- 26517134 TI - Application of iChip to Grow "Uncultivable" Microorganisms and its Impact on Antibiotic Discovery. AB - PURPOSE: Antibiotics have revolutionized modern medicine, allowing significant progress in healthcare and improvement in life expectancy. Development of antibiotic resistance by pathogenic bacteria is a natural phenomenon; however, the rate of antibiotic resistance emergence is increasing at an alarming rate, due to indiscriminate use of antibiotics in healthcare, agriculture and even everyday products. Traditionally, antibiotic discovery has been conducted by screening extracts of microorganisms for antimicrobial activity. However, this conventional source has been over-used to such an extent that it poses the risk of "running out" of new antibiotics. Aiming to increase access to a greater diversity of microorganisms, a new cultivation method with an in situ approach called iChip has been designed. The iChip has already isolated many novel organisms, as well as Teixobactin, a novel antibiotic with significant potency against gram-positive bacteria. PMID- 26517135 TI - Extracellular Vesicles as Natural Nanosized Delivery Systems for Small-Molecule Drugs and Genetic Material: Steps towards the Future Nanomedicines. AB - A new platform for drug, gene and peptide-protein delivery is emerging, under the common name of "extracellular vesicles". Extracellular vesicles (EVs) are 30-1000 nm-sized cell-derived, liposome-like vesicles. Current research on EVs as nano delivery systems for small-molecule drugs and genetic material, reveal that these tiny, biologically-derived vesicles carry a great potential to boost the efficacy of many therapeutic protocols. Several features of EVs; from efficacy to safety, from passive to active targeting ability, the opportunity to be biologically or chemically labelled, and most importantly, their eobiotic origin make them promising candidate for development of the next generation personalized nanomedicines. The aim of this article is to provide a view on the current research in which EVs are used as drug/genetic material delivery systems. Their application areas, drug loading and targeting strategies, and biodistribution properties are discussed. PMID- 26517136 TI - Retrospective and Prospective Human Intravenous and Oral Pharmacokinetic Projection of Dipeptidyl peptidase-IV Inhibitors Using Simple Allometric Principles - Case Studies of ABT-279, ABT-341, Alogliptin, Carmegliptin, Sitagliptin and Vildagliptin. AB - PURPOSE: The purpose of this exercise was to explore the utility of allometric scaling approach for the prediction of intravenous and oral pharmacokinetics of six dipeptidy peptidase-IV (DPP-IV) inhibitors viz. ABT-279, ABT-341, alogliptin, carmegliptin, sitagliptin and vildagliptin. METHODS: The availability of intravenous and oral pharmacokinetic data in animals enabled the allometry scaling of 6 DPP-IV inhibitors. The relationship between the main pharmacokinetic parameters [viz. volume of distribution (Vd) and clearance (CL)] and body weight was studied across three or four mammalian species, using double logarithmic plots to predict the human pharmacokinetic parameters of CL and Vd using simple allometry. RESULTS: A simply allometry relationship: Y = aWb was found to be adequate for the prediction of intravenous and oral human clearance/volume of distribution for DPP-IV inhibitors. The allometric equations for alogliptin, carmegliptin, sitagliptin, vildagliptin, ABT-279 and ABT-341 were 1.867W0.780, 1.170W0.756, 2.020W0.529, 1.959 W0.847, 0.672 W1.016, 1.077W 0.649, respectively, to predict intravenous clearance (CL) and the corresponding equations to predict intravenous volume of distribution (Vd) were: 3.313W0.987, 6.096W0.992, 7.140W0.805, 2.742W0.941, 1.299W0.695 and 5.370W0.803. With the exception of a few discordant values the exponent rule appeared to hold for CL (0.75) and Vd (1.0) for the predictions of various DPP-IV inhibitors. Regardless of the routes, the predicted values were within 2-3 fold of observed values and intravenous allometry was better than oral allometry. CONCLUSION: Simple allometry retrospectively predicted with reasonable accuracy the human reported values of gliptins and could be used as a prospective tool for this class of drugs. PMID- 26517137 TI - Dry Powder Coating using Planetary Centrifugal Mixer. AB - PURPOSE: Extemporaneous compounding is an important part of pharmacy practice, and should be standardized and sophisticated to ensure the quality of the compounded preparations. Recently, we applied a planetary centrifugal mixer (PCM) to powder blending, which has attracted interest for its small scale and lack of contamination. In this study, we aimed to reveal the feasibility of dry powder coating through ordered mixing of fine particles using PCM. METHODS: Cohesive lactose powders (Pharmatose450M) were dry coated with magnesium stearate (MgSt) using from 0.1 to 5%(w/w) content. The operational variables tested were operation time (1-30 min), operation speed (400-1000 rpm), vessel size (24-100 mL), and charging rate in the vessel (20-40%). The processed powders were evaluated for their surface morphology, flowability, and wettability. Furthermore, fine ibuprofen particles were coated with various lubricants, and then the dissolution profiles were examined. The crystallinity of ibuprofen was assessed using FT-IR and PXRD. RESULTS: Lactose powders were successfully coated with MgSt using PCM. When the level of MgSt was over 1%, the surface of the lactose powders was thoroughly covered. Angles of repose were 51 degrees and 41 degrees for unprocessed and processed powders with 1% MgSt, respectively. The contact angle of the water drop on the 1% MgSt sample leached to be 132 degrees , changing to a hydrophobic surface. Investigations under various operational conditions revealed that higher improvement was observed upon higher speed and longer time, and a smaller charging rate in the vessel. Vessel size had no impact. Moreover, improved dissolution of ibuprofen coated with both hydrophilic and hydrophobic lubricants was observed owing to good dispersing behavior. Besides, no alteration of crystallinity was detected. CONCLUSIONS: PCM is an effective tool for dry powder coating with low impact stress. The presented method will contribute a great deal to making crushed tablets a functional powder. PMID- 26517138 TI - The Implication of the Polymorphisms of COX-1, UGT1A6, and CYP2C9 among Cardiovascular Disease (CVD) Patients Treated with Aspirin. AB - PURPOSE: Enzymes potentially responsible for the pharmacokinetic variations of aspirin include cyclooxygenase-1 (COX-1), UDP-glucuronosyltransferase (UGT1A6) and P450 (CYP) (CYP2C9). We therefore aimed to determine the types and frequencies of variants of COX-1 (A-842G), UGT1A6 (UGT1A6*2; A541G and UGT1A6*3; A522C) and CYP2C9 (CYP2C9*3; A1075C) in the three major ethnic groups in Malaysia. In addition, the role of these polymorphisms on aspirin-induced gastritis among the patients was investigated. METHODS: A total of 165 patients with cardiovascular disease who were treated with 75-150 mg daily dose of aspirin and 300 healthy volunteers were recruited. DNA was extracted from the blood samples and genotyped for COX-1 (A-842G), UGT1A6 (UGT1A6*2 and UGT1A6*3) and CYP2C9 (CYP2C9*3; A1075C) using allele specific polymerase chain reaction (AS PCR). RESULTS: Variants UGT1A6*2,*3 and CYP2C9*3 were detected in relatively high percentage of 22.83%, 30.0% and 6.50%, respectively; while COX-1 (A-842G) was absent. The genotype frequencies for UGT1A6*2 and *3 were significantly different between Indians and Malays or Chinese. The level of bilirubin among patients with different genotypes of UGT1A6 was significantly different (p-value < 0.05). In addition, CYP2C9*3 was found to be associated with gastritis with an odd ratio of 6.8 (95 % Cl OR: 1.39 - 33.19; P = 0.033). CONCLUSION: Screening of patients with defective genetic variants of UGT1A6 and CYP2C9*3 helps in identifying patients at risk of aspirin induced gastritis. However, a randomised clinical study of bigger sample size would be needed before it is translated to clinical use. PMID- 26517139 TI - Quantitative Structure - Pharmacokinetics Relationships Analysis of Basic Drugs: Volume of Distribution. AB - PURPOSE: The early prediction of pharmacokinetic behavior is of paramount importance for saving time and resources and for increasing the success of new drug candidates. The steady-state volume of distribution (VDss) is one of the key pharmacokinetic parameters required for the design of a suitable dosage regimen. The aim of the study is to propose a quantitative structure - pharmacokinetics relationships (QSPkR) for VDss of basic drugs. METHODS: The data set consists of 216 basic drugs, divided to a modeling (n = 180) and external validation set (n = 36). 179 structural and physicochemical descriptors are calculated using validated commercial software. Genetic algorithm, stepwise regression and multiple linear regression are applied for variable selection and model development. The models are validated by internal and external test sets. RESULTS: A number of significant QSPkRs are developed. The most frequently emerged descriptors are used to derive the final consensus model for VDss with good explanatory (r2 0.663) and predictive ability (q2LOO-CV 0.606 and r2pred 0.593). The model reveals clear structural features determining VDss of basic drugs which are summarized in a short list of criteria for rapid discrimination between drugs with a large and small VDss. CONCLUSIONS: Descriptors like lipophilicity, fraction ionized as a base at pH 7.4, number of cycles and fused aromatic rings, presence of Cl and F atoms contribute positively to VDss, while polarity and presence of strong electrophiles have a negative effect. PMID- 26517141 TI - Design Space Approach for Preservative System Optimization of an Anti-Aging Eye Fluid Emulsion. AB - The use of preservatives must be optimized in order to ensure the efficacy of an antimicrobial system as well as the product safety. Despite the wide variety of preservatives, the synergistic or antagonistic effects of their combinations are not well established and it is still an issue in the development of pharmaceutical and cosmetic products. The purpose of this paper was to establish a space design using a simplex-centroid approach to achieve the lowest effective concentration of 3 preservatives (methylparaben, propylparaben, and imidazolidinyl urea) and EDTA for an emulsion cosmetic product. Twenty-two formulae of emulsion differing only by imidazolidinyl urea (A: 0.00 to 0.30% w/w), methylparaben (B: 0.00 to 0.20% w/w), propylparaben (C: 0.00 to 0.10% w/w) and EDTA (D: 0.00 to 0.10% w/w) concentrations were prepared. They were tested alone and in binary, ternary and quaternary combinations. Aliquots of these formulae were inoculated with several microorganisms. An electrochemical method was used to determine microbial burden immediately after inoculation and after 2, 4, 8, 12, 24, 48, and 168 h. An optimization strategy was used to obtain the concentrations of preservatives and EDTA resulting in a most effective preservative system of all microorganisms simultaneously. The use of preservatives and EDTA in combination has the advantage of exhibiting a potential synergistic effect against a wider spectrum of microorganisms. Based on graphic and optimization strategies, we proposed a new formula containing a quaternary combination (A: 55%; B: 30%; C: 5% and D: 10% w/w), which complies with the specification of a conventional challenge test. A design space approach was successfully employed in the optimization of concentrations of preservatives and EDTA in an emulsion cosmetic product. PMID- 26517140 TI - The Role of SIRT3 in Mediating Cardioprotective Effects of RAS Inhibition on Cardiac Ischemia-Reperfusion. AB - Cardiac ischemia-reperfusion stimulates the renin-angiotensin system (RAS) associated with elevated levels of circulating angiotensin II. Numerous studies demonstrate that the antagonist for the angiotensin II type 1 receptor, losartan improves cardiac function in animal models of ischemia-reperfusion. Molecular mechanisms of the cardioprotective effects of RAS inhibitors on cardiac ischemia reperfusion remain poorly understood, and are not associated with the anti hypertensive action of these drugs. This Commentary focuses on the study published in the Journal of Pharmacy and Pharmaceutical Sciences, 2015, 18:112 123, that elucidates the role of SIRT3 in the cardioprotective action of losartan against ischemic-reperfusion injury. We provide comprehensive discussion of the role of mitochondria in the cardioprotective effects of losartan through SIRT3. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26517142 TI - Initial steps towards an evidence-based classification system for golfers with a physical impairment. AB - PURPOSE: The present narrative review aims to make a first step towards an evidence-based classification system in handigolf following the International Paralympic Committee (IPC). It intends to create a conceptual framework of classification for handigolf and an agenda for future research. METHOD: Pubmed was searched on three themes: "Classification in Paralympic sports", "Performance determining factors in golf" and "Impact of impairments on golf performance". IPC regulations were gathered on the IPC-website and their official publications. RESULTS: In developing a classification system conform IPC-regulations, the main challenge is to identify the activity limitation caused by the impairment, not influenced by training, talent or motivation. Timing, accuracy and control, work per joint, range of motion, balance and flexibility are important performance determining factors in abled-bodied golf and should be considered when determining activity limitations in handigolf. Only five articles on handigolf were found, mainly addressing the asymmetric golf movement. Based on the present review, a conceptual framework for classification was developed, while a future research agenda was designated. The conceptual framework presents factors that are essential for sports performance categorized under "technology", "interface" and "athlete characteristics". It also includes impairment related factors essential for determining eligibility and classification. Ideally, measures to be used during classification need to be resistant against training, natural development of the athlete's talent and motivational changes. CONCLUSIONS: The conceptual framework and a multidimensional scientific research agenda will support further development of the knowledge base required for an evidence-based classification in handigolf, including multi-level analysis of player statistics, experimental analyses of biomechanics and modeling studies. Implications for Rehabilitation The main challenge in developing an evidence-based classification system conform IPC-regulations is defining eligibility criteria and sport classes based on activity limitation caused by only the impairment and not affected by training, talent and motivation. It is expected that a transparent classification system, a lively competition and admission to the Paralympic program will further promote participation in disabled golf. Timing, accuracy and control, work per joint, range of motion, balance and flexibility are of greater importance for golf performance in able-bodied golfers and expected to be of interest to incorporate in classification for handigolf. Side and level of amputation influence activity limitation in the asymmetric golf movement, and should be incorporated in classification. The proposed conceptual framework is fundamental to the research agenda that must further generate the knowledge-base to determine activity limitations caused by different impairments in handigolf and may serve as a guideline for other Paralympic sports in the development of evidence-based classification. PMID- 26517143 TI - Measurement of Lateral and Interfacial Thermal Conductivity of Single- and Bilayer MoS2 and MoSe2 Using Refined Optothermal Raman Technique. AB - Atomically thin materials such as graphene and semiconducting transition metal dichalcogenides (TMDCs) have attracted extensive interest in recent years, motivating investigation into multiple properties. In this work, we demonstrate a refined version of the optothermal Raman technique to measure the thermal transport properties of two TMDC materials, MoS2 and MoSe2, in single-layer (1L) and bilayer (2L) forms. This new version incorporates two crucial improvements over previous implementations. First, we utilize more direct measurements of the optical absorption of the suspended samples under study and find values ~40% lower than previously assumed. Second, by comparing the response of fully supported and suspended samples using different laser spot sizes, we are able to independently measure the interfacial thermal conductance to the substrate and the lateral thermal conductivity of the supported and suspended materials. The approach is validated by examining the response of a suspended film illuminated in different radial positions. For 1L MoS2 and MoSe2, the room-temperature thermal conductivities are 84 +/- 17 and 59 +/- 18 W/(m.K), respectively. For 2L MoS2 and MoSe2, we obtain values of 77 +/- 25 W and 42 +/- 13 W/(m.K). Crucially, the interfacial thermal conductance is found to be of order 0.1-1 MW/m(2) K, substantially smaller than previously assumed, a finding that has important implications for design and modeling of electronic devices. PMID- 26517144 TI - Non-communicable diseases in Brazil: a flood of data is coming! PMID- 26517145 TI - Lifestyles and chronic non-transmissible diseases of the Brazilian population according to the National Health Survey: balance of the main results. PMID- 26517146 TI - Frequency of nutritional disorders and their risk factors among children attending 13 nurseries in Sao Paulo, Brazil. A cross-sectional study. AB - CONTEXT AND OBJECTIVE: Nutritional disorders are associated with health problems earlier in life. The objective here was to estimate the frequency of nutritional disorders and their risk factors among children. DESIGN AND SETTING: Cross sectional study in nurseries at 13 day-care centers in Sao Paulo, Brazil. METHODS: The mothers of 482 children were interviewed, with anthropometry on these children. Children whose anthropometric indices for weight and height were greater than two standard deviations were considered to have nutritional disorders. RESULTS: Children in families with lower per capita income (odds ratio [OR]: 2.25; 95% confidence interval, CI: 1.08-4.67) and who presented neonatal risk (OR 8.08; 95% CI: 2.29-28.74), had incomplete vaccinations (OR 3.44; 95% CI: 1.15-10.31) or were male (OR 3.73; 95% CI: 1.63-8.56) were more likely to be malnourished. Children in families with lower per capita income were also less likely to be overnourished (OR 0.40; 95% CI: 0.19-0.88). Children who were exclusively breastfed for less than two months (OR 2.95; 95% CI: 1.35-6.44) or who were male (OR 2.18; 95% CI: 1.02-4.65) were also at greater risk of being overnourished. Children who presented neonatal risk (OR 3.41; 95% CI: 1.04 11.23), had incomplete vaccinations (OR 3.18; 95% CI: 1.307.76), or were male (OR 2.76; 95% CI: 1.56-4.90) were more likely to have a nutritional disorder. CONCLUSIONS: Nutritional disorders remain present in children attending nurseries in Sao Paulo. Actions should focus on boys, children who were exclusively breastfed for less than two months and those without up-to-date vaccinations. PMID- 26517147 TI - Cross-cultural adaptation of the Social and Emotional Questionnaire on Dementia for the Brazilian population. AB - CONTEXT AND OBJECTIVE: Impairments in social and emotional functioning may affect the communication skills and interpersonal relationships of people with dementia and their caregivers. This study had the aim of presenting the steps involved in the cross-cultural adaptation of the Social and Emotional Questionnaire (SEQ) for the Brazilian population. DESIGN AND SETTING: Cross-cultural adaptation study, conducted at the Center for Alzheimer's Disease and Related Disorders in a public university. METHODS: The process adopted in this study required six consecutive steps: initial translation, translation synthesis, back translation, committee of judges, pretesting of final version and submission to the original author. RESULTS: In general, the items had semantic, idiomatic, conceptual and experiential equivalence. During the first pretest, people with dementia and their caregivers had difficulties in understanding some items relating to social skills, which were interpreted ambiguously. New changes were made to allow better adjustment to the target population and, following this, a new pretest was performed. This pre-test showed that the changes were relevant and gave rise to the final version of the instrument. There was no correlation between education level and performance in the questionnaire, among people with dementia (P = 0.951). CONCLUSION: The Brazilian Portuguese version of the Social and Emotional Questionnaire was well understood and, despite the cultural and linguistic differences, the constructs of the original version were maintained. PMID- 26517148 TI - Main reasons for medical consultations in family healthcare units in the city of Recife, Brazil: a cross-sectional study. AB - CONTEXT AND OBJECTIVE: Only a few studies have focused on the main reasons for consultations at primary healthcare units within the Family Health Program. The aim here was to describe the reasons that led patients to seek assistance at four primary healthcare units in the city of Recife, Brazil. DESIGN AND SETTING: Cross sectional study at primary healthcare units in the city of Recife. METHODS: Among adult patients who were consecutively attended at four primary healthcare units in the city of Recife, their two main reasons for going there were recorded by medical students. The students did not interfere in the consultation dynamics. The data were gathered between September 2010 and March 2011 and between November 2012 and August 2013. The reasons for the consultations were grouped into broader categories in accordance with the International Classification of Primary Care (ICPC-2). RESULTS: 478 patients were included. Their mean age was 45.9 years (+/- 16 years) and 71% were female. Pain was the main reason for seeking medical attention (34%), followed by evaluation of tests, prescription renewal and medical certificates (17.6%). The most frequent types of pain were musculoskeletal pain (15.7%), headache (10.4%) and abdominal pain (8%). The main reasons for consultation according to ICPC-2 were in the general and nonspecific, musculoskeletal, nervous system-related and digestive tract categories. CONCLUSION: Pain was the most frequent reason for seeking medical attendance at these primary healthcare units. PMID- 26517149 TI - Possible implication of vagal nerve stimulation for treating refractory psoriasis. PMID- 26517150 TI - Antiviral treatment for Bell's palsy (idiopathic facial paralysis). PMID- 26517151 TI - Influenza vaccines for preventing cardiovascular disease. PMID- 26517152 TI - Spiroindole Alkaloids and Spiroditerpenoids from Aspergillus duricaulis and Their Potential Neuroprotective Effects. AB - Six new spiroindole alkaloids (1-6) and two new spiroditerpenoids (7 and 8) were isolated from an EtOAc extract of Aspergillus duricaulis culture media together with five known compounds. The structures of the isolated compounds were elucidated by analysis of NMR and MS data, and the absolute configurations of compounds 1-8 were confirmed by CD spectroscopic methods. All isolated compounds were evaluated for their inhibition of beta-amyloid (Abeta) aggregate-induced toxicity in PC12 cells and Abeta aggregation. Compounds 8-11 efficiently protected PC12 cells against Abeta aggregate-induced toxicity, but only compound 9 inhibited Abeta aggregation. On the other hand, compounds 4 and 5 exhibited moderate inhibitory effects on Abeta aggregation, but did not protect the cells from Abeta aggregate-induced toxicity. Preincubating Abeta monomers with compounds 4 and 5 rescued PC12 cells against Abeta aggregate-induced toxicity by reducing neurotoxic Abeta aggregates. Compound 9 inhibited both Abeta aggregate induced toxicity and Abeta aggregation. PMID- 26517153 TI - Local and long-range activation of innate immunity by infection and damage in C. elegans. AB - The nematode worm Caenorhabditis elegans lends itself naturally to investigation of innate immunity, from the scale of molecules to the whole animal. Numerous studies have begun to reveal the complex interplay of signalling mechanisms that underlie host defence in C. elegans. We discuss here research that illustrates the connection between cell and tissue-level homeostatic mechanisms and the activation of innate immune signalling pathways. These are woven together to provide a comprehensive organismal protection against perceived threats. PMID- 26517154 TI - Immune dysfunction in cirrhosis: Distinct cytokines phenotypes according to cirrhosis severity. AB - BACKGROUND/OBJECTIVES: Cirrhosis associated immune dysfunction has been proposed to switch from a pro-inflammatory phenotype in stable cirrhosis to an immunodeficient one in patients with decompensated cirrhosis and acute-on-chronic liver failure. The aim of the present study was to compare serum cytokine levels between healthy patients, stable cirrhosis, and decompensated cirrhotic patients with and without development of acute-on-chronic liver failure (ACLF); and to explore whether any of the measured cytokines is associated with cirrhosis severity and prognosis in ACLF patients. METHODS: Patients were enrolled from October 2013 to May 2014 in two hospitals located in Buenos Aires. Cirrhotic patients with an acute decompensating event were enrolled accordingly to the development of ACLF defined by the CANONIC study group. There were two control groups: healthy subjects (n=14) and stable cirrhotic patients (n=14). Demographic, clinical and biochemical data were obtained. Seventeen cytokines were measured using Bio-Plex Pro Human Cytokine 17-plex Assay. RESULTS: Of the 49 decompensated cirrhotic patients enrolled, 18 (36.7%) developed ACLF. Leukocyte count, MELD score at admission, Clif-SOFA at admission and day 7 were significantly higher in the ACLF group (p=0.046, p<0.001, p<0.001, p<0.001 respectively) as well as short-term mortality (p<0.001) compared to stable and decompensated cirrhotic patients. In comparison with healthy controls, stable cirrhotic and decompensated cirrhotic patients showed increased levels of pro inflammatory and anti-inflammatory cytokines: IL-6, IL-7, IL-8, IL-10, IL 12, and TNF-alpha. Decompensated cirrhotic patients with the development of ACLF showed a significant decrease of IL-7, IL-10, IL-12, TNF-alpha, MCP-1 and IFN-gamma, but a sustained response of IL-6 and IL-8. When evaluating cirrhosis severity, IL-6 and IL-8 correlated positively with MELD score, whereas only IL-6 correlated positively with Clif-SOFA score at day 7; IL-2 correlated negatively with Clif SOFA at admission. In comparison with all scores, leukocyte count showed positive correlation and IFN-gamma negative correlation with disease severity. When evaluating survival, only MELD and Clif-SOFA scores had a significant association with mortality. CONCLUSIONS: Pro-inflammatory cytokines and chemo-attractant elements are increased in cirrhosis in comparison with healthy subjects, and display higher values concomitantly with cirrhosis progression. However, in acute on-chronic liver failure an opposite cytokine pattern that can be resumed as a combination of immune paresis and excessive inflammatory response was observed. Several pro-inflammatory cytokines (IL-2, IL-6, IL-8 and IFN-gamma) showed correlation with disease severity; their utility as prognostic biomarkers needs to be further studied. PMID- 26517155 TI - Renal protective effects of arjunolic acid in a cisplatin-induced nephrotoxicity model. AB - Cisplatin is the first platinum-containing anti-cancer drugs. Cisplatin notable side effect of nephrotoxicity limits its use in clinic. Meanwhile, arjunolic acid possesses anti-inflammatory properties and plays protective roles against chemically induced organ pathophysiology. This study was conducted to find out whether arjunolic acid could attenuate kidney damage in rats, and to elucidate its possible mechanism of action. Fifty rats were treated with cisplatin (10mg/kg) in the presence/absence of 100 or 250mg/kg arjunolic acid. Arjunolic acid is given 1h after cisplatin. Morphological changes were assessed in kidney sections stained with Hematoxylin/Eosin and Masson Trichrome. Kidney samples were used for measurements of transforming growth factor (TGF)-beta1 and its type 1 receptor (TGF-betaR1), tumor necrosis factor (TNF)-alpha and interleukin (IL) 1beta by ELISA. Gene expression NFkappaB was determined by real time-PCR. Kidney tissue apoptosis was assessed by measuring the activities of caspase-3/8/9. The renal protective effect of arjunolic acid was confirmed by approximately normal appearance of renal tissue and the relatively unaffected serum creatinine and urea levels. Furthermore, arjunolic acid showed dose dependent reduction in cisplatin-induced elevation in renal levels of TGF-betaR1, TGF-beta1, TNF-alpha, IL-1beta and caspases. These findings demonstrated that arjunolic acid attenuates cisplatin nephrotoxicity either indirectly by enhancing body antioxidant activity or directly through several mechanisms, including inhibition of pro-inflammatory cytokines, blocking activation of TGF-beta1, and anti-apoptotic effects. PMID- 26517156 TI - National needs assessment of patients treated at the United States Federally Funded Hemophilia Treatment Centers. AB - AIM: The National Hemophilia Program Coordinating Center, with the U.S. Regional Hemophilia Network conducted a national needs assessment of U.S. Hemophilia Treatment Center (HTC) patients. The objectives were to determine: (i) To what extent do patients report that they receive needed services and education; (ii) How well do the services provided meet their needs; and (iii) What are the patients' perspectives about their care. METHODS: A survey was mailed to active patients of 129 HTCs. Respondents completed the anonymous surveys on line or returned them by mail. Questions focused on management and information, access and barriers to care, coping, resources, and transition. RESULTS: Of 24 308 questionnaires mailed, 4004 (16.5%) were returned. Most respondents reported very few gaps in needed services or information and reported that services and information met their needs. Over 90% agreed or strongly agreed that care was patient-centred and rated HTC care as important or very important. Identified gaps included dietary advice, genetic testing, information on ageing, sexual health and basic needs resources. Minority respondents reported more barriers. CONCLUSION: This survey is the largest assessment of the HTC population. Respondents reported that the services and information provided by the HTCs met their needs. Quality improvement opportunities include transition and services related to ageing and sexual health. Further investigation of barriers to care for minorities is underway. Results will help develop national priorities to better serve all patients in the US. HTCs. PMID- 26517158 TI - Understanding and Controlling Cost in Total Joint Arthroplasty. AB - Total joint arthrosplasty (TJA) is both a commonly performed successful intervention and an expensive procedure.As our population ages, the expense of these interventions is expected to grow and hence its impact on healthcare costs will also grow. To ensure that TJA is available to all those who would benefit, it is incumbent that healthcare providers control the cost of these procedures. As orthopaedic surgeons, we must be at the forefront of this effort. The purpose of this review is to outline strategies to control or even decrease TJA cost without negatively affecting outcomes.This concept is at the center of value based medicine and must guide our decision-making processes. PMID- 26517159 TI - Simultaneous Versus Staged Total Hip Arthroplasty A Review. AB - Total hip arthroplasty (THA) is considered one of the most effective treatments for hip arthritis, but the decision to perform simultaneous bilateral THA versus staged bilateral THA remains a source of controversy based primarily on the analysis of the risks and benefits of each approach. Many surgeons are reluctant to consider simultaneous total hip arthroplasty even though the procedure is associated with a shorter total hospitalization, shorter recovery and rehabilitation time, and decreased cost. However, in this review, we find that despite higher blood loss in the simultaneous group, there are no significant differences in terms of cardiopulmonary complications, thromboembolic events, stroke, surgical site infection, and rate of allogeneic transfusion between simultaneous and staged procedures. In addition, careful patient selection (ASA 1 and 2) can further minimize the risks of simultaneous bilateral total hip arthroplasty and increase the likelihood of consistent successful outcomes. PMID- 26517160 TI - Minimizing Blood Loss in Orthopaedic Surgery The Role of Antifibrinolytics. AB - Many common orthopaedic procedures are associated with a large volume of blood loss. Antifibrinolytics have a well-elucidated mechanism of action and a long history of clinical use. By inhibiting the enzymatic breakdown of fibrin, there has been a demonstrated ability to decrease total blood loss and reduce postoperative transfusion requirements. Despite substantial use in cardiac surgery, antifibrinolytic use in orthopaedic surgery has been limited due to concerns over the potential for venous thromboembolism. A growing body of evidence demonstrates the medications' efficacy and safety in arthroplasty and spine surgery. Due to the risks associated with allogenic blood transfusions and the limitations of alternative blood conservation strategies, antifibrinolytics are a reasonable strategy in blood conservation programs for patients undergoing major orthopaedic procedures. PMID- 26517161 TI - Sports Hernia and Extra-Articular Causes of Groin Pain in the Athlete. AB - Groin pain is a common complaint in athletes that use the musculature of the lower abdomen and proximal thigh. The complex anatomy of the groin region and broad differential diagnosis presents the sports medicine specialist with unique diagnostic and treatment challenges. Sports hernia, osteitis pubis, and adductor dysfunction are common extra-articular musculoskeletal causes of groin pain in athletes. The current paper reviews the pathogenesis, history and physical examination, imaging, non-operative treatment, surgical techniques, and outcomes for these conditions. Treatment algorithms are presented for management of patients with sports hernia, osteitis pubis, and adductor dysfunction. PMID- 26517162 TI - Meniscal Allograft Transplantation A Comprehensive Historical and Current Review. AB - Throughout the history of orthopaedics, our understanding of the function and necessity of the meniscus has significantly evolved, and with it, our techniques of treating, repairing, preserving, and replacing it have progressed in parallel. Currently, it is known that a meniscus deficiency is a predisposing factor to the development of degenerative changes of the knee. Thus, it is incumbent upon the surgeon to preserve the meniscus to the extent that biology will allow. Unfortunately, circumstances arise when the meniscus cannot be preserved, and young patients afflicted by irreparable meniscus deficiency may be potential candidates for a meniscus transplant. Though its indications are limited and its execution technically complex, meniscal allograft transplant has been shown to provide good subjective outcomes and is a potentially joint preserving surgery. This paper provides a comprehensive and historical review of the meniscus, a brief review of meniscus anatomy and biomechanics, and commentary on the role of meniscal allograft transplant for the treatment of meniscal deficiency, including patient selection, graft selection and sizing, surgical technique, and outcomes. PMID- 26517163 TI - Addressing the Hill-Sachs Lesion Humeral Head Bone Loss and Glenohumeral Instability. AB - Osseous injuries affecting the posterosuperolateral aspect of the humeral head, also known as the Hill-Sachs lesion, are common and can pose a difficult problem for the operating surgeon. Hill-Sachs lesions can lead to recurrent shoulder instability if not identified and addressed. This review will focus on osseous defects of the humeral head and address the pathoanatomy, diagnosis, indications, and surgical techniques for the treatment of these lesions. PMID- 26517164 TI - Biceps Tenodesis for Type II SLAP Tears. AB - Tears of the superior glenoid labrum are a common cause of shoulder pain and disability, especially in overhead athletes such as pitchers, swimmers, and volleyball players. Type II SLAP lesions have been the most clinically important superior labral pathology, and the management of this lesion has been a very controversial topic. Currently, there are no high level studies in the literature to guide treatment. While the few level 3 and level 4 evidence studies that are available following arthroscopic repair of type II SLAP lesions all report reasonable overall patient satisfaction, persistent postoperative pain is common and associated with a low return to pre-injury level of sports participation. There has been a recent school of thought that biceps tenodesis, which maintains the length-tension relationship of the long head of biceps, should be the procedure of choice for patients with isolated type II SLAP lesions. The current paper reviews the role biceps tenodesis plays in the management of type II SLAP tears. PMID- 26517165 TI - Alternative Therapeutic Modalities in Sports Medicine. AB - Bone marrow aspirate, prolotherapy, platelet-rich plasma,and autologous conditioned serum represent alternative treatment options that have emerged to address various musculoskeletal ailments. We have reviewed the basic science, physiology, and clinical evidence of each of these modalities and discovered that each treatment has its individual place in the management of common orthopaedic pathologies. Bone marrow aspirates are successful in treating early arthritis and cartilage defects. Prolotherapy and platelet-rich plasma have demonstrated good efficacy in treating inflammatory processes and early arthritis. Finally, autologous conditioned serum (Orthokine) represents a promising treatment option for chronic joint arthritis. The clinical evidence supporting these alternative treatment modalities is insufficient and further level 1 evidence is needed before we can begin to employ these techniques in our daily orthopaedic practice. PMID- 26517166 TI - The Role of Arthroscopy in the Management of Tibial Plateau Fractures. AB - Arthroscopy has been advocated as a possible adjunct to the operative treatment of tibial plateau fractures. This review article provides a historical perspective on the development of the technique while focusing on its current role in the management of these injuries. Topics include the possible utility of employing arthroscopy in the diagnosis and management of associated soft tissue lesions and potential for arthroscopic assistance to facilitate achieving fracture reduction without an open arthrotomy. Pertinent literature is reviewed and discussed, with an emphasis on the data related to patient outcomes. PMID- 26517167 TI - Osteochondral Lesions of the Talus Revisited Emerging Technologies. AB - Osteochondral lesions of the talus are becoming an increasingly recognized source of chronic ankle pain following injury. Although, once thought to be attributed to ischemic necrosis, acute or repetitive trauma is the contemporary theory regarding their etiology. Presently, there is no clear-cut consensus among surgeons on the best algorithm to manage these challenging injuries. Arthroscopic techniques along with emerging technologies in the field of cartilage repair are becoming increasingly popular treatment modalities. These innovative methods have potential to provide a new direction for the future and deliver improved clinical outcomes. The current review discusses opinions regarding the development of these lesions and also the approach to management, including the latest surgical modalities, such as osteochondral grafts and juvenile chondrocyte implantation. PMID- 26517168 TI - The Evaluation and Treatment of the Arthritic Distal Radioulnar Joint. AB - Distal radioulnar joint (DRUJ) arthritis presents a challenging problem. Surgical interventions include resection arthroplasties, such as the Darrach procedure and hemiresection arthroplasty, the Sauve-Kapandji procedure, and more recently prosthetic replacement for either the ulnar head or the entire DRUJ. Resection arthroplasties have been associated with complications, including instability and radioulnar convergence. The prosthetic replacements have been designed in an attempt to restore more normal DRUJ kinematics. This paper provides a review of the anatomy and biomechanics of the DRUJ and discusses the outcomes of the available surgical options for symptomatic DRUJ arthritis. The arthritic distal radioulnar joint (DRUJ) is a difficult problem. Many of the surgical interventions developed for this condition are associated with complications,such as instability and radioulnar convergence. Recently, prosthetic replacement of either the ulnar head or the entire DRUJ has been advocated in order to better restore the kinematics of the joint. A review of the anatomy and biomechanics of the DRUJ and a discussion of the numerous surgical options and their outcomes is provided. PMID- 26517169 TI - Digit Replantation The First 50 Years. AB - Since the first successful digit replantation by Japanese surgeons Komatsu and Tamai, the past half century has seen the field of digit replantation in the USA experience exponential growth followed by a steady decline in volume of cases and percentage of successful viable digits. The initial enthusiasm and technical progress of digital replantation has been tempered by mediocre functional outcomes, rising healthcare costs, and limited healthcare resources. The history and approach to digit replantation is reviewed and highlights the likely push toward the development of regional replant centers staffed by highly skilled teams to improve the functional outcomes following these complex procedures. More than 50 years have passed since the first successful digit replantation by Komatsu and Tamai who replanted a sharply amputated thumb in a 28-year-old male at the metacarpal-phalangeal joint level in a 4.5 hour procedure. Two arteries and 2 veins were anastomosed using 8-0 monofilament nylon and 7-0 braided silk suture. The patient remained in the hospital for 40 days and did not return to work for 4 months. News of this triumph of microvascular skill was heralded throughout the world as the first successful replantation of a completely amputated digit. Over the past half century, the field of digit replantation in the USA experienced exponential growth followed by a steady decline in volume of cases and percentage of successful viable digits. The initial enthusiasm and technical progress of digital replantation has been tempered by mediocre functional outcomes, rising healthcare costs, and limited healthcare resources. In the next 50 years, it is possible that the majority of digit replantation procedures in the USA may be performed in tertiary centers or regional replant centers by highly skilled teams. PMID- 26517170 TI - The Management of Domestic Animal Bites to the Hand. AB - Hand bites from domestic animals are extremely common. Though many may initially appear benign, it is important for treating physicians to be aware of the factors that place patients sustaining animal bites at additional risk for infection. As clinicians, we must be able to efficiently diagnose and treat these patients properly to avoid the morbidity that animal bites can provoke. The current paper reviews the evaluation and management of domestic animal bites to the hand. PMID- 26517171 TI - Longitudinal Urinary Protein Variability in Participants of the Space Flight Simulation Program. AB - Urine is a valuable material for the diagnosis of renal pathologies and to investigate the effects of their treatment. However, the variability in protein abundance in the context of normal homeostasis remains a major challenge in urinary proteomics. In this study, the analysis of urine samples collected from healthy individuals, rigorously selected to take part in the MARS-500 spaceflight simulation program, provided a unique opportunity to estimate normal concentration ranges for an extended set of urinary proteins. In order to systematically identify and reliably quantify peptides/proteins across a large sample cohort, a targeted mass spectrometry method was developed. The performance of parallel reaction monitoring (PRM) analyses was improved by implementing tight control of the monitoring windows during LC-MS/MS runs, using an on-the-fly correction routine. Matching the experimentally obtained MS/MS spectra with reference fragmentation patterns allowed dependable peptide identifications to be made. Following optimization and evaluation, the targeted method was applied to investigate protein abundance variability in 56 urine samples, collected from six volunteers participating in the MARS-500 program. The intrapersonal protein concentration ranges were determined for each individual and showed unexpectedly high abundance variation, with an average difference of 1 order of magnitude. PMID- 26517172 TI - Single-Crystal Diamond Nanowire Tips for Ultrasensitive Force Microscopy. AB - We report the fabrication, integration, and assessment of sharp diamond tips for ultrasensitive force microscopy experiments. Two types of tips, corresponding to the upper and lower halves of a diamond nanowire, were fabricated by top-down plasma etching from a single-crystalline substrate. The lower, surface-attached halves can be directly integrated into lithographically defined nanostructures, like cantilevers. The upper, detachable halves result in diamond nanowires with a tunable diameter (50-500 nm) and lengths of a few microns. Tip radii were around 10 nm and tip apex angles around 15 degrees . We demonstrate the integration of diamond nanowires for use as scanning tips onto ultrasensitive pendulum-style silicon cantilevers. We find the noncontact friction and frequency jitter to be exceptionally low, with no degradation in the intrinsic mechanical quality factor (Q ~ 130,000) down to tip-to-surface distances of about 10 nm. Our results are an encouraging step toward further improvement of the sensitivity and resolution of force-detected magnetic resonance imaging. PMID- 26517173 TI - Allele frequency data for 15 autosomal STR loci in eight Indonesian subpopulations. AB - Evolutionary and cultural history can affect the genetic characteristics of a population and influences the frequency of different variants at a particular genetic marker (allele frequency). These characteristics directly influence the strength of forensic DNA evidence and make the availability of suitable allele frequency information for every discrete country or jurisdiction highly relevant. Population sub-structure within Indonesia has not been well characterised but should be expected given the complex geographical, linguistic and cultural architecture of the Indonesian population. Here we use forensic short tandem repeat (STR) markers to identify a number of distinct genetic subpopulations within Indonesia and calculate appropriate population sub-structure correction factors. This data represents the most comprehensive investigation of population sub-structure within Indonesia to date using these markers. The results demonstrate that significant sub-structure is present within the Indonesian population and must be accounted for using island specific allele frequencies and corresponding sub-structure correction factors in the calculation of forensic DNA match statistics. PMID- 26517174 TI - Pacifiplex: an ancestry-informative SNP panel centred on Australia and the Pacific region. AB - The analysis of human population variation is an area of considerable interest in the forensic, medical genetics and anthropological fields. Several forensic single nucleotide polymorphism (SNP) assays provide ancestry-informative genotypes in sensitive tests designed to work with limited DNA samples, including a 34-SNP multiplex differentiating African, European and East Asian ancestries. Although assays capable of differentiating Oceanian ancestry at a global scale have become available, this study describes markers compiled specifically for differentiation of Oceanian populations. A sensitive multiplex assay, termed Pacifiplex, was developed and optimized in a small-scale test applicable to forensic analyses. The Pacifiplex assay comprises 29 ancestry-informative marker SNPs (AIM-SNPs) selected to complement the 34-plex test, that in a combined set distinguish Africans, Europeans, East Asians and Oceanians. Nine Pacific region study populations were genotyped with both SNP assays, then compared to four reference population groups from the HGDP-CEPH human diversity panel. STRUCTURE analyses estimated population cluster membership proportions that aligned with the patterns of variation suggested for each study population's currently inferred demographic histories. Aboriginal Taiwanese and Philippine samples indicated high East Asian ancestry components, Papua New Guinean and Aboriginal Australians samples were predominantly Oceanian, while other populations displayed cluster patterns explained by the distribution of divergence amongst Melanesians, Polynesians and Micronesians. Genotype data from Pacifiplex and 34 plex tests is particularly well suited to analysis of Australian Aboriginal populations and when combined with Y and mitochondrial DNA variation will provide a powerful set of markers for ancestry inference applied to modern Australian demographic profiles. On a broader geographic scale, Pacifiplex adds highly informative data for inferring the ancestry of individuals from Oceanian populations. The sensitivity of Pacifiplex enabled successful genotyping of population samples from 50-year-old serum samples obtained from several Oceanian regions that would otherwise be unlikely to produce useful population data. This indicates tests primarily developed for forensic ancestry analysis also provide an important contribution to studies of populations where useful samples are in limited supply. PMID- 26517175 TI - Revealing latitudinal patterns of mitochondrial DNA diversity in Chileans. AB - The territory of Chile is particularly long and narrow, which combined with its mountainous terrain, makes it a unique scenario for human genetic studies. We obtained 995 control region mitochondrial DNA (mtDNA) sequences from Chileans representing populations living at different latitudes of the country from the North to the southernmost region. The majority of the mtDNA profiles are of Native American origin (~88%). The remaining haplotypes are mostly of recent European origin (~11%), and only a minor proportion is of recent African ancestry (~1%). While these proportions are relatively uniform across the country, more structured patterns of diversity emerge when examining the variation from a phylogeographic perspective. For instance, haplogroup A2 reaches ~9% in the North, and its frequency decreases gradually to ~1% in the southernmost populations, while the frequency of haplogroup D (sub-haplogroups D1 and D4) follows the opposite pattern: 36% in the southernmost region, gradually decreasing to 21% in the North. Furthermore, there are remarkable signatures of founder effects in specific sub-clades of Native American (e.g. haplogroups D1j and D4p) and European (e.g. haplogroups T2b3 and K1a4a1a+195) ancestry. We conclude that the magnitude of the latitudinal differences observed in the patterns of mtDNA variation might be relevant in forensic casework. PMID- 26517176 TI - Transcriptional changes in Atlantic salmon (Salmo salar) after embryonic exposure to road salt. AB - Road salt is extensively used as a deicing chemical in road maintenance during winter and has in certain areas of the world led to density stratifications in lakes and ponds, and adversely impacted aquatic organisms in the recipients of the road run-off. Aquatic vertebrates such as fish have been particularly sensitive during fertilisation, as the fertilisation of eggs involves rapid uptake of the surrounding water, reduction in egg swelling and in ovo exposure to high road salt concentrations. The present study aimed to identify the persistent molecular changes occurring in Atlantic salmon (Salmo salar) eggs after 24h exposure to high concentrations (5000 mg/L) of road salt at fertilisation. The global transcriptional changes were monitored by a 60k salmonid microarray at the eyed egg stage (cleavage stage, 255 degree days after fertilisation) and identified a high number of transcripts being differentially regulated. Functional enrichment, pathway and gene-gene interaction analysis identified that the differentially expressed genes (DEGs) were mainly associated with toxiciologically relevant processes involved in osmoregulation, ionregulation, oxidative stress, metabolism (energy turnover), renal function and developmental in the embryos. Quantitative rtPCR analysis of selected biomarkers, identified by global transcriptomics, were monitored in the eggs for an extended range of road salt concentrations (0, 50, 100, 500 and 5000 mg/L) and revealed a positive concentration-dependent increase in cypa14, a gene involved in lipid turnover and renal function, and nav1, a gene involved in neuraxonal development. Biomarkers for osmoregulatory responses such as atp1a2, the gene encoding the main sodium/potassium ATP-fueled transporter for chloride ions, and txdc9, a gene involved in regulation of cell redox homeostasis (oxidative stress), displayed apparent concentration-dependency with exposure, although large variance in the control group precluded robust statistical discrimination between the groups. A No Transcriptional Effect Level (NOTEL) of 50mg/L road salt was found to be several orders of magnitude lower than the adverse effects documented in developing fish embryos elsewhere, albeit at concentrations realistic in lotic systems receiving run-off from road salt. It remains to be determined whether these transcriptional changes may cause adverse effects in fish at ecologically relevant exposure concentrations of road salt. PMID- 26517177 TI - External gamma irradiation-induced effects in early-life stages of zebrafish, Danio rerio. AB - In the general context of validation of tools useful for the characterization of ecological risk linked to ionizing radiation, the effects of an external gamma irradiation were studied in zebrafish larvae irradiated for 96 h with two dose rates: 0.8 mGy/d, which is close to the level recommended to protect ecosystems from adverse effects of ionizing radiation (0.24 mGy/d) and a higher dose rate of 570 mGy/d. Several endpoints were investigated, such as mortality, hatching, and some parameters of embryo-larval development, immunotoxicity, apoptosis, genotoxicity, neurotoxicity and histological alterations. Results showed that an exposure to gamma rays induced an acceleration of hatching for both doses and a decrease of yolk bag diameter for the highest dose, which could indicate an increase of global metabolism. AChE activity decreased with the low dose rate of gamma irradiation and alterations were also shown in muscles of irradiated larvae. These results suggest that gamma irradiation can induce damages on larval neurotransmission, which could have repercussions on locomotion. DNA damages, basal ROS production and apoptosis were also induced by irradiation, while ROS stimulation index and EROD biotransformation activity were decreased and gene expression of acetylcholinesterase, choline acetyltransferase, cytochrome p450 and myeloperoxidase increased. These results showed that ionizing radiation induced an oxidative stress conducting to DNA damages. This study characterized further the modes of action of ionizing radiation in fish. PMID- 26517178 TI - Application of flow cytometry for myelodysplastic syndromes: Pitfalls and technical considerations. AB - The application of flow cytometry (FC) is recommended as part of the diagnostic approach for MDS. The complexity of flow cytometric analysis of bone marrow cells in MDS has been an obstacle for general application. However, in the past years several studies showed practical flow cytometric approaches for the diagnosis and prognosis of MDS. In this report we discuss technical considerations and highlight issues that require special attention when handling and analyzing bone marrow samples of patients with cytopenia and suspicion of MDS. (c) 2015 Clinical Cytometry Society. PMID- 26517179 TI - Self-Assembled Cyclophane-Type Copper(I) Complexes of 2,4,6 Tris(diphenylphosphino)-1,3,5-triazine and Their Catalytic Application. AB - The triazine-based trisphosphine, 2,4,6-tris(diphenylphosphino)-1,3,5-triazine (1) was prepared in improved yield by reacting cyanuric chloride with 3 equiv of trimethylsilyldiphenylphosphine. The solid-state structure of 1 showed short intermolecular P...P contacts of 3.362 A, which is significantly shorter than the sum of the van der Waals radii of phosphorus atoms (3.6 A). The reaction of 2,4,6 tris(diphenylphosphino)-1,3,5-triazine (1) with copper(I) salts in a 2:3 molar ratio yielded various cyclophane-type complexes in quantitative yield. The solid state structures of these clusters have been found to depend on the size of the halide ions, the solvent employed, and the reaction conditions. Copper(I) chloride formed a monomeric metallocyclophane, whereas copper(I) bromide and copper(I) iodide derivatives preferred dimeric and 1D-polymeric structures, respectively. The tricationic complexes derived from Cu(I) ion and 2,4,6 tris(diphenylphosphino)-1,3,5-triazine also adopted monomeric metallocyclophane structures. These complexes have been employed in the A(3) coupling reaction under microwave irradiation. The copper(I) iodide derivative showed excellent catalytic efficiency. PMID- 26517180 TI - Polyallelic structural variants can provide accurate, highly informative genetic markers focused on diagnosis and therapeutic targets: Accuracy vs. Precision. AB - Structural variants (SVs) include all insertions, deletions, and rearrangements in the genome, with several common types of nucleotide repeats including single sequence repeats, short tandem repeats, and insertion-deletion length variants. Polyallelic SVs provide highly informative markers for association studies with well-phenotyped cohorts. SVs can influence gene regulation by affecting epigenetics, transcription, splicing, and/or translation. Accurate assays of polyallelic SV loci are required to define the range and allele frequency of variable length alleles. PMID- 26517181 TI - Improvement of Protein Immobilization and Bioactivity of Magnetic Carriers Using a Brushed Beads-on-Beads Structure. AB - To achieve higher protein immobilization and bioactivity, as well as automatic manipulation, we prepared a new type of biocarrier based on the brushed beads-on beads structure. Many poly(acrylic acid) (PAA) brushed nanoparticles were packed onto the surface of amino-functionalized magnetic particles through an efficient carbodiimide-assisted coupling reaction to attain a hierarchical structure, a unique three-dimensional (3D) space and automatic manipulation characteristics. The proposed biocarrier was evaluated in the recognition capability of the immunocomplex and showed a 6.7-fold increase compared with control beads with a hard surface. The results of this study suggest promising applications in targeted capture and high-performance biodetection processes. PMID- 26517183 TI - Hepatocytes come out of left field. PMID- 26517182 TI - A follow-up on Acute Pain Services in Germany compared to international survey data. AB - BACKGROUND: After the introduction of instruments for benchmarking, certification and a national guideline for acute pain management, the aim of this study was to describe the current structure, processes and quality of German acute pain services (APS). METHODS: All directors of German departments of anaesthesiology were invited to complete a postal questionnaire on structures und processes of acute pain management. The survey asked for staff, techniques and quality criteria, which enabled a comparison to previous data from 1999 and surveys from other countries. RESULTS: Four hundred and eight (46%) questionnaires were returned. APS have increased considerably and are now available in 81% of the hospitals, mainly anaesthesia based. However, only 45% fulfilled the minimum quality criteria, such as the assignment of personnel, the organization of patient care during nights and weekends, written protocols for postoperative pain management, regular assessments and documenting pain scores. Staff resources varied considerably, but increased compared to 1999. Two daily rounds were performed in 71%, either by physicians and nurses (42%), by physicians only (25%) or by supervised nurses (31%). Most personnel assigned to the APS shared this work along with other duties. Only 53% of the hospitals had an integrated rotation for training their specialty trainees. CONCLUSIONS: The availability of APS in Germany and other countries has increased over the last decade; however, the quality of nearly half of the APS is questionable. Against the disillusioning background of recently reported unfavourable pain-related patient outcomes, the structures, organization and quality of APS should be revisited. PMID- 26517184 TI - Categorization of drugs implicated in causing liver injury: Critical assessment based on published case reports. AB - An important element in assessing causality in drug-induced liver injury is whether the implicated agent is known to cause hepatotoxicity. We classified drugs into categories based on the number of published reports of convincingly documented, clinically apparent, idiosyncratic liver injury. Drugs described in the website LiverTox (http://livertox.nih.gov) were classified into five categories based on the number of published cases (category A, >=50; category B, 12-49; category C, 4-11; category D, 1-3; category E, none). Case reports in categories C and D were individually reanalyzed using the Roussel Uclaf Causality Assessment Method. Drugs with fatal cases or with rechallenge were noted. Among 671 individual drugs or closely related agents, 353 (53%) were considered convincingly linked to liver injury in published case reports; 48 (13%) were assigned to category A, 76 (22%) were assigned to category B, 96 (27%) were assigned to category C, and 126 (36%) were assigned to category D. Another 7 (2%) were direct hepatotoxins but only in high doses and placed in a separate category (T). The remaining 318 (47%) drugs had no convincing case report of hepatoxicity in the literature (category E). All except one in category A have been available since 1999, 98% had at least one fatal case and 89% a positive rechallenge. In category B, 54% had a fatal case and 41% a rechallenge. Drugs in categories C and D less frequently had instances of fatal (23% and 7%) or rechallenge cases (26% and 11%). CONCLUSION: Documentation of hepatoxicity in the medical literature is variable, and many published instances do not stand up to critical review. A standardized system for categorizing drugs for hepatotoxicity potential will help develop objective and reliable, computer-based instruments for assessing causality in drug-induced liver injury. PMID- 26517186 TI - Enantioselective Desymmetrization of Glutarimides Catalyzed by Oxazaborolidines Derived from cis-1-Amino-indan-2-ol. AB - Enantioselective reductive desymmetrization of glutarimides has been achieved employing an oxazaborolidine catalyst derived from cis-1-amino-indan-2-ol. The reaction was found to proceed through a stereoablative process that upgraded the enantioselectivity of an intermediate hydroxy-lactam. The reaction was generally tolerant of a number of substituents in the 4-position, giving enantiomeric excesses of greater than 82%. PMID- 26517187 TI - Reaction of CN(-) with F, Cl, O, and S Atoms: Attachment or Associative Detachment? AB - Highly correlated ab initio wave functions within the UCCSD(T)-F12 approach have been used to map the potential energy surfaces (PESs) describing the reactivity of the CN(-) (X(1)Sigma(+)) anion with neutral atoms present in interstellar media (F, Cl, O, and S). With the H atom, for comparison, the reaction [CN( )((1)Sigma(+)) + H((2)S)] evolves along the PES of the X(2)Sigma(+) electronic ground state of HCN(-) (or HNC(-)) until the crossing with the X(1)Sigma(+) electronic ground state of HCN (or HNC), where electron detachment occurs. The process is rather similar to the two halogen atoms F and Cl, with some differences due to the larger electron affinity of the halogens, making possible the existence of ClCN(-) in a (2)Sigma(+) state. The reaction of CN(-) with O and S atoms proceeds via a multistep mechanism. The lowest electronic state at long distance, the (3)Pi state arising from the [CN(-)((1)Sigma(+)) + O/S((3)P)] reaction channel, does not correlate with the X(1)Sigma(+) ground state of the XCN(-) anion (X = O or S). This (3)Pi state and its bent components cross at medium RXC (RXN) distances the X(1)Sigma(+) ground state of XCN(-) or XNC(-), and at shorter distances the X(2)Pi state of the neutral XCN or XNC where the extra electron can detach. With both O and S atoms, it is shown that the spin-orbit couplings can efficiently lead the [CN(-)((1)Sigma(+)) + O/S((3)P)] reaction toward the stable X(1)Sigma(+) ground state of XCN(-) and XNC(-). PMID- 26517188 TI - EEG-detected olfactory imagery to reveal covert consciousness in minimally conscious state. AB - PRIMARY OBJECTIVE: To reveal covert abilities in a minimally conscious state (MCS) through an innovative activation paradigm based on olfactory imagery. RESEARCH DESIGN: Case study. METHODS AND PROCEDURES: A patient in MCS was asked to 'imagine an unpleasant odour' or to 'relax' in response to the appearance on a screen of a downward pointing arrow or a cross, respectively. Electrophysiological responses to stimuli were investigated by means of an 8 channel EEG equipment and analysed using a specific threshold algorithm. The protocol was repeated for 10 sessions separated from each other by 2 weeks. Accuracy, defined as the number of successes with respect to the total number of trials, was used to evaluate the number of times in which the classification strategy was successful. MAIN OUTCOMES AND RESULTS: Analyses of accuracy showed that the patient was able to activate and to relax himself purposefully and that he optimized his performances with the number of sessions, probably as a result of training-related improvements. CONCLUSIONS: Subtle signs of consciousness may be under-estimated and need to be revealed through specific activation tasks. This paradigm may be useful to detect covert signs of consciousness, especially when patients are precluded from carrying out more complex cognitive tasks. PMID- 26517189 TI - Staphylococcus epidermidis as a cause of bacteremia. AB - Staphylococcus epidermidis is a biofilm-producing commensal organism found ubiquitously on human skin and mucous membranes, as well as on animals and in the environment. Biofilm formation enables this organism to evade the host immune system. Colonization of percutaneous devices or implanted medical devices allows bacteria access to the bloodstream. Isolation of this organism from blood cultures may represent either contamination during the blood collection procedure or true bacteremia. S. epidermidis bloodstream infections may be indolent compared with other bacteria. Isolation of S. epidermidis from a blood culture may present a management quandary for clinicians. Over-treatment may lead to patient harm and increases in healthcare costs. There are numerous reports indicating the difficulty of predicting clinical infection in patients with positive blood cultures with this organism. No reliable phenotypic or genotypic algorithms currently exist to predict the pathogenicity of a S. epidermidis bloodstream infection. This review will discuss the latest advances in identification methods, global population structure, pathogenicity, biofilm formation, antimicrobial resistance and clinical significance of the detection of S. epidermidis in blood cultures. Previous studies that have attempted to discriminate between invasive and contaminating strains of S. epidermidis in blood cultures will be analyzed. PMID- 26517191 TI - Gold(I)-Catalyzed Dearomative [2+2]-Cycloaddition of Indoles with Activated Allenes: A Combined Experimental-Computational Study. AB - The gold-catalyzed synthesis of methylidene 2,3-cyclobutane-indoles is documented through a combined experimental/computational investigation. Besides optimizing the racemic synthesis of the tricyclic indole compounds, the enantioselective variant is presented to its full extent. In particular, the scope of the reaction encompasses both aryloxyallenes and allenamides as electrophilic partners providing high yields and excellent stereochemical controls in the desired cycloadducts. The computational (DFT) investigation has fully elucidated the reaction mechanism providing clear evidence for a two-step reaction. Two parallel reaction pathways explain the regioisomeric products obtained under kinetic and thermodynamic conditions. In both cases, the dearomative C?C bond-forming event turned out to be the rate-determining step. PMID- 26517190 TI - Resistance to reverse transcriptase inhibitors used in the treatment and prevention of HIV-1 infection. AB - Inhibitors that target the retroviral enzyme reverse transcriptase (RT) have played an indispensable role in the treatment and prevention of HIV-1 infection. They can be grouped into two distinct therapeutic groups, namely the nucleoside and nucleotide RT inhibitors (NRTIs), and the non-nucleoside RT inhibitors (NNRTIs). NRTIs form the backbones of most first- and second-line antiretroviral therapy (ART) regimens formulated for the treatment of HIV-1 infection. They are also used to prevent mother-to-child transmission, and as pre-exposure prophylaxis in individuals at risk of HIV-1 infection. The NNRTIs nevirapine (NVP), efavirenz and rilpivirine also used to form part of first-line ART regimens, although this is no longer recommended, while etravirine can be used in salvage ART regimens. A single-dose of NVP administered to both mother and child has routinely been used in resource-limited settings to reduce the rate of HIV-1 transmission. Unfortunately, the development of HIV-1 resistance to RT inhibitors can compromise the efficacy of these antiviral drugs in both the treatment and prevention arenas. Here, we provide an up-to-date review on drug-resistance mutations in HIV-1 RT, and discuss their cross-resistance profiles, molecular mechanisms and clinical significance. PMID- 26517192 TI - Oxidative Damage to Biomimetic Membrane Systems: In Situ Fe(II)/Ascorbate Initiated Oxidation and Incorporation of Synthetic Oxidized Phospholipids. AB - Damage to cellular membranes from oxidative stress has been implicated in aging related diseases. We report the effects of oxidative damage on the structure and properties of biomimetic phospholipid membrane systems. Two oxidation methods were used, in situ oxidation initiated using Fe(II) and ascorbate, and the incorporation of a synthetic "oxidized" phospholipid, PoxnoPC, into biomimetic membranes. The biomimetic systems employed included multibilayer stacks, tethered bilayers, and phospholipid monolayers studied using a combination of reflectometry, attenuated total reflection infrared spectroscopy, electrochemical impedance spectroscopy, and neutron diffraction. We show that oxidation with Fe(II) and ascorbate caused an increase in the order of the membrane, attributed to cross-linking of the phospholipids, and a change in the electrical permeability of the membrane, but no significant impact on the thickness or completeness of the membrane. Incorporation of PoxnoPC, on the other hand, had a larger impact on the structure of the membrane. Inversion of the aldehyde terminated truncated sn-2 chain of PoxnoPC into the head group region was observed, along with a slight decrease in the thickness and order of the membrane. PMID- 26517194 TI - ATM serine-1981 phosphorylation is a plausible biomarker. PMID- 26517195 TI - Appetite for ER/nucleus destruction. PMID- 26517196 TI - Tetraploidy and CIN: a dangerous combination. PMID- 26517197 TI - Short-term effects of ambient air pollutants on asthma-related emergency department visits in Indianapolis, Indiana, 2007-2011. AB - OBJECTIVE: We estimate the short-term associations between daily changes in ambient air pollutants and daily asthma-related emergency department (ED) visits in Indianapolis, IN. METHODS: We identified asthma-related ED visits among Indianapolis residents aged >=5 years. We used Poisson regression in a time series framework to estimate the increased risk for asthma-related ED visits from exposure to ambient SO2, PM2.5 and ozone during the warm season (April-September) and SO2 and PM2.5 during the cold (October-March) season, from 2007 to 2011. Our models controlled for measured confounders, including weather and respiratory infections, as well as unmeasured confounders using a natural cubic spline to account for long-term seasonal trends. RESULTS: During 2007-2011 in Indianapolis, 165,056 asthma-related ED visits occurred. We found statistically significant positive associations (p < 0.05) between ambient air pollutants and ED visits during the warm season for persons aged 5-44 years. Interquartile range increases in daily ozone concentrations with same day, 2-day lagged, and 3-day moving average were associated with increased risks for ED visits of 3.2% (95% CI: 0.2%, 6.3%), 4.4% (0.1%, 8.9%) and 4.8% (0.2%, 9.6%), respectively. Interquartile range increases in 3-day moving averages for SO2 were associated with an increased risk of 3.3% (95% CI: 0.2%, 6.5%). We identified statistically significant associations (p < 0.05) between increased SO2 and PM2.5 levels and decreased ED visits among some age groups, primarily during the cold season, and no significant positive associations between changes in PM2.5 concentration and asthma-related ED visits. CONCLUSIONS: During the warm season, increases in ozone and SO2 concentrations were associated with increased asthma morbidity in children and young adults in Indianapolis. These results will enable reliable estimation of the health impacts of increases in these pollutants on asthma related ED visits in Indianapolis and similar communities. PMID- 26517199 TI - Efficacy and safety of abatacept in a patient with rheumatoid arthritis and concomitant Staphylococcus aureus osteomyelitis. PMID- 26517200 TI - NF-kappaB Inhibition Resolves Cognitive Deficits in Experimental Type 2 Diabetes Mellitus through CREB and Glutamate/GABA Neurotransmitters Pathway. AB - Diabetes is associated with deficits in memory and cognitive functions and sustained inflammation. Recently, involvement of NF-kappaB (nuclear factor kappa light-chain-enhancer of activated B cells) has been postulated in many cognitive functions, immune system and inflammation. Despite of role of NF-kappaB in inflammation, a large gap remains in understanding of the mechanisms and consequences of NF-kappaB activation in the central nervous system.In this study, we have evaluated the effects of NF-kappaB activation inhibitor on memory function, neurotransmitter levels changes and brain inflammatory cytokines in type-2 diabetic rats. BAY 11-7082 (BAY) was used as a pharmacological inhibitor of IkappaBalpha (inhibitor of kappa B alpha) phosphorylation to block NF-kappaB activation. Type-2 diabetic rats showed significant memory impairment at 15(th) week. Three weeks BAY treatment produced significant increase in Morris water maze test learning and memory performance. Diabetic animals also showed improved performance in passive avoidance and Y-maze test paradigm following treatment with NF-kappaB inhibitor BAY. BAY treatment did not show any significant effect on blood glucose and insulin levels. NF-kappaB inhibition significantly reduced neuroinflammation as evidenced by decrease in IL-6 and TNF-alpha levels. BAY treatment in diabetic rats also increased the phosphorylation of CREB which indicates that the NF-kappaB activation inhibitor engage a CREB regulated mechanism in-vivo. Moreover, BAY also reversed the alterations in brain glutamate and GABA levels in diabetic rats. These findings corroborate that NF-kappaB inhibition may be an effective treatment strategy in diabetes associated cognitive deficits. PMID- 26517201 TI - A Novel Approach to Improve Time to First Shock in Prehospital STEMI Complicated by Ventricular Fibrillation. AB - Lethal cardiac arrhythmias such as ventricular fibrillation and pulseless ventricular tachycardia (VF/pVT) complicate up to 6% of all out-of-hospital STEMIs. Typically, paramedics respond to this by applying defibrillation pads and delivering a shock as soon as possible. A recently introduced "pads-on" protocol directed paramedics to apply defibrillation pads to all STEMI patients (regardless of clinical stability) with the aim of decreasing time to first shock. In this article we present two cases of prehospital STEMI complicated by VF to illustrate times to first shock for the two different protocols. One case each of a STEMI complicated by VF before implementation of the pads-on protocol and after the implementation of the protocol is presented. An important difference in the time to first shock is noted between the two patients with STEMI complicated by VF. While it took 2 min 43 s for the pads-off patient to be defibrillated, only 27 s elapsed before the pads-on patient was defibrillated. These two cases demonstrate that the application of defibrillation pads immediately following the diagnosis of prehospital STEMI has the potential to decrease the time to shock in patients suffering VF/pVT. PMID- 26517202 TI - Effect of aripiprazole lauroxil on agitation and hostility in patients with schizophrenia. AB - This study aimed to evaluate the effects of aripiprazole lauroxil on hostility and aggressive behavior in patients with schizophrenia. Patients aged 18-70 years with a diagnosis of schizophrenia and currently experiencing an acute exacerbation or relapse were randomized to intramuscular (IM) aripiprazole lauroxil 441 mg (n=207), 882 mg (n=208), or placebo (n=207) for 12 weeks. In post hoc analyses, hostility and aggression were assessed by the Positive and Negative Syndrome Scale (PANSS) Hostility item (P7) and a specific antihostility effect was assessed by adjusting for positive symptoms of schizophrenia, somnolence, and akathisia. The PANSS excited component score [P4 (Excitement), P7 (Hostility), G4 (Tension), G8 (Uncooperativeness), and G14 (Poor impulse control)], and the Personal and Social Performance scale disturbing and aggressive behavior domain were also assessed. Of the 147 patients who received aripiprazole lauroxil 882 mg and with a baseline PANSS Hostility item P7 more than 1, there was a significant (P<0.05) improvement versus placebo on the PANSS Hostility item P7 score by mixed model repeated-measures at the end of the study, which remained significant when PANSS-positive symptoms and somnolence or akathisia were included as additional covariates. The proportion with PANSS Hostility item P7 more than 1 at endpoint was significantly (P<0.05) lower with aripiprazole lauroxil versus placebo (53.6, 46.1, and 66.3% for 441, 882 mg, and placebo). A significant (P<0.05) improvement was found with aripiprazole lauroxil versus placebo for change from baseline in the PANSS excited component score. The proportion of patients with aggressive behavior on the Personal and Social Performance scale was significantly (P<0.05) lower for aripiprazole lauroxil: 30.0% for 441 mg versus 44.1% for placebo (P=0.006) and 22.2% for 881 mg (P<0.001 versus placebo). Treatment with aripiprazole lauroxil resulted in decreases in agitation and hostility in patients with schizophrenia and this antihostility effect appears to be independent of a general antipsychotic effect. PMID- 26517203 TI - Histopathology, Immunohistochemistry, and Electron Microscopic features of a Dacryocystorhinostomy Ostium Cicatrix. AB - PURPOSE: The aim of this study is to report the histopathological, Immunohistochemical, and ultrastructural features of a dacryocystorhinostomy ostium cicatrix. METHODS: A prospective histopathological study was performed in a tertiary eye care setting. Scarred nasal mucosal tissues obtained during endoscopic revisions of 10 previously failed dacryocystorhinostomies secondary to complete cicatricial closure of the ostia were studied. The tissue specimens were analyzed using hematoxylin and eosin, periodic acid-Schiff staining. Special stains used include Masson's trichrome and Alizarin red. Immunohistochemistry was performed using vimentin, smooth muscle actin, CD3, CD5, and CD20. Specimens were processed for ultrastructural analysis as per standard protocols for transmission electron microscopy. RESULTS: The respiratory epithelial regeneration was noted to be complete. Irregular laying of deeply eosinophilic and hyalinized collagen with intervening fibroblasts was noted. Focal areas of new bone formation were seen within the cicatricial tissue with osteocytes and ongoing osteoblastic rimming. The infiltrates were mixture of both T and B lymphocytes and were positive for CD3, CD5, and CD20 immunostaining. Electron microscopy showed disorganized collagen fibrils with numerous fibroblasts and mononuclear inflammatory infiltrate. Amorphous bony osteoid within a fibrillar background with metabolically active osteoblasts showed a vesicular cytoplasm, hyperplastic proliferating mitochondria, large Golgi apparatus, and dense endoplasmic reticulum. CONCLUSION: There is new bone formation within the dense connective tissues of a dacryocystorhinostomy cicatrix. This study may provide useful inputs for further basic science studies aimed at better understanding of wound healing in failed dacryocystorhinostomy. PMID- 26517204 TI - Solid-State Conversion Chemistry of Multicomponent Nanocrystals Cast in a Hollow Silica Nanosphere: Morphology-Controlled Syntheses of Hybrid Nanocrystals. AB - During thermal transformation of multicomponent nanocrystals in a silica nanosphere, FeAuPd alloy nanocrystals migrate outward and thereby leave a cavity in the silica matrix. Oxidation then converts these nanocrystals back into phase segregated hybrid nanocrystals, AuPd@Fe3O4, with various morphologies. The FeAuPd to-AuPd@Fe3O4 transformation was cast by the in situ generated hollow silica mold. Therefore, the morphological parameters of the transformed AuPd@Fe3O4 are defined by the degree of migration of the FeAuPd in the hollow silica nanoshell. This hollow silica-cast nanocrystal conversion was studied to develop a solid state protocol that can be used to produce a range of hybrid nanocrystals and that allows for systematic and sophisticated control of the resulting morphologies. PMID- 26517205 TI - Analysis of Panel Reactive Antibodies in Renal Transplant Recipients Detected by Luminex: A Single-Center Experience. AB - OBJECTIVES: The role of panel reactive antibody has gained universal acceptance in solid-organ transplant. This parameter is used to gauge the level of sensitization of prospective solid-organ recipients. More than one-third of patients on wait lists for kidney transplant are sensitized. Most have previously formed donor-specific and non-donor-specific serum antibodies and/or positive crossmatch by complement-dependent cytotoxicity and/or flow cytometry. We present the rate of positivity at our institution for human leukocyte antigen antibodies and describe the condensation of antibodies in human leukocyte antigens for renal pretransplant recipients. MATERIALS AND METHODS: Between January 2011 and December 2012, six hundred twenty consecutive renal transplant recipients on the wait list at the Baskent University were evaluated for this retrospective study. Panel reactive antibody screening and definition tests were studied with Luminex assays for the combination of class I (A, B, C) and class II antigens (DR, DQ). RESULTS: We found a panel reactive antibody screening positivity in 20.4% of our patients on renal transplant waiting list. Panel reactive antibody defining tests were meaningful in 12.2% of the whole list. We observed that only panel reactive antibody class I positivity was seen in 2.2%, only panel reactive antibody class II positivity was seen in 2.7%, and both panel reactive antibody class I and class II positivities were seen in 7.2% of the defining tests. CONCLUSIONS: The estimated risk of sensitization for patients with a living donor is determined from the combined results of the crossmatch with the donor and those of the recipient's panel reactive and donor-specific antibodies. Compared with complement-dependent cytotoxicity crossmatch, Luminex assays provide greater sensitivity and specificity in detection of donor-specific antibodies. PMID- 26517206 TI - Observation of residual disorder in the centre of amorphous solid water films after pore collapse at 125 K. AB - The rapid structural re-organisation of porous amorphous solid water, grown to thicknesses in the range 2.5-70 MUm by vapour deposition on a copper substrate at 75 K, after heating to 125 K has been found to leave a MUm-wide band of residual disorder-for example, nm-sized closed pores-in the centre of the film. This layer was revealed by thinning the film by sublimation and continuously measuring the fraction of 1.5 keV positrons implanted into the film which forms ortho positronium in the top 150 nm and decays into three gamma photons. PMID- 26517208 TI - Here comes the sun: the era of genetics. PMID- 26517209 TI - Challenges to understand the mitochondrial respiratory diseases caused by mitochondrial DNA mutations. PMID- 26517207 TI - Summary of Notifiable Noninfectious Conditions and Disease Outbreaks: Elevated Blood Lead Levels Among Employed Adults - United States, 1994-2012. PMID- 26517210 TI - Genetic predisposition to higher production of interleukin-6 through -174 G > C polymorphism predicts global cognitive decline in oldest-old with cognitive impairment no dementia. AB - Interleukin 6 (IL-6) is a pro-inflammatory cytokine upregulated in neurodegenerative contexts. The polymorphism IL-6 -174 G > C influences release levels of this cytokine. We aimed to evaluate the influence of IL-6 -174 G > C on global cognitive score of a group with cognitive impairment no dementia in one year of follow-up.Methods The subjects were categorized in two groups: short-term decline in global cognitive score and those with short-term stability or improvement. IL-6 174 G > C information were compared among these groups.Results We observed that individuals with cognitive impairment no dementia with GGlowergenotype were more frequent among global cognitive score non-decliners while carriers of at least one Chigherallele were more frequent in the group with global cognitive score decliners (p = 0.012; RR = 3.095 IC95%= 1.087 8.812).Conclusion These results suggest that the higher expression of IL-6 gene may be an independent risk factor for cognitive decline among individuals with cognitive impairment no dementia. PMID- 26517211 TI - Idiopathic very late-onset cerebellar ataxia: a Brazilian case series. AB - The authors present a Brazilian case series of eight patients with idiopathic very-late onset (mean 75.5 years old) cerebellar ataxia, featuring predominantly gait ataxia, associated with cerebellar atrophy. METHOD: 26 adult patients with a diagnosis of idiopathic late onset cerebellar ataxia were analyzed in a Brazilian ataxia outpatient clinic and followed regularly over 20 years. Among them, 8 elderly patients were diagnosed as probable very late onset cerebellar ataxia. These patients were evaluated with neurological, ophthalmologic and Mini-Mental Status examinations, brain MRI, and EMG. RESULTS: 62.5% of patients were males, mean age was 81.9 years-old, and mean age of onset was 75.5 years. Gait cerebellar ataxia was observed in all patients, as well as, cerebellar atrophy on brain MRI. Mild cognitive impairment and visual loss, due to macular degeneration, were observed in 50% of cases. Chorea was concomitantly found in 3 patients. CONCLUSION: We believe that this condition is similar the one described by Marie-Foix-Alajouanine presenting with mild dysarthria, associated with gait ataxia, and some patients had cognitive dysfunction and chorea. PMID- 26517212 TI - The competition with a concurrent cognitive task affects posturographic measures in patients with Parkinson disease. AB - OBJECTIVES: To estimate the impact of a sensory-motor- cognitive task on postural balance, in Parkinson disease patients (Hoehn and Yahr 2-3) and to investigate possible relationships between posturography and functional balance clinical scales. METHOD: Parkinson disease patients (n = 40) and healthy controls (n = 27) were evaluated with fluency tests, Berg Balance scale, Mini Best test and static posturography on the conditions eyes open, eyes closed and dual-task (simultaneous balance and fluency tasks). RESULTS: Posturographic data showed that Parkinson disease patients performed worse than controls in all evaluations. In general, balance on dual-task was significantly poorer than balance with eyes closed. Posturographic data were weakly correlated to clinical balance scales. CONCLUSION: In clinical practice, Parkinson disease patients are commonly assessed with eyes closed, to sensitize balance. Our study showed that adding a cognitive task is even more effective. Static posturographic data should be carefully overgeneralized to infer functional balance impairments. PMID- 26517213 TI - Temporomandibular disorder is more prevalent among patients with primary headaches in a tertiary outpatient clinic. AB - OBJECTIVE: The aim of this study was to estimate the prevalence of signs and symptoms of temporomandibular disorders (TMD) in patients with primary headaches attended in a tertiary neurology ambulatory. METHOD: Authorized by the Ethics Committee, the present cross-sectional study was conducted with a random sample of patients screened for orofacial pain and primary headaches at a tertiary hospital in Northeast of Brazil. RESULTS: The sample consisted in 42 patients with primary headache, 59.5% male. The prevalence of > 6 TMD signs and symptoms was 54.8%. In those patients with migraine TMD was present in 71.4% and in tension-type headache in 38.1% (p = 0.030; OR = 4.1). TMD was related to the clinical status of headache associated or attributed to medication overuse (p = 0.001). CONCLUSION: TMD has a high prevalence in patients with primary headaches (54.8%). Special attention must be given to patients with migraine and headache associated or attributed to medication overuse. PMID- 26517214 TI - Alpha power oscillation in the frontal cortex under Bromazepam and Modafinil effects. AB - OBJECTIVE: Our aim was to investigate and compare the neuromodulatory effects of bromazepam (6 mg) and modafinil (200 mg) during a sensorimotor task analyzing the changes produced in the absolute alpha power. METHOD: The sample was composed of 15 healthy individuals exposed to three experimental conditions: placebo, modafinil and bromazepam. EEG data were recorded before, during and after the execution of the task. A three-way ANOVA was applied, in order to compare the absolute alpha power among the factors: Group (control, bromazepam and modafinil) Condition (Pre and Post-drug ingestion) and Moment (pre and post-stimulus). RESULTS: Interaction was found between the group and condition factors for Fp1, F4 and F3. We observed a main effect of moment and condition for the Fp2, F8 and Fz electrodes. CONCLUSION: We concluded that drugs may interfere in sensorimotor processes, such as in the performance of tasks carried out in an unpredictable scenario. PMID- 26517215 TI - Gross-total resection of temporal low grade gliomas is a critically important factor in achieving seizure-freedom. AB - OBJECTIVE: To present a surgical series of patients with low grade temporal gliomas causing intractable epilepsy, focusing on long-term seizure outcome. METHOD: A retrospective study was conducted with patients with temporal low-grade gliomas (LGG). RESULTS: Sixty five patients with were operated in our institution. Males were more affected than females and the mean age at surgery was 32.3 +/- 8.4 (9-68 years). The mean age at seizure onset was 25.7 +/- 9.2 (11 66 years). Seizure outcome was classified according with Engel classification. After one year of follow up, forty two patients (64.6%) were Engel I; seventeen (26.2%) Engel II; four (6.2%) Engel III and two (3.1%) Engel IV. Statistically significant difference in seizure outcome was obtained when comparing the extension of resection. Engel I was observed in 39 patients (69.6%) with total resection and in only 3 (33.3%) patients with partial resection. CONCLUSION: Gross-total resection of temporal LGGs is a critically important factor in achieving seizure-freedom. PMID- 26517216 TI - Screening of cognitive impairment in patients with Parkinson's disease: diagnostic validity of the Brazilian versions of the Montreal Cognitive Assessment and the Addenbrooke's Cognitive Examination-Revised. AB - OBJECTIVE: The aim of the present study is to examine the accuracy of the Brazilian versions of the Montreal Cognitive Assessment (MoCA) and the Addenbrooke's Cognitive Examination-Revised (ACE-R) to screen for mild cognitive impairment (PDMCI) and dementia (PDD) in patients with Parkinson's disease (PD). METHOD: Both scales were administered to a final convenience sample of 79 patients with PD. Patients were evaluated by a neurologist, a psychiatrist and a neuropsychologist using UPDRS, Hoehn and Yahr and Schwab and England scales, global deterioration scale, a psychiatric structured interview, Mattis Dementia Rating Scale and other cognitive tests. RESULTS: There were 32 patients with PDMCI and 17 patients with PDD. The MoCA and the ACE-R were able to discriminate patients with PDD from the others. CONCLUSION: Both scales showed to be useful to screen for dementia but not for mild cognitive impairment in patients with PD. PMID- 26517217 TI - Is the omega sign a reliable landmark for the neurosurgical team? An anatomical study about the central sulcus region. AB - The central sulcus region is an eloquent area situated between the frontal and parietal lobes. During neurosurgical procedures, it is sometimes difficult to understand the cortical anatomy of this region.Objective Find alternative ways to anatomically navigate in this region during neurosurgical procedures.Method We analyzed eighty two human hemispheres using a surgical microscope and completed a review of the literature about central sulcus region.Results In 68/82 hemispheres, the central sulcus did not reach the posterior ramus of the lateral sulcus. A knob on the second curve of the precentral gyrus was reliably identified in only 64/82 hemispheres.Conclusion The morphometric data presented in this article can be useful as supplementary method to identify the central sulcus region landmarks. PMID- 26517218 TI - Cross-cultural adaptation of the SCATBI instrument for cognitive-linguistic abilities after traumatic brain injury. AB - OBJECTIVE: To perform the cross-cultural adaptation of the "Scales of Cognitive Ability for Traumatic Brain Injury" (SCATBI). METHOD: After the translation and back-translation phases, a multidisciplinary committee judged and elaborated versions in order to maintain its conceptual equivalence, content, comprehensibility and contextual adjustment for Brazilian population. The final version was tested on 55 healthy subjects. RESULTS: The individuals' mean age was 41.75 +/- 17.40 years (range = 18-81), 69% were women and they had a mean schooling of 12.96 +/- 4.55 years. Higher total scores were positively correlated with years of schooling (p < 0.001) and social-economic status (p = 0.001), while older aged individuals performed worse than younger ones (p = 0.001). Both genders performed similarly on all domains of the instrument, except for "organization" ability, where women performed significantly better than men (p = 0.02). CONCLUSION: The Brazilian version of SCATBI is a useful tool for the diagnosis and monitoring of cognitive impairments after a traumatic brain injury. PMID- 26517219 TI - Recent developments in the genetics of childhood epileptic encephalopathies: impact in clinical practice. AB - Recent advances in molecular genetics led to the discovery of several genes for childhood epileptic encephalopathies (CEEs). As the knowledge about the genes associated with this group of disorders develops, it becomes evident that CEEs present a number of specific genetic characteristics, which will influence the use of molecular testing for clinical purposes. Among these, there are the presence of marked genetic heterogeneity and the high frequency of de novo mutations. Therefore, the main objectives of this review paper are to present and discuss current knowledge regarding i) new genetic findings in CEEs, ii) phenotype-genotype correlations in different forms of CEEs; and, most importantly, iii) the impact of these new findings in clinical practice. Accompanying this text we have included a comprehensive table, containing the list of genes currently known to be involved in the etiology of CEEs. PMID- 26517220 TI - When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis? AB - Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical manifestations of the disease: stroke-like episodes, encephalopathy, evidence of mitochondrial dysfunction (laboratorial or histological) and known mitochondrial DNA gene mutations. Clinical features of MELAS are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALeu(UUR) gene of the DNAmt, mainly A3243G, are responsible for more of 80% of MELAS cases. Morphological changes seen upon muscle biopsy in MELAS include a substantive proportion of ragged red fibers (RRF) and the presence of vessels with a strong reaction for succinate dehydrogenase. In this review, we discuss mainly diagnostic criterion, clinical and laboratory manifestations, brain images, histology and molecular findings as well as some differential diagnoses and current treatments. PMID- 26517221 TI - Life and death of Vladimir Mikhailovich Bekhterev. AB - Vladimir Mikhailovich Bekhterev was a Russian innovative neuroscientist, extraordinary in the study, diagnosis, and research in the fields of neurology, psychology, morphology, physiology, and psychiatry. Considering the ample and multifaceted scientific feats, only some are touched in a very brief manner. However, it is necessary to highlight his contributions to neurology, with the description of structures, signs and syndromes, to physiology, including reflexology, which later underpinned behaviorism, to psychology, including objective psychology and suggestion. His accomplishments and legacy remained until the present days. Some comments about the scenery that involved his death are also presented. PMID- 26517222 TI - Friedrich Nietzsche: the wandering and learned neuropath under Dionisius. AB - Friedrich Nietzsche (1844-1900) was a remarkable philologist-philosopher while remaining in a condition of ill-health. Issues about his wandering/disruptive behavior that might be a consequence and/or protection against his cognitive decline and multifaceted disease are presented. The life complex that raises speculations about its etiology is constituted by: insight, creativity and wandering behavior besides several symptoms and signs of disease(s), mainly neurological one. The most important issue to be considered at the moment is not the disease diagnosis (Lissauer's general paresis or CADASIL, e.g.), but the probable Nietzsche's great cognitive reserve linked to the multifactorial etiology (genetic and environmental), and shared characteristics both to creativity and psychopathology. This makes any disease seems especial regarding Nietzsche, and whichever the diagnostic hypothesis has to consider the Nietzsche's unique background to express any disease(s). PMID- 26517223 TI - MRI of trigeminal zoster. PMID- 26517224 TI - Acute post-infectious cerebellitis. PMID- 26517225 TI - Improvement initiative in stroke care. PMID- 26517226 TI - Lean thinking to mind the gap in healthcare management. PMID- 26517228 TI - Survival Impact of Pulmonary Metastasis as Recurrence of Pancreatic Ductal Adenocarcinoma. AB - AIM: This study aimed at investigating the survival impact of pancreatic ductal adenocarcinoma (PDAC) recurrence as pulmonary metastasis. METHODS: We performed a retrospective case-control study of 142 patients who underwent curative resection for PDAC at our institution between 2003 and 2012. Clinicopathological features were compared among patients stratified according to the recurrence pattern and pulmonary metastasis treatment strategy. RESULTS: Patients underwent pancreaticoduodenectomy (n = 96), distal (n = 42), or total pancreatectomy (n = 4). At the last follow-up, 99 patients had developed recurrent post-resection PDAC, including 14 cases of isolated pulmonary recurrence. The median overall survival was significantly longer for patients with isolated pulmonary recurrence (40.3 months) than with other metastases (20.9 months; HR 5.85; p = 0.0156). Two patients underwent resection for isolated pulmonary recurrence, and both survived for ~70 months after primary resection. CONCLUSION: Patients with first recurrence of PDAC as pulmonary metastasis had a better prognosis than patients with other types of metastases. Moreover, when isolated pulmonary metastasis is controlled for a certain period, pulmonary resection is likely to improve patient survival. PMID- 26517229 TI - Light harvesting in photonic crystals revisited: why do slow photons at the blue edge enhance absorption? AB - Light harvesting enhancement by slow photons in photonic crystal catalysts or dye sensitized solar cells is a promising approach for increasing the efficiency of photoreactions. This structural effect is exploited in inverse opal TiO2 photocatalysts by tuning the red edge of the photonic band gap to the TiO2 electronic excitation band edge. In spite of many experimental demonstrations, the slow photon effect is not fully understood yet. In particular, observed enhancement by tuning the blue edge has remained unexplained. Based on rigorous couple wave analysis simulations, we quantify light harvesting enhancement in terms of absorption increase at a specific wavelength (monochromatic UV illumination) or photocurrent increase (solar light illumination), with respect to homogeneous flat slab of equivalent material thickness. We show that the commonly accepted explanation relying on light intensity confinement in high (low) dielectric constant regions at the red (blue) edge is challenged in the case of TiO2 inverse opals because of the sub-wavelength size of the material skeleton. The reason why slow photons at the blue edge are also able to enhance light harvesting is the loose confinement of the field, which leads to significant resonantly enhanced field intensity overlap with the skeleton in both red and blue edge tuning cases, yet with different intensity patterns. PMID- 26517230 TI - Knee Osteoarthritis in Type 2 Diabetes Mellitus: Does Insulin Therapy Retard Osteophyte Formation? AB - OBJECTIVE: The aim of this study was to investigate whether or not radiographic changes observed in knee osteoarthritis (OA) in type 2 diabetes mellitus (T2DM) patients on insulin therapy differed from those not on insulin. MATERIAL AND METHODS: A cross-sectional study was performed in 311 subjects: 211 T2DM patients and 100 without diabetes (controls) in Mubarak Hospital, Kuwait. Patients were categorized into 3 groups: T2DM patients not on insulin (G1, n = 99), T2DM patients on insulin (G2, n = 112) and a nondiabetic control group (G3, n = 100). Plain X-ray of both knees was used to assess the changes of knee OA and graded using the Kellegren-Lawrence scale (0-4) and the Osteoarthritis Research Society International Atlas grading scale (0-3). A total of 622 knee X-rays were evaluated. SPSS version 21.0 was used for data analysis. RESULTS: A highly significant association (p < 0.0001) was observed for joint space narrowing (JSN) as well as for osteophyte formation between the three groups. Comparing G2 and G3, a highly significant association (p < 0.0001) was retained for JSN [201 (89.7%) vs. 199 (99.5%)] and for osteophyte formation [26 (11.7%) vs. 72 (36.0%)]. Comparing G1 and G2, significantly less osteophyte formation was noted in G2 patients compared to G1 patients [26 (11.7%) vs. 39 (19.7%), p = 0.02]. Multivariate logistic regression analysis showed that the G2 group had less chance of osteophyte formation than either the G1 group or G3 control group (OR = 0.294, p = 0.008 and OR = 0.098, p < 0.001, respectively). CONCLUSION: Our findings show that T2DM patients with OA knees on insulin therapy have less radiographic osteophytes compared to T2DM patients not on insulin. PMID- 26517231 TI - Two Serious Complications of Peripherally Inserted Central Catheters Indicating the Need to Formalize Training for Placing Central Venous Vascular Access Devices. AB - Peripherally inserted central catheters are being used in increasing numbers. Common (thrombosis, infection, phlebitis, malfunction, or disconnection) and rare complications (pericardial tamponade) have been well explored. We describe 2 serious complications that resolved without sequelae. Both complications occurred in the context of limited provider competence. We conclude that vascular access is more than "just" placing a catheter; it can have serious clinical impact and has evolved into a specialist skill. With increasing use of intravascular catheters, the need for a formalized training becomes urgent. PMID- 26517232 TI - Improving Intensive Care Unit and Ward Utilization by Adapting Master Surgery Schedules. AB - With increasing organizational and financial pressure on hospitals, each individual surgical treatment has to be reviewed and planned thoroughly. Apart from the expensive operating room facilities, proper staffing and planning of downstream units, like the wards or the intensive care units (ICUs), should be considered as well. In this article, we outline the relationship between a master surgery schedule (MSS), i.e., the assignment of surgical blocks to medical specialties, and the bed demand in the downstream units using an analytical model. By using historical data retrieved from the clinical information system and a patient flow model, we applied a recently developed algorithm for predicting bed demand based on the MSSs for patients of 3 surgical subspecialties of a hospital. Simulations with 3 different MSSs were performed. The impact on the required amount of beds in the downstream units was analyzed. We show the potential improvements of the current MSS considering 2 main goals: leveling workload among days and reduction of weekend utilization. We discuss 2 different MSSs, one decreasing the weekend ICU utilization by 20% and the other one reducing maximum ward bed demand by 7%. A test with 12 months of real-life data validates the results. The application of the algorithm provides detailed insights for the hospital into the impact of MSS designs on the bed demand in downstream units. It allowed creating MSSs that avoid peaks in bed demand and high weekend occupancy levels in the ICU and the ward. PMID- 26517233 TI - Anesthesia Management for Palliative Surgery of Massive Hepatic Metastatic Melanoma. AB - We report the perioperative management of a patient with melanoma. Surgical intervention was withheld at multiple institutions because of the presence of metastases; the patient was undergoing experimental immunotherapy and had responded everywhere except in the liver. She underwent hepatic right trisegmentectomy to improve her quality of life and to allow resumption of immunotherapy. Dyspnea because of heart compression, pleural effusion, lung collapse, and pulmonary emboli improved. She died of late complications. This case highlights physiologic and ethical considerations. PMID- 26517234 TI - Perioperative Care Coordination Measurement: A Tool to Support Care Integration of Pediatric Surgical Patients. AB - The relationship of care coordination activities and outcomes to resource utilization and personnel costs has been evaluated for a number of pediatric medical home practices. One of the first tools designed to evaluate the activities and outcomes for pediatric care coordination is the Care Coordination Measurement Tool (CCMT). It has become widely used as an instrument for health care providers in both primary and subspecialty care settings. This tool enables the user to stratify patients based on acuity and complexity while documenting the activities and outcomes of care coordination. We tested the feasibility of adapting the CCMT to a pediatric surgical population at Boston Children's Hospital. The tool was used to assess the preoperative care coordination activities. Care coordination activities were tracked during the interval from the date the patient was scheduled for a surgical or interventional procedure through the day of the procedure. A care coordination encounter was defined as any task, whether face to face or not, supporting the development or implementation of a plan of care. Data were collected to enable analysis of 5675 care coordination encounters supporting the care provided to 3406 individual surgical cases (patients). The outcomes of care coordination, as documented by the preoperative nursing staff, included the elaboration of the care plan through patient-focused communication among specialist, facilities, perioperative team, and primary care physicians in 80.5% of cases. The average time spent on care coordination activities increased incrementally by 30 minutes with each additional care coordination encounter for a surgical case. Surgical cases with 1 care coordination encounter took an average of 35.7 minutes of preoperative care coordination, whereas those with >=4 care coordination encounters reported an average of 121.6 minutes. We successfully adapted and implemented the CCMT for a pediatric surgical population and measured nonface-to-face, nonbillable encounters performed by perioperative nursing staff. The care coordination activities integrated into the preoperative process include elaboration of care plans and identification and remediation of discrepancies. Capturing the activities and outcomes of care coordination for preoperative care provides a framework for quality improvement and enables documentation of the value of nonface-to-face perioperative nursing encounters that comprise care coordination. PMID- 26517235 TI - Analysis of Resident Case Logs in an Anesthesiology Residency Program. AB - Our goal in this study was to examine Accreditation Council for Graduate Medical Education case logs for Stanford anesthesia residents graduating in 2013 (25 residents) and 2014 (26 residents). The resident with the fewest recorded patients in 2013 had 43% the number of patients compared with the resident with the most patients, and in 2014, this equaled 48%. There were residents who had 75% more than the class average number of cases for several of the 12 case types and 3 procedure types required by the Accreditation Council for Graduate Medical Education. Also, there were residents with fewer than half as many for some of the required cases or procedure types. Some of the variability may have been because of the hazards of self-reporting. PMID- 26517236 TI - Significance of the DNA-Histone Complex Level as a Predictor of Major Adverse Cardiovascular Events in Hemodialysis Patients: The Effect of Uremic Toxin on DNA Histone Complex Formation. AB - BACKGROUND: Neutrophils can release the DNA-histone complex into circulation following exposure to inflammatory stimuli. This prospective study investigated whether the DNA-histone complex and other biomarkers could predict major cardiovascular adverse events (MACEs) in hemodialysis (HD) patients. METHODS: The levels of circulating DNA-histone complexes, cell-free DNA, interleukin (IL)-6, and neutrophil elastase were measured in 60 HD patients and 28 healthy controls. MACE was assessed at 24 months. Uremic toxin-induced neutrophil released contents were measured in vitro. RESULTS: Compared with controls, HD patients showed higher levels of DNA-histone complexes and IL-6. The DNA-histone complex level was inversely associated with the Kt/V. In a multivariable Cox analysis, the high level of DNA-histone complexes was a significant independent predictor of MACE. The uremic toxins induced DNA-histone complex formation in normal neutrophils in vitro. CONCLUSION: The DNA-histone complex is a potentially useful marker to predict MACE in HD patients. Uremic toxins induced DNA-histone complex formation in vitro. PMID- 26517237 TI - Intelligent Analysis of Samples by Semiquantitative Inductively Coupled Plasma Mass Spectrometry (ICP-MS) Technique: A Review. AB - Inductively coupled plasma-mass spectrometry (ICP-MS) is a popular and routine analytical method that has been used for determination of trace elements since the 1980s. It provides fast quantitative analysis and allows the determination of more than 70 elements with good accuracy and very low detection limits, but requires an intricate calibration procedure. In analyses of samples for which very low detection limits are not required a semiquantitative ICP-MS analysis mode can be used. This approach is more time- and cost-effective, and it uses a simple calibration procedure. This article presents a critical review of the semiquantitative (SQ) mode of ICP-MS and describes current and future applications of SQ analysis. PMID- 26517238 TI - RNase L is a negative regulator of cell migration. AB - RNase L is a regulated endoribonuclease that functions in the interferon antiviral response. Activation of RNase L by 2', 5'-oligoadenylates has been linked to apoptosis, autophagy and inflammation. Genetic studies have also suggested the possible involvement of the RNase L gene (RNASEL) on chromosome 1q25.3 in several types of cancer. Here we report that ablation of RNase L in human prostate cancer PC3 cells by CRISPR/Cas9 gene editing technology enhanced cell migration as determined both by transwell assays and scratch wound healing assays. In addition, RNase L knockdown by means of RNAi increased migration of PC3 and DU145 cells in response to either fibronectin or serum stimulation, as did homozygous disruption of the RNase L gene in mouse embryonic fibroblasts. Serum or fibronectin stimulation of focal adhesion kinase (FAK) autophosphorylation on tyrosine-397 was increased by either knockdown or ablation of RNase L. In contrast, a missense mutant RNase L (R667A) lacking catalytic activity failed to suppress cell migration in PC3 cells. However, a nuclease inactive mutant mouse RNase L (W630A) was able to partially inhibit migration of mouse fibroblasts. Consistent with a role for the catalytic activity of RNase L, transfection of PC3 cells with the RNase L activator, 2', 5'-oligoadenylate, suppressed cell migration. RNase L knockdown in PC3 cells enhanced tumor growth and metastasis following implantation in the mouse prostate. Our results suggest that naturally occurring mutations in the RNase L gene might promote enhanced cell migration and metastasis. PMID- 26517239 TI - The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. AB - ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM deficient lung cancer xenografts. PMID- 26517240 TI - Radioresistant human lung adenocarcinoma cells that survived multiple fractions of ionizing radiation are sensitive to HSP90 inhibition. AB - Despite the common usage of radiotherapy for the treatment of NSCLC, outcomes for these cancers when treated with ionizing radiation (IR) are still unsatisfactory. A better understanding of the mechanisms underlying resistance to IR is needed to design approaches to eliminate the radioresistant cells and prevent tumor recurrence and metastases. Using multiple fractions of IR we generated radioresistant cells from T2821 and T2851 human lung adenocarcinoma cells. The radioresistant phenotypes present in T2821/R and T2851/R cells include multiple changes in DNA repair genes and proteins expression, upregulation of EMT markers, alterations of cell cycle distribution, upregulation of PI3K/AKT signaling and elevated production of growth factors, cytokines, important for lung cancer progression, such as IL-6, PDGFB and SDF-1 (CXCL12). In addition to being radioresistant these cells were also found to be resistant to cisplatin.HSP90 is a molecular chaperone involved in stabilization and function of multiple client proteins implicated in NSCLC cell survival and radioresistance. We examined the effect of ganetespib, a novel HSP90 inhibitor, on T2821/R and T2851/R cell survival, migration and radioresistance. Our data indicates that ganetespib has cytotoxic activity against parental T2821 and T2851 cells and radioresistant T2821/R and T2851/R lung tumor cells. Ganetespib does not affect proliferation of normal human lung fibroblasts. Combining IR with ganetespib completely abrogates clonogenic survival of radioresistant cells.Our data show that HSP90 inhibition can potentiate the effect of radiotherapy and eliminate radioresistant and cisplatin -resistant residual cells, thus it may aid in reducing NSCLC tumor recurrence after fractionated radiotherapy. PMID- 26517241 TI - Increased expression of CX43 on stromal cells promotes leukemia apoptosis. AB - Connexin 43 (Cx43) induced apoptosis has been reported in solid tumors, but the effect of Cx43 expressed by bone marrow stromal cells (BMSC) in leukemia has not been fully investigated. Manipulating Cx43 expression could be a potential therapeutic strategy for leukemia. Here, we investigate the effect of Cx43 expressed by BMSCs (human Umbilical Cord Stem Cells over-expressed CX43, Cx43 hUCSC) on leukemia cells. When co-cultured with Cx43-hUCSC, leukemia cells show significant lower growth rate with increasing apoptosis activity, and more leukemia cells enter S phase. Functional assays of fluorescence recovery after photo bleaching (FRAP) showed improved gap junctional intercellular communication (GJIC) on leukemia cells when co-cultured with Cx43-hUCSC (p < 0.01). In a mouse minimal disease model, the mean survival time and mortality rate were significantly improved in mice transplanted with Cx43-hUCSC. Our results indicate that Cx43 expressed by BMSC induces apoptosis on leukemia cells. Small molecules or other pharmaceutical approaches for modulating Cx43 expression in BMSCs could be used for delaying relapse of leukemia. PMID- 26517242 TI - JAM3 methylation status as a biomarker for diagnosis of preneoplastic and neoplastic lesions of the cervix. AB - DNA methylation is clinically relevant to important tumorigenic mechanisms. This study evaluated the methylation status of candidate genes in cervical neoplasia and determined their diagnostic performance in clinical practice. Cervical cancer and normal cervix tissue was used to select the top 5 discriminating loci among 27 loci in 4 genes (CCNA1, CADM1, DAPK1, JAM3), and one locus of JAM3 (region M4) was identified and confirmed with 267 and 224 cervical scrapings from 2 independent colposcopy referral studies. For patients with atypical squamous cells of unknown significance and those with low-grade squamous intraepithelial lesion, with JAM3-M4 compared to a triage marker of hrHPV testing, the specificity for cervical intraepithelial neoplasia 3 CIN3 and cancer cases (CIN3+) / no neoplasia and CIN1 (CIN1-) was significantly increased, from 21.88 to 81.82 and 15.38 to 85.18, respectively. The corresponding positive predictive value (PPV) was increased from 26.47 to 57.14 and 18.52 to 63.64, respectively. For hrHPV-positive patients, compared to a triage marker of cytology testing, JAM3-M4 showed increased specificity and PPV, from 30.67 to 87.65 and 38.82 to 82.14, respectively. We assessed whether JAM3-M4 could distinguish productive from transforming CIN2; the coincidence rate of JAM3-M4 and P16 was as high as 60.5%. PMID- 26517243 TI - Epigenetic silencing of tumor suppressor miR-3151 contributes to Chinese chronic lymphocytic leukemia by constitutive activation of MADD/ERK and PIK3R2/AKT signaling pathways. AB - We hypothesize that miR-3151, localized to a GWAS-identified chronic lymphocytic leukemia (CLL) risk locus (8q22.3), is a tumor suppressor miRNA silenced by promoter DNA methylation in CLL. The promoter of miR-3151 was methylated in 5/7 (71%) CLL cell lines, 30/98 (31%) diagnostic primary samples, but not normal controls. Methylation of miR-3151 correlated inversely with expression. Treatment with 5-Aza-2'-deoxycytidine led to promoter demethylation and miR-3151 re expression. Luciferase assay confirmed MAP-kinase activating death domain (MADD) and phosphoinositide-3-kinase, regulatory subunit 2 (PIK3R2) as direct targets of miR-3151. Moreover, restoration of miR-3151 resulted in inhibition of cellular proliferation and enhanced apoptosis, repression of MADD and PIK3R2, downregulation of MEK/ERK and PI3K/AKT signaling, and repression of MCL1. Lastly, miR-3151 methylation was significantly associated with methylation of miR-203 and miR-34b/c in primary CLL samples. Therefore, this study showed that miR-3151 is a tumor suppressive miRNA frequently hypermethylated and hence silenced in CLL. miR 3151 silencing by DNA methylation protected CLL cells from apoptosis through over expression of its direct targets MADD and PIK3R2, hence constitutive activation of MEK/ERK and PI3K/AKT signaling respectively, and consequently over-expression of MCL1. PMID- 26517244 TI - Salmonella overcomes tumor immune tolerance by inhibition of tumor indoleamine 2, 3-dioxygenase 1 expression. AB - Over the past decades, Salmonella has been proven capable of inhibiting tumor growth. It can specifically target tumors and due to its facultative anaerobic property, can be more penetrative than other drug therapies. However, the molecular mechanism by which Salmonella inhibits tumor growth is still incompletely known. The antitumor therapeutic effect mediated by Salmonella is associated with an inflammatory immune response at the tumor site and a T cell dependent immune response. Many tumors have been proven to have a high expression of indoleamine 2, 3-dioxygenase 1 (IDO), which is a rate-limiting enzyme that catalyzes tryptophan to kynurenine, thus causing immune tolerance within the tumor microenvironment. With decreased expression of IDO, increased immune response can be observed, which might be helpful when developing cancer immunotherapy. The expression of IDO was decreased after tumor cells were infected with Salmonella. In addition, Western blot analysis showed that the expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and phospho-p70 ribosomal s6 kinase (P-p70s6K) in tumor cells were decreased after Salmonella infection. In conclusion, our results indicate that Salmonella inhibits IDO expression and plays a crucial role in anti tumor therapy, which might be a promising strategy combined with other cancer treatments. PMID- 26517245 TI - Recombinase polymerase amplification: Emergence as a critical molecular technology for rapid, low-resource diagnostics. AB - Isothermal molecular diagnostics are bridging the technology gap between traditional diagnostics and polymerase chain reaction-based methods. These new techniques enable timely and accurate testing, especially in settings where there is a lack of infrastructure to support polymerase chain reaction facilities. Despite this, there is a significant lack of uptake of these technologies in developing countries where they are highly needed. Among these novel isothermal technologies, recombinase polymerase amplification (RPA) holds particular potential for use in developing countries. This rapid nucleic acid amplification approach is fast, highly sensitive and specific, and amenable to countries with a high burden of infectious diseases. Implementation of RPA technology in developing countries is critically required to assess limitations and potentials of the diagnosis of infectious disease, and may help identify impediments that prevent adoption of new molecular technologies in low resource- and low skill settings. This review focuses on approaching diagnosis of infectious disease with RPA. PMID- 26517246 TI - Ebola vaccine and corporate responsibility. PMID- 26517247 TI - Dissent as a Prelude to Advancement. PMID- 26517248 TI - Growing Up and Aging with Progressive Hearing Loss. PMID- 26517249 TI - Updates in Molecular Pathology of Central Nervous System Gliomas in Adults. AB - Central nervous system (CNS) tumors are a heterogeneous group of neoplasms divided into two broad categories, glial and non-glial. Non-glial tumors are derived from such diverse structures as the pineal gland, meninges, germ cells, and hematopoietic cells, as well as metastases. Primary glial neoplasms, or those which originate from astrocytes, oligodendrocytes, or ependymal cells, include astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas. Each entity has a unique morphology and pattern of biologic behavior which portends a distinct prognosis and outcome. Individual outcomes show some variability based on tumor location and age of symptom onset; however, the underlying aggressiveness of the tumor often dictates the time course of the disease. With the advent and widespread use of fluorescent in-situ hybridization and polymerase chain reaction (PCR) techniques, molecular phenotyping of brain tumors has become mainstream and is now an integral part of patient care. The molecular genetics of CNS tumors is a rapidly growing field, and the volume of discoveries is growing at an ever increasing rate, compelling the need for updates in this exciting area of science. PMID- 26517250 TI - Therapeutic Molecular Biomarkers in Gynecological Cancers. PMID- 26517251 TI - Genetics and diffuse large B-Cell lymphoma. AB - Diffuse large B-Cell lymphoma (DLBCL) is one of the most common and aggressive subtypes of non-Hodgkin's lymphoma (NHL). Gene expression profiling (GEP) studies have identified at least two distinct molecular subtypes of DLBCL termed as germinal center B-cell (GCB) and activated B-cell (ABC). These molecular subtypes represent lymphomas that are driven by very different intracellular oncogenic signaling pathways which have prognostic value and could potentially be exploited for therapeutic benefit in future. There are other oncogenes, namely BCL-2, BCL-6 and MYC, which have been associated with the pathogenesis of DLBCL. Concurrent presence of two oncogenes is present in about 5% of DLBCL and it is termed "double hit lymphoma" (DHL). DHL are associated with an aggressive clinical course and do not respond well to the standard DLBCL immune-chemotherapy regimen, RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). Other aggressive therapeutic approaches including autologous bone marrow transplant have not shown any survival benefit in this subgroup of DLBCL patients. New strategies in development to address this resistance in DHL include the regimen DA-EPOCH-R (dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab). Recent studies have shown increased sensitivity of DHL to DA-EPOCH-R chemotherapy and will likely be the new standard of care in this subset of DLBCL patients in the future. PMID- 26517252 TI - Genomics in acute myeloid leukemia: from identification to personalization. AB - Acute Myeloid Leukemia (AML) is an aggressive bone marrow malignancy that is fatal if left untreated. Previous classification was strictly based on morphology, which gave little information in terms of prognosis or guide to treatment. Recent research has provided vital information into the chromosomal and molecular pathogenesis of leukemia development. The discovery of these abnormalities via proteomics and genomics have provided two key insights. First, these novel discoveries provide prognostic significance into the predictive result of chemotherapy. Second, these chromosomal and protein abnormalities have provided potential drug targets for new treatment modalities. This article will elaborate on many of these new molecular findings and discuss their implications on the treatment of AML. PMID- 26517253 TI - Melanoma Genomics and Immunotherapy. AB - Over the last decade the molecular characterization of melanoma has progressed. Since a majority of melanoma cases arise from repeated intermittent ultra violet radiation (UVR) exposure, the role of UVR has been evaluated extensively. Recent work has identified two mechanisms in which the carcinogenesis of melanoma may result; Ultra violet radiation has been demonstrated to lead to down regulation in immune responses and result in pyrimidine dimerization. Given these links and more significant immunogenic antigen profile of melanoma, as compared to other malignancies, there has been significant therapeutics breakthroughs based on these molecular pathways. PMID- 26517254 TI - Oral Hygiene in Patients with Parkinson's Disease. AB - Parkinson's disease is a chronic progressive neurodegenerative disorder with a multifactorial etiology. The symptoms are characterized by motor disorders - tremor, rigidity, bradykinesia and postural instability, which hinder oral hygiene. Oral and dental health in Parkinson's disease has been under-documented and findings are conflicting. Moreover, a number of dentists have limited experience regarding the management of these patients. This article reviews literature published within the last fifteen years, to better understand the impact of this disease in oral health. A literature search (MEDLINE and PUBMED), using keywords Parkinson Disease and Oral Hygiene, yielded 27 articles, from which 20 were selected. All of the articles were published in English in the last 15 years. PMID- 26517255 TI - High-Pressure Injection to the Great Toe with River Water. AB - CASE: A 53-year-old male sustained a high-pressure water injection injury to his foot while working in a river. He was taken to the operating room for emergent irrigation and debridement of copious riverbed sediment. Cultures taken from the operating room were positive for multiple anaerobes, fungus and mold and he was treated with appropriate antibiotics. To date, his only residual deficit is a 1 cm area of numbness at the entrance wound. CONCLUSION: High-pressure water injections to the foot are uncommon injuries. These are serious injuries that require emergent antibiotics, tetanus and surgical debridement. PMID- 26517256 TI - Chest Pain and a Sore Throat. PMID- 26517257 TI - Intimate Partner Violence/Problem and Victims in Rhode Island. PMID- 26517258 TI - Josh Schiffman, MD: Genetic clues as to why elephants rarely get cancer. Providence native hopes research will help target pediatric cancers. PMID- 26517259 TI - Computational Design of Hypothetical New Peptides Based on a Cyclotide Scaffold as HIV gp120 Inhibitor. AB - Cyclotides are a family of triple disulfide cyclic peptides with exceptional resistance to thermal/chemical denaturation and enzymatic degradation. Several cyclotides have been shown to possess anti-HIV activity, including kalata B1 (KB1). However, the use of cyclotides as anti-HIV therapies remains limited due to the high toxicity in normal cells. Therefore, grafting anti-HIV epitopes onto a cyclotide might be a promising approach for reducing toxicity and simultaneously improving anti-HIV activity. Viral envelope glycoprotein gp120 is required for entry of HIV into CD4+ T cells. However, due to a high degree of variability and physical shielding, the design of drugs targeting gp120 remains challenging. We created a computational protocol in which molecular modeling techniques were combined with a genetic algorithm (GA) to automate the design of new cyclotides with improved binding to HIV gp120. We found that the group of modified cyclotides has better binding scores (23.1%) compared to the KB1. By using molecular dynamic (MD) simulation as a post filter for the final candidates, we identified two novel cyclotides, GA763 and GA190, which exhibited better interaction energies (36.6% and 22.8%, respectively) when binding to gp120 compared to KB1. This computational design represents an alternative tool for modifying peptides, including cyclotides and other stable peptides, as therapeutic agents before the synthesis process. PMID- 26517260 TI - Procedural Metacognition and False Belief Understanding in 3- to 5-Year-Old Children. AB - Some studies, so far limited in number, suggest the existence of procedural metacognition in young children, that is, the practical capacity to monitor and control one's own cognitive activity in a given task. The link between procedural metacognition and false belief understanding is currently under theoretical discussion. If data with primates seem to indicate that procedural metacognition and false belief understanding are not related, no study in developmental psychology has investigated this relation in young children. The present paper aims, first, to supplement the findings concerning young children's abilities to monitor and control their uncertainty (procedural metacognition) and, second, to explore the relation between procedural metacognition and false belief understanding. To examine this, 82 3- to 5-year-old children were presented with an opt-out task and with 3 false belief tasks. Results show that children can rely on procedural metacognition to evaluate their perceptual access to information, and that success in false belief tasks does not seem related to success in the task we used to evaluate procedural metacognition. These results are coherent with a procedural view of metacognition, and are discussed in the light of recent data from primatology and developmental psychology. PMID- 26517261 TI - Wireless Tri-Axial Trunk Accelerometry Detects Deviations in Dynamic Center of Mass Motion Due to Running-Induced Fatigue. AB - Small wireless trunk accelerometers have become a popular approach to unobtrusively quantify human locomotion and provide insights into both gait rehabilitation and sports performance. However, limited evidence exists as to which trunk accelerometry measures are suitable for the purpose of detecting movement compensations while running, and specifically in response to fatigue. The aim of this study was therefore to detect deviations in the dynamic center of mass (CoM) motion due to running-induced fatigue using tri-axial trunk accelerometry. Twenty runners aged 18-25 years completed an indoor treadmill running protocol to volitional exhaustion at speeds equivalent to their 3.2 km time trial performance. The following dependent measures were extracted from tri axial trunk accelerations of 20 running steps before and after the treadmill fatigue protocol: the tri-axial ratio of acceleration root mean square (RMS) to the resultant vector RMS, step and stride regularity (autocorrelation procedure), and sample entropy. Running-induced fatigue increased mediolateral and anteroposterior ratios of acceleration RMS (p < .05), decreased the anteroposterior step regularity (p < .05), and increased the anteroposterior sample entropy (p < .05) of trunk accelerometry patterns. Our findings indicate that treadmill running-induced fatigue might reveal itself in a greater contribution of variability in horizontal plane trunk accelerations, with anteroposterior trunk accelerations that are less regular from step-to-step and are less predictable. It appears that trunk accelerometry parameters can be used to detect deviations in dynamic CoM motion induced by treadmill running fatigue, yet it is unknown how robust or generalizable these parameters are to outdoor running environments. PMID- 26517262 TI - Wavelet Domain Radiofrequency Pulse Design Applied to Magnetic Resonance Imaging. AB - A new method for designing radiofrequency (RF) pulses with numerical optimization in the wavelet domain is presented. Numerical optimization may yield solutions that might otherwise have not been discovered with analytic techniques alone. Further, processing in the wavelet domain reduces the number of unknowns through compression properties inherent in wavelet transforms, providing a more tractable optimization problem. This algorithm is demonstrated with simultaneous multi slice (SMS) spin echo refocusing pulses because reduced peak RF power is necessary for SMS diffusion imaging with high acceleration factors. An iterative, nonlinear, constrained numerical minimization algorithm was developed to generate an optimized RF pulse waveform. Wavelet domain coefficients were modulated while iteratively running a Bloch equation simulator to generate the intermediate slice profile of the net magnetization. The algorithm minimizes the L2-norm of the slice profile with additional terms to penalize rejection band ripple and maximize the net transverse magnetization across each slice. Simulations and human brain imaging were used to demonstrate a new RF pulse design that yields an optimized slice profile and reduced peak energy deposition when applied to a multiband single-shot echo planar diffusion acquisition. This method may be used to optimize factors such as magnitude and phase spectral profiles and peak RF pulse power for multiband simultaneous multi-slice (SMS) acquisitions. Wavelet based RF pulse optimization provides a useful design method to achieve a pulse waveform with beneficial amplitude reduction while preserving appropriate magnetization response for magnetic resonance imaging. PMID- 26517264 TI - Characterization of the IGF2 Imprinted Gene Methylation Status in Bovine Oocytes during Folliculogenesis. AB - DNA methylation reprogramming occurs during mammalian gametogenesis and embryogenesis. Sex-specific DNA methylation patterns at specific CpG islands controlling imprinted genes are acquired during this window of development. Characterization of the DNA methylation dynamics of imprinted genes acquired by oocytes during folliculogenesis is essential for understanding the physiological and genetic aspects of female gametogenesis and to determine the parameters for oocyte competence. This knowledge can be used to improve in vitro embryo production (IVP), specifically because oocyte competence is one of the most important aspects determining the success of IVP. Imprinted genes, such as IGF2, play important roles in embryo development, placentation and fetal growth. The aim of this study was to characterize the DNA methylation profile of the CpG island located in IGF2 exon 10 in oocytes during bovine folliculogenesis. The methylation percentages in oocytes from primordial follicles, final secondary follicles, small antral follicles, large antral follicles, MII oocytes and spermatozoa were 73.74 +/- 2.88%, 58.70 +/- 7.46%, 56.00 +/- 5.58%, 65.77 +/- 5.10%, 56.35 +/- 7.45% and 96.04 +/- 0.78%, respectively. Oocytes from primordial follicles showed fewer hypomethylated alleles (15.5%) than MII oocytes (34.6%) (p = 0.039); spermatozoa showed only hypermethylated alleles. Moreover, MII oocytes were less methylated than spermatozoa (p<0.001). Our results showed that the methylation pattern of this region behaves differently between mature oocytes and spermatozoa. However, while this region has a classical imprinted pattern in spermatozoa that is fully methylated, it was variable in mature oocytes, showing hypermethylated and hypomethylated alleles. Furthermore, our results suggest that this CpG island may have received precocious reprogramming, considering that the hypermethylated pattern was already found in growing oocytes from primordial follicles. These results may contribute to our understanding of the reprogramming of imprinted genes during bovine oogenesis. PMID- 26517263 TI - Different Tissue-Derived Stem Cells: A Comparison of Neural Differentiation Capability. AB - BACKGROUND: Stem cells are capable of self-renewal and differentiation into a wide range of cell types with multiple clinical and therapeutic applications. Stem cells are providing hope for many diseases that currently lack effective therapeutic methods, including strokes, Huntington's disease, Alzheimer's and Parkinson's disease. However, the paucity of suitable cell types for cell replacement therapy in patients suffering from neurological disorders has hampered the development of this promising therapeutic approach. AIM: The innovative aspect of this study has been to evaluate the neural differentiation capability of different tissue-derived stem cells coming from different tissue sources such as bone marrow, umbilical cord blood, human endometrium and amniotic fluid, cultured under the same supplemented media neuro-transcription factor conditions, testing the expression of neural markers such as GFAP, Nestin and Neurofilaments using the immunofluorescence staining assay and some typical clusters of differentiation such as CD34, CD90, CD105 and CD133 by using the cytofluorimetric test assay. RESULTS: Amniotic fluid derived stem cells showed a more primitive phenotype compared to the differentiating potential demonstrated by the other stem cell sources, representing a realistic possibility in the field of regenerative cell therapy suitable for neurodegenerative diseases. PMID- 26517265 TI - Sustainability of Evidence-Based Practices for HIV Prevention among Female Sex Workers in Mexico. AB - OBJECTIVE: This study examined service provider perceptions of requirements for successful sustainment of an efficacious intervention for preventing HIV/AIDS and STIs in female sex workers (FSWs) in Mexico. METHODS: Semi-structured interviews were conducted with 77 leaders and counselors from 12 community-based reproductive health clinics located throughout Mexico participating in a large hybrid effectiveness-implementation randomized controlled trial to scale-up the use of Mujer Segura, a psychoeducational intervention designed to promote condom use and enhance safer sex negotiation skills among FSWs. RESULTS: Five sets of requirements for sustainment were identified: 1) characteristics of the provider, including competence in delivering the intervention, need for continued technical support and assistance from outside experts, and satisfaction with addressing the needs of this population; 2) characteristics of the clients (i.e., FSWs), including client need and demand for services and incentives for participation; 3) characteristics of the organization, including its mission, benefits, and operations; 4) characteristics of the outer setting, including financial support and relationship with the community-based organization's central offices, and transportation and security in areas where FSWs live and work; and 5) outcomes associated with the intervention itself, including a reduction of risk through education and increased outreach through referrals from FSWs who received the intervention. CONCLUSIONS: Although the requirements for successful sustainment of interventions like Mujer Segura are consistent with the factors identified in many models of implementation, the results illustrate the importance of local context in assigning priority to these model elements and suggest that the five categories are not discrete entities but interconnected. PMID- 26517266 TI - Virulence of Hymenoscyphus albidus and H. fraxineus on Fraxinus excelsior and F. pennsylvanica. AB - European ash (Fraxinus excelsior) is currently battling an onslaught of ash dieback, a disease emerging in the greater part of its native area, brought about by the introduction of the ascomycete Hymenoscyphus fraxineus (= Hymenoscyphus pseudoalbidus). The closely-related fungus Hymenoscyphus albidus, which is indigenous to Europe, is non-pathogenic when in contact with F. excelsior, but could pose a potential risk to exotic Fraxinus species. The North American green ash (Fraxinus pennsylvanica) is planted widely throughout Europe and regenerates naturally within this environment but little is known about the susceptibility of this species to ash dieback. We performed wound inoculations with both fungi (nine strains of H. fraxineus and three strains of H. albidus) on rachises and stems of F. excelsior and F. pennsylvanica under field conditions in Southern Poland. Necrosis formation was evaluated after two months on the rachises and after 12 months on the stems. After inoculation of H. albidus, only small lesions (of up to 1.3 cm in length) developed on the F. excelsior and F. pennsylvanica rachises, but with no significant distinction from the controls. Hymenoscyphus albidus did not cause necrotic lesions on the stems of either Fraxinus species. In contrast, H. fraxineus induced necroses on all inoculated rachises of both ash species with mean lengths of 8.4 cm (F. excelsior) and 1.9 cm (F. pennsylvanica). Necroses also developed on all of the inoculated F. excelsior stems (mean length 18.0 cm), whereas on F. pennsylvanica such lesions only occurred on about 5% of the stems (mean length 1.9 cm). The differences between strains were negligible. No necroses were observed on the control plants. Reisolations of H. albidus were only successful in around 8-11% of the cases, while H. fraxineus was reisolated from 50-70% of the inoculated organs showing necrotic lesions. None of the Hymenoscyphus species were isolated from the control plants. Our data confirm H. fraxineus' high virulence with regards to F. excelsior and demonstrate a low virulence in relation to F. pennsylvanica under field conditions in Poland. Hymenoscyphus albidus did not express any perceivable pathogenicity on both host species. PMID- 26517267 TI - Correction: No Major Host Genetic Risk Factor Contributed to A(H1N1)2009 Influenza Severity. PMID- 26517269 TI - Effects of the standing program with hip abduction on hip acetabular development in children with spastic diplegia cerebral palsy. AB - PURPOSE: Early identification and intervention with conservative measures is important to help manage hip dysplasia in children with a high adductor and iliopsoas tone and delay in weight bearing. The effect of a daily standing program with hip abduction on hip acetabular development in ambulatory children with cerebral palsy was studied. METHOD: The participants were 26 children with spastic diplegia cerebral palsy (CP), classified at Level III according to the Gross Motor Function Classification System (GMFCS). Thirteen children stood with hip abduction at least 1 h daily from 12 to 14 months of age to 5 years with an individually fabricated standing frame with hip abduction. RESULTS: At the age of 5 years, radiologic results of the study group were compared with a comparison group of 13 children with spastic diplegia CP who had not taken part in a standing program. The migration percentage in all children who stood with abduction remained within stable limits (13-23%) at 5 years of age, in comparison to children who did not stand in abduction (12-47%) (p < 0.01). CONCLUSIONS: The results indicate that a daily standing program with hip abduction in the first 5 years may enhance acetabular development in ambulatory children with spastic diplegia CP. IMPLICATIONS FOR REHABILITATION: Abnormal acetabular development is a problem related to mobility problems and spasticity muscles around the hip. The literature suggests that postural management and standing programs could reduce levels of hip subluxation and increase function in children with cerebral palsy. A standing program with hip abduction can be a beneficial to develop more stable hips in children with spastic diplegic GMFCS level III. PMID- 26517268 TI - Repeated Reticulate Evolution in North American Papilio machaon Group Swallowtail Butterflies. AB - Hybridization between distinct populations or species is increasingly recognized as an important process for generating biodiversity. However, the interaction between hybridization and speciation is complex, and the diverse evolutionary outcomes of hybridization are difficult to differentiate. Here we characterize potential hybridization in a species group of swallowtail butterflies using microsatellites, DNA sequences, and morphology, and assess whether adaptive introgression or homoploid hybrid speciation was the primary process leading to each putative hybrid lineage. Four geographically separated hybrid populations were identified in the Papilio machaon species group. One distinct mitochondrial DNA clade from P. machaon was fixed in three hybrid taxa (P. brevicauda, P. joanae, and P. m. kahli), while one hybrid swarm (P. zelicaon x machaon) exhibited this hybrid mtDNA clade as well as widespread parental mtDNA haplotypes from both parental species. Microsatellite markers and morphology showed variable admixture and intermediacy, ranging from signatures of prolonged differential introgression from the paternal species (P. polyxenes/P. zelicaon) to current gene flow with both parental species. Divergences of the hybrid lineages dated to early- to mid-Pleistocene, suggesting that repeated glaciations and subsequent range shifts of parental species, particularly P. machaon hudsonianus, facilitated initial hybridization. Although each lineage is distinct, P. joanae is the only taxon with sufficient evidence (ecological separation from parental species) to define it as a homoploid hybrid species. The repetition of hybridization in this group provides a valuable foundation for future research on hybridization, and these results emphasize the potential for hybridization to drive speciation in diverse ways. PMID- 26517270 TI - SCARN a Novel Class of SCAR Protein That Is Required for Root-Hair Infection during Legume Nodulation. AB - Rhizobial infection of legume root hairs requires a rearrangement of the actin cytoskeleton to enable the establishment of plant-made infection structures called infection threads. In the SCAR/WAVE (Suppressor of cAMP receptor defect/WASP family verpolin homologous protein) actin regulatory complex, the conserved N-terminal domains of SCAR proteins interact with other components of the SCAR/WAVE complex. The conserved C-terminal domains of SCAR proteins bind to and activate the actin-related protein 2/3 (ARP2/3) complex, which can bind to actin filaments catalyzing new actin filament formation by nucleating actin branching. We have identified, SCARN (SCAR-Nodulation), a gene required for root hair infection of Lotus japonicus by Mesorhizobium loti. Although the SCARN protein is related to Arabidopsis thaliana SCAR2 and SCAR4, it belongs to a distinct legume-sub clade. We identified other SCARN-like proteins in legumes and phylogeny analyses suggested that SCARN may have arisen from a gene duplication and acquired specialized functions in root nodule symbiosis. Mutation of SCARN reduced formation of infection-threads and their extension into the root cortex and slightly reduced root-hair length. Surprisingly two of the scarn mutants showed constitutive branching of root hairs in uninoculated plants. However we observed no effect of scarn mutations on trichome development or on the early actin cytoskeletal accumulation that is normally seen in root hair tips shortly after M. loti inoculation, distinguishing them from other symbiosis mutations affecting actin nucleation. The C-terminal domain of SCARN binds to ARPC3 and ectopic expression of the N-terminal SCAR-homology domain (but not the full length protein) inhibited nodulation. In addition, we found that SCARN expression is enhanced by M. loti in epidermal cells and that this is directly regulated by the NODULE INCEPTION (NIN) transcription factor. PMID- 26517271 TI - Gene Expression Analysis of Pak Choi in Response to Vernalization. AB - Pak choi is a seed vernalization-type plant whose vernalization mechanism is currently unclear. Therefore, it is critical to discover genes related to vernalization and research its functions during vernalization in pak choi. Here, the gene expression profiles in the shoot apex were analyzed after low temperature treatment using high-throughput RNA sequencing technology. The results showed that there are 1,664 and 1,192 differentially expressed genes (DEGs) in pak choi in cold treatment ending and before flower bud differentiation, respectively, including 42 genes that exhibited similar expression trend at both stages. Detailed annotation revealed that the proteins encoded by the DEGs are located in the extracellular region, cell junction and extracellular matrix. These proteins exhibit activity such as antioxidant activity and binding protein/transcription factor activity, and they are involved in signal transduction and the immune system/biological processes. Among the DEGs, Bra014527 was up-regulated in low temperature treatment ending, Bra024097 was up-regulated before flower bud differentiation and Bra035940 was down regulated at both stages in low temperature-treated shoot apices. Homologues of these genes in A. thaliana, AT3G59790, AT4G30200 and AT5G61150, are involved in flowering and vernalization, suggesting that they take part in the vernalization process in pak choi. Further pathway enrichment analysis revealed that most genes were enriched in the tryptophan metabolism and glucosinolate biosynthesis pathways. However, the functions of tryptophan and glucosinolate in vernalization are not yet clear and require further analysis. PMID- 26517272 TI - Frontline Health Service Providers' Perspectives on HIV Vaccine Trials among Female Sex Workers and Men Who Have Sex with Men in Karnataka, South India. AB - BACKGROUND: Little qualitative research is available on the role of frontline health service providers (FHSPs) in the implementation of clinical trials, particularly in developing countries. This paper presents findings from a qualitative study about the perspectives of FHSPs on future HIV vaccine trials involving female sex workers (FSWs) and men who have sex with men (MSM) in three districts of Karnataka, India. In particular, we explore FHSPs' knowledge of and views on clinical trials in general, and examine their potential willingness to play a role if such trials were introduced or implemented in the region. METHODS: A field team of four researchers from Karnataka-two of whom self-identified with FSW or MSM communities ("community researchers") and two with backgrounds in social work-conducted in-depth interviews with FHSPs. Including community researchers in the study helped to build rapport with FSW and MSM participants and facilitate in-depth discussions. A coding scheme for transcribed and translated data was developed using a framework analysis approach. Data was then analysed thematically using a combination of a priori and emergent codes. RESULTS: Over half of FHSPs demonstrated limited knowledge or understanding of clinical trials. Despite reported skepticism around the testing of HIV vaccines in developing countries and concerns around potential side effects, most FHSPs strongly advocated for the implementation of HIV vaccine clinical trials in Karnataka. Further, most FHSPs expressed their willingness to be involved in future HIV vaccine clinical trials in varying capacities. CONCLUSION: Given that FHSPs are often directly involved in the promotion of health and well-being of FSWs and MSM, they are well-positioned to play leadership, ethical, and communicative roles in future HIV vaccine trials. However, our findings reveal a lack of awareness of clinical trials among FHSP participants, suggesting an important area for capacity building and staff development before viable and ethical clinical trials can be set up in the region. PMID- 26517274 TI - A BIL Population Derived from G. hirsutum and G. barbadense Provides a Resource for Cotton Genetics and Breeding. AB - To provide a resource for cotton genetics and breeding, an interspecific hybridization between Gossypium hirsutum cv. Emian22 and G. barbadense acc. 3-79 was made. A population of 54 BILs (backcross inbred lines, BC1F8) was developed with the aim of transferring G. barbadense genes into G. hirsutum in order to genetically analyze these genes' function in a G. hirsutum background and create new germplasms for breeding. Preliminary investigation of the morphological traits showed that the BILs had diverse variations in plant architecture, seed size, and fuzz color; the related traits of yield and fiber quality evaluated in 4 environments also showed abundant phenotypic variation. In order to explore the molecular diversity of the BIL population, 446 SSR markers selected at an average genetic distance of 10 cM from our interspecific linkage map were used to genotype the BIL population. A total of 393 polymorphic loci accounting for 84.4% MAF (major allele frequency) > 0.05 and 922 allele loci were detected, and the Shannon diversity index (I) was 0.417 per locus. The average introgression segment length was 16.24 cM, and an average of 29.53 segments were introgressed in each BIL line with an average background recovery of 79.8%. QTL mapping revealed 58 QTL associated with fiber quality and yield traits, and 47 favored alleles derived from the donor parent were discovered. This study demonstrated that the interspecific BIL population was enriched with much phenotypic and molecular variation which could be a resource for cotton genetics and breeding. PMID- 26517275 TI - Bioaccumulation of copper, lead, and zinc in six macrophyte species grown in simulated stormwater bioretention systems. AB - Stormwater bioretention (BR) systems collect runoff containing heavy metals, which can concentrate in soil environments and potentially leach into groundwater. This greenhouse experiment evaluated differences among six plant species undergoing three varying hydraulic and pollutant loads in their bioaccumulation potential when subjected to continual application of low metal concentrations as a means of preventing copper, lead, and zinc accumulation in the BR soil. Results show that >92% of metal mass applied to the treatments via synthetic stormwater was removed from the exfiltrate within 27 cm of soil depth. Compacted soil conditions of unplanted controls retained significantly more Cu, Pb, and Zn than Carex praegracilis, and Carex microptera treatments. Differences in above and below ground plant tissue concentrations differed among species, resulting in significant differences in mass accumulation. In the above ground tissue, from highest to lowest, Phragmites australis accumulated 8 times more Cu than Scirpus acutus, and C. microptera accumulated 18 times more Pb, and 6 times more Zn than Scirpus validus. These results, and differences among species in mass distribution of the metals recovered at the end of the study, reveal various metal accumulation mechanisms. PMID- 26517273 TI - Neutrophils as a Source of Chitinases and Chitinase-Like Proteins in Type 2 Diabetes. AB - PURPOSE: The pathophysiological role of human chitinases and chitinase-like proteins (CLPs) is not fully understood. We aimed to determine the levels of neutrophil-derived chitotriosidase (CHIT1), acidic mammalian chitinase (AMCase) and chitinase 3-like protein 1 (YKL-40) in patients with type 2 diabetes (T2D) and verify their association with metabolic and clinical conditions of these patients. METHODS: Neutrophils were obtained from the whole blood by gradient density centrifugation from 94 T2D patients and 40 control subjects. The activities of CHIT1 and AMCase as well as leukocyte elastase (LE) were measured fluorometrically and concentration of YKL-40 immunoenzymatically. Also, routine laboratory parameters in serum/plasma were determined by standard methods. RESULTS: The levels of all three examined proteins were about 2-times higher in diabetic patients in comparison to control subjects. They were significantly correlated with the activity of LE and increased progressively across tertiles of LE activity. Moreover, the activities of CHIT1 and AMCase were significantly correlated with each other. Metabolic compensation of diabetes did not influence the levels of these proteins. In the subgroup of patients with inflammatory evidence only YKL-40 concentration was significantly higher compared to those without inflammation. The highest levels of all three proteins were observed in patients with macroangiopathies. Insulin therapy was associated with lower levels of examined proteins. CONCLUSIONS: We revealed that neutrophils may be an important source of the increased levels of chitinases and CLPs in T2D, and these proteins may participate in inflammatory mechanisms in the course of the disease and consequent development of diabetic angiopathies. PMID- 26517276 TI - Pasture BMP effectiveness using an HRU-based subarea approach in SWAT. AB - Many conservation programs have been established to motivate producers to adopt best management practices (BMP) to minimize pasture runoff and nutrient loads, but a process is needed to assess BMP effectiveness to help target implementation efforts. A study was conducted to develop and demonstrate a method to evaluate water-quality impacts and the effectiveness of two widely used BMPs on a livestock pasture: off-stream watering site and stream fencing. The Soil and Water Assessment Tool (SWAT) model was built for the Pottawatomie Creek Watershed in eastern Kansas, independently calibrated at the watershed outlet for streamflow and at a pasture site for nutrients and sediment runoff, and also employed to simulate pollutant loads in a synthetic pasture. The pasture was divided into several subareas including stream, riparian zone, and two grazing zones. Five scenarios applied to both a synthetic pasture and a whole watershed were simulated to assess various combinations of widely used pasture BMPs: (1) baseline conditions with an open stream access, (2) an off-stream watering site installed in individual subareas in the pasture, and (3) stream or riparian zone fencing with an off-stream watering site. Results indicated that pollutant loads increase with increasing stocking rates whereas off-stream watering site and/or stream fencing reduce time cattle spend in the stream and nutrient loads. These two BMPs lowered organic P and N loads by more than 59% and nitrate loads by 19%, but TSS and sediment-attached P loads remained practically unchanged. An effectiveness index (EI) quantified impacts from the various combinations of off stream watering sites and fencing in all scenarios. Stream bank contribution to pollutant loads was not accounted in the methodology due to limitations of the SWAT model, but can be incorporated in the approach if an amount of bank soil loss is known for various stocking rates. The proposed methodology provides an adaptable framework for pasture BMP assessment and was utilized to represent a consistent, defensible process to quantify the effectiveness of BMP proposals in a BMP auction in eastern Kansas. PMID- 26517277 TI - Prototypic automated continuous recreational water quality monitoring of nine Chicago beaches. AB - Predictive empirical modeling is used in many locations worldwide as a rapid, alternative recreational water quality management tool to eliminate delayed notifications associated with traditional fecal indicator bacteria (FIB) culturing (referred to as the persistence model, PM) and to prevent errors in releasing swimming advisories. The goal of this study was to develop a fully automated water quality management system for multiple beaches using predictive empirical models (EM) and state-of-the-art technology. Many recent EMs rely on samples or data collected manually, which adds to analysis time and increases the burden to the beach manager. In this study, data from water quality buoys and weather stations were transmitted through cellular telemetry to a web hosting service. An executable program simultaneously retrieved and aggregated data for regression equations and calculated EM results each morning at 9:30 AM; results were transferred through RSS feed to a website, mapped to each beach, and received by the lifeguards to be posted at the beach. Models were initially developed for five beaches, but by the third year, 21 beaches were managed using refined and validated modeling systems. The adjusted R(2) of the regressions relating Escherichia coli to hydrometeorological variables for the EMs were greater than those for the PMs, and ranged from 0.220 to 0.390 (2011) and 0.103 to 0.381 (2012). Validation results in 2013 revealed reduced predictive capabilities; however, three of the originally modeled beaches showed improvement in 2013 compared to 2012. The EMs generally showed higher accuracy and specificity than those of the PMs, and sensitivity was low for both approaches. In 2012 EM accuracy was 70-97%; specificity, 71-100%; and sensitivity, 0-64% and in 2013 accuracy was 68-97%; specificity, 73-100%; and sensitivity 0-36%. Factors that may have affected model capabilities include instrument malfunction, non point source inputs, and sparse calibration data. The modeling system developed is the most extensive, fully-automated system for recreational water quality developed to date. Key insights for refining and improving large-scale empirical models for beach management have been developed through this multi-year effort. PMID- 26517278 TI - A simplified approach for the computation of steady two-phase flow in inverted siphons. AB - Hydraulic, sanitary, and sulfide control conditions of inverted siphons, particularly in large wastewater systems, can be substantially improved by continuous air injection in the base of the inclined rising branch. This paper presents a simplified approach that was developed for the two-phase flow of the rising branch using the energy equation for a steady pipe flow, based on the average fluid fraction, observed slippage between phases, and isothermal assumption. As in a conventional siphon design, open channel steady uniform flow is assumed in inlet and outlet chambers, corresponding to the wastewater hydraulic characteristics in the upstream and downstream sewers, and the descending branch operates in steady uniform single-phase pipe flow. The proposed approach is tested and compared with data obtained in an experimental siphon setup with two plastic barrels of different diameters operating separately as in a single-barrel siphon. Although the formulations developed are very simple, the results show a good adjustment for the set of the parameters used and conditions tested and are promising mainly for sanitary siphons with relatively moderate heights of the ascending branch. PMID- 26517279 TI - Publisher's Note: Digital phantoms generated by spectral and spatial light modulators. PMID- 26517280 TI - Solvothermal Metal Metathesis on a Metal-Organic Framework with Constricted Pores and the Study of Gas Separation. AB - Metal-organic frameworks (MOFs) with constricted pores can increase the adsorbate density of gas and facilitate effective CO2 separation from flue gas or natural gas due to their enhanced overlapping of potential fields of the pores. Herein, an MOF with constricted pores, which was formed by narrow channels and blocks of functional groups, was fabricated from the assembly of a methyl-functionalized ligand and Zn(II) centers (termed NPC-7-Zn). Structural analysis of the as synthesized NPC-7-Zn reveals a series of zigzag pores with pore diameters of ~0.7 nm, which could be favorable for CO2 traps. For reinforcing the framework stability, a solvothermal metal metathesis on the pristine MOF NPC-7-Zn was performed, and a new Cu(II) MOF (termed NPC-7-Cu) with an identical framework was produced. The influence of the reaction temperatures on the metal metathesis process was investigated. The results show that the constricted pores in NPC-7-Zn can induce kinetic issues that largely slow the metal metathesis process at room temperature. However, this kinetic issue can be solved by applying higher reaction temperatures. The modified MOF NPC-7-Cu exhibits significant improvements in framework stability and thus leads to a permanent porosity for this framework. The constricted pore structure enables enhanced potential fields for these pores, rendering this MOF with high adsorbate densities for CO2 and high adsorption selectivity for a CO2/N2 gas mixture. The adsorption kinetic studies reveal that CH4 has a faster diffusion rate constant than CO2, showing a surface diffusion controlled mechanism for CO2 and CH4 adsorption. PMID- 26517281 TI - Features and outcome of fetal cardiac aneurysms and diverticula: a single center experience in China. AB - OBJECTIVES: We aimed to describe the prenatal features and clinical outcome of fetal cardiac aneurysms (CA) and cardiac diverticula (CD). METHODS: Retrospective single center study reporting on antenatal findings and interventions and clinical outcome of fetuses with CA or CD are assessed in a ten year's period. RESULTS: Thirteen CA and 16 CD identified, mostly located at the cardiac apex. The average size of the CA was significantly larger than that of the CD (223.2 +/ 84.4 vs 80.6 +/- 57.9 mm(2) , respectively; p < 0.05). The bulge longitudinal strain, systolic strain rate, and diastolic strain rate in CA were significantly lower compared with CD (respectively, -12.9 +/- 3.7 vs -20.0 +/- 5.4% for strain and -1.3 +/- 0.4 vs -2.0 +/- 0.5 s(-1) for the systolic strain rate, 1.2 +/- 0.4 vs 1.9 +/- 0.4 s(-1) for the diastolic strain rate; all p < 0.05). CA coincided more frequently with arrhythmia and CD more frequently with pericardial effusion (p < 0.05). Adverse outcomes were more likely in children with CA [83.3% (5/6) vs 8.3% (1/12), respectively, p < 0.01]. CONCLUSION: Fetal cardiac aneurysms and diverticula are two distinct entities with different morphology and outcome. An isolated fetal CA has a less favourable outcome than fetal CD. (c) 2015 John Wiley & Sons, Ltd. PMID- 26517282 TI - ent-Kaurene Glycosides from Ageratina cylindrica. AB - The aqueous extract of the leaves of Ageratina cylindrica afforded six new ent kaurenoic acid glycosides together with the known diterpenoid paniculoside V, the flavonoid astragalin, chlorogenic acid, and L-chiro-inositol. The structures were elucidated mainly by NMR and MS methods, and the absolute configuration was established by vibrational circular dichroism spectroscopy. The new compounds showed moderate antiprotozoal activity against Entamoeba histolytica and Giardia lamblia trophozoites. PMID- 26517283 TI - Thrombin generation and bleeding in haemophilia inhibitor patients during immune tolerance induction. AB - BACKGROUND: Inhibitor formation complicates haemophilia treatment and requires immune tolerance induction to rid inhibitors over 5 BU. In the prospective, randomized International Immune Tolerance Study, immune tolerance induction was equally effective with high-dose (HD) (200 IU kg-1 day-1 ) and low-dose (LD) (50 IU kg-1 3* per week) factor VIII, but haemorrhages were twofold higher in the LD arm. This finding was unexpected as inhibitors neutralize FVIII activity. We hypothesized that the thrombin generation assay (TGA), a global measure of clot formation, might predict bleeding better than FVIII levels. METHODS: We evaluated TGA using relipidated tissue factor (TF) on 83 thawed, recalcified corn trypsin inhibitor/citrate plasma samples from 31 subjects (17 HD, 14 LD) who participated on the ITI study, and who had sufficient sample available and appropriate informed consent. RESULTS: There were no significant differences in peak thrombin, estimated thrombin potential, maximum rate or lag time between HD and LD arms; between pre-, during and post-ITI time points, or after FVIII spiking. In 19 subjects (12 HD, 7 LD) with anti-FVIII<1.0 BU, the prevalence of non neutralizing antibody (NNA) and neutralizing antibody (NA) was 89.5% (17/19), and the latter strongly correlated with anti-VIII titer, r = 0.73 [95% CI: 0.55, 0.88]. CONCLUSION: In haemophilia inhibitor patients, thrombin generation is present, but does not predict bleeding risk. Following tolerance induction, NNA remains detectable in the majority. PMID- 26517284 TI - Modeling developmental neuropsychiatric disorders with iPSC technology: challenges and opportunities. AB - The development of cellular reprogramming methods to generate human induced pluripotent stem cells (iPSC) has led to the establishment of lines from hundreds of patients with a variety of neurologic and psychiatric diseases. One of the fundamental powers of iPSC technology lies in the competency of these cells to be directed to become any cell type in the body, thus allowing researchers to examine disease mechanisms and identify and test novel therapeutics in relevant cell types. The field has now exited the phase of 'proof-of-principle' studies showing the potential of the model systems, and it has now entered an exciting new era where iPSC studies are contributing to the field's understanding of mechanisms of disease. Here, we describe the challenges of iPSC modeling of neuropsychiatric disorders, and highlight studies where some of these challenges have been addressed to provide novel insights into disease mechanisms. PMID- 26517285 TI - Microglial genes regulating neuroinflammation in the progression of Alzheimer's disease. AB - Neuroinflammation is a pathological hallmark of Alzheimer's disease (AD), and microglia, the brain's resident phagocyte, are pivotal for the immune response observed in AD. Microglia act as sentinel and protective cells, but may become inappropriately reactive in AD to drive neuropathology. Recent Genome Wide Association Studies (GWAS) have identified more than 20 gene variants associated with an increased risk of late-onset AD (LOAD), the most prevalent form of AD [1]. The findings strongly implicate genes related to the immune response (CR1, CD33, MS4A, CLU, ABCA7, EPHA1 and HLA-DRB5-HLA-DRB1), endocytosis (BIN1, PICALM, CD2AP, EPHA1 and SORL1) and lipid biology (CLU, ABCA7 and SORL1) [2-8], and many encode proteins which are highly expressed in microglia [1]. Furthermore, recent identification of a low frequency mutation in the gene encoding the triggering receptor expressed in myeloid cells 2 protein (TREM2) confers increased risk of AD in LOAD cohorts with an effect size similar to that for APOE, until recently the only identified genetic risk factor associated with LOAD [9,10(**)] (Figure 1). The present review summarises our current understanding of the probable roles of microglial genes in the regulation of neuroinflammatory processes in AD and their relation to other processes affecting the disease's progression. PMID- 26517286 TI - Early rescue of interneuron disease trajectory in developmental epilepsies. AB - The discovery of over 150 monogenic epilepsies and advances in early genetic diagnoses have launched a search for molecular strategies and developmental timetables to reverse or even prevent the course of these debilitating brain disorders. Orthologous rodent models of key disease genes are providing important examples of the range of targets, and serve as valuable test systems for perinatal therapeutic approaches. While gene-specific analyses of single rare 'orphan' diseases are each narrow in scope, they illuminate downstream pathways converging onto interneurons, and treatments that strengthen inhibition during cortical maturation may provide broad protection against these seemingly disparate gene errors. Several genes, even those linked to malformations, show promise for postnatal correction before the onset of their clinical phenotype. PMID- 26517287 TI - Cross-Sectional Associations of Serum Perfluoroalkyl Acids and Thyroid Hormones in U.S. Adults: Variation According to TPOAb and Iodine Status (NHANES 2007 2008). AB - BACKGROUND: Perfluoroalkyl acids (PFASs) are suspected thyroid toxicants, but results from epidemiological studies are inconsistent. OBJECTIVES: We examined associations between serum PFASs and thyroid hormones (THs) in a representative, cross-sectional sample of U.S. adults. We hypothesized that people with high thyroid peroxidase antibodies and low iodine would be more susceptible to PFAS induced thyroid disruption. METHODS: Our sample included 1,525 adults (>= 18 years) from the 2007-2008 NHANES study with available serum PFASs and THs. We examined associations between four serum PFASs [perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA), perfluorooctanoate (PFOA), and perfluorooctane sulfonate (PFOS)], and serum THs [free triiodothyronine (fT3), free thyroxine (fT4), fT3/fT4, thyroid-stimulating hormone (TSH), total T3 (TT3), and total T4 (TT4)] using multivariable linear regression. We stratified subjects into four groups by two indicators of thyroid "stress": thyroid peroxidase antibody (TPOAb >= 9 IU/mL) and iodine status (< 100 MUg/L urine). RESULTS: Of 1,525 participants, 400 (26%) had low iodine only (T0I1), 87 (6%) had high TPOAb only (T1I0), and 26 (2%) had both high TPOAb and low iodine (T1I1). In general, associations were similar among participants in the groups with neither (T0I0) or only one thyroid stressor (T0I1 or T1I0), suggesting that PFAS-TH associations were not modified by high TPOAb or low iodine alone. However, PFHxS and PFOS were negatively associated (p < 0.05) with fT4, and all four PFASs were positively associated (p < 0.05) with fT3, fT3/fT4, TSH, and TT3 in the group with joint exposure to high TPOAb and low iodine (T1I1). CONCLUSIONS: We found evidence of PFAS-associated thyroid disruption in a subset of U.S. adults with high TPOAb (a marker of autoimmune hypothyroidism) and low iodine status, who may represent a vulnerable subgroup. However, the small sample size, cross-sectional design, and possibility of reverse causation are limitations of this work. CITATION: Webster GM, Rauch SA, Ste Marie N, Mattman A, Lanphear BP, Venners SA. 2016. Cross sectional associations of serum perfluoroalkyl acids and thyroid hormones in U.S. adults: variation according to TPOAb and iodine status (NHANES 2007-2008). Environ Health Perspect 124:935-942; http://dx.doi.org/10.1289/ehp.1409589. PMID- 26517288 TI - Bacterial Thymidylate Synthase Binds Two Molecules of Substrate and Cofactor without Cooperativity. AB - Thymidylate synthase (TSase) is a clinically important enzyme because it catalyzes synthesis of the sole de novo source of deoxy-thymidylate. Without this enzyme, cells die a "thymineless death" since they are starved of a crucial DNA synthesis precursor. As a drug target, TSase is well studied in terms of its structure and reaction mechanism. An interesting mechanistic feature of dimeric TSase is that it is "half-the-sites reactive", which is a form of negative cooperativity. Yet, the basis for this is not well-understood. Some experiments point to cooperativity at the binding steps of the reaction cycle as being responsible for the phenomenon, but the literature contains conflicting reports. Here we use ITC and NMR to resolve these inconsistencies. This first detailed thermodynamic dissection of multisite binding of dUMP to E. coli TSase shows the nucleotide binds to the free and singly bound forms of the enzyme with nearly equal affinity over a broad range of temperatures and in multiple buffers. While small but significant differences in DeltaC degrees P for the two binding events show that the active sites are not formally equivalent, there is little-to-no allostery at the level of DeltaG degrees bind. In addition NMR titration data reveal that there is minor intersubunit cooperativity in formation of a ternary complex with the mechanism based inhibitor, 5F-dUMP, and cofactor. Taken together, the data show that functional communication between subunits is minimal for both binding steps of the reaction coordinate. PMID- 26517289 TI - Mapping of Strain Fields in GaAs/GaAsP Core-Shell Nanowires with Nanometer Resolution. AB - We report the nanoscale quantification of strain in GaAs/GaAsP core-shell nanowires. By tracking the shifting of higher-order Laue zone (HOLZ) lines in convergent beam electron diffraction patterns, we observe unique variations in HOLZ line separation along different facets of the core-shell structure, demonstrating the nonuniform strain fields created by the heterointerface. Furthermore, through the use of continuum mechanical modeling and Bloch wave analysis we calculate expected HOLZ line shift behavior, which are directly matched to experimental results. This comparison demonstrates both the power of electron microscopy as a platform for nanoscale strain characterization and the reliability of continuum models to accurately calculate complex strain fields in nanoscale systems. PMID- 26517290 TI - Deaths due to Intentional Explosions in Selected Governorates of Iraq from 2010 to 2013: Prospective Surveillance. AB - INTRODUCTION: The aim of this study was to describe the most recent trends and epidemiologic patterns of fatal injuries resulting from explosions in Iraq, one of the countries most affected by violence from explosive devices. METHODS: Iraqi Ministry of Health (MoH) routine prospective injury surveillance collects information on all fatal injuries recorded by coroners from physical examinations, police reports, and family members in eight governorates of Iraq: Baghdad, Al-Anbar, Basrah, Erbil, Kerbala, Maysan, Ninevah, and Al-Sulaimaniya. This study analyzed explosive-related fatal injuries that occurred from January 1, 2010 through December 31, 2013. RESULTS: Analysis included 2,803 fatal injuries. The number of fatal injuries declined from 2010 through 2012, followed by an increase in 2013. One-thousand one-hundred and one explosion-related fatalities were documented in 2013, more than twice as many as in 2012 or in 2011. Most fatalities were among men aged 20-39 years. Of all causalities, 194 (6.9%) were among females and 302 (10.8%) were among children aged less than 18 years. The majority of fatalities were caused by improvised explosive devices (IEDs): car bombs (15.3%), suicide bombs (4.0%), and other IEDs (29.6%). The highest number of fatalities occurred in streets and roads. Of all deaths, 95.6% occurred in three governorates: Baghdad, Ninevah, and Al-Anbar. CONCLUSIONS: Explosives continue to result in a high number of fatal injuries in Iraq. Following a period of declining violence from explosives, in 2013, fatalities increased. Most explosion-related injuries resulted from IEDs; males aged 20-39 years were at greatest risk. PMID- 26517291 TI - "Just Advil": Harm reduction and identity construction in the consumption of over the-counter medication for chronic pain. AB - Direct-to-consumer marketing has sparked ongoing debate concerning whether ads empower consumers to be agents of their own care or shift greater control to the pharmaceutical industry. Ads for over-the-counter (OTC) medications in particular portend to offer simple, harmless solutions for meeting the demands of social life. Rather than join the longstanding debate between consumer agency and social control in pharmaceutical advertising, I approach self-medication with over-the counter (OTC) analgesics using Harm Reduction as a framework. From this perspective, consumption of OTC analgesics by chronic pain sufferers is a means of seeking some level of relief while also avoiding the stigma associated with prescription pain medication. Qualitative methods are used to analyze data from two sources: (1) semi-structured qualitative interviews with 95 participants in a trial examining the effectiveness of Traditional Chinese Medicine for Temporomandibular Disorders (TMD) from 2006 to 2011 in Tucson, AZ and Portland, OR; and (2) print, online, and television advertisements for three major brands of OTC pain medication. Participants described their use of OTC medications as minimal, responsible, and justified by the severity of their pain. OTC medication advertising, while ostensibly ambiguous and targeting all forms of pain, effectively lends support to the consumption of these medications as part of the self-projects of chronic pain sufferers, allowing them to reconcile conflicting demands for pain relief while being stoic and maintaining a positive moral identity. Describing OTC medication as "just over-the-counter" or "not real pain medication," sufferers engage in ideological harm reduction, distinguishing themselves from "those people who like taking pain medication" while still seeking relief. Justifying one's use of OTC medication as minimal and "normal," regardless of intake, avoids association with the addictive potential of prescription pain medications and aligns the identity of the chronic pain sufferer with a culturally sanctioned identity as stoic bearer of pain. PMID- 26517293 TI - From patient deference towards negotiated and precarious informality: An Eliasian analysis of English general practitioners' understandings of changing patient relations. AB - This article contributes to sociological debates about trends in the power and status of medical professionals, focussing on claims that deferent patient relations are giving way to a more challenging consumerism. Analysing data from a mixed methods study involving general practitioners in England, we found some support for the idea that an apparent 'golden age' of patient deference is receding. Although not necessarily expressing nostalgia for such doctor-patient relationships, most GPs described experiencing disruptive or verbally abusive interactions at least occasionally and suggested that these were becoming more common. Younger doctors tended to rate patients as less respectful than their older colleagues but were also more likely to be egalitarian in attitude. Our data suggest that GPs, especially younger ones, tend towards a more informal yet limited engagement with their patients and with the communities in which they work. These new relations might be a basis for mutual respect between professionals and patients in the consulting room, but may also generate uncertainty and misunderstanding. Such shifts are understood through an Eliasian framework as the functional-democratisation of patient-doctor relations via civilising processes, but with this shift existing alongside decivilising tendencies involving growing social distance across broader social figurations. PMID- 26517292 TI - Communal bereavement and resilience in the aftermath of a terrorist event: Evidence from a natural experiment. AB - RATIONALE: Sociological analyses of the psychological distress experienced by persons indirectly exposed to traumatic stressors have been conceptualized as a form of communal bereavement, defined by Catalano and Hartig (2001) as the experience of distress among persons not attached to the deceased. Their theory predicts communal bereavement responses particularly in the setting of loss of essential state, religious, or economic institutions. OBJECTIVE: To estimate the extent to which the September 11, 2001 attacks on the U.S. World Trade Center had a causal effect on psychological distress nationwide. METHODS: We used a difference-in-differences framework applied to repeated cross-sectional data from more than 300,000 participants in the 2000 and 2001 Behavioral Risk Factor Surveillance System surveys. Psychological distress was measured using three questions eliciting days of poor mental health-related quality of life. The September 11 attacks served as our exposure of interest. RESULTS: The September 11 attacks had a statistically significant, adverse, causal effect on psychological distress nationally. Both the magnitude and statistical significance of the estimated effects were larger in the New York City region compared to the rest of the country. Our estimates were robust to probes of the parallel trends assumption and potential sources of selection bias, as well as to falsification tests. However, these effects had largely resolved within four weeks. CONCLUSIONS: Contrary to findings from the medical and public health literature, we conclude that the September 11 attacks did not have lasting effects on communal bereavement. PMID- 26517294 TI - 'He always thinks he is nothing': The psychosocial impact of discrimination on adolescent refugees in urban Uganda. AB - Armed conflict causes massive displacement, erodes the social fabric of communities, and threatens the healthy development of a nation's future - its youth. Although more than half of the world's registered refugees under the age of eighteen currently reside in urban areas, research on the unique needs of and realities experienced by this population remain limited. In Uganda, as in many refugee-receiving countries, most regulated refugee protections and entitlements fail to extend beyond the confines of official settlements or camps. This dearth of support, in combination with few material resources, uncertain local connections, and little knowledge of the language, leaves refugee families vulnerable to the added burden of an unwelcome reception in cities. Drawing on qualitative data from a study conducted in March and April 2013 with Congolese and Somali adolescents, caregivers, and service providers in refugee settlements in Kampala, this manuscript explores the pervasive nature of discrimination against urban refugees and its effects upon adolescent well-being. Findings suggest that discrimination not only negatively impacts acculturation as youth pursue social recognition in the classroom and among neighborhood peers, but it also impedes help-seeking behavior by caregivers and restricts their ability to ameliorate protection concerns, thereby lowering adolescents' psychosocial well being. Youth reported low self-worth, withdrawal from school, and an adverse turn toward street connections. Targeted and innovative strategies along with reformed policies that address the unique challenges facing urban refugees are paramount to ensuring that young people in this population experience greater protection, well-being, and future success. PMID- 26517295 TI - Participatory health system priority setting: Evidence from a budget experiment. AB - Budget experiments can provide additional guidance to health system reform requiring the identification of a subset of programs and services that accrue the highest social value to 'communities'. Such experiments simulate a realistic budget resource allocation assessment among competitive programs, and position citizens as decision makers responsible for making 'collective sacrifices'. This paper explores the use of a participatory budget experiment (with 88 participants clustered in social groups) to model public health care reform, drawing from a set of realistic scenarios for potential health care users. We measure preferences by employing a contingent ranking alongside a budget allocation exercise (termed 'willingness to assign') before and after program cost information is revealed. Evidence suggests that the budget experiment method tested is cognitively feasible and incentive compatible. The main downside is the existence of ex-ante "cost estimation" bias. Additionally, we find that participants appeared to underestimate the net social gain of redistributive programs. Relative social value estimates can serve as a guide to aid priority setting at a health system level. PMID- 26517297 TI - Monocyclometalated Gold(III) Complexes Bearing pi-Accepting Cyanide Ligands: Syntheses, Structural, Photophysical, and Electrochemical Investigations. AB - The synthesis, structural, photophysical, and electrochemical investigations of a series of gold(III) monocyclometalated complexes bearing ancillary ligands with pi-accepting properties is reported. Complexes of the type [(C(?)N)Au(C=N)2] [C(?)N = 2-phenylpyridine (ppy) (1), 2-(p-tolyl)pyridine (tpy) (2), 2-(2-thienyl) pyridine (thpy) (3), 2-(5-methyl-2-thienyl)pyridine (5m-thpy) (4), 1 phenylisoquinoline (piq) (5)], and [(N(?)N)Au(C=N)2] [N(?)N = 3,5-bis(phenyl)-2 (2'-pyridyl)pyrrole (pyrpy) (6)] were prepared, and the influence of both the cyanide as an ancillary ligand as well as the different electronic properties of the cyclometalating ligands (1-5) and the chelating bidentate (6) on the triplet emission properties were studied. The physicochemical properties were evaluated by a variety of physical methods, and the structure of selected complexes was further confirmed by X-ray diffraction studies. Complexes 1-5 display long-lived emission in solution, neat solid, spin coated PMMA films, and at 77 K in 2-MeTHF. The emission energies were strongly dictated by the cyclometalating ligands independent of the cyanide ligand, which is in quite a contrast to the previously reported dicyano complexes of iridium(III) and the isoelectronic platinum(II) complexes. The nonemissive behavior of complex 6 in any medium further highlights the importance that the good sigma-donating properties of the cyclometalating ligand alone is not decisive in rendering the gold complexes emissive, but also the appropriate placement of the energy level of the ligand orbitals is also important. Detailed photophysical studies in conjunction with density functional theory and time-dependent density functional theory calculations support the origin of the emission to be a metal perturbed intra ligand (3)IL (pi-pi*) delocalized over the cyclometalating ligand. The stability of the complexes combined with good emission quantum yields and tunability of the emission energies makes these complexes suitable alternatives to the relatively less stable monocyclometalated gold(III) diaryl or dialkyne complexes for organic light emitting device applications. PMID- 26517296 TI - Immunophenotypic and cytogenetic findings of B-lymphoblastic leukemia/lymphoma associated with combined IGH/BCL2 and MYC rearrangement. AB - BACKGROUND: B-lymphoblastic leukemias (B-LBL) with combined IGH/BCL2 and MYC rearrangement are rare and their clinical, cytogenetic and immunophenotypic features are not well characterized. Here, we describe a case of a 61-year-old woman with B-LBL associated with these cytogenetic alterations and present a review of the literature of this disease. METHODS: Four-color flow cytometry (FC) was performed on a BD FACSCanto II flow cytometer. Data were analyzed with BD FACSDiva software. Cytogenetic, fluorescence in situ hybridization (FISH), and molecular studies were performed by conventional methods. A review of the literature was performed by a PubMed-assisted search. RESULTS: Including our case, eight B-LBLs associated with a documented "double-hit" karyotype (IGH/BCL2 and 8q24/MYC rearrangement) were identified in the literature (male/female 2/6, age 15-65). Three occurred de-novo, and five had a history of a CD10+ B-cell lymphoma. The typical immunophenotype was CD10, CD19, TdT positive, and negative for CD34 and surface immunoglobulin (Ig), established either by FC or immunohistochemistry. Seven cases were CD20-, and one case was CD20+. Translocation partners of MYC varied, and included IGH, lambda light chain, and an unknown gene on chromosome 9. Prognosis was poor with median survival of five months. CONCLUSIONS: Patients with B-LBL associated with a combined IGH/BCL2 and MYC rearrangement often have a history of a mature B-cell lymphoma. The immunophenotype of these cases is different from that of mature "double-hit" lymphomas; FC is essential to differentiate the B-LBL cases from the leukemic phase of mature B-cell lymphomas. (c) 2015 International Clinical Cytometry Society. PMID- 26517298 TI - Association of keloids with systemic medical conditions: a retrospective analysis. PMID- 26517299 TI - Multidimensional Polycation beta-Cyclodextrin Polymer as an Effective Aqueous Binder for High Sulfur Loading Cathode in Lithium-Sulfur Batteries. AB - Although the lithium-sulfur battery has attracted significant attention because of its high theoretical energy density and low cost of elemental sulfur, its real application is still hindered by multiple challenges, especially the polysulfides shuttled between the cathode and anode electrodes. By originating from beta cyclodextrin and introducing a quaternary ammonium cation into beta-cyclodextrin polymer, a new multifunctional aqueous polycation binder (beta-CDp-N(+)) for the sulfur cathode is obtained. The unique hyperbranched network structure of the new binder beta-CDp-N(+) as well as its multidimensional noncovalent interactions and the introduced cations endowed beta-CDp-N(+) with some new abilities: a sulfur electrode-stabilized ability, a polysulfides-immobilized ability, and a volume accommodated ability, which help to ease the primary problems of the lithium sulfur battery, i.e., the shuttle of polysulfides and the volume change of the sulfur during charge and discharge. It is demonstrated that cycling performance and rate capability of the cathodes can be the improved by using beta-CDp-N(+) as the binder compared to other well-known binders. Even with high sulfur loading of 5.5 mg cm(-2), the cathode with beta-CDp-N(+) still can deliver an areal capacity of 4.4 mAh cm(-2) at 50 mA g(-1) after 45 cycles, which is much higher than that achieved using the cathode with the conventional binder (0.9 mAh cm(-2)). PMID- 26517300 TI - The effect of gabapentin and ketorolac on allodynia and conditioned place preference in antibody-induced inflammation. AB - BACKGROUND: Glucose-6-phosphate isomerase and collagen type II antibody-induced arthritis models (K/BxN and CAIA, respectively) have an inflammatory and a post inflammatory phase. Both phases display robust tactile allodynia. In previous work, inflammatory phase allodynia was reversed by gabapentin and ketorolac, whereas in late phase only gabapentin was effective. Here, we sought to determine if the effects of these two drugs during the early and late phases of the two arthritis models were observed in the conditioned place preference (CPP) paradigm, indicating a differential drug effect on the aversive state. METHODS: Male C57BL/6 mice received K/BxN serum intraperitoneally, while male BALB/c mice received collagen type II antibody cocktail intravenously. After onset of inflammation and allodynia, we assessed effects of i.p. gabapentin (100 mg/kg) or ketorolac (15 mg/kg) using a CPP paradigm: 2 days adaptation, 2 days conditioning (vehicle in morning and drug in afternoon), preference testing on day 5. RESULTS: Consistent with the effects upon allodynia, both gabapentin and ketorolac produced a preference for the drug-paired compartment in the early phase of the K/BxN model, while gabapentin, but not ketorolac, resulted in a place preference during late phase. In the CAIA model, consistent with differential effects upon allodynia, gabapentin produced a preference in the early phase and a trend in the late phase, whereas ketorolac was ineffective at either time. CONCLUSIONS: CPP validated the aversive state in the inflammatory and post-inflammatory phases of the K/BxN and CAIA arthritis models and correspondence between the anti hyperpathic pharmacology as defined by thresholds and CPP. PMID- 26517301 TI - Functional decline in patients with cirrhosis awaiting liver transplantation: Results from the functional assessment in liver transplantation (FrAILT) study. AB - Cirrhosis is characterized by sarcopenia and malnutrition, leading to progressive functional decline. We aimed to objectively measure functional decline in patients with cirrhosis awaiting liver transplantation and its association with waiting list mortality. Consecutive adults listed for liver transplantation with laboratory Model for End-Stage Liver Disease (MELD) >=12 at a single center underwent functional status assessments at every outpatient visit using the Short Physical Performance Battery (0 = impaired to 12 = robust), consisting of gait, chair stands, and balance tests. Joint linear time-to-event analyses modeled the simultaneous impact of the longitudinal trajectory of physical function on waiting list mortality (=death or delisted for being too sick for liver transplantation). Included were 309 liver transplantation candidates. Median laboratory MELD was 15, serum albumin was 3.0 g/dL, 28% had ascites, 18% had hepatic encephalopathy, and 83% were Child class B or C. At a median follow-up of 14 months, 15% died or were delisted and 28% underwent liver transplantation. Average physical function worsened per 3 months on the waiting list: -0.38 kg in grip strength, -0.05 meters/second in gait, 0.03 seconds in chair stands, and 0.16 Short Physical Performance Battery points. In joint models of longitudinal trajectories of physical function and waiting list mortality adjusted for MELD Na, albumin, hepatocellular carcinoma, and baseline physical function, the longitudinal trajectories of each physical function measure were significantly associated with waiting list mortality: grip (hazard ratio = 0.89, 95% confidence interval 0.83-0.95), gait (hazard ratio = 0.72, 95% confidence interval 0.62 0.84), chair stands (hazard ratio = 1.17, 95% confidence interval 1.09-1.25), and Short Physical Performance Battery <10 (hazard ratio = 1.45, 95% confidence interval 1.15-2.20). CONCLUSION: Liver transplantation candidates experience significant functional decline on the waiting list, despite modest wait time and low baseline MELD; decline in physical function is associated with an increased risk of death or delisting, independent of liver disease severity. PMID- 26517302 TI - Detection and Characterization of the Effect of AB-FUBINACA and Its Metabolites in a Rat Model. AB - Synthetic cannabinoids were originally developed by academic and pharmaceutical laboratories with the hope of providing therapeutic relief from the pain of inflammatory and degenerative diseases. However, recreational drug enthusiasts have flushed the market with new strains of these potent drugs that evade detection yet endanger public health and safety. Although many of these drug derivatives were published in the medical literature, others were merely patented without further characterization. AB-FUBINACA is an example of one of the new indazole-carboxamide synthetic cannabinoids introduced in the past year. Even though AB-FUBINACA has become increasingly prominent in forensic drug and toxicology specimens analyses, little is known about the pharmacology of this substance. To study its metabolic fate, we utilized Wistar rats to study the oxidative products of AB-FUBINACA in urine and its effect on gene expressions in liver and heart. Rats were injected with 5 mg/kg of AB-FUBINACA each day for 5 days. Urine samples were collected every day at the same time. On day 5 after treatment, we collected the organs such as liver and heart. The urine samples were analyzed by mass spectrometry, which revealed several putative metabolites and positioning of the hydroxyl addition on the molecule. We used quantitative PCR gene expression array to analyze the hepatotoxicity and cardiotoxicity on these rats and confirmed by real-time quantitative RT-PCR. We identified three genes significantly associated with dysfunction of oxidation and inflammation. Our study reports in vivo metabolites of AB-FUBINACA in urine and its effect on the gene expressions in liver and heart. PMID- 26517303 TI - Synthesis and In Vivo PET Imaging of Hyaluronan Conjugates of Oligonucleotides. AB - Synthesis for (68)Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelated oligonucleotide hyaluronan (HA) tetra- and hexasaccharide conjugates is described. A solid-supported technique is used to introduce NOTA-chelator into the 3'-terminus of oligonucleotides and a copper-free strain promoted azide alkyne cycloaddition (SPAAC) to HA/oligonucleotide conjugation. Protecting group manipulation, required for the HA-moieties, is carried out after the SPAAC conjugation. Positron emission tomography (PET) is used (1) in the whole-body distribution kinetic studies of the conjugates in healthy rats and (2) to show the potential of hyaluronan-induced targeting of oligonucleotides into the infarcted area of rats with myocardial infarction. PMID- 26517305 TI - Raman Vibrational Shifts of Small Clusters of Hydrogen Isotopologues. AB - Raman vibrational shifts of small parahydrogen (pH2), orthodeuterium (oD2), and paratritium (pT2) clusters with respect to the free molecules are calculated by combining a first order perturbation theory approach with Langevin equation Path Integral Ground State (LePIGS) simulations [ J. Phys. Chem. A 2013 , 117 , 7461 ]. Our theoretical predictions are compared to existing cryogenic free jet expansion results for pure (pH2)N clusters [ Phys. Rev. Lett. 2004 , 92 , 223401 ] and to new measurements for (oD2)N clusters reported here. This method has been successfully used before to predict the Raman vibrational shifts of (pH2)N clusters [ J. Chem. Phys. 2014 , 141 , 014310 ]. The 6-D interaction potential of Hinde [ J. Chem. Phys. 2008 , 128 , 154308 ] is reduced to 1-D using the Adiabatic Hindered Rotor approximation to yield effective pair potentials for both molecules being in the ground vibrational state, and for one of them carrying one quantum of vibrational excitation. These reduced 1-D potentials are fitted to a Morse Long Range analytic form for later convenience. Good agreement between experiment and theory is found for the smaller clusters, but significant deviations remain for the larger ones. PMID- 26517304 TI - Dysregulation of Antiviral Function of CD8(+) T Cells in the Chronic Obstructive Pulmonary Disease Lung. Role of the PD-1-PD-L1 Axis. AB - RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) are susceptible to respiratory viral infections that cause exacerbations. The mechanisms underlying this susceptibility are not understood. Effectors of the adaptive immune response-CD8(+) T cells that clear viral infections-are present in increased numbers in the lungs of patients with COPD, but they fail to protect against infection and may contribute to the immunopathology of the disease. OBJECTIVES: CD8(+) function and signaling through the programmed cell death protein (PD)-1 exhaustion pathway were investigated as a potential key mechanism of viral exacerbation of the COPD lung. METHODS: Tissue from control subjects and patients with COPD undergoing lung resection was infected with live influenza virus ex vivo. Viral infection and expression of lung cell markers were analyzed using flow cytometry. MEASUREMENTS AND MAIN RESULTS: The proportion of lung CD8(+) T cells expressing PD-1 was greater in COPD (mean, 16.2%) than in controls (4.4%, P = 0.029). Only epithelial cells and macrophages were infected with influenza, and there was no difference in the proportion of infected cells between controls and COPD. Infection up-regulated T-cell PD-1 expression in control and COPD samples. Concurrently, influenza significantly up-regulated the marker of cytotoxic degranulation (CD107a) on CD8(+) T cells (P = 0.03) from control subjects but not on those from patients with COPD. Virus-induced expression of the ligand PD-L1 was decreased on COPD macrophages (P = 0.04) with a corresponding increase in IFN-gamma release from infected COPD explants compared with controls (P = 0.04). CONCLUSIONS: This study has established a signal of cytotoxic immune dysfunction and aberrant immune regulation in the COPD lung that may explain both the susceptibility to viral infection and the excessive inflammation associated with exacerbations. PMID- 26517306 TI - Chemoenzymatic Synthesis of Proxyphylline Enantiomers. AB - A novel synthetic route for preparation of proxyphylline enantiomers using a kinetic resolution (KR) procedure as the key step is presented. The reactions were catalyzed by immobilized Candida antarctica lipase B in acetonitrile. Three types of reactions were examined: (i) enantioselective transesterification of racemic proxyphylline with vinyl acetate as well as (ii) hydrolysis and (iii) methanolysis of its esters. The influence of reaction conditions on the substrate conversion and enantiomeric purity of the products were investigated. Studies on analytical scale reactions revealed that the titled API enantiomers could be successfully obtained with excellent enantiomeric excess (up to >99% ee). The process was easily conducted on a 5 g scale at 100 g/L. In a preparative-scale reaction, unreacted (S)-(+)-butanoate (97% ee) and (R)-(-)-alcohol (96% ee) were obtained after 2 days in yields of 45% and 46%, respectively. When the reaction time was extended to 6 days, (S)-(+)-butanoate was isolated in >99% ee and acceptable high enantioselectivity (E = 90). Importantly, the KR's products could be conveniently isolated by exploiting varying solubility of the ester/alcohol in acetonitrile at room temperature. In addition, a chiral preference of the CAL-B active site for the R-enantiomer was rationalized by in sillico docking studies. PMID- 26517307 TI - Height Growth and Percentage of Body Fat in Relation to Early Menarche in Girls from Merida, Yucatan, Mexico. AB - Early menarche (EM) (i.e., age at menarche [AAM] <12 years of age) is related to short height and higher body fatness. In a mixed-longitudinal study done in Merida, Yucatan, height, body mass index (BMI), and percentage of body fat (BF%) were recorded at a one-year interval among 258 postmenarcheal (EM = 94) girls. Anthropometric measurements were recorded of the age cohorts in 2008-09 when participants were 13-17 years of age (baseline), and in the one-year follow-up study (+/- 6 days) the girls were 14-18 years of age. The BF% was estimated through bioelectrical impedance analysis. Mean AAM was 10.59 years in EM girls and 12.54 years in not early menarche (NEM) girls. Height growth (cm/year) was greater in NEM girls. Mean values of BMI, BF%, and frequencies of stunting (low height-for-age) and excess weight (overweight + obesity) were higher in EM girls than in their NEM age peers. PMID- 26517308 TI - Facilitators and Barriers to Traditional Food Consumption in the Cree Community of Mistissini, Northern Quebec. AB - To identify barriers to traditional food consumption and factors that facilitate it among the Cree community of Mistissini, a series of four focus groups was conducted with a total of twenty-three people. Two ecological models were created, one for facilitating factors and a second for obstacles, illustrating the role of numerous interconnected influences of traditional food consumption. Environmental impact project, laws and regulation, local businesses, traditional knowledge, youth influence, employment status, and nonconvenience of traditional food were named among numerous factors influencing traditional food consumption. The findings of this study can be used by political and public health organizations to promote traditional food where more emphasis should be invested in community and environmental strategies. PMID- 26517309 TI - The prevalence of compulsive buying: a meta-analysis. AB - AIMS: To estimate the pooled prevalence of compulsive buying behaviour (CBB) in different populations and to determine the effect of age, gender, location and screening instrument on the reported heterogeneity in estimates of CBB and whether publication bias could be identified. METHODS: Three databases were searched (Medline, PsychInfo, Web of Science) using the terms 'compulsive buying', 'pathological buying' and 'compulsive shopping' to estimate the pooled prevalence of CBB in different populations. Forty studies reporting 49 prevalence estimates from 16 countries were located (n = 32,000). To conduct the meta analysis, data from non-clinical studies regarding mean age and gender proportion, geographical study location and screening instrument used to assess CBB were extracted by multiple independent observers and evaluated using a random effects model. Four a priori subgroups were analysed using pooled estimation (Cohen's Q) and covariate testing (moderator and meta-regression analysis). RESULTS: The CBB pooled prevalence of adult representative studies was 4.9% (3.4 6.9%, eight estimates, 10,102 participants), although estimates were higher among university students: 8.3% (5.9-11.5%, 19 estimates, 14,947 participants) in adult non-representative samples: 12.3% (7.6-19.1%, 11 estimates, 3929 participants) and in shopping-specific samples: 16.2% (8.8-27.8%, 11 estimates, 4686 participants). Being young and female were associated with increased tendency, but not location (United States versus non-United States). Meta-regression revealed large heterogeneity within subgroups, due mainly to diverse measures and time-frames (current versus life-time) used to assess CBB. CONCLUSIONS: A pooled estimate of compulsive buying behaviour in the populations studied is approximately 5%, but there is large variation between samples accounted for largely by use of different time-frames and measures. PMID- 26517310 TI - Structure-enhanced methods in the development of non-nucleoside inhibitors targeting HIV reverse transcriptase variants. AB - Resistance continues to emerge as a leading cause for antiretroviral treatment failure. Several mutations in HIV reverse transcriptase (RT) confer resistance to non-nucleoside inhibitors (NNRTIs), vital components of antiretroviral combination therapies. Since the majority of mutations are located in the NNRTI binding pocket, crystal structures of RT variants in complex with NNRTIs have provided ideas for new drug design strategies. This article reviews the impact of RT crystal structures on the multidisciplinary design and development of new inhibitors with improved resistance profiles. PMID- 26517311 TI - Mesoporous Silica Nanoparticles under Sintering Conditions: A Quantitative Study. AB - Thin films made of mesoporous silica nanoparticles (MSNs) are finding new applications in catalysis, optics, as well as in biomedicine. The fabrication of MSNs thin films requires a precise control over the deposition and sintering of MSNs on flat substrates. In this study, MSNs of narrow size distribution (150 nm) are synthesized, and then assembled onto flat silicon substrates, by means of a dip-coating process. Using concentrated MSN colloidal solutions (19.5 mg mL(-1) SiO2), withdrawal speed of 0.01 mm s(-1), and well-controlled atmospheric conditions (ambient temperature, ~ 70% of relative humidity), monolayers are assembled under well-structured compact patterns. The thin films are sintered up to 900 degrees C, and the evolution of the MSNs size distributions are compared to those of their pore volumes and densities. Particle size distributions of the sintered thin films were precisely fitted using a model specifically developed for asymmetric particle size distributions. With increasing temperature, there is first evidence of intraparticle reorganization/relaxation followed by intraparticle sintering followed by interparticle sintering. This study is the first to quantify the impact of sintering on MSNs assembled as thin films. PMID- 26517312 TI - Benefits and risks of add-on therapies for Alzheimer's disease. AB - Despite three decades of intensive research, the efforts of scientific society and industry and the expenditures, numerous attempts to develop effective treatments for Alzheimer's disease have failed. Currently, approved and widely used medications to treat cognitive deficits in Alzheimer's disease are symptomatic only and show at best modest efficacy. In this context, the need to develop a successful, disease-modifying treatment is loudly expressed. One way to achieve this goal is the use of add-on therapies or various combinations of existing 'conventional' drugs. Results of several clinical studies and post hoc analyses of combination therapy with all cholinesterase inhibitors and memantine are published. Moreover, there is a need for studies on long-term efficacy of combination therapy in Alzheimer's. PMID- 26517313 TI - TRPV1 channel modulation by hyaluronan reduces pain. PMID- 26517314 TI - Improving morbidity and mortality in peripheral ulcerative keratitis associated with rheumatoid arthritis. PMID- 26517316 TI - Treatment of Thin Linear Scars on the Scalp. PMID- 26517315 TI - Mesenchymal Extratesticular Tumors and Tumorlike Conditions: From the Radiologic Pathology Archives. AB - Both benign and malignant tumors and tumorlike conditions can arise from the nonepididymal extratesticular tissues. Benign tumors are far more common than malignant tumors, with lipoma being the most common lesion found at this site. Several imaging features can help narrow the differential diagnosis of these lesions, including the presence of fat and imaging features suggestive of fibrous tissue. Lesions that contain fat represent lipoma, liposarcoma, or angiomyofibroblastoma (AMF)-like tumor. If enhancing soft tissue is present in conjunction with fat, the differential diagnosis narrows further to just liposarcoma and AMF-like tumor. Lesions that display magnetic resonance imaging characteristics compatible with fibrous tissue are likely to be fibrous pseudotumor. However, many of the lesions in this location have overlapping imaging findings, and surgical excision is most often necessary for accurate diagnosis. The ability to narrow the differential diagnosis with imaging, however, is helpful for the clinician for both treatment planning and patient counseling. PMID- 26517317 TI - Reconstruction of Partial Helical Defects. PMID- 26517318 TI - Management of a Nasal Spindle Cell Lipoma: Diagnostic and Therapeutic Considerations. PMID- 26517319 TI - Commentary on the Oval Female Facial Shape--A Study in Beauty. PMID- 26517320 TI - Clinical and Pathologic Factors Predictive of Positive Radiologic Findings in High-Risk Cutaneous Squamous Cell Carcinoma. AB - BACKGROUND: At present, there exists considerable clinical uncertainty regarding the role of radiologic imaging in the staging and management of high-risk cutaneous squamous cell carcinoma (hrSCC). OBJECTIVE: The authors sought to investigate the clinical and pathologic features predictive of bony invasion, perineural invasion, or lymphadenopathy in patients that had undergone head and neck imaging for hrSCC. MATERIALS AND METHODS: The authors conducted a single center retrospective chart review of patients (n = 82) that had undergone head and neck imaging for hrSCC. RESULTS: Twenty-nine percent (24/82) of patients in the study had positive findings on radiologic imaging. Immunocompromised patients were more likely to have the radiologic finding of lymphadenopathy (p = .04). Tumor size was found to correlate with the radiologic finding of bony invasion (correlation coefficient = 0.40, p = .0002). There was no relationship between either high risk location or high risk histopathology and positive radiologic findings. The low number of patients and its retrospective nature are study limitations. CONCLUSION: The clinical features of host immunosuppression and tumor size are predictive of positive imaging findings in hrSCC. The decision to perform radiologic imaging in patients with hrSCC may be influenced by these factors, but continue to be more firmly guided by physical exam and clinical suspicion. PMID- 26517322 TI - Things that Work, Things that Don't Work, and Things that Matter--Including Words. PMID- 26517321 TI - Deconstructing Interocular Suppression: Attention and Divisive Normalization. AB - In interocular suppression, a suprathreshold monocular target can be rendered invisible by a salient competitor stimulus presented in the other eye. Despite decades of research on interocular suppression and related phenomena (e.g., binocular rivalry, flash suppression, continuous flash suppression), the neural processing underlying interocular suppression is still unknown. We developed and tested a computational model of interocular suppression. The model included two processes that contributed to the strength of interocular suppression: divisive normalization and attentional modulation. According to the model, the salient competitor induced a stimulus-driven attentional modulation selective for the location and orientation of the competitor, thereby increasing the gain of neural responses to the competitor and reducing the gain of neural responses to the target. Additional suppression was induced by divisive normalization in the model, similar to other forms of visual masking. To test the model, we conducted psychophysics experiments in which both the size and the eye-of-origin of the competitor were manipulated. For small and medium competitors, behavioral performance was consonant with a change in the response gain of neurons that responded to the target. But large competitors induced a contrast-gain change, even when the competitor was split between the two eyes. The model correctly predicted these results and outperformed an alternative model in which the attentional modulation was eye specific. We conclude that both stimulus-driven attention (selective for location and feature) and divisive normalization contribute to interocular suppression. PMID- 26517323 TI - A Call for National Standards and Oversight of State Physician Health Programs. AB - OBJECTIVES: Many physicians are referred to state physician health programs (PHPs) for evaluation, monitoring, and treatment of mental health and substance use disorders. If the physician agrees to cooperate with the PHP and adhere to any recommendations it might make, the physician often can avoid disciplinary action and remain in practice. Despite their considerable power, many PHPs operate with little oversight. METHODS: I review recommendations that a co-author and I previously made regarding oversight of PHPs and then review some of the findings from a recent performance audit of the North Carolina Physicians Health Program by the North Carolina Auditor's Office. RESULTS: Physicians who might object to the conclusions and recommendations of PHPs in many states do not have the ability to appeal and lack due process. Additionally, given that many of the evaluation and treatment centers to which PHPs refer their clients also sponsor meetings of PHPs, there is significant potential for conflict of interest in the standard operations of PHPs. CONCLUSIONS: National standards should be put in place for the day-to-day operation of PHPs and include avenues for appealing decisions and recommendations by them. Also, PHPs should be routinely audited to ensure the soundness and fairness of their practice. PMID- 26517324 TI - Patterns and Quality of Buprenorphine Opioid Agonist Treatment in a Large Medicaid Program. AB - OBJECTIVES: Use of buprenorphine - an effective treatment for opioid use disorders (OUDs) - has increased rapidly in recent years and is often financed by Medicaid. We investigated predictors of buprenorphine treatment, patterns of care, and quality of care in a large state Medicaid program. METHODS: Data from Pennsylvania Medicaid from 2007 to 2012 provided information regarding diagnoses, demographic characteristics, enrollment, and use of inpatient and outpatient services, and prescription drugs. We identified adult enrollees using buprenorphine, and examined prevalence of OUD diagnosis and patterns of use (duration and dose) and quality of care (physician visits, receipt of behavioral health counseling, urine drug screens, and other prescription drug use). We use a mixed logistic regression model to examine enrollee characteristics associated with buprenorphine use. RESULTS: The share of enrollees with OUD filling prescriptions for buprenorphine increased from 2985 (9.8%) to 12,691 (25.2%) from 2007 to 2012. Between 26.2 and 32.0% of enrollees using buprenorphine had no diagnosis of OUD, depending on the year. Only 60.1% of enrollees with buprenorphine use received at least one urine drug screen, 41.0% had behavioral health counseling services, and 34.7 and 38.0% had other opioid and benzodiazepine claims, respectively, concomitant with buprenorphine use. Quality of care was lower among those with no OUD diagnosis recorded. The mean daily doses of buprenorphine decreased over time. We found wide variation in likelihood of buprenorphine use among those with OUD based upon age, sex, and race. CONCLUSIONS: Increases in buprenorphine treatment in a Medicaid population were observed across time; however, increases varied by age, sex, and rate, and the quality of care received seemed to be generally poor. The quality of the provision of buprenorphine treatment occurring in Medicaid populations should be further explored. PMID- 26517325 TI - Quality Assessment Errors and Study Misclassification Threaten Systematic Review Validity: Community Opioid Overdose Prevention and Naloxone Distribution Programs Review: Re: Clark AK, Wilder CM, Winstanley EL. A systematic review of community opioid overdose prevention and naloxone distribution programs. J Addict Med 2014 May-June;8(3): 153-163. PMID- 26517326 TI - Response to "Quality Assessment Errors and Study Misclassification Threaten Systematic Review Validity: Community Opioid Overdose Prevention and Naloxone Distribution Programs Review". PMID- 26517328 TI - Detection Yield and Tolerability of String Test for Diagnosis of Childhood Intrathoracic Tuberculosis. AB - BACKGROUND: Difficulty to obtain sputum in children complicates diagnosis of intrathoracic tuberculosis (TB). The intragastric string test (ST) used for retrieval of enteric pathogens might be an alternative specimen collection method but requires further evaluation of its utility in TB diagnosis. We conducted a cross-sectional study comparing the TB detection yield and the tolerability of ST and sputum induction (SI) in children. METHODS: Two ST and SI procedures were performed in children (3-14 years of age) who were clinically suspected of having TB. The string was removed after a 2-hour gastric downtime, and SI was done after a maximum of 20 minutes nebulization with 5% saline solution. LED-fluorescence microscopy and mycobacterial cultures were performed on all specimens, and XpertMTB/RIF assay was performed on stored specimen sediments. Tolerability questionnaires were administered to parents of children. RESULTS: Of 137 included children (median age: 8.1 years; 33.3% with HIV infection), 14 (10.2%) were diagnosed with TB, 10 (71.4%) by ST and 12 (85.7%) by SI. Among 105 children with both ST and SI performed, 5 (4.8%) versus 4 (3.8%) were smear positive using ST and SI, respectively (McNemar P = 1.00). Nine (8.6%) in each group had positive cultures (P = 1.00). Of 64 children tested with XpertMTB/RIF, 3 (4.7%) of the ST group versus 4 (6.3%) of the SI group were TB positive (P = 1.00). No adverse serious events were reported. ST could not be performed in 22 of 137 (16.1%) children because they were unable to swallow the capsule. CONCLUSIONS: TB detection yield was comparable between ST and SI. The tolerability of ST in young children might be improved by the reduction of the size of the capsule. PMID- 26517329 TI - Clinical and Microbiologic Assessment of Cases of Pediatric Community-associated Clostridium difficile Infection Reveals Opportunities for Improved Testing Decisions. AB - BACKGROUND: Most children with Clostridium difficile infection (CDI) experience community onset of CDI symptoms. METHODS: We retrospectively compared hospital onset healthcare facility-associated CDI cases to community-associated (CA) CDI cases diagnosed by Cepheid Xpert tcdB polymerase chain reaction (PCR) at an academic children's hospital over a 1-year period. Saved stools from CDI cases additionally underwent anaerobic stool culture and multiplex gastrointestinal pathogen PCR testing. RESULTS: Compared with 25 hospital-onset healthcare facility-associated CDI cases, the 74 CA-CDI cases were more frequently <2 years old (18% vs. 0%, P = 0.034) and less frequently had antibiotic exposure in the past 30 days (26% vs. 88%, P < 0.0001), proton pump inhibitor exposure (16% vs. 36%, P = 0.036) or a gastrostomy tube (11% vs. 32%, P = 0.013). Among children diagnosed with CA-CDI, 19 (26%) had no identified CDI risk factors (immunocompromised; gastrostomy tube; recent antibiotic, proton pump inhibitor or inpatient/outpatient healthcare exposures). Clinical testing for viral pathogens was uncommon among children thought to have CA-CDI. Multiplex PCR testing of saved stool samples failed to identify C. difficile among 23% of cases diagnosed with CA-CDI by the Cepheid Xpert tcdB PCR assay. CDI antibiotic therapy was provided to nearly all patients testing positive by tcdB PCR irrespective of CDI risk factors. CONCLUSIONS: Many children diagnosed with CA-CDI by PCR lack CDI risk factors and have discordant results when additional CDI testing methods are performed, suggesting overdiagnosis of CDI in children with community-onset diarrhea. More selective CDI testing of low-risk pediatric patients is needed to more accurately diagnose CDI and limit unnecessary CDI antibiotic treatment in children. PMID- 26517330 TI - Global Burden of Neonatal Invasive Pneumococcal Disease: A Systematic Review and Meta-analysis. AB - BACKGROUND: This study aimed to estimate the global burden of invasive pneumococcal disease (IPD) incidence among neonates during the pre-pneumococcal conjugate vaccine era. METHODS: A systematic search of published and unpublished data was undertaken. Bias assessment and qualitative synthesis of the included studies were carried out. Random effects models using the method of DerSimonian and Laird were constructed. Subgroup analyses, sensitivity analyses and meta influence analysis were undertaken. Sources of heterogeneity were investigated. RESULTS: From 26 neonatal IPD data points in the pre-pneumococcal conjugate vaccine era, the overall pooled neonatal IPD incidence, in the general population, combining all 3 United Nations (UN) country strata was estimated to be 36.0 per 100,000 live births [95% confidence interval (CI): 20.0-64.7 per 100,000]. The pooled neonatal IPD incidence in the general population in the less developed UN country strata was estimated to be 16.0 per 100,000 live births (95% CI: 3.9-65.6 per 100,000) and in the more-developed stratum was 41.1 per 100,000 live births (95% CI: 29.1-58.1 per 100,000). This counter-intuitive finding is likely to have been affected by data quantity and confounding by time. A pooled estimate for the least-developed stratum was not computable as there was only 1 study in this stratum-a study from The Gambia with an unweighted IPD incidence of 369.5 per 100,000 (95% CI: 119.2-1138.5 per 100,000). CONCLUSIONS: Pneumococcus was a recognized pathogen among neonates in all development regions of the world. The burden of neonatal IPD, particularly in the least-developed UN country stratum, requires substantial further evaluation. PMID- 26517331 TI - Clinical and Serologic Response to the 23-valent Polysaccharide Pneumococcal Vaccine in Children and Teens with Recurrent Upper Respiratory Tract Infections and Selective Antibody Deficiency. AB - We report the clinical and serological response of 72 children and adolescents after immunization with the 23-valent polysaccharide pneumococcal vaccine (PPV23). All had been diagnosed with recurrent upper respiratory tract infections and low antipneumococcal immunity. Forty-five (62%) of these patients had received PCV7, the 7-serotype pneumococcal conjugated vaccine (Prevnar7). After immunization with the polysaccharide vaccine, 69 (96%) patients, including 42 of the 45 who had previously been immunized with the conjugate vaccine, had a positive clinical response including 12 patients (17%) whose serological response to the polysaccharide vaccine was inadequate. Clinical and serological response to PPV23 was assessed at approximately 1, 3 and 6 months after immunization. Our study also confirmed that a small group of patients with recurrent upper respiratory tract infections are unable to develop a normal response to pneumococcal and other bacterial polysaccharides despite vaccination with the newer conjugated vaccines. This immunodeficiency has been named selective antibody deficiency with normal immunoglobulins or impaired polysaccharide responsiveness. These patients did well after administration of intravenous IgG. PMID- 26517332 TI - Perspectives on Development and Regulation of Therapeutic Products for CED-Based Therapy of Neurodegenerative Diseases. AB - Neurodegenerative diseases (NDs) caused by the progressive degeneration of brain neurons affect millions of people worldwide and pose significant public health challenges. Despite therapeutic advances in the treatment of these diseases, drug delivery to desired brain targets is difficult due to the intrinsic resistance of the blood-brain barrier (BBB). Many research groups are investigating novel strategies of transporting drug molecules across this barrier. Convection enhanced delivery (CED) is a neurosurgical administration technique that has been recognized as an effective means of bypassing the BBB to deliver drugs to their clinical targets in pharmacologically relevant quantities. Currently, the drugs and devices being used in CED therapy remain at an investigational stage and have not been approved for use in actual treatment. This article provides a brief introduction of the etiologies of NDs, technical insights into CED and perspectives on the development and regulation of therapeutic products for the CED-based therapy of NDs. PMID- 26517333 TI - Cyclodextrin-based Polymeric Nanoparticles as Efficient Carriers for Anticancer Drugs. AB - Among the difficulties encountered in the treatment of cancer are the physico chemical properties of the chemotherapeutic agents; in particular low water solubility and low stability, resulting in poor efficacy. Due to their capability to form molecular inclusions with apolar molecules (or part of them) cyclodextrins constitute a powerful tool to prepare more efficient chemotherapeutic delivery systems such as nanoparticles. This review focuses on polymeric nanoparticles for cancer therapy prepared from either cyclodextrin molecules, or polymer and cyclodextrins. PMID- 26517334 TI - Optimization of the RNeasy Mini Kit to obtain high-quality total RNA from sessile cells of Staphylococcus aureus. AB - Biofilm formed by Staphylococcus aureus is considered an important virulence trait in the pathogenesis of infections associated with implantable medical devices. Gene expression analyses are important strategies for determining the mechanisms involved in production and regulation of biofilm. Obtaining intact RNA preparations is the first and most critical step for these studies. In this article, we describe an optimized protocol for obtaining total RNA from sessile cells of S. aureus using the RNeasy Mini Kit. This method essentially consists of a few steps, as follows: 1) addition of acetone-ethanol to sessile cells, 2) lysis with lysostaphin at 37 degrees C/10 min, 3) vigorous mixing, 4) three cycles of freezing and thawing, and 5) purification of the lysate in the RNeasy column. This simple pre-kit procedure yields high-quality total RNA from planktonic and sessile cells of S. aureus. PMID- 26517335 TI - Hypertension is associated with greater heat exchange during exercise recovery in a hot environment. AB - Individuals with systemic arterial hypertension have a higher risk of heat related complications. Thus, the aim of this study was to examine the thermoregulatory responses of hypertensive subjects during recovery from moderate intensity exercise performed in the heat. A total of eight essential hypertensive (H) and eight normotensive (N) male subjects (age=46.5+/-1.3 and 45.6+/-1.4 years, body mass index=25.8+/-0.8 and 25.6+/-0.6 kg/m2, mean arterial pressure=98.0+/-2.8 and 86.0+/-2.3 mmHg, respectively) rested for 30 min, performed 1 h of treadmill exercise at 50% of maximal oxygen consumption, and rested for 1 h after exercise in an environmental chamber at 38 degrees C and 60% relative humidity. Skin and core temperatures were measured to calculate heat exchange parameters. Mean arterial pressure was higher in the hypertensive than in the normotensive subjects throughout the experiment (P<0.05, unpaired t-test). The hypertensive subjects stored less heat (H=-24.23+/-3.99 W.m-2vs N=-13.63+/ 2.24 W.m-2, P=0.03, unpaired t-test), experienced greater variations in body temperature (H=-0.62+/-0.05 degrees C vsN=-0.35+/-0.12 degrees C, P=0.03, unpaired t-test), and had more evaporated sweat (H=-106.1+/-4.59 W.m-2vs N= 91.15+/-3.24 W.m-2, P=0.01, unpaired t-test) than the normotensive subjects during the period of recovery from exercise. In conclusion, essential hypertensive subjects showed greater sweat evaporation and increased heat dissipation and body cooling relative to normotensive subjects during recovery from moderate-intensity exercise performed in hot conditions. PMID- 26517337 TI - Investigating protein conformational energy landscapes and atomic resolution dynamics from NMR dipolar couplings: a review. AB - Nuclear magnetic resonance spectroscopy is exquisitely sensitive to protein dynamics. In particular inter-nuclear dipolar couplings, that become measurable in solution when the protein is dissolved in a dilute liquid crystalline solution, report on all conformations sampled up to millisecond timescales. As such they provide the opportunity to describe the Boltzmann distribution present in solution at atomic resolution, and thereby to map the conformational energy landscape in unprecedented detail. The development of analytical methods and approaches based on numerical simulation and their application to numerous biologically important systems is presented. PMID- 26517336 TI - Computed tomography findings of hepatic veno-occlusive disease caused by Sedum aizoon with histopathological correlation. AB - This study investigated the value of computed tomography (CT) in the diagnosis and treatment of hepatic veno-occlusive disease (HVOD) caused by Sedum aizoon (SA). The clinical manifestations, treatment results, imaging findings, and histological findings of the liver were analyzed in 39 patients with HVOD caused by SA. Hepatomegaly, liver dysfunction, abdominal effusion, and geographic density changes on liver CT scans were found in all 39 patients. The pathological findings of histological liver examination included swelling and point-like necrosis of liver cells, significant expansion and congestion of the sinuses, endothelial swelling, and wall thickening with incomplete lumen occlusion of small liver vessels. CT geographic density changes were confirmed by histological examination of the liver in 18 patients. Sixteen patients with small amounts of ascites that started within 4 weeks of treatment recovered completely or significantly improved after symptomatic and supportive treatment. However, only 43.75% of the patients with larger amounts of ascites improved following symptomatic and supportive treatment. In conclusion, liver CT examination is a valuable, safe, and noninvasive tool for the diagnosis of HVOD caused by SA. In selected cases, liver CT examination may replace liver biopsy and histological analysis. PMID- 26517338 TI - Military and Veteran Health Research: Shaping the Future. PMID- 26517339 TI - Comfort Theory: Unraveling the Complexities of Veterans' Health Care Needs. AB - The health care needs of veterans, especially those who have served in combat zones and their families are complicated, challenging, and interrelated. Physical limitations impact mental health, and mental health problems affect every aspect of adjustment to civilian life. Comfort theory offers a simple and holistic pattern for identifying needs, creating interventions to meet those needs, and evaluating the effects of those interventions. The aim of this article is to demonstrate how comfort theory has been applied throughout 1 Veterans Administration System to fulfill the goal of providing quality veteran-centric care. The application of comfort theory to daily patient and family care, discharge planning, and follow-up in various settings, as well as ways to enhance institutional integrity and branding are discussed. PMID- 26517340 TI - Service Members' Experiences in Staying Connected With Family While Deployed. AB - The purpose of this study was to describe the communication issues experienced by service members staying connected with families while deployed. Qualitative design guided data collection using interviews with 20 key informants who had been deployed in Iraq or Afghanistan. Inductive content analysis and NVivo software enabled data analysis. From the data, 5 main themes emerged: Creating Normalcy Through Connecting With Others; Understanding the Spoken and Unspoken; Connecting and Disconnecting; Changing Sense of Self; and Sustaining a Common Bond. A collective understanding of common communication challenges emerged that had an impact on service member/family relationships, mission focus, and safety. PMID- 26517341 TI - Screening for Obstructive Sleep Apnea in Veterans Seeking Treatment of Posttraumatic Stress Disorder. AB - Disrupted sleep is an often intractable symptom of posttraumatic stress disorder (PTSD); however, non-PTSD-related causes of disrupted sleep are rarely considered in clinical practice. Study objectives were to determine obstructive sleep apnea (OSA) risk among veterans seeking PTSD treatment and to investigate the relationship between OSA risk and PTSD symptom severity. Veterans (N = 264; 25.8% female) completed measures of PTSD symptoms and OSA risk factors. The rate of OSA risk was 72.7% for the whole sample, 77.2% among men, and 59.7% among women. OSA risk was not significantly correlated with PTSD symptom severity. Detection and treatment of OSA in veterans with PTSD may result in decreased insomnia in affected individuals. PMID- 26517342 TI - Veteran Competencies for Undergraduate Nursing Education. AB - Military Veterans comprise approximately 10% of the US population. Most Veterans do not receive their health care through Veterans Affairs facilities, are seen across the health care system, and their prior military service and associated health issues often go unrecognized. In this study, a modified Delphi design was used to develop a set of 10 Veteran Care Competencies and associated knowledge, skills, and attitudes for Undergraduate Nursing Education: Military and Veteran Culture, Post Traumatic Stress Disorder, Amputation and Assistive Devices, Environmental/Chemical Exposures, Substance Use Disorder, Military Sexual Trauma, Traumatic Brain Injury, Suicide, Homelessness, and Serious Illness Especially at the End of Life. PMID- 26517343 TI - Joyce Clifford the Scholar: In Her Own Words. AB - Dr Joyce H. Clifford was world renowned for her excellence in nursing administration and leadership. The purpose of this article is to examine her complete body of published scholarship and analyze her papers as a method of understanding her intellectual progression as a leader in the discipline, as well as to document how her conceptualization of professional practice and the practice environment advanced nursing practice and patient and family care. Using the qualitative method of narrative inquiry, a systematic analysis of her papers was conducted to describe the evolution of her scholarship and her impact on the discipline and patient care. We reviewed all known existing papers, categorized them into 3 stages, and discuss them here. Using quotes from her work, we have added her voice to the compelling professional practice issues she addressed in her lifetime. PMID- 26517345 TI - Promoting Immigrant Women's Cardiovascular Health Redesigning Patient Education Interventions. AB - Cardiovascular disease is the most common cause of death among women from low- to middle-income countries. The most common cardiovascular nursing intervention is that of patient education. However, the applicability of this intervention is questionable, as these educational initiatives are typically designed and evaluated using samples of "white" homogeneous males. Using the social determinants of health framework, this discursive article identifies specific strategies for redesigning existing cardiovascular education interventions to enhance their applicability to immigrant women. The recommendations will allow nurses to enhance the educational support offered resulting in the reduction and/or prevention of cardiovascular-related symptoms and/or complications. PMID- 26517344 TI - The Influence of Religiosity and Spirituality on Rural Parents' Health Decision Making and Human Papillomavirus Vaccine Choices. AB - General health implications of religiosity and spirituality on health have been associated with health promotion, so the purpose of this study was to examine the influence of religiosity and spirituality on rural parents' decision making to vaccinate their children against human papillomavirus (HPV). The associations of religiosity and spirituality with parental HPV vaccine decisions were examined in a sample of parents residing in small rural communities (N = 37). Parents of children aged 9 to 13 years participated in focus groups held in rural community contexts. Religiosity (i.e., participation in religious social structures) was a recurring and important theme when discussing HPV vaccination. Spirituality (i.e., subjective commitment to spiritual or religious beliefs) was found to influence the ways in which parents perceived their control over and coping with health issues potentially related to HPV vaccination. Together, religiosity and spirituality were found to play integral roles in these parents' lives and influenced their attitudes toward HPV vaccination uptake for their children. PMID- 26517346 TI - Patient Experiences of Loneliness: An Evolutionary Concept Analysis. AB - Loneliness is a painful experience for patients. To clarity the concept of patient loneliness, this study undertook an evolutionary concept analysis based on a literature search in the main relevant databases. We identified 7 dimensions in adult patients' experiences of loneliness. These dimensions of loneliness have different causes and theoretical foundations, which have different implications for patient care. Patients may be lonely in their different relationships, including those with nurses and doctors. Loneliness in relation to health care professionals is a new application of the concept of loneliness that provides a useful starting point for future research. PMID- 26517347 TI - Encapsulation of dyes in metal-organic frameworks and their tunable nonlinear optical properties. AB - Two series of cationic dyes, named DM-n and DP-n, were encapsulated in three anionic isostructural MOFs with a 1D channel. Ordered arrangement of the dyes in the channel was investigated by using the microscope polarized absorption spectra of different dye and MOF composites. Furthermore, the tunable second order nonlinear optical properties of these MOF?dye materials were observed. PMID- 26517348 TI - Addition of milk to tea infusions: Helpful or harmful? Evidence from in vitro and in vivo studies on antioxidant properties. AB - Tea consumption is practised as a tradition, and has shown potential to improve human health. Maximal uptake of tea antioxidants and milk proteins without a negative impact on tea flavor is highly desired by consumers. There is a conflicting evidence of the effect of milk addition to tea on antioxidant activity. Differences in the type of tea, the composition, type and amount of milk, preparation method of tea-milk infusions, the assays used to measure antioxidant activity, and sampling size likely account for different findings. Interactions between tea polyphenols and milk proteins, especially between catechins and caseins, could account for a decrease in antioxidant activity, although other mechanisms are also possible, given the similar effects between soy and bovine milk. The role of milk fat globules and the milk fat globule membrane surface is also important when considering interactions and loss of polyphenolic antioxidant activity, which has not been addressed in the literature. PMID- 26517349 TI - LRG1 expression indicates unfavorable clinical outcome in hepatocellular carcinoma. AB - Leucine-rich-alpha-2-glycoprotein1 (LRG1) is a novel oncogene-associated protein which has been clarified vital to the progression of human cancers, but its role in hepatocellular carcinoma (HCC) remains unclear. Here, we showed that the expression of LRG1 was noticeably increased in HCC tissues, compared to the nontumorous tissues. High LRG1 expression was significantly associated with tumor size (P = 0.004), tumor differentiation (P = 0.010), TNM stage (P < 0.001) and vascular invasion (P = 0.019). Kaplan-Meier analysis showed that LRG1 expression was closely correlated to overall survival and disease-free survival in a training cohort of 474 patients with HCC. The correlation was further validated in an independent cohort of 303 HCC patients. The prognostic implication of LRG1 was confirmed by stratified survival analyses. Multivariate Cox regression model indicated LRG1 as an independent poor prognostic indicator for overall survival (Hazard ratio = 1.582, 95% confident interval: 1.345-1.862, P < 0.001) and disease-free survival (Hazard ratio = 1.280, 95% confident interval: 1.037-1.581, P = 0.022) in HCC. In vitro data showed that LRG1 markedly promoted cell migration but has no effect on cell proliferation. Collectively, our data show that LRG1 is markedly up-regulated and serves as an independent factor of poor outcomes in HCC. Our study therefore provides a promising biomarker for prognostic prediction in clinical management of HCC. PMID- 26517350 TI - Controllable permeability of blood-brain barrier and reduced brain injury through low-intensity pulsed ultrasound stimulation. AB - It has been shown that the blood-brain barrier (BBB) can be locally disrupted by focused ultrasound (FUS) in the presence of microbubbles (MB) while sustaining little damage to the brain tissue. Thus, the safety issue associated with FUS induced BBB disruption (BBBD) needs to be investigated for future clinical applications. This study demonstrated the neuroprotective effects induced by low intensity pulsed ultrasound (LIPUS) against brain injury in the sonicated brain. Rats subjected to a BBB disruption injury received LIPUS exposure for 5 min after FUS/MB application. Measurements of BBB permeability, brain water content, and histological analysis were then carried out to evaluate the effects of LIPUS. The permeability and time window of FUS-induced BBBD can be effectively modulated with LIPUS. LIPUS also significantly reduced brain edema, neuronal death, and apoptosis in the sonicated brain. Our results show that brain injury in the FUS induced BBBD model could be ameliorated by LIPUS and that LIPUS may be proposed as a novel treatment modality for controllable release of drugs into the brain. PMID- 26517351 TI - Clinical significance of high c-MYC and low MYCBP2 expression and their association with Ikaros dysfunction in adult acute lymphoblastic leukemia. AB - Increased expression of c-MYC is observed in both Acute Myeloid Leukemia (AML) and T-cell Acute Lymphoblastic Leukemia (T-ALL). MYC binding protein 2 (MYCBP2) is a probable E3 ubiquitin ligase and its function in leukemia is unknown. IKZF1 deletion is associated with the development and poor outcome of ALL. Here, we observed significant high c-MYC expression and low MYCBP2 expression in adult ALL patients. Patients with high c-MYC expression and/or low MYCBP2 expression had higher WBC counts and a higher percentage of CD34+ or CD33+ cells, as well as splenomegaly, liver infiltration, higher BM blasts, and lower CR rate. Ikaros bound to the regulatory regions of c-MYC and MYCBP2, suppressed c-MYC and increased MYCBP2 expression in ALL cells. Expression of c-MYC mRNA was significantly higher in patients with IKZF1 deletion; conversely MYCBP2 mRNA expression was significantly lower in those patients. A CK2 inhibitor, which acts as an Ikaros activator, also suppressed c-MYC and increased MYCBP2 expression in an Ikaros (IKZF1) dependent manner in the ALL cells. In summary, our data indicated the correlation of high c-MYC expression, low MYCBP2 expression and high c-MYC plus low MYCBP2 expression with high-risk factors and proliferation markers in adult ALL patients. Our data also revealed an oncogenic role for an Ikaros/MYCBP2/c-MYC axis in adult ALL, providing a mechanism of target therapies that activate Ikaros in adult ALL. PMID- 26517352 TI - Germline HOXB13 p.Gly84Glu mutation and cancer susceptibility: a pooled analysis of 25 epidemiological studies with 145,257 participates. AB - Numerous studies have investigated association between the germline HOXB13 p.Gly84Glu mutation and cancer risk. However, the results were inconsistent. Herein, we performed this meta-analysis to get a precise conclusion of the associations. A comprehensive literature search was conducted through Medline (mainly Pubmed), Embase, Cochrane Library databases. Crude odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by STATA 12.1 software to evaluate the association of HOXB13 p.Gly84Glu mutation and cancer susceptibility. Then, 25 studies including 51,390 cases and 93,867 controls were included, and there was significant association between HOXB13 p.Gly84Glu mutation and overall cancer risk (OR = 2.872, 95% CI = 2.121-3.888, P < 0.001), particularly in prostate cancer (OR = 3.248, 95% CI = 2.313-4.560, P < 0.001), while no association was found in breast (OR = 1.424, 95% CI = 0.776-2.613, P = 0.253) and colorectal cancers (OR = 2.070, 95% CI = 0.485-8.841, P = 0.326). When we stratified analysis by ethnicity, significant association was found in Caucasians (OR = 2.673, 95%CI = 1.920-3.720, P < 0.001). Further well-designed with large samples and other various cancers should be performed to validate our results. PMID- 26517353 TI - Fusarochromanone-induced reactive oxygen species results in activation of JNK cascade and cell death by inhibiting protein phosphatases 2A and 5. AB - Recent studies have shown that fusarochromanone (FC101), a mycotoxin, is cytotoxic in a variety of cell lines. However, the molecular mechanism underlying its cytotoxicity remains elusive. Here we found that FC101 induced cell death in COS7 and HEK293 cells in part by activating JNK pathway. This is evidenced by the findings that inhibition of JNK with SP600125 or expression of dominant negative c-Jun partially prevented FC101-induced cell death. Furthermore, we observed that FC101-activated JNK pathway was attributed to induction of reactive oxygen species (ROS). Pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger and antioxidant, suppressed FC101-induced activation of JNK and cell death. Moreover, we noticed that FC101 inhibited the serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5) in the cells, which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented FC101-induced activation of JNK and cell death. The results indicate that FC101-induced ROS inhibits PP2A and PP5, leading to activation of JNK pathway and consequently resulting in cell death. PMID- 26517354 TI - Mutational profiling of colorectal cancers with microsatellite instability. AB - Microsatellite instability (MSI) is caused by defective mismatch repair in 15-20% of colorectal cancers (CRCs). Higher mutation loads in tumors with mismatch repair deficiency can predict response to pembrolizumab, an anti-programmed death 1 (PD-1) immune checkpoint inhibitor. We analyzed the mutations in 113 CRCs without MSI (MSS) and 29 CRCs with MSI-High (MSI-H) using the 50-gene AmpliSeq cancer panel. Overall, MSI-H CRCs showed significantly higher mutations than MSS CRCs, including insertion/deletion mutations at repeat regions. MSI-H CRCs showed higher incidences of mutations in the BRAF, PIK3CA, and PTEN genes as well as mutations in the receptor tyrosine kinase families. While the increased mutations in BRAF and PTEN in MSI-H CRCs are well accepted, we also support findings of mutations in the mTOR pathway and receptor tyrosine kinase family genes. MSS CRCs showed higher incidences of mutations in the APC, KRAS and TP53 genes, confirming previous findings. NGS assays may be designed to detect driver mutations for targeted therapeutics and to identify tumors with high mutation loads for potential treatment with immune checkpoint blockade therapies. Further studies may be warranted to elucidate potential targeted therapeutics against mutations in the mTOR pathway and the receptor tyrosine kinase family in MSI-H CRCs as well as the benefit of anti-PD-1 immunotherapy in hypermutated MSS CRCs or other cancers. PMID- 26517355 TI - HER3 over-expression and overall survival in gastrointestinal cancers. AB - Published studies on the association between human epidermal factor receptor 3 (HER3) expression and overall survival (OS) in gastrointestinal cancers have yielded conflicting results. The aim of this study was to explore the association of HER3 over-expression with OS in gastrointestinal cancers. A systematic search was performed through Medline/PubMed, Embase, Science Direct and Elsevier. The summary odds ratio (OR) with 95% confidence interval (CI) was calculated to estimate the strength of the association. Overall, we observed that HER3 over expression was associated with worse OS at five years (OR = 1.38, 95% CI: 1.04 1.82); however, HER3 over-expression was not associated with worse OS at three years (OR = 1.33, 95% CI: 0.97-1.84). The cumulative meta-analysis showed similar results. In subgroup analyses by tumor type, HER3 over-expression in gastric cancers was associated with worse OS at both three years (OR = 1.69, 95% CI: 1.28 2.25) and five years (OR = 1.74, 95% CI: 1.26-2.41). In conclusion, our results suggest that HER3 over-expression may be associated with worse overall survival in gastric cancers. Well-designed studies with a large sample size are required to further confirm our findings. PMID- 26517356 TI - Combined 3D-QSAR and Molecular Docking Study for Identification of Diverse Natural Products as Potent Pf ENR Inhibitors. AB - An in-house library of 200 molecules from natural plant products was designed in order to evaluate their binding to Plasmodium ACP enoyl reductase (ENR), a promising biological target for antimalarial chemotherapeutics. The binding site of PfENR was explored computationally and the molecules were docked using AutoDock. Furthermore, the top-ranked scaffolds from docking studies were also compared with known PfENR inhibitors using 3D-QSAR. To this effect, a 3D-QSAR model was derived from a set of experimentally established PfENR inhibitors, using Comparative Molecular Force Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The best optimum CoMFA model exhibited a leave-one-out correlation coefficient (q2) and a noncross- validated correlation coefficient (r2) of 0.630 and 0.911, respectively. The result of this cumulative approach proposed five structurally distinct natural products as potent PfENR inhibitors. This study may lay a stepping stone towards Functional oriented synthesis (FOS) of novel PfENR inhibitors in future. PMID- 26517357 TI - The Coronary Microcirculation in Hamster-to-Rat Cardiac Xenografts. AB - BACKGROUND: The aim of this study was to establish a new experimental model to directly analyse the coronary microcirculation in cardiac xenografts. METHODS: Intravital fluorescence microscopy (IVM) of the subepicardial microcirculation in heterotopically transplanted hamster-to-rat cardiac xenografts was performed at 30 and 90 min of reperfusion. We quantitatively assessed the microcirculatory perfusion characteristics as well as the interactions of leukocytes and platelets with the endothelium of postcapillary coronary venules in non-sensitised as well as sensitised recipients. RESULTS: In this first experimental IVM study of cardiac xenografts, we successfully visualised the subepicardial microcirculation, i.e. feeding arterioles, nutritive capillaries and draining postcapillary venules, during reperfusion. Leukocyte-endothelial and platelet endothelial cell interactions could be quantified. In the non-sensitised group, the myocardial microcirculation remained stable during the observation period of 90 min, whereas in the sensitised group, xenografts were rejected immediately. CONCLUSIONS: We established a model for the assessment of the microcirculatory dysfunction and inflammation during ischaemia/reperfusion injury in hamster-to rat cardiac xenografts. PMID- 26517358 TI - The Use of Superselective Arteriography in the Evaluation of the Influence of Intracapsular Hip Joint Pressure on the Blood Flow of the Femoral Head. AB - OBJECTIVE: We aimed to analyze the intracapsular pressure of the hip joint following femoral neck fracture and its relationship to the position of the hip or to traction and (using superselective arteriography) to evaluate the blood supply to the femoral head and the influence of traction and hip position on the blood supply. SUBJECTS AND METHODS: Twenty-six cases of fresh Garden type I-III femoral neck fractures were enrolled. After being placed in the neutral position, in internal rotation or with traction of 3 and 5 kg, respectively, intracapsular manometric changes were measured. Eight cases underwent superselective arteriography of the medial circumflex femoral artery and its branches under the manometric changes of the hip joint capsule. RESULTS: Twenty-four to 48 h after the injury, the intracapsular pressure was significantly higher on the fractured side than on the normal side. The mean pressure was 28.41 +/- 9.339 mm Hg in fully extended hips in the neutral position, 79.92 +/- 12.80 mm Hg in internally rotated hips, 51.39 +/- 15.41 mm Hg in hips with 3 kg of traction and 64.81 +/- 13.56 mm Hg in hips with 5 kg of traction. The arteriographic findings revealed that traction and internal rotation reduced the perfusion of the femoral head at the medial circumflex femoral artery and its branches, and also negatively influenced venous reflux. CONCLUSION: Traction and internal rotation both caused the intracapsular pressure of the hip joint to rise considerably, which reduced the femoral head perfusion and impeded venous reflux. This could lead to avascular necrosis of the femoral head. PMID- 26517359 TI - Replication Stress and Telomere Dysfunction Are Present in Cultured Human Embryonic Stem Cells. AB - Replication stress causes DNA damage at fragile sites in the genome. DNA damage at telomeres can initiate breakage-fusion-bridge cycles and chromosome instability, which can result in replicative senescence or tumor formation. Little is known about the extent of replication stress or telomere dysfunction in human embryonic stem cells (hESCs). hESCs are grown in culture with the expectation of being used therapeutically in humans, making it important to minimize the levels of replication stress and telomere dysfunction. Here, the hESC line UCSF4 was cultured in a defined medium with growth factor Activin A, exogenous nucleosides, or DNA polymerase inhibitor aphidicolin. We used quantitative fluorescence in situ hybridization to analyze individual telomeres for dysfunction and observed that it can be increased by aphidicolin or Activin A. In contrast, adding exogenous nucleosides relieved dysfunction, suggesting that telomere dysfunction results from replication stress. Whether these findings can be applied to other hESC lines remains to be determined. However, because the loss of telomeres can lead to chromosome instability and cancer, we conclude that hESCs grown in culture for future therapeutic purposes should be routinely checked for replication stress and telomere dysfunction. PMID- 26517360 TI - Interpretation of cytogenetic results in multiple myeloma for clinical practice. AB - The interpretation of cytogenetic abnormalities in multiple myeloma (MM) is often a challenging task. MM is characterized by several cytogenetic abnormalities that occur at various time points in the disease course. The interpretation of cytogenetic results in MM is complicated by the number and complexity of the abnormalities, the methods used to detect them and the disease stage at which they are detected. Specific cytogenetic abnormalities affect clinical presentation, progression of smoldering multiple myeloma (SMM) to MM, prognosis of MM and management strategies. The goal of this paper is to provide a review of how MM is classified into specific subtypes based on primary cytogenetic abnormalities and to provide a concise overview of how to interpret cytogenetic abnormalities based on the disease stage to aid clinical practice and patient management. PMID- 26517361 TI - Integrating knowledge of Mycobacterium tuberculosis pathogenesis for the design of better vaccines. AB - Today, tuberculosis (TB) still remains one of the main global causes of mortality and morbidity, and an effective vaccine against both TB disease and Mycobacterium tuberculosis infection is essential to reach the updated post-2015 Millennium development goal of eradicating TB by 2050. During the last two decades much knowledge has accumulated on the pathogenesis of TB and the immune responses to infection by M. tuberculosis. Furthermore, many vaccine candidates are under development, and close to 20 of them have entered clinical assessment at various levels. Nevertheless, the M. tuberculosis-host interaction is very complex, and the full complexity of this interaction is still not sufficiently well understood to develop novel, rationally designed vaccines. However, some of the recent knowledge is now integrated into the design of various types of vaccine candidates to be used either as pre-exposure, as post-exposure or as therapeutic vaccines, as will be discussed in this paper. PMID- 26517362 TI - Contribution of the After-School Period to Children's Daily Participation in Physical Activity and Sedentary Behaviours. AB - OBJECTIVES: Children's after-school physical activity (PA) and sedentary behaviours (SB) are not well understood, despite the potential this period holds for intervention. This study aimed to describe children's after-school physical activity and sedentary behaviours; establish the contribution this makes to daily participation and to achieving physical activity and sedentary behaviours guidelines; and to determine the association between after-school moderate- to vigorous-intensity physical activity (MVPA), screen-based sedentary behaviours and achieving the physical activity and sedentary behaviour guidelines. METHODS: Children (n = 406, mean age 8.1 years, 58% girls) wore an ActiGraph GT3X accelerometer. The percentage of time and minutes spent sedentary (SED), in light physical activity (LPA) and MVPA between the end-of-school and 6pm (weekdays) was calculated. Parents (n = 318, 40 years, 89% female) proxy-reported their child's after-school participation in screen-based sedentary behaviours. The contribution that after-school SED, LPA, MVPA, and screen-based sedentary behaviours made to daily levels, and that after-school MVPA and screen-based sedentary behaviours made to achieving the physical activity/sedentary behaviour guidelines was calculated. Regression analysis determined the association between after-school MVPA and screen-based sedentary behaviours and achieving the physical activity/sedentary behaviours guidelines. RESULTS: Children spent 54% of the after-school period SED, and this accounted for 21% of children's daily SED levels. Boys spent a greater percentage of time in MVPA than girls (14.9% vs. 13.6%; p<0.05), but this made a smaller contribution to their daily levels (27.6% vs 29.8%; p<0.05). After school, boys and girls respectively performed 18.8 minutes and 16.7 minutes of MVPA, which is 31.4% and 27.8% of the MVPA (p<0.05) required to achieve the physical activity guidelines. Children spent 96 minutes in screen-based sedentary behaviours, contributing to 84% of their daily screen based sedentary behaviours and 80% of the sedentary behaviour guidelines. After school MVPA was positively associated with achieving the physical activity guidelines (OR: 1.31, 95%CI 1.18, 1.44, p<0.05), and after-school screen-based sedentary behaviours were negatively associated with achieving the sedentary behaviours guidelines (OR: 0.97, 95%CI: 0.96, 0.97, p<0.05). CONCLUSIONS: The after-school period plays a critical role in the accumulation of children's physical activity and sedentary behaviours. Small changes to after-school behaviours can have large impacts on children's daily behaviours levels and likelihood of meeting the recommended levels of physical activity and sedentary behaviour. Therefore interventions should target reducing after-school sedentary behaviours and increasing physical activity. PMID- 26517363 TI - Effect of Exogenous Cues on Covert Spatial Orienting in Deaf and Normal Hearing Individuals. AB - Deaf individuals have been known to process visual stimuli better at the periphery compared to the normal hearing population. However, very few studies have examined attention orienting in the oculomotor domain in the deaf, particularly when targets appear at variable eccentricity. In this study, we examined if the visual perceptual processing advantage reported in the deaf people also modulates spatial attentional orienting with eye movement responses. We used a spatial cueing task with cued and uncued targets that appeared at two different eccentricities and explored attentional facilitation and inhibition. We elicited both a saccadic and a manual response. The deaf showed a higher cueing effect for the ocular responses than the normal hearing participants. However, there was no group difference for the manual responses. There was also higher facilitation at the periphery for both saccadic and manual responses, irrespective of groups. These results suggest that, owing to their superior visual processing ability, the deaf may orient attention faster to targets. We discuss the results in terms of previous studies on cueing and attentional orienting in deaf. PMID- 26517364 TI - New Insights on the Burstein-Moss Shift and Band Gap Narrowing in Indium-Doped Zinc Oxide Thin Films. AB - The Burstein-Moss shift and band gap narrowing of sputtered indium-doped zinc oxide (IZO) thin films are investigated as a function of carrier concentrations. The optical band gap shifts below the carrier concentration of 5.61 * 1019 cm-3 are well-described by the Burstein-Moss model. For carrier concentrations higher than 8.71 * 1019 cm-3 the shift decreases, indicating that band gap narrowing mechanisms are increasingly significant and are competing with the Burstein-Moss effect. The incorporation of In causes the resistivity to decrease three orders of magnitude. As the mean-free path of carriers is less than the crystallite size, the resistivity is probably affected by ionized impurities as well as defect scattering mechanisms, but not grain boundary scattering. The c lattice constant as well as film stress is observed to increase in stages with increasing carrier concentration. The asymmetric XPS Zn 2p3/2 peak in the film with the highest carrier concentration of 7.02 * 1020 cm-3 suggests the presence of stacking defects in the ZnO lattice. The Raman peak at 274 cm-1 is attributed to lattice defects introduced by In dopants. PMID- 26517365 TI - Klotho Regulates 14-3-3zeta Monomerization and Binding to the ASK1 Signaling Complex in Response to Oxidative Stress. AB - The reactive oxygen species (ROS)-sensitive apoptosis signal-regulating kinase 1 (ASK1) signaling complex is a key regulator of p38 MAPK activity, a major modulator of stress-associated with aging disorders. We recently reported that the ratio of free ASK1 to the complex-bound ASK1 is significantly decreased in Klotho-responsive manner and that Klotho-deficient tissues have elevated levels of free ASK1 which coincides with increased oxidative stress. Here, we tested the hypothesis that: 1) covalent interactions exist among three identified proteins constituting the ASK1 signaling complex; 2) in normal unstressed cells the ASK1, 14-3-3zeta and thioredoxin (Trx) proteins simultaneously engage in a tripartite complex formation; 3) Klotho's stabilizing effect on the complex relied solely on 14-3-3zeta expression and its apparent phosphorylation and dimerization changes. To verify the hypothesis, we performed 14-3-3zeta siRNA knock-down experiments in conjunction with cell-based assays to measure ASK1-client protein interactions in the presence and absence of Klotho, and with or without an oxidant such as rotenone. Our results show that Klotho activity induces posttranslational modifications in the complex targeting 14-3-3zeta monomer/dimer changes to effectively protect against ASK1 oxidation and dissociation. This is the first observation implicating all three proteins constituting the ASK1 signaling complex in close proximity. PMID- 26517366 TI - Somatic Variation of T-Cell Receptor Genes Strongly Associate with HLA Class Restriction. AB - Every person carries a vast repertoire of CD4+ T-helper cells and CD8+ cytotoxic T cells for a healthy immune system. Somatic VDJ recombination at genomic loci that encode the T-cell receptor (TCR) is a key step during T-cell development, but how a single T cell commits to become either CD4+ or CD8+ is poorly understood. To evaluate the influence of TCR sequence variation on CD4+/CD8+ lineage commitment, we sequenced rearranged TCRs for both alpha and beta chains in naive T cells isolated from healthy donors and investigated gene segment usage and recombination patterns in CD4+ and CD8+ T-cell subsets. Our data demonstrate that most V and J gene segments are strongly biased in the naive CD4+ and CD8+ subsets with some segments increasing the odds of being CD4+ (or CD8+) up to five fold. These V and J gene associations are highly reproducible across individuals and independent of classical HLA genotype, explaining ~11% of the observed variance in the CD4+ vs. CD8+ propensity. In addition, we identified a strong independent association of the electrostatic charge of the complementarity determining region 3 (CDR3) in both alpha and beta chains, where a positively charged CDR3 is associated with CD4+ lineage and a negatively charged CDR3 with CD8+ lineage. Our findings suggest that somatic variation in different parts of the TCR influences T-cell lineage commitment in a predominantly additive fashion. This notion can help delineate how certain structural features of the TCR-peptide HLA complex influence thymic selection. PMID- 26517367 TI - Correction: N-3 Polyunsaturated Fatty Acids (PUFAs) Reverse the Impact of Early Life Stress on the Gut Microbiota. PMID- 26517368 TI - The stroke impact scale: performance as a quality of life measure in a community based stroke rehabilitation setting. AB - PURPOSE: The objective of this study was to assess the psychometric properties of the Stroke Impact Scale (SIS). METHODS: Data was derived from a study assessing a community-based stroke rehabilitation program. Patients were administered the SIS and Euroqol-5D (EQ-5D-5L) on admission to the study, and at six month and 12 month follow-up. The psychometric performance of each domain of the SIS was assessed at each time point. RESULTS: A total of 164 patients completed outcome measures at baseline, 108 patients at six months and 37 patients at 12 months. Correlation of the SIS domains with the EQ-5D-5L suggested that the dimensions of health contributing to a patient's perception of health-related quality of life changes over time. CONCLUSION: The SIS performed well in a sample of patients undergoing stroke rehabilitation in the community. Our findings suggest that the multidimensionality of the SIS may allow health professionals to track patient progress and tailor rehabilitation interventions to target the dimensions of health that are most important to a patient's overall health and perceived quality of life over time. Implications for Rehabilitation There is an increased need for valid and reliable measures to evaluate the outcomes of patients recovering from stroke in the community. The Stroke Impact Scale (SIS) measures multiple domains of health and is well-suited for use in patients recovering from stroke in the community. There is a high level of internal consistency in the eight SIS domains with no evidence of floor effects; ceiling effects were noted for several domains. Correlation of the SIS with the Euroqol-5D suggested that the dimensions of health contributing to a patient's perception of health related quality of life changes over time. PMID- 26517369 TI - Sequencing and Analysis of the Pseudomonas fluorescens GcM5-1A Genome: A Pathogen Living in the Surface Coat of Bursaphelenchus xylophilus. AB - It is known that several bacteria are adherent to the surface coat of pine wood nematode (Bursaphelenchus xylophilus), but their function and role in the pathogenesis of pine wilt disease remains debatable. The Pseudomonas fluorescens GcM5-1A is a bacterium isolated from the surface coat of pine wood nematodes. In previous studies, GcM5-1A was evident in connection with the pathogenicity of pine wilt disease. In this study, we report the de novo sequencing of the GcM5-1A genome. A 600-Mb collection of high-quality reads was obtained and assembled into sequence contigs spanning a 6.01-Mb length. Sequence annotation predicted 5,413 open reading frames, of which 2,988 were homologous to genes in the other four sequenced P. fluorescens isolates (SBW25, WH6, Pf0-1 and Pf-5) and 1,137 were unique to GcM5-1A. Phylogenetic studies and genome comparison revealed that GcM5 1A is more closely related to SBW25 and WH6 isolates than to Pf0-1 and Pf-5 isolates. Towards study of pathogenesis, we identified 79 candidate virulence factors in the genome of GcM5-1A, including the Alg, Fl, Waa gene families, and genes coding the major pathogenic protein fliC. In addition, genes for a complete T3SS system were identified in the genome of GcM5-1A. Such systems have proved to play a critical role in subverting and colonizing the host organisms of many gram negative pathogenic bacteria. Although the functions of the candidate virulence factors need yet to be deciphered experimentally, the availability of this genome provides a basic platform to obtain informative clues to be addressed in future studies by the pine wilt disease research community. PMID- 26517370 TI - Nucleostemin Knockdown Sensitizes Hepatocellular Carcinoma Cells to Ultraviolet and Serum Starvation-Induced Apoptosis. AB - Nucleostemin (NS) is a GTP-binding protein that is predominantly expressed in embryonic and adult stem cells but not in terminally differentiated cells. NS plays an essential role in maintaining the continuous proliferation of stem cells and some types of cancer cells. However, the role of NS in hepatocellular carcinoma (HCC) remains unclear. Therefore, this study aimed to clarify the role of NS in HCC. First, we demonstrated high expression of NS in most HCC cell lines and liver cancer tissues. NS knockdown induced a severe decline in cell viability of MHCC97H cells as detected by MTT and cell proliferation assays. Next, we used ultraviolet (UV) and serum starvation-induced apoptosis models to investigate whether NS suppression or up-regulation affects HCC cell apoptosis. After UV treatment or serum starvation, apoptosis was strongly enhanced in MHCC97H and Bel7402 cells transfected with small interfering RNA against NS, whereas NS overexpression inhibited UV- and serum-induced apoptosis of HCC cells. Furthermore, after UV irradiation, inhibition of NS increased the expression of pro-apoptosis protein caspase 3 and decreased the expression of anti-apoptosis protein Bcl-2. A caspase 3 inhibitor could obviously prevent NS knockdown-induced apoptosis. In conclusion, our study demonstrated overexpression of NS in most HCC tissues compared with their matched surrounding tissues, and silencing NS promoted UV- and serum starvation-induced apoptosis of MHCC97H and Bel7402 cells. Therefore, the NS gene might be a potential therapeutic target of HCC. PMID- 26517371 TI - Dispersion Behaviour of Silica Nanoparticles in Biological Media and Its Influence on Cellular Uptake. AB - Given the increasing variety of manufactured nanomaterials, suitable, robust, standardized in vitro screening methods are needed to study the mechanisms by which they can interact with biological systems. The in vitro evaluation of interactions of nanoparticles (NPs) with living cells is challenging due to the complex behaviour of NPs, which may involve dissolution, aggregation, sedimentation and formation of a protein corona. These variable parameters have an influence on the surface properties and the stability of NPs in the biological environment and therefore also on the interaction of NPs with cells. We present here a study using 30 nm and 80 nm fluorescently-labelled silicon dioxide NPs (Rubipy-SiO2 NPs) to evaluate the NPs dispersion behaviour up to 48 hours in two different cellular media either supplemented with 10% of serum or in serum-free conditions. Size-dependent differences in dispersion behaviour were observed and the influence of the living cells on NPs stability and deposition was determined. Using flow cytometry and fluorescence microscopy techniques we studied the kinetics of the cellular uptake of Rubipy-SiO2 NPs by A549 and CaCo-2 cells and we found a correlation between the NPs characteristics in cell media and the amount of cellular uptake. Our results emphasize how relevant and important it is to evaluate and to monitor the size and agglomeration state of nanoparticles in the biological medium, in order to interpret correctly the results of the in vitro toxicological assays. PMID- 26517372 TI - Sensitivity of Bovine Tuberculosis Surveillance in Wildlife in France: A Scenario Tree Approach. AB - Bovine tuberculosis (bTB) is a common disease in cattle and wildlife, with an impact on animal and human health, and economic implications. Infected wild animals have been detected in some European countries, and bTB reservoirs in wildlife have been identified, potentially hindering the eradication of bTB from cattle populations. However, the surveillance of bTB in wildlife involves several practical difficulties and is not currently covered by EU legislation. We report here the first assessment of the sensitivity of the bTB surveillance system for free-ranging wildlife launched in France in 2011 (the Sylvatub system), based on scenario tree modelling. Three surveillance system components were identified: (i) passive scanning surveillance for hunted wild boar, red deer and roe deer, based on carcass examination, (ii) passive surveillance on animals found dead, moribund or with abnormal behaviour, for wild boar, red deer, roe deer and badger and (iii) active surveillance for wild boar and badger. The application of these three surveillance system components depends on the geographic risk of bTB infection in wildlife, which in turn depends on the prevalence of bTB in cattle. We estimated the effectiveness of the three components of the Sylvatub surveillance system quantitatively, for each species separately. Active surveillance and passive scanning surveillance by carcass examination were the approaches most likely to detect at least one infected animal in a population with a given design prevalence, regardless of the local risk level and species considered. The awareness of hunters, which depends on their training and the geographic risk, was found to affect surveillance sensitivity. The results obtained are relevant for hunters and veterinary authorities wishing to determine the actual efficacy of wildlife bTB surveillance as a function of geographic area and species, and could provide support for decision-making processes concerning the enhancement of surveillance strategies. PMID- 26517373 TI - The Genomic Aftermath of Hybridization in the Opportunistic Pathogen Candida metapsilosis. AB - Candida metapsilosis is a rarely-isolated, opportunistic pathogen that belongs to a clade of pathogenic yeasts known as the C. parapsilosis sensu lato species complex. To gain insight into the recent evolution of C. metapsilosis and the genetic basis of its virulence, we sequenced the genome of 11 clinical isolates from various locations, which we compared to each other and to the available genomes of the two remaining members of the complex: C. orthopsilosis and C. parapsilosis. Unexpectedly, we found compelling genomic evidence that C. metapsilosis is a highly heterozygous hybrid species, with all sequenced clinical strains resulting from the same past hybridization event involving two parental lineages that were approximately 4.5% divergent in sequence. This result indicates that the parental species are non-pathogenic, but that hybridization between them formed a new opportunistic pathogen, C. metapsilosis, that has achieved a worldwide distribution. We show that these hybrids are diploid and we identified strains carrying loci for both alternative mating types, which supports mating as the initial mechanism for hybrid formation. We trace the aftermath of this hybridization at the genomic level, and reconstruct the evolutionary relationships among the different strains. Recombination and introgression -resulting in loss of heterozygosis- between the two subgenomes have been rampant, and includes the partial overwriting of the MTLa mating locus in all strains. Collectively, our results shed light on the recent genomic evolution within the C. parapsilosis sensu lato complex, and argue for a re definition of species within this clade, with at least five distinct homozygous lineages, some of which having the ability to form hybrids. PMID- 26517374 TI - A Potential Mechanism of High-Dose Ticagrelor in Modulating Platelet Activity and Atherosclerosis Mediated by Thymic Stromal Lymphopoietin Receptor. AB - Abnormal expression of thymic stromal lymphopoietin (TSLP) and its receptor (TSLPR) was found in patients with acute coronary syndrome. Ticagrelor, an oral platelet ADP P2Y12 receptor antagonist, is widely used in these patients. The aim of this study was to verify whether different doses of ticagrelor regulated plaque progression and platelet activity by modulating TSLP/TSLPR. Seventy-five ApoE-/- mice were randomly divided into five groups: (1) high-cholesterol diet (HCD, n = 15); (2) HCD plus ticagrelor 25 mg/kg/d (T1, n = 15); (3) HCD plus ticagrelor 50 mg/kg/d (T2, n = 15); (4) HCD plus ticagrelor 100 mg/kg/d (T3, n = 15); and (5) a normal diet group (ND, n = 15). At day 0 and at week 16, blood lipids and serum TSLP levels, expression of TSLPR, CD62, and CD63, platelet aggregation, platelet ATP release, PI3K/Akt signaling pathway, and plaque morphology were assessed. HCD increased TSLPR expression and atherosclerosis progression but high-dose ticagrelor (100 mg/kg) moderated this trend. TSLPR was positively correlated with Akt1, platelet aggregation, corrected plaque area, and vulnerability index in the T3 group (P<0.01). In conclusion, low-dose ticagrelor only inhibited platelet activity. Besides this inhibition, high-dose ticagrelor modulated platelet activity and atherosclerosis mediated by TSLPR, potentially through the PI3K/Akt signal pathway. PMID- 26517375 TI - The Influence of Mirror-Visual Feedback on Training-Induced Motor Performance Gains in the Untrained Hand. AB - The well-documented observation of bilateral performance gains following unilateral motor training, a phenomenon known as cross-limb transfer, has important implications for rehabilitation. It has recently been shown that provision of a mirror image of the active hand during unilateral motor training has the capacity to enhance the efficacy of this phenomenon when compared to training without augmented visual feedback (i.e., watching the passive hand), possibly via action observation effects [1]. The current experiment was designed to confirm whether mirror-visual feedback (MVF) during motor training can indeed elicit greater performance gains in the untrained hand compared to more standard visual feedback (i.e., watching the active hand). Furthermore, discussing the mechanisms underlying any such MVF-induced behavioural effects, we suggest that action observation and the cross-activation hypothesis may both play important roles in eliciting cross-limb transfer. Eighty participants practiced a fast-as possible two-ball rotation task with their dominant hand. During training, three different groups were provided with concurrent visual feedback of the active hand, inactive hand or a mirror image of the active hand with a fourth control group receiving no training. Pre- and post-training performance was measured in both hands. MVF did not increase the extent of training-induced performance changes in the untrained hand following unilateral training above and beyond those observed for other types of feedback. The data are consistent with the notion that cross-limb transfer, when combined with MVF, is mediated by cross activation with action observation playing a less unique role than previously suggested. Further research is needed to replicate the current and previous studies to determine the clinical relevance and potential benefits of MVF for cases that, due to the severity of impairment, rely on unilateral training programmes of the unaffected limb to drive changes in the contralateral affected limb. PMID- 26517376 TI - Clustering Acoustic Segments Using Multi-Stage Agglomerative Hierarchical Clustering. AB - Agglomerative hierarchical clustering becomes infeasible when applied to large datasets due to its O(N2) storage requirements. We present a multi-stage agglomerative hierarchical clustering (MAHC) approach aimed at large datasets of speech segments. The algorithm is based on an iterative divide-and-conquer strategy. The data is first split into independent subsets, each of which is clustered separately. Thus reduces the storage required for sequential implementations, and allows concurrent computation on parallel computing hardware. The resultant clusters are merged and subsequently re-divided into subsets, which are passed to the following iteration. We show that MAHC can match and even surpass the performance of the exact implementation when applied to datasets of speech segments. PMID- 26517377 TI - Continuous Modeling of Arterial Platelet Thrombus Formation Using a Spatial Adsorption Equation. AB - In this study, we considered a continuous model of platelet thrombus growth in an arteriole. A special model describing the adhesion of platelets in terms of their concentration was derived. The applications of the derived model are not restricted to only describing arterial platelet thrombus formation; the model can also be applied to other similar adhesion processes. The model reproduces an auto wave solution in the one-dimensional case; in the two-dimensional case, in which the surrounding flow is taken into account, the typical torch-like thrombus is reproduced. The thrombus shape and the growth velocity are determined by the model parameters. We demonstrate that the model captures the main properties of the thrombus growth behavior and provides us a better understanding of which mechanisms are important in the mechanical nature of the arterial thrombus growth. PMID- 26517378 TI - Identification of 5-Methoxyflavone as a Novel DNA Polymerase-Beta Inhibitor and Neuroprotective Agent against Beta-Amyloid Toxicity. AB - Cell-cycle reactivation is a core feature of degenerating neurons in Alzheimer's disease (AD) and Parkinson's disease (PD). A variety of stressors, including beta amyloid (Abeta) in the case of AD, can force neurons to leave quiescence and to initiate an ectopic DNA replication process, leading to neuronal death rather than division. As the primary polymerase (pol) involved in neuronal DNA replication, DNA pol-beta contributes to neuronal death, and DNA pol-beta inhibitors may prove to be effective neuroprotective agents. Currently, specific and highly active DNA pol-beta inhibitors are lacking. Nine putative DNA pol-beta inhibitors were identified in silico by querying the ZINC database, containing more than 35 million purchasable compounds. Following pharmacological evaluation, only 5-methoxyflavone (1) was validated as an inhibitor of DNA pol-beta activity. Cultured primary neurons are a useful model to investigate the neuroprotective effects of potential DNA pol-beta inhibitors, since these neurons undergo DNA replication and death when treated with Abeta. Consistent with the inhibition of DNA pol-beta, 5-methoxyflavone (1) reduced the number of S-phase neurons and the ensuing apoptotic death triggered by Abeta. 5-Methoxyflavone (1) is the first flavonoid compound able to halt neurodegeneration via a definite molecular mechanism rather than through general antioxidant and anti-inflammatory properties. PMID- 26517379 TI - Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic (PBPK) modelling software. AB - PURPOSE: To use a physiologically based pharmacokinetic (PBPK) modelling system to predict the serum levels achieved by two different intravenous loading doses of phenytoin. METHODS: A phenytoin pharmacokinetic model was used in the Simcyp population-based ADME simulator, simulating 100 children age 2-10 years receiving intravenous phenytoin (18 and 20mg/kg). Visual checks were used to evaluate the predictive performance of the candidate model. RESULTS: Loading with doses of 18 mg/kg, blood levels were sub-therapeutic in 22/100 (concentration at 2h post infusion (C2h) <10 MUg/mL), therapeutic in 62/100 (C2h 10-20 MUg/mL), and supra therapeutic in 16/100 (C2h>20 MUg/mL). Loading with 20mg/kg, the percentages were 15, 59, and 26, respectively. Increasing from 18 to 20 mg/kg increased the mean C2h from 16.0 to 17.9 MUg/mL, and the mean AUC from 145 to 162 MUg/mL/h. A C2h>30 MUg/mL was predicted in 4% and 8% of children in the 18 and 20 mg/kg doses, with 3% predicted to have a C2h>40 MUg/mL following either dose. For maintenance doses, a 1st dose of 2.5 or 5mg/kg (intravenous) given at 12h (after either 18 or 20 mg/kg loading) gives the highest percentages of 10-20 MUg/mL serum concentrations. For sub-therapeutic concentrations following intravenous loading (20 mg/kg), a 1st maintenance dose (intravenous) of 10mg/kg will achieve therapeutic concentrations in 93%. CONCLUSION: Use of PBPK modelling suggests that children receiving the 20 mg/kg intravenous loading dose are at slightly increased risk of supra-therapeutic blood levels. Ideally, therapeutic drug monitoring is required to monitor serum concentrations, although the dose regime suggested by the BNFc appear appropriate. PMID- 26517380 TI - Blood Cadmium Levels and Incident Cardiovascular Events during Follow-up in a Population-Based Cohort of Swedish Adults: The Malmo Diet and Cancer Study. AB - BACKGROUND: Cadmium exposure may increase the risk of cardiovascular disease. The only published longitudinal study on cadmium and incident cardiovascular disease was performed in American Indians with relatively high cadmium exposure. OBJECTIVES: Our aim was to examine the association between blood cadmium at baseline and incident cardiovascular events in a population-based study of Swedish men and women with cadmium levels similar to those of most European and U.S. METHODS: A Swedish population-based cohort (n = 6,103, age 46-67 years) was recruited between 1991 and 1994. After we excluded those with missing data on smoking, 4,819 participants remained. Acute coronary events, other major cardiac events, stroke, and cardiovascular mortality were followed until 2010. Associations with blood cadmium (estimated from cadmium in erythrocytes) were analyzed using Cox proportional hazards regression including potential confounders and important cardiovascular risk factors. RESULTS: Hazard ratios for all cardiovascular end points were consistently increased for participants in the 4th blood cadmium quartile (median, 0.99 MUg/L). In models that also included sex, smoking, waist circumference, education, physical activity, alcohol intake, serum triglycerides, HbA1c, and C-reactive protein, the hazard ratios comparing the highest and lowest quartiles of exposure were 1.8 (95% CI: 1.2, 2.7) for acute coronary events, and 1.9 (1.3, 2.9) for stroke. Hazard ratios in never smokers were consistent with these estimates. CONCLUSIONS: Blood cadmium in the highest quartile was associated with incident cardiovascular disease and mortality in our population-based samples of Swedish adults. The consistent results among never-smokers are important because smoking is a strong confounder. Our findings suggest that measures to reduce cadmium exposures are warranted, even in populations without unusual sources of exposure. CITATION: Barregard L, Sallsten G, Fagerberg B, Borne Y, Persson M, Hedblad B, Engstrom G. 2016. Blood cadmium levels and incident cardiovascular events during follow-up in a population-based cohort of Swedish adults: the Malmo Diet and Cancer Study. Environ Health Perspect 124:594-600; http://dx.doi.org/10.1289/ehp.1509735. PMID- 26517381 TI - Chocolate as medicine. PMID- 26517382 TI - Locomotor and behavioural responses of empire gudgeons (Hypseleotris compressa) exposed to coal mine wastewater. AB - Coal mining generates large quantities of complex effluent and may pose a threat to aquatic wildlife. Despite this, few studies have explored the consequences of exposure to mine wastewater on aquatic organisms, and this is particularly true for the Australian environment. We investigated sub-lethal behavioural responses in a native Australian fish exposed to wastewater from two releasing dams (CMW1 and CMW2) located at an open cut coal mine in Central Queensland. Swimming activity and movement of empire gudgeons (Hypseleotris compressa) were assessed during a two-week exposure using video-tracking software. Increased activity was observed in exposed fish after 7 and 14 days. Specifically, we found a significant increase in the mean velocity and mobility of fish exposed to CMW1 treatments. Exposed fish also spent on average 23% more time in the peripheral zone compared to controls after 14-d exposures. A similar response pattern was observed in fish exposed to CMW2, but differences between treated and control fish did not generally reach statistical significance. Alterations to normal swimming activity and movement patterns can be indicative of a stress response in fish, and could subsequently lead to negative population-level impacts by increasing the conspicuousness of exposed individuals to predators, or by altering foraging abilities. More research is warranted to explore relationships between behavioural and physiological outcomes, including endocrine disruption, and subsequent population-level outcomes in aquatic organisms at risk of exposure to coal process-affected water. PMID- 26517383 TI - Leaching potential of nano-scale titanium dioxide in fresh municipal solid waste. AB - With the rapid development in nanotechnology in recent years, the number of commercially available products containing engineered nanomaterials (ENMs) has increased significantly. It is expected that large fractions of these ENMs will end up in landfills for final disposal. Despite the wide use of ENMs, little data is available on their fate within landfills. This study examined the leaching behavior of nanoscale titanium dioxide (nano-TiO2), one of the mostly used ENMs, in fresh municipal solid wastes (MSWs). Batch reactors containing municipal waste samples were spiked with a range of nano-TiO2 concentrations at different pH and ionic strength conditions. The Ti concentrations in leachate decreased rapidly and reached steady state after about 12-24 h. Results suggest that, for the environmental conditions considered, approximately 3-19% of the added nano-TiO2 remained in leachate. Batch tests conducted with individual synthetically prepared solid waste components also showed low leaching potential (5.2% for organic waste, 3.3% for glass, 1.7% for both textile and paper and 0.6% for metal), indicating that all components of MSW contributed to the retention of the nano-TiO2 mass within the solid matrix. PMID- 26517384 TI - Poly- and perfluoroalkyl substances (PFASs) in indoor dust and food packaging materials in Egypt: Trends in developed and developing countries. AB - PFASs concentrations in dust samples collected from three microenvironments in Cairo ranged from 1.3 to 69 ng g(-1) with FTOHs being dominant. The 8:2 FTOH was detected in all samples. Among the FOSAs and FOSEs the MeFOSE was dominant while among ionic PFASs, PFOS and PFOA were most prominent. The concentrations of PFASs were among the lowest worldwide. Correlations between worldwide concentrations of PFOS + PFOA and country development indexes highlight higher usage and human exposure in more developed countries. Food packaging was analyzed for PFSAs, PFCAs and PAPs. The 6:2 and 8:2 monoPAPs were found to be above the MDL in 18% of the samples. PFOA was detected in 79% of the samples with median concentration of 2.40 ng g(-1). PFOS was detected in 58% of the samples with median concentration of 0.29 ng g(-1) while PFHxS and PFDS were below detection limit. Different human exposure scenarios were estimated. PMID- 26517385 TI - Uptake of selenium and mercury by captive mink: Results of a controlled feeding experiment. AB - Captive, juvenile, ranch-bred, male mink (Neovison vison) were fed diets containing various concentrations of methyl-mercury (MeHg) and selenium (Se) for a period of 13 weeks and then sacrificed to determine total Hg levels in fur, blood, brain, liver and kidneys and total Se concentrations in brain tissue. As MeHg concentrations in the diet increased, concentrations of total Hg in the tissues also increased with the highest level occurring in the fur > liver = kidney > brain > blood. Concentrations of Hg in the fur were correlated (r(2) > 0.97) with liver, kidney, blood and brain concentrations. The addition of Se to the mink diet did not appear to affect most tissue concentrations of total Hg nor did it affect the partitioning of Hg between the liver:blood, kidney:blood and brain:blood; however, partitioning of Hg between fur and blood was apparently affected. PMID- 26517386 TI - Speciation and source identification of organic compounds in PM10 over Seoul, South Korea. AB - Seventy three individual organic compounds in the atmospheric particulate matter with an aerodynamic diameter of less than or equal to a nominal 10 MUm (PM10) over Seoul were identified and quantified from April 2010 to April 2011 using gas chromatography/mass spectrometry (GC/MS). These organic compounds were classified into five groups, n-alkanes, polycyclic aromatic hydrocarbons (PAHs), mono carboxylic acids, di-carboxylic acids (DCAs), and sugars based on their chemical structures and properties. The organic compounds showed higher seasonal average concentrations from fall to winter than from spring to summer due to source strength, except some organic compounds among mono-carboxylic acids, DCAs, sugars such as undecanoic acid, methylmalonic acid, and fructose. Through qualitative data analysis using seasonal concentration variations and relevant diagnostic parameters, it was found that (1) anthropogenic sources such as combustion of fossil fuel and biomass burning attributed more to the formation of the organic aerosols than biogenic sources, and (2) the ambient level of n-alkanes, PAHs, and some compounds of DCAs and sugars was elevated in winter due to the increased primary emissions and larger transport from outside of the organic compounds in winter. PMID- 26517387 TI - Trophic transfer of naturally produced brominated aromatic compounds in a Baltic Sea food chain. AB - Brominated aromatic compounds (BACs) are widely distributed in the marine environment. Some of these compounds are highly toxic, such as certain hydroxylated polybrominated diphenyl ethers (OH-PBDEs). In addition to anthropogenic emissions through use of BACs as e.g. flame retardants, BACs are natural products formed by marine organisms such as algae, sponges, and cyanobacteria. Little is known of the transfer of BACs from natural producers and further up in the trophic food chain. In this study it was observed that total sum of methoxylated polybrominated diphenyl ethers (MeO-PBDEs) and OH-PBDEs increased in concentration from the filamentous red alga Ceramium tenuicorne, via Gammarus sp. and three-spined stickleback (Gasterosteus aculeatus) to perch (Perca fluviatilis). The MeO-PBDEs, which were expected to bioaccumulate, increased in concentration accordingly up to perch, where the levels suddenly dropped dramatically. The opposite pattern was observed for OH-PBDEs, where the concentration exhibited a general trend of decline up the food web, but increased in perch, indicating metabolic demethylation of MeO-PBDEs. Debromination was also indicated to occur when progressing through the food chain resulting in high levels of tetra-brominated MeO-PBDE and OH-PBDE congeners in fish, while some penta- and hexa-brominated congeners were observed to be the dominant products in the alga. As it has been shown that OH-PBDEs are potent disruptors of oxidative phosphorylation and that mixtures of different congener may act synergistically in terms of this toxic mode of action, the high levels of OH-PBDEs detected in perch in this study warrants further investigation into potential effects of these compounds on Baltic wildlife, and monitoring of their levels. PMID- 26517388 TI - Matrix changes due to the toxic effects of metronidazole in intestinal tissue of fish (Onchorhynchus mykiss). AB - Metranidazole (MTZ) is an antibiotic used for parasitic infections in a number of species. Accumulation of this drug in the environment and its interaction with fish of economic value makes this drug particularly important. In the present study, we examined the histopathological effects of MTZ on the intestinal tissue of Oncorhynchus mykiss. The fish in aquarium were exposed to MTZ at doses of 5, 10, 20 mg/L for 2, 4 and 8 days. At the end of the experiments, macroscopic pathology or death were not observed at these doses. Histochemical staining with Haematoxylene-Eosin, Periodic Acid Schiff and Gomori Trichrome showed, depending on increased dose and prolonged duration, areas of necrosis, edema, inflammation, small tears at the tips of the villi and excretion with heterogenic distribution of the Goblet cells. Moreover, changes in the connective tissue of the intestines due to toxicity of MTZ and decreases in immunostaining of matrix proteins such as laminin and collagen IV, especially in the epithelium were observed. Findings of the present study would be useful to demonstrate the adverse effects of MTZ use, emphasizing the importance of the effect on fish which could be very important public health. PMID- 26517389 TI - Dual enhancement-inhibition roles of polycarboxylates in Cr(VI) reduction and organic pollutant oxidation in electrical plasma system. AB - In this study, the roles of polycarboxylates in synergistic Cr(VI) reduction and organic pollutant oxidation are investigated in glow discharge electrolysis (GDE). H2O2 generated in GDE plays a primary role for Cr(VI) reduction, and the presence of polycarboxylates can significantly enhance the reduction of Cr(VI) to Cr(III) with less value of [H2O2](consumption)/[Cr(VI)](reduction). Simultaneously, polycarboxylates inhibit the production of .OH via chromium-based Fenton-like reaction, leading to the retarded oxidation of other pollutant oxidation, i.e., RhB. The formation of peroxochromate(V) is a requisite both for Cr(VI) reduction to Cr(III) and .OH formation via Fenton-like reaction. Polycarboxylates can form complexes with peroxochromate(V), which can transform to Cr(III) spontaneously, thereby interrupting the pathway for additional .OH production. These influences induced by polycarboxylate were found closely relative to the number and position of -OH group in polycarboxylates. Besides, 162.7 mg L(-1) Cr(VI) in actual electroplating effluent can be rapidly and almost completely reduced in GDE with introducing polycarboxylate containing nickel electroplating effluent. Generally, the present study provides a versatile strategy for Cr(VI) reduction, exhibiting a bright application future for real wastewater treatment. PMID- 26517390 TI - N-nitrosodimethylamine (NDMA) formation during ozonation of wastewater and water treatment polymers. AB - N-Nitrosodimethylamine (NDMA) formation by ozonation was investigated in the effluents of four different wastewater treatment plants destined for alternative reuse. Very high levels of NDMA formation were observed in wastewaters from treatment plants non operating with biological nitrogen removal. Selected experiments showed that hydroxyl radical did not have a significant role in NDMA formation during ozonation of wastewater. Furthermore, ozonation of three different polymers used for water treatment, including polyDADMAC, anionic polyacrylamide, and cationic polyacrylamide, spiked in wastewater did not increase the NDMA formation. Effluent organic matter (EfOM) likely reduced the availability of ozone in water able to react with polymers and quenched the produced .OH radicals which limited polymer degradation and subsequent NDMA production. Excellent correlations were observed between NDMA formation, UV absorbance at 254 nm, and total fluorescence reduction. These data provide evidence that UV and fluorescence surrogates could be used for monitoring and/or controlling NDMA formation during ozonation. PMID- 26517391 TI - Predicting persistence in the sediment compartment with a new automatic software based on the k-Nearest Neighbor (k-NN) algorithm. AB - The ability of a substance to resist degradation and persist in the environment needs to be readily identified in order to protect the environment and human health. Many regulations require the assessment of persistence for substances commonly manufactured and marketed. Besides laboratory-based testing methods, in silico tools may be used to obtain a computational prediction of persistence. We present a new program to develop k-Nearest Neighbor (k-NN) models. The k-NN algorithm is a similarity-based approach that predicts the property of a substance in relation to the experimental data for its most similar compounds. We employed this software to identify persistence in the sediment compartment. Data on half-life (HL) in sediment were obtained from different sources and, after careful data pruning the final dataset, containing 297 organic compounds, was divided into four experimental classes. We developed several models giving satisfactory performances, considering that both the training and test set accuracy ranged between 0.90 and 0.96. We finally selected one model which will be made available in the near future in the freely available software platform VEGA. This model offers a valuable in silico tool that may be really useful for fast and inexpensive screening. PMID- 26517392 TI - Human placental transfer of perfluoroalkyl acid precursors: Levels and profiles in paired maternal and cord serum. AB - Perfluoroalkyl acids (PFAAs) precursors, the indirect source of PFAA exposure, have been observed in environmental and human samples. However, the maternal fetal transfer of these chemicals has not been well examined. In this study, 50 paired maternal and cord serum samples collected in Jiangsu province of China were analyzed for fifteen PFAA precursors. Among the detected PFAAs, 6:2 fluorotelomer sulfonate (6:2 FTS), N-methyl- and N-ethyl perfluorooctanesulfonamidoacetates had comparable detection rate in both maternal and cord sera, while the mean concentrations and detection rates of 8:2 FTS and perfluorooctane sulfonamide (PFOSA) were higher in maternal sera compared to cord sera (Mann-Whitney U test, P < 0.05). Analysis of variance and least significant difference tests showed that the youngest maternal age group (21-24 years old) had the highest concentration of 6:2 FTS in cord sera. Maternal serum PFOSA was found significantly correlated with the cord serum perfluorooctanesulfonate (PFOS) (Spearman test, r = 0.361, P = 0.010), indicating that maternal serum PFOSA might be an indirect source of PFOS in fetuses. The obtained results suggested the potential prenatal exposure and human placental transfer of perfluoroalkyl acid precursors. PMID- 26517393 TI - Adsorption of naphthalene from aqueous solution onto fatty acid modified walnut shells. AB - The removal of polycyclic aromatic hydrocarbons (PAHs) from aqueous solution is challenging to environmental technologists. Agricultural waste is apparently the most attractive materials in removing PAHs because of its abundance, renewability, and economic advantage. The adsorption of PAHs (e.g., naphthalene) onto walnut shell (WNS) and its fatty acid (e.g., capric acid, lauric acid, palmitic acid, and oleic acid)-modified equivalent were investigated in this work to develop low-cost biosorbents for hydrophobic organic compounds. Compared with other modified sorbents, oleic acid graftted walnut shell (OWNS) showed the maximum partition coefficient (4330 +/- 8.8 L kg(-1)) because of its lowest polarity and highest aromaticity. The adsorption capacity (7210 MUg g(-1)) of OWNS at the temperature of 298 K was observed for an initial naphthalene concentration of 25 mg L(-1) with contact time of 40 h, sorbent dosage of 1 g L( 1), and in neutral condition. Furthermore, the regeneration capability of OWNS implied that it was a promising biosorbent for naphthalene removal. PMID- 26517394 TI - Organization and Dynamics of Receptor Proteins in a Plasma Membrane. AB - The interactions of membrane proteins are influenced by their lipid environment, with key lipid species able to regulate membrane protein function. Advances in high-resolution microscopy can reveal the organization and dynamics of proteins and lipids within living cells at resolutions <200 nm. Parallel advances in molecular simulations provide near-atomic-resolution models of the dynamics of the organization of membranes of in vivo-like complexity. We explore the dynamics of proteins and lipids in crowded and complex plasma membrane models, thereby closing the gap in length and complexity between computations and experiments. Our simulations provide insights into the mutual interplay between lipids and proteins in determining mesoscale (20-100 nm) fluctuations of the bilayer, and in enabling oligomerization and clustering of membrane proteins. PMID- 26517395 TI - Defect-Induced Nucleation and Epitaxy: A New Strategy toward the Rational Synthesis of WZ-GaN/3C-SiC Core-Shell Heterostructures. AB - In this work, we demonstrate a new strategy to create WZ-GaN/3C-SiC heterostructure nanowires, which feature controllable morphologies. The latter is realized by exploiting the stacking faults in 3C-SiC as preferential nucleation sites for the growth of WZ-GaN. Initially, cubic SiC nanowires with an average diameter of ~100 nm, which display periodic stacking fault sections, are synthesized in a chemical vapor deposition (CVD) process to serve as the core of the heterostructure. Subsequently, hexagonal wurtzite-type GaN shells with different shapes are grown on the surface of 3C-SiC wire core. In this context, it is possible to obtain two types of WZ-GaN/3C-SiC heterostructure nanowires by means of carefully controlling the corresponding CVD reactions. Here, the stacking faults, initially formed in 3C-SiC nanowires, play a key role in guiding the epitaxial growth of WZ-GaN as they represent surface areas of the 3C-SiC nanowires that feature a higher surface energy. A dedicated structural analysis of the interfacial region by means of high-resolution transmission electron microscopy (HRTEM) revealed that the disordering of the atom arrangements in the SiC defect area promotes a lattice-matching with respect to the WZ-GaN phase, which results in a preferential nucleation. All WZ-GaN crystal domains exhibit an epitaxial growth on 3C-SiC featuring a crystallographic relationship of [1210](WZ GaN) //[011](3C-SiC), (0001)(WZ-GaN)//(111)(3C-SiC), and d(WZ-GaN(0001)) ~ 2d(3C SiC(111)). The approach to utilize structural defects of a nanowire core to induce a preferential nucleation of foreign shells generally opens up a number of opportunities for the epitaxial growth of a wide range of semiconductor nanostructures which are otherwise impossible to acquire. Consequently, this concept possesses tremendous potential for the applications of semiconductor heterostructures in various fields such as optics, electrics, electronics, and photocatalysis for energy harvesting and environment processing. PMID- 26517396 TI - Generation of a molecular clone of an attenuated lentivirus, a first step in understanding cytopathogenicity and virulence. AB - Small ruminant lentiviruses infect goats and sheep, inducing clinical disease in a minority of infected animals. Following an eradication campaign, clinical cases may disappear in a population. The complete elimination of these lentiviruses is however difficult to achieve and the spreading of less virulent strains often parallels the elimination of their virulent counterparts. Here, we characterized three such strains isolated from a flock in the post-eradication phase. We completely sequenced their genomes, showing that one of the isolates was most probably the product of a recombination event between the other two viruses. By comparing the sequences of these isolates with those of virulent strains, we found evidence that particular LTR mutations may explain their attenuated phenotype. Finally, we constructed an infectious molecular clone representative of these viruses, analyzing its replication characteristics in different target cells. This clone will permit us to explore the molecular correlates of cytopathogenicity and virulence. PMID- 26517397 TI - Interferon induction by avian reovirus. AB - We have previously shown that the replication of avian reovirus (ARV) in chicken embryo fibroblasts (CEF) is more resistant to the antiviral action of interferon (IFN) than the replication of vesicular stomatitis virus (VSV) or vaccinia virus (VV). In this study we examined the capacity of these three viruses to induce the expression of IFN when infecting avian cells. Efficient expression of both type alpha and type-beta IFNs, as well as of the double-stranded RNA (dsRNA)-activated protein kinase (PKR), takes place in ARV-infected CEF, but not in cells infected with VSV or VV. PKR expression is not directly induced by ARV infection, but by the IFN secreted by ARV-infected cells. IFN induction in ARV-infected cells requires viral uncoating, but not viral gene expression, a situation similar to that reported for apoptosis induction by ARV-infected cells. However, our results demonstrate that IFN induction by ARV-infected CEF occurs by a caspase independent mechanism. PMID- 26517399 TI - The human endogenous retrovirus K(HML-2) has a broad envelope-mediated cellular tropism and is prone to inhibition at a post-entry, pre-integration step. AB - The HERV-K(HML-2) family is the most recent addition to the collection of human endogenous retroviruses. It comprises proviruses that encode functional proteins that can assemble into replication defective particles carrying the envelope protein. Using a reconstituted HERV-K113 envelope sequence, we have analyzed its ability to mediate entry into a set of 33 cell lines from 10 species. Of these, 30 were permissive, demonstrating an amphotropism consistent with a broad expression of receptor protein(s). In an initial effort to identify a receptor for HERV-K(HML-2) we investigated whether transferrin receptor 1 and hyaluronidase 2, known cellular receptors of the closely related betaretroviruses mouse mammary tumor virus (MMTV) and Jaagsiekte sheep retrovirus (JSRV), could facilitate HERV-K(HML-2) entry. However, neither of these proteins could serve as a receptor for HERV-K(HML-2). Moreover, during attempts to further characterize the tropism of HERV-K(HML-2), we identified a cellular activity that inhibits infection at a post-entry, pre-integration step. PMID- 26517398 TI - Expression of the small T antigen of Lymphotropic Papovavirus is sufficient to transform primary mouse embryo fibroblasts. AB - Polyomaviruses induce cell proliferation and transformation through different oncoproteins encoded within the early region (ER): large T antigen (LT), small T antigen (sT) and, in some cases, additional components. Each virus utilizes different mechanisms to achieve transformation. For instance, the LTs of Simian virus 40 (SV40), BK and/or JC virus can induce transformation; but Merkel Cell Polyomavirus (MCPyV) requires expression of sT. Lymphotropic Papovavirus (LPV) is closely related to Human Polyomavirus 9 (HuPyV9) and, under similar conditions, mice expressing LPV.ER exhibit higher rates of tumor formation than mice expressing SV40.ER. We have investigated the contributions of individual LPV.ER components to cell transformation. In contrast to SV40, LPV.ER transforms mouse embryonic fibroblasts (MEFs), but expression of LPV LT is insufficient to transform MEFs. Furthermore, LPV sT induces immortalization and transformation of MEFs. Thus, in the case of LPV, sT is the main mediator of oncogenesis. PMID- 26517400 TI - Molecular Characterization of Acute Cellular Rejection Occurring During Intentional Immunosuppression Withdrawal in Liver Transplantation. AB - Acute cellular rejection occurs frequently during the first few weeks following liver transplantation. During this period, its molecular phenotype is confounded by peri- and postoperative proinflammatory events. To unambiguously define the molecular profile associated with rejection, we collected sequential biological specimens from 55 patients at least 3 years after liver transplantation who developed rejection during trials of intentional immunosuppression withdrawal. We analyzed liver tissue and blood samples obtained before initiation of drug withdrawal and at rejection, alongside blood samples collected during the weaning process. Gene expression profiling was conducted using whole-genome microarrays and real-time polymerase chain reaction. Rejection resulted in distinct blood and liver tissue transcriptional changes in patients who were either positive or negative for hepatitis C virus (HCV). Gene expression changes were mostly independent from pharmacological immunosuppression, and their magnitude correlated with severity of histological damage. Differential expression of a subset of genes overlapped across all conditions. These were used to define a blood predictive model that accurately identified rejection in HCV-negative, but not HCV-positive, patients. Changes were detectable 1-2 mo before rejection was diagnosed. Our results provide insight into the molecular processes underlying acute cellular rejection in liver transplantation and help clarify the potential utility and limitations of transcriptional biomarkers in this setting. PMID- 26517401 TI - A study of cortisol reactivity and recovery among young adolescents: Heterogeneity and longitudinal stability and change. AB - The dominance of reactivity-based theories of the cortisol response and lack of attention to cortisol recovery makes it difficult to compile an integrated theory of the stress response. This report examined a reactivity and recovery model of the cortisol response using variable-centered and person-centered approaches. Age and sex differences and heterogeneity in the pattern of cortisol response were examined. Participants were 135 healthy young adolescents participating in a three-wave longitudinal study of puberty and psychological development. At each wave, five saliva-cortisol samples were collected prior to and following a modified Trier Social Stressor Test for Children. Linear, quadratic, and piece wise models of latent growth curve analyses and latent class analyses were conducted. Age differences in cortisol reactivity and recovery were found at wave 1 and sex differences in cortisol reactivity emerged at wave 3. Meaningful heterogeneity in the pattern of cortisol response was found cross-sectionally and longitudinally. The implications of heterogeneity in the cortisol response during early adolescence for developmental science are discussed. PMID- 26517402 TI - Superelastic Few-Layer Carbon Foam Made from Natural Cotton for All-Solid-State Electrochemical Capacitors. AB - Flexible/stretchable devices for energy storage are essential for future wearable and flexible electronics. Electrochemical capacitors (ECs) are an important technology for supplement batteries in the energy storage and harvesting field, but they are limited by relatively low energy density. Herein, we report a superelastic foam consisting of few-layer carbon nanowalls made from natural cotton as a good scaffold to growth conductive polymer polyaniline for stretchable, lightweight, and flexible all-solid-state ECs. As-prepared superelastic bulk tubular carbon foam (surface area ~950 m(2)/g) can withstand >90% repeated compression cycling and support >45,000 times its own weight but no damage. The flexible device has a high specific capacitance of 510 F g(-1), a specific energy of 25.5 Wh kg(-1) and a power density of 28.5 kW kg(-1) in weight of the total electrode materials and withstands 5,000 charging/discharging cycles. PMID- 26517403 TI - Cone-Photoreceptor Density in Adolescents With Type 1 Diabetes. AB - PURPOSE: Changes to retinal structure and function occur in individuals with diabetes before the onset of diabetic retinopathy. It is still unclear if these changes initially affect vascular or neural retina, or if particular retinal areas are more susceptible than others. This paper examines the distribution of cone photoreceptor density in the retina of adolescents with type 1 diabetes. METHODS: This cross-sectional prospective study includes 29 adolescents and young adults with type 1 diabetes and no diabetic retinopathy and 44 control participants recruited at the Hospital for Sick Children. Adaptive-optics enhanced retinal imaging of the cone photoreceptor mosaic was performed in four quadrants at an eccentricity of ~7 degrees from the fovea. After image registration and averaging, cone photoreceptors were counted and photoreceptor density was calculated. Analysis of variance with repeated measures was used to assess the differences in photoreceptor density between groups. RESULTS: Cone density was similar in both control participants and participants with diabetes. There was a small effect of retinal hemisphere; participants with diabetes did not show the expected radial asymmetry observed in control participants. CONCLUSIONS: Cone density in the parafoveal retina is not reduced in adolescents with type 1 diabetes. PMID- 26517404 TI - Blink Rate and Incomplete Blinks in Six Different Controlled Hard-Copy and Electronic Reading Conditions. AB - PURPOSE: To evaluate spontaneous eye blink rate (SEBR) and percentage of incomplete blinks in different hard-copy and visual display terminal (VDT) reading conditions, compared with baseline conditions. METHODS: A sample of 50 participants (29 females, age range, 18-74 years) were recruited for this study. All participants had good ocular health and reported no symptoms of dry eye (OSDI score < 15). Face video recordings were captured while participants observed in silence a landscape picture at 2 m (baseline) and during six different, 6-minute controlled reading experimental conditions. Texts were presented in electronic (tablet and computer display at 100% and 330% zoom levels) and hard-copy (text in book position in silence and aloud and text pasted on the computer display) formats. Video analysis was subsequently conducted to assess blink parameters. RESULTS: All reading conditions resulted in a decrease in SEBR when compared with baseline conditions (all P < 0.001), with the least negative impact corresponding to reading in a 330% expanded display. The percentage of incomplete blinks was found to increase when reading was conducted on an electronic platform, in contrast to hard-copy text. CONCLUSIONS: The high cognitive demands associated with a reading task led to a reduction in SEBR, irrespective of type of reading platform. However, only electronic reading resulted in an increase in the percentage of incomplete blinks, which may account for the symptoms experienced by VDT users. Spanish Abstract. PMID- 26517405 TI - Lack of Association Between Corneal Hysteresis and Corneal Resistance Factor With Glaucoma Severity in Primary Angle Closure Glaucoma. AB - PURPOSE: We investigated the association between corneal hysteresis (CH) and corneal resistance factor (CRF) with glaucoma severity in primary angle closure glaucoma (PACG). METHODS: We recruited 204 subjects with PACG. Each subject underwent CH and CRF measurements using the Ocular Response Analyzer (ORA), optic nerve head topography measurement using scanning laser ophthalmoscopy, and visual field assessment. Glaucoma severity was based on the visual field mean deviation (MD) and classified as mild (71), moderate (55), and severe (78). RESULTS: The mean age +/- SD of study subjects was 68.7 +/- 8.9 years, with most being Chinese (n = 186; 91.2%). Corneal hysteresis and CRF were lowest in the severe PACG group (9.32 +/- 1.86 and 9.50 +/- 1.67 mm Hg) followed by moderate PACG (9.38 +/- 1.88 and 9.73 +/- 1.88 mm Hg) and mild PACG (9.47 +/- 1.90 and 9.85 +/- 1.75 mm Hg) respectively, but the differences were not significant (P = 0.89 and P = 0.46, respectively). There was a significant positive correlation between CH and central corneal thickness (CCT; correlation coefficient [r] = 0.26, P < 0.001), CRF and CCT (r = 0.43, P < 0.001), and negative correlation between CRF and vertical cup-disc ratio (VCDR; r = -0.20, P = 0.004), and CRF with cup-disc area (r = -0.14, P = 0.04). Corneal hysteresis and CRF were not correlated with MD (r = 0.01 for CH, r = 0.1 for CRF). After multivariate analyses, adjusting for age, sex, CCT, axial length, intraocular pressure, and number of glaucoma medication, no significant associations were noted between CH and CRF with MD, VCDR, disc area, rim area, or cup area. CONCLUSIONS: Corneal biomechanical parameters measured by the ORA are not associated with severity of glaucoma in PACG. PMID- 26517406 TI - Relationship of Virulence Factors and Clinical Features in Keratitis Caused by Pseudomonas aeruginosa. AB - PURPOSE: To examine bacterial virulence factors in Pseudomonas aeruginosa isolates from contact lens (CL) wearers and non-CL wearers with P. aeruginosa keratitis, and to investigate relationships between virulence factors and clinical features of keratitis. METHODS: The study involved 25 subjects including 18 CL and 7 non-CL-related P. aeruginosa keratitis patients. Slit-lamp photographs of all subjects were captured, and the focus occupancy ratio (FOR) was defined as the total focus area/entire cornea area, using image processing software. Twenty-five clinical P. aeruginosa isolates from keratitis were assessed for protease production, elastase production, biofilm formation, bacterial swimming and swarming motility, cell surface hydrophobicity, and genes encoding the type III secretion system (TTSS) effectors (ExoU and ExoS). RESULTS: Ring abscess was found in 9 of 18 CL-related P. aeruginosa keratitis cases (CL[+] ring[+] group) but not in another 9 cases (CL[+] ring[-] group). Expression or prevalence of virulence factors in P. aeruginosa isolates from the CL(+) ring(+) group, CL(+) ring(-) group, and CL(-) group were compared. The FOR for CL(+) ring(+) or CL(-) was higher than for CL(+) ring(-) (P < 0.05 and P < 0.01, respectively). The rate of positive swimming motility for CL(+) ring(+) or CL(-) was higher than for CL(+) ring(-) (P < 0.05), whereas the rate of positive swarming motility for CL(+) ring(+) was higher than for CL(+) ring(-) or CL(-) (P < 0.05). Prevalence of an exoS+/exoU-genotype for CL(+) ring(+) or CL(-) was higher than for CL(+) ring(-) (P < 0.05). In the CL-related group, expression of elastase and swarming motility significantly correlated with FOR. CONCLUSIONS: Swimming motility, swarming motility, and TTSS ExoS could play a major role in the determination of clinical features of P. aeruginosa keratitis. PMID- 26517408 TI - Nonalcoholic fatty liver disease activity score and mortality: Imperfect but not insignificant. PMID- 26517409 TI - Engineering Hybrid Metallic Nanostructures Using a Single Domain of Block Copolymer Templates. AB - Building complex nanostructures using a simple patterned template is challenging in material science and nanotechnology. In the present work, three different strategies have been exploited for the successful fabrication of hybrid dots-on wire metallic nanostructures through combining an in-situ method with an ex-situ method. Basically, plasma etching was applied to generate a metallic wire-like nanostructure, and preformed nanoparticles could be placed through multiple means before or after the formation of the wire-like nanostructure. Various monometallic and bimetallic nanostructures have been obtained by utilizing only one functional domain of block copolymer templates. In these cases, full utilization of the functional domain or introduction of the molecular linker is critical to engineering hybrid metallic nanostructures. Other complex and multifunctional hybrid nanostructures can be developed via these strategies similarly, and these nanostructures are promising for useful applications such as optics and surface-enhanced Raman spectroscopy (SERS). PMID- 26517407 TI - Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. AB - BACKGROUND: Current arthritis treatments often have side-effects attributable to active compounds as well as route of administration. Cannabidiol (CBD) attenuates inflammation and pain without side-effects, but CBD is hydrophobic and has poor oral bioavailability. Topical drug application avoids gastrointestinal administration, first pass metabolism, providing more constant plasma levels. METHODS: This study examined efficacy of transdermal CBD for reduction in inflammation and pain, assessing any adverse effects in a rat complete Freund's adjuvant-induced monoarthritic knee joint model. CBD gels (0.6, 3.1, 6.2 or 62.3 mg/day) were applied for 4 consecutive days after arthritis induction. Joint circumference and immune cell invasion in histological sections were measured to indicate level of inflammation. Paw withdrawal latency (PWL) in response to noxious heat stimulation determined nociceptive sensitization, and exploratory behaviour ascertained animal's activity level. RESULTS: Measurement of plasma CBD concentration provided by transdermal absorption revealed linearity with 0.6-6.2 mg/day doses. Transdermal CBD gel significantly reduced joint swelling, limb posture scores as a rating of spontaneous pain, immune cell infiltration and thickening of the synovial membrane in a dose-dependent manner. PWL recovered to near baseline level. Immunohistochemical analysis of spinal cord (CGRP, OX42) and dorsal root ganglia (TNFalpha) revealed dose-dependent reductions of pro inflammatory biomarkers. Results showed 6.2 and 62 mg/day were effective doses. Exploratory behaviour was not altered by CBD indicating limited effect on higher brain function. CONCLUSIONS: These data indicate that topical CBD application has therapeutic potential for relief of arthritis pain-related behaviours and inflammation without evident side-effects. PMID- 26517410 TI - Gene Network Analysis of Metallo Beta Lactamase Family Proteins Indicates the Role of Gene Partners in Antibiotic Resistance and Reveals Important Drug Targets. AB - Metallo Beta (beta) Lactamases (MBL) are metal dependent bacterial enzymes that hydrolyze the beta-lactam antibiotics. In recent years, MBL have received considerable attention because it inactivates most of the beta-lactam antibiotics. Increase in dissemination of MBL encoding antibiotic resistance genes in pathogenic bacteria often results in unsuccessful treatments. Gene interaction network of MBL provides a complete understanding on the molecular basis of MBL mediated antibiotic resistance. In our present study, we have constructed the MBL network of 37 proteins with 751 functional partners from pathogenic bacterial spp. We found 12 highly interconnecting clusters. Among the 37 MBL proteins considered in the present study, 22 MBL proteins are from B3 subclass, 14 are from B1 subclass and only one is from B2 subclass. Global topological parameters are used to calculate and compare the probability of interactions in MBL proteins. Our results indicate that the proteins associated within the network have a strong influence in antibiotic resistance mechanism. Interestingly, several drug targets are identified from the constructed network. We believe that our results would be helpful for researchers exploring MBL mediated antibiotic resistant mechanisms. PMID- 26517411 TI - It Starts at the Beginning: Effect of Particulate Matter In Utero. PMID- 26517412 TI - Lung Cancer Screening in Individuals with Chronic Obstructive Pulmonary Disease. Finding the Sweet Spot. PMID- 26517413 TI - Low Doses of Long-Acting beta-Agonists/Long-Acting Muscarinic Agents with Large Effects. The FLIGHT Study. PMID- 26517414 TI - Ultrasonographic Monitoring of the Diaphragm during Mechanical Ventilation: The Vital Pump Is Vivid, Plastic, and Vulnerable. PMID- 26517415 TI - Screening and Early Detection of Pulmonary Arterial Hypertension in Connective Tissue Diseases. It Is Time to Institute It! PMID- 26517416 TI - Turning Dreams into Nightmares: Different Metabolic Effects of Obstructive Events in Rapid Eye Movement versus Non-Rapid Eye Movement Sleep. PMID- 26517417 TI - Update in Chronic Obstructive Pulmonary Disease 2014. PMID- 26517418 TI - A Vanished Heart: Tension Pneumomediastinum. PMID- 26517419 TI - Greenness and Incident Childhood Asthma: A 10-Year Follow-up in a Population based Birth Cohort. PMID- 26517420 TI - Role of NOD2 Pathway Genes in Sarcoidosis Cases with Clinical Characteristics of Blau Syndrome. PMID- 26517421 TI - Middle East Respiratory Syndrome: A Concern. PMID- 26517422 TI - Reply: Middle East Respiratory Syndrome: A Concern. PMID- 26517423 TI - Endobronchial Ultrasound-guided Transbronchial Needle Aspiration under General Anesthesia. PMID- 26517424 TI - Reply: Endobronchial Ultrasound-guided Transbronchial Needle Aspiration under General Anesthesia. PMID- 26517425 TI - Effects of Mild Chronic Obstructive Pulmonary Disease on Gas Exchange during Cycling and Walking. PMID- 26517426 TI - Reply: Effects of Mild Chronic Obstructive Pulmonary Disease on Gas Exchange during Cycling and Walking. PMID- 26517427 TI - Dynamics of Complex-Forming Bimolecular Reactions: A Comparative Theoretical Study of the Reactions of H Atoms with O2((3)Sigmag(-)) and O2((1)Deltag). AB - The atomic-level mechanism of the reaction of H atoms with triplet and singlet molecular oxygen, H((2)S) + O2((3)Sigmag(-)) -> O((3)P) + OH((2)Pig) ( R1 ) and H((2)S) + O2((1)Deltag) -> O((3)P) + OH((2)Pig) ( R2 ) is analyzed in terms of the topology of the potential energy surfaces (PES) of the two reactions. Both PES exhibit a deep potential well corresponding to the ground and first excited electronic state of HO2. The ground-state reaction is endothermic with no barrier on either side of the well; the excited-state reaction is exothermic with a barrier in the entrance valley of the PES. The differences of the PES are manifested in properties such as the excitation functions, which show reaction R1 to be much slower and the effect of rotational excitation on reactivity, which speeds up reaction R1 and has little effect on R2 . Numerous common dynamics features arise from the presence of the deep potential well on the PES. Such are the significant role of isomerization (for example, 90% of reactive collisions in R2 involve at least one H atom transfer from one of the O atoms to the other in reaction R2 ), which is shown to give rise to a significant rotational excitation of the product OH radicals. Common is the significant sideways scattering of the products that originates from collisions in propeller-type arrangements induced by the presence of two bands of acceptance around the O2 molecule. The HO2 complex in both reactions proves to behave nonstatistically, with signatures of the dynamics in lifetime distributions, angular distributions, opacity functions, and product quantum-state distributions. PMID- 26517428 TI - Arylmercapto Substituted Tetraazaperopyrene Derivatives and Their Oxidation to Tetrasulfones: Photophysics and Electrochemistry. AB - Fourfold arylmercapto substituted tetraazaperopyrene (TAPP) derivatives were obtained by direct nucleophilic substitution of the tetrabrominated TAPP or via Cu-catalyzed S-C coupling. These new materials display a characteristic bathochromic shift of their visible absorption and emission bands by ca. 200 nm compared to the unsubstituted parent compound. Two of the sulfide derivatives were oxidized with periodate to give their corresponding sulfones. PMID- 26517429 TI - Persistency with estrogen replacement therapy among hysterectomized women after the Women's Health Initiative study. AB - OBJECTIVES: Many women are reluctant to undergo estrogen replacement therapy (ERT) and discontinue the treatment within 12 months. The aim of this study was to investigate the persistence rates of ERT in hysterectomized women over the past decade, reflecting changes in the post-Women's Health Initiative (WHI) era. METHODS: We analyzed 8045 patients receiving ERT from 2004 to 2013 using the Disease Analyzer database. RESULTS: After 12 months of follow-up, only 24.6% of patients receiving 1 mg and 24.5% of patients receiving 2 mg of oral ERT were still on treatment (p < 0.0001). The persistency rate of patients receiving <50 MUg of transdermal ERT was 28.6% compared to 33.5% for patients receiving >50 MUg within the 12 months of follow-up. ERT that began in 2007-2009 was associated with a higher discontinuation rate (hazard ratio 1.06, p = 0.0660) than ERT that began in 2010-2013 (hazard ratio 0.88, p = 0.0001). CONCLUSIONS: Our results indicate low persistency rates in women on ERT irrespective of the dose as well as the route of administration. However, a decrease in discontinuation rates was found when comparing women in the early vs. late post WHI era. PMID- 26517430 TI - Antimicrobial compounds from root, stem bark and seeds of Melia volkensii. AB - Three compounds, toosendanin (1), kulactone (2) and scopoletin (3), were isolated from either the root bark and/or the stem bark of Melia volkensii. Their structures were determined on the basis of spectroscopic data generated and by comparison with data from the literature. 1 and 2, isolated for the first time from M. volkensii, exhibited significant (p < 0.05) activity against Escherichia coli with minimum inhibitory concentration of 12.5 MUg/mL, close to that of neomycin (6.25 MUg/mL). The compounds also exhibited high activity against Aspergillus niger (MIC 6.25 MUg/mL compared to 2.5 MUg/mL for clotrimazole). Dichloromethane and methanol seed, hexane stem bark and methanol root bark extracts exhibited activities towards Escherichia coli, Staphylococcus aureus, Aspergillus niger and Plasmodium falciparum, respectively. Antimicrobial activity of the plant towards A. niger, P. falciparum and S. aureus is reported for the first time in the current work. PMID- 26517432 TI - Study of the Use of Lipid Panels as a Marker of Insulin Resistance to Determine Cardiovascular Risk. AB - CONTEXT: When assessing the lipid panel, practical physicians tend to focus on the low-density lipoprotein cholesterol (LDL-c). However, an elevated triglyceride/high-density lipoprotein cholesterol (HDL-c) ratio, suggesting insulin resistance, also effectively predicts cardiovascular outcomes but requires different treatments than an elevated LDL-c. We tested whether high triglyceride/HDL-c ratios are associated with more risk than high LDL-c concentrations or other lipid markers of atherogenicity. METHODS: We followed 103,646 members aged 50 to 75 years without cardiovascular disease or diabetes in a community health plan. Subjects were categorized as insulin sensitive or insulin resistant on the basis of triglyceride and HDL-c in the index year. The primary outcome was ischemic heart disease. The percentage of subjects with a primary outcome after 8 years was stratified by insulin category, lipid measures, and blood pressure. Hazard ratios (HR) for insulin resistance, LDL-c, age, sex, and the presence of hypertension were determined in a multivariate analysis. RESULTS: Subjects with insulin resistance but lipid measures healthier than the median had worse outcomes than those who were insulin sensitive but had unhealthier lipid measures such as non-HDL-c and the ratios of total cholesterol/HDL-c and LDL-c/HDL-c. The HR for a 60 mg/dL increase in LDL-c was 1.14 (95% confidence interval [CI], 1.10-1.18); the HR for an LDL-c greater than 160 mg/dL was 1.19 (95% CI, 1.12-1.28). In contrast, the hazard ratio for having an insulin-resistant triglyceride/HDL-c ratio was 1.68 (95% CI, 1.57-1.80), compared with an insulin-sensitive ratio. There was no difference in outcomes between insulin-resistant but normotensive patients and insulin-sensitive but hypertensive patients. CONCLUSION: Insulin resistance, as manifested by a high triglyceride/HDL-c ratio, was associated with adverse cardiovascular outcomes more than other lipid metrics, including LDL-c, which had little concordance. Physicians and patients should not overlook the triglyceride/HDL-c ratio. PMID- 26517433 TI - Patient Satisfaction after Thoracoscopic Sympathectomy for Palmar Hyperhidrosis: Do Method and Level Matter? AB - CONTEXT: Although surgery is widely recognized as the best treatment for palmar hyperhidrosis (PH), the decision to perform a sympathicotomy, sympathectomy, or clipping of the thoracic sympathetic chain is based on surgeon preference. OBJECTIVE: We investigated the outcomes of patients who underwent surgical intervention for PH with regard to method used and level of sympathetic chain interrupted. DESIGN: This was a retrospective medical chart review. Patients who underwent thoracoscopic intervention for PH were mailed questionnaires regarding their presenting and postoperative symptoms and satisfaction 6 months to 15 years after their procedure. Analyses were performed to investigate whether the surgical method applied affected these outcomes. RESULTS: A total of 635 patients underwent bilateral thoracoscopic procedures for PH between April 1995 and February 2010, and 210 (33%) responded to the questionnaires. Sixteen surgeons performed 108 sympathicotomies, 83 sympathectomies, and 19 ligations with titanium clips for PH. Mean follow-up was 5.5 years. Overall palmar success was 85.4% and was not affected by the surgical method. The rate of compensatory hyperhidrosis was significantly lower if the operative level did not include the R2 ganglion (66.7% vs 80.6%, p = 0.028). Nevertheless, 76.2% of patients were satisfied with the results, and 85.7% would repeat the procedure if given the option to do it again. CONCLUSION: Most patients reported relief of their PH and were satisfied with surgical intervention, regardless of method used. Although postoperative compensatory hyperhidrosis was common, this did not appear to affect overall patient satisfaction. The inclusion of rib level 2 ganglion resulted in a significantly increased incidence of compensatory hyperhidrosis. PMID- 26517431 TI - Diffuse Midline Gliomas with Histone H3-K27M Mutation: A Series of 47 Cases Assessing the Spectrum of Morphologic Variation and Associated Genetic Alterations. AB - Somatic mutations of the H3F3A and HIST1H3B genes encoding the histone H3 variants, H3.3 and H3.1, were recently identified in high-grade gliomas arising in the thalamus, pons and spinal cord of children and young adults. However, the complete range of patients and locations in which these tumors arise, as well as the morphologic spectrum and associated genetic alterations remain undefined. Here, we describe a series of 47 diffuse midline gliomas with histone H3-K27M mutation. The 25 male and 22 female patients ranged in age from 2 to 65 years (median = 14). Tumors were centered not only in the pons, thalamus, and spinal cord, but also in the third ventricle, hypothalamus, pineal region and cerebellum. Patients with pontine tumors were younger (median = 7 years) than those with thalamic (median = 24 years) or spinal (median = 25 years) tumors. A wide morphologic spectrum was encountered including gliomas with giant cells, epithelioid and rhabdoid cells, primitive neuroectodermal tumor (PNET)-like foci, neuropil-like islands, pilomyxoid features, ependymal-like areas, sarcomatous transformation, ganglionic differentiation and pleomorphic xanthoastrocytoma (PXA)-like areas. In this series, histone H3-K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co-occurred with BRAF-V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10. PMID- 26517434 TI - An Education Program for Patient Self-Management of Warfarin. AB - INTRODUCTION: Although improved anticoagulation therapy outcomes have been demonstrated in clinical trials evaluating warfarin patient self-management (PSM) programs, these studies did not provide detailed information regarding PSM program development and patient training. OBJECTIVE: To evaluate the feasibility of and methods for developing and administering an education program to support a novel pilot warfarin PSM program. METHODS: Patients receiving warfarin for atrial fibrillation were recruited to participate in a prospective, intervention-only, open-label pilot PSM program that released venipuncture international normalized ratio results to patients via a secure, online Web site. To support the pilot, a warfarin PSM education program with a dosing algorithm was developed and delivered to patients during a two-hour classroom session. MAIN OUTCOME MEASURE: A comparison of participants' PSM competency test scores before and after attending the PSM program. RESULTS: Forty-four patients attended the education program. The mean age of participants was 71 years and 50% were women. Patients declining study participation were older (p = 0.003) and had a greater burden of chronic disease (p = 0.005) than participants. Following PSM training, the mean competency score improved from 55.8% to 88.8% (p < 0.001), and the proportion achieving a passing score increased from 34.9% to 95.3% (p < 0.001). In the poststudy survey, 100% of responders perceived that PSM training prepared them to self-manage warfarin, and 92.9% of responders were comfortable changing warfarin doses on their own. CONCLUSION: Developing and administering a warfarin PSM education program for patients with atrial fibrillation was feasible. Improvement in PSM competency and high levels of self-reported comfort with warfarin PSM were identified. PMID- 26517435 TI - Anxiety's Impact on Length of Stay Following Lumbar Spinal Surgery. AB - INTRODUCTION: Despite some evidence that anxiety may affect length of stay (LOS), relatively little inquiry exists regarding this in neurosurgical literature. OBJECTIVE: To determine the influence of anxiety on LOS after elective lumbar decompression and fusion (LDF) surgery. METHODS: The medical records of 307 patients who consecutively underwent elective LDF surgery from October 1, 2010, through September 30, 2013, were retrospectively reviewed. Each patient's medications and comorbidities were determined using the medical history. The impact of their medications on LOS was studied using multivariate analysis. Linear regression was also used to assess the relationship between anxiolytic use and LOS. An independent sample t test was used to compare the mean LOS of the group of patients receiving muscle relaxants with that of the group who were not. RESULTS: Those with a diagnosis of anxiety who were taking anxiolytics (n = 32) stayed 1.8 days longer than those with no diagnosis of anxiety and who were not taking anxiolytics (n = 224) after LDF surgery (p = 0.003). Those with a diagnosis of anxiety who were taking anxiolytics (n = 32) stayed 1.9 days longer than those with no diagnosis of anxiety and who were taking anxiolytics (n = 24) after LDF surgery (p = 0.003). CONCLUSION: Our study suggests that those with a diagnosis of anxiety who take medications for that condition have a longer LOS than those with no diagnosis of anxiety and who are not medicated for the condition. This could be because these patients are more vulnerable to states of anxiety when required to be nil per os for 12 hours before surgery. PMID- 26517436 TI - Navigating the Next Accreditation System: A Dashboard for the Milestones. AB - INTRODUCTION: In July 2014, all residency programs accredited by the Accreditation Council for Graduate Medical Education (ACGME) were enrolled in a new system called the Next Accreditation System. Residency programs may not be clear on how best to comply with these new accreditation requirements. Large amounts of data must be collected, evaluated, and submitted twice a year to the council's Web-based data collection system. One challenge is that the new "end-of rotation" evaluations must reflect specialty-specific milestones, on which many faculty members are not well versed. Like other residency programs, we tried to address the challenges using our local resources. METHODS: We used our existing electronic goals and objectives for each rotation coupled with appropriate end-of rotation evaluations reflecting the specialty-specific milestones through a process of editing and mapping. RESULTS: Data extracted from these evaluations were added to an interactive dashboard that also contained evaluations on additional program-specific modifiers of residents' performance. A resident's final overall performance was visually represented on a plot graph. The novel dashboard included features to save evaluations for future comparisons and to track residents' progress during their entire training. It proved simple to use and was able to reduce the time needed for each resident evaluation to 5 to 10 minutes. CONCLUSION: This tool has made it much easier and less challenging for the members of our Clinical Competency Committee to start deliberation about each resident's performance. PMID- 26517437 TI - SQUIRE 2.0 (Standards for QUality Improvement Reporting Excellence): Revised Publication Guidelines from a Detailed Consensus Process. AB - Since the publication of Standards for Quality Improvement Reporting Excellence (SQUIRE 1.0) guidelines in 2008, the science of the field has advanced considerably. In this manuscript we describe the development of SQUIRE 2.0 and its key components. We undertook the revision between 2012 and 2015, using 1) semistructured interviews and focus groups to evaluate SQUIRE 1.0 plus feedback from an international steering group; 2) two face-to-face consensus meetings to develop interim drafts; and 3) pilot testing with authors and a public comment period. SQUIRE 2.0 emphasizes the reporting of three key components of systematic efforts to improve the quality, value, and safety of health care: the use of formal and informal theory in planning, implementing, and evaluating improvement work; the context in which the work is done; and the study of the intervention(s). SQUIRE 2.0 is intended for reporting the range of methods used to improve health care, recognizing that they can be complex and multidimensional. It provides common ground to share these discoveries in the scholarly literature (www.squire-statement.org). PMID- 26517438 TI - Primary Epithelial Neuroendocrine Tumors of the Retroperitoneum. AB - Neuroendocrine tumors are either epithelial or neural in origin. Neuroendocrine tumors of the retroperitoneum are mostly metastatic. Primary epithelial neuroendocrine tumors of the retroperitoneum are exceedingly rare. We describe a case of a retroperitoneal tumor that was discovered incidentally during exploratory laparotomy for small-bowel obstruction. Histopathologic and immunochemical analyses of the biopsied mass were consistent with an epithelial neuroendocrine tumor. The tumor was subsequently removed and final analyses confirmed the initial diagnosis. No evidence of lymph nodes or paraganglia were found within the tumor on histologic examination. Extensive evaluation did not reveal any other primary or metastatic lesions. Therefore, the diagnosis of primary epithelial neuroendocrine tumor of the retroperitoneum was made. The literature is reviewed and discussed. To date, this is only the fifth reported case of primary epithelial retroperitoneal neuroendocrine tumor. Although extremely rare, the possibility of such diagnosis should be included in the differential diagnosis of a retroperitoneal tumor. PMID- 26517439 TI - High-Dose Viscum album Extract Treatment in the Prevention of Recurrent Bladder Cancer: A Retrospective Case Series. AB - INTRODUCTION: Viscum album extract (European mistletoe), containing immuno-active compounds with dose-dependent cytotoxic activity, is being used as an adjuvant cancer treatment in Europe. Few studies have yet been done with high-dose, fever inducing Viscum album treatment. OBJECTIVE: To explore whether subcutaneous injections of high-dose Viscum album have a preventive effect on risk of recurrence of bladder cancer. METHODS: We retrospectively analyzed the case records of patients with resectable bladder cancer who underwent initiation of high-dose Viscum album treatment at our clinic between January 2006 and December 2012. MAIN OUTCOME MEASURES: We calculated tumor recurrence and progression risk and explored case records to assess whether treatment had a likely, possible, or unlikely beneficial effect. RESULTS: Eight patients were identified, 7 of whom had nonmuscle-invasive bladder cancer and 1 with muscle-invasive cancer. Four patients had frequently recurring tumors before treatment. Among the 8 patients, 28 episodes of recurrence were observed. Median tumor-free follow-up duration was 48.5 months. High-dose Viscum album showed a possible beneficial effect in 5 of 8 patients, could not be assessed in 2 patients, and had an uncertain effect in 1 patient. No tumor progression was observed. Treatment was generally well tolerated and no patient stopped treatment because of side effects. CONCLUSION: High-dose Viscum album treatment may have interrupted frequently recurring tumors in individual patients with recurrent bladder cancer. Prospective studies are needed to assess whether this treatment offers an additional, bladder-sparing preventive option for patients with intermediate- to high-risk nonmuscle-invasive bladder cancer.. Treatment was generally well tolerated and no patient stopped treatment because of side effects. PMID- 26517440 TI - Strategies to Increase Physical Activity. AB - The benefits of physical activity are well known and well publicized. Healthy People 2020 has determined that physical activity is one of their key interventions to improve health in America. Despite wide acceptance that physical activity is a low-cost alternative to disease treatment and prevention, most Americans still do not exercise the recommended minimum of 150 minutes per week. Underpinning such recommendations is the growing concern that unless we change our behavior around active living, health care costs to treat preventable disease will become unsustainable and have a substantial impact on the financial health of the US. For this reason, physicians, health care executives, and community leaders are working together to improve total health for all Americans. One key intervention to prevent preventable diseases and to make health care more affordable is to increase the percentage of Americans who are physically active. No single intervention will increase activity rates, but a group of interventions working together in synergy may be the stimulus needed to get Americans moving. The five strategies discussed in this paper include 1) measure physical activity as a vital sign; 2) encourage patients to be physically active at least 150 minutes per week; 3) create healthy environments by making it easier for patients to be physically active where they live, learn, work, play, and pray; 4) monitor disease incidence of patients who are physically active vs those who are not physically active; and 5) spread best practices. PMID- 26517441 TI - Research Letter: Sensor-Based Systems and the Objective Measure of Physical Activity. AB - Similar to medication adherence, objective measures of physical activity may allow physicians to improve activity rates among individual patients and patient populations, which should improve health care outcomes. Sensor-based systems may become a best practice for objective measurement of physical activity and the management of physical activity programs. Given the ease of tracking with these new devices and the ability to upload information automatically, a sensor-based system has the potential to prevent preventable diseases and lower health care costs. PMID- 26517442 TI - Adsorption of Antimony by Bagasse Fly Ash: Chemical Modification and Adsorption Mechanism. AB - Modification of bagasse fly ash (BFA) and the adsorption mechanism of antimony (Sb) by modified BFA were studied. It was found that BFA grafted with acrylic acid (BFAG) and BFA treated with hydrochloric acid (BFA/HCl) led to a decrease in the pH of the zero point of charge (pHzpc) of the adsorbents. The pHzpc of BFA, BFAG, BFA/HCl and activated carbon (AC) were 8.3, 6.4, 6.2 and 8.2, respectively. The maximum adsorption capacities (Qmax) of Sb by BFA, BFAG, BFA/HCl and AC were 0.14, 0.34, 0.38 and 0.29 mg Sb/g adsorbent, respectively. Modified BFA had Qmax higher than AC although the BET surface area of AC was the highest. This was due to the system pH of BFAG and BFA/HCl was 5.20-6.00 and the pHzpc of BFAG and BFA/HCl accounted for 6.4 and 6.2, respectively. Therefore, the adsorbent surface had a positive charge, resulting in increasing adsorption of Sb. PMID- 26517443 TI - Natural products as a source of drug leads to overcome drug resistance. AB - Novel antibacterials may be found that can enhance the pipeline of therapeutics capable of overcoming antibiotic resistance by a return to exploration of natural products. Such novel products may be derived from both standard and previously uncultivable sources, and enriched by expression of previously unseen antibiotics predicted by genome mining of productive bacterial genera. Hypersensitive whole cell phenotypic screens can be used to detect novel secondary metabolites from both standard and newly uncovered sources. PMID- 26517444 TI - Targeting cerebrovascular impairments in Huntington's disease: a novel treatment perspective. PMID- 26517445 TI - Phosphoinositide regulation of TRPM channels - TRPM3 joins the club! PMID- 26517446 TI - Budesonide suspension nebulization treatment in Chinese pediatric patients with cough variant asthma: a multi-center observational study. AB - OBJECTIVE: To describe the impact of nebulized budesonide inhalation suspension (BIS) on guardian-reported symptoms in Chinese pediatric patients with cough variant asthma (CVA). METHODS: This was a secondary analysis of a prospective, non-interventional study conducted at 39 Chinese sites. Patients with CVA aged <=5 years were classified according to the severity of baseline symptoms: mild (symptom score <=3) or severe (symptom score >3). Daytime and night-time symptom scores, disease control, use of bronchodilators, and improvements in symptoms control were compared after 1, 3, 5 and 7 weeks of treatment between groups. RESULTS: Among 914 patients, 821 (89.8%) completed the 7-week treatment. Among all patients, 368 (40.3%) were classified as mild CVA and 529 (57.9%), as severe CVA. Symptom scores in the severe group were higher than those in the mild group at weeks 1, 3, and 5 (p < 0.05), but not at week 7 (p > 0.05). Further, more patients in the mild group achieved disease control at any time point (98.6% at 3 weeks and 99.7% at 7 weeks), compared with the patients in the severe group (p < 0.001). The proportion of patients requiring bronchodilators differed between the groups until week 5 (p < 0.001). No severe or drug-related adverse events were reported. CONCLUSIONS: Individualized BIS treatment should be formulated according to the severity of baseline symptoms in CVA patients. Patients with mild CVA showed improvement after a shorter treatment time, while patients with severe CVA might require a longer time to respond to the treatment. PMID- 26517447 TI - Comments on "Preliminary study of high mobility group box chromosomal protein 1(HMGB1) in ankylosing spondylitis patients ". PMID- 26517448 TI - Assessment of Malignant Potential in Intraductal Papillary Mucinous Neoplasms of the Pancreas: Comparison between Multidetector CT and MR Imaging with MR Cholangiopancreatography. AB - PURPOSE: To compare the diagnostic performance of multidetector computed tomography (CT) and magnetic resonance (MR) imaging with MR cholangiopancreatography (MRCP) in identifying the malignant potential of pancreatic intraductal papillary neoplasms (IPMNs) and evaluate their intermodality agreement. MATERIALS AND METHODS: Institutional review board approval was obtained, and the requirement for informed consent was waived for this retrospective study. In 129 patients with pathologically proved pancreatic IPMNs, three reviewers independently evaluated their preoperative CT and MR imaging with MRCP findings. Intermodality agreement between multidetector CT and MR imaging with MRCP, as well as interobserver agreement of each imaging modality, for depicting high-risk stigmata and worrisome features were assessed. Diagnostic values of other signs of overt malignancy, including the presence of a parenchymal mass and local-regional extension, were analyzed. Diagnostic performance and intermodality agreement were assessed by using receiver operating characteristics (ROC) curve analysis and weighted kappa statistics. RESULTS: Overall, multidetector CT and MR imaging with MRCP were similar in their ability to depict signs suspicious or indicative of malignancy in patients with IPMN (area under the ROC curve [AUC] = 0.82 for both), with good intermodality agreement (kappa = 0.75) and moderate interobserver agreement (kappa = 0.47-0.59) when high-grade dysplasia was used as the cutoff for malignancy. When parenchymal masses and local-regional extensions were also considered as overt signs of malignancy, the ability to identify invasive IPMNs significantly increased (AUC = 0.87 for CT and AUC = 0.88 for MR imaging), with high sensitivity (94.3%), while maintaining specificity (69.1%). CONCLUSION: The diagnostic performance of multidetector CT and MR imaging with MRCP for identifying the malignant potential of pancreatic IPMNs was similar and showed good intermodality agreement, suggesting that follow-up with either modality may be used. PMID- 26517449 TI - Use of the RISK21 roadmap and matrix: human health risk assessment of the use of a pyrethroid in bed netting. AB - The HESI-coordinated RISK21 roadmap and matrix are tools that provide a transparent method to compare exposure and toxicity information and assess whether additional refinement is required to obtain the necessary precision level for a decision regarding safety. A case study of the use of a pyrethroid, "pseudomethrin," in bed netting to control malaria is presented to demonstrate the application of the roadmap and matrix. The evaluation began with a problem formulation step. The first assessment utilized existing information pertaining to the use and the class of chemistry. At each stage of the step-wise approach, the precision of the toxicity and exposure estimates were refined as necessary by obtaining key data which enabled a decision on safety to be made efficiently and with confidence. The evaluation demonstrated the concept of using existing information within the RISK21 matrix to drive the generation of additional data using a value-of-information approach. The use of the matrix highlighted whether exposure or toxicity required further investigation and emphasized the need to address the default uncertainty factor of 100 at the highest tier of the evaluation. It also showed how new methodology such as the use of in vitro studies and assays could be used to answer the specific questions which arise through the use of the matrix. The matrix also serves as a useful means to communicate progress to stakeholders during an assessment of chemical use. PMID- 26517450 TI - The Relation Between Child Versus Parent Report of Chronic Fatigue and Language/Literacy Skills in School-Age Children with Cochlear Implants. AB - OBJECTIVES: Preliminary evidence suggests that children with hearing loss experience elevated levels of chronic fatigue compared with children with normal hearing. Chronic fatigue is associated with decreased academic performance in many clinical populations. Children with cochlear implants as a group exhibit deficits in language and literacy skills; however, the relation between chronic fatigue and language and literacy skills for children with cochlear implants is unclear. The purpose of this study was to explore subjective ratings of chronic fatigue by children with cochlear implants and their parents, as well as the relation between chronic fatigue and language and literacy skills in this population. DESIGN: Nineteen children with cochlear implants in grades 3 to 6 and one of their parents separately completed a subjective chronic fatigue scale, on which they rated how much the child experienced physical, sleep/rest, and cognitive fatigue over the past month. In addition, children completed an assessment battery that included measures of speech perception, oral language, word reading, and spelling. RESULTS: Children and parents reported different levels of chronic child physical and sleep/rest fatigue. In both cases, parents reported significantly less fatigue than did children. Children and parents did not report different levels of chronic child cognitive fatigue. Child report of physical fatigue was related to speech perception, language, reading, and spelling. Child report of sleep/rest and cognitive fatigue was related to speech perception and language but not to reading or spelling. Parent report of child fatigue was not related to children's language and literacy skills. CONCLUSIONS: Taken as a whole, results suggested that parents under-estimate the fatigue experienced by children with cochlear implants. Child report of physical fatigue was robustly related to language and literacy skills. Children with cochlear implants are likely more accurate at reporting physical fatigue than cognitive fatigue. Clinical practice should take fatigue into account when developing treatment plans for children with cochlear implants, and research should continue to develop a comprehensive model of fatigue in children with cochlear implants. PMID- 26517451 TI - Exploring the Relationship Between Working Memory, Compressor Speed, and Background Noise Characteristics. AB - OBJECTIVES: Previous work has shown that individuals with lower working memory demonstrate reduced intelligibility for speech processed with fast-acting compression amplification. This relationship has been noted in fluctuating noise, but the extent of noise modulation that must be present to elicit such an effect is unknown. This study expanded on previous study by exploring the effect of background noise modulations in relation to compression speed and working memory ability, using a range of signal to noise ratios. DESIGN: Twenty-six older participants between ages 61 and 90 years were grouped by high or low working memory according to their performance on a reading span test. Speech intelligibility was measured for low-context sentences presented in background noise, where the noise varied in the extent of amplitude modulation. Simulated fast- or slow-acting compression amplification combined with individual frequency gain shaping was applied to compensate for the individual's hearing loss. RESULTS: Better speech intelligibility scores were observed for participants with high working memory when fast compression was applied than when slow compression was applied. The low working memory group behaved in the opposite way and performed better under slow compression compared with fast compression. There was also a significant effect of the extent of amplitude modulation in the background noise, such that the magnitude of the score difference (fast versus slow compression) depended on the number of talkers in the background noise. The presented signal to noise ratios were not a significant factor on the measured intelligibility performance. CONCLUSION: In agreement with earlier research, high working memory allowed better speech intelligibility when fast compression was applied in modulated background noise. In the present experiment, that effect was present regardless of the extent of background noise modulation. PMID- 26517453 TI - A Multidisciplinary Evaluation of Prescribing Practices for Prophylactic Antibiotics in Operative and Nonoperative Facial Fractures. AB - BACKGROUND: Evidence supports short-term perioperative prophylaxis for facial fractures. It is unknown, however, whether there is any professional consensus on how to manage these injuries. No multidisciplinary evaluation of the prophylactic antibiotic prescribing patterns for neither operative nor nonoperative facial fractures has been performed. AIM: To evaluate the prophylactic antibiotic prescribing patterns of multiple specialties in operative and nonoperative facial fractures. METHODS: A 14 question anonymous online-based survey was distributed to members of the American Society of Maxillofacial Surgeons (ASMS) and the American Association of Facial Plastic Surgeons to evaluate current practices. RESULTS AND CONCLUSIONS: 205 respondents, including 89 plastic surgeons, 98 otolaryngologists, 12 oral and maxillofacial surgeons, and 7 with double board certification practicing throughout the United States with ranging experience from 11 to 30 years. As expected, preoperative, perioperative, or postoperative prophylactic antibiotics are either "always" or "sometimes" prescribed, 100% of the time with more varied practice upon further inspection. A total of 85.1% either "always" or "sometimes" use antibiotics while awaiting surgery. Dentate segment fractures are the most frequent type of facial fractures to receive prophylactic antibiotics for both operative (90.5%) and nonoperative (84.1%) fractures. Duration of antibiotic use is more varied with the majority providing 3 to 7 days despite current evidence. First generation cephalosporins alone are prescribed by 49% of respondents, which may not adequately cover oral flora. There is no multidisciplinary consensus for prophylactic antibiotics for specific operative fracture types or nonoperative facial fractures, an area with little published evidence. PMID- 26517455 TI - Fast and Early Mandibular Osteodistraction: The Long-Term Follow-Up of Mandibular Distraction Osteogenesis on Teeth Position. AB - Pierre Robin Sequence is a congenital pathology defined by the triad micrognathia, glossoptosis and often a U-shaped cleft of soft palate. Newborns affected by airways obstruction may necessitate more invasive options: tongue-lip adhesion, tracheostomy and mandibular distraction osteogenesis. The authors analyzed the effect of fast and early mandibular osteodistraction on deciduous dental development in patients affected by Pierre Robin Sequence. Analysis of the patients treated for severe form was performed by a team composed by maxillofacial surgeons and dentists. Five patients were included for the analysis: before and long term clinical and radiological assessments were considered. All patients underwent fast and early mandibular osteodistraction; two years follow up computed tomography and panorex reconstructions showed bone consolidation, 33 of 35 teeth analyzed before ostedistraction are present after distraction protocol; no positional changes were detected at the follow up analysis either deciduous teeth and molar permanent buds. No deformities regarding molar buds were detected. In conclusion external mandibular distractor devices have been associated with dental injuries and facial scaring. Even though, the dental complications identified can not be unambiguously connected to the external distractor devices. PMID- 26517457 TI - Endoscopy-Assisted Single-Incision Technique to Harvest the Conchal Cartilage and Temporal Fascia Simultaneously by Using Phaco Slit Knife. AB - Conchal cartilage and temporal fascia grafts are useful materials for secondary rhinoplasty cases. Generally, surgeons require to access autologous grafts fast and effortlessly. Harvesting 2 different types of graft, such as cartilage and fascia, however, are associated with limitations, such as additional surgery time, extra incisions, and postoperative additional distortions at the graft-host interface. The authors evolved a modified single incision that would harvest conchal cartilage and temporal fascia simultaneously by using 4 mm endoscope and 3 mm angled phaco slit knife. PMID- 26517458 TI - Temporal Bone Localized Chondroblastoma. AB - Chondroblastoma is a highly destructive tumor originating from immature cartilage cells. Although chondroblastoma is defined as a benign tumor, it may exhibit malign tumor behaviors such as invasion or metastasis on neighboring structures. Magnetic resonance (MR) image is a solid mass lesion, which included heterogeneous hypointense in T2A and heterogeneous minimal hyperintense in T1A with destructive expansile characteristics and millimetric calcifications. Temporal bone chondroblastomas may complicate the diagnosis because of their different histologic characteristics. Microscopically, chondroblastic cell nests and calcification of locally "chicken wire" type around the cells are observed. These tumors secrete s-100 and vimentin and are used for differential diagnosis. In this study, a temporal bone localized chondroblastoma case is presented. PMID- 26517459 TI - Infant Fibrolipoma Mimicking Hemangioma in Neck Region. AB - Fibrolipoma is an extremely rare variant of lipoma. And it usually presents clinically as a slowly growing mass with a firm or soft consistency and usually occurs in middle-aged person. The authors report an unusual case of infant fibrolipma with fast-growing speed, which was misdiagnosis and mistreatment as hemangioma in local hospital. The diagnosis of hemangioma was ruled out by fine needle aspiration cytology in authors' hospital. Operation was performed in authors' hospital and the prognosis of fibrolipma was good. PMID- 26517460 TI - Simultaneous Correction of Temporomandibular Joint Ankylosis and Secondary Dentofacial Deformities in Adult Patients: Surgical Technique, Treatment Outcomes, and a Consideration of the Factors Involved. AB - BACKGROUND: Temporomandibular joint (TMJ) ankylosis causes serious problems in oral functions. When it occurs in childhood, it can cause secondary dentofacial deformities. This study described our experience in the simultaneous correction of TMJ ankylosis and secondary dentofacial deformities performed in a single operation. METHODS: Twenty-seven patients with TMJ ankylosis and secondary deformities were treated in a single surgery from January 2009 to December 2013. Clinical outcomes were assessed based on the oral function, radiography, and medical photography. RESULTS: No relapse (of TMJ ankylosis) occurred in any of the patients during the follow-up period. Oral function and skeletal deformities had (were) significantly improved in all the patients. Most of the patients were satisfied with the final outcome. CONCLUSIONS: One-stage treatment permits the simultaneous correction of both the TMJ functional deficit and skeletal deformities in a single operation, which suggests that it is an effective approach for the treatment of patents with TMJ ankylosis and secondary dentofacial deformities. PMID- 26517461 TI - Analysis of Pediatric Maxillofacial Fractures Requiring Operative Treatment: Characteristics, Management, and Outcomes. AB - Maxillofacial fractures in pediatric trauma patients require significant force and frequently are associated with concomitant injuries. The anatomic and developmental differences between the adult and child that impact patterns of injury also affect management and outcomes. The aim of this study was to analyze fracture location, mechanism, concomitant injuries as well as methods of surgical treatment and outcomes, to improve management of this patient population. A retrospective review was conducted of pediatric patients with maxillofacial fractures presenting to a level-1 trauma center during an 8-year span. Only patients requiring surgical intervention, 204, were included in this study. Data pertaining to the location of injury, mechanism, associated injuries, surgical treatment, outcomes, and complications were analyzed. The most common fracture location was the mandible (36.3%), then the nasal bone (35.3%), followed by the tripod fracture (10.8%). A total of 30.7% of patients were involved in motor vehicle accidents, with the next most common mechanisms being sports (24.4%), and assault (13.7%). A total of 46% of the patients sustained concomitant injuries, with the majority involving cerebral trauma (14.7%) or the extremities (9.3%). Total 75.4% of all fractures, excluding the nose, were treated with open reduction and internal fixation (ORIF). Our complication rate was 11.2%. Pediatric craniofacial trauma remains a frequent presentation to the emergency department of trauma centers. Facial fracture patterns and mechanism of trauma observed in the pediatric population presenting to this facility are consistent with incidences reported in the literature. Knowledge of treatment options and potential complications is an important tool in the management of the pediatric trauma patient. PMID- 26517462 TI - An Analysis of Surgical Treatment Results of Patients With Tympanosclerosis. AB - OBJECTIVE: The authors aimed to evaluate the intraoperative features and the results of postoperative hearing gain successes of patients with tympanosclerosis who were treated surgically in our clinic. MATERIAL AND METHODS: A retrospective analysis was conducted on 151 ears with tympanosclerosis of 138 patients who operated because of chronic otitis media or only tympanosclerosis, between January 2007 and June 2014. They were evaluated by appealing complain, complain duration, accompanying systemic disorders, tympanic membrane condition, localization of sclerotic plaque, damage in ossicular chain, existence of cholesteatoma, operation procedure type, hearing reconstruction type, preoperative, and last postoperative audiometric findings in every frequency both bone and air way. RESULTS: In the group of Wielinga-Kerr Group 3 (isolated stapes fixation), no statistically significant results were found in preoperative and last postoperative audiometric findings in every frequency both bone and air conduction (BC and AC) (P > 0.05). In the Wielinga-Kerr Group some results had significant (P < 0.05) and some results had highly significant (P < 0.001). CONCLUSIONS: Patients with less impact on ossicular chain and limited localization of sclerotic plaques have better hearing gain. Although surgery is still controversial in tympanosclerosis; it is the most effective treatment till new effective medication is discovered. PMID- 26517463 TI - Severe Agnathia-Otocephaly Complex: Surgical Management and Longitudinal Follow up From Birth Through Adulthood. AB - Agnathia-otocephaly complex (AOC) is characterized by mandibular hypo- or aplasia, ear abnormalities, microstomia, and microglossia. Though rare and often fatal, this is the first report detailing various reconstructive strategies beyond infancy as well as longitudinal follow-up into adulthood. All patients with AOC treated at our institution over a 30 year period were reviewed. Four patients were identified, one with agnathia, one with micrognathia. Two males with nanognathia (defined as a symphyseal remnant without body nor ramus) were also included. The mean follow-up was 17 years. All four underwent perinatal tracheostomy and gastrostomy-tube placement. Commissuroplasties were typically performed before 3 years of age and repeated as necessary to allow for oral hygiene. Mandibular reconstruction was most successful with rib between ages 3 and 8, after which time, free fibula transfer was utilized. Due to some resoprtion or extrusion, all patients underwent repeated bone grafting procedures. Tissue expansion of the neck was used to restore the lower third of the face, but was most successful in the teenage years. At last follow-up of the eldest patients, one was in college while another was pursuing graduate education. AOC need not be a fatal nor untreatable condition; a reasonable quality of life can be achieved. Although the lower-facial contour may be improved, and a stoma created, the lack of musculature make deglutition virtually impossible with current therapies. Just as transplantation has emerged as a modality for facial restoration following severe trauma, so too may it be a future option for congenital deformities. PMID- 26517464 TI - Microtia Combined With Split Sole of Feet, Deformed Middle Fingers and Cafe -au lait Spots on the Trunk: A New Association. AB - Microtia is a spectrum of congenital deformities. Approximately, half of the patients are associated with hemifacial microtia. The birth rate of microtia ranges from 2 per 10,000 to 17.4 per 10,000. Microtia and limb deformities sometimes occurred simultaneously as described in the literature. In this report, the patient was found to be with unilateral microtia combined with bilateral split sole of feet, deformed middle fingers on both hands, and cafe-au-lait spots on the trunk. Despite a thorough literature search, the authors could not achieve a satisfactory diagnosis for the current case with respect to the type of anomalies seen in the case. PMID- 26517465 TI - Maximizing Technological Resources in Plastic Surgery Resident Education. AB - Modern plastic surgery resident education demands the acquisition of an ever increasing fund of knowledge and familiarity with more surgical techniques than ever before. This all must take place within the context and boundaries of Accreditation Council for Graduate Medical Education-mandated restrictions on work hours as well as balance of education and service. Technological resources have been developed and can be used to complement the skills that residents acquire while performing their day-to-day activities such as taking care of patients, reading textbooks and journal articles, and assisting or performing surgical procedures. Those complementary resources provide the benefits of portability and accessibility, and can thus be conveniently incorporated into the hectic daily life of a resident. This article presents a summary of the most commonly used currently available advanced technologies in plastic surgery resident education, and suggestions for integration of those technologies into a curriculum. PMID- 26517466 TI - From Residency to Lifelong Learning. AB - The residency training experience is the perfect environment for learning. The university/institution patient population provides a never-ending supply of patients with unique management challenges. Resources abound that allow the discovery of knowledge about similar situations. Senior teachers provide counseling and help direct appropriate care. Periodic testing and evaluations identify deficiencies, which can be corrected with future study. What happens, however, when the resident graduates? Do they possess all the knowledge they'll need for the rest of their career? Will medical discovery stand still limiting the need for future study? If initial certification establishes that the physician has the skills and knowledge to function as an independent physician and surgeon, how do we assure the public that plastic surgeons will practice lifelong learning and remain safe throughout their career? Enter Maintenance of Certification (MOC). In an ideal world, MOC would provide many of the same tools as residency training: identification of gaps in knowledge, resources to correct those deficiencies, overall assessment of knowledge, feedback about communication skills and professionalism, and methods to evaluate and improve one's practice. This article discusses the need; for education and self-assessment that extends beyond residency training and a commitment to lifelong learning. The American Board of Plastic Surgery MOC program is described to demonstrate how it helps the diplomate reach the goal of continuous practice improvement. PMID- 26517467 TI - The Plastic Surgery Milestones: Friend or Foe? PMID- 26517468 TI - Successfully Integrating Research into Plastic Surgery Training Programs. AB - Successful integration of research into the educational mission of a plastic surgery residency program requires the support and dedication of the faculty members to create a culture that promotes innovation, discovery, and advancement of the field of plastic surgery. Dedicated research time during plastic surgery training is beneficial to both the resident and training program. Regardless of whether residents plan to pursue an academic career or enter private practice, participating in research provides an opportunity to develop skills to think critically and mature professionally. In this article, we review the benefits of resident research to both the trainee and training program and discuss strategies to overcome barriers to integrating research into the curriculum. PMID- 26517469 TI - International Programs in the Education of Residents: Benefits for the Resident and the Home Program. AB - There is a significant need for basic surgical care worldwide. In recent years, modest improvement in fulfilling this demand has been achieved through international medical mission trips from various organizations. These humanitarian endeavors and global health experiences have generated increasing interest in participating in international missions from surgical residents. However, many academic institutions currently do not have the infrastructure or desire to support surgical residents participating in medical missions. This paper aims to illustrate that careful, planned integration of medical mission trips into the residency curriculum will develop and enhance resident education and experience by fulfilling all six Accreditation Council for Graduate Medical Education (ACGME) core competencies and by benefitting the native program. PMID- 26517470 TI - Milestones Contributing to the Evolution of Craniofacial Surgery. AB - Craniofacial surgery (CFS) has a rich history of collaboration with a wide variety of surgical and nonsurgical specialties. This has resulted in a large volume of publications across this spectrum of subspecialties cataloging the advancements across the field. The authors aim to analyze the characteristics of the most cited articles in CFS. A literature search was performed using the Thomson/Reuters Web of Knowledge database to identify the top 50 most cited articles in CFS. The articles were analyzed for journal distribution, total citations, year of publication, citations per year, number of authors, type of article, institution, departmental affiliation, national affiliation, and top contributors. The articles were extracted from an assortment of 21 journals. The number of citations per article ranged from 115 to 1092 (average of 185). Forty eight percent of articles were published in the 1990s, and 22% in the 2000s. The average number of years since publication until the present time was 21.34 (range 6-45 y). The most cited article (1092 citations and 52 citations/y) was an article by McCarthy et al on human mandible lengthening via gradual distraction. Departmental distribution indicated that the majority were attributable to departments of Plastic and Reconstructive Surgery for 21 articles (42%). Twenty articles were categorized under cranial defect/bone substitutes, 12 under craniosynostosis, 7 under surgical modeling, 6 under distraction osteogenesis, and the remaining 5 under other. These articles qualitatively represent important milestones in CFS. This study affirms the potential value of "number of citations" as a meaningful metric when assessing the importance of an article within CFS. PMID- 26517471 TI - Departmental Status: A Key to Future Plastic Surgery Education. PMID- 26517472 TI - Preserving and Improving the Trade: Best Practices in Plastic Surgery Education. PMID- 26517474 TI - The Stanford Integrated Psychosocial Assessment for Transplantation: A Prospective Study of Medical and Psychosocial Outcomes. AB - BACKGROUND: Psychosocial factors may significantly affect post-transplant outcomes. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) was developed as an assessment tool to enhance the pre-transplant psychosocial evaluation. METHODS: We identified heart, lung, liver, or kidney transplant recipients assessed with the SIPAT pre-transplantation and transplanted between June 1, 2008, and July 31, 2011, at our institution. We analyzed prospectively accumulated psychosocial and medical outcomes at 1 year of follow-up. RESULTS: 217 patients were identified and included in the analysis. The primary outcomes of organ failure and mortality occurred in 12 and 21 patients, respectively, and were not significantly associated with the pre transplant SIPAT scores. On the other hand, SIPAT scores were significantly correlated with the probability of poor medical and psychosocial outcomes (secondary outcomes). In fact, higher SIPAT scores predicted higher rates of rejection episodes (Spearman rho = 0.15, 95% 95% confidence interval [CI] = 0.02 0.28, p = .023), medical hospitalizations (rho = 0.29, 95% CI = 0.16-0.41, p < .001), infection rates (p = .020), psychiatric decompensation (p = .005), and support system failure (area under the curve = 0.70, 95% CI = 0.60-0.79, p < .001). The relationship with nonadherence suggested a trend, but no statistical significance was observed (area under the curve = 0.60, 95% CI = 0.50-0.71, p = .058). CONCLUSIONS: Study outcomes suggest that SIPAT is a promising pre transplantation assessment tool that helps identify candidate's areas of psychosocial vulnerability and whose scores are associated with both psychosocial and medical outcomes after transplantation. PMID- 26517475 TI - Doubly Bayesian Analysis of Confidence in Perceptual Decision-Making. AB - Humans stand out from other animals in that they are able to explicitly report on the reliability of their internal operations. This ability, which is known as metacognition, is typically studied by asking people to report their confidence in the correctness of some decision. However, the computations underlying confidence reports remain unclear. In this paper, we present a fully Bayesian method for directly comparing models of confidence. Using a visual two-interval forced-choice task, we tested whether confidence reports reflect heuristic computations (e.g. the magnitude of sensory data) or Bayes optimal ones (i.e. how likely a decision is to be correct given the sensory data). In a standard design in which subjects were first asked to make a decision, and only then gave their confidence, subjects were mostly Bayes optimal. In contrast, in a less-commonly used design in which subjects indicated their confidence and decision simultaneously, they were roughly equally likely to use the Bayes optimal strategy or to use a heuristic but suboptimal strategy. Our results suggest that, while people's confidence reports can reflect Bayes optimal computations, even a small unusual twist or additional element of complexity can prevent optimality. PMID- 26517476 TI - Correction to Gd(III)-Labeled Peptide Nanofibers for Reporting on Biomaterial Localization in Vivo. PMID- 26517477 TI - Healthcare-associated infections in intensive care units: epidemiology and infection control in low-to-middle income countries. AB - Healthcare-associated infections (HAIs) are major patient safety problems in hospitals, especially in intensive care units (ICUs). Patients in ICUs are prone to HAIs due to reduced host defense mechanisms, low compliance with infection prevention and control (IPC) measures due to lack of education and training, and heavy workload and low staffing levels, leading to cross-transmission of microorganisms from patient to patient. Patients with HAIs have prolonged hospital stays, and have high morbidity and mortality, thus adding economic burden on the healthcare system. For various reasons, in low-to-middle income countries (LMICs), the scale of the problem is huge; each year, many people die from HAIs. In this review, epidemiology of HAIs and infection prevention and control measures in ICUs is discussed, with especial emphasis on LMICs. High rates of HAIs caused by multidrug-resistant organisms (MDROs) are serious problems in ICUs in LMICs. In view of increasing prevalence of MDROs, LMICs should establish effective IPC infrastructure, appoint IPC teams, and provide adequate training and resources. These resources to establish and appoint IPC teams can be released by avoiding ritualistic, wasteful, and unsafe IPC practices, and by diverting resources to implement basic IPC measures, including early detection of infection, isolation of patients, application of appropriate IPC precautions, adherence to hand hygiene, and implementation of HAIs care bundles and basic evidence-based practices. PMID- 26517478 TI - Are healthcare workers' mobile phones a potential source of nosocomial infections? Review of the literature. AB - Mobile communication devices help accelerate in-hospital flow of medical information, information sharing and querying, and contribute to communications in the event of emergencies through their application and access to wireless media technology. Healthcare-associated infections remain a leading and high-cost problem of global health systems despite improvements in modern therapies. The objective of this article was to review different studies on the relationship between mobile phones (MPs) and bacterial cross-contamination and report common findings. Thirty-nine studies published between 2005 and 2013 were reviewed. Of these, 19 (48.7%) identified coagulase-negative staphylococci (CoNS), and 26 (66.7%) identified Staphylococcus aureus; frequency of growth varied. The use of MPs by healthcare workers increases the risk of repetitive cyclic contamination between the hands and face (e.g., nose, ears, and lips), and differences in personal hygiene and behaviors can further contribute to the risks. MPs are rarely cleaned after handling. They may transmit microorganisms, including multiple resistant strains, after contact with patients, and can be a source of bacterial cross-contamination. To prevent bacterial contamination of MPs, hand washing guidelines must be followed and technical standards for prevention strategies should be developed. PMID- 26517479 TI - Characterization of Leptospira interrogans serovar Pomona isolated from swine in Brazil. AB - INTRODUCTION: Leptospira interrogans swine infection is a cause of serious economic loss and a potential human health hazard. In Brazil, the most common serovars associated with swine infections are Pomona, Icterohaemorrhagie and Tarassovi. Cross-reactions among serovars and the failure of infected animals to seroconvert may complicate the interpretation of serological tests. Molecular methods with better discriminatory powers are useful tools for swine leptospirosis characterization and diagnosis. METHODOLOGY: This study evaluated nine L. interrogans isolates from the States of Sao Paulo and Minas Gerais during different time periods. Isolates from diseased and apparently healthy swine were characterized by microscopic agglutination tests with polyclonal antibodies and were genotyped by VNTR, PFGE and MLST techniques. Broth microdilution was used to determine the minimal inhibitory concentration of the antimicrobials of veterinary interest. RESULTS: The strains were identified as L. interrogans serogroup Pomona serovar Pomona Genotype A, while MLST grouped all of the isolates in sequence type 37. The PFGE analysis resulted in two pulsotypes with more than 70% similarity, distinguishing serovar Pomona isolates from the serovar Kennewicki reference strain. All of the isolates presented low MIC values to penicillin, ampicillin, ceftiofur and tulathromycin. High MIC values for fluoroquinolones, tiamulin, gentamicin, tetracyclines, neomycin, tilmicosin and sulfas were also observed. CONCLUSIONS: All molecular techniques were concordant in L. interrogans serovar Pomona identification. This serovar may have a different antibiotic susceptibility profile than previously reported for Leptospira isolates. PMID- 26517480 TI - Oral teicoplanin for successful treatment of severe refractory Clostridium difficile infection. AB - INTRODUCTION: Clostridium difficile is the leading cause of hospital-acquired diarrhoea. There is no defined protocol for treating severe Clostridium difficile infection (CDI) refractory to vancomycin or vancomycin and metronidazole combination therapy. The aim of this study was to evaluate the rate of clinical cure, time to resolution of diarrhoea and recurrence rate in patients with severe refractory CDI treated with oral teicoplanin. METHODOLOGY: A one-year prospective study was carried out in the Clinic for Infectious and Tropical Diseases, Clinical Center Serbia. Patients with severe and complicated CDI who failed to respond to oral vancomycin and intravenous metronidazole combination therapy were enrolled. They were given oral teicoplanin 100 mg bi-daily. Patients were followed for recurrence for eight weeks. RESULTS: Nine patients with a mean age of 70.8+/-9.4 years were analyzed. All patients had pseudomembranous colitis, and five had complicated disease. In four patients intracolonic delivery of vancomycin was also performed in addition to oral vancomycin and intravenous metronidazole prior to initiating teicoplanin, but without improvement. After teicoplanin initiation all patients achieved clinical cure. The mean time to resolution of diarrhoea after teicoplanin introduction was 6.3+/-4.5 days. There was no statistically significant difference in time to resolution of diarrhoea according to initial leucocyte count, age over 65 years, the presence of ileus, complicated disease and the use of concomitant antibiotic therapy (p = 0.652, 0,652, 0.374, 0.374, and 0,548, respectively). None of the patients experienced recurrence. CONCLUSIONS: Oral teicoplanin might be a potential treatment for severe and complicated refractory CDI, but further studies are required. PMID- 26517481 TI - Presence of virulence genes and pathogenicity islands in extraintestinal pathogenic Escherichia coli isolates from Brazil. AB - INTRODUCTION: Extraintestinal pathogenic Escherichia coli (ExPEC) is associated with various diseases such as urinary tract infections, neonatal meningitis and septicemia. There are many virulence factors (VF) encoded by genes in ExPEC, including papC, papG, ecpA, iroN, fyuA, iutA, ompTp, tsh, hlyF, hlyA and iss. These virulence genes may be present in pathogenicity islands (PAI) or plasmids. METHODOLOGY: In this study, we analyzed the presence of VF encoding genes, PAI sequences and phylogenetic groups of 96 ExPEC strains isolated from the urine and blood of patients at the University Hospital of Londrina, and we compared them with 50 faecal commensal strains from healthy individuals. RESULTS: The VF fyuA (65.60%) was detected in pathogenic strains and commensal strains (46%). A comparison of the distribution of ExPEC and commensal strains in the phylogenetic groups showed that more ExPEC strains belonged to group B2 whereas more of the commensal isolates belonged to group A. The distribution of the seven PAI sequences between commensal strains and ExPEC strains showed that PAI IV536 was common in both ExPEC and commensal isolates. CONCLUSIONS: These results showed that the ExPEC strains that belonged to group B2 had more PAI sequences compared to those of the other groups, especially group B1, which had virulence genes but the lowest percentage of PAI sequences, which leads us to conclude that the virulence of ExPEC strains characterized as B2 is likely attributed to PAI encoded genes, whereas the virulence of ExPEC strains belonging to phylogenetic group B1 is likely due to plasmid encoded virulence genes. PMID- 26517482 TI - Multidrug-resistant tuberculosis and risk factors associated with its development: a retrospective study. AB - INTRODUCTION: Multidrug-resistant tuberculosis (MDR-TB) has emerged as a major clinical public health threat and challenges the national TB control program in Malaysia. Data that elaborates on the risk factors associated with the development of MDR-TB is highly limited in this country. This study was aimed to determine the risk factors associated with the development of MDR-TB patients in peninsular Malaysia. METHODOLOGY: This was a case control study; the data were collected from medical records of all the registered MDR-TB patients at five referral TB hospitals in peninsular Malaysia from January 2010 to April 2014. The 105 cases were all confirmed by a positive sputum culture of Mycobacterium tuberculosis for MDR-TB and extensively drug-resistant (XDR)-TB. As a comparison, a total of 209 non-MDR-TB cases were randomly selected as controls. RESULTS: A total of 105 MDR-TB and 209 non MDR-TB patients were studied. The risk factors associated with MDR-TB within the multivariate analysis were previous tuberculosis treatment, HIV infection, being an immigrant, and high load of positive for acid-fast bacillus (AFB) smear. CONCLUSIONS: The findings of this study revealed that patients who had received previous treatment for tuberculosis, were infected with HIV, were immigrants, and had a high burden of positive testing for AFB smear were more likely to have MDR-TB. An enhanced understanding of the risk factors associated with MDR-TB strains is imperative in the development of a national policy for public health interventions. PMID- 26517483 TI - Ceftaroline activity on certain respiratory tract and wound infection agents at the minimum inhibitory concentration level. AB - INTRODUCTION: The aim of this study was to investigate the effectiveness of ceftaroline against agents frequently isolated from respiratory tract and wound infections. METHODOLOGY: The study included a total of 250 strains isolated from various clinical specimens, among which were Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysagalactiae, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catharralis. The bacteria were identified using the matrix-assisted laser desorption/ionization time-of-flight method and conventional methods. The bacteria's antibiotic susceptibility was tested using appropriate broth microdilution. Mueller-Hinton broth with 4% lysed horse blood, Haemophilus test medium broth, and Mueller-Hinton broth were used. Ceftaroline fosamil results at the minimum inhibitory concentration (MIC) were evaluated using Clinical and Laboratory Standards Institute (CLSI) criteria. For quality assurance, E. coli ATCC 35218, S. aureus ATCC 29213, S. aureus ATCC 43300, S. pneumoniae ATCC 49619, H. influenzae ATCC 49766, H. influenzae ATCC 10211, and H. influenzae ATCC 49247 standard strains were used. RESULTS: According to CLSI criteria, resistance was not detected in any strains. Due to the absence of CLSI criteria for M. catharralis, the susceptibility state for this bacterium was not evaluated. The various strains' MIC50-MIC90 values were as follows: for S. pyogenes, 0.015-0.06; for S. agalactiae, 0.03-0.125; for S. dysagalactiae, 0.03 0.06; for S. pneumoniae, 0.06-0.125; for H. influenzae, 0.015-0.125; and for M. catharralis, 0.5-1. CONCLUSIONS: The results indicate that ceftaroline is quite effective against bacteria that are frequently isolated from respiratory tract and wound infections. PMID- 26517484 TI - Correlation of quorum sensing and virulence factors in Pseudomonas aeruginosa isolates in Egypt. AB - INTRODUCTION: Pseudomonas aeruginosa is one of the most virulent nosocomial pathogens worldwide. Quorum sensing (QS) regulates the production of pathogenic virulence factors and biofilm formation in P. aeruginosa. The four genes lasR, lasI, rhlR,and rhlI were found to regulate this QS system. In this study, we aimed to assess the correlation between these four genes and QS-dependent virulence factors and to detect the inhibitory effect of clove oil on QS. METHODOLOGY: Fifty P. aeruginosa clinical isolates were collected. Susceptibility to different antibiotics was tested. Virulence factors including biofilm formation, pyocyanin production, and twitching motility were phenotypically detected. QS genes were amplified by polymerase chain reaction (PCR), and one strain subsequently underwent sequencing. The inhibitory effect of clove oil on virulence factors was also tested. RESULTS: A positive correlation was found between biofilm formation and the presence of lasR and rhlI genes. Twitching motility was positively correlated with the presence of lasR, lasI, and rhlI genes. On the other hand, no correlation was found between pyocyanin production and any of the studied genes. Only one isolate amplified all the tested QS gene primers, but it did not express any of the tested virulence factors phenotypically. Sequence analyses of this isolate showed that the four genes had point mutations. CONCLUSIONS: Results emphasize the importance of QS in P. aeruginosa virulence; however, QS-deficient clinical isolates occur and are still capable of causing clinical infections in humans. Also, clove oil has an obvious inhibitory effect on QS, which should be clinically exploited. PMID- 26517485 TI - Emergence of multidrug resistant isolates and mortality predictors in patients with solid tumors or hematological malignancies. AB - INTRODUCTION: Infections are an important preventable cause of death in cancer patients. The aim of this study was to clarify the epidemiologic characteristics and resistance patterns of causative isolates and mortality predictors in infections of cancer patients. METHODOLOGY: Patients with sterile site infections were evaluated in a retrospective cohort study. Etiological agents, antimicrobial resistance patterns of the isolates, and possible risk factors for mortality were recorded. Survivors and non-survivors on day 30 after each infection onset were compared to identify the predictors of mortality. RESULTS: A total of 205 infection episodes of 132 patients were included in this study. Of them, 75% had hematologic malignancies and 25% had solid tumors. Febrile neutropenia was diagnosed in 61.5%. Bloodstream infections were the most frequent infection (78%). The majority of the pathogens were Enterobacteriaceae (44.3%) and nonfermentative isolates (17.6%). Multidrug-resistant (MDR) infections were responsible for 40% of the episodes. The mortality rate was 23.4%. Inadequate initial antibiotic treatment (OR = 4.04, 95% CI = 1.80-9.05, p = 0.001), prolonged neutropenia (> 7 days) before infection (OR = 3.61, 95% CI = 1.48-8.80, p = 0.005), infection due to Klebsiella species (OR = 3.75, 95% CI = 1.31-10.7, p = 0.013), and Acinetobacter baumannii (OR = 5.00, 95% CI = 1.38-18.2, p = 0.014) were independent predictors of mortality. CONCLUSIONS: Gram-negative isolates were found to be the predominant pathogens with higher mortality rates. Local epidemiological data should be taken into account when administering empirical therapy since the inadequacy of initial antibiotherapy is associated with a poor outcome. PMID- 26517486 TI - Relationship of interleukin-1B gene promoter region polymorphism with Helicobacter pylori infection and gastritis. AB - INTRODUCTION: Helicobacter pylori infection is associated with gastritis, peptic ulcer disease and gastric carcinoma. The severity of damage is determined by the interplay between environmental/behavioral factors, bacterial pathogenicity genes and host genetic polymorphisms that can influence the secretion levels of inflammatory cytokines. Accordingly, this study aimed to identify polymorphisms in the IL-1B and IL-1RN genes and their associations with H. pylori infection, cagA gene of H. pylori, and gastroduodenal diseases. METHODOLOGY: Gastric biopsy samples from 151 patients infected with H. pylori and 76 uninfected individuals were analyzed. H. pylori infection was diagnosed by histology and PCR. Polymorphisms at positions -511, -31 and +3954 of the IL-1B gene were detected by PCR-RFLP, and an analysis of the VNTR polymorphism of the IL-1RN gene was performed by PCR. RESULTS: It was observed that the presence of the T/T genotype at position -511 and the C/C genotype at position -31 were associated with H. pylori infection and with an increased risk of gastritis in H. pylori-positive patients. Additionally, strains from patients H. pylori-positive carrying the cagA gene was significantly related with the T/T genotype at position -511 of IL 1B. No association of polymorphisms at position +3954 of IL-1B and in the IL-1RN with H. pylori infection and with risk of severe gastric diseases was found. CONCLUSIONS: We demonstrated that polymorphisms in the promoter region of the IL 1B gene (at positions -511 and -31) are associated with an enhanced risk of H. pylori infection as well as gastritis in H. pylori-positive patients. PMID- 26517487 TI - Detection of novel strains genetically related to Anaplasma platys in Tunisian one-humped camels (Camelus dromedarius). AB - INTRODUCTION: Little information is currently available regarding the presence of Anaplasma species in North African dromedaries. To fill this gap in knowledge, the prevalence, risk factors, and genetic diversity of Anaplasma species were investigated in Tunisian dromedary camels. METHODOLOGY: A total of 226 camels from three different bioclimatic areas were sampled and tested for the presence of Anaplasma species by quantitative polymerase chain reaction (qPCR) and nested polymerase chain reaction (nPCR) assays. Detected Anaplasma strains were characterized by 16S rRNA sequence analysis. RESULTS: Overall infection rate of Anaplasma spp. was 17.7%, and was significantly higher in females. Notably, A. marginale, A. centrale, A. bovis, and A. phagocytophilum were not detected. Animals were severely infested by three tick species belonging to the genus Hyalomma (H. dromedarii, H. impeltatum, and H. excavatum). Alignment, similarity comparison, and phylogenetic analysis of the 16S rRNA sequence variants obtained in this study suggest that Tunisian dromedaries are infected by more than one novel Anaplasma strain genetically related to A. platys. CONCLUSIONS: This study reports the presence of novel Anaplasma sp. strains genetically related to A. platys in dromedaries from various bioclimatic areas of Tunisia. Findings raise new concerns about the specificity of the direct and indirect diagnostic tests routinely used to detect different Anaplasma species in ruminants and provide useful molecular information to elucidate the evolutionary history of bacterial species related to A. platys. PMID- 26517488 TI - Outbreak of Chikungunya virus in the north Caribbean area of Colombia: clinical presentation and phylogenetic analysis. AB - INTRODUCTION: The Caribbean area of Colombia has been severely affected by a Chikungunya virus (CHIKV) outbreak since 2014. METHODOLOGY: The study was carried out on 100 patients during a fever outbreak from August to September 2014 in two small rural villages in the northern Caribbean area of Colombia. The molecular assays performed by reverse transcription polymerase chain reaction (RT-PCR) on acute patient sera were collected within one to five days of the appearance of symptoms. Sequence analyses were carried out based on phylogenetic analyses of genes NS1 and E2. For serological assays, 49 (49%) patients at >= 6 days of disease onset were tested with NovaLisa Chikungunya IgG/IgM u-capture enzyme linked immunosorbent assay (ELISA). RESULTS: The main signs or symptoms associated with Chikungunya infection were arthralgia of the lower limbs (96%), fever (91%), arthralgia of the upper limbs (85%), rash (64%), and headache (57%). Ninety-four percent (46/49) of patients were positive for either IgM or IgG; the remaining three (6%) patients were seronegative. Viral loads were detected in 25 patients. Based on phylogenetic analysis of NS1 and E2, the characterization of the Colombian CHIKV indicated that it was a strain closely related to the British Virgin Islands strain and to the Asian genotype. CONCLUSIONS: This study shows the phylogenetic and clinical description of CHIKV in Colombia. The main symptoms shown were: arthralgia, fever, and rash. CHIKV sequences detected in Colombian patients were within the Asian genotype and closely related to the British Virgin Islands strain. PMID- 26517489 TI - A hospital based pilot study on Epstein-Barr virus in suspected infectious mononucleosis pediatric patients in India. AB - INTRODUCTION: Infectious mononucleosis (IM) caused by the Epstein-Barr virus (EBV) is commonly diagnosed by detection of antibodies in the patient's sera. Differentiation of acute from chronic and differential diagnosis of EBV-induced IM from IM-like syndrome caused by human cytomegalovirus (CMV) is important. The objective of this study was to standardize and use polymerase chain reaction (PCR) for diagnosis of EBV and evaluate it against enzyme-linked immunosorbent assay (ELISA). METHODOLOGY: ELISA for detection of IgM and IgG antibodies to viral capsid antigen (VCA) and PCR targeting the VCA and EBNA1 gene of EBV and mtrII gene of CMV were performed on180 peripheral blood samples collected from 180 patients with suspected IM. The analytical sensitivity of PCR was evaluated against that of ELISA. RESULTS: Using the standard serological profile as the reference, the EBV-VCA gene was detected in 41 (95%) of 45 samples collected from patients with early primary infections, in 41 (54%) of 75 with recent primary infections, and in7 (17%) of 39 with past infections. The result of VCA PCR was statistically significant in virus detection during early or primary stage of infection. Nineteen (49%) EBV-seropositive samples were positive for CMV by PCR. All control samples tested negative for both VCA and EBNA1by PCR. CONCLUSIONS: VCA PCR is sensitive for the detection of EBV DNA in the early or primary stage of infection and can be considered a reliable method to rule out the cross reactivity and differential diagnosis of EBV-induced IM from IM-like syndrome. PMID- 26517490 TI - Clinical report of serious complications associated with measles pneumonia in children hospitalized at Shengjing hospital, China. AB - INTRODUCTION: Despite tremendous progress made toward elimination, measles continues to pose a great threat to the health of children in developing countries. The objective of this study was to summarize and analyze the clinical characteristics and treatment experience of serious complications of measles pneumonia in children. METHODOLOGY: The study group comprised 58 infants with severe measles pneumonia who were admitted to the Second Pediatric Intensive Care Unit, Shengjing Hospital of China Medical University, from December 2013 through May 2014. The clinical characteristics of complications such as hypoxemia, acute respiratory distress syndrome (ARDS), sepsis, pneumothorax, multiple organ dysfunction syndrome (MODS), and intracranial infection were retrospectively analyzed; in addition, the death cases were summarized and analyzed. RESULTS: The 58 infants experienced the following: hypoxemia, 100%; ARDS, 21%; sepsis, 34%; pneumothorax, 14%; MODS, 16%; and intracranial infection, 9%. A total of 7 infants developed a secondary bacterial infection, and 12 infants received mechanical ventilation (5 with high-frequency mechanical ventilation and 3 with mechanical ventilation and NO inhalation); the average duration of mechanical ventilation was 10.08 days, and 3 infants expired. CONCLUSIONS: Children with measles pneumonia may experience multiple serious complications, among which ARDS and pneumothorax are particularly serious. If a patient's condition changes abruptly, it is crucial to promptly respond to the change and to administer mechanical ventilation and appropriate antibiotics. For patients with a severe pneumothorax, and especially those with severe mediastinal emphysema, timely, continuous, retrosternal, closed thoracic drainage can effectively relieve compression. PMID- 26517491 TI - Expression of Toll-like receptor (TLR) 2 and TLR4 in the livers of mice infected by Clonorchis sinensis. AB - INTRODUCTION: Clonorchis sinensis is one of the most important foodborne pathogens in humans, and can cause biliary diseases such as gallstones, cholecystitis, cholangitis, and cholangiocarcinoma. Toll-like receptors (TLRs) as sensors are crucial to initiating both innate and adaptive immune defenses against pathogens. However, little is known about the hepatic expression of TLRs of hosts induced by C. sinensis infection. METHODOLOGY: In the present study, the expression and distribution of TLR2 and TLR4 were investigated in a mouse model of clonorchiasis on days 28, 56, 84, and 112 post-infection (PI) using real-time quantitative reverse transcription polymerase chain reaction (PCR) and immunohistochemically staining, respectively. The levels of cytokines that are mediated by TLR2 and TLR4 were also evaluated using a cytometric bead array. RESULTS: Results showed that the transcripts of TLR2 and TLR4 were upregulated on day 28 PI in C. sinensis-infected mice compared with non-infected ones (p < 0.01). In addition, their proteins were strongly immunohistochemically positive in the cytoplasm and membrane of endothelial cells, fibroblasts, and biliary epithelium cells of C. sinensis-infected mice. The levels of interleukin (IL)-4, IL-10, tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) were increased with activation of TLR2 and TLR4. CONCLUSIONS: The expression of TLR2 and TLR4 is upregulated against C. sinensis infection, which suggests that TLR2 and TLR4 might be involved in immune responses during C. sinensis infection. PMID- 26517492 TI - Minor Salmonella: potential pathogens in eggs in Algeria. AB - INTRODUCTION: Salmonellosis is one of the major foodborne diseases known to be closely related to the consumption of contaminated eggs, infected poultry, and poultry products. Control and survey of the poultry chain are the key elements and the most critical steps in the prevention of human transmission of Salmonella. METHODOLOGY: This study was carried out in East Algeria on 150 eggs meant for consumption collected from mini-markets and immediately tested for Salmonella using standard methods (ISO AFNOR 6579 modified in 2002). Briefly, the shell surfaces were carefully wiped using sterile appropriated tissues while the white and yellow yolks were separated. All 10 samples were pooled together and a total of 45 samples were carefully analyzed. RESULTS: A contamination rate of 4.4% was found, and two strains of Salmonella bradford were isolated from white and yellow yolks. The results showed that XLT4 was the best medium for Salmonella isolation from yolks. Screening for other Salmonella in parental chickens using an enzyme-linked immunosorbent assay (ELISA) test revealed seropositive cases of Salmonella enteritidis at the top of the poultry production pyramid. CONCLUSIONS: Occurrence of Salmonella in yolks and seropositive results for S. in parental chickens is a serious and potential danger to public health. Radical and preventive measures must be taken at the critical points to control and to avoid human transmission. These measures must be installed at all levels of egg production through the application of appropriate and strict regulations, and use of good hygienic practices in transport, storage, and food preparation. PMID- 26517493 TI - Clonal relatedness and resistance patterns of Salmonella Corvallis from poultry carcasses in a Brazilian slaughterhouse. AB - INTRODUCTION: Salmonella is a major cause of foodborne disease, and poultry products are important contributors to the transmission of this zoonotic pathogen. Although considered to be rare in most countries, Salmonella Corvallis has been reported in specific geographic areas isolated from both human and non human sources. The aim of this study was to report the occurrence, the antimicrobial resistance profiles including the extended-spectrum beta-lactamase (ESBL) production, and the clonal relatedness of S. Corvallis strains. METHODOLOGY: A total of 132 fragments of poultry carcasses from a slaughterhouse in Sao Paulo State, Brazil, were collected at different stages of the manufacturing process (post-bleeding, post-plucking, and post-chilling) and analyzed for the presence of Salmonella. Antimicrobial resistance was determined by disc diffusion method and Etest. Clonal relatedness was determined by pulsed field gel electrophoresis (PFGE). RESULTS: Among the 272 Salmonella strains recovered, fourteen were S. Corvallis. Ten (71.4%) showed ESBL production and resistance to at least three antimicrobial agents. Nalidixic acid resistance and reduced ciprofloxacin susceptibility was verified in four (28.6%) strains. PFGE analyses showed that all the S. Corvallis strains belonged to the same pulsotype. CONCLUSION: This study identified genetically related S. Corvallis strains exhibiting ESBL production and reduced susceptibility to quinolone. The results suggest the need to improve the sanitary conditions in the slaughterhouse. Moreover, from a public health perspective, continuous surveillance on Salmonella is needed to control the dissemination of this important zoonotic pathogen and its resistance determinants. PMID- 26517494 TI - Poliovirus and other enteroviruses in children infected with intestinal parasites in Nigeria. AB - INTRODUCTION: Poliovirus, an enterovirus, still persists in Nigeria despite the global efforts tailored towards its eradication. This study aimed to assess the impacts of poliovirus and other enteroviruses on the susceptibility of individuals to intestinal parasite infections. METHODOLOGY: A cross-sectional study on the prevalence of intestinal parasites was conducted on two-sample stool specimens of 717 Nigerian children (between 1 and 19 years of age) whose poliovirus/other enteroviruses infection status had been determined. RESULTS: The overall prevalence of Sabin poliovirus and other related enteroviruses infections were 6.6% and 13.8%, respectively. The prevalence of Ascaris lumbricoides was significantly higher than that of other intestinal parasites (p < 0.05), with children in the 0-4 year age group being the most predisposed age group to intestinal parasitic infection (OR = 11.7, CI = 9.2-15.0). While the prevalence of all species of parasites except S. mansoni showed no significant variations in children with Sabin poliovirus (p > 0.05), the prevalence of hookworms and Taenia spp. was significantly higher in children with other enteroviral infections (p < 0.05). CONCLUSIONS: The high risk of children of acquiring enteroviral infection through some intestinal parasites is an indication of possible association of the parasites in a more poliovirus-endemic population. A combined intervention approach for the two infections is advocated. PMID- 26517495 TI - Secondary hemophagocytic lymphohistiocytosis in children with brucellosis: report of three cases. AB - Brucellosis is a systemic zoonotic infectious disease that may cause fever, fatigue, sweating, arthritis, hepatosplenomegaly, cytopenia, and lymphadenopathy. It continues to be an important health problem worldwide. Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever, hepatosplenomegaly, cytopenias, high serum levels of ferritin and triglycerides, low serum fibrinogen levels, and hemophagocytosis in bone marrow, lymph nodes, spleen, or liver. Hemophagocytic lymphohistiocytosis associated with brucellosis is a very rare condition in the pediatric age group. Here, three pediatric cases of secondary HLH associated with brucellosis are reported. Hemophagocytic lymphohistiocytosis should be considered in patients with brucellosis having cytopenias. Hemophagocytosis in brucellosis seems to be cured with appropriate antibiotics and intravenous immunoglobulin. PMID- 26517496 TI - Mutant prevention concentration of tigecycline for Klebsiella pneumoniae isolates with four different resistance statuses. PMID- 26517498 TI - Modulatory effect of iron chelators on adenosine deaminase activity and gene expression in Trichomonas vaginalis. AB - Trichomonas vaginalis is a flagellate protozoan that parasitises the urogenital human tract and causes trichomoniasis. During the infection, the acquisition of nutrients, such as iron and purine and pyrimidine nucleosides, is essential for the survival of the parasite. The enzymes for purinergic signalling, including adenosine deaminase (ADA), which degrades adenosine to inosine, have been characterised in T. vaginalis. In the evaluation of the ADA profile in different T. vaginalis isolates treated with different iron sources or with limited iron availability, a decrease in activity and an increase in ADA gene expression after iron limitation by 2,2-bipyridyl and ferrozine chelators were observed. This supported the hypothesis that iron can modulate the activity of the enzymes involved in purinergic signalling. Under bovine serum limitation conditions, no significant differences were observed. The results obtained in this study allow for the assessment of important aspects of ADA and contribute to a better understanding of the purinergic system in T. vaginalis and the role of iron in establishing infection and parasite survival. PMID- 26517497 TI - Lutzomyia longipalpis urbanisation and control. AB - Since the description of Lutzomyia longipalpis by Lutz and Neiva more than 100 years ago, much has been written in the scientific literature about this phlebotomine species. Soares and Turco (2003) and Lainson and Rangel (2005) have written extensive reviews focused on vector-host-parasite interactions and American visceral leishmaniasis ecology. However, during the last two decades, the success of Lu. longipalpis in colonising urban environments and its simultaneous geographical spreading have led to new theoretical and operational questions. Therefore, this review updates the general information about this species and notes the more challenging topics regarding the new scenario of urbanisation-spreading and its control in America. Here, we summarise the literature on these issues and the remaining unsolved questions, which pose recommendations for operational research. PMID- 26517499 TI - Yellow fever impact on brown howler monkeys (Alouatta guariba clamitans) in Argentina: a metamodelling approach based on population viability analysis and epidemiological dynamics. AB - In South America, yellow fever (YF) is an established infectious disease that has been identified outside of its traditional endemic areas, affecting human and nonhuman primate (NHP) populations. In the epidemics that occurred in Argentina between 2007-2009, several outbreaks affecting humans and howler monkeys (Alouatta spp) were reported, highlighting the importance of this disease in the context of conservation medicine and public health policies. Considering the lack of information about YF dynamics in New World NHP, our main goal was to apply modelling tools to better understand YF transmission dynamics among endangered brown howler monkey (Alouatta guariba clamitans) populations in northeastern Argentina. Two complementary modelling tools were used to evaluate brown howler population dynamics in the presence of the disease: Vortex, a stochastic demographic simulation model, and Outbreak, a stochastic disease epidemiology simulation. The baseline model of YF disease epidemiology predicted a very high probability of population decline over the next 100 years. We believe the modelling approach discussed here is a reasonable description of the disease and its effects on the howler monkey population and can be useful to support evidence based decision-making to guide actions at a regional level. PMID- 26517500 TI - Osteoporosis Diagnosis and Management in Long-Term Care Facility. AB - BACKGROUND: Contemporary estimates of the prevalence of diagnosed osteoporosis among long-term care facility residents are limited. METHODS: This chart review collected data between April 1, 2012 and August 31, 2013 for adult (age >= 30 years) residents of 11 long-term care facilities affiliated with the Louisiana State University Health Sciences Center in the New Orleans metropolitan area. Data (demographics; comorbidities; osteoporosis diagnosis, risk factors, diagnostic assessments, treatments; fracture history; fall risk; activities of daily living) were summarized. Data for residents with and without diagnosed osteoporosis were compared using chi tests and t tests. RESULTS: The study included 746 residents (69% women, mean [SD] age: 76.3 [13.9] years, median length of stay approximately 18.5 months). An osteoporosis diagnosis was recorded for 132 residents (18%), 30% of whom received a pharmacologic osteoporosis therapy. Fewer than 2% of residents had bone mineral density assessments; 10% had previous fracture. Calcium and vitamin D use was more prevalent in residents with diagnosed osteoporosis compared with other residents (calcium: 49% versus 12%, vitamin D: 52% versus 28%; both P < 0.001). Over half (304/545) of assessed residents had a high fall risk. Activities of daily living were similarly limited regardless of osteoporosis status. CONCLUSIONS: The prevalence of diagnosed osteoporosis was higher than previously reported for long-term care residents, but lower than epidemiologic estimates of osteoporosis prevalence for the noninstitutional U.S. POPULATION: In our sample, osteoporosis diagnostic testing was rare and treatment rates were low. Our results suggest that osteoporosis may be underdiagnosed and undertreated in long-term care settings. PMID- 26517501 TI - Prognostic Significance of Secreted Frizzled-Related Protein 2 Expression in Cytogenetically Normal Primary Acute Myeloid Leukemia. AB - BACKGROUND: Deregulation of secreted frizzled-related protein 2 (sFRP2) has been found in many types of cancer. However, the pattern of sFRP2 expression in acute myeloid leukemia (AML) is still unclear. METHODS: This study aimed to validate the prognostic significance of sFRP2 expression in 54 older patients with cytogenetic normal acute myeloid leukemia (CN-AML) using real-time quantitative polymerase chain reaction. RESULTS: sFRP2 expression was decreased markedly in patients compared with controls (P < 0.001). No correlation was found between sFRP2 gene expression and WBCs, hemoglobin, platelets, FAB type, NMP1 and FLT3/ITD mutations at diagnosis. All patients were treated with standard induction chemotherapy. Patients with high sFRP2 expression had higher incidence of complete remission rate (P = 0.04) and better overall survival (P = 0.026). Multivariate analysis revealed that high sFRP2 expression was a prognostic factor for older patients with CN-AML. CONCLUSIONS: This study demonstrated that sFRP2 gene expression at diagnosis had an impact on outcome of elderly CN-AML patients. PMID- 26517502 TI - Transpulmonary Thermodilution-Based Management of Neurogenic Pulmonary Edema After Subarachnoid Hemorrhage. AB - Neurogenic pulmonary edema (NPE) is a potentially catastrophic but treatable systemic event after subarachnoid hemorrhage (SAH). The development of NPE most frequently occurs immediately after SAH, and the severity is usually self limiting. Despite extensive research efforts and a breadth of collective clinical experience, accurate diagnosis of NPE can be difficult, and effective hemodynamic treatment options are limited. Recently, a bedside transpulmonary thermodilution device has been introduced that traces physiological patterns consistent with current theories regarding the mechanism (hydrostatic or permeability PE) of NPE. This article provides an overview of the clinical usefulness of the advanced technique for use in the neurointensive care unit for the diagnosis and management of post-SAH NPE. PMID- 26517503 TI - Gold Thread Acupuncture for a Headache. PMID- 26517504 TI - Hughes-Stovin Syndrome Presenting With Hematuria. PMID- 26517505 TI - Bizarre Radiographic Finding in a Female Soldier. PMID- 26517506 TI - Growth control of sessile microbubbles in PDMS devices. AB - In a microfluidic environment, the presence of bubbles is often detrimental to the functionality of the device, leading to clogging or cavitation, but microbubbles can also be an indispensable asset in other applications such as microstreaming. In either case, it is crucial to understand and control the growth or shrinkage of these bodies of air, in particular in common soft lithography devices based on polydimethylsiloxane (PDMS), which is highly permeable to gases. In this work, we study the gas transport into and out of a bubble positioned in a microfluidic device, taking into account the direct gas exchange through PDMS as well as the transport of gas through the liquid in the device. Hydrostatic pressure regulation allows for the quantitative control of growth, shrinkage, or the attainment of a stable equilibrium bubble size. We find that the vapor pressure of the liquid plays an important role for the balance of gas transport, accounting for variability in experimental conditions and suggesting additional means of bubble size control in applications. PMID- 26517507 TI - Review on microbial degradation of aflatoxins. AB - Aflatoxin (AF) contamination presents one of the most insidious challenges to combat, in food safety. Its adulteration of agricultural commodities presents an important safety concern as evident in the incidences of its health implication and economic losses reported widely. Due to the overarching challenges presented by the contamination of AFs in foods and feeds, there is an urgent need to evolve cost-effective and competent strategies to combat this menace. In our review, we tried to appraise the cost-effective methods for decontamination of AFs. We identified the missing links in adopting microbial degradation as a palliative to decontamination of AFs and its commercialization in food and feed industries. Cogent areas of further research were also highlighted in the review paper. PMID- 26517508 TI - LGR5 regulates pro-survival MEK/ERK and proliferative Wnt/beta-catenin signalling in neuroblastoma. AB - LGR5 is a marker of normal and cancer stem cells in various tissues where it functions as a receptor for R-spondins and increases canonical Wnt signalling amplitude. Here we report that LGR5 is also highly expressed in a subset of high grade neuroblastomas. Neuroblastoma is a clinically heterogenous paediatric cancer comprising a high proportion of poor prognosis cases (~40%) which are frequently lethal. Unlike many cancers, Wnt pathway mutations are not apparent in neuroblastoma, although previous microarray analyses have implicated deregulated Wnt signalling in high-risk neuroblastoma. We demonstrate that LGR5 facilitates high Wnt signalling in neuroblastoma cell lines treated with Wnt3a and R spondins, with SK-N-BE(2)-C, SK-N-NAS and SH-SY5Y cell-lines all displaying strong Wnt induction. These lines represent MYCN-amplified, NRAS and ALK mutant neuroblastoma subtypes respectively. Wnt3a/R-Spondin treatment also promoted nuclear translocation of beta-catenin, increased proliferation and activation of Wnt target genes. Strikingly, short-interfering RNA mediated knockdown of LGR5 induces dramatic Wnt-independent apoptosis in all three cell-lines, accompanied by greatly diminished phosphorylation of mitogen/extracellular signal-regulated kinases (MEK1/2) and extracellular signal-regulated kinases (ERK1/2), and an increase of BimEL, an apoptosis facilitator downstream of ERK. Akt signalling is also decreased by a Rictor dependent, PDK1-independent mechanism. LGR5 expression is cell cycle regulated and LGR5 depletion triggers G1 cell-cycle arrest, increased p27 and decreased phosphorylated retinoblastoma protein. Our study therefore characterises new cancer-associated pathways regulated by LGR5, and suggest that targeting of LGR5 may be of therapeutic benefit for neuroblastomas with diverse etiologies, as well as other cancers expressing high LGR5. PMID- 26517509 TI - Iron deficient erythropoiesis might play key role in development of anemia in cancer patients. AB - INTRODUCTION: Multifactorial pathogenesis is involved in anemia of cancer patients and defining the causes of anemia is not always simple. METHODS: The incidence of anemia among 4 major cancers (gastric, colorectal, lung cancer and hepatocellular carcinoma), and biochemical features of anemia using ferritin, CRP, hepcidin and soluble transferrin receptor (sTfR) were assessed. Anemia was defined either by hemoglobin (Hb) <=11 g/dL or a drop of Hb 2 g/dL or more during anticancer treatment. RESULTS: Among the 345 patients including 152 lung cancer, 101 gastric cancer, 69 colorectal cancer and 23 hepatocellular carcinoma, 49 patients (14.2%) had anemia at their initial diagnosis of cancer. During treatment, 129 (37.4%) experienced anemia, and 34 (26.4%) were treated mostly by transfusion. Biochemical feature of anemia was examined with 39 patients' samples. When comparing to the reference value from general population, cancer patients showed numerically higher ferritin, sTfR, CRP and hepcidin level. Among the cancer patients, anemic patients had significantly higher ferritin (p = 0.050) and sTfR (p = 0.009) level compared to non-anemic patients. CONCLUSION: Anemia is a common issue in cancer patients and is largely undertreated with sub optimal diagnoses of cause. The rates of anemia increase significantly during anti-cancer treatment and appear to be largely associated with iron deficiency. PMID- 26517510 TI - Heterogeneous glioblastoma cell cross-talk promotes phenotype alterations and enhanced drug resistance. AB - Glioblastoma multiforme is the most lethal of brain cancer, and it comprises a heterogeneous mixture of functionally distinct cancer cells that affect tumor progression. We examined the U87, U251, and U373 malignant cell lines as in vitro models to determine the impact of cellular cross-talk on their phenotypic alterations in co-cultures. These cells were also studied at the transcriptome level, to define the mechanisms of their observed mutually affected genomic stability, proliferation, invasion and resistance to temozolomide. This is the first direct demonstration of the neural and mesenchymal molecular fingerprints of U87 and U373 cells, respectively. U87-cell conditioned medium lowered the genomic stability of U373 (U251) cells, without affecting cell proliferation. In contrast, upon exposure of U87 cells to U373 (U251) conditioned medium, U87 cells showed increased genomic stability, decreased proliferation rates and increased invasion, due to a plethora of produced cytokines identified in the co-culture media. This cross talk altered the expression 264 genes in U87 cells that are associated with proliferation, inflammation, migration, and adhesion, and 221 genes in U373 cells that are associated with apoptosis, the cell cycle, cell differentiation and migration. Indirect and direct co-culturing of U87 and U373 cells showed mutually opposite effects on temozolomide resistance. In conclusion, definition of transcriptional alterations of distinct glioblastoma cells upon co culturing provides better understanding of the mechanisms of glioblastoma heterogeneity, which will provide the basis for more informed glioma treatment in the future. PMID- 26517511 TI - High incidence of MYC and BCL2 abnormalities in mantle cell lymphoma, although only MYC abnormality predicts poor survival. AB - The incidence and prognostic role of MYC and BCL2 rearrangements in mature B-cell lymphomas have been extensively studied, except the infrequent mantle cell lymphoma (MCL). Here, we analyzed the MYC and BCL2 abnormalities and other cytogenetic aberrations by fluorescence in situ hybridization (FISH) in 50 MCL patients with bone marrow involvement. Eighteen patients (36.0%) had MYC gains and/or amplifications, and twelve patients (24.0%) had BCL2 gains and/or amplifications. Among the 18 patients with MYC abnormality, four had simultaneous MYC translocations, but no BCL2 translocation was detected among patients with BCL2 abnormality. Only two patients (4.0%) had both MYC and BCL2 abnormalities. The patients with a MYC abnormality had a significantly higher tumor burden, a higher percentage of medium/high risk MIPI group and genomic instability compared to those without this abnormality. However, no significant difference was observed between patients with or without a BCL2 abnormality in terms of clinical and cytogenetic factors. Patients with a MYC abnormality had poorer progress-free survival (PFS) (9.0 vs. 48.0 months, p = .000) and overall survival (OS) (12.0 vs. 94.5 months, p = .000), but the presence of a BCL2 abnormality did not significantly influence either PFS or OS. In multivariate analysis, the MYC abnormality was the independent adverse factor for both PFS and OS, and intensive chemotherapy did not improve the outcome of these patients. Thus, the presence of a MYC but not BCL2 abnormality predicted the poor survival of MCL patients, and a new treatment strategy should be developed for these patients. PMID- 26517512 TI - The copy number of Epstein-Barr virus latent genome correlates with the oncogenicity by the activation level of LMP1 and NF-kappaB. AB - A tumor model that Epstein-Barr virus (EBV) latent infection facilitated the tumorigenicity was previously established using the Maxi-EBV system. In the present approach, EBV-lost cell clones demonstrated significantly decreased tumorigenesis. On the other hand, the LMP1 gene in Maxi-EBV genome was replaced by that of nasopharyngeal carcinoma origin. The resultant cell line, 293-1/NL showed much lower malignancy than the original 293-EBV. The result was opposite to our expectation. The change of 293 sublineage cells for EBV harboring also got similar result. To seek the underlying reason, the copy number of EBV genome in all the cell lines was detected. The result indicated that 293-EBV contained about 4.5-fold higher EBV copies than 293-1/NL did. Parallel EBV genomes led to relatively stable copies in different 293 sublineages, suggesting the viral genome structure is a factor for the sustainability of EBV's copy number. Moreover, the LMP1 transcription in high copy-containing cells showed abnormally high level. Furthermore, the main LMP1-driven pathway, transcription factor NF kappaB, was highly activated in high-copy cells. Here we first manifest by experimental model that the copy number of EBV latent genome correlates with the viral pathogenesis, which depends on the activation level of LMP1 and NF-kappaB. Overall, both the presence and amount of EBV genome are crucial for the viral oncogenicity. PMID- 26517513 TI - Disulfiram inhibits TGF-beta-induced epithelial-mesenchymal transition and stem like features in breast cancer via ERK/NF-kappaB/Snail pathway. AB - Disulfiram (DSF), an anti-alcoholism drug, has been reported as an inhibitor of NF-kappaB. NF-kappaB is involved in epithelial-mesenchymal transition (EMT) and self-renewal of breast cancer stem cells (CSCs). In this study, we treated MCF-7 and MDA-MB-231 breast cancer cells with TGF-beta to induce EMT and cancer stem like features and studied whether DSF can reverse this process. We found that DSF inhibited TGF-beta induced EMT in breast cancer cells in a dose-dependent manner. Also, DSF inhibited EMT-associated stem-like features, migration and invasion of tumor cells as well as tumor growth in xenograft model. The activation of NF kappaB was linked with EMT and stem-like cells. We conclude that DSF can suppress NF-kappaB activity and downregulate ERK/NF-kappaB/Snail pathway, leading to reverse EMT and stem-like features. Our data suggest that DSF inhibits EMT and stem-like properties in breast cancer cells associated with inhibition of the ERK/NF-kappaB/Snail pathway. PMID- 26517514 TI - Mutual regulation between CHD5 and EZH2 in hepatocellular carcinoma. AB - Chromodomain helicase DNA binding protein 5 (CHD5) acts as a tumor suppressor in many cancers. In the present study, we demonstrated that reduced levels of CHD5 in hepatocellular carcinoma (HCC) tissues were significantly associated with metastasis and poor prognosis. Gain-of-function assays revealed that CHD5 suppressed motility and invasion of HCC cells. Subsequent investigations showed that CHD5 was epigenetically silenced by polycomb repressive complex 2 (PRC2) mediated the trimethylation of histone H3 at lysine 27 (H3K27me3) in HCC cells. Furthermore, overexpression of CHD5 repressed enhancer of zeste homolog 2 (EZH2) and activated PRC2 target genes, such as p16 and p21. Chromatin immunoprecipitation and luciferase reporter assays also showed that CHD5 and EZH2 bind to each other's promoters and inhibit transcription. These findings uncovered, for the first time, a mutual suppression regulation between CHD5 and EZH2, which may provide new insights into their potential therapeutic significance for HCC. PMID- 26517515 TI - The BH3-mimetic gossypol and noncytotoxic doses of valproic acid induce apoptosis by suppressing cyclin-A2/Akt/FOXO3a signaling. AB - Previously we reported that valproic acid (VPA) acts in synergy with GOS to enhance cell death in human DU145 cells. However, the underlying mechanism remains elusive. In this study, we observed that such synergistic cytotoxicity of GOS and VPA could be extended to human A375, HeLa, and PC-3 cancer cells. GOS and VPA co-treatment induced robust apoptosis as evidenced by caspase-8/-9/-3 activation, PARP cleavage, and nuclear fragmentation. GOS and VPA also markedly decreased cyclin A2 protein expression. Owing to the reduction of cyclin A2, Akt signaling was suppressed, leading to dephosphorylation of FOXO3a. Consequently, FOXO3a was activated and the expression of its target genes, including pro apoptotic FasL and Bim, was upregulated. Supporting this, FOXO3a knockdown attenuated FasL and Bim upregulation and apoptosis induction in GOS+VPA-treated cells. Furthermore, blocking proteasome activity by MG132 prevented the downregulation of cyclin A2, dephosphorylation of Akt and FOXO3a, and induction of apoptosis in cells co-treated with GOS and VPA. In mouse model, GOS and VPA combination significantly inhibited the growth of A375 melanoma xenografts. Our findings indicate that GOS and VPA co-treatment induces apoptosis in human cancer cells by suppressing the cyclin-A2/Akt/FOXO3a pathway. PMID- 26517516 TI - Identification of the beta-catenin/JNK/prothymosin-alpha axis as a novel target of sorafenib in hepatocellular carcinoma cells. AB - Sorafenib is a kinase inhibitor used as anticancer drug against various human tumors, including advanced hepatocellular carcinoma (HCC). beta-Catenin and prothymosin alpha (PTMA) are overexpressed in HCC and other tumors. Previous studies have shown that PTMA expression modulates the response of HCC cells to sorafenib. However, the underlying mechanism of PTMA activity in this context remains unclear. We show here that sorafenib inhibits both beta-catenin and PTMA in a dose-dependent manner. Silencing beta-catenin reduces PTMA level and sensitizes HCC cells to sorafenib. In contrast, ectopic expression of beta catenin induces PTMA expression and cell resistance to the drug. Sorafenib inhibits PTMA expression at the transcriptional level by inhibiting the beta catenin pathway. Nucleotide deletion analysis of the PTMA gene promoter reveals that a DNA segment lying 1,500-1,600 bp upstream of the PTMA transcription start site represents an AP-1-binding site that is critical for beta-catenin modulation of gene transcription in response to sorafenib. In addition, chemical inhibitors that target JNK abrogate beta-catenin/AP-1 binding to the endogenous PTMA gene and reduces PTMA transcription and protein expression. Silencing of beta-catenin or c-Fos induces similar effects on gene regulation and these are reversed by ectopic expression of beta-catenin. Mutations in the PTMA promoter at the predicted beta-catenin/AP-1 binding site partly abrogate sorafenib's effects on PTMA transcription. These results indicate that PTMA is induced by the oncoprotein beta-catenin and protects HCC cells against sorafenib-induced cell death. The beta-catenin/JNK/PTMA axis may thus represent a novel target for chemotherapy against HCC. PMID- 26517517 TI - Bone marrow-derived mesenchymal stem cell-secreted IL-8 promotes the angiogenesis and growth of colorectal cancer. AB - Mesenchymal stem cells (MSCs) have recently been shown to home to tumors and contribute to the formation of the tumor-associated stroma. In addition, MSCs can secrete paracrine factors to facilitate tumor progression. However, the involvement of MSC-derived cytokines in colorectal cancer (CRC) angiogenesis and growth has not been clearly addressed. In this study, we report that interleukin 8 (IL-8) was the most highly upregulated pro-angiogenic factor in MSCs co cultured with CRC cells and was expressed at substantially higher levels in MSCs than CRC cells. To evaluate the effect of MSC-derived IL-8 on CRC angiogenesis and growth, we used MSCs that expressed small hairpin (interfering) RNAs (shRNA) targeting IL-8 (shIL-8-MSCs). We found that MSC-secreted IL-8 promoted human umbilical vein endothelial cell (HUVEC) proliferation and migration, tube formation ability and CRC cell proliferation. Additionally, in vivo studies showed that MSCs promoted tumor angiogenesis partially through IL-8. Taken together, these findings suggest that IL-8 secreted by MSCs promotes CRC angiogenesis and growth and can therefore serve as a potential novel therapeutic target. PMID- 26517518 TI - Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling. AB - In breast cancer it has been proposed that the presence of cancer stem cells may drive tumor initiation, progression and recurrences. IL-8, up-regulated in breast cancer, and associated with poor prognosis, increases CSC self-renewal in cell line models. It signals via two cell surface receptors, CXCR1 and CXCR2. Recently, the IL-8/CXCR1 axis was proposed as an attractive pathway for the design of specific therapies against breast cancer stem cells. Reparixin, a powerful CXCR1 inhibitor, was effective in reducing in vivo the tumour-initiating population in several NOD/SCID mice breast cancer models, showing that the selective targeting of CXCR1 and the combination of reparixin and docetaxel resulted in a concomitant reduction of the bulk tumour mass and CSC population. The available data indicate that IL-8, expressed by tumour cells and induced by chemotherapeutic treatment, is a key regulator of the survival and self-renewal of the population of CXCR1-expressing CSC. Consequently, this investigation on the mechanism of action of the reparixin/paclitaxel combination, was based on the observation that reparixin treatment contained the formation of metastases in several experimental models. However, specific data on the formation of breast cancer brain metastases, which carry remarkable morbidity and mortality to a substantial proportion of advanced breast cancer patients, have not been generated. The obtained data indicate a beneficial use of the drug combination reparixin and paclitaxel to counteract brain tumour metastasis due to CSC, probably due to the combined effects of the two drugs, the pro-apoptotic action of paclitaxel and the cytostatic and anti-migratory effects of reparixin. PMID- 26517519 TI - Phenotype and function of CXCR5+CD45RA-CD4+ T cells were altered in HBV-related hepatocellular carcinoma and elevated serum CXCL13 predicted better prognosis. AB - The present study reveals an immunological characterization of circulating and tumor-infiltrating T follicular helper cells (Tfh), namely CXCR5+CD45RA-CD4+ T cells, and their related cytokines in hepatitis B virus-related hepatocellular carcinoma (HCC) patients. In HCC patients, circulating Tfh cells showed a CCR7+ and/or ICOS+ phenotype with increased Th2-like cells and decreased Th1-like and Th17-like subsets. Although the bulk frequency of circulating Tfh cells was not altered in HCC patients, the frequency of infiltrated CXCR5+CD45RA-CD4+ CD3+cells was higher in tumor than in para-tumor tissues, and Th1-like cells were the predominant phenotype. Circulating Tfh cells in HCC patients were defective in the production of IL-21 in vitro, which was in accordance with lower IL-21 levels in tumor tissues than in para-tumor tissues. Serum CXCL13 was increased in HCC patients and associated with recurrence-free survival after hepatectomy. This was confirmed in an additional HCC cohort of 111 patients with up to 5 years follow up. Immunohistochemical staining indicated that the percentage of CXCR5+ or CXCL13+ cells was higher in poorly differentiated than in well-differentiated tumors. In conclusion, patients with HBV-related HCC showed altered phenotypes and impaired function of Tfh cells or subpopulations. CXCL13 could be a potential biomarker for predicting recurrence in HCC patients after hepatectomy. PMID- 26517520 TI - 244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells. AB - The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer(NSCLC). Several EGFR tyrosine kinase inhibitors(TKIs), such as gefitinib, have been used as effective clinical therapies for patients with NSCLC. Unfortunately, acquired resistance to gefitinib commonly occurs after 6-12 months of treatment. The resistance is associated with the appearance of the L858R/T790M double mutation of the EGFR. In our present study, we discovered a compound,referred to as 244-MPT, which could suppress either gefitinib-sensitive or -resistant lung cancer cell growth and colony formation, and also suppressed the kinase activity of both wildtype and double mutant (L858R/T790M) EGFR. The underlying mechanism reveals that 244-MPT could interact with either the wildtype or double-mutant EGFR in an ATP-competitive manner and inhibit activity. Treatment with 244-MPT could substantially reduce the phosphorylation of EGFR and its downstream signaling pathways, including Akt and ERK1/2 in gefitinib sensitive and -resistant cell lines. It was equally effective in suppressing EGFR phosphorylation and downstream signaling in NL20 cells transfected with wildtype, single-mutant (L858R) or mutant (L858R/T790M) EGFR. 244-MPT could also induce apoptosis in a gefitinib-resistant cell line and strongly suppress gefitinib resistant NSCLC tumor growth in a xenograft mouse model. In addition, 244-MPT could effectively reduce the size of tumors in a gefitinib-resistant NSCLC patient-derived xenograft (PDX) SCID mouse model. Overall, 244-MPT could overcome gefitinib-resistance by directly targeting the EGFR. PMID- 26517521 TI - Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma. AB - Melanoma is the most aggressive and deadly form of cutaneous neoplasm due to its propensity to metastasize. Oncogenic BRAF drives sustained activation of the BRAF/MEK/ERK (MAPK) pathway and cooperates with PI3K/AKT/mTOR (PI3K) signaling to induce epithelial to mesenchymal transition (EMT), leading to cell invasion and metastasis. Therefore, targeting these pathways is a promising preventive/therapeutic strategy. We have shown that fisetin, a flavonoid, reduces human melanoma cell invasion by inhibiting EMT. In addition, fisetin inhibited melanoma cell proliferation and tumor growth by downregulating the PI3K pathway. In this investigation, we aimed to determine whether fisetin can potentiate the anti-invasive and anti-metastatic effects of sorafenib in BRAF-mutated melanoma. We found that combination treatment (fisetin + sorafenib) more effectively reduced the migration and invasion of BRAF-mutated melanoma cells both in vitro and in raft cultures compared to individual agents. Combination treatment also effectively inhibited EMT as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin both in vitro and in xenograft tumors. Furthermore, combination therapy effectively inhibited Snail1, Twist1, Slug and ZEB1 protein expression compared to monotherapy. The expression of MMP-2 and MMP 9 in xenograft tumors was further reduced in combination treatment compared to individual agents. Bioluminescent imaging of athymic mice, intravenously injected with stably transfected CMV-luciferase-ires-puromycin.T2A.EGFP-tagged A375 melanoma cells, demonstrated fewer lung metastases following combination treatment versus monotherapy. Our findings demonstrate that fisetin potentiates the anti-invasive and anti-metastatic effects of sorafenib. Our data suggest that fisetin may be a worthy adjuvant chemotherapy for the management of melanoma. PMID- 26517522 TI - Integrin beta3 and LKB1 are independently involved in the inhibition of proliferation by lovastatin in human intrahepatic cholangiocarcinoma. AB - Human intrahepatic cholangiocarcinomas are one of the most difficult cancers to treat. In our study, Lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme-CoA (HMG CoA) reductase inhibitor, demonstrated anticancer properties by inhibiting cancer cell proliferation, cell migration and cell adhesion. Lovastatin inhibited the expressions of transforming growth factor (TGF)-beta1, cyclooxygenase (COX)-2, and intercellular adhesion molecule (ICAM)-1. Furthermore, lovastatin inhibited the expressions of integrin beta1 and integrin beta3 but not integrin alphav or integrin beta5. While Lovastatin's inhibitory effects on TGFbeta1, COX2, and ICAM 1 expression were independently controlled by the tumor suppressor LKB1, integrin beta3 expression was not affected. Lovastatin's inhibitory effect on cell adhesion was associated with the decreased expression of integrin beta3 and cell surface heterodimer integrin alphavbeta3. Quantitative real time PCR, fluorescent microscopy, and cell migration assays all confirmed that Lovastatin inhibits integrin alphavbeta3 downstream signaling including FAK activation, and beta catenin, vimentin, ZO-1, and beta-actin. Overall, Lovastatin reduced tumor cell proliferation and migration by modifying the expression of genes involved in cell adhesion and other critical cellular processes. Our study highlights novel anti cancer properties of Lovastatin and supports further exploration of statins in the context of cholangiocarcinoma therapy. PMID- 26517525 TI - Cancer stemness and progression: mitochondria on the stage. PMID- 26517523 TI - Cross-talk between chronic lymphocytic leukemia (CLL) tumor B cells and mesenchymal stromal cells (MSCs): implications for neoplastic cell survival. AB - Leukemic cells from Chronic Lymphocytic Leukemia (CLL) patients interact with stromal cells of the surrounding microenvironment. Mesenchymal Stromal Cells (MSCs) represent the main population in CLL marrow stroma, which may play a key role for disease support and progression. In this study we evaluated whether MSCs influence in vitro CLL cell survival. MSCs were isolated from the bone marrow of 46 CLL patients and were characterized by flow cytometry analysis. Following co culture of MSCs and leukemic B cells, we demonstrated that MSCs were able to improve leukemic B cell viability, this latter being differently dependent from the signals coming from MSCs. In addition, we found that the co-culture of MSCs with leukemic B cells induced an increased production of IL-8, CCL4, CCL11, and CXCL10 chemokines.As far as drug resistance is concerned, MSCs counteract the cytotoxic effect of Fludarabine/Cyclophosphamide administration in vivo, whereas they do not protect CLL cells from the apoptosis induced by the kinase inhibitors Bafetinib and Ibrutinib. The evidence that leukemic clones are conditioned by environmental stimuli suggest new putative targets for therapy in CLL patients. PMID- 26517524 TI - Co-delivery of cisplatin and paclitaxel by folic acid conjugated amphiphilic PEG PLGA copolymer nanoparticles for the treatment of non-small lung cancer. AB - An amphiphilic copolymer, folic acid (FA) modified poly(ethylene glycol) poly(lactic-co-glycolic acid) (FA-PEG-PLGA) was prepared and explored as a nanometer carrier for the co-delivery of cisplatin (cis-diaminodichloroplatinum, CDDP) and paclitaxel (PTX). CDDP and PTX were encapsulated inside the hydrophobic inner core and chelated to the middle shell, respectively. PEG provided the outer corona for prolonged circulation. An in vitro release profile of the CDDP + PTX encapsulated nanoparticles revealed that the PTX chelation cross-link prevented an initial burst release of CDDP. After an incubation period of 24 hours, the CDDP+PTX-encapsulated nanoparticles exhibited a highly synergistic effect for the inhibition of A549 (FA receptor negative) and M109 (FA receptor positive) lung cancer cell line proliferation. Pharmacokinetic experiment and distribution research shows that nanoparticles have longer circulation time in the blood and can prolong the treatment times of chemotherapeutic drugs. For the in vivo treatment of A549 cells xeno-graft lung tumor, the CDDP+PTX-encapsulated nanoparticles displayed an obvious tumor inhibiting effect with an 89.96% tumor suppression rate (TSR). This TSR was significantly higher than that of free chemotherapy drug combination or nanoparticles with a single drug. For M109 cells xeno-graft tumor, the TSR was 95.03%. In vitro and in vivo experiments have all shown that the CDDP+PTX-encapsulated nanoparticles have better targeting and antitumor effects in M109 cells than CDDP+PTX-loaded PEG-PLGA nanoparticles (p < 0.05). In addition, more importantly, the enhanced anti-tumor efficacy of the CDDP+PTX-encapsulated nanoparticles came with reduced side-effects. No obvious body weight loss or functional changes occurred within blood components, liver, or kidneys during the treatment of A549 and M109 tumor-bearing mice with the CDDP+PTX-encapsulated nanoparticles. Thus, the FA modified amphiphilic copolymer based combination of CDDP and PTX may provide useful guidance for effective and safe cancer chemotherapy, especially in tumors with high FA receptor expression. PMID- 26517527 TI - Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. AB - BACKGROUND: The therapeutic role of 6-mercaptopurine (6-MP) and azathioprine (AZA) remains controversial due to their perceived relatively slow-acting effect and adverse effects. An updated meta-analysis was performed to evaluate the efficacy of these agents for the maintenance of remission in quiescent Crohn's disease. OBJECTIVES: To assess the efficacy of AZA and 6-MP for maintenance of remission in quiescent Crohn's disease. SEARCH METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library from inception to June 30, 2015. SELECTION CRITERIA: Randomized controlled trials of oral azathioprine or 6-mercaptopurine compared to placebo or active therapy involving adult patients (> 18 years) with quiescent Crohn's disease were considered for inclusion. Patients with surgically induced remission were excluded. DATA COLLECTION AND ANALYSIS: At least two authors independently extracted data and assessed study quality using the Cochrane risk of bias tool. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (CI). The primary outcomes was maintenance of remission. Secondary outcomes included steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. All data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. MAIN RESULTS: Eleven studies (881 participants) were included. Comparisons included AZA versus placebo (7 studies, 532 participants), AZA or 6-MP versus mesalazine or sulfasalazine (2 studies, 166 participants), AZA versus budesonide (1 study, 77 participants), AZA and infliximab versus infliximab (1 study, 36 patients), 6-MP versus methotrexate (1 study, 31 patients), and early AZA versus conventional management (1 study, 147 participants). Two studies were rated as low risk of bias. Three studies were rated as high risk of bias for being non-blinded. Six studies were rated as unclear risk of bias. A pooled analysis of six studies (489 participants) showed that AZA (1.0 to 2.5 mg/kg/day) was significantly superior to placebo for maintenance of remission over a 6 to 18 month period. Seventy-three per cent of patients in the AZA group maintained remission compared to 62% of placebo patients (RR 1.19, 95% CI 1.05 to 1.34). The number needed to treat for an additional beneficial outcome was nine. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (327 events) and unclear risk of bias. A pooled analysis of two studies (166 participants) showed no statistically significant difference in the proportion of patients who maintained remission between AZA (1.0 to 2.5 mg/kg/day) or 6-MP (1.0 mg/day) and mesalazine (3 g/day) sulphasalazine (0.5 g/15 kg) therapy. Sixty-nine per cent of patients in the AZA/6-MP group maintained remission compared to 67% of mesalazine/sulphasalazine patients (RR 1.09, 95% CI 0.88 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (113 events) and high or unclear risk of bias. One small study found AZA (2.0 to 2.5 mg/kg/day) to be superior to budesonide (6 to 9 mg/day) for maintenance of remission at one year. Seventy-six per cent (29/38) of AZA patients maintained remission compared to 46% (18/39) of budesonide patients (RR 1.65, 95% CI 1.13 to 2.42). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (47 events) and high risk of bias. One small study found no difference in maintenance of remission rates at one year between combination therapy with AZA (2.5 mg/kg) and infliximab (5 mg/kg every 8 weeks) compared to infliximab monotherapy. Eighty-one per cent (13/16) of patients in the combination therapy group maintained remission compared to 80% (16/20) of patients in the infliximab group (RR 1.02, 95% CI 0.74 to 1.40). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (29 events) and unclear risk of bias. One small study found no difference in maintenance of remission rates at one year between 6-MP (1 mg/day) and methotrexate (10 mg/week). Fifty per cent (8/16) of 6-MP patients maintained remission at one year compared to 53% (8/15) of methotrexate patients (RR 0.94, 95% CI 0.47 to 1.85). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (16 events) and high risk of bias. One study (147 participants) failed to show any significant benefit for early azathioprine treatment over a conventional management strategy. In the early azathioprine treatment group 67% (11-85%) of the trimesters were spent in remission compared to 56% (29-73%) in the conventional management group. AZA when compared to placebo had significantly increased risk of adverse events (RR 1.29, 95% CI 1.02 to 1.64), withdrawal due to adverse events (3.12, 95% CI 1.59 to 6.09) and serious adverse events (RR 2.45, 95% CI 1.22 to 4.90). AZA/6-MP also demonstrated a significantly higher risk of serious adverse events when compared to mesalazine or sulphasalazine (RR 9.37, 95% CI 1.84 to 47.7). AZA/6-MP did not differ significantly from other active therapies with respect to adverse event data. Common adverse events included pancreatitis, leukopenia, nausea, allergic reaction and infection. AUTHORS' CONCLUSIONS: Low quality evidence suggests that AZA is more effective than placebo for maintenance of remission in Crohn's disease. Although AZA may be effective for maintenance of remission its use is limited by adverse effects. Low quality evidence suggests that AZA may be superior to budesonide for maintenance of remission but because of small study size and high risk of bias, this result should be interpreted with caution. No conclusions can be drawn from the other active comparator studies because of low and very low quality evidence. Adequately powered trials are needed to determine the comparative efficacy and safety of AZA and 6-MP compared to other active maintenance therapies. Further research is needed to assess the efficacy and safety of the use of AZA with infliximab and other biologics and to determine the optimal management strategy for patients quiescent Crohn's disease. PMID- 26517526 TI - Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse model. AB - Chromatin acetylation is attributed with distinct functional relevance with respect to gene expression in normal and diseased conditions thereby leading to a topical interest in the concept of epigenetic modulators and therapy. We report here the identification and characterization of the acetylation inhibitory potential of an important dietary flavonoid, luteolin. Luteolin was found to inhibit p300 acetyltransferase with competitive binding to the acetyl CoA binding site. Luteolin treatment in a xenografted tumor model of head and neck squamous cell carcinoma (HNSCC), led to a dramatic reduction in tumor growth within 4 weeks corresponding to a decrease in histone acetylation. Cells treated with luteolin exhibit cell cycle arrest and decreased cell migration. Luteolin treatment led to an alteration in gene expression and miRNA profile including up regulation of p53 induced miR-195/215, let7C; potentially translating into a tumor suppressor function. It also led to down-regulation of oncomiRNAs such as miR-135a, thereby reflecting global changes in the microRNA network. Furthermore, a direct correlation between the inhibition of histone acetylation and gene expression was established using chromatin immunoprecipitation on promoters of differentially expressed genes. A network of dysregulated genes and miRNAs was mapped along with the gene ontology categories, and the effects of luteolin were observed to be potentially at multiple levels: at the level of gene expression, miRNA expression and miRNA processing. PMID- 26517528 TI - Pharmacotherapy of Sickle Cell Disease in Children. AB - Sickle cell disease (SCD) is a potentially devastating and life threatening condition that is caused by an autosomal recessive inherited hemoglobinopathy which results in vaso-occlusive phenomena and hemolysis. The severity of this disorder is widely variable, but overall mortality is increased and life expectancy decreased when compared to the general population. Care of patients with sickle cell disease is largely supportive. In fact, hydroxyurea is the only drug used that modifies disease pathogenesis. Painful vaso-occlusive events are the most common complication experienced by both children and adults with sickle cell disease and hydroxyurea is the only treatment option available to prevent the development of these events. Most events are managed with traditional supportive care measures (i.e. aggressive hydration, antiinflammatory and narcotic analgesics) that have not changed in decades. As such, there is an overwhelming need for both the development of new agents and new approaches to treatment with existing modalities for patients with sickle cell disease. PMID- 26517529 TI - The In-Situ One-Step Synthesis of a PDC Macromolecular Pro-Drug and the Fabrication of a Novel Core-Shell Micell. AB - The development of slow release nano-sized carriers for efficient antineoplastic drug delivery with a biocompatible and biodegradable pectin-based macromolecular pro-drug for tumor therapy has been reported in this study. Pectin-doxorubicin conjugates (PDC), a macromolecular pro-drug, were prepared via an amide condensation reaction, and a novel amphiphilic core-shell micell based on a PDC macromolecular pro-drug (PDC-M) was self-assembled in situ, with pectin as the hydrophilic shell and doxorubicin (DOX) as the hydrophobic core. Then the chemical structure of the PDC macromolecular pro-drug was identified by both Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy ((1)H-NMR), and proved that doxorubicin combined well with the pectin and formed macromolecular pro-drug. The PDC-M were observed to have an unregularly spherical shape and were uniform in size by scanning electron microscopy (SEM). The average particle size of PDC-M, further measured by a Zetasizer nanoparticle analyzer (Nano ZS, Malvern Instruments), was about 140 nm. The encapsulation efficiency and drug loading were 57.82% +/- 3.7% (n = 3) and 23.852% +/-2.3% (n = 3), respectively. The in vitro drug release behaviors of the resulting PDC-M were studied in a simulated tumor environment (pH 5.0), blood (pH 7.4) and a lysosome media (pH 6.8), and showed a prolonged slow release profile. Assays for antiproliferative effects and flow cytometry of the resulting PDC-M in HepG2 cell lines demonstrated greater properties of delayed and slow release as compared to free DOX. A cell viability study against endothelial cells further revealed that the resulting PDC-M possesses excellent cell compatibilities and low cytotoxicities in comparison with that of the free DOX. Hemolysis activity was investigated in rabbits, and the results also demonstrated that the PDC-M has greater compatibility in comparison with free DOX. This shows that the resulting PDC-M can ameliorate the hydrophobicity of free DOX. This work proposes a novel strategy for in-situ one-step synthesis of macromolecular pro-drugs and fabrication of a core-shell micelle, demonstrating great potential for cancer chemotherapy. PMID- 26517530 TI - Autophagy and AML--food for thought. PMID- 26517531 TI - Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis. AB - A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that Gab-cKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti- and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure. PMID- 26517532 TI - c-Abl-p38alpha signaling plays an important role in MPTP-induced neuronal death. AB - Oxidative stress is a major cause of sporadic Parkinson's disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38alpha as a major substrate of c-Abl both in vitro and in vivo and c-Abl-mediated phosphorylation is critical for the dimerization of p38alpha. Furthermore, p38alpha inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl-p38alpha signaling may represent a therapeutic target for PD. PMID- 26517533 TI - Optimal management of low-risk gestational trophoblastic neoplasia. AB - Low-risk gestational trophoblastic neoplasia is a highly curable form of gestational trophoblastic neoplasia that arises largely from molar pregnancy and, on rare occasions, from other types of gestations. Risk is defined as the risk of developing drug resistance as determined by the WHO Prognostic Scoring System. All patients with non-metastatic disease and patients with risk scores <7 are considered to have low-risk disease. The sequential use of methotrexate and actinomycin D is associated with a complete remission rate of 80%. The most commonly utilized regimen for the treatment of patients resistant to single-agent chemotherapy is a multiagent regimen consisting of etoposide, methotrexate, actinomycin D, vincristine and cyclophosphamide. The measurement of human chorionic gonadotropin provides an accurate and reliable tumor marker for diagnosis, monitoring the effects of chemotherapy and follow-up to determine recurrence. Pregnancy is allowed after 12 months of normal serum tumor marker. Pregnancy outcomes are similar to those of normal population. PMID- 26517534 TI - New Genetic Forms of Childhood-Onset Primary Osteoporosis. AB - Recent developments in genetic technology have given us the opportunity to look at diseases in a new and more detailed way. This Mini Review discusses monogenetic forms of childhood-onset primary osteoporosis, with the main focus on osteoporosis caused by mutations in WNT1 and PLS3, two of the most recently discovered genes underlying early-onset osteoporosis. The importance of WNT1 in the accrual and maintenance of bone mass through activation of canonical WNT signaling was recognized in 2013. WNT1 was shown to be a key ligand for the WNT signaling pathway, which is of major importance in the regulation of bone formation. More recently, mutations in PLS3, located on the X chromosome, were shown to be the cause of X-linked childhood-onset primary osteoporosis affecting mainly males. The function of PLS3 in bone metabolism is still not completely understood, but it has been speculated to have an important role in mechanosensing by osteocytes and in matrix mineralization. In this new era of genetics, our knowledge on genetic causes of childhood-onset osteoporosis expands constantly. These discoveries bring new possibilities, but also new challenges. Guidelines are needed to implement this new genetic knowledge to clinical patient care and to guide genetic investigations in affected families. PMID- 26517535 TI - The Impact of Resveratrol on Oxidative Stress Induced by Methotrexate in Rat Ileum Tissue: Evaluation of Biochemical and Histopathological Features and Analysis of Gene Expression. AB - OBJECTIVE: The aim of this study was to assess the impact of resveratrol (RST) on oxidative stress induced by methotrexate in rat ileum tissue. MATERIALS AND METHODS: Twenty-four rats were divided into 4 groups with 6 in each group. Each rat was orally administered the following every day for 30 days: group 1 (MTXG), methotrexate (MTX; 5 mg/kg); group 2 (RMTXG), MTX (5 mg/kg) plus RST (25 mg/kg/day); group 3 (RSTG), RST alone (25 mg/kg/day), and group 4 (controls), distilled water. After the rats had been sacrified, the ilea were removed for the assessment of malondialdehyde (MDA), total glutathione (tGSH) and glutathione peroxidase (GSH-Px). Gene expression analyses for interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO) were also performed. Hematoxylin and eosin-stained paraffin-embedded sections of the ileum were analyzed under a light microscope and the findings were recorded. Statistical analyses of the data were performed using one-way ANOVA. RESULTS: The administration of MTX in group 1 yielded a higher level of MDA (8.33 +/- 2.5 MUmol/g protein, p < 0.001) and lower levels of tGSH (0.97 +/- 0.29 nmol/g protein) and GSH-Px (5.22 +/- 0.35 U/g protein, p < 0.001) compared to the other groups. MTX also increased IL-1beta (40.33 +/- 5.43 gene expression levels), TNF alpha (6.08 +/- 0.59) and MPO gene expression (9 +/- 1.41) in group 1 compared to the controls (11.33 +/- 2.07, 2.15 +/- 0.33 and 3.43 +/- 0.48, respectively, p < 0.001). The impact of RST on IL-1beta, TNF-alpha and MPO gene expression induced by MTX was observed as a reversal of these findings (p < 0.05). Severe inflammation, damage to the villus epithelium and crypt necrosis was observed histopathologically in the MTXG group, whereas only mild inflammation was seen in the RMTXG group. CONCLUSION: In this study, ileal damage caused by MTX was inhibited by RST. PMID- 26517536 TI - A New Therapeutic Era in GCB and ABC Diffuse Large B-cell Lymphoma Molecular Subtypes: A Cell of Origin-Driven Review. AB - In the past 15 years, advances in molecular biology have exposed the genetic and physiopathologic heterogeneity of diffuse large B-cell lymphoma (DLBCL). Subsets of patients have been identified in which current chemoimmunotherapies may not be as efficacious, such as the activated B-cell subtype (ABC). In this review, we present an in-depth study of the differences between the two main DLBCL subsets (germinal center B cell [GCB] and ABC), focusing specifically on their different genetic features, active tumoral pathways, and pathologic features. We also discuss the bridges that have been built from the bench to the forefront of patient care through translational research, including the use of immunohistochemistry versus gene profiling to categorize patients with DLBCL and current clinical trial data pertaining to new possible targeted therapies for patients with these two subtypes of DLBCL. We hope that clinicians use this review as a tool to better understand the complexity of the two more prevalent DLBCL subtypes seen in the day to day practice and update their knowledge in both current and upcoming novel treatment options that can potentially change the outcomes of this population. PMID- 26517537 TI - Functional Link between BRCA1 and BAP1 through Histone H2A, Heterochromatin and DNA Damage Response. AB - BRCA1, a breast and ovarian tumor suppressor, maintains genome stability through its functions in DNA repair, cell-cycle checkpoints, heterochromatin formation and centrosome amplification. BRCA1 interacts with BARD1 to constitute a RING heterodimer-type E3 ubiquitin ligase. BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that also regulates similar cellular events, including cell-cycle control, transcription, chromatin modification and DNA damage response. Germline mutations in BRCA1 predispose individuals to breast, ovarian, fallopian tube, peritoneal, pancreatic and prostate cancers, whereas BAP1 mutations combined with certain types of DNA damage provoke malignant mesothelioma, uveal and cutaneous melanoma, lung adenocarcinoma and renal cell carcinoma. Although BAP1 was initially discovered as a BRCA1-associated protein, recent mass-spectrometric screens of BAP1 interactors failed to detect BRCA1, raising questions about their presumed endogenous interaction. However, in addition to physical interaction, new evidence indicates a functional correlation between the two proteins. This review summarizes BAP1 function in histone modification and the DNA damage response, focusing on BAP1's relevance to BRCA1 function. An understanding of the cooperative functions between BRCA1 and BAP1 may uncover opportunities for new drug targets in a variety of related cancers. PMID- 26517538 TI - Indoleamine 2,3-dioxygenase (IDO): Biology and Target in Cancer Immunotherapies. AB - Indoleamine 2,3-dioxygenase (IDO) is a heme-containing oxidoreductase that catalyzes the initial and rate-limiting step in the breakdown of non-dietary tryptophan. The biology and immunomodulatory role for IDO is discussed in this review with a focus on its interaction with immune cells and its potential therapeutic target in the clinic. IDO has been revealed to be a central regulator of immune responses in a broad variety of physiological and pathological settings, mostly serving as a multifaceted negative feedback mechanism, to self regulate immune responses. IDO is considered a therapeutic target in cancer and the use of IDO inhibitors as single agent or in combination with other treatment modalities are under active investigation. PMID- 26517539 TI - NUP214-RAC1 and RAC1-COL12A1 Fusion in Complex Variant Translocations Involving Chromosomes 6, 7 and 9 in an Acute Myeloid Leukemia Case with DEK-NUP214. AB - DEK-NUP214 gene fusion in acute myeloid leukemia (AML) is associated with poor prognosis. It is most often a sole translocation and more rarely observed as complex chromosomal forms. We describe an AML case with complex karyotype abnormalities involving chromosome bands 6p23, 6q13, 7p22, and 9q34. RNA sequencing analysis revealed that exon 17 of NUP214 (9q34) was fused to exon 2 of RAC1 (7p22). We also detected that the 5'-end of intron 1 of RAC1 was fused with the antisense strand of intron 5 of COL12A1 (6q13). RT-PCR analysis confirmed the expression of DEK-NUP214, NUP214-RAC1, RAC1-COL12A1, NUP214, and RAC1. These results suggest that the 5'- and 3'-ends of NUP214 from the breakpoint in the same locus were fused to RAC1 and DEK, respectively, and the 5'-end of RAC1 was fused to COL12A1. The reading frame of NUP214 was not matched with RAC1; however, high expression of the RAC1 protein was detected by Western blotting. This study identifies the variant complex fusion genesNUP214-RAC1 and RAC1- COL12A1 in a case of AML. PMID- 26517540 TI - Reproducibility and Temporal Structure in Weekly Resting-State fMRI over a Period of 3.5 Years. AB - Resting-state functional MRI (rs-fMRI) permits study of the brain's functional networks without requiring participants to perform tasks. Robust changes in such resting state networks (RSNs) have been observed in neurologic disorders, and rs fMRI outcome measures are candidate biomarkers for monitoring clinical trials, including trials of extended therapeutic interventions for rehabilitation of patients with chronic conditions. In this study, we aim to present a unique longitudinal dataset reporting on a healthy adult subject scanned weekly over 3.5 years and identify rs-fMRI outcome measures appropriate for clinical trials. Accordingly, we assessed the reproducibility, and characterized the temporal structure of, rs-fMRI outcome measures derived using independent component analysis (ICA). Data was compared to a 21-person dataset acquired on the same scanner in order to confirm that the values of the single-subject RSN measures were within the expected range as assessed from the multi-participant dataset. Fourteen RSNs were identified, and the inter-session reproducibility of outcome measures-network spatial map, temporal signal fluctuation magnitude, and between network connectivity (BNC)-was high, with executive RSNs showing the highest reproducibility. Analysis of the weekly outcome measures also showed that many rs fMRI outcome measures had a significant linear trend, annual periodicity, and persistence. Such temporal structure was most prominent in spatial map similarity, and least prominent in BNC. High reproducibility supports the candidacy of rs-fMRI outcome measures as biomarkers, but the presence of significant temporal structure needs to be taken into account when such outcome measures are considered as biomarkers for rehabilitation-style therapeutic interventions in chronic conditions. PMID- 26517542 TI - The potential for non-invasive brain stimulation to improve function after amputation. AB - PURPOSE: Lower limb amputee rehabilitation has traditionally focussed on restoration of gait and balance through use of prosthetic limbs and mobility aids. Despite these efforts, some amputees continue to experience difficulties with mastering prosthetic mobility. Emerging techniques in rehabilitation, such as non-invasive brain stimulation (NIBS), may be an appropriate tool to enhance prosthetic rehabilitation outcomes by promoting "normal" brain reorganisation and function. The purpose of this review is to highlight the potential of NIBS to improve functional outcomes for lower limb amputees. METHODS: To demonstrate the rationale for applying NIBS to amputees, this study will first review literature regarding human motor control of gait, followed by neurophysiological reorganisation of the motor system after amputation and the relationship between brain reorganisation and gait function. We will conclude by reviewing literature demonstrating application of NIBS to lower limb muscle representations and evidence supportive of subsequent functional improvements. RESULTS: Imaging, brain stimulation and behavioural evidence indicate that the cortex contributes to locomotion in humans. Following amputation both hemispheres reorganise with evidence suggesting brain reorganisation is related to functional outcomes in amputees. Previous studies indicate that brain stimulation techniques can be used to selectively promote neuroplasticity of lower limb cortical representations with improvements in function. CONCLUSIONS: We suggest NIBS has the potential to transform lower limb amputee rehabilitation and should be further investigated. Implications for Rehabilitation Despite extensive rehabilitation some amputees continue to experience difficulty with prosthetic mobility Brain reorganisation following amputation has been related to functional outcomes and may be an appropriate target for novel interventions Non-invasive brain stimulation is a promising tool which has potential to improve functional outcomes for lower limb amputees. PMID- 26517541 TI - Prevalence of Cognitive Impairment in Recently Diagnosed Type 2 Diabetes Patients: Are Chronic Inflammatory Diseases Responsible for Cognitive Decline? AB - OBJECTIVE: To estimate the prevalence of cognitive impairment (CI) among patients recently diagnosed with type 2 diabetes (RDD) and to identify any relationships between CI and RDD comorbidities. METHODS: One thousand seven hundred twelve patients with RDD participated in a cross-sectional study. The patients' sociodemographic and clinical data were registered. RESULTS: The sample population had an average age of 51 +/- 11 years, and 63.26% of the patients were female. CI was diagnosed in 38 patients (2.2%) and was more common among both females (2.8% vs. 1.3%, p = 0.063) and the elderly (0% at an age <= 30 years vs. 10.4% at an age > 70 years, p = 0.0001). Rheumatoid arthritis (present in 15.8% vs. absent in 2.1%) and asthma (13% vs. 2.1%) correlated significantly with CI based on the results of our logistic regression analysis. CONCLUSION: Age, female gender, rheumatoid arthritis and asthma are risk factors for CI in the setting of RDD. PMID- 26517543 TI - Critical Care Needs in Patients with Diffusion-Weighted Imaging Negative MRI after tPA--Does One Size Fit All? AB - BACKGROUND AND PURPOSE: Patients who receive intravenous (IV) tissue plasminogen activator (tPA) for ischemic stroke are currently monitored in an intensive care unit (ICU) or a comparable stroke unit for at least 24 hours due to the high frequency of neurological exams and vital sign checks. The present study evaluates ICU needs in patients with diffusion-weighted imaging (DWI) negative MRI after IV tPA. METHODS: A retrospective chart review was performed for 209 patients who received IV tPA for acute stroke. Data on stroke risk factors, physiologic parameters, stroke severity, MRI characteristics, and final diagnosis were collected. The timing and nature of ICU interventions, if needed, was recorded. Multivariable logistic regression was used to determine factors associated with subsequent ICU needs. RESULTS: Patients with cerebral infarct on MRI after tPA had over 9 times higher odds of requiring ICU care compared to patients with DWI negative MRI (OR 9.2, 95% CI 2.49-34.15). All DWI negative patients requiring ICU care did so by the end of tPA infusion (p = 0.006). Among patients with DWI negative MRI, need for ICU interventions was associated with higher NIH Stroke Scale (NIHSS) scores (p<0.001), uncontrolled hypertension (p<0.001), seizure at onset (p = 0.002), and reduced estimated glomerular filtration rate (eGFR) (p = 0.010). CONCLUSIONS: Only a small number of DWI negative patients required ICU care. In patients without critical care needs by the end of thrombolysis, post-tPA MRI may be considered for triaging DWI negative patients to a less resource intense monitoring environment. PMID- 26517544 TI - An Assessment of Engineered Calcium Oxalate Crystal Formation on Plant Growth and Development as a Step toward Evaluating Its Use to Enhance Plant Defense. AB - The establishment of new approaches to control chewing insects has been sought not only for direct use in reducing crop loss but also in managing resistance to the pesticides already in use. Engineered formation of calcium oxalate crystals is a potential strategy that could be developed to fulfill both these needs. As a step toward this development, this study investigates the effects of transforming a non-calcium oxalate crystal accumulating plant, Arabidopsis thaliana, into a crystal accumulating plant. Calcium oxalate crystal accumulating A. thaliana lines were generated by ectopic expression of a single bacterial gene encoding an oxalic acid biosynthetic enzyme. Biochemical and cellular studies suggested that the engineered A. thaliana lines formed crystals of calcium oxalate in a manner similar to naturally occurring crystal accumulating plants. The amount of calcium oxalate accumulated in leaves also reached levels similar to those measured in the leaves of Medicago truncatula in which the crystals are known to play a defensive role. Visual inspection of the different engineered lines, however, suggested a phenotypic consequence on plant growth and development with higher calcium oxalate concentrations. The restoration of a near wild-type plant phenotype through an enzymatic reduction of tissue oxalate supported this observation. Overall, this study is a first to provide initial insight into the potential consequences of engineering calcium oxalate crystal formation in non crystal accumulating plants. PMID- 26517546 TI - Correction: Neutralizing Antibody Response after Intramuscular Purified Vero Cell Rabies Vaccination (PVRV) in Iranian Patients with Specific Medical Conditions. PMID- 26517545 TI - Predictors of High Profit and High Deficit Outliers under SwissDRG of a Tertiary Care Center. AB - PRINCIPLES: Case weights of Diagnosis Related Groups (DRGs) are determined by the average cost of cases from a previous billing period. However, a significant amount of cases are largely over- or underfunded. We therefore decided to analyze earning outliers of our hospital as to search for predictors enabling a better grouping under SwissDRG. METHODS: 28,893 inpatient cases without additional private insurance discharged from our hospital in 2012 were included in our analysis. Outliers were defined by the interquartile range method. Predictors for deficit and profit outliers were determined with logistic regressions. Predictors were shortlisted with the LASSO regularized logistic regression method and compared to results of Random forest analysis. 10 of these parameters were selected for quantile regression analysis as to quantify their impact on earnings. RESULTS: Psychiatric diagnosis and admission as an emergency case were significant predictors for higher deficit with negative regression coefficients for all analyzed quantiles (p<0.001). Admission from an external health care provider was a significant predictor for a higher deficit in all but the 90% quantile (p<0.001 for Q10, Q20, Q50, Q80 and p = 0.0017 for Q90). Burns predicted higher earnings for cases which were favorably remunerated (p<0.001 for the 90% quantile). Osteoporosis predicted a higher deficit in the most underfunded cases, but did not predict differences in earnings for balanced or profitable cases (Q10 and Q20: p<0.00, Q50: p = 0.10, Q80: p = 0.88 and Q90: p = 0.52). ICU stay, mechanical and patient clinical complexity level score (PCCL) predicted higher losses at the 10% quantile but also higher profits at the 90% quantile (p<0.001). CONCLUSION: We suggest considering psychiatric diagnosis, admission as an emergency case and admission from an external health care provider as DRG split criteria as they predict large, consistent and significant losses. PMID- 26517547 TI - Pattern matching approach to pseudosymmetry problems in electron backscatter diffraction. AB - We demonstrate an approach to overcome Kikuchi pattern misindexing problems caused by crystallographic pseudosymmetry in electron backscatter diffraction (EBSD) measurements. Based on the quantitative comparison of experimentally measured Kikuchi patterns with dynamical electron diffraction simulations, the algorithm identifies the best-fit orientation from a set of pseudosymmetric candidates. Using measurements on framboidal pyrite (FeS2) as an example, we also show the improvement of the orientation precision using this approach. PMID- 26517548 TI - AFM tip characterization by using FFT filtered images of step structures. AB - The measurement resolution of an atomic force microscope (AFM) is largely dependent on the radius of the tip. Meanwhile, when using AFM to study nanoscale surface properties, the value of the tip radius is needed in calculations. As such, estimation of the tip radius is important for analyzing results taken using an AFM. In this study, a geometrical model created by scanning a step structure with an AFM tip was developed. The tip was assumed to have a hemispherical cone shape. Profiles simulated by tips with different scanning radii were calculated by fast Fourier transform (FFT). By analyzing the influence of tip radius variation on the spectra of simulated profiles, it was found that low-frequency harmonics were more susceptible, and that the relationship between the tip radius and the low-frequency harmonic amplitude of the step structure varied monotonically. Based on this regularity, we developed a new method to characterize the radius of the hemispherical tip. The tip radii estimated with this approach were comparable to the results obtained using scanning electron microscope imaging and blind reconstruction methods. PMID- 26517549 TI - Bacillus subtilis Bactofilins Are Essential for Flagellar Hook- and Filament Assembly and Dynamically Localize into Structures of Less than 100 nm Diameter underneath the Cell Membrane. AB - Bactofilins are a widely conserved protein family implicated in cell shape maintenance and in bacterial motility. We show that the bactofilins BacE and BacF from Bacillus subtilis are essential for motility. The proteins are required for the establishment of flagellar hook- and filament structures, but apparently not for the formation of basal bodies. Functional YFP fusions to BacE and to BacF localize as discrete assemblies at the B. subtilis cell membrane, and have a diameter of 60 to 70 nm. BacF assemblies are relatively static, and partially colocalize with flagellar basal bodies, while BacE assemblies are fewer per cell than those of BacF and are highly mobile. Tracking of BacE foci showed that the assemblies arrest at a single point for a few hundred milliseconds, showing that a putative interaction with flagellar structures would be transient and fast. When overexpressed or expressed in a heterologous cell system, bactofilins can form filamentous structures, and also form multimers as purified proteins. Our data reveal a propensity for bactofilins to form filaments, however, in B. subtilis cells, bactofilins assemble into defined size assemblies that show a dynamic localization pattern and play a role in flagellar assembly. PMID- 26517552 TI - The Relative Age Effect and Its Influence on Academic Performance. AB - INTRODUCTION AND PURPOSE: The policy of school organisation for grouping students in the same academic year is based on date of birth. The differences in the experiences and maturation of older students involve a relatively better performance in academic settings, which is known as the relative age effect (RAE). This effect is more important the younger the student is. The goal of this study is to identify the connections of influence that RAE, socioeconomic status (SES), and type of institution have on academic performance in a school population of eighth graders. METHODS: The study is based on a population-based, representative sample of 15,234 8th graders (50.4% female; average age = 13.61 years) in the 2011 National System of Quality Assessment in Education Survey (SIMCE) from Chile. The SIMCE for global academic performance consists of 4 tests: reading, mathematics, social studies, and science. All tests consist of multiple-choice and closed questions. In addition, in order to have the information of general academic performance, an extra variable expressing the average score of each student was created. Also, the SIMCE includes additional variables for the evaluation process such as SES or type of school. Students were assigned to one of five age groups in terms of date of birth (G1, G2, G3, G4, and G5), in which students belonging to G1 are the oldest and students belonging to G5 are the youngest. RESULTS: The results achieved in the structural equation modelling indicate a good global fit. Individual relationships show significant effects of the three variables observed on academic performance, although SES received the highest values. The influence of RAE took place both in the full sample and sub-samples composed according to the SES and academic performance, showing higher values for students with lower scores. Although the influence of RAE decreases when SES is controlled, its effect is still significant and contributes to additionally explain the performance. CONCLUSIONS: The RAE remains, even with residual values, an explanatory factor in academic performance even in eighth graders. Since the RAE decreases as the influence of schooling increases, the potential adverse effects for some students would be placed in previous and initial moments of formal schooling. These findings may be useful into taking steps towards flexibilisation on age of entry in compulsory schooling. Moreover, the need to implement early, comprehensive evaluation systems which include aspects related to neurodevelopment in order to provide maximum information to parents and educators is also drawn. PMID- 26517550 TI - Right Ventricular Adaptation Is Associated with the Glu298Asp Variant of the NOS3 Gene in Elite Athletes. AB - Nitric oxide (NO), an important endogenous pulmonary vasodilator is synthetized by the endothelial NO synthase (NOS3). Reduced NO bioavailability and thus the Glu298Asp polymorphism of NOS3 may enhance right ventricular (RV) afterload and hypertrophic remodeling and influence athletic performance. To test this hypothesis world class level athletes (water polo players, kayakers, canoeists, rowers, swimmers, n = 126) with a VO2 maximum greater than 50ml/kg/min were compared with non-athletic volunteers (n = 155). Cardiopulmonary exercise tests and cardiac magnetic resonance imaging (cMRI) were performed to determine structural or functional changes. Genotype distribution of the NOS3 Glu298Asp polymorphism was not affected by gender or physical performance. Cardiac MRI showed increased stroke volume with eccentric hypertrophy in all athletes regardless of their genotype. However, the Asp allelic variant carriers had increased RV mass index (32+/-6g versus 27+/-6g, p<0.01) and larger RV stroke volume index (71+/-10ml versus 64+/-10ml, p<0.01) than athletes with a Glu/Glu genotype. Genotype was not significantly associated with athletic performance. In the non-athletic group no genotype related differences were detected. The association between the NOS3 Glu298Asp polymorphism and RV structure and dimension in elite athletes emphasizes the importance of NOS3 gene function and NO bioavailability in sport related cardiac adaptation. PMID- 26517551 TI - Comparison of Mouse and Human Retinal Pigment Epithelium Gene Expression Profiles: Potential Implications for Age-Related Macular Degeneration. AB - BACKGROUND: The human retinal pigment epithelium (RPE) plays an important role in the pathogenesis of age related macular degeneration (AMD). AMD is the leading cause of blindness worldwide. There is currently no effective treatment available. Preclinical studies in AMD mouse models are essential to develop new therapeutics. This requires further in-depth knowledge of the similarities and differences between mouse and human RPE. METHODS: We performed a microarray study to identify and functionally annotate RPE specific gene expression in mouse and human RPE. We used a meticulous method to determine C57BL/6J mouse RPE signature genes, correcting for possible RNA contamination from its adjacent layers: the choroid and the photoreceptors. We compared the signature genes, gene expression profiles and functional annotations of the mouse and human RPE. RESULTS: We defined sets of mouse (64), human (171) and mouse-human interspecies (22) RPE signature genes. Not unexpectedly, our gene expression analysis and comparative functional annotation suggested that, in general, the mouse and human RPE are very similar. For example, we found similarities for general features, like "organ development" and "disorders related to neurological tissue". However, detailed analysis of the molecular pathways and networks associated with RPE functions, suggested also multiple species-specific differences, some of which may be relevant for the development of AMD. For example, CFHR1, most likely the main complement regulator in AMD pathogenesis was highly expressed in human RPE, but almost absent in mouse RPE. Furthermore, functions assigned to mouse and human RPE expression profiles indicate (patho-) biological differences related to AMD, such as oxidative stress, Bruch's membrane, immune-regulation and outer blood retina barrier. CONCLUSION: These differences may be important for the development of new therapeutic strategies and translational studies in age related macular degeneration. PMID- 26517553 TI - The Validity of Conscientiousness Is Overestimated in the Prediction of Job Performance. AB - INTRODUCTION: Sensitivity analyses refer to investigations of the degree to which the results of a meta-analysis remain stable when conditions of the data or the analysis change. To the extent that results remain stable, one can refer to them as robust. Sensitivity analyses are rarely conducted in the organizational science literature. Despite conscientiousness being a valued predictor in employment selection, sensitivity analyses have not been conducted with respect to meta-analytic estimates of the correlation (i.e., validity) between conscientiousness and job performance. METHODS: To address this deficiency, we reanalyzed the largest collection of conscientiousness validity data in the personnel selection literature and conducted a variety of sensitivity analyses. RESULTS: Publication bias analyses demonstrated that the validity of conscientiousness is moderately overestimated (by around 30%; a correlation difference of about .06). The misestimation of the validity appears to be due primarily to suppression of small effects sizes in the journal literature. These inflated validity estimates result in an overestimate of the dollar utility of personnel selection by millions of dollars and should be of considerable concern for organizations. CONCLUSION: The fields of management and applied psychology seldom conduct sensitivity analyses. Through the use of sensitivity analyses, this paper documents that the existing literature overestimates the validity of conscientiousness in the prediction of job performance. Our data show that effect sizes from journal articles are largely responsible for this overestimation. PMID- 26517554 TI - Defining Key Structural Determinants for the Pro-osteogenic Activity of Flavonoids. AB - Epidemiological studies suggest that fruits and vegetables may play a role in promoting bone growth and preventing age-related bone loss, attributable, at least in part, to phytochemicals such as flavonoids stimulating osteoblastogenesis. Through systematically screening the effect of flavonoids on the osteogenic differentiation of human mesenchymal stem cells in vitro and correlating activity with chemical structure using comparative molecular field analysis, we have successfully identified important structural features that relate to their activity, as well as reliably predicted the activity of compounds with unknown activity. Contour maps emphasized the importance of electronegativity, steric bulk, and a 2-C-3-C double bond at the flavonoid C ring, as well as overall electropositivity and reduced steric bulk at the flavonoid B-ring. These results support a role for certain flavonoids in promoting osteogenic differentiation, thus their potential for preventing skeletal deterioration, as well as providing a foundation for the lead optimization of novel bone anabolics. PMID- 26517555 TI - Single Strand Annealing Plays a Major Role in RecA-Independent Recombination between Repeated Sequences in the Radioresistant Deinococcus radiodurans Bacterium. AB - The bacterium Deinococcus radiodurans is one of the most radioresistant organisms known. It is able to reconstruct a functional genome from hundreds of radiation induced chromosomal fragments. Our work aims to highlight the genes involved in recombination between 438 bp direct repeats separated by intervening sequences of various lengths ranging from 1,479 bp to 10,500 bp to restore a functional tetA gene in the presence or absence of radiation-induced DNA double strand breaks. The frequency of spontaneous deletion events between the chromosomal direct repeats were the same in recA+ and in DeltarecA, DeltarecF, and DeltarecO bacteria, whereas recombination between chromosomal and plasmid DNA was shown to be strictly dependent on the RecA and RecF proteins. The presence of mutations in one of the repeated sequence reduced, in a MutS-dependent manner, the frequency of the deletion events. The distance between the repeats did not influence the frequencies of deletion events in recA+ as well in DeltarecA bacteria. The absence of the UvrD protein stimulated the recombination between the direct repeats whereas the absence of the DdrB protein, previously shown to be involved in DNA double strand break repair through a single strand annealing (SSA) pathway, strongly reduces the frequency of RecA- (and RecO-) independent deletions events. The absence of the DdrB protein also increased the lethal sectoring of cells devoid of RecA or RecO protein. gamma-irradiation of recA+ cells increased about 10-fold the frequencies of the deletion events, but at a lesser extend in cells devoid of the DdrB protein. Altogether, our results suggest a major role of single strand annealing in DNA repeat deletion events in bacteria devoid of the RecA protein, and also in recA+ bacteria exposed to ionizing radiation. PMID- 26517556 TI - Curcumin Mitigates the Intracellular Lipid Deposit Induced by Antipsychotics In Vitro. AB - SCOPE: First- and second-generation antipsychotics (FGAs and SGAs, respectively), both inhibit cholesterol biosynthesis and impair the intracellular cholesterol trafficking, leading to lipid accumulation in the late endosome/lysosome compartment. In this study we examined if curcumin, a plant polyphenol that stimulates exosome release, can alleviate antipsychotic-induced intracellular lipid accumulation. METHODS: HepG2 hepatocarcinoma cells were treated with antipsychotics or placebo and DiI-labelled LDL for 18 h and then exposed to curcumin for the last 2 h. Cells and media were collected separately and used for biochemical analyses, electron microscopy and immunocytochemistry. Exosomes were isolated from the incubation medium by ultracentrifugation. RESULTS: Curcumin treatment reduced the number of heterolysosomes and shifted their subcellular localization to the periphery, as revealed by electron microscopy, and stimulated the release of lysosomal beta-hexosaminidase and exosome markers flotillin-2 and CD63 into the media. The presence of DiI in exosomes released by cells preloaded with DiI-LDL demonstrated the endolysosomal origin of the microvesicles. Furthermore, curcumin increased the secretion of cholesterol as well as LDL derived DiI and [3H]-cholesterol, in association with a decrease of intracellular lipids. Thus, the disruption of lipid trafficking induced by FGAs or SGAs can be relieved by curcumin treatment. This polyphenol, however, did not mitigate the reduction of cholesterol esterification induced by antipsychotics. CONCLUSION: Curcumin stimulates exosome release to remove cholesterol (and presumably other lipids) accumulated within the endolysosomal compartment, thereby normalizing intracellular lipid homeostasis. This action may help minimize the adverse metabolic effects of antipsychotic treatment, which should now be evaluated in clinical trials. PMID- 26517557 TI - Combining Metabolite-Based Pharmacophores with Bayesian Machine Learning Models for Mycobacterium tuberculosis Drug Discovery. AB - Integrated computational approaches for Mycobacterium tuberculosis (Mtb) are useful to identify new molecules that could lead to future tuberculosis (TB) drugs. Our approach uses information derived from the TBCyc pathway and genome database, the Collaborative Drug Discovery TB database combined with 3D pharmacophores and dual event Bayesian models of whole-cell activity and lack of cytotoxicity. We have prioritized a large number of molecules that may act as mimics of substrates and metabolites in the TB metabolome. We computationally searched over 200,000 commercial molecules using 66 pharmacophores based on substrates and metabolites from Mtb and further filtering with Bayesian models. We ultimately tested 110 compounds in vitro that resulted in two compounds of interest, BAS 04912643 and BAS 00623753 (MIC of 2.5 and 5 MUg/mL, respectively). These molecules were used as a starting point for hit-to-lead optimization. The most promising class proved to be the quinoxaline di-N-oxides, evidenced by transcriptional profiling to induce mRNA level perturbations most closely resembling known protonophores. One of these, SRI58 exhibited an MIC = 1.25 MUg/mL versus Mtb and a CC50 in Vero cells of >40 MUg/mL, while featuring fair Caco-2 A-B permeability (2.3 x 10-6 cm/s), kinetic solubility (125 MUM at pH 7.4 in PBS) and mouse metabolic stability (63.6% remaining after 1 h incubation with mouse liver microsomes). Despite demonstration of how a combined bioinformatics/cheminformatics approach afforded a small molecule with promising in vitro profiles, we found that SRI58 did not exhibit quantifiable blood levels in mice. PMID- 26517558 TI - Leishmanicidal Effect of Synthetic trans-Resveratrol Analogs. AB - BACKGROUND: Stilbene-based compounds show antitumoral, antioxidant, antihistaminic, anti-inflammatory and antimicrobial activities. Here, we evaluated the effect of the trans-resveratrol analogs, pterostilbene, piceatannol, polydatin and oxyresveratrol, against Leishmania amazonensis. METHODOLOGY/PRINCIPAL FINDINGS: Our results demonstrated a low murine macrophage cytotoxicity of all four analogs. Moreover, pterostilbene, piceatannol, polydatin and oxyresveratrol showed an anti-L. amazonensis activity with IC50 values of 18 MUM, 65 MUM, 95 MUM and 65 MUM for promastigotes, respectively. For intracellular amastigotes, the IC50 values of the analogs were 33.2 MUM, 45 MUM, 29 MUM and 30.5 MUM, respectively. Among the analogs assayed only piceatannol altered the cell cycle of the parasite, increasing 5-fold the cells in the Sub-G0 phase and decreasing 1.7-fold the cells in the G0-G1 phase. Piceatannol also changed the parasite mitochondrial membrane potential (DeltaPsim) and increased the number of annexin-V positive promastigotes, which suggests incidental death. CONCLUSION/SIGNIFICANCE: Among the analogs tested, piceatannol, which is a metabolite of resveratrol, was the more promising candidate for future studies regarding treatment of leishmaniasis. PMID- 26517559 TI - Activation and Allosteric Modulation of Human MU Opioid Receptor in Molecular Dynamics. AB - Allosteric protein modulation has gained increasing attention in drug design. Its application as a mechanism of action could bring forth safer and more effective medicines. Targeting opioid receptors with allosteric modulators can result in better treatment of pain, depression, and respiratory and immune disorders. In this work we use recent reports on negative modulators of MU opioid receptor as a starting point for identification of allosteric sites and mechanisms of opioid receptor modulation using homology modeling and docking and molecular dynamics studies. An allosteric binding site description is presented. Results suggest a shared binding region for lipophilic allosteric ligands, reveal possible differences in the modulation mechanism between cannabinoids and salvinorin A, and show ambiguous properties of the latter. Also, they emphasize the importance of native-like environment in molecular dynamics simulations and uncover relationships between modulator and orthosteric ligand binding and receptor behavior. Relationships between ligands, transmission switch, and hydrophobic lock are analyzed. PMID- 26517561 TI - One-pot synthesis of PEGylated plasmonic MoO(3-x) hollow nanospheres for photoacoustic imaging guided chemo-photothermal combinational therapy of cancer. AB - Engineering design of plasmonic nanomaterials as on-demand theranostic nanoagents with imaging, drug carrier, and photothermal therapy (PTT) functions have profound impact on treatment of cancer. Here, a facile 'one-pot' template-free hydrothermal route was firstly developed for synthesis of plasmonic oxygen deficiency molybdenum oxide hollow nanospheres functionalized by poly(ethylene glycol) (PEG-MoO(3-x) HNSs). The as-prepared PEG-MoO(3-x) HNSs not only have good biocompatibility but also exhibit obvious localized surface plasmon resonance (LSPR) absorption in the near-infrared (NIR) region. Especially, due to its intrinsic mesoporous properties and effective photothermal conversion efficiency upon 808-nm NIR laser irradiation, the PEG-MoO(3-x) HNSs can be applied as a pH/NIR laser dual-responsive camptothecin (CPT) drug delivery nanoplatform for chemotherapy as well as PTT to cancer cells. A remarkably improved synergistic therapeutic effect to pancreatic (PANC-1) tumor-bearing mice was obtained compared to the result of chemotherapy or PTT alone. Apart from its application for drug delivery, the PEG-MoO(3-x) HNSs can also be employed as an effective contrast nanoagent for photoacoustic (PAT) imaging because of its high NIR absorption, making it promising as a theranostic nanoagent for PAT imaging-guided chemo-photothermal combinational cancer therapy in the nanomedicine field. PMID- 26517560 TI - Reduced susceptibility to biocides in Acinetobacter baumannii: association with resistance to antimicrobials, epidemiological behaviour, biological cost and effect on the expression of genes encoding porins and efflux pumps. AB - OBJECTIVES: The objective of this study was to analyse whether there is an association between reduced susceptibility to biocides in Acinetobacter baumannii and (i) antimicrobial resistance (co-resistance), (ii) prevalent (epidemic) clones, (iii) changes in the fitness or (iv) expression of genes related to efflux pumps and porins. METHODS: Susceptibility to biocides and antimicrobials was determined in 49 clonally unrelated isolates of A. baumannii. Biological cost, in terms of mean generation time, was determined by spectrophotometry. Quantitative real-time RT-PCR was used to determine the relative expression of genes encoding several efflux pumps and porins. RESULTS: Reduced susceptibility to chlorhexidine digluconate, benzalkonium chloride and Irgasan((r)) was associated with resistance to aminoglycosides, tetracycline and ciprofloxacin (P < 0.05). The MICs of carbapenems, aminoglycosides, doxycycline and ciprofloxacin for isolate Ab70 (epidemic clone) exposed to these biocides increased by >=2 dilutions. Reduced susceptibility to Orsan((r)) was more frequent among prevalent clones than non-prevalent clones (P < 0.05). Mean generation times for Ab70 before and after exposure to benzalkonium chloride were 57.8 and 78.1 min, respectively (P = 0.02). Relative expression of abeS and adeB was increased in Ab46 and Ab70 after exposure to chlorhexidine digluconate, but was decreased for ompA and carO after exposure to Irgasan((r)). CONCLUSIONS: Reduced susceptibility to biocides is associated with co-resistance to carbapenems, aminoglycosides, tetracycline and ciprofloxacin. Reduced susceptibility to Orsan((r)) may be a marker of prevalent clones. Acquisition of reduced susceptibility to benzalkonium chloride has a biological cost. Exposure to biocides affects the relative expression of genes related to some efflux pump genes (increased expression) or porins (reduced expression). PMID- 26517562 TI - A porphyrin-PEG polymer with rapid renal clearance. AB - Tetracarboxylic porphyrins and polyethylene glycol (PEG) diamines were crosslinked in conditions that gave rise to a water-soluble porphyrin polyamide. Using PEG linkers 2 kDa or larger prevented fluorescence self-quenching. This networked porphyrin mesh was retained during dialysis with membranes with a 100 kDa pore size, yet passed through the membrane when centrifugal filtration was applied. Following intravenous administration, the porphyrin mesh, but not the free porphyrin, was rapidly cleared via renal excretion. The process could be monitored by fluorescence analysis of collected urine, with minimal background due to the large Stokes shift of the porphyrin (230 nm separating excitation and emission peaks). In a rhabdomyolysis mouse model of renal failure, porphyrin mesh urinary clearance was significantly impaired. This led to slower accumulation in the bladder, which could be visualized non-invasively via fluorescence imaging. Without further modification, the porphyrin mesh was chelated with (64)Cu for dynamic whole body positron emission tomography imaging of renal clearance. Together, these data show that small porphyrin-PEG polymers can serve as effective multimodal markers of renal function. PMID- 26517563 TI - Chitosan-film enhanced chitosan nerve guides for long-distance regeneration of peripheral nerves. AB - Biosynthetic nerve grafts are developed in order to complement or replace autologous nerve grafts for peripheral nerve reconstruction. Artificial nerve guides currently approved for clinical use are not widely applied in reconstructive surgery as they still have limitations especially when it comes to critical distance repair. Here we report a comprehensive analysis of fine-tuned chitosan nerve guides (CNGs) enhanced by introduction of a longitudinal chitosan film to reconstruct critical length 15 mm sciatic nerve defects in adult healthy Wistar or diabetic Goto-Kakizaki rats. Short and long term investigations demonstrated that the CNGs enhanced by the guiding structure of the introduced chitosan film significantly improved functional and morphological results of nerve regeneration in comparison to simple hollow CNGs. Importantly, this was detectable both in healthy and in diabetic rats (short term) and the regeneration outcome almost reached the outcome after autologous nerve grafting (long term). Hollow CNGs provide properties likely leading to a wider clinical acceptance than other artificial nerve guides and their performance can be increased by simple introduction of a chitosan film with the same advantageous properties. Therefore, the chitosan film enhanced CNGs represent a new generation medical device for peripheral nerve reconstruction. PMID- 26517564 TI - How specific is CRISPR/Cas9 really? AB - The specificity of RNA-guided nucleases has gathered considerable interest as they become broadly applied to basic research and therapeutic development. Reports of the simple generation of animal models and genome engineering of cells raised questions about targeting precision. Conflicting early reports led the field to believe that CRISPR/Cas9 system was promiscuous, leading to a variety of strategies for improving specificity and increasingly sensitive methods to detect off-target events. However, other studies have suggested that CRISPR/Cas9 is a highly specific genome-editing tool. This review will focus on deciphering and interpreting these seemingly opposing claims. PMID- 26517566 TI - Mechanobiology - chemical origin of membrane mechanical resistance and force dependent signaling. AB - The cell membrane is a highly complex designed material with remarkable physicochemical properties; comprised mainly of lipid moieties, it is capable of self-assembling, changing morphology, housing a range of distinct proteins, and withstanding electrical, chemical and mechanical perturbations. All of these fundamental cellular functions occurring within a 5nm thick film is an astonishing feat of engineering, made possible due to the interplay of a variety of intermolecular forces. Elucidating how the interactions within the chemically distinct partners influence the nanomechanical properties of the membrane is essential to gain a comprehensive understanding of a wide-variety of both force triggered and force-sensing mechanisms that dictate essential cellular processes. PMID- 26517567 TI - Secrets of a covalent interaction for biomaterials and biotechnology: SpyTag and SpyCatcher. AB - SpyTag is a short peptide that forms an isopeptide bond upon encountering its protein partner SpyCatcher. This covalent peptide interaction is a simple and powerful tool for bioconjugation and extending what protein architectures are accessible. Here we review the origin and mechanism of SpyTag/SpyCatcher, focusing on recent innovative applications. Ligation of targeting-antibody with antigen provided a simple route to vaccine generation. SpyRings, from head-to tail cyclisation, gave major enhancements in enzyme resilience. Linking multiple SpyCatchers gave dendrimers for T-cell activation or Spy networks forming hydrogels for stem cell culture. Synthetic biology applications include integrating amyloid biomaterials with living bacteria, for irreversible derivatisation of biofilms with enzymes or nanoparticles. We also discuss further opportunities to apply and enhance SpyTag/SpyCatcher technology. PMID- 26517565 TI - Dynamics of co-translational protein targeting. AB - Most membrane and secretory proteins are delivered co-translationally to protein translocation channels in their destination membrane by the signal recognition particle (SRP) and its receptor. This co-translational molecular machinery is conserved across all kingdoms of life, though it varies in composition and function. Here we report recent progress towards understanding the mechanism of SRP function, focusing on findings about Escherichia coli SRP's conformational dynamics throughout the targeting process. These insights shed light on a key checkpoint in the targeting cycle: how SRP regulates engagement of an actively translating ribosome with the translocation machinery at the membrane. PMID- 26517568 TI - N7 methylation alters hydrogen-bonding patterns of guanine in duplex DNA. AB - N7-Alkyl-2'-deoxyguanosines are major adducts in DNA that are generated by various alkylating mutagens and drugs. However, the effect of the N7 alkylation on the hydrogen-bonding patterns of the guanine remains poorly understood. We prepared N7-methyl-2'-deoxyguanosine (N7mdG)-containing DNA using a transition state destabilization strategy, developed a novel polbeta-host-guest complex system, and determined eight crystal structures of N7mdG or dG paired with dC, dT, dG, and dA. The structures of N7mdG:dC and N7mdG:dG are very similar to those of dG:dC and dG:dG, respectively, indicating the involvement of the keto tautomeric form of N7mdG in the base pairings with dC and dG. On the other hand, the structure of N7mdG:dT shows that the mispair forms three hydrogen bonds and adopts a Watson-Crick-like geometry rather than a wobble geometry, suggesting that the enol tautomeric form of N7mdG involves in its base pairing with dT. In addition, N7mdG:dA adopts a novel shifted anti:syn base pair presumably via the enol tautomeric form of N7mdG. The polbeta-host-guest complex structures reveal that guanine-N7 methylation changes the hydrogen-bonding patterns of the guanine when paired with dT or dA and suggest that N7 alkylation may alter the base pairing patterns of guanine by promoting the formation of the rare enol tautomeric form of guanine. PMID- 26517569 TI - Stereoselective Total Synthesis of (-)-Depudecin. AB - The total synthesis of the natural product depudecin, an antiangiogenic microbial polyketide with inhibitory activity against histone deacetylases, is reported. Characterized by a highly oxidized 11-carbon chain containing two epoxides conjugated through a trans-disubstituted olefin, its total synthesis was efficiently accomplished by a novel asymmetric methodology of epoxide formation based on a new class of chiral sulfonium salts, allowing for the construction of the oxirane rings in an efficient and stereoselective fashion. PMID- 26517570 TI - Fc-Gamma Receptor Polymorphisms Predispose Patients to Infectious Complications After Liver Transplantation. AB - We investigated the impact of polymorphisms in host innate immunoregulatory genes on the development of infectious complications after liver transplantation (LT). The single-nucleotide polymorphisms (SNPs) of C1QA [276A/G], FCGR2A [131H/R], and FCGR3A [158F/V], genes encoding the Fc gamma receptor (FcgammaR), were analyzed in 89 living donor LT recipients in relation to the occurrences of postoperative infectious complications within 30 days after LT. Consistent with a lower affinity of the isoform encoded by FCGR3A [158F] to both IgG1 and IgG3, a significantly higher incidence of bloodstream infections (BSI) was observed in the FCGR3A [158F/V or F/F] than in the FCGR3A [158V/V] individuals. The combination of FCGR2A and FCGR3A SNPs further stratified the incidence of BSI, regardless of C1QA SNP. The predominant causative pathogen of BSI in the FCGR3A [158F/F or F/V] patients was gram-positive cocci (73.3%), of which one third was methicillin-resistant Staphylococcus aureus. No differences were observed in the incidence of fungal infections or in cytomegalovirus infections with respect to the three gene polymorphisms. Our findings indicate that FcgammaR SNPs are predisposing factors for BSI and can predict mortality after LT. This study provides a foundation for further prospective studies on a larger scale. PMID- 26517571 TI - Aquatic predicted no-effect concentrations of 16 polycyclic aromatic hydrocarbons and their ecological risks in surface seawater of Liaodong Bay, China. AB - Polycyclic aromatic hydrocarbons (PAHs), a class of ubiquitous pollutants in marine environments, exhibit moderate to high adverse effects on aquatic organisms and humans. However, the lack of PAH toxicity data for aquatic organism has limited evaluation of their ecological risks. In the present study, aquatic predicted no-effect concentrations (PNECs) of 16 priority PAHs were derived based on species sensitivity distribution models, and their probabilistic ecological risks in seawater of Liaodong Bay, Bohai Sea, China, were assessed. A quantitative structure-activity relationship method was adopted to achieve the predicted chronic toxicity data for the PNEC derivation. Good agreement for aquatic PNECs of 8 PAHs based on predicted and experimental chronic toxicity data was observed (R(2) = 0.746), and the calculated PNECs ranged from 0.011 ug/L to 205.3 ug/L. A significant log-linear relationship also existed between the octanol-water partition coefficient and PNECs derived from experimental toxicity data (R(2) = 0.757). A similar order of ecological risks for the 16 PAH species in seawater of Liaodong Bay was found by probabilistic risk quotient and joint probability curve methods. The individual high ecological risk of benzo[a]pyrene, benzo[b]fluoranthene, and benz[a]anthracene needs to be determined. The combined ecological risk of PAHs in seawater of Liaodong Bay calculated by the joint probability curve method was 13.9%, indicating a high risk as a result of co exposure to PAHs. Environ Toxicol Chem 2016;35:1587-1593. (c) 2015 SETAC. PMID- 26517572 TI - Copper(I) Complexes of Zwitterionic Imidazolium-2-Amidinates, a Promising Class of Electroneutral, Amidinate-Type Ligands. AB - The first complexes containing imidazolium-2-amidinates as ligands (betaine-type adducts of imidazolium-based carbenes and carbodiimides, NHC-CDI) are reported. Interaction of the sterically hindered betaines ICyCDI(DiPP) and IMeCDI(DiPP) [both bearing 2,6-diisopropylphenyl (DiPP) substituents on the terminal N atoms] with Cu(I) acetate affords mononuclear, electroneutral complexes 1a and 1b, which contain NHC-CDI and acetate ligands terminally bound to linear Cu(I) centers. In contrast, the less encumbered ligand ICyCDI(p-Tol), with p-tolyl substituents on the nitrogen donor atoms, affords a dicationic trigonal paddlewheel complex, [Cu2(MU-ICyCDI(p-Tol))3](2+)[OAc(-)]2 (2-OAc). The nuclear magnetic resonance (NMR) resonances of this compound are broad and indicate that in solution the acetate anion and the betaine ligands compete for binding the Cu atom. Replacing the external acetate with the less coordinating tetraphenylborate anion provides the corresponding derivative 2-BPh4 that, in contrast with 2-OAc, gives rise to sharp and well-defined NMR spectra. The short Cu-Cu distance in the binuclear dication [Cu2(MU-ICyCDI(p-Tol))3](2+) observed in the X-ray structures of 2-BPh4 and 2-OAc, ca. 2.42 A, points to a relatively strong "cuprophilic" interaction. Attempts to force the bridging coordination mode of IMeCDI(DiPP) displacing the acetate anion with BPh4(-) led to the isolation of the cationic mononuclear derivative [Cu(IMeCDI(DiPP))2](+)[BPh4](-) (3b) that contains two terminally bound betaine ligands. Compound 3b readily decomposes upon being heated, cleanly affording the bis-carbene complex [Cu(IMe)2](+)[BPh4(-)] (4) and releasing the corresponding carbodiimide (C(?N-DiPP)2). PMID- 26517574 TI - Effect of Fluorine Substitution on Photovoltaic Properties of Alkoxyphenyl Substituted Benzo[1,2-b:4,5-b']dithiophene-Based Small Molecules. AB - Two new small molecules, C3T-BDTP and C3T-BDTP-F with alkoxyphenyl-substituted benzo[1,2-b:4,5-b']dithiophene (BDT) and meta-fluorinated-alkoxyphenyl substituted BDT as the central donor blocks, respectively, have been synthesized and used as donor materials in organic solar cells (OSCs). With the addition of 0.4% v/v 1,8-diiodooctane (DIO), the blend of C3T-BDTP-F/PC71BM showed a higher hole mobility of 8.67 * 10(-4) cm(2) V(-1) s(-1) compared to that of the blend of C3T-BDTP/PC71BM. Two types of interlayers, zirconium acetylacetonate (ZrAcac) and perylene diimide (PDI) derivatives (PDINO and PDIN), were used to further optimize the performance of OSCs. With a device structure of ITO/PEDOT:PSS/donor:PC71BM/PDIN/Al, the OSCs based on C3T-BDTP delivered a satisfying power conversion efficiency (PCE) of 5.27% with an open circuit voltage (V(oc)) of 0.91 V, whereas the devices based on C3T-BDTP-F showed an enhanced PCE of 5.42% with a higher V(oc) of 0.97 V. PMID- 26517573 TI - Vagal tone during infant contingency learning and its disruption. AB - This study used contingency learning to examine changes in infants' vagal tone during learning and its disruption. The heart rate of 160 five-month-old infants was recorded continuously during the first of two training sessions as they experienced an audiovisual event contingent on their pulling. Maternal reports of infant temperament were also collected. Baseline vagal tone, a measure of parasympathetic regulation of the heart, was related to vagal levels during the infants' contingency learning session, but not to their learner status. Vagal tone levels did not vary significantly over session minutes. Instead, vagal tone levels were a function of both individual differences in learner status and infant soothability. Vagal levels of infants who learned in the initial session were similar regardless of their soothability; however, vagal levels of infants who learned in a subsequent session differed as a function of soothability. Additionally, vagal levels during contingency disruption were significantly higher among infants in this group who were more soothable as opposed to those who were less soothable. The results suggest that contingency learning and disruption is associated with stable vagal tone in the majority of infants, but that individual differences in attention processes and state associated with vagal tone may be most readily observed during the disruption phase. PMID- 26517575 TI - Optimization of Neuromodulation for Bladder Control in a Rat Cystitis Model. AB - OBJECTIVES: In a bladder overactivity model of cystitis induced by intravesical infusion of acetic acid (a.a.), several parameters of spinal nerve stimulation (SNS) were optimized using continuous infusion cystometry. The optimal stimulation was further characterized through measurements of urodynamic function using single-fill cystometry. MATERIALS AND METHODS: In anesthetized male rats, a cannula was placed into the bladder dome for saline or 0.3% a.a. infusion and intravesical pressure monitoring. For SNS, two teflon-coated stainless steel electrodes were placed bilaterally under each of the L6 spinal nerves, and current stimulation was controlled independently using two Grass stimulators. RESULTS: Stimulation of 1 Hz or 50 Hz at motor threshold (Tmot ) was ineffective for altering bladder activities, but 10-Hz SNS increased the infused volume (IV) in a stimulation intensity-dependent fashion (P < 0.01, mixed model repeated analysis). Pairwise comparisons of IV differences to each stimulation intensity show that IV during 1 * Tmot stimulation was significantly larger than 0 * Tmot (no stim, P = 0.001), while the IV during 2 * Tmot stimulation was significantly larger than other intensities tested (P < 0.01). The mean IV (+/-SEM) during 0 * Tmot (no stim), 0.5 * Tmot , 1 * Tmot , and 2 * Tmot were 0.23 +/- 0.04 mL, 0.25 +/- 0.03 mL, 0.26 +/- 0.03 mL, and 0.40 +/- 0.04 mL, respectively. In single-fill cystometry, 10-Hz SNS at 1 * Tmot and 2 * Tmot stimulation increased the IV, or voiding duration and threshold pressure. SNS did not produce significant effects on basal pressure and micturition pressure. CONCLUSIONS: SNS significantly attenuates hypersensitive micturition reflex; 10 Hz and high-intensity stimulation are mostly effective. Acute peripheral nerve activation increases the functional bladder capacity, which may be via mechanisms on the afferent arm of the bladder micturition reflex. PMID- 26517576 TI - Covered transjugular intrahepatic portosystemic shunt versus endoscopic therapy + beta-blocker for prevention of variceal rebleeding. AB - Gastroesophageal variceal bleeding in patients with cirrhosis is associated with significant morbidity and mortality, as well as a high rebleeding risk. Limited data are available on the role of transjugular intrahepatic portosystemic shunt (TIPS) with covered stents in patients receiving standard endoscopic, vasoactive, and antibiotic treatment. In this multicenter randomized trial, long-term endoscopic variceal ligation (EVL) or glue injection + beta-blocker treatment was compared with TIPS placement in 72 patients with a first or second episode of gastric and/or esophageal variceal bleeding, after hemodynamic stabilization upon endoscopic, vasoactive, and antibiotic treatment. Randomization was stratified according to Child-Pugh score. Kaplan-Meier (event-free) survival estimates were used for the endpoints rebleeding, death, treatment failure, and hepatic encephalopathy. During a median follow-up of 23 months, 10 (29%) of 35 patients in the endoscopy + beta-blocker group, as compared to 0 of 37 (0%) patients in the TIPS group, developed variceal rebleeding (P = 0.001). Mortality (TIPS 32% vs. endoscopy 26%; P = 0.418) and treatment failure (TIPS 38% vs. endoscopy 34%; P = 0.685) did not differ between groups. Early hepatic encephalopathy (within 1 year) was significantly more frequent in the TIPS group (35% vs. 14%; P = 0.035), but during long-term follow-up this difference diminished (38% vs. 23%; P = 0.121). CONCLUSIONS: In unselected patients with cirrhosis, who underwent successful endoscopic hemostasis for variceal bleeding, covered TIPS was superior to EVL + beta-blocker for reduction of variceal rebleeding, but did not improve survival. TIPS was associated with higher rates of early hepatic encephalopathy. PMID- 26517577 TI - Fast One-Pot Synthesis of MoS2/Crumpled Graphene p-n Nanonjunctions for Enhanced Photoelectrochemical Hydrogen Production. AB - Aerosol processing enables the preparation of hierarchical graphene nanocomposites with special crumpled morphology in high yield and in a short time. Using modular insertion of suitable precursors in the starting solution, it is possible to synthesize different types of graphene-based materials ranging from heteroatom-doped graphene nanoballs to hierarchical nanohybrids made up by nitrogen-doped crumpled graphene nanosacks that wrap finely dispersed MoS2 nanoparticles. These materials are carefully investigated by microscopic (SEM, standard and HR TEM), diffraction (grazing incidence X-ray diffraction (GIXRD)) and spectroscopic (high resolution photoemission, Raman and UV-visible spectroscopy) techniques, evidencing that nitrogen dopants provide anchoring sites for MoS2 nanoparticles, whereas crumpling of graphene sheets drastically limits aggregation. The activity of these materials is tested toward the photoelectrochemical production of hydrogen, obtaining that N-doped graphene/MoS2 nanohybrids are seven times more efficient with respect to single MoS2 because of the formation of local p-n MoS2/N-doped graphene nanojunctions, which allow an efficient charge carrier separation. PMID- 26517578 TI - Dental clinical research: an illustration of the value of standardized diagnostic terms. AB - OBJECTIVE: Secondary data are a significant resource for in-depth epidemiologic and public health research. It also allows for effective quality control and clinical outcomes measurement. To illustrate the value of structured diagnostic entry, a use case was developed to quantify adherence to current practice guidelines for managing chronic moderate periodontitis (CMP). METHODS: Six dental schools using the same electronic health record (EHR) contribute data to a dental data repository (BigMouth) based on the i2b2 data-warehousing platform. Participating institutions are able to query across the full repository without being able to back trace specific data to its originating institution. At each of the three sites whose data are included in this analysis, the Dental Diagnostic System (DDS) terminology was used to document diagnoses in the clinics. We ran multiple queries against this multi-institutional database, and the output was validated by manually reviewing a subset of patient charts. RESULTS: Over the period under study, 1,866 patients were diagnosed with CMP. Of these, 15 percent received only periodontal prophylaxis treatment, 20 percent received only periodontal maintenance treatment, and only 41 percent received periodontal maintenance treatment in combination with other AAP guideline treatments. CONCLUSIONS: Our results showed that most patients with CMP were not treated according to the AAP guidelines. On the basis of this use case, we conclude that the availability and habitual use of a structured diagnosis in an EHR allow for the aggregation and secondary analyses of clinical data to support downstream analyses for quality improvement and epidemiological assessments. PMID- 26517581 TI - Quantum Features of Anionic Species He*- and He2*- in Small He(N) Clusters. AB - We present variational calculations on systems containing a few boson helium atoms attached to electronically excited atomic and molecular helium anions He*- and He2*- and characterize their structures and energetics. Previously reported high-level ab initio results [Huber, S. E.; Mauracher, A. Mol. Phys. 2014, 112, 794] to describe the interactions between excited (metastable) anions and a neutral He atom have been employed. For the case of the atomic species He*-, the corresponding interaction with He suggests large anharmonicity effects due to the presence of a deep well of ~17,500 cm-1 at short distances, together with a more external shallow secondary well of ~4 cm-1, both supporting bound levels. Moreover, when a sum of pairwise interactions is assumed to describe the full PES corresponding to the presence of several neutral He atoms, geometrical constraints already predict the complete solvation of the anionic impurity by six helium atoms, giving rise to a bipyramidal structure. In turn, for the anisotropic weak interaction He-He2*-, where the anionic dimer is considered as a rigid rotor, the obtained structures show the tendency of the helium atoms to pack themselves together and largely far away from the dopant, thereby confirming the heliophobic character of He2*-. PMID- 26517579 TI - Structure and unfolding of the third type III domain from human fibronectin. AB - Fibronectin is a modular extracellular matrix protein that is essential for vertebrate development. The third type III domain (3FN3) in fibronectin interacts with other parts of fibronectin and with anastellin, a protein fragment that causes fibronectin aggregation. 3FN3 opens readily both as an isolated domain in solution and when part of fibronectin in stretched fibrils, and it was proposed that this opening is important for anastellin binding. We determined the structure of 3FN3 using nuclear magnetic resonance spectroscopy, and we investigated its stability, folding, and unfolding. Similar to most other FN3 domains, 3FN3 contains two antiparallel beta-sheets that are composed of three (A, B, and E) and four (C, D, F, and G) beta-strands, respectively, and are held together by a conserved hydrophobic interface. cis-trans isomerization of P847 at the end of beta-strand C leads to observable conformational heterogeneity in 3FN3, with a cis peptide bond present in almost one-quarter of the molecules. The chemical stability of 3FN3 is relatively low, but the folding rate constant in the absence of denaturant is in the same range as those of other, more stable FN3 domains. Interestingly, the unfolding rate constant in the absence of denaturant is several orders of magnitude higher than the unfolding rate constants of other FN3 domains investigated to date. This unusually fast rate is comparable to the rate of binding of 3FN3 to anastellin at saturating anastellin concentrations, consistent with the model in which 3FN3 has to unfold to interact with anastellin. PMID- 26517582 TI - Regioselectivity-Tunable Self-1,3-Dipolar [3+3] Cyclizations of Azomethine Ylides To Assemble Dispirooxindole-piperazines. AB - A series of novel 2,3- or 2,5-dispirooxindole-piperazine ring systems were efficiently constructed through the acid-promoted self-1,3-dipolar [3+3] cyclizations of azomethine ylides derived from isatin with various primary or cyclic secondary amines. Interestingly, the regioselectivity of this self-[3+3] cyclization could be effectively tuned by varying the structural features of substrates. The unprecedented 2,5-dispirooxindole-piperazine skeleton was achieved in good diastereoselectivity by employing 1,2,3,4 tetrahydroisoquinoline, while using pyrrolidine or glycine methyl ester furnished the 2,3-dispirooxindole-piperazine scaffold in excellent diastereoselectivity (only a single isomer formed). PMID- 26517580 TI - Neutrophil-Expressed p21/waf1 Favors Inflammation Resolution in Pseudomonas aeruginosa Infection. AB - Neutrophil-associated inflammation during Pseudomonas aeruginosa lung infection is a determinant of morbidity in cystic fibrosis (CF). Neutrophil apoptosis is a key factor in inflammation resolution and is controlled by cytosolic proliferating cell nuclear antigen (PCNA). p21/Waf1, a cyclin-dependent kinase inhibitor, is a partner of PCNA, and its mRNA is up-regulated in human neutrophils during LPS challenge. We show here that, after 7 days of persistent infection with P. aeruginosa, neutrophilic inflammation was more prominent in p21(-/-) compared with wild-type (WT) mice. Notably, no intrinsic defect in the phagocytosis of apoptotic cells by macrophages was found in p21(-/-) compared with WT mice. Inflammatory cell analysis in peritoneal lavages after zymosan induced peritonitis showed a significantly increased number of neutrophils at 48 hours in p21(-/-) compared with WT mice. In vitro analysis was consistent with delayed neutrophil apoptosis in p21(-/-) compared with WT mice. Ectopic expression of p21/waf1 in neutrophil-differentiated PLB985 cells potentiated apoptosis and reversed the prosurvival effect of PCNA. In human neutrophils, p21 messenger RNA was induced by TNF-alpha, granulocyte colony-stimulating factor, and LPS. Neutrophils isolated from patients with CF showed enhanced survival, which was reduced after treatment with a carboxy-peptide derived from the sequence of p21/waf1. Notably, p21/waf1 was detected by immunohistochemistry in neutrophils within lungs from patients with CF. Our data reveal a novel role for p21/waf1 in the resolution of inflammation via its ability to control neutrophil apoptosis. This mechanism may be relevant in the neutrophil-dominated inflammation observed in CF and other chronic inflammatory lung conditions. PMID- 26517583 TI - MsFLASH participants' priorities for alleviating menopausal symptoms. AB - OBJECTIVE: To describe self-reported menopausal symptom priorities and their association with demographics and other symptoms among participants in an intervention trial for vasomotor symptoms (VMS). METHODS: Cross-sectional study embedded in the MsFLASH 02 trial, a three-by-two factorial design of yoga vs. exercise vs. usual activity and omega-3-fatty acid vs. placebo. At baseline, women (n = 354) completed hot flush diaries, a card sort task to prioritize symptoms they would most like to alleviate, and standardized questionnaires. RESULTS: The most common symptom priorities were: VMS (n = 322), sleep (n = 191), concentration (n = 140), and fatigue (n = 116). In multivariate models, women who chose VMS as their top priority symptom (n = 210) reported significantly greater VMS severity (p = 0.004) and never smoking (p = 0.012), and women who chose sleep as their top priority symptom (n = 100) were more educated (p <= 0.001) and had worse sleep quality (p < 0.001). ROC curves identified sleep scale scores that were highly predictive of ranking sleep as a top priority symptom. CONCLUSIONS: Among women entering an intervention trial for VMS and with relatively low prevalence of depression and anxiety, VMS was the priority symptom for treatment. A card sort may be a valid tool for quickly assessing symptom priorities in clinical practice and research. PMID- 26517585 TI - Applying the salutogenic framework to nutrition research and practice. AB - SYNOPSIS: Much research has identified a sea of factors related to unhealthy diets to make sense of why people struggle to eat healthy diets. However, little is known of factors that empower healthy eating. Antonovsky's salutogenesis provides an innovative framework to study these factors and identify resources and mechanisms underlying healthy eating practices. We give recommendations for future research and provide examples of how salutogenesis has inspired our own research to gain new insights into the origins of healthy eating. Lastly, implications of using future findings in designing novel nutrition promotion strategies are outlined. PMID- 26517584 TI - Glomerular filtration rate measured by (99m) Tc-DTPA renal dynamic imaging is significantly lower than that estimated by the CKD-EPI equation in horseshoe kidney patients. AB - AIM: Gate's glomerular filtration rate (gGFR) measured by (99m) Tc-DTPA renal dynamic imaging and estimated GFR (eGFR) estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation are two indexes used to evaluate renal function. However, little is known about whether gGFR can be used to accurately assess renal function in horseshoe kidney (HSK) patients with renal fusion anomalies. METHODS: Nineteen HSK patients (HSK group) diagnosed by renal imaging and 38 CKD patients with "normal kidney shape" (non-HSK group) matched to the HSK patients in terms of gender, age and biochemical indicators at Chinese PLA General Hospital were enrolled in this study. Gender, age, serum total protein (TP), albumin (ALB), blood urea nitrogen (BUN), serum creatinine (Scr), gGFR and eGFR were recorded and analyzed using chi(2) test, t-test, and Wilcoxon test which was presented as median(IQR). RESULTS: (1) There were no significant differences in gender, age, TP, ALB, BUN, Scr, or eGFR between these two groups. (2) In HSK patients, the renogram showed abnormal renal axis with the lower poles orientated medially. The timed uptake curve showed that the isotope excretion in the HSK group was slower than that in the non-HSK group. (3) For all HSK patients, gGFR was significantly lower than eGFR (range -12.52 mL/min per 1.73m(2) to -93.18 mL/min per 1.73m(2) ). There was no significant difference in eGFR between the HSK [96.42 (36.02) mL/min per 1.73 m(2) ] and non-HSK groups [94.46 (33.00) mL/min per 1.73 m(2) ]. The gGFR of the HSK group [41.18 (16.60) mL/min per 1.73m(2) ] was much lower than that of the non-HSK group [86.42(26.40) mL/min per 1.73m(2) , P < 0.001] and the eGFR of the HSK group (P < 0.001). The gGFR and eGFR of the non-HSK group were not significantly different. CONCLUSION: gGFR measured by (99m) Tc-DTPA renal dynamic imaging is significantly lower than eGFR estimated by the CKD-EPI equation, which indicates that isotope renogram cannot accurately evaluate the GFR of HSK patients. PMID- 26517586 TI - Why we need more than just randomized controlled trials to establish the effectiveness of online social networks for health behavior change. AB - SYNOPSIS: Despite their popularity and potential to promote health in large populations, the effectiveness of online social networks (e.g., Facebook) to improve health behaviors has been somewhat disappointing. Most of the research examining the effectiveness of such interventions has used randomized controlled trials (RCTs). It is asserted that the modest outcomes may be due to characteristics specific to both online social networks and RCTs. The highly controlled nature of RCTs stifles the dynamic nature of online social networks. Alternative and ecologically valid research designs that evaluate online social networks in real-life conditions are needed to advance the science in this area. PMID- 26517587 TI - Stages of change and patient activation measure scores in the context of incentive-based health interventions. AB - PURPOSE: To determine if two widely used behavioral change measures-Stages of Change (SoC) and Patient Activation Measure (PAM)-correlate with each other, are affected by financial incentives, or predict positive outcomes in the context of incentive-based health interventions. DESIGN: Secondary analysis of two randomized controlled trials of incentives for weight loss and for improved diabetes self-monitoring. SETTING: Philadelphia, Pennsylvania; Newark, New Jersey. SUBJECTS: A total of 132 obese and 75 diabetic adults enrolled in one of two trials. MEASURES . SoC and PAM scores; weight loss and usage rate of diabetes self-monitoring equipment. ANALYSIS: Multiple regression; Kruskal-Wallis test. RESULTS: We found no association between baseline SoC and PAM scores in either study (p = .30 and p = .89). Regression models showed no association between baseline PAM score and SoC and subsequent outcomes for either study (weight loss study: PAM: p = .14, SoC: p = .1; diabetes study: PAM: p = .45, SoC: p = .61). Change in PAM score and SoC among participants in the intervention groups did not differ by study arm or among participants with better outcomes. CONCLUSION . PAM score and SoC may not effectively predict success or monitor progress among individuals enrolled in incentive-based interventions. PMID- 26517589 TI - Editor's desk: the contrarians issue. PMID- 26517591 TI - Evaluating your health promotion program for the Return on Allocated Resources (ROAR) factor. PMID- 26517593 TI - Patient Involvement as a Means to Improving Care Quality. PMID- 26517594 TI - Outcome-Relevant Effects of Shared Decision Making. AB - BACKGROUND: Shared decision making (SDM) is considered a gold standard for the cooperation of doctor and patient. SDM improves patients' overall satisfaction and their confidence in decisions that have been taken. The extent to which it might also positively affect patient-relevant, disease-related endpoints is a matter of debate. METHODS: We systematically searched the PubMed database and the Cochrane Library for publications on controlled intervention studies of SDM. The quality of the intervention and the risk of bias in each publication were assessed on the basis of pre-defined inclusion and exclusion criteria. The effects of SDM on patient-relevant, disease-related endpoints were compared, and effect sizes were calculated. RESULTS: We identified 22 trials that differed widely regarding the patient populations studied, the types of intervention performed, and the mode of implementation of SDM. In ten articles, 57% of the endpoints that were considered relevant were significantly improved by the SDM intervention compared to the control group. The median effect size (Cohen's d) was 0.53 (0.14-1.49). In 12 trials, outcomes did not differ between the two groups. In all 22 studies identified, 39% of the relevant outcomes were significantly improved compared with the control groups. CONCLUSION: The trials performed to date to addressing the effect of SDM on patient-relevant, disease related endpoints are insufficient in both quantity and quality. Although just under half of the trials reviewed here indicated a positive effect, no final conclusion can be drawn. A consensus-based standardization of both SDM-promoting measures and appropriate clinical studies are needed. PMID- 26517592 TI - Long non-coding RNA regulation of reproduction and development. AB - Noncoding RNAs (ncRNAs) have long been known to play vital roles in eukaryotic gene regulation. Studies conducted over a decade ago revealed that maturation of spliced, polyadenylated coding mRNA occurs by reactions involving small nuclear RNAs and small nucleolar RNAs; mRNA translation depends on activities mediated by transfer RNAs and ribosomal RNAs, subject to negative regulation by micro RNAs; transcriptional competence of sex chromosomes and some imprinted genes is regulated in cis by ncRNAs that vary by species; and both small-interfering RNAs and piwi-interacting RNAs bound to Argonaute-family proteins regulate post translational modifications on chromatin and local gene expression states. More recently, gene-regulating noncoding RNAs have been identified, such as long intergenic and long noncoding RNAs (collectively referred to as lncRNAs)--a class totaling more than 100,000 transcripts in humans, which include some of the previously mentioned RNAs that regulate dosage compensation and imprinted gene expression. Here, we provide an overview of lncRNA activities, and then review the role of lncRNAs in processes vital to reproduction, such as germ cell specification, sex determination and gonadogenesis, sex hormone responses, meiosis, gametogenesis, placentation, non-genetic inheritance, and pathologies affecting reproductive tissues. Results from many species are presented to illustrate the evolutionarily conserved processes lncRNAs are involved in. PMID- 26517595 TI - Shared Decision Making and the Use of Decision Aids. AB - BACKGROUND: In shared decision making (SDM), the patient and the physician reach decisions in partnership. We conducted a trial of SDM training for physicians who treat patients with cancer. METHODS: Physicians who treat patients with cancer were invited to participate in a cluster-randomized trial and carry out SDM together with breast or colon cancer patients who faced decisions about their treatment. Decision-related physician-patient conversations were recorded. The patients filled out questionnaires immediately after the consultations (T1) and three months later (T2). The primary endpoints were the patients' confidence in and satisfaction with the decisions taken. The secondary endpoints were the process of decision making, anxiety, depression, quality of life, and externally assessed physician competence in SDM. The physicians in the intervention group underwent 12 hours of training in SDM, including the use of decision aids. RESULTS: Of the 900 physicians invited to participated in the trial, 105 answered the invitation. 86 were randomly assigned to either the intervention group or the control group (44 and 42 physicians, respectively); 33 of the 86 physicians recruited at least one patient for the trial. A total of 160 patients participated in the trial, of whom 55 were treated by physicians in the intervention group. There were no intergroup differences in the primary endpoints. Trained physicians were more competent in SDM (Cohen's d = 0.56; p<0.05). Patients treated by trained physicians had lower anxiety and depression scores immediately after the consultation (d = -0.12 and -0.14, respectively; p<0.10), and markedly lower anxiety and depression scores three months later (d = -0.94 and -0.67, p<0.01). CONCLUSION: When physicians treating cancer patients improve their competence in SDM by appropriate training, their patients may suffer less anxiety and depression. These effects merit further study. PMID- 26517596 TI - Additions. PMID- 26517597 TI - In Reply. PMID- 26517598 TI - Bacterial resistance in biofilm-associated bacteria. AB - Biofilms are structured groups of different bacterial species that are responsible for most chronic and recurrent infections. Biofilm-related infections reoccur in approximately 65-80% of cases. Bacteria associated with the biofilm are highly resistant to antibiotics. Knowledge of biofilm formation, its propagation and the resistance associated with it is scant and a multidisciplinary approach is followed to understand the science and develop strategies to address this problem. This article discusses the role of various biochemical factors, molecular mechanisms and altered host environment causes associated with bacterial resistance in biofilm. It also reveals the target sites and different multidisciplinary strategies adapted for destroying or preventing the formation of biofilms. PMID- 26517599 TI - Progressive multifocal leukoencephalopathy associated to natalizumab extended dosing regimen. AB - A risk for developing progressive multifocal leukoencephalopathy is a major barrier to natalizumab use. Extended dosing intervals have been proposed as a way to maintain therapeutic efficacy and reduce progressive multifocal leukoencephalopathy incidence. This is the first reported case of progressive multifocal leukoencephalopathy in a patient using an extended dosing regimen (300 mg/6 weeks). A close clinical and imaging monitoring allowed early detection, which is a major prognostic factor. A favorable outcome was seen with a therapy comprising plasma exchange therapy, mirtazapine, mefloquine and cidofovir. Further studies will be needed to assess the potential role of extended dosing intervals to improve prognosis in patients receiving natalizumab and also to measure its impact clinically and/or radiologically. PMID- 26517601 TI - Cost-effectiveness of lenalidomide plus dexamethasone vs. bortezomib plus melphalan and prednisone in transplant-ineligible U.S. patients with newly diagnosed multiple myeloma. AB - OBJECTIVE: To conduct a cost-effectiveness assessment of lenalidomide plus dexamethasone (Rd) vs bortezomib plus melphalan and prednisone (VMP) as initial treatment for transplant-ineligible patients with newly-diagnosed multiple myeloma (MM), from a U.S. payer perspective. METHODS: A partitioned survival model was developed to estimate expected life-years (LYs), quality-adjusted LYs (QALYs), direct costs and incremental costs per QALY and LY gained associated with use of Rd vs VMP over a patient's lifetime. Information on the efficacy and safety of Rd and VMP was based on data from multinational phase III clinical trials and a network meta-analysis. Pre-progression direct costs included the costs of Rd and VMP, treatment of adverse events (including prophylaxis) and routine care and monitoring associated with MM. Post-progression direct costs included costs of subsequent treatment(s) and routine care and monitoring for progressive disease, all obtained from published literature and estimated from a U.S. payer perspective. Utilities were obtained from the aforementioned trials. Costs and outcomes were discounted at 3% annually. RESULTS: Relative to VMP, use of Rd was expected to result in an additional 2.22 LYs and 1.47 QALYs (discounted). Patients initiated with Rd were expected to incur an additional $78,977 in mean lifetime direct costs (discounted) vs those initiated with VMP. The incremental costs per QALY and per LY gained with Rd vs VMP were $53,826 and $35,552, respectively. In sensitivity analyses, results were found to be most sensitive to differences in survival associated with Rd vs VMP, the cost of lenalidomide and the discount rate applied to effectiveness outcomes. CONCLUSIONS: Rd was expected to result in greater LYs and QALYs compared with VMP, with similar overall costs per LY for each regimen. Results of this analysis indicated that Rd may be a cost-effective alternative to VMP as initial treatment for transplant-ineligible patients with MM, with an incremental cost effectiveness ratio well within the levels for recent advancements in oncology. PMID- 26517600 TI - Tolerance to noninherited maternal antigens, reproductive microchimerism and regulatory T cell memory: 60 years after 'Evidence for actively acquired tolerance to Rh antigens'. AB - Compulsory exposure to genetically foreign maternal tissue imprints in offspring sustained tolerance to noninherited maternal antigens (NIMA). Immunological tolerance to NIMA was first described by Dr. Ray D. Owen for women genetically negative for erythrocyte rhesus (Rh) antigen with reduced sensitization from developmental Rh exposure by their mothers. Extending this analysis to HLA haplotypes has uncovered the exciting potential for therapeutically exploiting NIMA-specific tolerance naturally engrained in mammalian reproduction for improved clinical outcomes after allogeneic transplantation. Herein, we summarize emerging scientific concepts stemming from tolerance to NIMA that includes postnatal maintenance of microchimeric maternal origin cells in offspring, expanded accumulation of immune suppressive regulatory T cells with NIMA specificity, along with teleological benefits and immunological consequences of NIMA-specific tolerance conserved across mammalian species. PMID- 26517603 TI - Subclinical labial salivary gland involvement in IgG4-related disease affected with vital organs. PMID- 26517602 TI - Regulation of the primary quinone binding conformation by the H subunit in reaction centers from Rhodobacter sphaeroides. AB - Unlike photosystem II (PSII) in higher plants, bacterial photosynthetic reaction centers (bRCs) from Proteobacteria have an additional peripheral membrane subunit "H". The H subunit is necessary for photosynthetic growth, but can be removed chemically in vitro. The remaining LM dimer retains its activity to perform light induced charge separation. Here we investigate the influence of the H subunit on interactions between the primary semiquinone and the protein matrix, using a combination of site-specific isotope labeling, pulsed electron paramagnetic resonance (EPR), and density functional theory (DFT) calculations. The data reveal substantially weaker binding interactions between the primary semiquinone and the LM dimer than observed for the intact bRC; the amount of electron spin transferred to the nitrogen hydrogen bond donors is significantly reduced, the methoxy groups are more free to rotate, and the spectra indicate a heterogeneous mixture of bound semiquinone states. These results are consistent with a loosening of the primary quinone binding pocket in the absence of the H subunit. PMID- 26517604 TI - Influence of basketball shoe mass, outsole traction, and forefoot bending stiffness on three athletic movements. AB - Prior research has shown that footwear can enhance athletic performance. However, public information is not available on what basketball shoe properties should be selected to maximise movement performance. Therefore, the purpose of the study was to investigate the influence of basketball shoe mass, outsole traction, and forefoot bending stiffness on sprinting, jumping, and cutting performance. Each of these three basketball shoe properties was systematically varied by +/- 20% to produce three shoe conditions of varying mass, three conditions of varying traction, and three conditions of varying bending stiffness. Each shoe was tested by 20 recreational basketball players completing maximal effort sprints, vertical jumps, and a cutting drill. Outsole traction had the largest influence on performance, as the participants performed significantly worse in all tests when traction was decreased by 20% (p < 0.001), and performed significantly better in the cutting drill when traction was increased by 20% (p = 0.005). Forefoot bending stiffness had a moderate effect on sprint and cutting performance (p = 0.013 and p = 0.016 respectively) and shoe mass was found to have no effect on performance. Therefore, choosing a shoe with relatively high outsole traction and forefoot bending stiffness should be prioritised, and less concern should be focused on selecting the lightest shoe. PMID- 26517605 TI - The effect of time-of-day on static and dynamic balance in recreational athletes. AB - The purpose of this study was to investigate the effect of time-of-day (morning vs. afternoon) on static and dynamic balance in recreational athletes. A total of 34 recreational athletes completed the single-leg stance test with or without eyes open, lower quarter Y-balance test, upper quarter Y-balance test, and single leg landing balance test in a random order in the morning (7:00-10:00 am) and afternoon (3:00-6:00 pm) for two consecutive days. Compared with the morning, participants demonstrated decreased centre of pressure (COP) sway areas (p = 0.002; Cohen's d (d) = 0.28) and sway speeds (p = 0.002; d = 0.17) during the eyes-open single-leg stance test, increased stance time (p = 0.031; d = 0.16) and decreased COP sway areas (p = 0.029; d = 0.22) during the eyes-closed single-leg stance test, and increased reaching distances (p = 0.024; d = 0.10) during the upper quarter Y-balance test in the afternoon. The between-day effect (day 1 vs. day 2) was observed for several parameters. Time-of-day had a minimal effect on dynamic balance and a noticeable effect on static balance. Time-of-day may be considered as a factor in designing balance training programmes and intervention studies for recreational athletes. PMID- 26517607 TI - Rumors of the demise of the extension veterinarian. PMID- 26517608 TI - CAABs lend helping hand. PMID- 26517609 TI - What Is Your Diagnosis? Dentigerous cyst. PMID- 26517610 TI - ECG of the Month. Focal atrial tachycardia. PMID- 26517611 TI - Theriogenology Question of the Month. Neoplasms of the penis and testis. PMID- 26517612 TI - Animal Behavior Case of the Month. Reactional urine marking. PMID- 26517613 TI - Pathology in Practice. Lymphomatoid granulomatosis of lung tissue and mediastinal lymph node in a dog. PMID- 26517614 TI - Pathology in Practice. Concurrent metastatic mammary adenocarcinoma and ovarian cystadenocarcinoma in a jaguar. PMID- 26517615 TI - A systematic review of the effects of euthanasia and occupational stress in personnel working with animals in animal shelters, veterinary clinics, and biomedical research facilities. AB - BACKGROUND: The study of occupational stress and compassion fatigue in personnel working in animal-related occupations has gained momentum over the last decade. However, there remains incongruence in understanding what is currently termed compassion fatigue and the associated unique contributory factors. Furthermore, there is minimal established evidence of the likely influence of these conditions on the health and well-being of individuals working in various animal-related occupations. OBJECTIVE: To assess currently available evidence and terminology regarding occupational stress and compassion fatigue in personnel working in animal shelters, veterinary clinics, and biomedical research facilities. DATA SOURCE: Studies were identified by searching the following electronic databases with no publication date restrictions: ProQuest Research Library, ProQuest Social Science Journals, PsycARTICLES, Web of Science, Science Direct, Scopus, PsychINFO databases, and Google Scholar. Search terms included (euthanasia AND animals) OR (compassion fatigue AND animals) OR (occupational stress AND animals). STUDY APPRAISAL AND SYNTHESIS: Only articles published in English in peer-reviewed journals that included use of quantitative or qualitative techniques to investigate the incidence of occupational stress or compassion fatigue in the veterinary profession or animal-related occupations were included. On the basis of predefined criteria, 1 author extracted articles, and the data set was then independently reviewed by the other 2 authors. RESULTS: 12 articles met the selection criteria and included a variety of study designs and methods of data analysis. Seven studies evaluated animal shelter personnel, with the remainder evaluating veterinary nurses and technicians (2), biomedical research technicians (1), and personnel in multiple animal-related occupations (2). There was a lack of consistent terminology and agreed definitions for the articles reviewed. Personnel directly engaged in euthanasia reported significantly higher levels of work stress and lower levels of job satisfaction, which may have resulted in higher employee turnover, psychological distress, and other stress-related conditions. LIMITATIONS AND CONCLUSIONS: Results of this review suggested a high incidence of occupational stress and euthanasia-related strain in animal care personnel. The disparity of nomenclature and heterogeneity of research methods may contribute to general misunderstanding and confusion and impede the ability to generate high-quality evidence regarding the unique stressors experienced by personnel working with animals. The present systematic review provided insufficient foundation from which to identify consistent causal factors and outcomes to use as a basis for development of evidence-based stress management programs, and it highlights the need for further research. PMID- 26517616 TI - Evaluation of an enzyme immunoassay for antibodies to a recombinant Blastomyces adhesin-1 repeat antigen as an aid in the diagnosis of blastomycosis in dogs. AB - OBJECTIVE: To evaluate the sensitivity and specificity of an enzyme immunoassay (EIA) for antibodies to a recombinant Blastomyces adhesin-1 repeat antigen (rBAD 1) to aid in the diagnosis of blastomycosis in dogs and compare the findings with results from other tests used for this purpose. DESIGN: Prospective analytic study. SAMPLE: Serum and urine from 70 dogs with and without blastomycosis. PROCEDURES: Serum and urine samples were collected from dogs with blastomycosis (n = 21), histoplasmosis (8), or nonfungal pulmonary disease (21) and from healthy control dogs living in a blastomycosis-endemic area (20). Serum was tested for antibodies against Blastomyces dermatitidis with the rBAD-1 antibody EIA and an A-antigen antibody agar gel immunodiffusion (AGID) assay. Serum and urine were tested for B dermatitidis antigen with a quantitative EIA. RESULTS: Sensitivity of the quantitative antigen EIA was 100% in serum and urine samples from dogs with blastomycosis, with specificity of 95% in urine samples from dogs with nonfungal pulmonary disease and 100% in urine samples from healthy dogs. Sensitivity of the rBAD-1 antibody EIA (95%) was significantly greater than that of the A-antigen antibody AGID assay (65%). Specificity of the antibody EIA was 88% in dogs with histoplasmosis, 95% in healthy dogs, and 100% in dogs with nonfungal pulmonary disease. CONCLUSIONS AND CLINICAL RELEVANCE: The rBAD-1 antibody EIA had greater sensitivity than the A-antigen antibody AGID assay in dogs with blastomycosis. This antibody EIA may assist in distinguishing histoplasmosis from blastomycosis. Further evaluation in a larger prospective study is needed to verify these results. PMID- 26517617 TI - Incidence rates and risk factors for owner-reported adverse events following vaccination of dogs that did or did not receive a Leptospira vaccine. AB - OBJECTIVE: To determine incidence rates (IRs) and potential risk factors for owner-reported adverse events (AEs) following vaccination of dogs that did or did not receive a Leptospira vaccine. DESIGN: Observational, retrospective cohort study. ANIMALS: 130,557 dogs. PROCEDURES: Electronic records of mobile veterinary clinics from June 2012 to March 2013 were searched to identify dogs that received >= 1 vaccine in a given visit. Signalment data, vaccinations received, medications administered, and owner-reported clinical signs consistent with AEs that developed <= 5 days after vaccination were recorded. Associations between potential risk factors and owner-reported AEs were evaluated by logistic regression analysis. RESULTS: The IR/10,000 dogs for owner-reported postvaccination AEs was 26.3 (95% CI, 23.6 to 29.2), whereas that for dogs that received a Leptospira vaccine alone or with other vaccines was 53.0 (95% CI, 42.8 to 64.9). Significant factors for increasing or decreasing risk of AEs were as follows: receiving a Leptospira vaccine (adjusted OR, 2.13), age at vaccination 1 to < 7 or >= 7 years (vs a referent of < 6 months; adjusted OR, 0.54 and 0.44, respectively), and weight 13.6 to < 22.7 kg (30 to < 50 lb) and 22.7 to < 45.5 kg (50 to 100 lb [vs a referent of < 4.5 kg {10 lb}]; adjusted OR, 0.48 and 0.55, respectively). Hypersensitivity reactions were rare (IR, 6.5/10,000 dogs), and IRs for these events did not differ significantly between dogs vaccinated with or without a Leptospira component. CONCLUSIONS AND CLINICAL RELEVANCE: The overall IR for owner-reported postvaccination AEs was low. Results suggested vaccination against Leptospira (an organism that can cause fatal disease) is safe in the majority of cases, slightly increasing the risk of owner-reported AEs but not associated with a significant increase in hypersensitivity reactions, compared with other vaccinations administered. PMID- 26517618 TI - Outcomes of dogs undergoing radiotherapy for treatment of oral malignant melanoma: 111 cases (2006-2012). AB - OBJECTIVE: To evaluate the characteristics and outcomes of dogs with stage I, II, III, or IV oral malignant melanoma treated by various types of radiotherapy. DESIGN: Retrospective case series. ANIMALS: 111 dogs. PROCEDURES: Medical records of dogs with oral malignant melanoma treated by radiotherapy (with or without adjunctive treatments) at a veterinary medical center between July 2006 and December 2012 were reviewed. Information regarding signalment, tumor location, disease stage, treatment protocols, adverse effects, and survival time were obtained from medical records and by telephone follow-up. Associations between variables of interest and outcome were analyzed. RESULTS: Dogs received orthovoltage x-ray (n = 68), megavoltage x-ray (39), or electron beam (4) radiotherapy. Adjunctive treatments included debulking surgery (n = 18), chemotherapy (39), or both (27). Median survival times for dogs with stage I, II, III, and IV melanoma were 758 days (n = 19), 278 days (24), 163 days (37), and 80 days (31), respectively, and differed significantly between dogs with stage I disease and those with all other disease stages. Among dogs with stage III melanoma, risk of death was significantly higher in those that received orthovoltage x-ray treatment than in those that received megavoltage x-ray treatment. Severe (primary or secondary) adverse effects were identified in 9 dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Median survival time was significantly longer for dogs with stage I oral malignant melanoma than for dogs with more advanced disease at the time of staging. The staging system used may be a useful tool for prognosis prediction in dogs undergoing similar treatment protocols for oral malignant melanomas. PMID- 26517619 TI - External skeletal fixator intramedullary pin tie-in for the repair of tibiotarsal fractures in raptors: 37 cases (1995-2011). AB - OBJECTIVE: To evaluate the outcome of the application of an external skeletal fixator intramedullary pin tie-in (TIF) to tibiotarsal fractures in raptors. DESIGN: Retrospective case series. ANIMALS: Thirty-four raptors with 37 tibiotarsal fractures. PROCEDURES: Medical records and radiographs for raptors with tibiotarsal fractures that were treated at The Raptor Center at the University of Minnesota between 1995 and 2011 were reviewed. Descriptive statistics were generated and univariate logistic regression analyses were used to assess whether age, sex, body weight, location and nature of the fracture, and type of surgical reduction were significantly associated with whether the fracture healed following surgical reduction and TIF application. RESULTS: 31 of 37 (84%) tibiotarsal fractures successfully healed following surgical reduction and TIF application. The mean healing time was 38 days (range, 15 to 70 days). None of the variables assessed were significantly associated with whether the tibiotarsal fracture healed. Twenty of the 34 (59%) raptors were eventually rehabilitated and released. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that most tibiotarsal fractures were successfully managed by surgical reduction and stabilization with a TIF. However, other comorbidities (eg, systemic infections and visual deficits) negatively affected the rehabilitation of raptors and sometimes resulted in euthanasia despite the fact that the tibiotarsal fracture had healed, and those comorbidities, along with the variables evaluated (eg, age, sex, and nature of the fracture), should be used as triage criteria and prognostic indicators. PMID- 26517620 TI - Predictor variables for and complications associated with Streptococcus equi subsp equi infection in horses. AB - OBJECTIVE: To evaluate predictor variables for and complications associated with Streptococcus equi subsp equi infection (strangles) in horses. DESIGN: Retrospective case-control study. ANIMALS: 108 horses with strangles (cases) and 215 horses without strangles (controls). PROCEDURES: Medical records from January 2005 through July 2012 were reviewed. Cases were defined as horses with clinical signs of strangles (pyrexia, retropharyngeal lymphadenopathy, and mucopurulent nasal discharge) that were associated with a confirmed strangles outbreak or had positive results for S equi on PCR assay or bacteriologic culture. Controls were defined as horses with pyrexia that did not meet the other criteria for cases. Data compared between cases and controls included signalment, clinical signs, diagnostic test results, and disease complications and outcome. Logistic regression was used to identify variables associated with strangles and its complications. RESULTS: Clinical signs of strangles were not evident in 12 of 25 cases classified as S equi carriers (infected > 40 days). Predictor variables associated with strangles included mucopurulent nasal discharge and external abscesses in the pharyngeal region. Strangles was more likely to be diagnosed in the spring than in the summer. Cases with anemia were more likely to develop purpura hemorrhagica than were cases without anemia. No risk factors were identified for the development of guttural pouch empyema or metastatic abscesses. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that not all horses infected with S equi develop clinical signs of strangles. We recommend that guttural pouch endoscopy and lavage with PCR assay of lavage fluid samples be performed to identify S equi carrier horses. PMID- 26517621 TI - Randomized controlled trial comparing endoscopic ligation with or without sclerotherapy for secondary prophylaxis of variceal bleeding. AB - OBJECTIVES: A recently published network meta-analysis showed that ligation combined with sclerotherapy might be the most efficacious intervention for secondary prophylaxis of variceal bleeding. Most studies excluded patients with concomitant gastric varices; thus, the outcomes in such patients have not yet been reported. The present study aimed to investigate the efficacy of two endoscopic procedures for secondary prophylaxis in cirrhotic patients presenting with both esophageal and gastric varices. MATERIALS AND METHODS: A randomized controlled study was carried out in a tertiary care referral center. Patients were randomized into two groups: sclerotherapy- and sclerotherapy+ group. Continued endoscopic ligation was used to treat esophageal varices in the sclerotherapy- group, whereas combined ligation and sclerotherapy with lauromacrogol was performed in the sclerotherapy+ group. A cyanoacrylate injection was used for gastric varices in both groups. All participants were followed up for 6 months. RESULTS: Overall, 96 patients were included between 25 March 2012 and 25 June 2013. Three patients were lost during follow-up (one in the sclerotherapy- group and two in the sclerotherapy+ group). The cumulative recurrence rate of bleeding was significantly higher in the sclerotherapy+ group (14.6 vs. 35.4%, P=0.013). The cumulative mortality rate (2.1 vs. 6.3%, P=0.286) and the incidence rate of adverse events were similar between the two groups. CONCLUSION: Continued ligation+cyanoacrylate injection was superior to combined ligation and sclerotherapy+cyanoacrylate injection during the first 6 months in terms of rebleeding in cirrhotic patients presenting with both esophageal and gastric varices. Long-term results entail further investigation (http://www.clinicaltrials.gov, NCT01592578). PMID- 26517622 TI - Suprasellar Primitive Neuroectodermal Tumor in an Adult. AB - Primitive neuroectodermal tumors (PNET) of the central nervous system (CNS) are a heterogeneous group of embryonal malignancies that are composed of undifferentiated or poorly differentiated neuroepithelial cells. Supratentorial PNET is the second most common CNS embryonal malignancy in children, but it is rare in adults. We report the case of a 31-year-old woman with bilateral vision loss and a bitemporal hemianopia. Neuroimaging revealed a suprasellar mass, and pathology was consistent with PNET. After surgical debulking of the tumor followed by radiation therapy and chemotherapy, the patient had significant visual recovery and remained stable over 14 months of follow-up. PMID- 26517623 TI - The role of multiparametric flow cytometry in the detection of minimal residual disease in acute leukaemia. AB - Flow cytometry is the most accessible method for minimal residual disease (MRD) detection due to its availability in most haematological centres. Using a precise combination of different antibodies, immunophenotypic detection of MRD in acute leukaemia can be performed by identifying abnormal combinations or expressions of antigens on malignant cells at diagnosis, during and post treatment. These abnormal phenotypes, referred to as leukaemia-associated immunophenotypes (LAIPs) are either absent or expressed at low frequency in normal bone marrow (BM) cells and are used to monitor the behaviour and quantitate the amount of residual disease following treatment. In paediatric acute lymphoblastic leukaemia (ALL), the level of MRD by multiparametric flow cytometry (MPFC) during therapy is recognised as an important predictor of outcome. Although less extensively studied, adult ALL and adult and paediatric acute myeloid leukaemia (AML) have also demonstrated similar findings. The challenge now is incorporating this information for risk-stratification so that therapy can be tailored individually and ultimately improve outcome while also limiting treatment-related toxicity. In this review we will elaborate on the current and future role of MPFC in MRD in acute leukaemia while also addressing its limitations. PMID- 26517624 TI - Reassessment of H&E stained clot specimens and immunohistochemistry of phosphorylated Stat5 for histological diagnosis of MDS/MPN. AB - Few studies have comprehensively analysed histopathological findings of bone marrow clots for diagnosis of haematopoietic cell dysplasia. In particular, a limited number of studies have assessed the use of haematoxylin and eosin (H&E) staining, which is generally considered less informative than May-Giemsa staining. In the current study, the utility of bone marrow clot specimens for diagnosis was examined using H&E staining and immunohistochemistry. Patients with myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN), including chronic myelomonocytic leukaemia (CMML), atypical chronic myeloid leukaemia (aCML) lacking Philadelphia chromosome, and juvenile myelomonocytic leukaemia (JMML), were selected for histological evaluation. H&E stained specimens were advantageous for observation of atypical basophilic staining of the cytoplasm and nucleus related to dysplasia. This finding was significantly supported for both MDS and MDS/MPN (p < 0.05 versus May-Giemsa staining); therefore, we concluded that H&E staining could be used for identification of dysplastic cells. In addition, despite the loss of tissue structure, phosphorylated Stat5 immunostaining was sufficiently useful for the observation of myelodysplastic blasts. Thus, clot specimens are useful for diagnosis of haematopoietic dysplasia by pathologists. PMID- 26517625 TI - Antibiotic susceptibility of diverse Mycobacterium abscessus complex strains in New South Wales, Australia. AB - Members of the Mycobacterium abscessus complex are emerging pathogens of increasing importance, causing both respiratory and soft tissue infections, but precise speciation is problematic. This study was performed to examine the subspecies and antibiotic susceptibility of M. abscessus complex isolates collected during 2013 at the statewide New South Wales Mycobacterium Reference Laboratory (NSW MRL), Australia. Mycobacterium abscessus subsp. abscessus accounted for more than half of all M. abscessus isolates (n = 24, 57.1%), and M. abscessus subsp. massiliense comprised the remainder of the isolates (n = 18, 42.9%). There were no M. abscessus subsp. bolletii isolates. The prevalence of antibiotic resistance to all antibiotics, apart from amikacin was high, with 26.3% of isolates being reliably susceptible to only amikacin. Most M. abscessus subsp. abscessus isolates (80%) demonstrated inducible clarithromycin resistance whereas the majority of M. abscessus subsp. massiliense isolates (94.4%) remained susceptible to clarithromycin. There was a good correlation between the erm(41) genotype and clarithromycin susceptibility results after 14 days of incubation for most isolates with only three exceptions. Further studies correlating in vitro susceptibility profiles with clinical outcomes of M. abscessus infections treated with combination antimicrobial therapy are warranted. PMID- 26517626 TI - Foamy gland changes in gastric-type endocervical neoplasia. AB - Foamy gland (FG) change is a distinctive morphological alteration most widely recognised in adenocarcinomas of the prostate and pancreas, and characterised by cells showing prominent cytoplasmic microvacuolation often with deceptively bland nuclear appearances. To our knowledge, FG alteration has not been described in endocervical neoplasia. We report four patients with gastric-type endocervical neoplasms (3 invasive and 1 in situ) in which FG change was present in 30-80% of the tumour cells. The mean age was 56.5 years (range 45-66 years) and three patients, one of whom also had post-coital bleeding, had atypical glandular cells detected on cervical cytology. Three cases showed a pure gastric phenotype and benign gastric-type changes including pyloric metaplasia, tunnel clusters and/or lobular endocervical glandular hyperplasia were also present. These cases were MUC6 positive and p16 negative on immunohistochemistry while HPV was not detected. One adenocarcinoma showed a mixed histological pattern including usual type endocervical carcinoma and gastric-type adenocarcinoma: only the latter component expressed MUC6 and this case was p16 and HPV18 positive. This report expands the morphological spectrum exhibited by gastric-type endocervical lesions and the range of anatomical sites in which neoplasms with FG features may be encountered. PMID- 26517627 TI - Clinicopathological characterisation of duodenal adenocarcinoma with high CD44 variant 9 expression. AB - CD44 has been identified as a cancer stem cell (CSC) biomarker in various malignancies. The aim of this study was to elucidate the clinicopathological features of CD44v9 positive cells in duodenal adenocarcinoma (DA).Twenty-nine DA patients were selected from medical archives at our hospital. CD44v9 expression was analysed together with that of MUC2, MUC5AC, and MUC6 by immunohistochemistry. High levels of CD44v9 expression weakly correlated with inflammatory cell infiltration (r = 0.431, p = 0.020) and MUC6 expression (r = 0.425, p = 0.022). Furthermore, double immunofluorescence staining of CD44v9 and Ki-67 or cleaved caspase 3 (CC3) was performed. High- and low-density areas of CD44v9 positive cells were designated as CD44v9 positive and negative areas, respectively. Within CD44v9 positive areas, the level of Ki-67 positivity among CD44v9 positive cells was significantly lower than that of CD44v9 negative cells (p = 0.002). Meanwhile, the level of CC3 positivity among CD44v9 positive cells was significantly lower than that of CD44v9 negative cells (p < 0.001).CD44v9 expression may be affected by mononuclear cell infiltration and MUC6 expression in DA. CD44v9 positive cells also have a low mitotic activity and resist apoptosis. These characteristics suggest that CD44v9 positive cells possess CSC like properties in DA. PMID- 26517628 TI - Evaluation of the Dual Path Platform syphilis point of care test in North Queensland. PMID- 26517629 TI - Giant inflammatory polyposis with Crohn disease-like colitis. PMID- 26517630 TI - Laminated saccules: a residuum of an ovarian mature cystic teratoma. PMID- 26517631 TI - B3 thymoma arising within thymolipoma. PMID- 26517632 TI - BAP1 deficient malignant melanoma arising from the intradermal component of a congenital melanocytic naevus. PMID- 26517634 TI - Transfusions, troubled breathing, and transient neutropenia. PMID- 26517633 TI - Combined serous carcinoma and neuroendocrine carcinoma of the fallopian tube. PMID- 26517635 TI - Evaluation of Abbott Architect high-sensitivity troponin I assay for haemolysis interference. PMID- 26517636 TI - Giant cell tumour of the gallbladder can mimic undifferentiated/anaplastic carcinoma clinically and pathologically. PMID- 26517637 TI - Amoebic encephalitis in a farmer. PMID- 26517638 TI - Tumour procurement, DNA extraction, coverage analysis and optimisation of mutation-detection algorithms for human melanoma genomes. AB - Whole genome sequencing (WGS) of cancer patients' tumours offers the most comprehensive method of identifying both novel and known clinically-actionable genomic targets. However, the practicalities of performing WGS on clinical samples are poorly defined.This study was designed to test sample preparation, sequencing specifications and bioinformatic algorithms for their effect on accuracy and cost-efficiency in a large WGS analysis of human melanoma samples.WGS was performed on melanoma cell lines (n = 15) and melanoma fresh frozen tumours (n = 222). The appropriate level of coverage and the optimal mutation detection algorithm for the project pipeline were determined.An incremental increase in sequencing coverage from 36X to 132X in melanoma tissue samples and 30X to 103X for cell lines only resulted in a small increase (1-2%) in the number of mutations detected, and the quality scores of the additional mutations indicated a low probability that the mutations were real. The results suggest that 60X coverage for melanoma tissue and 40X for melanoma cell lines empower the detection of 98-99% of informative single nucleotide variants (SNVs), a sensitivity level at which clinical decision making or landscape research projects can be carried out with a high degree of confidence in the results. Likewise the bioinformatic mutation analysis methodology strongly influenced the number and quality of SNVs detected. Detecting mutations in the blood genomes separate to the tumour genomes generated 41% more SNVs than if the blood and melanoma tissue genomes were analysed simultaneously. Therefore, simultaneous analysis should be employed on matched melanoma tissue and blood genomes to reduce errors in mutation detection.This study provided valuable insights into the accuracy of SNV with WGS at various coverage levels in human clinical cancer specimens. Additionally, we investigated the accuracy of the publicly available mutation detection algorithms to detect cancer specific SNVs which will aid researchers and clinicians in study design and implementation of WGS for the identification of somatic mutations in other cancers. PMID- 26517639 TI - A rare perivascular epithelioid cell tumour (PEComa) of the duodenum misdiagnosed by endoscopic needle aspiration biopsy. PMID- 26517640 TI - Cancer stem cell markers in prostate cancer: an immunohistochemical study of ALDH1, SOX2 and EZH2. AB - The aims of this study were to investigate the immunohistochemical expression and potential prognostic significance of putative cancer stems cell markers ALDH1, EZH2 and SOX2 in prostate cancer.A total of 142 consecutive radical prostatectomies submitted to one laboratory with a diagnosis of prostatic adenocarcinoma between 2008 and 2012 were retrieved and retrospectively studied. Immunohistochemistry for the three markers was performed in each case and both univariate and multivariate analyses were undertaken to evaluate the correlation between the staining patterns and known histopathological prognostic features.ALDH1 showed a statistically significant association with tumour stage p < 0.001), extraprostatic extension (p < 0.001) and lymphovascular invasion (p = 0.001). EZH2 correlated with Gleason score (p = 0.044) and lymph node metastases (p = 0.023). SOX2 showed a statistically significant correlation with lymphovascular invasion only (p = 0.018) in both univariate and multivariate analyses.Cancer stem cell markers are variably expressed in prostate adenocarcinoma and immunohistochemical staining for ALDH1 and EZH2 may have a role in predicting tumour aggressiveness before treatment of prostate cancer. PMID- 26517641 TI - Epithelioid rhabdomyosarcoma: a clinicopathological study of seven additional cases supporting a distinctive variant with aggressive biological behaviour. AB - We present our experience with seven cases of epithelioid rhabdomyosarcoma (RMS) to further characterise its clinicopathological features. There were five males and two females with ages ranging from 19 to 84 years (mean 56 years). Four tumours occurred in the somatic soft tissue, two in organs and one in the bone. The mean tumour size was 10.7 cm (range 3.5-15 cm). Histologically, six tumours were characterised by sheet-like growth of uniform epithelioid cells with large vesicular nuclei, prominent nucleoli, high mitotic activity and moderate to abundant amphophilic-to-eosinophilic cytoplasm. One tumour was composed of dyscohesive cells with rhabdoid appearance embedded in a myxoid matrix. Features suggestive of rhabdomyoblastic differentiation were absent. However, immunohistochemical study revealed skeletal muscle differentiation in all cases. Of note, focal expression of epithelial markers with co-expression of neuroendocrine markers was noted in five and three cases, respectively. Of six patients with follow-up, one experienced local recurrence and three developed metastases. To date, three patients have died of disease within 14 months. This study further demonstrates that epithelioid RMS represents a distinct variant of RMS with an aggressive behaviour. It may be misdiagnosed as poorly differentiated neuroendocrine carcinoma due to co-expression of epithelial and neuroendocrine markers. PMID- 26517642 TI - Prognostic relevance of proliferation markers (Ki-67, PHH3) within the cross relation of ERG translocation and androgen receptor expression in prostate cancer. AB - We evaluated the prognostic value of the mitosis-associated marker phosphorylated histone H3 (PHH3) and Ki-67 in prostate cancer with respect to ERG status and androgen receptor (AR) expression.PHH3 and Ki-67 expression was immunohistochemically detected and digitally quantitated in a radical prostatectomy cohort (n = 640). The results were correlated to clinicopathological parameters including biochemical recurrence times. Prognostic values of PHH3 and Ki-67 were analysed by Cox regression and Kaplan-Meier statistics.In prostate cancer, mean Ki-67 and PHH3 rates were 3.40% (95%CI 3.16 3.63%) and 0.0152% (95%CI 0.0112-0.0191%), respectively.Ki-67 showed a significant correlation with Gleason scores, pT status, margin status, and AR expression, while PHH3 showed a significant correlation with Gleason scores and pT status. Univariate analyses for biochemical recurrence times demonstrated a significant prognostic value for median Ki-67 rate and for the PHH3 rate of the 90th percentile. Of importance, in patient subgroups stratified according to AR expression and ERG translocation, the prognostic power of proliferation markers PHH3 and Ki-67 was markedly enhanced in ERG translocation negative and high-level AR expressing ERG translocation positive prostate cancers.As expected, the proliferation markers PHH3 and Ki-67 predict adverse outcome of prostate cancer and have a particularly pronounced prognostic value in specific molecular subsets of prostate cancer (ERG- or AR+). PMID- 26517643 TI - Predicting discordant HER2 results in ipsilateral synchronous invasive breast carcinomas: experience from a single institution. AB - With the emergence of multiple lines of highly effective Human Epidermal Growth Factor Receptor 2 (HER2) directed therapy, accurate identification of HER2 positive tumour has become a critical aspect in the histopathological analysis of breast cancers. Multifocal invasive breast carcinomas are relatively common, and given the aggressive inherent biology of HER2 positive disease, identification of even small tumours with HER2 positive status may be of importance for treatment planning. There are currently no clear guidelines as to whether all of these foci should be tested for HER2 status. We reviewed the results of 172 patients in whom HER2 in situ hybridisation (ISH) testing was performed on at least two ipsilateral synchronous invasive carcinomas. Discordant results in different invasive foci were relatively uncommon and occurred in only eight (5%) of the 172 patients. This showed a statistically significant correlation with similarly discordant oestrogen receptor (ER) results. In addition HER2 discordance was more likely amongst different tumour foci if these arose in distinct and separate areas of DCIS. An algorithm based on a combination of College of American Pathologists (CAP) recommendation for HER2 testing, differing ER status and background DCIS profile may be useful in detecting these discordant cases. PMID- 26517644 TI - Concordance of HER2 expression in paired primary and metastatic sites of gastric and gastro-oesophageal junction cancers. AB - HER2 is amplified/overexpressed in a subset of gastric and gastro-oesophageal junction cancers. Addition of anti-HER2 therapy has been shown to provide survival benefit in this setting. However, there are limited data assessing the concordance of HER2 status between primary and metastatic sites.A total of 113 samples from 43 paired primary and metastatic tumours were tested for HER2 status, by immunohistochemistry (IHC) for protein expression and silver in situ hybridisation (SISH) for gene amplification.Primary sites tested included endoscopic biopsies (n = 30) and resections (n = 24). Metastatic samples included lymph nodes (n = 29), peritoneal effusions (n = 21) and miscellaneous sites (n = 9). The overall HER2+ rate was 11%. Of 41 (95%; 95% CI 88.5-100%) concordant cases, 38 were HER2- and three were HER2+. There were two (5%) discordant cases, one of which showed heterogeneity of HER2 expression.This series confirms a high concordance rate of 95%, supporting that testing of primary tumours and metastases is equally valid and providing clinical rationale for the addition of anti-HER2 therapy in HER2+ disseminated disease. PMID- 26517645 TI - Mammary analogue secretory carcinoma: an evaluation of its clinicopathological and genetic characteristics. AB - Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland malignancy. We evaluate the clinicopathological characteristics and long term clinical behaviour of MASCs. A total of 190 primary salivary gland malignancies at a single institution were reviewed along with relevant immunohistochemical and fluorescent in situ hybridisation (FISH) studies to identify MASCs. Nine MASCs were identified predominantly in the parotid with an equal incidence in men and women and mean age of 36 years. The tumour size ranged from 14 to 50 mm (mean 22 mm). MASCs were composed of monotonous cells with vacuolated eosinophilic cytoplasm and a small nucleus with a distinctive nucleolus. All cases showed immunoreactivity with S-100, MUC4, CK7 and mammoglobin, and lacked immunoreactivity with DOG1, p63, CK5/6 and calponin. ETV6 rearrangement was seen in all cases. No mutations were identified using the OncoCarta Panel v1.0 Kit. Follow up was available for 0.4 to 22 years (median 4 years). Intraparotid lymph node involvement and local recurrence were seen in one patient each. There were no distant metastases. MASCs have specific histopathological features and immunohistochemical profile that distinguish them from their mimics. FISH plays a confirmatory role. An indolent long-term clinical course was observed in this cohort despite involvement of intraparotid lymph node and microscopically involved/close margins. PMID- 26517646 TI - Nephrotic syndrome in a man with Carney-Stratakis syndrome. PMID- 26517647 TI - Strain Loading Mode Dependent Bandgap Deformation Potential in ZnO Micro/Nanowires. AB - The electronic-mechanical coupling in semiconductor nanostructures under different strain loading modes can modulate their photoelectric properties in different manners. Here, we report the systematic investigation on the strain mode dependent bandgap deformation potential of ZnO micro/nanowires under both uniaxial tensile and bending strains at room temperature. Uniaxial stretching photoluminescence results show that the deformation potential of the smaller ZnO nanowire (with diameter d = 260 nm) is -30.6 meV/%, and is close to the bulk value, whereas it deviates the bulk value and becomes to be -10.6 meV/% when the wire diameter is increased to d = 2 MUm. This unconventional size dependence stems from surface effect induced inhomogeneous strain in the surface layer and the core of the ZnO micro/nanowires under uniaxial tension. For bending load mode, the in situ high-resolution transmission electron microscope analysis reveals that the local strain distributes linearly in the bending cross section. Further cathodoluminescence measurements on a bending ZnO microwire (d = 1.8 MUm) demonstrate that the deformation potential is -27 meV/%, whose absolute value is much larger than that of the ZnO microwire under uniaxial tension. Further analysis reveals that the distinct deformation potentials originate from the different deforming modes in ZnO micro/nanowires under bending or uniaxial tensile strains. Our results should facilitate the design of flexible optoelectronic nanodevices. PMID- 26517648 TI - High-Level Pressure Support Ventilation Attenuates Ventilator-Induced Diaphragm Dysfunction in Rabbits. AB - BACKGROUND: The effects of different modes of mechanical ventilation in the same ventilatory support level on ventilator-induced diaphragm dysfunction onset were assessed in healthy rabbits. METHODS: Twenty New Zealand rabbits were randomly assigned to 4 groups (n = 5 in each group). Group 1: no mechanical ventilation; group 2: controlled mechanical ventilation (CMV) for 24 hours; group 3: assist/control ventilation (A/C) mode for 24 hours; group 4: high-level pressure support ventilation (PSV) mode for 24 hours. Heart rate, mean arterial blood pressure, PH, partial pressure of arterial oxygen/fraction of inspired oxygen and partial pressure of arterial carbon dioxide were monitored and diaphragm electrical activity was analyzed in the 4 groups. Caspase-3 was evaluated by protein analysis and diaphragm ultra structure was assessed by electron microscopy. RESULTS: The centroid frequency and the ratio of high frequency to low frequency were significantly reduced in the CMV, A/C and PSV groups (P < 0.001). The percent change in centroid frequency was significantly lower in the PSV group than in the CMV and A/C groups (P = 0.001 and P = 0.028, respectively). Electromyography of diaphragm integral amplitude decreased by 90% +/- 1.48%, 67.8% +/- 3.13% and 70.2% +/- 4.72% in the CMV, A/C and PSV groups, respectively (P < 0.001). Caspase-3 protein activation was attenuated in the PSV group compared with the CMV and A/C groups (P = 0.035 and P = 0.033, respectively). Irregular swelling of mitochondria along with fractured and fuzzy cristae was observed in the CMV group, whereas mitochondrial cristae were dense and rich in the PSV group. The mitochondrial injury scores (Flameng scores) in the PSV group were the lowest among the 3 ventilatory groups (0.93 +/- 0.09 in PSV versus 2.69 +/- 0.05 in the CMV [P < 0.01] and PSV versus A/C groups [2.02 +/- 0.08, P < 0.01]). CONCLUSIONS: The diaphragm myoelectric activity was reduced in the PSV group, although excessive oxidative stress and ultra-structural changes of diaphragm were found. However, partial diaphragm electrical activity was retained and diaphragm injury was minimized using the PSV mode. PMID- 26517649 TI - A historical perspective on malaria control in Brazil. AB - Malaria has always been an important public health problem in Brazil. The early history of Brazilian malaria and its control was powered by colonisation by Europeans and the forced relocation of Africans as slaves. Internal migration brought malaria to many regions in Brazil where, given suitable Anopheles mosquito vectors, it thrived. Almost from the start, officials recognised the problem malaria presented to economic development, but early control efforts were hampered by still developing public health control and ignorance of the underlying biology and ecology of malaria. Multiple regional and national malaria control efforts have been attempted with varying success. At present, the Amazon Basin accounts for 99% of Brazil's reported malaria cases with regional increases in incidence often associated with large scale public works or migration. Here, we provide an exhaustive summary of primary literature in English, Spanish and Portuguese regarding Brazilian malaria control. Our goal was not to interpret the history of Brazilian malaria control from a particular political or theoretical perspective, but rather to provide a straightforward, chronological narrative of the events that have transpired in Brazil over the past 200 years and identify common themes. PMID- 26517650 TI - Toxocara canis and the allergic process. AB - The protective effect of infectious agents against allergic reactions has been thoroughly investigated. Current studies have demonstrated the ability of some helminths to modulate the immune response of infected hosts. The objective of the present study was to investigate the relationship between Toxocara canis infection and the development of an allergic response in mice immunised with ovalbumin (OVA). We determined the total and differential blood and bronchoalveolar lavage fluid cells using BALB/c mice as a model. To this end, the levels of interleukin (IL)-4, IL-5 and IL-10 and anti-OVA-IgE were measured using an ELISA. The inflammatory process in the lungs was observed using histology slides stained with haematoxylin and eosin. The results showed an increase in the total number of leukocytes and eosinophils in the blood of infected and immunised animals at 18 days after infection. We observed a slight lymphocytic inflammatory infiltrate in the portal space in all infected mice. Anti-OVA-IgE levels were detected in smaller proportions in the plasma of immunised and infected mice compared with mice that were only infected. Therefore, we concluded that T. canis potentiates inflammation in the lungs in response to OVA, although anti-OVA-IgE levels suggest a potential reduction of the inflammatory process through this mechanism. PMID- 26517651 TI - Evaluation of a recombinant rhoptry protein 2 enzyme-linked immunoassay for the diagnosis of toxoplasmosis acquired during pregnancy. AB - The aim of this study was to evaluate an enzyme-linked immunoassay with recombinant rhoptry protein 2 (ELISA-rROP2) for its ability to detect Toxoplasma gondii ROP2-specific IgG in samples from pregnant women. The study included 236 samples that were divided into groups according to serological screening profiles for toxoplasmosis: unexposed (n = 65), probable acute infection (n = 48), possible acute infection (n = 58) and exposed to the parasite (n = 65). When an indirect immunofluorescence assay forT. gondii-specific IgG was considered as a reference test, the ELISA-rROP2 had a sensitivity of 61.8%, specificity of 62.8%, predictive positive value of 76.6% and predictive negative value of 45.4% (p = 0.0002). The ELISA-rROP2 reacted with 62.5% of the samples from pregnant women with probable acute infection and 40% of the samples from pregnant women with previous exposure (p = 0.0180). Seropositivity was observed in 50/57 (87.7%) pregnant women with possible infection. The results underscored that T. gondii rROP2 is recognised by specific IgG antibodies in both the acute and chronic phases of toxoplasmosis acquired during pregnancy. However, the sensitivity of the ELISA-rROP2 was higher in the pregnant women with probable and possible acute infections and IgM reactivity. PMID- 26517652 TI - Angiostrongylus cantonensis infection in molluscs in the municipality of Sao Goncalo, a metropolitan area of Rio de Janeiro, Brazil: role of the invasive species Achatina fulica in parasite transmission dynamics. AB - The aim of this study was to analyse the infection dynamics of Angiostrongylus cantonensisin its possible intermediate hosts over two years in an urban area in the state of Rio de Janeiro where the presence ofA. cantonensis had been previously recorded in molluscs. Four of the seven mollusc species found in the study were exotic.Bradybaena similaris was the most abundant, followed by Achatina fulica, Streptaxis sp., Subulina octona, Bulimulus tenuissimus, Sarasinula linguaeformis and Leptinaria unilamellata. Only A. fulica and B. similaris were parasitised by A. cantonensis and both presented co-infection with other helminths. The prevalence of A. cantonensis in A. fulica was more than 50% throughout the study. There was an inverse correlation between the population size ofA. fulica and the prevalence of A. cantonensis and abundance of the latter was negatively related to rainfall. The overall prevalence of A. cantonensis in B. similaris was 24.6%. A. fulica was the most important intermediary host of A. cantonensis in the studied area and B. similaris was secondary in importance for A. cantonensis transmission dynamics. PMID- 26517653 TI - Detection of Oropouche virus segment S in patients and inCulex quinquefasciatus in the state of Mato Grosso, Brazil. AB - This study aimed to investigate the circulation of Orthobunyavirus species in the state of Mato Grosso (MT) Brazil. During a dengue outbreak in 2011/2012, 529 serum samples were collected from patients with acute febrile illness with symptoms for up to five days and 387 pools of female Culex quinquefasciatus captured in 2013 were subjected to nested-reverse transcription-polymerase chain reaction for segment S of the Simbu serogroup followed by nucleotide sequencing and virus isolation in Vero cells. Patients (5/529; 0.9%) from Cuiaba (n = 3), Varzea Grande (n = 1) and Nova Mutum (n = 1) municipalities were positive for the S segment of Oropouche virus (OROV). Additionally, eight/387 Cx. quinquefasciatus pools were positive for the segment, with a minimum infection rate of 2.3. Phylogenetic analysis indicated that all the samples belong to the subgenotype Ia, presenting high homology with OROV strains obtained from humans and animals in the Brazilian Amazon. The present paper reports the first detection of an Orthobunyavirus, possibly OROV, in patients and in Cx. quinquefasciatus mosquitoes in MT. This finding reinforces the notion that arboviruses frequently reported in the Amazon Region circulate sporadically in MT during dengue outbreaks. PMID- 26517654 TI - Evaluation of Haemophilus influenzae type b carrier status among children 10 years after the introduction of Hib vaccine in Brazil. AB - The aim of the present study was to assess the prevalence of Haemophilus influenzae type b (Hib) nasopharyngeal (NP) colonisation among healthy children where Hib vaccination using a 3p+0 dosing schedule has been routinely administered for 10 years with sustained coverage (> 90%). NP swabs were collected from 2,558 children who had received the Hib vaccine, of whom 1,379 were 12-< 24 months (m) old and 1,179 were 48-< 60 m old. Hi strains were identified by molecular methods. Hi carriage prevalence was 45.1% (1,153/2,558) and the prevalence in the 12-< 24 m and 48-< 60 m age groups were 37.5% (517/1,379) and 53.9% (636/1,179), respectively. Hib was identified in 0.6% (16/2,558) of all children in the study, being 0.8% (11/1,379) and 0.4% (5/1,179) among the 12-< 24 m and 48-< 60 m age groups, respectively. The nonencapsulate Hi colonisation was 43% (n = 1,099) and was significantly more frequent at 48-< 60 m of age (51.6%, n = 608) compared with that at 12-< 24 m of age (35.6%, n = 491). The overall resistance rates to ampicillin and chloramphenicol were 16.5% and 3.7%, respectively; the co-resistance was detected in 2.6%. Our findings showed that the Hib carrier rate in healthy children under five years was very low after 10 years of the introduction of the Hib vaccine. PMID- 26517655 TI - New classification of natural breeding habitats for Neotropical anophelines in the Yanomami Indian Reserve, Amazon Region, Brazil and a new larval sampling methodology. AB - Here we present the first in a series of articles about the ecology of immature stages of anophelines in the Brazilian Yanomami area. We propose a new larval habitat classification and a new larval sampling methodology. We also report some preliminary results illustrating the applicability of the methodology based on data collected in the Brazilian Amazon rainforest in a longitudinal study of two remote Yanomami communities, Parafuri and Toototobi. In these areas, we mapped and classified 112 natural breeding habitats located in low-order river systems based on their association with river flood pulses, seasonality and exposure to sun. Our classification rendered seven types of larval habitats: lakes associated with the river, which are subdivided into oxbow lakes and nonoxbow lakes, flooded areas associated with the river, flooded areas not associated with the river, rainfall pools, small forest streams, medium forest streams and rivers. The methodology for larval sampling was based on the accurate quantification of the effective breeding area, taking into account the area of the perimeter and subtypes of microenvironments present per larval habitat type using a laser range finder and a small portable inflatable boat. The new classification and new sampling methodology proposed herein may be useful in vector control programs. PMID- 26517656 TI - A randomised double-blind clinical trial of two yellow fever vaccines prepared with substrains 17DD and 17D-213/77 in children nine-23 months old. AB - This randomised, double-blind, multicentre study with children nine-23 months old evaluated the immunogenicity of yellow fever (YF) vaccines prepared with substrains 17DD and 17D-213/77. YF antibodies were titered before and 30 or more days after vaccination. Seropositivity and seroconversion were analysed according to the maternal serological status and the collaborating centre. A total of 1,966 children were randomised in the municipalities of the states of Mato Grosso do Sul, Minas Gerais and Sao Paulo and blood samples were collected from 1,714 mothers. Seropositivity was observed in 78.6% of mothers and 8.9% of children before vaccination. After vaccination, seropositivity rates of 81.9% and 83.2%, seroconversion rates of 84.8% and 85.8% and rates of a four-fold increase over the pre-vaccination titre of 77.6% and 81.8% were observed in the 17D-213/77 and 17DD subgroups, respectively. There was no association with maternal immunity. Among children aged 12 months or older, the seroconversion rates of 69% were associated with concomitant vaccination against measles, mumps and rubella. The data were not conclusive regarding the interference of maternal immunity in the immune response to the YF vaccine, but they suggest interference from other vaccines. The failures in seroconversion after vaccination support the recommendation of a booster dose in children within 10 years of the first dose. PMID- 26517657 TI - High interleukin-4 expression and interleukin-4 gene polymorphisms are associated with susceptibility to human paracoccidioidomycosis. AB - Paracoccidioidomycosis (PCM) is caused by dimorphic fungi from the Paracoccidioides brasiliensis complex. Previous studies have demonstrated that the severity of disease is associated with a T-helper 2 immune response characterised by high interleukin (IL)-4 production. In the present study we analysed two polymorphisms in the IL-4 gene (-590 C/T and intron-3 microsatellite) in 76 patients with PCM and 73 control subjects from an endemic area. The production of IL-4 by peripheral blood mononuclear cells after antigen or phytohaemagglutinin stimulation was determined by ELISA. A significant correlation was observed between the RP2/RP2 intron-3 genotype and infection with Paracoccidioides sp.(p = 0.011), whereas the RP1/RP1 genotype was correlated with resistance. No significant correlation was observed for the IL-4 promoter polymorphism. Furthermore, the low IL-4 expression observed in the control group compared with patients was associated with the RP1/RP1 genotype. These results suggest that IL-4 polymorphisms might be associated with the ability of the host to control Paracoccidioides sp.infection. The relevance of this polymorphism is supported by the observation that patients with disease produce high levels of IL 4 following mitogen or antigen stimulation. The IL-4 gene is located in the cytokine cluster region of chromosome 5 where other polymorphisms have also been described. PMID- 26517658 TI - Molecular characterisation of the NSP4 gene of group A human rotavirus G2P[4] strains circulating in Sao Paulo, Brazil, from 1994 and 2006 to 2010. AB - Group A human rotaviruses (HuRVA) are causative agents of acute gastroenteritis. Six viral structural proteins (VPs) and six nonstructural proteins (NSPs) are produced in RV-infected cells. NSP4 is a diarrhoea-inducing viral enterotoxin and NSP4 gene analysis revealed at least 15 (E1-E15) genotypes. This study analysed the NSP4 genetic diversity of HuRVA G2P[4] strains collected in the state of Sao Paulo (SP) from 1994 and 2006-2010 using reverse transcription-polymerase chain reaction, sequencing and phylogenetic analysis. Forty (97.6%) G2P[4] strains displayed genotype E2; one strain (2.4%) displayed genotype E1. These results are consistent with the proposed linkage between VP4/VP7 (G2P[4]) and the NSP4 (E2) genotype of HuRVA. NSP4 phylogenetic analysis showed distinct clusters, with grouping of most strains by their genotype and collection year, and most strains from SP were clustered together with strains from other Brazilian states. A deduced amino acid sequence alignment for E2 showed many variations in the C terminal region, including the VP4-binding domain. Considering the ability of NSP4 to generate host immunity, monitoring NSP4 variations, along with those in the VP4 or VP7 protein, is important for evaluating the circulation and pathogenesis of RV. Finally, the presence of one G2P[4]E1 strain reinforces the idea that new genotype combinations emerge through reassortment and independent segregation. PMID- 26517659 TI - Thermal preferences and limits of Triatoma brasiliensis in its natural environment--field observations while host searching. AB - The goal of this work was to explore the thermal relationship between foraging Triatoma brasiliensis and its natural habitat during the hottest season in the state of Ceara, Brazil. The thermal profiles were determined using infrared analysis. Although the daily temperature of rock surfaces varied in a wide range, T. brasiliensis selected to walk through areas with temperatures between 31.7 40.5oC. The temperature of T. brasiliensis body surface ranged from 32.8-34.4oC, being higher in legs than the abdomen. A strong relationship was found between the temperature of the insect and the temperature of rock crevices where they were hidden (r: 0.96, p < 0.05). The species was active at full sunlight being a clear example of how the light-dark rhythm may be altered, even under predation risk. Our results strongly suggest a thermal borderline for T. brasiliensis foraging activity near 40oC. The simultaneous determination of insect body and rock temperatures here presented are the only obtained in natural habitats for this or other triatomines. PMID- 26517660 TI - Leishmania (Viannia) naiffi: rare enough to be neglected? AB - In the Brazilian Amazon, American tegumentary leishmaniasis (ATL) is endemic and presents a wide spectrum of clinical manifestations due, in part, to the circulation of at least seven Leishmania species. Few reports of Leishmania (Viannia) naiffi infection suggest that its occurrence is uncommon and the reported cases present a benign clinical course and a good response to treatment. This study aimed to strengthen the clinical and epidemiological importance of L. (V.) naiffi in the Amazon Region (Manaus, state of Amazonas) and to report therapeutic failure in patients infected with this species. Thirty Leishmania spp samples isolated from cutaneous lesions were characterised by multilocus enzyme electrophoresis. As expected, the most common species was Leishmania (V.) guyanensis (20 cases). However, a relevant number of L. (V.) naiffi patients (8 cases) was observed, thus demonstrating that this species is not uncommon in the region. No patient infected with L. (V.) naiffi evolved to spontaneous cure until the start of treatment, which indicated that this species may not have a self limiting nature. In addition, two of the patients experienced a poor response to antimonial or pentamidine therapy. Thus, either ATL cases due to L. (V.) naiffi cannot be as uncommon as previously thought or this species is currently expanding in this region. PMID- 26517661 TI - Evaluation of light-emitting diodes as attractant for sandflies (Diptera: Psychodidae: Phlebotominae) in northeastern Brazil. AB - Hoover Pugedo light traps were modified for use with green and blue-light emitting diodes to trap phlebotomine sandflies in northeastern Brazil. A total of 2,267 specimens belonging to eight genera and 15 species were sampled. The predominant species were Nyssomyia whitmani(34.41%) and Micropygomyia echinatopharynx(17.25%).The green LED trap prevailed over the blue and control lights; however, no statistically significant difference could be detected among the three light sources. Even without statistical significance, we suggest using LEDs as an attractant for the capture of sandflies because of several advantages over the conventional method with incandescent lamps. PMID- 26517662 TI - Evaluating anti-Orthopoxvirus antibodies in individuals from Brazilian rural areas prior to the bovine vaccinia era. AB - Vaccinia virus naturally circulates in Brazil and is the causative agent of a zoonotic disease known as bovine vaccinia (BV). We retrospectively evaluated two populations from the Amazon and Southeast Regions. BV outbreaks had not been reported in these regions before sample collection. Neutralising antibodies were found in 13 individuals (n = 132) with titres ranging from 100 >= 6,400 neutralising units/mL. Univariate analysis identified age and vaccination as statistically significant risk factors in individuals from the Southeast Region. The absence of detectable antibodies in vaccinated individuals raises questions about the protection of smallpox vaccine years after vaccination and reinforces the need for surveillance of Orthopoxvirus in Brazilian populations without evidence of previous outbreaks. PMID- 26517663 TI - Pattern of cytokine and chemokine production by THP-1 derived macrophages in response to live or heat-killed Mycobacterium bovis bacillus Calmette-Guerin Moreau strain. AB - Tuberculosis has great public health impact with high rates of mortality and the only prophylactic measure for it is the Mycobacterium bovis bacillus Calmette Guerin (BCG) vaccine. The present study evaluated the release of cytokines [interleukin (IL)-1, tumour necrosis factor and IL-6] and chemokines [macrophage inflammatory protein (MIP)-1alpha and MIP-1beta] by THP-1 derived macrophages infected with BCG vaccine obtained by growing mycobacteria in Viscondessa de Moraes Institute medium medium (oral) or Sauton medium (intradermic) to compare the effects of live and heat-killed (HK) mycobacteria. Because BCG has been reported to lose viability during the lyophilisation process and during storage, we examined whether exposing BCG to different temperatures also triggers differences in the expression of some important cytokines and chemokines of the immune response. Interestingly, we observed that HK mycobacteria stimulated cytokine and chemokine production in a different pattern from that observed with live mycobacteria. PMID- 26517664 TI - Whole-genome sequencing of a Plasmodium vivax isolate from the China-Myanmar border area. AB - Currently, there is a trend of an increasing number of Plasmodium vivax malaria cases in China that are imported across its Southeast Asia border, especially in the China-Myanmar border area (CMB). To date, little is known about the genetic diversity of P. vivax in this region. In this paper, we report the first genome sequencing of a P. vivax isolate (CMB-1) from a vivax malaria patient in CMB. The sequencing data were aligned onto 96.43% of the P. vivax Salvador I reference strain (Sal I) genome with 7.84-fold coverage as well as onto 98.32% of 14 Sal I chromosomes. Using the de novo assembly approach, we generated 8,541 scaffolds and assembled a total of 27.1 Mb of sequence into CMB-1 scaffolds. Furthermore, we identified all 295 known vir genes, which is the largest subtelomeric multigene family in malaria parasites. These results provide an important foundation for further research on P. vivax population genetics. PMID- 26517665 TI - Genomic analysis of a nontoxigenic, invasive Corynebacterium diphtheriae strain from Brazil. AB - We report the complete genome sequence and analysis of an invasive Corynebacterium diphtheriae strain that caused endocarditis in Rio de Janeiro, Brazil. It was selected for sequencing on the basis of the current relevance of nontoxigenic strains for public health. The genomic information was explored in the context of diversity, plasticity and genetic relatedness with other contemporary strains. PMID- 26517666 TI - Parvovirus B19 1A complete genome from a fatal case in Brazil. AB - Parvovirus B19 (B19V) infects individuals worldwide and is associated with an ample range of pathologies and clinical manifestations. B19V is classified into three distinct genotypes, all identified in Brazil. Here, we report a complete sequence of a B19V genotype 1A that was obtained by high-throughput metagenomic sequencing. This genome provides information that will contribute to the studies on B19V epidemiology and evolution. PMID- 26517667 TI - Draft genome sequence of Bacillus thuringiensis 147, a Brazilian strain with high insecticidal activity. AB - Bacillus thuringiensis is a ubiquitous Gram-positive and sporulating bacterium. Its crystals and secreted toxins are useful tools against larvae of diverse insect orders and, as a consequence, an alternative to recalcitrant chemical insecticides. We report here the draft genome sequence of B. thuringiensis147, a strain isolated from Brazil and with high insecticidal activity. The assembled genome contained 6,167,994 bp and was distributed in seven replicons (a chromosome and 6 plasmids). We identified 12 coding regions, located in two plasmids, which encode insecticidal proteins. PMID- 26517668 TI - Methods for measuring water activity (aw) of foods and its applications to moisture sorption isotherm studies. AB - Moisture sorption isotherm is commonly determined by saturated salt slurry method, which has defects of long time cost, cumbersome labor, and microbial deterioration of samples. Thus, a novel method, aw measurement (AWM) method, has been developed to overcome these drawbacks. Fundamentals and applications of this fast method have been introduced with respects to its typical operational steps, a variety of equipment set-ups and applied samples. The resultant rapidness and reliability have been evaluated by comparing with conventional methods. This review also discussed factors impairing measurement precision and accuracy, including inappropriate choice of predryingwetting techniques and unachieved moisture uniformity in samples due to inadequate time. This analysis and corresponding suggestions can facilitate improved AWM method with more satisfying accuracy and time cost. PMID- 26517669 TI - Membrane Mechanics of Endocytosis in Cells with Turgor. AB - Endocytosis is an essential process by which cells internalize a piece of plasma membrane and material from the outside. In cells with turgor, pressure opposes membrane deformations, and increases the amount of force that has to be generated by the endocytic machinery. To determine this force, and calculate the shape of the membrane, we used physical theory to model an elastic surface under pressure. Accurate fits of experimental profiles are obtained assuming that the coated membrane is highly rigid and preferentially curved at the endocytic site. The forces required from the actin machinery peaks at the onset of deformation, indicating that once invagination has been initiated, endocytosis is unlikely to stall before completion. Coat proteins do not lower the initiation force but may affect the process by the curvature they induce. In the presence of isotropic curvature inducers, pulling the tip of the invagination can trigger the formation of a neck at the base of the invagination. Hence direct neck constriction by actin may not be required, while its pulling role is essential. Finally, the theory shows that anisotropic curvature effectors stabilize membrane invaginations, and the loss of crescent-shaped BAR domain proteins such as Rvs167 could therefore trigger membrane scission. PMID- 26517670 TI - Variants in the genes DCTN2, DNAH10, LRIG3, and MYO1A are associated with intermediate Charcot-Marie-Tooth disease in a Norwegian family. AB - INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is a heterogeneous inherited neuropathy. The number of known CMT genes is rapidly increasing mainly due to next-generation sequencing technology, at present more than 70 CMT-associated genes are known. We investigated whether variants in the DCTN2 could cause CMT. MATERIAL AND METHODS: Fifty-nine Norwegian CMT families from the general population with unknown genotype were tested by targeted next-generation sequencing (NGS) for variants in DCTN2 along with 32 CMT genes and 19 other genes causing other inherited neuropathies or neuronopathies, due to phenotypic overlap. In the family with the DCTN2 variant, exome sequencing was then carried out on all available eight family members to rule out the presence of more potential variants. RESULTS: Targeted NGS identified in one family a variant of DCTN2, c.337C>T, segregating with the phenotype in five affected members, while it was not present in the three unaffected members. The DCTN2 variant c.337C>T; p.(His113Tyr) was neither found in in-house controls nor in SNP databases. Exome sequencing revealed a singular heterozygous shared haplotype containing four genes, DCTN2, DNAH10, LRIG3, and MYO1A, with novel sequence variants. The haplotype was shared by all the affected members, while the unaffected members did not have it. CONCLUSIONS: This is the first time a haplotype on chromosome 12 containing sequence variants in the genes DCTN2, DNAH10, LRIG3, and MYO1A has been linked to an inherited neuropathy in humans. PMID- 26517671 TI - The herbal compound Songyou Yin (SYY) inhibits hepatocellular carcinoma growth and improves survival in models of chronic fibrosis via paracrine inhibition of activated hepatic stellate cells. AB - Chronic fibrosis is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathological progression of hepatic fibrosis has been linked to cellular processes that promote tumor growth and metastasis. Several recent studies have highlighted the cross-talk between tumor cells and activated hepatic stellate cells (aHSCs) in HCC. The herbal compound Songyou Yin (SYY) is known to attenuate hepatoma cell invasion and metastasis via down-regulation of cytokine secretion by aHSCs. However the underlying mechanism of SYY treatment in reversal of hepatic fibrosis and metastasis of liver cancers is not known. In the current study, a nude mouse model with liver fibrosis bearing orthotopic xenograft was established and we found that SYY could reduce associated fibrosis, inhibit tumor growth and improve survival. In the subcutaneous tumor model with fibrosis, we found that SYY could inhibit liver cancer. In vitro, hepatoma cells incubated with conditioned media (CM) from SYY treated aHSCs showed reduced proliferation, decrease in colony formation and invasive potential. SYY treated group showed altered gene expression, with 1205 genes up-regulated and 1323 genes down regulated. Gene cluster analysis indicated that phosphatidylinositol-3-kinase (PI3K) was one of the key genes altered in the expression profiles. PI3K related markers were all significantly down-regulated. ELISA also indicated decreased secretion of cytokines which were regulated by PI3K/AKT signaling after SYY treatment in the hepatic stellate cell line, LX2. These data clearly demonstrate that SYY therapy inhibits HCC invasive and metastatic potential and improves survival in nude mice models with chronic fibrosis background via inhibition of cytokine secretion by activated hepatic stellate cells. PMID- 26517672 TI - Niacin alleviates TRAIL-mediated colon cancer cell death via autophagy flux activation. AB - Niacin, also known as vitamin B3 or nicotinamide is a water-soluble vitamin that is present in black beans and rice among other foods. Niacin is well known as an inhibitor of metastasis in human breast carcinoma cells but the effect of niacin treatment on TRAIL-mediated apoptosis is unknown. Here, we show that niacin plays an important role in the regulation of autophagic flux and protects tumor cells against TRAIL-mediated apoptosis. Our results indicated that niacin activated autophagic flux in human colon cancer cells and the autophagic flux activation protected tumor cells from TRAIL-induced dysfunction of mitochondrial membrane potential and tumor cell death. We also demonstrated that ATG5 siRNA and autophagy inhibitor blocked the niacin-mediated inhibition of TRAIL-induced apoptosis. Taken together, our study is the first report demonstrating that niacin inhibits TRAIL-induced apoptosis through activation of autophagic flux in human colon cancer cells. And our results also suggest that autophagy inhibitors including genetic and pharmacological tools may be a successful therapeutics during anticancer therapy using TRAIL. PMID- 26517674 TI - YpT1-2N0 rectal cancer after neoadjuvant chemoradiation has lower survival compared with pT1-2N0 rectal cancer. AB - Pathologic T1-2N0 rectal cancer shows an excellent prognosis without preoperative or postoperative chemoradiation. However, oncologic outcome of ypT1-2N0 remains unclear and undetermined. Thus, the aim of this study was to compare the survival of ypT1-2 and pT1-2 rectal cancer patients after radical resection and identify risk factors of ypT1-2 rectal cancer in Surveillance, Epidemiology, and End Results Program (SEER)-registered rectal cancer patients. The results showed that ypT1-2N0 rectal cancer after neoadjuvant chemoradiation has lower survival compared with pT1-2N0 rectal cancer and mucinous/signet-ring cancer and less than 12 lymph nodes retrieval were two risk factors in ypT1-2 patients. These results suggest that ypT1-2 patients with one or two risk factors may benefit from postoperative adjuvant chemotherapy. PMID- 26517673 TI - Identification of CD146 as a marker enriched for tumor-propagating capacity reveals targetable pathways in primary human sarcoma. AB - Tumor-propagating cells (TPCs) are believed to drive cancer initiation, progression and recurrence. These cells are characterized by enhanced tumorigenicity and self-renewal. The ability to identify such cells in primary human sarcomas relies on the dye exclusion ability of tumor side population (SP) cells. Here, we performed a high-throughput cell surface antigen screen and found that CD146 is enriched in the SP population. In vivo serial transplantation assays showed that CD146+ cells are highly tumorigenic, capable of self-renewal and thus enriches for the TPC population. In addition, depletion of SP cells from the CD146+ population show that CD146+ cells and SP cells are a distinct and overlapping TPC populations. Gene expression profiling of CD146+ and SP cells revealed multiple pathways commonly upregulated in both of these populations. Inhibition of one of these upregulated pathways, Notch signaling, significantly reduced tumor growth and self-renewal. Our data demonstrate that CD146 is an effective cell surface marker for enriching TPCs in primary human sarcomas. Targeting differentially activated pathways in TPCs may provide new therapeutic strategies for treating sarcoma. PMID- 26517675 TI - An mRNA expression signature for prognostication in de novo acute myeloid leukemia patients with normal karyotype. AB - Although clinical features, cytogenetics, and mutations are widely used to predict prognosis in patients with acute myeloid leukemia (AML), further refinement of risk stratification is necessary for optimal treatment, especially in cytogenetically normal (CN) patients. We sought to generate a simple gene expression signature as a predictor of clinical outcome through analyzing the mRNA arrays of 158 de novo CN AML patients. We compared the gene expression profiles of patients with poor response to induction chemotherapy with those who responded well. Forty-six genes expressed differentially between the two groups. Among them, expression of 11 genes was significantly associated with overall survival (OS) in univariate Cox regression analysis in 104 patients who received standard intensive chemotherapy. We integrated the z-transformed expression levels of these 11 genes to generate a risk scoring system. Higher risk scores were significantly associated with shorter OS (median 17.0 months vs. not reached, P < 0.001) in ours and another 3 validation cohorts. In addition, it was an independent unfavorable prognostic factor by multivariate analysis (HR 1.116, 95% CI 1.035~1.204, P = 0.004). In conclusion, we developed a simple mRNA expression signature for prognostication in CN-AML patients. This prognostic biomarker will help refine the treatment strategies for this group of patients. PMID- 26517676 TI - Comparative effectiveness study of breast-conserving surgery and mastectomy in the general population: A NCDB analysis. AB - PURPOSE: Recent studies have revealed that breast-conserving surgery (BCS) with radiotherapy (RT) led to better survival than mastectomy in some populations. We compared the efficacy of BCS+RT and mastectomy using the National Cancer Database (NCDB, USA). RESULTS: A total of 160,880 patients with a median follow-up of 43.4 months were included. The respective 8-year OS values were 86.5%, 72.3% and 70.4% in the BCS+RT, mastectomy alone and mastectomy+RT group, respectively (P < 0.001). After exclusion of patients with comorbidities, mastectomy (alone or with RT) remained associated with a lower OS in N0 and N1 patients. However, the OS of mastectomy+RT was equivalent to BCS+RT in N2-3 patients. Among patients aged 50 or younger, the OS benefit of BCS+RT over mastectomy alone was statistically significant (HR1.42, 95% CI 1.16-1.74), but not clinically significant (<5%) in N0 patients, whereas in N2-3 patients, the OS of BCS+RT was equivalent to mastectomy+RT (85.2% vs. 84.8%). The results of the propensity analysis were similar. METHODS: Non-metastatic breast cancers in the NCDB from 2004-2011 were identified.The Kaplan-Meier method, Coxregression and propensity score analysis were used to compare the overall survival (OS) among patients with BCS+RT, mastectomy alone and mastectomy+RT. CONCLUSIONS: BCS+RT resulted in improved OS compared with mastectomy +/- RT in N0 and N1 patients. In N2-3 patients, BCS+RT has an OS similar to mastectomy+RT when patients with comorbidities were excluded. Among patients aged 50 or younger, the OS of BCS+RT is equivalent to mastectomy +/- RT. PMID- 26517677 TI - Morphometric analysis of immunoselection against hyperploid cancer cells. AB - An at least transient increase of ploidy, usually by whole genome duplication, is a frequent event in oncogenesis, explaining the cytogenetic features of at least 40% of solid cancers. Here, we show that fibrosarcomas induced by the carcinogen methylcholanthrene (MCA) are distinct with respect to their ploidy status when they arise in immunocompetent wild type versus severely immunodeficient Rag2-/ gammac-/- mice. MCA-induced fibrosarcomas are particularly hyperploid if they develop in an immunodeficient setting, correlating with higher DNA content, increased nuclear surface, as well as hyperphosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha), a biomarker indicating endoplasmic reticulum (ER) stress. Upon transfer of such cells into wild type mice, such hyperploid, ER-stressed cells (that originated in Rag2-/-gammac-/- mice) fail to proliferate and actually induce a protective anticancer immune response. In contrast, such cells do form tumors in Rag2-/-gammac-/- recipients (which lack T, B and NK cells) as well as in Rag2-/- recipients (which only lack T and B lymphocytes) and conserve their hyperploidy as well as eIF2alpha hyperphosphorylation. To measure these parameters, we developed a morphometric analysis tool that is applicable to immunohistochemistry of formaldehyde-fixed, paraffin-embedded tissues. This software automatically identifies and quantifies the surface of nuclei and determines the intensity of eIF2alpha phosphorylation within a perinuclear region of interest. Comparative analyses performed on cultured cells and tissue sections validated the accuracy of this method, which can be used to investigate ploidy and ER stress in cancers in situ. PMID- 26517678 TI - Inhibition of Lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance. AB - Although proteasome inhibition with bortezomib (BTZ) is a validated treatment for relapsed or refractory mantle cell lymphoma (MCL), many patients show resistance to BTZ. However, the molecular mechanism of BTZ resistance in MCL has not been elucidated. In the present study, we investigated BTZ-resistant MCL cells in vitro and in vivo. We demonstrate that BTZ-resistant MCL cells showed highly increased expression of the B-cell receptor (BCR) components CD79A and CD19. Activation of the BCR signaling pathway enhanced the activity of Src family kinases (SFKs), especially Lyn, and downstream kinases PI3K/AKT/mTOR in BTZ resistant MCL cells. Depletion of CD79A and Lyn significantly reduced several kinase activities involved in PI3K signaling, leading to inhibition of proliferation. In addition, the SFKs inhibitor dasatinib inhibited the proliferation of BTZ-resistant cells, preventing the binding of CD19 with Lyn and PI3K p85. We also verified our findings with the mouse xenograft tumor model. Dasatinib treatment significantly decreased tumor size in the mouse bearing BTZ resistant MCL cells, but not in the mouse bearing BTZ-sensitive MCL cells. Collectively, our data show that overexpression of the BCR and its activated signaling confers BTZ resistance in MCL cells. Thus, targeting BCR signaling with dasatinib could be a novel therapeutic approach for patients with MCL that has relapsed or is refractory to treatment with BTZ. PMID- 26517679 TI - Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells. AB - The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC. PMID- 26517680 TI - The BIM deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia. AB - Both germline polymorphisms and tumor-specific genetic alterations can determine the response of a cancer to a given therapy. We previously reported a germline deletion polymorphism in the BIM gene that was sufficient to mediate intrinsic resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML), as well as other cancers [1]. The deletion polymorphism favored the generation of BIM splice forms lacking the pro-apoptotic BH3 domain, conferring a relative resistance to the TKI imatinib (IM). However, CML patients with the BIM deletion polymorphism developed both partial and complete IM resistance. To understand the mechanisms underlying the latter, we grew CML cells either with or without the BIM deletion polymorphism in increasing IM concentrations. Under these conditions, the BIM deletion polymorphism enhanced the emergence of populations with complete IM resistance, mimicking the situation in patients. Importantly, the combined use of TKIs with the BH3 mimetic ABT-737 overcame the BCR-ABL1 dependent and -independent resistance mechanisms found in these cells. Our results illustrate the interplay between germline and acquired genetic factors in confering TKI resistance, and suggest a therapeutic strategy for patients with complete TKI resistance associated with the BIM deletion polymorphism. PMID- 26517681 TI - Clinical significance of age at diagnosis among young non-small cell lung cancer patients under 40 years old: a population-based study. AB - BACKGROUND: Young non-small cell lung cancer (NSCLC) patients under the age of 40 can further be categorized into different age subgroups. Whether they have homogeneous clinical features and survival outcomes remains unexplored. METHODS: Information of 4623 NSCLC patients up to 40 years old from 1988 to 2012 was retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Clinicopathologic characteristics and survival outcomes were compared between patients diagnosed at 18-30 years old (younger group) and those at 31-40 years old (older group). RESULTS: The proportion of patients in the younger group among all lung cancer patients was stable between 1988 and 2012. However, the proportion of patients in the older group decreased from 1.2% to 0.5%. The younger patients had a higher proportion of adenocarcinoma (P = 0.016), a lower proportion of large cell carcinoma (P = 0.008), a higher proportion of stage I disease (P = 0.002) and a lower proportion of stage III disease (P < 0.001). The younger patients had significantly better lung cancer-specific survival (LCSS) in the whole cohort (P < 0.001) and in the subgroup of patients with stage I (P = 0.038) or stage IV (P < 0.001) disease. Multivariate survival analysis showed that patients under 30 years old was an independent predictor of both better LCSS (P = 0.010) and overall survival (OS) (P = 0.018). CONCLUSIONS: Adult NSCLC patients under 30 years old had distinctive clinicopathologic characteristics and survival outcomes compared to patients diagnosed at 31-40 years old. PMID- 26517682 TI - Expression of young HERV-H loci in the course of colorectal carcinoma and correlation with molecular subtypes. AB - BACKGROUND: Expression of the human endogenous retrovirus (HERV)-H family has been associated with colorectal carcinomas (CRC), yet no individual HERV-H locus expression has been thoroughly correlated with clinical data.Here, we characterized HERV-H reactivations in clinical CRC samples by integrating expression profiles, molecular patterns and clinical data. Expression of relevant HERV-H sequences was analyzed by qRT-PCR on two well-defined clinical cohorts (n = 139 pairs of tumor and adjacent normal colon tissue) including samples from adenomas (n = 21) and liver metastases (n = 16). Correlations with clinical and molecular data were assessed. RESULTS: CRC specific HERV-H sequences were validated and found expressed throughout CRC disease progression. Correlations between HERV-H expression and lymph node invasion of tumor cells (p = 0.0006) as well as microsatellite instable tumors (p < 0.0001) were established. No association with regard to age, tumor localization, grading or common mutations became apparent. Interestingly, CRC expressed elements belonged to specific young HERV-H subfamilies and their 5' LTR often presented active histone marks. CONCLUSION: These results suggest a functional role of HERV-H sequences in colorectal carcinogenesis. The pronounced connection with microsatellite instability warrants a more detailed investigation. Thus, HERV-H sequences in addition to tumor specific mutations may represent clinically relevant, truly CRC specific markers for diagnostic, prognostic and therapeutic purposes. PMID- 26517683 TI - A Polycomb-mir200 loop regulates clinical outcome in bladder cancer. AB - Bladder cancer (BC) is a highly prevalent disease, ranking fifth in the most common cancers worldwide. Various miRNAs have recently emerged as potential prognostic biomarkers in cancer. The miR-200 family, which repressed the epithelial-to-mesenchymal transition (EMT), is repressed in multiple advanced cancers. However, its expression and function in BC is still poorly understood. Here we show that miR-200 family displays increased expression, probably due to the activation of specific oncogenic signaling pathways, and reduced promoter methylation, in BC compared to normal bladder samples. Furthermore, we show that the expression of these miRNAs is decreased in high grade and stage tumors, and the down-regulation is associated with patient's poor clinical outcome. Our data indicate that the miR-200 family plays distinct roles in Non-Muscle (NMIBC) and Muscle-Invasive BC (MIBC). In MIBC, miR-200 expression post transcriptionally regulates EMT-promoting transcription factors ZEB1 and ZEB2, whereas suppresses BMI1 expression in NMIBC. Interestingly, we show that increased EZH2 and/or BMI1 expression repress the expression of miR-200 family members. Collectively, these findings support a model of BC progression through a coordinated action between the Polycomb Repression Complex (PRC) members repressing the miR-200 expression, which ultimately favors invasive BC development. Since pharmacological inhibition of EZH2 in BC cell lines lead to increased miR-200 expression, our findings may support new therapeutic strategies for BC clinical management. PMID- 26517684 TI - Multiple spatially related pharmacophores define small molecule inhibitors of OLIG2 in glioblastoma. AB - Transcription factors (TFs) are a major class of protein signaling molecules that play key cellular roles in cancers such as the highly lethal brain cancer glioblastoma (GBM). However, the development of specific TF inhibitors has proved difficult owing to expansive protein-protein interfaces and the absence of hydrophobic pockets. We uniquely defined the dimerization surface as an expansive parental pharmacophore comprised of several regional daughter pharmacophores. We targeted the OLIG2 TF which is essential for GBM survival and growth, we hypothesized that small molecules able to fit each subpharmacophore would inhibit OLIG2 activation. The most active compound was OLIG2 selective, it entered the brain, and it exhibited potent anti-GBM activity in cell-based assays and in pre clinical mouse orthotopic models. These data suggest that (1) our multiple pharmacophore approach warrants further investigation, and (2) our most potent compounds merit detailed pharmacodynamic, biophysical, and mechanistic characterization for potential preclinical development as GBM therapeutics. PMID- 26517685 TI - Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients. AB - BACKGROUND: The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer. METHODS: A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis. RESULTS: A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype. CONCLUSION: A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling. PMID- 26517686 TI - Clinical analysis of intraoperative radiotherapy during breast-conserving surgery of early breast cancer in the Chinese Han population. AB - PURPOSE: While results of intraoperative radiotherapy (IORT) during breast conserving surgery (BCS) have been reported when used either as a boost at the time of surgery or as the sole radiation treatment, the clinical safety and cosmetic outcome of IORT in the Chinese Han population has not. This report reviews oncologic and cosmetic outcomes for Chinese Han breast cancer patients who received IORT either as a boost or as their sole radiation treatment at our hospital. METHODS: From July 2008 to December 2012, 50 early-stage Chinese Han breast cancer patients received BCS and IORT, either as boost or as their sole radiation treatment. Patients received adjuvant chemotherapy or hormonal therapy, according to our institution's guidelines. Patients were followed to determine oncologic events, short-term toxicity and overall cosmesis. RESULTS: With a median follow-up of 51.8 months (range 22.6 months to 75.7 months), 2 patients (4.0%) developed local relapses and were salvaged by mastectomy. There were no metastases and no deaths. The average wound healing time was 17 days. Three patients (6.0%) developed postoperative infection, 5 patients (10.0%) had delayed wound healing, and 2 patients (4.0%) experienced wound edema. There were no lyponecrosis or hematomas observed. The evaluation of cosmetic outcome showed 44 patients (88.0%) graded as excellent or good while 6 patients (12.0%) were graded as fair or poor. No patients experienced radiotherapy related acute hematological toxicity, but 3 patients (6.0%), all IORT boost patients, developed skin pigmentation. CONCLUSIONS: For early-stage breast cancer patients, intraoperative radiotherapy after breast-conserving surgery in the Chinese Han population is both safe and reliable and has resulted in very acceptable cosmetic outcomes. PMID- 26517687 TI - A novel chemical, STF-083010, reverses tamoxifen-related drug resistance in breast cancer by inhibiting IRE1/XBP1. AB - Recent studies show that the unfolded protein response (UPR) within the endoplasmic reticulum is correlated with breast cancer drug resistance. In particular, human X-box binding protein-1(XBP1), a transcription factor which participates in UPR stress signaling, is reported to correlate with poor clinical responsiveness to tamoxifen. In this study, we develop a tamoxifen-resistant MCF 7 cell line by treating the cell line with low concentration of tamoxifen, and we find that XBP1 is indeed up-regulated at both the mRNA and protein levels compared to normal MCF-7 cells. STF-083010, a novel inhibitor which specifically blocks the XBP1 splicing, reestablishes tamoxifen sensitivity to resistant MCF-7 cells. Moreover, co-treatment with STF-083010 and tamoxifen can significantly delay breast cancer progression in a xenograft mammary tumor model. We next investigate the expression of XBP1s in over 170 breast cancer patients' samples and the results demonstrate that XBP1s expression level is highly correlated with overall survival in the ER+ subgroup, but not in the ER- subgroup, suggesting a potential therapeutic application of XBP1 inhibitors in ER+breast cancer treatment. PMID- 26517688 TI - Tetracycline-inducible shRNA targeting long non-coding RNA PVT1 inhibits cell growth and induces apoptosis in bladder cancer cells. AB - Recent studies show that long non-coding RNAs (lncRNAs) may be significant functional regulators in tumor development, including bladder cancer. Here, we found that PVT1 was upregulated in bladder cancer tissues and cells. Further experiments revealed that PVT1 promoted cell proliferation and suppressed cell apoptosis. Furthermore we also used the emerging technology, synthetic biology, to create tetracycline-inducible small hairpin RNA (shRNA) vectors which silenced PVT1 in a dosage-dependent manner to inhibit the progression of bladder cancer. In conclusion, data suggest that PVT1 could be an oncogene and may be a therapeutic target in bladder cancer. Synthetic "tetracycline-on" switch system can be used to quantitatively control the expression of PVT1 in bladder cancer in response to different concentration of doxycycline to suppress the progression of bladder cancer. PMID- 26517689 TI - Novel p53-dependent anticancer strategy by targeting iron signaling and BNIP3L induced mitophagy. AB - This study identifies BNIP3L as the key regulator of p53-dependent cell death mechanism in colon cancer cells targeted by the novel gallium based anticancer drug, KP46. KP46 specifically accumulated into mitochondria where it caused p53 dependent morphological and functional damage impairing mitochondrial dynamics and bioenergetics. Furthermore, competing with iron for cellular uptake, KP46 lowered the intracellular labile iron pools and intracellular heme. Accordingly, p53 accumulated in the nucleus where it activated its transcriptional target BNIP3L, a BH3 only domain protein with functions in apoptosis and mitophagy. Upregulated BNIP3L sensitized the mitochondrial permeability transition and strongly induced PARKIN-mediated mitochondrial clearance and cellular vacuolization. Downregulation of BNIP3L entirely rescued cell viability caused by exposure of KP46 for 24 hours, confirming that early induced cell death was regulated by BNIP3L. Altogether, targeting BNIP3L in wild-type p53 colon cancer cells is a novel anticancer strategy activating iron depletion signaling and the mitophagy-related cell death pathway. PMID- 26517690 TI - P2X3 purinergic receptor overexpression is associated with poor recurrence-free survival in hepatocellular carcinoma patients. AB - P2 purinergic receptors are overexpressed in certain cancer tissues, but the pathophysiologic relevance of purinergic signaling in hepatocellular carcinoma (HCC) remains unknown. To examine the role of P2 purinergic signaling in the pathogenesis of HCC and characterize extracellular nucleotide effects on HCC cell proliferation, two independent HCC patient cohorts were analyzed for P2 purinergic receptor expression, and nucleotide treated HCC cell lines were evaluated for effects on proliferation and cell cycle progression. Our studies suggest that multiple P2 purinergic receptor isoforms are overexpressed in liver tumors, as compared to uninvolved liver, and dysregulation of P2 purinergic receptor expression is apparent in HCC cell lines, as compared to human primary hepatocytes. High P2X3 purinergic receptor expression is associated with poor recurrence-free survival (RFS), while high P2Y13 expression is associated with improved RFS. Extracellular nucleotide treatment alone is sufficient to induce cell cycle progression, via activation of JNK signaling, and extracellular ATP mediated activation of P2X3 receptors promotes proliferation in HCC cells. CONCLUSION: Our analysis of HCC patient livers and HCC cells in vitro identifies a novel role for dysregulation of P2 purinergic signaling in the induction of hyper-proliferative HCC phenotype and identifies P2X3 purinergic receptors as potential new targets for therapy. PMID- 26517691 TI - Molecular profiling of cetuximab and bevacizumab treatment of colorectal tumours reveals perturbations in metabolic and hypoxic response pathways. AB - Angiogenesis and epidermal growth factor receptor (EGFR) inhibition has been shown to have anti-tumour efficacy, and enhance the therapeutic effects of cytotoxic chemotherapy in metastatic colorectal cancer. The interplay of signalling alterations and changes in metabolism and hypoxia in tumours following anti-VEGF and anti-EGFR treatment is not well understood. We aimed to explore the pharmacodynamics of cetuximab and bevacizumab treatment in human colon carcinoma tumour cells in vitro and xenograft models through proteomic profiling, molecular imaging of metabolism and hypoxia, and evaluation of therapy-induced changes in tumour cells and the tumour microenvironment. Both cetuximab and bevacizumab inhibited tumour growth in vivo, and this effect was associated with selectively perturbed glucose metabolism and reduced hypoxic volumes based on PET/MRI imaging. Global proteomic profiling of xenograft tumours (in presence of cetuximab, bevacizumab, and combination treatments) revealed alterations in proteins involved in glucose, lipid and fatty acid metabolism (e.g., GPD2, ATP5B, STAT3, FASN), as well as hypoxic regulators and vasculogenesis (e.g., ATP5B, THBS1, HSPG2). These findings correlated with western immunoblotting (xenograft lysates) and histological examination by immunohistochemistry. These results define important mechanistic insight into the dynamic changes in metabolic and hypoxic response pathways in colorectal tumours following treatment with cetuximab and bevacizumab, and highlight the ability of these therapies to selectively impact on tumour cells and extracellular microenvironment. PMID- 26517692 TI - A prospective, multicenter, observational study of long-term decitabine treatment in patients with myelodysplastic syndrome. AB - This prospective observational study evaluated the efficacy and safety of long term decitabine treatment in patients with myelodysplastic syndrome (MDS). Decitabine 20 mg/m(2)/day was administered intravenously for 5 consecutive days every 4 weeks to MDS patients in intermediate-1 or higher International Prognostic Scoring System (IPSS) risk categories. Active antimicrobial prophylaxis was given to prevent infectious complications. Overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to response were evaluated, as were adverse events. The final analysis included 132 patients. IPSS risk was intermediate-2/high in 34.9% patients. The patients received a median of 5 cycles, with responders receiving a median of 8 cycles (range, 2-30). ORR was 62.9% (complete response [CR], 36; partial response [PR], 3; marrow complete response [mCR], 19; and hematologic improvement, 25). Among responders, 39% showed first response at cycle 3 or later. OS at 2 years was 60.9%, with 17% progressing to acute myeloid leukemia. PFS at 2 years was 51.0%. Patients achieving mCR showed comparable survival outcomes to those with CR/PR. With active antibiotic prophylaxis, febrile neutropenia events occurred in 61 of 1,033 (6%) cycles. Long-term decitabine treatment with antibiotic prophylaxis showed favorable outcomes in MDS patients, and mCR predicted favorable survival outcomes. PMID- 26517693 TI - SDF1 induction by acidosis from principal cells regulates intercalated cell subtype distribution. AB - The nephron cortical collecting duct (CCD) is composed of principal cells, which mediate Na, K, and water transport, and intercalated cells (ICs), which are specialized for acid-base transport. There are two canonical IC forms: acid secreting alpha-ICs and HCO3-secreting beta-ICs. Chronic acidosis increases alpha ICs at the expense of beta-ICs, thereby increasing net acid secretion by the CCD. We found by growth factor quantitative PCR array that acidosis increases expression of mRNA encoding SDF1 (or CXCL12) in kidney cortex and isolated CCDs from mouse and rabbit kidney cortex. Exogenous SDF1 or pH 6.8 media increased H+ secretion and decreased HCO3 secretion in isolated perfused rabbit CCDs. Acid dependent changes in H+ and HCO3 secretion were largely blunted by AMD3100, which selectively blocks the SDF1 receptor CXCR4. In mice, diet-induced chronic acidosis increased alpha-ICs and decreased beta-ICs. Additionally, IC-specific Cxcr4 deletion prevented IC subtype alterations and magnified metabolic acidosis. SDF1 was transcriptionally regulated and a target of the hypoxia-sensing transcription factor HIF1alpha. IC-specific deletion of Hif1a produced no effect on mice fed an acid diet, as alpha-ICs increased and beta-ICs decreased similarly to that observed in WT littermates. However, Hif1a deletion in all CCD cells prevented acidosis-induced IC subtype distribution, resulting in more severe acidosis. Cultured principal cells exhibited an HIF1alpha-dependent increase of Sdf1 transcription in response to media acidification. Thus, our results indicate that principal cells respond to acid by producing SDF1, which then acts on adjacent ICs. PMID- 26517694 TI - Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma. AB - Alterations in chromatin modifications, such as histone methylation, have been suggested as mediating chemotherapy resistance in several cancer types; therefore, elucidation of the epigenetic mechanisms that underlie drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified histone H3-lysine 27 (H3K27) as a critical residue for epigenetic modification in multiple myeloma. We determined that abrogation of drug-induced H3K27 hypermethylation is associated with cell adhesion-mediated drug resistance (CAM-DR), which is the most important form of drug resistance, using a coculture system to evaluate stroma cell adhesion-dependent alterations in multiple myeloma cells. Cell adhesion counteracted anticancer drug-induced hypermethylation of H3K27 via inactivating phosphorylation of the transcription regulator EZH2 at serine 21, leading to the sustained expression of antiapoptotic genes, including IGF1, B cell CLL/lymphoma 2 (BCL2), and hypoxia inducible factor 1, alpha subunit (HIF1A). Pharmacological and genetic inhibition of the IGF 1R/PI3K/AKT pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. Together, our findings identify and characterize an epigenetic mechanism that underlies CAM DR and suggest that kinase inhibitors to counteract EZH2 phosphorylation should be included in combination chemotherapy to increase therapeutic index. PMID- 26517695 TI - MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. AB - Cellular metabolism is increasingly recognized as a controller of immune cell fate and function. MicroRNA-33 (miR-33) regulates cellular lipid metabolism and represses genes involved in cholesterol efflux, HDL biogenesis, and fatty acid oxidation. Here, we determined that miR-33-mediated disruption of the balance of aerobic glycolysis and mitochondrial oxidative phosphorylation instructs macrophage inflammatory polarization and shapes innate and adaptive immune responses. Macrophage-specific Mir33 deletion increased oxidative respiration, enhanced spare respiratory capacity, and induced an M2 macrophage polarization associated gene profile. Furthermore, miR-33-mediated M2 polarization required miR-33 targeting of the energy sensor AMP-activated protein kinase (AMPK), but not cholesterol efflux. Notably, miR-33 inhibition increased macrophage expression of the retinoic acid-producing enzyme aldehyde dehydrogenase family 1, subfamily A2 (ALDH1A2) and retinal dehydrogenase activity both in vitro and in a mouse model. Consistent with the ability of retinoic acid to foster inducible Tregs, miR-33-depleted macrophages had an enhanced capacity to induce forkhead box P3 (FOXP3) expression in naive CD4(+) T cells. Finally, treatment of hypercholesterolemic mice with miR-33 inhibitors for 8 weeks resulted in accumulation of inflammation-suppressing M2 macrophages and FOXP3(+) Tregs in plaques and reduced atherosclerosis progression. Collectively, these results reveal that miR-33 regulates macrophage inflammation and demonstrate that miR-33 antagonism is atheroprotective, in part, by reducing plaque inflammation by promoting M2 macrophage polarization and Treg induction. PMID- 26517696 TI - Endothelial-to-mesenchymal transition drives atherosclerosis progression. AB - The molecular mechanisms responsible for the development and progression of atherosclerotic lesions have not been fully established. Here, we investigated the role played by endothelial-to-mesenchymal transition (EndMT) and its key regulator FGF receptor 1 (FGFR1) in atherosclerosis. In cultured human endothelial cells, both inflammatory cytokines and oscillatory shear stress reduced endothelial FGFR1 expression and activated TGF-beta signaling. We further explored the link between disrupted FGF endothelial signaling and progression of atherosclerosis by introducing endothelial-specific deletion of FGF receptor substrate 2 alpha (Frs2a) in atherosclerotic (Apoe(-/-)) mice. When placed on a high-fat diet, these double-knockout mice developed atherosclerosis at a much earlier time point compared with that their Apoe(-/-) counterparts, eventually demonstrating an 84% increase in total plaque burden. Moreover, these animals exhibited extensive development of EndMT, deposition of fibronectin, and increased neointima formation. Additionally, we conducted a molecular and morphometric examination of left main coronary arteries from 43 patients with various levels of coronary disease to assess the clinical relevance of these findings. The extent of coronary atherosclerosis in this patient set strongly correlated with loss of endothelial FGFR1 expression, activation of endothelial TGF-beta signaling, and the extent of EndMT. These data demonstrate a link between loss of protective endothelial FGFR signaling, development of EndMT, and progression of atherosclerosis. PMID- 26517698 TI - The biogeography of the atlantic salmon (Salmo salar) gut microbiome. AB - Although understood in many vertebrate systems, the natural diversity of host associated microbiota has been little studied in teleosts. For migratory fishes, successful exploitation of multiple habitats may affect and be affected by the composition of the intestinal microbiome. We collected 96 Salmo salar from across the Atlantic encompassing both freshwater and marine phases. Dramatic differences between environmental and gut bacterial communities were observed. Furthermore, community composition was not significantly impacted by geography. Instead life cycle stage strongly defined both the diversity and identity of microbial assemblages in the gut, with evidence for community destabilisation in migratory phases. Mycoplasmataceae phylotypes were abundantly recovered in all life-cycle stages. Patterns of Mycoplasmataceae phylotype recruitment to the intestinal microbial community among sites and life-cycle stages support a dual role for deterministic and stochastic processes in defining the composition of the S. salar gut microbiome. PMID- 26517697 TI - Saturated phosphatidic acids mediate saturated fatty acid-induced vascular calcification and lipotoxicity. AB - Recent evidence indicates that saturated fatty acid-induced (SFA-induced) lipotoxicity contributes to the pathogenesis of cardiovascular and metabolic diseases; however, the molecular mechanisms that underlie SFA-induced lipotoxicity remain unclear. Here, we have shown that repression of stearoyl-CoA desaturase (SCD) enzymes, which regulate the intracellular balance of SFAs and unsaturated FAs, and the subsequent accumulation of SFAs in vascular smooth muscle cells (VSMCs), are characteristic events in the development of vascular calcification. We evaluated whether SMC-specific inhibition of SCD and the resulting SFA accumulation plays a causative role in the pathogenesis of vascular calcification and generated mice with SMC-specific deletion of both Scd1 and Scd2. Mice lacking both SCD1 and SCD2 in SMCs displayed severe vascular calcification with increased ER stress. Moreover, we employed shRNA library screening and radiolabeling approaches, as well as in vitro and in vivo lipidomic analysis, and determined that fully saturated phosphatidic acids such as 1,2 distearoyl-PA (18:0/18:0-PA) mediate SFA-induced lipotoxicity and vascular calcification. Together, these results identify a key lipogenic pathway in SMCs that mediates vascular calcification. PMID- 26517699 TI - Diversification of DnaA dependency for DNA replication in cyanobacterial evolution. AB - Regulating DNA replication is essential for all living cells. The DNA replication initiation factor DnaA is highly conserved in prokaryotes and is required for accurate initiation of chromosomal replication at oriC. DnaA-independent free living bacteria have not been identified. The dnaA gene is absent in plastids and some symbiotic bacteria, although it is not known when or how DnaA-independent mechanisms were acquired. Here, we show that the degree of dependency of DNA replication on DnaA varies among cyanobacterial species. Deletion of the dnaA gene in Synechococcus elongatus PCC 7942 shifted DNA replication from oriC to a different site as a result of the integration of an episomal plasmid. Moreover, viability during the stationary phase was higher in dnaA disruptants than in wild type cells. Deletion of dnaA did not affect DNA replication or cell growth in Synechocystis sp. PCC 6803 or Anabaena sp. PCC 7120, indicating that functional dependency on DnaA was already lost in some nonsymbiotic cyanobacterial lineages during diversification. Therefore, we proposed that cyanobacteria acquired DnaA independent replication mechanisms before symbiosis and such an ancestral cyanobacterium was the sole primary endosymbiont to form a plastid precursor. PMID- 26517700 TI - Impact of Polypharmacy on Adherence to Evidence-Based Medication in Patients who Underwent Percutaneous Coronary Intervention. AB - BACKGROUND: The primary objective of this study was to evaluate the impact of polypharmacy on primary and secondary adherence to evidence-based medication (EBM) and to measure factors associated with non-adherence among patients who underwent percutaneous coronary intervention (PCI). METHODS: We conducted a retrospective analysis for patients who underwent PCI at a tertiary cardiac care hospital in Qatar. Patients who had polypharmacy (defined as >=6 medications) were compared with those who had no polypharmacy at hospital discharge in terms of primary and secondary adherence to dual antiplatelet therapy (DAPT), beta blockers (BB), angiotensin converting enzyme inhibitors (ACEIs) and statins. RESULTS: A total of 557 patients (mean age: 53+/-10 years; 85%; males) who underwent PCI were included. The majority of patients (84.6%) received >=6 medications (polypharmacy group) while only 15.4% patients received >=5 medications (nonpolypharmacy group). The two groups were comparable in term of gender, nationality, socioeconomic status and medical insurance. The non polypharmacy patients had significantly higher adherence to first refill of DAPT compared with patients in the polypharmacy group (100 vs. 76.9%; p=0.001). Similarly, the non-polypharmacy patients were significantly more adherent to secondary preventive medications (BB, ACEI and statins) than the polypharmacy group. CONCLUSION: In patients who underwent PCI, polypharmacy at discharge could play a negative role in the adherence to the first refill of EBM. Further studies should investigate other parameters that contribute to long term non-adherence. PMID- 26517701 TI - Venous Thromboembolism Risk and Adequacy of Prophylaxis in High Risk Pregnancy in the Arabian Gulf. AB - OBJECTIVES: To estimate the prevalence of venous thromboembolism (VTE) risk factors in pregnancy and the proportion of pregnancies at risk of VTE that received the recommended prophylaxis according to the American College of Chest Physicians (ACCP) 2012 published guidelines in antenatal clinics in the Arabian Gulf. METHODS: The evaluation of venous thromboembolism (EVE)-Risk project was a non-interventional, cross-sectional, multi-centre, multi-national study of all eligible pregnant women (>=17 years) screened during antenatal clinics from 7 centres in the Arabian Gulf countries (United Arab Emirates, Kuwait, Bahrain, Qatar and Oman). Pregnant women were recruited during a 3-month period between September and December 2012. RESULTS: Of 4,131 screened pregnant women, 32% (n=1,337) had >=1 risk factors for VTE. Common VTE risk factors included obesity (76%), multiparity (33%), recurrent miscarriages (9.1%), varicose veins (6.9%), thrombophilia (2.6%), immobilization (2.0%), sickle cell disease (2.8%) and previous VTE (1.6%). Only 8.3% (n=111) of the high risk patients were on the recommended VTE prophylaxis. Enoxaparin was used in 80% (n=89) of the cases followed by tinzaparin (4%; n=4). Antiplatelet agents were prescribed in 11% (n=149) of pregnant women. Of those on anticoagulants (n=111), 59% (n=66) were also co-prescribed antiplatelet agents. Side effects (mainly local bruising at the injection site) were reported in 12% (n=13) of the cases. CONCLUSION: A large proportion of pregnant women in the Arabian Gulf countries have >=1 VTE risk factor with even a smaller fraction on prophylaxis. VTE risk assessment must be adopted to identify those at risk who would need VTE prophylaxis. PMID- 26517702 TI - A concise iterative method using the Bezier technique for baseline construction. AB - A novel approach, coined the Corner-Cutting method (CC, for short), is presented in this paper which affords the efficient construction of the baseline for analytical data streams. It was derived from techniques used in computer aided geometric design, a field established to produce curves and surfaces for the aviation and automobile industries. This corner-cutting technique provided a very efficient baseline calculation through an iterative process. Furthermore, a terminal condition was developed to make the process fully automated and truly non-parametric. Finally, we employed a Bezier curve to convert the iterating result into a smooth baseline solution. Compared to other iterative schemes used for baseline detection, our method was significantly efficient, easier to implement, and had a broader range of applications. PMID- 26517703 TI - Erratum. Correction to: Educational session as a tool to increase patient satisfaction of switching etanercept from the prefilled syringe to the autoinjection pen. PMID- 26517704 TI - Evaluating Behavior in Mouse Models of the Behavioral Variant of Frontotemporal Dementia: Which Test for Which Symptom? AB - The behavioral variant of frontotemporal dementia (bvFTD) is a neurodegenerative disease affecting people in their early sixties, characterized by dramatic changes in individual and social behavior. Despite the heterogeneity in the presentation of the clinical symptoms of bvFTD, some characteristic changes can be highlighted. Social disinhibition, changes in food preferences as well as loss of empathy and apathy are commonly described. This is accompanied by a characteristic and dramatic atrophy of the prefrontal cortex with the accumulation of protein aggregates in the neurons in this area. Several causative mutations in different genes have been discovered, allowing the development of transgenic animal models, especially mouse models. In mice, attention has been focused on the histopathological aspects of the pathology, but now studies are taking interest in assessing the behavioral phenotype of FTD models. Finding the right test corresponding to human symptoms is quite challenging, especially since the frontal cortex is much less developed in mice than in humans. Although challenging, the ability to detect relevant prefrontal cortex impairments in mice is crucial for therapeutic approaches. In this review, we aim to present the approaches that have been used to model the behavioral symptoms of FTD and to explore other relevant approaches to assess behavior involving the prefrontal cortex, as well as the deficits associated with FTD. PMID- 26517705 TI - The Structure, Pathogenicity and Immunogenicity of Two Virion Fractions Harvested from Cell Cultures Infected with the CA16 Virus. AB - OBJECTIVES: To investigate the biological characteristics of the two types of virion fractions of Coxsackievirus A 16 (CA16), which include the real virion fraction and pseudo-virion fraction in their structure, pathogenicity and immunogenicity. METHODS: We obtained the two CA16 virion fractions by density gradient centrifugation. The morphology of virion fractions was analyzed by electron microscopy, while the antigenic characteristics and immunogenicity of two virion fractions were determined by ELISA, SDS-PAGE, Western blot, qRT-PCR, and the mouse model of immune response. RESULTS: The two virion fractions contained the major viral antigen components in their structures, showed similar pathogenicity in a neonatal murine model and were capable of inducing an effective primary immune response in adult mice, regardless of the essential distinction between the two virion fractions, which was the cleavage of VP0 to VP2 and VP4. CONCLUSIONS: The two CA16 virion fractions showed antigenicity and immunogenicity with inducing a specific immune response in animals. PMID- 26517706 TI - Comparison of the Efficacy between Pemetrexed plus Platinum and Non-Pemetrexed plus Platinum as First-Line Treatment in Patients with Wild-Type Epidermal Growth Factor Receptor Nonsquamous Non-Small Cell Lung Cancer: A Retrospective Analysis. AB - BACKGROUND: Despite the development of molecular research and targeted therapy, patients with wild-type epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) still receive platinum doublet chemotherapy as the standard first-line treatment. We investigated the efficacy of first-line regimens in patients with wild-type EGFR nonsquamous NSCLC. METHODS: We retrospectively analyzed the efficacy of various platinum doublet regimens as first-line treatments. Between 2007 and 2013, a total of 165 patients with wild-type EGFR nonsquamous NSCLC were included in this study. RESULTS: Seventy-one (43.0%) patients were treated with pemetrexed plus platinum (PP) and 94 (57.0%) with non pemetrexed plus platinum (NPP). The overall response rate was not different between the PP- and NPP-treated groups (26.8 vs. 28.7%, respectively; p = 0.78). The median progression-free survival (PFS) and overall survival (OS) also showed no differences between the two treatment groups (p = 0.12 for PFS, p = 0.42 for OS). The median PFS and OS for the PP group were 4.6 months (95% CI, 3.8-5.4) and 18.7 months (95% CI, 11.7-25.8), respectively, and for the NPP group, they were 4.2 months (95% CI, 3.4-5.0) and 12.2 months (95% CI, 10.3-14.1), respectively. In the subgroup analysis, most subgroups showed no significant difference in PFS and OS between the two treatment groups. CONCLUSION: Our data showed that the efficacy of various platinum doublet regimens was similar in patients with wild type EGFR nonsquamous NSCLC. PMID- 26517707 TI - RNA Editing in Chloroplasts of Spirodela polyrhiza, an Aquatic Monocotelydonous Species. AB - RNA editing is the post-transcriptional conversion from C to U before translation, providing a unique feature in the regulation of gene expression. Here, we used a robust and efficient method based on RNA-seq from non-ribosomal total RNA to simultaneously measure chloroplast-gene expression and RNA editing efficiency in the Greater Duckweed, Spirodela polyrhiza, a species that provides a new reference for the phylogenetic studies of monocotyledonous plants. We identified 66 editing sites at the genome-wide level, with an average editing efficiency of 76%. We found that the expression levels of chloroplast genes were relatively constant, but 11 RNA editing sites show significant changes in editing efficiency, when fronds turn into turions. Thus, RNA editing efficiency contributes more to the yield of translatable transcripts than steady state mRNA levels. Comparison of RNA editing sites in coconut, Spirodela, maize, and rice suggests that RNA editing originated from a common ancestor. PMID- 26517708 TI - Everything in Moderation--Dietary Diversity and Quality, Central Obesity and Risk of Diabetes. AB - Diet guidelines recommend increasing dietary diversity. Yet, metrics for dietary diversity have neither been well-defined nor evaluated for impact on metabolic health. Also, whether diversity has effects independent of diet quality is unknown. We characterized and evaluated associations of diet diversity and quality with abdominal obesity and type II diabetes (T2D) in the Multi-Ethnic Study of Atherosclerosis. At baseline (2000-02), diet was assessed among 5,160 Whites, Hispanic, Blacks, and Chinese age 45-84 y and free of T2D, using a validated questionnaire. Three different aspects of diet diversity were characterized including count (number of different food items eaten more than once/week, a broad measure of diversity), evenness (Berry index, a measure of the spread of the diversity), and dissimilarity (Jaccard distance, a measure of the diversity of the attributes of the foods consumed). Diet quality was characterized using aHEI, DASH, and a priori pattern. Count and evenness were weakly positively correlated with diet quality (r with AHEI: 0.20, 0.04), while dissimilarity was moderately inversely correlated (r = -0.34). In multivariate models, neither count nor evenness was associated with change in waist circumference (WC) or incident T2D. Greater food dissimilarity was associated with higher gain in WC (p-trend<0.01), with 120% higher gain in participants in the highest quintile of dissimilarity scores. Diet diversity was not associated with incident T2D. Also, none of the diversity metrics were associated with change in WC or incident T2D when restricted to only healthier or less healthy foods. Higher diet quality was associated with lower risk of T2D. Our findings provide little evidence for benefits of diet diversity for either abdominal obesity or diabetes. Greater dissimilarity among foods was actually associated with gain in WC. These results do not support the notion that "eating everything in moderation" leads to greater diet quality or better metabolic health. PMID- 26517710 TI - Implementation of an inpatient opioid overdose prevention program. PMID- 26517709 TI - Psychometric modeling of abuse and dependence symptoms across six illicit substances indicates novel dimensions of misuse. AB - AIMS: This study explored the factor structure of DSM III-R/IV symptoms for substance abuse and dependence across six illicit substance categories in a population-based sample of males. METHOD: DSM III-R/IV drug abuse and dependence symptoms for cannabis, sedatives, stimulants, cocaine, opioids and hallucinogens from 4179 males born 1940-1970 from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders were analyzed. Confirmatory factor analyses tested specific hypotheses regarding the latent structure of substance misuse for a comprehensive battery of 13 misuse symptoms measured across six illicit substance categories (78 items). RESULTS: Among the models fit, the latent structure of substance misuse was best represented by a combination of substance-specific factors and misuse symptom-specific factors. We found no support for a general liability factor to illicit substance misuse. CONCLUSIONS: Results indicate that liability to misuse illicit substances is drug class specific, with little evidence for a general liability factor. Additionally, unique dimensions capturing propensity toward specific misuse symptoms (e.g., tolerance, withdrawal) across substances were identified. While this finding requires independent replication, the possibility of symptom specific misuse factors, present in multiple substances, raises the prospect of genetic, neurobiological and behavioral predispositions toward distinct, narrowly defined features of drug abuse and dependence. PMID- 26517711 TI - Beyond pre-loading: Understanding the associations between pre-, side- and back loading drinking behavior and risky drinking. AB - This study examined the interaction between pre-, side- and back-loading drinking behaviors and their relationship to risky drinking, modeling to account for demographic characteristics. The study was based on an online non-probability panel survey of Victorian adults (18+) who purchased packaged liquor for off premises consumption in the previous 12months. Initially, 2545 participants entered the study, with 536 screened out, leaving a sample of 2008 respondents. While pre-loading was the most commonly reported loading behavior, back-loading and side-loading were reported almost as frequently. We found a clear association between loading and risky drinking behavior. Respondents who reported engaging in all loading behaviors were more likely to report regular very risky drinking. Age and sex were significant factors influencing the relationship between loading types and risky drinking behavior; income, marital status, and the interaction between sex and age were not significant factors. We show a broad range of loading behaviors associated with increased levels of risky drinking. Future research should seek to investigate these loading behaviors among a general population sample. PMID- 26517712 TI - Outcomes associated with adolescent marijuana and alcohol use among urban young adults: A prospective study. AB - OBJECTIVE: This study identifies and compares outcomes in young adulthood associated with longitudinal patterns of alcohol and marijuana use during adolescence among urban youth. METHOD: Data come from a cohort of 678 urban, predominantly Black children followed from ages 6-25 (1993-2012). Analyses are based on the 608 children who participated over time (53.6% male). Longitudinal patterning of alcohol and marijuana use were based on annual frequency reports from grades 8-12 and estimated through latent profile analysis. RESULTS: We identified four classes of alcohol and marijuana use including Non-Use (47%), Moderate Alcohol Use (28%), Moderate Alcohol/Increasing Marijuana Use (12%) and High Dual Use (13%). A marijuana only class was not identified. Analyses show negative outcomes in adulthood associated with all three adolescent substance use classes. Compared to the non-use class, all use classes had statistically significantly higher rates of substance dependence. Those in the 'High Dual Use' class had the lowest rate of high school graduation. Comparing classes with similar alcohol but different marijuana patterns, the 'Moderate Alcohol/Increasing Marijuana Use' class had a statistically significant increased risk of having a criminal justice record and developing substance use dependence in adulthood. CONCLUSION: Among urban youth, heterogeneous patterns of alcohol and marijuana use across adolescence are evident, and these patterns are associated with distinct outcomes in adulthood. These findings suggest a need for targeted education and intervention efforts to address the needs of youth using both marijuana and alcohol, as well as the importance of universal early preventive intervention efforts. PMID- 26517713 TI - Alteration of Gene Expression Profile in Kidney of Spontaneously Hypertensive Rats Treated with Protein Hydrolysate of Blue Mussel (Mytilus edulis) by DNA Microarray Analysis. AB - Marine organisms are rich sources of bioactive components, which are often reported to have antihypertensive effects. However, the underlying mechanisms have yet to be fully identified. The aim of this study was to investigate the antihypertensive effect of enzymatic hydrolysis of blue mussel protein (HBMP) in rats. Peptides with in vitro ACE inhibitory activity were purified from HBMP by ultrafiltration, gel filtration chromatography and reversed-phase high performance liquid chromatography. And the amino acid sequences of isolated peptides were estimated to be Val-Trp, Leu-Gly-Trp, and Met-Val-Trp-Thr. To study its in vivo action, spontaneously hypertensive rats (SHRs) were orally administration with high- or low-dose of HBMP for 28 days. Major components of the renin-angiotensin (RAS) system in serum of SHRs from different groups were analyzed, and gene expression profiling were performed in the kidney of SHRs, using the Whole Rat Genome Oligonucleotide Microarray. Results indicated although genes involved in RAS system were not significantly altered, those related to blood coagulation system, cytokine and growth factor, and fatty acids metabolism were remarkablely changed. Several genes which were seldom reported to be implicated in pathogenesis of hypertension also showed significant expression alterations after oral administration of HBMP. These data provided valuable information for our understanding of the molecular mechanisms that underlie the potential antihypertensive activities of HBMP, and will contribute towards increased value-added utilization of blue mussel protein. PMID- 26517714 TI - Identification of Host-Plant Volatiles and Characterization of Two Novel General Odorant-Binding Proteins from the Legume Pod Borer, Maruca vitrata Fabricius (Lepidoptera: Crambidae). AB - Chemoreception is a key feature in selection of host plant by phytophagous insects, and odorant-binding proteins (OBPs) are involved in chemical communication of both insects and vertebrates. The legume pod borer, Maruca vitrata Fabricius (Lepidoptera: Crambidae) is one of the key pest species of cowpea and widely distributed throughout tropical and subtropical regions, causing up to 80% of yield loss. In this study, we investigated the electrophysiological responses of female M. vitrata to floral volatiles from V. unguiculata. Seventeen electroantennogram-active compounds were identified from floral volatiles of V. unguiculata by coupled gas chromatography electroantennography (GC-EAD) and gas chromatography-mass spectrometry (GC-MS). Then, we cloned two novel full-length GOBP genes (MvitGOBP1 and MvitGOBP2) from the antennae of M. vitrata using reverse transcription PCR. Protein sequence analysis indicated that they shared high sequence similarity with other Pyralididae insect GOBPs and had the typical six-cysteine signature. Real-time PCR analysis indicated that MvitGOBP1-2 mRNA was highly expressed in the antennae of female adult with several thousands-fold difference compare to other tissue. Next, the recombinant MvitGOBP1-2 was expressed in Escherichia coli and purified using Ni ion affinity chromatography. Fluorescence binding assays demonstrated that MvitGOBP1-2 had different binding affinities with 17 volatile odorant molecules including butanoic acid butyl ester, limonene, 4-ethylpropiophenone, 1H indol-4-ol, butanoic acid octyl ester and 2-methyl-3-phenylpropanal. In the field trapping experiment, these six floral volatiles could effectively attract female moths and showed significant difference compared with the blank lure. These results suggested that MvitGOBPs and the seventeen floral volatiles are likely to function in the olfactory behavior response of female moths, which may have played crucial roles in the selection of oviposition sites. The six compounds that we have identified from the volatiles of V. unguiculata may provide useful information for exploring efficiency monitoring and integrated pest management strategies of this legume pod borer in the field. PMID- 26517715 TI - Genetic Structuration, Demography and Evolutionary History of Mycobacterium tuberculosis LAM9 Sublineage in the Americas as Two Distinct Subpopulations Revealed by Bayesian Analyses. AB - Tuberculosis (TB) remains broadly present in the Americas despite intense global efforts for its control and elimination. Starting from a large dataset comprising spoligotyping (n = 21183 isolates) and 12-loci MIRU-VNTRs data (n = 4022 isolates) from a total of 31 countries of the Americas (data extracted from the SITVIT2 database), this study aimed to get an overview of lineages circulating in the Americas. A total of 17119 (80.8%) strains belonged to the Euro-American lineage 4, among which the most predominant genotypic family belonged to the Latin American and Mediterranean (LAM) lineage (n = 6386, 30.1% of strains). By combining classical phylogenetic analyses and Bayesian approaches, this study revealed for the first time a clear genetic structuration of LAM9 sublineage into two subpopulations named LAM9C1 and LAM9C2, with distinct genetic characteristics. LAM9C1 was predominant in Chile, Colombia and USA, while LAM9C2 was predominant in Brazil, Dominican Republic, Guadeloupe and French Guiana. Globally, LAM9C2 was characterized by higher allelic richness as compared to LAM9C1 isolates. Moreover, LAM9C2 sublineage appeared to expand close to twenty times more than LAM9C1 and showed older traces of expansion. Interestingly, a significant proportion of LAM9C2 isolates presented typical signature of ancestral LAM-RDRio MIRU-VNTR type (224226153321). Further studies based on Whole Genome Sequencing of LAM strains will provide the needed resolution to decipher the biogeographical structure and evolutionary history of this successful family. PMID- 26517716 TI - Preparative purification of plasmin activity stimulating phenolic derivatives from Gastrodia elata using centrifugal partition chromatography. AB - Gastrodia rhizome, a dried and steamed tuber of Gastrodia elata Blume (Orchidaceae), has been traditionally used in Korea, China and Japan for the treatment of neurological and nervous disorders such as headaches, dizziness, vertigo and convulsive illnesses. The ethyl acetate and water extracts of G. elata stimulated plasmin activity. The active ethyl acetate fraction was subjected to centrifugal partition chromatography (CPC) with a two-phase solvent system, composed of n-hexane-ethyl acetate-methanol-water (3:7:4:6, v/v) followed by semi-preparative HPLC purification to separate active compounds and the water fraction was purified by Diaion HP-20 resin and semi-preparative HPLC. In ethyl acetate extract, 4-hydroxybenzyl alcohol (1), 4-hydroxybenzoic acid (2), 4 hydroxybenzaldehyde (3), 4-ethoxymethylphenol (4), 4,4'-oxybis(methylene)diphenol (5) and 4,4'-methylenediphenol (6) were obtained with high purities. Parishin (7) and parishin B (8) were isolated from water extract. Among isolated compounds, 4 hydroxybenzyl alcohol (1), 4-hydroxybenzaldehyde (3) and 4-ethoxymethylphenol (4) significantly stimulated plasmin activity. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26517717 TI - Correction: Aureonitol, a Fungi-Derived Tetrahydrofuran, Inhibits Influenza Replication by Targeting Its Surface Glycoprotein Hemagglutinin. PMID- 26517718 TI - Altered acetylation of proteins in patients with rheumatoid arthritis revealed by acetyl-proteomics. AB - OBJECTIVES: Post-translational modifications (PTMs) are often critical for the function of proteins as well as antigenicity of proteins. We here tried to elucidate alteration of PTMs in Rheumatoid arthritis (RA), focusing on acetylation. We applied acetyl-proteomics to peripheral blood mononuclear cells (PBMCs) to elucidate PTM difference between patients with RA and healthy donors. METHODS: Proteins, extracted from peripheral blood mononuclear cells (PBMCs) of 7 RA patients and 7 healthy donors, were separated by 2-dimansional electrophoresis. Acetylation ratios of each protein spot were estimated by the combination of Sypro Ruby staining and anti-acetylated lysine antibodies. Proteins highly acetylated in the RA group were identified by mass spectrometry. Focusing on alpha-enolase (ENO1), one of the identified proteins, involvement of histone deacetylases (HDACs) in the high acetylation was investigated. Furthermore, the effects of acetylation on the activity of ENO1 were investigated. RESULTS: In PBMCs from the patients with RA, 29 acetylated protein spots were detected. One of highly acetylated proteins in the RA patients was identified as ENO1. The acetylation of ENO1 was found to be regulated in part by HDAC1. The enzymatic activity of ENO1 was up-regulated by acetylation. CONCLUSIONS: Highly acetylated ENO1 may play roles in the pathophysiology of RA through the maintenance of activated lymphocytes by increasing glycolysis-derived energy supply. PMID- 26517719 TI - DisPredict: A Predictor of Disordered Protein Using Optimized RBF Kernel. AB - Intrinsically disordered proteins or, regions perform important biological functions through their dynamic conformations during binding. Thus accurate identification of these disordered regions have significant implications in proper annotation of function, induced fold prediction and drug design to combat critical diseases. We introduce DisPredict, a disorder predictor that employs a single support vector machine with RBF kernel and novel features for reliable characterization of protein structure. DisPredict yields effective performance. In addition to 10-fold cross validation, training and testing of DisPredict was conducted with independent test datasets. The results were consistent with both the training and test error minimal. The use of multiple data sources, makes the predictor generic. The datasets used in developing the model include disordered regions of various length which are categorized as short and long having different compositions, different types of disorder, ranging from fully to partially disordered regions as well as completely ordered regions. Through comparison with other state of the art approaches and case studies, DisPredict is found to be a useful tool with competitive performance. DisPredict is available at https://github.com/tamjidul/DisPredict_v1.0. PMID- 26517720 TI - A Validated Smartphone-Based Assessment of Gait and Gait Variability in Parkinson's Disease. AB - BACKGROUND: A well-established connection exists between increased gait variability and greater fall likelihood in Parkinson's disease (PD); however, a portable, validated means of quantifying gait variability (and testing the efficacy of any intervention) remains lacking. Furthermore, although rhythmic auditory cueing continues to receive attention as a promising gait therapy for PD, its widespread delivery remains bottlenecked. The present paper describes a smartphone-based mobile application ("SmartMOVE") to address both needs. METHODS: The accuracy of smartphone-based gait analysis (utilizing the smartphone's built in tri-axial accelerometer and gyroscope to calculate successive step times and step lengths) was validated against two heel contact-based measurement devices: heel-mounted footswitch sensors (to capture step times) and an instrumented pressure sensor mat (to capture step lengths). 12 PD patients and 12 age-matched healthy controls walked along a 26-m path during self-paced and metronome-cued conditions, with all three devices recording simultaneously. RESULTS: Four outcome measures of gait and gait variability were calculated. Mixed-factorial analysis of variance revealed several instances in which between-group differences (e.g., increased gait variability in PD patients relative to healthy controls) yielded medium-to-large effect sizes (eta-squared values), and cueing mediated changes (e.g., decreased gait variability when PD patients walked with auditory cues) yielded small-to-medium effect sizes-while at the same time, device-related measurement error yielded small-to-negligible effect sizes. CONCLUSION: These findings highlight specific opportunities for smartphone-based gait analysis to serve as an alternative to conventional gait analysis methods (e.g., footswitch systems or sensor-embedded walkways), particularly when those methods are cost-prohibitive, cumbersome, or inconvenient. PMID- 26517721 TI - Non-Selective Cannabinoid Receptor Antagonists, Hinokiresinols Reduce Infiltration of Microglia/Macrophages into Ischemic Brain Lesions in Rat via Modulating 2-Arachidonolyglycerol-Induced Migration and Mitochondrial Activity. AB - Growing evidence suggests that therapeutic strategies to modulate the post ischemic inflammatory responses are promising approaches to improve stroke outcome. Although the endocannabinoid system has been emerged as an endogenous therapeutic target to regulate inflammation after stroke insult, the downstream mechanisms and their potentials for therapeutic intervention remain controversial. Here we identified trans- and cis-hinokiresinols as novel non selective antagonists for two G-protein-coupled cannabinoid receptors, cannabinoid receptor type 1 and type 2. The Electric Cell-substrate Impedance Sensing and Boyden chamber migration assays using primary microglial cultures revealed that both hinokiresinols significantly inhibited an endocannabinoid, 2 arachidonoylglycerol-induced migration. Hinokiresinols modulated 2 arachidonoylglycerol-induced mitochondrial bioenergetics in microglia as evidenced by inhibition of ATP turnover and reduction in respiratory capacity, thereby resulting in impaired migration activity. In rats subjected to transient middle cerebral artery occlusion (1.5-h) followed by 24-h reperfusion, post ischemic treatment with hinokiresinols (2 and 7-h after the onset of ischemia, 10 mg/kg) significantly reduced cerebral infarct and infiltration of ED1-positive microglial/macrophage cells into cerebral ischemic lesions in vivo. Co administration of exogenous 2-AG (1 mg/kg, i.v., single dose at 2 h after starting MCAO) abolished the protective effect of trans-hinokiresionol. These results suggest that hinokiresinols may serve as stroke treatment by targeting the endocannabinoid system. Alteration of mitochondrial bioenergetics and consequent inhibition of inflammatory cells migration may be a novel mechanism underlying anti-ischemic effects conferred by cannabinoid receptor antagonists. PMID- 26517722 TI - Activated p38 MAPK in Peripheral Blood Monocytes of Steroid Resistant Asthmatics. AB - Steroid resistance is a significant problem in management of chronic inflammatory diseases, including asthma. Accessible biomarkers are needed to identify steroid resistant patients to optimize their treatment. This study examined corticosteroid resistance in severe asthma. 24 asthmatics with forced expiratory volume in one second of less then 80% predicted were classified as steroid resistant or steroid sensitive based on changes in their lung function following a week of treatment with oral prednisone. Heparinised blood was collected from patients prior to oral prednisone administration. Phosphorylated mitogen activated kinases (MAPK) (extracellular regulated kinase (ERK), p38 and jun kinase (JNK)) were analyzed in whole blood samples using flow cytometry. Activation of phospho-p38 MAPK and phospho-mitogen- and stress-activated protein kinase 1 (MSK1) in asthmatics' peripheral blood mononuclear cells (PBMC) were confirmed by Western blot. Dexamethasone suppression of the LPS-induced IL-8 mRNA production by steroid resistant asthmatics PBMC in the presence of p38 and ERK inhibitors was evaluated by real time PCR. Flow cytometry analysis identified significantly stronger p38 phosphorylation in CD14+ monocytes from steroid resistant than steroid sensitive asthmatics (p = 0.014), whereas no difference was found in phosphorylation of ERK or JNK in CD14+ cells from these two groups of asthmatics. No difference in phosphorylated p38, ERK, JNK was detected in CD4+, CD8+ T cells, B cells and NK cells from steroid resistant vs. steroid sensitive asthmatics. P38 MAPK pathway activation was confirmed by Western blot, as significantly higher phospho-p38 and phospho-MSK1 levels were detected in the PBMC lysates from steroid resistant asthmatics. P38 inhibitor significantly enhanced DEX suppression of LPS-induced IL-8 mRNA by PBMC of steroid resistant asthmatics. This is the first report demonstrating selective p38 MAPK pathway activation in blood monocytes of steroid resistant asthmatics, suggesting that p38 and MSK1 phosphorylation can serve as blood biomarkers of steroid resistance. PMID- 26517723 TI - Identification of Novel Components Influencing Colonization Factor Antigen I Expression in Enterotoxigenic Escherichia coli. AB - Colonization factors (CFs) mediate early adhesion of Enterotoxigenic Escherichia coli (ETEC) in the small intestine. Environmental signals including bile, glucose, and contact with epithelial cells have previously been shown to modulate CF expression in a strain dependent manner. To identify novel components modulating CF surface expression, 20 components relevant to the intestinal environment were selected for evaluation. These included mucin, bicarbonate, norepinephrine, lincomycin, carbon sources, and cations. Effects of individual components on surface expression of the archetype CF, CFA/I, were screened using a fractional factorial Hadamard matrix incorporating 24 growth conditions. As most CFs agglutinate erythrocytes, surface expression was evaluated by mannose resistant hemagglutination. Seven components, including porcine gastric mucin, lincomycin, glutamine, and glucose were found to induce CFA/I surface expression in vitro in a minimal media while five others were inhibitory, including leucine and 1,10-phenanthroline. To further explore the effect of components positively influencing CFA/I surface expression, a response surface methodology (RSM) was designed incorporating 36 growth conditions. The optimum concentration for each component was identified, thereby generating a novel culture media, SP1, for CFA/I expression. CFs closely related to CFA/I, including CS4 and CS14 were similarly induced in SP1 media. Other epidemiologically relevant CFs were also induced when compared to the level obtained in minimal media. These results indicate that although CF surface expression is complex and highly variable among strains, the CF response can be predicted for closely related strains. A novel culture media inducing CFs in the CF5a group was successfully identified. In addition, mucin was found to positively influence CF expression in strains expressing either CFA/I or CS1 and CS3, and may function as a common environmental cue. PMID- 26517724 TI - Laboratory Investigations of African Pouched Rats (Cricetomys gambianus) as a Potential Reservoir Host Species for Monkeypox Virus. AB - Monkeypox is a zoonotic disease endemic to central and western Africa, where it is a major public health concern. Although Monkeypox virus (MPXV) and monkeypox disease in humans have been well characterized, little is known about its natural history, or its maintenance in animal populations of sylvatic reservoir(s). In 2003, several species of rodents imported from Ghana were involved in a monkeypox outbreak in the United States with individuals of three African rodent genera (Cricetomys, Graphiurus, Funisciurus) shown to be infected with MPXV. Here, we examine the course of MPXV infection in Cricetomys gambianus (pouched Gambian rats) and this rodent species' competence as a host for the virus. We obtained ten Gambian rats from an introduced colony in Grassy Key, Florida and infected eight of these via scarification with a challenge dose of 4X104 plaque forming units (pfu) from either of the two primary clades of MPXV: Congo Basin (C-MPXV: n = 4) or West African (W-MPXV: n = 4); an additional 2 animals served as PBS controls. Viral shedding and the effect of infection on activity and physiological aspects of the animals were measured. MPXV challenged animals had significantly higher core body temperatures, reduced activity and increased weight loss than PBS controls. Viable virus was found in samples taken from animals in both experimental groups (C-MPXV and W-MPXV) between 3 and 27 days post infection (p.i.) (up to 1X108 pfu/ml), with viral DNA found until day 56 p.i. The results from this work show that Cricetomys gambianus (and by inference, probably the closely related species, Cricetomys emini) can be infected with MPXV and shed viable virus particles; thus suggesting that these animals may be involved in the maintenance of MPXV in wildlife mammalian populations. More research is needed to elucidate the epidemiology of MPXV and the role of Gambian rats and other species. PMID- 26517725 TI - Intraocular Pressure Changes during Accommodation in Progressing Myopes, Stable Myopes and Emmetropes. AB - PURPOSE: To investigate the changes of intraocular pressure (IOP) induced by 3 diopter (3 D) accommodation in progressing myopes, stable myopes and emmetropes. DESIGN: Cross-sectional study. PARTICIPANTS: 318 subjects including 270 myopes and 48 emmetropes. METHODS: 195 progressing myopes, 75 stable myopes and 48 emmetropes participated in this study. All subjects had their IOP measured using iCare rebound tonometer while accommodative stimuli of 0 D and 3 D were presented. MAIN OUTCOME MEASURES: IOP values without accommodation and with 3 D accommodation were measured in all subjects. Baseline IOPs and IOP changes were compared within and between groups. RESULTS: There was no significant difference in IOPs between progressing myopes, stable myopes and emmetropes when no accommodation was induced (17.47+/-3.46, 16.62+/-2.98 and 16.80+/-3.62 respectively, p>0.05). IOP experienced an insignificantly slight decrease after 3 D accommodation in three groups (mean change -0.19+/-2.16, -0.03+/-1.68 and 0.39+/-2.65 respectively, p>0.05). Subgroup analysis showed in progressing myopic group, IOP of children (<18 years old) declined with accommodation while IOP of adults (>=18 years) increased, and the difference was statistically significant (p = 0.008). However, after excluding the age factor, accommodation induced IOP changes of high progressing myopes (<=-6 D), low, moderate and non-myopes (>-6 D) was not significantly different after Bonferroni correction (p = 0.838). CONCLUSIONS: Although no difference was detected between the baseline IOPs and accommodation induced IOP changes in progressing myopes, stable myopes and emmetropes, this study found accommodation could cause transient IOP elevation in adult progressing myopes. PMID- 26517726 TI - Synthesis and Biological Evaluation of Novel Gigantol Derivatives as Potential Agents in Prevention of Diabetic Cataract. AB - As a continuation of our efforts directed towards the development of natural anti diabetic cataract agents, gigantol was isolated from Herba dendrobii and was found to inhibit both aldose reductase (AR) and inducible nitric oxide synthase (iNOS) activity, which play a significant role in the development and progression of diabetic cataracts. To improve its bioefficacy and facilitate use as a therapeutic agent, gigantol (compound 14f) and a series of novel analogs were designed and synthesized. Analogs were formulated to have different substituents on the phenyl ring (compounds 4, 5, 8, 14a-e), substitute the phenyl ring with a larger steric hindrance ring (compounds 10, 17c) or modify the carbon chain (compounds 17a, 17b, 21, 23, 25). All of the analogs were tested for their effect on AR and iNOS activities and on D-galactose-induced apoptosis in cultured human lens epithelial cells. Compounds 5, 10, 14a, 14b, 14d, 14e, 14f, 17b, 17c, 23, and 25 inhibited AR activity, with IC50 values ranging from 5.02 to 288.8 MUM. Compounds 5, 10, 14b, and 14f inhibited iNOS activity with IC50 ranging from 432.6 to 1188.7 MUM. Compounds 5, 8, 10, 14b, 14f, and 17c protected the cells from D-galactose induced apoptosis with viability ranging from 55.2 to 76.26%. Of gigantol and its analogs, compound 10 showed the greatest bioefficacy and is warranted to be developed as a therapeutic agent for diabetic cataracts. PMID- 26517727 TI - Domestic Larval Control Practices and Malaria Prevalence among Under-Five Children in Burkina Faso. AB - INTRODUCTION: Larval source management has contributed to malaria decline over the past years. However, little is known about the impact of larval control practices undertaken at the household level on malaria transmission. METHODS: The study was conducted in Kaya health district after the 2010 mass distribution of insecticide treated-nets and the initiation of malaria awareness campaigns in Burkina Faso. The aim was to (i) estimate the level of domestic larval control practices (cleaning of the house and its surroundings, eradication of larval sources, and elimination of hollow objects that might collect water); (ii) identify key determinants; and (iii) explore the structural relationships between these practices, participation in awareness-raising activities and mothers' knowledge/attitudes/practices, and malaria prevalence among under-five children. RESULTS: Overall, 2004 households were surveyed and 1,705 under-five children were examined. Half of the mothers undertook at least one action to control larval proliferation. Mothers who had gone to school had better knowledge about malaria and were more likely to undertake domestic larval control practices. Living in highly exposed rural areas significantly decreased the odds of undertaking larval control actions. Mothers' participation in malaria information sessions increased the adoption of vector control actions and bednet use. Malaria prevalence was statistically lower among children in households where mothers had undertaken at least one vector control action or used bed-nets. There was a 0.16 standard deviation decrease in malaria prevalence for every standard deviation increase in vector control practices. The effect of bednet use on malaria prevalence was of the same magnitude. CONCLUSION: Cleaning the house and its surroundings, eradicating breeding sites, and eliminating hollow objects that might collect water play a substantial role in preventing malaria among under five. There is a need for national malaria control programs to include or reinforce training activities for community health workers aimed at promoting domestic larval control practices. PMID- 26517728 TI - Increased growth and root Cu accumulation of Sorghum sudanense by endophytic Enterobacter sp. K3-2: Implications for Sorghum sudanense biomass production and phytostabilization. AB - Endophytic bacterial strain K3-2 was isolated from the roots of Sorghum sudanense (an bioenergy plant) grown in a Cu mine wasteland soils and characterized. Strain K3-2 was identified as Enterobacter sp. based on 16S rRNA gene sequence analysis. Strain K3-2 exhibited Cu resistance and produced 1-aminocyclopropane-1 carboxylate (ACC) deaminase, indole-3-acetic acid (IAA), siderophores, and arginine decarboxylase. Pot experiments showed that strain K3-2 significantly increased the dry weight and root Cu accumulation of Sorghum sudanense grown in the Cu mine wasteland soils. Furthermore, increase in total Cu uptake (ranging from 49% to 95%) of the bacterial inoculated-Sorghum sudanense was observed compared to the control. Notably, most of Cu (83-86%) was accumulated in the roots of Sorghum sudanense. Furthermore, inoculation with strain K3-2 was found to significantly increase Cu bioconcentration factors and the proportions of IAA- and siderophore-producing bacteria in the root interiors and rhizosphere soils of Sorghum sudanense compared with the control. Significant decrease in the available Cu content was also observed in the rhizosphere soils of the bacterial inoculated Sorghum sudanense. The results suggest that the endophytic bacterial strain K3-2 may be exploited for promoting Sorghum sudanense biomass production and Cu phytostabilization in the Cu mining wasteland soils. PMID- 26517729 TI - Evaluation of genetic damage in tobacco and arsenic exposed population of Southern Assam, India using buccal cytome assay and comet assay. AB - Ground water is the principal source of drinking water in Assam. Ground water contamination of arsenic in drinking water is a great concern for human health and considered as a human carcinogen. The present cytogenetic biomonitoring study was undertaken to investigate the genotoxic effects associated with people of southern Assam consuming arsenic contaminated water and chewing tobacco. Employing the buccal cytome assay, exfoliated cells were analyzed in 138 individuals of age range 22-42 years and divided into four groups. Group I (n=54) are participants residing in localities where ground water contains arsenic concentration below the permissible limit (<10MUg/l) and without any tobacco chewing history. Group II (n=32) participants from the same area but they are tobacco chewers. Group III (n=24) participants from localities where significantly high arsenic contamination in ground water were observed. Whereas the Group IV (n=28) consists of participants from the arsenic contaminated area and also tobacco chewers. Body mass index (BMI) in all the groups are found to be nearly same and in normal range. Statistically significant (P<0.001) increase in genotoxic, cell death parameters and cell proliferation biomarkers were observed in the Group IV compared to other groups. In the comet assay, percent of tail DNA gradually increases among the groups and has statistical significance. Spearman correlation revealed strong positive correlation between the arsenic exposed peoples and the binucleated cells (r=0.4763; P<0.001). Amount of chewing tobacco had significant positive correlation with micronucleus frequency (r=0.268; P<0.05) and karyolitic cells (r=0.217; P<0.05) and also in the percentage of tail DNA (r=0.5532, P<0.001). A statistically significant increase in glucose content and decrease in hemoglobin content as well as acetylcholine esterase in the blood of exposed individuals was observed. Our preliminary study indicate that population exposed to arsenic through drinking water may become more susceptible towards chewing tobacco induced nuclear damage as evaluated by buccal cytome assay and comet assay. PMID- 26517730 TI - Detection and identification of protein citrullination in complex biological systems. AB - Protein citrullination is a post-translational modification of arginine that is catalyzed by the Protein Arginine Deiminase (PAD) family of enzymes. Aberrantly increased citrullination is associated with a host of inflammatory diseases and cancer and PAD inhibitors have shown remarkable efficacy in a range of diseases including rheumatoid arthritis, lupus, atherosclerosis, and ulcerative colitis. In rheumatoid arthritis, citrullinated proteins serve as key antigens for rheumatoid arthritis-associated autoantibodies. These data suggest that citrullinated proteins may serve more generally as biomarkers of specific disease states, however, the identification of citrullinated residues remains challenging due to the small 1Da mass change that occurs upon citrullination. Herein, we highlight the available techniques to identify citrullinated proteins/residues focusing on advanced MS techniques as well as chemical derivatization strategies that are currently being employed to identify citrullinated proteins as well as the specific residues modified within those proteins. PMID- 26517732 TI - Ni(II)-Catalyzed Highly Stereo- and Regioselective Syntheses of Isoindolinones and Isoquinolinones from in Situ Prepared Aldimines Triggered by Homoallylation/Lactamization Cascade. AB - An efficient route to isoindolinones and isoquinolinones has been achieved via a domino Ni-catalyzed homoallylation/lactamization from in situ prepared imines, derived from o-formyl benzoates and o-formyl arylacetates, with conjugated dienes promoted by diethylzinc. The reaction proceeds smoothly at room temperature for a variety of aldehydes, amines, and dienes. The method involves one C-C and two C-N bond forming events under operationally simple conditions. PMID- 26517731 TI - Cation-Anion Interactions within the Nucleic Acid Ion Atmosphere Revealed by Ion Counting. AB - The ion atmosphere is a critical structural, dynamic, and energetic component of nucleic acids that profoundly affects their interactions with proteins and ligands. Experimental methods that "count" the number of ions thermodynamically associated with the ion atmosphere allow dissection of energetic properties of the ion atmosphere, and thus provide direct comparison to theoretical results. Previous experiments have focused primarily on the cations that are attracted to nucleic acid polyanions, but have also showed that anions are excluded from the ion atmosphere. Herein, we have systematically explored the properties of anion exclusion, testing the zeroth-order model that anions of different identity are equally excluded due to electrostatic repulsion. Using a series of monovalent salts, we find, surprisingly, that the extent of anion exclusion and cation inclusion significantly depends on salt identity. The differences are prominent at higher concentrations and mirror trends in mean activity coefficients of the electrolyte solutions. Salts with lower activity coefficients exhibit greater accumulation of both cations and anions within the ion atmosphere, strongly suggesting that cation-anion correlation effects are present in the ion atmosphere and need to be accounted for to understand electrostatic interactions of nucleic acids. To test whether the effects of cation-anion correlations extend to nucleic acid kinetics and thermodynamics, we followed the folding of P4-P6, a domain of the Tetrahymena group I ribozyme, via single-molecule fluorescence resonance energy transfer in solutions with different salts. Solutions of identical concentration but lower activity gave slower and less favorable folding. Our results reveal hitherto unknown properties of the ion atmosphere and suggest possible roles of oriented ion pairs or anion-bridged cations in the ion atmosphere for electrolyte solutions of salts with reduced activity. Consideration of these new results leads to a reevaluation of the strengths and limitations of Poisson-Boltzmann theory and highlights the need for next generation atomic-level models of the ion atmosphere. PMID- 26517733 TI - Good quality of life outcomes after treatment of prosthetic joint infection with debridement and prosthesis retention. AB - Patients treated for early prosthetic joint infection (PJI) with surgical debridement and prosthesis retention have a rate of successful infection eradication that is similar to patients treated with the traditional approach of prosthesis exchange. It is therefore important to consider other outcomes after prosthetic joint infection treatment that may influence management decisions, such as quality of life (QOL). Our aim was to describe infection cure rates and quality of life for patients with prosthetic joint infection treated with debridement and prosthesis retention and to determine if treatment with this approach was a risk factor for poor quality of life outcomes. Prospectively collected pre and post-arthroplasty data were available for 2,134 patients, of which PJI occurred in 41. For patients treated for prosthetic joint infection, the 2-year survival free of treatment failure was 87% (95%CI 84-89). Prosthetic joint infection cases treated with debridement and retention had a similar improvement from pre-arthroplasty to 12-months post-arthroplasty as patients without PJI in QOL according to the SF-12 survey. Prosthetic joint infection treated with debridement and retention was not a risk factor for poor quality of life on univariate or multivariate analysis. Prosthetic joint infection treated with debridement and prosthesis retention results in good cure rates and quality of life. Further studies are required that directly compare quality of life for different surgical approaches for prosthetic joint infection to better inform management decisions. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:898-902, 2016. PMID- 26517734 TI - A Promoter Polymorphism in the CD59 Complement Regulatory Protein Gene in Donor Lungs Correlates With a Higher Risk for Chronic Rejection After Lung Transplantation. AB - Complement activation leads primarily to membrane attack complex formation and subsequent target cell lysis. Protection against self-damage is regulated by complement regulatory proteins, including CD46, CD55, and CD59. Within their promoter regions, single-nucleotide polymorphisms (SNPs) are present that could influence transcription. We analyzed these SNPs and investigated their influence on protein expression levels. A single SNP configuration in the promoter region of CD59 was found correlating with lower CD59 expression on lung endothelial cells (p = 0.016) and monocytes (p = 0.013). Lung endothelial cells with this SNP configuration secreted more profibrotic cytokine IL-6 (p = 0.047) and fibroblast growth factor beta (p = 0.036) on exposure to sublytic complement activation than cells with the opposing configuration, whereas monocytes were more susceptible to antibody-mediated complement lysis (p < 0.0001). Analysis of 137 lung transplant donors indicated that this CD59 SNP configuration correlates with impaired long term survival (p = 0.094) and a significantly higher incidence of bronchiolitis obliterans syndrome (p = 0.046) in the recipient. These findings support a role for complement in the pathogenesis of this posttransplant complication and are the first to show a deleterious association of a donor CD59 promoter polymorphism in lung transplantation. PMID- 26517735 TI - Biological responses of Vicia faba seedlings to the imidazolium-based ionic liquid 1-hexyl-3-methylimidazolium chloride in soil. AB - Although there are a few studies on the toxicity of ionic liquids (ILs), relatively little is known about their toxic effects on plants in soil. In the present study, the toxic effects of 1-hexyl-3-methylimidazolium chloride ([Hmim]Cl) in the soil on Vicia faba seedlings and the influences of [Hmim]Cl on the physicochemical properties of the soil were studied. Organic matter content, pH, and conductivity of the tested soil were significantly altered at [Hmim]Cl concentrations greater than 1000 mg kg(-1) . Moreover, shoot length, root length, dry weight, and pigment content of the V. faba seedlings were greatly inhibited when the [Hmim]Cl concentration was greater than 500 mg kg(-1) . The roots were the most seriously affected organ and stopped growing at 3000 mg kg(-1) . In addition, [Hmim]Cl caused an increase in the level of reactive oxygen species at [Hmim]Cl concentrations above 250 mg kg(-1) that resulted in lipid peroxidation, DNA damage, and oxidative stress in the V. faba seedlings. The present study provides information that is useful for evaluation of the environmental safety of ILs in soil. Environ Toxicol Chem 2016;35:1502-1510. (c) 2015 SETAC. PMID- 26517736 TI - Selective Extraction of Americium(III) over Europium(III) with the Pyridylpyrazole Based Tetradentate Ligands: Experimental and Theoretical Study. AB - 1,3-Bis[3-(2-pyridyl)pyrazol-1-yl]propane (Bippp) and 1,2-bis[3-(2 pyridyl)pyrazyl-1-methyl]benzene (Dbnpp), the pyridylpyrazole based tetradentate ligands, were synthesized and characterized by MS, NMR, and FT-IR. The solvent extraction and complexation behaviors of Am(III) and Eu(III) with the ligands were investigated experimentally and theoretically. In the presence of 2 bromohexanoic acid, the two ligands can effectively extract Am(III) over Eu(III) and other rare earth(III) metals (RE(III)) in HNO3 solution with the separation factors (SFAm/RE) ranging from 15 to 60. Slope analyses showed that both Am(III) and Eu(III) were extracted as monosolvated species, which agrees well with the results observed from X-ray crystallography and MS analyses. The stability constants (log K) obtained from UV-vis titration for Eu(III) complexes with Bippp and Dbnpp are 4.75 +/- 0.03 and 4.45 +/- 0.04, respectively. Both UV-vis titration and solvent extraction studies indicated that Bippp had stronger affinity for Eu(III) than Dbnpp, which is confirmed by density functional theory (DFT) calculations. DFT calculations revealed that the AmL(NO3)3 (L = Bippp and Dbnpp) complexes are thermodynamically more stable in water than their Eu(III) analogues, which is caused by greater covalency of the Am-N than Eu-N bonds. Theoretical studies gave an insight into the nature of the M(III)-ligand bonding interactions. PMID- 26517737 TI - Long-Cycle-Life Na-Ion Anodes Based on Amorphous Titania Nanotubes--Interfaces and Diffusion. AB - Amorphous self-assembled titania nanotube layers are fabricated by anodization in ethylene glycol based baths. The nanotubes having diameters between 70-130 nm and lengths between 4.5-17 MUm are assembled in Na-ion test cells. Their sodium insertion properties and electrochemical behavior with respect to sodium insertion is studied by galvanostatic cycling with potential limitation and cyclic voltammetry. It is found that these materials are very resilient to cycling, some being able to withstand more than 300 cycles without significant loss of capacity. The mechanism of electrochemical storage of Na(+) in the investigated titania nanotubes is found to present significant particularities and differences from a classical insertion reaction. It appears that the interfacial region between titania and the liquid electrolyte is hosting the majority of Na(+) ions and that this interfacial layer has a pseudocapacitive behavior. Also, for the first time, the chemical diffusion coefficients of Na(+) into the amorphous titania nanotubes is determined at various electrode potentials. The low values of diffusion coefficients, ranging between 4 * 10(-20) to 1 * 10(-21) cm(2)/s, support the interfacial Na(+) storage mechanism. PMID- 26517738 TI - Cold snaring diminutive polyps: can we make of a polyp ... a better polyp? PMID- 26517739 TI - Outbreaks linked to duodenoscopes: microbiological control should be improved. PMID- 26517740 TI - Reply to Saliou et al. PMID- 26517745 TI - Video Comment on Frederike G. I. van Vilsteren et al. PMID- 26517746 TI - Video Comment on Dimitri Christophorou et al. PMID- 26517747 TI - Video Comment on Wouter F. W. Kappelle et al. PMID- 26517748 TI - Video Comment on Tsuyoshi Hamada et al. PMID- 26517749 TI - Correction to Capillary Pressure-Saturation Relations for Supercritical CO2 and Brine in Limestone/Dolomite Sands: Implications for Geologic Carbon Sequestration in Carbonate Reservoirs. PMID- 26517750 TI - Clinical characteristics and outcomes of pyogenic vertebral osteomyelitis in patients with cirrhosis. PMID- 26517751 TI - Deconstructing the Iboga Alkaloid Skeleton: Potentiation of FGF2-induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound. AB - Modulation of growth factor signaling pathways in the brain represents a new experimental approach to treating neuropsychiatric disorders such as depression, anxiety, and addiction. Neurotrophins and growth factors exert synaptic, neuronal, and circuit level effects on a wide temporal range, which suggests a possibility of rapid and lasting therapeutic effects. Consequently, identification of small molecules that can either enhance the release of growth factors or potentiate their respective pathways will provide a drug-like alternative to direct neurotrophin administration or viral gene delivery and thus represents an important frontier in chemical biology and drug design. Glial cell line-derived neurotrophic factor (GDNF), in particular, has been implicated in marked reduction of alcohol consumption in rodent addiction models, and the natural product ibogaine, a substance used traditionally in ritualistic ceremonies, has been suggested to increase the synthesis and release of GDNF in the dopaminergic system in rats. In this report, we describe a novel iboga analog, XL-008, created by unraveling the medium size ring of the ibogamine skeleton, and its ability to induce release of GDNF in C6 glioma cells. Additionally, XL-008 potentiates the release of GDNF induced by fibroblast growth factor 2 (FGF2), another neurotrophin implicated in major depressive disorder, increasing potency more than 2-fold (from 7.85 +/- 2.59 ng/mL to 3.31 +/- 0.98 ng/mL) and efficacy more than 3-fold. The GDNF release by both XL-008 and the FGF2/XL-008 mixture was found to be mediated through the MEK and PI3K signaling pathways but not through PLCgamma in C6 glioma cells. PMID- 26517753 TI - The bleomycin model: in pursuit of relevant biomakers. PMID- 26517752 TI - Short-Term Efficacy Reliably Predicts Long-Term Clinical Benefit in Rheumatoid Arthritis Clinical Trials as Demonstrated by Model-Based Meta-Analysis. AB - The objective of this study was to assess the relationship between short-term and long-term treatment effects measured by the American College of Rheumatology (ACR) 50 responses and to assess the feasibility of predicting 6-month efficacy from short-term data. A rheumatoid arthritis (RA) database was constructed from 68 reported trials. We focused on the relationship between 3- and 6-month ACR50 treatment effects and developed a generalized nonlinear model to quantify the relationship and test the impact of covariates. The DeltaACR50 at 6 months strongly correlated with that at 3 months, moderately correlated with that at 2 months, and only weakly correlated with results obtained at <2 months. A scaling factor that reflected the ratio of 6- to 3-month treatment effects was estimated to be 0.997, suggesting that the treatment effects at 3 months are approaching a "plateau." Drug classes, baseline Disease Activity Score in 28 Joints, and the magnitude of control arm response did not show significant impacts on the scaling factor. This work quantitatively supports the empirical clinical development paradigm of using 3-month efficacy data to predict long-term efficacy and to inform the probability of clinical success based on early efficacy readout. PMID- 26517754 TI - Reply: the bleomycin model: in pursuit of relevant biomakers. PMID- 26517756 TI - Influence of treatment of vulvovaginal atrophy with intravaginal prasterone on the male partner. AB - OBJECTIVE: The aim was to analyze the opinion of the male partner of women treated for vulvovaginal atrophy (VVA) with intravaginal 0.50% DHEA (prasterone), thus providing information on both members of the couple. METHODS: On a voluntary basis, in a prospective, randomized, double-blind and placebo-controlled phase III clinical trial, the male partner filled a questionnaire at baseline and at 12 weeks stating his observations related to his penis and intercourse before and after VVA treatment. RESULTS: Sixty-six men having a partner treated with intravaginal DHEA and 34 others having a partner treated with placebo answered the questionnaires. Concerning the feeling of vaginal dryness of their female partner, the severity score following DHEA treatment improved by 81% (0.76 units) over placebo (p = 0.0347). Thirty-six percent of men having a partner treated with DHEA did not feel the vaginal dryness of the partner at the end of treatment compared to 7.8% in the placebo group. When analyzing the situation at 12 weeks compared to baseline, an improved score of 1.09 units was the difference found for the DHEA group compared to 0.76 for the placebo group (p = 0.05 vs. placebo). In the DHEA group, 38% of men scored very improved compared to 18% in the placebo group. No adverse event has been reported. CONCLUSION: The male partner had a very positive evaluation of the treatment received by his female partner. PMID- 26517757 TI - Neural Activity Associated with Visual Search for Line Drawings on AAC Displays: An Exploration of the Use of fMRI. AB - Visual aided augmentative and alternative communication (AAC) consists of books or technologies that contain visual symbols to supplement spoken language. A common observation concerning some forms of aided AAC is that message preparation can be frustratingly slow. We explored the uses of fMRI to examine the neural correlates of visual search for line drawings on AAC displays in 18 college students under two experimental conditions. Under one condition, the location of the icons remained stable and participants were able to learn the spatial layout of the display. Under the other condition, constant shuffling of the locations of the icons prevented participants from learning the layout, impeding rapid search. Brain activation was contrasted under these conditions. Rapid search in the stable display was associated with greater activation of cortical and subcortical regions associated with memory, motor learning, and dorsal visual pathways compared to the search in the unpredictable display. Rapid search for line drawings on stable AAC displays involves not just the conceptual knowledge of the symbol meaning but also the integration of motor, memory, and visual-spatial knowledge about the display layout. Further research must study individuals who use AAC, as well as the functional effect of interventions that promote knowledge about array layout. PMID- 26517758 TI - Overcoming drug resistance for macro parasites. AB - Helminth infections impose burden on human and livestock populations, and their control predominantly relies on periodic mass administration of anthelmintic drugs. However, recent emergence of drug resistance among parasites to currently available drugs raises serious problems for continuation of control strategies and achievement of elimination of parasitic diseases. This review discusses the problem of anthelmintic resistance in humans and livestock, and suggests steps that can be taken to overcome this problem. To achieve the goals of morbidity reduction or elimination of infection we need to develop novel tools, including more efficacious drugs, vaccines and/or antivectorial agents; new diagnostics for infection and assessment of drug efficacy; and markers for possible anthelmintic resistance. Harnessing the knowledge generated from sequencing of parasite genome sequences is the key to identify genes responsible for drug resistance, which can be used as a starting point for discovery of target-specific pharmacological or genetic modulation to test the functional importance of individual genes and pathways. Involvement of chemical genetic screens and Caenorhabditis elegans as a model system for drug discovery needs to be explored in greater detail. Collective effort from several quarters is needed to think of a world that is free of parasitic infections. PMID- 26517760 TI - Absorption F-sum rule for the exciton binding energy in methylammonium lead halide perovskites. AB - Advances of optoelectronic devices based on methylammonium lead halide perovskites depend on understanding the role of excitons, whether it is marginal as in inorganic semiconductors, or crucial, like in organics. However, a consensus on the exciton binding energy and its temperature dependence is still lacking, even for widely studied methylammonium lead iodide and bromide materials (MAPbI3, MAPbBr3). Here we determine the exciton binding energy based on an f-sum rule for integrated UV-vis absorption spectra, circumventing the pitfalls of least-squares fitting procedures. In the temperature range 80-300 K, we find that the exciton binding energy in MAPbBr3 is EB = (60 +/- 3) meV, independent of temperature; for MAPbI3, in the orthorhombic phase (below 140 K) EB = (34 +/- 3) meV, while in the tetragonal phase the binding energy softens to 29 meV at 170 K and stays constant up to 300 K. Implications of binding energy values on solar cell and LED workings are discussed. PMID- 26517759 TI - Mild cognitive impairment: an update in Parkinson's disease and lessons learned from Alzheimer's disease. AB - Cognitive dysfunction is an important focus of research in Parkinson's disease (PD) and Alzheimer's disease (AD). While the concept of amnestic mild cognitive impairment (MCI) as a prodrome to AD has been recognized for many years, the construct of MCI in PD is a relative newcomer with recent development of diagnostic criteria, biomarker research programs and treatment trials. Controversies and challenges, however, regarding PD-MCI's definition, application, heterogeneity and different trajectories have arisen. This review will highlight current research advances and challenges in PD-MCI. Furthermore, lessons from the AD field, which has witnessed an evolution in MCI/AD definitions, relevant advances in biomarker research and development of disease modifying and targeted therapeutic trials will be discussed. PMID- 26517761 TI - Transient mixed chimerism for allograft tolerance. AB - Mixed chimerism discovered in Freemartin cattle by Ray Owen 70 years ago paved the way for research on immune tolerance. Since his discovery, significant progress has been made in the effort to induce allograft tolerance via mixed chimerism in various murine models. However, induction of persistent mixed chimerism has proved to be extremely difficult in major histocompatibility complex mismatched humans. Chimerism induced in humans tends to either disappear or convert to full donor chimerism, depending on the intensity of the conditioning regimen. Nevertheless, our studies in both NHPs and humans have clearly demonstrated that renal allograft tolerance can be induced by transient mixed chimerism. Our studies have shown that solid organ allograft tolerance via transient mixed chimerism 1) requires induction of multilineage hematologic chimerism, 2) depends on peripheral regulatory mechanisms, rather than thymic deletion, for long-term maintenance, 3) is organ specific (kidney and lung but not heart allograft tolerance are feasible). A major advantage of tolerance induction via transient mixed chimerism is exclusion of the risk of graft-versus host disease. Our ongoing studies are directed toward improving the consistency of tolerance induction, reducing the morbidity of the conditioning regimen, substituting clinically available agents, such as Belatacept for the now unavailable anti-CD2 monoclonal antibody, and extending the protocol to recipients of deceased donor allografts. PMID- 26517762 TI - Treatment of flexion-type supracondylar fractures in children: the 'push-pull' method for closed reduction and percutaneous K-wire fixation. AB - Flexion-type supracondylar fractures are challenging to treat because, unlike extension-type fractures, it is difficult to take advantage of the intact periosteal hinge to stabilize the fracture fragments during percutaneous pinning. Some authors have described closed reduction of these fractures with the elbow in extension, followed by percutaneous K-wire fixation. However, percutaneous pinning with elbow in extension is technically difficult, time consuming, and usually requires the help of a skilled assistant because of persistent fracture instability. To circumvent these difficulties, we utilized a 'push-pull' maneuver, which simplifies the closed reduction and fixation of these difficult fractures. We describe the surgical technique for the 'push-pull' method and report radiographic outcomes of a case series of children with flexion-type supracondylar fractures treated using this technique. A retrospective review of medical records and radiographs of all children who underwent operative treatment of a flexion-type supracondylar humeral fracture using the 'push-pull' method in a tertiary-level children's hospital between January 2009 and January 2014 was carried out. Radiographic outcomes were reported using descriptive statistics. There were a total of nine patients (five females, four males), average age 9.8 years (4-14 years). Seventy-eight percent (7/9 patients) of the children had type III injuries, whereas 22% (two children) had type II injuries. The average duration of surgery was 41 min (24-60 min). No intraoperative or postoperative complications were recorded. Postoperative radiographic measures showed that the anterior humeral line passed through the middle third of capitellum in 78% of patients (7/9 patients), whereas it passed posterior to it in 22% (two patients). The average humerocapitellar angle was 30 degrees (21-44 degrees ) and the anterior coronoid line was unbroken in 44% (4/9 patients). The average humeroulnar angle was 13 degrees (8-20 degrees ) of valgus. The 'push-pull' is a safe, effective, and easy method to treat unstable flexion-type supracondylar fractures in children with good radiographic postoperative outcomes. LEVEL OF EVIDENCE: level IV. PMID- 26517764 TI - The Dexamethasone Intravitreal Implant for Noninfectious Uveitis: Practice Patterns Among Uveitis Specialists. AB - PURPOSE: To describe the practice patterns and perceptions of uveitis specialists regarding the use of the intravitreal dexamethasone (DEX) implant for the treatment of noninfectious uveitis. METHODS: We invited uveitis specialists to participate in an anonymous online survey. RESULTS: Among the 45 respondents, 76.5% identified uveitic macular edema as the most common clinical finding for which they use the DEX implant. The most common contraindications to DEX implantation were aphakia and glaucoma requiring >2 medications. Nearly two thirds (64.3%) felt that the advent of the DEX implant did not change the frequency with which they used the fluocinolone acetonide (FA) implant, and about one-third (32.3%) preferred to use at least one DEX implant, before committing a patient to an FA implant. CONCLUSIONS: Uveitis physicians use the DEX implant for a wide range of clinical findings and uveitic diagnoses. There was no clear consensus on preferences regarding the use of DEX versus FA implants. PMID- 26517765 TI - Reply to: "Effusive-constrictive pericarditis successfully treated with anakinra" G. Lazaros et al. Interleukin-1beta receptor antagonist and pericardial constriction. PMID- 26517763 TI - M1 RNA is important for the in-cell solubility of its cognate C5 protein: Implications for RNA-mediated protein folding. AB - It is one of the fundamental questions in biology how proteins efficiently fold into their native conformations despite off-pathway events such as misfolding and aggregation in living cells. Although molecular chaperones have been known to assist the de novo folding of certain types of proteins, the role of a binding partner (or a ligand) in the folding and in-cell solubility of its interacting protein still remains poorly defined. RNase P is responsible for the maturation of tRNAs as adaptor molecules of amino acids in ribosomal protein synthesis. The RNase P from Escherichia coli, composed of M1 RNA and C5 protein, is a prototypical ribozyme in which the RNA subunit contains the catalytic activity. Using E. coli RNase P, we demonstrate that M1 RNA plays a pivotal role in the in cell solubility of C5 protein both in vitro and in vivo. Mutations in either the C5 protein or M1 RNA that affect their interactions significantly abolished the folding of C5 protein. Moreover, we find that M1 RNA provides quality insurance of interacting C5 protein, either by promoting the degradation of C5 mutants in the presence of functional proteolytic machinery, or by abolishing their solubility if the machinery is non-functional. Our results describe a crucial role of M1 RNA in the folding, in-cell solubility, and, consequently, the proteostasis of the client C5 protein, giving new insight into the biological role of RNAs as chaperones and mediators that ensure the quality of interacting proteins. PMID- 26517766 TI - Shunting in cryptococcal meningitis. AB - OBJECT Patients with cryptococcal meningitis often develop symptomatic intracranial hypertension. The need for permanent CSF diversion in these cases remains unclear. METHODS Cases of cryptococcal meningitis over a 5-year period were reviewed from a single, large teaching hospital. Sources of identification included ICD-9 codes, operative logs, and microscopy laboratory records. RESULTS Fifty cases of cryptococcal meningitis were identified. Ninety-eight percent (49/50) of patients were HIV positive. Opening pressure on initial lumbar puncture diagnosing cryptococcal meningitis was elevated (> 25 cm H2O) in 33 cases and normal (<= 25 cm H2O) in 17 cases. Thirty-eight patients ultimately developed elevated opening pressure over a follow-up period ranging from weeks to years. Serial lumbar punctures for relief of intracranial hypertension were performed in 29 cases. Thirteen of these patients ultimately had shunting procedures performed after failing to improve clinically. Two factors were significantly associated with the need for shunting: patients undergoing shunt placement were more likely to be women (5/13 vs 0/16; p = 0.01) and to have a pattern of increasing CSF cryptococcal antigen (10/13 vs 3/16 cases; p = 0.003). All patients re-presenting with mycological relapse either underwent or were offered shunt placement. CONCLUSIONS Neurosurgeons are often asked to consider CSF diversion in cases of cryptococcal meningitis complicated by intracranial hypertension. Most patients do well with serial lumbar punctures combined with antifungal therapy. When required, shunting generally provided sustained relief from intracranial hypertension symptoms. Ventriculoperitoneal shunts are the favored method of diversion. To the authors' knowledge, the present study is the largest series on diversionary shunts in primarily HIV-positive patients with this problem. PMID- 26517767 TI - Neurosurgery for schizophrenia: an update on pathophysiology and a novel therapeutic target. AB - The main objectives of this review were to provide an update on the progress made in understanding specific circuit abnormalities leading to psychotic symptoms in schizophrenia and to propose rational targets for therapeutic deep brain stimulation (DBS). Refractory schizophrenia remains a major unsolved clinical problem, with 10%-30% of patients not responding to standard treatment options. Progress made over the last decade was analyzed through reviewing structural and functional neuroimaging studies in humans, along with studies of animal models of schizophrenia. The authors reviewed theories implicating dysfunction in dopaminergic and glutamatergic signaling in the pathophysiology of the disorder, paying particular attention to neurosurgically relevant nodes in the circuit. In this context, the authors focused on an important pathological circuit involving the associative striatum, anterior hippocampus, and ventral striatum, and discuss the possibility of targeting these nodes for therapeutic neuromodulation with DBS. Finally, the authors examined ethical considerations in the treatment of these vulnerable patients. The functional anatomy of neural circuits relevant to schizophrenia remains of great interest to neurosurgeons and psychiatrists and lends itself to the development of specific targets for neuromodulation. Ongoing progress in the understanding of these structures will be critical to the development of potential neurosurgical treatments of schizophrenia. PMID- 26517768 TI - Trigeminal neuropathic pain as a complication of anterior temporal lobectomy: report of 2 cases. AB - Cranial nerve (CN) deficits following anterior temporal lobectomy (ATL) are an uncommon but well-recognized complication. The usual CNs implicated in post-ATL complications include the oculomotor, trochlear, and facial nerves. To the authors' knowledge, injury to the trigeminal nerve leading to neuropathic pain has not been previously described in the literature. This paper presents 2 cases of trigeminal neuropathic pain following temporal lobe resections for pharmacoresistant epilepsy. The possible pathophysiological mechanisms are discussed and the microsurgical anatomy of surgically relevant structures is reviewed. PMID- 26517769 TI - Biological and clinical impact of hemangioblastoma-associated peritumoral cysts in von Hippel-Lindau disease. AB - OBJECTIVE: Peritumoral cysts are frequently associated with CNS hemangioblastomas and often underlie neurological morbidity and mortality. To determine their natural history and clinical impact, the authors prospectively analyzed hemangioblastoma-associated peritumoral cysts in patients with von Hippel-Lindau (VHL) disease. METHODS: Patients with VHL disease who had 2 or more years of follow-up and who were enrolled in a prospective study at the National Institutes of Health were included. Serial prospectively acquired laboratory, genetic, imaging, and clinical data were analyzed. RESULTS: One hundred thirty-two patients (of 225 in the VHL study with at least 2 years of follow-up) had peritumoral cysts that were followed for more than 2 years (total of 292 CNS peritumoral cysts). The mean age at study entrance was 37.4 +/- 13.1 years ([mean +/- SD], median 37.9, range 12.3-65.1 years). The mean follow-up was 7.0 +/- 1.7 years (median 7.3, range 2.1-9.0 years). Over the study period, 121 of the 292 peritumoral cysts (41.4%) became symptomatic. Development of new cysts was associated with a larger number cysts at study enrollment (p = 0.002) and younger age (p < 0.0001). Cyst growth rate was associated with anatomical location (cerebellum cysts grew faster than spine and brainstem cysts; p = 0.0002 and p = 0.0008), younger age (< 35 years of age; p = 0.0006), and development of new neurological symptoms (p < 0.0001). Cyst size at symptom production depended on anatomical location (p < 0.0001; largest to smallest were found, successively, in the cerebellum, spinal cord, and brainstem). The most common location for peritumoral cysts was the cerebellum (184 cysts [63%]; p < 0.0001). CONCLUSIONS: Peritumoral cysts frequently underlie symptom formation that requires surgical intervention in patients with VHL disease. Development of new cysts was associated with a larger number of cysts at study enrollment and younger age. Total peritumoral cyst burden was associated with germline partial deletion of the VHL gene. PMID- 26517770 TI - A checklist for endonasal transsphenoidal anterior skull base surgery. AB - OBJECT Approximately 250 million surgical procedures are performed annually worldwide, and data suggest that major complications occur in 3%-17% of them. Many of these complications can be classified as avoidable, and previous studies have demonstrated that preoperative checklists improve operating room teamwork and decrease complication rates. Although the authors' institution has instituted a general preoperative "time-out" designed to streamline communication, flatten vertical authority gradients, and decrease procedural errors, there is no specific checklist for transnasal transsphenoidal anterior skull base surgery, with or without endoscopy. Such minimally invasive cranial surgery uses a completely different conceptual approach, set-up, instrumentation, and operative procedure. Therefore, it can be associated with different types of complications as compared with open cranial surgery. The authors hypothesized that a detailed, procedure-specific, preoperative checklist would be useful to reduce errors, improve outcomes, decrease delays, and maximize both teambuilding and operational efficiency. Thus, the object of this study was to develop such a checklist for endonasal transsphenoidal anterior skull base surgery. METHODS An expert panel was convened that consisted of all members of the typical surgical team for transsphenoidal endoscopic cases: neurosurgeons, anesthesiologists, circulating nurses, scrub technicians, surgical operations managers, and technical assistants. Beginning with a general checklist, procedure-specific items were added and categorized into 4 pauses: Anesthesia Pause, Surgical Pause, Equipment Pause, and Closure Pause. RESULTS The final endonasal transsphenoidal anterior skull base surgery checklist is composed of the following 4 pauses. The Anesthesia Pause consists of patient identification, diagnosis, pertinent laboratory studies, medications, surgical preparation, patient positioning, intravenous/arterial access, fluid management, monitoring, and other special considerations (e.g., Valsalva, jugular compression, lumbar drain, and so on). The Surgical Pause is composed of personnel introductions, planned procedural elements, estimation of duration of surgery, anticipated blood loss and fluid management, imaging, specimen collection, and questions of a surgical nature. The Equipment Pause assures proper function and availability of the microscope, endoscope, cameras and recorders, guidance systems, special instruments, ultrasonic microdoppler, microdebrider, drills, and other adjunctive supplies (e.g., Avitene, cotton balls, nasal packs, and so on). The Closure Pause is dedicated to issues of immediate postoperative patient disposition, orders, and management. CONCLUSIONS Surgical complications are a considerable cause of death and disability worldwide. Checklists have been shown to be an effective tool for reducing preventable errors surrounding surgery and decreasing associated complications. Although general checklists are already in place in most institutions, a specific checklist for endonasal transsphenoidal anterior skull base surgery was developed to help safeguard patients, improve outcomes, and enhance teambuilding. PMID- 26517772 TI - Erratum: Hypertonic saline reduces cumulative and daily intracranial pressure burdens after severe traumatic brain injury. PMID- 26517771 TI - Lower rates of symptom recurrence and surgical revision after primary compared with secondary endoscopic third ventriculostomy for obstructive hydrocephalus secondary to aqueductal stenosis in adults. AB - OBJECT Endoscopic third ventriculostomy (ETV) is the treatment of choice for obstructive hydrocephalus; however, the success of ETV in patients who have previously undergone shunt placement remains unclear. The present study analyzed 103 adult patients with aqueductal stenosis who underwent ETV for obstructive hydrocephalus and evaluated the effect of previous shunt placement on post-ETV outcomes. METHODS This study was a retrospective review of 151 consecutive patients who were treated between 2007 and 2013 with ETV for hydrocephalus. One hundred three (68.2%) patients with aqueductal stenosis causing obstructive hydrocephalus were included in the analysis. Postoperative ETV patency and aqueductal and cisternal flow were assessed by high-resolution, gradient-echo MRI. Post-ETV Mini-Mental State Examination, Timed Up and Go, and Tinetti scores were compared with preoperative values. Univariate and multivariate analyses were performed comparing the post-ETV outcomes in patients who underwent a primary (no previous shunt) ETV (n = 64) versus secondary (previous shunt) ETV (n = 39). RESULTS The majority of patients showed significant improvement in symptoms after ETV; however, no significant differences were seen in any of the quantitative tests performed during follow-up. Symptom recurrence occurred in 29 (28.2%) patients after ETV, after a median of 3.0 (interquartile range 0.8-8.0) months post-ETV failure. Twenty-seven (26.2%) patients required surgical revision after their initial ETV. Patients who received a secondary ETV had higher rates of symptom recurrence (p = 0.003) and surgical revision (p = 0.003), particularly in regard to additional shunt placement/revision post-ETV (p = 0.005). These differences remained significant after multivariate analysis for both symptom recurrence (p = 0.030) and surgical revision (p = 0.043). CONCLUSIONS Patients with obstructive hydrocephalus due to aqueductal stenosis exhibit symptomatic improvement after ETV, with a relatively low failure rate. Patients with a primary history of shunt placement who undergo ETV as a secondary intervention are at increased risk of symptom recurrence and need for surgical revision post ETV. PMID- 26517773 TI - Early versus late Gamma Knife radiosurgery following transsphenoidal resection for nonfunctioning pituitary macroadenomas: a matched cohort study. AB - OBJECT Gamma Knife radiosurgery (GKRS) is frequently employed to treat residual or recurrent nonfunctioning pituitary macroadenomas. There is no consensus as to whether GKRS should be used early after surgery or if radiosurgery should be withheld until there is evidence of radiographic progression of tumor. METHODS This is a retrospective review of patients with nonfunctioning pituitary macroadenomas who underwent transsphenoidal surgery followed by GKRS between 1996 and 2013 at the University of Virginia Health System. Patients were stratified based on the interval between resection and radiosurgery. Operative results and imaging and clinical outcomes were compared across groups following early (<= 6 months) or late (> 6 months) radiosurgery. RESULTS Sixty-four patients met the study criteria and were grouped based on early (n = 32) or late (n = 32) GKRS following transsphenoidal resection. There was a greater risk of tumor progression after GKRS in the late radiosurgical group (p = 0.027) over a median radiographic follow-up period of 68.5 months. Furthermore, there was a significantly higher occurrence of post-GKRS endocrinopathy in the late radiosurgical cohort (p = 0.041). Seventeen percent of patients without endocrinopathy in the early cohort developed new endocrinopathies during the follow-up period versus 64% in the late cohort (p = 0.036). This difference was primarily due to a significantly higher rate of tumor growth during the observation period of the late treatment cohort (p = 0.014). Of these patients with completely new endocrinopathies, radiation-associated pituitary insufficiency developed in 1 of 2 patients in the early group and in 3 of 7 (42.9%) patients in the late group. CONCLUSIONS Early treatment with GKRS appears to decrease the rate of radiographic and symptomatic progression of subtotally resected nonfunctioning pituitary macroadenomas compared with late GKRS treatment after a period of expectant management. Delaying radiosurgery may place the patient at increased risk for adenoma progression and endocrinopathy. PMID- 26517775 TI - Enlargement of the middle meningeal artery on MR angiography in chronic subdural hematoma. AB - OBJECT The middle meningeal artery (MMA) is suspected to play an important role in the development of chronic subdural hematoma (CSDH). The aim of this study was to clarify whether the MMA was enlarged in patients with CSDHs. METHODS The authors retrospectively assessed 55 patients in whom CSDH was diagnosed between 2010 and 2014 and who underwent MR angiography (MRA) after the onset of CSDH. The authors compared MMA diameters between hemispheres with and without CSDHs on MR angiograms. A case-control study was also performed with 55 sex- and age-matched patients with incidental unruptured aneurysms as controls. RESULTS In 55 patients with CSDHs, the diameters of the 79 MMAs on the CSDH side were significantly larger than the diameters of the 31 MMAs on the non-CSDH side (p < 0.05). In 24 patients with bilateral CSDHs, no significant difference was found between the MMA diameters on the larger hematoma side and those on the smaller hematoma side. In 13 patients who underwent MRA before the onset of the CSDH, the MMAs on MR angiograms acquired after onset of the CSDH were significantly larger than those on MR angiograms acquired before the CSDH onset (p < 0.05). The diameters of the MMAs in 55 patients with CSDHs were significantly larger than those of the MMAs in the 55 control patients (p < 0.05). CONCLUSIONS The MMA is enlarged with development of a CSDH. Information about the MMA observed on MRA in patients with CSDHs may be useful in developing a strategy for future treatment of CSDHs. PMID- 26517774 TI - Microsurgical anatomy and internal architecture of the brainstem in 3D images: surgical considerations. AB - OBJECT Brainstem surgery remains a challenge for the neurosurgeon despite recent improvements in neuroimaging, microsurgical techniques, and electrophysiological monitoring. A detailed knowledge of the microsurgical anatomy of the brainstem surface and its internal architecture is mandatory to plan appropriate approaches to the brainstem, to choose the safest point of entry, and to avoid potential surgical complications. METHODS An extensive review of the literature was performed regarding the brainstem surgical approaches, and their correlations with the pertinent anatomy were studied and illustrated through dissection of human brainstems properly fixed with 10% formalin. The specimens were dissected using the fiber dissection technique, under *6 to *40 magnification. 3D stereoscopic photographs were obtained (anaglyphic 3D) for better illustration of this study. RESULTS The main surgical landmarks and their relationship with the cerebellum and vascular structures were identified on the surface of the brainstem. The arrangements of the white matter (ascending and descending pathways as well as the cerebellar peduncles) were demonstrated on each part of the brainstem (midbrain, pons, and medulla oblongata), with emphasis on their relationships with the surface. The gray matter, constituted mainly by nuclei of the cranial nerves, was also studied and illustrated. CONCLUSIONS The objective of this article is to review the microsurgical anatomy and the surgical approaches pertinent to the brainstem, providing a framework of its external and internal architecture to guide the neurosurgeon during its related surgical procedures. PMID- 26517776 TI - Vincent du Vigneaud: following the sulfur trail to the discovery of the hormones of the posterior pituitary gland at Cornell Medical College. AB - In 1955, Vincent du Vigneaud (1901-1978), the chairman of the Department of Biochemistry at Cornell University Medical College, was awarded the Nobel Prize for Chemistry for his research on insulin and for the first synthesis of the posterior pituitary hormones-oxytocin and vasopressin. His tremendous contribution to organic chemistry, which began as an interest in sulfur containing compounds, paved the way for a better understanding of the pituitary gland and for the development of diagnostic and therapeutic tools for diseases of the pituitary. His seminal research continues to impact neurologists, endocrinologists, and neurosurgeons, and enables them to treat patients who had no alternatives prior to du Vigneaud's breakthroughs in peptide structure and synthesis. The ability of neurosurgeons to aggressively operate on parasellar pathology was directly impacted and related to the ability to replace these hormones after surgery. The authors review the life and career of Vincent du Vigneaud, his groundbreaking discoveries, and his legacy of the understanding and treatment of the pituitary gland in health and disease. PMID- 26517778 TI - Histone deactylase gene expression profiles are associated with outcomes in blunt trauma patients. AB - BACKGROUND: Treatment with histone deacetylase (HDAC) inhibitors, such as valproic acid, increases survival in animal models of trauma and sepsis. Valproic acid is a pan-inhibitor that blocks most of the known HDAC isoforms. Targeting individual HDAC isoforms may increase survival and reduce complications, but little is known of the natural history of HDAC gene expression following trauma. We hypothesized that distinct HDAC isoform gene expression patterns would be associated with differences in outcomes following trauma. METHODS: Twenty-eight day longitudinal HDAC leukocyte gene expression profiles in 172 blunt trauma patients were extracted from the Inflammation and the Host Response to Injury (Glue Grant) data set. Outcome was classified as complicated (death or no recovery by Day 28, n = 51) or uncomplicated (n = 121). Mixed modeling was used to compare the HDAC expression trajectories between the groups, corrected for Injury Severity Score (ISS), base deficit, and volume of blood products transfused during the initial 12 hours following admission. Weighted gene correlation network analysis identified modules of genes with significant coexpression, and HDAC genes were mapped to these modules. Biologic function of these modules was investigated using the Gene Ontology database. RESULTS: Elevated longitudinal HDAC expression trajectories for HDAC1, HDAC3, HDAC6, and HDAC11 were associated with complicated outcomes. In contrast, suppressed expression of Sirtuin 3 (SIRT3) was associated with adverse outcome (p < 0.01). Weighted gene correlation network analysis identified significant coexpression of HDAC and SIRT genes with genes involved in ribosomal function and down-regulation of protein translation in response to stress (HDAC1), T-cell signaling, and T cell selection (HDAC3) as well as coagulation and hemostasis (SIRT3). No coexpression of HDAC11 was identified. CONCLUSION: Expression trajectories of HDAC1, HDAC3, HDAC6, HDAC11, and SIRT3 correlate with outcomes following trauma and may potentially serve as biomarkers. They may also be promising targets for pharmacologic intervention. The effects of HDAC and SIRT gene expression in trauma may be mediated through pathways involved in ribosomal and T-cell function as well as coagulation and hemostasis. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 26517777 TI - The burden and risk factors of ventriculostomy occlusion in a high-volume cerebrovascular practice: results of an ongoing prospective database. AB - OBJECT Ventriculostomy occlusion is a known complication after external ventricular drain (EVD) placement. There have been no prospective published series that primarily evaluate the incidence of and risk factors for EVD occlusion. These phenomena are investigated using a prospective database. METHODS An ongoing prospective study of all patients undergoing frontal EVD placement in the Neurosurgery Intensive Care Unit at the University of Florida was accessed for the purposes of this analysis. Demographic, procedural, and radiographic data were recorded prospectively and retrospectively. The need for catheter irrigation or replacement was meticulously documented. Univariate and multivariate regression analyses were performed. RESULTS Ninety-eight of 101 total enrolled patients had accessible data, amounting to 131 total catheters and 1076 total catheter days. Nineteen percent of patients required at least 1 replacement. Forty-one percent of catheters developed at least 1 temporary occlusion, with an average of 2.4 irrigations per patient. Intracranial hemorrhage occurred in 28% of patients after the first EVD placement (2% resulting in new neurological deficit) and in 62% of patients after 1 replacement. The cost of occlusion is estimated at $615 per enrolled patient. Therapeutic anticoagulation and use of small EVD catheters were statistically significant predictors of permanent occlusion (p = 0.01 and 0.04, respectively). CONCLUSIONS EVD occlusion is frequent and imparts a significant burden in terms of patient morbidity, physician upkeep, and cost. This study suggests that developing strategies or devices to prevent EVD occlusion, such as the preferential use of larger diameter catheters, may be beneficial in reducing the burden associated with ventriculostomy malfunction. PMID- 26517779 TI - The efficacy and safety of adrenergic blockade after burn injury: A systematic review and meta-analysis. AB - BACKGROUND: The hypermetabolic state after severe burns is a major problem that can lead to several pathophysiologic changes and produce multiple sequelae. Adrenergic blockade has been widely used to reverse these changes and improve outcomes in burned patients but has not been rigorously evaluated. The aim of this systematic review was to investigate the efficacy and safety of the use of adrenergic blockade after burn injury. METHODS: The databases MEDLINE via OVID, PubMed, EMBASE, CINAHL, Cochrane Library, and Web of Science were searched from inception to December 2014 with search terms including burns and beta-blockers with appropriate synonyms. Articles were restricted to those published in English, French, or Spanish. Randomized controlled trials, nonrandomized controlled trials, and systematic reviews were screened. After an independent screening and full-text review, 10 articles were selected, and an appraisal of risk of bias was performed. RESULTS: From 182 articles screened, 9 randomized controlled trials and 1 nonrandomized controlled trial met the inclusion criteria. Pooled analyses were performed to calculate effect sizes and 95% confidence intervals (CIs). There was a positive effect favoring propranolol use that significantly decreased resting energy expenditure (g = -0.64; 95% CI, -0.8 to -0.5; p < 0.001) and trunk fat (g = -0.3; 95% CI, -0.4 to -0.1; p < 0.001) as well as improved peripheral lean mass (g = 0.45; 95% CI, 0.3-0.6; p < 0.001) and insulin resistance (g = -1.35; 95% CI, -2.0 to -0.6; p < 0.001). Occurrence of adverse events was not significantly different between the treated patients the and controls. CONCLUSION: Limited evidence suggests beneficial effects of propranolol after burn injury, and its use seems safe. However, further trials on adult population with a broader range of outcome measures are warranted. LEVEL OF EVIDENCE: Systematic review and meta-analysis, level III. PMID- 26517780 TI - Geographic distribution of trauma centers and injury-related mortality in the United States. AB - BACKGROUND: Regionalized trauma care improves outcomes; however, access to care is not uniform across the United States. The objective was to evaluate whether geographic distribution of trauma centers correlates with injury mortality across state trauma systems. METHODS: Level I or II trauma centers in the contiguous United States were mapped. State-level age-adjusted injury fatality rates per 100,000 people were obtained and evaluated for spatial autocorrelation. Nearest neighbor ratios (NNRs) were generated for each state. A NNR less than 1 indicates clustering, while a NNR greater than 1 indicates dispersion. NNRs were tested for difference from random geographic distribution. Fatality rates and NNRs were examined for correlation. Fatality rates were compared between states with trauma center clustering versus dispersion. Trauma center distribution and population density were evaluated. Spatial-lag regression determined the association between fatality rate and NNR, controlling for state-level demographics, population density, injury severity, trauma system resources, and socioeconomic factors. RESULTS: Fatality rates were spatially autocorrelated (Moran's I = 0.35, p < 0.01). Nine states had a clustered pattern (median NNR, 0.55; interquartile range [IQR], 0.48-0.60), 22 had a dispersed pattern (median NNR, 2.00; IQR, 1.68-3.99), and 10 had a random pattern (median NNR, 0.90; IQR, 0.85-1.00) of trauma center distribution. Fatality rate and NNR were correlated (rho = 0.34, p = 0.03). Clustered states had a lower median injury fatality rate compared with dispersed states (56.9 [IQR, 46.5-58.9] vs. 64.9 [IQR, 52.5-77.1]; p = 0.04). Dispersed compared with clustered states had more counties without a trauma center that had higher population density than counties with a trauma center (5.7% vs. 1.2%, p < 0.01). Spatial-lag regression demonstrated that fatality rates increased by 0.02 per 100,000 persons for each unit increase in NNR (p < 0.01). CONCLUSION: Geographic distribution of trauma centers correlates with injury mortality, with more clustered state trauma centers associated with lower fatality rates. This may be a result of access relative to population density. These results may have implications for trauma system planning and require further study to investigate underlying mechanisms. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 26517781 TI - How much esophageal pressure-guided end-expiratory transpulmonary pressure is sufficient to maintain lung recruitment in lavage-induced lung injury? AB - BACKGROUND: Because of limitations of the esophageal balloon technique, the value of using esophageal pressure (Pes)-guided end-expiratory transpulmonary pressure (PL-exp) to maintain lung recruitment in adult respiratory distress syndrome is controversial. This study aimed to investigate whether tailoring PL-exp to greater than 0 was enough to maintain lung recruitment. METHODS: Ten pigs with severe lavage-induced lung injury were mechanically ventilated in a decremental positive end-expiratory pressure (PEEP) trial that was reduced from 20 to 6 cm H2O after full-lung recruitment. Respiratory mechanics, blood gases, hemodynamic data, and whole-lung computed tomography scans were recorded at each PEEP level. Open-lung PEEP (OL-PEEP) was determined by computed tomography, while Pes-guided PEEP (Pes-PEEP) was to maintain PL-exp greater than 0. RESULTS: OL-PEEP was higher than Pes-PEEP, which induced a higher PL-exp at OL-PEEP than at Pes-PEEP (4.6 [1.6] cm H2O vs. 1.2 [0.6] cm H2O, p < 0.001). Compared with OL-PEEP, the nonaerated lung region was significantly increased at Pes-PEEP. Superimposed pressure (SP) of the lung tissue between the esophageal plane and the dorsal level was higher at Pes-PEEP than at OL-PEEP, whereas PL-exp at the dorsal level was lower at Pes-PEEP than at OL-PEEP (-1.5 [0.7] cm H2O vs. 2.5 [1.5] cm H2O, p < 0.001). The SP correlated with PL-exp at the dorsal level and the nonaerated lung region. CONCLUSION: In this surfactant-depleted model, maintaining PL-exp just greater than 0 using Pes was unable to maintain lung recruitment; this was partly caused by a lack of compensation for the increased SP between the esophageal plane and the dorsal level. PMID- 26517782 TI - The giving back: Battlefield lesson to national preparedness. PMID- 26517783 TI - Ulinastatin and/or thymosin alpha1 for severe sepsis: A systematic review and meta-analysis. AB - OBJECTIVE: Ulinastatin (UTI) and thymosin alpha1 (Talpha1) have been investigated for their immunoregulatory properties in patients with severe sepsis. However, it is unclear whether immunomodulatory therapy using UTI combined with Talpha1 (UCT), UTI alone (UA), or Talpha1 alone (TA) improves the disease outcome. The objective of this study was to analyze the effectiveness of UCT, UA, and TA for the treatment of severe sepsis. METHODS: PubMed, EMBASE, and Cochrane Library databases were investigated from inception to September 2015. Randomized controlled trials (RCTs) examining the treatment of patients with severe sepsis by UCT, UA, and TA were defined as eligible. Data were analyzed using Review Manager 5.3, and the RCTs were evaluated by the Cochrane Handbook 5.1.0. The quality of the evidence was evaluated according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). RESULTS: Ten articles and 12 studies were included in this systematic review and meta analysis. The primary outcome measures indicated that UCT was associated with significantly lower 28-day mortality (risk ratio [RR], 0.67; 95% confidence interval [CI], 0.57-0.80; p < 0.00001; n = 915; GRADE rating, moderate) and 90 day mortality (RR, 0.75; 95% CI, 0.61-0.93; p = 0.009; n = 547; GRADE rating, moderate); UA was associated with no significant difference in the 28-day mortality (RR, 0.60; 95% CI, 0.30-1.20; p = 0.15; n = 182; GRADE rating, low), and there was no report on 90-day mortality; TA was associated with significantly lower 28-day mortality (RR, 0.72; 95% CI, 0.55-0.93; p = 0.01; n = 494; GRADE rating, low), but there was no significant difference in the 90-day mortality (RR, 0.84; 95% CI, 0.54-1.31; p = 0.45; n = 91; GRADE rating, very low). In the secondary outcome measures, there was obvious heterogeneity in the length of the intensive care unit stay and that of the mechanical ventilation, length of the antibiotics and vasopressor use, and 28-day Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. CONCLUSION: Treatment of severe sepsis with UCT reduced both the 28-day and the 90-day mortality, whereas treatment with TA reduced only the 28-day mortality. The effects of UCT, UA, and TA on intensive care unit stay, mechanical ventilation, antibiotics and vasopressor use, and 28 day APACHE II scores of septic patients are still unclear. Additional high quality RCTs are needed to define clearly the guidelines for the treatment of severe sepsis. LEVEL OF EVIDENCE: Systematic review, level IV. PMID- 26517784 TI - Estimating annual medical and out-of-pocket expenditures associated with traumatic injuries in the United States. AB - BACKGROUND: Every year, as many as 31 million Americans sustain traumatic injuries, leaving survivors with risks of disabilities and health settings with staggering medical costs. Little is known on the societal burden of injuries in terms of medical and out-of-pocket expenditures. Therefore, we used a nationally representative sample to evaluate the association between injuries and health expenditures among a nationally representative US sample. METHODS: This study used years 2006 to 2010 (Panels 11-14; n = 53,065) of the Medical Expenditure Panel Survey. Each panel was followed up for 2 years. Total expenditures included insurance payments and out-of-pocket costs. Two-part models were constructed to examine differences in annual medical expenditures between injured and noninjured populations controlling for confounding effects. RESULTS: A total of 4,210 individuals (7.9%) reported injuries representing 21.5 million individuals. Injured individuals were more likely to be males, to be white, and to report higher medical expenditures in the second year than the reference population (p < 0.01). Adjusted analyses showed that reporting any injury was associated with $2,577 (95% confidence interval [CI], $2,049-$3,103) and $186 (95% CI, $142-$230) increase in total and out-of-pocket costs, respectively. While a moderate or severe injury was associated with $4,779 (95% CI, $3,947-$5,610) increase in the average of medical expenditures and $256 (95% CI, $190-$322) increase in out-of pocket costs adjusting for covariates. Our adjusted national medical cost of injuries was estimated at $56 billion and out-of-pocket cost to be approximately $4 billion. CONCLUSION: Injuries pose a substantial burden on medical expenditures in the United States. Investment in injury prevention can facilitate reducing medical expenditures and save resources. Prevention programs may use the out-of-pocket findings to highlight injury burden on individual's prosperity and thus facilitate engagement of the public in prevention. LEVEL OF EVIDENCE: Economic and evaluation study, level III. PMID- 26517785 TI - Early leukocyte gene expression associated with age, burn size, and inhalation injury in severely burned adults. AB - BACKGROUND: In the patient with burn injury, older age, larger percentage of total body surface area (TBS) burned, and inhalation injury are established risk factors for death, which typically results from multisystem organ failure and sepsis, implicating burn-induced immune dysregulation as a contributory mechanism. We sought to identify early transcriptomic changes in circulating leukocytes underlying increased mortality associated with these three risk factors. METHODS: We performed a retrospective analysis of the Glue Grant database. From 2003 to 2010, 324 adults with 20% or greater TBS burned were prospectively enrolled at five US burn centers, and 112 provided blood samples within 1 week after burn. RNA was extracted from pooled leukocytes for hybridization onto Affymetrix HU133 Plus 2.0 GeneChips. A multivariate regression model was constructed to determine risk factors for mortality. Testing for differential gene association associated with age, burn size, and inhalation injury was based on linear models using a fold change threshold of 1.5 and false discovery rate of 0.05. RESULTS: After adjusting for potential confounders, age greater than 60 years (relative risk [RR], 4.53; 95% confidence interval [CI], 2.93-6.99), burn size greater than 40% TBS (RR, 4.24; 95% CI, 2.61-6.91), and inhalation injury (RR, 2.08; 95% CI, 1.35-3.21) were independently associated with mortality. No genes were differentially expressed in association with age greater than 60 years or inhalation injury. Fifty-one probe sets representing 39 unique genes were differentially expressed in leukocytes from patients with burn size greater than 40% TBS; these genes were associated with platelet activation and degranulation/exocytosis, and gene-set enrichment analysis suggested increased cellular proliferation and down-regulation of proinflammatory cytokines. CONCLUSION: Among adults with large burns, older age, increasing burn size, and inhalation injury have a modest effect on the leukocyte transcriptome in the context of the "genomic storm" induced by a 20% or greater than TBS burned. The 39-gene signature we identified may provide novel targets for the development of therapies to reduce morbidity and mortality associated with burns greater than 40% TBS. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 26517786 TI - The Massive Transfusion Score as a decision aid for resuscitation: Learning when to turn the massive transfusion protocol on and off. AB - BACKGROUND: Previous work proposed a Massive Transfusion Score (MTS) calculated from values obtained in the emergency department to predict likelihood of massive transfusion (MT). We hypothesized the MTS could be used at Hour 6 to differentiate who continues to require balanced resuscitation in Hours 7 to 24 and to predict death at 28 days. METHODS: We prospectively enrolled patients in whom the MT protocol was initiated from 2005 to 2011. Data including timing of blood products were determined at Hours 0, 6, 12, and 24. For each patient, transfusion needs were defined based on either an inappropriately low hemoglobin response to transfusion or a hemoglobin decrease of greater than 1 g/dL if no transfusion. Timing and cause of death were used to account for survivor bias. Multivariate logistic regression was used to determine independent predictors of outcome. RESULTS: A total of 190 MT protocol activations were included, and by Hour 6, 61% required 10 U or greater packed red blood cells. Calculated at initial presentation, a revised MTS (systolic blood pressure < 90 mm Hg, base deficit >= 6, temperature < 35.5 degrees C, international normalized ratio > 1.5, hemoglobin < 11 g/dL) was superior to the original MTS (including heart rate >= 120 beats per minute, Focused Assessment With Sonography in Trauma [FAST] status, mechanism) or the Assessment of Blood Consumption (ABC) score for predicting MT (area under the curve [AUC] MT at 6 hours, 0.68; 95% confidence interval [CI], 0.57-0.79; at 24 hours, 0.72; 0.61-0.83; p < 0.05). For those alive at Hour 6, the revised MTS was predictive of future packed red blood cell need (AUC, 0.87) in Hours 7 to 12, 24-hour mortality (AUC, 0.95), and 28-day mortality (AUC, 0.77). For each additional positive trigger of the MTS at Hour 6, the odds of death at 24 hours and 28 days were substantially increased (24-hour odds ratio, 4.6; 95% CI, 2.3-9.3; 28-day odds ratio, 2.2; 95% CI, 1.5-3.2; p < 0.0001). CONCLUSION: Early end points of resuscitation adopted from the components of the revised MTS are predictive of ongoing transfusion. Failure to normalize these components by Hour 6 portends a particularly poor prognosis. LEVEL OF EVIDENCE: Prognostic study, level 3. PMID- 26517787 TI - Breathing-synchronised electrical stimulation of the abdominal muscles in patients with acute tetraplegia: A prospective proof-of-concept study. AB - OBJECTIVE: To examine whether, by enhancing breathing depth and expectoration, early use of breathing-synchronised electrical stimulation of the abdominal muscles (abdominal functional electrical stimulation, AFES) is able to reduce pulmonary complications during the acute phase of tetraplegia. DESIGN: Prospective proof-of-concept study. SETTING: Spinal cord unit at a level 1 trauma center. METHOD: Following cardiovascular stabilisation, in addition to standard treatments, patients with acute traumatic tetraplegia (ASIA Impairment Scale A or B) underwent breathing-synchronised electrical stimulation of the abdominal muscles to aid expiration and expectoration. The treatment was delivered in 30 minute sessions, twice a day for 90 days. The target was for nine of 15 patients to remain free of pneumonia meeting Centers for Disease Control and Prevention (CDC) diagnostic criteria. RESULTS: Eleven patients were recruited to the study between October 2011 and November 2012. Two patients left the study before completion. None of the patients contracted pneumonia during the study period. No complications from electrical stimulation were observed. AFES led to a statistically significant increase in peak inspiratory and expiratory flows and a non-statistically significant increase in tidal volume and inspiratory and expiratory flow. When surveyed, 6 out of 9 patients (67%) reported that the stimulation procedure led to a significant improvement in breathing and coughing. CONCLUSION: AFES appears to be able to improve breathing and expectoration and prevent pneumonia in the acute phase of tetraplegia (up to 90 days post-trauma). This result is being validated in a prospective multicentre comparative study. PMID- 26517789 TI - Acidified and ultrafiltered recovered coagulants from water treatment works sludge for removal of phosphorus from wastewater. AB - This study used a range of treated water treatment works sludge options for the removal of phosphorus (P) from primary wastewater. These options included the application of ultrafiltration for recovery of the coagulant from the sludge. The treatment performance and whole life cost (WLC) of the various recovered coagulant (RC) configurations have been considered in relation to fresh ferric sulphate (FFS). Pre-treatment of the sludge with acid followed by removal of organic and particulate contaminants using a 2kD ultrafiltration membrane resulted in a reusable coagulant that closely matched the performance FFS. Unacidified RC showed 53% of the phosphorus removal efficiency of FFS, at a dose of 20 mg/L as Fe and a contact time of 90 min. A longer contact time of 8 h improved performance to 85% of FFS. P removal at the shorter contact time improved to 88% relative to FFS by pre-acidifying the sludge to pH 2, using an acid molar ratio of 5.2:1 mol H(+):Fe. Analysis of the removal of P showed that rapid phosphate precipitation accounted for >65% of removal with FFS. However, for the acidified RC a slower adsorption mechanism dominated; this was accelerated at a lower pH. A cost-benefit analysis showed that relative to dosing FFS and disposing waterworks sludge to land, the 20 year WLC was halved by transporting acidified or unacidified sludge up to 80 km for reuse in wastewater treatment. A maximum inter-site distance was determined to be 240 km above the current disposal route at current prices. Further savings could be made if longer contact times were available to allow greater P removal with unacidified RC. PMID- 26517788 TI - The role of aromatic precursors in the formation of haloacetamides by chloramination of dissolved organic matter. AB - Water treatment utilities are diversifying their water sources and often rely on waters enriched in nitrogen-containing compounds (e.g., ammonia, organic nitrogen such as amino acids). The disinfection of waters exhibiting high levels of nitrogen has been associated with the formation of nitrogenous disinfection byproducts (N-DBPs) such as haloacetonitriles (HANs) and haloacetamides (HAcAms). While the potential precursors of HANs have been extensively studied, only few investigations are available regarding the nature of HAcAm precursors. Previous research has suggested that HAcAms are hydrolysis products of HANs. Nevertheless, it has been recently suggested that HAcAms can be formed independently, especially during chloramination of humic substances. When used as a disinfectant, monochloramine can also be a source of nitrogen for N-DBPs. This study investigated the role of aromatic organic matter in the formation of N-DBPs (HAcAms and HANs) upon chloramination. Formation kinetics were performed from various fractions of organic matter isolated from surface waters or treated wastewater effluents. Experiments were conducted with (15)N-labeled monochloramine ((15)NH2Cl) to trace the origin of nitrogen. N-DBP formation showed a two-step profile: (1) a rapid formation following second-order reaction kinetics and incorporating nitrogen atom originating from the organic matrix (e.g., amine groups); and (2) a slower and linear increase correlated with exposure to chloramines, incorporating inorganic nitrogen ((15)N) from (15)NH2Cl into aromatic moieties. Organic matter isolates showing high aromatic character (i.e., high SUVA) exhibited high reactivity characterized by a major incorporation of (15)N in N-DBPs. A significantly lower incorporation was observed for low-aromatic-content organic matter. (15)N-DCAcAm and (15)N-DCAN formations exhibited a linear correlation, suggesting a similar behavior of (15)N incorporation as SUVA increases. Chloramination of aromatic model compounds (i.e., phenol and resorcinol) showed higher HAcAm and HAN formation potentials than nitrogenous precursors (i.e., amino acids) usually considered as main precursors of these N-DBPs. These results demonstrate the importance of aromatic organic compounds in the formation of N-DBPs, which is of significant importance for water treatment facilities using chloramines as final disinfectant. PMID- 26517790 TI - Impact of leachate composition on the advanced oxidation treatment. AB - Advanced oxidation processes (AOPs) are gaining importance as an alternative to the biological or physicochemical treatments for the management of leachates. In this work, it has been studied the effect of the characteristics of the leachate (content in humic acids, landfill age and degree of stabilization) on the wet oxidation process and final quality of the treated effluent. A high concentration of humic acids in the leachate had a positive effect on the COD removal because this fraction is more easily oxidizable. Additionally, it has been demonstrated that the simultaneous presence of humic acid and the intermediates generated during the oxidation process improved the degradation of this acid, since such intermediates are stronger initiators of free radicals than the humic acid itself. Similar values of COD removals (49% and 51%) and biodegradability indices (0.30 and 0.35) were observed, after 8 h of wet oxidation, for the stabilised leachate (biologically pretreated) and the raw one, respectively. Nevertheless, final colour removal was much higher for the stabilised leachate, achieving values up to 91%, whereas for the raw one only 56% removal was attained for the same reaction time. Besides, wet oxidation treatment was more efficient for the young leachate than for the old one, with final COD conversions of 60% and 37%, respectively. Eventually, a triangular "three-lump" kinetic model, which considered direct oxidation to CO2 and partial oxidation through intermediate compounds, was here proposed. PMID- 26517791 TI - Evanescent Light-Scattering Microscopy for Label-Free Interfacial Imaging: From Single Sub-100 nm Vesicles to Live Cells. AB - Advancement in the understanding of biomolecular interactions has benefited greatly from the development of surface-sensitive bioanalytical sensors. To further increase their broad impact, significant efforts are presently being made to enable label-free and specific biomolecule detection with high sensitivity, allowing for quantitative interpretation and general applicability at low cost. In this work, we have addressed this challenge by developing a waveguide chip consisting of a flat silica core embedded in a symmetric organic cladding with a refractive index matching that of water. This is shown to reduce stray light (background) scattering and thereby allow for label-free detection of faint objects, such as individual sub-20 nm gold nanoparticles as well as sub-100 nm lipid vesicles. Measurements and theoretical analysis revealed that light scattering signals originating from single surface-bound lipid vesicles enable characterization of their sizes without employing fluorescent lipids as labels. The concept is also demonstrated for label-free measurements of protein binding to and enzymatic (phospholipase A2) digestion of individual lipid vesicles, enabling an analysis of the influence on the measured kinetics of the dye labeling of lipids required in previous assays. Further, diffraction-limited imaging of cells (platelets) binding to a silica surface showed that distinct subcellular features could be visualized and temporally resolved during attachment, activation, and spreading. Taken together, these results underscore the versatility and general applicability of the method, which due to its simplicity and compatibility with conventional microscopy setups may reach a widespread in life science and beyond. PMID- 26517792 TI - Yellow may: an active campaign to prevent road traffic injury. PMID- 26517793 TI - Alcohol and brief intervention for trauma victims. AB - OBJECTIVE: to describe the causes and severities of trauma in patients who met the criteria for alcohol abuse or dependence according to Mini International Neuropsychiatric Interview, and to display the pattern of alcohol consumption and subsequent changes one year after trauma. METHODS: a transversal and longitudinal quantitative study carried out between November 2012 and September 2013 in the ED. Medical and nursing students collected blood samples, applied the J section of the Mini International Neuropsychiatric Interview (MINI) and submitted alcohol abusers and dependents to BI. One year after admission, patients were contacted and asked about their patterns of alcohol use and their reasons for any changes. RESULTS: from a sample of 507 patients admitted to the ED for trauma, 348 responded to MINI, 90 (25.9%) being abusers and 36 (10.3%) dependent on alcohol. Among the abusers, the most frequent cause of injury was motorcycle accident (35.6%) and among the dependents it was predominantly interpersonal violence (22.2%). Positive blood samples for alcohol were identified in 31.7% of the abusers and 53.1% of the dependents. One year after trauma, 66 abusers and 31 dependents were contacted, and it was ascertained that 36.4% of the abusers and 19.4% of the dependents had decreased alcohol consumption. The main reported reason for the reduction was the experienced trauma. CONCLUSION: the motorcycle accident was the most common cause of injury. The detection of problematic alcohol use and implementation of BI are important strategies in the ED, however for alcohol abusers and dependents, BI was not the most reported reason for any changes in patterns of alcohol use. PMID- 26517794 TI - Night admission is an independent risk factor for mortality in trauma patients - a systemic error approach. AB - OBJECTIVE: to assess the impact of the shift inlet trauma patients, who underwent surgery, in-hospital mortality. METHODS: a retrospective observational cohort study from November 2011 to March 2012, with data collected through electronic medical records. The following variables were statistically analyzed: age, gender, city of origin, marital status, admission to the risk classification (based on the Manchester Protocol), degree of contamination, time / admission round, admission day and hospital outcome. RESULTS: during the study period, 563 patients injured victims underwent surgery, with a mean age of 35.5 years (+/- 20.7), 422 (75%) were male, with 276 (49.9%) received in the night shift and 205 (36.4%) on weekends. Patients admitted at night and on weekends had higher mortality [19 (6.9%) vs. 6 (2.2%), p=0.014, and 11 (5.4%) vs. 14 (3.9%), p=0.014, respectively]. In the multivariate analysis, independent predictors of mortality were the night admission (OR 3.15), the red risk classification (OR 4.87), and age (OR 1.17). CONCLUSION: the admission of night shift and weekend patients was associated with more severe and presented higher mortality rate. Admission to the night shift was an independent factor of surgical mortality in trauma patients, along with the red risk classification and age. PMID- 26517795 TI - Evaluation of the use of tomography in penetrating neck trauma. AB - OBJECTIVE: the study has the intention of evaluate the accuracy of computed tomography for the diagnosis of cervical lesions on penetrating neck trauma and also identify the most frequent mechanisms of trauma. Most injured structures, determine the age range and the most prevalent sex. METHODS: observational descriptive retrospective study executed by the systematic retrospective review of medical records of all patients victims of penetrating neck trauma that went through surgery and CT scans, admitted into Hospital do Trabalhador, between January 2009 and December 2013. RESULTS: the final sample was of 30 patients, 96.7% of the male sex, the median age was of 28 years old. Most patients suffered injuries by gun (56.7%) and 33,3% suffered stab wounds. The most stricken area of the neck was Zone II (77.8%) and the left side (55.2%). Regarding the structures injured, the CT showed 6.7% lesions on airways but the surgery showed 40% of damaged, with a value of p=0.002. As to damages of the esophagus and pharynx the CT detected 10% of lesions, while surgery found 30% of lesions, therefore with a significant value of p=0.013. As for the analysis the CT showed reliable. As for the analysis of vascular damage, the CT showed to be, in most cases, reliable to the findings during the surgical act. CONCLUSION: besides the great use of CT for the diagnosis of penetrating neck injuries we can say that this is an exam with low accuracy for the diagnosis of lesions of aerodigestive tract, therefore it is important a clinical correlation for a good diagnosis.as for the vascular lesions and of other structures, the CT had high sensibility and specificity, thus a good exam to be used in overall. PMID- 26517796 TI - Complementary exams in blunt torso trauma. Perform only radiographs and fast: is it safe? AB - OBJECTIVE: to evaluate effectiveness of using chest X-ray (CXR), pelvis X-ray (RXP) and FAST (Focused Abdominal Sonography on Trauma) to exclude significant lesions of the body in blunt trauma. METHODS: a prospective study involving 74 patients whom made the three tests (CXR, RXP and FAST) during the initial evaluation between October 2013 and February 2014. The results were compared to the tomography of the same patients or clinical outcome. If the patient did not have alterations on the CT scans or during the observation time, the initial workup was considered safe. All patients were evaluated at the Hospital Joao XXIII, Belo Horizonte, Brazil. RESULTS: of the 74 patients studied the average age was 33 years, RTS: 6.98, ECG: 12. From 44 (59.45%) patients with exams (radiographs and FAST) unchanged, three had significant injuries (two splenic injuries and one liver injury) diagnosed by clinical monitoring. The remaining patients - 30 (40.55%) - had at least one alteration in conventional tests. Of these group 27 (90%) had significant injuries and three (10%) minor injuries. The sensitivity of all three tests for screening considerable lesions was 90% and the specificity was 93%. The negative predictive value was 93% and the positive predictive value 89%. CONCLUSION: this research showed that all the three exams - chest X-ray, pelvis and FAST - are safe to lead with the blunt trauma if well used and associated with clinical examination. PMID- 26517797 TI - Associated factors to empyema in post-traumatic hemotorax. AB - OBJECTIVE: to analyze the associated factors with empyema in patients with post traumatic retained hemothorax. METHODS: prospective observational study. Data were collected in patients undergoing PD during emergency duty. Variables analyzed were age, sex, mechanism of injury, side of the chest injury, intrathoracic complications of RH, laparotomy, specific injuries, rib fractures, trauma scores, days to diagnosis, diagnostic method of RH, primary indication of PD, initial volume drained, length of the first tube removal, surgical procedure. Cumulative incidence of empyema, pneumonia and pulmonary contusion and the proportion of patients with empyema or without empyema in each category of each variable analyzed were obtained. RESULTS: the cumulative incidence of PD among trauma patients was 1.83% and the RH among those with PD was 10.63%. There were 20 cases of empyema (32.8%). Most were male in the age from 20 to 29, victims of injury by firearm on the left side of the thorax. The incidence of empyema in patients with injury by firearms was lower compared to those with stab wound or blunt trauma; higher among those with drained volume between 300 and 599 ml. The median hospital lenght of stay was higher among those with empyema. CONCLUSION: the incidence of PD was 1.83% and RH was 10.63%, these results are consistent with the low severity of the patients involved in this study and consistent with the literature. The incidence of empyema proved to be negatively associated with the occurrence of injury by firearms and positively associated with a drained volume between 300 and 599 ml, compared with lower or higher volumes. PMID- 26517798 TI - The impact of a chest tube management protocol on the outcome of trauma patients with tube thoracostomy. AB - OBJECTIVE: to investigate the effect of standardized interventions in the management of tube thoracostomy patients and to assess the independent effect of each intervention. METHODS: A chest tube management protocol was assessed in a retrospective cohort study. The tube thoracostomy protocol (TTP) was implemented in August 2012, and consisted of: antimicrobial prophylaxis, chest tube insertion in the operating room (OR), admission post chest tube thoracostomy (CTT) in a hospital floor separate from the emergency department (ED), and daily respiratory therapy (RT) sessions post-CTT. The inclusion criteria were, hemodynamic stability, patients between the ages of 15 and 59 years, and injury severity score (ISS) < 17. All patients had isolated injuries to the chest wall, lung, and pleura. During the study period 92 patients were managed according to the standardized protocol. The outcomes of those patients were compared to 99 patients treated before the TTP. Multivariate logistic regression analysis was performed to assess the independent effect of each variable of the protocol on selected outcomes. RESULTS: Demographics, injury severity, and trauma mechanisms were similar among the groups. As expected, protocol compliance increased after the implementation of the TTP. There was a significant reduction (p<0.05) in the incidence of retained hemothoraces, empyemas, pneumonias, surgical site infections, post-procedural complications, hospital length of stay, and number of chest tube days. Respiratory therapy was independently linked to significant reduction (p<0.05) in the incidence of seven out of eight undesired outcomes after CTT. Antimicrobial prophylaxis was linked to a significant decrease (p<0.05) in retained hemothoraces, despite no significant (p<0.10) reductions in empyema and surgical site infections. Conversely, OR chest tube insertion was associated with significant (p<0.05) reduction of both complications, and also significantly decreased the incidence of pneumonias. CONCLUSION: Implementation of a TTP effectively reduced complications after CTT in trauma patients. PMID- 26517799 TI - Isolated liver gunshot injuries: nonoperative management is feasible? AB - OBJECTIVE: to evaluate the safety and effectiveness of non-operative management (NOM) of liver injury, being the only abdominal injury, from gunshot wounds to the abdomen. METHODS: patients who had liver damage diagnosed as single abdominal injury caused by PAF in the right thoracoabdominal region, hemodynamically stable were studied. All underwent examination with computed tomography. Were analyzed: age, gender, levels of trauma, hemodynamic condition and the abdominal examination on admission, the results of the CT scan, the extra-abdominal lesions found, the serum levels of hemoglobin, clinical course, complications, length of hospital stay, outpatient treatment and death. RESULTS: during the study period 169 patients, treated non-operatively, presented liver gunshot wounds. Of these, only 28 patients (16.6%) had liver injury as the only abdominal injury and consequently met the inclusion criteria for this study. The average age was 27.7 years and 25 patients (89.2%) were male. The overall average of verified trauma scores were: RTS 7.45, ISS 10.9, and TRISS 98.7%. The most frequent injuries were grade II and grade III (85.7%). Complications occurred in only one patient who presented a progressive decline in hemoglobin. He underwent a CT scan which showed blush in the liver parenchyma. An arteriography was performed, which showed a successfully embolized arteriovenous fistula. There were no deaths in the patient sample. The average hospital stay was 5.3 days. CONCLUSION: isolated hepatic injury in gunshot abdominal trauma is uncommon. However, the NOM protocol for this type of injury is safe and has low morbidity. This approach should only be followed in institutions with adequate infrastructure, where an experienced and cohesive team is able to follow a specific protocol, with rigorous periodic evaluation of its results. PMID- 26517800 TI - Vascular trauma in the Amazon - the challenge of great distances. AB - OBJECTIVE: to evaluate the incidence of unfavorable outcomes in vascular trauma patients and their possible correlation to the distance between the city where the injury was sustained and the hospital where the patient received definitive treatment. METHODS: descriptive and retrospective study. Data were collected from medical records of patients submitted to surgical procedures for arterial or venous injuries from February 2011 to February 2013 at the only trauma center providing vascular surgery in a vast area of the Amazon region. Trauma date, patient gender and age, mechanism and anatomic topography of injury, surgical management, need for surgical re-intervention, hospitalization period, postoperative complications, mortality and limb amputation rates were analyzed. The incidence of unfavorable outcomes was assessed according to the distance between the city where the vascular injury was sustained and the trauma center. RESULTS: One hundred seventy-three patients with 255 vascular injuries were analyzed; 95.95% were male (p<0.05), mean age of 28.92 years; 47.4% were caused by firearm projectiles (p<0.05); topographic distribution: 45.66% lower limbs (p<0.05), 37.57% upper limbs, 6.94% abdominal, 5.2% thoracic and 4.62% were cervical vascular injuries; 51.42% of patients required hospitalization for seven days or less (p<0.05); limb amputation was necessary in 15.6% and the overall mortality was 6.36%. CONCLUSION: distances greater than 200 Km were associated to longer hospitalization period; distances greater than 300 Km were associated to increased limb amputation probability; severe vascular trauma have an increased death probability when patients need to travel more than 200 Km for surgical treatment. PMID- 26517801 TI - Comparative analysis of the frequency and the severity of diagnosed lesions between pedestrians struck by motor vehicles and other blunt trauma mechanisms victims. AB - OBJECTIVE: to compare the frequency and the severity of diagnosed injuries between pedestrians struck by motor vehicles and victims of other blunt trauma mechanisms. METHODS: retrospective analysis of data from the Trauma Registry, including adult blunt trauma patients admitted from 2008 to 2010. We reviewed the mechanism of trauma, vital signs on admission and the injuries identified. Severity stratification was carried using RTS, AIS-90, ISS e TRISS. Patients were assigned into group A (pedestrians struck by motor vehicle) or B (victims of other mechanisms of blunt trauma). Variables were compared between groups. We considered p<0.05 as significant. RESULTS: a total of 5785 cases were included, and 1217 (21,0%) of which were in group A. Pedestrians struck by vehicles presented (p<0.05) higher mean age, mean heart rate upon admission, mean ISS and mean AIS in head, thorax, abdomen and extremities, as well as lower mean Glasgow coma scale, arterial blood pressure upon admission, RTS and TRISS. They also had a higher frequency of epidural hematomas, subdural hematomas, subarachnoid hemorrhage, brain swelling, cerebral contusions, costal fractures, pneumothorax, flail chest, pulmonary contusions, as well as pelvic, superior limbs and inferior limbs fractures. CONCLUSION: pedestrian struck by vehicles sustained intracranial, thoracic, abdominal and extremity injuries more frequently than victims of other blunt trauma mechanism as a group. They also presented worse physiologic and anatomic severity of the trauma. PMID- 26517802 TI - Risk factors for mortality in blunt abdominal trauma with surgical approach. AB - OBJECTIVE: identify risk factors for mortality in patients who underwent laparotomy after blunt abdominal trauma. METHODS: retrospective study, case control, which were reviewed medical records of blunt trauma victims patients undergoing laparotomy, from March 2013 to January 2015, and compared the result of the deaths group with the group healed. RESULTS: of 86 patients, 63% were healed, 36% died, and one patient was excluded from the study. Both groups had similar epidemiology and trauma mechanism, predominantly young adults males, automobilistic accident. Most cases that evolved to death had hemodynamic instability as laparotomy indication - 61% against 38% in the other group (p=0.02). The presence of solid organ injury was larger in the group of deaths - 80% versus 48% (p=0.001) and 61% of them had other associated abdominal injury compared to 25% in the other group (p=0.01). Of the patients who died 96% had other serious injuries associated (p=0.0003). Patients requiring damage control surgery had a higher mortality rate (p=0.0099). Only one of 18 patients with isolated hollow organ lesion evolved to death (p=0.0001). The mean injury score of TRISS of cured (91.70%) was significantly higher than that of deaths (46.3%) (p=0.002). CONCLUSION: the risk factors for mortality were hemodynamic instability as an indication for laparotomy, presence of solid organ injury, multiple intra-abdominal injuries, need for damage control surgery, serious injury association and low index of trauma score. PMID- 26517803 TI - Implementation of the trauma registry as a tool for quality improvement in trauma care in a brazilian hospital: the first 12 months. AB - OBJECTIVE: to analyze the implementation of a trauma registry in a university teaching hospital delivering care under the unified health system (SUS), and its ability to identify points for improvement in the quality of care provided. METHODS: the data collection group comprised students from medicine and nursing courses who were holders of FAPESP scholarships (technical training 1) or otherwise, overseen by the coordinators of the project. The itreg (ECO Sistemas RJ/SBAIT) software was used as the database tool. Several quality "filters" were proposed to select those cases for review in the quality control process. RESULTS: data for 1344 trauma patients were input to the itreg database between March and November 2014. Around 87.0% of cases were blunt trauma patients, 59.6% had RTS>7.0 and 67% ISS<9. Full records were available for 292 cases, which were selected for review in the quality program. The auditing filters most frequently registered were laparotomy four hours after admission and drainage of acute subdural hematomas four hours after admission. Several points for improvement were flagged, such as control of overtriage of patients, the need to reduce the number of negative imaging exams, the development of protocols for achieving central venous access, and management of major TBI. CONCLUSION: the trauma registry provides a clear picture of the points to be improved in trauma patient care, however, there are specific peculiarities for implementing this tool in the Brazilian milieu. PMID- 26517804 TI - Curbing Inflammation in hemorrhagic trauma: a review. AB - Trauma is one of the world's leading causes of death within the first 40 years of life and thus a significant health problem. Trauma accounts for nearly a third of the lost years of productive life before 65 years of age and is associated with infection, hemorrhagic shock, reperfusion syndrome, and inflammation. The control of hemorrhage, coagulopathy, optimal use of blood products, balancing hypo and hyperperfusion, and hemostatic resuscitation improve survival in cases of trauma with massive hemorrhage. This review discusses inflammation in the context of trauma-associated hemorrhagic shock. When one considers the known immunomodulatory effects of traumatic injury, allogeneic blood transfusion, and the overlap between patient populations, it is surprising that so few studies have assessed their combined effects on immune function. We also discuss the relative benefits of curbing inflammation rather than attempting to prevent it. PMID- 26517805 TI - The structure of tagetitoxin. AB - Based on detailed analysis of newly acquired NMR data, we show that the previously revised structure of tagetitoxin is incorrect. A new structure of tagetitoxin is proposed which is consistent with the NMR and MS data. PMID- 26517806 TI - Natural colorants: Pigment stability and extraction yield enhancement via utilization of appropriate pretreatment and extraction methods. AB - Natural colorants from plant-based materials have gained increasing popularity due to health consciousness of consumers. Among the many steps involved in the production of natural colorants, pigment extraction is one of the most important. Soxhlet extraction, maceration, and hydrodistillation are conventional methods that have been widely used in industry and laboratory for such a purpose. Recently, various non-conventional methods, such as supercritical fluid extraction, pressurized liquid extraction, microwave-assisted extraction, ultrasound-assisted extraction, pulsed-electric field extraction, and enzyme assisted extraction have emerged as alternatives to conventional methods due to the advantages of the former in terms of smaller solvent consumption, shorter extraction time, and more environment-friendliness. Prior to the extraction step, pretreatment of plant materials to enhance the stability of natural pigments is another important step that must be carefully taken care of. In this paper, a comprehensive review of appropriate pretreatment and extraction methods for chlorophylls, carotenoids, betalains, and anthocyanins, which are major classes of plant pigments, is provided by using pigment stability and extraction yield as assessment criteria. PMID- 26517807 TI - Effect of five therapeutic strategies on the coagulation defect induced by the thrombomodulin c.1611C>A mutation. PMID- 26517808 TI - Infiltrating neutrophils increase bladder cancer cell invasion via modulation of androgen receptor (AR)/MMP13 signals. AB - Early studies indicated that several inflammatory immune cells, including macrophages, mast cells, B and T cells in the tumor microenvironment, might influence cancer progression. Here we found that bladder cancer (BCa) cells could recruit more neutrophils than normal bladder cells. The consequences of recruiting more neutrophils might then increase BCa cell invasion via up regulating androgen receptor (AR) signals. Mechanism dissection revealed infiltrating neutrophils could up-regulate AR signals via either increased AR mRNA/protein expression or increased AR transactivation. The increased AR signals might then enhance BCa cell invasion via increasing MMP13 expression. Together, these results might provide us a new potential therapeutic approach to better battle BCa metastasis via targeting the newly identified signaling from infiltrating neutrophils to BCa through AR to MMP13 signals. PMID- 26517809 TI - Novel insights into Notum and glypicans regulation in colorectal cancer. AB - The connection between colorectal cancer (CRC) and Wnt signaling pathway activation is well known, but full elucidation of the underlying regulation of the Wnt/beta-catenin pathway and its biological functions in CRC pathogenesis is still needed. Here, the azoxymethane/dextran sulfate sodium salt (AOM/DSS) murine model has been used as an experimental platform able to mimic human sporadic CRC development with predictable timing. We performed genome-wide expression profiling of AOM/DSS-induced tumors and normal colon mucosa to identify potential novel CRC biomarkers. Remarkably, the enhanced expression of Notum, a conserved feedback antagonist of Wnt, was observed in tumors along with alterations in Glypican-1 and Glypican-3 levels. These findings were confirmed in a set of human CRC samples. Here, we provide the first demonstration of significant changes in Notum and glypicans gene expression during CRC development and present evidence to suggest them as potential new biomarkers of CRC pathogenesis. PMID- 26517810 TI - Peptide mediated active targeting and intelligent particle size reduction mediated enhanced penetrating of fabricated nanoparticles for triple-negative breast cancer treatment. AB - Triple-negative breast cancer (TNBC) is one of the most invasively malignant human cancers and its incidence increases year by year. Effective therapeutics against them needs to be developed urgently. In this study, a kind of angiopep-2 modified and intelligently particle size-reducible NPs, Angio-DOX-DGL-GNP, was designed for accomplishing both high accumulation and deep penetration within tumor tissues. On one hand, for improving the cancerous targeting efficiency of NPs, angiopep-2 was anchored on the surface of NPs to facilitate their accumulation via binding with low density lipoprotein-receptor related protein (LRP) overexpressed on TNBC. On the other hand, for achieving high tumor retention and increasing tumor penetration, an intelligently particle size reducible NPs were constructed through fabricating gelatin NPs (GNP) with doxorubicin (DOX) loaded dendrigraft poly-lysine (DGL). In vitro cellular uptake and ex-vivo imaging proved the tumor targeting effect of Angio-DOX-DGL-GNP. Additionally, the degradation of large-sized Angio-DOX-DGL-GNP by matrix metalloproteinase-2 (MMP-2) led to the size reduction from 185.7 nm to 55.6 nm. More importantly, the penetration ability of Angio-DOX-DGL-GNP after incubation with MMP-2 was dominantly enhanced in tumor spheroids. Due to a combinational effect of active targeting and deep tumor penetration, the tumor growth inhibition rate of Angio-DOX-DGL-GNP was 74.1% in a 4T1 breast cancer bearing mouse model, which was significantly higher than other groups. Taken together, we successfully demonstrated a promising and effective nanoplatform for TNBC treatment. PMID- 26517811 TI - Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases. AB - The activation of immune cells by targeting checkpoint inhibitors showed promising results with increased patient survival in distinct primary cancers. Since only limited data exist for human brain metastases, we aimed at characterizing tumor infiltrating lymphocytes (TILs) and expression of immune checkpoints in the respective tumors. Two brain metastases cohorts, a mixed entity cohort (n = 252) and a breast carcinoma validation cohort (n = 96) were analyzed for CD3+, CD8+, FOXP3+, PD-1+ lymphocytes and PD-L1+ tumor cells by immunohistochemistry. Analyses for association with clinico-epidemiological and neuroradiological parameters such as patient survival or tumor size were performed. TILs infiltrated brain metastases in three different patterns (stromal, peritumoral, diffuse). While carcinomas often show a strong stromal infiltration, TILs in melanomas often diffusely infiltrate the tumors. Highest levels of CD3+ and CD8+ lymphocytes were seen in renal cell carcinomas (RCC) and strongest PD-1 levels on RCCs and melanomas. High amounts of TILs, high ratios of PD-1+/CD8+ cells and high levels of PD-L1 were negatively correlated with brain metastases size, indicating that in smaller brain metastases CD8+ immune response might get blocked. PD-L1 expression strongly correlated with TILs and FOXP3 expression. No significant association of patient survival with TILs was observed, while high levels of PD-L1 showed a strong trend towards better survival in melanoma brain metastases (Log-Rank p = 0.0537). In summary, melanomas and RCCs seem to be the most immunogenic entities. Differences in immunotherapeutic response between tumor entities regarding brain metastases might be attributable to this finding and need further investigation in larger patient cohorts. PMID- 26517812 TI - A combination of tyrosine kinase inhibitors, crizotinib and dasatinib for the treatment of glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Despite the advances in surgery, radiotherapy and chemotherapy, patient survival averages only 14.6 months. In most GBM tumors, tyrosine kinases show increased activity and/or expression and actively contribute to the development, recurrence and onset of treatment resistance; making their inhibition an appealing therapeutic strategy. We compared the cytotoxicity of 12 tyrosine kinase inhibitors in vitro. A combination of crizotinib and dasatinib emerged as the most cytotoxic across established and primary human GBM cell lines. The combination treatment induced apoptotic cell death and polyploidy. Furthermore, the combination treatment led to the altered expression and localization of several tyrosine kinase receptors such as Met and EGFR and downstream effectors as such as SRC. Furthermore, the combination treatment reduced the migration and invasion of GBM cells and prevented endothelial cell tube formation in vitro. Overall, our study demonstrated the broad specificity of a combination of crizotinib and dasatinib across multiple GBM cell lines. These findings provide insight into the development of alternative therapy for the treatment of GBM. PMID- 26517813 TI - Oxygen-Driven Tumour Growth Model: A Pathology-Relevant Mathematical Approach. AB - Xenografts--as simplified animal models of cancer-differ substantially in vasculature and stromal architecture when compared to clinical tumours. This makes mathematical model-based predictions of clinical outcome challenging. Our objective is to further understand differences in tumour progression and physiology between animal models and the clinic. To achieve that, we propose a mathematical model based upon tumour pathophysiology, where oxygen--as a surrogate for endocrine delivery--is our main focus. The Oxygen-Driven Model (ODM), using oxygen diffusion equations, describes tumour growth, hypoxia and necrosis. The ODM describes two key physiological parameters. Apparent oxygen uptake rate (k'R) represents the amount of oxygen cells seem to need to proliferate. The more oxygen they appear to need, the more the oxygen transport. k'R gathers variability from the vasculature, stroma and tumour morphology. Proliferating rate (kp) deals with cell line specific factors to promote growth. The KH,KN describe the switch of hypoxia and necrosis. Retrospectively, using archived data, we looked at longitudinal tumour volume datasets for 38 xenografted cell lines and 5 patient-derived xenograft-like models. Exploration of the parameter space allows us to distinguish 2 groups of parameters. Group 1 of cell lines shows a spread in values of k'R and lower kp, indicating that tumours are poorly perfused and slow growing. Group 2 share the value of the oxygen uptake rate (k'R) and vary greatly in kp, which we interpret as having similar oxygen transport, but more tumour intrinsic variability in growth. However, the ODM has some limitations when tested in explant-like animal models, whose complex tumour-stromal morphology may not be captured in the current version of the model. Incorporation of stroma in the ODM will help explain these discrepancies. We have provided an example. The ODM is a very simple -and versatile- model suitable for the design of preclinical experiments, which can be modified and enhanced whilst maintaining confidence in its predictions. PMID- 26517814 TI - Heat acclimation provides sustained improvement in functional recovery and attenuates apoptosis after traumatic brain injury. PMID- 26517815 TI - Assessing cerebral glucose metabolism in patients with idiopathic rapid eye movement sleep behavior disorder. PMID- 26517816 TI - Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation of mTOR Signaling in Macrophages. AB - BACKGROUND: Septic kidney injury is one of the most common complications in critically ill patients with a high risk of developing chronic kidney disease (CKD). Emerging data indicate that mammalian target of rapamyci (mTOR) signaling plays a major role in septic inflammation by regulating the immune response of macrophage. This study was designed to evaluate the role of mTOR signaling in kidney macrophages during endotoxemia-induced chronic kidney injury and subsequent fibrogenesis. METHODS: Male C57BL/6 mice were used for all animal studies (n=9 for each group). Lipopolysaccharide (LPS) was injected intraperitoneally (1 mg/kg) every 2 days to induce persistent endotoxemia. Rapamycin (1 mg/kg.day) was administered to a subgroup of mice 1 day prior to LPS treatment and continued to termination of the experiment. In ex-vivo experiment, RAW264.7 cells were cultured and treated with LPS (2 ug/ml) for 48 h while a subgroup of cells were incubated in the presence of rapamycin (50 nmol) for 2 h. RESULTS: Continuous administration of LPS resulted in progressive macrophage infiltration, tubular injury and collagen deposition in mice kidneys. Rapamycin markedly ameliorated LPS-induced kidney pathological changes. Expression of pS6K was rarely observed in normal kidney macrophages, but significantly increased with time by LPS treatment. In ex-vivo study, LPS induced prominent production of IL-1beta and MCP-1 in cultured RAW264.7 cells, which was significantly suppressed by rapamycin. CONCLUSION: Taken together, our findings show that endotoxemia results in activation of mTOR signaling in macrophages, leading to progressive kidney inflammatory injuries and subsequent fibrosis. Our study may reveal a mechanism involved in the development of sepsis-associated CKD and kidney fibrosis. PMID- 26517817 TI - Electrochemical behavior of palmatine and its sensitive determination based on an electrochemically reduced L-methionine functionalized graphene oxide modified electrode. AB - A new and sensitive voltammetric sensor for palmatine, based on an electrochemically reduced L-methionine functionalized graphene oxide modified glassy carbon electrode (L-Met-ERGO/GCE), is reported. The electrochemical characteristics of palmatine at the proposed sensor were studied systematically and some dynamic parameters were calculated for the first time. A reasonable reaction mechanism for palmatine on the L-Met-ERGO/GCE electrode was proposed and discussed, and this could be a reference for the pharmacological action of palmatine in clinical study. Under optimized conditions, the peak current had a linear relationship with palmatine concentration in the range of 1 * 10(-7) to 5 * 10(-5) mol L(-1) with a detection limit of 6 * 10(-8) mol L(-1). Additionally, the proposed method was also used to detect palmatine in human urine samples, medicinal tablets and the Chinese herb Fibraurea recisa Pierre with satisfactory results. PMID- 26517818 TI - The preclinical discovery and development of dolutegravir for the treatment of HIV. AB - INTRODUCTION: Integration of the viral genome into the host cell chromatin is a central step in the replication cycle of HIV. Blocking the viral integrase (IN) enzyme therefore provides an attractive therapeutic strategy, as evidenced by the recent clinical approval of three IN strand transfer inhibitors. Dolutegravir is a therapy that is unique in its ability to evade HIV drug resistance in treatment naive patients. AREAS COVERED: This review starts by providing a brief summary of the history of HIV-1 IN inhibitors. The authors follow this with details of the discovery and preclinical and clinical developments of dolutegravir. Finally, the authors provide details of dolutegravir's post-launch including the launch of the combination pill of dolutegravir, abacavir and lamivudine in August 2014. EXPERT OPINION: The launch of raltegravir, the first IN inhibitor from Merck & Co., has created new hopes for the patient. Indeed, pharmaceutical companies have not lost courage by attempting to address the major drawbacks of this first-in-class molecule. And while the drug elvitegravir has been inserted into a four-drug combination pill providing a once-daily dosing alternative, dolutegravir has demonstrated superiority in terms of its efficacy and resistance. PMID- 26517819 TI - Erratum. Correction to: Recent progress in tight junction modulation for improving bioavailability. PMID- 26517821 TI - The Protective Action of the Aqueous Extract of Auricularia polytricha in Paracetamol Induced Hepatotoxicity in Rats. AB - Natural antioxidant products are increasingly being used to treat various pathological liver injuries considering the role of oxidative stress in their pathogenesis. Auricularia polytricha has been used as food or medicine due to its antioxidant activity. The aim of the study was to evaluate the protective effect of the aqueous extract of the fruiting bodies of A. polytricha against paracetamol-induced liver toxicity in rats. Liver toxicity was induced in Sprague Dawley rats by oral administration of 2g/kg paracetamol on the 15th day after the administration of aqueous extract and silymarin 100 mg/kg. Aqueous extract of A. polytricha was administered orally at 250 and 500 mg/kg doses, daily for a period of 14 days. Aspartate aminotransferase (AST), Alanine transaminase (ALT) and Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH), Total bilirubin (TB), Total protein (TP), Triglycerides (TG) and cholesterol were measured to assess the effect of the extract on paracetamol-induced hepatic damage. The patent on Auricularia Polytricha (EP0413052A1) assisted in selecting the extraction procedure. The study also included histopathological examination of liver sections to assess hepatoprotective activity. Paracetamol significantly (P<0.001) increased the serum AST, ALT, ALP, LDH, TB, TG and cholesterol and decreased TP levels. Extract treatment significantly (P<0.001 to P<0.05) attenuated the paracetamol induced increase in AST, ALT, ALP, LDH, TB, TG and cholesterol and increased the diminished TP in a dose dependent manner. The standard drug, silymarin produced significant (P<0.001) decrease in AST, ALT, ALP, LDH, TB, TG and cholesterol and increase in TP. Histopathological examination of animals treated with paracetamol showed large areas of centrilobular necrosis with congestion and dilatation in both central and portal veins. These results indicate that the aqueous extract of A. polytricha has significant protective effect against paracetamol-induced liver toxicity in rats, due to its potent antioxidant activity. PMID- 26517823 TI - Postmortem redistribution of olanzapine following intramuscular administration of olanzapine pamoate in dogs. AB - The potential for postmortem redistribution of olanzapine was investigated in beagle dogs. Olanzapine pamoate monohydrate was administered once every 14 days by intramuscular injection for 3 months to fed male dogs (n=15) at a dose of 20 mg/kg olanzapine (equivalent to 46 mg/kg olanzapine pamoate monohydrate). Blood samples were collected after the fifth (Day 57) and sixth (Day 71) doses to determine olanzapine and N-oxide olanzapine concentrations. On Day 71 at 72 h postdose, dogs were euthanized and placed on their backs without additional manipulation and held for postmortem blood, urine, and tissue collection at room temperature for up to 168 h postdose (96 h after euthanasia). Concentrations of olanzapine and N-oxide olanzapine were determined by liquid chromatography-mass spectroscopy/mass spectroscopy (LC-MS/MS). Postmortem olanzapine concentrations in blood increased up to seven-fold compared to the last quantified antemortem blood concentration. Olanzapine concentrations in vein tissue samples (surrogates for peripheral blood) also increased, whereas other tissue concentrations, such as myocardium, lung, liver, and kidney decreased over the postmortem period. An increase in blood concentration of olanzapine after death was observed in all but one animal, suggesting that postmortem redistribution may occur in dogs following biweekly intramuscular administration of olanzapine pamoate monohydrate. The rise in olanzapine concentrations in blood after death in this study may potentially be attributed to diffusion from multiple tissues to blood and, to a lesser extent, reduction of the N-oxide olanzapine metabolite back to olanzapine. However, the generalizability of these results to humans cannot be confirmed by the present study. PMID- 26517822 TI - Nitric Oxide Increases the Expression of Aquaporin-4 Protein in Rat Optic Nerve Astrocytes through the Cyclic Guanosine Monophosphate/Protein Kinase G Pathway. AB - AIMS: Nitric oxide (NO) is associated with neuroinflammation in the central nervous system. We determined whether NO increases the expression of aquaporin-4 (AQP4) in optic nerve astrocytes of rats. METHODS: Isolated astrocytes were incubated under normoxic or hypoxic conditions with or without glucose (5.5 mM). The astrocytes were also exposed to different concentrations of S-nitroso-N acetyl-DL-penicillamine (SNAP, 1.0-100 MUM), an NO donor. The expression of AQP4 was determined by Western blot analyses, and NO formation was measured by the Griess reaction. The changes in astrocytic cellular volumes were determined by flow cytometry. RESULTS: Hypoxia and glucose deprivation increased AQP4 expression and NO formation. Inhibition of NO synthetase (NOS) significantly suppressed these changes. SNAP caused a significant increase in AQP4 expression, and the increase was significantly suppressed by carboxy-PTIO, a scavenger of NO. Incubation with 8-Br-cyclic guanosine monophosphate (cGMP) mimicked the effects of SNAP, while the addition of either 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1 one (ODQ; inhibitor of soluble guanylate cyclase) or KT5823 (protein kinase G inhibitor) suppressed the SNAP-induced increase in AQP4 significantly. SNAP also caused a significant increase in astrocytic cellular volume through the AQP4 channels. CONCLUSIONS: NO increased the AQP4 expression of optic nerve astrocytes through the cGMP/protein kinase G pathway and enlarged their volume. PMID- 26517824 TI - Seizures of doping substances at the Swiss Border--a descriptive investigation. AB - This retrospective study evaluates the content, the destination and the source of 960 postal items seized by the Swiss customs authorities at the Swiss border between 2013 and 2014. The packages were seized because they contained at least one prohibited doping product as identified by the Swiss law on encouraging sports and physical activity. A total number of 1825 different doping products were confiscated from these parcels, accounting for an average of 1.9 doping products per seized item. In 74% of the cases, where seizures were made, anabolic androgenic steroids, mostly testosterone esters, were discovered. An obvious trading channel for doping products was identified in this study. The seized compounds were predominately manufactured in Asian countries, but sent to Switzerland mostly via South Eastern Europe countries. Due to the unique collaboration between the Swiss customs authorities and the national anti-doping agency, this study uncovered an alarming trend of illegal doping product trafficked to Switzerland. PMID- 26517825 TI - Opinion Formation by Social Influence: From Experiments to Modeling. AB - Predicting different forms of collective behavior in human populations, as the outcome of individual attitudes and their mutual influence, is a question of major interest in social sciences. In particular, processes of opinion formation have been theoretically modeled on the basis of a formal similarity with the dynamics of certain physical systems, giving rise to an extensive collection of mathematical models amenable to numerical simulation or even to exact solution. Empirical ground for these models is however largely missing, which confine them to the level of mere metaphors of the real phenomena they aim at explaining. In this paper we present results of an experiment which quantifies the change in the opinions given by a subject on a set of specific matters under the influence of others. The setup is a variant of a recently proposed experiment, where the subject's confidence on his or her opinion was evaluated as well. In our realization, which records the quantitative answers of 85 subjects to 20 questions before and after an influence event, the focus is put on characterizing the change in answers and confidence induced by such influence. Similarities and differences with the previous version of the experiment are highlighted. We find that confidence changes are to a large extent independent of any other recorded quantity, while opinion changes are strongly modulated by the original confidence. On the other hand, opinion changes are not influenced by the initial difference with the reference opinion. The typical time scales on which opinion varies are moreover substantially longer than those of confidence change. Experimental results are then used to estimate parameters for a dynamical agent based model of opinion formation in a large population. In the context of the model, we study the convergence to full consensus and the effect of opinion leaders on the collective distribution of opinions. PMID- 26517826 TI - Sumoylation of the Tumor Suppressor Promyelocytic Leukemia Protein Regulates Arsenic Trioxide-Induced Collagen Synthesis in Osteoblasts. AB - BACKGROUND/AIMS: Promyelocytic leukemia (PML) protein is a tumor suppressor that fuses with retinoic acid receptor-alpha (PML-RARalpha) to contribute to the initiation of acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) upregulates expression of TGF-beta1, promoting collagen synthesis in osteoblasts, and ATO binds directly to PML to induce oligomerization, sumoylation, and ubiquitination. However, how ATO upregulates TGF-beta1 expression is uncertain. Thus, we suggested that PML sumoylation is responsible for regulation of TGF beta1 protein expression. METHODS: Kunming mice were treated with ATO, and osteoblasts were counted under scanning electron microscopy. Masson's staining was used to quantify collagen content. hFOB1.19 cells were transfected with siRNA against UBC9 or RNF4, and then treated with ATO or FBS. TGF-beta1, PML expression, and sumoylation were quantified with Western blot, and collagen quantified via immunocytochemistry. RESULTS: ATO enhanced osteoblast accumulation, collagen synthesis, and PML-NB formation in vivo. Knocking down UBC9 in hFOB1.19 cells inhibited ATO- and FBS-induced PML sumoylation, TGF-beta1 expression, and collagen synthesis. Conversely, knocking down RNF4 enhanced ATO- and FBS-induced PML sumoylation, TGF-beta1 expression, and collagen synthesis. CONCLUSION: These data suggest that PML sumoylation is required for ATO-induced collagen synthesis in osteoblasts. PMID- 26517827 TI - Enhancement of Treatment Efficiency of Recalcitrant Wastewater Containing Textile Dyes Using a Newly Developed Iron Zeolite Socony Mobil-5 Heterogeneous Catalyst. AB - Fenton oxidation, an advanced oxidation process, is an efficient method for the treatment of recalcitrant wastewaters. Unfortunately, it utilizes H2O2 and iron based homogeneous catalysts, which lead to the formation of high volumes of sludge and secondary pollutants. To overcome these problems, an alternate option is the usage of heterogeneous catalyst. In this study, a heterogeneous catalyst was developed to provide an alternative solution for homogeneous Fenton oxidation. Iron Zeolite Socony Mobile-5 (Fe-ZSM-5) was synthesized using a new two-step process. Next, the catalyst was characterized by scanning electron microscopy, energy-dispersive X-ray spectroscopy, fourier transform infrared spectroscopy, and Brunauer-Emmett-Teller analysis and tested against a model wastewater containing the azo dye Acid Blue 113. Results showed that the loading of iron particles reduced the surface area of the catalyst from 293.59 to 243.93 m2/g; meanwhile, the average particle size of the loaded material was 12.29 nm. Furthermore, efficiency of the developed catalyst was evaluated by performing heterogeneous Fenton oxidation. Taguchi method was coupled with principal component analysis in order to assess and optimize mineralization efficiency. Experimental results showed that under optimized conditions, over 99.7% degradation and 77% mineralization was obtained, with a 90% reduction in the consumption of the developed catalyst. Furthermore, the developed catalyst was stable and reusable, with less than 2% leaching observed under optimized conditions. Thus, the present study proved that newly developed catalyst has enhanced the oxidation process and reduced the chemicals consumption. PMID- 26517829 TI - Combination of B cell biomarkers as independent predictors of response in patients with rheumatoid arthritis treated with rituximab. AB - OBJECTIVES: Identification of B cell biomarkers predictive of response prior to therapy with rituximab (RTX) and evaluation of the efficacy of long-term treatment in patients with rheumatoid arthritis (RA). METHODS: 302 RA patients failing one TNFi were treated with two applications of 1000 mg RTX (FIRST study). During the follow-up study (ReFIRST) the patients were treated for up to three more courses if they showed measurable clinical response but RA was still active. In a substudy on 154 RA patients peripheral B cell subsets were determined by flow cytometry before starting RTX. Rheumatoid factor (RF), RF-isotypes and anti citrullinated protein antibodies (ACPA) were also measured. RESULTS: Based on multivariate analyses patients with positive RF and normal (>lower limit) levels of CD19+ B cells (RF+CD19+) showed better treatment effects compared to patients who had only one or none of those parameters. Considering the RF status of the patients, analysis of B cell subpopulations yielded a correlation between higher ER rates and "double negative" CD19+CD27-IgD- B cells. Lowest ER rates were observed for RF negative patients in combination with low numbers of CD19+CD27 IgD- B cells as independent risk factors, thus defining a group with lower responses. Conversely, higher CD19+CD27-IgD- B cells identified a responder group within RF negative patients. CONCLUSIONS: The data of this large biomarker study suggest that beyond RF positivity, normal levels of CD19+ B cells together with increased CD19+CD27-IgD- B cells predict response to RTX in RA, in particular when all parameters were present. PMID- 26517828 TI - Dual Mutation Events in the Haemagglutinin-Esterase and Fusion Protein from an Infectious Salmon Anaemia Virus HPR0 Genotype Promote Viral Fusion and Activation by an Ubiquitous Host Protease. AB - In Infectious salmon anaemia virus (ISAV), deletions in the highly polymorphic region (HPR) in the near membrane domain of the haemagglutinin-esterase (HE) stalk, influence viral fusion. It is suspected that selected mutations in the associated Fusion (F) protein may also be important in regulating fusion activity. To better understand the underlying mechanisms involved in ISAV fusion, several mutated F proteins were generated from the Scottish Nevis and Norwegian SK779/06 HPR0. Co-transfection with constructs encoding HE and F were performed, fusion activity assessed by content mixing assay and the degree of proteolytic cleavage by western blot. Substitutions in Nevis F demonstrated that K276 was the most likely cleavage site in the protein. Furthermore, amino acid substitutions at three sites and two insertions, all slightly upstream of K276, increased fusion activity. Co-expression with HE harbouring a full-length HPR produced high fusion activities when trypsin and low pH were applied. In comparison, under normal culture conditions, groups containing a mutated HE with an HPR deletion were able to generate moderate fusion levels, while those with a full length HPR HE could not induce fusion. This suggested that HPR length may influence how the HE primes the F protein and promotes fusion activation by an ubiquitous host protease and/or facilitate subsequent post-cleavage refolding steps. Variations in fusion activity through accumulated mutations on surface glycoproteins have also been reported in other orthomyxoviruses and paramyxoviruses. This may in part contribute to the different virulence and tissue tropism reported for HPR0 and HPR deleted ISAV genotypes. PMID- 26517831 TI - Directed meta-Selective Bromination of Arenes with Ruthenium Catalysts. AB - A Ru-catalyzed direct C?H activation/meta-bromination of arenes bearing pyridyl, pyrimidyl, and pyrazolyl directing groups has been developed. A series of bromo aryl pyridines and pyrimidines have been synthesized, and further coupling reactions have also been demonstrated for a number of representative functionalized arenes. Preliminary mechanistic studies have revealed that this reaction may proceed through radical-mediated bromination when NBS is utilized as the bromine source. This type of transformation has opened up a new direction for the radical non-ipso functionalization of metal with regard to future C?H activation development that would allow the remote functionalization of aromatic systems. PMID- 26517830 TI - A Scale-Corrected Comparison of Linkage Disequilibrium Levels between Genic and Non-Genic Regions. AB - The understanding of non-random association between loci, termed linkage disequilibrium (LD), plays a central role in genomic research. Since causal mutations are generally not included in genomic marker data, LD between those and available markers is essential for capturing the effects of causal loci on localizing genes responsible for traits. Thus, the interpretation of association studies requires a detailed knowledge of LD patterns. It is well known that most LD measures depend on minor allele frequencies (MAF) of the considered loci and the magnitude of LD is influenced by the physical distances between loci. In the present study, a procedure to compare the LD structure between genomic regions comprising several markers each is suggested. The approach accounts for different scaling factors, namely the distribution of MAF, the distribution of pair-wise differences in MAF, and the physical extent of compared regions, reflected by the distribution of pair-wise physical distances. In the first step, genomic regions are matched based on similarity in these scaling factors. In the second step, chromosome- and genome-wide significance tests for differences in medians of LD measures in each pair are performed. The proposed framework was applied to test the hypothesis that the average LD is different in genic and non-genic regions. This was tested with a genome-wide approach with data sets for humans (Homo sapiens), a highly selected chicken line (Gallus gallus domesticus) and the model plant Arabidopsis thaliana. In all three data sets we found a significantly higher level of LD in genic regions compared to non-genic regions. About 31% more LD was detected genome-wide in genic compared to non-genic regions in Arabidopsis thaliana, followed by 13.6% in human and 6% chicken. Chromosome-wide comparison discovered significant differences on all 5 chromosomes in Arabidopsis thaliana and on one third of the human and of the chicken chromosomes. PMID- 26517833 TI - Correction: New Operational Matrices for Solving Fractional Differential Equations on the Half-Line. PMID- 26517832 TI - Novel Reporter for Faithful Monitoring of ERK2 Dynamics in Living Cells and Model Organisms. AB - Uncoupling of ERK1/2 phosphorylation from subcellular localization is essential towards the understanding of molecular mechanisms that control ERK1/2-mediated cell-fate decision. ERK1/2 non-catalytic functions and discoveries of new specific anchors responsible of the subcellular compartmentalization of ERK1/2 signaling pathway have been proposed as regulation mechanisms for which dynamic monitoring of ERK1/2 localization is necessary. However, studying the spatiotemporal features of ERK2, for instance, in different cellular processes in living cells and tissues requires a tool that can faithfully report on its subcellular distribution. We developed a novel molecular tool, ERK2-LOC, based on the T2A-mediated coexpression of strictly equimolar levels of eGFP-ERK2 and MEK1, to faithfully visualize ERK2 localization patterns. MEK1 and eGFP-ERK2 were expressed reliably and functionally both in vitro and in single living cells. We then assessed the subcellular distribution and mobility of ERK2-LOC using fluorescence microscopy in non-stimulated conditions and after activation/inhibition of the MAPK/ERK1/2 signaling pathway. Finally, we used our coexpression system in Xenopus laevis embryos during the early stages of development. This is the first report on MEK1/ERK2 T2A-mediated coexpression in living embryos, and we show that there is a strong correlation between the spatiotemporal subcellular distribution of ERK2-LOC and the phosphorylation patterns of ERK1/2. Our approach can be used to study the spatiotemporal localization of ERK2 and its dynamics in a variety of processes in living cells and embryonic tissues. PMID- 26517834 TI - Morphologic and Genotypic Characterization of Psoroptes Mites from Water Buffaloes in Egypt. AB - Species delimitation of Psoroptes spp. and identity of the parasite in water buffaloes remain poorly defined. In this study, Psoroptes infestation on three water buffalo farms in Egypt was examined based on morphometric characteristics, especially the opisthosomal setae of adult male mites. Clinical investigations showed that 28% (196/700) of the sampled animals had mange infestation. Microscopic examinations of 80 skin scrapings indicated the occurrence of Psoroptes mites in 17 (21.3%) samples, Sarcoptes mites in 27 (33.7%) samples, and the concurrence of both in 36 (45.0%) samples. Morphologically, the Psoroptes parasite was identified as Psoroptes natalensis. DNA sequence analysis of the second internal transcribed spacer (ITS2) in 11 representative samples confirmed the diagnosis and suggested the presence of a distinct variety of Psoroptes natalensis in Egypt. PMID- 26517835 TI - Characterising Uncertainty in Expert Assessments: Encoding Heavily Skewed Judgements. AB - When limited or no observed data are available, it is often useful to obtain expert knowledge about parameters of interest, including point estimates and the uncertainty around these values. However, it is vital to elicit this information appropriately in order to obtain valid estimates. This is particularly important when the experts' uncertainty about these estimates is strongly skewed, for instance when their best estimate is the same as the lowest value they consider possible. Also this is important when interest is in the aggregation of elicited values. In this paper, we compare alternative distributions for describing such estimates. The distributions considered include the lognormal, mirror lognormal, Normal and scaled Beta. The case study presented here involves estimation of the number of species in coral reefs, which requires eliciting counts within broader taxonomic groups, with highly skewed uncertainty estimates. This paper shows substantial gain in using the scaled Beta distribution, compared with Normal or lognormal distributions. We demonstrate that, for this case study on counting species, applying the novel encoding methodology developed in this paper can facilitate the acquisition of more rigorous estimates of (hierarchical) count data and credible bounds. The approach can also be applied to the more general case of enumerating a sampling frame via elicitation. PMID- 26517836 TI - Computational Identification of MoRFs in Protein Sequences Using Hierarchical Application of Bayes Rule. AB - MOTIVATION: Intrinsically disordered regions of proteins play an essential role in the regulation of various biological processes. Key to their regulatory function is often the binding to globular protein domains via sequence elements known as molecular recognition features (MoRFs). Development of computational tools for the identification of candidate MoRF locations in amino acid sequences is an important task and an area of growing interest. Given the relative sparseness of MoRFs in protein sequences, the accuracy of the available MoRF predictors is often inadequate for practical usage, which leaves a significant need and room for improvement. In this work, we introduce MoRFCHiBi_Web, which predicts MoRF locations in protein sequences with higher accuracy compared to current MoRF predictors. METHODS: Three distinct and largely independent property scores are computed with component predictors and then combined to generate the final MoRF propensity scores. The first score reflects the likelihood of sequence windows to harbour MoRFs and is based on amino acid composition and sequence similarity information. It is generated by MoRFCHiBi using small windows of up to 40 residues in size. The second score identifies long stretches of protein disorder and is generated by ESpritz with the DisProt option. Lastly, the third score reflects residue conservation and is assembled from PSSM files generated by PSI-BLAST. These propensity scores are processed and then hierarchically combined using Bayes rule to generate the final MoRFCHiBi_Web predictions. RESULTS: MoRFCHiBi_Web was tested on three datasets. Results show that MoRFCHiBi_Web outperforms previously developed predictors by generating less than half the false positive rate for the same true positive rate at practical threshold values. This level of accuracy paired with its relatively high processing speed makes MoRFCHiBi_Web a practical tool for MoRF prediction. AVAILABILITY: http://morf.chibi.ubc.ca:8080/morf/. PMID- 26517837 TI - Association of Processed Meat Intake with Hypertension Risk in Hemodialysis Patients: A Cross-Sectional Study. AB - In this cross-sectional study, we hypothesized that hemodialysis patients consuming greater processed meat is associated with hypertension risk, which can be partly explained by the high sodium content in processed meat. From September 2013 to May 2014, one hundred and four patients requiring chronic hemodialysis treatment were recruited from hemodialysis centers. Data on systolic blood pressure and diastolic blood pressure before receiving dialysis, and 3-day dietary records of the recruited patients were collected. HD patients with systolic and diastolic blood pressures greater than140 mmHg and higher than 90 mmHg, respectively, were considered hypertension risk. Protein foods were divided into 4 categories: red meat, white meat, soybeans, and processed meat (e.g., sausage and ham). In a model adjusted for energy intake and hypertension history, additional servings of processed meats was positively associated to systolic blood pressure >140 mmHg (odds ratio [95% confidence interval]: 2.1 [1.0-4.3]), and diastolic blood pressure > 90 mmHg (odds ratio: 2.5 [1.2-5.5]). After adjustment for dietary sodium contents or body mass index (BMI), most associations were substantially attenuated and were no longer significant. In systolic blood pressure greater than140 mmHg, one serving per day of red meats (beta = -1.22, P < .05) and white meats (beta = -0. 75, P = .05) was associated with a reduced risk compared with one serving per day of processed meats. Similarly, compared with one serving per day of processed meat, a reduced risk of diastolic blood pressure higher than 90 mmHg was associated with one serving per day of red meat (beta = -1. 59, P < .05), white meat (beta = -0. 62, P < .05). Thus, in these hemodialysis patients, intake of processed meat is significantly positively associated with higher blood pressure risk, and both sodium contents in processed meat and BMI significantly contributes to this association. PMID- 26517838 TI - The Expression of Tristetraprolin and Its Relationship with Urinary Proteins in Patients with Diabetic Nephropathy. AB - OBJECTIVE: Tristetraprolin (TTP), also known as zinc finger protein 36, is an RNA binding protein that has a significant role in regulating the expression of mRNAs containing AU-rich elements. We postulated that TTP might regulate interleukin (IL)-6 and IL-18 expression in diabetes. This study aimed to test the hypothesis that the levels of TTP are correlated with nephropathy in patients with type 2 diabetes. METHODS: Eighty-seven patients (61.3+/-9.6 years old) who had been diagnosed with type 2 diabetes mellitus and 41 age and sex matched healthy control subjects were enrolled. The diabetes patients were classified into those without proteinuria, with microalbuminuria, and with clinical proteinuria groups according to the ratio of urinary excretion of albumin/creatinine (ACR). RESULTS: Serum and urinary levels of IL-6 and IL-18 were significantly elevated, but those of TTP were significantly decreased in patients with diabetes as compared with control subjects. In addition, serum and urinary levels of IL-6 and IL-18 were significantly higher, but those of TTP were significantly lower in patients with proteinuria than in patients without proteinuria or with microalbuminuria. There was a significant correlation between serum TTP and IL-6/IL-18 (correlation coefficients of -0.572 and -0.685, P < 0.05). CONCLUSION: These results show that diabetes with clinical proteinuria is accompanied by decreased urinary and serum level of TTP and increased levels of IL-6 and IL-18. Decreased TTP expression might occur prior to the increase in IL-6 and IL-18, and decrease of TTP might provide an earlier marker for glomerular dysfunction than IL-6 and IL-18. PMID- 26517839 TI - Further Assessment of Monkeypox Virus Infection in Gambian Pouched Rats (Cricetomys gambianus) Using In Vivo Bioluminescent Imaging. AB - Monkeypox is a zoonosis clinically similar to smallpox in humans. Recent evidence has shown a potential risk of increased incidence in central Africa. Despite attempts to isolate the virus from wild rodents and other small mammals, no reservoir host has been identified. In 2003, Monkeypox virus (MPXV) was accidentally introduced into the U.S. via the pet trade and was associated with the Gambian pouched rat (Cricetomys gambianus). Therefore, we investigated the potential reservoir competence of the Gambian pouched rat for MPXV by utilizing a combination of in vivo and in vitro methods. We inoculated three animals by the intradermal route and three animals by the intranasal route, with one mock infected control for each route. Bioluminescent imaging (BLI) was used to track replicating virus in infected animals and virological assays (e.g. real time PCR, cell culture) were used to determine viral load in blood, urine, ocular, nasal, oral, and rectal swabs. Intradermal inoculation resulted in clinical signs of monkeypox infection in two of three animals. One severely ill animal was euthanized and the other affected animal recovered. In contrast, intranasal inoculation resulted in subclinical infection in all three animals. All animals, regardless of apparent or inapparent infection, shed virus in oral and nasal secretions. Additionally, BLI identified viral replication in the skin without grossly visible lesions. These results suggest that Gambian pouched rats may play an important role in transmission of the virus to humans, as they are hunted for consumption and it is possible for MPXV-infected pouched rats to shed infectious virus without displaying overt clinical signs. PMID- 26517840 TI - Changes in the Metabolome of Picea balfouriana Embryogenic Tissues That Were Linked to Different Levels of 6-BAP by Gas Chromatography-Mass Spectrometry Approach. AB - Embryogenic cultures of Picea balfouriana, which is an important commercial species for reforestation in Southern China, easily lose their embryogenic ability during long-term culture. Embryogenic tissue that proliferated at lower concentrations (3.6 MUM and 2.5 MUM) of 6-benzylaminopurine (6-BAP) were more productive, and generated 113 +/- 6 and 89 +/- 3 mature embryos per 100 mg embryogenic tissue, respectively. A metabolomic approach was used to study the changes in metabolites linked to embryogenic competence related to three different 6-BAP concentrations (2.5 MUM, 3.6 MUM, and 5 MUM). A total of 309 compounds were obtained, among which 123 metabolites mapped to Kyoto Encyclopedia of Genes and genomes (KEGG) pathways. The levels of 35 metabolites were significantly differentially regulated among the three 6-BAP treatments, and 32 metabolites differed between the 2.5 MUM and 5 MUM treatments. A total of 17 metabolites appeared only once among the three comparisons. The combination of a score plot and a loading plot showed that in the samples with higher embryogenic ability (3.6 MUM and 2.5 MUM), up-regulated metabolites were mostly amino acids and down-regulated metabolites were mostly primary carbohydrates (especially sugars). These results suggested that 6-BAP may influence embryogenic competence by nitrogen metabolism, which could cause an increase in amino acid levels and higher amounts of aspartate, isoleucine, and leucine in tissues with higher embryogenic ability. Furthermore, we speculated that 6-BAP may affect the amount of tryptophan in tissues, which would change the indole-3-acetic acid levels and influence the embryogenic ability. PMID- 26517841 TI - RNA-Seq Based Identification of Candidate Parasitism Genes of Cereal Cyst Nematode (Heterodera avenae) during Incompatible Infection to Aegilops variabilis. AB - One of the reasons for the progressive yield decline observed in cereals production is the rapid build-up of populations of the cereal cyst nematode (CCN, Heterodera avenae). These nematodes secrete so-call effectors into their host plant to suppress the plant defense responses, alter plant signaling pathways and then induce the formation of syncytium after infection. However, little is known about its molecular mechanism and parasitism during incompatible infection. To gain insight into its repertoire of parasitism genes, we investigated the transcriptome of the early parasitic second-stage (30 hours, 3 days and 9 days post infection) juveniles of the CCN as well as the CCN infected tissue of the host Aegilops variabilis by Illumina sequencing. Among all assembled unigenes, 681 putative genes of parasitic nematode were found, in which 56 putative effectors were identified, including novel pioneer genes and genes corresponding to previously reported effectors. All the 681 CCN unigenes were mapped to 229 GO terms and 200 KEGG pathways, including growth, development and several stimulus related signaling pathways. Sixteen clusters were involved in the CCN unigene expression atlas at the early stages during infection process, and three of which were significantly gene-enriched. Besides, the protein-protein interaction network analysis revealed 35 node unigenes which may play an important role in the plant-CCN interaction. Moreover, in a comparison of differentially expressed genes between the pre-parasitic juveniles and the early parasitic juveniles, we found that hydrolase activity was up-regulated in pre J2s whereas binding activity was upregulated in infective J2s. RT-qPCR analysis on some selected genes showed detectable expression, indicating possible secretion of the proteins and putative role in infection. This study provided better insights into the incompatible interaction between H. avenae and the host plant Ae. varabilis. Moreover, RNAi targets with potential lethality were screened out and primarily validated, which provide candidates for engineering-based control of cereal cyst nematode in crops breeding. PMID- 26517843 TI - Hepacivirus cross-species transmission and the origins of the hepatitis C virus. AB - Just 5 years ago the hepatitis C virus (HCV) - a major cause of liver disease infecting >3% of people worldwide - was the sole confirmed member of the Hepacivirus genus. Since then, genetically-diverse hepaciviruses have been isolated from bats, dogs, cows, horses, primates and rodents. Here we review current information on the hepaciviruses and speculate on the zoonotic origins of the viruses in humans, horses and dogs. Recent and direct cross-species transmission from horses to dogs appears plausible, but the zoonotic origins of HCV in humans remain opaque. Mechanical transmission by biting insects, notably tabanids, could, in theory, connect all three host species. Much further work is needed to understand the transmission and zoonotic potential of hepaciviruses in natural populations. PMID- 26517844 TI - Stanford Type A Acute Retrograde Aortic Dissections: From Surgical to Endovascular Strategy? AB - Acute type A retrograde aortic dissection is characterized by a port of entry located in the descending aorta near the subclavian take-off, and is currently treated with surgery. Our experience with two patients who underwent a complicated postoperative course stimulated a review of the current literature and discussion of possible alternative strategies in light of recent advances in endovascular treatment. PMID- 26517842 TI - Client Proteins and Small Molecule Inhibitors Display Distinct Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and Their Conformationally Restricted Mutants. AB - The two cytosolic/nuclear isoforms of the molecular chaperone HSP90, stress inducible HSP90alpha and constitutively expressed HSP90beta, fold, assemble and maintain the three-dimensional structure of numerous client proteins. Because many HSP90 clients are important in cancer, several HSP90 inhibitors have been evaluated in the clinic. However, little is known concerning possible unique isoform or conformational preferences of either individual HSP90 clients or inhibitors. In this report, we compare the relative interaction strength of both HSP90alpha and HSP90beta with the transcription factors HSF1 and HIF1alpha, the kinases ERBB2 and MET, the E3-ubiquitin ligases KEAP1 and RHOBTB2, and the HSP90 inhibitors geldanamycin and ganetespib. We observed unexpected differences in relative client and drug preferences for the two HSP90 isoforms, with HSP90alpha binding each client protein with greater apparent affinity compared to HSP90beta, while HSP90beta bound each inhibitor with greater relative interaction strength compared to HSP90alpha. Stable HSP90 interaction was associated with reduced client activity. Using a defined set of HSP90 conformational mutants, we found that some clients interact strongly with a single, ATP-stabilized HSP90 conformation, only transiently populated during the dynamic HSP90 chaperone cycle, while other clients interact equally with multiple HSP90 conformations. These data suggest different functional requirements among HSP90 clientele that, for some clients, are likely to be ATP-independent. Lastly, the two inhibitors examined, although sharing the same binding site, were differentially able to access distinct HSP90 conformational states. PMID- 26517845 TI - Impact of the clip and snare method using the prelooping technique for colorectal endoscopic submucosal dissection. AB - BACKGROUND AND STUDY AIM: Endoscopic submucosal dissection (ESD) is more difficult to perform for colorectal tumors, but the use of traction to facilitate direct submucosal layer visualization is a promising method to reduce procedure times and complication rates. This study aimed to evaluate the efficacy and safety of the clip and snare method (CSM) with a prelooping technique (PLT) for colorectal tumors. PATIENTS AND METHODS: A total of 140 colorectal tumors were treated: 17 using the CSM with PLT; 123, used as controls, by standard ESD without these techniques. Therapeutic efficacy and safety were retrospectively assessed. RESULTS: All tumors were successfully resected en bloc using the CSM with PLT. Multisegment resection was found in four tumors in the control group. There was a significant difference in the procedure time between the patients in the CSM with PLT group and the control group (45.6 vs. 70.1 minutes; P = 0.047). There were no significant differences in the complication rates (5.9 % vs. 8.1 %; P = 1.00). CONCLUSIONS: The CSM with PLT was effective and safe in this study. PMID- 26517846 TI - Management of the complications of submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors. AB - BACKGROUND AND STUDY AIMS: Submucosal tunneling endoscopic resection (STER) has become a potential option for the endoscopic treatment of a selected group of patients with submucosal tumors (SMTs) originating from the muscularis propria layer in the upper gastrointestinal tract. The aim of this retrospective study was to analyze the incidence and management of STER-related complications. PATIENTS AND METHODS: From January 2011 to August 2013, 290 patients with upper gastrointestinal SMTs treated by STER were included in the study. Clinicopathological characteristics and complication data were collected and analyzed retrospectively. RESULTS: Mucosal injury occurred in three cases (1.0 %) and major bleeding occurred in five cases (1.7 %). The gas-related complications were very common; however, only nine cases of major pneumothorax (> 30 % lung collapse) needed therapeutic intervention (3.1 %). Thoracic effusion occurred in 49 patients, 11 of whom had low grade fever or segmental atelectasis that required thoracentesis and drainage (3.8 %). Thus, although the overall incidence of complications was 23.4 % (68/290), only 10.0 % of procedures (29/290) required intervention for complications. Based on the statistical analysis, irregular shape, tumor in the deep muscularis propria layer, long procedure time, and air insufflation were risk factors of STER-related major complications. CONCLUSION: Although the incidence of STER-related complications was relatively high, most of these complications were minor and did not require therapeutic intervention. STER is a safe technique for the treatment of upper gastrointestinal SMTs. PMID- 26517847 TI - Design of the Polish Colonoscopy Screening Program: a randomized health services study. AB - BACKGROUND AND STUDY AIMS: Colonoscopy screening for colorectal cancer has been implemented without evidence from randomized controlled trials quantifying its benefit and invariably as an opportunistic program, both of which are contrary to the European Union guideline recommendations. The aim of this paper is to describe the rationale and design of the first population-based colonoscopy screening program (PCSP), which was launched in Poland in 2012 as a randomized health services (RHS) study. METHODS: The PCSP is a natural extension of opportunistic colonoscopy screening implemented in 2000. It uses colonoscopy capacity, a quality assurance program, and a network of 92 centers built up during the opportunistic screening phase to develop a countrywide PCSP. Within the PCSP, single screening colonoscopy is offered to a target population aged 55 64 years. The PCSP uses an RHS design, which means that eligible individuals drawn from population registries are randomly assigned to immediate or postponed invitation to screening. Individuals from birth cohorts that will reach the upper age limit for screening before full implementation of the PCSP are randomly assigned, in a 1:1:1 ratio, to "immediate" screening, "postponed" screening, or a "never invited" control group. The RHS design is a natural platform that will evaluate the effectiveness of screening, and compare different age ranges for screening, invitation procedures, and quality improvement interventions. Up to 2015, 24 centers have been developed, with 34.2% geographic coverage and 851,535 individuals enrolled. CONCLUSIONS: The PCSP sets an example for implementation of population-based colonoscopy screening with experimental design to ensure proper evaluation of its effectiveness. PMID- 26517848 TI - Endoscopic ultrasound-guided choledochoduodenostomy vs. transpapillary stenting for distal biliary obstruction. AB - BACKGROUND AND STUDY AIMS: Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) has gained popularity as an alternative to percutaneous biliary drainage for patients in whom endoscopic retrograde cholangiopancreatography has failed. There are no previous studies comparing EUS-CDS with endoscopic transpapillary stenting (ETS) as first-line treatment for distal malignant obstruction. The aim of this study was to compare the clinical efficacy and safety of EUS-CDS and ETS as first-line treatment in patients with distal malignant biliary obstruction. PATIENTS AND METHODS: A total of 82 patients with distal malignant biliary obstruction underwent initial biliary drainage using self-expandable metal stents at a tertiary care university hospital. ETS was performed between June 2009 and May 2012, and EUS-CDS was performed between May 2012 and March 2014. Clinical success rates, adverse event rates, and reintervention rates were retrospectively evaluated for EUS-CDS and ETS. RESULTS: A total of 26 patients underwent EUS-CDS and 56 underwent ETS. Clinical success rates were equivalent between the groups (EUS-CDS 96.2 %, ETS 98.2 %; P = 0.54). The mean procedure time was significantly shorter with EUS-CDS than with ETS (19.7 vs. 30.2 minutes; P < 0.01). The rate of overall adverse events was not significantly different between the groups (EUS-CDS 26.9 %, ETS 35.7 %; P = 0.46). Post-procedural pancreatitis was only observed in the ETS group (0 % vs. 16.1 %; P = 0.03). The reintervention rate at 1 year was 16.6 % and 13.6 % for EUS-CDS and ETS, respectively (P = 0.50). CONCLUSIONS: EUS-CDS performed by expert endoscopists was associated with a short procedure time and no risk of pancreatitis, and would therefore be feasible as a first-line treatment for patients with distal malignant biliary obstruction. PMID- 26517849 TI - cAMP and cGMP Play an Essential Role in Galvanotaxis of Cell Fragments. AB - Cell fragments devoid of the nucleus and major organelles are found in physiology and pathology, for example platelets derived from megakaryocytes, and cell fragments from white blood cells and glioma cells. Platelets exhibit active chemotaxis. Fragments from white blood cells display chemotaxis, phagocytosis, and bactericidal functions. Signaling mechanisms underlying migration of cell fragments are poorly understood. Here we used fish keratocyte fragments and demonstrated striking differences in signal transduction in migration of cell fragments and parental cells in a weak electric field. cAMP or cGMP agonists completely abolished directional migration of fragments, but had no effect on parental cells. The inhibition effects were prevented by pre-incubating with cAMP and cGMP antagonists. Blocking cAMP and cGMP downstream signaling by inhibition of PKA and PKG also recovered fragment galvanotaxis. Both perturbations confirmed that the inhibitory effect was mediated by cAMP or cGMP signaling. Inhibition of cathode signaling with PI3K inhibitor LY294002 also prevented the effects of cAMP or cGMP agonists. Our results suggest that cAMP and cGMP are essential for galvanotaxis of cell fragments, in contrast to the signaling mechanisms in parental cells. PMID- 26517850 TI - UHPLC-MS/MS method with automated on-line solid phase extraction for the quantification of entecavir in peripheral blood mononuclear cells of HBV+ patients. AB - To date five nucleoside analogs are used in the treatment of chronic hepatitis B: among these, entecavir is the most used. Nevertheless a few information about its distribution in tissues is currently known. Since the determination of entecavir disposition in the hepatocytes is impracticable because of its invasiveness, the quantification in an "easier-to-obtain" cellular model could be a good choice. In this work, we developed and validated an ultra performance liquid chromatography tandem mass spectrometry assay based on an automated on-line SPE, to quantify entecavir concentrations in peripheral blood mononucleated cells (PBMCs), in both its phosphorylated and un-phosphorylated forms. To achieve this, each PBMC isolate was divided in two aliquots, one was treated with acid phosphatase to convert entecavir phosphorylated metabolites into free form, the other one was not-treated. Standards and quality controls were prepared in PBMCs, isolated from healthy donors, and underwent the same process. 20 MUL of the resulting solutions were injected in the on-line SPE system. Thymidine was used as internal standard. Calibration curves fitted a linear model for entecavir levels in a range from 0.039 ng to 5 ng (mean r(2)=0.998). Accuracy, intra-day and inter-day precision of the method fitted FDA guidelines recommendations. Moreover, recovery was consistent and matrix effect resulted low and reproducible. We tested this method by monitoring entecavir concentrations in PBMCs from 28HBV mono-infected patients, confirming its reliability and suitability for the evaluation of intracellular entecavir penetration. PMID- 26517851 TI - Use of 'dilute-and-shoot' liquid chromatography-high resolution mass spectrometry in preclinical research: application to a DMPK study of perhexiline in mouse plasma. AB - This work describes a simple, sensitive and rapid liquid chromatography-high resolution mass spectrometry method for the quantitation of perhexiline and the simultaneous detection of perhexiline metabolites in C57bl/6 mice plasma. Only 5 MUL of plasma was used for analysis. Pretreatment was limited to a 100-fold dilution ('dilute-and-shoot'). The analyte was detected by high resolution mass spectrometry (OrbitrapTM technology). Three scan events were performed over the entire chromatogram. Targeted single ion monitoring with data dependent acquisition was employed for perhexiline quantitation and confirmation, while full scan was used to perform untargeted detection of perhexiline phase I and phase II circulating metabolites. The calibration curve was linear (r(2)=0.990) ranging from 0.305 ng/mL (LLOQ) to 10000 ng/mL. Matrix effect was limited to 6.1%. The method was applied to a pharmacokinetic study of perhexiline in mouse plasma and the results obtained were compared to a standard sample preparation method based on protein precipitation and liquid chromatography-tandem mass spectrometry (MRM mode) detection. The new approach provided comparable results in terms of pharmacokinetics parameters estimate with a high sensitivity, additional information on perhexiline circulating metabolites and a low consumption of biological sample. The combination of the 'dilute-and-shoot' approach together with HRMS targeted and untargeted detection represents a suitable alternative to classic bioanalytical approaches in preclinical research. PMID- 26517852 TI - Development and validation of an enantioselective LC-MS/MS method for the analysis of the anthelmintic drug praziquantel and its main metabolite in human plasma, blood and dried blood spots. AB - Praziquantel (PZQ) is the treatment of choice against various trematode and cestode infections. To study the pharmacokinetics of PZQ in patients infected with the liver fluke Opisthorchis viverrini, we developed and validated an enantioselective liquid chromatography coupled to tandem mass spectrometry method for the analysis of R - and S -PZQ and its R -trans-4-OH-PZQ metabolite in human plasma, blood and dried blood spots (DBS). The analytes were detected in the positive mode using selected reaction monitoring (R- and S-PZQ: m/z 312.2 -> 202.2; R-trans -4-OH-PZQ: m/z 328.0 -> 202.0). Prior to the chiral separation with a cellulose tris(3-chloro-4-methylphenylcarbamate) column, the analytes were purified from matrix contaminants and concentrated on a C-18 trapping column. The analytical range for each PZQ enantiomer was 0.01-2.5 MUg/mL, and 0.1-25 MUg/mL for the metabolite. The method met the requirements regarding precision (+/- 15%, +/- 20% at the lower limit of quantification-LLOQ), intra- and inter-assay accuracy (85-115%, 80-120% at LLOQ), and linearity (R(2) >= 0.998). The analytes were stable in stock solutions as well as in plasma, blood and DBS. For DBS, the influences of hematocrit and blood spot size were considered as minor. Our validation results show that the method presented here is precise, accurate and selective, and can be used for pharmacokinetic studies. Moreover, the enantioselective separation was achieved with a run time of 11.5 min and a simple sample processing method. PMID- 26517853 TI - Freshwater clam extract supplement-induced acute cholestasis. PMID- 26517855 TI - Intrathecal Baclofen Dosing Regimens: A Retrospective Chart Review. AB - OBJECTIVES: To examine dosing patterns in patients receiving baclofen via intrathecal baclofen pumps to assess for common patterns by diagnosis, ambulation ability, and affected limbs distribution. MATERIALS AND METHODS: This trial study included 25 patients with baclofen pumps selected from the 356 patients enrolled in our center's baclofen pump program. Selection was done by splitting all patients into diagnostic categories of stroke, multiple sclerosis, traumatic/anoxic brain injury, cerebral palsy, and spinal cord injury, and then, five patients were randomly selected from each diagnosis.A systematic chart review was then conducted for each patient from Jan 1, 2008, through September 16, 2013, to look at factors including mean daily dose at end of study, and among those implanted during the study mean initial stable dose and time to initial stable dose. RESULTS: Analysis of mean daily dose across diagnoses found significant differences, with brain injury, cerebral palsy, and spinal cord injury patients having higher doses while multiple sclerosis and stroke patients required lower doses. Nonambulatory patients strongly trended to have higher daily doses than ambulatory patients. Similar trends of mean initial stable dose being higher in a similar pattern as that of end mean daily dose were seen according to diagnoses and ambulatory status, although statistical significance could not be achieved with the small sample size. CONCLUSION: Significant differences in dosing were found between diagnoses and trended to differ by ambulatory status at the end of the study, and similar trends could be observed in achieving initial stable dose. PMID- 26517856 TI - Effects of Preoperative beta-Blocker Use on Clinical Outcomes after Coronary Artery Bypass Grafting: A Report from the Japanese Cardiovascular Surgery Database. AB - BACKGROUND: The authors evaluated the effect of preoperative beta-blocker use on early outcomes in patients undergoing coronary artery bypass grafting (CABG) in Japan. METHODS: The authors analyzed 34,980 cases of isolated CABGs, performed between 2008 and 2011, at the 333 sites recorded in the Japanese Cardiovascular Surgical Database. In addition to the use of multivariate models, a one-to-one matched analysis, based on estimated propensity scores for patients with or without preoperative beta-blocker use, was performed. RESULTS: The study population (mean age, 68 yr) comprised 20% women, and beta-blockers were used in 10,496 patients (30%), who were more likely to have risk factors and comorbidities than patients in whom beta-blockers were not used. In the beta blocker and non-beta-blocker groups, the crude in-hospital mortality rate was 1.7 versus 2.5%, whereas the composite complication rate was 9.7 versus 11.6%, respectively. However, after adjustment, preoperative beta-blocker use was not a predictor of in-hospital mortality (odds ratio, 1.00; 95% CI, 0.82 to 1.21) or complications (odds ratio, 0.99; 95% CI, 0.91 to 1.08). When the outcomes of the two propensity-matched patient groups were compared, differences were not seen in the 30-day operative mortality (1.6 vs. 1.5%, respectively; P = 0.49) or postoperative complication (9.8 vs. 9.7%; P = 1.00) rates. The main findings were broadly consistent in a subgroup analysis of low-risk and high-risk groups. CONCLUSION: In this nationwide registry, the use of preoperative beta-blockers did not affect short-term mortality or morbidity in patients undergoing CABG. PMID- 26517857 TI - Management of the Traumatized Airway. AB - There is a lack of evidence-based approach regarding the best practice for airway management in patients with a traumatized airway. General recommendations for the management of the traumatized airway are summarized in table 5. Airway trauma may not be readily apparent, and its evaluation requires a high level of suspicion for airway disruption and compression. For patients with facial trauma, control of the airway may be significantly impacted by edema, bleeding, inability to clear secretions, loss of bony support, and difficulty with face mask ventilation. With the airway compression from neck swelling or hematoma, intubation attempts can further compromise the airway due to expanding hematoma. For patients with airway disruption, the goal is to pass the tube across the injured area without disrupting it or to insert the airway distal to the injury using a surgical approach. If airway injury is extensive, a surgical airway distal to the site of injury may be the best initial approach. Alternatively, if orotracheal intubation is chosen, spontaneous ventilation may be maintained or RSI may be performed. RSI is a common approach. Thus, some of the patients intubated may subsequently require tracheostomy. A stable patient with limited injuries may not require intubation but should be watched carefully for at least several hours. Because of a paucity of evidence-based data, the choice between these approaches and the techniques utilized is a clinical decision depending on the patient's condition, clinical setting, injuries to airway and other organs, and available personnel, expertise, and equipment. Inability to obtain a definitive airway is always an absolute indication for an emergency cricothyroidotomy or surgical tracheostomy. PMID- 26517859 TI - A nanogroove-guided slot-die coating technique for highly ordered polymer films and high-mobility transistors. AB - A nanogroove-guided slot-die coating technique has been developed to manipulate the alignment of polymer chains within a short processing time. A combination of directional movement of slot-die and uniaxial nanogrooves on the substrate for the unidirectional flow of solution suppresses the multiple degrees of conformational freedom, resulting in long-range oriented polymer films and a high field effect mobility of ~5 cm(2) V(-1) s(-1). PMID- 26517858 TI - Efficacy of Duloxetine in Chronic Low Back Pain with a Neuropathic Component: A Randomized, Double-blind, Placebo-controlled Crossover Trial. AB - BACKGROUND: Among patients with chronic low back pain (CLBP), approximately 37% show signs of a neuropathic pain component (radicular pain). Treatment of this condition remains challenging. Therefore, the current study aimed to investigate the efficacy of duloxetine in the treatment of CLBP patients with neuropathic leg pain. METHODS: The study was conducted as a prospective, randomized, placebo controlled, double-blind crossover trial. CLBP with a visual analog scale (VAS) score greater than 5 and a neuropathic component that was assessed clinically and by the painDETECT questionnaire (score > 12) were required for inclusion. Patients were randomly assigned to either duloxetine or placebo for 4 weeks followed by a 2-week washout period before they crossed over to the alternate phase that lasted another 4 weeks. Duloxetine was titrated up to 120 mg/day. The primary outcome parameter was mean VAS score during the last week of treatment in each phase (VAS(week4)). RESULTS: Of 41 patients, 21 patients completed both treatment phases. In the intention-to-treat analysis (n = 25), VAS(week4) was significantly lower in the duloxetine phase compared with placebo (4.1 +/- 2.9 vs. 6.0 +/- 2.7; P = 0.001), corresponding to an average pain reduction of 32%. The painDETECT score at the end of each treatment phase was significantly lower in the duloxetine phase compared with placebo (17.7 +/- 5.7 vs. 21.3 +/- 3.6 points; P = 0.0023). Adverse events were distributed equally between the duloxetine (65%) and placebo phases (62%) (P = 0.5). CONCLUSION: In this crossover study, duloxetine proved to be superior to placebo for the treatment of CLBP with a neuropathic leg pain. PMID- 26517860 TI - Temporal Gillespie Algorithm: Fast Simulation of Contagion Processes on Time Varying Networks. AB - Stochastic simulations are one of the cornerstones of the analysis of dynamical processes on complex networks, and are often the only accessible way to explore their behavior. The development of fast algorithms is paramount to allow large scale simulations. The Gillespie algorithm can be used for fast simulation of stochastic processes, and variants of it have been applied to simulate dynamical processes on static networks. However, its adaptation to temporal networks remains non-trivial. We here present a temporal Gillespie algorithm that solves this problem. Our method is applicable to general Poisson (constant-rate) processes on temporal networks, stochastically exact, and up to multiple orders of magnitude faster than traditional simulation schemes based on rejection sampling. We also show how it can be extended to simulate non-Markovian processes. The algorithm is easily applicable in practice, and as an illustration we detail how to simulate both Poissonian and non-Markovian models of epidemic spreading. Namely, we provide pseudocode and its implementation in C++ for simulating the paradigmatic Susceptible-Infected-Susceptible and Susceptible Infected-Recovered models and a Susceptible-Infected-Recovered model with non constant recovery rates. For empirical networks, the temporal Gillespie algorithm is here typically from 10 to 100 times faster than rejection sampling. PMID- 26517861 TI - Glia-Mediated Retinal Neuroinflammation as a Biomarker in Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common type of dementia worldwide; it is characterized by a progressive decline in cognitive functions and memory, resulting from synaptic and cell loss, and accompanied by a strong neuroinflammatory response. Besides the vast progress in the understanding of the pathophysiology of AD in the past decades, there is still no effective treatment. Moreover, the diagnosis occurs usually at an advanced stage of the disease, where the neurological damage has already occurred. The identification of biomarkers that would allow an early diagnosis of this disease is a major goal that would also help managing AD progression. Due to its cellular and physiological resemblances with the brain, the retina has long been regarded as a window to the brain. Several brain manifestations have been associated with retinal alterations. In AD patients, some structural and functional alterations in the retina can be associated with disease onset. However, only a few studies have focused on the alterations in retinal glial cells associated with AD. This review aims at giving an overview of the AD-associated retinal alterations, particularly in glial cells. The documented alterations in retinal glia will be discussed concerning their potential to predict the brain alterations occurring in AD. PMID- 26517862 TI - Editorial: Recent Advances in Developmental Drug Disposition. PMID- 26517863 TI - Correction: Modeling the Citation Network by Network Cosmology. PMID- 26517865 TI - Correction: Formation of a Polarised Primitive Endoderm Layer in Embryoid Bodies Requires Fgfr/Erk Signalling. PMID- 26517864 TI - Exogenous Bradykinin Inhibits Tissue Factor Induction and Deep Vein Thrombosis via Activating the eNOS/Phosphoinositide 3-Kinase/Akt Signaling Pathway. AB - BACKGROUND/AIMS: Bradykinin has been shown to exert a variety of protective effects against vascular injury, and to reduce the levels of several factors involved in the coagulation cascade. A key determinant of thrombin generation is tissue factor (TF). However, whether bradykinin can regulate TF expression remains to be investigated. METHODS: To study the effect of bradykinin on TF expression, we used Lipopolysaccharides (LPS) to induce TF expression in human umbilical vein endothelial cells and monocytes. Transcript levels were determined by RT-PCR, protein abundance by Western blotting. In the in vivo study, bradykinin and equal saline were intraperitoneally injected into mice for three days ahead of inferior cava vein ligation that we took to induce thrombus formation, after which bradykinin and saline were injected for another two days. Eventually, the mice were sacrificed and tissues were harvested for tests. RESULTS: Exogenous bradykinin markedly inhibited TF expression in mRNA and protein level induced by LPS in a dose-dependent manner. Moreover, the NO synthase antagonist L-NAME and PI3K inhibitor LY294002 dramatically abolished the inhibitory effects of bradykinin on tissue factor expression. PI3K/Akt signaling pathway activation induced by bradykinin administration reduced the activity of GSK-3beta and MAPK, and reduced NF-x03BA;B level in the nucleus, thereby inhibiting TF expression. Consistent with this, intraperitoneal injection of C57/BL6 mice with bradykinin also inhibited the thrombus formation induced by ligation of inferior vena cava. CONCLUSION: Bradykinin suppressed TF protein expression in human umbilical vein endothelial cells and monocytes in vitro; in line with this, it inhibits thrombus formation induced by ligation of inferior vena cava in vivo. PMID- 26517866 TI - Correction: The Role of Self-Compassion in Buffering Symptoms of Depression in the General Population. PMID- 26517867 TI - Effects of High-Intensity Interval Training versus Continuous Training on Physical Fitness, Cardiovascular Function and Quality of Life in Heart Failure Patients. AB - INTRODUCTION: Physical fitness is an important prognostic factor in heart failure (HF). To improve fitness, different types of exercise have been explored, with recent focus on high-intensity interval training (HIT). We comprehensively compared effects of HIT versus continuous training (CT) in HF patients NYHA II III on physical fitness, cardiovascular function and structure, and quality of life, and hypothesize that HIT leads to superior improvements compared to CT. METHODS: Twenty HF patients (male:female 19:1, 64+/-8 yrs, ejection fraction 38+/ 6%) were allocated to 12-weeks of HIT (10*1-minute at 90% maximal workload alternated by 2.5 minutes at 30% maximal workload) or CT (30 minutes at 60-75% of maximal workload). Before and after intervention, we examined physical fitness (incremental cycling test), cardiac function and structure (echocardiography), vascular function and structure (ultrasound) and quality of life (SF-36, Minnesota living with HF questionnaire (MLHFQ)). RESULTS: Training improved maximal workload, peak oxygen uptake (VO2peak) related to the predicted VO2peak, oxygen uptake at the anaerobic threshold, and maximal oxygen pulse (all P<0.05), whilst no differences were present between HIT and CT (N.S.). We found no major changes in resting cardiovascular function and structure. SF-36 physical function score improved after training (P<0.05), whilst SF-36 total score and MLHFQ did not change after training (N.S.). CONCLUSION: Training induced significant improvements in parameters of physical fitness, although no evidence for superiority of HIT over CT was demonstrated. No major effect of training was found on cardiovascular structure and function or quality of life in HF patients NYHA II-III. TRIAL REGISTRATION: Nederlands Trial Register NTR3671. PMID- 26517868 TI - Composition of Overlapping Protein-Protein and Protein-Ligand Interfaces. AB - Protein-protein interactions (PPIs) play a major role in many biological processes and they represent an important class of targets for therapeutic intervention. However, targeting PPIs is challenging because often no convenient natural substrates are available as starting point for small-molecule design. Here, we explored the characteristics of protein interfaces in five non-redundant datasets of 174 protein-protein (PP) complexes, and 161 protein-ligand (PL) complexes from the ABC database, 436 PP complexes, and 196 PL complexes from the PIBASE database and a dataset of 89 PL complexes from the Timbal database. In all cases, the small molecule ligands must bind at the respective PP interface. We observed similar amino acid frequencies in all three datasets. Remarkably, also the characteristics of PP contacts and overlapping PL contacts are highly similar. PMID- 26517869 TI - Correction: Toxoplasma gondii Infection in Alpine Red Deer (Cervus elaphus): Its Spread and Effects on Fertility. PMID- 26517870 TI - Association between the BsmI Polymorphism in the Vitamin D Receptor Gene and Breast Cancer Risk: Results from a Pakistani Case-Control Study. AB - BACKGROUND: Vitamin D is postulated to decrease the risk of breast cancer by inhibiting cell proliferation via the vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNPs) in the VDR gene, rs1544410 (BsmI) and rs2228570 (FokI), are inconsistently associated with breast cancer risk in Caucasian populations, while data for Asians are scarce. Here, we investigated the possible contribution of these SNPs to breast cancer risk in Pakistani breast cancer patients and in controls participating in a hospital-based breast cancer case control study (PAK-BCCC). METHODS: Genotyping of the BsmI and FokI SNPs was performed by PCR-based restriction fragment length polymorphism (RFLP) analysis of 463 genetically enriched female breast cancer cases with known BRCA1/2 status and in 1,012 controls from Pakistan. The association between SNP genotypes and breast cancer risk was investigated by logistic regression adjusted for potential breast cancer risk factors and stratified by BRCA1/2 status and family history. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. RESULTS: The b allele of the BsmI was associated with an increased breast cancer risk (per b allele OR 1.28, 95% CI 1.09-1.49, P = 0.003). Subgroup analysis revealed that this effect was restricted to BRCA1/2 non-carriers (per b allele OR 1.33, 95% CI 1.11-1.59, P = 0.002) and was stronger in those who reported a positive family history of breast and/or ovarian cancer (per b allele OR 1.64, 95% CI 1.20-2.22, P = 0.002). No association with breast cancer risk was detected for the FokI SNP. CONCLUSIONS: The BsmI polymorphism in the VDR gene may be associated with an increased breast cancer risk in Pakistani women negative for BRCA1/2 germline mutations. PMID- 26517871 TI - Dynamic Metabolic Disruption in Rats Perinatally Exposed to Low Doses of Bisphenol-A. AB - Along with the well-established effects on fertility and fecundity, perinatal exposure to endocrine disrupting chemicals, and notably to xeno-estrogens, is strongly suspected of modulating general metabolism. The metabolism of a perinatally exposed individual may be durably altered leading to a higher susceptibility of developing metabolic disorders such as obesity and diabetes; however, experimental designs involving the long term study of these dynamic changes in the metabolome raise novel challenges. 1H-NMR-based metabolomics was applied to study the effects of bisphenol-A (BPA, 0; 0.25; 2.5, 25 and 250 MUg/kg BW/day) in rats exposed perinatally. Serum and liver samples of exposed animals were analyzed on days 21, 50, 90, 140 and 200 in order to explore whether maternal exposure to BPA alters metabolism. Partial Least Squares-Discriminant Analysis (PLS-DA) was independently applied to each time point, demonstrating a significant pair-wise discrimination for liver as well as serum samples at all time-points, and highlighting unequivocal metabolic shifts in rats perinatally exposed to BPA, including those exposed to lower doses. In BPA exposed animals, metabolism of glucose, lactate and fatty acids was modified over time. To further explore dynamic variation, ANOVA-Simultaneous Component Analysis (A-SCA) was used to separate data into blocks corresponding to the different sources of variation (Time, Dose and Time*Dose interaction). A-SCA enabled the demonstration of a dynamic, time/age dependent shift of serum metabolome throughout the rats' lifetimes. Variables responsible for the discrimination between groups clearly indicate that BPA modulates energy metabolism, and suggest alterations of neurotransmitter signaling, the latter finding being compatible with the neurodevelopmental effect of this xenoestrogen. In conclusion, long lasting metabolic effects of BPA could be characterized over 200 days, despite physiological (and thus metabolic) changes connected with sexual maturation and aging. PMID- 26517872 TI - Theroa zethus Caterpillars Use Acid Secretion of Anti-Predator Gland to Deactivate Plant Defense. AB - In North America, notodontid caterpillars feed almost exclusively on hardwood trees. One notable exception, Theroa zethus feeds instead on herbaceous plants in the Euphorbiaceae protected by laticifers. These elongate canals follow leaf veins and contain latex under pressure; rupture causes the immediate release of sticky poisonous exudate. T. zethus larvae deactivate the latex defense of poinsettia and other euphorbs by applying acid from their ventral eversible gland, thereby creating furrows in the veins. The acid secretion softens the veins allowing larvae to compress even large veins with their mandibles and to disrupt laticifers internally often without contacting latex. Acid secretion collected from caterpillars and applied to the vein surface sufficed to create a furrow and to reduce latex exudation distal to the furrow where T. zethus larvae invariably feed. Larvae with their ventral eversible gland blocked were unable to create furrows and suffered reduced growth on poinsettia. The ventral eversible gland in T. zethus and other notodontids ordinarily serves to deter predators; when threatened, larvae spray acid from the gland orifice located between the mouthparts and first pair of legs. To my knowledge, T. zethus is the first caterpillar found to use an antipredator gland for disabling plant defenses. The novel combination of acid application and vein constriction allows T. zethus to exploit its unusual latex-bearing hosts. PMID- 26517873 TI - Feeding on Host Plants with Different Concentrations and Structures of Pyrrolizidine Alkaloids Impacts the Chemical-Defense Effectiveness of a Specialist Herbivore. AB - Sequestration of chemical defenses from host plants is a strategy widely used by herbivorous insects to avoid predation. Larvae of the arctiine moth Utetheisa ornatrix feeding on unripe seeds and leaves of many species of Crotalaria (Leguminosae) sequester N-oxides of pyrrolizidine alkaloids (PAs) from these host plants, and transfer them to adults through the pupal stage. PAs confer protection against predation on all life stages of U. ornatrix. As U. ornatrix also uses other Crotalaria species as host plants, we evaluated whether the PA chemical defense against predation is independent of host plant use. We fed larvae from hatching to pupation with either leaves or seeds of one of eight Crotalaria species (C. incana, C. juncea, C. micans, C. ochroleuca, C. pallida, C. paulina, C. spectabilis, and C. vitellina), and tested if adults were preyed upon or released by the orb-weaving spider Nephila clavipes. We found that the protection against the spider was more effective in adults whose larvae fed on seeds, which had a higher PA concentration than leaves. The exceptions were adults from larvae fed on C. paulina, C. spectabilis and C. vitellina leaves, which showed high PA concentrations. With respect to the PA profile, we describe for the first time insect-PAs in U. ornatrix. These PAs, biosynthesized from the necine base retronecine of plant origin, or monocrotaline- and senecionine-type PAs sequestered from host plants, were equally active in moth chemical defense, in a dose-dependent manner. These results are also partially explained by host plant phylogeny, since PAs of the host plants do have a phylogenetic signal (clades with high and low PA concentrations in leaves) which is reflected in the adult defense. PMID- 26517874 TI - Rationality of Antimicrobial Prescriptions in Community Pharmacy Users. AB - BACKGROUND: Although there is a conflict between the treatment benefits for a single individual and society, restrictions on antibiotic use are needed to reduce the prevalence of resistance to these drugs, which is the main result of irrational use. Brazil, cataloged as a pharmemerging market, has implemented restrictive measures for the consumption of antibiotics. The objective of this study was to investigate the quality of antimicrobial prescriptions and user knowledge of their treatment with these drugs. METHODS AND FINDINGS: A two-stage cross-sectional, combined and stratified survey of pharmacy users holding an antimicrobial prescription was conducted in the community between May and November 2014. A pharmacist analyzed each prescription for legibility and completeness, and applied a structured questionnaire to the users or their caregivers on their knowledge regarding treatment and user sociodemographic data. An estimated 29.3% of prescriptions had one or more illegible items, 91.3% had one or more missing items, and 29.0% had both illegible and missing items. Dosing schedule and patient identification were the most commonly unreadable items in prescriptions, 18.81% and 12.14%, respectively. The lack of complete patient identification occurred in 90.53% of the prescriptions. It is estimated that 40.3% of users have used antimicrobials without prescription and that 46.49% did not receive any guidance on the administration of the drug. CONCLUSIONS: Despite the measures taken by health authorities to restrict the misuse of antimicrobials, it was observed that prescribers still do not follow the criteria of current legislation, particularly relating to items needed for completion of the prescription. Moreover, users receive little information about their antimicrobial treatment. PMID- 26517875 TI - Orally-Induced Intestinal CD4+ CD25+ FoxP3+ Treg Controlled Undesired Responses towards Oral Antigens and Effectively Dampened Food Allergic Reactions. AB - The induction of peripheral tolerance may constitute a disease-modifying treatment for allergic patients. We studied how oral immunotherapy (OIT) with milk proteins controlled allergy in sensitized mice (cholera toxin plus milk proteins) upon exposure to the allergen. Symptoms were alleviated, skin test was negativized, serum specific IgE and IgG1 were abrogated, a substantial reduction in the secretion of IL-5 and IL-13 by antigen-stimulated spleen cells was observed, while IL-13 gene expression in jejunum was down-regulated, and IL-10 and TGF-beta were increased. In addition, we observed an induction of CD4+CD25+FoxP3+ cells and IL-10- and TGF-beta-producing regulatory T cells in the lamina propria. Finally, transfer experiments confirmed the central role of these cells in tolerance induction. We demonstrated that the oral administration of milk proteins pre- or post-sensitization controlled the Th2-immune response through the elicitation of mucosal IL-10- and TGF-beta-producing Tregs that inhibited hypersensitivity symptoms and the allergic response. PMID- 26517876 TI - Affect and Cognition in Attitude Formation toward Familiar and Unfamiliar Attitude Objects. AB - At large attitudes are built on earlier experience with the attitude object. If earlier experiences are not available, as is the case for unfamiliar attitude objects such as new technologies, no stored evaluations exist. Yet, people are still somehow able to construct attitudes on the spot. Depending on the familiarity of the attitude object, attitudes may find their basis more in affect or cognition. The current paper investigates differences in reliance on affect or cognition in attitude formation toward familiar and unfamiliar realistic attitude objects. In addition, individual differences in reliance on affect (high faith in intuition) or cognition (high need for cognition) are taken into account. In an experimental survey among Dutch consumers (N = 1870), we show that, for unfamiliar realistic attitude objects, people rely more on affect than cognition. For familiar attitude objects where both affective and cognitive evaluations are available, high need for cognition leads to more reliance on cognition, and high faith in intuition leads to more reliance on affect, reflecting the influence of individually preferred thinking style. For people with high need for cognition, cognition has a higher influence on overall attitude for both familiar and unfamiliar realistic attitude objects. On the other hand, affect is important for people with high faith in intuition for both familiar and unfamiliar attitude objects and for people with low faith in intuition for unfamiliar attitude objects; this shows that preferred thinking style is less influential for unfamiliar objects. By comparing attitude formation for familiar and unfamiliar realistic attitude objects, this research contributes to understanding situations in which affect or cognition is the better predictor of overall attitudes. PMID- 26517877 TI - Pilot Field Trial of the EG95 Vaccine Against Ovine Cystic Echinococcosis in Rio Negro, Argentina: Second Study of Impact. AB - BACKGROUND: Cystic echinococcosis (CE) is an important zoonotic disease caused by the cestode parasite Echinococcus granulosus. It occurs in many parts of the world where pastoral activities predominate, including the Rio Negro province of Argentina. Although CE control activities have been undertaken in the western regions of Rio Negro for more than two decades, the disease continues to remain prevalent in both the human and livestock animal populations. Vaccination of animal intermediate hosts of CE with the EG95 vaccine may provide a new opportunity to improve the effectiveness of CE control measures, although data are lacking about field application of the vaccine. AIMS: Evaluate the impact of EG95 vaccination in sheep on the transmission of Echinococcus granulosus in a field environment. METHODOLOGY: Two trial sites were established in western Rio Negro province within indigenous communities. Vaccination of lambs born into one trial site was introduced and continued for 6 years. Prior to initiation of the trial, and at the end of the trial, the prevalence of CE in sheep was determined by necropsy. Weaned lambs received two injections of EG95 vaccine, approximately one month apart, and a single booster injection one year later. Vaccination was not implemented at the second trial site. A total of 2725 animals were vaccinated in the first year. Animals from this cohort as well as age-matched sheep from the control area were evaluated by necropsy. KEY RESULTS: Introduction of the vaccine led to a statistically significant in the number and size of hydatid cysts in comparison to the situation prior to the introduction of the vaccine, or compared to CE prevalence in the control area where the vaccine was not applied. The prevalence of infection in the vaccinated area was also significantly reduced by 62% compared to the re-intervention level, being lower than the prevalence seen in the control area, although the difference from the control area after the intervention was not significant possibly due to limitations in the numbers of animals available for necropsy. CONCLUSIONS: Vaccination of sheep with the EG95 vaccine provides a valuable new tool which improves the effectiveness of CE control activities. Vaccination was effective even in a difficult, remote environment where only approximately half the lambs born into the communities were fully vaccinated. PMID- 26517878 TI - The Role of Long Polar Fimbriae in Escherichia coli O104:H4 Adhesion and Colonization. AB - A renewed interest in Shiga toxin-producing Escherichia coli (STEC) strains was sparked due to the appearance of an outbreak in 2011, causing 3,816 diarrheal cases and some deaths in Europe. The causative strain was classified as enteroaggregative E. coli of serotype O104:H4 that had acquired Shiga toxin genes. The ability of STEC O104:H4 to cause disease relies greatly on the bacteria's capacity to colonize, persist, and produce Shiga toxin. However, not much is known about the colonization factors of this strain. Because long polar fimbriae (lpf) lpf1 and lpf2 operons encode important colonization factors in other STEC isolates and E. coli O104:H4 possesses both loci, we hypothesized that Lpf is required for adhesion and colonization. In this study, isogenic lpfA1 and lpfA2 major fimbrial subunit mutants were constructed. To determine their role in O104:H4's virulence, we assessed their ability to adhere to non-polarized and polarized intestinal epithelial cells. The DeltalpfA1 showed decreased adherence in both cell systems, while the DeltalpfA2 only showed a decrease in adherence to polarized Caco-2 cells. We also tested the O104:H4 mutants' ability to form biofilm and found that the DeltalpfA1 was unable to form a stable biofilm. In an in vivo murine model of intestinal colonization, the DeltalpfA1 had a reduced ability to colonize the cecum and large intestine, consistent with the in vitro data. Further, we tested the lpfA1 mutants' ability to compete against the wild type. We found that in the in vitro and in vivo models, the presence of the wild type O104:H4 facilitates increased adherence of the DeltalpfA1 to levels exceeding that of the wild type. Overall, our data demonstrated that Lpf1 is one of the factors responsible for O104:H4 intestinal adhesion and colonization. PMID- 26517879 TI - Mapping nonlinear receptive field structure in primate retina at single cone resolution. AB - The function of a neural circuit is shaped by the computations performed by its interneurons, which in many cases are not easily accessible to experimental investigation. Here, we elucidate the transformation of visual signals flowing from the input to the output of the primate retina, using a combination of large scale multi-electrode recordings from an identified ganglion cell type, visual stimulation targeted at individual cone photoreceptors, and a hierarchical computational model. The results reveal nonlinear subunits in the circuity of OFF midget ganglion cells, which subserve high-resolution vision. The model explains light responses to a variety of stimuli more accurately than a linear model, including stimuli targeted to cones within and across subunits. The recovered model components are consistent with known anatomical organization of midget bipolar interneurons. These results reveal the spatial structure of linear and nonlinear encoding, at the resolution of single cells and at the scale of complete circuits. PMID- 26517880 TI - LynA regulates an inflammation-sensitive signaling checkpoint in macrophages. AB - Clustering of receptors associated with immunoreceptor tyrosine-based activation motifs (ITAMs) initiates the macrophage antimicrobial response. ITAM receptors engage Src-family tyrosine kinases (SFKs) to initiate phagocytosis and macrophage activation. Macrophages also encounter nonpathogenic molecules that cluster receptors weakly and must tune their sensitivity to avoid inappropriate responses. To investigate this response threshold, we compared signaling in the presence and absence of receptor clustering using a small-molecule inhibitor of Csk, which increased SFK activation and produced robust membrane-proximal signaling. Surprisingly, receptor-independent SFK activation led to a downstream signaling blockade associated with rapid degradation of the SFK LynA. Inflammatory priming of macrophages upregulated LynA and promoted receptor independent signaling. In contrast, clustering the hemi-ITAM receptor Dectin-1 induced signaling that did not require LynA or inflammatory priming. Together, the basal-state signaling checkpoint regulated by LynA expression and degradation and the signaling reorganization initiated by receptor clustering allow cells to discriminate optimally between pathogens and nonpathogens. PMID- 26517882 TI - Probing the dynamic regulation of peripheral membrane proteins using hydrogen deuterium exchange-MS (HDX-MS). AB - Many cellular signalling events are controlled by the selective recruitment of protein complexes to membranes. Determining the molecular basis for how lipid signalling complexes are recruited, assembled and regulated on specific membrane compartments has remained challenging due to the difficulty of working in conditions mimicking native biological membrane environments. Enzyme recruitment to membranes is controlled by a variety of regulatory mechanisms, including binding to specific lipid species, protein-protein interactions, membrane curvature, as well as post-translational modifications. A powerful tool to study the regulation of membrane signalling enzymes and complexes is hydrogen deuterium exchange-MS (HDX-MS), a technique that allows for the interrogation of protein dynamics upon membrane binding and recruitment. This review will highlight the theory and development of HDX-MS and its application to examine the molecular basis of lipid signalling enzymes, specifically the regulation and activation of phosphoinositide 3-kinases (PI3Ks). PMID- 26517883 TI - Self-generated covalent cross-links in the cell-surface adhesins of Gram-positive bacteria. AB - The ability of bacteria to adhere to other cells or to surfaces depends on long, thin adhesive structures that are anchored to their cell walls. These structures include extended protein oligomers known as pili and single, multi-domain polypeptides, mostly based on multiple tandem Ig-like domains. Recent structural studies have revealed the widespread presence of covalent cross-links, not previously seen within proteins, which stabilize these domains. The cross-links discovered so far are either isopeptide bonds that link lysine side chains to the side chains of asparagine or aspartic acid residues or ester bonds between threonine and glutamine side chains. These bonds appear to be formed by spontaneous intramolecular reactions as the proteins fold and are strategically placed so as to impart considerable mechanical strength. PMID- 26517881 TI - Signalling to eIF4E in cancer. AB - Translational control plays a critical role in the regulation of gene expression in eukaryotes and affects many essential cellular processes, including proliferation, apoptosis and differentiation. Under most circumstances, translational control occurs at the initiation step at which the ribosome is recruited to the mRNA. The eukaryotic translation initiation factor 4E (eIF4E), as part of the eIF4F complex, interacts first with the mRNA and facilitates the recruitment of the 40S ribosomal subunit. The activity of eIF4E is regulated at many levels, most profoundly by two major signalling pathways: PI3K (phosphoinositide 3-kinase)/Akt (also known and Protein Kinase B, PKB)/mTOR (mechanistic/mammalian target of rapamycin) and Ras (rat sarcoma)/MAPK (mitogen activated protein kinase)/Mnk (MAPK-interacting kinases). mTOR directly phosphorylates the 4E-BPs (eIF4E-binding proteins), which are inhibitors of eIF4E, to relieve translational suppression, whereas Mnk phosphorylates eIF4E to stimulate translation. Hyperactivation of these pathways occurs in the majority of cancers, which results in increased eIF4E activity. Thus, translational control via eIF4E acts as a convergence point for hyperactive signalling pathways to promote tumorigenesis. Consequently, recent works have aimed to target these pathways and ultimately the translational machinery for cancer therapy. PMID- 26517885 TI - Bespoke RNA recognition by Pumilios. AB - Pumilio is an RNA-binding protein originally identified in Drosophila, with a Puf domain made up of eight Puf repeats, three helix bundles arranged in a rainbow architecture, where each repeat recognizes a single base of the RNA-binding sequence. The eight-base recognition sequence can therefore be modified simply via mutation of the repeat that recognizes the base to be changed and this is understood in detail via high-resolution crystal structures. The binding mechanism is also altered in a variety of homologues from different species, with bases flipped out from the binding site to regenerate a consensus sequence. Thus Pumilios can be designed with bespoke RNA recognition sequences and can be fused to nucleases, split GFP, etc. as tools in vitro and in cells. PMID- 26517884 TI - The role of chordin fragments generated by partial tolloid cleavage in regulating BMP activity. AB - Chordin-mediated regulation of bone morphogenetic protein (BMP) family growth factors is essential in early embryogenesis and adult homoeostasis. Chordin binds to BMPs through cysteine-rich von Willebrand factor type C (vWC) homology domains and blocks them from interacting with their cell surface receptors. These domains also self-associate and enable chordin to target related proteins to fine-tune BMP regulation. The chordin-BMP inhibitory complex is strengthened by the secreted glycoprotein twisted gastrulation (Tsg); however, inhibition is relieved by cleavage of chordin at two specific sites by tolloid family metalloproteases. As Tsg enhances this cleavage process, it serves a dual role as both promoter and inhibitor of BMP signalling. Recent developments in chordin research suggest that rather than simply being by-products, the cleavage fragments of chordin continue to play a role in BMP regulation. In particular, chordin cleavage at the C terminus potentiates its anti-BMP activity in a type-specific manner. PMID- 26517886 TI - In search of the boundary between repetitive and non-repetitive protein sequences. AB - Tandem repeats (TRs) are frequently not perfect, containing a number of mutations accumulated during evolution. One of the main problems is to distinguish between the sequences that contain highly imperfect TRs and the aperiodic sequences. The majority of proteins with TRs in sequences have repetitive arrangements in their 3D structures. Therefore, the 3D structures of proteins can be used as a benchmarking criterion for TR detection in sequences. Different TR detection tools use their own scoring procedures to determine the boundary between repetitive and non-repetitive protein sequences. Here we described these scoring functions and benchmark them by using known structural TRs. Our survey shows that none of the existing scoring procedures are able to achieve an appropriate separation between genuine structural TRs and non-TR regions. This suggests that if we want to obtain a collection of structurally and functionally meaningful TRs from a large scale analysis of proteomes, the TR scoring metrics need to be improved. PMID- 26517887 TI - Creating functional sophistication from simple protein building blocks, exemplified by factor H and the regulators of complement activation. AB - Complement control protein modules (CCPs) occur in numerous functionally diverse extracellular proteins. Also known as short consensus repeats (SCRs) or sushi domains each CCP contains approximately 60 amino acid residues, including four consensus cysteines participating in two disulfide bonds. Varying in length and sequence, CCPs adopt a beta-sandwich type fold and have an overall prolate spheroidal shape with N- and C-termini lying close to opposite poles of the long axis. CCP-containing proteins are important as cytokine receptors and in neurotransmission, cell adhesion, blood clotting, extracellular matrix formation, haemoglobin metabolism and development, but CCPs are particularly well represented in the vertebrate complement system. For example, factor H (FH), a key soluble regulator of the alternative pathway of complement activation, is made up entirely from a chain of 20 CCPs joined by short linkers. Collectively, therefore, the 20 CCPs of FH must mediate all its functional capabilities. This is achieved via collaboration and division of labour among these modules. Structural studies have illuminated the dynamic architectures that allow FH and other CCP-rich proteins to perform their biological functions. These are largely the products of a highly varied set of intramolecular interactions between CCPs. The CCP can act as building block, spacer, highly versatile recognition site or dimerization mediator. Tandem CCPs may form composite binding sites or contribute to flexible, rigid or conformationally 'switchable' segments of the parent proteins. PMID- 26517888 TI - The alphaRep artificial repeat protein scaffold: a new tool for crystallization and live cell applications. AB - We have designed a new family of artificial proteins, named alphaRep, based on HEAT (acronym for Huntingtin, elongation factor 3 (EF3), protein pphosphatase 2A (PP2A), yeast kinase Tor1) repeat proteins containing an alpha-helical repeated motif. The sequence of the repeated motifs, first identified in a thermostable archae protein was optimized using a consensus design strategy and used for the construction of a library of artificial proteins. All proteins from this library share the same general fold but differ both in the number of repeats and in five highly randomized amino acid positions within each repeat. The randomized side chains altogether provide a hypervariable surface on alphaRep variants. Sequences from this library are efficiently expressed as soluble, folded and very stable proteins. alphaRep binders with high affinity for various protein targets were selected by phage display. Low micromolar to nanomolar dissociation constants between partners were measured and the structures of several complexes (specific alphaRep/protein target) were solved by X-ray crystallography. Using GFP as a model target, it was demonstrated that alphaReps can be used as bait in pull-down experiments. alphaReps can be expressed in eukaryotic cells and specifically interact with their target addressed to different cell compartments. PMID- 26517889 TI - Biomolecular templating of functional hybrid nanostructures using repeat protein scaffolds. AB - The precise synthesis of materials and devices with tailored complex structures and properties is a requisite for the development of the next generation of products based on nanotechnology. Nowadays, the technology for the generation of this type of devices lacks the precision to determine their properties and is accomplished mostly by 'trial and error' experimental approaches. The use of bottom-up approaches that rely on highly specific biomolecular interactions of small and simple components is an attractive approach for the templating of nanoscale elements. In nature, protein assemblies define complex structures and functions. Engineering novel bio-inspired assemblies by exploiting the same rules and interactions that encode the natural diversity is an emerging field that opens the door to create nanostructures with numerous potential applications in synthetic biology and nanotechnology. Self-assembly of biological molecules into defined functional structures has a tremendous potential in nano-patterning and the design of novel materials and functional devices. Molecular self-assembly is a process by which complex 3D structures with specified functions are constructed from simple molecular building blocks. Here we discuss the basis of biomolecular templating, the great potential of repeat proteins as building blocks for biomolecular templating and nano-patterning. In particular, we focus on the designed consensus tetratricopeptide repeats (CTPRs), the control on the assembly of these proteins into higher order structures and their potential as building blocks in order to generate functional nanostructures and materials. PMID- 26517890 TI - Comparison of protein repeat classifications based on structure and sequence families. AB - Tandem repeats (TR) in proteins are common in nature and have several unique functions. They come in various forms that are frequently difficult to recognize from a sequence. A previously proposed structural classification has been recently implemented in the RepeatsDB database. This defines five main classes, mainly based on repeat unit length, with subclasses representing specific folds. Sequence-based classifications, such as Pfam, provide an alternative classification based on evolutionarily conserved repeat families. Here, we discuss a detailed comparison between the structural classes in RepeatsDB and the corresponding Pfam repeat families and clans. Most instances are found to map one to-one between structure and sequence. Some notable exceptions such as leucine rich repeats (LRRs) and alpha-solenoids are discussed. PMID- 26517892 TI - Repeat proteins challenge the concept of structural domains. AB - Structural domains are believed to be modules within proteins that can fold and function independently. Some proteins show tandem repetitions of apparent modular structure that do not fold independently, but rather co-operate in stabilizing structural forms that comprise several repeat-units. For many natural repeat proteins, it has been shown that weak energetic links between repeats lead to the breakdown of co-operativity and the appearance of folding sub-domains within an apparently regular repeat array. The quasi-1D architecture of repeat-proteins is crucial in detailing how the local energetic balances can modulate the folding dynamics of these proteins, which can be related to the physiological behaviour of these ubiquitous biological systems. PMID- 26517891 TI - The centriolar protein CPAP G-box: an amyloid fibril in a single domain. AB - Centrioles are evolutionarily conserved cylindrical cell organelles with characteristic radial symmetry. Despite their considerable size (400 nm * 200 nm, in humans), genetic studies suggest that relatively few protein components are involved in their assembly. We recently characterized the molecular architecture of the centrosomal P4.1-associated protein (CPAP), which is crucial for controlling the centriolar cylinder length. Here, we review the remarkable architecture of the C-terminal domain of CPAP, termed the G-box, which comprises a single, entirely solvent exposed, antiparallel beta-sheet. Molecular dynamics simulations support the stability of the G-box domain even in the face of truncations or amino acid substitutions. The similarity of the G-box domain to amyloids (or amyloid precursors) is strengthened by its oligomeric arrangement to form continuous fibrils. G-box fibrils were observed in crystals as well as in solution and are also supported by simulations. We conclude that the G-box domain may well represent the best analogue currently available for studies of exposed beta-sheets, unencumbered by additional structural elements or severe aggregations problems. PMID- 26517893 TI - Structural advances on titin: towards an atomic understanding of multi-domain functions in myofilament mechanics and scaffolding. AB - Titin is a gigantic filamentous protein of the muscle sarcomere that plays roles in myofibril mechanics and homoeostasis. 3D-structures of multi-domain fragments of titin are now available that start revealing the molecular mechanisms governing its mechanical and scaffolding functions. This knowledge is now being translated into the fabrication of self-assembling biopolymers. Here we review the structural advances on titin, the novel concepts derived from these and the emerging translational avenues. PMID- 26517894 TI - Designing repeat proteins for biosensors and medical imaging. AB - Advances in protein engineering tools, both computational and experimental, has afforded many new protein structures and functions. Here, we present a snapshot of repeat-protein engineering efforts towards new, versatile, alternative binding scaffolds for use in analytical sensors and as imaging agents. Analytical assays, sensors and imaging agents based on the direct binding of analyte are increasingly important for research and diagnostics in medicine, food safety, and national security. PMID- 26517895 TI - Two repetitive, biofilm-forming proteins from Staphylococci: from disorder to extension. AB - Staphylococcus aureus and Staphylococcus epidermidis are an important cause of medical device-related infections that are difficult to treat with antibiotics. Biofilms, in which bacteria are embedded in a bacterially-produced exopolymeric matrix, form on the surface of the implanted medical device. Our understanding of the molecular mechanisms underlying the initial surface attachment and subsequent intercellular interactions as the biofilm matures is improving. Biofilm accumulation can be mediated by a partially deacetylated form of poly-N acetylglucosamine (PNAG) but, more recently, the role of bacterial surface proteins is being recognized. Here we describe the structure and function of two S. aureus cell surface proteins, FnBPA and SasG, implicated in host interactions and biofilm accumulation. These multifunctional proteins employ intrinsic disorder for distinct molecular outcomes. In the case of FnBPA, disorder generates adhesive arrays that bind fibronectin (Fn); in the case of SasG, disorder is, counterintuitively, used to maintain a strong extended fold. PMID- 26517896 TI - Emergence of de novo proteins from 'dark genomic matter' by 'grow slow and moult'. AB - Proteins are the workhorses of the cell and, over billions of years, they have evolved an amazing plethora of extremely diverse and versatile structures with equally diverse functions. Evolutionary emergence of new proteins and transitions between existing ones are believed to be rare or even impossible. However, recent advances in comparative genomics have repeatedly called some 10%-30% of all genes without any detectable similarity to existing proteins. Even after careful scrutiny, some of those orphan genes contain protein coding reading frames with detectable transcription and translation. Thus some proteins seem to have emerged from previously non-coding 'dark genomic matter'. These 'de novo' proteins tend to be disordered, fast evolving, weakly expressed but also rapidly assuming novel and physiologically important functions. Here we review mechanisms by which 'de novo' proteins might be created, under which circumstances they may become fixed and why they are elusive. We propose a 'grow slow and moult' model in which first a reading frame is extended, coding for an initially disordered and non-globular appendage which, over time, becomes more structured and may also become associated with other proteins. PMID- 26517897 TI - A designed repeat protein as an affinity capture reagent. AB - Repeat proteins are an attractive target for protein engineering and design. We have focused our attention on the design and engineering of one particular class: tetratricopeptide repeat (TPR) proteins. In previous work, we have shown that the structure and stability of TPR proteins can be manipulated in a rational fashion [Cortajarena (2011) Prot. Sci. 20: , 1042-1047; Main (2003) Structure 11: , 497 508]. Building on those studies, we have designed and characterized a number of different peptide-binding TPR modules and we have also assembled these modules into supramolecular arrays [Cortajarena (2009) ACS Chem. Biol. 5: , 545-552; Cortajarena (2008) ACS Chem. Biol. 3: , 161-166; Jackrel (2009) Prot. Sci. 18: , 762-774; Kajander (2007) Acta Crystallogr. D Biol. Crystallogr. 63: , 800-811]. Here we focus on the development of one such TPR-peptide interaction for a practical application, affinity purification. We illustrate the general utility of our designed protein interaction. Furthermore, this example highlights how basic research on protein-peptide interactions can lead to the development of novel reagents with important practical applications. PMID- 26517898 TI - Dissecting and reprogramming the folding and assembly of tandem-repeat proteins. AB - Studying protein folding and protein design in globular proteins presents significant challenges because of the two related features, topological complexity and co-operativity. In contrast, tandem-repeat proteins have regular and modular structures composed of linearly arrayed motifs. This means that the biophysics of even giant repeat proteins is highly amenable to dissection and to rational design. Here we discuss what has been learnt about the folding mechanisms of tandem-repeat proteins. The defining features that have emerged are: (i) accessibility of multiple distinct routes between denatured and native states, both at equilibrium and under kinetic conditions; (ii) different routes are favoured for folding compared with unfolding; (iii) unfolding energy barriers are broad, reflecting stepwise unravelling of an array repeat by repeat; (iv) highly co-operative unfolding at equilibrium and the potential for exceptionally high thermodynamic stabilities by introducing consensus residues; (v) under force, helical-repeat structures are very weak with non-co-operative unfolding leading to elasticity and buffering effects. This level of understanding should enable us to create repeat proteins with made-to-measure folding mechanisms, in which one can dial into the sequence the order of repeat folding, number of pathways taken, step size (co-operativity) and fine-structure of the kinetic energy barriers. PMID- 26517899 TI - Structural basis for the mechanism of ABC transporters. AB - The ATP-binding cassette (ABC) transporters are primary transporters that couple the energy stored in adenosine triphosphate (ATP) to the movement of molecules across the membrane. ABC transporters can be divided into exporters and importers; importers mediate the uptake of essential nutrients into cells and are found predominantly in prokaryotes whereas exporters transport molecules out of cells or into organelles and are found in all organisms. ABC exporters have been linked with multi-drug resistance in both bacterial and eukaryotic cells. ABC transporters are powered by the hydrolysis of ATP and transport their substrate via the alternating access mechanism, whereby the protein alternates between a conformation in which the substrate-binding site is accessible from the outside of the membrane, outward-facing and one in which it is inward-facing. In this mini-review, the structures of different ABC transporter types in different conformations are presented within the context of the alternating access mechanism and how they have shaped our current understanding of the mechanism of ABC transporters. PMID- 26517900 TI - Characterizing diverse orthologues of the cystic fibrosis transmembrane conductance regulator protein for structural studies. AB - As an ion channel, the cystic fibrosis transmembrane conductance regulator (CFTR) protein occupies a unique niche within the ABC family. Orthologues of CFTR are extant throughout the animal kingdom from sharks to platypods to sheep, where the osmoregulatory function of the protein has been applied to differing lifestyles and diverse organ systems. In humans, loss-of-function mutations to CFTR cause the disease cystic fibrosis, which is a significant health burden in populations of white European descent. Orthologue screening has proved fruitful in the pursuit of high-resolution structural data for several membrane proteins, and we have applied some of the princples developed in previous studies to the expression and purification of CFTR. We have overexpressed this protein, along with evolutionarily diverse orthologues, in Saccharomyces cerevisiae and developed a purification to isolate it in quantities sufficient for structural and functional studies. PMID- 26517902 TI - The CydDC ABC transporter of Escherichia coli: new roles for a reductant efflux pump. AB - The CydDC complex of Escherichia coli is a heterodimeric ATP-binding cassette (ABC) transporter that exports cysteine and glutathione to the periplasm. These reductants are thought to modulate periplasmic redox poise, impacting upon the disulfide folding of periplasmic and secreted proteins involved in bacterial virulence. Diminished CydDC activity abolishes the assembly of functional bd-type respiratory oxidases and perturbs haem ligation during the assembly of c-type cytochromes. The focus herein is upon a newly-discovered interaction of the CydDC complex with a haem cofactor; haem has recently been shown to modulate CydDC activity and structural modelling reveals a potential haem-binding site on the periplasmic surface of the complex. These findings have important implications for future investigations into the potential roles for the CydDC-bound haem in redox sensing and tolerance to nitric oxide (NO). PMID- 26517901 TI - Molecular action of sulphonylureas on KATP channels: a real partnership between drugs and nucleotides. AB - Sulphonylureas stimulate insulin secretion from pancreatic beta-cells primarily by closing ATP-sensitive K(+) channels in the beta-cell plasma membrane. The mechanism of channel inhibition by these drugs is unusually complex. As direct inhibitors of channel activity, sulphonylureas act only as partial antagonists at therapeutic concentrations. However, they also exert an additional indirect inhibitory effect via modulation of nucleotide-dependent channel gating. In this review, we summarize current knowledge and recent advances in our understanding of the molecular mechanism of action of these drugs. PMID- 26517903 TI - ABCA3, a key player in neonatal respiratory transition and genetic disorders of the surfactant system. AB - Genetic disorders of the surfactant system are rare diseases with a broad range of clinical manifestations, from fatal respiratory distress syndrome (RDS) in neonates to chronic interstitial lung disease (ILD) in children and adults. ABCA3 [ATP-binding cassette (ABC), subfamily A, member 3] is a lung-specific phospholipid transporter critical for intracellular surfactant synthesis and storage in lamellar bodies (LBs). Its expression is developmentally regulated, peaking prior to birth under the influence of steroids and transcription factors. Bi-allelic mutations of the ABCA3 gene represent the most frequent cause of congenital surfactant deficiency, indicating its critical role in lung function. Mutations affect surfactant lipid and protein processing and LBs' morphology, leading to partial or total surfactant deficiency. Approximately 200 mutations have been reported, most of which are unique to individuals and families, which makes diagnosis and prognosis challenging. Various types of mutations, affecting different domains of the protein, account in part for phenotype diversity. Disease-causing mutations have been reported in most coding and some non-coding regions of the gene, but tend to cluster in the first extracellular loop and the second nucleotide-binding domain (NBD), leading to defective glycosylation and trafficking defects and interfering with ATP binding and hydrolysis respectively. Mono-allelic damaging and benign variants are often subclinical but may act as disease modifiers in lung diseases such as RDS of prematurity or associate with mutations in other surfactant-related genes. Diagnosis is complex but essential and should combine pathology and ultrastructure studies on lung biopsy with broad spectrum genetic testing of surfactant-related genes, made possible by recent technology advances in the massive parallel sequencing technology. PMID- 26517904 TI - Understanding the function of ABCA7 in Alzheimer's disease. AB - ATP-binding cassette transporter A7 (ABCA7) is highly expressed in the brain. Recent genome-wide association studies (GWAS) identify ABCA7 single nt polymorphisms (SNPs) that increase Alzheimer's disease (AD) risk. It is now important to understand the true function of ABCA7 in the AD context. We have begun to address this using in vitro and in vivo AD models. Our initial studies showed that transient overexpression of ABCA7 in Chinese hamster ovary cells stably expressing human amyloid precursor protein (APP) resulted in an approximate 50% inhibition in the production of the AD-related amyloid-beta (Abeta) peptide as compared with mock-transfected cells. This increased ABCA7 expression was also associated with alterations in other markers of APP processing and an accumulation of cellular APP. To probe for a function of ABCA7 in vivo, we crossed Abca7(-/-) mice with J20 mice, an amyloidogenic transgenic AD mouse model [B6.Cg-Tg(PDGFB-APPSwInd)20Lms/J] expressing a mutant form of human APP bearing both the Swedish (K670N/M671L) and Indiana (V717F) familial AD mutations. We found that ABCA7 loss doubled insoluble Abeta levels and amyloid plaques in the brain. This did not appear to be related to changes in APP processing (C-terminal fragment analysis), which led us to assess other mechanism by which ABCA7 may modulate Abeta homoeostasis. As we have shown that microglia express high levels of ABCA7, we examined a role for ABCA7 in the phagocytic clearance of Abeta. Our data indicated that the capacity for bone marrow-derived macrophages derived from Abca7(-/-) mice to phagocytose Abeta was reduced by 51% compared with wild-type (WT) mice. This suggests ABCA7 plays a role in the regulation of Abeta homoeostasis in the brain and that this may be related to Abeta clearance by microglia. PMID- 26517906 TI - Plant ABC transporters: time for biochemistry? AB - ATP-binding cassette (ABC) proteins form a large and ubiquitous family, most members of which are membrane-associated primary transporters. Plant genomes code for a particularly large number of these ABC proteins, with more than 120 genes present in both Arabidopsis thaliana and Oryza sativa (rice). Although plant ABC transporters were initially identified as detoxifiers, sequestering xenobitotics into the vacuole, they were later found to be involved in a wide range of essential physiological processes. Currently, the exact substrates transported by most of these transporters are still unknown and we therefore cannot exclude that a single substrate (e.g. a hormone) is responsible for the diversity of physiological roles. This gap in our knowledge is mainly due to the fact that only a few studies have used direct methods to identify the substrates of these membrane transporters. To address this issue, transport assays involving isolated cells, vesicular membranes or reconstituted liposomes are essential. In this review, we will highlight the importance of the direct biochemical characterization of plant ABC transporters and give some insights into the current status of the homologous and heterologous expression of such proteins. PMID- 26517905 TI - The role of ABCG-type ABC transporters in phytohormone transport. AB - Plant hormones (phytohormones) integrate endogenous and exogenous signals thus synchronizing plant growth with environmental and developmental changes. Similar to animals, phytohormones have distinct source and target tissues, hence controlled transport and focused targeting are required for their functions. Many evidences accumulated in the last years about the regulation of long-distance and directional transport of phytohormones. ATP-binding cassette (ABC) transporters turned out to play major roles in routing phytohormones not only in the plant body but also towards the outer environment. The ABCG-type proteins ABCG25 and ABCG40 are high affinity abscisic acid (ABA) transporters. ABCG14 is highly co expressed with cytokinin biosynthesis and is the major root-to-shoot cytokinin transporter. Pleiotropic drug resistance1 (PDR1) from Petunia hybrida transports strigolactones (SLs) from the root tip to the plant shoot but also outside to the rhizosphere, where SLs are the main attractants to mycorrhizal fungi. Last but not least, ABCG36 and ABCG37 possibly play a dual role in coumarine and IBA transport. PMID- 26517907 TI - Role of family D ATP-binding cassette transporters (ABCD) in cancer. AB - ATP-binding cassette (ABC) transporters, belonging to the family D, are expressed in peroxisomes, endoplasmic reticulum or lysosomes. ABCD transporters play a role in transport of lipids, bile acids and vitamin B12 and associate with peroxisomal disorders. ABCD1 performs transport of coenzyme A esters of very-long-chain fatty acids (VLCFA) in peroxisomes and a number of mutations in ABCD1 gene were linked to an X-linked adrenoleucodystrophy (X-ALD). The role of ABCD transporters in tumour growth has not been studied in detail, but there is some evidence that ABCDs levels differ between undifferentiated stem or tumour cells and differentiated cells suggesting a possible link to tumorigenesis. In this mini review, we discuss the available information about the role of ABCD transporters in cancer. PMID- 26517908 TI - Structures and functions of mitochondrial ABC transporters. AB - A small number of physiologically important ATP-binding cassette (ABC) transporters are found in mitochondria. Most are half transporters of the B group forming homodimers and their topology suggests they function as exporters. The results of mutant studies point towards involvement in iron cofactor biosynthesis. In particular, ABC subfamily B member 7 (ABCB7) and its homologues in yeast and plants are required for iron-sulfur (Fe-S) cluster biosynthesis outside of the mitochondria, whereas ABCB10 is involved in haem biosynthesis. They also play a role in preventing oxidative stress. Mutations in ABCB6 and ABCB7 have been linked to human disease. Recent crystal structures of yeast Atm1 and human ABCB10 have been key to identifying substrate-binding sites and transport mechanisms. Combined with in vitro and in vivo studies, progress is being made to find the physiological substrates of the different mitochondrial ABC transporters. PMID- 26517909 TI - Homology modelling of human P-glycoprotein. AB - P-glycoprotein (P-gp) is an ATP-binding cassette transporter that exports a huge range of compounds out of cells and is thus one of the key proteins in conferring multi-drug resistance in cancer. Understanding how it achieves such a broad specificity and the series of conformational changes that allow export to occur form major, on-going, research objectives around the world. Much of our knowledge to date has been derived from mutagenesis and assay data. However, in recent years, there has also been great progress in structural biology and although the structure of human P-gp has not yet been solved, there are now a handful of related structures on which homology models can be built to aid in the interpretation of the vast amount of experimental data that currently exists. Many models for P-gp have been built with this aim, but the situation is complicated by the apparent flexibility of the system and by the fact that although many potential templates exist, there is large variation in the conformational state in which they have been crystallized. In this review, we summarize how homology modelling has been used in the past, how models are typically selected and finally illustrate how MD simulations can be used as a means to give more confidence about models that have been generated via this approach. PMID- 26517911 TI - Learning from each other: ABC transporter regulation by protein phosphorylation in plant and mammalian systems. AB - The ABC (ATP-binding cassette) transporter family in higher plants is highly expanded compared with those of mammalians. Moreover, some members of the plant ABC subfamily B (ABCB) display very high substrate specificity compared with their mammalian counterparts that are often associated with multi-drug resistance phenomena. In this review, we highlight prominent functions of plant and mammalian ABC transporters and summarize our knowledge on their post transcriptional regulation with a focus on protein phosphorylation. A deeper comparison of regulatory events of human cystic fibrosis transmembrane conductance regulator (CFTR) and ABCB1 from the model plant Arabidopsis reveals a surprisingly high degree of similarity. Both physically interact with orthologues of the FK506-binding proteins that chaperon both transporters to the plasma membrane in an action that seems to involve heat shock protein (Hsp)90. Further, both transporters are phosphorylated at regulatory domains that connect both nt binding folds. Taken together, it appears that ABC transporters exhibit an evolutionary conserved but complex regulation by protein phosphorylation, which apparently is, at least in some cases, tightly connected with protein-protein interactions (PPI). PMID- 26517910 TI - Peroxisomal ABC transporters: functions and mechanism. AB - Peroxisomes are arguably the most biochemically versatile of all eukaryotic organelles. Their metabolic functions vary between different organisms, between different tissue types of the same organism and even between different developmental stages or in response to changed environmental conditions. New functions for peroxisomes are still being discovered and their importance is underscored by the severe phenotypes that can arise as a result of peroxisome dysfunction. The beta-oxidation pathway is central to peroxisomal metabolism, but the substrates processed are very diverse, reflecting the diversity of peroxisomes across species. Substrates for beta-oxidation enter peroxisomes via ATP-binding cassette (ABC) transporters of subfamily D; (ABCD) and are activated by specific acyl CoA synthetases for further metabolism. Humans have three peroxisomal ABCD family members, which are half transporters that homodimerize and have distinct but partially overlapping substrate specificity; Saccharomyces cerevisiae has two half transporters that heterodimerize and plants have a single peroxisomal ABC transporter that is a fused heterodimer and which appears to be the single entry point into peroxisomes for a very wide variety of beta-oxidation substrates. Our studies suggest that the Arabidopsis peroxisomal ABC transporter AtABCD1 accepts acyl CoA substrates, cleaves them before or during transport followed by reactivation by peroxisomal synthetases. We propose that this is a general mechanism to provide specificity to this class of transporters and by which amphipathic compounds are moved across peroxisome membranes. PMID- 26517912 TI - Exploiting species differences to understand the CFTR Cl- channel. AB - The anion channel cystic fibrosis transmembrane conductance regulator (CFTR) is a unique ATP-binding cassette (ABC) transporter. CFTR plays a pivotal role in transepithelial ion transport as its dysfunction in the genetic disease cystic fibrosis (CF) dramatically demonstrates. Phylogenetic analysis suggests that CFTR first appeared in aquatic vertebrates fulfilling important roles in osmosensing and organ development. Here, we review selectively, knowledge of CFTR structure, function and pharmacology, gleaned from cross-species comparative studies of recombinant CFTR proteins, including CFTR chimeras. The data argue that subtle changes in CFTR structure can affect strongly channel function and the action of CF mutations. PMID- 26517913 TI - Oxidative footprinting in the study of structure and function of membrane proteins: current state and perspectives. AB - Membrane proteins, such as receptors, transporters and ion channels, control the vast majority of cellular signalling and metabolite exchange processes and thus are becoming key pharmacological targets. Obtaining structural information by usage of traditional structural biology techniques is limited by the requirements for the protein samples to be highly pure and stable when handled in high concentrations and in non-native buffer systems, which is often difficult to achieve for membrane targets. Hence, there is a growing requirement for the use of hybrid, integrative approaches to study the dynamic and functional aspects of membrane proteins in physiologically relevant conditions. In recent years, significant progress has been made in the field of oxidative labelling techniques and in particular the X-ray radiolytic footprinting in combination with mass spectrometry (MS) (XF-MS), which provide residue-specific information on the solvent accessibility of proteins. In combination with both low- and high resolution data from other structural biology approaches, it is capable of providing valuable insights into dynamics of membrane proteins, which have been difficult to obtain by other structural techniques, proving a highly complementary technique to address structure and function of membrane targets. XF MS has demonstrated a unique capability for identification of structural waters and conformational changes in proteins at both a high degree of spatial and a high degree of temporal resolution. Here, we provide a perspective on the place of XF-MS among other structural biology methods and showcase some of the latest developments in its usage for studying water-mediated transmembrane (TM) signalling, ion transport and ligand-induced allosteric conformational changes in membrane proteins. PMID- 26517914 TI - Providing a molecular mechanism for P-glycoprotein; why would I bother? AB - It is almost 40 years since the drug efflux pump P-glycoprotein (permeability glycoprotein or P-gp) was shown to confer multi-drug resistance in cancer cells. This protein has been one of the most extensively investigated transport proteins due to its intriguing mechanism and its affect in oncology. P-gp is known to interact with over 300 compounds and the ability to achieve this has not yet been revealed. Following the binding of substrate and nucleotide, a complex series of conformational changes in the membrane and cytosolic domains translocates substrate across the membrane. Despite over 30 years of biochemical investigation, the availability of structural data and a plethora of chemical tools to modulate its function, the molecular mechanism remains a mystery. In addition, overcoming its activity in resistant cancer cells has not been achieved in the clinic, thereby garnering some degree of pessimism in the field. This review highlights the progress that has been achieved in understanding this complex protein and the value of undertaking molecular studies. PMID- 26517915 TI - Lipid flopping in the liver. AB - Bile is synthesized in the liver and is essential for the emulsification of dietary lipids and lipid-soluble vitamins. It is a complex mixture of amphiphilic bile acids (BAs; which act as detergent molecules), the membrane phospholipid phosphatidylcholine (PC), cholesterol and a variety of endogenous metabolites and waste products. Over the last 20 years, the combined effort of clinicians, geneticists, physiologists and biochemists has shown that each of these bile components is transported across the canalicular membrane of the hepatocyte by its own specific ATP-binding cassette (ABC) transporter. The bile salt export pump (BSEP) ABCB11 transports the BAs and drives bile flow from the liver, but it is now clear that two lipid transporters, ABCB4 (which flops PC into the bile) and the P-type ATPase ATP8B1/CDC50 (which flips a different phospholipid in the opposite direction) play equally critical roles that protect the biliary tree from the detergent activity of the bile acids. Understanding the interdependency of these lipid floppases and flippases has allowed the development of an assay to measure ABCB4 function. ABCB4 harbours numerous mis-sense mutations which probably reflects the spectrum of liver disease rooted in ABCB4 aetiology. Characterization of the effect of these mutations at the protein level opens the possibility for the development of personalized prognosis and treatment. PMID- 26517916 TI - The substrate-binding protein in bacterial ABC transporters: dissecting roles in the evolution of substrate specificity. AB - ATP-binding cassette (ABC) transporters, although being ubiquitous in biology, often feature a subunit that is limited primarily to bacteria and archaea. This subunit, the substrate-binding protein (SBP), is a key determinant of the substrate specificity and high affinity of ABC uptake systems in these organisms. Most prokaryotes have many SBP-dependent ABC transporters that recognize a broad range of ligands from metal ions to amino acids, sugars and peptides. Herein, we review the structure and function of a number of more unusual SBPs, including an ABC transporter involved in the transport of rare furanose forms of sugars and an SBP that has evolved to specifically recognize the bacterial cell wall-derived murein tripeptide (Mtp). Both these examples illustrate that subtle changes in binding-site architecture, including changes in side chains not directly involved in ligand co-ordination, can result in significant alteration of substrate range in novel and unpredictable ways. PMID- 26517917 TI - ABCB1 in children's brain tumours. AB - Tumours of the central nervous system are the most common solid tumour, accounting for a quarter of the 1500 cases of childhood cancer diagnosed each year in the U.K. They are the most common cause of cancer-related death in children. Treatment consists of surgery followed by adjuvant chemotherapy and/or radiotherapy. Survival rates have generally increased, but many survivors suffer from radiotherapy-related neurocognitive and endocrine side effects as well as an increased risk of secondary cancer. Adjuvant chemotherapy is normally given in combination to circumvent chemoresistance, but several studies have demonstrated it to be ineffective in the absence of radiotherapy. The identification of children with drug-resistant disease at the outset could allow stratification of those that are potentially curable by chemotherapy alone. Ultimately, however, what is required is a means to overcome this drug resistance and restore the effectiveness of chemotherapy. Medulloblastomas and ependymomas account for over 30% of paediatric brain tumours. Advances in neurosurgery, adjuvant radiotherapy and chemotherapy have led to improvements in 5-year overall survival rates. There remain, however, significant numbers of medulloblastoma patients that have intrinsically drug-resistant tumours and/or present with disseminated disease. Local relapse in ependymoma is also common and has an extremely poor prognosis with only 25% of children surviving first relapse. Each of these is consistent with the acquisition of drug and radiotherapy resistance. Since the majority of chemotherapy drugs currently used to treat these patients are transport substrates for ATP-binding cassette sub-family B member 1 (ABCB1) we will address the hypothesis that ABCB1 expression underlies this drug resistance. PMID- 26517918 TI - Investigating the dynamic nature of the ABC transporters: ABCB1 and MsbA as examples for the potential synergies of MD theory and EPR applications. AB - ABC transporters are primary active transporters found in all kingdoms of life. Human multidrug resistance transporter ABCB1, or P-glycoprotein, has an extremely broad substrate spectrum and confers resistance against chemotherapy drug treatment in cancer cells. The bacterial ABC transporter MsbA is a lipid A flippase and a homolog to the human ABCB1 transporter, with which it partially shares its substrate spectrum. Crystal structures of MsbA and ABCB1 have been solved in multiple conformations, providing a glimpse into the possible conformational changes the transporter could be going through during the transport cycle. Crystal structures are inherently static, while a dynamic picture of the transporter in motion is needed for a complete understanding of transporter function. Molecular dynamics (MD) simulations and electron paramagnetic resonance (EPR) spectroscopy can provide structural information on ABC transporters, but the strength of these two methods lies in the potential to characterise the dynamic regime of these transporters. Information from the two methods is quite complementary. MD simulations provide an all atom dynamic picture of the time evolution of the molecular system, though with a narrow time window. EPR spectroscopy can probe structural, environmental and dynamic properties of the transporter in several time regimes, but only through the attachment sites of an exogenous spin label. In this review the synergistic effects that can be achieved by combining the two methods are highlighted, and a brief methodological background is also presented. PMID- 26517919 TI - ABC transporter research: going strong 40 years on. AB - In most organisms, ABC transporters constitute one of the largest families of membrane proteins. In humans, their functions are diverse and underpin numerous key physiological processes, as well as being causative factors in a number of clinically relevant pathologies. Advances in our understanding of these diseases have come about through combinations of genetic and protein biochemical investigations of these transporters and the power of in vitro and in vivo investigations is helping to develop genotype-phenotype understanding. However, the importance of ABC transporter research goes far beyond human biology; microbial ABC transporters are of great interest in terms of understanding virulence and drug resistance and industrial biotechnology researchers are exploring the potential of prokaryotic ABC exporters to increase the capacity of synthetic biology systems. Plant ABC transporters play important roles in transport of hormones, xenobiotics, metals and secondary metabolites, pathogen responses and numerous aspects of development, all of which are important in the global food security area. For 3 days in Chester, this Biochemical Society Focused Meeting brought together researchers with diverse experimental approaches and with different fundamental questions, all of which are linked by the commonality of ABC transporters. PMID- 26517920 TI - Watching conformational dynamics of ABC transporters with single-molecule tools. AB - ATP-binding cassette (ABC) transporters play crucial roles in cellular processes, such as nutrient uptake, drug resistance, cell-volume regulation and others. Despite their importance, all proposed molecular models for transport are based on indirect evidence, i.e. functional interpretation of static crystal structures and ensemble measurements of function and structure. Thus, classical biophysical and biochemical techniques do not readily visualize dynamic structural changes. We recently started to use single-molecule fluorescence techniques to study conformational states and changes of ABC transporters in vitro, in order to observe directly how the different steps during transport are coordinated. This review summarizes our scientific strategy and some of the key experimental advances that allowed the substrate-binding mechanism of prokaryotic ABC importers and the transport cycle to be explored. The conformational states and transitions of ABC-associated substrate-binding domains (SBDs) were visualized with single-molecule FRET, permitting a direct correlation of structural and kinetic information of SBDs. We also delineated the different steps of the transport cycle. Since information in such assays are restricted by proper labelling of proteins with fluorescent dyes, we present a simple approach to increase the amount of protein with FRET information based on non-specific interactions between a dye and the size-exclusion chromatography (SEC) column material used for final purification. PMID- 26517921 TI - Tribbles at the cross-roads.... PMID- 26517922 TI - Tribbles and arthritis: what are the links? AB - The pseudo-kinase family of tribbles (TRIB) proteins has been linked to a variety of cell signalling pathways and appears to have functionally divergent roles with respect to intracellular protein degradation and the ability to regulate signal transduction pathways. In the arthritides, inflammation and a wide variety of pro inflammatory pathways have been implicated to drive the cartilage destruction and consequent disability associated with both rheumatoid arthritis (RA) and osteoarthritis (OA). Despite burgeoning evidence linking the TRIB to inflammation related pathologies such as diabetes, multiple sclerosis and cancer, very little is known about their roles in arthritis. The present review discusses current knowledge of the impact of TRIB on pro-inflammatory cellular mechanisms and pathways known to be important in the pathogenesis of RA and OA. PMID- 26517923 TI - Conservation of gene and tissue networks regulating insulin signalling in flies and vertebrates. AB - Fruit flies have emerged as a powerful tool to investigate metabolism. Not only are gene structures and gene networks that control metabolism conserved through evolution, but the interactions among organs to store and process metabolites have strong similarities between flies and humans. Accordingly, the Drosophila system has the potential to address human disorders associated with metabolic dysfunction including obesity, type 2 diabetes and lipotoxicity. PMID- 26517924 TI - The role of TRIB1 in lipid metabolism; from genetics to pathways. AB - The plasma concentration of lipids is a heritable risk factor for the development of atherosclerosis and related coronary artery diseases (CAD). Mammalian tribbles homologue 1 (TRIB1) is a human locus, the downstream linkage disequilibrium (LD) block of which affects plasma low-density lipoprotein (LDL)-associated cholesterol, triglyceride (TG) levels and CAD across multiple ethnic groups. In addition, association of TRIB1 with non-alcoholic fatty liver disease (NAFLD) has also been shown. A regulatory sequence that enhances TRIB1 promoter activity was identified in the LD block and the minor allele of a single nt polymorphism (SNP, rs6982502) in this regulatory sequence reduces the activity of the TRIB1 promoter. The minor allele of rs6982502 is a risk allele for increasing plasma lipid levels and NAFLD. Trib1 deficiency increases plasma cholesterol and TGs in mice and overexpression of TRIB1 in mouse liver reduces these factors. Expression of rate-limiting lipogenic enzymes is increased in Trib1-knockout mouse liver and decreased with overexpression. Recently, carbohydrate-responsive element-binding protein (ChREBP) emerged as a novel binding partner of TRIB1. Furthermore, novel binding partner, Sin3A (Swi-independent 3A)-associated protein, 18 kDa, was identified, which activates microsomal TG transfer protein (MTTP) expression by binding with MTTP regulatory elements in co-ordination with mSin3A and TRIB1. Very recently, a small molecular compound that up-regulates TRIB1 expression in HepG2 cells has been discovered. Further exploration of the binding partners of TRIB1 and their involvement in lipid metabolism may aid discovery of novel pharmacological targets for the management of dyslipidaemia and steatosis. PMID- 26517925 TI - Tribbles in inflammation. AB - Inflammation is part of the physiological innate immune response to invading pathogens and tissue injury. However, unresolved inflammation leads to human disease. The tribbles (TRIB) family of pseudokinase proteins has been shown to modulate key inflammatory signalling pathways, including the MAPK (mitogen activated protein kinase) and PI3K (phosphoinositide 3-kinase) networks. This review summarizes our current knowledge on TRIBs in the context of inflammation, both at the level of molecular mechanisms and in disease development. PMID- 26517926 TI - Deciphering the role of TRIB1 in regulatory T-cells. AB - The role of regulatory T-cells (Tregs) is crucial to maintain immune homoeostasis by controlling peripheral tolerance. A better understanding in the molecular mechanisms involved in the biology of these Tregs could improve their expansion and selection to treat immune-related diseases, achieve immunosuppression-free organ transplantation and to specifically target them in cancer. We reported on the overexpression of tribbles-1 (TRIB1) in Tregs compared with their counterpart naive T-cells and that TRIB1 interacts with the master molecule of Tregs, forkhead box P3 (FOXP3), a transcription factor essential for Treg suppressive activity. We demonstrated that these two molecules interact together in the nucleus of Tregs and TRIB1 overexpression is associated with a decrease in their proliferative capacities. Since TRIB1 was reported to be overexpressed in the blood of renal transplanted patients with chronic antibody-mediated rejection (CAMR), altogether, these results suggest TRIB1 could be linked to the decrease proportion of Tregs in patients exhibiting CAMR and a key player in Tregs through its FOXP3 interaction. In addition, yeast two-hybrid screening experiments highlighted that TRIB1 potentially interacts with molecules playing roles in intracellular events following T-cell activation and particularly cluster of differentiation (CD)4(+) T-cells. This suggests still non explored potential links between TRIB1 in Tregs. Our goal is thus to decipher the role of TRIB1 in the Treg biology, notably in pathways known to involved its partner and main transcriptional factor of Tregs, FOXP3 and to determine the role of TRIB1 in immune pathologies. PMID- 26517928 TI - Tribbles breaking bad: TRIB2 suppresses FOXO and acts as an oncogenic protein in melanoma. AB - TRIB2 (tribbles homolog 2) encodes one of three members of the tribbles family in mammals. These members share a Trb (tribbles) domain, which is homologous to protein serine-threonine kinases, but lack the active site lysine. The tribbles proteins interact and modulate the activity of signal transduction pathways in a number of physiological and pathological processes. TRIB2 has been identified as an oncogene that inactivates the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha) and causes acute myelogenous leukaemia (AML). Recent research provided compelling evidence that TRIB2 can also act as oncogenic driver in solid tumours, such as lung and liver cancer. In particular, our recent work demonstrated that TRIB2 is dramatically overexpressed in malignant melanomas compared with normal skin and promotes the malignant phenotype of melanoma cells via the down-regulation of FOXO (forkhead box protein O) tumour suppressor activity in vitro and in vivo. TRIB2 was found to be expressed in normal skin, but its expression consistently increased in benign nevi, melanoma and was highest in samples from patients with malignant melanoma. The observation that TRIB2 strongly correlates with the progression of melanocyte-derived malignancies suggests TRIB2 as a meaningful biomarker to both diagnose and stage melanoma. In addition, interfering with TRIB2 activity might be a therapeutic strategy for the treatment of several different tumour types. PMID- 26517927 TI - Tribbles-1: a novel regulator of hepatic lipid metabolism in humans. AB - The protein tribbles-1, encoded by the gene TRIB1, is increasingly recognized as a major regulator of multiple cellular and physiological processes in humans. Recent human genetic studies, as well as molecular biological approaches, have implicated this intriguing protein in the aetiology of multiple human diseases, including myeloid leukaemia, Crohn's disease, non-alcoholic fatty liver disease (NAFLD), dyslipidaemia and coronary artery disease (CAD). Genome-wide association studies (GWAS) have repeatedly identified variants at the genomic TRIB1 locus as being significantly associated with multiple plasma lipid traits and cardiovascular disease (CVD) in humans. The involvement of TRIB1 in hepatic lipid metabolism has been validated through viral-mediated hepatic overexpression of the gene in mice; increasing levels of TRIB1 decreased plasma lipids in a dose dependent manner. Additional studies have implicated TRIB1 in the regulation of hepatic lipogenesis and NAFLD. The exact mechanisms of TRIB1 regulation of both plasma lipids and hepatic lipogenesis remain undetermined, although multiple signalling pathways and transcription factors have been implicated in tribbles-1 function. Recent reports have been aimed at developing TRIB1-based lipid therapeutics. In summary, tribbles-1 is an important modulator of human energy metabolism and metabolic syndromes and worthy of future studies aimed at investigating its potential as a therapeutic target. PMID- 26517929 TI - TRIB2 and the ubiquitin proteasome system in cancer. AB - Tribbles family of pseudokinase proteins are known to mediate the degradation of target proteins in Drosophila and mammalian systems. The main protein proteolysis pathway in eukaryotic cells is the ubiquitin proteasome system (UPS). The tribbles homolog 2 (TRIB2) mammalian family member has been well characterized for its role in murine and human leukaemia, lung and liver cancer. One of the most characterized substrates for TRIB2-mediated degradation is the myeloid transcription factor CCAAT enhancer binding protein alpha (C/EBPalpha). However, across a number of cancers, the molecular interactions that take place between TRIB2 and factors involved in the UPS are varied and have differential downstream effects. This review summarizes our current knowledge of these interactions and how this information is important for our understanding of TRIB2 in cancer. PMID- 26517930 TI - Tribbles pseudokinases: novel targets for chemical biology and drug discovery? AB - Tribbles (TRIB) proteins are pseudokinase mediators of eukaryotic signalling that have evolved important roles in lipoprotein metabolism, immune function and cellular differentiation and proliferation. In addition, an evolutionary conserved modulation of PI3K/AKT signalling pathways highlights them as novel and rather unusual pharmaceutical targets. The three human TRIB family members are uniquely defined by an acidic pseudokinase domain containing a 'broken' alpha C helix and a MEK (MAPK/ERK)-binding site at the end of the putative C-lobe and a distinct C-terminal peptide motif that interacts directly with a small subset of cellular E3 ubiquitin ligases. This latter interaction drives proteasomal dependent degradation of networks of transcription factors, whose rate of turnover determines the biological attributes of individual TRIB family members. Defining the function of individual Tribs has been made possible through evaluation of individual TRIB knockout mice, siRNA/overexpression approaches and genetic screening in flies, where the single TRIB gene was originally described 15 years ago. The rapidly maturing TRIB field is primed to exploit chemical biology approaches to evaluate endogenous TRIB signalling events in intact cells. This will help define how TRIB-driven protein-protein interactions and the atypical TRIB ATP-binding site, fit into cellular signalling modules in experimental scenarios where TRIB-signalling complexes remain unperturbed. In this mini-review, we discuss how small molecules can reveal rate-limiting signalling outputs and functions of Tribs in cells and intact organisms, perhaps serving as guides for the development of new drugs. We predict that appropriate small molecule TRIB ligands will further accelerate the transition of TRIB pseudokinase analysis into the mainstream of cell signalling. PMID- 26517931 TI - The role of Trib1 in myeloid leukaemogenesis and differentiation. AB - Tribbles homolog 1 (Trib1) was identified as a common integration site of the Homeobox a9 (Hoxa9)/murine ecotropic virus integration site 1 (Meis1) retrovirus in acute myeloid leukaemia (AML). Trib1 is by itself a transforming gene for myeloid cells but also significantly accelerates progression of Hoxa9/Meis1 induced AML. The strong transforming activity of Trib1 depends on its bi directional function in CCAAT/enhancer-binding protein (C/EBPalpha) degradation and MAPK/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) activation. TRIB1 is also involved in a certain type of human AML and a TRIB1 somatic point mutation R107L was identified in a case of Down syndrome (DS)-related acute megakaryocytic leukaemia. Although Trib1 knockout (KO) did not suppress haematopoiesis in mouse bone marrow significantly, increase in mature granulocytes was observed and promotion of myeloid differentiation was associated with the increased C/EBPalpha protein. Trib1 thus plays an important role in myeloid cell development and transformation. PMID- 26517932 TI - The TRIB3 Q84R polymorphism, insulin resistance and related metabolic alterations. AB - Insulin resistance is pathogenic for many prevalent disorders including type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), polycystic ovary syndrome, non-alcoholic fatty liver disease, Alzheimer's and Parkinson's diseases and several cancers. Unravelling molecular abnormalities of insulin resistance may therefore pave the way for tackling such heavy weight on healthcare systems. This review will be focused on studies addressing the role of genetic variability of TRIB3, an inhibitor of insulin signalling at the AKT level on insulin resistance and several related abnormalities. Studies carried out in several cultured cells clearly report that the TRIB3 Q84R missense polymorphism, is a gain-of-function amino acid substitution, with the Arg(84) variant being a stronger inhibitor of insulin-mediated AKT activation as compared with the more frequent Gln(84) variant. Given the key role of AKT in modulating not only insulin signalling but also insulin secretion, it was not surprising that beta cells and human pancreatic islets carrying the Arg(84) variant showed also impaired insulin secretion. Also, of note is that in human vein endothelial cells carrying the Arg(84) variant showed a reduced insulin-induced nitric oxide release, an established early atherosclerotic step. Accordingly with in vitro studies, in vivo studies indicate that TRIB3 Arg(84) is associated with insulin resistance, T2DM and several aspects of atherosclerosis, including overt CVD. In all, several data indicate that the TRIB3 Arg(84) variant plays a role on several aspects of glucose homoeostasis and atherosclerotic processes, thus unravelling new molecular pathogenic mechanisms of highly prevalent disorders such as T2DM and CVD. PMID- 26517933 TI - Tribbles in normal and malignant haematopoiesis. AB - The tribbles protein family, an evolutionarily conserved group of pseudokinases, have been shown to regulate multiple cellular events including those involved in normal and malignant haematopoiesis. The three mammalian Tribbles homologues, Trib1, Trib2 and Trib3 are characterized by conserved motifs, including a pseudokinase domain and a C-terminal E3 ligase-binding domain. In this review, we focus on the role of Trib (mammalian Tribbles homologues) proteins in mammalian haematopoiesis and leukaemia. The Trib proteins show divergent expression in haematopoietic cells, probably indicating cell-specific functions. The roles of the Trib proteins in oncogenesis are also varied and appear to be tissue specific. Finally, we discuss the potential mechanisms by which the Trib proteins preferentially regulate these processes in multiple cell types. PMID- 26517934 TI - Tribbles role in reproduction. AB - Tribbles (TRIB) proteins, a family of evolutionary conserved psuedokinase proteins, modulate various signalling pathways within the cell. The regulatory roles of TRIB make them an important part of a number of biological processes ranging from cell proliferation to metabolism, immunity, inflammation and carcinogenesis. Innate immune system plays a pivotal role during the regulation of reproductive processes that allows successful creation of an offspring. Its involvement initiates from fertilization of the oocyte by spermatozoon and lasts throughout early embryonic development, pregnancy and labour. Therefore, there is a close cooperation between the reproductive system and the innate immune system. Evidence from our lab has demonstrated that improper activation of the innate immune system can reduce embryo implantation, thus leading to infertility. Therefore, control mechanisms regulating the innate immune system function can be critical for successful reproductive events. PMID- 26517935 TI - Oncosuppressive functions of tribbles pseudokinase 3. AB - Tribbles pseudokinase 3 (TRIB3) belongs to the tribbles family of pseudokinases. In this article, we summarize several observation obtained by our laboratories supporting that TRIB3 plays a crucial role in the anti-cancer activity of cannabinoids (a novel family of potential anti-cancer agents derived from marijuana) and that TRIB3 genetic inactivation enhances cancer generation and progression. PMID- 26517936 TI - Osteoid Osteoma of the Femoral Neck in Athletes: Two Case Reports Differentiating From Femoral Neck Stress Injuries. AB - The diagnosis of an intra-articular osteoid osteoma can be a challenging and lengthy process, with reports of delayed diagnosis of greater than 2 years. In the young, athletic patient with an atraumatic onset of groin pain, an overuse injury or muscle strain is the most likely etiology. However, an overuse injury of femoral neck stress fracture must be identified because of the potentially disastrous outcome of fracture completion. The similar clinical presentation of a femoral neck stress fracture and intra-articular osteoid osteoma of the femoral neck can further delay the diagnosis of the osteoid osteoma. In a patient with these differential diagnoses that do not improve with a period of nonweightbearing activity, a more intensive workup must ensue. The purpose of this case report is to describe the initial presentations, subsequent follow-up, and imaging findings leading to the diagnosis of osteoid osteoma as well as to differentiate an osteoid osteoma from femoral neck stress injuries. PMID- 26517937 TI - Sports Specialization, Part II: Alternative Solutions to Early Sport Specialization in Youth Athletes. AB - CONTEXT: Many coaches, parents, and children believe that the best way to develop elite athletes is for them to participate in only 1 sport from an early age and to play it year-round. However, emerging evidence to the contrary indicates that efforts to specialize in 1 sport may reduce opportunities for all children to participate in a diverse year-round sports season and can lead to lost development of lifetime sports skills. Early sports specialization may also reduce motor skill development and ongoing participation in games and sports as a lifestyle choice. The purpose of this review is to employ the current literature to provide evidence-based alternative strategies that may help to optimize opportunities for all aspiring young athletes to maximize their health, fitness, and sports performance. EVIDENCE ACQUISITION: Nonsystematic review with critical appraisal of existing literature. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. CONCLUSION: Based on the current evidence, parents and educators should help provide opportunities for free unstructured play to improve motor skill development and youth should be encouraged to participate in a variety of sports during their growing years to influence the development of diverse motor skills. For those children who do choose to specialize in a single sport, periods of intense training and specialized sport activities should be closely monitored for indicators of burnout, overuse injury, or potential decrements in performance due to overtraining. Last, the evidence indicates that all youth should be involved in periodized strength and conditioning (eg, integrative neuromuscular training) to help them prepare for the demands of competitive sport participation, and youth who specialize in a single sport should plan periods of isolated and focused integrative neuromuscular training to enhance diverse motor skill development and reduce injury risk factors. STRENGTH OF RECOMMENDATION TAXONOMY SORT: B. PMID- 26517938 TI - The Brassinosteroid-Activated BRI1 Receptor Kinase Is Switched off by Dephosphorylation Mediated by Cytoplasm-Localized PP2A B' Subunits. AB - Brassinosteroid (BR) binding activates the receptor kinase BRI1 by inducing heterodimerization with its co-receptor kinase BAK1; however, the mechanisms that reversibly inactivate BRI1 remain unclear. Here we show that cytoplasm-localized protein phosphatase 2A (PP2A) B' regulatory subunits interact with BRI1 to mediate its dephosphorylation and inactivation. Loss-of-function and overexpression experiments showed that a group of PP2A B' regulatory subunits, represented by B'eta, negatively regulate BR signaling by decreasing BRI1 phosphorylation. BR increases the expression levels of these B' subunits, and B'eta interacts preferentially with phosphorylated BRI1, suggesting that the dynamics of BR signaling are modulated by the PP2A-mediated feedback inactivation of BRI1. Compared with PP2A B'alpha and B'beta, which promote BR responses by dephosphorylating the downstream transcription factor BZR1, the BRI1-inactivating B' subunits showed similar binding to BRI1 and BZR1 but distinct subcellular localization. Alteration of the nuclear/cytoplasmic localization of the B' subunits revealed that cytoplasmic PP2A dephosphorylates BRI1 and inhibits the BR response, whereas nuclear PP2A dephosphorylates BZR1 and activates the BR response. Our findings not only identify the PP2A regulatory B subunits that mediate the binding and dephosphorylation of BRI1, but also demonstrate that the subcellular localization of PP2A specifies its substrate selection and distinct effects on BR signaling. PMID- 26517939 TI - Target organ profiles in toxicity studies supporting human dosing: Does severity progress with longer duration of exposure? AB - We have previously reported the profile of target organs (defined as organs showing histopathological changes) in rodent and non-rodent toxicity studies conducted prior to first-time-in-man (FTiM) for 77 AstraZeneca candidate drugs (CDs). Here, we test the assumption that toxicity is exacerbated by dosing duration by comparing the incidence and severity of target organ toxicities in these <= 6 week FTiM studies with those observed in subsequent subchronic/chronic (>= 3 month) studies. Looking at the effect of dosing duration on severity (pathological score) and incidence (percentage of animals within the group) for the 39 CDs that met the criteria for inclusion (comparable doses between FTiM and subchronic/chronic studies), new toxicities appeared for 31 target organs but existing ones resolved for 29 target organs. Increased severity was more frequent for rodent (16 target organs) than for non-rodent (4 target organs). Most notable changes were a large increase in severity/incidence in liver and in non-rodent lung in contrast to a large decrease in severity and incidence for kidneys/ureter and for the non-rodent thymus. Overall this analysis shows that, even with continued exposure, target organ toxicities of CDs are as likely to show partial or complete recovery as they are to progress in severity. PMID- 26517940 TI - Porous membranes for ballast water treatment from microalgae-rich seawater. AB - The ballast waters from ships pose a major threat to oceans, notably because of the spread of microorganisms. The present study evaluates the techno-economic feasibility of implementing the membrane process to remove microalgae from seawater to be ballasted in a single step during planktonic bloom. The optimal conditions for the microfiltration of complex and reproducible synthetic seawater are a permeate flux and specific filtered volume of 100 L.h(-1).m(-2) and 75 L.m( 2).cycle(-1), respectively. Recovery of the membrane process represents about 76.6% and 62.7% of the annual cost for a cruise ship (5400 passengers) and liquefied natural gas (LNG) carrier (75,000 m3 of liquid natural gas), followed by the membrane replacement cost (13.4% and 21.9%, respectively). The treatment costs are competitive with conventional treatments, even when the membrane process is more feasible for cruise ships due to its smaller capital cost and footprint. PMID- 26517941 TI - Evaluation of the boundary condition influence on PAH concentrations in the water column during the sediment dredging of a port. AB - The mobilisation of sediments and related contaminants connected to dredging activities is one of the most critical issues to the environmental risk and exposure assessment of a dredging project. The aim of this paper was an investigation of the mobilisation of polycyclic aromatic hydrocarbons (PAHs) due to the dredging of the Port of Genoa (Italy) to identify the temporal and spatial extent of the contaminant transport, and the influence of the dredging and the boundary conditions on it. The results showed relatively low background PAH concentrations in the water column and confirmed the dredging as the primary rising factor of concentrations in the water column, but also showed a complex scenario in which the different environmental and dredging factors forced the concentrations at different levels and moments. The post dredging phase showed PAH values close to the background conditions and the concentrations remained relatively high only for a few PAHs. PMID- 26517942 TI - Modeling increased riverine nitrogen export: Source tracking and integrated watershed-coast management. AB - The global NEWS model was calibrated and then used to quantify the long term trend of dissolved inorganic nitrogen (DIN) export from two tributaries of Jiulong River (SE China). Anthropogenic N inputs contributed 61-92% of river DIN yield which increased from 337 in 1980s to 1662 kg N km(-2) yr(-1) in 2000s for the North River, and from 653 to 3097 kg N km(-2) yr(-1) for the West River. North River and West River contributed 55% and 45% respectively of DIN loading to the estuary. Rapid development and poor management driven by national policies were responsible for increasing riverine N export. Scenario analysis and source tracking suggest that reductions of anthropogenic N inputs of at least 30% in the North River (emphasis on fertilizer and manure) and 50% in the West River (emphasis on fertilizer) could significantly improve water quality and mitigate eutrophication in both river and coastal waters. PMID- 26517943 TI - Valence Tautomerization of High-Valent Manganese(V)-Oxo Corrole Induced by Protonation of the Oxo Ligand. AB - The addition of an organic acid to the manganese(V)-oxo corrole complex (tpfc)Mn(V)(O) (tpfc = 5,10,15-tris(pentafluorophenyl)corrole) induces valence tautomerization resulting in the formation of (tpfc(+*))Mn(IV)(OH) in acetonitrile at 298 K. The corrole radical cation manganese(IV) hydroxo complex has been fully characterized by EPR, (1)H NMR, and UV-vis spectroscopy. The reactivity of the valence tautomer (tpfc(+*))Mn(IV)(OH) is compared to that of (tpfc)Mn(V)(O) in three reaction types: hydrogen atom transfer (HAT), electron transfer (ET), and oxygen atom transfer (OAT). (tpfc(+*))Mn(IV)(OH) shows a dramatic 5 orders of magnitude enhancement in the rate of ET but surprisingly does not undergo OAT with PhSMe. The high-valent (tpfc)Mn(V)(O) complex is moderately more reactive toward HAT with substituted phenol and shows superior activity in OAT. PMID- 26517944 TI - Role of PACAP on testosterone and 17beta-estradiol production in the testis of wall lizard Podarcis sicula. AB - Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide that in mammalian testis is involved in the control of testosterone and 17beta-estradiol synthesis. A similar involvement was recently postulated in the testis of a nonmammalian vertebrate, the wall lizard Podarcis sicula. Indeed, we reported the presence of PACAP and its receptors throughout the reproductive cycle within both germ and somatic cells. Now, we investigated the effects of PACAP on steroidogenesis in significant periods of Podarcis reproductive cycle: winter stasis, reproductive period and summer stasis. Using different in vitro treatments, in the absence or presence of receptor antagonists, we demonstrated that in P. sicula testis PACAP is involved in the control of testosterone and 17beta-estradiol production. In particular we demonstrated that treatment with PACAP induced a testosterone increase only in stasis periods (winter and summer stasis); differently they induced a 17beta-estradiol production in all periods analyzed (summer stasis, winter stasis and reproductive period). PMID- 26517945 TI - A novel antagonist of CXCR4 prevents bone marrow-derived mesenchymal stem cell mediated osteosarcoma and hepatocellular carcinoma cell migration and invasion. AB - Recent findings suggest that bone marrow-derived mesenchymal stem cells (BM-MSCs) are recruited into the microenvironment of developing tumors, where they contribute to metastatic processes. The aim of this study was to investigate the role of BM-MSCs in promoting osteosarcoma and hepatocellular carcinoma cell progression in vitro and the possible mechanisms involved in these processes. U2OS and SNU-398 are osteosarcoma and hepatocellular carcinoma cell lines, respectively, that can be induced to proliferate when cultured in the presence of BM-MSCs. To determine the effect of BM-MSCs on U2OS and SNU-398 cells, the AKT and ERK signaling pathways were investigated, and increases were observed in active P-Akt and P-Erk forms. Moreover, BM-MSCs caused an increase in tumor cell migration and invasion that was derived from the enhancement of CXCR4 levels. Thus, when tumor cells were treated with the CXCR4 antagonist AMD3100, a reduction in their migration and invasion was observed. Furthermore, a new CXCR4 inhibitor, Peptide R, which was recently developed as an anticancer agent, was used to inhibit BM-MSC-mediated tumor invasion and to overcome AMD3100 toxicity. Taken together, these results suggest that inhibiting CXCR4 impairs the cross talk between tumor cells and BM-MSCs, resulting in reduced metastatic potential in osteosarcoma and hepatocellular carcinoma cells. PMID- 26517946 TI - Safety and Efficacy Analyses of Angioplasty and Stenting for Severe Intracranial Arterial Stenosis: A Single-Center Retrospective Study in China. AB - BACKGROUND: The value of percutaneous transluminal angioplasty and stenting (PTAS) in the context of aggressive medical treatment for severe intracranial artery stenosis (ICAS) is under debate. This study compared the effects of PTAS and aggressive medical treatment in patients with severe ICAS and transient ischemic attack or stroke. MATERIAL AND METHODS: A retrospective cohort study was performed. Patients with severe ICAS were assigned to a PTAS group or aggressive medical treatment group, according to the angiographic features of the stenotic lesions. The primary outcome was defined as stroke or death within 30 days or cerebral ischemia occurring ipsilaterally to the qualifying artery beyond 30 days. RESULTS: We included 220 patients: 48 in the PTAS group and 172 in the medical group. The median follow-up was 32 months. PTAS was not associated with an increased incidence of the primary outcomes (10/42 vs. 39/172, p=0.96) or increased risks of the secondary outcomes of stroke, cardiovascular events, major bleeding, or mortality. The results of log-rank tests did not support a significant difference in event-free survival as a primary outcome between the 2 groups (chi-square=0.07, p=0.79). Moreover, although not significantly greater, the mean survival of patients in the PTAS group appeared to be better than that among patients in the medical group, as indicated by the curve for cumulative survival. CONCLUSIONS: A suitable PTAS procedure is safe for patients with severe ICAS, and no significant differences in incidence of recurrent stroke or death were found between PTAS and aggressive medication treatment. PMID- 26517947 TI - Endovascular treatment of cerebral venous sinus thrombosis (CVST): Is a complete recanalization required for a good clinical outcome? AB - The usual therapy in cerebral venous sinus thrombosis (CVST) is based on anticoagulant treatment with adjusted-dose unfractionated heparin. When medical treatment fails, endovascular techniques, such as mechanical thrombectomy, are available. We report a case of a 21-year-old woman with a diagnosis of left CVST, treated by a neurointerventional approach with mechanical thrombectomy using the Penumbra((r)) System. Despite the fact that only incomplete recanalization was achieved, a gradual resolution of the thrombus and a progressive clinical improvement occurred. PMID- 26517948 TI - Distribution of Mitral Annular and Aortic Valve Calcium as Assessed by Unenhanced Multidetector Computed Tomography. AB - Aging is associated with calcium deposits in various cardiovascular structures, but patterns of calcium deposition, if any, are unknown. In search of such patterns, we performed quantitative assessment of mitral annular calcium (MAC) and aortic valve calcium (AVC) in a broad clinical sample. Templates were created from gated computed tomography (CT) scans depicting the aortic valve cusps and mitral annular segments in relation to surrounding structures. These were then applied to CT reconstructions from ungated, clinically indicated CT scans of 318 subjects, aged >=65 years. Calcium location was assigned using the templates and quantified by the Agatston method. Mean age was 76 +/- 7.3 years; 48% were men and 58% were white. Whites had higher prevalence (p = 0.03) and density of AVC than blacks (p = 0.02), and a trend toward increased MAC (p = 0.06). Prevalence of AVC was similar between men and women, but AVC scores were higher in men (p = 0.008); this difference was entirely accounted for by whites. Within the aortic valve, the left cusp was more frequently calcified than the others. MAC was most common in the posterior mitral annulus, especially its middle (P2) segment. For the anterior mitral annulus, the medial (A3) segment calcified most often. In conclusion, AVC is more common in whites than blacks, and more intense in men, but only in whites. Furthermore, calcium deposits in the mitral annulus and aortic valve favor certain locations. PMID- 26517949 TI - Effect of Right Ventricular Pacing on Right Ventricular Mechanics and Tricuspid Regurgitation in Patients With High-Grade Atrioventricular Block and Sinus Rhythm (from the Protection of Left Ventricular Function During Right Ventricular Pacing Study). AB - Right ventricular (RV) pacing has been linked with lead-induced tricuspid regurgitation (TR), left ventricular (LV) dysfunction, and dyssynchrony, but the effect of pacing on RV function is unclear. We sought to investigate the effect of pacing on RV synchrony, RV function, and TR, and their association with LV function. In this substudy of the PROTECT-PACE (Protection of left ventricular function during right ventricular pacing) study of the effects of RV pacing in patients with preserved ejection fraction, 145 patients (76 RV apex and 69 non-RV apex pacing) had measurable RV parameters. We assessed tricuspid annular plane systolic excursion (TAPSE), time difference between peak TAPSE and peak mitral annular plane systolic excursion (TM-APSE-dif), global LV longitudinal strain, E/e', TR vena contracta, and TR peak gradient. Echocardiography was performed just after implantation and at 2 years. TR parameters significantly worsened after 2 years, but pacing site was not associated with changes in RV and TR parameters. No temporal change in TAPSE and TM-APSE-dif was observed overall, but worsening of TM-APSE-dif was associated with worsening TAPSE. Global longitudinal strain and E/e' both deteriorated over 2 years; these changes were significantly associated. In a multivariate regression, worsening global longitudinal strain and worsening TM-APSE-dif were significantly associated with deterioration of TAPSE. Furthermore, increased E/e' and its deterioration were associated with worsening TR vena contracta and TR peak gradient, respectively. Decreased TAPSE was also associated with deterioration of TR vena contracta. In conclusion, RV pacing appears to worsen TR, an effect which might be caused by elevated LV filling pressure due to LV dysfunction. In this study, RV pacing did not affect RV function during 2-year follow-up, but such an effect might occur if RV dyssynchrony or LV dysfunction occurred after pacing. The effect of RV pacing site on RV and TR mechanics was minor. PMID- 26517950 TI - To reconsider (limit) the use of phosphate based food and beverages additives. A real need for health preservation. PMID- 26517951 TI - PhyreStorm: A Web Server for Fast Structural Searches Against the PDB. AB - The identification of structurally similar proteins can provide a range of biological insights, and accordingly, the alignment of a query protein to a database of experimentally determined protein structures is a technique commonly used in the fields of structural and evolutionary biology. The PhyreStorm Web server has been designed to provide comprehensive, up-to-date and rapid structural comparisons against the Protein Data Bank (PDB) combined with a rich and intuitive user interface. It is intended that this facility will enable biologists inexpert in bioinformatics access to a powerful tool for exploring protein structure relationships beyond what can be achieved by sequence analysis alone. By partitioning the PDB into similar structures, PhyreStorm is able to quickly discard the majority of structures that cannot possibly align well to a query protein, reducing the number of alignments required by an order of magnitude. PhyreStorm is capable of finding 93+/-2% of all highly similar (TM score>0.7) structures in the PDB for each query structure, usually in less than 60s. PhyreStorm is available at http://www.sbg.bio.ic.ac.uk/phyrestorm/. PMID- 26517952 TI - Role of TrkB kinase activity in aging diaphragm neuromuscular junctions. AB - Brain derived neurotrophic factor (BDNF) acting through the tropomyosin-related kinase receptor B (TrkB) enhances neuromuscular transmission in the diaphragm muscle of adult mice, reflecting presynaptic effects. With aging, BDNF enhancement of neuromuscular transmission is lost. We hypothesize that disrupting BDNF/TrkB signaling in early old age will reveal a period of susceptibility evident by morphological changes at neuromuscular junctions (NMJ). Adult, male TrkB(F616A) mice (n=25) at 6 and 18 months of age, were used to examine the structural properties of diaphragm muscle NMJs (n=1097). Confocal microscopy was used to compare pre- and post-synaptic morphology and denervation following a 7 day treatment with the phosphoprotein phosphatase-1 derivative 1NMPP1, which inhibits TrkB kinase activity in TrkB(F616A) mice vs. vehicle treatment. In early old age (18 months), presynaptic terminal volume decreased compared to 6 month old diaphragm NMJs (~20%). Inhibition of TrkB kinase activity significantly decreased the presynaptic terminal volume (~20%) and motor end-plate 2D planar area (~10%), independent of age group. Inhibition of TrkB kinase activity in early old age significantly reduced overlap of pre- and post-synaptic structures and increased the proportion of denervated NMJs (to ~20%). Collectively these results support a period of susceptibility in early old age when BDNF/TrkB signaling at diaphragm NMJs supports the maintenance of NMJs structure and muscle innervation. PMID- 26517953 TI - Prolonged performance of a high repetition low force task induces bone adaptation in young adult rats, but loss in mature rats. AB - We have shown that prolonged repetitive reaching and grasping tasks lead to exposure-dependent changes in bone microarchitecture and inflammatory cytokines in young adult rats. Since aging mammals show increased tissue inflammatory cytokines, we sought here to determine if aging, combined with prolonged performance of a repetitive upper extremity task, enhances bone loss. We examined the radius, forearm flexor muscles, and serum from 16 mature (14-18 months of age) and 14 young adult (2.5-6.5 months of age) female rats after performance of a high repetition low force (HRLF) reaching and grasping task for 12 weeks. Young adult HRLF rats showed enhanced radial bone growth (e.g., increased trabecular bone volume, osteoblast numbers, bone formation rate, and mid-diaphyseal periosteal perimeter), compared to age-matched controls. Mature HRLF rats showed several indices of radial bone loss (e.g., decreased trabecular bone volume, and increased cortical bone thinning, porosity, resorptive spaces and woven bone formation), increased osteoclast numbers and inflammatory cytokines, compared to age-matched controls and young adult HRLF rats. Mature rats weighed more yet had lower maximum reflexive grip strength, than young adult rats, although each age group was able to pull at the required reach rate (4 reaches/min) and required submaximal pulling force (30 force-grams) for a food reward. Serum estrogen levels and flexor digitorum muscle size were similar in each age group. Thus, mature rats had increased bone degradative changes than in young adult rats performing the same repetitive task for 12 weeks, with increased inflammatory cytokine responses and osteoclast activity as possible causes. PMID- 26517956 TI - Meta-analysis of the effect of tertiary survey on missed injury rate in trauma patients. AB - BACKGROUND: Missed injuries are considered as an important issue in trauma patients and can lead to significant morbidity and even mortality. It has been shown that the standard primary and secondary surveys, recommended by the Advanced Trauma Life Support (ATLS) guidelines, are associated with missed injuries. It has been suggested that tertiary survey can minimise the number and effect of missed injuries. The present paper aimed to identify comparative evidence about the effect of tertiary survey on missed injury rate in trauma patients. METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards, we performed a systematic review. Electronic databases MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched to identify randomised and non-randomised studies evaluating effect of tertiary survey on missed injury rate in trauma patients. The Newcastle-Ottawa scale was used to assess the methodological quality and risk of bias of the selected studies. Random-effects models were applied to calculate pooled outcome data. RESULTS: Four prospective and three retrospective cohort studies, enrolling a total of 12,581 trauma patients, were selected for analysis. Pooled odds ratio (OR) analysis of 5727 patients showed that detection of missed injuries was better in trauma patients who had tertiary survey compared to patients who did not have tertiary survey [OR=2.65, (95% CI:1.40-5.01), P=0.003]. A moderate level of heterogeneity among the studies existed (I(2)=68%, P=0.008). Also, analysis of 6,854 patients showed that fewer injuries were missed in trauma patients who had tertiary survey compared to patients who did not have tertiary survey [OR=0.63, (95% CI: 0.44 0.90), P=0.01]. CONCLUSIONS: The best available evidence demonstrates a constant trend in favour of tertiary survey in terms of missed injury reduction, and supports its use in management of trauma patients. Further studies are required to clarify the most cost-effective and systematic way of addressing missed injuries in the first 24h. We recommend use of "missed injury detection rate" and "missed injury rate" as two different outcomes in future studies in order to address the issue of heterogeneity in definition of missed injury in the current literature. PMID- 26517954 TI - The Impact of Motivational Interviewing on Delinquent Behaviors in Incarcerated Adolescents. AB - The impact of Motivational Interviewing (MI) on risky behaviors of incarcerated adolescents and adults has been investigated with promising results. Findings suggest that MI reduces substance use, improves motivation and confidence to reduce use, and decreases risky behaviors. The current study investigated the impact of MI on general, alcohol-related, and marijuana-related delinquent behaviors in incarcerated adolescents. Participants in the study were incarcerated adolescents in a state correctional facility in the Northeast region and were assessed as part of a larger randomized clinical trial. Adolescents were randomly assigned to receive MI or relaxation therapy (RT) (N=189) treatment. Delinquent behaviors and depressive symptomatology were measured using the Delinquent Activities Scale (DAS; Reavy, Stein, Paiva, Quina, & Rossi, 2012) and the Center for Epidemiological Studies-Depression scale (CES-D; Radloff, 1991) respectively. Findings indicate that depression moderated treatment effects. Compared to RT, MI was better at reducing predatory aggression and alcohol related predatory aggression 3 months post-release when depressive symptoms were low. Identifying an efficacious treatment for these adolescents may benefit society in that it may decrease crimes against persons (i.e., predatory aggression) post release. PMID- 26517957 TI - Minimally invasive approach to the radial nerve--A new technique. AB - PURPOSE: To describe a minimally invasive approach to find the radial nerve (RN) simply and safely by tracing the posterior antebrachial cutaneous nerve (PACN) without damaging muscles, using only the surgeon's hand to define a window for the skin incision. BACKGROUND: Although it is absolutely necessary to locate the radial nerve during osteosynthesis of the humerus, the literature lacks guidelines on how to do so. METHODS: We have dissected the upper extremities of 54 adult human cadavers, embalmed using Thiel's method. After the PACN was identified in a defined space, its course was traced proximally by incising the lateral intermuscular septum (LIS) of the upper arm and thereby reaching the radial nerve (RN). Subsequently, using the lateral epicondyle (LE) of the humerus as a reference point, the distances to the points where the PACN perforated the LIS, and where the RN was identified, were measured. These individual data were related to the total length of the humerus. RESULTS: The results indicate that with this approach and without harming musculature, the RN can be reached by tracing the PACN at a height of 11.1-13.0 cm (females) and 11.9-14.0 cm (males) starting from the LE. CONCLUSION: Our examination shows the PACN to be a convenient guide to the RN. PMID- 26517958 TI - Structural characterization and anti-tumor activity of polysaccharide produced by Hirsutella sinensis. AB - HSP-III, a novel homogeneous polysaccharide with 513.89 kDa molecular weight, was fractionated from submerged cultures of Hirsutella sinensis by Sevag and chromatography on Sephadex G-100 column. The total sugar content of HSP-III was amounted to 89.87%. Based on the results of high performance gel permeation chromatogram (HPGPC), FT-IR, NMR spectroscopy, GC, periodate oxidation-smith degradation and methylation analysis, it showed that HSP-III was mainly composed of mannose and galactose, and a small amount of rhamnose, arabinose, xylose, and glucose. The molar ratio of Rha:Ara:Xyl:Man:Glu:Gal was 1.00:2.44:13.11:74.13:13.80:54.39. The main chain of HSP-III was majorly composed of (1->3) glucose. The tumor inhibition ratio on H22 cell was 79.04% at 100 MUg/mL of HSP-III. PMID- 26517959 TI - Purification and characterization of Ras related protein, Rab5a from Tinospora cordifolia. AB - Ras related protein (Rab5a) is one of the most important member of the Rab family which regulates the early endosome fusion in endocytosis, and it also helps in the regulation of the budding process. Here, for the first time we report a simple and reproducible method for the purification of the Rab5a from a medicinal plant Tinospora cordifolia. We have used weak cation-exchange (CM-Sepharose-FF) followed by gel-filtration chromatography. A purified protein of 22-kDa was observed on SDS-PAGE which was identified as Rab5a using MALDI-TOF/MS. Our purification procedure is fast and simple with high yield. The purified protein was characterized using circular dichroism for the measurement of secondary structure followed by GdmCl- and urea-induced denaturation to calculate the values of Gibbs free energy change (DeltaGD), DeltaGD degrees , midpoint of the denaturation Cm, i.e. molar GdmCl [GdmCl] and molar urea [Urea] concentration at which DeltaGD=0; and m, the slope (=?DeltaGD/?[d]) values. Furthermore, thermodynamic properties of Rab5a were also measured by differential scanning calorimeter. Here, using isothermal calorimeteric measurements we further showed that Rab5a binds with the GTP. This is a first report on the purification and biophysical characterization of Rab5a protein from T. cordifolia. PMID- 26517960 TI - In vitro characterization of insulin containing thiomeric microparticles as nasal drug delivery system. AB - This study focused on a novel two step preparation method for the generation of insulin containing thiomer microparticles. The first step utilized the interpolymer complexation between poly(vinyl pyrrolidone) (PVP) and poly(acrylic acid) (PAA) or poly(acrylic acid)-cysteine (PAA-Cys), respectively, in the presence of insulin. Thereafter lyophilized coprecipitates were micronized via air jet mill. Particles were evaluated regarding size, morphology, insulin release and the effect on ciliary beat frequency of human nasal epithelial cells in vitro. Results displayed mean particle sizes of 2.6+/-1.6MUm and 2.8+/-1.7MUm for PAA/PVP/insulin and PAA-Cys/PVP/insulin microparticles, respectively, in a range where volitional impaction of particles on nasal epithelium takes place. Multi unit dosage forms showed in addition release for the incorporated insulin and nasal safety as to results of ciliary beat frequency studies (CBF). The introduced jet milled microparticles might in conclusion display a safe nasal insulin drug delivery system leading to improved absorption. PMID- 26517961 TI - Synthesis and characterization of a novel radioiodinated phenylacetamide and its homolog as theranostic agents for malignant melanoma. AB - Melanin is an attractive target for the diagnosis and treatment of malignant melanoma. This study reports the preparation and biological characterizations of N-(2-(diethylamino)ethyl)-2-(3-(123/131)I-iodo-4- hydroxyphenyl)acetamide and N (2-(diethylamino)ethyl)-3-(3-(123/131)I-iodo-4-hydroxyphenyl)propanamide (123/131)I-IHPA and 123/131I-IHPP) as novel melanin-specific theranostic agents. These two tracers were hydrophilic, exhibited good serum stability and high binding affinity to melanin. In vitro and in vivo studies revealed rapid, high and tenacious uptakes of both 131I-IHPA and 131I-IHPP in melanotic B16F0 cell line and in C57BL/6 mice bearing B16F0 melanoma, but not in amelanonic A375 cell line and tumors. Small-animal SPECT imaging also clearly delineate B16F0 melanoma since 1 h postinjection of 123I-IHPA and 123I-IHPP in tumor-bearing mice. Owing to the favorable biodistribution of 131I-IHPA and 131I-IHPP after intravenous administration, the estimated absorption dose was low in most normal organs and relatively high in melanotic tumor. The melanin-specific binding ability, sustained tumor retention, fast normal tissues clearance and acceptable projected human dosimetry supported that these two tracers are promising theranostic agents for melanin-positive melanoma. PMID- 26517963 TI - Pharmacokinetics, tissue distribution and excretion of 40kDa PEG and PEGylated rFVIII (N8-GP) in rats. AB - The biologic fate of the [(3)H]PEG-moiety incorporated into N8-GP was evaluated based on single i.v. bolus doses to rats. Furthermore, the 40kDa [(3)H]PEG-moiety was given separately to rats by single i.v. bolus doses, to investigate if the pharmacokinetics were dose-dependent. For both compounds, plasma pharmacokinetics, distribution and excretion pathways were investigated, based on total radioactivity measurements ([(3)H]N8-GP: 0.17-4.1mg/kg;~1300-30,000U/kg, PEG load of ~0.03-0.7mg/kg); ([(3)H]PEG: 0.6, 1, 12, 100 and 200mg/kg). The plasma concentration of the intact N8-GP conjugate was also measured by ELISA. After single i.v. administration to rats, both [(3)H]N8-GP and [(3)H]PEG were shown to be widely distributed, mainly in highly vascularized tissues, with the lowest levels of radioactivity found in the CNS. Though a slow elimination of radioactivity was observed over the 12-week study period, approximately half of the radioactive dose of either compound was removed from the body 1week post dose. The radioactivity was eliminated mainly via the kidney into urine but also via the liver into feces, with a larger fraction found in the feces for [(3)H]N8 GP. Elimination of the 40kDa PEG-moiety was shown to be dose-dependent with faster elimination at lower dose levels. The clinical dose of N8-GP provides a substantially lower PEG exposure (50-75U/kg; PEG load of <0.002mg/kg) when compared to the PEG doses investigated in this paper (0.03-200mg/kg). This may imply an even faster clearance of the PEG-moiety after N8-GP administration of clinically relevant doses. PMID- 26517962 TI - Development and in vitro evaluation of core-shell type lipid-polymer hybrid nanoparticles for the delivery of erlotinib in non-small cell lung cancer. AB - Core-shell type lipid-polymer hybrid nanoparticles (CSLPHNPs) have emerged as a multifunctional drug delivery platform. The delivery system combines mechanical advantages of polymeric core and biomimetic advantages of the phospholipid shell into a single platform. We report the development of CSLPHNPs composed of the lipid monolayer shell and the biodegradable polymeric core for the delivery of erlotinib, an anticancer drug, clinically used to treat non-small cell lung cancer (NSCLC). Erlotinib loaded CSLPHNPs were prepared by previously reported single-step sonication method using polycaprolactone (PCL) as the biodegradable polymeric core and phospholipid-shell composed of hydrogenated soy phosphatidylcholine (HSPC) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [methoxy(polyethylene glycol)-2000 (DSPE-PEG2000). Erlotinib loaded CSLPHNPs were characterized for physicochemical properties including mean particle size, polydispersity index (PDI), zeta potential, morphology, thermal and infrared spectral analysis, drug loading, in vitro drug release, in vitro serum stability, and storage stability. The effect of critical formulation and process variables on two critical quality attributes (mean particle size and drug entrapment efficiency) of erlotinib loaded CSLPHNPs was studied and optimized. In addition, in vitro cellular uptake, luminescent cell viability assay and colony formation assay were performed to evaluate efficacy of erlotinib loaded CSLPHNPs in A549 cells, a human lung adenocarcinoma cell line. Optimized erlotinib loaded CSLPHNPs were prepared with mean particle size of about 170nm, PDI<0.2, drug entrapment efficiency of about 66% with good serum and storage stability. The evaluation of in vitro cellular efficacy results indicated enhanced uptake and efficacy of erlotinib loaded CSLPHNPs compared to erlotinib solution in A549 cells. Therefore, CSLPHNPs could be a potential delivery system for erlotinib in the therapy of NSCLC. PMID- 26517964 TI - Postnatal survival after endoscopic equatorial laser for the treatment of twin-to twin transfusion syndrome. AB - BACKGROUND: Endoscopic laser coagulation of placental anastomoses is the first line treatment for severe twin-to-twin transfusion syndrome. A recent randomized controlled trial reported that laser coagulation along the entire vascular equator was associated with a similar dual survival and survival of at least 1 twin compared with the group that was treated with the selective technique. In addition, there was a significantly lower incidence of postoperative recurrence of twin-to-twin transfusion syndrome and the development of twin anemia polycythemia sequence in the equatorial group. OBJECTIVE: The purpose of this study was to report on neonatal survival in twin-to-twin transfusion syndrome pregnancies that were treated with endoscopic laser therapy with the use of the equatorial technique and to examine the relationship between preoperative factors and twin loss. STUDY DESIGN: Endoscopic equatorial laser therapy was carried out as the primary treatment for twin-to-twin transfusion syndrome in all consecutive monochorionic diamniotic twin pregnancies that were referred at a single fetal surgery Center over a 4-year period. All visible placental anastomoses were coagulated; additional laser ablation of the placental tissue between the coagulated vessels was carried out. Pre-laser ultrasound data, periprocedural complications, pregnancy outcome, and postnatal survival at hospital discharge were recorded and analyzed. RESULTS: A total of 106 pregnancies were treated during the study period. Median gestational age at laser therapy was 19.7 weeks (range, 15.1-27.6 weeks). There was postoperative recurrence of twin-to-twin transfusion syndrome or the development of twin anemia-polycythemia sequence in 2 (1.9%) and 2 (1.9%) cases, respectively. The survival rates of both and at least 1 twin were 56.6% and 83.0%, respectively. Donor survival was significantly lower compared with the recipient co-twin (64.2% vs 75.5%, respectively; P < .05). The rate of fetal death, which was the most common cause of twin loss, was significantly higher in donors compared with recipient fetuses (23.6% vs 10.4%, respectively; P < .05). In cases with absent or reversed end-diastolic velocity in the donor umbilical artery, dual and donor survival rates were significantly lower compared with the remaining twin-to-twin transfusion syndrome pregnancies (40.0% vs 64.8% and 40.0% vs 76.1%, respectively; P < .05). There were no significant differences between the 2 groups in the survival of at least 1 twin and in the recipient survival. CONCLUSIONS: Endoscopic equatorial laser therapy was associated with a survival of both and at least 1 twin of approximately 55% and 83%, respectively, with a low rate of recurrent twin-to-twin transfusion syndrome and twin anemia-polycythemia sequence. In addition, the preoperative finding of abnormal donor umbilical artery Doppler on ultrasound identified a subgroup of twin-to-twin transfusion syndrome pregnancies with a lower dual survival rate caused by increased intrauterine deaths of donor twins. PMID- 26517965 TI - Blood flow-restricted walking in older women: does the acute hormonal response associate with muscle hypertrophy? AB - Low-load exercise can increase serum hormones such as growth hormone (GH) concentration in young adults when combined with blood flow restriction (BFR), but it is unclear whether walking with BFR (BFR-walk) can elevate them for older adults. Furthermore, it remained untested whether changes in these purported anabolic hormones contribute to BFR-walk-induced muscle hypertrophy. To examine the relationship between the acute and chronic effects of BFR-walk, seven women (age: 64 +/- 2 years) performed treadmill walking with (BFR-walk) and without BFR (CON-walk) at 45% of heart rate reserve for 20 min in a randomized crossover design. During BFR-walk, subjects wore 5-cm cuffs on the proximal part of the upper legs. Blood samples were taken before (PRE), immediately after (POST-1) and 15 min post (POST-2) exercise. There was a main effect of time for GH (P<0.01) with levels increasing following exercise. In addition, there was a condition and time main effect for insulin; with insulin increasing to a greater degree with BFR at POST-2. Noradrenaline increased across time for both BFR-walk (P = 0.012) and CON-walk (P<0.001); but BFR-walk induced greater elevations at POST-1 and POST-2. The change in GH, insulin and noradrenaline was not significantly correlated with BFR-walk-induced muscle hypertrophy. These preliminary results suggest that the BFR-walk-induced elevation in the purported anabolic hormones may not have a large impact on muscle growth. PMID- 26517966 TI - Expression of polyQ aggregates in Malpighian tubules leads to degeneration in Drosophila melanogaster. AB - BACKGROUND: Polyglutamine (polyQ) disorders are caused by expanded CAG (Glutamine) repeats in neurons in the brain. The expanded repeats are also expressed in the non-neuronal cells, however, their contribution to disease pathogenesis is not very well studied. In the present study, we have expressed a stretch of 127 Glutamine repeats in Malpighian tubules (MTs) of Drosophila melanogaster as these tissues do not undergo ecdysone induced histolysis during larval to pupal transition at metamorphosis. RESULTS: Progressive degeneration, which is the hallmark of neurodegeneration is also observed in MTs. The mutant protein forms inclusion bodies in the nucleus resulting in expansion of the nucleus and affect chromatin organization which appear loose and open, eventually resulting in DNA fragmentation and blebbing. A virtual absence of tubule lumen was observed followed by functional abnormalities. As development progressed, severe abnormalities affecting pupal epithelial morphogenesis processes were observed resulting in complete lethality. Distribution of heterogeneous RNA binding protein (hnRNP), HRB87F, Wnt/wingless and JNK signaling and expression of Relish was also found to be affected. Expression of resistance genes following polyQ expression was up regulated. CONCLUSION: The present study gives an insight into the effects of polyQ aggregates in non-neuronal tissues. PMID- 26517967 TI - The spatio-temporal domains of Frizzled6 action in planar polarity control of hair follicle orientation. AB - In mammals, hair follicles cover most of the body surface and exhibit precise and stereotyped orientations relative to the body axes. Follicle orientation is controlled by the planar cell polarity (PCP; or, more generally, tissue polarity) system, as determined by the follicle mis-orientation phenotypes observed in mice with PCP gene mutations. The present study uses conditional knockout alleles of the PCP genes Frizzled6 (Fz6), Vangl1, and Vangl2, together with a series of Cre drivers to interrogate the spatio-temporal domains of PCP gene action in the developing mouse epidermis required for follicle orientation. Fz6 is required starting between embryonic day (E)11.5 and E12.5. Eliminating Fz6 in either the anterior or the posterior halves of the embryo or in either the feet or the torso leads to follicle mis-orientation phenotypes that are limited to the territories associated with Fz6 loss, implying either that PCP signaling is required for communicating polarity information on a local but not a global scale, or that there are multiple independent sources of global polarity information. Eliminating Fz6 in most hair follicle cells or in the inter-follicular epidermis at E15.5 suggests that PCP signaling in developing follicles is not required to maintain their orientation. The asymmetric arrangement of Merkel cells around the base of each guard hair follicle dependents on Fz6 expression in the epidermis but not in differentiating Merkel cells. These experiments constrain current models of PCP signaling and the flow of polarity information in mammalian skin. PMID- 26517968 TI - A critical role for alpha-synuclein in development and function of T lymphocytes. AB - Alpha-synuclein is highly expressed in the central nervous system and plays an important role in pathogenesis of neurodegenerative disorders such as Parkinson's disease and Lewy body dementia. Previous studies have demonstrated the expression of alpha-synuclein in hematopoietic elements and peripheral blood mononuclear cells, although its roles in hematopoiesis and adaptive immunity are not studied. Using an alpha-synuclein knock out (KO) mouse model, we have recently shown that alpha-synuclein deficiency is associated with a mild defect in late stages of hematopoiesis. More importantly, we demonstrated a marked defect in B lymphocyte development and IgG, but not IgM production in these mice. Here we show a marked defect in development of T lymphocytes in alpha-synuclein KO mice demonstrated by a significant increase in the number of CD4 and CD8 double negative thymocytes and significant decreases in the number of CD4 single positive and CD8 single positive T cells. This resulted in markedly reduced peripheral T lymphocytes. Interestingly, splenic CD4(+) and CD8(+) T cells that developed in alpha synuclein KO mice had a hyperactivated state with higher expression of early activation markers and increased IL-2 production. Moreover, splenic CD4(+) T cells from alpha-synuclein KO mice produced lower levels of IL-4 upon antigenic stimulation suggesting a defective Th2 differentiation. Our data demonstrate an important role for alpha-synuclein in development of T lymphocytes and regulation of their phenotype and function. PMID- 26517969 TI - Structured telephone support or non-invasive telemonitoring for patients with heart failure. AB - BACKGROUND: Specialised disease management programmes for heart failure aim to improve care, clinical outcomes and/or reduce healthcare utilisation. Since the last version of this review in 2010, several new trials of structured telephone support and non-invasive home telemonitoring have been published which have raised questions about their effectiveness. OBJECTIVES: To review randomised controlled trials (RCTs) of structured telephone support or non-invasive home telemonitoring compared to standard practice for people with heart failure, in order to quantify the effects of these interventions over and above usual care. SEARCH METHODS: We updated the searches of the Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology AsseFssment Database (HTA) on the Cochrane Library; MEDLINE (OVID), EMBASE (OVID), CINAHL (EBSCO), Science Citation Index Expanded (SCI EXPANDED), Conference Proceedings Citation Index- Science (CPCI-S) on Web of Science (Thomson Reuters), AMED, Proquest Theses and Dissertations, IEEE Xplore and TROVE in January 2015. We handsearched bibliographies of relevant studies and systematic reviews and abstract conference proceedings. We applied no language limits. SELECTION CRITERIA: We included only peer-reviewed, published RCTs comparing structured telephone support or non-invasive home telemonitoring to usual care of people with chronic heart failure. The intervention or usual care could not include protocol-driven home visits or more intensive than usual (typically four to six weeks) clinic follow-up. DATA COLLECTION AND ANALYSIS: We present data as risk ratios (RRs) with 95% confidence intervals (CIs). Primary outcomes included all-cause mortality, all-cause and heart failure-related hospitalisations, which we analysed using a fixed-effect model. Other outcomes included length of stay, health-related quality of life, heart failure knowledge and self care, acceptability and cost; we described and tabulated these. We performed meta-regression to assess homogeneity (the null hypothesis) in each subgroup analysis and to see if the effect of the intervention varied according to some quantitative variable (such as year of publication or median age). MAIN RESULTS: We include 41 studies of either structured telephone support or non invasive home telemonitoring for people with heart failure, of which 17 were new and 24 had been included in the previous Cochrane review. In the current review, 25 studies evaluated structured telephone support (eight new studies, plus one study previously included but classified as telemonitoring; total of 9332 participants), 18 evaluated telemonitoring (nine new studies; total of 3860 participants). Two of the included studies trialled both structured telephone support and telemonitoring compared to usual care, therefore 43 comparisons are evident.Non-invasive telemonitoring reduced all-cause mortality (RR 0.80, 95% CI 0.68 to 0.94; participants = 3740; studies = 17; I2 = 24%, GRADE: moderate quality evidence) and heart failure-related hospitalisations (RR 0.71, 95% CI 0.60 to 0.83; participants = 2148; studies = 8; I2 = 20%, GRADE: moderate-quality evidence). Structured telephone support reduced all-cause mortality (RR 0.87, 95% CI 0.77 to 0.98; participants = 9222; studies = 22; I2 = 0%, GRADE: moderate quality evidence) and heart failure-related hospitalisations (RR 0.85, 95% CI 0.77 to 0.93; participants = 7030; studies = 16; I2 = 27%, GRADE: moderate quality evidence).Neither structured telephone support nor telemonitoring demonstrated effectiveness in reducing the risk of all-cause hospitalisations (structured telephone support: RR 0.95, 95% CI 0.90 to 1.00; participants = 7216; studies = 16; I2 = 47%, GRADE: very low-quality evidence; non-invasive telemonitoring: RR 0.95, 95% CI 0.89 to 1.01; participants = 3332; studies = 13; I2 = 71%, GRADE: very low-quality evidence).Seven structured telephone support studies reported length of stay, with one reporting a significant reduction in length of stay in hospital. Nine telemonitoring studies reported length of stay outcome, with one study reporting a significant reduction in the length of stay with the intervention. One telemonitoring study reported a large difference in the total number of hospitalisations for more than three days, but this was not an analysis of length of stay per hospitalisation. Nine of 11 structured telephone support studies and five of 11 telemonitoring studies reported significant improvements in health-related quality of life. Nine structured telephone support studies and six telemonitoring studies reported costs of the intervention or cost effectiveness. Three structured telephone support studies and one telemonitoring study reported a decrease in costs and two telemonitoring studies reported increases in cost, due both to the cost of the intervention and to increased medical management. Adherence was rated between 55.1% and 98.5% for those structured telephone support and telemonitoring studies which reported this outcome. Participant acceptance of the intervention was reported in the range of 76% to 97% for studies which evaluated this outcome. Seven of nine studies that measured these outcomes reported significant improvements in heart failure knowledge and self-care behaviours. AUTHORS' CONCLUSIONS: For people with heart failure, structured telephone support and non-invasive home telemonitoring reduce the risk of all-cause mortality and heart failure-related hospitalisations; these interventions also demonstrated improvements in health-related quality of life and heart failure knowledge and self-care behaviours. Studies also demonstrated participant satisfaction with the majority of the interventions which assessed this outcome. PMID- 26517970 TI - Evaluation of Permanent or Transient Complete Heart Block after Open Heart Surgery for Congenital Heart Disease. AB - BACKGROUND: The features of pediatric patients with postoperative transient and permanent complete atrioventricular (AV) block (CAVB) were compared. METHODS: Patients who developed CAVB in postoperative period after congenital cardiac surgery between 2010-2015 were included in the study. They were classified as patients with transient CAVB and with permanent CAVB. The demographics and perioperative and postoperative variables of the groups were evaluated. RESULTS: A total of 1,550 patients underwent surgery during the study period. CAVB was determined in 96 patients (6.2%) in the early postoperative period: 66 had transient CAVB, 30 had permanent CAVB that necessitated pacemaker implantation. The median body weight and age at surgery were similar in both groups. The most frequent diagnosis was tetralogy of Fallot (TOF, n = 22), complete AV septal defect (AVSD, n = 15), and ventricular septal defect (n = 13). Junctional ectopic tachycardia (JET) developed in 27 patients with transient CAVB and in four with permanent CAVB (P < 0.05). There were no significant differences in the congenital cardiac pathology, the cardiopulmonary bypass time, cross-clamp time, and the presence of preoperative arrhythmia between the groups (P > 0.05). The duration of intensive care unit stay was 6 days (range 2-25) for patients with transient CAVB and 13 days (range 4-90) for patients with permanent CAVB. The duration of hospital stay was 10 days (range 2-33) for patients with transient CAVB and 20 days (range 10-90) for patients with permanent CAVB. Both were significantly longer in the patients with permanent CAVB. CONCLUSIONS: Complete AVSD and TOF are the most risky operations for the development of postoperative AV block. Ninety-seven percent of the patients with transient CAVB regained AV conduction within the first 10 postoperative days. The high incidence of JET in patients with transient CAVB was striking. PMID- 26517971 TI - Organization of the nitrergic neuronal system in the primitive bony fishes Polypterus senegalus and Erpetoichthys calabaricus (Actinopterygii: Cladistia). AB - Cladistians are a group of basal actinopterygian fishes that constitute a good model for studying primitive brain features, most likely present in the ancestral bony fishes. The analysis of the nitrergic neurons (with the enzyme nitric oxide synthase; NOS) has helped in understanding important aspects of brain organization in all vertebrates studied. We investigated the nitrergic system of two cladistian species by means of specific antibodies against NOS and NADPH diaphorase (NADPH-d) histochemistry, which, with the exception of the primary olfactory and terminal nerve fibers, labeled only for NADPH-d, yielded identical results. Double immunohistochemistry was conducted for simultaneous detection of NOS with tyrosine hydroxylase, choline acetyltransferase, calbindin, calretinin, and serotonin, to establish accurately the localization of the nitrergic neurons and fibers and to assess possible interactions between these neuroactive substances. The pattern of distribution in both species showed only subtle differences in the density of labeled cells. Distinct groups of NOS immunoreactive cells were observed in pallial and subpallial areas, paraventricular region, tuberal and retromammillary hypothalamic areas, posterior tubercle, prethalamic and thalamic areas, optic tectum, torus semicircularis, mesencephalic tegmentum, interpeduncular nucleus, superior and middle reticular nuclei, magnocellular vestibular nucleus, solitary tract nucleus, nucleus medianus magnocellularis, the spinal cord and amacrine cells in the retina. Large neurons in cranial nerve sensory ganglia were also labeled. The comparison of these results with those from other vertebrates, using a neuromeric analysis, reveals a conserved pattern of organization of the nitrergic system from this primitive fish group to amniotes, including mammals. PMID- 26517972 TI - Transplacental Transfer of Interleukin-1 Receptor Agonist and Antagonist Following Maternal Immune Activation. AB - PROBLEM: Prenatal exposure to inflammation increases the incidence of neonatal brain injury. This raise the question whether maternally produced cytokines, especially interleukin (IL)-1 elevated in pathological pregnancies and known to alter fetal development, can cross the placental barrier and affect the fetus directly. METHOD OF STUDY: We addressed if IL-1 agonist/antagonist could cross the placenta. RESULTS: Radiolabelled-IL-1 injected maternally reached the fetus in minimal amount. 3% of the amount detected within the placenta was transferred into the fetal liver and less than 1% recovered in the fetal brain 30 min after the injection Importantly, transfer of IL-1 was not affected by maternal exposure to LPS. Maternal administration of IL-1 receptor antagonist also reached the fetus in low concentration. CONCLUSIONS: This suggests that minimal amount of maternally produced IL-1 family members cross the placental barrier. Their negative effects are likely indirect, through their deleterious placental actions. PMID- 26517973 TI - Objective measurement of erythema in psoriasis using digital color photography with color calibration. AB - BACKGROUND: Traditional metrics for evaluating the severity of psoriasis are subjective, which complicates efforts to measure effective treatments in clinical trials. METHODS: We collected images of psoriasis plaques and calibrated the coloration of the images according to an included color card. Features were extracted from the images and used to train a linear discriminant analysis classifier with cross-validation to automatically classify the degree of erythema. The results were tested against numerical scores obtained by a panel of dermatologists using a standard rating system. RESULTS: Quantitative measures of erythema based on the digital color images showed good agreement with subjective assessment of erythema severity (kappa = 0.4203). The color calibration process improved the agreement from kappa = 0.2364 to kappa = 0.4203. CONCLUSION: We propose a method for the objective measurement of the psoriasis severity parameter of erythema and show that the calibration process improved the results. PMID- 26517974 TI - Pediatric Inpatient Headache Therapy: What is Available. AB - Status migrainosus is defined by the international classification of headache disorders (ICHD) criteria as a debilitating migraine lasting more then 72 hours. The epidemiology of status migrainosus is still unknown in adult and children, and frequently underdiagnosed. Children and adolescents often end up in the emergency room with an intractable headache that failed outpatient therapy. Six to seven percent of these children do not respond to acute infusion therapy and require hospitalization. It is imperative that more aggressive therapy is considered when patients are affected by a severe intractable headache to prevent further disability and returning the child to baseline activity. Multiple therapies are available for adults and children. Studies for acute therapy in the emergency room are available in adults and pediatric groups. Small studies are available for inpatient therapy in children and, along with available therapies for children and adolescents, are described in this review. A review of the literature shows growing evidence regarding the use of dihydroergotamine intravenously once patients are hospitalized. Effectiveness and safety have been proven in the last decades in adults and small studies in the pediatric populations. PMID- 26517975 TI - Sample-directed pseudotargeted method for the metabolic profiling analysis of rice seeds based on liquid chromatography with mass spectrometry. AB - Rice is one of the most important food crops in the world. Metabolite composition in rice seeds varies significantly depending on genetic variety, climatic alternation and agricultural practice. Metabolomics is a powerful tool to reveal the metabolic response of rice to various conditions. In this work, a rice seed sample-directed pseudotargeted metabolomics method was first established and validated based on ultra high performance liquid chromatography with triple quadrupole mass spectrometry in the multiple reaction monitoring mode. A total of 749 and 617 ion pairs in positive and negative modes were achieved, respectively. Among them, about 200 metabolites were identified or tentatively identified. The developed method showed better linearity and repeatability than those of non targeted metabolomics method. Good intra-day and inter-day precisions, recoveries and wide linear range were also obtained. Furthermore, the method was applied for the investigation of metabolic variation of rice seeds with two wild cultivars and their transgenic lines that were grown in two locations. Principal component analysis indicated that the effects of cultivar and location on metabolic variations were far more than those of gene modification. The nonparametric Mann Whitney U test revealed that most metabolites were influenced by cultivar, location and gene modifications together. PMID- 26517976 TI - The forgotten yeast model of Hailey-Hailey disease. PMID- 26517977 TI - Experimental and simulation studies on focused ultrasound triggered drug delivery. AB - To improve drug delivery efficiency in cancer therapy, many researchers have recently concentrated on drug delivery systems that use anticancer drug loaded micro- or nanoparticles. In addition, induction methods, such as ultrasound, magnetic field, and infrared light, have been considered as active induction methods for drug delivery. Among these, focused ultrasound has been regarded as a promising candidate for the active induction method of drug delivery system because it can penetrate a deep site in soft tissue, and its energy can be focused on the targeted lesion. In this research, we employed focused ultrasound as an active induction method. For an anticancer drug loaded microparticles, we fabricated poly-lactic-co-glycolic acid docetaxel (PLGA-DTX) nanoparticle encapsulated alginate microbeads using the single-emulsion technique and the aeration method. To select the appropriate operating parameter for the focused ultrasound, we measured the pressure and temperature induced by the focused ultrasound at the focal area using a needle-type hydrophone and a digital thermal detector, respectively. Additionally, we conducted a simulation of focused ultrasound using COMSOL Multiphysics 4.3a. The experimental measurement results were compared with the simulation results. In addition, the drug release rates of the PLGA-DTX-encapsulated alginate microbeads induced by the focused ultrasound were tested. Through these experiments, we determined that the appropriate focused ultrasound parameter was peak pressure of 1 MPa, 10 cycle/burst, and burst period of 20 MUSec. Finally, we performed the cell cytotoxicity and drug uptake test with focused ultrasound induction and found that the antitumor effect and drug uptake efficiency were significantly enhanced by the focused ultrasound induction. Thus, we confirmed that focused ultrasound can be an effective induction method for an anticancer drug delivery system. PMID- 26517978 TI - Characterization and follow-up of esophagogastric junction outflow obstruction detected by high resolution manometry. AB - BACKGROUND: Esophagogastric junction outflow obstruction (EGJOO) is a newly described diagnostic entity growing in importance due to the use of high resolution manometry (HRM). There is little knowledge regarding its incidence, etiopathogeny, long-term evolution, and most suitable treatment. Our objective was to increase the awareness of EGJOO to optimize the management of these patients. METHODS: We conducted a historical (retrospective and prospective) study of patients diagnosed with EGJOO using HRM combined with multichannel intraluminal impedance, comparing their manometric and impedance characteristics with those of a control group. Symptoms, etiology of obstruction, acid exposure, clinical course (and its associated factors), and response to treatment were also evaluated in the EGJOO group. KEY RESULTS: Forty-four subjects were included (28 patients and 16 controls). Esophagogastric junction outflow obstruction patients presented incomplete esophageal transit more frequently than controls. Patients with structural obstruction had dysphagia more frequently than patients with functional obstruction, and different manometric, impedance, and pH-metric patterns. Over one-third of the EGJOO patients presented a spontaneous resolution of symptoms without EGJOO treatment. In the multivariate analysis, the variables associated with this spontaneous symptomatic resolution included typical symptoms of gastro-esophageal reflux disease or epigastralgia as the main symptom and resting or basal pressure of the upper esophageal sphincter <50 mmHg. CONCLUSIONS & INFERENCES: The majority of EGJOO patients presented intact peristalsis which may compensate for the lack of EGJ relaxation. In the EGJOO patients presenting favorable factors associated with a spontaneous resolution of symptoms, invasive treatments should be considered with special caution. Structural etiologies are more amenable to management, while the remainder may improve without intervention. PMID- 26517979 TI - Virological characteristics of hepatitis B genotype G/A2 recombination virus in Japan. AB - AIM: We identified four cases of infection with hepatitis B virus genotype G and A2 recombinant (HBV/G/A2) strains, which were initially overlooked by enzyme immunoassay-based genotyping. The patients were all men who have sex with men (MSM) and inhabited several metropolitan areas of Japan, suggesting that the recombinant strains may be circulating among high-risk groups such as MSM. Here, we investigated the genomic structure and virological properties of the HBV/G/A2 strains. METHODS: Complete genome sequences of the isolates were determined and phylogenetically analyzed. Replication efficiency of HBV/G/A2 was investigated by transfecting plasmids containing 1.24-fold viral genome. The in vivo viral kinetics of HBV/G/A2 were investigated using chimeric mice with humanized livers. RESULTS: Phylogenetic analysis revealed that the four strains were almost identical (>99.7% homologous). The preS2/S region of these strains was highly homologous to that of genotype A2 and the remaining region was almost identical to that of genotype G, reflecting inter-genotypic recombination. Interestingly, in all four cases, genotype A was co-infected as a minor population. In vitro analysis revealed that HBV/G/A2 had a low replication rate. Although detectable viremia was not measurable following the inoculation of HBV/G/A2 into chimeric mice, subsequent superinfection of HBV genotype A greatly enhanced HBV/G/A2 replication and viral spread. CONCLUSION: We found that four cases of HBV/G/A2 recombinant among MSM patients in the metropolitan areas of Japan, and HBV/A co infections are required for its efficient replication. High-risk groups such as MSM should be carefully tested for infection of genotype G-derived variants. PMID- 26517980 TI - Psoriasis in elderly patients in the Cote d'Ivoire: socio-demographic, clinical, and therapeutic aspects, and follow-up. AB - BACKGROUND: Psoriasis is a chronic, inflammatory, and recurrent dermatological disease. In the Cote d'Ivoire, it is about 0.75% of dermatology cases. Psoriasis care is challenging in elderly patients. We aimed to show its specificities related to the sociodemographic, clinical, and therapeutic aspects, and follow-up in geriatric patients. METHODS: Cross-sectional and descriptive study over a period of 10 years (January 2004-December 2013). RESULTS: The prevalence of patients 60 years of age and older was about 0.1% (47 of 46,623 cases). The average age was 67 +/- 1 years ranging from 60 to 85 years. The sex ratio was 1 : 9 in favor of men. The average time course of psoriasis was 25 +/- 2 months. Comorbidity was found in 27 cases (57.5%). The most observed type of psoriasis in our study was chronic plaque psoriasis in 51.1% of cases. We found severe cases of psoriasis in 25.5% of cases. More than 10% of the body surface area was affected in 27.6% of cases. We used topical treatments in the majority of cases (83%). The course of psoriasis under treatment was good in 63.8% of cases, and only 6.4% of cases were worsening. CONCLUSION: Topical agents could be the first line treatment in geriatric patients in poor countries. If necessary, systemic agents should be used by taking into account the severity of psoriasis, presence of comorbidity factors, immune system level, and lifestyle. PMID- 26517981 TI - Factors associated with dust dispersed in the air of indoor riding arenas. AB - REASONS FOR PERFORMING STUDY: Environmental factors contribute to respiratory diseases in horses and man. During exercise, equine ventilation is increased, potentially increasing exposure of the airways to inhaled particulates. Currently, there is very little information on the quality of air in riding arenas. OBJECTIVES: To evaluate air quality and dust particle concentrations in indoor riding arenas before and after use for riding. STUDY DESIGN: Longitudinal study. METHODS: Air quality was assessed in 4 indoor riding arenas in Saxony Anhalt, Germany on a monthly basis for 1 year. Concentrations of particles in 6 particle fractions from 0.3 to 5.0 MUm were measured in air collected at 4 points in the riding arenas approximately at the height of the horses' (1.5 m) and riders' noses (2.5 m), before and after the arenas were used by one horse performing standardised riding session. RESULTS: There were significant differences in the numbers of particles between the arenas within months and between months within the arenas. Particle numbers were significantly influenced by the month and activities in the arenas before and after riding. The effect of the month on differences in the dust concentration may relate to surface watering. A significant increase in numbers of particles was observed after the riding session. Significant interactions were found between measuring heights and month within arena (P<0.01) and there was an interaction between measuring height and time points (before and after riding, P = 0.02). CONCLUSIONS: The amount of dust dispersed in the air increases during riding in indoor arenas and this appears to be influenced by footing material, direct connections between the arena and stables and season, possibly reflecting surface watering practices. PMID- 26517983 TI - Are there any potentially dangerous pharmacological effects of combining ADHD medication with alcohol and drugs of abuse? A systematic review of the literature. AB - BACKGROUND: Among young people up to 18 years of age, approximately 5% have attention deficit hyperactivity disorder (ADHD), many of whom have symptoms persisting into adulthood. ADHD is associated with increased risk of co-morbid psychiatric disorders, including substance misuse. Many will be prescribed medication, namely methylphenidate, atomoxetine, dexamphetamine and lisdexamfetamine. If so, it is important to know if interactions exist and if they are potentially toxic. METHODS: Three databases (Medline, EMBASE and PsychINFO) from a 22 year period (1992 - June 2014) were searched systematically. Key search terms included alcohol, substance related disorders, methylphenidate, atomoxetine, dexamphetamine, lisdexamfetamine, and death, which identified 493 citations (344 after removal of duplicates). The eligibility of each study was assessed jointly by two investigators, leaving 20 relevant articles. RESULTS: We identified only a minimal increase in side-effects when ADHD medication (therapeutic doses) was taken with alcohol. None of the reviewed studies showed severe sequelae among those who had overdosed on ADHD medication and other coingestants, including alcohol. CONCLUSIONS: The numbers across all the papers studied remain too low to exclude uncommon effects. Also, studies of combined effects with novel psychoactive substances have not yet appeared in the literature. Nevertheless, no serious sequelae were identified from combining ADHD medication with alcohol/illicit substances from the pre-novel psychoactive substance era. PMID- 26517982 TI - Critical role of actin-associated proteins in smooth muscle contraction, cell proliferation, airway hyperresponsiveness and airway remodeling. AB - Asthma is characterized by airway hyperresponsiveness and airway remodeling, which are largely attributed to increased airway smooth muscle contractility and cell proliferation. It is known that both chemical and mechanical stimulation regulates smooth muscle contraction. Recent studies suggest that contractile activation and mechanical stretch induce actin cytoskeletal remodeling in smooth muscle. However, the mechanisms that control actin cytoskeletal reorganization are not completely elucidated. This review summarizes our current understanding regarding how actin-associated proteins may regulate remodeling of the actin cytoskeleton in airway smooth muscle. In particular, there is accumulating evidence to suggest that Abelson tyrosine kinase (Abl) plays a critical role in regulating airway smooth muscle contraction and cell proliferation in vitro, and airway hyperresponsiveness and remodeling in vivo. These studies indicate that Abl may be a novel target for the development of new therapy to treat asthma. PMID- 26517984 TI - Adult-onset autosomal dominant spastic paraplegia linked to a GTPase-effector domain mutation of dynamin 2. AB - BACKGROUND: Hereditary Spastic Paraplegia (HSP) represents a large group of clinically and genetically heterogeneous disorders linked to over 70 different loci and more than 60 recognized disease-causing genes. A heightened vulnerability to disruption of various cellular processes inherent to the unique function and morphology of corticospinal neurons may account, at least in part, for the genetic heterogeneity. METHODS: Whole exome sequencing was utilized to identify candidate genetic variants in a four-generation Siberian kindred that includes nine individuals showing clinical features of HSP. Segregation of candidate variants within the family yielded a disease-associated mutation. Functional as well as in-silico structural analyses confirmed the selected candidate variant to be causative. RESULTS: Nine known patients had young-adult onset of bilateral slowly progressive lower-limb spasticity, weakness and hyperreflexia progressing over two-to-three decades to wheel-chair dependency. In the advanced stage of the disease, some patients also had distal wasting of lower leg muscles, pes cavus, mildly decreased vibratory sense in the ankles, and urinary urgency along with electrophysiological evidence of a mild distal motor/sensory axonopathy. Molecular analyses uncovered a missense c.2155C > T, p.R719W mutation in the highly conserved GTP-effector domain of dynamin 2. The mutant DNM2 co-segregated with HSP and affected endocytosis when expressed in HeLa cells. In-silico modeling indicated that this HSP-associated dynamin 2 mutation is located in a highly conserved bundle-signaling element of the protein while dynamin 2 mutations associated with other disorders are located in the stalk and PH domains; p.R719W potentially disrupts dynamin 2 assembly. CONCLUSION: This is the first report linking a mutation in dynamin 2 to a HSP phenotype. Dynamin 2 mutations have previously been associated with other phenotypes including two forms of Charcot-Marie-Tooth neuropathy and centronuclear myopathy. These strikingly different pathogenic effects may depend on structural relationships the mutations disrupt. Awareness of this distinct association between HSP and c.2155C > T, p.R719W mutation will facilitate ascertainment of additional DNM2 HSP families and will direct future research toward better understanding of cell biological processes involved in these partly overlapping clinical syndromes. PMID- 26517985 TI - MicroRNA and mRNA expression profiling analysis revealed the regulation of plant height in Gossypium hirsutum. AB - BACKGROUND: Dwarf cottons are more resistant to damage from wind and rain and associated with stable, increased yields, and also desirable source for breeding the machine harvest varieties. In an effort to uncover the transcripts and miRNA networks involved in plant height, the transcriptome and small RNA sequencing were performed based on dwarf mutant Ari1327 (A1), tall-culm mutant Ari3697 (A3) and wild type Ari971 (A9) in Gossypium hirsutum. METHODS: The stem apexes of wild type upland cotton (Ari971) and its dwarf mutant (Ari1327) and tall-culm mutant (Ari3697) at the fifth true leaf stage were extracted for RNA, respectively. Transcriptome and small RNA libraries were constructed and subjected to next generation sequencing. RESULTS: The transcriptome sequencing analysis showed that the enriched pathways of top 3 differentially expressed genes (DEGs) were categorized as carotenoid biosynthesis, plant-pathogen interaction and plant hormone signal transduction in both A1-A9 and A3-A9. The ABA and IAA related factors were differentially expressed in the mutants. Importantly, we found the lower expressed SAUR and elevated expressed GH3, and ABA related genes such as NCED and PP2C maybe relate to reduced growth of the plant height in Ari1327 which was consistent with the higher auxin and ABA content in this mutant. Furthermore, miRNA160 targeted to the auxin response factor (ARF) and miRNA166 (gma-miR166u and gma-miR166h-3p) targeted to ABA responsive element binding factor were related to the mutation in cotton. We have noticed that the cell growth related factors (smg7 targeted by gra-miR482 and 6 novel miRNAs and pectate-lyases targeted by osa-miR159f), the redox reactions related factors (Cytochrome P450 targeted by miR172) and MYB genes targeted by miR828, miR858 and miR159 were also involved in plant height of the cotton mutants. A total of 226 conserved miRNAs representing 32 known miRNA families were obtained, and 38 novel miRNAs corresponding to 23 unique RNA sequences were identified. Total 531 targets for 211 conserved miRNAs were obtained. Using PAREsnip, 27 and 29 miRNA/target conserved interactions were validated in A1-A9 and A3-A9, respectively. Furthermore, miRNA160, miRNA858 and miRNA172 were validated to be up-regulated in A1-A9 but down-regulated in A3-A9, whereas miRNA159 showed the opposite regulation. CONCLUSIONS: This comprehensive interaction of the transcriptome and miRNA at tall-culm and dwarf mutant led to the discovery of regulatory mechanisms in plant height. It also provides the basis for in depth analyses of dwarf mutant genes for further breeding of dwarf cotton. PMID- 26517986 TI - Effect of boundary conditions on yield properties of human femoral trabecular bone. AB - Trabecular bone plays an important mechanical role in bone fractures and implant stability. Homogenized nonlinear finite element (FE) analysis of whole bones can deliver improved fracture risk and implant loosening assessment. Such simulations require the knowledge of mechanical properties such as an appropriate yield behavior and criterion for trabecular bone. Identification of a complete yield surface is extremely difficult experimentally but can be achieved in silico by using micro-FE analysis on cubical trabecular volume elements. Nevertheless, the influence of the boundary conditions (BCs), which are applied to such volume elements, on the obtained yield properties remains unknown. Therefore, this study compared homogenized yield properties along 17 load cases of 126 human femoral trabecular cubic specimens computed with classical kinematic uniform BCs (KUBCs) and a new set of mixed uniform BCs, namely periodicity-compatible mixed uniform BCs (PMUBCs). In stress space, PMUBCs lead to 7-72 % lower yield stresses compared to KUBCs. The yield surfaces obtained with both KUBCs and PMUBCs demonstrate a pressure-sensitive ellipsoidal shape. A volume fraction and fabric based quadric yield function successfully fitted the yield surfaces of both BCs with a correlation coefficient [Formula: see text]. As expected, yield strains show only a weak dependency on bone volume fraction and fabric. The role of the two BCs in homogenized FE analysis of whole bones will need to be investigated and validated with experimental results at the whole bone level in future studies. PMID- 26517987 TI - Radiotherapy and subsequent thyroid cancer in German childhood cancer survivors: a nested case-control study. AB - BACKGROUND: Radiotherapy is associated with a risk of subsequent neoplasms (SN) in childhood cancer survivors. It has been shown that children's thyroid glands are especially susceptible. The aim is to quantify the risk of a second neck neoplasm after primary cancer radiotherapy with emphasis on thyroid cancer. METHODS: We performed a nested case-control study: 29 individuals, diagnosed with a solid SN in the neck region, including 17 with thyroid cancer, in 1980-2002 and 57 matched controls with single neoplasms were selected from the database of the German Childhood Cancer Registry. We investigated the risk associated with radiotherapy exposure given per body region, adjusted for chemotherapy. RESULTS: 16/17 (94.1 %) thyroid SN cases, 9/12 (75 %) other neck SN cases and 34/57 (59.6 %) controls received radiotherapy, with median doses of 27.8, 25 and 24 Gy, respectively. Radiotherapy exposure to the neck region increased the risk of the other neck SNs by 4.2 % (OR = 1.042/Gy (95 %-CI 0.980-1.109)) and of thyroid SN by 5.1 % (OR = 1.051/Gy (95 %-CI 0.984-1.123)), and radiotherapy to the neck or spine region increased the thyroid risk by 6.6 % (OR = 1.066/Gy (95 %-CI 1.010 1.125)). Chemotherapy was not a confounder. Exposure to other body regions was not associated with increased risk. CONCLUSIONS: Radiotherapy in the neck or spine region increases the risk of thyroid cancer, while neck exposure increases the risk of any other solid SN to a similar extent. Other studies showed a decreasing risk of subsequent thyroid cancer for very high doses; we cannot confirm this. PMID- 26517988 TI - Cellular magnetic resonance imaging contrast generated by the ferritin heavy chain genetic reporter under the control of a Tet-On switch. AB - INTRODUCTION: Despite the strong appeal of ferritin as a magnetic resonance imaging (MRI) reporter for stem cell research, no attempts have been made to apply this genetic imaging reporter in stem cells in an inducible manner, which is important for minimizing the potential risk related to the constitutive expression of an imaging reporter. The aim of the present study was to develop an inducible genetic MRI reporter system that enables the production of intracellular MRI contrast as needed. METHODS: Ferritin heavy chain (FTH1) was genetically modified by adding a Tet-On switch. A C3H10T1/2 cell line carrying Tet-FTH1 (C3H10T1/2-FTH1) was established via lentiviral transduction. The dose- and time-dependent expression of FTH1 in C3H10T1/2 cells was assessed by western blot and immunofluorescence staining. The induced "ON" and non-induced "OFF" expressions of FTH1 were detected using a 3.0 T MRI scanner. Iron accumulation in cells was analyzed by Prussian blue staining and transmission electron microscopy (TEM). RESULTS: The expression of FTH1 was both dose- and time-dependently induced, and FTH1 expression peaked in response to induction with doxycycline (Dox) at 0.2 MUg/ml for 72 h. The induced expression of FTH1 resulted in a significant increase in the transverse relaxation rate of C3H10T1/2-FTH1 cells following iron supplementation. Prussian blue staining and TEM revealed extensive iron accumulation in C3H10T1/2-FTH1 cells in the presence of Dox. CONCLUSIONS: Cellular MRI contrast can be produced as needed via the expression of FTH1 under the control of a Tet-On switch. This finding could lay the groundwork for the use of FTH1 to track stem cells in vivo in an inducible manner. PMID- 26517989 TI - Formal caregivers' perceptions of quality of care for older people: associating factors. AB - BACKGROUND: Despite the growing number of studies concerning quality of care for older people, there is a lack of studies depicting factors associated with good quality of care from the formal caregivers' perspective. The aim was to describe formal caregivers' perceptions of quality of care for older people in the community and explore factors associated with these perceptions. In total, 70 nursing assistants, 163 enrolled nurses and 198 registered nurses from 14 communities in central Sweden participated in the study. They filled out the following questionnaires: a modified version of Quality from the Patient's Perspective, Creative Climate Questionnaire, Stress of Conscience Questionnaire, items regarding education and competence, Health Index and Sense of coherence questionnaire. The overall response rate was 57% (n = 431). RESULTS: In the perceived reality of quality of care respondents assessed the highest mean value in the dimension medical-technical competence and physical technical conditions and lower values in the dimensions; identity-oriented approach, socio-cultural atmosphere and in the context specific dimension. The caregivers estimated their competence and health rather high, had lower average values in sense of coherence and organizational climate and low values in stress of conscience. CONCLUSIONS: The PR of quality of care were estimated higher among NA/ENs compared to RNs. Occupation, organizational climate and stress of conscience were factors associated with quality of care that explained 42% of the variance. Competence, general health and sense of coherence were not significantly associated to quality of care. The mentioned factors explaining quality of care might be intertwined and showed that formal caregivers' working conditions are of great importance for quality of care. PMID- 26517990 TI - Content of metals and metabolites in honey originated from the vicinity of industrial town Kosice (eastern Slovakia). AB - Composition of three types of honey (mixed forest honey and monofloral-black locust and rapeseed honeys) originated from the vicinity of an industrial town (Kosice, Slovak Republic) was compared. Higher content of minerals including toxic metals in forest honey (1358.6 ng Ni/g, 85.6 ng Pb/g, and 52.4 ng Cd/g) than in rapeseed and black locust honeys confirmed that botanical origin rather than the distance for eventual source of pollution (steel factory) affects metal deposition. Benzoic acid derivatives were typically more accumulated in forest but cinnamic acid derivatives and some flavonoids in rapeseed honey (in free and/or glycoside-bound fraction). In terms of quantity, p-hydroxybenzoic and p coumaric acids were mainly abundant. Total phenols, thiols, and proteins were abundant in forest honey. Some metals and phenols contributed to separation of honeys based on principal component analysis (PCA). Native amount of 5 (hydroxymethyl)furfural was not related to honey type (~11 MUg/g) and was elevated after strong acid hydrolysis (200-350 MUg/g) but it did not interfere with the assay of phenols by Folin-Ciocalteu reagent. This is the first report of metals and metabolites in the same study, and data are discussed with available literature. We conclude that black locust (acacia) honey is the most suitable for daily use and that central European monofloral honeys contain lower amounts of toxic metals in comparison with other geographical regions. PMID- 26517991 TI - Isolation and characterization of two novel psychrotrophic decabromodiphenyl ether-degrading bacteria from river sediments. AB - Decabromodiphenyl ether (BDE-209) is a brominated flame retardant and a priority contaminant. Currently, little information is available about its significance in the environment, specifically about its susceptibility to aerobic biotransformation at low temperature. In this work, five phylogenetically diverse BDE-209-degrading bacterial strains were isolated from river sediments of northern China. These strains were distributed among four different genera Acinetobacter, Pseudomonas, Bacillus and Staphylococcus. All five isolates were capable of growing on BDE-209, among which two isolates show better growth. By detailed morphological, physiological, and biochemical characteristics and 16S rDNA sequence analysis, the two strains were identified and named as Staphylococcus haemolyticus LY1 and Bacillus pumilus LY2. The two bacteria can grow in mineral salt medium containing BDE-209 substrate across the temperatures ranging from 2.5 to 35 degrees C, with an optimum temperature of 25 degrees C which could be considered as psychrotrophs accordingly. The degradation experiment showed that more than 70.6 and 85.5 % of 0.5 mg/L BDE-209 were degraded and the highest mineralization efficiencies of 29.8 and 39.2 % were achieved for 0.5 mg/L BDE-209 by S. haemolyticus LY1 and B. pumilus LY2, respectively. To the best of our knowledge, this is the first demonstration for the biodegradation of BDE-209 by two psychrotrophic bacteria isolated from environment. PMID- 26517993 TI - Erratum to: Geochemical behavior and environmental risks related to the use of abandoned base-metal tailings as construction material in the upper-Moulouya district, Morocco. PMID- 26517992 TI - Interactions between sewage sludge-amended soil and earthworms--comparison between Eisenia fetida and Eisenia andrei composting species. AB - Vermicomposting is an eco-friendly technology, where earthworms are introduced in the waste, inter alia sewage sludge, to cooperate with microorganisms and enhance decomposition of organic matter. The main aims of the present study was to determine the influence of two different earthworm species, Eisenia fetida and Eisenia andrei, on the changes of selected metallic trace elements content in substratum during vermicomposting process using three different sewage sludge mainly differentiated by their metal contents. Final vermicompost has shown a slight reduction in Cd, Cu, Ni, and Pb, while the Zn concentration tends to increase. Accumulation of particular heavy metals in earthworms' bodies was assessed. Both species revealed high tendency to accumulate Cd and Zn, but not Cu, Ni, and Pb, but E. andrei has higher capabilities to accumulate some metals. Riboflavin content, which content varies depending on metal pollution in several earthworms species, was measured supravitaly in extruded coelomocytes. Riboflavin content decreased slightly during the first 6 weeks of exposure and subsequently restored till the end of the 9-week experiment. Selected agronomic parameters have also been measured in the final product (vermicompost) to assess the influence of earthworms on substratum. PMID- 26517994 TI - Runoff, nitrogen (N) and phosphorus (P) losses from purple slope cropland soil under rating fertilization in Three Gorges Region. AB - Soil erosion along with soil particles and nutrients losses is detrimental to crop production. We carried out a 5-year (2010 to 2014) study to characterize the soil erosion and nitrogen and phosphorus losses caused by rainfall under different fertilizer application levels in order to provide a theoretical evidence for the agricultural production and coordinate land management to improve ecological environment. The experiment took place under rotation cropping, winter wheat-summer maize, on a 15 degrees slope purple soil in Chongqing (China) within the Three Gorges Region (TGR). Four treatments, control (CK) without fertilizer, combined manure with chemical fertilizer (T1), chemical fertilization (T2), and chemical fertilizer with increasing fertilization (T3), were designed on experimental runoff plots for a long-term observation aiming to study their effects on soil erosion and nutrients losses. The results showed that fertilization reduced surface runoff and nutrient losses as compared to CK. T1, T2, and T3, compared to CK, reduced runoff volume by 35.7, 29.6, and 16.8 %, respectively and sediment yield by 40.5, 20.9, and 49.6 %, respectively. Regression analysis results indicated that there were significant relationships between soil loss and runoff volume in all treatments. The combined manure with chemical fertilizer (T1) treatment highly reduced total nitrogen and total phosphorus losses by 41.2 and 33.33 %, respectively as compared with CK. Through this 5-year experiment, we can conclude that, on the sloping purple soil, the combined application of manure with fertilizer is beneficial for controlling runoff sediments losses and preventing soil erosion. PMID- 26517995 TI - Nicosulfuron application in agricultural soils drives the selection towards NS tolerant microorganisms harboring various levels of sensitivity to nicosulfuron. AB - The action mode of sulfonylurea herbicides is the inhibition of the acetohydroxyacid synthase (AHAS) required for the biosynthesis of amino acids valine and isoleucine in plants. However, this enzyme is also present in a range of non-targeted organisms, among which soil microorganisms are known for their pivotal role in ecosystem functioning. In order to assess microbial toxicity of sulfonylurea herbicide nicosulfuron (NS), a tiered microcosm (Tier I) to field (Tier II) experiment was designed. Soil bacteria harboring AHAS enzyme tolerant to the herbicide nicosulfuron were enumerated, isolated, taxonomically identified, and physiologically characterized. Results suggested that application of nicosulfuron drives the selection towards NS-tolerant bacteria, with increasing levels of exposure inducing an increase in their abundance and diversity in soil. Tolerance to nicosulfuron was shown to be widespread among the microbial community with various bacteria belonging to Firmicutes (Bacillus) and Actinobacteria (Arthrobacter) phyla representing most abundant and diverse clusters. While Arthrobacter bacterial population dominated community evolved under lower (Tier II) nicosulfuron selection pressure, it turns out that Bacillus dominated community evolved under higher (Tier I) nicosulfuron selection pressure. Different NS-tolerant bacteria likewise showed different levels of sensitivity to the nicosulfuron estimated by growth kinetics on nicosulfuron. As evident, Tier I exposure allowed selection of populations able to better cope with nicosulfuron. One could propose that sulfonylureas-tolerant bacterial community could constitute a useful bioindicator of exposure to these herbicides for assessing their ecotoxicity towards soil microorganisms. PMID- 26517996 TI - Autoclave treatment of pig manure does not reduce the risk of transmission and transfer of tetracycline resistance genes in soil: successive determinations with soil column experiments. AB - The increasing use of antibiotics, especially tetracycline, in livestock feed adversely affects animal health and ecological integrity. Therefore, approaches to decrease this risk are urgently needed. High temperatures facilitate antibiotic degradation; whether this reduces transmission risk and transfer of tetracycline-resistant bacteria (TRBs) and tetracycline resistance genes (TRGs) in soil remains unknown. Successive experiments with soil columns evaluated the effects of autoclaving pig manure (APM) on soil TRB populations and TRGs over time at different soil depths. The data showed sharp increases in TRB populations and TRGs in each subsoil layer of PM (non-APM) and APM treatments within 30 days, indicating that TRBs and TRGs transferred rapidly. The level of TRBs in the upper soil layers was approximately 15-fold higher than in subsoils. TRBs were not dependent on PM and APM levels, especially in the late phase. Nevertheless, higher levels of APM led to rapid expansion of TRBs as compared to PM. Moreover, temporal changes in TRB frequencies in total culturable bacteria (TCBs) were similar to TRBs, indicating that the impact of PM or APM on TRBs was more obvious than for TCBs. TRBs were hypothesized to depend on the numbers of TRGs and indigenous recipient bacteria. In the plough layer, five TRGs (tetB, tetG, tetM, tetW, and tetB/P) existed in each treatment within 150 days. Selective pressure of TC may not be a necessary condition for the transfer and persistence of TRGs in soil. High temperatures might reduce TRBs in PM, which had minimal impact on the transmission and transfer of TRGs in soil. Identifying alternatives to decrease TRG transmission remains a major challenge. PMID- 26517997 TI - People with diabetes, respiratory, liver or mental disorders, higher urinary antimony, bisphenol A, or pesticides had higher food insecurity: USA NHANES, 2005 2006. AB - This study was aimed to examine the prevalence of food insecurity and what social, health, and environmental characteristics could constitute such situation in a national and population-based setting. Data was retrieved from the National Health and Nutrition Examination Survey, 2005-2006. Information on demographics, lifestyle factors, self-reported ever medical conditions in the past and self reported food security conditions in the last 12 months calculated on the household level was obtained by household interview. Bloods and urines (subsample) were collected at the interview as well. Only adults aged 20 years and above (n = 4979) were included for statistical analysis in the present study. Chi-square test, t test, and survey-weighted logistic regression modeling were performed. Three thousand eight hundred thirty-four (77.9%) people were with full food security, 466 (9.5%) people were with marginal food security and 624 (12.7%) people were with low or very low food security. Being younger, having higher ratios of family income to poverty thresholds (due to low level of education or lack of financial support), having prior asthma, arthritis, chronic bronchitis, depression, diabetes, eczema, emphysema or liver problems, having higher levels of serum cotinine, urinary antimony, bisphenol A, pesticides, or having lower levels of urinary Benzophenone-3 were associated with food insecurity. In addition to socioeconomic and smoking conditions, evidence on people with several prior health conditions and being exposed to environmental chemicals and food insecurity is further provided. Future social, health and environmental policy, and programs protecting people from food insecurity by considering both health and environmental factors mentioned above would be suggested. PMID- 26517998 TI - Degradation of sunscreen agent p-aminobenzoic acid using a combination system of UV irradiation, persulphate and iron(II). AB - Increased usage and discharge of sunscreens have led to ecological safety crisis, and people are developing the advanced oxidation processes (AOPs) to treat them. The present study aimed to determine the degradation efficiency and mechanism of the sunscreen agent p-aminobenzoic acid (PABA) using the UV/Fe(2+)/persulphate (PS) method. A series of irradiation experiments were conducted to optimise the system conditions and to study the impacts of the natural anion. Free radicals and degradation products were identified in order to clarify the degradation mechanism. Initial PS and Fe(2+) concentrations showed significant impacts on PABA degradation. Natural anions, such as Cl(-), NO3 (-), H2PO4 (-) and HCO3 (-), impeded PABA degradation because of ion (Fe(2+)) capture, radical scavenging or pH effects. Hydroxyl (HO.) and sulphate (SO4 (.-)) radicals were two main radicals observed in the UV/Fe(2+)/PS system; of these, SO4 (.-) showed greater effects on PABA degradation. Over 99 % of the available PABA was completely degraded into carbon dioxide (CO2) and water (H2O) by the UV/Fe(2+)/PS system, and the remaining PABA participated in complex radical reactions. By-products were identified by total ion chromatography and mass spectrometry. Our research provides a treatment process for PABA with high degradation efficiency and environmental safety and introduces a new strategy for sunscreen degradation. PMID- 26517999 TI - Natural forest expansion on reclaimed coal mines in Northern Spain: the role of native shrubs as suitable microsites. AB - The characterization of suitable microsites for tree seedling establishment and growth is one of the most important tasks to achieve the restoration of native forest using natural processes in disturbed sites. For that, we assessed the natural Quercus petraea forest expansion in a 20-year-old reclaimed open-cast mine under sub-Mediterranean climate in northern Spain, monitoring seedling survival, growth, and recruitment during 5 years in three contrasting environments (undisturbed forest, mine edge, and mine center). Seedling density and proportion of dead branches decreased greatly from undisturbed forest towards the center of the mine. There was a positive effect of shrubs on Q. petraea seedling establishment in both mine environments, which increase as the environment undergoes more stress (from the mine edge to the center of the mine), and it was produced by different shrub structural features in each mine environment. Seedling survival reduction through time in three environments did not lead to a density reduction because there was a yearly recruitment of new seedlings. Seedling survival, annual growth, and height through time were greater in mine sites than in the undisturbed forest. The successful colonization patterns and positive neighbor effect of shrubs on natural seedlings establishment found in this study during the first years support the use of shrubs as ecosystem engineers to increase heterogeneity in micro-environmental conditions on reclaimed mine sites, which improves late-successional Quercus species establishment. PMID- 26518000 TI - The rural carbonaceous aerosols in coarse, fine, and ultrafine particles during haze pollution in northwestern China. AB - The carbonaceous aerosol concentrations in coarse particle (PM10: Dp <= 10 MUm, particulate matter with an aerodynamic diameter less than 10 MUm), fine particle (PM2.5: Dp <= 2.5 MUm), and ultrafine particle (PM0.133: Dp <= 0.133 MUm) carbon fractions in a rural area were investigated during haze events in northwestern China. The results indicated that PM2.5 contributed a large fraction in PM10. OC (organic carbon) accounted for 33, 41, and 62 % of PM10, PM2.5, and PM0.133, and those were 2, 2.4, and 0.4 % for EC (elemental carbon) in a rural area, respectively. OC3 was more abundant than other organic carbon fractions in three PMs, and char dominated EC in PM10 and PM2.5 while soot dominated EC in PM0.133. The present study inferred that K(+), OP, and OC3 are good biomass burning tracers for rural PM10 and PM2.5, but not for PM0.133 during haze pollution. Our results suggest that biomass burning is likely to be an important contributor to rural PMs in northwestern China. It is necessary to establish biomass burning control policies for the mitigation of severe haze pollution in a rural area. PMID- 26518001 TI - Effects of improving nitrogen management on nitrogen utilization, nitrogen balance, and reactive nitrogen losses in a Mollisol with maize monoculture in Northeast China. AB - Traditional fertilization led to higher apparent N surplus, and optimized fertilization can reduce residual nitrogen in soils with keeping high yield. But in continuous spring maize cropping zone in Mollisol in Northeast China, the effect of the optimized N management on N balance and comprehensive environment was not clear. The primary objective of this study was to compare the differences of two fertilizations (traditional farmer N management (FNM) with single basal fertilizer and improvement N management (INM) by soil testing with top-dressing) in gain yield, N uptake and N efficiency, soil N balance, reactive N losses, and environment assessment. The results showed that INM treatment has no remarkable effect on grain yield and N uptake; N partial factor productivity (PFPN) of INM treatment was 19.8 % significantly higher than the FNM treatment. Nmin in soils of INM treatment reached to 111.0 kg ha(-1), which was 27.1 % lower than the FNM treatment after 6 years of continuous maize cropping; the apparent N Losses (ANL) and apparent N surplus (ANS) of INM were only half of FNM by soil N balance analysis. In reactive N losses, comparing with FNM treatment, INM treatment reduced NH3 volatilization, N2O emission, N leaching, and N runoff by 17.8, 35.6, 45, and 38.3 %, respectively, during planting period, and in integrated environment assessment by life cycle assessment (LCA) method, producing 1 t maize grain, energy depletion, acidification, eutrophication, and climate change impacts of INM treatment decreased 26.19, 30.16, 32.61, and 22.75 %, respectively. Therefore, INM treatment is a better N management strategy in comprehensive analysis. PMID- 26518002 TI - A rose by any other name. PMID- 26518003 TI - Left main disease diagnosis: The Achilles heel or the great strength of modern cardiac imaging? PMID- 26518004 TI - GeXP analyzer-based multiplex reverse-transcription PCR assay for the simultaneous detection and differentiation of eleven duck viruses. AB - BACKGROUND: Duck viral pathogens primarily include the avian influenza virus (AIV) subtypes H5, H7, and H9; duck hepatitis virus (DHV); duck tembusu virus (DTMUV); egg drop syndrome virus (EDSV); duck enteritis virus (DEV); Newcastle disease virus (NDV); duck circovirus (DuCV); muscovy duck reovirus (MDRV); and muscovy duck parvovirus (MDPV). These pathogens cause great economic losses to China's duck breeding industry. RESULT: A rapid, specific, sensitive and high throughput GeXP-based multiplex PCR assay consisting of chimeric primer-based PCR amplification with fluorescent labeling and capillary electrophoresis separation was developed and optimized to simultaneously detect these eleven viral pathogens. Single and mixed pathogen cDNA/DNA templates were used to evaluate the specificity of the GeXP-multiplex assay. Corresponding specific DNA products were amplified from each pathogen. Other pathogens, including duck Escherichia coli, duck Salmonella, duck Staphylococcus aureus, Pasteurella multocida, infectious bronchitis virus, and Mycoplasma gallisepticum, did not result in amplification products. The detection limit of GeXP was 10(3)copies when all twelve pre-mixed plasmids containing the target genes of eleven types of duck viruses were present. To further evaluate the reliability of GeXP, 150 clinical field samples were evaluated. Comparison with the results of conventional PCR methods for the field samples, the GeXP-multiplex PCR method was more sensitive and accurate. CONCLUSION: This GeXP-based multiplex PCR method can be utilized for the rapid differential diagnosis of clinical samples as an effective tool to prevent and control duck viruses with similar clinical symptoms. PMID- 26518005 TI - Identifying Infants and Toddlers at High Risk for Persistent Delays. AB - OBJECTIVES: Little is known about the extent to which a developmental delay identified in infancy persists into early childhood. This study examined the persistence of developmental delays in a large nationally representative sample of infants and toddlers who did not receive early intervention. METHODS: In a sample (n ~ 8700) derived from the early childhood longitudinal study, birth cohort, we examined developmental changes between 9 and 24 months. Motor and cognitive delays were categorized as none, mild, and moderate/severe. Adjusted ordinal logistic regression models estimated the likelihood of worse developmental delay at 24 months. RESULTS: About 24 % of children had a cognitive delay and 27 % had a motor delay at either 9- or 24-months. About 77 % of children with mild and 70 % of children with moderate/severe cognitive or motor developmental delay at 9-months had no delay at 24-months. Children with mild cognitive delay at 9-months had 2.4 times the odds of having worse cognitive function at 24-months compared to children with no cognitive delay at 9 months. Children with moderate/severe cognitive delay at 9-months had three times the odds of having worse cognitive abilities at 24-months than children who had no cognitive delay at 9-months. Similar results were found for motor skills. CONCLUSIONS: Developmental delays in infants are changeable, often resolving without treatment. This work provides knowledge about baseline trajectories of infants without and without cognitive and motor delays. It documents the proportion of children's delays that are likely to be outgrown without EI and the rate at which typically-developing infants are likely to display developmental delays at 2-years of age. PMID- 26518006 TI - Shared Decision Making in the Care of Children with Developmental and Behavioral Disorders. AB - OBJECTIVE: Shared decision making (SDM) is most needed when there are multiple treatment options and no "right" choice. As with quality and experience of care, frequency of SDM may vary by health condition. The objectives of this study were (1) to compare parent report of SDM between a physical and a behavioral health condition and; (2) to compare parent report of SDM between two different behavioral health conditions. METHODS: Data on children age 3-17 years with asthma, attention deficit/hyperactivity disorder (ADHD), and/or autism spectrum disorder (ASD) were drawn from the 2009/10 National Survey of Children with Special Health Care Needs. Weighted logistic regression was used to compare a parent-reported, composite measure of SDM. Analyses controlled for sociodemographic factors that may influence experience of SDM. RESULTS: Compared to parents of children with asthma, parents of children with ADHD were significantly less likely to report experiencing consistent SDM (AOR 0.73). Compared to parents of children with ADHD, those of children with ASD had significantly lower odds of experiencing consistent SDM (AOR 0.59). Those with both ADHD and ASD had the same odds as those with ASD alone of experiencing consistent SDM. CONCLUSION: Use of SDM is particularly limited in developmental and behavioral conditions, such as ADHD and ASD. These data suggest that challenges to implementing SDM may include disease type, complexity, and use of specialty care. Research to identify specific barriers and facilitators of SDM is needed to inform interventions that will promote SDM in developmental and behavioral conditions. PMID- 26518007 TI - Implications for Improving Fetal Death Vital Statistics: Connecting Reporters' Self-Identified Practices and Barriers to Third Trimester Fetal Death Data Quality in New York City. AB - OBJECTIVES: Perinatal mortality prevention strategies that target fetal deaths often utilize vital records data sets shown to contain critical quality deficiencies. To understand the causes of deficient data, we linked survey responses of fetal death reporters with facility fetal death data quality indicators. METHODS: In 2011, we surveyed the person most responsible for fetal death reporting at New York City healthcare facilities on their attitudes, barriers, and practices regarding reporting. We compared responses by 2 facility data quality indicators (data completeness and ill-defined cause of fetal death) for third trimester fetal death registrations using Chi squared tests. RESULTS: Thirty-nine of 50 facilities completed full questionnaires (78 % response rate); responding facilities reported 84 % (n = 11,891) of all 2011 fetal deaths, including 329 third trimester fetal deaths. Facilities citing >=1 reporting barrier were approximately five times more likely to have incomplete third trimester registrations than facilities citing no substantial barriers (37.5 vs 7.9 %; RR 4.7; 95 % CI [1.6-14.2]). Reported barriers included onerous reporting requirements (n = 10; 26 %) and competing physician priorities (n = 11; 28 %). Facilities citing difficulty involving physicians in reporting were more likely to report fetal deaths with nonspecific cause-of-death information (70.9 vs 56.6 %; RR 1.3; 95 % CI [1.1-1.5]). CONCLUSIONS: Self-reported challenges correlate with completeness and accuracy of reported fetal death data, suggesting that such barriers are likely contributing to low quality data. We identified several improvement opportunities, including in-depth training and reducing the information collected, especially for early fetal deaths (<20 weeks' gestation), the majority of events reported. PMID- 26518008 TI - But We're Not Like the People on TV: A Qualitative Examination of How Media Messages are Perceived by Pregnant and Parenting Youth. AB - OBJECTIVES: The media has long been established as influential in the formation of youth attitudes. It remains unknown, however, whether popular media depictions of teenage pregnancy and motherhood shape the meanings pregnant and parenting youth (PPY) construct. This study explored PPY's perceptions of media messages portraying PPY. METHODS: Five focus groups were conducted at three urban centres that service pregnant youth and young parents. Convenience sample of 26 participants was recruited across sites. Focus groups were audio recorded, transcribed verbatim and analyzed thematically. RESULTS: Participants were a mean age of 18.7 years. Participants felt that the storylines in television reality programs featuring PPY were highly incongruent with their lived experiences and that these representations glamorized teenage pregnancy while failing to capture other realities, such as financial hardship. Further, it was felt that such representations informed public opinion and created a double standard for teen parents. Participants felt that healthcare providers were not immune to media messaging; some participants reported withdrawing socially and others delayed accessing health services because of what they perceived as negative media fuelled public views. CONCLUSION: This study highlights the need for heightened awareness of the influence of popular media on the portrayal of PPY. Acknowledging and challenging stereotypes of teen pregnancy, as well as initiating dialogue with youth about the impact media has on their lives should be encouraged as a means of facilitating ongoing engagement with health care services. PMID- 26518009 TI - Disparities in Adverse Preconception Risk Factors Between Women with and Without Disabilities. AB - OBJECTIVE: The objective of this study was to compare the prevalence of select preconception health indicators among women with and without disabilities. METHODS: 2010 Behavioral Risk Factor Surveillance System data were used to estimate the prevalence of health behaviors, health status indicators, and preventive health care among non-pregnant women ages 18-44 years with (N = 8370) and without (N = 48,036) disabilities. Crude percentages were compared with Chi square statistics. Multivariable logistic regressions adjusted for socio demographic factors. RESULTS: Women with disabilities were more likely than women without disabilities to currently smoke (30.5 vs. 14.5 %, p < 0.0001) and less likely to exercise in the past month (67.1 vs. 79.8 %, p < 0.0001). Heavy drinking was similar in the two groups (4.4 vs. 4.5 %, p = 0.9). Health status indicators were worse among women with disabilities, with 35.0 % reporting fair/poor health and 12.4 % reporting diabetes, compared with 6.7 and 5.6 %, respectively, among women with no disabilities (p < 0.0001 for both). Frequent mental distress, obesity, asthma, and lack of emotional support were also higher among women with disabilities compared with their non-disabled counterparts. Women with disabilities were more likely to receive some types of preventive care, (HIV), but less likely to receive others (recent dental cleaning, routine checkup). Disparities in health behaviors and health status indicators between the two groups remained after adjusting for socio-demographic factors. CONCLUSION: Women with disabilities at reproductive age are more vulnerable to risk factors associated with adverse pregnancy outcomes compared to their counterparts without disabilities. Our findings highlight the need for preconception health care for women with disabilities. PMID- 26518010 TI - Genetic variation and dynamics of infections of equid herpesvirus 5 in individual horses. AB - Equid herpesvirus 5 (EHV-5) is related to the human Epstein-Barr virus (human herpesvirus 4) and has frequently been observed in equine populations worldwide. EHV-5 was previously assumed to be low to non-pathogenic; however, studies have also related the virus to the severe lung disease equine multinodular pulmonary fibrosis (EMPF). Genetic information of EHV-5 is scanty: the whole genome was recently described and only limited nucleotide sequences are available. In this study, samples were taken twice 1 year apart from eight healthy horses at the same professional training yard and samples from a ninth horse that was diagnosed with EMPF with samples taken pre- and post-mortem to analyse partial glycoprotein B (gB) gene of EHV-5 by using next-generation sequencing. The analysis resulted in 27 partial gB gene sequences, 11 unique sequence types and five amino acid sequences. These sequences could be classified within four genotypes (I-IV) of the EHV-5 gB gene based on the degree of similarity of the nucleotide and amino acid sequences, and in this work horses were shown to be identified with up to three different genotypes simultaneously. The observations showed a range of interactions between EHV-5 and the host over time, where the same virus persists in some horses, whereas others have a more dynamic infection pattern including strains from different genotypes. This study provides insight into the genetic variation and dynamics of EHV-5, and highlights that further work is needed to understand the EHV-5 interaction with its host. PMID- 26518011 TI - Portal Vein Stenting for Portal Biliopathy with Jaundice. AB - Portal biliopathy refers to obstruction of the bile duct by dilated peri- or para ductal collateral channels following the main portal vein occlusion from various causes. Surgical shunt operation or endoscopic treatment has been reported. Herein, we report a case of portal biliopathy that was successfully treated by interventional portal vein recanalization. PMID- 26518012 TI - Lorentz contact resonance spectroscopy for nanoscale characterisation of structural and mechanical properties of biological, dental and pharmaceutical materials. AB - Scanning probe microscopy has been widely used to obtain topographical information and to quantify nanostructural properties of different materials. Qualitative and quantitative imaging is of particular interest to study material material interactions and map surface properties on a nanoscale (i.e. stiffness and viscoelastic properties). These data are essential for the development of new biomedical materials. Currently, there are limited options to map viscoelastic properties of materials at nanoscale and at high resolutions. Lorentz contact resonance (LCR) is an emerging technique, which allows mapping viscoelasticity of samples with stiffness ranging from a few hundred Pa up to several GPa. Here we demonstrate the applicability of LCR to probe and map the viscoelasticity and stiffness of 'soft' (biological sample: cell treated with nanodiamond), 'medium hard' (pharmaceutical sample: pMDI canister) and 'hard' (human teeth enamel) specimens. The results allowed the identification of nanodiamond on the cells and the qualitative assessment of its distribution based on its nanomechanical properties. It also enabled mapping of the mechanical properties of the cell to demonstrate variability of these characteristics in a single cell. Qualitative imaging of an enamel sample demonstrated variations of stiffness across the specimen and precise identification of enamel prisms (higher stiffness) and enamel interrods (lower stiffness). Similarly, mapping of the pMDI canister wall showed that drug particles were adsorbed to the wall. These particles showed differences in stiffness at nanoscale, which suggested variations in surface composition-multiphasic material. LCR technique emerges as a valuable tool for probing viscoelasticity of samples of varying stiffness's. PMID- 26518013 TI - In situ formation of adhesive hydrogels based on PL with laterally grafted catechol groups and their bonding efficacy to wet organic substrates. AB - Adhesives with catechol moieties have been widely investigated in recent years. However, actually how much catechol groups for these mussel bio-inspired adhesives, especially in their natural form under physiological condition, is appropriate to bond with organic substrates has not been studied intensively. This study blends epsilon-polylysine (PL), featuring laterally grafted catechols under physiological conditions (pH 7.4), with oxidized dextran to form a hydrogel in situ via the Schiff base without introducing small cytotoxic molecules as crosslinking agents. It finds that the amount of catechol groups imposes an obvious influence on gelation time, swelling behavior, and hydrogel morphology. Both the storage modulus and adhesion strength are found to increase first and decrease afterwards with an increase of pendent catechol content. Furthermore, catechol hydrogen interactions and the decrease in the crosslink density derived from the decrease of amino groups on PL are simultaneously found to affect the storage modulus. Meanwhile, multiple hydrogen-bonding interactions of catechol with amino, hydroxyl, and carboxyl groups, which are in abundance on the surface of tissue, are mainly found to provide an adhesive force. The study finds that with more catechol, there is a greater chance that the cohesive force will weaken, making the entire adhesion strength of the hydrogel decrease. Using a cytotoxicity test, the nontoxicity of the hydrogel towards the growth of L929 cells is proven, indicating that hydrogels have potential applications in soft tissue repair under natural physiological conditions. PMID- 26518014 TI - Central Anticholinergic Adverse Effects and Their Measurement. AB - Drugs with anticholinergic properties are widely used. However, they may evoke a variety of adverse reactions (such as dry mouth and constipation, but also drowsiness and confusion), and therefore unnecessary use of drugs with anticholinergic properties should be avoided. In particular, older people are particularly vulnerable to the central anticholinergic effects of drugs. However, monitoring of drug-induced anticholinergic effects and drug concentrations in serum is challenging. In addition to the 'pure' anticholinergics such as atropine and oxybutynin, several other drugs whose principal mode of action is not anticholinergic, possess anticholinergic properties, thus increasing the risk of anticholinergic adverse effects. In this paper, we focus on the central anticholinergic effects of drugs, and on the usefulness of the serum anticholinergic assay (SAA) in the prediction of anticholinergic effects. Results on the anticholinergic effects of drugs on cognition are mixed. This may be because of differences in the populations as well as in the drugs used. In addition, the clinical conditions of the patients may affect the results. The SAA has been used in an attempt to measure anticholinergic burden. However, the results are variable and the SAA levels do not necessarily reflect the medication used by the patient. Therefore, its usefulness in determining anticholinergic adverse reactions is questionable. PMID- 26518015 TI - Evidence against global attention filters selective for absolute bar-orientation in human vision. AB - The finding that an item of type A pops out from an array of distractors of type B typically is taken to support the inference that human vision contains a neural mechanism that is activated by items of type A but not by items of type B. Such a mechanism might be expected to yield a neural image in which items of type A produce high activation and items of type B low (or zero) activation. Access to such a neural image might further be expected to enable accurate estimation of the centroid of an ensemble of items of type A intermixed with to-be-ignored items of type B. Here, it is shown that as the number of items in stimulus displays is increased, performance in estimating the centroids of horizontal (vertical) items amid vertical (horizontal) distractors degrades much more quickly and dramatically than does performance in estimating the centroids of white (black) items among black (white) distractors. Together with previous findings, these results suggest that, although human vision does possess bottom up neural mechanisms sensitive to abrupt local changes in bar-orientation, and although human vision does possess and utilize top-down global attention filters capable of selecting multiple items of one brightness or of one color from among others, it cannot use a top-down global attention filter capable of selecting multiple bars of a given absolute orientation and filtering bars of the opposite orientation in a centroid task. PMID- 26518016 TI - [Erratum to: Perioperative CRP quantification for appendectomy : Clinically useful or a waste of money?]. PMID- 26518017 TI - Prognostic and clinical significance of syndecan-1 in colorectal cancer: a meta analysis. AB - BACKGROUND: Syndecan-1 plays a vital role in the suppression, transformation, and migration of several cancer types, including colorectal cancer (CRC). However, the prognostic and clinical significance of syndecan-1 in CRC remains conflicting. Therefore, we performed a meta-analysis to clarify this relationship. METHODS: A comprehensive literature search for relevant studies published up to December 2014 was performed using PubMed, EMBASE, and Ovid library database. The odds ratio (OR) and pooled hazard ratio (HR) with their 95 % confidence intervals (CI) were used to estimate the effects. RESULTS: Ten studies with 888 CRC patients were selected for evaluation. The results showed that syndecan-1 expression was lower in CRC tissue than in normal colorectal tissue (OR = 0.02, 95 % CI = 0.00-0.09), and lower in the advanced stage than in the early stage (OR = 2.24, 95 % CI = 1.14 - 4.42). Additionally, syndecan-1 expression was higher in well and moderately differentiated CRC than in poorly differentiated CRC (OR = 2.91, 95 % CI = 1.21-6.98); no significant difference was found in patients with or without lymph node metastasis (OR = 0.91, 95 % CI = 0.34-2.43) and distant metastasis (OR = 0.89, 95 % CI = 0.19-4.21). The pooled results showed that syndecan-1 expression was not associated with survival in CRC patients (HR = 0.93, 95 % CI = 0.86-1.01). CONCLUSION: This meta-analysis indicated that loss of syndecan-1 expression is associated with CRC development, histological differentiation, and clinical stage, but not with lymph node metastasis and distant metastasis. In addition, these findings fail to support the prognostic significance of syndecan-1 in CRC. PMID- 26518019 TI - Digital versus screen-film mammography: impact of mammographic density and hormone therapy on breast cancer detection. AB - Most studies that have examined the effects of mammographic density and hormone therapy use on breast cancer detection have included screen-film mammography. This study further examines this association in post-menopausal women screened by digital mammography. Approved by the University of Toronto Research Ethics Board, this study identified 688,418 women of age 50-74 years screened with digital or screen-film mammography from 2008 to 2009 within the Ontario Breast Screening Program. Of 2993 eligible women with invasive breast cancer, 2450 were contacted and 1421 participated (847 screen-film mammography, 574 digital direct radiography). Mammographic density was measured by study radiologists using the standard BI-RADS classification system and by a computer-assisted method. Information on hormone therapy use was collected by a telephone-administered questionnaire. Logistic regression and two-tailed tests for significance evaluated associations between factors and detection method by mammography type. Women with >75 % radiologist-measured mammographic density compared to those with <25 % were more likely to be diagnosed with an interval than screen-detected cancer, with the difference being greater for those screened with screen-film (OR = 6.40, 95 % CI 2.30-17.85) than digital mammography (OR = 2.41, 95 % CI 0.67 8.58) and aged 50-64 years screened with screen-film mammography (OR = 10.86, 95 % CI 2.96-39.57). Recent former hormone therapy users were also at an increased risk of having an interval cancer with the association being significant for women screened with digital mammography (OR = 2.08, 95 % CI 1.17-3.71). Breast screening using digital mammography lowers the risk of having an interval cancer for post-menopausal women aged 50-64 with greater mammographic density. PMID- 26518018 TI - Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank. AB - Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE, MAPT, and TMEM106B. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future studies addressing clinical correlates of CTE pathology are needed. PMID- 26518021 TI - A randomized controlled trial of cognitive-behavioral stress management in breast cancer: survival and recurrence at 11-year follow-up. AB - Non-metastatic breast cancer patients often experience psychological distress which may influence disease progression and survival. Cognitive-behavioral stress management (CBSM) improves psychological adaptation and lowers distress during breast cancer treatment and long-term follow-ups. We examined whether breast cancer patients randomized to CBSM had improved survival and recurrence 8-15 years post-enrollment. From 1998 to 2005, women (N = 240) 2-10 weeks post-surgery for non-metastatic Stage 0-IIIb breast cancer were randomized to a 10-week, group based CBSM intervention (n = 120) or a 1-day psychoeducational seminar control (n = 120). In 2013, 8-15 years post-study enrollment (11-year median), recurrence and survival data were collected. Cox Proportional Hazards Models and Weibull Accelerated Failure Time tests were used to assess group differences in all-cause mortality, breast cancer-specific mortality, and disease-free interval, controlling for biomedical confounders. Relative to the control, the CBSM group was found to have a reduced risk of all-cause mortality (HR = 0.21; 95 % CI [0.05, 0.93]; p = .040). Restricting analyses to women with invasive disease revealed significant effects of CBSM on breast cancer-related mortality (p = .006) and disease-free interval (p = .011). CBSM intervention delivered post surgery may provide long-term clinical benefit for non-metastatic breast cancer patients in addition to previously established psychological benefits. Results should be interpreted with caution; however, the findings contribute to the limited evidence regarding physical benefits of psychosocial intervention post surgery for non-metastatic breast cancer. Additional research is necessary to confirm these results and investigate potential explanatory mechanisms, including physiological pathways, health behaviors, and treatment adherence changes. PMID- 26518022 TI - Quality of life outcomes from the Exercise and Nutrition Enhance Recovery and Good Health for You (ENERGY)-randomized weight loss trial among breast cancer survivors. AB - Obesity is a poor prognostic factor and is negatively related to quality of life (QOL) in breast cancer survivors. Exercise and Nutrition to Enhance Recovery and Good Health for You is the largest weight loss trial completed among cancer survivors. Percent losses in body weight with an intensive group-based intervention versus an attention control were 6.0 versus 1.5 % (p < 0.0001) and 3.7 versus 1.3 % (p < 0.0001) at 12 and 24 months, respectively. ENERGY also was designed to answer the research question: Does weight loss significantly improve vitality and physical function (key components of QOL)? 692 breast cancer survivors (BMI: 25-45 kg/m(2)) at 4 US sites were randomized to a year-long intensive intervention of 52 group sessions and telephone counseling contacts versus a non-intensive (control) of two in-person counseling sessions. Weight, self-reported QOL, and symptoms were measured semi-annually for two years. Significant decreases in physical function and increases in symptoms were observed among controls from baseline to 6 months, but not in the intervention arm, -3.45 (95 % Confidence Interval [CI] -6.10, -0.79, p = 0.0109) and 0.10 (95 %CI 0.04, 0.16, p = 0.0021), respectively. Improvements in vitality were seen in both arms but trended toward greater improvement in the intervention arm -2.72 (95 % CI -5.45, 0.01, p = 0.0508). These differences diminished over time; however, depressive symptoms increased in the intervention versus control arms and became significant at 24 months, -1.64 (95 % CI -3.13, -0.15, p = 0.0308). Increased QOL has been reported in shorter term diet and exercise trials among cancer survivors. These longer term data suggest that diet and exercise interventions improve some aspects of QOL, but these benefits may diminish over time. PMID- 26518023 TI - Effects of cigarette smoking and alcohol use on neurocognition and BDNF levels in a Chinese population. AB - OBJECTIVE: Few studies have examined the potential interactive effect of both smoking and drinking on cognition. Brain-derived neurotrophic factor (BDNF) plays a critical role in cognition. This is the first study to examine the neurocognitive consequences of cigarette smoking combined with chronic alcohol consumption and their relationship to serum BDNF levels in a Chinese Han population. MATERIALS AND METHODS: We recruited 191 healthy male subjects, including 47 isolated smokers, 31 isolated chronic alcohol users, 58 combined smokers and chronic alcohol users, and 55 non-smokers and non-alcohol users. We then compared the repeatable battery for the assessment of neuropsychological status (RBANS) scores and serum BDNF levels in these four groups. RESULTS: When compared to the non-smoking + non-alcohol-using group, the smoking group performed worse on immediate memory, attention, language, and RBANS total score. There were no significant differences in the RBANS scores between the alcohol using group and non-smoking + non-alcohol-using group, or between the smoking group and smoking + alcohol-using group. We did not find an association between BDNF and smoking or drinking status or between BDNF and cognitive performance. In the smoking group, there was a significant correlation between BDNF and carbon monoxide concentration, and between BDNF and the Fagerstrom Test for Nicotine Dependence (FTND) total score. CONCLUSIONS: Our results suggest that smoking is associated with cognitive decline, but not with BDNF levels in a normal population. However, smoking severity is positively associated with BDNF levels. Concomitant alcohol use does not worsen the cognitive decline caused by smoking. PMID- 26518024 TI - M3 muscarinic receptor in the ventral medial prefrontal cortex modulating the expression of contextual fear conditioning in rats. AB - RATIONALE: Basal forebrain cholinergic neurons modulate the activation of cortical neurons by several stimuli such as fear and anxiety. However, the role of the muscarinic receptor in the medial prefrontal cortex (MPFC) in the modulation of the conditioned emotional response (CER) evoked in the model contextual conditioned fear remains unclear. OBJECTIVES: The objective of this study is to test the hypothesis that inhibition of the muscarinic receptor in ventral MPFC modulates CER observed during animal's re-exposure to the aversive context. METHODS: Rats implanted with cannulae aimed at the prelimbic (PL) or the infralimbic (IL) were submitted to a high-intensity contextual fear conditioning protocol. Before the test session, they received microinjections of the hemicholinium (choline reuptake blocker), atropine (muscarinic antagonist), J104129 fumarate (M1-M3 muscarinic antagonists), pirenzepine (M1 muscarinic antagonist), neostigmine (inhibitor acetylcholinesterase enzyme), or the systemic administration of the FG7142 (inverse benzodiazepine agonist). Additional independent groups received the neostigmine or FG7142 before the ineffective doses of J104129 fumarate in the low-intensity protocol of contextual fear conditioning. RESULTS: In the high-intensity protocol, the administration of hemicholinium (1 nmol), atropine (0.06-6 nmol), J104129 fumarate (6 nmol), or pirenzepine (6 nmol) attenuated the expression of CER in rats. However, in the low-intensity protocol, only J10129 fumarate (0.06 nmol) reduced the expression of the CER. Finally, neostigmine (0.1-1 nmol) or FG7142 (8 mg/Kg) increased CER expression, an effect inhibited by the low dose of the J10129 fumarate. CONCLUSIONS: These results indicated that the blockade of M3 muscarinic receptor in the vMPFC attenuates the CER expression. PMID- 26518026 TI - Photo-Catalytic Properties of TiO2 Supported on MWCNTs, SBA-15 and Silica-Coated MWCNTs Nanocomposites. AB - Mesoporous silica, specifically SBA-15, acid-treated multi-walled carbon nanotubes and a hybrid nanocomposite of SBA-15 coated onto the sidewalls acid treated multi-walled carbon nanotubes (CNTs) were prepared and used as supports for anatase TiO2. Sol-gel methods were adapted for the synthesis of selected supports and for coating the materials with selected wt% loading of titania. Physical and chemical properties of the supports and catalyst composite materials were investigated by powder X-ray diffraction (XRD), Raman spectroscopy, thermogravimetric analysis, scanning electron microscope (SEM), high-resolution transmission electron microscope (HRTEM), UV-vis diffuse reflectance spectroscopy and fluorescence spectroscopy. The photo-activity of the catalyst composites were evaluated on the decolorisation of methylene blue as a model pollutant. Coating CNTs with SBA-15 improved the thermal stability and textural properties of the nanotubes. All supported titania composites had high surface areas (207-301 m(2)/g), altered band gap energies and reduced TiO2 crystallite sizes. The TiO2/SBA-CNT composite showed enhanced photo-catalytic properties and activity than the TiO2/SBA-15 and TiO2/CNT composites. In addition, an interesting observation was noted with the TiO2/SBA-15 nanocomposites, which had a significantly greater photo-catalytic activity than the TiO2/CNT nanocomposites in spite of the high electron-hole recombination phenomena observed with the photoluminescence results. Discussions in terms of morphological, textural and physical-chemical aspects to account for the result are presented. PMID- 26518025 TI - Rivastigmine improves isolation rearing-induced prepulse inhibition deficits via muscarinic acetylcholine receptors in mice. AB - RATIONALE: The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine are used for the treatment of Alzheimer's disease. We previously demonstrated that donepezil and galantamine differentially affect isolation rearing-induced prepulse inhibition (PPI) deficits and that this might be due to differential effects on brain muscarinic acetylcholine (mACh) receptor function in mice. OBJECTIVES: We examined the effects of rivastigmine on isolation rearing induced PPI deficits, brain ACh levels, and mACh receptor function in mice. METHODS: Acoustic startle responses were measured in a startle chamber. Microdialysis was performed, and the levels of dopamine and ACh in the prefrontal cortex were measured. RESULTS: Rivastigmine (0.3 mg/kg) improved PPI deficits, and this improvement was antagonized by the mACh receptor antagonist telenzepine but not by the nicotinic ACh receptor antagonist mecamylamine. Rivastigmine increased extracellular ACh levels by approximately 2-3-fold, less than the increase produced by galantamine. Rivastigmine enhanced the effect of the mACh receptor agonist N-desmethylclozapine on prefrontal dopamine release, a marker of mACh receptor function, and this increase was blocked by telenzepine. In contrast, galantamine did not affect N-desmethylclozapine-induced dopamine release. Furthermore, rivastigmine did not affect cortical dopamine release induced by the serotonin1A receptor agonist osemozotan, suggesting that the effect of rivastigmine has specificity for mACh receptors. CONCLUSIONS: Taken together with our previous finding that marked increases in ACh levels are required for the PPI deficit improvement induced by galantamine, our present results suggest that rivastigmine improves isolation rearing-induced PPI deficits by increasing ACh levels and by concomitantly enhancing mACh receptor function. PMID- 26518027 TI - Self-Etching-Induced Morphological Evolution of ZnO Microrods Grown on FTO Glass by Hydrothermal Method. AB - In this research, the zinc oxide (ZnO) microrods were grown by hydrothermal method on fluorine-doped tin oxide (FTO) glass functionalized by self-assembled monolayer of octadecyltrimethoxysilane (ODS; CH3(CH2)17Si(OCH3)3). The sharp-tip or polygonal shape with specific facets at the top end of ZnO microrods can be obtained by post retention at low temperature. The morphologies were characterized by the field-emission scanning electron microscope (FESEM) and transmission electron microscopy (TEM). The results confirm that the morphology change at the top end is due to self-etching. The mechanism responsible for the formation of various top-end morphologies was proposed. The specific facets that left after 6-h retention were identified. The room-temperature micro photoluminescence spectra showed a strong ultraviolet emission at 387 nm, and a broad emission at a range of from 500 to 700 nm. The morphology change also influences the photoluminescence (PL) spectra. A satellite peak in the UV emission spectra was observed. The peak may be attributed to the morphology effect of the microrods. PMID- 26518028 TI - Growth of Silicon Nanosheets Under Diffusion-Limited Aggregation Environments. AB - The two-dimensional (2D) growth of cubic-structured (silicon) Si nanosheets (SiNSs) was investigated. Freestanding, single-crystalline SiNSs with a thickness of 5-20 nm were grown on various Si substrates under an atmospheric chemical vapor deposition process. Systematic investigation indicated that a diffusion limited aggregation (DLA) environment that leads to dendritic growth in <110> directions at the initial stage is essential for 2D growth. The kinetic aspects under DLA environments that ascribe to the dendritic and 2D growth were discussed. Under the more dilute conditions made by addition of Ar to the flow of H2, the SiNSs grew epitaxially on the substrates with periodic arrangement at a specific angle depending on the orientation of the substrate. It reveals that SiNSs always grew two dimensionally with exposing (111) surfaces. That is thermodynamically favorable. PMID- 26518029 TI - Advances in Pd Nanoparticle Size Decoration of Mesoporous Carbon Spheres for Energy Application. AB - Pd nanoparticles with different sizes and diameter distributions were successfully deposited on the surface of disordered mesoporous carbon spheres (DMHCS). The size and diameter distribution of the Pd particles were controlled by the application of different experimental conditions. Two methods of synthesis (reflux and impregnation) and two Pd precursors (palladium (II) acetyloacetonate (Pd(acac) 2) and palladium (II) acetate (Pd(OAc)2)) were investigated and compared for the preparation of Pd-decorated DMHCS. The hydrogen storage properties of the pristine DMHCS and Pd-modified DMHCS at 40 degrees C and a pressure range of 0-45 bar were studied. The results showed that Pd-supported carbon samples synthesized in the presence of Pd(OAc)2 exhibited enhanced hydrogen storage capacity in respect to the pristine DMHCS. The maximum hydrogen storage of 0.38 wt.% exhibited the sample with the Pd nanoparticle diameter distribution of 2-14 nm and the average Pd crystallite size of 7.6 nm. It was found that the Pd nanoparticle content, size, and diameter distribution have a noticeable influence on H2 storage capacity. PMID- 26518031 TI - High-Throughput Screening Assay for Inhibitors of TonB-Dependent Iron Transport. AB - The TonB-dependent Gram-negative bacterial outer membrane protein FepA actively transports the siderophore ferric enterobactin (FeEnt) into the periplasm. We developed a high-throughput screening (HTS) assay that observes FeEnt uptake through FepA in living Escherichia coli, by monitoring fluorescence quenching that occurs upon binding of FeEnt, and then unquenching as the bacteria deplete it from solution by transport. We optimized the labeling and spectroscopic methods to screen for inhibitors of TonB-dependent iron uptake through the outer membrane. The assay works like a molecular switch that is on in the presence of TonB activity and off in its absence. It functions in 96-well microtiter plates, in a variety of conditions, with Z factors of 0.8-1.0. TonB-dependent iron transport is energy dependent, and the inhibitory effects of the metabolic inhibitors carbonyl cyanide m-chlorophenylhydrazone, 2,4-dinitrophenol, azide, cyanide, and arsenate on FeEnt uptake were readily detected by the assay. Because iron acquisition is a determinant of bacterial pathogenesis, HTS with this method may identify inhibitors that block TonB function and constitute novel therapeutics against infectious disease caused by Gram-negative bacteria. PMID- 26518032 TI - High-Throughput Screening for Internalizing Antibodies by Homogeneous Fluorescence Imaging of a pH-Activated Probe. AB - Antibody-drug conjugates (ADCs) represent a rapidly growing class of biotherapeutics that deliver drugs specifically to target cells by binding of the antibody component to surface receptors. The majority of ADCs require receptor internalization depending on intrinsic features of the specific ADC-antigen interaction. The development of potent ADCs would greatly benefit from the identification of efficiently internalizing antibodies at early stages of discovery. We developed a highly sensitive and rapid antibody internalization assay using an indirect Cypher5E label. The pH-activated CypHer5E label becomes fluorescent upon internalization into the acidic environment of endocytic organelles, whereas background fluorescence of noninternalized CypHer5E is minimal. The pH-dependency of the CypHer5E signal enables robust discrimination of antibody internalization from surface binding. The favorable signal-over background ratio allows a homogeneous assay design with high-throughput fluorescence imaging in 384- and 1536-well formats. The biophysical readout of the primary internalization event substantially shortens incubation times compared to killing assays using toxin internalization. The assay was validated with tumor-relevant targets, including receptor tyrosine kinases (EGFR and HER2) and a class II cytokine receptor (TF) expressed by A431, AU565, and SKOV-3 cells and transient expression systems (CHO-S). Our method enables functional screening of large antibody libraries to identify therapeutic antibody candidates with internalization characteristics favorable for the development of ADCs. PMID- 26518033 TI - Bone metabolism in very preterm infants receiving total parenteral nutrition: do intravenous fat emulsions have an impact? AB - Very preterm infants (<32 weeks' gestation) are at high risk for impaired skeletal development because of factors that limit the provision of extrauterine nutrients. Cumulative net deficiencies of calcium, phosphorus, docosahexaenoic acid (DHA), and arachidonic acid (ARA) are evident in these infants after prolonged administration of total parenteral nutrition (TPN). This is significant because minerals as well as metabolites of DHA and ARA are important modulators of bone cell differentiation, lengthening of bone, and bone matrix deposition. Furthermore, diets containing only precursors of DHA and ARA result in suboptimal skeletal growth. With the emergence of new intravenous lipid emulsions, it is important to understand the impact of fatty acids on bone metabolism in the third trimester in order to optimize the provision of TPN in very preterm infants. The purpose of this review is to evaluate current evidence regarding intravenous lipid emulsions and bone metabolism in very preterm infants receiving prolonged TPN and to identify areas of research needed. PMID- 26518034 TI - Potential link between excess added sugar intake and ectopic fat: a systematic review of randomized controlled trials. AB - CONTEXT: The effect of added sugar intake on ectopic fat accumulation is a subject of debate. OBJECTIVE: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to examine the potential effect of added sugar intake on ectopic fat depots. DATA SOURCES: MEDLINE, CAB Abstracts, CAB Global Health, and EBM (Evidence-Based Medicine) Reviews - Cochrane Central Register of Controlled Trials databases were searched for studies published from 1973 to September 2014. DATA EXTRACTION: RCTs with a minimum of 6 days' duration of added sugar exposure in the intervention group were selected. The dosage of added sugar intake as a percentage of total energy was extracted or calculated. Means and standard deviations of pre- and post-test measurements or changes in ectopic fat depots were collected. DATA SYNTHESIS: Fourteen RCTs were included. Most of the studies had a medium to high risk of bias. Meta-analysis showed that, compared with eucaloric controls, subjects who consumed added sugar under hypercaloric conditions likely increased ectopic fat, particularly in the liver (pooled standardized mean difference = 0.9 [95%CI, 0.6-1.2], n = 6) and muscles (pooled SMD = 0.6 [95%CI, 0.2-1.0], n = 4). No significant difference was observed in liver fat, visceral adipose tissue, or muscle fat when isocaloric intakes of different sources of added sugars were compared. CONCLUSIONS: Data from a limited number of RCTs suggest that excess added sugar intake under hypercaloric diet conditions likely increases ectopic fat depots, particularly in the liver and in muscle fat. There are insufficient data to compare the effect of different sources of added sugars on ectopic fat deposition or to compare intake of added sugar with intakes of other macronutrients. Future well-designed RCTs with sufficient power and duration are needed to address the role of sugars on ectopic fat deposition. PMID- 26518035 TI - Nepenthes ampullaria (Nepenthaceae) Pitchers Are Unattractive to Gravid Aedes aegypti and Aedes albopictus (Diptera: Culicidae). AB - Nepenthes pitcher plants are colonized by a variety of specialized arthropods. As Aedes mosquitoes are container breeders, Nepenthes pitchers are a potential candidate oviposition site for vector species, such as Aedes aegypti (L.) and Aedes albopictus (Skuse). However, Aedes spp. are not commonly encountered in Nepenthes pitchers, and the environment inside the pitchers of some species is lethal to them. One exception is Nepenthes ampullaria Jack, whose pitchers are known to be colonized by Ae. albopictus on very rare occasions. Given that Ae. albopictus larvae can survive in N. ampullaria pitcher fluids, we sought to determine why pitcher colonization is rare, testing the hypothesis that gravid Aedes mosquitoes are deterred from ovipositing into container habitats that have similar characteristics to N. ampullaria pitchers. Using plastic ovitraps of different sizes, colors, and with different types of fluids (based on the characteristics of N. ampullaria pitchers), we compared oviposition rates by Aedes mosquitoes in urban and rural areas within the geographical range of N. ampullaria near Kuala Lumpur, Malaysia. Ovitraps that were black and large (>250 ml capacity) accumulated significantly more eggs than ovitraps that were smaller, or green in color. In terms of size and color, small, green ovitraps are analogous to N. ampullaria pitchers, indicating that these pitchers are not particularly attractive to gravid Ae. albopictus. Although Aedes spp. are capable of colonizing N. ampullaria pitchers, the pitchers are relatively unattractive to gravid females and do not represent a significant habitat for larvae of dengue vectors at present. PMID- 26518036 TI - Cardamom Bushy Dwarf Virus Infection in Large Cardamom Alters Plant Selection Preference, Life Stages, and Fecundity of Aphid Vector, Micromyzus kalimpongensis (Hemiptera: Aphididae). AB - Cardamom bushy dwarf virus (CBDV) causes foorkey disease of large cardamom (Ammomum subulatum Roxburgh) in the eastern sub-Himalayan mountains. Although the aphid Micromyzus kalimpongensis Basu (Hemiptera: Aphididae) is known as a vector of CBDV, its behavior in dissemination of CBDV has not been investigated. In the present study, M. kalimpongensis was observed to colonize in higher number on CBDV-infected large cardamom plants compared with the healthy plants in the several plantations in Sikkim and Darjeeling hills. The affinity of M. kalimpongensis to the diseased large cardamom plants was further confirmed in a contained field experiment with intact plant as well as in a laboratory bioassay with the plant extract, where significantly higher number of aphids settled on the diseased plants or extracts compared with the healthy counterparts. Aphids grown on CBDV-infected large cardamom plants had shortened nymphal period and increased longevity and fecundity compared with those grown on the healthy plants. In the contained field experiment, M. kalimpongensis migrated to the CBDV infected plants, colonized there, acquired CBDV, and once the diseased plants withered, migrated to healthy plants, which eventually became diseased. Our results suggest a general pattern of spread of CBDV by M. kalimpongensis where CBDV-infected plants attract or arrest and stimulate emergence and migration of viruliferous aphids that otherwise are sedentary in the underground plant parts of large cardamom. To our knowledge, this is the first study that shows the influence of a plant virus from the family Nanoviridae in altering behavior of its insect vector that favors its dissemination. PMID- 26518037 TI - Key experiences of community engagement and social mobilization in the Ebola response. AB - The ongoing outbreak of the Ebola virus in West Africa is the largest on record; it has undermined already fragile healthcare systems and presented new challenges to contain the spread of the disease. Based on our observations in the field and insights from referenced sources, we aimed to identify key experiences of community engagement and social mobilization efforts in the current Ebola response. We concluded that there is no excuse not to actively involve local people and that the United Nations (UN) agencies and other partners did learn from their earlier mistakes to make a genuine attempt to better engage with communities. However, bottom-up approaches have not been widely implemented during the response and the reasons for not doing so must be further assessed. Health promotion can make an important contribution, because it shows how to enable people to take more control over their lives and health. This commentary can provide a guide to agencies to understand an appropriate way forward when the next Ebola outbreak inevitably occurs. PMID- 26518038 TI - Community matters - why outbreak responses need to integrate health promotion. AB - Communities are characterized by common interests, common ecology, and common social system or structure. These characteristics, qualities, and processes involved in the community affect both health behaviors and health outcomes during disease outbreaks. Hence, health promotion theorists and practitioners emphasize working 'with' rather than 'on' communities. They believe health promotion, with all its experiences in community mobilization, empowerment, and health literacy programs, should be part of disease prevention and control efforts from the very beginning. Health promotion knowledge needs to be fully integrated into infectious disease control, especially in the context of outbreaks. PMID- 26518039 TI - Imaging Excited Orbitals of Quantum Dots: Experiment and Electronic Structure Theory. AB - Electronically excited orbitals play a fundamental role in chemical reactivity and spectroscopy. In nanostructures, orbital shape is diagnostic of defects that control blinking, surface carrier dynamics, and other important optoelectronic properties. We capture nanometer resolution images of electronically excited PbS quantum dots (QDs) by single molecule absorption scanning tunneling microscopy (SMA-STM). Dots with a bandgap of ~1 eV are deposited on a transparent gold surface and optically excited with red or green light to produce hot carriers. The STM tip-enhanced laser light produces a large excited-state population, and the Stark effect allows transitions to be tuned into resonance by changing the sample voltage. Scanning the QDs under laser excitation, we were able to image electronic excitation to different angular momentum states depending on sample bias. The shapes differ from idealized S- or P-like orbitals due to imperfections of the QDs. Excitation of adjacent QD pairs reveals orbital alignment, evidence for electronic coupling between dots. Electronic structure modeling of a small PbS QD, when scaled for size, reveals Stark tuning and variation in the transition moment of different parity states, supporting the simple one-electron experimental interpretation in the hot carrier limit. The calculations highlight the sensitivity of orbital density to applied field, laser wavelength, and structural fluctuations of the QD. PMID- 26518043 TI - Phenotype and Polyfunctional Deregulation Involving Interleukin 6 (IL-6)- and IL 10-Producing Monocytes in HIV-Infected Patients Receiving Combination Antiretroviral Therapy Differ From Those in Healthy Older Individuals. AB - BACKGROUND: Despite the relevance of monocytes as promoters of the inflammatory response, whether human immunodeficiency virus (HIV) infection induces premature age-related changes to the phenotype and function of monocytes or whether these alterations are different and/or specifically driven by HIV remains to be mechanistically determined. METHODS: We assayed the activation phenotype and the responsiveness in vitro to Toll-like receptor (TLR) agonists in classical, intermediate, and nonclassical subsets of monocytes by assessing intracellular interleukin 1alpha (IL-1alpha), IL-1beta, interleukin 6 (IL-6), interleukin 8, tumor necrosis factor alpha, and interleukin 10 (IL-10) production in 20 HIV infected patients receiving combination antiretroviral therapy (cART) and 2 groups of uninfected controls (20 age-matched young individuals and 20 older individuals aged >65 years). RESULTS: HIV-infected patients showed a more activated phenotype of monocytes than older controls. Regarding functionality, under unstimulated conditions HIV-infected patients showed a higher percentage of classical monocytes producing IL-6 and IL-10 than control subjects. The percentage of cells with production of multiple cytokines (polyfunctionality), including IL-10, in response to TLR agonists was greater among HIV-infected patients than among control subjects. CONCLUSIONS: Inflammatory alterations associated with monocytes during HIV infection are different from those in aging individuals. This monocyte dysfunction, mainly characterized by high levels of IL 6- and IL-10-producing monocytes, may have clinical implications in HIV-infected patients that are different from those in aging individuals. PMID- 26518044 TI - Cross-protection of the Bivalent Human Papillomavirus (HPV) Vaccine Against Variants of Genetically Related High-Risk HPV Infections. AB - BACKGROUND: Results from the Costa Rica Vaccine Trial (CVT) demonstrated partial cross-protection by the bivalent human papillomavirus (HPV) vaccine, which targets HPV-16 and HPV-18, against HPV-31, -33, and -45 infection and an increased incidence of HPV-51 infection. METHODS: A study nested within the CVT intention-to-treat cohort was designed to assess high-risk HPV variant lineage specific vaccine efficacy (VE). The 2 main end points were (1) long-term incident infections persisting for >=2 years and/or progression to high-grade squamous intraepithelial lesions (ie, cervical intraepithelial neoplasia grade 2/3 [CIN 2/3]) and (2) incident transient infections lasting for <2 years. For efficiency, incident infections due to HPV-16, -18, -31, -33, -35, -45, and -51 resulting in persistent infection and/or CIN 2/3 were matched (ratio, 1:2) to the more frequent transient viral infections, by HPV type. Variant lineages were determined by sequencing the upstream regulatory region and/or E6 region. RESULTS: VEs against persistent or transient infections with HPV-16, -18, -33, 35, -45, and -51 did not differ significantly by variant lineage. As the possible exception, VEs against persistent infection and/or CIN 2/3 due to HPV-31 A/B and HPV-31C variants were -7.1% (95% confidence interval [CI], -33.9% to 0%) and 86.4% (95% CI, 65.1%-97.1%), respectively (P = .02 for test of equal VE). No difference in VE was observed by variant among transient HPV-31 infections (P = .68). CONCLUSIONS: Overall, sequence variation at the variant level does not appear to explain partial cross-protection by the bivalent HPV vaccine. PMID- 26518045 TI - Improving Control of Antibiotic-Resistant Gonorrhea by Integrating Research Agendas Across Disciplines: Key Questions Arising From Mathematical Modeling. AB - The rise in gonococcal antibiotic resistance and the threat of untreatable infection are focusing attention on strategies to limit the spread of drug resistant gonorrhea. Mathematical models provide a framework to link the natural history of infection and patient behavior to epidemiological outcomes and can be used to guide research and enhance the public health impact of interventions. While limited knowledge of key disease parameters and networks of spread has impeded development of operational models of gonococcal transmission, new tools in gonococcal surveillance may provide useful data to aid tracking and modeling. Here, we highlight critical questions in the management of gonorrhea that can be addressed by mathematical models and identify key data needs. Our overarching aim is to articulate a shared agenda across gonococcus-related fields from microbiology to epidemiology that will catalyze a comprehensive evidence-based clinical and public health strategy for management of gonococcal infections and antimicrobial resistance. PMID- 26518046 TI - Vertical Cytomegalovirus Transmission From HIV-Infected Women Randomized to Formula-Feed or Breastfeed Their Infants. AB - BACKGROUND: Cytomegalovirus (CMV) is associated with morbidity and mortality in human immunodeficiency virus (HIV)-exposed infants. We assessed the effect of and relative contribution of breastfeeding to CMV acquisition among infants delivered by HIV-infected mothers. METHODS: Between 1993 and 1998 pregnant, HIV-infected women in Nairobi, Kenya, were randomly assigned to breastfeed or formula-feed their infants in an HIV transmission study. Women were allocated equally between treatment arms, and the study was not blinded. The primary endpoint of this nested study was time to infant CMV infection. RESULTS: CMV infection was assessed in 138 breastfed and 134 formula-fed infants. Baseline characteristics were similar between arms. Breastfed infants acquired CMV earlier than formula fed infants (median age of acquisition, 4.26 vs 9.87 months; P < .001) and had a higher 1-year probability of CMV infection (0.89 vs 0.69; P < .001). Breastfeeding was associated with a 1.6-fold increased risk of infant CMV acquisition independent of infant HIV status (multivariable hazard ratio, 1.61; 95% confidence interval, 1.20-2.16; P = .002). Approximately one third of CMV infections occurred during the peripartum period, with 40% acquired through breastfeeding and the remainder acquired through modes other than breast milk. CONCLUSIONS: Preventing CMV acquisition may be a priority for HIV-exposed infants, but there is a narrow window of opportunity for intervention. Approaches that reduce maternal cervical and breast milk CMV reactivation may help delay infant infection. PMID- 26518047 TI - Factors influencing the efficacy of rilpivirine in HIV-1 subtype C in low- and middle-income countries. AB - OBJECTIVES: The use of the NNRTI rilpivirine in low- and middle-income countries (LMICs) is under debate. The main objective of this study was to provide further clinical insights and biochemical evidence on the usefulness of rilpivirine in LMICs. PATIENTS AND METHODS: Rilpivirine resistance was assessed in 5340 therapy naive and 13,750 first-generation NNRTI-failed patients from Europe and therapy naive HIV-1 subtype C (HIV-1C)-infected individuals from India (n = 617) and Ethiopia (n = 127). Rilpivirine inhibition and binding affinity assays were performed using patient-derived HIV-1C reverse transcriptases (RTs). RESULTS: Primary rilpivirine resistance was rare, but the proportion of patients with >100,000 HIV-1 RNA copies/mL pre-ART was high in patients from India and Ethiopia, limiting the usefulness of rilpivirine as a first-line drug in LMICs. In patients failing first-line NNRTI treatments, cross-resistance patterns suggested that 73% of the patients could benefit from switching to rilpivirine based therapy. In vitro inhibition assays showed ~ 2-fold higher rilpivirine IC50 for HIV-1C RT than HIV-1B RT. Pre-steady-state determination of rilpivirine binding affinities revealed 3.7-fold lower rilpivirine binding to HIV-1C than HIV 1B RT. Structural analysis indicated that naturally occurring polymorphisms close to the NNRTI-binding pocket may reduce rilpivirine binding, leading to lower susceptibility of HIV-1C to rilpivirine. CONCLUSIONS: Our clinical and biochemical findings indicate that the usefulness of rilpivirine has limitations in HIV-1C-dominated epidemics in LMICs, but the drug could still be beneficial in patients failing first-line therapy if genotypic resistance testing is performed. PMID- 26518048 TI - Efficacy of dalbavancin in the treatment of MRSA rat sternal osteomyelitis with mediastinitis. AB - OBJECTIVES: Dalbavancin, a semi-synthetic lipoglycopeptide, is characterized by a long plasma half-life, which allows weekly dosing. Dalbavancin may be a good treatment option for patients with deep sternal wound infections owing to its improved pharmacokinetic profile and antibacterial activity compared with currently used antibiotics. Here we evaluated the efficacy of 7 or 14 days of treatment with dalbavancin, compared with vancomycin and with saline, in reducing sternal bone MRSA counts in a rat Staphylococcus aureus deep sternal wound infection model. METHODS: A mid-sternal wound was surgically induced in anaesthetized rats. A clinical strain of MRSA was injected into the sternum to establish infection. Rats were treated intraperitoneally for 7 or 14 days with dalbavancin, vancomycin or saline. The number of cfu per gram of sternum or spleen tissue was determined using viable counts. The antibacterial efficacy was determined by the reduction in bacterial counts per gram of sternum or spleen tissue in each treatment group. RESULTS: Treatment with dalbavancin was superior to treatment with saline for 7 days (0.75 log reduction in bone cfu) or 14 days (>3 log reduction in bone cfu) and similar to treatment with vancomycin. Additionally, dalbavancin was also effective in reducing systemic dissemination of MRSA. CONCLUSIONS: Dalbavancin is effective in the treatment of MRSA rat sternal osteomyelitis. PMID- 26518049 TI - Increase in bacteraemia cases in the East Midlands region of the UK due to MDR Escherichia coli ST73: high levels of genomic and plasmid diversity in causative isolates. AB - OBJECTIVES: The objective of this study was to determine the population structure of Escherichia coli ST73 isolated from human bacteraemia and urinary tract infections. METHODS: The genomes of 22 E. coli ST73 isolates were sequenced using the Illumina HiSeq platform. High-resolution SNP typing was used to create a phylogenetic tree. Comparative genomics were also performed using a pangenome approach. In silico and S1-PFGE plasmid profiling was conducted, and isolates were checked for their ability to survive exposure to human serum. RESULTS: E. coli ST73 isolates circulating in clinically unrelated episodes show a high degree of diversity at a whole-genome level, but exhibit conservation in gene content, particularly in virulence-associated gene carriage. The isolates also contain a highly diverse plasmid pool that confers MDR via carriage of CTX-M genes. CONCLUSIONS: Our data show that a rise in incidence of MDR E. coli ST73 clinical isolates is not due to a circulating outbreak strain as in E. coli ST131. Rather the ST73 circulating strains are distantly related and carry a diverse set of resistance plasmids. This suggests that the evolutionary events behind emergence of drug-resistant E. coli differ between lineages. PMID- 26518050 TI - Primary antifungal prophylaxis in adult patients with acute lymphoblastic leukaemia: a multicentre audit. AB - OBJECTIVES: The primary objectives were to investigate the prescribing practices of primary antifungal prophylaxis (PAP) and incidence of invasive fungal disease (IFD) in adult patients with ALL receiving induction-consolidation chemotherapy. Secondary objectives were to determine risk factors for IFD and resource utilization associated with IFD. METHODS: A retrospective chart review of adult patients with ALL from commencement of induction until completion of consolidation chemotherapy was undertaken from January 2008 to June 2013 in four hospitals in Melbourne, Australia. IFD was classified according to the revised European Organisation for Research and Treatment of Cancer criteria. Cost analysis was performed from an Australian public hospital perspective. RESULTS: Ninety-eight patients were included in the audit; 83 (85%) received PAP. Most patients (49/83, 59%) switched between two different antifungal agents, predominantly between liposomal amphotericin B and an azole. Five proven/probable and six possible IFD cases were identified. Proven/probable IFD was most common in patients receiving the BFM95 chemotherapy protocol. The incidence of proven/probable IFD was significantly lower in patients receiving PAP compared with those who did not (2/78, 2.6% versus 3/14, 21.4%; P = 0.024). For every five patients receiving PAP, one proven/probable IFD case would be prevented. Proven/probable IFD was associated with an additional median cost of 121,520 Australian dollars (95% CI: 90,781-180,141 Australian dollars; P < 0.001) compared with patients without IFD. CONCLUSIONS: This is the first multicentre study evaluating PAP use in patients with ALL. With the caveats of interpretation of retrospective, non-randomized data, PAP was associated with a reduced IFD risk. PMID- 26518051 TI - A single-day point-prevalence study of faecal carriers in long-term care hospitals in Madrid (Spain) depicts a complex clonal and polyclonal dissemination of carbapenemase-producing Enterobacteriaceae. AB - OBJECTIVES: The objective of this study was to describe the prevalence and microbiological characteristics of carbapenemase-producing Enterobacteriaceae (CPE) colonizing patients in long-term care hospitals (LTCHs) in Madrid, Spain. METHODS: Three LTCHs were included in a single-day point-prevalence survey (September 2013). Rectal swabs, collected from all hospitalized patients (137 in LTCH-A, 121 in LTCH-B and 83 in LTCH-C), were plated onto chromogenic media. Population structure (PFGE and MLST), genes encoding carbapenemases and ESBLs and plasmids carrying carbapenemase genes were characterized. RESULTS: The prevalence of CPE carriers was 4.1% (14/341) [2.9% (4/137), LTCH-A; 4.1% (5/121), LTCH-B; and 6.0% (5/83), LTCH-C]. OXA-48 was the most prevalent carbapenemase (nine Klebsiella pneumoniae, two Escherichia coli, one Enterobacter cloacae and one Citrobacter braakii) followed by VIM-1 (one K. pneumoniae and one Raoultella ornithinolytica). One patient (LTCH-C) was co-colonized with OXA-48-producing K. pneumoniae and E. coli. K. pneumoniae and E. coli isolates also coproduced CTX-M 15 (n = 11) or CTX-M-9 (n = 1) enzymes. K. pneumoniae clustered into six PFGE types corresponding to ST11 (n = 1), ST15 (n = 6), ST307 (n = 1) and ST405 (n = 2). E. coli from LTCH-A and LTCH-C exhibited two different PFGE types associated with ST68. OXA-48 and VIM-1 enzymes were found in different clones in LTCH-A and LTCH-C. However, OXA-48 was the only carbapenemase detected in LTCH-B, mainly associated with K. pneumoniae ST15. KPC, IMP and NDM enzymes were not detected. blaOXA-48 was located on an ~ 60 kb plasmid with a pOXA-48a-IncL/M backbone. CONCLUSIONS: We describe the first point-prevalence study of CPE faecal carriers in LTCHs in Spain. OXA-48, the most prevalent carbapenemase, showed a complex dissemination pattern with clonal and polyclonal bacterial populations. PMID- 26518052 TI - Lateral dissemination and inter-patient transmission of blaKPC-3: role of a conjugative plasmid in spreading carbapenem resistance. AB - OBJECTIVES: The objective of this study was to describe the nosocomial spread of carbapenemase-producing enterobacteria and characterize a plasmid involved in KPC dissemination. METHODS: Two Klebsiella pneumoniae, one Escherichia coli and one Citrobacter freundii isolated from two patients were studied. Susceptibility profiles were obtained using Etest. Carbapenemase activity was detected using the Carba NP test. beta-Lactamase gene content was screened by PCR and sequencing. K. pneumoniae isolates were genotyped by MLST and PFGE. KPC plasmid sizes were estimated by S1-DNA digestion and PFGE-Southern blot. Plasmids were sequenced using Illumina's technology and Sanger sequencing. RESULTS: Two patients sharing a room on a surgical unit were positive for carbapenemase-producing K. pneumoniae. One patient was also colonized with carbapenemase-producing C. freundii and E. coli. Neither patient had known risk factors for carbapenemase acquisition, although one patient had recent surgery at another Toronto hospital; the other patient's husband had surgery in New York City 3 years prior to her presentation. An extensive investigation was conducted at both hospitals, but no additional cases were identified. blaKPC-3 was detected in all clinical isolates. Variable carbapenem resistance levels were observed. Both K. pneumoniae belonged to the same clone by PFGE and MLST (ST277). pKPC-SMH (~ 53 kb) was identified in all the clinical isolates, showing identity only with structurally similar IncN plasmids. CONCLUSIONS: We describe intra- and inter-patient dissemination of blaKPC. The involvement of a clone related to the successful K. pneumoniae ST258 and the blaKPC-3 gene detected in an active Tn4401 transposon carried on a conjugative broad-host-range plasmid increased the potential for this horizontal transmission. PMID- 26518053 TI - Prostaglandin E2-stimulated prostanoid EP4 receptors induce prolonged de novo prostaglandin E2 synthesis through biphasic phosphorylation of extracellular signal-regulated kinases mediated by activation of protein kinase A in HCA-7 human colon cancer cells. AB - Approximately two decades have passed since E-type prostanoid 4 (EP4) receptors were cloned, and the signaling pathways mediated by these receptors have since been implicated in cancer development through the alliance of Galphai protein/phosphatidylinositol 3-kinase (PI3K)/extracellular signal-regulated kinases (ERKs) activation. Although prostanoid EP4 receptors were initially identified as Galphas-coupled receptors, the specific/distinctive role(s) of prostanoid EP4 receptor-induced cAMP/protein kinase A (PKA) pathways in cancer development have not yet been elucidated in detail. We previously reported using HCA-7 human colon cancer cells that prostaglandin E2 (PGE2)-stimulated prostanoid EP4 receptors induced cyclooxygenase-2 (COX-2) as an initiating event in development of colon cancer. Moreover, this induction of COX-2 was mediated by transactivation of epidermal growth factor (EGF) receptors. However, direct activation of EGF receptors by EGF also induced similar amounts of COX-2 in this cell line. Thus, the emergence of unique role(s) for prostanoid EP4 receptors is expected by clarifying the different signaling mechanisms between PGE2-stimulated prostanoid EP4 receptors and EGF-stimulated EGF receptors to induce COX-2 and produce PGE2. We here demonstrated that prostanoid EP4 receptor activation by PGE2 in HCA-7 cells led to PKA-dependent re-activation of ERKs, which resulted in prolonged de novo synthesis of PGE2. Although EGF-stimulated EGF receptors in cells also induced COX-2 and the de novo synthesis of PGE2, the activation of this pathway was transient and not mediated by PKA. Therefore, the novel mechanism underlying prolonged de novo synthesis of PGE2 has provided an insight into the importance of prostanoid EP4 receptor-mediated Galphas-protein/cAMP/PKA pathway in development of colon cancer. PMID- 26518054 TI - Elevated Lifetime Lead Exposure Impedes Osteoclast Activity and Produces an Increase in Bone Mass in Adolescent Mice. AB - The heavy metal lead (Pb) has a deleterious effect on skeletal health. Because bone mass is maintained through a balance of bone formation and resorption, it is important to understand the effect of Pb levels on osteoblastic and osteoclastic activity. Pb exposure is associated with low bone mass in animal models and human populations; however, the correlation between Pb dosing and corresponding bone mass has been poorly explored. Thus, mice were exposed to increasing Pb and at higher levels (500 ppm), there was unexpectedly an increase in femur-tibial bone mass by 3 months of age. This is contrary to several studies alluded to earlier. Increased bone volume (BV) was accompanied by a significant increase in cortical thickness of the femur and trabecular bone that extended beyond the epiphyseal area into the marrow cavity. Subsequent evaluations revealed an increase in osteoclast numbers with high Pb exposure, but a deficiency in osteoclastic activity. These findings were substantiated by observed increases in levels of the resorption-altering hormones calcitonin and estrogen. In addition we found that pro-osteoclastic nuclear factor-kappa beta (NF-kappaB) pathway activity was dose dependently elevated with Pb, both in vivo and in vitro. However, the ability of osteoclasts to resorb bone was depressed in the presence of Pb in media and within test bone wafers. These findings indicate that exposure to high Pb levels disrupts early life bone accrual that may involve a disruption of osteoclast activity. This study accentuates the dose dependent variation in Pb exposure and consequent effects on skeletal health. PMID- 26518055 TI - Monomethylarsonous acid (MMA+3) Inhibits IL-7 Signaling in Mouse Pre-B Cells. AB - Our previously published data show that As(+3) in vivo and in vitro, at very low concentrations, inhibits lymphoid, but not myeloid stem cell development in mouse bone marrow. We also showed that the As(+3) metabolite, monomethylarsonous acid (MMA(+3)), was responsible for the observed pre-B cell toxicity caused by As(+3). Interleukin-7 (IL-7) is the primary growth factor responsible for pre-lymphoid development in mouse and human bone marrow, and Signal Transducer and Activator of Transcription 5 (STAT5) is a transcriptional factor in the IL-7 signaling pathway. We found that MMA(+3) inhibited STAT5 phosphorylation at a concentration as low as 50 nM in mouse bone marrow pre-B cells. Inhibition of STAT5 phosphorylation by As(+3) occurred only at a concentration of 500 nM. In the IL-7 dependent mouse pre-B 2E8 cell line, we also found selective inhibition of STAT5 phosphorylation by MMA(+3), and this inhibition was dependent on effects on JAK3 phosphorylation. IL-7 receptor expression on 2E8 cell surface was also suppressed by 50 nM MMA(+3) at 18 h. As further evidence for the inhibition of STAT5, we found that the induction of several genes required in B cell development, cyclin D1, E2A, EBF1, and PAX5, were selectively inhibited by MMA(+3). Since 2E8 cells lack the enzymes responsible for the conversion of As(+3) to MMA(+3) in vitro, the results of these studies suggest that As(+3) induced inhibition of pre-B cell formation in vivo is likely dependent on the formation of MMA(+3) which in turn inhibits IL-7 signaling at several steps in mouse pre-B cells. PMID- 26518056 TI - IFN-gamma and IgA against non-methylated heparin-binding hemagglutinin as markers of protective immunity and latent tuberculosis: Results of a longitudinal study from an endemic setting. AB - BACKGROUND: Heparin-binding hemagglutinin (HBHA) is a surface protein involved in epithelial attachment and extrapulmonary dissemination of Mycobacterium tuberculosis. HBHA is attracting increasing attention for its vaccine and diagnostic potential. In a longitudinal study, we investigated non-methylated, recombinant HBHA-specific cytokine and antibody profiles in cohorts of TB patients, their contacts and community controls in an endemic setting. METHODS: Whole blood assay was done at baseline, 6 and 12 months in patients and contacts, and at entry in controls. ELISA was used to measure IFN-gamma, TNF-alpha and IL 10 (from supernatants), and IgG, IgM and IgA (from sera). RESULTS: Fifty-three percent of controls and 72.1% of contacts were QFT-GIT positive. Baseline IFN gamma was significantly higher in community controls and contacts compared to untreated TB patients (p < 0.0001). Controls had significantly higher IgA and lower IgM compared to both untreated TB patients and contacts (p < 0.0001). IL-10 was significantly higher in untreated TB patients compared to contacts and controls (p < 0.0001). In treated TB patients, IFN-gamma significantly increased (p < 0.0001) whereas IL-10 significantly decreased (p < 0.001). CONCLUSION: This study reports for the first time that anti-HBHA IgA could have the potential as a biomarker of protective immunity. In addition, non-methylated, recombinant HBHA induced IFN-gamma could be used as a biomarker of protective immunity and latent TB. PMID- 26518058 TI - Impact of antifungal prescription on relative distribution and susceptibility of Candida spp. - Trends over 10 years. AB - INTRODUCTION: The incidence of Candida spp. infections is worrisome, particularly in critically ill patients. Previous reports suggested that increasing use of antifungal therapy might affect resistance profiles of invasive strains. The study objective was to describe the distribution resistance profile of Candida spp. strains, and to correlate it with antifungal consumptions within one ICU. METHOD: Antifungal drug consumption was measured as the number of defined daily doses per 1000 hospital days. The distribution of Candida spp. over a 10 year period 2004-2013 and the MICs of antifungal drugs over 2007-2013 were determined. Time series analyses were performed. RESULTS: Of 2403 identified Candida spp. from 5360 patients, Candida albicans predominated (53.1%), followed by Candida glabrata (16.2%), Candida parapsilosis (7.9%) and Candida tropicalis (7.5%). C. parapsilosis increased from 5.7% in 2004 to 8.4% in 2013 (P = 0.02). The increase in caspofungin use is correlated with the increase in caspofungin MICs of C. parapsilosis (P = 0.01), C. glabrata (P = 0.001) and C. albicans (P = 0.02). Polyenes consumption correlated with an increase in amphotericin B MICs of C. glabrata (P = 0.04). CONCLUSION: Previous history of antifungal prescription within an ICU influences Candida species distribution and susceptibility profile to antifungal agents. The significant selective pressure exerted by caspofungin and amphotericin B on C. glabrata is a concern. PMID- 26518057 TI - HHV-6 infection after allogeneic hematopoietic stem cell transplantation: From chromosomal integration to viral co-infections and T-cell reconstitution patterns. AB - OBJECTIVES: Human herpes virus 6 (HHV-6) can reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with significant clinical manifestations. METHODS: Case control study of HHV-6 infections after allo-HSCT. Chromosomal integration (ciHHV-6) for viral loads >= 5.5-log10 copies/mL was investigated. Viral co-infections, T-cell recovery, risk factors and outcome were compared in HHV-6- and non-HHV-6-infected patients. Antiviral treatment strategies were reviewed. RESULTS: Among 366 adult allo-HSCT recipients, 75 HHV-6 infections occurred. Three (4%) recipients were ciHHV-6. HHV 6 infections were associated with CMV (p = 0.05; sdHR 1.73, CI 0.99-3.02) and/or BKV infections (p < 0.0001; sdHR 4.63, CI 2.04-10.53) but not EBV reactivation (p = 0.34). A slower CD8+ T-cells recovery was observed until 6 months after allo HSCT in the HHV-6-infected group (p < 0.001), independently of acute and/or chronic graft-versus-host disease. The overall probability of survival after allo HSCT was diminished for active HHV-6-infected patients (p = 0.0326). Cord blood unit recipients had a higher risk of developing HHV-6 infection compared to bone marrow recipients (p = 0.0007; sdHR 3.82, CI 1.76-8.27). Anti-HHV-6 treatment achieved complete response in only 2/3 of the cases. CONCLUSIONS: In this series of allo-HSCT recipients, 4% were ciHHV-6, active HHV-6 infection was likely associated with CMV and BKV co-reactivations, delayed CD8+ T-cell recovery and poorer outcome. PMID- 26518059 TI - Combining dynamic contrast enhanced magnetic resonance imaging and microvessel density to assess the angiogenesis after PEI in a rabbit VX2 liver tumor model. AB - OBJECTIVES: To evaluate the correlation between parameters of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and microvessel density (MVD) measurements in rabbit VX2 liver tumor models after percutaneous ethanol injection (PEI) and to observe influence of PEI on angiogenesis in a rabbit VX2 liver tumor model with dynamic contrast enhanced magnetic resonance imaging (DCE MRI). MATERIALS AND METHODS: Forty five New Zealand white rabbits were used in this study. VX2 tumor tissue blocks were implanted in the left lobe of liver by percutaneous puncture under CT guidance. 2 weeks later, all rabbits underwent conventional MRI (T1WI, T2WI) to determine the successful models. Then those successful implanted VX2 liver tumor models in the study were randomly divided into the control group and the experimental group, the former did not have processing, and the latter underwent PEI under CT guidance. MRI (T1WI, T2WI and DCE-MRI) was performed 1 week later again, the parameters of DCE-MRI (Ktrans, Kep, Ve and iAUC60) of viable tumor portions were observed. Then all the liver samples were processed for hematoxylin and eosin (H&E) staining and immunohistochemical staining for CD31 to determine MVD. At last, data (including DCE-MRI perfusion parameters and MVD) were compared between experimental and control groups, correlation of DCE-MRI perfusion parameters and MVD was evaluated. RESULTS: Twenty six VX2 liver tumor models underwent all examinations (thirteen models for each group) 1 week later after PEI. For the experimental group, the parameters Ktrans (r=0.6382, P=0.0189) and iAUC60 (r=0.6591, P=0.0143) in viable tumor portions were positively moderately correlated with MVD, whereas the parameters Kep (r=0.4656, P=0.1088) and Ve (r=0.2918, P=0.3333) were not correlated with MVD. For the control group, the parameters Ktrans (r=0.6385, P=0.0188) and iAUC60 (r=0.6391, P=0.0187) in viable tumor portions were also positively moderately correlated with MVD, while the parameters Kep (r=0.5518, P=0.0506) and Ve (r=-0.0824, P=0.789) were not correlated with MVD. Ktrans, Kep, Ve, iAUC60 and MVD of residual viable tumors in the experimental group 1 week later after PEI were similar to the viable tumors of the control group (P>0.05). CONCLUSIONS: DCE-MRI could be used to evaluate the efficiency of VX2 liver tumor after PEI. The quantitative parameter Ktrans and semi-quantitative parameter iAUC60 of DCE-MRI are correlated with MVD, which can assess tumor angiogenesis noninvasively of VX2 liver tumor model, and ethanol has no significant impact on angiogenesis of viable tumor 1week later after PEI. PMID- 26518060 TI - Brain glioma growth model using reaction-diffusion equation with viscous stress tensor on brain MR images. AB - In this paper, a new reaction-diffusion model with viscous stress tensor is proposed for modeling the diffusion and invasion of brain glioma cells, which is based on the model in Yuan J.J., Liu L., Hu Q.M. Mathematical modeling of brain glioma growth using modified reaction-diffusion equation on brain MR images. Comput Biol Med 2013;43:2007-2013. The corresponding parameters are computed. The viscous stress tensor is introduced into reaction-diffusion equation, and can describe more accurately the adhesion of gliomas and normal cells. The experimental results demonstrate the effectiveness and accuracy of the proposed reaction-diffusion equation with viscous stress tensor for real brain glioma MR images. PMID- 26518061 TI - Hemodynamic safety and efficacy of ferumoxytol as an intravenous contrast agents in pediatric patients and young adults. AB - PURPOSE: To evaluate the safety and feasibility of off-label use of ferumoxytol as an intravenous MRI contrast agents in pediatric patients and young adults. MATERIALS AND METHODS: With HIPAA compliance and IRB approval, 86 consecutive patients who had undergone 3 T or 1.5 T MRI with ferumoxytol were retrospectively identified. The blood pressure and heart rate of patients before and after ferumoxytol injection were compared. The overall image quality was evaluated independently by two radiologists with a four-point scale. Interobserver agreement was calculated using weighted kappa statistics. RESULTS: The mean+/ standard deviation (SD) pre and post-contrast systolic blood pressures (SBP) were 101+/-18 and 95+/-20, respectively. There was a statistically significant difference between pre-SBP and post-SBP (P=0.003). The pre-contrast diastolic blood pressure (DBP) and the post-contrast diastolic blood pressure (DBP) were 60+/-14 and 51+/-17, respectively. There was a statistically significant difference between pre-DBP and post-DBP (P<0.001). The number of patients with SBP and DBP increase, SBP increase and DBP decrease, SBP decrease and DBP increase, SBP and DBP decrease, SBP increase and DBP unchanged were 14 (16%), 9 (10%), 6 (7%), 56 (65%), 1 (1%), respectively. There was moderate agreement on all individual assessments of image quality (kappa=0.45). Eighty-two of 86 (95.4%) studies were scored 3 or above (at least diagnostic quality) by both readers, with 90% confidence interval of 92-99%. CONCLUSION: Ferumoxytol is effective as an MR contrast agent. In our sample, there was on average a small but clinically insignificant drop in SBP and DBP post-contrast injection. Large, randomized, controlled trials are needed to establish optimal dosing, imaging procedures, and safety monitoring. PMID- 26518062 TI - Time trend analysis of cervical high-risk human papillomavirus (HPV) in HIV infected women in an urban cohort from Rio de Janeiro, Brazil: the rise of non 16/18 HPV. AB - OBJECTIVES: HIV-infected women are at increased risk of human papillomavirus (HPV) infection. Time trends in annual prevalences of cervical high-risk human papillomavirus (HR-HPV) genotypes among a non-vaccinated, HIV-infected female cohort in urban Brazil were assessed for the period 2006-2012. METHODS: Cervical specimens were collected for HPV genotyping yearly between January 2006 and December 2012 in a cross-sectional analysis of participants aged >=18 years enrolled in the Women's HIV Cohort at Fiocruz in Rio de Janeiro, Brazil. Age adjusted generalized estimating equation models with an exchangeable matrix were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for annual HPV positivity (reference year: 2006). RESULTS: Among the 590 participants, the median age across all study years ranged from 35.5 to 40.0 years. The prevalence of any HR-HPV was >=53% every year; prevalences of HR-HPV 16, 58, 59, and 68 were >=24% in at least 1 year. The odds of HPV 16 and 68 decreased in 2012. HPV 58 prevalence followed a U-shape, beginning and ending at >20%. HPV 59 prevalence followed a linear trend, with increased odds in 2012 (OR 16.0, 95% CI 3.8-67.3; Bonferroni-adjusted p-value <0.01). CONCLUSIONS: The prevalences of HR-HPV 58, 59, and 68 were high in this cohort. Given current HR-HPV vaccine coverage and availability, further investigations are needed to optimize vaccine recommendations for this population. PMID- 26518063 TI - Secondary structure conservation of the stem-loop IV sub-domain of internal ribosomal entry sites in human rhinovirus clinical isolates. AB - OBJECTIVES: The aim of this study was to investigate the genetic diversity in the stem-loop (SL) IV sub-domain of the human rhinovirus (HRV) internal ribosomal entry site (IRES), which plays key roles in the initiation of viral translation by host protein interaction. METHODS: The primary SL-IV sequences of 194 HRVs, consisting of 97 reference strains and 97 clinical isolates, including the IRES sub-domains SL-IVa, SL-IVb, SL-IVc, and SL-IVd, were analyzed using Lasergene, MEGA 4, and WebLogo. Additionally, secondary structures of SL-IV were predicted and classified by RNAfold and CentroidHomfold-LAST. RESULTS: The predicted secondary structures of SL-IV showed variations in the position of bulbs, size of the loop, and length of stems. SL-IVc had the most highly conserved nucleotide sequence, with structures classified into two groups by the location of the poly(C) loop. Of the SL-IV sequences analyzed, 74 (79.56%) were classified in the major group and 19 (20.44%) in the minor group. Thirteen compensatory substitution pairs of SL-IVc contributed to maintaining the stem structure. CONCLUSIONS: This study showed that the IRES secondary structures of a large number of reference and clinical HRVs were highly conserved, with several compensatory substitutions. It is expected that these results will facilitate investigations into HRV function based on IRES secondary structures. PMID- 26518064 TI - Bacteremic community-acquired infections due to Klebsiella pneumoniae: clinical and microbiological presentation in New Caledonia, 2008-2013. AB - OBJECTIVES: To provide data on severe bacteremic community-acquired infections due to Klebsiella pneumoniae in New Caledonia. METHODS: All patients admitted with bacteremic community-acquired infections due to K. pneumoniae at the only tertiary medical center in New Caledonia, from 2008 to 2013, were included retrospectively in this study. Clinical and microbiological characteristics were analyzed, as well as risk factors for mortality. RESULTS: The characteristics of 119 patients were analyzed. The most common clinical presentation was urinary tract infection (40 cases, 33%), followed by pneumonia (28 cases, 23%), deep abscesses (15 cases, 13%), liver abscess (12 cases, 9%), meningitis in (five cases, 4%), and endophthalmitis (two cases, 1%). Multiple localizations were reported in 18 cases (15%) and isolated bacteremia was reported in 22 cases (18%). The overall mortality rate was 22% (26/119) and the mortality rate in the intensive care unit was 33% (14/42). Renal impairment, chronic liver disease, pneumonia, and isolated bacteremia were independent risk factors for mortality. CONCLUSIONS: K. pneumoniae is a dominant cause of severe community-acquired bacteremic infection in New Caledonia. Physicians should be aware of the poor prognosis of any patient with a bacteremic K. pneumoniae infection and should monitor patients presenting with risk factors closely. PMID- 26518065 TI - Single- and multiple-dose pharmacokinetics of ethambutol and rifampicin in a tuberculosis patient with acute respiratory distress syndrome undergoing extended daily dialysis and ECMO treatment. AB - The dosing of drugs in critically ill patients undergoing renal replacement therapy is based on limited data. We report for the first time single- and multiple-dose pharmacokinetics of ethambutol (EMB), which is cleared renally to 80%, and rifampicin (RIF), which is cleared renally to <30%, in a patient requiring both extracorporeal membrane oxygenation (ECMO) and renal replacement therapy. Extended dialysis removed a considerable amount of both EMB and RIF, with a dialyser plasma clearance ranging between 37 and 95 ml/min for EMB and between 39 and 53 ml/min for RIF. The EMB peak level (3h after a 2-h infusion) using a dose of 1000 mg/day on the first day of treatment was 2.3mg/l, which is in the low therapeutic range (2-5mg/l). Doubling the dose to 2000 mg/day resulted in peak levels slightly to markedly above the recommended range. There was no detectable effect of the ECMO membrane on the removal of both drugs. After an initial dose as for patients without renal impairment (15 mg/kg/day), therapeutic drug monitoring should be used to guide EMB dosing in patients undergoing extended daily dialysis. PMID- 26518067 TI - Obesity and recurrent urinary tract infections in premenopausal women: a retrospective study. AB - OBJECTIVES: Studies on the association between obesity and the risk of urinary tract infection (UTI) show inconsistent results. The aim of this study was to determine whether there is any association between obesity and recurrent UTIs (RUTIs) among premenopausal women. METHODS: A retrospective case-control study was conducted in the outpatient clinics of the internal medicine departments of three hospitals. All consecutive non-pregnant premenopausal women aged 20-55 years, who presented with RUTIs over a 2-year period, were included; these women were compared to randomly selected women from the same outpatient clinics who had no history of RUTI and were age-matched +/-5 years. RUTI was defined as a symptomatic UTI that followed the resolution of a previous UTI, or three or more symptomatic episodes over a 12-month period. RESULTS: Six hundred and ninety-one premenopausal women with UTI were evaluated during the study period. A total 122 of 162 subjects with RUTIs were included in this study and compared to 122 control cases without a history of RUTI. The overall prevalence of RUTIs among the premenopausal women with UTI was 23.4% (162/691). Approximately half of those with RUTIs were obese. The mean age of women with RUTIs was 43.8+/-9 vs. 40+/-10 years among the controls (p=0.839). The mean body mass index of women with RUTIs was significantly higher than that of controls: 35+/-4 vs. 26+/-3kg/m(2) (p<0.001). Multivariate regression analysis showed that obesity was associated with RUTIs in premenopausal women (odds ratio 4.00, 95% confidence interval 3.2 4.61; p=0.001). CONCLUSIONS: Obesity was found to be associated with RUTIs in premenopausal women. PMID- 26518066 TI - Molecular epidemiology and characterization of multiple drug-resistant (MDR) clinical isolates of Acinetobacter baumannii. AB - OBJECTIVES: The aim of this study was to identify the genetic relatedness of multiple drug-resistant (MDR) Acinetobacter baumannii clinical isolates recovered from a hospital in Los Angeles. METHODS: Twenty-one MDR A. baumannii isolates were collected and their antibiotic susceptibilities determined according to Clinical and Laboratory Standards Institute guidelines. Genes coding for antibiotic resistance were identified by PCR, and their identities were confirmed by DNA sequencing. Clonal relationships were studied by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). RESULTS: MDR consistently correlated with the presence of oxacillinases, mostly in the form of the plasmid-mediated OXA-23 enzyme, which was detected in 12 (57.1%) isolates. GES-type carbapenemases were found in 20 (95.2%) strains, AAC in all 21 (100%) strains, and PER in seven (33.3%) strains, and ISAba1 was detected in 16 (76.2%) isolates. The association between ISAba1 and resistance genes confirms insertion elements as a source of beta-lactamase production. Of the 21 clinical isolates, five were found to be related to sequence type 1 (ST1) and 16 to ST2, as analyzed by MLST. PFGE demonstrated that the majority of clinical isolates were highly related (>85%). CONCLUSIONS: This study supports a more complete understanding of genotyping of antibiotic resistance for better assessment of MDR strain transmission. PMID- 26518068 TI - Pesticide chlorpyrifos acts as an endocrine disruptor in adult rats causing changes in mammary gland and hormonal balance. AB - Endocrine disruptors (EDs) are compounds that interfere with hormone regulation and influence mammary carcinogenesis. We have previously demonstrated that the pesticide chlorpyrifos (CPF) acts as an ED in vitro, since it induces human breast cancer cells proliferation through estrogen receptor alpha (ERalpha) pathway. In this work, we studied the effects of CPF at environmental doses (0.01 and 1mg/kg/day) on mammary gland, steroid hormone receptors expression and serum steroid hormone levels. It was carried out using female Sprague-Dawley 40-days old rats exposed to the pesticide during 100 days. We observed a proliferating ductal network with a higher number of ducts and alveolar structures. We also found an increased number of benign breast diseases, such as hyperplasia and adenosis. CPF enhanced progesterone receptor (PgR) along with the proliferating cell nuclear antigen (PCNA) in epithelial ductal cells. On the other hand, the pesticide reduced the expression of co-repressors of estrogen receptor activity REA and SMRT and it decreased serum estradiol (E2), progesterone (Pg) and luteinizing hormone (LH) levels. Finally, we found a persistent decrease in LH levels among ovariectomized rats exposed to CPF. Therefore, CPF alters the endocrine balance acting as an ED in vivo. These findings warn about the harmful effects that CPF exerts on mammary gland, suggesting that this compound may act as a risk factor for breast cancer. PMID- 26518069 TI - Influence of water quality on nitrifier regrowth in two full-scale drinking water distribution systems. AB - The potential for regrowth of nitrifying microorganisms was monitored in 2 full scale chloraminated drinking water distribution systems in Ontario, Canada, over a 9-month period. Quantitative PCR was used to measure amoA genes from ammonia oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA), and these values were compared with water quality parameters that can influence nitrifier survival and growth, including total chlorine, ammonia, temperature, pH, and organic carbon. Although there were no severe nitrification episodes, AOB and AOA were frequently detected at low concentrations in samples collected from both distribution systems. A culture-based presence-absence test confirmed the presence of viable nitrifiers. AOB were usually present in similar or greater numbers than AOA in both systems. As well, AOB showed higher regrowth potential compared with AOA in both systems. Statistically significant correlations were measured between several water quality parameters of relevance to nitrification. Total chlorine was negatively correlated with both nitrifiers and heterotrophic plate count (HPC) bacteria, and ammonia levels were positively correlated with nitrifiers. Of particular importance was the strong correlation between HPC and AOB, which reinforced the usefulness of HPC as an operational parameter to measure general microbiological conditions in distribution systems. PMID- 26518070 TI - Molecular biomarkers in primary open-angle glaucoma: from noninvasive to invasive. AB - Glaucoma, the first cause of irreversible blindness worldwide, is a neurodegenerative disease characterized by the progressive loss of retinal ganglion cells. There are different subtypes of glaucoma, all expression of a common optic neuropathy; primary open-angle glaucoma (POAG) is the most diffuse subtype in western countries. To date, unfortunately, several questions still remain unsolved in the glaucoma management, such as the availability of powerful methods for screening high-risk populations, early diagnosis, timely detection of damage progression, and prediction of response to therapy. Over the last years, biomarkers have gained immense scientific and clinical interest to solve these issues, with countless molecules that have been candidate as potential biomarkers. In the present review, we summarize the current knowledge about the most robust molecular biomarkers proposed in POAG, distinguishing noninvasive from minimally invasive, and invasive biomarkers, according to the procedure adopted to collect fluid samples. PMID- 26518071 TI - Cerebrospinal fluid pressure in the pathogenesis of glaucoma. AB - The optic nerve head forms the interface between the intraocular compartment and the retrobulbar compartment. The former is characterized by what we term intraocular pressure (IOP) and the latter by orbital cerebrospinal fluid pressure (CSFP). The trans-lamina cribrosa pressure difference (TLCPD) is defined as the difference between the pressures in the two compartments. Any change in one of them can be associated with a disturbance of homeostasis of the optic nerve head, such as papilledema or glaucomatous optic neuropathy. In particular, glaucomatous optic neuropathy may be due to either an elevated IOP and/or an abnormally low orbital CSFP, or due to a change in the time-dependent relationship between the pulse-synchronous changes in IOP and orbital CSFP. Based on the triangular relationships between IOP, CSFP, and blood pressure, glaucoma may be described as an imbalance between these three pressure parameters, eventually leading to an increased TLCPD. Because the retinal and choroidal venous blood drains through the CSFP space, elevated CSFP may be associated with dilated retinal veins, increased incidence of retinal vein occlusions, higher prevalence and severity of diabetic retinopathy, and thicker choroid. PMID- 26518072 TI - Links among glaucoma, neurodegenerative, and vascular diseases of the central nervous system. AB - Glaucoma is the leading cause of irreversible blindness worldwide. Although the intraocular pressure (IOP) has been considered for long time the key point and the only treatable risk factor of the disease, there are cases in which glaucoma continues to progress despite normal IOP values. Vision loss in glaucoma is related to a selective decrease in the number of retinal ganglion cells by apoptosis that is associated to alterations of the central visual pathways. Interestingly, similar events have been also described in disorders of the central nervous system (CNS), such as Alzheimer's disease, Parkinson's disease, Leber's hereditary optic neuropathy, and cerebrovascular diseases. In this review, we discuss recent evidence supporting pathological links between glaucoma and disorders of the CNS. PMID- 26518073 TI - New technologies for measuring intraocular pressure. AB - The level of intraocular pressure (IOP) is the main known risk factor for the development and progression of glaucomatous optic neuropathy. Despite Goldmann applanation tonometry (GAT) being the gold standard for determining IOP since the last century, its limitations were obvious from the start and include substantial effects of several eye variables such as axial length, curvature, rigidity, and corneal thickness. These limitations have prompted the development of numerous formulas and nomograms designed to compensate for the ocular characteristics effect on GAT, but none of these methods has been entirely satisfactory. Similarly, as a result of efforts to mitigate some of the limitations of conventional tonometry, several new tonometers have appeared on the scene. PMID- 26518074 TI - Emerging risk factors for glaucoma onset and progression. AB - Glaucoma is a complex, multifactorial neurodegenerative disease process that leads to progressive damage to the optic nerve and irreversible visual impairment. Identification of ocular and systemic risk factors for disease onset and progression is critical for disease detection and surveillance. Although a great deal is known about risk factors for glaucoma, our expanding knowledge of glaucoma genotypes and phenotypes combined with advancements in technology and understanding of disease progression is rapidly enhancing our understanding of who is at greatest risk for glaucomatous visual impairment. PMID- 26518075 TI - Strategies to improve early diagnosis in glaucoma. AB - Early diagnosis and treatment of glaucoma is important to reduce the risk of progressive and irreversible visual loss. The key to diagnosis is recognition of morphological changes to the optic nerve head and retinal nerve fiber layer, but in some patients, functional abnormalities are detected first. This review describes recent innovations with the potential to improve the early detection of glaucoma. Developments in imaging include novel optic nerve head metrics such as Bruch's membrane opening-minimum rim width, enhanced ability to quantify inner layers of the glaucomatous macula, and ability to image deep optic nerve head structures, including the lamina cribrosa. Developments in detection of early glaucomatous functional loss include novel perimetric tests using frequency doubling technology and flicker-defined form stimuli. Methods to combine results of structural and functional assessments are also presented that may improve early detection of glaucoma. PMID- 26518076 TI - How to detect progression in glaucoma. AB - Detecting glaucoma progression remains one of the most challenging aspects of glaucoma management, since it can be hard to distinguish disease progression from exam variability and changes due to aging. In this review article, we discuss the use of perimetry, confocal scanning laser tomography and optical coherence tomography to detect glaucoma progression, and the techniques available to evaluate change with these modalities. Currently, there is no consensus on the best technique or criteria to detect glaucoma progression, or what amount of change would be clinically meaningful. New techniques have been developed to assess glaucoma progression, which make more comprehensive and complex use of data. They have the potential of detecting progression with better accuracy, with shorter follow-up periods, and generating better prognostics. Further validation of these new techniques is still required, but their incorporation into clinical practice is likely to yield significant benefits. PMID- 26518077 TI - Brain imaging in glaucoma from clinical studies to clinical practice. AB - Recent advances in Magnetic Resonance Imaging (MRI) technology have brought new insight in central nervous system (CNS) manifestation of glaucoma. New MR techniques allowed to identify in vivo and noninvasively alterations along all the visual pathway in both early and late stages of the disease. Conventional neuroimaging still plays an important role, mostly in the anatomy description and in the differential diagnosis with space occupying lesions but it should be supported by other advanced MR techniques such as diffusion tensor imaging, functional imaging (BOLD-ASL), and magnetic resonance spectroscopy, which offer the possibility to investigate deep white matter tracts integrity and cortical gray matter changes. In a future perspective, MR quantification of CNS damage associated with glaucoma will be of pivotal importance for prognostic stratification and evaluation of neuroprotective therapy response. PMID- 26518078 TI - Primary congenital glaucoma. AB - Primary congenital glaucoma (PCG) is the most common nonsyndromic glaucoma in infancy, which can lead to blindness, or a lifetime of vision when diagnosed and treated properly. PCG is more common in populations with a higher prevalence of consanguinity and is associated with CYP1B1 gene mutations which show variable expressivity and phenotypes. The immature angle appearance of PCG likely results from arrested development of tissues of neural crest origin in the third trimester, with the severity of abnormality varying according to the stage at which arrested development occurred. Classic symptoms at presentation include tearing, photophobia, blepharospasm, eye rubbing, and irritability. Examination may reveal elevated intraocular pressure, corneal edema, increased corneal diameter, Haab striae, or enlarged axial length. Angle surgery remains the first line treatment for PCG with a recent advance being circumferential trabeculotomy with the potential to incise the whole angle during one operation as oppose to an incremental approach and the associated multiple anesthetics. Once angle surgery fails, either trabeculectomy or glaucoma drainage device surgery may be appropriate. PMID- 26518079 TI - New findings in the diagnosis and treatment of primary angle-closure glaucoma. AB - Glaucoma is the second cause of blindness worldwide. In the next years, approximately one-fourth of all glaucoma cases will be angle-closure types. Older age, female sex, and Asian ethnicities are described risk factors as well as shorter axial length, shallow anterior chamber depth, lens position, and thickness. New findings suggest iris volume and choroidal thickness to have a key role in the mechanisms of angle closure. Classical clinical conditions are acute, intermittent, and chronic forms. Ultrasound biomicroscopy and anterior segment optical coherence tomography contribute to a better understanding of the mechanisms of angle closure, helping the ophthalmologists in the diagnosis and treatment. The therapy includes laser iridotomy, argon laser peripheral iridoplasty, lens extraction, goniosynechialysis, filtering surgery, drainage implant, and cyclodestruction. PMID- 26518080 TI - Advance in the pathogenesis and treatment of normal-tension glaucoma. AB - Normal-tension glaucoma (NTG) is a multifactorial disease where mechanical stresses and vascular alterations to the optic nerve head probably represent the key pathogenic moments. Although intraocular pressure (IOP) plays a crucial role in the retinal ganglion cell loss, the IOP reduction does not necessarily reduces the disease progression. Therefore, several IOP-independent factors such as glutamate toxicity, oxidative stress, autoimmunity, and vascular dysregulation have been considered in the pathogenesis of NTG. Numerous evidences documented an impairment of the ocular blood flow, involved both in the onset and progression of the disease. The IOP reduction remains the main strategy to reduce the damage progression in NTG. Recently, new treatment strategies have been proposed to improve the control of the disease. Neuroprotection is a rapidly expanding area of research, which represents a promising tool. In the present review, we summarize the recent scientific advancements in the pathogenesis and treatment of NTG. PMID- 26518081 TI - Exfoliative glaucoma: new evidence in the pathogenesis and treatment. AB - Exfoliation or pseudoexfoliation syndrome (PXF) is an age-related ocular and systemic disease in which abnormal extracellular material is produced and accumulates in many tissues. PXF is the most common identifiable cause of open angle glaucoma (OAG). PXFG is a particularly aggressive type of OAG, which runs with a faster rate of progression and poorer response to medical therapy than primary OAG (POAG). The prevalence of the condition shows huge variations among different population, Scandinavian and Mediterranean race being the most affected. Many genetics and environmental factors are involved in the pathogenesis and remarkable progresses in understanding the involved factors have been achieved in the past years. Population-based studies have identified mutations on the lysil-oxidase-like 1(LOXL1) gene as a risk factor for PXFS. Environmental and behavioral factors such as latitude of residence, caffeine intake, and vitamins deficiency are under investigation for a possible involvement in determining the disease in genetically predisposed individuals. Treatment options are similar to those recommended for POAG. Exfoliation syndrome predisposes to capsular rupture, zonular dehiscence, and vitreous loss during cataract extraction. Laser trabeculoplasty has been demonstrated to show good clinical outcomes in PXF patients. A review of the current literature and scientific evidences on pathogenesis and treatment is presented. PMID- 26518082 TI - Uveitis and glaucoma: new insights in the pathogenesis and treatment. AB - Glaucoma is a potentially blinding complication of uveitis, where intraocular inflammation, secondary corticosteroid response, and varying types and degrees of angle abnormalities contribute to its pathogenesis. Management of uveitic glaucoma remains challenging. Treatment is targeted at reducing the inflammation and lowering the intraocular pressure. Recent studies have highlighted the role of viruses, such as cytomegalovirus, herpes simplex virus, and more recently Ebola virus, in the pathogenesis of uveitic glaucoma. Antiviral therapy may be beneficial in eyes with detectable viral DNA. The success of glaucoma surgery is decreased in eyes with uveitic glaucoma, and surgical interventions are associated with a higher incidence of postoperative complications. Novel glaucoma surgical and laser treatments may improve the predictability of surgery for uveitic glaucoma, but these require further evaluation. PMID- 26518083 TI - Glaucoma risks in advanced corneal surgery. AB - Penetrating corneal transplant (PKP) surgery has been performed for centuries as the procedure of choice to restore vision in cases of advanced corneal disease. However, the last two decades have seen the introduction of lamellar corneal surgery (deep anterior lamellar keratoplasty, DALK; Descemet stripping-automated endothelial keratoplasty, DSAEK; and Descemet membrane endothelial keratoplasty, DMEK) which has shown several advantages over PKP and has rapidly gained popularity, given its benefits. Glaucoma after corneal graft surgery is an important cause of visual loss and graft failure. The main risk factors for developing glaucoma after any type of corneal graft are steroid-related intraocular hypertension and pre-existing glaucoma. The incidence of glaucoma after corneal graft surgery varies according to the specific risk factors and the type of corneal graft performed. One major advantage of modern layer selective lamellar keratoplasty is the reduced risk of glaucoma compared with PKP. This reduced glaucoma risk after corneal lamellar graft surgery is mainly due to the less destructive surgical nature of the lamellar procedures and also the reduced use of postoperative steroid treatment. Glaucoma can complicate not only corneal transplantation but has also been observed following other anterior segment procedures from laser refractive surgery to keratoprosthesis. The aim of this chapter is to describe the incidence, etiology, and management of glaucoma after corneal transplant and some common corneal surgical procedures. PMID- 26518084 TI - Twenty-four hour efficacy of glaucoma medications. AB - Current medical therapy of glaucoma aims to attain a meaningful and consistent reduction of intraocular pressure (IOP) to a predetermined level of target IOP, which will commensurate with either stability, or delayed progression of visual loss. Glaucoma is a 24-h disease and the damaging effect of elevated IOP is continuous. Therefore, it is reasonable that we should endeavor to identify the true efficacy of currently available and future antiglaucoma medications throughout the 24-h period. This review chapter deals first with the concept and value of diurnal and 24-h pressure monitoring. It then evaluates existing evidence on the 24-h efficacy of medical therapy options. Unfortunately, significant gaps exist in our present understanding of the short-term and particularly the long-term 24-h efficacy of most antiglaucoma medications. More long-term controlled evidence is needed in the future to improve our understanding of the 24-h efficacy of current medical glaucoma therapy, the ideal 24-h target pressure and the precise impact of IOP characteristics upon the different stages of the various forms of glaucoma. PMID- 26518085 TI - Modulation of wound healing in glaucoma surgery. AB - Glaucoma is a neurodegenerative disease and is the second most important cause of irreversible blindness. Filtration surgery remains the most effective therapy to reduce intraocular pressure in glaucoma patients. The main determinant of long term surgical success is the healing response. Excessive postoperative wound healing with subsequent fibrosis may lead to obstruction of the created channel which frequently results in early surgical failure and consequent progression of visual field loss. Preoperative use of antimitotics, such as mitomycin-C and 5 fluorouracyl, effectively improves surgery outcome. However, the use of these nonspecific antiproliferative agents can be associated with severe side effects. This review provides an overview of the most important efforts that have been made to explore novel, more specific, and safer agents to prevent glaucoma filtration failure and improve surgery outcome. PMID- 26518086 TI - Emerging surgical therapy in the treatment of glaucoma. AB - There is general consensus that surgery gives a better intraocular pressure (IOP) control than medical therapy, but surgery may be affected by complications and failures, and for this reason nowadays, it is reserved to advanced or clearly progressive glaucoma. In recent years, there have been a lot of efforts to enhance safety and efficacy of conventional surgery as to find new techniques more safer and more effective. Actually, this is a field in rapid evolution, and we have a great number of innovative procedures, often working on complete different basis. These procedures are classified according to their mechanism of action and the type of surgical approach, in order to clearly understand of what we are speaking about. From a general point of view, surgical procedures may be divided in procedures that increase outflow and procedures that reduce aqueous production: most of these procedures can be performed with an ab externo or an ab interno approach. The ab interno approach has great advantages and enormous potential of development; probably, its diffusion will be facilitated by the development of new devices for angle visualization. Nevertheless, it is important to remember that actually none of the new procedures has been validated in large controlled clinical trials and none of the new procedures is indicated when IOP target is very low. PMID- 26518087 TI - Visual disability and quality of life in glaucoma patients. AB - Glaucoma is an optic neuropathy that can result in progressive and irreversible vision loss, thereby affecting quality of life (QoL) of patients. Several studies have shown a strong correlation between visual field damage and visual disability in patients with glaucoma, even in the early stages of the disease. Visual impairment due to glaucoma affects normal daily activities required for independent living, such as driving, walking, and reading. There is no generally accepted instrument for assessing quality of life in glaucoma patients; different factors involved in visual disability from the disease are difficult to quantify and not easily standardized. This chapter summarizes recent works from clinical and epidemiological studies, which describe how glaucoma affects the performance of important vision-related activities and QoL. PMID- 26518088 TI - Preface: new trends in basic and clinical research of glaucoma: a neurodegenerative disease of the visual system part B. PMID- 26518089 TI - Reply to Letter: Should the heart rate including the heart rate variability be important prognosticators in cardiac arrest? PMID- 26518091 TI - Unraveling the complexity of leukotriene and prostaglandin inflammatory signaling. PMID- 26518090 TI - Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. AB - BACKGROUND: Short-term targeted treatment can potentially prevent fall asthma exacerbations while limiting therapy exposure. OBJECTIVE: We sought to compare (1) omalizumab with placebo and (2) omalizumab with an inhaled corticosteroid (ICS) boost with regard to fall exacerbation rates when initiated 4 to 6 weeks before return to school. METHODS: A 3-arm, randomized, double-blind, double placebo-controlled, multicenter clinical trial was conducted among inner-city asthmatic children aged 6 to 17 years with 1 or more recent exacerbations (clincaltrials.gov #NCT01430403). Guidelines-based therapy was continued over a 4 to 9-month run-in phase and a 4-month intervention phase. In a subset the effects of omalizumab on IFN-alpha responses to rhinovirus in PBMCs were examined. RESULTS: Before the falls of 2012 and 2013, 727 children were enrolled, 513 were randomized, and 478 were analyzed. The fall exacerbation rate was significantly lower in the omalizumab versus placebo arms (11.3% vs 21.0%; odds ratio [OR], 0.48; 95% CI, 0.25-0.92), but there was no significant difference between omalizumab and ICS boost (8.4% vs 11.1%; OR, 0.73; 95% CI, 0.33-1.64). In a prespecified subgroup analysis, among participants with an exacerbation during the run-in phase, omalizumab was significantly more efficacious than both placebo (6.4% vs 36.3%; OR, 0.12; 95% CI, 0.02-0.64) and ICS boost (2.0% vs 27.8%; OR, 0.05; 95% CI, 0.002-0.98). Omalizumab improved IFN-alpha responses to rhinovirus, and within the omalizumab group, greater IFN-alpha increases were associated with fewer exacerbations (OR, 0.14; 95% CI, 0.01-0.88). Adverse events were rare and similar among arms. CONCLUSIONS: Adding omalizumab before return to school to ongoing guidelines-based care among inner-city youth reduces fall asthma exacerbations, particularly among those with a recent exacerbation. PMID- 26518092 TI - Frequent occurrence of T cell-mediated late reactions revealed by atopy patch testing with hypoallergenic rBet v 1 fragments. AB - BACKGROUND: Late allergic reactions are common in the course of allergen-specific immunotherapy and even occur with allergy vaccines with reduced IgE reactivity. OBJECTIVE: We sought to study atopy patch test (APT) reactions and T-cell responses to the recombinant birch pollen allergen Bet v 1 and recombinant hypoallergenic T-cell epitope-containing Bet v 1 fragments in patients with birch pollen allergy with and without atopic dermatitis (AD). METHODS: A clinical study was conducted in 15 patients with birch pollen allergy with AD (group 1), 5 patients with birch pollen allergy without AD (group 2), 5 allergic patients without birch pollen allergy (group 3), and 5 nonallergic subjects (group 4) by performing skin prick tests and APTs with rBet v 1 and hypoallergenic rBet v 1 fragments. T-cell, cutaneous lymphocyte antigen (CLA)(+) and CCR4(+) T-cell and cytokine responses were studied by thymidine uptake, carboxyfluorescein diacetate succinimidyl ester staining, and Luminex technology, respectively. RESULTS: rBet v 1 and hypoallergenic rBet v 1 fragments induced APT reactions in not only most of the patients with birch pollen allergy with AD (11/15) but also in most of those without AD (4/5). Patients with birch pollen allergy with AD had higher Bet v 1-specific proliferation of CLA(+) and CCR4(+) T cells compared with patients with birch pollen allergy without AD. There were no differences in Bet v 1 specific CLA(+) and CCR4(+) proliferation and cytokine secretion in patients with and without APT reactions. CONCLUSION: Hypoallergenic rBet v 1 fragments induce T cell-dependent late reactions not only in patients with birch pollen allergy with AD but also in those without AD, which can be determined based on APT results but not based on in vitro parameters. PMID- 26518093 TI - Reply: To PMID 25747720. PMID- 26518095 TI - The common food additive carrageenan and the alpha-gal epitope. PMID- 26518094 TI - Distinguishing benign from pathologic TH2 immunity in atopic children. AB - BACKGROUND: Although most children with asthma and rhinitis are sensitized to aeroallergens, only a minority of sensitized children are symptomatic, implying the underlying operation of efficient anti-inflammatory control mechanisms. OBJECTIVE: We sought to identify endogenous control mechanisms that attenuate expression of IgE-associated responsiveness to aeroallergens in sensitized children. METHODS: In 3 independent population samples we analyzed relationships between aeroallergen-specific IgE and corresponding allergen-specific IgG (sIgG) and associated immunophenotypes in atopic children and susceptibility to asthma and rhinitis, focusing on responses to house dust mite and grass. RESULTS: Among mite-sensitized children across all populations and at different ages, house dust mite-specific IgG/IgE ratios (but not IgG4/IgE ratios) were significantly lower in children with asthma compared with ratios in those without asthma and lowest among the most severely symptomatic. This finding was mirrored by relationships between rhinitis and antibody responses to grass. Depending on age/allergen specificity, 20% to 40% of children with allergen-specific IgE (sIgE) of 0.35 kU/L or greater had negative skin test responses, and these children also expressed the high sIgG/sIgE immunophenotype. sIgG1 from these children inhibited allergen-induced IgE-dependent basophil activation in a dose-dependent fashion. Profiling of aeroallergen-specific CD4(+) TH memory responses revealed positive associations between sIgG/sIgE ratios and IL-10-dependent gene signatures and significantly higher IL-10/TH2 cytokine (protein) ratios among nonsymptomatic children. CONCLUSION: In addition to its role in blocking TH2 effector activation in the late-phase allergic response, IL-10 is a known IgG1 switch factor. We posit that its production during allergen-induced memory responses contributes significantly to attenuation of inflammation through promoting IgG1-mediated damping of the FcepsilonRI-dependent acute-phase reaction. sIgG1/sIgE balance might represent a readily accessible therapeutic target for asthma/rhinitis control. PMID- 26518096 TI - Sex and ethnic differences in the associations between lipoprotein(a) and peripheral arterial disease in the Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVE: Higher lipoprotein(a) [Lp(a)] has been linked with peripheral arterial disease (PAD). Also, elevated Lp(a) serum levels have been observed in women and African Americans (AAs). It remains uncertain if sex and ethnicity modify the association between Lp(a) and PAD. METHODS: Lp(a) mass concentration was measured with a latex-enhanced turbidimetric immunoassay, from blood collected at baseline clinic visits after a 12-hour fast, in a multiethnic cohort. Also at baseline, the ankle-brachial index was measured. PAD was defined as an ankle-brachial index <1.0. Multivariable logistic regression was used to determine sex and ethnic differences in associations of log-transformed Lp(a) and the presence of PAD. RESULTS: In 4618 participants, the mean age was 62 +/- 10 years; Lp(a) mean was 30 +/- 32 mg/dL and median (interquartile range) was 18 (8-40 mg/dL); 48% were male; 36% were European American, 29% were AA, 23% were Hispanic American (HA), and 12% were Chinese American; and 11% had PAD. Across all ethnic groups, serum Lp(a) was higher among women compared with men and highest among AAs compared with other ethnicities. After adjustments for traditional cardiovascular disease risk factors (age, sex, ethnicity, hypertension, diabetes, smoking, total cholesterol, and high-density lipoprotein cholesterol) as well as interleukin-6, fibrinogen, D-dimer, and homocysteine levels, one log unit increase in Lp(a) was associated with greater odds for PAD (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.01-1.25). In fully adjusted models, significant gender(*)ln[Lp(a)] and ethnicity(*)ln[Lp(a)] interactions were observed (P = .08 for both). The association between higher Lp(a) and PAD was strongest in HA men (OR, 1.73; 95% CI, 1.07-2.80) and HA women (OR, 1.49; 95% CI, 1.07-2.08). Nonsignificant associations were observed for European American, AA, and Chinese American men and women. CONCLUSIONS: We observed a significant and independent association between elevated Lp(a) and PAD only among HA women and men, despite higher serum Lp(a) levels among AAs. Future studies are needed to determine the role that lowering of Lp(a) may have on the burden of PAD in HAs. PMID- 26518098 TI - Discussion. PMID- 26518097 TI - Evolving practice pattern changes and outcomes in the era of hybrid aortic arch repair. AB - OBJECTIVE: The role of hybrid repair in the management of aortic arch pathology, and long-term outcomes with these techniques, remains uncertain. We report a decade of experience with hybrid arch repair (HAR) and assess institutional practice patterns with regard to the use of hybrid and open techniques. METHODS: Hybrid and open total and distal arch procedures performed between July 2005 and January 2015 were identified from a prospectively maintained, institutional aortic surgery database. Perioperative morbidity and mortality, freedom from reintervention, and long-term survival were calculated. Hybrid and open procedural volumes over the study period were assessed to evaluate for potential practice pattern changes. RESULTS: During the study period 148 consecutive procedures were performed for repair of transverse and distal aortic arch pathology, including 101 hybrid repairs and 47 open total or distal arch repairs. Patients in the hybrid repair group were significantly older with a greater incidence of chronic kidney disease, peripheral vascular disease, and chronic lung disease. Perioperative mortality and outcomes were not significantly different between the hybrid and open groups, aside from decreased median length of stay after hybrid repair. Need for subsequent reintervention was significantly greater after hybrid repair. Unadjusted long-term survival was superior after open repair (70% 5-year survival open vs 47% hybrid; P = .03), although aorta specific survival was similar (98% 5-year aorta-specific survival open vs 93% hybrid; P = .59). Institutional use of HAR decreased over the final 3 years of the study, with an associated increased use of open total or distal arch repairs. This was primarily the result of decreased use of native zone 0 hybrid procedures. Concurrent with this apparent increased stringency around patient selection for HAR, perioperative morbidity and mortality was reduced, including avoidance of retrograde type A dissection. CONCLUSIONS: HAR remains a viable option for higher-risk patients with transverse arch pathology with perioperative outcomes and long-term aorta-specific survival similar to open repair, albeit at a cost of increased reintervention. This observational single-institution study would suggest decreased use in more recent years in favor of open repair due to avoidance of native zone 0 hybrid procedures. This decline in the institutional use of native zone 0 hybrid repairs was associated with improved perioperative outcomes. PMID- 26518099 TI - Sedentary behavior is associated with impaired biomarkers in claudicants. AB - OBJECTIVE: Time spent in sedentary behavior has been associated with worse inflammation and cardiometabolic biomarkers in various populations. However, the association between time spent in sedentary behavior and biomarkers remains unknown in patients with intermittent claudication. The aim of the current study was to analyze the relationship between sedentary behavior and inflammatory and cardiometabolic biomarkers in patients with symptomatic peripheral arterial disease (PAD). METHODS: The sample included 297 patients with intermittent claudication. Sedentary behavior was assessed using a step activity monitor. Biomarkers of inflammation, oxidative stress, lipid profile, insulin resistance, and endogenous fibrinolysis were assessed. Demographic data, body mass index, physical activity status, and measures of severity of PAD (ankle-brachial index, peak walking time, and ischemic window) also were obtained. RESULTS: Time spent in sedentary behavior was related with high-sensitivity C-reactive protein (b = 0.187; P = .005), glucose (b = 0.238; P < .001), fibrinogen (b = 0.167; P = .017), plasminogen activator inhibitor 1 activity (b = 0.143; P = .036), and high density lipoprotein cholesterol (b = -0.133; P = .029). After adjustment for sex, age, physical activity status, body mass index, and severity of PAD, sedentary behavior remained related with high-sensitivity C-reactive protein (b = 0.170; P = .015), glucose (b = 0.178; P = .004), fibrinogen (b = 0.189; P = .010), and high-density lipoprotein cholesterol (b = -0.128; P = .032). CONCLUSIONS: Time spent in sedentary activities was associated with worse inflammatory and cardiometabolic profile in patients with intermittent claudication. PMID- 26518100 TI - Cloquet's canal (II). PMID- 26518101 TI - An Emerging Role of Natriuretic Peptides: Igniting the Fat Furnace to Fuel and Warm the Heart. AB - Natriuretic peptides are produced in the heart and have been well characterized for their actions in the cardiovascular system to promote diuresis and natriuresis, thereby contributing to maintenance of extracellular fluid volume and vascular tone. For this review, we scanned the literature using PubMed and MEDLINE using the following search terms: beiging, adipose tissue, natriuretic peptides, obesity, and metabolic syndrome. Articles were selected for inclusion if they represented primary data or review articles published from 1980 to 2015 from high-impact journals. With the advent of the newly approved class of drugs that inhibit the breakdown of natriuretic peptides, thereby increasing their circulation, we highlight additional functions for natriuretic peptides that have recently become appreciated, including their ability to drive lipolysis, facilitate beiging of adipose tissues, and promote lipid oxidation and mitochondrial respiration in skeletal muscle. We provide evidence for new roles for natriuretic peptides, emphasizing their ability to participate in body weight regulation and energy homeostasis and discuss how they may lead to novel strategies to treat obesity and the metabolic syndrome. PMID- 26518102 TI - Schwann-cell cylinders grown inside hyaluronic-acid tubular scaffolds with gradient porosity. AB - Cell transplantation therapies in the nervous system are frequently hampered by glial scarring and cell drain from the damaged site, among others. To improve this situation, new biomaterials may be of help. Here, novel single-channel tubular conduits based on hyaluronic acid (HA) with and without poly-l-lactide acid fibers in their lumen were fabricated. Rat Schwann cells were seeded within the conduits and cultured for 10days. The conduits possessed a three-layered porous structure that impeded the leakage of the cells seeded in their interior and made them impervious to cell invasion from the exterior, while allowing free transport of nutrients and other molecules needed for cell survival. The channel's surface acted as a template for the formation of a cylindrical sheath like tapestry of Schwann cells continuously spanning the whole length of the lumen. Schwann-cell tubes having a diameter of around 0.5mm and variable lengths can thus be generated. This structure is not found in nature and represents a truly engineered tissue, the outcome of the specific cell-material interactions. The conduits might be useful to sustain and protect cells for transplantation, and the biohybrids here described, together with neuronal precursors, might be of help in building bridges across significant distances in the central and peripheral nervous system. STATEMENT OF SIGNIFICANCE: The paper entitled "Schwann cell cylinders grown inside hyaluronic-acid tubular scaffolds with gradient porosity" reports on the development of a novel tubular scaffold and on how this scaffold acts on Schwann cells seeded in its interior as a template to produce macroscopic hollow continuous cylinders of tightly joined Schwann cells. This cellular structure is not found in nature and represents a truly engineered novel tissue, which obtains as a consequence of the specific cell-material interactions within the scaffold. PMID- 26518103 TI - Surfactant-free preparation of highly stable zwitterionic poly(amido amine) nanogels with minimal cytotoxicity. AB - Narrowly dispersed zwitterionic poly(amido amine) (PAA) nanogels with a diameter of approximately 100nm were prepared by a high-yielding and surfactant-free, inverse nanoprecipitation of PAA polymers. The resulting, negatively charged, nanogels (PAA-NG1) were functionalized with N,N-dimethylethylenediamine via EDC/NHS coupling chemistry. This resulted in nanogels with a positive surface charge (PAA-NG2). Both types of nanogels were fluorescently labelled via isothiocyanate coupling. PAA-NG1 displays high colloidal stability both in PBS and Fetal Bovine Serum solution. Moreover, both nanogels exhibit a distinct zwitterionic swelling profile in response to pH changes. Cellular uptake of FITC labelled nanogels with RAW 264.7, PC-3 and COS-7 cells was evaluated by fluorescence microscopy. These studies showed that nanogel surface charge greatly influences nanogel-cell interactions. The PAA polymer and PAA-NG1 showed minimal cell toxicity as was evaluated by MTT assays. The findings reported here demonstrate that PAA nanogels possess interesting properties for future studies in both drug delivery and imaging. STATEMENT OF SIGNIFICANCE: The use of polymeric nanoparticles in biomedical applications such as drug delivery and imaging, shows great potential for medical applications. However, these nanoparticles are often not stable in biological environments. Zwitterionic polymers have shown excellent biocompatibility, but these materials are not easily degradable in biological environments. With the aim of developing a nanoparticle for drug delivery and imaging we synthesized a biomimetic and readily biodegradable zwitterionic polymer, which was incorporated into nanogels. These nanogels showed excellent stability in the presence of serum and minimal cytotoxicity, which was tested in three cell lines. Because of their negative surface charge and excellent serum stability, these nanogels are therefore promising carriers for drug delivery and molecular imaging. PMID- 26518104 TI - An assessment of ultra fine grained 316L stainless steel for implant applications. AB - Ultra fine-grained metals obtained by severe plastic deformation exhibit higher specific strength that is useful for many applications and show promise for use as body implants. This work studied the microstructural evolution, mechanical and sliding wear behavior and corrosion behavior of 316L stainless steel warm multi axially forged at 600 degrees C. Microstructural evolution studied using electron backscatter diffraction technique and transmission electron microscopy confirmed the formation of ultra fine-grained structure. Average grain size reduced from 30MUm to 0.86MUm after nine strain steps. A combination of Hall-Petch strengthening and strain hardening increased the hardness. Improved sliding wear resistance is attributed to a transition from micro cutting to wedge-forming mode of abrasive wear. Load-bearing orthopedic implants often fail from pitting initiated corrosion fatigue. Potentiodynamic tests, cyclic polarization, and FeCl3 immersion tests revealed enhanced pitting resistance of forged steel that is confirmed by Mott-Schottky analysis. This is ascribed to an increase in the grain boundary volume, and homogenization of pit inducing impurities and non metallic phases due to severe deformation, which influenced the passive film properties. These model studies on 316L steel demonstrate that severely deformed ultra fine-grained metals have potential to deliver improved implant performance. STATEMENT OF SIGNIFICANCE: This model study on 316L steel demonstrates that severely deformed ultra fine-grained (UFG) metals have potential to deliver improved load-bearing implant performance. It is as interesting as is unclear as to how such severely deformed UFG material behaves electrochemically in the corrosive body fluids. This work is on studying the inter-relationship between structure, and mechanical, wear, and corrosion behavior of warm multiaxially forged (MAFed) UFG 316L stainless steel. Warm MAF is a bulk processing method capable of yielding large volume of UFG material and is an easily readily adaptable technique in industry. It can be a promising alternative to the expensive metallic alloys available for implant applications. PMID- 26518105 TI - Polystyrene scaffolds based on microfibers as a bone substitute; development and in vitro study. AB - We created non-resorbable porous scaffolds of polystyrene by electrospinning usable as a bone grafting material. Aligned and random fibers were prepared with a diameter ranging from 1 to 4.5MUm. Influence of microfiber diameter and alignment were determined by culturing MC3T3 osteoblast-like cells and evaluation of adherence, proliferation and differentiation at day 14 and 28 on the scaffolds. Scanning electron microscopy (SEM), nanocomputed tomography (nanoCT) and confocal microscopy were used to observe microfibers and morphology of cells seeded on the scaffolds. Nile Red was used to label the fibers, DAPI for nuclear staining and calcein for the calcium/phosphate deposits. MC3T3 were more adherent on the randomly distributed fibers having the highest diameter. MC3T3 proliferated equally on scaffolds made with aligned fibers but cell density was lower on random fibers with the smaller diameter. Alkaline phosphatase activity (a marker of osteoblastic differentiation) was not influenced by the fibers apart from on random fibers with the smallest diameter. Calcospherites also developed at the surface of the fibers in long term culture. Cytometric determination of the nuclei shape factors evidenced that cells were elongated along the main direction of fibers only on the aligned fibers. This study shows that porous scaffolds based on microfibers allow adhesion, spreading, orientation and proliferation of cells. STATEMENT OF SIGNIFICANCE: We prepared polystyrene porous scaffolds composed of microfibers as a bone substitute by electrospinning. Polystyrene is a cytocompatible and non-resorbable polymer which can support osteoconduction. Scaffolds with different micro-diameters and orientation, (aligned and random) were seeded with osteoblast-like cells to evaluate cell adherence, proliferation and differentiation. Characterization of microfibers and cell morphology was done by scanning electron microscopy, nanocomputed tomography and confocal microscopy. We evidenced that initial adherence of cells was increased on randomly disposed fibers with a high diameter (3.5MUm). Cell proliferation and differentiation seems not to be influenced by fiber diameter and orientation, apart from random fibers of 1MUm diameter which had a lower cell attachment. Morphometric analysis of cell nuclei showed that cells were stretched along the aligned fibers. PMID- 26518106 TI - Investigation of functional selenium nanoparticles as potent antimicrobial agents against superbugs. AB - Developing highly effective antibacterial agents is important for a wide range of applications. However, the emergence of multiple antibiotic-resistant bacteria poses a public health threat. Many developed agents have limited practical application due to chemical instability, low biocompatibility, and poor long-term antibacterial efficiency. In the following study, we synthesize a synergistic nanocomposite by conjugating quercetin (Qu) and acetylcholine (Ach) to the surface of Se nanoparticles (Qu-Ach@SeNPs). Quercetin has been reported to exhibit a wide range of biological activities related to their antibacterial activity and acetylcholine as a neurotransmitter, which can combine with the receptor on the bacterial cell. Arrows indicate NPs and arrowheads indicate compromised cell walls. The study demonstrated how Qu-Ach@SeNPs exhibit a synergistically enhanced antibacterial performance against the multidrug resistant superbugs (MDRs) compared to Qu@SeNPs and Ach@SeNPs alone. Qu-Ach@SeNPs are effective against MDRs, such as Methicillin-resistant Staphylococcus aureus (MRSA), at a low dose. The mechanistic studies showed that Qu-Ach@SeNPs attach to the bacterial cell wall, causing irreversible damage to the membrane, and thereby achieving a remarkable synergistic antibacterial effect to inhibit MRSA. The findings suggested that the synergistic properties of quercetin and acetylcholine enhance the antibacterial activity of SeNPs. In this way, Qu-Ach@SeNPs comprise a new class of inorganic nano-antibacterial agents that can be used as useful applications in biomedical devices. STATEMENT OF SIGNIFICANCE: The Qu-Ach@SeNPs have low cytotoxicity when tested on normal human cells in vitro. Qu-Ach@SeNPs are effective against MDRs, such as Methicillin-resistant S. aureus (MRSA), at a low dose. Importantly, Qu-Ach@SeNPs showed no emergence of resistance. These results suggest that Qu-Ach@SeNPs have excellent antibacterial activities. These agents can serve as good antibacterial agents against superbugs. Our data suggest that these antibacterial agents may have widespread application in the field of medicine for combating infectious diseases caused by MDRs, as well as other infectious diseases. PMID- 26518108 TI - Process evaluation of physical activity counselling with and without the use of mobile technology: A mixed methods study. AB - BACKGROUND: A monitoring-and-feedback tool was developed to stimulate physical activity by giving feedback on physical activity performance to patients and practice nurses. The tool consists of an activity monitor (accelerometer), wirelessly connected to a Smartphone and a web application. Use of this tool is combined with a behaviour change counselling protocol (the Self-management Support Programme) based on the Five A's model (Assess-Advise-Agree-Assist Arrange). OBJECTIVES: To examine the reach, implementation and satisfaction with the counselling protocol and the tool. DESIGN: A process evaluation was conducted in two intervention groups of a three-armed cluster randomised controlled trial, in which the counselling protocol was evaluated with (group 1, n=65) and without (group 2, n=66) the use of the tool using a mixed methods design. SETTINGS: Sixteen family practices in the South of the Netherlands. PARTICIPANTS: Practice nurses (n=20) and their associated physically inactive patients (n=131), diagnosed with Chronic Obstructive Pulmonary Disease or Type 2 Diabetes, aged between 40 and 70 years old, and having access to a computer with an Internet connection. METHODS: Semi structured interviews about the receipt of the intervention were conducted with the nurses and log files were kept regarding the consultations. After the intervention, questionnaires were presented to patients and nurses regarding compliance to and satisfaction with the interventions. Functioning and use of the tool were also evaluated by system and helpdesk logging. RESULTS: Eighty-six percent of patients (group 1: n=57 and group 2: n=56) and 90% of nurses (group 1: n=10 and group 2: n=9) responded to the questionnaires. The execution of the Self-management Support Programme was adequate; in 83% (group 1: n=52, group 2: n=57) of the patients, the number and planning of the consultations were carried out as intended. Eighty-eight percent (n=50) of the patients in group 1 used the tool until the end of the intervention period. Technical problems occurred in 58% (n=33). Participants from group 1 were significantly more positive: patients: chi(2)(2, N=113)=11.17, p=0.004, and nurses: chi(2)(2, N=19)=6.37, p=0.040. Use of the tool led to greater awareness of the importance of physical activity, more discipline in carrying it out and more enjoyment. CONCLUSIONS: The interventions were adequately executed and received as planned. Patients from both groups appreciated the focus on physical activity and personal attention given by the nurse. The most appreciated aspect of the combined intervention was the tool, although technical problems frequently occurred. Patients with the tool estimated more improvement of physical activity than patients without the tool. PMID- 26518107 TI - Factors associated with infant feeding of human milk at discharge from neonatal intensive care: Cross-sectional analysis of nurse survey and infant outcomes data. AB - CONTEXT: Nurses are principal caregivers in the neonatal intensive care unit and support mothers to establish and sustain a supply of human milk for their infants. Whether an infant receives essential nutrition and immunological protection provided in human milk at discharge is an issue of health care quality in this setting. OBJECTIVES: To examine the association of the neonatal intensive care unit work environment, staffing levels, level of nurse education, lactation consultant availability, and nurse-reported breastfeeding support with very low birth weight infant receipt of human milk at discharge. DESIGN AND SETTING: Cross sectional analysis combining nurse survey data with infant discharge data. PARTICIPANTS: A national sample of neonatal intensive care units (N=97), nurses (N=5614) and very low birth weight infants (N=6997). METHODS: Sequential multivariate linear regression models were estimated at the unit level between the dependent variable (rate of very low birth weight infants discharged on "any human milk") and the independent variables (nurse work environment, nurse staffing, nursing staff education and experience, lactation consultant availability, and nurse-reported breastfeeding support). RESULTS: The majority of very low birth weight infants (52%) were discharged on formula only. Fewer infants (42%) received human milk mixed with fortifier or formula. Only 6% of infants were discharged on exclusive human milk. A 1 SD increase (0.25) in the Practice Environment Scale of the Nursing Work Index composite score was associated with a four percentage point increase in the fraction of infants discharged on human milk (p<0.05). A 1 SD increase (0.15) in the fraction of nurses with a bachelor's degree in nursing was associated with a three percentage point increase in the fraction infants discharged on human milk (p<0.05). The acuity-adjusted staffing ratio was marginally associated with the rate of human milk at discharge (p=.056). A 1 SD increase (7%) in the fraction of infants who received breastfeeding support was associated with an eight percentage point increase in the fraction of infants discharged on human milk (p<0.001). CONCLUSIONS: Neonatal intensive care units with better work environments, better educated nurses, and more infants who receive breastfeeding support by nurses have higher rates of very low birth weight infants discharged home on human milk. Investments by nurse administrators to improve work environments and support educational preparation of nursing staff may ensure that the most vulnerable infants have the best nutrition at the point of discharge. PMID- 26518109 TI - Comparison of Holmium Laser Prostate Enucleation Outcomes in Patients with or without Preoperative Urinary Retention. AB - PURPOSE: We determine whether outcomes of holmium laser enucleation of the prostate are similar in patients with and those without preoperative urinary retention. MATERIALS AND METHODS: From May 2008 to July 2014, 231 patients underwent holmium laser prostate enucleation for symptomatic benign prostatic hyperplasia. Retrospective analysis was performed to evaluate for differences in postoperative outcomes for patients with and those without preoperative urinary retention. RESULTS: Overall 95 patients (41%) had urinary retention before holmium laser prostate enucleation while 136 (59%) did not. Mean followup for all patients was 15.3 months. Patients with retention tended to be older, have larger prostates, and have higher scores on the AUA SS and bother questionnaires (all p <0.05). Postoperatively there was no difference in rates of complications, including urinary retention. Both groups showed significant improvement in AUA SS and bother score after the procedure at all postoperative points. Median post void residual was less than 60 ml and median maximum flow rate on uninstrumented uroflow was greater than 18 ml per second at all postoperative points for all patients regardless of preoperative retention status. No patients required long term catheterization and rates of postoperative complications did not differ significantly during the followup period. CONCLUSIONS: This study represents the first direct comparison to our knowledge of holmium laser prostate enucleation outcomes in patients with or without urinary retention. There was no increased risk of postoperative urinary retention in patients with preoperative retention, and both groups demonstrated significant postoperative improvement in subjective and objective voiding measures. PMID- 26518110 TI - Preventive Effect of Hydrogen Water on the Development of Detrusor Overactivity in a Rat Model of Bladder Outlet Obstruction. AB - PURPOSE: Bladder ischemia and oxidative stress contribute to the pathogenesis of bladder dysfunction caused by bladder outlet obstruction. H2 reportedly acts as an effective antioxidant. We investigated whether oral ingestion of H2 water would have a beneficial effect on bladder function in a rat model of bladder outlet obstruction. MATERIALS AND METHODS: H2 water was made by dissolving H2 gas in ordinary drinking water using a hydrogen water producing apparatus. The bladder outlet obstruction model was surgically induced in male rats. Rats with obstruction were fed H2 water or ordinary drinking water. On week 4 postoperatively cystometry was performed. Oxidative stress markers and the bladder nerve growth factor level were determined. Bladder tissues were processed for pharmacological studies and histological analysis. RESULTS: The micturition interval and micturition volume significantly decreased in obstructed rats given ordinary drinking water. These decreases were significantly suppressed by oral ingestion of H2 water. Increased post-void residual volume in obstructed rats was significantly reduced by H2 water. Obstruction led to a significant increase in bladder weight, oxidative stress markers and nerve growth factor. H2 water significantly suppressed these increases without affecting bladder weight. There was no significant difference in histological findings between rats with bladder obstruction given H2 water and ordinary drinking water. Decreased responses of detrusor muscle strips from obstructed bladders to KCl, carbachol and electrical field stimulation were reversed by H2 water ingestion. CONCLUSIONS: Results suggest that H2 water could ameliorate bladder dysfunction secondary to bladder outlet obstruction by attenuating oxidative stress. PMID- 26518111 TI - The Impact of Prior Radiation Therapy on Artificial Urinary Sphincter Device Survival. AB - PURPOSE: The literature on artificial urinary sphincter device survival in individuals with a history of radiation therapy is conflicting. We assess device survival outcomes among individuals after prior radiation therapy exposure undergoing primary artificial urinary sphincter placement. MATERIALS AND METHODS: An institutional review board approved database of all patients who underwent artificial urinary sphincter surgery from 1999 to 2011 was used to assess device survival in patients treated with radiotherapy compared to individuals without radiotherapy exposure. Hazard regression and competing risk analysis were used to determine the association between radiation therapy and device outcomes. RESULTS: From 1999 to 2011 a total of 872 patients underwent artificial urinary sphincter surgery at our institution. Of these patients 489 underwent primary artificial urinary sphincter placement, with 181 of 489 (37%) having received radiation therapy. Patients with prior radiation therapy were older (median age 72.0 vs 70.1 years, p <0.01) and had a higher median body mass index (29.4 vs 28.6 kg/m(2), p <0.03) than those without radiation exposure. Rates of diabetes mellitus and hypertension were similar between the 2 groups. There was no significant difference in overall device survival between individuals who received radiation therapy and those without radiation therapy exposure, with 1 and 5-year device survival rates of 92% vs 90% and 77% vs 74%, respectively (p=0.24). CONCLUSIONS: While individuals who underwent radiation therapy were significantly older and had a higher body mass index, device survival was not significantly different between the 2 groups when using a cuff size greater than 3.5 cm. These findings will assist the urologist with the preoperative counseling of men undergoing primary artificial urinary sphincter placement with a history of radiation therapy. PMID- 26518112 TI - Parental Decisional Regret after Primary Distal Hypospadias Repair: Family and Surgery Variables, and Repair Outcomes. AB - PURPOSE: Decisional regret is defined as distress after making a health care choice and can be an issue for parents electing distal hypospadias repair for their sons. We assessed the influence on decisional regret of variables related to the family, surgery and outcomes. MATERIALS AND METHODS: Charts for 372 patients undergoing primary distal hypospadias repair between 2005 and 2012 were reviewed, and validated questionnaires, including the Decisional Regret Scale, Pediatric Penile Perception Score and Dysfunctional Voiding and Incontinence Scoring System, were administered to parents. RESULTS: Data were available for 172 of 372 families (response rate 46.2%). Of 323 parents 128 (39.6%) presented with moderately strong decisional regret, with good agreement within couples. Predictors of decisional regret included intermediate parental educational level (OR 3.19, 95% CI 1.52-6.69), patient not being the first born (OR 2.01, 95% CI 1.07-3.78), family history of hypospadias (OR 4.42, 95% CI 1.96-9.97), initial desire to avoid surgery (OR 2.07, 95% CI 1.04-4.12), younger age at followup (OR 0.81, 95% CI 0.72-0.91), presence of lower urinary tract symptoms (OR 4.92, 95% CI 1.53-15.81) and lower Pediatric Penile Perception Score (OR 0.86, 95% CI 0.75 0.99). Decisional regret was unrelated to parental desire to avoid circumcision, surgical variables, development of complications and duration of followup. CONCLUSIONS: Decisional regret is a problem in a significant proportion of parents electing distal hypospadias repair for their sons. In our experience family variables seemed to be predictors of decisional regret, while surgical variables did not. Predictors of decisional regret included worse parental perception of penile appearance and the presence of lower urinary tract symptoms. However, the latter could be unrelated to surgery. Irrespective of the duration of followup, decisional regret seems decreased in parents of older patients. PMID- 26518113 TI - Tetramethylpyrazine induces SH-SY5Y cell differentiation toward the neuronal phenotype through activation of the PI3K/Akt/Sp1/TopoIIbeta pathway. AB - Tetramethylpyrazine (TMP) is an active compound extracted from the traditional Chinese medicinal herb Chuanxiong. Previously, we have shown that TMP induces human SH-SY5Y neuroblastoma cell differentiation toward the neuronal phenotype by targeting topoisomeraseIIbeta (TopoIIbeta), a protein implicated in neural development. In the present study, we aimed to elucidate whether the transcriptional factors specificity protein 1 (Sp1) and nuclear factor Y (NF-Y), in addition to the upstream signaling pathways ERK1/2 and PI3K/Akt, are involved in modulating TopoIIbeta expression in the neuronal differentiation process. We demonstrated that SH-SY5Y cells treated with TMP (80MUM) terminally differentiated into neurons, characterized by increased neuronal markers, tubulin betaIII and microtubule associated protein 2 (MAP2), and increased neurite outgrowth, with no negative effect on cell survival. TMP also increased the expression of TopoIIbeta, which was accompanied by increased expression of Sp1 in the differentiated neuron-like cells, whereas NF-Y protein levels remained unchanged following the differentiation progression. We also found that the phosphorylation level of Akt, but not ERK1/2, was significantly increased as a result of TMP stimulation. Furthermore, as established by chromatin immunoprecipitation (ChIP) assay, activation of the PI3K/Akt pathway increased Sp1 binding to the promoter of the TopoIIbeta gene. Blockage of PI3K/Akt was shown to lead to subsequent inhibition of TopoIIbeta expression and neuronal differentiation. Collectively, the results indicate that the PI3K/Akt/Sp1/TopoIIbeta signaling pathway is necessary for TMP-induced neuronal differentiation. Our findings offer mechanistic insights into understanding the upstream regulation of TopoIIbeta in neuronal differentiation, and suggest potential applications of TMP both in neuroscience research and clinical practice to treat relevant diseases of the nervous system. PMID- 26518114 TI - Mineral metabolism in chronic kidney disease. PMID- 26518115 TI - Quencher-free hairpin probes for real-time detection of T4 polynucleotide kinase activity. AB - Traditional methods of assaying polynucleotide kinase (PNK) activity are discontinuous, time-consuming, and laborious. Here we report a new quencher-free approach to real-time monitoring of PNK activity using a 2-aminopurine probe. When the 2-aminopurine probe was 5'-phosphorylated by PNK, it could be efficiently degraded by lambda exonuclease to release free 2-aminopurine molecules and generate a fluorescence signal. This method not only provides a universal approach to real-time monitoring of PNK activity, but also shows great potential for screening suitable inhibitor drugs for PNK. PMID- 26518118 TI - Mechanosensing in cell-matrix adhesions - Converting tension into chemical signals. AB - Cell-matrix adhesions have since long been recognized to be critical for the survival and proliferation of cells. In fact, these adhesive structures do not only physically anchor cells, but they also induce vital intracellular signaling at cell-matrix adhesion sites. Recent progress in the cell adhesion field is now starting to provide data and ideas how this so far enigmatic signaling process is induced and regulated by intracellular acto-myosin tension, or stiffness of the extracellular matrix. Understanding how cells are using this mechanosignaling system will be key to control biological processes such as development, cancer growth, metastasis formation and tissue regeneration. In this review, we illustrate and discuss the mechanosignaling mechanisms important in the regulation of cell-matrix adhesions at the molecular level. PMID- 26518119 TI - Pro-inflammatory cytokine TNF-alpha is a key inhibitory factor for lactose synthesis pathway in lactating mammary epithelial cells. AB - Lactose is a milk-specific carbohydrate synthesized by mammary epithelial cells (MECs) in mammary glands during lactation. Lactose synthesis is downregulated under conditions causing inflammation such as mastitis, in which MECs are exposed to high concentrations of inflammatory cytokines. In this study, we investigated whether inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) directly influence the lactose synthesis pathway by using two types of murine MEC culture models: the monolayer culture of MECs to induce lactogenesis; and the three-dimensional culture of MECs surrounded by Matrigel to induce reconstitution of the alveolar structure in vitro. TNF-alpha caused severe down-regulation of lactose synthesis related genes concurrently with the degradation of glucose transporter 1 (GLUT1) from the basolateral membranes in MECs. IL-1beta also caused degradation of GLUT1 along with a decrease in the expression level of beta-1,4-galactosylransferase 3. IL-6 caused both up-regulation and down-regulation of the expression levels of lactose synthesis-related genes in MECs. These results indicate that TNF-alpha, IL-1beta, and IL-6 have different effects on the lactose synthesis pathway in MECs. Furthermore, TNF-alpha triggered activation of NFkappaB and inactivation of STAT5, suggesting that NFkappaB and STAT5 signaling pathways are involved in the multiple adverse effects of TNF-alpha on the lactose synthesis pathway. PMID- 26518121 TI - Handling of recent plagiarism in JER. PMID- 26518120 TI - Is self-reported physical functioning associated with incident cardiometabolic abnormalities or the metabolic syndrome? AB - BACKGROUND: Physical functioning may be an important pre-clinical marker of chronic disease, used as a tool to identify patients at risk for future cardiometabolic abnormalities. This study evaluated if self-reported physical functioning was associated with the development of cardiometabolic abnormalities or their clustering (metabolic syndrome) over time. METHODS: Participants (n = 2,254) from the Study of Women's Health Across the Nation who reported physical functioning on the Short Form health survey and had a metabolic syndrome assessment (elevated fasting glucose, blood pressure, triglycerides and waist circumference; reduced HDL cholesterol) in 2000 were included. Discrete survival analysis was used to assess the 10-year risk of developing metabolic syndrome or a syndrome component through 2010. RESULTS: At baseline, the prevalence of metabolic syndrome was 22.0%. Women with substantial limitations (OR = 1.60; 95% CI: 1.12, 2.29) in physical functioning were significantly more likely to develop the metabolic syndrome compared with women reporting no limitations. Self reported physical functioning was significantly associated with incident hypertension and increased waist circumference. CONCLUSIONS: Simple screening tools for cardiometabolic risk in clinical settings are needed. Self-reported physical functioning assessments are simple tools that may allow healthcare providers to more accurately predict the course of chronic conditions. PMID- 26518122 TI - Impact of single embryo transfer policy on perinatal outcomes in fresh and frozen cycles-analysis of the Japanese Assisted Reproduction Technology registry between 2007 and 2012. AB - OBJECTIVE: To investigate whether the introduction of single embryo transfer (SET) policy in Japan has improved perinatal outcomes. DESIGN: A retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 140,718 live births and 510 stillbirths (after 22 weeks of gestation) conceived by assisted reproductive technology in Japan between 2007 and 2012 were reviewed. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Preterm birth (PTB), low birth weight (LBW), very low birth weight (VLBW), small for gestational age (SGA), large for gestational age (LGA), perinatal mortality, and other pregnancy complications. RESULT(S): The rate of SET increased significantly from 52.2% in 2007 to 82.6% in 2012, while the rate of multiple pregnancy decreased significantly from 10.7% to 4.1% over the same period. The rates of PTB, LBW, and SGA decreased significantly, while that of LGA increased. Perinatal mortality decreased from 0.70% to 0.40% in fresh cycles, while that of frozen cycles did not change. Double ET or more was associated with a significantly increased risk for multiple pregnancy, placenta accreta, preterm premature rupture of membrane, cesarean section (CS), PTB, LBW, SGA, and early neonatal death compared with SET. Compared with before the SET policy was launched, the risks of multiple pregnancy, CS, early PTB before 32 weeks, LBW, VLBW, and SGA were significantly decreased after the policy was launched, with significant interactions of fresh/frozen status. CONCLUSION(S): The results suggest that the SET policy improved perinatal outcomes in Japan. The impact of SET policy was different in fresh and frozen cycles for several perinatal outcomes. PMID- 26518123 TI - Designing metallic iron based water filters: Light from methylene blue discoloration. AB - Available water filtration systems containing metallic iron (Fe(0) filters) are pragmatically designed. There is a lack of sound design criteria to exploit the full potential of Fe(0) filters. A science-based design relies on valuable information on processes within a Fe(0) filter, including chemical reactions, hydrodynamics and their relation to the performance of the filter. The aim of this study was to establish a simple method to evaluate the initial performance of Fe(0) filters. The differential adsorptive affinity of methylene blue (MB) onto sand and iron oxide is exploited to characterize the evolution of a Fe(0)/sand system using the pure sand system as operational reference. Five systems were investigated for more than 70 days: pure sand, pure Fe(0), Fe(0)/sand, Fe(0)/pumice and Fe(0)/sand/pumice. Individual systems were characterized by the extent of changes in pH value, iron breakthrough, MB breakthrough and hydraulic conductivity. Results showed that for MB discoloration (i) pure sand was the most efficient system, (ii) hybrid systems were more sustainable than the pure Fe(0) system, and (iii) the pores of used pumice are poorly interconnected. Characterizing the initial reactivity of Fe(0) filters using MB discoloration has introduced a powerful tool for the exploration of various aspects of filter design. PMID- 26518124 TI - Detection and characterization of potentially pathogenic Aeromonas sobria isolated from fish Hypophthalmichthys molitrix (Cypriniformes: Cyprinidae). AB - The current study focuses on the detection and characterization of potentially pathogenic Aeromonas sobria from fish silver carp (Hypophthalmichthys molitrix). Assessment of clinical, microbiological, pathological and biochemical characteristics of A. sobria were taken into account in order to understand the epidemiology, frequency and occurrence of this infection. Clinically the infected fish (H. molitrix) was observed for various types of symptoms. A total of 33 colonies of A. sobria strain were isolated from 20 cultured H. molitrix, collected from controlled fish pond. Microscopic examination revealed that the strains were rod-shaped, Gram negative bacteria. The revealed percent probability identification of A. sobria from the biochemical characterization in VITEK system was 93% with gram negative (GN) card. The histopathology of Gills caused by this bacterium, A. sobria indicate haemorrhagic gill epithelia and epithelial hyperplasia. Lamelar epithelial hypertrophy and hyperplasia with degenerative changes of the epithelium and hypertrophic epitheliocystis infected cells on gills of H. molitrix were observed during the present study. PMID- 26518125 TI - Relationship between phylogenetic groups, antibiotic resistance and patient characteristics in terms of adhesin genes in cystitis and pyelonephritis isolates of Escherichia coli. AB - Extraintestinal pathogenic Escherichia coli (E. coli) is considered as the main causative agent of urinary tract infections worldwide. The relationship between antimicrobial resistance, phylogenetic groups, patient characteristics and adhesin virulence genes are complex and not fully understood. In this study, among 146 urinary isolates of E. coli, phylogenetic groups and various adhesin virulence genes were examined with multiplex Polymerase Chain Reaction methods. Patient characteristics divided into sex, cystitis and pyelonephritis; community acquired and hospital-acquired; complicated and uncomplicated infection. Antimicrobial resistance was also determined. The papAH gene was seen more often in pyelonephritis than cystitis and female than male patients. iha gene was more frequent in hospital-acquired infections than in community-acquired infections. sfa/focDE was more frequent in ampicillin, amikacin, gentamicin, nalidixic acid, norfloxacin, cefuroxime, ceftriaxone, cefazolin, cefotaxime, ciprofloxacin and trimethoprim/sulfamethoxazole susceptible and extended-spectrum beta-lactamase (ESBL) and multi-drug resistance (MDR) negative isolates. focG was seen more often in nalidixic acid, norfloxacin, cefuroxime, ceftriaxone, ciprofloxacin susceptible and MDR negative isolates. fimH and papAH were more commonly observed in amoxicillin/clavulanic acid and cefotaxime susceptible isolates, respectively. iha and afa/draBC genes were more frequent in resistant isolates than the susceptible ones; for iha, in ampicillin, amoxicillin/clavulanic acid, nalidixic acid, cefuroxime, ceftriaxone resistant and ESBL and MDR positive isolates; for afa/draBC, in cefotaxime, cefuroxime, ciprofloxacin, trimethoprim/sulfamethoxazole resistant and ESBL and MDR positive isolates, this trend was observed. ST 131 E. coli virulence gene pattern has a direct effect on resistance profile. Isolates belong to that clonal group has MDR and commonly harbour afa/draBC and iha genes. Our findings may provide new insights into the relationships between pathogenesis, patient characteristics and resistance of E. coli UTI. PMID- 26518126 TI - Editorial introduction: Special issue: "Microbiota of the periodontal pocket: Pathogens and commensals". PMID- 26518127 TI - Primary cardiac lymphoma: two cases and a review of literature. AB - BACKGROUND: Primary cardiac lymphoma is one of the rarest tumours of the heart. It belongs to the extra-nodal non-Hodgkin's lymphomas. The most common type of this tumour is diffuse large B cell lymphoma. Usually, right atrium and right ventricle are involved. This tumour is fatal unless diagnosed and treated in time. In this article two female patients who were diagnosed with primary cardiac lymphoma and treated at our clinic are described. The first patient went to remission after the treatment, while the second patient died. The goals of this article are to show the difficulties of diagnosing and treating this disease, the role of cardiac surgery in its treatment and to raise awareness of this disease. CASE REPORTS: In this article two female patients who were diagnosed with primary cardiac lymphoma and treated at our clinic are described. The first patient went to remission after the treatment, while the second patient died. CONCLUSIONS: Primary cardiac lymphoma is a very rare disease. At the moment the most effective treatment is chemotherapy. Palliative surgery may be necessary to correct hemodynamics when venous blood flow to the lungs is disturbed. PMID- 26518128 TI - Immunotherapeutic effects of chitin in comparison with chitosan against Leishmania major infection. AB - Chitin and chitosan microparticles (MPs) are important immune system stimulators. The aim of this study was to evaluate the protective effects of these compounds in comparison with each other against Leishmania infection in BALB/c mice infected with Leishmania major (L. major). Female BALB/c mice were injected subcutaneously with 2*10(5) promastigotes. Chitin and/or chitosan MPs (<40 MUm) were subcutaneously injected in the BALB/c mice with two-day intervals until two weeks. Mice in all groups were sacrificed at 12 weeks post-infection. Enumeration of viable parasites was performed using limiting dilution assay. Furthermore, the animals (5 mice/group) were sacrificed two weeks post-infection. The lymph node cells were isolated and the effects of the chitinous MPs on the proliferation and production of cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-10 (IL-10) were determined. The mean sizes of lesions were significantly smaller in chitin (0.6+/-0.12 mm) and chitosan treated groups (1.2+/-0.8 mm) than in the control group (6.2+/-1.7 mm) (P<0.05). The parasite load in the lymph nodes of the treated mice was significantly lower than that in the lymph nodes of controls (1.31*10(6) vs 8.24*10(7) parasite/lymph node [P=0.032] and 7.49*10(6) vs 8.24*10(7) parasite/lymph node [P=0.05] for chitin and chitosan MPs treatment, respectively). We found that chitinous MPs induced cell proliferation and that chitin but not chitosan increased TNF-alpha and IL-10 production. Chitin appears that it has more effect than chitosan against leishmaniasis. The current study revealed that chitinous MPs had significant activity against L. major and could be considered as new therapeutic modality in leishmaniasis. PMID- 26518130 TI - One Step Further: Seoul Reflections. PMID- 26518131 TI - One should judge a community by how it treats its least fortunate. PMID- 26518129 TI - The Leishmania metaphylome: a comprehensive survey of Leishmania protein phylogenetic relationships. AB - BACKGROUND: Leishmaniasis is a neglected parasitic disease with diverse clinical manifestations and a complex epidemiology. It has been shown that its parasite related traits vary between species and that they modulate infectivity, pathogenicity, and virulence. However, understanding of the species-specific adaptations responsible for these features and their evolutionary background is limited. To improve our knowledge regarding the parasite biology and adaptation mechanisms of different Leishmania species, we conducted a proteome-wide phylogenomic analysis to gain insights into Leishmania evolution. RESULTS: The analysis of the reconstructed phylomes (totaling 45,918 phylogenies) allowed us to detect genes that are shared in pathogenic Leishmania species, such as calpain like cysteine peptidases and 3'a2rel-related proteins, or genes that could be associated with visceral or cutaneous development. This analysis also established the phylogenetic relationship of several hypothetical proteins whose roles remain to be characterized. Our findings demonstrated that gene duplication constitutes an important evolutionary force in Leishmania, acting on protein families that mediate host-parasite interactions, such as amastins, GP63 metallopeptidases, cathepsin L-like proteases, and our methods permitted a deeper analysis of their phylogenetic relationships. CONCLUSIONS: Our results highlight the importance of proteome wide phylogenetic analyses to detect adaptation and evolutionary processes in different organisms and underscore the need to characterize the role of expanded and species-specific proteins in the context of Leishmania evolution by providing a framework for the phylogenetic relationships of Leishmania proteins. Phylogenomic data are publicly available for use through PhylomeDB (http://www.phylomedb.org). PMID- 26518133 TI - The alpha1, alpha2, alpha3, and gamma2 subunits of GABAA receptors show characteristic spatial and temporal expression patterns in rhombencephalic structures during normal human brain development. AB - gamma-Aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in adult mammalian brain, mediating its actions chiefly via a pentameric chloride ion channel, the GABAA receptor. Nineteen different subunits (alpha1-6, beta1-3, gamma1-3, delta, epsilon, pi, theta, rho1-3) can give rise to multiple receptor subtypes that are the site of action of many clinically important drugs. In the developing brain, however, GABAA receptors mediate excitatory actions due to an increased chloride concentration within neurons and seem to control cell proliferation, migration, differentiation, synapse maturation, and cell death. Little is known about the distribution of single subunits in the human brain. Here we describe developmental changes in the immunohistochemical distribution of four subunits (alpha1, alpha2, alpha3, and gamma2) in the human rhombencephalon. The gamma2 was the most abundant subunit in all rhombencephalic structures during development and in adults, whereas alpha subunits showed a structure- and age characteristic distribution. The alpha1 was expressed prenatally in the molecular and Purkinje cell layer, but only postnatally in the granule cell layer and the dentate nucleus. Expression was completely absent in the inferior olivary nucleus. The alpha2 gradually increased during development, showing some layer specificity in the cerebellar cortex. The alpha3-immunoreactivity in the cerebellar cortex was relatively weak, but it was abundantly observed in different cell populations in the subcortical cerebellar structures. Structure- and age-characteristic colocalization between subunits during development suggests differences in GABAA receptor composition. Interestingly, subunit expression in several instances differed between human and rodent brain, underlining the importance of immunohistochemical studies in humans. PMID- 26518132 TI - Effectiveness of combined chloroquine and primaquine treatment in 14 days versus intermittent single dose regimen, in an open, non-randomized, clinical trial, to eliminate Plasmodium vivax in southern Mexico. AB - BACKGROUND: In Mexico, combined chloroquine (CQ) and primaquine (PQ) treatment has been used since the late 1950s to treat Plasmodium vivax infections. Although malaria transmission has declined, current treatment strategies must be evaluated to advance towards malaria elimination. METHODS: The clinical and parasitological outcome of treating symptomatic P. vivax with the 14-day (T14) treatment or intermittent single dose (ISD) regimen was evaluated in southern Mexico between February 2008 and September 2010. Patients over 12 months old with P. vivax mono infection and asexual parasitaemia >=500 parasites/ul were treated under supervision. After diagnosis (day 0), treatment began immediately. T14 patients received CQ for 3 days (10, 10 and 5 mg/kg) and PQ daily for 14 days (0.25 mg/kg), while ISD patients received a single dose of CQ (10 mg/kg) and PQ (0.75 mg/kg) on days 0, 30, 60, 180, 210, and 240. Follow-up was done by observing clinical and laboratory (by microscopy, serology and PCR) outcome, considering two endpoints: primary blood infection clearance and clinical response at ~28 days, and the incidence of recurrent blood infection during 12 months. Parasite genotypes of primary/recurrent blood infections were analysed. RESULTS: During the first 28 days, no differences in parasite clearance or clinical outcome were observed between T14 (86 patients) and ISD (67 patients). On day 3, 95 % of patients in both groups showed no blood parasites, and no recurrences were detected on days 7-28. Contrarily, the therapeutic effectiveness (absence of recurrent parasitaemia) was distinct for T14 versus ISD at 12 months: 83.7 versus 50 %, respectively (p = 0.000). Symptomatic and asymptomatic infections were recorded on days 31-352. Some parasite recurrences were detected by PCR and/or serological testing. CONCLUSIONS: T14 was effective for opportune elimination of the primary blood infection and preventing relapse episodes. The first single dose of CQ-PQ eliminated primary blood infection as efficiently as the initial three-dose scheme of T14, but the ISD regimen should be abandoned. A single combined dose administered to symptomatic patients in remote areas while awaiting parasitological diagnosis may contribute to halting P. vivax transmission. Alternatives for meeting the challenge of T14 supervision are discussed. TRIAL REGISTRATION: NIH-USA, ClinicalTrial.gov Identifier: NCT02394197. PMID- 26518134 TI - Introduction to the special issue on swine reproduction. PMID- 26518135 TI - Magnetic resonance correlation of iron content with neuromelanin in the substantia nigra of early-stage Parkinson's disease. AB - BACKGROUND AND PURPOSE: Magnetic resonance (MR) studies have demonstrated a significant reduction of neuromelanin in the substantia nigra (SN) of Parkinson's disease (PD) patients with high accuracy for differential diagnosis compared to non-PD controls and essential tremor. However, studies state that not knowing how paramagnetic effects of iron influence neuromelanin signal is a limitation. In this study a neuromelanin-sensitive MR sequence was combined with T2* relaxometry iron quantification analysis to study the SN of early-stage PD patients to investigate the correlation between these parameters. METHODS: The inclusion criteria were untreated de novo PD patients and a 2-5 year disease duration (early PD); in addition, age-matched controls were enrolled. These were studied at 3.0 T with a high-resolution T1-weighted MR sequence to visualize neuromelanin and a relaxometry sequence for iron quantification. The primary outcome was the correlation of the width of the neuromelanin high signal region and the T2* values in the lateral, central and medial segments of the SN. RESULTS: Very weak correlations of T2* values with neuromelanin width, positive for global and negative for the medial and lateral SN segments, were found in both PD groups and control subjects. The SN neuromelanin width was markedly reduced in the de novo and early PD groups compared with controls in all SN segments, but no significant difference in T2* values was found between the groups. CONCLUSIONS: The SN neuromelanin signal does not have a significant correlation with iron content in PD patients or controls. The neuromelanin MR signal reduction in PD does not seem to be significantly influenced by paramagnetic iron effects. PMID- 26518136 TI - Report of cold agglutinins in a patient with acute ischemic stroke. AB - BACKGROUND: Studies on the role of cold agglutinins in the pathogenesis of acute ischemic stroke are scarce. We present a case of an elderly man with acute cerebral infarction probably due to cold agglutinin disease. CASE PRESENTATION: On a cold morning, a 71-year-old male of Han nationality with a complaint of sudden onset left-sided weakness and difficulty in speaking was brought to the emergency department. Diffusion weighted magnetic resonance imaging of the brain showed a high-intensity area in the right basal ganglia and corona radiata. Laboratory test showed the presence of high titers of cold agglutinins. There was no history of common risk factors of atherosclerosis, such as hypertension, diabetes mellitus, coronary artery disease or smoking. After being exposed to warm temperature, and with corticosteroid therapy and blood transfusion, the patient's symptoms relieved rapidly. CONCLUSION: We report here the first case of cerebral infarction probably due to the cold agglutinin disease. The underlying mechanism of cold agglutinins in the pathogenesis of acute ischemic stroke needs to be investigated further. PMID- 26518137 TI - Interaction between bound water molecules and local protein structures: A statistical analysis of the hydrogen bond structures around bound water molecules. AB - Water molecules play an important role in protein folding and protein interactions through their structural association with proteins. Examples of such structural association can be found in protein crystal structures, and can often explain protein functionality in the context of structure. We herein report the systematic analysis of the local structures of proteins interacting with water molecules, and the characterization of their geometric features. We first examined the interaction of water molecules with a large local interaction environment by comparing the preference of water molecules in three regions, namely, the protein-protein interaction (PPI) interfaces, the crystal contact (CC) interfaces, and the non-interfacial regions. High preference of water molecules to the PPI and CC interfaces was found. In addition, the bound water on the PPI interface was more favorably associated with the complex interaction structure, implying that such water-mediated structures may participate in the shaping of the PPI interface. The pairwise water-mediated interaction was then investigated, and the water-mediated residue-residue interaction potential was derived. Subsequently, the types of polar atoms surrounding the water molecules were analyzed, and the preference of the hydrogen bond acceptor was observed. Furthermore, the geometries of the structures interacting with water were analyzed, and it was found that the major structure on the protein surface exhibited planar geometry rather than tetrahedral geometry. Several previously undiscovered characteristics of water-protein interactions were unfolded in this study, and are expected to lead to a better understanding of protein structure and function. PMID- 26518139 TI - It is time to change primary biliary cirrhosis (PBC): New nomenclature from "cirrhosis" to "cholangitis", and upcoming treatment based on unveiling pathology. AB - Primary biliary cirrhosis (PBC) is a chronic, organ-specific, autoimmune liver disease characterized by progressive cholestasis, eventually leading to cirrhosis. Several lines of evidence have revealed a crucial role of adaptive as well as innate immune responses in the etiopathogenesis of PBC, and more recently, the biology of bile duct cells and genome-wide association studies (GWAS) demonstrated several key molecules and pathways in this enigmatic disease. Although ursodeoxycholic acid (UDCA) has been the only approved drug for PBC with clinical evidences for improvement of long-term outcomes, a substantial population have suboptimal responses to UDCA, resulting in unfavorable outcomes. In this regard, second-line treatment for patients refractory to UDCA is strongly awaited. In Japan, bezafibrate (BF) has been frequently used for this purpose, yet recent clinical trials failed to clearly demonstrate clinical efficacy of BF. Novel pharmacotherapies targeted to key molecules and pathways in PBC are upcoming. Finally, we sincerely call on all members of the Japan Society of Hepatology to use from this moment on the name "primary biliary cholangitis" for the disease known by its abbreviation PBC, in keeping with a very recent global agreement. PMID- 26518138 TI - Structure-activity relationship studies on rhodamine B-based fluorogenic probes and their activation by anticancer platinum(II) compounds. AB - Fluorescence microscopy has emerged as an attractive technique for imaging intracellular Pt species arising from exposure to clinical anticancer drugs such as cisplatin. A rhodamine-B based fluorogenic probe termed Rho-DDTC can be activated selectively in the presence of Pt(II) compounds, and possesses the ability to discriminate Pt(II) species from Pt(IV) carboxylate prodrug complexes, thereby providing a unique platform to investigate the reduction of these Pt(IV) complexes after cell entry. In this report, we seek to establish the mechanism of activation of Rho-DDTC through a structure-activity relationship study on its structural analogues. PMID- 26518140 TI - A quinoxaline urea analog uncouples inflammatory and pro-survival functions of IKKbeta. AB - Activation of the NF-kappaB pathway is causally linked to initiation and progression of diverse cancers. Therefore, IKKbeta, the key regulatory kinase of the canonical NF-kappaB pathway, should be a logical target for cancer treatment. However, existing IKKbeta inhibitors are known to induce paradoxical immune activation, which limits their clinical usefulness. Recently, we identified a quinoxaline urea analog 13-197 as a novel IKKbeta inhibitor that delays tumor growth without significant adverse effects in xenograft tumor models. In the present study, we found that 13-197 had little effect on LPS-induced NF-kappaB target gene induction by primary mouse macrophages while maintaining considerable anti-proliferative activities. These characteristics may explain absence of inflammatory side effects in animals treated with 13-197. Our data also demonstrate that the inflammation and proliferation-related functions of IKKbeta can be uncoupled, and highlight the utility of 13-197 to dissect these downstream pathways. PMID- 26518141 TI - Contradicting roles of miR-182 in both NK cells and their host target hepatocytes in HCV. AB - BACKGROUND AND AIM: Natural killer cells are part of the innate immunity involved in viral eradication and were shown to be greatly affected by HCV infection. Epigenetic regulation of NK cell function by microRNAs was not efficiently studied before and was never studied in HCV infection; therefore the aim of this study was to assess for the first time the role of microRNAs in regulating the function of NK cells of HCV-infected patients and hence viral replication in the target HCV-infected Huh7 cells. METHODOLOGY: NK cells were isolated from PBMCs of HCV-infected patients as well as controls, and HCV-infected liver biopsies as well as Huh7 cells infected with the virus were used. For the infection of Huh7 cells, first viral vector was in-vitro transcribed into viral RNA that was then used to infect naive Huh7 cells. Supernatant from the infected cells was then collected and used for further infection. For manipulation of NK cells or Huh7 cells, miR-182 mimics and inhibitors were transfected via lipofection method. RNA was extracted from each cell population, reverse transcribed. Gene expression as well as viral load was quantified using qPCR. RESULTS: Screening of NKG2A and NKG2D between patients and controls showed no difference in expression of NKG2A, while NKG2D was found to be downregulated. In view of that, bioinformatics analysis was performed and showed that miR-182 has potential binding sites on both the inhibitory receptor NKG2A and the activating receptor NKG2D, and on its ligand ULBP2, as well as on the viral genome itself. In NK cells of HCV-infected patients, miR-182 was found to be over-expressed compared to controls; its ectopic expression was found to decrease NKG2D mRNA level, while miR-182 inhibitors were able to decrease NKG2A mRNA compared to untransfected cells. In addition, co-culturing genotype 4 or 2 HCV-infected Huh7 cells with miR-182 mimicked NK cells of HCV-infected patients showed decreased viral replication, suggesting an enhanced NK cell function. On the other hand, miR-182 and ULBP2 were both found to be downregulated in HCV liver tissues and HCV-infected Huh7 cells compared to their controls. miR-182 mimics were found to decrease ULBP2 mRNA and increase viral replication in genotypes 4 and 2 HCV-infected target (Huh7) cells compared to controls, while miR-182 inhibitor decreased viral replication in the cell models. CONCLUSION: miR-182 was never investigated before, neither in HCV infection nor in NK cells, and we found it to have dysregulated expression in both liver tissues and NK cells of HCV-infected patients compared to control. In addition to that, miR-182 was found to have a contradicting effect in both effector cell and its HCV-infected target cell regarding HCV replication. PMID- 26518142 TI - Prime/boost immunization with HIV-1 MPER-V3 fusion construct enhances humoral and cellular immune responses. AB - Development of an effective vaccine against HIV-1 infection is a main concern in worldwide. A potent vaccine for HIV-1 requires the induction and maintenance of both humoral and cellular immunity. In this study, the levels of humoral and cellular immune responses were compared using MPER-V3 injection in three immunization strategies such as DNA/DNA, peptide/peptide, and DNA/peptide (prime boost). MPG peptide and Montanide 720 were used as a DNA delivery system, and as a peptide adjuvant, respectively. Our results demonstrated that MPG forms stable non-covalent nanoparticles with plasmid DNA at N/P ratio of 10:1 (~ 110-130 nm). The in vitro transfection efficiency of MPER-V3 DNA using MPG was comparable with lipofectamine and turbofect reagents as a common delivery system. In vivo prime boost immunization using HIV-1 MPER-V3 could significantly enhance humoral and cellular immune responses as compared to control groups. The mixture of IgG1 and IgG2a was observed for each strategy, but IFN-gamma production was significantly higher in prime-boost and peptide immunizations than that in DNA immunizations, inducing Th1 response. Moreover, our data showed that prime immunization with low dose of the nanoparticles (MPER-V3 DNA: MPG at ratio of 1:10) followed by MPER-V3 peptide drives T cell responses towards a Th1-type similar to high dose of the naked DNA prime/peptide boost immunization. Generally, the prime-boost strategy could improve both immune responses against MPER and especially V3 peptides suggesting its application as a promising HIV vaccine candidate in future. PMID- 26518143 TI - Comparison of a standalone consumer grade smartphone with a specialist inertial measurement unit for quantification of movement symmetry in the trotting horse. AB - REASONS FOR PERFORMING STUDY: Equine inertial measurement unit (IMU) gait analysis has gained in popularity for use in horses. Similar transducers are now found in consumer grade smartphones. However, to date there are no scientific data evaluating their use for assessment of movement (a)symmetry in the horse. OBJECTIVES: To establish limits of agreement (LoA, mean difference +/-2 s.d.) between a validated specialist IMU system and IMU data collected with a consumer grade smartphone for quantification of movement symmetry and range of motion (ROM) of pelvic movement in the trotting horse. STUDY DESIGN: Method comparison study based on quantitative gait data. METHODS: Twenty horses were equipped with a specialist IMU (MTw, Xsens) and a consumer grade smartphone (Apple iPhone6), both securely attached immediately in front of one another in the midline over the sacrum. Horses were trotted in-hand and lunged on both reins on a soft arena surface. Median values for movement symmetry and ROM were determined over a series of strides for each exercise condition. Data collection was repeated in 6 horses to determine the effect of mediolateral sensor positioning on outcome parameters. RESULTS: Valid data from 17 horses resulted in LoA values of -3.7 +/- 9.2 mm for MinDiff (difference between left and right hind mid stance), -0.6 +/- 6.0 mm for MaxDiff (difference between left and right hind propulsion) and -0.8 +/- 7.4 mm for ROM across horses and exercises. LoAs were narrower for straight line exercise and the negative bias was considerably reduced when moving the smartphone to the right of the midline. CONCLUSIONS: The consumer grade smartphone provided meaningful gait data in horses: LoAs in particular for in hand exercise and when adjusting the mediolateral positioning are similar to published asymmetry thresholds. Owing to the sensitivity to mediolateral positioning, particular care should be taken when placing an IMU over the midline of the horse. PMID- 26518145 TI - Indurated papules and plaques on left hemithorax: a clinicopathologic challenge. PMID- 26518144 TI - Evaluation of the pathogenicity of West Nile virus (WNV) lineage 2 strains in a SPF chicken model of infection: NS3-249Pro mutation is neither sufficient nor necessary for conferring virulence. AB - Lineage 2 West Nile virus (WNV) strains were reported for the first time in Europe in 2004. Despite an almost silent circulation around their entry point in Hungary, an upsurge of pathogenicity occurred in 2010 as 262 people suffered from neuroinvasive disease in Greece. This increase in virulence was imputed to the emergence of a His249Pro mutation in the viral NS3 helicase, as previously evidenced in American crows experimentally infected with the prototype lineage 1 North-American WNV strain. However, since 2003, WNV strains bearing the NS3Pro genotype are regularly isolated in Western-Mediterranean countries without being correlated to any virulent outbreak in vertebrates. We thus sought to evaluate the weight of the NS3249Pro genotype as a virulence marker of WNV in an in vivo avian model of WNV infection. We therefore characterized three genetically related Eastern-Europe lineage 2 WNV strains in day-old specific pathogen-free (SPF) chickens: Hun2004 and Aus2008 which are both characterized by a NS3249His genotype, and Gr2011 which is characterized by a NS3249Pro genotype. Unlike Hun2004 and Aus2008, Gr2011 was weakly virulent in SPF chicks as Gr2011-induced viremia was lower and waned quicklier than in the Hun2004 and Aus2008 groups. Overall, this study showed that the presence of a proline residue at position 249 of the viral NS3 helicase is neither sufficient nor necessary to confer pathogenicity to any given lineage 2 WNV strain in birds. PMID- 26518146 TI - Tumorigenesis of smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone is related to its ability to stimulate thromboxane synthase and enhance stemness of non-small cell lung cancer stem cells. AB - Lung cancer stem cells (LCSCs) play a critical role in lung cancer development, however, it is unknown whether thromboxane synthase (TXS) plays a role in the maintenance of LCSCs stemness. This study aimed to determine the in vivo role of TXS in lung cancer induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a smoking carcinogen. Results showed that ozagrel, a TXS blocker, suppressed NNK-induced lung tumors in mice. The expressions of CD133 and ALDH1A1 were positively associated with TXS. Similar results were observed in human NSCLC tumor samples. NNK significantly stimulated TXS and enhanced the generation of LCSCs, evident by the upregulation of CD133 and ALDH1A1 expression, and the increase in the number and size of tumor spheres. NNK also promoted the expression of LCSC-related molecules including beta-catenin and Nanog. All these NNK-mediated effects could be offset by ozagrel. In the colony formation assay, NNK increased whereas ozagrel decreased the number of colonies. Collectively, LCSCs and TXS participate in NNK-induced lung cancer. Our data suggest that TXS is a promising therapeutic target as it is a key molecular in NNK-mediated stemness of LCSCs. PMID- 26518147 TI - Oncoproteomics: Trials and tribulations. AB - Oncoproteomics is the study of cancer-associated proteins and their interactions using proteomic technologies. It is expected to play a crucial role in the detection and surveillance of cancer, as well as in the development of personalized medicine for oncology. In this review, we will outline the current status, advantages, and limitations of oncoproteomics. Further, we will discuss available strategies arising from a better understanding of oncoproteomics, including integrated omics approaches, to overcome current problems in the discovery and validation of biomarkers, identification of novel drug targets, and management of personalized medicine. PMID- 26518148 TI - Discordance between Auto Mode Switch (AMS) Episodes and Atrial Tachyarrhythmia (AT/AF) Burden. PMID- 26518149 TI - Impact of cage stocking density on egg laying characteristics and related stress and immunity parameters of Japanese quails in subtropics. AB - The aim of this study was to investigate the effects of different cage stocking densities on egg production parameters, as well as related stress and immunity indices in Japanese quails under subtropical Egyptian conditions. Two hundred and sixteen birds of Japanese quail at 14th week of age were used in this experiment. The birds were divided randomly into three groups: 60, 72 and 84. Each group subdivided into 4 replicates, where the cages' floor spaces were 200 (S1 ), 167 (S2 ) and 143 (S3 ) cm(2) /bird, respectively. Birds housed at 200 cm(2) /bird (S1 ) had superior fertility (fertility % (p = 0.013) and hatchability % (p = 0.041)), egg production (egg weight (p = 0.034) and egg mass (p = 0.001)) and immunity parameters (higher geometric mean of antibody titres against Newcastle disease virus, p = 0.024). Furthermore, they had higher internal egg quality score: albumen height (p = 0.003), yolk height (p = 0.023), yolk index (p = 0.006) and Haugh unit (p = 0.035). Birds housed at 143 cm(2) /bird (S3 ) had the lowest total leucocytic count and lymphocyte % (p = 0.022), but the highest H/L ratio (p = 0.001). Corticosterone concentration was lower in S1 group (p = 0.031) than that in groups housed at higher densities. Japanese quail housed at high densities revealed drop in fertility, hatchability, production and immunity parameters, indicating a detrimental effects on both welfare and economic income. PMID- 26518150 TI - Young Adults With Headaches: The Transition From Adolescents to Adults. AB - Migraine is a common condition that for many begins in childhood and may progress over the course of one's life. The transition from adolescence to adulthood is a critical time for those who suffer from migraine and can be marked by a variety of important considerations for the patient and practitioner. Medication choices may be a challenge during adolescent years as Food and Drug Administration (FDA) approved options are few and many more studies are needed to understand the benefits and risks of use of these agents in adolescents. However, as patients transition to adulthood, FDA approved options and the level of evidence improve significantly. Late adolescents may also struggle with a variety of psychiatric comorbidities that may simultaneously create challenges in determining treatment but also open opportunities to manage multiple comorbidities and address underlying depression, anxiety, and behavioral issues. For late adolescent girls, the beginning of sexual activity, onset of gynecologic conditions, or presence of irregular or painful menses may raise questions regarding the use of oral contraceptives (OCs). Given data on the risks of these medications in women with migraine, especially those with aura or those who smoke, important conversations between physicians and their migraine patients can help risk stratify and determine the risk/benefit profile for the potential use of these agents. Much more data are needed to fully understand the transition from adolescence to adulthood for those suffering with migraine and this article seeks to shed light on the limited understanding currently available in established literature. PMID- 26518151 TI - Responses of sex steroid hormones to different intensities of exercise in endurance athletes. AB - Previous studies have shown that acute exercise elevates sex steroid hormone concentrations in rodents and that sprint exercise increases circulating testosterone in healthy young men. However, the effect of different exercise intensities on sex steroid hormone responses at different levels of physical fitness is still unclear. In this study, we compared circulating sex steroid hormone responses at different exercise intensities in athletes and non-athletes. Eight male endurance athletes and 11 non-athletes performed two 15 min sessions of submaximal exercise at 40 and 70% peak oxygen uptake (V(O2peak)), respectively, and exercised at 90% V(O2peak) until exhaustion. Venous blood samples were collected during the last minute of each submaximal exercise session and immediately after exhaustion. Acute exercise at 40, 70 and 90% V(O2peak) induced significant increases in serum dehydroepiandrosterone (DHEA) and free testosterone concentrations in non-athletes. On the contrary, only 90% VO2 peak exercise led to an increase in serum DHEA and free testosterone concentrations in athletes. Serum 5alpha-dihydrotestosterone concentrations increased with 90% V(O2peak) exercise in both athletes and non-athletes. Additionally, serum estradiol concentrations were significantly increased at moderate and high exercise intensities in both athletes and non-athletes. These results indicate that in endurance athletes, serum sex steroid hormone concentrations, especially serum DHEA and 5alpha-dihydrotestosterone concentrations, increased only with high-intensity exercise, suggesting that different responses of sex steroid hormone secretion are induced by different exercise intensities in individuals with low and high levels of physical fitness. In athletes, therefore, high intensity exercise may be required to increase circulating sex steroid hormone concentrations. PMID- 26518152 TI - What is an epitheliome, anyway? PMID- 26518153 TI - Quantifying and predicting depression literacy of undergraduates: a cross sectional study in Sri Lanka. AB - BACKGROUND: The high rates of depression and low rates of related help-seeking among undergraduates are matters for concern. In response to the need to examine their knowledge about depression and its management, and the dearth of such research from non-western developing countries, this study examined the depression literacy of undergraduates in Sri Lanka. METHODS: A questionnaire was administered among 4671 undergraduates to examine their depression literacy relating to problem-recognition, measured using a vignette of a depressed undergraduate, and their treatment beliefs measured by assessing their perceptions about the helpfulness of various options of help for the presented problem. Responses for the latter aspect were quantified using a scale comprising the options of help endorsed by Sri Lankan mental health professionals. Regression analysis models were used to identify the correlates of these aspects of depression literacy. RESULTS: Females, medical undergraduates and those in higher years of study (compared to first-years) were more likely to recognise the problem as depression. The undergraduates obtained a mean percentage score of 76% on the constructed Depression Treatment Beliefs Scale. Scores on this scale were higher among females, medical undergraduates, those who got help for the problem after trying to deal with it alone and those who recognised the problem as depression, as well as those who used other mental health-related labels for this purpose. Scores were lower among undergraduates in years 2-4 (compared to first years), those with family or friends with the problem and those with higher stigma on a Social Distance Scale. However, the effect sizes of these relationships were small. CONCLUSIONS: As factors such as gender, discipline, year of study, exposure to depression and stigma are associated with differences in the depression literacy of these undergraduates, concerning their ability to recognise the problem and their related treatment beliefs, these must be considered when designing related educational initiatives. Recognising the problem as depression or the use of other mental health-related labels is associated with better treatment beliefs as per expert consensus, indicating that such labelling could have value for appropriate help-seeking. PMID- 26518154 TI - [Vaccination in the early post-partum: Guidelines]. AB - OBJECTIVES: To propose guidelines for clinical practice regarding pertussis, influenza, varicella and rubella vaccination in the early post-partum. MATERIALS AND METHODS: Bibliographic searches were performed with PubMed and Cochrane databases, and within national guidelines and their references. RESULTS: Women that have not got vaccinated in the past 10 years should receive a dose of diphtheria-tetanus-acellular pertussis-poliomyelitis vaccine in the early post partum, and the family and friends should be included in the cocooning strategy (professional consensus). During seasonal influenza epidemic, influenza vaccine should be offered to women, who were not vaccinated during pregnancy, and delivered a vulnerable neonate (professional consensus). For all other women, the vaccination can be discussed on a case-by-case basis (professional consensus). In order to prevent congenital or neonatal varicella in a subsequent pregnancy, scientific data are weak to suggest a systematic screening and vaccination against varicella in women with no history or uncertain status about varicella, excepted in women coming from sub-Saharan Africa, East and Central Europe, more likely to have a negative serology for varicella (professional consensus). In order to prevent severe varicella in adulthood, the vaccination should be discussed with potentially seronegative women as recommended by the French High Council for Public Health (professional consensus). Rubella vaccine is recommended in the early post-partum with women with negative serology during pregnancy with a dose of measles-mumps-rubella vaccine (professional consensus). A new pregnancy should be avoided in the month following rubella and varicella vaccination, but contraception is not obligatory (professional consensus). Breastfeeding, recent rhesus immunoglobulin injection and blood transfusion do not prevent to perform vaccination in the early post-partum (professional consensus). PMID- 26518155 TI - [Performance and indications of noninvasive prenatal testing using cell free circulating fetal DNA (cffDNA) for the detection of fetal trisomy 21, 18 and 13 in France]. AB - OBJECTIVES: To evaluate de performances of noninvasive prenatal testing using cell free circulating fetal DNA (cffDNA) for the detection of fetal trisomy 21, 18 and 13 in a French population. MATERIALS AND METHODS: cffDNA analysis was performed by massive parallel sequencing during a multicenter, non interventional, prospective study and the results were compared with a standard fetal karyotype. RESULTS: Results were available for 886 patients who have been classified as high- or moderate-risk depending on the presence of fetal abnormalities on ultrasound examination. For the high-risk group (n=376), the sensitivity and specificity of the test were 100% and 99.9% for trisomy 21, 88% and 99.9% for trisomy 18 and 100% and 99.9% for trisomy 13. The rate of other pathogenic chromosomal abnormalities with a negative NIPT was 7.9%. In the low risk group (n=510), the sensitivity was 100% and the specificity 99.8% for trisomy 21, and only 0.4% of pathogenic chromosomal abnormalities were revealed by fetal karyotyping but not detected by cffDNA analysis. CONCLUSION: Noninvasive prenatal testing using cffDNA for high risk patients without fetal anomalies at ultrasound could be recommended in France after counseling on the possible risk of undiagnosed anomalies. PMID- 26518157 TI - Congenital hypertrichosis universalis in Mexican female twins. PMID- 26518156 TI - The secreted autotransporter toxin (Sat) does not act as a virulence factor in the probiotic Escherichia coli strain Nissle 1917. AB - BACKGROUND: Escherichia coli Nissle 1917 (EcN) is a probiotic used in the treatment of intestinal diseases. Although it is considered safe, EcN is closely related to the uropathogenic E. coli strain CFT073 and contains many of its predicted virulence elements. Thus, it is relevant to assess whether virulence associated genes are functional in EcN. One of these genes encodes the secreted autotransporter toxin (Sat), a member of the serine protease autotransporters of Enterobacteriaceae (SPATEs) that are secreted following the type V autotransporter pathway. Sat is highly prevalent in certain E. coli pathogenic groups responsible for urinary and intestinal infections. In these pathogens Sat promotes cytotoxic effects in several lines of undifferentiated epithelial cells, but not in differentiated Caco-2 cells. RESULTS: Here we provide evidence that sat is expressed by EcN during the colonization of mouse intestine. The EcN protein is secreted as an active serine protease, with its 107 kDa-passenger domain released into the medium as a soluble protein. Expression of recombinant EcN Sat protein in strain HB101 increases paracellular permeability to mannitol in polarized Caco-2 monolayers. This effect, also reported for the Sat protein of diffusely adherent E. coli, is not observed when this protein is expressed in the EcN background. In addition, we show that EcN supernatants confer protection against Sat-mediated effects on paracellular permeability, thus indicating that other secreted EcN factors are able to prevent barrier disruption caused by pathogen-related factors. Sat is not required for intestinal colonization, but the EcNsat::cat mutant outcompetes wild-type EcN in the streptomycin-treated mouse model. Analysis of the presence of sat in 29 strains of the ECOR collection isolated from stools of healthy humans shows 34.8 % positives, with high prevalence of strains of the phylogenetic groups D and B2, related with extra intestinal infections. CONCLUSIONS: Sat does not act as a virulence factor in EcN. The role of Sat in intestinal pathogenesis relies on other genetic determinants responsible for the bacterial pathotype. PMID- 26518158 TI - Xyloglucan for the treatment of acute diarrhea: results of a randomized, controlled, open-label, parallel group, multicentre, national clinical trial. AB - BACKGROUND: There is a strong rationale for the use of agents with film-forming protective properties, like xyloglucan, for the treatment of acute diarrhea. However, few data from clinical trials are available. METHODS: A randomized, controlled, open-label, parallel group, multicentre, clinical trial was performed to evaluate the efficacy and safety of xyloglucan, in comparison with diosmectite and Saccharomyces in adult patients with acute diarrhea due to different causes. Patients were randomized to receive a 3-day treatment. Symptoms (stools type, nausea, vomiting, abdominal pain and flatulence) were assessed by a self administered ad-hoc questionnaire 1, 3, 6, 12, 24, 48 and 72 h following the first dose administration. Adverse events were also recorded. RESULTS: A total of 150 patients (69.3 % women and 30.7 % men, mean age 47.3 +/- 14.7 years) were included (n = 50 in each group). A faster onset of action was observed in the xyloglucan group compared with the diosmectite and S. bouliardii groups. At 6 h xyloglucan produced a statistically significant higher decrease in the mean number of type 6 and 7 stools compared with diosmectite (p = 0.031). Xyloglucan was the most efficient treatment in reducing the percentage of patients with nausea throughout the study period, particularly during the first hours (from 26 % at baseline to 4 % after 6 and 12 h). An important improvement of vomiting was observed in all three treatment groups. Xyloglucan was more effective than diosmectite and S. bouliardii in reducing abdominal pain, with a constant improvement observed throughout the study. The clinical evolution of flatulence followed similar patterns in the three groups, with continuous improvement of the symptom. All treatments were well tolerated, without reported adverse events. CONCLUSIONS: Xyloglucan is a fast, efficacious and safe option for the treatment of acute diarrhea. TRIAL REGISTRATION: EudraCT number 2014-001814-24 (date: 2014 04-28) ISRCTN number: 90311828. PMID- 26518160 TI - A new lumazine peptide penilumamide E from the fungus Aspergillus terreus. AB - A new rare lumazine peptide, penilumamide E (1), together with 13 known compounds (2-14) were isolated from the fungus Aspergillus terreus. Their structures were identified by spectroscopic techniques. The relative configuration of 1 was confirmed by single-crystal X-ray diffraction analysis. Compound 10 exhibited antimalarial activity against Plasmodium falciparum with IC50 values of 2.83 MUg/mL. Compounds 4 and 6 showed weak cytotoxicity against cholangiocarcinoma (CCA) cell lines. In addition, 4 and 11 exhibited weak cytotoxicity against human hepatoma cell line. PMID- 26518159 TI - Laparoscopic hysterectomy after concurrent radiochemotherapy in locally advanced cervical cancer compared to laparotomy: A multi institutional prospective pilot study of cost, surgical outcome and quality of life. AB - OBJECTIVE: Laparoscopy allows hysterectomies after chemoradiation to be performed without opening the abdominal wall. We measured the costs and quality of life for locally advanced cervical cancer patients operated on via laparoscopy compared to laparotomy. STUDY DESIGN: We conducted an observational prospective multicenter study on locally advanced cervical cancer patients undergoing an extrafascial hysterectomy after concurrent chemoradiotherapy (CRT). We assessed the costs from the medical visit before surgery up to the first month after surgery from the providers' perspective and measured the quality of life using the EORTC QLQ-C30 and QLQ-CX24 up to six months. RESULTS: Sixty two patients (39 laparoscopy and 23 laparotomy) from December 2008 to November 2011 were included. There was no difference in operative time, or intraoperative and post-operative complication rates between the two groups. Intraoperative transfusion and abdominal drain were significantly lower in the laparoscopy group (respectively, p = 0.04 and p < 0.01), as well as the duration of hospital stay (7.3 d vs. 5.7 d, p < 0.001). All patients who underwent laparoscopic hysterectomy were discharged to home, whereas 4 laparotomy patients used convalescence homes (p = 0.01). Mean costs at one month were ?10,991 for laparotomy and ?11,267 for laparoscopy (p = 0.76). Sexual activity is better for the laparoscopy group at six months (p = 0.01). CONCLUSION: Laparoscopy for an extrafascial hysterectomy after CRT in locally advanced cervical cancer patients brought better quality of life with similar costs compared to laparotomy, and should therefore be the first choice for surgeons. PMID- 26518161 TI - Variation in metastatic workup for patients with invasive breast cancer. AB - BACKGROUND: Despite guidelines, surgeons vary in the metastatic workup they order for their breast cancer patients. METHODS: Surgeons were surveyed as to their practices in ordering staging studies for their breast cancer patients using a Web-based survey. Nonparametric analyses were performed to determine factors associated with guideline adherence. RESULTS: Two hundred fifty-three surgeons responded to the survey; 55.8% had practices with >=50% breast patients; 7.3% of respondents stated they always did a metastatic workup before surgery, 8.6% never did; only 52.4% ordered a metastatic workup only in patients with clinical stage III disease. Surgeons who had >=50% breast-related practices were more likely to follow these guidelines (P = .031). Only 17% stated that a computed tomography chest/abdomen and bone scan was their "usual" metastatic workup. CONCLUSIONS: Nearly 40% of surgeons perform metastatic workup when they are not indicated, and few adhere to National Comprehensive Cancer Network guidelines in terms of the tests ordered. PMID- 26518162 TI - The effect of supplemental parenteral nutrition on outcomes of necrotizing enterocolitis in premature, low birth weight neonates. AB - BACKGROUND: We hypothesized that supplemental parenteral nutrition (PN) decreases the need for surgery and mortality associated with necrotizing enterocolitis (NEC). METHODS: Single institution retrospective review of all premature, low birth weight infants with NEC from January 2006 to December 2013 was conducted. RESULTS: NEC was identified in 114 premature, low birth weight infants, 59 (51.8%) of which required surgical management. Surgical NEC infants were born younger (25.8 +/- 4.0 vs 27.8 +/- 3.3 weeks, P = .005) and weighed less at birth (829 +/- 281 vs 938 +/- 271 g, P = .038) than those managed medically. There was no difference in the use of PN (37.7% vs 31.4%, P = .541) between surgical and medical NEC patients. There was no statistically significant difference in mortality at discharge between patients who had PN at NEC onset and those who did not (31.4% vs 42.6%, P = .294) CONCLUSION: In this single-center study, supplemental PN at NEC onset does not appear to significantly improve outcomes as demonstrated by rates of surgical intervention and in-hospital mortality. PMID- 26518163 TI - Understanding pre-enrollment surgical outcomes for hospitals participating in Medicare Accountable Care Organizations. AB - BACKGROUND: To anticipate the effects of accountable care organizations (ACOs) on surgical care, we examined pre-enrollment utilization, outcomes, and costs of inpatient surgery among hospitals currently enrolled in Medicare ACOs vs nonenrolling facilities. METHODS: Using the Nationwide Inpatient Sample (2007 to 2011), we compared patient and hospital characteristics, distributions of surgical specialty care, and the most common inpatient surgeries performed between ACO-enrolling and nonenrolling hospitals before implementation of Medicare ACOs. We used multivariable regression to compare pre-enrollment inpatient mortality, length of stay (LOS), and costs. RESULTS: Hospitals now participating in Medicare ACO programs were more frequently nonprofit (P < .001) and teaching institutions (P = .01) that performed more specialty procedures (P < .001). We observed no clinically meaningful pre-enrollment differences for inpatient mortality, prolonged length of stay, or costs for procedures performed at ACO-enrolling vs nonenrolling hospitals. CONCLUSIONS: Medicare ACO hospitals had pre-enrollment outcomes that were similar to nonparticipating facilities. Future studies will determine whether ACO participation yields differential changes in surgical quality or costs. PMID- 26518164 TI - Interferon-alpha2b gene-modified human bone marrow mesenchymal stem cells inhibit hepatocellular carcinoma by reducing the Notch1 levels. AB - AIMS: Hepatocellular carcinoma (HCC) is the most common liver cancer worldwide. IFN-alpha has been used in clinics as a potential therapeutic strategy to treat HCC. In spite of the therapeutic effects, IFN-alpha caused many side effects due to its short half-life and high dose. Here, we aim to detect the anti-tumor effect of a novel gene delivery system - IFN-alpha2b gene-modified human bone marrow mesenchymal stem cells (BMSCs) in HCC. MAIN METHODS: Two HCC cell lines, HepG2 and Huh7 were used in the current study. The secretion of IFN-alpha2b in the BMSC cultured conditioned media (CM) was measured by ELISA. The cell cycle was determined by flow cytometry. The Xenografted NOD/SCID mouse tumor model was generated by subcutaneous inoculation with HepG2 cells. KEY FINDINGS: We found that the IFN-alpha2b-modified BMSC (BMSC/IFN-alpha2b) could express IFN-alpha2b stably. The CM from BMSC/IFN-alpha2b inhibited the proliferation of HCC cells with a much lower growth rate compared with BMSC/vector-CM or DMEM culture group. We further demonstrated that the population of G2/M phase was higher in BMSC/IFN alpha2b-CM treated cells than the other two groups. In addition, BMSC/IFN-alpha2b could significantly inhibit tumor growth in NOD/SCID mice. Moreover, we found that BMSC/IFN-alpha2b-CM could significantly decrease the mRNA and protein levels of Notch signaling molecules of HCC in vitro and in vivo. SIGNIFICANCE: Our data demonstrated that BMSC/IFN-alpha2b could significantly inhibit HCC cell growth through negatively regulating the Notch signaling, which suggested that IFN alpha2b-modified BMSC may be used as an effective therapeutic strategy for hepatomas. PMID- 26518165 TI - Pituitary adenylate cyclase-activating polypeptide is regulated by alternative splicing of transcriptional repressor REST/NRSF in nerve injury. AB - AIMS: The pathophysiological mechanism for neuropathic pain (NP), one of the most common types of intractable pain, remains largely unknown. We previously reported that pituitary adenylate-cyclase activating polypeptide (PACAP) is required for the development of spinal sensitization and induction of NP. Previous in vitro studies suggest that PACAP transcription unit has two RE1-like elements and that the transcriptional repressor REST controls expression of PACAP gene. However the regulation of PACAP gene through its RE1 sites in vivo has not been studied. We have analyzed the functional role of PACAP gene RE1 element following nerve injury. MAIN METHODS: An L5-spinal nerve transection (L5-SNT) in mice was used as a model of spinal injury. DRGs after the L5-SNT were studied. KEY FINDINGS: PACAP mRNA increased in the DRG following spinal nerve injury. REST4, an alternatively spliced isoform of REST was shown to be regulated by the splicing activator (nSR100) and nSR100 itself also increased. Overexpression of either REST4 or nSR100 in vitro increased PACAP expression, while overexpression of REST repressed PACAP mRNA production. Reporter gene analysis showed that a novel RE1 previously predicted by in silico analysis was indeed functional. ChIP analysis showed that REST bound significantly to this RE1 in the DRG of naive mice, while REST binding to this RE1 was decreased following spinal nerve injury. The expression of REST was decreased by nSR100-dependent alternative splicing of the REST gene, leading to derepression of PACAP. SIGNIFICANCE: PACAP expression in the DRG following spinal nerve injury is controlled through a novel RE1 by REST. PMID- 26518166 TI - Sources of adaptation of inferior temporal cortical responses. AB - Neurons of different brain regions change their response when a stimulus is repeated. In inferior temporal cortex (IT), stimulus repetition typically reduces the responses of single neurons, i.e., IT neurons show repetition suppression. Single unit recordings in IT showed that individual neurons vary in their degree of adaptation effects, ranging from strong suppression to slight enhancement of the response to the repeated stimulus. The suppression is maximal after the peak of the response and then reduces during the further course of the response. Repetition suppression in IT is still present for interstimulus intervals of at least 900 msec. I discuss the contribution of mechanisms that have been proposed to explain adaptation effects of IT responses. Firing-rate dependent response fatigue, e.g., a prolonged hyperpolarization, intrinsic to the recorded neuron cannot explain the stimulus specificity of the adaptation effect. The latter can be explained by synaptic depression or an adapted input from other IT neurons. We observed repetition suppression of IT neurons when adapter and test stimuli were presented at locations that differed by 8 degree of visual angle, suggesting that at least part of the adaptation effect is not inherited from retinotopic visual areas with small receptive fields. We observed no effect of repetition probability on repetition suppression in macaque IT using images of various categories, suggesting a dissociation between top-down expectation effects and repetition suppression. Together, our data agree with the hypothesis that adaptation in IT serves to reduce the saliency of recently seen stimuli, highlighting stimuli that differ from recently presented ones. PMID- 26518167 TI - Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome: Identification of nine novel mutations across BBS1, BBS2, BBS4, BBS7, BBS9, BBS10 genes. AB - Bardet-Biedl Syndrome (BBS) is a rare, autosomal-recessive ciliopathy characterized by obesity, rod-cone dystrophy, postaxial polydactyly, renal abnormalities, genital abnormalities and learning difficulties. To date, mutations in 21 different genes have been described as being responsible for BBS. Recently sequential gene sequencing has been replaced by next generation sequencing (NGS) applications. In this study, 15 patients with clinically diagnosed BBS were investigated using a next generation sequencing panel which included 17 known BBS causing genes (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, NPHP6, WDPCP, SDCCAG8, NPHP1). A genetic diagnosis was achieved in 13 patients (86.6%) and involved 9 novel and 3 previously described pathogenic variants in 6 of 17 BBS causing genes. BBS10 and BBS1 were the most commonly involved genes with frequencies of 31% and 23% respectively. Three of the 13 patients had an affected sibling. All affected siblings were found to be homozygous for the mutation detected in the proband. No evidence of triallelic inheritance was detected. Although limited association between certain genes and phenotypic features has been observed in this study, it is considered that additional studies are needed to better characterize the genotype-phenotype correlation of BBS. Our results demonstrate that NGS panels are feasible and effective method for providing high diagnostic yields in the diseases caused by multiple genes such as BBS. PMID- 26518168 TI - A novel mutation in the C7orf11 gene causes nonphotosensitive trichothiodystrophy in a multiplex highly consanguineous kindred. AB - Trichothiodystrophy (TTD), also known as sulfur-deficient brittle hair syndrome, is a rare autosomal recessive multisystem disorder, which manifests with brittle hair, mental retardation, ichthyosis and decreased fertility. Mutations in the TTDN1 (C7orf11) gene have been shown to cause a nonphotosensitive type of trichothiodystrophy. We report of a 19 years old male, born to consanguineous parents of Arab-Muslim descent, who presented due to severe renal failure, but exhibited additional unique features, including developmental delay, mental retardation, splenomegaly, pancytopenia, hypogonadism and brittle hair. Following the clinical diagnosis of nonphotosensitive TTD, sequencing of the coding exons of C7orf11 was performed and revealed the patient to be homozygous for a novel c.505dupA mutation. As the severe renal failure following which the proband was referred to our care is not typically characteristic of this disorder, its significance is discussed. Molecular diagnosis of this highly affected family should enable genetic counseling and prenatal diagnosis for future pregnancies. PMID- 26518169 TI - WITHDRAWN: A novel mitochondrial DNA deletion in a patient with Pearson syndrome and neonatal diabetes mellitus provides insight into disease etiology, severity and progression. PMID- 26518170 TI - Leaf application of a sprayable bioplastic-based formulation of biocontrol Aspergillus flavus strains for reduction of aflatoxins in corn. AB - BACKGROUND: Applying non-aflatoxin-producing Aspergillus flavus isolates to the soil has been shown to be effective in reducing aflatoxin levels in harvested crops, including peanuts, cotton and corn. The aim of this study was to evaluate the possibility of controlling aflatoxin contamination using a novel sprayable formulation consisting of a partially gelatinized starch-based bioplastic dispersion embedded with spores of biocontrol A. flavus strains, which is applied to the leaf surfaces of corn plants. RESULTS: The formulation was shown to be adherent, resulting in colonization of leaf surfaces with the biocontrol strain of A. flavus, and to reduce aflatoxin contamination of harvested kernels by up to 80% in Northern Italy and by up to 89% in the Mississippi Delta. The percentage of aflatoxin-producing isolates in the soil reservoir under leaf-treated corn was not significantly changed, even when the soil was amended with additional A. flavus as a model of changes to the soil reservoir that occur in no-till agriculture. CONCLUSIONS: This study indicated that it is not necessary to treat the soil reservoir in order to achieve effective biocontrol of aflatoxin contamination in kernel corn. Spraying this novel bioplastic-based formulation to leaves can be an effective alternative in the biocontrol of A. flavus in corn. (c) 2015 Society of Chemical Industry. PMID- 26518171 TI - Comorbid autoimmune diseases in patients with vitiligo: A cross-sectional study. AB - BACKGROUND: Few large-scale studies have quantified the burden of comorbid autoimmune diseases in patients with vitiligo. OBJECTIVE: We sought to determine the prevalence of comorbid autoimmune diseases in patients with vitiligo. METHODS: We conducted a manual chart review on a cohort of 1873 patients with vitiligo seen between January 2002 and October 2012 at the Henry Ford Health System in Detroit, MI. Patients were excluded if they had fewer than 2 dermatology notes (N = 595) or if they were never given a diagnosis of vitiligo by a dermatologist (N = 180). RESULTS: Of 1098 patients with vitiligo, nearly 20% had at least 1 comorbid autoimmune disease. Compared with the general US population, we found a higher prevalence of thyroid disease (12.9%, P < .001), alopecia areata (3.8%, P < .001), inflammatory bowel disease (0.9%, P = .046), pernicious anemia (0.5%, P = .007), systemic lupus erythematosus (0.3%, P = .048), Guillain-Barre syndrome (0.3%, P < .001), discoid lupus (0.2%, P = .003), linear morphea (0.2%, P < .001), myasthenia gravis (0.2%, P = .002), and Sjogren syndrome (0.2%, P = .011). LIMITATIONS: The study lacked a control group. This was a single-institution study with possible selection bias, and thus the findings may not be representative of the overall population of patients with vitiligo. CONCLUSIONS: We observed a high prevalence of comorbid autoimmune diseases in patients with vitiligo and report several new associations. PMID- 26518172 TI - Lymphomatoid papulosis: Treatment response and associated lymphomas in a study of 180 patients. AB - BACKGROUND: Lymphomatoid papulosis (LyP) is a CD30(+) lymphoproliferative disorder, with a self-regressing clinical course and malignant histopathology. OBJECTIVE: The aim of this study was to evaluate characteristics, risk factors, associated malignancies, long-term outcome, and treatment of LyP in a large cohort representing the experience of the MD Anderson Cancer Center. METHODS: Patient charts and clinical and histopathologic data of 180 patients with LyP were retrospectively assessed. RESULTS: A total of 56.7% of patients was men. Histologic subtype A was found in 47.2%, type B in 17.2%, type C in 22.8%, type D in 7.8%, type E in 0.6%, and mixed subtype in 4.4% of the patients. One hundred fourteen lymphomas were observed in 93 patients, with mycosis fungoides (61.4%) and anaplastic large cell lymphoma (26.3%) being the most common forms. Risk factors for development of lymphoma included sex and histologic subtype. Number of lesions and symptom severity were not associated with lymphoma development. Patients with type D were less likely to have lymphomas. Treatment provided symptomatic relief but did not prevent progression to lymphoma. LIMITATIONS: The limitation of this study is the retrospective study design. CONCLUSION: Patients with LyP are at increased risk of associated lymphomas. Thorough patient counseling is needed and long follow-up periods are required to detect and treat secondary lymphomas. PMID- 26518173 TI - Clinical, dermoscopic, and pathologic features of onychopapilloma: A review of 47 cases. AB - BACKGROUND: Onychopapilloma is a benign neoplasm of the nail bed and the distal matrix. Although not uncommon in our experience, only up to 32 cases of this tumor have been reported in the literature. OBJECTIVE: We sought to review the clinical, dermoscopic, and pathologic features of onychopapilloma. METHODS: We retrospectively analyzed the clinical features of 47 patients with pathologically confirmed onychopapilloma diagnosed within the last 5 years, and reviewed the published literature. RESULTS: The most common clinical presentation was longitudinal erythronychia (n = 25); followed by longitudinal leukonychia (n = 7); longitudinal melanonychia (n = 4); long splinter hemorrhages without erythronychia, leukonychia, or melanonychia (n = 8); and short splinter hemorrhages without erythronychia, leukonychia, or melanonychia (n = 3), with subungual mass (n = 47) and distal fissuring (n = 11). Pathology was consistent with acanthosis of the nail bed and distal matrix, with matrix metaplasia underlying distal subungual hyperkeratosis. LIMITATIONS: This was a retrospective analysis. CONCLUSION: To our knowledge, our series of onychopapilloma is the largest so far. Among various clinical presentations, longitudinal erythronychia is the most common. Dermoscopy of the free edge of the nail plate showing a small subungual keratotic mass where the band reaches the nail plate margin provides a clue for the diagnosis. PMID- 26518174 TI - Incidence and determinants of neonatal morbidity after elective caesarean section at the national referral hospital in Kampala, Uganda. AB - BACKGROUND: Elective caesarean sections (ECS) have been implicated in increased risk of adverse neonatal outcomes. The primary objective was to assess the incidence and determinants of neonatal morbidity after elective caesarean section deliveries. The secondary objective was to describe the maternal morbidity associated with elective caesarean section. METHODS: This was a prospective cohort study of women admitted for ECS, as well as their newborns, conducted at Mulago hospital from March 1, 2013 to February 28, 2014. These were followed from the time of the operation until 6 weeks after hospitalization following the caesarean delivery. Data was collected using an interviewer-administered questionnaire and review of medical records for demographic characteristics, obstetric history, current pregnancy complications and pregnancy outcomes up to hospital discharge. Study outcomes were maternal and neonatal morbidity. The data was analyzed using Stata version 12. RESULTS: There were 25,846 deliveries during the study period, of which 20,083 (77.7%) were vaginal deliveries or assisted deliveries, and 5763 (22.3%) were caesarean sections. Of the caesarean sections, 920 (15.9%) were ECS. The commonest maternal morbidity was hemorrhage (17.2%). A birth weight less than 2500 g (aRR 11.0 [95% CI 8.1-17.2]) or more than 4000 g (aRR 12.2 [95% CI 10.6-23.2]), delivery at gestation age less than or equal to 38 weeks (aRR 1.62 [95% 1.20-2.10]), multigravidity (aRR 1.70 [95% CI 1.20-2.90]) and using general anaesthesia (aRR 2.43 [95% CI 1.20-5.90]) were associated with risk of neonatal morbidity. The commonest neonatal morbidity is respiratory distress especially if delivery occurs at a gestation age of 37 weeks or lower, if the birth weight is less than 2500 g or more than 4000 g, and if general anesthesia is used. CONCLUSION: Our study shows that at Mulago Hospital, ECS is associated with significant neonatal and maternal morbidity. We recommend that elective caesarean sections be performed after 39 weeks of gestation, and preferably avoid using general anaesthesia. PMID- 26518175 TI - All-trans-retinoic acid and retinol binding to the FA1 site of human serum albumin competitively inhibits heme-Fe(III) association. AB - Retinoids are a class of chemicals derived from vitamin A metabolism, playing important and diverse functions. Vitamin A, also named all-trans-retinol (all trans-ROL), is coverted into two classes of biologically active retinoids, i.e. 11-cis-retinoids and acidic retinoids. Among acidic retinoids, all-trans-retinoic acid (all-trans-RA) and 9-cis-retinoic acid (9-cis-RA) represent the main metabolic products. Specific and aspecific proteins solubilize, protect, and detoxify retinoids in the extracellular environment. The retinoid binding protein 4 (RBP4), the epididymal retinoid-binding protein (ERBP), and the interphotoreceptor matrix retinoid-binding protein (IRBP) play a central role in ROL transport, whereas lipocalin-type prostaglandin D synthase (also named beta trace) and human serum albumin (HSA) transport preferentially all-trans-RA. Here, the modulatory effect of all-trans-RA and all-trans-ROL on ferric heme (heme Fe(III)) binding to HSA is reported. All-trans-RA and all-trans-ROL binding to the FA1 site of HSA competitively inhibit heme-Fe(III) association. Docking simulations and local structural comparison of HSA with all-trans-RA- and all trans-ROL-binding proteins support functional data indicating the preferential binding of all-trans-RA and all-trans-ROL to the FA1 site of HSA. Present results may be relevant in vivo, in fact HSA could act as a secondary carrier of retinoids in human diseases associated with reduced levels of RBP4 and IRBP. PMID- 26518176 TI - Advancing nursing enterprises: A cross-country comparison. AB - BACKGROUND: Health system transformations in the United States are creating new opportunities for nursing innovation, although financial sustainability has limited the expansion of nurse managed clinics. PURPOSE: We explore case studies of nursing enterprises in the developing world and discuss their potential for informing related work in the United States. METHODS: Cases were selected from the Center for Health Market Innovations. DISCUSSION: We describe a professional association network of clinics in Tanzania, a social franchise in Kenya, and a cooperative in the Philippines. All programs empowered nurses to own, lead, and advance their professional influence. They had a social mission of improving access to care for disadvantaged populations, while increasing employment and autonomy of women. They also provided a shared platform for branding, purchasing, and quality assurance. CONCLUSION: Organization sponsors in these models may be relevant to different actors in the United States. Each demonstrates the importance of a collective approach to advancing nursing enterprises. PMID- 26518177 TI - Current evidence on antenatal care provision for women with intellectual disabilities: A systematic review. AB - BACKGROUND: changing attitudes, alongside integration, more independent living and recognition of rights to family life have meant a steady rise in women with intellectual disabilities becoming pregnant. However, existing evidence shows that women with intellectual disabilities are less likely to seek or attend for regular antenatal care. This population experiences poorer maternal wellbeing and worse pregnancy outcomes compared to the general population, including preterm and low-birthweight babies. PURPOSE: to identify and review the existing evidence on the provision of antenatal care among women with intellectual disabilities. METHODS: a systematic search strategy was formulated using key Medical Sub Headings terms and related text words for pregnancy, antenatal care and intellectual disability. Comprehensive searches dating back to 1980 using pre determined criteria followed by a hand search of reference lists and citations were undertaken. Data were extracted using a data extraction form and methodological quality assessed using the framework developed by Caldwell et al. (2011). A three stage textual narrative synthesis was used to integrate the findings from the included studies. RESULTS: searches identified 16 papers that met the inclusion criteria. A majority of the papers focused on women's experience of pregnancy and antenatal care with a paucity of papers identified on midwives knowledge and experience. The four broad themes of the analysis and synthesis performed included: In the Family Way ('I've a baby inside. I've got a life inside of me.'); Knowledge and advocacy ('...everyone was looking at one another and no one was talking to me...'); Midwives educational needs ('...helpful to have guidance...') and Midwives Attitudes ('...women with [intellectual disabilities]...should not be pregnant'). KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: significant gaps in the evidence base were apparent, however evidence was identified which showed that intellectually disabled pregnant women struggle to understand antenatal information communicated during pregnancy which was often text based. Maternity care providers need to make adjustments to their services so that antenatal communication, information and care is appropriate for this group of women. Midwives identified that they lacked knowledge in this area and wanted antenatal guidance on how to meet the care and communication needs of women with intellectual disabilities. PMID- 26518178 TI - Autocrine protective mechanisms of human granulocyte colony-stimulating factor (G CSF) on retinal ganglion cells after optic nerve crush. AB - This study investigated the role of autocrine mechanisms in the anti-apoptotic effects of human granulocyte colony-stimulating factor (G-CSF) on retinal ganglion cells (RGCs) after optic nerve (ON) crush. We observed that both G-CSF and G-CSF receptor (G-CSFR) are expressed in normal rat retina. Further dual immunofluorescence staining showed G-CSFR immunoreactive cells were colocalized with RGCs, Muller cells, horizontal and amacrine cells. These results confirm that G-CSF is an endogenous ligand in the retina. The semi-quantitative RT-PCR finding demonstrated the transcription levels of G-CSF and G-CSFR were up regulated after ON crush injury. G-CSF treatment further increased and prolonged the expression level of G-CSFR in the retina. G-CSF has been shown to enhance transdifferentiation of the mobilized hematopoietic stem cells into tissue to repair central nervous system injury. We test the hypothesis that the hematopoietic stem cells recruited by G-CSF treatment can transdifferentiate into RGCs after ON crush by performing sublethal irradiation of the rats 5 days before ON crush. The flow cytometric analysis showed the number of CD34 positive cells in the peripheral blood is significantly lower in the irradiated, crushed and G CSF-treated group than the sham control group or crush and G-CSF treated group. Nevertheless, the G-CSF treatment enhances the RGC survival after sublethal irradiation and ON crush injury. These data indicate that G-CSF seems unlikely to induce hematopoietic stem cell transdifferentiation into RGCs after ON crush injury. In conclusion, G-CSF may serve an endogenous protective signaling in the retina through direct activation of intrinsic G-CSF receptors and downstream signaling pathways to rescue RGCs after ON crush injury, exogenous G-CSF administration can enhance the anti-apoptotic effects on RGCs. PMID- 26518179 TI - The effect of intravitreal vascular endothelial growth factor on inner retinal oxygen delivery and metabolism in rats. AB - Vascular endothelial growth factor (VEGF) is stimulated by hypoxia and plays an important role in pathologic vascular leakage and neovascularization. Increased VEGF may affect inner retinal oxygen delivery (DO2) and oxygen metabolism (MO2), however, quantitative information is lacking. We tested the hypotheses that VEGF increases DO2, but does not alter MO2. In 10 rats, VEGF was injected intravitreally into one eye, whereas balanced salt solution (BSS) was injected into the fellow eye, 24 h prior to imaging. Vessel diameters and blood velocities were determined by red-free and fluorescent microsphere imaging, respectively. Vascular PO2 values were derived by phosphorescence lifetime imaging of an intravascular oxyphor. Retinal blood flow, vascular oxygen content, DO2 and MO2 were calculated. Retinal arterial and venous diameters were larger in VEGF injected eyes compared to control eyes (P < 0.03), however no significant difference was observed in blood velocity (P = 0.21). Thus, retinal blood flow was greater in VEGF-injected eyes (P = 0.007). Retinal vascular PO2 and oxygen content were similar between control and VEGF-injected eyes (P > 0.11), while the arteriovenous oxygen content difference was marginally lower in VEGF-injected eyes (P = 0.05). DO2 was 950 +/- 340 and 1380 +/- 650 nL O2/min in control and VEGF-injected eyes, respectively (P = 0.005). MO2 was 440 +/- 150 and 490 +/- 190 nL O2/min in control and VEGF-injected eyes, respectively (P = 0.31). Intravitreally administered VEGF did not alter MO2 but increased DO2, suggesting VEGF may play an offsetting role in conditions characterized by retinal hypoxia. PMID- 26518180 TI - Ultrasonographic Features of Immunoglobulin G4-Related Sialadenitis. AB - The aim of this study was to determine the role of ultrasonography in the diagnosis and follow-up evaluation of immunoglobulin G4-related sialadenitis. In this study, 42 patients with immunoglobulin G4-related sialadenitis underwent ultrasonography of the parotid and submandibular glands, and the sonographic appearance was compared with the pathologic findings. Post-treatment ultrasonographic appearance was compared with the pre-treatment findings in 30 patients who received immunomodulatory therapy. The ultrasonographic appearance of the affected glands was divided into five patterns: superficial hypo-echoic, multiple hypo-echoic foci, whole-gland heterogeneity, space occupying and normal echo. Histopathologic examination revealed marked lymphoplasmacytic inflammation and inter-lobular fibrosis, which were more severe in the superficial than deep portion of the affected glands. After treatment, the volume of the affected gland decreased significantly, the internal echo became more homogeneous and the superficial hypo-echoic area disappeared or was reduced. In conclusion, ultrasonography may play an important role in the diagnosis and follow-up evaluation of immunoglobulin G4-related sialadenitis. PMID- 26518181 TI - Acute Right Lower Quadrant Abdominal Pain: An Uncommon Culprit. PMID- 26518182 TI - A Gallbladder Polyp in a Patient with Chronic Hepatitis B. PMID- 26518183 TI - Walter (Pete) L. Peterson, MD, 1943-2015. PMID- 26518184 TI - Pancreatic Head Mass Leading to Transient Obstructive Jaundice and Diabetes Mellitus in an Adolescent. PMID- 26518185 TI - Post-mortem as preventative medicine in Papua New Guinea: a case in point. AB - CONTEXT: Sorcery-related killing and violence has increased in Papua New Guinea (PNG) in recent years. The international community has condemned the violence and a number of non-government organisations have called for action; however, effective and appropriate interventions at a community level remain elusive. It has been suggested within some communities and in the literature that post mortems may help to reduce fears of sorcery and associated violence by providing an alternative biomedical explanation of death. Evidence to support this proposal, however, is limited. ISSUE: In 2012 the author was working in Ok Tedi Hospital, Tabubil, a remote mining town in the Star Mountains of PNG. The area is notable for a recent rise in sorcery-related violence and murders since 2009. In March 2012 a family from a nearby village requested a post-mortem following a relative's sudden death. They clearly stated that violence and killings against suspected perpetrators of sorcery had occurred due to a similar sudden death only a year before. As such they were concerned that the nature of their relative's death would rouse suspicions of sorcery and result in violence. The family hoped that a medical explanation of their relative's death would prevent rumours of sorcery developing and reduce the risk of violence against suspected perpetrators of sorcery. LESSONS LEARNED: The post-mortem, led by a consultant surgeon and performed in Ok Tedi Hospital, Tabubil, concluded that death was due to complications from an acute myocardial infarction. As requested these results were presented at the funeral to a congregation of approximately 80 people. Following the funeral presentation the author received feedback that fears of sorcery had been alleviated and during a 2-week follow-up period no related violence against suspected perpetrators of sorcery was observed. This case is a unique and intriguing example of biomedical and sociocultural integration in the Highlands of PNG. The presence of Ok Tedi Mine, which has provided wealth, education, transport and medical resources to the area for over 30 years, no doubt can partly explain the family's actions. For the family, however, a recent increase in sorcery-related violence would appear to be the primary reason for requesting a post-mortem. Whether these actions reduced suspicions of sorcery and the risk of subsequent violence as the family had anticipated is unclear. However, given a recent rise in post-mortem requests from regions of PNG with some of the highest rates of sorcery-related killings it seems prudent to further investigate the role of post-mortems in the prevention of sorcery-related violence and killings. PMID- 26518186 TI - Netrin-1 induces local translation of down syndrome cell adhesion molecule in axonal growth cones. AB - Down syndrome cell adhesion molecule (DSCAM) plays an important role in many neurodevelopmental processes such as axon guidance, dendrite arborization, and synapse formation. DSCAM is located in the Down syndrome trisomic region of human chromosome 21 and may contribute to the Down syndrome brain phenotype, which includes a reduction in the formation of long-distance connectivity. The local translation of a select group of mRNA transcripts within growth cones is necessary for the formation of appropriate neuronal connectivity. Interestingly, we have found that Dscam mRNA is localized to growth cones of mouse hippocampal neurons, and is dynamically regulated in response to the axon guidance molecule, netrin-1. Furthermore, netrin-1 stimulation results in an increase in locally translated DSCAM protein in growth cones. Deleted in colorectal cancer (DCC), a netrin-1 receptor, is required for the netrin-1-induced increase in Dscam mRNA local translation. We also find that two RNA-binding proteins-fragile X mental retardation protein (FMRP) and cytoplasmic polyadenylation element binding protein (CPEB)-colocalize with Dscam mRNA in growth cones, suggesting their regulation of Dscam mRNA localization and translation. Finally, overexpression of DSCAM in mouse cortical neurons results in a severe stunting of axon outgrowth and branching, suggesting that an increase in DSCAM protein results in a structural change having functional consequences. Taken together, these results suggest that netrin-1-induced local translation of Dscam mRNA during embryonic development may be an important mechanism to regulate axon growth and guidance in the developing nervous system. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 799-816, 2016. PMID- 26518187 TI - Development of an in vitro test to identify respiratory sensitizers in bronchial epithelial cells using gene expression profiling. AB - Chemicals that induce asthma at the workplace are substances of concern. At present, there are no widely accepted methods to identify respiratory sensitizers, and classification of these substances is based on human occupational data. Several studies have contributed to understanding the mechanisms involved in respiratory sensitization, although uncertainties remain. One point of interest for respiratory sensitization is the reaction of the epithelial lung barrier to respiratory sensitizers. To elucidate potential molecular effects of exposure of the epithelial lung barrier, a gene expression profile was created based on a DNA microarray experiment using the bronchial epithelial cell line 16 HBE14o(-). The cells were exposed to 12 respiratory sensitizers and 10 non-sensitizers. For statistical analysis, we used a class prediction approach that combined three machine learning algorithms, leave-one compound-out cross validation, and majority voting per tested compound. This approach allowed for a prediction accuracy of 95%. Identified predictive genes were mainly associated with the cytoskeleton and barrier function of the epithelial cell. Several of these genes were reported to be associated with asthma as well. Taken together, this indicates that pulmonary barrier function is an important target for respiratory sensitizers and associated genes can be used to predict the respiratory sensitization potential of chemicals. PMID- 26518188 TI - Sleep apnea syndrome in acromegalic patients: Can morphological evaluation guide us to optimize treatment? PMID- 26518189 TI - A meta-analysis-derived proposal for a clinical, ultrasonographic, and cytological scoring system to evaluate thyroid nodules: the "CUT" score. AB - The purpose of this study is to develop a new cancer risk score for preoperative assessment of thyroid nodules (TN) trying to reduce unnecessary thyroidectomies. On the basis of a recent meta-analysis of published literature, we assigned a matching value to the clinical (C) and ultrasonographic (U) features of TN with increased malignancy risk (MR). The created "CUT" score derived from "C+U" score, (CU[1-10] ), along with the five-tiered "T" (T[1-5] ), represents the cytologic result of the fine-needle aspiration. The C+U score was prospectively applied to 683 consecutive patients with 705 TN and validated through a ROC curve analysis. The CUT score was correlated with the histopathological diagnoses of 110 surgically resected TN. Fifty-five histologically benign TN had a mean C+U score of 2.4 versus 5.7 of 55 malignant TN (p < 0.001). Three categories were identified: low risk for C+U score <=2.5 (MR: 9 %), intermediate risk for C+U score >=2.75 and <=5 (MR: 38 %), and high risk for C+U score >=5.25 (MR: 95 %). Sensitivity and specificity were, respectively, 95 and 60 % for a cut-off value >2.5, and 69 and 96 % for >5. The "CUT" score can be easily applied, aiding clinicians in the evaluation of TN, especially in cases with indeterminate or repeated non-diagnostic FNA. PMID- 26518190 TI - Postprandial hyperglycemia was ameliorated by taking metformin 30 min before a meal than taking metformin with a meal; a randomized, open-label, crossover pilot study. AB - Taking metformin with a meal has been shown to decrease bioavailability of metformin. We hypothesized that taking metformin 30 min before a meal improves glucose metabolism. As an animal model, 18 Zucker-rats were divided into three groups as follows: no medication (Control), metformin (600 mg/kg) with meal (Met), and metformin 10 min before meal (pre-Met). In addition, five diabetic patients were recruited and randomized to take metformin (1000 mg) either 30 min before a meal (pre-Met protocol) or with a meal (Met protocol). In the animal model, the peak glucose level of pre-Met (7.8 +/- 1.5 mmol/L) was lower than that of Control (12.6 +/- 2.5 mmol/L, P = 0.010) or Met (14.1 +/- 2.9 mmol/L, P = 0.020). Although there was no statistical difference among the three groups, total GLP-1 level at t = 0 min of pre-Met (7.4 +/- 2.7 pmol/L) tended to be higher than that of Control (3.7 +/- 2.0 pmol/L, P = 0.030) or Met (3.9 +/- 1.2 pmol/L, P = 0.020). In diabetic patients, the peak glucose level of pre-Met protocol (7.0 +/- 0.4 mmol/L) was lower than that of Met protocol (8.5 +/- 0.9 mmol/L, P = 0.021). Total GLP-1 level at t = 30 min of pre-Met protocol (11.0 +/- 6.1 pmol/L) was higher than that of Met protocol (6.7 +/- 3.9 pmol/L, P = 0.033). Taking metformin 30 min before a meal ameliorated postprandial hyperglycemia. This promises to be a novel approach for postprandial hyperglycemia. PMID- 26518191 TI - The activity of RTA2, a downstream effector of the calcineurin pathway, is required during tunicamycin-induced ER stress response in Candida albicans. AB - In this study, we demonstrate a novel function of a downstream effector molecule of the calcineurin pathway, RTA2 (Resistance To Aminocholesterol), in ER stress response. The deletion of RTA2 increases susceptibility to the ER stressor tunicamycin and morpholine-like drug, 7-aminocholesterol. Additionally, the expression of RTA2 is also transcriptionally induced by ergosterol biosynthesis inhibitors and cell-wall-damaging agents. As tunicamycin induces the unfolded protein response pathway (UPR) via the transcription factor, HAC1, we monitored the expression of a subset of HAC1-dependent UPR target genes in rta2Delta/Delta cells. Upon tunicamycin exposure, rta2Delta/Delta cells displayed a significantly reduced expression of UPR genes, in spite of only a moderate decrease in the HAC1 spliced mRNA levels and no change in Hac1 protein levels. Furthermore, hac1Delta/Deltarta2Delta/Delta cells display an exacerbated sensitivity to tunicamycin compared to the single mutants. We propose that functional RTA2 is requisite for the regulation of Hac1p-dependent UPR target genes to maximal levels, thereby assisting survival during ER stress. Collectively, this study proposes, for the first time, existence of an interplay between the Hac1p- and calcineurin- controlled networks via a downstream effector molecule of the latter, RTA2, to facilitate survival during ER stress in Candida albicans. PMID- 26518193 TI - Involvement of two consecutive vertebral bodies and intervertebral disc space in dorsal spinal hydatid disease. PMID- 26518192 TI - Carnosine and taurine treatments diminished brain oxidative stress and apoptosis in D-galactose aging model. AB - D-galactose (GAL) has been used as an animal model for brain aging and antiaging studies. GAL stimulates oxidative stress in several tissues including brain. Carnosine (CAR; beta-alanil-L-histidine) and taurine (TAU; 2-aminoethanesulfonic acid) exhibit antioxidant properties. CAR and TAU have anti-aging and neuroprotective effects. We investigated the effect of CAR and TAU supplementations on oxidative stress and brain damage in GAL-treated rats. Rats received GAL (300 mg/kg; s.c.; 5 days per week) alone or together with CAR (250 mg/kg/daily; i.p.; 5 days per week) or TAU (2.5% w/w; in rat chow) for 2 months. Brain malondialdehyde (MDA), protein carbonyl (PC) and glutathione (GSH) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione transferase (GST) and acetylcholinesterase (AChE) activities were determined. Expressions of B cell lymphoma-2 (Bcl-2), Bax and caspase-3 were also evaluated in the brains by immunohistochemistry. GAL treatment increased brain MDA and PC levels and AChE activities. It decreased significantly brain GSH levels, SOD and GSH-Px but not GST activities. GAL treatment caused histopathological changes and increased apoptosis. CAR and TAU significantly reduced brain AChE activities, MDA and PC levels and elevated GSH levels in GAL-treated rats. CAR, but not TAU, significantly increased low activities of SOD and GSH-Px. Both CAR and TAU diminished apoptosis and ameliorated histopathological findings in the brain of GAL-treated rats. Our results indicate that CAR and TAU may be effective to prevent the development of oxidative stress, apoptosis and histopathological deterioration in the brain of GAL-treated rats. PMID- 26518194 TI - DICOM Data Warehouse: Part 2. AB - In 2010, the DICOM Data Warehouse (DDW) was launched as a data warehouse for DICOM meta-data. Its chief design goals were to have a flexible database schema that enabled it to index standard patient and study information, modality specific tags (public and private), and create a framework to derive computable information (derived tags) from the former items. Furthermore, it was to map the above information to an internally standard lexicon that enables a non-DICOM savvy programmer to write standard SQL queries and retrieve the equivalent data from a cohort of scanners, regardless of what tag that data element was found in over the changing epochs of DICOM and ensuing migration of elements from private to public tags. After 5 years, the original design has scaled astonishingly well. Very little has changed in the database schema. The knowledge base is now fluent in over 90 device types. Also, additional stored procedures have been written to compute data that is derivable from standard or mapped tags. Finally, an early concern is that the system would not be able to address the variability DICOM-SR objects has been addressed. As of this writing the system is indexing 300 MR, 600 CT, and 2000 other (XA, DR, CR, MG) imaging studies per day. The only remaining issue to be solved is the case for tags that were not prospectively indexed-and indeed, this final challenge may lead to a noSQL, big data, approach in a subsequent version. PMID- 26518195 TI - Obesity, ethnicity, and quality of life among breast cancer survivors and women without breast cancer: the long-term quality of life follow-up study. AB - PURPOSE: The purpose of this study was to examine the relationship between obesity and quality of life (QOL) among Hispanic and non-Hispanic white breast cancer survivors and population-based controls from the 'Long-Term Quality of Life Study'--a 12- to 15-year follow-up study of breast cancer cases/survivors and controls from New Mexico (n = 451). METHODS: Using multiple linear regressions, obesity measures [body mass index (BMI) >= 30 kg/m(2)] at baseline and follow-up interview were modeled with composite scores for physical and mental health from the SF-36 Quality of Life Survey. Interaction between ethnicity and BMI and change in BMI were evaluated. All models were adjusted for age, ethnicity, Charlson Index, depression, fatigue, and physical activity. RESULTS: Baseline obesity (beta = -6.58, p = 0.04) was significantly associated with decreased mental health among survivors, but not among controls. Obesity at baseline and follow-up were significantly associated with decreased physical health among survivors (baseline beta = -10.51, p = 0.004; follow-up beta = 7.16, p = 0.02) and controls (baseline beta = -11.07, p < 0.001; follow-up beta = -5.18, p = 0.04). No significant interactions between ethnicity and BMI were observed. CONCLUSIONS: Our findings provide unique information about a diverse population of breast cancer survivors and controls and the impact of obesity on the mental and physical aspects of QOL. PMID- 26518196 TI - Patterns and correlates of accelerometer-assessed physical activity and sedentary time among colon cancer survivors. AB - BACKGROUND: Understanding of the physical activity and sedentary behavior of cancer survivors is limited by reliance on self-reported data. Here, we report the correlates, and patterns of accumulation, of physical activity (light, and moderate-vigorous; MVPA) and sedentary behavior, in colon cancer survivors, using accelerometer-based assessments. METHODS: Colon cancer survivors from Alberta, Canada (n = 92), and Western Australia (n = 93) (overall response rate = 21 %) wore an Actigraph((r)) GT3X+ accelerometer for seven consecutive days and completed a questionnaire in 2012-2013. Accelerometer data (60 s epochs) were summarized using Freedson activity cutpoints and were adjusted for wear time. Linear regression analyses, conducted 2014-2015, examined correlates for different intensities of activity. RESULTS: Younger age, being employed, higher family income, and lower BMI were significantly correlated with MVPA, while gender, educational attainment, and BMI were correlated with light-intensity physical activity. Gender, comorbidities, and BMI were correlated with sedentary time. MVPA did not vary by day of the week, whereas the remaining time (as a sedentary/light ratio) showed significant variation, with Saturdays being less sedentary than average [corrected]. When considering time of day, we found that evenings were when the likelihood of both MVPA and sedentary time was highest. CONCLUSIONS: The low level of MVPA and high volume of sedentary time demonstrated by these objective data highlight the need for intervention in colon cancer survivors. The correlates and accumulation patterns described by this study may better inform interventions and translational research designed to increase physical activity and reduce sedentary behavior in colon cancer survivors. PMID- 26518197 TI - Vitamin D, PTH, and calcium and tumor aggressiveness in prostate cancer: a prospective nested case-control study. AB - PURPOSE: Epidemiological studies suggest that low levels of vitamin D (25OHD) constitute a risk factor for more aggressive prostate cancer. We examined the relationship between pre-diagnostic serum levels of vitamin D, parathyroid hormone (PTH), and calcium and risk of prostate cancer according to tumor aggressiveness. METHODS: We performed a nested case-control study within the Malmo Diet and Cancer Study on 943 incident prostate cancer cases. Tumor aggressiveness was defined by Gleason score, TNM stage, and serum levels of total prostate-specific antigen. Odds ratios (OR) were calculated for different quartiles of serum levels of 25OHD, PTH, and calcium, and for interactions between them. RESULTS: We found no significant association when comparing aggressive to non-aggressive disease regarding vitamin D, PTH, or calcium. There was a trend toward an increased risk in low-grade tumors, i.e., Gleason score <=6, and a significant association regarding Gleason score 7 tumors with OR 1.70 (1.09-2.65) in the highest quartile of vitamin D. Stratifying the analysis yielded several significant findings demonstrating a nonspecific interaction between the metabolites. In men with PTH above median, the risk of aggressive prostate cancer was double in the highest vitamin D quartile, OR 2.01 (1.24 3.25), and for non-aggressive cancer 1.82 (1.25-2.66). There was an inverse effect on risk of prostate cancer in men with PTH above median and vitamin D <=50 nmol/L, OR 0.25 (0.09-0.71) and calcium <=2.37 mmol/L, OR 0.53 (0.34-0.82) for aggressive cancer. CONCLUSIONS: This study showed no significant association when comparing aggressive to non-aggressive disease. There was a possible relationship between vitamin D and low-risk tumors. There were both positive and negative interactions between PTH, calcium, and vitamin D and risk of prostate cancer. These results were similar for low-risk and aggressive cases. PMID- 26518198 TI - Breast cancer recurrence in relation to antidepressant use. AB - PURPOSE: Women with breast cancer frequently use antidepressants; however, questions about the effect of these medications on breast cancer recurrence remain. METHODS: We identified 4,216 women >=18 years with an incident stage I or II breast cancer diagnosed between 1990 and 2008 in a mixed-model healthcare delivery system linked to a cancer registry. Recurrences were ascertained from chart review. Medication exposures were extracted from electronic pharmacy records. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) to assess the association between antidepressant use and breast cancer recurrence and mortality. We also conducted analyses restricted to tamoxifen users. RESULTS: Antidepressants overall, tricyclic antidepressants, and selective serotonin reuptake inhibitors were not associated with risk of breast cancer recurrence or mortality. Women taking paroxetine only (adjusted HR: 1.66; 95 % CI 1.02, 2.71) and trazodone only (adjusted HR: 1.76; 95 % CI 1.06, 2.92), but not fluoxetine only (adjusted HR: 0.92; 95 % CI 0.55, 1.53), had higher recurrence risks than antidepressant nonusers. There was some suggestion of an increased recurrence risk with concurrent paroxetine and tamoxifen use compared with users of tamoxifen only (adjusted HR: 1.49; 95 % CI 0.79, 2.83). CONCLUSIONS: In general, antidepressants did not appear increase risk of breast cancer recurrence, though there were some suggested increases in risk that warrant further investigation in other datasets. Our results combined systematically and quantitatively with results from other studies may be useful for patients and providers making decisions about antidepressant use after breast cancer diagnosis. PMID- 26518199 TI - Completing a Questionnaire at Home Prior to Needs Assessment in General Practice: A Qualitative Study of Cancer Patients' Experience. AB - BACKGROUND: Systematic assessments of cancer patients' rehabilitation needs are recommended, and questionnaires are considered to be useful tools when making such assessments. OBJECTIVE: The aim of this study was to explore patients' experience of completing a questionnaire about their problems and distress at home prior to a needs assessment in general practice. METHODS: Sixteen patients were recruited by their general practitioners (GPs). Semi-structured interviews were conducted in the home of the participants and at the general practice, with one interview taking place over the phone. Data were analyzed using systematic text condensation. RESULTS: Twelve women and four men aged between 49 and 83 years of age, and diagnosed with various cancers between 1 month and 4 years ago, participated in the study. The results showed how the completion of a questionnaire at home provided patients with an opportunity to reflect on different problems, and the importance of these problems to the patient's everyday life, as well as an opportunity to articulate which problems they wanted to discuss with their GPs. CONCLUSIONS: The results demonstrate that completing a questionnaire seems to stimulate patients' ability to reflect on their situation, clarify the importance of different problems to their everyday lives, and articulate these considerations to their GPs. Furthermore, we have shown that a questionnaire has the ability to interact with the patient and instigate a process of awareness. It is important to acknowledge this process of interaction between patient and questionnaire as an important part of understanding how and why questionnaires may support the patient when completing a questionnaire prior to a clinical encounter. PMID- 26518200 TI - Variation in Treatment Priorities for Chronic Hepatitis C: A Latent Class Analysis. AB - BACKGROUND: Data describing patients' priorities, or main concerns, are essential to inform important decisions in healthcare, including treatment planning, diagnostic testing, and the development of programs to improve access and delivery of care. To date, the majority of studies performed does not account for variability in patients' priorities, and as a consequence may not effectively inform end users. The objective of this study was to examine the value of segmentation analysis as a method to illustrate variability in priorities for treatment of chronic hepatitis C (HCV). METHODS: We elicited patients' main concerns when considering antiviral therapy for HCV using a Best-Worst Scaling experiment (Case 1) with ten objects. Latent class analysis was used to estimate part-worth utilities and the probability that each respondent belongs to each segment. RESULTS: In the aggregate, subjects (N = 162) had three main concerns: (1) not being cured; (2) experiencing a lot of side effects; and (3) developing viral resistance to therapy. Segmentation into two groups demonstrated that both groups prioritized the likelihood of cure and coping with side effects, but that only one group (n = 78) was concerned about developing viral resistance to therapy, while subjects in the second group (n = 84) prioritized being able to keep up with their responsibilities. Further segmentation revealed distinct clusters of patients with unique priorities. CONCLUSIONS: Patients' priorities vary significantly. Preference studies should consider including methods to determine whether distinct clusters of priorities and/or concerns exist in order to accurately inform end users' decision making. PMID- 26518201 TI - Validation of the Chinese Version of the Quality of Recovery-15 Score and Its Comparison with the Post-Operative Quality Recovery Scale. AB - BACKGROUND: The Quality of Recovery-15 scale (QoR-15) is an easy-to-use score for assessing the quality of post-operative recovery. OBJECTIVES: The primary aim of the present study was to translate the QoR-15 into the Chinese language and validate it. The secondary aim was to compare it with the Post-operative Quality Recovery Scale (PQRS). METHODS: The Chinese version of the QoR-15 (QoR-15C) was developed according to the methods adopted by the International Quality of Life Assessment project. A total of 470 patients undergoing surgery and general anesthesia completed the QoR-15C and the PQRS before or on the day of surgery, and on post-operative days (POD)-1, -3, and -30. To validate the QoR-15C, we assessed validity, reliability, responsiveness, and clinical feasibility and compared them with those of the PQRS. RESULTS: Convergent validity showed the Pearson's r coefficient of the QoR-15C with visual analog scale and the PQRS to be 0.63 and 0.10, respectively. Predictive validity showed it had significant correlations with duration of anesthesia, duration of operation, time in post anesthesia care unit, time in intensive care unit, and length of hospital stay. Discriminant validity showed it differed between patients who had a good or poor recovery, and decreased with increasing grades (indicating difficulty and complexity) of surgery. The intraclass correlation coefficient, split-half coefficient, and Cronbach's alpha were 0.99, 0.70, and 0.76, respectively. The standardized effect size ranged from 0.85 to 1.20, and the standardized response mean ranged from 0.93 to 1.27. Compared with the QoR-15C, the PQRS may have inferior convergent validity (0.36 vs. 0.63), and split-half reliability (0.63 vs. 0.70). Furthermore, the PQRS took longer to complete: 4.20 (standard deviation 0.79) versus 1.57 (standard deviation 0.65) min. CONCLUSIONS: Similar to the original English version, the QoR-15C reveals satisfactory psychometric properties. Furthermore, it may be a more valid, reliable, and easy-to-use scale than the PQRS. PMID- 26518202 TI - Feasibility of Using Qualitative Interviews to Explore Patients' Treatment Goals: Experience from Dermatology. AB - INTRODUCTION: Qualitative interviews are used to assess understandability and content validity of patient-reported outcomes. However, the common approach of asking patients to paraphrase items may not be sufficient to completely reveal item content as understood by patients. OBJECTIVE: We used qualitative interviews to elicit more detailed information about patients' understanding of treatment goal items for the Patient Benefit Index 2.0 (PBI 2.0). This questionnaire measures patient-relevant benefit from treatments for skin diseases by assessing goal importance prior to and goal attainment after treatment. METHODS: We interviewed 16 patients with psoriasis, atopic dermatitis, leg ulcers, and vitiligo. Patients were asked to elaborate in detail on their understanding of 15 treatment goal items. Subsequently, they were asked to suggest changes in item wording and to name missing treatment goals. Interview transcripts were analyzed according to an adapted approach of content analysis. RESULTS: The task was easy for the patients to understand, and they shared detailed information on what each goal meant to them. Results of the content analysis induced a range of revisions of the PBI 2.0 items, including changes in wording (four items) and item order (two items). Four items were deleted because they were found to be redundant or irrelevant, and one item was added to the list of treatment goals. CONCLUSIONS: Asking patients to elaborate on their item understanding in qualitative interviews provided detailed insight into item content and understandability. This method has helped considerably to improve feasibility and content validity of the PBI 2.0. PMID- 26518203 TI - Pre-metastatic conditioning of organ microenvironments by tumors: beyond preparing the soil. PMID- 26518204 TI - [Complaints of imbalance in elderly people]. AB - Balance disorders in the elderly often have several contributing causes. The search for these causes focuses on vision, proprioception, coordination and medication. The peripheral vestibular system is often overlooked. This is probably due to the fact that most clinicians overlook the vestibular system, when complaints of vertigo are missing. However, dysfunction of the vestibular system may cause imbalance without vertigo. Three cases are presented. One case illustrates several contributing causes leading to imbalance. Two other cases illustrate causes of vestibular dysfunction resulting in imbalance without vertigo: a bilateral vestibulopathy and benign paroxysmal positional vertigo. Symptoms, examination and treatment are discussed. All patients with imbalance should undergo a Head Impulse Test and Dix-Hallpike maneuver. PMID- 26518205 TI - Feasibility of Automatic Extraction of Electronic Health Data to Evaluate a Status Epilepticus Clinical Protocol. AB - Status epilepticus is a common neurologic emergency in children. Pediatric medical centers often develop protocols to standardize care. Widespread adoption of electronic health records by hospitals affords the opportunity for clinicians to rapidly, and electronically evaluate protocol adherence. We reviewed the clinical data of a small sample of 7 children with status epilepticus, in order to (1) qualitatively determine the feasibility of automated data extraction and (2) demonstrate a timeline-style visualization of each patient's first 24 hours of care. Qualitatively, our observations indicate that most clinical data are well labeled in structured fields within the electronic health record, though some important information, particularly electroencephalography (EEG) data, may require manual abstraction. We conclude that a visualization that clarifies a patient's clinical course can be automatically created using the patient's electronic clinical data, supplemented with some manually abstracted data. Future work could use this timeline to evaluate adherence to status epilepticus clinical protocols. PMID- 26518206 TI - Erratum to: Neighborhood matters: the impact of Hispanic ethnic density on future depressive symptoms 1-year following an ACS event among Hispanic patients. PMID- 26518207 TI - A preliminary investigation into whether early intervention can improve weight loss among those initially non-responsive to an internet-based behavioral program. AB - This study examined whether providing additional support to individuals with poor initial weight loss improves 12-week outcomes. Participants were randomized to a 12-week internet-delivered behavioral weight loss program (IBWL; n = 50) or the identical internet program plus the possibility of extra support (IBWL + ES; n = 50). IBWL + ES participants losing <2.3% at Week 4 (early non-responders; n = 12) received one individual meeting and two follow-up phone calls with an interventionist, and were compared to IBWL 'early non-responders' who did not receive extra support (n = 21), and to 'early responders' in both treatment arms (i.e., 4-week weight loss >=2.3%; n = 59). IBWL + ES early non-responders had greater program adherence (p's < 0.055) and lost twice as much weight (p = 0.036) compared to IBWL early non-responders. Program adherence did not differ between early responders and IBWL + ES early non-responders. However, 12-week weight loss was greater in the early responders compared to both early non-responder groups (p's > 0.05). Providing additional intervention to early non-responders in an Internet program improves treatment outcomes. PMID- 26518208 TI - Temporal bone carcinoma: a first glance beyond the conventional clinical and pathological prognostic factors. AB - Temporal bone squamous cell carcinoma (TBSCC) is an uncommon, aggressive malignancy with a poor prognosis in advanced cases. The dismal outcome is partially related to: the lack of reliable clinical or pathological prognostic factors and the largely unstandardized surgical and integrated treatments adopted. There is an undeniable need for novel diagnostic/therapeutic strategies to improve the prognosis. The purpose of this critical review was to explore the level of available knowledge concerning the molecular markers involved in the biology of TBSCC that have a prognostic potential. The Pub-Med and Scopus electronic databases were searched without publication date limits for studies investigating molecular markers in cohorts of patients with primary TBSCC. The search terms used were: "temporal bone cancer", "temporal bone carcinoma", "temporal bone malignancy", "ear cancer", "ear carcinoma", and "ear malignancy". We decided preliminarily not to consider series with less than five cases. Nine retrospective case series of TBSCC were found in which different analytical techniques had been used to study the role of several biomarkers (HPV, vimentin, transforming growth factor beta, CD105, RECK, matrix metalloproteinase-9, MASPIN, EBV, p16, TP53 mutation, pSTAT3, relaxin-2). CD105 expression (in tumor vessel endothelial cells) and MASPIN cytoplasmic expression (in carcinoma cells) were, respectively, found directly and inversely related with the neoplasm's recurrence rate. CD105 expression was also inversely related with disease-free survival in TBSCC. A future goal of such analyses should be to ascertain the radio- and chemo sensitivity profiles of individual TBSCCs, enabling truly personalized therapies. A further, more ambitious goal will be to find targets for therapeutic agents that might prove crucial in improving the disease-specific survival for patients with advanced TBSCC. PMID- 26518209 TI - Different activations of toll-like receptors and antimicrobial peptides in chronic rhinosinusitis with or without nasal polyposis. AB - Both up- and down-regulation of the Toll-like receptors (TLRs) and antimicrobial peptides (AMPs) of the sinonasal mucosa have already been associated with the pathogenesis of chronic rhinosinusitis with (CRSwNP) or without (CRSsNP) nasal polyps. The objective of this study was to determine the expression of all known TLR and several AMP genes and some selected proteins in association with allergy, asthma and aspirin intolerance (ASA) in CRS subgroups. RT-PCR was applied to measure the mRNA expressions of 10 TLRs, four defensins, lysozyme, cathelicidin and lactoferrin (LTF) in sinonasal samples from patients with CRSsNP (n = 19), CRSwNP [ASA(-): 17; ASA(+): 7] and in control subjects (n = 12). Protein expressions were detected with immunohistochemistry (n = 10). Statistical analysis was done with the Kruskal-Wallis ANOVA, Mann-Whitney U, and Student t test. TLR2, TLR5, TLR6, TLR7, TLR8, TLR9, beta-defensins 1 and 4, cathelicidin and LTF mRNA expressions were significantly (p < 0.05) increased in CRSwNP, whereas only TLR2 and LTF were up-regulated in CRSsNP compared to controls. There was no statistical difference in respect of allergy, aspirin intolerance and smoking between CRSsNP, ASA(-) and ASA(+) CRSwNP patients. TLR2, TLR3, TLR4, LTF, beta defensin 2 and lysozyme protein expressions were found to be elevated in macrophages of CRSwNP samples (p < 0.05). Gene expression analysis showed markedly different expressions in CRSwNP (6 out of 10 TLR and 4 out of 7 AMP genes were up-regulated) compared to CRSsNP (1/10, 1/7). The distinct activation of the innate immunity may support the concept that CRSsNP and CRSwNP are different subtypes of CRS. These findings were found to be independent from allergy, asthma, smoking, aspirin intolerance and systemic steroid application. PMID- 26518210 TI - The nature of working memory gating in Parkinson's disease: A multi-domain signal detection examination. AB - Distractions are ubiquitous; our brains are inundated with task-irrelevant information. Thus, to remember successfully, one must actively maintain relevant information and prevent distraction from entering working memory. Researchers suggest the basal ganglia-prefrontal pathways are vital to this process by acting as a working memory gate. Using Parkinson's disease as a model of frontostriatal functioning and with signal detection analyses, the present study aims to better characterize the contribution of frontostriatal pathways of this gating process and to determine how it operates across multiple domains. To achieve this, Parkinson's disease patients and healthy controls completed verbal and spatial working memory tasks consisting of three conditions: low-load without distraction; low-load with distraction; and high-load without distraction. Patients were tested both ON and OFF dopaminergic medication, allowing for assessment of the contribution of dorsal and ventral frontostriatal pathways. The results demonstrate that when medication is withheld, Parkinson's patients have a response bias to answer "NO" across all conditions and domains, supporting our hypothesis that the basal ganglia-prefrontal pathways allow or prevent updates of working memory. Contrastingly, medication status affects d' in the distraction condition but not in the high- or low-load conditions. We attribute this to stimulus valuation processes that were impaired by dopaminergic medication overdosing the ventral pathway. These findings are both consistent with the hypothesis that the working memory gate filters spatial and verbal information before it enters into the working memory system, adding support for the gate being a domain-general mechanism of the central executive. PMID- 26518211 TI - Phase 3 trial of three thalidomide-containing regimens in patients with newly diagnosed multiple myeloma not transplant-eligible. AB - The introduction of agents such as thalidomide, lenalidomide, and bortezomib has changed the management of patients with multiple myeloma who are not eligible for autologous transplantation, many of whom are elderly. We sought to compare three thalidomide-based oral regimens among such patients in Latin America. We randomized patients with newly diagnosed multiple myeloma with measurable disease to one of the following regimens: melphalan, prednisone, and thalidomide (MPT); cyclophosphamide, thalidomide, and dexamethasone (CTD); and thalidomide and dexamethasone (TD). The TD arm was closed prematurely and was analyzed only descriptively. The primary endpoint was the overall response rate (ORR), whereas progression-free survival (PFS) and overall survival (OS) were secondary endpoints. The accrual rate was slower than expected, and the study was terminated after 82 patients had been randomized. The ORRs were 67.9 % with MPT, 89.7 % with CTD, and 68.7 % with TD (p = 0.056 for the comparison between MPT and CTD). The median PFS was 24.1 months for MPT, 25.9 months for CTD, and 21.5 months for TD. There were no statistically significant differences in PFS or OS between MPT and CTD. In an unplanned logistic regression analysis, ORR was significantly associated with treatment with CTD (p = 0.046) and with performance status of 0 or 1 (p = 0.035). Based on the current results, no definitive recommendations can be made regarding the comparative merit of the regimens tested. Nevertheless and until the results of further studies become available, we recommend either CTD or MPT as suitable frontline regimens for patients with multiple myeloma who are not candidates to transplantation in settings where lenalidomide and bortezomib are not available. PMID- 26518212 TI - The Maize PI/GLO Ortholog Zmm16/sterile tassel silky ear1 Interacts with the Zygomorphy and Sex Determination Pathways in Flower Development. AB - In monocots and eudicots, B class function specifies second and third whorl floral organ identity as described in the classic ABCE model. Grass B class APETALA3/DEFICIENS orthologs have been functionally characterized; here, we describe the positional cloning and characterization of a maize (Zea mays) PISTILLATA/GLOBOSA ortholog Zea mays mads16 (Zmm16)/sterile tassel silky ear1 (sts1). We show that, similar to many eudicots, all the maize B class proteins bind DNA as obligate heterodimers and positively regulate their own expression. However, sts1 mutants have novel phenotypes that provide insight into two derived aspects of maize flower development: carpel abortion and floral asymmetry. Specifically, we show that carpel abortion acts downstream of organ identity and requires the growth-promoting factor grassy tillers1 and that the maize B class genes are expressed asymmetrically, likely in response to zygomorphy of grass floral primordia. Further investigation reveals that floral phyllotactic patterning is also zygomorphic, suggesting significant mechanistic differences with the well-characterized models of floral polarity. These unexpected results show that despite extensive study of B class gene functions in diverse flowering plants, novel insights can be gained from careful investigation of homeotic mutants outside the core eudicot model species. PMID- 26518213 TI - Sleep-dependent memory consolidation and its implications for psychiatry. AB - Both sleep disturbance and memory impairment are very common in psychiatric disorders. Since sleep has been shown to play a role in the process of transferring newly acquired information into long-term memory, i.e., consolidation, it is important to highlight this link in the context of psychiatric disorders. Along these lines, after providing a brief overview of healthy human sleep, current neurobiological models on sleep-dependent memory consolidation and resultant opportunities to manipulate the memory consolidation process, recent findings on sleep disturbances and sleep-dependent memory consolidation in patients with insomnia, major depression, schizophrenia, and post-traumatic stress disorder are systematically reviewed. Furthermore, possible underlying neuropathologies and their implications on therapeutic strategies are discussed. This review aims at sensitizing the reader for recognizing sleep disturbances as a potential contributor to cognitive deficits in several disorders, a fact which is often overlooked up to date. PMID- 26518214 TI - Variability and anatomical specificity of the orbitofrontothalamic fibers of passage in the ventral capsule/ventral striatum (VC/VS): precision care for patient-specific tractography-guided targeting of deep brain stimulation (DBS) in obsessive compulsive disorder (OCD). AB - Deep Brain Stimulation (DBS) is a neurosurgical procedure that can reduce symptoms in medically intractable obsessive-compulsive disorder (OCD). Conceptually, DBS of the ventral capsule/ventral striatum (VC/VS) region targets reciprocal excitatory connections between the orbitofrontal cortex (OFC) and thalamus, decreasing abnormal reverberant activity within the OFC-caudate pallidal-thalamic circuit. In this study, we investigated these connections using diffusion magnetic resonance imaging (dMRI) on human connectome datasets of twenty-nine healthy young-adult volunteers with two-tensor unscented Kalman filter based tractography. We studied the morphology of the lateral and medial orbitofrontothalamic connections and estimated their topographic variability within the VC/VS region. Our results showed that the morphology of the individual orbitofrontothalamic fibers of passage in the VC/VS region is complex and inter individual variability in their topography is high. We applied this method to an example OCD patient case who underwent DBS surgery, formulating an initial proof of concept for a tractography-guided patient-specific approach in DBS for medically intractable OCD. This may improve on current surgical practice, which involves implanting all patients at identical stereotactic coordinates within the VC/VS region. PMID- 26518215 TI - Root Canal Morphology and Configuration of 179 Maxillary First Molars by Means of Micro-computed Tomography: An Ex Vivo Study. AB - INTRODUCTION: The objective of this study was to propose a root canal configuration description method and to investigate the root canal system morphology of the maxillary first molar by means of micro-computed tomographic imaging. METHODS: The root canal configuration, foramina, and accessory canal frequency of 179 maxillary first molars were investigated by means of micro computed tomographic imaging and 3-dimensional software imaging. The root canal configuration and main foramina number are described from coronal to apical with a 4-digit system. RESULTS: The most frequent root canal configurations were 1-1 1/1 (45.8%), 2-2-2/2 (25.1%) and 2-2-1/1 (10.1%) in mesiobuccal roots and 1-1-1/1 in distobuccal (97.2%) and palatal (98.9%) roots. The first mesiobuccal (MB1) root canal had 1 accessory canal in 26.3% of the teeth, the distobuccal root canal had 12.3%, and the palatal root canal had 9.5%; in the second mesiobuccal root canal, there was rarely 1 accessory canal. There was 1 accessory canal in 26.3%, 12.3%, and 9.5% in the MB1, distobuccal, and palatal root canals, respectively. The MB1, distobuccal, and palatal root canals had 1 main foramen. The MB2 had 1 main foramen in 39.0% of the teeth and no main foramen in 61.0%. CONCLUSIONS: The root canal configuration of maxillary first molars is quite diversified. Contrary to our expectations in this research, the mesiobuccal root has predominantly 1 root canal entrance and only 1 main foramen. Anatomic variations including connecting and accessory canals occur in any third of root. PMID- 26518216 TI - Effect of Root Filling on Stress Distribution in Premolars with Endodontic Periodontal Lesion: A Finite Elemental Analysis Study. AB - INTRODUCTION: Endodontic-periodontal (EP) lesions require both endodontic and periodontal therapies. Impermeable sealing of the root canal system after cleaning and shaping is essential for a successful endodontic treatment. However, complete healing of the hard and soft tissue lesions takes time, and diseased bone, periodontal ligament, and tooth fibrous joints are reported to have an increased failure risk for a given load. Considering that EP lesions may affect the biomechanics of teeth, this finite elemental analysis study aimed to test the effect of root fillings on stress distribution in premolars with EP lesions. METHODS: Three finite elemental analysis models representing 3 different types of EP lesions (primary endodontic disease [PED], PED with secondary periodontic involvement, and true combined) were created. The root canals were assumed as nonfilled or filled with gutta-percha, gutta-percha/apical mineral trioxide aggregate (MTA) plug, and MTA-based sealer. Materials used were assumed to be homogenous and isotropic. A 300-N load was applied from the buccal cusp of the crown with a 135 degrees angle. The Cosmoworks structural-analysis program (SolidWorks Corp, Waltham, MA) was used for analysis. Results were presented considering von Mises criteria. RESULTS: Stresses at the root apex increased with an increase in lesion dimensions. Root filling did not affect stress distribution in the PED model. An MTA plug or MTA-based sealer created more stress areas within the root compared with the others in the models representing PED with periodontic involvement and true combined lesions. CONCLUSIONS: Stresses at the apical end of the root increase with increases in lesion dimensions. MTA-based sealers or an MTA plug creates more stresses when there is periodontic involvement or a true combined lesion. PMID- 26518217 TI - Addition of a Fluoride-containing Radiopacifier Improves Micromechanical and Biological Characteristics of Modified Calcium Silicate Cements. AB - INTRODUCTION: Calcium silicate cements (CSCs) with the addition of nanohydroxyapatite and calcium carbonate play a critical role in dental applications. To further improve their properties, particularly radiopacity and biointeractivity, the fluoride-containing radiopacifier ytterbium trifluoride (YbF3) was added to their composition, and biological and mechanical characteristics were evaluated. METHODS: YbF3 was added to 3 different CSCs: cement I (CSC + calcium carbonate), cement II (CSC + nanohydroxyapatite), and Portland cement. Material characterization encompassed measurements of pH, calcium, ytterbium, and fluoride ion release; radiopacity; setting time; porosity; microindentation properties; wettability; and Fourier transform infrared spectroscopic, x-ray diffraction, and scanning electron microscopic analyses. Osteoblast- and osteoclast-like cells were grown on the materials' surface to evaluate their adherence. RESULTS: The addition of calcium carbonate, nanohydroxyapatite, and 30 wt% of YbF3 improved radiopacity and the setting time of experimental cements. The pH values did not differ among the groups. The greatest ytterbium and fluoride releases occurred in the Portland cement + YbF3 group. Combined x-ray diffraction and Fourier transform infrared spectroscopic analysis showed the presence of calcium hydroxide and calcium silicate hydrates. In addition, the presence of calcium ytterbium fluoride and ytterbium oxide proved that YbF3 reacted with cement compounds. Wettability of cement I + YbF3 was superior to other formulations, but its porosity and microindentation properties were weaker than in the Portland cement + YbF3 mixture. Cement II + YbF3 presented micromechanical indentation and porosity characteristics similar to the Portland-based cement formulation. Osteoclast- and osteoblast-like cells adhered to the cements' surfaces without alteration of the cell structural integrity. CONCLUSIONS: YbF3-containing CSCs with nanostructured hydroxyapatite and calcium carbonate are well suited for dental application. PMID- 26518218 TI - Preparedness, Evaluation, and Care of Pediatric Patients Under Investigation for Ebola Virus Disease: Experience from a Pediatric Designated Care Facility. PMID- 26518219 TI - Pleural effusion caused by a malpositioned umbilical venous catheter in a neonate. AB - Umbilical venous catheterisation (UVC) insertion is a common procedure performed in most neonatal units. We report a case of a neonate who developed pleural and pericardial effusions and ascites due to a malpositioned UVC causing diaphragmatic perforation. Timely diagnosis using bedside sonography and prompt removal of the catheter resulted in resolution of the effusions without undue complications. PMID- 26518220 TI - An alien in the group: eusocial male bees sharing nonspecific reproductive aggregations. AB - Sexual selection predicts that individuals competing for access to sexual partners should maximize their chances of mating by looking for sites where the chances of finding partners are more likely to occur. However, males of stingless bees have been observed sharing nonspecific reproductive aggregations. This uncommon behavior appears to confer no obvious increase of individual fitness. It has been suggested that this reproductive strategy is due to the similarity between male odors common to different stingless bee species. Cuticular hydrocarbons (CHCs) are candidate odors of interest because their nonvolatile pheromone nature allows them to play an important role in sexual behavior and species recognition. Here, we review the literature to evaluate whether any phylogenetic patterns exist among male stingless bees that aggregate with closely or distantly related species. We also compared the CHC profiles of males of Neotropical stingless bee species (Plebeia sp. Schwarz, Trigona spinipes (F.), Tetragona clavipes (F.), Nannotrigona testaceicornis (Lepeletier), Scaptotrigona aff. depilis (Moure), Tetragonisca angustula (Latreille), and Melipona subnitida (Ducke) to reveal any chemical similarities among their male odors. We found males of 21 stingless bee species involved in interspecific interactions mainly from Neotropical and Indo-Malayan/Australasian regions. Alien males did not necessarily visit host aggregations of closely related species. Furthermore, the CHC profiles of different studied species were very distinct from each other and do not overlapped at all. It is unclear yet why this apparently nonadaptive behavior carried out by some stingless bee males. PMID- 26518221 TI - Epidemiology and Healthcare Resource Utilization Associated With Children With Short Bowel Syndrome in the United States. AB - BACKGROUND: There is a lack of large database research relating to the epidemiology and health resource utilization associated with short bowel syndrome (SBS) in the United States. METHODS: We analyzed the Kids' Inpatient Database for the year 2012 and utilized International Classification of Diseases, Ninth Revision, and Clinical Modification ( ICD-9-CM) diagnosis codes to identify patients 0-3 years of age with SBS, who were matched by age and sex to children without SBS. The study variables included patient and hospital demographics, All Patient Refined Diagnosis Related Groups, in-hospital mortality, hospital length of stay, and hospitalization costs. We also determined the most frequent ICD-9-CM diagnostic and procedural codes associated with SBS. RESULTS: Children with SBS demonstrated a higher rate of mortality than that of children without SBS (1.6% vs 0.7%; P < .001). Children with SBS also experienced a longer length of stay (median days [interquartile range]: 8 [15] vs 2 [3]; P < .001) and higher hospital costs ($17,000 [$34,000] vs $3000 [$5000]; P < .001). The most frequent medical diagnoses associated with SBS were infection (62%), anemia (29%), and liver disease (17%). Children with SBS also demonstrated more severe illness as assessed by an All Patient Refined Diagnosis Related Group score of 3 or 4 (94.30% vs 16.20%; P < .001). CONCLUSIONS: Children hospitalized with SBS have a high severity of illness and experience complicated inpatient courses related to their disease. Our study represents the first use of national U.S. data to study the epidemiology and health resource utilization associated with SBS. PMID- 26518222 TI - Sex differences in the photoperiodic regulation of RF-Amide related peptide (RFRP) and its receptor GPR147 in the syrian hamster. AB - RF-(Arg-Phe) related peptides (RFRP-1 and -3) are considered to play a role in the seasonal regulation of reproduction; however, the effect of the peptides depends on species and gender. This study aimed at comparing the RFRP system in male and female Syrian hamsters over long and short photoperiods to investigate the neuroanatomical basis of these differential effects. The neuroanatomical distribution of RFRP neurons and fibers, revealed using an antiserum recognizing RFRP-1 and -3, as well as GPR147 mRNA, are similar in male and female Syrian hamsters. RFRP neurons are mainly found in the medial hypothalamus, whereas RFRP projections and GPR147 mRNA are observed in the preoptic area, anteroventral periventricular nucleus, suprachiasmatic nucleus, paraventricular nucleus, bed nucleus of the stria terminalis, ventromedial hypothalamus, habenular nucleus, and arcuate nucleus. The number of RFRP neurons is higher in females than in males, and in both sexes, the number of RFRP neurons is reduced in short photoperiods. GPR147 mRNA levels are higher in females than in males and are downregulated in short photoperiods, particularly in females. Interestingly, the number of RFRP-positive fibers in the anteroventral-periventricular nucleus is higher only in females adjusted to a short photoperiod. Our results suggest that the RFRP system, which is strongly regulated by photoperiod in both male and female Syrian hamsters, is particularly important in females, with a distinct role in the anteroventral-periventricular nucleus, possibly in the regulation of the preovulatory luteinizing hormone surge via kisspeptin neurons. PMID- 26518223 TI - Nivolumab plus ipilimumab in the treatment of advanced melanoma. AB - Advanced melanoma has historically been a difficult disease to treat due to few effective systemic treatment options. However, over the past few years, scientific advancements in immune checkpoint inhibition have resulted in several novel approaches that have changed front-line management of advanced melanoma. Despite these exciting developments, there remains room for improvement in treatment outcomes. Combination immunotherapy, in particular combined cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) blockade, represents an important first step in this direction. PMID- 26518224 TI - Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. AB - BACKGROUND AND PURPOSE: Vitamin D status has been associated with inflammatory activity in multiple sclerosis (MS), but it is not known if it is associated with gray matter volume, the loss of which predicts long-term disability in MS. The association of vitamin D levels with brain volume measures and inflammatory activity in patients with clinically isolated syndrome (CIS) was investigated. METHODS: In the phase 2 CIS trial of atorvastatin, 25-hydroxyvitamin D levels were evaluated for their age-adjusted associations with normalized gray matter and brain parenchymal volumes on brain magnetic resonance imaging (MRI). The relationships between 25-hydroxyvitamin D levels and clinical and MRI measures of inflammatory activity were also assessed. RESULTS: In 65 patients in this substudy, each 25 nmol/l higher 25-hydroxyvitamin D level was associated with 7.8 ml higher gray matter volume (95% confidence interval 1.0, 14.6, P = 0.025). There was a tendency for an inverse association of average 25-hydroxyvitamin D levels and the composite end-point of >=3 new brain T2 lesions or >=1 relapse within a year (odds ratio per 25 nmol/l higher 25-hydroxyvitamin D level 0.66, 95% confidence interval 0.41, 1.08, P = 0.096). CONCLUSIONS: Vitamin D status may impact neurodegeneration after CIS, although these results should be replicated in a second study. If confirmed in clinical trials, vitamin D supplementation may reduce long-term disability. PMID- 26518225 TI - A clinical communication tool for the assessment of psychotropic medication side effects. AB - The primary aim was to assess usability of the My Medicines and Me Questionnaire (M3Q) as a self-reported questionnaire for mental health patients to subjectively express side effects experienced with their psychotropic medications. The secondary aim was to evaluate patients' attitudes towards treatment and psychotropic medications following dialogue with their clinicians about side effects. Questionnaires were administered at six adult mental health facilities. A total of 205 participants were divided into intervention (facilitated dialogue) and non-intervention groups (no facilitated dialogue). The mean completion time for the M3Q was 15min (SD=6.5) with only 11 (5%) patients requiring assistance. The most commonly reported side effect was sedation (77%) and weight gain was ranked as the most bothersome (23%). The previously validated M3Q provided patients with the opportunity to express the impact these effects had on their lives. Side effects were the most common reason given for non-adherence. There were no significant changes in patient attitudes towards treatment and medications in the intervention group, mainly due to the logistical challenges in the clinicians' ability to view the questionnaire for the subsequent meeting with the patient. The M3Q demonstrated its usability in allowing patients to easily express their subjective experiences with side effects. PMID- 26518226 TI - Social factors ameliorate psychiatric disorders in community-based asylum seekers independent of visa status. AB - The impact of industrialised host nations' deterrent immigration policies on the mental health of forced migrants has not been well characterised. The present study investigated the impact of Australia's refugee determination process (RDP) on psychiatric morbidity in community-based asylum-seekers (AS) and refugees. Psychiatric morbidity was predicted to be greater in AS than refugees, and to persist or increase as a function of time in the RDP. The effect on mental health of demographic and socio-political factors such as health cover and work rights were also investigated. Psychiatric morbidity was measured prospectively on five mental health indices at baseline (T1, n=131) and an average of 15.7 months later (T2, n=56). Psychiatric morbidity in AS significantly decreased between time points such that it was no longer greater than that of refugees at T2. Caseness of PTSD and demoralisation reduced in AS who gained protection; however, those who maintained asylum-seeker status at T2 also had a significant reduction in PTS and depression symptom severity. Reduced PTS and demoralisation symptoms were associated with securing work rights and health cover. Living in the community with work rights and access to health cover significantly improves psychiatric symptoms in forced migrants irrespective of their protection status. PMID- 26518227 TI - Feasibility of an inpatient exercise intervention for children undergoing hematopoietic stem cell transplant. AB - With improving survival rates following HSCT in children, QOL and management of short- and long-term effects need to be considered. Exercise may help mitigate fatigue and declines in fitness and strength. The aims of this study were to assess the feasibility of an inpatient exercise intervention for children undergoing HSCT and observe the changes in physical and psychological health. Fourteen patients were recruited, mean age 10 yr. A 6MWT, isometric upper and lower body strength, balance, fatigue, and QOL were assessed prior to Tx and six wk post-Tx. A supervised exercise program was offered five days per week during the inpatient period and feasibility assessed through uptake rate. The study had 100% program completion and 60% uptake rate of exercise sessions. The mean (+/- s.d.) weekly activity was 117.5 (+/- 79.3) minutes. Younger children performed significantly more minutes of exercise than adolescents. At reassessment, strength and fatigue were stabilized while aerobic fitness and balance decreased. QOL revealed a non-statistical trend towards improvement. No exercise-related adverse events were reported. A supervised inpatient exercise program is safe and feasible, with potential physiological and psychosocial benefits. PMID- 26518228 TI - Identification of a lead like inhibitor of the hepatitis C virus non-structural NS2 autoprotease. AB - Hepatitis C virus (HCV) non-structural protein 2 (NS2) encodes an autoprotease activity that is essential for virus replication and thus represents an attractive anti-viral target. Recently, we demonstrated that a series of epoxide based compounds, previously identified as potent inhibitors of the clotting factor, FXIII, also inhibited NS2-mediated proteolysis in vitro and possessed anti-viral activity in cell culture models. This suggested that a selective small molecule inhibitor of the NS2 autoprotease represents a viable prospect. In this independent study, we applied a structure-guided virtual high-throughput screening approach in order to identify a lead-like small molecule inhibitor of the NS2 autoprotease. This screen identified a molecule that was able to inhibit both NS2-mediated proteolysis in vitro and NS2-dependent genome replication in a cell-based assay. A subsequent preliminary structure-activity relationship (SAR) analysis shed light on the nature of the active pharmacophore in this compound and may inform further development into a more potent inhibitor of NS2 mediated proteolysis. PMID- 26518229 TI - Historical inability to control Aedes aegypti as a main contributor of fast dispersal of chikungunya outbreaks in Latin America. AB - The arrival of chikungunya fever (CHIKF) in Latin American countries has been expected to trigger epidemics and challenge health systems. Historically considered as dengue-endemic countries, abundant Aedes aegypti populations make this region highly vulnerable to chikungunya virus (CHIKV) circulation. This review describes the current dengue and CHIKF epidemiological situations, as well as the role of uncontrolled Ae. aegypti and Aedes albopictus vectors in spreading the emerging CHIKV. Comments are included relating to the vector competence of both species and failures of surveillance and vector control measures. Dengue endemicity is a reflection of these abundant and persistent Aedes populations that are now spreading CHIKV in the Americas. This article forms part of a symposium in Antiviral Research on "Chikungunya discovers the New World." PMID- 26518230 TI - ELISA Detection of Phenazepam, Etizolam, Pyrazolam, Flubromazepam, Diclazepam and Delorazepam in Blood Using Immunalysis(r) Benzodiazepine Kit. AB - Phenazepam and etizolam were the first uncontrolled benzodiazepines available for sale in the UK. Pyrazolam, flubromazepam and diclazepam are not used medicinally anywhere in the world; they are produced exclusively for the uncontrolled, recreational market. It is important to know whether potentially abused drugs like these can be detected in routine toxicological screening tests. The purpose of this study was to evaluate whether the Immunalysis(r) Benzodiazepines ELISA kit could detect phenazepam, etizolam, pyrazolam, flubromazepam, diclazepam and its metabolite delorazepam. Their cross-reactivity was assessed by comparing the absorbance of the drug with that of oxazepam, the reference standard. This study found that these uncontrolled benzodiazepines cross-react sufficiently to produce a positive result with the Immunalysis(r) Benzodiazepine ELISA kit. Cross reactivity ranged from 79 to 107% for phenazepam, etizolam, pyrazolam, flubromazepam, diclazepam and delorazepam fortified into blood. The results show that it is possible to detect these newer benzodiazepines with traditional forensic toxicology laboratory tools and it is important to include these benzodiazepines in the confirmation tests. PMID- 26518231 TI - Neuronal chromatolysis in the subgemmal plexus of gustatory papillae in horses with grass sickness. AB - REASONS FOR PERFORMING STUDY: Diagnosis of equine grass sickness (EGS) can be challenging. We hypothesised that subgemmal plexus neurons are chromatolytic in EGS. If correct, histopathological examination of gustatory papillae biopsies could aid premortem diagnosis of EGS, and EGS could represent a spontaneous model of subgemmal neuronal chromatolysis to facilitate study of the pathology of structures involved in taste. OBJECTIVE: To compare subgemmal plexi and gustatory papillae in EGS and control horses. STUDY DESIGN: Observational study. METHODS: Conventional histology and immunohistochemistry were used to compare subgemmal plexi and gustatory papillae in post mortem samples from 10 EGS and 13 control horses. RESULTS: Chromatolytic neurons were present in all 57 EGS sections which had identifiable neurons, and in only one of 57 control sections. Blinded examination of all haematoxylin-eosin stained sections from each horse for chromatolysis facilitated accurate differentiation of EGS and control horses, with a sensitivity of 100% (95% confidence interval 93.7-100) and specificity of 98.2% (90.6-100) for diagnosing EGS; however, the presence of chromatolytic neurons in one control section indicated that multiple sections per horse must be analysed to achieve diagnostic accuracy. Equine grass sickness was not associated with alterations in taste bud density or morphology, proportion of taste buds with neurofilament immunopositive intragemmal axons or proportion of taste buds containing cells undergoing apoptosis, suggesting taste buds had adequate neurotrophic support at the time of sampling. Horses with EGS had no detectable alteration in lingual gland morphology, but had increased proportions of apoptotic lingual serous gland cells. CONCLUSIONS: While identification of chromatolytic subgemmal neurons in post mortem samples correctly differentiated EGS and control horses, further study is required to evaluate this technique for premortem EGS diagnosis. Equine grass sickness represents a spontaneous model of subgemmal neuronal chromatolysis that facilitates study of the pathology of structures involved in taste. PMID- 26518234 TI - Characterization of Escherichia coli bloodstream isolates associated with mortality. AB - Extra-intestinal pathogenic Escherichia coli (ExPEC) are the predominant cause of Gramnegative bloodstream infections. In this study, 20 E. coli isolates that were the causative agents of bacteraemia and subsequent mortality were characterized. Whole-genome sequencing was used to define the predominant sequence types (ST) among the isolates and to identify virulence factors associated with pathogenicity of ExPEC. The ability of the isolates to resist killing by both serum and polymorphonuclear leukocytes (PMNLs) was also assessed. In line with global trends, ST131 occurred most frequently among the bloodstream isolates and all isolates of this sequence type were multidrug resistant. Other common STs included ST73 and ST69. All isolates encoded multiple virulence factors across a range of categories, including factors involved in adhesion, immune evasion, iron acquisition and synthesis of toxins. None of these factors could be associated with serum and neutrophil resistance. The majority of isolates were resistant to the bactericidal action of serum and PMNLs, and most of those that were sensitive were isolated from patients with compromised immunity. PMID- 26518233 TI - Intake of macro- and micronutrients in Danish vegans. AB - BACKGROUND: Since information about macro- and micronutrient intake among vegans is limited we aimed to determine and evaluate their dietary and supplementary intake. METHODS: Seventy 18-61 years old Danish vegans completed a four-day weighed food record from which their daily intake of macro- and micronutrients was assessed and subsequently compared to an age-range-matched group of 1,257 omnivorous individuals from the general Danish population. Moreover, the vegan dietary and supplementary intake was compared to the 2012 Nordic Nutrition Recommendations (NNR). RESULTS: Dietary intake differed significantly between vegans and the general Danish population in all measured macro- and micronutrients (p < 0.05), except for energy intake among women and intake of carbohydrates among men. For vegans the intake of macro- and micronutrients (including supplements) did not reach the NNR for protein, vitamin D, iodine and selenium. Among vegan women vitamin A intake also failed to reach the recommendations. With reference to the NNR, the dietary content of added sugar, sodium and fatty acids, including the ratio of PUFA to SFA, was more favorable among vegans. CONCLUSIONS: At the macronutrient level, the diet of Danish vegans is in better accordance with the NNR than the diet of the general Danish population. At the micronutrient level, considering both diet and supplements, the vegan diet falls short in certain nutrients, suggesting a need for greater attention toward ensuring recommended daily intake of specific vitamins and minerals. PMID- 26518232 TI - The epigenetic processes of meiosis in male mice are broadly affected by the widely used herbicide atrazine. AB - BACKGROUND: Environmental factors such as pesticides can cause phenotypic changes in various organisms, including mammals. We studied the effects of the widely used herbicide atrazine (ATZ) on meiosis, a key step of gametogenesis, in male mice. METHODS: Gene expression pattern was analysed by Gene-Chip array. Genome wide mapping of H3K4me3 marks distribution was done by ChIP-sequencing of testis tissue using Illumina technologies. RT-qPCR was used to validate differentially expressed genes or differential peaks. RESULTS: We demonstrate that exposure to ATZ reduces testosterone levels and the number of spermatozoa in the epididymis and delays meiosis. Using Gene-Chip and ChIP-Seq analysis of H3K4me3 marks, we found that a broad range of cellular functions, including GTPase activity, mitochondrial function and steroid-hormone metabolism, are affected by ATZ. Furthermore, treated mice display enriched histone H3K4me3 marks in regions of strong recombination (double-strand break sites), within very large genes and reduced marks in the pseudoautosomal region of X chromosome. CONCLUSIONS: Our data demonstrate that atrazine exposure interferes with normal meiosis, which affects spermatozoa production. PMID- 26518235 TI - Relationship between body mass index and mean arterial pressure in normotensive and chronic hypertensive pregnant women: a prospective, longitudinal study. AB - BACKGROUND: Being overweight is associated with both higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) during pregnancy and increased risk of gestational hypertensive disorders. The objective of this study was to determine and quantify the effect of body mass index (BMI) on mean arterial pressure (MAP) at several time points throughout pregnancy in normotensive (NT) and chronic hypertensive pregnant (HT) women. METHODS: A prospective longitudinal study was carried out in 461 singleton pregnancies (429 low-risk and 32 with chronic arterial hypertension), with measurements taken at the 1(st), 2(nd), and 3(rd) trimesters and at delivery. Linear mixed-effects regression models were used to evaluate the time-progression of BMI, SBP, DBP and MAP during pregnancy (NT vs. HT). The longitudinal effect of BMI on MAP, adjusted for the hypertensive status, was investigated by the same methodology. RESULTS: BMI consistently increased with time in both NT and HT women. In contrast, MAP decreased during the first half of pregnancy, after which it increased until the moment of delivery in both groups. A 5-unit increase in BMI was predicted to produce an increase of approximately 1 mmHg in population MAP values. This effect is independent from the time period and from hypertensive status. CONCLUSIONS: In both NT and HT pregnant women, MAP is strongly (and significantly) influenced by increases in BMI. PMID- 26518236 TI - Primary cutaneous plasmacytoma in an HIV-positive patient. PMID- 26518237 TI - A Model to Study the Phenotypic Changes of Insect Cell Transfection by Copepod Super Green Fluorescent Protein (cop-GFP) in Baculovirus Expression System. AB - BACKGROUND: Baculovirus expression system is one of the most attractive and powerful eukaryotic expression systems for the production of recombinant proteins. The presence of a biomarker is required to monitor transfection efficiency or protein expression levels in insect cells. METHODS: The aim of this study was to construct a baculovirus expression vector encoding a copepod super green fluorescent protein (copGFP). In this light, the resultant vector was constructed and used for transfection of Spodoptera frugiperda cells. RESULTS: Expression of the copGFP protein in insect cells was confirmed by fluorescent microscopy and Western-blot analysis. CONCLUSION: The application of copGFP control bacmid can be considered as an appropriate control for insect cell transfection. PMID- 26518238 TI - New Government Accountability Office Report on Regenerative Medicine Provides an Excellent Assessment of the Field. PMID- 26518239 TI - Chronic High-Fat Feeding Affects the Mesenchymal Cell Population Expanded From Adipose Tissue but Not Cardiac Atria. AB - Mesenchymal stem cells offer a promising approach to the treatment of myocardial infarction and prevention of heart failure. However, in the clinic, cells will be isolated from patients who may be suffering from comorbidities such as obesity and diabetes, which are known to adversely affect progenitor cells. Here we determined the effect of a high-fat diet (HFD) on mesenchymal stem cells from cardiac and adipose tissues. Mice were fed a HFD for 4 months, after which cardiosphere-derived cells (CDCs) were cultured from atrial tissue and adipose derived mesenchymal cells (ADMSCs) were isolated from epididymal fat depots. HFD raised body weight, fasted plasma glucose, lactate, and insulin. Ventricle and liver tissue of HFD-fed mice showed protein changes associated with an early type 2 diabetic phenotype. At early passages, more ADMSCs were obtained from HFD-fed mice than from chow-fed mice, whereas CDC number was not affected by HFD. Migratory and clonogenic capacity and release of vascular endothelial growth factor did not differ between cells from HFD- and chow-fed animals. CDCs from chow-fed and HFD-fed mice showed no differences in surface marker expression, whereas ADMSCs from HFD-fed mice contained more cells positive for CD105, DDR2, and CD45, suggesting a high component of endothelial, fibroblast, and hematopoietic cells. Both Noggin and transforming growth factor beta-supplemented medium induced an early stage of differentiation in CDCs toward the cardiomyocyte phenotype. Thus, although chronic high-fat feeding increased the number of fibroblasts and hematopoietic cells within the ADMSC population, it left cardiac progenitor cells largely unaffected. SIGNIFICANCE: Mesenchymal cells are a promising candidate cell source for restoring lost tissue and thereby preventing heart failure. In the clinic, cells are isolated from patients who may be suffering from comorbidities such as obesity and diabetes. This study examined the effect of a high-fat diet on mesenchymal cells from cardiac and adipose tissues. It was demonstrated that a high-fat diet did not affect cardiac progenitor cells but increased the number of fibroblasts and hematopoietic cells within the adipose-derived mesenchymal cell population. PMID- 26518240 TI - VEGF-mediated NF-kappaB activation protects PC12 cells from damage induced by hypoxia. AB - Neuronal apoptosis is a contributing cause of disability and death in cerebral ischemia. Nuclear factor-kappaB (NF-kappaB) may become a potential therapeutic target for hypoxic/ischemic neuron damage because NF-kappaB is inactivated after hypoxia exposure. Vascular endothelial growth factor (VEGF) has been found to improve neurological function recovery in cerebral ischemic injury although the exact molecular mechanisms that underlie the neuroprotective function of VEGF remain largely unknown. Here we defined the mechanism by which VEGF antagonized neuron-like PC12 cells apoptosis induced by hypoxia mimetic agent cobalt chloride (CoCl2) is through restoration of NF-kappaB activity. Depletion of VEGF with small interfering RNA (siRNA) in PC12 cells conferred CoCl2-induced cytotoxicity which was mitigated by VEGF administration. Treatment of PC12 cells with VEGF attenuated the CoCl2-induced cytotoxicity in both dose- and time-dependent manner. Mechanistically, VEGF increased IkappaBalpha phosphorylation and ubiquitination, promoted P65 nuclear translocation as well as upregulated XIAP and CCND1 expression. Meanwhile, VEGF administration reversed the dysregulation of IkappaBalpha phosphorylation and ubiquitination, P65 nuclear translocation as well as XIAP and CCND1 expression induced by CoCl2. Notably, the VEGF-dependent cytoprotection was abolished by pretreatment with BAY 11-7085, a specific inhibitor of NF-kappaB. Our data suggest that VEGF/NF-kappaB signalling pathway represents an adaptive mechanism that protects neural cells against hypoxic damage. PMID- 26518241 TI - Tai Chi training reduced coupling between respiration and postural control. AB - In order to maintain stable upright stance, the postural control system must account for the continuous perturbations to the body's center-of-mass including those caused by spontaneous respiration. Both aging and disease increase "posturo respiratory synchronization;" which reflects the degree to which respiration affects postural sway fluctuations over time. Tai Chi training emphasizes the coordination of respiration and bodily movements and may therefore optimize the functional interaction between these two systems. The purpose of the project was to examine the effect of Tai Chi training on the interaction between respiration and postural control in older adults. We hypothesized that Tai Chi training would improve the ability of the postural control system to compensate for respiratory perturbations and thus, reduce posturo-respiratory synchronization. Participants were recruited from supportive housing facilities and randomized to a 12-week Tai Chi intervention (n=28; 86 +/- 5 yrs) or educational-control program (n=34, 85 +/ 6 yrs). Standing postural sway and respiration were simultaneously recorded with a force plate and respiratory belt under eyes-open and eyes-closed conditions. Posturo-respiratory synchronization was determined by quantifying the variation of the phase relationship between the dominant oscillatory mode of respiration and corresponding oscillations within postural sway. Groups were similar in age, gender distribution, height, body mass, and intervention compliance. Neither intervention altered average sway speed, sway magnitude or respiratory rate. As compared to the education-control group, however, Tai Chi training reduced posturo-respiratory synchronization when standing with eyes open or closed (p<0.001). Tai Chi training did not affect traditional parameters of standing postural control or respiration, yet reduced the coupling between respiration and postural control. The beneficial effects of Tai Chi training may therefore stem in part from optimization of this multi-system interaction. PMID- 26518242 TI - Protective effects of Ephedra sinica extract on blood-brain barrier integrity and neurological function correlate with complement C3 reduction after subarachnoid hemorrhage in rats. AB - Early brain injury, which is associated with brain cell death, blood-brain barrier disruption, brain edema, and other pathophysiological events, is thought to be the main target in the prevention of poor outcomes after subarachnoid hemorrhage (SAH). Emerging evidences indicates that complement system, especially complement C3 is detrimental to neurological outcomes of SAH patients. Recently, Ephedra sinica extract was extracted and purified, which exhibits ability to block the activity of the classical and alternative pathways of complement, and improve neurological outcomes after spinal cord injury and ischemic brain injury. However, it is still unclear whether Ephedra sinica extract could attenuate early brain injury after SAH. In the present study, a standard endovascular perforation model was used to produce the experimental SAH in Sprague-Dawley rats. Ephedra sinica extract (15mg/kg) was orally administrated daily and evaluated for effects on modified Garcia score, brain water content, Evans blue extravasation and fluorescence, cortex cell death by TUNEL staining, and the expressions of complement C3/C3b, activated C3, sonic hedgehog, osteopontin and matrix metalloproteinase-9 by western bolt and immunofluorescence staining. We founded that the Ephedra sinica extract alleviated the blood-brain barrier disruption and brain edema, eventually improved neurological functions after SAH in rats. These neuroprotective effects was associated with the inhibition of complement C3, possibly via upregulating sonic hedgehog and osteopontin signal, and reducing the expressions of matrix metalloproteinase-9. Taking together, these observations suggested complement C3 inhibition by the Ephedra sinica extract may be a protective factor against early brain injury after SAH. PMID- 26518243 TI - Potential role of N-benzylcinnamide in inducing neuronal differentiation from human amniotic fluid mesenchymal stem cells. AB - Neurodegenerative disorders are characterized by chronic and progressive loss of neurons in structure and function related to aging, such as Alzheimer's disease, the latter characterized by the degeneration of cholinergic neurons in basal forebrain connected to the cerebral cortex and hippocampus. Amniotic fluid mesenchymal stem cells (AF-MSCs) have been proposed as one of the candidates for stem cell therapy of nervous system disorders. This study demonstrates that incubation of AF-MSCs, obtained from 16 to 20 week pregnant women, with 10ng/ml bone morphogenetic protein (BMP)-9 for 48h in conditioned medium resulted in transdifferentiation to cholinergic neuronal-like cells. This phenomenon could also be obtained with N-benzylcinnamide (PT-3). Pre-treatment for 1h with 10nM PT 3 augmented BMP-9 transdifferentiation effect, elevated betaIII-tubulin cell numbers and fluorescence intensity of immunoreactive ChAT, ameliorated BMP-9 related production of reactive oxygen species and enhanced anti-apoptosis status of the neuronal-like cells. The transdiffirentiation process was accompanied by increased p53 but decreased Notch1 and SIRT1 (p53 deacetylase) levels, and activation of p38, ERK1/2 MAPK, and PI3K/Akt pathways, in concert with inactivation of JNK, all of which were accentuated by PT-3 pre-treatment. These findings suggest that N-benzylcinnamide may provide a useful adjuvant in BMP-9 induced transdifferentiation of AFMSCs into ultimately cholinergic neurons. PMID- 26518244 TI - Patterns of Mycobacterium tuberculosis-complex excretion and characterization of super-shedders in naturally-infected wild boar and red deer. AB - Wild boar (Sus scrofa) and red deer (Cervus elaphus) are the main maintenance hosts for bovine tuberculosis (bTB) in continental Europe. Understanding Mycobacterium tuberculosis complex (MTC) excretion routes is crucial to define strategies to control bTB in free-ranging populations, nevertheless available information is scarce. Aiming at filling this gap, four different MTC excretion routes (oronasal, bronchial-alveolar, fecal and urinary) were investigated by molecular methods in naturally infected hunter-harvested wild boar and red deer. In addition MTC concentrations were estimated by the Most Probable Number method. MTC DNA was amplified in all types of excretion routes. MTC DNA was amplified in at least one excretion route from 83.0% (CI95 70.8-90.8) of wild ungulates with bTB-like lesions. Oronasal or bronchial-alveolar shedding were detected with higher frequency than fecal shedding (p < 0.001). The majority of shedders yielded MTC concentrations <10(3) CFU/g or mL. However, from those ungulates from which oronasal, bronchial-alveolar and fecal samples were available, 28.2% of wild boar (CI95 16.6-43.8) and 35.7% of red deer (CI95 16.3-61.2) yielded MTC concentrations >10(3) CFU/g or mL (referred here as super-shedders). Red deer have a significantly higher risk of being super-shedders compared to wild boar (OR = 11.8, CI95 2.3-60.2). The existence of super-shedders among the naturally infected population of wild boar and red deer is thus reported here for the first time and MTC DNA concentrations greater than the minimum infective doses were estimated in excretion samples from both species. PMID- 26518247 TI - Are Village Animal Health Workers Able to Assist in Strengthening Transboundary Animal Disease Control in Cambodia? AB - A cross-sectional survey of 445 Village Animal Health Workers (VAHWs) from 19 provinces in Cambodia was undertaken. The aim was to establish their levels of training, farm visit frequency, reasons for visits and disease reporting practices, enabling the strengths and weaknesses of the VAHW system in Cambodia to be determined, in providing both a fee-based smallholder livestock clinical service and a government partnership in transboundary animal disease (TAD) surveillance and control. The study used 'guided group interviews' and identified that VAHWs had good contact with farmers with 61.5% making more than one farm visit daily. However, incomes from services remained low, with 45% VAHWs obtaining between 20 and 40% of their household income from VAHW activities. VAHWs recorded relatively high rates of disease reporting, with 72% claiming they report diseases immediately and 74% undertaking monthly reporting to veterinary authorities. Logistic regression analysis revealed VAHW contact frequency with district and/or provincial officers was associated with more VAHW farm visits, and frequency of VAHW visits to smallholder farms was positively associated with average monthly expenditure on animal medication and equipment. This suggests that increased veterinary extension to VAHWs and access to veterinary equipment, vaccines and drugs may further increase VAHW-farmer engagement. VAHWs provide an accessible, market-based, animal health 'treatment and reporting' service linked to livestock smallholders across Cambodia. However, for improved TAD prevention and more efficient control of outbreaks, research that assesses provision of an animal health 'preventive-based' business model is urgently needed to reduce both the costs to farmers and the risks to the economy due to foot-and-mouth disease and other TADs in Cambodia. PMID- 26518245 TI - Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: a randomized clinical trial. AB - AIMS: To determine the efficacy of losartan vs. atenolol in aortic dilation progression in Marfan syndrome (MFS) patients. METHODS AND RESULTS: A phase IIIb, randomized, parallel, double-blind study was conducted in 140 MFS patients, age range: 5-60 years, with maximum aortic diameter <45 mm who received losartan (n = 70) or atenolol (n = 70). Doses were raised to a maximum of 1.4 mg/kg/day or 100 mg/day. The primary end-point was the change in aortic root and ascending aorta maximum diameter indexed by body surface area on magnetic resonance imaging after 36 months of treatment. No serious drug-related adverse effects were observed. Five patients presented aortic events during a follow-up (one in the losartan and four in the atenolol groups, P = 0.366). After 3 years of follow-up, aortic root diameter increased significantly in both groups: 1.1 mm (95% CI 0.6-1.6) in the losartan and 1.4 mm (95% CI 0.9-1.9) in the atenolol group, with aortic dilatation progression being similar in both groups: absolute difference between losartan and atenolol -0.3 mm (95% CI -1.1 to 0.4, P = 0.382) and indexed by BSA 0.5 mm/m2 (95% CI -1.2 to 0.1, P = 0.092). Similarly, no significant differences were found in indexed ascending aorta diameter changes between the losartan and atenolol groups: -0.3 mm/m2 (95% CI -0.8 to 0.3, P = 0.326). CONCLUSION: Among patients with MFS, the use of losartan compared with atenolol did not result in significant differences in the progression of aortic root and ascending aorta diameters over 3 years of follow-up. PMID- 26518248 TI - Prophylactic use of the Arabin cervical pessary in fetuses with severe congenital diaphragmatic hernia treated by fetoscopic endoluminal tracheal occlusion (FETO): preliminary experience. AB - OBJECTIVE: The aim of this study was to describe whether the prophylactic use of a cervical pessary decreases the rate of premature birth in congenital diaphragmatic hernia (CDH) fetuses treated with fetoscopic tracheal occlusion (FETO). METHODS: The study concerns a consecutive series of cases with CDH and FETO and a group of CDH without FETO. In a subgroup of the FETO group, a prophylactic cervical pessary was inserted the day following the procedure. Gestational age (GA) at birth was the primary outcome. RESULTS: Fifty-nine fetuses with FETO and 47 expectantly managed were included. The last 15 FETO had a cervical pessary inserted. The median GA at delivery in the FETO group with pessary was 35.1 weeks and was not different from that in the FETO group without a pessary (34.3 weeks; p = 0.28) but was below that in the expectantly managed group (38.3 weeks; p < 0.001). CONCLUSION: Early results suggest that prophylactic use of an Arabin cervical pessary does not prolong gestation of CDH fetuses treated with FETO. (c) 2015 John Wiley & Sons, Ltd. PMID- 26518249 TI - Depression as a mediator of the relation between family functioning and functional disability in youth with chronic headaches. AB - OBJECTIVE: This retrospective chart review examined a mediation model of parent and family functioning, childhood depression, and functional disability in youth with chronic headaches. Specifically, we evaluated whether depression mediates the relations between protective parenting and functional disability and between family functioning and functional disability. BACKGROUND: Children and adolescents with chronic and recurrent headache report elevated symptoms of depression. Children with chronic pain conditions, including chronic headaches, have also been found to originate from families with greater conflict, poorer cohesion, and lower organizational structure, and impaired family functioning is associated with greater disability in youth with chronic pain. METHODS: Three hundred and eighty-two patients ages 5-17 years who underwent a multidisciplinary evaluation at a tertiary pediatric headache clinic were included in this study. Participants completed a pain intensity rating, the Children's Depression Inventory, and the Functional Disability Inventory. A parent completed the Family Relationship Index and the Adult Responses to Children's Symptoms questionnaires. Structural equation modeling was used to examine a mediation model and several alternative models. RESULTS: Mediation was not supported, but an alternative model with both direct and indirect pathways provided excellent fit to the data: chi2(1) = 0.745, P = .39; comparative fit index = 1.00, root mean square error of approximation = 0.00 (CI: 0.00-0.17). Family functioning (beta = -0.19, P < .01) and protective parenting (beta = 0.17, P < .01) were associated with depression, but not disability. Depression was linked to disability (beta = 0.24, P < .01). There was an indirect pathway from family functioning to depression to disability (beta = -0.05, P < .05). CONCLUSIONS: Family context is an important variable to consider in youth with chronic headaches and disability. While many studies have identified family functioning and depressive symptoms as separately linked to functional impairment, to our knowledge, we are the first to demonstrate depression as an intermediary variable between family dysfunction and disability within the pediatric headache population. PMID- 26518250 TI - Directed random walks and constraint programming reveal active pathways in hepatocyte growth factor signaling. AB - An effective means to analyze mRNA expression data is to take advantage of established knowledge from pathway databases, using methods such as pathway enrichment analyses. However, pathway databases are not case-specific and expression data could be used to infer gene-regulation patterns in the context of specific pathways. In addition, canonical pathways may not always describe the signaling mechanisms properly, because interactions can frequently occur between genes in different pathways. Relatively few methods have been proposed to date for generating and analyzing such networks, preserving the causality between gene interactions and reasoning over the qualitative logic of regulatory effects. We present an algorithm (MCWalk) integrated with a logic programming approach, to discover subgraphs in large-scale signaling networks by random walks in a fully automated pipeline. As an exemplary application, we uncover the signal transduction mechanisms in a gene interaction network describing hepatocyte growth factor-stimulated cell migration and proliferation from gene-expression measured with microarray and RT-qPCR using in-house perturbation experiments in a keratinocyte-fibroblast co-culture. The resulting subgraphs illustrate possible associations of hepatocyte growth factor receptor c-Met nodes, differentially expressed genes and cellular states. Using perturbation experiments and Answer Set programming, we are able to select those which are more consistent with the experimental data. We discover key regulator nodes by measuring the frequency with which they are traversed when connecting signaling between receptors and significantly regulated genes and predict their expression-shift consistently with the measured data. The Java implementation of MCWalk is publicly available under the MIT license at: https://bitbucket.org/akittas/biosubg. PMID- 26518251 TI - SNAC-As, stress-responsive NAC transcription factors, mediate ABA-inducible leaf senescence. AB - Leaf senescence is the terminal phenotype of plant leaf development, and ethylene is a major plant hormone inducing leaf senescence. Recent studies have shown that abscisic acid (ABA) also induces leaf senescence. However, the detailed mechanisms of ABA-induced leaf senescence remain unclear. We focused on the A subfamily of stress-responsive NAC (SNAC-A) transcription factors, the expression of which is induced by abiotic stresses, particularly ABA. Gene expression analysis revealed that seven SNAC-A genes including ANAC055, ANAC019, ANAC072/RD26, ANAC002/ATAF1, ANAC081/ATAF2, ANAC102 and ANAC032 were induced by long-term treatment with ABA and/or during age-dependent senescence. The SNAC-A septuple mutant clearly showed retardation of ABA-inducible leaf senescence. Microarray analysis indicated that SNAC-As induce ABA- and senescence-inducible genes. In addition, comparison of the expression profiles of the downstream genes of SNAC-As and ABA-responsive element (ABRE)-binding protein (AREB)/ABRE-binding factor (ABF) (AREB/ABFs) indicates that SNAC-As induce a different set of ABA inducible genes from those mediated by AREB/ABFs. These results suggest that SNAC As play crucial roles in ABA-induced leaf senescence signaling. We also discuss the function of SNAC-As in the transcriptional change of leaf senescence as well as in ABA response under abiotic stress conditions. PMID- 26518252 TI - Differentiation and characterization of human pluripotent stem cell-derived brain microvascular endothelial cells. AB - The blood-brain barrier (BBB) is a critical component of the central nervous system (CNS) that regulates the flux of material between the blood and the brain. Because of its barrier properties, the BBB creates a bottleneck to CNS drug delivery. Human in vitro BBB models offer a potential tool to screen pharmaceutical libraries for CNS penetration as well as for BBB modulators in development and disease, yet primary and immortalized models respectively lack scalability and robust phenotypes. Recently, in vitro BBB models derived from human pluripotent stem cells (hPSCs) have helped overcome these challenges by providing a scalable and renewable source of human brain microvascular endothelial cells (BMECs). We have demonstrated that hPSC-derived BMECs exhibit robust structural and functional characteristics reminiscent of the in vivo BBB. Here, we provide a detailed description of the methods required to differentiate and functionally characterize hPSC-derived BMECs to facilitate their widespread use in downstream applications. PMID- 26518253 TI - Characterizing pain and associated coping strategies in methadone and buprenorphine-maintained patients. AB - BACKGROUND: Chronic pain is common among patients receiving opioid maintenance treatment (OMT) for opioid use disorder. To aid development of treatment recommendations for coexisting pain and opioid use disorder, it is necessary to characterize pain treatment needs and assess whether needs differ as a function of OMT medication. METHODS: A point-prevalence survey assessing pain and engagement in coping strategies was administered to 179 methadone and buprenorphine-maintained patients. RESULTS: Forty-two percent of participants were categorized as having chronic pain. Methadone patients had greater severity of pain relative to buprenorphine patients, though both groups reported high levels of interference with daily activities, and participants with pain attended the emergency room more frequently relative to participants without pain. Only 2 coping strategies were being utilized by more than 50% of participants (over-the counter medication, prayer). CONCLUSIONS: Results indicate that pain among OMT patients is common, severe, and of significant impairment. Methadone patients reported greater severity pain, particularly worse pain in the past 24h, though interference from pain in daily activities did not vary as a function of OMT. Most participants with pain were utilizing few evidenced-based pain coping strategies. Increasing OMT patient access to additional pain treatment strategies is an opportunity for immediate intervention, and similarities across OMT type suggest interventions do not need to be customized to methadone vs. buprenorphine patients. PMID- 26518254 TI - Differentiating patterns of prescription stimulant medical and nonmedical use among youth 10-18 years of age. AB - OBJECTIVE: To assess the past 30-day prevalence of prescription stimulant use, report different forms of nonmedical use, and investigate different characteristics associated with Medical Users Only, Nonmedical Users Only, and youth who reported both medical and nonmedical use (MU+NMU youth). METHODS: The National Monitoring of Adolescent Prescription Stimulants Study recruited 11,048 youth aged 10-18 years from entertainment venues in 10 US cities. RESULTS: In this study, 6.8% youth used prescription stimulants in the past 30 days, with 3.0% reporting Medical Use Only (MU Only), 1.1% reporting Both Medical and Nonmedical Use (MU+NMU), and 2.5% reporting Nonmedical Use Only (NMU Only). Use of other's stimulants was the most frequently reported form of nonmedical use (88.4%), followed by using more than prescribed (38.9%), and using outside of the prescribed route (32.2%). Medical Users Only and MU+NMU youth did not differ from Non-Users in cigarette, alcohol, and illicit drug use. MU+NMU youth tended to have more conduct problem behaviors compared to Medical Users Only (p=0.0011) and Nonmedical Users Only (p=0.0132). Compared to MU+NMU youth, Nonmedical Users Only were more likely to have close friends who tried Adderall (p=0.0123), endorse binge drinking (p=0.0118) and illicit drug use (p<0.0015). CONCLUSIONS: Future research should investigate the sources of the nonmedically used prescription stimulants and how they were diverted. Intervention programs need to acknowledge the differences between MU+NMU youth and Nonmedical Users Only, and employ different strategies to prevent nonmedical use in these subgroups. PMID- 26518255 TI - Psychometric validation of the Psoriasis Symptom Diary using Phase III study data from patients with chronic plaque psoriasis. AB - OBJECTIVES: This analysis aimed to confirm the reliability, validity, and responsiveness of the Psoriasis Symptom Diary (PSD) using data from two Phase III studies in patients with moderate to severe chronic plaque psoriasis. METHODS: Data from two randomized, double-blind, double-dummy, placebo-controlled, multicenter Phase III studies (n = 820) assessing the efficacy and safety of secukinumab were used. The PSD (24-h recall; 0-10 numeric rating scale) was electronically administered each evening. Test-retest reliability was determined using intraclass correlations. Construct validity hypotheses were evaluated via correlations with the Psoriasis Area and Severity Index (PASI), Investigator's Global Assessment (IGA), Dermatology Life Quality Index (DLQI), EuroQoL 5 Dimension Health Status Questionnaire, and Patient Global Impression of Change (PGIC). Discriminating ability and responsiveness were evaluated by estimating mean differences and effect sizes between known groups (using the PASI and IGA). Phase II-derived, anchor-based PGIC thresholds and cumulative distribution function (CDF) plots described meaningful change. RESULTS: Items on the PSD yielded high intraclass coefficients (>0.90). Correlations were in the anticipated direction and by week 12 were moderate to strong (0.41-0.73) in magnitude, demonstrating construct validity. Average PSD item scores differed predictably and significantly between known groups. Responsiveness effect size estimates were moderate to large (0.6-1.5), and CDF plots showed the percentage of responders to be consistently higher in treatment than in placebo arms across the range of change in PSD scores. CONCLUSIONS: The PSD is reliable, valid, and responsive, and represents a valid tool to enhance treatment decisions in patients with moderate to severe plaque psoriasis. PMID- 26518256 TI - [Does sleep apnea disappear once acromegaly is adequately treated?]. AB - Acromegaly is a rare hormonal disease related to excessive growth hormone secretion. It can result in a range of complications, including cardiovascular, respiratory, metabolic, articular and neoplastic disorders. Among patients with the condition, obstructive sleep apnea syndrome occurs frequently and the effect of treatment is inconstant: improvement, statu quo or deterioration can be observed. We here report three clinical cases, which illustrate the unpredictable evolution of this condition. PMID- 26518257 TI - [Validation of an evaluation questionnaire for COPD acute exacerbations (Exascore)]. AB - BACKGROUND: Early identification of acute exacerbations of COPD facilitates better care. This study was designed to validate a short questionnaire (Exascore) developed to help patients, relatives and carers to diagnose acute exacerbations. METHOD: We first addressed content validity that allowed the elaboration of two questionnaires, one assessing the current status and the other stable status (transition). The second step tested their construction validity, reproducibility and concomitant validity among 126 COPD patients aged 64.4+/-9.9 years. They included 56 presenting with an exacerbation and 70 in stable state, of whom 57 completed the questionnaire a second time after 7 days. The diagnosis of exacerbation and assessment of severity (gold standard) were established by the treating respiratory physician and confirmed by two independent experts. RESULTS: Factorial analyses established a "current status" questionnaire comprising 8 items and 2 dimensions. Cronbach's alpha coefficients were satisfactory, 0.867 for "respiratory impact", 0.886 for "psychosocial impact" and 0.886 for the total score. Concomitant validity and reproducibility were also adequate. The transition questionnaire did not obtain convincing psychometric results. CONCLUSIONS: The "current status" Exascore questionnaire satisfies psychometric quality criteria while being usable in clinical practice. It helps in diagnosing acute exacerbations and assessing their intensity. Further studies will need to test the adequacy of proposed thresholds, the factorial structure of the score in healthcare professionals and patients' relatives, and its predictive power. PMID- 26518258 TI - Exogenous lipoid pneumonia caused by repeated sesame oil pulling: a report of two cases. AB - BACKGROUND: Exogenous lipoid pneumonia is a rare disease caused by aspiration or inhalation of oily substances. CASE PRESENTATION: A 66-year-old male with dry cough (Case 1) and a 38-year-old female with shortness of breath (Case 2) demonstrated ground-glass opacities on chest computed tomography and were diagnosed with lipoid pneumonia based on the confirmation of lipid-laden alveolar macrophages. Both patients habitually performed sesame oil pulling via nasal or mouth washing for several months prior to the diagnosis. CONCLUSION: Steroid therapy and bronchoalveolar lavage resulted in improvement in Case 1, and no intensive therapy was required for Case 2. Sesame oil pulling has been rarely been reported to cause lipoid pneumonia. PMID- 26518259 TI - The effects of daily co-occurrence of affect on older adults' reactivity to health stressors. AB - OBJECTIVES: The present study examined age differences among older adults in the daily co-occurrence of affect and its potential role in buffering the negative effects of health stressors. DESIGN: Participants were from the Veterans Affairs Normative Aging Study and included 249 young-old adults (age = 60-79 years, M = 71.6) and 64 old-old adults (age = 80-89, M = 82.9) who completed questionnaires assessing stressors, physical health symptoms, and positive and negative affect for eight consecutive days. RESULTS: An independent samples t-test showed young old and old-old adults did not significantly differ in their mean levels of daily co-occurrence of affect. The between-person relationships among stressors, health and daily co-occurrence of affect revealed that neither stressors nor health were significantly related to daily co-occurrence of affect. However, results from a multilevel model revealed a three-way cross-level interaction (health stressor * age group * co-occurrence of affect) where old-old adults with higher levels of co-occurrence of affect were less emotionally reactive to health stressors than young-old adults. CONCLUSION: These findings provide support for the assertion that co-occurrence of affect functions in an adaptive capacity and highlight the importance of examining domain-specific stressors. PMID- 26518260 TI - High-fat diet-induced obesity exacerbates kainic acid-induced hippocampal cell death. AB - BACKGROUND: Obesity has deleterious effects on the brain, and metabolic dysfunction may exacerbate the outcomes of seizures and brain injuries. However, it is unclear whether obesity affects excitotoxicity-induced neuronal cell death. The purpose of this study was to investigate the effects of a high-fat diet (HFD) on neuroinflammation and oxidative stress in the hippocampus of kainic acid (KA) treated mice. RESULTS: Mice were fed with a HFD or normal diet for 8 weeks and then received a systemic injection of KA. HFD-fed mice showed hypercholesterolemia, insulin resistance, and hepatic steatosis. HFD-fed mice showed greater susceptibility to KA-induced seizures, an increased number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, neuroinflammation, and oxidative stress. Furthermore, we found that KA treatment increased HFD-induced calpain1, nuclear factor E2-related factor 2, and heme oxygenase-1 expression in the hippocampus. CONCLUSIONS: These findings imply that complex mechanisms affected by obesity-induced systemic inflammation, neuroinflammation, ER stress, calcium overload, and oxidative stress may contribute to neuronal death after brain injury. PMID- 26518262 TI - Growth hormone deficiency and pituitary malformation in a recurrent Cat-Eye syndrome: a family report. AB - Growth hormone deficiency affects roughly between one in 3000 and one in 4000 children with most instances of growth hormone deficiency being idiopathic. Growth hormone deficiency can also be associated with genetic diseases or chromosome abnormalities. Association of growth hormone deficiency together with hypothalamic-pituitary axis malformation and Cat-Eye syndrome is a very rare condition. We report a family with two brothers presenting with growth delay due to a growth hormone deficiency associated with a polymalformation syndrome. They both displayed pre-auricular pits and tags, imperforate anus and Duane retraction syndrome. Both parents and a third unaffected son displayed normal growth pattern. Cerebral MRI showed a hypothalamic-pituitary axis malformation in the two affected brothers. Cytogenetic studies revealed a type I small supernumerary marker chromosome derived from chromosome 22 resulting in a tetrasomy 22pter 22q11.21 characteristic of the Cat-Eye syndrome. The small supernumerary marker chromosome was present in the two affected sons and the mother in a mosaic state. Patients with short stature due to growth hormone deficiency should be evaluated for chromosomal abnormality. Family study should not be underestimated. PMID- 26518263 TI - The gut microbiome as a target for regulatory T cell-based immunotherapy: induction of regulatory lymphocytes by oral administration of anti-LPS enriched colostrum alleviates immune mediated colitis. AB - BACKGROUND: Gut-derived bacterial endotoxin is an important cofactor in the pathogenesis of IBD. Regulatory T cells (Tregs) are essential for maintenance of peripheral tolerance and can prevent and alleviate IBD. To determine the immune modulatory effect of anti-LPS enriched hyperimmune colostrum, its ability to induce Tregs and alleviate immune mediated colitis. METHODS: Immune-mediated colitis was induced in mice by intra-colonic instillation of Trinitrobenzene Sulfonate (TNBS). Four groups of mice were orally administered with two dosages of IgG-enriched colostrum fractions. The fractions were harvested from cows immunized against LPS derived from intestinal Escherichia coli bacteria (Imm124E). Control mice received non-immunized colostrum or vehicle (PBS). Treatment was administered one day following sensitization and four additional days following the administration of TNBS. The following parameters in the mice were tracked: body weight, bowel histology, serum cytokine levels and regulatory T cells. RESULTS: Oral administration of Imm124E hyperimmune colostrum ameliorated immune-mediated colitis. Significant amelioration of weight reduction was noted in treated mice. Oral administration of Imm124E improved bowel histology. Both the extent of the disease, inflammation score, and colitis damage and regeneration scores decreased in Imm-124E treated animals. These effects were associated with an increase in serum IL10 anti inflammatory cytokine levels, and an increase in CD4 + CD25+ and CD4 + Foxp3+ Tregs. CONCLUSIONS: Oral administration of Imm124E promoted Tregs and alleviated bowel inflammation in immune mediated colitis. The present data suggests that the microbiome may serve as a target for Tregs-based immunotherapy. PMID- 26518264 TI - Influence of microbiome species in hard-to-heal wounds on disease severity and treatment duration. AB - BACKGROUND: Infections, mostly those associated with colonization of wound by different pathogenic microorganisms, are one of the most serious health complications during a medical treatment. Therefore, this study is focused on the isolation, characterization, and identification of microorganisms prevalent in superficial wounds of patients (n=50) presenting with bacterial infection. METHODS: After successful cultivation, bacteria were processed and analyzed. Initially the identification of the strains was performed through matrix-assisted laser desorption/ionization time-of-flight mass spectrometry based on comparison of protein profiles (2-30kDa) with database. Subsequently, bacterial strains from infected wounds were identified by both matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and sequencing of 16S rRNA gene 108. RESULTS: The most prevalent species was Staphylococcus aureus (70%), and out of those 11% turned out to be methicillin-resistant (mecA positive). Identified strains were compared with patients' diagnoses using the method of artificial neuronal network to assess the association between severity of infection and wound microbiome species composition. Artificial neuronal network was subsequently used to predict patients' prognosis (n=9) with 85% success. CONCLUSIONS: In all of 50 patients tested bacterial infections were identified. Based on the proposed artificial neuronal network we were able to predict the severity of the infection and length of the treatment. PMID- 26518265 TI - Transmission heterogeneity and autoinoculation in a multisite infection model of HPV. AB - The human papillomavirus (HPV) is sexually transmitted and can infect oral, genital, and anal sites in the human epithelium. Here, we develop a multisite transmission model that includes autoinoculation to study HPV and other multisite diseases. Under a homogeneous-contacts assumption, we analyze the basic reproduction number R0, as well as type and target reproduction numbers, for a two-site model. In particular, we find that R0 occupies a space between taking the maximum of next generation matrix terms for same site transmission and taking the geometric average of cross-site transmission terms in such a way that heterogeneity in the same-site transmission rates increases R0 while heterogeneity in the cross-site transmission decreases it. Additionally, autoinoculation adds considerable complexity to the form of R0. We extend this analysis to a heterosexual population, which additionally yields dynamics analogous to those of vector-host models. We also examine how these issues of heterogeneity may affect disease control, using type and target reproduction numbers. PMID- 26518266 TI - Linker histones in hormonal gene regulation. AB - In the present review, we summarize advances in our knowledge on the role of the histone H1 family of proteins in breast cancer cells, focusing on their response to progestins. Histone H1 plays a dual role in gene regulation by hormones, both as a structural component of chromatin and as a dynamic modulator of transcription. It contributes to hormonal regulation of the MMTV promoter by stabilizing a homogeneous nucleosome positioning, which reduces basal transcription whereas at the same time promoting progesterone receptor binding and nucleosome remodeling. These combined effects enhance hormone dependent gene transcription, which eventually requires H1 phosphorylation and displacement. Various isoforms of histone H1 have specific functions in differentiated breast cancer cells and compact nucleosomal arrays to different extents in vitro. Genome wide studies show that histone H1 has a key role in chromatin dynamics of hormone regulated genes. A complex sequence of enzymatic events, including phosphorylation by CDK2, PARylation by PARP1 and the ATP-dependent activity of NURF, are required for H1 displacement and gene de-repression, as a prerequisite for further nucleosome remodeling. Similarly, during hormone-dependent gene repression a dedicated enzymatic mechanism controls H1 deposition at promoters by a complex containing HP1gamma, LSD1 and BRG1, the ATPase of the BAF complex. Thus, a broader vision of the histone code should include histone H1, as the linker histone variants actively participate in the regulation of the chromatin structure. How modifications of the core histones tails affect H1 modifications and vice versa is one of the many questions that remains to be addressed to provide a more comprehensive view of the histone cross-talk mechanisms. PMID- 26518268 TI - Evaluation of the endophytic nature of Bacillus amyloliquefaciens strain GYL4 and its efficacy in the control of anthracnose. AB - BACKGROUND: Endophytic bacteria are viewed as a potential new source of biofungicides because they have beneficial characteristics as control agents for plant disease. This study was performed to examine the endophytic feature and disease control efficacy of Bacillus amyloliquefaciens strain GYL4 and to identify the antifungal compounds produced by this strain. RESULTS: B. amyloliquefaciens strain GYL4 was isolated from leaf tissue of pepper plants (Capsicum annuum L.). Anthracnose symptoms were markedly reduced in the leaves of pepper plants colonised by GYL4. An egfp-expressing strain of GYL4 (GYL4-egfp) was constructed and reintroduced into pepper plants, which confirmed its ability to colonise the internal tissues of pepper plants. GYL4-egfp was observed in the root and stem tissues 4 days after treatment and abundantly found in the internal leaf tissue 9 days after treatment. Bacillomycin derivatives purified from the culture extract of GYL4 displayed control efficacy on anthracnose development in cucumber (Cucumis sativus L. cv. Chunsim). CONCLUSION: The present study is the first report on evaluation of the endophytic and systemic nature of B. amyloliquefaciens strain GYL4 and its potential as a biocontrol agent for anthracnose management. (c) 2015 Society of Chemical Industry. PMID- 26518267 TI - Heterogeneous nuclear ribonucleoprotein A1 post-transcriptionally regulates Drp1 expression in neuroblastoma cells. AB - Excessive mitochondrial fission is associated with the pathogenesis of neurodegenerative diseases. Dynamin-related protein 1 (Drp1) possesses specific fission activity in the mitochondria and peroxisomes. Various post-translational modifications of Drp1 are known to modulate complex mitochondrial dynamics. However, the post-transcriptional regulation of Drp1 remains poorly understood. Here, we show that the heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) regulates Drp1 expression at the post-transcriptional level. hnRNP A1 directly interacts with Drp1 mRNA at its 3'UTR region, and enhances translation potential without affecting mRNA stability. Down-regulation of hnRNP A1 induces mitochondrial elongation by reducing Drp1 expression. Moreover, depletion of hnRNP A1 suppresses 3-NP-mediated mitochondrial fission and dysfunction. In contrast, over-expression of hnRNP A1 promotes mitochondrial fragmentation by increasing Drp1 expression. Additionally, hnRNP A1 significantly exacerbates 3-NP induced mitochondrial dysfunction and cell death in neuroblastoma cells. Interestingly, treatment with 3-NP induces subcellular translocation of hnRNP A1 from the nucleus to the cytoplasm, which accelerates the increase in Drp1 expression in hnRNP A1 over-expressing cells. Collectively, our findings suggest that hnRNP A1 controls mitochondrial dynamics by post-transcriptional regulation of Drp1. PMID- 26518269 TI - Reply to: Nasal photodisinfection and chlorhexidine: post hoc ergo propter hoc? (J Hosp Infect 2015;90:83-84). PMID- 26518270 TI - Cannula-related infection in adult medical intensive care unit patients undergoing extracorporeal life support and extracorporeal membrane oxygenation. PMID- 26518271 TI - Alcohol hand rub or soap and water for removal of norovirus from hands - the debate continues. PMID- 26518272 TI - Disinfectant wipes are appropriate to control microbial bioburden from surfaces: use of a new ASTM standard test protocol to demonstrate efficacy. AB - BACKGROUND: The use of disinfectant pre-soaked wipes (DPW) to decontaminate high touch environmental surfaces (HTES) by wiping is becoming increasingly widespread in the healthcare environment. However, DPW are rarely tested using conditions simulating their field use, and the label claims of environmental surface disinfectants seldom include wiping action. AIM: To evaluate the new E2967-15 standard test specific to wipes, particularly their ability to decontaminate surfaces and to transfer acquired contamination to clean surfaces. METHODS: ASTM Standard E2967-15 was used by three independent laboratories to test the efficacy of five types of commercially available wipe products. All data generated were pulled together, and reproducibility and repeatability of the standard were measured. FINDINGS: All the commercial DPW tested achieved a >4log10 (>99.99%) reduction in colony-forming units (CFU) of Staphylococcus aureus and Acinetobacter baumanii with 10s of wiping, but only one DPW containing 0.5% accelerated H2O2 prevented the transfer of bacteria to another surface. CONCLUSION: This newly introduced standard method represents a significant advance in assessing DPW for microbial decontamination of HTES, and should greatly assist research and development, and in making more relevant and reliable claims on marketed DPW. PMID- 26518273 TI - Stop hunting for zebras in Texas: end the diagnostic culture of "rule-out": We need to make the most of clinical context rather than order every investigation, writes Saurabh Jha. PMID- 26518274 TI - Effects of Treadmill Incline and Speed on Ankle Muscle Activity in Subjects After a Stroke. AB - OBJECTIVES: To examine the effects of walking on a treadmill at varying gradients and speeds on ankle muscle activation in stroke survivors, and to compare the effect of increasing speed on plantarflexor muscle activity in participants grouped according to spasticity severity. DESIGN: Within-subject and cross sectional design. Participants walked on a standard treadmill at 3 different inclines (0 degrees , 3 degrees , 6 degrees ) and speeds (self-selected, self selected+20%, self selected+40%). SETTING: University laboratory. PARTICIPANTS: A convenience sample of stroke survivors (N=19; 13 men, 6 women) available in university clinics. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Electromyographic activity of medial gastrocnemius (MG) and tibialis anterior (TA) muscles at push-off phase of the gait. RESULTS: Paretic MG muscle activity increased (but TA did not change) at faster speeds irrespective of the incline (P<.05). In contrast, MG muscle activity increased at a higher incline in the nonparetic side (P<.05), but not in the paretic side (P>.05). In the high spasticity subgroup (Tardieu Scale >= 2), paretic MG activity increased as walking speed increased (P=.004). CONCLUSIONS: Stroke survivors appear to use distinct muscle activation strategies on the paretic and nonparetic sides in response to different walking speeds and inclines. Our data indicates that individuals with stroke can be safely trained on a treadmill to walk 20% to 40% above the self-selected pace to improve MG output without adversely affecting TA output. The speed-dependent characteristic of spasticity may help generate greater MG activity during push-off. PMID- 26518275 TI - In vitro antioxidant and free radical scavenging activity of different parts of Tabebuia pallida growing in Bangladesh. AB - BACKGROUND: In humans, many diseases are associated with the accumulation of free radicals. Antioxidants can scavenge free radicals and minimize their impact. Therefore, the search for naturally occurring antioxidants of plant origin is imperative. Here, we aimed to investigate the antioxidant and free radical scavenging properties of methanolic extracts from Tabebuia pallida (T. pallida) stem bark (TPSB), root bark (TPRB), leaves (TPL), and flowers (TPF). METHODS: The antioxidant and free radical scavenging activity were determined by several standard methods using spectrophotomer. Total phenolic and flavonoid contents were estimated using Folin-Ciocalteu reagent and aluminum chloride colorimetric assay methods, respectively. RESULTS: Among the extracts, TPL showed the highest total antioxidant capacity followed by TPRB, TPF, and TPSB. Based on DPPH and hydroxyl radical scavenging activity, TPL showed strong scavenging activity (91.05 +/- 1.10 and 62.00 +/- 0.57) with IC50 of 9.20 +/- 0.28 and 46.00 +/- 2.84 MUg/mL, respectively when compared with standard BHT (IC50 of 7.00 +/- 0.25 MUg/mL) and CA (75.00 +/- 0.14 MUg/mL). These results suggest that TPL had the highest radical scavenging activity among the extractives that closely resembled the standard's. In lipid peroxidation inhibition assay, TPL exhibited the most potent inhibitory activity (83.18 +/- 2.12 %) with IC50 of 12.00 +/- 2.12 MUg/mL, which closely resembled standard CA (IC50 of 10.50 +/- 0.28 MUg/mL). Also, the reducing capacity on ferrous ion was in the following order: TPL > TPRB > TF > TPSB. The phenolic and flavonoid contents of TPL were higher than other extractives. A positive correlation (p value <0.001) was observed between phenolic content and free radical (DPPH(.) and (.)OH) scavenging efficiencies and lipid peroxidation inhibition activity. CONCLUSION: Methanolic extract of T. pallida leaf is a potential source of natural antioxidants and serves as an effective free radical scavenger and/or inhibitor. Hence, T. pallida might be a good plant-based pharmaceutical product for several diseases caused by free radicals. PMID- 26518276 TI - Sonographic Detection and Clinical Importance of Growth Restriction in Pregnancies With Gastroschisis. AB - OBJECTIVES: The purpose of this study was to estimate the utility of sonography to detect small-for-gestational-age (SGA) neonates in pregnancies with gastroschisis and to evaluate neonatal outcomes according to birth weight percentile. METHODS: We conducted a retrospective cohort study of singleton pregnancies with fetal gastroschisis delivered at our hospital between August 1997 and December 2012. Diagnosis of growth restriction was based on estimated fetal weight below the 10th percentile using the nomogram of Hadlock et al (Am J Obstet Gynecol 1985; 151:333-337), evaluated at 4-week intervals throughout gestation and compared with subsequent birth weight, to evaluate the accuracy of sonography to detect and exclude SGA neonates. Pregnancy and neonatal outcomes were evaluated according to birth weight percentile. RESULTS: There were 111 births with gastroschisis (6 per 10,000), and one-third (n = 37) had birth weight below the 10th percentile. The sensitivity and negative predictive value of sonography for an SGA neonate both approached 90% by 32 weeks and were approximately 95% thereafter. Detection increased with advancing gestational age (P = .02). The birth weight percentile was not associated with preterm birth, infection, bowel complications requiring surgery, duration of hospitalization, or perinatal mortality. Delayed closure of the gastroschisis defect was more frequent with birth weights at or below the 3rd percentile (P = .03). CONCLUSIONS: Sonography reliably identified SGA neonates with gastroschisis in our series, and its utility improved with advancing gestation. Apart from delayed closure of the defect, a low birth weight percentile was not associated with an increased risk of morbidity or mortality in the immediate neonatal period. PMID- 26518277 TI - Ultrasound-Guided Biceps Peritendinous Injections in the Absence of a Distended Tendon Sheath: A Novel Rotator Interval Approach. AB - This retrospective study evaluated the technical success rate of a novel injection into the long head of the biceps tendon sheath by a rotator interval approach in 26 patients. A 25-gauge, 1.5-in needle was positioned into the rotator interval from a lateral approach, where a therapeutic injection was performed. Postinjection sonograms images were reviewed to assess for fluid within the sheath to calculate the technical success rate. Fluid distention of the biceps tendon sheath was shown in all 26 cases, corresponding to a 100% technical success rate. In addition, postinjection ultrasound imaging of the anterior shoulder provided additional diagnostic findings in 6 of 26 patients (23%). PMID- 26518278 TI - Feasibility, Safety, and Efficacy of Accurate Uterine Fibroid Ablation Using Magnetic Resonance Imaging-Guided High-Intensity Focused Ultrasound With Shot Sonication. AB - The aim of this study was to investigate the feasibility, safety, and efficacy of uterine fibroid treatment using magnetic resonance imaging (MRI)-guided high intensity focused ultrasound (US) with shot sonication for accurate ablation. Forty-three patients with 51 symptomatic uterine fibroids were treated with MRI guided high-intensity focused US with shot sonication, which was a small acoustic focus of higher intensity with a shorter time (2 seconds) of US exposure and a shorter cooling time (2-3 seconds). The treatment efficacy and adverse events were analyzed, and the changes in the severity of symptoms and the reduction in fibroid volume were assessed 3 and 6 months after the procedure. All patients were successfully treated in a single session, without major complications, and the mean nonperfused volume ratio +/- SD was 84.3% +/- 15.7% (range, 33.8% 100%).Complete ablation was achieved in 13 T2-hypointense fibroids from 10 patients, and partial ablation was achieved in 38 fibroids from 33 patients. The overall mean treatment time was 135.0 +/- 50.9 minutes (2.2 +/- 0.8 hours). The transformed symptom severity scores and mean fibroid volumes decreased significantly after treatment (P < .05). In conclusion, MRI-guided high-intensity focused US with shot sonication is a feasible, safe, and effective technique for ablation of uterine fibroids and complete ablation of T2-hypointense fibroids. PMID- 26518279 TI - Sonographic Detection of Extracapsular Extension in Papillary Thyroid Cancer. AB - OBJECTIVES: To identify and evaluate sonographic features suggestive of extracapsular extension in papillary thyroid cancer. METHODS: Three board certified radiologists blinded to the final pathologic tumor stage reviewed sonograms of pathologically proven cases of papillary thyroid cancer for the presence of extracapsular extension. The radiologists evaluated the following features: capsular abutment, bulging of the normal thyroid contour, loss of the echogenic capsule, and vascularity extending beyond the capsule. RESULTS: A total of 129 cases of pathologically proven thyroid cancer were identified. Of these, 51 were excluded because of lack of preoperative sonography, and 16 were excluded because of pathologic findings showing anaplastic carcinoma, follicular carcinoma, or microcarcinoma (<10 mm). The final analysis group consisted of 62 patients with papillary thyroid carcinoma, 16 of whom had pathologically proven extracapsular extension. The presence of capsular abutment had 100% sensitivity for detection of extracapsular extension. Conversely, lack of capsular abutment had a 100% negative predictive value (NPV) for excluding extracapsular extension. Contour bulging had 88% sensitivity for detection of extracapsular extension and when absent had an 87% NPV. Loss of the echogenic capsule was the best predictor of the presence of extracapsular extension, with an odds ratio of 10.23 (P = .034). This sonographic finding had 75% sensitivity, 65% specificity, and an 88% NPV. Vascularity beyond the capsule had 89% specificity but sensitivity of only 25%. CONCLUSIONS: Sonographic features of capsular abutment, contour bulging, and loss of the echogenic thyroid capsule have excellent predictive value for excluding or detecting extracapsular extension and may help in biopsy selection, surgical planning, and treatment of patients with papillary thyroid cancer. PMID- 26518280 TI - Sonographic Diagnosis of Complicated Cholecystitis. AB - OBJECTIVES: Early detection of the complications of cholecystitis is important for clinical management, yet only a small percentage of patients have a correct diagnosis before surgery. The purpose of our study was to identify sonographic findings that are associated with complicated cholecystitis. METHODS: Sonographic, surgical, and pathologic reports were reviewed for 70 patients who underwent early cholecystectomies from January 2010 to August 2014. Sonograms were assessed for 16 independent variables. Statistical analyses were performed to evaluate associations between various sonographic features and complicated cholecystitis. RESULTS: Sonographic signs associated with complicated cholecystitis (P< .05) were a greater short-axis gallbladder diameter (mean, 4.4 versus 4.0 cm), a greater mean wall thickness (5.6 versus 4.2 mm), and the likelihood of wall striations, gallbladder echogenic content, pericholecystic free fluid, and local inflammatory fat changes. Specific sonographic signs, such as sloughed intraluminal membranes, were detected in a small percentage of cases (10%). None of the sonographic features evaluated in this study was found to be sensitive and specific enough to indicate complicated cholecystitis. In most cases, sonograms reflected severe inflammation, with multiple sonographic signs. CONCLUSIONS: Although multiple sonographic signs are associated with complicated cholecystitis, none of them is sensitive and specific enough to definitively diagnose it. Sonograms usually reflect severe inflammation, with numerous sonographic signs. Thus, in the right clinical context, sonograms of severe cholecystitis should alert radiologists to the possibility of complications. PMID- 26518281 TI - Sagittal kinematics of mobile unicompartmental knee replacement in anterior cruciate ligament deficient knees. AB - BACKGROUND: There is a greater risk of tibial component loosening when mobile unicompartmental knee replacement is performed in anterior cruciate ligament deficient knees. We previously reported on a cohort of anterior cruciate ligament deficient patients (n=46) who had undergone surgery, but no difference was found in implant survivorship at a mean 5-year follow-up. The purpose of this study was to examine the kinematic behaviour of a subcohort of these patients. METHODS: The kinematic behaviour of anterior cruciate deficient knees (n=16) after mobile unicompartmental knee replacement was compared to matched intact knees (n=16). Sagittal plane knee fluoroscopy was taken while patients performed step-up and forward lunge exercises. The patellar tendon angle, knee flexion angle and implant position was calculated for each video frame. FINDINGS: The patellar tendon angle was 5 degrees lower in the deficient group, indicating greater anterior tibial translation compared to the intact group between 30 and 40 degrees of flexion. Large variability, particularly from 40-60 degrees of flexion, was observed in the bearing position of the deficient group, which may represent different coping mechanisms. The deficient group took 38% longer to perform the exercises. INTERPRETATION: Kinematic differences were found between the deficient and intact knees after mobile unicompartmental knee replacement; but these kinematic changes do not seem to affect the medium-term clinical outcome. Whether these altered knee kinematics will have a clinical impact is as yet undetermined, but more long-term outcome data is required before mobile unicompartmental knee replacement can be recommended for an anterior cruciate ligament deficient patient. PMID- 26518282 TI - Pedobarographic analysis of body weight distribution on the lower limbs and balance after Ilizarov corticotomies. AB - BACKGROUND: Symmetrical distribution of the load of the lower limbs and balance are among the determinants of proper biomechanics of the musculoskeletal system. So far, it has not been elucidated whether the correction of the axis and the equalization of the length of the lower limbs allow for achieving proper balance and load distribution. The aim of the present study was to compare load distribution and balance of patients who underwent Ilizarov method corticotomies with healthy controls. METHODS: The clinical studies evaluated 57 patients, who underwent corticotomy with the Ilizarov method. The control group consisted of 59 healthy volunteers. The evaluation assessed the distribution of the load of the lower limbs and balance using pedobarographic platform. FINDINGS: In the study group operated limb bore 48.02% of the load on average, while the healthy limb 51.98%. These differences were not statistically significant. The average percentage of load in limbs in treated and control groups did not differ significantly. In the study group, the average length of path of the center of gravity was 145.47cm. In the control group, the average length of path of the center of gravity was 112.69cm. In the study group, the average area of the center of gravity was 7.54cm(2), while in the control group it was 5.19cm(2). INTERPRETATION: Ilizarov method corticotomy allows for the obtainment value of the load distribution of the lower limbs in the study group not significantly different from those in a control group, but does not ensure the achievement of completely normal balance. PMID- 26518283 TI - Scavenging system obstruction: A cause of raised PEEP during a magnetic resonance guided neurosurgical procedure. PMID- 26518284 TI - [Unusual complication of probe Sengstaken-Blakemore]. PMID- 26518285 TI - Azithromycin protects mice against ischemic stroke injury by promoting macrophage transition towards M2 phenotype. AB - To develop novel and effective treatments for ischemic stroke, we investigated the neuroprotective effects of the macrolide antibiotic azithromycin in a mouse model system of transient middle cerebral artery occlusion. Intraperitoneal administration of azithromycin significantly reduced blood-brain barrier damage and cerebral infiltration of myeloid cells, including neutrophils and inflammatory macrophages. These effects resulted in a dose-dependent reduction of cerebral ischemic damage, and in a remarkable amelioration of neurological deficits up to 7 days after the insult. Neuroprotection was associated with increased arginase activity in peritoneal exudate cells, which was followed by the detection of Ym1- and arginase I-immunopositive M2 macrophages in the ischemic area at 24-48 h of reperfusion. Pharmacological inhibition of peritoneal arginase activity counteracted azithromycin-induced neuroprotection, pointing to a major role for drug-induced polarization of migratory macrophages towards a protective, non-inflammatory M2 phenotype. PMID- 26518286 TI - Perceived ease of access to alcohol, tobacco and other substances in rural and urban US students. AB - INTRODUCTION: Ease of access to substances has been shown to have a direct and significant relationship with substance use for school-aged children. Previous research involving rural samples of middle and high school students reveals that perceived ease of access to substances is a significant predictor of recent use among rural adolescents; however, it is unclear if perceived access to substances varies between rural and urban areas. The purpose of the present study was to examine rural-urban differences in perceived ease of access to alcohol, smoking and chewing tobacco, marijuana, and seven other substances in the US state of Georgia in order to better inform and promote future substance use prevention and programming efforts in rural areas. METHODS: Data were analyzed from the 2013 Georgia Student Health Survey II, administered in all public and interested private/charter schools in the state of Georgia. A total of 513 909 students (18.2% rural) indicated their perceived ease of access to 11 substances on a four point Likert-type scale. Rural-urban differences were investigated using chi2 analysis. RESULTS: In general, it appeared the rural-urban differences fell along legal/illicit lines. For middle school students, a significant difference in perceived ease of access was found for each substance, with rural students reporting greater access to smoking tobacco, chewing tobacco, and steroids, and urban students reporting greater access to alcohol, marijuana, cocaine, inhalants, ecstasy, methamphetamine, hallucinogens, and prescription drugs. Rural high school students reported higher access to alcohol, smoking tobacco, chewing tobacco, and steroids, with urban students reporting higher access to marijuana, cocaine, inhalants, ecstasy, and hallucinogens. Perceptions of ease of access more than doubled for each substance in both geographies between middle and high school. CONCLUSIONS: The present study found multiple and fairly consistent differences between rural and urban students' perceived ease of access to a variety of substances, with rural students reporting higher levels of access to legal substances and urban students reporting higher levels of access predominantly to illicit substances. Most troubling were the high levels of perceived access to substances, particularly among high school students. Even within rural students who reported lower ease of access, more than half of students reported having at least somewhat easy access to marijuana. More than 60% of both rural and urban high school students reported easy access to alcohol. Future research should investigate ways to decrease the perceptions of access to substances in order to prevent use and abuse. PMID- 26518287 TI - RNA interference suppression of the receptor tyrosine kinase Torso gene impaired pupation and adult emergence in Leptinotarsa decemlineata. AB - In Drosophila melanogaster prothoracic gland (PG) cells, Torso mediates prothoracicotropic hormone (PTTH)-triggered mitogen activated protein kinase (MAPK) pathway (consisting of four core components Ras, Raf, MEK and ERK) to stimulate ecdysteroidogenesis. In this study, LdTorso, LdRas, LdRaf and LdERK were cloned in Leptinotarsa decemlineata. The four genes were highly or moderately expressed in the larval prothoracic glands. At the first- to third instar stages, their expression levels were higher just before and right after the molt, and were lower in the mid instars. At the fourth-instar stage, their transcript levels were higher before prepupal stage. RNA interference-mediated knockdown of LdTorso delayed larval development, increased pupal weight, and impaired pupation and adult emergence. Moreover, knockdown of LdTorso decreased the mRNA levels of LdRas, LdRaf and LdERK, repressed the transcription of two ecdysteroidogenesis genes (LdPHM and LdDIB), lowered 20E titer, and downregulated the expression of several 20E-response genes (LdEcR, LdUSP, LdHR3 and LdFTZ-F1). Furthermore, silencing of LdTorso induced the expression of a JH biosynthesis gene LdJHAMT, increased JH titer, and activated the transcription of a JH early inducible gene LdKr-h1. Thus, our results suggest that Torso transduces PTTH triggered MAPK signal to regulate ecdysteroidogenesis in the PGs in a non drosophiline insect. PMID- 26518288 TI - Genetic variation in NIN1 and C/VIF1 genes is significantly associated with Populus angustifolia resistance to a galling herbivore, Pemphigus betae. AB - The identification of genes associated with ecologically important traits provides information on the potential genetic mechanisms underlying the responses of an organism to its natural environment. In this study, we investigated the genetic basis of host plant resistance to the gall-inducing aphid, Pemphigus betae, in a natural population of 154 narrowleaf cottonwoods (Populus angustifolia). We surveyed genetic variation in two genes putatively involved in sink-source relations and a phenology gene that co-located in a previously identified quantitative trait locus for resistance to galling. Using a candidate gene approach, three major findings emerged. First, natural variation in tree resistance to galling was repeatable. Sampling of the same tree genotypes 20 years after the initial survey in 1986 show that 80% of the variation in resistance was due to genetic differences among individuals. Second, we identified significant associations at the single nucleotide polymorphism and haplotype levels between the plant neutral invertase gene NIN1 and tree resistance. Invertases are a class of sucrose hydrolyzing enzymes and play an important role in plant responses to biotic stress, including the establishment of nutrient sinks. These associations with NIN1 were driven by a single nucleotide polymorphism (NIN1_664) located in the second intron of the gene and in an orthologous sequence to two known regulatory elements. Third, haplotypes from an inhibitor of invertase (C/VIF1) were significantly associated with tree resistance. The identification of genetic variation in these two genes provides a starting point to understand the possible genetic mechanisms that contribute to tree resistance to gall formation. We also build on previous work demonstrating that genetic differences in sink-source relationships of the host influence the ability of P. betae to manipulate the flow of nutrients and induce a nutrient sink. PMID- 26518289 TI - The effect of temperature on development of Sarconesia chlorogaster, a blowfly of forensic importance. AB - PURPOSE: The blowfly Sarconesia chlorogaster (Diptera: Calliphoridae) is of limited forensic use in South America, due to the poorly known relationship between development time and temperature. The purpose of this study was to determine development time of S. chlorogaster at different constant temperatures, thereby enabling the forensic use of this fly. METHODS: Development time of this species was examined by observing larval development at six temperatures (10, 15, 20, 25, 30, 35 degrees C). The thermal constant (K), the minimum development threshold (t 0), and development rate were calculated using linear regressions of the development time interval at five temperatures (10-30 degrees C). RESULTS: Development interval from egg to adult varied from 14.2 to 95.2 days, depending on temperature. The t0 calculated for total immature development is 6.33 degrees C and the overall thermal constant is 355.51 degree-days (DD). Temperature affected the viability of pupae, at 35 degrees C 100 % mortality was observed. CONCLUSION: Understanding development rate across these temperatures now makes development of S. chlorogaster a forensically useful tool for estimating postmortem interval. PMID- 26518290 TI - Coculture with astrocytes reduces the radiosensitivity of glioblastoma stem-like cells and identifies additional targets for radiosensitization. AB - Toward developing a model system for investigating the role of the microenvironment in the radioresistance of glioblastoma (GBM), human glioblastoma stem-like cells (GSCs) were grown in coculture with human astrocytes. Using a trans-well assay, survival analyses showed that astrocytes significantly decreased the radiosensitivity of GSCs compared to standard culture conditions. In addition, when irradiated in coculture, the initial level of radiation-induced gammaH2AX foci in GSCs was reduced and foci dispersal was enhanced suggesting that the presence of astrocytes influenced the induction and repair of DNA double strand breaks. These data indicate that astrocytes can decrease the radiosensitivity of GSCs in vitro via a paracrine-based mechanism and further support a role for the microenvironment as a determinant of GBM radioresponse. Chemokine profiling of coculture media identified a number of bioactive molecules not present under standard culture conditions. The gene expression profiles of GSCs grown in coculture were significantly different as compared to GSCs grown alone. These analyses were consistent with an astrocyte-mediated modification in GSC phenotype and, moreover, suggested a number of potential targets for GSC radiosensitization that were unique to coculture conditions. Along these lines, STAT3 was activated in GSCs grown with astrocytes; the JAK/STAT3 inhibitor WP1066 enhanced the radiosensitivity of GSCs under coculture conditions and when grown as orthotopic xenografts. Further, this coculture system may also provide an approach for identifying additional targets for GBM radiosensitization. PMID- 26518291 TI - Molecular cloning and production of caprine recombinant Oct4 protein for generation induced pluripotent stem cells. AB - Oct4, pluripotency marker and transcription factor, expresses in embryonic stem cells. It plays a pivotal role in determination of stem cells fate. Up and down regulation of Oct4 causes differentiation of embryonic stem cells. It is one of the main transcription factors which remained concerned in every study related to induced pluripotent stem cell. Here, we report the production of goat Oct4 protein using plasmid and lentiviral based vectors. Firstly, Oct4 ORF was cloned in pAcGFP1-N1 plasmid vector and positive clones were screened with colony PCR. Oct4 was over-expressed in CHO-K1 cell line and expression was confirmed by observing green florescent protein expression in CHO-K1 cells. Secondly, Oct4 lentiviral expression construct has been prepared using pLenti-gw vector. Oct4 ORF was cloned into pLenti4/V5-DEST vector and viral particles were produced in 293FT cells. Oct4 viral particles were used to infect goat fibroblast cells. Oct4 expression was observed and confirmed in transfected goat fibroblast cells using RT-PCR. Detection of Oct4 protein in western blotting assay affirmed the capacity of over-expression of our Oct4 lentiviral vector. The lentiviral expression construct and recombinant Oct4 protein may be used for reprogramming of somatic cell into induced pluripotent stem cell. PMID- 26518292 TI - Typologies of Post-divorce Coparenting and Parental Well-Being, Parenting Quality and Children's Psychological Adjustment. AB - The aim of this study was to identify post-divorce coparenting profiles and examine whether these profiles differentiate between levels of parents' well being, parenting practices, and children's psychological problems. Cluster analysis was conducted with Portuguese heterosexual divorced parents (N = 314) to yield distinct post-divorce coparenting patterns. Clusters were based on parents' self-reported coparenting relationship assessed along four dimensions: agreement, exposure to conflict, undermining/support, and division of labor. A three cluster solution was found and replicated. Parents in the high-conflict coparenting group exhibited significantly lower life satisfaction, as well as significantly higher divorce-related negative affect and inconsistent parenting than parents in undermining and cooperative coparenting clusters. The cooperative coparenting group reported higher levels of positive family functioning and lower externalizing and internalizing problems in their children. These results suggested that a positive coparenting alliance may be a protective factor for individual and family outcomes after parental divorce. PMID- 26518293 TI - Cost Effectiveness of Ofatumumab Plus Chlorambucil in First-Line Chronic Lymphocytic Leukaemia in Canada. AB - OBJECTIVE: Our objective was to estimate the cost effectiveness of ofatumumab plus chlorambucil (OChl) versus chlorambucil in patients with chronic lymphocytic leukaemia for whom fludarabine-based therapies are considered inappropriate from the perspective of the publicly funded healthcare system in Canada. METHODS: A semi-Markov model (3-month cycle length) used survival curves to govern progression-free survival (PFS) and overall survival (OS). Efficacy and safety data and health-state utility values were estimated from the COMPLEMENT-1 trial. Post-progression treatment patterns were based on clinical guidelines, Canadian treatment practices and published literature. Total and incremental expected lifetime costs (in Canadian dollars [$Can], year 2013 values), life-years and quality-adjusted life-years (QALYs) were computed. Uncertainty was assessed via deterministic and probabilistic sensitivity analyses. RESULTS: The discounted lifetime health and economic outcomes estimated by the model showed that, compared with chlorambucil, first-line treatment with OChl led to an increase in QALYs (0.41) and total costs ($Can27,866) and to an incremental cost effectiveness ratio (ICER) of $Can68,647 per QALY gained. In deterministic sensitivity analyses, the ICER was most sensitive to the modelling time horizon and to the extrapolation of OS treatment effects beyond the trial duration. In probabilistic sensitivity analysis, the probability of cost effectiveness at a willingness-to-pay threshold of $Can100,000 per QALY gained was 59 %. CONCLUSIONS: Base-case results indicated that improved overall response and PFS for OChl compared with chlorambucil translated to improved quality-adjusted life expectancy. Sensitivity analysis suggested that OChl is likely to be cost effective subject to uncertainty associated with the presence of any long-term OS benefit and the model time horizon. PMID- 26518294 TI - Economic Evidence of Pneumococcal Vaccination in Older Adults: Uncertain Modelling or Competitive Tendering? PMID- 26518295 TI - Detection of Hepatitis E Virus in Archived Rabbit Serum Samples, Germany 1989. AB - We detected Hepatitis E virus in serum samples of wild rabbits that were hunted in 1989 around the city of Greifswald, Germany. The recovery of one partial sequence and subsequent phylogenetic analysis indicates a close relationship to rabbit HEV sequences from France and suggests a long-established circulation of rabbit HEV in Europe. PMID- 26518296 TI - Microglia in dementia with Lewy bodies. AB - Microglial activation (neuroinflammation) is often cited as a pathogenic factor in the development of neurodegenerative diseases. However, there are significant caveats associated with the idea that inflammation directly causes either alpha synuclein pathology or neurofibrillary degeneration (NFD). We have performed immunohistochemical studies on microglial cells in five cases of dementia with Lewy bodies (DLB), median age 87, and nine cases of non-demented (ND) controls, median age 74, using tissue samples from the temporal lobe and the superior frontal gyrus. Three different antibodies known to label microglia and macrophages were employed: iba1, anti-CD68, and anti-ferritin. All DLB cases showed both alpha-synuclein pathology (Lewy bodies and neurites) and NFD ranging from Braak stage II to IV. In contrast, all controls were devoid of alpha synuclein pathology but did show NFD ranging from Braak stage I to III. Using iba1 labeling, our current results show a notable absence of activated microglia in all cases with the exception of two controls that showed small focal areas of microglial activation and macrophage formation. Both iba1 and ferritin antibodies revealed a mixture of ramified and dystrophic microglial cells throughout the regions examined, and there were no measurable differences in the prevalence of dystrophic microglial cells between DLB and controls. Double-labeling for alpha synuclein and iba1-positive microglia showed that cortical Lewy bodies were surrounded by both ramified and dystrophic microglial cells. We found an increase in CD68 expression in DLB cases relative to controls. Since microglial dystrophy has been linked to NFD and since it did not appear to be worse in DLB cases over controls, our findings support the idea that the additional Lewy body pathology in DLB is not the result of intensified microglial dystrophy. CD68 is likely associated with lipofuscin deposits in microglial cells which may be increased in DLB cases because of impaired proteostasis. Overall, we conclude that neurodegenerative changes in DLB are unlikely to result directly from activated microglia but rather from dysfunctional ones. PMID- 26518297 TI - Psychological stress and infectious illnesses: One step closer to understanding the mechanisms. PMID- 26518298 TI - Can postmortem MRI be used to assess trajectories in gunshot victims? AB - PURPOSE: Multi-detector computed tomography (MDCT) has proven to be of value for the reconstruction of trajectories of projectiles and the assessment of the injuries in deceased gunshot victim. For the depiction of soft tissue injury, MRI is superior to MDCT and MRI may be of value to assess trajectories. In a clinical setting, there are guidelines for the application of MRI in patients with projectiles or projectile fragments and with precautions MRI is safe for these patients. However, this has not been studied for the postmortem application of MRI from a forensic point of view. SUBJECTS AND METHOD: To assess the behaviour of projectiles, two ferromagnetic and one non-ferromagnetic projectile were exposed to the magnetic field of a 1.5- and 3-T MRI. Projectiles were placed in six phantoms with the characteristics of human muscle tissue, with and without a simulated trajectory in the gel. Before and after exposure to the magnetic field, the gelatine phantoms were imaged with MDCT to assess the position of the projectiles. RESULTS: The ferromagnetic projectiles rotate to a position where their long axis is parallel to the z-axis of the magnetic field and five out of the six projectiles moved through, either through the simulated trajectory or through a new trajectory. This was observed in both the 1.5- and 3-T systems. CONCLUSION: Ferromagnetic projectiles can rotate and migrate in a gelatine phantom. It is very likely that these projectiles will also migrate in a human body in a MRI system. Therefore, from a forensic point of view, postmortem MR will make a reconstruction of the trajectories in the body and of the reconstruction of the incident as a whole less reliable. PMID- 26518299 TI - Forensic age diagnostics using projection radiography of the clavicle: a prospective multi-center validation study. AB - The radiological investigation of the ossification stage of the medial clavicular epiphysis represents the crucial tool for assessing whether a living individual has completed the age of 18 years. However, exposure to radiation cannot always be accepted due to legal reasons and radiation-free methods still lack reference data or are not available. Therefore, this study examines the role of pre existing radiographic material of the clavicles, making it necessary to prospectively validate the established five-stage classification system for evaluating the clavicular ossification process as well as to enlarge the so far very limited pool of available reference data. Accordingly, standard posterior anterior projection radiographs of 836 sternoclavicular joints prospectively obtained during 418 forensic autopsies (age range 15-30 years) were analyzed. Stage III was first found at ages 16 and 15 (males/females), stage IV at ages 22 and 21 (males/females), and stage V at age 26 in both sexes. The presented results principally corroborate the previous reference data from 2004, suggesting reliability of the five-stage classification system. In conclusion, chest radiographs may still be useful for forensic age diagnostics in living individuals but only in certain cases. In age estimations which can be planned in advance, projection radiography of the clavicle must still be considered obsolete. PMID- 26518300 TI - MicroRNA-138 Inhibits Periodontal Progenitor Differentiation under Inflammatory Conditions. AB - Inflammatory conditions as they occur during periodontal disease often result in decreased alveolar bone levels and a loss of connective tissue homeostasis. Here we have focused on the effect of microRNA-138 (miR-138) as a potential regulator of periodontal stem cells as they affect homeostasis during inflammatory conditions. Our data indicate that miR-138 was significantly upregulated in our periodontal disease animal model. Interaction of miR-138 with a predicted targeting site on the osteocalcin (OC) promoter resulted in a 3.7-fold reduction of luciferase activity in promoter assays compared with controls; and miR-138 overexpression in periodontal progenitors significantly inhibited OC (3.4-fold), Runx2 (2.8-fold), and collagen I (2.6-fold). Moreover, treatment with inflammatory modulators such as interleukin (IL)-6 and lipopolysaccharide (LPS) resulted in a significant 2.2-fold (IL-6) or 1.9-fold (LPS) increase in miR-138 expression, while OC and Runx2 expression was significantly decreased as a result of treatment with each inflammatory mediator. Further defining the role of miR 138 in the OC-mediated control of mineralization, we demonstrated that the LPS induced downregulation of OC expression was partially reversed after miR-138 knockdown. LPS, miR-138 mimic, and OC small interfering RNA inhibited osteoblast differentiation marker alkaline phosphatase activity, while miR-138 inhibitor and OC protein addition enhanced alkaline phosphatase activity. Supporting the role of OC as an essential modulator of osteoblast differentiation, knockdown of miR 138 or addition of OC protein partially rescued alkaline phosphatase activity in periodontal ligament (PDL) cells subjected to LPS treatment. Our data establish miR-138 inhibitor as a potential therapeutic agent for the prevention of the bone loss associated with advanced periodontal disease. PMID- 26518302 TI - [Treatment mapping of prostate cancer in DVPZ prostate centers in Germany]. AB - BACKGROUND: In prostate centers of the Governing Body of German Prostate Centers (DVPZ, Dachverband der Prostatazentren Deutschlands e.V.) treatment data from 3 university clinics, 21 treatment clinics, 3 private clinics and 330 general practitioners incorporated under 22 certificates are collated, in order to document the quality and type of cross-sectoral and interdisciplinary treatment, in particular of prostate cancer (PCA) patients. METHODS: This analysis is based on the DVPZ UroCloud data sets from 20 July 2015. The UroCloud reflects the web based chronological disease development and quality parameters. For the descriptive analysis of particular key figures, available complete data sets were selected. RESULTS: Of the centers 22 held a valid certificate and fulfilled all required case numbers and structural prerequisites at the primary certification or recertification. In three cases a reauditing led to requirements before certification. Since 2005 a total of 9650 PCA patients have been pseudonymized and followed up (41,247 follow-up forms, 4.3 forms per patient). In 2014 the median number of newly documented PCA patients was 61 per center (minimum 7 and maximum 295). Radical prostatectomy (RP) dominated with 4491 (56 %) cases followed by primary hormonal therapy (1210 cases, 15 %), irradiation (809, 10 %) and non-interventional therapy, such as active surveillance (AS) or watchful waiting (WW) in 760 cases (10 %). A prostate-specific antigen (PSA) reduction was documented in 50 % of the patients with a preoperative PSA value > 20, in 60 % of pT4 tumors and in 50 % of patients with a tumor Gleason score of 9-10. A positive incision margin (R+) was found in in 15 % of pT2 stages, 41 % of pT3 stages and 85 % of pT4 stages. A secondary intervention was documented in 6.5 % of RP. CONCLUSION: The DVPZ certificate reflects the complete spectrum of treatment of PCA patients. The strength of the certificate lies in the documentation of patient development and a simultaneous collation of quality parameters. PMID- 26518305 TI - [Quality of life of patients with prostate cancer under androgen deprivation with GnRH analogues: Results of the noninterventional study TRIPTOSIX]. AB - BACKGROUND: In Germany, data on the quality of life (QoL) of patients with advanced prostate cancer (PCa) under therapy with gonadotropin-releasing hormone (GnRH) analogues are limited. OBJECTIVES: Androgen deprivation (ADT) is a palliative therapy for patients with advanced PCa, which is given over long periods and usually continued in combination with other therapies even after progression of the disease. The present study aimed to assess prospectively (over 1 year) different aspects of patients' QoL therapy with triptorelin in daily practice. PATIENTS AND METHODS: This prospective, noninterventional study at 129 centers in Germany included 608 patients with advanced PCa treated with triptorelin. Quality of life was assessed at baseline and after 6 and 12 months, using validated EORTC QLQ-C30 and QLQ-PR25 questionnaires. Predefined subgroup analyses were performed to assess the impact of demographics, anamnestic and clinical parameters on QoL. RESULTS AND DISCUSSION: The majority of patients with PCa under therapy with triptorelin showed generally stable global QoL over 1 year; approximately one-quarters of the patients had a clinically relevant improvement of their global QoL. In patients without previous PCa therapy and GnRH analogue treatment, significant improvements in global QoL were seen. At the same time, these patients also reported increased treatment-related symptoms. These data indicate that the perception of global QoL is not only influenced by subjective impairment through ADT-related side effects. PMID- 26518303 TI - [S2e guideline of the German urologists: Conservative and pharmacologic treatment of benign prostatic hyperplasia]. AB - This report summarizes the relevant aspects of the S2e guideline of the German Urologists for the conservative and pharmacological treatment of lower urinary tract symptoms due to benign prostatic hyperplasia. Recommendations are given regarding watchful waiting, behavioral therapy, phytotherapy and pharmacological mono- and combination therapy. The influence of the different therapeutic options on bladder outlet obstruction (BOO) is described in detail. PMID- 26518304 TI - [S2e guideline of the German urologists: Instrumental treatment of benign prostatic hyperplasia]. AB - This report summarizes the relevant aspects of the S2e guideline of the German Urologists for the instrumental treatment of the lower urinary tract symptoms due to benign prostatic hyperplasia. Recommendations are given regarding open and transurethral procedures (TUR-P, bipolar TUR-P, TUI-P, HE-TUMT, TUNA, and the different Laser techniques). Recommendations are also given concerning intraprostatic stents and injection therapies. The influence of the different therapeutic options on bladder outlet obstruction (BOO) is described in detail. PMID- 26518306 TI - A novel approach for analysis of altered gait variability in amyotrophic lateral sclerosis. AB - Gait variability reflects important information for the maintenance of human beings' health. For pathological populations, changes in gait variability signal the presence of abnormal motor control strategies. Quantitative analysis of the altered gait variability in patients with amyotrophic lateral sclerosis (ALS) will be helpful for either diagnosing or monitoring pathological progression of the disease. Thus, we applied Teager energy operator, an energy measure that can highlight the deviations from moment to moment of a time series, to produce an instantaneous energy time series. Then, two important features were extracted to assess the variability of the new time series. First, the standard deviation statistics were used to measure the magnitude of the variability. Second, to quantify the temporal structural characteristics of the variability, the permutation entropy was applied as a tool from the nonlinear dynamics. In the classification experiments, the two proposed features were input to the support vector machine classifier, and the dataset consists of 12 ALS patients and 16 healthy control subjects. The experimental results showed that an area of 0.9643 under the receiver operating characteristic curve was achieved, and the classification accuracy evaluated by leave-one-out cross-validation method could reach 92.86 %. PMID- 26518308 TI - There is no convincing evidence that working memory training is NOT effective: A reply to Melby-Lervag and Hulme (2015). AB - Our recent meta-analysis concluded that training on working memory can improve performance on tests of fluid intelligence (Au et al., Psychon Bull Rev, 22(2), 366-377, 2015). Melby-Lervag and Hulme (Psychon Bull Rev, doi: 10.3758/s13423-015 0862-z ) challenge this conclusion on the grounds that it did not take into consideration baseline differences on a by-study level and that the effects were primarily driven by purportedly less rigorous studies that did not include active control groups. Their re-analysis shows that accounting for baseline differences produces a statistically significant, but considerably smaller, overall effect size (g = 0.13 vs g = 0.24 in Au et al.), which loses significance after excluding studies without active controls. The present report demonstrates that evidence of impact variation by the active/passive nature of control groups is ambiguous and also reveals important discrepancies between Melby-Lervag and Hulme's analysis and our original meta-analysis in terms of the coding and organization of data that account for the discrepant effect sizes. We demonstrate that there is in fact no evidence that the type of control group per se moderates the effects of working memory training on measures of fluid intelligence and reaffirm the original conclusions in Au et al., which are robust to multiple methods of calculating effect size, including the one proposed by Melby-Lervag and Hulme. PMID- 26518309 TI - Ivermectin inhibits porcine reproductive and respiratory syndrome virus in cultured porcine alveolar macrophages. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a devastating viral pathogen of swine that causes huge financial losses in the pig industry worldwide. Ivermectin is known to be a potent inhibitor of importin alpha/beta mediated nuclear transport and exhibits antiviral activity towards several RNA viruses by blocking the nuclear trafficking of viral proteins. Although PRRSV replication occurs exclusively in the cytoplasm of infected cells, the nucleocapsid (N) protein has been shown to distinctly localize in the nucleus and nucleolus throughout infection. Here, we sought to assess whether ivermectin suppresses PRRSV replication in cultured porcine alveolar macrophage (PAM) cells and to investigate the effect of ivermectin on the subcellular localization of the PRRSV N protein. Our data demonstrate that ivermectin treatment inhibits PRRSV infection in PAM-pCD163 cells in a dose-dependent manner. The antiviral activity of ivermectin on PRRSV replication was most effective when cells were treated during the early stage of infection. Treatment of PRRSV-infected cells with ivermectin significantly suppressed viral RNA synthesis, viral protein expression, and progeny virus production. However, immunofluorescence and cell fractionation assays revealed that ivermectin was incapable of disrupting the nuclear localization of the N protein, both in PRRSV-infected PAM-pCD163 cells and in PAM cells stably expressing the PRRSV N protein. This finding suggests that an alternative mechanism of action accounts for the ability of ivermectin to diminish PRRSV replication. Taken together, our results suggest that ivermectin is an invaluable therapeutic or preventative agent against PRRSV infection. PMID- 26518307 TI - Of monkeys and men: Impatience in perceptual decision-making. AB - For decades sequential sampling models have successfully accounted for human and monkey decision-making, relying on the standard assumption that decision makers maintain a pre-set decision standard throughout the decision process. Based on the theoretical argument of reward rate maximization, some authors have recently suggested that decision makers become increasingly impatient as time passes and therefore lower their decision standard. Indeed, a number of studies show that computational models with an impatience component provide a good fit to human and monkey decision behavior. However, many of these studies lack quantitative model comparisons and systematic manipulations of rewards. Moreover, the often-cited evidence from single-cell recordings is not unequivocal and complimentary data from human subjects is largely missing. We conclude that, despite some enthusiastic calls for the abandonment of the standard model, the idea of an impatience component has yet to be fully established; we suggest a number of recently developed tools that will help bring the debate to a conclusive settlement. PMID- 26518310 TI - [Not Available]. PMID- 26518311 TI - Neonatal EEG and neurodevelopmental outcome in preterm infants born before 32 weeks. AB - OBJECTIVE: To assess the value of neonatal EEG for predicting non-optimal neurodevelopmental outcomes in very preterm infants, using a multimodal strategy of evaluation comprising brain imaging and clinical assessment. DESIGN AND SETTING: Between 2003 and 2009, we performed an observational, population-based study. Out of 2040 eligible preterm infants born before 32 weeks, 1954 were enrolled in the French regional Loire Infant Follow-Up Team (LIFT) cohort. 1744 (89%) of these completed the follow-up. Neonatal EEGs were recorded prospectively as two EEGs during the first 2 weeks of life and then one every 2 weeks up to 33 weeks. MAIN OUTCOME MEASURES: The neurodevelopmental outcome was assessed by physical examination, the Brunet-Lezine Test and/or the Age and Stages Questionnaire at 2 years of corrected age. RESULTS: Of the 1744 infants assessed at 2 years, 422 had a non-optimal outcome. A total of 4804 EEGs were performed, and 1345 infants had at least one EEG. EEG abnormalities were predictive of non optimal outcomes after controlling for confounding factors such as severe intracranial lesions detected by brain imaging. Transient moderate and severe abnormalities were independent predictors of non-optimal outcomes with an OR and 95% CI of 1.49 (1.08 to 2.04) and 2.38 (1.49 to 3.81), respectively. In the validation group, the predictive risk stratification tree identified severe abnormalities as a factor contributing to the prognosis of two subgroups: infants with severe cranial lesions and infants with a normal examination at discharge and without severe cranial lesions. PMID- 26518312 TI - Heart rate characteristic index monitoring for bloodstream infection in an NICU: a 3-year experience. AB - BACKGROUND: Bloodstream infection (BSI) among neonatal intensive care unit (NICU) infants is a frequent problem associated with poor outcomes. Monitoring for abnormal heart rate characteristics (HRCs) may decrease infant mortality by alerting clinicians to sepsis before it becomes clinically apparent. METHODS: HRC scores were acquired using the HRC (HeRO) monitor system from Medical Predictive Science Corporation and entered into the electronic medical record by bedside staff. We retrospectively analysed HRC scores recorded twice daily in the medical record during a 30-month period (1 January 2010 through 30 June 2012) for infants in the NICU at the Monroe Carell Jr. Children's Hospital at Vanderbilt. We identified infants that met Centers for Disease Control criteria for late-onset BSI (>3 days of life) during the study period. RESULTS: During the study period, we recorded 127 673 HRC scores from 2384 infants. We identified 46 infants with BSI. Although 8% (9701/127 673) of the HRC scores were >=2 and 1% (1387/127 673) were >=5, BSI (at any time) was observed in just 5% of patients with HRC scores >=2, and 9% of patients with HRC scores >=5. Of infants with BSI, 5/46 (11%) had at least one HRC score >=5 and 17/46 (37%) had at least one score >=2 recorded in the 48 h period prior to the evaluation that resulted in the first positive blood culture of the episode. CONCLUSIONS: In our single-centre retrospective study, elevated HRC scores had limited ability to detect BSI. BSI was infrequent at any time during hospitalisation in infants with significantly elevated HRC scores. PMID- 26518313 TI - Tyrosol Attenuates High Fat Diet-Induced Hepatic Oxidative Stress: Potential Involvement of Cystathionine beta-Synthase and Cystathionine gamma-Lyase. AB - The Mediterranean diet is known for its cardioprotective effects. Recently, its protective qualities have also been reported in patients with non-alcoholic fatty liver disease (NAFLD). Oxidative stress is one of the important factors responsible for the development and progression of NAFLD. Hydrogen sulfide (H2S), a multifaceted gasotransmitter, has emerged as a potential therapeutic target in NAFLD. Cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) are major enzymes responsible for endogenous H2S synthesis. Since oxidative stress contributes to NAFLD pathogenesis, the objective of this study was to investigate the effect of tyrosol, a major compound in olive oil and white wine, on high fat diet-induced hepatic oxidative stress and the mechanisms involved. Mice (C57BL/6) were fed for 5 weeks with a control diet (10 % kcal fat), a high fat diet (60 % kcal fat, HFD) or a HFD supplemented with tyrosol. High fat diet feeding induced hepatic oxidative stress, as indicated by the significant increase in lipid peroxidation and NADPH oxidase activity. Tyrosol supplementation significantly increased hepatic CBS and CSE expression and H2S synthesis in high fat diet-fed mice. Such effects were associated with the attenuation of high fat diet-induced hepatic lipid peroxidation and the restoration of the redox equilibrium of the antioxidant glutathione. Tyrosol also inhibited palmitic acid-induced oxidative stress in hepatocytes (HepG2 cells). These results suggest that the antioxidant properties of tyrosol may be mediated through functional changes in CBS and CSE activity, which might contribute to the hepatoprotective effect of the Mediterranean diet. PMID- 26518315 TI - A research framework for pharmacovigilance in health social media: Identification and evaluation of patient adverse drug event reports. AB - Social media offer insights of patients' medical problems such as drug side effects and treatment failures. Patient reports of adverse drug events from social media have great potential to improve current practice of pharmacovigilance. However, extracting patient adverse drug event reports from social media continues to be an important challenge for health informatics research. In this study, we develop a research framework with advanced natural language processing techniques for integrated and high-performance patient reported adverse drug event extraction. The framework consists of medical entity extraction for recognizing patient discussions of drug and events, adverse drug event extraction with shortest dependency path kernel based statistical learning method and semantic filtering with information from medical knowledge bases, and report source classification to tease out noise. To evaluate the proposed framework, a series of experiments were conducted on a test bed encompassing about postings from major diabetes and heart disease forums in the United States. The results reveal that each component of the framework significantly contributes to its overall effectiveness. Our framework significantly outperforms prior work. PMID- 26518314 TI - Can we improve accuracy and reliability of MRI interpretation in children with optic pathway glioma? Proposal for a reproducible imaging classification. AB - INTRODUCTION: Magnetic resonance (MR) images from children with optic pathway glioma (OPG) are complex. We initiated this study to evaluate the accuracy of MR imaging (MRI) interpretation and to propose a simple and reproducible imaging classification for MRI. METHODS: We randomly selected 140 MRIs from among 510 MRIs performed on 104 children diagnosed with OPG in France from 1990 to 2004. These images were reviewed independently by three radiologists (F.T., 15 years of experience in neuroradiology; D.L., 25 years of experience in pediatric radiology; and J.L., 3 years of experience in radiology) using a classification derived from the Dodge and modified Dodge classifications. Intra- and interobserver reliabilities were assessed using the Bland-Altman method and the kappa coefficient. These reviews allowed the definition of reliable criteria for MRI interpretation. RESULTS: The reviews showed intraobserver variability and large discrepancies among the three radiologists (kappa coefficient varying from 0.11 to 1). These variabilities were too large for the interpretation to be considered reproducible over time or among observers. A consensual analysis, taking into account all observed variabilities, allowed the development of a definitive interpretation protocol. Using this revised protocol, we observed consistent intra- and interobserver results (kappa coefficient varying from 0.56 to 1). The mean interobserver difference for the solid portion of the tumor with contrast enhancement was 0.8 cm(3) (limits of agreement = -16 to 17). CONCLUSION: We propose simple and precise rules for improving the accuracy and reliability of MRI interpretation for children with OPG. Further studies will be necessary to investigate the possible prognostic value of this approach. PMID- 26518316 TI - Risk Stratification Using Human Papillomavirus Testing among Women with Equivocally Abnormal Cytology: Results from a State-Wide Surveillance Program. AB - BACKGROUND: Clinical guidelines for cervical cancer screening have incorporated comparative risks of cervical intraepithelial neoplasia grade 3 or cancer (CIN3(+)) for various screening outcomes to determine management. Few cohorts are large enough to distinguish CIN3(+) risks among women with minor abnormalities versus negative cytology because of low incidence. The New Mexico Human Papillomavirus (HPV) Pap Registry offers a unique opportunity to evaluate cervical cancer screening in a diverse population across a broad-spectrum of health service delivery. METHODS: Kaplan-Meier and logistic-Weibull survival models were used to estimate cumulative risks of CIN3(+) among women ages 21 to 64 who were screened in New Mexico between 2007 and 2011 with negative, equivocal or mildly abnormal cytology, that is, atypical squamous cells of undetermined significance (ASC-US; with or without HPV triage), or low-grade squamous intraepithelial lesions (LSIL). RESULTS: We identified 452,045 women meeting the selection criteria. The 3-year CIN3(+) risks for women with negative, ASC-US, and LSIL cytology were 0.30%, 2.6%, and 5.2%, respectively. HPV triage of ASC-US stratified 3-year CIN3(+) risks were 0.72% for HPV-negative and 7.7% for HPV positive. Risks tended to decline after age 30 for all screening results. CONCLUSIONS: In this state-wide population-based cohort, cytology and HPV triage of ASC-US stratified women's CIN3(+) risk into similar patterns observed previously, suggesting the validity of screening guidelines for diverse populations in the United States. Absolute risk estimates should be compared across other large populations. IMPACT: Strategies for HPV triage of ASC-US derived from clinical trials are upheld in large clinical practice settings and across diverse screening populations in the United States. PMID- 26518317 TI - Advances in pediatrics in 2014: current practices and challenges in allergy, gastroenterology, infectious diseases, neonatology, nutrition, oncology and respiratory tract illnesses. AB - Major advances in the conduct of pediatric practice have been reported in the Italian Journal of Pediatrics in 2014. This review highlights developments in allergy, gastroenterology, infectious diseases, neonatology, nutrition, oncology and respiratory tract illnesses. Investigations endorse a need to better educate guardians and improve nutritional management in food allergy. Management of hyperbilirubinemia in neonates and of bronchiolitis have been improved by position statements of scientific societies. Novel treatments for infant colic and inflammatory bowel diseases have emerged. Studies suggest the diagnostic utility of ultrasonography in diagnosing community-acquired pneumonia. Progress in infectious diseases should include the universal varicella vaccination of children. Recommendations on asphyxia and respiratory distress syndrome have been highlighted in neonatology. Studies have evidenced that malnutrition remains a common underestimated problem in developing countries, while exposure to cancer risk factors in children is not negligible in Western countries. Advances in our understanding of less common diseases such as cystic fibrosis, plastic bronchitis, idiopathic pulmonary hemosiderosis facilitate diagnosis and management. Researches have led to new therapeutic approaches in patent ductus arteriosus and pediatric malignancies. PMID- 26518318 TI - Staged rotation flap scrotoplasty and orchidopexy in a patient with inguinal ectopic scrotum. AB - Ectopic scrotum is a rare and unusual presentation to paediatric urology. It is usually characterized by accessory scrotum with adequate scrotum in the anatomically normal position. We describe a case of inguinal ectopia of the right hemiscrotum containing the right testis, and its staged surgical management by rotation flap scrotoplasty and subsequent orchidopexy. PMID- 26518319 TI - Commentary on "The Impact of Uninterrupted Warfarin on Hand and Wrist Surgery". PMID- 26518320 TI - Commentary on "A Comparison of K-Wire Versus Screw Fixation on the Outcomes of Distal Phalanx Fractures". PMID- 26518321 TI - Commentary for "Distal Radioulnar Joint Reaction Force Following Ulnar Shortening: Diaphyseal Osteotomy Versus Wafer Resection". PMID- 26518322 TI - Reconstruction of the Distal Oblique Bundle of the Interosseous Membrane: A Technique to Restore Distal Radioulnar Joint Stability. AB - The distal radioulnar ligament reconstruction is a technique that may be used for distal radioulnar joint instability without arthritis and failed nonsurgical management; clinical results demonstrate resolved or improved stability. Recent literature has focused on the distal oblique bundle of the interosseous membrane and its contributions to stability. This article describes a technically simple surgical technique to reconstruct the distal oblique bundle and restore distal radioulnar joint stability. PMID- 26518323 TI - Wafer Resection of the Distal Ulna. AB - The wafer procedure is an effective treatment for ulnar impaction syndrome, which decompresses the ulnocarpal junction through a limited open or arthroscopic approach. In comparison with other common decompressive procedures, the wafer procedure does not require bone healing or internal fixation and also provides excellent exposure of the proximal surface of the triangular fibrocartilage complex. Results of the wafer procedure have been good and few complications have been reported. PMID- 26518324 TI - In Reply. PMID- 26518325 TI - Letter Regarding "Dupuytren Contracture Recurrence Following Treatment With Collagenase Clostridium Histolyticum (CORDLESS [Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study]): 5-Year Data". PMID- 26518326 TI - The "Rocking Chair Sign" for Floating Lunate. PMID- 26518327 TI - Adherence to and efficacy of different compression methods for treating chronic venous insufficiency in the elderly. AB - Objectives To investigate the adherence to and efficacy of different compression methods in elderly patients. Methods A retrospective review of compression therapy in 120 elderly patients (>=65 years) with chronic venous insufficiency was performed to study the initially preferred compression method, adherence to each method, and its efficacy. Results Initially, an oversize strong stocking (24%), an appropriate size moderate stocking (19%), and bandages (37%) were equally preferred. Adherence at 1 month was 69%, 96%, and 91%, respectively, and they reduced ankle circumferences in C3 patients by 1.8 +/- 1.9 cm, 0.3 +/- 1.7 cm, and 2.9 +/- 1.7 cm, respectively. The improvement rates of C4 symptoms were 79%, 60%, and 91%, respectively. Only three patients (2%) preferred an appropriate size strong stocking. Conclusions In elderly patients, an appropriate size strong stocking was not preferred. The best adherence was achieved by using a moderate stocking, while the best efficacy was achieved by using bandages. PMID- 26518328 TI - Gemcitabine plus S-1: a hopeful frontline treatment for Asian patients with unresectable advanced pancreatic cancer. AB - OBJECTIVE: Gemcitabine-based chemotherapy is widely used for unresectable advanced pancreatic cancer which contains locally advanced and metastatic pancreatic cancer. We performed meta-analysis to examine whether gemcitabine plus S-1 could improve treatment efficacy as first-line chemotherapy for those patients when compared with gemcitabine alone. METHODS: STATA was used to estimate the summary hazard ratios or odds ratios and their 95% confidence intervals. Heterogeneity among trials was examined by Cochran's chi(2) test. Publication bias was evaluated by Begg's and Egger's tests. Subgroup analysis based on the extent of disease was performed. RESULTS: Four randomized controlled trials including 878 Asian patients were analyzed. In total meta-analysis, gemcitabine plus S-1 significantly improved overall survival (hazard ratio, 0.82; 95% confidence interval, 0.70-0.96; P = 0.015), progression-free survival (hazard ratio, 0.64; 95% confidence interval, 0.55-0.74; P < 0.001), overall response rate (odds ratio, 3.00; 95% confidence interval, 2.04-4.41; P < 0.001) and disease control rate (odds ratio, 1.78; 95% confidence interval, 1.32 to 2.39; P < 0.001), and was associated with more but manageable hematologic (leukocytopenia, neutropenia, thrombocytopenia) and non-hematologic (diarrhea, stomatitis, nausea, rash) adverse events. In subgroup analysis, gemcitabine plus S-1, comparing with gemcitabine, significantly improved overall survival in locally advanced patients (hazard ratio, 0.69; 95% confidence interval, 0.48 to 0.99; P = 0.022) but not in metastatic patients (hazard ratio, 0.75; 95% confidence interval, 0.46-1.23; P = 0.256). CONCLUSION: This meta-analysis confirmed the survival benefits of gemcitabine plus S-1 as first-line treatment for unresectable advanced pancreatic cancer at least in Asia, while good Eastern Cooperative Oncology group performance status was warranted. Importantly, we highlighted the significant overall survival benefit of gemcitabine plus S-1 in locally advanced patients but not in metastatic patients. PMID- 26518330 TI - Differential roles of GABAB1 subunit isoforms on locomotor responses to acute and repeated administration of cocaine. AB - GABAB receptors are crucial modulators of the behavioural effects of drug abuse, and agonists and positive allosteric modulators show promise as pharmacological strategies for anti-addiction therapeutics. GABAB receptors are functional heterodimers of GABAB1 and GABAB2 subunits. The predominant neuronal GABAB1 subunit isoforms are GABAB1a and GABAB1b. Selective ablation of these isoforms in mice revealed differential behavioural responses in fear, cognition and stress sensitivity. However, the influence of the two GABAB1 isoforms on responses to drugs of abuse is unclear. Therefore we examined the responses of GABAB1 subunit isoform null mice to cocaine in acute locomotor activity and conditioned place preference (CPP) paradigms. During habituation for the acute locomotor activity assay, GABAB1b(-/-) mice showed higher levels of locomotor activity relative to wild-type (WT) and GABAB1a(-/-) mice, in accordance with previous studies. Acute cocaine (10 mg/kg) increased locomotor activity in habituated mice of all three genotypes, with GABAB1a(-/-) mice showing sustained hyperlocomotor responses 30 min after cocaine relative to WT and GABAB1b(-/-) mice. No genotypes demonstrated a cocaine-induced place preference, however, GABAB1a(-/-) mice demonstrated enhanced locomotor sensitisation to chronic cocaine in the CPP paradigm in comparison to WT mice, whereas GABAB1b(-/-) mice failed to develop locomotor sensitisation, despite higher levels of basal locomotor activity. These findings indicate that GABAB1a and GABAB1b isoforms differentially regulate behavioural responses to cocaine, with deletion of GABAB1a enhancing cocaine-induced locomotor activity and deletion of GABAB1b protecting from cocaine-induced sensitisation. PMID- 26518331 TI - Unmasking a novel disease gene NEO1 associated with autism spectrum disorders by a hemizygous deletion on chromosome 15 and a functional polymorphism. AB - BACKGROUND: Autism spectrum disorders (ASD) are neurodevelopmental disorders with a high degree of heritability, but the genetic basis is exceedingly heterogeneous. Microdeletions of chromosome 15q24 have been demonstrated to be recurrent genomic alterations in ASD patients. Of interest, neuronal migration genes are of particular relevance to the pathogenesis of ASD. NEO1 is located in 15q24 and encodes for neogenin, a membrane receptor involved in cortical interneuron migration and axon guidance. We postulated that the ASD patient has one copy of the NEO1 gene deleted and the other copy disrupted by intragenic mutation. RESULTS: We identify genetic changes in both alleles of NEO1 in two individuals from a cohort of 66 Han Chinese patients with ASD. In one patient, we detected a hemizygous 1.97-Mb deletion at 15q23q24.1 encompassing the NEO1 gene, a missense variant in NEO1, c.3388C>T (p.Arg1130Cys), and a duplication, c.2204 14_2204-2dup, in the acceptor splice site of intron 14 of NEO1. Furthermore, we identified a second patient was a compound heterozygote for NEO1. A novel missense variant in NEO1, c.302G>A (p.Arg101His), in addition to c.3388C>T and c.2204-14_2204-2dup was detected in the second patient. The c.3388C>T is a single nucleotide polymorphism with allele frequency of 0.045 in Han Chinese individuals. In silico and functional analyses indicated that p.Arg1130Cys, located at the nuclear localization signal (NLS) domain of neogenin led to defective nuclear translocation of neogenin. CONCLUSIONS: The hemizygous 15q deletion unmasks the recessive functional polymorphism in NEO1 which plays a pivotal role in cortical interneuron development. Our study provides the first evidence linking NEO1 with ASD in humans. PMID- 26518329 TI - Developmental aspects of a life course approach to healthy ageing. AB - We examine the mechanistic basis and wider implications of adopting a developmental perspective on human ageing. Previous models of ageing have concentrated on its genetic basis, or the detrimental effects of accumulated damage, but also have raised issues about whether ageing can be viewed as adaptive itself, or is a consequence of other adaptive processes, for example if maintenance and repair processes in the period up to reproduction are traded off against later decline in function. A life course model places ageing in the context of the attainment of peak capacity for a body system, starting in early development when plasticity permits changes in structure and function induced by a range of environmental stimuli, followed by a period of decline, the rate of which depends on the peak attained as well as the later life conditions. Such path dependency in the rate of ageing may offer new insights into its modification. Focusing on musculoskeletal and cardiovascular function, we discuss this model and the possible underlying mechanisms, including endothelial function, oxidative stress, stem cells and nutritional factors such as vitamin D status. Epigenetic changes induced during developmental plasticity, and immune function may provide a common mechanistic process underlying a life course model of ageing. The life course trajectory differs in high and low resource settings. New insights into the developmental components of the life course model of ageing may lead to the design of biomarkers of later chronic disease risk and to new interventions to promote healthy ageing, with important implications for public health. PMID- 26518332 TI - Infralimbic cortex controls the activity of the hypothalamus-pituitary-adrenal axis and the formation of aversive memory: Effects of environmental enrichment. AB - The aim of the present study was to investigate the effects of the stimulation and inhibition of the ventral part of the medial prefrontal cortex (infralimbic cortex) on basal and stress-induced plasma levels of corticosterone and on the acquisition of aversive memory in animals maintained in control and environmental enrichment (EE) conditions. Intracortical microinjections of the GABAA antagonist picrotoxin and agonist muscimol were performed in male Wistar rats to stimulate and inhibit, respectively, the activity of the infralimbic cortex. Injections were performed 60 min before foot shock stress and training in the inhibitory avoidance task. Picrotoxin injections into the infralimbic cortex increased basal plasma levels of corticosterone. These increases were higher in EE rats which suggest that EE enhances the control exerted by infralimbic cortex over the hypothalamus-pituitary-adrenal (HPA) axis and corticosterone release. Muscimol injections into the infralimbic cortex reduced the stress-induced plasma levels of corticosterone and the retention latency 24h after training in the inhibitory avoidance performance in control and EE animals, respectively. These results further suggest that the infralimbic cortex is required for the activation of the HPA axis during stress and for the acquisition of contextual aversive memories. PMID- 26518333 TI - Correlation of rabbit antithymocyte globulin serum levels and clinical outcomes in children who received hematopoietic stem cell transplantation from an alternative donor. AB - We analyzed the correlation between rabbit ATG (rATG) serum levels and clinical outcomes in 37 children who received rATG at a total dose of 10 or 15 mg/kg during HSCT conditioning from an alternative donor. Fourteen patients had advanced malignant diseases, 13 had severe AA, and 10 had inherited disorders. Complete engraftment was achieved in all patients, and no rejection occurred. The cumulative incidence of grades II-IV acute GVHD and extensive chronic GVHD was 27% (95% CI, 12.5-39.6%) and 8.1% (95% CI, 0-23.1%), respectively. Multivariate analysis identified lower rATG levels at week 4 as an independent risk factor in the development of grades II-IV acute GVHD (p = 0.037). Serious infections were not observed in any patient following HSCT. No correlation was found between EBV reactivation and rATG levels at week 2 and week 4 after HSCT. Furthermore, no correlation was found between relapse and rATG levels two and four wk post transplantation. The probability of five-yr OS among patients was 70.3% (95% CI, 59.8-79.2%). Our results suggest that targeted rATG administration may protect patients from severe acute GVHD without increasing the risk of EBV reactivation or relapse. PMID- 26518334 TI - Variation detection based on next-generation sequencing of type Chinese 1 strains of Toxoplasma gondii with different virulence from China. AB - BACKGROUND: Toxoplasma gondii is an intracellular protozoan that affects most species of endothermic animals including humans with a great infection rate. The vertical transmission of T. gondii causes abortion, constituting a serious threat to humans and leading to great losses in livestock production. Distinct from population structure of T. gondii in North America and Europe, Chinese 1 (ToxoDB #9) is a dominant genotype prevalent in China. Among the isolates of Chinese 1, the Wh3 and Wh6 have different virulence and pathogenicity in mice. However, little has been known about their difference at the genomic level. Thus the next generation sequencing (NGS) approach was used to discover the association of the phenotypical variations with the genome sequencing data and the expression and polymorphisms of the key effectors. RESULTS: We successfully sequenced the genome of Chinese 1 strains of Wh3 and Wh6. The average sequencing depths were 63.91 and 63.61 for Wh3 and Wh6, respectively. The variations of both isolates were identified in comparison with reference genome of type I GT1 strain. There were 505,645 and 505,856 SNPs, 30,658 and 30,004 indels, 4661 and 2320 SVs, and 1942 and 3080 CNVs for Wh3 and Wh6, respectively. In target search variations of particular factors of T. gondii, the dense granule protein 3 (GRA3) and rhoptry neck protein 3 (RON3) were found to have 35 SNPs, 2 indels and 89 SNPs, 6 indels, respectively. GRA3 and RON3 were both found to have higher expression levels in less virulent Wh6 than in virulent Wh3. Both strains of type Chinese 1 share polymorphic GRA15II and ROPI/III with type I, II, and III strains. CONCLUSIONS: Sequencing of the two strains revealed that genome structure of Chinese 1 and type I strains has considerable genomic variations. Sequencing and qRT-PCR analyses of 26 effectors displayed a remarkable variation that may be associated with phenotype and pathogenic differences. PMID- 26518335 TI - Growth and sporulation defects in Bacillus subtilis mutants with a single rrn operon can be suppressed by amplification of the rrn operon. AB - The genome of Bacillus subtilis strain 168 encodes ten rRNA (rrn) operons. We previously reported that strains with only a single rrn operon had a decreased growth and sporulation frequency. We report here the isolation and characterization of suppressor mutants from seven strains that each have a single rrn operon (rrnO, A, J, I, E, D or B). The suppressor mutants for strain RIK656 with a single rrnO operon had a higher frequency of larger colonies. These suppressor mutants had not only increased growth rates, but also increased sporulation frequencies and ribosome levels compared to the parental mutant strain RIK656. Quantitative PCR analyses showed that all these suppressor mutants had an increased number of copies of the rrnO operon. Suppressor mutants were also isolated from the six other strains with single rrn operons (rrnA, J, I, E, D or B). Next generation and capillary sequencing showed that all of the suppressor mutants had tandem repeats of the chromosomal locus containing the remaining rrn operon (amplicon). These amplicons varied in size from approximately 9 to 179 kb. The amplifications were likely to be initiated by illegitimate recombination between non- or micro-homologous sequences, followed by unequal crossing-over during DNA replication. These results are consistent with our previous report that rrn operon copy number has a major role in cellular processes such as cell growth and sporulation. PMID- 26518336 TI - Differential spectral quantitative electroencephalography patterns between control and Parkinson's disease cohorts. AB - BACKGROUND AND PURPOSE: It is believed that progressive Lewy-type synucleinopathy (LTS) is primarily responsible for the worsening of motor and non-motor Parkinson's disease (PD) signs and symptoms. Characterization of quantitative electroencephalography (QEEG) abnormalities across the spectrum of LTS to PD dementia (PD-D) may provide insight into the pathophysiology of PD cortical dysfunction. Here our enlarged EEG database was leveraged to characterize spectral QEEG abnormalities in asymptomatic autopsy-defined groups of control participants and incidental Lewy body disease (ILBD) and three clinically defined groups of participants with PD (cognitively normal PD, mild cognitive impairment PD, and PD-D). METHODS: The PD cohort was studied as part of the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). AZSAND utilizes its Brain and Body Donation Program to perform prospective, standardized, regular longitudinal pre-mortem assessments until death. Resting EEG from subjects was analyzed for spectral domain QEEG measures of background rhythm frequency and global relative power in delta, theta, alpha and beta bands. RESULTS: The various spectral QEEG measures showed differential changes specific to the groups compared. Important findings were background rhythm frequency showing the most pairwise differences across the groups, and this also was the only significant difference between control and ILBD. An increase in delta bandpower was characteristic of worsening cognitive deficits. CONCLUSIONS: Different patterns of change amongst QEEG measures across LTS and PD cognitive states suggest that they correlate with heterogeneous pathophysiologies of cortical dysfunction within the PD clinical spectrum. In addition, the biomarker application of a specific spectral QEEG measure needs to be selectively suited to its study purpose. PMID- 26518337 TI - Determinants of postnatal care use at health facilities in rural Tanzania: multilevel analysis of a household survey. AB - BACKGROUND: Postnatal care (PNC) for the mother and infant is a neglected area, even for women who give birth in a health facility. Currently, there is very little evidence on the determinants of use of postnatal care from health facilities in Tanzania. METHODS: This study examined the role of individual and community-level variables on the use of postnatal health services, defined as a check up from a heath facility within 42 days of delivery, using multilevel logistic regression analysis. We analyzed data of 1931 women, who had delivered in the preceding 2-14 months, from a two-stage household survey in 4 rural districts of Morogoro region, Tanzania. Individual level explanatory variables included i) Socio-demographic factors: age, birth order, education, and wealth, ii) Factors related to pregnancy: frequency of antenatal visits, history of complications, mode of delivery, place of delivery care, and counseling received. Community level variables included community levels of family planning, health service utilization, trust, poverty and education, and distance to health facility. RESULTS: Less than one in four women in Morogoro reported having visited a health facility for postnatal care. Individual-level attributes positively associated with postnatal care use were women's education of primary level or higher [Odds Ratio (OR) 1.37, 95 % Confidence Interval (CI) 1.04-1.81], having had a caesarean section or forceps delivery (2.95, 1.8-4.81), and being counseled by a community health worker to go for postnatal care at a health facility (2.3, 1.36-3.89). Other positive associations included those recommended HIV testing for baby (1.94, 1.19-3.15), and whose partners tested for HIV (1.41, 1.07-1.86). High community levels of postpartum family planning usage (2.48, 1.15 5.37) and high level of trust in health system (1.77, 1.12-2.79) were two significant community-level predictors. Lower postnatal care use was associated with having delivered at a hospital (0.5, 0.33-0.76), health center (0.57, 0.38 0.85), or dispensary (0.48, 0.33-0.69), and having had severe swelling of face and legs during pregnancy (0.65, 0.43-0.97). CONCLUSIONS: In the context of low postnatal care use in a rural setting, programs should direct efforts towards reaching women who do not avail themselves of postnatal care as identified in our study. PMID- 26518338 TI - Effect of temperature and humidity on post-gel shrinkage, cusp deformation, bond strength and shrinkage stress - Construction of a chamber to simulate the oral environment. AB - OBJECTIVES: Evaluate the effect of environment on post-gel shrinkage (Shr), cuspal strains (CS), microtensile bond strength (MUTBS), elastic modulus (E) and shrinkage stress in molars with large class II restorations. METHODS: Sixty human molars received standardized Class II mesio-oclusal-distal cavity preparations. Restorations were made with two composites (CHA, Charisma Diamond, Heraus Kulzer and IPS Empress Direct, Ivoclar-Vivadent) using three environment conditions (22 degrees C/50% humidity, 37 degrees C/50% humidity and 37 degrees C/90% humidity) simulated in custom developed chamber. Shr was measured using the strain gauge technique (n=10). CS was measured using strain gauges. Half of the teeth (n=5) were used to assess the elastic modulus (E) and Knoop hardness (KHN) at different depths using microhardness indentation. The other half (n=5) was used to measure the MUTBS. The composites and environment conditions were simulated in a two dimensional finite element analysis of a tooth restoration. Polymerization shrinkage was modeled using Shr data. The Shr, CS, MUTBS, KHN and E data were statistically analyzed using two-way ANOVA and Tukey test (significance level: 0.05). RESULTS: Both composites had similar Shr, CS, MUTBS and shrinkage stress. CHA had higher elastic modulus than IPS. Increasing temperature and humidity significantly increased Shr, CS and shrinkage stress. MUTBS were similar for groups with lower humidity, irrespective of temperature, and higher with higher humidity. E and KHN were constant through the depth for CHA. E and KHN values were affected by environment only for IPS, mainly deeper in the cavity. Shrinkage stress at dentin/composite interface had high inverse correlation with MUTBS. Shrinkage stress in enamel had high correlation with CS. CONCLUSIONS: Increasing temperature and humidity caused higher post-gel shrinkage and cusp deformation with higher shrinkage stresses in the tooth structure and tooth/restoration interface for both composites tested. The chamber developed for simulating the oral environment conditions will improve the realism of in vitro studies. Clinical significance Simulating oral temperature and humidity is important to better determine the biomechanical behavior of composite resin restoration. Avoiding high humidity during restorative procedures using rubber dam isolation may reduce cuspal deformation and shrinkage stress and improve the bonding strength of posterior composite restorations. PMID- 26518339 TI - Functional monomer impurity affects adhesive performance. AB - OBJECTIVE: The functional monomer 10-MDP has been considered as one of the best performing functional monomers for dental adhesives. Different adhesives containing 10-MDP are commercially available, among which many so-called 'universal' adhesives. We hypothesize that the quality of the functional monomer 10-MDP in terms of purity may affect bonding performance. METHODS: We therefore characterized three different 10-MDP versions (10-MDP_KN provided by Kuraray Noritake; 10-MDP_PCM provided by PCM; 10-MDP_DMI provided by DMI) using NMR, and analyzed their ability to form 10-MDP_Ca salts on dentin using XRD. The 'immediate' and 'aged' micro-tensile bond strength (MUTBS) to dentin of three experimental 10-MDP primers was measured. The resultant interfacial adhesive dentin ultra-structure was characterized using TEM. RESULTS: NMR disclosed impurities and the presence of 10-MDP dimer in 10-MDP_PCM and 10-MDP_DMI. 10 MDP_PCM and 10-MDP_DMI appeared also sensitive to hydrolysis. 10-MDP_KN, on the contrary, contained less impurities and dimer, and did not undergo hydrolysis. XRD revealed more intense 10-MDP_Ca salt deposition on dentin induced by 10 MDP_KN. The adhesive based on the experimental 10-MDP_KN primer resulted in a significantly higher 'immediate' bond strength that remained stable upon aging; the MUTBS of the experimental 10-MDP_PCM and 10-MDP_DMI adhesives significantly dropped upon aging. TEM revealed thicker hybridization and more intense nano layering for 10-MDP_KN. SIGNIFICANCE: It was concluded that primer impurities and the presence of 10-MDP dimer affected not only hybridization, but also reduced the formation of 10-MDP_Ca salts and nano-layering. 10-MDP in a high purity grade is essential to achieve durable bonding. PMID- 26518340 TI - HMMvar-func: a new method for predicting the functional outcome of genetic variants. AB - BACKGROUND: Numerous tools have been developed to predict the fitness effects (i.e., neutral, deleterious, or beneficial) of genetic variants on corresponding proteins. However, prediction in terms of whether a variant causes the variant bearing protein to lose the original function or gain new function is also needed for better understanding of how the variant contributes to disease/cancer. To address this problem, the present work introduces and computationally defines four types of functional outcome of a variant: gain, loss, switch, and conservation of function. The deployment of multiple hidden Markov models is proposed to computationally classify mutations by the four functional impact types. RESULTS: The functional outcome is predicted for over a hundred thyroid stimulating hormone receptor (TSHR) mutations, as well as cancer related mutations in oncogenes or tumor suppressor genes. The results show that the proposed computational method is effective in fine grained prediction of the functional outcome of a mutation, and can be used to help elucidate the molecular mechanism of disease/cancer causing mutations. The program is freely available at http://bioinformatics.cs.vt.edu/zhanglab/HMMvar/download.php. CONCLUSION: This work is the first to computationally define and predict functional impact of mutations, loss, switch, gain, or conservation of function. These fine grained predictions can be especially useful for identifying mutations that cause or are linked to cancer. PMID- 26518341 TI - Cytokine, catabolic enzyme and structural matrix gene expression in synovial fluid following intra-articular administration of triamcinolone acetonide in exercised horses. AB - REASON FOR PERFORMING STUDY: The frequent use of intra-articular triamcinolone acetonide (TA) in performance horses warrants further study of the duration of as well as the beneficial and detrimental effects on gene expression associated with administration. OBJECTIVES: To assess the effects of intra-articular administration of TA on the expression of selected anti- and proinflammatory and structural matrix genes following its administration into joints of exercised Thoroughbred horses and to correlate these effects with plasma and synovial fluid drug concentrations. STUDY DESIGN: Block design experiment. METHODS: Eight exercised horses received a single intra-articular administration of 9 mg of TA. Synovial fluid samples were collected from the treated and contralateral joints prior to and up to 49 days following drug administration. Microarray and quantitative reverse transcription polymerase chain reaction analysis were used to assess changes in expression levels of various inflammatory and structural genes post drug administration. RESULTS: Drug concentrations in plasma and synovial fluid, were no longer quantifiable by 6 and 28 days following drug administration respectively. In total, the expression level of 5490 genes were significantly altered on micro array analysis, following intra-articular TA administration. Of the genes selected for further study by quantitative reverse transcription polymerase chain reaction analysis, significant changes in inflammatory genes (annexin type 1, cyclooxygenase-1 and tumour necrosis factor stimulated gene 6) and structural genes (collagen and aggrecan) were noted. CONCLUSIONS: This study supports the use of synovial fluid as a biological matrix for studying the effects of corticosteroids on gene expression. For the majority of genes studied the effects on expression relative to baseline for both inflammatory and matrix genes were prolonged relative to plasma and synovial fluid TA concentrations. Downregulation of collagen gene expression warrants the careful use of TA in horses. PMID- 26518342 TI - Revisiting Plant Plasma Membrane Lipids in Tobacco: A Focus on Sphingolipids. AB - The lipid composition of plasma membrane (PM) and the corresponding detergent insoluble membrane (DIM) fraction were analyzed with a specific focus on highly polar sphingolipids, so-called glycosyl inositol phosphorylceramides (GIPCs). Using tobacco (Nicotiana tabacum) 'Bright Yellow 2' cell suspension and leaves, evidence is provided that GIPCs represent up to 40 mol % of the PM lipids. Comparative analysis of DIMs with the PM showed an enrichment of 2-hydroxylated very-long-chain fatty acid-containing GIPCs and polyglycosylated GIPCs in the DIMs. Purified antibodies raised against these GIPCs were further used for immunogold-electron microscopy strategy, revealing the distribution of polyglycosylated GIPCs in domains of 35 +/- 7 nm in the plane of the PM. Biophysical studies also showed strong interactions between GIPCs and sterols and suggested a role for very-long-chain fatty acids in the interdigitation between the two PM-composing monolayers. The ins and outs of lipid asymmetry, raft formation, and interdigitation in plant membrane biology are finally discussed. PMID- 26518343 TI - A Systems Genetics Approach Identifies Gene Regulatory Networks Associated with Fatty Acid Composition in Brassica rapa Seed. AB - Fatty acids in seeds affect seed germination and seedling vigor, and fatty acid composition determines the quality of seed oil. In this study, quantitative trait locus (QTL) mapping of fatty acid and transcript abundance was integrated with gene network analysis to unravel the genetic regulation of seed fatty acid composition in a Brassica rapa doubled haploid population from a cross between a yellow sarson oil type and a black-seeded pak choi. The distribution of major QTLs for fatty acids showed a relationship with the fatty acid types: linkage group A03 for monounsaturated fatty acids, A04 for saturated fatty acids, and A05 for polyunsaturated fatty acids. Using a genetical genomics approach, expression quantitative trait locus (eQTL) hotspots were found at major fatty acid QTLs on linkage groups A03, A04, A05, and A09. An eQTL-guided gene coexpression network of lipid metabolism-related genes showed major hubs at the genes BrPLA2-ALPHA, BrWD-40, a number of seed storage protein genes, and the transcription factor BrMD-2, suggesting essential roles for these genes in lipid metabolism. Three subnetworks were extracted for the economically important and most abundant fatty acids erucic, oleic, linoleic, and linolenic acids. Network analysis, combined with comparison of the genome positions of cis- or trans-eQTLs with fatty acid QTLs, allowed the identification of candidate genes for genetic regulation of these fatty acids. The generated insights in the genetic architecture of fatty acid composition and the underlying complex gene regulatory networks in B. rapa seeds are discussed. PMID- 26518344 TI - In Vivo Quantification of Peroxisome Tethering to Chloroplasts in Tobacco Epidermal Cells Using Optical Tweezers. AB - Peroxisomes are highly motile organelles that display a range of motions within a short time frame. In static snapshots, they can be juxtaposed to chloroplasts, which has led to the hypothesis that they are physically interacting. Here, using optical tweezers, we tested the dynamic physical interaction in vivo. Using near infrared optical tweezers combined with TIRF microscopy, we were able to trap peroxisomes and approximate the forces involved in chloroplast association in vivo in tobacco (Nicotiana tabacum) and observed weaker tethering to additional unknown structures within the cell. We show that chloroplasts and peroxisomes are physically tethered through peroxules, a poorly described structure in plant cells. We suggest that peroxules have a novel role in maintaining peroxisome organelle interactions in the dynamic environment. This could be important for fatty acid mobilization and photorespiration through the interaction with oil bodies and chloroplasts, highlighting a fundamentally important role for organelle interactions for essential biochemistry and physiological processes. PMID- 26518345 TI - Hard-to-reach populations of men who have sex with men and sex workers: a systematic review on sampling methods. AB - BACKGROUND: In public health, hard-to-reach populations are often recruited by non-probabilistic sampling methods that produce biased results. In order to overcome this, several sampling methods have been improved and developed in the last years. The aim of this systematic review was to identify all current methods used to survey most-at-risk populations of men who have sex with men and sex workers. The review also aimed to assess if there were any relations between the study populations and the sampling methods used to recruit them. Lastly, we wanted to assess if the number of publications originated in middle and low human development (MLHD) countries had been increasing in the last years. METHODS: A systematic review was conducted using electronic databases and a total of 268 published studies were included in the analysis. RESULTS: In this review, 11 recruitment methods were identified. Semi-probabilistic methods were used most commonly to survey men who have sex with men, and the use of the Internet was the method that gathered more respondents. We found that female sex workers were more frequently recruited through non-probabilistic methods than men who have sex with men (odds = 2.2; p < 0.05; confidence interval (CI) [1.1-4.2]). In the last 6 years, the number of studies based in middle and low human development countries increased more than the number of studies based in very high and high human development countries (odds = 2.5; p < 0.05; CI [1.3-4.9]). CONCLUSIONS: This systematic literature review identified 11 methods used to sample men who have sex with men and female sex workers. There is an association between the type of sampling method and the population being studied. The number of studies based in middle and low human development countries has increased in the last 6 years of this study. PMID- 26518346 TI - De novo lipogenesis in Atlantic salmon adipocytes. AB - BACKGROUND: Carnivorous teleost fish utilize glucose poorly, and the reason for this is not known. It is possible that the capacity of adipocytes to synthesize lipids from carbohydrate precursors through a process known as "de novo lipogenesis" (DNL) is one of the factors that contributes to glucose intolerance in Atlantic salmon. METHODS: Primary adipocytes from Atlantic salmon differentiated in vitro were incubated with radiolabelled glucose in order to explore the capacity of salmon adipocytes to synthesize and deposit lipids from glucose through DNL. The lipid-storage capacity of adipocytes incubated with glucose was compared with that of cells incubated with the fatty acid palmitic acid. Quantitative PCR and immunohistochemistry were used to assess changes of genes and proteins involved in glucose and lipid transport and metabolism. RESULTS: Less than 0.1% of the radiolabelled glucose was metabolized to the fatty acids 16:0 and the stearoyl-CoA desaturase products 16:1 and 18:1 by DNL, whereas approximately 40% was converted to glycerol to form the triacylglycerol backbone of lipids. Transcriptional analysis indicated that adipocytes ensure the availability of necessary cofactors and other substrates for lipid synthesis and storage from glycolysis, the pentose phosphate pathway and glyceroneogenesis. CONCLUSIONS: We have shown for the first time that the DNL pathway is active in fish adipocytes. The capacity of the pathway to convert glucose into cellular lipids for storage is relatively low. GENERAL SIGNIFICANCE: The limited capacity of adipocytes to utilize glucose as a substrate for lipid deposition may contribute to glucose intolerance in salmonids. PMID- 26518347 TI - Influence of a family 29 carbohydrate binding module on the activity of galactose oxidase from Fusarium graminearum. AB - BACKGROUND: Galactose oxidase (GaO) selectively oxidizes the primary hydroxyl of galactose to a carbonyl, facilitating targeted chemical derivatization of galactose-containing polysaccharides, leading to renewable polymers with tailored physical and chemical properties. Here we investigate the impact of a family 29 glucomannan binding module on the activity and binding of GaO towards various polysaccharides. Specifically, CBM29-1-2 from Piromyces equi was separately linked to the N- and C-termini of GaO. RESULTS: Both GaO-CBM29 and CBM29-GaO were successfully expressed in Pichia pastoris, and demonstrated enhanced binding to galactomannan, galactoglucomannan and galactoxyloglucan. The position of the CBM29 fusion affected the enzyme function. Particularly, C-terminal fusion led to greatest increases in galactomannan binding and catalytic efficiency, where relative to wild-type GaO, kcat/Km values increased by 7.5 and 19.8 times on guar galactomannan and locust bean galactomannan, respectively. The fusion of CBM29 also induced oligomerization of GaO-CBM29. MAJOR CONCLUSIONS: Similar to impacts of cellulose-binding modules associated with cellulolytic enzymes, increased substrate binding impeded the action of GaO fusions on more concentrated preparations of galactomannan, galactoglucomannan and galactoxyloglucan; this was especially true for GaO-CBM29. Given the N-terminal positioning of the native galactose-binding CBM32 in GaO, the varying impacts of N-terminal versus C terminal fusion of CBM29-1-2 may reflect competing action of neighboring CBMs. GENERAL SIGNIFICANCE: This study thoroughly examines and discusses the effects of CBM fusion to non-lignocellulytic enzymes on soluble polysaccharides. Herein kinetics of GaO on galactose containing polysaccharides is presented for the first time. PMID- 26518348 TI - Proton pump inhibitors drastically modify triosephosphate isomerase from Giardia lamblia at functional and structural levels, providing molecular leads in the design of new antigiardiasic drugs. AB - BACKGROUND: Proton pump inhibitors (PPIs) are extensively used in clinical practice because of their effectiveness and safety. Omeprazole is one of the best selling drugs worldwide and, with other PPIs, has been proposed to be potential drugs for the treatment of several diseases. We demonstrated that omeprazole shows cytotoxic effects in Giardia and concomitantly inactivates giardial triosephosphate isomerase (GlTIM). Therefore, we evaluated the efficiency of commercially available PPIs to inactivate this enzyme. METHODS: We assayed the effect of PPIs on the GlTIM WT, single Cys mutants, and the human counterpart, following enzyme activity, thermal stability, exposure of hydrophobic regions, and susceptibility to limited proteolysis. RESULTS: PPIs efficiently inactivated GlTIM; however, rabeprazole was the best inactivating drug and was nearly ten times more effective. The mechanism of inactivation by PPIs was through the modification of the Cys 222 residue. Moreover, there are important changes at the structural level, the thermal stability of inactivated-GlTIM was drastically diminished and the structural rigidity was lost, as observed by the exposure of hydrophobic regions and their susceptibility to limited proteolysis. CONCLUSIONS: Our results demonstrate that rabeprazole is the most potent PPI for GlTIM inactivation and that all PPIs tested have substantial abilities to alter GITIM at the structural level, causing serious damage. GENERAL SIGNIFICANCE: This is the first report demonstrating the effectiveness of commercial PPIs on a glycolytic parasitic enzyme, with structural features well known. This study is a step forward in the use and understanding the implicated mechanisms of new antigiardiasic drugs safe in humans. PMID- 26518349 TI - Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors. AB - BACKGROUND: We have previously shown that some synthetic hydroxylated stigmastanes derived from plant sterols inhibit in vitro HSV-1 replication in ocular cell lines and decrease cytokine production in stimulated macrophages, suggesting that these steroids might combine antiviral and immunomodulating properties. In this paper we report the synthesis of some analogs fluorinated at C-6 in order to study the effect of this modification on bioactivity. METHODS: The following methods were used: organic synthesis of fluorinated analogs, cytotoxicity determination with MTT assays, cytokine production quantification with ELISAs, glucocorticoid activity determination by displacement assays, immunofluorescence and transcriptional activity assays, studies of the activation of signaling pathways by Western blot, antiviral activity evaluation through virus yield reduction assays. RESULTS: We report the chemical synthesis of new fluorinated stigmastanes and show that this family of steroidal compounds exerts its immunomodulating activity by inhibiting ERK and Akt signaling pathways, but do not act as glucocorticoids. We also demonstrate that fluorination enhances the antiviral activity. CONCLUSIONS: Fluorination on C-6 did not enhance the anti inflammatory effect, however, an increase in the in vitro antiviral activity was observed. Thus, our results suggest that it is possible to introduce chemical modifications on the parent steroids in order to selectively modulate one of the effects. GENERAL SIGNIFICANCE: This family of steroids could allow the development of an alternative treatment for ocular immunopathologies triggered by HSV-1, without the undesirable side effects of the currently used drugs. PMID- 26518350 TI - Study of the phase transition in lysozyme crystals by Raman spectroscopy. AB - BACKGROUND: Recently, it has been revealed that tetragonal lysozyme crystals show a phase transition at 307 K upon heating. The underlying mechanisms of the phase transition are still not fully understood. Here we focus on the study of high frequency vibrational modes arising from the protein and their temperature evolution in the vicinity of Tph as well as on the detailed study of crystalline water dynamics near Tph. METHODS: Raman experiments have been performed at temperatures 295-323 K including Tph. The low-frequency modes and the modes of fingerprint region, CH- and OH-stretching regions have been analyzed. RESULTS AND CONCLUSIONS: In spite of the absence of noticeable rearrangements in protein structure, the high-frequency vibrational modes of lysozyme located in the fingerprint region have been found to exhibit the features of critical dynamics near Tph. Pronounced changes in the dynamics of alpha-helixes and Tyr residues exposed on the protein surface point to the important role of H-bond rearrangements at the phase transition. Additionally the study of temperature evolution of OH-stretching modes has shown an increase in distortions of tertahedral H-bond network of crystalline water above Tph. These changes in water dynamics could play a crucial role in the mechanisms of the phase transition. GENERAL SIGNIFICANCE: The present results shed light on the mechanisms of the phase transition in lysozyme crystals. PMID- 26518351 TI - Communication Within Hospice Interdisciplinary Teams: A Narrative Review. AB - Hospice care is coordinated through an interdisciplinary team (IDT), which assures that a holistic care plan based on the patient's wishes is implemented. The extent to which an IDT provides quality care may be associated with how effectively they communicate within the team as well as with patients, caregivers, and families. This review seeks to characterize communication strategies among hospice IDT members and to determine how such strategies impact patient care. Although the existing literature sheds some light on communication within hospice IDTs, further research is needed. Inquiry into the communicative process of IDTs in settings other than team meetings, such as during patient visits or informal settings, would provide a more comprehensive representation of how communication influences IDT dynamics and overall team functioning. PMID- 26518352 TI - The Effect of Using an Electric Fan on Dyspnea in Chinese Patients With Terminal Cancer. AB - BACKGROUND: Fan therapy is often suggested for relieving the symptom of dyspnea in patients with advanced cancer, but relevant literature among Asians is limited. OBJECTIVE: Phase 2 clinical trial to assess the clinical feasibility and outcome of using an electric fan to alleviate the symptom of dyspnea in Chinese patients with advanced cancer. METHODS: Thirty patients with advanced cancer having unresolved breathlessness were recruited from Hospice and Palliative Care Centre of Kiang Wu Hospital in Macau. Participants were randomly and equally allocated to the experimental group and the control group, respectively. OUTCOME MEASURES: Verbal numerical rating scale (NRS) of breathlessness, respiratory rate (RR), and saturation of peripheral oxygen (SpO2) was collected before and after the intervention. RESULTS: T test was used to analyze the data collected. There was a significant difference in the NRS scores of the experimental group ( P < .01), indicating a significant reduction in the patients' sensation of breathlessness after fan therapy, whereas no significant difference was found in the objective statistic results of RR and SpO2. No significant difference ( P > .05) was found in the control group for all the 3 variables before and after routine treatment. CONCLUSION: The results of the study suggested that fan therapy could be effective in alleviating dyspnea in Chinese patients with advanced cancer. It should be considered as one of the nonpharmacological treatment option. Future large-scale phase 3 clinical trials are warranted. PMID- 26518353 TI - Migraine headache and risk of self-harm and suicide: A population-based study in Ontario, Canada. AB - BACKGROUND: Migraine has been associated with mental illness, and may also be associated with increased risk of suicidal behavior. OBJECTIVE: The aim of this article was to examine the association between migraine headache and self-harm and suicide mortality using population-based health administrative data from Ontario, Canada. METHODS: The sample included 101,114 participants in a population-based health survey in the province of Ontario, Canada, who responded to the survey in 2003, 2005, or 2007, and provided health card numbers for linkage to population-based health administrative data. Participants self reported a physician diagnosis of migraine headache. Heath administrative data were used to calculate (1) Follow-up time until first presentation to the emergency department for intentional self-harm; (2) Follow-up time until death by suicide. Proportional subdistribution hazards regression was used to compare time until death among those with and without history of migraine, after accounting for competing risks of death and adjusting for confounders. RESULTS: Physician diagnosis of migraine was reported by 11.2% of the sample (11,314 individuals). Mean follow-up time was 7.3 years. Emergency department visits for self-harm during the follow-up period were almost 50% more likely in those with migraine (76.4 vs 35.7 per 100,000 person years; adjusted hazard ratio = 1.48; 95%CI: 1.11,1.96). Death by suicide was rare with only 55 suicides in the follow-up period (7.45 per 100,000 person-years). Risk of suicide was similar for both those with and without history of migraine headache (adjusted hazard ratio=0.60; 95%CI: 0.22,1.65). CONCLUSIONS: Physician diagnosis of migraine headache was found to be prospectively associated with increased risk of deliberate self-harm, but there was no evidence linking it to suicide mortality. Definitively linking migraine to death by suicide may require very large samples. Health care professionals should consider monitoring suicidal risk in individuals with migraine headache. PMID- 26518354 TI - Adult pancreatic hemangioma in pregnancy--concerns and considerations of a rare case. AB - BACKGROUND: Pancreatic tumors in pregnancy are rare but clinically challenging. Careful diagnostic workup, including appropriate imaging examinations, should be performed to evaluate surgery indications and timing . In the present case a diagnosis of an adult pancreatic hemangioma was made. We were not able to identify a similar case in the very sparse literature on this rare disease. CASE PRESENTATION: A 30-year-old woman at 12 weeks of gestation was diagnosed with a large pancreatic tumor having a cystic pattern based on imaging. Although the preoperative diagnosis was uncertain, patient preference and clinical symptoms and signs suggested surgery. Open distal pancreatic resection including splenectomy was performed, and complete resection of the large cystic tumor was successfully achieved, with no postoperative complications. Although a solid pseudopapillary epithelial neoplasm (SPEN) was suspected, specimen morphology, including immunohistochemistry, supported the diagnosis of an adult benign pancreatic hemangioma. CONCLUSION: Although mucinous cystic neoplasm (MCN) and adenocarcinoma are the most common pancreatic tumors during pregnancy, various other malignant and benign lesions can be encountered. This report adds to the very small number of pancreatic hemangiomas reported in the literature and involves the first patient diagnosed with this rare condition during pregnancy. Careful clinical considerations regarding diagnostic workup and treatments are required to ensure that mother and child receive the best possible care. PMID- 26518355 TI - Folliculotropic mycosis fungoides presenting as non-inflammatory scarring scalp alopecia associated with comedo-like lesions. PMID- 26518356 TI - Changes in T-cell subsets identify responders to FcR-nonbinding anti-CD3 mAb (teplizumab) in patients with type 1 diabetes. AB - The mechanisms whereby immune therapies affect progression of type 1 diabetes (T1D) are not well understood. Teplizumab, an FcR nonbinding anti-CD3 mAb, has shown efficacy in multiple randomized clinical trials. We previously reported an increase in the frequency of circulating CD8(+) central memory (CD8CM) T cells in clinical responders, but the generalizability of this finding and the molecular effects of teplizumab on these T cells have not been evaluated. We analyzed data from two randomized clinical studies of teplizumab in patients with new- and recent-onset T1D. At the conclusion of therapy, clinical responders showed a significant reduction in circulating CD4(+) effector memory T cells. Afterward, there was an increase in the frequency and absolute number of CD8CM T cells. In vitro, teplizumab expanded CD8CM T cells by proliferation and conversion of non CM T cells. Nanostring analysis of gene expression of CD8CM T cells from responders and nonresponders versus placebo-treated control subjects identified decreases in expression of genes associated with immune activation and increases in expression of genes associated with T-cell differentiation and regulation. We conclude that CD8CM T cells with decreased activation and regulatory gene expression are associated with clinical responses to teplizumab in patients with T1D. PMID- 26518357 TI - The Inhibitory Effect of Ciprofloxacin on the beta-Glucuronidase-mediated Deconjugation of the Irinotecan Metabolite SN-38-G. AB - The enterohepatic recycling of a drug consists of its biliary excretion and intestinal reabsorption, which is sometimes accompanied by hepatic conjugation and intestinal deconjugation reactions. beta-Glucuronidase, an intestinal bacteria-produced enzyme, can break the bond between a biliary excreted drug and glucuronic acid. Antibiotics such as ciprofloxacin can reduce the enterohepatic recycling of glucuronide-conjugated drugs. In this study, we established an in vitro system to evaluate the beta-glucuronidase-mediated deconjugation of the irinotecan metabolite SN-38-G to its active SN-38 form and the effect of ciprofloxacin thereon. SN-38 formation increased in a time-dependent manner from 5 to 30 min. in the presence of beta-glucuronidase. Ciprofloxacin and phenolphthalein-beta-D-glucuronide (PhePG), a typical beta-glucuronidase substrate, significantly decreased SN-38-G deconjugation and, hence SN-38 formation. Similarly, the antibiotics enoxacin and gatifloxacin significantly inhibited the conversion of SN-38-G to SN-38, which was not observed for levofloxacin, streptomycin, ampicillin and amoxicillin/clavulanate. Ciprofloxacin showed a dose-dependent inhibitory effect on the beta-glucuronidase-mediated conversion of SN-38-G to SN-38 with a half-maximal inhibitory concentration (IC50 ) value of 83.8 MUM. PhePG and ciprofloxacin afforded the inhibition in a competitive and non-competitive manner, respectively. These findings suggest that the reduction in the serum SN-38 concentration following co-administration of ciprofloxacin during irinotecan treatment is due, at least partly, to the decreased enterohepatic circulation of SN-38 through the non-competitive inhibition of intestinal beta-glucuronidase-mediated SN-38-G deconjugation. PMID- 26518358 TI - N-Acetyl-l-cysteine effects on multi-species oral biofilm formation and bacterial ecology. AB - Future therapies for the treatment of dental decay have to consider the importance of preserving bacterial ecology while reducing biofilm adherence to teeth. A multi-species plaque-derived (MSPD) biofilm model was used to assess how concentrations of N-acetyl-l-cysteine (NAC) (0, 0.1, 1, 10%) affected the growth of complex oral biofilms. Biofilms were grown (n = 96) for 24 h on hydroxyapatite discs in BMM media with 0.5% sucrose. Bacterial viability and biomass formation was examined on each disc using a microtitre plate reader. In addition, fluorescence microscopy and Scanning Electron Microscopy was used to qualitatively examine the effect of NAC on bacterial biofilm aggregation, extracellular components and bacterial morphology. The total biomass was significantly decreased after exposure of both 1% (from 0.48, with a 95% confidence interval of (0.44, 0.57) to 0.35, with confidence interval (0.31, 0.38)) and 10% NAC (0.14 with confidence interval (0.11, 0.17)). 16S rRNA amplicon sequencing analysis indicated that 1% NAC reduced biofilm adherence while preserving biofilm ecology. SIGNIFICANCE AND IMPACT OF THE STUDY: As a compound with a wide safety margin, N-acetyl-l-cysteine (NAC) has the potential to be used as a long term anti-plaque bacteriostatic agent for managing chronic dental decay without substantially altering biofilm's bacterial ecology. The potential anti-caries benefit of NAC is directly related to reducing the biofilm coverage which reduces the degree of acid generation and the amount of time that the surface is exposed to a lower pH. PMID- 26518359 TI - Postoperative Knee Flexion Angle Is Affected by Lateral Laxity in Cruciate Retaining Total Knee Arthroplasty. AB - BACKGROUND: Although many studies have reported that postoperative knee flexion is influenced by preoperative conditions, the factors which affect postoperative knee flexion have not been fully elucidated. We tried to investigate the influence of intraoperative soft tissue balance on postoperative knee flexion angle after cruciate-retaining (CR) total knee arthroplasty (TKA) using a navigation and an offset-type tensor. METHODS: We retrospectively analyzed 55 patients with osteoarthritis who underwent TKA using e.motion-CR (B. Braun Aesculap, Germany) whose knee flexion angle could be measured at 2 years after operation. The exclusion criteria included valgus deformity, severe bony defect, infection, and bilateral TKA. Intraoperative varus ligament balance and joint component gap were measured with the navigation (Orthopilot 4.2; B. Braun Aesculap) while applying 40-lb joint distraction force at 0 degrees to 120 degrees of knee flexion using an offset-type tensor. Correlations between the soft tissue parameters and postoperative knee flexion angle were analyzed using simple linear regression models. RESULTS: Varus ligament balance at 90 degrees of flexion (R = 0.56; P < .001) and lateral compartment gap at 90 degrees of flexion (R = 0.51; P < .001) were positively correlated with postoperative knee flexion angle. In addition, as with past studies, joint component gap at 90 degrees of flexion (R = 0.30; P < .05) and preoperative knee flexion angle (R = 0.63; P < .001) were correlated with postoperative knee flexion angle. CONCLUSION: Lateral laxity as well as joint component gap at 90 degrees of flexion is one of the most important factors affecting postoperative knee flexion angle in CR-TKA. PMID- 26518360 TI - Factors Associated with the Emergence of Highly Pathogenic Avian Influenza A (H5N1) Poultry Outbreaks in China: Evidence from an Epidemiological Investigation in Ningxia, 2012. AB - In April 2012, highly pathogenic avian influenza virus of the H5N1 subtype (HPAIV H5N1) emerged in poultry layers in Ningxia. A retrospective case-control study was conducted to identify possible risk factors associated with the emergence of H5N1 infection and describe and quantify the spatial variation in H5N1 infection. A multivariable logistic regression model was used to identify risk factors significantly associated with the presence of infection; residual spatial variation in H5N1 risk unaccounted by the factors included in the multivariable model was investigated using a semivariogram. Our results indicate that HPAIV H5N1-infected farms were three times more likely to improperly dispose farm waste [adjusted OR = 0.37; 95% CI: 0.12-0.82] and five times more likely to have had visitors in their farm within the past month [adjusted OR = 5.47; 95% CI: 1.97 15.64] compared to H5N1-non-infected farms. The variables included in the final multivariable model accounted only 20% for the spatial clustering of H5N1 infection. The average size of a H5N1 cluster was 660 m. Bio-exclusion practices should be strengthened on poultry farms to prevent further emergence of H5N1 infection. For future poultry depopulation, operations should consider H5N1 disease clusters to be as large as 700 m. PMID- 26518361 TI - Lack of genetic isolation by distance, similar genetic structuring but different demographic histories in a fig-pollinating wasp mutualism. AB - Historical abiotic factors such as climatic oscillations and extreme climatic events as well as biotic factors have shaped the structuring of species' genetic diversity. In obligate species-specific mutualisms, the biogeographic histories of the interacting species are tightly linked. This could be particularly true for nuclear genes in the Ficus-pollinating wasp mutualistic association as the insects disperse pollen from their natal tree. In this study, we compare spatial genetic structure of plant and pollinator for the Ficus hirta-Valisia javana association throughout southeast China including Hainan Island, for both nuclear and cytoplasmic markers. We show that dispersal of the insect leads to plant and insect presenting similar signatures of lack of genetic isolation by distance for nuclear genes on the continent over a distance of 1000 km. But we also show that the demographic histories of plant and insect are strikingly different. This is in agreement with extreme climatic events leading to transient regional extinctions of the insects, associated with local survival of the plants. We also observe evidence of genetic differentiation for both wasps and fig-tree between the continent and Hainan Island, although the Qiongzhou Strait is only on average 30 km wide, suggesting that geographic isolation by itself has not been sufficient to generate this differentiation. Hence, our results suggest that in highly dispersive mutualistic systems, isolation-by-dispersal limitation across a geographic barrier could be supplemented by isolation by adaptation, and maybe by coevolution, allowing further genetic divergence. In such systems, species may frequently be composed of a single population. PMID- 26518362 TI - Gene expression profiling reveals the role of RIG1 like receptor signaling in p53 dependent apoptosis induced by PUVA in keratinocytes. AB - Photochemotherapy using 8-methoxypsoralen in combination with UVA radiation (PUVA) is an effective treatment for various skin dermatosis including psoriasis however its molecular mechanism is not clear. Previously we demonstrated that PUVA differentially regulates miRNA expression profile with a significant up regulation of hsa-miR-4516. To study in detail the molecular mechanism of PUVA in keratinocytes, we investigated the genome wide transcriptomic changes using Illumina whole genome gene expression beadchip. Microarray analysis revealed 1932 differentially expressed gene and their Insilico analysis revealed Retinoic Acid Inducible Gene-I (RIG-1) signaling, apoptosis and p53 pathway to be associated with PUVA induced effects. We demonstrate that miR-4516 mediated down-regulation of UBE2N promotes p53 nuclear translocation and pro-apoptotic activity of PUVA is independent of IRF3 but is mediated by the RIG-I in a p53 and NFkappaB dependent manner. Additionally, PUVA inactivated the AKT/mTOR pathway in concert with inhibition of autophagy and suppressed cell migration. Taken together this study broadens our understanding about the mechanism of action of PUVA providing possible new strategy targeting proapoptotic function of RIG-1, a regulator of innate immune response or p53 for psoriasis therapy. PMID- 26518363 TI - Meta-analysis of psychosocial interventions on survival time in patients with cancer. AB - OBJECTIVE: This study was to evaluate the effects of psychosocial interventions on survival in adult patients with cancer. METHOD: MEDLINE via PubMed, Cochrane Library CENTRAL, CINAHL, and Korean electronic databases (September 2014) were searched. Methodological quality was assessed using Cochrane's Risk of Bias for randomized studies. The RevMan 5.3 program of the Cochrane library was used for data analysis. RESULTS: Fifteen randomized controlled trials met the inclusion criteria, with a total of 2940 participants. Overall, psychosocial interventions was not associated with better survival (HR = .83, 95% CI [.68, 1.10], p = .06, I(2) = 64%). In subgroup analysis, based on six trials with 1448 subjects, psychoeducational interventions for cancer patients with non-metastatic at intervention implementation resulted in a 41% reduction in the risk of dying of cancer (HR = .59, 95% CI [.49, .71], p < .001, I(2) = 0%). For psychoeducational intervention, significant survival benefit were found when health staff delivered the intervention and at a follow-up time of more than 10 years. CONCLUSIONS: Use of psychoeducational interventions for cancer patients at early stage appeared to have beneficial effects on survival, preferably for delivering of health staff. However, conduct of further psychosocial studies with adequate power will lead to better understanding of the effects of treatments on survival outcome. PMID- 26518364 TI - The diagnostic challenge of mapping elephantiasis in the Tigray region of northern Ethiopia. AB - BACKGROUND: In Ethiopia, lymphatic filariasis and podoconiosis are the two neglected tropical diseases planned to be mapped together within the recently launched Ethiopian neglected tropical diseases master plan (2013-2015). However, other disorders cause tropical lymphedema, and this report aims to identify clinical epidemiological aspects of limb swelling in northern Ethiopia and to provide an algorithm orienting the clinical diagnosis. METHODS: Medical records of patients with lower limb elephantiasis attending the Italian Dermatological Centre of Mekele, Tigray capital city, over a 4-year period (2005-2009) were retrospectively analyzed. Nine variables were collected from the charts comprising demographic data, job, origin, literacy, clinical, histopathologic, microscopic, and cultural findings. RESULTS: Over a total of 511 patients, lymphedema resulted from trauma (40.7%), chronic venous insufficiency (12.5%), deep mycoses (10.8%), lymphatic filariasis (9.2%), elephantiasis nostras verrucosa (7.0%), tropical ulcer (6.3%), leprosy (4.9%), recurrent infections (3.1%), podoconiosis (1.8%), tuberculosis (1.0%), malignancy (1.3%), Kaposi's sarcoma (1.0%), leishmaniasis (0.2%), and neurofibromatosis (0.2%). CONCLUSIONS: Advanced-stage elephantiasis, chronic osteomyelitis, and podoconiosis not previously reported in Tigray were observed. Further epidemiological investigation and training programs addressed to healthcare providers at the peripheral level are needed to detect elephantiasis early, prevent disabilities, and improve patients' quality of life. PMID- 26518365 TI - Automatic analysis of the 3-D microstructure of fruit parenchyma tissue using X ray micro-CT explains differences in aeration. AB - BACKGROUND: 3D high-resolution X-ray imaging methods have emerged over the last years for visualising the anatomy of tissue samples without substantial sample preparation. Quantitative analysis of cells and intercellular spaces in these images has, however, been difficult and was largely based on manual image processing. We present here an automated procedure for processing high-resolution X-ray images of parenchyma tissues of apple (Malus * domestica Borkh.) and pear (Pyrus communis L.) as a rapid objective method for characterizing 3D plant tissue anatomy at the level of single cells and intercellular spaces. RESULTS: We isolated neighboring cells in 3D images of apple and pear cortex tissues, and constructed a virtual sieve to discard incorrectly segmented cell particles or unseparated clumps of cells. Void networks were stripped down until their essential connectivity features remained. Statistical analysis of structural parameters showed significant differences between genotypes in the void and cell networks that relate to differences in aeration properties of the tissues. CONCLUSIONS: A new model for effective oxygen diffusivity of parenchyma tissue is proposed that not only accounts for the tortuosity of interconnected voids, but also for significant diffusion across cells where the void network is not connected. This will significantly aid interpretation and analysis of future tissue aeration studies. The automated image analysis methodology will also support pheno- and genotyping studies where the 3D tissue anatomy plays a role. PMID- 26518366 TI - A stereoselective esterase from Bacillus megaterium: Purification, gene cloning, expression and catalytic properties. AB - Esterases (EC 3.1.1.X) have been used as biocatalysts due to their good stability, high chemo-, regio- and stereoselectivity. In our previous studies, Bacillus megaterium WZ009 harboring esterase displayed the unique capability to convert (S)-4-Chloro-3-hydroxyethylbutyrate (CHBE) in the racemate to (S)-3 hydroxy-gamma-butyrolactone (HL) through stereoselective hydrolysis, dechlorination, and lactonization. The remaining (R)-CHBE and formed (S)-HL could be obtained in a one-pot enzymatic reaction. An esterase from B. megaterium WZ009 was purified and was found to have 466 encoded amino acids and an apparent molecular mass of 55 kDa. The purified esterase exhibited maximal activity at a temperature of 25 degrees C and at a pH of 11.5 towards 100 mM CHBE. When the stereoselective biocatalysis of rac-CHBE was performed using the recombinant Escherichia coli BL21 (DH3) cells harboring the esterase, the catalytic activity increased by 20-fold compared with the original strain B. megaterium WZ009. With the addition of activated carbon (62 g/L) in the reaction system, the conversion was increased from 39% to 45% at a substrate concentration of 750 mM. Another remarkable advantage is that both of the obtained residual (R)-CHBE and the formed (S)-HL had high optical purities (e.e.s > 99.9%, e.e.p > 99.9%), thereby making this esterase a usable biocatalyst for industrial application. PMID- 26518367 TI - High-efficiency secretory expression of human neutrophil gelatinase-associated lipocalin from mammalian cell lines with human serum albumin signal peptide. AB - Human neutrophil gelatinase associated lipocalin (NGAL) is a secretory glycoprotein initially isolated from neutrophils. It is thought to be involved in the incidence and development of immunological diseases and cancers. Urinary and serum levels of NGAL have been investigated as a new biomarker of acute kidney injury (AKI), for an earlier and more accurate detection method than with creatinine level. However, expressing high-quality recombinant NGAL is difficult both in Escherichia coli and mammalian cells for the low yield. Here, we cloned and fused NGAL to the C-terminus of signal peptides of human NGAL, human interleukin-2 (IL2), gaussia luciferase (Gluc), human serum albumin preproprotein (HSA) or an hidden Markov model-generated signal sequence (HMM38) respectively for transient expression in Expi293F suspension cells to screen for their ability to improve the secretory expression of recombinant NGAL. The best results were obtained with signal peptide derived from HSA. The secretory recombinant protein could react specifically with NGAL antibody. For scaled production, we used HSA signal peptide to establish stable Chinese hamster ovary cell lines. Then we developed a convenient colony-selection system to select high-expression, stable cell lines. Moreover, we purified the NGAL with Ni-Sepharose column. The recombinant human NGAL displayed full biological activity. We provide a method to enhance the secretory expression of recombinant human NGAL by using the HSA signal peptide and produce the glycoprotein in mammalian cells. PMID- 26518368 TI - Stumbling reactions during perturbed walking: Neuromuscular reflex activity and 3 D kinematics of the trunk - A pilot study. AB - Reflex activity of the lower leg muscles involved when compensating for falls has already been thoroughly investigated. However, the trunk's role in this compensation strategy remains unclear. The purpose of this study, therefore, was to analyze the kinematics and muscle activity of the trunk during perturbed walking. Ten subjects (29 +/- 3 yr;79 +/- 11 cm;74 +/- 14 kg) walked (1m/s) on a split-belt treadmill, while 5 randomly timed, right-sided perturbations (treadmill belt deceleration: 40 m/s(2)) were applied. Trunk muscle activity was assessed with a 12-lead-EMG. Trunk kinematics were measured with a 3D-motion analysis system (12 markers framing 3 segments: upper thoracic area (UTA), lower thoracic area (LTA), lumbar area (LA)). The EMG-RMS [%] (0-200 ms after perturbation) was analyzed and then normalized to the RMS of normal walking. The total range of motion (ROM;[ degrees ]) for the extension/flexion, lateral flexion and rotation of each segment were calculated. Individual kinematic differences between walking and stumbling [%; ROM] were also computed. Data analysis was conducted descriptively, followed by one- and two-way ANOVAs (alpha=0.05). Stumbling led to an increase in ROM, compared to unperturbed gait, in all segments and planes. These increases ranged between 107 +/- 26% (UTA/rotation) and 262 +/- 132% (UTS/lateral flexion), significant only in lateral flexion. EMG activity of the trunk was increased during stumbling (abdominal: 665 +/- 283%; back: 501 +/- 215%), without significant differences between muscles. Provoked stumbling leads to a measurable effect on the trunk, quantifiable by an increase in ROM and EMG activity, compared to normal walking. Greater abdominal muscle activity and ROM of lateral flexion may indicate a specific compensation pattern occurring during stumbling. PMID- 26518369 TI - Initiatives on early detection and intervention to proactively identify health and social problems in older people: experiences from the Netherlands. AB - BACKGROUND: Over the last years, several initiatives on early detection and intervention have been put in place to proactively identify health and social problems in (frail) older people. An overview of the initiatives currently available in the Netherlands is lacking, and it is unknown whether they meet the preferences and needs of older people. Therefore, the objectives of this study were threefold: 1. To identify initiatives on early detection and intervention for older people in the Netherlands and compare their characteristics; 2. To explore the experiences of professionals with these initiatives; and 3. To explore to what extent existing initiatives meet the preferences and needs of older people. METHODS: We performed a qualitative descriptive study in which we conducted semi-structured interviews with seventeen experts in preventive elderly care and three group interviews with volunteer elderly advisors. Data were analysed using the framework analysis method. RESULTS: We identified eight categories of initiatives based on the setting (e.g. general practitioner practice, hospital, municipality) in which they were offered. Initiatives differed in their aims and target groups. The utilization of peers to identify problems and risks, as was done by some initiatives, was seen as a strength. Difficulties were experienced with identifying the target group that would benefit from proactive delivery of care and support most, and with addressing prevalent issues among older people (e.g. psychosocial issues, self-reliance issues). CONCLUSION: Although there is a broad array of initiatives available, there is a discrepancy between supply and demand. Current initiatives insufficiently address needs of (frail) older people. More insight is needed in "what should be done by whom, for which target group and at what moment", in order to improve current practice in preventive elderly care. PMID- 26518370 TI - Neuronal oscillations: A physiological correlate for targeting mitochondrial dysfunction in neurodegenerative diseases? AB - Increasingly in the realm of neurological disorders, particularly those involving neurodegeneration, mitochondrial dysfunction is emerging at the core of their pathogenic processes. Most of these diseases still lack effective treatment and are hampered by a shortfall in the development of novel medicines. Clearly new targets that translate well to the clinic are required. Physiological parameters in the form of neuronal network activity are increasingly being used as a therapeutic screening approach in drug development and disorders with mitochondrial dysfunction generally display neuronal network activity disturbance. However research directly linking the disturbances in neuronal network activity with mitochondrial dysfunction is only just starting to emerge. This review will summarize the breadth of knowledge linking neuronal network activity to mitochondrial dysfunction in neurodegenerative diseases and suggest potential avenues for exploration in respect to future drug development. PMID- 26518371 TI - Purinergic receptors in psychiatric disorders. AB - Psychiatric disorders describe different mental or behavioral patterns, causing suffering or poor coping of ordinary life with manifold presentations. Multifactorial processes can contribute to their development and progression. Purinergic neurotransmission and neuromodulation in the brain have attracted increasing therapeutic interest in the field of psychiatry. Purine nucleotides and nucleosides are well recognized as signaling molecules mediating cell to cell communication. The actions of ATP are mediated by ionotropic P2X and metabotropic P2Y receptor subfamilies, whilst the actions of adenosine are mediated by P1 (A1 or A2) adenosine receptors. Purinergic mechanisms and specific receptor subtypes have been shown to be linked to the regulation of many aspects of behavior and mood and to dysregulation in pathological processes of brain function. In this review the recent knowledge on the role of purinergic receptors in the two most frequent psychiatric diseases, major depression and schizophrenia, as well as on related animal models is summarized. At present the most promising data for therapeutic strategies derive from investigations of the adenosine system emphasizing a unique function of A2A receptors at neurons and astrocytes in these disorders. Among the P2 receptor family, in particular P2X7 and P2Y1 receptors were related to disturbances in major depression and schizophrenia, respectively. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID- 26518372 TI - Venoarterial Extracorporeal Membrane Oxygenation for Acute Fulminant Myocarditis in Adult Patients: A 5-Year Multi-Institutional Experience. AB - BACKGROUND: Acute fulminant myocarditis (AFM) may represent a life-threatening event, characterized by rapidly progressive cardiac compromise that ultimately leads to refractory cardiogenic shock or cardiac arrest. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides effective cardiocirculatory support in this circumstance, but few clinical series are available about early and long-term results. Data from a multicenter study group are reported which analyzed subjects affected by AFM and treated with VA-ECMO during a 5-year period. METHOD: From hospital databases, 57 patients with diagnoses of AFM treated with VA-ECMO in the past 5 years were found and analyzed. Mean age was 37.6 +/- 11.8 years; 37 patients were women. At VA-ECMO implantation, cardiogenic shock was present in 38 patients, cardiac arrest in 12, and severe hemodynamic instability in 7. A peripheral approach was used with 47 patients, whereas 10 patients had a central implantation or other access. RESULTS: Mean VA-ECMO support was 9.9 +/- 19 days (range, 2 to 24 days). Cardiac recovery with ECMO weaning was achieved in 43 patients (75.5%), major complications were observed in 40 patients (70.1%), and survival to hospital discharge occurred in 41 patients (71.9%). After hospital discharge (median follow-up, 15 months) there were 2 late deaths. The 5-year actual survival was 65.2% +/- 7.9%, with recurrent self-recovering myocarditis observed in 2 patients (at 6 and 12 months from the first AFM event), and 1 heart transplantation. CONCLUSIONS: Cardiopulmonary support with VA-ECMO provides an invaluable tool in the treatment of AFM, although major complications may characterize the hospital course. Long-term outcome appears favorable with rare episodes of recurrent myocarditis or cardiac-related events. PMID- 26518373 TI - Current Experience With Acute Type B Aortic Dissection: Validity of the Complication-Specific Approach in the Present Era. AB - BACKGROUND: Our group proposed in 1992 a "complication-specific approach" for the management of acute aortic dissection type B (TBAD), with uncomplicated cases being treated with medical therapy. In this study, we evaluate the efficacy of this management in in-hospital and postdischarge survival. METHODS: Between 1999 and 2014, 123 consecutive acute TBAD patients were treated at our institution. We compared complicated (rupture/impending rupture, malperfusion, expansion) vs uncomplicated TBAD, as well as TBAD with a dissection flap vs intramural hematoma/penetrating aortic ulcer. RESULTS: A total of 103 patients (84%) were strictly managed according to the complication-specific approach, with 93% in hospital survival. Twenty deviated from complication-specific approach management (triaged to operation by complication-specific approach, but inoperable for a variety of reasons). Independent risk factors for a complicated course in the dissection flap subgroup (n = 89) were history of coronary artery disease (odds ratio. 3.139; p = 0.04) and maximum aortic diameter exceeding 5 cm (odds ratio, 4.586; p = 0.005). Uncomplicated patients were treated medically with antiimpulse therapy. Among the 103 patients treated with the complication-specific approach, long-term survival was 83%, 78%, 71% and 47% at 1, 3, 5, and 10 years, respectively. Between the uncomplicated and complicated groups, 8-year survival was 55% and 49%, respectively (log-rank p = 0.03). Uncomplicated patients showed comparable 6-year survival (log-rank p = 0.06) to matched normal population controls. CONCLUSIONS: Patients managed with the complication-specific approach showed an overall satisfactory long-term survival over 10 years. No in-hospital deaths occurred in patients with uncomplicated, medically treated acute TBAD, with comparable long-term survival to a matched normal population. These good long-term results provide counterbalancing perspective when considering routine thoracic endovascular aortic repair for all TBAD patients. PMID- 26518374 TI - Long-Term Survival and Quality of Life of Patients Undergoing Emergency Coronary Artery Bypass Grafting for Postinfarction Cardiogenic Shock. AB - BACKGROUND: This study evaluated the long-term outcome of patients undergoing emergency coronary artery bypass grafting (eCABG) for cardiogenic shock after acute myocardial infarction. METHODS: Sixty-seven consecutive patients underwent eCABG for cardiogenic shock at 2 European institutions during an 11-year period. Preoperative, intraoperative, postoperative, and long-term follow-up data of all patients were prospectively collected. RESULTS: Hospital survival was 86% (58 of 67), with all deaths due to cardiac causes. At a mean follow-up of 78 +/- 48 months (range, 1 to 153 months), 43 of the 58 patients (74%) discharged from the hospital were alive. Causes of death in 9 of the 15 follow-up deaths (60%) were noncardiac. Overall survival rate at the end of follow-up was 64% (43 of 67). Of the 43 survivors, 41 (95%) were in New York Heart Association Functional Classification I to II, ischemia free, had a Karnofsky performance status exceeding 80, and an excellent quality of life as assessed by the Seattle Angina Questionnaire. The use of cardiopulmonary bypass and the internal thoracic artery were associated with significantly better long-term survival. CONCLUSIONS: The long-term survival and quality of life of patients who undergo eCABG for cardiogenic shock after acute myocardial infarction are good, and eCABG should be considered a valuable therapeutic option in this setting. The use of cardiopulmonary bypass and the internal thoracic artery at the time of the operation are strongly advocated. PMID- 26518375 TI - Potts Shunt and Pediatric Pulmonary Hypertension: What We Have Learned. AB - BACKGROUND: A Potts shunt has been proposed as effective palliative therapy in children with severe pulmonary hypertension (PH) who have suprasystemic right ventricular pressures. METHODS: A retrospective single-center study was performed to assess outcomes in 5 children who underwent a Potts shunt for severe PH. RESULTS: All 5 children were in World Health Organization functional class IV. Only 3 children were classified as having idiopathic pulmonary arterial PH. Preoperatively, 4 children were receiving intravenous prostacyclins, and 3 were placed on intravenous inotropes for acute right-side heart failure. Three children were potential lung transplant candidates. All but 1 child had evidence for suprasystemic right heart pressures immediately before their operation. All 5 children survived the procedure without significant complications. Four of the 5 children were successfully discharged from the hospital and have had sustained clinical improvement with follow-up ranging from approximately 5 to 16 months. The child who did not have suprasystemic right-side heart pressures before the operation did not benefit from the Potts shunt. CONCLUSIONS: The Potts shunt can be an effective palliation for children with severe PH. Our results further suggest that (1) a Potts shunt should be considered early in a child's clinical course, before right ventricular deterioration develops; (2) a Potts shunt should be considered in any child with severe, intractable PH regardless of etiology; (3) one might consider a Potts shunt in lieu of intravenous prostacyclins; and (4) a Potts shunt should be considered before lung transplantation and does not preclude future transplantation candidacy. PMID- 26518376 TI - Meta-Analysis of Medium and Long-Term Efficacy of Loading Statins After Coronary Artery Bypass Grafting. AB - BACKGROUND: The aim of this study was to evaluate the medium- and long-term efficacy of loading statins after coronary artery bypass grafting (CABG) by comparing using a loading dose of statins or a regular dose of statins in patients undergoing CABG. METHODS: We conducted a literature search of numerous databases for randomized controlled trials on the efficacy of a loading dose of statins in patients undergoing CABG. The quality of included studies was evaluated according to the Newcastle-Ottawa Scale. Statistical results of treatment were represented by weighted mean difference, odds ratio, and 95% confidence interval. RESULTS: There were 8 studies including 8,676 patients (4,352 who had a loading dose of statins and 4,324 who had a regular dose). Meta analysis showed statistically significant differences in the following in patients who took a loading dose of statins: lower level of low-density lipoprotein cholesterol (LDL-C) after CABG (p < 0.00001), fewer deaths caused by myocardial infarction (p = 0.005), fewer patients with myocardial infarction (p = 0.004), fewer patients undergoing secondary CABG (p < 0.00001), and fewer patients undergoing graft restenosis by intravascular ultrasonography (p < 0.0001). CONCLUSIONS: Comparing patients receiving a loading dose of statins with those receiving a regular dose after CABG, the medium- and long-term efficacy of a loading dose showed significant reduction in LDL-C, lower occurrence of adverse cardiac events, and reduction in graft restenosis. Although the incidence of drug related side effects was slightly higher in the loading-dose group, in the majority of patients they were not serious. Overall, a loading dose of statins is superior to regular dosing of statins after CABG. PMID- 26518377 TI - Is Tracheal Transplantation Possible With Cryopreserved Tracheal Allograft and Hyperbaric Oxygen Therapy? An Experimental Study. AB - BACKGROUND: Allografts have achieved prominence for tracheal reconstruction because of their natural physiologic and anatomic structure, which preserves respiratory tract flexibility and lumen patency. The immunomodulatory effects of cryopreservation prevent tracheal allograft rejection. In addition, hyperbaric oxygen therapy (HBOT) accelerates wound healing by promoting epithelization and neovascularization. This experimental study investigated the early and late effects of HBOT on cryopreserved tracheal allografts (CTAs). METHODS: The study used 33 outbred Wistar rats weighing 300 to 350 g as allograft transplantation donors and recipients. Among these, 22 recipient rats were randomly assigned to the HBOT (n = 11) and control (n = 11) groups. Rats in the HBOT group were treated with 100% oxygen for 60 minutes at 2.5 atmospheres of absolute pressure for 7 days. Recipient rats in both groups were euthanized at 1 week (n = 5) and 4 weeks (n = 6) after transplantation, defined as the early and late periods, respectively. RESULTS: In the early period, no significant histopathologic differences were observed between groups (p > 0.05). However, microscopic evaluation of the control group during the late period showed low epithelization of the CTA. In contrast, microscopic evaluation of the HBOT group during this same period revealed epithelium covering the transplanted CTA lumen. Significant epithelization and vascularization and significantly reduced inflammation and fibrosis were found in the HBOT group compared with the control group (p < 0.05). CONCLUSIONS: HBOT may be effective in tracheal reconstruction by increasing epithelization and neovascularization after extended tracheal resection. HBOT, therefore, should be considered in CTA transplantation. PMID- 26518378 TI - Are Reviewers' Scores Influenced by Citations to Their Own Work? An Analysis of Submitted Manuscripts and Peer Reviewer Reports. AB - STUDY OBJECTIVE: Academic medical researchers are judged by how often their publications are cited in the literature. When serving as journal reviewers, they may be more favorably disposed to manuscripts that cite their work. We investigate whether manuscripts that contain a citation to the reviewer's work receive higher evaluations than those that do not and whether peer reviewers encourage authors to cite that reviewer's work. METHODS: We analyzed all research manuscripts submitted in 2012 to Annals of Emergency Medicine to determine whether they contained citations to each reviewer's work. To determine whether citation affected reviewer scores, we obtained each reviewer's score of the manuscript's overall desirability (1=worst to 5=best) and used descriptive statistics and regression modeling to compare scores of cited and noncited reviewers. We also enumerated how often reviewers suggested that authors add citations to the reviewer's work or other work. RESULTS: There were 395 manuscripts and 999 corresponding reviews with an manuscript desirability score. The 83 reviews by cited reviewers (8.3%) had a mean score of 2.8 (SD 1.4); the 916 reviews by noncited reviewers (91.7%), 2.5 (1.2; Delta=0.3; 95% confidence interval [CI] 0 to 0.6). The mean score in the 117 reviews of the noncited reviewers of the 57 manuscripts that had both cited and noncited reviewers was 2.9 (SD 1.2) compared with 2.9 (SD 1.1) for the 68 reviews by cited reviewers (Delta=0; 95% CI -0.3 to 0.4). In the final ordinal regression model, the unadjusted OR for the manuscript desirability score was 1.6 (95% CI 1.0 to 2.7); when adjusting for the manuscripts' mean desirability score, it was 1.4 (95% CI 0.8 to 2.2), demonstrating that manuscript quality was a confounder. Authors were asked to add a citation to the reviewer's work in 28 reviews (3%) but to others' work in 98 (10%). CONCLUSION: In a leading specialty journal, cited reviewers gave higher scores than noncited reviewers. However, this was likely due to their being assigned higher-quality manuscripts and not because they were cited in the manuscript. Reviewer requests that their work be cited were rare. PMID- 26518379 TI - Results of left thoracoscopic Collis gastroplasty with laparoscopic Nissen fundoplication for the surgical treatment of true short oesophagus in gastro oesophageal reflux disease and Type III-IV hiatal hernia. AB - OBJECTIVES: Controversy exists regarding surgery for true short oesophagus (TSOE). We compared the results of thoracoscopic Collis gastroplasty-laparoscopic Nissen procedure for the treatment of TSOE with the results of standard laparoscopic Nissen fundoplication. METHODS: Between 1995 and 2013, the Collis Nissen procedure was performed in 65 patients who underwent minimally invasive surgery when the length of the abdominal oesophagus, measured intraoperatively after maximal oesophageal mediastinal mobilization, was <=1.5 cm. The results of the Collis-Nissen procedure were frequency-matched according to age, sex and period of surgical treatment with those of 65 standard Nissen fundoplication procedures in patients with a length of the abdominal oesophagus >1.5 cm. Postoperative mortality and morbidity were evaluated according to the Accordion classification. The patients underwent a timed clinical-instrumental follow-up that included symptoms assessment, barium swallow and endoscopy. Symptoms, oesophagitis and global results were graded according to semi-quantitative scales. The results were considered to be excellent in the absence of symptoms and oesophagitis, good if symptoms occurred two to four times a month in the absence of oesophagitis, fair if symptoms occurred two to four times a week in the presence of hyperaemia, oedema and/or microscopic oesophagitis and poor if symptoms occurred on a daily basis in the presence of any grade of endoscopic oesophagitis, hiatal hernia of any size or type, or the need for antireflux medical therapy. The follow-up time was calculated from the time of surgery to the last complete follow-up. RESULTS: The postoperative mortality rate was 1.5% for the Collis-Nissen and 0 for the Nissen procedure. The postoperative complication rate was 24% for the Collis-Nissen and 7% for Nissen (P = 0.001) procedure. The complication rate for the Collis-Nissen procedure was 43% in the first 32 cases and 6% in the last 33 cases (P < 0.0001). The median follow-up period was 96 months. The results were: excellent in 27% of Collis-Nissen and 29% of Nissen; good in 64% of Collis-Nissen and 55% of Nissen; fair in 3% of Collis Nissen and 11% of Nissen and poor in 6% of Collis-Nissen and 5% of Nissen (P = 0.87). CONCLUSIONS: In patients affected by a TSOE, the Collis-Nissen procedure may achieve equally satisfactory results as the standard Nissen procedure in uncomplicated patients. CLINICAL REGISTRATION NUMBER: NCT02288988. PMID- 26518381 TI - Open aortic arch surgery in chronic dissection with visceral arteries originating from different lumens. AB - OBJECTIVES: Surgical management of chronic aortic dissection is controversial, especially when the dissection extends into the abdominal aorta in which the visceral arteries originate from different lumens and is combined with aortic arch pathology necessitating surgery. The aim of the study was to evaluate the results of open surgery in this complex aortic pathology. METHODS: Between June 2002 and 2015, a total of 17 patients (median age 57, range 32-76 years) necessitating complete arch replacement presented complex chronic dissection of the thoraco-abdominal aorta with the visceral arteries originating from different lumens. Fourteen patients (82%) had had previous cardiac surgery, which was performed on the proximal aorta in all but one because of acute type A dissection. Nine patients without considerable dilatation of the descending aorta received aortic arch replacement with distal resection of the dissection membrane, and 8 patients with progressive dilatation of the thoracic aorta underwent aortic arch and descending aorta replacement via clamshell approach. RESULTS: No early (defined as 30-day, 90-day and in-hospital period) deaths, strokes or spinal cord injuries occurred. Only 1 patient (6%) presented temporary neurological dysfunctions (delirium, agitation), which resolved completely before discharge, and an injury of the recurrent laryngeal nerve was documented in 2 patients (12%). Temporary dialysis was necessary in 1 case. The follow-up was complete for all patients. All but one patient, who died due to leukaemia 23 months after surgery, were alive at the last follow-up (median duration 33 months, range 2-118 months). No patient needed a reoperation or an intervention on the thoracic and/or abdominal aorta. Moreover, no noticeable progression of the chronic dissection in the downstream aorta was documented in any patient. CONCLUSIONS: The results after conventional aortic arch repair with distal resection of the dissection membrane and, if necessary, with replacement of the progressively dilated chronic dissected thoracic aorta can offer excellent results in experienced hands and, therefore, this technique may be considered as a preferable option for surgical treatment of chronic aortic dissection with involvement of the aortic arch and the visceral arteries originating from different lumens. PMID- 26518380 TI - Porcine xenograft for aortic, mitral and double valve replacement: long-term results of 2544 consecutive patients. AB - OBJECTIVES: The aim of this study was to evaluate the results after stented porcine xenograft implantation with LinxTM anticalcification treatment in the aortic and/or mitral position in elderly patients. METHODS: Over a decade, a total of 2544 patients receiving aortic (AVR = 1920), mitral (MVR = 347) or double valve (DVR = 277) replacement (between November 2001 and March 2012) were evaluated. The study was designed on an 'all comers' basis including all patients with elective, urgent or emergent need for valve replacement. Outcome was assessed by reviewing the prospectively acquired hospital database as well as regular follow-up information obtained by annual written interviews. RESULTS: Mean patient age was 76.5 +/- 6 (AVR), 73.8 +/- 7 (MVR) and 74.2 +/- 7 (DVR) years, respectively; 54.2%/41.9%/42.0% were male, and active endocarditis was diagnosed in 4.5%/19.9%/22.1%; indication for valve surgery and the logistic EUROSCORE I predicted risk for mortality was 15.4 +/- 15%/19.9 +/- 19%/22.3 +/- 21%, respectively. Concomitant mitral valve repair was required in 196 (10.2%) (AVR) patients; coronary artery bypass graft surgery (CABG) in 840 (43.8%) (AVR), 82 (23.7%) (MVR) and 94 (34.1%) (DVR) patients; cryoablation in 232 (12.1%)/81 (23.4%)/67 (24.3%) patients and surgery on the thoracic aorta in 166 (8.7%)/12 (3.5%)/41 (14.9%) patients, respectively. The mean follow-up was 4.5 +/- 3.5 years. The rate of freedom from endocarditis after 10 years was 98.3 +/- 0.4%/97.5 +/- 1.0%/97.4 +/- 1.6% (P = n.s.). The rate of freedom from structural valve disease was 96.3 +/- 0.6%/93.8 +/- 2.4%/92.8 +/- 2.2% (AVR versus DVR, P = 0.009), and from thromboembolic events was 94.8 +/- 1.0%/91.5 +/- 2.9%/97.9 +/- 1.3%. The 30-day survival rate was 97.3 +/- 0.4%/95.1 +/- .1.2%/92.8 +/- 1.6% and the 10-year survival rate was 42.1 +/- 1.5%/33.9 +/- 4.7%/22.1 +/- 7.1%, respectively. CONCLUSIONS: The EpicTM stented porcine xenograft is associated with acceptable survival, with large proportions of patients free from valve related complications and freedom from valve reintervention for all older, in coming patients. PMID- 26518382 TI - Influenza Vaccination Among US Children With Asthma, 2005-2013. AB - BACKGROUND: Children with asthma face higher risk of complications from influenza. Trends in influenza vaccination among children with asthma are unknown. METHODS: We used 2005-2013 National Health Interview Survey data for children 2 to 17 years of age. We assessed, separately for children with and without asthma, any vaccination (received August through May) during each of the 2005-2006 through 2012-2013 influenza seasons and, for the 2010-2011 through 2012 2013 seasons only, early vaccination (received August through October). We used April-July interviews each year (n = 31,668) to assess vaccination during the previous influenza season. Predictive margins from logistic regression with time as the independent and vaccination status as the dependent variable were used to assess time trends. We also estimated the association between several sociodemographic variables and the likelihood of influenza vaccination. RESULTS: From 2005 to 2013, among children with asthma, influenza vaccination receipt increased about 3 percentage points per year (P < .001), reaching 55% in 2012 2013. The percentage of all children with asthma vaccinated by October (early vaccination) was slightly above 30% in 2012-2013. In 2010-2013, adolescents, the uninsured, children of parents with some college education, and those living in the Midwest, South, and West were less likely to be vaccinated. CONCLUSIONS: The percentage of children 2 to 17 years of age with asthma receiving influenza vaccination has increased since 2004-2005, reaching approximately 55% in 2012 2013. PMID- 26518383 TI - Takotsubo cardiomyopathy caused by epinephrine-treated bee sting anaphylaxis: a case report. AB - INTRODUCTION: Stress-induced cardiomyopathy (Takotsubo) after bee stings in patients who have received catecholamines is rare. Endogenous as well as exogenous administration of catecholamines is thought to trigger stress-induced cardiomyopathy. CASE PRESENTATION: A 37-year-old healthy white woman was stung by an unknown Hymenoptera that resulted in an anaphylactic reaction. Intravenous adrenaline (0.9 mg) was administered at a nearby clinic; she was transferred to our emergency room. Cardiogenic shock was diagnosed and mechanical ventilation commenced. Hemodynamic stabilization was not achieved by inotropic support and intra-aortic balloon pump insertion. Initial coronary angiography did not demonstrate any coronary obstructive lesions while her left ventricular systolic function was severely depressed. Peripheral femoral venoarterial extracorporeal membrane oxygenation was inserted as a bridge to recovery assuming possible reversible cause of the cardiogenic shock. Over the following 48 hours she was extubated and gradually weaned off venoarterial extracorporeal membrane oxygenation and inotropic support. She was discharged with a near normal left ventricular ejection fraction and in 3 weeks she was asymptomatic with normal electrocardiographic and echocardiographic examinations (left ventricular ejection fraction >65 %). CONCLUSIONS: A Hymenoptera sting may be a specific cause of catecholamine cardiac depression. The presence of cardiogenic shock and its etiology should prompt aggressive management including extracorporeal membrane oxygenation as a bridge to cardiac functional recovery in such rare scenarios. PMID- 26518384 TI - Dimerization interface and dynamic properties of yeast IF1 revealed by Site Directed Spin Labeling EPR spectroscopy. AB - The mitochondrial ATPase inhibitor, IF1, regulates the activity of the mitochondrial ATP synthase. The oligomeric state of IF1 related to pH is crucial for its inhibitory activity. Although extensive structural studies have been performed to characterize the oligomeric states of bovine IF1, only little is known concerning those of yeast IF1. While bovine IF1 can be found as an inhibitory dimer at low pH and a non-inhibitory tetramer at high pH, a monomer/dimer equilibrium has been described for yeast IF1, high pH values favoring the monomeric state. Combining different strategies involving the grafting of nitroxide spin labels combined with Electron Paramagnetic Resonance (EPR) spectroscopy, the present study brings the first structural characterization, at the residue level, of yeast IF1 in its dimeric form. The results show that the dimerization interface involves the central region of the peptide revealing that the dimer corresponds to a non-inhibitory state. Moreover, we demonstrate that the C-terminal region of the peptide is highly dynamic and that this segment is probably folded back onto the central region. Finally, the pH-dependence of the inter-label distance distribution has been observed indicating a conformational change between two structural states in the dimer. PMID- 26518385 TI - The N-terminal domain of Lhcb proteins is critical for recognition of the LHCII kinase. AB - The light-harvesting chlorophyll (Chl) a/b complex of photosystem (PS) II (LHCII) plays important roles in the distribution of the excitation energy between the two PSs in the thylakoid membrane during state transitions. In this process, LHCII, homo- or heterotrimers composed of Lhcb1-3, migrate between PSII and PSI depending on the phosphorylation status of Lhcb1 and Lhcb2. We have studied the mechanisms of the substrate recognition of a thylakoid threonine kinase using reconstituted site-directed trimeric Lhcb protein-pigment complex mutants. Mutants lacking the positively charged residues R/K upstream of phosphorylation site (Thr) in the N-terminal domain of Lhcb1 were no longer phosphorylated. Besides, the length of the peptide upstream of the phosphorylated site (Thr) is also crucial for Lhcb phosphorylation in vitro. Furthermore, the two N-terminal residues of Lhcb appear to play a key role in the phosphorylation kinetics because Lhcb with N-terminal RR was phosphorylated much faster than with RK. Therefore, we conclude that the substrate recognition of the LHCII kinase is determined to a large extent by the N-terminal sequence of the Lhcb proteins. The study provides new insights into the interactions of the Lhcb proteins with the LHCII kinase. PMID- 26518386 TI - The expression of UCP3 directly correlates to UCP1 abundance in brown adipose tissue. AB - UCP1 and UCP3 are members of the uncoupling protein (UCP) subfamily and are localized in the inner mitochondrial membrane. Whereas UCP1's central role in non shivering thermogenesis is acknowledged, the function and even tissue expression pattern of UCP3 are still under dispute. Because UCP3 properties regarding transport of protons are qualitatively identical to those of UCP1, its expression in brown adipose tissue (BAT) alongside UCP1 requires justification. In this work, we tested whether any correlation exists between the expression of UCP1 and UCP3 in BAT by quantification of protein amounts in mouse tissues at physiological conditions, in cold-acclimated and UCP1 knockout mice. Quantification using recombinant UCP3 revealed that the UCP3 amount in BAT (0.51ng/(MUg total tissue protein)) was nearly one order of magnitude higher than that in muscles and heart. Cold-acclimated mice showed an approximate three-fold increase in UCP3 abundance in BAT in comparison to mice in thermoneutral conditions. Surprisingly, we found a significant decrease of UCP3 in BAT of UCP1 knockout mice, whereas the protein amount in skeletal and heart muscles remained constant. UCP3 abundance decreased even more in cold-acclimated UCP1 knockout mice. Protein quantification in UCP3 knockout mice revealed no compensatory increase in UCP1 or UCP2 expression. Our results do not support the participation of UCP3 in thermogenesis in the absence of UCP1 in BAT, but clearly demonstrate the correlation in abundance between both proteins. The latter is important for understanding UCP3's function in BAT. PMID- 26518388 TI - Levosimendan for Prevention of Acute Kidney Injury After Cardiac Surgery: A Meta analysis of Randomized Controlled Trials. AB - BACKGROUND: Levosimendan has been shown to confer direct renoprotection in renal endotoxemic and ischemia-reperfusion injury and could increase renal blood flow in patients with low-cardiac-output heart failure. Results from clinical trials of levosimendan on acute kidney injury (AKI) following cardiac surgery are controversial. STUDY DESIGN: A random-effect meta-analysis was conducted based on evidence from PubMed, EMBASE, and Cochrane Library. SETTINGS & POPULATION: Adult patients undergoing cardiac surgery. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials comparing the renal effect of levosimendan versus placebo or other inotropic drugs during cardiac surgery. INTERVENTION: Perioperative levosimendan continuous infusion at a rate of 0.1 to 0.2MUg/kg/min following a loading dose (6-24MUg/kg) for 24 hours or only 1 loading dose (24MUg/kg) within 1 hour. OUTCOMES: AKI, need for renal replacement therapy, mechanical ventilation duration, intensive care unit stay during hospitalization, and postoperative mortality (in-hospital or within 30 days). RESULTS: 13 trials with a total of 1,345 study patients were selected. Compared with controls, levosimendan reduced the incidence of postoperative AKI (40/460 vs 78/499; OR, 0.51; 95% CI, 0.34 0.76; P=0.001; I(2)=0.0%), renal replacement therapy (22/492 vs 49/491; OR, 0.43; 95% CI, 0.25-0.76; P=0.002; I(2)=0.0%), postoperative mortality (35/658 vs 94/657; OR, 0.41; 95% CI, 0.27-0.62; P<0.001; I(2)=0.0%), mechanical ventilation duration (in days; n=235; weighted mean difference, -0.34; 95% CI, -0.58 to 0.09; P=0.007], and intensive care unit stay (in days; n=500; weighted mean difference, -2.2; 95% CI, -4.21 to -0.13; P=0.04). LIMITATIONS: Different definitions for AKI among studies. Small sample size for some trials. CONCLUSIONS: Perioperative administration of levosimendan in patients undergoing cardiac surgery may reduce complications. Future trials are needed to determine the dose effect of levosimendan in improving outcomes, especially in patients with decreased baseline kidney function. PMID- 26518389 TI - Intestinal Gas Capsules: A Proof-of-Concept Demonstration. PMID- 26518390 TI - Editorial: How clinically significant is minimal extrathyroidal extension in papillary thyroid cancer? PMID- 26518391 TI - Total laparoscopic left hepatectomy for primary hepatolithiasis: Eight-year experience in a single center. AB - BACKGROUND: Primary hepatolithiasis is prevalent in some Asian countries. Hepatectomy is a definitive treatment for this disease. Whether laparoscopic left hepatectomy (LLH) is suitable for primary hepatolithiasis remains controversial, because LLH is more challenging technically. The aim of this study was to evaluate the outcomes of LLH for primary hepatolithiasis in a single center. METHODS: This retrospective study included 96 consecutive patients who underwent LLH for primary hepatolithiasis in the Sir Run Run Shaw Hospital from May 2005 to December 2012. In addition, 105 patients who met the same inclusion criteria for LLH but underwent open left hepatectomy (OLH) for hepatolithiasis during the same period were reviewed for comparison. The patient characteristics, operative features, postoperative course, residual stone rate, and recurrent stone rate were analyzed. RESULTS: In the LLH group, 81 patients (84.4%) underwent total LLH and 15 (15.6%) were converted to open hepatectomy. The volume of intraoperative blood loss was less in the LLH than OLH group (383 +/- 281 vs 554 +/- 517 mL; P = .005). The intraoperative transfusion rate was also significantly lower in the LLH group (8.3% vs 30.5%; P < .001). There were no differences between the LLH and OLH groups in operation time, duration of postoperative hospitalization, postoperative complication rate, residual stone rate, or recurrent stone rate. CONCLUSION: In experienced hands, total LLH is a safe, effective, and promising treatment for patients with hepatolithiasis. PMID- 26518392 TI - Prognostic factor analysis of circulating tumor cells in peripheral blood of patients with peritoneal carcinomatosis of colon cancer origin treated with cytoreductive surgery plus an intraoperative hyperthermic intraperitoneal chemotherapy procedure (CRS + HIPEC). AB - PURPOSE: Complete cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has changed the therapeutic landscape, improving overall survival in patients with peritoneal carcinomatosis with a colonic origin. The main limitation of this aggressive locoregional procedure, however, is extra abdominal or distant spread. The objective of this study was to identify the prognostic value of circulating tumor cells (CTCs) in patients with peritoneal carcinomatosis of colonic origin undergoing CRS + HIPEC. PATIENTS AND METHODS: Fourteen patients diagnosed with peritoneal carcinomatosis from colon cancer and suitable for potentially curative treatment with CRS + HIPEC were included in this study. CTCs were isolated from the peripheral blood by immunomagnetic techniques by the use of a multi-cytokeratin-specific antibody and detected via immunocytochemical methods. The phenotypic characterization of EGFR on CTCs was analyzed by immunofluorescence. RESULTS: At baseline, 50% of the patients were positive for CTCs, with a mean value of 5.5 CTCs per 10 mL of peripheral blood. After surgery, 28.57% of the patients presented CTCs, with a mean value of 6.75 CTCs per 10 mL. A positive correlation was found between the presence of CTC negative, epidermal growth factor receptor-positive at baseline and the patients who had symptoms of intestinal obstruction (21.4%). In addition, the presence of CTCs identified patients with distant dissemination and was also significantly correlated with progression-free survival (P = .0024). CONCLUSION: The detection and characterization of CTCs are good prognostic and predictive markers in patients with peritoneal carcinomatosis resulting from colon cancer. These analyses could be used as a new tool to identify subpopulations of patients who could benefit from CRS + HIPEC treatment. PMID- 26518393 TI - What Can We Learn From Measles? No New HIV Infections. AB - Reducing the incidence of HIV infection until there are no new infections depends on driving the number of secondary infections produced by a typical source infection in a completely susceptible population (basic reproduction number; R0) down to less than 1. Components of R0 that must be addressed are the number of sexual contacts the infectious person makes per unit of time (C), the probability of transmission per single sexual contact with the infectious person (P), and the duration that the infected person is infectious to others (D) (R0 = C * P * D). Numerous strategies may contribute to driving transmission of HIV infection down to zero, including early initiation of antiretroviral treatment and pre- or postexposure prophylaxis. This article summarizes a presentation by Davey M. Smith, MD, at the IAS-USA continuing education program held in San Francisco, California, in March 2015. PMID- 26518394 TI - Management of the Hepatitis B Virus/HIV-Coinfected Patient. AB - All patients with HIV infection should be screened for hepatitis B virus (HBV) infection. Preventive HBV vaccination is less effective in HIV-infected patients than in those without HIV infection. Emtricitabine, lamivudine, and tenofovir disoproxil fumarate (tenofovir) each have activity against HIV and HBV. In HBV/HIV-coinfected patients, if HBV or HIV treatment is needed, it should be initiated with tenofovir and emtricitabine or tenofovir and lamivudine as the nucleoside analogue reverse transcriptase inhibitor backbone of a fully suppressive antiretroviral regimen. If HBV treatment is needed and tenofovir cannot be used safely, entecavir is recommended in addition to a fully suppressive antiretroviral regimen. Initiation of treatment for HBV infection is based on the presence of cirrhosis and on HBV DNA level, alanine aminotransferase level, and biopsy results. Current HBV treatments are associated with low functional cure rates. This article summarizes a presentation by Kenneth E. Sherman, MD, PhD, at the IAS-USA continuing education program held in San Francisco, California, in March 2015. PMID- 26518395 TI - HIV-Related Opportunistic Infections Are Still Relevant in 2015. AB - The incidence of HIV-related opportunistic infections (OIs) has declined in the United States with the increasing use of effective antiretroviral therapy for the treatment of HIV infection. However, the absolute number of patients with OIs remains high and there continues to be considerable associated mortality. OI guidelines from the National Institutes of Health, Centers for Disease Control and Prevention, and Infectious Diseases Society of America continue to be updated on a regular basis, several times per year, as optimal strategies for prevention and therapy evolve. Recommendations that have changed in these guidelines include: screening for cryptococcal antigen and treatment of asymptomatic antigenemia; empiric treatment of shigellosis infection in light of the recent spread of multidrug-resistant strains; the relative roles of vancomycin and metronidazole in diarrheal illness related to Clostridium difficile; and diagnosis of Pneumocystis jiroveci pneumonia (PCP; formerly Pneumocystis carinii pneumonia). This article summarizes a presentation by Henry Masur, MD, at the IAS USA continuing education program held in Washington, DC, in May 2015. PMID- 26518396 TI - Chronic Pain in Patients With HIV Infection: What Clinicians Need To Know. AB - Chronic pain is common in individuals with HIV infection. The primary goal of treatment of chronic pain is not only to improve pain but also to improve physical and emotional function. Patients with chronic pain should be assessed for concurrent psychiatric and substance use disorders, as these conditions often coexist. Treatment of chronic pain may have limited success in the absence of treatment of psychiatric disorders. Treatments for chronic pain include nonopioid pharmacologic therapies and nonpharmacologic therapies (eg, cognitive and behavioral therapy, physical therapy), and the latter option is often the most effective for improving patient function. Care must be taken when initiating or continuing treatment with opioids, and the risks and benefits of treatment with opioids should be regularly assessed. This article summarizes a presentation by Jessica S. Merlin, MD, MBA, at the IAS-USA continuing education program held in New York, New York, in March 2015. PMID- 26518397 TI - "Everybody just wants to do what's best for their child": Understanding how pro vaccine parents can support a culture of vaccine hesitancy. AB - BACKGROUND: Although a large majority of parents vaccinate their children, vaccine hesitancy has become more widespread. It is not well understood how this culture of vaccine hesitancy has emerged and how it influences parents' decisions about vaccine schedules. OBJECTIVE: We sought to examine how attitudes and beliefs of parents who self-report as pro-vaccine are developed and contribute to immunization decisions, including delaying or spacing vaccines. METHODS: Open ended, in-depth interviews (N=23) were conducted with upper-middle class parents with young children living in Philadelphia. Interview data were coded and key themes identified related to vaccine decision-making. RESULTS: Parents who sought out vaccine information were often overwhelmed by the quantity and ambiguity when interpreting that information, and, consequently, had to rely on their own instinct or judgment to make vaccine decisions. In particular, while parents in this sample did not refuse vaccines, and described themselves as pro-vaccine, they did frequently delay or space vaccines. This experience also generated sympathy for and tolerance of vaccine hesitancy in other parents. Parents also perceived minimal severe consequences for deviating from the recommended immunization schedule. CONCLUSION: These findings suggest that the rise in and persistence of vaccine hesitancy and refusal are, in part, influenced by the conflicts in the information parents gather, making it difficult to interpret. Considerable deviations from the recommended vaccination schedule may manifest even within a pro-vaccine population due to this perceived ambiguity of available information and resulting tolerance for vaccine hesitancy. PMID- 26518398 TI - Functional anti-polysaccharide IgG titres induced by unadjuvanted pneumococcal conjugate vaccine when delivered by microprojection-based skin patch. AB - Adequate access to effective and affordable vaccines is essential for the prevention of mortality due to infectious disease. Pneumonia--a consequence of Streptococcus pneumoniae infection--is the world's leading cause of death in children aged under 5 years. The development of a needle-free, thermostable pneumococcal-conjugate vaccine (PCV) could revolutionise the field by reducing cold-chain and delivery constraints. Skin patches have been used to deliver a range of vaccines, with some inducing significantly higher vaccine-specific immunogenicity than needle-injected controls in pre-clinical models, though they have yet to be used to deliver a PCV. We dry-coated a licensed PCV onto a microprojection-based patch (the Nanopatch) and delivered it to mouse skin. We analysed resulting anti-polysaccharide IgG responses. With and without adjuvant, anti-polysaccharide IgG titres induced by Nanopatch immunisation were significantly higher than dose-matched intramuscular controls. These improved responses were primarily obtained against pneumococcal serotypes 4 and 14. Importantly, capsule-specific IgG correlated with functionality in an opsonophagocytic killing assay. We demonstrate enhanced anti-PCV immunogenicity when delivered by Nanopatch over intramuscular injection. As the first study of a PCV delivered by a skin vaccination technology, this report indicates the potential for reduced costs and greater global distribution of such a vaccine. PMID- 26518399 TI - Generation of switched memory B cells in response to vaccination in Down syndrome children and their siblings. AB - BACKGROUND: Immunodeficiency is an integral aspect of Down syndrome, as demonstrated by the increased susceptibility to infection of affected. Mortality is still higher than in general population, with respiratory infections among the major causes of death. As more people with Down syndrome are living today than ever before, it is indispensable to develop strategies to prevent and cure the associated disorders. Vaccination is the most successful instrument of preventive medicine. Special seasonal influenza and pneumococcal vaccination strategies have been designed for individuals with risk conditions of all ages. Down syndrome individuals are not included in the high-risk categories. METHODS: We enrolled in our study 15 children with Down syndrome and their siblings, vaccinated for the first time with seasonal influenza vaccine and receiving a booster dose of a glyco-conjugated pneumococcal vaccine. We compared the immunological features and response to vaccination measuring serum antibody titers and frequency of specific memory B cells. RESULTS: We confirm that a severe reduction of switched memory B cells is always associated to Down syndrome. After primary vaccination Down syndrome children generate significantly less specific switched memory B cells than their siblings. The response to a booster dose of vaccine is instead comparable in both groups. The production of specific antibodies was equally effective in Down syndrome and controls both after primary and secondary immunization. CONCLUSIONS: Down syndrome individuals should be considered a high risk group, because of their increased susceptibility to infection and reduced number of switched memory B cells. Tailored vaccination protocols are needed in order to reduce their burden of infections throughout life. PMID- 26518400 TI - Cumulative and episodic vaccine aluminum exposure in a population-based cohort of young children. AB - BACKGROUND: In addition to antigens, vaccines contain small amounts of preservatives, adjuvants, and residual substances from the manufacturing process. Some parents have concerns about the safety of these ingredients, yet no large epidemiological studies have specifically examined associations between health outcomes and vaccine ingredients, other than thimerosal. This study examined the extent to which the Vaccine Safety Datalink (VSD) could be used to study vaccine ingredient safety in children. METHODS: Children born 2004-2011 were identified in VSD data. Using immunization records, two cohorts were identified: children who were up-to-date and children who were undervaccinated before age 2 years. A database was also created linking vaccine type and manufacturer with ingredient amounts documented in vaccine package inserts. Thirty-four ingredients in two or more infant vaccines were identified. However, only amounts (in mg) for aluminum were consistently documented and commonly contained in infant vaccines. Analyses compared vaccine aluminum exposure across cohorts and determined the statistical power for studying associations between aluminum exposure and hypothetical vaccine adverse events. RESULTS: Among 408,608 children, mean cumulative vaccine aluminum exposure increased from 1.11 to 4.00 mg between ages 92-730 days. Up-to date children were exposed to 11-26% more aluminum from vaccines than undervaccinated children. Power analyses demonstrated that safety studies of aluminum could detect relative risks ranging from 1.1 to 5.8 for a range of adverse event incidence. CONCLUSIONS: The safety of vaccine aluminum exposure can be feasibly studied in the VSD. However, possible biological mechanisms and confounding variables would need to be considered before conducting any studies. PMID- 26518401 TI - Toxoplasma gondii: Vaccination with a DNA vaccine encoding T- and B-cell epitopes of SAG1, GRA2, GRA7 and ROP16 elicits protection against acute toxoplasmosis in mice. AB - Toxoplasma gondii (T. gondii) is an obligate, intracellular, protozoan parasite that infects large variety of warm-blooded animals including humans, livestock, and marine mammals, and causes the disease toxoplasmosis. Although T. gondii infection rates differ significantly from country to country, it still has a high morbidity and mortality. In these circumstances, developing an effective vaccine against T. gondii is urgently needed for preventing and treating toxoplasmosis. The aim of this study was to construct a multi-epitopes DNA vaccine and evaluate the immune protective efficacy against acute toxoplasmosis in mice. Therefore, twelve T- and B-cell epitopes from SAG1, GRA2, GRA7 and ROP16 of T. gondii were predicted by bioinformatics analysis, and then a multi-epitopes DNA vaccine was constructed. Mice immunized with the multi-epitopes DNA vaccine gained higher levels of IgG titers and IgG2a subclass titers, significant production of gamma interferon (IFN-gamma), percentage of T lymphocyte subsets, and longer survival times against the acute infection of T. gondii compared with those of mice administered with empty plasmid and those in control groups. Furthermore, a genetic adjuvant pEGFP-RANTES (pRANTES) could enhance the efficacy of the multi epitopes DNA vaccine associating with humoral and cellular (Th1, CD8(+) T cell) immune responses. Above all, the DNA vaccine and the genetic adjuvant revealed in this study might be new candidates for further vaccine development against T. gondii infection. PMID- 26518402 TI - The use of dissolved oxygen-controlled, fed-batch aerobic cultivation for recombinant protein subunit vaccine manufacturing. AB - A simple "off-the-shelf" fed-batch approach to aerobic bacterial cultivation for recombinant protein subunit vaccine manufacturing is presented. In this approach, changes in the dissolved oxygen levels are used to adjust the nutrient feed rate (DO-stat), so that the desired dissolved oxygen level is maintained throughout cultivation. This enables high Escherichia coli cell densities and recombinant protein titers. When coupled to a kLa-matched scale-down model, process performance is shown to be consistent at the 2L, 20L, and 200L scales for two recombinant E. coli strains expressing different protein subunit vaccine candidates. Additionally, by mining historical DO-stat nutrient feeding data, a method to transition from DO-stat to a pre-determined feeding profile suitable for larger manufacturing scales without using feedback control is demonstrated at the 2L, 20L, and 200L scales. PMID- 26518403 TI - Malaria vaccines getting close to clinical reality. PMID- 26518404 TI - A Japanese study to assess immunogenicity and safety of a typhoid Vi polysaccharide vaccine. AB - BACKGROUND: Although typhoid fever is rare in Japan, imported cases have been reported occasionally in travelers returning from endemic areas. To achieve licensing of a typhoid Vi polysaccharide vaccine (Typhim Vi((r))) and make it widely available in Japan, this study was conducted at the request of the Japanese Ministry of Health Labor and Welfare to assess the immunogenicity and safety of this vaccine when given as a single dose (the recommended schedule of administration) in a Japanese population. METHODS: In this multi-center, open label, non-comparative, intervention study performed in Japan, 200 healthy volunteers (188 adults [>= 18 years of age], 7 adolescents [12-17 years of age] and 5 children [2-11 years of age]) were administered Typhim Vi((r)). Immunogenicity was assessed 28 days after vaccinations using an ELISA method of anti-Vi antibody detection. A 4-fold increase in anti-Vi titer was considered as the threshold for seroconversion for anti-Vi antibodies. Safety was assessed up to 28 days following vaccination. RESULTS: Overall, 92.0% (95% confidence interval [CI]: 87.3-95.4%) of participants achieved seroconversion 28 days after a single dose of typhoid Vi polysaccharide vaccine. GMTs of Vi antibody titers increased from 6.6 (95% CI: 5.8-7.4) prior to vaccination to 157.3 (95% CI: 135.1 183.2) on Day 28 after vaccination. The geometric mean of individual anti-Vi antibody titer ratios (Day 28/Day 0) was 23.9 (95% CI: 20.3-28.3). There were no immediate adverse events and no adverse events led to the discontinuation of participants from the study. Across all age groups, pain and myalgia were the most frequently reported injection site and systemic reactions, respectively. Most of these reactions were mild in intensity and resolved within 7 days. CONCLUSIONS: A single dose of typhoid Vi polysaccharide vaccine, Typhim Vi((r)), demonstrated good safety and immunogenicity profile in a Japanese population. PMID- 26518405 TI - Surveillance of adverse events after the first trivalent inactivated influenza vaccine produced in mammalian cell culture (Flucelvax((r))) reported to the Vaccine Adverse Event Reporting System (VAERS), United States, 2013-2015. AB - BACKGROUND: In November 2012, the first cell cultured influenza vaccine, a trivalent subunit inactivated influenza vaccine (Flucelvax((r)), ccIIV3), was approved in the US for adults aged >= 18 years. OBJECTIVE: To assess adverse events (AEs) after ccIIV3 reported to the US Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting surveillance system. METHODS: We searched VAERS for US reports after ccIIV3 among persons vaccinated from July 1, 2013 March 31, 2015. Medical records were requested for reports classified as serious (death, hospitalization, prolonged hospitalization, disability, life-threatening illness), and those suggesting anaphylaxis and Guillain-Barre syndrome (GBS). Physicians reviewed available information and assigned a primary clinical category using MedDRA system organ classes (SOC) to each report. Empirical Bayesian data mining was used to identify disproportional AE reporting following ccIIV3. RESULTS: VAERS received 629 reports following ccIIV3 of which 313 were for administration of vaccine to persons <18 years. Among 309 reports with an AE documented, 19 (6.1%) were serious and the most common categories were 152 (49.2%) general disorders and administration site conditions (mostly injection site and systemic reactions) and 73 (23.6%) immune system disorders with two reports of anaphylaxis. Four reports of GBS were submitted. Disproportional reporting was identified for 'drug administered to patient of inappropriate age.' CONCLUSIONS: Review of VAERS reports did not identify any concerning pattern of AEs after ccIIV3. Injection site and systemic reactions were the most commonly reported AEs, similar to the pre-licensure clinical trials. Reports following ccIIV3 in persons <18 years highlight the need for education of healthcare providers regarding approved ccIIV3 use. PMID- 26518406 TI - Costing RTS,S introduction in Burkina Faso, Ghana, Kenya, Senegal, Tanzania, and Uganda: A generalizable approach drawing on publicly available data. AB - Recent results from the phase 3 trial of RTS,S/AS01 malaria vaccine show that the vaccine induced partial protection against clinical malaria in infants and children; given the high burden of the disease it is currently considered for use in malaria endemic countries. To inform adoption decisions the paper proposes a generalizable methodology to estimate the cost of vaccine introduction using routinely collected and publicly available data from the cMYP, UNICEF, and WHO CHOICE. Costing is carried out around a set of generic activities, assumptions, and inputs for delivery of immunization services adapted to a given country and deployment modality to capture among other factors the structure of the EPI program, distribution model, geography, and demographics particular to the setting. The methodology is applied to estimate the cost of RTS,S introduction in Burkina Faso, Ghana, Kenya, Senegal, Tanzania, and Uganda. At an assumed vaccine price of $5 per dose and given our assumptions on coverage and deployment strategy, we estimate total economic program costs for a 6-9 months cohort within $23.11-$28.28 per fully vaccinated child across the 6 countries. Net of procurement, costs at country level are substantial; for instance in Tanzania these could add as much as $4.2 million per year or an additional $2.4 per infant depending on the level of spare capacity in the system. Differences in cost of vaccine introduction across countries are primarily driven by differences in cost of labour. Overall estimates generated with the methodology result in costs within the ranges reported for other new vaccines introduced in SSA and capture multiple sources of heterogeneity in costs across countries. Further validation with data from field trials will support use of the methodology while also serving as a validation for cMYP and WHO-CHOICE as resources for costing health interventions in the region. PMID- 26518407 TI - Predictive value of cord blood bilirubin for hyperbilirubinemia in neonates at risk for maternal-fetal blood group incompatibility and hemolytic disease of the newborn. AB - OBJECTIVE: To determine the predictive ability of cord blood bilirubin (CBB) for hyperbilirubinemia in a population at risk for maternal-fetal blood group incompatibility and hemolytic disease of the newborn. STUDY DESIGN: This is a single center retrospective case-control study. Cases received phototherapy; controls did not. Cases were matched 1:3 to controls by gender and treating physician. Inclusion criteria included: >=35 weeks gestation, CBB, and one or more total serum bilirubin (TSB) concentrations. The primary outcome was CBB. Secondary outcomes were a TSB >75th percentile, length of stay, and neonatal intensive care unit admission. The prognostic ability of CBB for phototherapy and TSB >75th percentile was assessed using area under the receiver operating characteristic (ROC) curve. Logistic regression analyses were performed to determine predictors for phototherapy and TSB >75th percentile. RESULT: When compared to controls (n = 142), cases (n = 54) were more likely to have a positive Coombs' test (82% vs. 41% , p < 0.001) and TSB >75th percentile (85% vs. 21% , p < 0.001). When compared to controls, cases had a higher mean (+/-SD) CBB (2.5 +/- 0.5 vs. 1.8 +/- 0.4 mg/dL, p < 0.001). The area under the ROC curve (+/-SEM) for CBB for phototherapy and TSB >75th percentile was 0.87 +/- 0.03 (p < 0.001, 95% CI 0.82, 0.93) and 0.87 +/- 0.03 (p < 0.001, 95% CI 0.82, 0.92), respectively. CONCLUSION: In this study, the mean CBB concentration was higher in neonates who received phototherapy compared to those who did not. CBB concentrations may help predict severe hyperbilirubinemia and phototherapy in a population at risk for hemolytic disease of the newborn. PMID- 26518408 TI - Death by neurologic criteria in a neonate: Implications for organ donation. AB - We illustrate a unique case of neonatal organ donation in a full-term newborn with severe hypoxic ischemic encephalopathy (HIE) and multi-organ dysfunction that underwent therapeutic hypothermia. Prolonged hypothermia permitted adequate time for recovery of certain end-organs before such time that death by neurologic criteria was declared. Parental values aligned with the opportunity for organ donation. PMID- 26518410 TI - Hot Topics in Neonatology, December 6-9, 2015: Washington DC, USA. PMID- 26518409 TI - Pregnancy outcomes in two growth restricted fetuses with in utero cerebral lactate. AB - Elevated cerebral lactate is increasingly detected by magnetic resonance spectroscopy in the human fetus diagnosed with various pathologic conditions. However, the significance of detectable cerebral lactate remains uncertain. We present two cases of fetal cerebral lactate with adverse pregnancy outcomes. PMID- 26518411 TI - Robust depth filter sizing for centrate clarification. AB - Cellulosic depth filters embedded with diatomaceous earth are widely used to remove colloidal cell debris from centrate as a secondary clarification step during the harvest of mammalian cell culture fluid. The high cost associated with process failure in a GMP (Good Manufacturing Practice) environment highlights the need for a robust process scale depth filter sizing that allows for (1) stochastic batch-to-batch variations from filter media, bioreactor feed and operation, and (2) systematic scaling differences in average performance between filter sizes and formats. Matched-lot depth filter media tested at the same conditions with consecutive batches of the same molecule were used to assess the sources and magnitudes of process variability. Depth filter sizing safety factors of 1.2-1.6 allow a filtration process to compensate for random batch-to-batch process variations. Matched-lot depth filter media in four different devices tested simultaneously at the same conditions was used with a common feed to assess scaling effects. All filter devices showed <11% capacity difference and the Pod format devices showed no statistically different capacity differences. PMID- 26518412 TI - Non-invasive and Non-destructive Characterization of Tissue Engineered Constructs Using Ultrasound Imaging Technologies: A Review. AB - With the rapid expansion of biomaterial development and coupled efforts to translate such advances toward the clinic, non-invasive and non-destructive imaging tools to evaluate implants in situ in a timely manner are critically needed. The required multi-level information is comprehensive, including structural, mechanical, and biological changes such as scaffold degradation, mechanical strength, cell infiltration, extracellular matrix formation and vascularization to name a few. With its inherent advantages of non-invasiveness and non-destructiveness, ultrasound imaging can be an ideal tool for both preclinical and clinical uses. In this review, currently available ultrasound imaging technologies that have been applied in vitro and in vivo for tissue engineering and regenerative medicine are discussed and some new emerging ultrasound technologies and multi-modality approaches utilizing ultrasound are introduced. PMID- 26518413 TI - Erratum to: Six Degree-of-Freedom Measurements of Human Mild Traumatic Brain Injury. PMID- 26518415 TI - Survival of Colorectal Cancer in Patients With or Without Inflammatory Bowel Disease: A Meta-Analysis. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC), but little is known about the influence of IBD on CRC prognosis. AIMS: The aim of this study was to perform a meta-analysis to compare survival in CRC patients with IBD (IBD-CRC) and without IBD. METHODS: An electronic search was conducted via PubMed, Embase, and the Cochrane Library to identify eligible trials until July 2015. We pooled the hazard ratios (HRs) and their 95% confidence intervals (CIs) to quantitatively assess the survival of CRC in patients with or without IBD. In addition, clinicopathological parameters of IBD-CRC versus non-IBD CRC were evaluated. RESULTS: Twelve studies containing a total of 3472 IBD-CRC patients were eligible according to our selection criteria. Our analysis indicated that CRC patients with IBD had shorter overall survival than those without IBD (HR 1.24, 95% CI 1.19-1.29). IBD-CRC showed a propensity to develop in proximal colon [odds ratio (OR) 2.52, 95% CI 1.35-4.72] and correlated with worse differentiation of tumor (OR 1.59, 95% CI 1.26-1.99) compared to non-IBD CRC. Meta-regression analysis showed that sample size (P = 0.002) could explain 99.01% inter-study heterogeneity. CONCLUSION: This meta analysis found poorer overall survival in CRC patients with IBD than CRC patients without IBD, and further prospective research to confirm these findings is warranted. PMID- 26518414 TI - Risk Factors for Aspiration Pneumonia After Endoscopic Hemostasis. AB - BACKGROUND: Although all types of endoscopic procedures harbor risk of aspiration, little is understood about risk factors for aspiration pneumonia developing after endoscopic hemostasis. AIMS: The present study aimed to identify risk factors for aspiration pneumonia after endoscopic hemostasis. METHODS: Charts from consecutive patients with upper gastrointestinal bleeding that had been treated by endoscopic hemostasis at a single center between January 2004 and January 2015 were retrospectively reviewed. Patient information and clinical characteristics including cause of hemorrhage, established prognostic scales, laboratory data, comorbidities, medications, duration of endoscopic hemostasis, vital signs, sedative use, and the main operator during the procedure were compared between patients who developed aspiration pneumonia and those who did not. RESULTS: Aspiration pneumonia developed in 24 (4.8%) of 504 patients after endoscopic hemostasis. Endotracheal intubation was required for three of them, and one died of the complication. Multivariate analysis revealed that age >75 years (odds ratio (OR) 4.4; 95% confidence interval (CI) 1.5-13.6; p = 0.0073), procedural duration >30 min (OR 5.6; 95% CI 1.9-18.2; p = 0.0023), hemodialysis (OR 3.6; 95% CI 1.2-11; p = 0.024), and a history of stroke (OR 3.8; 95% CI 1-14; p = 0.041) were independent risk factors for developing aspiration pneumonia. CONCLUSIONS: Specific risk factors for aspiration pneumonia after endoscopic hemostasis were identified. Endoscopists should carefully consider aspiration pneumonia when managing older patients who are on hemodialysis, have a history of stroke, and undergo a longer procedure. PMID- 26518416 TI - Mellow Yellow: Diagnosis and Management of Multifactorial Postoperative Jaundice. PMID- 26518417 TI - Endoscopic Ultrasound-Guided Biliary Drainage: A Systematic Review and Meta Analysis. AB - BACKGROUND AND AIMS: Variable success and adverse event rates have been reported for endoscopic ultrasound-guided biliary drainage (EUS-BD) utilizing either extrahepatic or intrahepatic approach. We aimed to conduct a proportion meta analysis to evaluate the cumulative efficacy and safety of EUS-BD and to compare the two approaches and transluminal methods of EUS-BD. METHODS: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ISI Web of Science, and Scopus from January 2001 through January 5, 2015, to identify studies reporting technical success and adverse events of EUS-BD. A sample size of more than 20 patients was a further criterion. Weighted pooled rate (WPR) for technical success and post-procedure complications was calculated for overall studies and predefined subgroups. Pooled odds ratios were calculated for technical success and adverse events for two approaches and transluminal methods of EUS-BD for distal common bile duct (CBD) strictures. RESULTS: The WPR with 95% confidence interval (CI) for technical success and post-procedure adverse events was 90% (86, 93%) and 17% (13, 22%), respectively, with considerable heterogeneity (I(2) = 77%). For high-quality studies, the WPR for technical success was 94% (91, 96 %), I(2) = 0% and WPR for post-procedure adverse event was 16% (12, 19%), I(2) = 39%. In meta-regression model, distal CBD stricture and transpapillary drainage were associated with higher technical success and intrahepatic access route was associated with higher adverse event rate. There was no difference in technical success using either approach OR 1.27 (0.52, 3.13), I(2) = 0% or transluminal method OR 1.32 (0.51, 3.38), I(2) = 0%. However, the extrahepatic approach appeared significantly safer as compared to the intrahepatic approach OR 0.35 (0.19, 0.67), I(2) = 27%. Likewise, choledochoduodenostomy was found to have less adverse events as compared to hepaticogastrostomy, OR 0.40 (0.18, 0.87), I (2) = 0%. CONCLUSION: In cases of failure of traditional ERC to achieve biliary drainage, EUS-BD appears to be an emerging therapeutic modality with a cumulative success rate of 90% and cumulative adverse events rate of 17%. Randomized controlled trials are required to further evaluate the efficacy and safety of the procedure along with the comparison to traditional modalities like percutaneous transhepatic biliary drainage. PMID- 26518418 TI - Macrophages Are Involved in Gut Bacterial Translocation and Reversed by Lactobacillus in Experimental Uremia. AB - BACKGROUND: Uremia causes gut microbiome dysbiosis, which is characterized by a reduction in beneficial bacteria. Intestinal bacterial translocation (BT) contributes to microinflammation in uremia, which is associated with adverse outcomes. Whether macrophages are involved in BT remains unclear. AIMS: We investigated the involvement of macrophages in BT and microinflammation in uremic rats and whether Lactobacillus LB can influence macrophage activity. METHODS: Male Sprague-Dawley rats were randomly divided into three groups: sham, uremia, and uremia + probiotic. Macrophages and GFP-labeled tracer bacteria in intestinal and extraintestinal tissues were observed by fluorescence microscopy. The macrophage ultrastructure was examined by transmission electron microscopy. Immunochemistry was used to analyze the expression of cluster of differentiation 11a (CD11a), inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1). RT-PCR and Western blot were employed to assess the mRNA and protein expression of early growth response gene 1 (EGR1) and toll-like receptor 4 (TLR4). RESULTS: In uremic rats, the colocalization of GFP-labeled tracer bacteria and macrophages was visible in intestinal and extraintestinal tissues. Compared with the sham group, the uremic macrophages showed fewer cytoplasmic protrusions and pseudopodia. Administration of Lactobacillus LB restored the protrusions and pseudopodia. Compared with the sham group, the uremia group exhibited macrophages with higher staining intensities for CD11a, iNOS, and ICAM 1, and higher mRNA and protein expression of TLR4 and EGR1. CONCLUSIONS: Intestinal macrophages in the uremic rats are polarized toward a proinflammatory phenotype, resulting in microinflammation. Macrophages with impaired phagocytic function are associated with BT. Lactobacillus LB reduces BT by enhancing macrophage phagocytosis. PMID- 26518419 TI - Low level arsenic contaminated water consumption and birth outcomes in Romania-An exploratory study. AB - Women are exposed to drinking water with low arsenic concentrations (<10.0MUg/L) worldwide, yet little work has been done to assess the risk. To begin to address this data gap, we conducted an exploratory study of birth outcomes in Timis County, Romania. We prospectively followed 122 women with singleton deliveries, for whom we constructed individual exposure indicators using self-reported water consumption weighted by arsenic measured in drinking water sources. There were no overall confounder-adjusted effects for arsenic exposure on birth outcomes. Yet, higher average arsenic (10MUg/L) was associated with a -2.45 lower birth weight Z score (P=0.021) and a -1.17 shorter birth length Z-score (P=0.029) among smokers. Higher average iAs (10MUg/L) was also associated with smaller ponderal index in boys (P=0.023). Our results suggest smoking may potentiate an otherwise benign arsenic exposure. A larger, more definitive biomarker-based study is needed to investigate the potential risks in conjunction with smoking. PMID- 26518420 TI - One-year outcome of a prospective trial stopping dual antiplatelet therapy at 3 months after everolimus-eluting cobalt-chromium stent implantation: ShortT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt chromium stent (STOPDAPT) trial. AB - There has been no previous prospective study evaluating dual antiplatelet therapy (DAPT) duration shorter than 6 months after cobalt-chromium everolimus-eluting stent (CoCr-EES) implantation. STOPDAPT trial is a prospective multi-center single-arm study evaluating 3-month DAPT duration after CoCr-EES implantation. The primary endpoint was a composite of cardiovascular death, myocardial infarction (MI), stroke, definite stent thrombosis (ST) and TIMI major/minor bleeding at 1 year. Between September 2012 and October 2013, a total of 1525 patients were enrolled from 58 Japanese centers, with complete 1-year follow-up in 1519 patients (99.6 %). Thienopyridine was discontinued within 4 months in 1444 patients (94.7 %). The event rates beyond 3 months were very low (cardiovascular death: 0.5 %, MI: 0.1 %, ST: 0 %, stroke: 0.7 %, and TIMI major/minor bleeding: 0.8 %). Cumulative 1-year incidence of the primary endpoint was 2.8 % [upper 97.5 % confidence interval (CI) 3.6 %], which was lower than the pre-defined performance goal of 6.6 % (P < 0.0001). Using the CoCr-EES group in the RESET trial as a historical comparison group, where nearly 90 % of patients had continued DAPT at 1 year, cumulative incidence of the primary endpoint tended to be lower in the STOPDAPT than in the RESET (2.8 versus 4.0 %, P = 0.06) and adjusted hazard ratio was 0.64 (95 % CI 0.42-0.95, P = 0.03). The cumulative incidence of definite/probable ST was lower in the STOPDAPT than in the RESET [0 patient (0 %) versus 5 patients (0.3 %), P = 0.03]. In conclusion, stopping DAPT at 3 months in selected patients after CoCr-EES implantation was at least as safe as the prolonged DAPT regimen adopted in the historical control group. PMID- 26518422 TI - Stephen William Kuffler (1913-1980). PMID- 26518421 TI - Impact of Candidate Genetic Polymorphisms in Prostate Cancer: An Overview. AB - In the last few years, the presence of single nucleotide polymorphisms (SNPs) has been investigated in many tumors as predictor of disease aggressiveness and clinical outcome. We searched for relevant articles from 1998 to 2015 about the impact of SNPs in prostate cancer. Particularly, in this article, we review the pathogenetic, prognostic and predictive significance of gene polymorphisms in prostate tumor, providing a brief overview of studies in which the possible role of genetic variants was investigated in clinical settings. Because conflicting results often emerge about the impact of gene polymorphisms in prostate cancer, further larger studies are warranted in order to introduce gene polymorphism into clinical practice as biomarkers. PMID- 26518423 TI - Stratification of ALS patients' survival: a population-based study. AB - The natural history of amyotrophic lateral sclerosis (ALS) and patient risk stratification are areas of considerable research interest. We aimed (1) to describe the survival of a representative cohort of French ALS patients, and (2) to identify covariates associated with various patterns of survival using a risk classification analysis. ALS patients recruited in the FRALim register (2000 2013) were included. Time-to-death analyses were performed using Kaplan-Meier method and Cox model. A recursive partitioning and amalgamation (RECPAM) algorithm analysis identified subgroups of patients with different patterns of survival. Among 322 patients, median survival times were 26.2 and 15.6 months from time of onset and of diagnosis, respectively. Four groups of patients were identified, depending on their baseline characteristics and survival (1) ALSFRS-R slope >0.46/month and definite or probable ALS (median survival time (MST) 10.6 months); (2) ALSFRS-R slope >0.46/month and possible or probable laboratory supported ALS (MST: 18.1 months); (3) ALSFRS-R slope <=0.46/month and definite or probable ALS (MST: 22.5 months), and (4) ALSFRS-R slope <=0.46/month and possible or probable laboratory-supported ALS (MST: 37.6 months). Median survival time is among the shortest ever reported by a worldwide population-based study. This is probably related to the age structure of the patients (the oldest identified to date), driven by the underlying population (30 % of subjects older than 60 years). Further research in the field of risk stratification could help physicians better anticipate prognosis of ALS patients, and help improve the design of randomized controlled trials. PMID- 26518424 TI - Hybrid PET/optical imaging of integrin alphaVbeta3 receptor expression using a (64)Cu-labeled streptavidin/biotin-based dimeric RGD peptide. AB - BACKGROUND: Hybrid PET/optical imaging provides quantitative and complementary information for diagnosis of tumors. Herein, we developed a (64)Cu-labeled AlexaFluor 680-streptavidin ((AF)SAv)/biotin-based dimeric cyclic RGD peptide (RGD2) for hybrid PET/optical imaging of integrin alphaVbeta3 expression. METHODS: (64)Cu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-(AF)SAv/biotin-PEG-RGD2 was prepared by formation of a complex comprising DOTA-(AF)SAv and biotin-PEG-RGD2, followed by radiolabeling with (64)Cu. Receptor binding studies of DOTA-(AF)SAv/biotin-PEG-RGD2 were performed using U87MG cells and (125)I-RGDyK as the radioligand, and cellular uptake studies of (64)Cu-DOTA (AF)SAv/biotin-PEG-RGD2 were also performed. MicroPET imaging followed by optical imaging of U87MG tumor-bearing mice was acquired after injection of the hybrid probe, and region of interest (ROI) analysis of tumors was performed. Ex vivo PET/optical imaging and biodistribution studies of the major tissues were performed after the in vivo imaging, and immunofluorescence staining of the tumor tissue sections was carried out. RESULTS: (64)Cu-DOTA-(AF)SAv/biotin-PEG-RGD2 was prepared in 52.1 +/- 5.4 % radiochemical yield and with specific activity of 1.0 +/- 0.1 GBq/mg. Receptor binding studies showed that DOTA-(AF)SAv/biotin-PEG-RGD2 had higher binding affinity for integrin alphaVbeta3 than RGD2, reflecting a possible polyvalency effect. Moreover, the hybrid probe revealed time-dependent uptake by U87MG cells. In a microPET/optical imaging study, the hybrid probe demonstrated high accumulation in tumors; ROI analysis revealed 2.7 +/- 0.2 % ID/g at 1 h and 4.7 +/- 0.2 % ID/g at 21 h after injection, and subsequently acquired optical images showed tumors with strong fluorescence intensity. Ex vivo PET/optical images of the major tissues confirmed the in vivo imaging data, and biodistribution studies demonstrated high and specific uptake in tumors (4.8 +/- 0.1 % ID/g). Immunofluorescence staining showed the formation of new blood vessels in tumor tissues, suggesting that the tumor uptake was due to specific binding of the hybrid probe to integrin alphaVbeta3 expressed on tumor cells. CONCLUSIONS: These results indicate that a (64)Cu-DOTA-(AF)SAv/biotin-PEG-RGD2 is able to provide quantitative information on hybrid PET/optical imaging of integrin alphaVbeta3 expression. PMID- 26518425 TI - Mechanisms of thaxtomin A-induced root toxicity revealed by a thaxtomin A sensitive Arabidopsis mutant (ucu2-2/gi-2). AB - KEY MESSAGE: The Arabidopsis mutant ( ucu2 - 2/gi - 2 ) is thaxtomin A, isoxaben and NPA-sensitive indicated by root growth and ion flux responses providing new insights into these compounds mode of action and interactions. Thaxtomin A (TA) is a cellulose biosynthetic inhibitor (CBI) that promotes plant cell hypertrophy and cell death. Electrophysiological analysis of steady-state K(+) and Ca(2+) fluxes in Arabidopsis thaliana roots pretreated with TA for 24 h indicated a disturbance in the regulation of ion movement across the plant cell membrane. The observed inability to control solute movement, recorded in rapidly growing meristematic and elongation root zones, may partly explain typical root toxicity responses to TA treatment. Of note, the TA-sensitive mutant (ucu2-2/gi-2) was more susceptible with K(+) and Ca(2+) fluxes altered between 1.3 and eightfold compared to the wild-type control where fluxes altered between 1.2 and threefold. Root growth inhibition assays showed that the ucu2-2/gi-2 mutant had an increased sensitivity to the auxin 2,4-D, but not IAA or NAA; it also had increased sensitivity to the auxin efflux transport inhibitor, 1-naphthylphthalamic acid (NPA), but not 2,3,5- Triiodobenzoic acid (TIBA), when compared to the WT. The NPA sensitivity data were supported by electrophysiological analysis of H(+) fluxes in the mature (but not elongation) root zone. Increased sensitivity to the CBI, isoxaben (IXB), but not dichlobenil was recorded. Increased sensitivity to both TA and IXB corresponded with higher levels of accumulation of these toxins in the root tissue, compared to the WT. Further root growth inhibition assays showed no altered sensitivity of ucu2-2/gi-2 to two other plant pathogen toxins, alternariol and fusaric acid. Identification of a TA-sensitive Arabidopsis mutant provides further insight into how this CBI toxin interacts with plant cells. PMID- 26518426 TI - Ectopic overexpression of WsSGTL1, a sterol glucosyltransferase gene in Withania somnifera, promotes growth, enhances glycowithanolide and provides tolerance to abiotic and biotic stresses. AB - KEY MESSAGE: Overexpression of sterol glycosyltransferase (SGTL1) gene of Withania somnifera showing its involvement in glycosylation of withanolide that leads to enhanced growth and tolerance to biotic and abiotic stresses. Withania somnifera is widely used in Ayurvedic medicines for over 3000 years due to its therapeutic properties. It contains a variety of glycosylated steroids called withanosides that possess neuroregenerative, adaptogenic, anticonvulsant, immunomodulatory and antioxidant activities. The WsSGTL1 gene specific for 3beta hydroxy position has a catalytic specificity to glycosylate withanolide and sterols. Glycosylation not only stabilizes the products but also alters their physiological activities and governs intracellular distribution. To understand the functional significance and potential of WsSGTL1 gene, transgenics of W. somnifera were generated using Agrobacterium tumefaciens-mediated transformation. Stable integration and overexpression of WsSGTL1 gene were confirmed by Southern blot analysis followed by quantitative real-time PCR. The WsGTL1 transgenic plants displayed number of alterations at phenotypic and metabolic level in comparison to wild-type plants which include: (1) early and enhanced growth with leaf expansion and increase in number of stomata; (2) increased production of glycowithanolide (majorly withanoside V) and campesterol, stigmasterol and sitosterol in glycosylated forms with reduced accumulation of withanolides (withaferin A, withanolide A and withanone); (3) tolerance towards biotic stress (100 % mortality of Spodoptera litura), improved survival capacity under abiotic stress (cold stress) and; (4) enhanced recovery capacity after cold stress, as indicated by better photosynthesis performance, chlorophyll, anthocyanin content and better quenching regulation of PSI and PSII. Our data demonstrate overexpression of WsSGTL1 gene which is responsible for increase in glycosylated withanolide and sterols, and confers better growth and tolerance to both biotic and abiotic stresses. PMID- 26518427 TI - A novel cis-acting element in the GmERF3 promoter contributes to inducible gene expression in soybean and tobacco after wounding. AB - KEY MESSAGE: Using in silico and functional analyses, we cloned and validated the expression profile of an inducible soybean promoter (GmERF3) along with its novel wound-induced and delayed expression (WIDE) element. Promoters and their contributing promoter elements are the main regulators of gene expression at the transcriptional level. Although the Ethylene Response Factor (ERF) gene family is one of the most well-studied stress-responsive gene families in plants, their promoter regions have received little attention. In this study, we investigated the expression patterns driven by the soybean (Glycine max) GmERF3 promoter and its cis-acting elements in soybean and tobacco. Transcriptomic data revealed that the native GmERF3 gene was differentially expressed in organs and tissues of plants. In transgenic soybeans containing a 1.3 kb GmERF3 promoter fused to the green fluorescent protein (gfp) gene, organ- and tissue-specificity was observed in untreated plants while mechanical wounding led to induction of GFP expression. Further in silico and in planta analyses of the GmERF3 promoter sequence in soybean revealed different cis-acting elements, including a novel cis-acting element, which contributed to increased expression, 1-2 days after mechanical wounding. We have named this DNA motif the wound-induced and delayed expression element (GGATTCAAGTTTAACC). A synthetic promoter containing a tetrameric repeat of this element showed high but late wound-induced GFP expression in leaves of transgenic tobacco. Our study expands the toolbox of inducible promoters and promoter elements for potential use in basic and applied research. PMID- 26518428 TI - Over-expression of AQUA1 in Populus alba Villafranca clone increases relative growth rate and water use efficiency, under Zn excess condition. AB - KEY MESSAGE: Transgenic Populus alba over-expressing a TIP aquaporin ( aqua1) showed a higher growth rate under Zn excess, suggesting that aqua1 could be involved in water homeostasis, rather than in Zn homeostasis. Populus is the internationally accepted model for physiological and developmental studies of tree traits under stress. In plants, aquaporins facilitate and regulate the diffusion of water, however, few poplar aquaporins have been characterized to date. In this study, we reported for the first time an in vivo characterization of Populus alba clone Villafranca transgenic plants over-expressing a TIP aquaporin (aqua1) of P. x euramericana clone I-214. An AQUA1:GFP chimeric construct, over-expressed in P. alba Villafranca clones, shows a cytoplasmic localization in roots, and it localizes in guard cells in leaves. When over expressed in transgenic plants, aqua1 confers a higher growth rate compared to wild-type (wt) plants, without affecting chlorophyll accumulation, relative water content (RWC), and fluorescence performances, but increasing the intrinsic Transpiration Efficiency. In response to Zn (1 mM), transgenic lines did not show a significant increase in Zn accumulation as compared to wt plants, even though the over-expression of this gene confers higher tolerance in root tissues. These results suggest that, in poplar plants, this gene could be principally involved in regulation of water homeostasis and biomass production, rather than in Zn homeostasis. PMID- 26518429 TI - Alternative pathway is involved in the tolerance of highland barley to the low nitrogen stress by maintaining the cellular redox homeostasis. AB - KEY MESSAGE: Alternative pathway (AP) is involved in the tolerance of highland barley seedlings to the low-nitrogen stress by dissipating excessive reducing equivalents generated by photosynthesis and maintaining the cellular redox homeostasis. Low nitrogen (N) is a major limiting factor for plant growth and crop productivity. In this study, we investigated the roles of the alternative pathway (AP) in the tolerance of two barley seedlings, highland barley (Kunlun12) and barley (Ganpi6), to low-N stress. The results showed that the chlorophyll content and the fresh weight decreased more in Ganpi6 than those in Kunlun12 under low-N stress, suggesting that Kunlun12 has higher tolerance to low-N stress than Ganpi6. AP capacity was markedly induced by low-N stress; and it was higher in Kunlun12 than in Ganpi6. Comparatively, the cytochrome pathway capacity was not affected under all conditions. Western-blot analysis showed that the protein level of the alternative oxidase (AOX) increased under low-N stress in Kunlun12 but not in Ganpi6. Under low-N stress, the NAD(P)H content and the NAD(P)H to NAD(P)(+)+NAD(P)H ratio in Ganpi6 increased more than those in Kunlun12. Furthermore, photosynthetic parameters (Fv/Fm, qP, ETR and Yield) decreased markedly and qN increased, indicating photoinhibition occurred in both barley seedlings, especially in Ganpi6. When AP was inhibited by salicylhydroxamic acid (SHAM), the NAD(P)H content and the NAD(P)H to NAD(P)(+)+NAD(P)H ratio dramatically increased under all conditions, resulting in the marked accumulation of H(2)O(2) and malondialdehyde in leaves of both barley seedlings. Meanwhile, the malate-oxaloacetate shuttle activity and the photosynthetic efficiency were further inhibited. Taken together, AP is involved in the tolerance of highland barley seedlings to low-N stress by dissipating excess reducing equivalents and maintaining the cellular redox homeostasis. PMID- 26518430 TI - Transcriptome-based gene expression profiling identifies differentially expressed genes critical for salt stress response in radish (Raphanus sativus L.). AB - KEY MESSAGE: Transcriptome-based gene expression analysis identifies many critical salt-responsive genes in radish and facilitates further dissecting the molecular mechanism underlying salt stress response. Salt stress severely impacts plant growth and development. Radish, a moderately salt-sensitive vegetable crop, has been studied for decades towards the physiological and biochemical performances under salt stress. However, no systematic study on isolation and identification of genes involved in salt stress response has been performed in radish, and the molecular mechanism governing this process is still indistinct. Here, the RNA-Seq technique was applied to analyze the transcriptomic changes on radish roots treated with salt (200 mM NaCl) for 48 h in comparison with those cultured in normal condition. Totally 8709 differentially expressed genes (DEGs) including 3931 up- and 4778 down-regulated genes were identified. Functional annotation analysis indicated that many genes could be involved in several aspects of salt stress response including stress sensing and signal transduction, osmoregulation, ion homeostasis and ROS scavenging. The association analysis of salt-responsive genes and miRNAs exhibited that 36 miRNA-mRNA pairs had negative correlationship in expression trends. Reverse-transcription quantitative PCR (RT qPCR) analysis revealed that the expression profiles of DEGs were in line with results from the RNA-Seq analysis. Furthermore, the putative model of DEGs and miRNA-mediated gene regulation was proposed to elucidate how radish sensed and responded to salt stress. This study represents the first comprehensive transcriptome-based gene expression profiling under salt stress in radish. The outcomes of this study could facilitate further dissecting the molecular mechanism underlying salt stress response and provide a valuable platform for further genetic improvement of salt tolerance in radish breeding programs. PMID- 26518431 TI - Brassinosteroid (BR) biosynthetic gene lhdd10 controls late heading and plant height in rice (Oryza sativa L.). AB - KEY MESSAGE: A Brd2 allele suppresses heading date by altering the expression of heading date regulators such as OsMADS50 , and also negatively regulates chlorophyll biosynthesis. Heading date and plant height are important determinants of yield in rice (Oryza sativa L.). In this study, we characterized a late heading, dwarf mutant known as lhdd10 selected following ethyl methane sulfonate (EMS)-treatment of ssp. indica cultivar 93-11. lhdd10 showed late heading, dwarfness and slightly darker-green leaves than wild-type 93-11 under long-day and short-day conditions. We isolated lhdd10 by map-based cloning; it encoded a putative FAD-linked oxidoreductase protein (a brassinosteroid biosynthetic gene) that localized to the nucleus. LHDD10 was constitutively expressed in various tissues, but more so in shoot apices and panicles. Our data showed that lhdd10 influences heading date by controlling the expression of heading date regulators, such as OsMADS50 in both LD and SD conditions. lhdd10 also negatively regulated expression of chlorophyll biosynthetic genes to reduce the chlorophyll content. Our data indicated that BRs play important roles in regulating heading date and chlorophyll biosynthesis. This work provides material that will allow study of how BRs regulate heading date in rice. PMID- 26518432 TI - Bacterial communities in termite fungus combs are comprised of consistent gut deposits and contributions from the environment. AB - Fungus-growing termites (subfamily Macrotermitinae) mix plant forage with asexual spores of their plant-degrading fungal symbiont Termitomyces in their guts and deposit this blend in fungus comb structures, within which the plant matter is degraded. As Termitomyces grows, it produces nodules with asexual spores, which the termites feed on. Since all comb material passes through termite guts, it is inevitable that gut bacteria are also deposited in the comb, but it has remained unknown which bacteria are deposited and whether distinct comb bacterial communities are sustained. Using high-throughput sequencing of the 16S rRNA gene, we explored the bacterial community compositions of 33 fungus comb samples from four termite species (three genera) collected at four South African geographic locations in 2011 and 2013. We identified 33 bacterial phyla, with Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, and Candidate division TM7 jointly accounting for 92 % of the reads. Analyses of gut microbiotas from 25 of the 33 colonies showed that dominant fungus comb taxa originate from the termite gut. While gut communities were consistent between 2011 and 2013, comb community compositions shifted over time. These shifts did not appear to be due to changes in the taxa present, but rather due to differences in the relative abundances of primarily gut-derived bacteria within fungus combs. This indicates that fungus comb microbiotas are largely termite species-specific due to major contributions from gut deposits and also that environment affects which gut bacteria dominate comb communities at a given point in time. PMID- 26518433 TI - Status of gastric lavage in neonates born with meconium stained amniotic fluid: a randomized controlled trial. AB - BACKGROUND: Neonates born with meconium stained amniotic fluid (MSAF) can develop feed intolerance during first few days of post -natal period. A randomized controlled trial was conducted with the objectives of to find out the incidence of feed intolerance in vigorous neonates with MSAF who received gastric lavage (GL) as compared to those in whom it was not performed. METHODS: This was a randomized controlled trial on 500 neonates satisfying the inclusion criteria, 230 were allocated to GL and 270 to no lavage group through computer generated random numbers. RESULTS: No significant difference in the incidence of vomiting was found between GL and no lavage group (8.7 % vs 11.5 %, p = 0.305). Feed intolerance had no relationship with gestational age, gender, birth weight and mode of delivery. No neonates of GL group developed any complications related to the procedure. CONCLUSION: Thus, it may be concluded that gastric lavage is not required in neonates born with MSAF. PMID- 26518434 TI - Sex-specific differences in genetic and nongenetic determinants of mean platelet volume: results from the Gutenberg Health Study. AB - Mean platelet volume (MPV), a measure of platelet size, is a potential biological marker of platelet function. To date, a comprehensive analysis including known genetic and nongenetic factors that determine MPV is still lacking. MPV has been evaluated in 15 010 individuals from the population-based Gutenberg Health Study. Genetic information was available for 4175 individuals. Our results showed that age (beta, 0.0346; 95% confidence interval [CI], 0.0255 to 0.0436), cardiovascular risk factors (CVRFs) such as smoking (beta, 0.178; 95% CI, 0.128 to 0.229), hypertension (beta, 0.05; 95% CI, 0.00289 to .0981), and high glucose level (beta, 0.00179; 95% CI, 0.0006 to 0.00299) were linked with higher MPV in males only. Intake of oral contraceptives (beta, 0.150; 95% CI, 0.0649 to 0.236) and menstruation (beta, 0.123; 95% CI, 0.0231 to 0.224) were strongly associated with higher MPV in females. Seven single nucleotide polymorphisms (SNPs) for females and 4 SNPs for males were associated with higher MPV. The full model, including age, CVRFs, laboratory parameters, medications, and genetic variation, explained 20.4% of the MPV variance in females and 18.6% in males. The curves of cumulative mortality, stratified for sex, showed worse survival for males only with MPV > 9.96 fL vs MPV <= 9.96 fL (P < .0001). This study provides evidence for heterogeneity in the profile of determinants for MPV between sexes. The observed interactions between genetic variability, CVRFs, and MPV and its association with the development of cardiovascular disease or thrombotic risk need to be further investigated. PMID- 26518436 TI - Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis. AB - Immunoassays are essential in the workup of patients with suspected heparin induced thrombocytopenia. However, the diagnostic accuracy is uncertain with regard to different classes of assays, antibody specificities, thresholds, test variations, and manufacturers. We aimed to assess diagnostic accuracy measures of available immunoassays and to explore sources of heterogeneity. We performed comprehensive literature searches and applied strict inclusion criteria. Finally, 49 publications comprising 128 test evaluations in 15 199 patients were included in the analysis. Methodological quality according to the revised tool for quality assessment of diagnostic accuracy studies was moderate. Diagnostic accuracy measures were calculated with the unified model (comprising a bivariate random effects model and a hierarchical summary receiver operating characteristics model). Important differences were observed between classes of immunoassays, type of antibody specificity, thresholds, application of confirmation step, and manufacturers. Combination of high sensitivity (>95%) and high specificity (>90%) was found in 5 tests only: polyspecific enzyme-linked immunosorbent assay (ELISA) with intermediate threshold (Genetic Testing Institute, Asserachrom), particle gel immunoassay, lateral flow immunoassay, polyspecific chemiluminescent immunoassay (CLIA) with a high threshold, and immunoglobulin G (IgG)-specific CLIA with low threshold. Borderline results (sensitivity, 99.6%; specificity, 89.9%) were observed for IgG-specific Genetic Testing Institute-ELISA with low threshold. Diagnostic accuracy appears to be inadequate in tests with high thresholds (ELISA; IgG-specific CLIA), combination of IgG specificity and intermediate thresholds (ELISA, CLIA), high-dose heparin confirmation step (ELISA), and particle immunofiltration assay. When making treatment decisions, clinicians should be a aware of diagnostic characteristics of the tests used and it is recommended they estimate posttest probabilities according to likelihood ratios as well as pretest probabilities using clinical scoring tools. PMID- 26518435 TI - Platelet transactivation by monocytes promotes thrombosis in heparin-induced thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT) is characterized by a high incidence of thrombosis, unlike other antibody-mediated causes of thrombocytopenia. We have shown that monocytes complexed with surface-bound platelet factor 4 (PF4) activated by HIT antibodies contribute to the prothrombotic state in vivo, but the mechanism by which this occurs and the relationship to the requirement for platelet activation via fragment crystallizable (Fc)gammaRIIA is uncertain. Using a microfluidic model and human or murine blood, we confirmed that activation of monocytes contributes to the prothrombotic state in HIT and showed that HIT antibodies bind to monocyte FcgammaRIIA, which activates spleen tyrosine kinase and leads to the generation of tissue factor (TF) and thrombin. The combination of direct platelet activation by HIT immune complexes through FcgammaRIIA and transactivation by monocyte-derived thrombin markedly increases Annexin V and factor Xa binding to platelets, consistent with the formation of procoagulant coated platelets. These data provide a model of HIT wherein a combination of direct FcgammaRIIA-mediated platelet activation and monocyte-derived thrombin contributes to thrombosis in HIT and identifies potential new targets for lessening this risk. PMID- 26518437 TI - ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice. AB - Cytokine storm syndromes, such as familial hemophagocytic lymphohistiocytosis (FHL), are lethal disorders caused by uncontrolled, systemic immune activation. In the murine model of FHL, in which perforin-deficient (Prf1(-/-)) mice are infected with lymphocytic choriomeningitis virus (LCMV), disease is driven by overabundant interferon (IFN)gamma-producing LCMV-specific CD8(+) T cells thought to arise from excessive antigen stimulation through the T-cell receptor. However, this paradigm is insufficient to explain several fundamental aspects of FHL, namely, the inability of many pathogenic antigens to induce hyperinflammation, and the previously identified role of MyD88 in the disease. We now show a novel role for the MyD88-dependent interleukin-33 (IL-33) receptor, ST2, in FHL. Expression of IL-33 and ST2 is upregulated in LCMV-infected Prf1(-/-) mice. Blockade of ST2 markedly improves survival of LCMV-infected Prf1(-/-) mice and reduces the severity of multiple disease parameters, including serum levels of IFNgamma. This decrease in IFNgamma corresponds to a reduction in both the frequency of IFNgamma(+) LCMV-specific CD8(+) and CD4(+) T cells and the magnitude of IFNgamma expression in these cells. These findings demonstrate that disruption of ST2 signaling in the murine model of FHL reduces T cell-mediated production of IFNgamma and suggest a revised paradigm in which danger signals such as IL-33 are crucial amplifiers of immune dysregulation in FHL. Furthermore, this study provides evidence to support blockade of ST2 as a novel therapeutic strategy for FHL. PMID- 26518439 TI - Sqh is involved in the regulation of Ci stability in Hh signaling pathway. PMID- 26518438 TI - Is Math Anxiety Always Bad for Math Learning? The Role of Math Motivation. AB - The linear relations between math anxiety and math cognition have been frequently studied. However, the relations between anxiety and performance on complex cognitive tasks have been repeatedly demonstrated to follow a curvilinear fashion. In the current studies, we aimed to address the lack of attention given to the possibility of such complex interplay between emotion and cognition in the math-learning literature by exploring the relations among math anxiety, math motivation, and math cognition. In two samples-young adolescent twins and adult college students-results showed inverted-U relations between math anxiety and math performance in participants with high intrinsic math motivation and modest negative associations between math anxiety and math performance in participants with low intrinsic math motivation. However, this pattern was not observed in tasks assessing participants' nonsymbolic and symbolic number-estimation ability. These findings may help advance the understanding of mathematics-learning processes and provide important insights for treatment programs that target improving mathematics-learning experiences and mathematical skills. PMID- 26518440 TI - Platelet reactivity in patients with impaired renal function receiving dual antiplatelet therapy with clopidogrel or ticagrelor. AB - BACKGROUND: Suboptimal platelet inhibition still represents an important challenge, especially for patients undergoing percutaneous coronary interventions (PCI). Chronic kidney disease (CKD) is a common comorbidity of patients with coronary artery disease, and may potentially influence platelet reactivity. So far only few studies have assessed the role of CKD on response to dual antiplatelet therapy (DAPT) with conflicting results. Therefore, the aim of our study was to evaluate the impact of CKD on platelet function in patients treated with DAPT after a recent acute coronary syndrome (ACS) or PCI. METHODS: Patients treated with DAPT, acetylsalicylic acid (ASA)+adenosine diphosphate antagonist (ADP-antagonist) such as clopidogrel or ticagrelor, for ACS or elective patients undergoing PCI were scheduled for platelet function assessment at 30-90 days post discharge. Platelet function was assessed by whole blood impedance aggregometry (Multiplate(r)- Roche Diagnostics AG), high residual platelet reactivity (HRPR) was considered for ASPI test >862 AU*min (for ASA) and ADP test values >= 417 AU*min (for ADP-antagonists). Chronic renal failure was defined as an estimated glomerular filtration rate of 60 mol/min/1.73 m(2) or less, calculated by applying MDRD (Modification of Diet in renal Disease) formula. RESULTS: Our population included a total of 537 patients of which 308 (57.3%) received ASA and clopidogrel and 229 (42.6%) received ASA and ticagrelor. Patients with renal failure at baseline (101 out of 537, 18.8%) were older, with higher prevalence of hypertension, previous myocardial infarction and coronary artery bypass graft surgery. Moreover, they had a lower ejection fraction at baseline and were more often in therapy with diuretics, but less often with statins at admission. They had lower haemoglobin and higher glycated haemoglobin. HRPR was observed in 1.5% of patients treated with ASA with no difference according to renal function (p=0.18). HRPR for ADP-antagonists was observed in 23.7% of patients, with no difference according to renal function (p=0.50). This result was confirmed either with clopidogrel (31.9% versus 38%, p=0.41) and ticagrelor (13.1% versus 10.8%, p=0.99), also after correction for all baseline confounders (clopidogrel: adjusted OR[95%CI]=1.26 [0.60-2.63], p=0.54) (ticagrelor: adjusted OR[95%CI]=0.95 [0.54-1.65], p=0.84). The absence of association between renal function and platelet reactivity was confirmed at linear regression analysis both with clopidogrel (r=-0.04, p=0.52) and ticagrelor (r=0.006, p=0.92). CONCLUSION: In patients receiving DAPT, chronic renal failure did not influence ADP-mediated platelet reactivity, with both ticagrelor or clopidogrel. No influence of chronic renal failure was found on the effectiveness of ASA. PMID- 26518442 TI - The predatory life cycle of Myxococcus xanthus. AB - Myxococcus xanthus is a predatory bacterium and a model system for social behaviour in bacteria. Myx. xanthus forms thin biofilms, where cells work together to colonize new territory, invade prey colonies and lyse prey cells. Prey-cell lysis occurs at close proximity, and utilizes antibiotics such as myxovirescin, hydrolytic enzymes such as the protease MepA and extracellular outer-membrane vesicles that may facilitate delivery. Many questions about the mechanism of prey lysis remain, as well as a complete understanding of the vast hydrolytic and secondary metabolite potential present in the Myx. xanthus genome. However, it is clear that predation presents unique challenges for this bacterium, which are solved, in part, through the social behaviours at the disposal of Myx. xanthus. Here, we discuss the life cycle of Myx. xanthus, and the hypothesis that multicellular behaviour in this organism is critical to, and derives from, the challenges of growth as a bacterial predator. PMID- 26518441 TI - Microbial inoculants for the biocontrol of Fusarium spp. in durum wheat. AB - BACKGROUND: Fusarium head blight (FHB) is a severe disease caused by different Fusarium species, which affects a wide range of cereal crops, including wheat. It determines from 10 to 30% of yield loss in Europe. Chemical fungicides are mainly used to reduce the incidence of FHB, but low environmental impact solutions are looked forward. Applications of soil/rhizobacteria as biocontrol agents against FHB in wheat are described in literature, whereas the potential use of lactobacilli in agriculture has scarcely been explored. RESULTS: The aim of this work was to study the inhibitory effect of two bacterial strains, Lactobacillus plantarum SLG17 and Bacillus amyloliquefaciens FLN13, against Fusarium spp. in vitro and to assess their efficacy in field, coupled to the study of the microbial community profile of wheat seeds. Antimicrobial assays were performed on agar plates and showed that the two antagonistic strains possessed antimicrobial activity against Fusarium spp. In the field study, a mixture of the two strains was applied to durum wheat i) weekly from heading until anthesis and ii) at flowering, compared to untreated and fungicide treated plots. The FHB index, combining both disease incidence and disease severity, was used to evaluate the extent of the disease on wheat. A mixture of the two microorganisms, when applied in field from heading until anthesis, was capable of reducing the FHB index. Microbial community profile of seeds was studied via PCR-DGGE, showing the presence of L. plantarum SLG17 in wheat seeds and thus underlining an endophytic behavior of the strain. CONCLUSIONS: L. plantarum SLG17 and B. amyloliquefaciens FLN13, applied as biocontrol agents starting from the heading period until anthesis of wheat plants, are promising agents for the reduction of FHB index. PMID- 26518443 TI - The Rationale and Timing of Molecular Genetic Testing for Dilated Cardiomyopathy. AB - The genetic evaluation of dilated cardiomyopathy (DCM) has been challenging, owing in large part to marked genetic heterogeneity. However, lower costs from next-generation sequencing have enabled gene discovery and the expansion of genetic testing panels. These advances have improved molecular diagnostics and predictive testing in DCM. We provide a rationale and recommendation for clinical genetic testing in all DCM cases. PMID- 26518445 TI - The Rapidly Evolving Role of Titin in Cardiac Physiology and Cardiomyopathy. AB - The giant muscle filament protein titin is encoded by a single gene consisting of 364 exons. In the past, because of its enormous size and complexity, only few titin mutations were discovered causing different cardiac and skeletal muscle conditions; however, the overall role for heritable diseases, in particular dilated cardiomyopathy (DCM), has been significantly underestimated. Recently performed systematic studies using next-generation sequencing (NGS) recognized TTN as the major human disease gene for DCM, but at the same time those data sets revealed that unique genetic variations are also more common in the general population than previously expected. Truncating variants in TTN have been reported in about 25% of patients with DCM and in 2%-3% of controls; however, most of the disease-associated truncation variants were found in constitutively expressed exons across the gene and in A-band titin, which is abundant in both major cardiac isoforms N2B and N2BA. Titin isoform composition and switch is an important factor for determination and modulation of titin-based stiffness in health and heart disease. Moreover, other factors, including post-translational modification resulting from phosphorylation and oxidative modifications of titin spring elements contribute at the cellular level to titin's stiffness. A better understanding of titin's role in cardiac (patho)physiology will achieve further insights into the molecular mechanisms leading to heart failure and arrhythmias in patients with DCM caused by titin truncation mutations and may provide potential targets for future therapeutic interventions. PMID- 26518446 TI - Mitochondrial Diseases and Cardiomyopathies. AB - Mitochondrial cardiomyopathies are clinically and genetically heterogeneous. An integrative approach encompassing clinical, biochemical, and molecular investigations is required to reach a specific diagnosis. In this review we summarize the clinical and genetic aspects of mitochondrial disorders associated with cardiomyopathy, including disorders of oxidative phosphorylation. It also describes groups of disorders that, although not usually classified as mitochondrial disorders, stem from defects in mitochondrial function (eg, disorders of beta-oxidation and the carnitine cycle), are associated with secondary mitochondrial impairment (eg, organic acidurias), and are important diagnostically because they are treatable. Current biochemical and molecular techniques for the diagnosis of mitochondrial cardiomyopathies are described, and a diagnostic algorithm is proposed, to help clinicians in their approach to cardiomyopathies in the context of mitochondrial diseases. PMID- 26518444 TI - The Genetic Challenges and Opportunities in Advanced Heart Failure. AB - The causes of heart failure are diverse. Inherited causes represent an important clinical entity and can be divided into 2 major categories: familial and metabolic cardiomyopathies. The distinct features that might be present in early disease states can become broadly overlapping with other diseases, such as in the case of inherited cardiomyopathies (ie, familial hypertrophic cardiomyopathy or mitochondrial diseases). In this review article, we focus on genetic issues related to advanced heart failure. Because of the emerging importance of this topic and its breadth, we sought to focus our discussion on the known genetic forms of heart failure syndromes, genetic testing, and newer data on pharmacogenetics and therapeutics in the treatment of heart failure, to primarily encourage clinicians to place a priority on the diagnosis and treatment of these potentially treatable conditions. PMID- 26518447 TI - A Family History of Sudden Death Should Not Be a Primary Indication for an Implantable Cardioverter Defibrillator in Hypertrophic Cardiomyopathy. AB - Sudden cardiac death (SCD) is a tragic outcome in hypertrophic cardiomyopathy, but it occurs at a low frequency overall and is challenging to predict accurately. Many important predictors of SCD have emerged over the past 50 years, one of which is a family history of SCD. The available data are limited by their retrospective nature and variability in the definition of family history across studies. We advocate a novel model of risk stratification in which no individual predictor has primacy; rather the overall clinical picture of the patient is used to determine their SCD risk. PMID- 26518448 TI - Case-control study of glucocorticoid receptor and corticotrophin-releasing hormone receptor gene variants and risk of perinatal depression. AB - BACKGROUND: Depression during pregnancy or after childbirth is the most frequent perinatal illness affecting women of reproductive age. It could result in unfavourable outcomes for both women and their newborns. The incidence of perinatal depression is higher for those with family history of depression and other mental illness, suggesting the contribution of genetic factors. There is postulation that disruption or fluctuation of reproductive hormones could play a part in women who are sensitive to such changes. METHODS: This is a case-control study comparing the frequencies of candidate gene variants in patients with perinatal depression with controls. Patients of Chinese descent (N = 725) were recruited from the outpatient clinics of the hospital between 2010 and 2013. Controls were patients who came for postnatal consultations at the obstetrics clinics and scored <= 7 on the Edinburgh Postnatal Depression Scale (EPDS) at the postnatal screening programme of the hospital. Cases with confirmed diagnosis of clinical (major) depression related to pregnancy/postpartum were recruited from the hospital's outpatient clinic. Genomic DNA was extracted from saliva samples and genotyped for the polymorphisms of interest. Differences between groups were assessed by chi-square analysis. RESULTS: CRHR1 rs242939 and rs1876828 were not polymorphic in the study population. There was no statistically significant association of perinatal depression for CRHR1 rs242941 and GR rs41423247 (BclI). When all subjects were grouped based on family history of mental illness, there was a statistically significant association of CRHR1 rs242941 with family history regardless of depression status (P = 0.043). There was also a statistically significant difference for GR rs41423247 and regularity of menstrual periods (P < 0.000). Although not statistically significant, women with perinatal depression showed a trend towards higher frequency of self-reported menstrual irregularity. CONCLUSIONS: No evidence was found for the association of any of the genetic markers with perinatal depression in this study cohort. Instead, the possible genetic links were found in women with positive family history of mental illness and menstrual irregularity, suggesting these could be identifying risk markers for women. PMID- 26518449 TI - Notification that new names of prokaryotes, new combinations and new taxonomic opinions have appeared in volume 65, part 7, of the IJSEM. AB - This listing of names of prokaryotes published in a previous issue of the IJSEM is provided as a service to bacteriology to assist in the recognition of new names and new combinations. This procedure was proposed by the Judicial Commission [Minute 11(ii), Int J Syst Bacteriol 41 (1991), p. 185]. The names given herein are listed according to the Rules of priority (i.e. page number and order of valid publication of names in the original articles). PMID- 26518450 TI - Reduced graphene oxide induces transient blood-brain barrier opening: an in vivo study. AB - BACKGROUND: The blood-brain barrier (BBB) is a complex physical and functional barrier protecting the central nervous system from physical and chemical insults. Nevertheless, it also constitutes a barrier against therapeutics for treating neurological disorders. In this context, nanomaterial-based therapy provides a potential alternative for overcoming this problem. Graphene family has attracted significant interest in nanomedicine because their unique physicochemical properties make them amenable to applications in drug/gene delivery and neural interface. RESULTS: In this study, reduced graphene oxide (rGO) systemically injected was found mainly located in the thalamus and hippocampus of rats. The entry of rGO involved a transitory decrease in the BBB paracellular tightness, as demonstrated at anatomical (Evans blue dye infusion), subcellular (transmission electron microscopy) and molecular (junctional protein expression) levels. Additionally, we examined the usefulness of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) as a new imaging method for detecting the temporal distribution of nanomaterials throughout the brain. CONCLUSIONS: rGO was able to be detected and monitored in the brain over time provided by a novel application for MALDI-MSI and could be a useful tool for treating a variety of brain disorders that are normally unresponsive to conventional treatment because of BBB impermeability. PMID- 26518451 TI - HLA, GVHD, and parenteral nutrition are risk factors for hepatic complications in pediatric HSCT. AB - Hepatic dysfunction is common after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this retrospective study was to determine the risk factors, frequency, and outcome of hepatic complications post-HSCT in children. Two hundred and thirty-seven cases of allogeneic HSCT in children were included. Data on biochemical liver function at start of HSCT, at +1, +3, +6, and +9 months, and at each subsequent yearly follow-up were extracted. Patients were stratified into groups with hepatocellular (none and mild, and moderate to severe) and hepatobiliary (none and present) dysfunction. Statistical analysis included variables such as diagnosis, age, conditioning regimen, and HLA type. RESULTS: One hundred and fifty-six (66%) patients displayed hepatocellular dysfunction post-HSCT. In most cases transient, but 32% had a persistent abnormality three yr post-HSCT. Risk factors were chronic GVHD (OR 4.20, p = 0.003) and donor HLA-A*01 (OR 2.97, p = 0.02). HLA-DQB1*03 decreased the risk (OR 0.35, p = 0.02). Hepatobiliary dysfunction was less frequent (12%) but carried a poor prognosis. aGVHD grade II-IV (OR 2.7, p = 0.02) and long-term TPN (OR 3.25, p = 0.01) increased the risk. CONCLUSION: GVHD is an important risk factor for liver dysfunction post-HSCT. Specific HLA types may also contribute as a risk factor, while others seem to have a protective effect. PMID- 26518452 TI - Defining the surface anatomy of the central venous system in children. AB - Pediatric emergency physicians, pediatric critical care specialists, and pediatric surgeons perform central venous catheterization in many clinical settings. Complications of the procedure are not uncommon and can be fatal. Despite the frequency of application, the evidence-base describing the surface landmarks involved is missing. The aim of the current study was to critically investigate the surface markings of the central venous system in children. The superior vena cava/right atrial (SVC/RA) junction, superior vena cava (SVC) formation, and brachiocephalic vein (BCV) formation were examined independently by two investigators. Three hundred computed tomography (CT) scans collected across multiple centers were categorized by age group into: 0-3 years, 4-7 years, and 8-11 years. Scans with pathology that distorted or obscured the regional anatomy were excluded. The BCV formation was commonly found behind the ipsilateral medial clavicular head throughout childhood. This contrasts with the variable levels of SVC formation, SVC length, and SVC/RA junction. In the youngest group, SVC formation was most commonly at the second costal cartilage (CC), but moved to the first CC/first intercostal space (ICS) as the child grew. The SVC/RA junction was at the fourth CC in the youngest group and moved to the third CC/third ICS as the child grew. This study demonstrates the variable anatomy of SVC formation and the SVC/RA junction with respect to rib level. This variability underscores the unreliability of surface anatomical landmarks of the SVC/RA junction as a guide to catheter tip position. PMID- 26518453 TI - FoxO1 mediates TGF-beta1-dependent cardiac myofibroblast differentiation. AB - Cardiac fibroblast differentiation to myofibroblast is a crucial process in the development of cardiac fibrosis and is tightly dependent on transforming growth factor beta-1 (TGF-beta1). The transcription factor forkhead box O1 (FoxO1) regulates many cell functions, including cell death by apoptosis, proliferation, and differentiation. However, several aspects of this process remain unclear, including the role of FoxO1 in cardiac fibroblast differentiation and the regulation of FoxO1 by TGF-beta1. Here, we report that TGF-beta1 stimulates FoxO1 expression, promoting its dephosphorylation, nuclear localization and transcriptional activity in cultured cardiac fibroblasts. TGF-beta1 also increases differentiation markers such as alpha-smooth muscle actin, connective tissue growth factor, and pro-collagen I, whereas it decreases cardiac fibroblast proliferation triggered by fetal bovine serum. TGF-beta1 also increases levels of p21waf/cip-cycle inhibiting factor protein, a cytostatic factor promoting cell cycle arrest and cardiac fibroblast differentiation. In addition, TGF-beta1 increases cardiac fibroblast contractile capacity as assessed by collagen gel contraction assay. The effect of TGF-beta1 on cardiac fibroblast differentiation was prevented by FoxO1 down-regulation and enhanced by FoxO1 overexpression. Thus, our findings reveal that FoxO1 is regulated by TGF-beta1 and plays a critical role in cardiac fibroblast differentiation. We propose that FoxO1 is an attractive new target for anti-fibrotic therapy. PMID- 26518455 TI - Alterations in juvenile flatfish gill epithelia induced by sediment-bound toxicants: A comparative in situ and ex situ study. AB - Juvenile Solea senegalensis were exposed in the laboratory (ex situ) and field (in situ) to different sediments of a moderately impacted estuary (the Sado, Portugal) for 28 days. A qualitative histopathological screening yielded scant lesions to gills, albeit alterations such as epithelial hyperplasia being evident and more frequent in fish exposed ex situ. Fully quantitative traits, namely chloride and goblet cell count and size revealed differences between the two bioassay approaches, with ex situ experiments likely enhancing bioavailability of toxicants. Chloride cells endured autolytic processes that could, at least in part, relate to contamination by mixed metals and polycyclic aromatic hydrocarbons (PAHs). Goblet cells did not reveal changes in the chemistry of mucous. Still, their number and size was reduced in fish exposed ex situ to the sediments most contaminated by PAHs, with evidence for adaptation. Also, copper histochemistry revealed the potential role of mucocytes in the regulation of metals. PMID- 26518454 TI - Stable and bicistronic expression of two genes in somite- and lateral plate derived tissues to study chick limb development. AB - BACKGROUND: Components of the limb musculoskeletal system have distinct mesoderm origins. Limb skeletal muscles originate from somites, while the skeleton and attachments (tendons and connective tissues) derive from limb lateral plate. Despite distinct mesoderm origins, the development of muscle, skeleton and attachments is highly coordinated both spatially and temporally to ensure complete function of the musculoskeletal system. A system to study molecular interactions between somitic-derived tissues (muscles) and lateral-plate-derived tissues (skeletal components and attachments) during limb development is missing. RESULTS: We designed a gene delivery system in chick embryos with the ultimate aim to study the interactions between the components of the musculoskeletal system during limb development. We combined the Tol2 genomic integration system with the viral T2A system and developed new vectors that lead to stable and bicistronic expression of two proteins at comparable levels in chick cells. Combined with limb somite and lateral plate electroporation techniques, two fluorescent reporter proteins were co-expressed in stoichiometric proportion in the muscle lineage (somitic-derived) or in skeleton and their attachments (lateral-plate-derived). In addition, we designed three vectors with different promoters to target muscle cells at different steps of the differentiation process. CONCLUSION: Limb somite electroporation technique using vectors containing these different promoters allowed us to target all myogenic cells, myoblasts or differentiated muscle cells. These stable and promoter-specific vectors lead to bicistronic expression either in somitic-derived myogenic cells or lateral plate-derived cells, depending on the electroporation sites and open new avenues to study the interactions between myogenic cells and tendon or connective tissue cells during limb development. PMID- 26518456 TI - Development of the faecal microbiota in foals. AB - REASONS FOR PERFORMING STUDY: The intestinal microbiota is a complex polymicrobial ecosystem that exerts extremely important roles in the development and maintenance of health. Recently, as new sequencing technologies have become more available, there has been a revolution in the understanding of the equine intestinal microbiota. However, studies characterising the pioneer intestinal bacteria colonising foals and its development over time are still limited. OBJECTIVES: The objectives of this study were to characterise the intestinal bacterial colonisation of newborn foals and to follow individual animals over time until age 9 months. STUDY DESIGN: Longitudinal study. METHODS: Eleven pregnant mares from one farm were enrolled and faecal samples were collected longitudinally from mares and foals during their first day post partum and again periodically until foals were age 9 months. The V4 region of the 16S rRNA gene was amplified and sequenced using the Illumina MiSeq platform. RESULTS: Newborn foals had a rich and diverse bacterial community, which was mainly comprised of the Firmicutes phylum with several low abundant genera being unique at this age. Foals aged 2-30 days had significantly decreased diversity compared to older animals, with the majority of organisms classified as Akkermansia spp. After 60 days of life, the intestinal microbiota structure tended to remain stable, but differences in community membership were still present between 9-month-old animals and mature mares. Several differences at the phylum level were observed between different ages, including a higher abundance of Fibrobacteres after weaning. CONCLUSIONS: The intestinal microbiota of the equine newborn is already complex by the first day of life. Microbiota adaptation occurs during the first month and the microbiota of foals older than 60 days resemble the mother's microbiota, although differences in community membership are still present. PMID- 26518457 TI - Post-operative swallowing in multiple system atrophy. AB - BACKGROUND: Some patients with multiple system atrophy (MSA) require surgical interventions such as tracheostomy and aspiration prevention. Few studies have investigated the postoperative clinical course of MSA patients. The aim of this study was to determine a management strategy for dysphagia and respiratory disorder in MSA. METHODS: From 2001 to 2014, 18 MSA patients (13 males and 5 females, 52-76 years) underwent tracheostomy (TR, n = 11) or laryngeal closure (LC, n = 12). Five patients underwent LC following TR. Vocal fold impairment, the degree of dysphagia and pre/post-operative oral ingestion, and postoperative survival time were evaluated retrospectively. Swallowing function was assessed using the penetration aspiration scale (PAS). RESULTS: TR was performed due to respiratory disorder in seven patients and due to dysphagia in four patients. PAS scores ranged 1-8 in TR patients and 7-8 in LC patients. Seven of 11 patients who underwent TR displayed worsened PAS scores, and no patients displayed improved PAS scores following TR. All patients who underwent LC regained complete or partial oral intake after surgery. There were no significant differences in postoperative survival time between the two groups. CONCLUSIONS: Considering the impacts of TR and LC on survival time, postoperative feeding and swallowing, LC is a good option for treating MSA patients with dysphagia. PMID- 26518458 TI - Schmallenberg virus antibody development and decline in a naturally infected dairy cattle herd in Germany, 2011-2014. AB - In late 2011, the novel insect-transmitted orthobunyavirus Schmallenberg virus (SBV) emerged in Central Europe. Since that year, a dairy cattle herd kept in the German region in which the virus was initially detected was continuously monitored. In order to evaluate the development of the within-herd seroprevalence, but also to assess the long-term persistence of antibodies against SBV in individual animals, blood samples of all cows older than 24 months were taken yearly after the respective vector season and serologically analyzed. In December 2011, in 74% of the tested animals SBV-specific antibodies were detectable. Additional scattered seroconversions were observed between the 2011 and 2012 vector seasons, thereafter all seronegative animals remained negative. Until December 2014, the intra-herd seroprevalence decreased to 58%. A total of 122 cows infected presumable in autumn 2011 were sampled every year, 9 of them became seronegative until December 2014. Consequently, though SBV-specific antibodies were detected in about 90% of the monitored animals for more than three years, a lifelong antibody-based immunity is not expected in every animal. The loss of anti-SBV antibodies in individual animals combined with the missing infection of young stock results in a declining herd seroprevalence and increases the risk of a renewed virus circulation to a greater extent within the next years. PMID- 26518459 TI - Effects of chronic cerebral hypoperfusion and low-dose progesterone treatment on apoptotic processes, expression and subcellular localization of key elements within Akt and Erk signaling pathways in rat hippocampus. AB - The present study attempted to investigate how chronic cerebral hypoperfusion (CCH) and repeated low-dose progesterone (P) treatment affect gene and protein expression, subcellular distribution of key apoptotic elements within protein kinase B (Akt) and extracellular signal-regulated kinases (Erk) signal transduction pathways, as well as neurodegenerative processes and behavior. The results revealed the absence of Erk activation in CCH in cytosolic and synaptosomal fractions, indicating a lower threshold of Akt activation in brain ischemia, while P increased their levels above control values. CCH induced an increase in caspase 3 (Casp 3) and poly (ADP-ribose) polymerase (PARP) gene and protein expression. However, P restored expression of examined molecules in all observed fractions, except for the levels of Casp 3 in synapses which highlighted its possible non-apoptotic or even protective function. Our study showed the absence of nuclear factor kappa-light-chain-enhancer of activated b cells (NF kappaB) response to this type of ischemic condition and its strong activation under the influence of P. Further, the initial increase in the number of apoptotic cells and amount of DNA fragmentation induced by CCH was significantly reduced by P. Finally, P reversed the CCH-induced reduction in locomotor activity, while promoting a substantial decrease in anxiety-related behavior. Our findings support the concept that repeated low-dose post-ischemic P treatment reduces CCH-induced neurodegeneration in the hippocampus. Neuroprotection is initiated through the activation of investigated kinases and regulation of their downstream molecules in subcellular specific manner, indicating that this treatment may be a promising therapy for alleviation of CCH-induced pathologies. PMID- 26518460 TI - Repetitive transcranial magnetic stimulation enhances spatial learning and synaptic plasticity via the VEGF and BDNF-NMDAR pathways in a rat model of vascular dementia. AB - This study aimed to evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) on learning and memory in a rat model of vascular dementia (VaD) and to analyze the associated mechanisms. Bilateral carotid artery occlusion (2-VO) was used to establish a rat model of VaD. High-frequency (5Hz) rTMS was performed on rats for four weeks. Spatial learning and memory abilities were evaluated using the Morris water maze (MWM), and synaptic plasticity in the hippocampus was assessed via long-term potentiation (LTP). Hippocampal expression of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF) and three subunits of the N-methyl-D-aspartic acid receptor (NMDAR), NR1, NR2A and NR2B, was analyzed by Western blotting. Compared with the VaD group, escape latency was decreased (P<0.05) and the time spent in the target quadrant and the percentage of swimming distance within that quadrant were increased (P<0.05) in the rTMS group. LTP at hippocampal CA3-CA1 synapses was enhanced by rTMS (P<0.05). VEGF expression was up-regulated following 2-VO and was further increased by rTMS (P<0.05). BDNF, NR1 and NR2B expression was decreased in the VaD group and increased by rTMS (P<0.05). There were no significant differences in NR2A expression among the three groups. These results suggest that rTMS improved learning and memory in the VaD model rats via the up-regulation of VEGF, BDNF and NMDARs. In addition, NR2B may be more important than NR2A for LTP induction in the hippocampus during rTMS treatment of VaD. PMID- 26518461 TI - Right hemisphere dominance directly predicts both baseline V1 cortical excitability and the degree of top-down modulation exerted over low-level brain structures. AB - Right hemisphere dominance for visuo-spatial attention is characteristically observed in most right-handed individuals. This dominance has been attributed to both an anatomically larger right fronto-parietal network and the existence of asymmetric parietal interhemispheric connections. Previously it has been demonstrated that interhemispheric conflict, which induces left hemisphere inhibition, results in the modulation of both (i) the excitability of the early visual cortex (V1) and (ii) the brainstem-mediated vestibular-ocular reflex (VOR) via top-down control mechanisms. However to date, it remains unknown whether the degree of an individual's right hemisphere dominance for visuospatial function can influence, (i) the baseline excitability of the visual cortex and (ii) the extent to which the right hemisphere can exert top-down modulation. We directly tested this by correlating line bisection error (or pseudoneglect), taken as a measure of right hemisphere dominance, with both (i) visual cortical excitability measured using phosphene perception elicited via single-pulse occipital trans cranial magnetic stimulation (TMS) and (ii) the degree of trans-cranial direct current stimulation (tDCS)-mediated VOR suppression, following left hemisphere inhibition. We found that those individuals with greater right hemisphere dominance had a less excitable early visual cortex at baseline and demonstrated a greater degree of vestibular nystagmus suppression following left hemisphere cathodal tDCS. To conclude, our results provide the first demonstration that individual differences in right hemisphere dominance can directly predict both the baseline excitability of low-level brain structures and the degree of top down modulation exerted over them. PMID- 26518462 TI - An age-related reduction of brain TBPH/TDP-43 levels precedes the onset of locomotion defects in a Drosophila ALS model. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. The average age of onset of both sporadic and familial cases is 50-60 years of age. The presence of cytoplasmic inclusions of the RNA-binding protein TAR DNA-binding protein-43 (TDP-43) in the affected neurons is seen in 95% of the ALS cases, which results in TDP-43 nuclear clearance and loss of function. The Drosophila melanogaster ortholog of TDP-43 (TBPH) shares many characteristics with the human protein. Using a TDP-43 aggregation inducer previously developed in human cells, we created a transgenic fly that shows an adult locomotive defect. Phenotype onset correlates with a physiologically age-related drop of TDP-43/TBPH mRNA and protein levels, seen both in mice and flies. Artificial reduction of mRNA levels, in vivo, anticipates the locomotion defect to the larval stage. Our study links, for the first time, aggregation and the age-related, evolutionary conserved reduction of TDP-43/TBPH levels with the onset of an ALS-like locomotion defect in a Drosophila model. A similar process might trigger the human disease. PMID- 26518463 TI - Expression and cellular function of vSNARE proteins in brain astrocytes. AB - Gray matter protoplasmic astrocytes, a major type of glial cell in the mammalian brain, extend thin processes ensheathing neuronal synaptic terminals. Albeit electrically silent, astrocytes respond to neuronal activity with Ca(2+) signals that trigger the release of gliotransmitters, such as glutamate, d-serine, and ATP, which modulate synaptic transmission. It has been suggested that the astrocytic processes, together with neuronal pre- and post-synaptic elements, constitute a tripartite synapse, and that astrocytes actively regulate information processing. Astrocytic vesicles expressing VAMP2 and VAMP3 vesicular SNARE (vSNARE) proteins have been suggested to be a key feature of the tripartite synapse and mediate gliotransmitter release through Ca(2+)-regulated exocytosis. However, the concept of exocytotic release of gliotransmitters by astrocytes has been challenged. Here we review studies investigating the expression profile of VAMP2 and VAMP3 vSNARE proteins in rodent astrocytes, and the functional implication of VAMP2/VAMP3 vesicles in astrocyte signaling. We also discuss our recent data suggesting that astrocytic VAMP3 vesicles regulate the trafficking of glutamate transporters at the plasma membrane and glutamate uptake. A better understanding of the functional consequences of the astrocytic vSNARE vesicles on glutamate signaling, neuronal excitability and plasticity, will require the development of new strategies to selectively interrogate the astrocytic vesicles trafficking in vivo. PMID- 26518464 TI - Prenatal valproic acid exposure disrupts tonotopic c-Fos expression in the rat brainstem. AB - Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties with communication and social interactions, restricted, repetitive behaviors and sensory abnormalities. Additionally, the vast majority of subjects with ASD suffer some degree of auditory dysfunction and we have previously identified significant hypoplasia and dysmorphology in auditory brainstem centers in individuals with ASD. Prenatal exposure to the antiepileptic drug valproic acid (VPA) is associated with an increased risk of ASD. In rodents, prenatal exposure to VPA is utilized as an animal model of ASD and is associated with a number of anatomical, physiological and behavioral deficits, including hypoplasia and dysmorphology in the auditory brainstem. Based on these observations, we hypothesized that such dysmorphology in VPA-exposed animals would translate into abnormal activity in brainstem circuits and irregular tonotopic maps. Herein, we have subjected control and VPA-exposed animals to 4 or 16 kHz tones and examined neuronal activation with immunohistochemistry for c-Fos. After these sound exposures, we found significantly more c-Fos-positive neurons in the auditory brainstem of VPA-exposed animals. Further, we found a larger dispersion of c-Fos positive neurons and shifted tonotopic bands in VPA-exposed rats. We interpret these findings to suggest hyper-responsiveness to sounds and disrupted mapping of sound frequencies after prenatal VPA exposure. Based on these findings, we suggest that such abnormal patterns of activation may play a role in auditory processing deficits in ASD. PMID- 26518465 TI - The utility of procedural training in neurology residency training. PMID- 26518466 TI - Transoral robotic surgery for sleep apnea in children: Is it effective? AB - OBJECTIVES: Children with obstructive sleep apnea/hypopnea syndrome (OSAHS) as a result of base of tongue (BOT) or lingual tonsillar hypertrophy do not improve following adenotonsillectomy. In adults, transoral robotic surgery (TORS) offers a means of treating such patients, however the efficacy of this technique for children is not known. In this study, we examine the effectiveness of TORS BOT reduction and lingual tonsillectomy for treatment of pediatric OSAHS. METHODS: This was a retrospective study of nine patients (5 non-syndromic; 4 syndromic) who underwent isolated BOT reduction and lingual tonsillectomy for OSAHS between 2012 and 2014 at a tertiary care pediatric medical center. Differences between pre and post surgical polysomnograms (PSGs) were utilized to measure the procedural effectiveness. Patient age, sex, body mass index (BMI), developmental status, and comorbid conditions were also examined. RESULTS: The average patient age was 10.5 years (range 5.2-18.5). There were 5 males and 4 females. The mean pre-operative obstructive AHI (O-AHI) was 27.1 compared to 10.9 post-operatively (mean difference=16.1, t=2.27, p<=0.05). Statistically significant reductions were also noted in hypopneic events (mean difference=61.3, t=2.64, p<0.05) and lowest oxygen saturation (mean difference=9.0, t=-3.29, p<=0.01). One patient developed a post-operative bleed that was controlled operatively. CONCLUSIONS: In children with airway obstruction associated with BOT and lingual tonsillar hypertrophy, TORS is a useful and effective tool. Patients' who underwent TORS demonstrated a significant decrease in obstructive events. All patients reviewed exhibited at least a 50% reduction in O-AHI. PMID- 26518467 TI - The role of tympanostomy tubes in surgery for acquired retraction pocket cholesteatoma. AB - OBJECTIVE: 1. To determine whether intraoperative tympanostomy tubes (TT) during surgery for acquired retraction pocket cholesteatoma (ARPC) can decrease recurrence of ARPC and retraction pockets (RP). 2. To determine the need for subsequent TT in children that did not initially receive TT. STUDY DESIGN: Retrospective review of children who underwent primary surgery for ARPC. SETTING: Tertiary care children's hospital. SUBJECTS AND METHODS: Audiometry, operative reports, office findings, and recurrence of ARPC and RP were analyzed. Univariate analysis with Fisher's exact test, Wilcoxon rank-sum and t test, as well as multivariate analysis with logistical regression, were used for statistical analyses. RESULTS: 21 patients had TT at initial surgery and 34 patients did not. The recurrence of ARPC was 24% for the TT Group versus 44% for the no TT group (p=0.09). The incidence of RP was 33% in the TT group versus 41% in the no TT groups (p=0.35). 35% of the no TT group subsequently required TT. Audiometric outcomes were not different between groups. TT placement did not significantly affect the odds of recurrent ARPC and RP (95% CI 0.12-1.83, p=0.28 for ARPC and 95% CI 0.30-4.60, p=0.82 for RP). However, the odds of recurrent ARPC and RP were significantly increased in children with stapes and malleus erosion by cholesteatoma. Children with stapes and malleus involvement had 5.28 and 11.8 times higher odds of recurrent ARPC compared to those without ossicular erosion (95% CI 1.09-25.6, p=0.04 stapes and 95% CI 1.58-88.3, p=0.02 malleus). Similarly, children with malleus involvement had an 18.6 times higher odds of recurrent RP (95% CI 1.62-214, p=0.02) compared to those who did not. Incus erosion was not a significant predictor for recurrent ARPC and RP. CONCLUSION: There was no statistical difference in recurrence or audiometric outcomes between patients who underwent TT versus those who did not during initial surgery for ARPC. However malleus and stapes erosion were significantly associated with recurrent ARPC and RP. These findings suggest that TT at initial ARPC surgery did not play a role in preventing recurrence, but malleus and incus erosion, was predictive of recurrent disease. A larger, prospective study of TT at initial surgery for ARPC is needed. PMID- 26518468 TI - Erythema necroticans exhibiting transepidermal migration of lepra bacilli as a probable source of infection to other family members. PMID- 26518469 TI - The Dynamic Relationship Between Clinical Symptomatology and Viral Shedding in Naturally Acquired Seasonal and Pandemic Influenza Virus Infections. AB - BACKGROUND: Although the pattern of viral shedding over time has been documented in volunteer challenge studies, understanding of the relationship between clinical symptomatology and viral shedding in naturally acquired influenza infections in humans remains limited. METHODS: In a community-based study in Hong Kong from 2008 to 2014, we followed up initially healthy individuals and identified 224 secondary cases of natural influenza virus infection in the household setting. We examined the dynamic relationship between patterns of clinical symptomatology and viral shedding as quantified using reverse transcription polymerase chain reaction and viral culture in 127 cases with a clinical picture of acute respiratory infection. RESULTS: Viral shedding in influenza A virus infections peaked on the first 1-2 days of clinical illness, and decreased gradually to undetectable levels by day 6-7, matching closely with the dynamics of clinical illness. Viral shedding in influenza B virus infections rose up to 2 days prior to symptom onset and persisted for 6-7 days after onset with a bimodal pattern. CONCLUSIONS: Our results suggest that while clinical illness profiles may serve as a proxy for clinical infectiousness in influenza A virus infections, patients may potentially be infectious even before symptom onset or after clinical improvement in influenza B virus infections. PMID- 26518470 TI - Editorial Commentary: Symptoms and Viral Shedding in Naturally Acquired Influenza Infections. PMID- 26518471 TI - Dendritic-cell expression of Ship1 regulates Th2 immunity to helminth infection in mice. AB - In mouse models of infection with the gastrointestinal parasite Trichuris muris, appropriate dendritic-cell (DC) Ag sampling, migration, and presentation to T cells are necessary to mount a protective Th2-polarized adaptive immune response, which is needed to clear infection. SH2-containing inositol 5'-phosphatase 1 (SHIP-1) has been shown to be an important regulator of DC function in vitro through the negative regulation of the phosphoinositide 3-kinase (PI3K) pathway, but its role in vivo is relatively unexplored. In the current work, mice with a specific deletion of SHIP-1 in DCs (Ship1(DeltaDC) ) were infected with the parasite T. muris. Ship1(DeltaDC) mice were susceptible to infection due to ineffective priming of Th2-polarized responses. This is likely due to an increased production of interleukin (IL) 12p40 by SHIP-1-deficient DCs, as in vivo antibody blockade of IL-12p40 was able to facilitate the clearing of infection in Ship1(DeltaDC) mice. Our results describe a critical role for SHIP-1 in regulating the ability of DCs to efficiently prime Th2-type responses. PMID- 26518472 TI - Synthesis and Evaluation of 2-Alkylthio-4-(N-substituted sulfonamide)pyrimidine Hydroxamic Acids as Anti-myeloma Agents. AB - A series of pyrimidine hydroxamic acids with a sulfide substituent at the second position and a sulfonamide substituent at the fourth position have been synthesized and evaluated for their activity against human myeloma cell line RPMI 8226. Several compounds exhibited significant anti-cancer potency. It was found that representative compound 6a selectively killed cancerous but not normal cells. Moreover, compound 6a was effective in causing apoptosis in RPMI 8226 cells and exhibited promising HDAC-inhibitory activities. PMID- 26518473 TI - The short- and long-term outcomes of radical antegrade modular pancreatosplenectomy for adenocarcinoma of the body and tail of the pancreas. AB - BACKGROUND: Radical antegrade modular pancreatosplenectomy (RAMPS) is a relatively new modification of the standard distal pancreatosplenectomy. In this method, dissection proceeds from right-to-left to achieve negative posterior resection margins. However, short-term and long-term outcomes of RAMPS for pancreatic cancer have not yet been clarified. The aim of this study is to evaluate short-term and long-term outcomes in the patients who have undergone RAMPS. METHODS: Consecutive 49 patients were selected from the retrospective database of the Kanagawa Cancer Center from 2000 to 2014. Data from the operative notes, pathology reports, postoperative data, and outpatient data (recurrence and survival) were entered into the database. RESULTS: All patients were undergone anterior RAMPS. The median operation time was 278 min (range from 140 to 625 mins). The median blood loss in operation was 850 ml (range from 60 to 2790 ml). The overall incidence of morbidity was 51.4% and the incidence of mortality was 0%. Forty-one patients (83.7%) had negative resection margins. The mean number of lymph nodes harvested was 15 and 27 patients had lymph node metastasis. After the median follow-up period was 41.1 months, 1-year and 3-year overall survival rates were 84.1 and 38.6%, respectively. Median overall survival was 22.6 months. CONCLUSIONS: The present study results suggested that RAMPS procedure might be safe and feasible without an increase in morbidity and morbidity and have survival benefit compared with standard DP. PMID- 26518474 TI - TMEM107 Is a Critical Regulator of Ciliary Protein Composition and Is Mutated in Orofaciodigital Syndrome. AB - The proximate causes of multiple human genetic syndromes (ciliopathies) are disruptions in the formation or function of the cilium, an organelle required for a multitude of developmental processes. We previously identified Tmem107 as a critical regulator of cilia formation and embryonic organ development in the mouse. Here, we describe a patient with a mutation in TMEM107 that developed atypical Orofaciodigital syndrome (OFD), and show that the OFD patient shares several morphological features with the Tmem107 mutant mouse including polydactyly and reduced numbers of ciliated cells. We show that TMEM107 appears to function within cilia to regulate protein content, as key ciliary proteins do not localize normally in cilia derived from the Tmem107 mouse mutant and the human patient. These data indicate that TMEM107 plays a key, conserved role in regulating ciliary protein composition, and is a novel candidate for ciliopathies of unknown etiology. PMID- 26518475 TI - Listeria monocytogenes isolates from food and food environment harbouring tetM and ermB resistance genes. AB - Listeria monocytogenes is a foodborne pathogen that has become an important cause of human and animal diseases worldwide. The purpose of this study was to evaluate the serotypes, virulence potential, antimicrobial resistance profile, and genetic relationships of 50 L. monocytogenes isolates from food and food environment in southern Brazil. In this study, the majority of L. monocytogenes isolates belonged to the serotypes 1/2b (42%) and 4b (26%), which are the main serotypes associated with human listeriosis. In addition, all isolates harboured internalin genes (inlA, inlC, inlJ), indicating a virulence potential. The isolates were sensitive to most of the antimicrobial compounds analysed, and five isolates (10%) were multi-resistant. Two isolates harboured antimicrobial resistance genes (tetM and ermB) and in one of them, the gene was present in the plasmid. Moreover, according to the pulsed field gel electrophoresis assay, two multi resistant isolates were a single clone isolated from food and the processing plant. The isolates were susceptible to the most frequently used antibiotics for listeriosis treatment. However, the presence of multidrug-resistant isolates and antimicrobial resistance genes including in the plasmid could even be transferred between bacterial species, suggesting a potential health risk to consumers and a potential risk of spreading multi-resistance genes to other bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Listeria monocytogenes is an important agent of foodborne diseases. The results of this study suggest a potential capacity of L. monocytogenes isolates from food and food environment to cause human infections. Antimicrobial multi-resistance profiles were detected in 10%, and two isolates harboured tetM and ermB resistance genes. Moreover, the present research can help to build up a better knowledge about antimicrobial resistance of L. monocytogenes. Additionally, we found one isolate carrying tetM resistance gene in a plasmid, that suggests a possible transmission between commensal and/or other pathogenic bacteria of food environment, thereby raising up concerns regarding bacterial resistance. PMID- 26518476 TI - Foot-and-Mouth Disease Seroprevalence in Cattle in Eritrea. AB - Information about seroprevalence of foot-and-mouth disease (FMD) and virus serotypes in Eritrea is unavailable, but is very important as it may guide the choice of intervention measures including vaccination to be implemented. We carried out a cross-sectional study from February to June 2011 in Eritrea with a two-stage cluster design, sampling cattle in 155 villages with the objective of determining the seroprevalence of FMD in four administrative regions of the country. We analysed cattle sera (n = 2429) for FMD virus antibodies using the non-structural ELISA (NS ELISA) and virus neutralization test (VNT). The overall seroprevalence was 26% and 30% for the NS ELISA and VNT, respectively. FMD virus serotypes O (14%) and A (11%) were the most prevalent. Gash Barka showed the highest (39%) seroprevalence both in NS ELISA and VNT compared to the other three administrative regions. Strategic FMD virus vaccination with type O and A (matching circulating strains) in combination of zoo-sanitary measures would be the best control option for Eritrea which could be started in areas where the disease is less endemic. PMID- 26518478 TI - Predicting mortality rates: Comparison of an administrative predictive model (hospital standardized mortality ratio) with a physiological predictive model (Acute Physiology and Chronic Health Evaluation IV)--A cross-sectional study. AB - INTRODUCTION: Direct comparison of mortality rates has limited value because most deaths are due to the disease process. Predicting the risk of death accurately remains a challenge. METHODS: A cross-sectional study compared the expected mortality rate as calculated with an administrative model to a physiological model, Acute Physiology and Chronic Health Evaluation IV. The combined cohort and stratified samples (<0.1, 0.1-0.5, or >0.5 predicted mortality) were considered. A total of 47,982 patients were scored from 1 July 2013 to 30 June 2014, and 46,061 records were included in the analysis. RESULTS: A moderate correlation was shown for the combined cohort (Pearson correlation index, 0.618; 95% confidence interval [CI], 0.380-0.779; R(2) = 0.38). A very good correlation for the less than 10% stratum (Pearson correlation index, 0.884; R(2) = 0.78; 95% CI, 0.79 0.937) and a moderate correlation for 0.1 to 0.5 predicted mortality rates (Pearson correlation index, 0.782; R(2) = 0.61; 95% CI, 0.623-0.879). There was no significant positive correlation for the greater than 50% predicted mortality stratum (Pearson correlation index, 0.087; R(2) = 0.007; 95% CI, -0.23 to 0.387). CONCLUSION: At less than 0.1, the models are interchangeable, but in spite of a moderate correlation, greater than 0.1 hospital standardized mortality ratio cannot be used to predict mortality. PMID- 26518477 TI - A unique ecological niche fosters hybridization of oak-tree and vineyard isolates of Saccharomyces cerevisiae. AB - Differential adaptation to distinct niches can restrict gene flow and promote population differentiation within a species. However, in some cases the distinction between niches can collapse, forming a hybrid niche with features of both environments. We previously reported that distinctions between vineyards and oak soil present an ecological barrier that restricts gene flow between lineages of Saccharomyces cerevisiae. Vineyard isolates are tolerant to stresses associated with grapes while North American oak strains are particularly tolerant to freeze-thaw cycles. Here, we report the isolation of S. cerevisiae strains from Wisconsin cherry trees, which display features common to vineyards (e.g. high sugar concentrations) and frequent freeze-thaw cycles. Genome sequencing revealed that the isolated strains are highly heterozygous and represent recent hybrids of the oak * vineyard lineages. We found that the hybrid strains are phenotypically similar to vineyard strains for some traits, but are more similar to oak strains for other traits. The cherry strains were exceptionally good at growing in cherry juice, raising the possibility that they have adapted to this niche. We performed transcriptome profiling in cherry, oak and vineyard strains and show that the cherry-tree hybrids display vineyard-like or oak-like expression, depending on the gene sets, and in some cases, the expression patterns linked back to shared stress tolerances. Allele-specific expression in these natural hybrids suggested concerted cis-regulatory evolution at sets of functionally regulated genes. Our results raise the possibility that hybridization of the two lineages provides a genetic solution to the thriving in this unique niche. PMID- 26518479 TI - Effect of omega-3 on hepatic regeneration in adult living donors undergoing hepatic resections for liver transplantation: A randomized controlled trial. AB - BACKGROUND: Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) have been shown to improve liver regeneration in experimental models. Aim was to evaluate the effects of omega-3 PUFAs on hepatic regeneration in adult living donors undergoing partial hepatectomy for liver transplantation (LDLT). METHODS: Forty LDLT donors were categorized into 2 groups: received either intravenous omega-3 PUFA-enriched lipid emulsion 20% infusion 7 mL/kg once a day for 2 days before surgery and postoperative day (POD) 0 (S group) or glucose 5% (C group). Hepatic regeneration was assessed by volume of the liver after 1 month using computed tomography, and serial serum levels of hepatocyte growth factor were measured at POD 1, 3, and 5. RESULTS: Liver volume after 1 month was significantly larger in the S group than the C group (1286.75 +/- 122.781 cm(3) vs 1169.15 +/- 128.3, respectively; P = .00). Both the regeneration index and the regeneration percentage were significantly higher in the S group than the C group (P = .02 and P = .00, respectively). Serum levels of hepatocyte growth factor were significantly higher in the S group on POD 1, 3, and 5 than the C group ([in pg/mL] 188.10 +/- 74.25 vs 123.30 +/- 13.56, P = .00; 127.55 +/- 32.40 vs 109.25 +/- 8.89, P = .02; and 109.45 +/- 21.44 vs 96.70 +/- 5.57, P = .01; respectively). CONCLUSION: Omega-3 polyunsaturated fatty acids effectively promoted liver regeneration and functional recovery following portal hypertension in the setting of LDLT. PMID- 26518480 TI - High mutational rates of large-scale duplication and deletion in Daphnia pulex. AB - Knowledge of the genome-wide rate and spectrum of mutations is necessary to understand the origin of disease and the genetic variation driving all evolutionary processes. Here, we provide a genome-wide analysis of the rate and spectrum of mutations obtained in two Daphnia pulex genotypes via separate mutation-accumulation (MA) experiments. Unlike most MA studies that utilize haploid, homozygous, or self-fertilizing lines, D. pulex can be propagated ameiotically while maintaining a naturally heterozygous, diploid genome, allowing the capture of the full spectrum of genomic changes that arise in a heterozygous state. While base-substitution mutation rates are similar to those in other multicellular eukaryotes (about 4 * 10(-9) per site per generation), we find that the rates of large-scale (>100 kb) de novo copy-number variants (CNVs) are significantly elevated relative to those seen in previous MA studies. The heterozygosity maintained in this experiment allowed for estimates of gene conversion processes. While most of the conversion tract lengths we report are similar to those generated by meiotic processes, we also find larger tract lengths that are indicative of mitotic processes. Comparison of MA lines to natural isolates reveals that a majority of large-scale CNVs in natural populations are removed by purifying selection. The mutations observed here share similarities with disease-causing, complex, large-scale CNVs, thereby demonstrating that MA studies in D. pulex serve as a system for studying the processes leading to such alterations. PMID- 26518481 TI - Phylogenomic evidence for ancient hybridization in the genomes of living cats (Felidae). AB - Inter-species hybridization has been recently recognized as potentially common in wild animals, but the extent to which it shapes modern genomes is still poorly understood. Distinguishing historical hybridization events from other processes leading to phylogenetic discordance among different markers requires a well resolved species tree that considers all modes of inheritance and overcomes systematic problems due to rapid lineage diversification by sampling large genomic character sets. Here, we assessed genome-wide phylogenetic variation across a diverse mammalian family, Felidae (cats). We combined genotypes from a genome-wide SNP array with additional autosomal, X- and Y-linked variants to sample ~150 kb of nuclear sequence, in addition to complete mitochondrial genomes generated using light-coverage Illumina sequencing. We present the first robust felid time tree that accounts for unique maternal, paternal, and biparental evolutionary histories. Signatures of phylogenetic discordance were abundant in the genomes of modern cats, in many cases indicating hybridization as the most likely cause. Comparison of big cat whole-genome sequences revealed a substantial reduction of X-linked divergence times across several large recombination cold spots, which were highly enriched for signatures of selection-driven post divergence hybridization between the ancestors of the snow leopard and lion lineages. These results highlight the mosaic origin of modern felid genomes and the influence of sex chromosomes and sex-biased dispersal in post-speciation gene flow. A complete resolution of the tree of life will require comprehensive genomic sampling of biparental and sex-limited genetic variation to identify and control for phylogenetic conflict caused by ancient admixture and sex-biased differences in genomic transmission. PMID- 26518482 TI - Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains. AB - Recent advances enabled by the Hi-C technique have unraveled many principles of chromosomal folding that were subsequently linked to disease and gene regulation. In particular, Hi-C revealed that chromosomes of animals are organized into topologically associating domains (TADs), evolutionary conserved compact chromatin domains that influence gene expression. Mechanisms that underlie partitioning of the genome into TADs remain poorly understood. To explore principles of TAD folding in Drosophila melanogaster, we performed Hi-C and poly(A)(+) RNA-seq in four cell lines of various origins (S2, Kc167, DmBG3-c2, and OSC). Contrary to previous studies, we find that regions between TADs (i.e., the inter-TADs and TAD boundaries) in Drosophila are only weakly enriched with the insulator protein dCTCF, while another insulator protein Su(Hw) is preferentially present within TADs. However, Drosophila inter-TADs harbor active chromatin and constitutively transcribed (housekeeping) genes. Accordingly, we find that binding of insulator proteins dCTCF and Su(Hw) predicts TAD boundaries much worse than active chromatin marks do. Interestingly, inter-TADs correspond to decompacted inter-bands of polytene chromosomes, whereas TADs mostly correspond to densely packed bands. Collectively, our results suggest that TADs are condensed chromatin domains depleted in active chromatin marks, separated by regions of active chromatin. We propose the mechanism of TAD self-assembly based on the ability of nucleosomes from inactive chromatin to aggregate, and lack of this ability in acetylated nucleosomal arrays. Finally, we test this hypothesis by polymer simulations and find that TAD partitioning may be explained by different modes of inter-nucleosomal interactions for active and inactive chromatin. PMID- 26518483 TI - MicroRNA evolution, expression, and function during short germband development in Tribolium castaneum. AB - MicroRNAs are well-established players in the development of multicellular animals. Most of our understanding of microRNA function in arthropod development comes from studies in Drosophila. Despite their advantages as model systems, the long germband embryogenesis of fruit flies is an evolutionary derived state restricted to several holometabolous insect lineages. MicroRNA evolution and expression across development in animals exhibiting the ancestral and more widespread short germband mode of embryogenesis has not been characterized. We sequenced small RNA libraries of oocytes and successive intervals covering the embryonic development of the short germband model organism, Tribolium castaneum. We analyzed the evolution and temporal expression of the microRNA complement and sequenced libraries of total RNA to investigate the relationships with microRNA target expression. We show microRNA maternal loading and sequence-specific 3' end nontemplate oligoadenylation of maternally deposited microRNAs that is conserved between Tribolium and Drosophila. We further uncover large clusters encoding multiple paralogs from several Tribolium-specific microRNA families expressed during a narrow interval of time immediately after the activation of zygotic transcription. These novel microRNAs, together with several early expressed conserved microRNAs, target a significant number of maternally deposited transcripts. Comparison with Drosophila shows that microRNA-mediated maternal transcript targeting is a conserved process in insects, but the number and sequences of microRNAs involved have diverged. The expression of fast-evolving and species-specific microRNAs in the early blastoderm of T. castaneum is consistent with previous findings in Drosophila and shows that the unique permissiveness for microRNA innovation at this stage is a conserved phenomenon. PMID- 26518484 TI - Nascent RNA folding mitigates transcription-associated mutagenesis. AB - Transcription is mutagenic, in part because the R-loop formed by the binding of the nascent RNA with its DNA template exposes the nontemplate DNA strand to mutagens and primes unscheduled error-prone DNA synthesis. We hypothesize that strong folding of nascent RNA weakens R-loops and hence decreases mutagenesis. By a yeast forward mutation assay, we show that strengthening RNA folding and reducing R-loop formation by synonymous changes in a reporter gene can lower mutation rate by >80%. This effect is diminished after the overexpression of the gene encoding RNase H1 that degrades the RNA in a DNA-RNA hybrid, indicating that the effect is R-loop-dependent. Analysis of genomic data of yeast mutation accumulation lines and human neutral polymorphisms confirms the generality of these findings. This mechanism for local protection of genome integrity is of special importance to highly expressed genes because of their frequent transcription and strong RNA folding, the latter also improves translational fidelity. As a result, strengthening RNA folding simultaneously curtails genotypic and phenotypic mutations. PMID- 26518485 TI - Tissue oxygen saturation as an early indicator of delayed lactate clearance after cardiac surgery: a prospective observational study. AB - BACKGROUND: In this observational study near infrared spectroscopy (NIRS) was evaluated as a non-invasive monitor of impaired tissue oxygenation (StO2) after cardiac surgery. StO2, cardiac output, mixed venous oxygen saturation and mean arterial pressure were compared with lactate clearance as established measure for sufficient tissue perfusion and oxygen metabolism. METHODS: Forty patients after cardiac surgery (24 aortocoronary bypass grafting, 5 heart valve, 3 ascending aorta and 8 combined procedures) were monitored until postoperative day 1 with NIRS of the thenar muscle (InSpectraTM StO2-monitor, Hutchinson Technology), a pulmonary-artery catheter and intermittent blood gas analyses for the assessment of lactate clearance. RESULTS: StO2 was reduced 4 h after surgery (75 +/- 6 %), but recovered at day 1 (84 +/- 5 %), while lactate concentration remained increased. Using uni- and multivariate regression analysis, minimum StO2 (r = 0.46, p <0.01) and cardiac index (r = 0.40, p <0.05) correlated with lactate clearance at day 1, while minimum mixed venous saturation and mean arterial pressure did not. In a receiver-operating characteristics (ROC) analysis, minimum StO2 (with a threshold of 75 %) predicted a lactate clearance <10 % at day 1 with an area under the ROC-curve of 0.83, a sensitivity of 78 % and a specificity of 88 %. In the subgroup with StO2 <75 %, troponin and creatine kinase MB were significantly increased at day 1. CONCLUSIONS: StO2 below 75 % in the first hours after surgery was a better early indicator of persistent impaired lactate clearance at day 1 than cardiac index, mixed venous oxygen saturation or mean arterial pressure. PMID- 26518486 TI - What Do Your Fingernails Say About You? Can They Indicate That You Have Diabetes? PMID- 26518488 TI - Incomplete Kawasaki disease induced by measles in a 6-month-old male infant. PMID- 26518489 TI - Antigen Cross-Presentation and Heat Shock Protein-Based Vaccines. AB - Vaccines currently in the clinical use contain adjuvants stimulating preferably Th2 type of immune response associated with the production of specific antibodies, mostly of neutralizing isotypes. This kind of immune response is effective only against some types of pathogens and has limited effect against tumors and many viruses where parallel activation of antigen-specific humoral and cell-mediated immunity is required. One of the main objectives of the current vaccine research is the development of approaches leading to the induction of antigen-specific CD8(+) T cell response including cytotoxic T lymphocyte (CTL). Induction of antigen-specific CD8(+) T cell response to exogenously delivered antigen requires their cross-presentation by antigen presenting cells, especially dendritic cells. The cross-presentation principles seem to be crucial for effective activation of CTL. In this paper, we discuss some approaches to employing heat shock proteins for induction of antigen-specific CD8(+) T cells in the context of cross-presentation and cross-priming principles. PMID- 26518490 TI - A salting out-acetonitrile homogeneous extraction coupled with gas chromatography mass spectrometry method for the simultaneous determination of thirteen N nitrosamines in skin care cosmetics. AB - A sensitive gas chromatography-mass spectrometry method was established for the simultaneous determination of thirteen N-nitrosamines (NAs) in skin care cosmetics. The cosmetics samples were firstly dispersed by water and subsequently extracted and purified using salting out-acetonitrile homogeneous extraction method. Finally, the extracting solution was concentrated by slow nitrogen gas blowing. All of the samples were separated by INNOWAX capillary chromatographic column, and detected by selected ion monitoring (SIM) mode of gas chromatography mass spectrometry (GC-MS) and quantified by isotope internal standard method. The method was validated for linearity and range, accuracy, precision and sensitivity. Under the optimized condition, the calibration curves were linear over the selected concentration ranges of 2-500MUg/L for all the thirteen analytes, with calculated coefficients of determination (R(2)) of greater than 0.996. The limits of detection (LODs) and the limits of quantitation (LOQs) of the method were 3-15MUg/kg and 10-50MUg/kg, respectively. Recoveries were calculated at three levels of concentration spiked in two kinds of cosmetics (skin care cream and water). The values were found between 93.8% and 121.0% with relative standard deviation (RSD) values of 2.5-7.2% for intra-day precision (n=6) and 3.3-6.7% for inter-day precision (n=5). The method was successfully applied to analyze twenty-two cosmetics samples and N-nitrosodimethylamine (NDMA) was detected in one sample with the concentration of 207MUg/kg. PMID- 26518487 TI - Methicillin-resistant Staphylococcus aureus (MRSA) catheter-related bacteraemia in haemodialysis patients. AB - BACKGROUND: The aim of the study was to determine clinical and microbiological differences between patients with methicillin-resistant Staphylococcus aureus (MRSA) catheter-related bacteraemia (CRB) undergoing or not undergoing haemodialysis, and to compare outcomes. METHODS: Prospective multicentre study conducted at 21 Spanish hospitals of patients with MRSA bacteraemia diagnosed between June 2008 and December 2009. Patients with MRSA-CRB were selected. Data of patients on haemodialysis (HD-CRB) and those not on haemodialysis (non-HD-CRB) were compared. RESULTS: Among 579 episodes of MRSA bacteraemia, 218 (37.7%) were CRB. Thirty-four (15.6%) were HD-CRB and 184 (84.4%) non-HD-CRB. All HD-CRB patients acquired the infection at dialysis centres, while in 85.3% of the non-HD CRB group the infection was nosocomial (p < .001). There were no differences in age, gender or severity of bacteraemia (Pitt score); comorbidities (Charlson score >= 4) were higher in the HD-CRB group than in the non-HD-CRB group (73.5% vs. 46.2%, p = .003). Although there were no differences in VAN-MIC >= 1.5 mg/L according to microdilution, using the E-test a higher rate of VAN-MIC >= 1.5 mg/L was observed in HD-CRB than in non-HD-CRB patients (63.3% vs. 44.1%, p = .051). Vancomycin was more frequently administered in the HD-CRB group than in the non HD-CRB group (82.3% vs. 42.4%, p = <.001) and therefore the appropriate empirical therapy was significantly higher in HD-CRB group (91.2% vs. 73.9%, p = .029). There were no differences with regard to catheter removal (79.4% vs. 84.2%, p = .555, respectively). No significant differences in mortality rate were observed between both groups (Overall mortality: 11.8% vs. 27.2%, p = .081, respectively), but there was a trend towards a higher recurrence rate in HD-CRB group (8.8% vs. 2.2%, p = .076). CONCLUSIONS: In our multicentre study, ambulatory patients in chronic haemodialysis represented a significant proportion of cases of MRSA catheter-related bacteraemia. Although haemodialysis patients with MRSA catheter related bacteraemia had significantly more comorbidities and higher proportion of strains with reduced vancomycin susceptibility than non-haemodialysis patients, overall mortality between both groups was similar. PMID- 26518491 TI - One pot synthesis of magnetic graphene/carbon nanotube composites as magnetic dispersive solid-phase extraction adsorbent for rapid determination of oxytetracycline in sewage water. AB - A simple and time-saving one pot synthesis of magnetic graphene/carbon nanotube composites (M-G/CNTs) was developed that could avoid the tedious drying process of graphite oxide, and G/CNTs were modified by Fe3O4 nanoparticles in the reduction procedure. It contributed to a shorten duration of the synthesis process of M-G/CNTs. The obtained M-G/CNTs were characterized and the results indicated that CNTs and Fe3O4 nanoparticles were served as spacer distributing to the layers of graphene, which was beneficial for enlarging surface area and improving extraction efficiency. Moreover, M-G/CNTs showed good magnetic property and outstanding thermal stability. Then M-G/CNTs were applied as adsorbent of magnetic dispersive solid-phase extraction for rapid extraction and determination of oxytetracycline in sewage water. Under the optimum conditions, good linearity was obtained in the range of 20-800ngmL(-1) and the recoveries were ranged from 95.5% to 112.5% with relative standard deviations less than 5.8%. PMID- 26518492 TI - Surface modification of polytetrafluoroethylene column for two-stationary phase separations by counter-current chromatography. AB - To improve the separation capability of CCC, a novel solid-liquid two-stationary phases CCC (ASP-CCC) column was prepared employing graphene oxide (GO) conjugated poly-dopamine (PD) coating (GO/PD) as auxiliary stationary phase (ASP). The results of Scanning electron microscopy (SEM), contact angle and X-ray photoelectron spectroscopy (XPS) indicated that nanostructured GO and PD were successfully grafted on the inner wall of the PTFE column. Three alkaloid compounds were selected as the target analytes to evaluate the performance of the novel column. Because of the intermolecular force (hydrogen bond, electrostatic interaction and pi-pi interaction) between the ASP and model compounds, three analytes were well separated with this novel ASP-CCC column. Additionally, the novel column exhibited higher stationary phase retention ratio, about 8%, than original column without changing the chromatographic condition. Furthermore, the eluotropic sequence of analytes on novel column was in accordance with that in the original column. This suggested that the novel column is a CCC column with auxiliary stationary phase (ASP) in its own right, and the present separation mode is the combination of partition chromatography and adsorption chromatography. PMID- 26518493 TI - Directing membrane chromatography to manufacture alpha1-antitrypsin from human plasma fraction IV. AB - The surging demand for plasma proteins, mainly driven by the growing market and the development of new therapeutic indications, is promoting manufacturers to improve the throughput of plasma proteins. Due to the inherent convective mass transfer, membrane chromatography has been proved to be an efficient approach for extracting a small amount of target proteins from large-volume feed. In this study, alpha1-antitrypsin (AAT) was extracted from human plasma fraction IV by a two-step membrane chromatography. An anion-exchange membrane chromatography (AEMC) was used to capture the plasma proteins in bind/elute mode, and the obtained effluent was further polished by a hydrophobic interaction membrane chromatography (HIMC) in flow-through mode. Under optimal conditions, the recovery and purity of AAT achieved 87.0% and 0.58 AAT/protein (g/g) by AEMC, respectively. After the precise polishing by HIMC, the purity of AAT was 1.22 AAT/protein (g/g). The comparison results showed that membrane chromatography outperformed column chromatography in both steps because of its high throughput. This two-step membrane chromatography could obtain an AAT recovery of 83.3% and an activity recovery of 91.4%. The outcome of this work not only offers an alternative process for protein purification from plasma, but also provides guidelines for manufacturing product from a large-volume feed with multi components by membrane chromatography. PMID- 26518494 TI - Composite polymeric beads containing N,N,N',N'-tetraoctyldiglycolamide for actinide ion uptake from nitric acid feeds: Batch uptake, kinetic modelling and column studies. AB - Polyethersulphone (PES) based composite polymeric beads (CPB) containing TODGA (N,N,N',N'-tetraoctyldiglycolamide) as the extractant were prepared by conventional phase inversion technique and were tested for the uptake of actinide ions such as Am(3+), UO2(2+), Pu(4+), Np(4+) and fission product ions such as Eu(3+) and Sr(2+). The CPBs containing 2.5-10wt.% TODGA were characterized by various physical methods and their porosity, size, surface morphology, surface area and the degradation profile by thermogravimetry were analyzed. The batch uptake studies involved kinetics of metal ion sorption, uptake as a function of nitric acid concentration, kinetic modelling and adsorption isotherms and most of the studies involved the Am(3+) ions. The batch saturation sorption capacities for Eu(3+) loading at 3M HNO3 were determined to be 6.6+/-0.02, 9.1+/-0.02 and 22.3+/-0.04mgg(-1) of CRBs with 2.5wt.%, 5wt.% and 10wt.% TODGA, respectively. The sorption isotherm analysis with Langmuir, D-R and Freundlisch isotherms indicated chemisorption monolayer mechanism. Chromatographic studies indicated breakthrough of Eu(3+) (using a solution containing Eu carrier) after about 0.75 bed volume (3.5-4mL). Elution of the loaded Eu was carried out using 0.01M EDTA as the eluent. PMID- 26518495 TI - Rapid screening of haloacetamides in water using salt-assisted liquid-liquid extraction coupled injection-port silylation gas chromatography-mass spectrometry. AB - The rapid screening of trace amounts of the nitrogenous disinfection by-products, haloacetamides (HAcAms), in drinking and swimming pool water was performed by a simple and reliable procedure based on salt-assisted liquid-liquid extraction (SALLE) combined with injection-port silylation gas chromatography-mass spectrometry (IPS-GC-MS) method. The optimal SALLE conditions involved the injection of 4-mL of ethyl acetate into a 10-mL water sample (pH 7) containing 3 g of sodium sulfate. After vortex extraction for 1min and centrifugation, 10MUL of the extract (mixed with 1MUL of MTBSTFA) was directly determined by IPS-GC-MS. The limits of quantitation (LOQs) were determined to be 0.03-0.3MUg/L. Precision, as indicated by relative standard deviations (RSDs), was less than 10% for both intra- and inter-day analysis. Accuracy, expressed as the mean extraction recovery, was between 76% and 94%. The SALLE plus IPS-GC-MS was successfully applied to quantitatively determine HAcAms from drinking and swimming pool water samples, and the total concentrations of the compounds ranged from 0.43 to 4.03MUg/L. PMID- 26518496 TI - Simple equations to simulate closed-loop recycling liquid-liquid chromatography: Ideal and non-ideal recycling models. AB - The ideal (the column outlet is directly connected to the column inlet) and non ideal (includes the effects of extra-column dispersion) recycling equilibrium cell models are used to simulate closed-loop recycling counter-current chromatography (CLR CCC). Simple chromatogram equations for the individual cycles and equations describing the transport and broadening of single peaks and complex chromatograms inside the recycling closed-loop column for ideal and non-ideal recycling models are presented. The extra-column dispersion is included in the theoretical analysis, by replacing the recycling system (connecting lines, pump and valving) by a cascade of Nec perfectly mixed cells. To evaluate extra-column contribution to band broadening, two limiting regimes of recycling are analyzed: plug-flow, Nec->infinity, and maximum extra-column dispersion, Nec=1. Comparative analysis of ideal and non-ideal models has shown that when the volume of the recycling system is less than one percent of the column volume, the influence of the extra-column processes on the CLR CCC separation may be neglected. PMID- 26518497 TI - Salting-out assisted liquid-liquid extraction for the determination of biogenic amines in fruit juices and alcoholic beverages after derivatization with 1 naphthylisothiocyanate and high performance liquid chromatography. AB - A new method for determining biogenic amines in fruit juices and alcoholic beverages is described involving reaction of biogenic amines with 1 naphthylisothiocyanate followed by extraction of 1-naphthylthiourea derivatives with water-miscible organic solvent acetonitrile when solvents phase separation occurred using ammonium sulphate, a process called salting-out assisted liquid liquid extraction. The extract was analyzed by high-performance liquid chromatography with UV detection at 254nm. The new reagent avoided many of the inconveniences as observed with existing derivatizing agents, such as dansyl chloride and benzoyl chloride, in regard to their inselectivity, instability, adverse effect of excess reagent, and necessity to remove excess reagent. The procedure has been optimized with respect to reaction time and temperature, water miscible extraction solvent, and salt for solvents phase separation. Use of reagent as dispersed phase in aqueous medium produced derivatives in high yield. A linear calibration was obtained between the amount of biogenic amines in range 1-1000MUgL(-1) and peak areas of corresponding thioureas formed; the correlation coefficient was 0.9965, and the limit of detection and limit of quantification found were 1.1MUgL(-1) and 3.2MUgL(-1), respectively. The pre-concentration method gave an average enrichment factor of 94. The application of the method has been demonstrated in the determination of biogenic amines in commercial samples of fruit juices and alcoholic beverages. In spiking experiments to real samples, the average recovery found by the present method was 94.5% that agreed well with 95.8% obtained by established comparison methods. PMID- 26518498 TI - Design of insulator-based dielectrophoretic devices: Effect of insulator posts characteristics. AB - Insulator-based dielectrophoresis (iDEP) is a leading technique for the enrichment and manipulation of target bioparticles by exploiting physical and electrical properties of the particles and the suspending medium. Dielectrophoretic forces are produced by employing insulator posts that distort an otherwise uniform electric field. The optimal design for iDEP devices involves a careful balance between electrokinetics (EK) and dielectrophoresis (DEP) in the DEP-active area, where the design of the insulator posts is crucial for their performance. This contribution demonstrates the selection of a geometrical set of parameters that enhances particle capture and enrichment in an iDEP device. Numerical simulations, comprising an average trapping condition (TC) and the average lateral-to-longitudinal force ratio (FR) experienced by particles, were used to determine improved geometrical parameters (e.g., shape, length and width) and arrangement (e.g., lateral and longitudinal spacing) of the insulator posts. Experiments with polystyrene particles demonstrated the enhancement in particle enrichment, validating the employed key output parameters. The fabrication feasibility of the improved devices by a soft-lithographic process was also explored through numerical simulations and experiments. Optimal designs for this study were selected and their capture capacity was examined, demonstrating a decrease up to 84% in the electric potential necessary to generate a clear band of trapped particles. The findings from this study provide a systematic approach toward the design of high performance iDEP devices for their lab-on-a-chip integration. PMID- 26518499 TI - Marked reduction in compliance with central line insertion practices (CLIP) when accounting for missing CLIP data and incomplete line capture. AB - Adherence to central line insertion practices can significantly reduce infections and is used as a hospital benchmark for quality. However, current national standards for central line insertion practices (CLIP) compliance calculation do not include missing CLIP forms. We found adherence rates significantly decreased when accounting for all lines at an academic medical center. PMID- 26518500 TI - The acceptable duration between occupational exposure to hepatitis B virus and hepatitis B immunoglobulin injection: Results from a Korean nationwide, multicenter study. AB - BACKGROUND: Postexposure prophylaxis for occupational exposure to hepatitis B virus (HBV) plays an important role in the prevention of HBV infections in health care workers (HCWs). We examined data concerning the acceptable duration between occupational exposure and administration of a hepatitis B immunoglobulin (HBIG) injection in an occupational clinical setting. METHODS: A retrospective analysis was conducted with data from 143 cases of HCWs exposed to HBV in 15 secondary and tertiary teaching hospitals between January 2005 and June 2013. Data were taken from the infection control records of each hospital. RESULTS: Active vaccination after HBV exposure was started in 119 cases (83.2%) and postvaccination testing for hepatitis B antibody showed positive seroconversion in 93% of cases. In 98 cases (68.5%), HBIG was administered within 24 hours after HBV exposure; however, 45 HCWs (31.5%) received an HBIG injection more than 24 hours postexposure and 2 among the 45 received an injection after 7 days. Although 31.5% received an HBIG injection more than 24 hours postexposure, no cases of seroconversion to hepatitis b antibody positivity occurred. CONCLUSIONS: For susceptible HCWs, HBIG administered between 24 hours and 7 days postexposure may be as effective as administration within 24 hours in preventing occupational HBV infection. PMID- 26518501 TI - Walking the line: Understanding pedestrian behaviour and risk at rail level crossings with cognitive work analysis. AB - Pedestrian fatalities at rail level crossings (RLXs) are a public safety concern for governments worldwide. There is little literature examining pedestrian behaviour at RLXs and no previous studies have adopted a formative approach to understanding behaviour in this context. In this article, cognitive work analysis is applied to understand the constraints that shape pedestrian behaviour at RLXs in Melbourne, Australia. The five phases of cognitive work analysis were developed using data gathered via document analysis, behavioural observation, walk-throughs and critical decision method interviews. The analysis demonstrates the complex nature of pedestrian decision making at RLXs and the findings are synthesised to provide a model illustrating the influences on pedestrian decision making in this context (i.e. time, effort and social pressures). Further, the CWA outputs are used to inform an analysis of the risks to safety associated with pedestrian behaviour at RLXs and the identification of potential interventions to reduce risk. PMID- 26518502 TI - Effects of dietary soybean isoflavones on non-specific immune responses and hepatic antioxidant abilities and mRNA expression of two heat shock proteins (HSPs) in juvenile golden pompano Trachinotus ovatus under pH stress. AB - This study determined the effect of dietary soybean isoflavones on non-specific immunity and on mRNA expression of two HSPs in juvenile golden pompano Trachinotus ovatus under pH stress. Six diets were formulated to contain 0, 10, 20, 40, 60 and 80 mg/kg of soybean isoflavones. Each diet was fed to triplicate groups of fish in cylindrical tanks. After 56 days of feeding, 15 fish per tank were exposed to pH stress (pH ~ 9.2) for 24 h. Serum total protein (TP), respiratory burst activity (RBA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), lysozyme (LYZ), complement 3 (C3), complement 4 (C4), cortisol, hepatic total antioxidant capacity (T-AOC), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT) and the relative mRNA expression of heat shock protein 70 (HSP70) and 90 (HSP90) were investigated. The results showed that after pH stress, serum TP, RBA, LYZ, C4, hepatic T-AOC and CAT levels were significantly reduced (P < 0.05) while serum ALT, hepatic MDA and HSP70 and HSP90 mRNA expression levels were significantly increased (P < 0.05). On the other hand, supplementation with soybean isoflavones significantly reduced levels of serum ALT (20, 40, 60 mg/kg soybean isoflavones groups) and hepatic MDA (40, 60 and 80 mg/kg soybean isoflavones groups). Supplemented groups had increased serum TP content (40 mg/kg soybean isoflavones groups), RBA (20 and 40 mg/kg soybean isoflavones groups), LYZ (40 and 60 mg/kg soybean isoflavones groups), C3(20, 40, 60 and 80 mg/kg soybean isoflavones groups), hepatic SOD activity (40, 60 and 80 mg/kg soybean isoflavones groups) as well as increased relative mRNA expression of hepatic HSP70 (40, 60 and 80 mg/kg soybean isoflavones groups) and HSP90 (40 and 60 mg/kg soybean isoflavones groups) (P < 0.05). These results indicate that ingestion of a basal diet supplemented with 40-60 mg/kg soybean isoflavones could enhance resistance against pH stress in T. Ovatus to some degree. PMID- 26518503 TI - Humoral and mucosal defense molecules rhythmically oscillate during a light-dark cycle in permit, Trachinotus falcatus. AB - Circadian rhythm provides organisms with an internal system to maintain temporal order in a dynamic environment. This is typified by a 24-h cycle for a number of physiological processes, including immunity. The present study characterized the humoral and mucosal defense molecules and their dynamics during a light-dark (LD) cycle in juvenile permit, Trachinotus falcatus. All studied defense molecules were constitutively identified in serum and skin mucus. Serum generally exhibited higher levels of these defenses than skin mucus, with the exception of anti protease (ANTIPRO). The difference in ANTIPRO, lysozyme (LYZ), esterase (ESA) and catalase (CAT) levels between serum and skin mucus was not affected by the phase of the daily cycle. However, a clear phase-dependent difference was observed in protease (PRO), globulin (GLOB), myeloperoxidase (MPO), alkaline phosphatase (ALP) and glutathione peroxidase (GPX) levels. Activities of ALP and GPX displayed significant daily rhythmicity in both serum and skin mucus. Circadian profile of ALP was identical in both biofluids, but an antiphasic feature was exhibited by GPX. GLOB and MPO levels also exhibited significant daily oscillation but only in serum with acrophases registered at ZT 14.5 and 6.15, respectively. Mucus PRO and serum ANTIPRO demonstrated significant temporal variations during a daily cycle albeit not rhythmic. Cluster analysis of the defense molecules in serum and skin mucus revealed two different daily profiles suggesting a possibility of distinct circadian control between humoral and mucosal immunity. These observations indicate that LD cycle had a remarkable impact in the defense molecules characterizing the humoral and mucosal immunity in permit. Daily rhythmic patterns of these defense molecules contribute to our understanding of the barely explored interplay of immunity and circadian rhythm in teleost fish. Lastly, the results could be useful in developing aquaculture practices aiming at modifying the immune functions of permit for improved health. PMID- 26518504 TI - Jian carp (Cyprinus carpio var. Jian) intestinal immune responses, antioxidant status and tight junction protein mRNA expression are modulated via Nrf2 and PKC in response to dietary arginine deficiency. AB - This study investigated the effect of dietary arginine on the immune response, antioxidant status and tight junction mRNA expression in the intestine of juvenile Jian carp (Cyprinus carpio var. Jian). A total of 1200 juvenile Jian carp with an average initial weight of 6.33 +/- 0.03 g were fed graded levels of arginine (9.8-24.5 g kg(-1) diet) for nine weeks. The study showed that arginine deficiency up-regulated interleukin 1, interleukin 8 and transforming growth factor-beta and down-regulated tumour necrosis factor alpha gene expression (P < 0.05). Additionally, arginine deficiency increased malondialdehyde (MDA), protein carbonyl (PC) and glutathione contents and decreased the activities of copper/zinc superoxide dismutase (SOD1), glutathione peroxidase (GPx), catalase (CAT) and glutathione reductase (GR) and glutathione-S-transferase (GST) (P < 0.05). Meanwhile, arginine deficiency significantly increased claudin 7, occludin, protein kinase C, NF-E2-related factor 2 and Kelch-like-ECH- associated protein 1 mRNA expression and decreased SOD1, CAT and GR mRNA expression (P < 0.05). All of these results indicated that arginine deficiency impaired intestinal immune function via the regulation of mRNA expression of cytokines, tight junction proteins, antioxidant enzymes, Nrf2/Keap1 and PKC in fish intestine. PMID- 26518505 TI - Four pro-inflammatory cytokines of rohu (Labeo rohita) during early developmental stages, their tissue distribution and expression by leucocytes upon in-vitro stimulation. AB - Cytokines are important components of both adaptive and innate immunity, and are required to initiate and regulate immune responses following infection. The ontogeny and tissue specific distribution of four pro-inflammatory cytokines, interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), IL-8 and IL-1beta in rohu (Labeo rohita), and their responses by leucocytes from anterior kidney/head-kidney (HKLs), spleen (SPLs) and peripheral blood (PBLs) following stimulation with concanavalin A (ConA), ConA with phorbol 12-myristate 13-acetate (ConA/PMA) and formalin-killed Aeromonas hydrophila cells (FAH) were studied. In ontogeny study, mRNA levels of IL-6 and IL-1beta were evident in unfertilized egg stages of L. rohita whereas IL-8 and TNF-alpha transcripts were found from 1 to 3 h post-fertilization (hpf) onwards till day 15 post-fertilization, respectively. Basal level of all four cytokines was observed in all twelve tissues (eye, brain, heart, gill, anterior kidney, posterior kidney, spleen, liver, skin, muscle, hindgut and foregut) of L. rohita juveniles. Expression levels of IL-6 and IL-8 were found to be the highest in liver and heart tissues, respectively, while TNF alpha transcripts were high in anterior kidney and liver tissues. Transcripts of IL-1beta showed high expression in muscle, heart and spleen. Upon in vitro stimulation of leucocytes, there was variable up-regulation of all the four cytokines following different treatments throughout the experimental time period. Induction of cytokines was more pronounced in PBLs stimulated with FAH compared to other stimuli. However, an up-regulated IL-8 expression was evident in all the leucocytes following stimulation with FAH thus indicating IL-8 could be used as an indicator or indirect marker to monitor vaccine status or health status of L. rohita during bacterial infection. PMID- 26518506 TI - Trunk rotation affects temporal order judgments with direct saccades: Influence of handedness. AB - Manipulation of the trunk midline has been shown to improve visuospatial performance in patients with unilateral visual neglect. The goal of the present study was to disentangle motor and perceptual components of egocentric midline manipulations and to investigate the contribution of individual hand preference. Two versions of visual temporal order judgment (TOJ) tasks were tested in healthy right- and left-handed subjects while trunk rotation was varied. In the congruent version, subjects were required to execute a saccade to the first of two horizontal stimuli presented with different stimulus onset asynchronies (SOA). In the incongruent version, subjects were required to perform a vertical saccade to a pre-learned color target, thereby dissociating motor response from the perceptual stimulus location. The main findings of this study are a trunk rotation and response direction specific impact on temporal judgments in form of a prior entry bias for right hemifield stimuli during rightward trunk rotation, but only in the congruent task. This trunk rotation-induced spatial bias was most pronounced in left-handed participants but had the same sign in the right-handed group. Results suggest that egocentric midline shifts in healthy subjects induce a spatially-specific motor, but not a perceptual, bias and underline the importance of taking individual differences in functional laterality such as handedness and mode of perceptual report into account when evaluating effects of trunk rotation in either healthy subjects or neurological patients. PMID- 26518507 TI - Settling the debate on birth order and personality. PMID- 26518508 TI - Genetic architecture of key social trait differs significantly between primitive and advanced eusocial species. PMID- 26518509 TI - Impact of bed capacity on spatiotemporal shifts in Ebola transmission. PMID- 26518510 TI - Bronsted slopes based on single-molecule imaging data help to unveil the chemically coupled rotation in F1-ATPase. PMID- 26518512 TI - Relationship between renal function and renal volume in autosomal dominant polycystic kidney disease: cross-sectional study. AB - OBJECTIVE: To determine in patients with autosomal dominant polycystic kidney disease the relationship between total renal volume (the sum of both kidneys, TRV) as measured by magnetic resonance and renal function; and its behaviour according to sex and the presence of arterial hypertension, hypercholesterolaemia and hyperglycemia. METHOD: Cross-sectional study including patients with autosomal dominant polycystic kidney disease who underwent periodic reviews at Nephrology external consultations at Hospital de las Nieves de Granada, and who underwent an magnetic resonance to estimate renal volume between January 2008 and March 2011. RESULTS: We evaluated 67 patients (59.7% women, average age of 48+/ 14.4 years) and found a significant positive association between TRV and serum creatinine or urea, which was reversed compared with estimated glomerular filtration by MDRD-4 and Cockcroft-Gault. Women showed an average serum creatinine level and a significantly lower TRV level compared with males. Subgroups affected by arterial hypertension and hyperuricemia presented average values for serum creatinine and urea, higher for TRV and lower for estimated glomerular filtration. The hypercholesterolaemia subgroup showed higher average values for urea and lower for estimated glomerular filtration, without detecting significant differences compared with TRV. CONCLUSION: The volume of polycystic kidneys measured by magnetic resonance is associated with renal function, and can be useful as a complementary study to monitor disease progression. The presence of arterial hypertension, hyperuricemia or hypercholesterolaemia is associated with a poorer renal function. PMID- 26518513 TI - Central Plasticity in Brachial Plexus Injury: A Neural Domino Effect. PMID- 26518514 TI - Effect of the omega-3 fatty acid plus vitamin E supplementation on subjective global assessment score, glucose metabolism, and lipid concentrations in chronic hemodialysis patients. AB - SCOPE: This study was conducted to determine the effects of omega-3 fatty acid plus vitamin E supplementation on subjective global assessment (SGA) score and metabolic profiles in chronic hemodialysis (HD) patients. METHODS AND RESULTS: This randomized double-blind placebo-controlled clinical trial was conducted among 120 chronic HD patients. Participants were randomly divided into four groups to receive: (i) 1250 mg/day omega-3 fatty acid containing 600 mg eicosapentaenoic acid and 300 mg docosahexaenoic acid + vitamin E placebo (n = 30), (ii) 400 IU/day vitamin E + omega-3 fatty acids placebo (n = 30), (iii) 1250 mg omega-3 fatty acids/day + 400 IU/day vitamin E (n = 30), and (iv) omega-3 fatty acids placebo + vitamin E placebo (n = 30) for 12 wk. Fasting blood samples were taken at baseline and after 12-wk intervention to measure metabolic profiles. Patients who received combined omega-3 fatty acids and vitamin E supplements compared with vitamin E, omega-3 fatty acids, and placebo had significantly decreased SGA score (p < 0.001), fasting plasma glucose (p = 0.01), serum insulin levels (p = 0.001), homeostasis model of assessment insulin resistance (p = 0.002), and improved quantitative insulin sensitivity check index (p = 0.006). CONCLUSION: Omega-3 fatty acids plus vitamin E supplementation for 12 wk among HD patients had beneficial effects on SGA score and metabolic profiles. PMID- 26518517 TI - Unusual localization of a primary pleomorphic malignant fibrous histiocytoma on the mitral valve: a case report and review of the literature. AB - INTRODUCTION: It has been reported that cardiac malignant fibrous histiocytomas occur more frequently in the left side of the heart, especially in the left atrium, but rarely invade the mitral valve. We present a case with a giant malignant fibrous histiocytoma with an unusual localization involving almost the entire left atrium, mitral valve, and left superior pulmonary vein. CASE PRESENTATION: We describe the case of a 54-year-old woman from Kosovo admitted to our emergency department with dyspnea. A transthoracic echocardiography demonstrated a giant mass localized on her left atrium. Our patient underwent emergent total surgical removal of the mass. The mass extended between her left superior pulmonary vein, and extended to her left atrium and the posterior mitral valve leaflet. We formulated a surgical plan for total separation of the mass from the endocardium. Total removal was performed and her left side pulmonary veins were entirely freed from the mass. We then performed a mitral valve replacement. The differential diagnosis included other masses of the left atrium, including thrombi, vegetations, and cardiac tumors. Postsurgical histopathologic results showed a pleomorphic malignant fibrous histiocytoma. Six monthly follow up cardiac and abdominal sonographic examinations revealed no tumor recidivism. CONCLUSION: We reviewed 90 cases with malignant fibrous histiocytoma reported in the literature. Our case was especially unusual because of the primary location in the mitral valve, the pleomorphic variant, and the dimensions and extension. Complete surgical resection is mandatory to ameliorate symptoms and to obtain histologic information. PMID- 26518518 TI - Soaping the NMDA receptor: Various types of detergents influence differently [(3)H]MK-801 binding to rat brain membranes. AB - Membranes prepared from rat brain were treated with increasing concentrations of cationic, neutral, anionic and zwitterionic surfactants. Potent inactivation of [(3)H]MK-801 binding to NMDA receptors (NRs) was provided by the cation cetyl pyridinium (IC50 25 MUM) and the neutral digitonin (IC50 37 MUM). A 2 h incubation of rat brain membranes at 24 degrees C with 100 MUM of the neutral Triton X-100 resulted in about 50% reversible inhibition (without inactivation). Reversible inhibition was also effected by the anion deoxycholate (IC50 700 MUM), and by the zwitterions N-lauryl sulfobetaine (12-SB(+/-), 400 MUM) and CHAPS (1.5 mM), with inactivation at higher concentrations. Keeping the NR cation channel in the closed state significantly protected against inactivation by cations and by 12-SB(+/-), but not by the other detergents. Inactivation depended differentially on the amount of the membranes, on the duration of the treatment, and on the temperature. Varying the amount of membranes by a factor 8 yielded for cetyl trimethylammonium (16-NMe3(+)) IC50s of inactivation from 10 to 80 MUM, while for deoxycholate the IC50 of inactivation was 1.2 mM for all tissue quantities. Some compounds inactivated within a few min (16-NMe3(+), digitonin, CHAPS), while inactivation by others took at least half an hour (Triton X-100, deoxycholate, 12 SB(+/-)). These last 3 ones also exhibited the steepest temperature dependence. Knowledge about the influence of various parameters is helpful in selecting appropriate conditions allowing the treatment of brain membranes with amphiphiles without risking irreversible inactivation. PMID- 26518519 TI - Liposomes with diverse compositions are protected during desiccation by LEA proteins from Artemia franciscana and trehalose. AB - Intracellular accumulation of Late Embryogenesis Abundant (LEA) proteins and the disaccharide trehalose is associated with cellular desiccation tolerance in a number of animal species. Two LEA proteins from anhydrobiotic embryos of the brine shrimp Artemia franciscana were tested for the ability to protect liposomes of various compositions against desiccation-induced damage in the presence and absence of trehalose. Damage was assessed by carboxyfluorescein leakage after drying and rehydration. Further, using a cytoplasmic-localized (AfrLEA2) and a mitochondrial-targeted (AfrLEA3m) LEA protein allowed us to evaluate whether each may preferentially stabilize membranes of a particular lipid composition based on the protein's subcellular location. Both LEA proteins were able to offset damage during drying of liposomes that mimicked the lipid compositions of the inner mitochondrial membrane (with cardiolipin), outer mitochondrial membrane, and the inner leaflet of the plasma membrane. Thus liposome stabilization by AfrLEA3m or AfrLEA2 was not dependent on lipid composition, provided physiological amounts of bilayer and non-bilayer-forming lipids were present (liposomes with a non biological composition of 100% phosphatidylcholine were not protected by either protein). Additive protection by LEA proteins plus trehalose was dependent on the lipid composition of the target membrane. Minimal additional damage occurred to liposomes stored at room temperature in the dried state for one week compared to liposomes rehydrated after 24h. Consistent with the ability to stabilize lipid bilayers, molecular modeling of the secondary structures for AfrLEA2 and AfrLEA3m revealed bands of charged amino acids similar to other amphipathic proteins that interact directly with membranes. PMID- 26518520 TI - A (2)H magic-angle spinning solid-state NMR characterisation of lipid membranes in intact bacteria. AB - This work proposes a new approach to characterize cell membranes in intact cells by (2)H solid-state nuclear magnetic resonance (NMR) in only a few hours using magic-angle spinning (MAS) and spectral moment analysis. The method was first validated on model dipalmitoylphosphatidylcholine (DPPC) membranes, allowing the detection of lipid fluctuations below the main transition temperature. Then the lipid dynamics in Escherichia coli membranes was compared in bacteria grown under different diets. More specifically, deuterated palmitic acid was used to isotopically label the phospholipid acyl chains in bacteria membranes, with or without the presence of protonated oleic acid. Our results showed improved lipid fluidity when bacteria were grown in the presence of oleic acid, which helps preserving the natural fatty acid profile in E. coli membranes. The MAS (2)H solid-state NMR study of membranes combined with spectral moment analysis showed to be a fast method compatible with in vivo bacterial studies, and should also be applicable to other micro-organisms to obtain molecular information on living cells by solid-state NMR. PMID- 26518521 TI - Editorial Comment. PMID- 26518523 TI - Endoscopic and histologic findings in serrated polyposis syndrome. PMID- 26518524 TI - Use of over-the-scope clip to treat bleeding duodenal ulcers. PMID- 26518525 TI - Time reverse modeling of acoustic emissions in a reinforced concrete beam. AB - The time reverse modeling (TRM) is applied for signal-based acoustic emission (AE) analysis of reinforced concrete (RC) specimens. TRM uses signals obtained from physical experiments as input. The signals are re-emitted numerically into a structure in a time-reversed manner, where the wavefronts interfere and appear as dominant concentrations of energy at the origin of the AE. The experimental and numerical results presented for selected AE signals confirm that TRM is capable of localizing AE activity in RC caused by concrete cracking. The accuracy of the TRM results is corroborated by three-dimensional crack distributions obtained from X-ray computed tomography images. PMID- 26518526 TI - Anti-plane transverse waves propagation in nanoscale periodic layered piezoelectric structures. AB - In this paper, anti-plane transverse wave propagation in nanoscale periodic layered piezoelectric structures is studied. The localization factor is introduced to characterize the wave propagation behavior. The transfer matrix method based on the nonlocal piezoelectricity continuum theory is used to calculate the localization factor. Additionally, the stiffness matrix method is applied to compute the wave transmission spectra. A cut-off frequency is found, beyond which the elastic waves cannot propagate through the periodic structure. The size effect or the influence of the ratio of the internal to external characteristic lengths on the cut-off frequency and the wave propagation behavior are investigated and discussed. PMID- 26518527 TI - Intraoral Vertical Ramus Osteotomy Results in Good Long-Term Mandibular Stability in Patients With Mandibular Prognathism and Anterior Open Bite. AB - PURPOSE: Few studies have evaluated the outcomes of intraoral vertical ramus osteotomy (IVRO) for the correction of skeletal Class III malocclusion with an anterior open bite and the potential for postoperative relapse. Therefore, this study evaluated the stability of outcomes of IVRO for mandibular prognathism with and without an anterior open bite. MATERIAL AND METHODS: This retrospective cohort study included consecutive patients with skeletal Class III malocclusion with (AOB group) and without (NAOB group) an anterior open bite who underwent IVRO at Yonsei Dental Hospital (Seoul, Korea). Lateral cephalograms were analyzed for predictor (open bite, yes or no) and outcome (horizontal and vertical relapse in the mandible) variables before and 7 days, 1 year, and 2 years after surgery. Other variables included the patients' demographic characteristics. Data were analyzed using independent t tests, repeated measures analysis of variance, Pearson correlation coefficients, and multiple linear regression analysis. RESULTS: The 2 groups (n = 15 each) were matched for baseline demographic characteristics. During the 2-year postoperative period, anterior and superior mandibular movements were observed in the NAOB group, whereas posterior and superior movements were observed in the AOB group. However, there were no meaningful intergroup differences in horizontal and vertical relapses of the mandible at all time points, although the amount of postoperative inferior relapse increased with a decrease in the amount of initial overbite. CONCLUSIONS: IVRO for the correction of skeletal Class III malocclusion resulted in good postoperative stability over time, regardless of the presence of a preoperative open bite, although the amount of postoperative inferior relapse showed a weak negative correlation with the initial overbite. Thus, IVRO can be a clinically acceptable treatment for skeletal Class III malocclusion with an anterior open bite. PMID- 26518528 TI - First Bite Syndrome After Bilateral Temporomandibular Joint Replacement: Case Report. AB - First bite syndrome (FBS) refers to intense pain in the parotid region, which coincides with the first bite of every meal, gradually subsides over the next several bites, but returns with the first bite of the next meal. The definitive diagnosis can be readily established by the characteristic onset of pain after the first bite of every meal. Pain is typically most intense at the first meal of the day, although some patients experience symptoms when thinking of food or salivating. FBS is a recognized complication of surgery within the parapharyngeal space; however, other surgical procedures involving the upper neck have been associated with this syndrome. The extreme rarity of FBS complicates a thorough understanding of its pathophysiology. Various medical agents have been used, with variable success, for the management of patients with FBS. Although proved effective, more radical treatment modalities are commonly reserved for persistent or refractory cases, because there is potential of spontaneous decrease in the severity of symptoms with time. This report describes the case of a patient presenting with symptoms of FBS after bilateral temporomandibular joint replacement. To the authors' knowledge, this is the first case of FBS in the literature occurring after temporomandibular joint replacement. PMID- 26518529 TI - Why people use and don't use technologies: Introduction to the special issue on assistive technologies for cognition/cognitive support technologies. AB - This special issue focuses on assistive technologies for cognition/cognitive support technologies as well as the ways in which individuals are assessed and trained in their use. We provide eleven diverse articles that give information on products, why they are used and not used, and best professional practices in service provision. Our goal is to highlight a broad topic that has received limited research investigation and offer an insight into how different countries and programs are promoting access to and use of assistive technologies for cognition/cognitive support technologies. PMID- 26518530 TI - Extracting neurophysiological signals reflecting users' emotional and affective responses to BCI use: A systematic literature review. AB - BACKGROUND: Brain-computer interfaces (BCIs) allow persons with impaired mobility to communicate and interact with the environment, supporting goal-directed thinking and cognitive function. Ideally, a BCI should be able to recognize a user's internal state and adapt to it in real-time, to improve interaction. OBJECTIVE: Our aim was to examine studies investigating the recognition of affective states from neurophysiological signals, evaluating how current achievements can be applied to improve BCIs. METHODS: Following the PRISMA guidelines, we performed a literature search using PubMed and ProQuest databases. We considered peer-reviewed research articles in English, focusing on the recognition of emotions from neurophysiological signals in view of enhancing BCI use. RESULTS: Of the 526 identified records, 30 articles comprising 32 studies were eligible for review. Their analysis shows that the affective BCI field is developing, with a variety of combinations of neuroimaging techniques, selected neurophysiological features, and classification algorithms currently being tested. Nevertheless, there is a gap between laboratory experiments and their translation to everyday situations. CONCLUSIONS: BCI developers should focus on testing emotion classification with patients in ecological settings and in real time, with more precise definitions of what they are investigating, and communicating results in a standardized way. PMID- 26518531 TI - The use of assistive technology for cognition to support the performance of daily activities for individuals with cognitive disabilities due to traumatic brain injury: The current state of the research. AB - BACKGROUND: Many individuals with traumatic brain injury (TBI) are young and could have many years of productivity ahead of them. However, cognitive impairments may hinder individuals' ability to perform daily tasks. Assistive technology for cognition (ATC) can be effective in helping compensate for cognitive impairments. OBJECTIVE: This study examined the current state of the research on using ATCs to support daily activities for individuals with cognitive disabilities that are due to TBI. METHODS: A comprehensive systematic literature search was performed to identify peer-reviewed articles published between 2000 and 2015. To evaluate the nature of the research, qualitative data were extracted pertaining to recruitment, participant characteristics, intervention design, type of ATCs and their functions, matching individuals with ATCs, training for using the ATC, and outcomes. RESULTS: Research examining the effectiveness of ATCs as everyday compensatory tools for cognitive impairments that are due to TBI is limited. The majority of studies were case studies or quasi-experimental studies with small sample sizes. Studies showed positive associations between use of ATCs and individuals' abilities to perform tasks regardless of age, TBI severity, and time since injury. CONCLUSIONS: Future research should assess the match between the individual and the technology, study the impact of training on using ATCs, and analyze the usability of ATCs. PMID- 26518532 TI - Assistive technology to help persons in a minimally conscious state develop responding and stimulation control: Performance assessment and social rating. AB - BACKGROUND: Post-coma persons in a minimally conscious state (MCS) and with extensive motor impairment and lack of speech tend to be passive and isolated. OBJECTIVE: This study aimed to (a) further assess a technology-aided approach for fostering MCS participants' responding and stimulation control and (b) carry out a social validation check about the approach. METHODS: Eight MCS participants were exposed to the aforementioned approach according to an ABAB design. The technology included optic, pressure or touch microswitches to monitor eyelid, hand or finger responses and a computer system that allowed those responses to produce brief periods of positive stimulation during the B (intervention) phases of the study. Eighty-four university psychology students and 42 care and health professionals were involved in the social validation check. RESULTS: The MCS participants showed clear increases in their response frequencies, thus producing increases in their levels of environmental stimulation input, during the B phases of the study. The students and care and health professionals involved in the social validation check rated the technology-aided approach more positively than a control condition in which stimulation was automatically presented to the participants. CONCLUSIONS: A technology-aided approach to foster responding and stimulation control in MCS persons may be effective and socially desirable. PMID- 26518533 TI - Neurorehabilitation applied to specific learning disability: Study of a single case. AB - BACKGROUND: Specific Learning Disorders (SLD) therefore represent chronic, not temporary disorders with varying degrees of expression throughout life. The beginning of imaging, anatomy and genetics studies have made it possible to investigate the brain organization of individuals suffering from SLD (Deheane, 2009). OBJECTIVES: The purpose of this paper is to describe a treatment method for reading and writing disorders through an intervention based on the integration of a sublexical method and a neuropsychological approach, with assistive technologies in the study of a single case. METHODS: The protocol is based on the modularization theory (Karmiloff-Smith, 1990). The data presented in this paper with a A-B-A basic experimental drawing. RESULTS: This study confirms the degree of effectiveness of the treatments based on the automated identification of syllables and words together with the integrated enhancement of neuropsychological aspects such as visual attention and phonological loop (Benso, 2008), although in the follow-up condition only some abilities maintain the progress achieved. CONCLUSIONS: As previously mentioned, the SLD represents a chronic disorder, consequently the treatment does not solve the root cause of the problem, but can grant a use of the process decidedly more instrumental to everyday life. PMID- 26518534 TI - Systematic instruction of assistive technology for cognition (ATC) in an employment setting following acquired brain injury: A single case, experimental study. AB - BACKGROUND: Assistive technology for cognition (ATC) can be an effective means of compensating for cognitive impairments following acquired brain injury. Systematic instruction is an evidence-based approach to training a variety of skills and strategies, including the use of ATC. OBJECTIVE: This study experimentally evaluated systematic instruction applied to assistive technology for cognition (ATC) in a vocational setting. METHODS: The study used a single case, multiple-probe design across behaviors design. The participant was a 50 year old female with cognitive impairments following an acquired brain injury (ABI). As a part-time employee, she was systematically instructed on how to operate and routinely use selected applications (apps) on her iPod Touch to support three work-related skills: (a) recording/recalling the details of work assignments, (b) recording/recalling work-related meetings and conversations, and (c) recording/performing multi-step technology tasks. The experimental intervention was systematic instruction applied to ATC. The dependent measures were: (a) the use of ATC at work as measured by an ATC routine task analysis; and (b) recall of work-related tasks and information. RESULTS: Treatment effects were replicated across the three work-related skills and were maintained up to one year following the completion of intensive training across behaviors with periodic review (booster sessions). CONCLUSIONS: Systematic instruction is a critical component to teaching the routine use of ATC to compensate for cognitive impairments following ABI. PMID- 26518535 TI - Project Career: A qualitative examination of five college students with traumatic brain injuries. AB - BACKGROUND: Project Career is an interprofessional five-year development project designed to improve the employment success of undergraduate college and university students with traumatic brain injury (TBI). The case study information was collected and synthesized by the project's Technology and Employment Coordinators (TECs) at each of the project's three university sites. The project's evaluation is occurring independently through JBS International, Inc. OBJECTIVE: Five case studies are presented to provide an understanding of student participants' experiences within Project Career. Each case study includes background on the student, engagement with technology, vocational supports, and interactions with his/her respective TEC. METHODS: A qualitative analysis from the student's case notes is provided within each case study, along with a discussion of the overall qualitative analysis. RESULTS: Across all five students, the theme Positive Outcomes was mentioned most often in the case notes. Of all the different type of challenges, Cognitive Challenges were most often mentioned during meetings with the TECs, followed by Psychological Challenges, Physical Challenges, Other Challenges, and Academic Challenges, respectively. CONCLUSION: Project Career is providing academic enrichment and career enhancement that may substantially improve the unsatisfactory employment outcomes that presently await students with TBI following graduation. PMID- 26518536 TI - Integrating cognitive rehabilitation: A preliminary program description and theoretical review of an interdisciplinary cognitive rehabilitation program. AB - BACKGROUND: Interdisciplinary cognitive rehabilitation is emerging as the expected standard of care for individuals with mild to moderate degrees of cognitive impairment for a variety of etiologies. There is a growing body of evidence in cognitive rehabilitation literature supporting the involvement of multiple disciplines, with the use of cognitive support technologies (CSTs), in delivering cognitive therapy to individuals who require cognitive rehabilitative therapies. This article provides an overview of the guiding theories related to traditional approaches of cognitive rehabilitation and the positive impact of current theoretical models of an interdisciplinary approach in clinical service delivery of this rehabilitation. OBJECTIVE: A theoretical model of the Integrative Cognitive Rehabilitation Program (ICRP) will be described in detail along with the practical substrates of delivering specific interventions to individuals and caregivers who are living with mild to moderate cognitive impairment. The ultimate goal of this article is to provide a clinically useful resource for direct service providers. It will serve to further clinical knowledge and understanding of the evolution from traditional silo based treatment paradigms to the current implementation of multiple perspectives and disciplines in the pursuit of patient centered care. METHODS: The article will discuss the theories that contributed to the development of the interdisciplinary team and the ICRP model, implemented with individuals with mild to moderate cognitive deficits, regardless of etiology. The development and implementation of specific assessment and intervention strategies in this cognitive rehabilitation program will also be discussed. RESULTS: The assessment and intervention strategies utilized as part of ICRP are applicable to multiple clinical settings in which individuals with cognitive impairment are served. CONCLUSIONS: This article has specific implications for rehabilitation which include: (a) An Interdisciplinary Approach is an effective method for cognitive rehabilitation; and (b) Recent theories offer beneficial evaluation and intervention techniques for cognitive rehabilitation. PMID- 26518537 TI - The expression of the Cuphea palustris thioesterase CpFatB2 in Yarrowia lipolytica triggers oleic acid accumulation. AB - The conversion of industrial by-products into high-value added compounds is a challenging issue. Crude glycerol, a by-product of the biodiesel production chain, could represent an alternative carbon source for the cultivation of oleaginous yeasts. Here, we developed five minimal synthetic glycerol-based media, with different C/N ratios, and we analyzed the production of biomass and fatty acids by Yarrowia lipolytica Po1g strain. We identified two media at the expense of which Y. lipolytica was able to accumulate ~5 g L(-1) of biomass and 0.8 g L(-1) of fatty acids (0.16 g of fatty acids per g of dry weight). These optimized media contained 0.5 g L(-1) of urea or ammonium sulfate and 20 g L(-1) of glycerol, and were devoid of yeast extract. Moreover, Y. lipolytica was engineered by inserting the FatB2 gene, coding for the CpFatB2 thioesterase from Cuphea palustris, in order to modify the fatty acid composition towards the accumulation of medium-chain fatty acids. Contrary to the expected, the expression of the heterologous gene increased the production of oleic acid, and concomitantly decreased the level of saturated fatty acids. PMID- 26518538 TI - Developing a census of brain cells for the corticoendogram of human consciousness. PMID- 26518539 TI - Impact of provider level, training and gender on the utilization of palliative care and hospice in neuro-oncology: a North-American survey. AB - Specialized palliative care (PC) services have emerged to address symptoms and provide end-of-life management for patients with brain tumors. The utilization patterns of PC in neuro-oncology are unknown. A 22-question survey was distributed to participants of the society for neuro-oncology annual meeting 2012 (n = 4487). Nonparametric methods including Wilcoxon two-sample and Kruskal Wallis tests were used to assess differences in responses. 239 (5.3 %) evaluable responses were received; 79 % of respondents were physicians, and 17 % were nurses or midlevel providers. Forty-seven percent were medical or neuro oncologists, 31 % neurosurgeons and 11 % radiation oncologists. Forty percent had no formal training in PC, 57 % had some formal training and 3 % completed a PC fellowship. Seventy-nine percent practiced in an academic setting. Of the respondents, 57 % referred patients to PC when symptoms required treatment and 18 % at end of life. Only 51 % of all providers felt comfortable dealing with end-of life issues and symptoms, while 33 % did not. Fifty-one percent preferred a service named "Supportive Care" rather than "Palliative Care" (MDs > midlevel providers, p < 0.001), and 32 % felt that patient expectations for ongoing therapy hindered their ability to make PC referrals. Female gender, formal training in neuro-oncology and PC, and medical versus surgical neuro-oncology training were significantly associated with hospice referral, comfort in dealing with end-of-life issues, and ease of access to PC services. Provider level, specialty, gender, training in PC and neuro-oncology have significant impact on the utilization of PC and hospice in neuro-oncology. PMID- 26518540 TI - Prospective evaluation of serum glial fibrillary acidic protein (GFAP) as a diagnostic marker for glioblastoma. AB - Glioblastoma (GBM) is the most common malignant primary brain tumor. Although clinical presentation and brain imaging might be suggestive, histopathological evaluation by means of a brain biopsy is routinely performed to establish the diagnosis. A serum marker indicative of GBM may simplify the diagnostic work-up of patients suspected to having a brain tumor. We prospectively examined 113 patients with newly diagnosed single supratentorial or infratentorial space occupying brain lesions. Glial fibrillary acidic protein (GFAP) levels were determined from venous blood samples via a prototype ELISA assay prior to any invasive procedures. Serum levels of GFAP were correlated with histopathological findings and MRI parameters. GFAP values were significantly higher in GBM patients (n = 33) compared to all other tumors (p < 0.001). A GFAP serum concentration of >=0.01 ug/L revealed a sensitivity of 85 % and a specificity of 70 % for differentiating GBM from other entities. By applying a GFAP cut-off point of 0.20 ug/L, specificity was maximized (99 %), but sensitivity dropped to 27 %. In GBM patients, serum GFAP values were significantly correlated with tumor volume. GBM patients with high GFAP levels showed more in vivo GFAP expression as well as more necrosis and perilesional edema compared to GBM patients having low or non-detectable GFAP levels. GFAP serum concentrations differentiated between patients with GBM and patients with cerebral mass lesions of other entities with a moderate diagnostic accuracy. Serum GFAP levels in GBM patients were positively correlated with tumor volume and histopathological tumor characteristics. PMID- 26518541 TI - Prognostic value of combined visualization of MR diffusion and perfusion maps in glioblastoma. AB - We analyzed whether the combined visualization of decreased apparent diffusion coefficient (ADC) values and increased cerebral blood volume (CBV) in perfusion imaging can identify prognosis-related growth patterns in patients with newly diagnosed glioblastoma. Sixty-five consecutive patients were examined with diffusion and dynamic susceptibility-weighted contrast-enhanced perfusion weighted MRI. ADC and CBV maps were co-registered on the T1-w image and a region of interest (ROI) was manually delineated encompassing the enhancing lesion. Within this ROI pixels with ADC values the 70th percentile (CBVmax) and the intersection of pixels with ADCmin and CBVmax were automatically calculated and visualized. Initially, all tumors with a mean intersection greater than the upper quartile of the normally distributed mean intersection of all patients were subsumed to the first growth pattern termed big intersection (BI). Subsequently, the remaining tumors' growth patterns were categorized depending on the qualitative representation of ADCmin, CBVmax and their intersection. Log-rank test exposed a significantly longer overall survival of BI (n = 16) compared to non-BI group (n = 49) (p = 0.0057). Thirty-one, four and 14 patients of the non-BI group were classified as predominant ADC-, CBV- and mixed growth group, respectively. In a multivariate Cox regression model, the BI-, CBV- and mixed groups had significantly lower adjusted hazard ratios (p-value, alpha(Bonferroni) < 0.006) when compared to the reference group ADC: 0.29 (0.0027), 0.11 (0.038) and 0.33 (0.0059). Our study provides evidence that the combination of diffusion and perfusion imaging allows visualization of different glioblastoma growth patterns that are associated with prognosis. A possible biological hypothesis for this finding could be the interpretation of the ADCmin fraction as the invasion-front of tumor cells while the CBVmax fraction might represent the vascular rich tumor border that is "trailing behind" the invasion-front in the ADC group. PMID- 26518542 TI - Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors. AB - Chemotherapies active in preclinical studies frequently fail in the clinic due to lack of efficacy, which limits progress for rare cancers since only small numbers of patients are available for clinical trials. Thus, a preclinical drug development pipeline was developed to prioritize potentially active regimens for pediatric brain tumors spanning from in vitro drug screening, through intracranial and intra-tumoral pharmacokinetics to in vivo efficacy studies. Here, as an example of the pipeline, data are presented for the combination of 5 fluoro-2'-deoxycytidine and tetrahydrouridine in three pediatric brain tumor models. The in vitro activity of nine novel therapies was tested against tumor spheres derived from faithful mouse models of Group 3 medulloblastoma, ependymoma, and choroid plexus carcinoma. Agents with the greatest in vitro potency were then subjected to a comprehensive series of in vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies culminating in preclinical efficacy trials in mice harboring brain tumors. The nucleoside analog 5-fluoro-2'-deoxycytidine (FdCyd) markedly reduced the proliferation in vitro of all three brain tumor cell types at nanomolar concentrations. Detailed intracranial PK studies confirmed that systemically administered FdCyd exceeded concentrations in brain tumors necessary to inhibit tumor cell proliferation, but no tumor displayed a significant in vivo therapeutic response. Despite promising in vitro activity and in vivo PK properties, FdCyd is unlikely to be an effective treatment of pediatric brain tumors, and therefore was deprioritized for the clinic. Our comprehensive and integrated preclinical drug development pipeline should reduce the attrition of drugs in clinical trials. PMID- 26518544 TI - A new approach to the study of impedance characteristics of tympanic membrane. AB - A new approach to studying the tympanic membrane impedance characteristics, based on the analysis of polyharmonic acoustic signals reflected by the tympanic membrane, is described. For this purpose, the acoustic pressure and the phase difference between the acoustic vibrations in two sections of a waveguide sealingly connecting the external auditory meatus and a generator of polyharmonic audio signals is measured. By processing the results of measurements, the estimates of the frequency-dependent reflection coefficients, absorption coefficients, and components of the acoustic impedance of the tympanic membrane are calculated. The features that principally distinguish the developed approach from other approaches are the absence of the necessity to create a positive pressure in the external auditory meatus, the absence of ultrasonic radiation into the external auditory meatus and a high-intensity sound, and the possibility of direct measurement of the tympanic membrane impedance in the audio frequency range with any step. PMID- 26518543 TI - Somatic cell transfer of c-Myc and Bcl-2 induces large-cell anaplastic medulloblastomas in mice. AB - A highly aggressive subgroup of the pediatric brain tumor medulloblastoma is characterized by overexpression of the proto-oncogene c-Myc, which encodes a transcription factor that normally maintains neural progenitor cells in an undifferentiated, proliferating state during embryonic development. Myc-driven medulloblastomas typically show a large-cell anaplastic (LCA) histological pattern, in which tumor cells display large, round nuclei with prominent nucleoli. This subgroup of medulloblastoma is therapeutically challenging because it is associated with a high rate of metastatic dissemination, which is a powerful predictor of short patient survival times. Genetically engineered mouse models have revealed important insights into the pathogenesis of medulloblastoma and served as preclinical testing platforms for new therapies. Here we report a new mouse model of Myc-driven medulloblastoma, in which tumors arise in situ after retroviral transfer and expression of Myc in Nestin-expressing neural progenitor cells in the cerebella of newborn mice. Tumor induction required concomitant loss of Tp53 or overexpression of the antiapoptotic protein Bcl-2. Like Myc-driven medulloblastomas in humans, the tumors induced in mice by Myc + Bcl-2 and Myc - Tp53 showed LCA cytoarchitecture and a high rate of metastatic dissemination to the spine. The fact that Myc - Tp53 tumors arose only in Tp53(-/ ) mice, coupled with the inefficient germline transmission of the Tp53-null allele, made retroviral transfer of Myc + Bcl-2 a more practical method for generating LCA medulloblastomas. The high rate of spinal metastasis (87% of brain tumor-bearing mice) will be an asset for testing new therapies that target the most lethal aspect of medulloblastoma. PMID- 26518545 TI - Synaptosome-associated protein 25 (SNAP25) synthesis in terminal buttons of mouse motor neuron. AB - Previously, we formulated the hypothesis of compartmentalized protein synthesis in axons of motor neurons. In the axon hillock, along the entire length of the axon and in its ending, specific proteins are locally synthesized, which ensure the function of each compartment. In support of this hypothesis, in this work we studied the local protein synthesis in mouse motor nerve ending. PMID- 26518546 TI - Electrosynthesis and binding properties of molecularly imprinted poly-o phenylenediamine as artificial antibodies for electroanalysis of myoglobin. AB - Molecularly imprinted poly-o-phenylenediamine with template myoglobin molecules (i.e., polymeric antibodies to myoglobin, molecularly imprinted polymer, MIP) was synthesized via electropolymerization. Electropolymerization, washing, and the interaction of the polymeric antibodies with myoglobin was examined by square wave voltammetry and microgravimetry. The analysis of myoglobin was carried out through direct electrochemical detection of the reduction peak of Fe(3+) of the hemeprotein on screen-printed graphite electrodes modified by the MIP. According to the electrochemical analysis, MIP surfaces demonstrated remarkably higher ability to bind the protein compared to that of surfaces prepared by the same route under the same conditions but in the absence of myoglobin (surfaces of the non-imprinted polymer, NIP). The imprinting factor I max(MIP)/I max(NIP) was found to be 2-4. The equilibrium dissociation constant K d of the interaction of myoglobin with MIP electrodes was evaluated as (2.4 +/- 0.5) * 10(-8) M. The lower detection limit of myoglobin by a MIP sensor was determined as 0.5 * 10(-9) M, the range of detectable concentrations being 10(-9)-10(-5) M. PMID- 26518547 TI - Involvement of the Arp2/3 complex and WASP proteins in the effect of glutoxim and molixan on intracellular Ca(2+) concentration in macrophages. AB - The Fura-2AM fluorescent Ca(2+) probe was used to study the possibility that the Arp2/3 complex and WASP proteins are involved in the effects of glutoxim and molixan on the intracellular Ca(2+) concentration in macrophages. It has been demonstrated that preincubation of macrophages with inhibitors of the Arp2/3 complex or WASP proteins (CK-0944666 or wiskostatin, respectively) results in a significant suppression of Ca(2+)-responses induced by glutoxim or molixan. This suggests that polymerization of actin filaments is a process involved in the effect of glutoxim or molixan on intracellular Ca(2+) concentration in macrophages. PMID- 26518548 TI - The expression of R genes in genetic and induced resistance to potato cyst nematode Globodera rostochiensis (Wollenweber, 1923) Behrens, 1975. AB - The characteristics of expression of two genes, H1 and Gro1-4, which determine the resistance to the sedentary parasitic nematode Globodera rostochiensis (Wollenweber, 1923) Behrens, 1975, in the resistant (Krepysh) and susceptible (Nevskii) potato cultivars was studied under a short-term exposure to low temperatures. Such treatment of susceptible plants at the early stages of ontogeny led to the activation of expression of H1 and Gro1-4 genes in roots and the H1 gene in leaves. The transcriptional activity of R genes was detected not only in roots but also in leaves (i.e., in tissue remote from the site of direct injury by the nematode) in the case of both genetic and induced resistance, indicating the development of a systemic defense response of plants to infection. PMID- 26518549 TI - Longitudinal orientation of cross-linked polypeptide gamma chains in fibrin fibrils. AB - The crosslinking of fibrin gamma-polypeptide chains under the influence of the plasma fibrin-stabilizing factor (FXIIIa), which causes their conversion to gamma gamma dimers, is the major enzyme reaction of covalent fibrin stabilization. We studied the self-assembly of soluble cross-linked fibrin oligomers. The results of analytical ultracentrifugation as well as elastic and dynamic light scattering showed that the double-stranded fibrin oligomers formed under the influence of moderate concentrations of urea are cross-linked only due to formation of gamma gamma dimers, which can dissociate into single-stranded structure when the concentration of urea increases. This fact proves that gamma-gamma dimers are formed in the end-to-end manner. PMID- 26518550 TI - The first dipeptide ligand of translocator protein: Design and anxiolytic activity. AB - On the basis of the structure of Alpidem, a pyrazolopyrimidine ligand of the translocator protein (TSPO), a dipeptide TSPO ligand, N-carbobenzoxy-L tryptophanyl-L-isoleucine amide (GD-23), was designed and synthesized using our own original peptide design strategy. This compound exhibited anxiolytic activity in BALB/cAnN mice in the "open-field" test and in outbred CD1 mice in the "elevated plus maze" test. The stereoselectivity of the anxiolytic effect of GD 23 is demonstrated. The results of this study suggest that GD-23 is a ligand of the translocator protein, and its structure can become the basis for creating anxiolytics with a fundamentally new mechanism of action. PMID- 26518551 TI - Nonconventional three-finger toxin BMLCL from krait Bungarus multicinctus venom with high affinity interacts with nicotinic acetylcholine receptors. AB - Nonconventional three-finger toxin BMLCL was isolated from B. multicinctus venom, and its interaction with different subtypes of nicotinic acetylcholine receptor (nAChR) was studied. It was found that BMLCL is able to interact with high efficiency with both alpha7 and muscle type nAChRs. PMID- 26518552 TI - Characteristics of oxygen transport through the surface of the isolated perfused rat liver. AB - It is shown that the transport of oxygen through the surface of the isolated perfused rat liver is an energy-dependent process that requires the energy of ATP hydrolysis. PMID- 26518553 TI - Proteolysis of His-Phe-Arg-Trp-Pro-Gly-Pro in the blood and brain of rats in vivo. AB - The kinetics of the content of His-Phe-Arg-Trp-Pro-Gly-Pro (ACTH (6-9)PGP) and its hydrolysis products in the blood and brain of rats in the case of intranasal administration and intravenous injection of tritiated ACTH(6-9)PGP was studied. The parameters of bioavailability of ACTH(6-9)PGP administered intranasally were higher, indicating certain prospects in the intranasal application in clinical practice. We also found that the factor that determines ACTH(6-9)PGP proteolysis in experiments both in vivo and in vitro is aminopeptidases. The main products of ACTH(6-9)PGP during its metabolism in rats are short peptides and amino acids. PMID- 26518554 TI - The use of artificial transcription terminators for creating transgenic plants with high-level expression of reporter gene. AB - In this study, we investigated the possibility of increasing the level of transgene expression using DNA element that can terminate transcription. PMID- 26518555 TI - Changes in plasma catecholamines levels as preclinical biomarkers in experimental models of Parkinson's disease. AB - The goal of this study was to investigate the changes in the concentrations of blood plasma catecholamines as possible biomarkers of Parkinson's disease (PD) in the mouse experimental model of PD induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). A significant decrease was detected in the levels of dopamine and L-DOPA in the PD preclinical stage model as a result of the catecholamines systemic metabolism disfunction. In the PD early clinical stage models, the level of L-DOPA and dihydroxyphenylacetic acid decreased, which is consistent with the results of blood tests in untreated patients. PMID- 26518556 TI - Nuclear localization of translocation partners in differentiating B-cells. AB - We studied the nuclear localization and relative position in the nuclear space of malignant translocation partner genes c-Myc, CCND1, and IGH locus in naive and differentiating B cells. We have shown that, during B-cell maturation, c-Myc and IGH loci become closer to each other. In differentiating lymphocytes, those alleles of c-Myc and IGH that are in close spatial proximity to each other are closer to the nucleolus. For the CCND1 locus, no correlation between the proximity of loci and nuclear localization was found. These data suggest that the close spatial proximity of c-Myc and IGH loci during B-cell maturation increase the probability of malignant translocation. PMID- 26518557 TI - A comprehensive study of interactions between lectins and glycoproteins for the development of effective theranostic nanoagents. AB - A comprehensive study of the interactions between lectins and glycoproteins possessing different glycosylation profiles in the composition of nanoparticles was carried out in order to find specifically interacting protein pairs for the creation of novel classes of multifunctional nanoagets that based on protein assisted selfassembly. We obtained information about specific interactions of certain lectins with selected glycoproteins as well as about the ability of certain monosaccharides to competitively inhibit binding of glycoproteins with lectins. These protein-mediated interactions may be involved in the formulation of self-assembled nanoparticles for therapy and diagnostics of various diseases. PMID- 26518558 TI - Mathematical justification of the acoustic method for measuring the impedance of the respiratory tract. AB - A new method for measuring a complex frequency-dependent acoustic impedance of the respiratory tract based on two-microphone method was developed. The measuring device consists of a waveguide connected through a mouthpiece to the patient's mouth. A sound field with a frequency range from 5 to 100 Hz is created in the waveguide. The impedance of the respiratory tract is determined at free respiration of the patient in the set frequency range; the duration of examination does not exceed 15 s. The criteria for the recognition of respiratory tract pathologies are proposed. PMID- 26518559 TI - Novel bivalent positive allosteric modulators of AMPA receptor. AB - A positive allosteric modulator of AMPA receptors has been designed using computer-aided molecular modeling techniques. It possessed a record high experimentally confirmed potency in the picomolar concentration range and belongs to a new type of bivalent AMPA receptor ligands containing bicyclo[3.3.1]nonane scaffold. The suggested structure could serve as a basis for further optimization and development of drugs for the treatment of neurodegenerative diseases, cognition enhancement, and improvement of memory. PMID- 26518560 TI - Electroanalysis of Shewanella oneidensis MR-1. AB - Electrochemical parameters of bacterial cells Shewanella oneidensis MR-1 were investigated. For registration of the direct electron transfer between S. oneidensis MR-1 and electrode, bacterial cells were pretreated with didodecyldimethylammonium bromide (DDAB), a synthetic membrane-like substance of polycationic nature that exhibits membrane-loosening properties. Such pretreatment of S. oneidensis MR-1 allowed increasing the efficiency of extracellular electron transfer by the proteobacterium due to better availability of electroactive proteins for registration of electron transfer processes. The electroanalysis of bacterial cells S. oneidensis MR-1 under anaerobic conditions allows registering redox-active proteins and biomolecules in the range of potentials of-0.40,-0.16, and-0 V, which corresponds to flavohemoproteins, quinone derivatives, and c-type cytochromes of the external membrane of S. oneidensis MR-1 cells. PMID- 26518561 TI - DNA methylation of genes of the main components of the telomerase complex in Danio rerio. AB - The methylation status of the genes of telomerase reverse transcriptase (tert) and telomerase RNA (terc) was determined in brain tissues of Danio rerio of different age. It is found that, regardless of the age of fish, the regulatory region of the tert gene was completely methylated, whereas the coding region remained unmethylated in all cases. The level of methylation of the region located downstream of the coding region of the terc gene changes with age. This region was analyzed in the samples of other tissues, and its methylation status was also nonuniform. The alteration of the methylation status in the 3' untranslated region of the terc gene suggests the possibility of transcription of the antisense strand in this region. PMID- 26518562 TI - Doxorubicin causes transient activation of protein poly(ADP-ribosyl)ation in H9c2 cardiomyocytes. AB - Possible involvement of the system of protein poly(ADP-ribosyl)ation in the mechanisms of cardiotoxicity of doxorubicin, one of the most frequently used anticancer drug, was studied in cultures of cardiomyocytes H9c2. The treatment of H9c2 cells with doxorubicin (1 uM) led to a transient (after 6 h of incubation) increase in the nuclear level of poly(ADP-ribosyl)ated proteins. The observed data indirectly indicate the development of genotoxic stress in the doxorubicin treated cells, probably caused by the stimulatory effects of doxorubicin and its metabolites on the production of reactive oxygen and nitrogen species. PMID- 26518563 TI - Creation and study of triterpenoid nanoparticles and radioprotective substance genistein. AB - This work is devoted to the study and obtaining of new radioprotective agents based on natural flavonoid genistein and spherical amorphous nanoparticles (SANPs) produced from a mixture of birch bark triterpenoids. The physicochemical characteristics of the nanoparticles were studied by electron microscopy, dynamic light scattering, and UV-VIS spectroscopy. The radioprotective efficacy of the nanodrug in vivo and the possibility of its use as a radioprotective agent was shown. PMID- 26518564 TI - Effect of SkQ1 eye drops on the rat lens metabolomic composition and the chaperone activity of alpha-crystallin. AB - The ability of SkQ1 eye drops to slow down the cataract development is demonstrated on the senescence-accelerated OXYS rats: the SkQ1 treatment leads to the considerable improvement of the lens condition as compared to the control group. The comparison of the chaperone activities of alpha-crystallins isolated from the rat lenses did not reveal significant difference between SkQ1-treated and control rats. The contents of major metabolites (23 compounds) in lenses of SkQ1-treated and untreated rats are also very similar, though the concentration of reduced glutathione (GSH) in lenses of SkQ1-treated rats is 12% lower. This difference may be attributed to the reduction of the oxidative stress under action of SkQ1 eye drops, and to the decreased requirement to produce high amounts of this antioxidant. PMID- 26518565 TI - Structural basis for inhibition of the Tob-CNOT7 interaction by a fragment screening approach. PMID- 26518566 TI - Lymphopenia as prognostic factor for mortality and hospital length of stay for elderly hospitalized patients. AB - BACKGROUND: Lymphopenia is a common finding in elderly patients and its relevance is unknown. AIMS: To evaluate the clinical prognostic value of lymphopenia on the admission of elderly hospitalized patients. METHODS: From 2012 to 2013, all consecutive patients >75 hospitalized because of medical conditions were prospectively included in the study. Sociodemographic, clinical and laboratory data were collected. Lymphopenia was considered by a plasmatic lymphocyte count of <1100 * 10(9)/l. Hospital length of stay, in-hospital mortality and mortality after a 1-year follow-up were assessed. RESULTS: The total sample consisted of 180 patients, 90 of whom were females (50 %). Mean age was 83.8 years (SD 5.4). Lymphopenia was present in 45 patients (25 %) upon admission. When compared, those patients with lymphopenia showed a longer hospital stay (19.9 vs. 15.7 days; p 0.002) and higher in-hospital mortality (26.7 vs 7.7 %; p 0.001). The odds ratio for in-hospital mortality in patients with lymphopenia was 3.9 (p 0.03) and the hazard ratio for 1-year mortality 1.9 (p 0.038). Both groups of elderly patients, with and without lymphopenia on admission, showed no differences related to sociodemographic, clinical, or other laboratory data. The study showed no difference in rate of infections between the groups. CONCLUSION: A quarter of our elderly hospitalized patients had lymphopenia on admission. Furthermore, lymphopenia seemed to constitute as a predictor for bad outcome in terms of a longer hospital stay, in-hospital mortality and 1-year mortality after discharge. PMID- 26518567 TI - Acute abdominal compartment syndrome: current diagnostic and therapeutic options. AB - BACKGROUND: If untreated, the abdominal compartment syndrome (ACS) has a mortality of nearly 100 %. Thus, its early recognition is of major importance for daily rounds on surgical intensive care units. Intraabdominal hypertension (IAH) is a poorly recognized entity, which occurs if intraabdominal pressure arises >12 mmHg. Measurement of the intravesical pressure is the gold standard to diagnose IAH, which can be detected in about one fourth of surgical intensive care patients. PURPOSE: The aim of this manuscript is to outline the current diagnostic and therapeutic options for IAH and ACS. While diagnosis of IAH and ACS strongly depends on clinical experience, new diagnostic markers could play an important role in the future. Therapy of IAH/ACS consists of five treatment "columns": intraluminal evacuation, intraabdominal evacuation, improvement of abdominal wall compliance, fluid management, and improved organ perfusion. If conservative therapy fails, emergency laparotomy is the most effective therapeutic approach to achieve abdominal decompression. Thereafter, patients with an open abdomen require intensive care and are permanently threatened by the quadrangle of fluid loss, muscle proteolysis, heat loss, and an impaired immune function. As a consequence, complication rate dramatically increases after 8 days of open abdomen therapy. CONCLUSION: Despite many efforts, the mortality of patients with ACS remains unacceptably high. Permanent clinical education and surgical trials will be necessary to improve the outcome of our critically ill surgical patients. PMID- 26518568 TI - Is it possible to define early distal cholangiocarcinoma? AB - PURPOSE: The feasibility of defining early cholangiocarcinoma has not been adequately evaluated. The surgical outcomes of patients who had undergone pancreatoduodenectomy (PD) for pathological T1 (pT1) distal cholangiocarcinoma (DCC) were evaluated to determine whether it is possible to define early DCC. METHODS: The clinicopathological data of 18 patients with pT1 DCC who had undergone PD were reviewed retrospectively. Depth of fibromuscular (fm) layer invasion was divided into two categories: fm1 and fm2 (without adventitia fascia invasion and with adventitia fascia invasion). Comparative analyses were performed according to the depth of invasion. RESULTS: Disease-specific survival rates of patients with five mucosal tumors and 13 fm-invasive tumors were 80 and 61.9 % at 5 years and 80 and 41.2 % at 10 years, respectively. There was no significant difference in disease-specific survival rates between the two groups (P = 0.244). Disease-specific survival rates of patients with 7 fm1-invasive tumors and 6 fm2-invasive tumors were 85.7 and 40 % at 5 years and 85.7 and 0 % at 10 years. A significant difference in disease-specific survival rates was observed between mucosal tumors and fm2-invasive tumors (P = 0.043), and disease specific survival rates of mucosal tumors and fm1-invasive tumors were similar (P = 0.968). CONCLUSIONS: Defining early DCC as carcinoma confined to the fm of the bile duct might be inappropriate; early DCC should be limited to the mucosal carcinoma. PMID- 26518569 TI - A Philosophical vs. a Psychological Perspective on Borders. AB - This paper questions to what extent borders are to be understood from a philosophical or a psychological perspective. This is done by investigating the distinction between philosophy and psychology that comes up as a result of Immanuel Kant's investigation of the pure reason. Ontology is found as a demarcation criterion between the two fields in the sense that it is of crucial importance in philosophy, but not of certain interest from a psychological point of view. An investigation of three assumptions in the perspective of affective loading follows this up, which confirms the efficiency of borders in psychological meaning production. PMID- 26518570 TI - Genome-wide association study, genomic prediction and marker-assisted selection for seed weight in soybean (Glycine max). AB - KEY MESSAGE: Twenty-two loci for soybean SW and candidate genes conditioning seed development were identified; and prediction accuracies of GS and MAS were estimated through cross-validation and validation with unrelated populations. Soybean (Glycine max) is a major crop for plant protein and oil production, and seed weight (SW) is important for yield and quality in food/vegetable uses of soybean. However, our knowledge of genes controlling SW remains limited. To better understand the molecular mechanism underlying the trait and explore marker based breeding approaches, we conducted a genome-wide association study in a population of 309 soybean germplasm accessions using 31,045 single nucleotide polymorphisms (SNPs), and estimated the prediction accuracy of genomic selection (GS) and marker-assisted selection (MAS) for SW. Twenty-two loci of minor effect associated with SW were identified, including hotspots on Gm04 and Gm19. The mixed model containing these loci explained 83.4% of phenotypic variation. Candidate genes with Arabidopsis orthologs conditioning SW were also proposed. The prediction accuracies of GS and MAS by cross-validation were 0.75-0.87 and 0.62-0.75, respectively, depending on the number of SNPs used and the size of training population. GS also outperformed MAS when the validation was performed using unrelated panels across a wide range of maturities, with an average prediction accuracy of 0.74 versus 0.53. This study convincingly demonstrated that soybean SW is controlled by numerous minor-effect loci. It greatly enhances our understanding of the genetic basis of SW in soybean and facilitates the identification of genes controlling the trait. It also suggests that GS holds promise for accelerating soybean breeding progress. The results are helpful for genetic improvement and genomic prediction of yield in soybean. PMID- 26518571 TI - Genetic variation and inheritance of phytosterol and oil content in a doubled haploid population derived from the winter oilseed rape Sansibar * Oase cross. AB - KEY MESSAGE: Identification of QTL for phytosterol content, oil content, fatty acids content, protein content of defatted meal, and seed weight by multiple interval mapping in a Brassica napus DH population. Phytosterols are minor seed constituents in oilseed rape which have recently drawn wide-interest from the food and nutrition industry due to their health benefit in lowering LDL cholesterol in humans. To understand the genetic basis of phytosterol content and its relationship with other seed quality traits in oilseed rape, QTL mapping was performed in a segregating DH population derived from the cross of two winter oilseed rape varieties, Sansibar and Oase, termed SODH population. Both parental lines are of canola quality which differ in phytosterol and oil content in seed. A genetic map was constructed for SODH population based on a total of 1638 markers organized in 23 linkage groups and covering a map length of 2350 cM with a mean marker interval of 2.0 cM. The SODH population and the parental lines were cultivated at six environments in Europe and were phenotyped for phytosterol content, oil content, fatty acids content, protein content of the defatted meal, and seed weight. Multiple interval mapping identified between one and six QTL for nine phytosterol traits, between two and six QTL for four fatty acids, five QTL for oil content, four QTL for protein content of defatted meal, and three QTL for seed weight. Colocalizations of QTL for different traits were more frequently observed than individual isolated QTL. Major QTL (R (2) >= 25%) were all located in the A genome, and the possible candidate genes were investigated by physical localization of the QTL to the reference genome sequence of Brassica rapa. PMID- 26518572 TI - Identification of environmentally stable QTL for resistance against Leptosphaeria maculans in oilseed rape (Brassica napus). AB - KEY MESSAGE: Six stable QTL for resistance against L. maculans (phoma stem canker) have been identified by QTL * environment interaction analysis using data from five winter oilseed rape field experiments. Phoma stem canker, caused by Leptosphaeria maculans, is a disease of worldwide importance on oilseed rape (Brassica napus). Quantitative trait loci (QTL)-mediated resistance against L. maculans in B. napus is considered to be race non-specific and potentially durable. Identification and evaluation of QTL for resistance to L. maculans is important for breeding oilseed rape cultivars with durable resistance. An oilseed rape mapping population was used to detect QTL for resistance against L. maculans in five winter oilseed rape field experiments under different environments. A total of 17 QTL involved in 'field' quantitative resistance against L. maculans were detected and collectively explained 51% of the phenotypic variation. The number of QTL detected in each experiment ranged from two to nine and individual QTL explained 2-25% of the phenotypic variation. QTL * environment interaction analysis suggested that six of these QTL were less sensitive to environmental factors, so they were considered to be stable QTL. Markers linked to these stable QTL will be valuable for selection to breed for effective resistance against L. maculans in different environments, which will contribute to sustainable management of the disease. PMID- 26518573 TI - Effector-driven marker development and cloning of resistance genes against Phytophthora infestans in potato breeding clone SW93-1015. AB - KEY MESSAGE: We show the usefulness of integrating effector screening in a breeding program and in resistance gene cloning, with Phytophthora resistance in the Swedish potato breeding clone SW93-1015 as an example. Phytophthora infestans is one of the most devastating plant pathogens worldwide. We have earlier found that the SW93-1015 potato breeding clone has an efficient resistance against P. infestans under field conditions in Sweden, which has an unusually high local diversity of the pathogen. This potato clone has characteristics that are different from classical R-gene-mediated resistance such as elevated levels of hydrogen peroxide (H2O2) under controlled conditions. Analysis of 76 F1 potato progenies from two individual crosses resulted in nearly 50% resistant clones, from both crosses. This result suggests that the SW93-1015 clone has a simplex genotype for this trait. Screening with over 50 different P. infestans effectors, containing the conserved motif RXLR (for Arg, any amino acid, Leu, Arg), revealed a specific response to Avr2, which suggests that SW93-1015 might contain a functional homolog of the R2 resistance gene. We cloned eight R2 gene homologs from SW93-1015, whereof seven have not been described before and one gene encoded a protein identical to Rpi-ABPT. Expression of this gene in potato cultivar Desiree provided R2-specific resistance, whereas other homologues did not. Using RNAseq analyses we designed a new DNA marker for the R2 resistance in SW93-1015. In summary, we have demonstrated the use of effector screening in practical breeding material and revealed the key resistance mechanism for SW93-1015. PMID- 26518575 TI - A Single Fluorescent Sensor for Hg(2+) and Discriminately Detection of Cr(3+) and Cr(VI). AB - An iminocrown ether was synthesized and its fluorescence properties were studied in the presence of a variety of cations and anions in 99 % aqueous medium. The results revealed the interesting ability of the iminocrown ether in discriminately detection of Cr(III) and Cr(VI) ions in addition to detection of Hg(2+) ion. Among various environmentally relevant metal ions, Cr(3+) and Hg(2+) enhanced and quenched the fluorescence emission, respectively and among anions only dichromate ion, Cr(VI), quenched the emission while the rest of ions insignificantly influenced the fluorescence emission. Selectivity of the iminocrown ether was also investigated and proved in the presence of excess of common competing ions. Furthermore, the fluorescence intensity of the iminocrown ether was studied as a function of concentrations of the three ions by performing a titration experiment for each one of them. The detection limits of 5.36 * 10( 8), 2.06 * 10(-6), and 7.49 * 10(-8) mol L(-1) were also calculated for Hg(2+), Cr(3+), and Cr(VI), respectively. PMID- 26518574 TI - Identification and mapping of Tril, a homeodomain-leucine zipper gene involved in multicellular trichome initiation in Cucumis sativus. AB - KEY MESSAGE: Using map-based cloning of Tril gene, we identified a homeodomain leucine zipper gene involved in the initiation of multicellular trichomes (including the spines of fruit) in cucumber. ABSTRACT: Fruit spines are a special type of trichome that impacts the quality and appearance of cucumber (Cucumis sativus L.) fruit. Scanning electron microscopy revealed that the trichome-less (tril) mutant originating from European greenhouse cucumber has a completely glabrous phenotype on cotyledons, hypocotyls, young leaves, fruits, and fruit stalks. Genetic analysis revealed that tril was inherited as a recessive allele at a single locus. Using 1058 F2 individuals derived from a cross between cucumber tril mutant CGN19839 and the micro-trichome (mict) mutant 06-2, tril was mapped to chromosome 6, and narrowed down to a 37.4 kb genomic region which carries seven predicted genes. Genetic and molecular analyses revealed that gene Cucsa.045360 is a possible candidate gene for the differentiation of epidermal cells to trichomes. It is a member of the class IV homeodomain-leucine zipper (HD Zip IV) family and encodes homeodomain and START domain, sharing 66.7% predicted amino acid sequence identity to PROTODERMAL FACTOR2 (PDF2) and 35.0% to GLABRA2 (GL2) of Arabidopsis. The homeobox domain had changed amino acid sequence because of an insertion in tril mutant. The results of genetic analysis and transcriptome profiling indicated that the Tril gene had an epistatic effect on the Mict gene in trichome development. Phenotypes of the tril mutant such as glabrous fruits and female flowers at every node could be used in developing new cultivars. PMID- 26518577 TI - Optical Properties of Some Fluorinated Poly(1,3,4-Oxadiazole-Ether)s in Homogeneous and Heterogeneous Media. Changes Induced by SnO2, NiO and SnO2/NiO Mixed-Oxide Nanoparticles. AB - Optical characteristics of some fluorinated poly(1,3,4-oxadiazole-ether)s in presence of SnO2, NiO and SnO2/NiO mixed-oxide nanoparticles (NPs) was investigated. The interactions between polymers and metal oxide NPs were studied by steady-state UV-Vis absorption and fluorescence spectroscopy techniques. The absorption and fluorescence signals of all investigated polymers was modified by presence of both pure and mixed-oxide nanoparticles. The moderate values of Stern Volmer quenching constant and non-linear trend of Scott plot indicate the less affinity between metal oxide NPs and polymers. The solvation behavior of some fluorinated poly(1,3,4-oxadiazole-ether)s in chloroform-N,N-dimethylformamide and N,N-dimethylformamide-dimethylsulfoxide mixtures was discussed. PMID- 26518576 TI - Highly Fluorescent Imidazole Probes for the Pico Molar Detection of CN(-) ion and Application in Living Cells. AB - A series of four imidazole based fluorescent receptors (R1-R4) containing two different signaling units were synthesized for the sensing of specific anions. R1 and R2 act as excellent colorimetric sensors via color change from yellow to orange and pink in presence of F (-) , AcO (-) and CN (-) ions. R1 and R2 show intramolecular charge transfer (ICT) band at 414 nm and 434 nm and were red shifted into 500 nm and 510 nm respectively, with the addition of above anions. Anion complexes of R1 and R2 were found to exhibit remarkable orange and red fluorescence under UV light which is consistent with an emission observed at 594 nm and 618 nm respectively. Likewise, quenching in the green fluorescence of R3 and R4 was found under UV light accompanied with quenching of emission at 530 nm and 541 nm. Selective colorimetric sensing of CN (-) ion is also achieved in 3 % aq. DMF medium. Intracellular uptake of CN (-) ion by R1 was achieved in living RAW 264.7 cells. Finally, practical application of R2 to detect CN (-) and F (-) ions present in aqueous solution of cassava flour and toothpaste also performed. PMID- 26518578 TI - A Rhodamine-Benzimidazole Based Chemosensor for Fe(3+) and its Application in Living Cells. AB - A rhodamine-benzimidazole based chemosensor was designed and prepared for Fe(3+) via opening of the spiro-ring to give fluorescent and colored species. L exhibited high selectivity and excellent sensitivity in both absorbance and fluorescence detection of Fe(3+) in aqueous solution with comparatively wide pH range (5.8-7.4). The detection limit of this newly developed probe was shown to be up to 2.74 MUM. The reversibility establishes the potential of both probes as chemosensors for Fe(3+) detection. Fluorescence imaging experiments of Fe(3+) in living MGC803 cells demonstrated its value of practical applications in biological systems. PMID- 26518579 TI - Cd-Cysteine Nanorods as a Fluorescence Sensor for Determination of Fe (III) in Real Samples. AB - A new Cd-Cysteine complex nanorods (Cd-Cys NRs) were synthesized in one step at room temperature, and its morphology, structure and spectral properties were characterized by transmission electron microscopy (TEM), elemental analysis (EA), X-Ray diffraction (XRD), solid state and normal UV-Vis, Fourier transform infrared (FTIR) and spectrofluorometry. The developed Cd-Cys NRs were used as a fluorescence sensor for detection of Fe (III) in different aqueous matrices. The selectivity and sensitivity of the fabricated nano-sensor based on its fluorescence quenching in the presence of Fe (III) were probed according to the Stern-Volmer equation. The detection limit of the method was in micro-molar per liter range. Cd-Cys NRs response tested in different complex samples such as Rosemary plant leaves, exhibited a well-defined response. Anticoagulation measurements were performed to evaluate their blood biocompatibility. PMID- 26518580 TI - Subclinical autism spectrum symptoms in pediatric obsessive-compulsive disorder. AB - The literature on subclinical autism spectrum (ASD) symptoms in pediatric obsessive-compulsive disorder (OCD) is scarce, and it remains unclear whether ASD symptoms are related to OCD severity. The aims of the present study were to assess the prevalence of ASD symptoms and age and sex differences in children and adolescents with OCD, and to explore the relation between ASD symptoms and OCD severity. This is the largest study of ASD symptoms in an OCD population to date, and the first directly aimed at elucidating sex and age differences in this matter. The study used baseline data from the Nordic Long-term OCD Treatment Study in which parents of 257 children and adolescents with OCD aged 7-17 completed the Autism Spectrum Screening Questionnaire. OCD severity was assessed with the Children's Yale-Brown Obsessive Compulsive Scale. Pediatric OCD patients were found to exhibit elevated rates of ASD symptoms compared to a norm group of school-age children. ASD symptoms were concentrated in a subgroup with a prevalence of 10-17 %. This subgroup was characterized by a male preponderance with a sex ratio of approximately 2.6:1, while children versus adolescents with OCD exhibited similar rates. Autism-specific social and communication difficulties were not related to OCD severity, while restricted repetitive behavior was positively related to OCD severity. The results indicate that clinicians need to be aware of ASD symptoms in children and adolescents with OCD since one out of ten exhibits such symptoms at a clinical sub-threshold. PMID- 26518581 TI - Neonatal Ureaplasma urealyticum colonization increases pulmonary and cerebral morbidity despite treatment with macrolide antibiotics. AB - OBJECTIVE: To evaluate the influence of Ureaplasma urealyticum (UU) colonization on neonatal pulmonary and cerebral morbidity. METHODS: Single-center case-control study including all preterm infants with positive UU tracheal colonization between 1990 and 2012. Cases were matched with controls by birth year, gestational age, birth weight, and sex. All cases had received macrolide antibiotics for UU infection starting at the time of first positive culture results from tracheal aspirates. Main outcome parameters included presence and severity of hyaline membrane disease (IRDS), duration of ventilation, bronchopulmonary dysplasia at 36 postmenstrual age and neurological morbidities (seizures, intra-/periventricular hemorrhages-I/PVH, periventricular leukomalacia PVL). RESULTS: Of 74 cases identified 8 died and 4 had to be excluded; thus, 62 preterm infants were compared to 62 matched controls. UU was significantly associated with IRDS (79 vs. 61 %, p = 0.015), BPD (24 vs. 6 %, p = 0.003), seizures (23 vs. 5 %, p = 0.002) and I/PVH (45 vs. 24 %, p = 0.028). Cases had longer duration of mechanical ventilation and total duration of invasive and non invasive ventilation (median 11 vs. 6 days p = 0.006 and 25 vs. 16.5 days p = 0.019, respectively). CONCLUSION: UU was found to be significantly associated with pulmonary short- and long-term morbidity and mild cerebral impairment despite treatment with macrolide antibiotics. PMID- 26518582 TI - MRI and diffusion-weighted MRI to diagnose a local tumour regrowth during long term follow-up of rectal cancer patients treated with organ preservation after chemoradiotherapy. AB - OBJECTIVES: To assess the value of MRI and diffusion-weighted imaging (DWI) for diagnosing local tumour regrowth during follow-up of organ preservation treatment after chemoradiotherapy for rectal cancer. METHODS: Seventy-two patients underwent organ preservation treatment (chemoradiotherapy + transanal endoscopic microsurgery or "wait-and-see") and were followed with MRI including DWI (1.5 T) every 3 -months during the first year and 6 months during following years. Two readers scored each MRI for local regrowth using a confidence level, first on standard MRI, then on standard MRI+DWI. Histology and clinical follow-up were the standard reference. Receiver operating characteristic curves were constructed and areas under the curve (AUC) and corresponding accuracy figures calculated on a per-scan basis. RESULTS: Four hundred and forty MRIs were assessed. Twelve patients developed local regrowth. AUC/sensitivity/specificity for standard MRI were 0.95/58 %/98 % (R1) and 0.96/58 % /100 % (R2). For standard MRI+DWI, these numbers were 0.86/75 %/97 % (R1) and 0.98/75 %/100 % (R2). After adding DWI, the number of equivocal scores decreased from 22 to 7 (R1) and from 40 to 20 (R2). CONCLUSIONS: Although there was no overall improvement in diagnostic performance in terms of AUC, adding DWI improved the sensitivity of MRI for diagnosing local tumour regrowth and lowered the rate of equivocal MRIs. KEY POINTS: * DWI improves sensitivity for detecting local tumour regrowth after organ preservation treatment. * In particular, DWI can aid in detecting small local recurrence. * DWI reduces the number of equivocal scores. PMID- 26518583 TI - CT following US for possible appendicitis: anatomic coverage. AB - OBJECTIVE: To determine superior-inferior anatomic borders for CT following inconclusive/nondiagnostic US for possible appendicitis. METHODS: Ninety-nine patients with possible appendicitis and inconclusive/nondiagnostic US followed by CT were included in this retrospective study. Two radiologists reviewed CT images and determined superior-inferior anatomic borders required to diagnose or exclude appendicitis and diagnose alternative causes. This "targeted" coverage was used to estimate potential reduction in anatomic coverage compared to standard abdominal/pelvic CT. RESULTS: The study group included 83 women and 16 men; mean age 32 (median, 29; range 18-73) years. Final diagnoses were: nonspecific abdominal pain 50/99 (51%), appendicitis 26/99 (26%), gynaecological 12/99 (12%), gastrointestinal 9/99 (10%), and musculoskeletal 2/99 (2%). Median dose-length product for standard CT was 890.0 (range, 306.3 - 2493.9) mGy.cm. To confidently diagnose/exclude appendicitis or identify alternative diagnoses, maximum superior inferior anatomic CT coverage was the superior border of L2-superior border of pubic symphysis, for both reviewers. Targeted CT would reduce anatomic coverage by 30-55% (mean 39%, median 40%) compared to standard CT. CONCLUSIONS: When CT is performed for appendicitis following inconclusive/nondiagnostic US, targeted CT from the superior border of L2-superior border of pubic symphysis can be used resulting in significant reduction in exposure to ionizing radiation compared to standard CT. KEY POINTS: * When CT is used following inconclusive/ nondiagnostic ultrasound, anatomic coverage can be reduced. * CT from L2 to pubic symphysis can be used to diagnose/exclude appendicitis. * Reduced anatomic coverage for CT results in reduced exposure to ionizing radiation. PMID- 26518584 TI - Extracorporeal decarboxylation in patients with severe traumatic brain injury and ARDS enables effective control of intracranial pressure. AB - INTRODUCTION: Acute respiratory distress syndrome (ARDS) with concomitant impairment of oxygenation and decarboxylation represents a complex problem in patients with increased intracranial pressure (ICP). Permissive hypercapnia is not an option to obtain and maintain lung-protective ventilation in the presence of elevated ICP. Pumpless extracorporeal lung assist (pECLA) devices (iLA Membrane Ventilator; Novalung, Heilbronn, Germany) can improve decarboxylation without aggravation associated with invasive ventilation. In this pilot series, we analyzed the safety and efficacy of pECLA in patients with ARDS and elevated ICP after severe traumatic brain injury (TBI). METHODS: The medical records of ten patients (eight male, two female) with severe ARDS and severe TBI concurrently managed with external ventricular drainage in the neurointensive care unit (NICU) were retrospectively analyzed. The effect of pECLA on enabling lung-protective ventilation was evaluated using the difference between plateau pressure and positive end-expiratory pressure, defined as driving pressure (DeltaP), during the 3 days preceding the implant of pECLA devices until 3 days afterward. The ICP threshold was set at 20 mmHg. To evaluate effects on ICP, the volume of daily cerebrospinal fluid (CSF) drainage needed to maintain the set ICP threshold was compared pre- and postimplant. RESULTS: The DeltaP values after pECLA implantation decreased from a mean 17.1 +/- 0.7 cm/H2O to 11.9+/-0.5 cm/H2O (p = 0.011). In spite of this improved lung-protective ventilation, carbon dioxide pressure decreased from 46.6 +/- 3.9 mmHg to 39.7 +/- 3.5 mmHg (p = 0.005). The volume of daily CSF drainage needed to maintain ICP at 20 mmHg decreased significantly from 141.5 +/- 103.5 ml to 62.2 +/- 68.1 ml (p = 0.037). CONCLUSIONS: For selected patients with concomitant severe TBI and ARDS, the application of pECLA is safe and effective. pECLA devices improve decarboxylation, thus enabling lung-protective ventilation. At the same time, potentially detrimental hypercapnia that may increase ICP is avoided. Larger prospective trials are warranted to further elucidate application of pECLA devices in NICU patients. PMID- 26518589 TI - Does a Video Improve Knowledge of HIV/AIDS and HIV Testing among a Global Internet Audience? AB - The objectives of this study were to determine if a video improved HIV/AIDS and HIV testing knowledge among a global sample of Internet users, to discern if this improvement was the same for English and Spanish speakers, and to ascertain if the video was efficacious for those with lower health literacy. A worldwide sample of English- or Spanish-speaking Internet users was solicited. Participants completed a 25-item questionnaire to assess their HIV/AIDS and HIV testing knowledge before and after watching the video. Mean scores on the questionnaire improved after watching the video for both English speakers (after: 19.6 versus before: 16.4; Delta = 3.2; 95% confidence interval [CI]: 2.8-3.5) and Spanish speakers (20.7 versus 17.3; Delta = 3.4; 95% CI: 3.0-3.8). There was no difference in improvement of scores between English and Spanish speakers (Delta = -0.24; 95% CI: -0.79 to 0.31), and this video was equally efficacious for those with lower and higher health literacy skills. PMID- 26518590 TI - Implementation of a Peer HIV Community Support Worker Program in Rural Ethiopia to Promote Retention in Care. AB - Retention in care is a major challenge for HIV treatment programs, including in rural and in resource-limited settings. To help reduce loss to follow-up (LTFU) for HIV-infected patients new to care in rural Ethiopia, 142 patients were assigned 1 of 13 trained community health support workers (CHSWs) who were HIV positive and from the same neighborhood/village. The CHSWs provided HIV and health education, counseling/social support, and facilitated communication with the HIV clinics. With 7 deaths and 3 transfers, the 12-month retention rate was 94% (95% CI = 89%-97%), and no client was LTFU in the project. Between enrollment and 12 months, clients had significant ( P <= .001) improvements in HIV knowledge (17% increase), physical and mental quality of life (81% and 21% increase), internalized stigma (97% decrease), and perceived social support (24% increase). In rural and resource-limited settings, community-based CHSW programs can complement facility-based care in reducing LTFU and improving positive outcomes for HIV-infected people who enter care. PMID- 26518591 TI - Cholesterol Levels in HIV- and/or HCV-Infected Drug Users Living in Argentina. AB - Improved understanding of cholesterol levels in HIV- and hepatitis C virus (HCV) infected persons in Argentina will guide optimal antiretroviral therapy. The authors conducted a cross-sectional study in Argentina to describe associations between HIV, HCV, and cholesterol. Of the 202 participants, 21 were HIV infected, 15 were HCV infected, 46 were HIV/HCV coinfected, and 120 were HIV/HCV uninfected. HIV/HCV-uninfected participants had the highest total cholesterol (TC) and low-density lipoprotein (LDL) levels. Multivariate modeling revealed that HIV/HCV-coinfected patients had the lowest TC levels (-28.7 mg/dL, P < .001) compared to the HIV/HCV-uninfected reference group. Hepatitis C virus and HIV/HCV coinfection were associated with lower LDL levels (-21.4 mg/dL, P = .001 and 20.3 mg/dL, P < .0001, respectively). HIV and HIV/HCV coinfection, but not HCV alone, were associated with lower high-density lipoprotein levels (-9.1 mg/dL, P = .0008 and -6.8 mg/dL, P = .0006, respectively). Further study is needed to examine whether the more favorable lipid profile observed in HIV/HCV-coinfected persons is associated with a reduction in cardiovascular risk. PMID- 26518592 TI - A multilocus sequence analysis scheme for characterization of Flavobacterium columnare isolates. AB - BACKGROUND: Columnaris disease caused by Flavobacterium columnare is a serious problem in aquaculture, annually causing large economic losses around the world. Despite considerable research, the molecular epidemiology of F. columnare remains poorly understood. METHODS: We investigated the population structure and spatiotemporal changes in the genetic diversity of F. columnare population in Finland by using a multilocus sequence typing (MLST) and analysis (MLSA) based on DNA sequence variation within six housekeeping genes. A total of 83 strains of F. columnare were collected from eight different areas located across the country between 2003 and 2012. RESULTS: Partial sequencing of six housekeeping genes (trpB, tuf, atpA, rpoD, gyrB and dnaK) revealed eight sequence types and a moderate level of genetic diversity (H=0.460). Phylogenetic analysis of the concatenated protein-encoding gene sequence data (ca. 3,509 nucleotides) formed two lineages, which could be further divided into five clusters. All analysed F. columnare strains appeared to have a genetic origin distinct from that of another important fish pathogen form the genus Flavobacterium, F. psychrophilum. Although the value of the index of association between alleles, 0.292 (P<0.001), supports some degree of clonality for this species in Finland, recombination has introduced molecular diversity to the population almost three times more than mutation. CONCLUSION: The results suggest that Finnish F. columnare strains have an epidemic population structure followed by clonal expansion of successful genotypes. Our study with reproducible methodology and comparable results establishes a robust framework for the discrimination and phylogenetic analysis of F. columnare isolates, which will help to improve our understanding about geographic distribution and epidemiology of columnaris disease. PMID- 26518593 TI - Effects of Wind Turbine Noise on Self-Reported and Objective Measures of Sleep. AB - STUDY OBJECTIVES: To investigate the association between self-reported and objective measures of sleep and wind turbine noise (WTN) exposure. METHODS: The Community Noise and Health Study, a cross-sectional epidemiological study, included an in-house computer-assisted interview and sleep pattern monitoring over a 7 d period. Outdoor WTN levels were calculated following international standards for conditions that typically approximate the highest long-term average levels at each dwelling. Study data were collected between May and September 2013 from adults, aged 18-79 y (606 males, 632 females) randomly selected from each household and living between 0.25 and 11.22 kilometers from operational wind turbines in two Canadian provinces. Self-reported sleep quality over the past 30 d was assessed using the Pittsburgh Sleep Quality Index. Additional questions assessed the prevalence of diagnosed sleep disorders and the magnitude of sleep disturbance over the previous year. Objective measures for sleep latency, sleep efficiency, total sleep time, rate of awakening bouts, and wake duration after sleep onset were recorded using the wrist worn Actiwatch2(r) from a subsample of 654 participants (289 males, 365 females) for a total of 3,772 sleep nights. RESULTS: Participant response rate for the interview was 78.9%. Outdoor WTN levels reached 46 dB(A) with an arithmetic mean of 35.6 and a standard deviation of 7.4. Self-reported and objectively measured sleep outcomes consistently revealed no apparent pattern or statistically significant relationship to WTN levels. However, sleep was significantly influenced by other factors, including, but not limited to, the use of sleep medication, other health conditions (including sleep disorders), caffeine consumption, and annoyance with blinking lights on wind turbines. CONCLUSIONS: Study results do not support an association between exposure to outdoor WTN up to 46 dB(A) and an increase in the prevalence of disturbed sleep. Conclusions are based on WTN levels averaged over 1 y and, in some cases, may be strengthened with an analysis that examines sleep quality in relation to WTN levels calculated during the precise sleep period time. PMID- 26518594 TI - A Unified Model of Performance: Validation of its Predictions across Different Sleep/Wake Schedules. AB - STUDY OBJECTIVES: Historically, mathematical models of human neurobehavioral performance developed on data from one sleep study were limited to predicting performance in similar studies, restricting their practical utility. We recently developed a unified model of performance (UMP) to predict the effects of the continuum of sleep loss-from chronic sleep restriction (CSR) to total sleep deprivation (TSD) challenges-and validated it using data from two studies of one laboratory. Here, we significantly extended this effort by validating the UMP predictions across a wide range of sleep/wake schedules from different studies and laboratories. METHODS: We developed the UMP on psychomotor vigilance task (PVT) lapse data from one study encompassing four different CSR conditions (7 d of 3, 5, 7, and 9 h of sleep/night), and predicted performance in five other studies (from four laboratories), including different combinations of TSD (40 to 88 h), CSR (2 to 6 h of sleep/night), control (8 to 10 h of sleep/night), and nap (nocturnal and diurnal) schedules. RESULTS: The UMP accurately predicted PVT performance trends across 14 different sleep/wake conditions, yielding average prediction errors between 7% and 36%, with the predictions lying within 2 standard errors of the measured data 87% of the time. In addition, the UMP accurately predicted performance impairment (average error of 15%) for schedules (TSD and naps) not used in model development. CONCLUSIONS: The unified model of performance can be used as a tool to help design sleep/wake schedules to optimize the extent and duration of neurobehavioral performance and to accelerate recovery after sleep loss. PMID- 26518595 TI - Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity. AB - STUDY OBJECTIVES: Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells. METHODS: HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4,043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles. RESULTS: HLA-A*11:01 (OR = 1.49 [1.18-1.87] P = 7.0*10(-4)), C*04:01 (OR = 1.34 [1.10-1.63] P = 3.23*10(-3)), and B*35:01 (OR = 1.46 [1.13-1.89] P = 3.64*10(-3)) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A Tyr(9) (OR = 1.32 [1.15-1.52] P = 6.95*10(-5)) and HLA-C-Ser(11) (OR = 1.34 [1.15 1.57] P = 2.43*10(-4)). CONCLUSIONS: Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons. PMID- 26518596 TI - Sleep Strengthens but does Not Reorganize Memory Traces in a Verbal Creativity Task. AB - STUDY OBJECTIVES: Sleep after learning promotes the quantitative strengthening of new memories. Less is known about the impact of sleep on the qualitative reorganization of memory content. This study tested the hypothesis that sleep facilitates both memory strengthening and reorganization as indexed by a verbal creativity task. METHODS: Sixty healthy university students (30 female, 30 male, 20-30 years) were investigated in a randomized, controlled parallel-group study with three experimental groups (sleep, sleep deprivation, daytime wakefulness). At baseline, 60 items of the Compound Remote Associate (CRA) task were presented. At retest after the experimental conditions, the same items were presented again together with 20 new control items to disentangle off-line incubation from online performance effects. RESULTS: Sleep significantly strengthened formerly encoded memories in comparison to both wake conditions (improvement in speed of correctly resolved items). Offline reorganization was not enhanced following sleep, but was enhanced following sleep-deprivation in comparison to sleep and daytime wakefulness (solution time of previously incubated, newly solved items). Online performance did not differ between the groups (solution time of new control items). CONCLUSIONS: The results support the notion that sleep promotes the strengthening, but not the reorganization, of newly encoded memory traces in a verbal creativity task. Future studies are needed to further determine the impact of sleep on different types of memory reorganization, such as associative thinking, creativity and emotional memory processing, and potential clinical translations, such as the augmentation of psychotherapy through sleep interventions. PMID- 26518598 TI - Low fat diets are no better than others for long term weight loss, research finds. PMID- 26518597 TI - Effects of a midwife psycho-education intervention to reduce childbirth fear on women's birth outcomes and postpartum psychological wellbeing. AB - BACKGROUND: High levels of childbirth fear impact birth preparation, obstetric outcomes and emotional wellbeing for around one in five women living in developed countries. Higher rates of obstetric intervention and caesarean section (CS) are experienced in fearful women. The efficacy of interventions to reduce childbirth fear is unclear, with no previous randomised controlled trials reporting birth outcomes or postnatal psychological wellbeing following a midwife led intervention. METHOD: Between May 2012 and June 2013 women in their second trimester of pregnancy were recruited. Women with a fear score >= 66 on the Wijma Delivery Expectancy / Experience Questionnaire (W-DEQ) were randomised to receive telephone psycho-education by a midwife, or usual maternity care. A two armed non blinded parallel (1:1) multi-site randomised controlled trial with participants allocated in blocks of ten and stratified by hospital site and parity using an electronic centralised computer service. The outcomes of the RCT on obstetric outcomes, maternal psychological well-being, parenting confidence, birth satisfaction, and future birth preference were analysed by intention to treat and reported here. RESULTS: 1410 women were screened for high childbirth fear (W-DEQ >=66). Three hundred and thirty-nine (n = 339) women were randomised (intervention n = 170; controls n = 169). One hundred and eighty-four women (54 %) returned data for final analysis at 6 weeks postpartum (intervention n = 91; controls n = 93). Compared to controls the intervention group had a clinically meaningful but not statistically significant reduction in overall caesarean section (34 % vs 42 %, p = 0.27) and emergency CS rates (18 % vs 25 %, p = 0.23). Fewer women in the intervention group preferred caesarean section for a future pregnancy (18 % vs 30 %, p = 0.04). All other obstetric variables remained similar. There were no differences in postnatal depression symptoms scores, parenting confidence, or satisfaction with maternity care between groups, but a lower incidence of flashbacks about their birth in the intervention group compared to controls (14 % vs 26 %, p = 0.05). Postnatally women who received psycho-education reported that the 'decision aid' helped reduce their fear (53 % vs 37 %, p = 0.02). CONCLUSION: Following a brief antenatal midwife-led psycho education intervention for childbirth fear women were less likely to experience distressing flashbacks of birth and preferred a normal birth in a future pregnancy. A reduction in overall CS rates was also found. Psycho-education for fearful women has clinical benefits for the current birth and expectations of future pregnancies. TRIAL REGISTRATION: Australian New Zealand Controlled Trials Registry ACTRN12612000526875 , 17th May 2012. PMID- 26518599 TI - Understanding and Changing Food Consumption Behavior Among Children: The Comprehensive Child Consumption Patterns Model. AB - Current theoretical models attempting to explain diet-related weight status among children center around three individual-level theories. Alone, these theories fail to explain why children are engaging or not engaging in health-promoting eating behaviors. Our Comprehensive Child Consumption Patterns model takes a comprehensive approach and was developed specifically to help explain child food consumption behavior and addresses many of the theoretical gaps found in previous models, including integration of the life course trajectory, key influencers, perceived behavioral control, and self-regulation. Comprehensive Child Consumption Patterns model highlights multiple levels of the socioecological model to explain child food consumption, illustrating how negative influence at multiple levels can lead to caloric imbalance and contribute to child overweight and obesity. Recognizing the necessity for multi-level and system-based interventions, this model serves as a template for holistic, integrated interventions to improve child eating behavior, ultimately impacting life course health development. PMID- 26518600 TI - Motivation for smoking cessation among drug-using smokers under methadone maintenance treatment in Vietnam. AB - BACKGROUND: Smoking cessation treatment service is concerned to be a critical element in methadone maintenance treatment (MMT) in order to diminish the effect of smoke on health outcomes. To implement the smoking cessation services in Vietnam, we examined the stages of change to quit and determined associated factors among MMT patients. METHODS: We conducted a cross-sectional survey with 1016 MMT patients in five clinics in Hanoi and Nam Dinh province, of those, 932 (91.7%) were ever-smokers. Patients were classified into four groups: "pre contemplation," "contemplation," "preparation," and "action and maintenance" by using the transtheoretical model. Multivariate logistic regression was applied to determine the associated factor for intention and action to quit smoking. RESULTS: Overall, 96% were not actively trying to quit or maintain abstinence. Age older than 45, HIV-positive status, and residence in Hanoi were negatively associated with intention to quit. Meanwhile, higher levels of nicotine dependence and number of years of smoking negatively associated with quitting and abstinence. CONCLUSIONS: The study indicated the high rate of MMT smokers being in pre-contemplation stage but low proportion of quitting and maintaining abstinence. It emphasizes the importance of availability and accessibility of information about smoking cessation therapies and services. Integrating cessation programs into health-care services should be considered to provide tailored interventions for different patient groups. PMID- 26518601 TI - Reinekea marina sp. nov., isolated from seawater, and emended description of the genus Reinekea. AB - A Gram-stain-negative, curved rod-shaped and non-pigmented strain, HME8277T, was isolated from surface seawater of the Yellow Sea in the Republic of Korea. Phylogenetic analysis based on 16S rRNA gene sequences showed that the novel strain was related most closely to Reinekea blandensis MED297T (96.4 % 16S rRNA gene sequence similarity), Reinekea aestuarii IMCC4489T (96.3 %) and Reinekea marinisedimentorum KMM 3655T (95.8 %). The major fatty acids were summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c; 43.0 %), C16 : 0 (19.0 %) and summed feature 8 (comprising C18 : 1omega7c and/or C18 : 1omega6c; 15.0 %). The DNA G+C content was 46.1 mol%. The predominant respiratory quinone was Q-8. The major polar lipids of strain HME8277T comprised diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, four unidentified phospholipids and four unidentified lipids. On the basis of polyphasic analyses, strain HME8277T represents a novel species of the genus Reinekea, for which the name Reinekea marina sp. nov. is proposed. The type strain HME8277T ( = KACC 17315T = CECT 8288T). An emended description of the genus Reinekea is also provided. PMID- 26518602 TI - Cryptic diversity in Hipposideros commersoni sensu stricto (Chiroptera: Hipposideridae) in the western portion of Madagascar. AB - BACKGROUND: The Commerson's leaf-nosed bat, Hipposideros commersoni sensu stricto, is endemic to Madagascar and is relatively common in the western portion of the island, where it is found in areas, including forested zones, from sea level to 1325 m. A previous study on morphological patterns of geographic variation within the species highlighted the presence of two distinct morphotypes; larger individuals in the north portion of the island and smaller individuals in the south. The main aim of this study was to use a combination of craniodental morphology and molecular data (mitochondrial and nuclear) to test previous hypotheses based on morphology and clarify the evolutionary history of the species group. METHODS: We sequenced mitochondrial and nuclear genes from Hipposideros commersoni obtained from the western portion of Madagascar, and compared them with other African species as outgroups. We analyzed the sequence data using Maximum Likelihood and Bayesian phylogenetic inference. Divergence dates were estimated using Bayesian molecular clock approach. Variation in craniodental variables was also assessed from sequenced individuals. RESULTS: The molecular analyses suggest that H. commersoni is not monophyletic, with strong support for the presence of several independently evolving lineages. Two individuals amongst those sequenced from Isalo (south central) and Itampolo (southwest) form a separate clade (Clade A), distinct from other H. commersoni, and sister to continental African H. vittatus and H. gigas. Within the H. commersoni clade, the molecular data support two geographically distributed clades; one from the south (Clade B) and the other from the north (Clade C), which diverged approximately 3.38 million years ago. Morphometric data were consistent with the molecular analyses, suggesting a north-south break within H. commersoni. However, at some localities, animals from both clades occurred in sympatry and these individuals could not be differentiated based on external and craniodental measurements. CONCLUSIONS: Using a combination of molecular and morphological characters, this study presents evidence of cryptic diversity in H. commersoni on Madagascar. Further fine-scale phylogeographic studies are needed to fully resolve the systematics of H. commersoni. This study highlights the utility of the combined approach in employing both morphological and molecular data to provide insights into the evolutionary history of Malagasy population currently assigned to H. commersoni. PMID- 26518604 TI - A tenascin C targeted nanoliposome with navitoclax for specifically eradicating of cancer-associated fibroblasts. AB - Cancer-associated fibroblasts (CAFs) play a vitally important role during tumor progression. Navitoclax (Nav) can specifically induce apoptosis in CAFs. The present study aims to develop a novel CAF-targeted nanoliposome for cancer therapy. Nav-loaded nanoliposomes modified with peptide FH (FH-SSL-Nav), which specifically binds to tenascin C, a protein mainly expressed by CAFs, were formulated and characterized. Several experiments were performed to evaluate CAFs selective apoptosis, targeting and eradicating. Compared with SSL-Nav, FH-SSL-Nav achieved higher cellular uptake, and exhibited stronger cytotoxicity in vitro. The in vivo tumor stroma targeting effect was further confirmed by near infrared imaging. Accordingly, FH-SSL-Nav displayed improved tumor growth inhibition by eradicating CAFs in Hep G2 tumor-bearing nude mice model. In conclusion, FH-SSL Nav could achieve targeting delivery of Nav to CAFs in vitro and in vivo, and may offer a potential strategy for cancer therapy based on tumor stroma. From the Clinical Editor: The progression of cancer cells often depends on the underlying tumor microenvironment, in which cancer-associated fibroblasts play an important role. In this article, the authors developed targeted therapy against CAFs using liposomes as carriers. This new modality was shown to be more effective in tumor killing both in vitro and in vivo. The finding may open a new era in cancer therapy. PMID- 26518605 TI - Differential physiological response of the grapevine varieties Touriga Nacional and Trincadeira to combined heat, drought and light stresses. AB - Worldwide, extensive agricultural losses are attributed to drought, often in combination with heat in Mediterranean climate regions, where grapevine traditionally grows. The available scenarios for climate change suggest increases in aridity in these regions. Under natural conditions plants are affected by a combination of stresses, triggering synergistic or antagonistic physiological, metabolic or transcriptomic responses unique to the combination. However the study of such stresses in a controlled environment can elucidate important mechanisms by allowing the separation of the effects of individual stresses. To gather those effects, cuttings of two grapevine varieties, Touriga Nacional (TN) and Trincadeira (TR), were grown under controlled conditions and subjected to three abiotic stresses (drought - WS, heat - HS and high light - LS) individually and in combination two-by-two (WSHS, WSLS, HSLS) or all three (WSHSLS). Photosynthesis, water status, contents of H2 O2 , abscisic acid and metabolites of the ascorbate-glutathione cycle were measured in the leaves. Common and distinct response features were identified in the different stress combinations. Photosynthesis was not hindered in TN by LS, while even individual stresses severely affect photosynthesis in TR. Abscisic acid may be implicated in grapevine osmotic responses since it is correlated with tolerance parameters, especially in combined stresses involving drought. Overall, the responses to drought-including treatments were clearly distinct to those without drought. From the specific behaviours of the varieties, it can be concluded that TN shows a higher capacity for heat dissipation and for withstanding high light intensities, indicating better adjustment to warm conditions, provided that water supply is plentiful. PMID- 26518603 TI - Nanoparticle facilitated inhalational delivery of erythropoietin receptor cDNA protects against hyperoxic lung injury. AB - Our goals were to develop and establish nanoparticle (NP)-facilitated inhalational gene delivery, and to validate its biomedical application by testing the hypothesis that targeted upregulation of pulmonary erythropoietin receptor (EpoR) expression protects against lung injury. Poly-lactic-co-glycolic acid (PLGA) NPs encapsulating various tracers were characterized and nebulizated into rat lungs. Widespread NP uptake and distribution within alveolar cells were visualized by magnetic resonance imaging, and fluorescent and electron microscopy. Inhalation of nebulized NPs bearing EpoR cDNA upregulated pulmonary EpoR expression and downstream signal transduction (ERK1/2 and STAT5 phosphorylation) in rats for up to 21 days, and attenuated hyperoxia-induced damage in lung tissue based on apoptosis, oxidative damage of DNA, protein and lipid, tissue edema, and alveolar morphology compared to vector-treated control animals. These results establish the feasibility and therapeutic efficacy of NP facilitated cDNA delivery to the lung, and demonstrate that targeted pulmonary EpoR upregulation mitigates acute oxidative lung damage. FROM THE CLINICAL EDITOR: Acute lung injury often results in significant morbidity and mortality, and current therapeutic modalities have proven to be ineffective. In this article, the authors developed nanocarrier based gene therapy in an attempt to upregulate the expression of pulmonary erythropoietin receptor in an animal model. Inhalation delivery resulted in reduction of lung damage. PMID- 26518606 TI - Effect of timing of insemination after CIDR removal with or without GnRH on pregnancy rates in Nili-Ravi buffalo. AB - There are limited studies available on when to inseminate, if using CIDR or CIDR GnRH protocols for optimal fertility in buffalo. Therefore, the objective of the present study was to determine the optimum time of AI in relation to CIDR removal with or without GnRH in buffalo. All buffalo (n=201) received CIDR on Day 0, PGF2alpha on Day 6 and CIDR were removed on Day 7. In 50 of these buffalo GnRH was administered 36 h after CIDR removal. Furthermore, CIDR (n=151) and CIDR-GnRH (n=50) were randomly divided to receive timed artificial insemination (TAI), either at 48, 60 or 72 h after CIDR removal. Ultrasonography was performed for follicular development and for pregnancy diagnosis. The results revealed that, mean interval to ovulation was shorter (P<0.05) in buffalo receiving CIDR-GnRH than CIDR (68.40 +/- 1.73 compared with 76.13 +/- 1.66 h, respectively). The pregnancy rates were higher (P<0.05) in buffalo inseminated either at 48 (50%) or 60 (59%) than at 72 h (18%) in CIDR-GnRH protocol; whereas, in CIDR buffalo pregnancy rates were higher (P<0.05), at 60 (37%) or 72 (40%) than at 48 h (10%). In conclusion, the optimal time of AI is between 48-60 h in CIDR-GnRH and between 60-72 h in CIDR protocol for enhancing fertility in buffalo. PMID- 26518607 TI - Central calcifying epithelial odontogenic tumour in the posterior maxilla: a case report. AB - The calcifying epithelial odontogenic tumour (CEOT), or Pindborg tumour, is a rare, benign odontogenic tumour. CEOT is usually asymptomatic and an incidental radiological finding, often presenting as a mandibular radiolucency with flecks of calcific material. We report an unusual case of CEOT in the left posterior maxilla of a 46-year-old male that was associated with an unerupted tooth. The tumour in this case caused non-specific sinus symptoms and appeared radiographically similar to an odontoma or ossifying fibroma due to its dense calcific contents. Diagnosis was confirmed histologically following surgical removal of the lesion, which showed classic CEOT histomorphology. We report this case to highlight the unusual clinico-radiologic presentation and illustrate the diagnostic difficulties that can occur with radiolucent and/or radiopaque lesions in the jaws. PMID- 26518608 TI - The clinical anatomy of high take-off coronary arteries. AB - A number of criteria are used in the literature to describe high take-off coronary arteries, which can in part, explain the divide in the literature on the pathological significance of this anomaly. This study presents the anatomical variations of high take-off coronary arteries to draw attention to the possible clinical implications they may cause during angiography and other surgical procedures. The English Literature was searched to review high take-off coronary arteries. A high take-off coronary artery arising at least 1 cm in adults or 20% the depth of the sinus in children above the sinutubular junction, is considered of greater clinical relevance and was included in our meta-analysis. High take off coronaries by other criteria was also included as part of the comprehensive review. Exclusion criteria were reports made in case studies or case reviews. The prevalence of high take-off coronary arteries in our study was 26 of 12,899 (0.202%). High take-off coronary arteries were found to originate up to 5 cm above the sinutubular junction. Right coronary arteries made up 84.46% of high take-off coronary arteries reported in the literature. Three (0.023%) cases that originated more than one centimeter above the sinutubular junction was associated with sudden cardiac death. This is a higher reported association than in studies that used other criteria for classification. It is important for clinicians to recognize the importance of correctly diagnosing high take-off coronary arteries in patients with coexisting cardiac morbidities so that suitable management plans can be developed. PMID- 26518609 TI - Efficacy of a typing scheme for Campylobacter based on the combination of true and questionable CRISPR. AB - This study evaluates an improved scheme for Campylobacter genotyping based on the combination of true and questionable CRISPR (clustered regularly interspaced short palindromic repeats) elements. A total of 180 Campylobacter strains (Campylobacter jejuni n=93 and Campylobacter coli n=87), isolated from neck skin and caecal content of broilers, poultry meat and sewage water were analysed. Another 97 C. jejuni DNA samples from cases of human campylobacteriosis were assessed. Sixty-three genotypes were found in C. jejuni considering only true CRISPR, and 16 additional genotypes were identified when questionable CRISPR were also taken into account. Likewise in C. coli the number of genotypes increased from eight for only true CRISPR to 14 after including questionable CRISPR elements. The number of typeable C. jejuni and C. coli isolates was 115 (60.5%) and 17 (19.5%) respectively considering only true CRISPR. These percentages increased to 92.7% (n=176) and 39.1% (n=34) respectively when both true and questionable CRISPR were considered. 60.9% of the C. coli isolates were non typeable by CRISPR due to the lack of any PCR amplifiable CRISPR loci, which raises questions about CRISPR analysis as an appropriate method for C. coli typing. However the assessment of true and questionable CRISPR has proved to be fairly useful for typing C. jejuni due to its high discriminatory power (Simpson's index=0.960) and typeability (92.7%) values. The results of the present work show that our genotyping method based on the combination of true and questionable CRISPR elements may be used as a suitable complementary tool to existing C. jejuni genotyping methods. PMID- 26518610 TI - Human choice under schedules of negative reinforcement. AB - The generalized matching equation provides a good description of response allocation in concurrent schedules of positive reinforcement in nonhumans as well as in humans. The present experiment was conducted to further investigate the allocation of responding under concurrent schedules of negative reinforcement (i.e., timeouts from pressing a force cell) in humans. Each of three participants was exposed to different reinforcement ratios (9:1, 1:1 and 1:9) in the terminal links of a concurrent-chains schedule of negative reinforcement. The allocation of responding under this schedule was well described by the generalized matching equation, for each participant. These results replicate previous findings obtained with nonhumans and humans under concurrent schedules of positive reinforcement. In addition, they extend the results reported by Alessandri and Riviere (2013) showing that human behavior maintained by timeouts from an effortful response is sensitive to changes in relative reinforcement ratios as well as relative delays of reinforcement. PMID- 26518611 TI - Mechanism of Mcl-1 Conformational Regulation Upon Small Molecule Binding Revealed by Molecular Dynamic Simulation. AB - Inhibition of interactions between Mcl-1 and proapoptotic proteins is considered to be a therapeutic strategy to induce apoptosis in cancer cells. Here, we adopted molecular dynamics simulation with molecular mechanics-Poisson Boltzmann/surface area method (MM-PB/SA) to study the inhibition mechanism of three Mcl-1 inhibitors, compounds 1, 2 and 3. Analysis of energy components shows that the better binding free energy of compound 3 than compounds 1 and 2 is attributable to the van der Waals energy (DeltaEvdw ) and non-polar solvation energy (DeltaGnp ) upon binding. In addition to the excellent agreement with previous experimentally determined affinities, our simulation results further show a bend of helix 4 on Mcl-1 upon compound 3 binding, which is driven by hydrophobic interaction with residue Val(253) , leading to a narrowed BH3-binding groove to impede Puma(BH) (3) binding. The computational result is consistent with our competitive isothermal titration calorimetry (ITC) assays, which shows that the competitive ability of compound 3 toward Mcl-1/Puma(BH) (3) complex is improved beyond its direct binding affinity toward Mcl-1 itself, and compound 3 exhibits much more efficiency to compete with Puma(BH) (3) than compound 2. Our study provides a new strategy to improve inhibitory activity on Mcl-1 based on the conformational dynamic change. PMID- 26518612 TI - Systematic review on the use of anticholinergic scales in poly pathological patients. AB - PURPOSE: Anticholinergic drugs may increase the risk of cognitive and functional disorders in older patients. There are anticholinergic scales on which said risk is estimated. The objectives of this study are: to identify the scales described in literature that are applicable to polypathological patients and analyze their clinical outcomes. MATERIAL AND METHODS: A systematic review was performed. Data sources were MEDLINE, EMBASE and Web of Science which were consulted until August 2014. INCLUSION CRITERIA: (1) studies that specify the list of drugs, describe the methodology for their elaboration and how they calibrate the anticholinergic potential and (2) studies that use the scales identified as a tool to measure exposure to anticholinergic drugs in polypathological patients or those with similar characteristics. The main differences between the scales and main results on cognitive, functional and mortality status were collected. RESULTS: 25 articles were included. 10 scales were identified. For their preparation, 8 were based on literature about drugs with anticholinergic activity and/or previously published scales as well as expert opinions. Exposure to anticholinergic drugs has been linked to cognitive disorders (basically measured with Anticholinergic Risk Scale (ARS), Anticholinergic Cognitive Burden Scale (ACB) and Drug Burden Index (DBI)) and functional scale (with ARS and DBI). However, there is no clear relationship with mortality. The Anticholinergic Drug Scale was the only one that obtained no association with any of the variables studied. CONCLUSIONS: There is a great variety of scales published and applied to older patients. The clinical results are different depending on the scale used which is probably due to the different methodology in their elaboration. PMID- 26518613 TI - Calciphylaxis: a case series and the role of radiology in diagnosis. AB - BACKGROUND: Calciphylaxis is a syndrome of vascular calcification most commonly affecting patients with end-stage renal disease (ESRD) on hemodialysis. Because of its high mortality rate, early diagnosis and treatment are necessary. Although diagnosis is usually based on skin biopsy, histopathology is often nonspecific. As the role of imaging in calciphylaxis has not been studied extensively, we examined the utility of radiology in the diagnosis of this disease. METHODS: A thorough review of electronic medical records for 2005-2013 at Loyola University Medical Center yielded 10 patients with biopsy-proven calciphylaxis. Using the radiological picture archiving and communication system (PACS), all imaging studies of the affected body part obtained within 6 months of diagnosis were analyzed and tabulated. RESULTS: All 10 patients had undergone imaging (computed tomography, ultrasound, plain radiography, and/or mammography) of the affected anatomy prior to diagnosis by skin biopsy. Nine of these patients were noted to have moderate-to-severe soft tissue vascular calcification in the area of skin biopsy. CONCLUSIONS: This case series supports the suggestion that findings of superficial vascular calcifications on imaging studies are sensitive for the diagnosis of calciphylaxis. Used in conjunction with histopathological, clinical, and laboratory data, radiology can serve an important role in the diagnosis of calciphylaxis. PMID- 26518614 TI - Elevated and cross-responsive CD1a-reactive T cells in bee and wasp venom allergic individuals. AB - The role of CD1a-reactive T cells in human allergic disease is unknown. We have previously shown that circulating CD1a-reactive T cells recognize neolipid antigens generated by bee and wasp venom phospholipase, and here tested the hypothesis that venom-responsive CD1a-reactive T cells associate with venom allergy. Circulating T cells from bee and wasp venom allergic individuals, before and during immunotherapy, were exposed to CD1a-transfected K562 cells in the presence of wasp or bee venom. T-cell response was evaluated based on IFNgamma, GM-CSF, and IL-13 cytokine production. Venom allergic individuals showed significantly higher frequencies of IFN-gamma, GM-CSF, and IL-13 producing CD1a reactive T cells responsive to venom and venom-derived phospholipase than healthy individuals. Venom-responsive CD1a-reactive T cells were cross-responsive between wasp and bee suggesting shared pathways of allergenicity. Frequencies of CD1a reactive T cells were initially induced during subcutaneous immunotherapy, peaking by weeks 5, but then reduced despite escalation of antigen dose. Our current understanding of venom allergy and immunotherapy is largely based on peptide and protein-specific T cell and antibody responses. Here, we show that lipid antigens and CD1a-reactive T cells associate with the allergic response. These data have implications for mechanisms of allergy and approaches to immunotherapy. PMID- 26518615 TI - Factors predictive of return to work after stroke in patients with mild-moderate disability in India. AB - BACKGROUND: Successful return to work after stroke may improve economic circumstances, quality of life and overall life satisfaction, but not all stroke survivors are able to return to work. AIM: Our aim was to determine what proportion of previously employed patients return to work after an acute stroke resulting in mild to moderate disability and to examine factors associated with a successful return to work. METHODS: Patients 18-60 years of age who were previously employed and who had a first-ever stroke 3 months to 2 years previously resulting in mild to moderate disability (modified Rankin score <=3) were recruited. Socio-demographic and clinical information was collected and anxiety, depression and social support were assessed using previously validated instruments. Multivariate logistic regression was used to assess factors associated with a successful return to work. RESULTS: Of 141 patients (mean age +/- SD 48 +/- 8.8 years), 74 (52.5%) returned to work after stroke. Multivariate analysis demonstrated that a lower modified Rankin scale at 3 months [odds ratio (OR) 3.70, 95% confidence interval (CI) 1.77-7.76], younger age (OR 2.24, 95% CI 1.07-4.67) and a professional or business job (OR 3.02, 95% CI 1.44-6.34) were significantly associated with successful return to work and revealed that anxiety, depression and social support score did not affect patients' decision to return to work (P = 0.17, 0.61 and 0.27, respectively). CONCLUSIONS: Amongst patients with mild to moderate disability after stroke, almost half do not return to work, and this is determined by functional disability and type of job rather than psychosocial factors such as anxiety and depression. PMID- 26518616 TI - A facile method to compare EFTEM maps obtained from materials changing composition over time. AB - Energy Filtered Transmission Electron Microscopy (EFTEM) is an analytical tool that has been successfully and widely employed in the last two decades for obtaining fast elemental maps in TEM mode. Several studies and efforts have been addressed to investigate limitations and advantages of such technique, as well as to improve the spatial resolution of compositional maps. Usually, EFTEM maps undergo post-acquisition treatments by changing brightness and contrast levels, either via dedicated software or via human elaboration, in order to maximize their signal-to-noise ratio and render them as visible as possible. However, elemental maps forming a single set of EFTEM images are usually subjected to independent map-by-map image treatment. This post-acquisition step becomes crucial when analyzing materials that change composition over time as a consequence of an external stimulus, because the map-by-map approach doesn't take into account how the chemical features of the imaged materials actually progress, in particular when the investigated elements exhibit very low signals. In this article, we present a facile procedure applicable to whole sets of EFTEM maps acquired on a sample that is evolving over time. The main aim is to find a common method to treat the images features, in order to make them as comparable as possible without affecting the information there contained. PMID- 26518618 TI - Spatiotemporal analysis of gene flow in Chesapeake Bay Diamondback Terrapins (Malaclemys terrapin). AB - There is widespread concern regarding the impacts of anthropogenic activities on connectivity among populations of plants and animals, and understanding how contemporary and historical processes shape metapopulation dynamics is crucial for setting appropriate conservation targets. We used genetic data to identify population clusters and quantify gene flow over historical and contemporary time frames in the Diamondback Terrapin (Malaclemys terrapin). This species has a long and complicated history with humans, including commercial overharvesting and subsequent translocation events during the early twentieth century. Today, terrapins face threats from habitat loss and mortality in fisheries bycatch. To evaluate population structure and gene flow among Diamondback Terrapin populations in the Chesapeake Bay region, we sampled 617 individuals from 15 localities and screened individuals at 12 polymorphic microsatellite loci. Our goals were to demarcate metapopulation structure, quantify genetic diversity, estimate effective population sizes, and document temporal changes in gene flow. We found that terrapins in the Chesapeake Bay region harbour high levels of genetic diversity and form four populations. Effective population sizes were variable. Among most population comparisons, estimates of historical and contemporary terrapin gene flow were generally low (m ~ 0.01). However, we detected a substantial increase in contemporary gene flow into Chesapeake Bay from populations outside the bay, as well as between two populations within Chesapeake Bay, possibly as a consequence of translocations during the early twentieth century. Our study shows that inferences across multiple time scales are needed to evaluate population connectivity, especially as recent changes may identify threats to population persistence. PMID- 26518617 TI - Phylogenetic group distributions, virulence factors and antimicrobial resistance properties of uropathogenic Escherichia coli strains isolated from patients with urinary tract infections in South Korea. AB - Urinary tract infections (UTIs) are one of the most common diseases by which humans seek medical help and are caused mainly by uropathogenic Escherichia coli (UPEC). Studying the virulence and antibiotic resistance of UPEC with respect to various phylogenetic groups is of utmost importance in developing new therapeutic agents. Thus, in this study, we analysed the virulence factors, antibiotic resistance and phylogenetic groups among various UPEC isolates from children with UTIs. The phylogenetic analysis revealed that majority of the strains responsible for UTIs belonged to the phylogenetic groups B2 and D. Of the 58 E. coli isolates, 79.31% belonged to group B2, 15.51% to group D, 3.44% to group A and 1.72% to B1. Simultaneously, the number of virulence factors and antibiotic resistance exhibited were also significantly high in groups B2 and D compared to other groups. Among the isolates, 44.8% were multidrug resistant and of that 73% belonged to the phylogenetic group B2, indicating the compatibility of antibiotic resistance and certain strains carrying virulence factor genes. The antibiotic resistance profiling of UPEC strains elucidates that the antimicrobial agents such as chloramphenicol, cefoxitin, cefepime, ceftazidime might still be used in the therapy for treating UTIs. SIGNIFICANCE AND IMPACT OF THE STUDY: As the antibiotic resistance pattern of uropathogenic Escherichia coli varies depending on different geographical regions, the antibiotic resistance pattern from this study will help the physicians to effectively administer antibiotic therapy for urinary tract infections. In addition, the frequency of virulence factors and antibiotic resistance genes among various phylogenic groups could be effectively used to draw new targets for uropathogenic Escherichia coli antibiotic independent therapies. The study emphasizes need of public awareness on multidrug resistance and for more prudent use of antimicrobials. PMID- 26518619 TI - Belgian Wildlife as Potential Zoonotic Reservoir of Hepatitis E Virus. AB - Hepatitis E is an acute human liver disease in healthy individuals but may become chronic in immunocompromised patients. It is caused by the hepatitis E virus (HEV) and can have a zoonotic origin, particularly in high-income countries. In this study, 383 sera from wild boars were selected for serology; for virological analyses, 69 sera and 61 livers from young wild boars were used. A total of 189 and 235 sera of, respectively, red deer and roe deer were collected for serological analysis. For virological analyses, 84 and 68 sera and 29 and 27 livers from, respectively, red and roe deer were sampled. An apparent seroprevalence of 34% (95% CI 29.71-39.46) was found in wild boars, of 1% (95% CI 0-2.4) in red deer and 3% (95% CI 0.8-4.2) in roe deer. To assess the ELISA screening prevalence, Western blot (WB) analyses were carried out, a receiver operating characteristic curve analysis was performed and different scenarios with varying ELISA specificities relative to WB were analysed. Seroprevalence remained high whatever the scenario in the wild boar population. In wild boar, 4 of 69 sera and 4 of 61 livers were detected as positive for HEV RNA. All sequences obtained from sera belonged to genotype HEV-3. HEV RNA, belonging to genotype HEV-3, was detected in one of 29 red deer livers. Wild boar can be considered as a host reservoir of the virus in Belgium. However, in contrast to the epidemiological role played by them in other countries, the low prevalence in deer makes these species an unlikely reservoir. This evidence needs further investigation to determine in which situation deer can serve as reservoir. These results also raise the question of the dynamics of HEV infection between wild fauna, domestic pigs and humans. PMID- 26518621 TI - Functional Genomics Analysis of Big Data Identifies Novel Peroxisome Proliferator Activated Receptor gamma Target Single Nucleotide Polymorphisms Showing Association With Cardiometabolic Outcomes. AB - BACKGROUND: Cardiovascular disease and type 2 diabetes mellitus represent overlapping diseases where a large portion of the variation attributable to genetics remains unexplained. An important player in their pathogenesis is peroxisome proliferator-activated receptor gamma (PPARgamma) that is involved in lipid and glucose metabolism and maintenance of metabolic homeostasis. We used a functional genomics methodology to interrogate human chromatin immunoprecipitation-sequencing, genome-wide association studies, and expression quantitative trait locus data to inform selection of candidate functional single nucleotide polymorphisms (SNPs) falling in PPARgamma motifs. METHODS AND RESULTS: We derived 27 328 chromatin immunoprecipitation-sequencing peaks for PPARgamma in human adipocytes through meta-analysis of 3 data sets. The PPARgamma consensus motif showed greatest enrichment and mapped to 8637 peaks. We identified 146 SNPs in these motifs. This number was significantly less than would be expected by chance, and Inference of Natural Selection from Interspersed Genomically coHerent elemenTs analysis indicated that these motifs are under weak negative selection. A screen of these SNPs against genome-wide association studies for cardiometabolic traits revealed significant enrichment with 16 SNPs. A screen against the MuTHER expression quantitative trait locus data revealed 8 of these were significantly associated with altered gene expression in human adipose, more than would be expected by chance. Several SNPs fall close, or are linked by expression quantitative trait locus to lipid-metabolism loci including CYP26A1. CONCLUSIONS: We demonstrated the use of functional genomics to identify SNPs of potential function. Specifically, that SNPs within PPARgamma motifs that bind PPARgamma in adipocytes are significantly associated with cardiometabolic disease and with the regulation of transcription in adipose. This method may be used to uncover functional SNPs that do not reach significance thresholds in the agnostic approach of genome-wide association studies. PMID- 26518620 TI - Seatbelt sign in a case of blunt abdominal trauma; what lies beneath it? AB - BACKGROUND: The reported incidence of hollow viscus injuries (HVI) in blunt trauma patients is approximately 1%. The most common site of injury to the intestine in blunt abdominal trauma (BAT) is the small bowel followed by colon, with mesenteric injuries occurring three times more commonly than bowel injuries. Isolated colon injury is a rarely encountered condition. Clinical assessment alone in patients with suspected intestinal or mesenteric injury after blunt trauma is associated with unacceptable diagnostic delays. CASE PRESENTATION: This is a case of a 31-year-old man, admitted to the emergency department after being the restrained driver, involved in a car accident. After initial resuscitation, focused assessment with sonography for trauma examination (FAST) was performed revealing a subhepatic mass, suspicious for intraperitoneal hematoma. A computed tomography scan (CT) that followed showed a hematoma of the mesocolon of the ascending colon with active extravasation of intravenous contrast material. An exploratory laparotomy was performed, hemoperitomeum was evacuated, and a subserosal hematoma of the cecum and ascending colon with areas of totally disrupted serosal wall was found. Hematoma of the adjacent mesocolon expanding to the root of mesenteric vessels was also noted. A right hemicolectomy along with primary ileocolonic anastomosis was performed. Patient's recovery progressed uneventfully. CONCLUSION: Identifying an isolated traumatic injury to the bowel or mesentery after BAT can be a clinical challenge because of its subtle and nonspecific clinical findings; meeting that challenge may eventually lead to a delay in diagnosis and treatment with subsequent increase in associated morbidity and mortality. Isolated colon injury is a rare finding after blunt trauma and usually accompanied by other intra-abdominal organ injuries. Abdominal 'seatbelt' sign, ecchymosis of the abdominal wall, increasing abdominal pain and distension are all associated with HVI. However, the accuracy of these findings remains low. Diagnostic peritoneal lavage, ultrasound, CT and diagnostic laparoscopy are used to evaluate BAT. Although CT has become the main diagnostic tool for this type of injuries, there are few pathognomonic signs of colon injury on CT. Given the potential for devastating outcomes, prompt diagnosis and treatment is necessary and high clinical suspicion is required. PMID- 26518622 TI - A case of phytodermatitis due to Ranunculus arvensis used as an herbal remedy. PMID- 26518623 TI - A six question screen to facilitate primary cardiovascular disease prevention. AB - BACKGROUND: European guidelines on primary prevention of cardiovascular disease (CVD) recommend the SCORE risk charts for determining CVD risk, which include blood pressure and serum cholesterol as risk parameters. To facilitate cost effective large-scale screening, we aimed to construct a risk score with 'non invasive' parameters as a first screening step to identify persons at increased CVD risk requiring further risk assessment. METHODS: We used data of Dutch employees from 25 organisations participating in a health risk assessment between August 2007 and January 2013. Backward multivariate logistic regression analysis was employed to select non-invasive, independent predictors of high CVD risk, defined as the 10-year risk of fatal CVD of >=5 % based on the SCORE formula. The total CVD risk score was calculated as the summed coefficients of the retained variables. RESULTS: Data of 6189 male participants was used for the development and validation of the risk score. Age, tobacco use, history of hypertension, alcohol consumption, BMI, and waist circumference were independent predictors of high CVD risk. Ten-fold cross-validation resulted in an area under the curve of 0.95 (SE 0.01, 95 % confidence interval 0.94-0.96). A cut-off score >=45 on the CVD risk score yielded a sensitivity of 0.93, and a specificity of 0.85. CONCLUSIONS: We developed a simple, non-invasive risk score that accurately identifies persons at increased CVD risk according to the SCORE formula in a population of working men. The risk score enables a stepwise approach in large screening programmes, strongly reducing the number of persons that require full risk estimation including blood pressure and cholesterol measures. PMID- 26518624 TI - Sialic acids in cancer biology and immunity. AB - During malignant transformation, glycosylation is heavily altered compared with healthy tissue due to differential expression of glycosyltransferases, glycosidases and monosaccharide transporters within the cancer microenvironment. One key change of malignant tissue glycosylation is the alteration of sialic acid processing that leads to a general upregulation of sialylated glycans (hypersialylation) on cell surfaces and an increased introduction of the non human sialic acid N-glycolyl-neuraminic acid (Neu5Gc) instead of N-acetyl neuraminic acid into cell surface glycans. These changes have been shown to be the result of altered sialyltransferase and sialidase expression. Functionally, cancer-associated hypersialylation appears to directly impact tumor cell interaction with the microenvironment, in particular the modulation of sialic acid-binding lectins on immune cells. Moreover, Neu5Gc expression in human tissues enhances inflammation due to an anti-Neu5Gc immune response, which can potentially influence inflammation-induced cancer and cancer-associated inflammation. In this review, we summarize the changes of sialic acid biology within the malignant microenvironment and the resulting effect on cancer immunity. PMID- 26518625 TI - Molecular epidemiology of hepatitis B virus infection in Switzerland: a retrospective cohort study. AB - BACKGROUND: Chronic hepatitis B virus (HBV) infection affects up to 7% of the European population. Specific HBV genotypes are associated with rapid progression to end-stage liver disease and sub-optimal interferon treatment responses. Although the geographic distribution of HBV genotypes differs between regions, it has not been studied in Switzerland, which lies at the crossroads of Europe. METHODS: In a retrospective analysis of 465 HBV samples collected between 2002 and 2013, we evaluated the HBV genotype distribution and phylogenetic determinants, as well as the prevalence of serological evidence of hepatitis delta, hepatitis C and HIV infections in Switzerland. Baseline characteristics of patients were compared across their region of origin using Fisher's exact test and ANOVA, and risk factors for HBeAg positivity were assessed using logistic regression. RESULTS: The Swiss native population represented 15.7% of HBV infected patients living in Switzerland. In the overall population, genotype D was most prevalent (58.3%), whereas genotype A (58.9%) was the predominant genotype among the Swiss native population. The prevalence of patients with anti HDV antibodies was 4.4%. Patients of Swiss origin were most likely to be HBeAg positive (38.1%). HBV genotypes of patients living in Switzerland but sharing the same original region of origin were consistent with their place of birth. CONCLUSIONS: The molecular epidemiology of HBV infection in Switzerland is driven by migration patterns and not by the genotype distribution of the native population. The prevalence of positive anti-HDV antibodies in our cohort was very low. PMID- 26518626 TI - Experiences of frequent visits to the emergency department by residents with dementia in assisted living. AB - Assisted living (AL) is a growing option for housing for older adults with dementia in the United States. Typically, nurses are not employed in AL in California. The purpose of this paper is to describe the health care incidents and experiences of residents and their family members who are transferred from AL to an (emergency department) ED. Data were collected from two dementia-only AL communities in California over a period of six months. In this study, only 32% of ED visits resulted in admission to acute care. Of the 71 residents, eight (11%) were responsible for 47% of the ED visits. Qualitative interviews with 3 employees and 9 family members and focus groups with 11 employee caregivers were conducted to augment the quantitative data. The qualitative theme of frustration and helplessness by family and staff to prevent repeated falling and ED transfers was identified, which complemented the quantitative findings. PMID- 26518628 TI - Association of age-related macular degeneration and reticular macular disease with cardiovascular disease. AB - Age-related macular degeneration is the leading cause of adult blindness in the developed world. Thus, major endeavors to understand the risk factors and pathogenesis of this disease have been undertaken. Reticular macular disease is a proposed subtype of age-related macular degeneration correlating histologically with subretinal drusenoid deposits located between the retinal pigment epithelium and the inner segment ellipsoid zone. Reticular lesions are more prevalent in females and in older age groups and are associated with a higher mortality rate. Risk factors for developing age-related macular degeneration include hypertension, smoking, and angina. Several genes related to increased risk for age-related macular degeneration and reticular macular disease are also associated with cardiovascular disease. Better understanding of the clinical and genetic risk factors for age-related macular degeneration and reticular macular disease has led to the hypothesis that these eye diseases are systemic. A systemic origin may help to explain why reticular disease is diagnosed more frequently in females as males suffer cardiovascular mortality at an earlier age, before the age of diagnosis of reticular macular disease and age-related macular degeneration. PMID- 26518627 TI - Human microRNAs profiling in response to influenza A viruses (subtypes pH1N1, H3N2, and H5N1). AB - MicroRNAs (miRNAs) play an important role in regulation of gene silencing and are involved in many cellular processes including inhibition of infected viral replication. This study investigated cellular miRNA expression profiles operating in response to influenza virus in early stage of infection which might be useful for understanding and control of viral infection. A549 cells were infected with different subtypes of influenza virus (pH1N1, H3N2 and H5N1). After 24 h post infection, miRNAs were extracted and then used for DNA library construction. All DNA libraries with different indexes were pooled together with equal concentration, followed by high-throughput sequencing based on MiSeq platform. The miRNAs were identified and counted from sequencing data by using MiSeq reporter software. The miRNAs expressions were classified into up and downregulated miRNAs compared to those found in non-infected cells. Mostly, each subtype of influenza A virus triggered the upregulated responses in miRNA expression profiles. Hsa-miR-101, hsa-miR-193b, hsa-miR-23b, and hsa-miR-30e* were upregulated when infected with all three subtypes of influenza A virus. Target prediction results showed that virus infection can trigger genes in cellular process, metabolic process, developmental process and biological regulation. This study provided some insights into the cellular miRNA profiling in response to various subtypes of influenza A viruses in circulation and which have caused outbreaks in human population. The regulated miRNAs might be involved in virus-host interaction or host defense mechanism, which should be investigated for effective antiviral therapeutic interventions. PMID- 26518629 TI - Extensive learning is associated with gray matter changes in the right hippocampus. AB - Longitudinal voxel-based morphometry studies have demonstrated increases in gray matter volume in hippocampal areas following extensive cognitive learning. Moreover, there is increasing evidence for the relevance of the subiculum in the context of learning and memory. Using longitudinal FreeSurfer analyses and hippocampus subfield segmentation the present study investigated the effects of 14weeks of intensive learning on hippocampal and subicular gray matter volume in a sample of medical students compared to control subjects not engaged in any cognitive learning activities. We found that extensive learning resulted in a significant increase of right hippocampal volume. Volume of the left hippocampus and the subiculum remained unchanged. The current findings emphasize the role of the hippocampus in semantic learning and memory processes and provide further evidence for the neuroplastic ability of the hippocampus in the context of cognitive learning. PMID- 26518630 TI - Reconstruction of shape contours from V1 activity at high resolution. AB - The role of primary visual cortex (V1) in encoding physical stimulus features is well known, while stimulus categorization is mainly attributed to higher visual areas. However, visual experience is not stripped down to invariant, categorical only "labels." Rather, visual experiences are remarkably rich with details resulting in high-resolution perception of objects. If V1 is involved in this process, high-resolution readout of shape contours should be possible from V1 activity. To test this, we presented various shapes to awake, fixating monkeys while recording V1 population activity using voltage-sensitive dye imaging. A simplified bottom-up model was constructed based on known cortical properties and without an image prior. Contours were reconstructed from single trials, in sub degree resolution by applying the inverse model to neuronal responses. These novel reconstruction results suggest V1 can be an important constituent in the detailed internal representation of visual experiences. PMID- 26518631 TI - Direct detection of optogenetically evoked oscillatory neuronal electrical activity in rats using SLOE sequence. AB - The direct detection of neuronal electrical activity is one of the most challenging goals in non-BOLD fMRI research. Previous work has demonstrated its feasibility in phantom and cell culture studies, but attempts in in vivo studies remain few and far between. Most recent in vivo studies used T2*-weighted sequences to directly detect neuronal electrical activity evoked by sensory stimulus. As neuronal electrical signal is usually comprised of a series of spectrally distributed oscillatory waveforms rather than being a direct current, it is most likely to be detected using oscillatory current sensitive sequences. In this study, we explored the potential of using the spin-lock oscillatory excitation (SLOE) sequence with spiral readout to directly detect optogenetically evoked oscillatory neuronal electrical activity, whose main spectral component can be manipulated artificially to match the resonance frequency of spin-lock RF field. In addition, experiments using the stimulus-induced rotary saturation (SIRS) sequence with spiral readout were also performed. Electrophysiological recording and MRI data acquisition were conducted on separate animals. Robust optogenetically evoked oscillatory LFP signals were observed and significant BOLD signals were acquired with the GE-EPI sequence before and after the whole SLOE and SIRS acquisitions, but no significant neuronal current MRI (ncMRI) signal changes were detected. These results indicate that the sensitivity of oscillatory current sensitive sequences needs to be further improved for direct detection of neuronal electrical activity. PMID- 26518633 TI - Identification of causal relations in neuroimaging data with latent confounders: An instrumental variable approach. AB - We consider the task of inferring causal relations in brain imaging data with latent confounders. Using a priori knowledge that randomized experimental conditions cannot be effects of brain activity, we derive statistical conditions that are sufficient for establishing a causal relation between two neural processes, even in the presence of latent confounders. We provide an algorithm to test these conditions on empirical data, and illustrate its performance on simulated as well as on experimentally recorded EEG data. PMID- 26518632 TI - Time-dependence of graph theory metrics in functional connectivity analysis. AB - Brain graphs provide a useful way to computationally model the network structure of the connectome, and this has led to increasing interest in the use of graph theory to quantitate and investigate the topological characteristics of the healthy brain and brain disorders on the network level. The majority of graph theory investigations of functional connectivity have relied on the assumption of temporal stationarity. However, recent evidence increasingly suggests that functional connectivity fluctuates over the length of the scan. In this study, we investigate the stationarity of brain network topology using a Bayesian hidden Markov model (HMM) approach that estimates the dynamic structure of graph theoretical measures of whole-brain functional connectivity. In addition to extracting the stationary distribution and transition probabilities of commonly employed graph theory measures, we propose two estimators of temporal stationarity: the S-index and N-index. These indexes can be used to quantify different aspects of the temporal stationarity of graph theory measures. We apply the method and proposed estimators to resting-state functional MRI data from healthy controls and patients with temporal lobe epilepsy. Our analysis shows that several graph theory measures, including small-world index, global integration measures, and betweenness centrality, may exhibit greater stationarity over time and therefore be more robust. Additionally, we demonstrate that accounting for subject-level differences in the level of temporal stationarity of network topology may increase discriminatory power in discriminating between disease states. Our results confirm and extend findings from other studies regarding the dynamic nature of functional connectivity, and suggest that using statistical models which explicitly account for the dynamic nature of functional connectivity in graph theory analyses may improve the sensitivity of investigations and consistency across investigations. PMID- 26518636 TI - Team of Titans: Arthur Abramson, Albert Einstein, and a Second Generation of Physiatrists. PMID- 26518635 TI - Regulatory T cells in atherosclerosis: critical immune regulatory function and therapeutic potential. AB - Atherosclerosis is a chronic inflammatory disease that is mediated by innate and adaptive immune responses. The disease is characterized by sub-endothelial accumulation and modification of lipids in the artery wall triggering an inflammatory reaction which promotes lesion progression and eventual plaque rupture, thrombus formation, and the respective clinical sequelae such as myocardial infarction or stroke. During the past decade, T-cell-mediated immune responses, especially control of pro-inflammatory signals by regulatory T cells (Tregs), have increasingly attracted the interest of experimental and clinical researchers. By suppression of T cell proliferation and secretion of anti inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta, Tregs exert their atheroprotective properties. Atherosclerosis prone, hyperlipidemic mice harbor systemically less Tregs compared to wild-type mice, suggesting an imbalance of immune cells which affects local and systemic inflammatory and potentially metabolic processes leading to atherogenesis. Restoring or increasing Treg frequency and enhancing their suppressive capacity by various modulations may pose a promising approach for treating inflammatory conditions such as cardiovascular diseases. In this review, we briefly summarize the immunological basics of atherosclerosis and introduce the role and contribution of different subsets of T cells. We then discuss experimental data and current knowledge pertaining to Tregs in atherosclerosis and perspectives on manipulating the adaptive immune system to alleviate atherosclerosis and cardiovascular disease. PMID- 26518638 TI - Correction for Cao et al., Characterization of the Human Transcription Elongation Factor Rtf1: Evidence for Nonoverlapping Functions of Rtf1 and the Paf1 Complex. PMID- 26518637 TI - The effects of omega-3 polyunsaturated fatty acids and genetic variants on methylation levels of the interleukin-6 gene promoter. AB - SCOPE: Omega-3 PUFAs (n-3 PUFAs) reduce IL-6 gene expression, but their effects on transcription regulatory mechanisms are unknown. We aimed to conduct an integrated analysis with both population and in vitro studies to systematically explore the relationships among n-3 PUFA, DNA methylation, single nucleotide polymorphisms (SNPs), gene expression, and protein concentration of IL6. METHODS AND RESULTS: Using data in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study and the Encyclopedia of DNA Elements (ENCODE) consortium, we found that higher methylation of IL6 promoter cg01770232 was associated with higher IL 6 plasma concentration (p = 0.03) and greater IL6 gene expression (p = 0.0005). Higher circulating total n-3 PUFA was associated with lower cg01770232 methylation (p = 0.007) and lower IL-6 concentration (p = 0.02). Moreover, an allele of IL6 rs2961298 was associated with higher cg01770232 methylation (p = 2.55 * 10(-7) ). The association between n-3 PUFA and cg01770232 methylation was dependent on rs2961298 genotype (p = 0.02), but higher total n-3 PUFA was associated with lower cg01770232 methylation in the heterozygotes (p = 0.04) not in the homozygotes. CONCLUSION: Higher n-3 PUFA is associated with lower methylation at IL6 promoter, which may be modified by IL6 SNPs. PMID- 26518639 TI - Correction for Fukuda et al., Conditional Transgenic System for Mouse Aurora A Kinase: Degradation by the Ubiquitin Proteasome Pathway Controls the Level of the Transgenic Protein. PMID- 26518642 TI - Response letter. PMID- 26518641 TI - Effects of artemisinin in broiler chickens challenged with Eimeria acervulina, E. maxima and E. tenella in battery trials. AB - Four experiments were conceived in order to test the efficacy of artemisinin, a sesquiterpene lactone derived from Artemisia annua, in single experimental infection of broiler chickens with Eimeria acervulina (1 * 10(5) oocysts), Eimeria maxima (5 * 10(4) oocysts) or Eimeria tenella (1 * 10(4) oocysts), and mixed infection with all 3 species (3.2 * 10(4) Eimeria spp. oocysts). For each experiment, three different dosages of artemisinin (5, 50 and 500 ppm) were compared with a negative control (uninfected, unmedicated), a positive control (infected, unmedicated) and a classical anticoccidial (monensin). The weight gain (WG), feed conversion ratio (FCR), oocysts shedded per gram of feces (OPG), lesion score, oocysts sporulation rates and mortality rate were recorded in all groups. The dosage of 5 ppm of artemisinin improved the WG and FCR for the chickens infected with E. acervulina. The OPG was significantly decreased in all the groups medicated with artemisinin and challenged with a mixed infection (p <= 0.01). The lesion score of the chickens challenged with Eimeria was reduced by different concentrations of artemisinin, depending on the species involved, but this compound did not have a positive effect on the lesions caused by E. acervulina. Histopathological analysis revealed superficial erosions of the intestinal mucosa, mixt. mononuclear and heterophilic inflammatory infiltrate in the lamina propria and intralesional presence of various developmental stages of parasite in groups infected with Eimeria spp.The sporulation rate of E. acervulina and E. maxima oocysts was significantly affected by 500 ppm of artemisinin, whilst the dosage of 5 ppm affected the sporulation of E. tenella oocysts. These data suggest that artemisinin is not effective against single eimerian infections but could be used as an alternative in mixed coccidiosis, especially if its effect on the oocysts sporulation would be fully investigated. PMID- 26518643 TI - Toxocara vitulorum infection in a cohort of beef calves in Iowa. AB - Toxocara vitulorum, an ascarid that infects bovines, is largely considered a parasite of tropical and sub-tropical areas of the world. Infections in more temperate climates have been reported but little is known about T. vitulorum transmission in North America. Herein, we detail an investigation of an Iowa beef farm where necropsy of a 20 day old beef calf revealed a mass of large ascarid nematodes occluding the small intestine. Gross histopathological, and molecular features of nematodes recovered from the calf were consistent with T. vitulorum. Fecal samples obtained from calves in the herd revealed 14 of 34 (40%) were shedding T. vitulorum eggs. Calves continued to shed eggs following a single dose of a topical moxidectin product. These results suggest that T. vitulorum may be more widespread in the United States than previously recognized. Due to the pathogenic nature of this parasite, further investigation into the prevalence and transmission of T. vitulorum in North America is warranted. PMID- 26518644 TI - Efficacy of major anthelmintics for reduction of fecal shedding of strongyle-type eggs in horses in the Mid-Atlantic region of the United States. AB - In the last decade there have been numerous reports of anthelmintic resistant cyathostomins in many parts of the world. The objective of the present study was to evaluate the efficacy of the commercially available anthelmintics against cyathostomin egg shedding in the Mid-Atlantic region of the United States. A total of 989 horses from 67 different farms located in southeastern Pennsylvania, northern Delaware, and northeastern Maryland were treated with fenbendazole, oxibendazole, pyrantel pamoate, ivermectin, or moxidectin at their recommended dosages. Fecal egg count reduction testing was used to determine the efficacy of each anthelmintic on those horses with fecal egg counts of >= 200 eggs per gram on the day of treatment (272 horses). Decreased efficacy (reduction of strongyle type fecal egg counts by less than 90%) was found for fenbendazole, oxibendazole, and pyrantel pamoate, with only 6%, 21% and 43% of horses showing reductions of greater than 90%, respectively. The macrocyclic lactones showed high efficacy in all horses sampled in this study. The decreased anthelmintic efficacy detected in this study adds further evidence for the existence of resistant cyathostomins throughout much of the eastern United States. Findings from this study can be used to create a more sustainable approach for parasite control programs. PMID- 26518645 TI - Prevalence and magnitude of helminth infections in organic laying hens (Gallus gallus domesticus) across Europe. AB - Helminths are associated with health- and welfare problems in organic laying hens. The present observational cross-sectional study therefore aimed to estimate the prevalence and worm burdens of intestinal helminths in organic flocks of laying hens in 8 European countries, and to identify management factors that might be associated with helminth infections, with emphasis on Ascaridia galli. Data on flock-level management factors (e.g. nutritional factors, litter quality, housing system, opening- and closing hours of popholes, pasture rotation and provision of occupational materials) were collected during a farm visit when the hens were on average 62 weeks old. Worm counts were performed for 892 hens from 55 flocks and the number of ascarid (presumably primarily A. galli) eggs per g faeces (EPG) for 881 hens from 54 flocks. The association between parasitological parameters (prevalence, worm burden and EPG) and the management factors were analysed by multivariate models. Results showed that A. galli was highly prevalent across Europe with an overall mean prevalence of 69.5% and mean worm burden of 10 worms per hen. The overall mean prevalence and worm burden for Heterakis spp. were 29.0% and 16 worms per hen, respectively, with a large variation between countries. On average, the hens excreted 576 ascarid EPG. The mean prevalence of Raillietina spp. was 13.6%. A positive correlation was found between mean A. galli worm burden and ascarid EPG. Of the analysed management factors, only pasture access time had a significant negative association with A. galli worm burden which was in contrast to the general belief that outdoor access may increase the risk of helminth infections in production animals. In conclusion, the complexity of on-farm transmission dynamics is thus a challenge when evaluating the relative importance of management factors in relation to helminth infections. PMID- 26518646 TI - Diamide accelerates opening of the Tl(+)-induced permeability transition pore in Ca(2+)-loaded rat liver mitochondria. AB - Opening of the mitochondrial permeability transition pore (MPTP) in the inner membrane is due to matrix Ca(2+) overload and matrix glutathione loss. Fixing the 'm' conformation of the adenine nucleotide translocase (ANT) by ADP or N ethylmaleimide (NEM) inhibits opening of the MPTP. Oxidants (diamide or tert butylhydroperoxide (tBHP)) fix the ANT in 'c' conformation, and the ability of ADP to inhibit the MPTP is thus attenuated. Earlier we found (Korotkov and Saris, 2011) that calcium load of rat liver mitochondria resulted in Tl(+)-induced MPTP opening, which was accompanied by a decrease in state 3, state 4, and 2,4 dinitrophenol-uncoupled respiration, as well as increased swelling and membrane potential dissipation. These effects, which were increased by diamide and tBHP, were visibly reduced in the presence of the MPTP inhibitors (ADP, NEM, and cyclosporine A). Our data suggest that conformational changes of the ANT and matrix glutathione loss may be directly involved in opening the Tl(+)-induced MPTP in the inner membrane of Ca(2+)-loaded rat liver mitochondria. PMID- 26518647 TI - Effect of resveratrol on sirtuins expression and cardiac complications in diabetes. AB - Sirtuins are the protein deacetylases, which are linked to metabolic diseases and aging. There are seven sirtuins present in cell, whose regulation in diabetic heart is yet to be explored. Resveratrol is a well-known activator of SIRT-1, but its effect on other sirtuins is not yet clear. In the present study, we focused to find out the expression and regulation of all sirtuins in diabetic heart with the effect of resveratrol administration on them. We have induced T1DM rat model using steptozotocin and T2DM rat model by feeding high fructose diet for a period of eight weeks and analyzed the myocardial changes. Resveratrol was administrated to both the models simultaneously. Increased oxidative stress and cardiac phenotype alterations shows the induction of cardiac abnormalities in both models. We have observed decreased SIRT-1 and increased SIRT-3 activity in the T2DM rat heart. Moreover, in case of T1DM, gene and protein expression of all sirtuins was down, except SIRT-2 whose protein levels were increased. Administration of resveratrol prevented the alteration in SIRT-1 in T2DM and SIRT 1, 2, 3 and SIRT-5 in T1DM rat heart. Altered level of protein acetylation was observed corresponding to the changes in sirtuins. In conclusion, sirtuins are perturbed in both types of diabetic heart and can be considered as druggable target for therapeutic intervention. PMID- 26518648 TI - Nanomedicine: Past, present and future - A global perspective. AB - Nanomedicine is an emerging and rapidly evolving field and includes the use of nanoparticles for diagnosis and therapy of a variety of diseases, as well as in regenerative medicine. In this mini-review, leaders in the field from around the globe provide a personal perspective on the development of nanomedicine. The focus lies on the translation from research to development and the innovation supply chain, as well as the current status of nanomedicine in industry. The role of academic professional societies and the importance of government funding are discussed. Nanomedicine to combat infectious diseases of poverty is highlighted along with other pertinent examples of recent breakthroughs in nanomedicine. Taken together, this review provides a unique and global perspective on the emerging field of nanomedicine. PMID- 26518649 TI - Editorial: Brave new world - Focus on nanomedicine. PMID- 26518651 TI - Cardiomyocyte specific expression of Acyl-coA thioesterase 1 attenuates sepsis induced cardiac dysfunction and mortality. AB - Compromised cardiac fatty acid oxidation (FAO) induced energy deprivation is a critical cause of cardiac dysfunction in sepsis. Acyl-CoA thioesterase 1 (ACOT1) is involved in regulating cardiac energy production via altering substrate metabolism. This study aims to clarify whether ACOT1 has a potency to ameliorate septic myocardial dysfunction via enhancing cardiac FAO. Transgenic mice with cardiomyocyte specific expression of ACOT1 (alphaMHC-ACOT1) and their wild type (WT) littermates were challenged with Escherichia coli lipopolysaccharide (LPS; 5 mg/kg i.p.) and myocardial function was assessed 6 h later using echocardiography and hemodynamics. Deteriorated cardiac function evidenced by reduction of the percentage of left ventricular ejection fraction and fractional shortening after LPS administration was significantly attenuated by cardiomyocyte specific expression of ACOT1. alphaMHC-ACOT1 mice exhibited a markedly increase in glucose utilization and cardiac FAO compared with LPS-treated WT mice. Suppression of cardiac peroxisome proliferator activated receptor alpha (PPARa) and PPARgamma coactivator-1alpha (PGC1a) signaling observed in LPS-challenged WT mice was activated by the presence of ACOT1. These results suggest that ACOT1 has potential therapeutic values to protect heart from sepsis mediated dysfunction, possibly through activating PPARa/PGC1a signaling. PMID- 26518650 TI - Thermodynamic and NMR analyses of NADPH binding to lipocalin-type prostaglandin D synthase. AB - Lipocalin-type prostaglandin D synthase (L-PGDS) is one of the most abundant proteins in human cerebrospinal fluid (CSF) with dual functions as a prostaglandin D2 (PGD2) synthase and a transporter of lipophilic ligands. Recent studies revealed that L-PGDS plays important roles in protecting against various neuronal diseases induced by reactive oxygen species (ROS). However, the molecular mechanisms of such protective actions of L-PGDS remain unknown. In this study, we conducted thermodynamic and nuclear magnetic resonance (NMR) analyses, and demonstrated that L-PGDS binds to nicotinamide coenzymes, including NADPH, NADP(+), and NADH. Although a hydrophilic ligand is not common for L-PGDS, these ligands, especially NADPH showed specific interaction with L-PGDS at the upper pocket of its ligand-binding cavity with an unusually bifurcated shape. The binding affinity of L-PGDS for NADPH was comparable to that previously reported for NADPH oxidases and NADPH in vitro. These results suggested that L-PGDS potentially attenuates the activities of NADPH oxidases through interaction with NADPH. Given that NADPH is the substrate for NADPH oxidases that play key roles in neuronal cell death by generating excessive ROS, these results imply a novel linkage between L-PGDS and ROS. PMID- 26518652 TI - Augmentation of invadopodia formation in temozolomide-resistant or adopted glioma is regulated by c-Jun terminal kinase-paxillin axis. AB - Temozolomide (TMZ) is one of the few effective anticancer agents against gliomas. However, acquisition of TMZ resistance or adaptation by gliomas is currently a crucial problem, especially increased invasiveness which is critical for the determination of clinical prognosis. This study investigated the molecular regulatory mechanisms of TMZ resistance in gliomas involved in invasiveness, particularly invadopodia formation, a molecular complex formed at the invasive front to cause extracellular matrix degradation during cellular local invasion. The TMZ-resistant clone of the U343 MG human glioma cell line (U343-R cells) was established. U343-R cells demonstrated higher invadopodia formation compared with U343 cells without TMZ resistance (U343-Con cells). Immunoblot analysis of DNA damage-related mitogen-activated protein kinase signals found increased phosphorylation of c-Jun terminal kinase (JNK) and higher activation of its downstream signaling in U343-R cells compared with U343-Con cells. Treatment of U343-R cells with specific inhibitors of JNK or siRNA targeting JNK suppressed up regulation of invadopodia formation. In addition, paxillin, one of the known JNK effectors which is phosphorylated and affects cell migration, was phosphorylated at serine 178 in JNK activity-dependent manner. Expression of paxillin with mutation of the serine 178 phosphorylation site in U343-R cells blocked invadopodia formation. The present findings suggest that increased formation of invadopodia in U343-R cells is mediated by hyperactivation of JNK-paxillin signaling, and both JNK and paxillin might become targets of novel therapies against TMZ-resistant gliomas. PMID- 26518653 TI - Parathyroid hormone-related peptide protects cardiomyocytes from oxidative stress induced cell death: First evidence of a novel endocrine-cardiovascular interaction. AB - Although there is a growing interest in the molecular cross-talk between the endocrine and cardiovascular systems, the cardiac effects of calcium-regulating hormones (i.e., parathyroid hormone-related peptide (PTHrP)) have not been explored. In this study, we examined the effect of PTHrP on the viability of isolated adult mouse cardiomyocytes subjected to oxidative stress. Myocytes from 19 to 22 week old male 129J/C57BL6 mice were exposed to oxidative insult in the form of H2O2 which led to more than 70% loss of cell viability. Herein we demonstrate, for the first time, that pretreatment with 100 nM PTHrP prior to 100 MUM H2O2 incubation prevents H2O2 -induced cell death by more than 50%. Immunoblot analysis revealed H2O2 induction of MKP-1 protein expression while PTHrP decreased MKP-1 expression. Moreover, myocytes derived from MKP1 KO mice were resistant to oxidative injury. No added benefit of PTHrP treatment was noted in MKP-1 null cardiomyocytes. Using specific pharmacological inhibitors we demonstrated that P-p38, P-ERK and P-AKT mediated PTHrP's cardioprotective action. These data provide novel evidence that: i) down-regulation of MKP1 affords profound protection against oxidative stress; and ii) PTHrP is cardioprotective, possibly via down-regulation of MKP-1 and activation of MAPK and PI3K/AKT signaling. PMID- 26518654 TI - Fire eater's pneumonia: The role of computed tomography. PMID- 26518655 TI - Pulmonary venous varix: A rare entity imitating arteriovenous malformation. PMID- 26518656 TI - Hemoptysis in tuberculosis: The importance of contrast-enhanced computed tomography. PMID- 26518657 TI - Diagnosis and treatment of hemothorax caused by intercostal artery pseudoaneurysm. PMID- 26518658 TI - Reversed halo sign: Criteria for narrowing the differential diagnosis. PMID- 26518659 TI - Cystic lung disease: The importance of a multidisciplinary approach. PMID- 26518660 TI - Pulmonary benign metastasizing leiomyoma, a rare cause of pulmonary nodules. PMID- 26518662 TI - Variable postpartum responsiveness among humans and other primates with "cooperative breeding": A comparative and evolutionary perspective. AB - This article is part of a Special Issue "Parental Care".Until recently, evolutionists reconstructing mother-infant bonding among human ancestors relied on nonhuman primate models characterized by exclusively maternal care, overlooking the highly variable responsiveness exhibited by mothers in species with obligate reliance on allomaternal care and provisioning. It is now increasingly recognized that apes as large-brained, slow maturing, and nutritionally dependent for so long as early humans were, could not have evolved unless "alloparents" (group members other than genetic parents), in addition to parents, had helped mothers to care for and provision offspring, a rearing system known as "cooperative breeding." Here I review situation-dependent maternal responses ranging from highly possessive to permissive, temporarily distancing, rejecting, or infanticidal, documented for a small subset of cooperatively breeding primates. As in many mammals, primate maternal responsiveness is influenced by physical condition, endocrinological priming, prior experience and local environments (especially related to security). But mothers among primates who evolved as cooperative breeders also appear unusually sensitive to cues of social support. In addition to more "sapient" or rational decision-making, humankind's deep history of cooperative breeding must be considered when trying to understand the extremely variable responsiveness of human mothers. PMID- 26518661 TI - The Paf1 complex factors Leo1 and Paf1 promote local histone turnover to modulate chromatin states in fission yeast. AB - The maintenance of open and repressed chromatin states is crucial for the regulation of gene expression. To study the genes involved in maintaining chromatin states, we generated a random mutant library in Schizosaccharomyces pombe and monitored the silencing of reporter genes inserted into the euchromatic region adjacent to the heterochromatic mating type locus. We show that Leo1-Paf1 [a subcomplex of the RNA polymerase II-associated factor 1 complex (Paf1C)] is required to prevent the spreading of heterochromatin into euchromatin by mapping the heterochromatin mark H3K9me2 using high-resolution genomewide ChIP (ChIP exo). Loss of Leo1-Paf1 increases heterochromatin stability at several facultative heterochromatin loci in an RNAi-independent manner. Instead, deletion of Leo1 decreases nucleosome turnover, leading to heterochromatin stabilization. Our data reveal that Leo1-Paf1 promotes chromatin state fluctuations by enhancing histone turnover. PMID- 26518663 TI - Androgens regulate sex differences in signaling but are not associated with male variation in morphology in the weakly electric fish Parapteronotus hasemani. AB - Sexually dimorphic signaling is widespread among animals and can act as an honest indicator of mate quality. Additionally, differences in signaling and morphology within a sex can be associated with different strategies for acquiring mates. Weakly electric fish communicate via self-generated electrical fields that transmit information about sex, reproductive state, and social status. The weakly electric knifefish Parapteronotus hasemani exhibits sexual dimorphism in body size as well as substantial within-male variation in body size and jaw length. We asked whether P. hasemani exhibits hormonally mediated sexual dimorphism in electrocommunication behavior. We also asked whether males with short versus long jaws differed significantly from each other in morphology, behavior, hormone levels, or reproductive maturity. Males produced longer chirps than females, but other signal parameters (electric organ discharge frequency; chirp rate and frequency modulation) were sexually monomorphic. Pharmacologically blocking androgen receptors in males reduced chirp duration, suggesting that this sexually dimorphic trait is regulated at least in part by the activational effects of androgens. Males sorted into two distinct morphological categories but did not differ in circulating 11-ketotestosterone or testosterone. Short-jawed males and long-jawed males also did not differ in any aspects of signaling. Thus, chirping and high levels of 11-ketotestosterone were reliably associated with reproductively active males but do not necessarily indicate male type or quality. This contrasts with other alternative male morph systems in which males that differ in morphology also differ in androgen profiles and signaling behavior. PMID- 26518664 TI - PTEN mRNA detection by chromogenic, RNA in situ technologies: a reliable alternative to PTEN immunohistochemistry. AB - Immunohistochemical staining for phosphatase and tensin homolog (PTEN) does not have either an acceptable standard protocol or concordance of scoring between pathologists. Evaluation of PTEN mRNA with a unique and verified sequence probe may offer a realistic alternative providing a robust and reproducible protocol. In this study, we have evaluated an in situ hybridization (ISH) protocol for PTEN mRNA using RNAScope technology and compared it with a standard protocol for PTEN immunohistochemistry (IHC). PTEN mRNA expression by ISH was consistently more sensitive than PTEN IHC, with 56% of samples on a mixed-tumor tissue microarray (TMA) showing high expression by ISH compared with 42% by IHC. On a prostate TMA, 49% of cases showed high expression by ISH compared with 43% by IHC. Variations in PTEN mRNA expression within malignant epithelium were quantifiable using image analysis on the prostate TMAs. Within tumors, clear overexpression of PTEN mRNA on malignant epithelium compared with benign epithelium was frequently observed and quantified. The use of SpotStudio software in the mixed-tumor TMA allowed for clear demonstration of varying levels of PTEN mRNA between tumor samples by the mRNA methodology. This was evident by the quantifiable differences between distinct oropharyngeal tumors (up to 3-fold increase in average number of spots per cell between 2 cases). mRNA detection of PTEN or other biomarkers, for which optimal or standardized immunohistochemical techniques are not available, represents a means by which heterogeneity of expression within focal regions of tumor can be explored with more confidence. PMID- 26518665 TI - Infliximab-associated fulminant hepatic failure in ulcerative colitis: a case report. AB - INTRODUCTION: Infliximab, an antibody against tumor necrosis factor alpha, is used to treat inflammatory bowel disease and has well-established efficacy and proven safety. Complications of this treatment are related to immunosuppression and include higher risk of serious infections and malignant neoplasia. Although extremely rare, fulminant liver damage related to infliximab therapy has been reported. CASE PRESENTATION: We present the case of a 38-year-old Afro-Brazilian woman with refractory ulcerative colitis who was started on infliximab. She had no previous history of liver disease, alcohol abuse, or infection. After the fifth dose of the medication, drug-induced liver injury was diagnosed. Treatment was discontinued but our patient's condition was aggravated by severe cholestasis and grade III/IV encephalopathy, requiring liver transplantation. CONCLUSION: Drug-induced liver injury is an uncommon complication of infliximab. Current consensus recommends screening for liver dysfunction prior to and during therapy. This case emphasizes the need for vigilance and highlights a rare and potentially lethal complication. PMID- 26518666 TI - Transvenous Implantable Cardioverter-Defibrillator (ICD) Lead Performance: A Meta Analysis of Observational Studies. AB - BACKGROUND: Despite the widespread use of implantable cardioverter-defibrillators (ICDs) in clinical practice, concerns exist regarding ICD lead durability. The performance of specific lead designs and factors determining this in large populations need clarification. METHODS AND RESULTS: The Medline, Embase, and Cochrane Collaboration databases were searched for studies including >=2 of the most commonly implanted leads. The Mantel-Haenszel random-effects model was used. Seventeen studies were selected, including a total of 49 871 patients-5538 implanted with Durata (St. Jude Medical Inc), 10 605 with Endotak Reliance (Boston Scientific), 16 119 with Sprint Quattro (Medtronic Corp), 11 709 with Sprint Fidelis (Medtronic Corp), and 5900 with Riata (St. Jude Medical Inc)-with follow-up of 136 509 lead-years. Although the Durata lead presented a numerically higher rate, no statistically significant differences in the mean incidence of lead failure (0.29%-0.45% per year) were observed in comparison of the 3 nonrecalled leads. A higher event rate was documented with the Riata (1.0% per year increase) and Sprint Fidelis (>2.0% per-year increase) leads compared with nonrecalled leads. An indication of increased incidence of Durata lead failure versus Sprint Quattro and Endotak Reliance leads was observed in 1 of 3 included studies, allowing for comparison of purely electrical lead failure, but this requires further evaluation. CONCLUSIONS: Endotak Reliance (8F), Sprint Quattro (8F), and Durata (7F) leads displayed low annual incidence of failure; however, long-term follow-up data are still scarce. More data are needed to clarify the performance and safety of the Durata lead. PMID- 26518667 TI - Reprint of: Cytotoxicity, cell uptake and microscopic analysis of titanium dioxide and silver nanoparticles in vitro. AB - Commercially manufactured nanomaterials are used massively for modification of products of everyday use, including products intended for children. Therefore their potential risks have to be ultimately studied. Aside from toxicity of nanomaterials with known specific parameters, the end-consumer is potentially endangered by materials with unknown specification. Commercially available products are not usually accompanied by parameter/specification sheet providing the consumer with sufficient chemico-physical parameters allowing the evaluation of possible toxic effects. The aim of this work was to evaluate the declared parameters of commercially available TiO2 and Ag NPs employing chemico-physical methods and consequently in vitro cytotoxicity and genotoxicity tests performed on non-cancer cell lines. Based on the results of our complex study we can conclude that the data provided by the producers are not in good agreement with the performed measurements. Furthermore, all tested NPs penetrated into the SVK14 cells and all NPs had significant effect on the kinetics of ROS production in all cell lines (note: the ROS production has not been established as the major mechanism of cell damage elicited by Ag NPs). The study revealed greater cytotoxic potential of Ag NPs in comparison with TiO2 NPs and all of the studied NPs caused significant DNA damage. PMID- 26518668 TI - Retrospective analysis of cardiac tolerability of concurrent administration of trastuzumab and anthracycline-based regimen for breast cancer, to address one year-term issues in LVEF. AB - BACKGROUND: Patients with HER2-positive breast cancer, who received paclitaxel (P) followed by epirubicin at 75 mg/m2, fluorouracil, and cyclophosphamide (FEC75) and concurrent trastuzumab (Trastuzumab Group) show good cardiac tolerability. We assessed left ventricular ejection fraction (LVEF) of these patients regularly, and compared with that of HER2-negative breast cancer patients who administered P followed by FEC100 (Standard Group), and followed for more one year, and address the longer-term issues in LVEF. OBJECTIVE & METHODS: We routinely assessed LVEF, at the time of initiation, after P, after FEC, and after 1 year, and compared them between 49 patients in Trastuzumab Group and 45 patients in Standard Group. RESULTS: In Trastuzumab Group, LVEF was reduced from the initial level (63.1%) to 60.4 at ''After FEC'' (p= 0.007), but had recovered to 60.9% at ''After 1 year''. A two-way repeated-measures ANOVA demonstrated a significant decline in LVEF level along the time course (p< 0.002), but there was no interaction revealed between time course of LVEF and treatment with or without trastuzumab (p= 0.834). In addition, there was no significant difference between groups (p= 0.386)CONCLUSIONS: P followed by FEC75 with concurrent trastuzumab could provide enough evidence of cardiac safety. PMID- 26518669 TI - Delayed restraint procedure enhances cognitive recovery of spatial function after fimbria-fornix transection. AB - PURPOSE: To i) evaluate the effect of a restraint procedure (7 days, 2 h/day) on place learning after fimbria-fornix transection (FF), ii) investigate effects of early vs. late administration of restraint, and iii) establish effects of the restraint procedure on expression of brain derived neurotrophic factor (BDNF) in prefrontal cortex and hippocampus. METHODS: Fifty rats subjected to FF or sham surgery and divided into groups exposed to restraint immediately (early restraint) or 21 days (late restraint) after surgery were trained to acquire an allocentric place learning task. In parallel, 29 animals were subjected to FF or sham surgery and an identical restraint procedure in order to measure concentrations of BDNF and corticosterone. RESULTS: The performance of the sham operated rats was positively affected by the late restraint. In FF-lesioned animals, the late restraint significantly improved task performance compared to the lesioned group with no restraint, while the early restraint was associated with a negative impact on task acquisition. Biochemical analysis after restraint procedure revealed a lesion-induced upregulation of BDNF in FF animals. CONCLUSIONS: The improved task performance of lesioned animals suggests a therapeutic effect of this manipulation, independent of BDNF. This effect is sensitive to the temporal administration of treatment. PMID- 26518670 TI - Neurophysiologic predictors of motor function in stroke. AB - PURPOSE: Understanding the neural mechanisms of stroke recovery is of paramount importance for neurorehabilitation. METHODS: For this purpose, we analyzed several TMS and EEG variables and their association with motor recovery. Thirty five subjects with chronic stroke were recruited. The neurophysiological examination included assessments by transcranial magnetic stimulation (TMS), intra- and inter-hemispheric EEG coherence in different frequency bands (e.g. alpha (8-13 Hz)) as determined by quantitative electroencephalography (qEEG). Motor function was measured by Fugl-Meyer (FM). Multiple univariate and multivariate linear regression analyses were performed to identify the predictors for FM. RESULTS: Multivariate analyses, showed a significant interaction effect of motor threshold (MT) in the lesioned hemisphere and beta coherence in the unlesioned hemisphere. This interaction suggests that higher beta activity in the unlesioned hemisphere strengthens the negative association between MT and FM scores. CONCLUSIONS: Our results suggest that MT in the lesioned hemisphere is the strongest predictors of motor recovery after stroke. Moreover, cortical activity in the unlesioned hemisphere measured by qEEG provides additional information, specifying the association between MT and FM scores. Therefore, complementary application of EEG and TMS can help constitute a better model of the lesioned and the unlesioned hemispheres that supports the importance of bihemispheric activity in recovery. PMID- 26518671 TI - Integration and binding in rehabilitative sensory substitution: Increasing resolution using a new Zooming-in approach. AB - PURPOSE: To visually perceive our surroundings we constantly move our eyes and focus on particular details, and then integrate them into a combined whole. Current visual rehabilitation methods, both invasive, like bionic-eyes and non invasive, like Sensory Substitution Devices (SSDs), down-sample visual stimuli into low-resolution images. Zooming-in to sub-parts of the scene could potentially improve detail perception. Can congenitally blind individuals integrate a 'visual' scene when offered this information via different sensory modalities, such as audition? Can they integrate visual information -perceived in parts - into larger percepts despite never having had any visual experience? METHODS: We explored these questions using a zooming-in functionality embedded in the EyeMusic visual-to-auditory SSD. Eight blind participants were tasked with identifying cartoon faces by integrating their individual components recognized via the EyeMusic's zooming mechanism. RESULTS: After specialized training of just 6-10 hours, blind participants successfully and actively integrated facial features into cartooned identities in 79+/-18% of the trials in a highly significant manner, (chance level 10% ; rank-sum P < 1.55E-04). CONCLUSIONS: These findings show that even users who lacked any previous visual experience whatsoever can indeed integrate this visual information with increased resolution. This potentially has important practical visual rehabilitation implications for both invasive and non-invasive methods. PMID- 26518672 TI - Stability, purification, and applications of bromelain: A review. AB - Bromelain is a cysteine protease found in pineapple tissue. Because of its anti inflammatory and anti-cancer activities, as well as its ability to induce apoptotic cell death, bromelain has proved useful in several therapeutic areas. The market for this protease is growing, and several studies exploring various properties of this molecule have been reported. This review aims to compile this data, and summarize the main findings on bromelain in the literature to date. The physicochemical properties and stability of bromelain under different conditions are discussed. Several studies on the purification of bromelain from crude extracts using a wide range of techniques such as liquid-liquid extractions by aqueous two-phase system, ultrafiltration, precipitation, and chromatography, have been reported. Finally, the various applications of bromelain are presented. This review therefore covers the main properties of bromelain, aiming to provide an up-to-date compilation of the data reported on this enzyme. PMID- 26518673 TI - Increased hepatocellular protein carbonylation in human end-stage alcoholic cirrhosis. AB - OBJECTIVE: Oxidative stress is a significant contributing factor in the pathogenesis of alcoholic liver disease (ALD). In the murine models of chronic alcohol consumption, induction of oxidative stress results in increased peroxidation of polyunsaturated fatty acids to form highly reactive electrophilic alpha/beta unsaturated aldehydes that post-translationally modify proteins altering activity. Data are presented here suggesting that oxidative stress and the resulting carbonylation of hepatic proteins is an ongoing process involved in alcohol-induced cirrhosis. METHODS: Using age-matched pooled hepatic tissue obtained from healthy humans and patients with end stage cirrhotic ALD, overall carbonylation was assessed by immunohistochemistry and LC-MS/MS of streptavidin purified hepatic whole cell extracts treated with biotin hydrazide. Identified carbonylated proteins were further evaluated using bioinformatics analyses. RESULTS: Using immunohistochemistry and Western blotting, protein carbonylation was increased in end stage ALD occurring primarily in hepatocytes. Mass spectrometric analysis revealed a total of 1224 carbonylated proteins in normal hepatic and end-stage alcoholic cirrhosis tissue. Of these, 411 were unique to cirrhotic ALD, 261 unique to normal hepatic tissue and 552 common to both groups. Bioinformatic pathway analysis of hepatic carbonylated proteins revealed a propensity of long term EtOH consumption to increase post-translational carbonylation of proteins involved in glutathione homeostatic, glycolytic and cytoskeletal pathways. Western analysis revealed increased expression of GSTA4 and GSTpi in human ALD. Using LC-MS/MS analysis, a nonenaldehyde post translational modification was identified on Lysine 235 of the cytoskeletal protein vimentin in whole cell extracts prepared from human end stage ALD hepatic tissue. CONCLUSIONS: These studies are the first to use LC-MS/MS analysis of carbonylated proteins in human ALD and begin exploring possible mechanistic links with end-stage alcoholic cirrhosis and oxidative stress. PMID- 26518674 TI - Cu/Zn-superoxide dismutase and glutathione are involved in response to oxidative stress induced by protein denaturing effect of alachlor in Saccharomyces cerevisiae. AB - Alachlor is a widely used pre-emergent chloroacetanilide herbicide which has been shown to have many harmful ecological and environmental effects. However, the mechanism of alachlor-induced oxidative stress is poorly understood. We found that, in Saccharomyces cerevisiae, the intracellular levels of reactive oxygen species (ROS) including superoxide anions were increased only after long-term exposure to alachlor, suggesting that alachlor is not a pro-oxidant. It is likely that alachlor-induced oxidative stress may result from protein denaturation because alachlor rapidly induced an increased protein aggregation, leading to upregulation of SSA4 and HSP82 genes encoding heat shock proteins (Hsp) of Hsp70 and Hsp90 family, respectively. Although only SOD1 encoding Cu/Zn-superoxide dismutase (SOD), but not SOD2 encoding Mn-SOD, is essential for alachlor tolerance, both SODs play a crucial role in reducing alachlor-induced ROS. We found that, after alachlor exposure, glutathione production was inhibited while its utilization was increased, suggesting the role of glutathione in protecting cells against alachlor, which becomes more important when lacking Cu/Zn-SOD. Based on our results, it seems that alachlor primarily causes damages to cellular macromolecules such as proteins, leading to an induction of endogenous oxidative stress, of which intracellular antioxidant defense systems are required for elimination. PMID- 26518675 TI - Morphological Differentiation Towards Neuronal Phenotype of SH-SY5Y Neuroblastoma Cells by Estradiol, Retinoic Acid and Cholesterol. AB - Human SH-SY5Y neuroblastoma cells maintain their potential for differentiation and regression in culture conditions. The induction of differentiation could serve as a strategy to inhibit cell proliferation and tumor growth. Previous studies have shown that differentiation of SH-SY5Y cells can be induced by all trans-retinoic-acid (RA) and cholesterol (CHOL). However, signaling pathways that lead to terminal differentiation of SH-SY5Y cells are still largely unknown. The goal of this study was to examine in the RA and CHOL treated SH-SY5Y cells the additive impacts of estradiol (E2) and brain-derived neurotrophic factor (BDNF) on cell morphology, cell population growth, synaptic vesicle recycling and presence of neurofilaments. The above features indicate a higher level of neuronal differentiation. Our data show that treatment for 10 days in vitro (DIV) with RA alone or when combined with E2 (RE) or CHOL (RC), but not when combined with BDNF (RB), significantly (p < 0.01) inhibited the cell population growth. Synaptic vesicle recycling, induced by high-K(+) depolarization, was significantly increased in all treatments where RA was included (RE, RC, RB, RCB), and when all agents were added together (RCBE). Specifically, our results show for the first time that E2 treatment can alone increase synaptic vesicle recycling in SH-SY5Y cells. This work contributes to the understanding of the ways to improve suppression of neuroblastoma cells' population growth by inducing maturation and differentiation. PMID- 26518676 TI - Brazilian Pampa Biome Honey Protects Against Mortality, Locomotor Deficits and Oxidative Stress Induced by Hypoxia/Reperfusion in Adult Drosophila melanogaster. AB - We aimed to investigate the potential beneficial effects of the Brazilian Pampa biome honey in a Drosophila-based hypoxia model. Adult flies were reared in standard medium in the presence or absence of honey (at a final concentration of 10 % in medium). Then, control flies (4 % sucrose in medium) and honey-treated flies were submitted to hypoxia. Subsequently, flies were analyzed for mortality, neurolocomotor behavior (negative geotaxis), mitochondrial/oxidative stress parameters and expression of hypoxia/stress related genes by RT-qPCR. The HPLC analysis revealed the presence of phenolics and flavonoids in the studied honey. Caffeic acid was the major compound followed by p-coumaric acid and kaempferol. The presence of such compounds was correlated with a substantial antioxidant activity in vitro. Flies subjected to hypoxia presented marked mortality, locomotor deficits and changes in oxidative stress and mitochondrial activity parameters. Honey treatment was able to completely block mortality and locomotor phenotypes. In addition, honey was able to reverse ROS production and hypoxia induced changes in mitochondrial complex I and II activity. Hypoxia also induced an up-regulation in mRNA expression of Sima (HIF-1), NFkappabeta, NRF2, HOX, AKT 1, InR, dILP2, dILP5 and HSP27. Honey treatment was not able to modulate changes in the tested genes, indicating that its protective effects involve additional mechanisms other than transcriptional activity of hypoxia-driven adaptive responses in flies. Our results demonstrated, for the first time, the beneficial effects of honey against the deleterious effects of hypoxia/reperfusion processes in a complex organism. PMID- 26518677 TI - Dose-response behavior of the bacterium Vibrio fischeri exposed to pharmaceuticals and personal care products. AB - The presence of pharmaceuticals and personal care products (PPCPs) in the environment has become a real and widespread concern in recent years. Therefore, the primary goal of this study was to investigate 20 common and widely used PPCPs to assess their individual and combined effect on an important species in one trophic level, i.e., bacteria. The ecotoxicological effects of PPCPs at two different concentration ranges were determined in the bacterium Vibrio fischeri using Microtox((r)) and were statistically analyzed using three models in the GraphPad Prism 6 program for Windows, v.6.03. A four-parameter model best fit the majority of the compounds. The half maximal effective concentration (EC50) of each PPCP was estimated using the best-fitting model and was compared with the results from a recent study. Comparative analysis indicated that most compounds showed the same level of toxicity. Moreover, the stimulatory effects of PPCPs at environmental concentrations (low doses) were assessed. These results indicated that certain compounds have traditional inverted U- or J-shaped dose-response curves, and 55% of them presented a stimulatory effect below the zero effect concentration point. Effective concentrations of 0 (EC0), 5 (EC5) and 50% (EC50) were calculated for each PPCP as the ecotoxicological points. All compounds that presented narcosis as a mode of toxic action at high doses also exhibited stimulation at low concentrations. The maximum stimulatory effect of a mixture was higher than the highest stimulatory effect of each individually tested compound. Moreover, when the exposure time was increased, the hormetic effect decreased. Hormesis is being increasingly included in dose-response studies because this may have a harmful, beneficial or indifferent effect in an environment. Despite the results obtained in this research, further investigations need to be conducted to elucidate the behavior of PPCPs in aquatic environments. PMID- 26518679 TI - Do High-Risk Young Adults Use the HIV Self-Test Appropriately? Observations from a Think-Aloud Study. AB - The purpose of this study was to understand high-risk young adults' use of the rapid human immunodeficiency virus (HIV) self-test. The highest rate of new HIV infections occurs in people between 15 and 24 years. Improving identification of young people infected with HIV is a critical public health priority. The first rapid HIV self-testing kit was approved in the US in 2012. Despite the product's promise, its use by untrained young adults is not well-understood. We conducted a mixed methods study using surveys, a think-aloud protocol, observations, and in depth interviews. A systematic checklist was developed to assess participants' use of the test. A total of 21 racial and/or ethnic minority young adults aged 18 24 participated in this study. Analysis of our interview data was guided by the theory of reasoned action (TRA). Participants completed the initial procedures of the test with a mean time of 8:36 min (range of 2:04'-16:33'). On a 14-point checklist, participants had a mean score of 10.8 (SD 2.26, range 3-14). In the qualitative analysis of the participants' interviews, guided by the theoretical constructs of the TRA, the following themes emerged: "Did I use it correctly?", "Can I trust the results?" (attitude); "How will my partner react?!", "What will people think?" (subjective norm); "Quick, easy and blood free," and "Avoids the hassle of dealing with the healthcare system" (behavioral intention). This study provided evidence of the usefulness of the test perceived by young adults, especially in light of their concerns about lack of privacy in medical settings. Since many participants did not follow all of the instructions while using the test, it is not evident that young adults can correctly use the HIV self-test. Development of instructions manuals that are understandable and guide proper use of medical devices is a great need, especially in the context of home testing technology. PMID- 26518678 TI - Orbital tumours and tumour-like lesions: exploring the armamentarium of multiparametric imaging. AB - Although the orbit is a small anatomical space, the wide range of structures present within it are often the site of origin of various tumours and tumour-like conditions, both in adults and children. Cross-sectional imaging is mandatory for the detection, characterization, and mapping of these lesions. This review focuses on multiparametric imaging of orbital tumours. Each tumour is reviewed in relation to its clinical presentation, compartmental location, imaging characteristics, and its histological features. We herein describe orbital tumours as lesions of the globe (retinoblastoma, uveal melanoma), optic nerve sheath complex (meningioma, optic nerve glioma), conal-intraconal compartment (hemangioma), extraconal compartment (dermoid/epidermoid, lacrimal gland tumours, lymphoma, rhabdomysarcoma), and bone and sinus compartment (fibrous dysplasia). Lesions without any typical compartmental localization and those with multi compartment involvement (veno-lymphatic malformation, plexiform neurofibroma, idiopathic orbital pseudotumour, IgG4 related disease, metastases) are also reviewed. We discuss the role of advanced imaging techniques, such as MR diffusion-weighted imaging (DWI), diffusion tensor imaging, fluoro-2-deoxy-D glucose positron emission tomography CT (FDG-PET CT), and positron emission tomography MRI (MRI PET) as problem-solving tools in the evaluation of those orbital masses that present with non-specific morphologic imaging findings. Main messages/Teaching points * A compartment-based approach is essential for the diagnosis of orbital tumours. * CT and MRI play a key role in the work-up of orbital tumours. * DWI, PET CT, and MRI PET are complementary tools to solve diagnostic dilemmas. * Awareness of salient imaging pearls and diagnostic pitfalls avoids interpretation errors. PMID- 26518680 TI - Varicocele and concomitant dilation of the periprostatic venous plexus: effects on semen viscosity sperm parameters. AB - INTRODUCTION: Since varicocele is often associated with other venous abnormalities, this study was undertaken to evaluate the frequency of dilation of the periprostatic venous plexus (DPVP) in these patients and the effects of this association on sperm parameters before and after varicocelectomy. MATERIALS AND METHODS: Sperm parameters were evaluated using the conventional WHO criteria, and seminal fluid viscosity was further evaluated by quantitative viscometry, in 50 patients (aged 20-38 years) who underwent surgical treatment for grade III bilateral varicocele. RESULTS: Thirty patients with varicocele had also DPVP (DPVP+) (60 %). Sperm concentration and the percentage of spermatozoa with normal morphology did not differ significantly in patients with DPVP- or DPVP+ before or after surgical repair. On the other hand, sperm progressive motility was low in all patients and increased significantly after varicocele repair, but only in DPVP- patients. Before varicocele treatment, a significantly higher number of DPVP+ patients (25/30 = 83.3 %) had seminal fluid hyperviscosity compared to DPVP patient (2/20 = 10.0 %). Viscosity quantitative measurement was significantly higher in DPVP+ patients both before and after varicocele repair compared to DPVP patients. These latter showed a statistically significant reduction of sperm viscosity after varicocele surgical repair compared to pretreatment values. Finally, periprostatic venous plexus diameter and seminal fluid viscosity correlated directly in DPVP+ patients. CONCLUSIONS: In conclusion, these results showed that a large number of patients with varicocele had a concomitant DPVP. This subset of patients did not take advantage from varicocele surgical repair since only DPVP- varicocele patients showed a significant improvement of sperm progressive motility and seminal fluid viscosity. These findings suggest the evaluation of the periprostatic venous plexus and seminal fluid viscosity before patients with varicocele undergo surgical repair for asthenozoospemia. PMID- 26518681 TI - A novel heterozygous RIT1 mutation in a patient with Noonan syndrome, leukopenia, and transient myeloproliferation-a review of the literature. AB - Noonan syndrome (NS) is a genetic condition presenting with typical facies, cardiac defects, short stature, variable developmental deficit, cryptorchidism, skeletal, and other abnormalities. Germline mutations in genes involved in the RAS/MAPK signaling have been discovered to underlie NS. Recently, missense mutations in RIT1 have been reported as causative for individuals with clinical signs of NS. We report on a 2.5-year-old boy with NS phenotype with a novel heterozygous change in the RIT1 gene. The patient was born prematurely from pregnancy monitored for polyhydramnios. At 7 months of age, non-immune neutropenia and splenomegaly have been observed. During the severe pneumonia at 10 months, significant progression of hepatosplenomegaly, leukopenia with monocytosis (15-29 %), and thrombocytopenia occurred. Bone marrow evaluation showed myeloid hyperplasia and monocytosis, suggestive of myeloproliferative syndrome. Clinical phenotype (facial dysmorphism, soft hair, short neck, broad chest, widely spaced nipples, mild pectus carinatum, deep palmar creases, unilateral cryptorchidism), and moderate pulmonary valve stenosis with mild psychomotor delay were indicative of NS. DNA analysis identified a de novo heterozygous variant c.69A >T, p.(Lys23Asn) in exon 2 of the RIT1 gene, presumed to be causative. CONCLUSION: We present a patient with a clinical suspicion of NS carrying a novel substitution in RIT1 and hematologic findings not being observed in RIT1 positive patients to date. Thus, the case broadens variability of hematologic symptoms in RIT1 positive NS individuals. WHAT IS KNOWN: * Noonan syndrome is a common genetically heterogeneous disorder of autosomal dominant inheritance characterized by craniofacial dysmorphism, short stature, congenital heart defects, variable cognitive deficit, and other anomalies. What is new: * We report on a 2.5-year-old male patient with clinical signs of NS and hematologic abnormalities, in whom a novel heterozygous substitution in RIT1 with probable pathogenicity was detected. PMID- 26518683 TI - Of mice (dogs) and men: getting to the heart of obesity-associated cardiac dysfunction. PMID- 26518682 TI - Prospective associations between sedentary time, physical activity, fitness and cardiometabolic risk factors in people with type 2 diabetes. AB - AIMS/HYPOTHESIS: The aim of this study was to examine the prospective associations between objectively measured physical activity energy expenditure (PAEE), sedentary time, moderate-to-vigorous-intensity physical activity (MVPA), cardiorespiratory fitness (CRF) and cardiometabolic risk factors over 4 years in individuals with recently diagnosed diabetes. METHODS: Among 308 adults (mean age 61.0 [SD 7.2] years; 34% female) with type 2 diabetes from the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION)-Plus study, we measured physical activity using individually calibrated combined heart rate and movement sensing. Multivariable linear regression models were constructed to examine the associations between baseline PAEE, sedentary time, MVPA, CRF and cardiometabolic risk factors and clustered cardiometabolic risk (CCMR) at follow-up, and change in these exposures and change in CCMR and its components over 4 years of follow-up. RESULTS: Individuals who increased their PAEE between baseline and follow-up had a greater reduction in waist circumference (-2.84 cm, 95% CI -4.84, -0.85) and CCMR (-0.17, 95% CI 0.29, -0.04) compared with those who decreased their PAEE. Compared with individuals who decreased their sedentary time, those who increased their sedentary time had a greater increase in waist circumference (3.20 cm, 95% CI 0.84, 5.56). Increases in MVPA were associated with reductions in systolic blood pressure (-6.30 mmHg, 95% CI -11.58, -1.03), while increases in CRF were associated with reductions in CCMR (-0.23, 95% CI -0.40,-0.05) and waist circumference (-3.79 cm, 95% CI -6.62, -0.96). Baseline measures were generally not predictive of cardiometabolic risk at follow-up. CONCLUSIONS/INTERPRETATION: Encouraging people with recently diagnosed diabetes to increase their physical activity and decrease their sedentary time may have beneficial effects on their waist circumference, blood pressure and CCMR. PMID- 26518684 TI - Association of the average rate of change in HbA1c with severe adverse events: a longitudinal evaluation of audit data from the Bavarian Disease Management Program for patients with type 2 diabetes mellitus. AB - AIMS/HYPOTHESIS: In patients with type 2 diabetes mellitus, the effects of HbA1c variability on macrovascular events remain uncertain. The present investigation evaluates the association of HbA1c variability with non-fatal cardiovascular events, emergency admissions and episodes of severe hypoglycaemia in a cohort of patients newly started on insulin therapy. METHODS: HbA1c variability was defined as the rate of change in values between observations. The medical records of 406,356 patients enrolled in a disease management programme for type 2 diabetes mellitus were analysed to identify a cohort of 13,777 patients with observed transition to insulin therapy. The cohort was observed for a period of at least 5 years. Cox regression models were applied to quantify the association of HbA1c variability with the events of interest. RESULTS: The models reveal a significant non-linear association between HbA1c variability and the risk of experiencing myocardial infarction, stroke and hypoglycaemia. The lowest risk is seen with a variability of approximately 0.5% (5.5 mmol/mol) per quarter. Using Cox models to predict survival curves for the cohort with hypothetical HbA1c variability of 0.5% (5.5 mmol/mol) and 1.5% (16.4 mmol/mol) per quarter, the proportion experiencing myocardial infarction within 2 years increases significantly from 1% to 10%. The proportion experiencing stroke increases from 1% to 29%, hypoglycaemia from 2% to 24% and the risk of emergency admission from 2% to 21%. CONCLUSIONS/INTERPRETATION: In patients newly started on insulin therapy, rapid and higher HbA1c variability is associated with an increased risk of myocardial infarction, stroke, severe hypoglycaemia and emergency admission. PMID- 26518686 TI - The Temporal Stability and Predictive Ability of the Gambling Outcome Expectancies Scale (GOES): A Prospective Study. AB - Previous research using the Gambling Outcome Expectancies Scale (GOES; Flack and Morris in J Gambl Stud, 2015. doi: 10.1007/s10899-014-9484-z ) revealed the instrument has excellent psychometric properties and differentially predicts gambling frequency and problem gambling scores. However, like the existing gambling motivation scales, the GOES psychometric properties and predictive utility have not been tested outside of cross sectional studies. The current study used a prospective survey design to redress this issue. Eight hundred and ninety-three participants, drawn from the general community, completed the second wave of the gambling survey. Temporal invariance testing revealed the GOES was reliable. Furthermore, the ability of the GOES to predict gambling behaviour using baseline and concurrent measures of gambling outcome expectancies was demonstrated. Specifically, consistent with the Wave 1 results, the gambling outcome expectancies that reflect diverse reasons for gambling (e.g., social, escape, and money) preferentially predicted gambling frequency whereas the narrower range of emotion focused reasons (e.g., excitement, escape, and ego enhancement) predicted gambling problems. Considered in light of the Wave 1 findings, these results underscore the need for gambling harm minimisation initiatives to take into account the emotion-oriented reasons for gambling. PMID- 26518685 TI - Aldehyde dehydrogenase activity is necessary for beta cell development and functionality in mice. AB - AIMS/HYPOTHESIS: Pancreatic beta cells maintain glucose homeostasis and beta cell dysfunction is a major risk factor in developing diabetes. Therefore, understanding the developmental regulatory networks that define a fully functional beta cell is important for elucidating the genetic origins of the disease. Aldehyde dehydrogenase activity has been associated with stem/progenitor cells and we have previously shown that Aldh1b1 is specifically expressed in pancreas progenitor pools. Here we address the hypothesis that Aldh1b1 may regulate the timing of the appearance and eventual functionality of beta cells. METHODS: We generated an Aldh1b1-knockout mouse line (Aldh1b1 (tm1lacZ)) and used this to study pancreatic development, beta cell functionality and glucose homeostasis in the absence of Aldh1b1 function. RESULTS: Differentiation in the developing pancreas of Aldh1b1 (tm1lacZ) null mice was accelerated. Transcriptome analyses of newborn and adult islets showed misregulation of key beta cell transcription factors and genes crucial for beta cell function. Functional analyses showed that glucose-stimulated insulin secretion was severely compromised in islets isolated from null mice. Several key features of beta cell functionality were affected, including control of oxidative stress, glucose sensing, stimulus-coupling secretion and secretory granule biogenesis. As a result of beta cell dysfunction, homozygous mice developed glucose intolerance and age-dependent hyperglycaemia. CONCLUSIONS/INTERPRETATION: These findings show that Aldh1b1 influences the timing of the transition from the pancreas endocrine progenitor to the committed beta cell and demonstrate that changes in the timing of this transition lead to beta cell dysfunction and thus constitute a diabetes risk factor later in life. Gene Expression Omnibus (GEO) accession: GSE58025. PMID- 26518687 TI - Theoretical study on monometallic cyanide cluster fullerenes MCN@C74 (M=Y, Tb). AB - New monometallic cyanide cluster endohedral fullerenes MCN@C74 (M=Y, Tb) have been investigated using density functional theory. Four isomers of MCN@C74 are considered based on four lowest energy C74 (2-) isomers, namely one cage with isolated pentagons and three isomers with a pentagon-pentagon junction. The results show that the variation of the cluster size has slight influence on the structures and relative stabilities of MCN@C74. The MCN@D3h(14246)-C74 derived from the only C74 cage with the isolated pentagons are predicted to possess the lowest energy. More importantly, in MCN@D3h(14246)-C74, the encapsulated YCN or TbCN cluster is triangular, similar to the results reported on YCN@Cs(6)-C82 and TbCN@C2(5)-C82. Furthermore, IR spectra and (13)C NMR spectra have also been explored to assist future experimental characterization. PMID- 26518688 TI - Theoretical insight into the conversion of xylose to furfural in the gas phase and water. AB - Furfural (FF) is a valuable ring-containing organic compound in the decomposition of xylose and can be produced massively in hydrothermal condition. In this study, density functional theory (DFT) methods are employed to investigate the formation mechanism of FF from xylose and the solvent effects on FF formation. Kinetic and thermodynamic analyses indicate that xylulose could be the intermediate that leads to the formation of FF in the gas phase and water. The formation of xylulose is initiated by a six-membered transition state with energy barriers of 163.6 and 150.8 kJ mol(-1) in the gas phase and water, respectively. It is found that the strong stabilization of the reactants and transition states and the overall energy barriers of formation pathways of FF are reduced in water. The formation of FF is more thermodynamically favored in water compared with that in the gas phase. In addition, the inclusion of an explicit water molecule transforms four-membered transition states of ring-opening reaction, hydrogenation-cyclization, and dehydrations into less distorted six-membered transition states, which leads to the significant reduction of reaction barriers of FF formation. PMID- 26518689 TI - Substituent effects on the croconate dyes in dye sensitized solar cell applications: a density functional theory study. AB - Using the density functional theory (DFT), we studied two model croconate dyes, one with an electron-donating substituent (CR1) and the other with an electron withdrawing group (CR2). The geometric, electronic, and optical properties of these dyes were compared. Upon switching from CR1 to CR2, a considerable bathochromic shift was observed in the electronic absorption spectrum. We also investigated the adsorption behavior of the two dyes on a TiO2 (101) anatase surface by employing periodic DFT simulations. The periodic electronic-structure calculations revealed that the diketo group of CR1 bound more strongly to the TiO2 surface than that of CR2, with a binding strength comparable to that of a typical organic D-pi-A dye. In this work we evaluate in particular the effect of the electron withdrawing/donating nature of the substituent on the electronic, optical, and adsorption properties of the croconate dyes. Finally, we hope that the present study will help in the design of highly efficient dyes for dye sensitized solar cells by considering substituent effects. Graphical abstract Effect of substituent on binding energy and charge transfer. PMID- 26518690 TI - Molecular design and screening of energetic nitramine derivatives. AB - Six nitramines (N1-6) were designed with all possible arrangements of N-NO2 groups on a cyclic skeleton and structural optimization was performed using the density functional theory (DFT). We observed that all nitramines have high positive heats of formation proportionate to the number of N-NO2 groups in their molecular structure. Among the designed nitramines, N5 and N6 have crystal densities of 1.77 and 1.81 g cm(-3), respectively, which lead to reasonable respective detonation velocities (D = 8.70 and 9.07 km s(-1)) and detonation pressures (P = 33.23 and 36.57 GPa) comparable to those of RDX. To understand the relationship between sensitivity and molecular structure, bond dissociation energies, impact sensitivities (h 50), free space in crystal lattice, imbalance between the positive and negative surface potentials and heats of detonation (Q) were investigated. The comparable performance of N5 and N6 with RDX highlights the potential application of these nitramine derivatives as high energy materials and also supports the advantage of N-N bonds in the backbone and substitution of N-NO2 groups. Graphical Abstract Electrostatic potential on the 0.001 electron/bohr(3) molecular surface of N6. PMID- 26518691 TI - Recent Advances in Pediatric Use of Oral Paracetamol in Fever and Pain Management. AB - Paracetamol is a common analgesic and antipyretic drug for management of fever and mild-to-moderate pain in infants and children, and it is considered as first line therapy for the treatment of both according to international guidelines and recommendations. The mechanism of action of paracetamol is complex and multifactorial, and several aspects of the pharmacology impact its clinical use, especially in the selection of the correct analgesic and antipyretic dose. A systematic literature search was performed by following procedures for transparent reporting of systematic reviews and meta-analyses. To maximize efficacy and avoid delays in effect, use of the appropriate dose of paracetamol is paramount. Older clinical studies using paracetamol at subtherapeutic doses of <=10 mg/kg generally show that it is less effective than non-steroidal anti inflammatory drugs (NSAIDs). However, recent evidence shows that when used at dose of 15 mg/kg for fever and pain management, paracetamol is significantly more effective than placebo, and at least as effective as NSAIDs. Paracetamol 15 mg/kg has a tolerability profile similar to that of placebo and NSAIDs such as ibuprofen and ketoprofen used for short-term treatment of fever. However, when used at repetitive doses for consecutive days, paracetamol shows lower risk of adverse events compared to NSAIDs. Also, unlike NSAIDs, paracetamol is indicated for use in children of all ages. Overall, clinical evidence qualifies paracetamol 15 mg/kg a safe and effective option for treatment of pain and fever in children. PMID- 26518692 TI - Ectopies from the superior vena cava after pulmonary vein isolation in patients with atrial fibrillation. AB - Episodes of atrial fibrillation (AF) are mainly initiated by triggers from pulmonary veins (PVs). The superior vena cava (SVC) has been identified as a second major substrate of non-PV foci, but the electrophysiologic features of the SVC have not been fully investigated. We hypothesized that SVC ectopies are suppressed by predominant features of PV ectopies and tend to appear after PV isolation (PVI). We evaluated the electrophysiological characteristics and clinical implications of SVC ectopies in patients with AF during catheter ablation using high-dose isoproterenol and the atrial overdrive pacing maneuver. The manifestation patterns and modes of onset (coupling interval and appearance interval) of ectopies from both the PVs and SVC were investigated. 205 patients were enrolled [153 males and 52 females; mean age 64 +/- 10 years; paroxysmal in 143 patients (69.8 %), persistent in 40 (19.5 %), and long-standing persistent in 22 patients (10.7 %)]. Before PVI, PV ectopies were detected in 182/205 patients (89 %). SVC ectopies were rarely observed before PVI but were significantly more frequent after the completion of PVI (3/205 vs. 14/205 patients, p = 0.011). The coupling interval (CI) and % CI (CI/preceding the A-A interval * 100) of PV ectopies were significantly shorter than those of SVC ectopies (211 +/- 78 vs. 282 +/- 106 ms, p = 0.021, and 34 +/- 9 vs. 51 +/- 17 %, p < 0.001, respectively). The appearance intervals of the PV ectopies were shorter than those of the SVC ectopies (6.3 +/- 4.0 vs. 10.7 +/- 6.7 s, p = 0.030). During repeat procedures, PVs with reconnection to the left atrium were less frequently observed in patients with SVC firing than in patients without SVC firing (1.7 +/- 1.5 vs. 2.9 +/- 1.1 PVs, p = 0.029). We demonstrated that PVI tends to manifest SVC ectopies with less spontaneous activity and that an elimination of predominant ectopies from the PVs may affect appearance of SVC ectopy. PMID- 26518693 TI - Origin of pronounced differences in 77 K fluorescence of the green alga Chlamydomonas reinhardtii in state 1 and 2. AB - In response to changes in the reduction state of the plastoquinone pool in its thylakoid membrane, the green alga Chlamydomonas reinhardtti is performing state transitions: remodelling of its thylakoid membrane leads to a redistribution of excitations over photosystems I and II (PSI and PSII). These transitions are accompanied by marked changes in the 77 K fluorescence spectrum, which form the accepted signature of state transitions. The changes are generally thought to reflect a redistribution of light-harvesting complexes (LHCs) over PSII (fluorescing below 700 nm) and PSI (fluorescing above 700 nm). Here we studied the picosecond fluorescence properties of C. reinhardtti over a broad range of wavelengths with very low excitation intensities (0.2 nJ per laser pulse). Cells were directly used for time-resolved fluorescence measurements at 77 K without further treatment, such as medium exchange with glycerol. It is observed that upon going from state 1 (relatively more fluorescence below 700 nm) to state 2 (relatively more fluorescence above 700 nm), a large part of the fluorescence of LHC/PSII becomes substantially quenched in concurrence with LHC detachment from PSII, whereas the absolute amount of PSI fluorescence hardly changes. These results are in agreement with the recent proposal that the amount of LHC moving from PSII to PSI upon going from state 1 to state 2 is rather limited (Unlu et al. Proc Natl Acad Sci USA 111 (9):3460-3465, 2014). PMID- 26518694 TI - Quantum dot effects upon the interaction between porphyrins and phospholipids in cell membrane models. AB - This study employed surface pressure isotherms and spectroscopic techniques to investigate the effect of quantum dots on the interaction between porphyrins and phospholipids using Langmuir monolayers and Langmuir-Blodgett films formed from negatively charged DMPA (the sodium salt of dimyristoyl-sn-glycero-phosphatidyl acid) and zwitterionic DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) as cell membrane models in the presence of 5,10,15,20-tetrakis(4-N-tetradecyl-pyridyl) porphyrin (TMPyP), 5,10,15,20-tetrakis(p-sulfonato-phenyl) porphyrin (TPPS4) and PEG-coated CdSe/ZnS quantum dots (QD). The porphyrins present at the monolayer subphase affected the organization of the lipids at the air/liquid interface, as shown by the changes in the surface pressure-surface area isotherms. QDs enhanced the interaction of TMPyP with DMPA, improving their transference from the liquid monolayers to solid supports. A higher amount of TMPyP was transferred to DMPA Langmuir-Blodgett films when the QDs were present in the subphase as evidenced by the UV-Vis data. For DPPC the surface effects due to the presence of QDs are less evident. PMID- 26518695 TI - Network analysis of gene essentiality in functional genomics experiments. AB - Many genomic techniques have been developed to study gene essentiality genome wide, such as CRISPR and shRNA screens. Our analyses of public CRISPR screens suggest protein interaction networks, when integrated with gene expression or histone marks, are highly predictive of gene essentiality. Meanwhile, the quality of CRISPR and shRNA screen results can be significantly enhanced through network neighbor information. We also found network neighbor information to be very informative on prioritizing ChIP-seq target genes and survival indicator genes from tumor profiling. Thus, our study provides a general method for gene essentiality analysis in functional genomic experiments ( http://nest.dfci.harvard.edu ). PMID- 26518696 TI - Comparative analysis of lipopolysaccharides of pathogenic and intermediately pathogenic Leptospira species. AB - BACKGROUND: Lipopolysaccharides (LPS) are complex, amphipathic biomolecules that constitute the major surface component of Gram-negative bacteria. Leptospira, unlike other human-pathogenic spirochetes, produce LPS, which is fundamental to the taxonomy of the genus, involved in host-adaption and also the target of diagnostic antibodies. Despite its significance, little is known of Leptospira LPS composition and carbohydrate structure among different serovars. RESULTS: LPS from Leptospira interrogans serovar Copenhageni strain L1-130, a pathogenic species, and L. licerasiae serovar Varillal strain VAR 010, an intermediately pathogenic species, were studied. LPS prepared from aqueous and phenol phases were analyzed separately. L. interrogans serovar Copenhageni has additional sugars not found in L. licerasiae serovar Varillal, including fucose (2.7%), a high amount of GlcNAc (12.3%), and two different types of dideoxy HexNAc. SDS PAGE indicated that L. interrogans serovar Copenhageni LPS had a far higher molecular weight and complexity than that of L. licerasiae serovar Varillal. Chemical composition showed that L. interrogans serovar Copenhageni LPS has an extended O-antigenic polysaccharide consisting of sugars, not present in L. licerasiae serovar Varillal. Arabinose, xylose, mannose, galactose and L-glycero D-mannoheptose were detected in both the species. Fatty acid analysis by gas chromatography-mass spectrometry (GC-MS) showed the presence of hydroxypalmitate (3-OH-C16:0) only in L. interrogans serovar Copenhageni. Negative staining electron microscopic examination of LPS showed different filamentous morphologies in L. interrogans serovar Copenhageni vs. L. licerasiae serovar Varillal. CONCLUSIONS: This comparative biochemical analysis of pathogenic and intermediately pathogenic Leptospira LPS reveals important carbohydrate and lipid differences that underlie future work in understanding the mechanisms of host adaptation, pathogenicity and vaccine development in leptospirosis. PMID- 26518697 TI - Approach to the Complicated Alcohol Withdrawal Patient. AB - Alcohol withdrawal syndromes are common causes for admission to the intensive care unit. As many as one-fifth of the admitted patients have an alcohol associated disorder. Identifying the benefit of the gamma-aminobutyric acid (GABA) agonists has shifted toward methods to improve benzodiazepine (BZD) utilization. Literature validating this treatment approach in severe withdrawal, especially in the critical care setting, is limited, and extrapolation to this population may be dangerous. Multiple therapies have been suggested or utilized in the literature including continuous infusion of GABA agonists, ethanol, dexmedetomidine, antiepileptics, and antipsychotics, introducing a significant amount of variability into clinical practice. This variability in treatment approaches highlights the lack of uniformity and recommendations available for the treatment of severe refractory patients. In patients progressing to severe withdrawal, it may be warranted to escalate care with adjunctive or more aggressive therapies. Although multiple practices are commonly used, the evidence supporting their use after failing symptom-triggered or aggressive therapy with BZDs is virtually nonexistent. These patients commonly receive a multimodal approach, which varies substantially between providers and institutions. Further literature should be directed at the approach most likely to provide benefit when standard of care has failed. PMID- 26518698 TI - Impact of Randomization, Clinic Visits, and Medical and Psychiatric Cormorbidities on Continuous Positive Airway Pressure Adherence in Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: To evaluate factors associated with continuous positive airway pressure (CPAP) adherence in patients with obstructive sleep apnea (OSA) in the Apnea Positive Pressure Long-term Efficacy Study (APPLES) cohort. METHODS: The data from a prospective 6-mo multicenter randomized controlled trial with 558 subjects randomized to active CPAP and 547 to sham CPAP were analyzed to assess adherence to CPAP during first 2 mo (early period) and during months 5-6 (late period). RESULTS: Participants randomized to active CPAP had higher hours of nightly adherence compared to the sham CPAP group at both 2 (4.9 +/- 2.0 h versus 4.07 +/- 2.14 h, p < 0.001) and 6 mo (4.70 +/- 2.08 h versus 3.41 +/- 2.19 h, p < 0.001). Those assigned to sham CPAP were more likely to correctly identify their treatment group (70.0% versus 55.2%, p < 0.001). Irrespective of treatment group assignment, those who believed they were receiving active CPAP had higher hours of adherence than those who thought they were in the sham CPAP group at both 2 mo (4.91 +/- 2.01 versus 4.17 +/- 2.17, p < 0.001) and 6 mo (4.65 +/- 2.10 versus 3.65 +/- 2.22, p < 0.001). Among those randomized to active CPAP, older age was significantly related to CPAP use > 4 h per night. Presence of cardiovascular disorders was associated with higher hours of CPAP use, whereas presence of anxiety was associated with a trend toward lower hours of CPAP use. Presence of nasal congestion was associated with a decrease in mean daily CPAP use between the early and the late adherence period. The adherence during the week prior to a clinic visit was higher than the average adherence during the 2-mo period prior to the visit. CONCLUSIONS: Randomization to active therapy, belief that one is in the active treatment group, older age, and possibly presence of cardiovascular disorders are positively linked to CPAP adherence. Nasal congestion and anxiety are negatively associated with CPAP adherence. CPAP nightly usage increases as clinic visits approach. PMID- 26518699 TI - Decision Modeling in Sleep Apnea: The Critical Roles of Pretest Probability, Cost of Untreated Obstructive Sleep Apnea, and Time Horizon. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with increased morbidity and mortality, and treatment with positive airway pressure (PAP) is cost-effective. However, the optimal diagnostic strategy remains a subject of debate. Prior modeling studies have not consistently supported the widely held assumption that home sleep testing (HST) is cost-effective. METHODS: We modeled four strategies: (1) treat no one; (2) treat everyone empirically; (3) treat those testing positive during in-laboratory polysomnography (PSG) via in laboratory titration; and (4) treat those testing positive during HST with auto PAP. The population was assumed to lack independent reasons for in-laboratory PSG (such as insomnia, periodic limb movements in sleep, complex apnea). We considered the third-party payer perspective, via both standard (quality adjusted) and pure cost methods. RESULTS: The preferred strategy depended on three key factors: pretest probability of OSA, cost of untreated OSA, and time horizon. At low prevalence and low cost of untreated OSA, the treat no one strategy was favored, whereas empiric treatment was favored for high prevalence and high cost of untreated OSA. In-laboratory backup for failures in the at-home strategy increased the preference for the at-home strategy. Without laboratory backup in the at-home arm, the in-laboratory strategy was increasingly preferred at longer time horizons. CONCLUSION: Using a model framework that captures a broad range of clinical possibilities, the optimal diagnostic approach to uncomplicated OSA depends on pretest probability, cost of untreated OSA, and time horizon. Estimating each of these critical factors remains a challenge warranting further investigation. PMID- 26518700 TI - Neck Circumference-Height Ratio as a Predictor of Sleep Related Breathing Disorder in Children and Adults. AB - STUDY OBJECTIVES: While neck circumference (NC) is a useful predictor of obstructive sleep apnea (OSA) in adults, childhood OSA is difficult to predict clinically. We utilized the neck circumference-height ratio (NHR) to normalize NC in growing children. Our study aimed to determine if (1) NC is a reproducible clinical measurement; (2) NHR predicts OSA in children; (3) this metric translates to adults. METHODS: For this retrospective study, paired NC measurements (from clinic and sleep laboratory) in 100 consecutive adult subjects were used to confirm inter-observer reproducibility. Polysomnographic (PSG) and anthropometric data from children aged 5-18 years presenting consecutively between July 2007 and February 2012 was obtained. Children with genetic syndromes, severe neurological disorders, craniofacial abnormalities, tracheostomy, past adenotonsillectomy, in-hospital PSG or sleep efficiency < 80% were excluded. Data were analyzed using chi(2) test and logistic and linear regression models. These analyses were also applied to 99 adult patients with similar exclusion criteria. RESULTS: Adult NC measurement had inter-observer correlation of 0.85 (N = 100). Among children, after correcting for BMI-Z scores, NHR conferred additional predictive value, in both logistic regression and linear models, for both apnea-hypopnea index (AHI) > 2 and > 5 (N = 507). In children, for NHR > 0.25, the odds ratio of AHI > 2 was 3.47. In adults, for NHR > 0.25, the odds ratio of AHI > 5 was 18. CONCLUSIONS: NHR can be included as a simple screening tool for OSA in children and adults, which along with other predictors, may improve the ability of clinicians to triage children and adults at risk for OSA for further evaluation with PSG. PMID- 26518701 TI - Breathing and Snoring Sound Characteristics during Sleep in Adults. AB - STUDY OBJECTIVES: Sound level meter is the gold standard approach for snoring evaluation. Using this approach, it was established that snoring intensity (in dB) is higher for men and is associated with increased apnea-hypopnea index (AHI). In this study, we performed a systematic analysis of breathing and snoring sound characteristics using an algorithm designed to detect and analyze breathing and snoring sounds. The effect of sex, sleep stages, and AHI on snoring characteristics was explored. METHODS: We consecutively recruited 121 subjects referred for diagnosis of obstructive sleep apnea. A whole night audio signal was recorded using noncontact ambient microphone during polysomnography. A large number (> 290,000) of breathing and snoring (> 50 dB) events were analyzed. Breathing sound events were detected using a signal-processing algorithm that discriminates between breathing and nonbreathing (noise events) sounds. RESULTS: Snoring index (events/h, SI) was 23% higher for men (p = 0.04), and in both sexes SI gradually declined by 50% across sleep time (p < 0.01) independent of AHI. SI was higher in slow wave sleep (p < 0.03) compared to S2 and rapid eye movement sleep; men have higher SI in all sleep stages than women (p < 0.05). Snoring intensity was similar in both genders in all sleep stages and independent of AHI. For both sexes, no correlation was found between AHI and snoring intensity (r = 0.1, p = 0.291). CONCLUSIONS: This audio analysis approach enables systematic detection and analysis of breathing and snoring sounds from a full night recording. Snoring intensity is similar in both sexes and was not affected by AHI. PMID- 26518702 TI - Central Apneas and REM Sleep Behavior Disorder as an Initial Presentation of Multiple System Atrophy. AB - ABSTRACT: We present the case of a patient with multiple system atrophy who presented with central apnea as the only sleep disordered breathing, associated with REM behavior disorder and restless legs syndrome. This presentation of the disease is unusual and probably reflects more widespread involvement at the onset. With this case, we show the importance of considering this kind of disease in the differential diagnosis of central sleep apnea syndromes. PMID- 26518703 TI - Obstructive Sleep Apnea Syndrome in Company Workers: Development of a Two-Step Screening Strategy with a New Questionnaire. AB - STUDY OBJECTIVES: To develop and evaluate a screening questionnaire and a two step screening strategy for obstructive sleep apnea syndrome (OSAS) in healthy workers. METHODS: This is a cross-sectional study of 1,861 employees comprising healthy blue- and white-collar workers in two representative plants in the Netherlands from a worldwide consumer electronic company who were approached to participate. Employees were invited to complete various sleep questionnaires, and undergo separate single nasal flow recording and home polysomnography on two separate nights. RESULTS: Of the 1,861 employees, 249 provided informed consent and all nasal flow and polysomnography data were available from 176 (70.7%). OSAS was diagnosed in 65 (36.9%). A combination of age, absence of insomnia, witnessed breathing stops, and three-way scoring of the Berlin and STOPBANG questionnaires best predicted OSAS. Factor analysis identified a six-factor structure of the resulting new questionnaire: snoring, snoring severity, tiredness, witnessed apneas, sleep quality, and daytime well-being. Subsequently, some questions were removed, and the remaining questions were used to construct a new questionnaire. A scoring algorithm, computing individual probabilities of OSAS as high, intermediate, or low risk, was developed. Subsequently, the intermediate risk group was split into low and high probability for OSAS, based on nasal flow recording. This two-step approach showed a sensitivity of 63.1%, and a specificity of 90.1%. Specificity is important for low prevalence populations. CONCLUSION: A two-step screening strategy with a new questionnaire and subsequent nasal flow recording is a promising way to screen for OSAS in a healthy worker population. CLINICAL TRIAL REGISTRATION: Development and validation of a screening instrument for obstructive sleep apnea syndrome in healthy workers. Netherlands Trial Register (www.trailregister.nl), number: NTR2675. PMID- 26518704 TI - How Reliable Is Self-Reported Body Position during Sleep? AB - ABSTRACT: Many patients with obstructive sleep apnea (OSA) exhibit worsening event indices while supine. Positional therapy is an option if indices normalize in non-supine sleep. Although several methods are available for patients choosing positional therapy, monitoring adherence remains challenging in part because the reliability of self-reported sleep position is uncertain. We analyzed self reported sleep position in a sample of 300 patients who underwent clinical polysomnography (PSG) in our center. We found a broad range of discrepancy with objective body position, which was not correlated with demographics, PSG metrics, or confidence in the self-report. The results suggest that objective position monitoring can be an important complement to self-report in the management of patients opting for positional therapy. PMID- 26518705 TI - The Humanistic and Economic Burden of Narcolepsy. AB - STUDY OBJECTIVES: To evaluate the burden of narcolepsy--with respect to psychiatric comorbidities, Health-Related Quality of Life (HRQoL), direct costs for healthcare resource utilization, and indirect costs for reported work loss through comparison of patients to matched controls. METHODS: This analysis was conducted on data from the 2011, 2012, and 2013 US National Health and Wellness Survey (NHWS; 2011 NHWS n = 75,000, 2012 NHWS n = 71,157, and 2013 NHWS n = 75,000). Patients who reported a narcolepsy diagnosis (n = 437) were matched 1:2 with controls (n = 874) on age, sex, race/ethnicity, marital status, education, household income, body mass index, smoking status, alcohol use, exercise, and physical comorbidity. Chi-square tests and one-way analyses of variance were used to assess whether the narcolepsy and control groups differed on psychiatric comorbidities, HRQoL, labor force participation, work productivity, and healthcare resource utilization. RESULTS: Patients with narcolepsy, in comparison to matched controls, reported substantially (two to four times) greater psychiatric comorbidity, HRQoL impairment, prevalence of long-term disability, absenteeism, and presenteeism, and greater resource use in the past 6 mo as indicated by higher mean number of hospitalizations, emergency department visits, traditional healthcare professional visits, neurologist visits, and psychiatrist visits (each p < 0.05). CONCLUSIONS: These population-based data suggest that a narcolepsy diagnosis is associated with substantial adverse impact on mental health, HRQoL, and key economic burdens that include work impairment, resource use, and both direct and indirect costs. Although this study is cross-sectional, the results highlight the magnitude of the potential opportunity to improve mental health, lower costs, and augment work-related productivity through effective assessment and treatment of narcolepsy. PMID- 26518706 TI - Revise Respiratory Event Criteria or Revise Severity Thresholds for Sleep Apnea Definition? PMID- 26518707 TI - The Evolution of the AASM Clinical Practice Guidelines: Another Step Forward. AB - ABSTRACT: One of the goals of the American Academy of Sleep Medicine (AASM) is to provide clear, evidence-based recommendations in our clinical practice guidelines. Periodically, the AASM will assess and update the process by which these guidelines are developed so that it is in line with the standards currently being used for guideline development. The AASM is now taking the next step forward by fully adopting GRADE (Grading of Recommendation Assessment, Development and Evaluation) as the methodology used for evaluating evidence and forming clinical practice guidelines recommendations. Starting this year, AASM recommendations will be based on the following four interdependent domains: 1. quality of evidence; 2. balance of desirable and undesirable consequences; 3. patients' values and preferences; and 4. resource use (when known). AASM strengths of recommendations will be dichotomized into two categories: "Strong" and "Weak," either for or against a patient-care strategy. In an effort to provide clarity and transparency, all AASM recommendations will be actionable statements that include the specific patient population for which the patient care strategy is recommended, and clearly define the comparator against which the patient-care strategy was evaluated. In some recommendations, the comparator will be an alternative patient-care strategy (e.g., a "gold standard" or previously available alternative), while in other recommendations the comparator will be a placebo or no treatment; this is determined by the availability of evidence, and analyses decisions made by the AASM task force. Implementation of the complete GRADE criteria by the AASM allows us the best path forward towards continuing to provide high quality clinical practice guidelines. PMID- 26518709 TI - Too many numbers and complexity: time to update the classifications of neurogenetic disorders? PMID- 26518710 TI - Third of men with treatment resistant prostate cancer respond to drug that targets gene defect, study finds. PMID- 26518708 TI - NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas. AB - BACKGROUND: HPV-associated HNSCCs have a distinct etiologic mechanism and better prognosis than those with non-HPV associated HNSCCs. However, even within the each group, there is heterogeneity in survival time. Here, we test the hypothesis that specific candidate gene methylation markers (CCNA1, NDN, CD1A, DCC, p16, GADD45A) are associated with tumor recurrence and survival, in a well characterized, prospective, cohort of 346 HNSCC patients. METHODS: Kaplan-Meier curves were used to estimate survival time distributions. Multivariable Cox Proportional Hazards models were used to test associations between each methylation marker and OST/RPFT after adjusting for known or identified prognostic factors. Stratified Cox models included an interaction term between HPV and methylation marker to test for differences in the associations of the biomarker with OST or RPFT across HPV status. RESULTS: Methylation markers were differentially associated with patient characteristics. DNA hypermethylation of NDN and CD1A was found to be significantly associated with overall survival time (OST) in all HNSCC patients (NDN hazard ratio (HR): 2.35, 95% CI: 1.40-3.94; CD1A HR: 1.31, 95% CI: 1.01-1.71). Stratification by HPV status revealed hypermethylation of CD1A was associated with better OST and recurrence/persistence-free time (RPFT) (OST HR: 3.34, 95% CI: 1.88-5.93; RPFT HR: 2.06, 95% CI: 1.21-3.49), while hypomethylation of CCNA1 was associated with increased RPFT in HPV (+) patients only (HR: 0.31, 95% CI: 0.13-0.74). CONCLUSIONS: This study is the first to describe novel epigenetic alterations associated with survival in an unselected, prospectively collected, consecutive cohort of patients with HNSCC. DNA hypermethylation of NDN and CD1A was found to be significantly associated with increased overall survival time in all HNSCC patients. However, stratification by the important prognostic factor of HPV status revealed the immune marker, CD1A, and the cell cycle regulator, CCNA1 to be associated with prognosis in HPV (+) patients, specifically. Here, we identified novel methylation markers and specific, epigenetic molecular differences associated with HPV status, which warrant further investigation. PMID- 26518711 TI - Marinobacter aromaticivorans sp. nov., a polycyclic aromatic hydrocarbon degrading bacterium isolated from sea sediment. AB - A rod-shaped, Gram-stain-negative, slightly halotolerant bacterium, designated strain D15-8PT, was isolated from a sediment sample from the South China Sea. The strain could grow in NaCl concentrations ranging from 0.5 % to 10 % (w/v) (optimum 0.5-1.5 %), and could be cultivated at 10-40 degrees C (optimum 25 degrees C) and pH 5.5-9.5 (optimum pH 7.0-8.0). The strain was positive for catalase, oxidase, and hydrolysis of Tween 80, but negative for hydrolysis of DNA and gelatin, nitrite reduction, indole production, Voges-Proskauer reaction, and methyl red test. Strain D15-8PT could biodegrade naphthalene, phenanthrene, and anthracene. The major respiratory quinone was Q-9. The main cellular fatty acids were C12 : 0 (11.5 %), C14 : 0 3-methyl (22.0 %), C16 : 0 (19.2 %), C16 : 1omega9c (22.9 %), and C18 : 1omega9c (6.7 %). The polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an unidentified aminophospholipid and an unidentified phospholipid. The DNA G+C content was 56.8 mol%. Phylogenetic analyses based on 16S rRNA genes showed that strain D15-8PT was most closely related to Marinobacter maritimus JCM 12521T (98.5 % 16S rRNA gene sequence similarity), Marinobacter antarcticus CGMCC 1.10835T (98.1 %), Marinobacter lipolyticus DSM 15157T (97.1 %), and Marinobacter guineae CECT 7243T (97.0 %). Results of the gyrB gene analysis and DNA-DNA hybridization were both less than the cut-off values (90 % for gyrB gene sequence similarity and 70 % for DNA-DNA hybridization). On the basis of this taxonomic study using a polyphasic approach, strain D15-8PT represents a novel species of the genus Marinobacter, for which the name Marinobacter aromaticivorans sp. nov. is proposed. The type strain is D15-8PT ( = CGMCC 1.11015T = KCTC 23781T). PMID- 26518712 TI - Validation of a Dutch version of the Actionable 8-item screening questionnaire for neurogenic bladder overactivity in multiple sclerosis: an observational web based study. AB - BACKGROUND: In patients with multiple sclerosis (MS) the impact of urological symptoms on quality of life and daily activities is considerable. Yet, a substantial percentage of patients may not be urologically evaluated and thus fail to be treated concordantly. The 8-item Actionable questionnaire is a validated English screening tool for the detection of neurogenic bladder overactivity in MS. To enable the use of the 8-item Actionable in The Netherlands and Belgium we translated the questionnaire into the Dutch language and investigated the test-retest reliability and the concurrent validity of the Dutch version. METHODS: The process of translating the English Actionable questionnaire into the Dutch language included forward translations and back-translations. Then, in an online observational study, MS patients completed the Dutch Actionable at Days 1 and 8, and the Multiple Sclerosis Quality of Life 54-Items (MSQoL-54) and Multiple Sclerosis Impact Profile (MSIP) questionnaires at Day 1; the Expanded Disability Status Scale (EDSS) score was assessed by phone at Day 1. For assessment of the test-retest reliability Pearson's correlation coefficient (r) between the Day 1 and Day 8 Actionable scores was calculated. For assessment of the concurrent validity r values were calculated between the Day 1 Actionable score and the EDSS score, the Physical and Mental MSQoL-54 composites, and the MSIP domain and symptom disability scores. RESULTS: STUDY POPULATION: N = 141 (106 female, 35 male) (80 relapsing remitting, 48 progressive, 13 unknown), mean age 47.8 (standard deviation [SD] 10.4) years, mean EDSS score 4.7 (SD 1.8); 137 patients completed the Day 8 assessment. Pearson's r between Actionable scores Day 1 and Day 8: 0.85 (P < .0001). Pearson's r between Actionable score Day 1 and scores for EDSS 0.41 (P < 0.0001), MSQoL-54 Physical -0.31 (P = 0.0002), MSQoL-54 Mental -0.29 (P = 0.0005), MSIP Excretion and Reproductive Functions 0.44 (P < 0.0001), Muscle and Movement Functions 0.39 (P < .0001), Basic Movement Activities 0.37 (P < 0.0001), Activities of Daily Living 0.32 (P < 0.0001), Participation in Life Situations 0.29 (P = 0.0006) and Mental Functions 0.20 (P = 0.0189). CONCLUSIONS: The Dutch version of the Actionable urological screening tool for MS shows a good test-retest reliability and a good concurrent validity with disabilities and HRQoL. PMID- 26518713 TI - Psychopathy Checklist-Revised Use and Reporting Practices in Sexually Violent Predator Evaluations. AB - We surveyed evaluators who conduct sexually violent predator evaluations ( N = 95) regarding the frequency with which they use the Psychopathy Checklist-Revised (PCL-R), their rationale for use, and scoring practices. Findings suggest that evaluators use the PCL-R in sexually violent predator cases because of its perceived versatility, providing information about both mental disorder and risk. Several findings suggested gaps between research and routine practice. For example, relatively few evaluators reported providing the factor and facet scores that may be the strongest predictors of future offending, and many assessed the combination of PCL-R scores and sexual deviance using deviance measures (e.g., paraphilia diagnoses) that have not been examined in available studies. There was evidence of adversarial allegiance in PCL-R score interpretation, as well as a "bias blind spot" in PCL-R and other risk measure (Static-99R) scoring; evaluators tended to acknowledge the possibility of bias in other evaluators but not in themselves. Findings suggest the need for evaluators to carefully consider the extent to which their practices are consistent with emerging research and to be attuned to the possibility that working in adversarial settings may influence their scoring and interpretation practices. PMID- 26518714 TI - Genetic association meta-analysis: a new classification to assess ethnicity using the association of MCP-1 -2518 polymorphism and tuberculosis susceptibility as a model. AB - BACKGROUND: In meta-analyses of genetic association studies, ancestry and ethnicity are not accurately investigated. Ethnicity is usually classified using conventional race/ethnic categories or continental groupings even though they could introduce bias increasing heterogeneity between and within studies; thus decreasing the external validity of the results. In this study, we performed a meta-analysis using a novel ethnic classification system to test the association between MCP-1 -2518 polymorphism and pulmonary tuberculosis. Our new classification considers genetic distance, migration and linguistic origins, which will increase homogeneity within ethnic groups. METHODS: We included thirteen studies from three continents (Asia, Africa and Latin America) and considered seven ethnic groups (West Africa, South Africa, Saharan Africa, East Asia, South Asia, Persia and Latin America). RESULTS: The results were compared to the continental group classification. We found a significant association between MCP-1 -2518 polymorphism and TB susceptibility only in the East Asian and Latin American groups (OR 3.47, P = 0.08; OR 2.73, P = 0.02). This association is not observed in other ethnic groups that are usually considered in the Asian group, such as India and Persia, or in the African group. CONCLUSIONS: There is an association between MCP-1 -2518 polymorphism and TB susceptibility only in the East Asian and Latin American groups. We suggest the use of our new ethnic classification in future meta-analysis of genetic association studies when ancestry markers are not available. This new classification increases homogeneity for certain ethnic groups compared to the continental classification. We recommend considering previous data about migration, linguistics and genetic distance when classifying ethnicity in further studies. PMID- 26518715 TI - Laparoscopic Vaginal-Assisted Nerve-Sparing Radical Trachelectomy. AB - STUDY OBJECTIVE: To demonstrate a laparoscopic vaginal-assisted nerve-sparing radical trachelectomy. DESIGN: An edited educational video, including a step-by step description of the procedure. SETTING: Radical trachelectomy is the main surgical indication for selected cases of initial cervical cancer with a fertility-sparing approach. Although transvaginal access is the most traditional route, this technique has not gained widespread acceptance because of the complexity of the ureteral dissection and the limited amount of resected parametrial tissue. This video describes a laparoscopic technique including an adequate parametrial resection with autonomic preservation (C1 level) and a standard laparoscopic ureteric dissection under direct visualization. All parametrial dissections were performed by laparoscopy using a nerve-sparing technique. The uterine vessels were well dissected and transected at their origin. The colpotomy was performed by laparoscopy with a 1-cm vaginal margin using a monopolar energy hook. To achieve an adequate endocervical margin and to avoid thermal injury to the endocervix, the cervical section was performed transvaginally with a cold knife. The specimen was then retrieved, and a segment of the remaining cervix was removed for frozen section analysis. If the margin was free of tumor, the cervical-vaginal anastomosis was performed transvaginally. An endocervical device was placed to avoid postoperative cervical stenosis. INTERVENTIONS: Laparoscopic vaginal-assisted nerve-sparing radical trachelectomy. CONCLUSION: This video demonstrates a reproducible laparoscopic technique for radical trachelectomy with a nerve-sparing technique. The vaginal route was used at the moment of sectioning the cervix/isthmus to permit adequate margin evaluation. PMID- 26518716 TI - Role of Indocyanine Green in Sentinel Node Mapping in Gynecologic Cancer: Is Fluorescence Imaging the New Standard? AB - Sentinel lymph node biopsy has proven safe and feasible in a number of gynecologic cancers such as vulvar cancer, cervical cancer, and endometrial cancer. The proposed aim of lymphatic mapping and sentinel node identification is to decrease the associated morbidity of a complete lymphadenectomy, particularly the rate of lymphedema, while also increasing the detection of small tumor deposits in the node. Different tracers have been shown to be useful, including technetium-99 and blue dye, with a detection reported in 66% to 86%. Recently, there has been increasing interest in the use of fluorescent dies such as indocyanine green (ICG). In this report we provide a review of the existing literature regarding the use of ICG in cervical or endometrial cancer with the goal to provide details on its utility and compare it with other tracers. PMID- 26518717 TI - Databases of the marine metagenomics. AB - The metagenomic data obtained from marine environments is significantly useful for understanding marine microbial communities. In comparison with the conventional amplicon-based approach of metagenomics, the recent shotgun sequencing-based approach has become a powerful tool that provides an efficient way of grasping a diversity of the entire microbial community at a sampling point in the sea. However, this approach accelerates accumulation of the metagenome data as well as increase of data complexity. Moreover, when metagenomic approach is used for monitoring a time change of marine environments at multiple locations of the seawater, accumulation of metagenomics data will become tremendous with an enormous speed. Because this kind of situation has started becoming of reality at many marine research institutions and stations all over the world, it looks obvious that the data management and analysis will be confronted by the so-called Big Data issues such as how the database can be constructed in an efficient way and how useful knowledge should be extracted from a vast amount of the data. In this review, we summarize the outline of all the major databases of marine metagenome that are currently publically available, noting that database exclusively on marine metagenome is none but the number of metagenome databases including marine metagenome data are six, unexpectedly still small. We also extend our explanation to the databases, as reference database we call, that will be useful for constructing a marine metagenome database as well as complementing important information with the database. Then, we would point out a number of challenges to be conquered in constructing the marine metagenome database. PMID- 26518718 TI - Identification of gene markers in the development of smoking-induced lung cancer. AB - Lung cancer is a malignant tumor with high mortality in both women and men. To study the mechanisms of smoking-induced lung cancer, we analyzed microarray of GSE4115. GSE4115 was downloaded from Gene Expression Omnibus including 78 and 85 bronchial epithelium tissue samples separately from smokers with and without lung cancer. Limma package in R was used to screen differentially expressed genes (DEGs). Hierarchical cluster analysis for DEGs was conducted using orange software and visualized by distance map. Using DAVID software, functional and pathway enrichment analyses separately were conducted for the DEGs. And protein protein interaction (PPI) network was constructed using Cytoscape software. Then, the pathscores of enriched pathways were calculated. Besides, functional features were screened and optimized using the recursive feature elimination (RFE) method. Additionally, the support vector machine (SVM) method was used to train model. Total 1923 DEGs were identified between the two groups. Hierarchical cluster analysis indicated that there were differences in gene level between the two groups. And SVM analysis indicated that the five features had potential diagnostic value. Importantly, MAPK1 (degree=30), SRC (degree=29), SMAD4 (degree=23), EEF1A1 (degree=21), TRAF2 (degree=21) and PLCG1 (degree=20) had higher degrees in the PPI network of the DEGs. They might be involved in smoking induced lung cancer by interacting with each other (e.g. MAPK1-SMAD4, SMAD4 EEF1A1 and SRC-PLCG1). MAPK1, SRC, SMAD4, EEF1A1, TRAF2 and PLCG1 might be responsible for the development of smoking-induced lung cancer. PMID- 26518720 TI - Determining the role of smoking in myeloproliferative neoplasms: is it a matter of picking the right control group? PMID- 26518719 TI - IFPA Senior Award Lecture: Mammalian fetal membranes. AB - BACKGROUND: Fetal membrane development varies greatly across mammals with significant implications for models of human placentation. METHOD: Therefore the major patterns of fetal membrane development are reviewed with special focus on functions of the inverted yolk sac in murine rodents. FINDINGS: In most mammals, yolk sac and chorion form a choriovitelline placenta to support the early embryo, although this soon is supplanted by a chorioallantoic placenta. Human and haplorrhine primates follow a second pattern where precocious development of the extraembryonic mesoderm leads to formation of a secondary yolk sac within the exocoelom. In rodents there is an inverted visceral yolk sac that encloses the embryo and amnion and functions as an accessory to the chorioallantoic placenta through term. Where present, the inverted yolk sac performs a number of functions that in human are assumed by the syncytiotrophoblast of the chorioallantoic placenta. These include transfer of passive immunity, iron, cobalamin and lipoprotein; protein and lipid synthesis; haematopoiesis; and germ cell storage. Most mammals have a large, fluid-filled allantoic cavity. This is not the case in human and haplorrhine primates where there is an allantoic stalk but no allantoic cavity. Some rodents have a small allantoic cavity, but the mouse and other murine rodents do not. The evolution of amnion, yolk sac and allantois is explored. CONCLUSIONS: Fetal membranes deserve close attention. In particular, the mouse model is incomplete unless the yolk sac is studied along with the chorioallantoic placenta. PMID- 26518721 TI - Nanoparticle delivery to the brain--By focused ultrasound and self-assembled nanoparticle-stabilized microbubbles. AB - The blood-brain barrier (BBB) constitutes a significant obstacle for the delivery of drugs into the central nervous system (CNS). Nanoparticles have been able to partly overcome this obstacle and can thus improve drug delivery across the BBB. Furthermore, focused ultrasound in combination with gas filled microbubbles has opened the BBB in a temporospatial manner in animal models, thus facilitating drug delivery across the BBB. In the current study we combine these two approaches in our quest to develop a novel, generic method for drug delivery across the BBB and into the CNS. Nanoparticles were synthesized using the polymer poly(butyl cyanoacrylate) (PBCA), and such nanoparticles have been reported to cross the BBB to some extent. Together with proteins, these nanoparticles self assemble into microbubbles. Using these novel microbubbles in combination with focused ultrasound, we successfully and safely opened the BBB transiently in healthy rats. Furthermore, we also demonstrated that the nanoparticles could cross the BBB and deliver a model drug into the CNS. PMID- 26518722 TI - Targeting CD44 expressing cancer cells with anti-CD44 monoclonal antibody improves cellular uptake and antitumor efficacy of liposomal doxorubicin. AB - Although liposomes improve the safety and pharmacokinetic properties of free drugs, they have not sufficiently enhanced the therapeutic efficacy compared to them. To address this problem, targeted therapy of tumor cells holds great promise to further enhance therapeutic index and decreases off-target effects compared with non-targeted liposomes. In the context of antibody-mediated targeted cancer therapy, we evaluated the anti-tumor activity and therapeutic efficacy of Doxil, and that of Doxil modified with a monoclonal antibody (mAb) against CD44, which is one of the most well-known surface markers associated with Cancer Stem Cells (CSCs). Flow cytometry analyses and confocal laser scanning microscopy results showed significant enhanced cellular uptake of CD44-targeted Doxil (CD44-Doxil) in CD44-positive C-26 cells compared to Doxil. However, CD44 negative NIH-3T3 cells showed a similar uptake and in vitro cytotoxicity with both CD44-Doxil and non-targeted Doxil. In BALB/c mice bearing C-26 murine carcinoma, CD44-Doxil groups exhibited significantly higher doxorubicin concentration (than Doxil) inside the tumor cells, while their circulation time and distribution profile remained comparable. CD44-Doxil at doses of either 10 or 15 mg/kg resulted in superior tumor growth inhibition and higher inclination to tumor, indicating the potential of anti-CD44 mAb targeting in therapeutic efficacy improvement. This study provides proof-of-principle for actively tumor targeting concept and merits further investigations. PMID- 26518724 TI - Composites of malonic acid diamides and phospholipids--Impact of lipoplex stability on transfection efficiency. AB - The use of cationic lipids as gene delivery systems is a basic method in gene therapy. Through ongoing research, lipofection is currently the leader of non viral vectors in clinical trials. However, in order to unleash the full potential of lipofection further intensive investigations are indispensable. In this study, various lipoplex formulations were compared regarding their ability to bind DNA. To obtain information about a possible premature release of DNA at the cell surface, heparin and chondroitin dependent lipoplex destabilization experiments were carried out. Complementary investigations in cell culture were performed to quantify DNA outside the cell. Additionally, DNase I stability was investigated. In this regard a multitude of methods, namely confocal laser scanning microscopy (CLSM), polymerase chain reaction (PCR), cell culture experiments, ethidium bromide assay, gel electrophoresis, Langmuir-isotherm experiments, infrared reflection absorption spectroscopy (IRRAS), Brewster angle microscopy (BAM), zeta (zeta)-potential measurements, and dynamic light scattering (DLS), were applied. Although the complexation of DNA is a fundamental step, we show that the DNA release by biological agents (proteoglycans) and an unsuccessful cell attachment are major transfection limiting parameters. PMID- 26518725 TI - Predicting within-herd prevalence of infection with bovine leukemia virus using bulk-tank milk antibody levels. AB - Enzootic bovine leukosis (EBL) is an economically important infection of dairy cattle caused by bovine leukemia virus (BLV). Estimating the prevalence of BLV within dairy herds is a fundamental step towards pursuing efficient control programs. The objectives of this study were: (1) to determine the prevalence of BLV infection at the herd level using a bulk-tank milk (BTM) antibody ELISA in the Maritime region of Canada (3 provinces); and (2) to develop appropriate statistical models for predicting within-herd prevalence of BLV infection using BTM antibody ELISA titers. During 2013, three monthly BTM samples were collected from all dairy farms in the Maritime region of Canada (n=623) and tested for BLV milk antibodies using a commercial indirect ELISA. Based on the mean of the 3 BTM titers, 15 strata of herds (5 per province) were defined. From each stratum, 6 herds were randomly selected for a total of 90 farms. Within every selected herd, an additional BTM sample was taken (round 4), approximately 2 months after the third round. On the same day of BTM sampling, all cows that contributed milk to the fourth BTM sample were individually tested for BLV milk antibodies (n=6111) to estimate the true within-herd prevalence for the 90 herds. The association between true within-herd prevalence of BLV and means of various combinations of the BTM titers was assessed using linear regression models, adjusting for the stratified random sampling design. Herd level prevalence of BLV in the region was 90.8%. In the individual testing, 30.4% of cows were positive. True within-herd prevalences ranged from 0 to 94%. All linear regression models were able to predict the true within-herd prevalence of BLV reasonably well (R(2)>0.69). Predictions from the models were particularly accurate for low-to-medium spectrums of the BTM titers. In general, as a greater number of the four repeated BTM titers were incorporated in the models, narrower confidence intervals around the prediction lines were achieved. The model including all 4 BTM tests as the predictor had the best fit, although the models using 2 and 3 BTM tests provided similar results to 4 repeated tests. Therefore, testing two or three BTM samples with approximately two-month intervals would provide relatively precise estimates for the potential number of infected cows in a herd. The developed models in this study could be applied to control and eradication programs for BLV as cost effective tools. PMID- 26518726 TI - Sirtuins are Unaffected by PARP Inhibitors Containing Planar Nicotinamide Bioisosteres. AB - PARP-family ADP-ribosyltransferases (PARPs) and sirtuin deacetylases all use NAD(+) as cosubstrate for ADP-ribosyl transfer. PARP inhibitors are important research tools and several are being evaluated in cancer treatment. With the exception of a few tankyrase inhibitors, all current PARP inhibitors mimic the nicotinamide moiety in NAD(+) and block the nicotinamide binding pocket. We report here that while the activities of the four human sirtuin isoforms SIRT1, SIRT2, SIRT3 and SIRT6 are blocked by sirtuin inhibitor Ex527 in vitro, they are unaffected by the seven clinical and commonly used PARP inhibitors niraparib, olaparib, rucaparib, talazoparib, veliparib, PJ34, and XAV939. These findings indicate that PARP inhibitors containing planar nicotinamide mimetics do not bind to sirtuin cofactor sites. In conclusion, a simple commercially available assay can be used to rule out interference of novel PARP inhibitors with sirtuin NAD(+) binding. PMID- 26518723 TI - Nanoparticles and nanofibers for topical drug delivery. AB - This review provides the first comprehensive overview of the use of both nanoparticles and nanofibers for topical drug delivery. Researchers have explored the use of nanotechnology, specifically nanoparticles and nanofibers, as drug delivery systems for topical and transdermal applications. This approach employs increased drug concentration in the carrier, in order to increase drug flux into and through the skin. Both nanoparticles and nanofibers can be used to deliver hydrophobic and hydrophilic drugs and are capable of controlled release for a prolonged period of time. The examples presented provide significant evidence that this area of research has - and will continue to have - a profound impact on both clinical outcomes and the development of new products. PMID- 26518727 TI - Selection and sex-biased dispersal in a coastal shark: the influence of philopatry on adaptive variation. AB - Sex-biased dispersal is expected to homogenize nuclear genetic variation relative to variation in genetic material inherited through the philopatric sex. When site fidelity occurs across a heterogeneous environment, local selective regimes may alter this pattern. We assessed spatial patterns of variation in nuclear-encoded, single nucleotide polymorphisms (SNPs) and sequences of the mitochondrial control region in bonnethead sharks (Sphyrna tiburo), a species thought to exhibit female philopatry, collected from summer habitats used for gestation. Geographic patterns of mtDNA haplotypes and putatively neutral SNPs confirmed female philopatry and male-mediated gene flow along the northeastern coast of the Gulf of Mexico. A total of 30 outlier SNP loci were identified; alleles at over half of these loci exhibited signatures of latitude-associated selection. Our results indicate that in species with sex-biased dispersal, philopatry can facilitate sorting of locally adaptive variation, with the dispersing sex facilitating movement of potentially adaptive variation among locations and environments. PMID- 26518729 TI - Anticancer activity of 7-epiclusianone, a benzophenone from Garcinia brasiliensis, in glioblastoma. AB - BACKGROUND: Glioblastoma is the most common tumor of the central nervous system and one of the hardest tumors to treat. Consequently, the search for novel therapeutic options is imperative. 7-epiclusianone, a tetraprenylated benzophenone isolated from the epicarp of the native plant Garcinia brasiliensis, exhibits a range of biological activities but its prospect anticancer activity is underexplored. Thus, the aim of the present study was to evaluate the influence of 7-epiclusianone on proliferation, clonogenic capacity, cell cycle progression and induction of apoptosis in two glioblastoma cell lines (U251MG and U138MG). METHODS: Cell viability was measured by the MTS assay; for the clonogenic assay, colonies were stained with Giemsa and counted by direct visual inspection; For cell cycle analysis, cells were stained with propidium iodide and analyzed by cytometry; Cyclin A expression was determined by immunoblotting; Apoptotic cell death was determined by annexin V fluorescein isothiocyanate labeling and Caspase 3 activity in living cells. RESULTS: Viability of both cell lines was drastically inhibited; moreover, the colony formation capacity was significantly reduced, demonstrating long-term effects even after removal of the drug. 7-epiclusianone treatment at low concentrations also altered cell cycle progression, decreased the S and G2/M populations and at higher concentrations increased the number of cells at sub-G1, in concordance with the increase of apoptotic cells. CONCLUSION: The present study demonstrates for the first time the anticancer potential of 7 epiclusianone against glioblastoma cells, thus meriting its further investigation as a potential therapeutic agent. PMID- 26518728 TI - Neuronal effects of nicotine during auditory selective attention in schizophrenia. AB - Although nicotine has been shown to improve attention deficits in schizophrenia, the neurobiological mechanisms underlying this effect are poorly understood. We hypothesized that nicotine would modulate attention-associated neuronal response in schizophrenia patients in the ventral parietal cortex (VPC), hippocampus, and anterior cingulate based on previous findings in control subjects. To test this hypothesis, the present study examined response in these regions in a cohort of nonsmoking patients and healthy control subjects using an auditory selective attention task with environmental noise distractors during placebo and nicotine administration. In agreement with our hypothesis, significant diagnosis (Control vs. Patient) X drug (Placebo vs. Nicotine) interactions were observed in the VPC and hippocampus. The interaction was driven by task-associated hyperactivity in patients (relative to healthy controls) during placebo administration, and decreased hyperactivity in patients after nicotine administration (relative to placebo). No significant interaction was observed in the anterior cingulate. Task associated hyperactivity of the VPC predicted poor task performance in patients during placebo. Poor task performance also predicted symptoms in patients as measured by the Brief Psychiatric Rating Scale. These results are the first to suggest that nicotine may modulate brain activity in a selective attention dependent manner in schizophrenia. PMID- 26518731 TI - Child Passenger Safety Policy and Guidelines: Why Change Is Imperative. PMID- 26518730 TI - Left ventricular diastolic dysfunction in nonhuman primate model of dysmetabolism and diabetes. AB - BACKGROUND: Diabetes is one of the major risk factors for cardiomyopathy and heart failure with reduced ejection fraction (EF) and highly associated with left ventricular (LV) dysfunction in human. This study aimed 1) to noninvasively assess cardiac function using echocardiography; 2) to test the hypothesis that like diabetic human, cardiac function may also be compromised; in spontaneously developed obese, dysmetabolic and diabetic nonhuman primates (NHPs). METHODS: Cardiovascular functions were measured by noninvasive echocardiography in 28 control, 20 dysmetabolic/pre-diabetic and 41 diabetic cynomolgus monkeys based on fasting blood glucose and other metabolic status. RESULTS: The LV end-systolic volume (ESV) was higher while end-diastolic volume (EDV, 12 +/- 5.7 mL) and EF (63 +/- 12.8 %) significantly lower in the diabetic compared to control (14 +/- 7 mL and 68 +/- 9.8 %) group, respectively. The E/A ratio of LV trans-mitral peak flow rate during early (E) over late (A) diastole was significantly lower in the diabetic (1.19 +/- 0.45) than control (1.44 +/- 0.48) group. E-wave deceleration time (E DT) was prolonged in the diabetic (89 +/- 41 ms) compared to control (78 +/- 26 ms) group. Left atrial (LA) maximal dimension (LADmax) was significantly greater in the diabetic (1.3 +/- 0.17 cm) than control (1.1 +/- 0.16 cm) group. Biochemical tests showed that total cholesterol and LDL were significant higher in the diabetic (167 +/- 63 and 69 +/- 37 mg/dL) than both pre-diabetic (113 +/- 37 and 41 +/- 23 mg/dL) and control (120 +/- 28 and 41 +/- 17 mg/dL) groups, respectively. Multivariable logistic regression analysis demonstrated that LV systolic (reduced EF) and diastolic (abnormal E/A ratio) dysfunctions are significantly correlated with aging and hyperglycemia. Histopathology examination of the necropsy heart revealed inflammatory infiltration, cardiomyocyte hypertrophy and fragmentation, indicating the myocardial ischemia and remodeling which is consistent with the LV dysfunction phenotype. CONCLUSIONS: Using noninvasive echocardiography, the present study demonstrated for the first time that dysmetabolic and diabetic NHPs are associated with LV systolic (increased ESV, decreased EF, etc.) and diastolic (decreased EDV and E/A ratio, prolonged E DT, etc.) dysfunctions, accompanied by LA hypertrophic remodeling (increased LADmax), the phenotypes similarly to those found in diabetic patients. Thus, spontaneously developed dysmetabolic and diabetic NHPs is a highly translatable model to human diseases not only in the pathogenic mechanisms but also can be used for testing novel therapies for cardiometabolic disorders. PMID- 26518732 TI - Plasmacytoid dendritic cells are dispensable for noninfectious intestinal IgA responses in vivo. AB - Intestinal DCs orchestrate gut immune homeostasis by dampening proinflammatory T cell responses and inducing anti-inflammatory IgA responses. Although no specific DC subset has been strictly assigned so far to govern IgA response, some candidate subsets emerge. In particular, plasmacytoid DCs (pDCs), which notoriously promote anti-viral immunity and T-cell tolerance to innocuous antigens (Ags), contribute to IgA induction in response to intestinal viral infection and promote T-cell-independent IgA responses in vitro. Here, using two transgenic mouse models, we show that neither short-term nor long-term pDC depletion alters IgA class switch recombination in Peyer's patches and frequency of IgA plasma cells in intestinal mucosa at steady state, even in the absence of T-cell help. In addition, pDCs are dispensable for induction of intestinal IgA plasma cells in response to oral immunization with T-cell-dependent or T-cell independent Ags, and are not required for proliferation and IgA switch of Ag specific B cells in GALT. These results show that pDCs are dispensable for noninfectious IgA responses, and suggest that various DC subsets may play redundant roles in the control of intestinal IgA responses. PMID- 26518733 TI - Two cases of CD8-positive hypopigmented mycosis fungoides without TOX expression. PMID- 26518734 TI - Automated lesion detection on MRI scans using combined unsupervised and supervised methods. AB - BACKGROUND: Accurate and precise detection of brain lesions on MR images (MRI) is paramount for accurately relating lesion location to impaired behavior. In this paper, we present a novel method to automatically detect brain lesions from a T1 weighted 3D MRI. The proposed method combines the advantages of both unsupervised and supervised methods. METHODS: First, unsupervised methods perform a unified segmentation normalization to warp images from the native space into a standard space and to generate probability maps for different tissue types, e.g., gray matter, white matter and fluid. This allows us to construct an initial lesion probability map by comparing the normalized MRI to healthy control subjects. Then, we perform non-rigid and reversible atlas-based registration to refine the probability maps of gray matter, white matter, external CSF, ventricle, and lesions. These probability maps are combined with the normalized MRI to construct three types of features, with which we use supervised methods to train three support vector machine (SVM) classifiers for a combined classifier. Finally, the combined classifier is used to accomplish lesion detection. RESULTS: We tested this method using T1-weighted MRIs from 60 in-house stroke patients. Using leave one-out cross validation, the proposed method can achieve an average Dice coefficient of 73.1% when compared to lesion maps hand-delineated by trained neurologists. Furthermore, we tested the proposed method on the T1-weighted MRIs in the MICCAI BRATS 2012 dataset. The proposed method can achieve an average Dice coefficient of 66.5% in comparison to the expert annotated tumor maps provided in MICCAI BRATS 2012 dataset. In addition, on these two test datasets, the proposed method shows competitive performance to three state-of-the-art methods, including Stamatakis et al., Seghier et al., and Sanjuan et al. CONCLUSIONS: In this paper, we introduced a novel automated procedure for lesion detection from T1-weighted MRIs by combining both an unsupervised and a supervised component. In the unsupervised component, we proposed a method to identify lesioned hemisphere to help normalize the patient MRI with lesions and initialize/refine a lesion probability map. In the supervised component, we extracted three different-order statistical features from both the tissue/lesion probability maps obtained from the unsupervised component and the original MRI intensity. Three support vector machine classifiers are then trained for the three features respectively and combined for final voxel-based lesion classification. PMID- 26518735 TI - Development of a Gene Expression Assay for the Diagnosis of Mycobacterium bovis Infection in African Lions (Panthera leo). AB - Mycobacterium bovis infection, the cause of bovine tuberculosis (BTB), is endemic in wildlife in the Kruger National Park (KNP), South Africa. In lions, a high infection prevalence and BTB mortalities have been documented in the KNP; however, the ecological consequences of this disease are currently unknown. Sensitive assays for the detection of this infection in this species are therefore required. Blood from M. bovis-exposed, M. bovis-unexposed, M. tuberculosis-exposed and M. bovis-infected lions was incubated in QuantiFERON(r) TB Gold (QFT) tubes containing either saline or ESAT-6/CFP-10 peptides. Using qPCR, selected reference genes were evaluated for expression stability in these samples and selected target genes were evaluated as markers of antigen-dependent immune activation. The abundance of monokine induced by gamma interferon (MIG/CXCL9) mRNA, measured in relation to that of YWHAZ, was used as a marker of ESAT-6/CFP-10 sensitization. The gene expression assay results were compared between lion groups, and lenient and stringent diagnostic cut-off values were calculated. This CXCL9 gene expression assay combines a highly specific stimulation platform with a sensitive diagnostic marker that allows for discrimination between M. bovis-infected and M. bovis-uninfected lions. PMID- 26518736 TI - Performance of cognitive tests, individually and combined, for the detection of cognitive disorders amongst community-dwelling elderly people with memory complaints: the EVATEM study. AB - BACKGROUND AND PURPOSE: Dementia is a leading cause of dependence amongst the aged population. Early identification of cognitive impairment could help to delay advanced stages of dependence. This study aimed at assessing the performance of three neuropsychological tests to detect cognitive disorders in elderly subjects with memory complaints. METHODS: The EVATEM study is a prospective multicentre cohort with a 1-year follow-up. Subjects with memory complaints were selected during preventive health examinations, and three neuropsychological tests (five word, cognitive disorders examination, verbal fluency) were administered. Two groups were identified in memory clinics: (i) cognitively healthy individuals (CHI) and (ii) mild cognitive impairment or demented individuals (MCI-DI). Cross sectional analyses were performed on data at inclusion. The relationship between the diagnosis of MCI-DI/CHI and the neuropsychological tests was assessed using logistic regressions. The performance of the neuropsychological tests, individually and combined, to detect cognitive disorders was calculated. RESULTS: Of 585 subjects, 31.11% had cognitive disorders (MCI, 176 subjects; DI, six subjects). Amongst the three tests studied, the odds ratio for MCI-DI was higher for the five-word test <10 [odds ratio 3.2 (1.81; 5.63)]. The best performance was observed when the three tests were combined: specificity 90.5% and sensitivity 42.4% compared to respectively 89.2% and 28.3% for the five-word test. CONCLUSIONS: Despite the poor sensitivity of the five-word test, it seems to be the most adapted for the diagnosis of MCI-DI in older adults with a memory complaint, in prevention centres, taking into account its high specificity and its rapid administration compared to the other tests. PMID- 26518737 TI - When a melanoma is uncovered by a tattoo. PMID- 26518738 TI - Effect of X-ray treatments on Escherichia coli O157:H7, Listeria monocytogenes, Shigella flexneri, Salmonella enterica and inherent microbiota on whole mangoes. AB - The aims of this investigation were to; (i) study the effect of X-ray treatments in reducing Escherichia coli O157:H7, Listeria monocytogenes, Salmonella enterica and Shigella flexneri on whole mangoes, and (ii) study the effect of X-ray treatments on microflora counts (mesophilic counts, psychrotrophic counts and yeast and mould counts) of whole mangoes during storage at ambient temperature (22 degrees C) for 30 days. A mixture of three strains of each test organism was spot inoculated (100 MUl; approx. 8-9 log CFU ml(-1) ), separately, onto the surface (5 cm(2) ) of whole mangoes, air-dried (30 min), and then treated with different doses of X-ray (0, 0.1, 0.5, 1.0, and 1.5 kGy). Approximately 2.9, 1.8, 2.1 and 5.2 log CFU cm(-2) reduction of E. coli O157:H7, L. monocytogenes, Sh. flexneri and Salm. enterica were achieved by treatment with 0.5 kGy X-ray respectively. Furthermore, the populations of E. coli O157:H7, L. monocytogenes, Sh. flexneri and Salm. enterica were reduced to less than the detectable limit (2.0 log CFU cm(-2) ) by treatment with 1.5 kGy X-ray. Treatment with 1.5 kGy X ray significantly reduced the initial inherent microflora on skin of whole mangoes and inherent levels were significantly (P < 0.05) lower than the control sample throughout storage at 22 degrees C for 30 days. SIGNIFICANCE AND IMPACT OF THE STUDY: Fresh produce was associated with 770 outbreaks between 1990 and 2005, resulting in 35 060 cases of illness that costs the US $39 billion annually. The food industry is looking for new preservation methods. This investigation indicated that X-ray treatment was very effective against Escherichia coli O157:H7, Listeria monocytogenes, Shigella flexneri and Salmonella enterica and inherent microflora on whole mangoes which could offer an applicable approach to control pathogens and spoilage bacteria for the mango industry. PMID- 26518739 TI - Multigene phylogeny of the red algal subclass Nemaliophycidae. AB - The red algae (Rhodophyta) are a lineage of primary endosymbionts whose ancestors represent some of the first photosynthetic eukaryotes on the planet. They primarily inhabit marine ecosystems, with only ~5% of species found in freshwater systems. The subclass Nemaliophycidae is very diverse in ecological and life history features and therefore a useful model to study these traits, but the phylogenetic relationships among the orders are, for the most part, poorly resolved. To elucidate the phylogeny of the Nemaliophycidae, we constructed a nine-gene dataset comprised of nuclear, plastid, and mitochondrial markers for 67 red algal specimens. The resulting maximum likelihood (ML) phylogeny confirmed the monophyly of all orders. The sister relationship of the Acrochaetiales and Palmariales received high support and the relationship of the Balliales with Balbianiales and Entwisleiales with Colaconematales was moderately supported. The Nemaliales, Entwisleiales, Colaconematales, Palmariales and Acrochaetiales formed a highly supported clade. Unfortunately, all other relationships among the orders had low bootstrap support. Although the ML analysis did not resolve many of the relationships, further analyses suggested that a resolution is possible. A Phycas analysis supported a dichotomously branching tree and Bayesian analysis showed a similar topology with all relationships highly supported. Simulations extrapolating the number of nucleotide characters beyond the current size of the dataset suggested that most nodes in the phylogeny would be resolved if more data become available. Phylogenomic approaches will be necessary to provide a well supported phylogeny of this subclass with all relationships resolved such that the evolution of freshwater species from marine ancestors as well as reproductive traits can be explored. PMID- 26518740 TI - Implementing and testing the multispecies coalescent model: A valuable paradigm for phylogenomics. AB - In recent articles published in Molecular Phylogenetics and Evolution, Mark Springer and John Gatesy (S&G) present numerous criticisms of recent implementations and testing of the multispecies coalescent (MSC) model in phylogenomics, popularly known as "species tree" methods. After pointing out errors in alignments and gene tree rooting in recent phylogenomic data sets, particularly in Song et al. (2012) on mammals and Xi et al. (2014) on plants, they suggest that these errors seriously compromise the conclusions of these studies. Additionally, S&G enumerate numerous perceived violated assumptions and deficiencies in the application of the MSC model in phylogenomics, such as its assumption of neutrality and in particular the use of transcriptomes, which are deemed inappropriate for the MSC because the constituent exons often subtend large regions of chromosomes within which recombination is substantial. We acknowledge these previously reported errors in recent phylogenomic data sets, but disapprove of S&G's excessively combative and taunting tone. We show that these errors, as well as two nucleotide sorting methods used in the analysis of Amborella, have little impact on the conclusions of those papers. Moreover, several concepts introduced by S&G and an appeal to "first principles" of phylogenetics in an attempt to discredit MSC models are invalid and reveal numerous misunderstandings of the MSC. Contrary to the claims of S&G we show that recent computer simulations used to test the robustness of MSC models are not circular and do not unfairly favor MSC models over concatenation. In fact, although both concatenation and MSC models clearly perform well in regions of tree space with long branches and little incomplete lineage sorting (ILS), simulations reveal the erratic behavior of concatenation when subjected to data subsampling and its tendency to produce spuriously confident yet conflicting results in regions of parameter space where MSC models still perform well. S&G's claims that MSC models explain little or none (0-15%) of the observed gene tree heterogeneity observed in a mammal data set and that MSC models assume ILS as the only source of gene tree variation are flawed. Overall many of their criticisms of MSC models are invalidated when concatenation is appropriately viewed as a special case of the MSC, which in turn is a special case of emerging network models in phylogenomics. We reiterate that there is enormous promise and value in recent implementations and tests of the MSC and look forward to its increased use and refinement in phylogenomics. PMID- 26518741 TI - A Snapshot of the Extraordinary World of Social Microbiology. PMID- 26518742 TI - The effect of thyroid stimulating hormone suppressive therapy on bone geometry in the hip area of patients with differentiated thyroid carcinoma. AB - Subclinical hyperthyroidism has been reported to increase the fracture risk. However, the effect of thyroid stimulating hormone (TSH) suppressive therapy on bone geometry in the hip area of patients with differentiated thyroid carcinoma (DTC) is still unclear. The aim of this study was to investigate the effect of TSH suppression on bone geometry in the hip area of pre- and postmenopausal women with DTC. We conducted a retrospective cohort study including 99 women with DTC (25 pre- and 74 postmenopausal) who had received TSH suppressive therapy for at least 3years and 297 control subjects (75 and 222, respectively) matched for sex and age. Bone mineral density (BMD) in the spine and hip area and bone geometry at the femoral neck measured by dual energy X-ray absorptiometry (DXA) were compared between patients and controls. The association between thyroid hormone and bone parameters was investigated. All analyses of bone parameters were adjusted for age, body mass index, and serum calcium levels. In premenopausal subjects, TSH suppressive therapy was not associated with poor bone parameters. In postmenopausal subjects, patients with DTC undergoing TSH suppression showed lower cross-sectional moment of inertia (CSMI), cross-sectional area, and section modulus and thinner cortical thickness at the femoral neck than those of control subjects, whereas their femoral neck BMD was comparable with controls. Total hip BMD was lower in postmenopausal patients than in controls. CSMI and section modulus at the femoral neck were independently associated with serum free T4 levels in postmenopausal patients. The difference in femoral neck bone geometry between patients and controls was only apparent in postmenopausal DTC patients with free T4 >1.79ng/dL (23.04pmol/l), and not in those with free T4 levels <=1.79ng/dL (23.04pmol/l). TSH suppression in postmenopausal DTC patients was associated with decreased bone strength by altering bone geometry rather than BMD in the hip area, especially the femoral neck. This alteration in bone quality was observed only in patients with free T4 levels above the upper normal limit. PMID- 26518743 TI - Eye movements reveal epistemic curiosity in human observers. AB - Saccadic (rapid) eye movements are primary means by which humans and non-human primates sample visual information. However, while saccadic decisions are intensively investigated in instrumental contexts where saccades guide subsequent actions, it is largely unknown how they may be influenced by curiosity - the intrinsic desire to learn. While saccades are sensitive to visual novelty and visual surprise, no study has examined their relation to epistemic curiosity - interest in symbolic, semantic information. To investigate this question, we tracked the eye movements of human observers while they read trivia questions and, after a brief delay, were visually given the answer. We show that higher curiosity was associated with earlier anticipatory orienting of gaze toward the answer location without changes in other metrics of saccades or fixations, and that these influences were distinct from those produced by variations in confidence and surprise. Across subjects, the enhancement of anticipatory gaze was correlated with measures of trait curiosity from personality questionnaires. Finally, a machine learning algorithm could predict curiosity in a cross-subject manner, relying primarily on statistical features of the gaze position before the answer onset and independently of covariations in confidence or surprise, suggesting potential practical applications for educational technologies, recommender systems and research in cognitive sciences. With this article, we provide full access to the annotated database allowing readers to reproduce the results. Epistemic curiosity produces specific effects on oculomotor anticipation that can be used to read out curiosity states. PMID- 26518744 TI - Up-down asymmetry in vertical vection. AB - To investigate whether up-down asymmetry similar to that reported in vertical optokinetic nystagmus (OKN), that is, larger OKN responses for upward motion than for downward motion, would appear in vertical vection, we conducted three experiments. In all three experiments, participants viewed a vertically moving random-dot pattern. In Experiments 1 and 2, participants reported vection using a joystick. After each trial, they were also asked to rate the vection magnitude experienced during the stimulus presentation. In Experiment 3, eye movements and vection magnitude (rated after each trial) in response to the stimulus were measured. The results of Experiment 1 showed larger vection magnitude for the upward motion of the stimulus than for the downward motion of it. However, vection onset latency did not change much with stimulus motion direction. Experiment 2 revealed that the up-down asymmetry in vection manifested progressively during the latter part of the stimulus presentation period. Experiment 3 showed clear up-down asymmetry in both OKN and vection magnitude. These results not only indicate that up-down asymmetry similar to that reported in vertical OKN appears in vertical vection, but they also support the notion that the mechanisms underlying vection and OKN are closely related to each other. PMID- 26518745 TI - Coffee, tea, caffeine and risk of depression: A systematic review and dose response meta-analysis of observational studies. AB - SCOPE: The aim of the study was to systematically review and analyze results from observational studies on coffee, caffeine, and tea consumption and association or risk of depression. METHODS AND RESULTS: Embase and PubMed databases were searched from inception to June 2015 for observational studies reporting the odds ratios or relative risks (RRs) and 95% confidence intervals (CI) of depression by coffee/tea/caffeine consumption. Random effects models, subgroup analyses, and dose-response analyses were performed. Twelve studies with 23 datasets were included in the meta-analysis, accounting for a total of 346 913 individuals and 8146 cases of depression. Compared to individuals with lower coffee consumption, those with higher intakes had pooled RR of depression of 0.76 (95% CI: 0.64, 0.91). Dose-response effect suggests a nonlinear J-shaped relation between coffee consumption and risk of depression with a peak of protective effect for 400 mL/day. A borderline nonsignificant association between tea consumption and risk of depression was found (RR 0.70, 95% CI: 0.48, 1.01), while significant results were found only for analysis of prospective studies regarding caffeine consumption (RR = 0.84, 95% CI: 0.75, 0.93). CONCLUSION: This study suggests a protective effect of coffee and, partially, of tea and caffeine on risk of depression. PMID- 26518746 TI - Analysis of the genetic variability in Parkinson's disease from Southern Spain. AB - To date, a large spectrum of genetic variants has been related to familial and sporadic Parkinson's disease (PD) in diverse populations worldwide. However, very little is known about the genetic landscape of PD in Southern Spain, despite its particular genetic landscape coming from multiple historical migrations. We included 134 PD patients in this study, of which 97 individuals were diagnosed with late-onset sporadic PD (LOPD), 28 with early-onset sporadic PD (EOPD), and 9 with familial PD (FPD). Genetic analysis was performed through a next-generation sequencing panel to screen 8 PD-related genes (LRRK2, SNCA, PARKIN, PINK1, DJ-1, VPS35, GBA, and GCH1) in EOPD and FPD groups and direct Sanger sequencing of GBA exons 8-11 and LRRK2 exons 31 and 41 in the LOPD group. In the EOPD and FPD groups, we identified 11 known pathogenic mutations among 15 patients (40.5%). GBA (E326K, N370S, D409H, L444P) mutations were identified in 7 patients (18.9%); LRRK2 (p.R1441G and p.G2019S) in 3 patients (8.1%); biallelic PARK2 mutations (p.N52fs, p.V56E, p.C212Y) in 4 cases (10.8%) and PINK1 homozygous p.G309D in 1 patient (2.7%). An EOPD patient carried a single PARK2 heterozygous mutation (p.R402C), and another had a novel heterozygous mutation in VPS35 (p.R32S), both of unknown significance. Moreover, pathogenic mutations in GBA (E326K, T369M, N370S, D409H, L444P) and LRRK2 (p.R1441G and p.G2019S) were identified in 13 patients (13.4%) and 4 patients (4.1%), respectively, in the LOPD group. A large number of known pathogenic mutations related to PD have been identified. In particular, GBA and LRRK2 mutations appear to be considerably frequent in our population, suggesting a strong Jewish influence. Further research is needed to study the contribution of the novel found mutation p.R32S in VPS35 to the pathogenesis of PD. PMID- 26518747 TI - Iron deficiency anemia treatment response to oral iron therapy: a pooled analysis of five randomized controlled trials. PMID- 26518748 TI - Phase II trial of dose-adjusted EPOCH in untreated systemic anaplastic large cell lymphoma. PMID- 26518749 TI - The importance of eukaryotic ferritins in iron handling and cytoprotection. AB - Ferritins, the main intracellular iron storage proteins, have been studied for over 60 years, mainly focusing on the mammalian ones. This allowed the elucidation of the structure of these proteins and the mechanisms regulating their iron incorporation and mineralization. However, ferritin is present in most, although not all, eukaryotic cells, comprising monocellular and multicellular invertebrates and vertebrates. The aim of this review is to provide an update on the general properties of ferritins that are common to various eukaryotic phyla (except plants), and to give an overview on the structure, function and regulation of ferritins. An update on the animal models that were used to characterize H, L and mitochondrial ferritins is also provided. The data show that ferritin structure is highly conserved among different phyla. It exerts an important cytoprotective function against oxidative damage and plays a role in innate immunity, where it also contributes to prevent parenchymal tissue from the cytotoxicity of pro-inflammatory agonists released by the activation of the immune response activation. Less clear are the properties of the secretory ferritins expressed by insects and molluscs, which may be important for understanding the role played by serum ferritin in mammals. PMID- 26518750 TI - MyelStones: the executive roles of myelin basic protein in myelin assembly and destabilization in multiple sclerosis. AB - The classic isoforms of myelin basic protein (MBP, 14-21.5 kDa) are essential to formation of the multilamellar myelin sheath of the mammalian central nervous system (CNS). The predominant 18.5-kDa isoform links together the cytosolic surfaces of oligodendrocytes, but additionally participates in cytoskeletal turnover and membrane extension, Fyn-mediated signalling pathways, sequestration of phosphoinositides and maintenance of calcium homoeostasis. All MBP isoforms are intrinsically disordered proteins (IDPs) that interact via molecular recognition fragments (MoRFs), which thereby undergo local disorder-to-order transitions. Their conformations and associations are modulated by environment and by a dynamic barcode of post-translational modifications, particularly phosphorylation by mitogen-activated and other protein kinases and deimination [a hallmark of demyelination in multiple sclerosis (MS)]. The MBPs are thus to myelin what basic histones are to chromatin. Originally thought to be merely structural proteins forming an inert spool, histones are now known to be dynamic entities involved in epigenetic regulation and diseases such as cancer. Analogously, the MBPs are not mere adhesives of compact myelin, but active participants in oligodendrocyte proliferation and in membrane process extension and stabilization during myelinogenesis. A central segment of these proteins is pivotal in membrane-anchoring and SH3 domain (Src homology 3) interaction. We discuss in the present review advances in our understanding of conformational conversions of this classic basic protein upon membrane association, including new thermodynamic analyses of transitions into different structural ensembles and how a shift in the pattern of its post-translational modifications is associated with the pathogenesis and potentially onset of demyelination in MS. PMID- 26518752 TI - Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth. AB - Osteosarcoma (OS) is the most common form of primary malignant bone tumor and prevalent among children and young adults. Recently we have established a novel approach to bioengineering large quantity of microRNA-34a (miR-34a) prodrug for miRNA replacement therapy. This study is to evaluate combination treatment with miR-34a prodrug and doxorubicin, which may synergistically suppress human OS cell growth via RNA interference and DNA intercalation. Synergistic effects were indeed obvious between miR-34a prodrug and doxorubicin for the suppression of OS cell proliferation, as defined by Chou-Talalay method. The strongest antiproliferative synergism was achieved when both agents were administered simultaneously to the cells at early stage, which was associated with much greater degrees of late apoptosis, necrosis, and G2 cell cycle arrest. Alteration of OS cellular processes and invasion capacity was linked to the reduction of protein levels of miR-34a targeted (proto-)oncogenes including SIRT1, c-MET, and CDK6. Moreover, orthotopic OS xenograft tumor growth was repressed to a significantly greater degree in mouse models when miR-34a prodrug and doxorubicin were co-administered intravenously. In addition, multiple doses of miR-34a prodrug and doxorubicin had no or minimal effects on mouse blood chemistry profiles. The results demonstrate that combination of doxorubicin chemotherapy and miR-34a replacement therapy produces synergistic antiproliferative effects and it is more effective than monotherapy in suppressing OS xenograft tumor growth. These findings support the development of mechanism-based combination therapy to combat OS and bioengineered miR-34a prodrug represents a new natural miRNA agent. PMID- 26518753 TI - Domestic bioethanol-fireplaces--a new source of severe burn accidents. AB - BACKGROUND: Bioethanol-fueled fireplaces are popular interior home decoration accessories. Although their safety is promoted frequently, actual presentations of severe burn injuries in our burn intensive care unit (ICU) have focused the authors on safety problems with these devices. In this article we want to explore the mechanisms for these accidents and state our experiences with this increasingly relevant risk for severe burn injuries. MATERIALS AND METHODS: The computerized medical records of all burn intensive care patients in our burn unit between 2000 and 2014 were studied. Since 2010, 12 patients with bioethanol associated burn injuries were identified. Their data was compared to the values of all patients, except the ones injured by bioethanol fireplaces that presented themselves to our burn ICU between the years 2010 and 2014. RESULTS: At time of admission the bioethanol patients had a mean ABSI-score of 4.8 (+/- 2.2 standard deviation (SD)). A mean of 17 percent (+/- 9.1 SD) body surface area was burned. Involvement of face and hands was very common. An operative treatment was needed in 8 cases. A median of 20 days of hospitalization (range 3-121) and a median of 4.5 days on the ICU (range 1-64) were necessary. No patient died. In most cases the injuries happened while refilling or while starting the fire, even though safety instructions were followed. In the control group, consisting of 748 patients, the mean ABSI-score was 5.6 (+/- 2.7 SD). A mean of 16.5 percent (+/- 10.1 SD) body surface area was burned. Treatment required a median of 3 days on the burn ICU (range 1-120). Regarding these parameters, the burden of disease was comparable in both groups. CONCLUSION: Bioethanol-fueled fireplaces for interior home decoration are a potential source for severe burn accidents even by intended use. PMID- 26518754 TI - Evaluation of hemolysis in microcatheter directed blood infusion at different flow rates for transarterial salvage reperfusion: In-vitro study. AB - BACKGROUND: Microcatheter directed blood reperfusion is an endovascular salvage option for acute cerebral artery occlusions. It has not been investigated whether this technique may be associated with hemolysis. OBJECTIVE: Analysis of hemolysis during blood infusion through different microcatheters and infusion rates to assess related risks. METHODS: Four microcatheters with different inner diameters were perfused with blood samples at three infusion rates. Hemolytic markers including lactate-dehydrogenase (LDH) and haptoglobin were analyzed. Samples before and after blood infusion were compared using Student's t-test. Flow related degree of hemolysis was analyzed with regression analysis. Resulting shear stress was calculated and correlated with LDH and haptoglobin. RESULTS: Significant increase of LDH and decrease of haptoglobin was found after blood reperfusion through small microcatheters at progressive flow rates (p<0.05). No hemolysis was found with larger diameter microcatheters at all flow rates (p>0.05). Correlation between shear stress, LDH and haptoglobin was r=0.86 and r=0.75, respectively. CONCLUSIONS: Progressive hemolysis occurs during blood perfusion of small lumen microcatheters at increasing flow rates. This phenomenon may be related to turbulent flow, exposure time and increased shear stress. Larger microcatheters did not induce hemolysis and may be the preferred choice for stroke reperfusion. PMID- 26518755 TI - Taking Stock: Phosphorus Supply from Natural and Anthropogenic Pools in the 21st Century. PMID- 26518756 TI - Urban dust in the Guanzhong Basin of China, part I: A regional distribution of dust sources retrieved using satellite data. AB - Urban dust pollution has been becoming an outstanding environmental problem due to rapid urbanization in China. However, it is very difficult to construct an urban dust inventory, owing to its small horizontal scale and strong temporal/spatial variability. With the analysis of visual interpretation, maximum likelihood classification, extrapolation and spatial overlaying, we quantified dust source distributions of urban constructions, barrens and croplands in the Guanzhong Basin using various satellite data, including VHR (0.5m), Lansat-8 OLI (30 m) and MCD12Q1 (500 m). The croplands were the dominant dust sources, accounting for 40% (17,913 km(2)) of the study area in summer and 36% (17,913 km(2)) in winter, followed by barrens, accounting for 5% in summer and 10% in winter. Moreover, the total constructions were 126 km(2), including 84% of active and 16% inactive. In addition, 59% of the constructions aggregated on the only megacity of the study area, Xi'an. With high accuracy exceeding 88%, the proposed satellite-data based method is feasible and valuable to quantify distributions of dust sources. This study provides a new perspective to evaluate regional urban dust, which is seldom quantified and reported. In a companied paper (Part-2 of the study), the detailed distribution of the urban dust sources is applied in a dynamical/aerosol model (WRF-Dust) to assess the effect of dust sources on aerosol pollution. PMID- 26518757 TI - Process integration for recovery of recombinant collagen type I alpha1 from corn seed. AB - Because of safety concerns and product consistency issues with the use of animal derived collagen, several recombinant protein expression hosts have been considered for recombinant collagen corn seed. Full length, triple-helical, recombinant collagen (rCIalpha1) is expressed as a fusion with a foldon domain, which must later be removed. Here we have examined integration of purification and foldon removal by comparing advantages of removal before or after purification, using salt precipitation as the main purification step. Because expression levels in available maize lines are low, Pichia-produced recombinant collagens, both with and without foldon, were added to corn seed germ at the extraction step. Salt precipitation of an acidic corn seed extract yielded 100% of the collagen without foldon at >70% purity without the pepsin pretreatment. With pepsin pretreatment, yield was 94.0% with purity of 76.5%. Analysis of the protein molecular weight distribution of the pre- and post-treatment extracts showed that the corn proteins are largely resistant to pepsin proteolysis, explaining why little benefit was obtained by pepsin treatment. In the absence of pepsin treatment, the recovery of rCIalpha1 with foldon was still above 90% but the purity was only 44%. This still represented at about 13-fold purification with a 2.7-fold volume reduction which would reduce the pepsin requirement for post-recovery foldon cleavage. PMID- 26518758 TI - Interpretation of prenatal drug exposure functional imaging data. PMID- 26518759 TI - In vitro biomechanical analysis of torque capabilities of various 0.018" lingual bracket-wire systems: total torque play and slot size. AB - OBJECTIVES: To determine the total torque play of various rectangular titanium molybdenum alloy (TMA)/stainless steel (SS) wires in various 0.018" upper incisor lingual brackets and slot size measurements. METHODS: TMA (0.0175" * 0.0175", 0.0170" * 0.025", 0.0182" * 0.0182", 0.0182" * 0.025") and SS wires (0.016" * 0.022", 0.016" * 0.024", 0.018" * 0.025") were twisted in standard (Hiro, IncognitoTM, Joy(r), Kurz 7th generation, STbTM: fixation with elastic modules) and self-ligating brackets (Evolution SLT(r), In-Ovation(r) L MTM: closed ligation mechanism) from -20 degrees to +20 degrees with a custom-made machine. The total torque play was calculated by extrapolating the linear portion of the twist/moment curves to the x-axis and adding the absolute negative and positive angle values at the intercepts. The bracket slot height was measured before and after the experiments with a series of pin gauges with round profile. RESULTS: Brackets in ascending order for total torque play with the most slot-filling wire TMA 0.0182" * 0.025": Evolution SLT(r) (0 degree +/- 0 degree), IncognitoTM (2.2 degrees +/-1.1 degrees), Hiro (5.1 degrees +/-3.0 degrees), In-Ovation(r) L MTM (6.3 degrees +/-2.2 degrees), STbTM (6.6 degrees +/-1.8 degrees), Kurz 7th generation (7.1 degrees +/-0.8 degrees), and Joy(r) (12.0 degrees +/-0.8 degrees). Wires in ascending order for total torque play with the most precise slot IncognitoTM: TMA 0.0182" * 0.025" (2.2 degrees +/-1.1 degrees), TMA 0.0182" * 0.0182" (2.4 degrees +/-0.9 degrees), SS 0.018" * 0.025" (5.5 degrees +/-1.0 degrees), TMA 0.0170" * 0.025" (9.4 degrees +/-1.8 degrees), TMA 0.0175" * 0.0175" (13.0 degrees +/-1.5 degrees), SS 0.016" * 0.024" (16.1 degrees +/-1.4 degrees), SS 0.016" * 0.022" (17.8 degrees +/-1.0 degrees); differences between some of the experimental groups were not statistically significant. Bracket slot dimensions in ascending order: Evolution SLT(r) (less than 0.452mm), IncognitoTM (0.460mm +/-0.002mm), In-Ovation(r) L MTM (0.469mm +/-0.001mm), Hiro (0.469mm +/ 0.010mm), STbTM (0.471mm +/-0.002mm), Kurz 7th generation (0.473mm +/-0.002mm), and Joy(r) (greater than 0.498mm). LIMITATIONS: The applied method must be questioned when used with brackets with incomplete slot walls (Evolution SLT(r)). Slot measurement with pin gauges may not register bracket wing deformation. CONCLUSIONS: All brackets showed a differing slot size from the nominal 0.018" (0.457mm). IncognitoTM presented the most precise and Joy(r) the widest slot. The main wires for the retraction phase SS 0.016" * 0.022"/SS 0.016" * 0.024" showed poor torque control. Among the finishing TMA wires, TMA 0.0175" * 0.0175" exhibited the highest and TMA 0.0182" * 0.0182"/TMA 0.0182" * 0.025" the smallest torque play. SIGNIFICANCE: The manufacturers could profit from this investigation towards optimization of the dimensional precision of their products. The orthodontist must be aware of the torque play of the wire-bracket combinations to be able to plan and individualize the appliance by third order customization. PMID- 26518760 TI - "Herbal seizures"--atypical symptoms after ibogaine intoxication: a case report. AB - INTRODUCTION: Misuse of various new psychotropic substances such as ibogaine is increasing rapidly. Knowledge of their negative side effects is sparse. CASE PRESENTATION: We present a case of intoxication with the herbal substance ibogaine in a 22-year-old white man. After taking a cumulative dose of 38 g (taken in two doses), he developed visual memories, nausea and vomiting. He developed a generalized tonic-clonic seizure with additional grand mal seizures. He was treated with midazolam and levetiracetam. Extended drug screenings and computed tomography and magnetic resonance imaging findings were all negative. CONCLUSIONS: Knowledge of the side effects of ibogaine has mainly come from reports of cardiovascular complications; seizures are rarely mentioned and experimental findings are inconsistent. It seems that ibogaine acts like a proconvulsive drug at high doses. PMID- 26518761 TI - Proteomes of the Female Genital Tract During the Oestrous Cycle. AB - The female genital tract includes several anatomical regions whose luminal fluids successively interact with gametes and embryos and are involved in the fertilisation and development processes. The luminal fluids from the inner cervix, the uterus and the oviduct were collected along the oestrous cycle at oestrus (Day 0 of the cycle) and during the luteal phase (Day 10) from adult cyclic ewes. The proteomes were assessed by GeLC-MS/MS and quantified by spectral counting. A set of 940 proteins were identified including 291 proteins differentially present along the cycle in one or several regions. The global analysis of the fluid proteomes revealed a general pattern of endocrine regulation of the tract, with the cervix and the oviduct showing an increased differential proteins abundance mainly at oestrus while the uterus showed an increased abundance mainly during the luteal phase. The proteins more abundant at oestrus included several families such as the heat shock proteins (HSP), the mucins, the complement cascade proteins and several redox enzymes. Other proteins known for their interaction with gametes such as oviductin (OVGP), osteopontin, HSPA8, and the spermadhesin AWN were also overexpressed at oestrus. The proteins more abundant during the luteal phase were associated with the immune system such as ceruloplasmin, lactoferrin, DMBT1, or PIGR, and also with tissue remodeling such as galectin 3 binding protein, alkaline phosphatase, CD9, or fibulin. Several proteins differentially abundant between estrus and the luteal phase, such as myosin 9 and fibronectin, were also validated by immunohistochemistry. The potential roles in sperm transit and uterine receptivity of the proteins differentially regulated along the cycle in the female genital tract are discussed. PMID- 26518762 TI - The Expanding Landscape of the Thiol Redox Proteome. AB - Cysteine occupies a unique place in protein chemistry. The nucleophilic thiol group allows cysteine to undergo a broad range of redox modifications beyond classical thiol-disulfide redox equilibria, including S-sulfenylation (-SOH), S sulfinylation (-SO(2)H), S-sulfonylation (-SO(3)H), S-nitrosylation (-SNO), S sulfhydration (-SSH), S-glutathionylation (-SSG), and others. Emerging evidence suggests that these post-translational modifications (PTM) are important in cellular redox regulation and protection against oxidative damage. Identification of protein targets of thiol redox modifications is crucial to understanding their roles in biology and disease. However, analysis of these highly labile and dynamic modifications poses challenges. Recent advances in the design of probes for thiol redox forms, together with innovative mass spectrometry based chemoproteomics methods make it possible to perform global, site-specific, and quantitative analyses of thiol redox modifications in complex proteomes. Here, we review chemical proteomic strategies used to expand the landscape of thiol redox modifications. PMID- 26518763 TI - Pharmacokinetics, Tissue Distribution and Therapeutic Effect of Cationic Thermosensitive Liposomal Doxorubicin Upon Mild Hyperthermia. AB - PURPOSE: To evaluate pharmacokinetic profile, biodistribution and therapeutic effect of cationic thermosensitive liposomes (CTSL) encapsulating doxorubicin (Dox) upon mild hyperthermia (HT). METHODS: Non-targeted thermosensitive liposomes (TSL) and CTSL were developed, loaded with Dox and characterized. Blood kinetics and biodistribution of Dox-TSL and Dox-CTSL were followed in B16BL6 tumor bearing mice upon normothermia (NT) or initial hyperthermia conditions. Efficacy study in B16BL6 tumor bearing mice was followed with Dox-TSL or Dox-CTSL upon NT or HT. Efficacy study in LLC tumor bearing mice was performed upon two HT conditions. Intravital microscopy was performed on B16BL6 tumors implanted in dorsal-skin fold window-bearing mice. RESULTS: Targeting did not cause faster blood clearance of CTSL compared to TSL. Highest uptake of liposomes was observed in spleen, kidneys and liver. Applying HT prior to CTSL administration increased drug delivery to the tumor and CTSL delivered ~1.7 fold higher Dox concentration compared to TSL. Efficacy in B16BL6 murine melanoma showed that HT had a significant effect on CTSL in tumor suppression and prolonged survival. Efficacy in LLC Lewis lung carcinoma tumor model demonstrates that two HT treatments hold promises for a successful treatment option. CONCLUSION: CTSL have potency to increase drug efficacy in tumors due to their targeted and drug release functions. PMID- 26518764 TI - Applying a Big Data Approach to Biomarker Discovery: Running Before We Walk? PMID- 26518765 TI - Identifying Novel Biomarkers for Cardiovascular Events or Death in People With Dysglycemia. AB - BACKGROUND: Serum biomarkers may identify people at risk for cardiovascular (CV) outcomes. Biobanked serum samples from 8494 participants with dysglycemia in the completed Outcome Reduction With Initial Glargine Intervention trial were assayed for 284 biomarkers to identify those that could identify people at risk for a CV outcome or death when added to clinical measurements. METHODS AND RESULTS: A multiplex analysis measured a panel of cardiometabolic biomarkers in 1 mL of stored frozen serum from every participant who provided biobanked blood. After eliminating undetectable or unanalyzable biomarkers, 8401 participants who each had a set of 237 biomarkers were analyzed. Forward-selection Cox regression models were used to identify biomarkers that were each independent determinants of 3 different incident outcomes: (1) the composite of myocardial infarction, stroke, or CV death; (2) these plus heart failure hospitalization or revascularization; and (3) all-cause death. When added to clinical variables, 10 biomarkers were independent determinants of the 1405 CV composite outcomes observed during follow-up; 9 biomarkers (including 8 of these 10) were independent determinants of the 2435 expanded composite outcomes; and 15 (including the 10 CV composite biomarkers) were independent determinants of the 1340 deaths. Adjusted C statistics increased from 0.64 for the clinical variables to 0.71 and 0.68 for the 2 CV composite outcomes, respectively, with the greatest increase to 0.75 for death (P<0.001 for the change). CONCLUSIONS: A systematic hypothesis-free approach identified combinations of up to 15 cardiometabolic biomarkers as independent determinants of CV outcomes or death in people with dysglycemia. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00069784. PMID- 26518766 TI - Hypertrophic Cardiomyopathy in Children, Adolescents, and Young Adults Associated With Low Cardiovascular Mortality With Contemporary Management Strategies. AB - BACKGROUND: Youthful age has been considered the time of greatest risk for patients with hypertrophic cardiomyopathy (HCM), largely because of the possibility of sudden death. The last 2 decades have witnessed more reliable identification of at-risk patients and utilization of implantable cardioverter defibrillators for prevention of sudden death, and other contemporary treatment options. Whether such management advances have significantly altered the considerable mortality rate for young HCM patients remains unresolved. METHODS AND RESULTS: We studied long-term outcome in 474 consecutive HCM patients between 7 and 29 years of age presenting at 2 referral institutions. Over 7.1+/-5.1 years of follow-up (6.0 [3.0, 10.0]), 452 patients (95%) survived, with 95% experiencing no or mild symptoms. HCM-related death occurred in 18 patients (3%; 0.54%/y): arrhythmic sudden death (n=12), progressive heart failure and heart transplant complications (n=5), or postoperatively (n=1). In contrast, aborted life-threatening events occurred in 63 other high-risk patients (13%) with implantable cardioverter-defibrillator interventions for ventricular tachyarrhythmias (n=31), resuscitated out-of-hospital cardiac arrest (n=20), or heart transplant for advanced heart failure (n=12), 1.8%/y, 3-fold higher than HCM mortality. Five- and 10-year survival (considering only HCM deaths) was high (97% and 94%, respectively), virtually identical to that reported in middle-aged adult HCM patients (98% and 94%, P=0.23). CONCLUSIONS: In a large hospital-based cohort of young HCM patients, representing an age group considered at greatest risk, low mortality rates can be achieved with the application of contemporary cardiovascular treatment strategies, largely because of reliable identification of high-risk patients who benefited from implantable cardioverter-defibrillators for sudden death prevention, thereby creating the opportunity for extended longevity and good quality of life. PMID- 26518767 TI - Activation of the Akt-mTOR and MAPK pathways in dedifferentiated liposarcomas. AB - The Akt/mTOR and MAPK pathways play important roles in modulating cellular function in response to extracellular signals, and they are known to be activated in certain kinds of sarcomas. Few investigations have examined these pathways in dedifferentiated liposarcoma (DDLS), in relation to clinicopathological features. Clinicopathological and immunohistochemical analyses were conducted using 99 DDLS specimens. An in vitro study was also conducted to examine the antitumor effects of an mTOR inhibitor and a MEK inhibitor on two DDLS cell lines. The clinicopathological analyses revealed that the AJCC staging was a significant prognostic factor for overall survival and that the tumor size, depth, and location were significant prognostic factors for event-free survival. Phosphorylated Akt (pAkt), pmTOR, pS6RP, p4E-BP1, pMEK, and pERK expressions were positive in 57.4, 52.4, 71.4, 57.1, 84.1, and 50.8 % of the dedifferentiated component of the 63 primary DDLSs. Positive staining for pmTOR was significantly more frequent in the dedifferentiated component than the well-differentiated component. A univariate prognostic analysis revealed that pmTOR expression was associated with poor prognosis in the tumors in the retroperitoneum/ventral body cavity. The mTOR and MEK inhibitors dose-dependently inhibited the cell proliferation of both DDLS cell lines and decreased the expression of downstream pS6RP and pERK, respectively. The combined use of the two inhibitors enhanced antiproliferative activity. In conclusion, the Akt/mTOR and MAPK pathways were activated in DDLS specimens, and the inhibition of these pathways decreased cell proliferation in DDLS cell lines. Our findings suggest that these pathways could be a therapeutic target for patients with DDLS. PMID- 26518768 TI - MGMT testing allows for personalised therapy in the temozolomide era. AB - Adjuvant temozolomide (TMZ)-based chemoradiation is the standard of care for most glioblastoma patients (GBMs); however, a large proportion of these patients do not respond to TMZ. Silencing of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter is thought to induce chemosensitivity, and testing for methylation may allow for patient stratification; however, this has yet to become routine clinical practice despite an abundance of literature on the subject. The databases PubMed, Embase, The Cochrane Library, Science Direct and Medline were searched for relevant articles published between 1999 and 2015. Articles utilising MGMT testing in glioblastomas, and treatment of glioblastomas with temozolomide were assessed. Immunohistochemistry, methylation-specific PCR (MSP), reverse transcriptase PCR, pyrosequencing and bisulphite sequencing were the main testing methods identified. Nested-MSP techniques produced poor correlation with survival, whilst bisulphite sequencing showed no evident benefit over MSP. Testing is limited by sample quality and contamination; however, efforts are made to minimise this. Strong evidence for MGMT-based personalised therapy was presented in the elderly but remains controversial in the entire GBM population. MGMT testing presents many obstacles yet to be overcome, and these warrant attention prior to the routine implementation of MGMT testing to aid decision making in GBMs. However, there is evidence to support its use, particularly in the elderly. PMID- 26518769 TI - Genetic variants in miR-196a2 and miR-499 are associated with susceptibility to esophageal squamous cell carcinoma in Chinese Han population. AB - Esophageal squamous cell carcinoma (ESCC) is the dominant type of esophageal cancer in the East Asian population. MicroRNAs (miRNAs) have been studied to play important roles in tumorigenesis. Single nucleotide polymorphisms (SNPs) in miRNA lead to the aberrant expression and structural alteration of miRNA and are hypothesized to be involved in tumorigenesis and cancer development. We conducted a population-based case-control study to evaluate the association between SNPs in miRNAs and ESCC risk in 1400 ESCC cases and 2185 matched controls. Four SNPs including miR-196a2 rs11614913, miR-146a rs2910164, miR-499 rs3746444, and miR 423 rs6505162 were selected with comprehensive collection strategy and genotyped using the SNaPshot Multiplex System. Odds ratio (OR) and 95 % confidence interval (95 % CI) were used to assess the strength of association. The CC genotype of miR 196a2 rs11614913 was significantly associated with an increased ESCC risk compared with the TT genotype (OR 1.11, 95 % CI 1.01-1.22, P 0.049) and the TT/TC genotypes (OR 1.09, 95 % CI 1.01-1.19, P 0.043). The association was more pronounced in non-drinkers in the recessive model (OR 1.13, 95 % CI 1.01-1.27, P 0.029). A significantly increased risk of ESCC associated with miR-499 rs3746444 polymorphism was evident among patients who never smoking and drinking. This study suggests that miR-196a2 rs11614913 and miR-499 rs3746444 are associated with an increased ESCC risk in a Chinese population. PMID- 26518770 TI - Erratum to: Overexpression of long non-coding RNA HOTAIR leads to chemoresistance by activating the Wnt/beta-catenin pathway in human ovarian cancer. PMID- 26518771 TI - Higher incidence of the SNP Met 788 Ile in the coding region of A20 in diffuse large B cell lymphomas. AB - Genetic alterations causing constitutive activation of the nuclear factor kappa B (NF-kappaB) signaling pathway has been associated with the development of lymphomas. A20 (TNFAIP3) is a key regulator of NF-kappaB signaling. Its suppressor functions are often inactivated by deletions and/or mutations in various hematologic malignancies. Since we recently found the rs143002189 polymorphism in the A20 loci in our multiple myeloma samples, we further investigated this polymorphism in different lymphoid neoplasias. For this purpose, we tested 479 cases of the most common B cell malignancies for the presence of the rs143002189 polymorphism. We found a significant higher occurrence of the rs143002189 polymorphism in diffuse large B cell lymphoma (DLBCL) compared to non-neoplastic controls and other types of B cell malignancies. Furthermore, structure analyses of the mutated A20 protein led to the assumption that the new steric interaction within the protein is responsible for a reduced or inactivated A20 protein. Our data indicates that in a significant fraction of patients, rs143002189 might contribute to the development of DLBCL. PMID- 26518772 TI - Case-control studies require appropriate population controls: an example of error in the SSRI birth defect literature. PMID- 26518773 TI - Eugenol, alpha-pinene and beta-caryophyllene from Plectranthus barbatus essential oil as eco-friendly larvicides against malaria, dengue and Japanese encephalitis mosquito vectors. AB - Mosquito-borne diseases represent a deadly threat for millions of people worldwide. Eco-friendly mosquitocides are a priority. In Ayurvedic medicine, Plectranthus species have been used to treat heart disease, convulsions, spasmodic pain and painful urination. In this research, we evaluated the acute toxicity of essential oil from Plectranthus barbatus and its major constituents, against larvae of the malaria vector Anopheles subpictus, the dengue vector Aedes albopictus and the Japanese encephalitis vector Culex tritaeniorhynchus. The chemical composition of P. barbatus essential oil was analyzed by gas chromatography-mass spectroscopy. Nineteen components were identified. Major constituents were eugenol (31.12%), alpha-pinene (19.38%) and beta-caryophyllene (18.42%). Acute toxicity against early third-instar larvae of An. subpictus, Ae. albopictus and Cx. tritaeniorhynchus was investigated. The essential oil had a significant toxic effect against larvae of An. subpictus, Ae. albopictus and Cx. tritaeniorhynchus, with 50% lethal concentration (LC50) values of 84.20, 87.25 and 94.34 MUg/ml and 90% lethal concentration (LC90) values of 165.25, 170.56 and 179.58 MUg/ml, respectively. Concerning major constituents, eugenol, alpha-pinene and beta-caryophyllene appeared to be most effective against An. subpictus (LC50 = 25.45, 32.09 and 41.66 MUg/ml, respectively), followed by Ae. albopictus (LC50 = 28.14, 34.09 and 44.77 MUg/ml, respectively) and Cx. tritaeniorhynchus (LC50 = 30.80, 36.75 and 48.17 MUg/ml, respectively). Overall, the chance to use metabolites from P. barbatus essential oil against mosquito vectors seems promising, since they are effective at low doses and could be an advantageous alternative to build newer and safer mosquito control tools. PMID- 26518774 TI - A longitudinal study of suicidal ideation among homeless, mentally ill individuals. AB - PURPOSE: Previous cross-sectional studies have indicated that homeless individuals may present with high rates of suicidal ideation, which are strongly associated with completed suicide. We conducted the first known longitudinal study of suicidal ideation in the homeless. METHODS: We used data collected over 24 months in the Vancouver At Home project (N = 497), comprised two randomized controlled trials of housing interventions for homeless individuals with mental disorders. Presence of suicidal ideation was determined using the Colorado symptom index. RESULTS: Suicidal ideation significantly decreased over time [odds ratio (OR) = 0.31 at 24 months, 95 % confidence interval (CI) 0.21-0.46]. Baseline diagnoses of mood (OR = 2.18, 95 % CI 1.48-3.21) and anxiety disorders (OR = 2.05, 95 % CI 1.42-2.97), as well as depressive mood (OR = 2.52, 95 % CI 1.90-3.33), use of any substance (OR = 1.59, 95 % CI 1.09-2.32), and polysubstance use (OR = 1.90, 95 % CI 1.40-2.60) were significantly associated with suicidal ideation in the multivariate model. Baseline diagnosis of a psychotic disorder (protective effect), daily substance use, intravenous drug use, recent arrest, multiple physical illnesses and history of traumatic brain injury were significantly associated with suicidal ideation in the unadjusted model only. CONCLUSIONS: Interventions targeting depressive symptoms and substance use could help decrease suicide risk in homeless individuals. Mental health services need to be tailored to address the complex needs of socially marginalized individuals. TRIAL REGISTRATION: Current controlled trials: ISRCTN57595077 (Vancouver At Home study: Housing First plus Assertive Community Treatment versus congregate housing plus supports versus treatment as usual) and ISRCTN66721740 (Vancouver At Home study: Housing first plus intensive case management versus treatment as usual). Assigned 9 Oct. 2012. PMID- 26518775 TI - Absence of PRKD1 Mutation, a Salivary Tumor-Specific Mutation, in Solid Tumors and Leukemias. PMID- 26518776 TI - Violence in Advertisements in New York City Subway Stations: A Pilot Study. AB - Violence has become a public health concern in the United States. Violent visually stimulating content encompasses various techniques such as fear, humor, shock, or violence, to stimulate a response or appeal toward awareness of human emotion. Exposing impressionable youth to violent advertisements can be particularly problematic. This is especially true in places like New York City where violent crime is a prevalent problem. With annual ridership reaching over 1.7 billion in 2014, the New York City subway system is abundant with advertisements. The purpose of this pilot study was to determine the frequency and type of violent advertising on the Lexington Avenue/East Side Line in New York City, running through the Bronx and Manhattan to represent the lower and higher median income earning boroughs. There were no statistically different findings in median household income at site of station by number of ads or source of violent. Destruction was the most common form of violence (n = 32, 42.7 %) followed by intent to strike (n = 18, 24 %), showing a weapon (n = 15, 20 %) and horror (n = 10, 13.3 %). Most ads (n = 46, 61.3 %) were found in stations heading uptown toward and through the Bronx, the borough where median household income is lowest, whereas 29 (38.7 %) were found in stations heading downtown. Future studies could focus on additional boroughs and subways lines, and could be collected at multiple points in time to determine of how prevalent violent advertising is throughout New York City and at different time frames. PMID- 26518777 TI - Reciprocal Peer Support for Post-partum Patients with Diabetes: A Needs Assessment for the Diabetes Buddy Program. AB - While peer support has been investigated in multiple clinical contexts, its application to the postpartum setting is unknown. The aim was to assess acceptability of a postpartum peer support program for women with diabetes. Observational survey-based needs assessment of forty low-income women with diabetes, receiving care at a major medical institution. Mean age and gravidity were 30.7 years and 3.15 +/- 1.67 respectively. 45 % expressed interest in a "buddy." There was no significant difference between groups desiring and not desiring this program. A majority of respondents desired telephone, text messaging, and in-person contacts (79.2, 72.1, 83.8 %), with 72.5 % of patients desiring diabetes-related activities during clinic waiting time. Many women desire a postpartum diabetes reciprocal peer program for support outside of clinician visits. Patients are receptive to educational services during their wait and outside of clinic time, a potentially valuable opportunity to share important health information. PMID- 26518778 TI - Factors Associated with Tooth Loss in Older Adults in Rural Colorado. AB - The purpose of this paper is to examine factors that are associated with tooth loss in older adults living in the San Luis Valley (SLV), Colorado, which is a rural and large geographical area (roughly the size of Connecticut) that has a large population age 60 years or older. Data used in this manuscript were collected as a part of the SLV Community Health Survey. The analyzed sample included 308 adults over the age of 65 years who completed the survey. Basic descriptive statistics and a series of step-wise binary logistic regression analyses were conducted; the dependent variable was the number of permanent teeth removed because of tooth decay or gum disease. Fifty-two percent of the participants were male, Hispanic participants made up 40 % of the sample and 76 % of the participants had at least a high school education. Tooth loss was significantly associated with older age (OR = 1.09; p = 0.02), lower income (OR = 0.01; p = 0.00), less than high school education (OR = 0.32; p = 0.01), being Hispanic (OR = 2.15; p = 0.05), self-reported fair-poor health status (OR 2.94; p = 0.02), consumption of one or more than one sweet beverage per day (OR = 4.52; p = 0.00), no dental insurance (OR = 4.70; p = 0.01) and length of time since last dental visit (OR = 0.21; p = 0.01). The findings of the present study suggest possible causes for tooth loss in rural adults and underscore the need for in depth research to study the overall oral health of rural older adults living in SLV. PMID- 26518779 TI - Challenges in the Implementation of Measurement Feedback Systems. AB - This commentary on the articles published in the special section on the development and implementation of measurement feedback systems (MFSs) discusses three challenging themes in the process of MFS implementation: design and planning, organizational context, and sustainability and unintended consequences. It is argued that the implementation of MFSs is complex, but is an important step in improving outcomes in routine care for children and young persons. PMID- 26518780 TI - Measuring Limit-Setting Practices Used by Family Members Towards Relatives with Psychiatric Disorders. AB - Family members often set limits with relatives with psychiatric disorders (PD), however, no scale currently exists measuring the use of such limit-setting practices. The present article describes the development and results of a new measure, the Family Limit-Setting Scale (FLSS). Via a national online survey, the FLSS was completed by 573 adults residing in the U.S. who report having an adult relative with PD. We conducted exploratory and confirmatory factor analyses, examined internal consistencies and other indicators of construct validity, and performed invariance analyses assessing the generality of the optimal factor model to men, women, Caucasian respondents, and non-Caucasian respondents. Results indicate that the FLSS has an acceptable two factor structure (routine limit-setting and crisis prevention limit-setting) with both factors being highly generalizable to all groups of respondents examined. Internal consistencies and other indicators provide additional evidence of the FLSS' construct validity. Use of the FLSS will enable the conduction of quantitative research in this area. In addition, this measure may be employed in education/support organizations for families with a member with mental illness in an effort to identify persons using high levels of limit-setting practices who may benefit from extra support and/or guidance. PMID- 26518781 TI - Incidence and type of foot deformities in patients with spina bifida according to level of lesion. AB - AIM: The previously suggested association between the incidence of high-level foot deformity and muscle imbalance is no longer supported, when evaluated independent from motor and sensory loss and level of lesion, by current studies. The purpose of this study was to evaluate the association between level of lesion and foot deformity. METHODS: Of 545 patients, a total of 136 (272 feet) patients admitted to the spina bifida clinic between 2010 and 2014 were included in this study. Levels of all lesions were evaluated using initial operation data, the motor-sensory exams, and direct radiography. All patients were categorized into four different groups: Thoracic region (group 1), high-level lumbar-L1-2 region (group 2), mild and lower lumbar regions (L3-4-5) (group 3), and Sacral region (group 4). RESULTS: The mean follow-up time was 34.9 months (range 8-176 months). Group 1, group 2, group 3, and group 4 included 24 (17.6%), 14 (10.3%), 19 (14%), and 79 (58.1%) patients with regards to level of lesion, respectively. The incidences of foot deformity were 85.4, 85.7, 81.5, and 50.6% in groups 1, 2, 3, and 4, respectively. Of all patients, 22% (61 feet) had clubfoot, 16% (44 feet) pes cavus, 10% (26 feet) pes valgus, 6% (17 feet) isolated equinus, 6 % (17 feet) pes calcaneus, and 5% (13 feet) metatarsus adductus. Patients without a foot deformity (81% of normal feet) usually had a lesion at the sacral level (p <= 0.05). On the other hand, isolated equinus (70%) and clubfoot (49%) deformities were mostly observed in spinal lesions (p > 0.05). The incidence of pes calcaneus, pes valgus, and adductus deformities inclined as the lesion level decreased (p > 0.05). CONCLUSION: In this study, it was concluded that foot deformities were directly related to the level of lesion. The comparison of higher and lower level lesions revealed that the types of foot deformity differed significantly. The muscle imbalance due to spina bifida was not sufficient to explain the pathology. On the other hand, the level of spinal lesion is an important factor for the type of deformity. PMID- 26518782 TI - A genomic variant in IRF9 is associated with serum cytokine levels in pig. AB - The interferon regulatory factor 9 (IRF9) gene is a member of the IRF family and has been shown to play functionally diverse roles in the regulation of the immune system. Previous study revealed the IRF9 gene resides within the reported quantitative trait locus (QTLs) for cytokine levels. The aims of this study were to identify genomic variants in IRF9 and to test the association between the variants and cytokine levels in pig. A synonymous single-nucleotide polymorphism (c.459A>G) was identified in exon 4 of the IRF9 gene. Association analysis in 300 piglets (Landrace, n=68; large white, n=158; and Songliao black, n=74) showed that this variant was significantly associated with the level of interferon (IFN) gamma and the ratio of IFN-gamma to IL-10 in serum (P<0.05). Relative quantification of messenger RNA (mRNA) revealed that spleen had the highest expression level and individuals with genotype AA had higher expression than those with genotype AG. Transfection-based mRNA stability assay analysis further showed that the mutant allele G could reduce the RNA stability of IRF9. These findings suggest that the SNP (c.459A>G) could be a causative mutation for the association between IRF9 and the serum cytokine levels in swine. PMID- 26518786 TI - Pain after Hernia Surgery Must Be Avoided and Hopefully Treated. PMID- 26518785 TI - Inguinal Hernia: Crossfire Between the Meshes. PMID- 26518784 TI - Incisional Hernia: Difficult Cases 2. PMID- 26518787 TI - Abdominal Wall "Closure". PMID- 26518788 TI - Quality of Life after Hernia Surgery. PMID- 26518789 TI - Hiatal Hernia. PMID- 26518792 TI - Umbilical, Midline and Spigelian Hernia: What we Have to Do. PMID- 26518791 TI - Abdominal Wall: Register & Miscellaneous. PMID- 26518790 TI - Complex Cases in Abdominal Wall Repair and Prophilactic Mesh. PMID- 26518793 TI - Mesh & Prosthesis. PMID- 26518794 TI - Inguinal Hernia: Mesh Fixation. PMID- 26518795 TI - Inguinal Hernia: Recurrences, Tailored Surgery & Pubic Inguinal Pain Syndrome (Sportsman Hernia). PMID- 26518796 TI - Recent Innovations & Daily Problems. PMID- 26518797 TI - Incisional Hernia: Plastic Aspects, Component Separation, Technical Details & Pediatrics. PMID- 26518798 TI - Rare & Special Cases. PMID- 26518799 TI - Topic: Abdominal Wall and Inguino Femoral Hernia Repair as a Super Specialization. PMID- 26518801 TI - Topic: Abdominal Wall Hernia - EHS classification and choice of technique. PMID- 26518802 TI - Topic: Abdominal Wall Hernia - Epigastric hernia: choice of approach, repair, results, follow up. PMID- 26518800 TI - Topic: Abdominal Wall Hernia - Abdominal wall closure. PMID- 26518803 TI - Topic: Abdominal Wall Hernia - Prophylactic Mesh. PMID- 26518804 TI - Topic: Abdominal Wall Hernia - Spigelian hernia, anatomy, incidence, repair. PMID- 26518805 TI - Topic: Abdominal Wall Hernia - Umbilical hernia: choice of approach, repair, results, follow up. PMID- 26518806 TI - Topic: Educations from the Specialistic Society and from the University. PMID- 26518807 TI - Topic: Experimental Surgery. PMID- 26518808 TI - Topic: Femoral Hernia - Approach, results. PMID- 26518809 TI - Topic: Hiatal Hernia - New approaches. PMID- 26518812 TI - Topic: Incisional Hernia - Parastomal. PMID- 26518810 TI - Topic: Incisional Hernia - "Difficult case" as specialistic case: real loss of substance, multi recurrences, infections, fistulas, lombocel, burst abdomen, reconstruction of the entire wall. PMID- 26518811 TI - Topic: Incisional Hernia - "Easy case" as daily case: open vs lap, where the mesh, which fixation...in center midline cases. PMID- 26518813 TI - Topic: Incisional Hernia - Plastic surgery aspects. PMID- 26518814 TI - Topic: Incisional Hernia - Prophylactic Mesh. PMID- 26518815 TI - Topic: Incisional Hernia - The "risky" zone: sovrapubic, subxifoid, sub costal. PMID- 26518817 TI - Topic: Inguinal Hernia - Crossfire between the meshes. PMID- 26518816 TI - Parastomal Hernia, Risky Zone & Prophilactic Mesh. PMID- 26518819 TI - Topic: Inguinal Hernia - Influence of guidelines on daily practice. PMID- 26518818 TI - Topic: Inguinal Hernia - Fixation. PMID- 26518820 TI - Topic: Inguinal Hernia - Joined guidelines. PMID- 26518821 TI - Topic: Inguinal Hernia - Mesh vs non mesh. PMID- 26518822 TI - Topic: Inguinal Hernia - Post op chronic pain: incidence, evaluation, legal consequences, therapy, follow up. PMID- 26518823 TI - Topic: Inguinal Hernia - Primary inguinal hernia, state of the art in the different socio economic reality. PMID- 26518824 TI - Topic: Inguinal Hernia - Recurrences: incidence, approach, follow up. PMID- 26518827 TI - Debate "Young" Trialist Surgeons vs "Old" Experienced Surgeons - is Reality More Real than Science? PMID- 26518825 TI - Topic: Inguinal Hernia - Tailored surgery. PMID- 26518829 TI - Topic: Perineal Reconstruction. PMID- 26518828 TI - Topic: Mesh and Prosthesis. PMID- 26518826 TI - Topic: Inguinal Hernia - Unsolved problem in the daily practice. PMID- 26518830 TI - Topic: Pubic Inguinal Pain Syndrome (PIPS) - Sportsman. PMID- 26518833 TI - Complex Ventral Situation. PMID- 26518835 TI - Topic: Abdominal Wall and Inguino Femoral Hernia Repair as A Super Specialization. PMID- 26518836 TI - Topic: Abdominal Wall Hernia - Abdominal wall closure. PMID- 26518834 TI - Topic: Rectum Diastasis. PMID- 26518837 TI - Topic: Abdominal Wall Hernia - Epigastric hernia: choice of approach, repair, results, follow up. PMID- 26518831 TI - Topic: Rare and Special Cases, The Real "Strange Cases". PMID- 26518832 TI - Topic: Recent Innovations in Hernia Surgery. PMID- 26518838 TI - Topic: Abdominal Wall Hernia - Spigelian hernia, anatomy, incidence, repair. PMID- 26518839 TI - Topic: Abdominal Wall Hernia - Umbilical hernia: choice of approach, repair, results, follow up. PMID- 26518840 TI - Topic: Femoral Hernia - Approach, results. PMID- 26518841 TI - Topic: Femoral Hernia - Complications. PMID- 26518842 TI - Topic: Hiatal Hernia - New approaches. PMID- 26518843 TI - Humbilical & Epigastric Hernia. PMID- 26518845 TI - Topic: Incisional Hernia - "Easy case" as daily case: open vs lap, where the mesh, which fixation...in center midline cases. PMID- 26518844 TI - Topic: Incisional Hernia - "Difficult case" as specialistic case: real loss of substance, multi recurrences, infections, fistulas, lombocel, burst abdomen, reconstruction of the entire wall. PMID- 26518846 TI - Topic: Incisional Hernia - Parastomal. PMID- 26518847 TI - Topic: Incisional Hernia - The "risky" zone: sovrapubic, subxifoid, sub costal. PMID- 26518848 TI - Topic: Inguinal Hernia - Fixation. PMID- 26518849 TI - Topic: Inguinal Hernia - Pediatric repair. PMID- 26518851 TI - Topic: Inguinal Hernia - Primary inguinal hernia, state of the art in the different socio economic reality. PMID- 26518850 TI - Topic: Inguinal Hernia - Post op chronic pain: incidence, evaluation, legal consequences, therapy, follow up. PMID- 26518852 TI - Topic: Inguinal Hernia - Recurrences: incidence, approach, follow up. PMID- 26518853 TI - Topic: Inguinal Hernia - Tailored surgery. PMID- 26518854 TI - Topic: Inguinal Hernia - Unsolved Problem in The daily practice. PMID- 26518855 TI - Topic: Mesh and Prosthesis. PMID- 26518856 TI - Topic: Pubic Inguinal Pain Syndrome (PIPS) - Sportsman. PMID- 26518857 TI - TOpic: Rare and Special Cases, The Real "Strange Cases". PMID- 26518858 TI - Topic: Recent Innovations in Hernia Surgery. PMID- 26518859 TI - Trial & Guidelines. PMID- 26518861 TI - Incisional Hernia: Complications & Quality of Life. PMID- 26518860 TI - Abdominal Wall Miscellaneous. PMID- 26518862 TI - Inguinal Hernia: Lap vs Open. PMID- 26518863 TI - Education. PMID- 26518864 TI - Femoral & Experimental. PMID- 26518865 TI - Rectum Diastasis, Post Partum Floppy Wall & Obscure Groin Pain in Women. PMID- 26518868 TI - Incisional Hernia: Difficult Cases 1. PMID- 26518866 TI - Quick Hot Shot & Young Surgeon Presentation. PMID- 26518867 TI - Incisional Hernia: Daily Cases. PMID- 26518869 TI - Inguinal Hernia: Post OP Chronic Pain. PMID- 26518870 TI - Effect of consuming novel foods consisting high oleic canola oil, barley beta glucan, and DHA on cardiovascular disease risk in humans: the CONFIDENCE (Canola Oil and Fibre with DHA Enhanced) study - protocol for a randomized controlled trial. AB - BACKGROUND: Metabolic syndrome (MetS) has been identified as a major contributor to the development of cardiovascular disease (CVD). Current recommendations for dietary management of people with MetS involve quantitative and qualitative modifications of food intake, such as high consumption of vegetables, fruits, and whole grain foods. The results from our previous human trials revealed the potential of the dietary components high-oleic acid canola oil (HOCO) docosahexaenoic acid (DHA) and high molecular weight barley beta-glucan individually in managing CVD risk factors. Foods with a combination of HOCO-DHA and barley beta-glucan have never been tested for their effects on CVD risk. The objective is to determine the effects of consuming novel foods HOCO-DHA, and barley beta-glucan on managing CVD risk factors in people with MetS. METHODS/DESIGN: We are conducting a randomized, single-blind crossover trial with four treatment phases of 28 days each separated by a 4-week washout interval. Participants (n=35) will be provided with weight-maintaining, healthy balanced diet recommendations according to their energy requirements during the intervention periods. Participants will receive muffins and cookies as treatment foods in a random order and will consume at least one meal per day at the research center under supervision. The four treatments include muffins and cookies consisting of (1) all-purpose flour and HOCO-DHA (50 g/day); (2) barley flour (4.36 g/day of beta-glucan) and a blend of sunflower oil, safflower oil, and butter as control oil (50 g/day); (3) barley flour (4.36 g/day of beta glucan) and HOCO-DHA (50 g/day; dosage of DHA would be 3 g/day); and (4) all purpose flour and control oil (50 g/day). At the beginning and end of each phase, we will evaluate anthropometrics; systolic and diastolic blood pressure; blood lipid profile; low-density lipoprotein subfractions and particle size; 10-year Framingham CVD risk score; inflammatory status; and plasma and red blood cell fatty acid profiles, fecal microbiome, and body composition by dual-energy X-ray absorptiometry. CONCLUSION: Cholesterol synthesis will also be studied, using a stable isotope approach. The proposed study will lead to innovation of novel food products, which may result in improvement in the overall cardiovascular health of humans. TRIAL REGISTRATION: Clinical trials.gov identifier: NCT02091583 . Date of registration: 12 March 2014. PMID- 26518871 TI - Non-equivalence of Key Positively Charged Residues of the Free Fatty Acid 2 Receptor in the Recognition and Function of Agonist Versus Antagonist Ligands. AB - Short chain fatty acids (SCFAs) are produced in the gut by bacterial fermentation of poorly digested carbohydrates. A key mediator of their actions is the G protein-coupled free fatty acid 2 (FFA2) receptor, and this has been suggested as a therapeutic target for the treatment of both metabolic and inflammatory diseases. However, a lack of understanding of the molecular determinants dictating how ligands bind to this receptor has hindered development. We have developed a novel radiolabeled FFA2 antagonist to probe ligand binding to FFA2, and in combination with mutagenesis and molecular modeling studies, we define how agonist and antagonist ligands interact with the receptor. Although both agonist and antagonist ligands contain negatively charged carboxylates that interact with two key positively charged arginine residues in transmembrane domains V and VII of FFA2, there are clear differences in how these interactions occur. Specifically, although agonists require interaction with both arginine residues to bind the receptor, antagonists require an interaction with only one of the two. Moreover, different chemical series of antagonist interact preferentially with different arginine residues. A homology model capable of rationalizing these observations was developed and provides a tool that will be invaluable for identifying improved FFA2 agonists and antagonists to further define function and therapeutic opportunities of this receptor. PMID- 26518872 TI - Kruppel Homolog 1 Inhibits Insect Metamorphosis via Direct Transcriptional Repression of Broad-Complex, a Pupal Specifier Gene. AB - The Broad-Complex gene (BR-C) encodes transcription factors that dictate larval pupal metamorphosis in insects. The expression of BR-C is induced by molting hormone (20-hydroxyecdysone (20E)), and this induction is repressed by juvenile hormone (JH), which exists during the premature larval stage. Kruppel homolog 1 gene (Kr-h1) has been known as a JH-early inducible gene responsible for repression of metamorphosis; however, the functional relationship between Kr-h1 and repression of BR-C has remained unclear. To elucidate this relationship, we analyzed cis- and trans elements involved in the repression of BR-C using a Bombyx mori cell line. In the cells, as observed in larvae, JH induced the expression of Kr-h1 and concurrently suppressed 20E-induced expression of BR-C. Forced expression of Kr-h1 repressed the 20E-dependent activation of the BR-C promoter in the absence of JH, and Kr-h1 RNAi inhibited the JH-mediated repression, suggesting that Kr-h1 controlled the repression of BR-C. A survey of the upstream sequence of BR-C gene revealed a Kr-h1 binding site (KBS) in the BR C promoter. When KBS was deleted from the promoter, the repression of BR-C was abolished. Electrophoresis mobility shift demonstrated that two Kr-h1 molecules bound to KBS in the BR-C promoter. Based on these results, we conclude that Kr-h1 protein molecules directly bind to the KBS sequence in the BR-C promoter and thereby repress 20E-dependent activation of the pupal specifier, BR-C. This study has revealed a considerable portion of the picture of JH signaling pathways from the reception of JH to the repression of metamorphosis. PMID- 26518873 TI - Regulation of Hyaluronan (HA) Metabolism Mediated by HYBID (Hyaluronan-binding Protein Involved in HA Depolymerization, KIAA1199) and HA Synthases in Growth Factor-stimulated Fibroblasts. AB - Regulation of hyaluronan (HA) synthesis and degradation is essential to maintenance of extracellular matrix homeostasis. We recently reported that HYBID (HYaluronan-Binding protein Involved in hyaluronan Depolymerization), also called KIAA1199, plays a key role in HA depolymerization in skin and arthritic synovial fibroblasts. However, regulation of HA metabolism mediated by HYBID and HA synthases (HASs) under stimulation with growth factors remains obscure. Here we report that TGF-beta1, basic FGF, EGF, and PDGF-BB commonly enhance total amount of HA in skin fibroblasts through up-regulation of HAS expression, but molecular size of newly produced HA is dependent on HYBID expression levels. Stimulation of HAS1/2 expression and suppression of HYBID expression by TGF-beta1 were abrogated by blockade of the MAPK and/or Smad signaling and the PI3K-Akt signaling, respectively. In normal human skin, expression of the TGF-beta1 receptors correlated positively with HAS2 expression and inversely with HYBID expression. On the other hand, TGF-beta1 up-regulated HAS1/2 expression but exerted only a slight suppressive effect on HYBID expression in synovial fibroblasts from the patients with osteoarthritis or rheumatoid arthritis, resulting in the production of lower molecular weight HA compared with normal skin and synovial fibroblasts. These data demonstrate that although TGF-beta1, basic FGF, EGF, and PDGF-BB enhance HA production in skin fibroblasts, TGF-beta1 most efficiently contributes to production of high molecular weight HA by HAS up-regulation and HYBID down regulation and suggests that inefficient down-regulation of HYBID by TGF-beta1 in arthritic synovial fibroblasts may be linked to accumulation of depolymerized HA in synovial fluids in arthritis patients. PMID- 26518874 TI - miR-346 Up-regulates Argonaute 2 (AGO2) Protein Expression to Augment the Activity of Other MicroRNAs (miRNAs) and Contributes to Cervical Cancer Cell Malignancy. AB - MicroRNAs (miRNAs) are a class of post-transcriptional regulators of gene expression, and AGO2 is essential for miRNA activity. In this study, we focused on the regulation of AGO2 by miR-346 and the consequences in cervical cancer cells. miR-346 enhanced the expression of AGO2, resulting in the increased activity of other miRNAs and contributing to the malignancy of HeLa cells. GRSF1 participated in the regulation of AGO2 by miR-346, and the middle sequence of miR 346 was vital for the synergy effect of miR-346 and GRSF1. We determined that miR 346 promoted the migration and invasion of HeLa cells. In summary, we are the first to report that AGO2 is regulated positively by miRNA and that GRSF1 participates in the miRNA pathway. PMID- 26518875 TI - Alternatively Spliced Isoforms of KV10.1 Potassium Channels Modulate Channel Properties and Can Activate Cyclin-dependent Kinase in Xenopus Oocytes. AB - KV10.1 is a voltage-gated potassium channel expressed selectively in the mammalian brain but also aberrantly in cancer cells. In this study we identified short splice variants of KV10.1 resulting from exon-skipping events (E65 and E70) in human brain and cancer cell lines. The presence of the variants was confirmed by Northern blot and RNase protection assays. Both variants completely lacked the transmembrane domains of the channel and produced cytoplasmic proteins without channel function. In a reconstituted system, both variants co-precipitated with the full-length channel and induced a robust down-regulation of KV10.1 current when co-expressed with the full-length form, but their effect was mechanistically different. E65 required a tetramerization domain and induced a reduction in the overall expression of full-length KV10.1, whereas E70 mainly affected its glycosylation pattern. E65 triggered the activation of cyclin-dependent kinases in Xenopus laevis oocytes, suggesting a role in cell cycle control. Our observations highlight the relevance of noncanonical functions for the oncogenicity of KV10.1, which need to be considered when ion channels are targeted for cancer therapy. PMID- 26518876 TI - Taurocholate Induces Cyclooxygenase-2 Expression via the Sphingosine 1-phosphate Receptor 2 in a Human Cholangiocarcinoma Cell Line. AB - Cholangiocarcinoma (CCA) is a rare, but highly malignant primary hepatobiliary cancer with a very poor prognosis and limited treatment options. Our recent studies reported that conjugated bile acids (CBAs) promote the invasive growth of CCA via activation of sphingosine 1-phosphate receptor 2 (S1PR2). Cyclooxygenase 2 (COX-2)-derived prostaglandin E2 (PGE2) is the most abundant prostaglandin in various human malignancies including CCA. Previous studies have indicated that COX-2 was highly expressed in CCA tissues, and the survival rate of CCA patients was negatively associated with high COX-2 expression levels. It has also been reported that CBAs induce COX-2 expression, whereas free bile acids inhibit COX-2 expression in CCA mouse models. However, the underlying cellular mechanisms and connection between S1PR2 and COX-2 expression in CCA cells have still not been fully elucidated. In the current study, we examined the role of S1PR2 in conjugated bile acid (taurocholate, (TCA))-induced COX-2 expression in a human HuCCT1 CCA cell line and further identified the potential underlying cellular mechanisms. The results indicated that TCA-induced invasive growth of human CCA cells was correlated with S1PR2-medated up-regulation of COX-2 expression and PGE2 production. Inhibition of S1PR2 activation with chemical antagonist (JTE 013) or down-regulation of S1PR2 expression with gene-specific shRNA not only reduced COX-2 expression, but also inhibited TCA-induced activation of EGFR and the ERK1/2/Akt-NF-kappaB signaling cascade. In conclusion, S1PR2 plays a critical role in TCA-induced COX-2 expression and CCA growth and may represent a novel therapeutic target for CCA. PMID- 26518877 TI - alpha-Defensins Induce a Post-translational Modification of Low Density Lipoprotein (LDL) That Promotes Atherosclerosis at Normal Levels of Plasma Cholesterol. AB - Approximately one-half of the patients who develop clinical atherosclerosis have normal or only modest elevations in plasma lipids, indicating that additional mechanisms contribute to pathogenesis. In view of increasing evidence that inflammation contributes to atherogenesis, we studied the effect of human neutrophil alpha-defensins on low density lipoprotein (LDL) trafficking, metabolism, vascular deposition, and atherogenesis using transgenic mice expressing human alpha-defensins in their polymorphonuclear leukocytes (Def(+/+)). Accelerated Def(+/+) mice developed alpha-defensin.LDL complexes that accelerate the clearance of LDL from the circulation accompanied by enhanced vascular deposition and retention of LDL, induction of endothelial cathepsins, increased endothelial permeability to LDL, and the development of lipid streaks in the aortic roots when fed a regular diet and at normal plasma levels of LDL. Transplantation of bone marrow from Def(+/+) to WT mice increased LDL clearance, increased vascular permeability, and increased vascular deposition of LDL, whereas transplantation of WT bone marrow to Def(+/+) mice prevented these outcomes. The same outcome was obtained by treating Def(+/+) mice with colchicine to inhibit the release of alpha-defensins. These studies identify a potential new link between inflammation and the development of atherosclerosis. PMID- 26518878 TI - Metabolic Cooperation of Glucose and Glutamine Is Essential for the Lytic Cycle of Obligate Intracellular Parasite Toxoplasma gondii. AB - Toxoplasma gondii is a widespread protozoan parasite infecting nearly all warm blooded organisms. Asexual reproduction of the parasite within its host cells is achieved by consecutive lytic cycles, which necessitates biogenesis of significant energy and biomass. Here we show that glucose and glutamine are the two major physiologically important nutrients used for the synthesis of macromolecules (ATP, nucleic acid, proteins, and lipids) in T. gondii, and either of them is sufficient to ensure the parasite survival. The parasite can counteract genetic ablation of its glucose transporter by increasing the flux of glutamine-derived carbon through the tricarboxylic acid cycle and by concurrently activating gluconeogenesis, which guarantee a continued biogenesis of ATP and biomass for host-cell invasion and parasite replication, respectively. In accord, a pharmacological inhibition of glutaminolysis or oxidative phosphorylation arrests the lytic cycle of the glycolysis-deficient mutant, which is primarily a consequence of impaired invasion due to depletion of ATP. Unexpectedly, however, intracellular parasites continue to proliferate, albeit slower, notwithstanding a simultaneous deprivation of glucose and glutamine. A growth defect in the glycolysis-impaired mutant is caused by a compromised synthesis of lipids, which cannot be counterbalanced by glutamine but can be restored by acetate. Consistently, supplementation of parasite cultures with exogenous acetate can amend the lytic cycle of the glucose transport mutant. Such plasticity in the parasite's carbon flux enables a growth-and-survival trade-off in assorted nutrient milieus, which may underlie the promiscuous survival of T. gondii tachyzoites in diverse host cells. Our results also indicate a convergence of parasite metabolism with cancer cells. PMID- 26518880 TI - The Future of Molecular Analysis in Melanoma: Diagnostics to Direct Molecularly Targeted Therapy. AB - Melanoma is a malignancy of pigment-producing cells that is driven by a variety of genetic mutations and aberrations. In most cases, this leads to upregulation of the mitogen-activated protein kinase (MAPK) pathway through activating mutations of upstream mediators of the pathway including BRAF and NRAS. With the advent of effective MAPK pathway inhibitors, including the US FDA-approved BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitor trametinib, molecular analysis has become an integral part of the care of patients with metastatic melanoma. In this article, the key molecular targets and strategies to inhibit these targets therapeutically are presented, and the techniques of identifying these targets, in both tissue and blood, are discussed. PMID- 26518879 TI - Telomerase Deficiency Causes Alveolar Stem Cell Senescence-associated Low-grade Inflammation in Lungs. AB - Mutations of human telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) are associated with a subset of lung aging diseases, but the mechanisms by which TERC and TERT participate in lung diseases remain unclear. In this report, we show that knock-out (KO) of the mouse gene Terc or Tert causes pulmonary alveolar stem cell replicative senescence, epithelial impairment, formation of alveolar sacs, and characteristic inflammatory phenotype. Deficiency in TERC or TERT causes a remarkable elevation in various proinflammatory cytokines, including IL-1, IL-6, CXCL15 (human IL-8 homolog), IL-10, TNF-alpha, and monocyte chemotactic protein 1 (chemokine ligand 2 (CCL2)); decrease in TGF beta1 and TGFbetaRI receptor in the lungs; and spillover of IL-6 and CXCL15 into the bronchoalveolar lavage fluids. In addition to increased gene expressions of alpha-smooth muscle actin and collagen 1alpha1, suggesting myofibroblast differentiation, TERC deficiency also leads to marked cellular infiltrations of a mononuclear cell population positive for the leukocyte common antigen CD45, low affinity Fc receptor CD16/CD32, and pattern recognition receptor CD11b in the lungs. Our data demonstrate for the first time that telomerase deficiency triggers alveolar stem cell replicative senescence-associated low-grade inflammation, thereby driving pulmonary premature aging, alveolar sac formation, and fibrotic lesion. PMID- 26518881 TI - In vitro efficacy of daptomycin and teicoplanin combined with ethanol, clarithromycin or gentamicin as catheter lock solutions. AB - BACKGROUND: Despite widespread use, optimum choice of antimicrobial agents, concentrations, combinations and exposure times have not been determined for antibiotic lock technique (ALT). Our objective was to evaluate the efficacy of different antibiotic combinations using an in vitro model of catheter-related infection. Daptomycin (DAP) 5 mg/mL, teicoplanin (TEC) 5 mg/mL, both alone and combined with gentamicin (GM) 2.5 mg/mL, clarythromycin (CLA) 5 mg/mL or ethanol 35 % were evaluated against four clinical strains of methicillin resistant coagulase negative staphylococci. Lock solutions were renewed every 24 h. RESULTS: After 72 h catheters were reincubated with culture media to investigate bacterial regrowth. All antibiotic combinations resulted in significant reductions (p < 0.05) of Log(10) cfu/mL at 72 h for both organisms compared with controls. DAP resulted in significant reductions of Log(10) for all organism versus TEC (p = 0.001). Only DAP reached the limit of detection at 72 h, however did not prevent regrowth after 24 h of ALT removal. DAP + Ethanol and TEC + ethanol eradicated biofilm at 72 h, but only DAP + ethanol (against all strains) and DAP + CLA (against two strains) prevented regrowth at 24 h after ALT removal. CONCLUSIONS: Based on these data, ALT with DAP + ethanol and DAP + CLA should be explored in clinical trials. PMID- 26518882 TI - Shift-to-Shift Handoff Effects on Patient Safety and Outcomes. AB - Multiple health care organizations have identified handoffs as a source of clinical errors; however, few studies have linked handoff interventions to improved patient outcomes. This systematic review of English-language research articles, published January 2008 to May 2015 and focusing on shift-to-shift handoff interventions and patient outcomes, yielded 10 774 unique articles. Twenty-one articles met inclusion criteria, measuring each of the following: patient falls (n = 7), reportable events (n = 6), length of stay (n = 4), mortality (n = 4), code calls (n = 4), medication errors (n = 4), medical errors (n = 3), procedural complications (n = 2), pressure ulcers (n = 2), weekend discharges (n = 2), and nosocomial infections (n = 2). One study each also measured time to first intervention, restraint use, overnight transfusions, and out-of-hours deteriorations. Studies that reported funding had higher quality scores. It is difficult to identify trends in the handoff research because of simultaneous implementation of multiple interventions and heterogeneity of the interventions, outcomes measured, and settings. The authors call for increased handoff research funding, especially for studies that include patient outcome measures. PMID- 26518883 TI - Comparative analysis of 14-3-3 isoform expression and epigenetic alterations in colorectal cancer. AB - BACKGROUND: The 14-3-3 family is a group of intracellular proteins found in all eukaryotic organisms. Humans have seven isoforms that serve as scaffolds to promote interactions of regulatory phospho-proteins involved in many vital cellular processes and previous studies have shown that disturbances in native 14 3-3 levels can contribute significantly to the development of various cancers. METHODS: DNA and RNA was extracted from frozen tissue samples collected by the Human Cooperative Tissue Network. RNA samples were reverse transcribed and subjected to qRT-PCR analysis using fluorescently labelled probes. Genomic DNA was treated with bisulfite and cloned into bacterial vectors for subsequent high resolution sequencing. Mammalian NIH3T3 cells were transformed with 14-3-3 eta and Ras expression vectors synthesized from cDNA. Colonies were counted and transforming capability assessed after 21 days of growth. Cell lysates were analyzed by western blot to verify protein expression. RESULTS: Here we examined normal and cancerous 14-3-3 expression levels of all seven isoforms in a cohort of sporadic colorectal adenocarcinomas and in a group of tumors and their matched normals using qRT-PCR analysis. We found a statistically significant decrease in the levels of 14-3-3 sigma, eta, and zeta observed among adenocarcinomas compared to normal tissue. A parallel analysis of microarray data from the TCGA dataset confirmed that expression of sigma and eta were down-regulated in colon tumors. To explore the mechanisms behind 14-3-3 expression changes, we examined the methylation status of the sigma, eta, and zeta gene promoters in selected samples. Our data identified novel CpG methylation sites in the eta promoter consistent with epigenetic silencing of both 14-3-3 sigma and eta isoforms during colon tumorigenesis. Because epigenetic silencing is the hallmark of a tumor suppressor we tested eta in focus formation assays and found that it is capable of suppressing ras-induced transformation of NIH3T3 cells. CONCLUSION: To our knowledge, this is the first study to identify the 14-3-3 eta gene as a tumor suppressor and that its expression is suppressed in colon tumors by DNA hypermethylation. These data suggest a link between 14-3-3 expression levels and the development of colon cancers. PMID- 26518884 TI - Time-Varying Effects of Breast Cancer Adjuvant Systemic Therapy. AB - BACKGROUND: The benefits of breast cancer adjuvant systemic treatments are generally assumed to be proportional (or constant) over time, but limited data suggest that some treatment effects may vary with time. We therefore systematically assessed the proportional hazards assumption across all 19 breast cancer adjuvant systemic therapy trials in the National Surgical Adjuvant Breast and Bowel Project (NSABP) database. METHODS: The NSABP breast cancer trials were tested for the proportionality of hazard rates between randomized treatment groups for five endpoints: overall survival, disease-free survival and recurrence, local-regional recurrence, or distant recurrence as first events. When the proportional hazards assumption did not hold, a "change point for the relative risk" technique was used to identify the temporal breakdown of the treatment effect. RESULTS: Time-varying treatment effects were observed in nearly half of the trials (nine of 19). In six (B-05, B-11, B-12, B-14, B-16, and B-20), novel treatment benefits diminished statistically significantly at specific time points following surgery. In B-09 and B-31, novel treatment benefits were delayed and emerged more than one year after surgery (1.57 and 1.32 years correspondingly), but the benefit in B-09 reversed after the third year of follow up. In one trial (B-23), the initial advantage and subsequent disadvantage of one of the regimens was evident. CONCLUSIONS: Breast cancer adjuvant systemic therapy can have statistically significant time-varying effects, which should be considered in the design, analysis, reporting, and translation of clinical trials. These time-dependent effects will have greater relevance as the number of long-term breast cancer survivors increases. PMID- 26518885 TI - The novel extremely acidophilic, cell-wall-deficient archaeon Cuniculiplasma divulgatum gen. nov., sp. nov. represents a new family, Cuniculiplasmataceae fam. nov., of the order Thermoplasmatales. AB - Two novel cell-wall-less, acidophilic, mesophilic, organotrophic and facultatively anaerobic archaeal strains were isolated from acidic streamers formed on the surfaces of copper-ore-containing sulfidic deposits in south-west Spain and North Wales, UK. Cells of the strains varied from 0.1 to 2 MUm in size and were pleomorphic, with a tendency to form filamentous structures. The optimal pH and temperature for growth for both strains were 1.0-1.2 and 37-40 degrees C, with the optimal substrates for growth being beef extract (3 g l- 1) for strain S5T and beef extract with tryptone (3 and 1 g l- 1, respectively) for strain PM4. The lipid composition was dominated by intact polar lipids consisting of a glycerol dibiphytanyl glycerol tetraether (GDGT) core attached to predominantly glycosidic polar headgroups. In addition, free GDGT and small relative amounts of intact and core diether lipids were present. Strains S5T and PM4 possessed mainly menaquinones with minor fractions of thermoplasmaquinones. The DNA G+C content was 37.3 mol% in strain S5T and 37.16 mol% for strain PM4. A similarity matrix of 16S rRNA gene sequences (identical for both strains) showed their affiliation to the order Thermoplasmatales, with 73.9-86.3 % identity with sequences from members of the order with validly published names. The average nucleotide identity between genomes of the strains determined in silico was 98.75 %, suggesting, together with the 16S rRNA gene-based phylogenetic analysis, that the strains belong to the same species. A novel family, Cuniculiplasmataceae fam. nov., genus Cuniculiplasma gen. nov. and species Cuniculiplasma divulgatum sp. nov. are proposed based on the phylogenetic, chemotaxonomic analyses and physiological properties of the two isolates, S5T and PM4 ( = JCM 30641 = VKM B 2940). The type strain of Cuniculiplasma divulgatum is S5T ( = JCM 30642T = VKM B 2941T). PMID- 26518886 TI - Validation of the child oral health impact profile (COHIP) french questionnaire among 12 years-old children in New Caledonia. AB - BACKGROUND: The Child Oral Health Impact Profile (COHIP) is an Oral Health Related Quality of Life (OHRQOL) tool that assesses the impact of oral diseases on quality of life in children. This study aimed to assess the validity of the COHIP French questionnaire (45 items) and to evaluate the OHRQOL of 12-years children in New Caledonia. METHODS: After cultural adaptation of the COHIP questionnaire, data were collected from clinical oral examinations and self administered questionnaires in a representative sample of children aged 12 years in New Caledonia. Questions related to socio-demographic status or children's perception of their oral and general health were added to the COHIP questionnaire. Studying the association between COHIP scores and health subjective perceptions or dental status indicators assessed concurrent and discriminant validity. The items of the COHIP were subjected to principal components analysis. Finally, reproducibility and reliability were evaluated using Intraclass Correlation Coefficients (ICC) and Cronbach's alpha coefficient. RESULTS: Two hundred and thirty-six children participated in the main study; mean age was 12.6 +/- 0.31 years, 55.1 % were girls and diverse ethnic groups were represented. A preliminary reliability analysis has led to calculate COHIP scores with 34 items as in the English version, scores ranged from 35 to 131 (mean +/- SD, 101.9 +/- 16.84). Lower COHIP scores were significantly associated with the self-perception of poor general or oral health. COHIP was able to discriminate between participants according to gender, ethnic group, oral hygiene, dental attendance, dental fear and the presence of oral diseases. Test-retest reliability and scale reliability were excellent (ICC = 0.904; Cronbach's alpha coefficient = 0.880). Four components were identified from the factor analysis. CONCLUSION: The French 34-items COHIP showed excellent psychometric properties. Further testing will examine the structure and utility of the instrument in both clinical and epidemiological samples. PMID- 26518887 TI - A study of vertebra number in pigs confirms the association of vertnin and reveals additional QTL. AB - BACKGROUND: Formation of the vertebral column is a critical developmental stage in mammals. The strict control of this process has resulted in little variation in number of vertebrae across mammalian species and no variation within most mammalian species. The pig is quite unique as considerable variation exists in number of thoracic vertebrae as well as number of lumbar vertebrae. At least two genes have been identified that affect number of vertebrae in pigs yet considerable genetic variation still exists. Therefore, a genome-wide association (GWA) analysis was conducted to identify additional genomic regions that affect this trait. RESULTS: A total of 1883 animals were phenotyped for the number of ribs and thoracolumbar vertebrae as well as successfully genotyped with the Illumina Porcine SNP60 BeadChip. After data editing, 41,148 SNP markers were included in the GWA analysis. These animals were also phenotyped for kyphosis. Fifty-three 1 Mb windows each explained at least 1.0 % of the genomic variation for vertebrae counts while 16 regions were significant for kyphosis. Vertnin genotype significantly affected vertebral counts as well. The region with the largest effect for number of lumbar vertebrae and thoracolumbar vertebrae were located over the Hox B gene cluster and the largest association for thoracic vertebrae number was over the Hox A gene cluster. Genetic markers in significant regions accounted for approximately 50% of the genomic variation. Less genomic variation for kyphosis was described by QTL regions and no region was associated with kyphosis and vertebra counts. CONCLUSIONS: The importance of the Hox gene families in vertebral development was highlighted as significant associations were detected over the A, B and C families. Further evaluation of these regions and characterization of variants within these genes will expand our knowledge on vertebral development using natural genetic variants segregating in commercial swine. PMID- 26518888 TI - Lubricant use and condom use during anal sex in men who have sex with men in Tanzania. AB - The lack of data on condom and lubricant use among African men who have sex with men (MSM) hinders prevention efforts. We describe use, knowledge, and access to lubricants in Dar es Salaam and Tanga, Tanzania. Data were collected in 2012 and 2013 from a cross-sectional survey of 200 MSM in Dar es Salaam and 100 MSM in Tanga, Tanzania. The most common reason for not using condoms was dislike of condoms. Two-thirds of the men reported always using a lubricant for anal sex. Results showed that: fewer men who have sex with both men and women (MSMW) know about lubricants; more MSM look for, have difficulty finding, and find lubricants to be expensive; and MSM use lubricants to facilitate penetration. MSMW commonly receive their lubricants from their sexual partner, while MSM got them from friends and pharmacies. HIV-negative MSM used lubricants to facilitate penetration and reduce pain. HIV-positive MSM are likely to get their lubricants from pharmacies or friends. MSMW use Vaseline(r) significantly more than MSM as a lubricant. Results suggest that HIV prevention knowledge among MSM is greater, so HIV prevention efforts should emphasise carrying water-based lubricant among MSMW. Consequently, there is an opportunity to co-market condoms and water-based lubricants. PMID- 26518889 TI - David Oliver: I've nothing against golf. PMID- 26518890 TI - ASPP and iASPP: Implication in cancer development and progression. AB - The well-known guardian of genome, p53 plays critical roles in the induction of apoptosis typically upon DNA damage whereas mutant p53 containing cells are unable to undergo apoptosis which leads to aggressive tumor growth and drug resistance. Moreover, another molecule regulating wild-ype p53 function is ASPP (apoptosis stimulating proteins of p53) family. ASPP family consists of ASPP1 and ASPP2, and functions as tumor suppressors whereas the inhibitor of ASPP (iASPP) functions as oncogene. By binding to apoptosis regulating proteins such as p53, p63, p73, Bcl-2, NF-kappaB p65, etc., ASPP1 and ASPP2 promote apoptosis while overexpression of iASPP inhibits apoptotic cell death typically after DNA damage. In cancer cells, the aberrant expressions of ASPP1, ASPP2 and iASPP have been observed, especially, the high expression of iASPP in cancers is associated with worse disease status, therapy resistance and poor survival of patients with cancers. The molecular interactions between the members of ASPP family and their binding proteins in apoptotic pathway together with other regulators such as miR 124, NF-kappaB regulated Twist, snail, etc. form a complex signal transduction network to control apoptosis and tumor growth. Therefore, targeting ASPP family could regulate the aberrant communications in the signal transduction network to induce apoptosis and drug sensitivity. Several peptides, miRNAs and natural agents have been used to target ASPP family and show encouraging results in the induction of apoptosis of cancer cells; however, more in vivo animal studies and clinical trials are needed to confirm the true value of targeting ASPP family in the treatment of cancers. PMID- 26518891 TI - Association of NOTCH with different microRNAs in head and neck cancer. AB - Head and neck cancer is the sixth most common cancer worldwide with an alarming increase in Asian countries. Overwhelmingly increasing cell culture and preclinical studies are identifying wide ranging mechanisms which are instrumental in disease development, progression and resistance against different therapeutics. The scientists are unable to differentiate whether expressional mutation is a cause or a consequence of some other alterations occurring in the body. We partition this review into how NOTCH1 and p16 contribute in cancer development and how microRNAs quantitatively control NOTCH1 expression. Future studies must converge on identification of miRNAs which negatively regulate p16 and targeted inhibition of p16 targeting miRNAs will be helpful in inhibiting tumor growth, cell proliferation and induction of apoptosis. Detailed mechanistic insights related to miRNA mediated Notch regulation will also be useful in delivery of tumor suppressor miRNAs or mimics to effectively inhibit cancer. PMID- 26518892 TI - The role of microRNAs in the resistance to colorectal cancer treatments. AB - Colorectal cancer (CRC) is one of the leading cancer-related causes of death in the world. Several approaches such as surgery, chemotherapy, radiotherapy, targeted therapy, or combinations thereof have been used to treat CRC patients. However, the fact that many patients develop a drug resistance during the course of the treatment is a major obstacle. Understanding the mechanisms underlying resistance is critical in order to develop more effective targeted treatments. Recently, several studies have reported on the regulatory role of microRNAs (miRNAs) in the response to anti-cancer drugs and suggested them as a source of predictive biomarkers for the purpose of patient stratification and for the prognosis of treatment success. For example, overexpressing miR-34a, a master regulator of tumor suppression attenuates chemoresistance to 5-FU by downregulating silent information regulator 1 (SIRT1) and E2F3. MRX34, a miR-34a replacement is the first synthetic miRNA mimic to enter clinical testing. MiR-34a antagonizes cancer stemness, metastasis, and chemoresistance processes that are necessary for cancer viability. This example shows that miRNAs are coming into focus for the design of enhanced cancer therapies that aim to sensitise tumor cells for anti-cancer drugs. In this review, we provide an overview on the role of miRNAs in the resistance to current colorectal cancer therapies. Furthermore, we discuss the value of miRNAs as biomarkers for predicting chemosensitivity and their potential to enhance treatment strategies. PMID- 26518893 TI - The Notch signaling pathway in esophageal adenocarcinoma. AB - The Notch signaling pathway plays a critical role in embryonic development, self renewal of stem cells, and carcinogenesis. Aberrant Notch signaling has been linked to a wide variety of cancers, and can either suppress or promote tumors depending on the cell type and the context. Increasingly it is being realized that Notch signaling not only involves in the pathogenesis and development of esophageal adenocarcinoma (EAC), it also promotes the growth of EAC cells and also involved in the maintenance of EAC cancer stem cells. The efficacy of gamma secretase inhibitor (GSI) in EAC treatment could have a major impact on easing the burden of this devastating disease. Therefore, it appears that inhibition of Notch sensitizes EAC cells to chemotherapeutic agents, which should lead to a better and more durable response to neoadjuvant chemotherapy (NAC). In this review, we bring to highlight how Notch plays a role in the development, tumorigenicity, and stemness of EAC cells, and how Notch signaling pathway could be a promising therapeutic target for the treatment of human EAC. PMID- 26518894 TI - TRAIL and targeting cancer cells: between promises and obstacles. AB - Targeting cancer cells is one of the challenges of current treatment strategies. TRAIL represents a promising therapeutic approach and over the past decades there was an increased interest in targeting TRAIL signaling to treat cancer. Indeed, TRAIL can specifically target cancer cells and exhibits very low cytotoxicity towards normal cells. However, rapidly accumulating experimental evidence has started to shed light on multiple factors which induce resistance against TRAIL in cancer cells. This resistance consists of various mechanisms including downregulation of death receptors and caspase-8 and overexpression of decoy receptors as well as antiapoptotic factors such as members of Bcl-2 family. Even if several studies focused on elucidating those resistance mechanisms, there still remain gray areas that need to be fully elucidated. Thus, therapeutic approaches could consist of targeting both resistance signaling pathways and TRAIL signaling to enhance TRAIL therapy efficiency. PMID- 26518895 TI - Cancer stem cells in head and neck cancer: A Mini Review. AB - Head and neck cancer (HNC) is a multifaceted and genomically complex disease and rapidly emerging preclinical and clinical studies have provided a broader landscape of signaling. It is being realized that intra-tumor heterogeneity, genetic and epigenetic mutations considerably challenge wide ranging therapeutics and patients frequently develop locoregional recurrences, second primary tumours and distant metastases. Using high-throughput technologies, it has been revealed that existence of different subpopulations of cells within tumor mass with different phenotypic and functional properties with distinct tumour-initiating potential is responsible to HNC resistance. In light of accumulating evidence reported in recent years, it is now known that different intracellular proteins and cell surface markers have been used to study CSCs. This review provides an overview of CSC biomarkers in HNC treatment and their potential as therapeutic targets in improving the diagnosis, prognosis and treatment of HNC patients for new therapeutic strategies with information about estimation of prognosis and treatment decision. Further studies regarding biomarkers are necessary to determine the specific role of CSCs in HNC which could be useful in development of new therapeutic strategies to eliminate CSCs and maximize clinical outcome. Furthermore, CD44 still need more research in HNC once the studies show contradictions. Studies using lineage tracing and deep sequencing will provide a comprehensive understanding of CSC model and extent to which it is accountable for resistance against therapeutics and carcinogenesis. PMID- 26518896 TI - PARP inhibition: A promising therapeutic target in ovarian cancer. AB - Ovarian cancer is burdened by the highest mortality rate among gynecological cancers. Gold standard is represented by the association of platinum-taxane based chemotherapy and radical surgery. Despite several adjustments occurred in cytotoxic drug in last decades, most patients continue to relapse, and no significant enhancement has been reached in the overall survival. The development of drug resistance and the recurrence of disease have prompted the investigations of other targets that can be used in the treatment of ovarian cancers. Among such targets, polyadenosine diphosphate-ribose polymerase (PARP) represents a novel way to target specific patways involved in tumor growth. PARP accelerates the reaction of the polyADP-ribosylation of proteins implicated in DNA repair. PARP inhibitors have shown activity in cancers with BRCA mutations, with other deficient DNA repair genes or signaling pathways that modulate DNA repair, or in association with DNA damaging agents not involved in DNA repair dysfunction. A number of inhibitors for PARP has been developed, and such drugs are under investigation in clinical trials to identify their impact in the treatment of ovarian cancers. This review aims to summarize the recent researches and clinical progress on PARP inhibitors as novel target agents in ovarian cancer. PMID- 26518897 TI - Natural products are the future of anticancer therapy: Preclinical and clinical advancements of Viscum album phytometabolites. AB - Cancer is a multifaceted and genomically complex disease. Research over the years has gradually provided a near complete resolution of cancer landscape and it is now known that genetic/epigenetic mutations, inactivation of tumor suppressors, Overexpression of oncogenes, spatio-temporally dysregulated intracellular signaling cascades, epithelial to mesenchymal transition (EMT), metastasis and loss of apoptosis are some of the most extensively studied biological mechanisms that underpin cancer development and progression. Increasingly it is being realized that current therapeutic interventions are becoming ineffective because of tumor heterogeneity and rapidly developing resistance against drugs. Considerable biological activities exerted by bioactive ingredients isolated from natural sources have revolutionized the field of natural product chemistry and rapid developments in preclinical studies are encouraging. Viscum album has emerged as a deeply studied natural source with substantial and multifaceted biological activities. In this review we have attempted to provide recent breakthroughs in existing scientific literature with emphasis on targeting of protein network in cancer cells. We partition this review into different sections, highlighting latest information from cell culture studies, preclinical and clinically oriented studies. We summarized how bioactive ingredients of Viscum album modulated extrinsic and intrinsic pathways in cancer cells. However, surprisingly, none of the study reported stimulatory effects on TRAIL receptors. The review provided in-depth analysis of how Viscum album modulated Endoplasmic Reticulum Stress in cancer cells and how bioactive chemicals tactfully targeted cytoskeletal machinery in cancer cells as evidenced by cell culture studies. It is noteworthy that Viscum album has entered into various phases of clinical trials, however, there are still knowledge gaps in our understanding regarding how various bioactive constituents of Viscum album modulate intracellular signaling cascades in cancer. Better and deeper comprehension oncogenic signaling cascades will prove to be helful in getting a step closer to individualized medicine. PMID- 26518898 TI - Targeting post-translational modifications of histones for cancer therapy. AB - Post-translational modifications (PTMs) on histones including acetylation, methylation, phosphorylation, citrullination, ubiquitination, ADP ribosylation, and sumoylation, play important roles in different biological events including chromatin dynamics, DNA replication, and transcriptional regulation. Aberrant histones PTMs leads to abnormal gene expression and uncontrolled cell proliferation, followed by development of cancers. Therefore, targeting the enzymes required for specific histone PTMs holds a lot of potential for cancer treatment. In this review article, we retrospect the latest studies in the regulations of acetylation, methylation, and phosphorylation of histones. We also summarize inhibitors/drugs that target these modifications for cancer treatment. PMID- 26518899 TI - Saturated fatty acid induces cancer stem cell-like properties in human hepatoma cells. AB - Hepatic steatosis has been reported to be a risk factor for the development of liver cancer. The underlying mechanism for carcinogenesis remains to be elucidated. It has been postulated that cancer stem cells (CSCs) within tumor tissues are a subset of cells with stem cell properties of self-renewal and undifferentiation. The purpose of this study was to investigate the effects of a saturated fatty acid, palmitate (PA), on CSC-like properties of human hepatoma HepG2 cells. We investigated the effects of PA on HepG2 cells and primary rat hepatocytes (PRH) by exposing them to PA to induce lipid accumulation. Significant fat accumulation was observed by Oil Red O staining in cells exposed to PA, and it was accompanied by significant increase in NFkappaB (p65) nuclear translocation in HepG2 cells. Notably, PA significantly enhanced the sphere forming ability of HepG2 cells, but not PRH. Furthermore, PA significantly increased stemness gene expressions of Sox2 and Oct4, and sonic hedgehog (Shh) production. Notably, NFkappaB inhibitors, N-Acetyl-L-cysteine and pyrollidine dithiocarbamate, and a NOX inhibitor, diphenyleneiodonium, significantly attenuated PA-induced sphere forming ability of HepG2 cells. Our results suggest that lipid accumulation may not only induce pro-inflammatory responses in hepatocytes but may also activate CSC-like properties of hepatoma cells through NFkappaB activation. PMID- 26518900 TI - Hesperetin exerts apoptotic effect on A431 skin carcinoma cells by regulating mitogen activated protein kinases and cyclins. AB - Dietary agents and phytochemicals have been utilised for the management of cancer for many years. Hesperetin, a dietary flavonoid found abundantly in citrus fruits, was evaluated for its cytotoxic and pro-apoptotic activities in A431 human skin carcinoma cells. Effect of hesperetin in regulating MAPK (Mitogen Activated Protein Kinase) signalling pathway and levels of various cyclins and other downstream apoptotic proteins were investigated. Its critical role in regulating other apoptotic proteins especially p21, Bcl-2 and Bax were also assessed. Hesperetin stimulated alterations in MAPK (Mitogen-Activated Protein Kinase) signalling pathway by modulating the expression levels of ERK (Extracellular signal Regulated Kinase), JNK (c-Jun NH2-terminal Kinase) and p38; thereby induced apoptosis in A431 cells. Hesperetin regulated the levels of cyclin A2, B1, D1, D3 and E1. It also modulated the levels of various proteins involved in apoptotic pathway especially p21, Bcl-2 and Bax. The study revealed the efficiency of hesperetin against human skin carcinoma cells and proposed its mechanism of action; there by opens up new avenues for the use of this dietary flavonoid against skin malignancies. PMID- 26518901 TI - Indirect role of microRNAs and transcription factors in the regulation of important cancer genes: A network biology approach. AB - Cancer is one of the leading causes of death worldwide. Although the mechanisms of gene regulation in cancer have been the subject of intense investigation during the last decades, the precise role of regulatory processes in cancer is largely unknown. More specifically, it is not completely understood how microRNAs and transcription factors regulate and influence the cancer-related processes. In the present study, using cancer-specific biological networks we examine the role of microRNAs and transcription factors (TFs) in regulation of important cancer genes. The importance measures which are used in this study consider both network structure information and biological data on miRNA- and TF-based gene regulation. By analyzing cancer-specific PPI, signaling and metabolic networks, it was shown that microRNAs and transcription factors tend to regulate those genes which are in the neighborhood of important components of cancer-specific PPI, signaling, and metabolic networks. The role of microRNAs was found to be particularly important, which confirms our previously-published results on the importance of microRNAs in detecting important network components. Moreover, we highlight that the miRNAs appear to apply their function via regulating the "neighbors" of important cancer genes, which implies their indirect role in cancer, and presumably, in fine-tuning the effect of other cancer-related genes. PMID- 26518902 TI - Genetic variants in the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and death receptor (DR4) genes contribute to susceptibility to colorectal cancer in pakistani population. AB - TRAIL mediated signaling in cancer cells has emerged as one amongst the most deeply studied molecular phenomenon. Data obtained through genetic studies has highlighted highly polymorphic nature of DR4 and in accordance with this concept, we aimed to investigate the association between Colorectal cancer and polymorphisms in TRAIL and DR4 gene. We selected 100 patients with colorectal cancer and 100 healthy, sex and age matched volunteers randomly. C626G and A1322G in DR4 gene were analyzed using Polymerase Change Reaction (PCR) - Restriction Fragment Length Polymorphism (RFLP) and Amplification Refractory Mutation System (ARMS) techniques. PCR-RFLP was used to study TRAIL 1595 C>T. TRAIL gene 1595 C>T genotypes percentage in colorectal cancer patients was statistically non significant. CC was 43% in patients and 50% in controls. CT was 45% in patients and 43% in controls. TT was 12% in patients and 7% in controls. C allele was 0.655% in cancer patients and 0.715% in controls. T allele was 0.345% in patients and 0.285% in controls. DR4 gene 626 C>G genotypes percentage analysis indicated that CC was 28% in patients and 2% in controls. GC was 42% in patients and 40% in controls. GG was 30% in patients and 58% in controls. CC was statistically significant (p=0.00000207) in cancer patients. C allele was 0.49% in patients and 0.22% in controls. G allele was 0.51% in patients and 0.78% in controls. For DR4 A1322G, homozygous GG genotype was 36% in the patients and in controls. There was statistically insignificant difference (p> 0.05). The heterozygous GT genotype was 30% in patients and 29% in controls. This difference was statistically insignificant (p value > 0.05). Similarly, the homozygous genotype TT of the minor allele was (35%) in controls and patients (34 %). This difference was also statistically insignificant (p value > 0.05). C allele was 0.51% in patients and 0.5% in controls. T allele was 0.49% in patients and 0.495% in controls. Future studies must converge on a larger sample size, sporadic mutations of DR4 and TRAIL and expression profiling. PMID- 26518903 TI - The association among MDCT-derived three-dimensional visceral adiposities on cardiac diastology and dyssynchrony in asymptomatic population. AB - BACKGROUND: Visceral adipose tissue, a biologically active fat depot, has been proposed as a reliable marker for visceral adiposity and metabolic abnormalities. Effects of such adiposity on LV diastolic function and dyssynchrony remained largely unknown. METHODS: We assessed pericardial fat (PCF) and thoracic peri aortic fat (TPAF) by three-dimensional (3D) volume-vender multi-detector computed tomography (MDCT) (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA). Echo derived diastolic parameters and tissue Doppler imaging (TDI) defined mitral annular systolic (S'), early diastolic (E') velocities as well as LV filling (E/E') were all obtained. Intra-ventricular systolic (Sys-D) and diastolic (Dias D) dyssynchrony were assessed by TDI method. RESULTS: A total of 318 asymptomatic subjects (mean age: 53.5 years, 36.8 % female) were eligible in this study. Greater PCF and TPAF were both associated with unfavorable diastolic indices and higher diastolic dyssynchrony (all p < 0.05). These associations remained relatively unchanged in multi-variate models. PCF and TPAF set at 81.68 & 8.11 ml yielded the largest sensitivity and specificity (78.6 and 60 % for PCF, 75 and 66.6 % for TPAF, respectively) in predicting abnormally high LV diastolic dyssynchrony, which was defined as Dias-D?55 ms. CONCLUSION: Increasing visceral adiposity may be associated with adverse effects on myocardium, primarily featured by worse diastolic function and greater degree of dyssynchrony. PMID- 26518904 TI - Association between human leucocyte antigen subtypes and risk of end stage renal disease in Taiwanese: a retrospective study. AB - BACKGROUND: End stage renal disease (ESRD) is prevalent in Taiwan. Human leukocyte antigens (HLA) have been found to be associated with the pathogenesis of autoimmune diseases, allergies and inflammatory bowel diseases, and there are emerging evidences of correlations between HLA genotypes and renal diseases such as diabetic nephropathy, IgA nephropathy, and glomerulonephritis. The aim of this study is to investigate detailed HLA subtypes in a case-control study of Taiwanese individuals. METHODS: The polymorphisms of HLA class I and II antigens in ESRD patients and a healthy control group were retrospectively analyzed. The information of 141 ESRD patients was obtained from the medical record of the Keelung branch of Chang Gung Memorial Hospital and was compared to the HLA type of a control group comprized of 190 healthy unrelated Taiwanese from one of our previous studies. In order to standardize the HLA designation of prior low resolution typings with the more advanced DNA based typings, all HLA-A, -B and DR were analyzed using a low resolution serologic equivalent. RESULTS: The current work suggests that HLA-DR3 (odds ratio = 1.91, 95 % CI = 1.098-3.324, P = 0.024, Pc = 0.312) and HLA-DR11 (odds ratio = 2.06, 95 % CI = 1.133-3.761, P = 0.021, Pc = 0.273) may represent susceptibility risk factors for the development of ESRD in Taiwanese individuals. On the other hand, HLA-DR8 (odds ratio = 0.47, 95 % CI = 0.236-0.920, p = 0.027. Pc = 0.351) may be a protective factor. HLA-A and -B antigens did not show any contribution of progression to ESRD. However, we note that the significance of all these findings is lost when the results are corrected for multiple comparisons according to Bonferroni. Further investigation with a larger group of patients and control is needed to resolve this issue. CONCLUSIONS: HLA typing might be a useful clinical method for screening patients with high risk of progression to ESRD. PMID- 26518905 TI - Cytoprotective effect of palm kernel cake phenolics against aflatoxin B1-induced cell damage and its underlying mechanism of action. AB - BACKGROUND: Palm kernel cake (PKC), a by-product of the palm oil industry is abundantly available in many tropical and subtropical countries. The product is known to contain high levels of phenolic compounds that may impede the deleterious effects of fungal mycotoxins. This study focused on the evaluation of PKC phenolics as a potential cytoprotective agent towards aflatoxin B1 (AFB1) induced cell damage. METHODS: The phenolic compounds of PKC were obtained by solvent extraction and the product rich in phenolic compounds was labeled as phenolic-enriched fraction (PEF). This fraction was evaluated for its phenolic compounds composition. The antioxidant activity of PEF was determined by using 1,1-diphenyl-2-picryl-hydrazil scavenging activity, ferric reducing antioxidant power, inhibition of beta-carotene bleaching, and thiobarbituric acid reactive substances assays. The cytotoxicity assay and molecular biomarkers analyses were performed to evaluate the cytoprotective effects of PEF towards aflatoxin B1 (AFB1)-induced cell damage. RESULTS: The results showed that PEF contained gallic acid, pyrogallol, vanillic acid, caffeic acid, syringic acid, epicatechin, catechin and ferulic acid. The PEF exhibited free radical scavenging activity, ferric reducing antioxidant power, beta-carotene bleaching inhibition and thiobarbituric acid reactive substances inhibition. The PEF demonstrated cytoprotective effects in AFB1-treated chicken hepatocytes by reducing the cellular lipid peroxidation and enhancing antioxidant enzymes production. The viability of AFB1-treated hepatocytes was improved by PEF through up-regulation of oxidative stress tolerance genes and down-regulation of pro-inflammatory and apoptosis associated genes. CONCLUSIONS: The present findings supported the proposition that the phenolic compounds present in PKC could be a potential cytoprotective agent towards AFB1 cytotoxicity. PMID- 26518906 TI - Informal dementia care: Consequences for caregivers' health and health care use in 8 European countries. AB - BACKGROUND: Informal (dementia) care has economic consequences throughout the health care system. Whilst the health and wellbeing of the care recipient might improve, the health of the caregiver might also change, typically for the worse. Therefore, this analysis aims to examine the association between caregiving intensity and caregivers' health and health care utilization. DATA AND METHODS: The empirical analysis is based on cross-sectional survey data generated by the European Project "RightTimePlaceCare" (RTPC). RTPC was a prospective cohort study conducted in eight European countries (Estonia, Finland, France, Germany, Netherlands, Sweden, Spain and the United Kingdom). The health status of 1029 informal caregivers was assessed by measures of psychological wellbeing (GHQ-12) and self-rated overall health (EQ-VAS). Health care utilization was measured by (i) the self-stated proportion of health care use influenced by caregiving and (ii) the probability of at least one visit to a general practitioner within in the last 30 days. The association between caregiving intensity and caregivers' health and health care utilization was assessed by descriptive analysis and multivariate OLS- and probit-models. RESULTS: A higher amount of informal care was significantly related to negative health outcomes for informal caregivers. On average, one additional hour of informal caregiving per day was associated with a decrease of psychological wellbeing and self-rated overall health by 0.16 and 0.42 index points respectively. Furthermore, one more hour of informal caregiving corresponded with increased self-stated proportion of health care use by 0.56 percentage points. However, the claim of increased health care demand due to caregiving as measured by GP visits was only partly confirmed. CONCLUSION: When evaluating the full economic effect of informal care, the impact of providing care on caregivers' health and health care utilization has to be taken into account. PMID- 26518907 TI - Ethical considerations in the regulation of euthanasia and physician-assisted death in Canada. AB - On February 6th 2015 the Supreme Court of Canada (SCC) released their decision on Carter v Canada (Attorney General) to uphold a judgment from a lower court which determined that the current prohibition in Canada on physician-assisted dying violated the s. 7 [Charter of Rights and Freedoms] rights of competent adults whose medical condition causes intolerable suffering. The purpose of this piece is to briefly examine current regulations from Oregon (USA), Belgium, and the Netherlands, in which physician-assisted death and/or euthanasia is currently permitted, as well as from the province of Quebec which recently passed Bill-52, "An Act Respecting End-of-Life Care." We present ethical considerations that would be pertinent in the development of policies and regulations across Canada in light of this SCC decision: patient and provider autonomy, determining a relevant decision-making standard for practice, and explicating challenges with the SCC criteria for assisted-death eligibility with special consideration to the provision of assisted-death, and review of assisted-death cases. [It is not the goal of this paper to address all questions related to the regulation and policy development of euthanasia and assisted death in Canada, but rather to stimulate and guide the conversations in these areas for policy makers, professional bodies, and regulators.]. PMID- 26518908 TI - [Pediatric emergencies: Knowledge of basic measures for the emergency physician]. AB - Life-threatening pediatric emergencies are relatively rare in the prehospital setting. Thus, the treating emergency physician may not always be familiar with and well trained in these situations. However, pediatric emergencies require early recognition and initiation of specific diagnostic and therapeutic interventions to prevent further damage. The treatment of pediatric emergencies follows current recommendations as detailed in published international guidelines. The aim of this review is to familiarize the emergency physician with general aspects pertinent to this topic-most importantly anatomical and physiological characteristics in this cohort. Also, specific information with regard to analgesia and sedation, which may be warranted in the prehospital setting, will be provided. PMID- 26518909 TI - Sudden appearance of black macules on palmar aspect of two university chemistry students. PMID- 26518910 TI - A review of methods for subtyping Yersinia pestis: From phenotypes to whole genome sequencing. AB - Numerous subtyping methods have been applied to Yersinia pestis with varying success. Here, we review the various subtyping methods that have been applied to Y. pestis and their capacity for answering questions regarding the population genetics, phylogeography, and molecular epidemiology of this important human pathogen. Methods are evaluated in terms of expense, difficulty, transferability among laboratories, discriminatory power, usefulness for different study questions, and current applicability in light of the advent of whole genome sequencing. PMID- 26518911 TI - Multiple and mixed Helicobacter pylori infections: Comparison of two epidemiological situations in Tunisia and France. AB - Individuals can be infected by either a single or multiple strains of Helicobacter pylori. Multiple infection with genetically different isolates and particularly mixed infection with both antibiotic-susceptible and resistant isolates are difficult to detect and should impact the effectiveness of eradication treatment. It is largely assumed that multiple infections are more frequent in developing countries but an actual comparison developing/developed using a single methodology has never been reported. To compare the prevalence of multiple and mixed H. pylori infection in Tunisia and France, we conducted a prospective study including 42 H. pylori-culture positive infected patients (21 Tunisian and 21 French) never previously treated for H. pylori infection. One gastric biopsy was collected from antrum. Three to eleven (mean = 9) colonies were isolated from each biopsy. A total of 375 different isolates were genotyped using RAPD fingerprinting and antimicrobial susceptibility testing was performed on amoxicillin, clarithromycin, ciprofloxacin, rifampicin, tetracycline and metronidazole with E-tests. Multiple infection was defined by different RAPD fingerprintings among the different isolates from a single patient. Mixed infection was defined by different resistance profiles among the different isolates from a single patient. Multiple H. pylori infection is more prevalent in Tunisia than in France. It occurred in ten (48%) Tunisian patients and in one (5%) French patient (p < 0.001). Mixed infection is common (24%), it occurred in 4 (19%) Tunisian patients and in 6 (29%) French patients (p = 0.46) and was mainly (8/10) due to genetically related clones in single infection. PMID- 26518913 TI - Preface. PMID- 26518912 TI - Molecular genotyping and sub-genotyping of Cryptosporidium spp. isolates from symptomatic individuals attending two major public hospitals in Madrid, Spain. AB - Infections by members of the protozoan genus Cryptosporidium are among the most common causes of human gastrointestinal illness worldwide. In Spain cryptosporidiosis is not a compulsory notifiable disease, so the actual burden of the infection in both clinical and general populations remains largely unknown. We present here data on the diversity and frequency of the Cryptosporidium species and sub-genotypes identified in symptomatic individuals seeking medical care in two major hospitals in Madrid, Spain, between December 2013 and January 2015. Initial detection of the parasite was conducted on a total of 122 stool samples collected from 120 patients by microscopy with modified Ziehl-Neelsen and/or immunochromatographic tests. We used immunofluorescence, PCR-based methods and sequence analyses of the 60-kDa (GP60) glycoprotein and the small subunit ribosomal RNA (SSU rRNA) genes for confirmatory purposes and to characterize Cryptosporidium isolates. A total of 110 patients were confirmed with cryptosporidiosis. Overall, 101 isolates were successfully sub-genotyped at the GP60 locus, and an additional seven at the SSU rRNA locus. The analyses of all amplicons defined 10 distinct sequence types representing the GP60 family sub genotypes IbA10G2 (78.7%), IeA11G3T3 (3.7%) of C. hominis, and the GP60 family sub-types IIaA15G2R1 (5.6%), IIaA18G6R1 (0.9%), IIcA5G3a (0.9%), IIdA18G1 (0.9%), IIdA19G1 (0.9%), IIdA21G1 (0.9%), and IIdA22G1 (0.9%) of C. parvum. A single isolate was assigned to C. felis (0.9%), two C. parvum isolates (1.9%) could not be characterized at the sub-genotype level and an additional four isolates (3.7%) were not typable. These results strongly suggest that transmission of cryptosporidiosis is mostly anthroponotic in origin in the clinical sample under study. We expect that our molecular epidemiological data will make a significant contribution to unravel the actual epidemiological situation of cryptosporidiosis in Spain, providing health care and policy makers with solid baseline information to unavoidably improve the national surveillance system and allocate additional resources to research, diagnosis, and treatment of cryptosporidiosis. PMID- 26518914 TI - Medical Students for Tissue Procurement, a 10-Year Experience in a Large University Hospital: An Exportable Model? AB - OBJECTIVE: The objective of this study was to describe tissue procurement activity performed during 10 years (2004-2014) by trained medical students in a large university hospital. METHODS: In this study, third to sixth year medical students were trained as in-hospital Tissue Coordinators (Tc) to perform tissue procurement activity on a 24/7 schedule supervised by an on-call senior Transplant Coordinator (sTC) in a large university hospital. Tc duty consisted of detection, initial evaluation of all hospital deaths, donor's family approach for tissue donation, and retrieval logistics organization, including corneal tissue retrieval after training and certification. They also assist sTC in organ procurement activity. RESULTS: A total of 18,931 deaths were prospectively evaluated, 79% of whom (n = 14,879) presented medical contraindications for tissue donation. Of the remaining 4052 (21%) potential tissue donors (PTD), 2522 (62%) were not converted into real donors, mostly due to family refusal (66%; n = 1650) followed by detection system failure and other logistical issues (34%; n = 872). A total of 2814 corneal units, 225 skin donations, 327 muscleskeletal tissue donations, 91 blood vessels donations, and 177 heart valve donations were obtained from the remaining 1530 (38%) real donors. Tissue potentiality increased from 19% to 43% throughout the study period as a consequence of the fluctuating acceptance criteria used by tissue banks depending on tissue demand. CONCLUSIONS: The tissue donation program performed by trained students was successful in achieving a high and sustainable tissue donation rate in a large university hospital. PMID- 26518915 TI - Knowledge and Attitude of Health Personnel at the Garraf Health Consortium Regarding Donation and Transplantation. AB - INTRODUCTION: The main objective of this study was to determine the attitude and knowledge regarding donation and transplantation of the medical and nursing staff at a community hospital in the province of Barcelona. METHODS: This is descriptive, cross-sectional observational study was conducted in the Garraf Health Consortium, a second-level community hospital located in Sant Pere de Ribes. The study population consisted wholly of health professionals who agreed to participate voluntarily in the study. To determine the attitude and knowledge regarding donation and transplantation, a questionnaire was designed, consisting of 36 items divided into 3 sections: data on attitudes, knowledge about donation and transplantation, and sociodemographic and work-related data. We distributed 380 questionnaires; 236 were returned (62.10%). RESULTS: A total of 70.8% of respondents said they would like to be an organ and tissue donor compared with 1.7% who did not want to be a donor (mainly for fear of inferior medical care, for religious reasons, or both). Among the respondents, 98.7% agree with organ donation, 58.8% were not sure about the criteria for inclusion in the waiting list of Spain, and 69.1% agreed with the view that brain death is equivalent to death. CONCLUSIONS: We found a positive attitude toward donation and transplantation in the hospital, but more knowledge is needed to increase the donation rate. PMID- 26518916 TI - Clinical Significance of Contamination of the Preservation Solution in Liver Transplantation. AB - INTRODUCTION: The aim of the present study was to describe the incidence and microbiological profiles of positive cultures obtained from preservation solution (PS) and correlate these findings with infectious complications detected in the liver transplant (LT) recipient. PATIENTS: We conducted a single-center, retrospective study between December 2010 and August 2014 among 178 LT. In all grafts, a PS culture was carried out. All the infections in the receipt until hospital discharge were collected. In patients with >1, infection was considered the most severe according to Clavien-Dindo classification. RESULTS: PS culture was positive for bacterial or fungal agents in 79 of 178 LT recipients (44%). The most commonly cultured organisms were coagulase-negative staphylococci (64%), Enterobacteriaceae (17%), and Staphylococcus aureus (4.7%). In the 79 patients with positive PS, 49 blood cultures were requested in the period after LT. Twenty five postoperative infections (31.7%) were diagnosed. Only 4 of 79 patients (5%) with PS contamination had a postoperative infections related with isolated microorganism. CONCLUSIONS: Contamination of PS appears in a high percentage of liver grafts before LT, although there is a poor correlation with postoperative infections in LT recipient. In these patients, a standardized process including fungal and bacterial cultures could be useful. PMID- 26518917 TI - Does the Pulsatile Preservation Machine Have Any Impact in the Discard Rate of Kidneys From Older Donors After Brain Death? AB - BACKGROUND: Donors after brain death (DBD) older than 60 years have become 46.8% of our current activity, with higher risk of renal discard rate (RDR). Assessment of kidney suitability requires complementary strategies: macroscopic evaluation, kidney biopsy score (KBS), and renal hemodynamic evaluation with the Pulsatile Perfusion Machine (PPM). METHODS: Descriptive, cross-sectional, comparative study of kidneys procured and RDR, comparing 3 time periods: 2000 to June 2004, when only KBS were used; July 2004 to 2008 (introduction of PPM and learning period); and 2009 to 2013 (experienced use of PPM). Transplantation criteria were KBS <3 and PPM renal resistance <0.4 mm Hg/mL/min and arterial renal flow >70 mL/min. RESULTS: Between 2000 and 2013, a 59.2% reduction in DBD kidneys was observed. However, older kidneys had an increase from 33.5% to 46.8%. The RDR had increased, comparing the first to the third period from 25.4% to 38.3%. However, the RDR was lower when kidneys were evaluated with PPM than those evaluated only with KBS and preserved in cold storage (CS) (21.4% versus 43.7%). There was a significant difference in cold ischemia time, because CS kidney was grafted before PPM. During the third period, more kidneys with KBS >=4 were assigned to PPM. CONCLUSIONS: Notwithstanding the decrease in DBD-procured kidneys and the increase in older kidneys during last period, the use of PPM allowed low DR compared with CS. A bias in the results of PPM could be generated when kidneys with higher KBS were excluded from PPM. The use of KBS only to decide acceptance could preclude the use of an additional tool to evaluate suitability. PMID- 26518918 TI - Successful Example of How to Implement and Develop a Deceased Organ Donation System in the Caribbean Region: Five-Year Experience of the SEUSA Program in Trinidad and Tobago. AB - BACKGROUND: The SEUSA program, the Donation and Transplantation Institute foundation consultancy program, was implemented in Trinidad and Tobago (T&T) in 2010 with the support of the National Organ Transplant Unit (NOTU) and the Ministry of Health of T&T. METHODS: The SEUSA program included (1) diagnosis of the current situation using the ODDS (Organ Donation Diagnostic Surveys); (2) creation of a human resources structure through Transplant Procurement Management (TPM); (3) detection of all brain and cardiac deaths in the hospitals implementing the DAS (Decease Alert System); (4) in-hospital awareness based on the EODS (Essentials in Organ Donation); and (5) external hospital audits. Additionally continued monitoring is performed. RESULTS: Thus far, thanks to implementation of the SEUSA program in Trinidad and Tobago 175, healthcare professionals have been exposed to training programs in the organ donation field. The Living Kidney Program was reinforced and the structure of the Deceased Donation (DD) network was defined. Since 2010, 485 potential organ donors have been detected, and 9 have become actual organ donors; 74 patients have received a kidney transplant (59 from living and 15 from deceased donors). CONCLUSIONS: This project results demonstrate that the application of the SEUSA program is an efficient methodology to develop DD programs that increase and consolidate transplant programs in the Caribbean region. PMID- 26518919 TI - Desensitization Before Living Donor Kidney Transplantation in Highly HLA Sensitized Patients: A Single-Center Study. AB - BACKGROUND: Renal transplantation in highly sensitized patients represents a major clinical challenge leading to long periods on the waiting list. When a living donor is available, the use of different strategies to desensitize recipients with preformed human leukocyte antigen antibodies can allow a successful transplantation. METHODS: We performed a retrospective observational study including all living donor kidney transplantation (LDKT) with desensitization (DS) from 2008 to 2014 in our transplant unit. The rates of rejection and graft survival were evaluated. DS consisted of plasma exchange (PE), rituximab (RTX), and intravenous immunoglobulin (IVIG) induction with thymoglobulin and maintenance immunosuppression with tacrolimus, corticosteroids, and mycophenolate mofetil. RESULTS: From 2008 to 2014, we performed 368 LDKT, with 31 receiving desensitization. Seven cases from a clinical trial were excluded. Demographic data and outcomes were recorded. All of the patients received RTX + PE + IVIG. DS was performed for positive complement-dependent cytotoxicity cross-match (4.2%), T-cell- and/or B-cell-positive flow cytometry cross-match (87.5%) and presence of donor-specific antibodies alone (8.3%). We identified 23 episodes of rejection in 12 patients (50%); 79% were antibody mediated rejections (AMR). Graft failure was 12.5%, with a mean time to graft loss of 229 +/- 203 days. Mean follow-up was 37 +/- 27 months, and graft survival was 91% and 86% at 1 and 5 years, respectively. CONCLUSIONS: Desensitization in LDKT appears to offer an acceptable option for highly sensitized patients. In our series, 41% presented an AMR and 12.5% showed transplant glomerulopathy in protocol and/or indication biopsies. However, short-term outcomes and graft survival were satisfactory. PMID- 26518920 TI - Development of the National Kidney Transplantation Program in Uruguay. AB - The first kidney transplantation (KT) in Uruguay was performed in 1969. We report the rates of KT and survival of patients and grafts up to December 2014. The country has a surface of 176,215 km(2) and a population of 3,286,314 inhabitants (18.6 inhabitants per km(2)). Till December 31, 2014, 1,940 KT have been performed in Uruguay (41.8 pmp that year); 90.4% of them were from cadaveric donors (CD). Median age of recipients (R) was 44 +/- 14 years; R older than 55 years increased from 0 to 27% during the period. Our pre-emptive KT program started in 2007. Optimal donors (D) decreased from 65.2% to 35.5%, and D older than 45 years old increased from 9% to 37%. Trauma as cause of death decreased from 49% to 32% and stroke as cause of death increased from 25% to 39%. Patient survival rates at 1, 5, and 8 years were 93%, 87%, and 78%, respectively for KT performed between 1980 and 1989; they were 98%, 93%, and 89%, respectively, for KT performed between 1990 and1999; they were 97%, 91%, and 90%, respectively, for KT performed between 2000 and 2010. In December 2013, there were 1098 patients pmp in renal replacement therapy, 758 pmp in dialysis, and 340 pmp (30.9%) with a functioning graft. Our national KT program is mainly based (90.6%) on cadaveric donation. Epidemiological changes in the characteristics of R and D followed the changes in aging that occurred in the general population and the dialysis population. The survival rates from patients and kidneys are similar to those reported by the European and the American registries. PMID- 26518921 TI - Desensitization in ABO-Incompatible Kidney Transplantation With Low ABO Iso Agglutinin Titers. AB - BACKGROUND: In ABO-incompatible (ABOi) kidney transplantation (KT) with low iso agglutinin (IG) titers (IGT), standard pre-conditioning treatment might be excessive. To try to answer this question, we evaluated the pre-conditioning requirements of a group of ABOi KT with low ABO IGT in our center. Our main objective was to assess desensitization requirements for ABOi KT with low IGT (<16) at Hospital Clinic of Barcelona from 2006 to 2014. METHODS: A retrospective study of desensitization (rituximab and plasma exchange [PE]) requirements for ABOi KT with IGT <16 was conducted. RESULTS: One and 5 years after KT, patient survival was 100%. Renal graft survival was 90% at 1 and 5 years after KT. Mean PE performed before KT was 1.7 (standard deviation [SD], 1.703); 50% of the patients did not receive PE after transplantation, 30% received 2 sessions of PE, and 20% received only 1. The average is 0.8 (SD, 0.91).Follow-up IG determinations remained with low titers (<=8/8). No rebounds of titers were observed during the first 4 to 6 months after transplantation. CONCLUSIONS: Recipients with IGT <=8 required none or only 1 PE session to reach acceptable titers (titers <=4) to perform ABOi KT safely. This information is useful to assess the possibility of a minimized desensitization protocol in ABOi KT donors with low titers of IG to reduce adverse effects, reduce cost, and simplify pre transplant logistics. PMID- 26518922 TI - Outcomes of Monoclonal Gammopathy of Undetermined Significance in Patients Who Underwent Kidney Transplantation. AB - BACKGROUND: There are few reports about the clinical course and prognosis of monoclonal gammopathy of undetermined significance (MGUS) in long-term immunosuppressed patients. Our aim was to study the association and evolution of MGUS and renal transplantation. METHODS: Subjects submitted to renal transplantation between 1996 and 2011 who presented MGUS before or after immunosuppressive treatment was established were selected. RESULTS: Patients (N = 587) underwent kidney transplantation in our center during the selected period. MGUS was detected in 17 (2.9%) patients (10 men and 7 women with a mean age of 69.9 +/- 10.07 years), with a median follow-up of 6 years. All patients had a functioning graft. Nine had MGUS before transplantation. One patient had multiple myeloma, and 8 remained stable. Eight patients had development of MGUS after transplantation. Six patients remained stable, 1 showed no MGUS, and 1 displayed an increased monoclonal component in further controls. CONCLUSIONS: In our study, renal transplantation is not a risk factor for the development of malignant processes in patients with MGUS before transplantation. There is a group of patients who tend to have MGUS after transplantation; nevertheless, they had a benign evolution during a 6-year follow-up. PMID- 26518923 TI - Living Donor Transplantation: Long-Term Evolution Related to Age Matching. AB - The lack of donors is favoring living kidney donor (LKD) transplantation worldwide, quite often beyond the classic age-matching rules. We analysed renal function (RF) at 1 and 5 years in all donor and recipients as well as death censored graft and patient survival. LKD recipients were divided into 4 subgroups: young recipients-young donors (YR-YD; N = 355), elderly recipients young donors (ER-YD; N = 13), young recipients-elderly donors (YR-ED; N = 67), and elderly recipients-elderly donors (ER-ED; N = 38). "Elderly" was defined as >=60 years. RF was better in those who received a young allograft (YR-YD/ER-YD) at any time (P < .001). There was a trend toward higher proteinuria among the recipients of an old allograft (YR-ED/ER-ED) at any time (P = not significant [NS]). However, our population showed low levels of proteinuria and this was not a risk factor for graft failure. Logistic regression model showed that creatinine level at 1 year is a good predictor of graft losses. Graft survival was worse in the allografts from elderly donors (P < .001). Analysing the young recipients, renal survival was inferior in those who received an old kidney (YR-ED; P < .00005) as well as mortality rates at 14 years (P = .03). The RF of young (N = 295) and elderly donors (N = 98) was optimal with no progression to ESRD or deaths registered during follow-up. In conclusion, young recipients of elderly kidneys pay the price of a worse RF, allograft prognosis, and patient prognosis. The pair YR-ED is a doable option, but we recommend age matching when it is possible. PMID- 26518924 TI - Pre-Emptive Retransplantation in Patients With Chronic Kidney Graft Failure. AB - INTRODUCTION: The aim of this study was to compare the group of patients receiving a new kidney transplant before starting dialysis again (pre-reTR) with a group of patients receiving a new kidney transplant after restarting dialysis (reTR). METHODS: This retrospective cohort included all the kidney retransplantations (second transplantations) between 2000 and 2012 performed at our center and their follow-up until July 2014. We analysed graft and patient survival, rejection rates, and immunologic parameters of these patients. RESULTS: We studied 18 patients who had pre-reTR and 83 who had reTR. In the pre-reTR group no patient had panel-reactive assay (PRA) >10% at any time. In the reTR group 26.5% had PRA >10% at the time of transplantation (P = .014) and 54.2% had a historical highest PRA >10% (P < .001). The rejection rate was 11.1% in the pre reTR group and 27.7% in the reTR group during the first year post retransplantation (P = .227). Patient survival rate was 100% in the pre-reTR group at 5 years of follow-up, whereas in the reTR group at 1 year it was 95.2% and 85.9% at 5 years after retransplantation. Allograft survival at 1 and 5 years was 88% and 89%, respectively, in the pre-reTR group. On the other hand, in the reTR group it was 89% after the first year and 65% at 5 years post retransplantation. CONCLUSION: Pre-emptive renal retransplantation is a feasible option that should be assessed in patients with kidney graft failure and may help to minimize the morbidity associated with dialysis reinitiation. PMID- 26518925 TI - Recurrent Glomerulonephritis in Renal Transplantation: Experience in Our Renal Transplantation Center. AB - BACKGROUND: Post-transplant recurrent glomerulonephritis (RGN) is the third cause of graft failure in the first year after renal transplantation (RT). The purpose of this study was to analyze the incidence of RGN, clinical presentation, and clinical evolution of transplanted renal graft in patients who underwent RT at our center. METHODS: We studied patients with glomerulonephritis (GN) who underwent RT (2007 to 2013).We analyzed sex, age, time in dialysis, type of GN, type of RT, time to post-transplant RGN, kidney function at the time of diagnosis of RGN, and renal graft evolution. Renal biopsy samples were processed in the anatomic pathology laboratory. RESULTS: Three hundred sixteen patients received kidney transplantation during this time period. In 83 cases, the reason for transplantation was primary GN. Of these 83 patients, 15 (18%) had RGN confirmed by renal biopsy. Data for these 15 patients include sex: 73.3% men, 26.7% women; mean age: 42.2 (29-73) years; type of RT: 80% cadaveric donor (CD) versus 20% living donor (LD); type of GN: 18.4% immunoglobulin (Ig)A nephropathy, 35.7% membranous GN, 10.53% type I membrano-proliferative GN (MPGN I), and 16.6% focal segmental glomerular sclerosis (FSGS). The mean time to post-transplant RGN was 2 years (1 month to 16 years). Patients who received an LD transplant had a shorter time to post-transplant RGN than those who had a CD transplant. One patient with FSGS and one with MPGN I had a time to post-transplant RGN of less than 1 year. In the evolution of renal function, 33.3% of patients had graft failure. CONCLUSIONS: The incidence of RGN was lower (18%) than that published in the literature. Membranous nephropathy was the most frequent cause of post-transplant RGN. Patients who underwent LD transplantation and those with IgA nephropathy had a shorter interval of time to post-transplant RGN than patients with FSGS and MPGN I. PMID- 26518926 TI - Nodular Arteriolar Hyalinosis as Histopathologic Hallmark of Calcineurin Inhibitor Nephrotoxicity: Does It Always Have the Same Meaning? AB - INTRODUCTION: Nodular arteriolar hyalinosis (NAH) is a typical, although not specific, histological finding of calcineurin inhibitor toxicity (CNIT). The objective of our study was to assess the reason why some patients showing strong NAH in renal graft biopsies who underwent calcineurin inhibitor (CNI) withdrawal presented very poor outcome whereas others improved graft function. MATERIAL AND METHODS: We performed 207 renal graft biopsies between January 2011 and May 2014 due to clinical criteria. In 13 patients CNI withdrawal was performed, and the major histopathological finding was severe NAH. The results after this action were analyzed. RESULTS: We selected 2 groups: good outcome and poor outcome. Eight patients showed good results including stabilization or improvement of graft function. Five patients presented poor results requiring chronic hemodialysis. C4d staining was negative in all biopsy specimens, and peritubular capillaritis was not observed. To identify potential prognostic markers we retrospectively reviewed biopsy samples looking for minor or nonspecific features, especially inflammation scores both global and on fibrotic areas as per Banff classification. Mean serum creatinine level at time of biopsy and mean arteriolar hyalinosis score did not show significant differences between both groups. In contrast, the poor results group presented a higher mean global inflammation score compared with the good results patients. CONCLUSIONS: NAH is not a risk factor for poor renal graft outcome by itself. Other histopathologic findings, usually considered as secondary markers, like the inflammation score, should be considered before deciding CNI withdrawal. PMID- 26518927 TI - Late Onset of Cholesterol Embolism Leading to Graft Failure After Renal Transplantation: Report of Two Cases. AB - Cholesterol-crystal embolization (CE) usually presents as an acute or subacute multisystemic disease. When affecting native kidneys prognosis is poor, often leading to chronic kidney disease. Presentation in renal allografts is a rare condition although probably underdiagnosed. If renal CE originates from the recipient, allograft survival is usually good, whereas if the donor is the origin, graft dysfunction and subsequent graft loss are common. Associated risk factors are common to native and transplanted kidneys. We report 2 renal graft recipients of different cadaveric donors, both male and 68 years old, diagnosed with CE in renal grafts at 19 and 72 months after transplantation, respectively. They presented previous risk factors for CE, including severe atherosclerosis. They presented insidious and asymptomatic impairment of renal function initially. Renal graft biopsy specimens showed CE in the interlobular arteries. Potential triggers for CE were suspended and high doses of steroids were started. However, progressive decline in renal function and requirement of chronic dialysis occurred within the first year after diagnosis in both cases. Herein we discuss the causal or incidental role of CE in the graft failure of these cases, highlighting the serious outcome despite the recipient origin of the CE and the initiation of treatment. PMID- 26518928 TI - Mammalian Target of Rapamycin Inhibitor Monotherapy: Efficacy in Renal Transplantation. AB - BACKGROUND: Calcineurin inhibitors (CNI) have failed to improve long-term outcomes in renal transplantation. Anti-proliferative and anti-angiogenic effects of mammalian target of rapamycin inhibitors (m-TOR) without nephrotoxicity could improve long-term survival in selected transplant recipients. METHODS: We examined the evolution of 98 low-immunological risk renal transplant recipients on m-TOR monotherapy: 7 patients had induction without CNI and 91 were switched to m-TOR at 12 (p25-p75: 4-36) months after transplant. RESULTS: Median follow-up time was 46 (p25-p75: 28.5-72.0) months. Fifteen recipients dropped out of the study (15.3%): 8 patients (8.2%) had to change their immunosuppressive treatment because of complications and 7 (7.1%) lost their grafts as a result of chronic rejection (4 cases) or death with a functioning graft (3 cases). At the end of follow-up, 83 of 98 (84.6%) recipients remained on monotherapy. The rates of recipient and graft survivals were 100% and 98.8% at 2 years and 96.9% and 93.5% at 4 years; the percentages of patients on monotherapy after 2 and 4 years were 95.2% and 85.2%, respectively. Renal function improved significantly and proteinuria decreased but not significantly. Those patients switched to m-TOR significantly received more erythropoietin, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and hypotensive agents than before starting m-TOR, whereas there were no significant changes related to the use of statins, body weight, or percentage of diabetic patients. No case of non compliance was reported. CONCLUSIONS: This study supports the safety and efficacy of monotherapy with m-TOR in selected renal transplant recipients. PMID- 26518929 TI - Pre-Transplant Assessment of Vascular Calcification as a Risk Factor of Mortality, Graft Loss, and Cardiovascular Events in Renal Transplant Recipients. AB - BACKGROUND: Vascular calcification (VC) is known as an independent predictor of mortality in patients undergoing hemodialysis; nevertheless, there is a lack of studies about the impact of vascular calcification in renal transplant recipients, and none of them use the Kauppila Index (KI) as a predictor of patient and graft prognosis. METHODS: We conducted an observational, retrospective study of 119 renal transplants, evaluating abdominal aortic calcifications (L4-S1) with the KI. We established 2 categories: absence (KI = 0 2) and presence (KI = 3-24) of VCs before transplantation. We analyzed the impact of calcification in graft and patient survival, new-onset diabetes mellitus, hypertension, cardiovascular events, renal function, and mineral metabolism. RESULTS: VCs were observed in 50 patients (42%) before renal transplantation. Patients with VCs were older, but no statistical differences were found in the pre-transplant study between sex, diabetes, body mass index, and cardiovascular events. We found a major patient survival (limited to first 2 years after transplantation), graft survival, and death-censored graft survival in those without VCs (P = .037, P = .015, and P = .023, respectively). In line with results, a higher incidence of major cardiovascular events (MACE) and cardiovascular death was observed in the group with preexisting calcification (P = .016/P = .019). In the multivariable analysis, VCs were not an independent predictor for graft loss, death-censored graft loss, or major cardiovascular events. CONCLUSIONS: Simple evaluation of VCs with the use of the KI at the time of transplantation relates with graft and patient survival and with MACE after renal transplantation. PMID- 26518930 TI - Immunosuppression Strategies in the Treatment of Hepatocellular Carcinoma in Virgen de las Nieves University Hospital. AB - BACKGROUND: We describe an observational, retrospective study that included patients who underwent a liver transplantation (LT) for hepatocellular carcinoma (HCC) in our center between 2004 and 2012. METHODS: Clinical variables were recorded for donors and recipients as diagnosis and treatment, immunosuppressive therapy, toxicity, graft dysfunction, recurrence, and exitus. Fifty-eight patients were analyzed. The mean age was 57 +/- 8 years. The viral etiology of HCC was 50% (n = 29), alcoholic 26% (n = 15), and others, 24% (n = 14). Regarding initial immunosuppressive strategy (IS), 51 patients (87.9%) were treated with standard regimen with corticosteroids (CS) and tacrolimus (TA), compared with 7 patients with impaired renal function (12.1%) who underwent a delayed therapy with calcineurin inhibitors (CNI) + mycophenolate mophetil (MMF) + CS. Concomitant use of anti-CD25 monoclonal antibodies was less than 10%. Regarding maintenance, 43 patients (74.1%) were treated with MMF + CNI versus 15 treated only with TA (25.9%). RESULTS: Recurrence of HCC was approximately 12%: 7 patients (2 hepatic only, 5 also extra-hepatic). Exitus was established in 19 patients (32.75%); only 3 patients (5.17%) were attributable to HCC. Bivariate studies were conducted according to the initial IS (standard regimen versus delayed therapy) and maintenance therapy (MMF + TA versus TA alone), with no differences in any of them in recurrence, treatment toxicity, graft rejection, and dysfunction. CONCLUSIONS: In our experience with the IS, we found no differences in the development of recurrent disease, treatment toxicity, development of graft dysfunction, or rejection. We believe that individualized immunosuppressive therapy in these patients is safe and effective. PMID- 26518931 TI - Prognostic Value of 18-Fluorodeoxyglucose-Positron Emission Tomography After Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma Undergoing Orthotopic Liver Transplantation. AB - INTRODUCTION: The aim of this study was to analyze the correlation between 18-FDG positron emission tomography (PET)/computed tomography (CT), histological necrosis, and prognosis after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) patients undergoing orthotopic liver transplantation (OLT). PATIENTS: From January 2007 through December 2013, 81 patients with HCC and liver cirrhosis were included in our liver transplantation program. For this study we selected patients who underwent 18-FDG PET/CT pre-TACE and post-TACE. All patients underwent liver transplantation within 8 weeks after PET/CT. RESULTS: Twenty patients with a median age of 58 years (range, 46-69 years) underwent an 18-FDG PET/CT before and after TACE. The median Standardized Uptake Value (SUV) before TACE was 3.8 (range, 2.6-8.7), with a median post-TACE SUV of 0% (range, 0-4). Among patients whose post-TACE SUV decreased to <3, >70% necrosis was observed upon study of a hepatectomy sample, with a survival rate of 100% and 80% at 1 and 3 years, respectively. CONCLUSION: In conclusion, performance of an 18-FDG PET/CT before and after TACE with comparison of SUV values among patients with HCC awaiting OLT provided valuable information regarding the effectiveness of TACE. PMID- 26518932 TI - Present and Future of Regenerative Medicine: Liver Transplantation. AB - In recent years, the creation of new organs using bioengineering has been proposed as a possible solution to the shortage of organs for transplantation. After decellularization of livers, the remaining extracellular matrix can be used as scaffolds that can be reseeded with different kinds of cells. Mature hepatocytes and fetal liver cells have been used, showing viability, functionality, and differentiation into mature cells. After perfusion in a bioreactor, the seeded scaffold or liver organoid may be transplanted. However, viability of these transplanted scaffolds is poor owing to the formation of thrombosis. We analyzed the recent advances in decellularizing and recellularizing and the results after transplantation reported in the literature. PMID- 26518933 TI - Activated Regulatory T Cells Expressing CD4(+)CD25(high)CD45RO(+)CD62L(+) Biomarkers Could Be a Risk Factor in Liver Allograft Rejection. AB - Activated regulatory T cells (aTregs) are nowadays a hot topic in organ transplantation to establish their role during acute rejection (AR) episodes. The aim of this multi-center study was to monitor the frequency of aTregs within the first year after transplantation in a cohort of first-time liver transplant recipients enrolled from 2010 to 2012. aTregs frequency was analyzed by means of flow cytometry. Patients who had AR showed higher levels of aTregs during first year after transplantation in comparison with patients who did not have higher levels. High levels of aTregs in liver recipients might be used as a biomarker of AR; however, further studies must be done to address the potential role of aTregs as biomarkers of AR in liver transplantation. PMID- 26518934 TI - Benefits of Group Psychotherapy in Cirrhotic Patients on the Liver Transplant Waiting List. AB - INTRODUCTION: It is well-known that patients on the liver transplant (LT) waiting list experience a high rate of psychopathologic symptoms. However, few studies have been published about the use of group psychotherapy for these patients. We sought to assess (1) the psychopathologic data in patients on the LT waiting list and (2) the attitude toward a group psychotherapy procedure and its efficacy. MATERIAL AND METHODS: In the pretransplant consultation phase, group therapy was offered to 20 patients on the LT waiting list. Patients who received psychotherapy were assessed previously using the Beck Depression Inventory. RESULTS: Fifteen patients were included in the study. Significant differences were found between the psychopathologic assessment and the level of hepatopathy. In the first session, we observed that patients with hepatocarcinoma were much more reluctant to participate in the group therapy. In the second session, the group showed a high level of anxiety connected with a fear of transplantation. In the third session, a transplant physician answered all their questions, and at the end of the session patient anxiety had decreased. During the following sessions, family bonds and sharing experiences with other transplant patients were emphasized. CONCLUSIONS: Patients were initially reluctant to participate in the group psychotherapy, although this changed as sessions proceeded. It is necessary to provide more information about the transplant procedure itself to decrease anxiety. Group therapy was valued positively by all patients who participated. PMID- 26518935 TI - Risk of Respiratory Complications in Obese Liver Transplant Patients: A Study of 343 Patients. AB - INTRODUCTION: Obesity is a risk factor that increases the number of complications after orthotopic liver transplantation (LT). We sought to analyze the short-term respiratory complications in obese LT recipients and compare them with a control group of nonobese patients. MATERIAL AND METHODS: A retrospective analysis of LT patients in a hospital in the southeast of Spain (2007-2013), selecting the study cases using a body mass index (BMI) of >30 kg/m(2) and a control group (BMI < 30). Study variables were age, sex, indication for LT, demographic and clinical variables, respiratory complications during the first postoperative month, and mortality rate secondary to respiratory disease. RESULTS: Of the 343 LT recipients, 74 were obese (21.6%): 59 patients had a BMI between 30 and 35 (grade I obesity) and among them, 5% presented with respiratory complications, with a 33% mortality rate. Fifteen patients had a BMI of >35 (obesity grade II), and 20% presented with respiratory complications, with a 33% mortality rate. In the control group (n = 30), 17% experienced respiratory complications and there was a 20% mortality rate. There were no differences in respiratory complications between the obese and nonobese groups, or the different kinds of obesity (P > .05). CONCLUSIONS: There were no differences in short-term respiratory complications between obese LT recipients and those with a normal weight. PMID- 26518936 TI - Liver Transplant Patient Carriers of Polymorphism Cyp3a5*1 Donors May Need More Doses of Tacrolimus From the First Month After Transplantation. AB - BACKGROUND: The aim of this work was to evaluate the CYP3A5:CYP3A5*1/CYP3A5*3 (6986A>G) polymorphism related to the pharmacokinetic characteristics of tacrolimus during the first 3 months after transplantation, analyzing both donor and recipient genotype, in liver transplant patients. METHODS: This retrospective, single-center, cohort study included patients who had been treated with tacrolimus monotherapy with or without corticoids (n = 67). Donors and recipients were genotyped for the CYP3A5*3 allele polymorphism (6986A>G) by use of a TaqMan polymerase chain reaction technique. The presence or absence of the *1 allele ("minor-allele") was analyzed for correlation with the tacrolimus dose normalized ratio during the 3 months after transplantation. RESULTS: The following observations were obtained in the population studied: (1) Frequency of the minor allele*1 was much lower both in recipients (11.9% versus 88.1%) and donors (19.4% versus 80.6%), with no statistically significant differences between both distributions. (2) Recipient genotype for CYP3A5*1/*3-polymorphism had no influence in tacrolimus pharmacokinetics, with no differences between carriers and non-carriers of the minor-allele*1. (3) However, from the first month after transplantation, patients with grafts from donor carriers of minor allele*1 had lower concentration-dose ratios compared with patients with grafts from donor non-carriers of that allele (71.1 versus 119.3 and 90.5 versus 126.3, for 30 and 90 days after transplantation, respectively; P < .05). CONCLUSIONS: The presence of the CYP3A5-6986A>G-polymorphism in the donor affects tacrolimus pharmacokinetics in the recipient, although the difference was statistically significant only for the first month after transplantation. This means that in liver transplant patients receiving grafts from donors carrying the CYP3A5*1 polymorphism, a larger dose of tacrolimus from the first month after transplantation would be needed. The evidence provided in this study showed no effect of the recipient genotype. PMID- 26518937 TI - Role of Vascular Disease in the Evolution of Heart Transplant Patients. AB - BACKGROUND: The clinical profile of heart transplantation (HT) recipients has changed in recent years. Nowadays, we have to deal with a higher number of co morbidities, including peripheral vascular disease (PVD). Previous studies suggest an increase in post-HT morbidity and mortality associated with PVD, especially when it is symptomatic. Our study aims were to analyze the prognostic implications of the presence of PVD before transplantation and to determine the factors associated with its development after it. METHODS: HT patients (n = 217) who survived the first year after surgery were included in the study. Mean follow up was 9 +/- 5 years. RESULTS: There were no statistically significant differences in mortality rates between patients with PVD (before or after HT) and those without. One third of patients with PVD required surgery in the post-HT monitoring, either revascularization or amputation. Furthermore, the prevalence of PVD was doubled. Dyslipidemia before HT (odds ratio [OR]: 2.9, 95% confidence interval [CI]: 1.3-6.4; P < .01) and older recipient age (OR: 1.05, 95% CI: 1.01 1.09; P < .05) were independently associated with development of PVD by means of multivariate analysis. CONCLUSIONS: The presence of PVD must be evaluated individually in candidates for heart transplantation despite being a relative contraindication to it at the present time. PMID- 26518938 TI - Cost-Effectiveness of Highly Sensitive Cardiac Troponin T to Rule Out Acute Rejection After Heart Transplantation. AB - BACKGROUND: Endomyocardial biopsy (EMB) remains the gold standard for detecting acute rejection (AR) after heart transplantation (HTx). Non-invasive detection of AR thus far remains a challenge. Several studies have demonstrated that highly sensitive cardiac troponin T (hs-cTnT) concentrations have a low positive predictive value for diagnosing AR. Nevertheless, hs-cTnT proved to be useful for ruling out AR after HTx. An hs-cTnT concentration <17 ng/L, a value close to that used for rule-in or rule-out myocardial infarction, was associated with a 100% negative predictive value of AR. However, the cost-effectiveness of a strategy with the use of hs-cTnT for ruling out AR in HTx patients remains to be proven. METHODS: The cost-effectiveness of hs-cTnT determination for ruling out AR was assessed, comparing the costs of hs-cTnT measurements in 305 blood samples obtained at the time of EMB. Eighteen samples were excluded because the EMB was not assessable. RESULTS: Hs-cTnT determination cost 16.00? per sample, whereas EMB cost 1752.00? per biopsy; cost estimations included direct and indirect (30%) charges. Thirty-nine (13.6%) of the 287 blood samples presented hs-cTnT concentrations <17 ng/L; in none of them was an AR >2R degree found in the EMB. The cost of the assessment in the 287 blood samples and biopsies was of 4592.00? for hs-cTnT and 502,824.00? for EMB. Hs-cTnT systematic measurement would have avoided 39 EMB, with a saving of 68,328.00?, which represents the 13.5% of the total budget expended in these cases. CONCLUSIONS: The use of hs-cTnT values to rule out the need of EMB for AR diagnosis after HTx appears to be a cost effective procedure. PMID- 26518939 TI - In Contrast to Anti-C5 Therapy, Cobra Venom Factor Does Not Prevent Rejection of Xenogeneic Cartilage in Mice. AB - BACKGROUND: The use of xenogeneic chondrocytes may benefit the development of clinical tissue-engineering applications for cartilage repair. However, cartilage xenografts are slowly rejected by humoral and cellular mechanisms to which galactose alpha1,3-galactose (Gal) antigen and complement contribute. Accordingly, transgenic expression of human alpha1,2-fucosyltransferase (HT) in porcine cartilage helps to protect from the Gal-mediated immune response. Here, we aimed to assess the effect of the broadly used complement inhibitor cobra venom factor (CVF) in comparison with anti-C5 therapy in alpha1,3 galactosyltransferase knockout (Gal KO) mice transplanted with porcine cartilage. METHODS: Gal KO mice grafted with control or HT-transgenic cartilage were left untreated or treated systemically with either anti-C5 antibody or CVF for 5 weeks. The degree of rejection was evaluated by use of histopathological analysis, and serum anti-Gal antibodies were measured in all cohorts. RESULTS: The rejection process of control cartilage was well advanced by 5 weeks after transplantation in untreated Gal KO mice, whereas enhanced graft survival characterized by reduced cellular immune infiltrate was found in mice grafted with HT cartilage and/or treated with anti-C5. In contrast, CVF administration led to inconsistent results, with some grafts showing no improvement or even increased amounts of granulocytes. Regarding antibody titers, the anti-Gal immunoglobulin (Ig)M increased in the control transplant cohort and remained unchanged in the HT-graft recipients at 5 weeks after transplantation. Notably, a strong anti-Gal IgM response was readily detected in CVF-treated mice of both transplanted cohorts. CONCLUSIONS: CVF does not present advantages over anti-C5 therapy for preventing rejection of xenogeneic porcine cartilage. PMID- 26518940 TI - Donor-Derived Cell-Free DNA Is a Novel Universal Biomarker for Allograft Rejection in Solid Organ Transplantation. AB - BACKGROUND: In solid organ transplantation, sensitive real-time biomarkers to assess the graft health are desirable to enable early intervention, for example, to avoid full-blown rejections. During rejection, high amounts of graft-derived cell-free DNA (GcfDNA) are shed into the blood stream. The quantification of this GcfDNA in allotransplantation is considered to fulfill this need, because it can be measured with great precision and at reasonable cost. PATIENTS AND METHODS: Patients from 2 ongoing studies in kidney (KTx) and heart (HTx) transplantation were monitored blinded on a scheduled basis, by means of a published universal droplet digital polymerase chain reaction to quantify the GcfDNA. RESULTS: Immediately after engraftment, GcfDNA reaches high values (>5% of total cfDNA), with a rapid decrease to values of <0.5% within 1 week. Living-related KTx recipients show lower initial values, reflecting the absence of preservation injury. Episodes of rejection in KTx and HTx are accompanied by a significant increase of GcfDNA (>5-fold) above values in patients without complications, occurring earlier than clinical or biochemical hints to rejection. One case of rejection, which became clinically suspect after 1 year and was proven with biopsy, showed a significant 10-fold increase 3 months earlier. CONCLUSIONS: The quantification of GcfDNA has the potential to detect rejection episodes at early stages, when other means of diagnosis are not effective. The method's noninvasiveness enables the monitoring recipients at intervals that are desired to catch rejections at early actionable stages to prevent full-blown rejection. This biomarker will be particularly valuable in regimens to minimize immunosuppression. PMID- 26518942 TI - Orthotopic Liver Transplantation in an Adult With Biliary Atresia, Situs Inversus, and Inferior Cava Vein Absence: A Case Report. AB - BACKGROUND: We report the case of a 34-year-old man who underwent Kasai portoenterostomy for biliary atresia at 6 weeks of age. In 2011, pulmonary hypertension was diagnosed and he began treatment with sildenafil. In 2012, he presented with an episode of upper gastrointestinal bleeding secondary to esophageal varices resistant to treatment. Later, he exhibited liver dysfunction. He was included on the waiting list for transplantation on May 29, 2013, with a Model for End-stage Liver Disease score of 24. METHODS: He underwent liver transplantation with an isogroup graft from a brain dead donor on June 9, 2013. Native hepatectomy was laborious owing to important collateral circulation and adhesions after previous operations, which had injured loops of the small bowel (SB). Orthotopic implantation was accomplished with direct anastomosis of the upper liver cava vein to the right atrium of the receiver. Portal and arterial anastomoses were performed as usual. Biliary reconstruction surgery by hepatojejunostomy was delayed 24 hours owing to SB loops injuries. RESULTS: Graft viability was confirmed by normal hepatic function. Postoperative complications included abdominal compartment syndrome treated by decompressing laparotomy, severe pulmonary alveolar hemorrhage resolved with artery embolization and endotracheal intubation, intraabdominal abscess requiring percutaneous drain, and stroke requiring long-term rehabilitation. He is currently asymptomatic, presents normal graft function, and receives sildenafil because of pulmonary hypertension. CONCLUSIONS: The association of situs inversus and biliary atresia is low. There is no consensus on the optimal operative approach to liver transplantation. An individualized assessment and multidisciplinary patient management are required. PMID- 26518941 TI - Successful Pancreas Transplantation From a Deceased Donor Intoxicated With Oral Antidiabetic Agent: A Case Report. AB - Simultaneous kidney pancreas transplantation (SKP) is a common procedure for the patient with long-term type 1 diabetes mellitus (DM) with terminal renal failure. It is unusual to consider the pancreas from a deceased donor who died after an acute intoxication with oral antidiabetic agent (OAA), which would suggest an abnormal functionality of the organ and preclude the potential use of the graft. We present a case of a successful pancreatic transplantation from a donor who died of acute cerebral edema secondary to severe hypoglycemia induced by OAA acute intoxication. PMID- 26518943 TI - Liver Transplantation for Urea Cycle Disorders: Analysis of the United Network for Organ Sharing Database. AB - BACKGROUND: Urea cycle disorders (UCD) are caused by rare inherited defects in the urea cycle enzymes leading to diminished ability to convert ammonia to urea in the liver. The resulting excess of circulating ammonia can lead to central nervous system toxicity and irreversible neurologic damage. Most cases are identified in children. However, UCDs can also be diagnosed in adulthood, and liver transplant is occasionally required. METHODS: We examined the UNOS database to evaluate outcomes in adult and pediatric patients who underwent liver transplant as treatment for a UCD. We identified 265 pediatric and 13 adult patients who underwent liver transplant for a UCD between 1987 and 2010. RESULTS: The majority (68%) of these patients were transplanted before age 5 years. Ornithine transcarbamylase (OTC) deficiency was the most common UCD in both adults and children who underwent transplant. UCD patients who underwent liver transplant were younger, more likely to be male (67%), had lower pediatric end stage liver disease/model for end-stage liver disease scores, and were more likely to be Caucasian or Asian compared with all other patients transplanted during the same time period. UCD patients did not have an increased utilization of living donor transplantation in this US cohort. Univariate and multivariate risk factor analyses were performed and did not reveal any significant factors that were predictive of post-transplant death or graft loss. CONCLUSIONS: Excellent outcomes were seen in both children and adults with UCDs who underwent transplant with overall 1-, 5-, and 10-year survivals of 93%, 89%, and 87%, respectively. PMID- 26518944 TI - Investigation and Strategic Analysis of Public Willingness and Attitudes Toward Organ Donation in East China. AB - BACKGROUND: China officially initiated deceased organ donation in 2010. Much progress has been made since then. However, compared with the developed countries in Europe and America, there is still a large gap. In this study, we investigate the willingness and attitude of the general public in East China and the factors that affect organ donation, and propose specific recommendations for promoting it. METHODS: A simple and random sample was questioned. The data were analyzed statistically using SPSS 19.0 software, chi(2) test, and logistic regression. RESULTS: A total of 1200 questionnaires were issued; of these, 1105 were recovered, with 1074 effective questionnaires, for an effective rate of 89.5%. Among these, 426 respondents (39.7%) were willing to donate, 529 (49.3%) were in favor of donation but would not donate themselves; and 119 (11.1%) were against donation. Women (P < .01), persons with higher education (P < .01), those who understand organ donation (P < .01), and those who accept the concept of brain death (P < .01) had higher degrees of acceptance for organ donation. Reasons to hinder organ donation included imperfect laws and regulations, distrust on organ allocation, and insufficient promotion by relevant organizations. CONCLUSION: Much needs to be done to promote organ donation in China; targeted publicity will help to improve the work efficiency of organ donation; improvement of relevant policies and regulations, and establishment of a fair and transparent organ allocation system are key to the development of organ donation. PMID- 26518945 TI - Alloreactive T Cells to Identify Risk HLA Alleles for Retransplantation After Acute Accelerated Steroid-Resistant Rejection. AB - The risk of rejection by cellular alloreactivity to the transplant donor is not routinely assessed. Here we analyzed alloreactive T cells in kidney transplant recipients and report how their detection may have helped to prevent rejection of a second kidney graft in a patient with a history of acute accelerated steroid resistant nonhumoral rejection. Alloreactive CD4 and CD8 T cells were quantified using a flow-cytometric mixed lymphocyte reaction assay based on interferon-gamma induction. A group of 16 nonrejecting transplant recipients did not show any alloreactive T-cell immunity to their respective donors, whereas alloreactivity to third-party controls was detectable. In the patient with rejection, HLA specific antibodies were not detectable before and shortly after rejection, but after transplantation the patient showed exceptionally high frequencies of alloreactive T cells against 2 of 11 HLA-typed controls (0.604% and 0.791% alloreactive CD4 T cells and 0.792% and 0.978% alloreactive CD8 T cells) who shared HLA alleles (HLA-A*24, -B*44, -C*02, -DQB1*5) with the kidney donor. These HLA alleles were subsequently excluded for allocation of a second graft. No alloreactive T cells were observed toward the second kidney donor, and this transplantation was performed successfully. Thus, shared HLA alleles between the donor and third-party controls may suggest that alloreactive T cells had contributed to rejection of the first graft. The rejecting patient highlights that determination of cellular alloreactivity before transplantation may be applied to identify unacceptable mismatches and to reduce the risk for acute cellular rejection episodes. PMID- 26518946 TI - A Simple Novel Technique to Estimate Tacrolimus Dosages During the Early Post Kidney Transplantation Period. AB - BACKGROUND: Tacrolimus pharmacokinetics prediction by CYP3A5 genotyping is not available in many Asian resource-limited settings. Therefore, an alternative technique is needed to estimate the dose of tacrolimus perioperatively. The 12 hour level after the first dose (C12-0) is an alternative technique for estimating the dose of tacrolimus. This simple and inexpensive calculation technique can be used by any transplantation center. METHODS: A prospective study on a cohort of 57 incident post-kidney transplant recipients was conducted. The whole-blood tacrolimus trough level (C12-0) was measured at 12 hours after the first dose (0.1 mg/kg) of orally administered tacrolimus during transplantation. Concomitant medications with CYP3A5 inhibitors/inducers were not allowed. Genotyping for CYP3A5 expression was carried out by reverse transcription polymerase chain reaction. The dosages and trough levels of tacrolimus at postoperative day 7 and postoperative months 1 to 3 were measured and analyzed for the dose requirements for therapeutic levels (mg/kg/d). RESULTS: The doses of tacrolimus were widely diverse, ranging from 0.049 to 0.260 mg/kg/d and 0.031 to 0.298 mg/kg/d at day 7 and months 1 to 3, respectively. There were 9, 28, and 20 patients (15.8%, 49.1%, and 35.1%) with CYP3A5 *1/*1, *1/*3, and *3/*3, respectively. The CYP3A5 genotypes were significantly correlated with the target tacrolimus dose at day 7 (r(2) = 0.307) and the stable dose at months 1 to 3 (r(2) = 0.337). The C12-0 level also was significantly correlated with the dose of tacrolimus at day 7 (r(2) = 0.546) and the stable dose at months 1 to 3 (r(2) = 0.406). CONCLUSIONS: There were strong correlations between the C12-0 level and the tacrolimus doses during the perioperative period at day 7 and the stable period at 1 to 3 months. Countries with limited resources for genotype testing can use the C12-0 level as an alternative to estimate the tacrolimus dose. PMID- 26518947 TI - Efficacy and Safety of Basiliximab Versus Daclizumab in Kidney Transplantation: A Meta-Analysis. AB - BACKGROUND: Interleukin-2 receptor antagonists (IL-2RAs) have been extensively used in kidney transplant patients to prevent the occurrence of acute rejection. The efficacy and safety of basiliximab and daclizumab, the 2 most commonly used IL-2RAs in clinics, have been compared in a number of randomized controlled trials, but no definite conclusions have been drawn. OBJECTIVE: This meta analysis aimed to compare the efficacy and safety of basiliximab and daclizumab in kidney transplant patients. METHODS: We performed keyword searches in Pubmed, Embase, and the Cochrane library. In total, 6 randomized controlled trials with 509 patients were included in this meta-analysis. Data collected included patient survival, graft survival, acute rejection, infection, and cytomegalovirus infection. The outcome measure was the relative risk of basiliximab versus daclizumab. RESULTS: Therapy with basiliximab and daclizumab resulted in similar outcomes regarding acute rejection (6-month 95% confidence interval [CI], 0.09 1.14; 12-month 95% CI, 0.53-1.91), patient survival (95% CI, 0.97-1.04), graft survival (95% CI, 0.98-1.08), infection (95% CI, 0.66-1.01), and cytomegalovirus infection (95% CI, 0.45-1.14) within the follow-up period. There were no significant differences in safety and efficacy between the 2 drugs. CONCLUSIONS: The safety and efficacy of daclizumab and basiliximab are similar in kidney transplant recipients. PMID- 26518948 TI - Tacrolimus, Mycophenolate Mofetil, and Low-Dose Steroids With or Without Interleukin-2 Receptor Antibody Induction Therapy: A Retrospective Cohort Analysis. AB - BACKGROUND: Selective interleukin-2 receptor (IL2R) blockade is one option to decrease acute rejection rates in kidney transplant recipients. However, there are little data on the impact of basiliximab in a triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and low-dose steroids). Thus, this analysis aims at investigating the impact of basiliximab induction on rejection rates and immediate graft function following kidney transplantation. METHODS: Basiliximab was introduced in our center according to our center's policy in the beginning of 2011. Patients who received basiliximab (n = 83) were compared with patients without induction therapy (n = 65) transplanted before the introduction of IL2R antibody induction. RESULTS: The use of basiliximab as induction therapy decreased the incidence of biopsy-proven acute rejection (BPAR) within the 1st year after transplantation (21.5% vs 14.5%; P = .283). Overall rejection episodes (including BPAR and borderline rejection) were significantly reduced in patients with basiliximab compared with patients without (41.5% vs 24.1%; P = .033). However, graft function (incidence of delayed graft function, primary nonfunction, slow graft function, and serum creatinine decline) and overall outcome (patient and graft survivals) were similar in both groups. CONCLUSIONS: We found a favorable impact of basiliximab induction therapy on early acute rejection rate. The impact on long-term outcome must be addressed in further randomized controlled trials. PMID- 26518949 TI - Mortality Predictors in Acute Respiratory Distress Syndrome Renal Transplant Recipients With ESKAPE/rESKAPE Pneumonia. AB - BACKGROUND: A sustained immunosuppressive state in renal transplant recipients is a factor that can contribute to increased incidence of acute respiratory distress syndrome (ARDS) due to pneumonia. ARDS renal recipients with ESKAPE (E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter spp.) pneumonia are probably related to high morbidity and mortality. We therefore sought to investigate the frequency of ESKAPE and resistant ESKAPE (rESKAPE) pathogens isolated from respiratory tract specimens of renal recipients with ARDS and determine the risk factors for mortality. METHODS: A retrospective analysis of ARDS renal recipients with ESKAPE/rESKAPE pneumonia was reviewed. Multiple logistic regression analysis was conducted to identify the independent risk factors associated with infection-related mortality. RESULTS: During the study period, 88 ESKAPE pathogens obtained from respiratory tract specimens of 54 ARDS renal recipients were documented including 33 A. baumannii, 24 P. aeruginosa, 17 S. aureus, 6 K. pneumoniae, 8 Enterobacter species, and 0 E. Faecium. Among these ESKAPE organisms, 61.4% (54/88) were antimicrobial resistant. The risk factors for mortality independently associated with ARDS renal recipients with ESKAPE pneumonia were severe ARDS (odds ratio [OR] 4.3 (95% confidence interval [CI] 1.1 16.4), P = .032), serum creatinine level >1.5 mg/dL (OR 4.2 95% CI (1.0-17.9), P = .05) and body temperature less than 38 degrees C (OR 5.0 (95% CI 1.3-19.6), P = .02) at ARDS onset. The independent determinants of mortality were associated with ARDS renal recipients with rESKAPE pneumonia were serum creatinine level >1.5 mg/dL (OR 13.7, 95% CI 1.3-142.1, P = .028) and body temperature less than 38 degrees C (OR 5.5 (95% CI 1.1-26.6) at ARDS onset, P = .035). CONCLUSIONS: The majority of EPKAPE isolates were antimicrobial resistant. Mortality in ARDS renal recipients with ESKAPE/rESKAPE pneumonia was associated with the severity of ARDS, elevated serum creatinine level, or depressed febrile response at ARDS onset. PMID- 26518950 TI - Epidemiology of HIV-Associated Tuberculosis in Urumqi, China. AB - The aim of this work was to understand the epidemiologic characteristics of TB and human immunodeficiency virus (HIV) dual infection cases, thus providing the basis for effective prevention and control measures. On the basis of HIV/TB screening of new and old TB and HIV/acquired immunodeficiency syndrome (AIDS) patients registered in 4 regions of Urumqi, Xinjiang, People's Republic of China, from 2012 to 2014, an analysis was made of the epidemiologic characteristics and risk factors of people suffering from HIV/TB dual infection. A total of 2,645 TB patients were tested for HIV antibodies, of whom 128 tested positive, showing a detection rate of 4.8%; TB patients >=35 years old had 0.26 times (95% confidence interval [CI], 0.18-0.40) the risk of HIV infection than those 18-35 years old, and pulmonary and extrapulmonary TB patients with positive smear had, respectively, 0.43 times (95% CI, 0.28-0.66) and 1.79 times (95% CI, 1.09-2.94) the risk of HIV infection than those with negative smear. And 1,195 HIV/AIDS patients were screened for TB, of whom 91 were positive, showing an infection rate of 7.6%; male HIV/AIDS patients had 12.2 times (95% CI, 6.4-23.1) the risk of TB infection than female patients, and HIV/AIDS patients with CD4 cells <=200/MUL had 20.4 times (95% CI, 11.8-35.3) the risk of TB infection than those with CD4 cells >200/MUL. TB and HIV/AIDS patients in Urumqi from 2012 to 2014 suffered from high HIV and TB infection rates, so relevant measures should be taken to intervene, especially for TB patients >=35 years old, those with positive smear, extrapulmonary TB patients, male HIV/AIDS patients, and those with CD4 cells <=200/MUL. PMID- 26518951 TI - Risk Factors of Cytomegalovirus Disease in Kidney Transplant Recipients: A Single Center Study in Thailand. AB - BACKGROUND: Cytomegalovirus (CMV) infection significantly causes morbidity in kidney transplant (KT) recipients. This study aims to investigate the incidence, timing, and risk factors of CMV infection in KT recipients. METHODS: This is a single-center retrospective study at a tertiary referral hospital. Patients who underwent KT from January 2012 to September 2014 were included. CMV infection was defined as the presence of CMV measured by polymerase chain reaction. Logistic regression analysis was performed to assess independent risk factors of CMV infection after KT. RESULTS: Of 121 KT patients enrolled, 120 patients had CMV D(+)/R(+) serostatus, and 1 had D-/R(+). CMV infection occurred in 33 (27.2%) of patients with a median follow-up time of 16 (IQR 4-25) months. Of those, 25 had CMV viremia and 8 had CMV disease mainly involving the gastrointestinal system. In total, 86% of CMV cases occurred within 3 months. All recipients received anti IL-2 receptor antibody (IL-2 RA), low-dose rabbit antithymocyte globulin (rATG; total of 1.5 mg/kg), or standard-dose rATG (1.5 mg/kg/day for 3-5 days) for induction. Of those, the incidences of CMV infection were 19.6%, 50%, and 67%, respectively. Preemptive strategy was used in all but 1 patient in the IL-2 RA and low-dose rATG group, whereas universal prophylaxis was given in 67% of patients in the standard-dose rATG group. Independent risk factors of CMV infection were older recipient age (per 10-year increase, OR 1.5; 95% CI 1.04 2.23), and induction with standard (OR 8.19; 95% CI 2.29-34) and low-dose rATG (OR 3.87; 95% CI 1.06-12.23). CONCLUSIONS: More than 25% of KT recipients developed CMV infection within 6 months after KT. The risk is increased in older recipients and induction with rATG. The level of CMV risk in low-dose rATG is 52% lower than in standard-dose rATG. In a limited-resource setting such as Thailand, deferred or preemptive strategy may be acceptable in patients who received IL-2 RA and low-dose rATG, while prophylactic therapy should be given to patients who received standard-dose rATG. PMID- 26518952 TI - Risk Factors for the Development of BK Virus Nephropathy in Renal Transplant Recipients. AB - The BK polyoma virus has, in recent years, become a significant cause of renal allograft dysfunction and failure. Among 260 adult kidney transplant recipients, those with biopsy-proven BK virus nephropathy (BKVN) were compared with those without BKVN with regard to gender, age, race, rejection episodes, time on dialysis, number of organs transplanted, HLA match, live donor versus deceased donor, cold ischemia time, delayed graft function, cytomegalovirus (CMV) serostatus of donor and recipient, induction therapy, and maintenance immunosuppression. Episodes of rejection (35.7% of patients with BKVN vs 8.5% of patients without BKVN; P = .01), transplantation of >1 organ (35.7% of patients with BKVN vs 9.0% of patients without BKVN; P = .01), positive CMV serology in both donor and recipient (71.4% of patients with BKVN vs 41.1% of patients without BKVN; P = .03), and a greater cumulative dose of daclizumab use at the time of induction (2.24 +/- 0.05 mg/kg in patients with BKVN vs 2.03 +/- 0.14 mg/kg in patients without BKVN; P = .04) were statistically significant risk factors for the development of BKVN. Those who developed BKVN received a higher mean cumulative dose of rabbit antithymoglobulin for induction therapy, but that difference failed to achieve statistical significance (P = .07). PMID- 26518953 TI - Comparing Cardiopulmonary Exercise Testing in End-Stage Liver Disease Patients. AB - Poor cardiopulmonary fitness has been associated with worse outcomes in liver transplant candidates. PURPOSE: To determine if a modified 3-minute step test (potentially office based) is feasible and equivalent to standard cardiopulmonary exercise testing (CPET) in liver transplant candidates with severe decompensation. METHODS: Five patients with Childs-Pugh C end-stage liver disease and severe debility awaiting liver transplantation performed both standard CPET and the modified 3-minute step test (Shape medical systems). RESULTS: All 5 patients were able to complete both tests. Mean age was 59.8 +/- 9 years, mean MELD score was 20 (range 13-26), and mean BMI was 27.6 kg/m(2) (range 16.4-37.2). Peak Vo2 was similar with a mean of 901 mL/min (step test) compared to 856 mL/min (cycle test), P = .64. Vo2 at a respiratory exchange ratio (RER) of 1.0 was similar with both tests (681 mL/min (step) vs 646 mL/min (cycle), P = .69. Ve/Vco2 slope (ventilatory efficiency) was similar (40 vs 39, P = .94). The ventilatory compensation point (i.e. anaerobic threshold) was also similar (~80% of peak Vo2) for both studies. CONCLUSION: The modified 3-minute step test provides a simplified, potentially office-based assessment of cardiopulmonary exercise capacity and gas exchange measures as standard testing in patients with decompensated end-stage liver disease, with similar tolerability. PMID- 26518954 TI - Intraoperative Management and Postoperative Outcome in Intestine-Inclusive Liver Transplantation Versus Liver Transplantation. AB - BACKGROUND: Although intestine-inclusive liver transplantation (IILT) is performed regularly, its perioperative management has not been studied extensively. METHODS: Patients who underwent IILT and isolated liver transplantation (LT) at our center from January 2006 to December 2012 were identified. Among >1,000 LT patients, 90 were selected after matching by age, sex, surgery date, and status of preoperative ventilation for comparison with 45 IILT patients. RESULTS: There were no significant differences regarding preoperative variables between the 2 groups except for international normalized ratio. However, IILT patients had significantly higher intraoperative requirement of blood transfusion, incidences of post-reperfusion syndrome, and hyperkalemia compared with LT patients. Postoperatively, IILT patients had significantly longer hospital stay and higher 1-year mortality. Multivariate analysis indicated that IILT was a primary risk factor associated with the studied complications and adverse outcomes. CONCLUSIONS: Our findings suggest that, compared with LT patients, IILT patients were more prone to develop intraoperative complications and adverse outcomes and should be closely monitored and aggressively managed. PMID- 26518955 TI - L-Alanyl-Glutamine Attenuates Oxidative Stress in Liver Transplantation Patients. AB - BACKGROUND: Ischemia/reperfusion injury during liver transplantation can cause severe damage to the graft. The objective of this randomized, double-blind study was to evaluate the possible protective effects of L-alanyl-glutamine on the liver graft. METHODS: The sample included 33 patients from a liver transplantation service in Northeastern Brazil. Before cold ischemia, the patients received 50 g of L-alanyl-glutamine (treatment group) or saline (control group) through the portal vein. The graft was biopsied at the time of recovery, at the beginning of warm ischemia, and at the end of transplantation to determine malondialdehyde (MDA), heat-shock protein (Hsp)70, nuclear factor kappa-beta (NFkB), superoxide dismutase (SOD), and reduced glutathione (GSH) levels. RESULTS: The blood parameters were similar in the two groups. In the treatment group, MDA did not increase at the beginning of cold ischemia and decreased at the end of transplantation. This phenomenon was not observed in the control group. GSH, SOD, Hsp70, and NFkB levels were similar in the two groups. CONCLUSIONS: Our findings suggest that preconditioning with L-alanyl-glutamine attenuates the effects of ischemia/reperfusion-related oxidative stress and reduces lipid peroxidation in the grafts of liver transplantation patients. PMID- 26518956 TI - De Novo Malignancies After Liver Transplantation With 14 Cases at a Single Center. AB - OBJECTIVE: To analyze the clinical characteristics, risk factors, and prevention of de novo malignant tumors after liver transplantation. METHODS: Fourteen patients who underwent liver transplantation were identified as having de novo malignancies. The clinical characteristics and survival of these patients were retrospectively reviewed. RESULTS: Fourteen cases of de novo malignancies after liver transplantation occurred for an incidence rate of 1.94% (14/722), including 11 men (78.6%, mean age, 48 y) and 3 women (21.4%, mean age, 50 y). The mean period from transplantation to cancer diagnosis was 55 +/- 35 months. The distribution of tumor histologic types included colon cancer, lung cancer, esophageal cancer, nasopharyngeal cancer, liver cancer, parotid carcinoma, bone cancer, post-transplantation lymphoproliferative disorder, stomach cancer, bladder cancer, and laryngeal cancer. Twelve cases (85.7%) had hepatitis B. Five patients (35.7%) underwent operations, and the other 9 patients underwent chemotherapy or radiotherapy. During a mean follow-up period of 37 +/- 26 months after the diagnosis of de novo malignancy, 8 patients (57.1%) died, with only 1 dying of causes not related to the de novo malignancy. The survival analysis showed 1-, 5-, and 7-year survival rates of 85.7%, 71.4%, and 42.9%, respectively. CONCLUSIONS: De novo malignancies after organ transplantation have been suggested to be a major cause of late mortality. De novo malignancy after orthotopic liver transplantation was found to be related to smoking, sex, and low immune function due to immunosuppressive agents. Solid tumors should be removed, and the patient should receive chemotherapy or radiotherapy as early as possible. Early diagnosis and treatment are very important for improving the prognosis. PMID- 26518957 TI - Predictors of Biliary Leakage After T-Tube Removal in Living Donor Liver Transplantation Recipients. AB - BACKGROUND: Biliary leakage after T-tube removal is a frequent cause of morbidity in liver transplant recipients. The aim of this study was to determine the factors that predict the development of biliary leakage after T-tube removal in living donor liver transplantation (LDLT) recipients. METHODS: Of the 144 patients who underwent LDLT with right-lobe liver grafts during the period January 2007 to May 2013 at a single medical center, 40 received biliary anastomosis with T-tube placement. Subjects were grouped into either a biliary leakage or non-biliary leakage group on the basis of the presence or absence of abdominal symptoms associated with signs of peritoneal irritation after T-tube removal. Recipient, graft, operative, and postoperative factors were included in a forward, stepwise multiple logistic regression model to identify the most important risk factors for biliary leakage after T-tube removal. RESULTS: Biliary leakage developed in 9 (22.5%) patients after T-tube removal. Risk factors associated with biliary leakage included the number of abdominal surgeries performed [odds ratio (OR) = 12.6, 95% confidence interval (CI): 2.1-20.4] and duration of T-tube placement (OR = 6.9, 95% CI: 1.2-10.7). CONCLUSIONS: Biliary leakage after T-tube removal is associated with significant morbidity in LDLT recipients. We suggest that T-tube placement be used sparingly in LDLT biliary reconstruction. When used, a T-tube should not be removed earlier than 8 months after placement, especially in recipients who have received primary abdominal surgery. PMID- 26518958 TI - Considerable Risk of Restenosis After Endoscopic Treatment for Hepaticojejunostomy Stricture After Living-Donor Liver Transplantation. AB - BACKGROUND: There are few reports on the short- and long-term follow-up of endoscopic retrograde cholangiography (ERC) in adult patients with hepaticojejunostomy (HJS) stricture after living-donor liver transplantation (LDLT). METHODS: Nine LDLT recipients underwent ERC with the use of double balloon endoscopy (DBE) for HJS stricture at Nagoya University Hospital. We assessed the rate of reaching biliary anastomosis, procedure success rate, procedure duration, complications, improvement in liver function test results, and biliary anastomosis patency. RESULTS: In total, 19 ERC procedures with the use of DBE were performed for 9 adult LDLT recipients with HJS stricture from June 2006 to September 2014. Balloon dilation with the use of DBE was successfully performed in 5 of the 9 patients during the 1st procedure. Of the 4 patients in whom DBE-ERC failed to be completed, 3 patients underwent 2nd procedures successfully. Liver function test results were significantly improved in the successful cases. Four patients underwent 2nd DBE-ERC for stricture recurrence at a mean time of 2.3 years after the 1st successful procedure. Of those, 2 patients required 3rd procedures for stricture recurrence after the 2nd procedure. CONCLUSIONS: DBE-ERC is promising as a treatment for HJS stricture in adult LDLT recipients in the short term. However, the DBE-ERC procedure may have a considerable risk of restenosis. PMID- 26518959 TI - Laparoscopy After Liver Transplant: Result of an Initial Series. AB - There are few reports about laparoscopic approach after liver transplantation (LT). The aim of this paper is to analyze in terms of feasibility and therapeutic effectiveness an initial experience with laparoscopy in patients who have had a liver transplantation. METHODS: Laparoscopic procedures were divided into "early" and "late" laparoscopy. RESULTS: A total of 10 laparoscopic procedures after LT were performed in 9 patients: 3 early and 7 late. The early laparoscopic procedures were performed in 3 patients who had a torpid evolution in their liver transplant: 2 were diagnostic only and 1 was also therapeutic. There were no intraoperative events or conversions. We recorded 2 complications. In 7 patients a late laparoscopy was performed: 4 in the upper abdomen and 3 in the lower abdomen. Of the 4 in the upper abdomen, 3 were liver procedures and 1 was in the transverse colon, on the other side; in addition, 2 laparoscopic inguinal hernia repairs and 1 laparoscopic appendectomy also were performed. None of these 7 cases was converted, and there were no intraoperative events. CONCLUSIONS: The early postoperative period, in critically ill patients diagnostic and eventually therapeutic laparoscopy was feasible and effective in our cases. Late laparoscopy in the upper abdomen is difficult due to adhesions and adds to the risk of poor graft function, but was feasible for both diagnostic and therapeutic purposes. Late laparoscopy in the lower abdomen with good graft function has the same safety and efficacy as those performed on nontransplanted patients. PMID- 26518960 TI - A Single-center Experience on the Value of Pancreas Graft Biopsies and HLA Antibody Monitoring After Simultaneous Pancreas-Kidney Transplantation. AB - BACKGROUND: In simultaneous pancreas-kidney transplantation (SPKT), monitoring of the pancreas allograft is more complex than the kidney allograft due to difficulties in obtaining pancreas histology and weak clinical evidence supporting the role of donor-specific antibodies (DSA). METHODS: We performed a single-center retrospective analysis of all 17 SPKT recipients who underwent a total of 22 pancreas allograft indication biopsies from October 2009 to September 2012. Fifteen patients had at least 2 DSA measurements: pretransplantation and at the time of biopsy. RESULTS: All 7 patients (100%) with post-transplantation DSA positivity (de novo: n = 6; persistent: n = 1) at biopsy had at least 1 rejection episode either of the pancreas (n = 4) or the kidney (n = 3), with 3 antibody mediated rejections (AMR). In contrast, only 4 of 8 patients (50%) without post transplantation DSA had evidence of rejection, with 1 AMR. Findings during pancreas allograft biopsy procedures led to a change of immunosuppressive therapy in 11 of 15 (73%) patients. Patient survival, graft survival, and function were not adversely affected by the presence of post-transplantation DSA. One major and 2 minor procedure-related complications occurred during the pancreas biopsies. CONCLUSIONS: In this small retrospective analysis, pancreas allograft histology provided the most therapeutically relevant information, rather than the kidney histology or DSA monitoring. PMID- 26518961 TI - Confocal Scanning Microscopy in Assessment of Cardiac Allograft Rejection--A Pilot Study. AB - Cardiac allograft rejection is typically diagnosed on the basis of hematoxylin and eosin (H&E) histology of endomyocardial biopsies. This diagnosis is made based on the degree of immune cell infiltrate and associated myocyte damage. However, considerable variability in rejection grading between pathologists can occur. Confocal microscopy provides high contrast and high resolution imaging that has the potential to provide detailed views of pathological features of allograft rejection. In this pilot study we sought to determine if confocal microscopy could be used to detect features of cardiac rejection. This was achieved by collection of additional sample at 30 biopsy procedures from 15 heart transplant patients. Routine pathological grading of H&E histology identified 5 gradings of 0R, 21 gradings of 1R, and 3 gradings of 2R. From these gradings, 3 samples for 0R, 9 samples for 1R, and 3 samples for 2R were imaged by confocal microscopy. This was achieved by fluorescently labeling sections with DAPI, wheat germ agglutinin, and phalloidin, to visualize the cell nuclei, cell border and extracellular matrix, and muscle cell actin, respectively. Labeling with these fluorescent markers was of high contrast. However, we did note variability in DAPI and phalloidin labeling of tissue sections. Confocal imaging of these labels revealed the following features at high resolution: perivascular and/or interstitial infiltrate, myocyte damage, and Quilty lesions. In particular increased detail of damaged myocytes reveals distortion in myofilament organization that could be exploited to distinguish between 1R and 2R grades. In conclusion, confocal microscopy provided high contrast and resolution imaging of cardiac biopsies that could be explored further to aid assessment of cardiac allograft rejection. PMID- 26518962 TI - Tumor Necrosis Factor-alpha-Induced Protein 8-Like 2 Gene Overexpression Prolongs the Survival of Rat Allogeneic Heart Allografts. AB - BACKGROUND: The objective of the study was to examine whether overexpression of the tumor necrosis factor-alpha-induced protein 8-like 2 (TNFAIP8L2; TP8L2) gene might prolong the survival of a rat heart allograft and to explore the possibility of gene-induced immune tolerance and its specific mechanisms of action in rats. METHODS: A gene vector (AdC68) was constructed of a rat's TP8L2 gene to overexpress the TP8L2 gene in the models. The Wistar-to-Dawley rat allogeneic heart allograft models were created and randomly separated into 5 groups: control, no treatment after surgery; Fk506, treated with immune inhibitor FK506 0.5 mg/kg/d after surgery; TP8L2, treated with 0.25 * 10(9) Pfu recombinant TP8L2 adenovirus after surgery; FK506+TP8L2, treated with FK506 0.25 mg/kg/d and 0.25 * 10(9) Pfu recombinant TP8L2 adenovirus after surgery; and no-TP8L2, treated with 0.25 * 10(9) Pfu recombinant adenovirus without TP8L2 gene overexpression after surgery. We also examined whether the overexpressed TP8L2 gene can prolong the donor heart's mean survival time and detect the changes of various related indicators. RESULTS: The survival time of the donor heart in the TP8L2 and FK506+TP8L2 groups was significantly longer than that in the remaining groups; the difference was statistically significant (P < .05). The percentage of CD4(+)CD25(+) regulatory T cells in the TP8L2 and FK506+TP8L2 groups was significantly higher than that in the remaining groups; the difference was statistically significant (P < .05). The expression of interleukin (IL)-2, tumor necrosis factor-alpha, and interferon-gamma in the FK506+TP8L2 group was significantly lower and the expression of IL-4 and IL-10 was significantly higher than those in other groups; the differences in cytokine levels were significant (P < .05). CONCLUSIONS: TP8L2 plays an important role in the induction of immune tolerance in heart allografts. PMID- 26518963 TI - Effects of Fetal and Neonatal Murine Peripheral Blood Mononuclear Cells Infusion on MicroRNA-145 Expression in Renal Vascular Smooth Muscle Cells in MRL/lpr Mice. AB - For patients with refractory systemic lupus erythematosus, current medications are insufficient to control their condition, and new treatments are necessary. We aimed to evaluate the therapeutic effect of fetal and neonatal murine peripheral blood (FNPB) mononuclear cells and their impact on microRNA-145 (miR-145) in renal vascular smooth muscle cells (VSMCs) of MRL/lpr lupus-prone mice. MRL/lpr mice aged 20 weeks were randomized to 3 groups of 15 (control group, radiation group, infusion group). The renal tissues were subjected to pathological examination. In situ hybridization assay was applied to measure miR-145 expression in renal vessels of MRL/lpr mice. The infusion group had significantly better results for pathological renal tissue lesions than either the control or radiation group. In MRL/lpr mice, there was positive expression of miR-145 in renal VSMCs, although the expression of miR-145 was not discernible in renal vascular intima and adventitia. The miR-145 expression in renal VSMCs in the infusion group was significantly higher than in the control or radiation group, and higher in the radiation group than in the control group; however, the difference was not statistically significant. The increased expression of miR-145 in renal VSMCs might be one of the mechanisms supporting FNPB as a therapy for lupus nephritis; it also suggests that the miR-145 in renal vessels might be a new target for treatment of lupus nephritis. PMID- 26518964 TI - Food Restriction Prolongs Murine Cardiac Grafts. AB - Overeating and obesity lead to cardiovascular disease, diabetes, and eventually premature death, whereas food or energy restriction reduces risk factors for cardiovascular disease and diabetes and expands the life span. The aim of this study was to investigate the effect of food restriction (FR) in a murine heart transplant model. CBA male recipients (H2(k)) that underwent transplantation of C57BL/6 (H2(b)) hearts were assigned to free access group or FR groups with food intake at 60% (40% FR), 50% (50% FR), or 40% (60% FR) of the average food intake for 1 week after transplantation, and each median survival time was measured. We also performed cell proliferation, cytokine production, and flow cytometry assessments. The 60% FR CBA recipients showed prolongation of allograft survival (median survival time, 24 days). Cell proliferation and interferon-gamma were suppressed in the 60% FR CBA recipients. Flow cytometry studies showed a lower CD4(+)CD25(+)Foxp3(+) cell population in splenocytes from the 60% FR CBA recipients. In conclusion, the findings suggest that the prolongation of cardiac allograft resulted from not regulation of alloimmune responses, but partial impairment of alloimmune responses, linking energy restriction to low generation of splenic CD4(+)CD25(+)Foxp3(+) regulatory T cells. PMID- 26518965 TI - Plasma Cell-Rich Rejection After Kidney Transplantation and the Role of Donor Specific Antibodies: A Case Report and Review of the Literature. AB - OBJECTIVE: We report a case of the clinical course and pathologic findings for a kidney transplant recipient with plasma cell-rich rejection (PCRR) accompanied by antibody-mediated rejection (ABMR). METHODS: A 29-year-old man with end-stage renal disease caused by lupus nephritis received an ABO-compatible living kidney transplant. RESULTS: Eighteen months after transplantation, the patient presented with proteinuria and increased serum creatinine. An episode biopsy revealed severe tubulointerstitial infiltration with plasma cells accompanied by peritubular capillaritis and positive findings on immunofluorescent C4d staining. Donor-specific antibodies were positive for DR52, and the patient was subsequently diagnosed with PCRR accompanied by ABMR. Treatment was initiated with high-dose steroids, intravenous immunoglobulin, gusperimus hydrochloride, muronmonab antibody CD3, and rituximab. However, ABMR persisted and allograft failure developed 20 months after onset. CONCLUSIONS: We argue that PCRR accompanied by ABMR is a subtype of PCRR that can progress to allograft failure owing to persistent ABMR. PMID- 26518966 TI - Surgical Dead End in a Renal Transplant Recipient Associated With a Rare Thrombohemorrhagic Syndrome. AB - BACKGROUND: Primary breast angiosarcoma is an extremely rare malignancy. Association of this type of tumor with Kasabach-Merritt syndrome has only been reported in 3 cases in the past. To our knowledge, this is the first reported case of a solid-organ recipient. METHODS: A 53-year-old woman who underwent a deceased-donor renal transplantation 5 years previously presented with a 12-month history of a giant ulcerated lesion on her left breast. Biopsy of the overlying skin suggested primary angiosarcoma. Concurrently, the patient's bleeding from the site of the biopsy and hematology investigations indicated the presence of Kasabach-Merritt syndrome. RESULTS: The case was discussed in a multidisciplinary setting. The decision was to use anthracycline-based chemotherapy as up-front treatment to assess tumor response and gain a local benefit for a subsequent resection. After the completion of 1 cycle of chemotherapy, the patient died of cardiovascular insufficiency. Primary angiosarcoma of the breast occurs in the third to fourth decade and has been reported only in women. CONCLUSIONS: A high clinical suspicion and referral to a specialized center are necessary. Total mastectomy appears to be the only treatment conferring benefit; chemotherapy and radiation therapy are of little value. PMID- 26518967 TI - Successful Kidney Transplantation in Epstein Syndrome With Antiplatelet Antibodies and Donor-specific Antibodies: A Case Report. AB - An autosomal dominant hereditary disease, Epstein syndrome (ES) is characterized by sensorineural hearing impairment, macrothrombocytopenia, and hereditary nephritis, and can progress to end-stage kidney disease after puberty. Generally, kidney transplantation is difficult to perform in Epstein syndrome owing to the high risk of perioperative bleeding. Additionally, due to previous platelet transfusions, ES patients sometimes have antihuman leukocyte antigen (HLA) antibodies, including antiplatelet antibodies and donor-specific anti-HLA antibodies (DSA), which may result in refractoriness to platelet transfusion and antibody-mediated rejection (AMR). We report a case of successful kidney transplantation in a patient with ES who had DSA and antiplatelet antibodies. To prevent AMR, we used a desensitization protocol (a combination of plasmapheresis, rituximab, and basiliximab induction). Surveillance biopsy performed at 4 months and 1 year after transplantation showed no pathological findings suggesting AMR. To prevent perioperative bleeding complications, we infused the patient with HLA matched platelets, thereby maintaining the platelet count at >10.0 * 10(4)/MUL, and no postoperative episodes of bleeding occurred. PMID- 26518968 TI - Gastric Metastasis of Hepatocellular Carcinoma With Gastrointestinal Bleeding After Liver Transplant: A Case Report. AB - Gastrointestinal (GI) metastasis of hepatocellular carcinoma is very rare. This is the first report of post-transplantation gastric metastasis. A 43-year-old man with a history of hepatitis B-related hepatocellular carcinoma (HCC) in the right anterior segment of the liver received an orthotopic liver transplant. Three months after the transplantation, pulmonary metastasis was found by chest computed tomography, and he received 1 course of gamma knife treatment. He complained of melena with anemia 17 months post liver transplantation. Abdominal CT scan showed new occupying lesions in the liver and a mass in the stomach and around the spleen with embolus in the splenic vein. Endoscopy revealed a large irregular cauliflower-like mass in fundus with ulceration and bleeding on the surface. He received symptomatic treatment, but died of cancer-related bleeding 4 months later. GI bleeding may due to gastric metastasis after liver transplantation. PMID- 26518969 TI - Severe Acute Anemia After Liver Transplantation in an Elderly Jehovah's Witness Treated With High-dose Erythropoietin and Ferric Carboxymaltose: A Case Report. AB - BACKGROUND: There is no standard treatment for patients with severe anemia who refuse blood transfusion or cannot receive red blood cells. CASE REPORT: After an orthotopic liver transplantation, an elderly Jehovah's Witness who refused blood transfusion presented with severe acute anemia with hemorrhagic shock. The calculated red blood cell loss was near 70%. Associated with surgical treatment and supportive measures, the patient was treated with high-dose erythropoietin and ferric carboxymaltose. RESULTS: The patient presented a rapid increase in hemoglobin concentration and reticulocyte count with resolution of hemorrhagic shock after the proposed pharmacologic treatment combined with local hemostatic measures. She was transferred to a low-risk unit 4 days after transplantation and was discharged from the hospital on day 10. The hemoglobin concentration was normal 35 days after the bleeding event. CONCLUSION: This case demonstrated that a protocol with high-dose erythropoietin and ferric carboxymaltose may be an option for patients with severe anemia who refuse blood transfusion or cannot receive red blood cells. PMID- 26518970 TI - Response. PMID- 26518971 TI - Bacterial and Fungal Infections in the Early Post-Transplant Period After Kidney Transplantation: Etiological Agents and Their Susceptibility. PMID- 26518972 TI - Milk allergy is a minor cause of milk avoidance due to perceived hypersensitivity among schoolchildren in Northern Sweden. AB - AIM: We investigated phenotypes of milk hypersensitivity among schoolchildren aged 11-12 in Northern Sweden. METHODS: In a population-based cohort, 1824 (98%) children aged 11-12 participated in a questionnaire survey, skin prick testing, interviews on food hypersensitivity and assessment of body mass index (BMI). Of the 265 children reporting milk hypersensitivity, milk avoidance and no coeliac disease, 236 (89%) participated in a structured interview and blood samples for analyses of milk-specific Immunoglobulin E. The children were then categorised into milk hypersensitivity phenotypes according to preset criteria. RESULTS: In all, 14.5% reported milk hypersensitivity. Of these, 3% were categorised as current milk allergy, 23% as outgrown milk allergy, 40% as probable lactose intolerance and 11% as nondefinable. Furthermore, 23% had discontinued their elimination diet. Milk allergy was associated with other atopic disorders and lower BMI, with an odds ratio of 0.82 and 95% confidence interval of 0.80-0.98. Only 2% had previously undergone an oral challenge. CONCLUSION: The most common symptom phenotypes among Swedish children aged 11-12 with self-reported milk hypersensitivity and milk avoidance were probable intolerance and outgrown milk allergy, while current milk allergy was uncommon. Children with milk allergy had a lower BMI and most lacked a challenge-proven diagnosis. PMID- 26518973 TI - Alpha lipoic acid supplementation attenuates reactive oxygen species in hypothalamic paraventricular nucleus and sympathoexcitation in high salt-induced hypertension. AB - AIMS: High salt-induced oxidative stress plays an important role in the development of hypertension. Alpha lipoic acid (ALA) is extensively recognized as having a powerful superoxide inhibitory property. In this study, we determined whether ALA supplementation attenuates oxidative stress in hypothalamic paraventricular nucleus (PVN), decreases the sympathetic activity and arterial pressure in high salt-induced hypertension by cross-talking with renin angiotensin system (RAS) and pro-inflammatory cytokines (PICs). METHODS: Male Wistar rats were administered a normal-salt diet (NS, 0.3% NaCl) or a high-salt diet (HS, 8.0% NaCl) for 8 weeks. These rats received ALA (60mg/kg) dissolved in vehicle (0.9% saline) or an equal voleme of vehicle, by gastric perfusion for 9 weeks. RESULTS: High salt intake resulted in higher renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP). These rats also had higher levels of superoxide, gp91(phox), gp47(phox) (subunits of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), angiotensin II type1 receptor (AT1-R), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and lower levels of interleukin-10 (IL-10) and copper/zinc superoxide dismutase (Cu/Zn-SOD) than control animals. Treatment with ALA significantly attenuated the levels of superoxide, gp91(phox), gp47(phox), ACE, AT1-R, IL-1beta and IL-6, increased the levels of IL-10 and Cu/Zn-SOD, and decreased MAP and RSNA compared with high-salt induced hypertensive rats. The mRNA expression of gp47(phox) and gp91(phox) are in accordance with their protein expression. CONCLUSION: These findings suggest that supplementation of ALA obviously decreases the sympathetic activity and arterial pressure in high salt-induced hypertension by improving the superoxide inhibitory property, suppressing the activation of RAS and restoring the balance between pro- and anti-inflammatory cytokines in the PVN. PMID- 26518974 TI - Protein corona acts as a protective shield against Fe3O4-PEG inflammation and ROS induced toxicity in human macrophages. AB - Protein corona (PC) is the main biological entity of initial cell interaction and can define the toxicological response to Fe3O4 nanoparticles (IONP). Polymer coating to IONP, polyethilenglycol (PEG) and polyvinylpyrrolidone (PVP), is a widely accepted strategy to prevent toxicity and avoid excessive protein binding. The aim of this study was to assess the role of PC as a potential protector for ROS-induced cytotoxicity and pro-inflammatory response in THP-1 macrophages (exposed to three different IONP: bare, PVP or PEG coated). Cells were exposed to either IONP in RPMI-1640 media or IONP with a preformed human PC. All three IONP showed cytotoxic effects, which in the presence of PC was abolished. IONP-PEG exposure significantly increased ROS, mitochondrial dysfunction and pro inflammatory cytokines release (IL-1beta and TNF-alpha). PC presence on IONP-PEG promoted a decrease in ROS and prevented cytokine secretion. Also, presence of PC reduced cell uptake for IONP-bare, but had no influence on IONP-PVP or IONP-PEG. Hence, the reduction in IONP-PEG cytotoxicity can be attributed to PC shielding against ROS generation and pro-inflammatory response and not a differential uptake in THP-1 macrophages. The presence of the PC as a structural element of NP biological entity provides in vivo-relevant conditions for nanosafety testing. PMID- 26518975 TI - Synthesis, Antifolate and Anticancer Activities of N(5) -Substituted 8,10 Dideazatetrahydrofolate Analogues. AB - Based on our previous work, seven N(5) -substituted 8,10-dideazatetrahydrofolate analogues and one 8-deazatetrahydrofolate analogue were designed and synthesized as human dihydrofolate reductase (hDHFR) inhibitors. All compounds were assayed versus DHFR and five different cancer cell lines. The biological assay indicated that replacing N(10) with carbon would significantly increase inhibitory activities against DHFR and cytotoxicities against cancer cell lines. Compound 19a with 4-amino and N(5) -formyl showed great antitumour activities against HL 60, Bel-7402 and BGC823 which were much better than MTX. PMID- 26518977 TI - Whole brain fiber-based comparison (FBC)-A tool for diffusion tensor imaging based cohort studies. AB - We present a novel method for fiber-based comparison of diffusion tensor imaging (DTI) scans of groups of subjects. The method entails initial preprocessing and fiber reconstruction by tractography of each brain in its native coordinate system. Several diffusion parameters are sampled along each fiber and used in subsequent comparisons. A spatial correspondence between subjects is established based on geometric similarity between fibers in a template set (several choices for template are explored), and fibers in all other subjects. Diffusion parameters between groups are compared statistically for each template fiber. Results are presented at single fiber resolution. As an initial exploratory step in neurological population studies this method points to the locations affected by the pathology of interest, without requiring a hypothesis. It does not make any grouping assumptions on the fibers and no manual intervention is needed. The framework was applied here to 18 healthy subjects and 23 amyotrophic lateral sclerosis (ALS) patients. The results are compatible with previous findings and with the tract based spatial statistics (TBSS) method. Hum Brain Mapp 37:477-490, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26518976 TI - Peer-led interventions to prevent tobacco, alcohol and/or drug use among young people aged 11-21 years: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Peer-led interventions may offer a beneficial approach in preventing substance use, but their impact has not yet been quantified. We conducted a systematic review to investigate and quantify the effect of peer-led interventions that sought to prevent tobacco, alcohol and/or drug use among young people aged 11-21 years. METHODS: Medline, EMBASE, PsycINFO, CINAHL, ERIC and the Cochrane Library were searched from inception to July 2015 without language restriction. We included randomized controlled trials only. Screening and data extraction were conducted in duplicate and data from eligible studies were pooled in a random effects meta-analysis. RESULTS: We identified 17 eligible studies, approximately half of which were school-based studies targeting tobacco use among adolescents. Ten studies targeting tobacco use could be pooled, representing 13,706 young people in 220 schools. Meta-analysis demonstrated that the odds of smoking were lower among those receiving the peer-led intervention compared with control [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62-0.99, P = 0.040]. There was evidence of heterogeneity (I(2) = 41%, chi(2) 15.17, P = 0.086). Pooling of six studies representing 1699 individuals in 66 schools demonstrated that peer-led interventions were also associated with benefit in relation to alcohol use (OR = 0.80, 95% CI = 0.65-0.99, P = 0.036), while three studies (n = 976 students in 38 schools) suggested an association with lower odds of cannabis use (OR = 0.70, 0.50-0.97, P = 0.034). No studies were found that targeted other illicit drug use. CONCLUSIONS: Peer interventions may be effective in preventing tobacco, alcohol and possibly cannabis use among adolescents, although the evidence base is limited overall, and is characterized mainly by small studies of low quality. PMID- 26518978 TI - Authors' reply to radiotherapy did not increase thyroid cancer risk among women with breast cancer: A nationwide population-based cohort study. PMID- 26518980 TI - An open randomized controlled clinical trial to evaluate ridge preservation and repair using SocketKAP(TM) and SocketKAGE(TM) : part 2 - three-dimensional alveolar bone volumetric analysis of CBCT imaging. AB - OBJECTIVES: The aims of this study were (i) to evaluate the efficacy of ridge preservation and repair procedures involving the application of SocketKAP(TM) and SocketKAGE(TM) devices following tooth removal and (ii) to evaluate alveolar bone volumetric changes at 6 months post-extraction in intact sockets or those with facial wall dehiscence defects using 3-dimensional pre- and postoperative CBCT data. MATERIALS AND METHODS: Thirty-six patients required 61 teeth extracted. Five cohorts were established: Group A: Intact Socket Negative Control Group B: Intact Socket + SocketKAP(TM) Group C: Intact Socket Filled with Anorganic Bovine Bone Mineral (ABBM) + SocketKAP(TM) Group D: Facial Dehiscence Socket Negative Control Group E: Facial Dehiscence Socket Filled with ABBM + SocketKAP(TM) + SocketKAGE(TM) . Preoperative CBCT scans were obtained followed by digital subtraction of the test teeth. At 6 months post-extraction, another CBCT scan was obtained. The pre- and postoperative scans were then superimposed, allowing highly accurate quantitative determination of the 3D volumetric alveolar bone volume changes from baseline through 6 months. RESULTS: Significant volumetric bone loss occurred in all sockets, localized mainly in the 0-3 mm zone apical to the ridge crest. For intact sockets, SocketKAP(TM) + ABBM treatment led to a statistically significant greater percentage of remaining mineralized tissue volume when compared to negative control group. A significant difference favoring SocketKAP(TM) + SocketKAGE(TM) + ABBM treatment was observed for sockets with facial dehiscence defects compared to the negative control group. CONCLUSIONS: SocketKAP(TM) , with ABBM, appears effective in limiting post-extraction volumetric bone loss in intact sockets, while SocketKAP(TM) + SocketKAGE + ABBM appears effective in limiting post-extraction bone loss in sockets with dehiscence defects. PMID- 26518979 TI - Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multi-center, uncontrolled, open-label study. AB - PURPOSE: To evaluate the efficacy and safety of lamotrigine (LTG) monotherapy for treating Japanese and South Korean pediatric patients with newly diagnosed typical absence seizures. METHODS: Twenty patients with newly diagnosed typical absence seizures aged 4-12 years were enrolled in the study and were administered LTG at an initial dose of 0.3 mg/kg/day for 2 weeks, followed by 0.6 mg/kg/day for an additional 2 weeks. Thereafter, the dose was increased by 0.6 mg/kg/day up to a maximum of 10.2 mg/kg/day or 400 mg/day (whichever was the lower dose) until patients were confirmed to be seizure free induced by hyperventilation (HV). After confirmation, the dose was increased by one level (0.6 mg/kg/day). If the patient was found to be seizure free by HV-electroencephalography (EEG) on the following two consecutive visits, the patient entered the 12-week maintenance phase. After the maintenance phase, patients could enter the extension phase if clinically indicated. RESULTS: The seizure-free rate confirmed by HV-EEG at the end of the maintenance phase was 35.0% (7/20 patients). Most of patients who were confirmed to be seizure free during the escalation phase had maintained seizure control during the 12-week maintenance phase and the 12-week extension phase. The most frequently noted adverse events were bronchitis, headache, and rash (20% each). No serious adverse events were reported. CONCLUSION: Lamotrigine monotherapy in Japanese and South Korean children with typical absence seizures was well tolerated and 35.0% of patients were seizure free at the end of maintenance phase. PMID- 26518981 TI - Psychological maltreatment, emotional and behavioral problems in adolescents: The mediating role of resilience and self-esteem. AB - In this study, structural equation modeling was used to examine the mediating role of resilience and self-esteem in the relationships between psychological maltreatment-emotional problems and psychological maltreatment-behavioral problems in adolescents. Participants were 937 adolescents from different high schools in Turkey. The sample included 502 female (53.6%) and 435 male (46.4%) students, 14-19 years old (mean age=16.51, SD=1.15). Results indicated that psychological maltreatment was negatively correlated with resilience and self esteem, and positively correlated with behavioral problems and emotional problems. Resilience and self-esteem also predicted behavioral problems and emotional problems. Finally, psychological maltreatment predicted emotional and behavioral problems mediated by resilience and self-esteem. Resilience and self esteem partially mediated the relationship between psychological maltreatment behavioral and psychological maltreatment-emotional problems in adolescents. Thus, resilience and self-esteem appear to play a protective role in emotional problems and behavioral problems in psychologically maltreated individuals. Implications are discussed and suggestions for psychological counselors and other mental health professionals are presented. PMID- 26518983 TI - The role of stearate attachment to the hemagglutinin-esterase-fusion glycoprotein HEF of influenza C virus. AB - The only spike of influenza C virus, the hemagglutinin-esterase-fusion glycoprotein (HEF) combines receptor binding, receptor hydrolysis and membrane fusion activities. Like other hemagglutinating glycoproteins of influenza viruses HEF is S-acylated, but only with stearic acid at a single cysteine located at the cytosol-facing end of the transmembrane region. Previous studies established the essential role of S-acylation of hemagglutinin for replication of influenza A and B virus by affecting budding and/or membrane fusion, but the function of acylation of HEF was hitherto not investigated. Using reverse genetics we rescued a virus containing non-stearoylated HEF, which was stable during serial passage and showed no competitive fitness defect, but the growth rate of the mutant virus was reduced by one log. Deacylation of HEF does neither affect the kinetics of its plasma membrane transport nor the protein composition of virus particles. Cryo-electron microscopy showed that the shape of viral particles and the hexagonal array of spikes typical for influenza C virus were not influenced by this mutation indicating that virus budding was not disturbed. However, the extent and kinetics of haemolysis were reduced in mutant virus at 37 degrees C, but not at 33 degrees C, the optimal temperature for virus growth, suggesting that non-acylated HEF has a defect in membrane fusion under suboptimal conditions. PMID- 26518985 TI - Prosthetic rehabilitation with an implant-supported fixed prosthesis using computer-aided design and computer-aided manufacturing dental technology for a patient with a mandibulectomy: A clinical report. AB - The fabrication of dental prostheses with computer-aided design and computer aided manufacturing shows acceptable marginal fits and favorable treatment outcomes. This clinical report describes the management of a patient who had undergone a mandibulectomy and received an implant-supported fixed prosthesis by using additive manufacturing for the framework and subtractive manufacturing for the monolithic zirconia restorations. PMID- 26518984 TI - Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models. AB - AIMS: Pregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively. METHODS: Transplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy-physiologically based pharmacokinetic (p-PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models. RESULTS: Parameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo. CONCLUSION: The integration of ex vivo human placental perfusion parameters in a p-PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics. PMID- 26518986 TI - Evaluation of marginal fit of CAD/CAM restorations fabricated through cone beam computerized tomography and laboratory scanner data. AB - STATEMENT OF PROBLEM: Whether cone beam computed tomography (CBCT) images can be used for the fabrication of computer-aided design/computer-aided manufacturing (CAD/CAM) restorations is unknown. PURPOSE: The purpose of this in vitro study was to evaluate the marginal fit of CAD/CAM restorations fabricated by using data from CBCT scans with 3 different voxels and laser scanner images. MATERIAL AND METHODS: A crown preparation was made on an extracted premolar tooth according to ceramic crown preparation guidelines. The prepared tooth was scanned with a 3 dimensional (3D) extraoral laser scanner (D900; 3Shape), and CBCT scans were also made with an i-CAT cone beam 3D imaging system at 3 different voxel resolution settings: 0.125 mm, 0.20 mm, and 0.30 mm. The 3D images obtained from the laser scanner and CBCT scans were sent to CAD software, and a crown design was completed. Information was sent to CAM software to mill the crowns from poly(methyl methacrylate) (PMMA) blocks (n=9 from the laser scanner and 27 from 3 different CBCT scans). A total of 144 images (4 groups, 9 crowns per group, 4 sites per crown) were measured for vertical marginal discrepancy under a stereoscopic zoom microscope. One-way analysis of variance (ANOVA) was used to analyze the data. According to the assumption of homogeneity of variance, the post hoc Tukey multiple comparison test was performed (alpha=.05). RESULTS: The marginal gap values of crowns fabricated with an extraoral laser scanner were significantly lower than those of crowns fabricated with 0.3-, 0.2-, and 0.125 voxel CBCT images (P<.001). The marginal gap was greater when 0.3- and 0.2-voxel CBCT images were used than when 0.125-voxel CBCT images were used (P<.001). CONCLUSIONS: Crowns fabricated with the laser scanner images had lower and clinically acceptable marginal discrepancies than crowns fabricated with CBCT images in 3 different voxels. Of all the CBCT scans, only images with 0.125 voxel produced crowns with clinically acceptable marginal discrepancy. PMID- 26518987 TI - Digital approach to a ceramic-pressed-to-metal restoration. AB - Even though a traditional metal ceramic restoration is still popular, it demands both time and effort. A ceramic-pressed-to-metal restoration (PTM) can be an alternative because this restoration reduces the complicated laboratory procedure and risk of ceramic chipping. However, no method has yet been reported for fabricating a PTM without a stone cast. This article describes an accelerated technique for a PTM with an intraoral scanner and computer-aided design and computer-aided manufacturing technology. PMID- 26518988 TI - Effects of clip materials on stress distribution to maxillary implant overdentures with bar attachments. AB - STATEMENT OF PROBLEM: Fracture of maxillary implant overdentures (IODs) is a frequent complication. However, no studies have examined the effects of clip materials on the stress applied to maxillary IODs. PURPOSE: The purpose of this study was to investigate the effects of clip materials for bar attachments on the stress applied to maxillary IODs without palatal coverage. MATERIAL AND METHODS: This study included finite element analysis and a model study. An edentulous maxillary model with 4 implants and an experimental overdenture with bar attachments was fabricated. Strain gauges were attached on the denture surface adjacent to the end of each clip. Four clip conditions (n=5) were prepared: 3 plastic clips, 1 plastic clip, 3 metal clips, and 1 metal clip. A vertical load of 50 N was applied on the IOD. The maximum principle strain (MPS) was statistically analyzed by 2-way ANOVA and the post hoc Tukey HSD tests with clip materials and clip numbers as factors (alpha=.05). RESULTS: The greatest stress was observed on the resin surface around the end of the clip on the loaded side. The MPSs between both clip materials (P=.048) and numbers (P<.001) differed significantly on the palatal side of the end of the center clip on the loaded side: the MPSs of the metal clips were significantly larger than those of the plastic clips, and the MPS of 1 clip was significantly larger than for 3 clips. CONCLUSIONS: The stress around plastic clips tended to be lower than that around metal clips. PMID- 26518982 TI - Endostatin and endorepellin: A common route of action for similar angiostatic cancer avengers. AB - Traditional cancer therapy typically targets the tumor proper. However, newly formed vasculature exerts a major role in cancer development and progression. Autophagy, as a biological mechanism for clearing damaged proteins and oxidative stress products released in the tumor milieu, could help in tumor resolution by rescuing cells undergoing modifications or inducing autophagic-cell death of tumor blood vessels. Cleaved fragments of extracellular matrix proteoglycans are emerging as key players in the modulation of angiogenesis and endothelial cell autophagy. An essential characteristic of cancer progression is the remodeling of the basement membrane and the release of processed forms of its constituents. Endostatin, generated from collagen XVIII, and endorepellin, the C-terminal segment of the large proteoglycan perlecan, possess a dual activity as modifiers of both angiogenesis and endothelial cell autophagy. Manipulation of these endogenously-processed forms, located in the basement membrane within tumors, could represent new therapeutic approaches for cancer eradication. PMID- 26518989 TI - Disulfanyl peptide decreases melanin synthesis via receptor-mediated ERK activation and the subsequent downregulation of MITF and tyrosinase. AB - OBJECTIVE: Bioactive peptides are commonly used in cosmeceutical purpose. This study was performed to search for an effective and short hypopigmenting peptide using normal human melanocytes as a screening model. A peptide that exhibits multitarget activities will be a promising peptide. METHODS: Depigmenting effects were tested in normal human melanocytes. One peptide was selected, and signalling mechanism was investigated by Western blotting and immunofluorescent microscopic examination. RESULTS: A novel hypopigmenting peptide (dSHP) has been found to inhibit the production of melanin. This peptide significantly decreases tyrosinase activity but was not effective in a direct in vitro assay. It also induces the prolonged activation of ERK, and subsequently downregulates the levels of MITF. PD98059 abolished the dSHP-induced downregulation of MITF. These findings indicate that the dSHP-induced activation of ERK contributes to a reduced melanin synthesis via the downregulation of MITF. Fluorescent microscopic studies were consistent with such findings. Pertussis toxin reverses the downregulation of MITF, which means that the receptor-mediated ERK activation is involved. Moreover, it was also found that downregulation of MITF was clearly inhibited by lysosomal inhibitor (chloroquine). CONCLUSION: Novel tetrapeptide dSHP reduces the melanin synthesis by a receptor-mediated pathway. Furthermore, dSHP works by ERK activation and key transcription factor MITF degradation. Thus, it may be a good candidate as an effective hypopigmenting cosmetic agent. PMID- 26518990 TI - Hydration and collateral flow in acute stroke. PMID- 26518991 TI - Diet-induced dyslipidemia leads to nonalcoholic fatty liver disease and oxidative stress in guinea pigs. AB - Chronic dyslipidemia imposed by a high-fat and high-caloric dietary regime leads to debilitating disorders such as obesity, nonalcoholic fatty liver disease (NAFLD), and insulin resistance. As disease rates surge, so does the need for high validity animal models to effectively study the causal relationship between diet and disease progression. The dyslipidemic guinea pig displays a high similarity with the human lipoprotein profile and may in this aspect be superior to other rodent models. This study investigated the effects of 2 long-term Westernized diets (0.35% cholesterol, 18.5% vegetable oil and either 15% or 20% sucrose) compared with isocaloric standard chow in adult guinea pigs. Biochemical markers confirmed dyslipidemia in agreement with dietary regimens; however, both high-fat groups displayed a decreased tissue fat percentage compared with controls. Macroscopic appearance, histopathologic evaluation, and plasma markers of liver function confirmed NAFLD in high-fat groups, supported by liver redox imbalance and markers suggesting hepatic endothelial dysfunction. Plasma markers indicated endothelial dysfunction in response to a high-fat diet, although atherosclerotic lesions were not evident. Evaluation of glucose tolerance showed no indication of insulin resistance. The 5% increase in sucrose between the 2 high-fat diets did not lead to significant differences between groups. In conclusion, we find the dyslipidemic guinea pig to be a valid model of diet imposed dyslipidemia, particularly with regards to hepatic steatosis and endothelial dysfunction. Furthermore, the absence of obesity supports the present study setup as targeting NAFLD in nonobese individuals. PMID- 26518992 TI - Granulocyte colony-stimulating factor as a potential inducer of ovulation in infertile women with luteinized unruptured follicle syndrome. AB - Luteinized unruptured follicle (LUF) syndrome is one of the intractable ovulation disorders that are commonly observed during cycles of treatment with ovulation inducers, for which no effective therapy other than assisted reproductive technology is available. Here, we investigated whether granulocyte colony stimulating factor (G-CSF) could prevent the onset of LUF syndrome. We analyzed the effects of G-CSF in 68 infertile women with LUF syndrome who received ovulation induction (clomiphene + human chorionic gonadotropin [hCG] therapy or follicle-stimulating hormone + hCG therapy). G-CSF (lenograstim, 100 MUg) was administered subcutaneously. Onsets of LUF syndrome were compared between the cycle during which G-CSF was given in combination with the ovulation inducer (ie, the G-CSF treatment cycle) and the subsequent cycle during which only the ovulation inducer was given (ie, the G-CSF nontreatment control cycle). The results showed that LUF syndrome recurred in only 3 cycles during the G-CSF treatment cycle (4.4% [3/68 cycles]), whereas LUF syndrome recurred in 13 cycles during the subsequent G-CSF nontreatment control cycle (19.1% [13/68 cycles]). The additional use of G-CSF significantly prevented the onset of LUF syndrome during ovulation induction (P = 0.013, McNemar test). No serious adverse reactions because of the administration of G-CSF were observed. In conclusion, our findings indicate that G-CSF may become a useful therapy for LUF syndrome. PMID- 26518993 TI - A new responder criterion (relative effect per patient (REPP) > 0.2) externally validated in a large total hip replacement multicenter cohort (EUROHIP). AB - OBJECTIVE: To validate a new method to identify responders (relative effect per patient (REPP) >0.2) using the OMERACT-OARSI criteria as gold standard in a large multicentre sample. METHOD: The REPP ([score before - after treatment]/score before treatment) was calculated for 845 patients of a large multicenter European cohort study for THR. The patients with a REPP >0.2 were defined as responders. The responder rate was compared to the gold standard (OMERACT-OARSI criteria) using receiver operator characteristic (ROC) curve analysis for sensitivity, specificity and percentage of appropriately classified patients. RESULTS: With the criterion REPP>0.2 85.4% of the patients were classified as responders, applying the OARSI-OMERACT criteria 85.7%. The new method had 98.8% sensitivity, 94.2% specificity and 98.1% of the patients were correctly classified compared to the gold standard. CONCLUSION: The external validation showed a high sensitivity and also specificity of a new criterion to identify a responder compared to the gold standard method. It is simple and has no uncertainties due to a single classification criterion. PMID- 26518994 TI - Body composition is more closely related to the development of knee osteoarthritis in women than men: a cross-sectional study using the Fifth Korea National Health and Nutrition Examination Survey (KNHANES V-1, 2). AB - OBJECTIVE: To evaluate the association between knee osteoarthritis (OA) and body composition parameters, and to analyze the correlations of both obesity and lower extremity muscle mass with radiographic knee OA in relation to sex. METHODS: This was a cross-sectional study using data on body composition parameters measured using dual energy X-ray absorptiometry in 4246 participants in the Fifth Korea National Health and Nutrition Examination Survey. The relationships between knee OA and body composition parameters were evaluated. The associations between knee OA and the four subgroups corresponding to obesity and muscle mass percentage in both lower extremities were analyzed separately for each sex. RESULTS: The lower extremity muscle mass showed a decreasing trend, while fat parameters showed an increasing linear trend (P for trend <0.05) with increasing severity of knee OA in women. The odds ratio of each quarter percentile group (25 percentile) for fat parameters showed an increasing trend, while that of the lower extremity muscle mass showed a decreasing linear trend in relation to knee OA in women (P for trend < 0.05). In women, low percentage of lower extremity muscle mass was more associated with knee OA regardless of obesity (P < 0.05). However, there were no associations between all body composition parameters and knee OA in men. CONCLUSION: In women, high fat mass and low lower extremity muscle mass were associated with presence and severity of knee OA. Lower extremity muscle mass was more closely correlated with knee OA than obesity in women. PMID- 26518995 TI - Coincident diabetes mellitus modulates Th1-, Th2-, and Th17-cell responses in latent tuberculosis in an IL-10- and TGF-beta-dependent manner. AB - Type 2 diabetes mellitus (DM) is a risk factor for the development of active tuberculosis (TB), although its role in the TB-induced responses in latent TB (LTB) is not well understood. Since Th1, Th2, and Th17 responses are important in immunity to LTB, we postulated that coincident DM could alter the function of these CD4(+) T-cell subsets. To this end, we examined mycobacteria-induced immune responses in the whole blood of individuals with LTB-DM and compared them with responses of individuals without DM (LTB-NDM). T-cell responses from LTB-DM are characterized by diminished frequencies of mono- and dual-functional CD4(+) Th1, Th2, and Th17 cells at baseline and following stimulation with mycobacterial antigens-purified protein derivative, early secreted antigen-6, and culture filtrate protein-10. This modulation was at least partially dependent on IL-10 and TGF-beta, since neutralization of either cytokine resulted in significantly increased frequencies of Th1 and Th2 cells but not Th17 cells in LTB-DM but not LTB individuals. LTB-DM is therefore characterized by diminished frequencies of Th1, Th2, and Th17 cells, indicating that DM alters the immune response in latent TB leading to a suboptimal induction of protective CD4(+) T-cell responses, thereby providing a potential mechanism for increased susceptibility to active disease. PMID- 26518996 TI - Meralgia paresthetica successfully treated with topical 0.1% tacrolimus: a case report. PMID- 26518997 TI - Validating the diagnostic code for acne in a tertiary care dermatology centre. AB - BACKGROUND: Administrative databases provide valuable patient data and are used to conduct population-based studies. However, no studies have been conducted to validate the codes for dermatological conditions. OBJECTIVE: To evaluate the validity of ICD 9 code 706 for acne. METHODS: This was a retrospective chart review of patients seen in dermatology clinics at Sunnybrook Health Sciences Centre between March 1 and May 31, 2013. The billing code for a clinic visit was compared to the diagnosis documented in the medical chart. RESULTS: There were 4,248 participants; 201 with an ICD-9 code of acne. This code had a PPV and sensitivity with 95% confidence intervals (CI) of 84.58% (78.67-89.13%) and 86.29% (80.51-90.62%), respectively. The specificity was 99.20% (98.86-99.45%). CONCLUSIONS: We showed that ICD-9 code 706 can be used to accurately identify patients with acne in a dermatology setting. This information can be applied to future epidemiologic studies. PMID- 26518998 TI - The Region of Difference Four is a Robust Genetic Marker for Subtyping Mycobacterium caprae Isolates and is Linked to Spatial Distribution of Three Subtypes. AB - Alpine Mycobacterium caprae isolates found in cattle and red deer display at least three genetic variations in the region of difference four (RD4) that can be used for further differentiation of the isolates into the subtypes 'Allgau', 'Karwendel' and 'Lechtal'. Each genomic subtype is thereby characterized by a specific nucleotide deletion pattern in the 12.7-kb RD4 region. Even though M. caprae infections are frequently documented in cattle and red deer, little is known about the transmission routes. Hence, robust markers for M. caprae subtyping are needed to gain insight into the molecular epidemiology. For this reason, a rapid and robust multiplex PCR was developed for the simultaneous detection of three M. caprae RD4 subtypes and was used to subtype a total number of 241 M. caprae isolates from animals (145 cattle, 95 red deer and one fox) from Bavaria and Austria. All three subtypes occur spatially distributed and are found in cattle and in red deer suggesting transmission between the two species. As subtypes are genetically stable in both species it is hypothesized that the described genetic variations developed within the host due to 'within-host replication'. The results of this study recommend the genomic RD4 region as a reliable diagnostic marker for M. caprae subtype differentiation. PMID- 26518999 TI - [Pain in the elderly: Quality of life, functionality and associated factors. SABE Study, Bogota, Colombia]. AB - OBJECTIVE: To determine the impact of pain on the quality of life in older adults and its association with functionality. MATERIALS AND METHODS: Data was taken from SABE Bogota study. A cross-sectional study was carried out during 2012, interviewing 2,000 individuals of 60 years and older, as a probabilistic cluster and representative sample. The variable 'presence of pain' to was used to identify associations with sociodemographic factors, self-rated health, comorbidities, functional status, cognitive status, and quality of life. The latter was estimated using a visual analogue scale of the EuroQOL tool (EQ-VAS). RESULTS: The majority of older adults were women (63.4%); the mean age was 71.17 years (SD=8.05), with a higher frequency of individuals in the age group between 60 and 69years (48%). When comparing groups with pain vs. no pain, significantly lower scores were found in the group with pain (P<.001) in both the functionality and quality of life EQ-VAS scales. The strongest associations with pain were: joint diseases (OR: 3.08 [2.24-4.23]), severe depression (OR: 2.80 [1.63-4.79]) and functional impairment of the Basic Activities of Daily Living (BADL) (OR: 2.45 [1.31-4.58]). CONCLUSIONS: Pain negatively impacts the functional independence and the perception of the quality of life in older adults, predisposing them to adverse outcomes. PMID- 26519000 TI - Hospital-level Variation in the Quality of Benign Inpatient Urologic Surgery. AB - OBJECTIVE: To examine hospital-level variation in outcomes following benign urologic surgeries given that hospital-level variation in surgical outcomes can portend quality and appropriateness of care concerns and identify quality improvement opportunities in perioperative care. MATERIALS AND METHODS: Using the Washington State Comprehensive Hospital Abstract Reporting System, we identified patients who underwent transurethral resection of the prostate (TURP), percutaneous nephrostolithotomy (PCNL), and pyeloplasty from 2003 to 2008. We classified prolonged postoperative length of stay (LOS) as that exceeding the 75th percentile, and we measured the rate of Agency for Healthcare Quality Patient Safety Indicators, readmissions, and death. We calculated hospital specific observed-to-expected event rates using random effects multilevel multivariable models adjusted for age and comorbidity. RESULTS: We identified 6699 TURP patients at 54 hospitals, 2541 PCNL patients at 45 hospitals, and 584 pyeloplasty patients at 36 hospitals. Complication rates were highest after PCNL (22.9% prolonged LOS vs 17.3% for TURP and 13.9% for pyeloplasty, P < .001; 3.4% 90-day mortality vs 0.6% for TURP and 0% for pyeloplasty). Hospital-level variation was most substantial for LOS after TURP and pyeloplasty (8.1% and 14.3% of variance in prolonged LOS, respectively). CONCLUSION: Hospital-level variation is common after benign inpatient urologic surgeries and may relate to difference in perioperative provider practice patterns. The morbidity of PCNL in this study was higher than expected and merits further investigation. PMID- 26519001 TI - Abnormal Expression of Sg I is Closely Related to Seminal Vesiculitis. AB - OBJECTIVE: To investigate firstly the relationship between semenogelin I (Sg I) expression and seminal vesiculitis. Seminal vesiculitis is one of the most common diseases in male urogenital system. However, the cause and the pathogenesis of seminal vesiculitis remain unknown. Sg I, mainly synthesized and secreted by seminal vesicle, is abundant in human seminal plasma and has antibacterial activity. MATERIALS AND METHODS: Tissue samples were collected from 15 normal cases and 28 patients with seminal vesiculitis. Reverse transcription-polymerase chain reaction was performed to detect the expression difference of Sg I messenger ribonucleic acid (RNA) between normal seminal vesicle tissues and seminal vesiculitis tissues. Immunohistochemistry was applied to detect the expression difference of Sg I protein between the 2 groups. RESULTS: Reverse transcription-polymerase chain reaction showed the expression of Sg I messenger RNA in seminal vesiculitis tissues to be significantly lower than in normal seminal vesicle tissues. In most cases with seminal vesiculitis (78.6%), the same result was observed upon immunohistochemical analysis at the protein level. CONCLUSION: Abnormal expression of Sg I is closely related to seminal vesiculitis. Low expression of Sg I may play an important role in the occurrence and the development of seminal vesiculitis through weakening the antibacterial activity of seminal vesicle. PMID- 26519002 TI - WITHDRAWN: Reply. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.urology.2015.08.053. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26519003 TI - HDL-A molecule with a multi-faceted role in coronary artery disease. AB - BACKGROUND: High density lipoprotein cholesterol (HDL-C) is popularly known as "good cholesterol" due to its ability to protect against atherosclerosis. High density lipoprotein (HDL) is best known as a key player to promote efflux of cholesterol from cells and promote reverse cholesterol transport (RCT) which decreases the accumulation of foam cells in arterial walls. Several roles of HDL discovered recently include anti-oxidant effect, anti-inflammatory role, and anti thrombotic role, all of which potentiate the athero-protective role of HDL. METHOD: Relevant articles published in this field in various books, journals and on the websites of PubMed Central and National Library of Medicine were assessed to create a literature review article. RESULT: Besides reverse cholesterol transport, the antioxidant and anti-inflammatory properties of HDL may also play a major role in protection against development of atherosclerosis. Two different scales define the atheroprotective effects of HDL-quantity of HDL-C (measured in mg/deciliter or mmol/L) is inversely correlated with cardiovascular risk, the other is the quality or 'functionality' of HDL. CONCLUSION: The changes in HDL composition (primarily in protein components-apolipoproteins, paraoxonase etc.) can occur under pathological conditions and can affect the functionality of HDL. Thus, treatment alternatives to elevations in HDL-C must also involve strategies to maintain or enhance functionality of HDL. This literature review article discusses about the various athero-protective roles of HDL and the effects of changes in composition on its function. PMID- 26519005 TI - From autonomy to community; new perspectives on tumorigenicity and therapy resistance. AB - Subclones of cancer cells evading treatment represent the major challenge in oncology. Despite recent advances, tumors not responding to treatments are still a severe risk to cancer patients, and oncologists have, as of now, little effective therapy to offer patients with systemic cancer disease. The widely discussed cancer stem cell (CSC) paradigm was originally launched as an explanation to the existence of small cell populations resistant to therapy within the heterogeneous tumor, but has so far unfortunately, offered little concrete improvement in cancer treatment regimes. The launch of the CSC hypothesis did, however, highlight the significance of therapy targeting specific tumor-driving processes, and even more importantly, an increased awareness of a phenomenon well known to stem cell researchers; non-genetic phenotypic heterogeneity of cells with common origin. Here, the scientific background of the CSC theory is revisited and the evidence for CSCs is discussed, along with the importance of considering CSC's dependency of their habitat for survival and growth. Furthermore, recent advances in cancer cell heterogeneity and new possibilities for studying therapy responses in cell clones within the natural tumor environment using patient derived xenograft (PDX) models, are reviewed. PMID- 26519006 TI - Disabled women's attendance at community women's groups in rural Nepal. AB - There is strong evidence that participatory approaches to health and participatory women's groups hold great potential to improve the health of women and children in resource poor settings. It is important to consider if interventions are reaching the most marginalized, and therefore we examined disabled women's participation in women's groups and other community groups in rural Nepal. People with disabilities constitute 15% of the world's population and face high levels of poverty, stigma, social marginalization and unequal access to health resources, and therefore their access to women's groups is particularly important. We used a mixed methods approach to describe attendance in groups among disabled and non-disabled women, considering different types and severities of disability. We found no significant differences in the percentage of women that had ever attended at least one of our women's groups, between non disabled and disabled women. This was true for women with all severities and types of disability, except physically disabled women who were slightly less likely to have attended. Barriers such as poverty, lack of family support, lack of self-confidence and attendance in many groups prevented women from attending groups. Our findings are particularly significant because disabled people's participation in broader community groups, not focused on disability, has been little studied. We conclude that women's groups are an important way to reach disabled women in resource poor communities. We recommend that disabled persons organizations help to increase awareness of disability issues among organizations running community groups to further increase their effectiveness in reaching disabled women. PMID- 26519007 TI - Inflammatory and fatty lesions in the spine and sacroiliac joints on whole-body MRI in early axial spondyloarthritis--3-Year data of the ESTHER trial. AB - OBJECTIVE: To assess the relationship between active inflammation and development of chronic lesions in the spine and sacroiliac (SI)-joints on MRI in early axial spondyloarthritis (SpA) during treatment with etanercept. METHODS: Here, we analyzed the 41 patients of the ESTHER trial, who were treated with etanercept over 3 continuous years and of whom MRIs were available for baseline, year 2, and year 3. MRIs were scored for active inflammation (STIR sequences) and chronic changes (T1 sequence) such as fatty lesions, erosions, and ankylosis in the SI joints and spinal vertebral units (VUs). RESULTS: The mean fatty lesion scores increased between baseline and year 2 both in the spine (1.13 at baseline vs. 1.40 at year 2, p = 0.0254) and in the SI joints (4.76 at baseline vs. 5.46 at year 2, p = 0.27), but we found no further increase of the fatty lesion score between years 2 and 3. New fatty lesions at years 2 and 3 developed nearly exclusively in SI joint quadrants and VUs in which active MRI inflammation was present at baseline. Fatty lesions disappeared only in 3 SI joint quadrants and in none of VUs at years 2 and 3. Erosion and ankylosis scores remained unchanged. CONCLUSION: Our data indicate a relationship between the presence of active MRI inflammation and the new development of fatty lesions. Furthermore, there was no increase of fatty lesions during continuous treatment of axial SpA patients with etanercept after successful suppression of active inflammation. Whether this is predictive of stopping radiographic progression needs to be further investigated. PMID- 26519008 TI - Unraveling the intraguild competition between Oscheius spp. nematodes and entomopathogenic nematodes: Implications for their natural distribution in Swiss agricultural soils. AB - Entomopathogenic nematodes (EPN) are excellent biological control agents to fight soil-dwelling insect pests. In a previous survey of agricultural soils of Switzerland, we found mixtures of free-living nematodes (FLN) in the genus Oscheius, which appeared to be in intense competition with EPN. As this may have important implications for the long-term persistence of EPN, we studied this intraguild competition in detail. We hypothesized that (i) Oscheius spp. isolates act as scavengers rather than entomopathogens, and (ii) cadavers with relatively small numbers of EPN are highly suitable resources for Oscheius spp. reproduction. To study this, we identified Oscheius spp. isolated from Swiss soils, quantified the outcome of EPN/Oscheius competition in laboratory experiments, developed species-specific primers and probe for quantitative real time PCR, and evaluated their relative occurrence in the field in the context of the soil food web. Molecular analysis (ITS/D2D3) identified MG-67/MG-69 as Oscheius onirici and MG-68 as O. tipulae (Dolichura-group). Oscheius spp. indeed behaved as scavengers, reproducing in ~64% of frozen-killed cadavers from controlled experiments. Mixed infection in the laboratory by Oscheius spp. with low (3 IJs) or high (20 IJs) initial EPN numbers revealed simultaneous reproduction in double-exposed cadavers which resulted in a substantial reduction in the number of EPN progeny from the cadaver. This effect depended on the number of EPN in the initial inoculum and differed by EPN species; Heterorhabditis megidis was better at overcoming competition. This study reveals Oscheius spp. as facultative kleptoparasites that compete with EPN for insect cadavers. Using real time qPCR, we were able to accurately quantify this strong competition between FLN and EPN in cadavers that were recovered after soil baiting (~86% cadavers with >50% FLN production). The severe competition within the host cadavers and the intense management of the soils in annual crops readily explain the low EPN numbers in Swiss field samples. The developed molecular tools can be used to elucidate the extent to which the competitive interactions affect EPN populations. This can help to develop strategies to achieve good persistence and natural EPN recycling, in particular in systems where native EPN levels are low, such as annual crops. PMID- 26519009 TI - Psychosocial work experiences related to health: A study of Lithuanian hospital employees. AB - BACKGROUND: Research in the area of workplace health promotion from a salutogenic perspective is lacking in Eastern Europe. OBJECTIVE: To evaluate the relationship between psychosocial work environment and health from a salutogenic perspective among Lithuanian hospital workers. METHODS: Using a cross-sectional design a questionnaire was distributed to staff in a large hospital in Lithuania. Out of 811 employees, 714 completed the survey: 151 physicians, 449 nurses and 114 other staff members (e.g., psychologists, technicians, therapists). A response rate of 88.0% was achieved. The Work Experience Measurement Scale (WEMS) and the Salutogenic Health Indicator Scale (SHIS) were linguistically adapted and used for the first time in a Lithuanian context. Logistic and multiple linear regression models were used for the analyses. RESULTS: Supportive working conditions, positive internal work experiences and time experience contributed the most to good health, defined as a high SHIS index. Having an executive post was significantly related to good work experiences, i.e. a high WEMS score, while being at the age of 40-54 years was associated with a low WEMS score. Physicians had the highest score on supportive working conditions; while nurses had the lowest scores on autonomy. CONCLUSIONS: A salutogenic approach enables an organisation to identify how to improve working conditions for the employees by focusing on possibilities and resources. Individual activities for workplace health promotion among different work groups seem necessary. PMID- 26519011 TI - Living the academic life: A model for work-family conflict. AB - BACKGROUND: Work-family conflict (WFC) is an inter-role conflict, which suggests that fulfilling expectations of family roles makes it difficult to satisfy expectations of work roles, and vice versa. Living an academic life includes balancing multiple work demands and family responsibilities, which may generate WFC for many faculty members. Researchers have emphasized the need for further studies of how faculty integrate work and family demands. OBJECTIVE: This study explores WFC among Iranian faculty. We examine relationships among work hours, time spent with family, work-interference with family (WIF), family-interference with work (FIW), and job satisfaction. METHODS: Faculty members from 25 Iranian public universities completed a questionnaire. Structural equation modeling was used to test hypotheses in a single model. RESULTS: Findings suggest a positive relationship between faculty weekly work hours and WIF, and between time spent with family and FIW. WIF correlated negatively with job satisfaction, and work hours correlated positively with job satisfaction. Time spent with family and FIW had no influence on job satisfaction, and spouse employment moderated the relationship between WIF and job satisfaction. CONCLUSIONS: Findings have implications for human resources and organizational development professionals seeking insight into how faculty members and other knowledge workers experience work-family interrelationships. PMID- 26519010 TI - Global absenteeism and presenteeism in mental health patients referred through primary care. AB - BACKGROUND: Disability from mental health (MH) symptoms impairs workers' functioning. Most of what is known about the MH of workers relates to their experiences after intervention or work absence. OBJECTIVE: To profile the clinical symptoms, self-reported absenteeism and presenteeism and treatment response of workers with MH symptoms at the point of accessing MH care and compare the characteristics of patients referred with or without problems related to work. METHODS: Analysis of 11 years of patient data collected in a Shared Mental Health Care (SMHC) clinic referred within a primary care setting in Ontario, Canada. Multiple regression with MH disorders was used to predict absenteeism and presenteeism. Absenteeism and presenteeism were assessed using the 12-item self-administered version of the WHO-DAS 2. Symptom profiles were assessed with the Patient Health Questionnaire (PHQ). RESULTS: Some psychiatric disorders (depression, somatization, anxiety) contributed more to predicting absenteeism and presenteeism than others. Patients referred with work-related problems differed from the general SMHC population in terms of sex and type and number of symptoms. Treatment response was good in both groups after a mean of three treatment visits. CONCLUSIONS: Patients with work-related mental health complaints formed a distinct clinical group that benefitted equally from the intervention(s) provided by SMHC. PMID- 26519012 TI - Work experiences among attendees of day centres for people with psychiatric disabilities. AB - BACKGROUND: It is possible that people with psychiatric disabilities who visit day centres have previous work experiences that may be seen as resources for their current engagement in day centre activities. Research in this respect seems to lack, however. OBJECTIVE: To investigate work experiences among attendees at day centres for people with psychiatric disabilities and relationships with current type of day centre (work-oriented, meeting place-oriented or mixed), engagement in day centre activities, motivation and socio-demographic and health related factors. METHODS: Seventy-seven attendees responded to questionnaires. Global Assessment of Functioning, GAF, was also used. Work was categorised into Group I (professionals, semi-professionals), Group II (clerical support, services workers) and Group III (e.g. craft workers, elementary occupations). RESULTS: Almost everyone had previously had open-market employment; more than half for >= 10 years. Group I was more common in mixed centres, Group II in meeting place oriented ones and Group III in work-oriented ones. Group I more frequently had college degree and was rated high on GAF functioning. Women were over-represented in Group II, and men in Group III and in meeting place-oriented centres. Attending mixed centres was more likely when having a college degree, scoring high on GAF functioning and being highly engaged in activities. Attendees at work oriented day centres were characterised by being motivated for spending time alone and reporting a diagnosis of psychosis. CONCLUSIONS: The participants had unused working capacity. No clear-cut relationships were found between work experiences and the investigated correlates. PMID- 26519013 TI - Workplace exercise for changing health behavior related to physical activity. AB - BACKGROUND: Physical Activity in the workplace has received special attention from researchers who are looking to promote lifelong health and well-being. The workplace is being investigated as a possible place to assess and create strategies to help people to become healthier. The transtheoretical model and stages of change has been adapted as a tool to assess the stages of behavioral change towards exercising. OBJECTIVE: To assess the change in health behavior following a three-month exercise program based in the workplace. METHODS: A quasi experimental study design was used in which 165 employees participated in the study. An intervention program of workplace exercise was applied for three months. Participants were assessed through the transtheoretical model and stages of change questionnaire before and after intervention to understand changes in their position on the behavioral change continuum. RESULTS: The number of employees who were physically active increased after the workplace exercise intervention (13.9% , 95% CI 9.5 to 20.1; P = 0.009). There was a significant decrease in the proportion of employees in the pre-contemplation stage (-6.1% , 95% CI 3.3 to 10.8; P = 0.045) and contemplation stage (-11.5% , 95% CI 7.5 to 17.3; P = 0.017), and a significant increase in the action stage (10.9% , 95% CI 7.0 to 16.6; P = 0.003). CONCLUSIONS: Engaging in workplace exercise has a significant positive effect on health behavior and willingness to become more physically active. PMID- 26519014 TI - Informal employment in high-income countries for a health inequalities research: A scoping review. AB - BACKGROUND: Informal employment (IE) is one of the least studied employment conditions in public health research, mainly due to the difficulty of its conceptualization and its measurement, producing a lack of a unique concept and a common method of measurement. OBJECTIVE: The aim of this review is to identify literature on IE in order to improve its definition and methods of measurement, with special attention given to high-income countries, to be able to study the possible impact on health inequalities within and between countries. METHODS: A scoping review of definitions and methods of measurement of IE was conducted reviewing relevant databases and grey literature and analyzing selected articles. RESULTS: We found a wide spectrum of terms for describing IE as well as definitions and methods of measurement. We provide a definition of IE to be used in health inequalities research in high-income countries. Direct methods such as surveys can capture more information about workers and firms in order to estimate IE. CONCLUSIONS: These results can be used in further investigations about the impacts of this IE on health inequalities. Public health research must improve monitoring and analysis of IE in order to know the impacts of this employment condition on health inequalities. PMID- 26519015 TI - Managing workplace health promotion in municipal organizations: The perspective of senior managers. AB - BACKGROUND: Previous research indicates that companies manage workplace health in various ways, but more in-depth empirical knowledge of how workplace health promotion (WHP) is managed in public sector organizations is needed. OBJECTIVE: The aim of this study was to explore how WHP is managed and incorporated into the general management system in two large Swedish municipal organizations. METHODS: A qualitative descriptive approach was used. Fourteen senior managers were purposefully selected and interviewed using semi-structured interviews. Documents were used as supplementary data. All data were analysed using qualitative content analysis. RESULTS: The management of WHP was described as a set of components that together contribute to the organization's capacity for WHP. The informants described WHP as dominated by fitness programmes and as following a problem solving cycle, in which the annual employee survey emerged as an important managerial tool. Achieving feasible WHP measures and appropriate follow-ups were described as challenges. The provision of leadership competence for WHP and use of supportive resources were described as additional components. CONCLUSIONS: The WHP management approach needs to be broadened to include work environment and organizational factors. Further integration with occupational health and safety and the general management system in the organizations is also needed. PMID- 26519016 TI - Factors discriminating employment status following in-patient evaluation among persons with schizophrenia. AB - BACKGROUND: Employment is a key element in recovery from schizophrenia. Yet 60% 80% of people with schizophrenia are not involved in work occupations. Factors influencing employment were explored mostly in community settings, while the recovery process begins already during hospitalization. OBJECTIVE: The aim of the study was to investigate parameters that can distinguish during hospitalization between people with schizophrenia who will work in competitive employment, in sheltered employment or will not work after discharge. METHODS: The research followed 104 participants from acute hospitalization to the community, six months after discharge, to obtain employment related data. The participants' cognitive abilities, schizophrenia symptoms, and functional capacity were evaluated during hospitalization. In addition, demography and illness related factors were collected. RESULTS: The results indicate that persons with different employment statuses varied in several parameters during hospitalization. However, the most effective discriminant model includes negative symptoms, functional capacity measure and the number of hospitalizations. CONCLUSIONS: The study suggests that people with different employment statuses have unique characteristics already during hospitalization. In the future, appropriate rehabilitation programs may be suggested to each group based on these characteristics to promote employment among people with schizophrenia and contribute to recovery. PMID- 26519017 TI - Production practices affecting worker task demands in concrete operations: A case study. AB - BACKGROUND: Construction work involves significant physical, mental, and temporal task demands. Excessive task demands can have negative consequences for safety, errors and production. OBJECTIVE: This exploratory study investigates the magnitude and sources of task demands on a concrete operation, and examines the effect of the production practices on the workers' task demands. METHODS: The NASA Task Load Index was used to measure the perceived task demands of two work crews. The operation involved the construction of a cast-in-place concrete building under high schedule pressures. Interviews with each crew member were used to identify the main sources of the perceived demands. Extensive field observations and interviews with the supervisors and crews identified the production practices. RESULTS: The workers perceived different level of task demands depending on their role. The production practices influenced the task demands in two ways: (1) practices related to work organization, task design, resource management, and crew management mitigated the task demands; and (2) other practices related to work planning and crew management increased the crew's ability to cope with and adapt to high task demands. CONCLUSIONS: The findings identify production practices that regulate the workers' task demands. The effect of task demands on performance is mitigated by the ability to cope with high demands. PMID- 26519018 TI - Investigation of grip and pinch strengths in Iranian adults and their correlated anthropometric and demographic factors. AB - BACKGROUND: Grip and pinch strength measurement is important for objective evaluation of the function of the upper extremities in upper limbs injuries treatment and also for ergonomists as a way of optimizing the requirements of hand tool design. OBJECTIVE: The present study was conducted to investigate the correlation of anthropometric and demographic factors with hand strength as well as to develop regression models for grip and three types of pinch strengths including Tip, Key and Palmar in Iranian adult population. METHODS: The study population consisted of 1008 Iranian adults aged 20 to 107 years. Participants were selected using a stratified random sampling method from crowded places of the cities with the highest number of Persian ethnic group. Strength measurements were undertaken according to recommendations by the American Society of Hand Therapists (ASHT). RESULTS: This study found a positive and significant correlation between all measured strengths and anthropometric factors. The regression equations of grip and pinch strengths were developed for dominant and non-dominant hands. CONCLUSIONS: The results of this study provided more information about correlated factors of grip and pinch strengths. The regression equations developed in this research are applicable to clinical treatment and ergonomics programs. PMID- 26519019 TI - Emergency department nurses' experiences of occupational stress: A qualitative study from a public hospital in Bangkok, Thailand. AB - BACKGROUND: Occupational stress has been a health-related issue among nurses for many decades. Emergency department nurses are frequently confronted with occupational stress in their workplace; in particular, they encounter stressful situations and unpredictable events. These encounters could make them feel more stressed than nurses in other departments. Research considering occupational stress from the perspective of Thai emergency department nurses is limited. OBJECTIVE: This study aimed to explore nurses' perceptions of occupational stress in an emergency department. METHODS: A qualitative approach was used to gain an understanding of nurses' experiences and perceptions regarding stress in their workplace. Semi-structured interviews were used for data collection. Twenty-one emergency department nurses working in a public hospital in Thailand were interviewed, and the data were analyzed using content analysis. RESULTS: The findings comprised three themes: (1) perceived stress, (2) consequences of stress, and (3) stress management. CONCLUSIONS: The results of this study can be used by hospital management to help them adopt effective strategies, such as support programs involving co-workers/supervisors, to decrease occupational stress among emergency department nurses. Future research that explores each of the themes found in this study could offer a more comprehensive understanding of nurses' occupational stress in the emergency department. PMID- 26519020 TI - High prevalence of sedentary risk factors amongst university employees and potential health benefits of campus workplace exercise intervention. AB - BACKGROUND: Sedentariness and physical inactivity are often reported within white collar workers, including university campus employees. However, the prevalence of the associated sedentary risk factors and risk reduction intervention strategies within a university campus workplace are less known. OBJECTIVE: This study investigates whether the prevalence of sedentary risk factors within university campus employees could be reduced with a campus based exercise intervention. METHODS: 56 UK university employees (age = 50.7 +/- 10.2, stature = 1.68.8 +/- 8.6, body mass = 73.9 +/- 15.1) were tested for body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP) and maximal cardiorespiratory capacity (VO2max). The prevalence was analyzed across genders and job roles. An exercise intervention followed for the sedentary employees involving walking and running for 25 min twice/week for 10 weeks at an intensity corresponding to individual's ventilatory threshold (VT). RESULTS: The university workplace demonstrated a prevalence of higher BMI, SBP and DBP than the recommended healthy thresholds, with gender having a significant effect. Males' BMI, SBP and DBP were higher than in females (p < 0.05) and males' VO2max was lower than the recommended healthy thresholds. The exercise training intervention significantly improved VO2max, VT and VT velocity in both genders (all p < 0.05) with both groups meeting the recommended thresholds following the intervention. CONCLUSIONS: University campus employees have a high prevalence of sedentary risk factors across different genders and job roles. These risks can be reduced by an exercise-based intervention administered within the campus workplace, which should be considered in university workplace policies. PMID- 26519021 TI - The decision, implementation and assessment of a credit-bearing activity class by faculty in residence: A case study. AB - This case study reports on a programmatic decision to require a credit-bearing course that was made by Faculty in Residence (FIR), including its implementation and results over a two-year period from 2010-2012. The focus is on FIR and on the impact of their decision upon the students enrolled in their Living Learning Communities (LLCs). The credit-bearing course was a Kinesiology Activities class taken by all seven LLCs at Boise State University. Anonymous feedback from students was obtained via end of semester surveys; results were used to improve the course. Survey feedback was analyzed to assess the value students perceived to have gained from the course. The majority of students reported gaining value from the class. Students noted that it positively affected their time management/personal accountability, that it decreased their stress level and that it increased their awareness of the Recreational Center offerings. Some students were critical of the course, reporting little to no value or even resentment about the course requirement. The decision, implementation and improvements of the course required faculty leadership and full participation of all LLCs; perceptions of the FIR in terms of the effects of adding the required course on their LLC are reported. PMID- 26519022 TI - Expression and purification of the matrix protein of Nipah virus in baculovirus insect cell system. AB - Nipah virus (NiV) causes fatal respiratory illness and encephalitis in humans and animals. The matrix (M) protein of NiV plays an important role in the viral assembly and budding process. Thus, an access to the NiV M protein is vital to the design of viral antigens as diagnostic reagents. In this study, recombinant DNA technology was successfully adopted in the cloning and expression of NiV M protein. A recombinant expression cassette (baculovirus expression vector) was used to encode an N-terminally His-tagged NiV M protein in insect cells. A time course study demonstrated that the highest yield of recombinant M protein (400 500 MUg) was expressed from 107 infected cells 3 days after infection. A single step purification method based on metal ion affinity chromatography was established to purify the NiV M protein, which successfully yielded a purity level of 95.67% and a purification factor of 3.39. The Western blotting and enzyme-linked immunosorbent assay (ELISA) showed that the purified recombinant M protein (48 kDa) was antigenic and reacted strongly with the serum of a NiV infected pig. PMID- 26519023 TI - Inositol-1,4,5-trisphosphate-3-kinase-A controls morphology of hippocampal dendritic spines. AB - Long-lasting synaptic plasticity is often accompanied by morphological changes as well as formation and/or loss of dendritic spines. Since the spine cytoskeleton mainly consists of actin filaments, morphological changes are primarily controlled by actin binding proteins (ABPs). Inositol-1,4,5-trisphosphate-3 kinase-A (ITPKA) is a neuron-specific, actin bundling protein concentrated at dendritic spines. Here, we demonstrate that ITPKA depletion in mice increases the number of hippocampal spine-synapses while reducing average spine length. By employing actin to ABP ratios similar to those occurring at post synaptic densities, in addition to cross-linking actin filaments, ITPKA strongly inhibits Arp2/3-complex induced actin filament branching by displacing the complex from F actin. In summary, our data show that in vivo ITPKA negatively regulates formation and/or maintenance of synaptic contacts in the mammalian brain. On the molecular level this effect appears to result from the ITPKA-mediated inhibition of Arp2/3-complex F-actin branching activity. PMID- 26519024 TI - Dental erosion in patients seeking treatment for gastrointestinal complaints: a case series. AB - INTRODUCTION: Eating disorders which embrace anorexia nervosa, bulimia nervosa, and eating disorders not otherwise specified can be life-threatening due to general medical complications; however, the diagnosis of eating disorder is often delayed due to a low suspicion index. Gastroenterologists are health care providers who may come into contact with patients with undiagnosed eating disorders; it has been previously demonstrated that patients with eating disorders frequently have a significant association with functional dyspepsia. Signs of dental erosion have been described in patients with eating disorders; hence, they may help to identify eating disorders in patients who present with functional dyspepsia and deny having an eating disorder. CASE PRESENTATION: In this report we describe three cases (a 25-year-old white woman, a 24-year-old white woman, and a 40-year-old white man) with undiagnosed eating disorders, in which a more comprehensive approach, such as the recognition of dental erosion joined with a careful gastrointestinal investigation, was performed to reach a final diagnosis of an eating disorder. CONCLUSIONS: The screening for dental erosion in patients seeking or receiving medical treatment for dyspeptic symptoms in a gastrointestinal out-patient clinic could be an aid for gastroenterologists to recognize the presence of an underlying eating disorder. A close collaboration with dentists, in addition to psychiatrists, could provide a more favorable treatment outcome. PMID- 26519025 TI - External prolonged electrocardiogram monitoring in unexplained syncope and palpitations: results of the SYNARR-Flash study. AB - AIMS: SYNARR-Flash study (Monitoring of SYNcopes and/or sustained palpitations of suspected ARRhythmic origin) is an international, multicentre, observational, prospective trial designed to evaluate the role of external 4-week electrocardiogram (ECG) monitoring in clinical work-up of unexplained syncope and/or sustained palpitations of suspected arrhythmic origin. METHODS AND RESULTS: Consecutive patients were enrolled within 1 month after unexplained syncope or palpitations (index event) after being discharged from emergency room or hospitalization without a conclusive diagnosis. A 4-week ECG monitoring was obtained by external high-capacity loop recorder (SpiderFlash-T((r)), Sorin) storing patient-activated and auto-triggered tracings. Diagnostic monitorings included (i) conclusive events with reoccurrence of syncope or palpitation with concomitant ECG recording (with/without arrhythmias) and (ii) events with asymptomatic predefined significant arrhythmias (sustained supraventricular or ventricular tachycardia, advanced atrio-ventricular block, sinus bradycardia <30 b.p.m., pauses >6 s). SYNARR-Flash study enrolled 395 patients (57.7% females, 56.9 +/- 18.7 years, 28.1% with syncope, and 71.9% with palpitations) from 10 European centres. For syncope, the 4-week diagnostic yield was 24.5%, and predictors of diagnostic events were early start of recording (0-15 vs. >15 days after index event) (OR 6.2, 95% CI 1.3-29.6, P = 0.021) and previous history of supraventricular arrhythmias (OR 3.6, 95% CI 1.4-9.7, P = 0.018). For palpitations, the 4-week diagnostic yield was 71.6% and predictors of diagnostic events were history of recurrent palpitations (P < 0.001) and early start of recording (P = 0.001). CONCLUSION: The 4-week external ECG monitoring can be considered as first-line tool in the diagnostic work-up of syncope and palpitation. Early recorder use, history of supraventricular arrhythmia, and frequent previous events increased the likelihood of diagnostic events during the 4-week external ECG monitoring. PMID- 26519026 TI - Endogenous angiotensin-(1-7)/Mas receptor/NO pathway mediates the cardioprotective effects of pacing postconditioning. AB - The aim of the present study was to investigate the role of the ANG-(1-7) receptor (Mas) and nitric oxide (NO) in pacing postconditiong (PPC)-mediated cardioprotection against ischemia-reperfusion injury. Cardiac contractility and hemodynamics were assessed using a modified Langendorff system, cardiac damage was assessed by measuring infarct size and creatinine kinase levels, and levels of phosphorylated and total endothelial NO synthase (eNOS) were determined by Western blot analysis. Isolated hearts were subjected to 30 min of regional ischemia, produced by fixed position ligation of the left anterior descending coronary artery, followed by 30 min of reperfusion (n = 6). Hearts were also subjected to PPC (three cycles of 30 s of left ventricular pacing alternated with 30 s of right atrial pacing) and/or treated during reperfusion with ANG-(1-7), N(G)-nitro-l-arginine methyl ester, or the Mas antagonist (d-Ala7)-ANG I/II (1 7). The PPC-mediated improvement in cardiac contractility and hemodyanamics, cardiac damage, and eNOS phosphorylation were significantly attenuated upon treatment with (d-Ala7)-ANG I/II (1-7) or N(G)-nitro-l-arginine methyl ester. Treatment with ANG-(1-7) improved cardiac function and reduced infarct size and creatinine kinase levels; however, the effects of ANG-(1-7) were not additive with PPC. In conclusion, these data provide novel insights into the cardioprotective mechanisms of PPC in that they involve the Mas receptor and eNOS and further suggest a potential therapeutic role for ANG-(1-7) in cardiac ischemic injury. PMID- 26519027 TI - Damaging effects of hyperglycemia on cardiovascular function: spotlight on glucose metabolic pathways. AB - The incidence of cardiovascular complications associated with hyperglycemia is a growing global health problem. This review discusses the link between hyperglycemia and cardiovascular diseases onset, focusing on the role of recently emerging downstream mediators, namely, oxidative stress and glucose metabolic pathway perturbations. The role of hyperglycemia-mediated activation of nonoxidative glucose pathways (NOGPs) [i.e., the polyol pathway, hexosamine biosynthetic pathway, advanced glycation end products (AGEs), and protein kinase C] in this process is extensively reviewed. The proposal is made that there is a unique interplay between NOGPs and a downstream convergence of detrimental effects that especially affect cardiac endothelial cells, thereby contributing to contractile dysfunction. In this process the AGE pathway emerges as a crucial mediator of hyperglycemia-mediated detrimental effects. In addition, a vicious metabolic cycle is established whereby hyperglycemia-induced NOGPs further fuel their own activation by generating even more oxidative stress, thereby exacerbating damaging effects on cardiac function. Thus NOGP inhibition, and particularly that of the AGE pathway, emerges as a novel therapeutic intervention for the treatment of cardiovascular complications such as acute myocardial infarction in the presence hyperglycemia. PMID- 26519028 TI - Heterozygous deletion of sarcolipin maintains normal cardiac function. AB - Sarcolipin (SLN) is a small proteolipid and a regulator of sarco(endo)plasmic reticulum Ca(2+)-ATPase. In heart tissue, SLN is exclusively expressed in the atrium. Previously, we inserted Cre recombinase into the endogenous SLN locus by homologous recombination and succeeded in generating SLN-Cre knockin (Sln(Cre/+)) mice. This Sln(Cre/+) mouse can be used to generate an atrium-specific gene targeting mutant, and it is based on the Cre-loxP system. In the present study, we used adult Sln(Cre/+) mice atria and analyzed the effects of heterozygous SLN deletion by Cre knockin before use as the gene targeting mouse. Both SLN mRNA and protein levels were decreased in Sln(Cre/+) mouse atria, but there were no morphological, physiological, or molecular biological abnormalities. The properties of contractility and Ca(2+) handling were similar to wild-type (WT) mice, and expression levels of several stress markers and sarcoplasmic reticulum related protein levels were not different between Sln(Cre/+) and WT mice. Moreover, there was no significant difference in sarco(endo)plasmic reticulum Ca(2+)-ATPase activity between the two groups. We showed that Sln(Cre/+) mice were not significantly different from WT mice in all aspects that were examined. The present study provides basic characteristics of Sln(Cre/+) mice and possibly information on the usefulness of Sln(Cre/+) mice as an atrium-specific gene targeting model. PMID- 26519029 TI - Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction. AB - The stromal cell-derived factor-1 (SDF-1):CXCR4 is important in myocardial repair. In this study we tested the hypothesis that early upregulation of cardiomyocyte CXCR4 (CM-CXCR4) at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1:CXCR4 axis and improve cardiac repair. The effects of the hypoxia inducible factor (HIF) hydroxylase inhibitor dimethyloxalylglycine (DMOG) on CXCR4 expression was tested on H9c2 cells. In mice a myocardial infarction (MI) was produced in CM-CXCR4 null and wild-type controls. Mice were randomized to receive injection of DMOG (DMOG group) or saline (Saline group) into the border zone after MI. Protein and mRNA expression of CM-CXCR4 were quantified. Echocardiography was used to assess cardiac function. During hypoxia, DMOG treatment increased CXCR4 expression of H9c2 cells by 29 and 42% at 15 and 24 h, respectively. In vivo DMOG treatment increased CM CXCR4 expression at 15 h post-MI in control mice but not in CM-CXCR4 null mice. DMOG resulted in increased ejection fraction in control mice but not in CM-CXCR4 null mice 21 days after MI. Consistent with greater cardiomyocyte survival with DMOG treatment, we observed a significant increase in cardiac myosin-positive area within the infarct zone after DMOG treatment in control mice, but no increase in CM-CXCR4 null mice. Inhibition of cardiomyocyte death in MI through the stabilization of HIF-1alpha requires downstream CM-CXCR4 expression. These data suggest that engagement of the SDF-1:CXCR4 axis through the early upregulation of CM-CXCR4 is a strategy for improving cardiac repair after MI. PMID- 26519030 TI - MPST but not CSE is the primary regulator of hydrogen sulfide production and function in the coronary artery. AB - Hydrogen sulfide (H2S) has emerged as an important gasotransmitter in the vasculature. In this study, we tested the hypothesis that H2S contributes to coronary vasoregulation and evaluated the physiological relevance of two sources of H2S, namely, cystathionine-gamma-lyase (CSE) and 3-mercaptypyruvate sulfertransferase (MPST). MPST was detected in human coronary artery endothelial cells as well as rat and mouse coronary artery; CSE was not detected in the coronary vasculature. Rat coronary artery homogenates produced H2S through the MPST pathway but not the CSE pathway in vitro. In vivo coronary vasorelaxation response was similar in CSE knockout mice, wild-type mice (WT), and WT mice treated with the CSE inhibitor propargylglycine, suggesting that CSE-produced H2S does not have a significant role in coronary vasoregulation in vivo. Ex vivo, the MPST substrate 3-mercaptopyruvate (3-MP) and H2S donor sodium hydrosulfide (NaHS) elicited similar coronary vasoreactivity responses. Pyruvate did not have any effects on vasoreactivity. The vasoactive effect of H2S appeared to be nitric oxide (NO) dependent: H2S induced coronary vasoconstriction in the presence of NO and vasorelaxation in its absence. Maximal endothelial-dependent relaxation was intact after 3-MP and NaHS induced an increase in preconstriction tone, suggesting that endothelial NO synthase activity was not significantly inhibited. In vitro, H2S reacted with NO, which may, in part explain the vasoconstrictive effects of 3-MP and NaHS. Taken together, these data show that MPST rather than CSE generates H2S in coronary artery, mediating its effects through direct modulation of NO. This has important implications for H2S-based therapy in healthy and diseased coronary arteries. PMID- 26519032 TI - Lymph flow pattern in pleural diaphragmatic lymphatics during intrinsic and extrinsic isotonic contraction. AB - Peripheral rat diaphragmatic lymphatic vessels, endowed with intrinsic spontaneous contractility, were in vivo filled with fluorescent dextrans and microspheres and subsequently studied ex vivo in excised diaphragmatic samples. Changes in diameter and lymph velocity were detected, in a vessel segment, during spontaneous lymphatic smooth muscle contraction and upon activation, through electrical whole-field stimulation, of diaphragmatic skeletal muscle fibers. During intrinsic contraction lymph flowed both forward and backward, with a net forward propulsion of 14.1 +/- 2.9 MUm at an average net forward speed of 18.0 +/ 3.6 MUm/s. Each skeletal muscle contraction sustained a net forward-lymph displacement of 441.9 +/- 159.2 MUm at an average velocity of 339.9 +/- 122.7 MUm/s, values significantly higher than those documented during spontaneous contraction. The flow velocity profile was parabolic during both spontaneous and skeletal muscle contraction, and the shear stress calculated at the vessel wall at the highest instantaneous velocity never exceeded 0.25 dyne/cm(2). Therefore, we propose that the synchronous contraction of diaphragmatic skeletal muscle fibers recruited at every inspiratory act dramatically enhances diaphragmatic lymph propulsion, whereas the spontaneous lymphatic contractility might, at least in the diaphragm, be essential in organizing the pattern of flow redistribution within the diaphragmatic lymphatic circuit. Moreover, the very low shear stress values observed in diaphragmatic lymphatics suggest that, in contrast with other contractile lymphatic networks, a likely interplay between intrinsic and extrinsic mechanisms be based on a mechanical and/or electrical connection rather than on nitric oxide release. PMID- 26519031 TI - Myocardial steatosis as a possible mechanistic link between diastolic dysfunction and coronary microvascular dysfunction in women. AB - Women with coronary microvascular dysfunction (CMD) and no obstructive coronary artery disease (CAD) have increased rates of heart failure with preserved ejection fraction (HFpEF). The mechanisms of HFpEF are not well understood. Ectopic fat deposition in the myocardium, termed myocardial steatosis, is frequently associated with diastolic dysfunction in other metabolic diseases. We investigated the prevalence of myocardial steatosis and diastolic dysfunction in women with CMD and subclinical HFpEF. In 13 women, including eight reference controls and five women with CMD and evidence of subclinical HFpEF (left ventricular end-diastolic pressure >12 mmHg), we measured myocardial triglyceride content (TG) and diastolic function, by proton magnetic resonance spectroscopy and magnetic resonance tissue tagging, respectively. When compared with reference controls, women with CMD had higher myocardial TG content (0.83 +/- 0.12% vs. 0.43 +/- 0.06%; P = 0.025) and lower diastolic circumferential strain rate (168 +/- 12 vs. 217 +/- 15%/s; P = 0.012), with myocardial TG content correlating inversely with diastolic circumferential strain rate (r = -0.779; P = 0.002). This study provides proof-of-concept that myocardial steatosis may play an important mechanistic role in the development of diastolic dysfunction in women with CMD and no obstructive CAD. Detailed longitudinal studies are warranted to explore specific treatment strategies targeting myocardial steatosis and its effect on diastolic function. PMID- 26519033 TI - Autonomic nervous system activity and inflammation: good ideas, good treatments, or both? PMID- 26519035 TI - Disability Diversity Training in the Workplace: Systematic Review and Future Directions. AB - Purpose Misinformation and negative attitudes toward disability contribute to lower employment rates among people with disabilities. Diversity training is an intervention intended to improve intergroup relations and reduce prejudice. We conducted a systematic review to determine the use and effectiveness of disability diversity training aimed at improving employment outcomes for employees with disabilities. Methods Five databases were searched for peer reviewed studies of disability diversity training interventions provided within the workplace. Studies identified for inclusion were assessed for quality of methodology. Results Of the total of 1322 articles identified by the search, three studies met the criteria for inclusion. Two of the three articles focused specifically on training to improve outcomes related to workplace injuries among existing employees. The other study provided an initial test of a more general disability diversity training program. Conclusions There is currently a lack of empirically validated diversity training programs that focus specifically on disability. A number of disability diversity trainings and resources exist, but none have been well researched. Related literature on diversity training and disability awareness suggests the possibility for enhancing diversity training practices through training design, content, participant, and outcomes considerations. By integrating best practices in workplace diversity training with existing disability training resources, practitioners and researchers may be able to design effective disability diversity training programs. PMID- 26519034 TI - The cardioprotective compound cloxyquin uncouples mitochondria and induces autophagy. AB - Mitochondrial quality control mechanisms have been implicated in protection against cardiac ischemia-reperfusion (IR) injury. Previously, cloxyquin (5 chloroquinolin-8-ol) was identified via phenotypic screening as a cardioprotective compound. Herein, cloxyquin was identified as a mitochondrial uncoupler in both isolated heart mitochondria and adult cardiomyocytes. Additionally, cardiomyocytes isolated from transgenic mice expressing green fluorescent protein-tagged microtubule-associated protein light chain 3 showed increased autophagosome formation with cloxyquin treatment. The autophagy inhibitor chloroquine abolished cloxyquin-induced cardioprotection in both cellular and perfused heart (Langendorff) models of IR injury. Finally, in an in vivo murine left anterior descending coronary artery occlusion model of IR injury, cloxyquin significantly reduced infarct size from 31.4 +/- 3.4% to 16.1 +/- 2.2%. In conclusion, the cardioprotective compound cloxyquin simultaneously uncoupled mitochondria and induced autophagy. Importantly, autophagy appears to be required for cloxyquin-induced cardioprotection. PMID- 26519036 TI - PEDF and 34-mer inhibit angiogenesis in the heart by inducing tip cells apoptosis via up-regulating PPAR-gamma to increase surface FasL. AB - Pigment epithelial-derived factor (PEDF) is a potent anti-angiogenic factor whose effects are partially mediated through the induction of endothelial cell apoptosis. However, the underlying mechanism for PEDF and the functional PEDF peptides 34-mer and 44-mer to inhibit angiogenesis in the heart has not been fully established. In the present study, by constructing adult Sprague-Dawley rat models of acute myocardial infarction (AMI) and in vitro myocardial angiogenesis, we showed that PEDF and 34-mer markedly inhibits angiogenesis by selectively inducing tip cells apoptosis rather than quiescent cells. Peptide 44-mer on the other hand exhibits no such effects. Next, we identified Fas death pathway as essential downstream regulators of PEDF and 34-mer activities in inhibiting angiogenesis. By using peroxisome proliferator-activated receptor gamma (PPAR gamma) siRNA and PPAR-gamma inhibitor, GW9662, we found the effects of PEDF and 34-mer were extensively blocked. These data suggest that PEDF and 34-mer inhibit angiogenesis via inducing tip cells apoptosis at least by means of up-regulating PPAR-gamma to increase surface FasL in the ischemic heart, which might be a novel mechanism to understanding cardiac angiogenesis after AMI. PMID- 26519037 TI - Synergistic effect of apoptosis and necroptosis inhibitors in cisplatin-induced nephrotoxicity. AB - Necroptosis is a nonapoptotic cell death pathway. We aim to study the effect of necrostatin-1 (a specific necroptosis inhibitor) in cisplatin-induced injury. We analyzed the effect of the combined use of inhibitors of apoptosis (z-vad) and necroptosis (necrostatin-1) in acute kidney injury by cisplatin in human proximal tubule cells. Our results showed moderate effectiveness in cytoprotection after treatment with z-vad. But the concomitant use of inhibitors (z-vad and necrostatin-1) presented synergistic and additive protection. The present study analyzed the caspase-3 activity and we observed a significant decrease in the group treated with z-vad and cisplatin. However we did not observe changes in the group treated with both inhibitors (z-vad and necrostatin-1) and cisplatin. Thus, demonstrating that necroptosis is a caspase-independent mechanism. We also analyzed the effect of necrostatin-1 in vivo model. C57BL/6 mice were treated with cisplatin and/or inhibitors. The concomitant use of inhibitors (z-vad and necrostatin-1) recovered renal function and decreased levels of urinary Ngal. Additionally, we analyzed the expression of RIP-1, a specific marker for necroptosis. In animals treated with cisplatin and z-VAD levels of RIP-1 were higher. This result reinforces that necroptosis occurs only in conditions where apoptosis was blocked. However, the use of both inhibitors (z-vad and necrostatin 1) provided additional protection. In conclusion, our study has a significant potential to show in vitro and in vivo protection obtained by necrostatin-1. Therefore, our results suggest that necroptosis may be an important mechanism of cell death after kidney injury. PMID- 26519038 TI - Replication and hematological characterization of human platelet reactivity genetic associations in men from the Caerphilly Prospective Study (CaPS). AB - Platelet reactivity, an important factor in hemostasis and chronic disease, has widespread inter-individual variability with a substantial genetic contribution. Previously, our group performed a genome-wide association study of platelet reactivity identifying single nucleotide polymorphisms (SNPs) associated with ADP and epinephrine- induced aggregation, including SNPs in MRVI1, PIK3CG, JMJD1C, and PEAR1, among others. Here, we assessed the association of these previously identified SNPs with ADP-, thrombin-, and shear- induced platelet aggregation. Additionally, we sought to expand the association of these SNPs with blood cell counts and hemostatic factors. To accomplish this, we examined the association of 12 SNPs with seven platelet reactivity and various hematological measures in 1300 middle-aged men in the Caerphilly Prospective Study. Nine of the examined SNPs showed at least suggestive association with platelet reactivity. The strongest associations were with rs12566888 in PEAR1 to ADP-induced (p = 1.51 * 10(-7)) and thrombin-induced (p = 1.91 * 10(-6)) reactivity in platelet rich plasma. Our results indicate PEAR1 functions in a relatively agonist independent manner, possibly through subsequent intracellular propagation of platelet activation. rs10761741 in JMJD1C showed suggestive association with ADP-induced reactivity (p = 1.35 * 10(-3)), but its strongest associations were with platelet-related cell counts (p = 1.30 * 10(-9)). These associations indicate variation in JMJD1C influences pathways that modulate platelet development as well as those that affect reactivity. Associations with other blood cell counts and hemostatic factors were generally weaker among the tested SNPs, indicating a specificity of these SNPs' function to platelets. Future genome-wide analyses will further assess association of these genes and identify new genes important to platelet biology. PMID- 26519039 TI - The feasibility and efficacy of multi-channel intraluminal impedance monitoring in children. AB - INTRODUCTION: The diagnosis of gastro-oesophageal reflux is currently based on clinical presentation and oesophageal pH monitoring. In recent years, the use of multi-channel intraluminal impedance (MII) monitoring has gained increasing attention in the adult population. However, its use in the paediatric population is still in the developing stage with only limited number of publications. This study aims to review our early experience of MII application in children. METHODS: A retrospective study of all patients who underwent MII monitoring between 2011 and 2014 at a tertiary referral centre was performed. Patients' medical records were reviewed with demographic data extracted. Number of reflux episodes and other MII parameters were analysed. RESULTS: In total, 34 patients were identified during the study period, with 20 males and 14 females. Indication for study included previous aspiration pneumonia (n = 13), persistent reflux or vomiting symptom (n = 10) and as part of routine assessment before gastrostomy (n = 11). At the time of study the average age was 69 months (range 9-216 months). 28 patients showed significant gastro-oesophageal reflux. On average patient has 36.1 acidic and 22.3 non-acidic reflux episodes during the 24 h monitoring period. Non-acidic reflux accounts for 38.1 % of the overall reflux episodes. The sensitivity of MII monitoring to detect reflux was higher compared to conventional pH study (73 vs 50 %, p = 0.1). CONCLUSION: MII monitoring is safe and feasible in children. Non-acid reflux should not be underestimated in paediatric population. MII appears to be more sensitive than conventional pH monitoring in our study, but its true significance is yet to be confirmed by larger study in the future. PMID- 26519040 TI - Reduced expression of voltage-gated Kv11.1 (hERG) K(+) channels in aganglionic colon in Hirschsprung's disease. AB - PURPOSE: The pathophysiology of Hirschsprung's disease (HSCR) is not entirely understood. There is no clear explanation for the occurrence of the spastic or tonically contracted aganglionic segment of bowel. Kv11.1 (hERG) channels play a critical role in the regulation of the resting membrane potential as well as affecting either the force or frequency of contraction of smooth muscles. We designed this study to investigate the expression and distribution of hERG channels in the normal colon and the colon of patients with HSCR. METHODS: We investigated hERG protein expression in both the ganglionic and aganglionic regions of HSCR patients (n = 10) versus normal control colon (n = 10). Protein distribution was assessed using immunofluorescence and confocal microscopy. Gene and protein expressions were quantified using real-time polymerase chain reaction, western blot analysis and densitometry. RESULTS: Confocal microscopy of the normal colon revealed strong hERG channel expression in interstitial cells of Cajal, platelet-derived growth factor-alpha receptor- (PDGFRalpha(+)) positive cells and enteric neurons. hERG expression was markedly decreased in aganglionic bowel, whereas colonic hERG gene expression levels were significantly decreased in aganglionic compared to ganglionic bowel and controls (p < 0.05). Western blotting revealed decreased colonic hERG protein expression in aganglionic HSCR specimens compared to controls. CONCLUSIONS: We demonstrate, for the first time, the expression and distribution of hERG channels in the human colon. The decreased expression of hERG in the aganglionic colon may be responsible for the increased tone in the aganglionic narrow spastic segment of bowel. PMID- 26519041 TI - Mesenchymal expression of the FRAS1/FREM2 gene unit is decreased in the developing fetal diaphragm of nitrofen-induced congenital diaphragmatic hernia. AB - PURPOSE: Developmental mutations that inhibit normal formation of extracellular matrix (ECM) in fetal diaphragms have been identified in congenital diaphragmatic hernia (CDH). FRAS1 and FRAS1-related extracellular matrix 2 (FREM2), which encode important ECM proteins, are secreted by mesenchymal cells during diaphragmatic development. The FRAS1/FREM2 gene unit has been shown to form a ternary complex with FREM1, which plays a crucial role during formation of human and rodent diaphragms. Furthermore, it has been demonstrated that the diaphragmatic expression of FREM1 is decreased in the nitrofen-induced CDH model. We hypothesized that FRAS1 and FREM2 expression is decreased in the developing diaphragms of fetal rats with nitrofen-induced CDH. METHODS: Pregnant rats were exposed to either nitrofen or vehicle on gestational day 9 (D9), and fetuses were harvested on D13, D15 and D18. Microdissected diaphragms were divided into nitrofen-exposed/CDH and control samples (n = 12 per time-point and experimental group, respectively). Diaphragmatic gene expression levels of FRAS1 and FREM2 were analyzed by qRT-PCR. Immunofluorescence double staining for FRAS1 and FREM2 was combined with the mesenchymal marker GATA4 in order to evaluate protein expression and localization in pleuroperitoneal folds (PPFs) and fetal diaphragmatic tissue. RESULTS: Relative mRNA expression of FRAS1 and FREM2 were significantly reduced in PPFs of nitrofen-exposed fetuses on D13 (1.76 +/- 0.86 vs. 3.09 +/- 1.15; p < 0.05 and 0.47 +/- 0.26 vs. 0.82 +/- 0.36; p < 0.05), developing diaphragms of nitrofen-exposed fetuses on D15 (1.45 +/- 0.80 vs. 2.63 +/- 0.84; p < 0.05 and 0.41 +/- 0.16 vs. 1.02 +/- 0.49; p < 0.05) and fully muscularized diaphragms of CDH fetuses on D18 (1.35 +/- 0.75 vs. 2.32 +/- 0.92; p < 0.05 and 0.37 +/- 0.24 vs. 0.70 +/- 0.32; p < 0.05) compared to controls. Confocal laser scanning microscopy revealed markedly diminished FRAS1 and FREM2 immunofluorescence in diaphragmatic mesenchyme, which was associated with reduced proliferation of mesenchymal cells in nitrofen-exposed PPFs and fetal CDH diaphragms on D13, D15 and D18 compared to controls. CONCLUSION: Decreased mesenchymal expression of FRAS1 and FREM2 in the nitrofen-induced CDH model may cause failure of the FRAS1/FREM2 gene unit to activate FREM1 signaling, disturbing the formation of diaphragmatic ECM and thus contributing to the development of diaphragmatic defects in CDH. PMID- 26519042 TI - Outcome of esophageal atresia/tracheoesophageal fistula in extremely low birth weight neonates (<1000 grams). AB - PURPOSE: To review the outcomes of extremely low birth weight (ELBW, <1000 g) infants with esophageal atresia/tracheoesophageal fistula (EA/TEF). METHODS: Health records of ELBW EA/TEF infants treated at our institution from 2000 to 2014 were reviewed (REB1000046653). Demographics, operative approach and postoperative complications were analyzed. Data are reported as median (range). RESULTS: Of 268 EA/TEF infants, 8 (3 %, five females) were ELBW (930 g, 540-995). Gestational age was 28 weeks (23-32). Seven had type-C EA/TEF and one type B. OUTCOMES: One trisomy 18 infant received no treatment and died; one initially diagnosed as type A had primary repair at 126 days of life (DOL); six underwent TEF ligation (three trans-pleural) with primary repair in one and delayed anastomosis in two (DOL 120 and 178). The remaining three died (gastrostomy dehiscence and peritonitis, liver hemorrhage during peritoneal drain insertion, severe chronic lung disease and brain hemorrhages). At a median follow-up of 3 years (range 15 months-5 years), all survivors are thriving. CONCLUSION: ELBW infants with EA/TEF are rare and result in high morbidity and mortality. Mortality is mainly related to complications not associated with EA/TEF repair. Fistula ligation followed by delayed anastomosis seems to achieve a better outcome in ELBW infants. PMID- 26519043 TI - Using Medical Mannequins to Train Nurses in Stroke Swallowing Screening. AB - Screening patients admitted with stroke symptoms for risk of aspiration is often the responsibility of registered nurses (RNs). Simulation technology has become a widely used evidence-based form of training for healthcare professionals. The purpose of this study was to determine if the use of medical simulation mannequins as a training component is feasible when training and evaluating nurses administering swallowing screenings to stroke patients. A total of 32 RNs were divided into one of two training groups: didactic training only or didactic training plus simulation. Acquisition of skills was assessed immediately post training and compared between the groups revealing significant differences between simulation group and didactic-only group for interpretation (p = 0.01) and administration (p = 0.05) accuracies. Following training to 100 % accuracy for post-training baseline competency, maintenance of skills across participants was assessed three more times over 6 weeks with the third follow-up screening completed with a standardized patient (live patient actor). While interpretation performance at each subsequent trial never equaled the baseline 100 % post training accuracy (p = 0.001), steady improvement in performance was observed with each follow-up assessment. For screening administration, no significant differences in skills were evident between post-training baseline competency and the 6-week follow-up (p = 0.269) further confirming improvement in skills over time. Extension of screening administration and interpretation skills to the standardized patient was evident. Findings indicate that simulation training using medical mannequins can be used to train and evaluate nurses for obtainment and maintenance of swallowing screening competency. PMID- 26519044 TI - Regurgitation of Undigested Food: What is Your Diagnosis? PMID- 26519045 TI - Under-reporting of cardiovascular findings on chest CT. AB - PURPOSE: It is unclear whether (and, to what extent) radiologists look at and report cardiovascular abnormalities on non-cardio-synchronized standard chest computed tomography (CT). In this study, the frequency and the reporting rate of cardiovascular findings in chest CT examinations were retrospectively assessed. MATERIALS AND METHODS: This study was approved by the institutional review board of each participating center. Four academic centers provided data on 447 subjects who underwent non-ECG-synchronized chest CT examinations for evaluating pulmonary fibrosis (161/447, 36 %), suspected pulmonary embolism (140/447, 31.3 %), or lung cancer staging (146/447, 32.7 %). A total of 220/447 (53.7 %) and 227/447 CT (46.3 %) examinations were evaluated and reported by junior and senior chest radiologists, respectively. Two radiologists with training in cardiac imaging reviewed the same chest CT images looking for the presence of incidental cardiovascular abnormalities using a preformatted score sheet. Inter-observer agreement was assessed using the kappa coefficient of agreement (k). RESULTS: Inter-observer agreement between the study reviewers was moderate to good (0.4 0.73) for most of the incidental cardiovascular findings. At least one incidental cardiovascular finding not documented in the original report was identified by the study reviewers in 225/409 (55 %) of chest CT examinations. A total of 168/266 (63.2 %) potentially clinically significant cardiovascular findings were unreported in the original reports of 177/447 (39.6 %) subjects (p < 0.0001). Senior radiologists tended to more frequently report coronary artery calcification (p = 0.0006), cardiac valves calcification (p = 0.0003), and ascending aorta enlargement (p = 0.01) compared to junior radiologists. CONCLUSIONS: Several cardiovascular abnormalities can be reliably identified on standard chest CT. Yet, they are often under-reported, even when they might be relevant to the patient's work-up. PMID- 26519047 TI - Quantitative diagnosis of connective tissue disease-associated interstitial pneumonia using thoracic computed tomography images. AB - Patients with polymyositis (PM) or dermatomyositis (DM) frequently show interstitial pneumonia (IP), which is sometimes rapidly progressive or resistant to treatment, thereby significantly affecting the prognosis. The diagnosis and response evaluation of IP are commonly performed qualitatively based on imaging findings, which may cause disagreement among rheumatologists in the evaluation of early lesions and atypical interstitial changes. To determine whether IP could be diagnosed in a quantitative manner during the early stage of PM/DM using a workstation that allows quantitative image processing. Thoracic computed tomography (CT) images of 20 PM/DM patients were reconstructed into a three dimensional (3D) image using an image processing workstation. The CT values of the constituent voxels were arranged in a histogram of -1000 to +1000 Hounsfield units (HU). The most frequent lung field density was -900 to -801 HU, and relative size was as follows: IP (+) group 0.45 and IP (-) group 0.53. Between 1000 and -701 HU, relative size was not significantly different between the IP (+) group and IP (-) group. Between -700 and -1 HU, the relative size of the lung field was significantly larger in the IP (+) than in the IP (-) group, demonstrating its IP-diagnosing ability. Particularly, within the range from -700 to -301 HU, the macroscopically-assessed ground glass opacity was consistent with the CT value, which, in turn, was closely correlated with KL-6, the pre-existing marker for IP diagnosis. The results of this study may lead to the establishment of quantitative methods of evaluating IP and possible elucidation of the pathogenesis of IP. PMID- 26519046 TI - Effectiveness of a transdiagnostic internet-based protocol for the treatment of emotional disorders versus treatment as usual in specialized care: study protocol for a randomized controlled trial. AB - BACKGROUND: Emotional disorders (depression and anxiety disorders) are highly prevalent mental health problems. Although evidence showing the effectiveness of disorder-specific treatments exists, high comorbidity rates among emotional disorders limit the utility of these protocols. This has led some researchers to focus their interest on transdiagnostic interventions, a treatment perspective that might be more widely effective across these disorders. Also, the current way of delivering treatments makes it difficult provide assistance to all of the population in need. The use of the Internet in the delivery of evidence-based treatments may help to disseminate treatments among the population. In this study, we aim to test the effectiveness of EmotionRegulation, a new transdiagnostic Internet-based protocol for unipolar mood disorders, five anxiety disorders (panic disorder, agoraphobia, social anxiety disorder, generalized anxiety disorder and anxiety disorder not otherwise specified), and obsessive compulsive disorder in comparison to treatment as usual as provided in Spanish public specialized mental health care. We will also study its potential impact on basic temperament dimensions (neuroticism/behavioral inhibition and extraversion/behavioral activation). Expectations and opinions of patients about this protocol will also be studied. METHODS/DESIGN: The study is a randomized controlled trial. 200 participants recruited in specialized care will be allocated to one of two treatment conditions: a) EmotionRegulation or b) treatment as usual. Primary outcome measures will be the BAI and the BDI-II. Secondary outcomes will include a specific measure of the principal disorder, and measures of neuroticism/behavioral inhibition and extraversion/behavioral activation. Patients will be assessed at baseline, post-treatment, and 3- and 12 month follow-ups. Intention to treat and per protocol analyses will be performed. DISCUSSION: Although the effectiveness of face-to-face transdiagnostic protocols has been investigated in previous studies, the number of published transdiagnostic Internet-based programs is still quite low. To our knowledge, this is the first randomized controlled trial studying the effectiveness of a transdiagnostic Internet-based treatment for several emotional disorders in public specialized care. Combining both a transdiagnostic approach with an Internet-based therapy format may help to decrease the burden of mental disorders, reducing the difficulties associated with disorder-specific treatments and facilitating access to people in need of treatment. Strengths and limitations are discussed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02345668 . Registered 27 July 2015. PMID- 26519049 TI - PRescriptiOn PattERns of Oral Anticoagulants in Nonvalvular Atrial Fibrillation (PROPER study). AB - INTRODUCTION: Inappropriate use of oral anticoagulants (OACs) have not been well investigatedand, however, may be frequent in real-world practice in patients with nonvalvular atrial fibrillation (NVAF). This study was designed to evaluate the prescription patterns and appropriateness of OACs in patients with NVAF in real world clinical settings. METHODS: We performed a prospective, observational study (NCT02366338). A total of 148 patients with NVAF were screened for OAC prescription. Appropriateness of prescribing was evaluated using 9 criteria of the Medication Appropriateness Index (MAI): indication, choice, dosage, modalities and practicability of administration, drug-drug interactions, drug disease interactions, duplication, and duration. For each criterion, the evaluator has to rate whether the medication is (A) appropriate, (B) inappropriate but with limited clinical importance, and (C) inappropriate. RESULTS: Of 148 patients, 73 (50%) were on warfarin (group 1), 39 (26%) were on rivaroxaban (group 2), and 36 (24%) were on dabigatran therapy (group 3). The MAI showed that 83% of group 1, 28% of group 2, and 47% of group 3 patients had at least 1 inappropriate criterion. Moreover, according to the choice criterion, 37% of group 1, 8% of group 2 and 5% of group 3 were rated as inappropriate, and dosage was not appropriate in 77% of group 1, 23% of group 2, and 42% of group 3. CONCLUSION: Inappropriate drug use is frequent among patients with NVAF not only for warfarin but also for NOACs. Although there is an apparent improvement in thromboprophylaxis of NVAF, much more effort is needed for appropriate use of OACs. PMID- 26519048 TI - Correlation of thiamine metabolite levels with cognitive function in the non demented elderly. AB - Thiamine metabolism is critical for glucose metabolism and also vital for brain function, which is susceptible to decline in the elderly. This study aimed to investigate whether thiamine metabolites correlate with cognitive function in the non-demented elderly and their impact factors. Volunteers >60 years old were recruited and their blood thiamine metabolites and Mini-Mental State Examination (MMSE) scores were measured. The apolipoprotein E (APOE) genotype, routine blood parameters, liver and kidney function, and levels of fasting blood glucose and triglycerides were also measured. The results showed that the thiamine diphosphate (TDP) level weakly correlated with MMSE score in the non-demented elderly. Participants with high TDP levels performed better in Recall and Attention and Calculation than those with low TDP. TDP levels were associated with the APOE epsilon2 allele, body mass index, hemoglobin level, fasting blood glucose, and triglycerides. Our results suggest that TDP, which is easily affected by many factors, impacts cognitive function in the elderly. PMID- 26519050 TI - The underestimated diversity of phytoplasmas in Latin America. AB - Phytoplasmas ('Candidatus Phytoplasma') are insect-transmitted, cell-wall-less, plant-pathogenic bacteria that cause economically important crop diseases. Because phytoplasmas are difficult or impossible to culture in vitro, they are classified taxonomically according to the convention used for unculturable micro organisms. The first coherent scheme of classification of phytoplasmas, based on the RFLP pattern of the 16S rRNA-encoding gene generated with 17 restriction endonucleases, was updated several times until the development of the iPhyClassifier. iPhyClassifier is an interactive online tool capable of determining the species, group and subgroup of 'Candidatus Phytoplasma' of unknown samples using the 16S F2nR2 sequence. Latin America, an important geographical area in relation to food production, has a high incidence of plant diseases caused by phytoplasmas. However, many phytoplasmas associated with these diseases have not been properly classified. An extensive literature review and the use of iPhyClassifier allowed us to identify two new tentative groups (16SrXXXIII-A and 16SrXXXIV-A) and the following tentative new subgroups among Latin American strains that were either previously unclassified or misclassified: six in 16SrI, six in 16SrII, one in 16SrIII, one in 16SrVII, one in 16SrIX, one in 16SrXII and two in 16SrXIII. PMID- 26519051 TI - A novel isothermal microcalorimetry tool to assess drug effects on Ancylostoma ceylanicum and Necator americanus. AB - Soil-transmitted helminths, which affect the poorest communities, worldwide cause a range of symptoms and morbidity, yet few treatment options are available and drug resistance is a concern. To improve and accelerate anthelminthic drug discovery, novel drug screening tools such as isothermal microcalorimetry (IMC) have been tested with great potential. In this study, we used a novel microcalorimeter, the calScreenerTM, to study the viability on the hookworms Necator americanus and Ancylostoma ceylanicum as well as the whipworm Trichuris muris. Significant heat flow signals could be obtained with already one adult worm per channel for all three species. High-amplitude oscillations were observed for the hookworms; however, adult T. muris showed a twofold heat flow decrease during the first 24 h. Antinematodal effects of ivermectin and levamisole at 1, 10, and 100 MUg/ml were evaluated on adult N. americanus and A. ceylanicum. Levamisole-treated hookworms showed a decline in heat flow and oscillation amplitude in a dose-response manner. Heat flow for ivermectin-treated hookworms increased proportionally with increased concentrations of ivermectin, though the wavelet analysis showed an opposite trend as observed by flatter wavelets. In conclusion, the calScreenerTM is an excellent tool to study drug effects on intestinal hookworms at the adult worm stage as it offers a lower detection limit than other IMC devices and the possibility to monitor worm viability online. PMID- 26519052 TI - National health research systems in the WHO African Region: current status and the way forward. AB - BACKGROUND: A number of resolutions of the World Health Assembly and the WHO Regional Committee for Africa call upon African countries and their development partners to make the required investments in national health research systems (NHRS) to generate knowledge and promote its use in tackling priority public health challenges. Implementation of these resolutions is critical for Africa to progress with the rest of the world in achieving the post-2015 health sustainable development goal. This study assesses the current status of some NHRS components in the 47 countries of the WHO African Region, identifies the factors that enable and constrain NHRS, and proposes the way forward. METHODS: To track progress in NHRS components and for comparison, a questionnaire that was used in NHRS surveys in 2003 and 2009 was administered in all 47 countries in the African Region. The national health research focal persons were responsible for completing the questionnaire, which had been hand-delivered to them by the WHO country office staff in charge of research, who also briefed them on the survey, went through the questionnaire for clarity, and sought their informed consent. RESULTS: All the 47 countries responded to the questionnaire, but some did not answer all questions. Of the countries responding to various questions 49 % (23/47) had a national health research policy; 47 % (22/47) had a health strategic plan; 40 % (19/47) had legislation governing research; 53 % (25/47) had a national health research priority agenda; 51 % (24/47) reported having a functional NHRS and a national health research management forum; 91 % (43/47) had an ethical review committee; 49 % (23/47) had hospitals with ethical review committees to review clinical research proposals; 51 % (24/47) had a scientific review committee; 62 % (29/47) had health institutions with scientific review committees; 83 % (39/47) had a national health research focal point; 51 % (24/47) had a health research programme; 55 % (26/47) had a national health or medical research institute or council; 93 % (41/44) had at least one university faculty of health sciences that conducted health research; and 33 % (15/46) had a knowledge translation platform. Forty-seven percent of countries reported having a budget line for research for health in the ministry of health budget. Between 2003 and 2014, the countries with a functional NHRS increased from 30 % to 51 %. CONCLUSION: Compared with 2003 and 2009 surveys, our survey found many countries to have made progress in strengthening some of the functions of their NHRS. However, there remains an urgent need for countries without NHRS to establish them and for others to improve the functionality and efficiency of every NHRS component. This is necessary for the national governments to effectively execute their leadership and governance of NHRS and to create an enabling environment within which research for health can flourish. PMID- 26519054 TI - Merkel cell carcinoma mistaken for allergic contact dermatitis. PMID- 26519053 TI - Deep sequencing shows microRNA involvement in bovine mammary gland adaptation to diets supplemented with linseed oil or safflower oil. AB - BACKGROUND: Bovine milk fat composition is responsive to dietary manipulation providing an avenue to modify the content of fatty acids and especially some specific unsaturated fatty acid (USFA) isomers of benefit to human health. MicroRNAs (miRNAs) regulate gene expression but their specific roles in bovine mammary gland lipogenesis are unclear. The objective of this study was to determine the expression pattern of miRNAs following mammary gland adaptation to dietary supplementation with 5 % linseed or safflower oil using next generation RNA-sequencing. METHODS: Twenty-four Canadian Holstein dairy cows (twelve per treatment) in mid lactation were fed a control diet (total mixed ration of corn:grass silages) for 28 days followed by a treatment period (control diet supplemented with 5 % linseed or safflower oil) of 28 days. Milk samples were collected weekly for fat and individual fatty acid determination. RNA from mammary gland biopsies harvested on day-14 (control period) and on days +7 and +28 (treatment period) from six randomly selected cows per treatment was subjected to small RNA sequencing. RESULTS: Milk fat percentage decreased significantly (P < 0.001) during treatment with the two diets as compared to the control period. The individual saturated fatty acids C4:0, C6:0, C8:0, C14:0 and C16:0 decreased significantly (P < 0.05) while five USFAs (C14:1, C18:1n11t, C20:3n3, C20:5n3 and CLA:t10c12) increased remarkably (P < 0.05) in response to both treatments. Analysis of 361 million sequence reads generated 321 known bovine miRNAs and 176 novel miRNAs. The expression of fourteen and twenty-two miRNAs was affected (P < 0.05) by linseed and safflower oil treatments, respectively. Seven miRNAs including six up-regulated (bta-miR-199c, miR-199a-3p, miR-98, miR-378, miR-148b and miR-21-5p) and one down-regulated (bta-miR-200a) were found to be regulated (P < 0.05) by both treatments, and thus considered core differentially expressed (DE) miRNAs. The gene targets of core DE miRNAs have functions related to gene expression and general cellular metabolism (P < 0.05) and are enriched in four pathways of lipid metabolism (3-phosphoinositide biosynthesis, 3-phosphoinositide degradation, D-myo-inisitol-5-phosphate metabolism and the superpathway of inositol phosphate compounds). CONCLUSION: Our results suggest that DE miRNAs in this study might be important regulators of bovine mammary lipogenesis and metabolism. The novel miRNAs identified in this study will further enrich the bovine miRNome repertoire and contribute to understanding mammary gland biology. PMID- 26519055 TI - Reasons for encounter in young people consulting a family doctor in the French speaking part of Switzerland: a cross sectional study. AB - BACKGROUND: Knowledge of patient's reasons for encounter is useful to inform health service planning and health professional education. Our aim was to describe reasons for encounter as stated by an unselected group of young people attending primary care practices in the French-speaking part of Switzerland. METHODS: Consecutive patients aged between 15 and 24 years were recruited as part of the PRISM-Ado trial (n = 594). They completed an anonymous questionnaire in the waiting room, including their main reason for encounter (free text). Reasons for encounter were coded using ICPC-2 classification and analyzed according to sex, age and living in a rural or urban area. RESULTS: 95 % of questionnaires contained valid data about reasons for encounter (n = 567). General and unspecific (A) reasons were the most common in boys (44 %) and girls (42 %), followed by respiratory, musculoskeletal, dermatological and psychological reasons. Psychological reasons were more frequent in girls attending urban practices; musculoskeletal and dermatological reasons were more frequent in rural areas. Sexually transmitted infections or substance use were very rarely stated as a reason for encounter. CONCLUSIONS: This is the first study describing reasons for encounter as stated by young people themselves in primary care in Switzerland. These findings provide useful guidance for family doctors training and health service planning in Europe. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12608000432314 . PMID- 26519056 TI - Putative novel mediators of acute kidney injury in critically ill patients: handling by continuous venovenous hemofiltration and effect of anticoagulation modalities. AB - BACKGROUND: Novel putative mediators of acute kidney injury (AKI) include immune cell derived tumour necrosis factor-like weak inducer of apoptosis (TWEAK), angiopoietin-2 (Ang-2) and protein pentraxin-3 (PTX3). The effect of continuous venovenous hemofiltration (CVVH) and different anticoagulation regimens on plasma levels were studied. METHODS: At 0, 10, 60, 180 and 720 min of CVVH, samples were collected from pre- and postfilter blood and ultrafiltrate. No anticoagulation (n = 13), unfractionated heparin (n = 8) or trisodium citrate (n = 21) were compared. RESULTS: Concentrations of TWEAK, Ang-2 and PTX3 were hardly affected by CVVH since the mediators were not (TWEAK, PTX3) or hardly (Ang-2) detectable in ultrafiltrate, indicating negligible clearance by the filter in spite of molecular sizes (TWEAK, PTX3) at or below the cutoff of the membrane. Heparin use, however, was associated with an increase in in- and outlet plasma TWEAK. CONCLUSION: Novel AKI mediators are not cleared nor produced by CVVH. However, heparin anticoagulation increased TWEAK levels in patient's plasma whereas citrate did not, favouring the latter as anticoagulant in CVVH for AKI. PMID- 26519058 TI - Erratum to: Low Carbohydrate Diets and Type 2 Diabetes: What is the Latest Evidence? PMID- 26519057 TI - Lifelong learning of Chinese rural physicians: preliminary psychometrics and influencing factors. AB - BACKGROUND: There are more than 4.9 million rural health workers undertaking the health care need of rural population of over 629 million in China. The lifelong learning of physicians is vital in maintaining up-to-date and qualified health care, but rural physicians in many developing countries lack adequate medical professional developments. There has also been no empirical research focused on the lifelong learning of rural physician populations. The purpose of this study was to investigate the primary levels of lifelong learning of the rural physicians and to analyze group differences. METHODS: We conducted a cross sectional study on 1197 rural physicians using the Jefferson Scale of Physician Lifelong Learning (JSPLL). Cronbach's alpha coefficient, exploratory factor analysis, independent sample t-test, and one-way ANOVA followed by Student-Newman Keuls test were performed to analyze the data. RESULTS: For Chinese rural physicians, the JSPLL was reliable (Cronbach's alpha coefficient = 0.872) and valid, with exploratory factor analysis fitting a 3-factor model and accounting for a total of 60.46 % of the variance. The mean lifelong learning score was 45.56. Rural physicians generally performed worse in the technical skills in seeking information domain. Rural physicians with 21-30 working years have a lower score of lifelong learning (P < 0.05) than other phases of working years. Career satisfaction and professional titles had a significantly positive influence on physicians' orientation towards lifelong learning (P < 0.05). The overall lifelong learning scores of physicians who received more training after completion of medical school were higher than those with less additional post medical school training (P <0.05). CONCLUSIONS: The JSPLL is effective for the Chinese rural physician population. In order to cope with impacting factors on rural physicians' lifelong learning, the results of the study reinforced the importance of continuing medical education and career satisfaction for lifelong learning and the need for medical schools and hospitals to provide reasonable strategies and necessary support for rural physicians with different amounts of working years. Providing rural physicians more educational opportunities and helping them access educational resources may be an effective strategy for improving their orientation to lifelong learning. PMID- 26519059 TI - Molecular Pathways: Fatty Acid Synthase. AB - Therapies that target tumor metabolism represent a new horizon in anticancer therapies. In particular, cancer cells are dependent on the generation of lipids, which are essential for cell membrane synthesis, modification of proteins, and localization of many oncogenic signal transduction enzymes. Because fatty acids are the building blocks of these important lipids, fatty acid synthase (FASN) emerges as a unique oncologic target. FASN inhibitors are being studied preclinically and beginning to transition to first-in-human trials. Early generation FASN inhibitors have been studied preclinically but were limited by their pharmacologic properties and side-effect profiles. A new generation of molecules, including GSK2194069, JNJ-54302833, IPI-9119, and TVB-2640, are in development, but only TVB-2640 has moved into the clinic. FASN inhibition, either alone or in combination, holds promise as a novel therapeutic approach for patients with cancer. PMID- 26519061 TI - How to Use the Candida Genome Database. AB - Studying Candida biology requires access to genomic sequence data in conjunction with experimental information that provides functional context to genes and proteins. The Candida Genome Database (CGD) integrates functional information about Candida genes and their products with a set of analysis tools that facilitate searching for sets of genes and exploring their biological roles. This chapter describes how the various types of information available at CGD can be searched, retrieved, and analyzed. Starting with the guided tour of the CGD Home page and Locus Summary page, this unit shows how to navigate the various assemblies of the C. albicans genome, how to use Gene Ontology tools to make sense of large-scale data, and how to access the microarray data archived at CGD. PMID- 26519060 TI - Molecular Pathways: Targeting IDO1 and Other Tryptophan Dioxygenases for Cancer Immunotherapy. AB - Indoleamine 2, 3-dioxygenase 1 (IDO1), IDO2, and tryptophan 2, 3-dioxygenase (TDO) comprise a family of enzymes that catalyze the first- and rate-limiting step associated with the catabolic conversion of tryptophan (Trp) into kynurenine (Kyn). Through subsequent enzymatic and spontaneous reactions, Kyn is further converted into the energetic substrates, NAD(+) and ATP, to fuel cellular metabolic functions. Coincidently, the depletion of Trp and accumulation of Kyn has been demonstrated to induce effector T-cell apoptosis/dysfunction and immunosuppressive regulatory T-cell induction, respectively. Similar to other immune checkpoints, IDO1 and TDO are suggested to be important targets for immunotherapeutic intervention. This is represented by the recent growth of efforts to inhibit the Trp-to-Kyn pathway as a means to control immunosuppression. Inhibitors currently in clinical trials, INCB024360, GDC-0919, indoximod, and an IDO1 peptide-based vaccine, are being evaluated for their efficacy against a wide range of cancers including melanoma, glioblastoma, non small cell lung, pancreatic, and/or breast cancer, as well as metastatic disease. Despite the rapid development of potent clinical grade inhibitors, strategic questions remain. Here, we review the state of the literature with respect to current therapeutic inhibitors of tryptophan catabolism, evaluation of those efforts preclinically and clinically, compensatory changes that occur with therapeutic targeting, as well as newly recognized signaling features that raise critical questions to the field. Given the rapidly evolving interest in determining how IDO1/TDO, and to an unknown extent, IDO2, can be targeted for increasing cancer immunotherapeutic efficacy, we present a brief but comprehensive analysis that addresses critical questions, while highlighting the mechanics that remain to be explored. PMID- 26519062 TI - Transcriptional Profiling of Candida albicans in the Host. AB - Gene expression profiling has become an important tool for determining gene functions, performing phenotypic analysis, and quantifying the differential expression of individual transcripts under various conditions. Candida albicans gene expression is highly responsive to environmental conditions and rapidly adapts to various niches within the host. Here, we describe a mouse model of gastrointestinal colonization with C. albicans, the measurement of colonization in fecal pellets, and the collection of samples for transcriptional profiling. We describe how to extract and purify RNA suitable for analysis via RT-qPCR or microarray. PMID- 26519063 TI - SRYTH: A New Yeast Two-Hybrid Method. AB - Many biological processes are regulated by protein-protein interactions, and the analysis of these interactions has been a productive endeavor contributing to our understanding of cellular organization and function. The yeast two-hybrid technique is a widely used, powerful method of analyzing protein-protein interactions. The currently used formats, however, have inherent limitations, providing an opportunity to develop new alternatives that extend our ability to detect protein-protein interactions of biological relevance. Here we present a two-hybrid system named SRYTH (Ste11p/Ste50p related yeast two-hybrid) based on the Ste11p/Ste50p interaction that uses the activation of the HOG pathway of Saccharomyces cerevisiae as a reporter for interactions. The system is suitable for detecting cytoplasmic protein interactions in their natural subcellular environment, and has been successfully used to investigate protein-protein interactions, including transcription factor associations, in Candida albicans. PMID- 26519064 TI - Chromatin Immunoprecipitation (ChIP) Assay in Candida albicans. AB - Chromatin immunoprecipitation (ChIP) is a widely used technique which can determine the in vivo association of a specific protein on a particular DNA locus in the genome. In this method cross-linked chromatin is sheared and immunoprecipitated with antibodies raised against a target protein of interest. The end result of this process is the enrichment of DNA fragments associated with the desired protein. Thus, interactions between proteins and genomic loci in cellular context can be determined by this technique. Here, we are describing a ChIP protocol that is optimized for Candida albicans. The protocol requires 4-5 days for completion of the assay and has been used to produce robust ChIP results for diverse proteins in this organism and its related species including Candida dubliniensis and Candida tropicalis. PMID- 26519065 TI - Assessing Mitochondrial Functions in Candida albicans. AB - This chapter is designed to present methods for characterizing the annotation of genes associated with mitochondrial functions in Candida spp. Methods include drop plate assays for evaluating inhibitors of the respiratory electron transport system complexes as well as measuring the enzyme activity of complex I-V enzyme activities. Assays are also presented to measure toxic ROS production that accompanies gene mutations or gene loss and chronological aging that often is shortened in Complex I dysfunction. Also presented are methods to isolate mitochondria, visualize mitochondria, and extract mitochondrial proteins. PMID- 26519066 TI - Imaging Candida Infections in the Host. AB - Disseminated fungal infections caused by Candida species are associated with homing of the pathogen to specific organs in human and murine hosts. Kidneys are a primary target organ of Candida albicans, and invasion into the kidney medulla can lead to loss of renal function and death. Therefore, development of noninvasive methods to assess kidney infections could aid in the management of disseminated candidemia. We describe a magnetic resonance imaging method utilizing iron oxide-based contrast agents to noninvasively assess recruitment of phagocytes and kidney inflammation. C. albicans also colonizes the brain and can cause meningoencephalitis. We describe additional imaging methods to assess loss of the blood-brain barrier function that initiates brain infections. PMID- 26519067 TI - Identification of Secreted Candida Proteins Using Mass Spectrometry. AB - Analysis of fungal secretomes using mass spectrometry is a useful technique in cell biology. Knowledge of the secretome of a human fungal pathogen may yield important information of host-pathogen interactions and may be useful for identifying vaccines candidates or diagnostic markers for antifungal strategies. In this chapter, with a main focus on sample preparation aspects, we describe the methodology that we apply for gel-independent batch identification and quantification of proteins that are secreted during growth in liquid cultures. Using these techniques with Candida and other yeast species, the majority of the identified proteins are classical secretory proteins and cell wall proteins containing N-terminal signal peptides for secretion, although dependent on sample preparation quality and the mass spectrometric analysis also usually, a number of nonsecretory proteins are identified. PMID- 26519068 TI - In Vitro Models for Candida Biofilm Development. AB - Development of Candida spp. biofilms on medical devices such as catheters and voice prosthesis has been recognized as an increasing clinical problem. Different in vitro models are presented with increasing complexity. Each model system can be utilized for analysis of new active compounds to prevent or treat Candida biofilms as well as to study molecular processes involved in biofilm formation. Susceptibility studies of clinical isolates are generally performed in a simple 96-well model system similar to the CLSI standard. In the present chapter, optimized conditions that promote biofilm formation within individual wells of microtiter plates are described. In addition, the method has proven useful in preparing C. albicans biofilms for investigation by a variety of microscopic and molecular techniques. A more realistic and more complex biofilm system is presented by the Amsterdam Active Attachment (AAA) model. In this 24-well model all crucial steps of biofilm formation: adhesion, proliferation, and maturation, can be simulated on various surfaces, while still allowing a medium throughput approach. This model has been applied to study susceptibility, complex molecular mechanisms as well as interspecies (Candida-bacterium) interactions. Finally, a realistic microfluidics channel system is presented to follow dynamic processes in biofilm formation. In this Bioflux-based system, molecular mechanisms as well as dynamic processes can be studied at a high time-resolution. PMID- 26519069 TI - The Fungal Biome of the Oral Cavity. AB - Organisms residing in the oral cavity (oral microbiota) contribute to health and disease, and influence diseases like gingivitis, periodontitis, and oral candidiasis (the most common oral complication of HIV-infection). These organisms are also associated with cancer and other systemic diseases including upper respiratory infections. There is limited knowledge regarding how oral microbes interact together and influence the host immune system. Characterizing the oral microbial community (oral microbiota) in health and disease represents a critical step in gaining insight into various members of this community. While most of the studies characterizing oral microbiota have focused on bacterial community, there are few encouraging studies characterizing the oral mycobiome (the fungal component of the oral microbiota). Our group recently characterized the oral mycobiome in health and disease focusing on HIV. In this chapter we will describe the methods used by our group for characterization of the oral mycobiome. PMID- 26519070 TI - Experimental Models of C. albicans-Streptococcal Co-infection. AB - Interactions of C. albicans with co-colonizing bacteria at mucosal sites can be synergistic or antagonistic in disease development, depending on the bacterial species and mucosal site. Mitis group streptococci and C. albicans colonize the oral mucosa of the majority of healthy individuals. These streptococci have been termed "accessory pathogens," defined by their ability to initiate multispecies biofilm assembly and promote the virulence of the mixed bacterial biofilm community in which they participate. To demonstrate whether interactions with Mitis group streptococci limit or promote the potential of C. albicans to become an opportunistic pathogen, in vitro and in vivo co-infection models are needed. Here, we describe two C. albicans-streptococcal co-infection models: an organotypic oral mucosal tissue model that incorporates salivary flow and a mouse model of oral co-infection that requires reduced levels of immunosuppression compared to single fungal infection. PMID- 26519071 TI - Staphylococcus-Candida Interaction Models: Antibiotic Resistance Testing and Host Interactions. AB - The fungus Candida albicans and bacterium Staphylococcus aureus can coexist in polymicrobial biofilms. S. aureus attaches strongly to hyphae, but not to the yeast form, of C. albicans with important consequences for virulence. Hyphae associated S. aureus is less susceptible to antibiotic treatment. Furthermore, co inoculation of C. albicans and S. aureus causes more severe and widespread infection than either microorganism alone. In this chapter, a basic in vitro model for studying the interaction between C. albicans hyphae and S. aureus is presented, which makes use of a fluorescently labeled S. aureus strain. Furthermore, two protocols are described that allow investigation of the effect of C. albicans and S. aureus interaction on antibiotic susceptibility or on interactions with the host. The latter focuses on phagocytosis of C. albicans adhered S. aureus by macrophages. The protocols presented here may serve as a starting point to study the interaction of C. albicans with various other bacterial species. PMID- 26519072 TI - Genetic Screens for Determination of Mechanism of Action. AB - The search for new antifungal drugs and cell targets continues. During the discovery process, mechanism-of-action (MOA) studies are critical to the continued progress of the compound through the pipeline. There are many approaches that can be utilized in understanding the MOA. One of these approaches is a genetic screen utilizing the availability of Saccharomyces cerevisiae mutant libraries. Both null and heterozygous library mutants covering the entire genome of this model yeast are available. The desired phenotype when screening the new compound is either resistance (null mutants) or haploinsufficiency or loss of fitness (heterozygote mutants). Both types of mutants can be clustered by software into common targets that provide clues as to a pathway or other cell process. Below, methods are described for genetic screens. PMID- 26519073 TI - Microbroth Dilution Susceptibility Testing of Candida species. AB - Antifungal susceptibility testing for Candida species is now widely accepted as a methodology to predict the success or failure of antifungal therapy for some antifungal/Candida species combinations. There are many different ways to perform susceptibility testing of antifungal agents, but broth microdilution has become the most popular over the last 10 years. This chapter describes in detail two methods for antifungal susceptibility testing of Candida species using the commercially available microbroth dilution tray (YeastOne((r))) and a commercially available gradient agar diffusion technique (Etest((r))) for isolates that appear resistant. PMID- 26519074 TI - Biofilms and Antifungal Susceptibility Testing. AB - Yeasts and filamentous fungi both exist as single cells and hyphal forms, two morphologies used by most fungal organisms to create a complex multilayered biofilm structure. In this chapter we describe the most widely used assays for the determination of biofilm production and assessment of susceptibility of biofilms to antifungal agents or host phagocytes as various methods, the most frequent of which are staining, confocal laser scanning microscopy, quantification of extracellular DNA and protein associated with extracellular matrix and XTT metabolic reduction assay. Pathway-focused biofilm gene expression profiling is assessed by real-time reverse transcriptase polymerase chain reaction. PMID- 26519075 TI - Typing Candida Species Using Microsatellite Length Polymorphism and Multilocus Sequence Typing. AB - To gain more insight into the epidemiological relationships between isolates of Candida spp. obtained from various origins, several molecular typing techniques have been developed. Two methods have emerged in the 2000s as soon as enough knowledge of the Candida spp. genomes was available to choose adequate loci and primers, namely microsatellite length polymorphism (MLP) and multilocus sequence typing (MLST). To contrast with previous PCR-based methods, specific amplifications with stringent conditions easily reproducible are the basis of MLP and MLST. MLST relies on Sanger sequencing to detect single-nucleotide polymorphisms within housekeeping genes. MLP needs a first in silico step to select tandemly repeated stretches of two to five nucleotides. One of the two primers used to amplify a microsatellite locus is labeled and fragment sizing is automatically performed using high-resolution electrophoresis platforms. MLST provides results easily comparable between laboratories and active MLST schemes are publicly available for the main Candida species. For comparative studies, MLP needs standards to compensate for the electrophoretic variations depending on the platforms used. Both methods can help us gain insight into the genetic relatedness of fungal isolates, both with advantages and drawbacks, and the choice of one method rather than the other depends on the task in question. PMID- 26519076 TI - Diagnostic Methods for Detection of Blood-Borne Candidiasis. AB - beta-D-glucan (Fungitell) and polymerase chain reaction-based (T2Candida) assays of blood samples are FDA-approved adjuncts to cultures for diagnosing candidemia and other types of invasive candidiasis, but their clinical roles are unclear. In this chapter, we describe laboratory protocols for performing Fungitell and T2Candida assays. We then discuss step-by-step methods for interpreting test results at the bedside using a Bayesian framework, and for incorporating assays into rational patient management strategies. Prior to interpreting results, clinicians must recognize that test performance varies based on the type of invasive candidiasis being diagnosed. In general, the type of invasive candidiasis that is most likely in a given patient can be identified, and the pretest likelihood of disease estimated. From there, positive and negative predictive values (PPV, NPV) for an assay can be calculated. At a population level, tests can be incorporated into screening strategies for antifungal treatment. NPV and PPV thresholds can be defined for discontinuing antifungal prophylaxis or initiating preemptive treatment, respectively. Using the thresholds, it is possible to assign windows of pretest likelihood for invasive candidiasis (and corresponding patient populations) in which tests are most likely to valuable. At the individual patient level, tests may be useful outside of the windows proposed for screening populations. The interpretive and clinical decision-making processes we discuss will be applicable to other diagnostic assays as they enter the clinic, and to existing assays as more data emerge from various populations. PMID- 26519077 TI - Long-term effects of discharges of produced water the marine environment from petroleum-related activities at Sonda de Campeche, Gulf of Mexico. AB - Produced water from offshore oil platforms is a major source of oil and related chemicals into the sea. The large volume and high salinity of produced water could pose severe environmental impacts upon inadequate disposal. This study is based on direct field sampling of effluents released into the ocean in the years 2003 and 2013 at the Sonda de Campeche located in the southern part of the Gulf of Mexico. Metals and hydrocarbons were characterized in water, sediments, and fish tissues at the discharge site and compared with those obtained at two reference sites. Chemicals that exceeded risk-based concentrations in the discharge included the metals As, Pb, Cd, and Cr, and a variety of compounds polycyclic aromatic hydrocarbon (PAHs), including naphthalene, fluorenes, and low molecular weight PAHs. The values of low to high molecular weight polycyclic aromatic hydrocarbon (PAHs), and carbon preference index indicate that hydrocarbons in sediments of the discharge zone are originated from the produced water and combustion sources. Fish tissues at the discharge zone and reference site are contaminated with PAHs, dominated by 2- and 3-rings; 4-ring accounted for less than 1% of total PAHs (TPAHs) in 2003, but increased to 7% in 2013. Results suggest that, from 2003 to 2013, discharges of produced water have had a non-negligible impact on ecosystems at a regional level, so the possibility of subtle, cumulative effects from operational discharges should not be ignored. PMID- 26519078 TI - Evaluation and characterization of anti-estrogenic and anti-androgenic activities in soil samples along the Second Songhua River, China. AB - In the present study, re-combined estrogen receptor (ER) and androgen receptor (AR) gene yeast assays combined with a novel approach based on Monte Carlo simulation were used for evaluation and characterization of soil samples collected from Jilin along the Second Songhua River to assess their antagonist/agonist properties for ER and AR. The results showed that estrogenic activity only occurred in the soil samples collected in the agriculture area, but most soil samples showed anti-estrogenic activities, and the bioassay-derived 4 hydroxytamoxifen equivalents ranged from N.D. to 23.51 MUg/g. Hydrophilic substance fractions were determined as potential contributors associated with anti-estrogenic activity in these soil samples. Moreover, none of the soil samples exhibited AR agonistic potency, whereas 54% of the soil samples exhibited AR antagonistic potency. The flutamide equivalents varied between N.D. and 178.05 MUg/g. Based on Monte Carlo simulation-related mass balance analysis, the AR antagonistic activities were significantly correlated with the media polar and polar fractions. All of these results support that this novel calculation method can be adopted effectively to quantify and characterize the ER/AR agonists and antagonists of the soil samples, and these data could help provide useful information for future management and remediation efforts. PMID- 26519079 TI - Metals in Bone Tissue of Antillean Manatees from the Gulf of Mexico and Chetumal Bay, Mexico. AB - Concentrations of seven metals (As, Cd, Cr, Cu, Pb, Ni, and Zn) were analyzed in 33 bone tissue samples of Antillean manatees (Trichechus manatus manatus) found dead in lagoons and rivers of Tabasco and Campeche in the Gulf of Mexico and Chetumal Bay in the Caribbean region. The concentrations of Cr, Cu, Pb, and Zn were significantly different between regions, with greater levels found in the Gulf of Mexico group than in the Mexican Caribbean group (p < 0.05). Pb concentrations differed significantly between adults and calves. No differences were observed between sexes. Metal concentrations detected in the manatee bones were higher than most of those reported for bones in other marine mammals around the world. Future studies are necessary to establish whether the metal concentrations represent a risk to the health of the species. PMID- 26519080 TI - Radiotherapy of spinal cord gliomas : A retrospective mono-institutional analysis. AB - BACKGROUND: Due to the rarity of spinal cord gliomas, no consensus has been reached regarding the optimal treatment strategy. The aim of the present retrospective study was to identify patient and tumor characteristics and to evaluate the effectiveness of radiotherapy within this setting. PATIENTS AND METHODS: Patients diagnosed with spinal cord gliomas between 2003 and 2013 and treated at the Department of Radiation Oncology, University of Munich, were retrospectively analyzed. Overall survival was estimated with the Kaplan-Meier method and univariate analysis was performed by log-rank testing. RESULTS: A total of 16 patients were identified. The cohort consisted of seven primary spinal cord gliomas and eight cases of metastases of cerebral gliomas. Median follow-up was 42 months and median total radiation dose was 45.0 Gy. In all, 62.5 % of patients received a simultaneous chemotherapy with temozolomide. The median overall survival was 6 months (95% CI: 0-27.5 months). Surgical resection of the tumor was a significant predictor of improved survival, compared with radiotherapy alone (p = 0.001). Patients with the diagnosis of a primary spinal cord glioma survived significantly longer than those presenting with a metastatic deposit from a cerebral glioma (p < 0.001). A statistically significant dose response relationship at dose levels of >= 45 Gy vs. < 45 Gy could be derived (p < 0.001). Simultaneous chemotherapy did not influence survival outcome. CONCLUSION: Despite the aggressive treatment in the present study, the prognosis for spinal cord gliomas was still poor, with a median overall survival of 6 months. To the best of our knowledge, this is the largest study reporting the results of simultaneous chemoradiation in spinal cord gliomas. A combined chemoradiation treatment seems feasible and can be considered as a new treatment option in the management of spinal cord gliomas. PMID- 26519081 TI - Making Good Decisions in Healthcare with Multi-Criteria Decision Analysis: The Use, Current Research and Future Development of MCDA. AB - Healthcare decision making is usually characterized by a low degree of transparency. The demand for transparent decision processes can be fulfilled only when assessment, appraisal and decisions about health technologies are performed under a systematic construct of benefit assessment. The benefit of an intervention is often multidimensional and, thus, must be represented by several decision criteria. Complex decision problems require an assessment and appraisal of various criteria; therefore, a decision process that systematically identifies the best available alternative and enables an optimal and transparent decision is needed. For that reason, decision criteria must be weighted and goal achievement must be scored for all alternatives. Methods of multi-criteria decision analysis (MCDA) are available to analyse and appraise multiple clinical endpoints and structure complex decision problems in healthcare decision making. By means of MCDA, value judgments, priorities and preferences of patients, insurees and experts can be integrated systematically and transparently into the decision making process. This article describes the MCDA framework and identifies potential areas where MCDA can be of use (e.g. approval, guidelines and reimbursement/pricing of health technologies). A literature search was performed to identify current research in healthcare. The results showed that healthcare decision making is addressing the problem of multiple decision criteria and is focusing on the future development and use of techniques to weight and score different decision criteria. This article emphasizes the use and future benefit of MCDA. PMID- 26519082 TI - Characterization of two Lactococcus lactis zinc membrane proteins, Llmg_0524 and Llmg_0526, and role of Llmg_0524 in cell wall integrity. AB - BACKGROUND: Due to its extraordinary chemical properties, the cysteine amino acid residue is often involved in protein folding, electron driving, sensing stress, and binding metals such as iron or zinc. Lactococcus lactis, a Gram-positive bacterium, houses around one hundred cysteine-rich proteins (with the CX2C motif) in the cytoplasm, but only a few in the membrane. RESULTS: In order to understand the role played by this motif we focused our work on two membrane proteins of unknown function: Llmg_0524 and Llmg_0526. Each of these proteins has two CX2C motifs separated by ten amino-acid residues (CX2CX10CX2C). Together with a short intervening gene (llmg_0525), the genes of these two proteins form an operon, which is induced only during the early log growth phase. In both proteins, we found that the CX2CX10CX2C motif chelated a zinc ion via its cysteine residues, but the sphere of coordination was remarkably different in each case. In the case of Llmg_0524, two of the four cysteines were ligands of a zinc ion whereas in Llmg_0526, all four residues were involved in binding zinc. In both proteins, the cysteine-zinc complex was very stable at 37 degrees C or in the presence of oxidative agents, suggesting a probable role in protein stability. We found that the complete deletion of llmg_0524 increased the sensitivity of the mutant to cumene hydroperoxide whereas the deletion of the cysteine motif in Llmg_0524 resulted in a growth defect. The latter mutant was much more resistant to lysozyme than other strains. CONCLUSIONS: Our data suggest that the CX2CX10CX2C motif is used to chelate a zinc ion but we cannot predict the number of cysteine residue involved as ligand of metal. Although no other motif is present in sequence to identify roles played by these proteins, our results indicate that Llmg_0524 contributes to the cell wall integrity. PMID- 26519083 TI - The Roles of Technology in Primary HIV Prevention for Men Who Have Sex with Men. AB - Men who have sex with men (MSM) are at disproportionate risk for HIV infection globally. The past 5 years have seen considerable advances in biomedical interventions to reduce the risk of HIV infection. To be impactful in reducing HIV incidence requires the rapid and expansive scale-up of prevention. One mechanism for achieving this is technology-based tools to improve knowledge, acceptability, and coverage of interventions and services. This review provides a summary of the current gap in coverage of primary prevention services, how technology-based interventions and services can address gaps in coverage, and the current trends in the development and availability of technology-based primary prevention tools for use by MSM. Results from agent-based models of HIV epidemics of MSM suggest that 40-50 % coverage of multiple primary HIV prevention interventions and services, including biomedical interventions like preexposure prophylaxis, will be needed to reduce HIV incidence among MSM. In the USA, current levels of coverage for all interventions, except HIV testing and condom distribution, fall well short of this target. Recent findings illustrate how technology-based HIV prevention tools can be used to provide certain kinds of services at much larger scale, with marginal incremental costs. A review of mobile apps for primary HIV prevention revealed that most are designed by nonacademic, nonpublic health developers, and only a small proportion of available mobile apps specifically address MSM populations. We are unlikely to reach the required scale of HIV prevention intervention coverage for MSM unless we can leverage technologies to bring key services to broad coverage for MSM. Despite an exciting pipeline of technology-based prevention tools, there are broader challenges with funding structures and sustainability that need to be addressed to realize the full potential of this emerging public health field. PMID- 26519084 TI - Leukocyte telomere length and its association with mammographic density and proliferative diagnosis among women undergoing diagnostic image-guided breast biopsy. AB - BACKGROUND: Elevated mammographic density (MD) is a strong breast cancer risk factor but the mechanisms underlying the association are poorly understood. High MD and breast cancer risk may reflect cumulative exposures to factors that promote epithelial cell division. One marker of cellular replicative history is telomere length, but its association with MD is unknown. We investigated the relation of telomere length, a marker of cellular replicative history, with MD and biopsy diagnosis. METHODS: One hundred and ninety-five women, ages 40-65, were clinically referred for image-guided breast biopsies at an academic facility in Vermont. Relative peripheral blood leukocyte telomere length (LTL) was measured using quantitative polymerase chain reaction. MD volume was quantified in cranio-caudal views of the breast contralateral to the primary diagnosis in digital mammograms using a breast density phantom, while MD area (cm(2)) was measured using thresholding software. Associations between log-transformed LTL and continuous MD measurements (volume and area) were evaluated using linear regression models adjusted for age and body mass index. Analyses were stratified by biopsy diagnosis: proliferative (hyperplasia, in-situ or invasive carcinoma) or non-proliferative (benign or other non-proliferative benign diagnoses). RESULTS: Mean relative LTL in women with proliferative disease (n = 141) was 1.6 (SD = 0.9) vs. 1.2 (SD = 0.6) in those with non-proliferative diagnoses (n = 54) (P = 0.002). Mean percent MD volume did not differ by diagnosis (P = 0.69). LTL was not associated with MD in women with proliferative (P = 0.89) or non proliferative (P = 0.48) diagnoses. However, LTL was associated with a significant increased risk of proliferative diagnosis (adjusted OR = 2.46, 95% CI: 1.47, 4.42). CONCLUSIONS: Our analysis of LTL did not find an association with MD. However, our findings suggest that LTL may be a marker of risk for proliferative pathology among women referred for biopsy based on breast imaging. PMID- 26519087 TI - Verrucous presentation in patients with mycosis fungoides. AB - Mycosis fungoides is a potentially fatal skin condition whose variable clinical appearance may mimic a variety of benign, inflammatory dermatoses, making it a diagnostic challenge. Three patients with mycosis fungoides, treated with multiple approved topical and systemic therapies, presented with acquired verrucous lesions on the extremities. The verrucous presentation of mycosis fungoides is one of the many atypical forms of the disease, with a paucity of documented cases in the medical literature. Although rare, verrucous and hyperkeratotic lesions in mycosis fungoides may increase the risk of considerable diagnostic delay if clinicians do not maintain a high degree of suspicion in cases of acquired verrucous lesions in the appropriate clinical setting. PMID- 26519086 TI - Therapeutic Targets of Human AKI: Harmonizing Human and Animal AKI. AB - The opportunity to make advances in the prevention and treatment of AKI has never been greater than it is today. Major advances have been made in the understanding of the biology of AKI, the design of clinical trials, and the use of diagnostic and prognostic biomarkers. These advances have been supplemented by the coordinated effort of societies, federal agencies, and industry, such that we are poised in the ensuing years to positively address the unrelenting harm that this disorder has created. Over the past decade, major advances have been made in understanding the pathophysiology of AKI, mainly through the study of small animal models. However, translating these findings to human AKI remains a barrier, which is typified by the absence of effective therapeutic agents. The purpose of the Acute Dialysis Quality Initiative (ADQI) XIII was to harmonize human and animal studies and determine what is known about potential therapeutic targets and what gaps in knowledge remain. A series of invited reviews will distill key concepts from this initiative that focus on different pathogenic features of AKI, including hemodynamics, immunity and inflammation, cellular and molecular pathways, progression, and regeneration and repair. This series will convey the status of our knowledge of the pathophysiology of human AKI and propose therapeutic targets for further investigation. PMID- 26519085 TI - Progression after AKI: Understanding Maladaptive Repair Processes to Predict and Identify Therapeutic Treatments. AB - Recent clinical studies indicate a strong link between AKI and progression of CKD. The increasing prevalence of AKI must compel the nephrology community to consider the long-term ramifications of this syndrome. Considerable gaps in knowledge exist regarding the connection between AKI and CKD. The 13th Acute Dialysis Quality Initiative meeting entitled "Therapeutic Targets of Human Acute Kidney Injury: Harmonizing Human and Experimental Animal Acute Kidney Injury" convened in April of 2014 and assigned a working group to focus on issues related to progression after AKI. This article provides a summary of the key conclusions and recommendations of the group, including an emphasis on terminology related to injury and repair processes for both clinical and preclinical studies, elucidation of pathophysiologic alterations of AKI, identification of potential treatment strategies, identification of patients predisposed to progression, and potential management strategies. PMID- 26519088 TI - A new analgesia regimen after (adeno) tonsillectomy in children: a pilot study. AB - OBJECTIVE: The objective was to ascertain the efficacy of a new analgesic regimen introduced in children undergoing (adeno)tonsillectomy in view of the ban on codeine use in children <12 years by the European Medicines Agency (EMA) and UK Medicines and Healthcare Products Regulatory Agency (MHRA). DESIGN: Prospective pilot study at a paediatric tertiary referral centre. MATERIALS AND METHODS: A total of 176 children undergoing (adeno) tonsillectomy over a 5-month period (Sept 2013-Jan 2014) were included in the study. Data were prospectively collected on analgesia used peri-operatively and patients were discharged on regular paracetamol and ibuprofen for 7 days and three doses of oral morphine sulphate solution to be used on days 3, 4 and 5. Pain scores were recorded on days 1-10 post-operatively using the Wong Baker Faces Pain Rating scale. RESULTS: The pain scores were significantly better (P-value < 0.0001) in children who were compliant with morphine (n = 93) than those who were not (n = 32). We also found that children who were compliant with morphine were less likely to seek help out of hours (P-value < 0.001). CONCLUSIONS: Oral morphine sulphate solution provides a reasonable alternative to codeine, albeit one should bear in mind that parental concerns and adverse effects of the drug were seen in a minority of patients (n = 11) and anaesthetists were reluctant to prescribe the drug in cases of severe OSA or associated central apnoeas (n = 7). PMID- 26519089 TI - Evaluation of bilirubin interference and accuracy of six creatinine assays compared with isotope dilution-liquid chromatography mass spectrometry. AB - OBJECTIVES: The aim of this study was to estimate bilirubin interference and accuracy of six routine methods for measuring creatinine compared with isotope dilution-liquid chromatography mass spectrometry (ID-LC/MS). DESIGN AND METHODS: A total of 40 clinical serum samples from 31 patients with serum total bilirubin concentration >68.4MUmol/L were collected. Serum creatinine was measured using two enzymatic reagents and four Jaffe reagents as well as ID-LC/MS. Correlations between bilirubin concentration and percent difference in creatinine compared with ID-LC/MS were analyzed to investigate bilirubin interference. Bias estimations between the six reagents and ID-LC/MS were performed. Recovery tests using National Institute of Standards and Technology (NIST) Standard Reference Material (SRM) 967a were also performed. RESULTS: Both the enzymatic methods showed no bilirubin interference. However, three of the four Jaffe methods demonstrated significant bilirubin concentration-dependent interference in samples with creatinine levels <53MUmol/L, and two of them showed significant bilirubin interference in samples with creatinine levels ranging from 53.0 to 97.2MUmol/L. Comparison of these methods with ID-LC/MS using patients' samples with elevated bilirubin revealed that the tested methods failed to achieve the bias goal at especially low levels of creatinine. In addition, recovery test using NIST SRM 967a showed that bias in one Jaffe method and two enzymatic methods did not achieve the bias goal at either low or high level of creatinine, indicating they had calibration bias. One enzymatic method failed to achieve all the bias goals in both comparison experiment and recovery test. CONCLUSIONS: It is important to understand that both bilirubin interference and calibration traceability to ID-LC/MS should be considered to improve the accuracy of creatinine measurement. PMID- 26519091 TI - Implementation of automated testing for 1,25-dihydroxyvitamin D: Return of experience from a core-laboratory. AB - Measurement of 1,25(OH)2D, the most biologically active form of vitamin D, circulating levels is relevant in several physiopathological states such as chronic kidney disease, parathyroid dysfunction, sarcoidosis, and vitamin D dependent rickets. Our study determined the performances of a novel automated 1,25(OH)2D immunoassay in a core-laboratory environment. We observed satisfactory analytical performances for this assay and an excellent agreement with a well established LC-MS/MS method. Furthermore, this assay allows a reduced TAT, integration in automated core-laboratories and potential consolidation with other tests of the bone and mineral metabolism. PMID- 26519090 TI - Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as indicators of tubular damage in normoalbuminuric patients with type 2 diabetes. AB - OBJECTIVES: Renal dysfunction has been reported in normoalbuminuric patients, demonstrating the necessity to improve the diagnostic and prognostic tools for diabetic kidney disease (DKD) investigation. Therefore, the aim of this study was to investigate whether the urinary levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) are increased in type 2 diabetes mellitus (DM) patients with normal or mildly increased albuminuria. DESIGN AND METHODS: In this study, 117 type 2 DM patients classified into three groups according to urinary albumin/creatinine ratio (uACR): uACR<10mg/g creatinine, uACR 10-30mg/g creatinine and uACR>30mg/g creatinine were enrolled. Urinary concentrations of KIM-1 (uKIM-1) and NGAL (uNGAL) were measured. RESULTS: uKIM-1 levels increased progressively from uACR<10mg/g creatinine (69.0+/ 20.8pg/ml) to uACR 10-30mg/g creatinine (106.1+/-41.2pg/ml) and to uACR>30mg/g creatinine (166.0+/-31.9pg/ml) (P<0.001). In addition, uNGAL levels increased progressively from uACR<10mg/g creatinine (29.5+/-8.8ng/ml) to uACR 10-30mg/g creatinine (51.7+/-10.9ng/ml) and to uACR>30mg/g creatinine (71.0+/-9.6ng/ml) (P<0.001) patients. Similarly, both uKIM-1 and uNGAL adjusted by urinary creatinine were increased in patients with uACR 10-30mg/g creatinine. Significant and positive correlations were observed between uACR, uKIM-1 and uNGAL. CONCLUSIONS: uKIM-1 and uNGAL were increased in type 2 DM patients with normal or mildly increased albuminuria, which indicates that tubular and glomerular injuries may be occurring even at the earliest stage of DKD. PMID- 26519092 TI - High-frequency hearing in seals and sea lions. AB - Existing evidence suggests that some pinnipeds (seals, sea lions, and walruses) can detect underwater sound at frequencies well above the traditional high frequency hearing limits for their species. This phenomenon, however, is not well studied: Sensitivity patterns at frequencies beyond traditional high-frequency limits are poorly resolved, and the nature of the auditory mechanism mediating hearing at these frequencies is unknown. In the first portion of this study, auditory sensitivity patterns in the 50-180 kHz range were measured for one California sea lion (Zalophus californianus), one harbor seal (Phoca vitulina), and one spotted seal (Phoca largha). Results show the presence of two distinct slope-regions at the high-frequency ends of the audiograms of all three subjects. The first region is characterized by a rapid decrease in sensitivity with increasing frequency-i.e. a steep slope-followed by a region of much less rapid sensitivity decrease-i.e. a shallower slope. In the second portion of this study, a masking experiment was conducted to investigate how the basilar membrane of a harbor seal subject responded to acoustic energy from a narrowband masking noise centered at 140 kHz. The measured masking pattern suggests that the initial, rapid decrease in sensitivity on the high-frequency end of the subject's audiogram is not due to cochlear constraints, as has been previously hypothesized, but rather to constraints on the conductive mechanism. PMID- 26519093 TI - Temporal pattern of acoustic imaging noise asymmetrically modulates activation in the auditory cortex. AB - This study investigated the hemisphere-specific effects of the temporal pattern of imaging related acoustic noise on auditory cortex activation. Hemodynamic responses (HDRs) to five temporal patterns of imaging noise corresponding to noise generated by unique combinations of imaging volume and effective repetition time (TR), were obtained using a stroboscopic event-related paradigm with extra long (>=27.5 s) TR to minimize inter-acquisition effects. In addition to confirmation that fMRI responses in auditory cortex do not behave in a linear manner, temporal patterns of imaging noise were found to modulate both the shape and spatial extent of hemodynamic responses, with classically non-auditory areas exhibiting responses to longer duration noise conditions. Hemispheric analysis revealed the right primary auditory cortex to be more sensitive than the left to the presence of imaging related acoustic noise. Right primary auditory cortex responses were significantly larger during all the conditions. This asymmetry of response to imaging related acoustic noise could lead to different baseline activation levels during acquisition schemes using short TR, inducing an observed asymmetry in the responses to an intended acoustic stimulus through limitations of dynamic range, rather than due to differences in neuronal processing of the stimulus. These results emphasize the importance of accounting for the temporal pattern of the acoustic noise when comparing findings across different fMRI studies, especially those involving acoustic stimulation. PMID- 26519094 TI - Synaptic mechanisms shaping delay-tuned combination-sensitivity in the auditory thalamus of mustached bats. AB - For the processing of target-distance information, delay-tuned auditory neurons of the mustached bat show facilitative responses to a combination of signal elements of a biosonar pulse-echo pair with a specific echo delay. They are initially produced in the inferior colliculus by facilitative responses based on the coincidence of the rebound response following glycinergic inhibition to the first harmonic of the pulse and a short-latency response to the 2nd-4th harmonics of its echo. Here, we report that further facilitative responses to pulse-echo pairs of thalamic delay-tuned neurons are mediated by glutamate receptors (NMDA and non-NMDA receptors), and that GABAergic inhibition shortens the duration of facilitative responses mediated by NMDA-receptors, without changing the delay tuning of thalamic delay-tuned neurons. Different from collicular delay-tuned neurons, thalamic ones respond much more to pulse-echo pairs than individual signal elements. The neural mechanisms involved in shaping thalamic delay-tuning support a model of hierarchical signal processing in the auditory system. PMID- 26519095 TI - Graphene oxide reinforced polymeric ionic liquid monolith solid-phase microextraction sorbent for high-performance liquid chromatography analysis of phenolic compounds in aqueous environmental samples. AB - A graphene oxide reinforced polymeric ionic liquids monolith was obtained by copolymerization of graphene oxide doped 1-(3-aminopropyl)-3-(4 vinylbenzyl)imidazolium 4-styrenesulfonate monomer and 1,6-di-(3 vinylimidazolium) hexane bihexafluorophosphate cross-linking agent. Coupled to high-performance liquid chromatography, the monolith was used as a solid-phase microextraction sorbent to analyze several phenolic compounds in aqueous samples. Under the optimized extraction and desorption conditions, linear ranges were 5 400 MUg/L for 3-nitrophenol, 2-nitrophenol, and 2,5-dichlorophenol and 2-400 MUg/L for 4-chlorophenol, 2-methylphenol, and 2,4,6-trichlorophenol (R(2) = 0.9973-0.9988). The limits of detection were 0.5 MUg/L for 3-nitrophenol and 2 nitrophenol and 0.2 MUg/L for the rest of the analytes. The proposed method was used to determine target analytes in groundwater from an industrial park and river water. None of the analytes was detected. Relative recoveries were in the range of 75.5-113%. PMID- 26519096 TI - Design and interpretation of clinical research studies in oral medicine: a brief review. AB - The objective of this short review is to help researchers improve the designs of their clinical studies. Also included is a discussion of the level of evidence provided by the various clinical research study designs. PMID- 26519097 TI - Anticipation in Real-World Scenes: The Role of Visual Context and Visual Memory. AB - The human sentence processor is able to make rapid predictions about upcoming linguistic input. For example, upon hearing the verb eat, anticipatory eye movements are launched toward edible objects in a visual scene (Altmann & Kamide, 1999). However, the cognitive mechanisms that underlie anticipation remain to be elucidated in ecologically valid contexts. Previous research has, in fact, mainly used clip-art scenes and object arrays, raising the possibility that anticipatory eye-movements are limited to displays containing a small number of objects in a visually impoverished context. In Experiment 1, we confirm that anticipation effects occur in real-world scenes and investigate the mechanisms that underlie such anticipation. In particular, we demonstrate that real-world scenes provide contextual information that anticipation can draw on: When the target object is not present in the scene, participants infer and fixate regions that are contextually appropriate (e.g., a table upon hearing eat). Experiment 2 investigates whether such contextual inference requires the co-presence of the scene, or whether memory representations can be utilized instead. The same real world scenes as in Experiment 1 are presented to participants, but the scene disappears before the sentence is heard. We find that anticipation occurs even when the screen is blank, including when contextual inference is required. We conclude that anticipatory language processing is able to draw upon global scene representations (such as scene type) to make contextual inferences. These findings are compatible with theories assuming contextual guidance, but posit a challenge for theories assuming object-based visual indices. PMID- 26519098 TI - Valproic acid mediates miR-124 to down-regulate a novel protein target, GNAI1. AB - Valproic acid (VPA) is an anti-convulsant drug that is recently shown to have neuroregenerative therapeutic actions. In this study, we investigate the underlying molecular mechanism of VPA and its effects on Bdnf transcription through microRNAs (miRNAs) and their corresponding target proteins. Using in silico algorithms, we predicted from our miRNA microarray and iTRAQ data that miR 124 is likely to target at guanine nucleotide binding protein alpha inhibitor 1 (GNAI1), an adenylate cyclase inhibitor. With the reduction of GNAI1 mediated by VPA, the cAMP is enhanced to increase Bdnf expression. The levels of GNAI1 protein and Bdnf mRNA can be manipulated with either miR-124 mimic or inhibitor. In summary, we have identified a novel molecular mechanism of VPA that induces miR-124 to repress GNAI1. The implication of miR-124->GNAI1->BDNF pathway with valproic acid treatment suggests that we could repurpose an old drug, valproic acid, as a clinical application to elevate neurotrophin levels in treating neurodegenerative diseases. PMID- 26519099 TI - Neurorestorative effects of eugenol, a spice bioactive: Evidence in cell model and its efficacy as an intervention molecule to abrogate brain oxidative dysfunctions in the streptozotocin diabetic rat. AB - Eugenol (EU), an active principle of cloves, is also widely distributed in various other plants (eg. basil, cinnamon, etc). While its antioxidant and anti inflammatory properties are well established, biochemical insights related to its neuromodulatory potential in diabetic conditions are not clear. In the present study, initially we investigated its potential to modulate specific biochemical responses in SHSY5Y cells under experimentally -induced hyperglycemic condition. Co-exposure of cells with EU (5-10 MUM) not only enhanced the cell viability, but significantly offset glucose -associated oxidative stress (as evidenced by diminished levels of reactive oxygen species and hydroperoxides). Further EU enhanced the reduced glutathione (GSH) levels and also ameliorated the levels of 3 - nitrotyrosine and expression of HSP70. We subsequently examined its efficacy to attenuate biochemical aberrations in brain regions of a streptozotocin (STZ) diabetic rat employing an intervention approach. Brain regions of EU treated (10 mg/kg bw/d, post 6 weeks of STZ) diabetic rats showed diminished levels of oxidative markers and protein carbonyls in both cytosolic and mitochondrial fractions. EU treatment caused enhanced activities of enzymic antioxidants and diminished both GSH and total thiols. Further, activities of complex I - III, succinate dehydrogenase and citrate synthase in brain regions were also significantly restored. Interestingly, EU treatment differentially attenuated the elevated activity of acetylcholinesterase and levels of calcium in brain regions. Collectively, based on the data obtained in in vitro and in vivo models, we hypothesize that EU may be employed as an adjuvant therapeutic molecule to alleviate complications under diabetic conditions. PMID- 26519100 TI - Size of quadriceps femoris may contribute to thyrotoxic periodic paralysis. AB - Thyrotoxic periodic paralysis (TPP) frequently occurs on male individuals at their third and forth decades. The major site of involvement is the proximal muscles of lower limbs. Increasing evidence has shown that the occurrence of TPP is determined by multiple factors. We hypothesized that apart from hormonal fluctuations, skeletal muscle itself may explain for the age and sex variance as well. Our study was established to explore whether the size of lower limb skeletal muscles were related to TPP. We conducted a clinical experiment including 43 patients diagnosed with TPP (Group 1) and 39 pure hyperthyroidism individuals (Group 2). Current age, body mass index (BMI), thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), average girth of bilateral upper arm and thigh, physical activity level (PAL) were measured. We also adopted B mode ultrasound to quantify the muscle thickness (MT) of the major muscle involved in the disease, the quadriceps femoris (QF, including rectus femoris, RF; vastus intermedius, VI; vastus medialis, VM and vastus lateralis, VL). Patients were matched in TSH, FT4 and FT3. PAL was also statistically identical between groups. Age, BMI, thigh girth, the average of bilateral MT of QF were statistically different. After adjusting for age, BMI and girth, Group 1 still presented with larger MT of QF than Group 2, regardless of their current thyroid hormone level. There indeed exists an independent relationship between muscle thickness and TPP. PMID- 26519101 TI - The transcription, translation, transport-trail and autoimmunity: Guilt by association. AB - The autoimmune connective tissue diseases (ACTD) are a group of diseases which share clinical features and genetic inheritance. They are characterized by systemic autoimmunity and autoantibody production with a striking predilection for cellular components involved in transcription, translation and cellular transport. Although multiple triggers of autoimmunity have been proposed for this group of diseases including microbial agents such as viruses and bacteria, drugs, ultraviolet light, environmental toxins, stress, hormones and heavy metals, the prominence of autoantibodies to components of the transcription, translation, cellular transport-trail (TTTT) suggests that the agent(s) triggering the autoimmune response potentially utilize the TTTT. For the ACTD, viruses and viral agents are the likely triggers of autoimmunity as a result of aberrant viral latency with the production of autoantibodies to the components of the cellular TTTT machinery through multiple mechanisms, perhaps including molecular mimicry, bystander activation and epitope spreading. PMID- 26519102 TI - Adiponutrin (PNPLA3) in liver fibrogenesis: Is unaltered HepG2 cell line a better model system compared to murine models? AB - Alcoholic liver disease is a major source of morbidity and mortality worldwide. Twin studies had demonstrated heritability of alcoholic liver disease. Although to date only Adiponutrin (PNPLA3) rs738409 polymorphism (I148M) had been unequivocally proved to be associated with increased risk of alcoholic liver disease across different ethnicities. This protein was previously thought to have a predominant lipolytic role. However, recent investigations have provided evidence of lipogenic activity of this protein. The current hypothesis paper is summarizing the recent evidences gleaned in biological role of Adiponutrin and bioinformatic pointers towards a role in lipid trafficking. A critical appraisal of the utility of murine models and cell based systems in investigating Adiponutrin is also presented. As the HepG2 cell line harbors the I148M mutation in homozygous state it is hypothesized that this should represent an ideal model system for PNPLA3 biology. Thus, as Adiponutrin is proposed as having both lipolytic and lipogenic/lipid trafficking roles it is termed as a Yin-Yang protein in analogy to ancient Chinese wisdom. PMID- 26519104 TI - American college of surgeons clinical congress 2015. PMID- 26519103 TI - Reliability of muscle strength measures obtained with a hand-held dynamometer in an elderly population. AB - BACKGROUND: The objective of this study was to assess the reliability of a hand held dynamometer for isometric strength measurements among nursing home residents. METHODS: The isometric muscle strength of nursing home residents was assessed for eight different muscle groups, using a hand-held dynamometer, the MicroFET2 device. Strength measurements were performed at baseline and after 4 days by the same operator and after 8 days by a second operator. Intraclass coefficients (ICC) were computed to assess the relative reliability, whereas the minimal detectable change (MDC%) was calculated to assess the absolute reliability of the test-retest of the MicroFET2 used by one single operator or by two different ones. RESULTS: Thirty nursing home residents (75.0 +/- 11.2 years, 50% of women) were enrolled in this study. ICC of the test-retest with one single operator ranged from 0.60 (0.37-0.83) for the ankle extensors to 0.85 (0.74-0.95) for the elbow flexors. When considering the test-retest with two different operators, the ICC values ranged from 0.62 (0.41-0.84) for the ankle extensors to 0.87 (0.79-0.96) for the elbow extensors. For the absolute reliability, MDC% varies from 27.64 (elbow flexors) to 81.97 (ankle extensors) when performed in intra-observer. In interobserver condition, MDC%, respectively, varies from 24.38 (elbow extensors) 67.59 (ankle extensors). CONCLUSION: Using standardized protocol and standardized instructions to patients, a high relative and moderate absolute reliability was observed for all but ankle muscle groups, making this hand-held dynamometer a potential tool for research in the elderly population. PMID- 26519105 TI - Dynamic regulation of permissive histone modifications and GATA3 binding underpin acquisition of granzyme A expression by virus-specific CD8(+) T cells. AB - Numerous studies have focused on the molecular regulation of perforin (PFP) and granzyme B (GZMB) expression by activated cytotoxic T lymphocytes (CTLs), but little is known about the molecular factors that underpin granzyme A (GZMA) expression. In vitro activation of naive CD8(+) T cells, in the presence of IL-4, enhanced STAT6-dependent GZMA expression and was associated with GATA3 binding and enrichment of transcriptionally permissive histone posttranslational modifications (PTMs) across the Gzma gene locus. While GZMA expression by effector influenza A virus specific CTLs was also associated with a similar permissive epigenetic signature, memory CTL lacked enrichment of permissive histone PTMs at the Gzma locus, although this was restored within recalled secondary effector CTLs. Importantly, GZMA expression by virus-specific CTLs was associated with GATA3 binding at the Gzma locus, and independent of STAT6 mediated signaling. This suggests regulation of GZMA expression is underpinned by differentiation-dependent regulation of chromatin composition at the Gzma locus and that, given GATA3 is key for CTL differentiation in response to infection, GATA3 expression is regulated by a distinct, IL-4 independent, signaling pathway. Overall, this study provides insights into the molecular mechanisms that control transcription of Gzma during virus-induced CD8(+) T-cell differentiation. PMID- 26519106 TI - Web-Based STAR E-Learning Course Increases Empathy and Understanding in Dementia Caregivers: Results from a Randomized Controlled Trial in the Netherlands and the United Kingdom. AB - BACKGROUND: The doubling of the number of people with dementia in the coming decades coupled with the rapid decline in the working population in our graying society is expected to result in a large decrease in the number of professionals available to provide care to people with dementia. As a result, care will be supplied increasingly by untrained informal caregivers and volunteers. To promote effective care and avoid overburdening of untrained and trained caregivers, they must become properly skilled. To this end, the European Skills Training and Reskilling (STAR) project, which comprised experts from the domains of education, technology, and dementia care from 6 countries (the Netherlands, Sweden, Italy, Malta, Romania, and the United Kingdom), worked together to create and evaluate a multilingual e-learning tool. The STAR training portal provides dementia care training both for informal and formal caregivers. OBJECTIVE: The objective of the current study was to evaluate the user friendliness, usefulness, and impact of STAR with informal caregivers, volunteers, and professional caregivers. METHODS: For 2 to 4 months, the experimental group had access to the STAR training portal, a Web-based portal consisting of 8 modules, 2 of which had a basic level and 6 additional modules at intermediate and advanced levels. The experimental group also had access to online peer and expert communities for support and information exchange. The control group received free access to STAR after the research had ended. The STAR training portal was evaluated in a randomized controlled trial among informal caregivers and volunteers in addition to professional caregivers (N=142) in the Netherlands and the United Kingdom. Assessments were performed with self-assessed, online, standardized questionnaires at baseline and after 2 to 4 months. Primary outcome measures were user friendliness, usefulness, and impact of STAR on knowledge, attitudes, and approaches of caregivers regarding dementia. Secondary outcome measures were empathy, quality of life, burden, and caregivers' sense of competence. RESULTS: STAR was rated positively by all user groups on both usefulness and user friendliness. Significant effects were found on a person-centered care approach and on the total score on positive attitudes to dementia; both the experimental and the control group increased in score. Regarding empathy, significant improvements were found in the STAR training group on distress, empathic concern, and taking the perspective of the person with dementia. In the experimental group, however, there was a significant reduction in self-reported sense of competence. CONCLUSIONS: The STAR training portal is a useful and user-friendly e-learning method, which has demonstrated its ability to provide significant positive effects on caregiver attitudes and empathy. PMID- 26519107 TI - Suboptimal bonding impairs hormonal, epigenetic and neuronal development in preterm infants, but these impairments can be reversed. AB - This review aimed to raise awareness of the consequences of suboptimal bonding caused by prematurity. In addition to hypoxia-ischaemia, infection and malnutrition, suboptimal bonding is one of the many unnatural stimuli that preterm infants are exposed to, compromising their physiological development. However, the physiological consequences of suboptimal bonding are less frequently addressed in the literature than those of other threatening unnatural stimuli. CONCLUSION: This review found that suboptimal bonding significantly impaired hormonal, epigenetic and neuronal development, but these impairments could be reversed by bonding interventions. This suggests that neonatal intensive care units should focus more on interventions that optimise bonding. PMID- 26519108 TI - Purple livedo reticularis. PMID- 26519109 TI - Monocyte and macrophage subsets along the continuum to heart failure: Misguided heroes or targetable villains? AB - The important contribution of monocytes and macrophages to cardiovascular disease and heart failure pathophysiology has attracted significant attention in the past several years. Moreover, subsets of these cells have been shown to partake in the initiation and exacerbation of several cardiovascular pathologies including atherosclerosis, myocardial infarction, pressure overload, cardiac ischemia and fibrosis. This review focuses on the role of monocytes and macrophages along the continuum to heart failure and the contribution of different cell subsets in promoting or inhibiting cardiac injury or repair. It outlines a primary role for the monocyte/macrophage system as an important regulator of cardiac inflammation and extracellular matrix remodelling in early and late stage heart disease with particular focus on phenotypic plasticity and the inflammatory and fibrotic functions of these cells. It also summarizes evidence from pre-clinical and clinical studies evaluating monocyte type regulation and its functional significance for development of cardiovascular disease and heart failure. Finally, current and prospective therapeutic approaches based on monocyte and macrophage manipulation for the treatment of cardiovascular disease and heart failure are discussed. Based on these data, future work in this fertile research area may aid in identifying potential diagnostic biomarkers and novel therapies for chronic heart failure. PMID- 26519110 TI - deltaPKC interaction with the d subunit of F1Fo ATP synthase impairs energetics and exacerbates ischemia/reperfusion injury in isolated rat hearts. AB - Previously, we demonstrated protection against hypoxic injury in neonatal cardiac myocytes and reduced release of cardiac troponin I from perfused rat hearts by a novel peptide inhibitor [NH2 YGRKKRRQRRRMLATRALSLIGKRAISTSVCAGRKLALKTIDWVSFDYKDDDDK-] of the delta protein kinase C (deltaPKC) interaction with the "d" subunit of mitochondrial F1Fo ATP synthase (dF1Fo). This peptide was developed in our laboratory and contains: an HIV-Tat protein transduction domain; a mitochondrial targeting motif; the deltaPKC-dF1Fo inhibitor sequence; and a FLAG epitope. In the present study the deltaPKC-dF1Fo inhibitor attenuated co-immunoprecipitation of deltaPKC with dF1Fo, improved recovery of contractility, diminished levels of tissue t carbonyls and 4-hydroxy-2-nonenal (HNE), and reduced 2,3,5-triphenyltetrazolium chloride-monitored infarct size following simulated global ischemia/reperfusion (IR) exposures. Perfusion of hearts with this peptide prior to IR enhanced ATP levels 2.1-fold, improved ADP (state 3)- and FCCP (maximal)-stimulated respiration in mitochondrial oxygen consumption assays, and attenuated Ca(++) induced mitochondrial swelling following ischemic injury. Mitochondrial membrane potential (assessed by JC-1) was also improved 1.6-fold by the inhibitor in hearts subsequently exposed to IR injury. Brief IR exposures did not cause mitochondrial loss of cytochrome c in the presence or absence of the inhibitor. Additionally, the inhibitor did not modify accumulation of the autophagy marker LC3II after brief IR injury. Our results support the potential for this first-in class peptide as a translational agent for combating cardiac IR injury. PMID- 26519112 TI - The natural behavior of mononuclear phagocytes in HTS formation. AB - Hypertrophic scars (HTS) are caused by trauma or burn injuries to the deep dermis and are considered fibrosis in the skin. Monocytes, M1 and M2 macrophages are mononuclear phagocytes. Studies suggest that M2 macrophages are profibrotic and might contribute to HTS formation. Our lab has established a human HTS-like nude mouse model, in which the grafted human skin develops red, raised, and firm scarring, resembling HTS seen in humans. In this study, we observed the natural behavior of mononuclear phagocyte system in this nude mouse model of dermal fibrosis at multiple time points. Thirty athymic nude mice received human skin grafts and an equal number of mice received mouse skin grafts as controls. The grafted skin and blood were harvested at 1, 2, 3, 4, and 8 weeks. Wound area, thickness, collagen morphology and level, the cell number of myofibroblasts, M1- and M2-like macrophages in the grafted skin, as well as monocyte fraction in the blood were investigated at each time points. Xenografted mice developed contracted and thickened scars grossly. The xenografted skin resembled human HTS tissue based on enhanced thickness, fibrotic orientation of collagen bundles, increased collagen level, and infiltration of myofibroblasts. In the blood, monocytes dramatically decreased at 1 week postgrafting and gradually returned to normal in the following 8 weeks. In the xenografted skin, M1-like macrophages were found predominantly at 1-2 weeks postgrafting; whereas, M2-like macrophages were abundant at later time points, 3-4 weeks postgrafting coincident with the development of fibrosis in the human skin tissues. This understanding of the natural behavior of mononuclear phagocytes in vivo in our mouse model provides evidence for the role of M2-like macrophages in fibrosis of human skin and suggests that macrophage depletion in the subacute phases of wound healing might reduce or prevent HTS formation. PMID- 26519114 TI - Beneficial long-term effect of aldosterone antagonist added to a traditional blockade of the renin-angiotensin-aldosterone system among patients with obesity and proteinuria. AB - INTRODUCTION: Over the past decade, obesity has become a risk factor for developing chronic kidney disease. Proteinuria is known to be an independent determinant of the progression of chronic kidney disease, and adipose tissue is a recognized source of components of the renin-angiotensin-aldosterone system (RAAS). Recent studies have shown that plasma aldosterone levels are disproportionately higher in patients with obesity. Drugs that block the RAAS are unable to inhibit aldosterone in the long term. The aim of our study was to analyze the renoprotective effect of an aldosterone antagonist in combination with RAAS blockers in patients with obesity and proteinuric nephropathy. MATERIAL AND METHODS: This study is a substudy of previously published study on the renoprotective effect of mineralocorticoid receptor blockers in patients with proteinuric nephropathies. Patients with proteinuria levels >1g/24h who were taking spironolactone and were being treated with other RAAS blockers were divided according to body mass index (BMI) into an obesity group (BMI >=30kg/m2) and a control group. RESULTS: Seventy-one patients were included in the study, with a mean age of 56.7+/-15.1 years. More than 50% of the patients in both groups had diabetes. Thirty-two patients were included in the obesity group and 39 were included in the control group. There were no significant differences in renal function, proteinuria, blood pressure, serum potassium levels and the percentage of RAAS blockers in both groups. After a follow-up of 28.9 (14-84) months, there was a 59.4% reduction in proteinuria in the obesity group (2.8+/ 2.1 vs. 1.3+/-1.6g/24h, p<.05). The reduction in proteinuria was greater than 50% in 22 (68.8%) cases, and the mean blood pressure showed a significant decrease (from 100.6+/-9 to 92.1+/-7.4mm Hg, p<.05). The control group showed a 69.6% reduction in proteinuria (1.9+/-1.4 to 0.8+/-0.5, p<0.05). The reduction of proteinuria was higher than 50% in 22 (68.8%) cases in obese patients and in 33 (84.6%) cases in non-obese group. Renal function remained stable in both groups during the follow-up. Nine patients (28.1%) in the obesity group experienced gynecomastia. The incidence of hyperkalemia was similar for the 2 groups (6.3%). CONCLUSION: Aldosterone antagonist treatment in obese patients with proteinuric nephropathies induces a drastic and sustained reduction in proteinuria but not more than the non-obese group. There was a trend toward slowing progression of renal failure with few adverse events. PMID- 26519113 TI - Calcium signaling in membrane repair. AB - Resealing allows cells to mend damaged membranes rapidly when plasma membrane (PM) disruptions occur. Models of PM repair mechanisms include the "lipid-patch", "endocytic removal", and "macro-vesicle shedding" models, all of which postulate a dependence on local increases in intracellular Ca(2+) at injury sites. Multiple calcium sensors, including synaptotagmin (Syt) VII, dysferlin, and apoptosis linked gene-2 (ALG-2), are involved in PM resealing, suggesting that Ca(2+) may regulate multiple steps of the repair process. Although earlier studies focused exclusively on external Ca(2+), recent studies suggest that Ca(2+) release from intracellular stores may also be important for PM resealing. Hence, depending on injury size and the type of injury, multiple sources of Ca(2+) may be recruited to trigger and orchestrate repair processes. In this review, we discuss the mechanisms by which the resealing process is promoted by vesicular Ca(2+) channels and Ca(2+) sensors that accumulate at damage sites. PMID- 26519115 TI - Balance and gait performance of scoliotic subjects: A review of the literature. AB - INTRODUCTION: Scoliosis is one of the common spinal deformities and considered as lateral curvature of the spine. Scoliosis lead to changes in the synergy between body segments, spinal anatomy, left-right trunk symmetry and cause pathological gait pattern [1,4,5-7]. Scoliosis is a structural deformity, so it can alter center of mass (COM) position and weight distribution on lower limbs. This suggests that scoliotic patients show the poorer stability rather aged match normal group. It was controversial that scoliosis influences the balance and gait performances, and also the effects of brace on these parameters. Therefore, it was aimed to evaluate the available literatures on balance and gait of scoliotic subjects. MATERIALS AND METHODS: We conducted a search via PubMed, Google scholar and ISI web of knowledge to identify studies on scoliosis field and the effect of this deformity on kinetic and kinematic parameters as well as the influence of bracing on mentioned parameters. Some key words such as kinetic, kinematic, gait, stability, and walking were used in combination with scoliosis. The publication dates of the full-length articles were between 1998 and 2014. Down and Black tool was used to evaluate the quality of the articles. RESULTS: Our multiple Medline searches led to the find out 54 papers that 26 of which were relevant based on title and abstract. Based on their references, we retrieved 6 more articles. We ultimately included 31 articles in this literature review. The number of studies regarding the influence of brace on kinetic and kinematic parameters in scoliotic subject was small. Based on the results of various studies, there is no correlation between gait pathology and scoliotic curve direction, no difference between stability of scoliotic and normal subjects and no difference between range of motions of lower limb joints in scoliotic subjects while walking with and without orthosis. CONCLUSION: There was a not sufficient robust evidence to judge about the influence of scoliosis deformity on kinetic and kinematic parameters. However, it should be emphasized that use of orthosis may influence the symmetry of gait and improve standing stability in adult with idiopathic scoliosis. PMID- 26519116 TI - Rotation exercise classes did not improve function in women with non-specific chronic low back pain: A randomized single blind controlled study. AB - BACKGROUND: Exercise is considered the first line of treatment for people with non-specific chronic low back pain (NSCLBP) but the ideal exercise type is currently unclear. Given the unique anatomical structure of the lower lumbar spine and the lumbosacral junction transverse-plane rotation exercises may be helpful for people suffering from pain in this region. OBJECTIVE: We aimed to examine the effect of spinal rotation exercises delivered in a group format on range of motion, pain level and function parameters in women with NSCLBP. METHODS: This was a randomized controlled single-blinded study. Thirty-five women with NSCLBP, participated in either a bi-weekly rotation exercise classes (n= 20) or a 'wait-list' control group (n = 15). The exercises aimed at improving lumbar mobility in the transverse plane. Pain rated on a Visual Analog Scale, back specific disability (Rolland Morris questionnaire), and lumbar range of motion (flexion, extension and left and right rotation) were taken prior to intervention, immediately following 4 weeks of intervention and 8 weeks later. RESULTS: There were no significant differences for either group (p> 0.05) on all dependent variables at all times of measurements. CONCLUSIONS: A specific group program of rotation exercises had no effect on the functional status, pain level and lumbar range of motion in women with NSCLBP. PMID- 26519117 TI - Functional contributors to poor movement and balance control in patients with low back pain: A descriptive analysis. AB - BACKGROUND: Automatic and voluntary body position control is essential for postural stability; however, little is known about individual factors that impair the sensorimotor system associated with low back pain (LBP). OBJECTIVE: To evaluate automatic and voluntary motor control impairments causing postural instability in patients with LBP. METHODS: Motor control impairments associated with poor movement and balance control were analyzed prospectively in 32 patients with LBP. Numeric Rating Scale (NRS) for pain assessment, Oswestry Disability Index (ODI) for disability measurement, and computerized dynamic posturography (CDP) for analysis of postural responses were used to measure outcomes of all patients. Computerized dynamic posturography tests including Sensory organization test (SOT), limits of stability test (movement velocity, directional control, endpoint, and maximum excursion), rhythmic weight shift (rhythmic movement speed and directional control), and adaptation test (toes-up and toes-down tests) were performed and the results compared with NeuroCom normative data. RESULTS: The mean age of the patients was 40.50 +/- 12.28 years. Lower equilibrium scores were observed in SOT (p < 0.05). There was a significant increase in reaction time and decrease in movement velocity, directional control, and endpoint excursion (p < 0.05). Speed of rhythmic movement along the anteroposterior direction decreased, while speed increased along the lateral direction (p < 0.05). Poor directional control was recorded in the anteroposterior direction (p < 0.05). Toes-down test showed an increased COG sway in patients compared with that in the controls (p < 0.05). CONCLUSIONS: LBP causes poor voluntary control of body positioning, a reduction in movement control, delays in movement initiation, and a difficulty to adapt to sudden surface changes. PMID- 26519118 TI - Temporomandibular dysfunction and risk factors for anxiety and depression. AB - BACKGROUND: Anxiety and depression may cause temporomandibular joint (TMJ) complaints or TMJ disorders may trigger some of psychiatric problems. OBJECTIVE: The aim of this study was to determine the risk factors and the interactive role of anxiety and depression in patients with TMJ dysfunction. METHOD: A total of 273 patients who presented to the multidisciplinary outpatient clinic of TMJ diseases that were followed up for temporomandibular dysfunction (TMD), were included in this trial. Patients were classified in three sub-groups: patients with myofacial pain alone (group-1), patients with TMJ disorder alone (group-2), and patients with TMJ disorder and also myofacial pain (group-3). All patients were examined using the standard TMJ examination and were evaluated with the Hospital Anxiety Depression (HAD) scale in order to determine anxiety and depression. RESULTS: According to the univariate analysis, risk factors for patients with confirmed anxiety and/or depression were being female (p= 0.005), existence of myofacial pain (p= 0.01), effects of stress on complaints (p= 0.005) and insufficient social support (p< 0.001). According to regression analysis, presence of psychopathology was increased 3.7 times in those being female, 3.5 times with insufficient social support, and 1.2 times with myofacial pain. CONCLUSIONS: Among the patients with TMD, the groups who were considered to have anxiety and depression were female patients, patients with deficient social support system, and patients with myofacial pain alone or patients with myofacial pain accompanying an existing TMJ disorder. The existence of anxiety and depression should be considered in addition to musculoskeletal pathologies during the treatment plan of patients with TMJ who have these risk factors. PMID- 26519119 TI - Tai Chi vs. combined exercise prescription: A comparison of their effects on factors related to falls. AB - BACKGROUND: Regular exercise training is one of the core components of multifactorial fall-prevention programs. OBJECTIVE: To compare the effect of Tai Chi and combined exercise prescription that consists of three main components of an exercise prescription on static balance, dynamic balance, fear of falling and mood. METHODS: Sixty older adults aged 55-76 were randomly assigned to Group 1 (Tai Chi exercise) or Group 2 (combined exercise prescription). Exercise was performed three times a week over a period of 12 weeks. Single Leg-Stance-Eyes Open (SLS-EO), Single Leg-Stance Eyes Closed (SLS-EC), computerized balance measurements, the Timed Up and Go (TUG) test, Berg Balance Scale (BBS), the Survey of Activities and Fear of Falling in the elderly (SAFFE), the Geriatric Depression Scale (GDS), and the Beck Depression Scale (BDS) were assessed before and after the final training session. RESULTS: Both exercise groups yielded better results in dynamic balance assessments (TUG and BBS) at the 12th week (p< 0.05). Group 1 also showed significant improvements in the measurements of SLS EO, SLS-EC, SAFFE, GDS, and BDS during the post-intervention period (all p< 0.05). When the groups were compared, a significant difference was found between groups in favor of Group 1 in terms of the SLS-EO and SAFFE (p< 0.05). CONCLUSIONS: It can be concluded that Tai Chi may be a more successful exercise intervention for factors-related to falls in older people. PMID- 26519120 TI - Static balance after surgical decompression of lumbar spinal canal stenosis. AB - BACKGROUND AND OBJECTIVES: Spinal canal stenosis is the most common reason for spinal surgeries in patients over 65 years of age. The aim of the study was to assess static balance in patients prior to and after surgical decompression of lumbar spinal canal stenosis. MATERIAL AND METHODS: The study population consisted of 30 patients suffering from spinal canal stenosis. Their static balance was measured, i.e. quantitative analysis of balance reaction parameters in quiet standing was performed. RESULTS: The analysis of the collected data did not reveal any statistically significant differences between parameters measured prior to and after the surgery (for p< 0.05). A tendency for a decrease of measured parameters was observed. The regularity of changes was determined; in addition, for this analysis, the Spearman's rank correlation coefficient was used. CONCLUSIONS: The analysis of the collected data did not reveal any statistically significant improvement of balance reactions after spinal canal stenosis surgery. In spite of pain reduction, there was no improvement in balance reactions, as behavioural patterns for balance reactions had been fossilised before surgery. PMID- 26519121 TI - Factors that Influence Mycobacterium bovis Infection in Red Deer and Wild Boar in an Epidemiological Risk Area for Tuberculosis of Game Species in Portugal. AB - Bovine tuberculosis (bTB) is a worldwide zoonotic disease of domestic and wild animals. Eradication has proved elusive in those countries with intensive national programmes but with ongoing transmission between wildlife and cattle. In Portugal, a high-risk area for bTB was defined and specific measures implemented to assess and minimize the risk from wildlife. Data from the 2011 to 2014 hunting seasons for red deer (Cervus elaphus) and wild boar (Sus scrofa) were analysed with bovine demographic and bTB information to assess factors that determined the occurrence and distribution of bTB in both species. The likelihood of bTB-like lesions in wild boar was positively associated with density of red deer, wild boar and cattle, while for red deer, only their density and age were significant factors. The likelihood of Mycobacterium bovis isolation in wild boar was associated with density of cattle and red deer and also with the anatomical location of lesions, while for red deer, none of the variables tested were statistically significant. Our results suggest that, in the study area, the role of red deer and wild boar may be different from the one previously suggested by other authors for the Iberian Peninsula, as red deer may be the driving force behind M. bovis transmission to wild boar. These findings may assist the official services and game managing bodies for the management of hunting zones, what could also impact the success of the bTB eradication programme. PMID- 26519122 TI - The impact of tumor size on the association of the extent of lymph node resection and survival in clinical stage I non-small cell lung cancer. AB - INTRODUCTION: Lymph node evaluation for node-negative non-small cell lung cancer (NSCLC) is associated with long-term survival but it is not clear if smaller tumors require as extensive a pathologic nodal assessment as larger tumors. This study evaluated the relationship of tumor size and optimal extent of lymph node resection using the National Cancer Data Base (NCDB). MATERIALS AND METHODS: The incremental survival benefit of each additional lymph node that was evaluated for patients in the NCDB who underwent lobectomy for clinical Stage I NSCLC from 2003 to 2006 was evaluated using Cox multivariable proportional hazards regression modeling. The impact of tumor size was assessed by repeating the Cox analysis with patients stratified by tumor size >=2 cm vs <2 cm. RESULTS: A median of 7 [interquartile range: 4,11] lymph nodes were examined in 13,827 patients who met study criteria. Following adjustment, the evaluation of each additional lymph node demonstrated a significant survival benefit through 11 lymph nodes. After grouping patients by tumor size, patients with tumors <2 cm demonstrated a significant survival benefit for the incremental resection of each additional lymph node through 4 lymph nodes while patients with tumors >=2 cm had a significant survival benefit through 14 lymph nodes. CONCLUSION: Pathologic lymph node evaluation is associated with improved survival for clinically node-negative NSCLC, but the extent of the necessary evaluation varies by tumor size. These results have implications for guidelines for lymph node assessment as well as the choice of surgery vs other ablative techniques for clinical stage I NSCLC. PMID- 26519123 TI - First line crizotinib in anaplastic lymphoma kinase (ALK) rearranged squamous cell lung cancer. AB - Recently the superiority of Crizotinib to standard first-line pemetrexed-plus platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC has been demonstrated. We report of a 36-year-old never smoker with advanced squamous cell carcinoma, presenting with a left lower lobe lesion, N3 nodal disease and multiple metastases (pleura, adrenal, muscle, bone). Despite squamous histology we decided on molecular testing. IHC for ALK was positive and confirmatory fluorescent in situ hybridization showed translocation of ALK. Although there is little evidence on ALK rearrangements in squamous NSCLC we decided on first line treatment with Crizotinib (250 mg twice daily). Eight and twelve weeks after treatment initiation a whole-body FDG fusion PET/CT scan showed dramatic tumor response with little remaining metabolic uptake in the left lobe and a single bone lesion. This evidence raises the question whether ALK testing should be done in never smokers with squamous NSCLC in the absence of oncogenic driver mutations. To our knowledge, this the first report of first line treatment of full squamous ALK-positive NSCLC with crizotinib. PMID- 26519124 TI - Comparison of exchange of laryngeal mask airway and Igel for tracheal tube using Eschmann Tracheal Tube Introducer during simulated resuscitation. PMID- 26519125 TI - Streptococcus pneumoniae meningitis without pleocytosis of the cerebrospinal fluid. AB - Pleocytosis of the cerebrospinal fluid is a key finding for the diagnosis of bacterial meningitis. Bacterial meningitis presenting in normal cerebrospinal fluid is rare in adult patients. We describe the case of a patient with pneumococcal meningitis without cerebrospinal fluid pleocytosis. This case suggests that immediate antibiotic therapy should be started when meningitis is suspected, even with normal cerebrospinal fluid findings. (See Figure.) PMID- 26519126 TI - The contribution of radiotherapy to subsequent thyroid cancer risk may be confined to a subgroup of breast cancer patients. PMID- 26519127 TI - Immunohistochemical localization of progesterone receptor isoforms and estrogen receptor alpha in the chicken oviduct magnum during development. AB - In this work, the immunohistochemical expression of progesterone receptor (PR) isoforms and estrogen receptor alpha (ER-alpha), as well as the histomorphometric changes of the magnum region of the left oviduct from 8-day-old chicken embryos to one-month-old chickens were evaluated. Results indicate evident histological changes in the oviduct magnum during development mainly in the magnum's mucosa. Immunohistochemical analysis showed that the oviduct magnum from 8-day-old chicken embryos to one-day-old chickens did not present any PR isoform, but the oviduct magnum of one-week and one-month-old chickens expressed PR in the nuclei of all cell types. In epithelial cells, PR-B was the only isoform expressed; in muscle and serosa cells, PR-A isoform was the only isoform expressed; and stromal cells expressed both isoforms. The results also demonstrate positive ER-alpha immunostaining in the nuclei of different cells from embryonic life to later developmental stages of the oviduct magnum. Data indicate that the variations of ER-alpha or PR expression or dominance of either PR expression is differentially regulated depending on the cell type, the development of the oviduct, and in an age-specific manner. These variations in sex steroids hormone receptors are related with histological changes of the oviduct magnum through development. PMID- 26519128 TI - Beliefs about medication predict the misattribution of a common symptom as a medication side effect--Evidence from an analogue online study. AB - OBJECTIVE: Some perceived medication side effects may be 'normal' symptoms that patients misattribute to the medication. Using an analogue approach, we tested if medication beliefs predict whether participants misattribute a headache as a side effect and subsequently intend to stop medication. METHODS: We recruited 690 participants, 223 reporting a past asthma diagnosis. They received information about asthma and Molair, a fictitious asthma treatment modeled on a licensed treatment (montelukast). We varied the description of efficacy and side effects (which did not include headache). Pre-exposure to this information, participants completed the Beliefs about Medicine Questionnaire (BMQ)-General and the Perceived Sensitivity to Medicines Scale (PSM), post-exposure they completed the BMQ-Specific. Participants were asked to imagine they experienced a headache while taking Molair. Finally, they rated whether the headache was a side effect (misattribution) and if they would stop taking Molair (behavioral intention). RESULTS: Nearly a quarter (170) of participants misattributed the headache to Molair and 69 (10%) subsequently intended to stop Molair. Both outcomes were predicted by general and specific medication beliefs. Odds of misattribution (m) and behavioral intention (i) increased with higher General Harm (ORm=1.90, ORi=2.72), General Overuse (ORm=1.74, ORi=1.56) and Molair Concern beliefs (ORm=1.52, ORi=1.78, all p<.01), but decreased with General Benefit (ORm=0.72, ORi=0.53) and Molair Necessity beliefs (ORm=0.72, ORi=0.70, all p<.05). CONCLUSION: Symptom misattribution and subsequent intentions to stop Molair were predicted by pre-exposure beliefs about medicines in general and post-exposure beliefs about Molair. Patients with negative medication beliefs may be prone to misattribute symptoms and subsequently stop medication. PMID- 26519129 TI - Response. PMID- 26519130 TI - Tackling malnutrition: a systematic review of 15-year research evidence from INDEPTH health and demographic surveillance systems. AB - BACKGROUND: Nutrition is the intake of food in relation to the body's dietary needs. Malnutrition results from the intake of inadequate or excess food. This can lead to reduced immunity, increased susceptibility to disease, impaired physical and mental development, and reduced productivity. OBJECTIVE: To perform a systematic review to assess research conducted by the International Network for the Demographic Evaluation of Populations and their Health (INDEPTH) of health and demographic surveillance systems (HDSSs) over a 15-year period on malnutrition, its determinants, the effects of under and over nutrition, and intervention research on malnutrition in low- and middle-income countries (LMICs). METHODS: Relevant publication titles were uploaded onto the Zotero research tool from different databases (60% from PubMed). Using the keywords 'nutrition', 'malnutrition', 'over and under nutrition', we selected publications that were based only on data generated through the longitudinal HDSS platform. All titles and abstracts were screened to determine inclusion eligibility and full articles were independently assessed according to inclusion/exclusion criteria. For inclusion in this study, papers had to cover research on at least one of the following topics: the problem of malnutrition, its determinants, its effects, and intervention research on malnutrition. One hundred and forty eight papers were identified and reviewed, and 67 were selected for this study. RESULTS: The INDEPTH research identified rising levels of overweight and obesity, sometimes in the same settings as under-nutrition. Urbanisation appears to be protective against under-nutrition, but it heightens the risk of obesity. Appropriately timed breastfeeding interventions were protective against malnutrition. CONCLUSIONS: Although INDEPTH has expanded the global knowledge base on nutrition, many questions remain unresolved. There is a need for more investment in nutrition research in LMICs in order to generate evidence to inform policies in these settings. PMID- 26519131 TI - 'Women think pregnancy management means obstetric ultrasound': Vietnamese obstetricians' views on the use of ultrasound during pregnancy. AB - OBJECTIVE: To explore Vietnamese obstetricians' experiences and views on the role of obstetric ultrasound in clinical management of complicated pregnancy and in situations where maternal and fetal health interests conflict. DESIGN: Seventeen obstetricians in northern Vietnam were interviewed as part of the CROss-Country Ultrasound Study (CROCUS) project in 2013. Data were analysed using qualitative content analysis. RESULTS: The participants described ultrasound as a central tool in prenatal care, although they called for increased training and resources to prevent inappropriate management. A prevailing overuse driven by women's request and increased commercialisation was described. Other clinical examinations were seen as being disregarded by women in favour of ultrasound, resulting in missed opportunities for identifying potential pregnancy complications. The use of ultrasound for sex selection purposes raised concern among participants. Visualisation of human features or heartbeat during ultrasound was commonly described as the point where the fetus became regarded as a 'person'. Women were said to prioritise fetal health interests over their own health, particularly if a woman had difficulties becoming pregnant or had undergone assisted fertilisation. The woman's husband and his family were described as having an important role in decision-making in situations of maternal and fetal health conflicts. CONCLUSIONS: This study provides insight into issues surrounding ultrasound use in contemporary Vietnam, some of which may be specific to this low-income context. It is clear that ultrasound has become a central tool in prenatal care in Vietnam and that it has also been embraced by women. However, there seems to be a need to balance women's demands for obstetric ultrasound with better recognition of the valuable contribution to be made by the full range of clinical examinations in pregnancy, along with a more strategic allocation of resources, that is, use of obstetric ultrasound based on clinical indications. Better regulation of private obstetric practice also appears to be needed. While the root causes of sex selection need to be addressed at societal level, efforts are also required more immediately to find ways to combat the inappropriate use of ultrasound for the purpose of sex selection. PMID- 26519133 TI - Computer vision syndrome: A review. AB - BACKGROUND: Computer vision syndrome (CVS) is a collection of symptoms related to prolonged work at a computer display. OBJECTIVE: This article reviews the current knowledge about the symptoms, related factors and treatment modalities for CVS. METHODS: Relevant literature on CVS published during the past 65 years was analyzed. RESULTS: Symptoms reported by computer users are classified into internal ocular symptoms (strain and ache), external ocular symptoms (dryness, irritation, burning), visual symptoms (blur, double vision) and musculoskeletal symptoms (neck and shoulder pain). The major factors associated with CVS are either environmental (improper lighting, display position and viewing distance) and/or dependent on the user's visual abilities (uncorrected refractive error, oculomotor disorders and tear film abnormalities). CONCLUSION: Although the factors associated with CVS have been identified the physiological mechanisms that underlie CVS are not completely understood. Additionally, advances in technology have led to the increased use of hand-held devices, which might impose somewhat different visual challenges compared to desktop displays. Further research is required to better understand the physiological mechanisms underlying CVS and symptoms associated with the use of hand-held and stereoscopic displays. PMID- 26519134 TI - Vocational exploration in an extracurricular technology program for youth with autism. AB - BACKGROUND: Within a life span approach, introducing opportunities to explore careers through activities of interest provide ways for children to learn to explore, problem solve, and envision a future for themselves. However, little information exists about programs to promote social engagement and to explore potential career interests for youth with autism. OBJECTIVE: Explore engagement and learning in a technology-based extracurricular program (called iSTAR) for youth with autism. METHODS: The researchers used a qualitative approach with grounded-theory analysis to explore the processes that contributed to engagement and learning for youth with autism in an technology-based extracurricular program. FINDINGS: Youth Centered Learning and Opportunities to Demonstrate Skills emerged as themes that illuminated the processes by which engagement and learning occurred for the youth in the iSTAR program. Interest in the graphics program stimulated interactions amongst the youth with each other and with the adults. Modeling, demonstration, and scaffolded questioning supported engagement and learning for all the youth. Providing structure, encouraging choices, and following the youths' lead provided bridges for sharing and learning about the technology program. CONCLUSIONS: Career exploration through use of interests in technology can provide opportunities for youth with autism to develop social and technical skills needed later for employment. Providing an environment that recognizes and builds on the youths' strengths and supports their autonomy and choices are critical components to promote their positive development and career potential. PMID- 26519135 TI - At-line process analytical technology (PAT) for more efficient scale up of biopharmaceutical microfiltration unit operations. AB - Tangential flow microfiltration (MF) is a cost-effective and robust bioprocess separation technique, but successful full scale implementation is hindered by the empirical, trial-and-error nature of scale-up. We present an integrated approach leveraging at-line process analytical technology (PAT) and mass balance based modeling to de-risk MF scale-up. Chromatography-based PAT was employed to improve the consistency of an MF step that had been a bottleneck in the process used to manufacture a therapeutic protein. A 10-min reverse phase ultra high performance liquid chromatography (RP-UPLC) assay was developed to provide at-line monitoring of protein concentration. The method was successfully validated and method performance was comparable to previously validated methods. The PAT tool revealed areas of divergence from a mass balance-based model, highlighting specific opportunities for process improvement. Adjustment of appropriate process controls led to improved operability and significantly increased yield, providing a successful example of PAT deployment in the downstream purification of a therapeutic protein. The general approach presented here should be broadly applicable to reduce risk during scale-up of filtration processes and should be suitable for feed-forward and feed-back process control. PMID- 26519132 TI - Transgenic expression of human amphiregulin in mouse skin: inflammatory epidermal hyperplasia and enlarged sebaceous glands. AB - To explore the role of amphiregulin in inflammatory epidermal hyperplasia, we overexpressed human AREG (hAREG) in FVB/N mice using a bovine K5 promoter. A construct containing AREG coding sequences flanked by 5' and 3' untranslated region sequences (AREG-UTR) led to a >10-fold increase in hAREG expression compared to an otherwise-identical construct containing only the coding region (AREG-CDR). AREG-UTR mice developed tousled, greasy fur as well as elongated nails and thickened, erythematous tail skin. No such phenotype was evident in AREG-CDR mice. Histologically, AREG-UTR mice presented with marked epidermal hyperplasia of tail skin (2.1-fold increase in epidermal thickness with a 9.5 fold increase in Ki-67(+) cells) accompanied by significantly increased CD4+ T cell infiltration. Dorsal skin of AREG-UTR mice manifested lesser but still significant increases in epidermal thickness and keratinocyte hyperplasia. AREG UTR mice also developed marked and significant sebaceous gland enlargement, with corresponding increases in Ki-67(+) cells. To determine the response of AREG-UTR animals to a pro-inflammatory skin challenge, topical imiquimod (IMQ) or vehicle cream was applied to dorsal and tail skin. IMQ increased dorsal skin thickness similarly in both AREG-UTR and wild type mice (1.7- and 2.2-fold vs vehicle, P < 0.001 each), but had no such effect on tail skin. These results confirm that keratinocyte expression of hAREG elicits inflammatory epidermal hyperplasia, and are consistent with prior reports of tail epidermal hyperplasia and increased sebaceous gland size in mice expressing human epigen. PMID- 26519136 TI - Scrub typhus in pregnancy: a case series. AB - Scrub typhus, an acute febrile illness caused by Rickettsia and transmitted by mites, is a re-emerging endemic zoonosis in the Asia Pacific region. It is an uncommon entity and very few cases of this disease in pregnant women have been reported. We present a series of six such cases collected over 1 year with poor feto-maternal outcome in 50%. PMID- 26519137 TI - Cannabis induced recurrent acute pancreatitis. PMID- 26519138 TI - D-ribose-glycation of insulin prevents amyloid aggregation and produces cytotoxic adducts. PMID- 26519139 TI - The influence of the amyloid beta-protein and its precursor in modulating cerebral hemostasis. AB - Ischemic and hemorrhagic strokes are a significant cause of brain injury leading to vascular cognitive impairment and dementia (VCID). These deleterious events largely result from disruption of cerebral hemostasis, a well-controlled and delicate balance between thrombotic and fibrinolytic pathways in cerebral blood vessels and surrounding brain tissue. Ischemia and hemorrhage are both commonly associated with cerebrovascular deposition of amyloid beta-protein (Abeta). In this regard, Abeta directly and indirectly modulates cerebral thrombosis and fibrinolysis. Further, major isoforms of the Abeta precursor protein (AbetaPP) function as a potent inhibitor of pro-thrombotic proteinases. The purpose of this review article is to summarize recent research on how cerebral vascular Abeta and AbetaPP influence cerebral hemostasis. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID- 26519140 TI - Progress and challenges in viral vector manufacturing. AB - Promising results in several clinical studies have emphasized the potential of gene therapy to address important medical needs and initiated a surge of investments in drug development and commercialization. This enthusiasm is driven by positive data in clinical trials including gene replacement for Hemophilia B, X-linked Severe Combined Immunodeficiency, Leber's Congenital Amaurosis Type 2 and in cancer immunotherapy trials for hematological malignancies using chimeric antigen receptor T cells. These results build on the recent licensure of the European gene therapy product Glybera for the treatment of lipoprotein lipase deficiency. The progress from clinical development towards product licensure of several programs presents challenges to gene therapy product manufacturing. These include challenges in viral vector-manufacturing capacity, where an estimated 1-2 orders of magnitude increase will likely be needed to support eventual commercial supply requirements for many of the promising disease indications. In addition, the expanding potential commercial product pipeline and the continuously advancing development of recombinant viral vectors for gene therapy require that products are well characterized and consistently manufactured to rigorous tolerances of purity, potency and safety. Finally, there is an increase in regulatory scrutiny that affects manufacturers of investigational drugs for early phase clinical trials engaged in industry partnerships. Along with the recent increase in biopharmaceutical funding in gene therapy, industry partners are requiring their academic counterparts to meet higher levels of GMP compliance at earlier stages of clinical development. This chapter provides a brief overview of current progress in the field and discusses challenges in vector manufacturing. PMID- 26519141 TI - Aspirin promotes bone marrow mesenchymal stem cell-based calvarial bone regeneration in mini swine. AB - INTRODUCTION: Stem cells have great therapeutic potential due to their capacity for self-renewal and their potential for differentiating into multiple cell lineages. It has been recently shown that the host immune system has fundamental effects on the fate of transplanted mesenchymal stem cells during bone repair, where the topical administration of aspirin is capable of improving calvarial bone repair in rodents by inhibiting tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) production. This study investigates whether aspirin is capable of accelerating the regenerative potential of bone marrow mesenchymal stem cells (BMSC) in a mini swine calvarial bone defect model. METHODS: Calvarial bone defects (3 cm * 1.8 cm oval defect) in mini swine were treated with BMSC pretreated with 75 MUg/ml aspirin for 24 h seeded onto hydroxyaptite/tricalcium phosphatel (HA/TCP), or with BMSC with HA/TCP, or with HA/TCP only, or remained untreated. Animals were scanned with micro-computed tomography (microCT) at 2 days and 6 months postsurgery and were sacrificed at 6 months postsurgery with decalcified tissues being processed for histomorphometric examination. The cytokine levels, including TNF-alpha and IFN-gamma, were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: Aspirin at 75 MUg/ml promoted the osteogenesis of BMSC in vitro and in vivo, shown by Alizarin Red staining and new bone volume in the nude mice transplantation model (p < 0.01), respectively. Defects treated with aspirin-BMSC showed significantly greater new bone fill compared with other three groups at 6 months postsurgery (p < 0.01). Aspirin-BMSC treatment has significantly decreased the concentration of TNF-alpha and IFN gamma (p < 0.05). CONCLUSIONS: The present study shows that BMSC pretreated with aspirin have a greater capacity to repair calvarial bone defects in a mini swine model. The results suggest that the administration of aspirin is capable of improving BMSC-mediated calvarial bone regeneration in a big animal model. PMID- 26519142 TI - Scale-dependent effects of climate and geographic distance on bacterial diversity patterns across northern China's grasslands. AB - Patterns of variation in plant and animal diversity along precipitation gradients have been extensively studied, but much less is known about how and to what extent precipitation affects the biogeographic distribution of microbial diversity in arid areas across large spatial scales. Here we collected soils from 54 sites along a 3700 km transect covering a wide range of grassland ecosystems with distinct aridity gradients. We quantified the bacterial community diversity and the effects of climate, edaphic parameter and geographic distance on the bacterial community structure using high-throughput 16S rRNA gene sequencing. Of the 35 phyla detected, 6 were dominant: Actinobacteria, Acidobacteria, Alphaproteobacteria, Deltaproteobacteria, Bacteroidetes and Planctomycetes. Aridity was a major factor influencing bacterial diversity, community composition and taxon abundance. Although the pattern of bacterial species richness is markedly different from that of plant species richness, most soil bacteria were endemic to particular bioregions like macro-organisms. Community similarity significantly declined with environmental distance and geographic distance (r = 0.579 and -0.773, respectively). Geographic distance (historical contingencies) contributed more to bacterial community variation (36.02%) than combined environmental factors (24.06%). Overall, our results showed that geographic distance and climatic factors concurrently govern bacterial biogeographic patterns in arid and semi-arid grassland. PMID- 26519144 TI - Multiple Translations in Bilingual Memory: Processing Differences Across Concrete, Abstract, and Emotion Words. AB - Historically, the manner in which translation ambiguity and emotional content are represented in bilingual memory have often been ignored in many theoretical and empirical investigations, resulting in these linguistic factors related to bilingualism being absent from even the most promising models of bilingual memory representation. However, in recent years it was reported that the number of translations a word has across languages influences the speed with which bilinguals translate concrete and abstract words from one language into another (Tokowicz and Kroll in Lang Cogn Process 22:727-779, 2007). The current work examines how the number of translations that characterize a word influences bilingual lexical organization and the processing of concrete, abstract, and emotional stimuli. In Experiment 1, Spanish-English bilinguals translated concrete and abstract words with one and more than one translation. As reported by Tokowicz and Kroll, concreteness effects emerged only when words had more than one translation across languages. In Experiment 2, bilinguals translated emotion words with more than one translation. Concreteness effects emerged in both language directions for words with more than one translation, and in the L1-L2 language direction for words with a single translation across languages. These findings are discussed in terms of how multiple translations, specifically for emotion words, might be incorporated into current models of bilingual memory representation. PMID- 26519143 TI - Interpreting biochemical control response rates with first-generation somatostatin analogues in acromegaly. AB - CONTEXT: The somatostatin analogues octreotide LAR and lanreotide Autogel have been evaluated for the treatment of acromegaly in numerous clinical trials, with considerable heterogeneity in reported biochemical response rates. This review examines and attempts to account for these differences in response rates reported in the literature. EVIDENCE ACQUISITION: PubMed was searched for English-language studies of a minimum duration of 24 weeks that evaluated >=10 patients with acromegaly treated with octreotide LAR or lanreotide Autogel from 1990 to March 2015 and reported GH and/or IGF-1 data as the primary objective of the study. EVIDENCE SYNTHESIS: Of the 190 clinical trials found, 18 octreotide LAR and 15 lanreotide Autogel studies fulfilled the criteria for analysis. It is evident from the protocols of these studies that multiple factors are capable of impacting on reported response rates. Prospective studies reporting an intention to-treat analysis that evaluated medically naive patients and used the composite endpoint of both GH and IGF-1 control were associated with lower response rates. The use of non-composite biochemical control endpoints, heterogeneous patient populations, analyses that exclude treatment non-responders, assay variability and prior responsiveness to medical therapy are just a few of the factors identified that likely contribute to higher success rates. CONCLUSIONS: The wide range of reported response rates with somatostatin analogues may be confusing and could lead to misinterpretation by both the patient and the physician in certain situations. Understanding the factors that potentially drive the variation in response rates should allow clinicians to better gauge treatment expectations in specific patients. PMID- 26519145 TI - Response to dietary tannin challenges in view of the browser/grazer dichotomy in an Ethiopian setting: Bonga sheep versus Kaffa goats. AB - It has been suggested that goats (typical browser) are better adapted to digest tannin-rich diets than sheep (typical grazer). To evaluate this, Bonga sheep and Kaffa goats were used in a 2 * 3 randomized crossover design with two species, three diets, and three periods (15-day adaptation + 7-day collection). The dietary treatments consisted of grass-based hay only (tannin-free diet = FT), a high-tannin diet (36% Albizia schimperiana (AS) + 9% Ficus elastica (FE) + 55% FT (HT)), and HT + polyethylene glycol 6000 (PEG). Animals were individually fed at 50 g dry matter (DM)/kg body weight (BW) and had free access to clean drinking water and mineralized salt licks. Nutrient intake, apparent nutrient digestibility, nutrient conversion ratios, and live weight changes were determined. Condensed tannin concentrations in AS and FE were 110 and 191 g/kg DM, respectively. Both sheep and goats ate 47% more of HT than FT, and dry matter intake further increased by 9% when PEG was added, with clear difference in effect size between goats and sheep (P < 0.001). The effects of the tannin-rich diet and PEG addition were similarly positive for DM digestibility between sheep and goats, but crude protein (CP) digestibility was higher in HT + PEG-fed goats than in sheep fed the same diet. However, PEG addition induced a larger improvement in growth performance and feed efficiency ratio in sheep than in goat (P < 0.001). The addition of PEG as a tannin binder improved digestion and performance in both species, but with the highest effect size in sheep. PMID- 26519146 TI - Modelling the potential benefits of different strategies to control infection with Trypanosoma evansi in camels in Somaliland. AB - Trypanosoma evansi (T. evansi), the protozoan parasitic cause of camel trypanosomosis (Surra), constitutes one of the major veterinary problems worldwide. An infectious disease model of camel trypanosomosis (Surra) was adopted from one developed for buffalo and applied to study the impact of T. evansi infection on camel production. The model contained deterministic and stochastic components and the seroprevalence based on a survey conducted in Somaliland in 2011 and 2012 to simulate and estimate the economic benefits of four different control options against T. evansi infection in camels (1, 2, 3 and 4 regimens). The mean benefit per animal of controlling surra was calculated at US$354 (the treatment of all camels biannually), US$426 (the monthly targeted treatment of clinically sick camels) and US$287 (biannual targeted treatment of seropositive camels), respectively, compared with US$137 for untreated camels. Consequently, the model predicted that the total net benefit loss to a camel herd or village that was not applying the recommended effective surra control strategy was US$115,605 (69.4 billion shilling per annum). PMID- 26519147 TI - Marsupialization compared to open wound improves dressing change and wound care management after fistulectomy for low transsphincteric anal fistula. PMID- 26519148 TI - Laparoscopic sigmoidectomy for complicated diverticulitis: a modified caudal-to cranial approach and preliminay results in a single-center experience. PMID- 26519149 TI - Schizophrenia in celiac disease: a myth or reality? PMID- 26519150 TI - Is poultry intake associated with colorectal cancer? PMID- 26519151 TI - The role of low CRP values in the prediction of the development of acute diverticulitis. AB - PURPOSE: Computed tomography (CT) is the most appropriate imaging modality for the assessment of acute diverticulitis at the emergency unit. The aim of this study was to determine the clinical outcome of the patients presented first time with symptoms of acute diverticulitis and low CRP values. METHODS: Two-hundred patients, who presented with the symptoms of acute diverticulitis and had CRP values under 150 mg/L, underwent abdominal CT examination on admission to Oulu University Hospital. The clinical parameters and radiological findings were compared in relation to clinical outcome both by means of univariate and multivariate analyses. RESULTS: Seventy-one (35.5 %) of the 200 patients presented on admission with complicated diverticulitis. CRP values between 100 and 150 mg/L predicted complicated disease, but the mean values of CRP between uncomplicated disease, 89 mg/L +/- 39, and complicated disease, 101 mg/L +/- 39, did not differ significantly. Free intra-abdominal fluid in CT was the only independent risk factor of the need for interventional therapy and treatment in the intensive care unit. Longevity of the patients and free fluid in CT predicted significantly prolonged hospitalization. Mortality was 1 % and older patients were significantly affected. The recurrence rate of acute diverticulitis was 24 % (43/177) in the whole group and 18 % (23/129) after uncomplicated diverticulitis. CONCLUSIONS: Low CRP values do not reliably predict uncomplicated disease in patients presented first time at the emergency unit with acute diverticulitis. We recommend that the need for abdominal CT is carefully evaluated according to the patient's clinical status, always even when the CRP value is under 150 mg/L. PMID- 26519152 TI - Can the colour of per-rectal bleeding estimate the risk of lower gastrointestinal bleeding caused by malignant lesion? AB - PURPOSE: To estimate the risk of lower gastrointestinal bleeding (LGIB) caused by malignant lesion in patients presenting with per-rectal bleeding (PRB), by using visual aid as an objective measurement of PRB colour. METHODS: This was a prospective observational study on patients presented with PRB to Family Medicine Specialty Clinic, who undergo flexible sigmoidoscopy (FS) or colonoscopy (CLN) from December 2012 to September 2013. Patients aged 40 years old or above, haemodynamically stable, with normal haemoglobin level were included. Patients with a history of previous colonic surgery, refused to have FS or CLN, with ophthalmologic diseases such as colour blindness were excluded. Parameters including subjective description of PRB colour, number of chosen red colour by patients, source and distance of bleeding from anal verge were recorded for analysis. Receiver operating characteristic (ROC) curve was used to identify the optimal cutoff level of colour for diagnosing colonic lesion. Diagnostic accuracy was assessed by area under the ROC curve (AUC). Accountability of this model was assessed by logistic regression. RESULTS: The dark PRB colour was associated with diagnosis of tumour (p < 0.001) and advanced neoplastic polyp (p < 0.001). The light PRB colour was associated with the diagnosis of piles (p < 0.001). The performance of our model to predict tumour or advanced neoplastic polyps by colour (AUC, 0.798) had a better discriminative power than that to predict colonic lesion alone (AUC, 0.610) by ROC curve analysis. CONCLUSION: Objective measurement of PRB colour accurately estimated the risk of LGIB caused by malignant lesion in patients presenting with PRB. PMID- 26519153 TI - The Impact of Heller Myotomy on Integrated Relaxation Pressure in Esophageal Achalasia. AB - BACKGROUND: A new high-resolution manometry (HRM) parameter, the integrated relaxation pressure (IRP), has been proposed for the assessment of esophageal gastric junction (EGJ) relaxation. Our aim was to assess the effect of Heller myotomy on IRP in achalasia patients. METHODS: We prospectively collected data on achalasia patients who underwent HRM between 2009-2014. Barium swallow was used to assess esophageal diameter and shape. Manometric diagnoses were performed by using the Chicago Classification v3. All patients with a confirmed diagnosis of achalasia were treated surgically with Heller Myotomy RESULTS: One hundred thirty nine consecutive achalasia patients (M:F = 72:67) represented the study population. All the patients had 100% simultaneous waves but 11 had an IRP < 15 mmHg. At median follow-up of 28 months, the median of IRP was significantly lower after surgery (27.4 [IQR 20.4-35] vs 7.1 [IQR 4.4-9.8]; p < 0.001), and so were the lower esophageal sphincter (LES) resting pressure (27 [IQR 18-33] vs 6 [IQR 3 11]; p < 0.001). At univariate analysis, IRP correlated with the gender, LES resting residual pressure, and dysphagia score. CONCLUSIONS: This is the first study to have examined the role of IRP in achalasia, and how it changes after surgical treatment. An increased preoperative IRP correlated directly with a more severe dysphagia. The IRP was restored to normal by Heller myotomy. PMID- 26519155 TI - Medial temporal lobe atrophy, white matter hyperintensities and cognitive impairment among Nigerian African stroke survivors. AB - BACKGROUND: Neuroimaging features associated with vascular cognitive impairment have not been examined in sub-Saharan Africans. We determined magnetic resonance imaging (MRI) features associated with cognitive impairment in a sample of Nigerian stroke survivors. METHODS: Stroke survivors underwent brain MRI with standardized assessment of brain volumes and visual rating of medial temporal lobe atrophy (MTA), and white matter hyperintensities (WMH) at 3 months post stroke. Demographic, clinical and psychometric assessments of global cognitive function, executive function, mental speed and memory were related to changes in structural MRI. RESULTS: In our pilot sample of 58 stroke survivors (60.1 +/- 10.7 years old) MTA correlated significantly with age (r = 0.525), WMH (r = 0.461), memory (r = -0.702), executive function (r = -0.369) and general cognitive performance (r = -0.378). On univariate analysis, age >60 years (p = 0.016), low educational attainment (p < 0.001 to p < 0.003), total brain volume (p < 0.024 and p < 0.025) and MTA (p < 0.003 to p < 0.007) but not total WMH (p < 0.073, p = 0.610) were associated with cognitive outcome. In a two-step multivariate regression analysis, MTA (p < 0.035 and p < 0.016) and low educational attainment (p < 0.012 and p < 0.019) were sustained as independent statistical predictors of cognitive outcome. CONCLUSIONS: Medial temporal lobe atrophy was a significant neuroimaging predictor of early post-stroke cognitive dysfunction in the Nigerian African stroke survivors. These observations have implications for a vascular basis of MTA in older stroke survivors among sub Saharan Africans. PMID- 26519156 TI - Probe-based confocal laser endomicroscopy (pCLE): a preclinical investigation of the male genital tract. AB - The aim of this study was to assess the potential of probe-based confocal laser endomicroscopy (pCLE) as a new diagnostic imaging technique for the male genital tract. For this purpose, testes, epididymides, and vasa deferentia were obtained during transsexual surgery of healthy patients (n = 10, 26-52 years). Prior to this, testes of rats (n = 10, Sprague-Dawley) and mice (n = 8, wild-type) were examined. Ex vivo tissues were investigated by pCLE after topical fluorescence staining. Images and pCLE real-time video sequences were compared to images acquired by confocal laser scanning microscopy (CLSM); this allowed the identifying of corresponding microstructures. Interestingly, the seminiferous tubules of transsexual humans contained mainly spermatogonia due to long-term estrogen treatment, whereas the seminiferous tubules of the murine and rat spermatogenesis-related cell types were differentiated. Mosaicking improved the inspection potential by wide-angle views. Similarly, the microarchitecture of the epididymis and the vas deferens was successfully visualized in situ and on a cellular level by pCLE. In summary, pCLE allows for real-time identification of relevant microstructures responsible for spermatogenesis under ex vivo conditions. Additionally, pCLE enabled to localize vital spermatozoa in the testis thus opening up new ways to improve sperm retrieval rates during assisted reproduction. Both clinically relevant experiences hold promise to introduce this diagnostic method into a clinical study, and to investigate its potential as a clinical diagnostic procedure to expedite and improve the medical situation. PMID- 26519157 TI - A bis-Schiff base of isatin improves methylglyoxal mediated insulin resistance in skeletal muscle cells. AB - Methylglyoxal (MGO) is a highly reactive advanced glycation end products (AGEs) precursor and its abnormal accumulation causes damage to various tissues and organs. In our previous study, we synthesized a novel MGO inhibitor, MK-I-81, a bis-Schiff base derivative of isatin. In this study we demonstrate the mechanism of action of MK-I-81, on insulin resistance in skeletal muscle cells. MK-I-81 reduced AGEs formation and restored proximal insulin signaling by modulating IRS 1 phosphorylation. MK-I-81 also alleviated MGO mediated diminished distal insulin signaling by increasing protein kinase B and glycogen synthase kinase 3-beta phosphorylation. We also observed that MK-I-81 prevented reduced glucose uptake and glycogen synthesis induced by MGO in muscle cells. We found that the mechanism of action by which MK-I-81 reduced insulin resistance was suppression of production of MGO mediated ROS production in C2C12 cells. We evaluated deactivation of PKC-alpha and receptor for advanced glycation end products (RAGE) after treatment of cells with MK-I-81. MK-I-81 also reduced MGO mediated IRS-1, PKC-alpha and RAGE interaction in muscle cells. MK-I-81 also promoted nuclear factor erythroid 2-related factor-2 phosphorylation, heme oxygenase-1 and glyoxalase expression levels. We conclude that MK-I-81 can be a potential therapeutic target to address AGEs mediated insulin resistance. A novel Advanced Glycation End products (AGEs) inhibitor, MK-I-81 (a bis Schiff base of isatin), restored AGEs mediated down regulation of insulin signaling via modulating key molecules of proximal and distal insulin signaling. MK-I-81 also increased glucose uptake and glycogen synthesis in muscle cells. Novel bis-Schiff base of isatin showed significant antioxidant activity and also reduced receptor for AGEs (RAGE) expression and PKC-alpha activation therefore; MK-I-81 reduces AGEs induced insulin resistance. PMID- 26519158 TI - Adenovirus hexon modifications influence in vitro properties of pseudotyped human adenovirus type 5 vectors. AB - Commonly used human adenovirus (HAdV)-5-based vectors are restricted by their tropism and pre-existing immunity. Here, we characterized novel HAdV-5 vectors pseudotyped with hypervariable regions (HVRs) and surface domains (SDs) of other HAdV types. Hexon-modified HAdV-5 vectors (HV-HVR5, HV-HVR12, HV-SD12 and HV-SD4) could be reconstituted and amplified in human embryonic kidney cells. After infection of various cell lines, we measured transgene expression levels by performing luciferase reporter assays or coagulation factor IX (FIX) ELISA. Dose dependent studies revealed that luciferase expression levels were comparable for HV-HVR5, HV-SD12 and HV-SD4, whereas HV-HVR12 expression levels were significantly lower. Vector genome copy numbers (VCNs) from genomic DNA and nuclear extracts were then determined by quantitative real-time PCR. Surprisingly, determination of cell- and nuclear fraction-associated VCNs revealed increased VCNs for HV-HVR12 compared with HV-SD12 and HV-HVR5. Increased nuclear fraction-associated HV-HVR12 DNA molecules and decreased transgene expression levels were independent of the cell line used, and we observed the same effect for a hexon-modified high-capacity adenoviral vector encoding canine FIX. In conclusion, studying hexon-modified adenoviruses in vitro demonstrated that HVRs but also flanking hexon regions influence uptake and transgene expression of adenoviral vectors. PMID- 26519159 TI - Behaviour change techniques and contraceptive use in low and middle income countries: a review. AB - We aimed to identify effective behaviour change techniques to increase modern contraceptive use in low and middle income countries (LMICs). Literature was identified in Global Health, Web of Science, MEDLINE, PsycINFO and Popline, as well as peer reviewed journals. Articles were included if they were written in English, had an outcome evaluation of contraceptive use, modern contraceptive use, contraceptive initiation/uptake, contraceptive adherence or continuation of contraception, were a systematic review or randomised controlled trial, and were conducted in a low or middle income country. We assessed the behaviour change techniques used in each intervention and included a new category of male partner involvement. We identified six studies meeting the inclusion criteria. The most effective interventions were those that involve male partner involvement in the decision to initiate contraceptive use. The findings also suggest that providing access to contraceptives in the community promotes their use. The interventions that had positive effects on contraceptive use used a combination of behaviour change techniques. Performance techniques were not used in any of the interventions. The use of social support techniques, which are meant to improve wider social acceptability, did not appear except in two of the interventions. Our findings suggest that when information and contraceptives are provided, contraceptive use improves. Recommendations include reporting of behaviour change studies to include more details of the intervention and techniques employed. There is also a need for further research to understand which techniques are especially effective. PMID- 26519160 TI - Pyoblepharitis Vegetans in Association With Pyodermatitis-Pyostomatitis Vegetans: Expanding the Spectrum of a Rare, Multisystem Disorder. AB - BACKGROUND: Pyodermatitis-pyostomatitis vegetans (PDPSV) is a rare inflammatory disorder of the skin and oral mucosa that is commonly associated with inflammatory bowel disease (IBD). Ocular involvement is uncommon. OBJECTIVE: Given the association with IBD, it is important for dermatologists to be aware of the varying manifestations of PDPSV. METHODS: A biopsy was performed for diagnosis confirmation, and the literature was reviewed for similar cases. OBSERVATIONS: Our 48-year-old PDPSV patient presented with rare ocular findings. There have been 8 PDPSV reports of ocular involvement. Only 3 of those patients developed blepharitis and/or conjunctival disease. None showed simultaneous involvement of sites at disease onset like our patient. RESULTS: Our patient's concomitant presentation at onset of multiple mucocutaneous sites with blepharitis and conjunctivitis is unique. CONCLUSIONS: We propose the term pyoblepharitis vegetans (PBV) to describe vegetating lesions of the eyelids. The diagnosis of PDPSPBV should be considered with presentation of these signs. PMID- 26519162 TI - Acute coronary syndromes. PMID- 26519163 TI - Communicating with mismatch and tension: treatment provision experiences of primary care doctors treating patients with overactive bladder in Hong Kong. AB - BACKGROUND: Overactive bladder (OAB) is a common chronic bladder dysfunction worldwide. As the first contact point of health care, primary health care providers are often consulted by patients seeking initial consultation for OAB. The relatively short history of the existence of OAB in medicine and low public awareness of OAB in Hong Kong, however, often serve as a challenge to primary health care providers in treating patients with OAB. The experiences of patients and health care providers are often influenced by the interaction between these two groups, hence both health care providers and patients are key determinants of the entire treatment experience, and the perspectives of health care providers should not be overlooked. However, patient experiences have been the main focus of related studies, few of which have examined the treatment provision experiences and perspectives of health care providers. This research gap is notable considering that the satisfaction and morale of health care providers can influence treatment outcome. METHODS: This study adopted a qualitative research approach by conducting semistructured individual interviews with 30 private practice primary care doctors in Hong Kong between November 2013 and May 2014. RESULTS: Lacking confidence in treating OAB patients, encountering mismatch with patients in treatment expectations and communication style, and feeling embarrassed when communicating with OAB patients were the experiences reported by the sampled doctors. CONCLUSION: The sampled doctors' treatment provision experiences revealed a general lack of knowledge about OAB among primary care doctors in Hong Kong. Furthermore, the negative stereotype of and lack of trust in private practice doctors created tension between the doctors and patients. This lack of mutual trust was particularly unfavourable for the doctors to provide long-term treatment and support to patients with OAB. The embedded distrust of private practice doctors also affected the prescribing behaviour of the doctors, who prescribed medication only to satisfy patient demands, which may lead to antibiotic abuse and resistance. Finally, the expectations of doctor professionalism and behaviour in Chinese cultures and the cultural perceptions of urinary diseases caused challenging treatment provision experiences for the sampled doctors. PMID- 26519164 TI - Impact of initial dialysis modality on mortality: a propensity-matched study. AB - BACKGROUND: Whether the choice of dialysis modality in patients with end stage renal disease may impact mortality is undecided. No randomized controlled trial has properly addressed this issue. Propensity-matched observational studies could give important insight into the independent effect of peritoneal (PD) opposed to haemodialysis (HD) on all-cause and cardiovascular mortality. METHODS: To correct for case-mix differences between patients treated with PD and HD, propensity matched analyses were utilized in all patients who initiated dialysis as first renal replacement therapy in Norway in the period 2005-2012. PD patients were matched in a 1:1 fashion with HD patients, creating 692 pairs of patients with comparable baseline variables. As-treated and intention-to treat analyses were undertaken to assess cardiovascular and all-cause mortality. Interaction analyses were used to assess differences in the relationship between initial dialysis modality and mortality, between strata of age, gender and prevalent diabetes mellitus. RESULTS: In the as-treated analyses, initial dialysis modality did not impact 2-year (PD vs. HD: HR 0.87, 95 % CI 0.67-1.12) or 5-year all-cause mortality (HR 0.95, 95 % CI 0.77-1.17). In patients younger than 65 years, PD was superior compared to HD with regard to both 2-year (HR 0.39, 95 % CI 0.19-0.81), and 5-year all-cause mortality (HR 0.49, 95 % CI 0.27-0.89). Cardiovascular mortality was also lower in the younger patients treated with PD (5-year HR 0.38, 95 % CI 0.15-0.96). PD was not associated with impaired prognosis in any of the prespecified subgroups compared to HD. The results were similar in the as-treated and intention-to-treat analyses. CONCLUSION: Survival in PD was not inferior to HD in any subgroup of patients even after five years of follow-up. In patients below 65 years, PD yielded superior survival rates compared to HD. Increased use of PD as initial dialysis modality in ESRD patients could be encouraged. PMID- 26519161 TI - Genotypic and phenotypic analyses of a Pseudomonas aeruginosa chronic bronchiectasis isolate reveal differences from cystic fibrosis and laboratory strains. AB - BACKGROUND: Pseudomonas aeruginosa is an environmentally ubiquitous Gram-negative bacterium and important opportunistic human pathogen, causing severe chronic respiratory infections in patients with underlying conditions such as cystic fibrosis (CF) or bronchiectasis. In order to identify mechanisms responsible for adaptation during bronchiectasis infections, a bronchiectasis isolate, PAHM4, was phenotypically and genotypically characterized. RESULTS: This strain displays phenotypes that have been associated with chronic respiratory infections in CF including alginate over-production, rough lipopolysaccharide, quorum-sensing deficiency, loss of motility, decreased protease secretion, and hypermutation. Hypermutation is a key adaptation of this bacterium during the course of chronic respiratory infections and analysis indicates that PAHM4 encodes a mutated mutS gene responsible for a ~1,000-fold increase in mutation rate compared to wild type laboratory strain P. aeruginosa PAO1. Antibiotic resistance profiles and sequence data indicate that this strain acquired numerous mutations associated with increased resistance levels to beta-lactams, aminoglycosides, and fluoroquinolones when compared to PAO1. Sequencing of PAHM4 revealed a 6.38 Mbp genome, 5.9 % of which were unrecognized in previously reported P. aeruginosa genome sequences. Transcriptome analysis suggests a general down-regulation of virulence factors, while metabolism of amino acids and lipids is up-regulated when compared to PAO1 and metabolic modeling identified further potential differences between PAO1 and PAHM4. CONCLUSIONS: This work provides insights into the potential differential adaptation of this bacterium to the lung of patients with bronchiectasis compared to other clinical settings such as cystic fibrosis, findings that should aid the development of disease-appropriate treatment strategies for P. aeruginosa infections. PMID- 26519165 TI - Measuring evidence-based practice knowledge and skills in occupational therapy--a brief instrument. AB - BACKGROUND: Valid and reliable instruments are required to measure the effect of educational interventions to improve evidence-based practice (EBP) knowledge and skills in occupational therapy. The aims of this paper are to: 1) describe amendments to the Adapted Fresno Test of Competence in EBP (AFT), and 2) report the psychometric properties of the modified instrument when used with South African occupational therapists. METHODS: The clinical utility of the AFT was evaluated for use with South African occupational therapists and modifications made. The modified AFT was used in two studies to assess its reliability and validity. In Study 1 a convenience sample of 26 occupational therapists in private practice or government-funded health facilities in a South African province were recruited to complete the modified AFT on two occasions 1 week apart. Completed questionnaires were scored independently by two raters. Inter rater, test-retest reliability and internal consistency were determined. Study 2 was a pragmatic randomised controlled trial involving occupational therapists in four Western Cape Department of Health district municipalities (n = 58). Therapists were randomised in matched pairs to one of two educational interventions (interactive or didactic), and completed the modified AFT at baseline and 12 weeks after the intervention. An intention-to-treat analysis was performed. Data were not normally distributed, thus non-parametric statistics were used. RESULTS: In Study 1, 21 of 26 participants completed the questionnaire twice. Test-retest (ICC = 0.95, 95 % CI = 0.88-0.98) and inter-rater reliability (Time 1: ICC = 0.995, 95 % CI = 0.99-0.998; Time 2: ICC = 0.99, 95 % CI = 0.97 0.995) were excellent for total scores. Internal consistency based on time 1 scores was satisfactory (alpha = 0.70). In Study 2, 28 participants received an interactive educational intervention and completed the modified AFT at baseline and 12 weeks later. Median total SAFT scores increased significantly from baseline to 12-weeks (Z = -4.078, p < 0.001) with a moderate effect size (r = 0.55). CONCLUSION: The modified AFT has demonstrated validity for detecting differences in EBP knowledge between two groups. It also has excellent test retest and inter-rater reliability. The instrument is recommended for contexts where EBP is an emerging approach and time is at a premium. TRIAL REGISTRATION: Pan African Controlled Trials Register PACTR201201000346141 . Registered 31 January 2012. Clinical Trials NCT01512823 . Registered 1 February 2012. South African National Clinical Trial Register DOH2710093067 . Registered 27 October 2009. PMID- 26519167 TI - Introduction to Proteomics Technologies. AB - Compared to genomics or transcriptomics, proteomics is often regarded as an "emerging technology," i.e., as not having reached the same level of maturity. While the successful implementation of proteomics workflows and technology still requires significant levels of expertise and specialization, great strides have been made to make the technology more powerful, streamlined and accessible. In 2014, two landmark studies published the first draft versions of the human proteome.We aim to provide an introduction specifically into the background of mass spectrometry (MS)-based proteomics. Within the field, mass spectrometry has emerged as a core technology. Coupled to increasingly powerful separations and data processing and bioinformatics solution, it allows the quantitative analysis of whole proteomes within a matter of days, a timescale that has made global comparative proteome studies feasible at last. We present and discuss the basic concepts behind proteomics mass spectrometry and the accompanying topic of protein and peptide separations, with a focus on the properties of datasets emerging from such studies. PMID- 26519166 TI - Molecular characterization and evolutionary origins of farinin genes in Brachypodium distachyon L. AB - Farinins are one of the oldest members of the gluten family in wheat and Aegilops species, and they influence dough properties. Here, we performed the first detailed molecular genetic study on farinin genes in Brachypodium distachyon L., the model species for Triticum aestivum. A total of 51 b-type farinin genes were cloned and characterized, including 27 functional and 24 non-functional pseudogenes from 14 different B. distachyon accessions. All genes were highly similar to those previously reported from wheat and Aegilops species. The identification of deduced amino acid sequences showed that b-type farinins across Triticeae genomes could be classified as b1-, b2-, b3-, and b4-type farinins; however, B. distachyon had only b3- and b4-type farinins. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) revealed that farinin genes are transcribed into mRNA in B. distachyon at much lower levels than in Triticeae, despite the presence of cis-acting elements in promoter regions. Phylogenetic analysis suggested that Brachypodium farinins may have closer relationships with common wheat and further confirmed four different types of b type farinins in Triticeae and Brachypodium genomes, corresponding to b1, b2, b3 (group 1), and b4 (group 2). A putative evolutionary origin model of farinin genes in Brachypodium, Triticum, and the related species suggests that all b-type farinins diverged from their common ancestor ~3.2 million years ago (MYA). The b3 and b4 types could be considered older in the farinin family. The results explain the loss of b1- and b2-type farinin alleles in Brachypodium. PMID- 26519168 TI - Topics in Study Design and Analysis for Multistage Clinical Proteomics Studies. AB - This chapter discusses the design issues in clinical proteomics study and provides specific suggestions for addressing these questions when using the standard guidelines for the planning. It provides two methods for the sample size estimation in study design. The first method is used for the planning of a clinical proteomic study at the discovery or verification stage; the second method is proposed for the systematic planning of a multistage study. The second part of the chapter introduces three approaches to analyzing the clinical proteomic study and provides analyses for two case studies of clinical proteomic discoveries. PMID- 26519170 TI - Normalization of Reverse Phase Protein Microarray Data: Choosing the Best Normalization Analyte. AB - Reverse phase protein microarray (RPMA) are a relatively recent but widely used approach to measure a large number of proteins, in their original and posttranslational modified forms, in a small clinical sample. Data normalization is fundamental for this technology, to correct for the sample-to-sample variability in the many possible confounding factors: extracellular proteins, red blood cells, different number of cells in the sample. To address this need, we adopted gene microarray algorithms to tailor the RPMA processing and analysis to the specific study set. Using geNorm and NormFinder algorithms, we screened seven normalization analytes (ssDNA, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), alpha/beta-tubulin, mitochondrial ribosomal protein L11 (MRPL11), ribosomal protein L13a (RPL13a), beta-actin, and total protein) across different sample sets, including cell lines, blood contaminated tissues, and tissues subjected to laser capture microdissection (LCM), to identify the analyte with the lowest variability. Specific normalization analytes were found to be advantageous for different classes of samples, with ssDNA being the optimal analyte to normalize blood contaminated samples. PMID- 26519169 TI - Preprocessing and Analysis of LC-MS-Based Proteomic Data. AB - Liquid chromatography coupled with mass spectrometry (LC-MS) has been widely used for profiling protein expression levels. This chapter is focused on LC-MS data preprocessing, which is a crucial step in the analysis of LC-MS based proteomics. We provide a high-level overview, highlight associated challenges, and present a step-by-step example for analysis of data from LC-MS based untargeted proteomic study. Furthermore, key procedures and relevant issues with the subsequent analysis by multiple reaction monitoring (MRM) are discussed. PMID- 26519171 TI - Outlier Detection for Mass Spectrometric Data. AB - Mass spectrometry data are often generated from various biological or chemical experiments. However, due to technical reasons, outlying observations are often obtained, some of which may be extreme. Identifying the causes of outlying observations is important in the analysis of replicated MS data because elaborate pre-processing is essential in order to obtain successful analyses with reliable results, and because manual outlier detection is a time-consuming pre-processing step. It is natural to measure the variability of observations using standard deviation or interquartile range calculations, and in this work, these criteria for identifying outliers are presented. However, the low replicability and the heterogeneity of variability are often obstacles to outlier detection. Therefore, quantile regression methods for identifying outliers with low replication are also presented. The procedures are illustrated with artificial and real examples, while a software program is introduced to demonstrate how to apply these procedures in the R environment system. PMID- 26519172 TI - Visualization and Differential Analysis of Protein Expression Data Using R. AB - Data analysis is essential to derive meaningful conclusions from proteomic data. This chapter describes ways of performing common data visualization and differential analysis tasks on gel-based proteomic datasets using a freely available statistical software package (R). A workflow followed is illustrated using a synthetic dataset as example. PMID- 26519173 TI - False Discovery Rate Estimation in Proteomics. AB - With the advancement in proteomics separation techniques and improvements in mass analyzers, the data generated in a mass-spectrometry based proteomics experiment is rising exponentially. Such voluminous datasets necessitate automated computational tools for high-throughput data analysis and appropriate statistical control. The data is searched using one or more of the several popular database search algorithms. The matches assigned by these tools can have false positives and statistical validation of these false matches is necessary before making any biological interpretations. Without such procedures, the biological inferences do not hold true and may be outright misleading. There is a considerable overlap between true and false positives. To control the false positives amongst a set of accepted matches, there is a need for some statistical estimate that can reflect the amount of false positives present in the data processed. False discovery rate (FDR) is the metric for global confidence assessment of a large-scale proteomics dataset. This chapter covers the basics of FDR, its application in proteomics, and methods to estimate FDR. PMID- 26519174 TI - A Nonparametric Bayesian Model for Nested Clustering. AB - We propose a nonparametric Bayesian model for clustering where clusters of experimental units are determined by a shared pattern of clustering another set of experimental units. The proposed model is motivated by the analysis of protein activation data, where we cluster proteins such that all proteins in one cluster give rise to the same clustering of patients. That is, we define clusters of proteins by the way that patients group with respect to the corresponding protein activations. This is in contrast to (almost) all currently available models that use shared parameters in the sampling model to define clusters. This includes in particular model based clustering, Dirichlet process mixtures, product partition models, and more. We show results for two typical biostatistical inference problems that give rise to clustering. PMID- 26519175 TI - Set-Based Test Procedures for the Functional Analysis of Protein Lists from Differential Analysis. AB - The analysis of most high-throughput proteomics experiments involves the selection of differentially expressed proteins or peptides between two different sets of samples, e.g., from two experimental groups. As a result, a large list of selected features is reported, typically sorted by a measure for the expression fold change and a p-value from a statistical test. The biological interpretation of such a list is usually difficult since the features can typically be assigned to a large variety of biological classes. To facilitate the biological interpretation, set-based procedures focus on the analysis of feature subsets that all belong to the same biological class (e.g., same cellular component, biological process, molecular function, or pathway). Set-based procedures can roughly be divided into "enrichment methods" and "global test procedures," where the first involve all features of an experiment and the second only those features of a particular set. In this chapter we detail the working principle of these kind of statistical methods and describe how features can be classified into molecular subsets. We illustrate the use of the methods on a data example from a proteomics Parkinson study. PMID- 26519176 TI - Classification of Samples with Order-Restricted Discriminant Rules. AB - In recent years, mass spectrometry techniques have helped proteomics to become a powerful tool for the early diagnosis of cancer, as they help to discover protein profiles specific to each pathological state. One of the questions where proteomics is giving useful practical results is that of classifying patients into one of the possible severity levels of an illness, based on some features measured on the patient. This classification is usually made using one of the many discrimination procedures available in statistical literature. We present in this chapter recently developed restricted discriminant rules that use additional information in terms of orderings on the means, and we illustrate how to apply them to mass spectrometry data using R package dawai. Specifically, we use proteomic prostate cancer data, and we describe all steps needed, including data preprocessing and feature extraction, to build a discriminant rule that classifies samples in one of several disease stages, thus helping diagnosis. The restricted discriminant rules are compared with some standard classifiers that do not take into account the additional information, showing better performance in terms of error rates. PMID- 26519177 TI - Application of Discriminant Analysis and Cross-Validation on Proteomics Data. AB - High-throughput proteomic experiments have raised the importance and complexity of bioinformatic analysis to extract useful information from raw data. Discriminant analysis is frequently used to identify differences among test groups of individuals or to describe combinations of discriminant variables. However, even in relatively large studies, the number of detected variables typically largely exceeds the number of samples and the classifiers should be thoroughly validated to assess their performance for new samples. Cross validation is a widely approach when an external validation set is not available. In this chapter, different approaches for cross-validation are presented including relevant aspects that should be taken into account to avoid overly optimistic results and the assessment of the statistical significance of cross validated figures of merit. PMID- 26519178 TI - Protein Sequence Analysis by Proximities. AB - Sequence data are widely used to get a deeper insight into biological systems. From a data analysis perspective they are given as a set of sequences of symbols with varying length. In general they are compared using nonmetric score functions. In this form the data are nonstandard, because they do not provide an immediate metric vector space and their analysis using standard methods is complicated. In this chapter we provide various strategies for how to analyze these type of data in a mathematically accurate way instead of the often seen ad hoc solutions. Our approach is based on the scoring values from protein sequence data although be applicable in a broader sense. We discuss potential recoding concepts of the scores and discuss algorithms to solve clustering, classification and embedding tasks for score data for a protein sequence application. PMID- 26519179 TI - Statistical Method for Integrative Platform Analysis: Application to Integration of Proteomic and Microarray Data. AB - To perform integrative analysis on multiple genomic data sources, we propose to use Fisher's combined probability test for consolidated inference. The method combines the individual p-values from different data sources and constructs a chi square test statistics for the overall significance. This method is valid to combine results across independent data sources. We further improve the method to accommodate the scenario that the data sources are dependent or the data samples are too small to obtain valid p-values through exact distributions. The proposed method is convenient to use in practice and is robust to distributional assumptions and small sample sizes. PMID- 26519180 TI - Data Fusion in Metabolomics and Proteomics for Biomarker Discovery. AB - Proteomics and metabolomics provide key insights into status and dynamics of biological systems. These molecular studies reveal the complex mechanisms involved in disease or aging processes. Invaluable information can be obtained using various analytical techniques such as nuclear magnetic resonance, liquid chromatography, or gas chromatography coupled to mass spectrometry. Each method has inherent advantages and drawbacks, but they are complementary in terms of biological information.The fusion of different measurements is a complex topic. We describe here a framework allowing combining multiple data sets, provided by different analytical platforms. For each platform, the relevant information is extracted in the first step. The obtained latent variables are then fused and further analyzed. The influence of the original variables is then calculated back and interpreted. PMID- 26519181 TI - Reconstruction of Protein Networks Using Reverse-Phase Protein Array Data. AB - In this chapter, we describe an approach to reconstruct cellular signaling networks based on measurements of protein activation after different stimulation experiments. As experimental platform reverse-phase protein arrays (RPPA) are used. RPPA allow the measurement of proteins and phosphoproteins across many samples in parallel with minimal sample consumption using a panel of highly target protein-specific antibodies. Functional interactions of proteins are modeled using a Boolean network. We describe the Boolean network reconstruction approach ddepn (dynamic deterministic effects propagation networks), which uses time course data to derive protein interactions based on perturbation experiments. We explain how the method works, give a practical application example, and describe how the results can be interpreted. Furthermore prior knowledge on signaling pathways is essential for network reconstruction. Here we describe the use of our software rBiopaxParser to integrate prior knowledge on protein signaling available in public databases. All applied methods are freely available as open-source R software packages. We describe the preparation of RPPA data as well as all relevant programming steps to format the RPPA data, to infer the prior knowledge, and to reconstruct and analyze the protein signaling networks. PMID- 26519182 TI - Detection of Unknown Amino Acid Substitutions Using Error-Tolerant Database Search. AB - Recent studies have demonstrated that mass spectrometry-based variant detection is feasible. Typically, either genomic variant databases or transcript data are used to construct customized target databases for the identification of single amino acid variants in mass spectrometry data. However, both approaches require additional data to perform the identification of SAAVs. Here, we discuss the application of an error-tolerant peptide search engine such as BICEPS for identifying variants exclusively based on standard Uniprot databases. Thereby, unnecessary and redundant extensions of the search space are avoided. The workflow provides an unbiased view on the data; the search space is not limited to known variants and simultaneously does not require additional data. In a subsequent step a second identification search is performed to verify the initially identified variant peptides and aggregate information on the protein level. PMID- 26519183 TI - Data Analysis Strategies for Protein Modification Identification. AB - Mass spectrometry-based proteomics provides a powerful tool for large-scale analysis of protein modifications. Statistical and computational analysis of mass spectrometry data is a key step in protein modification identification. This chapter presents common and advanced data analysis strategies for modification identification, including variable modification search, unrestrictive approaches for modification discovery, false discovery rate estimation and control methods, and tools for modification site localization. PMID- 26519184 TI - Dissecting the iTRAQ Data Analysis. AB - In the era of large-scale quantitative biology, mass spectrometry-based quantitative proteomics is progressively becoming indispensable for gaining insights into the biological systems at molecular level. Various quantitative study designs rely on chemical tagging approaches to study disease, stress, or drug response and temporal studies aiming at disease/developmental progression in a biological system. Isobaric tags for relative and absolute quantitation (iTRAQ) is one of the most popular chemical labeling techniques which allows four, six, or eight samples to be multiplexed in a single run. As the iTRAQ tag has a balancer group to equalize all states of a labeled peptide to same mass, the differentially labeled iTRAQ peptides are mixed before chromatography and elute as a single combined peak in MS. This enhances the peptide signal and quantitation is performed during MS/MS along with sequencing, where reporter ions of different masses are released to give relative quantitation. Known amount of a spiked-in protein can also help in absolute quantitation of the proteins in a sample. PMID- 26519185 TI - Statistical Aspects in Proteomic Biomarker Discovery. AB - In the pursuit of a personalized medicine, i.e., the individual treatment of a patient, many medical decision problems are desired to be supported by biomarkers that can help to make a diagnosis, prediction, or prognosis. Proteomic biomarkers are of special interest since they can not only be detected in tissue samples but can also often be easily detected in diverse body fluids. Statistical methods play an important role in the discovery and validation of proteomic biomarkers. They are necessary in the planning of experiments, in the processing of raw signals, and in the final data analysis. This review provides an overview on the most frequent experimental settings including sample size considerations, and focuses on exploratory data analysis and classifier development. PMID- 26519186 TI - Return to sports and clinical outcomes in patients treated for peroneal tendon dislocation: a systematic review. AB - PURPOSE: The aim of this study was to determine the outcome following different surgical treatment techniques in the treatment of peroneal tendon dislocation and to establish whether return to sports was achieved universally following the procedures. METHODS: A systematic review and best-evidence synthesis was performed. PubMed and EMBASE were searched for eligible studies. The last search was done in March 2015. Quality assessment of pooled data was performed using a modified Macleod scale and a best-evidence synthesis was performed. In total, 14 studies were included. RESULTS: Surgical treatment provides improvement in the post-operative AOFAS score (p < 0.0001) and high satisfaction rates. The redislocation rate is less than 1.5% at long-term follow-up. Patients treated with both groove deepening and SPR repair have higher rates of return to sports than patients treated with SPR repair alone (p = 0.022). CONCLUSIONS: Surgical treatment of peroneal tendon dislocation provides good outcomes, high satisfaction and a quick return to sports. Rates in return to sports are significantly higher in patients treated with both groove deepening and SPR repair. To optimize treatment, the surgical management should involve increasing the superior peroneal tunnel volume by groove deepening and stabilizing the tendons by SPR repair. LEVEL OF EVIDENCE: Level IV, systematic review of level IV studies. PMID- 26519187 TI - The Oxford knee score and its subscales do not exhibit a ceiling or a floor effect in knee arthroplasty patients: an analysis of the National Health Service PROMs data set. AB - PURPOSE: In this study, we examined whether the OKS demonstrated a floor or a ceiling effect when used to measure the outcome of knee replacement surgery in a large national cohort. METHODS: NHS PROMs database, containing pre- to 6 month post-operative OKS on 72,154 patients, mean age 69 (SD 9.4), undergoing knee replacement surgery, was examined to establish the proportion of patients achieving top or bottom OKS values pre- and post-operatively. RESULTS: Pre operatively, none of patients achieved the maximum/'best' (48) and minimum (0) scores. Post-operatively, no patients (0 %) achieved the minimum/'worst' score, but the percentage achieving the maximum score increased to 2.7 %. Subgroup analyses demonstrated that the highest post-operative overall ceiling percentage was 3 %, in a subgroup of patients between 60 and 79 years of age and 13.7 % in a group of patients who had a pre-operative OKS above 41. Furthermore, 10.8 % of patients achieved the top post-operative OKS-PCS and 4.7 % top post-operative OKS FCS. CONCLUSION: Based on NHS PROMs data, the OKS does not exhibit a ceiling or floor effect overall, or for both its pain and function subscales, and remains a valid measure of outcomes for patients undergoing TKA. LEVEL OF EVIDENCE: Large scale retrospective observations study, Level II. PMID- 26519188 TI - The superficial medial collateral ligament is the primary medial restraint to knee laxity after cruciate-retaining or posterior-stabilised total knee arthroplasty: effects of implant type and partial release. AB - PURPOSE: The aim of this study was to quantify the contributions of medial soft tissues to stability following cruciate-retaining (CR) or posterior-stabilised (PS) total knee arthroplasty (TKA). METHODS: Using a robotic system, eight cadaveric knees were subjected to +/-90-N anterior-posterior force, +/-5-Nm internal-external and +/-8-Nm varus-valgus torques at various flexion angles. The knees were tested intact and then with CR and PS implants, and successive cuts of the deep and superficial medial collateral ligaments (dMCL, sMCL) and posteromedial capsule (PMC) quantified the percentage contributions of each structure to restraining the applied loads. RESULTS: In implanted knees, the sMCL restrained valgus rotation (62 % across flexion angles), anterior-posterior drawer (24 and 10 %, respectively) and internal-external rotation (22 and 37 %). Changing from CR TKA to PS TKA increased the load on the sMCL when resisting valgus loads. The dMCL restrained 11 % of external and 13 % of valgus rotations, and the PMC was significant at low flexion angles. CONCLUSIONS: This work has shown that medial release in the varus knee should be minimised, as it may inadvertently result in a combined laxity pattern. There is increasing interest in preserving constitutional varus in TKA, and this work argues for preservation of the sMCL to afford the surgeon consistent restraint and maintain a balanced knee for the patient. PMID- 26519190 TI - [Central venous pressure: evidence or expert opinion?] PMID- 26519189 TI - [S1 guidelines on airway management]. AB - Since the publication of the first german guidelines on airway management in 2014, new techniques have been established in the clinical routine and new insights into existing strategies have been published. As a consequence the new guidelines on airway management of the German Society of Anesthesiology and Intensive Care Medicine represent the current state of scientific knowledge and integrate the currently recommended techniques and strategies. The aim of these guidelines is to guarantee an optimal care of patients undergoing anesthesiological procedures and serve as an orientation and decision aid for users. PMID- 26519192 TI - Heimler's syndrome: a close mimic of Bart-Pumphrey syndrome. PMID- 26519191 TI - Use of Multiple Probes to Assess Transporter- and Cytochrome P450-Mediated Drug Drug Interaction Potential of the Pangenotypic HCV NS5A Inhibitor Velpatasvir. AB - BACKGROUND AND OBJECTIVES: Velpatasvir (VEL; GS-5816) is a potent, pangenotypic hepatitis C virus (HCV), non-structural protein 5A inhibitor in clinical development for the treatment of chronic HCV infection. In vitro studies indicate that VEL may inhibit several drug transporters and be a substrate for enzyme/drug transport systems in vivo. The purpose of this study was to evaluate the potential of VEL as a perpetrator or victim of metabolic- and transporter-based drug-drug interactions using complementary probe drugs. METHODS: This Phase 1 study was a randomized, cross-over, open-label, single- and multiple-dose, five cohort study. Serial blood samples were collected following oral administration of reference and test treatments. The primary pharmacokinetic parameters of each analyte were compared when administered alone or in combination. The 90% confidence intervals (CI) for the ratio of the geometric least-squares means of the test and reference treatments was calculated for each analyte and parameter of interest. RESULTS: This study demonstrated that VEL is a weak (P-gp, OATP) to moderate (breast cancer resistance protein) transport inhibitor. As a victim of interactions, VEL is moderately affected by potent inhibitors and to a greater extent, potent inducers of enzyme/drug transporter systems. CONCLUSIONS: The impact of specific transporters and overall contribution of drug transport vs. metabolizing enzymes on the disposition of VEL was characterized through the use of complementary probes, despite the lack of phenotypic specificity, and informs a broad range of drug-drug interaction recommendations. PMID- 26519193 TI - Antifungal activity of Myriocin on clinically relevant Aspergillus fumigatus strains producing biofilm. AB - BACKGROUND: The human pathogenic mold Aspergillus fumigatus is able to form a complex biofilm embedded in extracellular matrix. Biofilms confer antimicrobial resistance and it is well known that aspergillosis is often refractory to the conventional antifungal therapy. The treatment of biofilm-related infections poses a significant clinical challenge on a daily basis, promoting the search for new therapeutic agents. Our aim was to exploit the modulation of sphingolipid mediators as new therapeutic target to overcome antifungal resistance in biofilm related infections. RESULTS: Antifungal susceptibility testing was performed on 20 clinical isolates of Aspergillus fumigatus and one reference strain (A. fumigatus Af293) according the EUCAST protocol. Sessile MICs were assessed on 24 h preformed-biofilm by means of XTT-reduction assay. Myriocin (0.25-64 mg/L), a commercial sphingolipid synthesis inhibitor, was used. The MEC50 value (mg/L) of Myriocin was 8 (range 4-16) for both planktonic and sessile cells. Drug-induced morphological alterations were analyzed by optical and electron microscopy (TEM) on 24h preformed A. fumigatus Af293 biofilms. An evident hyphal damage, resulting in short, stubby, and highly branched hyphae was observed by optical microscopy. At 24h, TEM studies showed important morphological alterations, such as invaginations of the cell membrane, modification in the vacuolar system and presence of multilamellar bodies, in some cases within vacuoles. CONCLUSIONS: The direct antifungal activity, observed on both planktonic and sessile fungi, suggests that inhibition of sphingolipid synthesis could represent a new target to fight biofilm-related A. fumigatus resistance. PMID- 26519194 TI - Editor's Spotlight/Take 5: Time-driven Activity-based Costing More Accurately Reflects Costs in Arthroplasty Surgery. PMID- 26519195 TI - CORR Insights((r)): Sacral Insufficiency Fractures are Common after High-dose Radiation for Sacral Chordomas Treated With or Without Surgery. PMID- 26519196 TI - Open Surgical Treatment for Snapping Scapula Provides Durable Pain Relief, but so Does Nonsurgical Treatment. AB - BACKGROUND: Resection of the medial upper corner of the scapula is one option for treating patients with a painful chronic snapping scapula. However, the degree to which this procedure results in sustained relief of pain during long-term followup, and whether surgical treatment offers any compelling advantages over nonsurgical approaches at long-term followup, are not known. QUESTIONS/PURPOSES: We asked: (1) At long-term followup after surgical treatment of a painful snapping scapula, did patients' pain decrease? (2) Did scapulocostal crepitation improve? (3) Did patients return to work? METHODS: Between 1971 and 1992, 15 patients underwent surgery by one surgeon for persistent (> 1 year) and severely painful crepitus around the superomedial scapula that did not respond to nonsurgical approaches. The procedure consisted of an open resection of the superomedial corner of the scapula and release of the levator scapulae muscle. Patients treated surgically were compared with a group of nine patients treated nonsurgically between 1975 and 1997; their treatments included temporary physiotherapy, massage, and NSAIDs. In general, the patients treated nonsurgically presented with less pain. However, during much of this study period, objective pain and functional scales were not in common use, and so baseline scores were not available. Of the 15 patients treated surgically, nine participated in a clinical and questionnaire survey at a mean of 22 years (range, 16-35 years), and 12 participated in a questionnaire survey a mean 27 years after surgery (range, 23-43 years). Of the nine patients treated nonsurgically, seven participated in a clinical followup and questionnaire survey at a mean followup of 16 years (range, 10-25 years), and all nine completed a questionnaire survey at a mean of 22 years (range, 17-33 years). Patient age at onset of symptoms was a mean of 27 years. The clinical followup and questionnaires focused on pain, crepitation, and work status. RESULTS: With the numbers available, there was no difference in pain scores between patients treated surgically and those treated nonsurgically (mean VAS pain with exertion 0.8 +/- 1.3 versus 1.5 +/- 1.6; p = 0.357); in fact, pain scores were quite low in both groups. Pain improved promptly in seven of 12 patients treated surgically, but lasted for at least several years in all patients treated nonsurgically. Crepitus persisted variably in both groups at final followup, with no apparent difference between the groups in terms of its frequency, but it was not consistently associated with pain at final followup in either group (six of 12 patients treated surgically, all painless; and all of seven clinically examined patients treated nonsurgically, two without pain, had crepitus at latest followup; p = 0.004), whereas at initial presentation, the crepitus had been painful in all patients. All patients in both groups had returned to work after surgery or the first consultation. CONCLUSIONS: Carefully selected patients who undergo this procedure appear to obtain sustained relief of painful crepitus at long term, but so do patients treated nonsurgically. Since the decision to treat these patients surgically was somewhat subjective, and since patients treated nonsurgically did so well (although the surgically treated patients improved faster), we cannot conclude that surgery is better than nonsurgical treatment. Multicenter comparative studies with carefully applied indications are needed. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26519197 TI - Methylation status of TSHr in well-differentiated thyroid cancer by using cytologic material. AB - BACKGROUND: The role of methylation status of the thyroid stimulating hormone receptor gene (TSHr) in the discrimination of benign and malignant thyroid nodules has already been studied using paraffin blocks and cell lines. As cytological sampling plays an important role in assessment of thyroidal nodules, we have investigated the potential clinical use of TSHr methylation status of fine needle aspiration specimens reported according to Bethesda System. METHOD: Sixty nine patients who had both cytological and pathological diagnosis of the same nodule were selected. Four groups were composed according to cytological and pathological diagnoses: Benign (B), papillary thyroid carcinoma (PTC), atypia of unknown significance (AUS) and follicular neoplasia (FN). The latter 2 groups were further sub-classified into 2 as benign (AUS-B and FN-B) and malignant (AUS M and FN-M) according to final pathological diagnosis. DNAs were isolated from the fine needle aspiration cytology specimens and the methylation status of TSHr promotor region was investigated by using methylation specific polymerase chain reaction. RESULTS: Overall, TSHr methylation was present in 58% of cases; 71% of malignant and 46% of benign nodules. PTC group showed the highest TSHr methylation rate (87%), followed by 61% in AUS, 44% in B, and 30% in FN (p = 0.016). TSHr methylation rate was significantly higher in PTC group when compared to B (p = 0.013) and FN-B (p = 0.004) groups; but not in FN-M (p = 0.115) or AUS (p = 0.096) groups. All 9 cases of papillary thyroid carcinoma with lymph node metastasis showed TSHr methylation. Positive predictive value, negative predictive value, sensitivity and specificity of TSHr methylation in determination of malignancy were calculated as 60, 66, 71 and 54%, respectively. CONCLUSION: The eminent ratio of TSHr methylation in well-differentiated thyroid carcinoma against benign thyroidal nodules adduced that TSHr methylation status can be utilized as a tumor marker for well-differentiated thyroid cancer; however, it has a limited value. The determination of methylation status of TSHr gene had no efficiency on decision of the malignant potential for the nodules which are cytologically classified as atypia of undetermined significance. PMID- 26519198 TI - The duration of cough in patients with H1N1 influenza. AB - BACKGROUND: Cough is one of common symptoms of influenza, the cough duration and prevalence of postinfectious cough (PIC) after viral upper respiratory tract infection has not been well described. OBJECTIVES: We aim to investigate the duration of cough and prevalence of PIC and its relation with acute symptoms, airway inflammation and cough sensitivity in patients with H1N1 influenza. METHODS: Patients with acute symptoms of H1N1 influenza were enrolled and followed up until cough relived. Spirometry, induced sputum test, capsaicin challenge test were conducted in patients with PIC. Cough sensitivity was presented as logarithm of provocative concentration inducing five or more coughs (logC5). RESULTS: A total of 141 cases with H1N1 influenza were enrolled. In patients with H1N1 influenza, 97.2% of them complained cough. The duration of cough was as following: <1 week (73.0%); 1-2 weeks (7.8%); 2-3 weeks (7.8%); >=3 weeks (8.5%). Twelve (8.5%) patients had cough lasting more than 3 weeks (PIC), 4 (2.8%) patients developed chronic cough (>8 weeks). Acute symptoms, spirometry, bronchial responsiveness and sputum differential cell count were similar between patients with PIC and those without PIC, however, there was a higher prevalence of previous PIC (58.3% vs 14.7%, P < 0.05) and elevated cough sensitivity (lgC5: 1.18 +/- 0.58 vs 2.73 +/- 0.33, P < 0.01) in patients with PIC as compared with the patients without PIC. CONCLUSIONS: Acute cough is common in patients with H1N1 PIC, only a few of patients develop chronic cough. Acute symptoms cannot predict PIC which is related with previous PIC and increased cough sensitivity. PMID- 26519199 TI - IgE low affinity receptor (CD23) expression, Plasmodium falciparum specific IgE and tumor necrosis factor-alpha production in Thai uncomplicated and severe falciparum malaria patients. AB - Previous studies have suggested that Plasmodium falciparum (P. falciparum) specific IgE in the form of immune complexes crosslinking the low-affinity receptor (CD23) on monocyte results in tumor necrosis factor (TNF)-alpha and nitric oxide (NO) production. However, the roles of these parameters in severity and immune protection are still unclear. This study aimed to determine the association between CD23 expression on monocytes, plasma soluble CD23 (sCD23), total IgE, malaria-specific IgE and IgG, and TNF-alpha levels in P. falciparum infected patients. We evaluated 64 uncomplicated (UC) and 25 severe patients (S), admitted at the Hospital for Tropical Diseases, Mahidol University, and 34 healthy controls (C) enrolled in 2001. Flow cytometry and enzyme linked immunosorbent assays (ELISA) demonstrated that trends of the CD23 expression, levels of sCD23 and specific IgE were higher in the S group as compared to those in the UC and C groups. Plasma levels of P. falciparum specific IgE in the UC (p=0.011) and S groups (p=0.025) were significantly higher than those in C group. In contrast the TNF-alpha levels tended to be higher in the UC than those in the S (p=0.343) and significantly higher than those in C (p=0.004) groups. The specific IgG levels in UC were significantly higher than those in S and C (p<0.001) groups. At admission, a strong significant negative correlation was found between specific IgG and sCD23 (r=-0.762, p=0.028), and TNF-alpha and IgE IgG complexes (r=-0.715, p=0.002). Significant positive correlations between levels of specific IgE and TNF-alpha (r=0.575, p=0.010); and sCD23 (r=0.597, p=0.000) were also observed. In conclusion, our data suggest that CD23 expression and malaria-specific IgE levels may be involved in the severity of the disease while TNF-alpha and the malaria-specific IgG may correlate with protection against falciparum malaria. PMID- 26519200 TI - Intestinal helminth coinfection is associated with mucosal lesions and poor response to therapy in American tegumentary leishmaniasis. AB - The most severe clinical form of American tegumentary leishmaniasis (ATL) due to Leishmania braziliensis is mucosal leishmaniasis (ML), characterized by destructive lesions in the facial mucosa. We performed a retrospective cohort study of 109 ATL patients from Rio de Janeiro State, Brazil, where ATL is caused by L. braziliensis, to evaluate the influence of intestinal parasite coinfections in the clinical course of ATL. Parasitological stool examination (PSE) was performed with samples from all patients by the sedimentation, Kato-Katz and Baermann-Moraes methods. The diagnosis of ATL was made from lesion biopsies by direct observation of amastigotes in Giemsa-stained imprints, isolation of Leishmania promastigotes or histopathological examination. All patients were treated with meglumine antimoniate. Patients with positive PSE had a frequency of mucosal lesions significantly higher than those with negative PSE (p<0.005). The same was observed for infections with helminths in general (p<0.05), with nematodes (p<0.05) and with Ascaris lumbricoides (p<0.05), but not for protozoan infections. Patients with intestinal parasites had poor response to therapy (therapeutic failure or relapse) significantly more frequently than the patients with negative stool examination (p<0.005). A similar difference (p<0.005) was observed between patients with positive and negative results for intestinal helminths, but not for intestinal protozoa. Patients with positive PSE took significantly longer to heal than those with negative PSE (p<0.005). A similar difference was observed for intestinal helminth infections (p<0.005), but not for protozoan infections. Our results indicate a deleterious influence of intestinal helminth infections in the clinical course of ATL and evidence for the first time an association between ML and these coinfections, particularly with nematodes and A. lumbricoides. PMID- 26519201 TI - Extraction of organophosphorus pesticides by carbon-coated Fe3 O4 nanoparticles through response surface experimental design. AB - In this paper, carbon-coated Fe3 O4 nanoparticles were successfully synthesized and used as a magnetic solid-phase extraction absorbent for the preconcentration and extraction of organophosphorus pesticides in environmental water samples. The carbon-coated Fe3 O4 nanoparticles were characterized by transmission electron microscopy, X-ray powder diffraction, Fourier transform infrared spectroscopy, and vibrating sample magnetometry. The determination of organophosphorus pesticides in water samples with carbon-coated Fe3 O4 nanoparticles was investigated by high-performance liquid chromatography with a diode array detector. Furthermore, the response surface model based on the central composite design was applied to quantitatively investigate the effect of some important variables influencing the extraction efficiency, such as pH, treatment time, amount of nanoparticle sorbents, and amount of salt and to find the optimized conditions providing the highest extraction efficiency. Under optimized conditions, the calibration curve was linear in the range of 0.5-15.0 ng/mL with a regression coefficient of 0.9948, 0.9958, and 0.9931 for fenitrothion, diazinon, and ethion, respectively. The obtained results showed that this analytical method would be useful for the analysis of fenitrothion, diazinon, and ethion in tap water with high precision and accuracy. PMID- 26519202 TI - Alocasia denudata Engler treatment enhance open wound healing activities in Wistar rat's skin. AB - ETHNOPHARMACOLOGICAL RELEVANCE: A. denudata is traditionally used to treat various skin disorders, including wounds. It is widely used by the traditional healers as an effective wound treatment. AIM OF STUDY: This study was done to determine A. denudata treatment effects on open wound healing activities in Wistar rat's skin. MATERIALS AND METHODS: 120 Wistar rats (250-300 g) were divided into four main groups, 1.5% and 3% A. denudata stem juice treated group, 10% Solcoseryl(r) gel treated group as positive control and phosphate buffer saline (PBS) treated group as negative control. Six full thicknesses wounds (6mm) were induced bilaterally on the dorsal of the rat's skin. Rats were sacrificed on day 1, 3, 6, 10 and 14. The percentage of wound contraction, biochemical estimations, macroscopic observation and histological examinations were done to evaluate the wound healing activities. RESULTS: Results showed wounds treated with A. denudata stem juice possess a significant higher rate of wound contraction (p<0.001), total protein concentration (p<0.05), hexosamine concentration (p<0.001) and uronic acid concentration (p<0.001). Moreover, cathepsin B (p<0.05) and hydroxyproline (p<0.05) level showed lower concentration in wounds treated with A. denudata stem juice. Histological observation of wounds treated with A. denudata stem juice displayed organized epithelial layer with dense and compact collagen fibers. CONCLUSION: Both doses of A. denudata stem juice were found to enhance wound healing process. However, wounds treated with 3% A. denudata stem juice were reported to be more effective as a wound healing agent thus support its traditional usage. PMID- 26519203 TI - An ethnobotanical survey of medicinal plants used by communities of Northern Kordofan region, Sudan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The present study provides significant ethnopharmacological information on plant species used in North Kordofan region, western Sudan. The study was undertaken with an aim to document the medicinal uses of the species known to some Northern Kordofan communities. MATERIAL AND METHODS: The study was conducted between 2012 and 2013. The plants were identified and voucher specimens prepared. Information was collected by means of semi-structured interviews with 258 informants (195 men and 63 women). In addition, the use value (UV) of the species was determined and the informant consensus factor (ICF) was calculated for the medicinal plants researched in the study. Further analysis was carried out to compare results with previous studies from the study area and other regions of Sudan. RESULTS: A total of 44 plant species representing 24 families were found to be commonly used in the treatment of 73 different human health problems. The families most represented were Leguminosae (18%), Caesalpiniaceae (9%), Malvaceae (9%), Asclepiadaceae (6.8%) and Combretaceae (6.8%). The highest number of plant species are used against digestive system disorders (23 species) followed by microbial infections (21 species) and dermatology (19 species). Among all the plant parts leaves (20%), roots (19%), fruits and bark (14% each) were the most preferred plant parts used by the informants. There was strong agreement among the informants as to the usages of the plants (informant consensus factor 0.63-0.93). The most important plants on the basis of use-value were Acacia nilotica, Acacia seyal, Balanites aegyptiaca, Cassia occidentalis, Cassia senna, Guiera senegalensis and Tamarindus indica. CONCLUSION: This study has helped to document information that may otherwise be lost to future generations. This is the first ethnobotanical study in which statistical calculations about plants are carried out by means of the ICF and UV methods in the study area. Plants with high ICF and UV values should be subjected for further phytochemical and pharmacological investigation for scientific validation. PMID- 26519204 TI - Developmental competence of mature yak vitrified-warmed oocytes is enhanced by IGF-I via modulation of CIRP during in vitro maturation. AB - The objective of this study was to investigate whether developmental competence of mature vitrified-warmed yak (Bos grunniens) oocytes can be enhanced by supplemented insulin-like growth factor I (IGF-1) during in vitro maturation (IVM), and its relationship with the expression of cold-inducible RNA-binding protein (CIRP). In experiment 1, immature yak oocytes were divided into four groups, and IVM supplemented with 0, 50, 100 and 200 ng/mL IGF-1 was evaluated; the mRNA and protein expression levels of CIRP in mature oocytes in the four groups were evaluated using quantitative real-time PCR and western blotting analyses. In experiment 2, the mature yak oocytes in the four groups were cryopreserved using the Cryotop (CT) method, followed by chemical activation and in vitro culture for two days and eight days to determine cleavage, blastocyst rates, and total cell number in the blastocysts. Mature yak oocytes without vitrification served as a control group. The outcomes were as following: (1) the expression of CIRP in the matured oocytes was up-regulated in the IGF-1 groups and was highest expression was observed in the 100 ng/mL IGF-1 treatment group. (2) In the vitrified-warmed groups, the rates of cleavage and blastocyst were also highest in the 100 ng/mL IGF-1 treatment group (81.04 +/- 1.06%% and 32.16 +/- 1.01%), which were close to the rates observed in groups without vitrification (83.25 +/- 0.85% and 32.54 +/- 0.34%). The rates of cleavage and blastocyst in the other vitrified-warmed groups were 70.92 +/- 1.32% and 27.33 +/ 1.31% (0 ng/mL); 72.73 +/- 0.74% and 29.41 +/- 0.84% (50 ng/mL); 72.43 +/- 0.61% and 27.61 +/- 0.59% (200 ng/mL), respectively. There was no significant difference in the total cell number per blastocysts between the vitrified-warmed groups and group without vitrification. Thus, we conclude that the enhancement in developmental competence of mature yak vitrified-warmed oocytes after the addition of IGF-1 during IVM might result from the regulation of CIRP expression in mature yak oocytes prior to vitrification. PMID- 26519205 TI - Induction and regulation of murine emphysema by elastin peptides. AB - Emphysema is the major component of chronic obstructive pulmonary disease (COPD). During emphysema, elastin breakdown in the lung tissue originates from the release of large amounts of elastase by inflammatory cells. Elevated levels of elastin-derived peptides (EP) reflect massive pulmonary elastin breakdown in COPD patients. Only the EP containing the GXXPG conformational motif with a type VIII beta-turn are elastin receptor ligands inducing biological activities. In addition, the COOH-terminal glycine residue of the GXXPG motif seems a prerequisite to the biological activity. In this study, we endotracheally instilled C57BL/6J mice with GXXPG EP and/or COOH-terminal glycine deleted-EP whose sequences were designed by molecular dynamics and docking simulations. We investigated their effect on all criteria associated with the progression of murine emphysema. Bronchoalveolar lavages were recovered to analyze cell profiles by flow cytometry and lungs were prepared to allow morphological and histological analysis by immunostaining and confocal microscopy. We observed that exposure of mice to EP elicited hallmark features of emphysema with inflammatory cell accumulation associated with increased matrix metalloproteinases and desmosine expression and of remodeling of parenchymal tissue. We also identified an inactive COOH-terminal glycine deleted-EP that retains its binding-activity to EBP and that is able to inhibit the in vitro and in vivo activities of emphysema inducing EP. This study demonstrates that EP are key actors in the development of emphysema and that they represent pharmacological targets for an alternative treatment of emphysema based on the identification of EP analogous antagonists by molecular modeling studies. PMID- 26519206 TI - Systemic interleukin-2 administration improves lung function and modulates chorioamnionitis-induced pulmonary inflammation in the ovine fetus. AB - Chorioamnionitis, an inflammatory reaction of the fetal membranes to microbes, is an important cause of preterm birth and associated with inflammation-driven lung injury. However, inflammation in utero overcomes immaturity of the premature lung by inducing surfactant lipids and lung gas volume. Previously, we found that lipopolysaccharide (LPS)-induced chorioamnionitis resulted in pulmonary inflammation with increased effector T cells and decreased regulatory T cell (Treg) numbers. Because Tregs are crucial for immune regulation, we assessed the effects of interleukin (IL)-2-driven selective Treg expansion on the fetal lung in an ovine chorioamnionitis model. Instrumented fetuses received systemic prophylactic IL-2 treatment [118 days gestational age (dGA)] with or without subsequent exposure to intra-amniotic LPS (122 dGA). Following delivery at 129 dGA (term 147 dGA), pulmonary and systemic inflammation, morphological changes, lung gas volume, and phospholipid concentration were assessed. IL-2 pretreatment increased the FoxP3(+)/CD3(+) ratio, which was associated with reduced CD3 positive cells in the fetal lungs of LPS-exposed animals. Prophylactic IL-2 treatment did not prevent pulmonary accumulation of myeloperoxidase- and PU.1 positive cells or elevation of bronchoalveolar lavage fluid IL-8 and systemic IL 6 concentrations in LPS-exposed animals. Unexpectedly, IL-2 treatment improved fetal lung function of control lambs as indicated by increased disaturated phospholipids and improved lung gas volume. In conclusion, systemic IL-2 treatment in utero preferentially expanded Tregs and improved lung gas volume and disaturated phospholipids. These beneficial effects on lung function were maintained despite the moderate immunomodulatory effects of prophylactic IL-2 in the course of chorioamnionitis. PMID- 26519207 TI - Ozone-induced airway hyperresponsiveness: roles of ROCK isoforms. AB - Acute ozone (O3) inhalation has been shown to cause airway and pulmonary epithelial injury with accompanying inflammation responses. Robust evidence exists that O3 induces airway hyperresponsiveness (AHR) in humans and in animal models. Several pathways exist that culminate in airway smooth muscle contraction, but the mechanism(s) by which O3 elicits AHR are unclear. Here, we review the recent report by Kasahara et al. (Kasahara DI, Mathews JA, Park CY, Cho Y, Hunt G, Wurmbrand AP, Liao JK, Shore SA. Am J Physiol Lung Cell Mol Physiol 309: L736-L746, 2015.) describing the role of two Rho kinase (ROCK) isoforms in O3-induced AHR utilizing a murine haploinsufficiency model. Compared with wild-type (WT) mice, the authors report that ROCK1(+/-) and ROCK2(+/-) mice exhibited significantly reduced AHR following acute exposure to O3. Additionally, WT mice treated with fasudil, an FDA-approved ROCK1/2 inhibitor, recapitulated reduction in AHR as seen in ROCK haplotypes. It was suggested that, although the two ROCK isoforms are both induced by Rho, they have different mechanisms by which they mediate O3-induced AHR: ROCK1 via hyaluronan signaling vs. ROCK2 acting downstream of inflammation at the level of airway smooth muscle contraction. These observations provide an important framework to develop novel ROCK-targeting therapies for acute O3-induced AHR. PMID- 26519209 TI - Inherited Structural Heart Diseases With Potential Atrial Fibrillation Occurrence. AB - Inherited cardiac diseases inducing structural remodeling of the myocardium sometimes develop arrhythmias of various kinds. Among these rhythm disturbances, atrial fibrillation is well known to frequently worsen the prognosis of the primary disorder by increasing morbidity and mortality, especially because of a higher rate of heart failure. In this manuscript, we have reviewed the literature on the most important inherited structural cardiac diseases in whose clinical history atrial fibrillation may occur fairly often. PMID- 26519208 TI - Decreased endothelial nitric oxide synthase expression and function contribute to impaired mitochondrial biogenesis and oxidative stress in fetal lambs with persistent pulmonary hypertension. AB - Impaired vasodilation in persistent pulmonary hypertension of the newborn (PPHN) is characterized by mitochondrial dysfunction. We investigated the hypothesis that a decreased endothelial nitric oxide synthase level leads to impaired mitochondrial biogenesis and function in a lamb model of PPHN induced by prenatal ductus arteriosus constriction. We ventilated PPHN lambs with 100% O2 alone or with inhaled nitric oxide (iNO). We treated pulmonary artery endothelial cells (PAECs) from normal and PPHN lambs with detaNONOate, an NO donor. We observed decreased mitochondrial (mt) DNA copy number, electron transport chain (ETC) complex subunit levels, and ATP levels in PAECs and lung tissue of PPHN fetal lambs at baseline compared with gestation matched controls. Phosphorylation of AMP-activated kinase (AMPK) and levels of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1alpha) and sirtuin-1, which facilitate mitochondrial biogenesis, were decreased in PPHN. Ventilation with 100% O2 was associated with larger decreases in ETC subunits in the lungs of PPHN lambs compared with unventilated PPHN lambs. iNO administration, which facilitated weaning of FiO2 , partly restored mtDNA copy number, ETC subunit levels, and ATP levels. DetaNONOate increased eNOS phosphorylation and its interaction with heat shock protein 90 (HSP90); increased levels of superoxide dismutase 2 (SOD2) mRNA, protein, and activity; and decreased the mitochondrial superoxide levels in PPHN PAECs. Knockdown of eNOS decreased ETC protein levels in control PAECs. We conclude that ventilation with 100% O2 amplifies oxidative stress and mitochondrial dysfunction in PPHN, which are partly improved by iNO and weaning of oxygen. PMID- 26519210 TI - Optimizing the production of the biosurfactant lichenysin and its application in biofilm control. AB - AIMS: Apply response surface methodology (RSM) to develop and optimize an economical medium for lichenysin production, which is a surfactant produced by Bacillus licheniformis and evaluate the application of lichenysin in the prevention and disruption of pathogenic micro-organism biofilm that creates health problems in the food industry and hospitals. RESULTS: An economical medium containing molasses was optimized to enhance lichenysin production by RSM. A production of 3.2 g l(-1) of lichenysin was achieved with an optimum medium containing 107.82 g l(-1) of molasses, 6.47 g l(-1) of NaNO3 and 9.7 g l(-1) of K2 HPO4 /KH2 PO4 , in which molasses and phosphate salts had a significant effect on biosurfactant production. Lichenysin was effectively applied in a surface pre treatment to avoid microbial biofilm development of methicillin-resistant Staphylococcus aureus (MRSA) (68.73%) and Candida albicans (74.35%), with ED50 values of 8.3 and 17.2 MUg ml(-1) respectively. It was also very efficient in a surface post-treatment to remove biofilms of MRSA (55.74%) and Yersinia enterocolitica (51.51%), with an ED50 of 2.79 and 4.09 MUg ml(-1) respectively. CONCLUSIONS: Lichenysin was found to have notable anti-adhesion activity, being able to prevent and eliminate the biofilm formation by pathogenic strains associated with foodborne illness. This new medium resulted in a four-fold increase in production compared with the nonoptimized medium. SIGNIFICANCE AND IMPACT OF THE STUDY: Molasses can be regarded as a useful resource for biotechnological applications, such as the production of lichenysin. The use of agro-industrial substrates has an important role in the sustainable and competitive development of several industrial sectors, as well as in industrial residues management. Additionally, lichenysin is particularly effective in preventing biofilm formation by strains problematic for the food industry and in the hospital environment. Lichenysin also efficiently disrupts biofilm. PMID- 26519211 TI - Characterization of 5' promoter and exon 1-3 polymorphism of the RAET1E gene. AB - NKG2D is an activating receptor utilized by natural killer (NK) cells that recognizes upregulated ligands on infected, tumorigenic and damaged cells, leading to their cytolysis. However, the NKG2D ligand (NKG2DL) system is very complex with eight known gene loci encoding slightly different molecules. Furthermore, most NKG2DL gene loci such as MICA and MICB are highly polymorphic with potential for functional differences. NKG2DL expression on tumors varies depending on the malignancy and tumors can also release soluble NKG2DL that exert anergic effects on NK cells when engagement with NKG2D occurs, allowing escape from NK cell immunosurveillance. We carried out RAET1E typing of IHW cell line DNA, including a 580 bp proximal promoter fragment and exons 1-3 identifying 13 of 15 known RAET1E alleles. We determined 7 polymorphisms within the promoter region, including 2 already known that contributed to 9 promoter types. RAET1E alleles with variability in the extracellular region also differed with respect to promoter type and one allele, RAET1E(*)003, associated with 5 promoter types. We then identified putative transcription factor binding sites for RAET1E, and found 5 of the 7 promoter polymorphisms may disrupt these sites, abrogating binding of transcription factors and varying the potential level of expression. PMID- 26519212 TI - Integrity of the dorsolateral periaqueductal grey is essential for the fight-or flight response, but not the respiratory component of a defense reaction. AB - Periaqueductal grey is believed to be one of the key structures of the central respiratory stress network. Previous studies established that stimulation of the periaqueductal grey, especially its dorsolateral division (dlPAG), evokes tachypnea as well as increases in other autonomic parameters and motor activity. We investigated the effects of blockade of the dlPAG with GABAA agonist muscimol on respiration during stress and presentation of brief alerting stimuli in conscious unrestrained rats. We found that integrity of the dlPAG is not essential for stress-induced increase in basal/resting respiratory rate or for generation of respiratory responses to brief alerting stimuli. However, blockade of the dlPAG reduced the amount of motor activity and concomitant high-frequency respiratory activity during restraint and the first 5min of novelty stress. We conclude that the integrity of the dlPAG is not essential for generation of respiratory component of the defense reaction, but it mediates expression of the fight-or-flight response including its respiratory component. PMID- 26519213 TI - Postoperative volume balance: does stroke volume increase in Trendelenburg's position? AB - In healthy humans, stroke volume (SV) and cardiac output (CO) do not increase with expansion of the central blood volume by head-down tilt or administration of fluid. Here, we exposed 85 patients to Trendelenburg's position about one hour after surgery while cardiovascular variables were determined non-invasively by Modelflow. In Trendelenburg's position, SV (83 +/- 19 versus 89 +/- 20 ml) and CO (6.2 +/- 1.8 versus 6.8 +/- 1.8 l/min; both P<0.05) increased, while heart rate (75 +/- 15 versus 76 +/- 14 b min-1 ) and mean arterial pressure were unaffected (84 +/- 15 versus 84 +/- 16 mmHg). For the 33 patients (39%) with a > 10% increase in SV (from 78 +/- 16 to 90 +/- 17 ml) corresponding to an increase in CO from 5.9 +/- 1.5 to 6.9 +/- 1.6 l min-1 (P<0.05) when tilted head-down, administration of 250 ml Ringer's lactate solution increased SV (to 88 +/- 18 ml) and CO (to 6.8 +/- 1.7 l min-1 ). In conclusion, determination of SV and/or CO in Trendelenburg's position can be used to evaluate whether a patient is in need of IV fluid as here exemplified after surgery. PMID- 26519214 TI - Religion and menthol cigarette use in a US national sample. PMID- 26519215 TI - Acute on chronic liver failure because of acute hepatic insults: Etiologies, course, extrahepatic organ failure and predictors of mortality. AB - BACKGROUND AND AIM: Acute on chronic liver failure (ACLF) because of precipitating factors (variceal bleed/infections) identifies cirrhotics at risk for high short-term mortality. Information on ACLF because of acute hepatic insults is lacking. The aim of the study was to evaluate acute hepatic insults in ACLF and their effect on the course and outcome. METHODS: In a prospective study, 213 consecutive patients of ACLF because of acute hepatic insults were included. Etiology of acute hepatic insult, frequency of silent, and overt chronic liver disease (CLD), organ failure (OF), and outcomes were assessed. Prognostic models such as model for endstage liver disease (MELD), acute physiology and chronic health evaluation (APACHE II), and chronic liver failure-sequential organ failure (CLIF-SOFA) were evaluated. RESULTS: Etiologies of acute hepatic insult were hepatitis virus(es)- 81 (38%; HBV-42, HEV-39), continuous alcohol consumption-77 (33.3%), antituberculosis drugs-11 (5.2%), autoimmune hepatitis flare-5(2.3%), cryptogenic-44 (20.7%). The common causes of CLD were alcohol (n = 85/40%), HBV(n = 52/24%), and cryptogenic(n = 50/20%). The MELD, APACHE II, and CLIF-SOFA scores were similar among silent and overt CLD and did not influence outcome. Predominant etiologies of ACLF were hepatitis virus(es) reactivation or superinfection in silent CLD(52/112, 46.4%) and alcohol among overt CLD(43/101, 43%). Independent predictors of mortality included hepatic-encephalopathy (early, HR: 4.01; advanced, HR: 6.10), serum creatinine >=1.5 mg/dl (HR: 4.53), CLIF-SOFA >=8(HR: 1.69), and etiology of acute hepatic insult (alcohol, HR: 4.08; cryptogenic, HR: 3.18). HEV-ACLF had lower mortality (12.8% vs. 33-54% in other etiologies;P < 0.001). OF was major determinant of mortality. With increasing number of OF, mortality increased linearly(P = 0.001). CONCLUSIONS: Hepatitis virus(es) and continuous alcohol consumption are important causes of ACLF caused by acute hepatic insults. HEV-ACLF has lower mortality. OF is an important prognostic predictor. PMID- 26519216 TI - Severe atherosclerosis and a bewildering reticulated rash. PMID- 26519217 TI - The use of desiccation to treat Staphylococcus aureus biofilm-infected wounds. AB - Chronic wounds colonized with biofilm present a major burden to our healthcare system. While the current paradigm for wound healing is to maintain a moist environment, we sought to evaluate the effects of desiccation, and the ability of honey to desiccate wounds, on wound healing characteristics in Staphylococcus aureus biofilm wounds. In vivo biofilm wound healing after exposure to open-air desiccation, honey, molasses, and saline was analyzed using a rabbit ear model of S. aureus biofilm wounds previously developed by our group. Wound morphology was examined using scanning electron microscopy and granulation tissue deposition was measured using light microscopy with hematoxylin and eosin staining. Viable bacterial counts in rabbit ear biofilm wounds and scabs were measured using a drop dilution method. In vitro S. aureus growth curves were established using tryptic soy broth containing honey and glycerol. Gene expression analysis of rabbit ear wounds was performed using reverse transcription quantitative PCR. Rabbit ear S. aureus biofilm wounds exposed to open-air desiccation, honey, and molasses developed a dry scab, which displaced the majority of biofilm bacteria off of the wound bed. Wounds treated with open-air desiccation, honey, and molasses expressed lower levels of the inflammatory markers tumor necrosis factor alpha and interleukin-1beta at postoperative day 12 compared with wounds treated with saline, and had increased levels of granulation tissue formation. In vitro growth of S. aureus in tryptic soy broth was inhibited by the presence of honey to a greater extent than by the presence of osmolality-matched glycerol. Desiccation of chronic wounds colonized with biofilm via exposure to open air or honey leads to improved wound healing by decreasing bacterial burden and inflammation, and increasing granulation tissue formation. The ability of honey to help heal chronic wounds is at least in part due to its ability to desiccate bacterial biofilm, but other factors clearly contribute. PMID- 26519218 TI - The guardians of inherited oncogenic vulnerabilities. AB - Similar to seemingly maladaptive genes in general, the persistence of inherited cancer-causing mutant alleles in populations remains a challenging question for evolutionary biologists. In addition to traditional explanations such as senescence or antagonistic pleiotropy, here we put forward a new hypothesis to explain the retention of oncogenic mutations. We propose that although natural defenses evolve to prevent neoplasm formation and progression thus increasing organismal fitness, they also conceal the effects of cancer-causing mutant alleles on fitness and concomitantly protect inherited ones from purging by purifying selection. We also argue for the importance of the ecological contexts experienced by individuals and/or species. These contexts determine the locally predominant fitness-reducing risks, and hence can aid the prediction of how natural selection will influence cancer outcomes. PMID- 26519219 TI - Nonlinear robust dual-loop control for electro-hydraulic load simulator. AB - This paper investigates on the high performance torque control of electro hydraulic load simulator (EHLS). In order to suppress actuator's motion disturbance, a nonlinear robust dual-loop control scheme is developed, which consists of a open-loop nonlinear velocity feed-forward compensator and a closed loop nonlinear deterministic robust torque controller. The main function of the open-loop compensator is to decouple actuator's active motion disturbance, whereas the torque loop controller aims at guaranteeing the dynamics performance of tracking torque reference. Besides actuator's motion disturbance, both the nonlinearity characteristics and friction problem of the EHLS system are taken into consideration in this paper. The effectiveness of the developed method are verified through comparative co-simulations and experiments. PMID- 26519220 TI - A novel family of cyclic oligopeptides derived from ribosomal peptide synthesis of an in planta-induced gene, gigA, in Epichloe endophytes of grasses. AB - Fungal endophytes belonging to the genus Epichloe form associations with temperate grasses belonging to the sub-family Pooideae that range from mutualistic through to pathogenic. We previously identified a novel endophyte gene (designated gigA for grass induced gene) that is one of the most abundantly expressed fungal transcripts in endophyte-infected grasses and which is distributed and highly expressed in a wide range of Epichloe grass associations. Molecular and biochemical analyses indicate that gigA encodes a small secreted protein containing an imperfect 27 amino acid repeat that includes a kexin protease cleavage site. Kexin processing of GigA liberates within the plant multiple related products, named here as epichloecyclins, which we have demonstrated by MS/MS to be cyclic peptidic in nature. Gene deletion of gigA leads to the elimination of all epichloecyclins with no conspicuous phenotypic impact on the host grass, suggesting a possible bioactive role. This is a further example of a ribosomal peptide synthetic (RiPS) pathway operating within the Ascomycetes, and is the first description of such a pathway from a mutualistic symbiotic fungus from this Phylum. PMID- 26519221 TI - [Effects of a contraceptive counselling intervention in adolescents from deprived neighbourhoods with a high proportion of immigrants]. AB - OBJECTIVE: To evaluate the effectiveness of a contraceptive counselling intervention among adolescents by sex and origin. METHODS: A pre-post study with a 3-month follow-up was conducted in adolescents from three disadvantaged neighbourhoods. Participants received a counselling session at a community centre. Contraception use at last intercourse and knowledge, beliefs and self efficacy before and after the intervention were compared with chi(2) and McNemar tests, stratified by sex and origin (autochthonous or immigrant). RESULTS: A total of 138 (76%) participants completed the follow-up. Fifty-five percent of the participants were girls, 85% were aged 16-19 years and 71% were immigrants. Knowledge and several self-efficacies increased after the intervention. Condom use increased by 5.4% and the proportion not using any method declined by 7.7%. CONCLUSIONS: Contraceptive counselling in the community setting increased the use of contraception and improved psychosocial determinants, especially in immigrant adolescents. PMID- 26519223 TI - Chronic Oxidative Stress Increases Resistance to Doxorubicin-Induced Cytotoxicity in Renal Carcinoma Cells Potentially Through Epigenetic Mechanism. AB - Renal cell carcinoma is the most common form of kidney cancer and is highly resistant to chemotherapy. Although the role of oxidative stress in kidney cancer is known, the chemotherapeutic response of cancer cells adapted to chronic oxidative stress is not clear. Hence, the effect of oxidative stress on sensitivity to doxorubicin-induced cytotoxicity was evaluated using an in vitro model of human kidney cancer cells adapted to chronic oxidative stress. Results of MTT- and anchorage-independent growth assays and cell cycle analysis revealed significant decrease in sensitivity to doxorubicin in Caki-1 cells adapted to oxidative stress. Changes in the expression of genes involved in drug transport, cell survival, and DNA repair-dependent apoptosis further confirmed increased resistance to doxorubicin-induced cytotoxicity in these cells. Decreased expression of mismatch repair (MMR) gene MSH2 in cells exposed to oxidative stress suggests that loss of MMR-dependent apoptosis could be a potential mechanism for increased resistance to doxorubicin-induced cytotoxicity. Additionally, downregulation of HDAC1, an increase in the level of histone H3 acetylation, and hypermethylation of MSH2 promoter were also observed in Caki-1 cells adapted to chronic oxidative stress. DNA-demethylating agent 5-Aza-2dC significantly restored the expression of MSH2 and doxorubicin-induced cytotoxicity in Caki-1 cells adapted to chronic oxidative stress, suggesting the role of DNA hypermethylation in inactivation of MSH2 expression and consequently MMR-dependent apoptosis in these cells. In summary, this study for the first time provides direct evidence for the role of oxidative stress in chemotherapeutic resistance in renal carcinoma cells potentially through epigenetic mechanism. PMID- 26519222 TI - Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters. AB - Determining the structural elements that define substrates and inhibitors at the monoamine transporters is critical to elucidating the mechanisms underlying these disparate functions. In this study, we addressed this question directly by generating a series of N-substituted 3,4-methylenedioxyamphetamine analogs that differ only in the number of methyl substituents on the terminal amine group. Starting with 3,4-methylenedioxy-N-methylamphetamine, 3,4-methylenedioxy-N,N dimethylamphetamine (MDDMA) and 3,4-methylenedioxy-N,N,N-trimethylamphetamine (MDTMA) were prepared. We evaluated the functional activities of the compounds at all three monoamine transporters in native brain tissue and cells expressing the transporters. In addition, we used ligand docking to generate models of the respective protein-ligand complexes, which allowed us to relate the experimental findings to available structural information. Our results suggest that the 3,4 methylenedioxyamphetamine analogs bind at the monoamine transporter orthosteric binding site by adopting one of two mutually exclusive binding modes. 3,4 methylenedioxyamphetamine and 3,4-methylenedioxy-N-methylamphetamine adopt a high affinity binding mode consistent with a transportable substrate, whereas MDDMA and MDTMA adopt a low-affinity binding mode consistent with an inhibitor, in which the ligand orientation is inverted. Importantly, MDDMA can alternate between both binding modes, whereas MDTMA exclusively binds to the low-affinity mode. Our experimental results are consistent with the idea that the initial orientation of bound ligands is critical for subsequent interactions that lead to transporter conformational changes and substrate translocation. PMID- 26519225 TI - Contrast-enhanced ultrasound with perfusion analysis for the identification of malignant and benign tumours of the thyroid gland. AB - The aim of our study was to evaluate, whether the analysis of time intensity curves (TIC) of contrast enhanced ultrasound (CEUS) could help to differentiate between thyroid adenomas and carcinomas in daily clinical routine.B-mode, Colour Coded Doppler Sonography (CCDS), Power Doppler (PD) and CEUS were applied for 50 patients (27 men, 23 women; mean age 51 years, range 16-81 years).CEUS cine sequences were analysed using time intensity curves (TIC) and calculating time to peak (TTP) as well as the area under the curve (AUC).All 20 patients with carcinomas presented with a complete wash-out in the late phase of CEUS while this occurred only in three out of the 30 patients with adenomas.Marked differences were observed between adenomas and carcinomas concerning the mean AUC in the surrounding thyroid tissue (p = 0.041). In addition, TTP differed clearly between the centre and the surrounding of the carcinomas (p < 0.05) as well as between TTP in the border area and the surrounding tissue (p = 0.01). CEUS in combination with TIC analysis allows a dynamic evaluation of the microvascularisation of thyroid nodules and is helpful for the differentiation of benign and malignant nodules. PMID- 26519224 TI - Gbetagamma Binds to the Extreme C Terminus of SNAP25 to Mediate the Action of Gi/o-Coupled G Protein-Coupled Receptors. AB - Gi/o-coupled G protein-coupled receptors can exert an inhibitory effect on vesicle release through several G protein-driven mechanisms, more than one of which may be concurrently present in individual presynaptic terminals. The synaptosomal-associated protein of 25 kDa (SNAP25) is a key downstream effector of Gbetagamma subunits. It has previously been shown that proteolytic cleavage of SNAP25 by botulinum toxin A reduces the ability of Gbetagamma to compete with the calcium sensor synaptotagmin 1 (Syt1) for binding to SNAP25 in a calcium dependent manner. These truncated SNAP25 proteins sustain a low level of exocytosis but are unable to support serotonin-mediated inhibition of exocytosis in lamprey spinal neurons. Here, we generate a SNAP25 extreme C-terminal mutant that is deficient in its ability to bind Gbetagamma while retaining normal calcium-dependent Syt1 binding to soluble N-ethylmaleimide attachment protein receptor (SNARE) and vesicle release. The SNAP25Delta3 mutant, in which residue G204 is replaced by a stop codon, features a partial reduction in Gbeta1gamma2 binding in vitro as well as a partial reduction in the ability of the lamprey 5 hydroxytryptamine1b-type serotonin receptor to reduce excitatory postsynaptic current amplitudes, an effect previously shown to be mediated through the interaction of Gbetagamma with SNAP25. Syt1 calcium-dependent binding to SNAP25Delta3 was reduced by a small extent compared with the wild type. We conclude that the extreme C terminus of SNAP25 is a critical region for the Gbetagamma-SNARE interaction. PMID- 26519226 TI - Platelet-rich plasma stimulates dermal microvascular endothelial cells and adipose derived stem cells after external radiation. AB - BACKGROUND: Platelet-rich plasma (PRP) products are currently suggested in the treatment of chronic wounds due to possible pro-angiogenic effects. Microvascular compromise represents the major component in radiogenic wound healing complications. The effects of PRP on irradiated cells of the cutaneous wound healing process are still poorly understood. MATERIAL AND METHODS: Human dermal microvascular endothelial cells (HDMEC) and human adipose derived stem cells (hASC) were cultured and irradiated with doses of 2 to 12 Gy. PRP was activated, characterized and added to the incubation media in different concentrations after external radiation. Cell count was determined 48 h after radiation using a semi automated cell counting system. Levels of interleukin-6 (IL-6), basic fibroblast growth factor (bFGF) and soluble intercellular adhesion molecule-1 (sICAM-1) in the supernatants of HDMEC and hASC co-cultures were determined by enzyme-linked immunosorbent assay (ELISA). Non-irradiated hASC and HDMEC served as controls. RESULTS: The employed PRP preparations were characterized and contained platelet derived growth factor (PDGF-AB), vascular endothelial growth factor (VEGF), bFGF and high levels of sICAM-1. Addition of PRP to irradiated cultures of HDMEC and hASC prevented profound radiation-induced decline in cell numbers. 10% PRP restored cell numbers to levels of untreated, non-irradiated cultures. Basic FGF expression was decreased significantly in hASC monocultures treated with 10% PRP without external radiation and after irradiation with 6 and 12 Gy. These inhibitory effects of PRP were also observed in HDMEC. In contrast, co-cultures of HDMEC-ASC showed a dose-dependent increase in bFGF expression when treated with 5 or 10% PRP. Doses of 6 and 12 Gy increased IL-6 expression in cultures stimulated with 5% PRP. CONCLUSIONS: Use of PRP in co-cultures of hASC and HDMEC restores proliferative defects caused by external radiation probably by induction of bFGF. Under irradiated conditions, PRP might induce pro-inflammatory stimuli which could be beneficial in treatment of chronic wounds where healing processes are defective. Combined use of hASC and PRP products might be helpful in the treatment of radiogenic wounds. PMID- 26519227 TI - Biocompatibility of a novel zinc stent with a closed-cell-design. AB - Biomaterials made of zinc have been widely described to be antioxidative, hypothrombogenic, antiinflammatory and antiproliferative. Additionally in vivo zinc is toxic only in high concentrations and can completely be metabolized in vivo. Due to these properties zinc based vascular stents might be able to reduce the rate of restenosis in comparison to bare metal stents and zinc stents might be also able to limit the foreign body reaction. In the presented study we tested the biocompatibility and degradability of a stent made of zinc and characterized by a closed-cell-design to achieve high opening force and to increase stent stiffness. After 100 days of enzymatic and hydrolytic degradation in 15 ml blood serum (fetal calf serum) a significant loss of weight (1.72 wt% ) was measured. Zinc was compared to other metals in terms of degradation rates. After six weeks of incubation in physiologic sodium chloride solution zinc showed the slowest degradation time, 6 times less than stainless steel and 4 times less than magnesium. In the tests for cytotoxic effects the degraded zinc stent caused no changes in the LDH-release and cell membrane integrity (3T3 cells, mouse fibroblasts) respectively, in the cell activity/proliferation (MTS assay) and in the morphological characteristics of the cells and cell layers in comparison to the control material (polystyrene). Based on these results the tested zinc stent proved to be non-cytotoxic and to be characterized by degradation characteristics which might be advantageous in comparison to magnesium and stainless steel. PMID- 26519228 TI - Evaluation of multimodality imaging using image fusion with MRI and CEUS in an experimental animal model. AB - PURPOSE: To evaluate the diagnostic benefits of multimodality imaging using image fusion with magnetic-resonance-imaging (MRI) and contrast-enhanced-ultrasound (CEUS) in an experimental small-animal-squamous-cell-carcinoma-model for the assessment of tissue hemodynamics and morphology. MATERIAL AND METHODS: Human hypopharynx-carcinoma-cells were injected subcutaneously into the left flank of 15 female athymic nude rats. After 10 daysof subcutaneous tumor growth, CEUS and MRI measurements were performed using a high-end-ultrasound-system and 3-T-MRI. After successful point-to-point or plan registration, the registered MR-images were simultaneously shown with the respective ultrasound sectional plane. Data evaluation was performed using the digitally stored video sequence data sets by two experienced radiologists using a subjective 5-point scale. RESULTS: CEUS and MRI are well-known techniques for the assessment of tissue hemodynamics (score: mean 3.8 +/- 0.4 SD and score 3.8 +/- 0.4 SD). Real-time image fusion of MRI and CEUS yielded a significant (p < 0.001) improvement in score (score 4.8 +/- 0.4 SD). Reliable detection of small necrotic areas was possible in all animals with necrotic tumors. No significant intraobserver and interobserver variability was detected (kappa coefficient = +1). CONCLUSION: Image fusion of MRI and CEUS gives a significant improvement for reliable differentiation between different tumor tissue areas and simplifies investigations by showing the morphology as well as surrounding macro-/microvascularization. PMID- 26519229 TI - The effect of endothelialization on the epidermal differentiation in human three dimensional skin constructs - A morphological study. AB - INTRODUCTION: Inducing vascularization in three-dimensional skin constructs continues to be difficult. In this study, two variations of human full-thickness skin constructs were examined. Type KCFB consists of keratinocytes (epidermal equivalent) and fibroblasts that were embedded in a collagen matrix (dermal equivalent). Type KCFB-EC consists of keratinocytes as well as fibroblasts and vascular endothelial cells. The epidermal equivalent of KCFB-EC constructs underwent cellular alterations in their differentiation possibly induced by the presence of endothelial cells. The objective of the study was to assess the effect of endothelial cells, i.e., endothelialization of the dermal equivalent on the differentiation of keratinocytes by comparing the morphology and ultrastructure of the two types of skin constructs, as well as to excised normal human skin. HYPOTHESIS: The differentiation of keratinocytes is influenced by the presence of endothelial cells. METHODS, PATIENTS, MATERIAL: KCFB constructs (keratinocytes, fibroblasts) and KCFB-EC skin constructs(kera-tinocytes, fibroblasts, endothelial cells) were prepared according to Kuchler et al. [25]. After two weeks, the skin constructs were processed for analysis by light microscopy (LM) and electron microscopy (TEM), followed by quantitative, semi quantitative as well as qualitative assessment. For comparison, analysis by LM and TEM of excised normal human skin was also performed. RESULTS: Both KCFB and KCFB-EC skin constructs and the human skin had all strata of stratified soft cornified epidermis present. The comparison of the respective layers of the skin constructs brought the following characteristics to light: The KCFB-EC constructs had significantly more mitotic cells in the stratum spinosum, more cell layers in the stratum granulosum and more keratohyalin granules compared to KCFB skin constructs. Additionally, the epidermal architecture was unorganized in the endothelialized constructs and features of excessive epidermal differentiation appeared in KCFB-EC skin constructs. CONCLUSION: The endothelialization of the dermal equivalent caused changes in the differentiation of the epidermis of KCFB EC skin constructs that may be interpreted as an unbalanced, i.e., uncontrolled or enhanced maturation process. PMID- 26519230 TI - Effects of Therapeutic and Supratherapeutic Doses of Siponimod (BAF312) on Cardiac Repolarization in Healthy Subjects. AB - PURPOSE: The International Conference on Harmonisation E14 guideline mandates an intensive cardiac safety evaluation in a clinical thorough QT study, typically in healthy subjects, for all new non-antiarrhythmic drugs with systemic bioavailability. This thorough QT study investigated the effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod (BAF312) on cardiac repolarization in healthy subjects. METHODS: The study was a randomized, double blind, parallel-group, placebo- and moxifloxacin-controlled, multiple oral dose study. Eligible subjects were randomly assigned to 3 groups to receive siponimod (up-titration to 2 and 10 mg over 18 days), placebo (Days -1 to 18), or moxifloxacin 400 mg Days 10 and 18). Triplicate ECGs were extracted at prespecified time points from Holter ECGs recorded from 1 hour predose until 24 hours postdose at baseline and on-treatment assessment Days 10 and 18. The primary pharmacodynamic variable was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (DeltaDeltaQTcF) at steady-state conditions. In addition, the pharmacokinetic parameters of siponimod and its main circulating metabolite M3 and its metabolite M5 were evaluated. FINDINGS: Of the 304 enrolled subjects, 281 (92.4%) were included in the pharmacodynamic analysis and 270 (88.8%) completed the study. The upper bounds of the 2-sided 90% confidence intervals (CIs) for DeltaDeltaQTcF at both siponimod doses were within the regulatory threshold of 10 milliseconds (ms) at all predefined on-treatment time points, with the absence of any dose-related effects. The highest observed upper limits of the 2-sided 90% CIs of 9.8 and 9.6 ms for therapeutic and supratherapeutic doses, respectively, were both observed at 3 hours postdose. No treatment-emergent QTc values >480 ms and no QTc increases of >60 ms from baseline were observed. Similar results were obtained with individualized heart rate correction of cardiac repolarization (QTcI). Assay validity was demonstrated by maximum DeltaDeltaQTcF of >5 ms after 400 mg moxifloxacin on both on-treatment assessment days. The selected supratherapeutic dose produced approximately 5-fold higher exposures (Cmax and AUC) than the therapeutic dose, and was considered appropriate to investigate the effects of siponimod on QT/QTc at substantial multiples of the anticipated maximum therapeutic exposure. IMPLICATIONS: The findings provide evidence that siponimod is not associated with a significant arrhythmogenic potential related to QT prolongation. PMID- 26519231 TI - Pharmacokinetic Properties of Fostamatinib in Patients With Renal or Hepatic Impairment: Results From 2 Phase I Clinical Studies. AB - PURPOSE: Phase III trials of fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis have been completed. Herein, we report the effects of renal and hepatic impairment on the pharmacokinetic (PK) properties of the active metabolite of fostamatinib, R406, in plasma, and on the urinary excretion of R406 and its metabolite N-glucuronide. METHODS: Two Phase I, single-center, open-label clinical trials determined the PK properties and tolerability of fostamatinib in subjects with normal or impaired renal or hepatic function. Twenty-four subjects in the study in renal impairment (8 per group: normal renal function, moderate renal dysfunction, or end-stage renal disease [ESRD]), and 32 subjects in the study in hepatic impairment (8 per group: normal hepatic function or mild, moderate, or severe hepatic impairment) received a single 150-mg dose of fostamatinib. Patients with ESRD in the study in renal impairment participated in 2 treatment periods separated by a >=1-week washout. In these patients, fostamatinib was administered after dialysis or 2 hours before dialysis. FINDINGS: Geometric mean R406 Cmax and AUC values were less in the combined renally impaired group than in the group with normal renal function; Tmax was similar across groups. However, renal impairment had no apparent effect considered clinically relevant on unbound R406. In patients with ESRD, R406 exposure was less when fostamatinib was administered after compared with before dialysis. Urinary excretion of R406 N-glucuronide was decreased with increasing severity of renal impairment. Renal elimination of R406 was negligible in all groups. Varying degrees of hepatic impairment had no consistent effects on the PK properties of R406. R406 Cmax values were 10% to 15% less in all hepatically impaired groups than in the group with normal hepatic function. AUC and Tmax values were similar between the groups with normal and severely impaired hepatic function; in the groups with mild or moderate hepatic impairment, AUC was less and Tmax was greater. The geometric mean percentage of unbound R406 ranged from 0.64% to 1.95% and was greatest in the group with severe hepatic impairment. The urinary excretion of R406 was minimal. The amount of R406 N-glucuronide excreted in urine was greater in severely hepatically impaired patients. Fostamatinib 150 mg was generally well tolerated. IMPLICATIONS: In these patients, renal or hepatic impairment did not affect exposure to the active metabolite of fostamatinib, R406, to a clinically relevant extent. ClinicalTrials.gov identifiers: NCT01245790 (renal) and NCT01222455 (hepatic). PMID- 26519232 TI - Adherence to Immunosuppressive Medication in Renal Transplant Recipients From Follow-up Outpatient in China: Association of 2 Different Measurement Methods. AB - PURPOSE: Our aim was to investigate the association between self-report measure and serum concentration fluctuation of immunosuppressive medication (IM) in renal transplant recipients in China and examine the relationship between post transplantation time and IM adherence. METHODS: Renal transplant recipients at least 3 months post transplantation were recruited from a follow-up outpatient clinic. Both self-reported Morisky Medication Adherence Scale and serum concentration of IM (cyclosporine trough level and tacrolimus trough level) were used to measure drug adherence. FINDINGS: Two hundred and nine patients were recruited in the study. The majority of the patients received grafts from deceased donors (70.3%), were male (63.2%), and were married (83.3%). The nonadherence to IM was 31.7%, as measured by the Morisky Medication Adherence Scale. A statistically significant association between self-reported adherence and serum concentration fluctuation of tacrolimus trough level was identified (P < 0.001), but not for cyclosporine (P = 0.997). Serum concentration fluctuation of tacrolimus trough levels and self-report adherence of IM were associated with transplantation time (P < 0.001 and P = 0.003, respectively). IMPLICATIONS: The Morisky Medication Adherence Scale appears valid in measuring drug adherence when compared with serum concentration fluctuation. Both self-report questionnaire and serum concentration fluctuation of tacrolimus changed with different post transplantation time. These 2 measurements could be integrated into routine clinical practice for renal transplant recipients. PMID- 26519233 TI - Iron Chelation in Thalassemia Major. AB - PURPOSE: Iron chelation has improved survival and quality of life of patients with thalassemia major. there are currently 3 commercially available iron chelating drugs with different pharmacokinetic and pharmacodynamic activity. The choice of adequate chelation treatment should be tailored to patient needs and based on up-to-date scientific evidence. METHODS: A review of the most recent literature was performed. FINDINGS: The ability of the chelators to bind the redox active component of iron, labile plasma iron, is crucial for protecting the cells. Chelation therapy should be guided by magnetic resonance imaging that permits the tailoring of therapy according to the needs of the patient because different chelators preferentially clear iron from different sites. Normal levels of body iron seem to decrease the need for hormonal and cardiac therapy. IMPLICATIONS: The 3 chelators currently available have different benefits, different safety profiles, and different acceptance on the part of the patients. Good-quality, well-designed, randomized, long-term clinical trials continue to be needed. PMID- 26519234 TI - Highly Pathogenic Avian Influenza H5N8 Clade 2.3.4.4 Virus: Equivocal Pathogenicity and Implications for Surveillance Following Natural Infection in Breeder Ducks in the United Kingdom. AB - Since early 2014, several outbreaks involving novel reassortant highly pathogenic avian influenza (HPAI) A(H5N8) viruses have been detected in poultry and wild bird species in Asia, Europe and North America. These viruses have been detected in apparently healthy and dead wild migratory birds, as well as in domestic chickens, turkeys, geese and ducks. In this study, we describe the pathology of an outbreak of H5N8 HPAIV in breeder ducks in the UK. A holding with approximately 6000 breeder ducks, aged approximately 60 weeks, showed a gradual reduction in egg production and increased mortality over a 7-day period. Post mortem examination revealed frequent fibrinous peritonitis, with severely haemorrhagic ovarian follicles and occasional splenic and pancreatic necrosis and high incidence of mycotic granulomas in the air sacs and lung. Low-to-moderate levels of HPAI H5N8 virus were detected mainly in respiratory and digestive tract, with minor involvement of other organs. Although histopathological examination confirmed the gross pathology findings, intralesional viral antigen detection by immunohistochemistry was not observed. Immunolabelled cells were rarely only present in inflamed air sacs and serosa, usually superficial to granulomatous inflammation. Abundant bacterial microcolonies were observed in haemorrhagic ovaries and oviduct. The limited viral tissue distribution and presence of inter-current fungal and bacterial infections suggest a minor role for HPAIV H5N8 in clinical disease in layer ducks. PMID- 26519235 TI - So Many Variables: Joint Modeling in Community Ecology. AB - Technological advances have enabled a new class of multivariate models for ecology, with the potential now to specify a statistical model for abundances jointly across many taxa, to simultaneously explore interactions across taxa and the response of abundance to environmental variables. Joint models can be used for several purposes of interest to ecologists, including estimating patterns of residual correlation across taxa, ordination, multivariate inference about environmental effects and environment-by-trait interactions, accounting for missing predictors, and improving predictions in situations where one can leverage knowledge of some species to predict others. We demonstrate this by example and discuss recent computation tools and future directions. PMID- 26519236 TI - Sharing news of a lung cancer diagnosis with adult family members and friends: a qualitative study to inform a supportive intervention. AB - OBJECTIVE: Extensive research exists on breaking bad news by clinicians. This study examines perspectives of patients and those accompanying them at diagnosis giving of subsequently sharing news of lung cancer with adult family/friends, and views of healthcare professionals, to inform development of a supportive intervention. METHODS: Qualitative interviews with 20 patients, 17 accompanying persons; focus groups and interviews with 27 healthcare professionals from four Thoracic Oncology Units. Intervention development workshops with 24 healthcare professionals and six service users with experience of sharing a cancer diagnosis. Framework thematic analysis. RESULTS: Patients and accompanying persons shared news of lung cancer whilst coming to terms with the diagnosis. They recalled general support from healthcare professionals but not support with sharing bad news. Six elements were identified providing a framework for a potential intervention: 1-people to be told, 2-information to be shared, 3-timing of sharing, 4-responsibility for sharing, 5-methods of telling others and 6 reactions of those told. CONCLUSION: This study identifies the challenge of sharing bad news and a potential framework to guide delivery of a supportive intervention tailored to individual needs of patients. PRACTICE IMPLICATIONS: The identified framework could extend the portfolio of guidance on communication in cancer and potentially in other life-limiting conditions. PMID- 26519238 TI - Empirical relationships between numeracy and treatment decision making: A scoping review of the literature. AB - OBJECTIVES: To determine what is known from the existing literature about empirical relationships between numeracy and the three stages of the treatment decision making process (information exchange, deliberation, and deciding on the treatment to implement). We also examined if, and how, numeracy was mentioned in relation to health literacy. METHODS: A search of four databases returned 2772 records. After de-duplication and three levels of relevance screening, 38 primary studies were included in this review. RESULTS: Relationships between numeracy and the information exchange stage have received greater attention than relationships between numeracy and the deliberation and deciding on the treatment to implement stages. The lack of overlap in the empirical relationships examined in studies, the measure(s) of numeracy used, and the characteristics of study populations, made findings difficult to compare. Multiple knowledge gaps and measurement related problems were identified. Numeracy and health literacy have largely been treated as separate concepts. CONCLUSION: More research is needed to better understand the importance of numeracy and health literacy to treatment decision making. PRACTICE IMPLICATIONS: Decision aids designed for patients with different levels of health literacy may not meet the needs of patients with different levels of numeracy. The numeracy skills of health professionals require attention. PMID- 26519237 TI - Perceiving one's heart condition to be cured following hospitalization for acute coronary syndromes: Implications for patient-provider communication. AB - OBJECTIVE: We examined the proportion of patients perceiving their heart condition to be cured following hospitalization for ACS and identified characteristics associated with these perceptions. METHODS: We conducted a prospective cohort study of adults hospitalized with ACS (N=396). Patient interviews during hospitalization and one week post-discharge provided demographic and psychosocial characteristics. Medical records provided clinical characteristics. At one week, patients who rated "My heart condition is cured" as "definitely true" or "mostly true" were considered to perceive their heart condition cured. RESULTS: Participants were aged 60.7 (SD:11.0) years, 26.5% female, and 89.0% non-Hispanic white; 16.7% had unstable angina, 59.6% NSTEMI, and 23.7% STEMI. One week post-discharge, 30.3% perceived their heart condition to be cured. Characteristics associated with cure perceptions were older age (OR=2.2; 95% CI: 1.2-4.0 for >=65 years vs <55 years), male sex (OR=2.4; 95%CI: 1.3-4.2), history of hypertension (OR=1.8; 95%CI: 1.1-3.1), history of stroke (OR=4.2; 95%CI: 1.1-16.7), no history of CHD (OR=2.8; 95%CI: 1.6-4.9), and receipt of CABG during hospitalization (OR=4.8, 95%CI: 1.9-12.0 vs medical management). CONCLUSION: One week post-discharge, 3 in 10 patients perceived their heart condition to be cured. PRACTICE IMPLICATIONS: Conversations with patients should frame ACS as a chronic disease and dispel cure perceptions. PMID- 26519239 TI - A paired comparison between glioblastoma "stem cells" and differentiated cells. AB - Cancer stem cells (CSC) have been postulated to be responsible for the key features of a malignancy and its maintenances, as well as therapy resistance, while differentiated cells are believed to make up the rapidly growing tumour bulk. It is therefore important to understand the characteristics of those two distinct cell populations in order to devise treatment strategies which effectively target both cohorts, in particular with respect to cancers, such as glioblastoma. Glioblastoma is the most common primary brain tumour in adults, with a mean patient survival of 12-15 months. Importantly, therapeutic improvements have not been forthcoming in the last decade. In this study we compare key features of three pairs of glioblastoma cell populations, each pair consisting of stem cell-like and differentiated cells derived from an individual patient. Our data suggest that while growth rates and expression of key survival- and apoptosis-mediating proteins are more similar according to differentiation status than genetic similarity, we found no intrinsic differences in response to standard therapeutic interventions, namely exposure to radiation or the alkylating agent temozolomide. Interestingly, we could demonstrate that both stem cell-like and differentiated cells possess the ability to form stem cell containing tumours in immunocompromised mice and that differentiated cells could potentially be dedifferentiated to potential stem cells. Taken together our data suggest that the differences between tumour stem cell and differentiated cell are particular fluent in glioblastoma. PMID- 26519240 TI - Continuous flow left ventricular assist devices: Dare to compare. PMID- 26519241 TI - Taking care all along the way. PMID- 26519242 TI - Perioperative pharmacotherapy for lung resection: "Going for the gold"? PMID- 26519243 TI - Saying yes or saying no! PMID- 26519245 TI - Cardiothoracic Surgical Trials Network: Evidence-based surgery. PMID- 26519244 TI - Factors affecting Fontan length of stay: Results from the Single Ventricle Reconstruction trial. AB - BACKGROUND: In the Single Ventricle Reconstruction trial, infants with hypoplastic left heart syndrome (HLHS) who received a right-ventricle-to pulmonary-artery shunt (RVPAS) versus a modified Blalock-Taussig shunt (MBTS) had lower early postoperative mortality, but more complications at 14 months. We explored the effect of shunt type and other patient, medical, and surgical factors on postoperative length of stay (LOS) after the Fontan operation. METHODS: Fontan postoperative course was ascertained from medical record review. Cox proportional hazards modeling was used to identify factors associated with LOS. RESULTS: Of 327 subjects who underwent Fontan, 323 were analyzed (1 death, 1 biventricular repair, 2 with missing data). Median age and weight at Fontan were 2.8 years (interquartile range [IQR]: 2.3, 3.4) and 12.7 kg (IQR: 11.4, 14.1), respectively. Fontan type was extracardiac in 55% and lateral tunnel in 45%; 87% were fenestrated. The RVPAS and MBTS subjects had similar LOS (median 11 days [IQR: 9, 18] vs 10 days [IQR: 9, 13]; P = .23). Independent risk factors for longer LOS were treatment center (P < .01), LOS at stage II (hazard ratio [HR] 1.02 for each additional day; P < .01), and pre-Fontan complications (HR 1.03 for each additional complication; P = .04). Use of deep hypothermic circulatory arrest at Fontan (HR 0.64; P = .02) was independently associated with shorter LOS. When center was excluded from the model, pre-Fontan complications and use of circulatory arrest were no longer significant; instead, older age at stage II (HR 1.08 for each additional month; P = .01) predicted longer LOS. In 254 subjects who had a pre-Fontan echocardiogram, at least moderate tricuspid regurgitation was independently associated with longer LOS, both with center (HR 1.72; P < .01) and without center in the model (HR 1.49; P = .02). CONCLUSIONS: In this multicenter prospective cohort of subjects with HLHS, Norwood shunt type was not associated with Fontan LOS. Rather, global measures of earlier medical complexity indicate greater likelihood of longer LOS after the Fontan operation. PMID- 26519246 TI - What is the best approach for surgery of malignant pleural mesothelioma? It is to put our efforts into obtaining trustworthy evidence for practice. PMID- 26519247 TI - Transplantation in children with failed palliation of hypoplastic left heart syndrome: A good solution? PMID- 26519248 TI - Options for aortic valve replacement in children and young adults: "Okay, doctor, but which one do you think I should choose?". PMID- 26519249 TI - Near-Fatal ICD Lead Dysfunction with Implications for ICD Testing. AB - A 31-year-old male patient with an implantable cardioverter defibrillator (ICD) experienced ventricular fibrillation. After resuscitation, no communication between the device and an ICD programmer was possible. The ICD was explanted, no signs of destruction were visible, and the ICD leads revealed normal values. A new ICD was implanted, interrogation values were stable. However, immediately after defibrillation testing the connection between programmer and ICD was interrupted and could not be established again. The device showed burn marks and a hole in the can. Analysis revealed an isolation defect of the ICD lead, which was not detectable with standard interrogation. PMID- 26519250 TI - Do not be alarmed: understanding IL33-ST2 signalling in wound repair. PMID- 26519251 TI - Case Report: Apixaban-Associated Gluteal Artery Extravasation Reversed With PCC3 Without FFP. AB - Apixaban, an oral factor Xa inhibitor, has no commercially available assay to measure its activity and no specific antidote. To date, recommendations for managing bleeding associated with apixaban are based on studies with animal models and healthy volunteers (who do not have identified thrombogenic risk factors) and expert opinion. No clinical experience has been published in the literature. Ideally, apixaban would be reversed sufficiently to stop a perilous bleed without producing more thrombogenic risk than the patients' underlying risk factors. Three-factor prothrombin complex concentrate (PCC3) is the least thrombogenic among the suggested reversal agents. Fresh frozen plasma (FFP) is sometimes recommended to add to PCC3, but it adds considerable volume. We describe successful management of an active left gluteal arterial extravasation due to trauma and associated apixaban, in a patient with aortic stenosis and atrial fibrillation, by administration of PCC3 alone, without the added volume of FFP. PMID- 26519252 TI - Student Pharmacist Perceptions of a Behind-The-Counter Class of Medications. AB - OBJECTIVES: To report perceptions of PharmD candidates regarding a behind-the counter (BTC) class of medications and to identify perceived barriers to its successful implementation. METHODS: PharmD candidates in their second, third, and fourth professional years were invited to complete an online survey. Responses were used to assess perceptions of competency and willingness to participate in a BTC program and perceived preparedness of the current community pharmacy practice environment for a BTC class of medications with regard to 8 specific classes of medications. RESULTS: The survey response rate was 28%. In all, 78% of respondents agreed or strongly agreed that a BTC class of medications is a change that they would be willing to embrace, and 54% agreed or strongly agreed that their PharmD curriculum provided them with adequate training in laboratory and diagnostic test interpretation. Less than half of the respondents agreed or strongly agreed that community pharmacies are currently equipped with the resources necessary to clinically assess a patient and dispense BTC medications. CONCLUSION: PharmD candidates are prepared and willing to participate in a BTC program but believe that the current community practice environment lacks access to resources necessary to do so. PMID- 26519253 TI - Perceived Benefit of Teaching Patient Safety to Pharmacy Students by Integrating Classroom Teaching With Introductory (IPPE) Visits. AB - INTRODUCTION: Ensuring a culture that prioritizes and implements patient safety requires educating all future health care professionals to prepare them for their active role in reducing medical errors. There is limited literature describing integration of patient safety education into the curriculum of health care professionals, including pharmacists. The purpose of this study was to evaluate the perceived benefit of integrating patient safety education into a pharmacy curriculum. METHODS: Second-year pharmacy students (P2s) completed a patient safety self-study, followed by in-class and experiential application of a root cause analysis (RCA). An electronic, anonymous postsurvey was administered to P2s and third-year pharmacy students (P3s) who had not had formal patient safety education. RESULTS: Of the 310 students, 53% responded to the survey. Significantly more P2s reported more confidence to describe patient safety and its purpose ( P = .0092), describe factors that influence patient safety ( P = .0055), and conduct an RCA ( P < .001). P2s also reported significantly better ability to conduct a RCA compared to P3s (88.9% positive vs 58.7%, respectively; P <= .001). CONCLUSIONS: Both classes perceived patient safety education to be valuable; however, formal education resulted in some significant improvements in perceived confidence and understanding, including ability to conduct an RCA. PMID- 26519254 TI - The imperative to develop a human vaccine for the Hendra virus in Australia. AB - The Hendra virus (HeV) poses a significant challenge to public health in Australia. Expanding migratory patterns observed among bats and the mutation of the virus to seek and successfully infect new hosts is a significant departure from the generalized epidemiological trend. The recent discovery of equine related infections and deaths in addition to a canine infection demonstrates the inadequacy of the current equine vaccine developed in 2012. Traditional models for controlling the spread of the vector are futile given the rapid pace at which bats' habitats are eroded. Recent ongoing zoonotic epidemics, for example, Ebola and Middle East respiratory syndrome coronavirus, demonstrate that human-to-human transmission is a distinct reality rather than an obscure possibility. The development of a human HeV vaccine is essential for the biosecurity of Australia, as part of a multipronged strategy to control HeV in Australia. PMID- 26519256 TI - Durability of aneurysm treatments in patients with active Behcet's disease. AB - OBJECTIVE: Aneurysms in Behcet's disease are rare, serious, and recurrent. To achieve durable treatment, patients should receive immunosuppressive therapy before intervention to induce remission. We present early and long-term results of emergency cases of active Behcet's disease, which did not permit waiting for suppressive treatment. PATIENTS AND METHODS: The study was undertaken on all cases admitted to the vascular unit, King Fahd Hospital of University for aneurysm treatment in patients with active Behcet's disease over about 10 years. All patients had exclusion of the aneurysm either by open surgery or endovascular intervention. Morbidities and mortality were recorded within the hospital admission and on the follow-up. RESULTS: During the study period, three cases were included. All interventions were successful and lifesaving. However, two cases, treated with surgical interposition grafts, were blocked in the intermediate term follow-up (2-12 months) and one case, treated with endovascular treatment, complicated with pseudoaneurysm at femoral puncture site after six months. CONCLUSION: Although early results were good, intermediate ones were not satisfactory because of progressive graft thrombosis and formation of new aneurysms. Awareness of these rare cases help for early identification and proper immunosuppressive before emergency vascular intervention is warranted. PMID- 26519255 TI - Adipose-derived mesenchymal stem cells improve glucose homeostasis in high-fat diet-induced obese mice. AB - INTRODUCTION: Effective therapies for obesity and diabetes are still lacking. The aim of this study was to evaluate whether a single intravenous infusion of syngeneic adipose-derived mesenchymal stem cells (ASCs) can reduce obesity, lower insulin resistance, and improve glucose homeostasis in a high-fat diet-induced obese (DIO) mouse model. METHODS: Seven-week-old C57BL/6 mice were fed a high-fat diet for 20 weeks to generate the DIO mouse model. Mice were given a single intravenous infusion of ex vivo expanded syngeneic ASCs at 2 * 10(6) cells per mouse. DIO or CHOW mice injected with saline were used as controls. Body weights, blood glucose levels, glucose, and insulin tolerance test results were obtained before and 2 and 6 weeks after cell infusion. Triglyceride (TG), high-density lipoprotein (HDL), and insulin levels in serum were measured. Expressions of genes related to insulin resistance, including peroxisome proliferator-activated receptor gamma (PPARgamma) and insulin receptor (InsR), and inflammation (IL-6, F4/80, and nucleotide-binding oligomerization domain containing 2, or NOD2), were measured in livers at mRNA level by real-time-polymerase chain reaction analysis. Beta-cell mass in pancrheases from CHOW, DIO, and DIO + ASC mice was quantified. GFP(+) ASCs were injected, and the presence of GFP(+) cells in livers and pancreases was determined. RESULTS: DIO mice that had received ASCs showed reduced body weights, reduced blood glucose levels, and increased glucose tolerance. ASC treatment was found to reduce TG levels and increase serum HDL levels. In livers, less fat cell deposition was observed, as were increased expression of InsR and PPARgamma and reduction in expressions of IL-6 and F4/80. Treated mice showed well-preserved pancreatic beta-cell mass with reduced expression of F4/80 and TNF-alpha compared with DIO controls. GFP(+) cells were found in liver and pancreas tissues at 1 and 2 weeks after cell injection. CONCLUSIONS: ASC therapy is effective in lowering blood glucose levels and increasing glucose tolerance in DIO mice. The protective effects of ASCs arise at least in part from suppression of inflammation in the liver. In addition, ASCs are associated with better-preserved pancreatic beta-cell mass. PMID- 26519257 TI - The role of interleukin-8 (CXCL8) and CXCR2 in acquired chemoresistance of human colorectal carcinoma cells HCT116. AB - Colorectal cancer is one of the most common malignant diseases and is a leading cause of cancer mortality in the Western world. Primary or acquired resistance to chemotherapeutic drugs is a common phenomenon which causes a failure in cancer treatment. A diverse range of molecular mechanisms has been implicated in drug resistance: DNA damage repair, alterations in drug metabolism, mutation of drug targets, increased rates of drug efflux, and activation of survival signaling pathways. The aim of this study was to investigate the expression of CXCL8 CXCR1/2 pathway, its impact on cell proliferation and cytokine expression in human colorectal carcinoma HCT116 cells, and their chemotherapy-resistant subline. We found that IL-1 alpha stimulates the production of CXCL8 through IL-1 receptor signaling. Our data indicate that CXCL8 is upregulated in chemoresistant subline of colorectal cancer cells HCT116, and modulation of CXCR2 pathway can be a target for proliferation inhibition of chemoresistant colorectal cancer cells. PMID- 26519258 TI - Leveraging growth factor induced macropinocytosis for targeted treatment of lung cancer. AB - Targeted therapy focused on highly expressed growth factor receptors is increasingly becoming popular for the treatment of lung cancer. Cancer cells exhibit higher levels of macropinocytosis than the normally quiescent non cancerous cells, which can further be enhanced by growth factors. Here, we show the targeted enhancement of macropinocytosis in lung cancer cells for the delivery of the mitochondriotoxic peptide (KLAKLAK)2 using keratinocyte growth factor (KGF). We report the formation of a nanoparticle (NP) comprising of two chimeric fusion proteins, both fused to elastin-like polypeptide (ELP), (KLAKLAK)2-ELP and KGF-ELP. We show that (KLAKLAK)2-ELP nanoparticles are internalized via macropinocytosis and its internalization is facilitated by the interaction of the ELP domain with cell surface heparin sulfate proteoglycans. This internalization leads to mitochondrial depolarization and subsequent cell death. Also, we demonstrate that KGF-ELP selectively enhances macropinocytosis in cancer cells expressing high levels of the keratinocyte growth factor receptor (KGFR). Finally, the heterogeneous NPs consisting of (KLAKLAK)2-ELP and KGF-ELP selectively kill KGFR-expressing lung cancer cells. Hence, this multipronged approach of targeting highly active processes and receptors in cancer cells will be tremendously selective in the treatment of both early-stage and advanced-stage lung cancers, thereby improving patient's prognosis and survival rate. PMID- 26519259 TI - Preoperative Ticagrelor administration leads to a higher risk of bleeding during and after coronary bypass surgery in a case-matched analysis. AB - OBJECTIVES: To evaluate the effect of Ticagrelor on intra- and postoperative bleeding complications in patients undergoing coronary bypass surgery. METHODS: For this study, patients who underwent on-pump or off-pump coronary bypass surgery with preoperative acetylsalicylic acid (ASA) and Ticagrelor administration, between January 2014 and December 2014, were included. In the matched control group, continued dual antiplatelet therapy (DAPT) consisted of Clopidogrel and ASA. A total of 28 consecutive patients (24 males; 73 +/- 6.6 years) with preoperative Ticagrelor intake underwent elective (n = 22), urgent (n = 2) or emergency (n = 4) cardiac bypass surgery. The postoperative blood loss, red blood cell units given and intra- and postoperative bleeding complications were documented. To evaluate the effect of Ticagrelor treatment on bleeding during and after coronary bypass surgery in a non-randomized study, we used a case-matched analysis. RESULTS: Baseline parameters showed no important differences between the study group and the control group regarding the matching variables, left ventricular function, preoperative clinical status and risk stratification. The preoperative laboratory analysis showed no important differences regarding coagulation and blood cell count parameters. Overall blood loss was significantly higher in the study group with a mean loss of 1028.8 +/- 735.5 ml (P = 0.0002). Accordingly, units of red blood cells administered were also significantly higher in the study group (P = 0.0002). In the Ticagrelor group, there were six rethoracotomies due to postoperative bleeding with a blood loss of more than 1200 ml in the first 3 h. With no rethoracotomies in the Clopidogrel group, this also showed statistical significance for the postoperative course (P = 0.02). There were no differences found regarding ICU stay and ventilation time. Comparing the mean hospital stay, the study group presented a significantly longer stay than the control group (P = 0.001). CONCLUSIONS: Recent studies about bleeding complications in patients with Ticagrelor intake undergoing CABG in a real-life scenario presented inconsistent data. We were able to show in a case-matched analysis that Ticagrelor administration leads to significantly higher blood loss, more red blood cell units transfused and a higher rate of rethoracotomies. The data also present a longer hospital stay to the disadvantage of the study group. Consequently, Ticagrelor intake before CABG procedures should be avoided or at least discontinued 3 days before cardiac surgery. PMID- 26519261 TI - Inhibition of the hemolytic activity caused by Staphylococcus aureus alpha hemolysin through isatin-Schiff copper(II) complexes. AB - A great number of pathogens secrete pore-forming proteins during infection. Such molecules, from either bacterial or viral origin, are considered important virulence factors, which makes them attractive targets in the study of new therapeutic agents. Thus, the inhibitory activity of isatin-Schiff base copper(II) complexes was evaluated against membrane damage activity of Staphylococcus aureus alpha-hemolysin (alpha-HL). For this purpose, a standard hemolysis assay with rabbit erythrocytes and micromolar concentrations of the compounds was employed. Additionally, planar artificial lipid membranes with a single alpha-HL ion channel and molecular docking studies were used to elucidate the molecular mechanism of the complexes. Accordingly, the compounds were observed to possess a significant anti-hemolytic activity, capable of interacting with the constriction region of alpha-HL channel and blocking it in a potential dependent manner. Based on these results, it is expected that such isatin-Schiff base Copper(II) complexes may be employed as cotherapeutic agents for the treatment of staphylococcal infections. PMID- 26519260 TI - A set of GFP-based organelle marker lines combined with DsRed-based gateway vectors for subcellular localization study in rice (Oryza sativa L.). AB - In the post-genomic era, many useful tools have been developed to accelerate the investigation of gene functions. Fluorescent proteins have been widely used as protein tags for studying the subcellular localization of proteins in plants. Several fluorescent organelle marker lines have been generated in dicot plants; however, useful and reliable fluorescent organelle marker lines are lacking in the monocot model rice. Here, we developed eight different GFP-based organelle markers in transgenic rice and created a set of DsRed-based gateway vectors for combining with the marker lines. Two mitochondrial-localized rice ascorbate peroxidase genes fused to DsRed and successfully co-localized with mitochondrial targeted marker lines verified the practical use of this system. The co localization of GFP-fusion marker lines and DsRed-fusion proteins provide a convenient platform for in vivo or in vitro analysis of subcellular localization of rice proteins. PMID- 26519262 TI - Pedagogy and Purpose: Moral Imagination and the Teaching of Medical Ethics. AB - This essay is an exploration of the development of moral imagination as an important outcome in the teaching of medial ethics. It is contextualized within the growth of professionalism and pays attention to the formation of character of physicians in their formal training and in the first phase of their careers. Issues around formation as it is understood historically in the vocation of the clergy are also considered. Finally, there is discussion of the place rites of passage as they figure in the lives of those who teach medical ethics. PMID- 26519263 TI - Anxiolytic and Antidepressant Effects of Divaza and Brizantin. AB - The anxiolytic and antidepressant activities of complex preparations divaza and brizantin containing antibodies to brain-specific protein S100 were estimated using Vogel conflict test and Nomura forced swimming test. Course treatment (5 days) of brizantin in a dose of 2.5 ml/kg and divaza in a dose of 7.5 ml/kg significantly increased punished drinking in the Vogel conflict test in comparison with the control. Both drugs also improved general emotional behavior during training prior to the test procedure. Brizantin and divaza in a dose of 7.5 ml/kg increased the number of wheel revolutions in the Nomura forced swimming test in comparison with the control; the effect of divaza was more pronounced. High correlation coefficients between the number of wheel revolutions during the first and second 5-min sessions are also indicative of antidepressant action of divaza and brizantin. PMID- 26519264 TI - Effect of NMDA, a Specific Agonist to NMDA Receptor Complex, on Rat Hippocampus. AB - Removal of Mg2+ ions from perfusion medium provoked epileptiform activity in CA1 field of surviving rat hippocampal slices manifested in generation of extra population spikes. MK-801 (100 MUM), a specific non-competitive antagonist to NMDA-receptor complex, prevented this effect. NMDA (20 MUM), the specific agonist to this complex, produced no significant effect on the orthodromic population spikes, but when applied at concentrations of 30 or 40 MUM, it inhibited them partially (by 21-28%) or almost completely (by 98-99%), correspondingly. Thus, depending on concentration, NMDA can inhibit the synaptic transmission in Schaffer collaterals-hippocampal CA1 pyramidal neurons axis without triggering the epileptiform activity. D-AP5 (50 MUM), a competitive antagonist to NMDA receptor complex, completely prevented the inhibitory effect of NMDA (40 MUM). While MK-801 (100 MUM) almost completely prevented the inhibitory effect of NMDA, it did not eliminate it when applied after the agonist. Thus, MK-801 can prevent the inhibitory action of NMDA on synaptic transmission in Schaffer collaterals hippocampal CA1 pyramidal neurons axis via blocking the channel of NMDA-receptor complex, while NMDA exerts its effect only via activation of NMDA receptors. PMID- 26519265 TI - Effects of MU-Opioid Receptor Agonist DAMGO on Heart Contractility and Necrotic Injury to Cardiomyocytes during Ischemia and Reperfusion of Isolated Rat Heart. AB - We studied the effects of MU-opioid receptor activation in vivo and in vitro on the tolerance of isolated perfused rat heart to global ischemia (45 min) and reperfusion (30 min). Stimulation of MU-receptors in vivo by intraperitoneal administration of MU-opioid receptor agonist DAMGO (0.1 mg/kg) reduced reperfusion release of creatinine phosphokinase and promoted aggravation of postischemic systolic and diastolic dysfunction of the isolated heart. Activation of MU-opioid receptors in vitro by addition of selective agonist DAMGO in a concentration of 170 nM to perfusion solution had no effect on necrotic death of cardiomyocytes and aggravated reperfusion stunning of the heart. PMID- 26519266 TI - Effect of Afobazole and Betaine on DNA Damage in Placental and Embryonic Tissues of Rats with Experimental Streptozocin Diabetes. AB - DNA comet assay showed that the level of DNA damage in the placental and embryonic tissues of rats with streptozotocin-induced diabetes mellitus increased on gestation days 14 and 20. Afobazole and betaine administered per os effectively decreased the level of genotoxic damage; afobazole was most efficient in doses of 10 and 50 mg/kg and betaine in a dose of 100 mg/kg. PMID- 26519267 TI - Nociceptive Reactions in Rats during Repeated Stress Exposure. AB - Changes in nociceptive sensitivity of rats with various behavioral patterns in the open-field test were studied after repeated stress exposure on the model of daily 4-h immobilization for 8 days. The tail-flick latency in response to light heat stimulation in passive and active specimens decreased most significantly on days 2 and 7, respectively. However, this parameter did not differ from the baseline on day 8 of observations. Vocalization threshold during electrocutaneous stimulation in behaviorally active animals did not change over the first 7 days of repeated stress exposure, but increased significantly on day 8 of the study. The emotional component of nociception in passive animals increased on day 3, but decreased on days 4 and 6 of the experiment. Therefore, repeated stress exposure in rats is mainly accompanied by an increase in the perceptual component of nociception. Variations in the emotional component of nociceptive sensitivity after stress loads are manifested in the initial increase and subsequent decrease in this parameter. The observed changes are more pronounced in behaviorally passive rats than in active animals. These data illustrate the specifics of stress-induced changes in nociception of specimens with various individual and typological characteristics. Our results hold much promise for the development of new individual approaches to modulation of pain sensitivity in humans under conditions of negative emotiogenic exposures. PMID- 26519268 TI - Prospects of Using of kappa-Opioid Receptor Agonists U-50,488 and ICI 199,441 for Improving Heart Resistance to Ischemia/Reperfusion. AB - We studied the ability of the agonist of kappa1-opioid receptors U-50,488 in doses of 0.1 and 1 mg/kg to simulate ischemic pre- and postconditioning of the heart and kappa-opioid receptors ICI 199,441 in a dose of 0.1 mg/kg to simulate the antiarrhythmic effect of heart preconditioning. The duration of ischemia was 10 or 45 min and the duration of reperfusion was 10 min or 2 h. Administration of 1 mg/kg U-50,488 both before ischemia and 5 min before reperfusion produced a pronounced antiarrhythmic effect. U-50,488 injected 5 min before reperfusion 2 fold reduced the ratio of infarction to risk area. Administration of ICI 199,441 in a dose of 0.1 mg/kg 15 min before ischemia produced a potent antiarrhythmic effect. Antiarrhythmic effect of kappa-opioid receptor agonists depended on activation of kappa-opioid receptors. PMID- 26519269 TI - Effect of Green Light on Nitric Oxide Metabolism in Chick Embryos. A Possible Physiological Role. AB - The exposure to green light, which serves as a well-known activating factor for myogenesis during incubation of chicken eggs, contributes to intensification of embryonic metabolism of NO. A metabolic product, nitrate, is mainly accumulated in the muscles. These data suggest that light induces a NO-dependent activation of the factor, which intensifies muscle tissue development. PMID- 26519270 TI - Radioprotective Properties of Indralin in Combination with Monizol in the Treatment of Local Acute and Delayed Radiation Injuries Caused by Local Skin gamma-Irradiation. AB - Female rats were exposed to local gamma-irradiation of the right hindpaw in doses of 30-50 Gy at 131-154 sGy/min dose rate. Radioprotector indralin was administered per os 15 min prior to irradiation, monizol was injected intraperitoneally 5 min after irradiation. Indralin showed marked radioprotective properties both for acute and delayed symptoms of local radiation injuries. In combination with monizol, radioprotective effect of indralin was potentiated to dose reduction factor of 1.4-1.5 both for radiation burn severity reduction and for restriction of postradiational contracture development and amputation of the irradiated limb. PMID- 26519271 TI - Association of Cytokine Production with Hormone Level and Sensory Responses during the Formation of Psychoactive Drug Addiction in Men. AB - We performed immunophysiological examination of 144 men aged 17-25 years, patients with psychoactive substance dependence, episodic psychoactive drug users, and conditionally healthy individuals. Associations of proinflammatory cytokine production with age, sex, hormone levels, and olfactory and nociceptive indices were revealed in cases of psychoactive drug use and formation of addiction. Predictive models based on the use of androstenone aversion, pressure algometry testing, and immunological parameters were proposed. PMID- 26519272 TI - Effects of Inhibitors of Necroptosis and Autophagy on Morphofunctional Characteristics of the Myocardium during Static Cold Storage of Donor Rat Heart. AB - Cardioprotective effects of necrostatin-1 (necroptosis inhibitor) and 3 methyladenine (autophagy inhibitor) were studied on the model of long-term cold preservation of rat heart. Addition of necrostatin-1 (490 nmol/liter) or 3 methyladenine (4.5 mmol/liter) to custodiol preserving solution reduced myocardial infarction size and improved left-ventricular function during reperfusion after 8-h preservation at 4 degrees C. Inhibition of necroptosis and autophagy contributed to the cardioprotective effect under conditions of cold preservation of the donor heart. PMID- 26519273 TI - Association of Flavin Monooxygenase Gene E158K Polymorphism with Chronic Heart Disease Risk. AB - We studied the relationship between the risk of chronic heart disease and FMO3 gene polymorphism E158K analyzed by PCR and restriction fragment length polymorphism (RFLP) analysis. The homozygous 158KK genotype of FMO3 gene is associated with high risk of chronic heart disease in women, but not in men. FMO3 gene polymorphism E158K is a significant predictor of predisposition to chronic heart disease in women. PMID- 26519274 TI - Quantitative Indexes of Leukocytes in Spontaneously Hypertensive Rats During Various Periods of Arterial Hypertension Development. AB - SHR rats were examined in the period before arterial hypertension development (5th week), during the increase in BP (6th-10th weeks), and under conditions of constantly elevated BP (11th-12th weeks). The total number of leukocytes did not differ in SHR and normotensive WKY rats. However, the relative number of lymphocytes and monocytes was shown to differ in various periods of arterial hypertension development. Our results suggest that white blood cells (primarily lymphocytes) are involved in the development of arterial hypertension. PMID- 26519275 TI - Parameters of Pro- and Antioxidant Status in Ejaculate of Men of Fertile Age. AB - Parameters of LPO reflecting primary and end stages of oxidation and total antioxidant activity were evaluated in the seminal fluid of young fertile men living in Novosibirsk. By the results of andrological examination and spermogram analysis, various reproductive disorders and abnormal spermogram (pathospermia) were found in 48 patients. Shifts towards activation of prooxidant processes in LPO-antioxidant defense metabolic system were observed in men with reproductive disorders and pathospermia. The results of individual estimation of coefficient of oxidative stress, an integral parameter reflecting the balance in the LPO antioxidant defense system, attest to the development of oxidative stress in men with reproductive disorders and pathospermia. PMID- 26519276 TI - Morphology and Immunohistochemical Phenotype of the Thymus in Secondary Immunodeficiency. AB - The thymus of outbred male rats 5 months after splenectomy (experimental secondary immunodeficiency) was studied by common histological and immunohistochemical methods using monoclonal and polyclonal antibodies to CD3, CD30, CD68, synaptophysin, to S100, p53, bcl-2, and Ki-67 proteins. Removal of the spleen led to acute involution of the thymic parenchyma, which was replaced by the adipose tissue and was associated with restructuring of the thymopoietic and nonthymopoietic components of the gland, changes in cellular composition and antigenic phenotype of the lobular cortical and medullary matter, and by reduction of cell proliferation. PMID- 26519277 TI - Effect of Selective Blockade of alpha2C-Adrenoceptors on Cardiac Activity in Growing Rats. AB - Selective blockade of alpha2C-adrenoceptors had different effects on the cardiovascular system in rats of various age groups. Blockade of alpha2C adrenoceptors in adult rats and 3-week-old animals produced the positive and negative chronotropic effects, respectively. HR in 1-week-old and 6-week-old rats did not change during alpha2C-adrenoceptor blockade. Selective blockade of alpha2C-adrenoceptors in adult rats and 3-week-old animals was followed by the increase in BP. BP in 6-week-old rats was shown to decrease under these conditions. PMID- 26519278 TI - Glucocorticoid-Related Regulation of LPO in Brain Cortex during Anxiogenic Stress. AB - Under conditions of periodic exposures to anxiogenic stress, intensification of LPO in the brain cortex is a glucocorticoid-dependent process. Glucocorticoid receptor antagonist RU38486 prevented increase in monoamine oxidase B activity and content of LPO products of in brain cortex typical of anxiogenic stress. Normalization of LPO intensity under the effect of glucocorticoid receptor antagonist was associated with the correction of stress-induced disturbances. PMID- 26519279 TI - Effects of Geroprotectors on Age-Related Changes in Proteolytic Digestive Enzyme Activities at Different Lighting Conditions. AB - We studied the effect of melatonin and epithalon on age-related changes in proteolytic digestive enzyme activity in the pancreas and gastric mucosa of rats kept under different lighting conditions. In rats kept under standard illumination, pepsin activity and the total proteolytic activity in the stomach and pancreas increased by the age of 12 months, but then decreased. Constant and natural lighting disturbed the age dynamics of proteolytic digestive enzyme activity. Administration of melatonin and epithalon to animals exposed to constant lighting restored age dynamics of pepsin activity and little affected total proteolytic activity. PMID- 26519280 TI - Phenotypical Differences in Neuronal Cultures Derived via Reprogramming the Fibroblasts from Patients Carrying Mutations in Parkinsonian Genes LRRK2 and PARK2. AB - Fibroblasts isolated from skin biopsy specimens from patients with genetic forms of Parkinson's disease, carriers of mutations in LRRK2 and PARK2 genes, and from a healthy volunteer were reprogrammed using lentiviral vectors into induced pluripotent stem cells (iPSC). iPSC were differentiated into neuron-like cells using a cocktail of differentiation factors (N2, B27, and Noggin). The iPSC lines derived from patients with different mutations and from a healthy volunteer cultured under the same conditions were characterized by different proportion of neuronal precursors and differentiated neurons. Control Po2 line contained 56% precursors, while B15 line with LRRK2 gene mutation (G2019S) contained 35% precursor cells. Similar regularities were characteristic of Tr5 culture carrying compound heterozygous mutations in PARK2 gene (del202-203AG and IVS1+1G/A) and containing 4% neuronal precursors. Further comparative studies of iPSC carrying various mutations and comparison with normal human cells will help to understand the molecular pathogenesis of some genetic variants of Parkinson's disease. PMID- 26519281 TI - Sexual dysfunction and depression among Turkish women with infertile husbands: the invisible part of the iceberg. AB - PURPOSE: To determine the effect of male infertility on the sexual functions and level of depression among Turkish women. METHODS: Fifty-six women with an infertile partner (exposed) and 48 women who conceived and gave birth without treatment (unexposed) were included in this study. The Female Sexual Function Index (FSFI) and Beck Depression Inventory (BDI) were used to determine sexual function and depression status. Statistical analyses were performed by independent samples t, Fischer's exact, and Mann-Whitney U tests. RESULTS: There were no significant differences in terms of demographic characteristics between groups except that unexposed women had received education for longer period of time (11.6 vs. 7.1 years, p = 0.001). Mean FSFI scores were 19.1 +/- 5.5 for the exposed and 20.0 +/- 3.4 for the unexposed group. The scores of sexual desire domain (3.4 +/- 1.2 vs. 2.7 +/- 1.2, p < 0.05), sexual dysfunction in the axis of lubrication (3.6 +/- 1.4 vs. 4.0 +/- 0.2, p = 0.039), and pain (4.1 +/- 1.9 vs. 5.4 +/- 0.8, p = 0.001) were found to be significantly higher in women with an infertile partner. According to BDI scores, these women were feeling more depressed (9.7 +/- 7.3 vs. 1.4 +/- 2.8, p = 0.001) than the unexposed group. CONCLUSION: Comparison of these groups indicated similar levels of sexual dysfunction. Nonetheless, we found that women with infertile partners experienced sexual problems related to lubrication and pain, even though they were in the initial stages of the treatment process for infertility. Exposed group had also higher level of depression than the unexposed group. PMID- 26519282 TI - Quantitative analysis of absorption, metabolism, and excretion of benzoxazinoids in humans after the consumption of high- and low-benzoxazinoid diets with similar contents of cereal dietary fibres: a crossover study. AB - PURPOSE: Benzoxazinoids (BXs) are a group of wholegrain phytochemicals with potential pharmacological properties; however, limited information exists on their absorption, metabolism, and excretion in humans. The aim of this study was to investigate the dose-dependent uptake and excretion of dietary BXs in a healthy population. METHODS: Blood and urine were collected from 19 healthy participants from a crossover study after a washout, a LOW BX diet or HIGH BX diet, and analysed for 12 BXs and 4 phenoxazinone derivatives. RESULTS: We found that the plasma BX level peaked approximately 3 h after food intake, whereas BXs in urine were present even at 36 h after consuming a meal. No phenoxazinone derivatives could be detected in either plasma or urine. The dominant BX metabolite in both plasma and urine was 2-beta-D-glucopyranosyloxy-1,4-benzoxazin 3-one (HBOA-Glc), even though 2-beta-D-glucopyranosyloxy-4-hydroxy-1,4-benzoxazin 3-one (DIBOA-Glc) was the major component in the diet. CONCLUSION: The dietary BX treatment correlated well with the plasma and urine levels, illustrating strong dose-dependent BX absorption, which also had a rapid washout, especially from the plasma compartment. PMID- 26519283 TI - Capsule Commentary on Dzeng et al., Moral Distress Amongst American Physician Trainees Regarding Futile Treatments at the End of Life: a Qualitative Inquiry. PMID- 26519284 TI - An analysis of drug-induced liver injury, which showed histological findings similar to autoimmune hepatitis. AB - BACKGROUND: Drug-induced liver injury (DILI) sometimes resembles autoimmune hepatitis (AIH) in its hepatic histology. However, there is lacking data of a comparison of the characteristics between such DILI and DILI without histological findings like AIH. METHODS: We enrolled 62 patients with DILI who were diagnosed using the Roussel Uclaf Causality Assessment Method, and performed a liver biopsy. These patients were classified into two groups: DILI with histology like AIH (group A, n = 23) and DILI without such histology (group B, n = 39). Sixteen patients of group A could be further classified into two groups: patients with relapse of the liver injury (group C, n = 8) and without relapse (group D, n = 8), after the recovery of the DILI. We compared the clinical and histological findings between group A and B, and group C versus D. RESULTS: Group A was characterized by an older age (p = 0.043), higher immunoglobulin G level (p = 0.017), positive antinuclear antibody status (p = 0.044), and a higher frequency of complementary alternative medicines and Chinese herbal medicines as the causative drug (p = 0.008). There were no significant differences between group C and D regarding the clinical data and liver histological findings. CONCLUSIONS: The clinical characteristics of DILI, which showed histological findings similar to AIH, were revealed. In such patients, a liver biopsy is recommended in order to determine the appropriate treatment strategy. In DILI with histology like AIH patients, long-term follow-up is needed to perceive the relapse. PMID- 26519285 TI - Survey on composition of perennial vegetation in Sesa Mariam Monastery, Northwestern Ethiopia. AB - BACKGROUND: Sustainable use of natural resources is one of the leading agenda because anthropogenic activities are leading to the depletion of these resources. Ethiopia is one of the biodiversity reach areas in the world, but the floral diversity is being threatened before they are fully explored. In line with this, very little is known about the flora of Sesa Mariam monastery, found in northwest Ethiopia. The area is one of the few remnant monastery forests in the country with old aged tree species. The aim of the study was to explore and document the floristic composition, density and regeneration status of perennial plant species in order to provide base line information for the sustainable utilization and management of the forest resources. METHODOLOGY: Fifty-one (51) quadrats (20 m * 20 m each) were laid along established transect lines for census of perennial plant species. Two nested quadrats (2 m * 10 m) were also used at the beginning and at the end of every main quadrat for the assessment of seedlings and saplings. All woody plant species in each quadrat were counted and identified. Species diversity, richness and evenness were measured. RESULTS: One hundred and thirteen (113) plant species belonging to 89 genera and 54 families were identified. Moreover, there were 7 more species outside the study quadrats. Of these plant species 10 were endemic, 92 were indigenous, and the remaining 11 were exotic cultivated trees and shrubs. Fabaceae is the most dominant family with 14 species followed by Euphorbiaceae and Rutaceae, each with 6 species. The total basal area of the matured woody plants of the forest was 94.81 m(2) ha(-1) and the density was 1960.78 individuals ha(-1). The overall diversity and evenness of woody species were 3.81 and 0.85, respectively. When compared to other forests found in Ethiopia, it is better protected. CONCLUSION: The data from this study showed a relatively good conservation status. However, analysis from individual woody plant structure, and count of seedlings and saplings showed a need for conservation. Stopping or minimizing grazing by livestock and selective tree cuttings are the first measures to be taken for conservation. PMID- 26519286 TI - 6th National Congress of the Italian Society of ColoRectal Surgery Patients First: Quality of Care, Management, Multidisciplinary Approach : Treviso, October, 4-7, 2015 Presidents: Giulio A. Santoro, A. Infantino. PMID- 26519287 TI - Antegrade transverse or sigmoid colonic enema through a percutaneous endoscopic gastrostomy tube is an option in the treatment of colorectal dysfunction. AB - BACKGROUND: Antegrade colonic enemas are used in patients with colorectal dysfunction resistant to conservative therapy. A number of different operative techniques are applied, but their effectiveness is by and large unknown. We therefore evaluated the long-term usefulness of the left-sided percutaneous endoscopic gastrostomy (PEG) tube method in adult patients. METHODS: Twenty-one patients with colorectal dysfunction underwent insertion of a PEG tube colostomy by laparotomy between 1997 and 2006. In 2014, we evaluated how many of the patients had the tube still in place, how the patients coped with the tube, and what the reasons for the removal were. RESULTS: The main indications were severe constipation or fecal incontinence mainly related to neurological diseases. In 2014, 5 out of 21 patients had the tube still in use (median follow-up 14 years, range 11-17 years) and 4 out of 5 deceased patients had had the tube in use until their death, unrelated to this treatment (median follow-up 7 years, range 0-8 years). Four out of the 5 living patients considered the benefit of the tube to be good or excellent. Tubes were removed in 11 (52%) patients for various reasons, local skin irritation being the most common. CONCLUSIONS: A left-sided PEG tube colostomy was removed in over half of the patients, but despite that, it still seems to be a viable long-term option in the treatment of individual patients with colorectal dysfunction, when conservative methods are ineffective. PMID- 26519288 TI - Endoscopic submucosal dissection versus local excision for early rectal cancer: a systematic review and meta-analysis. AB - Endoscopic submucosal dissection (ESD) and local excision (LE) are minimally invasive procedures that can be used to treat early rectal cancer. There are no current guidelines or consensus on the optimal treatment strategy for these lesions. A systematic review was conducted to compare the efficacy and safety of ESD and LE. A meta-analysis was conducted following all aspects of the Cochrane Handbook for systematic reviews and preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement. To perform the statistical analysis, the odds ratio (OR) was used for categorical variables and the weighted mean difference (WMD) for continuous variables. Four studies, involving a total of 307 patients, were identified. The length of hospital stay was longer in the group of patients undergoing LE [weighted mean difference (WMD) -1.94; 95% CI 2.85 to -1.02; p < 0.0001]. The combined results of the individual studies showed no significant differences as regards en-bloc resection rate (OR 0.82; 95% CI 0.25-2.70; p = 0.74), R0 resection rate (OR 1.53; 95% CI 0.62-3.73; p = 0.35), overall complication rate (OR 0.67; 95% CI 0.26-1.69; p = 0.40), and tumor size (WMD 0.57; 95% CI -3.64 to 4.78; p = 0.79) between ESD and LE. When adopting the fixed effect model which takes into account the study size, ESD was associated with a lower recurrence rate than LE (OR 0.15; 95% CI 0.03-0.87; p = 0.03), while with the random-effect model the difference was not significant (OR 0.18; 95% CI 0.02-2.04; p = 0.17). Over the last decade improvements in technology have improved the technical feasibility of rectal ESD. In specialized centers with highly experienced endoscopists, ESD can provide high-quality en-bloc excision of rectal neoplasms equivalent to traditional local excision. PMID- 26519289 TI - Influence of Multi-Gene Allele Combinations on Grain Size of Rice and Development of a Regression Equation Model to Predict Grain Parameters. AB - BACKGROUND: Grain size is one of the key factors determining yield and quality in rice. A large number of genes are involved in the regulation of grain size parameters such as grain length and grain width. Different alleles of these genes have different impacts on the grain size traits under their control. However, the combined influence of multiple alleles of different genes on grain size remains to be investigated. Six key genes known to influence grain size were investigated in this study: GS3, GS5, GS6, GW2, qSW5/GW5, and GW8/OsSPL16. Allele and grain measurement data were used to develop a regression equation model that can be used for molecular breeding of rice with desired grain characteristics. RESULTS: A total of 215 diverse rice germplasms, which originated from or were developed in 28 rice-consuming countries, were used in this study. Genotyping analysis demonstrated that a relatively small number of allele combinations were preserved in the diverse population and that these allele combinations were significantly associated with differences in grain size. Furthermore, in several cases, variation at a single gene was sufficient to influence grain size, even when the alleles of other genes remained constant. The data were used to develop a regression equation model for prediction of rice grain size, and this was tested using data from a further 34 germplasms. The model was significantly correlated with three of the four grain size-related traits examined in this study. CONCLUSION: Rice grain size is strongly influenced by specific combinations of alleles from six different genes. A regression equation model developed from allele and grain measurement data can be used in rice breeding programs for the development of new rice varieties with desired grain size and shape. PMID- 26519290 TI - Novel human anti-claudin 1 mAbs inhibit hepatitis C virus infection and may synergize with anti-SRB1 mAb. AB - Hepatitis C virus (HCV) is a major cause of chronic hepatitis and liver carcinoma and new therapies based on novel targets are needed. The tight junction protein claudin 1 (CLDN-1) is essential for HCV cell entry and spread, and anti-CLDN-1 rat and mouse mAbs are safe and effective in preventing and treating HCV infection in a human liver chimeric mouse model. To accelerate translation of these observations into a novel approach to treat HCV infection and disease in humans, we screened a phage display library of human single-chain antibody fragments by using a panel of CLDN-1-positive and -negative cell lines and identified phage specifically binding to CLDN-1. The 12 clones showing the highest levels of binding were converted into human IgG4. Some of these mAbs displayed low-nanomolar affinity, and inhibited infection of human hepatoma Huh7.5 cells by different HCV isolates in a dose-dependent manner. Cross competition experiments identified six inhibitory mAbs that recognized distinct epitopes. Combination of the human anti-SRB1 mAb C-1671 with these anti-CLDN-1 mAbs could either increase or reduce inhibition of cell culture-derived HCV infection in vitro. These novel human anti-CLDN-1 mAbs are potentially useful to develop a new strategy for anti-HCV therapy and lend support to the combined use of antibodies targeting the HCV receptors CLDN-1 and SRB1, but indicate that care must be taken in selecting the proper combination. PMID- 26519291 TI - The concept of mechanism from a realist approach: a scoping review to facilitate its operationalization in public health program evaluation. AB - BACKGROUND: Public health interventions are complex by nature, and their evaluation requires unpacking their intervention logic and their interactions with open social systems. By focusing on the interrelationships between context, mechanism, and outcome, Pawson and Tilley's realist approach appears a promising innovation for public health-related evaluation works. However, and as expected of any methodological innovation, this approach is being constructed gradually by answering the multiple challenges to its operationalization that fall in its path. One of these challenges, users of this approach agree on, is the necessity of clarifying its key concept of mechanism. METHOD: We first collected the definitions of mechanism from published works of Pawson and colleagues. Secondly, a scoping review was conducted to identify the ones quoted by users of the realist approach for evaluating public health interventions (1997-2012). We then appraised the clarity and precision of this concept against the three dimensions defined by Daigneault and Jacobs "term, sense and referent." RESULTS: Of the 2344 documents identified in the scoping review, 49 documents were included. Term: Users of the realist approach use adjectives qualifying the term mechanism that were not specifically endorsed by Pawson and colleagues. Sense: None of the attributes stated by Pawson and colleagues has been listed in all of the documents analyzed, and some contributions clarified its attributes. Referent: The concept of mechanism within a realist approach can be ascribed to theory based evaluation, complex social interventions, and critical realism. CONCLUSION: This review led us to reconsider the concept of mechanism within the realist approach by confronting the theoretical stance of its proponents to the practical one of its users. This resulted in a clearer, more precise definition of the concept of mechanism which may in turn trigger further improvements in the way the realist approach is applied in evaluative practice in public health and potentially beyond. A mechanism is hidden but real, is an element of reasoning and reactions of agents in regard to the resources available in a given context to bring about changes through the implementation of an intervention, and evolves within an open space-time and social system of relationships. PMID- 26519294 TI - A Case of Empyema Necessitatis in a Child With Mycobacterium tuberculosis. PMID- 26519293 TI - (18)F-FDG PET in small-cell cervical cancer: a prospective study with long-term follow-up. AB - PURPOSE: Small-cell cervical cancer (SCCC) is rare and prone to metastasize. We conducted a prospective study to evaluate the role of (18)F-FDG PET in the management of this aggressive malignancy. METHODS: Patients with untreated primary, histologically confirmed SCCC were enrolled. (18)F-FDG PET (or PET/CT) was performed immediately after MRI or CT, for primary staging, monitoring response to treatment or restaging when there was suspicion of recurrence. The clinical impact of PET was determined on a scan basis. RESULTS: A total of 25 patients were recruited and 43 PET scans were performed. The PET images were obtained for primary staging (25 patients), monitoring response (10 patients) and restaging when there was suspicion of recurrence (8 patients). The median follow up time in event-free patients was 109.3 months (range 97.5 - 157.7 months). A positive impact of PET was found in 8 (18.6 %) of the 43 scans, which included detection of additional regions of distal lymph node (LN) metastasis (one primary staging scan, two restaging scans), bone metastasis (two primary staging scans, one monitoring response scan), and exclusion of false-positive lesions on MRI (one primary staging scan, one restaging scan). On the other hand, one negative impact was recorded as one false-positive lesion on a restaging PET scan. One positive impact was noted for monitoring response (bone metastasis). The impact of three scans was indeterminate. The positive impact of down-staging in avoiding overtreatment but finding additional distal LN (except one on restaging) or bone metastases had no beneficial effect on long-term survival. CONCLUSION: The results of this preliminary study suggest that PET is useful in the management of SCCC. PET could have more value in detecting occult metastases if future novel therapies are able to offer better control of extensive SCCC. PMID- 26519292 TI - FDG PET/CT in cancer: comparison of actual use with literature-based recommendations. AB - PURPOSE: The Region of Southern Denmark (RSD), covering 1.2 of Denmark's 5.6 million inhabitants, established a task force to (1) retrieve literature evidence for the clinical use of positron emission tomography (PET)/CT and provide consequent recommendations and further to (2) compare the actual use of PET/CT in the RSD with these recommendations. This article summarizes the results. METHODS: A Work Group appointed a professional Subgroup which made Clinician Groups conduct literature reviews on six selected cancers responsible for 5,768 (62.6 %) of 9,213 PET/CT scans in the RSD in 2012. Rapid Evidence Assessment was applied, using the methodology of systematic reviews with predefined limitations to search PubMed, Embase and the Cochrane Library for articles published in English/Danish/Swedish/Norwegian since 2002. PICO questions were defined, data recorded and quality appraised and rated with regard to strength and evidence level. Consequent recommendations for applications of PET/CT were established. The actual use of PET/CT was compared with these, where grades A and B indicated "established" and "useful" and grades C and D "potentially useful" and "non recommendable" indications, respectively. RESULTS: Of 11,729 citations, 1,729 were considered for review, and 204 were included. The evidence suggested usefulness of PET/CT in lung, lymphoma, melanoma, head and neck, and colorectal cancers, whereas evidence was sparse in gynaecological cancers. The agreement between actual use of PET/CT and literature-based recommendations was high in the first five mentioned cancers in that 96.2 % of scans were made for grade A or B indications versus only 22.2 % in gynaecological cancers. CONCLUSION: Evidence based usefulness was reported in five of six selected cancers; evidence was sparse in the sixth, gynaecological cancers. Actual use of PET/CT agreed well with recommendations. PMID- 26519295 TI - Functionally conserved enhancers with divergent sequences in distant vertebrates. AB - BACKGROUND: To examine the contributions of sequence and function conservation in the evolution of enhancers, we systematically identified enhancers whose sequences are not conserved among distant groups of vertebrate species, but have homologous function and are likely to be derived from a common ancestral sequence. Our approach combined comparative genomics and epigenomics to identify potential enhancer sequences in the genomes of three groups of distantly related vertebrate species. RESULTS: We searched for sequences that were conserved within groups of closely related species but not between groups of more distant species, and were associated with an epigenetic mark of enhancer activity. To facilitate inferring orthology between non-conserved sequences, we limited our search to introns whose orthology could be unambiguously established by mapping the bracketing exons. We show that a subset of these non-conserved but syntenic sequences from the mouse and zebrafish genomes have homologous functions in a zebrafish transgenic enhancer assay. The conserved expression patterns driven by these enhancers are probably associated with short transcription factor-binding motifs present in the divergent sequences. CONCLUSIONS: We have identified numerous potential enhancers with divergent sequences but a conserved function. These results indicate that selection on function, rather than sequence, may be a common mode of enhancer evolution; evidence for selection at the sequence level is not a necessary criterion to define a gene regulatory element. PMID- 26519297 TI - Acute kidney injury due to glomerular haematuria and obstructive erythrocyte casts associated with thrombocytopaenia and thin basement membrane disease: a case report. AB - BACKGROUND: Acute kidney injury due to glomerular bleeding has been described with IgA nephropathy and supratherapeutic warfarin anticoagulation. There is usually demonstrable tubular obstruction by erythrocyte casts associated with acute tubular injury. Although severe thrombocytopaenia increases the risk of bleeding, most cases of haematuria have been ascribed to non-glomerular or urological bleeding without a direct link to acute kidney injury. We describe a patient with acute kidney injury due to glomerular bleeding and tubular injury related to severe thrombocytopaenia, who was subsequently found to have thin basement membrane disease. CASE PRESENTATION: A 56 year old man presented with macroscopic haematuria, acute kidney injury and a platelet count of 35 * 10(9)/L, in the absence of anticoagulation. Urinalysis demonstrated an active urinary sediment. His kidney biopsy demonstrated extensive intraluminal erythrocyte casts associated with acute tubular injury, along with haemosiderin deposition suggestive of recurrent glomerular bleeding. There was no histological evidence of glomerular pathology but electron microscopy analysis demonstrated thin basement membrane disease and effacement of podocyte foot processes. During long term follow-up, thrombocytopaenia and intermittent haematuria persisted. At 9 months, the patient progressed to Stage 5 chronic kidney disease with the development of gross renal atrophy. CONCLUSION: Recurrent macroscopic haematuria may be a risk factor for progressive renal injury in patients with thin basement membrane. The mechanism may be due to recurrent acute kidney injury from glomerular bleeding leading to repeated tubular damage. In the absence of anticoagulation, severe thrombocytopaenia may be a risk factor for heavy glomerular bleeding and acute kidney injury in these patients. PMID- 26519296 TI - Western diet-induced hepatic steatosis and alterations in the liver transcriptome in adult Brown-Norway rats. AB - BACKGROUND: The purpose of this study was to investigate the effects of sub chronic high fat, high sucrose diet (also termed 'Westernized diet' or WD) feeding on the liver transcriptome during early nonalcoholic fatty liver disease (NAFLD) development. METHODS: Brown Norway male rats (9 months of age) were randomly assigned to receive ad libitum access to a control (CTL; 14 % kcal fat, 1.2 % sucrose by weight) diet or WD (42 % kcal from fat, 34 % sucrose by weight) for 6 weeks. RESULTS: Six weeks of WD feeding caused hepatic steatosis development as evidenced by the 2.25-fold increase in liver triacylglycerol content, but did not induce advanced liver disease (i.e., no overt inflammation or fibrosis) in adult Brown Norway rats. RNA deep sequencing (RNA-seq) revealed that 94 transcripts were altered in liver by WD feeding (46 up-, 48 down regulated, FDR < 0.05). Specifically, the top differentially regulated gene network by WD feeding was 'Lipid metabolism, small molecular biochemistry, vitamin and mineral metabolism' (Ingenuity Pathway Analysis (IPA) score 61). The top-regulated canonical signaling pathway in WD-fed rats was the 'Superpathway of cholesterol biosynthesis' (10/29 genes regulated, p = 1.68E-17), which coincides with a tendency for serum cholesterol levels to increase in WD-fed rats (p = 0.09). Remarkably, liver stearoyl-CoA desaturase (Scd) mRNA expression was by far the most highly-induced transcript in WD-fed rats (approximately 30-fold, FDR = 0.01) which supports previous literature underscoring this gene as a crucial target during NAFLD development. CONCLUSIONS: In summary, sub-chronic WD feeding appears to increase hepatic steatosis development over a 6-week period but only induces select inflammation-related liver transcripts, mostly acute phase response genes. These findings continue to outline the early stages of NAFLD development prior to overt liver inflammation and advanced liver disease. PMID- 26519298 TI - Re-inventing care planning in mental health: stakeholder accounts of the imagined implementation of a user/carer involved intervention. AB - BACKGROUND: Despite an increase in mental health innovations designed to increase service user and carer involvement in services, there is evidence that service users and carers are still relatively marginalised. This study aimed to identify key informants operating with knowledge of both policy and practice related to future models of mental health management in order to explore the potential de implementation of existing care planning and possibilities for the introduction of a training programme designed to implement a new user and carer involved and focussed process of mental health care planning. METHODS: 13 semi-structured interviews were carried out with key informants from a range of relevant disciplinary backgrounds and professional roles, who were involved locally and nationally in policy, practice and research. The aim of the interviews was to explore their perspectives on contemporary arrangements for care planning procedures and processes and to identify factors that might promote or inhibit the routine incorporation of user/carer led planning. Findings were compared to data derived from service users, carers and professionals to illuminate added value. RESULTS: Key stakeholders identified elements of the current care planning context that were likely to impact on the implementability of user - focussed care planning. Like other stakeholders, key informants felt that the proposed intervention coalesced with the increasing normalisation of user involvement as appropriate and desirable. Participants added to existing data by illuminating the need for organisational bureaucracy and the legacy of prior mental health policy and historical practice to be considered in implementation. Adequate relationships within the system were considered by all stakeholders to be crucial to successful implementation and key informants discussed how this could be eroded through attempts at practice standardisation and current connectivity and culture within services. CONCLUSIONS: The study demonstrated the value of incorporating the perspective of stakeholders not directly involved in service delivery in implementation research designed to inform an intervention at the point of design. Their contribution centred on the identification of factors that appeared not be obvious to those working in the system or emanated from political and policy arenas as well as developing the contextual understanding of themes raised by other stakeholders. PMID- 26519299 TI - Government proposes "Ofsted style" ratings for CCG services. PMID- 26519300 TI - High Resolution Mass Spectrometry of Polyfluorinated Polyether-Based Formulation. AB - High resolution mass spectrometry (HRMS) was successfully applied to elucidate the structure of a polyfluorinated polyether (PFPE)-based formulation. The mass spectrum generated from direct injection into the MS was examined by identifying the different repeating units manually and with the aid of an instrument data processor. Highly accurate mass spectral data enabled the calculation of higher order mass defects. The different plots of MW and the nth-order mass defects (up to n = 3) could aid in assessing the structure of the different repeating units and estimating their absolute and relative number per molecule. The three major repeating units were -C2H4O-, -C2F4O-, and -CF2O-. Tandem MS was used to identify the end groups that appeared to be phosphates, as well as the possible distribution of the repeating units. Reversed-phase HPLC separated of the polymer molecules on the basis of number of nonpolar repeating units. The elucidated structure resembles the structure in the published manufacturer technical data. This analytical approach to the characterization of a PFPE-based formulation can serve as a guide in analyzing not just other PFPE-based formulations but also other fluorinated and non-fluorinated polymers. The information from MS is essential in studying the physico-chemical properties of PFPEs and can help in assessing the risks they pose to the environment and to human health. Graphical Abstract ?. PMID- 26519301 TI - Time-Lapse Fluorescence Microscopy of Budding Yeast Cells. AB - The discovery of green fluorescent protein (GFP) allowed visualization of a wide variety of processes within living cells. Thanks to the development of differently colored fluorophores, it is now possible to simultaneously follow distinct subcellular events at the single cell level. Here, we describe a basic method to visualize multiple events during cytokinesis by time-lapse fluorescence microscopy in the budding yeast Saccharomyces cerevisiae. In this organism, contraction of an actomyosin-based ring drives ingression of the plasma membrane at the mother-bud division site to partition the cytoplasm of the dividing cell. Simultaneous visualization of distinct cytokinesis steps in living cells, such as ring contraction and membrane ingression, will facilitate a complete understanding of the mechanisms of eukaryotic cell division. PMID- 26519302 TI - Real-Time Visualization and Quantification of Contractile Ring Proteins in Single Living Cells. AB - Single-cell microscopy provides a powerful tool to visualize cellular and subcellular processes in wild-type and mutant cells by observing fluorescently tagged proteins. Here, we describe three simple methods to visualize fission yeast cells: gelatin slides, coverslip-bottom dishes, and tetrad fluorescence microscopy. These imaging methods and data analysis using free software make it possible to quantify protein localization, dynamics, and concentration with high spatial and temporal resolution. In fission yeast, the actomyosin contractile ring is essential for cytokinesis. We use the visualization and quantification of contractile ring proteins as an example to demonstrate how to use these methods. PMID- 26519303 TI - Fluorescence Recovery After Photo-Bleaching (FRAP) and Fluorescence Loss in Photo Bleaching (FLIP) Experiments to Study Protein Dynamics During Budding Yeast Cell Division. AB - The easiness of tagging any protein of interest with a fluorescent marker together with the advance of fluorescence microscopy techniques enable researchers to study in great detail the dynamic behavior of proteins both in time and space in living cells. Two commonly used techniques are FRAP (Fluorescent Recovery After Photo-bleaching) and FLIP (Fluorescence Loss In Photo bleaching). Upon single bleaching (FRAP) or constant bleaching (FLIP) of the fluorescent signal in a specific area of the cell, the intensity of the fluorophore is monitored over time in the bleached area and in surrounding regions; information is then derived about the diffusion speed of the tagged molecule, the amount of mobile versus immobile molecules as well as the kinetics with which they exchange between different parts of the cell. Thereby, FRAP and FLIP are very informative about the kinetics with which the different organelles of the cell separate into mother- and daughter-specific compartments during cell division. Here, we describe protocols for both FRAP and FLIP and explain how they can be used to study protein dynamics during cell division in the budding yeast Saccharomyces cerevisiae. These techniques are easily adaptable to other model organisms. PMID- 26519304 TI - High-Speed Super-Resolution Imaging of Live Fission Yeast Cells. AB - We describe a step-by-step method for high-speed fluorescence photoactivation localization microscopy (FPALM) of live fission yeast cells. The resolution with this method is tenfold better than spinning disk confocal microscopy. PMID- 26519305 TI - Monitoring Chitin Deposition During Septum Assembly in Budding Yeast. AB - The synthesis of the septum is a critical step during cytokinesis in the fungal cell. Moreover, in Saccharomyces cerevisiae septum assembly depends mostly on the proper synthesis and deposition of chitin and, accordingly, on the timely regulation of chitin synthases. In this chapter, we will see how to follow chitin synthesis by two complementary approaches: monitoring chitin deposition in vivo at the septum by calcofluor staining and fluorescence microscopy, and measuring the chitin synthase activities responsible for this synthesis. PMID- 26519306 TI - Imaging Septum Formation by Fluorescence Microscopy. AB - Fungal cleavage furrow formation during cytokinesis relays in the coordinated contraction of an actomyosin-based ring and the centripetal synthesis of both new plasma membrane and a special wall structure named division septum. Through transmission electron microscopy, the septum exhibits a three-layered structure with a central primary septum, flanked at both sides by the secondary septum. In contrast to the chitinous primary septum present in most of fungi, the fission yeast Schizosaccharomyces pombe does not contain chitin, instead it divides through the formation of a linear beta(1,3)glucan-rich primary septum, which has been shown to be specifically stained by the fluorochrome Calcofluor white. Recent findings in S. pombe have revealed the importance of septum synthesis for the steady contraction of the ring during cytokinesis. Therefore, to study the molecular mechanisms that connect the extracellular septum wall with the other components of the cytokinetic machinery located in the plasma membrane and cytoplasm, new experimental approaches are needed. Here we describe the methods developed to image the septum structure by fluorescence microscopy, with a special focus in the analysis of septum progression by the use of time-lapse microscopy. PMID- 26519307 TI - Visualization of Cytokinesis Events in Budding Yeast by Transmission Electron Microscopy. AB - In yeast cells, cytokinesis is accompanied by morphological changes due to cell wall growth during furrow ingression and abscission. The characteristics of the growing cell wall can be used as an indicator for the function of the contractile actomyosin ring, the Rho-GTPases Rho1 and Cdc42 and/or other factors that drive cytokinesis. The ultrastructural information of the cell wall can be easily acquired by transmission electron microscopy, which makes this technique an invaluable tool to analyze cell division in yeast cells. Here, we describe the process of embedding and staining budding yeast cells for transmission electron microscopic analysis of cytokinetic events. PMID- 26519308 TI - Visualization of Fission Yeast Cells by Transmission Electron Microscopy. AB - This chapter deals with the preparation of fission yeast (Schizosaccharomyces) cells for ultrastructural examination. The structure of the cell must be preserved as close to the in vivo situation as possible. This can be achieved by either chemical or cryofixation; the latter will not be dealt with in this chapter. Aldehydes that cross-link proteins and permanganates that besides cross linking also stain membranous and cell wall structures are used for chemical fixation. This step is followed by dehydration and embedding of the cells in epoxy or acrylic resin. Sectioning of the embedded material produces slices of the cells that have to be stained with heavy metals to increase contrast differences between different structures or can be used for immunodetection of antigens (polysaccharides or proteins) with specific primary antibodies and gold conjugated secondary antibodies. PMID- 26519309 TI - Characterization of Septin Ultrastructure in Budding Yeast Using Electron Tomography. AB - Septins are essential for the completion of cytokinesis. In budding yeast, Saccharomyces cerevisiae, septins are located at the bud neck during mitosis and are closely connected to the inner plasma membrane. In vitro, yeast septins have been shown to self-assemble into a variety of filamentous structures, including rods, paired filaments, bundles, and rings (Bertin et al. Proc Natl Acad Sci U S A, 105(24):8274-8279, 2008; Garcia et al. J Cell Biol, 195(6):993-1004, 2011; Bertin et al. J Mol Biol, 404(4):711-731, 2010). Using electron tomography of freeze-substituted sections and cryo-electron tomography of frozen sections, we determined the three-dimensional organization of the septin cytoskeleton in dividing budding yeast with molecular resolution (Bertin et al. Mol Biol Cell, 23(3):423-432, 2012; Bertin and Nogales. Commun Integr Biol 5(5):503-505, 2012). Here, we describe the detailed procedures used for our characterization of the septin cellular ultrastructure. PMID- 26519310 TI - Isolation of Cytokinetic Actomyosin Rings from Saccharomyces cerevisiae and Schizosaccharomyces pombe. AB - Cytokinesis is the final stage of cell division, through which cellular constituents of mother cells are partitioned into two daughter cells resulting in the increase in cell number. In animal and fungal cells cytokinesis is mediated by an actomyosin contractile ring, which is attached to the overlying cell membrane. Contraction of this ring after chromosome segregation physically severs the mother cell into two daughters. Here we describe methods for the isolation and partial purification of the actomyosin ring from the fission yeast Schizosaccharomyces pombe and the budding yeast Saccharomyces cerevisiae, which can serve as in vitro systems to facilitate biochemical and ultrastructural analysis of cytokinesis in these genetically tractable model systems. PMID- 26519311 TI - Measurements of Myosin-II Motor Activity During Cytokinesis in Fission Yeast. AB - Fission yeast myosin-II (Myo2p) represents the critical actin-based motor protein that drives actomyosin ring assembly and constriction during cytokinesis. We detail three different methods to measure Myo2p motor function. Actin-activated ATPases provide a readout of actomyosin ATPase motor activity in a bulk assay; actin filament motility assays reveal the speed and efficiency of myosin-driven actin filament gliding (when motors are anchored); myosin-bead motility assays reveal the speed and efficiency of myosin ensembles traveling along actin filaments (when actin is anchored). Collectively, these methods allow us to combine the standard in vivo approaches common to fission yeast with in vitro biochemical methods to learn more about the mechanistic action of myosin-II during cytokinesis. PMID- 26519312 TI - In Vitro Biochemical Characterization of Cytokinesis Actin-Binding Proteins. AB - Characterizing the biochemical and biophysical properties of purified proteins is critical to understand the underlying molecular mechanisms that facilitate complicated cellular processes such as cytokinesis. Here we outline in vitro assays to investigate the effects of cytokinesis actin-binding proteins on actin filament dynamics and organization. We describe (1) multicolor single-molecule TIRF microscopy actin assembly assays, (2) "bulk" pyrene actin assembly/disassembly assays, and (3) "bulk" sedimentation actin filament binding and bundling assays. PMID- 26519313 TI - Characterization of Cytokinetic F-BARs and Other Membrane-Binding Proteins. AB - Multiple membrane-binding proteins are key players in cytokinesis in yeast and other organisms. In vivo techniques for analyzing protein-membrane interactions are currently limited. In vitro assays allow characterization of the biochemical properties of these proteins to build a mechanistic understanding of protein membrane interactions during cytokinesis. Here, we describe two in vitro assays to characterize FCH-Bin/Amphyphysin/RVS (F-BAR) domains and other protein's interactions with membranes: liposome co-pelleting and giant unilamellar vesicle fluorescent binding. PMID- 26519314 TI - Analysis of Three-Dimensional Structures of Exocyst Components. AB - The exocyst is an octameric protein complex implicated in tethering secretory vesicles to the plasma membrane during exocytosis. To provide a mechanistic understanding of how it functions, it is of critical importance to elucidate its three-dimensional structure. This chapter briefly describes the protocols used in our structure determination of Exo70p and Exo84p, two subunits of the exocyst from Saccharomyces cerevisiae. Folding and domain arrangements of both proteins are predicted using bioinformatics tools. Limited proteolysis is carried out to define the boundaries of folded structures, which guides the design of suitable constructs for protein crystallization. The solved structures of both proteins validate the strategy and suggest it might be also used for structural studies of other proteins alike. PMID- 26519315 TI - Analysis of Rho-GTPase Activity During Budding Yeast Cytokinesis. AB - Rho-type small GTPases are involved in cytokinesis in various organisms, but their precise roles and regulation remain unclear. Rho proteins function as molecular switches by cycling between the active GTP-bound and inactive GDP-bound states; the GTP-bound proteins in turn interact with their downstream effectors to transmit the signal. Biochemical assays using Rho-binding domains of effector proteins have been used to specifically pull down GTP-bound Rho proteins from cell extracts. Here, we describe the application of such a method in combination with cell-cycle synchronization in the budding yeast Saccharomyces cerevisiae; this approach allows dissection of the activity of Rho1 at different stages of cytokinesis. We also present data showing the importance of caution in interpreting such biochemical data and of comparing to the results obtained with other approaches where possible. The principle of this protocol is also applicable to analyses of other Rho-type GTPases and cell-cycle events. PMID- 26519316 TI - Detection of Phosphorylation Status of Cytokinetic Components. AB - Yeast cells can be easily cultured, synchronized, and genetically modified making them a convenient model system to study molecular mechanisms underlying cytokinesis. Here, we describe simple methods that allow the analysis of the phosphorylation profile of cytokinetic proteins, both in vivo and in vitro, using standard laboratory equipment. In addition, we compare the ability of three different, standard, and optimized acrylamide gel conditions to separate phosphorylated forms, using the protein Inn1 as an example. PMID- 26519317 TI - Studying Protein-Protein Interactions in Budding Yeast Using Co immunoprecipitation. AB - Understanding protein-protein interactions and the architecture of protein complexes in which they work is essential to identify their biological role. Protein co-immunoprecipitation (co-IP) is an invaluable technique used in biochemistry allowing the identification of protein interactors. Here, we describe in detail an immunoaffinity purification protocol as a one-step or two step immunoprecipitation from budding yeast Saccharomyces cerevisiae cells to subsequently detect interactions between proteins involved in the same biological process. PMID- 26519318 TI - Conditional Budding Yeast Mutants with Temperature-Sensitive and Auxin-Inducible Degrons for Screening of Suppressor Genes. AB - The conditional control of protein expression is useful to characterize the function of proteins, especially of those that are essential for cell viability. Two degron-based systems, temperature-sensitive and auxin-inducible degrons, can be used to generate conditional mutants of budding yeast, simply by transforming appropriate cells with PCR-amplified DNA. We describe a protocol for the generation of temperature-sensitive and auxin-inducible degron mutants. We also show that a conditional mutant with few spontaneous revertants was generated by combining two degron systems for the Inn1 protein. Finally, we describe a suppressor screening method that uses the dual degron-Inn1 mutant to identify mutant proteins that suppress Inn1-K31A, which has a defect in cytokinesis. PMID- 26519319 TI - Synchronization of the Budding Yeast Saccharomyces cerevisiae. AB - A number of model organisms have provided the basis for our understanding of the eukaryotic cell cycle. These model organisms are generally much easier to manipulate than mammalian cells and as such provide amenable tools for extensive genetic and biochemical analysis. One of the most common model organisms used to study the cell cycle is the budding yeast Saccharomyces cerevisiae. This model provides the ability to synchronise cells efficiently at different stages of the cell cycle, which in turn opens up the possibility for extensive and detailed study of mechanisms regulating the eukaryotic cell cycle. Here, we describe methods in which budding yeast cells are arrested at a particular phase of the cell cycle and then released from the block, permitting the study of molecular mechanisms that drive the progression through the cell cycle. PMID- 26519320 TI - Fission Yeast Cell Cycle Synchronization Methods. AB - Fission yeast cells can be synchronized by cell cycle arrest and release or by size selection. Cell cycle arrest synchronization is based on the block and release of temperature-sensitive cell cycle mutants or treatment with drugs. The most widely used approaches are cdc10-129 for G1; hydroxyurea (HU) for early S phase; cdc25-22 for G2, and nda3-KM311 for mitosis. Cells can also be synchronized by size selection using centrifugal elutriation or a lactose gradient. Here we describe the methods most commonly used to synchronize fission yeast cells. PMID- 26519321 TI - A Review of Fluorescent Proteins for Use in Yeast. AB - The field of fluorescent proteins (FPs) is constantly developing. The use of FPs changed the field of life sciences completely, starting a new era of direct observation and quantification of cellular processes. The broad spectrum of FPs (see Fig. 1) with a wide range of characteristics allows their use in many different experiments. This review discusses the use of FPs for imaging in budding yeast (Saccharomyces cerevisiae) and fission yeast Schizosaccharomyces pombe). The information included in this review is relevant for both species unless stated otherwise. PMID- 26519322 TI - Visualization and Image Analysis of Yeast Cells. AB - When converting real-life data via visualization to numbers and then onto statistics the whole system needs to be considered so that conversion from the analogue to the digital is accurate and repeatable. Here we describe the points to consider when approaching yeast cell analysis visualization, processing, and analysis of a population by screening techniques. PMID- 26519323 TI - Toolbox for Protein Structure Prediction. AB - Protein tertiary structure prediction algorithms aim to predict, from amino acid sequence, the tertiary structure of a protein. In silico protein structure prediction methods have become extremely important, as in vitro-based structural elucidation is unable to keep pace with the current growth of sequence databases due to high-throughput next-generation sequencing, which has exacerbated the gaps in our knowledge between sequences and structures.Here we briefly discuss protein tertiary structure prediction, the biennial competition for the Critical Assessment of Techniques for Protein Structure Prediction (CASP) and its role in shaping the field. We also discuss, in detail, our cutting-edge web-server method IntFOLD2-TS for tertiary structure prediction. Furthermore, we provide a step-by step guide on using the IntFOLD2-TS web server, along with some real world examples, where the IntFOLD server can and has been used to improve protein tertiary structure prediction and aid in functional elucidation. PMID- 26519324 TI - From Structure to Function: A Comprehensive Compendium of Tools to Unveil Protein Domains and Understand Their Role in Cytokinesis. AB - Unveiling the function of a novel protein is a challenging task that requires careful experimental design. Yeast cytokinesis is a conserved process that involves modular structural and regulatory proteins. For such proteins, an important step is to identify their domains and structural organization. Here we briefly discuss a collection of methods commonly used for sequence alignment and prediction of protein structure that represent powerful tools for the identification homologous domains and design of structure-function approaches to test experimentally the function of multi-domain proteins such as those implicated in yeast cytokinesis. PMID- 26519325 TI - Efficacy of magnesium chloride in the treatment of Hailey-Hailey disease: some further considerations. PMID- 26519326 TI - Introduction to Special Issue ASD in Adulthood: Comorbidity and Intervention. PMID- 26519327 TI - Bilingualism as Conceptualized and Bilingualism as Lived: A Critical Examination of the Monolingual Socialization of a Child with Autism in a Bilingual Family. AB - This is an ethnographic and discourse analytic case study of a bilingual, minority-language family of a six-year-old child with autism whose family members were committed to speaking English with him. Drawing on family language policy, the study examines the tensions between the family members' stated beliefs, management efforts, and their actual practices around language use with their child. The findings show that many assumptions held by family members about language use and bilingualism were inconsistent with their everyday language practices. A practice and discourse-analytic approach to bilingualism offers a theoretical and methodological lens through which to investigate these discrepancies and to recast the interactional achievements between the child and his parents as situated bilingual practices. PMID- 26519328 TI - Site-specific colporrhaphy in posterior compartment pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: A posterior vaginal wall prolapse is the result of specific tears in the rectovaginal fascia. The prevalence of the different defect types (superior, inferior, overstretching) is unknown, as is the subjective results after operation according to defect type. The aims of this retrospective study were to investigate the prevalence of the different injury sites and the subjective effects after an operation concerning the symptomatic feeling of a vaginal bulge and urinary incontinence in relation to defect types. METHODS: Medical case records and data from the national Danish urogynecological database in patients with a prolapse operation including posterior vaginal wall prolapse for a 6-year period were reviewed. Four hundred and five patients were included. Patients completed the International Consultation on Incontinence-Urinary Incontinence Short Form and three questions on vaginal prolapse symptoms before and 3 months postoperatively. RESULTS: The majority of women suffered from a superior defect (77 %). There was a statistically significant improvement in prolapse symptoms after surgery, with no difference between patients with different defect types. Patients with a superior defect and overstretching also experienced a statistically significant improvement in urinary incontinence. CONCLUSIONS: The superior defect was the most common defect in the rectovaginal fascia. Patients experienced an improvement in subjective prolapse symptoms concerning the feeling of a vaginal bulge with no difference regarding defect type. Patients with a superior defect or overstretching experienced a statistically significant improvement in urinary incontinence. Similar results were found whether or not concomitant prolapse operations were performed in other compartments. PMID- 26519329 TI - [Violence against children]. AB - Violence against children is a widespread phenomenon. Interpersonal violence within the family context is typical in childhood, whereas violence occurs more frequently in the leisure and peer context during adolescence, often involving new media. The risk for experiencing violence is associated with many different factors, for example the age, psychosocial context, and cultural background of a child. Data on the prevalence of violence vary by country, depending on the available documentation systems. It is estimated that the number of unreported cases is high. Meta-analyses comprising mainly retrospective self-report studies indicate prevalence estimates between 12 and 19% for neglect, physical, and sexual abuse. Emotional child abuse is reported far more often, with a prevalence as high as 36.3%. German studies, however, weren't able to replicate these international findings. Here, child emotional abuse is reported less often. Violence against children has many negative consequences for physical, emotional, and psychosocial development. Violence prevention therefore comprises different international and national programs and strategies, which are able to successfully reduce violence against children. Programs focusing on the promotion of adequate parenting behavior show especially promising results. PMID- 26519330 TI - [Dealing with victims of domestic violence. Suggestions for daily practice]. AB - The recognition of victims of violence and their treatment in medical facilities is a subject which has been covered for several years in a number of ways. In medicine and in other disciplines, the focus of research, publication, and practical work has been on the quality of care provided. Guidelines for the treatment of victims of violence have been developed and needs have been assessed. These examples show there is an abundance of knowledge on the subject. Nevertheless, the transfer of this knowledge into the everyday practice of medicine at hospitals and doctors' offices is clearly still not functioning in an optimal way and faces a wide range of hurdles and stumbling blocks. Based on the experience gained in a pilot project involving the medical intervention in doctors' offices against violence perpetuated against women (Project MIGG, funded by the German Federal Ministry of Family, Senior Citizens, Women and Youth (BMFSFJ)), approaches for the optimal treatment of victims of violence in outpatient medical facilities are presented. The key steps to achieving the goal of optimal treatment are: (i) the entire practice team commits to establishing a victim-centered approach to care and (ii) the necessary processes and structures are implemented (i.e., adequate documentation in patient records, patient information is made available in the doctor's office, information on post treatment services and sources of support in the region are provided, contact is maintained with such institutions, and programs of further education are offered). This paper provides a catalogue of keywords with an overview illustrating how to optimize practice management to deal with cases of domestic violence. In addition, various areas of work are described, such the special requirements involving the collection of evidence. PMID- 26519331 TI - Euglycemic Diabetic Ketoacidosis in a Patient With Type 2 Diabetes After Treatment With Empagliflozin. PMID- 26519332 TI - Implementation and Evaluation of Diabetes Management via Clinical Video Telehealth. PMID- 26519334 TI - Gestational Age and Birth Weight and the Risk of Childhood Type 1 Diabetes: A Population-Based Cohort and Sibling Design Study. AB - OBJECTIVE: We investigated the effects of gestational age, birth weight, small for gestational age (SGA), and large for gestational age (LGA) on risk of childhood type 1 diabetes. RESEARCH DESIGN AND METHODS: We conducted a population based cohort study of all singleton live births in Sweden between 1973 and 2009 and a sibling control study. Perinatal data were extracted from the Swedish Medical Birth Register. Children with type 1 diabetes diagnosis were identified from the Swedish National Patient Register. Log-linear Poisson regression and conditional logistic regression were used for data analysis. RESULTS: The study cohort consisted of 3,624,675 singleton live births (42,411,054 person-years). There were 13,944 type 1 diabetes cases during the study period. The sibling control study consisted of 11,403 children with type 1 diabetes and 17,920 siblings. Gestational age between 33 and 36 weeks (relative risk [RR] 1.18 [95% CI 1.09, 1.28) and 37 and 38 weeks (RR 1.12 [95% CI 1.07, 1.17]) was associated with type 1 diabetes in the cohort study and remained significant in the sibling control study. SGA (RR 0.83 [95% CI 0.75, 0.93]) and LGA (RR 1.14 [95% CI 1.04, 1.24]) were associated with type 1 diabetes in the cohort study. The SGA association remained unchanged in the sibling study, while the LGA association disappeared. Very low birth weight was associated with a reduced risk of type 1 diabetes. CONCLUSIONS: The findings suggest a small association between gestational age and type 1 diabetes that is not likely due to familial confounding factors. Gestational age and type 1 diabetes may be related to insulin resistance due to early life growth restriction or altered gut microbiota in preterm babies. PMID- 26519333 TI - Positivity for Zinc Transporter 8 Autoantibodies at Diagnosis Is Subsequently Associated With Reduced beta-Cell Function and Higher Exogenous Insulin Requirement in Children and Adolescents With Type 1 Diabetes. AB - OBJECTIVE: This study assessed the relationship between autoantibodies against zinc transporter 8 (ZnT8A) and disease characteristics at diagnosis of type 1 diabetes and during the first 2 years. RESEARCH DESIGN AND METHODS: Children, younger than 15 years of age (n = 723) who were newly diagnosed with diabetes, were analyzed for ZnT8A, other diabetes-associated autoantibodies, HLA DR-DQ alleles, and metabolic status, which was monitored by pH, plasma glucose, and occurrence of ketoacidosis at diagnosis and through follow-up of C-peptide concentrations, exogenous insulin dose, and glycosylated hemoglobin for 2 years after the diagnosis. RESULTS: ZnT8A positivity was detected in 530 children (73%). Positivity for ZnT8A was associated with older age (median 8.9 vs. 8.2 years, P = 0.002) and more frequent ketoacidosis (24% vs. 15%, P = 0.013). Children carrying the HLA DR3 allele were less often ZnT8A positive (66% vs. 77%, P = 0.002) than others. ZnT8A-positive children had lower serum C-peptide concentrations (P = 0.008) and higher insulin doses (P = 0.012) over time than their ZnT8A-negative peers. CONCLUSIONS: Positivity for ZnT8A at diagnosis seems to reflect a more aggressive disease process before and after diagnosis. PMID- 26519335 TI - Predictive Value of Admission Hemoglobin A1c on Inpatient Glycemic Control and Response to Insulin Therapy in Medicine and Surgery Patients With Type 2 Diabetes. PMID- 26519336 TI - Issues With the Diagnosis and Classification of Hyperglycemia in Early Pregnancy. PMID- 26519338 TI - Ice Cube Tray-Shaped Insulin Lipoatrophy Throughout the Abdomen in a Subject With Type 2 Diabetes. PMID- 26519337 TI - Clinical Assessment of Individualized Glycemic Goals in Patients With Type 2 Diabetes: Formulation of an Algorithm Based on a Survey Among Leading Worldwide Diabetologists. AB - OBJECTIVE: Observations over the past few years have demonstrated the need to adjust glycemic targets based on parameters pertaining to individual patient characteristics and comorbidities. However, the weight and value given to each parameter will clearly vary depending on the experience of the provider, the characteristics of the patient, and the specific clinical situation. RESEARCH DESIGN AND METHODS: To determine if there is current consensus on a global level with regard to identifying these parameters and their relative importance, we conducted a survey among 244 key worldwide opinion-leading diabetologists. Initially, the physicians were to rank the factors they take into consideration when setting their patients' glycemic target according to their relative importance. Subsequently, six clinical vignettes were presented, and the experts were requested to suggest an appropriate glycemic target. The survey results were used to formulate an algorithm according to which an estimate of the patient's glycemic target based on individualized parameters can be computed. Three additional clinical cases were submitted to a new set of experts for validation of the algorithm. RESULTS: A total of 151 (61.9%) experts responded to the survey. The parameters "life expectancy" and "risk of hypoglycemia from treatment" were considered to be the most important. "Resources" and "disease duration" ranked the lowest. An algorithm was constructed based on survey results. It was validated by presenting three new cases to 57 leading diabetologists who suggested glycemic targets that were similar to those calculated by the algorithm. CONCLUSIONS: The resultant suggested algorithm is an additional decision-making tool offered to the clinician to supplement clinical decision making when considering a glycemic target for the individual patient with diabetes. PMID- 26519339 TI - Memantine ER/Donepezil: A Review in Alzheimer's Disease. AB - A once-daily, fixed-dose combination of memantine extended-release (ER)/donepezil 28/10 mg (NamzaricTM) is available in the USA for patients with moderate to severe Alzheimer's disease (AD) on stable memantine and donepezil therapy. The fixed-dose formulation is bioequivalent to coadministration of the individual drugs. In a 24-week, phase III trial in patients with moderate to severe AD, addition of memantine ER 28 mg once daily to stable cholinesterase inhibitor (ChEI) therapy was more effective than add-on placebo on measures of cognition, global clinical status, dementia behaviour and semantic processing ability, although between-group differences on a measure of daily function did not significantly differ. In subgroup analyses in donepezil-treated patients, add-on memantine ER was more effective than add-on placebo on measures of cognition, dementia behaviour and semantic processing, although there were no significant between-group differences on measures of global clinical status and daily function. Memantine ER plus ChEI combination therapy was generally well tolerated in the phase III trial, with diarrhoea, dizziness and influenza occurring at least twice as often with add-on memantine ER as add-on placebo in donepezil treated patients. Thus, memantine ER plus donepezil combination therapy is an effective and well tolerated treatment option for patients with moderate to severe AD. The fixed-dose combination is potentially more convenient than coadministration of the individual agents. PMID- 26519342 TI - Diversity within the entomopathogenic fungal species Metarhizium flavoviride associated with agricultural crops in Denmark. AB - BACKGROUND: Knowledge of the natural occurrence and community structure of entomopathogenic fungi is important to understand their ecological role. Species of the genus Metarhizium are widespread in soils and have recently been reported to associate with plant roots, but the species M. flavoviride has so far received little attention and intra-specific diversity among isolate collections has never been assessed. In the present study M. flavoviride was found to be abundant among Metarhizium spp. isolates obtained from roots and root-associated soil of winter wheat, winter oilseed rape and neighboring uncultivated pastures at three geographically separated locations in Denmark. The objective was therefore to evaluate molecular diversity and resolve the potential population structure of M. flavoviride. RESULTS: Of the 132 Metarhizium isolates obtained, morphological data and DNA sequencing revealed that 118 belonged to M. flavoviride, 13 to M. brunneum and one to M. majus. Further characterization of intraspecific variability within M. flavoviride was done by using amplified fragment length polymorphisms (AFLP) to evaluate diversity and potential crop and/or locality associations. A high level of diversity among the M. flavoviride isolates was observed, indicating that the isolates were not of the same clonal origin, and that certain haplotypes were shared with M. flavoviride isolates from other countries. However, no population structure in the form of significant haplotype groupings or habitat associations could be determined among the 118 analyzed M. flavoviride isolates. CONCLUSIONS: This study represents the first in-depth analysis of the molecular diversity within a large isolate collection of the species M. flavoviride. The AFLP analysis confirmed a high level of intra specific diversity within the species and lack of apparent association patterns with crop or location indicates limited ecological specialization. The relatively infrequent isolation of M. flavoviride directly from crop roots suggests low dependence of root association for the species. PMID- 26519340 TI - The Female Sexual Response: Current Models, Neurobiological Underpinnings and Agents Currently Approved or Under Investigation for the Treatment of Hypoactive Sexual Desire Disorder. AB - How a woman responds to sexual cues is highly dependent on a number of distinct, yet related, factors. Researchers have attempted to explain the female sexual response for decades, but no single model reigns supreme. Proper female sexual function relies on the interplay of somatic, psychosocial and neurobiological factors; misregulation of any of these components could result in sexual dysfunction. The most common sexual dysfunction disorder is hypoactive sexual desire disorder (HSDD). HSDD is a disorder affecting women across the world; a recent in-person diagnostic interview study conducted in the USA found that an estimated 7.4% of US women suffer from HSDD. Despite the disorder's prevalence, it is often overlooked as a formal diagnosis. In a survey of primary care physicians and obstetrics/gynaecology specialists, the number one reason for not assigning an HSDD diagnosis was the lack of a safe and effective therapy approved by the US Food and Drug Administration (FDA). This changed with the recent FDA approval of flibanserin (AddyiTM) for the treatment of premenopausal women with acquired, generalized HSDD; there are still, however, no treatments approved outside the USA. HSDD is characterized by a marked decrease in sexual desire, an absence of motivation (also known as avolition) to engage in sexual activity, and the condition's hallmark symptom, marked patient distress. Research suggests that HSDD may arise from an imbalance of the excitatory and inhibitory neurobiological pathways that regulate the mammalian sexual response; top-down inhibition from the prefrontal cortex may be hyperactive, and/or bottom-up excitation to the limbic system may be hypoactive. Key neuromodulators for the excitatory pathways include norepinephrine, oxytocin, dopamine and melanocortins. Serotonin, opioids and endocannabinoids serve as key neuromodulators for the inhibitory pathways. Evolving treatment strategies have relied heavily on these crucial research findings, as many of the agents currently being investigated as treatment options for HSDD target and influence key players within these excitatory and inhibitory pathways, including various hormone therapies and centrally acting drugs, such as buspirone, bupropion and bremelanotide. PMID- 26519343 TI - The Native Plasmid pML21 Plays a Role in Stress Tolerance in Enterococcus faecalis ML21, as Analyzed by Plasmid Curing Using Plasmid Incompatibility. AB - To investigate the role of the native plasmid pML21 in Enterococcus faecalis ML21's response to abiotic stresses, the plasmid pML21 was cured based on the principle of plasmid incompatibility and segregational instability, generating E. faecalis mutant strain ML0. The mutant and the wild strains were exposed to abiotic stresses: bile salts, low pH, H2O2, ethanol, heat, and NaCl, and their survival rate was measured. We found that curing of pML21 lead to reduced tolerance to stress in E. faecalis ML0, especially oxidative and osmotic stress. Complementation analysis suggested that the genes from pML21 played different role in stress tolerance. The result indicated that pML21 plays a role in E. faecalis ML21's response to abiotic stresses. PMID- 26519341 TI - Impact of Antidepressant Drugs on Sexual Function and Satisfaction. AB - Pleasurable sexual activity is important in many human relationships and can provide a sense of physical, emotional and social well-being. Depressive symptoms and depressive illness are associated with impairments in sexual function and sexual dissatisfaction in untreated and treated patients. Most currently available antidepressant drugs are associated with development or worsening of sexual dysfunction in a substantial proportion of patients. Sexual difficulties during antidepressant treatment often resolve as depression lifts, but can persist over long periods, reducing self-esteem and affecting mood and relationships adversely. Sexual difficulties during antidepressant treatment typically have many possible causes but the incidence and nature of dysfunction varies between drugs. Many interventions can be considered when managing sexual dysfunction associated with antidepressants but no approach is 'ideal'. Because treatment-emergent sexual difficulties are less frequent with certain drugs, presumably related to differences in pharmacological properties, and since current interventions are suboptimal, a lower incidence of sexual dysfunction is a relevant tolerability target when developing novel antidepressants. PMID- 26519344 TI - A Novel Potential Signal Peptide Sequence and Overexpression of ER-Resident Chaperones Enhance Heterologous Protein Secretion in Thermotolerant Methylotrophic Yeast Ogataea thermomethanolica. AB - The thermotolerant methylotrophic yeast Ogataea thermomethanolica is a host for heterologous protein expression via secretion to the culture medium. Efficient secretion is a major bottleneck for heterologous protein production in this strain. To improve protein secretion, we explored whether the use of a native signal peptide sequence for directing heterologous protein secretion and overexpression of native ER-resident chaperone genes could improve heterologous protein secretion in O. thermomethanolica. We cloned and characterized genes encoding alpha-mating factor (Otalpha-MF) and ER-resident chaperones OtBiP, OtCNE1, and OtPDI. The pre and pre-pro sequences of Otalpha-MF were shown to promote higher secretion of heterologous endoxylanase comparing with the classical pre-pro sequence of Saccharomyces cerevisiae. However, in the case of heterologous glycosylated phytase, only the Otalpha-MF pre-pro sequence significantly enhanced protein secretion. The effect of chaperone overexpression on heterologous protein secretion was tested in cotransformant cells of O. thermomethanolica. Overexpression of ER-resident chaperones improved protein secretion depending on heterologous protein. Overexpression of OtBiP, OtCNE1, and OtPDI significantly increased unglycosylated endoxylanase secretion at both 30 and 37 degrees C while only OtBiP overexpression enhanced glycosylated phytase secretion at 30 degrees C. These observations suggested the possibility to improve heterologous protein secretion in O. thermomethanolica. PMID- 26519346 TI - Empirical investigation on safety constraints of merging pedestrian crowd through macroscopic and microscopic analysis. AB - A recent crowd stampede during a New Year's Eve celebration in Shanghai, China resulted in 36 fatalities and over 49 serious injuries. Many of such tragic crowd accidents around the world resulted from complex multi-direction crowd movement such as merging behavior. Although there are a few studies on merging crowd behavior, none of them have conducted a systematic analysis considering the impact of both merging angle and flow direction towards the safety of pedestrian crowd movement. In this study, a series of controlled laboratory experiments were conducted to examine the safety constraints of merging pedestrian crowd movements considering merging angle (60 degrees , 90 degrees and 180 degrees ) and flow direction under slow running and blocked vision condition. Then, macroscopic and microscopic properties of crowd dynamics are obtained and visualized through the analysis of pedestrian crowd trajectory data derived from video footage. It was found that merging angle had a significant influence on the fluctuations of pedestrian flows, which is important in a critical situation such as emergency evacuation. As the merging angle increased, mean velocity and mean flow at the measuring region in the exit corridors decreased, while mean density increased. A similar trend was observed for the number of weaving and overtaking conflicts, which resulted in the increase of mean headway. Further, flow direction had a significant impact on the outflow of the individuals while blocked vision had an influence on pedestrian crowd interactions and merging process. Finally, this paper discusses safety assessments on crowd merging behaviors along with some recommendations for future research. Findings from this study can assist in the development and validation of pedestrian crowd simulation models as well as organization and control of crowd events. PMID- 26519345 TI - Dexamethasone intravitreal implant in previously treated patients with diabetic macular edema: subgroup analysis of the MEAD study. AB - BACKGROUND: Dexamethasone intravitreal implant 0.7 mg (DEX 0.7) was approved for treatment of diabetic macular edema (DME) after demonstration of its efficacy and safety in the MEAD registration trials. We performed subgroup analysis of MEAD study results to evaluate the efficacy and safety of DEX 0.7 treatment in patients with previously treated DME. METHODS: Three-year, randomized, sham controlled phase 3 study in patients with DME, best-corrected visual acuity (BCVA) of 34-68 Early Treatment Diabetic Retinopathy Study letters (20/200-20/50 Snellen equivalent), and central retinal thickness (CRT) >= 300 MUm measured by time-domain optical coherence tomography. Patients were randomized to 1 of 2 doses of DEX (0.7 mg or 0.35 mg), or to sham procedure, with retreatment no more than every 6 months. The primary endpoint was >= 15-letter gain in BCVA at study end. Average change in BCVA and CRT from baseline during the study (area-under the-curve approach) and adverse events were also evaluated. The present subgroup analysis evaluated outcomes in patients randomized to DEX 0.7 (marketed dose) or sham based on prior treatment for DME at study entry. RESULTS: Baseline characteristics of previously treated DEX 0.7 (n = 247) and sham (n = 261) patients were similar. In the previously treated subgroup, mean number of treatments over 3 years was 4.1 for DEX 0.7 and 3.2 for sham, 21.5% of DEX 0.7 patients versus 11.1 % of sham had >= 15-letter BCVA gain from baseline at study end (P = 0.002), mean average BCVA change from baseline was +3.2 letters with DEX 0.7 versus +1.5 letters with sham (P = 0.024), and mean average CRT change from baseline was -126.1 MUm with DEX 0.7 versus -39.0 MUm with sham (P < .001). Cataract-related adverse events were reported in 70.3% of baseline phakic patients in the previously treated DEX 0.7 subgroup; vision gains were restored following cataract surgery. CONCLUSIONS: DEX 0.7 significantly improved visual and anatomic outcomes in patients with DME previously treated with laser, intravitreal anti-vascular endothelial growth factor, intravitreal triamcinolone acetonide, or a combination of these therapies. The safety profile of DEX 0.7 in previously treated patients was similar to its safety profile in the total study population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00168337 and NCT00168389, registered 12 September 2005. PMID- 26519347 TI - Characteristics of Clinical and Induced Ventricular Tachycardia Throughout Multiple Ablation Procedures. AB - BACKGROUND: Optimal procedure endpoints of catheter ablation for ventricular tachycardia (VT) are not defined and multiple repeat procedures are sometimes required. However, there are few studies to compare the details of repeat procedures to the initial procedure. The aim of this study is to compare the characteristics of clinical and induced VT throughout multiple procedures and clarify their relations. METHODS AND RESULTS: Of 425 consecutive patients with structural heart disease who underwent catheter VT ablation, second, third and fourth procedures were performed in 101, 23, and 5 patients, respectively. Of 227 VTs that were induced during the second procedure, 68 (30%) VTs had previously been induced at the first procedure. In multivariable analysis, identification of an exit/isthmus site (HR = 0.29, P = 0.047), early termination of VT during radiofrequency application (HR 0.11, P = 0.037) and elimination of target VT at the end of first procedure (HR = 0.43, P = 0.036) were independently associated with noninducibility of the same VT at the second procedure. Over the course of multiple procedures the mean VT cycle length gradually lengthened (381 +/- 107, 413 +/- 111, 460 +/- 124, 507 +/- 99 milliseconds in first, second, third, and fourth procedure, respectively, P < 0.001) and more induced VTs became mappable (32%, 40%, 62%, and 70% in first, second, third, and fourth procedure, respectively, P < 0.001). CONCLUSIONS: Identification and ablation of VT exit/isthmus, early termination of VT during radiofrequency application and elimination of targeted VT are associated with absence of that VT during a repeat procedure, and recurrences are then mostly due to new VTs or other VTs that were not induced at the first procedure. PMID- 26519348 TI - XRCC1 rs25487 genetic variant and TP53 mutation at codon 249 predict clinical outcomes of hepatitis B virus-related hepatocellular carcinoma after hepatectomy: A cohort study for 10 years' follow up. AB - AIM: To investigate the effects of rs25487 (the DNA repair gene: x-ray repair complementing defective repair in Chinese hamster cells 1 [XRCC1]) and codon 249 mutation (TP53 gene) on clinical outcomes of post-hepatectomy hepatitis B virus (HBV)-related HCC. METHODS: The XRCC1 rs25487 polymorphism and TP53 mutation at codon 249 of 485 hepatitis B surface antigen positive patients subjected to hepatectomy were genotyped via direct sequencing. SPSS software version 16.0 (SPSS, Chicago, IL, USA) was used to calculate survival of HCC patients according to primary end-points. RESULTS: The presence of at least one A allele (AA/AG) of rs25487 was associated with unfavorable prognosis (P = 0.005). Moreover, A allele (AA/AG) carriers were significantly associated with high risk of vascular invasion (P = 0.025) and regional invasion (P = 0.005). Differences were not significant between mutant and wild-type TP53 cases with overall survival (adjusted P = 0.400). Among the 485 participants, patients (n = 73) carrying both the A allele (AA/AG) of rs25487 and 249Ser TP53 mutation displayed decreased overall survival, compared with patients (n = 184) with the GG genotype of rs25487 and wild-type codon 249 (adjusted P = 0.007). CONCLUSION: Polymorphisms of rs25487 may play a potential role in survival of HBV-related hepatocellular carcinoma patients following hepatectomy. While mutation at codon 249 of TP53 is not associated with HBV-related HCC survival in this study. PMID- 26519349 TI - Relation between exercise central haemodynamic response and resting cardiac structure and function in young healthy men. AB - BACKGROUND: Left ventricular (LV) structure and function are predictors of cardiovascular (CV) morbidity and mortality and are related to resting peripheral haemodynamic load in older adults. The central haemodynamic response to exercise may reveal associations with LV structure and function not detected by traditional peripheral (brachial) measures in a younger population. PURPOSE: To examine correlations between acute exercise-induced changes in central artery stiffness and wave reflections and measures of resting LV structure and function. METHODS: Sixteen healthy men (age 26 +/- 6 year; BMI 25.3 +/- 2.7 kg m-2 ) had measures of central haemodynamic load measured before/after a 30-s Wingate anaerobic test (WAT). Common carotid artery stiffness and reflected wave intensity were assessed via wave intensity analysis as a regional pulse wave velocity (PWV) and negative area (NA), respectively. Resting LV structure (LV mass) and function [midwall fractional shortening (mFS)] were assessed using M mode echocardiography in the parasternal short-axis view. RESULTS: There was a significant association between mFS and WAT-mediated change in carotid systolic BP (r = -0.57, P = 0.011), logNA (r = -0.58, P = 0.009) and PWV (r = -0.44, P = 0.045). There were no significant associations between resting mFS and changes in brachial systolic BP (r = -0.26, P>0.05). There were no associations between resting LV mass and changes in any haemodynamic variable (P>0.05). CONCLUSION: Exercise-induced increases in central haemodynamic load reveal associations with lower resting LV function in young healthy men undetected by traditional peripheral haemodynamics. PMID- 26519351 TI - EDUCATION AND IMAGING. Gastrointestinal: Duodenal metastatic epithelioid angiosarcoma. PMID- 26519350 TI - Stability of Phosphatidylethanol in Dry Blood Spot Cards. AB - BACKGROUND: The analysis of phosphatidylethanol, a promising direct ethanol metabolite, in dry blood spots (PEth-DBS) is advantageous due to ease of storage, transportation and minimal invasiveness of capillary blood collection. One potential application of PEth-DBS is to confirm prenatal alcohol exposure in newborns suspected of FASD; however, stability of PEth-DBS is largely unknown. METHODS: Phlebotomized samples from 31 adults with a history of alcoholism, admitted to the University of New Mexico Emergency Department, were analyzed for blood alcohol content and pipetted onto DBS cards (13 spots per patient). The first spot was analyzed within 2 weeks of collection for a baseline PEth; the remaining 12 spots were allocated into three temperature conditions (room temperature, 4 degrees C, -80 degrees C) for the repeated measures analysis. In addition, 5 newborn DBS samples with a baseline PEth>LOD were obtained from a prospective cohort at UNM and re-analyzed at 4 months after storage at -80 degrees C. A mixed linear model was fitted to examine the effects of temperature, time and temperature-time interaction on PEth degradation over the first 9 months. RESULTS: The baseline PEth levels were 592.8 +/- 86.7 ng/ml and 18.3 +/- 4.8 ng/ml in adult and newborn samples, respectively. All DBS samples remained positive in successive samples in all temperature conditions. Results of mixed linear model demonstrated a significant effect of temperature (P < 0.001) on PEth degradation over 9 months. CONCLUSIONS: PEth-DBS appears to be relatively stable, especially when stored at lower temperatures. These initial results are encouraging and highlight the PEth-DBS potential in retrospective assessment of alcohol exposure. PMID- 26519352 TI - Co-occurrence of nevus anemicus and Becker nevus: a possible instance of pseudodidymosis? PMID- 26519353 TI - Important role of phosphoramido linkage in imidazole-based dioleyl helper lipids for liposome stability and primary cell transfection. AB - BACKGROUND: To optimize synthetic gene delivery systems, there is a need to develop more efficient lipid formulations. Most cationic lipid formulations contain 'helper' neutral lipids because of their ability to increase DNA delivery, in particular by improving endosomal escape of DNA molecules via the pH buffering effect of protonatable groups and/or fusion with the lipid bilayer of endosomes. METHODS: We evaluated the influence of the linker structure between the two oleyl chains in the helper lipid on transfection efficiency in cell lines, as well as in primary cells (hepatocytes/cardiomyocytes). We reported the synthesis of two new pH-buffering imidazole helper lipids characterized by a polar headgroup containing one (compound 6) or two (compound 5) imidazole groups and two oleyl chains linked by an amide group. We studied their association with the aminoglycoside lipidic derivative dioleylsuccinylparomomycin (DOSP), which contains two oleyl chains linked to the aminoglycoside polar headgroup via an amide function. We compared the morphology and transfection properties of such binary liposomes of DOSP/5 and DOSP/6 with those of liposomes combining DOSP with another imidazole-based dioleyl helper lipid (MM27) in which a phosphoramido group acts as a linker between the two oleyl chains and imidazole function. RESULTS: The phosphoramido linker in the helper lipid induces a major difference in terms of morphology and resistance to decomplexation at physical pH for DOSP/helper lipid complexes. CONCLUSIONS: This hybrid dioleyl linker composition of DOSP/MM27 led to higher transfection efficiency in cell lines and in primary cells compared to complexes with homogeneous dioleyl linker. PMID- 26519354 TI - Discovery of a Partner Affair and Major Depressive Episode in a Probability Sample of Married or Cohabiting Adults. AB - Prior research has found that humiliating marital events are associated with depression. Building on this research, the current study investigated the association between one specific humiliating marital event-discovering that one's partner had an affair-and past-year major depressive episode (MDE) in a probability sample of married or cohabiting men and women who were at high risk for depression based on the criterion that they scored below the midpoint on a measure of marital satisfaction (N = 227). Results indicate that (i) women were more likely than men to report discovering their partner had an affair in the prior 12 months; (ii) discovering a partner affair was associated with a higher prevalence of past-year MDE and a lower level of marital adjustment; and (iii) the association between discovering a partner affair and MDE remained statistically significant when holding constant demographic variables and marital adjustment. These results support continued investigation into the impact that finding out about an affair has on the mental health of the person discovering a partner affair. PMID- 26519355 TI - Highly Pathogenic Avian Influenza H5N8 in Germany: Outbreak Investigations. AB - Epidemiological outbreak investigations were conducted in highly pathogenic avian influenza virus of the subtype H5N8 (HPAIV H5N8)-affected poultry holdings and a zoo to identify potential routes of entry of the pathogen via water, feedstuffs, animals, people, bedding material, other fomites (equipment, vehicles etc.) and the presence of wild birds near affected holdings. Indirect introduction of HPAIV H5N8 via material contaminated by infected wild bird seems the most reasonable explanation for the observed outbreak series in three commercial holdings in Mecklenburg-Western Pomerania and Lower Saxony, while direct contact to infected wild birds may have led to outbreaks in a zoo in Rostock and in two small free range holdings in Anklam, Mecklenburg-Western Pomerania. PMID- 26519357 TI - Phosphine Poisoning is Emerging as an Important Cause of Brugada Phenocopy. PMID- 26519356 TI - Intracortical connections are altered after long-standing deprivation of dorsal column inputs in the hand region of area 3b in squirrel monkeys. AB - A complete unilateral lesion of the dorsal column somatosensory pathway in the upper cervical spinal cord deactivates neurons in the hand region in contralateral somatosensory cortex (areas 3b and 1). Over weeks to months of recovery, parts of the hand region become reactivated by touch on the hand or face. To determine whether changes in cortical connections potentially contribute to this reactivation, we injected tracers into electrophysiologically identified locations in cortex of area 3b representing the reactivated hand and normally activated face in adult squirrel monkeys. Our results indicated that even when only partially reactivated, most of the expected connections of area 3b remained intact. These intact connections include the majority of intrinsic connections within area 3b; feedback connections from area 1, secondary somatosensory cortex (S2), parietal ventral area (PV), and other cortical areas; and thalamic inputs from the ventroposterior lateral nucleus (VPL). In addition, tracer injections in the reactivated hand region of area 3b labeled more neurons in the face and shoulder regions of area 3b than in normal monkeys, and injections in the face region of area 3b labeled more neurons in the hand region. Unexpectedly, the intrinsic connections within area 3b hand cortex were more widespread after incomplete dorsal column lesions (DCLs) than after a complete DCL. Although these additional connections were limited, these changes in connections may contribute to the reactivation process after injuries. J. Comp. Neurol. 524:1494-1526, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26519358 TI - A novel actor in skin biology: the mineralocorticoid receptor. PMID- 26519359 TI - Guideline concordant detection and management of depression among Alaska Native and American Indian people in primary care. AB - BACKGROUND: A tribal health organization in Alaska implemented a primary care depression screening, detection and management initiative amongst 55,000 Alaska Native/American Indian people (AN/AIs). OBJECTIVES: (a) To describe the proportion of AN/AIs screening positive for depression with depression noted or diagnosed and proportion with guideline concordant management and (b) to assess whether management varied by patient and provider factors. RESEARCH DESIGN: Secondary analysis of electronic and paper medical record information of 400 AN/AIs. MEASURES: Provider variables, patient demographics and patient clinical factors were electronically queried. Manual chart audits assessed depression notation, diagnoses and management within 12 weeks of positive screening. Multilevel ordinal logistic modelling assessed management by patient and provider factors. RESULTS: A depression diagnosis was present in 141 (35%) charts and 151 (38%) had depressive symptoms noted. Detection was higher among AN/AIs with moderate and severe depression (p<0.001). In total, 258 patients (66%) received guideline concordant management, 32 (8%) had some management, and 110 (28%) received no management. Younger patient age and increased provider tenure increased odds of management. CONCLUSIONS: Most AN/AIs screening positive for depression received initial guideline concordant management. Additional outreach to older patients and additional support for providers newer to practices appears warranted. PMID- 26519360 TI - Endothelial properties of third-trimester amniotic fluid stem cells cultured in hypoxia. AB - INTRODUCTION: Endothelial dysfunction is found in different pathologies such as diabetes and renal and heart diseases, representing one of the major health problems. The reduced vasodilation of impaired endothelium starts a prothrombotic state associated with irregular blood flow. We aimed to explore the potential of amniotic fluid stem (AFS) cells as a source for regenerative medicine in this field; for the first time, we focused on third-trimester amniotic fluid AFS cells and compared them with the already-described AFS cells from the second trimester. METHODS: Cells from the two trimesters were cultured, selected and expanded in normoxia (20 % oxygen) and hypoxia (5 % oxygen). Cells were analysed to compare markers, proliferation rate and differentiation abilities. Endothelial potential was assessed not only in vitro-Matrigel tube formation assay, acetylated human low-density lipoprotein (AcLDL) uptake-but also in vivo (Matrigel plug with cell injection and two animal models). Specifically, for the latter, we used established protocols to assess the involvement of AFS cells in two different mouse models of endothelial dysfunction: (1) a chronic ischemia model with local injection of cells and (2) an electric carotid damage where cells were systemically injected. RESULTS: We isolated and expanded AFS cells from third trimester amniotic fluid samples by using CD117 as a selection marker. Hypoxia enhanced the proliferation rate, the surface protein pattern was conserved between the trimesters and comparable differentiation was achieved after culture in both normoxia and hypoxia. Notably, the expression of early endothelial transcription factors and AngiomiRs was detected before and after induction. When in vivo, AFS cells from both trimesters expanded in hypoxia were able to rescue the surface blood flow when locally injected in mice after chronic ischemia damage, and importantly AFS cells at term of gestation possessed enhanced ability to fix carotid artery electric damage compared with AFS cells from the second trimester. CONCLUSIONS: To the best of our knowledge, this is the first research work that fully characterizes AFS cells from the third trimester for regenerative medicine purposes. The results highlight how AFS cells, in particular at term of gestation and cultured in hypoxia, can be considered a promising source of stem cells possessing significant endothelial regenerative potential. PMID- 26519361 TI - Cytometry-based single-cell analysis of intact epithelial signaling reveals MAPK activation divergent from TNF-alpha-induced apoptosis in vivo. AB - Understanding heterogeneous cellular behaviors in a complex tissue requires the evaluation of signaling networks at single-cell resolution. However, probing signaling in epithelial tissues using cytometry-based single-cell analysis has been confounded by the necessity of single-cell dissociation, where disrupting cell-to-cell connections inherently perturbs native cell signaling states. Here, we demonstrate a novel strategy (Disaggregation for Intracellular Signaling in Single Epithelial Cells from Tissue-DISSECT) that preserves native signaling for Cytometry Time-of-Flight (CyTOF) and fluorescent flow cytometry applications. A 21-plex CyTOF analysis encompassing core signaling and cell-identity markers was performed on the small intestinal epithelium after systemic tumor necrosis factor alpha (TNF-alpha) stimulation. Unsupervised and supervised analyses robustly selected signaling features that identify a unique subset of epithelial cells that are sensitized to TNF-alpha-induced apoptosis in the seemingly homogeneous enterocyte population. Specifically, p-ERK and apoptosis are divergently regulated in neighboring enterocytes within the epithelium, suggesting a mechanism of contact-dependent survival. Our novel single-cell approach can broadly be applied, using both CyTOF and multi-parameter flow cytometry, for investigating normal and diseased cell states in a wide range of epithelial tissues. PMID- 26519362 TI - Inflating bacterial cells by increased protein synthesis. AB - Understanding how the homeostasis of cellular size and composition is accomplished by different organisms is an outstanding challenge in biology. For exponentially growing Escherichia coli cells, it is long known that the size of cells exhibits a strong positive relation with their growth rates in different nutrient conditions. Here, we characterized cell sizes in a set of orthogonal growth limitations. We report that cell size and mass exhibit positive or negative dependences with growth rate depending on the growth limitation applied. In particular, synthesizing large amounts of "useless" proteins led to an inversion of the canonical, positive relation, with slow growing cells enlarged 7 to 8-fold compared to cells growing at similar rates under nutrient limitation. Strikingly, this increase in cell size was accompanied by a 3- to 4-fold increase in cellular DNA content at slow growth, reaching up to an amount equivalent to ~8 chromosomes per cell. Despite drastic changes in cell mass and macromolecular composition, cellular dry mass density remained constant. Our findings reveal an important role of protein synthesis in cell division control. PMID- 26519363 TI - Doublet BRAF/MEK inhibition versus single-agent BRAF inhibition in the management of BRAF-mutant advanced melanoma, biological rationale and meta-analysis of published data. AB - BACK GROUND: We executed a comparative systematic review and meta-analysis of the efficacy and toxicity of doublet BRAF/MEK inhibition versus single-agent BRAF inhibitor in the management of BRAF-mutant advanced melanoma. METHODS: Eligible studies included prospective studies evaluating doublet regimens versus BRAF inhibitor monotherapy for the management of BRAF-mutant advanced melanoma. RESULTS: Our search strategy yielded 200 potentially relevant citations from searched databases. After preclusion of ineligible studies, four studies were included in the final analysis. Efficacy analyses demonstrate that BRAF/MEK inhibition strategy is associated with a significant improvement in ORR [OR 1.35; 95 % CI (1.16, 1.58); P = 0.0002], PFS [HR 0.56; 95 % CI (0.49, 0.64); P < 0.00001] and OS [HR 0.70; 95 % CI (0.58, 0.84); P = 0.0001]. Moreover, this combination is associated with a higher RR for diarrhea [1.30; 95 % CI (1.30, 1.49); P = 0.0002], decreased ejection fraction [4.63; 95 % CI (2.56, 8.37); P = <0.00001], acneiform dermatitis [1.61; 95 % CI (1.03, 2.53); P = 0.04] and pyrexia [1.98; 95 % CI (1.72, 2.27); P < 0.00001]. CONCLUSIONS: Our meta-analysis has demonstrated that combination of MEK/BRAF inhibitors is associated with higher ORR, PFS and OS. However, this comes at the expense of a higher risk of selected toxicities. PMID- 26519364 TI - Late recurrence (more than 10 years) in early (tumors equal to or smaller than 2 cm) breast cancer patients. PMID- 26519365 TI - Wavelength-dependent photooxidation and photoreduction of protochlorophyllide and protochlorophyll in the innermost leaves of cabbage (Brassica oleracea var. capitata L.). AB - The photoreduction and photooxidation processes of different protochlorophyll(ide) forms were studied in the innermost leaves of cabbage (Brassica oleracea var. capitata L.) under monochromatic irradiations. Room temperature fluorescence emission spectra were measured from the same leaf spots before and after illumination to follow the wavelength dependence of the photochemical reactions. Short-wavelength light of 7 umol photons m(-2) s(-1) (625-630 nm) provoked mainly bleaching, and longer wavelengths (630-640 nm) caused both bleaching and photoreduction, while above 640 nm resulted in basically photoreduction. When bleached leaves were kept in darkness at room temperature, all protochlorophyll(ide) forms regenerated during 72 h. Oxygen reduced environment decreased the extent of bleaching suggesting the involvement of reactive oxygen species. These results confirm that the short-wavelength, 628 nm absorbing, and 633 nm emitting protochlorophyll(ide) form in etiolated cabbage leaves sensibilizes photooxidation. However, the 628 nm light at low intensities stimulates the photoreduction of the longer wavelength protochlorophyllide forms. Kinetic measurements showed that photoreduction saturates at a low PFD (photon flux density) compared to bleaching, suggesting that the quantum yield of photoreduction is higher than that of bleaching. PMID- 26519366 TI - Perspective Taking Explains Gender Differences in Late Adolescents' Attitudes Toward Disadvantaged Groups. AB - Adolescents' attitudes toward disadvantaged groups are surprisingly understudied. What we know from these few studies is that adolescents' attitudes tend to become more favorable over time and that adolescent girls display more favorable attitudes than do adolescent boys. However, researchers have not offered explanations for why these effects occur. We proposed that changes in social cognitive abilities that accompany adolescent development increase perspective taking and that the increased perspective taking facilitates more favorable attitudes toward disadvantaged groups. Because girls develop social-cognitive abilities earlier than boys, girls should show greater perspective taking and thus more positive attitudes toward disadvantaged groups than should boys. Importantly, we propose that these more positive attitudes are explained better by perspective taking than by gender. Participants were late adolescents (n = 803, 53.3 % female, ages 15-19) from high schools in north-central Florida (United States) participating in an ongoing, multi-wave study. Participants completed a measure of perspective-taking and reported their attitudes toward three disadvantaged groups (Black, gay, and poor people) during their third year of high school and, again, 6 months later during their fourth year of high school. Our findings provided strong support for our theorizing. Girls generally reported warmer attitudes than did boys toward disadvantaged groups, with the gender differences in warmth tending to diminish across time. Similarly, girls were higher than boys in perspective-taking abilities at both time points, although boys increased over time whereas girls did not. Crucially, perspective taking mediated observed gender differences in attitudes, suggesting that perspective taking is a mechanism for improving attitudes toward disadvantaged groups during late adolescence. PMID- 26519368 TI - Perceived Peer Delinquency and Externalizing Behavior Among Rural Youth: The Role of Descriptive Norms and Internalizing Symptoms. AB - Little research has examined the way in which perceptions of peer behavior (i.e., descriptive norms) influence externalizing behavior among rural adolescents. Using a social norms framework, the current study examined gender differences in the relationship between perceived delinquency among friends and externalizing behavior in a sample of rural adolescents. Based on previous research, the authors proposed that adolescents experience negative emotional responses when they believe that their peers are engaging in delinquency, which subsequently influences externalizing behavior. Consequently, internalizing symptoms were explored as a mediator of the relationship between perceived friend delinquency and externalizing behavior. Data came from the NC-ACE Rural Adaptation Project, a longitudinal panel study of adolescents in two rural, economically disadvantaged counties with exceptional racial/ethnic diversity (29 % White, 25 % African American, 25 % American Indian, 12 % Mixed Race/Other, 9 % Hispanic/Latino). Using multiple group structural equation modeling (N = 3489; 51 % female), results indicated that perceived friend delinquency was significantly related to externalizing behavior and this relationship did not vary by gender. Internalizing symptoms fully mediated the relationship between perceived friend delinquency and externalizing behavior and the path between perceived friend delinquency and internalizing symptoms was stronger for males. Implications of these relationships for prevention and intervention programming for externalizing behavior were highlighted. PMID- 26519369 TI - Regional Cortical Surface Area in Adolescents: A Preliminary MRI Twin Study of Genetic and Environmental Contributions. AB - Cortical surface area (CSA) has particular relevance for understanding development, behavior, and the connection between brain structure and function. Little is known about genetic and environmental determinants of CSA during development. We utilized bivariate twin methods to identify global and regionally specific genetic factors which influence CSA in a preliminary sample of typically developing adolescents, with hypotheses based on findings in middle-aged adults. Similar to previous findings, we observed high heritability for total CSA. There was also significant evidence for genetic influences on regional CSA, particularly when these were not adjusted for total CSA, with highest heritability in frontal cortex and relatively fewer genetic contributions to medial temporal cortical structures. Adjustment for total CSA reduced regional CSA heritability dramatically, but a moderate influence of genetic factors remained in some regions. Both global and regionally-specific genetic factors influence regional CSA during adolescence. PMID- 26519370 TI - Insights from mathematical modelling for T cell migration into the central nervous system. AB - The migration of immune cells from peripheral immune organs into the central nervous system (CNS) through the blood-brain barrier (BBB) is a tightly regulated process. The complex interplay between cells of the BBB and immune cells coordinates cell migration as a part of normal immune surveillance while its dysregulation is critically involved in the pathogenesis of various CNS diseases. To develop tools for a deeper understanding of distribution and migratory pattern of immune cells regulated by the BBB, we made use of a mathematical modelling approach derived from Markov chain theory. We present a data-driven model using a derivation of kinetic differential equations from a particle game. According to the theory of gases, these equations allow one to predict the mean behaviour of a large class of cells by modelling cell-cell interactions. We used this model to assess the distribution of naive, central memory and effector memory T lymphocytes in the peripheral blood and cerebrospinal fluid. Our model allows us to evaluate the impact of activation status, migratory capacity and cell death for cell distribution in the peripheral blood and the CNS. PMID- 26519371 TI - Evidence of autoantibodies against cardiac troponin I and sarcomeric myosin in peripartum cardiomyopathy. AB - Peripartum cardiomyopathy (PPCM) is a major cause of pregnancy-related maternal heart failure that develops towards the end of pregnancy or in the months following delivery. In small retrospective case series, autoimmune responses in the pathogenesis of PPCM have been proposed upon identification of autoantibodies (AABs) to cardiac antigens. However, their clinical and prognostic relevance still remain unclear. In this study, we evaluated the presence of circulating AABs against cardiac sarcomeric myosin (MHC) and troponin I (TnI) in the sera of PPCM patients and in relation to clinical presentation. In this case-control study, 70 patients diagnosed with PPCM and 50 pregnancy-matched healthy women with normal cardiac function were enrolled. Clinical assessment, echocardiography and blood tests were performed at baseline and at 6 +/- 2 months follow-up. The presence of serum AABs against MHC (anti-MHC) and TnI (anti-TnI) was determined with a custom-made enzyme-linked immunosorbent assay (ELISA). The seropositivity for these AABs was correlated with the severity of LV dysfunction and the occurrence of pericardial effusion indicative of perimyocardial inflammation at baseline. Potential impact of these AABs on disease progression was evaluated with regard to functional (left ventricular ejection fraction) and clinical improvement at follow-up. Either anti-MHC or anti-TnI or both AABs were detected in the serum of 46 % of PPCM patients and in 8 % of healthy controls. In PPCM the presence of either one of these AABs was associated with significantly lower baseline LVEF and lower rate of full cardiac recovery at follow-up. Patients who were seropositive for anti-TnI AABs showed more frequently pericardial effusion indicative of a more pronounced immune response of the peri-/myocardium in these patients. Further studies are required to clarify cellular and molecular circuits leading to elevated levels of AABs and their pathophysiological relevance for disease initiation and progression in PPCM. PMID- 26519372 TI - Historical responsibility and great trust of the times--review and outlook of 60 years of integrative medicine clinical sciences. PMID- 26519373 TI - Incorporating pattern identification of Chinese medicine into precision medicine: An integrative model for individualized medicine. AB - On 20 January, 2015, U.S. President Obama announced an ambitious plan called "Precision Medicine (PM) Initiative", aiming to deliver genetics-based medical treatments. PM has shown a promising prospect by tailoring disease treatments and preventions to individuals. However, a predominantly genetics-based method restricts its benefit and applicability in most chronic and complex diseases. Pattern identification (PI) is one of the representative characteristics of Chinese medicine implying the concept of holism and individualized treatment. It is another classification method taking environmental, psychosocial and other individual factors into account. Integrating PI with disease diagnosis of Western medicine will provide a strong complement to genetics-based PM, thus establish an integrative model for individualized medicine. PI provides new perspectives for PM, not only in clinical practice, but also in new drug development and clinical trial design. It is for sure that the integrative approach will ultimately lead to a safer, more convenient and effective patient-centered healthcare and most patients will benefit in the era of PM. PMID- 26519374 TI - The Core Outcome Measures Index (COMI) is a responsive instrument for assessing the outcome of treatment for adult spinal deformity. AB - INTRODUCTION: The Core Outcome Measures Index for the back (COMI-back) is a very brief instrument for assessing the main outcomes of importance to patients with back problems (pain, function, symptom-specific well-being, quality of life, disability). However, it might be expected to be less responsive than a disease specific instrument when evaluating specific pathologies. In patients with adult spinal deformity, we compared the performance of COMI-back with the widely accepted SRS-22 questionnaire. METHODS: At baseline and 12 months after non operative (N = 121) and surgical (N = 83) treatment, patients (175 F, 29 M) completed the following: COMI-back, SRS-22, Oswestry Disability Index (ODI) and SF-36 PCS. At 12 months' follow-up, patients also indicated on a 15-point Global Rating of Change Scale (GRCS) how their back problem had changed relative to 1 year ago. Construct validity for the COMI-back was assessed by the correlation between its scores and those of the comparator instruments; responsiveness was assessed with receiver operating characteristics (ROC) analysis of COMI-back change scores versus the criterion 'treatment success' (dichotomized GRCS). RESULTS: Baseline values for the COMI-back showed significant (p < 0.0001) correlations with SRS-22 (r = -0.85), ODI (r = 0.83), and SF-36 PCS (r = -0.82) scores; significantly worse scores for all measures were recorded in the surgical group. The correlation between the change scores (baseline to 12 months) for COMI and SRS-22 was 0.74, and between each of these change scores and the external criterion of treatment success were: COMI-back, r = 0.58; SRS-22, r = -0.58 (each p < 0.0001). The ROC areas under the curve for the COMI-back and SRS-22 change scores were 0.79 and 0.82, respectively. CONCLUSION: Both baseline and change scores for the COMI-back correlated strongly with those of the SRS-22, and differed significantly in surgical and non-operative patients, suggesting good construct validity. With the "change in the back problem" serving as external criterion, COMI-back showed similar external responsiveness to SRS-22. The COMI back was well able to detect important change. Coupled with its brevity, which minimizes patient burden, these favourable psychometric properties suggest the COMI-back is a suitable instrument for use in registries and can serve as a valid instrument in clinical studies emerging from such data pools. PMID- 26519375 TI - Impact of hemoglobin levels on renal and non-renal clinical outcomes differs by chronic kidney disease stages: the Gonryo study. AB - BACKGROUND: Anemia greatly affects the development of renal and cardiovascular outcomes in chronic kidney disease (CKD) patients. However, the impact based on CKD stage remains unclear. METHODS: We prospectively followed 2,602 Japanese CKD patients under the care of nephrologists. CKD was defined according to cause, estimated glomerular filtration rate <60 mL/min, and/or proteinuria. Patient outcomes [primary end-points: cardiovascular events (CVEs), all-cause mortality, and end-stage kidney disease (ESKD) requiring renal replacement therapy] were assessed in association with basal hemoglobin (Hb) levels (<10, 10-12 and >=12 g/dL), stratified by CKD stages. RESULTS: During follow-up, 123 patients developed CVEs, 41 died, and 220 progressed to ESKD. For stages G3, G4 and G5, ESKD frequencies were 2.8, 64.4, and 544.8 person-years, while CVEs and death were 25.6, 45.6, and 76.3 person-years, respectively. The combined endpoint rate was significantly higher in patients with Hb <10 versus Hb 10-12 g/dL, but a higher risk for CVEs and death with Hb <10 g/dL was found only in G3 [hazard ratio (HR) 4.49, (95 % confidence interval (95 % CI) 2.06-9.80)]. In contrast, risk for ESKD with Hb <10 g/dL was found only in G4 [HR 3.08 (95 % CI 1.40-6.79)] and G5 [HR 1.43 (95 % CI 1.01-2.05)]. No increased risks with higher Hb levels were found. CONCLUSION: The impact of renal anemia of Hb <10 g/dL on clinical outcomes differed by CKD stage, with a significantly high risk for CVEs and all cause mortality in G3 and progression to ESKD in G4 and G5. PMID- 26519376 TI - Role of renin-angiotensin system inhibitors in retardation of progression of end stage renal failure: a retrospective study. AB - BACKGROUND: Few studies have examined how renin-angiotensin system inhibitors (RASI) delay dialysis initiation in patients with advanced chronic kidney disease (CKD). We conducted a retrospective survey to examine this subject. METHODS: We reviewed the records of patients with advanced CKD for the 60-month period before dialysis initiation between 1990 and 2015. Patients were classified based on the decade of dialysis initiation into the 1990s, 2000s, and 2010s groups. The rates of antihypertensive medications administered were assessed. The rate of decline of renal function was evaluated by the slope of reciprocal serum creatinine (SRSC). Multiple regression analyses were conducted to evaluate factors contributing to renoprotection. RESULTS: The duration of RASI administration was longer in the 2010s than in 2000s and 1990s. Both diabetic and non-diabetic patients had lower SRSC in the 2010s compared to the 2000s. In the 2010s, the rate of RASI administration during the 60-month pre-dialysis period showed an initial rise followed by a downward trend, although the rates of administration of the other classes of antihypertensives increased continuously. Multivariate regression analyses identified age, blood pressure, diuretics, alpha-blockers, alpha-methyldopa and RASI as independent predictors of SRSC in the 2010s. The rate of RASI administration correlated with serum potassium concentration. CONCLUSION: Our findings suggest that in the 2010s, RASI with other antihypertensive agents contributed to renoprotection in advanced CKD patients, but they were underused because of the concern over hyperkalemia. In real-world clinical practice, physicians may feel great hesitation in using RASI in patients with advanced CKD. PMID- 26519377 TI - Availability, spatial accessibility, utilisation and the role of telehealth for multi-disciplinary paediatric cerebral palsy services in Queensland. AB - AIMS: The purpose of this study was to understand the methods of current delivery of health care services to cerebral palsy (CP) patients in Queensland, Australia. The study also examines the current use of telehealth by clinicians and their perceptions about telehealth use. METHODS: Patient records during July 2013-July 2014 were accessed from the Queensland Paediatric Rehabilitation Service (QPRS) to collect information relating to the service delivery for CP patients. Analysis was carried out to examine the patient locations and travel distances using ArcMap geoprocessing software. In addition, 13 face-to-face semi structured interviews were conducted with clinicians from the QPRS and the Cerebral Palsy Health Service (CPHS) to understand the perceptions of clinicians relating to the current level of health care delivery. We also examined the clinicians' current use of telehealth and their opinions about this method. RESULTS: Records of 329 paediatric CP patients were accessed and reviewed. The majority of patients (96%, n = 307) who attended the clinics at the Royal Children's Hospital (RCH), Brisbane, were from remote, rural or regional areas of Queensland. Only 4% of patients (n = 13) were from major cities. During 12 months, patients had attended nine outreach programmes that were conducted by the QPRS and CPHS. The study found that non-local patients were required to travel an average distance of 836 km to access QPRS and CPHS services in Brisbane. The average distance for receiving a consultation at an outreach clinic was 173 km. Clinicians perceived that access to health care services to CP patients in Queensland is inadequate. Nearly all clinicians interviewed had some experience in using telehealth. They had high satisfaction levels with the method. CONCLUSIONS: Traditional methods of delivering services to CP patients do not meet their needs. Clinicians have found telehealth is a feasible and satisfactory delivery method. However, the use of telehealth is still limited. PMID- 26519378 TI - Use of mobile technology in a community mental health setting. AB - INTRODUCTION: mHealth holds promise in transforming care for people with serious mental illness (SMI) and other disadvantaged populations. However, information about the rates of smartphone ownership and usage of mobile health apps among people with SMI is limited. The objective of this research is to examine the current ownership, usage patterns, and existing barriers to mobile health interventions for people with SMI treated in a public sector community mental health setting and to compare the findings with national usage patterns from the general population. METHODS: A survey was conducted to determine rates of ownership of smartphone devices among people with SMI. Surveys were administered to 100 patients with SMI at an outpatient psychiatric clinic. Results were compared with respondents to the 2012 Pew Survey of mobile phone usage. RESULTS: A total of 85% of participants reported that they owned a cell phone; of those, 37% reported that they owned a smartphone, as compared with 53% of respondents to the Pew Survey and 44% of socioeconomically disadvantaged respondents to the Pew Survey. DISCUSSION: While cell phone ownership is common among people with SMI, their adoption of smartphone technology lags behind that of the general population primarily due to cost barriers. Efforts to use mHealth in these populations need to recognize current mobile ownership patterns while planning for anticipated expansion of new technologies to poor populations as cost barriers are reduced in the coming years. PMID- 26519380 TI - Update on the Pharmacotherapy of Cerebellar Ataxia and Nystagmus. AB - Pharmacological treatment of cerebellar ataxias and cerebellar nystagmus still remains difficult. The efficacy of most of the agents recommended in the past for symptomatic or even causative therapy could not be proven in larger state-of-the art clinical trials. Exceptions are (a) 4-aminopyridine (4-AP) for episodic ataxia type 2 (EA2): one observational and one randomized controlled trial showed a significant effect on the number of attacks of ataxia and quality of life; (b) aminopyridines in cerebellar downbeat nystagmus (DBN): two randomized controlled trials and several observational studies demonstrate a significant improvement of the intensity of DBN, visual acuity, and postural imbalance. In both diseases the sustained-release form is evidently also efficient; (c) 4-AP in cerebellar gait ataxia: evidence comes from two observational studies. (d) chlorzoxazone in DBN which, however, was so far demonstrated in only one observational study; (e) the modified amino acid acetyl-DL-leucine: evidently effective in cerebellar ataxias, shown in three observational studies, one on patients with Niemann-Pick type C; its mode of action has to be evaluated in animal models and on a cellular/electrophysiological level. There are ongoing randomized placebo controlled trials on EA2 with 4-AP versus acetazolamide (EAT-2-TREAT), cerebellar gait ataxia with 4-AP (FACEG), and a multinational trial on cerebellar ataxia with acetyl-DL-leucine (ALCAT). PMID- 26519379 TI - Cerebellar Atrophy in Cortical Myoclonic Tremor and Not in Hereditary Essential Tremor-a Voxel-Based Morphometry Study. AB - Essential tremor (ET) presumably has a cerebellar origin. Imaging studies showed various cerebellar and also cortical structural changes. A number of pathology studies indicated cerebellar Purkinje cell pathology. ET is a heterogeneous disorder, possibly indicating different underlying disease mechanisms. Familial cortical myoclonic tremor with epilepsy (FCMTE), with evident Purkinje cell degeneration, can be an ET mimic. Here, we investigate whole brain and, more specifically, cerebellar morphological changes in hereditary ET, FCMTE, and healthy controls. Anatomical magnetic resonance images were preprocessed using voxel-based morphometry. Study 1 included voxel-wise comparisons of 36 familial, propranolol-sensitive ET patients, with subgroup analysis on age at onset and head tremor, and 30 healthy controls. Study 2 included voxel-wise comparisons in another nine ET patients, eight FCMTE patients, and nine healthy controls. Study 3 compared total cerebellar volume between 45 ET patients, 8 FCTME patients, and 39 controls. In our large sample of selected hereditary ET patients and ET subgroups, no local atrophy was observed compared to healthy controls or FCMTE. In ET patients with head tremor, a volume increase in cortical motor regions was observed. In FCMTE, a decrease in total cerebellar volume and in local cerebellar gray matter was observed compared to healthy controls and ET patients. The current study did not find local atrophy, specifically not in the cerebellum in hereditary ET, contrary to FCMTE. Volume increase of cortical motor areas in ET patients with head tremor might suggest cortical plasticity changes due to continuous involuntary head movements. PMID- 26519381 TI - FIG4 is a hepatitis C virus particle-bound protein implicated in virion morphogenesis and infectivity with cholesteryl ester modulation potential. AB - There is growing evidence that virus particles also contain host cell proteins, which provide viruses with certain properties required for entry and release. A proteomic analysis performed on double-gradient-purified hepatitis C virus (HCV) from two highly viraemic patients identified the phosphatidylinositol 3,5 bisphosphate 5-phosphatase FIG4 (KIAA0274) as part of the viral particles. We validated the association using immunoelectron microscopy, immunoprecipitation and neutralization assays in vitro as well as patient-derived virus particles. RNA interference-mediated reduction of FIG4 expression decreased cholesteryl ester (CE) levels along with intra- and extracellular viral infectivity without affecting HCV RNA levels. Likewise, overexpressing FIG4 increased intracellular CE levels as well as intra- and extracellular viral infectivity without affecting viral RNA levels. Triglyceride levels and lipid droplet (LD) parameters remained unaffected. The 3,5-bisphosphate 5-phosphatase active site of FIG4 was found to strongly condition these results. Whilst FIG4 was found to localize to areas corresponding to viral assembly sites, at the immediate vicinity of LDs in calnexin-positive and HCV core-positive regions, no implication of FIG4 in the secretory pathway of the hepatocytes could be found using either FIG4-null mice, in vitro morphometry or functional assays of the ERGIC/Golgi compartments. This indicates that FIG4-dependent modulation of HCV infectivity is unrelated to alterations in the functionality of the secretory pathway. As a result of the documented implication of CE in the composition and infectivity of HCV particles, these results suggest that FIG4 binds to HCV and modulates particle formation in a CE-related manner. PMID- 26519382 TI - Editorial: Education is.... AB - The Professional Development Section serves to provide the microbiology community with timely articles of interest to microbiologists at various stages of their career. Topics include education and training standards, best practice in publishing and data handling, plus matters impacting microbiologists such as safety standards, funding opportunities, research and teaching metrics, equality and diversity, outreach and widening participation. The Section also features relevant articles regarding the history of microbiology - though these are often featured in other Sections as well. PMID- 26519383 TI - Quantitative and Qualitative Change of Collagen of Achilles Tendons in Rats With Systemic Administration of Glucocorticoids. AB - BACKGROUND: It is unclear whether glucocorticoid (GC) therapy is directly related to Achilles tendon rupture (ATR), because many of the reported patients were receiving long-term GC therapy for underlying diseases. This study aimed to elucidate the mechanism by which systemic GC administration causes weakening of the Achilles tendon by biochemically, mechanically, and morphologically evaluating quantitative and qualitative changes in collagen. METHODS: Male 8-week old mice were subcutaneously treated with either prednisolone (10 mg/mL/kg; GC group) or saline (1 mL/kg; control group) for 8 weeks and then subjected to the following experiments: (1) a tensile strength test; (2) quantification of the gene expressions of type 1 collagen and lysyl oxidase; (3) quantification of collagen content, enzymatic crosslinks (immature + mature), and senescent crosslinks; and (4) measurement of collagen fiber diameter by electron microscopy. RESULTS: The maximum tensile load and gene expressions of type 1 collagen and lysyl oxidase were decreased in the GC group. Collagen content was significantly decreased in the GC group compared with the control group. The content of enzymatic crosslinks was significantly lower in the GC group than in the control group. The corresponding amount of senescent crosslinks was not significantly different. The mean collagen fiber diameter was significantly smaller in the GC group than in the control group. Histogram analysis showed a decreased number of thick fibers and an increased number of thin fibers in the GC group. CONCLUSION: These observations suggest that systemic GC administration causes decreased strength of the Achilles tendon by decreasing its collagen content, hindering the formation of enzymatic crosslinks and thereby keeping collagen fibers in an immature state with smaller diameters. CLINICAL RELEVANCE: This animal study showed that systemic GC administration directly prevents maturation of tendon collagen fibers and decreases tendon strength, regardless of the presence or absence of underlying disease. PMID- 26519384 TI - A Central Role for Monocyte-Platelet Interactions in Heart Failure. AB - Heart failure (HF) is an increasingly prevalent and costly multifactorial syndrome with high morbidity and mortality rates. The exact pathophysiological mechanisms leading to the development of HF are not completely understood. Several emerging paradigms implicate cardiometabolic risk factors, inflammation, endothelial dysfunction, myocardial fibrosis, and myocyte dysfunction as key factors in the gradual progression from a healthy state to HF. Inflammation is now a recognized factor in disease progression in HF and a therapeutic target. Furthermore, the monocyte-platelet interaction has been highlighted as an important pathophysiological link between inflammation, thrombosis, endothelial activation, and myocardial malfunction. The contribution of monocytes and platelets to acute cardiovascular injury and acute HF is well established. However, their role and interaction in the pathogenesis of chronic HF are not well understood. In particular, the cross talk between monocytes and platelets in the peripheral circulation and in the vicinity of the vascular wall in the form of monocyte-platelet complexes (MPCs) may be a crucial element, which influences the pathophysiology and progression of chronic heart disease and HF. In this review, we discuss the role of monocytes and platelets as key mediators of cardiovascular inflammation in HF, the mechanisms of cell activation, and the importance of monocyte-platelet interaction and complexes in HF pathogenesis. Finally, we summarize recent information on pharmacological inhibition of inflammation and studies of antithrombotic strategies in the setting of HF that can inform opportunities for future work. We discuss recent data on monocyte platelet interactions and the potential benefits of therapy directed at MPCs, particularly in the setting of HF with preserved ejection fraction. PMID- 26519385 TI - A Branch Point of Streptomyces Sulfur Amino Acid Metabolism Controls the Production of Albomycin. AB - Albomycin (ABM), also known as grisein, is a sulfur-containing metabolite produced by Streptomyces griseus ATCC 700974. Genes predicted to be involved in the biosynthesis of ABM and ABM-like molecules are found in the genomes of other actinomycetes. ABM has potent antibacterial activity, and as a result, many attempts have been made to develop ABM into a drug since the last century. Although the productivity of S. griseus can be increased with random mutagenesis methods, understanding of Streptomyces sulfur amino acid (SAA) metabolism, which supplies a precursor for ABM biosynthesis, could lead to improved and stable production. We previously characterized the gene cluster (abm) in the genome sequenced S. griseus strain and proposed that the sulfur atom of ABM is derived from either cysteine (Cys) or homocysteine (Hcy). The gene product, AbmD, appears to be an important link between primary and secondary sulfur metabolic pathways. Here, we show that propargylglycine or iron supplementation in growth media increased ABM production by significantly changing the relative concentrations of intracellular Cys and Hcy. An SAA metabolic network of S. griseus was constructed. Pathways toward increasing Hcy were shown to positively impact ABM production. The abmD gene and five genes that increased the Hcy/Cys ratio were assembled downstream of hrdBp promoter sequences and integrated into the chromosome for overexpression. The ABM titer of one engineered strain, SCAK3, in a chemically defined medium was consistently improved to levels ~400% of the wild type. Finally, we analyzed the production and growth of SCAK3 in shake flasks for further process development. PMID- 26519386 TI - Whole-Genome Sequencing Analysis Accurately Predicts Antimicrobial Resistance Phenotypes in Campylobacter spp. AB - The objectives of this study were to identify antimicrobial resistance genotypes for Campylobacter and to evaluate the correlation between resistance phenotypes and genotypes using in vitro antimicrobial susceptibility testing and whole genome sequencing (WGS). A total of 114 Campylobacter species isolates (82 C. coli and 32 C. jejuni) obtained from 2000 to 2013 from humans, retail meats, and cecal samples from food production animals in the United States as part of the National Antimicrobial Resistance Monitoring System were selected for study. Resistance phenotypes were determined using broth microdilution of nine antimicrobials. Genomic DNA was sequenced using the Illumina MiSeq platform, and resistance genotypes were identified using assembled WGS sequences through blastx analysis. Eighteen resistance genes, including tet(O), blaOXA-61, catA, lnu(C), aph(2")-Ib, aph(2")-Ic, aph(2')-If, aph(2")-Ig, aph(2")-Ih, aac(6')-Ie-aph(2") Ia, aac(6')-Ie-aph(2")-If, aac(6')-Im, aadE, sat4, ant(6'), aad9, aph(3')-Ic, and aph(3')-IIIa, and mutations in two housekeeping genes (gyrA and 23S rRNA) were identified. There was a high degree of correlation between phenotypic resistance to a given drug and the presence of one or more corresponding resistance genes. Phenotypic and genotypic correlation was 100% for tetracycline, ciprofloxacin/nalidixic acid, and erythromycin, and correlations ranged from 95.4% to 98.7% for gentamicin, azithromycin, clindamycin, and telithromycin. All isolates were susceptible to florfenicol, and no genes associated with florfenicol resistance were detected. There was a strong correlation (99.2%) between resistance genotypes and phenotypes, suggesting that WGS is a reliable indicator of resistance to the nine antimicrobial agents assayed in this study. WGS has the potential to be a powerful tool for antimicrobial resistance surveillance programs. PMID- 26519387 TI - Genus-Specific Primers for Study of Fusarium Communities in Field Samples. AB - Fusarium is a large and diverse genus of fungi of great agricultural and economic importance, containing many plant pathogens and mycotoxin producers. To date, high-throughput sequencing of Fusarium communities has been limited by the lack of genus-specific primers targeting regions with high discriminatory power at the species level. In the present study, we evaluated two Fusarium-specific primer pairs targeting translation elongation factor 1 (TEF1). We also present the new primer pair Fa+7/Ra+6. Mock Fusarium communities reflecting phylogenetic diversity were used to evaluate the accuracy of the primers in reflecting the relative abundance of the species. TEF1 amplicons were subjected to 454 high throughput sequencing to characterize Fusarium communities. Field samples from soil and wheat kernels were included to test the method on more-complex material. For kernel samples, a single PCR was sufficient, while for soil samples, nested PCR was necessary. The newly developed primer pairs Fa+7/Ra+6 and Fa/Ra accurately reflected Fusarium species composition in mock DNA communities. In field samples, 47 Fusarium operational taxonomic units were identified, with the highest Fusarium diversity in soil. The Fusarium community in soil was dominated by members of the Fusarium incarnatum-Fusarium equiseti species complex, contradicting findings in previous studies. The method was successfully applied to analyze Fusarium communities in soil and plant material and can facilitate further studies of Fusarium ecology. PMID- 26519388 TI - Influence of Iron on Production of the Antibacterial Compound Tropodithietic Acid and Its Noninhibitory Analog in Phaeobacter inhibens. AB - Tropodithietic acid (TDA) is an antibacterial compound produced by some Phaeobacter and Ruegeria spp. of the Roseobacter clade. TDA production is studied in marine broth or agar since antibacterial activity in other media is not observed. The purpose of this study was to determine how TDA production is influenced by substrate components. High concentrations of ferric citrate, as present in marine broth, or other iron sources were required for production of antibacterially active TDA. However, when supernatants of noninhibitory, low-iron cultures of Phaeobacter inhibens were acidified, antibacterial activity was detected in a bioassay. The absence of TDA in nonacidified cultures and the presence of TDA in acidified cultures were verified by liquid chromatography-high resolution mass spectrometry. A noninhibitory TDA analog (pre-TDA) was produced by P. inhibens, Ruegeria mobilis F1926, and Phaeobacter sp. strain 27-4 under low iron concentrations and was instantaneously converted to TDA when pH was lowered. Production of TDA in the presence of Fe(3+) coincides with formation of a dark brown substance, which could be precipitated by acid addition. From this brown pigment TDA could be liberated slowly with aqueous ammonia, and both direct infusion mass spectrometry and elemental analysis indicated a [Fe(III)(TDA)2]x complex. The pigment could also be produced by precipitation of pure TDA with FeCl3. Our results raise questions about how biologically active TDA is produced in natural marine settings where iron is typically limited and whether the affinity of TDA to iron points to a physiological or ecological function of TDA other than as an antibacterial compound. PMID- 26519389 TI - Pentanol and Benzyl Alcohol Attack Bacterial Surface Structures Differently. AB - The genus Methylobacterium tolerates hygiene agents like benzalkonium chloride (BAC), and infection with this organism is an important public health issue. Here, we found that the combination of BAC with particular alcohols at nonlethal concentrations in terms of their solitary uses significantly reduced bacterial viability after only 5 min of exposure. Among the alcohols, Raman spectroscopic analyses showed that pentanol (pentyl alcohol [PeA]) and benzyl alcohol (BzA) accelerated the cellular accumulation of BAC. Fluorescence spectroscopic assays and morphological assays with giant vesicles indicated that PeA rarely attacked membrane structures, while BzA increased the membrane fluidity and destabilized the structures. Other fluorescent spectroscopic assays indicated that PeA and BzA inactivate bacterial membrane proteins, including an efflux pump for BAC transportation. These findings suggested that the inactivation of membrane proteins by PeA and BzA led to the cellular accumulation but that only BzA also enhanced BAC penetration by membrane fluidization at nonlethal concentrations. PMID- 26519390 TI - Diversity of Pseudomonas Genomes, Including Populus-Associated Isolates, as Revealed by Comparative Genome Analysis. AB - The Pseudomonas genus contains a metabolically versatile group of organisms that are known to occupy numerous ecological niches, including the rhizosphere and endosphere of many plants. Their diversity influences the phylogenetic diversity and heterogeneity of these communities. On the basis of average amino acid identity, comparative genome analysis of >1,000 Pseudomonas genomes, including 21 Pseudomonas strains isolated from the roots of native Populus deltoides (eastern cottonwood) trees resulted in consistent and robust genomic clusters with phylogenetic homogeneity. All Pseudomonas aeruginosa genomes clustered together, and these were clearly distinct from other Pseudomonas species groups on the basis of pangenome and core genome analyses. In contrast, the genomes of Pseudomonas fluorescens were organized into 20 distinct genomic clusters, representing enormous diversity and heterogeneity. Most of our 21 Populus associated isolates formed three distinct subgroups within the major P. fluorescens group, supported by pathway profile analysis, while two isolates were more closely related to Pseudomonas chlororaphis and Pseudomonas putida. Genes specific to Populus-associated subgroups were identified. Genes specific to subgroup 1 include several sensory systems that act in two-component signal transduction, a TonB-dependent receptor, and a phosphorelay sensor. Genes specific to subgroup 2 contain hypothetical genes, and genes specific to subgroup 3 were annotated with hydrolase activity. This study justifies the need to sequence multiple isolates, especially from P. fluorescens, which displays the most genetic variation, in order to study functional capabilities from a pangenomic perspective. This information will prove useful when choosing Pseudomonas strains for use to promote growth and increase disease resistance in plants. PMID- 26519391 TI - Reciprocal Regulation of GlnR and PhoP in Response to Nitrogen and Phosphate Limitations in Saccharopolyspora erythraea. AB - Nitrogen and phosphate source sensing, uptake, and assimilation are essential for the growth and development of microorganisms. In this study, we demonstrated that SACE_6965 encodes the phosphate regulator PhoP, which controls the transcription of genes involved in phosphate metabolism in the erythromycin-producing Saccharopolyspora erythraea. We found that PhoP and the nitrogen regulator GlnR both regulate the transcription of glnR as well as other nitrogen metabolism related genes. Interestingly, both GlnR- and PhoP-binding sites were identified in the phoP promoter region. Unlike the nonreciprocal regulation of GlnR and PhoP observed in Streptomyces coelicolor and Streptomyces lividans, GlnR negatively controls the transcription of the phoP gene in S. erythraea. This suggests that GlnR directly affects phosphate metabolism and demonstrates that the cross talk between GlnR and PhoP is reciprocal. Although GlnR and PhoP sites in the glnR and phoP promoter regions are located in close proximity to one another (separated by only 2 to 4 bp), the binding of both regulators to their respective region was independent and noninterfering. These results indicate that two regulators could separately bind to their respective binding sites and control nitrogen and phosphate metabolism in response to environmental changes. The reciprocal cross talk observed between GlnR and PhoP serves as a foundation for understanding the regulation of complex primary and secondary metabolism in antibiotic-producing actinomycetes. PMID- 26519392 TI - Genetic Diversity of Clostridium sporogenes PA 3679 Isolates Obtained from Different Sources as Resolved by Pulsed-Field Gel Electrophoresis and High Throughput Sequencing. AB - Clostridium sporogenes PA 3679 is a nonpathogenic, nontoxic model organism for proteolytic Clostridium botulinum used in the validation of conventional thermal food processes due to its ability to produce highly heat-resistant endospores. Because of its public safety importance, the uncertain taxonomic classification and genetic diversity of PA 3679 are concerns. Therefore, isolates of C. sporogenes PA 3679 were obtained from various sources and characterized using pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing. The phylogenetic relatedness and genetic variability were assessed based on 16S rRNA gene sequencing and whole-genome single nucleotide polymorphism (SNP) analysis. All C. sporogenes PA 3679 isolates were categorized into two clades (clade I containing ATCC 7955 NCA3679 isolates 1961-2, 1990, and 2007 and clade II containing PA 3679 isolates NFL, UW, FDA, and Campbell and ATCC 7955 NCA3679 isolate 1961-4). The 16S maximum likelihood (ML) tree clustered both clades within proteolytic C. botulinum strains, with clade I forming a distinct cluster with other C. sporogenes non-PA 3679 strains. SNP analysis revealed that clade I isolates were more similar to the genomic reference PA 3679 (NCTC8594) genome (GenBank accession number AGAH00000000.1) than clade II isolates were. The genomic reference C. sporogenes PA 3679 (NCTC8594) genome and clade I C. sporogenes isolates were genetically distinct from those obtained from other sources (University of Wisconsin, National Food Laboratory, U.S. Food and Drug Administration, and Campbell's Soup Company). Thermal destruction studies revealed that clade I isolates were more sensitive to high temperature than clade II isolates were. Considering the widespread use of C. sporogenes PA 3679 and its genetic information in numerous studies, the accurate identification and genetic characterization of C. sporogenes PA 3679 are of critical importance. PMID- 26519393 TI - Novel Alginate Lyase (Aly5) from a Polysaccharide-Degrading Marine Bacterium, Flammeovirga sp. Strain MY04: Effects of Module Truncation on Biochemical Characteristics, Alginate Degradation Patterns, and Oligosaccharide-Yielding Properties. AB - Alginate lyases are important tools for oligosaccharide preparation, medical treatment, and energy bioconversion. Numerous alginate lyases have been elucidated. However, relatively little is known about their substrate degradation patterns and product-yielding properties, which is a limit to wider enzymatic applications and further enzyme improvements. Herein, we report the characterization and module truncation of Aly5, the first alginate lyase obtained from the polysaccharide-degrading bacterium Flammeovirga. Aly5 is a 566-amino acid protein and belongs to a novel branch of the polysaccharide lyase 7 (PL7) superfamily. The protein rAly5 is an endolytic enzyme of alginate and associated oligosaccharides. It prefers guluronate (G) to mannuronate (M). Its smallest substrate is an unsaturated pentasaccharide, and its minimum product is an unsaturated disaccharide. The final alginate digests contain unsaturated oligosaccharides that generally range from disaccharides to heptasaccharides, with the tetrasaccharide fraction constituting the highest mass concentration. The disaccharide products are identified as DeltaG units. While interestingly, the tri- and tetrasaccharide fractions each contain higher proportions of DeltaG to DeltaM ends, the larger final products contain only DeltaM ends, which constitute a novel oligosaccharide-yielding property of guluronate lyases. The deletion of the noncatalytic region of Aly5 does not alter its M/G preference but significantly decreases the enzymatic activity and enzyme stability. Notably, the truncated protein accumulates large final oligosaccharide products but yields fewer small final products than Aly5, which are codetermined by its M/G preference to and size enlargement of degradable oligosaccharides. This study provides novel enzymatic properties and catalytic mechanisms of a guluronate lyase for potential uses and improvements. PMID- 26519394 TI - Tissue Plasminogen Activator Coating on Implant Surfaces Reduces Staphylococcus aureus Biofilm Formation. AB - Staphylococcus aureus biofilm infections of indwelling medical devices are a major medical challenge because of their high prevalence and antibiotic resistance. As fibrin plays an important role in S. aureus biofilm formation, we hypothesize that coating of the implant surface with fibrinolytic agents can be used as a new method of antibiofilm prophylaxis. The effect of tissue plasminogen activator (tPA) coating on S. aureus biofilm formation was tested with in vitro microplate biofilm assays and an in vivo mouse model of biofilm infection. tPA coating efficiently inhibited biofilm formation by various S. aureus strains. The effect was dependent on plasminogen activation by tPA, leading to subsequent local fibrin cleavage. A tPA coating on implant surfaces prevented both early adhesion and later biomass accumulation. Furthermore, tPA coating increased the susceptibility of biofilm infections to antibiotics. In vivo, significantly fewer bacteria were detected on the surfaces of implants coated with tPA than on control implants from mice treated with cloxacillin. Fibrinolytic coatings (e.g., with tPA) reduce S. aureus biofilm formation both in vitro and in vivo, suggesting a novel way to prevent bacterial biofilm infections of indwelling medical devices. PMID- 26519395 TI - Ex Vivo Application of Secreted Metabolites Produced by Soil-Inhabiting Bacillus spp. Efficiently Controls Foliar Diseases Caused by Alternaria spp. AB - Bacterial biological control agents (BCAs) are largely used as live products to control plant pathogens. However, due to variable environmental and ecological factors, live BCAs usually fail to produce desirable results against foliar pathogens. In this study, we investigated the potential of cell-free culture filtrates of 12 different bacterial BCAs isolated from flower beds for controlling foliar diseases caused by Alternaria spp. In vitro studies showed that culture filtrates from two isolates belonging to Bacillus subtilis and Bacillus amyloliquefaciens displayed strong efficacy and potencies against Alternaria spp. The antimicrobial activity of the culture filtrate of these two biological control agents was effective over a wider range of pH (3.0 to 9.0) and was not affected by autoclaving or proteolysis. Comparative liquid chromatography mass spectrometry (LC-MS) analyses showed that a complex mixture of cyclic lipopeptides, primarily of the fengycin A and fengycin B families, was significantly higher in these two BCAs than inactive Bacillus spp. Interaction studies with mixtures of culture filtrates of these two species revealed additive activity, suggesting that they produce similar products, which was confirmed by LC-tandem MS analyses. In in planta pre- and postinoculation trials, foliar application of culture filtrates of B. subtilis reduced lesion sizes and lesion frequencies caused by Alternaria alternata by 68 to 81%. Taken together, our studies suggest that instead of live bacteria, culture filtrates of B. subtilis and B. amyloliquefaciens can be applied either individually or in combination for controlling foliar diseases caused by Alternaria species. PMID- 26519397 TI - Scrap Sunday GP appointments, review advises. PMID- 26519396 TI - Mechanisms of Inactivation by High-Voltage Atmospheric Cold Plasma Differ for Escherichia coli and Staphylococcus aureus. AB - Atmospheric cold plasma (ACP) is a promising nonthermal technology effective against a wide range of pathogenic microorganisms. Reactive oxygen species (ROS) play a crucial inactivation role when air or other oxygen-containing gases are used. With strong oxidative stress, cells can be damaged by lipid peroxidation, enzyme inactivation, and DNA cleavage. Identification of ROS and an understanding of their role are important for advancing ACP applications for a range of complex microbiological issues. In this study, the inactivation efficacy of in-package high-voltage (80 kV [root mean square]) ACP (HVACP) and the role of intracellular ROS were investigated. Two mechanisms of inactivation were observed in which reactive species were found to either react primarily with the cell envelope or damage intracellular components. Escherichia coli was inactivated mainly by cell leakage and low-level DNA damage. Conversely, Staphylococcus aureus was mainly inactivated by intracellular damage, with significantly higher levels of intracellular ROS observed and little envelope damage. However, for both bacteria studied, increasing treatment time had a positive effect on the intracellular ROS levels generated. PMID- 26519398 TI - Using GenBank. AB - GenBank((r)) is a comprehensive database of publicly available DNA sequences for 300,000 named organisms, more than 110,000 within the embryophyta, obtained through submissions from individual laboratories and batch submissions from large scale sequencing projects. Daily data exchange with the European Nucleotide Archive (ENA) in Europe and the DNA Data Bank of Japan ensures worldwide coverage. GenBank is accessible through the NCBI Entrez retrieval system that integrates data from the major DNA and protein sequence databases with taxonomy, genome, mapping, protein structure and domain information, as well as the biomedical journal literature in PubMed. BLAST provides sequence similarity searches of GenBank and other sequence databases. Complete bimonthly releases and daily updates of the GenBank database are available by FTP. GenBank usage scenarios ranging from local analyses of the data available via FTP to online analyses supported by the NCBI web-based tools are discussed. To access GenBank and its related retrieval and analysis services, go to the NCBI home page at www.ncbi.nlm.nih.gov . PMID- 26519399 TI - UniProtKB/Swiss-Prot, the Manually Annotated Section of the UniProt KnowledgeBase: How to Use the Entry View. AB - The Universal Protein Resource (UniProt, http://www.uniprot.org ) consortium is an initiative of the SIB Swiss Institute of Bioinformatics (SIB), the European Bioinformatics Institute (EBI) and the Protein Information Resource (PIR) to provide the scientific community with a central resource for protein sequences and functional information. The UniProt consortium maintains the UniProt KnowledgeBase (UniProtKB), updated every 4 weeks, and several supplementary databases including the UniProt Reference Clusters (UniRef) and the UniProt Archive (UniParc).The Swiss-Prot section of the UniProt KnowledgeBase (UniProtKB/Swiss-Prot) contains publicly available expertly manually annotated protein sequences obtained from a broad spectrum of organisms. Plant protein entries are produced in the frame of the Plant Proteome Annotation Program (PPAP), with an emphasis on characterized proteins of Arabidopsis thaliana and Oryza sativa. High level annotations provided by UniProtKB/Swiss-Prot are widely used to predict annotation of newly available proteins through automatic pipelines.The purpose of this chapter is to present a guided tour of a UniProtKB/Swiss-Prot entry. We will also present some of the tools and databases that are linked to each entry. PMID- 26519400 TI - KEGG Bioinformatics Resource for Plant Genomics and Metabolomics. AB - In the era of high-throughput biology it is necessary to develop not only elaborate computational methods but also well-curated databases that can be used as reference for data interpretation. KEGG ( http://www.kegg.jp/ ) is such a reference knowledge base with two specific aims. One is to compile knowledge on high-level functions of the cell and the organism in terms of the molecular interaction and reaction networks, which is implemented in KEGG pathway maps, BRITE functional hierarchies, and KEGG modules. The other is to expand knowledge on genes and proteins involved in the molecular networks from experimentally observed organisms to other organisms using the concept of orthologs, which is implemented in the KEGG Orthology (KO) system. Thus, KEGG is a generic resource applicable to all organisms and enables interpretation of high-level functions from genomic and molecular data. Here we first present a brief overview of the entire KEGG resource, and then give an introduction of how to use KEGG in plant genomics and metabolomics research. PMID- 26519401 TI - Plant Pathway Databases. AB - Pathway databases provide information about the role of chemicals, genes, and gene products in the form of protein or RNA, their interactions leading to the formulation of metabolic, transport, regulatory, and signaling reactions. The reactions can then be tethered by the principle of inputs and outputs of one or more reaction to create pathways. This chapter provides a list of various online databases that carry information about plant pathways and provides a brief overview of how to use the pathway databases such as WikiPathways Plants Portal, MapMan and the cereal crop pathway databases like RiceCyc and MaizeCyc, that were developed using the Pathway Tools software. PMID- 26519402 TI - The Plant Ontology: A Tool for Plant Genomics. AB - The use of controlled, structured vocabularies (ontologies) has become a critical tool for scientists in the post-genomic era of massive datasets. Adoption and integration of common vocabularies and annotation practices enables cross-species comparative analyses and increases data sharing and reusability. The Plant Ontology (PO; http://www.plantontology.org/ ) describes plant anatomy, morphology, and the stages of plant development, and offers a database of plant genomics annotations associated to the PO terms. The scope of the PO has grown from its original design covering only rice, maize, and Arabidopsis, and now includes terms to describe all green plants from angiosperms to green algae.This chapter introduces how the PO and other related ontologies are constructed and organized, including languages and software used for ontology development, and provides an overview of the key features. Detailed instructions illustrate how to search and browse the PO database and access the associated annotation data. Users are encouraged to provide input on the ontology through the online term request form and contribute datasets for integration in the PO database. PMID- 26519403 TI - Ensembl Plants: Integrating Tools for Visualizing, Mining, and Analyzing Plant Genomics Data. AB - Ensembl Plants ( http://plants.ensembl.org ) is an integrative resource presenting genome-scale information for a growing number of sequenced plant species (currently 33). Data provided includes genome sequence, gene models, functional annotation, and polymorphic loci. Various additional information are provided for variation data, including population structure, individual genotypes, linkage, and phenotype data. In each release, comparative analyses are performed on whole genome and protein sequences, and genome alignments and gene trees are made available that show the implied evolutionary history of each gene family. Access to the data is provided through a genome browser incorporating many specialist interfaces for different data types, and through a variety of additional methods for programmatic access and data mining. These access routes are consistent with those offered through the Ensembl interface for the genomes of non-plant species, including those of plant pathogens, pests, and pollinators.Ensembl Plants is updated 4-5 times a year and is developed in collaboration with our international partners in the Gramene ( http://www.gramene.org ) and transPLANT projects ( http://www.transplantdb.org ). PMID- 26519404 TI - Gramene: A Resource for Comparative Analysis of Plants Genomes and Pathways. AB - Gramene is an integrated informatics resource for accessing, visualizing, and comparing plant genomes and biological pathways. Originally targeting grasses, Gramene has grown to host annotations for economically important and research model crops, including wheat, potato, tomato, banana, grape, poplar, and Chlamydomonas. Its strength derives from the application of a phylogenetic framework for genome comparison and the use of ontologies to integrate structural and functional annotation data. This chapter outlines system requirements for end users and database hosting, data types and basic navigation within Gramene, and provides examples of how to (1) view a phylogenetic tree for a family of transcription factors, (2) explore genetic variation in the orthologues of a gene with a known trait association, and (3) upload, visualize, and privately share end user data into a new genome browser track.Moreover, this is the first publication describing Gramene's new web interface-intended to provide a simplified portal to the most complete and up-to-date set of plant genome and pathway annotations. PMID- 26519405 TI - PGSB/MIPS Plant Genome Information Resources and Concepts for the Analysis of Complex Grass Genomes. AB - PGSB (Plant Genome and Systems Biology; formerly MIPS-Munich Institute for Protein Sequences) has been involved in developing, implementing and maintaining plant genome databases for more than a decade. Genome databases and analysis resources have focused on individual genomes and aim to provide flexible and maintainable datasets for model plant genomes as a backbone against which experimental data, e.g., from high-throughput functional genomics, can be organized and analyzed. In addition, genomes from both model and crop plants form a scaffold for comparative genomics, assisted by specialized tools such as the CrowsNest viewer to explore conserved gene order (synteny) between related species on macro- and micro-levels.The genomes of many economically important Triticeae plants such as wheat, barley, and rye present a great challenge for sequence assembly and bioinformatic analysis due to their enormous complexity and large genome size. Novel concepts and strategies have been developed to deal with these difficulties and have been applied to the genomes of wheat, barley, rye, and other cereals. This includes the GenomeZipper concept, reference-guided exome assembly, and "chromosome genomics" based on flow cytometry sorted chromosomes. PMID- 26519406 TI - MaizeGDB: The Maize Genetics and Genomics Database. AB - MaizeGDB is the community database for biological information about the crop plant Zea mays. Genomic, genetic, sequence, gene product, functional characterization, literature reference, and person/organization contact information are among the datatypes stored at MaizeGDB. At the project's website ( http://www.maizegdb.org ) are custom interfaces enabling researchers to browse data and to seek out specific information matching explicit search criteria. In addition, pre-compiled reports are made available for particular types of data and bulletin boards are provided to facilitate communication and coordination among members of the community of maize geneticists. PMID- 26519407 TI - WheatGenome.info: A Resource for Wheat Genomics Resource. AB - An integrated database with a variety of Web-based systems named WheatGenome.info hosting wheat genome and genomic data has been developed to support wheat research and crop improvement. The resource includes multiple Web-based applications, which are implemented as a variety of Web-based systems. These include a GBrowse2-based wheat genome viewer with BLAST search portal, TAGdb for searching wheat second generation genome sequence data, wheat autoSNPdb, links to wheat genetic maps using CMap and CMap3D, and a wheat genome Wiki to allow interaction between diverse wheat genome sequencing activities. This portal provides links to a variety of wheat genome resources hosted at other research organizations. This integrated database aims to accelerate wheat genome research and is freely accessible via the web interface at http://www.wheatgenome.info/ . PMID- 26519408 TI - User Guidelines for the Brassica Database: BRAD. AB - The genome sequence of Brassica rapa was first released in 2011. Since then, further Brassica genomes have been sequenced or are undergoing sequencing. It is therefore necessary to develop tools that help users to mine information from genomic data efficiently. This will greatly aid scientific exploration and breeding application, especially for those with low levels of bioinformatic training. Therefore, the Brassica database (BRAD) was built to collect, integrate, illustrate, and visualize Brassica genomic datasets. BRAD provides useful searching and data mining tools, and facilitates the search of gene annotation datasets, syntenic or non-syntenic orthologs, and flanking regions of functional genomic elements. It also includes genome-analysis tools such as BLAST and GBrowse. One of the important aims of BRAD is to build a bridge between Brassica crop genomes with the genome of the model species Arabidopsis thaliana, thus transferring the bulk of A. thaliana gene study information for use with newly sequenced Brassica crops. PMID- 26519409 TI - TAG Sequence Identification of Genomic Regions Using TAGdb. AB - Second-generation sequencing (SGS) technology has enabled the sequencing of genomes and identification of genes. However, large complex plant genomes remain particularly difficult for de novo assembly. Access to the vast quantity of raw sequence data may facilitate discoveries; however the volume of this data makes access difficult. This chapter discusses the Web-based tool TAGdb that enables researchers to identify paired read second-generation DNA sequence data that share identity with a submitted query sequence. The identified reads can be used for PCR amplification of genomic regions to identify genes and promoters without the need for genome assembly. PMID- 26519410 TI - Short Read Alignment Using SOAP2. AB - Next-generation sequencing (NGS) technologies have rapidly evolved in the last 5 years, leading to the generation of millions of short reads in a single run. Consequently, various sequence alignment algorithms have been developed to compare these reads to an appropriate reference in order to perform important downstream analysis. SOAP2 from the SOAP series is one of the most commonly used alignment programs to handle NGS data, and it efficiently does so using low computer memory usage and fast alignment speed. This chapter describes the protocol used to align short reads to a reference genome using SOAP2, and highlights the significance of using the in-built command-line options to tune the behavior of the algorithm according to the inputs and the desired results. PMID- 26519411 TI - Tablet: Visualizing Next-Generation Sequence Assemblies and Mappings. AB - This chapter is designed to be a practical guide to using Tablet for the visualization of next/second-generation (NGS) sequencing data. NGS data is being produced more frequently and in greater data volumes every year. As such, it is increasingly important to have tools which enable biologists and bioinformaticians to understand and gain key insights into their data. Visualization can play a key role in the exploration of such data as well as aid in the visual validation of sequence assemblies and features such as single nucleotide polymorphisms (SNPs). We aim to show several use cases which demonstrate Tablet's ability to visually highlight various situations of interest which can arise in NGS data. PMID- 26519412 TI - Analysis of Genotyping-by-Sequencing (GBS) Data. AB - The development of genotyping-by-sequencing (GBS) to rapidly detect nucleotide variation at the whole genome level, in many individuals simultaneously, has provided a transformative genetic profiling technique. GBS can be carried out in species with or without reference genome sequences yields huge amounts of potentially informative data. One limitation with the approach is the paucity of tools to transform the raw data into a format that can be easily interrogated at the genetic level. In this chapter we describe bioinformatics tools developed to address this shortfall together with experimental design considerations to fully leverage the power of GBS for genetic analysis. PMID- 26519413 TI - Skim-Based Genotyping by Sequencing Using a Double Haploid Population to Call SNPs, Infer Gene Conversions, and Improve Genome Assemblies. AB - Genotyping by sequencing (GBS) is an emerging technology to rapidly call an abundance of Single Nucleotide Polymorphisms (SNPs) using genome sequencing technology. Several different methodologies and approaches have recently been established, most of these relying on a specific preparation of data. Here we describe our GBS-pipeline, which uses high coverage reads from two parents and low coverage reads from their double haploid offspring to call SNPs on a large scale. The upside of this approach is the high resolution and scalability of the method. PMID- 26519414 TI - Finding and Characterizing Repeats in Plant Genomes. AB - Plant genomes contain a particularly high proportion of repeated structures of various types. This chapter proposes a guided tour of available software that can help biologists to look for these repeats and check some hypothetical models intended to characterize their structures. Since transposable elements are a major source of repeats in plants, many methods have been used or developed for this large class of sequences. They are representative of the range of tools available for other classes of repeats and we have provided a whole section on this topic as well as a selection of the main existing software. In order to better understand how they work and how repeats may be efficiently found in genomes, it is necessary to look at the technical issues involved in the large scale search of these structures. Indeed, it may be hard to keep up with the profusion of proposals in this dynamic field and the rest of the chapter is devoted to the foundations of the search for repeats and more complex patterns. The second section introduces the key concepts that are useful for understanding the current state of the art in playing with words, applied to genomic sequences. This can be seen as the first stage of a very general approach called linguistic analysis that is interested in the analysis of natural or artificial texts. Words, the lexical level, correspond to simple repeated entities in texts or strings. In fact, biologists need to represent more complex entities where a repeat family is built on more abstract structures, including direct or inverted small repeats, motifs, composition constraints as well as ordering and distance constraints between these elementary blocks. In terms of linguistics, this corresponds to the syntactic level of a language. The last section introduces concepts and practical tools that can be used to reach this syntactic level in biological sequence analysis. PMID- 26519415 TI - Analysis of RNA-Seq Data Using TopHat and Cufflinks. AB - The recent advances in high throughput RNA sequencing (RNA-Seq) have generated huge amounts of data in a very short span of time for a single sample. These data have required the parallel advancement of computing tools to organize and interpret them meaningfully in terms of biological implications, at the same time using minimum computing resources to reduce computation costs. Here we describe the method of analyzing RNA-seq data using the set of open source software programs of the Tuxedo suite: TopHat and Cufflinks. TopHat is designed to align RNA-seq reads to a reference genome, while Cufflinks assembles these mapped reads into possible transcripts and then generates a final transcriptome assembly. Cufflinks also includes Cuffdiff, which accepts the reads assembled from two or more biological conditions and analyzes their differential expression of genes and transcripts, thus aiding in the investigation of their transcriptional and post transcriptional regulation under different conditions. We also describe the use of an accessory tool called CummeRbund, which processes the output files of Cuffdiff and gives an output of publication quality plots and figures of the user's choice. We demonstrate the effectiveness of the Tuxedo suite by analyzing RNA-Seq datasets of Arabidopsis thaliana root subjected to two different conditions. PMID- 26519416 TI - The first 50 live births after autologous oocyte vitrification in France. AB - PURPOSE: The study aims to describe the newborn health parameters of the 50 first children conceived after autologous oocyte vitrification in France. METHODS: The 50 children born after autologous oocyte vitrification/warming cycle (VAO children) have been retrospectively compared with 364 children conceived by micromanipulation using freshly recovered non-vitrified oocytes (ICSI children). Children included in the study were born between 2011 and 2015. Maternal characteristics (age, body mass index, smoking habits), obstetric outcomes (diabetes, hypertension, placenta previa, parity, mode of delivery), and perinatal outcome (twinning, sex, birth weight, macrosomia, birth defects) were analyzed. The generalized estimating equation for correlated data was performed to evaluate perinatal outcomes and caesarean section. RESULTS: No statistically significant difference was found between VAO children and ICSI children, even after adjusting confounding factors (low birth weigh odds ratio (OR) 0.8, 95 % confident interval (CI) 0.3-2.2, adjusted (AOR) 0.5, 95 % CI 0.2-1.7; large for gestational age OR 1.5, 95 % CI 0.3-7.0, AOR 1.6, 95 % CI 0.3-7.5; birth defects OR 0.4, 95 % CI 0.1-3.2, AOR 0.5, 95 % CI 0.1-3.7; caesarean section OR 1.8, 95 % CI 0.9-3.4, AOR 1.8, 95 % CI 0.9-3.7). CONCLUSIONS: According to our results, newborn health parameters of children conceived in our center by micromanipulation using vitrified/warmed autologous oocytes seem not to be different from children born after micromanipulation on freshly recovered oocytes. PMID- 26519417 TI - The cumulative incidence of and risk factors for latent beaking in patients with autoimmune diseases taking long-term glucocorticoids and bisphosphonates. AB - SUMMARY: The incidence of beaking, which has been reported to precede atypical femoral fracture, was high and increased over 2 years in patients with autoimmune diseases who were taking bisphosphonates and glucocorticoids. Regular femoral X rays are strongly recommended to screen for beaking, and bisphosphonate drug holidays should be considered. INTRODUCTION: Atypical femoral fractures (AFFs) have been recently recognized as complications associated with bisphosphonate (BP) use. AFFs are considered to be stress fractures; localized periosteal thickening of the lateral cortex is often present at the fracture site; this thickening is termed "beaking." Beaking has been reported to precede AFF. The aims of the present study were to evaluate the incidence of latent beaking in patients with autoimmune diseases taking BPs and glucocorticoids and to identify risk factors for beaking. METHODS: A total of 125 patients with autoimmune diseases who were taking BPs and glucocorticoids was included; 116 patients underwent X-rays and analysis of serum and urine bone metabolic markers annually for 2 years. Mean patient age was 54.5 years; there were 105 (90.5%) females and the mean duration of disease was 13.2 years. Focal lateral cortical thickening in femoral X-rays was defined as beaking. RESULTS: Beaking was detected in 15 femora of 10 patients (8.0%) at the time of recruitment. Over the 2-year observation period, the incidence of beaking increased to 21 femora of 12 patients (10.3%), and a complete AFF at the location of beaking occurred in one patient. Beaking was associated with a longer duration of BP treatment (6.1 +/- 1.0 years vs. 5.0 +/- 2.9 years, p = 0.01). Age 40-60 years, BP therapy >=4 years, and diabetes mellitus were significantly associated with beaking. CONCLUSIONS: The incidence of beaking was high, and increased over 2 years, in patients with autoimmune diseases who were taking BPs and glucocorticoids. Regular femoral X-rays are strongly recommended to screen for beaking. Long-term BP/glucocorticoid use was a risk factor for beaking in patients with autoimmune diseases; BP drug holidays should be considered. PMID- 26519418 TI - Increased treatment persistence and its determinants in women with osteoporosis with prior fracture compared to those without fracture. AB - SUMMARY: The purpose of this study is to analyze treatment persistence in patients with osteoporosis after fracture diagnosis in German primary care practices. We found that pain increased treatment persistence. One key next step is to demonstrate whether or not this pain is related to fracture. INTRODUCTION: To analyze treatment persistence in patients with osteoporosis after fracture diagnosis in German primary care practices. METHODS: This study included postmenopausal women with osteoporosis aged between 40 and 90 years from 1188 general and 175 orthopedist practices in Germany. Treatment started between 2004 and 2013. The primary outcome measure was treatment persistence within 12 months after therapy initiation. Discontinuation of treatment was defined as a period of at least 90 days without therapy. Persistence analyses were carried out using Kaplan-Meier curves and log-rank tests, and the analyses of the impact of fracture on discontinuation risk were based on Cox regression models (with and without adjustment for pain medications). RESULTS: Thirteen thousand nine hundred seventy-five subjects (mean age = 74.8 years) were included in the group with fracture before therapy initiation and 18,138 (mean age = 72.7 years) in the group without fracture. Within 12 months after treatment initiation, therapy persistence increased with the delay between osteoporosis diagnosis and therapy initiation, rising from 40.7% when the delay was lower than or equal to 12 months to 44.3% when it exceeded 36 months (p value <0.0001). Fracture only decreased the risk of treatment discontinuation when the model was not adjusted for pain medications (HR = 0.95, 95% CI 0.93-0.98, p value <0.0001). CONCLUSIONS: Pain increased treatment persistence in women with osteoporosis and fracture. Further studies are needed to better understand factors influencing persistence. PMID- 26519419 TI - A fatal case of DRESS induced by strontium ranelate associated with HHV-7 reactivation. AB - We report the first case of drug rash with eosinophilia and systemic symptoms (DRESS) following strontium ranelate (SR) treatment associated with systemic human HHV-7 reactivation. DRESS syndrome is a severe adverse drug-induced reaction presenting as a diffuse maculopapular skin rash with fever, hematological abnormalities (leukocytosis, eosinophilia, and/or atypical lymphocytosis), and multiorgan involvement. In our patient, diagnosis of DRESS was confirmed by the presence of six of the seven diagnostic criteria established in 2006 by the Japanese Research Committee on Severe Cutaneous Adverse Drug Reaction: maculopapular skin rash developing at least 3 weeks after starting therapy with a limited number of drugs, prolonged clinical symptoms after discontinuation of the causative drug, lymphadenopathy, fever, leukocyte abnormalities, and liver abnormalities. The diagnostic criteria of human herpesvirus (HHV)-6 reactivation have not been fulfilled in our patient, but a HHV-7 active infection was demonstrated by the presence of HHV-7 DNA and IgM in the patient's serum. In fact, in some DRESS instances, reactivation of HHVs other than HHV-6 may be detected, including HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). Our case underlines that not only HHV-6 but also HHV-7 systemic reactivation may be associated with a more severe and even fatal course of this syndrome. PMID- 26519420 TI - Reversal Strategies for NOACs: State of Development, Possible Clinical Applications and Future Perspectives. AB - The non-vitamin K antagonist oral anticoagulants (NOACs) are used for thromboembolic prophylaxis of patients with atrial fibrillation and in the treatment as well as secondary prophylaxis of patients with venous thromboembolism. Even though NOACs have a better safety profile than vitamin K antagonists (VKAs), there will still be bleeding complications on NOAC treatment. In some cases, stopping the NOAC and non-drug-related management such as manual compression and interventional endoscopy will be sufficient to stop the bleeding. In more serious bleeding events and before acute surgery, coagulation factor concentrates or NOAC-specific antidotes could be used. Coagulation factor concentrates can be used in patients with haemophilia and to reverse the effect of VKAs but, in NOAC-treated patients, results are inconsistent and these agents could potentially have pro-thrombotic effects. Specific antidotes for NOACs are expected to be on the market soon. Phase III clinical trials with a humanized antibody fragment directed against dabigatran (idarucizumab) and recombinant, modified factor Xa (andexanet alfa) are ongoing. A molecule (aripazine) with broad activity against various anticoagulants including NOACs is currently undergoing phase II trials. For use of these specific antidotes, it is desirable that measurements for coagulation activity with a short response delay are widely available for the different NOACs and further research in this field is needed. Furthermore, guidelines for antidote use, including general measures for the treatment of NOAC-related bleeding, should be available. PMID- 26519422 TI - In Vitro Therapeutic Potential of Tio2 Nanoparticles Against Human Cervical Carcinoma Cells. AB - Cellular and physiological responses to the degradation products of titanium implants are key indicators to determine the quality of biocompatibility of implant devices. The present study investigated titanium dioxide (TiO2) nanoparticle-induced cytotoxicity, apoptotic morphological modification, and apoptotic-related gene expressions in the human cervical carcinoma cells. TiO2 nanoparticle-induced cytotoxicity on cancer cells was determined by the sulphorhodamine-B assay. Apoptotic morphological modification such as nuclear fragmentation, rounding, cytoplasm shrinkage, loss of adhesion, and reduced cell volume were observed by an inverted, fluorescence, and confocal laser scanning microscope (CLSM). The DNA fragmentation study showed the occurrence of necrosis and apoptosis in nanoparticle-treated cells. The qPCR study showed the increased p53 and bax mRNA expression in the nanoparticle-treated cells compared to control. In addition, caspase 3 activity was increased in nanoparticle-treated cells, which indicates the increased auto-catalysis. Taking all these data together, it may suggest that TiO2 nanoparticle could inhibit the growth of HeLa cells. PMID- 26519423 TI - Assessing the Influence of Age and Ethnicity on the Association Between Iron Status and Lead Concentration in Blood: Results from the Canadian Health Measures Survey (2007-2011). AB - Inverse association has been reported between iron intake and blood lead concentration (PbB) in epidemiological studies. Data on this association at a low dose of lead exposure are scarce, and the potential influence of ethnicity and age has not been previously reported. This study aimed to estimate the relation between serum ferritin, haemoglobin, haematocrit, and mean corpuscular volume and PbB among 6-18-year-old individuals. Data from Canadian Health and Measures Survey (CHMS), cycle 1 (2007-2009) and cycle 2 (2009-2011), were accessed. A household interview followed by a physical examination (including collection of blood) was performed. The quantification of lead and trace elements in blood was performed by inductively coupled plasma mass spectrometry. The mean PbB was 0.79 MUg/dL (95 % confidence interval (95 % CI) 0.75-0.82). Except for haemoglobin levels, no association was found between PbB and any of the parameters of iron status, independently of age. A significant interaction was observed between ferritin levels and ethnicity in relation to PbB (p = 0.07). We found a little evidence of an association between iron status and PbB in the whole sample of subjects aged 6-18 years exposed to low levels of environmental lead. The significant interaction observed between ferritin levels and ethnicity in relation to BPb suggests that the influence of ferritin levels on lead uptake may change by ethnicity, even at low exposure. PMID- 26519424 TI - Pathogenesis of solute-free water retention in experimental ascitic cirrhosis: is vasopressin the only culprit? AB - Catecholamines trigger proximal tubular fluid retention and reduce renal excretion of solute-free water. In advanced cirrhosis, non-osmotic hypersecretion of vasopressin (antidiuretic hormone or ADH) is considered the cause of dilutional hyponatraemia, but ADH V2 receptor antagonists are not beneficial in long-term treatment of ascites. To test the hypothesis that water retention in experimental ascitic cirrhosis might depend primarily on adrenergic hyper function, hormonal status, renal function and tubular free-water reabsorption (TFWR) were assessed in six groups of rats with ascitic cirrhosis: rats with cirrhosis due to 13-week CCl4 (carbon tetrachloride) administration (group G1); cirrhotic rats receiving daily diuretics (0.5 mg/kg furosemide plus 2 mg/kg K(+) canrenoate) from the 11th to the 13th week of CCl4 (G2), diuretics associated with guanfacine oral prodrug (alpha2A-adrenergic receptor agonist and sympatholytic agent) at 2 (G3), 7 (G4) or 10 (G5) mg/kg, or with SSP-004240F1 (V2 receptor antagonist) at 1 mg/kg (G6). Natriuresis was lower in G1 than in G2, G4 and G6 (all P<0.05). Guanfacine, added to diuretics (i.e. G3 compared with G2), reduced serum noradrenaline from 423+/-22 to 211+/-41 ng/l (P<0.05), plasma renin activity (PRA) from 35+/-8 to 9+/-2 ng/ml/h (P<0.05) and TFWR from 45+/-8 to 20+/ 6 MUl/min (P<0.01). TFWR correlated with plasma aldosterone (r=0.51, P<0.01) and urinary potassium excretion (r=0.90, P<0.001). In ascitic cirrhosis, reduced volaemia, use of diuretics (especially furosemide) and adrenergic hyper-function cause tubular retention of water. Suitable doses of sympatholytic agents are effective aquaretics. PMID- 26519426 TI - Bounding formulas for selection bias. AB - Researchers conducting observational studies need to consider 3 types of biases: selection bias, information bias, and confounding bias. A whole arsenal of statistical tools can be used to deal with information and confounding biases. However, methods for addressing selection bias and unmeasured confounding are less developed. In this paper, we propose general bounding formulas for bias, including selection bias and unmeasured confounding. This should help researchers make more prudent interpretations of their (potentially biased) results. PMID- 26519425 TI - An apolipoprotein B100 mimotope prevents obesity in mice. AB - Although apolipoprotein B100 (ApoB100) plays a key role in peripheral fat deposition, it is not considered a suitable therapeutic target in obesity. In the present study we describe a novel ApoB100 mimotope, peptide pB1, and the use of pB1-based vaccine-like formulations (BVFs) against high-fat diet (HFD)-induced obesity. In HFD- compared with chow-fed adolescent mice, BVFs reduced the 3-month body-weight gains attributable to increased dietary fat by 44-65%, and prevented mesenteric fat accumulation and liver steatosis. The body-weight reductions paralleled the titres of pB1-reactive immunoglobulin G (IgG) antibodies, and pB1 reactive antibodies specifically recognized native ApoB100 and a synthetic peptide from the C-terminal half of ApoB100. In cultured 3T3L1 adipocytes, anti pB1 antibodies increased lipolysis and inhibited low-density lipoprotein (LDL) uptake. In cultured RAW 264.7 macrophages, the same antibodies enhanced LDL uptake (without causing foam cell formation). These findings make ApoB100 a promising target for an immunization strategy against HFD-induced obesity. PMID- 26519427 TI - School personnel smoking, school-level policies, and adolescent smoking in low- and middle-income countries. AB - OBJECTIVES: This paper examines the link between personnel and teacher smoking on school grounds, and student smoking in 62 low-income and middle-income countries. METHODS: We use a two-part model to estimate the effect of smoking by school personnel on youth smoking. In the first part, we model the decision to smoke for all students, using a linear probability model. In the second part, we estimate cigarette consumption among smokers. We employ country fixed effects to address country-level time-invariant unobservable factors and control for an array of local-level variables to address local-level heterogeneity. RESULTS: We find that smoking by personnel and teachers on school grounds is associated with higher smoking prevalence among all youths, and higher cigarette consumption among female smokers. Our findings suggest that consumption among female smokers is primarily affected by smoking among female personnel, and that younger personnel/teachers appear to be more influential in determining behaviours among young people. In addition, we find that smoking restrictions on staff are associated with reductions in average consumption among female students. CONCLUSIONS: Low-income and middle-income countries may reduce smoking among young people by banning smoking for teachers and school personnel on school grounds. PMID- 26519428 TI - Sex differences between APPswePS1dE9 mice in A-beta accumulation and pancreatic islet function during the development of Alzheimer's disease. AB - The pathogenesis of Alzheimer's disease (AD), a type of neurodegenerative disease characterized by learning and memory impairment, is often associated with pathological features, such as amyloid-beta (Abeta) accumulation and insulin resistance. The transgenic mouse, APPswePS1dE9 (APP/PS1), is one of the most commonly used animal models in pathogenesis studies of AD. The purpose of this study is to investigate the sex differences between APP/PS1 mice in the pathogenesis of AD. The impairment of glucose and insulin tolerance was found to develop earlier in male APP/PS1 mice than in females. Plasma insulin levels were significantly decreased in male APP/PS1 mice, while total cholesterol levels in male APP/PS1 mice were higher than those in females. Triglyceride levels in male mice in both the wild-type (WT) and APP/PS1 groups were higher than in their female littermates. Soluble and insoluble Abeta levels in female APP/PS1 mouse brains were higher than those in males. And the learning and memorizing abilities of female APP/PS1 mice were poorer than those of males. Our results concluded that there were sex differences in Abeta formation, pancreatic islet function and insulin sensitivity between male and female APP/PS1 mice during the pathogenesis of AD. PMID- 26519429 TI - Avoiding and Managing Intraoperative Complications During Cervical Spine Surgery. AB - The incidence of intraoperative complications in cervical spine surgery is low. However, when they do occur, such complications have the potential for causing considerable morbidity and mortality. Spine surgeons should be familiar with methods of minimizing such complications. Furthermore, if they do occur, surgeons must be prepared to immediately treat each potential complication to reduce any associated morbidity. PMID- 26519430 TI - Readability of Orthopaedic Oncology-related Patient Education Materials Available on the Internet. AB - INTRODUCTION: A person's health literacy is one of the most important indicators of a patient's health status. According to national recommendations, patient education materials should be written at no higher than the sixth- to eighth grade reading level. The purpose of our study was to assess the readability of online patient education materials related to orthopaedic oncology on the websites of the American Academy of Orthopaedic Surgeons (AAOS), American Cancer Society (ACS), Bone and Cancer Foundation (BCF), and National Cancer Institute (NCI). METHODS: We searched the online patient education libraries of the AAOS, ACS, BCF, and NCI for all articles related to orthopaedic oncology. The Flesch Kincaid (FK) readability score was calculated for each article and compared between sources. RESULTS: A total of 227 articles were identified with an overall mean FK grade level of 9.8. Stratified by source, the mean FK grade levels were 10.1, 9.6, 11.1, and 9.5 for the AAOS, ACS, BCF, and NCI, respectively (P < 0.003). Only 31 articles (14%) and 1 article (0.4%) were at or below the recommended eighth- and sixth-grade levels, respectively. DISCUSSION: Online patient education materials related to orthopaedic oncology appear to be written at a level above the comprehension ability of the average patient. PMID- 26519431 TI - Hierarchical Distribution of the Tau Cytoskeletal Pathology in the Thalamus of Alzheimer's Disease Patients. AB - In spite of considerable progress in neuropathological research on Alzheimer's disease (AD), knowledge regarding the exact pathoanatomical distribution of the tau cytoskeletal pathology in the thalamus of AD patients in the advanced Braak and Braak AD stages V or VI of the cortical cytoskeletal pathology is still fragmentary. Investigation of serial 100 MUm-thick brain tissue sections through the thalamus of clinically diagnosed AD patients with Braak and Braak AD stage V or VI cytoskeletal pathologies immunostained with the anti-tau AT8 antibody, along with the affection of the extraterritorial reticular nucleus of the thalamus, reveals a consistent and severe tau immunoreactive cytoskeletal pathology in the limbic nuclei of the thalamus (e.g., paraventricular, anterodorsal and laterodorsal nuclei, limitans-suprageniculate complex). The thalamic nuclei integrated into the associative networks of the human brain (e.g., ventral anterior and mediodorsal nuclei) are only mildly affected, while its motor precerebellar (ventral lateral nucleus) and sensory nuclei (e.g., lateral and medial geniculate bodies, ventral posterior medial and lateral nuclei, parvocellular part of the ventral posterior medial nucleus) are more or less spared. The highly stereotypical and characteristic thalamic distribution pattern of the AD-related tau cytoskeletal pathology represents an anatomical mirror of the hierarchical topographic distribution of the cytoskeletal pathology in the interconnected regions of the cerebral cortex of AD patients. These pathoanatomical parallels support the pathophysiological concept of a transneuronal spread of the disease process of AD along anatomical pathways. The AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric disease symptoms (e.g., dementia), attention deficits, oculomotor dysfunctions, altered non-discriminative aspects of pain experience of AD patients, and the disruption of their waking and sleeping patterns. PMID- 26519432 TI - Hyperactivity with Agitative-Like Behavior in a Mouse Tauopathy Model. AB - Tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. In addition to memory loss, patients experience behavioral symptoms such as agitation, aggression, depression, and insomnia. We explored the behavioral phenotype of a mouse model (rTg4510) carrying the human tau P301L mutation found in a familial form of FTD. We tested these mice in locomotor activity assays as well as in the Morris water maze to access spatial memory. In addition to cognitive impairments, rTg4510 mice exhibited a hyperactivity phenotype which correlated with progression of tau pathology and was dependent on P301L tau transgene expression. The hyperactive phenotype was characterized by significantly increased locomotor activity in a novel and in a simulated home cage environment together with a disturbed day/night cycle. The P301L-tau-dependent hyperactivity and agitative-like phenotype suggests that these mice may form a correlate to some of the behavioral disturbances observed in advanced AD and FTD. PMID- 26519433 TI - Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer's Disease Pathology. AB - Alzheimer's disease (AD) is characterized by a long pre-clinical phase (20-30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p-value <0.01). Decreased activity was evident at pre clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention. PMID- 26519434 TI - Mild Cognitive Impairment and Susceptibility to Scams in Old Age. AB - BACKGROUND: Falling victim to financial scams can have a significant impact upon social and financial wellbeing and independence. A large proportion of scam victims are older adults, but whether older victims with mild cognitive impairment (MCI) are at higher risk remains unknown. OBJECTIVE: We tested the hypothesis that older persons with MCI exhibit greater susceptibility to scams compared to those without cognitive impairment. METHODS: Seven hundred and thirty older adults without dementia were recruited from the Rush Memory and Aging Project, a community-based epidemiologic study of aging. Participants completed a five-item self-report measure of susceptibility to scams, a battery of cognitive measures, and clinical diagnostic evaluations. RESULTS: In models adjusted for age, education, and gender, the presence of MCI was associated with greater susceptibility to scams (B = 0.125, SE = 0.063, p-value = 0.047). Further, in analyses of the role of specific cognitive systems in susceptibility to scams among persons with MCI (n = 144), the level of performance in two systems, episodic memory and perceptual speed abilities, were associated with susceptibility. CONCLUSIONS: Adults with MCI may be more susceptible to scams in old age than older persons with normal cognition. Lower abilities in specific cognitive systems, particularly perceptual speed and episodic memory, may contribute to greater susceptibility to scams in those with MCI. PMID- 26519435 TI - Clinical and Demographic Factors Associated with the Cognitive and Emotional Efficacy of Regular Musical Activities in Dementia. AB - Recent evidence suggests that music-based interventions can be beneficial in maintaining cognitive, emotional, and social functioning in persons with dementia (PWDs). Our aim was to determine how clinical, demographic, and musical background factors influence the cognitive and emotional efficacy of caregiver implemented musical activities in PWDs. In a randomized controlled trial, 89 PWD caregiver dyads received a 10-week music coaching intervention involving either singing or music listening or standard care. Extensive neuropsychological testing and mood and quality of life (QoL) measures were performed before and after the intervention (n = 84) and six months later (n = 74). The potential effects of six key background variables (dementia etiology and severity, age, care situation, singing/instrument playing background) on the outcome of the intervention were assessed. Singing was beneficial especially in improving working memory in PWDs with mild dementia and in maintaining executive function and orientation in younger PWDs. Music listening was beneficial in supporting general cognition, working memory, and QoL especially in PWDs with moderate dementia not caused by Alzheimer's disease (AD) who were in institutional care. Both music interventions alleviated depression especially in PWDs with mild dementia and AD. The musical background of the PWD did not influence the efficacy of the music interventions. Our findings suggest that clinical and demographic factors can influence the cognitive and emotional efficacy of caregiver-implemented musical activities and are, therefore, recommended to take into account when applying and developing the intervention to achieve the greatest benefit. PMID- 26519436 TI - Development and Validation of the RxDx-Dementia Risk Index to Predict Dementia in Patients with Type 2 Diabetes and Hypertension. AB - BACKGROUND: Elderly patients with type 2 diabetes mellitus and hypertension are at high risk for developing dementia. In addition to comorbid disease conditions (Dx), prescription drugs (Rx) are important risk factors for dementia. OBJECTIVE: Develop and validate the RxDx-Dementia risk index by combining diagnosis and prescription information in a single risk index to predict incident dementia, and compare its performance with diagnosis-based Charlson comorbidity score (CCS) and prescription-based chronic disease score (CDS). METHODS: Elderly patients diagnosed with type 2 diabetes mellitus and hypertension, and without prior dementia were identified from the Clinical Practice Research Datalink (2003 2012). A Cox proportional hazard model was constructed to model the time to dementia by incorporating age, gender, and 31 RxDx disease conditions as independent variables. Points were assigned to risk factors to obtain summary risk score. Discrimination and calibration of the risk index were evaluated. Different risk indices were compared against RxDx-Dementia risk index using c statistic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: Of 133,176 patients with type 2 diabetes mellitus and hypertension, 3.42% patients developed dementia.The c-statistics value for RxDx Dementia risk index was 0.806 (95% CI, 0.799-0.812). Based on the c-statistics, NRI and IDI values, the RxDx-Dementia risk index performed better compared to CCS, CDS, and their combinations. CONCLUSION: The RxDx-Dementia risk index can be a useful tool to identify hypertensive and diabetic patients who are at high risk of developing dementia. This has implications for clinical management of patients with multiple comorbid conditions as well as risk adjustment for database studies. PMID- 26519437 TI - Hippocampal Lipid Homeostasis in APP/PS1 Mice is Modulated by a Complex Interplay Between Dietary DHA and Estrogens: Relevance for Alzheimer's Disease. AB - Current evidence suggests that lipid homeostasis in the hippocampus is affected by different genetic, dietary, and hormonal factors, and that its deregulation may be associated with the onset and progression of Alzheimer's disease (AD). However, the precise levels of influence of each of these factors and their potential interactions remain largely unknown, particularly during neurodegenerative processes. In the present study, we have performed multifactorial analyses of the combined effects of diets containing different doses of docosahexaenoic acid (DHA), estrogen status (ovariectomized animals receiving vehicle or 17beta-estradiol), and genotype (wild-type or transgenic APP/PS1 mice) in hippocampal lipid profiles. We have observed that the three factors affect lipid classes and fatty acid composition to different extents, and that strong interactions between these factors exist. The most aberrant lipid profiles were observed in APP/PS1 animals receiving DHA-poor diets and deprived of estrogens. Conversely, wild-type animals under a high-DHA diet and receiving estradiol exhibited a lipid profile that closely resembled that of the hippocampus of control animals. Interestingly, though the lipid signatures of APP/PS1 hippocampi markedly differed from wild-type, administration of a high-DHA diet in the presence of estrogens gave rise to a lipid profile that approached that of control animals. Paralleling changes in lipid composition, patterns of gene expression of enzymes involved in lipid biosynthesis were also altered and affected by combination of experimental factors. Overall, these results indicate that hippocampal lipid homeostasis is strongly affected by hormonal and dietary conditions, and that manipulation of these factors might be incorporated in AD therapeutics. PMID- 26519438 TI - The Evolution of Caregiver Burden in Frontotemporal Dementia with and without Amyotrophic Lateral Sclerosis. AB - BACKGROUND AND AIMS: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) represent a disease spectrum. Caregiver burden in subtypes of FTD has not yet been directly compared with those patients who have co-existent FTD and ALS (ALSFTD). METHOD: Perceived caregiver burden was evaluated using the short Zarit Burden Interview (ZBI) in patients with behavioral-variant FTD (bvFTD, n = 21), semantic dementia (SD, n = 18), and ALSFTD (n = 15) at the initial clinical presentation and follow-up assessments. The Mini-Addenbrooke's Cognitive Examination (M-ACE) and the Motor Neuron Disease Behaviour Scale (MiND B) were also used. Linear mixed effects models examined longitudinal changes on the ZBI, M-ACE, and MiND-B across groups. RESULTS: Burden at baseline was highest for the bvFTD group. Longitudinally, perceived burden increased for the SD and ALSFTD groups whereas in bvFTD, the level of burden which was high at baseline and remained high with disease progression. The severity of abnormal behaviors at baseline, as assessed by the MiND-B, correlated with baseline levels of caregiver burden and further accounted for 23% of the variance in caregiver burden at clinical follow-up. CONCLUSIONS: The trajectory of perceived burden differs across the FTD-ALS spectrum, with SD and ALSFTD caregivers demonstrating an increased burden that develops over time, compared to a persistently high level for bvFTD caregivers, evident throughout the disease course. The evolution of burden in these three syndromes likely reflects the initial presentation and clinical characterization that develops with time. Psycho-education programs for caregivers, which provide better coping strategies for challenging behaviors, may reduce levels of burden experienced with disease progression. PMID- 26519439 TI - Efficacy and Safety of MMFS-01, a Synapse Density Enhancer, for Treating Cognitive Impairment in Older Adults: A Randomized, Double-Blind, Placebo Controlled Trial. AB - BACKGROUND: Cognitive impairment is a major problem in elderly, affecting quality of life. Pre-clinical studies show that MMFS-01, a synapse density enhancer, is effective at reversing cognitive decline in aging rodents. OBJECTIVE: Since brain atrophy during aging is strongly associated with both cognitive decline and sleep disorder, we evaluated the efficacy of MMFS-01 in its ability to reverse cognitive impairment and improve sleep. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-designed trial in older adult subjects (age 50-70) with cognitive impairment. Subjects were treated with MMFS-01 (n = 23) or placebo (n = 21) for 12 weeks and cognitive ability, sleep quality, and emotion were evaluated. Overall cognitive ability was determined by a composite score of tests in four major cognitive domains. RESULTS: With MMFS-01 treatment, overall cognitive ability improved significantly relative to placebo (p = 0.003; Cohen's d = 0.91). Cognitive fluctuation was also reduced. The study population had more severe executive function deficits than age-matched controls from normative data and MMFS-01 treatment nearly restored their impaired executive function, demonstrating that MMFS-01 may be clinically significant. Due to the strong placebo effects on sleep and anxiety, the effects of MMFS-01 on sleep and anxiety could not be determined. CONCLUSIONS: The current study demonstrates the potential of MMFS-01 for treating cognitive impairment in older adults. PMID- 26519440 TI - Thyroid-Stimulating Hormone and Mild Cognitive Impairment: Results of the Heinz Nixdorf Recall Study. AB - BACKGROUND: Although some studies reported on the association of serum thyroid stimulating hormone (TSH) concentration and cognition, only one population-based study investigated the association of TSH concentration and mild cognitive impairment (MCI). OBJECTIVE: To investigate the gender-specific association of low- and high-normal TSH concentrations with MCI in euthyroid participants. METHODS: Analysis sample 1 included 2,563 euthyroid participants (aged 50-80 years) from the second examination of the population-based Heinz Nixdorf Recall study. Gender-specific TSH quintiles (Q1 low, Q2-Q4 middle, Q5 high TSH concentration) were determined and group comparisons of age- and education adjusted mean scores were performed for all cognitive subtests. Analysis sample 2 included 378 participants with MCI and 931 cognitively normal participants. MCI was diagnosed according to previously published MCI criteria. Multivariate logistic regression models were performed using TSH quintiles (Q2-Q4 as reference) to assess the association of low- and high-normal TSH concentration with MCI. Models were performed unadjusted and adjusted for sociodemographic and cardiovascular risk factors. RESULTS: Group comparisons showed significant differences only in the immediate recall of the verbal memory task in women. Only women showed a strong association of high-normal TSH concentration with MCI (unadjusted: odds ratio 2.09, 95% confidence interval 1.29-3.37, full adjusted: 1.86, 1.06-3.27). There was no association with low-normal TSH concentration in women and no association of either low- or high-normal TSH concentration with MCI in men. CONCLUSIONS: These results suggest that women with high-normal TSH concentration might be at higher risk of cognitive decline. This needs to be confirmed in the longitudinal analysis. PMID- 26519442 TI - Depressive Symptoms and Small Hippocampal Volume Accelerate the Progression to Dementia from Mild Cognitive Impairment. AB - Previous studies have highlighted that decreased hippocampal volume, an early neural correlate of dementia, is commonly observed in patients with mild cognitive impairment (MCI). However, it is unclear whether neurodegenerative and resultant clinical trajectories are accelerated in MCI patients with concomitant depressive symptoms, leading to a faster conversion to dementia stages than those who are not depressed. No longitudinal study has investigated whether depressed amnestic MCI (DEP+aMCI) patients show an earlier onset of progression to dementia than non-depressed amnestic MCI (DEP-aMCI) patients and whether progressive hippocampal volume reductions are related in the conversion process. Using data from Alzheimer's Disease Neuroimaging Initiative, we examined 2-year follow-up data from 38 DEP+aMCI patients and 38 matched DEP-aMCI patients and compared their ages of conversion from aMCI to AD and trajectories of progressive hippocampal volume changes. DEP+ and DEP- patients were defined as having baseline Geriatric Depression Scale scores of 5 or above and 0, respectively. DEP+ converters showed earlier ages of conversion to dementia (p = 0.009) and greater left hippocampal volume loss than both DEP- converters and DEP+ non converters over the 2-year period (p = 0.003, p = 0.001, respectively). These findings could not be explained by changes in total brain volume, differences in their clinical symptoms of dementia, daily functioning, or apolipoprotein E4 genotypes. No difference in conversion rate to dementia or progressive hippocampal volume change was found between DEP+ patients and DEP-patients, which suggested depressive symptoms themselves may not lead to progression of dementia from MCI. In conclusion, there is a synergistic effect of depressive symptoms and smaller left hippocampal volume in MCI patients that accelerates conversion to dementia. PMID- 26519443 TI - Prevalence and Risk Factor of Cognitive Impairment were Different between Urban and Rural Population: A Community-Based Study. AB - BACKGROUND: China is facing a continuously rising numbers of people with cognitive impairment (CI). OBJECTIVES: To investigate the prevalence and risk factors of CI among elderly people living in rural and urban communities. METHODS: We conducted a face-to-face survey of CI on 7,900 individuals aged 50 years or older meeting inclusion criteria in the Malu (rural community, n = 4,429) and Wuliqiao (urban community, n = 3,471) communities of Shanghai. The Mini-Mental State Examination (MMSE) was used to evaluate the cognitive function. Information on demographic features and potential risk factors for CI was collected during the interview. Multivariate logistic regression was performed to identify risk factors associated with CI. RESULTS: Based on the education modified MMSE score, we identified 329 CI cases in rural community and 227 in urban community. The prevalence of CI was 7.43% in rural population and 6.54% in urban population (p = 0.13). In the urban population, risk of having CI was associated with age (OR = 1.04; 95% CI: 1.01-1.08), lack of physical activities (OR = 2.25; 95% CI: 1.11-4.57), presence of diabetes mellitus (OR = 1.79; 95% CI: 1.04-3.07), and having three or more children (OR = 2.39; 95% CI: 1.27-4.50). In contrast, factors associated with rural populations included female gender (OR = 2.03; 95% CI: 1.08-3.82), age (OR = 1.06; 95% CI: 1.03-1.08), exposure to pesticides (OR = 4.68; 95% CI: 1.27-17.21), history of encephalitis or meningitis (OR = 6.02; 95% CI: 1.92-18.85) and head trauma (OR = 1.89; 95% CI: 1.10-3.24). CONCLUSIONS: Urban rural and populations showed different risk factors for CI, suggesting that different preventive strategies in these areas should be performed. PMID- 26519441 TI - Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians. AB - Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration. PMID- 26519445 TI - Structured antibiotic 'time-out' audits as recommended by the CDC reduce antibiotic use and costs. PMID- 26519446 TI - Life-Space Assessment composite score rationale. PMID- 26519447 TI - Modeling the transcriptome of genital tract epithelial cells and macrophages in healthy mucosa versus mucosa inflamed by Chlamydia muridarum infection. AB - Chlamydia trachomatis urogenital serovars are intracellular bacteria that parasitize human reproductive tract epithelium. As the principal cell type supporting bacterial replication, epithelial cells are central to Chlamydia immunobiology initially as sentries and innate defenders, and subsequently as collaborators in adaptive immunity-mediated bacterial clearance. In asymptomatic individuals who do not seek medical care a decisive struggle between C. trachomatis and host defenses occurs at the epithelial interface. For this study, we modeled the immunobiology of epithelial cells and macrophages lining healthy genital mucosa and inflamed/infected mucosa during the transition from innate to adaptive immunity. Upper reproductive tract epithelial cell line responses were compared to bone marrow-derived macrophages utilizing gene expression microarray technology. Those comparisons showed minor differences in the intrinsic innate defenses of macrophages and epithelial cells. Major lineage-specific differences in immunobiology relate to epithelial collaboration with adaptive immunity including an epithelial requirement for inflammatory cytokines to express MHC class II molecules, and a paucity and imbalance between costimulatory and coinhibitory ligands on epithelial cells that potentially limits sterilizing immunity (replication termination) to Chlamydia-specific T cells activated with limited or unconventional second signals. PMID- 26519448 TI - Failure of a heterologous recombinant Sca5/OmpB protein-based vaccine to elicit effective protective immunity against Rickettsia rickettsii infections in C3H/HeN mice. AB - Spotted fever group (SFG) rickettsial species are obligate intracellular tick borne pathogens that are responsible for important human diseases. Previous reports have demonstrated the feasibility of using recombinant surface cell antigen Sca5/OmpB to elicit protective immunity against homologous challenges using murine models of Mediterranean spotted fever and Rocky Mountain spotted fever. In addition, the feasibility of generating cross-protective immunity against related rickettsial species has also been established, but the molecular basis for these phenomena was not explored. Here, we demonstrate that vaccination of C3H/HeN mice with a recombinant OmpB domain derived from Rickettsia conorii induced high titer humoral immune responses that are capable of recognizing the native OmpB protein at the R. rickettsii outer membrane, but this immunization was not sufficient to induce effective protective immunity. In contrast, animals vaccinated with a corresponding OmpB domain derived from R. rickettsii protected animals from fatal outcomes. These results demonstrate that vaccination with nearly identical antigens may not be an effective strategy to induce wide-ranging protective immunity against related SFG Rickettsia species. PMID- 26519449 TI - Reply: Essential tremor in 'The tremulous hand of Worcester': additional comments. PMID- 26519450 TI - Essential tremor in 'The tremulous hand of Worcester': additional comments. PMID- 26519452 TI - From wandering to wayfaring: Reconsidering movement in people with dementia in long-term care. AB - The movement of people with dementia in long-term care continues to be an issue of concern among clinicians, caregivers and families. This article will examine the social construction "wandering" and its association with pathology, risk discourse and surveillance technologies. Further, the article will explore the recent shift from the term "wanderer" to the phrase "people who like to walk" in person-centred dementia care. Engaging with Ingold's concept of movement as wayfaring, an alternative becoming-centred understanding of movement and its significance for people with dementia will be presented and illustrated through a case study. The paper concludes that depathologizing movement opens the possibility to see movement in people with dementia as an intention to be alive and to grow, rather than as a product of disease and deterioration. Suggestions for future research and implications for care interventions are discussed. PMID- 26519451 TI - Directed evolution of human scFvs in DT40 cells. AB - Cells that constitutively diversify their immunoglobulin genes can be used for selection of novel antibodies and for refining existing affinities and specificities. Here, we report an adaptation of the chicken DT40 system wherein its capacity for somatic hypermutation is harnessed to evolve human antibodies expressed as single-chain variable fragments (scFvs). Expression of membrane anchored scFvs from within the rearranged Iglambda locus created self diversifying scFv libraries from which we could both select scFvs of a desired specificity and evolve both the specificity and affinity of existing scFvs by iterative expansion and selection. From these scFvs, we were able to create fully human IgG antibodies with nanomolar affinities. We further enhanced the functionality of the system by creating a pool of DT40 scFv lines with high levels of mutation driven by the overexpression of a hyperactive variant of activation-induced deaminase. From this library, we successfully isolated scFvs that bound the spliceosome factor CWC15 and the cytokine human IFNgamma. Our results demonstrate the flexibility and utility of DT40 for rapid generation of scFv repertoires and efficient selection, evolution and affinity maturation of scFv specificities. PMID- 26519453 TI - Music therapy: A nonpharmacological approach to the care of agitation and depressive symptoms for nursing home residents with dementia. AB - Depression, agitation, and wandering are common behaviors associated with dementia and frequently observed among nursing home residents. Even with pharmacological treatment, behaviors often persist, hindering quality of life for elders, their family, and paid caregivers. This study examined the use of music therapy for treatment of these symptoms among 132 people with moderate to severe dementia in nursing homes. Participants were evaluated for depressive symptoms, agitation, and wandering to determine their predominate behavior. There were two assessments, two weeks apart, prior to intervention, followed by a two-week intervention, and two follow-up assessments, also two weeks apart. A repeated measures ANOVA determined that after two weeks of music therapy, symptoms of depression and agitation were significantly reduced; there was no change for wandering. Multivariate analyses confirmed a relationship between music therapy and change in neuropsychiatric symptoms associated with dementia. Results suggest widespread use of music therapy in long-term care settings may be effective in reducing symptoms of depression and agitation. PMID- 26519454 TI - Glucocorticoid metabolism in the bovine cumulus-oocyte complex matured in vitro. AB - Glucocorticoid action in target organs is regulated by relative activities of 11beta-HSD type 1 (HSD11B1) that mainly converts cortisone to active cortisol and type 2 (HSD11B2) that inactivates cortisol to cortisone. HSD11Bs have been shown to be expressed in the ovary of various species. However, little is known about the expression and activity of HSD11Bs in the bovine cumulus-oocyte complex (COC). In the present study, we investigated the expression and activities of HSD11Bs in in vitro-matured (IVM) bovine COCs. Bovine COCs were matured in M199 supplemented with or without FSH and FCS. The expression of HSD11B1 and HSD11B2 was measured by using quantitative RT-PCR in denuded oocytes (DO) and cumulus cells (CC). Reductive and oxidative activities of HSD11Bs were determined by radiometric conversion assay using labeled cortisol, cortisone or dexamethasone in intact COCs, DO or CC in the presence or absence of 11-keto-progesterone (11kP), a selective inhibitor of HSD11B2. The presence of HSD11Bs in the oocyte was examined by immunofluorescence microscopy. Oocytes exclusively expressed HSD11B2 and its expression and activity were largely unchanged during IVM. CC, on the other hand, exclusively expressed HSD11B1 and its expression and activity were upregulated as IVM progressed. As a result, the net glucocorticoid metabolism shifted from inactivation to activation towards the end of IVM. These results indicate that the bovine COC is capable of modulating local glucocorticoid concentration and, by doing so, may create an environment that is favorable to ovulating oocyte for maturation, fertilization and subsequent development. PMID- 26519455 TI - Tracheostomy Complications as a Trigger for an Airway Rapid Response: Analysis and Quality Improvement Considerations. AB - OBJECTIVE: To analyze the subset of airway rapid response (ARR) calls related to tracheostomy identified over a 46-month period from August 2011 to May 2015 to determine proximate cause, intervention, and outcome and to develop process improvement initiatives. DESIGN: Single-institution multidisciplinary retrospective cohort study. SETTING: Tertiary care academic medical center in a large urban setting. SUBJECTS: Hospital inpatients with an in situ tracheostomy or laryngectomy who experienced an ARR. METHODS: Detailed review of operator, hospital, and patient records related to ARR system activations over a 46-month period. RESULTS: ARR was activated for 28 patients with existing tracheostomy. The cohort included open tracheostomy (n = 14), percutaneous tracheostomy (n = 8), laryngectomy stoma (n = 3), and indeterminate technique (n = 3). The most frequent triggers for emergency airway intervention were decannulation (n = 16), followed by mucus plugging (n = 4). The mean body mass index of ARR patients was higher than that of a comparator tracheostomy cohort (32.9 vs 26.3, P < .001). BMI was >40 in 9 ARR patients. There was 1 mortality in the series. CONCLUSIONS: Tracheostomy is a major trigger for ARR with potential fatal outcome. Factors that may contribute to tracheostomy emergencies include high body mass index, surgical technique for open tracheostomy or percutaneous tracheostomy, tracheostomy tube size, and bedside tracheostomy management. Results have triggered a hospital-wide practice improvement plan focused on tracheostomy awareness and documentation, discrete process changes, and implementation of guidelines for emergency management. PMID- 26519456 TI - Paranasal Sinus Balloon Catheter Dilation for Treatment of Chronic Rhinosinusitis: A Systematic Review and Meta-analysis. AB - OBJECTIVE: Paranasal sinus balloon catheter dilation (BCD) represents a commonly used tool in the management of chronic rhinosinusitis (CRS) for which the indications, utilization, and outcomes have not been well established. A systematic review and meta-analysis were undertaken to evaluate change in quality of life and sinus opacification following paranasal sinus BCD in the treatment of CRS. DATA SOURCES: MEDLINE and EMBASE databases. REVIEW METHODS: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were utilized to identify English-language studies reporting patient outcomes following BCD for CRS. Primary outcomes included the impact of BCD on validated measures of quality of life and sinonasal opacification. RESULTS: Systematic review identified 17 studies for qualitative analysis. Studies generally included cases with limited disease based on radiographic opacification. Five studies contained extractable data for change in 20-Item Sinonasal Outcome Test (SNOT-20) 1 year following BCD, with significant improvement in self-reported quality of life (P = .04). Five studies reported a significant change in paranasal sinus opacification following BCD (P < .001). Two studies directly compared change in SNOT-20 between BCD and endoscopic sinus surgery, without demonstration of significant difference in outcome (P = .07). Subgroup analysis found that change in SNOT-20 score was greater after BCD in the operating room than in the office (P = .004). CONCLUSION: Current evidence supporting the role of BCD in CRS remains incomplete. Long-term within-group improvements in quality-of-life and sinus opacification scores are demonstrated among a restricted adult population with CRS. Additional study is needed to further evaluate the role for BCD in specific settings and patient subgroups. PMID- 26519457 TI - Smoking Cessation and Electronic Cigarette Use among Head and Neck Cancer Patients. AB - OBJECTIVES: (1) Investigate electronic cigarette (e-cig) use among head and neck (HN) cancer patients; (2) define quit methods, success, motivations, and barriers to smoking cessation; and (3) determine the impact of e-cig use in smoking cessation. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary care center. METHODS: An in-office survey was administered to HN cancer patients >= 19 years of age with past/present tobacco use. Patient demographics were collected. Quit methods, success, and motivations/barriers were surveyed. The Alcohol Use Disorders Identification Test was used to correlate alcohol use and cessation. Independent variables associated with cessation were studied with Fisher's exact test and Student's t test. Subgroup analysis was performed for e-cig users. RESULTS: Of 110 eligible patients, 106 (96%) enrolled (83% male, 82% Caucasian), of whom 69 (65%) successfully quit. Age of first tobacco use did not differ between the smoking and cessation groups (P = .14), nor did hazardous drinking (30% smoking vs 14% cessation; P = .072). "Cold turkey" (ie, stopping abruptly without smoking cessation aids) was the most common method attempted (n = 88, 83%) and most successful (n = 65, 94%). There was no statistical difference in age, sex, race, drinking, or socioeconomic status between e-cig users and nonusers. Nonusers achieved higher quit rates as compared with e-cig users (72% vs 39%; P = .0057). E-cig use did not decrease the number of cigarettes smoked (463 cigarettes/month) versus that of nonusers (341 cigarettes/month; P = .2). Seventy percent of e-cig users wore a nicotine patch. CONCLUSIONS: HN cancer patients desire smoking cessation. E-cig did not decrease tobacco use, and patients who utilize e-cigs are less likely to achieve smoking cessation. PMID- 26519458 TI - Closer to the Mean: An Argument for Decreased Variance in Surgery. AB - Variation, long accepted to be the norm in otolaryngologic surgical practice, has recently come under scrutinization. Efforts can be seen daily in the operating room to standardize procedures with time-outs, checklists, and protocols. The thought is that by enforcing repetition and eliminating variation, it is possible to decrease human error and reduce cost. However, there is understandable resistance from surgeons in removing the "art" from surgery. We propose that standardization, if appropriately put into practice, can improve surgical outcomes and efficiency and even enhance resident education. PMID- 26519459 TI - Reduction of Pharyngocutaneous Fistulae in Laryngectomy Patients by a Comprehensive Performance Improvement Intervention. AB - OBJECTIVE: Pharyngocutaneous fistula is a common complication in laryngectomy patients, particularly in previously irradiated cases. We initiated a comprehensive performance improvement intervention in all head and neck surgery patients intended to reduce postoperative infection and fistulae rates. We report our review of outcomes within laryngectomy patients. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary referral center. SUBJECTS: Nineteen laryngectomy patients at risk of postoperative fistula formation. METHODS: We reviewed the medical records of all patients who had undergone laryngectomy procedures between January 2013 and April 2014. Clinicodemographic data were obtained, including history of diabetes, prior radiation therapy, type of reconstruction performed for closure of the pharyngeal defect, and the presence or absence of postoperative fistula. RESULTS: The study population comprised 19 laryngectomy patients. Prior to implementation of our performance improvement intervention, 8 of 11 (73%) patients undergoing laryngectomy developed postoperative fistulae. After intervention, 0 of 8 patients developed fistulae (P = .002). Prior radiation, diabetes mellitus, and overall stage were not associated with a reduction in fistula rate (P > .05). CONCLUSION: Comprehensive uniform application of a standard antibiotic prophylaxis, surgical technique, perioperative care, and treatment of comorbid conditions can significantly reduce and potentially eliminate fistulae in laryngectomy patients who are especially at risk. PMID- 26519460 TI - Tweaking Transcription to Stop AML Cell Growth. AB - A new compound with anti-leukemia activity perturbs gene transcription by modulating super-enhancer activity. PMID- 26519461 TI - Temporal Change in Phenotypic Behaviour in Patients with Crohn's Disease: Do Indian Patients Behave Differently from Western and Other Asian Patients? AB - BACKGROUND AND AIMS: In Western studies, one-third of patients with Crohn's disease have stricturing or penetrating disease at presentation and one-half will progress to complicated disease in 20 years. Asian studies indicate that the Asian disease phenotype may be different. Our aim was to study the disease behaviour in Indian patients with Crohn's disease. METHODS: In this hospital based study, we analysed [Montreal classification] disease phenotype, presence of perianal disease, need for intestinal surgery, and changes in the Montreal classification over time in Crohn's disease patients from our database. RESULTS: In the 178 patients (median age 35, interquartile range [IQR] 21 years; 97 males) with Crohn's disease, the proportion of various features was as follows. More patients had ileo-colonic[L3: 43.8%] than ileal[L1: 27.5%] or colonic[L2: 28.7%] disease. Perianal disease was seen in 11.8% at baseline. Non-stricturing, non fistulising disease[B1] was seen in 74.7%, 65.7%, 50%, and 44.4% at baseline, at 5, 10 and 15 years, respectively. Stricturing disease[B2] was seen in 21.4%, 21.9%, 28.9%, and 33.3%; penetrating disease[B3] in 3.9%, 11.4%, 21%, and 16.7%; and intestinal surgery was required in 10.7%, 20%, 34.2%, and 55.5%, respectively. KaplanMeier analysis showed no association between progression of disease and patient age or the location of the disease. CONCLUSIONS: Gender distribution and predominant ileo-colonic location of disease were similar to earlier Asian reports on Crohn's disease. Perianal disease was less frequent than reported in Western and other Asian studies. One-fourth of Indian patients had aggressive disease at diagnosis, but the tendency to progress towards aggressive disease over time was less pronounced than in Western patients. PMID- 26519463 TI - Donor Species Richness Determines Faecal Microbiota Transplantation Success in Inflammatory Bowel Disease. AB - BACKGROUND AND AIMS: Faecal microbiota transplantation is a successful therapy for patients with refractory Clostridium difficile infections. It has also been suggested as a treatment option for inflammatory bowel disease, given the role of the intestinal microbiota in this disease. We assessed the impact of faecal microbiota transplantation in patients with inflammatory bowel disease and studied predictors of clinical (non-)response in microbial profiles of donors and patients. METHODS: Fourteen refractory patients (8 with ulcerative colitis and 6 with Crohn's disease) underwent ileocolonoscopy with faecal microbiota transplantation through a nasojejunal (n = 9) or rectal (n = 5) tube. Efficacy was assessed by endoscopic healing at week 8, clinical activity scores and C reactive protein measurement. Faecal microbiota was analysed by 16S rDNA pyrosequencing. RESULTS: There was no significant improvement among the 6 patients with Crohn's disease at week 8 following faecal microbiota transplantation. One patient experienced temporary clinical remission for 6 weeks. In contrast, 2/8 patients with ulcerative colitis had endoscopic remission at week 8, and of the 6 remaining patients with ulcerative colitis, 1 reported temporary remission for 6 weeks. The donor microbiota richness and the number of transferred phylotypes were associated with treatment success. Persistent increased C-reactive protein 2 weeks after transplantation was predictive of failure of response. CONCLUSION: Faecal microbiota transplantation led to endoscopic and long-term (>2 years) remission in 2 out of 8 ulcerative colitis patients. Higher donor richness was associated with successful transplant. Therefore, faecal microbiota transplantation with donor prescreening could be a treatment option for selected refractory ulcerative colitis patients. PMID- 26519464 TI - Algorithmic co-optimization of genetic constructs and growth conditions: application to 6-ACA, a potential nylon-6 precursor. AB - Optimizing bio-production involves strain and process improvements performed as discrete steps. However, environment impacts genotype and a strain that is optimal under one set of conditions may not be under different conditions. We present a methodology to simultaneously vary genetic and process factors, so that both can be guided by design of experiments (DOE). Advances in DNA assembly and gene insulation facilitate this approach by accelerating multi-gene pathway construction and the statistical interpretation of screening data. This is applied to a 6-aminocaproic acid (6-ACA) pathway in Escherichia coli consisting of six heterologous enzymes. A 32-member fraction factorial library is designed that simultaneously perturbs expression and media composition. This is compared to a 64-member full factorial library just varying expression (0.64 Mb of DNA assembly). Statistical analysis of the screening data from these libraries leads to different predictions as to whether the expression of enzymes needs to increase or decrease. Therefore, if genotype and media were varied separately this would lead to a suboptimal combination. This is applied to the design of a strain and media composition that increases 6-ACA from 9 to 48 mg/l in a single optimization step. This work introduces a generalizable platform to co-optimize genetic and non-genetic factors. PMID- 26519465 TI - Zebrafish lacking functional DNA polymerase gamma survive to juvenile stage, despite rapid and sustained mitochondrial DNA depletion, altered energetics and growth. AB - DNA polymerase gamma (POLG) is essential for replication and repair of mitochondrial DNA (mtDNA). Mutations in POLG cause mtDNA instability and a diverse range of poorly understood human diseases. Here, we created a unique Polg animal model, by modifying polg within the critical and highly conserved polymerase domain in zebrafish. polg(+/-) offspring were indistinguishable from WT siblings in multiple phenotypic and biochemical measures. However, polg(-/-) mutants developed severe mtDNA depletion by one week post-fertilization (wpf), developed slowly and had regenerative defects, yet surprisingly survived up to 4 wpf. An in vivo mtDNA polymerase activity assay utilizing ethidium bromide (EtBr) to deplete mtDNA, showed that polg(+/-) and WT zebrafish fully recover mtDNA content two weeks post-EtBr removal. EtBr further reduced already low levels of mtDNA in polg(-/-) animals, but mtDNA content did not recover following release from EtBr. Despite significantly decreased respiration that corresponded with tissue-specific levels of mtDNA, polg(-/-) animals had WT levels of ATP and no increase in lactate. This zebrafish model of mitochondrial disease now provides unique opportunities for studying mtDNA instability from multiple angles, as polg(-/-) mutants can survive to juvenile stage, rather than lose viability in embryogenesis as seen in Polg mutant mice. PMID- 26519462 TI - Quality of Life in Swiss Paediatric Inflammatory Bowel Disease Patients: Do Patients and Their Parents Experience Disease in the Same Way? AB - BACKGROUND AND AIMS: Inflammatory bowel diseases (IBDs) may impair quality of life (QoL) in paediatric patients. We aimed to evaluate in a nationwide cohort whether patients experience QoL in a different way when compared with their parents. METHODS: Sociodemographic and psychosocial characteristics were prospectively acquired from paediatric patients and their parents included in the Swiss IBD Cohort Study. Disease activity was evaluated by the Paediatric Crohn's Disease Activity Index (PCDAI) and the Paediatric Ulcerative Colitis Activity Index (PUCAI). We assessed QoL using the KIDSCREEN questionnaire. The QoL domains were analysed and compared between children and parents according to type of disease, parents' age, origin, education and marital status. RESULTS: We included 110 children and parents (59 Crohn's disease [CD], 45 ulcerative colitis [UC], 6 IBD unclassified [IBDU]). There was no significant difference in QoL between CD and UC/IBDU, whether the disease was active or in remission. Parents perceived overall QoL, as well as 'mood', 'family' and 'friends' domains, lower than the children themselves, independently of their place of birth and education. However, better concordance was found on 'school performance' and 'physical activity' domains. Marital status and age of parents significantly influenced the evaluation of QoL. Mothers and fathers being married or cohabiting perceived significantly lower mood, family and friends domains than their children, whereas mothers living alone had a lower perception of the friends domain; fathers living alone had a lower perception of family and mood subscores. CONCLUSION: Parents of Swiss paediatric IBD patients significantly underestimate overall QoL and domains of QoL of their children independently of origin and education. PMID- 26519466 TI - Information Commons for Rice (IC4R). AB - Rice is the most important staple food for a large part of the world's human population and also a key model organism for plant research. Here, we present Information Commons for Rice (IC4R; http://ic4r.org), a rice knowledgebase featuring adoption of an extensible and sustainable architecture that integrates multiple omics data through community-contributed modules. Each module is developed and maintained by different committed groups, deals with data collection, processing and visualization, and delivers data on-demand via web services. In the current version, IC4R incorporates a variety of rice data through multiple committed modules, including genome-wide expression profiles derived entirely from RNA-Seq data, resequencing-based genomic variations obtained from re-sequencing data of thousands of rice varieties, plant homologous genes covering multiple diverse plant species, post-translational modifications, rice-related literatures and gene annotations contributed by the rice research community. Unlike extant related databases, IC4R is designed for scalability and sustainability and thus also features collaborative integration of rice data and low costs for database update and maintenance. Future directions of IC4R include incorporation of other omics data and association of multiple omics data with agronomically important traits, dedicating to build IC4R into a valuable knowledgebase for both basic and translational researches in rice. PMID- 26519469 TI - JuncDB: an exon-exon junction database. AB - Intron positions upon the mRNA transcript are sometimes remarkably conserved even across distantly related eukaryotic species. This has made the comparison of intron-exon architectures across orthologous transcripts a very useful tool for studying various evolutionary processes. Moreover, the wide range of functions associated with introns may confer biological meaning to evolutionary changes in gene architectures. Yet, there is currently no database that offers such comparative information. Here, we present JuncDB (http://juncdb.carmelab.huji.ac.il/), an exon-exon junction database dedicated to the comparison of architectures between orthologous transcripts. It covers nearly 40,000 sets of orthologous transcripts spanning 88 eukaryotic species. JuncDB offers a user-friendly interface, access to detailed information, instructive graphical displays of the comparative data and easy ways to download data to a local computer. In addition, JuncDB allows the analysis to be carried out either on specific genes, or at a genome-wide level for any selected group of species. PMID- 26519468 TI - ccmGDB: a database for cancer cell metabolism genes. AB - Accumulating evidence has demonstrated that rewiring of metabolism in cells is an important hallmark of cancer. The percentage of patients killed by metabolic disorder has been estimated to be 30% of the advanced-stage cancer patients. Thus, a systematic annotation of cancer cell metabolism genes is imperative. Here, we present ccmGDB (Cancer Cell Metabolism Gene DataBase), a comprehensive annotation database for cell metabolism genes in cancer, available at http://bioinfo.mc.vanderbilt.edu/ccmGDB. We assembled, curated, and integrated genetic, genomic, transcriptomic, proteomic, biological network and functional information for over 2000 cell metabolism genes in more than 30 cancer types. In total, we integrated over 260 000 somatic alterations including non-synonymous mutations, copy number variants and structural variants. We also integrated RNA Seq data in various primary tumors, gene expression microarray data in over 1000 cancer cell lines and protein expression data. Furthermore, we constructed cancer or tissue type-specific, gene co-expression based protein interaction networks and drug-target interaction networks. Using these systematic annotations, the ccmGDB portal site provides 6 categories: gene summary, phenotypic information, somatic mutations, gene and protein expression, gene co-expression network and drug pharmacological information with a user-friendly interface for browsing and searching. ccmGDB is developed and maintained as a useful resource for the cancer research community. PMID- 26519470 TI - Deciphering the mechanisms of developmental disorders: phenotype analysis of embryos from mutant mouse lines. AB - The Deciphering the Mechanisms of Developmental Disorders (DMDD) consortium is a research programme set up to identify genes in the mouse, which if mutated (or knocked-out) result in embryonic lethality when homozygous, and initiate the study of why disruption of their function has such profound effects on embryo development and survival. The project uses a combination of comprehensive high resolution 3D imaging and tissue histology to identify abnormalities in embryo and placental structures of embryonic lethal lines. The image data we have collected and the phenotypes scored are freely available through the project website (http://dmdd.org.uk). In this article we describe the web interface to the images that allows the embryo data to be viewed at full resolution in different planes, discuss how to search the database for a phenotype, and our approach to organising the data for an embryo and a mutant line so it is easy to comprehend and intuitive to navigate. PMID- 26519472 TI - The distinctive genetic architecture of ALS in mainland China. PMID- 26519467 TI - The current state of eukaryotic DNA base damage and repair. AB - DNA damage is a natural hazard of life. The most common DNA lesions are base, sugar, and single-strand break damage resulting from oxidation, alkylation, deamination, and spontaneous hydrolysis. If left unrepaired, such lesions can become fixed in the genome as permanent mutations. Thus, evolution has led to the creation of several highly conserved, partially redundant pathways to repair or mitigate the effects of DNA base damage. The biochemical mechanisms of these pathways have been well characterized and the impact of this work was recently highlighted by the selection of Tomas Lindahl, Aziz Sancar and Paul Modrich as the recipients of the 2015 Nobel Prize in Chemistry for their seminal work in defining DNA repair pathways. However, how these repair pathways are regulated and interconnected is still being elucidated. This review focuses on the classical base excision repair and strand incision pathways in eukaryotes, considering both Saccharomyces cerevisiae and humans, and extends to some important questions and challenges facing the field of DNA base damage repair. PMID- 26519473 TI - John Samuel Gould, MD (1939-2015). PMID- 26519471 TI - DNA targeting by the type I-G and type I-A CRISPR-Cas systems of Pyrococcus furiosus. AB - CRISPR-Cas systems silence plasmids and viruses in prokaryotes. CRISPR-Cas effector complexes contain CRISPR RNAs (crRNAs) that include sequences captured from invaders and direct CRISPR-associated (Cas) proteins to destroy corresponding invader nucleic acids. Pyrococcus furiosus (Pfu) harbors three CRISPR-Cas immune systems: a Cst (Type I-G) system with an associated Cmr (Type III-B) module at one locus, and a partial Csa (Type I-A) module (lacking known invader sequence acquisition and crRNA processing genes) at another locus. The Pfu Cmr complex cleaves complementary target RNAs, and Csa systems have been shown to target DNA, while the mechanism by which Cst complexes silence invaders is unknown. In this study, we investigated the function of the Cst as well as Csa system in Pfu strains harboring a single CRISPR-Cas system. Plasmid transformation assays revealed that the Cst and Csa systems both function by DNA silencing and utilize similar flanking sequence information (PAMs) to identify invader DNA. Silencing by each system specifically requires its associated Cas3 nuclease. crRNAs from the 7 shared CRISPR loci in Pfu are processed for use by all 3 effector complexes, and Northern analysis revealed that individual effector complexes dictate the profile of mature crRNA species that is generated. PMID- 26519474 TI - Hospital Alignment: What Does It Mean. PMID- 26519476 TI - Cadherin-11 endocytosis through binding to clathrin promotes cadherin-11-mediated migration in prostate cancer cells. AB - Cadherin-11 (Cad11) cell adhesion molecule plays a role in prostate cancer cell migration. Because disassembly of adhesion complexes through endocytosis of adhesion proteins has been shown to play a role in cell migration, we examined whether Cad11 endocytosis plays a role in Cad11-mediated migration. The mechanism by which Cad11 is internalized is unknown. Using a GST pulldown assay, we found that clathrin binds to the Cad11 cytoplasmic domain but not to that of E cadherin. Using deletion analysis, we identified a unique sequence motif, VFEEE, in the Cad11 membrane proximal region (amino acid residues 11-15) that binds to clathrin. Endocytosis assays using K(+)-depletion buffer showed that Cad11 internalization is clathrin dependent. Proximity ligation assays showed that Cad11 colocalizes with clathrin, and immunofluorescence assays showed that Cad11 localizes in vesicles that stain for the early endosomal marker Rab5. Deletion of the VFEEE sequence from the Cad11 cytoplasmic domain (Cad11-cla-Delta5) leads to inhibition of Cad11 internalization and reduces Cad11-mediated cell migration in C4-2B and PC3-mm2 prostate cancer cells. These observations suggest that clathrin mediated internalization of Cad11 regulates surface trafficking of Cad11 and that dynamic turnover of Cad11 regulates the migratory function of Cad11 in prostate cancer cells. PMID- 26519477 TI - Spatial control of Shoc2-scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5. AB - The scaffold protein Shoc2 accelerates activity of the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1) pathway. Mutations in Shoc2 result in Noonan-like RASopathy, a developmental disorder with a wide spectrum of symptoms. The amplitude of the ERK1/2 signals transduced through the complex is fine-tuned by the HUWE1-mediated ubiquitylation of Shoc2 and its signaling partner RAF-1. Here, we provide a mechanistic basis of how ubiquitylation of Shoc2 and RAF-1 is controlled. We demonstrate that the newly identified binding partner of Shoc2, the (AAA+) ATPase PSMC5, triggers translocation of Shoc2 to endosomes. At the endosomes, PSMC5 displaces the E3 ligase HUWE1 from the scaffolding complex to attenuate ubiquitylation of Shoc2 and RAF-1. We show that a RASopathy mutation that changes the subcellular distribution of Shoc2 leads to alterations in Shoc2 ubiquitylation due to the loss of accessibility to PSMC5. In summary, our results demonstrate that PSMC5 is a new and important player involved in regulating ERK1/2 signal transmission through the remodeling of Shoc2 scaffold complex in a spatially-defined manner. PMID- 26519478 TI - Plectin reinforces vascular integrity by mediating crosstalk between the vimentin and the actin networks. AB - Mutations in the cytoskeletal linker protein plectin result in multisystemic diseases affecting skin and muscle with indications of additional vascular system involvement. To study the mechanisms underlying vascular disorders, we established plectin-deficient endothelial cell and mouse models. We show that apart from perturbing the vimentin cytoskeleton of endothelial cells, plectin deficiency leads to severe distortions of adherens junctions (AJs), as well as tight junctions, accompanied by an upregulation of actin stress fibres and increased cellular contractility. Plectin-deficient endothelial cell layers were more leaky and showed reduced mechanical resilience in fluid-shear stress and mechanical stretch experiments. We suggest that the distorted AJs and upregulated actin stress fibres in plectin-deficient cells are rooted in perturbations of the vimentin cytoskeleton, as similar phenotypes could be mimicked in wild-type cells by disruption of vimentin filaments. In vivo studies in endothelium-restricted conditional plectin-knockout mice revealed significant distortions of AJs in stress-prone aortic arch regions and increased pulmonary vascular leakage. Our study opens a new perspective on cytoskeleton-controlled vascular permeability, where a plectin-organized vimentin scaffold keeps actomyosin contractility 'in check' and maintains AJ homeostasis. PMID- 26519479 TI - A mechanistic approach for modulation of chlorpyrifos-induced toxicity in human lymphocytes by melatonin, coenzyme Q10, and vinpocetine. AB - BACKGROUND: Chlorpyrifos (CP) is an organophosphorus pesticide that induces oxidative stress through the production of free radicals and depletes intracellular antioxidant reserves. In this study, the efficacy of three antioxidants (melatonin, coenzyme Q10 (CoQ10), and vinpocetine) on alleviation of toxic effects of CP was evaluated. MATERIALS AND METHODS: Cytotoxicity of CP, in the presence or absence of effective doses of melatonin, CoQ10, and vinpocetine, was determined in human peripheral blood lymphocytes after 72-h exposure. The levels of acetylcholinesterase (AChE) activity along with tumor necrosis factor alpha (TNF-alpha), as inflammatory index, were measured. Further, the viability and oxidative stress markers including cellular mitochondrial activity, cell death modes (apoptosis vs. necrosis), total antioxidant power (TAP), total thiol molecules (TTM), lipid peroxidation (LPO), and myeloperoxidase (MPO) activity were measured. RESULTS: CoQ10 and also the combination of the three antioxidants were the most notable in opposing toxicity of CP and led to increasing TAP and TTM; improvement of AChE activity; and lowering LPO, MPO, TNF-alpha, and apoptosis compared to CP alone. CONCLUSION: CP toxicity overwhelms the intracellular antioxidant defense mechanisms. Exogenous supplementation with antioxidants, such as the ones we have investigated, seems to be effective in the prevention of cytotoxicity of CP. PMID- 26519480 TI - A model of chlorpyrifos distribution and its biochemical effects on the liver and kidneys of rats. AB - This study investigated the main target sites of chlorpyrifos (CPF), its effect on biochemical indices, and the pathological changes observed in rat liver and kidney function using gas chromatography/mass spectrometry. Adult female Wistar rats (n = 12) were randomly assigned into two groups (one control and one test group; n = 6 each). The test group received CPF via oral gavage for 21 days at 5 mg/kg daily. The distribution of CPF was determined in various organs (liver, brain, heart, lung, kidney, ovary, adipose tissue, and skeletal muscle), urine and stool samples using GCMS. Approximately 6.18% of CPF was distributed in the body tissues, and the highest CPF concentration (3.80%) was found in adipose tissue. CPF also accumulated in the liver (0.29%), brain (0.22%), kidney (0.10%), and ovary (0.03%). Approximately 83.60% of CPF was detected in the urine. CPF exposure resulted in a significant increase in plasma transaminases, alkaline phosphatase, and total bilirubin levels, a significant reduction in total protein levels and an altered lipid profile. Oxidative stress due to CPF administration was also evidenced by a significant increase in liver malondialdehyde levels. The detrimental effects of CPF on kidney function consisted of a significant increase in plasma urea and creatinine levels. Liver and kidney histology confirmed the observed biochemical changes. In conclusion, CPF bioaccumulates over time and exerts toxic effects on animals. PMID- 26519481 TI - Vitamin D exposures reported to US poison centers 2000-2014: Temporal trends and outcomes. AB - There has been an increased use of vitamin D both by prescription and by the public as a widely available supplement. We evaluated 15 years of single substance vitamin D exposures to US poison centers. METHODS: Retrospective analysis of data from the National Poison Data System (NPDS) to evaluate clinical effects, trends, and outcomes of exposures to vitamin D over the period January 1, 2000 through June 30, 2014. Cases were limited to exposures involving vitamin D as a single substance. Multiple vitamin products that may have included vitamin D were not included in this study. RESULTS: From 2000 through June 30, 2014, there were 25,397 human exposures to vitamin D reported to NPDS. There was a mean of 196 cases per year from 2000 to 2005, followed by a 1600% increase in exposures between 2005 and 2011 to a new annual mean of 4535 exposures per year. The mean and median ages were 23.4 years and 10 years, respectively. There were no fatalities, but five (0.02%) major effect outcomes. Serious medical outcomes (major or moderate outcome) were infrequent, ranging from 2 patients/year to 22 patients/year. Clinical effects were primarily gastrointestinal (0.7-1.5%) and mild neurological effects (0.2-0.4%). There was a decline in the percentage of patients treated in a health care facility and of patients with serious medical outcome. CONCLUSION: Despite the enormous increase in number of exposures, there was not a significant increase in patients with a serious medical outcome. Rare severe outcomes may occur. PMID- 26519482 TI - Reduction in semen quality after mixed exposure to bisphenol A and isobutylparaben in utero and during lactation periods. AB - This study was performed to determine the effect of low-level exposure to a mixture of bisphenol A (BPA) and isobutylparaben (IBP) on male reproduction. Corn oil, BPA (0.05 mg/kg/day), IBP (2.5 mg/kg/day), and a BPA/IBP mixture (BPA 0.05 mg/kg/day and IBP 2.5 mg/kg/day) were administered once daily by oral gavage to female rats for 5 weeks from gestation day 6 to lactation day 21. Male pups were killed at postnatal day 70 and examined for developmental characteristics, body weight, testis and epididymis weight, steroid hormones, epididymal sperm count and motility, and histological changes in testis and epididymis. The BPA/IBP mixture produced a significant downregulation of epididymal sperm count and motility. BPA or IBP alone also reduced epididymal sperm count and motility compared to control. These results indicate that exposure to low-level BPA/IBP mixture, which showed no notable physiological response in early life stages, can decrease semen quality in adulthood. PMID- 26519483 TI - The Effect of Incorrect Reliability Information on Expectations, Perceptions, and Use of Automation. AB - OBJECTIVE: We examined how providing artificially high or low statements about automation reliability affected expectations, perceptions, and use of automation over time. BACKGROUND: One common method of introducing automation is providing explicit statements about the automation's capabilities. Research is needed to understand how expectations from such introductions affect perceptions and use of automation. METHOD: Explicit-statement introductions were manipulated to set higher-than (90%), same-as (75%), or lower-than (60%) levels of expectations in a dual-task scenario with 75% reliable automation. Two experiments were conducted to assess expectations, perceptions, compliance, reliance, and task performance over (a) 2 days and (b) 4 days. RESULTS: The baseline assessments showed initial expectations of automation reliability matched introduced levels of expectation. For the duration of each experiment, the lower-than groups' perceptions were lower than the actual automation reliability. However, the higher-than groups' perceptions were no different from actual automation reliability after Day 1 in either study. There were few differences between groups for automation use, which generally stayed the same or increased with experience using the system. CONCLUSION: Introductory statements describing artificially low automation reliability have a long-lasting impact on perceptions about automation performance. Statements including incorrect automation reliability do not appear to affect use of automation. APPLICATION: Introductions should be designed according to desired outcomes for expectations, perceptions, and use of the automation. Low expectations have long-lasting effects. PMID- 26519484 TI - Structural and functional diversity of peptide toxins from tarantula Haplopelma hainanum (Ornithoctonus hainana) venom revealed by transcriptomic, peptidomic, and patch clamp approaches. PMID- 26519485 TI - Signal transduction by BvgS sensor kinase. Binding of modulator nicotinate affects the conformation and dynamics of the entire periplasmic moiety. PMID- 26519486 TI - Discovery of Streptococcus pneumoniae serotype 6 variants with glycosyltransferases synthesizing two differing repeating units. PMID- 26519487 TI - Assessing the utility of an online registry for patients monitoring their own warfarin therapy. AB - AIMS: To evaluate the utility of an online self-report registry for patient self monitoring and self-management (PSM) of warfarin therapy. METHODS: A prospective observational study of UK-based patients undertaking PSM and recording their international normalised ratio (INR) data via an online registry. Consenting participants recorded INR test dates, results and warfarin dosages using the online registry for a period of 12 months. Participants reported demographic data, disease characteristics and treatment-related adverse events and provided feedback via a survey. Data accuracy was assessed through comparison of INR results recorded online with results stored on 19 INR testing devices. Percentage time spent within therapeutic time in range (TTR) was also examined. RESULTS: Eighty-seven per cent (39/45) completed the study period. Age ranged from 26 to 83 years, 44% had undertaken PSM for >5 years. Sixty-six per cent (25/38) reported that the registry was easy to navigate and use. Forty-two participants contributed a total of 1669 INR results. Agreement between self-reported INR results and source INR data was high (99%). Mean TTR was 76% (SD 18.58) with 83% having >60% TTR. CONCLUSIONS: Findings suggest that an online PSM registry is feasible, accurate and acceptable to patients. These findings require confirmation in a larger cohort of PSM patients. An online self-report registry could provide a valuable resource for gathering real world evidence of clinical effectiveness and safety of these developing models of care. PMID- 26519489 TI - Clinical Trial Registration. PMID- 26519491 TI - Living to Serve. PMID- 26519490 TI - Reply to the letter to the editor 'The ESMO Magnitude of Clinical Benefit Scaling Tool: from theory to practice' by Hartmann and the letter 'Comment on ESMO Magnitude of Clinical Benefit Scale' by Muhonen et al. PMID- 26519488 TI - IgG is involved in the migration and invasion of clear cell renal cell carcinoma. AB - OBJECTIVE: To investigate if IgG can be expressed in clear cell renal cell carcinoma (cRCC) , and the expression of IgG is involved in the cancer progression. If IgG expression can serve as a potential target in cancer therapies and be used for judging the prognosis. MATERIALS AND METHODS: By immunohistochemistry, we detected IgG in cRCC tissues(75 cRCC tissues and75 adjacent normal kidney tissues). Immunofluorescence and Western blot was used to detect the IgG in cRCC cell lines (786-0, ACHN and CAKI-I). By RT-PCR, the functional transcript of IgG heavy chain was detected. Knockdown of IgG was to analyze the proliferation, migration and invasion ability by CCK8, Transwell and Matrigel and apoptosis in cRCC cell lines. RESULTS: By immunohistochemistry, we found strong staining of IgG in 66 cases of 75 cRCC tissues and 63 cases of 75 adjacent normal kidney tissues. Immunofluorescence and Western blot was found IgG in cRCC cell lines. Knock-down IgG in cRCC cell lines resulted in significant inhibition of cell proliferation, migration and invasion, and the induction of apoptosis of the 786-0 cells. The immunohistochemistry analysis showed that high IgG expression significantly correlated with the poor differentiation and advanced stage of cRCC. CONCLUSION: IgG was over expressed in cRCC and was involved in the proliferation, migration and invasion of cancer cells. IgG expression may serve as a potential target in cancer therapies and could be used for judging the prognosis. PMID- 26519492 TI - Obstructive Sleep Apnea and the Role of Dental Hygienists. AB - PURPOSE: Obstructive Sleep Apnea (OSA) is the most commonly undiagnosed sleep disorder and is gaining more recognition in dentistry. Dental hygienists are at a pivotal position to discuss risks, characteristics, medical referrals and treatment options for OSA, as well as detect if an individual has OSA through questionnaires and other tools that can be done during an examination. Dental hygienists need to receive appropriate education about OSA and should be well versed in their knowledge to educate patients. The purpose of this literature review is to identify the role of the dental hygienist in detecting the risk of OSA and gain knowledge on the topic in order to educate patients. PMID- 26519493 TI - E-Model for Online Learning Communities. AB - PURPOSE: The purpose of this study was to explore the students' perspectives on the phenomenon of online learning communities while enrolled in a graduate dental hygiene program. METHODS: A qualitative case study method was designed to investigate the learners' experiences with communities in an online environment. A cross-sectional purposive sampling method was used. Interviews were the data collection method. As the original data were being analyzed, the researchers noted a pattern evolved indicating the phenomenon developed in stages. The data were re-analyzed and validated by 2 member checks. RESULTS: The participants' experiences revealed an e-model consisting of 3 stages of formal learning community development as core courses in the curriculum were completed and 1 stage related to transmuting the community to an informal entity as students experienced the independent coursework in the program. The development of the formal learning communities followed 3 stages: Building a Foundation for the Learning Community, Building a Supportive Network within the Learning Community and Investing in the Community to Enhance Learning. The last stage, Transforming the Learning Community, signaled a transition to an informal network of learners. The e-model was represented by 3 key elements: metamorphosis of relationships, metamorphosis through the affective domain and metamorphosis through the cognitive domain, with the most influential element being the affective development. CONCLUSION: The e-model describes a 4 stage process through which learners experience a metamorphosis in their affective, relationship and cognitive development. Synergistic learning was possible based on the interaction between synergistic relationships and affective actions. PMID- 26519495 TI - Performance of Dental Hygiene Students in Mass Fatality Training and Radiographic Imaging of Dental Remains. AB - PURPOSE: Mass fatality incidents can overwhelm local, state and national resources quickly. Dental hygienists are widely distributed and have the potential to increase response teams' capacity. However, appropriate training is required. The literature is void of addressing this type of training for dental hygienists and scant in dentistry. Hence, the purpose of this study was to assess one facet of such training: Whether the use of multimedia is likely to enhance educational outcomes related to mass fatality training. METHODS: A randomized, double-blind, pre- and post-test design was used to evaluate the effectiveness of comparable educational modules for 2 groups: a control group (n=19) that received low media training and a treatment group (n=20) that received multimedia training. Participants were second-year, baccalaureate dental hygiene students. Study instruments included a multiple-choice examination, a clinical competency based radiology lab scored via a standardized rubric, and an assessment of interest in mass fatality education as a specialty. ANOVA was used to analyze results. RESULTS: Participants' pre- and post-test scores and clinical competency based radiology lab scores increased following both educational approaches. Interest in mass fatality training also increased significantly for all participants (p=0.45). There was no significant difference in pre- and post-test multiple choice scores (p=0.6455), interest (p=0.9133) or overall competency based radiology lab scores (p=0.997) between groups. CONCLUSION: Various educational technique may be effective for mass fatality training. However, mass fatality training that incorporates multimedia is an appropriate avenue for training instruction. Continued research about multimedia's role in this specialty area is encouraged. PMID- 26519494 TI - Relationship of Musculoskeletal Disorder Pain to Patterns of Clinical Care in California Dental Hygienists. AB - PURPOSE: To relate self-reported levels of musculoskeletal disorder (MSD) pain and patterns of clinical care among members of the California Dental Hygienists' Association (CDHA), using a web-based survey. METHODS: The 24-item survey consisted of questions on patterns of clinical care, health habits, experience with MSD pain and demographic information. Recruitment information, including survey link and consent form, was emailed to the CDHA for distribution to its members. Descriptive analysis and cross tabulations were conducted using the online software program QualtricsTM. A Chi-square test determined statistical significant differences between the responses of the no/mild pain and moderate/severe pain groups. RESULTS: The response rate was 19% (500/2,700). Ninety-six percent of all respondents reported some level of MSD pain, causing nearly 25% of the respondents to miss work. Respondents, who reported moderate/severe pain, treated more patients per day (p=0.007) and on average treated greater numbers of moderate to heavy calculus patients (p=0.017) than those respondents reporting no/mild pain. Forty percent of the respondents in the moderate/severe group treated more than 8 patients per day. A higher percentage of respondents (p=0.000) in the moderate/severe pain group than in the no/mild group reported using proper posture less than 50% of treatment time. Using proper posture more than 50% of treatment time was more frequent in respondents who had practiced more than (p=0.012), compared with less than, 5 years. CONCLUSION: Workload and ergonomics are related to MSD pain. Educational programs need to emphasize the importance of these factors in the development and reduction of MSD pain. PMID- 26519496 TI - Assessing Evidence-Based Practice Knowledge, Attitudes, Access and Confidence Among Dental Hygiene Educators. AB - PURPOSE: To assess U.S. dental hygiene educators' evidence-based practice (EBP) knowledge, attitude, access and confidence and determine whether a correlation exists between assessment scores and level of education, length teaching and teaching setting (didactic, clinical or both). METHODS: A cross-sectional survey was conducted with a sample of dental hygiene faculty from all 334 U.S. dental hygiene schools. ANOVA and Pearson correlation coefficient statistical analysis were utilized to investigate relationships between demographic variables and application of evidence-based principles of patient care. RESULTS: This study involved a non-probability sample (n=124), since the total faculty among all U.S. dental hygiene schools was not determined. Analysis demonstrated a positive correlation between EBP knowledge, access and confidence scores indicating that as knowledge scores increased, so did confidence and access scores (r=0.313, p<0.01 and r=0.189, p<0.05, respectively). Study findings also revealed that faculty who held advanced educational degrees scored significantly higher in EBP knowledge (F3,120=2.81, p<0.04) and confidence (F3,120=7.26, p<0.00). CONCLUSION: This study suggests the level of EBP knowledge, attitude, access and confidence increases with additional education. Therefore, more EBP training may be necessary for faculty who do not possess advanced education. Results of the study indicate that further incorporation of EBP into dental hygiene curricula may occur as dental hygiene educators' knowledge of EBP increases, which in turn could enhance students' acquisition of EBP skills and their application of EBP principles toward patient care. PMID- 26519497 TI - Students' Perceptions of Teaching Methods That Bridge Theory to Practice in Dental Hygiene Education. AB - PURPOSE: Health care education requires students to connect classroom learning with patient care. The purpose of this study was to explore dental hygiene students' perceptions of teaching tools, activities and teaching methods useful in closing the gap between theory and practice as students transition from classroom learning into the clinical phase of their training. METHODS: This was an exploratory qualitative study design examining retrospective data from journal postings of a convenience sample of dental hygiene students (n=85). Open-ended questions related to patient care were given to junior and senior students to respond in a reflective journaling activity. A systematic approach was used to establish themes. RESULTS: Junior students predicted hands-on experiences (51%), critical thinking exercises (42%) and visual aids (27%) would be the most supportive in helping them connect theory to practice. Senior students identified critical thinking exercises (44%) and visual aids (44%) as the most beneficial in connecting classroom learning to patient care. Seniors also identified barriers preventing them from connecting theory to patient care. Barriers most often cited were not being able to see firsthand what is in the text (56%) and being unsure that what was seen during clinical practice was the same as what was taught (28%). CONCLUSION: Students recognized the benefits of critical thinking and problem solving skills after having experienced patient care and were most concerned with performance abilities prior to patient care experiences. This information will be useful in developing curricula to enhance critical thinking and problem solving skills. PMID- 26519499 TI - A message from the Guest Editor. PMID- 26519498 TI - Volunteerism among Dental Hygienists: The Relationship between a Practice Act Incentive, Behaviors, Perceptions and Motivational Orientations. AB - PURPOSE: Thirteen states in the nation authorize dental hygienists to satisfy re licensure requirements in part, by performing pro bono oral health services in lieu of participating in continuing education courses This study compared registered dental hygienists' donations of time and professional expertise, perceptions of volunteerism and motivational orientations as they practice in both the presence and absence of a practice act statute intended to incentivize volunteerism. METHODS: Volunteer behaviors, perceptions and motivational orientations of a non probability sample of 316 dental hygienists actively licensed by the states of Idaho or Utah, were assessed using an online survey which included the Self Determination Theory General Causality Orientations Scale (GCOS). Survey Monkey results were analyzed using Mann Whitney U tests, Chi Square analysis and an Independent Samples t-test at the 0.05 level of significance. RESULTS: No statistically significant differences were found between dental hygienists' volunteer behaviors, perceptions of volunteerism or scores on the GCOS Autonomy and Impersonal subscales in the 2 states studied. Statistical analysis of dental hygienists' mean scores on the GCOS measure of Controlled motivational orientation yielded a significant difference (p=0.001) among Utah and Idaho dental hygienists. CONCLUSION: Dental hygienists require evidence based practice statutes and regulations that keep pace with the need to provide universal access to comprehensive oral care. Additional research is required to determine the effectiveness of legislation intended to encourage registered dental hygienists' altruistic expressions. Dental hygienists are frequently unaware of opportunities to volunteer their services and how state practice act regulations impact those opportunities. PMID- 26519500 TI - Assessing the Role of Environmental Conditions on Efficacy Rates of Heterorhabditis indica (Nematoda: Heterorhabditidae) for Controlling Aethina tumida (Coleoptera: Nitidulidae) in Honey Bee (Hymenoptera: Apidae) Colonies: a Citizen Science Approach. AB - Certain species of entomopathogenic nematodes, such as Heterorhabditis indica Poinar, Karunakar & David, have the potential to be effective controls for Aethina tumida (Murray), or small hive beetles, when applied to the soil surrounding honey bee (Apis mellifera L.) hives. Despite the efficacy of H. indica, beekeepers have struggled to use them successfully as a biocontrol. It is believed that the sensitivity of H. indica to certain environmental conditions is the primary reason for this lack of success. Although research has been conducted to explore the impact of specific environmental conditions--such as soil moisture or soil temperature-on entomopathogenic nematode infectivity, no study to date has taken a comprehensive approach that considers the impact of multiple environmental conditions simultaneously. In exploring this, a multivariate logistic regression model was used to determine what environmental conditions resulted in reductions of A. tumida populations in honey bee colonies. To obtain the sample sizes necessary to run a multivariate logistic regression, this study utilized citizen scientist beekeepers and their hives from across the mid Atlantic region of the United States. Results suggest that soil moisture, soil temperatures, sunlight exposure, and groundcover contribute to the efficacy of H. indica in reducing A. tumida populations in A. mellifera colonies. The results of this study offer direction for future research on the environmental preferences of H. indica and can be used to educate beekeepers about methods for better utilizing H. indica as a biological control. PMID- 26519501 TI - CAMUR: Knowledge extraction from RNA-seq cancer data through equivalent classification rules. AB - MOTIVATION: Nowadays, knowledge extraction methods from Next Generation Sequencing data are highly requested. In this work, we focus on RNA-seq gene expression analysis and specifically on case-control studies with rule-based supervised classification algorithms that build a model able to discriminate cases from controls. State of the art algorithms compute a single classification model that contains few features (genes). On the contrary, our goal is to elicit a higher amount of knowledge by computing many classification models, and therefore to identify most of the genes related to the predicted class. RESULTS: We propose CAMUR, a new method that extracts multiple and equivalent classification models. CAMUR iteratively computes a rule-based classification model, calculates the power set of the genes present in the rules, iteratively eliminates those combinations from the data set, and performs again the classification procedure until a stopping criterion is verified. CAMUR includes an ad-hoc knowledge repository (database) and a querying tool.We analyze three different types of RNA-seq data sets (Breast, Head and Neck, and Stomach Cancer) from The Cancer Genome Atlas (TCGA) and we validate CAMUR and its models also on non-TCGA data. Our experimental results show the efficacy of CAMUR: we obtain several reliable equivalent classification models, from which the most frequent genes, their relationships, and the relation with a particular cancer are deduced. AVAILABILITY AND IMPLEMENTATION: dmb.iasi.cnr.it/camur.php CONTACT: emanuel@iasi.cnr.it SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26519502 TI - Bayesian inference with historical data-based informative priors improves detection of differentially expressed genes. AB - MOTIVATION: Modern high-throughput biotechnologies such as microarray are capable of producing a massive amount of information for each sample. However, in a typical high-throughput experiment, only limited number of samples were assayed, thus the classical 'large p, small n' problem. On the other hand, rapid propagation of these high-throughput technologies has resulted in a substantial collection of data, often carried out on the same platform and using the same protocol. It is highly desirable to utilize the existing data when performing analysis and inference on a new dataset. RESULTS: Utilizing existing data can be carried out in a straightforward fashion under the Bayesian framework in which the repository of historical data can be exploited to build informative priors and used in new data analysis. In this work, using microarray data, we investigate the feasibility and effectiveness of deriving informative priors from historical data and using them in the problem of detecting differentially expressed genes. Through simulation and real data analysis, we show that the proposed strategy significantly outperforms existing methods including the popular and state-of-the-art Bayesian hierarchical model-based approaches. Our work illustrates the feasibility and benefits of exploiting the increasingly available genomics big data in statistical inference and presents a promising practical strategy for dealing with the 'large p, small n' problem. AVAILABILITY AND IMPLEMENTATION: Our method is implemented in R package IPBT, which is freely available from https://github.com/benliemory/IPBT CONTACT: yuzhu@purdue.edu; zhaohui.qin@emory.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26519503 TI - MMR: a tool for read multi-mapper resolution. AB - MOTIVATION: Mapping high-throughput sequencing data to a reference genome is an essential step for most analysis pipelines aiming at the computational analysis of genome and transcriptome sequencing data. Breaking ties between equally well mapping locations poses a severe problem not only during the alignment phase but also has significant impact on the results of downstream analyses. We present the multi-mapper resolution (MMR) tool that infers optimal mapping locations from the coverage density of other mapped reads. RESULTS: Filtering alignments with MMR can significantly improve the performance of downstream analyses like transcript quantitation and differential testing. We illustrate that the accuracy (Spearman correlation) of transcript quantification increases by 15% when using reads of length 51. In addition, MMR decreases the alignment file sizes by more than 50%, and this leads to a reduced running time of the quantification tool. Our efficient implementation of the MMR algorithm is easily applicable as a post processing step to existing alignment files in BAM format. Its complexity scales linearly with the number of alignments and requires no further inputs. AVAILABILITY AND IMPLEMENTATION: Open source code and documentation are available for download at http://github.com/ratschlab/mmr Comprehensive testing results and further information can be found at http://bioweb.me/mmr. CONTACT: andre.kahles@ratschlab.org or gunnar.ratsch@ratschlab.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26519504 TI - Fit3D: a web application for highly accurate screening of spatial residue patterns in protein structure data. AB - The clarification of linkage between protein structure and function is still a demanding process and can be supported by comparison of spatial residue patterns, so-called structural motifs. However, versatile up-to-date resources to search for local structure similarities are rare. We present Fit3D, an easily accessible web application for highly accurate screening of structural motifs in 3D protein data. AVAILABILITY AND IMPLEMENTATION: The web application is accessible at https://biosciences.hs-mittweida.de/fit3d and program sources of the command line version were released under the terms of GNU GPLv3. Platform-independent binaries and documentations for offline usage are available at https://bitbucket.org/fkaiser/fit3d CONTACT: florian.kaiser@hs-mittweida.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26519505 TI - Two-pass alignment improves novel splice junction quantification. AB - MOTIVATION: Discovery of novel splicing from RNA sequence data remains a critical and exciting focus of transcriptomics, but reduced alignment power impedes expression quantification of novel splice junctions. RESULTS: Here, we profile performance characteristics of two-pass alignment, which separates splice junction discovery from quantification. Per sample, across a variety of transcriptome sequencing datasets, two-pass alignment improved quantification of at least 94% of simulated novel splice junctions, and provided as much as 1.7 fold deeper median read depth over those splice junctions. We further demonstrate that two-pass alignment works by increasing alignment of reads to splice junctions by short lengths, and that potential alignment errors are readily identifiable by simple classification. Taken together, two-pass alignment promises to advance quantification and discovery of novel splicing events. CONTACT: arul@med.umich.edu, nesvi@med.umich.edu AVAILABILITY AND IMPLEMENTATION: Two-pass alignment was implemented here as sequential alignment, genome indexing, and re-alignment steps with STAR. Full parameters are provided in Supplementary Table 2. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26519506 TI - Riboswitch Scanner: an efficient pHMM-based web-server to detect riboswitches in genomic sequences. AB - Riboswitches are non-coding RNA located in the 5' untranslated regions where they bind a target metabolite used to specify the riboswitch class and control the expression of associated genes. Accurate identification of riboswitches is the first step towards understanding their regulatory and functional roles in the cell. In this article, we describe a new web application named Riboswitch Scanner which provides an automated pipeline for pHMM-based detection of riboswitches in partial as well as complete genomic sequences rapidly, with high sensitivity and specificity. AVAILABILITY AND IMPLEMENTATION: Riboswitch Scanner can be freely accessed on the web at http://service.iiserkol.ac.in/~riboscan/ CONTACT: mukherjee.sumit89@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26519507 TI - Sources and range of long-term variability of rhythmic motor patterns in vivo. AB - The mechanisms of rhythmic motor pattern generation have been studied in detail in vitro, but the long-term stability and sources of variability in vivo are often not well described. The crab stomatogastric ganglion contains the well characterized gastric mill (chewing) and pyloric (filtering of food) central pattern generators. In vitro, the pyloric rhythm is stereotyped with little variation, but inter-circuit interactions and neuromodulation can alter both rhythm cycle frequency and structure. The range of variation of activity in vivo is, with few exceptions, unknown. Curiously, although the pattern-generating circuits in vivo are constantly exposed to hormonal and neural modulation, the majority of published data show only the unperturbed canonical motor patterns typically observed in vitro. Using long-term extracellular recordings (N=27 animals), we identified the range and sources of variability of the pyloric and gastric mill rhythms recorded continuously over 4 days in freely behaving Jonah crabs (Cancer borealis). Although there was no evidence of innate daily rhythmicity, a 12 h light-driven cycle did manifest. The frequency of both rhythms increased modestly, albeit consistently, during the 3 h before and 3 h after the lights changed. This cycle was occluded by sensory stimulation (feeding), which significantly influenced both pyloric cycle frequency and structure. This was the only instance where the structure of the rhythm changed. In unfed animals the structure remained stable, even when the frequency varied substantially. So, although central pattern generating circuits are capable of producing many patterns, in vivo outputs typically remain stable in the absence of sensory stimulation. PMID- 26519508 TI - Reproduction is not costly in terms of oxidative stress. AB - One of the core assumptions of life-history theory is the negative trade-off between current and future reproduction. Investment in current reproduction is expected to decrease future reproductive success or survival, but the physiological mechanisms underlying these costs are still obscure. To test for a role of oxidative stress, we measured oxidative damage to lipids and proteins in liver, heart, kidneys and muscles, as well as the level of antioxidants (total glutathione and catalase), in breeding and non-breeding bank voles. We used females from lines selected for high aerobic metabolism and non-selected control lines and manipulated their reproductive investment by decreasing or increasing litter size. Unlike in most previous studies, the females reared four consecutive litters (the maximum possible during a breeding season). Contrary to predictions, oxidative damage in reproducing females was decreased or not changed, and did not differ between the selected and control lines. Oxidative damage to lipids and proteins in the liver was lower in females that weaned enlarged litters than in non-breeding ones, and was intermediate in those with reduced litters. Oxidative damage to proteins in the heart also tended to be lower in breeding females than in non-breeding ones. A negative relationship between the level of oxidative damage and activity of catalase in kidneys indicated a protective action of antioxidants. In conclusion, our study falsified the hypothesis that oxidative stress is a part of the proximate physiological mechanism underlying the fundamental life-history trade-off between current and future reproduction. PMID- 26519509 TI - Experimental evidence that litter size imposes an oxidative challenge to offspring. AB - The post-natal environment in which young develop can substantially impact development, adult phenotype and fitness. In wild mice, competition among litter mates affects development rate and adult behaviour. We manipulated post-natal litter size in a cross-fostering design to investigate the effects of enlarged and reduced litter sizes on sexual signalling, oxidative stress and the links between them. Oxidative stress causes somatic damage that can limit reproductive success and lifespan, and is predicted to mediate investment in life-history traits, including sexual signals. We predicted that litter enlargement would cause an increase in potential oxidative stress, inhibit growth and reduce sexual signalling in male mice. Males reared in enlarged litters were smaller at weaning and, despite rapid growth immediately after weaning, remained smaller at 10 weeks of age than those reared in smaller litters. Females from enlarged litters were consistently smaller throughout post-weaning development and showed no increase in growth rate compared with females from reduced litters. In enlarged litters, protein thiol concentration was lower at weaning in the liver and kidneys, with this trend continuing at 10 weeks of age in the kidneys only. Aconitase enzyme activity was also lower in mice from enlarged litters at weaning and 10 weeks of age in the kidneys. Male mice from enlarged litters scent marked more frequently and had larger preputial glands than those from reduced litters, indicating greater sexual signalling investment irrespective of this increased oxidative challenge. The results of this study are the first to reveal oxidative costs of developmental stress in small mammals. PMID- 26519510 TI - Three-dimensional morphology and strain of the human Achilles free tendon immediately following eccentric heel drop exercise. AB - Our understanding of the immediate effects of exercise on Achilles free tendon transverse morphology is limited to single site measurements acquired at rest using 2D ultrasound. The purpose of this study was to provide a detailed 3D description of changes in Achilles free tendon morphology immediately following a single clinical bout of exercise. Freehand 3D ultrasound was used to measure Achilles free tendon length, and regional cross-sectional area (CSA), medio lateral (ML) diameter and antero-posterior (AP) diameter in healthy young adults (N=14) at rest and during isometric muscle contraction, immediately before and after 3*15 eccentric heel drops. Post-exercise reductions in transverse strain were limited to CSA and AP diameter in the mid-proximal region of the Achilles free tendon during muscle contraction. The change in CSA strain during muscle contraction was significantly correlated to the change in longitudinal strain (r= 0.72) and the change in AP diameter strain (r=0.64). Overall findings suggest the Achilles free tendon experiences a complex change in 3D morphology following eccentric heel drop exercise that manifests under contractile but not rest conditions, is most pronounced in the mid-proximal tendon and is primarily driven by changes in AP diameter strain and not ML diameter strain. PMID- 26519511 TI - The kinematics of directional control in the fast start of zebrafish larvae. AB - Larval fish use the 'fast start' escape response to rapidly evade the strike of a predator with a three-dimensional (3D) maneuver. Although this behavior is essential for the survival of fishes, it is not clear how its motion is controlled by the motor system of a larval fish. As a basis for understanding this control, we measured the high-speed kinematics of the body of zebrafish (Danio rerio) larvae when executing the fast start in a variety of directions. We found that the angular excursion in the lateral direction is correlated with the yaw angle in the initial stage of bending (stage 1). In this way, larvae moved in a manner similar to that reported for adult fish. However, larvae also have the ability to control the elevation of a fast start. We found that escapes directed downwards or upwards were achieved by pitching the body throughout the stages of the fast start. Changes in the pitching angle in each stage were significantly correlated with the elevation angle of the trajectory. Therefore, as a larva performs rapid oscillations in yaw that contribute to undulatory motion, the elevation of an escape is generated by more gradual and sustained changes in pitch. These observations are consistent with a model of motor control where elevation is directed through the differential activation of the epaxial and hypaxial musculature. This 3D motion could serve to enhance evasiveness by varying elevation without slowing the escape from a predator. PMID- 26519512 TI - Auditory modulation of wind-elicited walking behavior in the cricket Gryllus bimaculatus. AB - Animals flexibly change their locomotion triggered by an identical stimulus depending on the environmental context and behavioral state. This indicates that additional sensory inputs in different modality from the stimulus triggering the escape response affect the neuronal circuit governing that behavior. However, how the spatio-temporal relationships between these two stimuli effect a behavioral change remains unknown. We studied this question, using crickets, which respond to a short air-puff by oriented walking activity mediated by the cercal sensory system. In addition, an acoustic stimulus, such as conspecific 'song' received by the tympanal organ, elicits a distinct oriented locomotion termed phonotaxis. In this study, we examined the cross-modal effects on wind-elicited walking when an acoustic stimulus was preceded by an air-puff and tested whether the auditory modulation depends on the coincidence of the direction of both stimuli. A preceding 10 kHz pure tone biased the wind-elicited walking in a backward direction and elevated a threshold of the wind-elicited response, whereas other movement parameters, including turn angle, reaction time, walking speed and distance were unaffected. The auditory modulations, however, did not depend on the coincidence of the stimulus directions. A preceding sound consistently altered the wind-elicited walking direction and response probability throughout the experimental sessions, meaning that the auditory modulation did not result from previous experience or associative learning. These results suggest that the cricket nervous system is able to integrate auditory and air-puff stimuli, and modulate the wind-elicited escape behavior depending on the acoustic context. PMID- 26519513 TI - Mitochondrial Genetic Diversity of Eurasian Red Squirrels (Sciurus vulgaris) from Denmark. AB - Melanistic Eurasian red squirrels Sciurus vulgaris are commonly found on the Danish island of Funen. They are thought to represent native Danish squirrel types and are presently under threat from admixture with introduced red squirrels. In response, a conservation program was started in 2009 that involves the translocation of melanistic squirrels from Funen to the squirrel-free island of Langeland. Using mitochondrial DNA of 101 historical and modern samples from throughout Denmark, we assess for the first time population structure and mitochondrial genetic diversity of Danish squirrels compared to its larger pan Eurasian distribution. We find that Danish squirrels have low levels of genetic diversity, especially melanistic individuals. Bayesian skyline reconstructions show that Danish squirrels have most probably experienced a severe bottleneck within the last 200 years. Also, fine-scale genetic structure was found between squirrels from the regions of Funen, Zealand and Jutland, which mimics the insular geography of Denmark. Additional nuclear DNA analyses will be required to determine the precise admixture levels between original Danish and introduced squirrels and to locate unmixed candidate populations for specific conservation efforts. PMID- 26519514 TI - Plastic and Evolved Responses to Global Change: What Can We Learn from Comparative Transcriptomics? AB - Physiological plasticity and adaptive evolution may facilitate persistence in a changing environment. As a result, there is an interest in understanding species' capacities for plastic and evolved responses, and the mechanisms by which these responses occur. Transcriptome sequencing has become a powerful tool for addressing these questions, providing insight into otherwise unobserved effects of changing conditions on organismal physiology and variation in these effects among individuals and populations. Here, we review recent studies using comparative transcriptomics to understand plastic and evolutionary responses to changing environments. We focus on 2 areas where transcriptomics has played an important role: first, in understanding the genetic basis for local adaptation to current gradients as a proxy for future adaptation, and second, in understanding organismal responses to multiple stressors. We find most studies examining multiple stressors have tested the effects of each stressor individually; the few studies testing multiple stressors simultaneously have found synergistic effects on gene expression that would not have been predicted from single stressor studies. We discuss the importance of robust experimental design to allow for a more sophisticated characterization of transcriptomic responses and conclude by offering recommendations for future research, including integrating genomics with transcriptomics, testing gene regulatory networks, and comparing the equivalence of transcription to translation and the effects of environmental stress on the proteome. PMID- 26519515 TI - Novel localization of formin mDia2: importin beta-mediated delivery to and retention at the cytoplasmic side of the nuclear envelope. AB - The formin family proteins are important regulators of actin polymerization that are involved in many cellular processes. However, little is known about their specific cellular localizations. Here, we show that Diaphanous-related formin-3 (mDia2) localizes to the cytoplasmic side of the nuclear envelope. This localization of mDia2 to the nuclear rim required the presence of a nuclear localization signal (NLS) sequence at the mDia2 N-terminal. Consistent with this result, super-resolution images demonstrated that at the nuclear rim, mDia2 co localized with the nuclear pore complexes and a nuclear transport receptor, importin beta. Furthermore, an interaction between mDia2 and importin beta was detected by immunoprecipitation, and silencing of importin beta was shown to attenuate accumulation of mDia2 to the nuclear rim. We have shown previously that Ca(2+) entry leads to the assembly of perinuclear actin rim in an inverted formin 2 (INF2) dependent manner. mDia2, however, was not involved in this process since abolishing its localization at the nuclear rim by silencing of importin beta had no effect on actin assembly at the nuclear rim triggered by Ca(2+) stimulation. PMID- 26519516 TI - Context-specific comparison of sleep acquisition systems in Drosophila. AB - Sleep is conserved across phyla and can be measured through electrophysiological or behavioral characteristics. The fruit fly, Drosophila melanogaster, provides an excellent model for investigating the genetic and neural mechanisms that regulate sleep. Multiple systems exist for measuring fly activity, including video analysis and single-beam (SB) or multi-beam (MB) infrared (IR)-based monitoring. In this study, we compare multiple sleep parameters of individual flies using a custom-built video-based acquisition system, and commercially available SB- or MB-IR acquisition systems. We report that all three monitoring systems appear sufficiently sensitive to detect changes in sleep duration associated with diet, age, and mating status. Our data also demonstrate that MB IR detection appeared more sensitive than the SB-IR for detecting baseline nuances in sleep architecture, while architectural changes associated with varying life-history and environment were generally detected across all acquisition types. Finally, video recording of flies in an arena allowed us to measure the effect of ambient environment on sleep. These experiments demonstrate a robust effect of arena shape and size as well as light levels on sleep duration and architecture, and highlighting the versatility of tracking-based sleep acquisition. These findings provide insight into the context-specific basis for choosing between Drosophila sleep acquisition systems, describe a novel cost effective system for video tracking, and characterize sleep analysis using the MB IR sleep analysis. Further, we describe a modified dark-place preference sleep assay using video tracking, confirming that flies prefer to sleep in dark locations. PMID- 26519517 TI - Do circadian genes and ambient temperature affect substrate-borne signalling during Drosophila courtship? AB - Courtship vibratory signals can be air-borne or substrate-borne. They convey distinct and species-specific information from one individual to its prospective partner. Here, we study the substrate-borne vibratory signals generated by the abdominal quivers of the Drosophila male during courtship; these vibrations travel through the ground towards courted females and coincide with female immobility. It is not known which physical parameters of the vibrations encode the information that is received by the females and induces them to pause. We examined the intervals between each vibratory pulse, a feature that was reported to carry information for animal communication. We were unable to find evidence of periodic variations in the lengths of these intervals, as has been reported for fly acoustical signals. Because it was suggested that the genes involved in the circadian clock may also regulate shorter rhythms, we search for effects of period on the interval lengths. Males that are mutant for the period gene produced vibrations with significantly altered interpulse intervals; also, treating wild type males with constant light results in similar alterations to the interpulse intervals. Our results suggest that both the clock and light/dark cycles have input into the interpulse intervals of these vibrations. We wondered if we could alter the interpulse intervals by other means, and found that ambient temperature also had a strong effect. However, behavioural analysis suggests that only extreme ambient temperatures can affect the strong correlation between female immobility and substrate-borne vibrations. PMID- 26519518 TI - Mindbomb 2 is dispensable for embryonic development and Notch signalling in zebrafish. AB - The Mindbomb E3 ubiquitin protein ligase (Mib) family of proteins, Mib1 and Mib2, are RING finger ubiquitin ligases that share specific substrates. Mib1 is known to play essential roles in Notch signalling by ubiquitinating Notch ligands in vivo. Conversely, the functions of Mib2 in vivo are not fully understood, although Mib2 ubiquitinates multiple substrates, including Notch ligands, in vitro. To determine the Notch-dependent and Notch-independent functions of Mib2 in vivo, we generated mutant alleles of zebrafish mib2 using transcription activator-like effector nucleases (TALENs). We found that mib2 homozygous mutants were viable and fertile. Notch-mediated functions, such as early neurogenesis, somitogenesis, and pigment cell development, were not affected in mib2 mutant embryos. The lack of Notch-deficient phenotypes in mib2 mutants was not due to compensation by a mib2 maternal gene product because mib2 maternal-zygotic mutants also did not exhibit a distinct phenotype. We also showed that Mib2 does not redundantly act with Mib1 because the genetic ablation of mib2 neither enhanced mib(tfi91)-null phenotypes nor did it alleviate antimorphic mib(ta52b) phenotypes. Furthermore, the postulated Notch-independent roles of Mib2 in maintaining muscular integrity and N-methyl-D-aspartate receptor (NMDAR) activity were not evident: mib2 mutants did not show phenotypes different from that of the control embryos. These observations suggest that Mib2 is dispensable for embryonic development and does not have redundant functions with Mib1 in Notch signalling at least during early development stages in zebrafish. PMID- 26519520 TI - A message from the Editor-in-Chief. PMID- 26519521 TI - 'Moneyball' and time to be honest about preseason screening: it is a sham making no inroads on the 1 billion dollar injury costs in baseball. PMID- 26519519 TI - The marbled crayfish as a paradigm for saltational speciation by autopolyploidy and parthenogenesis in animals. AB - The parthenogenetic all-female marbled crayfish is a novel research model and potent invader of freshwater ecosystems. It is a triploid descendant of the sexually reproducing slough crayfish, Procambarus fallax, but its taxonomic status has remained unsettled. By cross-breeding experiments and parentage analysis we show here that marbled crayfish and P. fallax are reproductively separated. Both crayfish copulate readily, suggesting that the reproductive barrier is set at the cytogenetic rather than the behavioural level. Analysis of complete mitochondrial genomes of marbled crayfish from laboratory lineages and wild populations demonstrates genetic identity and indicates a single origin. Flow cytometric comparison of DNA contents of haemocytes and analysis of nuclear microsatellite loci confirm triploidy and suggest autopolyploidisation as its cause. Global DNA methylation is significantly reduced in marbled crayfish implying the involvement of molecular epigenetic mechanisms in its origination. Morphologically, both crayfish are very similar but growth and fecundity are considerably larger in marbled crayfish, making it a different animal with superior fitness. These data and the high probability of a divergent future evolution of the marbled crayfish and P. fallax clusters suggest that marbled crayfish should be considered as an independent asexual species. Our findings also establish the P. fallax-marbled crayfish pair as a novel paradigm for rare chromosomal speciation by autopolyploidy and parthenogenesis in animals and for saltational evolution in general. PMID- 26519522 TI - 'Serious thigh muscle strains': beware the intramuscular tendon which plays an important role in difficult hamstring and quadriceps muscle strains. AB - Why do some hamstring and quadriceps strains take much longer to repair than others? Which injuries are more prone to recurrence? Intramuscular tendon injuries have received little attention as an element in 'muscle strain'. In thigh muscles, such as rectus femoris and biceps femoris, the attached tendon extends for a significant distance within the muscle belly. While the pathology of most muscle injures occurs at a musculotendinous junction, at first glance the athlete appears to report pain within a muscle belly. In addition to the musculotendinous injury being a site of pathology, the intramuscular tendon itself is occasionally injured. These injuries have a variety of appearances on MRIs. There is some evidence that these injuries require a prolonged rehabilitation time and may have higher recurrence rates. Therefore, it is important to recognise the tendon component of a thigh 'muscle strain'. PMID- 26519523 TI - The anti-nociceptive potential of tilmicosin against chemical-induced but not thermal-induced pain in mice. AB - The aim of the present study was to assess the analgesic activity of the macrolide antibiotic tilmicosin at dose levels of 20 and 40 mg/kg of body weight, subcutaneously, against chemical- and thermal-induced acute pains, using acetic acid-induced writhing, formalin-induced pain, hot-plate, and tail-flick models in mice. Tilmicosin showed a dose-dependent significant decrease in the number of writhes in the acetic acid-induced writhing test and significant decrease in hind paw-licking time in the late phase of the formalin test. However, it did not cause any significant changes in the reaction times to heat stimuli in the hot plate and tail-flick models. In chemically-induced pains, both dose levels of tilmicosin showed significant effects compared to those of the corresponding standard peripheral analgesic, acetylsalicylic acid (200 mg/kg of body weight, subcutaneously) being 26.37+/-2.88 and 43.64+/-3.85% vs. 73.35+/-1.44% in acetic acid test; and 19.23+/-3.85 and 44.90+/-1.80% vs. 73.63+/-2.39% in the late phase of formalin test, respectively. These results may indicate that tilmicosin possesses a significant peripheral but not central analgesic potential that may be beneficial in symptomatic relief of pain when it is used in therapy, in addition to its well-established antibacterial effect. PMID- 26519524 TI - Effect of acetaminophen on sulfamethazine acetylation in male volunteers. AB - The effect of acetaminophen on sulfamethazine N-acetylation by human N acetyltrasferase-2 (NAT2) was studied in 19 (n=19) healthy male volunteers in two different phases. In the first phase of the study the volunteers were given an oral dose of sulfamethazine 500 mg alone and blood and urine samples were collected. After the 10-day washout period the same selected volunteers were again administered sulfamethazine 500 mg along with 1000 mg acetaminophen. The acetylation of sulfamethazine by human NAT2 in both phases with and without acetaminophen was determined by HPLC to establish their respective phenotypes. In conclusion obtained statistics of present study revealed that acetaminophen significantly (P<0.0001) decreased sulfamethazine acetylation in plasma of both slow and fast acetylator male volunteers. A highly significant (P<0.0001) decrease in plasma-free and total sulfamethazine concentration was also observed when acetaminophen was co-administered. Urine acetylation status in both phases of the study was found not to be in complete concordance with that of plasma. Acetaminophen significantly (P<0.0001) increased the acetyl, free and total sulfamethazine concentration in urine of both slow and fast acetylators. Urine acetylation analysis has not been found to be a suitable approach for phenotypic studies. PMID- 26519525 TI - The First Case of Pulmonary Alveolar Proteinosis With Small Cell Lung Carcinoma. AB - Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterized by alveolar accumulation of surfactant lipids and proteins. It is usually autoimmune and secondary to hematologic malignancy or infection. To date, only 5 case reports of PAP associated with lung cancers, including 2 cases of squamous cell carcinoma and 3 cases of adenocarcinoma, have been published. To the best of our knowledge, no case of PAP with small cell lung carcinoma has been reported thus far. We herein report the first case of PAP associated with small cell lung carcinoma. PMID- 26519526 TI - "Sclerosing" Pelvic Floor Rhabdomyoma. AB - PURPOSE: This article reports on a sclerosing perineal-perianal rhabdomyoma in an adult woman. A review of the literature disclosed no reference to this histological form of rhabdomyoma in women. METHODS AND RESULTS: We describe the case of a 48-year-old woman. At physical examination, a firm nodular lesion was identified in the left lateral perianal-perineal region. Histologically, it comprised rounded and elongated muscle fibers displaying no evident atypia, within a stroma exhibiting marked sclerosis and mild lymphoid infiltrate. At immunohistochemical examination, tumor cells stained for desmin, muscle-specific actin, and myogenin. CONCLUSIONS: Skeletal muscle rhabdomyomas are rare benign tumors, generally divided into 3 major categories depending on their clinical and morphological characteristics: fetal, adult, and genital. An unusual histological variant of the genital form has recently been reported in men, characterized by the presence of predominantly mature muscle fibers and marked sclerosis. We document such a lesion in a female patient for the first time. PMID- 26519528 TI - Inhibition of Histone Deacetylases Permits Lipopolysaccharide-Mediated Secretion of Bioactive IL-1beta via a Caspase-1-Independent Mechanism. AB - Histone deacetylase (HDAC) inhibitors (HDACi) are clinically approved anticancer drugs that have important immune-modulatory properties. We report the surprising finding that HDACi promote LPS-induced IL-1beta processing and secretion in human and murine dendritic cells and murine macrophages. HDACi/LPS-induced IL-1beta maturation and secretion kinetics differed completely from those observed upon inflammasome activation. Moreover, this pathway of IL-1beta secretion was dependent on caspase-8 but was independent of the inflammasome components NACHT, LRR, and PYD domains-containing protein 3, apoptosis-associated speck-like protein containing a carboxyl-terminal caspase-recruitment domain, and caspase-1. Genetic studies excluded HDAC6 and HDAC10 as relevant HDAC targets in this pathway, whereas pharmacological inhibitor studies implicated the involvement of HDAC11. Treatment of mice with HDACi in a dextran sodium sulfate-induced colitis model resulted in a strong increase in intestinal IL-1beta, confirming that this pathway is also operative in vivo. Thus, in addition to the conventional inflammasome-dependent IL-1beta cleavage pathway, dendritic cells and macrophages are capable of generating, secreting, and processing bioactive IL-1beta by a novel, caspase-8-dependent mechanism. Given the widespread interest in the therapeutic targeting of IL-1beta, as well as the use of HDACi for anti inflammatory applications, these findings have substantial clinical implications. PMID- 26519527 TI - Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN alpha Production in Women. AB - Increased IFN-alpha production contributes to the pathogenesis of infectious and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females produce more IFN-alpha upon TLR7 stimulation than pDCs from males, yet the mechanisms underlying this difference remain unclear. In this article, we show that basal levels of IFN regulatory factor (IRF) 5 in pDCs were significantly higher in females compared with males and positively correlated with the percentage of IFN alpha-secreting pDCs. Delivery of recombinant IRF5 protein into human primary pDCs increased TLR7-mediated IFN-alpha secretion. In mice, genetic ablation of the estrogen receptor 1 (Esr1) gene in the hematopoietic compartment or DC lineage reduced Irf5 mRNA expression in pDCs and IFN-alpha production. IRF5 mRNA levels furthermore correlated with ESR1 mRNA levels in human pDCs, consistent with IRF5 regulation at the transcriptional level by ESR1. Taken together, these data demonstrate a critical mechanism by which sex differences in basal pDC IRF5 expression lead to higher IFN-alpha production upon TLR7 stimulation in females and provide novel targets for the modulation of immune responses and inflammation. PMID- 26519529 TI - IL-21 Promotes Pulmonary Fibrosis through the Induction of Profibrotic CD8+ T Cells. AB - Type 2 effector production of IL-13, a demonstrated requirement in models of fibrosis, is routinely ascribed to CD4(+) Th2 cells. We now demonstrate a major role for CD8(+) T cells in a murine model of sterile lung injury. These pulmonary CD8(+) T cells differentiate into IL-13-producing Tc2 cells and play a major role in a bleomycin-induced model of fibrosis. Differentiation of these Tc2 cells in the lung requires IL-21, and bleomycin treated IL-21- and IL-21R-deficient mice develop inflammation but not fibrosis. Moreover, IL-21R-expressing CD8(+) cells are sufficient to reconstitute the fibrotic response in IL-21R-deficient mice. We further show that the combination of IL-4 and IL-21 skews naive CD8(+) T cells to produce IL-21, which, in turn, acts in an autocrine manner to support robust IL 13 production. Our data reveal a novel pathway involved in the onset and regulation of pulmonary fibrosis and identify Tc2 cells as key mediators of fibrogenesis. PMID- 26519530 TI - Myeloid Cell-Restricted Insulin/IGF-1 Receptor Deficiency Protects against Skin Inflammation. AB - Myeloid cells are key regulators of tissue homeostasis and disease. Alterations in cell-autonomous insulin/IGF-1 signaling in myeloid cells have recently been implicated in the development of systemic inflammation and insulin-resistant diabetes mellitus type 2 (DM). Impaired wound healing and inflammatory skin diseases are frequent DM-associated skin pathologies, yet the underlying mechanisms are elusive. In this study, we investigated whether myeloid cell restricted IR/IGF-1R signaling provides a pathophysiologic link between systemic insulin resistance and the development of cutaneous inflammation. Therefore, we generated mice lacking both the insulin and IGF-1 receptor in myeloid cells (IR/IGF-1R(MKO)). Whereas the kinetics of wound closure following acute skin injury was similar in control and IR/IGF-1R(MKO) mice, in two different conditions of dermatitis either induced by repetitive topical applications of the detergent SDS or by high-dose UV B radiation, IR/IGF-1R(MKO) mice were protected from inflammation, whereas controls developed severe skin dermatitis. Notably, whereas during the early phase in both inflammatory conditions the induction of epidermal proinflammatory cytokine expression was similar in control and IR/IGF 1R(MKO) mice, during the late stage, epidermal cytokine expression was sustained in controls but virtually abrogated in IR/IGF-1R(MKO) mice. This distinct kinetic of epidermal cytokine expression was paralleled by proinflammatory macrophage activation in controls and a noninflammatory phenotype in mutants. Collectively, our findings provide evidence for a proinflammatory IR/IGF-1R-dependent pathway in myeloid cells that plays a critical role in the dynamics of an epidermal dermal cross-talk in cutaneous inflammatory responses, and may add to the mechanistic understanding of diseases associated with disturbances in myeloid cell IR/IGF-1R signaling, including DM. PMID- 26519531 TI - Hydrophobic Interactions Are Key To Drive the Association of Tapasin with Peptide Transporter Subunit TAP2. AB - The transporter associated with Ag processing (TAP) translocates proteasomally derived cytosolic peptides into the endoplasmic reticulum. TAP is a central component of the peptide-loading complex (PLC), to which tapasin (TPN) recruits MHC class I (MHC I) and accessory chaperones. The PLC functions to facilitate and optimize MHC I-mediated Ag presentation. The heterodimeric peptide transporter consists of two homologous subunits, TAP1 and TAP2, each of which contains an N terminal domain (N-domain) in addition to a conserved transmembrane (TM) core segment. Each N-domain binds to the TM region of a single TPN molecule, which recruits one MHC I molecule to TAP1 and/or TAP2. Although both N-domains act as TPN-docking sites, various studies suggest a functional asymmetry within the PLC resulting in greater significance of the TAP2/TPN interaction for MHC loading. In this study, we demonstrate that the leucine-rich hydrophobic sequence stretches (with the central leucine residues L20 and L66) in the first and second TM helix of TAP2 form a functional unit acting as a docking site for optimal TPN/MHC I recruitment, whereas three distinct highly conserved arginine and/or aspartate residues inside or flanking these TM helices are dispensable. Moreover, we show that the physical interaction between TAP2 and TPN is disrupted by benzene, a compound known to interfere with hydrophobic interactions, such as those between pairing leucine zippers. No such effects were observed for the TAP1/TAP2 interaction or the complex formation between TPN and MHC I. We propose that TAP/TPN complex formation is driven by hydrophobic interactions via leucine zipper-like motifs. PMID- 26519532 TI - CD11c/CD18 Signals Very Late Antigen-4 Activation To Initiate Foamy Monocyte Recruitment during the Onset of Hypercholesterolemia. AB - Recruitment of foamy monocytes to inflamed endothelium expressing VCAM-1 contributes to the development of plaque during atherogenesis. Foamy CD11c(+) monocytes arise in the circulation during the onset of hypercholesterolemia and recruit to nascent plaque, but the mechanism of CD11c/CD18 and very late Ag-4 (VLA-4) activation and cooperation in shear-resistant cell arrest on VCAM-1 are ill defined. Within 1 wk of the onset of a Western high-fat diet (WD) in apolipoprotein E-deficient mice, an inflammatory subset of foamy monocytes emerged that made up one fourth of the circulating population. These cells expressed ~3-fold more CD11c/CD18 and 50% higher chemokine receptors than nonfoamy monocytes. Recruitment from blood to a VCAM-1 substrate under shear stress was assessed ex vivo using a unique artery-on-a-chip microfluidic assay. It revealed that foamy monocytes from mice on a WD increased their adhesiveness over 5 wk, rising to twice that of mice on a normal diet or CD11c(-/-) mice fed a WD. Shear-resistant capture of foamy human or mouse monocytes was initiated by high-affinity CD11c, which directly activated VLA-4 adhesion via phosphorylated spleen tyrosine kinase and paxillin within focal adhesion complexes. Lipid uptake and activation of CD11c are early and critical events in signaling VLA-4 adhesive function on foamy monocytes competent to recruit to VCAM-1 on inflamed arterial endothelium. PMID- 26519533 TI - Natural IgM Switches the Function of Lipopolysaccharide-Activated Murine Bone Marrow-Derived Dendritic Cells to a Regulatory Dendritic Cell That Suppresses Innate Inflammation. AB - We have previously shown that polyclonal natural IgM protects mice from renal ischemia/reperfusion injury (IRI) by inhibiting the reperfusion inflammatory response. We hypothesized that a potential mechanism involved IgM modulation of dendritic cells (DC), as we observed high IgM binding to splenic DC. To test this hypothesis, we pretreated bone marrow-derived DC (BMDC) with polyclonal murine or human IgM prior to LPS activation and demonstrated that 0.5 * 10(6) IgM/LPS pretreated BMDC, when injected into wild-type C57BL/6 mice 24 h before renal ischemia, protect mice from developing renal IRI. We show that this switching of LPS-activated BMDC to a regulatory phenotype requires modulation of BMDC function that is mediated by IgM binding to nonapoptotic BMDC receptors. Regulatory BMDC require IL-10 and programmed death 1 as well as downregulation of CD40 and p65 NF kappaB phosphorylation to protect in renal IRI. Blocking the programmed death ligand 1 binding site just before i.v. injection of IgM/LPS-pretreated BMDC or using IL-10 knockout BMDC fails to induce protection. Similarly, IgM/LPS pretreated BMDC are rendered nonprotective by increasing CD40 expression and phosphorylation of p65 NF-kappaB. How IgM/LPS regulatory BMDC suppress in vivo ischemia-induced innate inflammation remains to be determined. However, we show that suppression is dependent on other in vivo regulatory mechanisms in the host, that is, CD25(+) T cells, B cells, IL-10, and circulating IgM. There was no increase in Foxp3(+) regulatory T cells in the spleen either before or after renal IRI. Collectively, these findings show that natural IgM anti-leukocyte Abs can switch BMDC to a regulatory phenotype despite the presence of LPS that ordinarily induces BMDC maturation. PMID- 26519534 TI - beta-Glucan-Activated Human B Lymphocytes Participate in Innate Immune Responses by Releasing Proinflammatory Cytokines and Stimulating Neutrophil Chemotaxis. AB - B lymphocytes play an essential regulatory role in the adaptive immune response through Ab production during infection. A less known function of B lymphocytes is their ability to respond directly to infectious Ags through stimulation of pattern recognition receptors expressed on their surfaces. beta-Glucans are carbohydrates present in the cell wall of many pathogenic fungi that can be detected in the peripheral blood of patients during infection. They have been shown to participate in the innate inflammatory response, as they can directly activate peripheral macrophages and dendritic cells. However, their effect as direct stimulators of B lymphocytes has not been yet fully elucidated. The aim of this study was to examine the molecular mechanisms and cytokine profiles generated following beta-glucan stimulation of B lymphocytes, compared with the well-established TLR-9 agonist CpG oligodeoxynucleotide (CpG), and study the participation of beta-glucan-stimulated B cells in the innate immune response. In this article, we demonstrate that beta-glucan-activated B lymphocytes upregulate proinflammatory cytokines (TNF-alpha, IL-6, and IL-8). Of interest, beta-glucan, unlike CpG, had no effect on B lymphocyte proliferation or IgM production. When compared with CpG (TLR9 agonist), beta-glucan-activated cells secreted significantly higher levels of IL-8. Furthermore, IL-8 secretion was partially mediated by Dectin-1 and required SYK, MAPKs, and the transcription factors NF kappaB and AP-1. Moreover, we observed that conditioned media from beta-glucan stimulated B lymphocytes elicited neutrophil chemotaxis. These studies suggest that beta-glucan-activated B lymphocytes have an important and novel role in fungal innate immune responses. PMID- 26519535 TI - Type I IFNs Act upon Hematopoietic Progenitors To Protect and Maintain Hematopoiesis during Pneumocystis Lung Infection in Mice. AB - Although acquired bone marrow failure (BMF) is considered a T cell-mediated autoimmune disease, few studies have considered contributing roles of innate immune deviations following otherwise innocuous infections as a cause underlying the immune defects that lead to BMF. Type I IFN signaling plays an important role in protecting hematopoiesis during systemic stress responses to the opportunistic fungal pathogen Pneumocystis. During Pneumocystis lung infection, mice deficient in both lymphocytes and type I IFN receptor (IFrag(-/-)) develop rapidly progressing BMF associated with accelerated hematopoietic cell apoptosis. However, the communication pathway eliciting the induction of BMF in response to this strictly pulmonary infection has been unclear. We developed a conditional null allele of Ifnar1 and used tissue-specific induction of the IFrag(-/-) state and found that, following Pneumocystis lung infection, type I IFNs act not only in the lung to prevent systemic immune deviations, but also within the progenitor compartment of the bone marrow to protect hematopoiesis. In addition, transfer of sterile-filtered serum from Pneumocystis-infected mice as well as i.p. injection of Pneumocystis into uninfected IFrag(-/-) mice induced BMF. Although specific cytokine deviations contribute to induction of BMF, immune-suppressive treatment of infected IFrag(-/-) mice ameliorated its progression but did not prevent loss of hematopoietic progenitor functions. This suggested that additional, noncytokine factors also target and impair progenitor functions; and interestingly, fungal beta-glucans were also detected in serum. In conclusion, our data demonstrate that type 1 IFN signaling protects hematopoiesis within the bone marrow compartment from the damaging effects of proinflammatory cytokines elicited by Pneumocystis in the lung and possibly at extrapulmonary sites via circulating fungal components. PMID- 26519536 TI - WDR82 Negatively Regulates Cellular Antiviral Response by Mediating TRAF3 Polyubiquitination in Multiple Cell Lines. AB - Upon virus infection, retinoic acid-inducible gene I-like receptors in host cells recognize viral RNA and activate type I IFN expression. Previously, we identified WD repeat domain (WDR) 5 as one positive regulator for pathway activation. In this study, we report that WDR82, a homolog protein of WDR5, acts opposite to WDR5 and inhibits the activation of the retinoic acid-inducible gene I signaling pathway. WDR82 overexpression inhibits virus-triggered pathway activation, whereas its knockdown enhances induced IFN-beta expression. WDR82 is localized on the mitochondria, and its first N-terminal WD40 domain is critical for localization. WDR82 interacts with TNFR-associated factor (TRAF) 3, and its overexpression promotes K48-linked, but not K63-linked, polyubiquitination on TRAF3. Furthermore, WDR82 knockdown inhibits viral replication in the cell, whereas its overexpression has the opposite effect. Interestingly, WDR82 regulates Sendai virus-induced IFNB1 expression in a cell type-specific manner. Taken together, our findings demonstrate that WDR82 is a negative regulator of virus-triggered type I IFNs pathway through mediating TRAF3 polyubiquitination status and stability on mitochondria. PMID- 26519537 TI - Pak2 Controls Acquisition of NKT Cell Fate by Regulating Expression of the Transcription Factors PLZF and Egr2. AB - NKT cells constitute a small population of T cells developed in the thymus that produce large amounts of cytokines and chemokines in response to lipid Ags. Signaling through the Valpha14-Jalpha18 TCR instructs commitment to the NKT cell lineage, but the precise signaling mechanisms that instruct their lineage choice are unclear. In this article, we report that the cytoskeletal remodeling protein, p21-activated kinase 2 (Pak2), was essential for NKT cell development. Loss of Pak2 in T cells reduced stage III NKT cells in the thymus and periphery. Among different NKT cell subsets, Pak2 was necessary for the generation and function of NKT1 and NKT2 cells, but not NKT17 cells. Mechanistically, expression of Egr2 and promyelocytic leukemia zinc finger (PLZF), two key transcription factors for acquiring the NKT cell fate, were markedly diminished in the absence of Pak2. Diminished expression of Egr2 and PLZF were not caused by aberrant TCR signaling, as determined using a Nur77-GFP reporter, but were likely due to impaired induction and maintenance of signaling lymphocyte activation molecule 6 expression, a TCR costimulatory receptor required for NKT cell development. These data suggest that Pak2 controls thymic NKT cell development by providing a signal that links Egr2 to induce PLZF, in part by regulating signaling lymphocyte activation molecule 6 expression. PMID- 26519538 TI - Behavioral and cognitive outcomes for clinical trials in children with neurofibromatosis type 1. AB - OBJECTIVE: To evaluate the appropriateness of cognitive and behavioral outcome measures in clinical trials in neurofibromatosis type 1 (NF1) by analyzing the degree of deficits compared to reference groups, test-retest reliability, and how scores correlate between outcome measures. METHODS: Data were analyzed from the Simvastatin for cognitive deficits and behavioral problems in patients with neurofibromatosis type 1 (NF1-SIMCODA) trial, a randomized placebo-controlled trial of simvastatin for cognitive deficits and behavioral problems in children with NF1. Outcome measures were compared with age-specific reference groups to identify domains of dysfunction. Pearson r was computed for before and after measurements within the placebo group to assess test-retest reliability. Principal component analysis was used to identify the internal structure in the outcome data. RESULTS: Strongest mean score deviations from the reference groups were observed for full-scale intelligence (-1.1 SD), Rey Complex Figure Test delayed recall (-2.0 SD), attention problems (-1.2 SD), and social problems (-1.1 SD). Long-term test-retest reliability were excellent for Wechsler scales (r > 0.88), but poor to moderate for other neuropsychological tests (r range 0.52 0.81) and Child Behavioral Checklist subscales (r range 0.40-0.79). The correlation structure revealed 2 strong components in the outcome measures behavior and cognition, with no correlation between these components. Scores on psychosocial quality of life correlate strongly with behavioral problems and less with cognitive deficits. CONCLUSIONS: Children with NF1 show distinct deficits in multiple domains. Many outcome measures showed weak test-retest correlations over the 1-year trial period. Cognitive and behavioral outcomes are complementary. This analysis demonstrates the need to include reliable outcome measures on a variety of cognitive and behavioral domains in clinical trials for NF1. PMID- 26519539 TI - Moderate alcohol intake reduces risk of ischemic stroke in Korea. AB - OBJECTIVE: We undertook a population-based, case-control study to examine a dose response relationship between alcohol intake and risk of ischemic stroke in Koreans who had different alcoholic beverage type preferences than Western populations and to examine the effect modifications by sex and ischemic stroke subtypes. METHODS: Cases (n = 1,848) were recruited from patients aged 20 years or older with first-ever ischemic stroke. Stroke-free controls (n = 3,589) were from the fourth and fifth Korean National Health and Nutrition Examination Survey and were matched to the cases by age (+/-3 years), sex, and education level. All participants completed an interview using a structured questionnaire about alcohol intake. RESULTS: Light to moderate alcohol intake, 3 or 4 drinks (1 drink = 10 g ethanol) per day, was significantly associated with a lower odds of ischemic stroke after adjusting for potential confounders (no drinks: reference; <1 drink: odds ratio 0.38, 95% confidence interval 0.32-0.45; 1-2 drinks: 0.45, 0.36-0.57; and 3-4 drinks: 0.54, 0.39-0.74). The threshold of alcohol effect in women was slightly lower than that in men (up to 1-2 drinks in women vs up to 3-4 drinks in men), but this difference was not statistically significant. There was no statistical interaction between alcohol intake and the subtypes of ischemic stroke (p = 0.50). The most frequently used alcoholic beverage was one native to Korea, soju (78% of the cases), a distilled beverage with 20% ethanol by volume. CONCLUSIONS: Our findings suggest that light to moderate distilled alcohol consumption may reduce the risk of ischemic stroke in Koreans. PMID- 26519540 TI - Cognitive training in Parkinson disease: A systematic review and meta-analysis. AB - OBJECTIVE: To quantify the effects of cognitive training (CT) on cognitive and behavioral outcome measures in patients with Parkinson disease (PD). METHODS: We systematically searched 5 databases for randomized controlled trials (RCTs) of CT in patients with PD reporting cognitive or behavioral outcomes. Efficacy was measured as standardized mean difference (Hedges g) of post-training change. RESULTS: Seven studies encompassing 272 patients with Hoehn & Yahr Stages 1-3 were included. The overall effect of CT over and above control conditions was small but statistically significant (7 studies: g = 0.23, 95% confidence interval [CI] 0.014-0.44, p = 0.037). True heterogeneity across studies was low (I(2) = 0%) and there was no evidence of publication bias. Larger effect sizes were noted on working memory (4 studies: g = 0.74, CI 0.32-1.17, p = 0.001), processing speed (4 studies: g = 0.31, CI 0.01-0.61, p = 0.04), and executive function (5 studies: g = 0.30, CI 0.01-0.58, p = 0.042), while effects on measures of global cognition (4 studies), memory (5 studies), visuospatial skills (4 studies), and depression (5 studies), as well as attention, quality of life, and instrumental activities of daily living (3 studies each), were not statistically significant. No adverse events were reported. CONCLUSIONS: Though still small, the current body of RCT evidence indicates that CT is safe and modestly effective on cognition in patients with mild to moderate PD. Larger RCTs are necessary to examine the utility of CT for secondary prevention of cognitive decline in this population. PMID- 26519541 TI - Practice improvement requires more than guidelines and quality measures. AB - Increasing emphasis on improving health care quality has led to a variety of programs that require neurologists to be familiar with the concept of systematic quality improvement. While they vary in extent, these quality improvement programs and their attendant costs now have implications for physician payment and certification. In response to these factors, the American Academy of Neurology is establishing a clinical quality data registry. This article reviews evidence demonstrating the ability of quality improvement initiatives to improve care, the role of clinical quality data registries in the identification and mitigation of gaps in care, and the principles to be considered in development of registry-based quality improvement programs. It addresses the key question: Is the effort worthwhile? PMID- 26519542 TI - Differences in the burden of psychiatric comorbidity in MS vs the general population. AB - OBJECTIVE: We aimed to compare the incidence and prevalence of psychiatric comorbidity in the multiple sclerosis (MS) population and in controls matched for age, sex, and geographic area. METHODS: Using population-based administrative health data from 4 Canadian provinces, we identified 2 cohorts: 44,452 persons with MS and 220,849 controls matched for age, sex, and geographic area. We applied validated case definitions to estimate the incidence and prevalence of depression, anxiety, bipolar disorder, and schizophrenia from 1995 to 2005. We pooled the results across provinces using meta-analyses. RESULTS: Of the MS cases, 31,757 (71.3%) were women with a mean (SD) age at the index date of 43.8 (13.7) years. In 2005, the annual incidence of depression per 100,000 persons with MS was 979 while the incidence of anxiety was 638, of bipolar disorder was 328, and of schizophrenia was 60. The incidence and prevalence estimates of all conditions were higher in the MS population than in the matched population. Although the incidence of depression was higher among women than men in both populations, the disparity in the incidence rates between the sexes was lower in the MS population (incidence rate ratio 1.26; 95% confidence interval: 1.07-1.49) than in the matched population (incidence rate ratio 1.50; 95% confidence interval: 1.21-1.86). Incidence rates were stable over time while prevalence increased slightly. CONCLUSIONS: Psychiatric comorbidity is common in MS, and more frequently affected the MS population than a matched population, although the incidence was stable over time. Men with MS face a disproportionately greater relative burden of depression when they develop MS than women. PMID- 26519544 TI - The AAN and the triple aim. PMID- 26519543 TI - Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome. AB - OBJECTIVES: To describe the clinical and electrophysiologic features of synaptotagmin II (SYT2) mutations, a novel neuromuscular syndrome characterized by foot deformities and fatigable ocular and lower limb weakness, and the response to modulators of acetylcholine release. METHODS: We performed detailed clinical and neurophysiologic assessment in 2 multigenerational families with dominant SYT2 mutations (c.920T>G [p.Asp307Ala] and c.923G>A [p.Pro308Leu]). Serial clinical and electrophysiologic assessments were performed in members of one family treated first with pyridostigmine and then with 3,4-diaminopyridine. RESULTS: Electrophysiologic testing revealed features indicative of a presynaptic deficit in neurotransmitter release with posttetanic potentiation lasting up to 60 minutes. Treatment with 3,4-diaminopyridine produced both a clinical benefit and an improvement in neuromuscular transmission. CONCLUSION: SYT2 mutations cause a novel and potentially treatable complex presynaptic congenital myasthenic syndrome characterized by motor neuropathy causing lower limb wasting and foot deformities, with reflex potentiation following exercise and a uniquely prolonged period of posttetanic potentiation. PMID- 26519545 TI - Developmental effects of antiepileptic drugs and the need for improved regulations. AB - Antiepileptic drugs (AEDs) are among the most common teratogenic drugs prescribed to women of childbearing age. AEDs can induce both anatomical (malformations) and behavioral (cognitive/behavioral deficits) teratogenicity. Only in the last decade have we begun to truly discriminate differential AED developmental effects. Fetal valproate exposure carries a special risk for both anatomical and behavioral teratogenic abnormalities, but the mechanisms and reasons for individual variability are unknown. Intermediate anatomical risks exist for phenobarbital and topiramate. Several AEDs (e.g., lamotrigine and levetiracetam) appear to possess low risks for both anatomical and behavioral teratogenesis. Despite advances in the past decade, our knowledge of the teratogenic risks for most AEDs and the underlying mechanisms remain inadequate. Further, the long-term effects of AEDs in neonates and older children remain uncertain. The pace of progress is slow given the lifelong consequences of diminished developmental outcomes, exposing children unnecessarily to potential adverse effects. It is imperative that new approaches be employed to determine risks more expediently. Our recommendations include a national reporting system for congenital malformations, federal funding of the North American AED Pregnancy Registry, routine meta-analyses of cohort studies to detect teratogenic signals, monitoring of AED prescription practices for women, routine preclinical testing of all new AEDs for neurodevelopmental effects, more specific Food and Drug Administration requirements to establish differential AED cognitive effects in children, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms for AED-induced anatomical and behavioral teratogenesis. PMID- 26519546 TI - More than just a movement disorder: Why cognitive training is needed in Parkinson disease. PMID- 26519547 TI - Identification of biomarkers to measure HIV-specific mucosal and systemic CD8(+) T-cell immunity using single cell Fluidigm 48.48 Dynamic arrays. AB - Thirty genes composed of cytokines, chemokines, granzymes, perforin and integrins were evaluated in gut and splenic K(d)Gag197-205-specific single CD8(+) T cells using Fluidigm 48.48 Dynamic arrays, with the aim of identifying biomarkers to predict effective mucosal and systemic vaccine efficacy. The mRNA expression profiles were analyzed in three ways: (i) the "number" of K(d)Gag197-205-specific CD8(+) T cells expressing the biomarker, (ii) "level" of mRNA expression using principal component analysis (PCA) and (iii) poly-functionality in relation to RANTES expression. In total, 21 genes were found to be differentially expressed between the vaccine groups and the immune compartments tested. Overall, the PCA indicated that IL-13Ralpha2 or IL-4R antagonist adjuvanted vaccines that previously induced high-avidity mucosal/systemic CD8(+) T cells with better protective efficacy, the "level" of mRNA expression, specifically RANTES, MIP 1beta, and integrin alpha4 in gut K(d)Gag197-205-specific single CD8(+) T cells, were significantly elevated compared to unadjuvanted vaccine. Furthermore, significantly elevated granzymes/perforin levels were detected in IL-13(-/-) mice given the unadjuvanted vaccine, indicating that the degree of IL-13 inhibition (total, transient or no inhibition) can considerably alter the level of T-cell activity/poly-functionality. When splenic- and gut-K(d)Gag197-205-specific CD8(+) T cells were compared, PC1 vs. PC2 scores revealed that not only RANTES, MIP 1beta, and integrin alpha4 mRNA, but also perforin, granzymes A/B, and integrins beta1 and beta2 mRNA were elevated in spleen. Collectively, data suggest that RANTES, MIP-1beta, perforin, and integrins alpha4, beta1 and beta7 mRNA in single HIV-specific CD8(+) T cells could be used as a measure of effective mucosal and systemic vaccine efficacy. PMID- 26519549 TI - Superior immunogenicity profile of the new intradermal influenza vaccine compared to the standard subcutaneous vaccine in subjects 65 years and older: A randomized controlled phase III study. AB - BACKGROUND: Although the elderly are at high risk for influenza, the immunogenicity in the elderly is lower than that in younger adults. We developed the new type of seasonal influenza vaccine with the novel intradermal (ID) injection system. In the previous exploratory phase I/II study of the ID vaccine with a dose of 15 MUg HA per strain showed the superior immunogenicity profile to that of the standard subcutaneous (SC) injection vaccine in subjects aged 20 years and older. METHODS: In this multicenter, randomized, double-blind, active controlled study, 900 adults aged 65 years and older were randomized at an equal ratio to either the ID vaccine group or the licensed standard SC vaccine group. Immunogenicity was assessed using serum hemagglutination inhibition (HAI) titers. The co-primary endpoints were the geometrical mean titers (GMT) and the seroconversion rates (SCR) of HAI titers against 3 vaccine strains on Day 21 (21 days after vaccination). To evaluate the early phase immunogenicity, the GMTs and SCRs on Day 7 were also assessed in the same way as the secondary endpoints. RESULTS: The superiority of the ID vaccine in the GMTs and SCRs were demonstrated in all 3 vaccine strains both on Day 7 and Day 21. The frequency of any injection site reactions was higher in the ID vaccine group, while the severity of injection-site reactions and the frequency of systemic AEs were comparable between the ID and the SC vaccine groups. CONCLUSIONS: A single-dose of the influenza vaccine with the novel ID injection system and a dose of 15 MUg HA was suggested as an appropriate regimen for clinical use in influenza prevention and associated disease burden reduction. It was also suggested that the new ID vaccine has the potential to replace the standard influenza vaccine from the view point of immunogenicity and safety. TRIAL REGISTRATION: JAPIC Clinical Trials Information (JapicCTI-142493). PMID- 26519548 TI - A cost comparison of introducing and delivering pneumococcal, rotavirus and human papillomavirus vaccines in Rwanda. AB - BACKGROUND: Detailed cost evaluations of delivery of new vaccines such as pneumococcal conjugate, human papillomavirus (HPV), and rotavirus vaccines in low and middle-income countries are scarce. This paper differs from others by comparing the costs of introducing multiple vaccines in a single country and then assessing the financial and economic impact at the time and implications for the future. The objective of the analysis was to understand the introduction and delivery cost per dose or per child of the three new vaccines in Rwanda to inform domestic and external financial resource mobilization. METHODS: Start-up, recurrent, and capital costs from a government perspective were collected in 2012. Since pneumococcal conjugate and HPV vaccines had already been introduced, cost data for those vaccines were collected retrospectively while prospective (projected) costing was done for rotavirus vaccine. RESULTS: The financial unit cost per fully immunized child (or girl for HPV vaccine) of delivering 3 doses of each vaccine (without costs related to vaccine procurement) was $0.37 for rotavirus (RotaTeq((r))) vaccine, $0.54 for pneumococcal (Prevnar((r))) vaccine in pre-filled syringes, and $10.23 for HPV (Gardasil ((r))) vaccine. The financial delivery costs of Prevnar((r)) and RotaTeq((r)) were similar since both were delivered using existing health system infrastructure to deliver infant vaccines at health centers. The total financial cost of delivering Gardasil((r)) was higher than those of the two infant vaccines due to greater resource requirements associated with creating a new vaccine delivery system in for a new target population of 12-year-old girls who have not previously been served by the existing routine infant immunization program. CONCLUSION: The analysis indicates that service delivery strategies have an important influence on costs of introducing new vaccines and costs per girl reached with HPV vaccine are higher than the other two vaccines because of its delivery strategy. Documented information on financial commitments for new vaccines, particularly from government sources, is a useful input into country policy dialogue on sustainable financing and co-financing of new vaccines, as well as for policy decisions by donors such as Gavi, the Vaccine Alliance. PMID- 26519550 TI - Evaluation of impact of 23 valent pneumococcal polysaccharide vaccine following 7 valent pneumococcal conjugate vaccine in Australian Indigenous children. AB - BACKGROUND: High incidence and serotype diversity of invasive pneumococcal disease (IPD) in Indigenous children in remote Australia led to rapid introduction of 7-valent conjugate pneumococcal vaccine (7vPCV) at 2, 4 and 6 months in 2001, followed by 23-valent polysaccharide pneumococcal vaccine (23vPPV) in the second year of life. All other Australian children were offered 3 doses of 7vPCV without a booster from 2005. This study evaluated the impact of the unique pneumococcal vaccine schedule of 7vPCV followed by the 23vPPV booster among Indigenous Australian children. METHODS: Changes in IPD incidence derived from population-based passive laboratory surveillance in Indigenous children <5 years eligible for 23vPPV were compared to non-Indigenous eligible for 7vPCV only from the pre-vaccine introduction period (Indigenous 1994-2000; non-Indigenous 2002-2004) to the post-vaccine period (2008-2010 in both groups) using incidence rate ratios (IRRs) stratified by age into serotype groupings of vaccine (7v and 13vPCV and 23vPPV) and non-vaccine types. Vaccine coverage was assessed from the Australian Childhood Immunisation Register. RESULTS: At baseline, total IPD incidence per 100,000 was 216 (n=230) in Indigenous versus 55 (n=1993) in non Indigenous children. In 2008-2010, IRRs for 7vPCV type IPD were 0.03 in both groups, but for 23v-non7v type IPD 1.2 (95% CI 0.8-1.8) in Indigenous versus 3.1 (95% CI 2.5-3.7) in non-Indigenous, difference driven primarily by serotype 19A IPD (IRR 0.6 in Indigenous versus 4.3 in non-Indigenous). For non-7vPCV type IPD overall, IRR was significantly higher in those age-eligible for 23vPPV booster compared to those younger, but in both age groups was lower than for non Indigenous children. CONCLUSION: These ecologic data suggest a possible "serotype replacement sparing" effect of 23vPPV following 7vPCV priming, especially for serotype 19A with supportive evidence from other immunogenicity and carriage studies. Applicability post 10vPCV or 13v PCV priming in similar settings would depend on local serotype distribution of IPD. PMID- 26519551 TI - Expression and DNA methylation alterations of seven cancer-associated 3p genes and their predicted regulator miRNAs (miR-129-2, miR-9-1) in breast and ovarian cancers. AB - The methylation of promoter CpG islands and interactions between microRNAs (miRNAs) and messenger RNAs (mRNAs) of target genes are considered two crucial epigenetic mechanisms for inducing gene and pathway deregulation in tumors. Here, the expression levels of seven cancer-associated 3p genes (RASSF1(isoform A), RARB(isoform 2), SEMA3B, RHOA, GPX1, NKIRAS1, and CHL1) and their predicted regulator miRNAs (miR-129-2, miR-9-1) were analyzed in breast (BC, 40 samples) and ovarian (OC, 14 samples) cancers using RT-PCR and qPCR. We first revealed a negative correlation between the level of the miR-129-2 precursor and RASSF1(A) and GPX1 mRNA levels in BC (Spearman's correlation coefficient (rs) was - 0.26 in both cases). Similar results were observed for the miR-129-2 precursor and the RASSF1(A), GPX1, RARB(2), and CHL1 genes in OC (rs was in the range - 0.48 to - 0.54). Using methylation-specific PCR, a significant correlation was shown between promoter hypermethylation and the down-regulation of the RASSF1(A), GPX1, RARB(2), SEMA3B, MIR-129-2, and MIR-9-1 genes in BC (rs = 0.41 to 0.75) and of the RASSF1(A) gene in OC (rs = 0.67). We first demonstrated a high hypermethylation frequency of MIR-129-2 and SEMA3B (up to 45 to 48%) in both BC (69 samples) and OC (41 samples). Moreover, we observed a positive correlation between the hypermethylation of MIR-129-2 and the up-regulation of the RASSF1(A) and GPX1 genes in BC (rs = 0.38 and 0.42, respectively). QPCR analysis of the expression of RASSF1(A) and mature miR-129-2 in additional BC sample set (24 samples) revealed a negative correlation between them (rs = - 0.41) that strengthened the results obtained during the analysis of miR-129-2 precursor level. In summary, the obtained data indicate the involvement of methylation in the down-regulation of the studied coding and miRNA genes and suggest the involvement of miR-129-2 in the deregulation of RASSF1(A) via a direct interaction or/and mediators in common pathways (according to KEGG, Gene Ontology (FDR < 0.01), and GeneCards data) in the examined gynecological tumors. PMID- 26519552 TI - Pharmacology of novel small-molecule tubulin inhibitors in glioblastoma cells with enhanced EGFR signalling. AB - We recently reported that CMPD1, originally developed as an inhibitor of MK2 activation, primarily inhibits tubulin polymerisation and induces apoptosis in glioblastoma cells. In the present study we provide detailed pharmacological investigation of CMPD1 analogues with improved molecular properties. We determined their anti-cancer efficacy in glioblastoma cells with enhanced EGFR signalling, as deregulated EGFR often leads to chemoresistance. Eight analogues of CMPD1 with varying lipophilicity and basicity were synthesised and tested for efficacy in the cell viability assay using established glioblastoma cell lines and patient-derived primary glioblastoma cells. The mechanism of action for the most potent analogue 15 was determined using MK2 activation and tubulin polymerisation assays, together with the immunofluorescence analysis of the mitotic spindle formation. Apoptosis was analysed by Annexin V staining, immunoblotting analysis of bcl-2 proteins and PARP cleavage. The apoptotic activity of CMPD1 and analogue 15 was comparable across glioblastoma cell lines regardless of the EGFR status. Primary glioblastoma cells of the classical subtype that are characterized by enhanced EGFR activity were most sensitive to the treatment with CMPD1 and 15. In summary, we present mechanism of action for a novel small molecule tubulin inhibitor, compound 15 that inhibits tubulin polymerisation and mitotic spindle formation, induces degradation of anti apoptotic bcl-2 proteins and leads to apoptosis of glioblastoma cells. We also demonstrate that the enhanced EGFR activity does not decrease the efficacy of tubulin inhibitors developed in this study. PMID- 26519553 TI - An invisible touch: Body-related multisensory conflicts modulate visual consciousness. AB - The majority of scientific studies on consciousness have focused on vision, exploring the cognitive and neural mechanisms of conscious access to visual stimuli. In parallel, studies on bodily consciousness have revealed that bodily (i.e. tactile, proprioceptive, visceral, vestibular) signals are the basis for the sense of self. However, the role of bodily signals in the formation of visual consciousness is not well understood. Here we investigated how body-related visuo tactile stimulation modulates conscious access to visual stimuli. We used a robotic platform to apply controlled tactile stimulation to the participants' back while they viewed a dot moving either in synchrony or asynchrony with the touch on their back. Critically, the dot was rendered invisible through continuous flash suppression. Manipulating the visual context by presenting the dot moving on either a body form, or a non-bodily object we show that: (i) conflict induced by synchronous visuo-tactile stimulation in a body context is associated with a delayed conscious access compared to asynchronous visuo-tactile stimulation, (ii) this effect occurs only in the context of a visual body form, and (iii) is not due to detection or response biases. The results indicate that body-related visuo-tactile conflicts impact visual consciousness by facilitating access of non-conflicting visual information to awareness, and that these are sensitive to the visual context in which they are presented, highlighting the interplay between bodily signals and visual experience. PMID- 26519554 TI - Detecting syntactic and semantic anomalies in schizophrenia. AB - One of the major challenges in the study of language in schizophrenia is to identify specific levels of the linguistic structure that might be selectively impaired. While historically a main semantic deficit has been widely claimed, results are mixed, with also evidence of syntactic impairment. This might be due to heterogeneity in materials and paradigms across studies, which often do not allow to tap into single linguistic components. Moreover, the interaction between linguistic and neurocognitive deficits is still unclear. In this study, we concentrated on syntactic and semantic knowledge. We employed an anomaly detection task including short and long sentences with either syntactic errors violating the principles of Universal Grammar, or a novel form of semantic errors, resulting from a contradiction in the computation of the whole sentence meaning. Fifty-eight patients with diagnosis of schizophrenia were compared to 30 healthy subjects. Results showed that, in patients, only the ability to identify syntactic anomaly, both in short and long sentences, was impaired. This result cannot be explained by working memory abilities or psychopathological features. These findings suggest the presence of an impairment of syntactic knowledge in schizophrenia, at least partially independent of the cognitive and psychopathological profile. On the contrary, we cannot conclude that there is a semantic impairment, at least in terms of compositional semantics abilities. PMID- 26519555 TI - The impact of occipital lobe cortical thickness on cognitive task performance: An investigation in Huntington's Disease. AB - BACKGROUND: The occipital lobe is an important visual processing region of the brain. Following consistent findings of early neural changes in the occipital lobe in Huntington's Disease (HD), we examined cortical thickness across four occipital regions in premanifest (preHD) and early HD groups compared with controls. Associations between cortical thickness in gene positive individuals and performance on six cognitive tasks, each with a visual component, were examined. In addition, the association between cortical thickness in gene positive participants and one non-visual motor task was also examined for comparison. METHODS: Cortical thickness was determined using FreeSurfer on T1 weighted 3T MR datasets from controls (N=97), preHD (N=109) and HD (N=69) from the TRACK-HD study. Regression models were fitted to assess between-group differences in cortical thickness, and relationships between performance on the cognitive tasks, the motor task and occipital thickness were examined in a subset of gene-positive participants (N=141). RESULTS: Thickness of the occipital cortex in preHD and early HD participants was reduced compared with controls. Regionally specific associations between reduced cortical thickness and poorer performance were found for five of the six cognitive tasks, with the strongest associations in lateral occipital and lingual regions. No associations were found with the cuneus. The non-visual motor task was not associated with thickness of any region. CONCLUSIONS: The heterogeneous pattern of associations found in the present study suggests that occipital thickness negatively impacts cognition, but only in regions that are linked to relatively advanced visual processing (e.g., lateral occipital, lingual regions), rather than in basic visual processing regions such as the cuneus. Our results show, for the first time, the functional implications of occipital atrophy highlighted in recent studies in HD. PMID- 26519556 TI - Nicotinic receptors and lurasidone-mediated reversal of phencyclidine-induced deficit in novel object recognition. AB - BACKGROUND: Enhancement of cholinergic function via nicotinic acetylcholine (ACh) receptor (nAChR) agonism is a potential approach for the treatment of cognitive impairment associated with schizophrenia (CIAS). Some atypical antipsychotic drugs (AAPDs) enhance ACh release in rodent brain, indirectly stimulating these receptors. Here, we elucidate which nAChR subtypes mediate novel object recognition (NOR) in normal rats and contribute to the ability of the AAPD, lurasidone, to improve the NOR deficit in sub-chronic (sc) phencyclidine (PCP) treated rats, a model for CIAS. METHODS: The ability of lurasidone and nAChR ligands to reverse the scPCP-induced deficit in NOR was assessed in female, Long Evans rats. RESULTS: The broad acting nAChR antagonist, mecamylamine (MEC), induced a NOR deficit in normal rats. The NOR deficit secondary to scPCP was reversed by either selective alpha4beta2* nAChR agonism (A-85380) or alpha7 nAChRs agonism (PNU-282987); these effects were blocked by DHbetaE and MLA, selective antagonists of alpha4beta2* and alpha7 nAChR, respectively. The ability of lurasidone to reverse the scPCP-induced NOR deficit was blocked by MEC, but not MLA or DHbetaE. However, sub-effective doses (SED) of either A-85380 or PNU 282987 potentiated the ability of SED lurasidone to reverse the scPCP-induced NOR deficit. CONCLUSIONS: These results identify both alpha4beta2* and alpha7 nAChRs as candidates for enhancing the ability of lurasidone and other AAPDs, which increase the release of ACh, to improve CIAS. PMID- 26519557 TI - Altered functional interaction hub between affective network and cognitive control network in patients with major depressive disorder. AB - Emotional and cognitive dysregulation in major depressive disorder (MDD) have been consistently considered to be attributed to structural and functional abnormalities in affective network (AN) and cognitive control network (CCN). This study was to investigate the functional connectivity (FC) patterns and altered functional interactions between both networks in MDD. We investigated resting state functional connectivity magnetic resonance imaging in the AN and the CCN in 25 MDD and 35 healthy controls (HC). The seeds were from voxel-based morphometry (VBM) analysis results. Then FC within the AN was assessed from a seed placed in the left amygdala (AMG) and FC within CCN was determined by placing seeds in the right dorsolateral prefrontal cortex (DLPFC). Compared with HC, MDD showed reduced FC between left AMG and bilateral precuneus and right anterior cingulated cortex (ACC) within AN and reduced FC between right DLPFC and left cuneus, left lingual gyrus, and right ACC within CCN. An interaction hub of altered FC in MDD between AN and CCN located in the right ACC. Interestingly, the altered FC between right ACC and left AMG was negatively correlated with depressive symptom score while the altered FC between right ACC and DLPFC was positively correlated the executive function in MDD. The right ACC not only supports the cognitive and emotional processes, but also is an altered functional interaction hub between AN and CCN in MDD. It further suggest multiple sources of dysregulation in AN and CCN implicate both top-down cognitive control and bottom-up emotional expression dysfunction in MDD. PMID- 26519558 TI - Activation of muscarinic cholinoceptor ameliorates tumor necrosis factor-alpha induced barrier dysfunction in intestinal epithelial cells. AB - Impaired intestinal barrier function is one of the critical issues in inflammatory bowel diseases. The aim of this study is to investigate muscarinic cholinoceptor (mAChR)-mediated signaling for the amelioration of cytokine-induced barrier dysfunction in intestinal epithelium. Rat colon challenged with TNF-alpha and interferon gamma reduced transepithelial electrical resistance (TER). This barrier injury was attenuated by muscarinic stimulation. In HT-29/B6 intestinal epithelial cells, muscarinic stimulation suppressed TNF-alpha-induced activation of NF-kappaB signaling and barrier disruption. Finally, muscarinic stimulation promoted the shedding of TNFR1, which would be a mechanism for the attenuation of TNF-alpha/NF-kappaB signaling and barrier disruption via mAChR. PMID- 26519559 TI - JNK1 inhibits transcriptional and pro-apoptotic activity of TAp63gamma. AB - TAp63gamma is a homologue of tumor suppressor p53 and functions as a transcriptional factor playing key roles in cell cycle and cell apoptosis. In the present work, we find that JNK1 can physically interact with N-terminal transactivation domain (TAD) of TAp63. Overexpression of JNK1 inhibits TAp63gamma mediated transcription, while knockdown or inhibition of endogenous JNK1 increases transactivity of TAp63gamma. Further study reveals that Ser12 site in TAD is critical for JNK1-mediated inhibition of TAp63gamma. This JNK1-mediated inhibition can impair pro-apoptotic activity of TAp63gamma. Together, we report a novel regulation of TAp63gamma transactivity and pro-apoptotic activity mediated by JNK1. PMID- 26519560 TI - Low-temperature microRNA expression in the painted turtle, Chrysemys picta during freezing stress. AB - Natural freeze tolerance depends on cellular adaptations that address the multiple stresses imposed on cells during freezing. These adaptations preserve viability by suppressing energy-expensive cell processes in the frozen state. In this study, we explore the freeze-responsive expression of microRNA in hatchling painted turtles exposed to 20 h freezing. Furthermore, we also explore the possibility of unique temperature-sensitive microRNA targeting programs that aid in adapting turtles for survival in the frozen state. Interestingly, two freeze responsive 'cryo-miRs' (cpm-miR-16 and cpm-miR-21) were found to have unique low temperature mRNA targets enriched in biological processes that are known to be part of the stress response. PMID- 26519561 TI - Michael addition of dehydroalanine-containing MAPK peptides to catalytic lysine inhibits the activity of phosphothreonine lyase. AB - The phosphothreonine lyases OspF and SpvC irreversibly inactivate host dual phosphorylated mitogen-activated protein kinases (MAPKs) [pThr-X-pTyr motif] through beta-elimination. We found that dual-phosphorylated (pSer-X-pTyr) MAPK substrate peptides and their resulting catalytic products cross-link to OspF and SpvC. Mass spectrometry results revealed that these linkages form between lysine, which acts as a general base, and dehydroalanine (Dha) on catalytic products. The nucleophilic addition efficiency is dependent on the K136 residue being in a deprotonated state. Peptide cross-linking inhibits the activity of SpvC and blocks the inactivation of MAPK signaling by SpvC. Small compounds mimicking these sequences may act as phosphothreonine lyase inhibitors. PMID- 26519562 TI - High-level production of Bacillus cereus phospholipase C in Corynebacterium glutamicum. AB - Enzymatic oil degumming (removal of phospholipids) using phospholipase C (PLC) is a well-established and environmentally friendly process for vegetable oil refining. In this work, we report the production of recombinant Bacillus cereus PLC in Corynebacterium glutamicum ATCC 13869 in a high cell density fermentation process and its performance in soybean oil degumming. A final concentration of 5.5g/L of the recombinant enzyme was achieved when the respective gene was expressed from the tac promoter in a semi-defined medium. After treatment with trypsin to cleave the propeptide, the mature enzyme completely hydrolyzed phosphatidylcholine and phosphatidylethanolamine, which represent 70% of the phospholipids present in soybean oil. The results presented here show the feasibility of using B. cereus PLC for oil degumming and provide a manufacturing process for the cost effective production of this enzyme. PMID- 26519563 TI - Influence of rice field agrochemicals on the ecological status of a tropical stream. AB - Many tropical countries contain a high density of protected ecosystems, and these may often be bordered by intensive agricultural systems. We investigated the chemical and ecological status of a stream connecting an area with conventional rice production and a downstream protected nature reserve; Mata Redonda. Three sites were sampled: 1) an upstream control, 2) in the rice production area and 3) a downstream site in Mata Redonda. We sampled benthic macroinvertebrates and pesticides in water and sediments along with supporting physical and chemical data. Pesticide concentrations in water exceeded current safety thresholds at sites 2 and 3, especially during the rainy season, and sediment associated pesticide concentrations exceeded current safety thresholds in three of six samples. Importantly, the highest predicted pesticide toxicity in sediments was observed at site 3 in the Mata Redonda confirming that the nature reserve received critical levels of pesticide pollution from upstream sections. The currently used macroinvertebrate index in Costa Rica (BMWP-CR) and an adjusted version of the SPecies At Risk index (SPEAR) were not significantly correlated to any measure of anthropogenic stress, but the Average Score Per Taxon (ASPT) index was significantly correlated with the predicted pesticide toxicity (sumTUD.magna), oxygen concentrations and substrate composition. Our results suggest that pesticide pollution was likely involved in the impairment of the ecological status of the sampling sites, including site 3 in Mata Redonda. Based on our results, we give guidance to biomonitoring in Costa Rica and call for increased focus on pesticide transport from agricultural regions to protected areas. PMID- 26519564 TI - Assessing the implications of water harvesting intensification on upstream downstream ecosystem services: A case study in the Lake Tana basin. AB - Water harvesting systems have improved productivity in various regions in sub Saharan Africa. Similarly, they can help retain water in landscapes, build resilience against droughts and dry spells, and thereby contribute to sustainable agricultural intensification. However, there is no strong empirical evidence that shows the effects of intensification of water harvesting on upstream-downstream social-ecological systems at a landscape scale. In this paper we develop a decision support system (DSS) for locating and sizing water harvesting ponds in a hydrological model, which enables assessments of water harvesting intensification on upstream-downstream ecosystem services in meso-scale watersheds. The DSS was used with the Soil and Water Assessment Tool (SWAT) for a case-study area located in the Lake Tana basin, Ethiopia. We found that supplementary irrigation in combination with nutrient application increased simulated teff (Eragrostis tef, staple crop in Ethiopia) production up to three times, compared to the current practice. Moreover, after supplemental irrigation of teff, the excess water was used for dry season onion production of 7.66 t/ha (median). Water harvesting, therefore, can play an important role in increasing local- to regional-scale food security through increased and more stable food production and generation of extra income from the sale of cash crops. The annual total irrigation water consumption was ~4%-30% of the annual water yield from the entire watershed. In general, water harvesting resulted in a reduction in peak flows and an increase in low flows. Water harvesting substantially reduced sediment yield leaving the watershed. The beneficiaries of water harvesting ponds may benefit from increases in agricultural production. The downstream social-ecological systems may benefit from reduced food prices, reduced flooding damages, and reduced sediment influxes, as well as enhancements in low flows and water quality. The benefits of water harvesting warrant economic feasibility studies and detailed analyses of its ecological impacts. PMID- 26519565 TI - Dispersion of atmospheric fine particulate matters in simulated lung fluid and their effects on model cell membranes. AB - Atmospheric fine particulate matter (PM2.5) was collected to investigate its dispersion in simulated lung fluid (SLF) and its interaction with model cell membranes. Organic acids, NH4(+), SO4(2-) and NO3(-) were detected in PM2.5 soluble fraction, and heavy metals were detected from the total mass. The insoluble fraction contained kaolinite, CaCO3, aliphatic carbons, aromatic rings, carboxyl and hydroxyl groups reflected by the infrared spectra. Proteins dispersed PM2.5 in SLF, resulted in smaller hydrodynamic diameter (dH) and slower sedimentation rate. Conversely, phospholipids increased dH value and accelerated sedimentation rate. Giant unilamellar vesicles (GUVs) and supported lipid bilayers (SLBs) were used as model cell membranes. PM2.5 adhered on and disrupted the membrane containing positively-charged lipids but not the membrane containing neutrally- and negatively-charged lipids, which was monitored by microscopy and a quartz crystal microbalance with dissipation (QCM-D). The cationic sites on membrane were necessary for PM2.5 adhesion, but membrane should be disrupted by the combined action of electrostatic forces and hydrogen bonds between PM2.5 oxygen containing groups and the lipid phosphate groups. Our results specified the roles of proteins and phospholipids in PM2.5 dispersion and transport, highly suggested that the health hazard of PM2.5 was related to the biomolecules in the lung fluid and the particle surface groups. PMID- 26519566 TI - Multiple biomarker responses in Prochilodus lineatus subjected to short-term in situ exposure to streams from agricultural areas in Southern Brazil. AB - In order to assess the quality of streams susceptible to contamination by pesticides we apply biochemical and genotoxic biomarkers in the Neotropical fish Prochilodus lineatus submitted to in situ tests. Fish were caged, for 96 h, in two streams located in areas with intensive use of pesticides, the Apertados (AP) and the Jacutinga (JC), and in a small stream (Godoy stream - GD) found inside a forest fragment adjacent to a State Park. Biochemical parameters, such as biotransformation enzymes 7-ethoxyresorufin-O-deethylase (EROD) and glutathione-S transferase (GST), non-protein thiols (NPSH), lipoperoxidation (LPO), protein carbonylation (PCO) and acetylcholinesterase (AChE) were evaluated in various fish organs, as well as genotoxic biomarkers (damage to DNA and occurrence of micronuclei and erythrocyte nuclear abnormalities). Samples of water and sediment were collected for analysis of metals (Cu, Cr, Pb, Ni, Mn, Cd and Zn), organochloride pesticides, and triazine and glyphosate herbicides. We observed an increase in liver GST activity in fish at AP and gill GST activity in fish at JC. An increase in liver LPO was also observed in fish exposed to AP and JC. The same animals also exhibited increased DNA damage and erythrocyte nuclear abnormalities (ENAs) compared to the fish kept in GD. A number of compounds showed concentrations higher than the permitted levels, in particular, dichlorodiphenyltrichloroethane (DDT), its metabolites dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), hexachlorocyclohexanes (HCH), heptachloride, diclofluanid and aldrins. These pesticides were detected at higher concentrations in water and sediment samples from AP, followed by JC and GD. The Integrated Biomarker Response Index (IBR) indicated that AP and JC (AP: 21.7 > JC: 18.5 > GD: 12.6) have the worst environmental quality. Integrated biomarker analysis revealed that the alterations observed related well with the levels of environmental contaminants, demonstrating the effectiveness of this biomonitoring approach. PMID- 26519567 TI - Intense methane ebullition from open water area of a shallow peatland lake on the eastern Tibetan Plateau. AB - Methane fluxes from a shallow peatland lake (3450 m a.s.l., 1.6 km(2) in area, maximum depth <1m) on eastern Tibetan Plateau were measured with floating chamber method during May to August, 2009. The overall average of methane emission rate during the study period was 34.71+/-29.15 mg CH4 m(-2) h(-1). The occurrence of ebullition among the overall methane flux from Lake Medo was about 74%. The average rate of ebullition was 32.45+/-28.31 mg CH4 m(-2) h(-1), which accounted for 93% of the overall average of methane emission. Significant seasonal variation was found for occurrence (P<0.05) and rate (P<0.01) of ebullition, both peaking synchronously in mid-summer. Both the occurrence and rate of ebullition were found positively related to sediment temperature but negatively related to lake water depth. The high methane production in the lake sediment was likely fueled by organic carbon loaded from surrounding peatlands to the lake. The shallowness of the water column could be another important favorable factor for methane-containing bubble formation in the sediment and their transportation to the atmosphere. The methane ebullition must have been enhanced by the low atmospheric pressure (ca. 672 hPa) in the high-altitude environment. For a better understanding on the mechanism of methane emission from alpine lakes, more lakes on the Tibetan Plateau should be studied in the future for their methane ebullition. PMID- 26519568 TI - Direct and indirect effects of climate change on projected future fire regimes in the western United States. AB - We asked two research questions: (1) What are the relative effects of climate change and climate-driven vegetation shifts on different components of future fire regimes? (2) How does incorporating climate-driven vegetation change into future fire regime projections alter the results compared to projections based only on direct climate effects? We used the western United States (US) as study area to answer these questions. Future (2071-2100) fire regimes were projected using statistical models to predict spatial patterns of occurrence, size and spread for large fires (>400 ha) and a simulation experiment was conducted to compare the direct climatic effects and the indirect effects of climate-driven vegetation change on fire regimes. Results showed that vegetation change amplified climate-driven increases in fire frequency and size and had a larger overall effect on future total burned area in the western US than direct climate effects. Vegetation shifts, which were highly sensitive to precipitation pattern changes, were also a strong determinant of the future spatial pattern of burn rates and had different effects on fire in currently forested and grass/shrub areas. Our results showed that climate-driven vegetation change can exert strong localized effects on fire occurrence and size, which in turn drive regional changes in fire regimes. The effects of vegetation change for projections of the geographic patterns of future fire regimes may be at least as important as the direct effects of climate change, emphasizing that accounting for changing vegetation patterns in models of future climate-fire relationships is necessary to provide accurate projections at continental to global scales. PMID- 26519569 TI - Climate change effects on the hydrological regime of small non-perennial river basins. AB - Recent years have been witnessing an increasing interest on global climate change and, although we are only at the first stage of the projected trends, some signals of climate alteration are already visible. Climate change encompasses modifications in the characteristics of several interrelated climate variables, and unavoidably produces relevant effects on almost all the natural processes related to the hydrological cycle. This study focuses on potential impacts of climate variations on the streamflow regime of small river basins in Mediterranean, seasonally dry, regions. The paper provides a quantitative evaluation of potential modifications in the flow duration curves (FDCs) and in the partitioning between surface and subsurface contributions to streamflow, induced by climate changes projected over the next century in different basins, also exploring the role exerted by different soil-vegetation compositions. To this aim, it is used a recent hydrological model, which is calibrated at five Sicilian (Italy) basins using a past period with available streamflow observations. The model is then forced by daily precipitation and reference evapotranspiration series representative of the current climatic conditions and two future temporal horizons, referring to the time windows 2045-2065 and 2081 2100. Future climatic series are generated by a weather generator, based on a stochastic downscaling of an ensemble of General Circulation Models. The results show how the projected climatic modifications are differently reflected in the hydrological response of the selected basins, implying, in general, a sensible downshift of the FDCs, with a significant reduction in the mean annual streamflow, and substantial alterations in streamflow seasonality and in the relative importance of the surface and subsurface components. The projected climate change impact on the hydrological regime of ephemeral rivers could have important implications for the water resource management and for the sustainability of many riparian Mediterranean ecosystems. PMID- 26519570 TI - BPA and NP removal from municipal wastewater by tropical horizontal subsurface constructed wetlands. AB - It has been recognized that numerous synthetic compounds like Bisphenol A (BPA) and nonylphenols (NP) are present in effluents from wastewater treatment plants (WWTP) at levels of parts per billion (MUg L(-1)) or even parts per trillion (ng L(-1)) with a high potential to cause endocrine disruption in the aquatic environment. Constructed wetlands (CW) are a cost-effective wastewater treatment alternative with promising performance to treat these afore mentioned compounds. This research was aimed to evaluate the efficacy of CW treatment of WWTP effluent for mitigating the effects endocrine disrupting compounds (EDCs). This research goal was accomplished by (1) quantifying the removal of BPA and NP in CWs; (2) isolating CW fungal strains and testing for laccase production; and (3) performing endocrine disruption (reproduction) bioassays using the fruit fly Drosophila melanogaster. Three pilot scale horizontal subsurface flow constructed wetlands (HSSF-CW) were operated for eight weeks: one planted with Phragmites australis; one planted with Heliconia psitacorum; and one unplanted. The Heliconia CW showed a removal efficiency of 73.3(+/- 19%) and 62.8(+/- 20.1%) for BPA and NP, respectively; while the Phragmites CW demonstrated a similar removal for BPA (70.2 +/- 27%) and lower removal efficiency for NP 52.1(+/- 37.1%).The unplanted CW achieved 62.2 (+/- 33%) removal for BPA and 25.3(+/- 37%) removal for NP. Four of the eleven fungal strains isolated from the Heliconia-CW showed the capacity to produce laccase. Even though complete removal of EDCs was not achieved by the CWs, the bioassay confirmed a significant improvement (p < 0.05) in fly viability for all CWs, with Heliconia sp. being the most effective at mitigating adverse effects on first and second generational reproduction. This study showed that a CW planted with a native Heliconia sp. CW demonstrated a higher removal of endocrine disrupting compounds and better mitigation of reproductive disruption in the bioassay. PMID- 26519571 TI - Salmonella enterica resistant to antimicrobials in wastewater effluents and black headed gulls in the Czech Republic, 2012. AB - We investigated the presence and epidemiological relatedness of Salmonella isolates from a wastewater treatment plant (WWTP) in Brno, Czech Republic and from nestlings of black-headed gulls (Chroicocephalus ridibundus) at the Nove Mlyny waterworks, situated 35 km downstream from the WWTP. During 2012, we collected 37 wastewater samples and 284 gull cloacal swabs. From wastewater samples, we obtained 89 Salmonella isolates belonging to 19 serotypes. At least one resistant strain was contained in 89% of those samples. Ten different serotypes of Salmonella were detected in 38 young gulls, among which 14 (37%) were resistant to antimicrobials. Wastewater isolates were mostly resistant to sulphonamides and tetracycline, gull isolates to tetracycline and ampicillin. We detected the occurrence of blaTEM-1,tet(A), tet(B), tet(G), sul1, sul2, sul3, floR and strA resistance genes. For the first time, we identified a class 1 integron with the dfrA12-orfF-aadA2 gene cassette in S. Infantis. Using pulsed field gel electrophoresis, we confirmed the presence of identical clusters of S. Agona, S. Enteritidis PT8, S. Infantis and S. Senftenberg in wastewater and black headed gulls, thus indicating the possibility of resistant Salmonella isolates spreading over long distances in the environment. PMID- 26519572 TI - Seasonal variation in accumulation of persistent organic pollutants in an Arctic marine benthic food web. AB - The aim of the present study was to investigate seasonal variation in persistent organic pollutant (POP) concentrations, as well as food-web biomagnification, in an Arctic, benthic marine community. Macrozoobenthos, demersal fish and common eiders were collected both inside and outside of Kongsfjorden, Svalbard, during May, July and October 2007. The samples were analysed for a selection of legacy chlorinated POPs. Overall, low levels of POPs were measured in all samples. Although POP levels and accumulation patterns showed some seasonal variation, the magnitude and direction of change was not consistent among species. Overall, seasonality in bioaccumulation in benthic biota was less pronounced than in the pelagic system in Kongsfjorden. In addition, the results indicate that delta(15)N is not a good predictor for POP-levels in benthic food chains. Other factors, such as feeding strategy (omnivory, necrophagy versus herbivory), degree of contact with the sediment, and a high dependence on particulate organic matter (POM), with low POP-levels and high delta(15)N-values (due to bacterial isotope enrichment), seem to govern the uptake of the different POPs and result in loads deviating from what would be expected consulting the trophic position alone. PMID- 26519573 TI - Distribution and seasonal occurrence of UV filters in rivers and wastewater treatment plants in Korea. AB - The occurrence and distribution of eight UV filters benzophenone (BP), benzophenone-3 (BP-3), ethylhexyl methoxy cinnamate (EHMC), 4-methylbenzylidene camphor (4-MBC), 2-ethylhexyl 4-dimethylaminobenzoate (OD-PABA), 2-ethylhexyl salicylate (EHS), isoamyl benzoate, and benzyl cinnamate in eleven sites among three rivers, five sewage treatment plants (STPs), and four wastewater treatment plants (WWTPs) located in different parts of Korea was investigated. The total concentrations of UV filters in the three sampled seasons were 62.9-412 ng L(-1) (river), 417-5055 ng L(-1) (STP influent), 108-2201 ng L(-1) (STP effluent), 122 4154 ng L(-1) (WWTP influent), and 120-849 ng L(-1) (WWTP effluent). The concentration of the target pollutants in the influent of the treatment systems was directly proportional to the resident population density. A seasonal increase of >27% was observed in the total concentration of the UV filters in the rivers and influents of the treatment plants (TPs) during summer. BP, BP-3, EHMC, 4-MBC, and EHS were the most dominant, showing a distinct distribution pattern that was dependent on the effectiveness of the treatment process and properties of each compound. The concentrations of the UV filters were higher in the TPs influents than in the rivers, and the most dominant UV filters in the rivers were those with low removal rate. Although biological treatment processes favored the removal of the UV filter compounds in the TPs, complete removal was not achieved before discharge into the rivers. PMID- 26519574 TI - Isotopically exchangeable Al in coastal lowland acid sulfate soils. AB - Periodic discharges of high concentrations of aluminium (Al) causing fish kills and other adverse effects occur worldwide in waterways affected by coastal lowland acid sulfate soils (CLASS). The exchangeability - a metal's ability to readily transfer between the soil solid- and solution-phases - of Al in these soils is therefore of particular importance as it has implications for metal transport, plant availability and toxicity to living organisms. In the present study, the concentrations of isotopically exchangeable Al (E values) were measured in 27 CLASS and compared with common salt extractions (i.e. KCl and CuCl2) used to estimate exchangeable soil pools of Al. E values of Al were high in the soils, ranging from 357 to 3040 mg.kg(-1). Exchangeable concentrations estimated using 1 M KCl were consistently lower than measured E values, although a reasonable correlation was obtained between the two values (E=1.68*AlKCl, r(2)=0.66, n=25). The addition of a 0.2 M CuCl2 extraction step improved the 1:1 agreement between extractable and isotopically exchangeable Al concentrations, but lead to significant mobilisation of non-isotopically exchangeable Al in surficial 'organic-rich' CLASS having E values<1000 mg.kg(-1). It was concluded that currently used (i.e. 1 M KCl) methodology severely underestimates exchangeable Al and total actual acidity values in CLASS and should be corrected by a factor similar to the one determined here. PMID- 26519575 TI - Trends in exposure to second hand smoke at home among children and nonsmoker adolescents. AB - Data from National Health and Nutrition Examination Survey (NHANES) for the years 1999-2012 were used to evaluate trends in exposure to second hand smoke (SHS) at home among children aged 3-11 years and nonsmoker adolescents aged 12-19 years. A total of 12,815 children and 10,269 adolescents were included in the analyses. Serum cotinine was used as a biomarker for exposure to SHS at home. Regression models with log10 transformed values of serum cotinine as dependent variables and age, race/ethnicity, NHANES survey year, and family poverty income ratio as a surrogate measure of socioeconomic status were used in models for those with and without exposure to SHS at home. In addition, for those with exposure to SHS at home, number of smokers smoking inside home and number of cigarettes smoked at home every day were also used as independent variables. There was a biennial increase of 1.05 ng/L in adjusted serum cotinine levels for children with exposure to SHS at home over the period of 1999-2012. Serum cotinine levels among nonsmoker adolescents with exposure to SHS at home did not change over time. When there was no exposure to SHS at home, there was a statistically significant downward trend for serum cotinine levels for both children and nonsmoker adolescents. Serum cotinine levels attributable to SHS exposure increased with age among nonsmoker adolescents (p<=0.02) but decreased with age among children (p<0.01). For a unit decrease in family poverty income ratio, SHS exposure as measured by serum cotinine levels (Table 6) increased by 1.18 ng/L among children and by 1.30 ng/L among nonsmoker adolescents. In general, observed serum cotinine levels associated with SHS exposure at home were higher for children than they were for nonsmoker adolescents. PMID- 26519576 TI - A comparison of the spatial distribution of vadose zone water in forested and agricultural floodplains a century after harvest. AB - To improve quantitative understanding of the long-term impact of historic forest removal on floodplain vadose zone water regime, a study was implemented in fall 2010, in the Hinkson Creek Watershed, Missouri, USA. Automated, continuously logging capacitance-frequency probes were installed in a grid-like formation (n=6) and at depths of 15, 30, 50, 75, and 100 cm within a historic agricultural field (Ag) and a remnant bottomland hardwood forest (BHF). Data were logged at thirty minute intervals for the duration of the 2011, 2012, and 2013 hydrologic years. Results showed volumetric water content (VWC) to be significantly different between sites (p<0.01) during the study, with site averages of 33.1 and 32.8% at the Ag and BHF sites, respectively. Semi-variogram analyses indicate the presence of strong (<25%) horizontal and vertical spatial correlation of VWC at the Ag site, and a relatively short-range (25 cm) vertical spatial correlation at the BHF, but only indicate horizontal VWC spatial correlation in the top 30 cm of the BHF profile. Likely mechanisms contributing to patterns of observed differences are contrasting rates and depths of plant water use, and the presence of preferential flow paths in the below ground BHF. Results suggest historic forest removal and cultivation of the Ag site lead to an effective homogenization of the upper soil profile, and facilitated the development of strong VWC spatial dependency. Conversely, higher hydraulic conductivity of the more heterogeneous BHF subsurface likely results in a wetting of the deeper profile (75 cm) during climatically wet periods, and thus a more effective processing of hydrologic inputs. Collective results highlight the greater extent and degree to which forest vegetation impacts subsurface hydrology, relative to grassland/agricultural systems, and point to the value of reestablishing floodplain forests for fresh water routing, water quality, and flood mitigation in mixed-land-use watersheds. PMID- 26519577 TI - Insights into the chemical characterization and sources of PM(2.5) in Beijing at a 1-h time resolution. AB - As the widespread application of online instruments penetrates the environmental fields, it is interesting to investigate the sources of fine particulate matter (PM2.5) based on the data monitored by online instruments. In this study, online analyzers with 1-h time resolution were employed to observe PM2.5 composition data, including carbon components, inorganic ions, heavy metals and gas pollutants, during a summer in Beijing. Chemical characteristics, temporal patterns and sources of PM2.5 are discussed. On the basis of hourly data, the mean concentration value of PM2.5 was 62.16+/-39.37 MUg m(-3) (ranging from 6.69 to 183.67 MUg m(-3)). The average concentrations of NO3(-), SO4(2-), NH4(+), OC and EC, the major chemical species, were 15.18+/-13.12, 14.80+/-14.53, 8.90+/ 9.51, 9.32+/-4.16 and 3.08+/-1.43 MUg m(-3), respectively. The concentration of PM2.5 varied during the online-sampling period, initially increasing and then subsequently decreasing. Three factor analysis models, including principal component analysis (PCA), positive matrix factorization (PMF) and Multilinear Engine 2 (ME2), were applied to apportion the PM2.5 sources. Source apportionment results obtained by the three different models were in agreement. Four sources were identified in Beijing during the sampling campaign, including secondary sources (38-39%), crustal dust (17-22%), vehicle exhaust (25-28%) and coal combustion (15-16%). Similar source profiles and contributions of PM2.5 were derived from ME2 and PMF, indicating the results of the two models are reasonable. The finding provides information that could be exploited for regular air control strategies. PMID- 26519578 TI - Carbonaceous PM(2.5) and secondary organic aerosol across the Veneto region (NE Italy). AB - Organic and elemental carbon (OC-EC) were measured in 360 PM2.5 samples collected from April 2012 to February 2013 at six provinces in the Veneto region, to determine the factors affecting the carbonaceous aerosol variations. The 60 daily samples have been collected simultaneously in all sites during 10 consecutive days for 6 months (April, June, August, October, December and February). OC ranged from 0.98 to 22.34 MUg/m(3), while the mean value was 5.5 MUg/m(3), contributing 79% of total carbon. EC concentrations fluctuated from 0.19 to 11.90 MUg/m(3) with an annual mean value of 1.31 MUg/m(3) (19% of the total carbon). The monthly OC concentration gradually increased from April to December. The EC did not vary in accordance with OC. However the highest values for both parameters were recorded in the cold period. The mean OC/EC ratio is 4.54, which is higher than the values observed in most of the other European cities. The secondary organic carbon (SOC) contributed for 69% of the total OC and this was confirmed by both the approaches OC/EC minimum ratio and regression. The results show that OC, EC and SOC exhibited higher concentration during winter months in all measurement sites, suggesting that the stable atmosphere and lower mixing play important role for the accumulation of air pollutant and hasten the condensation or adsorption of volatile organic compounds over the Veneto region. Significant meteorological factors controlling OC and EC were investigated by fitting linear models and using a robust procedure based on weighted likelihood, suggesting that low wind speed and temperature favour accumulation of emissions from local sources. Conditional probability function and conditional bivariate probability function plots indicate that both biomass burning and vehicular traffic are probably the main local sources for carbonaceous particulate matter emissions in two selected cities. PMID- 26519579 TI - Contrasting water use pattern of introduced and native plants in an alpine desert ecosystem, Northeast Qinghai-Tibet Plateau, China. AB - Plant water use patterns reflect the complex interactions between different functional types and environmental conditions in water-limited ecosystems. However, the mechanisms underlying the water use patterns of plants in the alpine desert of the Qinghai-Tibet Plateau remain poorly understood. This study investigated seasonal variations in the water sources of herbs (Carex moorcroftii, Astragalus adsurgens) and shrubs (Artemisia oxycephala, Hippophae rhamnoides) using stable oxygen-18 isotope methods. The results indicated that the native herbs (C. moorcroftii, A. adsurgens) and one of the shrubs (A. oxycephala) mainly relied on water from the shallow layer (0-30 cm) throughout the growing season, while the introduced shrub (H. rhamnoides) showed plasticity in switching between water from shallow and deep soil layers depending on soil water availability. All studied plants primarily depended on water from shallow soil layers early in the season. The differences of water use patterns between the introduced and native plants are closely linked with the range of active root zones when competing for water. Our findings will facilitate the mechanistic understanding of plant-soil-water relations in alpine desert ecosystems and provide information for screening introduced species for sand fixation. PMID- 26519580 TI - High diversity of human polyomaviruses in environmental and clinical samples in Argentina: Detection of JC, BK, Merkel-cell, Malawi, and human 6 and 7 polyomaviruses. AB - New human polyomaviruses have been recently described. The aim of this work was to detect and characterize human polyomaviruses circulating in Argentina by recovering viruses from environmental and sewage samples and evaluating their potential role as viral indicators of human waste contamination. Analysis was performed in a wider context including viruses from clinical samples from an immunocompromised population. River water and sewage samples were analyzed as a strategy to study the molecular epidemiology of viruses excreted by millions of people. Samples belonged to the Matanza-Riachuelo River (2005-2006: n=25 and 2012: n=20) and sewage from Buenos Aires city and suburbs (2011 and 2013: n=24). Viral detection was performed by PCR and the amplified viral genomes were characterized by phylogenetic analysis. Polyomaviruses were detected in 95.8% of sewage samples, identifying BKPyV (87.5%), JCPyV (83.3%), MCPyV (8.3%) and HPyV6 (8.3%). Besides, one sample collected in 2009 resulted positive for HPyV7. In 2005-2006, polyomaviruses were detected in 84.0% of river water samples, with the highest detection for MCPyV (52.0%), followed by BKPyV (44.0%), JCPyV (20.0%) and MWPyV (4.0%). In 2012, polyomaviruses were detected in 85.0% of river samples, finding JCPyV (85.0%), BKPyV (75.0%), MCPyV (25.0%) and HPyV6 (25.0%). Also, polyomaviruses, including JCPyV, BKPyV and MCPyV, were detected in 63.2% of urine samples from patients infected with HIV (n=19). Characterization indicated the coexistence of different genotypes and variants for each virus, particularly in sewage. MCPyV sequences (the only sequences from Argentina) formed a monophyletic group with the single sequence available for South America (French Guiana). The high level of detection and viral diversity found by environmental surveillance, which involved the characterization of viruses not previously described in South America, reinforces the usefulness of this approach to monitor viral contamination and describe the viral epidemiology in the general population. PMID- 26519581 TI - Nitrogen and phosphorus co-limitation and grazing moderate nitrogen impacts on plant growth and nutrient cycling in sand dune grassland. AB - Atmospheric nitrogen (N) deposition alters plant biodiversity and ecosystem function in grasslands worldwide. This study examines the impact of 6 years of nutrient addition and grazing management on a sand dune grassland. Results indicate that co-limitation of N and phosphorus (P) moderates the impact of realistic rates of N addition (7.5, 15 kg N ha(1) year(-1)). Combined NP addition (15 kg N + 10 kg P ha(-1) year(-1)) was the only nutrient treatment to differ significantly from the control, with greater above-ground biomass (mainly moss), and enhanced N and P mineralisation rates. Grazing management altered plant functional group composition, reduced above-ground biomass and meso-faunal feeding rates, and decoupled N and P mineralisation. There were no synergistic effects of grazing and N treatment. Although NP co-limitation apparently prevents adverse impacts of N deposition above the critical load, excess N is likely to be stored in moss biomass and soil, with unknown future consequences. CAPSULE: This study shows that at realistic levels of N addition, NP co-limitation in a dune grassland appears to prevent adverse impacts of N on plant growth and nutrient cycling. PMID- 26519582 TI - Assessment of an action against environmental noise: Acoustic durability of a pavement surface with crumb rubber. AB - Environmental noise is a worldwide problem that has an adverse effect in the quality of life of urban population. Some work has shown that there is a correlation between environmental noise and health issues as sleep disturbance or annoyance. This study presents the time evolution of a test track fabricated with an asphalt mixture with 20% of crumb rubber by weight of bitumen, added by the wet process. A complete surface characterization has been performed by determining tire/pavement sound levels, road texture profiles, in-situ dynamic stiffness and sound absorption of compacted and extracted sample cores. Two measurement campaigns were performed: just after mixture laying and after 3 years in service. This study confirms that the use of crumb rubber as a modifier of bituminous binders (CRMB) can improve the pavement characteristics: gap-graded mixtures with crumb rubber can be used in the action plans as urban rehabilitation measure to fight noise pollution. However, this noise reduction seems to decrease with age at a rate of approximately 0.15 dB(A) per year. PMID- 26519583 TI - Arsenic distribution in soils and rye plants of a cropland located in an abandoned mining area. AB - A mining impacted cropland was studied in order to assess its As pollution level and the derived environmental and health risks. Profile soil samples (0-50 cm) and rye plant samples were collected at different distances (0-150 m) from the near mine dump and analyzed for their As content and distribution. These cropland soils were sandy, acidic and poor in organic matter and Fe/Al oxides. The soil total As concentrations (38-177 mg kg(-1)) and, especially, the soil soluble As concentrations (0.48-4.1 mg kg(-1)) importantly exceeded their safe limits for agricultural use of soils. Moreover, the soil As contents more prone to be mobilized could rise up to 25-69% of total As levels as determined using (NH4)2SO4, NH4H2PO4 and (NH4)2C2O4.H2O as sequential extractants. Arsenic in rye plants was primarily distributed in roots (3.4-18.8 mg kg(-1)), with restricted translocation to shoots (TF=0.05-0.26) and grains (TF=<0.02-0.14). The mechanism for this excluder behavior should be likely related to arsenate reduction to arsenite in roots, followed by its complexation with thiols, as suggested by the high arsenite level in rye roots (up to 95% of the total As content) and the negative correlation between thiol concentrations in rye roots and As concentrations in rye shoots (|R|=0.770; p<0.01). Accordingly, in spite of the high mobile and mobilizable As contents in soils, As concentrations in rye above ground tissues comply with the European regulation on undesirable substances in animal feed. Likewise, rye grain As concentrations were below its maximum tolerable concentration in cereals established by international legislation. PMID- 26519584 TI - Extreme weather and air pollution effects on cardiovascular and respiratory hospital admissions in Cyprus. AB - In many regions of the world, climatic change is associated with increased extreme temperatures, which can have severe effects on mortality and morbidity. In this study, we examine the effect of extreme weather on hospital admissions in Cyprus, for inland and coastal areas, through the use of synoptic weather classifications (air mass types). In addition, the effect of particulate air pollution (PM10) on morbidity is examined. Our results show that two air mass types, namely (a) warm, rainy days with increased levels of water vapour in the atmosphere and (b) cold, cloudy days with increased levels of precipitation, were associated with increased morbidity in the form of hospital admissions. This was true both for cardiovascular and respiratory conditions, for all age groups, but particularly for the elderly, aged over 65. Particulate air pollution was also associated with increased morbidity in Cyprus, where the effect was more pronounced for cardiovascular diseases. PMID- 26519585 TI - The legacy of organochlorine pesticide usage in a tropical semi-arid region (Jaguaribe River, Ceara, Brazil): Implications of the influence of sediment parameters on occurrence, distribution and fate. AB - Between the 1940s and 1990s, immeasurable amounts of organochlorine pesticides (OCPs) were used in endemic disease control campaigns and agriculture in the tropical semi-arid regions of Brazil. The present study evaluated the legacy of banned OCP usage, considering the levels, ecological risk and dependence on sediment physicochemical properties for the fate and distribution in the Jaguaribe River. The sum concentration of OCPs (SigmaOCPs) ranged from 5.09 to 154.43 ng.g(-1), comparable to the levels found in other tropical and subtropical regions that have traditionally used OCPs. The environmental and geographical distribution pattern of p,p-DDT, p,p-DDD and p,p-DDE shows that the estuarine zone contained more than 3.5 times the levels observed in the fluvial region, indicating that the estuary of the Jaguaribe River is a sink. The temporal pattern indicates application of dichloro-diphenyl-trichloroethanes (DDTs) in the past; however, there is evidence of recent input of these pesticides. High ecological risk was observed for levels of gamma-hexachlorocyclohexanes (gamma HCH) and heptachlor, and moderate ecological risk was observed for levels of DDTs in sediments from the Jaguaribe River. The heptachlor, gamma-HCH and hexachlorobenzene (HCB) concentrations depend on the organic and inorganic fractions of sediment from the Jaguaribe River, whereas the p,p-DDE, p,p-DDD, p,p DDT and alpha-endosulfan concentrations depend solely on the organic fraction of the sediment. PMID- 26519586 TI - The exposure metric choices have significant impact on the association between short-term exposure to outdoor particulate matter and changes in lung function: Findings from a panel study in chronic obstructive pulmonary disease patients. AB - BACKGROUND: The use of ambient air pollution data obtained from central air monitoring stations as surrogates for participants' exposures to outdoor air pollutants in previous studies may have introduced bias in the estimation of exposure-response associations. OBJECTIVES: We investigated and compared the effects of short-term exposure to outdoor particulate matter (PMout) and outdoor originated equivalent personal PM (PMeq) on lung function in chronic obstructive pulmonary disease (COPD) patients. METHODS: A total of 33 doctor-diagnosed stable COPD patients were recruited and repeatedly measured for lung function (totally 170 measurements) in 2013-2014. Daily PMout concentrations were obtained from central-monitoring stations, and daily time-weighted average PMeq concentrations were estimated based on PMout over the study. Associations of PM with lung function were estimated using mixed-effects models. RESULTS: Interquartile range increases in PM2.5out (111.0 MUg/m(3), 5-day) and PM10out (112.0 MUg/m(3), 3-day) were associated with a 3.3% (95% confidence interval [CI]: -5.8%, -0.8%) reduction and a 2.1% (95%CI: -3.9%, -0.3%) reduction in forced vital capacity (FVC), respectively. Similar results were found for forced expiratory volume in 1s (FEV1). An interquartile range increase in PM2.5eq (45.3 MUg/m(3), 3-day), but not PM10eq, was still associated with a 1.7% (95%CI: -3.3%, -0.1%) reduction in FVC. CONCLUSIONS: Our study may provide a novel approach to assess the association of ambient PM with health observations with improved accuracy. PMID- 26519587 TI - Impacts of management alternatives on rice yield and nitrogen losses to the environment: A case study in rural Sri Lanka. AB - Maintaining crop yields is vital as populations increase, but environmental degradation resulting from cultivation must be prevented. In particular, freshwater resources are at risk of nitrate leaching from superfluous fertilization. This research explores the tradeoffs between maximizing yield and limiting environmental impacts of rice production in Sri Lanka. The DeNitrification-DeComposition (DNDC) model was used to examine how various combinations of fertilization and irrigation management affect yield, nitrous oxide (N2O) emissions, and nitrogen (N) leaching in paddy systems under climate and soil conditions in the dry zone of Sri Lanka from 1991 to 2010. Simulated fertilizer application rates ranged from zero to 2700 kgN/ha and simulated irrigation schemes were continuously flooded, marginally flooded, and rain-fed. Increasing fertilizer levels from zero to 300 kgN/ha per year increased yield but application of fertilizer beyond that amount ceased to affect yield for any of the three irrigation schemes. The combination of management options for obtaining the maximum grain yield, near 9000 kgC/ha, with the greatest amount of N uptake and relatively low nitrate leaching was using 225 kgN/ha under a continuously flooded regime. This research explores how cultivation in rice-growing regions in south Asia affects the environment and the N cycle, and demonstrates how informed management of these systems can reduce external inputs of N fertilizer without impacting yield. PMID- 26519588 TI - Measurement and analysis of surface aerosol optical properties over urban Nanjing in the Chinese Yangtze River Delta. AB - Aerosol optical properties including aerosol scattering coefficient (sigmasp), absorption coefficient (sigmaap), single scattering albedo (SSA), PM2.5 mass concentration and their relationship with meteorological factors were measured and analyzed from 1st March to 30th April 2011. The observations were conducted at an urban-industrial site in Nanjing located in the Yangtze River Delta (YRD) region, China. The averaged sigmasp at 550 nm is found to be 329.3+/-321.6 Mm(-1) and occurred most frequently within the range of 100-200 Mm(-1). sigmaap at 532 nm is measured to be 28.1+/-17.6 Mm(-1), which is remarkably smaller than most of the measurements made over megacities in China and nearly equivalent to the observations made at rural sites in the YRD. The mean SSA at 532 nm is 0.89+/ 0.08 with the occurrence frequency of higher SSA (>0.9) accounting for about 60%, indicating that scattering-related aerosols are dominant over Nanjing during the study period. A bi-peak diurnal variation of sigmaap and sigmasp is found with the maximum during late at night and early morning and the minimum in the afternoon, but the diurnal pattern of SSA is just the opposite to this. Significant correlation coefficients are noticed between different aerosol optical properties. sigmasp and sigmaap showed a clear negative correlation with wind speed, temperature, and visibility. During the study period, the lower northwesterly and southeasterly winds are attributed to an increase in the aerosol optical properties. The sigmasp and sigmaap increased significantly during severe haze and dust episodes caused by the accumulation of pollutants from both local and regional sources under favorable weather conditions. PMID- 26519589 TI - Environmental life cycle optimization of essential terpene oils produced by the macroalga Ochtodes secundiramea. AB - The macroalga Ochtodes secundiramea is a well-known producer of essential terpene oils with promising biological activities and similar applications to those of microalgal biocompounds in the pharmaceutical, food or cosmetics sectors. This study assesses the environmental impacts associated with the production of five essential terpene oils (myrcene, 10Z-bromomyrcene, 10E-bromo-3-chloromyrcene, apakaochtodene B and acyclic C10H14Br2) by O. secundiramea cultivated in a closed airlift photobioreactor with artificial illumination. The results of the life cycle assessment (LCA) allowed analyzing the effect of implementing a semi continuous operation on several stages of the life cycle of the products, which may lead to impact reductions from 1% up to 25%. Regarding the most problematic aspects of the process, the cultivation in the photobioreactor (S4) was identified as the main stage responsible for the environmental burdens, with contributions ranging between 60% and 80% of the total impacts for a semi continuous production maintained during one year of operation. The electricity supply is the key activity affecting eight of the ten assessed categories and involves between 50% and 60% of the impact of the process. S4 is the main cause of the high energy requirements, with 86% of the total electricity consumption. Additionally, several scenarios aiming at improving the environmental profile of the system were evaluated. The application of LCA finally led to the proposal of two optimized scenarios with improvements between 8% and 40% with respect to the baseline case study. PMID- 26519590 TI - Selection of effective macroalgal species and tracing nitrogen sources on the different part of Yantai coast, China indicated by macroalgal delta(15)N values. AB - To determine the dominant nitrogen sources and select effective macroalgal species for monitoring eutrophication along the Yantai coast, the total carbon (TOC), total nitrogen (TN) and nitrogen stable isotope ratio (delta(15)N) in macroalgal tissue were analyzed in conjunction with environmental variables in seawater along the Yantai coastline. The ranges of macroalgal tissue delta(15)N values together with dissolved inorganic nitrogen (DIN) composition indicated that except for the atmospheric deposition, there were three dominant types of nitrogen sources along the Yantai coast, with the agricultural fertilizer usage and factorial wastewater input at the S1 (Zhifu Island coast), the sewage discharge at S2 (the Moon Bay coast), the sewage discharge together with aquaculture impacts at S3 (Fisherman Wharf coast) and S4 (the Horse Island coast). Macroalgal growth were not limited by DIN but limited by P at S2, S3 and S4. Macroalgal species suitable or not for DIN source tracing along the Yantai coast were discussed. For sites with low DIN concentration, many species of three phyla could be used for DIN sources tracing with Laurencia okamurai, Gloiopeltis furcata and Ulva pertusa being ideal species. For site with high DIN concentration, however, species of Rhodophyta were not suitable and only Scytosiphon lomentaria and Monostroma nitidium were chosen. PMID- 26519591 TI - Quantifying suspended sediment flux in a mixed-land-use urbanizing watershed using a nested-scale study design. AB - Suspended sediment (SS) remains the most pervasive water quality problem globally and yet, despite progress, SS process understanding remains relatively poor in watersheds with mixed-land-use practices. The main objective of the current work was to investigate relationships between suspended sediment and land use types at multiple spatial scales (n=5) using four years of suspended sediment data collected in a representative urbanized mixed-land-use (forest, agriculture, urban) watershed. Water samples were analyzed for SS using a nested-scale experimental watershed study design (n=836 samples*5 gauging sites). Kruskal Wallis and Dunn's post-hoc multiple comparison tests were used to test for significant differences (CI=95%, p<0.05) in SS levels between gauging sites. Climate extremes (high precipitation/drought) were observed during the study period. Annual maximum SS concentrations exceeded 2387.6 mg/L. Median SS concentrations decreased by 60% from the agricultural headwaters to the rural/urban interface, and increased by 98% as urban land use increased. Multiple linear regression analysis results showed significant relationships between SS, annual total precipitation (positive correlate), forested land use (negative correlate), agricultural land use (negative correlate), and urban land use (negative correlate). Estimated annual SS yields ranged from 16.1 to 313.0 t km( 2) year(-1) mainly due to differences in annual total precipitation. Results highlight the need for additional studies, and point to the need for improved best management practices designed to reduce anthropogenic SS loading in mixed land-use watersheds. PMID- 26519592 TI - Impact of natural organic matter on particle behavior and phototoxicity of titanium dioxide nanoparticles. AB - Due to their inherent phototoxicity and inevitable environmental release, titanium dioxide nanoparticles (nano-TiO2) are increasingly studied in the field of aquatic toxicology. One of the particular interests is the interactions between nano-TiO2 and natural organic matter (NOM). In this study, a series of experiments was conducted to study the impacts of Suwannee River natural organic matter (SRNOM) on phototoxicity and particle behaviors of nano-TiO2. For Daphnia magna, after the addition of 5mg/L SRNOM, LC50 value decreased significantly from 1.03 (0.89-1.20) mg/L to 0.26 (0.22-0.31) mg/L. For zebrafish larvae, phototoxic LC50 values were 39.9 (95% CI, 25.9-61.2) mg/L and 26.3 (95% CI, 18.3-37.8) mg/L, with or without the presence of 5mg/L SRNOM, respectively. There was no statistically significant change of these LC50 values. The impact of SRNOM on phototoxicity of nano-TiO2 was highly dependent on test species, with D. magna being the more sensitive species. The impact on particle behavior was both qualitatively and quantitatively examined. A global predictive model for particle behavior was developed with a three-way interaction of SRNOM, TiO2 concentration, and time and an additive effect of ionic strength. Based on power analyses, 96-h exposure in bioassays was recommended for nanoparticle-NOM interaction studies. The importance of reactive oxygen species (ROS) quenching of SRNOM was also systematically studied using a novel exposure system that isolates the effects of environmental factors. These experiments were conducted with minimal impacts of other important interaction mechanisms (NOM particle stabilization, NOM UV attenuation, and NOM photosensitization). This study highlighted both the particle stabilization and ROS quenching effects of NOM on nano-TiO2 in an aquatic system. There is an urgent need for representative test materials, together with key environmental factors, for future risk assessment and regulations of nanomaterials. PMID- 26519593 TI - Comparative contributions of solution geochemistry, microbial metabolism and aquatic photosynthesis to the development of high pH in ephemeral wetlands in South East Australia. AB - The development of alkaline conditions in lakes and wetlands is common but the process of alkalinisation is not well elaborated. In this study we investigated causes of the seasonal alkalinisation of ephemeral wetlands in the South East of South Australia where pH values above 10 are frequently observed. This research combined field observations, geochemical analysis of wetland sediment and surface water, with mesocosm studies under controlled conditions. The results revealed a complex interplay between a number of different processes. A primary cause was attributed to sequestration of CO2 from the water column by plant photosynthesis, coupled with slow diffusion of CO2 from the air which led to its depletion in the water. Abundant plant growth also modified the water chemistry via uptake of nutrient elements, in particular calcium and magnesium and increased carbonate alkalinity in the water. Assessment of field results and geochemical modeling showed that low Ca/(HCO3(-) and CO3(-2)) ratios in the water, coupled with carbonate mineral (calcite, Mg substituted calcite, dolomite) precipitation and evapoconcentration, create a high alkalinity and pH (>9) baseline in many wetlands. The high baseline pH is then further increased by CO2 depletion due to photosynthesis. We could find no evidence that reduction of sulfate to sulfides by sulfur-reducing bacteria significantly contributed to the very high pH conditions. PMID- 26519594 TI - Using multiple combined analytical techniques to characterize water extractable organic nitrogen from Lake Erhai sediment. AB - In this study, UV-vis absorbance, fluorescence, and FT-IR spectroscopy were combined to characterize the components and structure of the water extractable organic nitrogen (WEON) in Lake Erhai sediment. Lake Erhai sediment WEON comprised predominantly high molecular weight WEON, with the fraction with a molecular weight>1kDa accounting for 87.7% of the total. It was mainly composed of humic acid-like substances, with fewer simple aromatic proteins. Large amounts of aliphatic and amide compounds were detected by IR in the sediments. There were more polymerizable aromatic rings and carbonyl, carboxyl, hydroxyl, and ester compounds in the high molecular weight WEON than in the low molecular weight WEON. Additionally, fluorescence regional integration results implied that the ratio PIII+V,n/PI+II+IV,n can be indirectly taken as an indicator for WEON content in Erhai sediments. Furthermore, the composition and structural characteristics of the WEON were found to be closely related with their properties in the sediment. The large amount of aliphatic compounds in the sediment as well as the relatively high humification and aromatic degree in high molecular weight WEON, stabilizes the WEON in Lake Erhai sediment. Compared with other lake sediments of different trophic statues (such as Lake Dianchi, Lake Poyang, Lake Taihu and Lake Donghu), Erhai sediment exhibited a higher degree of humification, which benefited for reducing sediment WEON releasing risk. And it can be regarded as the reason why the nutrient content in Erhai sediment is very high, but its water quality is still good. PMID- 26519595 TI - Associations of acute exposure to fine and coarse particulate matter and mortality among older people in Tokyo, Japan. AB - Recent studies have reported adverse health effects of short-term exposure to coarse particles independent of particulate matter less than 2.5 MUm in diameter (PM2.5), but evidence in Asian countries is limited. We therefore evaluated associations between short-term exposure to particulate matter (PM) and mortality among older people in Tokyo, Japan. We used a time-stratified, case-crossover design. Study participants included 664,509 older people (>=65 years old) in the 23 urbanized wards of the Tokyo Metropolitan Government, who died between January 2002 and December 2013. We obtained PM2.5 and suspended particulate matter (SPM; PM<7 MUm in diameter) from one general monitoring station. We calculated PM7-2.5 by subtracting PM2.5 from SPM to account for coarse particles. We then used conditional logistic regression to estimate odds ratios (ORs) and 95 confidence intervals (CIs). Same-day PM2.5 and PM7-2.5 were independently associated with all-cause and cause-specific mortality related to cardiovascular and respiratory diseases; for example, both pollutants were positively associated with increased risk of all-cause mortality even after simultaneous adjustment for each pollutant: OR of 1.006 (95% CI: 1.003, 1.009) for PM2.5 and 1.016 (95% CI: 1.011, 1.022) for PM7-2.5. Even below concentrations stipulated by the Japanese air quality guidelines for PM2.5 and SPM (PM7), we observed adverse health effects. This study provides further evidence that acute exposure to PM2.5 and coarse particles is associated with increased risk of mortality among older people. Rigorous evaluation of air quality guidelines for daily average PM2.5 and larger particles should be continued. PMID- 26519596 TI - A novel insect-specific flavivirus replicates only in Aedes-derived cells and persists at high prevalence in wild Aedes vigilax populations in Sydney, Australia. AB - To date, insect-specific flaviviruses (ISFs) have only been isolated from mosquitoes and increasing evidence suggests that ISFs may affect the transmission of pathogenic flaviviruses. To investigate the diversity and prevalence of ISFs in Australian mosquitoes, samples from various regions were screened for flaviviruses by ELISA and RT-PCR. Thirty-eight pools of Aedes vigilax from Sydney in 2007 yielded isolates of a novel flavivirus, named Parramatta River virus (PaRV). Sequencing of the viral RNA genome revealed it was closely related to Hanko virus with 62.3% nucleotide identity over the open reading frame. PaRV failed to grow in vertebrate cells, with only Aedes-derived mosquito cell lines permissive to replication, suggesting a narrow host range. 2014 collections revealed that PaRV had persisted in A. vigilax populations in Sydney, with 88% of pools positive. Further investigations into its mode of transmission and potential to influence vector competence of A. vigilax for pathogenic viruses are warranted. PMID- 26519597 TI - Establishment of an in vitro equine papillomavirus type 2 (EcPV2) neutralization assay and a VLP-based vaccine for protection of equids against EcPV2-associated genital tumors. AB - The consistent and specific presence of Equus caballus papillomavirus type 2 (EcPV2) DNA and mRNA in equine genital squamous cell carcinoma (gSCC) is suggestive of an etiological role in tumor development. To further validate this concept, EcPV2-neutralizing serum antibody titers were determined by an EcPV2 pseudovirion (PsV) neutralization assay. Furthermore, an EcPV2 L1 virus-like particle (VLP)-based vaccine was generated and its prophylactic efficacy evaluated in vivo. All 6/6 gSCC-affected, but only 3/20 tumor-free age-matched animals revealed EcPV2-neutralizing serum antibody titers by PsV assay. Vaccination of NZW rabbits and BalbC mice with EcPV2 L1 VLP using Freund's or alum respectively as adjuvant induced high-titer neutralizing serum antibodies (1600-12,800). Passive transfer with rabbit EcPV2-VLP immune sera completely protected mice from experimental vaginal EcPV2 PsV infection. These findings support the impact of EcPV2 in equine gSCC development and recommend EcPV2 L1 VLP as prophylactic vaccine against EcPV2 infection and associated disease in equids. PMID- 26519598 TI - Monitoring the dynamics of emergence of a non-canonical recombinant of Tomato yellow leaf curl virus and displacement of its parental viruses in tomato. AB - Recombinant viruses are increasingly being reported but the dynamics of their emergence is rarely documented. A new recombinant Tomato yellow leaf curl virus (TYLCV-IS76) was detected for the first time in 2010 in Southern Morocco (Souss). An original diagnostic tool was needed to fit its unusual recombination profile. Although IS76 was detected following the appearance of Tylc symptoms on tolerant tomato plants, symptoms could not be associated to IS76 or to a synergy with criniviruses. According to infection profiles of Tylc-associated viruses determined on 879 plant samples collected between 1998 and 2014 and a Bayesian inference applied to genomic sequences of representatives of TYLCV, IS76 emerged in Southern Morocco at the end of the 1990s, replaced the parental viruses between 2004 and 2012 in Souss and is spreading towards the North of Morocco. The emergence of IS76 coincides with the increasing use of tolerant cultivars in the 2000s. PMID- 26519599 TI - Zebrafish as a useful model for zoonotic Vibrio parahaemolyticus pathogenicity in fish and human. AB - Vibrio parahaemolyticus is an important aquatic zoonotic pathogen worldwide that causes vibriosis in many marine fish, and sepsis, gastroenteritis and wound infection in humans. However, the pathogenesis of different sources of V. parahaemolyticus is not fully understood. Here, we examined the pathogenicity and histopathology of fish (V. parahaemolyticus 1.2164) and human (V. parahaemolyticus 17) strains in a zebrafish (Danio rerio). We found that different infection routes resulted in different mortality in zebrafish. Moreover, death due to V. parahaemolyticus 1.2164 infection occurred quicker than that caused by V. parahaemolyticus 17 infection. Hematoxylin-eosin staining of liver, kidney and intestine sections showed histological lesions in all three organs after infection with either strain. V. parahaemolyticus 1.2164 caused more severe damage than V. parahaemolyticus 17. In particular, V. parahaemolyticus 1.2164 treatment induced more serious hydropic degeneration and venous sinus necrosis in the liver than V. parahaemolyticus 17 treatment. The expression levels of three proinflammatory cytokines, interleukin 1beta (il1beta), interferon phi 1 (ifnphi1) and tumor necrosis factor alpha (tnfalpha), as determined by quantitative real-time PCR, were upregulated in all examined tissues of infected fish. Notably, the peak levels of tnfalpha were significantly higher than those of il1beta and ifnphi1, suggesting, together with pathological results, that tnfalpha and il1beta play an important role in acute sepsis. High amounts of tnfalpha may be related to acute liver necrosis, while ifnphi1 may respond to V. parahaemolyticus and play an antibacterial role for chronically infected adult zebrafish. Taken together, our results suggest that the zebrafish model of V. parahaemolyticus infection is useful for studying strain differences in V. parahaemolyticus pathogenesis. PMID- 26519600 TI - Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. AB - BACKGROUND & AIMS: Non-selective beta blockers (NSBBs) have been shown to have deleterious outcomes in patients with refractory ascites, alcoholic hepatitis and spontaneous bacterial peritonitis leading many physicians to stop the drug in these cases. Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation and high mortality. As NSBBs may have beneficial effects on gut motility and permeability and, systemic inflammation, the aims of this prospective, observational study were to determine whether ongoing use of NSBBs reduced 28-day mortality in ACLF patients. METHODS: The study was performed in 349 patients with ACLF included in the CANONIC study, which is a prospective observational investigation in hospitalized cirrhotic patients with acute deterioration. The data about the use of NSBBs, its type and dosage was specifically recorded. Patient characteristics at enrollment significantly associated with treatment and mortality were taken into account as potential confounders to adjust for treatment effect. A logistic regression model was fitted. RESULTS: 164 (47%) ACLF patients received NSBBs whereas 185 patients did not. Although the CLIF-C ACLF scores were similar at presentation, more patients in the NSBB treated group had lower grades of ACLF (p=0.047) at presentation and significantly more patients improved. Forty patients (24.4%) died in NSBB treated group compared with 63 patients (34.1%) (p=0.048) [estimated risk-reduction 0.596 (95%CI: 0.361-0.985; p=0.0436)]. This improvement in survival was associated with a significantly lower white cell count (NSBB: 8.5 (5.8); no NSBB: 10.8 (6.6); p=0.002). No long-term improvement in survival was observed. CONCLUSIONS: This study shows for the first time that ongoing treatment with NSBBs in cirrhosis is safe and reduces the mortality if they develop ACLF. Careful thought should be given before stopping NSBBs in cirrhotic patients. PMID- 26519601 TI - Cerium oxide nanoparticles reduce steatosis, portal hypertension and display anti inflammatory properties in rats with liver fibrosis. AB - BACKGROUND & AIMS: Cerium oxide nanoparticles (CeO2NPs) have proven to behave as free radical scavengers and/or anti-inflammatory agents. The aim of the study was to determine whether CeO2NPs display hepatoprotective properties in experimental chronic liver disease. METHODS: Systemic and hepatic effects of nanoparticles were assessed in CCl4-treated rats receiving CeO2NPs or vehicle twice weekly for two weeks and CCl4 treatment was continued for 8 additional weeks. Thereafter, mean arterial pressure and portal pressure (PP) were assessed and serum samples obtained to measure standard hepatic and renal function tests. Organ and subcellular distribution of NPs were assessed using mass spectrometry (ICP-MS) and transmission electron microscopy. Liver samples were obtained to evaluate steatosis, alpha-SMA expression, macrophage infiltration, apoptosis and mRNA expression of oxidative stress, inflammatory or vasoactive related genes. RESULTS: Most CeO2NPs were located in the liver and it reduced hepatic steatosis, ameliorated systemic inflammatory biomarkers and improved PP without affecting mean arterial pressure. In addition, a marked reduction in mRNA expression of inflammatory cytokines (TNFalpha, IL1beta, COX-2, iNOS), ET-1 and messengers related to oxidative (Epx, Ncf1, Ncf2) or endoplasmic reticulum (Atf3, Hspa5) stress signaling pathways was observed in the liver of rats receiving CeO2NPs. This was associated with reduced macrophage infiltration and reduced abundance of caspase-3, alpha-SMA and inflammatory cytokines. CONCLUSIONS: CeO2NPs administration to CCl4-treated rats protects against chronic liver injury by reducing liver steatosis and portal hypertension and markedly attenuating the intensity of the inflammatory response, thereby suggesting that CeO2NPs may be of therapeutic value in chronic liver disease. PMID- 26519602 TI - Management of the critically ill patient with cirrhosis: A multidisciplinary perspective. PMID- 26519603 TI - Peripheral oxytocin administration reduces ethanol consumption in rats. AB - The neuropeptide oxytocin interacts with mesolimbic dopamine neurons to mediate reward associated with filial behaviors, but also other rewarding behaviors such as eating or taking drugs of abuse. Based on its efficacy to decrease intake of other abused substances, oxytocin administration is implicated as a possible treatment for excessive alcohol consumption. We tested this hypothesis by measuring ethanol intake in male Sprague-Dawley rats injected with oxytocin or saline using two different ethanol self-administration paradigms. First, a dose response curve was constructed for oxytocin inhibition of fluid intake using a modified drinking-in-the-dark model with three bottles containing .05% saccharine, 10% ethanol in saccharine, and 15% ethanol in saccharine. Doses of oxytocin tested were 0.05, 0.1, 0.3, and 0.5mg/kg (I.P.). Next, rats received 0.3mg/kg oxytocin preceding operant sessions in which they were trained to lever press for either plain gelatin or ethanol gelatin in order to compare oxytocin inhibition of ethanol intake versus caloric intake. For the three-bottle choice study, rats consumed significantly less ethanol when treated with the three higher doses of oxytocin on the injection day. In the operant study, 0.3mg/kg oxytocin significantly decreased ethanol gel consumption to a greater extent than plain gel consumption, both in terms of the amount of gel eaten and calories consumed. These data affirm oxytocin's efficacy for decreasing ethanol intake in rats, and confirm clinical studies suggesting oxytocin as a potential treatment for alcoholism. PMID- 26519604 TI - Cumulative effects of noise and odour annoyances on environmental and health related quality of life. AB - Noise and odour annoyances are important considerations in research on health effects of air pollution and traffic noise. Cumulative exposures can occur via several chemical hazards or a combination of chemical and stressor-based hazards, and related health outcomes can be generalized as manifestations of physiological and/or psychological stress responses. A major research challenge in this field is to understand the combined health effects of physiological and psychological responses to exposure. The SF-12 Health Survey is a health related quality of life (HRQoL) instrument designed for the assessment of functional mental and physical health in clinical practice and therefore well suited to research on physiological health outcomes of exposure. However, previous research has not assessed its sensitivity to psychological stress as measured by noise annoyance and odour annoyance. The current study validated and tested this application of the SF-12 Health Survey in a cross-sectional study (n = 603) that included exposure assessment for traffic noise and air pollution in Windsor, Ontario, Canada. The results indicated that SF-12 scores in Windsor were lower than Canadian normative data. A structural equation model demonstrated that this was partially due to noise and odour annoyances, which were associated with covarying exposures to ambient nitrogen dioxide and traffic noise. More specifically, noise annoyance had a significant and negative effect on both mental and physical health factors of the SF-12 and there was a significant covariance between noise annoyance and odour annoyance. The study confirmed a significant effect of psychological responses to cumulative exposures on HRQoL. The SF-12 Health Survey shows promise with respect to assessing the cumulative health effects of outdoor air pollution and traffic noise. PMID- 26519605 TI - Multiple contexts of exposure: Activity spaces, residential neighborhoods, and self-rated health. AB - Although health researchers have made progress in detecting place effects on health, existing work has largely focused on the local residential neighborhood and has lacked a temporal dimension. Little research has integrated both time and space to understand how exposure to multiple contexts - where adults live, work, shop, worship, and seek healthcare - influence and shape health and well-being. This study uses novel longitudinal data from the Los Angeles Family and Neighborhood Survey to delve deeper into the relationship between context and health by considering residential and activity space neighborhoods weighted by the amount of time spent in these contexts. Results from multilevel cross classified logistic models indicate that contextual exposure to disadvantage, residential or non-residential, is independently associated with a higher likelihood of reporting poor or fair health. We also find support for a contextual incongruence hypothesis. For example, adults living in the most disadvantaged neighborhoods are more likely to report poor or fair health when they spend time in more advantaged neighborhoods than in more disadvantaged ones, while residents of more advantaged neighborhoods report worse health when they spend time in more disadvantaged areas. Our results suggest that certain types of place-based cumulative exposures are associated with a sense of relative neighborhood deprivation that potentially manifests in worse health ratings. PMID- 26519606 TI - The effect of feeding native warm season grasses in the stocker phase on the carcass quality, meat quality, and sensory attributes of beef loin steaks from grain-finished steers. AB - The objective of this study was to evaluate the effect of feeding native warm season grass (NWSG) to beef cattle during the stocker phase (110days) on carcass and meat quality. Treatments included Bermudagrass (BER), Indiangrass monoculture (IND), and a mixture of NWSG including Big Bluestem, Little Bluestem, and Indiangrass (MIX). Cattle were finished on grain (180days) in a commercial feedlot and carcass data were collected after harvest. The percentages of 'choice' carcasses were 100, 95.8, and 87 within MIX, BER, and IND treatments, respectively. Steaks from BER had greater (P<0.05) fat content, and lower (P<0.05) protein and moisture percentages when compared to steaks from IND and MIX treatments. However, steaks from the MIX and IND treatments had less (P<0.05) lipid oxidation than steaks from BER after 6days of refrigerated storage. Results indicate that NWSG could be effectively incorporated into forage systems for stocker cattle without compromising carcass and meat quality. PMID- 26519607 TI - Post-mortem prediction of primal and selected retail cut weights of New Zealand lamb from carcass and animal characteristics. AB - Post-mortem measurements (cold weight, grade and external carcass linear dimensions) as well as live animal data (age, breed, sex) were used to predict ovine primal and retail cut weights for 792 lamb carcases. Significant levels of variance could be explained using these predictors. The predictive power of those measurements on primal and retail cut weights was studied by using the results from principal component analysis and the absolute value of the t-statistics of the linear regression model. High prediction accuracy for primal cut weight was achieved (adjusted R(2) up to 0.95), as well as moderate accuracy for key retail cut weight: tenderloins (adj-R(2)=0.60), loin (adj-R(2)=0.62), French rack (adj R(2)=0.76) and rump (adj-R(2)=0.75). The carcass cold weight had the best predictive power, with the accuracy increasing by around 10% after including the next three most significant variables. PMID- 26519608 TI - Changes in taste compounds, breaking properties, and sensory attributes during dry aging of beef from Japanese black cattle. AB - Analysis of the quality of highly marbled beef during dry aging for 60days after slaughter showed that the changes in some qualities differed from those of conventional meat. The tenderness of these meats did not change during aging for 50days but then gradually increased until day 60. The juiciness of these meats, as determined by sensory evaluation, did not change during aging for 60days, except for a decrease on day 20. The umami intensity of these meats in the sensory evaluation and the value calculated by Glu and IMP quantification were highest on day 40. This high umami intensity was induced by the synergistic effect of umami compounds such as Glu and IMP. These results for tenderness, juiciness, umami intensity, and flavor intensity suggested that the best duration of dry aging for highly marbled beef was 40days. PMID- 26519609 TI - Tenderness and sensory attributes of the longissimus lumborum muscles with different quality grades from Chinese fattened yellow crossbred steers. AB - The objectives were to investigate intramuscular fat (IMF) content,Warner Bratzler shear force(WBSF) and sensory attributes of Chinese fattened yellow crossbred steer beef with different quality grades, and to determine the relationship between WBSF and Chinese consumers' sensory tender. WBSF of grades A1 to A5 decreased from 50.6 N to 33.1 N with IMF % increased from4.26 to 24.55 (P b 0.05). Consumer panelists showed more likeability grades A4 and A5 with no difference between them. Grades A2 and A3 were slightly preferred (P b 0.05). Grade A1 was undesirable. A regression relationship between WBSF and sensory tender was found, which indicated that consumers disliked beef when WBSF N55.43 N and preferred those with WBSF b41.4 N. The range of 41.4 N to 55.43 N was intermediate. Hence, WBSF N55.43 & b41.4 N allow classification of tough and tender for beef tenderness for Chinese consumers, and grade A4 was recommended as suitable top grade. PMID- 26519610 TI - Respiratory Muscle Strength in Chronic Stroke Survivors and Its Relation With the 6-Minute Walk Test. AB - OBJECTIVES: To compare respiratory muscle strength in stroke survivors (SS) with that in a control group (CG) of healthy people matched by age and sex, as well as to investigate any relation between respiratory muscle strength and the distance walked during the 6-minute walk test (6MWT). DESIGN: Cross-sectional study. SETTING: This study comprised patients from a private neurological rehabilitation center and a public association for patients with acquired brain injury. PARTICIPANTS: Chronic SS with a diagnosis of hemiplegia/hemiparesis who were able to walk (n=30) and healthy individuals matched by sex and age (n=30) (N=60). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Respiratory muscle strength was assessed using maximal expiratory pressure (MEP) and maximal inspiratory pressure (MIP) with a pressure transducer and a diver nozzle. The distance walked during the 6MWT was also registered for both groups. The motricity index and the Scale Impact of Stroke version 16.0 were also measured in SS. RESULTS: The Student t test revealed significantly lower values of MIP and MEP in SS than in the CG (MEP, 95.93+/-43.12cmH2O in SS vs 158.43+/-41.6cmH2O in the CG; MIP, 58.7+/-24.67cmH2O in SS vs 105.7+/-23.14cmH2O in the CG; P<.001). Moreover, these findings were clinically relevant because both MIP and MEP in SS were <60% of the predicted values. A positive correlation between the 6MWT and MIP was found using the Pearson coefficient (r=.43; P<.018). CONCLUSIONS: Respiratory muscle weakness should be considered in a holistic approach to stroke rehabilitation. PMID- 26519611 TI - Development of multiplex serological assay for the detection of human African trypanosomiasis. AB - Human African trypanosomiasis (HAT) is a disease caused by Kinetoplastid infection. Serological tests are useful for epidemiological surveillance. The aim of this study was to develop a multiplex serological assay for HAT to assess the diagnostic value of selected HAT antigens for sero-epidemiological surveillance. We cloned loci encoding eight antigens from Trypanosoma brucei gambiense, expressed the genes in bacterial systems, and purified the resulting proteins. Antigens were subjected to Luminex multiplex assays using sera from HAT and VL patients to assess the antigens' immunodiagnostic potential. Among T. b. gambiense antigens, the 64-kDa and 65-kDa invariant surface glycoproteins (ISGs) and flagellar calcium binding protein (FCaBP) had high sensitivity for sera from T. b. gambiense patients, yielding AUC values of 0.871, 0.737 and 0.858 respectively in receiver operating characteristics (ROC) analysis. The ISG64, ISG65, and FCaBP antigens were partially cross-reactive to sera from Trypanosoma brucei rhodesiense patients. The GM6 antigen was cross-reactive to sera from T. b. rhodesiense patients as well as to sera from VL patients. Furthermore, heterogeneous antibody responses to each individual HAT antigen were observed. Testing for multiple HAT antigens in the same panel allowed specific and sensitive detection. Our results demonstrate the utility of applying multiplex assays for development and evaluation of HAT antigens for use in sero epidemiological surveillance. PMID- 26519612 TI - The hydration properties of carboxybetaine zwitterion brushes. AB - Combined quantum mechanical calculations and classical molecular dynamics simulations were conducted to investigate the hydration properties of carboxybetaine zwitterion brushes with varying separation distances between the quaternary ammonium cation and carboxylic anion. The brushes consist of zwitterion trimers and are investigated to mimic interacting zwitterion chains grafted on a substrate as well as polymers with interacting zwitterion side chains. Our results show that the values of both positive and negative charges, their separation distances as well as chain interactions appear to play a critical role in the hydration properties of the zwitterions. The overall hydration property of these zwitterions is dictated by the competition between the strong hydration of the charged groups and the dehydration of the hydrocarbon chains. The strongest hydration occurs when the -CH2- unit in the hydrocarbon chain reaches 6-8 for these trimers. Further increase in the hydrocarbon chain length to 10-14 leads to significant and sudden dehydration of the trimers. The water structure and the water residence time surrounding the zwitterions also demonstrate substantial alteration at this length scale. This hydrophilic-to hydrophobic transition is induced by the hydrophobic interactions of the trimer chains. Our hydration results could explain the observed trend of the superiority of the methylated carbohydrates and poly(ethylene glycol) as antifouling materials compared to corresponding hydroxyl-terminated compounds. PMID- 26519614 TI - Mindfulness-based Stress Reduction in Addition to Usual Care Is Associated with Improvements in Pain, Fatigue, and Cognitive Failures Among Veterans with Gulf War Illness. AB - BACKGROUND: Many Gulf War I veterans report ongoing negative health consequences. The constellation of pain, fatigue, and concentration/memory disturbances is referred to as "Gulf War illness." Prior research suggests that mindfulness-based stress reduction may be beneficial for these symptoms, but mindfulness-based stress reduction has not been studied for veterans with Gulf War illness. The objective of this trial was to conduct a pilot study of mindfulness-based stress reduction for veterans with Gulf War illness. METHODS: Veterans (N = 55) with Gulf War illness were randomly assigned to treatment as usual plus mindfulness based stress reduction or treatment as usual only. Mindfulness-based stress reduction was delivered in 8 weekly 2.5-hour sessions plus a single 7-hour weekend session. Pain, fatigue, and cognitive failures were the primary outcomes, assessed at baseline, after mindfulness-based stress reduction, and 6 months follow-up. Secondary outcomes included symptoms of posttraumatic stress disorder and depression. RESULTS: In intention-to-treat analyses, at 6-month follow-up, veterans randomized to mindfulness-based stress reduction plus treatment as usual reported greater reductions in pain (f = 0.33; P = .049), fatigue (f = 0.32; P = .027), and cognitive failures (f = 0.40; P < .001). Depressive symptoms showed a greater decline after mindfulness-based stress reduction (f = 0.22; P = .050) and at 6 months (f = 0.27; P = .031) relative to treatment as usual only. Veterans with posttraumatic stress disorder at baseline randomized to mindfulness-based stress reduction plus treatment as usual experienced significantly greater reductions in symptoms of posttraumatic stress disorder after mindfulness-based stress reduction (f = 0.44; P = .005) but not at 6 months follow-up (f = 0.31; P = .082). CONCLUSIONS: Mindfulness-based stress reduction in addition to treatment as usual is associated with significant improvements in self-reported symptoms of Gulf War illness, including pain, fatigue, cognitive failures, and depression. PMID- 26519613 TI - Exposure to coplanar PCBs induces endothelial cell inflammation through epigenetic regulation of NF-kappaB subunit p65. AB - Epigenetic modifications of DNA and histones alter cellular phenotypes without changing genetic codes. Alterations of epigenetic marks can be induced by exposure to environmental pollutants and may contribute to associated disease risks. Here we test the hypothesis that endothelial cell dysfunction induced by exposure to polychlorinated biphenyls (PCBs) is mediated in part though histone modifications. In this study, human vascular endothelial cells were exposed to physiologically relevant concentrations of several PCBs congeners (e.g., PCBs 77, 118, 126 and 153) followed by quantification of inflammatory gene expression and changes of histone methylation. Only exposure to coplanar PCBs 77 and 126 induced the expression of histone H3K9 trimethyl demethylase jumonji domain-containing protein 2B (JMJD2B) and nuclear factor-kappa B (NF-kappaB) subunit p65, activated NF-kappaB signaling as evidenced by nuclear translocation of p65, and up regulated p65 target inflammatory genes, such as interleukin (IL)-6, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and IL-1alpha/beta. The increased accumulation of JMJD2B in the p65 promoter led to a depletion of H3K9me3 repression mark, which accounts for the observed up-regulation of p65 and associated inflammatory genes. JMJD2B gene knockdown confirmed a critical role for this histone demethylase in mediating PCB-induced inflammation of the vascular endothelium. Finally, it was determined, via chemical inhibition, that PCB-induced up-regulation of JMJD2B was estrogen receptor-alpha (ER-alpha) dependent. These data suggest that coplanar PCBs may exert endothelial cell toxicity through changes in histone modifications. PMID- 26519615 TI - Administrative Data and the Philosopher's Stone: Turning Heart Failure Claims Data into Quantitative Assessment of Left Ventricular Ejection Fraction. AB - BACKGROUND: Administrative data are widely used in observational assessment of patient-centered clinical outcomes. In studies of cardiovascular outcomes, claims data are limited by lack of quantitative information, such as left ventricular ejection fraction. We aimed to determine whether left ventricular ejection fraction can be assessed from heart failure claims. METHODS: This observational, retrospective study used administrative and echocardiographic databases to identify heart failure patients (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 428.XX) who received echocardiograms. The study cohort included patients with at least one inpatient or outpatient claim for systolic (428.2X) or diastolic (428.3X) heart failure from January 1, 2007, through July 10, 2013, who received an echocardiogram within 30 days of the claim. Receiver operating characteristic (ROC) curves were used to determine the optimal left ventricular ejection fraction cut-off threshold between ICD-9-CM heart failure codes 428.2 (systolic) and 428.3 (diastolic). Bootstrapping was used to determine a 95% confidence interval for the best cut-off. RESULTS: A total of 2714 echocardiograms with ascertainable left ventricular ejection fraction were performed within 30 days of a heart failure diagnosis. ICD-9-CM codes 428.2 and 428.3 accounted for 28.9% and 18.2%, respectively, of all heart failure codes. The resulting ROC curve had a best threshold cut-off for ejection fractions of 43.5% (confidence interval 39.5% 44.5%). The area under the curve was 0.812, with positive predictive value 0.72 and negative predictive value 0.81. CONCLUSIONS: Subject to study limitations, we conclude that assessing left ventricular ejection fraction using heart failure claims is possible. PMID- 26519616 TI - Quality Improvement of Staphylococcus aureus Bacteremia Management and Predictors of Relapse-free Survival. AB - PURPOSE: The purpose of this study is to improve the quality of care and patient outcomes for Staphylococcus aureus bacteremia. METHODS: A quasi-experimental pre- and postintervention study design was used to compare process and clinical endpoints before and after a quality-improvement initiative. All inpatients >18 years of age with a positive blood culture for S. aureus during the specified pre and postintervention period with clinical information available in the electronic medical record were included. An institutional protocol for the care of patients with S. aureus bacteremia was developed, formalized, and distributed to providers using a pocket card, an electronic order set, and targeted lectures over a 9-month period. RESULTS: There were 167 episodes of S. aureus bacteremia (160 patients) identified in the preintervention period, and 127 episodes (123 patients) in the postintervention period. Guideline adherence improved in the postintervention period for usage of transesophageal echocardiogram (43.9% vs 20.2%, P <.01) and adequate duration of intravenous therapy (71% vs 60%, P = .05). In a multivariate Cox proportional hazard model, the variables associated with increased relapse-free survival were postintervention period (hazard ratio [HR] 0.48; confidence interval [CI], 0.24-0.95; P .035) and appropriate source control (HR 0.53; CI, 0.24-0.92; P .027). Regardless of intervention, presence of cancer was associated with an increased risk of relapse or mortality at 90 days (HR 2.88; P <.0001; CI, 1.35-5.01). CONCLUSION: A bundled educational intervention to promote adherence to published guidelines for the treatment of S. aureus bacteremia resulted in a significant improvement in provider adherence to guidelines as well as increased 90-day relapse-free survival. PMID- 26519617 TI - Analysis of stereochemistry and biosynthesis of epicatechin in tea plants by chiral phase high performance liquid chromatography. AB - Tea (Camellia sinensis) is rich in flavan-3-ols (catechins), especially epicatechin (EC), which is the predominant extension unit of polymeric proanthocyanidins (PAs). However, studies assessing EC's stereochemistry are scarce. Here, a high performance liquid chromatography column using amylose tris (3, 5-dimethylphenylcarbamate) immobilized on silica-gel as chiral stationary phases (CSPs) was applied to explore its stereochemistry and biosynthetic pathway in tea plants. The results revealed (-)-epicatechin [(-)-EC] was the predominant di-hyroxy-non-galloylated-catechins, while (+)-epicatechin [(+)-EC] was not detected. Interestingly, (-)-EC was the only product obtained from cyanidin using the partially purified native C. sinensis anthocyanidin reductase (CsANR) in the presence of reduction nicotinamide adenine dinucleotide phosphate (NADPH); meanwhile, (+)-EC was the main product using recombinant CsANR in the same conditions. In addition, (-)-EC could be obtained from (+)-catechin [(+)-C] using recombinant CsANR, which displayed C3-epimerase activity in the presence of oxidation nicotinamide adenine dinucleotide phosphate (NADP(+)). But the partially purified native CsANR did not possess this function. Finally, (-)-EC could result from the de-gallate acid reaction of epicatechin gallate (ECG) catalyzed by a novel partially purified native galloylated catechins hydrolase (GCH) from tea leaves. In summary, (-)-EC is likely the product of native protein from the tea plants, and (+)-EC is only produced in a reaction catalyzed by recombinant CsANR in vitro. PMID- 26519618 TI - Validated UPLC-MS/MS method for simultaneous determination of simvastatin, simvastatin hydroxy acid and berberine in rat plasma: Application to the drug drug pharmacokinetic interaction study of simvastatin combined with berberine after oral administration in rats. AB - A rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay method was developed and validated for simultaneous quantification of simvastatin (SV), its metabolite simvastatin hydroxy acid (SVA) and berberine (BBR) in rat plasma. Separation was performed on Poroshell 120 EC-C18 column (4.6*50mm, 2.7MUm) using gradient elution by mobile phase containing acetonitrile and 10mM ammonium acetate (pH 4.5). Polarity switch (positive-negative-positive ionization mode) was performed in a total run time of 4.0min. The lower limits of quantification (LLOQ) for SV, SVA and BBR were 0.10, 0.20 and 0.10ng/mL, respectively. The response function was established for concentration range of 0.10-100ng/mL for SV and BBR and 0.20-3000ng/mL for SVA, with a coefficient of correlation of >0.99 for all the compounds. The proposed method was applied to the drug-drug pharmacokinetic interaction study of SV combined with BBR after oral administration in rats. PMID- 26519619 TI - Pharmacokinetics and tissue distribution study of ginkgolide L in rats by ultra high performance liquid chromatography coupled with tandem mass spectrometry. AB - An ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) approach was developed and validated for the determination of ginkgolide L (GL) in rat plasma and tissues using diazepam as internal standard (IS). Detection was performed on a triple quadrupole MS system using multiple reaction monitoring (MRM) mode in positive mode. Sample preparation was carried out through a liquid-liquid extraction with ethyl acetate. The chromatographic separation was achieved by using an Agilent ZORBAX SB-Aq column with a mobile phase of 0.5% aqueous formic acid (A) and methanol (B). The monitored transitions were set at m/z 391.14->271.10 for GL and m/z 285.08->193.10 for IS, respectively. The validated method was successfully applied to the pharmacokinetic and tissue distribution study of GL in rats after intravenous administration. Good linearity was found between 2.5-2000ng/mL (r>0.996) for plasma samples, and calibration curves were also linear for other tissue samples over a wide range. The results indicated that GL has linear pharmacokinetic properties after intravenous administration at three doses. GL could distribute to tissues quickly and the major distribution tissue of GL in rats was liver. This was the first report of pharmacokinetic and tissue distribution data for GL. PMID- 26519620 TI - Buckybowls as adsorbents for CO2, CH4, and C2H2: Binding and structural insights from computational study. AB - Noncovalent functionalization of buckybowls sumanene (S), corannulene (R), and coronene (C) with greenhouse gases (GGs) such as CO2 , CH4 (M), and C2 H2 (A) has been studied using hybrid density functional theory. The propensity and preferences of these small molecules to interact with the concave and convex surfaces of the buckybowls has been quantitatively estimated. The results indicate that curvature plays a significant role in the adsorption of these small molecules on the pi surface and it is observed that buckybowls have higher binding energies (BEs) compared with their planar counterpart coronene. The concave surface of the buckybowl is found to be more feasible for adsorption of small molecules. BEs of small molecules towards pi systems is CO2 > A > M and the BEs of pi systems toward small molecules is S > R > C. Obviously, the binding preference is dictated by the way in which various noncovalent interactions, such as pi...pi, lone pair...pi, and CH...pi manifest themselves on carbaneous surfaces. To delineate the intricate details of the interactions, we have employed Bader's quantum theory of atoms in molecule and localized molecular orbital energy decomposition analysis (LMO-EDA). LMO-EDA, which measures the contribution of various components and traces the physical origin of the interactions, indicates that the complexes are stabilized largely by dispersion interactions. PMID- 26519622 TI - The Updated Model: An Adjusted Serum Alpha-Fetoprotein-Based Algorithm for Hepatocellular Carcinoma Detection With Hepatitis C Virus-Related Cirrhosis. PMID- 26519623 TI - Prophenoloxidase genes and antimicrobial host defense of the model beetle, Tribolium castaneum. AB - In this study, we characterized prophenoloxidase (proPO, (PPO)) genes of Tribolium castaneum and examined their involvement in antimicrobial host defense. Amino acid sequence comparison with well-characterized PPO proteins from other insect species suggested that T. castaneum PPO genes encoded functional proenzymes, with crucial sequence motifs being conserved. Developmental kinetics of the mRNA of two PPO genes, PPO1 and PPO2 in the pupal stage were different to each other. The PPO1 mRNA levels consistently decreased during pupal development while that of PPO2 peaked at mid-pupal stage. The two mRNAs also exhibited distinct responses upon immune challenges with heat-killed model microbes. The PPO1 mRNA stayed nearly unchanged by 6h post challenge, and was somewhat elevated at 24h. In contrast, the PPO2 mRNA significantly decreased at 3, 6 and 24h post challenge. These trends exhibited by respective PPO genes were consistent irrespective of the microbial species used as elicitors. Finally, we investigated the involvement of T. castaneum PPO genes in antimicrobial host defense by utilizing RNA interference-mediated gene silencing. Survival assays demonstrated that double knockdown of PPO genes, which was accompanied by weakened hemolymph PO activities, significantly impaired the host defense against Bacillus subtilis. By contrast, the knockdown did not influence the induction of any of the T. castaneum antimicrobial peptide genes that were studied here, except for one belonging to the gene group that shows very weak or negligible microbial induction. PPO knockdown as well weakened host defense against Beauveria bassiana moderately but significantly depending on the combination of infection methods and targeted genes. Our results indicated that the PPO genes represented constituents of both antibacterial and antifungal host defense of T. castaneum. PMID- 26519624 TI - Reply to "Does progranulin account for the opposite effects of etanercept and infliximab/adalimumab in osteoarthritis?" by Wei et al. PMID- 26519625 TI - Losses, Expansions, and Novel Subunit Discovery of Adaptor Protein Complexes in Haptophyte Algae. AB - The phylum Haptophyta (Diaphoratickes) contains marine algae that perform biomineralization, extruding large, distinctive calcium carbonate scales (coccoliths) that completely cover the cell. Coccolith production is an important part of global carbon cycling; however, the membrane trafficking pathway by which they are secreted has not yet been elucidated. In most eukaryotes, post-Golgi membrane trafficking involves five heterotetrameric adaptor protein (AP) complexes, which impart cargo selection specificity. To better understand coccolith secretion, we performed comparative genomic, phylogenetic, and transcriptomic analyses of the AP complexes in Emiliania huxleyi strains 92A, Van556, EH2, and CCMP1516, and related haptophytes Gephyrocapsa oceanica and Isochrysis galbana; the latter has lost the ability to biomineralize. We show that haptophytes have a modified membrane trafficking system (MTS), as we found both AP subunit losses and duplications. Additionally, we identified a single conserved subunit of the AP-related TSET complex, whose expression suggests a functional role in membrane trafficking. Finally, we detected novel alpha adaptin ear and gamma adaptin ear proteins, the first of their kind to be described outside of opisthokonts. These novel ear proteins and the sculpting of the MTS may support the capacity for biomineralization in haptophytes, enhancing their ability to perform this highly specialized form of secretion. PMID- 26519626 TI - Silver nanoparticles in aquatic environments: Physiochemical behavior and antimicrobial mechanisms. AB - Nanosilver (silver nanoparticles or AgNPs) has unique physiochemical properties and strong antimicrobial activities. This paper provides a comprehensive review of the physicochemical behavior (e.g., dissolution and aggregation) and antimicrobial mechanisms of nanosilver in aquatic environments. The inconsistency in calculating the Gibbs free energy of formation of nanosilver [DeltaGf(AgNPs)] in aquatic environments highlights the research needed to carefully determine the thermodynamic stability of nanosilver. The dissolutive release of silver ion (Ag(+)) in the literature is often described using a pseudo-first-order kinetics, but the fit is generally poor. This paper proposes a two-stage model that could better predict silver ion release kinetics. The theoretical analysis suggests that nanosilver dissolution could occur under anoxic conditions and that nanosilver may be sulfidized to form silver sulfide (Ag2S) under strict anaerobic conditions, but more investigation with carefully-designed experiments is required to confirm the analysis. Although silver ion release is likely the main antimicrobial mechanism of nanosilver, the contributions of (ion-free) AgNPs and reactive oxygen species (ROS) generation to the overall toxicity of nanosilver must not be neglected. Several research directions are proposed to better understand the dissolution kinetics of nanosilver and its antimicrobial mechanisms under various aquatic environmental conditions. PMID- 26519627 TI - Recent developments of zinc oxide based photocatalyst in water treatment technology: A review. AB - Today, a major issue about water pollution is the residual dyes from different sources (e.g., textile industries, paper and pulp industries, dye and dye intermediates industries, pharmaceutical industries, tannery and craft bleaching industries, etc.), and a wide variety of persistent organic pollutants have been introduced into our natural water resources or wastewater treatment systems. In fact, it is highly toxic and hazardous to the living organism; thus, the removal of these organic contaminants prior to discharge into the environment is essential. Varieties of techniques have been employed to degrade those organic contaminants and advanced heterogeneous photocatalysis involving zinc oxide (ZnO) photocatalyst appears to be one of the most promising technology. In recent years, ZnO photocatalyst have attracted much attention due to their extraordinary characteristics. The high efficiency of ZnO photocatalyst in heterogeneous photocatalysis reaction requires a suitable architecture that minimizes electron loss during excitation state and maximizes photon absorption. In order to further improve the immigration of photo-induced charge carriers during excitation state, considerable effort has to be exerted to further improve the heterogeneous photocatalysis under UV/visible/solar illumination. Lately, interesting and unique features of metal doping or binary oxide photocatalyst system have gained much attention and became favourite research matter among various groups of scientists. It was noted that the properties of this metal doping or binary oxide photocatalyst system primarily depend on the nature of the preparation method and the role of optimum dopants content incorporated into the ZnO photocatalyst. Therefore, this paper presents a critical review of recent achievements in the modification of ZnO photocatalyst for organic contaminants degradation. PMID- 26519628 TI - Enhancement of Fenton and photo-Fenton processes at initial circumneutral pH for the degradation of the beta-blocker metoprolol. AB - The need for acidification in the Fenton and photo-Fenton process is often outlined as one of its major drawbacks, thus in this work the acidification of the Metoprolol (MET) is avoided by the addition of resorcinol (RES), which is used to simulate model organic matter. The experiments were carried out at natural pH (6.2) with different Fe(2+) (1, 2.5, 5, and 10 mg/L) and H2O2 (25, 50, 125 and 150 mg/L) concentrations. The performance of MET and RES degradation was assessed along the reaction time. Working with the highest concentrations (5 and 10 mg/L of ferrous iron and 125 and 150 mg/L of H2O2) more than 90% of MET and RES removals were reached within 50 and 20 min of treatment, respectively, by Fenton process. However a low mineralization was achieved in both cases, likely, due to by-products accumulation. Regarding to photo-Fenton process, within 3 min with the highest iron and hydrogen peroxide concentrations, a complete MET degradation was obtained and 95% of RES conversion was achieved. Parameters such Total Organic Carbon, Chemical Oxygen Demand, and AOS were measured. Intermediates were identified and MET degradation path was proposed in the presence of resorcinol. Finally, a comparison between Fenton and photo-Fenton processes at acid pH and at initial circumneutral pH was discussed. The positive effect of RES on Fenton and photo-Fenton systems has been confirmed, allowing the work at circumneutral pH. PMID- 26519629 TI - Concurrence of aqueous and gas phase contamination of groundwater in the Wattenberg oil and gas field of northern Colorado. AB - The potential impact of rapid development of unconventional oil and natural gas resources using hydraulic fracturing and horizontal drilling on regional groundwater quality has received significant attention. Major concerns are methane or oil/gas related hydrocarbon (such as TPHs, BTEX including benzene, toluene, ethybenzene and xylene) leaks into the aquifer due to the failure of casing and/or stray gas migration. Previously, we investigated the relationship between oil and gas activity and dissolved methane concentration in a drinking water aquifer with the major finding being the presence of thermogenic methane contamination, but did not find detectable concentrations of TPHs or BTEX. To understand if aqueous and gas phases from the producing formation were transported concurrently to drinking water aquifers without the presence of oil/gas related hydrocarbons, the ionic composition of three water groups was studied: (1) uncontaminated deep confined aquifer, (2) suspected contaminated groundwater - deep confined aquifer containing thermogenic methane, and (3) produced water from nearby oil and gas wells that would represent aqueous phase contaminants. On the basis of quantitative and spatial analysis, we identified that the "thermogenic methane contaminated" groundwater did not have similarities to produced water in terms of ionic character (e.g. Cl/TDS ratio), but rather to the "uncontaminated" groundwater. The analysis indicates that aquifer wells with demonstrated gas phase contamination have not been contacted by an aqueous phase from oil and gas operations according to the methodology we use in this study and the current groundwater quality data from COGCC. However, the research does not prove conclusively that this the case. The results may provide insight on contamination mechanisms since improperly sealed well casing may result in stray gas but not aqueous phase transport. PMID- 26519630 TI - Autotrophic antimonate bio-reduction using hydrogen as the electron donor. AB - Antimony (Sb), a toxic metalloid, is soluble as antimonate (Sb(V)). While bio reduction of Sb(V) is an effective Sb-removal approach, its bio-reduction has been coupled to oxidation of only organic electron donors. In this study, we demonstrate, for the first time, the feasibility of autotrophic microbial Sb(V) reduction using hydrogen gas (H2) as the electron donor without extra organic carbon source. SEM and EDS analysis confirmed the production of the mineral precipitate Sb2O3. When H2 was utilized as the electron donor, the consortium was able to fully reduce 650 MUM of Sb(V) to Sb(III) in 10 days, a rate comparable to the culture using lactate as the electron donor. The H2-fed culture directed a much larger fraction of it donor electrons to Sb(V) reduction than did the lactate-fed culture. While 98% of the electrons from H2 were used to reduce Sb(V) by the H2-fed culture, only 12% of the electrons from lactate was used to reduce Sb(V) by the lactate-fed culture. The rest of the electrons from lactate went to acetate and propionate through fermentation, to methane through methanogenesis, and to biomass synthesis. High-throughput sequencing confirmed that the microbial community for the lactate-fed culture was much more diverse than that for the H2 fed culture, which was dominated by a short rod-shaped phylotype of Rhizobium (alpha-Protobacteria) that may have been active in Sb(V) reduction. PMID- 26519631 TI - Impact of abdominal aortic calcification on long-term cardiovascular outcomes in patients with chronic kidney disease. AB - BACKGROUND: The presence of abdominal aortic calcification (AAC) can predict cardiovascular (CV) outcomes in hemodialysis patients. However, little is known about the predictive value of AAC for CV outcomes in chronic kidney disease (CKD) patients without hemodialysis. The aim of this study was to investigate the prevalence and the predictive value of AAC in asymptomatic CKD patients. METHODS: We prospectively evaluated 347 asymptomatic CKD patients without hemodialysis [median estimated glomerular filtration rate (eGFR): 43.2 mL/min/1.73 m(2)]. A non-contrast computed tomography scan was used to determine the abdominal aortic calcification index (ACI) as a semi-quantitative measure of AAC. The patients were divided into three groups according to the tertiles of ACI. RESULTS: Among the subjects, AAC was found (ACI > 0) in 296 patients (86.3%), and the median ACI was 11.4%. During the median follow-up of 41.5 months, a total of 33 CV events were observed. Patients with the highest tertile of ACI had the highest risk of CV outcomes compared with the other two groups (96.5%, 93.0%, and 74.3%, respectively; p < 0.001). The Cox proportional hazard models showed that ACI was an independent predictor of CV outcomes (hazard ratio 1.36, 95% confidence interval 1.17-1.60, p < 0.001). The C-index was also significantly increased by adding eGFR and ACI values to the model along with the other conventional risk factors (0.79 versus 0.66, p = 0.043). CONCLUSION: Evaluation of the AAC provides useful information for predicting adverse clinical outcomes among asymptomatic CKD patients without hemodialysis. PMID- 26519632 TI - Plasma apolipoprotein E and severity of suicidal behaviour. AB - There is evidence for association between low cholesterol levels and suicidal behaviour. Since apolipoprotein E (ApoE) is involved in the cholesterol metabolism in both the periphery and in the central nervous system; it may be of particular interest in the neurobiology of suicidal behaviour. Furthermore, hypothalamic-pituitary-adrenal (HPA) axis function, one of the main biological systems implicated in both suicidal behaviour and early-life adversity, affect ApoE levels. Very few studies have assessed plasma ApoE in relation to suicidal behaviour. The purpose of this study was to investigate levels of ApoE in plasma in relation to the severity of suicidal behaviour and life-time adversity in the form of exposure to interpersonal violence in suicide attempters. A total of 100 suicide attempters (67 women and 33 men) were enroled in the study. Information on earlier suicide attempts and age at onset of suicidal behaviour was gathered using the Karolinska Suicide History Interview. The Karolinska Interpersonal Violence Scale was used to assess exposure to interpersonal violence. Plasma ApoE was measured by immunonephelometry according to accredited routines. Patients with at least one earlier suicide attempt had significantly higher ApoE levels compared to suicide attempters debuting with suicidal behaviour at inclusion in the study. A higher number of earlier suicide attempts was significantly correlated with higher plasma ApoE levels. Age at onset was significantly negatively correlated with ApoE after adjusting for age. ApoE showed a significant positive correlation with exposure to interpersonal violence as a child in male suicide attempters. Our findings indicate that ApoE may be related to stress and trauma and the temporal severity of suicidal behaviour. PMID- 26519633 TI - Interpersonal stress and suicidal ideation in adolescence: An indirect association through perceived burdensomeness toward others. AB - BACKGROUND: Research has documented significant associations between life stress, especially interpersonal stress, and suicidal ideation in adolescents. Little is known about variables that explain the association between interpersonal stress and suicidal ideation. METHODS: The present study evaluated a conceptual model in which interpersonal stress (chronic and episodic) predicted suicidal ideation indirectly via thwarted belongingness and perceived burdensomeness among 180 inpatients (65.0% girls) ages 12-17 years (M=14.72, SD=1.49). Non-interpersonal stress was also examined to determine whether the model was specific to interpersonal stress or common to stress in general. RESULTS: Structural equation modeling identified a significant indirect effect of chronic interpersonal stress on suicidal ideation via perceived burdensomeness. Episodic interpersonal stress was significantly correlated with thwarted belongingness and suicidal ideation, but was not a significant predictor of suicidal ideation in a model that controlled for depressive and anxious symptoms. No significant associations were found between non-interpersonal stress and suicidal ideation. LIMITATIONS: Adolescents were the sole informant source, data on psychiatric diagnoses were not available, and the optimal time interval for examining stress remains unclear. The cross-sectional study design prevents conclusions regarding directionality. CONCLUSIONS: These findings highlight the role of chronic interpersonal stress in suicidal ideation in adolescents, as well as the potential promise of perceived burdensomeness as a target for programs designed to prevent or reduce suicidal ideation. PMID- 26519634 TI - Association of Pseudobulbar Affect symptoms with quality of life and healthcare costs in Veterans with traumatic brain injury. PMID- 26519635 TI - Personality and social support as predictors of first and recurrent episodes of depression. AB - BACKGROUND: Depression is a prevalent psychiatric disorder with high personal and public health consequences, partly due to a high risk of recurrence. This longitudinal study examines personality traits, structural and subjective social support dimensions as predictors of first and recurrent episodes of depression in initially non-depressed subjects. METHODS: Data were obtained from the Netherlands Study of Depression and Anxiety (NESDA). 1085 respondents without a current depression or anxiety diagnosis were included. 437 respondents had a prior history of depression, 648 did not. Personality dimensions were measured with the NEO-FFI, network size, partner-status, negative and positive emotional support were measured with the Close Person Questionnaire. Logistic regression analyses (unadjusted and adjusted for clinical variables and sociodemographic variables) examined whether these psychosocial variables predict a new episode of depression at two year follow up and whether this differed among persons with or without a history of depression. RESULTS: In the unadjusted analyses high extraversion (OR:.93, 95% CI (.91-.96), P<.001), agreeableness (OR:.94, 95% CI (.90-.97), P<.001), conscientiousness (OR:.93, 95% CI (.90-.96), P<.001) and a larger network size (OR:.76, 95% CI (.64-.90), P=.001) significantly reduced the risk of a new episode of depression. Only neuroticism predicted a new episode of depression in both the unadjusted (OR:1.13, 95% CI (1.10-1.15), P<.001) and adjusted analyses (OR:1.06, 95% CI (1.03-1.10), P<.001). None of the predictors predicted first or recurrent episodes of depression differently. LIMITATIONS: we used a relatively short follow up period and broad personality dimensions. CONCLUSIONS: Neuroticism seems to predict both first and recurrent episodes of depression and may be suitable for screening for preventive interventions. PMID- 26519636 TI - Sleep, residual mood symptoms, and time to relapse in recovered patients with bipolar disorder. AB - BACKGROUND: Sleep disturbance in bipolar disorder (BD) is common during and between mood episodes. In recovered (euthymic at least two months) BD patients, we assessed sleep compared to controls and its relationships with residual mood symptoms and mood episode recurrence. METHOD: Recovered Stanford University BD Clinic patients diagnosed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation and monitored with the STEP-BD Clinical Monitoring Form (CMF) for >1 year and healthy controls completed the Pittsburgh Sleep Quality Index (PSQI). PSQI parameters were compared in BD patients versus controls, and the most robustly differentiating PSQI parameter was assessed in relationship to residual mood symptoms, and time to mood episode recurrence in BD patients. RESULTS: Eighty nine recovered BD patients compared to 56 healthy controls had significantly worse PSQI global score, more sleep medication use, longer sleep latency, and worse daytime dysfunction. PSQI global score had the greatest BD patient versus control effect size, and among BD patients, correlated significantly with residual mood symptoms and predicted earlier mood episode recurrence, even after covarying for residual mood symptoms. LIMITATIONS: Use of subjective (PSQI) rather objective (polysomnography) sleep metric. Statistical power limited by small sample size. Potential psychotropic medication confound. Northern California tertiary BD clinic referral sample. CONCLUSION: Further research is needed to confirm that in recovered BD patients, poor sleep quality correlates with residual mood symptoms, and independently predicts mood episode recurrence. If confirmed, these observations suggest potential mood benefit for focusing on sleep quality in interventions for recovered BD patients. PMID- 26519637 TI - Prevalence and correlates of DSM-IV-TR major depressive disorder, self-reported diagnosed depression and current depressive symptoms among adults in Germany. AB - BACKGROUND: While standardized diagnostic interviews using established criteria are the gold standard for assessing depression, less time consuming measures of depression and depressive symptoms are commonly used in large population health surveys. We examine the prevalence and health-related correlates of three depression measures among adults aged 18-79 years in Germany. METHODS: Using cross-sectional data from the national German Health Interview and Examination Survey for Adults (DEGS1) (n=7987) and its mental health module (DEGS1-MH) (n=4483), we analysed prevalence and socio-demographic and health-related correlates of (a) major depressive disorder (MDD) established by Composite International Diagnostic Interview (CIDI) using DSM-IV-TR criteria (CIDI-MDD) in the last 12 months, (b) self-reported physician or psychotherapist diagnosed depression in the last 12 months, and (c) current depressive symptoms in the last two weeks (PHQ-9, score >=10). RESULTS: Prevalence of 12-month CIDI-MDD was 4.2% in men and 9.9% in women. Prevalence of 12-month self-reported health professional-diagnosed depression was 3.8% and 8.1% and of current depressive symptoms 6.1% and 10.2% in men and women, respectively. Case-overlap between measures was only moderate (32-45%). In adjusted multivariable analyses, depression according to all three measures was associated with lower self-rated health, lower physical and social functioning, higher somatic comorbidity (except for women with 12-month CIDI-MDD), more sick leave and higher health service utilization. LIMITATIONS: Persons with severe depression may be underrepresented. Associations between CIDI-MDD and correlates and overlap with other measures may be underestimated due to time lag between DEGS1 and DEGS1-MH. CONCLUSIONS: Prevalence and identified cases varied between these three depression measures, but all measures were consistently associated with a wide range of adverse health outcomes. PMID- 26519638 TI - Speed of recovery from disorientation may predict the treatment outcome of electroconvulsive therapy (ECT) in elderly patients with major depression. AB - BACKGROUND: No study has previously investigated whether the speed of recovery from disorientation in the post-ictal period may predict the short-term treatment outcome of electroconvulsive therapy (ECT). METHODS: This longitudinal cohort study included 57 elderly patients with unipolar or bipolar major depression, aged 60-85 years, treated with formula-based ECT. Treatment outcome was assessed weekly during the ECT course using the 17-item Hamilton Rating Scale for Depression (HRSD17). The post-ictal reorientation time (PRT) was assessed at the first and third treatments. RESULTS: Longer PRTs at the first and third treatments predicted a more rapid decline and a lower end-point in continuous HRSD17 scores (p=0.002 and 0.019, respectively). None of the patients who recovered from disorientation in less than 5 min met the remission criterion, defined as an HRSD17 score of 7 or less. A greater increment in stimulus dosage from the first to the third ECT session rendered a smaller relative decline in PRT (p<0.001). LIMITATIONS: The limited number of subjects may reduce the generalizability of the findings. CONCLUSIONS: The speed of recovery from disorientation at the first and third sessions seems to be a predictor of the treatment outcome of formula-based ECT, at least in elderly patients with major depression. It remains to be clarified how the PRT may be utilized to guide stimulus dosing. PMID- 26519639 TI - Further evidence of low baseline cortisol levels in suicide attempters. AB - BACKGROUND: Many, but not all studies of suicide attempters' cortisol response to stress-either social stress or pharmacological challenge-report an exaggerated response. Recent studies of resting baseline cortisol in past suicide attempters, however, have found lower baseline levels. METHODS: In this study, baseline salivary cortisols were obtained prior to a stress procedure from adults with lifetime diagnoses of a mood disorder (N=69), 31.9% of whom had made a prior suicide attempt. Data were collected during the piloting of this stress procedure, at various times of day and with/without an additional confederate in the room. RESULTS: Adjusting for procedural, demographic and clinical variables that affect salivary cortisol levels-including time of day of sampling, order of procedure with respect to other assessments, past alcohol abuse, current medication use, and bipolar diagnosis-past suicide attempters had lower baseline cortisol levels compared to non-attempters. LIMITATIONS: This is a pilot study with modest sample sizes using statistical, rather than experimental control of numerous variables affecting salivary cortisol levels. CONCLUSIONS: Results confirm previous studies. Low baseline cortisol levels have been associated with childhood adversity and externalizing disorders, suggesting a potential role in reducing inhibitions for risky and dangerous behaviors. Further research is needed to more fully characterize these associations and their role in suicidal behavior risk. PMID- 26519640 TI - 5-HTTLPR and gender differences in affective disorders: A systematic review. AB - BACKGROUND: Serotonin transporter-linked polymorphic region (5-HTTLPR) variants have been extensively studied in psychiatric disorders. Although gender effects have been reported, they have not been comprehensively reviewed. The aim of our study was to summarize literature findings on 5-HTTLPR and gender differences in affective disorders. METHODS: A systematic search of PubMed, ISI Web of Knowledge, and PsycINFO databases was performed for dates until January 2015. The included articles (n=78) analyzed the association between 5-HTTLPR and affective spectrum disorders, taking into account gender. The quality of each study was assessed through STROBE and CONSORT. RESULTS: 5-HTTLPR modulation of affective disorders varied by gender. The S allele (or SS genotype) seemed to be differently associated with an increased risk of depression, depressive symptoms, anxiety traits and symptoms, and symptoms of internalizing behavior among women and an increased risk of aggressiveness, conduct disorder and symptom counts of externalizing behavior among men. Moreover, the presence of stressful life events reinforced the association. Interestingly, these differences seemed to begin with adolescence and were not consistent among the elderly, suggesting a plausible role of hormonal fluctuations. LIMITATIONS: The review is limited by the small number of included papers, due to the paucity of information in the literature regarding 5-HTTLPR and gender. CONCLUSIONS: 5-HTTLPR variants may exert a differential modulation on a number of features depending on gender. Further studies are needed to more deeply investigate the effect of 5-HTTLPR*gender on the modulation of affective disorders. PMID- 26519641 TI - The enduring effects of depressive thoughts on working memory. AB - BACKGROUND: Depressive thoughts are known to persist in persons with depressed mood leading to rumination and exacerbation of depressive symptoms. What has not yet been examined is whether this persistence of depressive thoughts can lead to impairment of working memory (WM). METHODS: We assessed whether receiving a WM task featuring depressive cues could bias performance on a subsequent, non depressive WM task for dysphoric individuals (DIs) compared to non-DIs. RESULTS: DIs showed significantly attenuated performance on the WM task with depressive cues compared to non-DIs. Further, when DIs were given the WM task with depressive cues first, they showed deficits on a second WM task without depressive cues, compared to DIs given the non-depressive WM task first and non DIs in either condition. LIMITATIONS: Unselected recruitment procedures did not permit balanced sample sizes in each group. Future research is needed to assess whether these results extend to a clinically depressed sample and whether WM deficits are the consequence of depressed mood, or a risk factor for the development and maintenance of depressed mood. CONCLUSIONS: Results suggest that, for DIs, the influence of depressive cues on performance transfers to subsequent tasks in which these cues are no longer present. These results support the hypothesis that when depressive thoughts are part of depressed persons' conscious experience, cognitive deficits arise. Further, these results suggest an ecologically-relevant mechanism by which day-to-day cognitive deficits in depression can develop. PMID- 26519642 TI - The 33-item Hypomania Checklist (HCL-33): A new self-completed screening instrument for bipolar disorder. AB - BACKGROUND: Bipolar disorder (BD) is often misdiagnosed as major depressive disorder (MDD). This study tested the psychometric properties and the accuracy of the Chinese version of the 33-item Hypomania Checklist (HCL-33) to identify BD in Chinese clinical settings. METHODS: A total of 350 depressed patients were consecutively interviewed in a major psychiatric hospital in China. The patients' socio-demographic and clinical characteristics were recorded using standardized protocol and data collection procedures. The HCL-33 was completed by patients to detect symptoms characteristic of mania and hypomania. DSM-IV diagnoses were established using the Mini International Neuropsychiatric Interview (MINI). RESULTS: The HCL-33 showed high internal consistency with two-factorial dimensions. The optimal cut-off point on the HCL-33 to differentiate BD from MDD was 15, while cut-off points of 14 and 13 differentiated BD-I and BD-II from MDD, respectively. The maximum sensitivity was 0.62, 0.67 and 0.72 for differentiating BD, BD-I and BD-II from MDD, respectively. CONCLUSIONS: The HCL-33 is a useful tool for screening for BD in Chinese depressed patients. The routine clinical use of the HCL-33 as a screening instrument for BD in Chinese patients is recommended. PMID- 26519643 TI - Suicidality prospectively predicts greater urges to smoke following a cessation attempt: Mediation through perceived barriers to cessation. AB - Growing interest in developing more effective smoking cessation treatments has facilitated the need to further investigate cognitive-affective factors that inhibit successful smoking cessation, such as urges to smoke. Research has strongly supported an association between suicidality and smoking, yet no work has investigated whether suicidality may increase urges to smoke. The current study sought to evaluate the impact of suicidality on smoking-related cognitive affective factors predictive of smoking relapse among a community sample of 209 daily smokers engaged in a smoking cessation program. Structural equation modeling (SEM) was used to test the effects of self-reported pre-cessation suicidality on urges to smoke 1 month post-cessation as well as whether this effect was mediated by greater barriers to cessation. Results indicated that internal barriers to cessation significantly mediated the effect of pre-cessation suicidality on greater urges to smoke 1 month following smoking cessation attempt. These findings suggest that elevated suicidality may affect perceived internal barriers to cessation and subsequently urges to smoke 1 month following a quit attempt. PMID- 26519645 TI - Unplanned pregnancy and contraceptive use in Hull and East Yorkshire. AB - OBJECTIVE: This study has two aims. The first is to assess the proportion of unplanned pregnancies among women attending antenatal clinics (ANCs) and those undergoing induced abortion (IA). The second is to assess both their previous contraceptive use and contraceptive intention, with particular focus on the use or consideration of any long-acting reversible contraceptives in Hull and East Riding in order to inform service redesign. STUDY DESIGN: Consecutive women attending their first ANC appointment and women attending a gynecology clinic undergoing IA were asked to complete a two-page questionnaire that contained a validated pregnancy intendedness questionnaire [the London Measure of Unplanned Pregnancy (LMUP)] and questions to establish contraceptive use and access prior to this index pregnancy. RESULTS: The overall response rate was 69%. We received 648 evaluable questionnaires for women undergoing IA. Of these pregnancies, 75.8% [95% confidence interval (CI), 72.3%-79.0%] were unplanned (LMUP, score 0-3). We received 1001 evaluable questionnaires from women booking at ANCs. Of these pregnancies, 5.5% (95% CI, 4.2%-7.0%) were unplanned. Among those with unplanned pregnancies who were not using contraception, 31% reported that they were unable to obtain the method they wanted. Among those using a method immediately prior to the index unplanned pregnancy, 33% stated that it was not the method they wanted; of these, 75% would have preferred sterilization, the implant, injectable or intrauterine contraceptive. CONCLUSION: Unplanned pregnancies in this population are common among women undergoing IA but are uncommon among women attending an ANC. About a third of women not using contraception reported that they were unable to obtain the method they wanted, and about a third of women using contraception stated that they were not using the method they would have preferred. IMPLICATIONS: Opportunities to prevent unplanned pregnancies are missed when staff in primary and secondary care looking after women do not knowledgeably inform, discuss and offer contraception in a timely manner, particularly the most effective long-acting reversible contraceptive methods. Services should be deliverable where women are: this includes within pregnancy care services. Seeking patient experience is an essential component of service redesign. PMID- 26519644 TI - Traumatic stress and cardiopulmonary disease burden among low-income, urban heart failure patients. AB - BACKGROUND: Traumatic events and posttraumatic stress disorder (PTSD) are associated with increased risk for cardiopulmonary disease (CPD) in veterans, men, and primarily White populations. Less is known about trauma, PTSD, and CPD burden among low-income, racial minority residents who are at elevated risk for trauma and PTSD. It was hypothesized that traumatic events and PTSD would be significantly associated with CPD burden among low-income, racial minority residents. METHODS: We evaluated cross-sectional relationships between traumatic events, PTSD, depression, and CPD burden in 251 low-income, urban, primarily Black adults diagnosed with heart failure. Data were analyzed using bivariate analyses, logistic and linear regression. RESULTS: Forty-three percent endorsed at least one traumatic event. Twenty-one percent endorsed two or more traumatic events. In logistic regression analyses, traumatic events were associated with increased prevalence of coronary artery disease (adjusted odds=1.33, p<.05), hypertension (adjusted odds=1.28, p<.05), chronic obstructive pulmonary disease (adjusted odds=1.52, p<.01), and cardiac arrest (adjusted odds=1.27, p<.05). PTSD was also related to increased risk for chronic obstructive pulmonary disease (adjusted odds=1.22, p<.05) and was associated with earlier onset of heart failure (beta=-.13, p<.05). LIMITATIONS: The study utilizes cross-sectional, self report data. CONCLUSIONS: Findings support the link between traumatic events, PTSD, and CPD burden in low-income, primarily Black patients with heart failure. Depression appears to be less closely linked to CPD burden, despite receiving significant attention in the literature. The accumulation of traumatic events may exacerbate CPD burden among urban, low-income, racial minority residents with heart failure; findings highlight the importance of PTSD screening. PMID- 26519646 TI - Oral and injectable contraceptive use and HIV acquisition risk among women in four African countries: a secondary analysis of data from a microbicide trial. AB - OBJECTIVE: To assess the effect of oral and injectable contraceptive use compared to nonhormonal contraceptive use on HIV acquisition among Southern African women enrolled in a microbicide trial. STUDY DESIGN: This is a prospective cohort study using data from women enrolled in HIV Prevention Trials Network protocol 035. At each quarterly visit, participants were interviewed about self-reported contraceptive use and sexual behaviors and underwent HIV testing. Cox proportional hazards regression was used to assess the effect of injectable and oral hormonal contraceptive use on HIV acquisition. RESULTS: The analysis included 2830 participants, of whom 106 became HIV infected (4.07 per 100 person years). At baseline, 1546 (51%) participants reported using injectable contraceptives and 595 (21%) reported using oral contraceptives. HIV incidence among injectable, oral and nonhormonal contraceptive method users was 4.72, 2.68 and 3.83 per 100 person-years, respectively. Injectable contraceptive use was associated with a nonstatistically significant increased risk of HIV acquisition [adjusted hazard ratio (aHR)=1.17; 95% confidence interval (CI) 0.70, 1.96], while oral contraceptive use was associated with a nonstatistically significant decreased risk of HIV acquisition (aHR=0.76; 95% CI 0.37,1.55). CONCLUSION: In this secondary analysis of randomized trial data, a marginal, but nonstatistically significant, increase in HIV risk among women using injectable hormonal contraceptives was observed. No increased HIV risk was observed among women using oral contraceptives. Our findings support the World Health Organization's recommendation that women at high risk for acquiring HIV, including those using progestogen-only injectable contraception, should be strongly advised to always use condoms and other HIV prevention measures. IMPLICATIONS: Among Southern African women participating in an HIV prevention trial, women using injectable hormonal contraceptives had a modest increased risk of HIV acquisition; however, this association was not statistically significant. Continued research on the relationship between widely used hormonal contraceptive methods and HIV acquisition is essential. PMID- 26519647 TI - Risk of congenital cytomegalovirus infection among HIV-exposed uninfected infants is not decreased by maternal nelfinavir use during pregnancy. AB - BACKGROUND: Congenital cytomegalovirus (cCMV) infection is common among infants born to HIV-infected women. Nelfinavir (NFV), an antiretroviral drug that is safe during pregnancy, inhibits CMV replication in vitro at concentrations that standard doses achieve in plasma. We hypothesized that infants born to women receiving NFV for prevention of mother-to-child transmission of HIV (PMTCT) would have a reduced prevalence of cCMV infection. METHODS: The prevalence of cCMV infection was compared among HIV-uninfected infants whose HIV-infected mothers either received NFV for >4 weeks during pregnancy (NFV-exposed) or did not receive any NFV in pregnancy (NFV-unexposed). CMV PCR was performed on infant blood samples collected at <3 weeks from birth. RESULTS: Of the 1,255 women included, 314 received NFV for >4 weeks during pregnancy and 941 did not receive any NFV during pregnancy. The overall prevalence of cCMV infection in the infants was 2.2%, which did not differ by maternal NFV use. Maternal CD4 T cell counts were inversely correlated with risk of cCMV infection, independent of the time NFV was initiated during gestation. Infants with cCMV infection were born 0.7 weeks earlier (P = 0.010) and weighed 170 g less (P = 0.009) than uninfected infants. CONCLUSION: Among HIV-exposed uninfected infants, cCMV infection was associated with adverse perinatal outcomes. NFV use in pregnancy was not associated with protection against cCMV. Safe and effective strategies to prevent cCMV infection are needed. PMID- 26519648 TI - Targeted drug delivery to circulating tumor cells via platelet membrane functionalized particles. AB - Circulating tumor cells (CTCs) are responsible for metastases in distant organs via hematogenous dissemination. Fundamental studies in the past decade have suggested that neutralization of CTCs in circulation could represent an effective strategy to prevent metastasis. Current paradigms of targeted drug delivery into a solid tumor largely fall into two main categories: unique cancer markers (e.g. overexpression of surface receptors) and tumor-specific microenvironment (e.g. low pH, hypoxia, etc.). While relying on a surface receptor to target CTCs can be greatly challenged by cancer heterogeneity, targeting of tumor microenvironments has the advantage of recognizing a broader spectrum of cancer cells regardless of genetic differences or tumor types. The blood circulation, however, where CTCs transit through, lacks the same tumor microenvironment as that found in a solid tumor. In this study, a unique "microenvironment" was confirmed upon introduction of cancer cells of different types into circulation where activated platelets and fibrin were physically associated with blood-borne cancer cells. Inspired by this observation, synthetic silica particles were functionalized with activated platelet membrane along with surface conjugation of tumor-specific apoptosis inducing ligand cytokine, TRAIL. Biomimetic synthetic particles incorporated into CTC-associated micro-thrombi in lung vasculature and dramatically decreased lung metastases in a mouse breast cancer metastasis model. Our results demonstrate a "Trojan Horse" strategy of neutralizing CTCs to attenuate metastasis. PMID- 26519649 TI - MMP-mediated mesenchymal morphogenesis of pluripotent stem cell aggregates stimulated by gelatin methacrylate microparticle incorporation. AB - Matrix metalloproteinases (MMPs) remodel the extracellular matrix (ECM) to facilitate epithelial-to-mesenchymal transitions (EMTs) and promote cell specification during embryonic development. In this study, we hypothesized that introducing degradable ECM-based biomaterials to pluripotent stem cell (PSC) aggregates would modulate endogenous proteolytic activity and consequently enhance the differentiation and morphogenesis within 3D PSC aggregates. Gelatin methacrylate (GMA) microparticles (MPs) of low (~20%) or high (~90%) cross linking densities were incorporated into mouse embryonic stem cell (ESC) aggregates, and the effects on MMP activity and cell differentiation were examined with or without MMP inhibition. ESC aggregates containing GMA MPs expressed significantly higher levels of total MMP and MMP-2 than aggregates without MPs. GMA MP incorporation increased expression of EMT markers and enhanced mesenchymal morphogenesis of PSC aggregates. MMP inhibition completely abrogated these effects, and GMA MP-induced MMP activation within ESC aggregates was partially reduced by pSMAD 1/5/8 inhibition. These results suggest that GMA particles activate MMPs by protease-substrate interactions to promote EMT and mesenchymal morphogenesis of ESC aggregates in an MMP-dependent manner. We speculate that controlling protease activity via the introduction of ECM-based materials may offer a novel route to engineer the ECM microenvironment to modulate stem cell differentiation. PMID- 26519650 TI - Continuous harvest of stem cells via partial detachment from thermoresponsive nanobrush surfaces. AB - Stem cell culture is typically based on batch-type culture, which is laborious and expensive. Here, we propose a continuous harvest method for stem cells cultured on thermoresponsive nanobrush surfaces. In this method, stem cells are partially detached from the nanobrush surface by reducing the temperature of the culture medium below the critical solution temperature needed for thermoresponse. The detached stem cells are harvested by exchange into fresh culture medium. Following this, the remaining cells are continuously cultured by expansion in fresh culture medium at 37 degrees C. Thermoresponsive nanobrush surfaces were prepared by coating block copolymers containing polystyrene (for hydrophobic anchoring onto culture dishes) with three types of polymers: (a) polyacrylic acid with cell-binding oligopeptides, (b) thermoresponsive poly-N-isopropylacrylamide, and (c) hydrophilic poly(ethyleneglycol)methacrylate. The optimal coating durations and compositions for these copolymers to facilitate adequate attachment and detachment of human adipose-derived stem cells (hADSCs) and embryonic stem cells (hESCs) were determined. hADSCs and hESCs were continuously harvested for 5 and 3 cycles, respectively, via the partial detachment of cells from thermoresponsive nanobrush surfaces. PMID- 26519652 TI - Attempted caveolae-mediated phagocytosis of surface-fixed micro-pillars by human osteoblasts. AB - Cells are sensitive to their underlying micro- and nano-topography, but the complex interplay is not completely understood especially if sharp edges and ridges of stochastically modified surfaces interfere with an attached cell body. Micro-topography offers cues that evoke a large range of cell responses e.g. altered adhesion behavior and integrin expression resulting in disturbed cell functions. In this study, we analyzed why osteoblastic cells mimic the underlying geometrical micro-pillar structure (5 * 5 * 5 MUm, spacing of 5 MUm) with their actin cytoskeleton. Interestingly, we discovered an attempted caveolae-mediated phagocytosis of each micro-pillar beneath the cells, which was accompanied by increased intracellular reactive oxygen species (ROS) production and reduced intracellular ATP levels. This energy consuming process hampered the cells in their function as osteoblasts at the interface. The raft-dependent/caveolae mediated phagocytic pathway is regulated by diverse cellular components including caveolin-1 (Cav-1), cholesterol, actin cytoskeleton as well as actin-binding proteins like annexin A2 (AnxA2). Our results show a new aspect of osteoblast material interaction and give insight into how cells behave on extraordinary micro-structures. We conclude that stochastically structured implants used in orthopedic surgery should avoid any topographical heights which induce phagocytosis to prevent their successful ingrowth. PMID- 26519651 TI - Rational design of multifunctional magnetic mesoporous silica nanoparticle for tumor-targeted magnetic resonance imaging and precise therapy. AB - In this paper, a multifunctional theranostic magnetic mesoporous silica nanoparticle (MMSN) with magnetic core was developed for magnetic-enhanced tumor targeted MR imaging and precise therapy. The gatekeeper beta-cyclodextrin (beta CD) was immobilized on the surface of mesoporous silica shell via platinum(IV) prodrug linking for reduction-triggered intracellular drug release. Then Arg-Gly Asp (RGD) peptide ligand was further introduced onto the gatekeeper beta-CD via host-guest interaction for cancer targeting purpose. After active-targeting endocytosis by cancer cells, platinum(IV) prodrug in MMSNs would be restored to active platinum(II) drug in response to the innative reducing microenvironment in cancer cells, resulting in the detachment of beta-CD gatekeeper and thus simultaneously triggering the in situ release of anticancer drug doxorubicin (DOX) entrapped in the MMSNs to kill cancer cells. It was found that with the aid of an external magnetic field, drug loaded MMSNs showed high contrast in MR imaging in vivo and exhibited magnetically enhanced accumulation in the cancer site, leading to significant inhibition of cancer growth with minimal side effects. This multifunctional MMSN will find great potential as a theranostic nanoplatform for cancer treatment. PMID- 26519653 TI - Comorbid Disease Burden is Independently Associated with Higher Risk Disease at Prostatectomy in Patients Eligible for Active Surveillance. AB - PURPOSE: Comorbid medical conditions are highly prevalent among patients with prostate cancer and may be associated with more aggressive disease. We investigated the association between comorbidity burden and higher risk disease among men eligible for active surveillance. MATERIALS AND METHODS: Using the National Cancer Data Base we identified 29,447 cases of low risk (Gleason score 6 or less, cT1/T2a, prostate specific antigen less than 10 ng/ml) prostate cancer managed with prostatectomy from 2010 to 2011. The primary outcome was pathological upgrading (Gleason score greater than 6) or up staging (T3-T4/N1). The association between Charlson score and upgrading/up staging was analyzed using multivariate logistic regression. RESULTS: The study sample comprised 29,447 men, of which 449 (1.5%) had Charlson scores greater than 1. At prostatectomy 44% of cases were upgraded/up staged. On multivariate analysis Charlson score greater than 1, age 70 years or greater, nonwhite race, higher prostate specific antigen and higher percentage of cores involved with disease were significantly associated with upgrading/up staging. After further adjusting for age, race, prostate specific antigen and core involvement, Charlson score remained a significant predictor of upgrading/up staging for younger white men. Specifically, white men less than 70 years old with Charlson comorbidity index greater than 1 had 1.3-fold higher odds of upgrading/up staging than men with Charlson comorbidity index 1 or less (OR 1.31, 95% CI 1.03-1.67, p=0.029). CONCLUSIONS: Comorbidity burden is strongly and independently associated with pathological upgrading/up staging in men with clinically low risk prostate cancer. This finding may help improve disease risk assessment and clinical decision making in men with comorbidities considering active surveillance. PMID- 26519654 TI - Nanoparticle Improved Stem Cell Therapy for Erectile Dysfunction in a Rat Model of Cavernous Nerve Injury. AB - PURPOSE: Recently intracavernous injection of stem cells has garnered great interest as a potential treatment of erectile dysfunction. However, most stem cells are washed out immediately after intracavernous injection. The goal of this study was to investigate using NanoShuttleTM magnetic nanoparticles to maintain stem cells in the corpus cavernosum after intracavernous injection, thereby improving stem cell therapy of erectile dysfunction in an animal model. MATERIALS AND METHODS: Adipose derived stem cells were magnetized with NanoShuttle magnetic nanoparticles to create Nano-adipose derived stem cells. A total of 24 rats underwent bilateral cavernous nerve crush and were randomly assigned to 3 groups, including adipose derived stem cells, Nano-adipose derived stem cells and Nano adipose derived stem cells plus magnet. Cells were tracked at days 1, 3, 5 and 9 after intracavernous injection. Another 40 rats with bilateral cavernous nerve crush were randomly assigned to 4 groups, including bilateral cavernous nerve crush, bilateral cavernous nerve crush plus adipose derived stem cell intracavernous injection, bilateral cavernous nerve crush plus Nano-adipose derived stem cell intracavernous injection and bilateral cavernous nerve crush plus Nano-adipose derived stem cell intracavernous injection plus magnet. Functional testing and histological analysis were performed 4 weeks after intracavernous injection. RESULTS: In the in vitro study 1) NanoShuttle magnetic nanoparticles were successfully bound to adipose derived stem cells and 2) Nano adipose derived stem cells migrated toward the magnet. In the in vivo study 1) cell tracking showed that Nano-adipose derived stem cells were successfully retained in the corpus cavernosum using the magnet for up to 3 days while most adipose derived stem cells were washed out in other groups by day 1 after intracavernous injection, and 2) intracavernous pressure/mean arterial pressure, and alphaSMA (alpha-smooth muscle actin) and PECAM-1 (platelet endothelial cell adhesion molecule 1) expression in the Nano-adipose derived stem cell group was significantly higher than in the other groups. CONCLUSIONS: Magnetization of adipose derived stem cells with NanoShuttle magnetic nanoparticles kept adipose derived stem cells in the corpus cavernosum and improved adipose derived stem cell therapy of erectile dysfunction in an animal model. PMID- 26519655 TI - Could Testosterone Replacement Therapy in Hypogonadal Men Ameliorate Anemia, a Cardiovascular Risk Factor? An Observational, 54-Week Cumulative Registry Study. AB - PURPOSE: In this study we investigated if testosterone undecanoate attenuates anemia and the risk of cardiovascular disease in patients with hypogonadism. MATERIALS AND METHODS: A registry study consisted of 58 participants with a subnormal total testosterone level (less than 2.35 ng/ml) and at least mild symptoms of testosterone deficiency. All patients received an injection of 1,000 mg testosterone undecanoate at the initial visit, followed by injection at 6, 18, 30, 42 and 54 weeks. Serum hormones, hemoglobin, hematocrit, anemia risk factors, lipid profiles, whole blood viscosity and anthropometry were measured. RESULTS: Total testosterone (from mean +/- SD 1.87 +/- 1.09 to 5.52 +/- 1.92 ng/ml, p <0.001) and free testosterone (from 3.04 +/- 2.03 to 7.23 +/- 2.90 pg/ml, p <0.001) were restored by testosterone undecanoate therapy. Hemoglobin and hematocrit significantly increased after testosterone undecanoate therapy by an average of 2.46 gm/dl (p <0.001) and 3.03% (p <0.001), respectively. The prevalence of anemia (from 29.6% to 10.0%) significantly decreased (p <0.001) and patients with anemia showed a significant increase in erythropoietin after testosterone undecanoate therapy (p = 0.047). A reduction in total cholesterol (from 165.89 +/- 39.16 to 153.80 +/- 154.27 mg/dl, p = 0.002), increased whole blood viscosity and increased hematocrit were observed until 54 weeks compared with baseline. However, whole blood viscosity and hematocrit stabilized after 18 weeks. CONCLUSIONS: After 54 weeks testosterone undecanoate decreased the prevalence of anemia and components of the metabolic syndrome. A longer duration of testosterone undecanoate therapy of more than 18 weeks may be effective and safe in reducing blood viscosity and improving anemia. PMID- 26519656 TI - Inhibition of High Basal Level of Autophagy Induces Apoptosis in Human Bladder Cancer Cells. AB - PURPOSE: Cancer cells adapt to stress by activation of the autophagy pathway primed for survival. A high basal level of autophagic activity was found in human bladder cancer cell lines. We studied the significance of the phenomenon on cancer cell survival. MATERIALS AND METHODS: The immortalized human bladder epithelial cell line SV-HUC-1 and the human bladder cancer cell lines RT-4 and 5637 together with human bladder cancer specimens collected from patients were used. A commercially available bladder cancer microarray was applied to confirm the findings. LC3 (light chain-3) II protein detection was done to determine the presence of autophagy. Caspase 3 and DNA fragmentation was performed to detect apoptosis. RESULTS: Bladder cancer cell lines showed activated autophagic flux compared to SV-HUC-1 cells, prostate cancer cells and breast cancer cells. Results were confirmed in human bladder cancer specimens. Autophagy inhibition by Baf (bafilomycin) A1, or by knockdown of ATG (autophagy related protein) 7 or 12 induced cytotoxicity in multiple human bladder cell lines. Induction of apoptosis was found in cells with autophagy inhibition. Although the disruption of mitochondria membrane potential or the generation of reactive oxygen species was detected in Baf A1 treated cells, intensity was mild and not thought to be related to apoptosis of bladder cancer cells. CONCLUSIONS: Our results indicate that autophagy is required for the growth and survival of human bladder cancer cells. PMID- 26519657 TI - Kinetic and structural investigation of the cytokinin oxidase/dehydrogenase active site. AB - Cytokinins are hormones that regulate plant development and their environmental responses. Their levels are mainly controlled by the cytokinin oxidase/dehydrogenase (CKO), which oxidatively cleaves cytokinins using redox active electron acceptors. CKO belongs to the group of flavoproteins with an 8alpha-N1-histidyl FAD covalent linkage. Here, we investigated the role of seven active site residues, H105, D169, E288, V378, E381, P427 and L492, in substrate binding and catalysis of the CKO1 from maize (Zea mays, ZmCKO1) combining site directed mutagenesis with kinetics and X-ray crystallography. We identify E381 as a key residue for enzyme specificity that restricts substrate binding as well as quinone electron acceptor binding. We show that D169 is important for catalysis and that H105 covalently linked to FAD maintains the enzyme's structural integrity, stability and high rates with electron acceptors. The L492A mutation significantly modulates the cleavage of aromatic cytokinins and zeatin isomers. The high resolution X-ray structures of ZmCKO1 and the E381S variant in complex with N6-(2-isopentenyl)adenosine reveal the binding mode of cytokinin ribosides. Those of ZmCKO2 and ZmCKO4a contain a mobile domain, which might contribute to binding of the N9 substituted cytokinins. PMID- 26519658 TI - Evaluation of mechanical and optical behavior of current esthetic dental restorative CAD/CAM composites. AB - OBJECTIVES: To determine the mechanical and optical properties of CAD/CAM composites (LAVA Ultimate, Cerasmart, Shofu Block and two exp. CAD/CAM composites), a hybrid material (VITA Enamic), a leucite (IPS Empress CAD) and a lithium disilicate glass-ceramic (IPS e.max CAD). MATERIALS AND METHODS: Three point flexural strength (FS) was investigated according ISO 6872:2008 (N=240/n=30). Two-body wear (TBW) was analyzed in a chewing simulator (1,200,000 cycles, 50N, 5 degrees /55 degrees C) using human teeth as antagonists (N=120/n=15). Quantitative analysis of wear was carried out with a 3D-scanner and associated matching software. Discoloration rate (DR) after 14 days of storage in cress, curry, red wine, and distilled water (N=384/n=12), and translucency (T) (N=384/n=48) of CAD/CAM materials were measured in a spectrophotometer (400-700nm wavelength). Data were analyzed using two-/one-way ANOVA with Scheffe post-hoc test, Kruskal-Wallis-H test, and linear mixed models (alpha=0.05). RESULTS: IPS e.max CAD showed the highest FS (p<0.001), followed by LAVA Ultimate; however, not different from the remaining CAD/CAM composites (exception: Shofu Block). The lowest FS showed VITA Enamic and IPS Empress CAD (p<0.001). IPS Empress CAD, VITA Enamic, exp. CAD/CAM composite 2, followed by IPS e.max presented lower material TBW than the remaining CAD/CAM materials (p<0.001). The highest antagonist wear was observed for the tested glass-ceramics and the hybrid material (p<0.001). Storage medium (red wine>curry>cress>distilled water) exerted the highest influence on DR (p<0.001), closely followed by CAD/CAM material. Glass-ceramics showed lower DR than CAD/CAM composites (p<0.001). CONCLUSIONS: CAD/CAM composites presented moderate FS, high T and antagonist friendly behavior. Glass ceramic demonstrated the most favorable DR and lowest TBW on the material side. PMID- 26519659 TI - Traumatic brain injury and epilepsy: Underlying mechanisms leading to seizure. AB - Post-traumatic epilepsy continues to be a major concern for those experiencing traumatic brain injury. Post-traumatic epilepsy accounts for 10-20% of epilepsy cases in the general population. While seizure prophylaxis can prevent early onset seizures, no available treatments effectively prevent late-onset seizure. Little is known about the progression of neural injury over time and how this injury progression contributes to late onset seizure development. In this comprehensive review, we discuss the epidemiology and risk factors for post traumatic epilepsy and the current pharmacologic agents used for treatment. We highlight limitations with the current approach and offer suggestions for remedying the knowledge gap. Critical to this pursuit is the design of pre clinical models to investigate important mechanistic factors responsible for post traumatic epilepsy development. We discuss what the current models have provided in terms of understanding acute injury and what is needed to advance understanding regarding late onset seizure. New model designs will be used to investigate novel pathways linking acute injury to chronic changes within the brain. Important components of this transition are likely mediated by toll-like receptors, neuroinflammation, and tauopathy. In the final section, we highlight current experimental therapies that may prove promising in preventing and treating post-traumatic epilepsy. By increasing understanding about post traumatic epilepsy and injury expansion over time, it will be possible to design better treatments with specific molecular targets to prevent late-onset seizure occurrence following traumatic brain injury. PMID- 26519660 TI - The impact of lifestyle on Barrett's Esophagus: A precursor to esophageal adenocarcinoma. AB - BACKGROUND: Barrett's Esophagus (BE), particularly long-segment Barrett's Esophagus, and the age of onset of Barrett's Esophagus are risk factors for esophageal adenocarcinoma. However, it is unknown if lifestyle factors such as alcohol abuse, tobacco use, weight gains that increase the risk of developing BE and esophageal adenocarcinoma affect its length or age at diagnosis. METHODS: In a retrospective, cross-sectional analysis, we analyzed 158 newly diagnosed adult BE patients at a 600-bed tertiary care center in the United States from 1999 to 2008. We constructed generalized linear models for the outcomes of BE length and age at diagnosis. Predictors of interest included current or prior alcohol abuse, tobacco use, weight gain over the last 5 years, and body mass index (BMI). RESULTS: 71 (45%) had length >= 3 cm. Barrett's Esophagus length was positively correlated with hiatal hernia length (r=0.67, p<0.001) and heartburn duration (r=0.36, p<0.001). Multivariate results showed no significant relationship between alcohol abuse, tobacco use, weight gain or BMI and BE length. Patients with weight gain, current tobacco use, and male gender were diagnosed at a significantly younger age than their peers (for example, the adjusted mean age at diagnosis for current tobacco users vs. non-smokers was 49.2 years vs. 54.7 years, p=0.029). CONCLUSIONS: Lifestyle factors did not appear to affect Barrett's Esophagus length but weight gains, smoking, and male gender were associated with a diagnosis at a significantly younger age. PMID- 26519661 TI - Relationships between gross- and fine motor functions, cognitive abilities, and self-regulatory aspects of students with physical disabilities. AB - This article reports research on self-regulatory aspects (i.e., goal-setting, self-efficacy and self-evaluation) of secondary and post-secondary students with congenital motor disabilities, who performed a ball-throwing-at-a-target task. Participants were divided into four subgroups presenting distinct combinations of motor and cognitive abilities (i.e., normal cognitive development and mild physical disabilities, normal cognitive development and severe physical disabilities, mild-to-moderate intellectual disability and mild physical disabilities, and mild-to-moderate intellectual disability and severe physical disabilities). Results showed that students presenting mild motor disabilities exhibited a positive self-concept and self-regulation profile, irrespective of their cognitive functioning. Students with considerable motor disabilities, but without cognitive challenges, presented a negative, though realistic self-concept and self-regulation profile. Finally, students with considerable motor disabilities and mild-to-moderate cognitive disabilities showed a positive, though unrealistic, self-regulation profile. The nature of the diverse relationship of motor and cognitive (dis)abilities to specific self-regulatory aspects are discussed, and important instructional implications are mentioned. PMID- 26519662 TI - Interference with facial emotion recognition by verbal but not visual loads. AB - The ability to recognize emotions through facial characteristics is critical for social functioning, but is often impaired in those with a developmental or intellectual disability. The current experiments explored the degree to which interfering with the processing capacities of typically-developing individuals would produce a similar inability to recognize emotions through the facial elements of faces displaying particular emotions. It was found that increasing the cognitive load (in an attempt to model learning impairments in a typically developing population) produced deficits in correctly identifying emotions from facial elements. However, this effect was much more pronounced when using a concurrent verbal task than when employing a concurrent visual task, suggesting that there is a substantial verbal element to the labeling and subsequent recognition of emotions. This concurs with previous work conducted with those with developmental disabilities that suggests emotion recognition deficits are connected with language deficits. PMID- 26519663 TI - Differentiating low- and high-grade pediatric brain tumors using a continuous time random-walk diffusion model at high b-values. AB - PURPOSE: To demonstrate that a continuous-time random-walk (CTRW) diffusion model can improve diagnostic accuracy of differentiating low- and high-grade pediatric brain tumors. METHODS: Fifty-four children with histopathologically confirmed brain tumors underwent diffusion MRI scans at 3Twith 12 b-values (0-4000 s/mm(2) ). The diffusion imageswere fit to a simplified CTRW model to extract anomalous diffusion coefficient, Dm , and temporal and spatial heterogeneity parameters, alpha and beta, respectively. Using histopathology results as reference, a k means clustering algorithm and a receiver operating characteristic (ROC) analysis were employed to determine the sensitivity, specificity, and diagnostic accuracy of the CTRW parameters in differentiating tumor grades. RESULTS: Significant differences between the low- and high-grade tumors were observed in the CTRW parameters (p-values<0.001). The k-means analysis showed that the combination of three CTRW parameters produced higher diagnostic accuracy (85% vs. 75%) and specificity (83% vs. 54%) than the apparent diffusion coefficient (ADC) from a mono-exponential model. The ROC analysis revealed that any combination of the CTRW parameters gave a larger area under the curve (0.90-0.96) than using ADC (0.80). CONCLUSION: With its sensitivity to intravoxel heterogeneity, the simplified CTRW model is useful for non-invasive grading of pediatric brain tumors, particularly when surgical biopsy is not feasible. Magn Reson Med 76:1149 1157, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26519664 TI - Psychiatric disorders among 165 patients with juvenile myoclonic epilepsy in India and association with clinical and sociodemographic variables. AB - OBJECTIVE: The current study evaluated the association between clinical variables and psychiatric disorders (PDs) in patients with juvenile myoclonic epilepsy (JME). METHODS: Consecutive patients with JME who had at least two years of regular follow-up from May 2011 to April 2014 formed the study population. The association between clinical and sociodemographic data with psychiatric evaluation on structured clinical interview and quality of life in epilepsy - 31 (QOLIE-31) was evaluated using logistic regression analysis. RESULTS: Out of 165 patients in the current study, 77 (46.6%) patients were diagnosed with PDs; while 50 were categorized to having anxiety disorders, 27 patients had depressive disorders. The mean age of the study population was 25.35 +/- 7.6 years with 37.52% women. Patients with PDs had lower overall QOLIE score (55.84 +/- 13.07 vs 68.70 +/- 11.23, p<0.001) and lower social function score (80.95 +/- 19.22 vs 91.09 +/- 14.74, p<0.001). Being married was the strongest predictor of depressive disorders (beta=8.59; 95% CI, 1.44-51.28; p=0.018); whereas, lower emotional well-being (beta=0.942; 95% CI, 0.907-0.978; p=0.002) was the only variable associated with anxiety disorders. Patients with depressive disorders had longer duration of PDs (11.85 +/- 8.68 years vs 7.75 +/- 6.70 years, p=0.039), and a majority of them were married (66.7% vs 26.0%, p=0.001). Patients with depressive disorders scored low on emotional well-being (50.81 +/- 14.62 vs 61.02 +/- 13.05, p=0.002), energy levels (52.78 +/- 11.71 vs 62.80 +/- 10.84, p<0.001), and social function (70.96 +/- 20.69 vs 86.34 +/- 16.16, p=0.001). Depressive disorders were more prevalent among married patients above 35 years of age (5.2% vs 36.8%, p=0.042). SIGNIFICANCE: Nearly half of the patients with JME had coexisting PDs. The psychological profile of anxiety disorders was different from depressive disorders in patients with JME. Depressive disorders were more prevalent among older patients with JME, and marriage was strongly associated with depressive disorders. PMID- 26519665 TI - Perception of, attitudes toward, and knowledge of epilepsy among teachers and high school and college students in Sicily. AB - The study was aimed at investigating perception of, attitudes toward, and knowledge of epilepsy among college students of the University of Messina in Sicily (Italy), high school students, and teachers from Sicily in order to structure health educational programs to remediate inadequate knowledge and stigma about epilepsy. Participants in this study consisted of 932 subjects (571 males, 361 females) aged between 13 and 63 years old (M 21.75 +/- 8.7): 571 college students aged between 18 and 35 years old (M 21.54 +/- 2.59), 62 teachers aged between 38 and 63 years old (M 51.18 +/- 6.27), and 299 high school students aged between 13 and 19 years old (M 16.05 +/- 1.67). Measures were two anonymous questionnaires to collect sociodemographic information and to assess knowledge of, attitudes toward, and perception of epilepsy. Analyses were performed with descriptive statistical analysis (mean, standard deviation, frequency counts, and percentages) and Mann-Whitney U-test nonparametric for two independent samples. This study provides general information about psychosocial aspects of epilepsy in Sicily which provides the basis for further studies and the development of interventions to eliminate prejudices against persons with epilepsy and related myths. PMID- 26519666 TI - Language recovery after left hemispherotomy for Rasmussen encephalitis. AB - PURPOSE: Hemispherotomy (H) is the gold standard treatment to cure epilepsy in Rasmussen encephalitis (RE). Linguistic prognosis after surgery remains the main issue when the dominant hemisphere is involved. The topic of the present research is to specify the long-term linguistic profile of the right hemisphere after left dominant H for RE. METHODS: We followed 6 children 8.4 to 14.6 years of age who underwent left H for RE. Preoperatively, four children experienced aphasia, but for two, worsening occurred after surgery. Age at H ranged from 4.1 to 8.4 years. The mean duration of epilepsy was 1.2 years and 5.6 years for follow-up. Neuropsychological evaluation included longitudinal follow-up of intellectual efficiency measurement and a long-term outcome of language using various components of receptive and expressive oral speech with computerized tasks. KEY FINDINGS: Preoperatively, verbal comprehension index (VCI) was dramatically decreased in 4/6 patients, and performance reasoning index (PRI) was low in 5/6 participants, demonstrating a global impact of RE itself. Postoperatively, all children recovered sufficiently to attend a regular VCI (above 70) in a mean of 5 years after H, and 5/6 recovered normal or adapted school. There was a dissociation in favor of VCI, while PRI decreased in 5/6 patients. We found a specific linguistic profile for these children recovering language in the right hemisphere: normal verbal comprehension, and weakness of grammatical judgment, word repetition, statement production, semantic verbal fluency and metaphonological abilities. Language recovery scores were statistically correlated with those of Working Memory Index. SIGNIFICANCE: This study emphasizes for the first time the ability of the right hemisphere to functionally reorganize language over a long period of time following left H for RE. Syntactic abilities and phonology remain low and support the hypothesis of an early left hemispheric specialization. Nevertheless, lexico-semantic processes recover in the right hemisphere that could reflect a pre-existing potential of both hemispheres. Our results support a decision to proceed to H in classical left RE disease until the late childhood even if there is no complete aphasia before surgery. These data should be taken in account in the overall postoperative follow-up and rehabilitation strategy. PMID- 26519667 TI - Patterns of verbal learning and memory in children with intractable temporal lobe or frontal lobe epilepsy. AB - PURPOSE: The objective of this study was to provide a better understanding of the verbal learning and memory (VLM) patterns that might differentiate children with frontal lobe epilepsy (FLE) from children with temporal lobe epilepsy (TLE) and to examine the impact of variables thought to influence outcomes (seizure laterality, age at seizure onset, age at assessment, epilepsy duration, number of antiepileptic drugs). METHODS: Retrospective analyses were carried out for children with intractable unilateral TLE (n=100) and FLE (n=27) who completed standardized measures of VLM entailing lists of single words or lists of word pairs. RESULTS: Mean intelligent quotients and VLM scores on single words fell within the average range for both groups, whereas scores fell within the low average to borderline range on word pairs. No significant overall differences in VLM were found between the group with TLE and the group with FLE. Older age at assessment and older age at seizure onset were generally associated with better VLM in both groups but were related to better performance in a number of indices in the group with TLE and only fewer intrusions in the group with FLE. CONCLUSIONS: The VLM profiles of children with TLE and FLE are generally similar. Older age at assessment and older age at seizure onset have a favorable impact on both groups but are related to better encoding, retrieval, and monitoring processes for the group with TLE and improved memory monitoring (i.e., as indicated by fewer intrusions) in the group with FLE. PMID- 26519668 TI - Proliferative activity of elastin-like-peptides depends on charge and phase transition. AB - Elastin-like-peptides (ELPs) are stimulus-responsive protein-based polymers and are attractive biomaterials due to their biocompatibility and unique properties. This study shows that in addition to their physical properties, ELPs have biological activities that are conducive to tissue regeneration. Specifically, we found that ELPs induce fibroblast proliferation via cell surface heparan sulfate proteoglycans (HSPG). Furthermore, our data suggests that ELP based materials with differential proliferative potential can be designed by controlling the interaction of ELPs with HSPGs by incorporating either hydrophobic or positively charged residues within the ELP sequence. Fibroblast proliferation is important for granulation tissue formation which is important in chronic wounds as well as in healing of other tissues. The customizable biological activity of ELPs coupled with their unique physical properties will enable us to design novel, sustainable and cost effective therapies for different tissue regeneration applications. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 697-706, 2016. PMID- 26519669 TI - Interferon-free regimens containing setrobuvir for patients with genotype 1 chronic hepatitis C: a randomized, multicenter study. AB - BACKGROUND & AIMS: Setrobuvir is a direct-acting antiviral (DAA) non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study examined interferon free combinations containing setrobuvir, a ritonavir-boosted protease inhibitor (danoprevir/r) and ribavirin, with/without the nucleoside inhibitor mericitabine in HCV genotype (G)1 patients. METHODS: Non-cirrhotic treatment-naive patients (N = 110) were randomized to five groups. Three groups received a 14-day mericitabine/ribavirin lead-in followed by treatment with 3 DAAs (setrobuvir, danoprevir/r, mericitabine) plus ribavirin for 12 weeks (Group A: G1a; D: G1b) or 24 weeks (B: G1a), and two groups received 2 DAAs (setrobuvir, danoprevir/r) plus ribavirin for 12 weeks (E: G1b) or 24 weeks (C: G1a). Efficacy was defined as sustained virological response (HCV RNA <25 IU/ml after 12 weeks' follow-up, SVR12). RESULTS: Two groups met predefined futility criteria for breakthrough (C) or relapse (A) and were discontinued. SVR12 rates were 42.9% (3/7) and 74.1% (20/27) in G1a patients in Groups A and B, respectively, and 95.7% (22/23) and 68.2% (15/22) in G1b patients in Groups D and E respectively. All G1a patients assigned to 24 weeks of treatment who experienced a decrease in HCV RNA of >=2.3 log10 IU by the end of the lead-in period (n = 28) achieved SVR12. Overall, treatment was well tolerated and most adverse events were mild to moderate. No major safety signals were identified. CONCLUSIONS: An interferon-free setrobuvir based regimen (3 DAAs plus ribavirin) is safe and effective in treatment-naive G1 patients. PMID- 26519670 TI - An alternative way to assess aortic elasticity: Three-dimensional speckle tracking echocardiography-derived strain assessment (From the MAGYAR-Healthy Study). PMID- 26519671 TI - Excessive stent overhang as an uncommon cause of very late stent thrombosis: Usefulness of optical coherence tomography. PMID- 26519672 TI - Refined balloon pulmonary angioplasty driven by combined assessment of intra arterial anatomy and physiology--Multimodal approach to treated lesions in patients with non-operable distal chronic thromboembolic pulmonary hypertension- Technique, safety and efficacy of 50 consecutive angioplasties. AB - BACKGROUND/OBJECTIVES: Balloon pulmonary angioplasty (BPA) is an emerging therapeutic method in CTEPH. We aimed to prove the safety and efficacy of refined BPA driven by combined assessment of intra-arterial anatomy (IVUS/OCT) and physiology (pulmonary pressure ratio, PPR) in non-operable distal CTEPH. METHODS: 11 pts (mean age 76, 59-84, 7 males) were enrolled in the BPA program according to the following inclusion criteria: 1. Non-operable CTEPH; 2. RHC with mPAP > 30 mm Hg; 3. At least one segmental perfusion defect at lung scintigraphy; 4. WHO class > II. Overall, 9 pts underwent 27 BPA sessions (mean 3 sessions per patient, range 1-5), 50 pulmonary arteries were dilated (mean 6 vessels per patient, range 3-9; 2.03 dilated arteries per session). All the angioplasties were performed according to an algorithm, which incorporated anatomical and functional assessment of targeted lesions. RESULTS: We performed BPA of 32 web lesions, 5 ring-like stenosis and 13 complete obstructions. BPA resulted in clinical and hemodynamic improvement. WHO class improved from pre-BPA to post-BPA (p = 0.018), and 6 MWD increased from 304 m to 384 m (p = 0.03), NT-proBNP dropped from 1248 pg/ml to 730 pg/ml (p < 0.001). Mean PAP and PVR decreased (p = 0.01), while CO and CI increased (p = 0.01). All dilated arteries were patent at angiographic reassessment. No significant complications occurred and all treated patients are still alive. Insignificant transient reperfusion pulmonary oedema occurred in only 2 patients, who responded well to supplemental oxygen. CONCLUSIONS: Refined BPA with assessment of intrapulmonary physiology using a pressure wire and precise evaluation of anatomy with IVUS and OCT provides hemodynamic and functional improvement, with minimal complications in distal non operable CTEPH. This observation requires further validation in a large prospective study. PMID- 26519673 TI - Autopsy findings in takotsubo cardiomyopathy with special reference to the autonomic nervous system. PMID- 26519674 TI - In memoriam: The mentor, the teacher, the colleague, the healer, the scientist and friend: Kanu Chatterjee. PMID- 26519675 TI - 120 mmHg versus 140 mmHg: Facing the challenge of systolic blood pressure goal. PMID- 26519676 TI - Myocarditis associated with cannabis use in a 15-year-old boy: A rare case report. PMID- 26519677 TI - Determinants of outpatient clinic attendance amongst adults with congenital heart disease and outcome. AB - BACKGROUND: Adult congenital heart disease (ACHD) guidelines advise life-long, regular, follow up in predefined intervals for ACHD patients. However, limited data exist to support this position. We examine, herewith, compliance to scheduled outpatient clinic appointments and its impact on outcome. METHODS AND RESULTS: We examined 4461 ACHD patients (median age at entry 26.4years, 51% female) and their follow up records at our tertiary centre between 1991 and 2008. Clinic attendance was quantified from electronic hospital records. For survival analysis we employed the last clinic attendance before 2008 as starting of follow up. Overall 23% of scheduled clinic appointments were not attended. The main predictors of clinic non-attendance (CNA) were younger age, non-Caucasian ethnicity, lower socioeconomic status, number of previous CNAs and the lack of planned additional investigation/s (e.g. echocardiography) scheduled on the same day. During a cumulative follow-up time of 48,828 patient-years, 366 (8.2%) patients died. Both, the number of CNAs (HR=1.08, 95% CI 1.05-1.12 per CNA, P<0.001) and the ratio of CNA to follow up period (HR=1.23, 95% CI 1.04-1.44 per CNA/year, P=0.013) emerged as predictors of mortality independent of adjustment for patients' age, disease complexity, functional class and socioeconomic status. CONCLUSIONS: Patient adherence to scheduled ACHD outpatient-clinics is associated with better survival. Identifying patients at an increased risk of CNA in a single tertiary centre is feasible. Our data provides previously lacking evidence supporting the practice of periodic assessment of ACHD patients at tertiary clinics. Non-attenders should be specifically targeted and receive counselling to modulate their increased risk of death. PMID- 26519678 TI - Subcutaneous implantable cardioverter defibrillators in children, young adults and patients with congenital heart disease. AB - The demonstration of severe complications in patients implanted with a transvenous implantable cardioverter defibrillator (ICD) has led to the development of devices equipped with a subcutaneous lead. This new technique offers numerous advantages but also certain disadvantages. Various studies or anecdotal clinical cases have specifically been conducted with this subcutaneous defibrillation system in children and/or patients with congenital heart disease. Results of these studies suggest: 1) a high feasibility despite being limited by a selection process that excludes patients requiring permanent pacing and patients declared ineligible during pre-screening; 2) good efficacy of electrical shocks in reducing induced or spontaneous ventricular arrhythmias; 3) in this specific subset of patients, 2 types of complications have been particularly described: a risk of device exteriorization and infection, and a large number of inappropriate therapies primarily related to T-wave oversensing. The subcutaneous ICD could therefore constitute the gold standard for patients with complex congenital heart disease with no venous access to the heart or with a persistent shunt increasing the risk of systemic emboli as well as in young patients with channelopathy or hypertrophic cardiomyopathy not requiring long-term pacing. Technological change (reduction in device size, better differentiation between R- and T-waves, possibility of pacing if device coupled with a leadless pacemaker) could reduce the limitations and complications and thereby increase the indications in this sub-group of patients. PMID- 26519679 TI - Takotsubo syndrome/QTc interval prolongation/myocardial edema/cardiac sympathetic denervation/cardiac arrhythmias: A quintet needing exploration. PMID- 26519680 TI - Low miR-19b-1-5p expression in isolated platelets after aspirin use is related to aspirin insensitivity. PMID- 26519682 TI - Vitamin D receptor activation may play a protective role in myocardial ischemic/reperfusion injury. PMID- 26519681 TI - New-onset atrial fibrillation and increased mortality after transcatheter aortic valve implantation: A causal or spurious association? PMID- 26519683 TI - Strokes after cardioversion of atrial fibrillation--The FibStroke study. AB - BACKGROUND: Cardioversion of atrial fibrillation (AF) is associated with an increased risk for stroke. We identified all cardioversions during the 30 days preceding stroke or transient ischemic attack (TIA) in patients with a previously diagnosed AF, and sought to assess the characteristics of cardioversions leading to stroke or TIA. METHODS: FibStroke is a cross-sectional observational multicenter registry that included AF patients with an ischemic stroke or intracranial bleed identified from a discharge registry of four Finnish hospitals. In total 3677 consecutive AF patients suffered 3252 strokes and 956 TIA episodes during 2003-2012. This pre-specified analysis focused on the 1644 events that occurred to patients with paroxysmal or persistent AF at the time of stroke/TIA. RESULTS: A total of 78 strokes and 22 TIA episodes were preceded by a cardioversion. Post-cardioversion strokes accounted for 6.4% of strokes in patients with paroxysmal/persistent AF. Of the 100 cardioversions leading to an ischemic event, 77 were acute and 23 were elective, 63 events occurred in patients not using anticoagulation, and 5 patients had periprocedural INR < 2. Importantly, 21 patients were in low risk of stroke, i.e. CHA2DS2-VASc score < 2. The median delay from cardioversion to event was 2 days. All nine patients who after an unsuccessful cardioversion developed a stroke had a spontaneous cardioversion prior to stroke. CONCLUSIONS: Every sixteenth stroke of patients with paroxysmal/persistent AF is preceded by a cardioversion. Most post cardioversion strokes occur in patients not using oral anticoagulation before cardioversion of acute AF. PMID- 26519684 TI - Programmed death-1: a potential therapeutic target approaches for atherosclerosis. PMID- 26519685 TI - Coronary artery disease in Eisenmenger's syndrome--Rare but not to be forgotten. PMID- 26519686 TI - The medical and socioeconomic burden of heart failure: A comparative delineation with cancer. AB - Cardiovascular disease and cancer represent the two leading causes of death in the Western World. Still, cardiovascular disease causes more deaths and more hospitalizations than cancer. Although mortality rates of both conditions are generally declining, this is not true for heart failure (HF). The prevalence of HF is increasing, although its incidence has been stabilized, mainly because of the population aging. The survival of patients with HF is overall worse than those with cancer. In addition, HF failure is the most common reason for hospitalization in the elderly, while hospitalization for HF is followed by adverse prognosis and represents the main contributor to the huge financial expenditure caused by the syndrome. The outcome of HF patients and thus its medical and socioeconomic burden may be improved by the more efficient in hospital management of patients, the enhancement of adherence to guideline recommended therapies, the identification and treatment of comorbid conditions and the introduction of more effective medical therapies. PMID- 26519687 TI - Histological and proteomic profile of diabetic versus non-diabetic dilated cardiomyopathy. AB - BACKGROUND: Diabetic cardiomyopathy (DbCM) is indistinguishable from idiopathic dilated cardiomyopathy (IDCM) as specific histological and/or biochemical markers are unavailable. METHODS AND RESULTS: Comparative histology, electron microscopy, morphometry for cell volume composition and myocardial fibrosis, reactive oxygen species (ROS), polymerase chain reaction for cardiotropic viruses, immunohistochemistry for nitrotyrosine, inducible nitric oxide synthase (iNOS), 8 hydroxydeoxyguanosine (8-OH-dG) and proteomics have been evaluated in endomyocardial biopsies from 9 patients (pts) (5 male and 4 female, mean age 61 +/- 13 years) with DbCM (left ventricular end-diastolic diameter 65 +/- 2.3mm; ejection fraction 27 +/- 6) and type 2 diabetes mellitus and 9 pts with IDCM (mean age 60 +/- 9 years) matched for sex, age and severity of left ventricular (LV) dysfunction. Controls were surgical biopsies from 9 pts with mitral stenosis and normal LV dimensions and function. No qualitative morphological changes were observed between DbCM and IDCM although mitochondrial damage and myofibrillolysis appeared more pronounced in DbCM. ROS were 5 times higher in DbCM than in IDCM and controls and were associated with higher expression of cytoplasm iNOS and nitrotyrosine and nuclear 8-OH-dG. Apoptosis was 14 times higher in DbCM than in IDCM and 41 times higher than in controls. Proteomic profile showed in DbCM a reduced expression of proteins related to beta-oxidation and detoxification pathway. CONCLUSIONS: DbCM is a distinctive ROS-mediated disorder with oxidative damage of myocyte's structural proteins and DNA causing cell dysfunction and death. Reduced expression of beta-oxidation proteins suggests a decline of energy production and of mitochondrial function. PMID- 26519688 TI - LC-MS/MS determination and urinary excretion study of seven alkaloids in healthy Chinese volunteers after oral administration of Shuanghua Baihe tablets. AB - An LC-MS/MS method was developed and validated for the simultaneous determination of magnoflorine, berberrubine, jatrorrhizine, coptisine, epiberberine, palmatine and berberine in human urine. The sample preparation procedure involved the four fold dilution of the urine samples with acetonitrile/water (1:3, v/v). The chromatographic separation was achieved on a Hedera ODS-2 column under gradient elution at a flow rate of 0.4 mL/min with acetonitrile and water containing 0.5% formic acid as the mobile phase. The mass detection was performed in the positive mode. Calibration curves of the seven alkaloids showed good linearity (correlation coefficients>0.9973) over their concentration ranges. To meet the requirements of urinary excretion study for each alkaloid in human, the lower limit of quantification was set at different values from 0.05063 ng/mL to 2.034 ng/mL for the seven alkaloids, respectively. The intra- and inter-batch precision and accuracy were all within +/- 15%. No matrix effect was observed for the analytes. The validated method was applied to the excretion study for the seven alkaloids in healthy Chinese volunteers after oral administration of Shuanghua Baihe tablets. The average 72 h cumulative urinary excretion of magnoflorine, berberrubine, jatrorrhizine, coptisine, epiberberine, palmatine and berberine accounted for 1.81%, 0.27%, 0.29%, 0.046%, 0.027%, 0.010% and 0.021% of the respective administered dose. PMID- 26519689 TI - The Transcription Factor EB (TFEB) Regulates Osteoblast Differentiation Through ATF4/CHOP-Dependent Pathway. AB - Osteoblasts are bone-forming cells that produce large amounts of collagen type I and various bone matrix proteins. Although osteoblast differentiation is highly regulated by various factors, it remains unknown whether lysosomes are directly involved in osteoblast differentiation. Here, we demonstrate the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, modulates osteoblast differentiation. The expression levels of TFEB as well as those of endosomal/lysosomal proteins were up-regulated during osteoblast differentiation using mouse osteoblastic MC3T3-E1 cells. By gene knockdown (KD) experiments with small interfering RNA (siRNA), TFEB depletion caused markedly reduced osteoblast differentiation as compared with the control cells. Conversely, overexpression (OE) of TFEB resulted in strikingly enhanced osteoblastogenesis compared to the control cells. By analysis of down-stream effector molecules, TFEB KD was found to cause marked up-regulation of activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP), both of which are essential factors for osteoblastogenesis. In contrast, TFEB OE promoted osteoblast differentiation through reduced expression of ATF4 and CHOP without differentiation agents. Given the importance of ATF4 and CHOP in osteoblastogenesis, it is clear that the TFEB-regulated signaling pathway for osteoblast differentiation is involved in ATF4/CHOP-dependent signaling pathway. PMID- 26519690 TI - Crowdsourcing for quantifying transcripts: An exploratory study. AB - This exploratory study attempts to demonstrate the potential utility of crowdsourcing as a supplemental technique for quantifying transcribed interviews. Crowdsourcing is the harnessing of the abilities of many people to complete a specific task or a set of tasks. In this study multiple samples of crowdsourced individuals were asked to rate and select supporting quotes from two different transcripts. The findings indicate that the different crowdsourced samples produced nearly identical ratings of the transcripts, and were able to consistently select the same supporting text from the transcripts. These findings suggest that crowdsourcing, with further development, can potentially be used as a mixed method tool to offer a supplemental perspective on transcribed interviews. PMID- 26519691 TI - Significance of action plans in the development of occupational well-being in the schools of Finland and Estonia. AB - This article is part of a long term project "Promoting the Occupational Well Being of School Staff-Action Research Project in Finland and Estonia, 2009-2014." The purpose of this article is to describe the significance of action plans in the promotion of the occupational well-being of primary and upper secondary school staff in Finland and Estonia from 2010 to the turn of the year 2011-2012. An electronic open questionnaire was sent to occupational well-being groups in Finland (N=18) and in Estonia (N=39). In Finland, the questionnaire was responded to by 16 (n=16) occupational well-being groups, and in Estonia, by 38 (n=38) groups. The qualitative data were analyzed using the inductive-deductive method and content analysis. The obtained results indicate that the schools had named goals for action plans in all aspects of the promotion of occupational well-being in schools (worker and work, working conditions, professional competence, working community) and that these goals were mainly realized in the schools in a systematic way. Schools felt that the action plan for occupational well-being helped them to set goals for occupational well-being and that the planned actions were realized in a more systematic way than before. PMID- 26519692 TI - Explaining how unexploded ordnance clearance enhances livelihoods in the Lao PDR. AB - BACKGROUND: Following violent conflict, the continued presence of landmines and unexploded ordnance pose a barrier to rebuilding livelihoods. Mine action removes these explosive remnants of conflict to enable communities to safely return contaminated land to productive use. There is limited understanding, however, of how, why, in what context and in what respects mine action contributes to livelihoods. Yet, such information is required for effective resource allocation, checking underlying program assumptions, understanding benefits and potential harms. METHODS: The evaluation was undertaken in the Lao People's Democratic Republic. It used an interpretive case study design and applied the principles of realist evaluation. Program staff and local government authorities were interviewed (N=37) and program beneficiaries. In total, 38 individual interviews with program beneficiaries were conducted and eighteen focus group interviews (9 with males, 9 with females), each with 6-9 participants. RESULTS: The evaluation identified two main mechanisms through which the program 'worked': (1) communication pre- and post-clearance and (2) the delivery of the product (cleared land). CONCLUSION: The realist approach helped to refine the program theory, highlighted the role of self- and task-efficacy and community communication, assisted in identifying contextual factors that influence outcomes and suggested a revision of expected outcomes. PMID- 26519693 TI - High cut-off dialysis in chronic haemodialysis patients. AB - BACKGROUND: Haemodialysis patients suffer from chronic systemic inflammation and high incidence of cardiovascular disease. One cause for this may be the failure of diseased kidneys to eliminate immune mediators. Current haemodialysis treatment achieves insufficient elimination of proteins in the molecular weight range 15-45 kD. Thus, high cut-off dialysis might improve the inflammatory state. DESIGN: In this randomized crossover trial, 43 haemodialysis patients were treated for 3 weeks with high cut-off or high-flux dialysis. Inflammatory plasma mediators, monocyte subpopulation distribution and leucocyte gene expression were quantified. RESULTS: High cut-off dialysis supplemented by a low-flux filter did not influence the primary end-point, expression density of CD162 on monocytes. Nevertheless, treatment reduced multiple immune mediators in plasma. Such reduction proved - at least for some markers - to be a sustained effect over the interdialytic interval. Thus, for example, soluble TNF-receptor 1 concentration predialysis was reduced from median 13.3 (IQR 8.9-17.2) to 9.7 (IQR 7.5-13.2) ng/mL with high cut-off while remaining constant with high-flux treatment. The expression profile of multiple proinflammatory genes in leucocytes was significantly dampened. Treatment was well tolerated although albumin losses in high cut-off dialysis would be prohibitive against long-term use. CONCLUSIONS: The study shows for the first time that a dampening effect of high cut-off dialysis on systemic inflammation is achievable. Earlier studies had failed due to short study duration or insufficient dialysis efficacy. Removal of soluble mediators from the circulation influences cellular activation levels in leucocytes. Continued development of less albumin leaky membranes with similar cytokine elimination is justified. PMID- 26519694 TI - Scale-up of phosphate remobilization from sewage sludge in a microbial fuel cell. AB - Phosphate remobilization from digested sewage sludge containing iron phosphate was scaled-up in a microbial fuel cell (MFC). A 3litre triple chambered MFC was constructed. This reactor was operated as a microbial fuel cell and later as a microbial electrolysis cell to accelerate cathodic phosphate remobilization. Applying an additional voltage and exceeding native MFC power accelerated chemical base formation and the related phosphate remobilization rate. The electrolysis approach was extended using a platinum-RVC cathode. The pH rose to 12.6 and phosphate was recovered by 67% in 26h. This was significantly faster than using microbial fuel cell conditions. Shrinking core modelling particle fluid kinetics showed that the reaction resistance has to move inside the sewage sludge particle for considerable rate enhancement. Remobilized phosphate was subsequently precipitated as struvite and inductively coupled plasma mass spectrometry indicated low levels of cadmium, lead, and other metals as required by law for recycling fertilizers. PMID- 26519695 TI - Hydrothermal carbonization of industrial mixed sludge from a pulp and paper mill. AB - Mixed sludge from a pulp and paper mill was hydrothermally carbonized at 180-260 degrees C for 0.5-5h with the use of HCl or NaOH for determining the effect of acid and base additions during sludge carbonization. Based on the results carbonization was mainly governed by dehydration, depolymerization and decarboxylation of sludge components. Additive type had a statistically significant effect on hydrochar carbon content and carbon and energy yield, of which especially energy yield increased through the use of HCl. The theoretical energy efficiencies of carbonization increased with decreasing reaction temperature, retention time and the use of HCl and suggested that the energy requirement could be covered by the energy content of attained hydrochar. The BOD5/COD-ratios of analyzed liquid samples indicated that the dissolved organic components could be treated by conventional biological methods. PMID- 26519696 TI - A new method for modeling rough membrane surface and calculation of interfacial interactions. AB - Membrane fouling control necessitates the establishment of an effective method to assess interfacial interactions between foulants and rough surface membrane. This study proposed a new method which includes a rigorous mathematical equation for modeling membrane surface morphology, and combination of surface element integration (SEI) method and the composite Simpson's approach for assessment of interfacial interactions. The new method provides a complete solution to quantitatively calculate interfacial interactions between foulants and rough surface membrane. Application of this method in a membrane bioreactor (MBR) showed that, high calculation accuracy could be achieved by setting high segment number, and moreover, the strength of three energy components and energy barrier was remarkably impaired by the existence of roughness on the membrane surface, indicating that membrane surface morphology exerted profound effects on membrane fouling in the MBR. Good agreement between calculation prediction and fouling phenomena was found, suggesting the feasibility of this method. PMID- 26519697 TI - Combination of mechanical, alkaline and enzymatic treatments to upgrade paper grade pulp to dissolving pulp with high reactivity. AB - A modified process consisting of an initial mechanical refining (R) followed by a low-alkali (5.5% NaOH) cold caustic extraction (CCE) and finally an endoglucanase (EG) treatment (R-5.5%CCE-EG) was investigated for upgrading paper-grade pulp to dissolving pulp. Results showed that compared to the conventional process (9%CCE EG), the modified process can decrease the alkali concentration (from 9% to 5.5%) to achieve a similar hemicelluloses removal while simultaneously enhancing the Fock reactivity (from 62.2% to 81.0%). The improved results were due to the fact that the mechanical refining resulted in favorable fiber morphological changes, including increased pore volume/size, water retention value and specific surface area. Consequently, the hemicelluloses removal was enhanced even under the subsequent low-alkali CCE condition. A synergic effect of refining, low alkali concentration and enzymatic activation was responsible for the higher reactivity of resulting dissolving pulp. PMID- 26519698 TI - Bead milling for lipid recovery from thraustochytrid cells and selective hydrolysis of Schizochytrium DT3 oil using lipase. AB - Marine microalgae present a renewable alternative source for sustainable production of omega-3 fatty acids, as compared to conventional sources such as krill oil and fish oil. In this study, we optimised a method for lipid extraction from marine thraustochytrids using a bead mill and enzymatic concentration of omega-3 fatty acids from the thraustochytrid oil. The optimised lipid extraction conditions were, bead size 0.4-0.6MUm, 4500rpm, 4min of processing time at 5g biomass concentration. The maximum lipid yield (% dry weight basis) achieved at optimum conditions were 40.5% for Schizochytrium sp. S31 (ATCC) and 49.4% for Schizochytrium sp. DT3 (in-house isolate). DT3 oil contained 39.8% docosahexaenoic acid (DHA) as a percentage of lipid, a higher DHA percentage than S31. Partial hydrolysis of DT3 oil using Candida rugosa lipase was performed to enrich omega-3 polyunsaturated fatty acids (PUFAs) in the glyceride portion. Total omega-3 fatty acid content was increased to 88.7%. PMID- 26519699 TI - Is the continuous two-stage anaerobic digestion process well suited for all substrates? AB - Two-stage anaerobic digestion systems are often considered to be advantageous compared to one-stage processes. Although process conditions and fermenter setups are well examined, overall substrate degradation in these systems is controversially discussed. Therefore, the aim of this study was to investigate how substrates with different fibre and sugar contents (hay/straw, maize silage, sugar beet) influence the degradation rate and methane production. Intermediates and gas compositions, as well as methane yields and VS-degradation degrees were recorded. The sugar beet substrate lead to a higher pH-value drop 5.67 in the acidification reactor, which resulted in a six time higher hydrogen production in comparison to the hay/straw substrate (pH-value drop 5.34). As the achieved yields in the two-stage system showed a difference of 70.6% for the hay/straw substrate, and only 7.8% for the sugar beet substrate. Therefore two-stage systems seem to be only recommendable for digesting sugar rich substrates. PMID- 26519700 TI - Laccase-syringaldehyde-mediated degradation of trace organic contaminants in an enzymatic membrane reactor: Removal efficiency and effluent toxicity. AB - Redox-mediators such as syringaldehyde (SA) can improve laccase-catalyzed degradation of trace organic contaminants (TrOCs) but may increase effluent toxicity. The degradation performance of 14 phenolic and 17 non-phenolic TrOCs by a continuous flow enzymatic membrane reactor (EMR) at different TrOC and SA loadings was assessed. A specific emphasis was placed on the investigation of the toxicity of the enzyme (laccase), SA, TrOCs and the treated effluent. Batch tests demonstrated significant individual and interactive toxicity of the laccase and SA preparations. Reduced removal of resistant TrOCs by the EMR was observed for dosages over 50MUg/L. SA addition at a concentration of 10MUM significantly improved TrOC removal, but no removal improvement was observed at the elevated SA concentrations of 50 and 100MUM. The treated effluent showed significant toxicity at SA concentrations beyond 10MUM, providing further evidence that higher dosage of SA must be avoided. PMID- 26519701 TI - Recovery of nitrogen and water from landfill leachate by a microbial electrolysis cell-forward osmosis system. AB - A microbial electrolysis cell (MEC)-forward osmosis (FO) system was previously reported for recovering ammonium and water from synthetic solutions, and here it has been advanced with treating landfill leachate. In the MEC, 65.7+/-9.1% of ammonium could be recovered in the presence of cathode aeration. Without aeration, the MEC could remove 54.1+/-10.9% of ammonium from the leachate, but little ammonia was recovered. With 2M NH4HCO3 as the draw solution, the FO process achieved 51% water recovery from the MEC anode effluent in 3.5-h operation, higher than that from the raw leachate. The recovered ammonia was used as a draw solute in the FO for successful water recovery from the treated leachate. Despite the challenges with treating returning solution from the FO, this MEC-FO system has demonstrated the potential for resource recovery from wastes, and provide a new solution for sustainable leachate management. PMID- 26519702 TI - Heterotrophic nitrification and aerobic denitrification by Pseudomonas tolaasii Y 11 without nitrite accumulation during nitrogen conversion. AB - A hypothermia aerobic nitrite-denitrifying bacterium, Pseudomonas tolaasii strain Y-11, was found to display high removal capabilities for heterotrophic nitrification with ammonium and for aerobic denitrification with nitrate or nitrite nitrogen. When strain Y-11 was cultivated for 4days at 15 degrees C with the initial ammonium, nitrate and nitrite nitrogen concentrations of 209.62, 204.61 and 204.33mg/L (pH 7.2), the ammonium, nitrate and nitrite removal efficiencies were 93.6%, 93.5% and 81.9% without nitrite accumulation, and the corresponding removal rates reached as high as 2.04, 1.99 and 1.74mg/L/h, respectively. Additionally, ammonium was removed mainly during the simultaneous nitrification and denitrification process. All results demonstrate that P. tolaasii strain Y-11 has the particularity to remove ammonium, nitrate and nitrite nitrogen at low temperatures, which guarantees it for future application in winter wastewater treatment. PMID- 26519704 TI - Water and Sanitation for Development: High time for a Sanitary Awakening. PMID- 26519703 TI - Production, extraction and stabilization of lutein from microalga Chlorella sorokiniana MB-1. AB - The efficiencies of extraction and preservation of lutein from microalgae are critical for the success of its commercialization. In this study, lutein was produced by Chlorella sorokiniana MB-1 via semi-batch mixotrophic cultivation. The microalgal biomass with a lutein content of 5.21mg/g was pretreated by bead beating and high pressure cell disruption methods, and the lutein content was harvested by a reduced pressure extraction method. The effect of pretreatment, pressure, solvent type, extraction time and temperature on lutein recovery was investigated. Using high pressure pretreatment followed by extraction with tetrahydrofuran (THF) as solvent resulted in high lutein recovery efficiencies of 87.0% (20min) and 99.5% (40min) at 850mbar and 25 degrees C. In contrast, using ethanol as the solvent, 86.2% lutein recovery was achieved under 450mbar, 35 degrees C and 40min extraction. The extracted lutein was stabilized in olive oil or sunflower oil with half-lives of 53.1 and 63.8days, respectively. PMID- 26519705 TI - Placental Transfusion Improves Iron Stores at 6 Weeks of Age in Late Preterm Infants. PMID- 26519706 TI - Delayed Cord Clamping and Umbilical Cord Milking at Birth. PMID- 26519707 TI - Shift From PMTCT Program to ART Program. PMID- 26519708 TI - Umbilical Cord Milking and Hematological Parameters in Moderate to Late Preterm Neonates: A Randomized Controlled Trial. AB - OBJECTIVE: To investigate the effect of umbilical cord milking on hematological parameters at 6 weeks of age in late preterm neonates. DESIGN: Randomized controlled trial. SETTING: A tertiary care center of Northern India during 2013 14. PARTICIPANTS: 200 moderate to late preterm neonates randomly allocated to early cord clamping or umbilical cord milking group (100 in each). INTERVENTION: In milking group, 25 cm length of cord was milked towards the baby thrice after separating (within 30 s) it from placenta. MAIN OUTCOME MEASURES: Hemoglobin and serum ferritin at 6 weeks of age. RESULTS: Mean (SD) serum ferritin [428.9 (217.6) vs. 237.5 (118.6) ng/mL; P< 0.01] and hemoglobin [12.1 (1.5) vs. 10.4 (1.2) gm/dL; P<0.01] at 6 weeks were significantly higher in umbilical cord milking group. In early neonatal period, hemodynamic and hematological parameters were not significantly different. Higher incidence of jaundice with higher phototherapy rates (33% vs. 9%; P<0.01) were noted in umbilical cord milking group. CONCLUSIONS: In preterm neonates, umbilical cord milking at birth enhances iron stores at 6 weeks of age. Higher phototherapy rates with this intervention are a matter of concern. PMID- 26519710 TI - Pre exchange Albumin Administration in Neonates with Hyperbilirubinemia: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the efficacy of pre-exchange transfusion albumin priming in neonates with non-hemolytic hyperbilirubinemia. DESIGN: Single center, randomized controlled trial. SETTING: Level III Neonatal unit. PARTICIPANTS: Fifty healthy term and late preterm neonates with non-hemolytic hyperbilirubinemia requiring exchange transfusion. INTERVENTIONS: 5 mL/kg of either 20% human albumin (n=23) or 0.9% saline (n=27) infusion one hour prior to exchange transfusion. MAIN OUTCOME MEASURE: Post-exchange transfusion phototherapy duration. RESULTS: The post-exchange transfusion phototherapy duration was not different between albumin and saline groups [Median (IQR): 29 (24-48) h vs. 33 (24-43) h; P=0.76]. The total amount of bilirubin removed during exchange transfusion was also similar [Median (IQR): 34 (28-46) mg vs. 33 (27-38) mg; P=0.46]. Serial changes in total serum bilirubin following exchange transfusion and need for repeat exchange transfusion were comparable between the groups. CONCLUSIONS: In healthy late preterm and term neonates with non-hemolytic hyperbilirubinemia, priming with 1 g/kg of 20% albumin prior to exchange transfusion is not superior to equi-volume 0.9% saline in reducing post- exchange transfusion phototherapy duration or amount of bilirubin mass removed. PMID- 26519709 TI - Outcome of Prevention of Parent-to-Child Transmission of HIV in an Urban Population in Southern India. AB - OBJECTIVE: To analyze the outcomes of Prevention of Parent to Child Transmission (PPTCT) of HIV program in an urban Southern Indian setting. DESIGN: Observational study. SETTING: Anti-retroviral Therapy (ART) Centers/ Integrated Counseling and Testing Centers (ICTC) at four government Obstetrics Institutes in an urban area. PARTICIPANTS: 100 HIV-positive pregnant women and their infants delivered in the study centers. METHODS: Triple drug ART to HIV-positive pregnant women was started for maternal indications only. Rest of the pregnant women were given single dose Nevirapine (200 mg) at the onset of labor. All infants were given single dose Nevirapine (2 mg/kg) prophylaxis, according to National AIDS Control Organization guidelines. Mothers were counseled regarding breastfeeding and artificial feeding, and the choice was left to them. Whole blood HIV 1 DNA PCR was done for all infants at 6 weeks of life. A second PCR was done at 6 months or 6 weeks after stopping breastfeeds. PCR-positive infants were started on ART, and were followed-up till18 months of life. RESULTS: Four infants were PCR-positive for HIV. All of them were breastfed. They were born to mothers of HIV stage 1 or 2 who were not on ART as CD4 counts were >350 cells/mm3. Among the mothers in Stage 3 or 4 or CD4 count <200 cells/mm3 and on ART, none of the infants was HIV positive. The cumulative HIV-free survival at 18 months was 94%. CONCLUSIONS: Parent-to-child transmission rate in HIV was low with the currently used strategies. Triple drug ART to mother reduces mother-to-child transmission despite advanced maternal stage or low CD4 counts. PMID- 26519711 TI - Pulse Oximetry Screening to Detect Cyanotic Congenital Heart Disease in Sick Neonates in a Neonatal Intensive Care Unit. AB - OBJECTIVE: To evaluate pulse oximetry for detection of congenital cyanotic heart disease in sick neonates using echocardiography as gold standard. METHODS: Pulse oximetry readings were taken at admission from 950 neonates from right upper limb and either foot with infant breathing room air. Pulse oximetry was considered abnormal if oxygen saturation at room air measured <90% or difference between right hand and foot was more than 3%. Persistent abnormality was considered positive result. Echocardiography was performed on all neonates with positive pulse oximetry (study group) and on one subsequent neonate with negative screen for each neonate with positive screen (controls). RESULTS: Pulse oximetry was positive in 210 neonates. It detected 20 out of 21 (95.2%) true positives. The sensitivity, specificity, positive predictive value, negative predictive value and odds ratio (95% CI) of pulse oximetry was 95.2%, 52.4%, 9.5, 99.5 and 22 (5.3, 91.4), respectively. CONCLUSION: Pulse oximetry screening is useful in detecting cyanotic heart diseases in sick newborns. PMID- 26519712 TI - Waist-to-Height Ratio as an Indicator of High Blood Pressure in Urban Indian School Children. AB - OBJECTIVE: To examine the utility of waist-to-height ratio to identify risk of high blood pressure when compared to body mass index and waist circumference in South Indian urban school children. DESIGN: Secondary data analysis from a cross sectional study. SETTING: Urban schools around Bangalore, India. PARTICIPANTS: 1913 children (58.1% males) aged 6-16 years with no prior history of chronic illness (PEACH study). METHODS: Height, weight, waist circumference and of blood pressure were measured. Children with blood pressure ?90th percentile of age-, sex-, and height-adjusted standards were labelled as having high blood pressure. RESULTS: 13.9% had a high waist-to-height ratio, 15.1% were overweight /obese and 21.7% had high waist circumference. High obesity indicators were associated with an increased risk of high blood pressure. The adjusted risk ratios (95% CI) of high systolic blood pressure with waist-to-height ratio, body mass index and waist circumference were 2.48 (1.76, 3.47), 2.59 (1.66, 4.04) and 2.38 (1.74, 3.26), respectively. Similar results were seen with high diastolic blood pressure. CONCLUSION: Obesity indicators, especially waist-to-height ratio due to its ease of measurement, can be useful initial screening tools for risk of high blood pressure in urban Indian school children. PMID- 26519713 TI - Overweight and Obesity among Adolescents, A Comparative Study Between Government and Private Schools. AB - OBJECTIVE: To compare prevalence of overweight/obesity among adolescent school children of government and private schools. METHODS: A school-based cross sectional study was conducted in 1800 children aged 10-16 years. Body mass index (BMI), Waist circumference (WC), Hip circumference (HC), and Neck circumference (NC) were measured using standard guidelines. RESULTS: The prevalence of overweight obesity was 27.8% (private schools 45.2%, government schools 10.5%). BMI, WC, NC, and Waist-hip ratio were significantly higher among private school students. CONCLUSION: A differential strategic plan may be needed to prevent and control obesity among adolescent school children. PMID- 26519714 TI - Ocular Morbidity among Students in Relation to Classroom Illumination Levels. AB - OBJECTIVE: This cross-sectional study was done to find the prevalence of eye strain and other ocular morbidities among students in Udupi, Karnataka. METHODS: The study protocol included interview, visual acuity examination using Snellen chart, and measuring classroom illumination through lux meter. RESULTS: 26% students had visual morbidity and the most prevalent symptoms of eyestrain were headache (38.6%), watering of eyes (25.7%), pain around eyes (15.6%) and blurred vision (11.9%). 55.5% classrooms and 88.4% blackboards did not have proper illumination. CONCLUSION: Low classroom illumination levels may be a possible factor for development of visual morbidity. PMID- 26519715 TI - Teaching and Assessing Clinical Reasoning Skills. AB - Clinical reasoning is a core competency expected to be acquired by all clinicians. It is the ability to integrate and apply different types of knowledge, weigh evidence critically and reflect upon the process used to arrive at a diagnosis. Problems with clinical reasoning often occur because of inadequate knowledge, flaws in data gathering and improper approach to information processing. Some of the educational strategies which can be used to encourage acquisition of clinical reasoning skills are: exposure to a wide variety of clinical cases, activation of previous knowledge, development of illness scripts, sharing expert strategies to arrive at a diagnosis, forcing students to prioritize differential diagnoses; and encouraging reflection, metacognition, deliberate practice and availability of formative feedback. Assessment of clinical reasoning abilities should be done throughout the training course in diverse settings. Use of scenario based multiple choice questions, key feature test and script concordance test are some ways of theoretically assessing clinical reasoning ability. In the clinical setting, these skills can be tested in most forms of workplace based assessment. We recommend that clinical reasoning must be taught at all levels of medical training as it improves clinician performance and reduces cognitive errors. PMID- 26519716 TI - Hereditary Multiple Exostoses, A Tale of 50 years. PMID- 26519717 TI - Maternal Mild Thyroid Insufficiency and Risk of Attention Deficit Hyperactivity Disorder: Evidence-based Medicine Viewpoint. PMID- 26519720 TI - Multiple Pituitary Hormone Deficiency, Empty Sella and Ectopic Neurohypophysis in Turner Syndrome. AB - BACKGROUND: Multiple pituitary hormone deficiency and Turner syndrome have overlapping features in peripubertal girls and is a diagnostic challenge. CASE CHARACTERISTICS: 16-year-old girl having Turner phenotype undergoing evaluation for severe short stature and pubertal arrest. OBSERVATION: 45,X karyotype, and multiple pituitary hormone deficiency with empty sella. INTERVENTION: Levothyroxine, growth hormone and ethinyl-estradiol replacement resulted in 11 cm height gain with attainment of puberty over 2 years. MESSAGE: Patients of Turner syndrome with height <3rd percentile (Turner specific charts) warrant additional pathology evaluation. PMID- 26519721 TI - Novel Mutations in a Patient with Triple A Syndrome. AB - BACKGROUND: Triple A syndrome (Allgrove syndrome), a rare autosomal recessive disorder, is characterized by adrenal insufficiency, achalasia cardia and alacrimia. It is caused by mutations in AAAS gene which encodes a protein called ALADIN. CASE CHARACTERISTICS: 8-year-old boy who presented with hypoglycemic seizures, dysphagia, dry eyes and hyperpigmentation. Investigations confirmed achalasia cardia and adrenal insufficiency. Sequencing of AAAS gene revealed two novel mutations in compound heterozygous state (c.1101delG/ c.1310_1311delCT). OUTCOME: Patient was managed with hydrocortisone and artificial tears. MESSAGE: Sequencing analysis should be done to confirm the diagnosis of clinically suspected Triple A syndrome. PMID- 26519722 TI - Serum Copeptin Level as a Predictor of Outcome in Pneumonia. AB - This cross-sectional study included 41 children (age 2 mo-12 y) with pneumonia and 40 healthy controls. Assay of serum copeptin was done using ELISA. Median serum copeptin levels were significantly higher (P=0.03) in children with pneumonia, and in those who died (P=0.04). We conclude that serum copeptin levels seem to be associated with poor outcome in pneumonia. PMID- 26519723 TI - Screening for Thalassemia Carrier Status in Pregnancy and Pre-Natal Diagnosis. AB - This hospital-based study reports the results of antenatal screening for thalassemia in pregnant women visiting a hospital in Jodhpur, Rajasthan, India. Eighty-eight (5.9%) of 1500 women screened for thalassemia had thalassemia trait. Twenty at-risk couples were identified and two fetuses were detected to be having thalassemia major. PMID- 26519724 TI - HIV Status Non-disclosure in HIV-infected Families. PMID- 26519725 TI - HIV Status Non-disclosure: Authors Reply. PMID- 26519726 TI - Trisomy 8 Mosaicism in a Boy with Dysmorphic Features. PMID- 26519727 TI - Predictors of Survival in Children with Methymalonic Acidemia with Homocystinuria. PMID- 26519728 TI - Lactococcus garvieae: An Emerging Pathogen. PMID- 26519729 TI - New function of exonuclease and highly sensitive label-free colorimetric DNA detection. AB - Enzymatic manipulation and modulation of nucleic acids are a central part of cellular function, protection, and reproduction, while rapid and accurate detection of ultralow amount of nucleic acids remains a major challenge in molecular biology research and clinic diagnosis of genetic diseases. Herein, we reported that exonuclease III can degrade the G-quadruplex structure, indicating the new exonuclease's function. Basing on the function of exonuclease III, a novel G-quadruplex-hemin DNAzyme-based colorimetric detection of tumor suppressor gene p53 was successfully developed. Although only one oligonucleotide probe was involved, the sensing strategy could suppress the optical background and achieve an efficient G-quadruplex-hemin DNAzyme-based signal amplification. Specifically, a label-free functional nucleic acid probe (called THzyme probe) was designed via introducing target DNA probe-contained hairpin structure into G-quadruplex DNAzyme. Even if this probe can fold into G-quadruplex structure in the presence of hemin very different from the double-stranded DNA, it is easily degraded by exonuclease III. Thus, no change in UV-vis absorption intensity is detected in the absence of target DNA. However, the hybridization of target DNA can protect the integrity and catalytic activity of THzyme probe, producing the DNAzyme amplified colorimetric signal. As a result, the p53 gene was able to be detected down to 1.0 pM (final concentration in the signal-generating solution: 50.0 fM) and mismatched target DNAs were easily distinguished. It is expected that this simple sensing methodology for DNA detection can find its utility in point-of care applications. PMID- 26519730 TI - Quorum sensing signals affect spoilage of refrigerated large yellow croaker (Pseudosciaena crocea) by Shewanella baltica. AB - In this work we investigated the specific spoilage organism (SSO) of large yellow croaker (Pseudosciaena crocea) stored at 4 degrees C and role of quorum sensing (QS) system of SSO isolated from the spoiled fish. According to microbial count and 16S rRNA gene of the isolated pure strains, Shewanella, mainly Shewanella baltica and Shewanella putrefaciens, was predominant genera at the end of shelf life of P. crocea. Among Shewanella isolates, S.baltica02 was demonstrated as SSO in spoilage potential characteristics by inoculation into sterile fish juice using sensory and chemical analyses. Autoinducer 2 and two cyclic dipeptides (DKPs) including cyclo-(l-Pro-l-Leu) and cyclo-(l-Pro-l-Phe), no any AHLs, were detected in cell-free S. baltica culture. Interestingly, S.baltica02 had the highest QS activity among three spoilers of S. baltica. The production of biofilm, trimethylamines (TMA) and putrescine in these spoilers significantly increased in the presence of cyclo-(l-Pro-l-Leu), rather than cyclo-(l-Pro-l-Phe) and 4,5-dihydroxy-2,3-pentanedione (the AI-2 precursor, DPD). In accordance with the effect of signal molecules on the spoilage phenotype, exposure to exogenous cyclo-(l-Pro-l-Leu) was also showed to up-regulate the transcription levels of luxR, torA and ODC, and no effect of luxS indicated that S. baltica could sense cyclo-(l-Pro-l-Leu). In the fish homogenate, exogenous cyclo-(l-Pro-l-Leu) shortened lag phase durations and enhanced growth rates of the dominant bacteria, H2S producing bacteria, under refrigerated storage, while exogenous DPD retarded growth of competing bacteria, such as Enterobacteriaceae. Meanwhile, cyclo-(l-Pro l-Leu) also promoted the accumulation of metabolites on the spoilage process of homogenate. S.baltica02 luxS mutant preliminarily proved that AI-2 might not play a signaling role in the spoilage. The present study suggested that the spoilage potential of S. baltica in P. crocea might be regulated by DKP-based quorum sensing. PMID- 26519731 TI - Lidocaine induces ROCK-dependent membrane blebbing and subsequent cell death in rabbit articular chondrocytes. AB - Local anesthetics are administered intraarticularly for pain control in orthopedic clinics and surgeries. Although previous studies have shown that local anesthetics can be toxic to chondrocytes, the underlying cellular mechanisms remain unclear. The present study investigates acute cellular responses associated with lidocaine-induced toxicity to articular chondrocytes. Rabbit articular chondrocytes were exposed to lidocaine and their morphological changes were monitored with live cell microscopy. The viability of chondrocytes was evaluated using a fluorescence based LIVE/DEAD assay. Acute treatment of chondrocytes with lidocaine (3-30 mM) induced spherical protrusions on the cell surface (so called "membrane blebbing") in a time- and concentration-dependent manner. The concentration-response relationship for the lidocaine effect was shifted leftward by elevating extracellular pH, as expected for the non-ionized lidocaine being involved in the bleb formation. ROCK (Rho-kinase) inhibitors Y 27632 and fasudil completely prevented the lidocaine-induced membrane blebbing, suggesting that ROCK activation is required for bleb formation. Caspase-3 levels were unchanged by 10 mM lidocaine (p = 0.325) and a caspase inhibitor z-VAD-fmk did not affect the lidocaine-induced blebbing (p = 0.964). GTP-RhoA levels were significantly increased (p < 0.001), but Rho inhibitor-1 failed to suppress the membrane blebbing (p = 0.875). Lidocaine (30 mM) reduced the cell viability of isolated chondrocytes (p < 0.001) and in situ chondrocytes (p < 0.001). The chondrotoxicity was attenuated by pretreatment of cells with ROCK inhibitors or a myosin-II inhibitor blebbistatin (p < 0.001). These findings suggest that lidocaine induces ROCK-dependent membrane blebbing and thereby produces a cytotoxic effect on chondrocytes. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:754-762, 2016. PMID- 26519732 TI - A quantitative study of susceptibility and additional frequency shift of three common materials in MRI. AB - PURPOSE: This work quantifies magnetic susceptibilities and additional frequency shifts derived from different samples. METHODS: Twenty samples inside long straws were imaged with a multiecho susceptibility weighted imaging and analyzed with two approaches for comparisons. One approach applied our complex image summation around a spherical or cylindrical object method to phase distributions outside straws. The other approach utilized phase values inside each straw from two orientations. Both methods quantified susceptibilities of each sample at each echo time. The R2* value of each sample was measured too. Uncertainty of each measurement was also estimated. RESULTS: Quantified susceptibilities from complex image summation around a spherical or cylindrical object are consistent within uncertainties between different echo times. However, this is not the case for the other method. Nonetheless, most quantified susceptibilities are consistent between these two methods. Phase values due to additional frequency shifts in some of ferritin and nanoparticle samples have been identified. Only R2* values quantified from low concentration nanoparticle samples agree with the predictions from the static dephasing theory. CONCLUSION: This work suggests that using the sample sizes and phase values only outside samples can correctly quantify the susceptibilities of those samples. With the presence of a possible additional frequency shift inside a material, it will not be suitable to obtain susceptibility maps without taking that into account. Magn Reson Med 76:1263 1269, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26519733 TI - Resolving dual binding conformations of cellulosome cohesin-dockerin complexes using single-molecule force spectroscopy. AB - Receptor-ligand pairs are ordinarily thought to interact through a lock and key mechanism, where a unique molecular conformation is formed upon binding. Contrary to this paradigm, cellulosomal cohesin-dockerin (Coh-Doc) pairs are believed to interact through redundant dual binding modes consisting of two distinct conformations. Here, we combined site-directed mutagenesis and single-molecule force spectroscopy (SMFS) to study the unbinding of Coh:Doc complexes under force. We designed Doc mutations to knock out each binding mode, and compared their single-molecule unfolding patterns as they were dissociated from Coh using an atomic force microscope (AFM) cantilever. Although average bulk measurements were unable to resolve the differences in Doc binding modes due to the similarity of the interactions, with a single-molecule method we were able to discriminate the two modes based on distinct differences in their mechanical properties. We conclude that under native conditions wild-type Doc from Clostridium thermocellum exocellulase Cel48S populates both binding modes with similar probabilities. Given the vast number of Doc domains with predicted dual binding modes across multiple bacterial species, our approach opens up new possibilities for understanding assembly and catalytic properties of a broad range of multi-enzyme complexes. PMID- 26519734 TI - Non-classical amine recognition evolved in a large clade of olfactory receptors. AB - Biogenic amines are important signaling molecules, and the structural basis for their recognition by G Protein-Coupled Receptors (GPCRs) is well understood. Amines are also potent odors, with some activating olfactory trace amine associated receptors (TAARs). Here, we report that teleost TAARs evolved a new way to recognize amines in a non-classical orientation. Chemical screens de orphaned eleven zebrafish TAARs, with agonists including serotonin, histamine, tryptamine, 2-phenylethylamine, putrescine, and agmatine. Receptors from different clades contact ligands through aspartates on transmembrane alpha helices III (canonical Asp(3.32)) or V (non-canonical Asp(5.42)), and diamine receptors contain both aspartates. Non-classical monoamine recognition evolved in two steps: an ancestral TAAR acquired Asp(5.42), gaining diamine sensitivity, and subsequently lost Asp(3.32). Through this transformation, the fish olfactory system dramatically expanded its capacity to detect amines, ecologically significant aquatic odors. The evolution of a second, alternative solution for amine detection by olfactory receptors highlights the tremendous structural versatility intrinsic to GPCRs. PMID- 26519735 TI - Childhood injury after a parental cancer diagnosis. AB - A parental cancer diagnosis is psychologically straining for the whole family. We investigated whether a parental cancer diagnosis is associated with a higher-than expected risk of injury among children by using a Swedish nationwide register based cohort study. Compared to children without parental cancer, children with parental cancer had a higher rate of hospital contact for injury during the first year after parental cancer diagnosis (hazard ratio [HR] = 1.27, 95% confidence interval [CI] = 1.22-1.33), especially when the parent had a comorbid psychiatric disorder after cancer diagnosis (HR = 1.41, 95% CI = 1.08-1.85). The rate increment declined during the second and third year after parental cancer diagnosis (HR = 1.10, 95% CI = 1.07-1.14) and became null afterwards (HR = 1.01, 95% CI = 0.99-1.03). Children with parental cancer also had a higher rate of repeated injuries than the other children (HR = 1.13, 95% CI = 1.12-1.15). Given the high rate of injury among children in the general population, our findings may have important public health implications. PMID- 26519736 TI - Mapping of the cumulative beta-ray dose on the ground surface surrounding the Fukushima area. AB - A large amount of the fission products released by the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident on 11 March 2011 was deposited in a wide area from Tohoku to northern Kanto. A map of the estimated cumulative beta-ray dose (70 MUm dose equivalent) on the soil surface for one year after the FDNPP accident has been prepared using previously reported calculation methods and the 2-km mesh survey data by MEXT. From this map of estimated dose, areas with a high cumulative beta-ray dose on the soil surface for one year after the FDNPP accident were found to be located in the Akogi-Teshichiro to Akogi-Kunugidaira region in Namie Town, and in the southern Futaba Town to the northern Tomioka Town region. The highest estimated cumulative beta-ray dose was 710 mSv for one year at Akogi-Teshichiro, Namie Town. PMID- 26519737 TI - Sequence and structure analysis of a mirror tRNA located upstream of the cytochrome oxidase I mRNA in mouse mitochondria. AB - RNA fragments corresponding to the mirror tRNA that is located upstream of the cytochrome oxidase I (COXI) gene in the mouse mitochondrial genome were found in the sequences obtained from the mouse brain by the next generation sequencing. RNA fragments corresponding to the 5' terminal of COXI mRNA were also found and it was suggested that the precursor of the COXI mRNA is processed at three residues upstream of the first AUG codon. The mirror tRNA fragment has poly(A) in its 3' terminal and variable 5' terminal, suggesting that this RNA is produced during the 5' processing of COXI mRNA. Secondary structure prediction and NMR analysis indicated that the mirror tRNA is folded into a tRNA-like secondary structure, suggesting that the tRNA-like conformation of the 5' adjacent sequence of COXI mRNA is involved in the COXI mRNA maturation in the mouse mitochondria. PMID- 26519738 TI - Possible role of a histidine residue in the substrate specificity of yeast d aspartate oxidase. AB - D-Aspartate oxidase (DDO) catalyzes the oxidative deamination of acidic D-amino acids, whereas neutral and basic D-amino acids are substrates of D-amino acid oxidase (DAO). DDO of the yeast Cryptococcus humicola (ChDDO) has much higher substrate specificity to D-aspartate, but the structural features that confer this specificity have not been elucidated. A three-dimensional model of ChDDO suggested that a histidine residue (His56) in the active site might be involved in the unique substrate specificity, possibly through the interaction with the substrate side chain in the active site. His56 mutants with several different amino acid residues (H56A, H56D, H56F, H56K and H56N) exhibited no significant activity toward acidic D-amino acids, but H56A and H56N mutants gained the ability to utilize neutral D-amino acids as substrates, such as D-methionine, D phenylalanine and D-glutamine, showing the conversion of ChDDO to DAO by these mutations. This conversion was also demonstrated by the sensitivity of these mutants to competitive inhibitors of DAO. These results and kinetic properties of the mutants show that His56 is involved in the substrate specificity of ChDDO and possibly plays a role in the higher substrate specificity toward D-aspartate. PMID- 26519739 TI - Different spatial distributions of brain metastases from lung cancer by histological subtype and mutation status of epidermal growth factor receptor. AB - BACKGROUND: The purpose of this study was to test the hypothesis that the genetic backgrounds of lung cancers could affect the spatial distribution of brain metastases. METHODS: CT or MR images of 200 patients with a total of 1033 treatment-naive brain metastases from lung cancer were retrospectively reviewed (23 by CT and 177 by MRI). All images were standardized to the human brain MRI atlas provided by the Montreal Neurological Institute 152 database. Locations, depths from the brain surface, and sizes of the lesions after image standardization were analyzed. RESULTS: The posterior fossa, the anatomic "watershed areas," and the gray-white matter junction were confirmed to be more commonly affected by lung cancer brain metastases, and brain metastases with epidermal growth factor receptor (EGFR) L858R mutation occurred more often in the caudate, cerebellum, and temporal lobe than those with exon 19 deletion of EGFR. Median depths of the lesions from the brain surface were 13.7 mm (range, 8.6 21.9) for exon 19 deleted EGFR, 11.5 mm (6.6-16.8) for L858R mutated, and 15.0 mm (10.0-20.7) for wild-type EGFR. Lesions with L858R mutated EGFR were located significantly closer to the brain surface than lesions with exon 19 deleted or wild-type EGFR (P = .0032 and P < .0001, respectively). Furthermore, brain metastases of adenocarcinoma lung cancer patients with a history of chemotherapy but not molecular targeted therapy were located significantly deeper from the brain surface (P = .0002). CONCLUSION: This analysis is the first to reveal the relationship between EGFR mutation status and the spatial distribution of brain metastases of lung cancer. PMID- 26519741 TI - The effect of ultrafiltration with cardiopulmonary bypass on the removal of dabigatran from the circulation of adult pigs. AB - OBJECTIVE: Dabigatran etexilate is a direct thrombin inhibitor approved for use in patients with non-valvular atrial fibrillation. There is no currently available pharmacological therapy to reverse this renally cleared anticoagulant. Dabigatran has a low level of plasma protein binding and has been considered dialyzable. We used a pig model with renal artery ligation to exclude intrinsic drug excretion to examine the efficacy of ultrafiltration (UF) during cardiopulmonary bypass (CPB) for dabigatran removal. METHOD: Dabigatran was intravenously infused (20 mg) in Yorkshire pigs (male, n=7, 70+/-1 kg) following renal artery ligation. CPB with UF was initiated after heparinization and continued until a total volume of 6 liters of UF effluent was removed. Serial labs, including dabigatran concentration, activated coagulation times (ACT), hematocrit and creatinine were drawn at intervals before the start of CPB and then incrementally during UF (0, 2, 4 and 6 L removed). Hemodialysis (HD) was performed on one animal following UF. RESULTS: Dabigatran concentration (ng/mL) rose from undetectable levels at baseline to 296+/-70 (p<0.05) at the conclusion of infusion, but dropped significantly upon administration of heparin (178+/-40, p<0.05). A further decrement in dabigatran concentration was observed from the administration of heparin to the start of CPB (to 135+/-28, p<0.05). Once on CPB, dabigatran remained stable, with the end UF (eUF) dabigatran concentration being 133+/-34. Dabigatran concentration in the UF effluent was measured in one animal and was 98.8, with 6 L of effluent having been removed. The total recovery of dabigatran was calculated to be less than 5%. Dabigatran concentrations also did not decrease appreciably with HD on CPB following UF. CONCLUSIONS: UF in conjunction with CPB was ineffective at removing dabigatran. Heparin demonstrated a dabigatran-lowering effect, suggesting a possible drug interaction or assay impairment. Based on these findings, emergent cardiac surgery with UF on cardiopulmonary bypass to remove dabigatran is not advisable. Alternative forms of drug removal or reversal must be identified. PMID- 26519740 TI - MRI contrast agent for targeting glioma: interleukin-13 labeled liposome encapsulating gadolinium-DTPA. AB - BACKGROUND: Detection of glioma with MRI contrast agent is limited to cases in which the blood-brain barrier (BBB) is compromised as contrast agents cannot cross the BBB. Thus, an early-stage infiltrating tumor is not detectable. Interleukin-13 receptor alpha 2 (IL-13Ralpha2), which has been shown to be overexpressed in glioma, can be used as a target moiety. We hypothesized that liposomes conjugated with IL-13 and encapsulating MRI contrast agent are capable of passing through an intact BBB and producing MRI contrast with greater sensitivity. METHODS: The targeted MRI contrast agent was created by encapsulating Magnevist (Gd-DTPA) into liposomes conjugated with IL-13 and characterized by particle size distribution, cytotoxicity, and MRI relaxivity. MR image intensity was evaluated in the brain in normal mice post injection of Gd DTPA and IL-13-liposome-Gd-DTPA one day apart. The specificity for glioma detection by IL-13-liposome-Gd-DTPA was demonstrated in an intracranial glioma mouse model and validated histologically. RESULTS: The average size of IL-13 liposome-Gd-DTPA was 137 +/- 43 nm with relaxivity of 4.0 +/- 0.4 L/mmole-s at 7 Tesla. No significant cytotoxicity was observed with MTS assay and serum chemistry in mice. The MRI signal intensity was enhanced up to 15% post injection of IL-13-liposome-Gd-DTPA in normal brain tissue following a similar time course as that for the pituitary gland outside of the BBB. MRI enhanced by IL-13 liposome-Gd-DTPA detected small tumor masses in addition to those seen with Magnevist-enhanced MRI. CONCLUSIONS: IL-13-liposome-Gd-DTPA is able to pass through the uncompromised BBB and detect an early stage glioma that cannot be seen with conventional contrast-enhanced MRI. PMID- 26519742 TI - Use of PTFE patch for pericardial closure after minimal invasive LVAD implantation. AB - The left ventricular assist device (LVAD) is now a routine therapy for advanced heart failure. The thoracotomy approach for LVAD implantation, in which the left ventricle is approached through a pericardial rent, is becoming popular. We demonstrate closure of the pericardial rent with a polytetrafluoroethylene (PTFE) patch and its advantages. PMID- 26519743 TI - [Feeding the planet and global Public Health]. PMID- 26519744 TI - [The "Ice Bucket Challenge": wondering about the impact of social networks to promote public health interventions]. AB - The "Ice Bucket Challenge" was an activity launched to promote awareness of amyotrophic lateral sclerosis (ALS) and encourage donations to research for this disease. The campaign went viral on social media during July to August 2014. It consisted in nominating people and challenging them to donate 100 dollars to the ALS Association or pour a bucket of ice water over their head and post the video on the web. Participants in turn then had to challenge others to do the same. The initiative was hugely successful, involved millions of people and, just in the US, collected 35 times more money than in the same time period in 2013. We analyzed possible factors that determined the success of this initiative, to identify strengths and weaknesses of the activity and evaluate the possibility of applying the same model to promote public health interventions. Several features of the challenge were identified as strengths: the involvement of wellknown people from different contexts, the "public platform" which triggers a positive combination of competitiveness, social pressure and narcissism, the chain-letter like method of nomination, the ironic and entertaining nature of the performance. Besides these strengths, weaknesses were also identified: information spread via social media can only partially reach potential donors and supporters, due to the digital divide phenomenon which excludes people who do not have web access. Also, it is not possible to predict if the message will be long-lasting or will cease shortly after the end of the campaign. The latter could be acceptable for fund raising, where the aim is simply to collect as much money as possible, but not for a public health intervention program, whose success requires that the intended message has a long-lasting effect to produce an effective change in people's behavior. Despite the above-mentioned limits, social networks undeniably show great potential to spread messages to the community and to involve a large number of people. Their use as a complementary tool to increase the effectiveness of public health campaigns should therefore be encouraged. PMID- 26519745 TI - Efficacy of the ND:YAG laser therapy on EBV and HSV1 contamination in periodontal pockets. AB - AIM: The aim of this retrospective multicenter study was to verify the efficacy of Nd:YAG laser in the treatment of periodontal pockets infected by Epstein-Barr Virus (EBV) and Herpes Simplex Virus 1 (HSV1). METHODS: Subgingival plaque samples of 291 Italian periodontal patients were analyzed by Real Time PCR to evaluate the frequency of both viruses before and after Nd:YAG laser-assisted periodontal treatment. RESULTS: Before treatment, EBV and HSV1 were observed in 29.9% and in 3.8% of periodontal patients respectively, while co-infection with both viruses was detected in 1.7% of cases. Periodontal Nd:YAG laser treatment ("Periodontal Biological Laser-Assisted Therapy", PERIOBLAST) produced statistical significant benefits, especially in EBV periodontal infection: 78.2% of EBV positive patients became EBV-negative following treatment. CONCLUSIONS: Results of this preliminary study highlight that EBV is found in periodontal pockets more frequently than HSV1, supporting the theory of the potential role of EBV in the onset and progression of periodontal disease. Moreover, our data showed that Nd:YAG laser-assisted periodontal treatment (Perioblast) is also effective in case of viral infection, validating evidences that it represents a successful alternative approach to traditional periodontal protocols. PMID- 26519746 TI - [Survey to assess educational needs of personnel working at Departments of Prevention, Health Districts and Hospital Directions in Italy: questionnaire validation and preliminary results]. AB - AIM: The aim was of this pilot study was to validate a questionnaire to collect information on the number of health professionals, doctors and veterinarians working in the Departments of Prevention, Health Districts and Hospital Directions, their sociodemographic characteristics and cultural-background, define their educational needs, and subsequently extending the study to the maximum number of professionals in the classified services under study. METHODS: The survey was conducted through the use of a questionnaire, designed and prepared by the working group and subsequently reported on-line. Internal consistency of the questionnaire was measured by Cronbach's alpha. RESULTS: Overall, 128 health professionals were enrolled in the study. Their mean age was 57.5 years; 83.6% have a medical degree and 6.3% a degree in veterinary medicine. Most participants (64.8%) are employed by a Health District, 21.1% work in a Department of Prevention and 2.3% are part of a hospital clinical management staff. 32.3% are specialists in only one area, and, in particular, 22% of the sample is a Public Health specialist, 4% respectively are specialists in Occupational Medicine and Forensic Medicine. The alpha values for each section were, for Section A, 0.914; Section B, 0.963; Section C, 0.802; and Section D, 0.945. CONCLUSION: The questionnaire was shown to have good internal reliability. Identifying the educational needs of public health professionals, and the innovative and emerging issues that impact public health is essential to allow for National Health Service staff to be able to respond to the rapid cultural changes that characterize the current global health context. PMID- 26519747 TI - [Burden of medical errors in Italy: an analysis of the literature]. AB - INTRODUCTION: Medical malpractice and litigation have a significant impact on the Italian National Health Service. The aim of this study was to analyze the state of the art of medical errors in Italy, in particular, assessing which specialties are most affected. METHODS: We performed a literature search in PubMed, Google Scholar; institutional websites (Ministry of Health, Higher Institute of Health, National Agency for Regional Health Services, National Institute of Statistics, National Research Council, Court of Auditors), gray literature and specialized magazines. RESULTS: Results show that data regarding the frequency of medical errors and the effectiveness of prevention measures in Italy are scarce. Most papers published on this topic refer to a few specialties, including Surgery, Radiology, Cardiology, and Laboratory medicine. Surgery is the specialty most affected. CONCLUSIONS: Despite a growing attention towards patient safety and quality of healthcare, medical errors continue to occur in clinical practice. Most errors are not due to individual incompetence or negligence but they are rooted in system breakdowns. A systematic approach is therefore required, based on: an analysis of critical aspects in the system; the selection and implementation, at different levels of the system, of appropriate and evidence based risk management interventions involving all stakeholders; a context analysis to identify barriers and facilitators for change; a performance assessment to verify results and identify actions for improvement. PMID- 26519749 TI - [Validation of a questionnaire to assess consumer satisfaction with mammography screening, Rome (Italy)]. AB - Only 40% of women in the territory of the Local Health Unit RMA (Rome, Italy) adhere to the local breast cancer screening programme. A questionnaire was administered to participating women, to assess their level of satisfaction with the programme. A descriptive analysis, logistic regression and reliability analysis using the Cronbach's alpha as a measure of internal consistency, were performed. Most women who adhere to mammography screening are employers, retired, and with a low education. Factors that affect adherence include receiving a letter of invitation, intent to participate, age, and low education. The questionnaire is reliable for evaluating reasons affecting participation. PMID- 26519748 TI - [Shiga toxin-producing Escherichia coli and regulatory implications in the field of Public Health in light of recent outbreaks in Europe]. AB - The increasingly widespread habit of consuming ready-to-eat foods, especially foods not subjected to heat treatment, has contributed to the occurrence of new outbreaks of foodborne illness. In 2011, outbreaks caused by Shiga toxin producing Escherichia coli occurred in several European Union (EU) countries and this led to a legislative evolution on food safety at the EU level. This article outlines the recommendations made to ensure food safety within the food chains, especially in relation to foods potentially responsible for Escherichia coli VTEC infections, and focuses on measures adopted at EU level to ensure consumer protection. PMID- 26519750 TI - [Universal vaccination for Rotavirus infection control]. AB - Rotaviruses are the most common etiological cause for pediatric acute gastroenteritis, particularly in children under 5 years of age or immunocompromised. Since 2008, vaccination program has determined a decrease in Rotavirus-related hospitalization, outpatient's visits, emergency department visits and mortality. These indicators of illness for Rotaviruses diseases remain high in those countries where there is no access to rehydrating therapies. In Italy vaccine coverage is very low, even if the burden of RV disease is well known, and at present vaccination is offered free of charge in a single region. PMID- 26519751 TI - Segmental Mirroring: Does It Eliminate the Need for Intraoperative Readjustment of the Virtually Pre-Bent Reconstruction Plates and Is It Economically Valuable? AB - PURPOSE: The aim of this study was to compare segmental mirroring with mirroring of the entire unaffected side to determine which method obviates intraoperative readjustment of virtually planned pre-bent plates and to evaluate the effect on costs. MATERIALS AND METHODS: Patients eligible for inclusion in this prospective study had unilateral mandibular discontinuity defects. Patients were randomly divided into 2 groups. In group I, models were constructed by mirroring the entire unaffected side of the mandible at the midsagittal plane. In group II, only the resected segments were cut and replaced by the corresponding mirrored healthy segments. The lesions were resected, and their sites were reconstructed using pre-bent reconstruction plates. The need for intraoperative plate readjustment, plate placement time, operation time, and operation costs were reviewed. RESULTS: Fifty patients were enrolled in this study. All but 5 plates in group I required readjustment. In group II, plates were placed without intraoperative handling. Average operating times were 4.20 +/- 0.56 hours in group I and 3.186 +/- 0.28 hours in group II (P = .00002). Mean times for plate placement were 33.36 +/- 8.20 and 21.88 +/- 5.73 minutes in groups I and II, respectively. The difference resulted in an average time gain of 11.48 minutes. Average personal costs per minute were US$740.77 for group I and US$560.87 for group II. The difference resulted in an average saving of approximately US$179.90. CONCLUSION: Segmental mirroring is superior in reflecting the bone anatomy in 3-dimensional models, thus eliminating intraoperative plate readjustment and providing better plate adaptation with better contour. It decreases operating time and costs and thus can be recommended for lesions that do not cross the midline. PMID- 26519752 TI - Melatonin pretreatment prevents isoflurane-induced cognitive dysfunction by modulating sleep-wake rhythm in mice. AB - BACKGROUND: Sleep plays an important role in memory processing. However, its role in anesthesia-induced cognitive dysfunction was not revealed. Our study sought to investigate the connection between the cognition decline and sleep-wake rhythm disorders after long-term isoflurane anesthesia in mice. Also, we examined the effect of exogenous melatonin pretreatment on both cognitive function and circadian rhythm. Furthermore, we discussed whether NR2B (N-methyl-D-aspartate receptor 2B subunit)-CREB (cAMP-response element binding protein) signaling pathway was involved in this course. METHODS: 2-month-old male C57/BL-6J mice were submitted to long-term anesthesia using 1% isoflurane from CT (Circadian Time) 14 to CT20. Melatonin pretreatment were conducted before anesthesia for 7 Days. Intellicage for mice and Mini-Mitter were applied to monitor spatial memory and gross motor activity which can reflect cognition and sleep-wake rhythm. Messenger RNA and protein expression of right hippocampus NR2B and CREB were examined by RT-PCR and Western blot. RESULTS: 6h isoflurane anesthesia led to impaired spatial memory from Day 3 to Day 10 in mice accompanied by the disruption of sleep-wake rhythm. Meanwhile, the hippocampus CREB and NR2B expression declined in step. Melatonin pretreatment ameliorated disturbed sleep wake cycle, improved isoflurane-induced cognitive dysfunction, and reversed the down-regulation of CREB and NR2B expression. CONCLUSIONS: Our data demonstrate that sleep-wake rhythm is involved in the isoflurane-induced cognition impairment and pretreatment of melatonin has a positive effect on circadian normalization and cognition reversal. Also, NR2B-CREB signaling pathway has a critical role in this process. This study provides us a new strategy for anesthesia-induced cognitive dysfunction therapy. PMID- 26519753 TI - Evolution of myelin ultrastructure and the major structural myelin proteins. AB - Myelin sheaths, as the specialized tissue wrapping the nerve fibers in the central and peripheral nervous systems (CNS and PNS), are responsible for rapid conduction of electrical signals in these fibers. We compare the nerve myelin sheaths of different phylogenetic origins-including mammal, rodent, bird, reptile, amphibian, lungfish, teleost, and elasmobranch-with respect to periodicities and inter-membrane separations at their cytoplasmic and extracellular appositions, and correlate these structural parameters with biochemical composition. P0 glycoprotein and P0-like proteins are present in PNS of terrestrial species or land vertebrates (Tetrapod) and in CNS and PNS of aquatic species. Proteolipid protein (PLP) is a major component only in the CNS myelin of terrestrial species and is involved in compaction of the extracellular apposition. The myelin structures of aquatic garfish and lungfish, which contain P0-like protein both in CNS and PNS, are similar to those of terrestrial species, indicating that they may be transitional organisms between water and land species. This article is part of a Special Issue entitled SI: Myelin Evolution. PMID- 26519754 TI - Impact of the inflammatory microenvironment on T-cell phenotype in the progression from reflux oesophagitis to Barrett oesophagus and oesophageal adenocarcinoma. AB - The incidence of oesophageal adenocarcinoma (OAC), arising from reflux-induced Barrett oesophagus (BO), is increasing dramatically. T-cells have recently been implicated in the initiation of oesophagitis; however, their role in the progression from oesophagitis to BO and OAC has not been fully elucidated. Previous studies have examined the secreted cytokines from oesophageal tissue during disease progression but this study is the first to examine the activation phenotype and the inflammatory profile of CD4(+) and CD8(+) T-cells in human oesophagitis, BO and OAC tissue. Results demonstrated significantly higher levels of IL-4 producing CD4(+) T-cells and secreted levels of IL-6, confirming a Th2 phenotype in BO. In OAC tissue, both pro- and anti-inflammatory cytokines were secreted, with significantly higher levels of IL-6, IL-1beta, TNF-alpha, IFN gamma, IL-2 and IL-10 compared with normal oesophageal tissue. In addition, CD4(+) T-cells infiltrating OAC tissue displayed a decreased activation profile, with significantly lower CD45RO and CD69 expression compared with normal tissue. Data from this study suggest that factors in the tissue microenvironment may alter T-cell phenotype and function early during oesophageal disease progression and may represent targets for immune intervention. PMID- 26519755 TI - Human telomerase reverse transcriptase (hTERT) promotes cancer invasion by modulating cathepsin D via early growth response (EGR)-1. AB - Human telomerase reverse transcriptase (hTERT) contributes to tumor progression as well as maintaining telomere length, however, the mechanism by which hTERT promotes invasiveness is not yet completely understood. This study aims to unravel the precise mechanism through which hTERT promotes cancer invasion. We established an hTERT-overexpressed immortalized cell line (IHOK/hTERT). In orthotopic xenograft models, IHOK/hTERT harbors higher tumorigenicity than IHOK/Control. IHOK/hTERT showed much higher migration and invasion activities compared to IHOK/Control. IHOK/hTERT co-cultured with fibroblasts displayed increased invasion compared to IHOK/hTERT without fibroblasts. We screened for genes that play an important role in intermodulation between cancer cells and fibroblasts using a microarray and identified fibroblast activation protein (FAP). hTERT knockdown showed decreased expression of FAP and early growth response (EGR)-1, one of the transcriptional regulators of FAP in IHOK/hTERT and oral cancer cell line YD10B. Furthermore, EGR-1 knockdown in IHOK/hTERT and YD10B showed reduced invasion and reduced cathepsin D expression compared to Control siRNA cells. Taken together, this study provides evidence that hTERT overexpression is responsible for the upregulation of the cysteine protease cathepsin D by regulating EGR-1 to activate invasiveness in cancer progression. PMID- 26519756 TI - Expansion and functions of myeloid-derived suppressor cells in the tumor microenvironment. AB - Myeloid derived suppressor cells (MDSCs) are a group of immature myeloid cells accumulated in most cancer patients and mouse tumor models. MDSCs suppress host immune response and concurrently promote tumor angiogenesis, thereby promote tumor growth and progression. In this review, we discuss recent progresses in expansion and activity of tumor MDSCs, and describe new findings about immunosuppressive function of different subtypes of MDSCs in cancer. We also discussed tumor angiogenic activities and pro-tumor invasion/metastatic roles of MDSCs in tumor progression. PMID- 26519757 TI - Use of functional genomics to understand replication deficient poxvirus-host interactions. AB - High-throughput genomics technologies are currently being used to study a wide variety of viral infections, providing insight into which cellular genes and pathways are regulated after infection, and how these changes are related, or not, to efficient elimination of the pathogen. This article will focus on how gene expression studies of infections with non-replicative poxviruses currently used as vaccine vectors provide a global perspective of the molecular events associated with the viral infection in human cells. These high-throughput genomics approaches have the potential to lead to the identification of specific new properties of the viral vector or novel cellular targets that may aid in the development of more effective pox-derived vaccines and antivirals. PMID- 26519758 TI - Does the interaction between glucocorticoids and insulin-like growth factor 1 predict nestling fitness in a wild passerine? AB - The crucial question in evolutionary ecology is to find out how physiological traits have coevolved so animals fit their stochastic environments. The plasticity of these different physiological mechanisms is largely mediated by hormones, like glucocorticoids and insulin-like growth factor 1 (IGF-1). Brood size manipulation with nestlings of free-living great tits (Parus major) was carried out to see the way in which plasma IGF-1 and feather corticosterone, a predictor of long-term sustained plasma corticosterone level, are associated across different nutritional conditions and how this association predicts survival during the nestling phase. We showed that the association between levels of IGF-1 and corticosterone depended on physiological condition of nestlings. Namely, there was a positive association between the hormones in nestlings from the decreased broods and a negative association in nestlings from the enlarged broods. Furthermore, we showed that the interaction between levels of IGF-1 and corticosterone was also related with the survival of the nestlings. Our results suggest that signalling pathways of IGF-1 and corticosterone most likely interact with each other in a nutrition-dependent way to maximize the rate of development and survival of nestlings in their stochastic environment. PMID- 26519759 TI - Greater amberjack Fsh, Lh, and their receptors: Plasma and mRNA profiles during ovarian development. AB - To understand the endocrine regulation of ovarian development in a multiple spawning fish, the relationship between gonadotropins (Gths; follicle-stimulating hormone [Fsh] and luteinizing hormone [Lh]) and their receptors (Gthrs; Fshr and Lhr) were investigated in greater amberjack (Seriola dumerili). cDNAs encoding the Gth subunits (Fshbeta, Lhbeta, and glycoprotein alpha [Gpalpha]) and Gthrs were cloned. The in vitro reporter gene assay using recombinant hormones revealed that greater amberjack Fshr and Lhr responded strongly to their own ligands. Competitive enzyme-linked immunosorbent assays (ELISAs) were developed for measuring greater amberjack Fsh and Lh. Anti-Fsh and anti-Lh antibodies were raised against recombinant chimeric single-chain Gths consisting of greater amberjack Fshbeta (or Lhbeta) with rabbit GPalpha. The validation study showed that the ELISAs were precise (intra- and inter-assay coefficient of variation, <10%) and sensitive (detection limit of 0.2ng/ml for Fsh and 0.8ng/ml for Lh) with low cross-reactivity. A good parallelism between the standard curve and serial dilutions of greater amberjack plasma and pituitary extract were obtained. In female greater amberjack, pituitary fshb, ovarian fshr, and plasma E2 gradually increased during ovarian development, and plasma Fsh significantly increased during the post-spawning period. This suggests that Fsh plays a role throughout ovarian development and during the post-spawning period. Pituitary lhb, ovarian lhr, and plasma Lh were high during the spawning period, suggesting that the synthesis and secretion of Lh, and Lhr expression are upregulated to induce final oocyte maturation and ovulation. PMID- 26519760 TI - Cloning, mRNA expression and transcriptional regulation of five retinoid X receptor subtypes in yellow catfish Pelteobagrus fulvidraco by insulin. AB - Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily and mediate development, reproduction, homeostasis and cell differentiation processes in vertebrates. In this study, full-length cDNA sequences of five rxr subtypes from yellow catfish Pelteobagrus fulvidraco were cloned. Their mRNA expression patterns in different tissues and transcriptional regulation by insulin were determined. Five P. fulvidraco rxr (Pf-rxr) subtypes differed in the length of cDNA sequence and the open reading frame, but shared the similar domain structures as in typical nuclear receptors. Phylogenetic analysis revealed that the five Pf-rxr subtypes were paralogous genes, and that Pf-rxrbetaa and Pf rxrbetab had arisen during a teleost-specific genome duplication event. Five subtypes of Pf-rxr were detected in all the tested tissues. Overlapping and distinct expression patterns were found for different Pf-rxr subtypes, suggesting functional redundancy and divergence of these duplicates. Intraperitoneal insulin injection and incubation reduced the mRNA expression of Pf-rxrgb, but not other subtypes, in the liver and hepatocytes of P. fulvidraco, respectively, suggesting that Pf-rxrgb is the dominant rxr subtype involved in the insulin signaling pathway in P. fulvidraco. PMID- 26519761 TI - Molecular cloning, expression analysis and transcript localization of testicular orphan nuclear receptor 2 in the male catfish, Clarias batrachus. AB - Testicular receptor 2 (TR2; also known as Nr2c1) is one of the first orphan nuclear receptors identified and known to regulate various physiological process with or without any ligand. In this study, we report the cloning of full length nr2c1 and its expression analysis during gonadal development, seasonal testicular cycle and after human chorionic gonadotropin (hCG) induction. In addition, in situ hybridization (ISH) was performed to localize nr2c1 transcripts in adult testis and whole catfish (1day post hatch). Tissue distribution and gonadal ontogeny studies revealed high expression of nr2c1 in developing and adult testis. Early embryonic stage-wise expression of nr2c1 seems to emphasize its importance in cellular differentiation and development. Substantial expression of nr2c1 during pre-spawning phase and localization of nr2c1 transcripts in sperm/spermatids were observed. Significant upregulation after hCG induction indicate that nr2c1 is under the regulation of gonadotropins. Whole mount ISH analysis displayed nr2c1 expression in notochord indicating its role in normal vertebrate development. Taken together, our findings suggest that nr2c1 may have a plausible role in the testicular and embryonic development of catfish. PMID- 26519762 TI - Acute injections of corticosterone, norepinephrine and epinephrine retards food passage in the crop of chicks. AB - The purpose of the present study was to clarify whether acute injection of stress related hormones, corticosterone (CORT), norepinephrine (NE) and epinephrine (E) affect food passage in the crop of chicks (Gallus gallus). Subcutaneous (SQ) injection of CORT significantly retarded the food passage in the crop of chicks. Intraperitoneal (IP) injection of NE and E also significantly decreased the crop emptying rate. Additional experiments by using agonists of adrenergic receptors found that IP injection of phenylephrine and clonidine but not isoproterenol retarded the food passage in the crop of chicks. These results demonstrated that the effect of NE and E would be mediated by alpha-1-, alpha-2- rather than beta adrenergic receptor. Finally, we found that injection of CORT, NE and E had no effect on the number of defecations while intracerebroventricular injection of corticotropin-releasing hormone and urocortin-3 significantly increased it. These results suggest that CORT, NE and E might affect the food passage in the upper digestive tract in chicks. PMID- 26519763 TI - Childhood trauma and METH abuse among men who have sex with men: Implications for intervention. AB - Methamphetamine (METH) has become one of the most widely abused drugs in South Florida, particularly among MSM who may or may not be HIV seropositive. High rates of childhood trauma have been reported among HIV-infected MSM (Chartier et al., 2010), but, the association of childhood trauma, and mood disorders with methamphetamine use in HIV-infected men, has not been comprehensively explored. A better understanding of the association between these factors could improve existing substance abuse treatment intervention strategies and medical treatment programs (e.g., medication adherence; Carrico, 2010) to enhance positive health outcomes for male meth abusers living with the psychological consequences of childhood abuse. This study, as part of a larger study, examined the occurrence of childhood trauma and depression in a group of HIV seropositive METH abusing MSM. Significantly higher levels of depression symptom severity were found among METH users relative to non-METH users (p < .001). Irrespective of HIV status, METH users also reported higher frequencies of emotional, physical and sexual child abuse relative to non-METH users (p < .001). Among meth users, depression was predicted by childhood emotional neglect. These results suggest that childhood maltreatment may be implicated in the development of emotional distress (e.g., depression) and higher prevalence of methamphetamine/drug abuse in this population. These findings have important implications for substance abuse interventions, specifically targeting METH addiction among MSM. Addressing childhood trauma and depression may play a key role in enhancing the effectiveness of interventions for methamphetamine addiction. PMID- 26519764 TI - Attention-deficit hyperactivity disorder, its pharmacotherapy, and the risk of developing bipolar disorder: A nationwide population-based study in Taiwan. AB - In this study, we aimed to evaluate the relationship between attention deficit/hyperactivity disorder (ADHD) during childhood and subsequent diagnoses of bipolar disorder (BD), as well as to determine whether the pharmacotherapy for ADHD (methylphenidate and atomoxetine) influence the risks of developing BD. A nationwide cohort of patients newly diagnosed with ADHD (n = 144,920) and age- and gender-matching controls (n = 144,920) were found in Taiwan's National Health Insurance database from January 2000 to December 2011. Both patients and controls were observed until December 31, 2011. To determine the effect that the duration of methylphenidate and atomoxetine exposure had on BD, the difference in the risk of developing BD was compared among non-users, short-term users (<= 365 days), and long-term users (>365 days). In comparison to the control group, the ADHD group showed a significantly increased risk of developing BD (ADHD: 2.1% vs. CONTROLS: 0.4%; aHR: 7.85, 95% CI: 7.09-8.70), and had a younger mean age at the time of first diagnosis (ADHD: 12.0 years vs. CONTROLS: 18.8 years). Compared to ADHD patients that had never taken methylphenidate, patients with long-term use of methylphenidate were less likely to be diagnosed with BD (aOR: 0.72, 95% CI: 0.65-0.80). However, the duration of exposure to atomoxetine did not have a significant relationship to a BD diagnosis. The results suggested that a previous diagnosis of ADHD was a powerful indicator of BD, particularly juvenile-onset BD. Nevertheless, the exact mechanisms of the relationships among ADHD, its pharmacotherapy, and BD require further clarification in the future. PMID- 26519765 TI - Evidence for alterations of the glial syncytial function in major depressive disorder. AB - BACKGROUND: Glial cells are essential in maintaining synaptic function. In glutamatergic synapses astrocytes remove the products of neural activity, (i.e. potassium, glutamate and excess water) from the synaptic cleft and redistribute them across the glial network; these products of neural activity can then be recycled for neuronal use or released into the vascular compartment. This type of highly coupled cell network -or syncytium-maintains the balance of synaptic activity by restoring the basal levels of such molecules in the synaptic cleft. Previous studies have reported alterations of glia related genes in Major Depressive Disorder, including some genes related to syncytial function. METHODS: We used RNA isolated from hippocampal tissues of 13 MDD subjects and 10 healthy controls to broadly examine gene expression using microarrays. Hippocampal RNA samples were isolated by laser capture microdissection from human tissue sections carefully avoiding contamination from neighboring structures. Once RNA quality was validated RNA was labeled and hybridized to microarrays. RESULTS: Analysis of microarray data identified mRNA transcripts involved in glial syncytial function that were downregulated in MDD subjects compared to controls, including potassium and water channels (KCNJ10, AQP4), gap junction proteins (GJA1) and glutamate transporters (SLC1A2, SLC1A3). These gene expression differences were confirmed by qPCR. CONCLUSIONS: The downregulation of these genes related to the syncytial network activity of glial cells is consistent with the hypothesis that synaptic homeostasis is disrupted thereby disrupting hippocampal synaptic function in MDD patients. Such glial gene expression changes could contribute either to the onset or perpetuation of depressive symptoms and hence, represent targets for novel therapeutics. PMID- 26519766 TI - Predicting spectrums of adult mania, psychosis and depression by prospectively ascertained childhood neurodevelopment. AB - BACKGROUND: We used a novel approach to investigate early neurodevelopmental factors of later adult spectrums of mania, depression and psychosis as a means to identify etiological similarities and differences among the three constructs. METHODS: Participants were from the Mater University Study of Pregnancy (MUSP), a pre-birth cohort study started in Brisbane, Australia in 1981. A range of neurodevelopmental variables were ascertained at age 5, including measures of cognitive ability, developmental delay and behaviour problems. At age 21, offspring were assessed using a semi-structured psychiatric interview. We used structural equation modelling to establish three latent factors of mania, depression and psychotic symptoms. We then regressed these factors on the neurodevelopmental variables and covariates. RESULTS: In both univariate and multivariate analysis premorbid cognitive ability predicted only psychotic symptoms, developmental delay predicted only manic symptoms, while behaviour problems predicted both depressive and psychotic symptoms. In a supplementary analysis the three factors were also found to have unique relationships with a number of outcomes also measured at age 21, including anxiety and substance use. CONCLUSION: By assessing the impact of early childhood neurodevelopment on the continuous spectrums which underlie three serious adult psychiatric disorders in a general population sample, we provide unique evidence regarding potential etiological similarities and differences. Perhaps of most interest is that our findings suggest that the manic and depressive symptoms in bipolar depression, despite often overlapping in clinical presentations, may in fact be somewhat separate entities with origins that are at least partly unique to either disorder. PMID- 26519767 TI - New long term metabolite in human urine for metenolone misuse by liquid chromatography quadrupole time-of-flight mass spectrometry. AB - In this study, metenolone metabolic profiles were investigated. Metenolone was administered to one healthy male volunteer. Liquid-liquid extraction and direct injection were applied to processing urine samples. Urinary extracts were analyzed by liquid chromatography quadrupole time-of-flight mass spectrometry (LC QTOFMS) using full scan and product ion scan with accurate mass measurement for the first time. Due to the lack of useful fragment ion for structural elucidation, GC-MS instrumentation was employed to obtain structural details of the trimethylsilylated phase I metabolite released after hydrolysis, and the EI mass spectrum was always informative in steroidal structure studies owing to more useful fragment ions than the ESI mass spectrum. 16 metabolites including 6 glucuronide and 9 unreported sulfate conjugates were characterized and tentatively identified. All the metabolites were evaluated in terms of how long they could be detected. The sulfate conjugate S6 (1-methylen-5alpha-androst-3,17 dione-2xi-sulfate) was considered to be a new long term metabolite for metenolone misuse that could be detected 40 days by liquid-liquid extraction and up to 30 days by direct-injection analysis after oral administration. PMID- 26519768 TI - Synthesis of novel 13alpha-18-norandrostane-ferrocene conjugates via homogeneous catalytic methods and their investigation on TRPV1 receptor activation. AB - 13alpha-Steroid-ferrocene derivatives were synthesized via two reaction pathways starting from an unnatural 16-keto-18-nor-13alpha-steroid. The unnatural steroid was converted to ferrocene derivatives via copper-catalyzed azide-alkyne cycloaddition or palladium-catalyzed aminocarbonylation. 16-Azido- and 16-N-(prop 2-ynyl)-carboxamido-steroids were synthesized as starting materials for azide alkyne cycloaddition with the appropriate ferrocene derivatives. Based on our earlier work, aminocarbonylation of 16-iodo-16-ene and 16-iodo-15-ene derivatives was studied with ferrocenylmethylamine. The new products were obtained in moderate to good yields and were characterized by (1)H and (13)C NMR, IR and MS. The solid state structure of the starting material 13alpha-18-norandrostan-16-one and two carboxamide products were determined by X-ray crystallography. Evidences were provided that the N-propargyl-carboxamide compound as well as its ferrocenylmethyltriazole derivative are able to decrease the activation of TRPV1 receptor on TRG neurons. PMID- 26519769 TI - A new mass spectrometry based bioassay for the direct assessment of hyaluronidase activity and inhibition. AB - The development of drug resistance by bacterial pathogens is a growing threat. Drug resistant infections have high morbidity and mortality rates, and treatment of these infections is a major burden on the health care system. One potential strategy to prevent the development of drug resistance would be the application of therapeutic strategies that target bacterial virulence. Hyaluronidase is virulence factor that plays a role in the ability of Gram-positive bacteria such as Staphyloccus aureus and Streptococcus agalactiae to spread in tissue. As such, this enzyme could be a target for the development of future anti-virulence therapies. To facilitate the identification of hyaluronidase inhibitors, quantitative and reproducible assays of hyaluronidase activity are required. In the present study, we developed a new mass spectrometry based bioassay for this purpose. This assay directly measures the quantity of a degradation product (3-(4 deoxy-beta-D-gluc-4-enuronosyl)-N-acetyl-D-glucosamine) produced by the hyaluronidase enzyme. Validation parameters for the new assay are as follows: repeatability, <7%; intermediate precision, <10%; range, 0.78-50 MUM; limit of detection, 0.29 MUM; and limit of quantification, 0.78 MUM. Using the new assay, the IC50 value for a published inhibitor of S. agalactiae hyaluronidase, ascorbic acyl 6-palmitate, was 8.0+/-1.0 MUM. We also identified a new hyaluronidase inhibitor, n-cyclohexanecarbonylpentadecylamine, with an IC50 of 30.4+/-9.8 MUM. In conclusion, we describe a new, direct, and reproducible method for assessing hyaluronidase activity using mass spectrometry that can facilitate the discovery of inhibitors. PMID- 26519770 TI - EUCAST recommendations for antimicrobial susceptibility testing applied to the three main Campylobacter species isolated in humans. AB - Antimicrobial susceptibility testing of Campylobacter isolates is of great importance for treatment options especially in systemic diseases. The European Committee for Antimicrobial Susceptibility Testing (EUCAST) recently proposed epidemiological cut-offs (ECOFFs) for a limited number of antimicrobial compounds and for Campylobacter jejuni and Campylobacter coli only. In the present study, the EUCAST method was used after minor modifications to define antimicrobial susceptibility patterns for, 1997 C. jejuni, 419 C. coli and 100 Campylobacter fetus strains received at the French National Reference Center for Campylobacters and Helicobacters. Our results show that the ECOFFs defined by EUCAST for tetracycline and ciprofloxacin can be used for C. jejuni and C. coli. The same ECOFF can be used for erythromycin for the three species. The C. jejuni and C. coli ECOFFs for ciprofloxacin however cannot be applied to C. fetus. We also provide data to categorise two 2 beta-lactams of interest for systemic diseases, ampicillin and amoxicillin+clavulanate, for the three species. PMID- 26519771 TI - Validation of absolute quantitative real-time PCR for the diagnosis of Streptococcus agalactiae in fish. AB - Streptococcus agalactiae (GBS) are Gram-positive cocci responsible for substantial losses in tilapia fish farms in Brazil and worldwide. It causes septicemia, meningoencephalitis and mortality of whole shoals that can occur within 72 h. Thus, diagnostic methods are needed that are rapid, specific and sensitive. In this study, a pair of specific primers for GBS was generated based on the cfb gene sequence and initially evaluated by conventional PCR. The protocols for absolute quantitative real-time PCR (qPCR) were then adapted to validate the technique for the identification and quantification of GBS isolated by real-time detection of amplicons using fluorescence measurements. Finally, an infectivity test was conducted in tilapia infected with GBS strains. Total DNA from the host brain was subjected to the same technique, and the strains were re isolated to validate Koch's postulates. The assay showed 100% specificity for the other bacterial species evaluated and a sensitivity of 367 gene copies per 20 mg of brain tissue within 4 h, making this test a valuable tool for health monitoring programs. PMID- 26519772 TI - Role of glycogen phosphorylase in liver glycogen metabolism. AB - Liver glycogen is synthesized after a meal in response to an increase in blood glucose concentration in the portal vein and endocrine and neuroendocrine signals, and is degraded to glucose between meals to maintain blood glucose homeostasis. Glycogen degradation and synthesis during the diurnal cycle are mediated by changes in the activities of phosphorylase and glycogen synthase. Phosphorylase is regulated by phosphorylation of serine-14. Only the phosphorylated form of liver phosphorylase (GPa) is catalytically active. Interconversion between GPa and GPb (unphosphorylated) is dependent on the activities of phosphorylase kinase and of phosphorylase phosphatase. The latter comprises protein phosphatase-1 in conjunction with a glycogen-targeting protein (G-subunit) of the PPP1R3 family. At least two of six G-subunits (GL and PTG) expressed in liver are involved in GPa dephosphorylation. GPa to GPb interconversion is dependent on the conformational state of phosphorylase which can be relaxed (R) or tense (T) depending on the concentrations of allosteric effectors such as glucose, glucose 6-phosphate and adenine nucleotides and on the acetylation state of lysine residues. The G-subunit, GL, encoded by PPP1R3B gene is expressed at high levels in liver and can function as a phosphorylase phosphatase and a synthase phosphatase and has an allosteric binding site for GPa at the C-terminus which inhibits synthase phosphatase activity. GPa to GPb conversion is a major upstream event in the regulation of glycogen synthesis by glucose, its downstream metabolites and extracellular signals such as insulin and neurotransmitters. PMID- 26519773 TI - Development and dynamics of the photosynthetic apparatus in purple phototrophic bacteria. AB - The purple bacterium Rhodobacter sphaeroides provides a useful model system for studies of the assembly and dynamics of bacterial photosynthetic membranes. For the nascent developing membrane, proteomic analyses showed an ~2-fold enrichment in general membrane assembly factors, compared to chromatophores. When the protonophore carbonyl-cyanide m-chlorophenyl-hydrazone (CCCP) was added to an ICM inducing culture, an ~2-fold elevation in spectral counts vs. the control was seen for the SecA translocation ATPase, the preprotein translocase SecY, SecD and SecF insertion components, and chaperonins DnaJ and DnaK, which act early in the assembly process. It is suggested that these factors accumulated with their nascent polypeptides, as putative assembly intermediates in a functionally arrested state. Since in Synechocystis PCC 6803, a link has been established between Chl delivery involving the high-light HilD protein and the SecY/YidC requiring cotranslational insertion of nascent polypeptides, such a connection between BChl biosynthesis and insertion and folding of nascent Rba. sphaeroides BChl binding proteins is likely to also occur. AFM imaging studies of the formation of the reaction center (RC)-light harvesting 1 (LH1) complex suggested a cooperative assembly mechanism in which, following the association between the RC template and the initial LH1 unit, addition of successive LH1 units to the RC drives the assembly process to completion. Alterations in membrane dynamics as the developing membrane becomes filled with LH2-rings were assessed by fluorescence induction/relaxation kinetics, which showed a slowing in RC electron transfer rate thought to mainly reflect alterations in donor side electron transfer. This was attributed to an increased distance for electron flow in cytochrome c2 between the RC and cytochrome bc1 complexes, as suggested in the current structural models. This article is part of a Special Issue entitled Organization and dynamics of bioenergetic systems in bacteria, edited by Prof Conrad Mullineaux. PMID- 26519774 TI - Chloroplast NDH: A different enzyme with a structure similar to that of respiratory NADH dehydrogenase. AB - Eleven genes encoding chloroplast NADH dehydrogenase-like (NDH) complex have been discovered in plastid genomes on the basis of their homology with genes encoding respiratory complex I. Despite this structural similarity, chloroplast NDH and its evolutionary origin NDH-1 in cyanobacteria accept electrons from ferredoxin (Fd), indicating that chloroplast NDH is an Fd-dependent plastoquinone (PQ) reductase rather than an NAD(P)H dehydrogenase. In Arabidopsis thaliana, chloroplast NDH interacts with photosystem I (PSI); this interaction is needed to stabilize NDH, especially under high light. On the basis of these distinct characters of chloroplast and cyanobacterial NDH, it can be distinguished as a photosynthetic NDH from respiratory complex I. In fact, chloroplast NDH forms part of the machinery of photosynthesis by mediating the minor pathway of PSI cyclic electron transport. Along with the antimycin A-sensitive main pathway of PSI cyclic electron transport, chloroplast NDH compensates the ATP/NADPH production ratio in the light reactions of photosynthesis. In this review, I revisit the original concept of chloroplast NDH on the basis of its similarity to respiratory complex I and thus introduce current progress in the field to researchers focusing on respiratory complex I. I summarize recent progress on the basis of structure and function. Finally, I introduce the results of our examination of the process of assembly of chloroplast NDH. Although the process requires many plant-specific non-subunit factors, the core processes of assembly are conserved between chloroplast NDH and respiratory complex I. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt. PMID- 26519775 TI - Extracellular matrix component signaling in cancer. AB - Cell responses to the extracellular matrix depend on specific signaling events. These are important from early development, through differentiation and tissue homeostasis, immune surveillance, and disease pathogenesis. Signaling not only regulates cell adhesion cytoskeletal organization and motility but also provides survival and proliferation cues. The major classes of cell surface receptors for matrix macromolecules are the integrins, discoidin domain receptors, and transmembrane proteoglycans such as syndecans and CD44. Cells respond not only to specific ligands, such as collagen, fibronectin, or basement membrane glycoproteins, but also in terms of matrix rigidity. This can regulate the release and subsequent biological activity of matrix-bound growth factors, for example, transforming growth factor-beta. In the environment of tumors, there may be changes in cell populations and their receptor profiles as well as matrix constitution and protein cross-linking. Here we summarize roles of the three major matrix receptor types, with emphasis on how they function in tumor progression. PMID- 26519776 TI - Neural circuits and mechanisms involved in fear generalization: Implications for the pathophysiology and treatment of posttraumatic stress disorder. AB - Compelling evidence suggests that fear generalization (i.e. the transfer of fear from a particular stimulus to another one sharing similarities with the original stimulus) may contribute to the development of posttraumatic stress disorder (PTSD), for which current treatments are ineffective. Deficits in hippocampus mediated pattern separation, the process by which memories are stored as unique representations that are resistant to confusion, have been solely proposed as a putative underlying marker of generalization. We delineate instead an enlarged scenario, wherein conditioned and generalized fear memories share a common neurocircuitry, with the hippocampus being the nub of contextual fear, and the prefrontal cortex of both cued and contextual fear. The potential contribution of the amygdala and insula will be highlighted as well. Finally, we will consider vulnerability factors that may contribute to the development of PTSD, and suggest avenues for novel therapeutics. A better understanding of the mechanisms behind fear generalization is fundamental to provide further insight into treatment of debilitating conditions such as PTSD. PMID- 26519777 TI - Measuring nerve growth factor in saliva by immunoassay: A cautionary note. AB - Nerve growth factor (NGF), a neurotrophin, modulates a diverse set of physiologic processes in the nervous, immune, and endocrine systems. Studies suggest that NGF can be measured in saliva (sNGF). Historically, the method for measuring sNGF involves the off-label use of an enzyme immunoassay designed for use with cell culture supernatants/tissue extracts (Nam et al., 2007; Ruhl et al., 2004). In a series of experiments we reveal this measurement strategy is subject to non specific interference by constituents present in oral fluids. We conclude that the measurement of sNGF by this assay is not optimal for use with oral fluid specimens. PMID- 26519778 TI - Facebook behaviors associated with diurnal cortisol in adolescents: Is befriending stressful? AB - Facebook((c)) is changing the way people interact and socialize. Despite great interest in psychology and sociology, little is known about Facebook behaviors in relation to physiological markers of stress. Given that the brain undergoes important development during adolescence and that glucocorticoids--a major class of stress hormones-are known to modulate its development, it is important to study psychosocial factors that may influence secretion of stress hormones during adolescence. The goal of the present study was to explore the associations between Facebook behaviors (use frequency, network size, self-presentation and peer-interaction) and basal levels of cortisol among adolescent boys and girls. Eighty-eight adolescents (41 boys, 47 girls) aged between 12 and 17 (14.5 +/- 1.8) were recruited. Participants provided four cortisol samples per day for two non-consecutive weekdays. Facebook behaviors were assessed in accordance with the existing literature. Well-validated measures of perceived stress, perceived social support, self-esteem, and depressive symptoms were also included. A hierarchical regression showed that after controlling for sex, age, time of awakening, perceived stress, and perceived social support, cortisol systemic output (area under the curve with respect to ground) was positively associated with the number of Facebook friends and negatively associated with Facebook peer interaction. No associations were found among depressive symptoms, self-esteem, and cortisol. These results provide preliminary evidence that Facebook behaviors are associated with diurnal cortisol concentrations in adolescents. PMID- 26519779 TI - HPA axis dysregulation in men with hypersexual disorder. AB - Hypersexual disorder integrating pathophysiological aspects such as sexual desire deregulation, sexual addiction, impulsivity and compulsivity was suggested as a diagnosis for the DSM-5. However, little is known about the neurobiology behind this disorder. A dysregulation of the hypothalamic pituitary adrenal (HPA) axis has been shown in psychiatric disorders but has not been investigated in hypersexual disorder. The aim of this study was to investigate the function of the HPA axis in hypersexual disorder. The study includes 67 male patients with hypersexual disorder and 39 healthy male volunteers. Basal morning plasma levels of cortisol and ACTH were assessed and low dose (0.5mg) dexamethasone suppression test was performed with cortisol and ACTH measured post dexamethasone administration. Non-suppression status was defined with DST-cortisol levels >= 138 nmol/l. The Sexual Compulsive scale (SCS), Hypersexual disorder current assessment scale (HD:CAS), Montgomery-Asberg Depression Scale-self rating (MADRS S) and Childhood trauma questionnaire (CTQ), were used for assessing hypersexual behavior, depression severity and early life adversity. Patients with hypersexual disorder were significantly more often DST non-suppressors and had significantly higher DST-ACTH levels compared to healthy volunteers. The patients reported significantly more childhood trauma and depression symptoms compared to healthy volunteers. CTQ scores showed a significant negative correlation with DST-ACTH whereas SCS and HD:CAS scores showed a negative correlation with baseline cortisol in patients. The diagnosis of hypersexual disorder was significantly associated DST non-suppression and higher plasma DST-ACTH even when adjusted for childhood trauma. The results suggest HPA axis dysregulation in male patients with hypersexual disorder. PMID- 26519780 TI - Russell's viper venom affects regulation of small GTPases and causes nuclear damage. AB - Russell's viper with its five sub-species is found throughout the Indian subcontinent. Its venom is primarily hemotoxic. However, its envenomation causes damage to several physiological systems. The present work was aimed to study the dose and time dependent cytotoxic effects of Russell's viper venom (RVV) on human A549 cells grown in vitro. Time dependent changes have been observed in cellular morphology following exposure to RVV. Presence of stress granules, rounding-off of the cells, and formation of punctate structure and loss of cell-cell contact characterized the cellular effects. Fluorescence microscopic studies revealed that apoptotic cell population increased on exposure to RVV. Further to understand the mechanism of these effects, status of small GTPase (smGTPases) expression were studied by Western blot and RT-PCR; as smGTPases play pivotal roles in deciding the cellular morphology, polarity, cell movement and overall signaling cascade. It was shown for the first time that expression patterns of Rac, Rho and CDC42 genes are altered on exposure to RVV. Similarly, significant difference in the expression pattern of HSP70 and p53 at the mRNA levels were noted. Our results confirmed that RVV induces apoptosis in A549 cells; this was further confirmed by AO/EtBr staining as well as caspase-3 assay. All experiments were compared using RVV unexposed cells. We propose for the first time that RVV induces morphological changes in human A549 cells through modulation of smGTPase expression and affects the cellular-nuclear architecture which in turn interferes in proliferation and migration of these cells along with apoptosis. PMID- 26519781 TI - Accurate prediction of gestational age using newborn screening analyte data. AB - BACKGROUND: Identification of preterm births and accurate estimates of gestational age for newborn infants is vital to guide care. Unfortunately, in developing countries, it can be challenging to obtain estimates of gestational age. Routinely collected newborn infant screening metabolic analytes vary by gestational age and may be useful to estimate gestational age. OBJECTIVE: We sought to develop an algorithm that could estimate gestational age at birth that is based on the analytes that are obtained from newborn infant screening. STUDY DESIGN: We conducted a population-based cross-sectional study of all live births in the province of Ontario that included 249,700 infants who were born between April 2007 and March 2009 and who underwent newborn infant screening. We used multivariable linear and logistic regression analyses to build a model to predict gestational age using newborn infant screening metabolite measurements and readily available physical characteristics data (birthweight and sex). RESULTS: The final model of our metabolic gestational dating algorithm had an average deviation between observed and expected gestational age of approximately 1 week, which suggests excellent predictive ability (adjusted R-square of 0.65; root mean square error, 1.06 weeks). Two-thirds of the gestational ages that were predicted by our model were accurate within +/-1 week of the actual gestational age. Our logistic regression model was able to discriminate extremely well between term and increasingly premature categories of infants (c-statistic, >0.99). CONCLUSION: Metabolic gestational dating is accurate for the prediction of gestational age and could have value in low resource settings. PMID- 26519782 TI - Cervical cancer screening: evidence behind the guidelines. AB - Cervical cancer screening involves a complex process of cytology, human papillomavirus (HPV) testing, colposcopy, and a multitude of algorithms for the identification of preinvasive disease and prevention of invasive disease. High risk HPV is a prerequisite for the development of almost all types of cervical cancer; therefore, a test for high-risk HPV has become an integral part of new screening strategies. Major changes to screening guidelines in the last decade include initiation of screening at age 21 years, conservative management of young women with abnormal cytology, extended screening intervals for women age >=30 years, and cessation of screening in low-risk women at age 65 years. This review will focus on the evidence that has led to the current evidence-based guidelines. Evidence regarding primary HPV testing as well as postvaccine-based screening strategies will also be reviewed. PMID- 26519783 TI - Discordant pregnancy intentions in couples and rapid repeat pregnancy. AB - BACKGROUND: Rapid repeat pregnancy (RRP) is a major problem in the United States. Few studies have explored the influence of partner agreement on pregnancy intention and RRP. OBJECTIVE: We sought to examine the association between couple pregnancy intentions and RRP among women in the United States. STUDY DESIGN: Data came from the 2006 through 2010 National Survey of Family Growth. Multiparous women who cohabited with 1 husband/partner before conception of second pregnancy were included (N = 3463). The outcome, RRP, was categorized as experiencing a second pregnancy within 24 months of the first pregnancy resolution, or >=24 months from the first pregnancy resolution. Maternal and paternal pregnancy intentions were categorized into 4 dyads: both intended (M+P+); maternal intended and paternal unintended (M+P-); maternal unintended and paternal intended (M-P+); and both unintended (M-P-). Multiple logistic regression was conducted to determine the association between couple pregnancy intentions and RRP. RESULTS: Nearly half (49.4%) of women had RRP. Approximately 15% of respondents reported discordant couple pregnancy intentions and 22%, maternal and paternal unintendedness. Compared to couples who both intended their pregnancy (M+P+), the odds of RRP was higher when fathers intended pregnancy but not mothers (adjusted odds ratio, 2.51; 95% confidence interval, 1.45-4.35) and lower if fathers did not intend pregnancy but mothers did (adjusted odds ratio, 0.77; 95% confidence interval, 0.70-0.85). No difference was observed between concordant couple pregnancy intentions (M-P- vs M+P+). CONCLUSION: Findings highlight the important role of paternal intention in reproductive decisions. Study results suggest that RRP is strongly influenced by paternal rather than maternal pregnancy intentions. Clinicians and public health workers should involve partners in family planning discussions and counseling on optimal birth spacing. PMID- 26519784 TI - Patient characteristics associated with 17-alpha hydroxyprogesterone caproate use among a high-risk cohort. AB - BACKGROUND: Preterm birth (PTB) remains a significant cause of neonatal morbidity and mortality. Women with a prior PTB are at risk for recurrent PTB. Treatment with 17-alpha hydroxyprogesterone caproate (17OHP-C) has become standard of care for women with prior PTB to help reduce this risk. Factors that affect a woman's decision to use this medication are largely unknown. OBJECTIVE: The objective of our study was to investigate patient-level barriers to 17OHP-C. We studied a cohort of women eligible for 17OHP-C with the hypothesis that 17OHP-C is underutilized and certain patient characteristics, such as obstetrical history, influence its use. STUDY DESIGN: A cross-sectional study of all women seen at a specialty prematurity clinic from 2009 through 2013 was performed. Women with a singleton pregnancy were included if they had a prior spontaneous PTB (sPTB). The chi(2) tests were performed for univariate analyses. Multivariable logistic regression was used to control for confounders. RESULTS: In all, 243 women had 17OHP-C recommended to them based on obstetrical history. There were 218 women with a pregnancy during our study period that were included in our analysis. A total of 163 (74.7%) had documented 17OHP-C use. Women were more likely to accept 17OHP-C if they had a history of a second-trimester loss only (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.17-4.58) or received recommendation for cerclage due to a short cervical length (OR, 4.12; 95% CI, 1.55-10.99). Women with a prior full-term birth were less likely to accept 17OHP-C (OR, 0.48; 95% CI, 0.26-0.89), especially when the prior full-term birth was subsequent rather than prior to the PTB (OR, 0.19; 95% CI, 0.08-0.47). Race, obesity, and insurance status did not impact 17OHP-C use. There was no difference in the rate of sPTB between those who used and did not use 17OHP-C (37.2 vs 34.0%, P = .7). CONCLUSION: Obstetric history impacted 17OHP-C use. This study identifies biases regarding 17OHP-C at the patient level and can be used to develop strategies to increase its use. However, the similarity in the sPTB rate between users and nonusers highlights the importance of identifying specific populations where 17OHP-C is and is not effective in preventing PTB. PMID- 26519785 TI - Prevention of iatrogenic ureteral injuries during robotic gynecologic surgery: a review. AB - Iatrogenic ureteral injuries, more than half of which occur during gynecologic surgery, may have devastating consequences for both patients and physicians. Gynecologists have employed various techniques such as cystoscopy, ureteral stents, and lighted ureteral stents to prevent ureteral injuries. The emergence and increasing prevalence of robotic surgery necessitates that we not only reevaluate the utility of these techniques, but also develop new ones specific for the robotic modality. In the robotic setting, the surgeon lacks tactile feedback and must rely primarily on visual cues. The use of intraureteral indocyanine green and subsequent visualization under near-infrared fluorescence appears to be a promising technique to primarily and secondarily prevent ureteral injuries during robotic gynecologic surgery. PMID- 26519787 TI - Prediction of in-vivo iontophoretic drug release data from in-vitro experiments insights from modeling. AB - A strategy was developed to predict in-vivo plasma drug levels from data collected during in-vitro transdermal iontophoretic delivery experiments. The method used the principle of mass conservation and the Nernst-Planck flux equation to describe molecular transport across the skin. Distribution and elimination of the drug in the body followed a one- or two-compartment open model. Analytical expressions for the relaxation constant and plasma drug concentration were developed using Laplace transforms. The steady-state dermal flux was appropriate for predicting drug absorption under in-vivo conditions only when the time constant in the skin was far greater than its value in the blood compartment. A simulation study was conducted to fully assess the performance of estimations based on the equilibrium flux approximation. The findings showed that the normalized integral of squared error decreased exponentially as the ratio of the two time constants (blood/skin) increased. In the case of a single compartment, the error was reduced from 0.15 to 0.016 when the ratio increased from 10 to 100. The methodology was tested using plasma concentrations of a growth-hormone releasing factor in guinea pigs and naloxone in rats. PMID- 26519788 TI - Stochastic descriptors in an SIR epidemic model for heterogeneous individuals in small networks. AB - We continue here the work initiated in [13], and analyse an SIR epidemic model for the spread of an epidemic among the members of a small population of N individuals, defined in terms of a continuous-time Markov chain X. We propose a structure by levels and sub-levels of the state space of the process X, and present two different orders, Orders A and B, for states within each sub-level, which are related to a matrix and a scalar formalism, respectively, when developing our analysis. Stochastic descriptors regarding the length and size of an outbreak, the maximum number of individuals simultaneously infected during an outbreak, the fate of a particular individual within the population, and the number of secondary cases caused by a certain individual until he recovers, are deeply analysed. Our approach is illustrated by carrying out a set of numerical results regarding the spread of the nosocomial pathogen Methicillin-resistant Staphylococcus Aureus among the patients within an intensive care unit. In this application, our interest is in analysing the effectiveness of control strategies (the isolation of the patient initiating the outbreak and the proper room configuration of the intensive care unit) that intrinsically introduce heterogeneities among the members of the population. PMID- 26519786 TI - Risk of dementia and death in the long-term follow-up of the Pittsburgh Cardiovascular Health Study-Cognition Study. AB - INTRODUCTION: Increasing life expectancy has resulted in a larger population of older individuals at risk of dementia. METHODS: The Cardiovascular Health Study Cognition Study followed 532 participants from 1998-99 (mean age 79) to 2013 (mean age 93) for death and dementia. RESULTS: Risk of death was determined by extent of coronary artery calcium, high-sensitivity cardiac troponin, brain natriuretic peptide, and white matter grade. Significant predictors of dementia were age, apolipoprotein-E4, vocabulary raw score, hippocampal volume, ventricular size, cognitive performance, and number of blocks walked. By 2013, 160 of 532 were alive, including 19 cognitively normal. Those with normal cognition had higher grade education, better cognition test scores, greater hippocampal volume, faster gait speed, and number of blocks walked as compared with survivors who were demented. DISCUSSION: Few survived free of dementia and disability. Prevention and delay of cognitive decline for this older population is an imperative. PMID- 26519789 TI - Rinsing with antacid suspension reduces hydrochloric acid-induced erosion. AB - OBJECTIVE: Mouthrinsing with antacids, following erosive episodes, have been suggested as a preventative strategy to minimize tooth surface loss due to their neutralizing effect. The purpose of this in situ study was to evaluate the effect of an antacid suspension containing sodium alginate, sodium bicarbonate and calcium carbonate in controlling simulated erosion of enamel of intrinsic origin. DESIGN: The experimental units were 48 slabs (3*3*2mm) of bovine enamel, randomly divided among 12 volunteers who wore palatal appliances with two enamel slabs. One of them was exposed extra-orally twice a day to 25mL of a hydrochloric acid (HCl) solution (0.01M, pH 2) for 2min. There were two independent phases, lasting 5 days each. In the first phase, according to a random scheme, half of the participants rinsed with 10mL of antacid suspension (Gaviscon((r)), Reckitt Benckiser Healthcare Ltd.), while the remainder was rinsed with deionized water, for 1min. For the second phase, new slabs were inserted and participants switched to the treatment not received in the first stage. Therefore, the groups were as follows: (a) erosive challenge with HCl+antacid suspension; (b) erosive challenge with HCl+deionized water (DIW); (c) no erosive challenge+antacid suspension; (d) no erosive challenge+DIW. Specimens were assessed in terms of surface loss using optical profilometry and Knoop microhardness. The data were analyzed using repeated measures two-way analysis of variance and Tukey's tests. RESULTS: Compared to DIW rinses, surface loss of enamel was significantly lower when using an antacid rinse following erosive challenges (p=0.015). The Knoop microhardness of the enamel was significantly higher when the antacid rinse was used (p=0.026). CONCLUSIONS: The antacid suspension containing sodium alginate, sodium bicarbonate and calcium carbonate, rinsed after erosive challenges of intrinsic origin, reduced enamel surface loss. PMID- 26519790 TI - Intermicrobial Interactions as a Driver for Community Composition and Stratification of Oral Biofilms. AB - The oral cavity is accessible to microorganisms, and biofilms are present throughout on hard and soft tissues. The shedding of epithelial cell layers is usually effective for controlling biofilm development on soft tissues. Innate immune mechanisms are not so effective against biofilms on tooth surfaces, and oral hygiene measures such as brushing and flossing are required for the periodic removal of dental plaque. Even with good oral hygiene, microbial communities accumulate on teeth in areas that are protected from mechanical abrasion forces. Changes in the composition of these biofilms are associated with oral diseases such as dental caries or periodontitis. Newly formed biofilms and more mature dental plaque each have a level of spatial organization in the horizontal and vertical planes. Communities are shaped by many varied interactions between different species and genera within the biofilm, which include physical cell-cell associations known as coaggregation, interspecies signaling, secretion and turnover of antimicrobial compounds and the sharing of an extracellular matrix. Central to these interactions is the selection for metabolic synergies and it is becoming clear that the ability of communities to extract the maximum energy from the available metabolites is a potent driver for biofilm structure and stratification. This review discusses recent advances in our understanding of intermicrobial interactions in oral biofilms and the roles that they play in determining the spatial organization of biofilm communities. PMID- 26519791 TI - Mechanistic Insights from Structural Analyses of Ran-GTPase-Driven Nuclear Export of Proteins and RNAs. AB - Understanding how macromolecules are rapidly exchanged between the nucleus and the cytoplasm through nuclear pore complexes is a fundamental problem in biology. Exportins are Ran-GTPase-dependent nuclear transport factors that belong to the karyopherin-beta family and mediate nuclear export of a plethora of proteins and RNAs, except for bulk mRNA nuclear export. Exportins bind cargo macromolecules in a Ran-GTP-dependent manner in the nucleus, forming exportin-cargo-Ran-GTP complexes (nuclear export complexes). Transient weak interactions between exportins and nucleoporins containing characteristic FG (phenylalanine-glycine) repeat motifs facilitate nuclear pore complex passage of nuclear export complexes. In the cytoplasm, nuclear export complexes are disassembled, thereby releasing the cargo. GTP hydrolysis by Ran promoted in the cytoplasm makes the disassembly reaction virtually irreversible and provides thermodynamic driving force for the overall export reaction. In the past decade, X-ray crystallography of some of the exportins in various functional states coupled with functional analyses, single-particle electron microscopy, molecular dynamics simulations, and small-angle solution X-ray scattering has provided rich insights into the mechanism of cargo binding and release and also begins to elucidate how exportins interact with the FG repeat motifs. The knowledge gained from structural analyses of nuclear export is being translated into development of clinically useful inhibitors of nuclear export to treat human diseases such as cancer and influenza. PMID- 26519792 TI - A potent and selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitor, SKI2852, ameliorates metabolic syndrome in diabetic mice models. AB - 11beta-Hydroxysteroid dehydrogenase type 1 (11betaHSD1) has been targeted for new drugs to treat type 2 diabetes and metabolic syndrome. In this study, we determined whether the inhibition of 11betaHSD1 with a new selective inhibitor, SKI2852, could improve lipid profiles, glucose levels, and insulin sensitivity in type 2 diabetic and obese conditions. SKI2852 showed a potent inhibition of cortisone to cortisol conversion for over 80% in both liver and adipose tissue ex vivo from orally administered C57BL/6 mice, and in vivo analysis results were consistent with this. Repeated oral administrations of SKI2852 in diet-induced obesity (DIO) and ob/ob mice revealed a partially beneficial effect of SKI2852 in improving levels of cholesterols, triglycerides, free fatty acids, postprandial glucose, and/or blood hemoglobinA1c. SKI2852 significantly reduced body weight increase in ob/ob mice, and efficiently suppressed hepatic mRNA levels of gluconeogenic enzymes in DIO mice. Moreover, SKI2852 enhanced hepatic and whole body insulin sensitivities in hyperinsulinemic-euglycemic clamp experiment in DIO mice. In conclusion, these results indicate that selective and potent inhibition of 11betaHSD1 by SKI2852, thus blockade of active glucocorticoid conversion, may improve many aspects of metabolic parameters in type 2 diabetes and metabolic diseases, mainly by inhibitions of hepatic gluconeogenesis and partial improvements of lipid profiles. Our study strongly support that SKI2852 may have a great potential as a novel candidate drug for the treatment of diabetes and metabolic diseases. PMID- 26519793 TI - Sparse and Adaptive Diffusion Dictionary (SADD) for recovering intra-voxel white matter structure. AB - On the analysis of the Diffusion-Weighted Magnetic Resonance Images, multi compartment models overcome the limitations of the well-known Diffusion Tensor model for fitting in vivo brain axonal orientations at voxels with fiber crossings, branching, kissing or bifurcations. Some successful multi-compartment methods are based on diffusion dictionaries. The diffusion dictionary-based methods assume that the observed Magnetic Resonance signal at each voxel is a linear combination of the fixed dictionary elements (dictionary atoms). The atoms are fixed along different orientations and diffusivity profiles. In this work, we present a sparse and adaptive diffusion dictionary method based on the Diffusion Basis Functions Model to estimate in vivo brain axonal fiber populations. Our proposal overcomes the following limitations of the diffusion dictionary-based methods: the limited angular resolution and the fixed shapes for the atom set. We propose to iteratively re-estimate the orientations and the diffusivity profile of the atoms independently at each voxel by using a simplified and easier-to solve mathematical approach. As a result, we improve the fitting of the Diffusion Weighted Magnetic Resonance signal. The advantages with respect to the former Diffusion Basis Functions method are demonstrated on the synthetic data-set used on the 2012 HARDI Reconstruction Challenge and in vivo human data. We demonstrate that improvements obtained in the intra-voxel fiber structure estimations benefit brain research allowing to obtain better tractography estimations. Hence, these improvements result in an accurate computation of the brain connectivity patterns. PMID- 26519794 TI - Building dynamic population graph for accurate correspondence detection. AB - In medical imaging studies, there is an increasing trend for discovering the intrinsic anatomical difference across individual subjects in a dataset, such as hand images for skeletal bone age estimation. Pair-wise matching is often used to detect correspondences between each individual subject and a pre-selected model image with manually-placed landmarks. However, the large anatomical variability across individual subjects can easily compromise such pair-wise matching step. In this paper, we present a new framework to simultaneously detect correspondences among a population of individual subjects, by propagating all manually-placed landmarks from a small set of model images through a dynamically constructed image graph. Specifically, we first establish graph links between models and individual subjects according to pair-wise shape similarity (called as forward step). Next, we detect correspondences for the individual subjects with direct links to any of model images, which is achieved by a new multi-model correspondence detection approach based on our recently-published sparse point matching method. To correct those inaccurate correspondences, we further apply an error detection mechanism to automatically detect wrong correspondences and then update the image graph accordingly (called as backward step). After that, all subject images with detected correspondences are included into the set of model images, and the above two steps of graph expansion and error correction are repeated until accurate correspondences for all subject images are established. Evaluations on real hand X-ray images demonstrate that our proposed method using a dynamic graph construction approach can achieve much higher accuracy and robustness, when compared with the state-of-the-art pair-wise correspondence detection methods as well as a similar method but using static population graph. PMID- 26519795 TI - Effect of combined exposure to lead and decabromodiphenyl ether on neurodevelopment of zebrafish larvae. AB - The effect of combined exposure to decabromodiphenyl ether (BDE-209) and lead (Pb) on neurodevelopment of zebrafish (Danio rerio) larvae was investigated. Zebrafish embryos were exposed to Pb (0, 5, 10, 20 ug/L) and BDE-209 (0, 50, 100, 200 ug/L), either alone or in combination (Mix1: 5 + 50 ug/L, Mix2: 10 + 100 ug/L, Mix3: 20 + 200 ug/L) for up to 144 h post-fertilization. Growth of secondary motoneuron axons and expression of genes related to central nervous system development was significantly inhibited in Mix3 co-exposure group. A significant increase in reactive oxygen species (ROS), lipid peroxidation, DNA damage, and perturbation of the antioxidant system was detected in the Mix3 group compared to single-toxicant treatments or control. Depressed locomotor activity was recorded in the Mix2 and Mix3 groups. Addition of N-acetyl cysteine to Mix3 eliminated excessive ROS, and protected against lipid peroxidation, DNA damage, and locomotor dysfunction. Pb uptake was increased in the presence of BDE-209, but BDE-209 bioconcentration and the ability to metabolize BDE-209 were decreased in the presence of Pb. These results suggest that BDE-209 and Pb have a synergistic disruptive effect on neurodevelopment in zebrafish larvae by enhanced generation of ROS, which is a major factor that contributes to developmental neurotoxicity. PMID- 26519796 TI - Improved photocatalytic activity of gold decorated differently doped TiO2 nanoparticles: A comparative study. AB - In this paper, undoped and several differently doped (with Fe(3+), N(-), and gamma-Al2O3) TiO2-nanoparticle-based photocatalysts and those covered with ultrasmall gold nanoparticles (AuNPs) were engineered. Their photocatalytic performance was studied by utilizing them for the liquid-phase decomposition of the model dye methylene blue (MB) under visible-light irradiation. The structural, morphological, physico-chemical, and optical properties of the photocatalysts were investigated using X-ray diffraction, X-ray photoelectron spectroscopy, diffuse-reflectance UV-Vis absorption spectroscopy, Raman spectroscopy and transmission electron microscopy. Photodegradation kinetics of MB was followed by measuring the absorbance of MB at 664 nm at different irradiation times, whereas the mineralization of MB was examined by determining the total organic carbon (TOC) content. The photocatalytic activity of TiO2 nanoparticles was shown to be significantly increased by introducing dopants into the crystal lattice and depositing AuNPs on the surface. Among those, gamma-Al2O3 doped TiO2 nanoparticles covered with deposited AuNPs show the best photocatalytic performance. Altogether, the here engineered photocatalysts as consisting of doped TiO2 nanoparticles decorated with AuNPs establish novel three component nanocomposite systems, where synergetic interactions between surface AuNPs, dopants and TiO2 were shown to significantly enhance the photocatalytic activity. PMID- 26519797 TI - Class 1 integrase, sulfonamide and tetracycline resistance genes in wastewater treatment plant and surface water. AB - Wastewater treatment plants are considered hot spots for multiplication and dissemination of antibiotic-resistant bacteria and resistance genes. In this study, we determined the presence of class 1 integron integrase and genes conferring resistance to tetracyclines and sulfonamides in the genomes of culturable bacteria isolated from a wastewater treatment plant and the river that receives the treated wastewater. Moreover, using PCR-based metagenomic approach, we quantified intI1, tet and sul genes. Wastewater treatment caused the decrease in the total number of culturable heterotrophs and bacteria resistant to tetracycline and sulfonamides, along with the decrease in the number of intI1, sul and tet gene copies per ml, with significant reduction of tet(B). On the other hand, the treatment process increased both the frequency of tetracycline- and sulfonamide-resistant bacteria and intI1-positive strains, and the relative abundance of all quantified antibiotic resistance genes (ARGs) and intI1 gene; in the case of tet(A) and sul2 significantly. The discharge of treated wastewater increased the number of intI1, tet and sul genes in the receiving river water both in terms of copy number per ml and relative abundance. Hence, despite the reduction of the number of ARGs and ARBs, wastewater treatment selects for bacteria with ARGs in effluent. PMID- 26519798 TI - Transformation, products, and pathways of chlorophenols via electro-enzymatic catalysis: How to control toxic intermediate products. AB - Chlorophenols can be easily oxidized into chlorobenzoquinones (CBQs), which are highly toxic and have been linked to bladder cancer risk. Herein, we report the transformation, products, and pathways of 2,4-dichlorophenol (DCP) by horseradish peroxidase (HRP) and electro-generated hydrogen peroxide (H2O2) and suggest methods to control the formation of toxic intermediate products. After a 10-min electroenzymatic process, 99.7% DCP removal may be achieved under optimal conditions. A total of 16 reaction products, most of which are subsequently verified as DCP polymers and related quinone derivatives, are identified by using ultra-performance liquid chromatography-time-of-flight mass spectrometry (UPLC TOF-MS). A five-step reaction pathway for DCP transformation, including HRP driven substrate oxidation, substitution and radical coupling, quick redox equilibrium, nucleophilic reaction and precipitation from aqueous solution, is proposed. Current variations and the presence of CO2 could significantly affect these reaction pathways. In particular, higher currents enhance the hydroxylation process by promoting alkaline conditions and abundant H2O2 formation. As both OH( ) and H2O2 are strong nucleophiles, they easily react with CBQ products to form hydroxylated products, which can significantly reduce solution toxicity. An adequate supply of CO2 can provide favorable pH conditions and facilitate enzymatic steps, such as substrate oxidation and radical coupling, to generate precipitable polymerized products. All of the results suggest that toxic intermediate products can be effectively reduced and controlled during the electro-enzymatic process to remove DCP and other phenolic pollutants from wastewaters. PMID- 26519799 TI - The dual effects of carboxymethyl cellulose on the colloidal stability and toxicity of nanoscale zero-valent iron. AB - Nanoscale zero-valent iron (NZVI) particles are usually modified with surface coating to mitigate the particle stability in water during the environmental application. However, the surface coating may not only influence the particle stabilization but also the particle cytotoxicity. In this study, we investigated the dual effects of carboxymethyl cellulose (CMC) on the colloidal stability and cytotoxicity of NZVI towards gram-negative Escherichia coli (E. coli) and discussed the interrelation between particle stability and cytotoxicity. The effect of CMC concentration, ionic strength (Ca(2+)) and aging treatment on the particle cytotoxicity were also examined. Specifically, the aqueous stability of NZVI suspensions with CMC ratio dose-dependently strengthened within 1 h. The inactivation of E. coli by bare NZVI was significant and concentration- and time dependent. On the contrary, an increasing reduction in cytotoxicity of NZVI with CMC ratio increasing was observed, even though the particles became more dispersed. TEM analysis demonstrates the membrane disruption and the cellular internalization of nanoparticles after exposure of E. coli to NZVI. However, in the case of CMC-modified NZVI (CNZVI), the bacterial cell wall displays an outer shell of a layer of nanoparticles attached around the outer membrane, but the cell membrane was kept intact. The presence of Ca(2+) can either increase or decrease the cytotoxicity of NZVI and CNZVI, depending on the concentration. The aged NZVI and CNZVI particles did not seem to present obvious bactericidal effect due to the transformation of Fe(0) to the less toxic or non-toxic iron oxides, as indicated by the XRD analysis. PMID- 26519800 TI - Fructose as a novel photosensitizer: Characterization of reactive oxygen species and an application in degradation of diuron and chlorpyrifos. AB - The objective of this study was to identify reactive oxygen species (ROS) generated from the exposure of fructose solution to the 254 nm ultraviolet (UV) light and evaluate whether fructose can be used as a photosensitizer for accelerated photo-degradation of diuron and chlorpyrifos. We demonstrated that hydrogen peroxide, singlet oxygen ((1)O2) and acidic photolysis products were generated upon UV exposure of fructose. Consistent with these findings, UV induced degradation of chlorpyrifos and diuron was accelerated by the presence of 500 mM fructose. The average first order photo-degradation rate constants in the absence and presence of 500 mM fructose were 0.92 and 2.07 min(-1) respectively for diuron and 0.04 and 0.07 min(-1) for chlorpyrifos. The quantum yields (phi) for direct photo-degradation of diuron and chlorpyrifos were 0.003 and 0.001 respectively. In the presence of 500 mM fructose, these values increased to 0.006 and 0.002 respectively. Thus, fructose may be an effective photosensitizer. PMID- 26519801 TI - Biomonitoring of 20 elements in urine of children. Levels and predictors of exposure. AB - The levels of 20 elements in the urine of one hundred twenty children (Ages 6-11) from an agricultural and an urban area of Valencia Region, Spain, were assessed. The seven essential elements analysed (Co, Cu, Mn, Mo, Se, V, Zn) presented average concentrations (geometric mean) ranging from 0.22 ug L(-1) to 63 ug L(-1) (except Zn with 525 ug L(-1)). Eight out of the 13 toxic elements determined (As, Ba, Cd, Cs, Ni, Pb, Tl, Hg) had frequencies of detection of 100%, with geometric mean concentrations from 0.17 ug L(-1) (Cd) to 33.6 ug L(-1) (As). About 18% of children revealed urinary levels of total As higher than the normal range of 100 ug L(-1) accepted by the ATSDR. The urine analysis was combined with a survey to evaluate variations between subgroups and potential predictors of metal exposure in children population. For socio-demographic variables, age was the main exposure determinant for the majority of selected elements (p < 0.05-0.001), with higher concentrations in younger children (6-8 years). Significant differences were also obtained between the rural and urban area studied for As, Co, Cs, Se, U and Hg, with higher levels in children living in the urban area. In relation to diet, statistically significant higher levels of Hg (p < 0.01, median = 1 ug g( 1) creatinine) and Se (p < 0.05, median = 60.3 ug g(-1) creatinine) were obtained for children with elevated fish consumption, and lower levels of Cd, Ni, Se and V were found (p < 0.05-0.01) in children with high consumption of dairy products. PMID- 26519802 TI - Characterization of the metabolic pathway and catabolic gene expression in biphenyl degrading marine bacterium Pseudomonas aeruginosa JP-11. AB - Metabolic pathway of biphenyl assimilation and the catabolic gene expression in a marine bacterium Pseudomonas aeruginosa JP-11, isolated from the coastal sediments of Odisha, India have been studied. This strain utilized 98.86% +/- 2.29% of biphenyl within 72 h when supplied as the sole source of carbon, however, preferential utilization of glucose was observed over catechol and biphenyl when grown in a complex medium. Combination of chromatographic and spectrophotometric techniques confirmed the catechol pathway and identified 2 Hydroxy-6-oxo-6-phenylhexa-2, 4-dienoate as the intermediate metabolic product. Assimilation of biphenyl was initiated by its dioxygenation, forming cis-2, 3 dihydro-2, 3-dihydroxybiphenyl subsequently transformed to 2-hydroxy-6-oxo-6 phenylhexa-2, 4-dienoate. In the lower pathway, cis-1, 6-dihydroxy-2, 4 cyclohexadiene-1-carboxylic acid was detected which formed catechol before entering into the Krebs cycle. Detection of key enzyme catechol-1, 2-dioxygenase in the cell-free extract of P. aeruginosa JP-11 supported the proposed degradation pathway. The primary enzyme for biphenyl assimilation, biphenyl dioxygenase encoded by bphA gene was found in the genome of the isolate. On increasing biphenyl stress (50, 100, 150 and 200 mg L(-1)), bphA gene showed a significant (P < 0.01) up-regulation upto 43.5 folds. Production of biosurfactant was confirmed and the rhamnolipid synthesizing gene rhlAB was amplified. This gene also showed a significant (P < 0.01) up-regulation upto 258 folds on increasing biphenyl stress. PMID- 26519803 TI - Monitoring survey of the use patterns and pesticide residues on vegetables in the Niayes zone, Senegal. AB - The main objective of this work was to determine the impact of pesticide use practices on vegetables contamination in the Niayes zone of Dakar. A preliminary survey involving 200 farmers, showed the application of pesticides belonging to different groups on vegetable crops. Use practices in terms of application intervals and methods, measuring tools and dosage were not in compliance with good agricultural practices. In view of survey results, investigations on vegetable contamination were conducted. Therefore, 175 vegetable samples including cabbage (31 samples), lettuce (88 samples), tomato (57 samples) collected from four sites of the Niayes zone during four campaigns, were analyzed for residues of 21 pesticides, eighteen of which (18) were cited to be used by farmers. The results indicated that 65% of tomato samples, 71% of lettuce and 93% of cabbage contained one or more detectable residues. Among the monitored pesticides dicofol, chlorpyrifos, DDTs, dimethoate, and lambda-cyhalothrin were the most predominant, found in at least 35% of samples for each vegetable. The frequencies of pesticide detection were, generally in agreement with the citation frequencies. The results provided important information on vegetable contamination status and pointed an urgent need to control pesticide use. PMID- 26519804 TI - Isomers/enantiomers of perfluorocarboxylic acids: Method development and detection in environmental samples. AB - Perfluoroalkyl substances are globally distributed in both urban and remote settings, and routinely are detected in wildlife, humans, and the environment. One of the most prominent and routinely detected perfluoroalkyl substances is perfluorooctanoic acid (PFOA), which has been shown to be toxic to both humans and animals. PFOA exists as both linear and branched isomers; some of the branched isomers are chiral. A novel GC-NCI-MS method was developed to allow for isomer/enantiomer separation, which was achieved using two columns working in tandem; a 30-m DB-5MS column and a 30-m BGB-172 Analytik column. Samples were derivatized with diazomethane to form methyl esters of the PFOA isomers. In standards, at least eight PFOA isomers were detected, of which at least four were enantiomers of chiral isomers; one chiral isomer (P3) was sufficiently separated to allow for enantiomer-fraction calculations. Soil, sediment and plant samples from contaminated locations in Alabama and Georgia were analyzed. P3 was observed in most of these environmental samples, and was non-racemic in at least one sediment, suggesting the possibility of chirally selective generation from precursors or enantioselective sorption. In addition, the ratio of P3/linear PFOA was inversely related to distance from source, which we suggest might reflect a higher sorption affinity for the P3 over the linear isomer. This method focuses on PFOA, but preliminary results suggest that it should be broadly applicable to other chiral and achiral perfluorocarboxylic acids (PFCAs); e.g., we detected several other homologous PFCA isomers in our PFCA standards and some environmental samples. PMID- 26519805 TI - Acute toxicity, uptake and accumulation kinetics of nickel in an invasive copepod species: Pseudodiaptomus marinus. AB - Pseudodiaptomus marinus is a marine calanoid copepod originating of the Indo Pacific region, who has successfully colonized new areas and it was recently observed in the European side of the Mediterranean Sea as well as in the North Sea. Actually, many questions were posed about the invasive capacity of this copepod in several non-native ecosystems. In this context, the main aim of this study was to investigate the tolerance and the bioaccumulation of metallic stress in the invasive copepod P. marinus successfully maintained in mass culture at laboratory conditions since 2 years. In order to study the metallic tolerance levels of P. marinus, an emergent trace metal, the nickel, was chosen. First, lethal concentrations determination experiments were done for 24, 48, 72 and 96 h in order to calculated LC50% but also to select a relevant ecological value for the suite of experiments. Then, three types of experiments, using a single concentration of nickel (correspond the 1/3 of 96 h-LC50%) was carried in order to study the toxico-kinetics of nickel in P. marinus. Concerning lethal concentrations, we observed that P. marinus was in the same range of sensitivity compared to other calanoid copepods exposed to nickel in the same standardized experimental conditions. Results showed that the uptake of nickel in P. marinus depends from the pathways of entrance (water of food), but also that Isochrysis galbana, used as a food source, has an important bioaccumulation capacity and a rapid uptake of nickel. PMID- 26519806 TI - Linkage of iron elution and dissolved oxygen consumption with removal of organic pollutants by nanoscale zero-valent iron: Effects of pH on iron dissolution and formation of iron oxide/hydroxide layer. AB - The iron elution and dissolved oxygen (DO) consumption in organic pollutant removal by nanoscale zero-valent iron (nZVI) was examined in the range of solution pH from 3.0 to 9.0. Their behaviors were linked with the removal of organic pollutant through the dissolution of iron and the formation of iron oxide/hydroxide layer affected strongly by solution pH and DO. As an example of organic pollutants, azo-dye Orange II was chosen in this study. The chemical composition analyses before and after reaction confirmed the corrosion of nZVI into ions, the formation of iron oxide/hydroxide layer on nZVI surface and the adsorption of the pollutant and its intermediates. The complete decolorization of Orange II with nZVI was accomplished very quickly. On the other hand, the total organic carbon (TOC) removal was considerably slow and the maximum TOC removal was around 40% obtained at pH 9.0. The reductive cleavage of azo-bond by emitted electrons more readily took place as compared with the cleavage of aromatic rings of Orange II leading to the degradation to smaller molecules and subsequently the mineralization. A reaction kinetic model based on the Langmuir-Hinshelwood/Eley Rideal approach was developed to elucidate mechanisms for organic pollutant removal controlled by the formation of iron oxide/hydroxide layer, the progress of which could be characterized by considering the dynamic concentration changes in Fe(2+) and DO. The dynamic profiles of Orange II removal linked with Fe(2+) and DO could be reasonably simulated in the range of pH from 3.0 to 9.0. PMID- 26519807 TI - Penile incerceration-A tight affair. AB - A patient presents with penile ring incarceration after using it for penile enlargement and prolonging tumescence. We present a case study of removal of the penile ring under local anaesthesia in a setting where cutting tools were inadequate. PMID- 26519808 TI - Cervical cancer with a rare umbilical metastases in prior surgical site. AB - INTRODUCTION: Port-site metastasis of cervical cancer is a relatively rare occurrence, and has been reported in the published literature as a pre-terminal event. PRESENTATION OF CASE: We present the case of a 52-year-old female who was diagnosed with cervical cancer after presenting to our institution's hospital with urinary symptoms not relieved by multiple treatments with antibiotics. To fully evaluate the extent of disease, positron emission tomography-computed tomography imaging was obtained, showing an area of mildly increased fluorodeoxyglucose uptake in her umbilicus. While undergoing external-beam radiotherapy treatment for her cervical cancer, she began to experience pain in the umbilicus associated with a mass. A biopsy was taken, revealing metastatic cervical cancer at the site of a previous port-site incision for a cholecystectomy that the patient underwent 18 months before the finding. DISCUSSION: Port-site metastasis have been reported following kidney, bladder, and colon cancer resections, with reports of cervical cancer cases being exceedingly rare. Several hypotheses have emerged as potential explanations for port-site metastasis. CONCLUSION: To our knowledge, this represents the first reported case of a port-site metastasis to an incision site created for an unrelated laparoscopic surgery, performed well in advance of the diagnosis of cervical cancer. PMID- 26519809 TI - Pneumoperitoneum, pneumoretroperitoneum, pneumomediastinum and extensive subcutaneous emphysema in a patient with ulcerative colitis: A case report. AB - INTRODUCTION: Pneumo-mediastinum and subcutaneous emphysema are rare presentations of lower gastrointestinal tract perforation. PRESENTATION OF CASE: We are presenting the case of a middle aged man diagnosed with UC who presented with dyspnea and subcutaneous emphysema, attributed to multiple perforations including the stomach and colon. CASE DISCUSSION: Patients with ulcerative colitis (UC) are at an increased risk of perforations due to friability of colonic mucosa given the chronic inflammation and relapsing flares. Chronic use of steroids further predisposes to stress ulcers. These pathologies sometimes coexist and identification of each is crucial for the appropriate treatment plan. CONCLUSION: The case allows for a learning opportunity focusing on coexisting pathologies which may be differentiated based on anatomical knowledge and patient presentation. PMID- 26519810 TI - Colon cancer presented with sigmoid volvulus: A case report. AB - INTRODUCTION: Sigmoid volvulus is the most prevalent type of colonic volvulus. Colon cancer is seen less where sigmoid volvulus is common, so it is rare to see that colon cancer is synchronous with sigmoid volvulus. PRESENTATION OF CASE: We would like to present a case of sigmoid volvulus caused by colon cancer in a male patient aged 80 who was referred to the hospital with toxaemic shock presentation. DISCUSSION: Sigmoid cancer can be presented as sigmoid volvulus to the emergency department. In intestinal obstruction early diagnosis is of crucial importance. Computarized tomography is a diagnosis tool that should be preferred both in the diagnosis of obstruction and in detecting its cause, localisation, degree and complications. CONCLUSION: When surgery is performed due to the urgent colonic obstruction in colonic volvulus diagnosed patients, a colon tumour should be considered in the same column loops or in the distal colon. We believe that CT is the method that should be preferred in large-bowel obstruction suspected patients. PMID- 26519811 TI - Percutaneous endoscopic sigmoidopexy for sigmoid volvulus: A case report. AB - INTRODUCTION: Sigmoid volvulus often recurs and it is controversial whether preventive surgery should be performed in recurrent cases, especially in elderly and high-risk cases. Herein, we report a case of successful endoscopic sigmoidopexy using fixation to the abdominal wall. CASE PRESENTATION: The patient was an 86-year-old woman with multiple system atrophy, cerebral infarction, and disuse syndrome. She was admitted to our hospital with a recurrent sigmoid volvulus. Since surgery was considered high-risk, percutaneous endoscopic sigmoidopexy with fixation to the abdominal wall was indicated. DISCUSSION: Percutaneous endoscopic sigmoidopexy was performed for this high-risk case with recurrent sigmoid volvulus. This procedure is advantageous in that suture removal is not necessary because the fixation sutures are buried subcutaneously. Reviewing the relevant literature, we believe that this is the first case of percutaneous endoscopic sigmoidopexy using abdominal wall fixation with buried sutures. CONCLUSION: Although further experience is necessary, percutaneous endoscopic sigmoidopexy may be an acceptable treatment for recurrent sigmoid volvulus in high-risk patients. PMID- 26519812 TI - Perforation of intramural gastric metastasis during preoperative chemotherapy in a patient with thoracic esophageal squamous cell carcinoma. AB - INTRODUCTION: Perforation of intramural metastasis to the stomach (IMS) from esophageal cancer during chemotherapy has not been reported. PRESENTATION OF CASE: A 68-year-old male consulted our hospital due to appetite loss. He was diagnosed with advanced esophageal squamous cell carcinoma in the lower thoracic esophagus along with a large IMS in the upper stomach. The patient received preoperative chemotherapy of docetaxel, cisplatin, and 5-fluorouracil (DCF). During the second cycle of DCF, he had upper abdominal pain and was diagnosed with gastric perforation. Omental implantation repair for the perforation, peritoneal drainage, tube-gastrostomy, and tube-jejunostomy were performed. At 24 days after emergency surgery, he underwent thoracoscopic radical esophagectomy with total gastrectomy and reconstruction with colonic interposition. Pathological findings in the esophagus demonstrated complete replacement of the tumor by fibrosis. The gastric tumor was replaced by scar tissue with multinucleated giant cells along with a small amount of viable cancer cells. The patient was alive and healthy at 14 months after the radical operation, without tumor recurrence. DISCUSSION: The gastric perforation occurred due to rapid regression of the IMS which had involved the whole gastric wall before chemotherapy. Close monitoring to detect rapid tumor shrinkage during chemotherapy in patients with IMS may be warranted. A two-step operation was proposed to achieve safe curative treatment in patients with perforation of IMS during preoperative chemotherapy. CONCLUSION: We describe the first reported case of a patient with esophageal squamous cell carcinoma who showed perforation of IMS during preoperative chemotherapy. PMID- 26519813 TI - Late-presenting right congenital diaphragmatic hernia with severe hypotrophy of the right lobe of the liver. AB - INTRODUCTION: Congenital diaphragmatic hernia (CDH) presenting after 30 days of life is unusual and has a variant pattern of presentation. PRESENTATION OF CASE: We present a death case occurred to a 34-days-old infant. The infant arrived to our emergency department in cardiac arrest after having suffered from intermittent acute abdominal pain. Autopsy confirmed the presence of a right CDH, with herniation of the right lobe of the liver into the thorax. DISCUSSION: Most of the cases of CDH are diagnosed prenatally or in the neonatal period. However, some patients do not develop symptoms until after the neonatal period. The relevance of our case is the co-existence of right CDH and important hypotrophy of the right lobe of the liver. CONCLUSIONS: Evidence of this phenomenon represents an absolute novelty in the extant scientific literature. Even if rare, we suggest to suspect the presence of CDH in fetus with disparity in right and left liver lobe at prenatal ultrasound. PMID- 26519814 TI - Root and shoot performance of Arabidopsis thaliana exposed to elevated CO2: A physiologic, metabolic and transcriptomic response. AB - The responsiveness of C3 plants to raised atmospheric [CO2] levels has been frequently described as constrained by photosynthetic downregulation. The main goal of the current study was to characterize the shoot-root relationship and its implications in plant responsiveness under elevated [CO2] conditions. For this purpose, Arabidopsis thaliana plants were exposed to elevated [CO2] (800ppm versus 400ppm [CO2]) and fertilized with a mixed (NH4NO3) nitrogen source. Plant growth, physiology, metabolite and transcriptomic characterizations were carried out at the root and shoot levels. Plant growth under elevated [CO2] conditions was doubled due to increased photosynthetic rates and gas exchange measurements revealed that these plants maintain higher photosynthetic rates over extended periods of time. This positive response of photosynthetic rates to elevated [CO2] was caused by the maintenance of leaf protein and Rubisco concentrations at control levels alongside enhanced energy efficiency. The increased levels of leaf carbohydrates, organic acids and amino acids supported the augmented respiration rates of plants under elevated [CO2]. A transcriptomic analysis allowed the identification of photoassimilate allocation and remobilization as fundamental process used by the plants to maintain the outstanding photosynthetic performance. Moreover, based on the relationship between plant carbon status and hormone functioning, the transcriptomic analyses provided an explanation of why phenology accelerates under elevated [CO2] conditions. PMID- 26519815 TI - Atom probe tomography (APT) of carbonate minerals. AB - Atom probe tomography (APT) combines the highest spatial resolution with chemical data at atomic scale for the analysis of materials. For geological specimens, the process of field evaporation and molecular ion formation and interpretation is not yet entirely understood. The objective of this study is to determine the best conditions for the preparation and analysis by APT of carbonate minerals, of great importance in the interpretation of geological processes, focusing on the bulk chemical composition. Results show that the complexity of the mass spectrum is different for calcite and dolomite and relates to dissimilarities in crystalochemical parameters. In addition, APT bulk chemistry of calcite closely matches the expected stoichiometry but fails to provide accurate atomic percentages for elements in dolomite under the experimental conditions evaluated in this work. For both calcite and dolomite, APT underestimates the amount of oxygen based on their chemical formula, whereas it is able to detect small percentages of elemental substitutions in crystal lattices. Overall, our results demonstrate that APT of carbonate minerals is possible, but further optimization of the experimental parameters are required to improve the use of atom probe tomography for the correct interpretation of mineral geochemistry. PMID- 26519816 TI - The plant virus microscope image registration method based on mismatches removing. AB - The electron microscopy is one of the major means to observe the virus. The view of virus microscope images is limited by making specimen and the size of the camera's view field. To solve this problem, the virus sample is produced into multi-slice for information fusion and image registration techniques are applied to obtain large field and whole sections. Image registration techniques have been developed in the past decades for increasing the camera's field of view. Nevertheless, these approaches typically work in batch mode and rely on motorized microscopes. Alternatively, the methods are conceived just to provide visually pleasant registration for high overlap ratio image sequence. This work presents a method for virus microscope image registration acquired with detailed visual information and subpixel accuracy, even when overlap ratio of image sequence is 10% or less. The method proposed focus on the correspondence set and interimage transformation. A mismatch removal strategy is proposed by the spatial consistency and the components of keypoint to enrich the correspondence set. And the translation model parameter as well as tonal inhomogeneities is corrected by the hierarchical estimation and model select. In the experiments performed, we tested different registration approaches and virus images, confirming that the translation model is not always stationary, despite the fact that the images of the sample come from the same sequence. The mismatch removal strategy makes building registration of virus microscope images at subpixel accuracy easier and optional parameters for building registration according to the hierarchical estimation and model select strategies make the proposed method high precision and reliable for low overlap ratio image sequence. PMID- 26519817 TI - Cytotoxicity evaluation of large cyanobacterial strain set using selected human and murine in vitro cell models. AB - The production of cytotoxic molecules interfering with mammalian cells is extensively reported in cyanobacteria. These compounds may have a use in pharmacological applications; however, their potential toxicity needs to be considered. We performed cytotoxicity tests of crude cyanobacterial extracts in six cell models in order to address the frequency of cyanobacterial cytotoxicity to human cells and the level of specificity to a particular cell line. A set of more than 100 cyanobacterial crude extracts isolated from soil habitats (mainly genera Nostoc and Tolypothrix) was tested by MTT test for in vitro toxicity on the hepatic and non-hepatic human cell lines HepG2 and HeLa, and three cell systems of rodent origin: Yac-1, Sp-2 and Balb/c 3T3 fibroblasts. Furthermore, a subset of the extracts was assessed for cytotoxicity against primary cultures of human hepatocytes as a model for evaluating potential hepatotoxicity. Roughly one third of cyanobacterial extracts caused cytotoxic effects (i.e. viability<75%) on human cell lines. Despite the sensitivity differences, high correlation coefficients among the inhibition values were obtained for particular cell systems. This suggests a prevailing general cytotoxic effect of extracts and their constituents. The non-transformed immortalized fibroblasts (Balb/c 3T3) and hepatic cancer line HepG2 exhibited good correlations with primary cultures of human hepatocytes. The presence of cytotoxic fractions in strongly cytotoxic extracts was confirmed by an activity-guided HPLC fractionation, and it was demonstrated that cyanobacterial cytotoxicity is caused by a mixture of components with similar hydrophobic/hydrophilic properties. The data presented here could be used in further research into in vitro testing based on human models for the toxicological monitoring of complex cyanobacterial samples. PMID- 26519818 TI - Family association study between melatonin receptor gene polymorphisms and polycystic ovary syndrome in Han Chinese. AB - OBJECTIVE: The melatonin receptor (MTNR) gene, reported to be associated with insulin sensitivity, diabetes and metabolic syndrome, could be a plausible candidate gene for polycystic ovary syndrome (PCOS). This study was designed to investigate whether an association exists between two single nucleotide polymorphism (SNP) variants (rs2119882 and rs10830963) of the MTNR gene and PCOS in Han Chinese. STUDY DESIGN: In total, 263 family trios (789 participants) were enrolled in this family-based transmission disequilibrium test (TDT). Genotypes were obtained by sequencing. In total, 135 trios of rs2119882 and 127 trios of rs10830963 were tested. RESULTS: An association was detected between rs2119882 (p=0.0209) and PCOS, suggesting that the MTNR gene may indicate increased susceptibility to PCOS in Chinese. No significant association was found for rs10830963 (transmitted:non-transmitted=76:51, p=0.1573). The association between the MTNR gene variants and clinical characteristics of women with PCOS was investigated. CC genotype carriers had higher levels of clinical and metabolic features than the TC and TT genotypes. A significant difference in transmission of allele C of rs2119882 was found between obese and non-obese women with PCOS (Chi-squared=5.5983, p=0.018). CONCLUSION: This study may provide a basis for further studies of the MTNR gene in the aetiology of PCOS. PMID- 26519819 TI - Outcomes of patients who declined randomization to MiniMo trial. AB - OBJECTIVE: To evaluate lower urinary tract outcomes of eligible women who declined randomization to MiniArc((r)) versus MonarcTM (MiniMo) RCT. To explore reasons why eligible women declined participation. STUDY DESIGN: The medical records of 44 women who declined randomization to MiniMo were reviewed. Women had a phone questionnaire at a mean of 2.4 years after surgery (range 1.3-3.9) and asked to document their symptoms at 6 and 12 months after operation, if they had not attended previously. Objective cure was defined as a negative cough stress test. Subjective cure was defined as patient reporting no leak on cough, sneeze or exercise. Outcomes of patients who declined were compared with those who participated in the MiniMo RCT. Women were asked to outline their reasons for declining participation in the MiniMo RCT. RESULTS: Baseline characteristics were similar except for BMI, which was higher in the declined group compared to the randomized group. Subjective cure at 6 months (79% vs. 94%, p=0.01) and 12 months was significantly lower in the declined group (58% vs. 93%, p<0.001). The commonest reason for declining participation in this study was the requirement for additional follow up. CONCLUSIONS: Results of RCTs may be overstated compared to standard clinical care as seen in this study. PMID- 26519820 TI - Short-term response to waterlogging in Quercus petraea and Quercus robur: A study of the root hydraulic responses and the transcriptional pattern of aquaporins. AB - We characterized the short-term response to waterlogging in Quercus petraea (Matt.) Liebl. and Quercus robur L. as the initial response towards their known long-term differences in tolerance to waterlogging. One-month old seedlings were subjected to hypoxic stress and leaf gas exchange, shoot water potential (Psis) and root hydraulic conductivity (Lpr) were measured. In parallel, the expression of nine aquaporins (AQPs) along the primary root was analysed by quantitative RT PCR. Results showed a similar reduction in net assimilation (A) and stomatal conductance (gs) for the two species. Notably, the response of Lpr differed temporally between the two species. Q. robur seedlings exhibited a significant early decline of Lpr within the first 5 h that returned to control levels after 48 h, whereas Q. petraea seedlings showed a delayed response with a significant decrease of Lpr exhibited only after 48 h. Transcriptional profiling revealed that three genes (PIP1;3, TIP2;1 and TIP2;2) were differentially regulated under stress conditions in the two oak species. Taken together, these results suggested species-specific responses to short-term waterlogging in terms of root water transport. PMID- 26519821 TI - Cloning, heterologous expression and characterization of ascorbate peroxidase (APX) gene in laticifer cells of rubber tree (Hevea brasiliensis Muell. Arg.). AB - Ascorbate peroxidases (APXs) are a kind of crucial enzymes for removing reactive oxygen species (ROS) in plant cell. In the present study, a full-length cDNA encoding an APX, designated HbAPX, was isolated from Hevea brasiliensis by the rapid amplification of cDNA ends (RACE) method. HbAPX was 1174-bp in length and contained a 912-bp open reading frame (ORF) encoding a putative protein of 304 amino acids. The predicted molecular mass of HbAPX was 27.6 kDa (kDa) with an isoelectric point (pI) of 6.73. The phylogenetic analysis showed that HbAPX belonged to the cytosolic subgroup and was more relative to PtAPX and MdAPX2. By using PlantCare online analysis, such cis-acting elements as W-box and MRE were detected in the promoter region of HbAPX. Overproduction of recombinant HbAPX protein either in Escherichia coli or yeast enhanced their tolerance to such abiotic stresses as Cu(2+), Zn(2+), Na(2+) and hydrogen peroxide (H2O2). Ethrel application significantly down-regulated the expression of HbAPX and inhibited the activity of HbAPX in vivo. The ethrel-caused down-regulation of HbAPX may disturb the redox homeostasis in laticifer cells of rubber tree. PMID- 26519822 TI - Contribution of the finite volume point dilution method for measurement of groundwater fluxes in a fractured aquifer. AB - Measurement of groundwater fluxes is the basis of all hydrogeological study, from hydraulic characterization to the most advanced reactive transport modeling. Usual groundwater flux estimation with Darcy's law may lead to cumulated errors on spatial variability, especially in fractured aquifers where local direct measurement of groundwater fluxes becomes necessary. In the present study, both classical point dilution method (PDM) and finite volume point dilution method (FVPDM) are compared on the fractured crystalline aquifer of Ploemeur, France. The manipulation includes the first use of the FVPDM in a fractured aquifer using a double packer. This configuration limits the vertical extent of the tested zone to target a precise fracture zone of the aquifer. The result of this experiment is a continuous monitoring of groundwater fluxes that lasted for more than 4 days. Measurements of groundwater flow rate in the fracture (Q(t)) by PDM provide good estimates only if the mixing volume (V(w)) (volume of water in which the tracer is mixed) is precisely known. Conversely, the FVPDM allows for an independent estimation of V(w) and Q(t), leading to better precision in case of complex experimental setup such as the one used. The precision of a PDM does not rely on the duration of the experiment while a FVPDM may require long experimental duration to guarantees a good precision. Classical PDM should then be used for rapid estimation of groundwater flux using simple experimental setup. On the other hand, the FVPDM is a more precise method that has a great potential for development but may require longer duration experiment to achieve a good precision if the groundwater fluxes investigated are low and/or the mixing volume is large. PMID- 26519823 TI - Cadmium treatment suppresses DNA polymerase delta catalytic subunit gene expression by acting on the p53 and Sp1 regulatory axis. AB - Cadmium (Cd) is a carcinogenic and neurotoxic environmental pollutant. Among the proposed mechanisms for Cd toxic effects, its ability to promote oxidative stress and to inhibit, in vitro, the activities of some Base Excision DNA Repair (BER) enzymes, such as hOGG1, XRCC1 and APE1, have been already established. However, the molecular mechanisms at the basis of these processes are largely unknown especially at sub-lethal doses of Cd and no information is available on the effect of Cd on the expression levels of BER enzymes. Here, we show that non toxic treatment of neuronal cell lines, with pro-mitogenic doses of Cd, promotes a significant time- and dose-dependent down-regulation of DNA polymerase delta (POLD1) expression through a transcriptional mechanism with a modest effect on Polbeta, XRCC1 and APE1. We further elucidated that the observed transcriptional repression on Poldelta is acted by through competition by activated p53 on Sp1 at POLD1 promoter and by a squelching effect. We further proved the positive effect of Sp1 not only on POLD1 expression but also on Polbeta, XRCC1 and APE1 expression, suggesting that Sp1 has pleiotropic effects on the whole BER pathway. Our results indicated that Cd-mediated impairment of BER pathway, besides acting on the enzymatic functions of some key proteins, is also exerted at the gene expression level of Poldelta by acting on the p53-Sp1 regulatory axis. These data may explain not only the Cd-induced neurotoxic effects but also the potential carcinogenicity of this heavy metal. PMID- 26519824 TI - Poly(ADP-ribose)-binding promotes Exo1 damage recruitment and suppresses its nuclease activities. AB - Exonuclease 1 (Exo1) has important roles in DNA metabolic transactions that are essential for genome maintenance, telomere regulation and cancer suppression. However, the mechanisms for regulating Exo1 activity in these processes remain incompletely understood. Here, we report that Exo1 activity is regulated by a direct interaction with poly(ADP-ribose) (PAR), a prominent posttranslational modification at the sites of DNA damage. This PAR-binding activity promotes the early recruitment of Exo1 to sites of DNA damage, where it is retained through an interaction with PCNA, which interacts with the C-terminus of Exo1. The effects of both PAR and PCNA on Exo1 damage association are antagonized by the 14-3-3 adaptor proteins, which interact with the central domain of Exo1. Although PAR binding inhibits both the exonuclease activity and the 5' flap endonuclease activity of purified Exo1, the pharmacological blockade of PAR synthesis does not overtly affect DNA double-strand break end resection in a cell free Xenopus egg extract. Thus, the counteracting effects of PAR on Exo1 recruitment and enzymatic activity may enable appropriate resection of DNA ends while preventing unscheduled or improper processing of DNA breaks in cells. PMID- 26519825 TI - Versatility in phospho-dependent molecular recognition of the XRCC1 and XRCC4 DNA damage scaffolds by aprataxin-family FHA domains. AB - Aprataxin, aprataxin and PNKP-like factor (APLF) and polynucleotide kinase phosphatase (PNKP) are key DNA-repair proteins with diverse functions but which all contain a homologous forkhead-associated (FHA) domain. Their primary binding targets are casein kinase 2-phosphorylated forms of the XRCC1 and XRCC4 scaffold molecules which respectively coordinate single-stranded and double-stranded DNA break repair pathways. Here, we present the high-resolution X-ray structure of a complex of phosphorylated XRCC4 with APLF, the most divergent of the three FHA domain family members. This, combined with NMR and biochemical analysis of aprataxin and APLF binding to singly and multiply-phosphorylated forms of XRCC1 and XRCC4, and comparison with PNKP reveals a pattern of distinct but overlapping binding specificities that are differentially modulated by multi-site phosphorylation. Together, our data illuminate important differences between activities of the three phospho-binding domains, in spite of a close evolutionary relationship between them. PMID- 26519827 TI - Exo1 and Mre11 execute meiotic DSB end resection in the protist Tetrahymena. AB - The resection of 5'-DNA ends at a double-strand break (DSB) is an essential step in recombinational repair, as it exposes 3' single-stranded DNA (ssDNA) tails for interaction with a repair template. In mitosis, Exo1 and Sgs1 have a conserved function in the formation of long ssDNA tails, whereas this step in the processing of programmed meiotic DSBs is less well-characterized across model organisms. In budding yeast, which has been most intensely studied in this respect, Exo1 is a major meiotic nuclease. In addition, it exerts a nuclease independent function later in meiosis in the conversion of DNA joint molecules into ZMM-dependent crossovers. In order to gain insight into the diverse meiotic roles of Exo1, we investigated the effect of Exo1 deletion in the ciliated protist Tetrahymena. We found that Exo1 together with Mre11, but without the help of Sgs1, promotes meiotic DSB end resection. Resection is completely eliminated only if both Mre11 and Exo1 are missing. This is consistent with the yeast model where Mre11 promotes resection in the 3'-5' direction and Exo1 in the opposite 5' 3' direction. However, while the endonuclease activity of Mre11 is essential to create an entry site for exonucleases and hence to start resection in budding yeast, Tetrahymena Exo1 is able to create single-stranded DNA in the absence of Mre11. Excluding a possible contribution of the Mre11 cofactor Sae2 (Com1) as an autonomous endonuclease, we conclude that there exists another unknown nuclease that initiates DSB processing in Tetrahymena. Consistent with the absence of the ZMM crossover pathway in Tetrahymena, crossover formation is independent of Exo1. PMID- 26519826 TI - Role of mismatch repair proteins in the processing of cisplatin interstrand cross links. AB - Mismatch repair (MMR) deficiency gives rise to cisplatin resistance and can lead to poor prognosis in cancers. Various models have been proposed to explain this low level of resistance caused due to loss of MMR proteins. We have shown that MMR proteins are required to maintain cisplatin interstrand cross-links (ICLs) on the DNA leading to increased cellular sensitivity. In our previous studies, we have shown that BER processing of the cisplatin ICLs is mutagenic. Polymerase beta (Polbeta) can generate mismatches which leads to the activation and the recruitment of mismatch repair proteins. In this paper, we distinguished between the requirement of different downstream MMR proteins for maintaining cisplatin sensitivity. We show that the MutSalpha (MSH2-MSH6) heterocomplex is required to maintain cisplatin sensitivity, whereas the Mutsbeta complex has no effect. These results can be correlated with the increased repair of cisplatin ICLs and ICL induced DNA double strand breaks (DSBs) in the resistant cells. Moreover, we show that MLH1 proficient cells displayed a cisplatin sensitive phenotype when compared with the MLH1 deficient cells and the ATPase activity of MLH1 is essential to mediate this effect. Based on these results, we propose that MutSalpha as well as the downstream MMR pathway proteins are essential to maintain a cisplatin sensitive phenotype as a consequence of processing Polbeta induced mismatches at sites flanking cisplatin ICLs. PMID- 26519828 TI - Photobiomodulation with 660-nm and 780-nm laser on activated J774 macrophage-like cells: Effect on M1 inflammatory markers. AB - M1 profile macrophages exert a major influence on initial tissue repair process. Few days after the occurrence of injury, macrophages in the injured region exhibit a M2 profile, attenuate the effects of the M1 population, and stimulate the reconstruction of the damaged tissue. The different effects of macrophages in the healing process suggest that these cells could be the target of therapeutic interventions. Photobiomodulation has been used to accelerate tissue repair, but little is known regarding its effect on macrophages. In the present study, J774 macrophages were activated to simulate the M1 profile and irradiated with two different sets of laser parameters (780 nm, 70 mW, 2.6J/cm(2), 1.5s and 660 nm, 15 mW, 7.5 J/cm(2), 20s). IL-6, TNF-alpha, iNOS and COX-2 gene and protein expression were analyzed by RT-qPCR and ELISA. Both lasers were able to reduce TNF-alpha and iNOS expression, and TNF-alpha and COX-2 production, although the parameters used for 780 nm laser provided an additional decrease. 660 nm laser parameters resulted in an up-regulation of IL-6 expression and production. These findings imply a distinct, time-dependent modulation by the two different sets of laser parameters, suggesting that the best modulation may involve more than one combination of parameters. PMID- 26519829 TI - Chronic exposure to hexachlorobenzene results in down-regulation of connexin43 in the breast. AB - Decreased expression of connexins has been associated with cancer, but the underlying mechanisms are poorly understood. We have previously shown that a 5 day exposure to hexachlorobenzene (HCB) resulted in decreased connexins expression in hepatocytes 45 days later, and that this down-regulation was linked to activation of Akt through the ILK pathway. Because HCB promotes cancer in both the liver and breast, the present study aimed to determine if the mechanisms are similar in both tissues. MCF-12A breast cells were thus transfected with vectors coding for either Akt or a constitutively active form of Akt. In those cells, activation of Akt was correlated with decreased Cx43 levels. Female rats were then exposed to HCB by gavage either following the same protocol used previously for the liver or through a chronic exposure. While no changes were observed after the 5 days exposure protocol, chronic exposure to HCB resulted in increased Akt levels and decreased Cx43 levels in breast cells. In vitro, Akt was activated in MCF-12A cells exposed to HCB either for 7 days or chronically, but no changes were observed in junctional proteins. Together, these results suggested that, while activation of Akt can decrease Cx43 expression in breast cells in vitro, other mechanisms are involved during HCB exposure, leading to a decrease in Cx43 levels in a model- and duration-dependent manner. Finally, we showed that HCB effects are tissue specific, as we did not observe the same results in breast and liver tissues. PMID- 26519830 TI - The influence of extreme river discharge conditions on the quality of suspended particulate matter in Rivers Meuse and Rhine (The Netherlands). AB - As a consequence of climate change, increased precipitation in winter and longer periods of decreased precipitation in summer are expected to cause more frequent episodes of very high or very low river discharge in the Netherlands. To study the impact of such extreme river discharge conditions on water quality, toxicity profiles and pollutant profiles were determined of suspended particulate matter (SPM) collected from Rivers Meuse and Rhine. Archived (1993-2003) and fresh (2009 2011) SPM samples were selected from the Dutch annual monitoring program of the national water bodies (MWTL), representing episodes with river discharge conditions ranging from very low to regular to very high. SPM extracts were tested in a battery of in vitro bioassays for their potency to interact with the androgen receptor (AR), the estrogen receptor (ER), the arylhydrocarbon receptor (AhR), and the thyroid hormone transporter protein transthyretin (TTR). SPM extracts were further tested for their mutagenic potency (Ames assay) and their potency to inhibit bacterial respiration (Vibrio fischeri bioluminescence assay). Target-analyzed pollutant concentrations of the SPM samples and additional sample information were retrieved from a public database of MWTL results. In vitro toxicity profiles and pollutant profiles were analyzed in relation to discharge conditions and in relation to each other using correlation analysis and multivariate statistics. Compared to regular discharge conditions, composition of SPM during very high River Meuse and Rhine discharges shifted to more coarse, sandy, organic carbon (OC) poor particles. On the contrary, very low discharge led to a shift to more fine, OC rich material, probably dominated by algae. This shift was most evident in River Meuse, which is characterized by almost stagnant water conditions during episodes of drought. During such episodes, SPM extracts from River Meuse demonstrated increased potencies to inhibit bacterial respiration and to compete with thyroid hormone to bind to TTR, possibly due to the presence of fycotoxins. Meanwhile concentrations of polychlorobiphenyls (PCBs) in SPM were also increased. Very high River Meuse discharges on the other hand corresponded to increased androgenic and AhR agoniztic responses, which coincided with increased PAH levels and PAH-related in vivo risk estimates (i.e. multi-substance potentially affected fraction of species; msPAF). In River Rhine, very high discharges also corresponded to increasing androgenic potencies in SPM. Concentrations and corresponding msPAF values of PAHs (and metals), however, decreased with very high discharges in River Rhine in contrast to River Meuse. Mutagenicity was observed for SPM extracts from River Rhine collected during all discharge conditions, except during regular discharge. Aggregated toxicity index values, which were useful to identify toxicity profiles deviating from the generally observed pattern, did not correlate with river discharges, probably due to opposite effects of discharge conditions on different bioassay responses. In conclusion, SPM quality and related in vivo risk estimates changed during very low or very high discharge conditions but the changes were specific for the different toxic endpoints and pollutants in the different rivers. Moreover, bioassay responses to a series of consecutively collected samples from River Rhine during the Christmas flood of 1993 indicated that SPM quality is variable within a single episode of extreme discharge. PMID- 26519832 TI - Snapping Turtles (Chelydra serpentina) from Canadian Areas of Concern across the southern Laurentian Great Lakes: Chlorinated and brominated hydrocarbon contaminants and metabolites in relation to circulating concentrations of thyroxine and vitamin A. AB - The metabolites of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), as well as other halogenated phenolic contaminants (HPCs) have been shown to have endocrine-disrupting properties, and have been reported with increasing frequency in the blood of wildlife, and mainly in mammals and birds. However, little is known about the persistence, accumulation and distribution of these contaminants in long-lived freshwater reptiles. In the present study, in addition to a large suite of chlorinated and brominated contaminants, metabolites and HPCs, we assessed and compared hydroxylated (OH) PCBs and OH-PBDEs relative to PCBs and PBDEs, respectively, in the plasma of adult male common snapping turtles (Chelydra serpentina). Blood samples were collected from 62 snapping turtles (2001-2004) at 12 wetland sites between the Detroit River and the St. Lawrence River on the Canadian side of the Laurentian Great Lakes of North America. Turtles were sampled from sites designated as Areas of Concern (AOCs) and from a relatively clean reference site in southern Georgian Bay (Tiny Marsh), Lake Huron. Plasma concentrations of Sigma46PCB (10-340 ng/g wet weight (ww)) and Sigma28OH-PCB (3-83 ng/g ww) were significantly greater (p<0.05) in turtles from the Turkey Creek and Muddy Creek-Wheatley Harbour sites in Lake Erie compared with the reference site turtles. The HPC, pentachlorophenol (PCP), had a mean concentration of 9.6+/-1.1 ng/g ww. Of the 28 OH-CB congeners screened for, 4-OH CB187 (42+/-7 ng/g ww) was the most concentrated of all HPCs measured. Of the 14 OH-BDE congeners examined, four (4'-OH-BDE17, 3-OH-BDE47, 5-OH-BDE47 and 4'-OH BDE49) were consistently found in all plasma samples. p,p'-DDE was the most concentrated of the 18 organochlorine pesticides (OCPs) examined. The mean concentrations of circulating total thyroxine (TT4), dehydroretinol and retinol in the plasma of the male snapping turtles regardless of sampling site were 5.4+/ 0.3, 81+/-4.7 and 291+/-13 ng/mL, respectively. Significant (p<0.05) negative (e.g. cis-chlordane) or positive (e.g. BDE-99) correlations between some of the target contaminants and TT4, dehydroretinol or retinol were observed. To our knowledge, we report for the first time on HPC (e.g. OH-PCBs) and methylsulfonyl- (MeSO2-) PCB metabolite contaminants in the plasma of any freshwater turtle or freshwater reptilian species. Our findings also show that the accumulation of OH PCBs, MeSO2-PCBs, OH-PBDEs and some OCPs in the snapping turtles from Lake Erie and Lake Ontario (in 2001-2004) had the potential for eliciting endocrine disruption. Exposure to these contaminants and associated adverse effects on the endocrine system in freshwater reptiles and the related mechanisms require further investigation. PMID- 26519831 TI - Dialkyl phosphate urinary metabolites and chromosomal abnormalities in human sperm. AB - BACKGROUND: The past decade has seen numerous human health studies seeking to characterize the impacts of environmental exposures, such as organophosphate (OP) insecticides, on male reproduction. Despite an extensive literature on OP toxicology, many hormone-mediated effects on the testes are not well understood. OBJECTIVES: This study investigated environmental exposures to OPs and their association with the frequency of sperm chromosomal abnormalities (i.e., disomy) among adult men. METHODS: Men (n=159) from a study assessing the impact of environmental exposures on male reproductive health were included in this investigation. Multi-probe fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 was used to determine XX18, YY18, XY18 and total disomy in sperm nuclei. Urine was analyzed using gas chromatography coupled with mass spectrometry for concentrations of dialkyl phosphate (DAP) metabolites of OPs [dimethylphosphate (DMP); dimethylthiophosphate (DMTP); dimethyldithiophosphate (DMDTP); diethylphosphate (DEP); diethylthiophosphate (DETP); and diethyldithiophosphate (DEDTP)]. Poisson regression was used to model the association between OP exposures and disomy measures. Incidence rate ratios (IRRs) were calculated for each disomy type by exposure quartiles for most metabolites, controlling for age, race, BMI, smoking, specific gravity, total sperm concentration, motility, and morphology. RESULTS: A significant positive trend was seen for increasing IRRs by exposure quartiles of DMTP, DMDTP, DEP and DETP in XX18, YY18, XY18 and total disomy. A significant inverse association was observed between DMP and total disomy. Findings for total sum of DAP metabolites concealed individual associations as those results differed from the patterns observed for each individual metabolite. Dose-response relationships appeared nonmonotonic, with most of the increase in disomy rates occurring between the second and third exposure quartiles and without additional increases between the third and fourth exposure quartiles. CONCLUSIONS: This is the first epidemiologic study of this size to examine the relationship between environmental OP exposures and human sperm disomy outcomes. Our findings suggest that increased disomy rates were associated with specific DAP metabolites, suggesting that the impacts of OPs on testis function need further characterization in epidemiologic studies. PMID- 26519833 TI - Treatment of active duty military with PTSD in primary care: A follow-up report. AB - First-line trauma-focused therapies offered in specialty mental health clinics do not reach many veterans and active duty service members with posttraumatic stress disorder (PTSD). Primary care is an ideal environment to expand access to mental health care. Several promising clinical case series reports of brief PTSD therapies adapted for primary care have shown positive results, but the long-term effectiveness with military members is unknown. The purpose of this study was to determine the long-term outcome of an open trial of a brief cognitive-behavioral primary care-delivered protocol developed specifically for deployment-related PTSD in a sample of 24 active duty military (15 men, 9 women). Measures of PTSD symptom severity showed statistically and clinically significant reductions from baseline to posttreatment that were maintained at the 6-month and 1-year follow up assessments. Similar reductions were maintained in depressive symptoms and ratings of global mental health functioning. PMID- 26519834 TI - Histological responses and localization of the cytochrome P450 (CYP2AU1) in Crassostrea brasiliana exposed to phenanthrene. AB - Phenanthrene (PHE) is an abundant polycyclic aromatic hydrocarbon (PAH), widely distributed in aquatic environment. The aim of this study was to evaluate the histological and molecular effects in the native oyster Crassostrea brasiliana(Lamarck, 1819) exposed to 100 and 1000 MUg L(-1) PHE for 1, 5 and 10 days. Histological and chemical analyses were performed to evaluate, respectively, alterations in oyster tissues and bioaccumulation. In situ hybridization (ISH) was used to assess tissue distribution of CYP2AU1, a gene formerly identified as activated by PHE exposure in this species.Quantitative polymerase chain reaction (qPCR) in mantle was carried out to validate ISH data. Oysters bioaccumulated PHE increasingly along the exposure period in both exposure concentrations. Histologic changes, like tubular atrophy in digestive diverticula (digestive gland) and increased number of mucous cells in the mantle were observed in animals exposed to PHE for 10 days. ISH showed the presence of CYP2AU1transcripts in gills, digestive diverticula, mantle, intestine and gonads, but significant differences in transcript detection by ISH between treatments occurred only in gills, mantle and intestine. A positive and significant correlation between tubular atrophy and CYP2AU1hybridization signal was observed in digestive diverticula, suggesting that this gene product might be involved in energetic metabolism in C. brasiliana. Increased mucous cells and CYP2AU1transcript levels were observed in the mantle, where the inner and middle lobes showed higher intensity of hybridization signal. Mantle should be considered as a target organ for CYP2AU1 transcript evaluation and histological alterations in biomonitoring studies. CYP2AU1 signal in female gonads was observed in all follicular cells from different gonadic stages, while in male only the spermatic follicle cells of the wall in the pre-spawning stage showed this signal. ISH was an effective technique to evaluate the effects of PHE exposure and to locate CYP2AU1 transcripts in different tissues of oyster C. brasiliana. PMID- 26519835 TI - 17alpha-Ethinylestradiol (EE2) effect on global gene expression in primary rainbow trout (Oncorhynchus mykiss) hepatocytes. AB - The potential impact of endocrine disrupting chemicals (EDCs) in the aquatic environment has driven the development of screening assays to evaluate the estrogenic properties of chemicals and their effects on aquatic organisms such as fish. However, obtaining full concentration-response relationships in animal (in vivo) exposure studies are laborious, costly and unethical, hence a need for developing feasible alternative (non-animal) methods. Use of in vitro bioassays such as primary fish hepatocytes, which retain many of the native properties of the liver, has been proposed for in vitro screening of estrogen receptor (ER) agonists and antagonists. The aim of present study was to characterize the molecular mode of action (MoA) of the ER agonist 17alpha-ethinylestradiol (EE2) in primary rainbow trout (Oncorhynchus mykiss) hepatocytes. A custom designed salmonid 60,000-feature (60k) oligonucleotide microarray was used to characterize the potential MoAs after 48h exposure to EE2. The microarray analysis revealed several concentration-dependent gene expression alterations including classical estrogen sensitive biomarker gene expression (e.g. estrogen receptor alpha, vitellogenin, zona radiata). Gene Ontology (GO) analysis displayed transcriptional changes suggesting interference of cellular growth, fatty acid and lipid metabolism potentially mediated through the estrogen receptor (ER), which were proposed to be associated with modulation of genes involved in endocrine function and reproduction. Pathway analysis supported the identified GOs and revealed modulation of additional genes associated with apoptosis and cholesterol biosynthesis. Differentially expressed genes (DEGs) related to impaired lipid metabolism (e.g. peroxisome proliferator-activated receptor alpha and gamma), growth (e.g. insulin growth factor protein 1), phase I and II biotransformation (e.g. cytochrome P450 1A, sulfotransferase, UDP glucuronosyltransferase and glutathione S-transferase) provided additional insight into the MoA of EE2 in primary fish hepatocytes. Results from the present study suggest that biotransformation, estrogen receptor-mediated responses, lipid homeostasis, growth and cancer/apoptosis in primary fish hepatocytes may be altered after short-term exposure to ER-agonists such as EE2. In many cases the observed changes were similar to those reported for estrogen-exposed fish in vivo. In conclusion, global transcriptional analysis demonstrated that EE2 affected a number of toxicologically relevant pathways associated with an estrogenic MoA in the rainbow trout hepatocytes. PMID- 26519836 TI - The upper reference limit for thyroid peroxidase autoantibodies is method dependent: A collaborative study with biomedical industries. AB - BACKGROUND: The determination of the upper reference limit (URL) for thyroid peroxidase autoantibodies (TPOAbs) is a contentious issue, because of the difficulty in defining the reference population. The aim of this study was to establish the URL (eURL) for TPOAbs, according to the National Academy of Clinical Biochemistry (NACB) guidelines and to compare them with those obtained in a female counterpart, by the use of six commercial automated platforms. METHODS: 120 healthy males and 120 healthy females with NACB-required characteristics (<30years, TSH between 0.5 and 2.0mIU/L, normal thyroid ultrasound, without personal/family history of thyroid and non-thyroid autoimmune diseases) were studied. Sera were analyzed for TPOAbs concentration using six immunoassay methods applied in automated analyzers: Advia Centaur XP (CEN), Siemens Healthcare Diagnostics; Maglumi 2000 Plus, Shenzen New Industries Biomedical Engineering; Architect ci4100, Abbott; Cobas e411 (COB) Roche Diagnostics; Unicel DxI (UNI) and Lumipulse G1200, Fujirebio. RESULTS: Within each method, TPOAbs values had a high degree of dispersion and the eURLs were lower than those stated by the manufacturer. A statistically significant difference (p<0.05) between medians of males and females was observed only for COB and for UNI. However, the comparison of the male and female proportions positive for TPOAbs using the eURL of the counterpart, showed the lack of clinical significance of the above differences (Chi-square test, p>0.05). CONCLUSIONS: Despite the analytical harmonization, the wide dispersion of the results and the differences of the eURLs between methods suggest the need of further studies focusing on TPO antigen preparations as the possible source of variability between different assays. In addition, the lack of clinical significant difference between males and females, in terms of TPOAb eURLs, confirms the suitability of the NACB recommendations. PMID- 26519837 TI - Corynebacterium diphtheriae infections currently and in the past. AB - Along with the introduction of common obligatory vaccinations against diphtheria, the disease has been limited in developed countries. However, diphtheria is still endemic in developing countries. Due to a growing popularity of visiting these countries, there is a risk of importation of the disease to Europe. Studies revealed that over 60% of persons aged >40 years in the Polish population do not have a protective level of antibodies against diphtheria. Furthermore, an access to diphtheria antitoxin, which is essential in diphtheria treatment, is now hardly accessible in Europe. On the other hand, in many countries, including Poland, new infections caused by non-toxigenic Corynebacterium diphtheriae have been emerged. Such infections are frequently manifested by bacteraemia and endocarditis with a high fatality rate, amounting even to 41%. PMID- 26519838 TI - Tuberculosis in homeless persons in Poland. AB - The fall in rates of tuberculosis (TB) in many countries has been accompanied by the concentration of cases in the social risk groups including homeless persons. AIM: Comparison of TB features in homeless persons and in non-homeless patients. METHODS: TB cases reported to National TB Register in Poland in whom information about the social status was available (the data about the social status were collected obligatorily in the years 2004-2013 only) were analysed. The results of DSTs were obtained from laboratory records and were available for the cases reported since 2010. Treatment outcome after 12 months was analysed for the cases registered between 2004-2012. The significance (Si) of the differences in proportions was assessed with chi-square test. P<0.05 was regarded as statistically significant. Test F was used to evaluate the significance of differences of the means of age. The multivariate logistic regression models were applied to find out the independently operating determinants of not achieving of success of treatment. RESULTS: 2,349 homeless persons (HP) and 72,989 other patients (OP) with TB were included. In the group of HP, there was a greater proportion of males in comparison with OP (90.5% vs. 66.3%) (Si). The mean age of HP was 49.8 years (SD+/-10.9); of OP-52.9 years (SD+/-17.5) (Si). 16.6% of HP and 10.4% of OP were previously treated for TB (Si). The previous treatment was adequate in 62.2% of HP and in 85.8% of OP (Si). Pulmonary TB was in 98.0%, extrapulmonary TB in 2.0% of HP and, respectively, in 92.5% and 7.5% of OP (Si). Pulmonary TB was confirmed by culture in 76.3% of HP and in 64.5% of OP (Si). Sputum smears were positive in 70.7% of HP and in 62.5% of OP (Si). Caseous pneumonia occurred in 2.7% of homeless subjects and in 1.1% of OP (Si); infiltrative TB in 95.5% of HP and in 97.5% of OP (Si). Resistance to isoniazid was observed in 2.9% of HP and in 3.1% of OP; to rifampicin in 0.0% of HP and in 0.2% of OP; to isoniazid and rifampicin in 0.4% of HP and in 0.8% of OP. These differences were not Si. Treatment success rate among HP was 44.1%; default rate 24.8%; 4.0% of HP died from tuberculosis; 3.2% died from other causes; 5.2% were transferred and their outcomes were unknown; 0.4% were still on treatment; 0.4% had treatment failure; in 17.9% of HP results of treatment were not available. Among other TB patients the rate of success was 66.8%; of default--8.8%; 1.9% died from TB; 3.1% died from other causes; 2.6% were transferred; 0.5% were still treated; 0.2% had treatment failure; in 16.1% the results were not reported. Differences between both groups were Si, except for the category "died from other causes", "still on treatment" and "treatment failure". CONCLUSIONS: In the group of homeless persons with tuberculosis phenomena which indicate a delay in diagnosis of disease and in some cases the possibility of a recent infection and also unfavorable treatment outcomes occur in a greater proportion than among other patients. Targeted screening for TB and directly observed treatment could likely improve the epidemiological situation of tuberculosis in the population of homeless. PMID- 26519839 TI - Evaluation of detection and drug resistance of Mycobacterium tuberculosis in patients in the Lodzkie voivodship in 2009-2013. AB - STUDY AIM: Evaluation of detection and drug resistance of Mycobacterium tuberculosis in patients from the Lodzkie Voivodship in the period 2009 - 2013. MATERIAL AND METHODS: The data presented in the study include information obtained while diagnosing patients from the Lodzkie Voivodship in order to detect infections with Mycobacterium tuberculosis in the period 2009-2013. RESULTS: In 2009-2013 we analyzed clinical specimens for the purpose of detection of Mycobacterium tuberculosis. Tubercle bacilli were confirmed in 5621 specimens in 2196 patients; positive bacterioscopy results were observed in 1724 clinical specimens. In the study period 18 clinical specimens obtained from children contained tubercle bacilli. In the period 2009-2013 we noted multi-drug resistant (MDR) strain in 41 clinical specimens, which made up 1.8% of strains with known results of drug-sensitivity. In 5 clinical specimens we observed extensively-drug resistant (XDR) strain, which made up 0.2% of strains with known results of drug sensitiveness. 12 clinical specimens appeared to contain pre-XDR strain, which constituted 0.6% of strains with known results of drug-sensitivity. SUMMARY AND CONCLUSIONS: Despite advances in the diagnostics and treatment of tuberculosis (TB) this diseases still poses a serious medical problem. The detection level in the period 2009-2013 is relatively unchanged, with regards to both bacterioscopy and culture methods. Thus, the laboratory detection of tuberculosis bacilli is similar. It directly results from the enforcement of strict procedures regarding the quality of specimens collected for microbiological purposes and the control of the performed tests, which contributes to a greater number of confirmed cases of TB. In the study period the number of new cases of the infectious diseases is variable. Only in children this number remains stable over the years. Researchers observe that tubercle bacilli are resistant to basic first-line treatment drugs. They also note the occurrence of MDR, pre-XDR and XDR strains. Hence, it is important to regularly and carefully monitor the sensitivity of Mycobacterium tuberculosis to antibiotics administered in a long-term anti-tuberculosis therapy. PMID- 26519840 TI - Epidemiology of HCV infection in Central and Eastern Europe. AB - AIM OF STUDY: is the estimation of prevalence of HCV infection in fourteen Central and Eastern European countries (CEEC). MATERIAL AND METHODS: This review describes the comparative data of persons possessing anti-HCV antibodies and persons with HCV viremia (% of population and number) in fourteen Central and Eastern European countries (CEEC). The study was performed according to data on the >=15 years of age populations obtained from the Statistical Offices of the countries. RESULTS: The prevalence of anti-HCV in populations varied between 0.27 and 3.5%. The lowest values were reported from Kosovo, Hungary, Germany and the Czech Republic; 0.3-0.6%. The highest values of anti-HCV antibodies were noted in Latvia, Lithuania and Romania; 2.4, 2.85 and 3.5%, respectively. From eight countries the percentages of persons with HCV viremia were available (0.2-3.5%). CONCLUSIONS: The paper gives an estimate of the number of people infected with HCV in the general population of 8 countries from the CSEEC region. This number is approximately ~1.16 million. PMID- 26519841 TI - Hepatitis C oubreaks in Poland in 2003-2013. Medical procedures as a dominant route of HCV transmission. AB - BACKGROUND: According to the data from routine epidemiological surveillance in Poland, over 70% of patients diagnosed with HCV infection report exclusively medical exposure which suggests that infection was probably associated with procedures performed in health care settings. To a large extent, neither the source nor the mechanism of transmission, however, may be determined. Infections detected in an acute phase, accounting for ca 2-3% of registered hepatitis C cases per year, better reflect the actual routes of HCV transmission. Epidemiological investigations of acute hepatitis C outbreaks allow for identifying the procedures in which the virus is transmitted. OBJECTIVE: To identify mechanisms and breaches of safety procedures, which are most frequently associated with HCV infection, based on a review of recent hepatitis C outbreaks in health care settings in Poland. METHODS: A systematic review of reports on acute hepatitis C cases registered in routine surveillance in 2006-2013 and literature review in PubMed and SCOPUS. RESULTS: A total of six outbreaks were documented in which 116 cases were detected. Of them, four outbreaks were identified based on surveillance data, including one unconfirmed outbreak, and information on two outbreaks was retrieved from publications. Five of the described outbreaks were acquired in health care settings, including two outbreaks which occurred in dialysis units and one outbreak was associated with alternative medicine procedures. Probably, infections were most commonly transmitted due to mistakes of medical personnel resulting from negligence or ignorance of procedures, i.e. multiple use of disposable equipment and improper use of personal protective equipment (failure to change disposable gloves). In one case, neither breaches of procedure nor actions which could lead to HCV infection were determined. CONCLUSIONS: A detailed epidemiological investigation should be conducted in each registered case of acute hepatitis C as detected symptomatic cases allow for identifying the outbreaks. Epidemiological investigations of outbreaks should be improved by inclusion of molecular tests. Identification of breaches of binding procedures indicates a necessity of continuing training of personnel and enhanced control of compliance with binding recommendations, especially with regard to injection safety. PMID- 26519842 TI - Blood donors screening for blood born viruses in Poland. AB - Blood donor screening of viral markers in Poland is based on serologic testing for anti-HCV, HBsAg, anti-HIV1/2 (chemiluminescence tests) and on nucleic acid testing (NAT) for RNA HCV, RNA HIV-1 and DNA HBV performed in minipools of 6 with real-time PCR (MPX 2.0 test on cobas s201) or with TMA in individual donations (Ultrio Plus or Ultrio Elite). Donors of plasma for anti-D and anti-HBs production are tested for parvovirus B19 DNA. Before implementation tests and equipment are evaluated at the Institute of Hematology and Transfusion Medicine (IHTM). The last 20 years witnessed a decreasing trend for HBsAg in both first time and repeat donors (1%-0.3% and 0.1%-0.02% respectively). Prevalence of anti HCV repeat reactive results was stable and oscillated around 0.8% for first time donors and 0.2% for repeat donors. Elevated prevalence of seropositive HIV infected donors was recently observed (7.5-9 cases/100,000 donors). Since respective molecular markers implementation HCV RNA was detected on average in 1/119,235 seronegative donations, HIV RNA in 1/783,821 and HBV DNA in 1/61,047. HBV NAT yields were mostly occult hepatitis B (1/80,248); window period cases were less frequent (1/255,146). The efficiency of HBV DNA detection depends on the sensitivity of the HBV DNA screening system. PMID- 26519843 TI - Seroprevalence of parvovirus B19 antibodies among young pregnant women or planning pregnancy, tested for toxoplasmosis. AB - INTRODUCTION AND OBJECTIVE: Acute parvovirus B19 (B19V) infection is a proven risk for pregnant women and fetus. The aim of this study was to determine the prevalence of B19V antibodies among pregnant women or planning pregnancy, who were referred for preventive toxoplasmosis screening. MATERIAL AND METHODS: Between 2007-2010, 55 women in the age between 21 and 40 years were tested for both B19V IgG and IgM antibodies and sociodemographic information was collected. RESULTS: Among the study group, the mean age was 30 years, 43.6% of women were positive only for B19V IgG antibodies, 9% were positive for both B19V IgG and IgM antibodies and 11% were positive only for B19V IgM antibodies. Women negative for B19 IgG antibodies (47.3%) were considered as a high-risk group of B19V viremia. The serological profile indicating infection with Toxoplasma gondii was considered as a risk factor for fetal distress. The T. gondii IgG antibodies were detected in 51% cases, in 32.7% antibodies were positive for both IgG and IgM, while in 16.3% cases both IgG and IgM were negative. CONCLUSIONS: B19V infection and overlapping of other independent risk factors during pregnancy pose a significant hazard to fetus during development. Therefore, we recommend further broadening the epidemiological database of B19V infection prevalence among women. B19V infection should be taken into account during differential diagnosis as a cause of miscarriage. PMID- 26519844 TI - The prevalence of intestinal parasites in children in preschools and orphanages in the Warmia-Masuria province (North-Eastern Poland). AB - OBJECTIVE: A comparison of the prevalence of intestinal parasites (IP) in preschoolers and orphans in the Warmia-Masuria province (Poland). MATERIAL AND METHODS: Between 2003-2006 fecal samples and perianal swabs from 1052 preschoolers and 859 orphans were tested on the basis of direct saline and iodine mount, decantation test and the adhesive cellophane tape method. RESULTS: 10.8% of preschoolers and 46,3% of orphans were infected with IP. Among the six detected IP species the E. vermicularis was the most common. Infections of E. vermicularis were diagnosed in 9.5% of preschoolers and 36,7% of orphans. There were statistically significant differences in the distribution of IP between males and females in preschools. IP infections were the most frequent among 7 year-old children, 19.1% in preschools and 65.7% in orphanages, respectively. In preschools, the prevalence of IP was higher among preschoolers from the rural area (17.3%) than from the urban area (10.3%). CONCLUSION: Orphans and children from rural areas, especially at the age of 7, should be covered by systematic screening with parasitic tests throughout all of Poland. In this group of children, enterobiasis is the main health problem. The promotion of the awareness of IP infections and their prevention among parents and educational staff is required. PMID- 26519845 TI - Human babesiosis. AB - Babesiosis is an emerging parasitic, anthropo-zoonotic tick-borne disease, seldom diagnosed in humans. Caused by Protozoa, Babesia (also called Piroplasma) intraerytrocytic piriform microorganism. Infection of vertebrates is transmitted by ticks. Out of more than 100 Babesia species/genotypes described so far, only some were diagnosed in infected humans, mostly B. microti, B. divergens and B. venatorum (Babesia sp. EU1). Infection in humans is often asymptomatic or mild but is of a particular risk for asplenic individuals, those with congenital or acquired immunodeficiencies, and elderly. Infections transmitted with blood and blood products raise concerns in hemotherapy. Epidemiological situation of babesiosis varies around the world. In Europe, no increase in the number of cases was reported, but in the USA its prevalence is increasing and extension of endemic areas is observed. The aim of this publication is to describe the problems connected with the current epidemiological situation, diagnosis and treatment of human babesiosis with regard to clinical status of patients. PMID- 26519846 TI - Infection control in Polish medical wards--data from the PROHIBIT project. AB - INTRODUCTION: Nosocomial infections and the problem of their surveillance concern all patients, including patients treated in medical wards. The objective of the study was to ewaluate selected infection control practices in Polish medical wards in comparison with wards of European hospitals. MATERIAL AND METHODS: The study was conducted by means of a standardized questionnaire fullfiled by a total of 506 wards, including 10 Polish, in 24 European countries, as a part of the PROHIBIT project. RESULTS: The median number of beds in Polish wards (PW) was 35 vs. 30 in European ones (EW), while the proportion of beds in single rooms in Poland were almost ten times lower than in Europe. The number of nurses employed in PW was similar to EW. In all PW alcohol-based handrub solutions were available in more than 76% points of care and it was better situation than in EW. Similar situation in PW and EW was observed in case of existence of written procedure of UTI and CDI prevention. Differences between PW and EW were observed in the manner of usage of close drainage system in catheterized patients and in consumption of alcohol-based handrubs. CONCLUSIONS: In Poland, selected component of infection control is a challenge for the future and its implementation and realization require increasing the awareness of both medical staff and the management of hospitals. PMID- 26519847 TI - Level of knowledge among medical personnel about infections transferred through direct contact--results of questionnaire survey. AB - INTRODUCTION: Nosocomial infections are an important issue all over the world. The most important vector for transmitting infections in a hospital are the hands of the medical personnel, which is why their adequate hygiene is an essential prevention method. THE AIM OF THE STUDY: was to evaluate the medical personnel's level of knowledge on the prevention of nosocomial infections transferred through direct contact. MATERIAL AND METHODS: The diagnostic survey method with a proprietary questionnaire was used for the research. The research was conducted between May and June 2013 on a group of 100 randomly chosen medical workers of one of Cracow hospitals (nurses, doctors and paramedics). The age of the interviewees ranged from 23 to 60 years old. RESULTS: Despite the fact that most of the respondents took part in courses related to nosocomial infections and declared the will to take part in more courses related to this issue, the level of knowledge of the medical personnel on the prevention of nosocomial infections transferred through direct contact and the post-exposure procedures is insufficient. Only 28.0% of the respondents knew that the dominant hand decontamination method according to WHO is disinfection, 22.0% of the surveyed medical personnel admitted that they put covers on needles after they performed the injection and 11.0% of the interviewees mentioned that they change the gloves before contact with the patient only sometimes. CONCLUSIONS: The surveyed group has not demonstrated a sufficient knowledge of the rules of preventing infections transferred through direct contact and the post-exposure procedures. The level of knowledge of the surveyed medical personnel was dependent on, e.g., years of experience and taking part in courses on nosocomial infections. PMID- 26519848 TI - The analysis of the occurrence of nosocomial infections in the neurosurgical ward in the District Hospital from 2003-2012. AB - INTRODUCTION: The patients in the neurosurgical ward are exposed to many risk factors causing nosocomial infections. These factors are related to operations, invasive diagnosing and monitoring of the nervous system and mechanical support of vital functions. Therefore, the objective of the undertaken studies was to assess the prevalence and structure of the healthcare-associated infections (HAI) in patients hospitalized in the neurosurgical ward in the St. Lukas District Hospital in Tarnow. MATERIAL AND METHODS: The analyzed data concerned 13,351 patients hospitalized from 2003 to 2012. To analyze the data, the standard epidemiological methods and standardized definitions of nosocomial infections proposed by European Center for Disease Prevention and Control (ECDC) were used (1, 2). RESULTS: 516 cases of nosocomial infections were detected. The most common infections among these cases were surgical site infections (SSI). The number of SSIs cases was 140 and cumulative incidence rate (CI) per 100 operations was 1.72%, including: 52 cases of craniotomy (CRAN) (CI per 100 operations was 2.44%); 50 cases of spinal fusion (FUSN) (CI was 3.32%); 24 cases of laminectomy (LAM) (CI was 0.93%); 10 cases of ventricular shunt operations (VSHN) (CI was 3.75%); 4 cases of other operations (OTH) (CI was 0.23%). The second most common infections were bloodstream infections (BSI) with 128 cases (CI was 0.96%), including: 91 cases of primary BSI and 37 cases of secondary BSI and the incidence density rate (ID) was 4.75 per 1000 central catheter days. The third most common infection was pneumonia (PN) with 127 cases (CI was 1.02%), with incidence density rate of 51.07 per 1000 intubation-days. The next most common detected infections were urinary tract infections (UTI) with 74 cases (CI was 0.58%). This type of infections included: 65 cases of infections associated with a urinary catheter and 9 cases not associated with a urinary catheter. The incidence density for UTI with a urinary catheter was 1.93 per 1000 urinary catheter days. The list of detected infections is closed by gastrointestinal system infections (GI) with 35 cases (CI was 0.23%) and the skin and soft tissue infections (SST) with 12 cases (CI was 0.07%). The etiological agent that was most frequently isolated from materials gathered from patients diagnosed with SSI, BSI and SST was Staphylococcus aureus. Acinetobacter baumannii was the most frequently detected in the cases of PN, Escherichia coli in the cases of UTI, and Clostridium difficile in the cases of GI. CONCLUSIONS: Ten-year observation of infections detected in the neurosurgery ward gave the possibility to conduct a thorough epidemiological analysis of prevalence of nosocomial infections with recommendation aiming at reasons for prevention. PMID- 26519849 TI - Recommendations for the treatment of hepatitis C Polish group of HCV Experts- 2015. PMID- 26519850 TI - Evaluation of the efficiency of hospital antibiotic policy applied Dr Jan Biziel University Hospital No 2 in Bydgoszcz in 2009-2013. AB - The Hospital Infection Control Team (HICT) of Dr Jan Biziel University Hospital No 2 in Bydgoszcz developed and implemented the principles of a rational antibiotic therapy in 2008. A behavior algorithm has worked since 01.10.2008. Implementation of the principles of a rational antibiotic therapy was part of the hospital antibiotic policy. THE AIM OF THE STUDY: is to evaluate either introductory principles of the rational antibiotic therapy, after five-year experience lived up to expectations in the range specified by the authors. MATERIAL AND METHODS: Hospital microbiological maps, comparisons of antibiotic cost, specification of microbiological tests made before and after introduction of the principles of a rational antibiotic therapy have been analyzed. Annual antibiotic consumption has been counted according to the defined daily dose (DDD) index created by the WHO. RESULTS: After 6 years of implementation of the rational antibiotic therapy principles, the decrease in number of isolated strains which are resistant to Klebsiella pneumoniae ESBL and Acinetobacter baumanii (resistant to carbapenems) has been indicated. The number of the Pseudomonas aeruginosa isolates has increased approximately three times, and the number of resistant isolates to carbapenem has grown six times. The cost of antibiotics has been gradually decreased in 2012 in order to represent 9,66% of all drug budget (without drug programs). Detailed analysis of antibiotic consumption has showed that after the implementation of rational antibiotic therapy principles the consumption of meropenem has increased twice in comparison to the all drugs. The number of microbiological tests grew from 0,20 to 0,29 per one patient, which means material to microbiological tests has been taken from every third patient. Annual DDD index calculated on 100 person-days has been reduced from 59,552 in 2007 to 39,90 in 2009, and it is 47,88 in 2013. The principles of rational antibiotic therapy in comparison with the other elements of antibiotic policy in hospital have caused positive changes in antibiotic ordinance. CONCLUSIONS: 1. It is required to adhere to the principles of a rational antibiotic therapy by medical staff mainly on the administrative restriction of access to antibiotics. 2. Monitoring changes in drug resistance of hospital flora is an essential element of the principles of a rational antibiotic therapy modification. PMID- 26519851 TI - Evaluation of economic effects of population ageing--methodology of estimating indirect costs. AB - Process of demographic ageing, especially in recent decades, is steadily growing in dynamics and importance due to increasing health-related needs and expectations with regard to a guarantee of social services. Elaboration of the most effective model of care, tailored to Polish conditions, requires an estimation of actual costs of this care, including indirect costs which are greatly related to informal care. The fact that the costs of informal care are omitted, results from a determined approach to analyses. It is discussed only from a perspective of budget for health and does not cover societal aspects. In such situation, however, the costs borne by a receiver of services are neglected. As a consequence, the costs of informal care are underestimated or often excluded from calculations, even if they include indirect costs. Comprehensive methodological approach for estimating the costs of informal care seems to be important for a properly conducted economic evaluation in health care sector. PMID- 26519852 TI - Periodontal status and selected parameters of oral condition of Poles aged 65 to 74 years. AB - INTRODUCTION: The goal of this study was the evaluation of the periodontal health by means of CPI score in inhabitants of big and small cities in the age range from 65 to 74 and making comparison with previous Polish and European studies from XXI century. Also an average number of natural teeth, the edentulous persons percentage, the percentage of people with oral function maintenance and prevalence of oral mucosal diseases were evaluated. There were also attempts to evaluate essential behaviours related to the oral health and the percentage of people that are treated with use of non-reimbursed or reimbursed services. MATERIAL AND METHODS: Studies were conducted in 5 big cities: Warszawa, Szczecin, Wroclaw, Bialystok and Torun, as well as in 4 towns, such as Olawa, Police, Lobez and Elk. From sampling 7400 people aged from 65 to 74 years for the study reported only 807 people. In the mouth evaluated CPI score, number of natural teeth and prevalence of pathological lesions on cavity mucosa. Answers for questions on selected attitudes and health-seeking behaviours related to the oral health and the range of dental treatment were also analysed. RESULTS: Distribution of values of CPI codes in the whole group was as follows: CPI0-1.2%, CPI1-9.4%, CPI2-16.6%, CPI3-21.8%, CPI4-19.7% and the number of people excluded from examinations (1 tooth in the sextant or edentulous 31.3%). The state of the periodontium was worse in big cities and in men. An average number of teeth was 13.7 and was higher in big cities and in men. The percentage of edentulous persons was 28.9% and was higher in towns and in woman. The percentage of people with oral function maintenance was 25.15% and was higher in big cities and in men. The most three common pathologies of the oral cavity were leukoplakia and leukokeratosis that were found in 10.5% of examined people, candidiasis 5.82% and lichen planus 2.2%. CONCLUSION: The state of the periodontium of Poles at the age from 65 to 74 has not been improved in XXI century, but also does not significantly differ from an average European level. An average number of remaining teeth of Poles at this age has increased, but remains under a European average; also the prevalence of edentulism has decreased, but still remains one of the highest in Europe. The percentage of people with oral function maintenance is very low, thus needs for prosthetic treatment and rehabilitation of masticatory ability remain high. Precancerous lesions in the oral cavity are quite common in this age group. Health-seeking behaviours related to the oral health of older Poles are inadequate and result from a low level of knowledge on dental prophylaxis. PMID- 26519853 TI - Effectiveness of single medical advice on emergency phone number knowledge in urban adult population--"Health, Alcohol and Psychosocial Factors in Eastern Europe" substudy. AB - INTRODUCTION: Early access to Emergency Medical Services determines survival in out-of-hospital cardiac arrest. However, a significant proportion of adults do not know the emergency phone number (EN) and no intervention has been proposed to improve it. Therefore, we aimed to assess prospectively the effectiveness of single advice from a physician on knowledge of the EN in adult population. MATERIALS AND METHODS: The study was conducted among participants of "Health, Alcohol and Psychosocial Factors in Eastern Europe" study. A total of 942 persons (aged 48-82 years) randomly selected from an urban population registry were interviewed and then instructed about the correct EN (the intervention group). After 12 months knowledge of the EN was assessed in the intervention group (n=716) and in matched control group (n=435). RESULTS: The correct EN was given by 498 (69.6%) participants at baseline and in 550 (76.8%) participants 12 months afterwards (p<0.001). At follow-up the knowledge of EN was higher by in intervention group than in controls (76.8% vs 70.6%, p=0.02). Factors associated with better educational effect were male sex (OR 1.49; 95% CI 1.04-2.1) and secondary or higher level of education (OR 1.44; 95% CI 1.08-1.91). CONCLUSIONS: We concluded that a single instruction about the EN from a physician increases its long-term knowledge and should be offered during medical visits. PMID- 26519854 TI - Analysis of fatality due to cholera epidemics in Tuliszkow parish in 1852. AB - INTRODUCTION: Little is known about the correlation between age, gender distribution and fatality rate during cholera epidemics. AIM: To analyze the change in the fatality rate with regard to age and gender during cholera epidemics in 1852 in Tuliszkow Parish. MATERIAL AND METHODS: Data for the present study were retrieved from the archives. Information on fatal cases was obtained from the records of Tuliszkow Parish - The Register of Deaths (1851-1879). Age, gender of the deceased and place of residence in Tuliszkow Parish were analyzed. Data from the year in which the epidemic occurred (1852) and year preceding it (1851) were compared using Pearson's chi2 test. RESULTS: A total of 3200 persons lived in the Roman Catholic Parish of Tuliszkow during cholera epidemic in 1852. Having compared to the control year (1851), fatality rate distribution changed statistically significantly in the epidemic year (1852); (chi2=27.5665, p=0.0011). In particular, it applied to males (chi2=28.9476, p=0.0007). Irrespective of the gender, the highest increase of the fatality rate was observed in the 10-25 age group (chi2=5.0375, p=0.0248) while infant fatality rate decreased (chi2=19.2789, p=0.0000). CONCLUSIONS: Cholera epidemic resulted in a significant change of fatality rate in infants, males and the youth. Death of both parents aged up to 45 years old contributed to an increase in the number of orphans. PMID- 26519855 TI - Professor Wieslaw Jedrychowski (15th January,1932-19th May, 2015). PMID- 26519856 TI - Melt-processed polymeric cellular dosage forms for immediate drug release. AB - The present immediate-release solid dosage forms, such as the oral tablets and capsules, comprise granular matrices. While effective in releasing the drug rapidly, they are fraught with difficulties inherent in processing particulate matter. By contrast, liquid-based processes would be far more predictable; but the standard cast microstructures are unsuited for immediate-release because they resist fluid percolation and penetration. In this article, we introduce cellular dosage forms that can be readily prepared from polymeric melts by incorporating the nucleation, growth, and coalescence of microscopic gas bubbles in a molding process. We show that the cell topology and formulation of such cellular structures can be engineered to reduce the length-scale of the mass-transfer step, which determines the time of drug release, from as large as the dosage form itself to as small as the thickness of the cell wall. This allows the cellular dosage forms to achieve drug release rates over an order of magnitude faster compared with those of cast matrices, spanning the entire spectrum of immediate release and beyond. The melt-processed polymeric cellular dosage forms enable predictive design of immediate-release solid dosage forms by tailoring microstructures, and could be manufactured efficiently in a single step. PMID- 26519857 TI - Drug delivery of the future: Chasing the invisible gorilla. AB - For more than 60years drug delivery systems have produced numerous controlled release formulations helping patients improve compliance and maximize the drug efficacy. Development of new controlled drug delivery systems was very productive during the period 1950-1980. The productivity, as measured by the number of clinically used formulations, dropped significantly during 1980-2010. This reduced productivity needs to be understood so that the future development of drug delivery systems can be accelerated and prolific again. This requires critical evaluation of the current drug delivery field, so that the factors inhibiting rapid progress can be identified and resolved. The current drug delivery field is faced with an invisible gorilla syndrome, i.e., seeing a gorilla when it is not present and missing a gorilla when it actually exists. Overcoming this syndrome requires a new way of thinking, questioning the status quo. Advances in drug delivery technologies occur by an evolutionary process, and thus, the more trials and errors lead to faster advances. The drug delivery area needs to nurture the environment where vastly different ideas can be tested, and all data, positive or negative, need to be exchanged freely as they have equal importance. PMID- 26519858 TI - Species-specific patterns of nonapeptide brain gene expression relative to pair bonding behavior in grouping and non-grouping cichlids. AB - Comparative studies have revealed that vasopressin-oxytocin pathways are associated with both pair bonding and grouping behavior. However, the relationship between pair bonding and grouping behavior remains unclear. In this study, our aim was to identify whether two species that differ in grouping behavior display a corresponding difference in their pair bonds, and in the underlying vasopressin-oxytocin hormonal pathways. Using two species of cichlid fishes, the highly social Neolamprologus pulcher and the non-social Telmatochromis temporalis, we measured proximity of pairs during pair bond formation, and then measured social behaviors (proximity, aggression, submission, affiliation) and brain gene expression of isotocin and arginine vasotocin (the teleost homologues of oxytocin and vasopressin, respectively), as well as their receptors, after a temporary separation and subsequent reunion of the bonded pairs. Pairs of the social species spent more time in close proximity relative to the non-social species. Rates of aggression increased in both species following the separation and reunion treatment, relative to controls that were not separated. Overall, whole brain expression of isotocin was higher in the social species relative to the non-social species, and correlated with proximity, submission, and affiliation, but only in the social species. Our results suggest that both a social and a non-social cichlid species have similar behavioral responses to a temporary separation from a mate, and we found no difference in the brain gene expression of measured hormones and receptors based on our separation-reunion treatment. However, our results highlight the importance of isotocin in mediating submissive and affiliative behaviors in cichlid fishes, and demonstrate that isotocin has species-specific correlations with socially relevant behaviors. PMID- 26519860 TI - Seeing through thick and through thin: Retinal manifestations of thrombophilic and hyperviscosity syndromes. AB - The presence of retinal vasculopathy in the absence of typical predisposing factors should suggest a possible underlying hematologic abnormality. In such cases, a systemic investigation may reveal a potentially fatal hypercoagulability or hyperviscosity syndrome. Retinal vein occlusion is the most commonly encountered ophthalmic finding in such syndromes; however, abnormalities of the arterial system, the choroid, and the macula are also possible. Visual symptoms may be the only manifestation of the underlying process, making timely diagnosis by the ophthalmologist critical for both treatment and thrombotic prophylaxis. Moreover, as newer ophthalmic diagnostic technologies arise, there is an increasingly important role for eye physicians in the management of such syndromes. PMID- 26519859 TI - Whole Genome Sequencing of the Symbiont Pseudovibrio sp. from the Intertidal Marine Sponge Polymastia penicillus Revealed a Gene Repertoire for Host-Switching Permissive Lifestyle. AB - Sponges harbor a complex consortium of microbial communities living in symbiotic relationship benefiting each other through the integration of metabolites. The mechanisms influencing a successful microbial association with a sponge partner are yet to be fully understood. Here, we sequenced the genome of Pseudovibrio sp. POLY-S9 strain isolated from the intertidal marine sponge Polymastia penicillus sampled from the Atlantic coast of Portugal to identify the genomic features favoring the symbiotic relationship. The draft genome revealed an exceptionally large genome size of 6.6 Mbp compared with the previously reported genomes of the genus Pseudovibrio isolated from a coral and a sponge larva. Our genomic study detected the presence of several biosynthetic gene clusters-polyketide synthase, nonribosomal peptide synthetase and siderophore-affirming the potential ability of the genus Pseudovibrio to produce a wide variety of metabolic compounds. Moreover, we identified a repertoire of genes encoding adaptive symbioses factors (eukaryotic-like proteins), such as the ankyrin repeats, tetratrico peptide repeats, and Sel1 repeats that improve the attachment to the eukaryotic hosts and the avoidance of the host's immune response : The genome also harbored a large number of mobile elements (~5%) and gene transfer agents, which explains the massive genome expansion and suggests a possible mechanism of horizontal gene transfer. In conclusion, the genome of POLY-S9 exhibited an increase in size, number of mobile DNA, multiple metabolite gene clusters, and secretion systems, likely to influence the genome diversification and the evolvability. PMID- 26519861 TI - Impaired expression of neuronal nitric oxide synthase in the gracile nucleus is involved in neuropathic changes in Zucker Diabetic Fatty rats with and without 2,5-hexanedione intoxication. AB - These studies examined the influence of 2,5-hexanedione (2,5-HD) intoxication on expression of neuronal nitric oxide synthase (nNOS) in the brainstem nuclei in Zucker Diabetic Fatty (ZDF) vs. lean control (LC) rats. Functional neuropathic changes were also investigated following axonal damage and impaired axonal transport induced by the treatment. Animals were intoxicated by i.p. injection of 2,5-HD plus unilateral administration of 2,5-HD over the sciatic nerve. The mechanical thresholds and withdrawal latencies to heat and cold stimuli on the foot were measured at baseline and after intoxication. The medulla sections were examined by nNOS immunohistochemistry and NADPH-diaphorase histochemistry at the end of the treatments. The mechanical thresholds and withdrawal latencies were significantly decreased while nNOS immunostained neurons and NADPH-diaphorase positive cells were selectively reduced in the gracile nucleus at baseline in ZDF vs. LC rats. NADPH-diaphorase reactivity and nNOS positive neurons were increased in the ipsilateral gracile nucleus in LC rats following 2,5-HD intoxication, but its up-regulation was attenuated in ZDF rats. These results suggest that diabetic and chemical intoxication-induced nNOS expression is selectively reduced in the gracile nucleus in ZDF rats. Impaired axonal damage-induced nNOS expression in the gracile nucleus is involved in neuropathic pathophysiology in type II diabetic rats. PMID- 26519862 TI - Bovine meniscal tissue exhibits age- and interleukin-1 dose-dependent degradation patterns and composition-function relationships. AB - Despite increasing evidence that meniscal degeneration is an early event in the development of knee osteoarthritis, relatively little is known regarding the sequence or functional implications of cytokine-induced meniscal degradation or how degradation varies with age. This study examined dose-dependent patterns of interleukin-1 (IL-1)-induced matrix degradation in explants from the radially middle regions of juvenile and adult bovine menisci. Tissue explants were cultured for 10 days in the presence of 0, 1.25, 5, or 20 ng/ml recombinant human IL-1alpha. Juvenile explants exhibited immediate and extensive sulfated glycosaminoglycan (sGAG) loss and subsequent collagen release beginning after 4-6 days, with relatively little IL-1 dose-dependence. Adult explants exhibited a more graded response to IL-1, with dose-dependent sGAG release and a lower fraction of sGAG released (but greater absolute release) than juvenile explants. In contrast to juvenile explants, adult explants exhibited minimal collagen release over the 10-day culture. Compressive and shear moduli reflected the changes in explant composition, with substantial decreases for both ages but a greater relative decrease in juvenile tissue. Dynamic moduli exhibited stronger dependence on explant sGAG content for juvenile tissue, likely reflecting concomitant changes to both proteoglycan and collagen tissue components. The patterns of tissue degradation suggest that, like in articular cartilage, meniscal proteoglycans may partially protect collagen from cell-mediated degeneration. A more detailed view of functional changes in meniscal tissue mechanics with degeneration will help to establish the relevance of in vitro culture models and will advance understanding of how meniscal degeneration contributes to overall joint changes in early stage osteoarthritis. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:801-811, 2016. PMID- 26519863 TI - Application of zone-folding approach to the first-principles estimation of thermodynamic properties of carbon and ZrS2 -based nanotubes. AB - A zone-folding (ZF) approach is applied for the estimation of the phonon contributions to thermodynamic properties of carbon-and ZrS2 -based nanotubes (NTs) of hexagonal morphology with different chiralities. The results obtained are compared with those from the direct calculation of the thermodynamic properties of NTs using PBE0 hybrid exchange-correlation functional. The phonon contribution to the stability of NTs proved to be negligible for the internal energy and small for the Helmholtz free energy. It is found that the ZF approach allows us an accurate estimation of phonon contributions to internal energy, but slightly overestimates the phonon contributions to entropy. (c) 2015 Wiley Periodicals, Inc. PMID- 26519864 TI - HLA-G 14 bp insertion/deletion polymorphism and its association with sHLA-G levels in Behcet's disease Tunisian patients. AB - The purpose of this study was to investigate the HLA-G 3'UTR 14 bp polymorphism and sHLA-G levels in Tunisian patients with BD. The study included 119 patients with BD and 170 healthy blood donors (HD). HLA-G 14 bp polymorphism was genotyped by polymerase chain reaction. Serum levels of soluble HLA-G (sHLA-G) were measured using a commercial ELISA kit. A significant increased frequency of the 14 bp HLA-G allele was detected in patients with BD compared to HD (0.58 vs 0.49, p=0.023), and a significant increased frequency of HLA-G -14/-14 bp was observed in patients with BD compared to HD [0.37 vs 0.22, p=0.007, OR 2.04 (95% CI 1.21 3.42)]. The mean plasmatic concentration of sHLA-G levels were significantly increased in patients with active disease [231.63+/-286.4 U/mL] compared to those with inactive disease (103.14+/-77.8 U/mL, p=0.03) and HD (121.41+/-24.1 U/mL, p=0.04). Furthermore, our results showed that there is no association between HLA G 14 bp polymorphism and sHLA-G plasma levels. PMID- 26519865 TI - Diffusive dynamics of DNA unzipping in a nanopore. AB - When an electric field is applied to an insulating membrane, movement of charged particles through a nanopore is induced. The measured ionic current reports on biomolecules passing through the nanopore. In this work, we explored the kinetics of DNA unzipping in a nanopore using our coarse-grained model (Stachiewicz and Molski, J. Comput. Chem. 2015, 36, 947). Coarse graining allowed a more detailed analysis for a wider range of parameters than all-atom simulations. Dependence of the translocation mode (unzipping or distortion) on the pore diameter was examined, and the threshold voltages were estimated. We determined the potential of mean force, position-dependent diffusion coefficient, and position-dependent effective charge for the DNA unzipping. The three molecular profiles were correlated with the ionic current and molecular events. On the unzipping/translocation force profile, two energy maxima were found, one of them corresponding to the unzipping, and the other to the translocation barriers. The unzipping kinetics were further explored using Brownian dynamics. PMID- 26519866 TI - Susceptibility of HPV16 and 18 to high level disinfectants indicated for semi critical ultrasound probes. AB - Ultrasound probes used in endocavitary procedures have been shown to be contaminated with high-risk HPV after routine use and HPV is also known to be resistant to some high level disinfectants (HLDs). This study compared efficacy of two leading ultrasound probe HLD methods; liquid ortho-phthalaldehyde (Cidex(r) OPA) and an automated device using sonicated hydrogen peroxide (trophon(r) EPR) against HPV16 and HPV18 in a hard-surface carrier test. Native HPV16 and HPV18 virions were generated in organotypic epithelial raft cultures. Viral lysates were dried onto carriers with a 5% (v/v) protein soil. Efficacy tests were performed against the automated device at 35% and 31.5% H2 O2 and 0.55% OPA in quadruplicate with matched input, neutralization, and cytotoxicity controls. Hypochlorite was included as a positive control. Infectivity was determined by the abundance (qRT-PCR) of the spliced E1^E4 transcript in infected recipient cells. The automated HLD device showed excellent efficacy against HPV16 and HPV18 (>5 log10 reductions in infectivity) whereas OPA showed minimal efficacy (<0.6 log10 reductions). While HPV is highly resistant to OPA, sonicated hydrogen peroxide offers an effective disinfection solution for ultrasound probes. Disinfection methods that are effective against HPV should be adopted where possible. PMID- 26519867 TI - Testing anti-HIV activity of antiretroviral agents in vitro using flow cytometry analysis of CEM-GFP cells infected with transfection-derived HIV-1 NL4-3. AB - An assay, specifically optimized to evaluate the anti-HIV activity of antiretrovirals by flow cytometry analysis, is described. As widely used anti-HIV agents, zidovudine (AZT), abacavir (ABC), 2',3'-dideoxyinosine (DDI), lamivudine (3TC), nevirapine (NVP), and efavirenz (EFV), and as drugs of recent approval raltegravir (RAL), etravirine (ETR), and rilpivirine (RPV), were utilized as reference drugs. HIV-1 NL4-3 virus was prepared by transfection of HEK293T cells with purified plasmid DNA and quantified by p24 antigen-capture assay. For infection, CEM-GFP cells were exposed to vehicle or to several concentrations of the drugs for 2 hr at 37 degrees C before HIV-1 NL4-3 was added to each sample. The adsorption was prolonged for 3 hr at 37 degrees C. After 72 hr of incubation, HIV-induced GFP expression in infected CEM-GFP cells was assessed by flow cytometry analysis and expressed as % positive cells. For comparison, p24 production in supernatants was assessed by a commercial ELISA kit. On the basis of IC50 values, the anti-HIV activity, as assayed by this method, was EFV > 3TC > AZT > NVP > DDI > ABC and ETR > RPV > RAL. The comparison between the IC50 values calculated through flow cytometry and p24 production revealed overlapping results, showing that the optimized protocol of CEM-GFP infection with HIV NL4-3 is a suitable method to perform quantitative, rapid and low-expensive screening tests to evaluate the in vitro effect of new candidate anti-HIV drugs. PMID- 26519868 TI - Hb TAYBE: clinical and morphological findings IN 43 patients. AB - Hereditary sequence variants in globin genes are usually silent and are rarer in alpha-globin chains than beta-globin chains. Some may lead to an unstable protein with a hemolytic or thalassemic phenotype. Hb Taybe is an unstable alpha-chain hemoglobin variant caused by the deletion of a threonine residue at codon 38 or 39 of the alpha1 globin gene. This deletion results in a structural abnormality that affects the alpha1 beta2 contact and the alpha1 beta1 interface, producing a highly unstable Hb. OBJECTIVE: We describe the clinical, laboratory, and morphological characteristics of 43 patients with Hb Taybe, sixteen of whom are heterozygous, eight are homozygous, and nineteen are double heterozygous for Hb Taybe and other alpha-gene mutations or deletions. RESULTS: The clinical presentation is very variable from a mild hemolytic anemia to the need for red cell transfusion. Morphological characteristics include erythroid hyperplasia, defective hemoglobin production, and dyserythropoietic features. On electron microscopy dyserythropoiesis and cytoplasmic precipitation of globin compatible optical dense material is seen. CONCLUSIONS: This is the largest report of Hb Taybe patients. Previous reported cohorts are not related to these cases. We conclude that patients carrying Hb Taybe have a unique hematological and clinical phenotype distinct from other hemoglobinopathies and from congenital dyserythropoietic anemia. PMID- 26519870 TI - Reply: The effect of disc degeneration on anterior shear translation in the lumbar spine. PMID- 26519871 TI - Analysis of perfusion MRI in stroke: To deconvolve, or not to deconvolve. AB - PURPOSE: There is currently controversy regarding the benefits of deconvolution based parameters in stroke imaging, with studies suggesting a similar infarct prediction using summary parameters. We investigate here the performance of deconvolution-based parameters and summary parameters for dynamic-susceptibility contrast (DSC) MRI analysis, with particular emphasis on precision. METHODS: Numerical simulations were used to assess the contribution of noise and arterial input function (AIF) variability to measurement precision. A realistic AIF range was defined based on in vivo data from an acute stroke clinical study. The simulated tissue curves were analyzed using two popular singular value decomposition (SVD) based algorithms, as well as using summary parameters. RESULTS: SVD-based deconvolution methods were found to considerably reduce the AIF-dependency, but a residual AIF bias remained on the calculated parameters. Summary parameters, in turn, show a lower sensitivity to noise. The residual AIF dependency for deconvolution methods and the large AIF-sensitivity of summary parameters was greatly reduced when normalizing them relative to normal tissue. CONCLUSION: Consistent with recent studies suggesting high performance of summary parameters in infarct prediction, our results suggest that DSC-MRI analysis using properly normalized summary parameters may have advantages in terms of lower noise and AIF-sensitivity as compared to commonly used deconvolution methods. Magn Reson Med 76:1282-1290, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26519875 TI - First- and second-born adolescents' decision-making autonomy throughout adolescence. AB - First- and second-born adolescents' and their parents' perceptions of adolescents' decision-making autonomy were compared from ages 12 to 19 in a longitudinal sample of 145 predominantly White, middle class families. Utilizing a multivariate, multilevel modeling approach, differences in perceptions of adolescents' autonomy between parents and each adolescent, as well as by social cognitive domain were examined. The present study found that when comparing parents' perceptions of their children at the same age, second-borns were granted more autonomy regarding conventional issues than first-borns during early adolescence, but by later adolescence first-borns were granted more autonomy regarding prudential issues than second-borns. However, comparisons between adolescents' and siblings' perceptions showed no differences. Potential reasons for, and implications of, differences in perceptions of adolescent autonomy are discussed. PMID- 26519874 TI - Measuring psychological engagement in youth activity involvement. AB - Although psychological engagement (e.g., enjoyment, concentration) may be critical in fostering positive outcomes of youth activity participation, too few studies have been conducted to establish its role in development. Furthermore, an established measurement tool is lacking. In the current study, we evaluated a brief engagement measure with two Canadian samples of youth (Sample 1, N = 290, mean age = 16.9 years, 62% female; Sample 2, N = 1827, mean age = 13.1 years, 54% female). We conducted a confirmatory factor analysis with structural equation modeling to examine the hypothesized structure of the model. We also assessed the measure's validity by testing relations between engagement and both perceived outcomes and positive features of activity settings. Psychological engagement was best captured by three latent cognitive, affective, and relational/spiritual factors and a second-order latent factor. Also, as anticipated, psychological engagement was associated with features of the activity setting and perceived impact. PMID- 26519877 TI - Chitin from Penaeus merguiensis via microbial fermentation processing and antioxidant activity. AB - The ability of three proteases producing bacteria such as Pseudomonas aeruginosa, Serratia marcescens, and Bacillus pumilus on the demineralization and deproteinzation efficiency of shrimp waste, for chitin extraction, was investigated. Statistical analysis of data was showed a significant difference between the percentage of demineralization and deproteinization in different bacteria species (p<0.05). The highest deproteinization (74.76%) and demineralization rate (78.46%) was obtained with P. aeruginosa and the lowest was observed in the treatment of S. marcescens. Then, chitin was converted to chitosan by deacetylation in the presence of NaOH 50%. The antioxidant activity of chitosan solution was determined using different tests. The highest activity (DO 700 nm=0.74, DO 695 nm=0.31) was observed for chitosan sample at concentration of 1,000 MUg/ml. The antioxidant potential of the hydrolysates was also evaluated. The highest reducing power in a volume of 400 MUl hydrolysate of S. marcescens and the highest total antioxidant capacity in a volume 100 MUl hydrolysate of B. pumilus were observed. These results indicated that the P. aeruginosa bacterium in comparison with other bacterial strains, higher ability to remove proteins and mineral from shrimp waste. Therefore, the use of this bacterium is recommended for protein and mineral removal from marine crustaceans. PMID- 26519873 TI - Interferon-free therapy for genotype 1 hepatitis C in liver transplant recipients: Real-world experience from the hepatitis C therapeutic registry and research network. AB - Recurrent infection with the hepatitis C virus (HCV) after liver transplantation (LT) is associated with decreased graft and patient survival. Achieving sustained virological response (SVR) with antiviral therapy improves survival. Because interferon (IFN)-based therapy has limited efficacy and is poorly tolerated, there has been rapid transition to IFN-free direct-acting antiviral (DAA) regimens. This article describes the experience with DAAs in the treatment of posttransplant genotype (GT) 1 HCV from a consortium of community and academic centers (Hepatitis C Therapeutic Registry and Research Network [HCV-TARGET]). Twenty-one of the 54 centers contributing to the HCV-TARGET consortium participated in this study. Enrollment criteria included positive posttransplant HCV RNA before treatment, HCV GT 1, and documentation of use of a simeprevir (SMV)/sofosbuvir (SOF) containing DAA regimen. Safety and efficacy were assessed. SVR was defined as undetectable HCV RNA 64 days or later after cessation of treatment. A total of 162 patients enrolled in HCV-TARGET started treatment with SMV+SOF with or without ribavirin (RBV) following LT. The study population included 151 patients treated with these regimens for whom outcomes and safety data were available. The majority of the 151 patients were treated with SOF and SMV alone (n = 119; 79%) or with RBV (n = 32; 21%), The duration of therapy was 12 weeks for most patients, although 15 patients received 24 weeks of treatment. Of all patients receiving SOF/SMV with or without RBV, 133/151 (88%) achieved sustained virological response at 12 weeks after therapy and 11 relapsed (7%). One patient had virological breakthrough (n = 1), and 6 patients were lost to posttreatment follow-up. Serious adverse events occurred in 11.9%; 3 patients (all cirrhotic) died due to aspiration pneumonia, suicide, and multiorgan failure. One experienced LT rejection. IFN-free DAA treatment represents a major improvement over prior IFN-based therapy. Broader application of these and other emerging DAA regimens in the treatment of posttransplant hepatitis C is warranted. PMID- 26519872 TI - Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation. AB - Wilms' tumor gene 1 (WT1) is overexpressed in leukemia and WT1-derived CD8(+) T cell epitopes for immunotherapies targeting WT1 have been defined. Here, we analyzed expression of WT1 in 226 peripheral blood and bone marrow samples from patients with acute myeloid leukemia or myelodysplastic syndrome (AML/MDS) before and after allogeneic stem cell transplantation (SCT). Transcripts were assessed by quantitative polymerase chain reaction, and WT1-specific CD8+ cytotoxic T cells (CTL) were monitored by tetramer staining and enzyme-linked immunospot (ELISPOT) assays. Reduction of WT1 levels correlated with a longer survival (p < 0.01). Increment of WT1 transcripts eventually resulted in relapse and subsequent death of the patients. In patients with longer survival and continuous complete remission (cCR) after SCT, higher and enduring frequencies of WT1-specific CTL than in patients developing a relapse were detected. These cells were effector T cells secreting interferon gamma and granzyme B. In summary, WT1 is a suitable marker for the detection of minimal residual disease after SCT or chemotherapy. A rising WT1 signal correlated with a dismal prognosis of the patients. WT1 specific CD8(+) T cells might contribute to the maintenance of a cCR. Targeting WT-1 by peptide/protein vaccination as well as adoptive transfer of genetically modified T cells are future options in the individualized therapy for AML/MDS patients. PMID- 26519869 TI - Layer-by-layer inorganic/polymeric nanoparticles for kinetically controlled multigene delivery. AB - Nonviral gene delivery methods represent a potential safe and effective approach for treating myriad diseases. For many gene therapy applications, delivering multiple exogenous genes and controlling the time profile that these genes are expressed would be advantageous. Polymeric nonviral gene carriers are versatile and can be readily tailored for particular therapeutic applications, have the ability to carry multiple large genes within each particle, and can be more easily manufactured than viruses used for gene delivery. A layer-by-layer (LbL) theranostic-enabling nanoparticle was developed to incorporate two plasmid types which have differing expression time profiles. Temporally controlling the expression of exogenous DNA enables superior control over the microenvironment and could lead to better control over differentiation pathways and cell fate. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 707-713, 2016. PMID- 26519878 TI - MicroRNA-494 plays a role in fiber type-specific skeletal myogenesis in human induced pluripotent stem cells. AB - Mitochondrial oxidative capacity in skeletal muscle is known to decrease in diabetic patients, and sarcopenia is a risk factor for diabetes, particularly in elderly people. We previously revealed that microRNA (miR)-494 inhibits mitochondrial biogenesis during myogenic differentiation in murine C2C12 cells and others reported that exercise regulates miR-494 levels in obese sedentary individuals with increased risk of type 2 diabetes. In this study, to investigate the therapeutic potential of miR-494, we first investigated the role of miR-494 during human skeletal myogenesis. Using human induced pluripotent stem (hiPS) cells stably transfected with the Tet/ON-myogenic differentiation 1(MYOD1) gene (MyoD-hiPS cells), we found that miR-494 expression transiently increased and was downregulated after myogenic induction. In miR-494 transfected MyoD-hiPS cells, the level of high oxidative fiber (type IIa) marker proteins specifically decreased, while no change in the total number of cells was observed. In contrast, the expression of both type I and type IIx markers was unaffected by miR-494 overexpression. Furthermore, miR-494 overexpression suppressed basal oxygen consumption rate concomitant with the inhibition of myotube formation and without significant effects on the mitochondrial content. These results suggest that miR-494 plays a novel role in the fiber type-specific skeletal myogenesis in MyoD-hiPS cells, distinct from murine C2C12 myogenesis. PMID- 26519876 TI - Human breast cancer cell death induced by BnSP-6, a Lys-49 PLA2 homologue from Bothrops pauloensis venom. AB - This work shows the antitumoral effects of BnSP-6, a Lys 49 PLA2 isolated from Bothrops pauloensis venom, on human breast cancer MDA-MB-231 cells. BnSP-6 caused a dose-dependent cytotoxicity and inhibited cell adhesion. Interestingly, cytotoxic activity of BnSP-6 was significantly lower against MCF10A, a non tumorigenic breast cell line, suggesting that this PLA2 presented a possible preference for targets in cancer cells. Analysis of cell death on MDA-MB-231 cells showed that BnSP-6 stimulated the autophagy process, as evidenced by labeling of autophagic vacuoles. Moreover, apoptosis assays showed that BnSP-6 induced both early and late apoptosis. Apoptosis of MDA-MB-231 cells was also confirmed by up-regulation of different genes related to the apoptosis pathway, such as TNF, TNFRSF10B, TNFRSF1A and CASP8 and decreased expression of anti apoptotic genes (BCL2 and BCL2L). In addition, BnSP-6 caused a remarkable increase in gene expression of BRCA2 and TP53 tumor suppressors. Finally, BnSP-6 induced down-regulation of Angiopoetin 1 gene (potent pro-angiogenic factor) and inhibited adhesion and migration of MDA-MB-231 cells suggesting pharmaceutical applications of this PLA2 as an antiangiogenic and anti-metastatic agent. Taken together, our results show that the PLA2 BnSP-6 presents anticancer potential that can be exploited as prototype for the design of new therapies. PMID- 26519885 TI - Global partnerships are critical to advance the control of Neglected Zoonotic Diseases: The case of the Global Alliance for Rabies Control. AB - There is a need for innovation to improve control of all Neglected Zoonotic Diseases (NZDs). The Global Alliance for Rabies Control was formed to prevent human deaths from rabies and relieve the burden of rabies in other animal populations, especially dogs. It aims to identify reasons for the neglect of rabies in developing countries and to develop strategies to improve rabies control. Through initiatives such as World Rabies Day and the Partners for Rabies Prevention, progress has been made towards increased awareness of the burden of rabies transmitted by dogs at scales from local to international. An evidence base of the feasibility of canine rabies elimination has been built up and now easier access to information and tools enables countries to design and implement rabies elimination strategies in a logical way, utilizing the structures of regional networks for rabies control. The body of evidence has built consensus amongst international stakeholders in rabies control and is now being used to encourage international policy change, attract investment and increase delivery of effective rabies control programmes in canine rabies endemic countries. PMID- 26519883 TI - Implementation of new approaches for generating conventional reassortants for live attenuated influenza vaccine based on Russian master donor viruses. AB - Cold-adapted influenza strains A/Leningrad/134/17/57 (H2N2) and B/USSR/60/69, originally developed in Russia, have been reliable master donors of attenuation for preparing live attenuated influenza vaccines (LAIV). The classical strategy for generating LAIV reassortants is robust, but has some disadvantages. The generation of reassortants requires at least 3 passages under selective conditions after co-infection; each of these selective passages takes six days. Screening the reassortants for a genomic composition traditionally starts after a second limiting dilution cloning procedure, and the number of suitable reassortants is limited. We developed a new approach to shorten process of preparing LAIV seed viruses. Introducing the genotyping of reassortants by pyrosequencing and monitoring sequence integrity of surface antigens starting at the first selective passage allowed specific selection of suitable reassortants for the next cloning procedure and also eliminate one of the group selective passage in vaccine candidate generation. Homogeneity analysis confirmed that reducing the number of selective passages didn't affect the quality of LAIV seed viruses. Finally, the two-way hemagglutination inhibition test, implemented for all the final seed viruses, confirmed that any amino acid substitutions acquired by reassortants during egg propagation didn't affect antigenicity of the vaccine. Our new strategy reduces the time required to generate a vaccine and was used to generate seasonal LAIVs candidates for the 2012/2013, 2014/2015, and 2015/2016 seasons more rapidly. PMID- 26519881 TI - Critical role of ARID3B in the expression of pro-apoptotic p53-target genes and apoptosis. AB - ARID3A and ARID3B are transcriptional targets of p53. Recently, it has been reported that ARID3A plays a critical role in the transcriptional activation of pro-arrest p21 in response to DNA damage. However, the role of ARID3B in the p53 regulatory pathway remains poorly understood. Here we show that ARID3A and ARID3B specifically bind to putative ARID3-binding sites in p53 target genes in vitro and in vivo. ARID3B and, to a lesser extent, ARID3A silencing blocked transcriptional activation of pro-apoptotic p53 target genes, such as PUMA, PIG3, and p53. Furthermore, ectopic ARID3B, to a lesser extent, ARID3A expression activated the pro-apoptotic gene expression, and only ARID3B induced apoptosis. Finally, ARID3B but not ARID3A silencing blocked apoptosis induction following DNA damage. These results indicated that, although ARID3B and ARID3A share overlapping functions, ARID3B play a key role in the expression of pro-apoptotic p53-target genes and apoptosis. PMID- 26519879 TI - High fructose consumption induces DNA methylation at PPARalpha and CPT1A promoter regions in the rat liver. AB - DNA methylation status is affected by environmental factors, including nutrition. Fructose consumption is considered a risk factor for the conditions that make up metabolic syndrome such as dyslipidemia. However, the pathogenetic mechanism by which fructose consumption leads to metabolic syndrome is unclear. Based on observations that epigenetic modifications are closely related to induction of metabolic syndrome, we hypothesized that fructose-induced metabolic syndrome is caused by epigenetic alterations. Male SD rats were designated to receive water or 20% fructose solution for 14 weeks. mRNA levels for peroxisome proliferator activated receptor alpha (PPARalpha) and carnitine palmitoyltransferase 1A (CPT1A) was analyzed using Real-time PCR. Restriction digestion and real-time PCR (qAMP) was used for the analysis of DNA methylation status. Hepatic lipid accumulation was also observed by fructose intake. Fructose feeding also significantly decreased mRNA levels for PPARalpha and CPT1A. qAMP analysis demonstrated the hypermethylation of promoter regions of PPARalpha and CTP1A genes. Fructose-mediated attenuated gene expression may be mediated by alterations of DNA methylation status, and pathogenesis of metabolic syndrome induced by fructose relates to DNA methylation status. PMID- 26519880 TI - Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes. AB - Apolipoprotein E (apoE), a protein mainly involved in lipid metabolism, is associated with several neurodegenerative disorders including Alzheimer's disease. Despite numerous attempts to elucidate apoE gene regulation in the brain, the exact mechanism is still uncovered. The mechanism of apoE gene regulation in the brain involves the proximal promoter and multienhancers ME.1 and ME.2, which evolved by gene duplication. Herein we questioned whether thyroid hormones and their nuclear receptors have a role in apoE gene regulation in astrocytes. Our data showed that thyroid hormones increase apoE gene expression in HTB14 astrocytes in a dose-dependent manner. This effect can be intermediated by the thyroid receptor beta (TRbeta) which is expressed in these cells. In the presence of triiodothyronine (T3) and 9-cis retinoic acid, in astrocytes transfected to overexpress TRbeta and retinoid X receptor alpha (RXRalpha), apoE promoter was indirectly activated through the interaction with ME.2. To determine the location of TRbeta/RXRalpha binding site on ME.2, we performed DNA pull down assays and found that TRbeta/RXRalpha complex bound to the region 341-488 of ME.2. This result was confirmed by transient transfection experiments in which a series of 5'- and 3'-deletion mutants of ME.2 were used. These data support the existence of a biologically active TRbeta binding site starting at 409 in ME.2. In conclusion, our data revealed that ligand-activated TRbeta/RXRalpha heterodimers bind with high efficiency on tissue-specific distal regulatory element ME.2 and thus modulate apoE gene expression in the brain. PMID- 26519882 TI - Exendin-4 attenuates cardiac hypertrophy via AMPK/mTOR signaling pathway activation. AB - Diabetes mellitus is a prominent risk factor for cardiovascular diseases. Diabetic cardiomyopathy is an important complication of the heart independent of hypertension and coronary artery disease and is accompanied by cardiac hypertrophy. Cardiac hypertrophy easily leads to heart failure, which is a leading cause of morbidity and mortality. Glucagon-like peptide 1 (GLP-1) is an incretin hormone, which has various beneficial roles in the cardiovascular system, and exendin-4 is a highly potent glucagon-like peptide 1 receptor agonist. However, the role of GLP-1 in cardiac hypertrophy remains unknown. Our study revealed that exendin-4 treatment ameliorated phenylephrine (PE)-induced cardiac hypertrophy, which presented as decreased cardiac hypertrophic markers (ANP, BNP, and beta-MHC) and cell surface area. This condition was significantly reversed upon treatment with the GLP-1 receptor antagonist exendin9-39. We also discovered that Erk1/2 and AMPK signaling pathways were involved in this process. Furthermore, our data demonstrate that the AMPK inhibitor compound C inhibited the anti-hypertrophic effect of exendin-4, which is associated with the mTOR/p70S6K/4-EBP1 signaling pathway. Finally, exendin-4 enhanced the anti hypertrophic effect of rapamycin. In summary, our study disclosed that exedin-4 inhibits cardiac hypertrophy by upregulating GLP-1 receptor expression and activating the AMPK/mTOR signaling pathway. PMID- 26519884 TI - Neurocysticercosis in a rural population with extensive pig production in Angonia district, Tete Province, Mozambique. AB - Neurocysticercosis (NCC) is an important neurological disease in countries with high prevalence of Taenia solium infection and is emerging as a serious public health and economic problem. The aim of this study was to estimate the prevalence of NCC in Angonia district, Tete province, Mozambique based on: prevalence of human T. solium cysticercosis assessed by antigen Enzyme-linked Immunosorbent Assay (Ag-ELISA) seropositivity, history of epilepsy, and brain computed tomography (CT) scan results. A cross sectional study was conducted between September and November 2007 in Angonia district. Questionnaires and blood samples were collected from 1,723 study subjects. Brain CT-scans were carried out on 151 study subjects with confirmed history of epilepsy. A total of 77 (51.0% (95% CI, 42.7-59.2)) and 38 (25.2% (95% CI, 18.5-32.9)) subjects met the criteria for definitive and probable diagnosis of NCC, respectively. T. solium Ag-ELISA seropositivity was found in 15.5% (95% CI, 12.8-16.2) of the study subjects. The estimated life time prevalence of epilepsy was 8.8% (95% CI, 7.5-10.2). Highly suggestive lesions of NCC were found on CT-scanning in 77 (71.9%, (95% CI, 62.4 80.2)) of the seropositive and 8 (18.1%, (95% CI, 8.2-32.7)) of the seronegative study subjects, respectively. The present findings revealed a high prevalence of NCC among people with epilepsy in Angonia district. Determination of effective strategies for prevention and control of T. solium cysticercosis are necessary to reduce the burden of NCC among the affected populations. PMID- 26519886 TI - VPAC1 Targeted (64)Cu-TP3805 Positron Emission Tomography Imaging of Prostate Cancer: Preliminary Evaluation in Man. AB - OBJECTIVE: To evaluate (64)Cu-TP3805 as a novel biomolecule, to positron emission tomography (PET) image prostate cancer (PC), at the onset of which VPAC1, the superfamily of G protein-coupled receptors, is expressed in high density on PC cells, but not on normal cells. MATERIALS AND METHODS: Twenty-five patients undergoing radical prostatectomy were PET/X-ray computerized tomography imaged preoperatively with (64)Cu-TP3805. Standardized maximum uptake (SUVmax) values were determined and malignant lesions (standardized uptake value > 1.0) counted, and compared with histologic findings. Whole-mount pathology slides from 6 VPAC1 PET imaged patients, 3 benign prostatic hyperplasia patients, 1 malignant and 1 benign lymph node underwent digital autoradiography (DAR) after (64)Cu-TP3805 incubation and were compared to hematoxylin- and eosin-stained slides. RESULTS: In 25 patients who underwent PET imaging, 212 prostate gland lesions had SUVmax > 1.0 vs 127 lesions identified by histology of biopsy tissues. The status of the additional 85 PET identified prostate lesions remains to be determined. In 68 histologic slides from 6 PET imaged patients, DAR identified 105 of 107 PC foci, 19 of 19 high-grade prostatic intraepithelial neoplasias, and ejaculatory ducts and verumontanum involved with cancer. Additionally, DAR found 9 PC lesions not previously identified histologically. The positive and negative lymph nodes were correctly identified, and in 3 of 3 benign prostatic hyperplasia patients and 5 of 5 cysts, DAR was negative. CONCLUSION: This feasibility study demonstrated that (64)Cu-TP3805 delineates PC in vivo and ex vivo, provided normal images for benign masses, and is worthy of further studies. PMID- 26519887 TI - The chemical biology of hydropersulfides (RSSH): Chemical stability, reactivity and redox roles. AB - Recent reports indicate the ubiquitous prevalence of hydropersulfides (RSSH) in mammalian systems. The biological utility of these and related species is currently a matter of significant speculation. The function, lifetime and fate of hydropersulfides will be assuredly based on their chemical properties and reactivity. Thus, to serve as the basis for further mechanistic studies regarding hydropersulfide biology, some of the basic chemical properties/reactivity of hydropersulfides was studied. The nucleophilicity, electrophilicity and redox properties of hydropersulfides were examined under biological conditions. These studies indicate that hydropersulfides can be nucleophilic or electrophilic, depending on the pH (i.e. the protonation state) and can act as good one- and two electron reductants. These diverse chemical properties in a single species make hydropersulfides chemically distinct from other, well-known sulfur containing biological species, giving them unique and potentially important biological function. PMID- 26519889 TI - In the eye of the beholder: A simulator study of the impact of Google Glass on driving performance. AB - This study examined whether, and to what extent, driving is affected by reading text on Google Glass. Reading text requires a high level of visual resources and can interfere with safe driving. However, it is currently unclear if the impact of reading text on a head-mounted display, such as Google Glass (Glass), will differ from that found with more traditional head-down electronic devices, such as a dash-mounted smartphone. A total of 20 drivers (22-48 years) completed the Lane Change Test while driving undistracted and while reading text on Glass and on a smartphone. Measures of lateral vehicle control and event detection were examined along with subjective workload and secondary task performance. Results revealed that drivers' lane keeping ability was significantly impaired by reading text on both Glass and the smartphone. When using Glass, drivers also failed to detect a greater number of lane change signs compared to when using the phone or driving undistracted. In terms of subjective workload, drivers rated reading on Glass as subjectively easier than on the smartphone, which may possibly encourage greater use of this device while driving. Overall, the results suggest that, despite Glass allowing drivers to better maintain their visual attention on the forward scene, drivers are still not able to effectively divide their cognitive attention across the Glass display and the road environment, resulting in impaired driving performance. PMID- 26519890 TI - Genetic and molecular distinctions in spinal ependymomas: A review. AB - While gross total resection of spinal ependymomas prevents recurrence, this surgical result is not always possible. Increasing evidence suggests that ependymomas occurring in the spine are genetically distinct from those originating in the brain. Herein we review the most recent developments detailing the molecular and genetic characteristics of spinal ependymomas, which may inform more effective and personalized adjuvant therapies for spinal ependymomas that are ineligible for gross total resection. We performed a key-word search for articles published on the molecular, genetic, chromosomal, and epigenetic transformations inherent in spinal ependymomas. We reviewed appropriate articles and their relevant citations. While resection can often achieve favorable outcomes in the treatment of spinal ependymoma, more research on the unique molecular, genetic, chromosomal and epigenetic traits must be conducted in order to tailor treatment and intervention for those patients for whom total resection is not possible. PMID- 26519888 TI - Biochemical and biophysical characterization of maize-derived HBsAg for the development of an oral vaccine. AB - Although a vaccine against hepatitis B virus (HBV) has been available since 1982, it is estimated that 600,000 people die every year due to HBV. An affordable oral vaccine could help alleviate the disease burden and to this end the hepatitis B surface antigen (HBsAg) was expressed in maize. Orally delivered maize material induced the strongest immune response in mice when lipid was extracted by CO2 supercritical fluid extraction (SFE), compared to full fat and hexane-extracted material. The present study provides a biochemical and biophysical basis for these immunological differences by comparing the active ingredient in the differently treated maize material. Purified maize-derived HBsAg underwent biophysical characterization by gel filtration, transmission electron microscopy (TEM), dynamic light scattering (DLS), UV-CD, and fluorescence. Gel filtration showed that HBsAg forms higher-order oligomers and TEM demonstrated virus-like particle (VLP) formation. The VLPs obtained from SFE were more regular in shape and size compared to hexane or full fat material. In addition, SFE-derived HBsAg showed the greatest extent of alpha-helical structure by far UV-CD spectrum. Fluorescence experiments also revealed differences in protein conformation. This work establishes SFE-treated maize material as a viable oral vaccine candidate and advances the development of the first oral subunit vaccine. PMID- 26519891 TI - Microvascular decompression and MRI findings in trigeminal neuralgia and hemifacial spasm. A single center experience. AB - OBJECTIVE: For patients with medically unresponsive trigeminal neuralgia (TIC) and hemifacial spasm (HS), surgical microvascular decompression (MVD) is the procedure of choice. The authors of this report sought to review their outcomes with MVD in patients with TIC and HS, and the success of preoperative magnetic resonance imaging (MRI) in identifying the offending vascular compression. METHODS: Since 2004, there were a total of 51 patients with TIC and 12 with HS with available MRI scans. All patients underwent preoperative MRI to rule out non surgical etiologies for facial pain and facial spasm, and confirm vascular compression. Follow-up after surgery was 13 +/- 22 months for the patients with TIC and 33 +/- 27 months for the patients with HS. RESULTS: There were 45 responders to MVD in the TIC cohort (88%), with a Visual Analog Score (VAS) of 1 +/- 3. All patients with HS responded to MVD between 25 and 100%, with a mean of 75 +/- 22%. Wound complications occurred in 10% of patients with MVD for TIC, and 1 patient reported hearing loss after MVD for HS, documented by audiogram. The congruence rate between the preoperative MRI and operative findings of vascular compression was 84% in TIC and 75% in HS. CONCLUSION: MVD is an effective and safe modality of treatment for TIC and HS. In addition to ruling out structural lesions, MRI can offer additional information by highlighting vascular loops associated with compressions. On conventional scans as obtained here, the resolution of MRI was congruent with operative findings in 84% in TIC and 75% in HS. This review emphasizes that the decision to undertake MVD in TIC or HS should be based on clinical diagnosis and not visualization of a compressing vessel by MRI. Conversely, the presence of a compressing vessel by MRI demands perseverance by the surgeon until the nerve is decompressed. PMID- 26519892 TI - Cerebellar hypometabolism with normal structural findings in Cerebrotendinous xanthomatosis. A case report. PMID- 26519893 TI - Reliability for non-invasive somatosensory cortex localization: Implications for pre-surgical mapping. AB - OBJECTIVES: In patients with epilepsy or space occupying tumors in cortical regions, surgical resection is often considered as the primary treatment. Pre surgical neuroimaging can provide a detailed map of pathological and functional cortex, leading to safer surgery. Mapping can be achieved non-invasively using magnetoencephalography (MEG), and is concordant with invasive findings. However, the reliability of MEG mapping between sessions is not well established. The inter-session reliability is an important property in pre-surgical mapping to establish resection margins, but repeated scans are impracticable. The present study sought to quantify the intersession reliability of MEG localization of somatosensory cortex (S1). PATIENTS AND METHODS: Eighteen healthy individuals underwent MEG sessions on 3 consecutive days. Five participants were excluded due to technical issues during one of the three days. Each session included clinical style S1 localization using electrical stimuli to each median nerve at sub-motor thresholds. The 35 ms peak of the somatosensory evoked field was used for localizing S1 in each session using a single equivalent current dipole model. Intersession reliability was quantified using two methods. Average Euclidean Distance (AED) quantified the difference in localization between each session and the inter-session mean localization. Session Euclidean Distance (SED) quantified the difference in localization between each pair of sessions. RESULTS AND DISCUSSION: Results showed the AED was 4.8 +/- 1.9 mm, whereas the SED was 8.3 +/ 3.4mm. While the AED values obtained parallel those reported previously in smaller samples, the SED values were substantially larger. CONCLUSION: Clinicians should consider up to an 8mm confidence interval around the estimated location of S1 based on MEG pre-surgical mapping. PMID- 26519894 TI - Recurrent Guillain-Barre syndrome presenting stereotypic manifestations, positive antiganglioside antibodies, and rapid recovery. AB - OBJECTIVE: Recurrent Guillain-Barre syndrome (rGBS) has been described as a rare entity with distinct characteristics. However, little is known about rGBS in Asian group. The aim of this study was to identify the incidence and clinical course of rGBS, and to determine its clinical/pathophysiological implications. METHODS: The consecutive data of 117 GBS patients were retrieved from a single university-based hospital in Korea and analyzed in terms of clinical, serological, electrophysiological aspects. RESULTS: A thorough review revealed that three (2.6%) of the enrolled patients had experienced more than two definite recurrent attacks of GBS. Interestingly, all three cases exhibited clinically stereotypical features, serum antiganglioside antibodies, and rapid recovery after intravenous immunoglobulin treatment. Clinical, serological, and electrophysiological features of rGBS cases were described in detail. CONCLUSION: The stereotypic presentation of each attack in this variant suggests the importance of both host and genetic factors for the clinical manifestations. In addition, the simultaneous presence of serum antiganglioside antibodies and rapid recovery implicate reversible nerve conduction failure as the mechanism of rGBS. These features are different from typical monophasic GBS and acute onset of chronic inflammatory demyelinating polyneuropathy. PMID- 26519895 TI - Prediction of quality of life improvements in patients with lumbar stenosis following use of membrane stabilizing agents. AB - OBJECTIVE: Membrane stabilizing agents (MSAs) improves function and reduces neuropathic pain in a subset of patients with LSS. No study has investigated the pre-treatment demographic and psychosocial factors associated with quality of life (QOL) outcomes following the use of MSAs. In this study we sought to create prediction models for post-treatment outcome. METHODS: All patients who were diagnosed with LSS and treated with MSAs at a single institution between September 2010 and March 2013 were retrospectively reviewed. QOL outcomes were collected prospectively. Prediction tools were created using multivariable logistic regression and Cox proportional hazard models. Outcome measures were: 1 need for surgery within 1 year after initiating MSA treatment, 2 - time until surgery after initiating MSA treatment, 3 - any improvement in EuroQol (EQ)-5D QOL index, 4 - improvement in EQ-5D index exceeding the minimum clinically important difference (MCID). RESULTS: 1346 patients were included. For goal 1 (need for surgery), the prediction model was less robust. For goal 2 (time to surgery), only age was a significant predictor, with each 10-year increase in age causing the hazard of eventually having surgery to increase by 20%. 382 patients were available for analysis for goals 3 and 4 (predicting improvement in EQ-5D). Prediction models for these goals were good with C-statistics 0.73 and 0.85, respectively. Predictive factors for superior outcomes included lower baseline EQ 5D index (worse QOL), less baseline depression, greater median income, and being married. CONCLUSION: MSA treatment provides improvements in quality of life for those individuals with LSS. Treatment effects of MSAs will be greatest in those with worse quality of life, less depression, married patients, and those of higher socio-economic status. PMID- 26519896 TI - Increased functional connectivity between motor and sensory cortex in a patient with Lance-Adams syndrome. PMID- 26519898 TI - Important prognostic markers for craniopharyngioma recurrence. PMID- 26519897 TI - Which figure copy test is more sensitive for cognitive impairment in Parkinson's disease: Wire cube or interlocking pentagons? AB - BACKGROUND: Performance on figure copy tests has been shown to predict progressive cognitive decline in Parkinson's disease (PD). Historically, the interlocking pentagons from the Mini Mental State Exam (MMSE) have been the figure copy test most commonly used during cognitive screening evaluations. However, the wire cube from the Montreal Cognitive Assessment (MoCA) is increasingly being used. OBJECTIVE: To evaluate which of these figure copy tests is more sensitive for cognitive impairment in PD. METHODS: Sixty-three PD patients from UK and USA completed the MMSE and MoCA. Logistic regression and sensitivity/specificity analyses were used to evaluate the utility of each figure copy test for detecting global cognitive impairment. RESULTS: The wire cube was a significant indicator of cognitive impairment (OR=4.79, 95% CI=1.63-14.07, p=0.004), with a sensitivity/specificity of 0.74/0.63 in our sample. In contrast, interlocking pentagons were not a significant indicator of cognitive impairment (OR=1.88, 95% CI=0.54-6.50, p=0.32), with a sensitivity/specificity of 0.26/0.84. CONCLUSION: The wire cube is more sensitive to cognitive impairment in PD, most likely related to its greater complexity. The results have implications for clinicians who may have time for just one figure copying task as part of a brief screen for cognitive impairment in busy clinics and for researchers applying the PD mild cognitive impairment diagnostic criteria necessitating two tests of visuospatial function to be administered. PMID- 26519899 TI - Limited variation during circulation of a polyomavirus in the human population involves the COCO-VA toggling site of Middle and Alternative T-antigen(s). AB - We have recently shown that the trichodysplasia spinulosa-associated polyomavirus (TSPyV) belongs to a large monophyletic group of mammalian polyomaviruses that experienced accelerated codon-constrained Val-Ala (COCO-VA) toggling at a protein site common to both Middle and Alternative T-antigens (MT/ALTO). Here we analyzed thirteen, mostly newly sequenced TSPyV genomes, representing ~40% of reported TS disease cases world-wide. We found two deletions and 30 variable sites (<=0.6%) that included only four sites with non-synonymous substitutions (NSS). One NSS site was under positive selection in the exon shared by Small and Middle T antigens, while three others were segregated in MT/ALTO. Two MT/ALTO sites covaried with five sites elsewhere in the genome and determined separation of twelve TSPyVs into two most populous phylogenetic lineages. The other, most distant TSPyV was distinguished by NSS at the COCO-VA site, observed for the first time during intra-species evolution. Our findings reveal a connection between micro- and macro-evolution of polyomaviruses. PMID- 26519900 TI - Pharmacology and structure of P2Y receptors. AB - P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. There are eight mammalian P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14). P2Y receptors are widely expressed and play important roles in physiology and pathophysiology. One important example is the ADP-induced platelet aggregation mediated by P2Y1 and P2Y12 receptors. Active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel as well as the nucleoside analogue ticagrelor block P2Y12 receptors and thereby platelet aggregation. These drugs are used for the prevention and therapy of cardiovascular events. Moreover, P2Y receptors play important roles in the nervous system. Adenine nucleotides modulate neuronal activity and neuronal fibre outgrowth by activation of P2Y1 receptors and control migration of microglia by P2Y12 receptors. UDP stimulates microglial phagocytosis through activation of P2Y6 receptors. There is evidence for a role for P2Y2 receptors in Alzheimer's disease pathology. The P2Y receptor subtypes are highly diverse in both their amino acid sequences and their pharmacological profiles. Selective receptor ligands have been developed for the pharmacological characterization of the receptor subtypes. The recently published three-dimensional crystal structures of the human P2Y1 and P2Y12 receptors will facilitate the development of therapeutic agents that selectively target P2Y receptors. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID- 26519901 TI - BDNF - a key transducer of antidepressant effects. AB - How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knockout mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an essential determinant of antidepressant efficacy. PMID- 26519902 TI - Glutamatergic transmission in the central nucleus of the amygdala is selectively altered in Marchigian Sardinian alcohol-preferring rats: Alcohol and CRF effects. AB - The CRF system of the central nucleus of the amygdala (CeA) is important for the processing of anxiety, stress, and effects of acute and chronic ethanol. We previously reported that ethanol decreases evoked glutamate transmission in the CeA of Sprague Dawley rats and that ethanol dependence alters glutamate release in the CeA. Here, we examined the effects of ethanol, CRF and a CRF1 receptor antagonist on spontaneous and evoked glutamatergic transmission in CeA neurons from Wistar and Marchigian Sardinian Preferring (msP) rats, a rodent line genetically selected for excessive alcohol drinking and characterized by heightened activity of the CRF1 system. Basal spontaneous and evoked glutamate transmission in CeA neurons from msP rats was increased compared to Wistar rats. Ethanol had divergent effects, either increasing or decreasing spontaneous glutamate release in the CeA of Wistar rats. This bidirectional effect was retained in msP rats, but the magnitude of the ethanol-induced increase in glutamate release was significantly smaller. The inhibitory effect of ethanol on evoked glutamatergic transmission was similar in both strains. CRF also either increased or decreased spontaneous glutamate release in CeA neurons of Wistar rats, however, in msP rats CRF only increased glutamate release. The inhibitory effect of CRF on evoked glutamatergic transmission was also lost in neurons from msP rats. A CRF1 antagonist produced only minor effects on spontaneous glutamate transmission, which were consistent across strains, and no effects on evoked glutamate transmission. These results demonstrate that the genetically altered CRF system of msP rats results in alterations in spontaneous and stimulated glutamate signaling in the CeA that may contribute to both the anxiety and drinking behavioral phenotypes. PMID- 26519904 TI - Age-related differences in the motor planning of a lower leg target matching task. AB - While the development and execution of upper extremity motor plans have been well explored, little is known about how individuals plan and execute rapid, goal directed motor tasks with the lower extremities. Furthermore, the amount of time needed to integrate the proper amount of visual and proprioceptive feedback before being able to accurately execute a goal-directed movement is not well understood; especially in children. Therefore, the purpose of this study was to initially interrogate how the amount of motor planning time provided to a child before movement execution may influence the preparation and execution of a lower leg goal-directed movement. The results displayed that the amount of pre-movement motor planning time provided may influence the reaction time and accuracy of a goal directed leg movement. All subjects in the study had longer reaction times and less accurate movements when no pre-movement motor planning time was provided. In addition, the children had slower reaction times, slower movements, and less accurate movements than the adults for all the presented targets and motor planning times. These results highlight that children may require more time to successfully plan a goal directed movement with the lower extremity. This suggests that children may potentially have less robust internal models than adults for these types of motor skills. PMID- 26519905 TI - A unified approach for revealing multiple balance recovery strategies. AB - In human balance recovery, different strategies have been proposed with generally overlooked knee motions but extensive focus on the ankle, hip, and step strategies. It is not well understood whether maintaining balance is regulated at the lower "muscular-articular" level of coordinating segment joints or at a higher level of controlling whole body dynamics. Whether balance control is to minimize joint degrees of freedom (DOF) or utilize all the available DOF also remains unclear. This study aimed to use a realistic musculoskeletal human model to identify multiple balance recovery strategies with a single optimization criterion. Movements were driven by neural excitations (which activated muscle force generation) and were assumed to be symmetric. Balance recoveries were simulated with forward-inclined straight body postures as the initial conditions. When the position of the toes was fixed, balance was regained with virtually straight knees and mixed ankle/hip strategies. Under a severely perturbed condition, use of the forward hop strategy after releasing the fixed-toes constraint indicated spontaneous recruitment or suppression of DOF, which mimicked functions of optimally computed CNS commands in humans. The results also indicated that increase/decrease in the number of DOF depends on the imposed perturbation intensity and movement constraints. PMID- 26519906 TI - Adding adaptable toe stiffness affects energetic efficiency and dynamic behaviors of bipedal walking. AB - In human walking, toes play an important role in supporting the body and controlling the forward motion. These functions are achieved by muscles and tendons around toe joints. To further understand the importance of toe and how toe muscle functions affect the locomotion, we employ a simple bipedal walking model with compliant joints. The ankle joints and toe joints are modeled as torsional springs and the actuation patterns are similar to that of normal human walking. Experimental results show that adding adaptable compliant toe joints could benefit the stability and energy efficiency. By generating plantar flexion moment after heel-off, the toes contribute to stabilize the body and control the forward motion. In addition, multi-joint foot structure could improve the energy efficiency by reducing the energy consumption of ankle joints. A proper toe actuation pattern could result in a proper toe dorsiflexion and reduce the maximal ankle plantar flexion, leading to a smoother and more efficient locomotion. PMID- 26519903 TI - Purinergic receptors as potential therapeutic targets in Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory and cognitive ability and is a serious cause of mortality. Many of the pathological characteristics associated with AD are revealed post-mortem, including amyloid-beta plaque deposition, neurofibrillary tangles containing hyperphosphorylated tau proteins and neuronal loss in the hippocampus and cortex. Although several genetic mutations and risk factors have been associated with the disease, the causes remain poorly understood. Study of disease-initiating mechanisms and AD progression in humans is inherently difficult as most available tissue specimens are from late-stages of disease. Therefore, AD researchers rely on in vitro studies and the use of AD animal models where neuroinflammation has been shown to be a major characteristic of AD. Purinergic receptors are a diverse family of proteins consisting of P1 adenosine receptors and P2 nucleotide receptors for ATP, UTP and their metabolites. This family of receptors has been shown to regulate a wide range of physiological and pathophysiological processes, including neuroinflammation, and may contribute to the pathogenesis of neurodegenerative diseases like Parkinson's disease, multiple sclerosis and AD. Experimental evidence from human AD tissue has suggested that purinergic receptors may play a role in AD progression and studies using selective purinergic receptor agonists and antagonists in vitro and in AD animal models have demonstrated that purinergic receptors represent novel therapeutic targets for the treatment of AD. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID- 26519908 TI - Do Medicaid benefit expansions have teeth? The effect of Medicaid adult dental coverage on the use of dental services and oral health. AB - This article examines the effect of Medicaid adult dental coverage on use of dental care and dental health outcomes using state-level variation in dental coverage during 2000-2012. Our findings imply that dental coverage is associated with an increase in the likelihood of a recent dental visit, with the size of the effect increasing with Medicaid payment rates to dentists, and a reduction in the likelihood of untreated dental caries. We are among the first to detect an effect of Medicaid coverage on a clinical health outcome other than mortality. These findings may have implications for states expanding Medicaid coverage to adults with incomes of up to 138% of the federal poverty threshold under the Affordable Care Act as most of these states offer an adult dental benefit. PMID- 26519909 TI - Did you get your shots? Experimental evidence on the role of reminders. AB - Many families fail to vaccinate their children despite the supply of these services at no cost. This study tests whether personal reminders can increase demand for vaccination. A field experiment was conducted in rural Guatemala in which timely reminders were provided to families whose children were due for a vaccine. The six-month intervention increased the probability of vaccination completion by 2.2 percentage points among all children in treatment communities. Moreover, for children in treatment communities who were due to receive a vaccine, and whose parents were expected to be reminded about that due date, the probability of vaccination completion increased by 4.6 percentage points. The cost of an additional child with complete vaccination due to the intervention is estimated at about $7.50. PMID- 26519907 TI - Focal adhesions, stress fibers and mechanical tension. AB - Stress fibers and focal adhesions are complex protein arrays that produce, transmit and sense mechanical tension. Evidence accumulated over many years led to the conclusion that mechanical tension generated within stress fibers contributes to the assembly of both stress fibers themselves and their associated focal adhesions. However, several lines of evidence have recently been presented against this model. Here we discuss the evidence for and against the role of mechanical tension in driving the assembly of these structures. We also consider how their assembly is influenced by the rigidity of the substratum to which cells are adhering. Finally, we discuss the recently identified connections between stress fibers and the nucleus, and the roles that these may play, both in cell migration and regulating nuclear function. PMID- 26519911 TI - Spatiotemporal patterns of livestock manure nutrient production in the conterminous United States from 1930 to 2012. AB - Manure nitrogen (N) and phosphorus (P) from livestock husbandry are important components of terrestrial biogeochemical cycling. Assessment of the impacts of livestock manure on terrestrial biogeochemistry requires a compilation and analysis of spatial and temporal patterns of manure nutrients. In this study, we reconstructed county-level manure nutrient data of the conterminous United States (U.S.) in 4- to 5-year increments from 1930 to 2012. Manure N and P were 5.8 9 +/ 0.64 Tg N yr.(-1) (Mean +/- Standard Deviation) and 1.73 +/- 0.29 Tg Pyr.(-1) (1 Tg = 10(12)g), and increased by 46% and 92% from 1930 to 2012, respectively. Prior to 1970, manure provided more N to the U.S. lands than chemical fertilizer use. Since 1970, however, increasing chemical N fertilizer use has exceeded manure N production. Manure was the primary P source in the U.S. during 1930-1969 and 1987-2012, but was lower than P fertilizer use in 1974, 1978, and 1982. High nutrient-production regions shifted towards eastern and western areas of the U.S. Decreasing small farms and increasing Concentrated Animal Feeding Operations (CAFOs) induced concentrated spatial patterns in manure nutrient loads. Counties with cattle or poultry as the primary manure nutrient contributors expanded significantly from 1930 to 2012, whereas regions with sheep and hog as the primary contributors decreased. We identified regions facing environmental threats associated with livestock farming. Effective management of manure should consider the impacts of CAFOs in manure production, and changes in livestock population structure. The long-term county-level manure nutrient dataset provides improved spatial and temporal information on manure nutrients in the U.S. This dataset is expected to help advance research on nutrient cycling, ammonia volatilization, greenhouse gas (GHG) emissions from livestock husbandry, recovery and reuse of manure nutrients, and impacts of livestock feeding on human health in the context of global change. PMID- 26519910 TI - Spirochetal motility and chemotaxis in the natural enzootic cycle and development of Lyme disease. AB - Two-thirds of all bacterial genomes sequenced to-date possess an organelle for locomotion, referred to as flagella, periplasmic flagella or type IV pili. These genomes may also contain a chemotaxis-signaling system which governs flagellar rotation, thus leading a coordinated function for motility. Motility and chemotaxis are often crucial for infection or disease process caused by pathogenic bacteria. Although motility-associated genes are well-characterized in some organisms, the highly orchestrated synthesis, regulation, and assembly of periplasmic flagella in spirochetes are just being delineated. Recent advances were fostered by development of unique genetic manipulations in spirochetes coupled with cutting-edge imaging techniques. These contemporary advances in understanding the role of spirochetal motility and chemotaxis in host persistence and disease development are highlighted in this review. PMID- 26519912 TI - eHALOPH a Database of Salt-Tolerant Plants: Helping put Halophytes to Work. AB - eHALOPH (http://www.sussex.ac.uk/affiliates/halophytes/) is a database of salt tolerant plants-halophytes. Records of plant species tolerant of salt concentrations of around 80 mM sodium chloride or more have been collected, along with data on plant type, life form, ecotypes, maximum salinity tolerated, the presence or absence of salt glands, photosynthetic pathway, antioxidants, secondary metabolites, compatible solutes, habitat, economic use and whether there are publications on germination, microbial interactions and mycorrhizal status, bioremediation and of molecular data. The database eHALOPH can be used in the analysis of traits associated with tolerance and for informing choice of species that might be used for saline agriculture, bioremediation or ecological restoration and rehabilitation of degraded wetlands or other areas. PMID- 26519913 TI - Evaluation of multivariate calibration models with different pre-processing and processing algorithms for a novel resolution and quantitation of spectrally overlapped quaternary mixture in syrup. AB - A novel approach for the resolution and quantitation of severely overlapped quaternary mixture of carbinoxamine maleate (CAR), pholcodine (PHL), ephedrine hydrochloride (EPH) and sunset yellow (SUN) in syrup was demonstrated utilizing different spectrophotometric assisted multivariate calibration methods. The applied methods have used different processing and pre-processing algorithms. The proposed methods were partial least squares (PLS), concentration residuals augmented classical least squares (CRACLS), and a novel method; continuous wavelet transforms coupled with partial least squares (CWT-PLS). These methods were applied to a training set in the concentration ranges of 40-100 MUg/mL, 40 160 MUg/mL, 100-500 MUg/mL and 8-24 MUg/mL for the four components, respectively. The utilized methods have not required any preliminary separation step or chemical pretreatment. The validity of the methods was evaluated by an external validation set. The selectivity of the developed methods was demonstrated by analyzing the drugs in their combined pharmaceutical formulation without any interference from additives. The obtained results were statistically compared with the official and reported methods where no significant difference was observed regarding both accuracy and precision. PMID- 26519914 TI - Potential benefits of triethylamine as n-electron donor in the estimation of forskolin by electronic absorption and emission spectroscopy. AB - Diterpenoid forskolin was isolated from Coleus forskolii. The electronic absorption and emission studies of forskolin were investigated in various solvents with an aim to improve its detection limits. The two chromophores present in the diterpenoid are not conjugated leading to the poor absorption and emission of UV light. The absorption and fluorescence spectra were solvent specific. In the presence of a monodentate ligand, triethylamine the detection of forskolin is improved by 3.63 times in ethanol with the fluorescence method and 3.36 times in DMSO by the absorption spectral method. The longer wavelength absorption maximum is blue shifted while the lower energy fluorescence maximum is red shifted in the presence of triethylamine. From the wavelength of fluorescence maxima of the exciplex formed between excited forskolin and triethylamine it is concluded that the order of reactivity of hydroxyl groups in the excited state forskolin is in the reverse order to that of the order of the reactivity of hydroxyl groups in its ground state. PMID- 26519915 TI - Exploring the limits of cryospectroscopy: Least-squares based approaches for analyzing the self-association of HCl. AB - To rationalize the concentration dependent behavior observed for a large spectral data set of HCl recorded in liquid argon, least-squares based numerical methods are developed and validated. In these methods, for each wavenumber a polynomial is used to mimic the relation between monomer concentrations and measured absorbances. Least-squares fitting of higher degree polynomials tends to overfit and thus leads to compensation effects where a contribution due to one species is compensated for by a negative contribution of another. The compensation effects are corrected for by carefully analyzing, using AIC and BIC information criteria, the differences observed between consecutive fittings when the degree of the polynomial model is systematically increased, and by introducing constraints prohibiting negative absorbances to occur for the monomer or for one of the oligomers. The method developed should allow other, more complicated self associating systems to be analyzed with a much higher accuracy than before. PMID- 26519916 TI - Highly sensitive detection of bovine serum albumin based on the aggregation of triangular silver nanoplates. AB - A simple, fast and highly sensitive spectrophotometric method for the determination of bovine serum albumin (BSA) has been developed based on the interactions between triangular silver nanoplates (TAgNPs) and BSA in the presence of Britton-Robison buffer solution (BR). Particularly, the wavelength of absorption maximum (lambda(max)) of TAgNPs is red shifted in the presence of BSA together with Britton-Robinson buffer solution (BR, pH=2.56), and the color of the solution changed from blue to light blue. This may be due to the interactions between BSA molecules on the surface of TAgNPs through electrostatic forces, hydrogen bonds, hydrophobic effects and van der Waals forces at pH2.56, which leads to the aggregation of TAgNPs. The determination of BSA was achieved by measuring the change of lambda(max) corresponding to localized surface plasmon resonance (LSPR) from UV-visible spectrophotometry. It was found that the shift value in the wavelength of absorption maximum (Deltalambda, the difference in absorption maxima of the TAgNPs/BSA/BR mixture and the TAgNPs/BR mixture) was proportionate to the concentration of BSA in the range of 1.0 ng mL(-1) to 100.0 ng mL(-1) with the correlation coefficient of r=0.9969. The detection limit (3 sigma/k) for BSA was found to be as low as 0.5 ng mL(-1). PMID- 26519917 TI - A novel method for the calculation of bond stretching force constants of diatomic molecules. AB - Chemical hardness is one of the chemical reactivity descriptors of chemical species and this concept has widely benefited from the development of Density Functional Theory (DFT). In the present report, chemical hardness values for approximately fifty diatomic molecules have been calculated using a new molecular hardness (eta(M)) equation derived by us in recent times. Then, correlation between force constant (k) and chemical hardness for the above mentioned diatomic molecules that situate hydrides, halides, oxides and sulfides among them has been investigated. Consequently, a relation that can be presented by a simple equation between chemical hardness with bond stretching force constants has been found. PMID- 26519918 TI - Fluorescence study on the interaction of human serum albumin with Butein in liposomes. AB - The interaction of Butein with human serum albumin in L-egg lecithin phosphatidycholine (PC) liposome has been investigated by fluorescence and absorption spectroscopy. The results of the fluorescence measurement indicated that Butein effectively quenched the intrinsic fluorescence of HSA via static quenching. The Stern-Volmer plots in all the liposome solutions showed a positive deviation from the linearity. According to the thermodynamic parameters, the hydrophobic interactions appeared be the major interaction forces between Butein and HSA. The effect of Butein on the conformation of HSA was also investigated by the synchronous fluorescence under the same experimental conditions. In addition, the partition coefficient of the Butein in the PC liposomes was also determined by using the fluorescence quenching process. The obtained results can be of biological significance in pharmacology and clinical medicine. PMID- 26519919 TI - A comparative study of ICH validated novel spectrophotometric techniques for resolving completely overlapping spectra of quaternary mixtures. AB - A pharmaceutically marketed mixture of Yohimbine, Alpha-tocopheryl acetate, Niacin, and Caffeine co-formulated as a promising therapy for erectile dysfunction. Simultaneous determination of the aforementioned pharmaceutical formulation without prior separation steps was applied using mean centering of ratio spectra and triple divisor spectrophotometric methods. Mean centering of ratio spectra method depended on using the mean centered ratio spectra in three successive steps which eliminated the derivative steps and so the signal to noise ratio was improved. The absorption spectra of the prepared solutions were measured in the wavelength range of 215-300 nm in the concentration ranges of 1 15, 3-15, 1-20, and 3-15 MUg mL(-1) for Yohimbine, Alpha-tocopheryl acetate, Niacin, and Caffeine, respectively. The amplitudes of the mean centered third ratio spectra were measured at 250 nm and 268 nm for Yohimbine and Alpha tocopheryl acetate, respectively and at peak to peak 272-273 and 262-263 nm for Niacin and Caffeine, respectively. In triple divisor method each drug in the quaternary mixture was determined by dividing the spectrum of the quaternary mixture by a standard spectrum of a mixture containing equal concentrations of the other three drugs. First derivative of these ratio spectra was obtained where determination could be achieved without any interference from the other three drugs. Amplitudes of 1-15, 3-15, 1-15, and 3-15 MUg mL(-1) were used for selective determination of Yohimbine, Alpha-tocopheryl acetate, Niacin, and Caffeine, respectively. Laboratory prepared mixtures were analyzed by the developed novel methods to investigate their selectivity also, Super Act(r) capsules were successfully analyzed to ensure absence of interference from additives. The developed methods were validated according to the ICH guidelines. The proposed methods were statistically compared with each other and with the reported methods; using student t-test, F-test, and one way ANOVA, where no significant difference was found with respect to accuracy and precision. PMID- 26519920 TI - Rapid determination and chemical change tracking of benzoyl peroxide in wheat flour by multi-step IR macro-fingerprinting. AB - BPO is often added to wheat flour as flour improver, but its excessive use and edibility are receiving increasing concern. A multi-step IR macro-fingerprinting was employed to identify BPO in wheat flour and unveil its changes during storage. BPO contained in wheat flour (<3.0 mg/kg) was difficult to be identified by infrared spectra with correlation coefficients between wheat flour and wheat flour samples contained BPO all close to 0.98. By applying second derivative spectroscopy, obvious differences among wheat flour and wheat flour contained BPO before and after storage in the range of 1500-1400 cm(-1) were disclosed. The peak of 1450 cm(-1) which belonged to BPO was blue shifted to 1453 cm(-1) (1455) which belonged to benzoic acid after one week of storage, indicating that BPO changed into benzoic acid after storage. Moreover, when using two-dimensional correlation infrared spectroscopy (2DCOS-IR) to track changes of BPO in wheat flour (0.05 mg/g) within one week, intensities of auto-peaks at 1781 cm(-1) and 669 cm(-1) which belonged to BPO and benzoic acid, respectively, were changing inversely, indicating that BPO was decomposed into benzoic acid. Moreover, another autopeak at 1767 cm(-1) which does not belong to benzoic acid was also rising simultaneously. By heating perturbation treatment of BPO in wheat flour based on 2DCOS-IR and spectral subtraction analysis, it was found that BPO in wheat flour not only decomposed into benzoic acid and benzoate, but also produced other deleterious substances, e.g., benzene. This study offers a promising method with minimum pretreatment and time-saving to identify BPO in wheat flour and its chemical products during storage in a holistic manner. PMID- 26519921 TI - Characterization of hemispherical area X-ray detector based on set of proportional counters with needle anodes. AB - This work introduces a new, versatile and robust X-ray detector with hemispherical 2pi geometry, based on a set of 15 small cylindrical proportional counters located in a hexagonal and pentagonal fullerene C60 pattern, at the same distance from the center (where a sample is placed). The counteranode consists of stainless steel sewing needles with spherical tips measuring approximately 80 MUm in diameter. The space between the counters and the sample could contain air, the same gas as the counters or vacuum. This allows a significant increase in the count rates by a factor approximately equal to the number of counters connected. It is shown that an energy resolution of 20% for 5.9 keV photons can be obtained, and a global counting rate of around 10(6)counts/s is achievable by the 15 Needle Anode Proportional Counters (NAPCs) operating in parallel mode, in our setup. PMID- 26519922 TI - Diffusion of Na(I), Cs(I), Sr(II) and Eu(III) in smectite rich natural clay. AB - Diffusion of Na(I), Cs(I), Sr(II) and Eu(III) in smectite rich natural clay, proposed as a backfill material in the Indian geological repository, was studied using the out-diffusion method. Radiotracers (22)Na, (137)Cs, (85)Sr and (154)Eu were used; the first three are carrier-free enabling experimental work at sub micromolar metal ion concentration, and Eu(III) tracer (154)Eu was used at sub millimolar concentration. An out-diffusion methodology, wherein a thin planar source of radioactivity placed between two clay columns diffuses out, was used to obtain the apparent diffusion coefficient (Da) values. This methodology enabled determination of diffusion coefficient even for strongly sorbing (154)Eu. Da values for (22)Na, (137)Cs, (85)Sr and (154)Eu were 2.35 (+/-0.14) * 10(-11), 2.65 (+/-0.09) * 10(-12), 3.32 (+/-0.15) * 10(-11) and 1.23 (+/-0.15) * 10(-13) m(2) s(-1), respectively. Da values were found to be in fair agreement with literature data reported for similar mineralogical sediments. Sorption of radionuclides on the clay was also determined in the present study and differences in Da values were rationalized on the basis of sorption data. Distribution ratios (Kd) for Cs(I) and Eu(III) were higher than that for Sr(II), which in turn was higher than that for Na(I). PMID- 26519923 TI - Interception and transfer of wet-deposited (134)Cs to potato foliage and tubers. AB - Contamination levels on potato foliage and tubers were investigated by repeated sampling after multiple foliar contaminations of wet-deposited (134)Cs at five different growth stages in a micro-plot field experiment in three successive years. Application of the radionuclide early in the growing season (deposition date 19-27 June, growth stage II = plant establishment) resulted in low (134)Cs activity concentration in potato tubers across sampling occasions (mean 60, 25 and 115 Bq kg(-1) dry weight (D.W.) for years 1, 2 and 3, respectively). Following radionuclide deposition in the middle of the growing season (15-24 July, growth stage III = tuber initiation), (134)Cs activity concentration in tubers across sampling occasions was found to be highest (mean 150, 850 and 660 Bq kg(-1) D.W. for years 1, 2 and 3, respectively). When the radionuclide was sprayed on at later stages (5-7 August, growth stage IV = tuber bulking), (134)Cs activity concentrations in tubers across sampling dates decreased (mean 75, 310 and 395 Bq kg(-1) D.W. for years 1, 2 and 3, respectively). Deposition in the second half of August (15-28 August, late growth stage IV and beginning of growth stage V = tuber maturation) resulted in yet lower (134)Cs activity concentration in tubers. Potato tubers may concentrate as much as up to 2 times more (134)Cs than foliage depending on deposition date of radionuclide. PMID- 26519924 TI - Assessment of craniometric traits in South Indian dry skulls for sex determination. AB - The skeleton plays an important role in sex determination in forensic anthropology. The skull bone is considered as the second best after the pelvic bone in sex determination due to its better retention of morphological features. Different populations have varying skeletal characteristics, making population specific analysis for sex determination essential. Hence the objective of this investigation is to obtain the accuracy of sex determination using cranial parameters of adult skulls to the highest percentage in South Indian population and to provide a baseline data for sex determination in South India. Seventy adult preserved human skulls were taken and based on the morphological traits were classified into 43 male skulls and 27 female skulls. A total of 26 craniometric parameters were studied. The data were analyzed by using the SPSS discriminant function. The analysis of stepwise, multivariate, and univariate discriminant function gave an accuracy of 77.1%, 85.7%, and 72.9% respectively. Multivariate direct discriminant function analysis classified skull bones into male and female with highest levels of accuracy. Using stepwise discriminant function analysis, the most dimorphic variable to determine sex of the skull, was biauricular breadth followed by weight. Subjecting the best dimorphic variables to univariate discriminant analysis, high levels of accuracy of sexual dimorphism was obtained. Percentage classification of high accuracies were obtained in this study indicating high level of sexual dimorphism in the crania, setting specific discriminant equations for the gender determination in South Indian people. PMID- 26519925 TI - Two decades of adolescent suicides assessed at Milan University's medicolegal unit: Epidemiology, forensic pathology and psychopathology. AB - AIM: to analyze the cases of suicide committed by adolescents in and around the city of Milan over a 20-year period (1993-2012). MATERIALS AND METHODS: cases of suicide involving individuals between 10 and 19 years of age were drawn from 20,757 autopsies performed by the Medico-legal Unit at Milan University. Seventy eight cases were considered (20 females and 58 males, with the ratio of 1:2.9), and their clinical and circumstantial histories, epidemiology, forensic pathology and psychopathological issues were analyzed. RESULT: Adolescents were involved in 2.23% of all suicides committed in Milan during the period examined. The "mean" victim is a male without psychiatric disease, aged between 16 and 19, that commits suicide outdoors. CONCLUSIONS: In the majority of cases, there were no premonitory signs, nor any particular contingent or remote reason that might explain these violent deaths, which therefore remain "impulsive". PMID- 26519926 TI - Suicide whilst under GMC's fitness to practise investigation: Were those deaths preventable? AB - The suicide of doctors under regulatory investigation in the United Kingdom has recently been under scrutiny. Despite a commissioned report into the issues surrounding these deaths, we discuss a variety of procedural and legal lacunae not yet openly considered for reform. We identified that the UK coronial system has in place several legal instruments requiring coroners to report the physician suicides as preventable to the regulatory body, the General Medical Council (GMC). We were unable to identify that these suicides were reported in line with established legislation. We also explored the relationship between the GMC and its registered doctors, concluding that the GMC does indeed have a duty of care towards its members on this important matter and that there should be procedural reform to tackle the inherent risk of suicide whilst under investigation. PMID- 26519927 TI - An exploratory factor analysis of the Parenting strategies for Eating and physical Activity Scale (PEAS) for use in Hispanic mothers of adolescent and preadolescent daughters with overweight. AB - Existing measures of feeding and physical activity parenting strategies have not been validated for use among Hispanic mothers of adolescent and preadolescent daughters with overweight. The purpose of this study was to investigate the factor structure of the Parenting strategies for Eating and Activity Scale (PEAS) among 134 Hispanic mothers (Mage=38.81, SD+/-6.34) of adolescent and preadolescent daughters with overweight. Results from this exploratory study revealed that a three-factor structure (Limit Setting, Monitoring, and Discipline) and a 13-item revised PEAS measure might be better suited for use with this population. The revised Limit Setting, Monitoring, Discipline, and total subscales had good reliability (alpha=0.89, alpha=0.88, alpha=0.90, and alpha=0.87, respectively) and the subscale inter-item correlations were strong. To assess the concurrent validity, the revised PEAS subscales were correlated with both subscales of the Behavioral Strategies to Reduce Fat and Increase Fiber (Parent Report) in a subset of the sample (n=78). The Monitoring and Discipline subscales were found to be correlated with the Behavioral Strategies to Reduce Fat (r=.36 and r=.27, p<.05, respectively) and Increase Fiber (r=.40 and r=.35, p<.01, respectively) subscales. However, the revised PEAS Limit Setting subscale was not correlated with either Reduce Fat or Increase Fiber strategy. Taken together, these results indicated some degree of concurrent validity. Results from this study should be cross-validated using confirmatory factor analysis approaches. PMID- 26519928 TI - Synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxide derivatives as potent anticonvulsant agents. AB - An efficient synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1 dioxide derivatives has been achieved under aqueous medium for the first time in good to excellent yields. All the synthesized compounds were tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) screens, which are the most broadly employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotarod test. Seven compounds 4a, 4d, 4f, 4h, 4o, 4p and 4q showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 4d showed the MES-induced seizures with ED50 value of 10.2 mg/kg and TD50 value of 288.6 mg/kg after intraperitoneal injection to mice, which provided compound 4d with a protective index (TD50/ED50) of 28.3 in the MES test. PMID- 26519929 TI - Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel. AB - We synthesized and evaluated a series of compounds for their allosteric modulation at the Kv11.1 (hERG) channel. Most compounds were negative allosteric modulators of [(3)H]dofetilide binding to the channel, in particular 7f, 7h-j and 7p. Compounds 7f and 7p were the most potent negative allosteric modulators amongst all ligands, significantly increasing the dissociation rate of dofetilide in the radioligand kinetic binding assay, while remarkably reducing the affinities of dofetilide and astemizole in a competitive displacement assay. Additionally, both 7f and 7p displayed peculiar displacement characteristics with Hill coefficients significantly distinct from unity as shown by e.g., dofetilide, further indicative of their allosteric effects on dofetilide binding. Our findings in this investigation yielded several promising negative allosteric modulators for future functional and clinical research with respect to their antiarrhythmic propensities, either alone or in combination with known Kv11.1 blockers. PMID- 26519930 TI - Novel oxime-bearing coumarin derivatives act as potent Nrf2/ARE activators in vitro and in mouse model. AB - We have designed and synthesized certain novel oxime- and amide-bearing coumarin derivatives as nuclear factor erythroid 2 p45-related factor 2 (Nrf2) activators. The potency of these compounds was measured by antioxidant responsive element (ARE)-driven luciferase activity, level of Nrf2-related cytoprotective genes and proteins, and antioxidant activity. Among them, (Z)-3-(2-(hydroxyimino)-2 phenylethoxy)-2H-chromen-2-one (17a) was the most active, and more potent than the positive t-BHQ in the induction of ARE-driven luciferase activity. Exposure of HSC-3 cells to various concentrations of 17a strongly increased Nrf2 nuclear translocation and the expression level of Nrf2-mediated cytoprotective proteins in a concentration-dependent manner. HSC-3 cells pretreated with 17a significantly reduced t-BOOH-induced oxidative stress. In the animal experiment, Nrf2-mediated cytoprotective proteins, such as aldo-keto reductase 1 subunit C-1 (AKR1C1), glutathione reductase (GR), and heme oxygenase (HO-1), were obviously elevated in the liver of 17a-treated mice than that of control. These results suggested that novel oxime-bearing coumarin 17a is able to activate Nrf2/ARE pathway in vivo and are therefore seen as a promising candidate for further investigation. PMID- 26519931 TI - A non-penalty recurrent neural network for solving a class of constrained optimization problems. AB - In this paper, we explain a methodology to analyze convergence of some differential inclusion-based neural networks for solving nonsmooth optimization problems. For a general differential inclusion, we show that if its right hand side set valued map satisfies some conditions, then solution trajectory of the differential inclusion converges to optimal solution set of its corresponding in optimization problem. Based on the obtained methodology, we introduce a new recurrent neural network for solving nonsmooth optimization problems. Objective function does not need to be convex on R(n) nor does the new neural network model require any penalty parameter. We compare our new method with some penalty-based and non-penalty based models. Moreover for differentiable cases, we implement circuit diagram of the new neural network. PMID- 26519932 TI - A linear functional strategy for regularized ranking. AB - Regularization schemes are frequently used for performing ranking tasks. This topic has been intensively studied in recent years. However, to be effective a regularization scheme should be equipped with a suitable strategy for choosing a regularization parameter. In the present study we discuss an approach, which is based on the idea of a linear combination of regularized rankers corresponding to different values of the regularization parameter. The coefficients of the linear combination are estimated by means of the so-called linear functional strategy. We provide a theoretical justification of the proposed approach and illustrate them by numerical experiments. Some of them are related with ranking the risk of nocturnal hypoglycemia of diabetes patients. PMID- 26519933 TI - PKR-inhibitor binds efficiently with human microtubule affinity-regulating kinase 4. AB - MAP/microtubule affinity-regulating kinase 4 (MARK4) plays a central role in the cellular physiology, and it is inseparably linked with many human diseases including cancer, diet induced obesity, type2 diabetes and neurodegenerative disorders. Here, we studied the interaction of PKR-inhibitor with two variants of human MARK4. One variant is named as MARK4-F1 which has 59 N-terminal residues along with kinase domain while another variant is MARK4-F2 which has kinase domain only. Molecular-docking, molecular dynamics (MD) simulation and fluorescence-binding studies were undertaken to understand the role of N-terminal 59-residues in the binding of substrate/inhibitors. Molecular docking studies revealed that the PKR-inhibitor binds in the large hydrophobic cavity of the kinase domain of MARK4 through several hydrophobic and hydrogen-bonded interactions. Furthermore, MD simulation showed a stable parameters for the complexes of both MARK4-F1 and MARK4-F2 to PKR-inhibitor with marginal difference in their binding affinities. A significant decrease in the fluorescence intensity of MARK4 was observed on successive addition of the PKR-inhibitor. Using fluorescence data we have calculated the binding-affinity and the number of binding site of PKR-inhibitor to the MARK4. A significantly high binding affinity was observed for the PKR-inhibitor to the MARK4 variants. However, there is no any significant difference in the binding affinity of PKR-inhibitor to the MARK4 variants was observed, indicating that 59 N-terminal residues of MARK4-F1 are not playing a crucial role in the ligand binding. The present study will provide an insights into designing of new PKR-inhibitor derivative as potent and selective therapeutic agent against many life threatening diseases which are associated with MARK4. PMID- 26519934 TI - The effect of intensive speech rate and intonation therapy on intelligibility in Parkinson's disease. AB - PURPOSE: Most studies on treatment of prosody in individuals with dysarthria due to Parkinson's disease are based on intensive treatment of loudness. The present study investigates the effect of intensive treatment of speech rate and intonation on the intelligibility of individuals with dysarthria due to Parkinson's disease. METHODS: A one group pretest-posttest design was used to compare intelligibility, speech rate, and intonation before and after treatment. Participants included eleven Dutch-speaking individuals with predominantly moderate dysarthria due to Parkinson's disease, who received five one-hour treatment sessions per week during three weeks. Treatment focused on lowering speech rate and magnifying the phrase final intonation contrast between statements and questions. Intelligibility was perceptually assessed using a standardized sentence intelligibility test. Speech rate was automatically assessed during the sentence intelligibility test as well as during a passage reading task and a storytelling task. Intonation was perceptually assessed using a sentence reading task and a sentence repetition task, and also acoustically analyzed in terms of maximum fundamental frequency. RESULTS: After treatment, there was a significant improvement of sentence intelligibility (effect size .83), a significant increase of pause frequency during the passage reading task, a significant improvement of correct listener identification of statements and questions, and a significant increase of the maximum fundamental frequency in the final syllable of questions during both intonation tasks. CONCLUSION: The findings suggest that participants were more intelligible and more able to manipulate pause frequency and statement-question intonation after treatment. However, the relationship between the change in intelligibility on the one hand and the changes in speech rate and intonation on the other hand is not yet fully understood. Results are nuanced in the light of the operated research design. LEARNING OUTCOMES: The reader will be able to: (1) describe the effect of intensive speech rate and intonation treatment on intelligibility of speakers with dysarthria due to PD, (2) describe the effect of intensive speech rate treatment on rate manipulation by speakers with dysarthria due to PD, and (3) describe the effect of intensive intonation treatment on manipulation of the phrase final intonation contrast between statements and questions by speakers with dysarthria due to PD. PMID- 26519935 TI - Improvement of the surface wettability of silicone hydrogel contact lenses via layer-by-layer self-assembly technique. AB - The surface wettability and anti-protein adsorption of a silicone-based hydrogel that was synthesized by a block copolymer of polydimethylsiloxane (PDMS) and poly (ethylene glycol) methacrylate (PEGMA) was improved via polyelectrolyte multilayer (PEM) immobilization. Polysaccharide PEMs of chitosan (CS, as a positive-charged agent) and hyaluronic acid (HA, as a negative-charged and anti adhesive agent) were successfully assembled on the PDMS-PU-PEGMA silicone hydrogel in a layer-by-layer (LBL) self-assembly manner. Atomic force microscopy (AFM) and dyeing data verified the progressive buildup of the PEM silicone hydrogel. The results showed that the contact angle of the silicone hydrogel decreased with an increase in the number of PEM grafting layers. Furthermore, after immobilizing five layers of CS/HA, the protein adsorption decreased from 78 +/- 11 to 26 +/- 4 MUg/cm(2) for HSA and from 55 +/- 10 to 20 +/- 4 MUg/cm(2) for lysozymes. This indicates that CS/HA PEM-immobilized silicone hydrogels can resist protein adsorption. Furthermore, these hydrogels were non-cytotoxic according to an in vitro L929 fibroblast assay. Overall, the results demonstrated that the modified silicone hydrogels exhibited hydrophilicity and anti-protein adsorption, as well as relatively high oxygen permeability and optical transparency. Therefore, they would be applicable as a contact lens material. PMID- 26519936 TI - Interactions of liposomes with dental restorative materials. AB - The in vitro adsorption and retention of liposomes onto four common types of dental restorative materials (conventional and silorane-based resin composites as well as conventional and resin-modified glass ionomer cements (GIC)) have been investigated due to their potential use in the oral cavity. Uncoated liposomes (positively and negatively charged) and pectin (low- and high-methoxylated) coated liposomes were prepared and characterized in terms of particle size and zeta potential. The adsorption of liposomes was performed by immersion, quantified by fluorescence detection, and visualized by fluorescence imaging and atomic force microscopy. Positive liposomes demonstrated the highest adsorption on all four types of materials likely due to their attractive surface charge. They also retained well (minimum 40% after 60 min) on both conventional resin composite and GIC even when exposed to simulated salivary flow. Although an intermediate initial level of adsorption was found for the pectin coated liposomes, at least 70% high methoxylated-pectin coated liposomes still remained on the conventional resin composite after 60 min flow exposure. This indicates significant contribution of hydrophobic interactions in the prolonged binding of liposomes to resin composites. Based on these results, the present paper suggests two new possible applications of liposomes in the preservation of dental restorations. PMID- 26519937 TI - Effects of fluoride-ion-implanted titanium surface on the cytocompatibility in vitro and osseointegatation in vivo for dental implant applications. AB - As an attractive technique for the improvement of biomaterials, Plasma immersion ion implantation (PIII) has been applied to modifying the titanium material for dental implant application. The present study investigated the cytocompatibility and early osseointegration of fluoride-ion-implanted titanium (F-Ti) surface and implants, both characterizing in their composition of titanium oxide and titanium fluoride. The cytocompatibility of F-Ti was evaluated in vitro by using scanning electron microscope, Cell Counting Kit-8 assay, alkaline phosphatase activity assay, and quantitative real-time polymerase chain reaction. The results showed that the F-Ti weakened the effects that Porphyromonas gingivalis exerted on the MG-63 cells in terms of morphology, proliferation, differentiation, and genetic expression when MG-63 cells and Porphyromonas gingivalis were co-cultured on the surface of F-Ti. Meanwhile, the osteogenic activity of F-Ti implants was assessed in vivo via evaluating the histological morphology and estimating histomorphometric parameters. The analysis of toluidine blue staining indicated that the new bone was more mature in subjects with F-Ti group, which exhibited the Haversian system, and the mean bone-implant contact value of F-Ti group was slightly higher than that of cp-Ti group (p>0.05). Fluorescence bands were wider and brighter in the F-Ti group, and the intensity of fluorochromes deposited at the sites of mineralized bone formation was significantly higher for F-Ti surfaces than for cp-Ti surfaces, within the 2nd, 3rd and 4th weeks (p<0.05). An indication is that the fluoride modified titanium can promote cytocompatibility and early osseointegration, thus providing a promising alternative for clinical use. PMID- 26519938 TI - Fabrication of macroporous cryogels as potential hepatocyte carriers for bioartificial liver support. AB - Two different cryogels composed of copolymer of acrylonitrile (AN) and N-vinyl-2 pyrrolidone (NVP) (poly(AN-co-NVP)) and interpenetrated polymer networks (IPN) of chitosan and poly(N-isopropylacrylamide) (poly(NiPAAm)-chitosan) were fabricated by gelation at sub-zero temperatures. The two cryogels possess an interconnected network of macropores of size 20-100 MUm and efficient transport properties as determined by physiochemical analysis. Both cryogels support in vitro growth and function of fibroblasts (COS-7) and human liver hepatocarcinoma cells (HepG2). The cryogels are hemocompatible as demonstrated by low albumin adsorption and platelet adherence. Furthermore, in vivo implantation of poly(NiPAAm)-chitosan cryogel in mice shows its biocompatibility with the surrounding tissue. Primary rat hepatocytes grown on poly(NiPAAm)-chitosan cryogel for 96 h formed cellular aggregates and maintained their functions in terms of, ammonia removal, ureagenesis and drug detoxification. Cryogel-based closed continuous bioreactor systems could maintain HepG2 cells at high density for 7 days. Off-line clinical evaluation of these cryogel-based bioreactors showed the ability of immobilized cells to detoxify circulating plasma obtained from patients with acute on chronic liver failure (ACLF). Altogether, the presented data suggests cryogels as a potential bioreactor matrix for bio-artificial liver support system. PMID- 26519939 TI - Does progranulin account for the opposite effects of etanercept and infliximab/adalimumab in osteoarthritis?: Comment on Olson et al.: "Therapeutic Opportunities to Prevent Post-Traumatic Arthritis: Lessons From the Natural History of Arthritis After Articular Fracture". PMID- 26519941 TI - Paul Von Rague Schleyer (1930-2014). PMID- 26519940 TI - Pseudo-projection-driven, self-gated cardiac cine imaging using cartesian golden step phase encoding. AB - PURPOSE: To develop and evaluate a novel two-dimensional self-gated imaging technique for free-breathing cardiac cine MRI that is free of motion-detection overhead and requires minimal planning for motion tracking. METHODS: Motion along the readout direction was extracted solely from normal Cartesian imaging readouts near ky = 0. During imaging, the readouts below a certain |ky | threshold were scaled in magnitude and filtered in time to form "pseudo-projections," enabling projection-based motion tracking along readout without frequently acquiring the central phase encode. A discrete golden step phase encode scheme allowed the |ky | threshold to be freely set after the scan while maintaining uniform motion sampling. RESULTS: The pseudo-projections stream displayed sufficient spatiotemporal resolution for both cardiac and respiratory tracking, allowing retrospective reconstruction of free-breathing non-electrocardiogram (ECG) cines. The technique was tested on healthy subjects, and the resultant image quality, measured by blood-myocardium boundary sharpness, myocardial mass, and single slice ejection fraction was found to be comparable to standard breath-hold ECG gated cines. CONCLUSION: The use of pseudo-projections for motion tracking was found feasible for cardiorespiratory self-gated imaging. Despite some sensitivity to flow and eddy currents, the simplicity of acquisition makes the proposed technique a valuable tool for self-gated cardiac imaging. Magn Reson Med 76:417 429, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. PMID- 26519942 TI - Human papillomavirus infection in male patients with STI-related symptoms in Hanoi, Vietnam. AB - This cross-sectional study investigated the prevalence, genotypes, and risk factors for human papillomavirus (HPV) infection in Hanoi, Vietnam. The study included 192 males (mean age, 32.9 years) with symptoms related to sexually transmitted infections (STI). Urinary, penile, and urethral samples were collected in April and May, 2014. HPV DNA was detected with PCR, performed with modified and/or original GP5(+)/GP6(+) primers. HPV genotypes were determined with a gene array assay. Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) DNA were detected with loop-mediated isothermal amplification. HPV DNA, NG, and CT were detected in 48 (25.0%), 23 (12.0%), and 41 (21.4%) patients, respectively. HPV DNA appeared in penile samples (21.0%, 39/186) more frequently than in urinary (3.1%, 6/191, P < 0.001) and urethral (9.4%, 18/192, P = 0.002) samples. Among patients with HPV, genotype prevalence was: HPV81 (22.9%), HPV52 (18.8%), HPV18 (16.7%), and HPV16 (6.3%). Multiple-type and high risk-type HPV infections were determined in 33.3% and 64.6%, respectively. Multivariate analysis showed a significant association of HPV infection in urethra with younger sexual debut age. HPV52 was the most prevalent high-risk HPV genotype, whereas HPV16 was less common in the male Vietnamese patients with STI-related symptoms. Younger sexual-debut age was a risk factor for HPV infection in urethra. PMID- 26519943 TI - Increased expression and dysregulated association of restriction factors and type I interferon in HIV, HCV mono- and co-infected patients. AB - Host restriction factors and type I interferon are important in limiting HIV and HCV infections, yet the role of HIV, HCV mono- and co-infection in regulating these antiviral genes expression is not clear. In this study, we measured the levels of TRIM5alpha, TRIM22, APOBEC3G, and IFN-alpha, -beta mRNA expression in peripheral blood mononuclear cells of 43 HIV mono-infected, 70 HCV mono-infected and 64 HIV/HCV co-infected patients along with 98 healthy controls. We also quantified HIV and HCV viral loads in mono- and co-infected patients. The results showed that HCV, HIV mono- and co-infection differentially increased TRIM22, APOBEC3G, and IFN-alpha, -beta mRNA expression while the mRNA expression of TRIMalpha was upregulated only by HCV-mono infection. HIV/HCV co-infection was associated with higher viral load, compared to either HIV or HCV mono-infection. Additionally, we showed TRIMalpha and TRIM22 positively correlated with IFN alpha, -beta, which could be dysregulated by HIV, HCV mono- and co-infection. Furthermore, we found TRIM22 negatively correlated with HCV viral load in mono infected patients and APOBEC3G positively correlated with HCV viral load in co infected patients. Collectively, our findings suggest the potential role of restriction factors in restricting HIV, HCV mono- and co-infection in vivo, which appears to be a therapeutic target for potential drug discovery. PMID- 26519944 TI - Chronic myeloid leukemia in the Netherlands: a population-based study on incidence, treatment, and survival in 3585 patients from 1989 to 2012. AB - OBJECTIVE: To assess the impact and results of treatment of CML in the general population, we conducted a population-based, nationwide study on 3585 CML patients diagnosed between 1989 and 2012 in the Netherlands. METHODS: Patient demographics were obtained from the Netherlands Cancer Registry. Information on age, gender, year of diagnosis, first treatment, and date of death were recorded. Overall survival (OS) was adjusted for death rates in the normal population. RESULTS: Incidence in males decreased slightly from 1.2 per 100.000 person years (PY) in 1989-2000 to 0.9 in 2001-2012. For females, incidence remained stable with 0.7 per 100.000 PY in both periods. Incidence was age dependent and highest in males in the last decades of life. Treatment before 2000 mainly consisted of chemotherapy, while after 2007 TKI use was 88%. Five-year relative survival was only 36% before the introduction of TKIs but significantly increased to 79% after the introduction of TKI. CONCLUSIONS: This study gives insight into CML incidence, treatment, and survival in routine care in the Netherlands. Although OS improved since the introduction of TKIs, there is still room for further improvement. PMID- 26519945 TI - Anthropometric Cut Points for Definition of Sarcopenia Based on Incident Mobility and Physical Limitation in Older Chinese People. AB - BACKGROUND: The Foundation of the National Institutes for Health (FNIH) Sarcopenia Project derived cut points in appendicular lean mass (ALM) and grip strength, in relation to mobility limitation defined as a walking speed less than 0.8 m/s. METHODS: Using data from the Mr and Ms Os cohort of 4,000 community dwelling Chinese men and women aged 65 years and older and a similar data-driven approach, we examined whether the cutoff values are the same for Chinese people using baseline walking speed, incident physical limitation, and incident slow walking speed at 4 years. Physical limitation was determined by interviewer administered questionnaire. Height, weight, body composition (using dual-energy X ray absorptiometry), grip strength, and walking speed were measured. RESULTS: Cutoff values identified by Classification and Regression Tree (CART) analysis for grip strength were less than 27kg for men and less than 17kg for women. The values for ALM were less than 15.61kg in men and less than 12.42kg in women; the values for ALM/body mass index (BMI) were less than 0.72 in men and less than 0.47 in women. Using presence of physical limitation at 4 years as the outcome measure, cutoff values identified by CART analysis for grip strength were less than 27kg for men and less than 19kg for women; for ALM, less than 15.65kg for men and less than 11.26kg for women; for ALM/BMI, less than 0.69 for men and 0.52 for women. Cutoff values for grip strength were less than 28.5kg for men and less than 19kg for women; for ALM, less than 17.61kg for men and less than 10.84kg for women; for ALM/BMI, less than 0.81 for men and less than 0.53 for women. CONCLUSIONS: Cutoff values may differ between ethnic groups as a result of differences in body size and lifestyles. PMID- 26519947 TI - The effect of disc degeneration on anterior shear translation in the lumbar spine: Still more problems lie ahead. PMID- 26519946 TI - Cellulose-based porous scaffold for bone tissue engineering applications: Assessment of hMSC proliferation and differentiation. AB - Physical foaming combined with microwave-induced curing was used in this study to develop an innovative device for bone tissue regeneration. In the first step of the process, a stable physical foaming was induced using a surfactant (i.e. pluronic) as blowing agent of a homogeneous blend of Sodium salt of carboxymethylcellulose (CMCNa) and polyethylene glycol diacrylate (PEGDA700) solution. In the second step, the porous structure of the scaffold was chemically stabilized by radical polymerization induced by a homogeneous rapid heating of the sample in a microwave reactor. In this step 2,2-Azobis[2-(2-imidazolin-2 yl)propane]Dihydrochloride was used as thermoinitiator (TI). CMCNa and PEGDA were mixed with different blends to correlate the properties of final product with the composition. The chemical properties of each sample were evaluated by spectroscopy analysis ATR-IR (before and after curing) in order to maximize reaction yield, and optimize kinetic parameters (i.e. time curing, microwave power). The stability of the materials was evaluated in vitro by degradation test in Phosphate Buffered Saline. Biological analyses were performed to evaluate the effect of scaffold materials on cellular behavior in terms of proliferation and early osteogenic differentiation of human Mesenchymal Stem Cells. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 726-733, 2016. PMID- 26519948 TI - A semiadiabatic spectral-spatial spectroscopic imaging (SASSI) sequence for improved high-field MR spectroscopic imaging. AB - PURPOSE: MR spectroscopic imaging (MRSI) benefits from operation at 7T due to increased signal-to-noise ratio (SNR) and spectral separation. The 180 degrees radiofrequency (RF) pulses used in the conventional MRSI sequences are particularly susceptible to the variation in the transmitted RF (B1 ) field and severe chemical shift localization errors at 7T. RF power deposition, as measured by specific absorption rate (SAR), also increases with field strength. Adiabatic 180 degrees RF pulses may mitigate the effects of B1 variation. We designed and implemented a semiadiabatic spectral-spatial spectroscopic imaging (SASSI) pulse sequence to provide more uniform spectral data at 7T with reduced SAR. METHODS: The adiabatic Shinnar-Le Roux algorithm was used to generate a high bandwidth 180 degrees adiabatic spectral-spatial (SPSP) pulse that captured a spectral range containing the main metabolites of interest. A pair of 180 degrees SPSP pulses was used to refocus the signal excited by a 90 degrees SPSP pulse in order to select a 3D volume of interest in the SASSI sequence. RESULTS: The SASSI pulse sequence produced spectra with more uniform brain metabolite SNR when compared with the conventional nonadiabatic MRSI sequence. CONCLUSION: SASSI achieved comparable SNR to the current adiabatic alternative, semi-LASER, but with 1/3 of the SAR. Magn Reson Med 76:1071-1082, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26519949 TI - Trypanosoma cruzi extracts elicit protective immune response against chemically induced colon and mammary cancers. AB - Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease, has anticancer effects mediated, at least in part, by parasite-derived products which inhibit growth of tumor cells. We investigated whether immunity to T. cruzi antigens could induce antitumor activity, using two rat models which reproduce human carcinogenesis: colon cancer induced by 1,2-dimethylhydrazine (DMH), and mammary cancer induced by N-nitroso-N-methylurea (NMU). We found that vaccination with T. cruzi epimastigote lysates strongly inhibits tumor development in both animal models. Rats immunized with T. cruzi antigens induce activation of both CD4(+) and CD8(+) T cells and splenocytes from these animals showed higher cytotoxic responses against tumors as compared to rats receiving adjuvant alone. Tumor-associated immune responses included increasing number of CD11b/c(+) His48( ) MHC II(+) cells corresponding to macrophages and/or dendritic cells, which exhibited augmented NADPH-oxidase activity. We also found that T. cruzi lysate vaccination developed antibodies specific for colon and mammary rat cancer cells, which were capable of mediating antibody-dependent cellular cytotoxicity (ADCC) in vitro. Anti-T. cruzi antibodies cross-reacted with human colon and breast cancer cell lines and recognized 41/60 (68%) colon cancer and 38/63 (60%) breast cancer samples in a series of 123 human tumors. Our results suggest that T. cruzi antigens can evoke an integrated antitumor response involving both the cellular and humoral components of the immune response and provide novel insights into the understanding of the intricate relationship between parasite infection and tumor growth. PMID- 26519950 TI - Efficient generation of endothelial cells from human pluripotent stem cells and characterization of their functional properties. AB - Although endothelial cells (ECs) have been derived from human pluripotent stem cells (hPSCs), large-scale generation of hPSC-ECs remains challenging and their functions are not well characterized. Here we report a simple and efficient three stage method that allows generation of approximately 98 and 9500 ECs on day 16 and day 34, respectively, from each human embryonic stem cell (hESC) input. The functional properties of hESC-ECs derived in the presence and absence of a TGFbeta-inhibitory molecule SB431542 were characterized and compared with those of human umbilical vein endothelial cells (HUVECs). Confluent monolayers formed by SB431542 + hESC-ECs, SB431542- hESC-ECs, and HUVECs showed similar permeability to 10,000 Da dextran, but these cells exhibited striking differences in forming tube-like structures in 3D fibrin gels. The SB431542 + hESC-ECs were most potent in forming tube-like structures regardless of whether VEGF and bFGF were present in the medium; less potent SB431542- hESC-ECs and HUVECs responded differently to VEGF and bFGF, which significantly enhanced the ability of HUVECs to form tube-like structures but had little impact on SB431542- hESC-ECs. This study offers an efficient approach to large-scale hPSC-EC production and suggests that the phenotypes and functions of hPSC-ECs derived under different conditions need to be thoroughly examined before their use in technology development. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 678-687, 2016. PMID- 26519951 TI - Cohort Profile: Hamamatsu Birth Cohort for Mothers and Children (HBC Study). PMID- 26519952 TI - Psychosis, Delusions and the "Jumping to Conclusions" Reasoning Bias: A Systematic Review and Meta-analysis. AB - We did a systematic review and meta-analysis to investigate the magnitude and specificity of the "jumping to conclusions" (JTC) bias in psychosis and delusions. We examined the extent to which people with psychosis, and people with delusions specifically, required less information before making decisions. We examined (1) the average amount of information required to make a decision and (2) numbers who demonstrated an extreme JTC bias, as assessed by the "beads task." We compared people with psychosis to people with and without nonpsychotic mental health problems, and people with psychosis with and without delusions. We examined whether reduced data-gathering was associated with increased delusion severity. We identified 55 relevant studies, and acquired previously unpublished data from 16 authors. People with psychosis required significantly less information to make decisions than healthy individuals (k= 33,N= 1935,g= -0.53, 95% CI -0.69, -0.36) and those with nonpsychotic mental health problems (k= 13,N= 667,g= -0.58, 95% CI -0.80, -0.35). The odds of extreme responding in psychosis were between 4 and 6 times higher than the odds of extreme responding by healthy participants and participants with nonpsychotic mental health problems. The JTC bias was linked to a greater probability of delusion occurrence in psychosis (k= 14,N= 770, OR 1.52, 95% CI 1.12, 2.05). There was a trend-level inverse association between data-gathering and delusion severity (k= 18;N= 794;r= -.09, 95% CI -0.21, 0.03). Hence, nonaffective psychosis is characterized by a hasty decision-making style, which is linked to an increased probability of delusions. PMID- 26519953 TI - Exposure to Political Violence in Northern Ireland and Outcome of First Episode Psychosis. AB - The impact of political violence on individuals presenting with an episode of first episode psychosis has not been examined. Individuals were assessed for exposure to political violence in Northern Ireland (the "Troubles") by asking for a response to 2 questions: one asked about the impact of violence "on your area"; the second about the impact of violence "on you or your family's life." The participants were separated into 2 groups (highandlowimpact) for each question. Symptom profiles and rates of substance misuse were compared across the groups at baseline and at 3-year follow up. Of the 178 individuals included in the study 66 (37.1%) reported ahighimpact of the "Troubles" on their life and 81 (45.5%) ahighimpact of the "Troubles" on their area. There were no significant differences in symptom profile or rates of substance misuse betweenhighandlowgroups at presentation. At 3-year follow-uphighimpact of the "Troubles" on life was associated with higher Positive and Negative Symptom Scale (PANSS) Total (P= .01), PANSS-Positive (P< .05), and PANSS-General (P< .01) scores and lower global assessment of functioning disability (P< .05) scores, after adjusting for confounding factors. Impact of the "Troubles" on area was not associated with differences in symptom outcomes. This finding adds to the evidence that outcomes in psychosis are significantly impacted by environmental factors and suggests that greater attention should be paid to therapeutic strategies designed to address the impact of trauma. PMID- 26519955 TI - Dose and Effect Thresholds for Early Key Events in a PPARalpha-Mediated Mode of Action. AB - Current strategies for predicting adverse health outcomes of environmental chemicals are centered on early key events in toxicity pathways. However, quantitative relationships between early molecular changes in a given pathway and later health effects are often poorly defined. The goal of this study was to evaluate short-term key event indicators using qualitative and quantitative methods in an established pathway of mouse liver tumorigenesis mediated by peroxisome proliferator-activated receptor alpha (PPARalpha). Male B6C3F1 mice were exposed for 7 days to di (2-ethylhexyl) phthalate (DEHP), di-n-octyl phthalate (DNOP), and n-butyl benzyl phthalate (BBP), which vary in PPARalpha activity and liver tumorigenicity. Each phthalate increased expression of select PPARalpha target genes at 7 days, while only DEHP significantly increased liver cell proliferation labeling index (LI). Transcriptional benchmark dose (BMDT) estimates for dose-related genomic markers stratified phthalates according to hypothetical tumorigenic potencies, unlike BMDs for non-genomic endpoints (relative liver weights or proliferation). The 7-day BMDT values for Acot1 as a surrogate measure for PPARalpha activation were 29, 370, and 676 mg/kg/day for DEHP, DNOP, and BBP, respectively, distinguishing DEHP (liver tumor BMD of 35 mg/kg/day) from non-tumorigenic DNOP and BBP. Effect thresholds were generated using linear regression of DEHP effects at 7 days and 2-year tumor incidence values to anchor early response molecular indicators and a later phenotypic outcome. Thresholds varied widely by marker, from 2-fold (Pdk4 and proliferation LI) to 30-fold (Acot1) induction to reach hypothetical tumorigenic expression levels. These findings highlight key issues in defining thresholds for biological adversity based on molecular changes. PMID- 26519956 TI - 2,3',4,4',5-Pentachlorobiphenyl Induces Inflammatory Responses in the Thyroid Through JNK and Aryl Hydrocarbon Receptor-Mediated Pathway. AB - Polychlorinated biphenyls (PCBs) are durable and widely distributed environmental contaminants that can compromise the normal functions of multiple organs and systems; one important mechanism is the induction of inflammatory disorders. In this study, we explored the influences of 2,3',4,4',5-pentachlorobiphenyl (PCB118) on inflammatory responses and its underlying mechanisms in the thyroid. Wistar rats were administered PCB118 intraperitoneally at 0, 10, 100, and 1000 MUg/kg/d, 5 days a week for 13 weeks; rat thyroid FRTL-5 cells were treated with PCB118 (0, 0.25, 2.5, and 25 nM) for indicated time. Results revealed that PCB118 promoted the generation of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha), and intercellular adhesion molecule-1 (ICAM-1) in a time- and dose related manner and decreased sodium/iodide symporter (NIS) protein expression. Moreover, stimulation with PCB118 resulted in the upregulation of the aryl hydrocarbon receptor (AhR)-responsive gene cytochrome P450 1A1 in FRTL-5 cells; whereas pretreatment with the AhR inhibitor alpha-naphthoflavone or AhR small interfering RNA (siRNA) suppressed AhR, CYP1A1, IL-6, and ICAM-1 and restored NIS expression. In vivo and in vitro studies also suggested that the c-Jun N-terminal kinase (JNK) pathway was activated on PCB118 exposure, and the experiments using siRNA for JNK partially blocked PCB118-induced upregulation of IL-6 and ICAM-1 and downregulation of NIS. Altogether, PCB118 stimulates production of IL-6, TNF alpha, and ICAM-1 in the thyroid through AhR and JNK activations and subsequently interferes with NIS expression, resulting in the disruption of thyroid structure and function. PMID- 26519957 TI - Strigolactones spatially influence lateral root development through the cytokinin signaling network. AB - Strigolactones are important rhizosphere signals that act as phytohormones and have multiple functions, including modulation of lateral root (LR) development. Here, we show that treatment with the strigolactone analog GR24 did not affect LR initiation, but negatively influenced LR priming and emergence, the latter especially near the root-shoot junction. The cytokinin module ARABIDOPSIS HISTIDINE KINASE3 (AHK3)/ARABIDOPSIS RESPONSE REGULATOR1 (ARR1)/ARR12 was found to interact with the GR24-dependent reduction in LR development, because mutants in this pathway rendered LR development insensitive to GR24. Additionally, pharmacological analyses, mutant analyses, and gene expression analyses indicated that the affected polar auxin transport stream in mutants of the AHK3/ARR1/ARR12 module could be the underlying cause. Altogether, the data reveal that the GR24 effect on LR development depends on the hormonal landscape that results from the intimate connection with auxins and cytokinins, two main players in LR development. PMID- 26519959 TI - [The issue of prostate cancer surgery]. PMID- 26519958 TI - Prevalence and complications of chronic kidney disease in a representative elderly population in Iceland. AB - BACKGROUND: Chronic kidney disease (CKD) is common in the elderly, but data are limited on the distribution of glomerular filtration rate (GFR) and albuminuria and the prevalence of CKD and related complications in this population. METHODS: A cross-sectional study of 3173 older Icelandic adults [42% men; mean (standard deviation, SD) age of 80 (5) years] was performed to examine the distribution of estimated glomerular filtration rate (eGFR) from creatinine and cystatin C, the albumin-to-creatinine ratio (ACR), and CKD-related metabolic complications (hyperparathyroidism, anemia, hypoalbuminemia, increased anion gap, acidosis, hyperphosphatemia and hyperkalemia). RESULTS: There was substantial variability in eGFR [mean (SD) 64 (18) mL/min/1.73 m(2)] and ACR [median (interquartile range) 8 (5, 17) mg/g]. The prevalence (95% confidence interval) of reduced eGFR (<60 mL/min/1.73 m(2)), albuminuria (ACR >30 mg/g) and CKD (either reduced eGFR or albuminuria) was 40% (38-41), 14% (12-15) and 45% (43-47), respectively. The prevalence of complications was higher among those with versus without CKD: hyperparathyroidism (38 versus 15%), anemia (26 versus 14%), hypoalbuminemia (19 versus 13%), increased anion gap (9 versus 5%), acidosis (5 versus 1%); (P <= 0.02 for all), except hyperphosphatemia (1 versus 1%) and hyperkalemia (0% overall). CONCLUSIONS: The burden of CKD and CKD-related complications is high among community dwelling elderly Icelandic adults. The wide range of eGFR and ACR suggests heterogeneity in processes leading to CKD and that factors beyond aging contribute to the development of CKD in the elderly. PMID- 26519960 TI - [Oncological principles for local control of primary tumor]. AB - OBJECTIVE: Review of the databases of carcinogenesis and the principles of local control of the primary tumor in order to decrease the risk of tumor progression and predict metastatic behavior. MATERIALS AND METHODS: Review of the literature using Medline databases based on scientific relevance. Research was centered on the characteristics of solid tumor development, the basics of local control of the primary tumor, latest advance in genomics and the oncological principles applied on prostate cancer surgery. RESULTS: The cornerstone in order to cure a local or locally advanced cancer is to eradicate the primary tumor. This should be done using effective methods that can assure local control, decrease the risk of progression and metastasis. The oncological surgery is the most important step in order to have this tumor control, beside radiotherapy and systemic therapy associated. In localized prostate cancer, surgery remains the gold standard between the multiple therapeutic modalities proposed. CONCLUSION: The local control of solid malignant tumor is primordial in order to change the natural history of the disease and decrease its risk of progression. This is the goal of oncological surgery, and starting from these principles radical prostatectomy was favored. PMID- 26519961 TI - [Prostate cancer imaging: MRI and nuclear imaging]. AB - OBJECTIVES: Multiparametric magnetic resonance imaging (mp-MRI) and Tomography with Emission of Positons are increasingly used in prostate cancer. MATERIALS AND METHOD: A systematic review of the scientific literature was performed in the Medline database (PubMed), using different associations of the following keywords: MRI, PET MRI, prostate cancer. RESULTS: Accuracy in the detection of prostate cancer is improved by the combined use of standard T2-weighted MR imaging and advanced functional MR imaging techniques such as diffusion-weighted imaging and dynamic contrast-enhanced imaging. Multiparametric MR imaging provides the highest accuracy in detection, localization, and staging of prostate cancer. This accurate assessment is a prerequisite for optimal clinical management and therapy selection. Another recent advancement in the field is MR imaging guidance for targeted prostate biopsy, which is an alternative to the current standard of transrectal ultrasonography-guided systematic biopsy. Prostate MRI plays also an important role in tumor detection when there is clinical or biochemical suspicion of residual or recurrent disease after treatment. The emergence of new technologies such as Tomography with Emission of Positons (TEP) after injection of 18F-choline, allows to improve the staging of prostate cancer (nodes status, sentinel node and occult metastases) and thus to change the management, especially when relapse. CONCLUSION: The first results with modern imaging are already very promising, and numerous prospects are expected, either by improving technologies (parametric fusion of PET and MRI) or the appearance of new tracers more sensitive and more specific than the choline. Bone scan still retains an important place especially since its realization is now coupled with a tomographic study merged with a low dose scanner, thereby remarkably improving its diagnostic performance. PMID- 26519962 TI - [Preoperative assessment of patient candidate to prostate cancer surgery]. AB - OBJECTIVE: To determine the tools of therapeutic decision that push towards surgical treatment in non metastatic prostate cancer eligible to local treatment. The optimized assessment of the disease and eventual comorbidities improves the selection of patients. Patient's files will be presented in the uro-oncological multidisciplinary discussions to validate the customized therapeutic approach proposed. MATERIALS AND METHODS: Literature review using Medline (National library of medicine, Pubmed) and Med Science databases based on the scientific pertinence. Research was focused on the diagnosis of prostate cancer, the evaluation of the disease and patient's characteristics, and finally the elements that are with a surgical treatment (past medical history, past surgical history, functional status, patient's comorbidities, and life expectancy). RESULTS: The pretherapeutic oncologic evaluation allows to estimate the risks associated with prostate cancer; it is an essential aspect of therapeutic decision. Several clinical, biological, imaging and pathological criteria allow to guide decision making according to tumor aggressiveness and risk of recurrence, estimating the results of the different treatments proposed. On the other hand, the evaluation of lower urinary tract symptoms, urinary continence and sexual function, the integration of anatomical data, past medical and past surgical history are all essential for the therapeutic decision, in addition to the comorbidities (Charlson, ASA, ICD). These elements should be taken all together in order to decide for a radical or conservative management of PCa, they guide decision making in patients candidate for surgery. For example, age plays a key role in the choice of treatment, even in older men at risk of developing high-risk PCa that can affect overall survival. CONCLUSION: The combined evaluation of the patient and disease characteristics is of utmost importance in oncology, and especially in the treatment of non-metastatic PCa. The role of the anesthesiologist in the analysis and interpretation of comorbidities remains primordial and it is essential for the selection of the right candidates for surgery after being well informed, and orienting them toward surgery in agreement with the prerogatives programs of customized care. PMID- 26519963 TI - [Surgery of prostate cancer: Technical principles and perioperative complications]. AB - OBJECTIVE: To describe the surgical procedure of localized prostate cancer treated by radical prostatectomy. MATERIAL AND METHOD: Bibliography search was performed from the Medline database (National Library of Medicine, PubMed) selected according to the scientific relevance. The research was focused on historic of radical prostatectomy, surgical anatomy, surgical technics of radical prostatectomy and lymph nodes excision, and complications. RESULTS: During the last 30 years, evolution of radical prostatectomy was important, from open to mini-invasive surgery with or without robotic assistance. Anatomical knowledge of the prostate was useful to describe the different anatomical structure as urinary sphincter and fascias, and to develop different procedure of neurovascular bundles preservation to ameliorate functional results. Complications are well known and their taking-over more precise. Results of radical prostatectomy depend less of the surgical approach but more of the attitude of the surgeon according to the characteristics of the tumor and the functional status of the patient. CONCLUSION: Radical prostatectomy is an elaborate and challenging procedure when carcinological risk balances with functional results. Nevertheless, complications are quite rare. Improvement of results is due to adequation between surgical procedure and oncological and functional status. PMID- 26519964 TI - [Analysis and prognostic factors of the specimen of radical prostatectomy in prostate cancer]. AB - OBJECTIVES: Handling and pathologic analysis of radical prostatectomy specimens are crucial to confirm the diagnosis of prostate cancer and evaluate prognostic criteria. MATERIAL AND METHODS: A systematic review of the scientific literature was performed in the Medline database (PubMed), using different associations of the following keywords: prostate cancer; prostatectomy; specimen; handling; pathology; tumor staging; Gleason score; surgical margin; prognosis; frozen section; lymph node; biomarkers. A particular search was done on specimen management and characterization of tissue prognostic factors. RESULTS: Handling of both radical prostatectomy specimen and lymph node dissection is standardized according to international criteria. Although the main histoprognostic factors are still Gleason score, pathologic staging and margin status, these criteria have been refined these last 10 years, allowing to improve the prediction of relapse after surgical treatment. CONCLUSION: The standardization of handling and pathology reporting of radical prostatectomy specimens will be mandatory for treatment uniformization according to risk stratification in prostate cancer and personalization of therapeutic approaches. PMID- 26519965 TI - [Oncological outcomes of prostate cancer surgery]. AB - OBJECTIVE: Review of the oncological results of the radical prostatectomy as initial treatment of prostate cancer, according to the surgical approach and the risk stratification using D'Amico risk groups. MATERIALS AND METHODS: Review of literature using Medline databases and MedScience based on scientific relevance. Research focused on the oncological results of the radical prostatectomy in series and meta-analysis published since 10 years, taking into consideration the surgical approach if mentioned. RESULTS: The characteristics of the operated tumor highly impact the local control authenticated by the pathologic stage and the rates of positive surgical margins (PSM), in addition to the survival and the biochemical recurrence. Surgical technique adapted according to the tumor treated, was a constant challenge to the urologist, who counter balance between the oncological control and the conservation of urinary and sexual function by conditioning the type of radical prostatectomy. Results of radical prostatectomy acceptable in terms of PSM and survival are not influenced by the surgical approach but by the degree of surgical experience. CONCLUSION: Results of radical prostatectomy show the efficient local control of prostate cancer, taking into consideration the oncological rules and indications validated by multidisciplinary meetings, based on the national (CCAFU) and European oncological guidelines. Tendency is going toward considering radical prostatectomy indicated for patients with higher risk of disease progression, so integrating surgery in a multidisciplinary personalized approach. PMID- 26519966 TI - [Functional results and treatment of functional dysfunctions after radical prostatectomy]. AB - OBJECTIVE: To describe the functional results and treatment of functional dysfunctions after radical prostatectomy for localized prostate cancer. MATERIAL AND METHOD: Bibliography search was performed from the database Medline (National Library of Medicine, Pubmed) selected according to the scientific relevance. The research was focused on continence, potency, les dyserections, couple sexuality, incontinence, treatments of postoperative incontinence, dysrection and trifecta. RESULTS: Radical prostatectomy is an elaborate and challenging procedure when carcinological risk balances with functional results. Despite recent developments in surgical techniques, post-radical prostatectomy urinary incontinence (pRP-UI) continues to be one of the most devastating complications, which affects 9-16% of patients. Sphincter injury and bladder dysfunction are the most common causes or pRP-UI. The assessment of severity of pRP-UI that affects the choice of treatment is still not well standardized but should include at least a pad test and self administered questionnaires. The implantation of an artificial urinary sphincter AMS800 remains the gold standard treatment for patients with moderate to severe pRP-UI. The development of less invasive techniques such as the male sling of Pro ACT balloons has provided alternative therapeutic options for moderate and slight forms of pRP-UI. Most groups now consider the bulbo-urethral compressive sling as the treatment of choice for patients with non-severe pRP-UI. The most appropriate second-line therapeutic strategy is not clearly determined. Recent therapies such as adjustable artificial urinary sphincters and sling and stem cells injections have been investigated. Maintenance of a satisfying sex life is a major concern of a majority of men facing prostate cancer and its treatments. It is essential to assess the couple's sexuality before treating prostate cancer in order to deliver comprehensive information and consider early therapeutic solutions adapted to the couple's expectations. Active pharmacological erectile rehabilitation (intracavernous injections or phosphodiesterase type 5 inhibitors [PDE5i] on demand, during in the month following surgery) or passive (daily PDE5i after surgery) might improve the quality of erections especially in response to PDE5i. Unimpaired aspects of sexual response (orgasm) may, when the erection is not yet recovered, represent an alternative allowing the couple to preserve intimacy and complicity. Androgen blockade is a major barrier to maintain or return to a satisfying sex. Trifecta is a simple tool to present in one way the results of radical prostatectomy: in case of bilateral neurovascular preservation, Trifecta is 60% whatever the surgical approach. CONCLUSION: Radical prostatectomy is an elaborate and challenging procedure when carcinological risk balances with functional results. Various treatments of postoperative incontinence and dysrections exist. Functional disorders after surgery have to be treated to ameliorate quality of life of patients. PMID- 26519967 TI - [Comparative oncologic and functional outcomes of prostate cancer surgery with other curative treatments]. AB - OBJECTIVE: Review of the comparative results of different treatment strategies (surgery, radiotherapy, ultrasound, surveillance) of prostate cancer, in which the main goal is the local control and the second target is the tolerance of the side effects of those treatments. MATERIALS AND METHODS: Review of literature using Medline databases selected based on scientific relevance. Clinical keys centered on the oncological and functional outcomes of comparative series between different curative treatments. RESULTS: The numerous comparative series between surgery and other therapeutic modalities are essentially retrospective with significant methodological bias that is difficult to overcome in order to formulate the optimal thesis. However, there is a clear tendency toward surgery usually with young patients who have intermediate risk tumors without important comorbidity. CONCLUSION: In the absence of randomized comparative series with significant power, the oncological and functional results of the radical prostatectomy with or without adjuvant treatment seem at least the same, in a selected population of patients, compared with the combination of radiotherapy hormonotherapy in terms of survival, without biochemical recurrence, disease specific survival and overall survival, for the aggressive tumors necessitating curative local treatments. PMID- 26519968 TI - [Treatments around surgery of prostate cancer and surgery of recurrence]. AB - OBJECTIVE: To describe neoadjuvant and adjuvant treatments to surgery and the place of surgery in the recurrence after primary treatments. MATERIAL AND METHOD: Bibliography search was performed from the database Medline (National Library of Medicine, Pubmed), selected according to the scientific relevance. The research was focused on treatments before and after surgery, biological recurrence and surgery as the procedure in case of failure of other treatments of non-metastatic prostate cancer. RESULTS: Main oncological objectif of surgery is to decrease positive surgical margins by good adequation between technics and tumor and patient status. Neoadjuvant treatments are today disappointing; however, adjuvant radiotherapy and hormonotherapy demonstrated their interest in case of extracapsular extension, positive margins or invasion of lymph nodes. Nevertheless, superiority of adjuvant treatment to salvage treatment is still debated. Radical prostatectomy is still the only curative treatment in case of failure of another localized treatment. CONCLUSION: Radical prostatectomy has to be one of the main references of localized prostate cancer treatments especially in case of multimodal approach. Pathological exam of specimen and postoperative PSA value should precise the optimal management of prostate cancer. PMID- 26519969 TI - [Economic evaluation of the treatments of non-metastatic prostate cancer]. AB - OBJECTIVES: Prostate cancer is the most frequent cancer and the third leading cause of cancer death in men in France. The development of treatment for prostate cancer is fast and sometimes relies on costly innovations. Medico-economic studies are however rare in this area. This literature review aims to summarize available medico-economic data on the initial management of localized prostate cancer and discuss the quality and usability of existing economic studies on the subject. MATERIALS AND METHOD: Literature review was done using PubMed and Cochrane databases. Studies and articles were selected based on several criteria: population with initial treatment for localized prostate cancer (without metastasis), comparative studies with surgery as control treatment, studies in countries members of the OECD, articles in English or French published between 2004 and 2014. RESULTS: The surgical robot, one of the newest innovations, is more expensive than conventional open surgery or no robotic laparoscopy, even if it is associated with a reduction of the original period of stay. Radiation therapy seems more expensive than surgery as initial therapy of localized prostate cancer. CONCLUSION: Conclusions remain limited because of the rarity of reliable health economic studies on the subject. PMID- 26519970 TI - [Conclusion and perspectives]. PMID- 26519971 TI - Economics of production efficiency: Nutritional grouping of the lactating cow. AB - Nutritional grouping of lactating cows under total mixed ration (TMR) feeding systems has been discussed in the literature since 1970. Most studies have concluded that using multiple, more-homogeneous TMR feeding groups is economically beneficial because of either nutrient cost savings, improved productivity, or both. Nonetheless, no consensus has been formed around this technique nor has it been widely adopted. By using optimal criteria for grouping and more precise nutrient specifications of diets, the latest studies have reported a consistently greater income over feed cost ($/cow per year) with multiple TMR groups compared with 1 TMR (3 TMR=$46 and 2 TMR=$21 to $39). Critical factors that determine the economic value of nutritional grouping are: (1) criteria for grouping, (2) nutrient specifications of diets, (3) effects on milk production, (4) health and environmental benefits, (5) number, size, and frequency of grouping, and (6) additional costs and benefits. It has been documented that grouping cows according to their simultaneous nutritional requirements (a.k.a., cluster grouping) is optimal. Cluster grouping is superior to other methods, such as grouping according to days in milk, milk production, or production and body weight combined. However, the dairy industry still uses less than-optimal grouping criteria. Using cluster grouping will enhance the positive economic effects of multiple TMR. In addition, nutrient specifications of diets for groups do not seem optimal either. Milk lead factors, which are only based on group average milk production, are used. Diets could, however, be formulated more precisely based on overall group nutrient requirements. Providing more precise diets should also be in favor of grouping economics. Furthermore, an area that requires more attention is the potential negative effect of grouping on the milk production of moved cows because of either or both social interactions or diet concentration changes. Although the literature is inconclusive on this subject matter, the latest studies indicate that multiple TMR groups economically outperform 1 TMR, even after considering plausible potential milk losses when grouping. Moreover, additional positive effects of nutritional grouping of improved herd health and environmental stewardship should be translated into economic benefits. Finally, additional costs of management, labor, facilities, and equipment required for grouping are farm specific. The few studies that have integrated these factors in their analyses found that multiple TMR groups would still be economically superior to 1 TMR. PMID- 26519972 TI - The effect of extrinsic attributes on liking of cottage cheese. AB - Preference mapping studies with cottage cheese have demonstrated that cottage cheese liking is influenced by flavor, texture, curd size, and dressing content. However, extrinsic factors such as package, label claims, and brand name may also influence liking and have not been studied. The objective of this study was to evaluate the role of package attributes and brand on the liking of cottage cheese. A conjoint survey with Kano analysis (n=460) was conducted to explore the effect of extrinsic attributes (brand, label claim, milkfat content, and price) on liking. Following the survey, 150 consumers evaluated intrinsic attributes of 7 cottage cheeses with and without brand information in a 2-d crossover design. Results were evaluated by 2-way ANOVA and multivariate analyses. Milkfat content and price had the highest influence on liking by conjoint analysis. Cottage cheese with 2% milkfat and a low price was preferred. Specific label claims such as "excellent source of calcium (>10%)" were more attractive to consumers than "low sodium" or "extra creamy." Branding influenced overall liking and purchase intent for cottage cheeses to differing degrees. For national brands, acceptance scores were enhanced in the presence of the brand. An all-natural claim was more appealing than organic by conjoint analysis and this result was also confirmed with consumer acceptance testing. Findings from this study can help manufacturers, as well as food marketers, better target their products and brands with attributes that drive consumer choice. PMID- 26519973 TI - An investigation into genetic and phenotypic variation in time budgets and yield of dairy cows. AB - Time budgets (TB) of lactating Holstein cows in a freestall loose housing system were recorded twice in early and late lactation to study genetic and phenotypic variation in TB. Time budget traits were recorded using focal animal scanning at 10-min intervals for full 24-h sessions. The study included 243 first-lactation cows, with 389 TB records in early lactation (50 to 123 d in milk) and 403 records in late lactation (152 to 248 d in milk). Milk was recorded at 3-wk intervals during the same periods, and yield was expressed as energy-corrected milk. Time budget traits were analyzed with mixed linear models to obtain estimates of genetic variation (heritability) and permanent animal variance (repeatability). Correlations between TB traits and energy-corrected milk yield were estimated at the individual cow level. In early lactation, the cows spent, on average, 5.0 h eating and 1.8h at feed gates without eating while they were still locked in the gates. Cows lay down for 10.4h and stood in stalls for 3.2h. The cows also spent 2.8h standing in aisles, but only 0.5h in the milking area. In late lactation, cows spent 1h more lying, but less time standing in stalls and less time eating and at the feed gates. Time budget traits were moderately repeatable although highly consistent across lactation stages. Estimates of heritability were moderate for eating time (0.20) but almost zero for lying time. Correlations showed that cows with higher yield spent more time eating and less time lying. As there is a trade-off between lying time and eating time, lying time approached lower limits for cows with highest yields. It is suggested that time is viewed as an important but restricted resource that cows may be short of while trying to maintain high yields. PMID- 26519974 TI - Manufacture of probiotic Minas Frescal cheese with Lactobacillus casei Zhang. AB - In this study, the addition of Lactobacillus casei Zhang in the manufacture of Minas Frescal cheese was investigated. Minas Frescal cheeses supplemented with probiotic bacteria (Lactobacillus casei Zhang) were produced by enzymatic coagulation and direct acidification and were subjected to physicochemical (pH, proteolysis, lactic acid, and acetic acid), microbiological (probiotic and lactic bacteria counts), and rheological analyses (uniaxial compression and creep test), instrumental color determination (luminosity, yellow intensity, and red intensity) and sensory acceptance test. The addition of L. casei Zhang resulted in low pH values and high proteolysis indexes during storage (from 5.38 to 4.94 and 0.470 to 0.702, respectively). Additionally, the cheese protocol was not a hurdle for growth of L. casei Zhang, as the population reached 8.16 and 9.02 log cfu/g by means of the direct acidification and enzymatic coagulation protocol, respectively, after 21 d of refrigerated storage. The rheology data showed that all samples presented a more viscous-like behavior, which rigidity tended to decrease during storage and lower luminosity values were also observed. Increased consumer acceptance was observed for the control sample produced by direct acidification (7.8), whereas the cheeses containing L. casei Zhang presented lower values for all sensory attributes, especially flavor and overall liking (5.37 and 4.61 for enzymatic coagulation and 5.57 and 4.72 for direct acidification, respectively). Overall, the addition of L. casei Zhang led to changes in all parameters and affected negatively the sensory acceptance. The optimization of L. casei Zhang dosage during the manufacturing of probiotic Minas Frescal cheese should be performed. PMID- 26519975 TI - Effect of ceramic membrane channel diameter on limiting retentate protein concentration during skim milk microfiltration. AB - Our objective was to determine the effect of retentate flow channel diameter (4 or 6mm) of nongraded permeability 100-nm pore size ceramic membranes operated in nonuniform transmembrane pressure mode on the limiting retentate protein concentration (LRPC) while microfiltering (MF) skim milk at a temperature of 50 degrees C, a flux of 55 kg . m(-2) . h(-1), and an average cross-flow velocity of 7 m . s(-1). At the above conditions, the retentate true protein concentration was incrementally increased from 7 to 11.5%. When temperature, flux, and average cross-flow velocity were controlled, ceramic membrane retentate flow channel diameter did not affect the LRPC. This indicates that LRPC is not a function of the Reynolds number. Computational fluid dynamics data, which indicated that both membranes had similar radial velocity profiles within their retentate flow channels, supported this finding. Membranes with 6-mm flow channels can be operated at a lower pressure decrease from membrane inlet to membrane outlet (DeltaP) or at a higher cross-flow velocity, depending on which is controlled, than membranes with 4-mm flow channels. This implies that 6-mm membranes could achieve a higher LRPC than 4-mm membranes at the same DeltaP due to an increase in cross-flow velocity. In theory, the higher LRPC of the 6-mm membranes could facilitate 95% serum protein removal in 2 MF stages with diafiltration between stages if no serum protein were rejected by the membrane. At the same flux, retentate protein concentration, and average cross-flow velocity, 4-mm membranes require 21% more energy to remove a given amount of permeate than 6-mm membranes, despite the lower surface area of the 6-mm membranes. Equations to predict skim milk MF retentate viscosity as a function of protein concentration and temperature are provided. Retentate viscosity, retentate recirculation pump frequency required to maintain a given cross-flow velocity at a given retentate viscosity, and retentate protein determination by mid-infrared spectrophotometry were all useful tools for monitoring the retentate protein concentration to ensure a sustainable MF process. Using 6-mm membranes instead of 4-mm membranes would be advantageous for processors who wish to reduce energy costs or maximize the protein concentration of a MF retentate. PMID- 26519976 TI - Short communication: Physicochemical and antioxidant properties of Cheddar-type cheese fortified with Inula britannica extract. AB - Cheddar-type cheese was fortified with the antioxidant Inula britannica flower extract (IBE). Cheddar-type cheeses manufactured with varying concentrations of IBE (0, 0.25, 0.5, 0.75, and 1% wt/vol) were analyzed during storage at 4 degrees C, 0, 1, 2, and 3 wk after production. Higher IBE concentrations resulted in higher protein and ash contents, with a concomitant decrease in pH, total solid, and fat content relative to the unfortified control cheese. The total phenolic content also increased with IBE concentration, but decreased over longer storage periods. The antioxidant activities of the cheeses, determined as 2,2-diphenyl-1 picrylhydrazyl (DPPH) free-radical scavenging activity and ferric thiocyanate assay results, increased proportionally to the total phenolic content. The highest antioxidant effect was observed in the 1% IBE-fortified cheese, showing 79 and 86% antioxidant effects in the DPPH and ferric thiocyanate assays, respectively. At the 1-wk time point, the 5 cheese preparations underwent sensory evaluation for odor, taste, texture, color, and overall quality, determined using a descriptive analysis by a trained panel (n=20). The addition of IBE resulted in some increases in extract odor and taste. Overall, IBE showed good potential as an antioxidant supplement for dairy products. PMID- 26519977 TI - Hot topic: Early postpartum treatment of commercial dairy cows with nonsteroidal antiinflammatory drugs increases whole-lactation milk yield. AB - Previous research has shown that postpartum administration of the nonsteroidal antiinflammatory drug (NSAID) sodium salicylate can increase 305-d milk yield in older dairy cattle (parity 3 and greater). However, in this prior work, sodium salicylate was delivered to cows via the drinking water, a method that does not align well with current grouping strategies on commercial dairy farms. The objective of the current study was to replicate these results on a commercial dairy farm with a simplified treatment protocol and to compare sodium salicylate with another NSAID, meloxicam. Dairy cattle in their second lactation and greater (n=51/treatment) were alternately assigned to 1 of 3 treatments at parturition, with treatments lasting for 3d. Experimental treatments began 12 to 36 h after parturition and were (1) 1 placebo bolus on the first day and 3 consecutive daily drenches of sodium salicylate (125 g/cow per day; SAL); (2) 1 bolus of meloxicam (675 mg/cow) and 3 drenches of an equal volume of water (MEL); or (3) 1 placebo bolus and 3 drenches of water (CON). Blood samples were collected on the first day of treatment, immediately following the last day of treatment, and 7d after the last day of treatment; plasma was analyzed for glucose, beta-hydroxybutyrate (BHB), free fatty acids, haptoglobin, and paraoxonase. Milk production, body condition score, reproductive status, and retention in the herd were monitored for 365 d posttreatment, and effects of treatment, parity, days in milk, and interactions were evaluated in mixed effects models. Significance was declared at P<0.05. Whole-lactation milk and protein yields were greater in NSAID-treated cows, although 305-d fat production was not affected. There was a significant interaction of treatment and parity for plasma glucose concentration; MEL increased plasma glucose concentrations compared with CON and SAL in older cows. Sodium salicylate decreased plasma BHB concentration compared with MEL at 7d posttreatment, although no difference was detected immediately following treatment. Haptoglobin concentrations were elevated in SAL cows compared with CON. There was a tendency for CON cows to be removed from the herd more quickly than MEL cows (42 vs. 26% at 365 d posttreatment). Body condition score, concentrations of plasma free fatty acids and paraoxonase, and time to pregnancy were not affected by treatment. These results indicate that NSAID administration in postpartum cows has the potential to be a viable way to improve productivity and potentially longevity in commercial dairies, although further research is necessary to optimize recommendations for producers. PMID- 26519978 TI - Determination of Henry's constant, the dissociation constant, and the buffer capacity of the bicarbonate system in ruminal fluid. AB - Despite the clinical importance of ruminal acidosis, ruminal buffering continues to be poorly understood. In particular, the constants for the dissociation of H2CO3 and the solubility of CO2 (Henry's constant) have never been stringently determined for ruminal fluid. The pH was measured in parallel directly in the rumen and the reticulum in vivo, and in samples obtained via aspiration from 10 fistulated cows on hay- or concentrate-based diets. The equilibrium constants of the bicarbonate system were measured at 38 degrees C both using the Astrup technique and a newly developed method with titration at 2 levels of partial pressure of CO2 (pCO2; 4.75 and 94.98 kPa), yielding mean values of 0.234 +/- 0.005 mmol ? L(-1) ? kPa(-1) and 6.11 +/- 0.02 for Henry's constant and the dissociation constant, respectively (n/n = 31/10). Both reticular pH and the pH of samples measured after removal were more alkalic than those measured in vivo in the rumen (by DeltapH = 0.87 +/- 0.04 and 0.26 +/- 0.04). The amount of acid or base required to shift the pH of ruminal samples to 6.4 or 5.8 (base excess) differed between the 2 feeding groups. Experimental results are compared with the mathematical predictions of an open 2-buffer Henderson-Hasselbalch equilibrium model. Because pCO2 has pronounced effects on ruminal pH and can decrease rapidly in samples removed from the rumen, introduction of a generally accepted protocol for determining the acid-base status of ruminal fluid with standard levels of pCO2 and measurement of base excess in addition to pH should be considered. PMID- 26519979 TI - Combined alpha-1-antitrypsin deficiency and mannose-binding lectin deficiency. PMID- 26519980 TI - Rhinoconjunctivitis and occupational asthma in a furniture factory worker. PMID- 26519981 TI - Complication rates among peripherally inserted central venous catheters and centrally inserted central catheters in the medical intensive care unit. AB - PURPOSE: There are limited contemporary data describing the rates of catheter related deep vein thrombosis (CRDVT) and central line-associated bloodstream infection for peripherally inserted central venous catheters (PICCs) and centrally inserted central venous catheters (CICCs) in the medical intensive care unit (ICU). METHODS: We performed a retrospective cohort study of 200 PICCs (dual/triple lumen) and 200 CICCs (triple/quadruple lumen) placed in medical ICU adults at Mayo Rochester between 2012 and 2013. Central lines were followed from insertion time until hospital dismissal (primary analysis) or ICU discharge (secondary analysis). Symptomatic CRDVT was determined by Doppler ultrasound. Central line-associated bloodstream infection was defined according to federal reporting criteria. RESULTS: During 1730 PICC days and 637 CICC days, the incidence of CRDVT when followed until hospital dismissal was 4% and 1% (4.6 and 3.1 per 1000 catheter-days), respectively, P = .055. When censored at the time of ICU dismissal, the rates were 2% and 1% (5.3 and 3.7 per 1000 catheter-days), P = .685. Only 1 central line-associated bloodstream infection occurred in a PICC following ICU dismissal, P > .999. CONCLUSIONS: Thrombotic and infectious complications were uncommon following PICC and CICC insertion, with no significant difference in complication rates observed. Half of PICC DVTs occurred on the general floor, and like all central catheters placed in the ICU, PICCs should be aggressively discontinued when no longer absolutely needed. PMID- 26519982 TI - Improved image quality of helical computed tomography of the head in children by iterative reconstruction. AB - BACKGROUND AND PURPOSE: Iterative reconstruction (IR) offers noise reduction and improved image quality of computed tomography (CT). Our aim was to assess the imaging quality of non-contrast helical CT of the head in children using IR. MATERIALS AND METHODS: This study recruited 78 consecutive children aged <=5 years (range: from 3 months to 5 years; mean: 1.7 years) who underwent an emergent non-enhanced helical CT of the head with no abnormal findings. The acquired data were reconstructed using filtered back projection (FBP) and sinogram-affirmed IR (SAFIRE) with strength levels of 2 (IR2) and 4 (IR4). The imaging quality of FBP, IR2 and IR4 was scored by two experienced neuroradiologists in terms of the contrast between the gray-white matter junction and artifacts from the skull at the level of the semioval center, basal ganglia and fourth ventricle. FBP, IR2 and IR4 scores were compared at each slice level. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated for FBP, IR2 and IR4 and were compared among the three reconstruction algorithms. RESULTS: The score of IR2 and IR4 was significantly higher than that of FBP in terms of both the contrast between the gray-white matter junction and artifacts from the skull at each slice level (P<0.001). SNR and CNR on IR4 were the highest followed by those on IR2 and FBP (P<0.001). CONCLUSIONS: IR may improve the image quality of helical CT of the head in children. PMID- 26519983 TI - Social theories of aging: A review. PMID- 26519984 TI - What is aging? PMID- 26519985 TI - Future directions in risk stratification and therapy for advanced pediatric genitourinary rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) represents the most common soft tissue sarcoma in infants and children and the third most common pediatric solid tumor, accounting for 5% to 15% of all childhood solid tumors. Of these, 15% to 20% arise from the genitourinary tract, with the most common sites originating from the prostate, bladder, and paratesticular regions, followed by the vagina and uterus. Although upfront radical surgery was used at the initiation of Intergroup RMS Study-I (1972-1978), the treatment paradigm has shifted to include initial biopsy with the goal of organ preservation, systemic chemotherapy for all patients, and local control involving surgical resection with or without radiation therapy for most patients. Collaborative group clinical trials have led to dramatic improvement in survival rates from 1960 to 1996 among patients with low- or intermediate-risk disease; however, outcomes appear to have plateaued in more recent years, and the prognosis for patients with metastatic or relapsed/refractory disease remains poor. Current management goals include minimizing toxicity while maintaining the excellent outcomes in low-risk disease, as well as improving outcomes in patients with intermediate- and high-risk disease. Advances in genetic analysis have allowed further refinement in risk stratification of patients. Perhaps the most significant recent development in RMS research was the discovery of an association of alveolar RMS (ARMS) with translocations t(2;13) and t(1;13). Translocation fusion-positive tumors comprise 80% of ARMS and are more aggressive. Fusion-negative ARMS may have a clinical course similar to embryonal RMS. Future Children's Oncology Group sarcoma studies will likely incorporate fusion status into risk stratification and treatment allocation. Newer radiotherapy modalities hold promise for providing local control of disease while minimizing morbidity. The addition of traditional cytotoxic chemotherapeutic agents does not seem to improve outcomes in high-risk patients. Ultimately, the most substantial progress may arise from further elucidation of genetic and molecular pathways involved in RMS tumor formation in an effort to identify novel, targeted therapeutic approaches. PMID- 26519986 TI - Mechanism of action of the breast cancer-promoter hormone, 5alpha dihydroprogesterone (5alphaP), involves plasma membrane-associated receptors and MAPK activation. AB - Previous studies have shown that breast tissues and breast cell lines can convert progesterone to 5alpha-pregnane-3,20-dione (5aP), and that 5alphaP stimulates breast cell proliferation and detachment in vitro, and tumor formation in vivo, regardless of presence or absence of receptors for progesterone (PR) or estrogen (ER). Recently it was demonstrated, both in vitro and in vivo, that pro-cancer actions attributed to administered progesterone are due to the in situ produced 5alphaP. Because of the significant role of 5alphaP in breast cancers, it is important to understand its molecular mechanisms of action. The aims of the current studies were to identify 5alphaP binding sites and to determine if the mechanisms of action of 5alphaP involve the mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinases (ERK1/2) pathway. Binding studies, using tritium-labeled 5alphaP ([(3)H]5alphaP), carried out on membrane, cytosol and nuclear fractions from human breast cells (MCF-7, PR/ER-positive; MDA MB-231, PR/ER-negative) and on highly enriched membrane fractions, identified the plasma membrane as the site of ligand specific 5alphaP receptors. Localization of 5alphaP receptors to the cell membrane was confirmed visually with fluorescently labeled conjugate (5alphaP-BSA-FITC). Treatment of cells with either 5alphaP or membrane-impermeable 5alphaP-BSA resulted in significant increases in cell proliferation and detachment. 5alphaP and 5alphaP-BSA equally activated the MAPK/ERK1/2 pathway as evidenced by phosphorylation of ERK1/2. Inhibitors (PD98059, mevastatin and genistein) of specific sites along the Ras/Raf/MEK/ERK signaling pathway, blocked the phosphorylation and concomitantly inhibited 5alphaP-induced stimulation of cell proliferation and detachment. The study has identified high affinity, stereo-specific binding sites for 5alphaP that have the characteristics of a functional membrane 5alphaP receptor, and has shown that the cancer-promoter actions of 5alphaP are mediated from the liganded receptor via the MAPK/ERK1/2 signaling cascade. The findings enhance our understanding of the role of the progesterone metabolite 5alphaP in breast cancer and should promote new approaches to the development of breast cancer diagnostics and therapeutics. PMID- 26519987 TI - Impact of structural modifications at positions 13, 16 and 17 of 16beta-(m carbamoylbenzyl)-estradiol on 17beta-hydroxysteroid dehydrogenase type 1 inhibition and estrogenic activity. AB - The chemical synthesis of four stereoisomers (compounds 5a-d) of 16beta-(m carbamoylbenzyl)-estradiol, a potent reversible inhibitor of 17beta hydroxysteroid dehydrogenase type 1 (17beta-HSD1), and two intermediates (compounds 3a and b) was performed. Assignment of all nuclear magnetic resonance signals confirmed the stereochemistry at positions 13, 16 and 17. Nuclear overhauser effects showed clear correlations supporting a C-ring chair conformation for 5a and b and a C-ring boat conformation for 5c and d. These compounds were tested as 17beta-HSD1 inhibitors and to assess their proliferative activity on estrogen-sensitive breast cancer cells (T-47D) and androgen-sensitive prostate cancer cells (LAPC-4). Steroid derivative 5a showed the best inhibitory activity for the transformation of estrone to estradiol (95, 82 and 27%, at 10, 1 and 0.1MUM, respectively), but like the other isomers 5c and d, it was found to be estrogenic. The intermediate 3a, however, was weakly estrogenic at 1MUM, not at all at 0.1MUM, and showed an interesting inhibitory potency on 17beta-HSD1 (90, 59 and 22%, at 10, 1 and 0.1MUM, respectively). As expected, no compound showed an androgenic activity. The binding modes for compounds 3a and b, 5a-d and CC-156 were evaluated from molecular modeling. While the non-polar interactions were conserved for all the inhibitors in their binding to 17beta-HSD1, differences in polar interactions and in binding conformational energies correlated to the inhibitory potencies. PMID- 26519989 TI - Towards a Dynamic Understanding of Cadherin-Based Mechanobiology. AB - Cadherin-based cell-cell adhesions are a primary determinant of tissue structure. For several decades, it had been thought that the primary function of these ubiquitous structures was to resist external mechanical loads. Here we review recent evidence that cadherins also couple together the force-generating actomyosin cytoskeletons of neighbouring cells, serve as potent regulators of the actomyosin cytoskeleton, and activate diverse signalling pathways in response to applied load. In considering the force sensitivity of the molecular-scale processes that mediate these events, we propose a dynamic picture of the force sensitive processes in cell-cell contacts. This quantitative and physical understanding of the mechanobiology of cadherin cell-cell junctions will aid endeavours to study the fundamental processes mediating the development and maintenance of tissue structure. PMID- 26519988 TI - When Physics Takes Over: BAR Proteins and Membrane Curvature. AB - Cell membranes become highly curved during membrane trafficking, cytokinesis, infection, immune response, or cell motion. Bin/amphiphysin/Rvs (BAR) domain proteins with their intrinsically curved and anisotropic shape are involved in many of these processes, but with a large spectrum of modes of action. In vitro experiments and multiscale computer simulations have contributed in identifying a minimal set of physical parameters, namely protein density on the membrane, membrane tension, and membrane shape, that control how bound BAR domain proteins behave on the membrane. In this review, we summarize the multifaceted coupling of BAR proteins to membrane mechanics and propose a simple phase diagram that recapitulates the effects of these parameters. PMID- 26519990 TI - Unhelpful metacognitive beliefs in early psychosis are associated with affective symptoms and childhood social adjustment. AB - BACKGROUND: Previous studies have shown that individuals with schizophrenia exhibit higher levels of unhelpful metacognitive beliefs than healthy controls, but no studies have explored metacognitive beliefs in early psychosis. AIMS: We examined i) differences in levels of unhelpful metacognitive beliefs between psychosis spectrum disorders, and healthy controls, and ii) to what extent demographic and clinical characteristics predicted levels of metacognitive beliefs in the early treated phases of psychotic disorders. METHOD: Patients were included within two years of first treatment for a psychotic disorder (N=92). They were assessed on premorbid adjustment, psychotic symptoms, anxiety/depression, and self-reported metacognitive beliefs (MCQ-30). Ninety seven controls also completed MCQ-30. Predictors of metacognitive beliefs were explored with multiple linear regression analyses. RESULTS: Patients scored significantly higher than controls on all metacognitive subscales except positive beliefs about worry. The regression model explained 14-38% of the variance on each metacognitive subscale. Current affective symptoms explained a significant amount of variance on all subscales, except positive beliefs about worry. Childhood (premorbid) social adjustment predicted a significant amount of the variance on all subscales, except cognitive confidence. Duration of untreated psychosis contributed significantly to more unhelpful beliefs about cognitive confidence. Negative symptoms predicted lower scores on cognitive self consciousness. CONCLUSION: Affective symptoms and childhood social adjustment could be important predictors of unhelpful metacognitive beliefs in the early treated phases of psychosis, indicating potential psychopathological relationships that warrant further investigation for clinical relevance. PMID- 26519991 TI - Influence of Residual Tumor Volume and Radiation Dose Coverage in Outcomes for Clival Chordoma. AB - PURPOSE: The purpose of this study was to evaluate factors associated with tumor control in clival chordomas. METHODS AND MATERIALS: A retrospective review of 39 patients treated with surgery and proton therapy for clival chordomas between 2004 and 2014 was performed. The median prescribed dose was 77.4 Gy (relative biological effectiveness [RBE]); range was 70.2-79.2 Gy (RBE). Minimum and median doses to gross tumor volume (GTV), radiation dose received by 1 cm(3) of GTV (D1cm(3)), and the equivalent uniform dose were calculated. Receiver operating characteristics curves evaluated the predictive sensitivity and specificity for local failure of potential cutpoint values for GTV and D1cm(3). RESULTS: After a median follow-up of 51 months, the 5-year estimate of local control (LC) was 69.6% (95% confidence interval [CI] 50.0%-89.2%), and overall survival (OS) was 81.4% (95% CI: 65.3%-97.5%). Tumor histology, GTV at the time of radiation, and prescribed radiation dose were significantly associated with local control on multivariate analysis, whereas D1cm(3) was associated with overall survival. Compared to those patients whose conditions remained controlled, patients experiencing tumor failure had statistically significant larger GTVs and lower D1cm(3), and prescribed and median doses to GTV. A subset of 21 patients with GTV of <=20 cm(3) and D1cm(3) of >67 Gy (RBE) had a median follow-up of 47 months. The 5-year estimate of local control in this subset was 81.1% (95% CI: 61.7% 100%; P=.004, overall comparison by GTV <=20 cm(3) stratified by D1cm(3)). A D1cm(3) of 74.5 Gy (RBE) had 80% sensitivity for local control and 60% specificity, whereas a GTV of 9.3 cm(3) had 80% sensitivity for local control and 66.7% specificity. CONCLUSIONS: Local control of clival chordomas was associated with both smaller size of residual tumor and more complete high-dose coverage of residual tumor. Multidisciplinary care should seek maximal safe surgical resection, particularly to facilitate delivery of high-dose radiation therapy in proximity to critical structures. A D1cm(3) >=74.5 Gy (RBE) represents a proposed treatment planning objective. PMID- 26519992 TI - Heart failure family-based education: a systematic review. AB - OBJECTIVE: To systematically review evidence for the efficacy of family-based education for heart failure (HF) patients and carers. METHOD: A systematic review was conducted. Databases CINAHL, MEDLINE Complete, Cochrane, PubMed, Web of Science, EMBASE, PsycINFO, and Scopus were searched between 1 January 2005 and 1 May 2015. Randomised controlled trials included HF patient and carer dyads or carers alone. The primary outcome was HF knowledge. Secondary outcomes included self-care behaviour, dietary and treatment adherence, quality of life, depression, perceived control, hospital readmissions, and carer burden. RESULT: Six trials reported in nine papers were included. Wide variation in the quality of the studies was found. Two studies only examined HF knowledge; a significant improvement among patients and carers was reported. Other significant findings were enhanced patient self-care, boosted dietary and treatment adherence, enriched patient quality of life, improved perceived control among patients but not carers, and reduced carer burden CONCLUSION: Modest evidence was found for family-based education among HF patients and carers. Methodological shortcomings of trials signify the need for empirically sound future research. PRACTICE IMPLICATION: Family-based HF education needs to include strategies that are tailored to the HF patient and carer, and sustainable in nature. PMID- 26519993 TI - Relationships between personal attitudes about death and communication with terminally ill patients: How oncology clinicians grapple with mortality. AB - OBJECTIVE: Clinician discomfort with death may affect care of patients but has not been well-studied. This study explores oncology clinicians' attitudes surrounding their own death and how these attitudes both affect and are affected by their care of dying patients and their communication with them. METHODS: Qualitative interviews with physicians (n=25), nurse practitioners (n=7), and physician assistants (n=1) in medical or hematologic oncology clinical practices about communication styles, care of terminally ill patients, and personal perspectives about mortality. RESULTS: Clinicians described three communication styles used with patients about death and dying: direct, indirect, or selectively direct. Most reported an acceptance of their mortality that was "conditional," meaning that that they could not fully know how they would respond if actually terminally ill. For many clinicians, caring for dying patients affected their outlook on life and death, and their own perspectives on life and death affected their approach to caring for dying patients. CONCLUSION: An awareness of personal mortality may help clinicians to discuss death more openly with patients and to provide better care. PRACTICE IMPLICATIONS: Efforts to promote self-awareness and communication training are key to facilitating clear communication with and compassionate care of terminally ill patients. PMID- 26519994 TI - When Business and Science Clash, How Can We Avoid Harming Patients?: The Case of AVOID-HF. PMID- 26519995 TI - Aquapheresis Versus Intravenous Diuretics and Hospitalizations for Heart Failure. AB - OBJECTIVES: The AVOID-HF (Aquapheresis versus Intravenous Diuretics and Hospitalization for Heart Failure) trial tested the hypothesis that patients hospitalized for HF treated with adjustable ultrafiltration (AUF) would have a longer time to first HF event within 90 days after hospital discharge than those receiving adjustable intravenous loop diuretics (ALD). BACKGROUND: Congestion in hospitalized heart failure (HF) patients portends unfavorable outcomes. METHODS: The AVOID-HF trial, designed as a multicenter, 1-to-1 randomized study of 810 hospitalized HF patients, was terminated unilaterally and prematurely by the sponsor (Baxter Healthcare, Deerfield, Illinois) after enrollment of 224 patients (27.5%). Aquadex FlexFlow System (Baxter Healthcare) was used for AUF. A Clinical Events Committee, blinded to the randomized treatment, adjudicated whether 90-day events were due to HF. RESULTS: A total of 110 patients were randomized to AUF and 114 to ALD. Baseline characteristics were similar. Estimated days to first HF event for the AUF and ALD group were, respectively, 62 and 34 (p = 0.106). At 30 days, compared with the ALD group, the AUF group had fewer HF and cardiovascular events. Renal function changes were similar. More AUF patients experienced an adverse effect of special interest (p = 0.018) and a serious study product related adverse event (p = 0.026). The 90-day mortality was similar. CONCLUSIONS: Compared with the ALD group, the AUF group trended toward a longer time to first HF event within 90 days and fewer HF and cardiovascular events. More patients in the AUF group experienced special interest or serious product-related adverse event. Due to the trial's untimely termination, additional AUF investigation is warranted. PMID- 26519997 TI - Foreword. PMID- 26519996 TI - Heart Rate or Beta-Blocker Dose? Association With Outcomes in Ambulatory Heart Failure Patients With Systolic Dysfunction: Results From the HF-ACTION Trial. AB - OBJECTIVES: This study aimed to compare whether reduced heart rate (HR) or higher beta-blocker (BB) dose affected outcomes to a greater extent in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial population. BACKGROUND: Recent data have shown that HR is an important modifiable factor in reducing mortality in heart failure (HF) patients. It has also been shown that titration of doses of BBs improves outcomes of morbidity and mortality in chronic HF patients with reduced ejection fraction. We aimed to compare whether reduced HR or higher BB dose affected outcomes to a greater extent in the HF-ACTION trial population. METHODS: HF-ACTION was a randomized, multicenter trial enrolling 2,331 ambulatory HF patients with systolic dysfunction (New York Heart Association functional class II to IV, left ventricular ejection fraction <0.35) randomized to exercise training versus usual care, with median follow-up of 2.5 years. BB dose at baseline was standardized by use of carvedilol equivalents. BB dose and HR were analyzed by discrete groups (higher/lower dose; higher/lower HR). The relationship of BB dose, HR, and the primary endpoint of all-cause mortality or all-cause hospitalization and other cardiovascular secondary endpoints were determined before and after adjustment for variables found to be significantly associated with outcome in the HF-ACTION cohort. RESULTS: There was a significant inverse relationship between either BB dose (higher was better) or HR (lower was better) and all-cause death or hospitalization in unadjusted analysis; however, only BB dose was significant for improved mortality outcomes. After adjustment for other predictors of outcome, only BB dose remained significant for improving all-cause death or hospitalization. BB dose, but not HR, was associated with improved outcomes of other cardiovascular endpoints in unadjusted analysis but did not remain significant when adjusted for other predictors of outcome in this cohort. CONCLUSIONS: There were more associated improvements in outcomes with higher BB dose than with reduced HR in this well-treated HF cohort with systolic dysfunction, which suggests that titration of BB doses may confer a greater benefit than reduction of HR in such patients. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437). PMID- 26519998 TI - Genomic structure and promoter functional analysis of GnRH3 gene in large yellow croaker (Larimichthys crocea). AB - Gonadotropin-releasing hormone III (GnRH3) is considered to be a key neurohormone in fish reproduction control. In the present study, the cDNA and genomic sequences of GnRH3 were cloned and characterized from large yellow croaker Larimichthys crocea. The cDNA encoded a protein of 99 amino acids with four functional motifs. The full-length genome sequence was composed of 3797 nucleotides, including four exons and three introns. Higher identities of amino acid sequences and conserved exon-intron organizations were found between LcGnRH3 and other GnRH3 genes. In addition, some special features of the sequences were detected in partial species. For example, two specific residues (V and A) were found in the family Sciaenidae, and the unique 75-72 bp type of the open reading frame 2 and 3 existed in the family Cyprinidae. Analysis of the 2576 bp promoter fragment of LcGnRH3 showed a number of transcription factor binding sites, such as AP1, CREB, GATA-1, HSF, FOXA2, and FOXL1. Promoter functional analysis using an EGFP reporter fusion in zebrafish larvae presented positive signals in the brain, including the olfactory region, the terminal nerve ganglion, the telencephalon, and the hypothalamus. The expression pattern was generally consistent with the endogenous GnRH3 GFP-expressing transgenic zebrafish lines, but the details were different. These results indicate that the structure and function of LcGnRH3 are generally similar to the other teleost GnRH3 genes, but there exist some distinctions among them. PMID- 26519999 TI - Enhanced expression of OsSPL14 gene and its association with yield components in rice (Oryza sativa) under low nitrogen conditions. AB - Nitrogen use efficiency (NUE) in rice crop is the need of the hour for reduction of nitrous oxide emission resulting from excess nitrogen (N) fertilizer application and also in reduction of cost of cultivation. Ten rice genotypes were grown under low and recommended dose of N application and characterized in terms of parameters related to yield, yield related components and NUE indicators. Wide genetic variability under low N conditions was observed with significant variation for 15 yield related parameters in interactions of genotypes and treatment. Limitation of N has led to the decrease of all yield and yield related parameters, but for grain filling % and 1000 grain weight. Two genotypes, Rasi and Varadhan have shown minimum differences between low and recommended N conditions. Correlation analysis of various yield components showed the importance of the secondary branches for the total grains under low N. Expression analysis of OsSPL14 (LOC_Os08g39890) gene reported to be associated with increased panicle branching and higher grain yield through real time PCR in leaf and three stages of panicle has shown differential temporal expression and its association with yield and yield related components across the genotypes. The expression of OsSPL14 at panicle stage 3, has shown correlation (P<0.05) with N% in grain. Since OsSPL14 is a functional transcription activator, its association of expression in leaf and three panicle stages with yield components as observed in the present study suggests the role of nitrogen metabolism related genes in plant growth and development and its conversion into yield components in rice. PMID- 26520000 TI - Flap-free treatment of an oroantral communication with platelet-rich fibrin. PMID- 26520001 TI - Total reconstruction of the nose in settings where resources are limited. AB - We describe a series of 8 patients who had total reconstruction of the nose during 4 separate missions to Ethiopia. The aetiology was noma (n=3), assault (n=2), acid burn (n=1), squamous cell carcinoma (n=1), and a sequela of meningococcal septicaemia (n=1). Reconstruction was with forehead flaps when adequate tissue was available (n=6) and with radial forearm flaps when it was not (n=2). Some reconstructive approaches require procedures to be done in stages, and in settings where resources are limited, difficulties with the continuity of care and provision for the management of complications, must be overcome. PMID- 26520002 TI - Special training in maxillofacial surgery for medical students--economic burden or investment in the future? AB - We measured the motivation and interest of medical students in oral and maxillofacial surgery at a German university. After a detailed cost-benefit analysis of a course that used an ex-vivo animal model and active participation in the operating theatre, we measured changes in the students' interest in taking up a surgical specialty in the future. We found that practical experience could lower the expenses of the course by almost 70%. Twenty per cent of students chose oral and maxillofacial surgery as an elective in their final year. These students could be residents one day. PMID- 26520003 TI - On-treatment platelet reactivity: State of the art and perspectives. AB - High on-clopidogrel platelet reactivity (HcPR) during dual-antiplatelet therapy is a marker of vascular risk, in particular stent thrombosis, in patients with acute coronary syndromes (ACS). Genetic determinants (CYP2C19*2 polymorphism), advanced age, female gender, diabetes and reduced ventricular function are related to a higher risk to develop HcPR. In addition, inflammation and increased platelet turnover, as revealed by the elevated percentage of reticulated platelets in patients' blood, that characterize the acute phase of acute coronary syndromes, are associated with HcPR. To overcome the limitation of clopidogrel, new antiplatelet agents (prasugrel and ticagrelor) were developed and the demonstration of their superiority over clopidogrel was obtained in the two randomized trials, TRITON TIMI 38 and PLATO. Emerging evidence is accumulating on the role of high-on aspirin platelet reactivity (HaPR), especially in the clinical context of diabetes. Finally, the presence of new, potent antiplatelet drugs has shifted the focus from thrombotic to bleeding risk. Recent data document that low on-treatment platelet reactivity (LPR) is associated with a significantly higher bleeding risk. Due to the current possibility to choose between multiple antiplatelet strategies, the future perspective is to include in the management of ACS, in addition to clinical data and classical risk factors, the definition of platelet function during treatment in order to set a tailored therapy. PMID- 26520004 TI - Structured cues or modafinil for fatigue amelioration in clinicians? A double blind, randomized controlled trial of critical clinical information recall in fatigued clinicians. AB - OBJECTIVES: To evaluate the impact of modafinil on "free" and "cued" recall of clinical information in fatigued but nonsleep-deprived clinicians. SUMMARY BACKGROUND DATA: Despite attempts to minimize sleep deprivation through redesign of the roster of residents and staff surgeons, evidence suggests that fatigue remains prevalent. The wake-promoting agent modafinil improves cognition in the sleep-deprived fatigued state and may improve information recall in fatigued nonsleep-deprived clinicians. METHODS: Twenty-four medical undergraduates participated in a double-blind, parallel, randomized controlled trial (modafinil 200 mg:placebo). Medication was allocated 2 hours before a 90-minute fatigue inducing, continuous performance task (dual 2-back task). A case history memorization task was then performed. Clinical information recall was assessed as "free"(no cognitive aids) and "cued"(using aid memoirs). Open and closed cues represent information of increasing specificity to aid the recall of clinical information. Fatigue was measured objectively using the psychomotor vigilance task at induction, before and after the dual 2-back task. RESULTS: Modafinil decreased false starts and lapses (modafinil = 0.50, placebo = 9.83, P < .05) and improved psychomotor vigilance task performance (Decreased Performance, modafinil = 0.006, placebo = 0.098, P < .05). Modafinil improved free information recall (modafinil = 137.8, placebo = 106.0, P < .01). There was no significant difference between groups in the amount of information recalled with open (modafinil = 62.3, placebo = 52.8, P = .1) and closed cues (modafinil = 80.1, placebo = 75.9, P = .3). CONCLUSION: Modafinil attenuated fatigue and improved free recall of clinical information without improving cue-based recall under the design of our experimental conditions. Memory cues to aid retrieval of clinical information are convenient interventions that could decrease fatigue-related error without adverse effects of the neuropharmacology. PMID- 26520006 TI - Discussion. PMID- 26520005 TI - Sialomes and Mialomes: A Systems-Biology View of Tick Tissues and Tick-Host Interactions. AB - Tick saliva facilitates tick feeding and infection of the host. Gene expression analysis of tick salivary glands and other tissues involved in host-pathogen interactions has revealed a wide range of bioactive tick proteins. Transcriptomic analysis has been a milestone in the field and has recently been enhanced by next generation sequencing (NGS). Furthermore, the application of quantitative proteomics to ticks with unknown genomes has provided deeper insights into the molecular mechanisms underlying tick hematophagy, pathogen transmission, and tick host-pathogen interactions. We review current knowledge on the transcriptomics and proteomics of tick tissues from a systems-biology perspective and discuss future challenges in the field. PMID- 26520007 TI - Selective management strategy of interrupted aortic arch mitigates left ventricular outflow tract obstruction risk. AB - BACKGROUND: Left ventricular outflow tract obstruction (LVOTO) is an important problem after interrupted aortic arch (IAA) repair, especially when early reoperation is required during infancy. Several anatomic factors have been identified that increase LVOTO risk; surgical strategies such as concomitant resection of the conal septum or left ventricular outflow tract (LVOT) bypass (single-stage Yasui operation, or staged Norwood procedure, followed by the Rastelli procedure) have been proposed for such patients. METHODS: From 2002 to 2013, a total of 77 neonates underwent IAA repair. Based on the presence of anatomic substrate for LVOTO, patients underwent standard IAA repair and ventricular septal defect closure (n = 53; 69%), concomitant conal resection (n = 7; 9%), or LVOT bypass (n = 17; 22%, staged in 14). We analyzed anatomic details that influence procedure choice, and explored reoperation risk and survival after repair. RESULTS: Neonates who had conal resection or LVOT bypass had significantly smaller aortic valve and subaortic areas, as well as a trend toward a higher prevalence of type B IAA, aberrant right subclavian artery, and bicuspid aortic valve. Freedom from LVOT reoperation was 96% and 80%, at 1 and 8 years, respectively, and was lower after conal resection (P = .008). Most LVOT reoperations (73%) were for discrete subaortic obstruction. Survival was 86% at 8 years, and was not related to procedure choice, whereas freedom from all-cause reoperation was 65% at 8 years, and was higher after standard repair (P = .029). CONCLUSIONS: Compared with published reports, this selective management strategy, which is customized to the degree of aortic valve and subaortic area narrowing, has mitigated and delayed LVOTO risk. With this tailored approach, most LVOT reoperations occur after infancy and are commonly for discrete subaortic obstruction. The effect of aortic valve and LVOT narrowing on increased LVOTO risk is neutralized with LVOT bypass procedures; however, it continues to be the highest after conal resection, suggesting the superiority of LVOT bypass, compared with enlargement in neonates who are at risk of developing LVOTO. PMID- 26520008 TI - Outcomes of heart transplantation in children with hypoplastic left heart syndrome previously palliated with the Norwood procedure. AB - BACKGROUND: Following the Norwood operation, unfavorable hemodynamic or anatomic factors might disqualify children from progressing through subsequent palliative surgeries necessitating listing for heart transplantation. Those patients often have immune, clinical, or anatomic risk factors that could preclude donor allocation, increase operative risk, and diminish late survival. We studied transplantation outcomes in those patients using the Pediatric Heart Transplant Study database. METHODS: A total of 253 children who had prior Norwood were listed for transplantation (1993-2012). Competing risks analysis modeled events after listing (death, transplantation) and after transplantation (death, retransplantation) and examined factors affecting outcomes. RESULTS: Patients were listed following Norwood (n = 89, 35%), Glenn (n = 96, 38%), and Fontan (n = 68, 27%). Competing risk analysis showed that 1 year after listing, 23% of patients had died, 70% had received transplantation, and 7% were alive without transplantation. Factors associated with death without transplantation included UNOS status I (HR 3.44 [1.58-7.49], P = .002) and mechanical circulatory support (HR 4.13 [2.04-8.34], P < .001). Overall, 188 patients received transplantation. Competing risk analysis showed that 10 years following transplantation, 40% had died, 7% had received retransplantation, and 53% were alive without retransplantation. Factors associated with death following transplantation were race other than white (HR 2.18 [1.19-3.99], P = .01), and donor mode of death other than anoxic brain injury (HR 2.23 [1.00-5.01], P = .05). CONCLUSIONS: Heart transplantation can salvage children failing palliation following Norwood with outcomes comparable to those reported for other congenital cardiac anomalies. Efforts to stabilize patients and increase donor pool could improve survival by decreasing the high waiting list mortality. In patients who received transplantation, survival is not affected by last palliation stage or sensitization, reflecting current advances in perioperative management and immunosuppression management strategies. PMID- 26520009 TI - The contemporary evolution of mitral valve surgery. PMID- 26520010 TI - Harnessing regulatory B cells to prevent experimental obliterative bronchiolitis. PMID- 26520011 TI - Gastrointestinal bleeding after left ventricular assist device implantation: It is all about the platelets. PMID- 26520012 TI - The many challenges of interpreting recurrent moderate mitral regurgitation after MitraClip percutaneous mitral valve repair: What does it mean? PMID- 26520013 TI - Impact of Carvedilol versus beta1-selective beta blockers (bisoprolol, metoprolol, and nebivolol) in patients with acute myocardial infarction undergoing percutaneous coronary intervention. AB - Although beta blocker (BB) has constituted one of the mainstays of evidence-based therapy for patients with acute myocardial infarction (AMI), the comparative efficacy of different BBs remains uncertain. We sought to determine the comparative effectiveness of nonselective BB carvedilol and the most frequently prescribed beta1-selective BBs (bisoprolol, metoprolol, and nebivolol) in patients with AMI undergoing percutaneous coronary intervention (PCI). A total of 7,863 patients were selected from the prospective national AMI registry, and patients were divided into carvedilol group (n = 6,231) and beta1-selective BB group (n = 1,632) at hospital discharge. The primary end point was all-cause death or MI during follow-up. During a mean follow-up of 243 +/- 144 days, all cause death or MI occurred in 94 patients (1.5%) in the carvedilol group versus 31 patients (1.9%) in the beta1-selective BB group (adjusted hazard ratio 0.81, 95% confidence interval 0.54 to 1.22, p = 0.32). This result was consistent across various risk subgroups. The risks of all-cause death, cardiac death, and MI were also similar between the groups. After propensity-score matching, no difference was observed in the rate of all-cause death or MI (1.7% in the carvedilol vs 1.9% in the beta1-selective BB group, adjusted hazard ratio 0.84, 95% confidence interval 0.49 to 1.46, p = 0.55). In conclusion, no differences in the risk of all-cause death or MI were observed between the carvedilol and beta1 selective BB groups in contemporary practice of the treatment for AMI. PMID- 26520014 TI - Bioinformatics prioritization of SNPs perturbing microRNA regulation of hematological malignancy-implicated genes. AB - The contribution of microRNAs (miRNAs) to cancer has been extensively investigated and it became obvious that a strict regulation of miRNA-mRNA regulatory network is crucial for safeguarding cell health. Apart from the direct impact of miRNA dysregulation in cancer pathogenesis, genetic variations in miRNAs are likely to disrupt miRNA-target interaction. Indeed, many evidences suggested that SNPs within miRNA regulome are associated with the development of different hematological malignancies. However, a full catalog of SNPs within miRNAs target sites of genes relevant to hematopoiesis and hematological malignancies is still lacking. Accordingly, we aimed to systematically identify and characterize such SNPs and provide a prioritized list of most potentially disrupting SNPs. Although in the present study we did not address the functional significance of these potential disturbing variants, we believe that our compiled results will be valuable for researchers interested in determining the role of target-SNPs in the development of hematological malignancies. PMID- 26520016 TI - Energy-filtered real- and k-space secondary and energy-loss electron imaging with Dual Emission Electron spectro-Microscope: Cs/Mo(110). AB - Since its introduction the importance of complementary k||-space (LEED) and real space (LEEM) information in the investigation of surface science phenomena has been widely demonstrated over the last five decades. In this paper we report the application of a novel kind of electron spectromicroscope Dual Emission Electron spectroMicroscope (DEEM) with two independent electron optical channels for reciprocal and real space quasi-simultaneous imaging in investigation of a Cs covered Mo(110) single crystal by using the 800eV electron beam from an "in-lens" electron gun system developed for the sample illumination. With the DEEM spectromicroscope it is possible to observe dynamic, irreversible processes at surfaces in the energy-filtered real space and in the corresponding energy filtered k||-space quasi-simultaneously in two independent imaging columns. The novel concept of the high energy electron beam sample illumination in the cathode lens based microscopes allows chemically selective imaging and analysis under laboratory conditions. PMID- 26520018 TI - Impact of genioplasty during puberty on the upper airways. AB - AIM: Mouth breathing is a functional disorder that affects craniofacial and dento alveolar growth and also upper airway (UA) anatomy. This is apparent mainly in dimensional abnormalities of the UA caused by hypertrophy of Waldeyer's ring and excessive vertical development of the lower part, giving rise to labial incompetence that perpetuates the functional disorder. The main aim of this study was to evaluate the development of the oropharyngeal structures in young hyperdivergent patients who had undergone functional genioplasty in the context of orthodontic treatment. METHODS: This is a comparative retrospective study performed on 47 adolescents who were hyperdivergent, non-obese and exclusive or diurnal mouth breathers, treated at the Centre de soins, d'enseignement et de recherche dentaires (CSERD) in Montpellier, France. All were candidates for early genioplasty for vertical reduction, and were undergoing or at the end of treatment: 23 had been treated surgically (functional genioplasty), and 24 controls had received orthodontic treatment alone. Inter-group comparison of the changes in cephalometric measurements of the oro- and nasopharyngeal zones and maxillomandibular measurements was performed using covariance analysis (ANCOVA) to adjust for confounding factors. RESULTS: Concerning the skeletal structures: in the sagittal dimension, genioplasty led to significantly greater projection of the symphysis in the surgical group than in the control group (P<0.001). However, the sagittal position of the hyoid bone was unchanged. Similarly, in the vertical dimension, the reduction in divergence of the bony base was significantly greater in the surgical group (P<0.001), but with no change in the vertical position of the hyoid bone. Concerning the upper airways: at the level of the nasopharynx, there was a significantly greater increase in the velopharyngeal space in the surgical group (P<0.033). The same observation can be made on the level of the oropharynx, where there was a significant increase in the linguopharyngeal space in the surgical group (P<0.05), which was not the case in the control group. The change in the depth of the pharynx did not differ significantly between the two groups. CONCLUSION: Early genioplasty performed on adolescents during the growth phase helps to recalibrate the UA by encouraging spontaneous lip closure. PMID- 26520019 TI - Reasons for Underuse of Adjuvant Chemotherapy in Elderly Patients With Stage III Colon Cancer. AB - BACKGROUND: Undertreatment has been frequently reported in the elderly cancer patient population. For this reason, we aimed to characterize adjuvant chemotherapy (AC) use among elderly patients (EPs) with stage III colon cancer (CC) and to identify potential reasons for undertreatment. PATIENTS AND METHODS: Patients diagnosed with stage III CC between 2008 and 2010 were included in this review. Multivariate Cox regression models were constructed to evaluate the associations between AC and cancer-specific, disease-free, and overall survival and to determine whether these were modified by age. RESULTS: We identified 810 patients: 423 (52%) men, 423 (52%) young patients (YPs), and 603 (74%) received AC. Compared with YPs, EPs were less likely to receive AC (57% vs. 91%; P < .01), particularly 5-fluorouracil and oxaliplatin (FOLFOX) (32% vs. 74%, P < .01). Frequent reasons for nontreatment included age, comorbidities, and perceived minimal benefit from AC. When AC was given, EPs had similar rates of treatment discontinuations (34% vs. 26%; P > .05) and dose reductions (63% vs. 61%; P > .05) as YPs. Reasons for treatment interruptions included side effects, progressive disease, and patient choice. Receipt of either FOLFOX or capecitabine was correlated with improved cancer-specific survival, disease-free survival, and overall survival compared with surgery alone; this effect was not modified by age. CONCLUSION: Elderly patients with stage III CC frequently received either no AC or capecitabine monotherapy because of advanced age and comorbidities. The effect of AC on survival was similar across age groups, with comparable side effects and rates of treatment modifications. AC should not be withheld because of advanced age alone. PMID- 26520015 TI - Epigenetic Modifications and Plant Hormone Action. AB - The action of phytohormones in plants requires the spatiotemporal regulation of their accumulation and responses at various levels. Recent studies reveal an emerging relationship between the function of phytohormones and epigenetic modifications. In particular, evidence suggests that auxin biosynthesis, transport, and signal transduction is modulated by microRNAs and epigenetic factors such as histone modification, chromatin remodeling, and DNA methylation. Furthermore, some phytohormones have been shown to affect epigenetic modifications. These findings are shedding light on the mode of action of phytohormones and are opening up a new avenue of research on phytohormones as well as on the mechanisms regulating epigenetic modifications. PMID- 26520020 TI - Solvent modulation strategy for superior antibody monomer/aggregate separation in cation exchange chromatography. AB - Cation exchange chromatography (CEX) is an integral part of many downstream processes for monoclonal antibodies (mAbs). However, in some cases CEX methods with standard mobile phase conditions do not lead to a sufficient removal of soluble antibody aggregates. The addition of neutral polymers such as polyethylene glycol (PEG) to the mobile phase can improve the separation of proteins in IEC remarkably. The applicability of this solvent modulation technique is limited by protein precipitation at higher PEG concentrations. To overcome this limitation solubility enhancers like polyols and amino acids can be added to the mobile phase. These additives are known to inhibit PEG-induced protein precipitation in solution. This new solvent modulation strategy was tested with three different mAbs on two different CEX resins in the presence of PEG in combination with various solubility enhancers. In order to assess the general applicability of this method, mAbs were selected that show major differences with respect to their sensitivity to PEG-induced precipitation and monomer/aggregate resolution performance that is achieved by CEX under standard conditions. For all three mAbs precipitation could be prevented without elimination of the positive PEG-effect. The addition of solubility enhancers gives access to improved separation at elevated PEG concentrations and high protein loadings without running into precipitation issues. Our data indicate that this method is generically applicable and leads to a superior antibody monomer/aggregate separation. PMID- 26520021 TI - Affinity analysis and application of dipeptides derived from l-tyrosine in plasmid purification. AB - The developments in the use of plasmid DNA (pDNA) in gene therapy and vaccines have motivated the search and improvement of optimized purification processes. In this context, dipeptides l-tyrosine-l-tyrosine and l-tyrosine-l-arginine are synthetized to explore their application as affinity ligands for supercoiled (sc) plasmid DNA (pDNA) purification. The synthesis is based on the protection of N Boc-l-tyrosine, followed by condensation with l-tyrosine or l-arginine methyl esters in the presence of dicyclohexylcarbodiimide (DCC), which after hydrolysis and acidification give the afforded dipeptides. The supports are then obtained by coupling l-tyrosine, l-tyrosine-l-tyrosine and l-tyrosine-l-arginine to epoxy activated Sepharose and are characterized by high resolution magic angle spinning (HR-MAS) NMR and Fourier transform infrared spectroscopy (FTIR). Surface plasmon resonance (SPR) biosensor is used to establish the promising ligand to be used in the chromatographic experiments and ascertain experimental conditions. Sc isoform showed the highest affinity to the dipeptides, followed by linear (ln) pDNA, being the open circular (oc) the one that promoted the lowest affinity to l tyrosine-l-arginine. Saturation transfer difference (STD)-NMR experiments show that the interaction is mainly hydrophobic with the majority of the 5' mononucleotides, except for 5'-GMP with l-tyrosine-l-arginine Sepharose that is mainly electrostatic. The support l-tyrosine Sepharose used in chromatographic experiments promotes the separation of native pVAX1-LacZ and pcDNA3-FLAG-p53 samples (oc+sc) by decreasing the salt concentration. The results suggest that it is possible to purify different plasmids with the l-tyrosine Sepharose, with slight adjustments in the gradient conditions. PMID- 26520022 TI - Direct restoration modalities of fractured central maxillary incisors: A multi levels validated finite elements analysis with in vivo strain measurements. AB - OBJECTIVE: To quantify the influence of fracture geometry and restorative materials rigidity on the stress intensity and distribution of restored fractured central maxillary incisors (CMI) with particular investigation of the adhesive interfaces. Ancillary objectives are to present an innovative technology to measure the in vivo strain state of sound maxillary incisors and to present the collected data. METHODS: A validation experimental biomechanics approach has been associated to finite element analysis. FEA models consisted of CMI, periodontal ligament and the corresponding alveolar bone process. Three models were created representing different orientation of the fracture planes. Three different angulations of the fracture plane in buccal-palatal direction were modeled: the fracture plane perpendicular to the long axis in the buccal-palatal direction (0 degrees ); the fracture plane inclined bucco-palatally in apical-coronal direction (-30 degrees ); the fracture plane inclined palatal-buccally in apical coronal direction (+30 degrees ). First set of computing runs was performed for in vivo FE-model validation purposes. In the second part, a 50N force was applied on the buccal aspect of the CMI models. Ten patients were selected and subjected to the strain measurement of CMI under controlled loading conditions. RESULTS: The main differences were noticed in the middle and incisal thirds of incisors crowns, due to the presence of the incisal portion restoration. The stress intensity in -30 degrees models is increased in the enamel structure close to the restoration, due to a thinning of the remaining natural tissues. The rigidity of the restoring material slightly reduces such phenomenon. -30 degrees model exhibits the higher interfacial stress in the adhesive layer with respect to +30 degrees and 0 degrees models. The lower stress intensity was noticed in the 0 degrees models, restoration material rigidity did not influenced the interfacial stress state in 0 degrees models. On the contrary, material rigidity influenced the interfacial stress state in +30 degrees and -30 degrees models, higher rigidity restoring materials exhibits lower interfacial stress with respect to low rigidity materials. SIGNIFICANCE: Fracture planes inclined palatal-buccally in apical-coronal direction (+30 degrees ) reduce the interfacial stress intensity and natural tissues stress intensity with respect to the other tested configurations. PMID- 26520023 TI - The mysterious nature of bacterial surface (gliding) motility: A focal adhesion based mechanism in Myxococcus xanthus. AB - Motility of bacterial cells promotes a range of important physiological phenomena such as nutrient detection, harm avoidance, biofilm formation, and pathogenesis. While much research has been devoted to the mechanism of bacterial swimming in liquid via rotation of flagellar filaments, the mechanisms of bacterial translocation across solid surfaces are poorly understood, particularly when cells lack external appendages such as rotary flagella and/or retractile type IV pili. Under such limitations, diverse bacteria at the single-cell level are still able to "glide" across solid surfaces, exhibiting smooth translocation of the cell along its long axis. Though multiple gliding mechanisms have evolved in different bacterial classes, most remain poorly characterized. One exception is the gliding motility mechanism used by the Gram-negative social predatory bacterium Myxococcus xanthus. The available body of research suggests that M. xanthus gliding motility is mediated by trafficked multi-protein (Glt) cell envelope complexes, powered by proton-driven flagellar stator homologues (Agl). Through coupling to the substratum via polysaccharide slime, Agl-Glt assemblies can become fixed relative to the substratum, forming a focal adhesion site. Continued directional transport of slime-associated substratum-fixed Agl-Glt complexes would result in smooth forward movement of the cell. In this review, we have provided a comprehensive synthesis of the latest mechanistic and structural data for focal adhesion-mediated gliding motility in M. xanthus, with emphasis on the role of each Agl and Glt protein. Finally, we have also highlighted the possible connection between the motility complex and a new type of spore coat assembly system, suggesting that gliding and cell envelope synthetic complexes are evolutionarily linked. PMID- 26520024 TI - Usefulness of Transesophageal Echocardiography in Guiding Acute Aortic Dissection Management During Open Repair of an Abdominal Aortic Aneurysm. PMID- 26520025 TI - Preventive Strategies for Minimizing Hemodilution in the Cardiac Surgery Patient During Cardiopulmonary Bypass. PMID- 26520026 TI - Cardiac Tamponade in a Patient with a 50 mL SynCardia Total Artificial Heart. PMID- 26520027 TI - Modified Tricuspid Annular Plane Systolic Excursion Using Transesophageal Echocardiography for Assessment of Right Ventricular Function. AB - OBJECTIVES: The authors defined a modified tricuspid annular plane systolic excursion (m-TAPSE) measurement using the transesophageal echocardiography (TEE) midesophogeal 4-chamber view and investigated its clinical validity in comparison with other indices of heart function. DESIGN: Retrospective medical record review. SETTING: A single tertiary care medical center. PARTICIPANTS: One hundred ninety-six patients who underwent successful mitral valve repair. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were divided into 2 groups using a proposed guideline cutoff of 16 mm of m-TAPSE. m-TAPSE was measured by apical systolic/diastolic shortening as shown in the TEE midesophogeal 4-chamber view. Right ventricular fractional area change (RV FAC) was measured by using planimetry in the same view. Correlation analysis was performed for m-TAPSE and RV FAC. One hundred six (54.1%) patients showed m-TAPSE>16 mm and 90 patients (45.9%) showed m-TAPSE<16 mm. There were no significant differences in patient demographics and comorbidities between the 2 groups except for atrial fibrillation (7.5% in m-TAPSE>16 mm v 24.4% in m-TAPSE<16 mm, p<0.001). Compared to the m-TAPSE>16 mm group, the m-TAPSE<16 mm group demonstrated significantly lower RV FAC (38.0+/-10.4 v 26.4+/-8.1, p<0.001). The correlation coefficient between m-TAPSE and RV FAC was 0.618, p< 0.001. CONCLUSIONS: m-TAPSE validated a good correlation to right ventricular systolic function as reflected by RV FAC. m TAPSE should be considered as an easily measurable parameter to evaluate right ventricular systolic function. PMID- 26520028 TI - Accuracy, Precision, and Trending Ability of Uncalibrated Arterial Pressure Waveform Analysis of Cardiac Output in Patients With Impaired Left Ventricular Function: A Prospective, Observational Study. AB - OBJECTIVES: Uncalibrated arterial waveform analysis provides minimally invasive and continuous measurement of cardiac output (CO). This technique could be of great value in patients with impaired left ventricular function, but the validity in these patients is not well established. The aim of this study was to investigate the accuracy, precision, and trending ability of uncalibrated arterial waveform analysis of cardiac output in patients with impaired left ventricular function. DESIGN: Prospective, observational, method-comparison study. SETTING: Nonuniversity teaching hospital, single center. PARTICIPANTS: The study included 22 patients with a left ventricular ejection fraction of 40% or less undergoing elective coronary artery bypass grafting. INTERVENTIONS: In the period between induction of anesthesia and sternotomy, CO was measured using the FloTrac/Vigileo system (third-generation software) and intermittent pulmonary artery thermodilution before and after volume loading. MEASUREMENTS AND MAIN RESULTS: Accuracy and precision as determined using Bland-Altman analysis revealed a bias of -0.7 L/min, limits of agreement of -2.9 to 1.5 L/min, and a mean error of 55% for pooled data. Proportional bias and spread were present, indicating that bias and limits of agreement were underestimated for high CO values. Trending ability was assessed using 4-quadrant analysis, which revealed a concordance of 86%. Concordance from a clinical perspective was 36%. Polar plot analysis showed an angular bias of 13 degrees degrees, with radial limits of agreement of -55 degrees to 51 degrees . Polar concordance at+/-30 degrees was 50%. CONCLUSIONS: Arterial waveform analysis of cardiac output and pulmonary artery thermodilution cardiac output were not interchangeable in patients with impaired left ventricular function. PMID- 26520029 TI - Predicting Acute Kidney Injury Development After Open Vascular Surgery. PMID- 26520030 TI - EZ-Blocker in Tracheal Surgery. PMID- 26520031 TI - Stimulatory effects of interleukin-1 beta on development of porcine uterine epithelial cell are mediated by activation of the ERK1/2 MAPK cell signaling cascade. AB - Successful establishment of pregnancy depends on timely changes in the conceptus (embryo and associated extra-embryonic membranes) and uterine endometrium orchestrated by molecules from both the conceptus and uterus. Interleukin-1 beta (IL-1beta) is an important mediator of that communication regulating development of the peri-implantation conceptus and opening the window of implantation during early pregnancy. However, little is known about IL-1beta-mediated intracellular signaling cascades and functional effects in uterine luminal epithelium (LE) during the peri-implantation period of pregnancy in pigs. Therefore, this study determined, using an immortalized porcine LE (pLE) cell line from day 12 pregnant gilts: 1) the intracellular signaling cascade responsible for activities of IL 1beta in pLE cells, and 2) the changes in cellular activities induced by IL 1beta. IL-1beta stimulated phosphorylation of ERK1/2 proteins in pLE cells in a dose-dependent manner. Ten ng/ml IL-1beta increased levels of phosphorylated (p) ERK1/2 proteins in pLE cells within 15 min post-treatment, and this IL-1beta induced phosphorylated status was inhibited by increasing doses of U0126 (ERK1/2 inhibitor). In addition IL-1beta increased p-P70S6K, p-P90S6K, p-S6, and p-P38 proteins in a time-dependent manner, but IL-1beta-induced activation of P70S6K and S6 proteins was significantly decreased in the presence of pharmacological inhibitors for ERK1/2 (U0126), MTOR (rapamycin), and P38 (SB203580). Moreover, IL 1beta treatment potently increased the abundance of p-ERK1/2 proteins in the nucleus and cytoplasm. Similarly cytoplasmic p-S6 proteins were localized abundantly in the pLE cells treated with IL-1beta. Furthermore, IL-1beta increased proliferation of pLE cells by approximately 200%, and pretreatment of pLE cells with U0126 significantly inhibited this stimulatory effect. Collectively, results of this study indicate that IL-1beta plays an important role in development of uterine LE by stimulating cell proliferation, and that these effects are coordinately regulated by activation of the ERK1/2 and P38 MAPK cell signaling cascades. PMID- 26520032 TI - Fibroblast growth factor 4-induced migration of porcine trophectoderm cells is mediated via the AKT cell signaling pathway. AB - During early pregnancy, a well-coordinated communication network between the conceptus and maternal uterus is especially crucial in pigs in which there is a protracted pre-attachment phase prior to implantation. This network is regulated by an astonishing number of molecules such as growth factors. Fibroblast growth factor 4 (FGF4) is a multipotent growth factor that elicits diverse biological actions on various types of cells and tissues. In pigs, FGF4 and its receptors are expressed in the uterine endometrium and conceptus during early pregnancy, but less is known about the FGF4-mediated regulation of conceptus growth during peri-implantation period of pregnancy. Therefore, the aims of the present study were to investigate: 1) expression of endometrial FGF4 mRNA during early pregnancy; 2) up-regulation of FGF receptor expression in porcine trophectoderm (pTr) cells in response to FGF4; and 3) FGF-induced intracellular signaling and cellular activities in pTr cells. In vitro cultured pTr cells incubated with different concentrations of recombinant FGF4 (0-50 ng/ml) responded with a dose dependent increase in AKT phosphorylation of 2.9-fold at 20 ng/ml FGF4. Within 30 min after treatment with 20 ng/ml FGF4, the abundances of p-AKT, p-P90RSK and p RPS6 proteins increased 2.1-, 5.2- and 3.2-fold, respectively, and then returned to basal levels by 120 min. To ensure that the stimulatory effect of FGF4 on AKT signaling was p-AKT-dependent, pTr cells were pre-incubated with an AKT inhibitor (LY294002) for 1 h prior to FGF4 treatment. 20 MUM of LY294002 decreased FGF4 induced p-AKT, p-P90RSK and p-RPS6 proteins. Immunofluorescence analyses revealed that p-RPS6 proteins were abundant within the cytoplasm of FGF4-treated cells, but present at basal levels in the presence of LY294002. Furthermore, FGF4 increased migration of pTr cells and LY294002 significantly reduced this effect. Results of the present study suggest that activation of the FGF receptor(s) on trophectoderm cells by FGF4 secreted by conceptus/endometrium transduces its signal through the phosphatidylinositol 3-kinase (PI3K)/AKT pathway which is linked to migration of trophectoderm cells that is critical to development of the porcine conceptus. PMID- 26520033 TI - Gastrobronchial fistula following minimally invasive esophagectomy for esophageal cancer in a patient with myotonic dystrophy: Case report. AB - INTRODUCTION: Myotonic dystrophies are inherited multisystemic diseases characterized by musculopathy, cardiac arrythmias and cognitive disorders. These patients are at increased risk for fatal post-surgical complications from pulmonary hypoventilation. We present a case with myotonic dystrophy and esophageal cancer who had a minimally invasive esophagectomy complicated with gastrobronchial fistulisation. PRESENTATION OF CASE: A 44-year-old male with myotonic dystrophy type 1 and esophageal cancer had a minimally invasive esophagectomy performed instead of open surgery in order to reduce the risk for pulmonary complications. At day 15 respiratory failure occurred from a gastrobronchial fistula between the right intermediary bronchus (defect 7-8mm) and the esophagogastric anastomosis (defect 10mm). In order to minimize large leakage of air into the gastric conduit the anastomosis was stented and ventilation maintained at low airway pressures. His general condition improved and allowed extubation at day 29 and stent removal at day 35. Bronchoscopy confirmed that the fistula was healed. The patient was discharged from hospital at day 37 without further complications. DISCUSSION: The fistula was probably caused by bronchial necrosis from thermal injury during close dissection using the Ligasure instrument. Fistula treatment by non-surgical intervention was considered safer than surgery which could be followed by potentially life threatening respiratory complications. Indications for stenting of gastrobronchial fistulas will be discussed. CONCLUSIONS: Minimally invasive esophagectomy was performed instead of open surgery in a myotonic dystrophy patient as these patients are particularly vulnerable to respiratory complications. Gastrobronchial fistula, a major complication, was safely treated by stenting and low airway pressure ventilation. PMID- 26520034 TI - Sleeve gastrectomy to treat concomitant polycystyc ovary syndrome, insulin and leptin resistance in a 27-years morbidly obese woman unresponsive to insulin sensitizing drugs: A 3-year follow-up. AB - INTRODUCTION: Insulin resistance (IR), leptin resistance (LR), and polycystic ovary syndrome (PCOS) commonly coexists with obesity. IR and PCOS are often successfully treated with the use of insulin-sensitizing drugs (ISDs). However, some women are poorly responsive or intolerant to them. If we additionally consider that currently no medical treatment for LR exists, it is crucial for the physician to find different therapeutic ways to treat patients with such multifactorial endocrinopathy. PRESENTATION OF CASE: We present a case where sleeve gastrectomy (SG) was applied to a 27-year-old obese woman affected by concomitant IR, LR and PCOS, and unresponsive to ISDs. At three years from surgery the patient is now 71.6kg. More importantly, her levels of insulin and leptin started to improve at postoperative month 6 and became normal at postoperative month 24. Patient's ovaries that at baseline had characteristic aspects related to PCOS, at postoperative month 36 were normal. DISCUSSION: SG is one of the most commonly performed bariatric procedures. The literature has moved away from labeling SG as a purely restrictive procedure, as its interactions with several hormones (ghrelin, leptin, insulin, etc.) are now recognized. CONCLUSION: In the present report, SG was applied to resolve an intricate endocrinological framework confirming its therapeutic value not only in determining weight loss but also as endocrine/metabolic surgery able to treat multifactorial endocrinopathy. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering tremendous potential to reveal new targets for therapeutic intervention, mostly in those patients unresponsive to classical pharmacotherapy. PMID- 26520035 TI - Incidental De Garengeot's hernia: A case report of dual pathology to remember. AB - INTRODUCTION: A De Garengeot's hernia is the very rare dual pathology of a vermiform appendix within a femoral hernia. PRESENTATION OF CASE: We discuss the rare case of a 62 year old female who presented as an emergency with a strangulated femoral hernia. Within the hernia sac a partly necrotic vermiform appendix was discovered. The patient successfully underwent an appendicectomy and repair of her femoral hernia. The post-operative period was uneventful, with no further issues at follow-up. DISCUSSION: Our case report displays the successful treatment of a De Garengeot's hernia as an emergency admission, with a shorter than average admission time, and no post-operative complications. CONCLUSION: This is a rare case of dual pathology, of which we believe there are few published cases. PMID- 26520036 TI - Unusual presentation of left sided acute appendicitis in elderly male with asymptomatic midgut malrotation. AB - INTRODUCTION: Acute appendicitis in the setting of midgut malrotation is uncommon. Midgut malrotation commonly presents within the first month of life. A minority remain asymptomatic and may present with concomitant abdominal pathology making diagnosis difficult. PRESENTATION OF CASE: This paper reports a rare case of a 73-year-old male diagnosed with acute appendicitis and asymptomatic MM .The patient underwent a laparoscopic appendectomy, but had an unplanned return to theatre for washout of post-operative intra-abdominal haematoma. DISCUSSION: Midgut malrotation is commonly described by the stringer classification and type 1a is the most common in adults. There have only been a handful of documented cases of acute appendicitis with midgut malrotation occurring in the adult population. Previous delay in diagnosis has led to a delay in definitive management. Both laparoscopic and open surgery has been used in the past. CONCLUSION: Acute appendicitis with malrotation should be considered in elderly patients presenting with atypical signs and symptoms. Imaging offers significant advantage for timely and definitive management. PMID- 26520037 TI - Severe Cutaneous Drug Reactions: Do Overlapping Forms Exist? AB - Acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms are all severe hypersensitivity reactions to medications. While each of these reactions is a well-established entity with specific diagnostic criteria, clinicians see cases that fulfill criteria for more than one form, prompting discussion on the possibility of combined forms. Such overlapping clinical pictures meeting the criteria for 2 conditions have thus become a topic of debate in dermatology in recent years. We describe 2 patients with cutaneous drug reactions having the characteristics of both acute generalized exanthematous pustulosis and Stevens-Johnson syndrome -toxic epidermal necrolysis. We also review previously published cases and current thinking on such overlapping conditions. PMID- 26520038 TI - An integrated map correlation method and multiple-source sites drainage-area ratio method for estimating streamflows at ungauged catchments: A case study of the Western Black Sea Region, Turkey. AB - Stream gauges measure the temporal variation of water quantity; thus they are vital in managing water resources. The stream gauge network in Turkey includes a limited number of gauges and often streamflow estimates need to be generated at ungauged locations where reservoirs, small hydropower plants, weirs, etc. are planned. Prediction of streamflows at ungauged locations generally relies on donor gauges where flow is assumed to be similar to that at the ungauged location. Generally, donor stream gauges are selected based on geographical proximity. However, closer stream gauges are not always the most-correlated ones. The Map Correlation Method (MCM) enables development of a map that shows the spatial distribution of the correlation between a selected stream gauge and any other location within the study region. In this study, a new approach which combines MCM with the multiple-source site drainage-area ratio (DAR) method is used to estimate daily streamflows at ungauged catchments in the Western Black Sea Region. Daily streamflows predicted by the combined three-source sites DAR with MCM approach give higher Nash-Sutcliffe Efficiency (NSE) values than those predicted using the nearest stream gauge as the donor stream gauge, for most of the trial cases. Hydrographs and flow duration curves predicted using this approach are usually in better agreement with the observed hydrographs and flow duration curves than those predicted using the nearest catchment. PMID- 26520039 TI - S reactivity of an oil sands composite tailings deposit undergoing reclamation wetland construction. AB - This study is the first to characterize the S stability of a composite tailings (CT) deposit undergoing pilot wetland reclamation in the Athabasca Oil Sands Region (AOSR, Alberta, Canada). As CT is sulfur, organic carbon and bacterially rich, the goal of this study was to characterize the in situ aqueous distribution of sulfur compounds across the wetland, sand cap and underlying CT zones of the deposit, in an effort to establish the potential for microbial sulfur cycling and generation of H2S, an explosive, corrosive and toxicity risk. Porewater samples from three depths spanning the different layers of the deposit, as well as wetland surface ponded water samples were collected for geochemical analyses (July and Sept 2013), and for microbial enrichments (both S reducing and S oxidizing bacteria) in June 2014. While porewater SigmaH2S(aq) was detected at all depths across the three zones of the deposit, results identify that the sand cap layer required for construction, acts as a mixing zone generating the highest solution H2S concentrations (>500 uM or 18 mg/L) and H2S gas levels (over 100 and up to 180 ppm) observed. Porewater dissolved sulfate concentrations (0.14-6.97 mM) were orders of magnitude higher and did not correlate to the observed distribution of SigmaH2S concentrations throughout the deposit. Unique to the sandcap, dissolved organic carbon positively correlated with the observed maxima of SigmaH2S(aq) seen in this layer. The water management of the deposit is a critical factor in the observed S trends. Active dewatering of the CT resulted in migration of S rich water up into the sandcap, while downwelling labile organic carbon from the developing wetland acted in concert to stimulate microbial generation of the H2S in this structural layer to the highest levels observed. Functional enrichments identified that diverse S reducing and oxidizing microbial metabolisms are widespread throughout the deposit, indicating that these waste materials are biogeochemically reactive with implications for longterm stability. These results are of relevance to both the oil sands region, as well as other mine contexts where S rich wastes occur, identifying the need to consider the potential bacterially driven cycling of S and C in the generation of constituents of concern, as well as the water management of such waste deposits to minimize risk. PMID- 26520040 TI - The composition and depth of green roof substrates affect the growth of Silene vulgaris and Lagurus ovatus species and the C and N sequestration under two irrigation conditions. AB - Extensive green roofs are used to increase the surface area covered by vegetation in big cities, thereby reducing the urban heat-island effect, promoting CO2 sequestration, and increasing biodiversity and urban-wildlife habitats. In Mediterranean semi-arid regions, the deficiency of water necessitates the use in these roofs of overall native plants which are more adapted to drought than other species. However, such endemic plants have been used scarcely in green roofs. For this purpose, we tested two different substrates with two depths (5 and 10 cm), in order to study their suitability with regard to adequate plant development under Mediterranean conditions. A compost-soil-bricks (CSB) (1:1:3; v:v:v) mixture and another made up of compost and bricks (CB) (1:4; v:v) were arranged in two depths (5 and 10 cm), in cultivation tables. Silene vulgaris (Moench) Garcke and Lagurus ovatus L. seeds were sown in each substrate. These experimental units were subjected, on the one hand, to irrigation at 40% of the registered evapotranspiration values (ET0) and, on the other, to drought conditions, during a nine-month trial. Physichochemical and microbiological substrate characteristics were studied, along with the physiological and nutritional status of the plants. We obtained significantly greater plant coverage in CSB at 10 cm, especially for L. ovatus (80-90%), as well as a better physiological status, especially in S. vulgaris (SPAD values of 50-60), under irrigation, whereas neither species could grow in the absence of water. The carbon and nitrogen fixation by the substrate and the aboveground biomass were also higher in CSB at 10 cm, especially under L. ovatus - in which 1.32 kg C m( 2) and 209 g N m(-2) were fixed throughout the experiment. Besides, the enzymatic and biochemical parameters assayed showed that microbial activity and nutrient cycling, which fulfill a key role for plant development, were higher in CSB. Therefore, irrigation of 40% can maintain an adequate plant cover of both endemic species, particularly in a deeper and soil-containing substrate. PMID- 26520041 TI - Heavy metal removal from sludge with organic chelators: Comparative study of N, N bis(carboxymethyl) glutamic acid and citric acid. AB - The applicability and performance of a new generation of biodegradable chelator, N, N-Bis(carboxymethyl) glutamic acid (GLDA), for extracting heavy metals from sewage sludge was carried out and compared with citric acid (CA). Targeted metals included Cd, Co, Cu, Zn, Ni and Cr, and their contents in the raw sludge were 63.1, 73.4, 1103.2, 2060.3, 483.9 and 604.1 mg kg(-1) (dry sludge basis), respectively. Metals were divided into six fractions including water soluble, exchangeable, carbonates bound, Fe-Mn bound, organic matters bound and residual fraction via chemical fractionation. Washing results showed that in general GLDA exhibited better performance compared with CA, with removal efficiency of 83.9, 87.3, 81.2, 85.6, 89.3 and 90.2% for Cd, Co, Cu, Zn, Ni and Cr, respectively at equilibrium pH = 3.3. Residual metals were better stabilized in the GLAD-washed sludge than in the CA-washed sludge, and were mostly tightly bonded to the residual fraction. Furthermore, CA promoted phosphorus (P) release while GLDA had an opposite effect and tended to retain P within sludge, which could be beneficial for further application in agricultural use. Findings from this study suggested that GLDA could be a potential replacement for refractory and less environmentally-friendly chelators in the extraction of metals from sludge. PMID- 26520042 TI - Fuzzy cognitive mapping in support of integrated ecosystem assessments: Developing a shared conceptual model among stakeholders. AB - Ecosystem-based approaches, including integrated ecosystem assessments, are a popular methodology being used to holistically address management issues in social-ecological systems worldwide. In this study we utilized fuzzy logic cognitive mapping to develop conceptual models of a complex estuarine system among four stakeholder groups. The average number of categories in an individual map was not significantly different among groups, and there were no significant differences between the groups in the average complexity or density indices of the individual maps. When ordered by their complexity scores, eight categories contributed to the top four rankings of the stakeholder groups, with six of the categories shared by at least half of the groups. While non-metric multidimensional scaling (nMDS) analysis displayed a high degree of overlap between the individual models across groups, there was also diversity within each stakeholder group. These findings suggest that while all of the stakeholders interviewed perceive the subject ecosystem as a complex series of social and ecological interconnections, there are a core set of components that are present in most of the groups' models that are crucial in managing the system towards some desired outcome. However, the variability in the connections between these core components and the rest of the categories influences the exact nature of these outcomes. Understanding the reasons behind these differences will be critical to developing a shared conceptual model that will be acceptable to all stakeholder groups and can serve as the basis for an integrated ecosystem assessment. PMID- 26520043 TI - Tailored-CuO-nanowire decorated with folic acid mediated coupling of the mitochondrial-ROS generation and miR425-PTEN axis in furnishing potent anti cancer activity in human triple negative breast carcinoma cells. AB - Metal oxide nanoparticles are the forthcoming anti-tumor therapeutics and provide a versatile platform in the development of therapeutic approaches for drug resistant cancers such as triple negative breast cancer (TNBC). Copper oxide nanoparticles have been characterized as anti-cancer agents but its toxicity has been a matter of concern. Herein, we have developed a targeted CuO Nanowire fabricated with Folic acid (CuO-Nw-FA) that enables enhanced cellular uptake in TNBC cells without imparting significant toxicity in normal cellular system. In the present study, we enumerated that CuO-Nw-FA caused mitochondrial-dependent apoptosis in MDAMB-231 cells. Furthermore, CuO-Nw-FA mediated cytosolic retardation of NF-kappaB favoured inactivation of miR-425 and henceforth activated PTEN to induce apoptosis in TNBC cells. Simultaneously, CuO-Nw-FA also restricted the in-vitro cell migration through the miR-425/PTEN axis via pFAK. Studies extended to ex-ovo and in-vivo mice models further validated the efficacy of CuO-Nw-FA. Additionally, the accumulations of nanoparticles in tumor as well as different organs in mice were examined by in-vivo biodistribution and ex-vivo optical imaging studies. Thus our results cumulatively propose that CuO-Nw-FA cross-talks two distinct signalling pathways to induce apoptosis and retard migration in TNBC cells and raises the possibility for the use of CuO-Nw-FA as a potent anti-tumor agent. PMID- 26520044 TI - Complete tissue coverage achieved by scaffold-based tissue engineering in the fetal sheep model of Myelomeningocele. AB - Myelomeningocele (MMC) is the most severe form of spina bifida, one of the most common congenital anomalies. Although open fetal surgical repair of the MMC defect has been shown to result in improved outcomes, a less invasive approach applicable earlier in gestation than the current open surgical approach between 19 and 26 weeks of gestation is desirable for further improvement of neurological symptoms, as well as reduction of maternal and fetal risks. We previously reported the therapeutic potential of a scaffold-based tissue engineering approach in a fetal rat MMC model. The objective of this study was to confirm the long-term efficacy of this approach in the surgically created fetal sheep MMC model. Gelatin-based or gelatin/collagen hybrid sponges were prepared with and without basic fibroblast growth factor (bFGF) incorporation. The defect was covered by a sponge and secured by a supporting sheet with adhesive at 100 days of gestation or the gelatin/collagen hybrid with bFGF was secured with adhesive without the sheet. Although sheets were found detached at term (140 days' gestation), both gelatin-based and gelatin/collagen hybrid sponges had integrated within the newly formed granulation tissue, resulting in complete coverage of the MMC defect. The release of bFGF from sponges resulted in enhanced formation of granulation tissue and epithelialization. There was also evidence of improved preservation of the spinal cord with less associated damage on histological analysis and reversal of hindbrain herniation. These experiments provide important proof-of-principle evidence of the efficacy of scaffold-based tissue engineered coverage for the prenatal treatment of MMC. PMID- 26520045 TI - The association between glycated hemoglobin levels and mortality in non-diabetic elderly subjects. AB - BACKGROUND: Glycated hemoglobin (HgbA1c) is extensively used as a screening tool for the diagnosis of diabetes mellitus (DM). Although its prognostic value among diabetics has been extensively studied, similar data among non-diabetics is scarce. The aim of this study was to evaluate the association between HgbA1c and mortality in non-diabetic elderly individuals. METHODS: A review of a computerized database of a large health care organization was performed. Non diabetic individuals>=65years old with HgbA1c levels<6.5% evaluated during the years 2002-2012 were included in the analysis. Subjects were stratified into quintiles based on HgbA1c levels. Hazard ratios (HR) for mortality were compared between the quintiles. RESULTS: The cohort included 12,937 non-diabetic individuals>=65years who did not develop DM during the follow-up period. The lowest mortality rate was observed in the fourth HgbA1c quintile [HgbA1c 5.9-6.1% (41-43mmol/mol)]. Compared with the mortality rate in the fourth quintile, mortality rate was increased in the lowest (HgbA1c<5.39%, 35mmol/mol, HR 1.21 CI 1.09-1.35) and highest (HgbA1c>6.11%, 43mmol/mol, HR 1.17 CI 1.04-1.32) HgbA1c quintiles. This association persisted after adjustment for age, gender and co morbidities. CONCLUSIONS: The association between HgbA1c and all-cause mortality in non-diabetic elderly individuals has a U-shape form with the highest mortality in those with the lowest and highest HgbA1c levels. PMID- 26520046 TI - A CdS/ZnSe/TiO2 nanotube array and its visible light photocatalytic activities. AB - A novel CdS/ZnSe/TiO2 nanotube array (NTA) photoelectrode was prepared by deposition of ZnSe nanoparticles (NPs) using pulse electrodeposition technique onto a TiO2 NTA. By successive ion layer adsorption and reaction (SILAR), CdS quantum dots (QDs) deposit onto a ZnSe/TiO2 NTA photoelectrode. The as-prepared CdS/ZnSe/TiO2 NTA photoelectrode performance is significantly improved, which not only greatly extends spatial separation of charges, but also enhance the utilization efficiency of visible-light. This system exhibits excellent charges transport property. The maximum photocurrent density of an 8.25mAcm(-2) was observed in the CdS/ZnSe/TiO2 NTA photoelectrode, which is 37.5, 15.86 and 1.56 times higher than bare TiO2 NTA, ZnSe/TiO2 NTA, and CdS/TiO2NTA photoelectrodes, respectively. The photocatalytic activity of CdS/ZnSe/TiO2 NTA is tested by the degradation of methyl orange (MO) in distilled water under solar light irradiation of 100mW/cm(2). Within about 120min of irradiation, 90.05% MO are removed. PMID- 26520047 TI - HPV vaccination to prevent oropharyngeal carcinoma: What can be learned from anogenital vaccination programs? AB - Human papillomavirus (HPV) infections are well known causes of anogenital cancers. Recent studies show that HPV also plays a role in oropharyngeal cancer (OPC). A review on the role of HPV vaccination in the prevention of head and neck squamous cell carcinoma (HNSCC) with special emphasis on OPC was conducted and available vaccines and vaccination strategies in HNSCC and OPC are discussed. Prophylactic vaccination is known to be effective for prevention of anogenital HPV infection and precursor lesions in the cervix and anus. While the value of vaccination for prevention of OPC and possibly as an adjuvant treatment is still an open question, evidence to date supports the possibility that HPV vaccination may prove to be effective in reducing the incidence of this malignancy. PMID- 26520048 TI - Neoadjuvant chemotherapy and surgical margin in technically unresectable buccal mucosa cancers. PMID- 26520049 TI - Effect of nanofiber orientation of electrospun nanofibrous scaffolds on cell growth and elastin expression of muscle cells. AB - Tissue regeneration after smooth muscle tissue injury is a pivotal issue in tissue engineering. Good artificial scaffolds to continuously form long thin spindle-shaped smooth muscle cells in the damaged muscle tissues are important for tissue regeneration. In this work, poly(lactide-co-glycolide) (PLGA) and poly(epsilon-caprolactone) (PCL) were used to fabricate aligned or random electrospun nanofibrous scaffolds (ENSs) by using electrospinning technique. The cell growth and elastin expression of human vascular smooth muscle cells (HVSMCs) on these membranes were analyzed. Smooth PLGA/PCL film was used as control. The experimental results showed that the aligned ENS could maintain cell shapes of HVSMCs during the culture process. During the HVSMCs proliferation process, elastin expression firstly increase due to cell proliferation, and then decrease due to elastin degradation by elastase secreted by the cells. All these results suggest that aligned PLGA/PCL ENS can be a promising candidate for cell regeneration after smooth muscle tissue injury. PMID- 26520050 TI - Mechanisms of stem cell osteogenic differentiation on TiO2 nanotubes. AB - TiO2 nanotubes could stimulate osteogenic differentiation of stem cells, but the molecular mechanisms underlying the interactions between nanotubes and stem cells remain unclear. In this study, we investigated the response of bone marrow stromal cells to nanotubes of different diameters using microarray-based bioinformatics approach. Gene ontology (GO) and GO enrichment network analysis indicated that larger TiO2 nanotubes were more potent than smaller nanotubes in inducing the expression of genes involved in cell proliferation, differentiation, and immune responses, and inhibiting that of genes responsible for cell adhesion. The analysis of the signaling network containing significantly affected genes suggested that Na(+)/K(+) transporting ATPases ATP1A2 (alpha 2 polypeptide) and ATP1A3 (alpha 3 polypeptide), and MAP3K11 (mitogen-activated protein kinase kinase kinase 11) were important for inducing osteogenic differentiation of bone marrow stromal cells without additional osteogenic stimuli. The upregulation of the ATP1A2 and MAP3K11 genes confirmed by real-time PCR indicates that the response of bone marrow stromal cells to nanotube cues may be mediated by the pathways previously implicated in transducing mechanical stress signals. Our results revealed some molecular mechanisms by which TiO2 nanotubes may direct osteogenic differentiation of stem cells. PMID- 26520051 TI - Motor strategies of postural control after hemispheric stroke. AB - After stroke, the causes of balance disorders include motor disorders, sensory loss, perceptual deficits and altered spatial cognition. This review focuses on motor strategies for postural control after stroke. Weight-bearing asymmetry, smaller surface of stability, increased sway, body tilting and sometimes pushing syndrome are observed. Weakness and sensory impairments account only for some of these disturbances; altered postural reactions and anticipated postural adjustments as well as abnormal synergistic muscular activation play an important part. These disorders are often linked to cognitive impairments (visuospatial analysis, perception of verticality, use of sensory information, attention, etc.), which explain the preeminent disorders of postural control seen with right rather than left-hemisphere lesions. Most of the motor changes are due to an impaired central nervous system but some could be considered adaptive behaviors. These changes have consequences for rehabilitation and need further studies for building customized programs based on the motor comportment of a given patient. PMID- 26520052 TI - Francisella species in ticks and animals, Iberian Peninsula. AB - The presence of Francisella species in 2134 ticks, 93 lagomorphs and 280 small mammals from the Iberian Peninsula was studied. Overall, 19 ticks and 6 lagomorphs were positive for Francisella tularensis subsp. holarctica, suggesting, as described for other regions, that lagomorphs may have an important role in the maintenance of F. tularensis in nature. Of the 6 positive lagomorphs, 4 were identified as the European rabbit, Oryctogalus cuniculus. Additionally, 353 ticks and 3 small mammals were PCR positive for Francisella-like endosymbionts (FLEs) and one small mammal was also positive for Francisella hispaniensis-like DNA sequences. Among FLE positive specimens, a variety of sequence types were detected: ticks were associated with 5 lpnA sequence types, with only one type identified per tick, in contrast to 2 lpnA sequence types detected in a single wood mouse (Apodemus sylvaticus). To our knowledge, this is the first report of FLEs in free-living small mammals as well as the first detection of F. hispaniensis-like sequences in a natural setting. PMID- 26520053 TI - Distribution pattern and number of ticks on lizards. AB - The success of ectoparasites depends primarily on the site of attachment and body condition of their hosts. Ticks usually tend to aggregate on vertebrate hosts in specific areas, but the distribution pattern may depend on host body size and condition, sex, life stage or skin morphology. Here, we studied the distribution of ticks on lizards and tested the following hypothesis: occurrence or high abundance of ticks is confined with body parts with smaller scales and larger interscalar length because such sites should provide ticks with superior attachment conditions. This study was performed in field conditions in central Poland in 2008-2011. In total, 500 lizards (Lacerta agilis) were caught and 839 ticks (Ixodes ricinus, larvae and nymphs) were collected from them. Using generalised linear mixed models, we found that the ticks were most abundant on forelimbs and their axillae, with 90% of ticks attached there. This part of the lizard body and the region behind the hindlimb were covered by the smallest scales with relatively wide gaps between them. This does not fully support our hypothesis that ticks prefer locations with easy access to skin between scales, because it does not explain why so few ticks were in the hindlimb area. We found that the abundance of ticks was positively correlated with lizard body size index (snout-vent length). Tick abundance was also higher in male and mature lizards than in female and young individuals. Autotomy had no effect on tick abundance. We found no correlation between tick size and lizard morphology, sex, autotomy and body size index. The probability of occurrence of dead ticks was positively linked with the total number of ticks on the lizard but there was no relationship between dead tick presence and lizard size, sex or age. Thus lizard body size and sex are the major factors affecting the abundance of ticks, and these parasites are distributed nearly exclusively on the host's forelimbs and their axillae. PMID- 26520054 TI - The role of birth weight on litter size and mortality within 24h of life in purebred dogs: What aspects are involved? AB - In humans, scientific evidence emphasizes the role of birth weight on neonatal welfare, morbidity and mortality. In canine species, defining normal ranges of birth weight is a harder issue due to a great morphological variability in size, body weight and breed. The aim of this study was to correlate birth weight with litter size and mortality within 24h of life in 789 pups from 140 litters of purebred dogs and to investigate the aspects that might affect these factors. Birth weight was influenced by maternal size, weight and age (P<0.001). The lightest pups were from toy sized or weighing up to 10 kg bitches. Conversely, bitches aged 2-8 years whelped heavier pups than younger and older mothers. Birth weight was also related both to litter size, with heavier pups in smaller rather than in larger litters from medium sized bitches, and breed (P<0.05). Unexpectedly, birth weight did not differ between live born and stillborn pups. However, birth weight was lower in pups dying within 24h of life (P<0.05). High mortality of pups was related both to short pregnancies (P<0.05), also showing lighter litters (P<0.001), and to dystocic parturitions (P<0.001). Litter size was associated with parity, type and number of mating, and length of pregnancy (P<0.001). Low birth weight appears to predispose to early neonatal mortality suggesting a predominant role of the breed rather than size and weight in determining birth weight in pups. PMID- 26520055 TI - "Having the heart to be evaluated": The differential effects of fears of positive and negative evaluation on emotional and cardiovascular responses to social threat. AB - Accumulating evidence supports fear of evaluation in general as important in social anxiety, including fear of positive evaluation (FPE) and fear of negative evaluation (FNE). The present study examined state responses to an impromptu speech task with a sample of 81 undergraduates. This study is the first to compare and contrast physiological responses associated with FPE and FNE, and to examine both FPE- and FNE-related changes in state anxiety/affect in response to perceived social evaluation during a speech. FPE uniquely predicted (relative to FNE/depression) increases in mean heart rate during the speech; in contrast, neither FNE nor depression related to changes in heart rate. Both FPE and FNE related uniquely to increases in negative affect and state anxiety during the speech. Furthermore, pre-speech state anxiety mediated the relationship between trait FPE and diminished positive affect during the speech. Implications for the theoretical conceptualization and treatment of social anxiety are discussed. PMID- 26520056 TI - Transmembrane-6 superfamily member 2 (TM6SF2) E167K variant increases susceptibility to hepatic steatosis in obese children. PMID- 26520057 TI - The clinical presentation of coeliac disease in 1030 Swedish children: Changing features over the past four decades. AB - BACKGROUND: The features of paediatric coeliac disease have changed in recent decades. We hypothesised that the age at diagnosis might continue to increase, whereas the severity of symptoms should decrease. METHODS: In the present study, filed data on 1030 paediatric patients diagnosed with coeliac disease between 1973 and 2013 were analysed. The information available covered 99.8% of small bowel biopsies and included information on sex, age and clinical symptoms. RESULTS: The age at diagnosis increased significantly, from a mean of 2.2 years during the first 10 years to 8.2 years in recent years. The proportion of children with severe symptoms declined from 92.8% to 78%, as did the proportion of biopsies characterised by severe pathology. In recent years, the monosymptomatic form of coeliac disease has been more common, and the number of patients detected at screening has increased. The frequency of patients with gastrointestinal symptoms, extra-intestinal symptoms, and failure to thrive and/or short stature at presentation decreased. CONCLUSIONS: The mean age of newly diagnosed patients has increased over the last 15 years. Currently, coeliac disease shows a less severe picture in terms of symptoms and intestinal pathology. Younger children suffer primarily from gastrointestinal symptoms and growth failure, and adolescents from extra-intestinal manifestations. PMID- 26520058 TI - New norms new policies: Did the Adelaide Thinkers in Residence scheme encourage new thinking about promoting well-being and Health in All Policies? AB - Health systems have long been criticised for focussing on curing rather than preventing disease. This paper examines to what extent the Adelaide Thinkers in Residence (ATiR) scheme contributed to the change in norms whereby promoting well being and a strategy to achieve this - Health in All Policies (HiAP)--was adopted by the South Australian (SA) State Government from 2007. The data presented in this paper are drawn from a five year (2012-2016) detailed mixed methods case study of the SA HiAP initiative which involved document analysis, interviews and workshops with public servants and political actors. We adapt the framework used by Finnemore and Sikkink (1998) which explains how norm changes can lead to political changes in international affairs. We also use Kingdon's concept of policy entrepreneurs to determine whether these ideas moved to an implementable initiative with the help of both a specific ATiR program on HiAP and the broader TiR scheme which promoted a series of innovations relevant to health. The process involved the ATiR reinforcing the work of local norm entrepreneurs with that of powerful external policy entrepreneurs, adapting the discourse about the value of prevention and promoting well-being so that it fitted with the dominant economic one. The powerful organisational platform of the ATiR, which was under the Department of the Premier and Cabinet and linked to the South Australian Strategic Plan (SASP) was used to advance these ideas. The case study offers important lessons for other jurisdictions on how to shift policy to encourage intersectoral approaches to health. PMID- 26520059 TI - Gendering gametes: The unequal contributions of sperm and egg donors. AB - This paper compares three groups of gestational mothers who relied on gametes from donors they did not know. The three groups are women who have conceived with donor sperm and their own eggs, women who have conceived with donor eggs and a partner's sperm, and women who have conceived with embryos composed of both donor eggs and donor sperm. The paper explores three issues. First, it considers whether intending parents select sperm and egg donors for different attributes both when they are chosen as the only donor and when they are chosen as donors contributing to an entire embryo. Second, it examines how women imagine the donor. Finally, it looks at how women conceptualize the donor as an individual who contributes to their child's characteristics. Two significant findings emerged in this analysis of survey data. First, the data show that gametes are gendered with different attributes both when those gametes are separate and even more so when seen as complementary parts of a whole. Second, the data show that women minimize the impact of the egg donor (both when a sole contribution and especially when part of the complementary whole) and thus ignore the influence or impact of the egg donor relative to how they make sense of the influence or impact of the sperm donor. The data for this study comes from an online survey developed by the authors. PMID- 26520060 TI - Incidence of herpes zoster and associated events including stroke--a population based cohort study. AB - BACKGROUND: More detailed understanding of herpes zoster (HZ) is called for in the context of an increasing observed frequency of disease, and ongoing discussions regarding potential consequences of the disease. Thus, population based data on incidence and complications of HZ are needed. METHODS: We conducted a register-based cohort study in Vastra Gotaland County (population 1.5 million) in Sweden. We collected data on all patients diagnosed with HZ during the years 2008 to 2010 from population-based registers. Incidence rates (IR) of HZ and related complications were calculated and stratified by age and sex. RESULTS: There were 13 269 new HZ cases during the study period. Overall, the IR of herpes zoster in both genders was 3.25 (95% CI: 3.16-3.34) per 1000 person years in 2010. The incidence was consistently higher in women than in men and in older than in young. A history of immunosuppression was more common than in the general population. The incidence was highest in individuals over 80 years of age (IR 9.2 per 1000 person years, 95% CI: 8.8-9.6) during 2008-2010. The most common complications to HZ were ocular engagement and postherpetic neuralgia; risks for stroke and sepsis were significantly elevated during the one year following diagnosis, especially in the youngest age group of patients 0-39 years. CONCLUSIONS: Herpes zoster is more common in women, the elderly and immunosuppressed individuals. We verify a population-based association between herpes zoster and risk for stroke and sepsis, which may merit concern. PMID- 26520061 TI - Bird naming systems by Akan people in Ghana follow scientific nomenclature with potentials for conservation monitoring. AB - BACKGROUND: Studies on indigenous knowledge of fauna particular birds and its potential use in biodiversity conservation and management are rare globally. Characteristics used in creating indigenous bird names in many Ghanaian languages are undocumented. The main aim of this study is to answer the question "whether indigenous bird naming systems by the Akan tribes in Ghana follow scientific nomenclature and whether indigenous Akan bird knowledge can potentially help improve bird conservation efforts in Ghana. METHODS: Purposive sampling technique was employed in selecting 10 respondents from 25 communities in the five administrative districts in the Central Region. The study was conducted between November 2014 and March 2015. A mixed method approach was adopted in the data collection including key person interviews, focus group discussion, and structured interview supported by a participatory field observation. RESULTS: Indigenous people in the study area have reported 143 species of birds belonging to 44 families representing 57 % of total number of species with known local names in Ghana. The study revealed that just as Latin and common English naming systems, indigenous Akan bird names originated from features of the bird, including plumage, vocalizations or behavioural characteristics and belief systems of the indigenous people. The study also discovered that indigenous people in the study area have distinct names for different species within a particular family for most of the birds they could identify. However, they occasionally assign a single general name for either the entire family or all species therein. CONCLUSIONS: The study found evidence to support the prediction that indigenous bird naming systems in the Akan language follow scientific nomenclature. Indigenous knowledge and understanding of birds in the study area can be tapped and used in conservation planning and monitoring of birds. This research thus provides sufficient evidence to prove that indigenous knowledge by the Akan tribes in the study area can be useful in bird conservation and monitoring programs in Ghana. Further research in other Ghanaian languages is recommended. PMID- 26520062 TI - A meta-analysis of four randomized clinical trials to confirm the reliability and responsiveness of the Shortness of Breath with Daily Activities (SOBDA) questionnaire in chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by non reversible airflow limitation. A common symptom of COPD is dyspnea or shortness of breath. Dyspnea may vary daily, with a large impact on patients' lives. Previous clinical trials used patient-reported outcome (PRO) measures that quantified dyspnea at discrete intervals and hence did not reflect this variability. Recently the Shortness of Breath with Daily Activities (SOBDA) questionnaire was developed as a PRO measure of dyspnea utilizing a daily diary. This confirmatory post hoc meta-analysis of SOBDA data from a large clinical study program further supports the questionnaire and clarifies the minimum threshold of SOBDA response. METHODS: Data from four clinical trials (DB2113361, NCT01313637; DB2113373, NCT01313650; DB2113360, NCT01316900; DB2113374, NCT01316913) were analyzed. These 24-week trials were randomized, blinded studies investigating the efficacy and safety of several COPD treatments. These post hoc analyses focused on the SOBDA questionnaire properties. This electronic-diary consists of 13 items completed daily, in which patients rate their breathlessness level during common daily activities. Resultant SOBDA scores were compared with related, commonly used assessments: modified Medical Research Council Research Dyspnea Scale (mMRC), Baseline Dyspnea Index (BDI), Transition Dyspnea Index (TDI), St George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), and trough forced expiratory volume in 1 s (FEV1). The consistency, reliability, validity (convergent, known groups), and responsiveness of the SOBDA questionnaire was assessed. RESULTS: In total, 4967 patients with COPD provided data for these analyses. The SOBDA questionnaire had high internal consistency (Cronbach's alpha = 0.936), high test-retest reliability (Pearson's correlation coefficient = 0.86) and convergent validity with related measures (SGRQ total score, Pearson's correlation coefficient = 0.59; CAT, Spearman rank-order correlation coefficient = 0.50). SOBDA scores were statistically significantly lower in responders (as defined by TDI, SGRQ, CAT, and trough FEV1 levels) versus non-responders (p < 0.001 for all assessments and all time points). Using an anchor-based method, the threshold of a minimum response was calculated as a SOBDA score change of -0.2 (SOBDA score range = 1-4). CONCLUSIONS: The reliability, validity, and responsiveness of the SOBDA questionnaire as a PRO measure to quantify dyspnea was supported in a large clinical trial population of patients with moderate-very severe COPD. PMID- 26520064 TI - The use of a prefabricated radial forearm free flap for closure of a large tracheocutaneous fistula: a case report and review of the literature. AB - INTRODUCTION: The closure of complex tracheocutaneous fistulae is a surgical challenge. We describe a staged approach for management of a patient with a large tracheocutaneous fistula in the setting of prior surgery and local radiation therapy. CASE PRESENTATION: A 66-year-old Caucasian man who had undergone prior surgery and radiation therapy to the lower neck presented to our hospital for treatment of a large tracheocutaneous fistula that had developed with an adjacent area of tracheal stenosis. A prefabricated composite graft made up of an inner mucosal lining (buccal mucosa), a central cartilage structure (conchal cartilage), and external skin lining was constructed on the patient's distal volar forearm and subsequently harvested in a staged fashion. This graft was transferred as a free flap and successfully used to close the patient's defect following revascularization. Sixty months after surgery, the patient had no airway compromise or new dysphonia. CONCLUSIONS: The use of a prefabricated mucosally lined composite graft can allow for successful closure of large tracheocutaneous fistulae, even in the setting of prior radiation therapy. PMID- 26520063 TI - The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction in a rat model of type-1 diabetes mellitus. AB - BACKGROUND: Diabetes mellitus (DM) leads to the development of diabetic cardiomyopathy, which is associated with altered nitric oxide (NO)--soluble guanylate cyclase (sGC)--cyclic guanosine monophosphate (cGMP) signalling. Cardioprotective effects of elevated intracellular cGMP-levels have been described in different heart diseases. In the current study we aimed at investigating the effects of pharmacological activation of sGC in diabetic cardiomyopathy. METHODS: Type-1 DM was induced in rats by streptozotocin. Animals were treated either with the sGC activator cinaciguat (10 mg/kg/day) or with placebo orally for 8 weeks. Left ventricular (LV) pressure-volume (P-V) analysis was used to assess cardiac performance. Additionally, gene expression (qRT-PCR) and protein expression analysis (western blot) were performed. Cardiac structure, markers of fibrotic remodelling and DNA damage were examined by histology, immunohistochemistry and TUNEL assay, respectively. RESULTS: DM was associated with deteriorated cGMP signalling in the myocardium (elevated phosphodiesterase-5 expression, lower cGMP-level and impaired PKG activity). Cardiomyocyte hypertrophy, fibrotic remodelling and DNA fragmentation were present in DM that was associated with impaired LV contractility (preload recruitable stroke work (PRSW): 49.5 +/- 3.3 vs. 83.0 +/- 5.5 mmHg, P < 0.05) and diastolic function (time constant of LV pressure decay (Tau): 17.3 +/- 0.8 vs. 10.3 +/- 0.3 ms, P < 0.05). Cinaciguat treatment effectively prevented DM related molecular, histological alterations and significantly improved systolic (PRSW: 66.8 +/- 3.6 mmHg) and diastolic (Tau: 14.9 +/- 0.6 ms) function. CONCLUSIONS: Cinaciguat prevented structural, molecular alterations and improved cardiac performance of the diabetic heart. Pharmacological activation of sGC might represent a new therapy approach for diabetic cardiomyopathy. PMID- 26520065 TI - Comparison of the quadriceps-sparing and subvastus approaches versus the standard parapatellar approach in total knee arthroplasty: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The quadriceps-sparing and subvastus approaches are two of the most commonly used minimally-invasive approaches in total knee arthroplasty (TKA). However, the conclusion among studies still remains controversial. The purpose of this meta-analysis was to compare the clinical efficacy of the subvastus and quadriceps-sparing approaches with the standard parapatellar approach in TKA. METHODS: Randomized controlled trials (RCTs) comparing the quadriceps-sparing or subvastus approach with the standard parapatellar approach was identified in the databases of PubMed, the Cochrane library, EMBASE and Web of Science up to July 2014. Two authors extracted the following data: the basic characteristics of patients, the methodological quality and clinical outcomes from the included RCTs independently. RevMan 5.2.7 software was used for meta-analysis. RESULTS: A total of 19 RCTs (1578 patients) were included for meta-analysis. The results suggested that the quadriceps-sparing approach showed better outcomes in knee society score (KSS) and visual analog score (VAS), but this approach required a longer operative time than the standard parapatellar approach. There were no differences in total complications, wound infection, deep vein thrombosis, blood loss and hospital stay between the quadriceps-sparing and standard approaches. The subvastus approach showed better outcomes in VAS, knee range of motion (ROM), straight leg raise and lateral retinacular release than the standard parapatellar approach. There were no differences in KSS, total complication, wound infection, deep vein thrombosis, blood loss and hospital stay between the quadriceps-sparing and standard approaches. CONCLUSIONS: The current evidence showed that, when compared with the standard parapatellar approach, the quadriceps-sparing approach was associated with better outcomes in KSS and VAS but required a longer operative time, and the subvastus approach was associated with better outcomes in VAS, ROM, straight leg raise and lateral retinacular release. PMID- 26520067 TI - Analysis of unstable periodic orbits and chaotic orbits in the one-dimensional linear piecewise-smooth discontinuous map. AB - In this paper, we analytically examine the unstable periodic orbits and chaotic orbits of the 1-D linear piecewise-smooth discontinuous map. We explore the existence of unstable orbits and the effect of variation in parameters on the coexistence of unstable orbits. Further, we show that this structuring is different from the well known period adding cascade structure associated with the stable periodic orbits of the same map. Further, we analytically prove the existence of chaotic orbit for this map. PMID- 26520066 TI - Effect of systemic high dose enzyme replacement therapy on the improvement of CNS defects in a mouse model of mucopolysaccharidosis type II. AB - BACKGROUND: Mucopolysaccharidosis type II (MPS II, Hunter syndrome), is caused by a deficiency of iduronate-2-sulfatase (IDS). Despite the therapeutic effect of intravenous enzyme replacement therapy (ERT), the central nervous system (CNS) defects persist because the enzyme cannot cross the blood-brain barrier (BBB). There have been several trials of direct infusion to the cerebrospinal space showing promising results; however, this approach may have limitations in clinical situations such as CNS infection. The objective of this study was to improve the CNS defect with systemic high-dose ERT. METHODS: Systemic ERT was performed using three doses (1, 5, and 10 mg/kg weekly) of IDS for three different durations (1, 3, and 6 months) in IDS knock out (KO) mice of two age groups (2 months, 8 months). GAG measurement in tissues, brain pathology, and behavioral assessment were analyzed. RESULTS: Brain IDS activities increased in parallel with the concentrations of IDS injected. The glycosaminoglycan (GAG) level and histopathology in the brains of the young mice improved in a dose- and duration-dependent manner; however, those were not improved in the old mice, even at higher doses of IDS. The spontaneous alternation behavior was recovered in young KO mice treated with >= 5 mg/kg IDS; however, no significant improvement was observed in old KO mice. CONCLUSIONS: These results suggest that high-dose ERT given to mice of earlier ages may play a role in preventing GAG accumulation and preventing CNS damage in IDS KO mice. Therefore, ERT above the present standard dose, starting in early childhood, could be a promising treatment regimen for reducing neurological impairment in Hunter syndrome. PMID- 26520068 TI - Dynamics of social contagions with limited contact capacity. AB - Individuals are always limited by some inelastic resources, such as time and energy, which restrict them to dedicate to social interaction and limit their contact capacities. Contact capacity plays an important role in dynamics of social contagions, which so far has eluded theoretical analysis. In this paper, we first propose a non-Markovian model to understand the effects of contact capacity on social contagions, in which each adopted individual can only contact and transmit the information to a finite number of neighbors. We then develop a heterogeneous edge-based compartmental theory for this model, and a remarkable agreement with simulations is obtained. Through theory and simulations, we find that enlarging the contact capacity makes the network more fragile to behavior spreading. Interestingly, we find that both the continuous and discontinuous dependence of the final adoption size on the information transmission probability can arise. There is a crossover phenomenon between the two types of dependence. More specifically, the crossover phenomenon can be induced by enlarging the contact capacity only when the degree exponent is above a critical degree exponent, while the final behavior adoption size always grows continuously for any contact capacity when degree exponent is below the critical degree exponent. PMID- 26520069 TI - Nonlinear multi-analysis of agent-based financial market dynamics by epidemic system. AB - Based on the epidemic dynamical system, we construct a new agent-based financial time series model. In order to check and testify its rationality, we compare the statistical properties of the time series model with the real stock market indices, Shanghai Stock Exchange Composite Index and Shenzhen Stock Exchange Component Index. For analyzing the statistical properties, we combine the multi parameter analysis with the tail distribution analysis, the modified rescaled range analysis, and the multifractal detrended fluctuation analysis. For a better perspective, the three-dimensional diagrams are used to present the analysis results. The empirical research in this paper indicates that the long-range dependence property and the multifractal phenomenon exist in the real returns and the proposed model. Therefore, the new agent-based financial model can recurrence some important features of real stock markets. PMID- 26520070 TI - Soliton radiation beat analysis of optical pulses generated from two continuous wave lasers. AB - We propose a fibre-based approach for generation of optical frequency combs (OFCs) with the aim of calibration of astronomical spectrographs in the low and medium-resolution range. This approach includes two steps: in the first step, an appropriate state of optical pulses is generated and subsequently moulded in the second step delivering the desired OFC. More precisely, the first step is realised by injection of two continuous-wave (CW) lasers into a conventional single-mode fibre, whereas the second step generates a broad OFC by using the optical solitons generated in step one as initial condition. We investigate the conversion of a bichromatic input wave produced by two initial CW lasers into a train of optical solitons, which happens in the fibre used as step one. Especially, we are interested in the soliton content of the pulses created in this fibre. For that, we study different initial conditions (a single cosine hump, an Akhmediev breather, and a deeply modulated bichromatic wave) by means of soliton radiation beat analysis and compare the results to draw conclusion about the soliton content of the state generated in the first step. In case of a deeply modulated bichromatic wave, we observed the formation of a collective soliton crystal for low input powers and the appearance of separated solitons for high input powers. An intermediate state showing the features of both, the soliton crystal and the separated solitons, turned out to be most suitable for the generation of OFC for the purpose of calibration of astronomical spectrographs. PMID- 26520071 TI - Complex network approach to fractional time series. AB - In order to extract correlation information inherited in stochastic time series, the visibility graph algorithm has been recently proposed, by which a time series can be mapped onto a complex network. We demonstrate that the visibility algorithm is not an appropriate one to study the correlation aspects of a time series. We then employ the horizontal visibility algorithm, as a much simpler one, to map fractional processes onto complex networks. The degree distributions are shown to have parabolic exponential forms with Hurst dependent fitting parameter. Further, we take into account other topological properties such as maximum eigenvalue of the adjacency matrix and the degree assortativity, and show that such topological quantities can also be used to predict the Hurst exponent, with an exception for anti-persistent fractional Gaussian noises. To solve this problem, we take into account the Spearman correlation coefficient between nodes' degrees and their corresponding data values in the original time series. PMID- 26520072 TI - Direct experimental visualization of the global Hamiltonian progression of two dimensional Lagrangian flow topologies from integrable to chaotic state. AB - Countless theoretical/numerical studies on transport and mixing in two dimensional (2D) unsteady flows lean on the assumption that Hamiltonian mechanisms govern the Lagrangian dynamics of passive tracers. However, experimental studies specifically investigating said mechanisms are rare. Moreover, they typically concern local behavior in specific states (usually far away from the integrable state) and generally expose this indirectly by dye visualization. Laboratory experiments explicitly addressing the global Hamiltonian progression of the Lagrangian flow topology entirely from integrable to chaotic state, i.e., the fundamental route to efficient transport by chaotic advection, appear non-existent. This motivates our study on experimental visualization of this progression by direct measurement of Poincare sections of passive tracer particles in a representative 2D time-periodic flow. This admits (i) accurate replication of the experimental initial conditions, facilitating true one-to-one comparison of simulated and measured behavior, and (ii) direct experimental investigation of the ensuing Lagrangian dynamics. The analysis reveals a close agreement between computations and observations and thus experimentally validates the full global Hamiltonian progression at a great level of detail. PMID- 26520073 TI - On the statistical and transport properties of a non-dissipative Fermi-Ulam model. AB - The transport and diffusion properties for the velocity of a Fermi-Ulam model were characterized using the decay rate of the survival probability. The system consists of an ensemble of non-interacting particles confined to move along and experience elastic collisions with two infinitely heavy walls. One is fixed, working as a returning mechanism of the colliding particles, while the other one moves periodically in time. The diffusion equation is solved, and the diffusion coefficient is numerically estimated by means of the averaged square velocity. Our results show remarkably good agreement of the theory and simulation for the chaotic sea below the first elliptic island in the phase space. From the decay rates of the survival probability, we obtained transport properties that can be extended to other nonlinear mappings, as well to billiard problems. PMID- 26520074 TI - Global chaotization of fluid particle trajectories in a sheared two-layer two vortex flow. AB - In a two-layer quasi-geostrophic approximation, we study the irregular dynamics of fluid particles arising due to two interacting point vortices embedded in a deformation flow consisting of shear and rotational components. The two vortices are arranged within the bottom layer, but an emphasis is on the upper-layer fluid particle motion. Vortices moving in one layer induce stirring of passive scalars in the other layer. This is of interest since point vortices induce singular velocity fields in the layer they belong to; however, in the other layer, they induce regular velocity fields that generally result in a change in passive particle stirring. If the vortices are located at stagnation points, there are three different types of the fluid flow. We examine how properties of each flow configuration are modified if the vortices are displaced from the stagnation points and thus circulate in the immediate vicinity of these points. To that end, an analysis of the steady-state configurations is presented with an emphasis on the frequencies of fluid particle oscillations about the elliptic stagnation points. Asymptotic relations for the vortex and fluid particle zero-oscillation frequencies are derived in the vicinity of the corresponding elliptic points. By comparing the frequencies of fluid particles with the ones of the vortices, relations between the parameters that lead to enhanced stirring of fluid particles are established. It is also demonstrated that, if the central critical point is elliptic, then the fluid particle trajectories in its immediate vicinity are mostly stable making it harder for the vortex perturbation to induce stirring. Change in the type of the central point to a hyperbolic one enhances drastically the size of the chaotic dynamics region. Conditions on the type of the central critical point also ensue from the derived asymptotic relations. PMID- 26520075 TI - Controlled generation of switching dynamics among metastable states in pulse coupled oscillator networks. AB - Switching dynamics among saddles in a network of nonlinear oscillators can be exploited for information encoding and processing (hence computing), but stable attractors in the system can terminate the switching behavior. An effective control strategy is presented to sustain switching dynamics in networks of pulse coupled oscillators. The support for the switching behavior is a set of saddles, or unstable invariant sets in the phase space. We thus identify saddles with a common property, localize the system in the vicinity of them, and then guide the system from one metastable state to another to generate desired switching dynamics. We demonstrate that the control method successfully generates persistent switching trajectories and prevents the system from entering stable attractors. In addition, there exists correspondence between the network structure and the switching dynamics, providing fundamental insights on the development of a computing paradigm based on the switching dynamics. PMID- 26520076 TI - Computation of entropy and Lyapunov exponent by a shift transform. AB - We present a novel computational method to estimate the topological entropy and Lyapunov exponent of nonlinear maps using a shift transform. Unlike the computation of periodic orbits or the symbolic dynamical approach by the Markov partition, the method presented here does not require any special techniques in computational and mathematical fields to calculate these quantities. In spite of its simplicity, our method can accurately capture not only the chaotic region but also the non-chaotic region (window region) such that it is important physically but the (Lebesgue) measure zero and usually hard to calculate or observe. Furthermore, it is shown that the Kolmogorov-Sinai entropy of the Sinai-Ruelle Bowen measure (the physical measure) coincides with the topological entropy. PMID- 26520077 TI - Interplay between the local information based behavioral responses and the epidemic spreading in complex networks. AB - The spreading of an infectious disease can trigger human behavior responses to the disease, which in turn plays a crucial role on the spreading of epidemic. In this study, to illustrate the impacts of the human behavioral responses, a new class of individuals, S(F), is introduced to the classical susceptible-infected recovered model. In the model, S(F) state represents that susceptible individuals who take self-initiate protective measures to lower the probability of being infected, and a susceptible individual may go to S(F) state with a response rate when contacting an infectious neighbor. Via the percolation method, the theoretical formulas for the epidemic threshold as well as the prevalence of epidemic are derived. Our finding indicates that, with the increasing of the response rate, the epidemic threshold is enhanced and the prevalence of epidemic is reduced. The analytical results are also verified by the numerical simulations. In addition, we demonstrate that, because the mean field method neglects the dynamic correlations, a wrong result based on the mean field method is obtained-the epidemic threshold is not related to the response rate, i.e., the additional S(F) state has no impact on the epidemic threshold. PMID- 26520078 TI - Rogue waves, rational solitons, and modulational instability in an integrable fifth-order nonlinear Schrodinger equation. AB - We analytically study rogue-wave (RW) solutions and rational solitons of an integrable fifth-order nonlinear Schrodinger (FONLS) equation with three free parameters. It includes, as particular cases, the usual NLS, Hirota, and Lakshmanan-Porsezian-Daniel equations. We present continuous-wave (CW) solutions and conditions for their modulation instability in the framework of this model. Applying the Darboux transformation to the CW input, novel first- and second order RW solutions of the FONLS equation are analytically found. In particular, trajectories of motion of peaks and depressions of profiles of the first- and second-order RWs are produced by means of analytical and numerical methods. The solutions also include newly found rational and W-shaped one- and two-soliton modes. The results predict the corresponding dynamical phenomena in extended models of nonlinear fiber optics and other physically relevant integrable systems. PMID- 26520079 TI - A coupled "AB" system: Rogue waves and modulation instabilities. AB - Rogue waves are unexpectedly large and localized displacements from an equilibrium position or an otherwise calm background. For the nonlinear Schrodinger (NLS) model widely used in fluid mechanics and optics, these waves can occur only when dispersion and nonlinearity are of the same sign, a regime of modulation instability. For coupled NLS equations, rogue waves will arise even if dispersion and nonlinearity are of opposite signs in each component as new regimes of modulation instability will appear in the coupled system. The same phenomenon will be demonstrated here for a coupled "AB" system, a wave-current interaction model describing baroclinic instability processes in geophysical flows. Indeed, the onset of modulation instability correlates precisely with the existence criterion for rogue waves for this system. Transitions from "elevation" rogue waves to "depression" rogue waves are elucidated analytically. The dispersion relation as a polynomial of the fourth order may possess double pairs of complex roots, leading to multiple configurations of rogue waves for a given set of input parameters. For special parameter regimes, the dispersion relation reduces to a cubic polynomial, allowing the existence criterion for rogue waves to be computed explicitly. Numerical tests correlating modulation instability and evolution of rogue waves were conducted. PMID- 26520080 TI - Integrable equations of the infinite nonlinear Schrodinger equation hierarchy with time variable coefficients. AB - We present an infinite nonlinear Schrodinger equation hierarchy of integrable equations, together with the recurrence relations defining it. To demonstrate integrability, we present the Lax pairs for the whole hierarchy, specify its Darboux transformations and provide several examples of solutions. These resulting wavefunctions are given in exact analytical form. We then show that the Lax pair and Darboux transformation formalisms still apply in this scheme when the coefficients in the hierarchy depend on the propagation variable (e.g., time). This extension thus allows for the construction of complicated solutions within a greatly diversified domain of generalised nonlinear systems. PMID- 26520081 TI - Discrimination of time-dependent inflow properties with a cooperative dynamical system. AB - Many physical, chemical, and biological systems exhibit a cooperative or sigmoidal response with respect to the input. In biochemistry, such behavior is called an allosteric effect. Here, we demonstrate that a system with such properties can be used to discriminate the amplitude or frequency of an external periodic perturbation. Numerical simulations performed for a model sigmoidal kinetics illustrate that there exists a narrow range of frequencies and amplitudes within which the system evolves toward significantly different states. Therefore, observation of system evolution should provide information about the characteristics of the perturbation. The discrimination properties for periodic perturbation are generic. They can be observed in various dynamical systems and for different types of periodic perturbation. PMID- 26520082 TI - Nonlinear forecasting of intertidal shoreface evolution. AB - Natural systems dominated by sediment transport are notoriously difficult to forecast. This is particularly true along the ocean coastline, a region that draws considerable human attention as economic investment and infrastructure are threatened by both persistent, long-term and acute, event driven processes (i.e., sea level rise and storm damage, respectively). Forecasting the coastline's evolution over intermediate time (daily) and space (tens of meters) scales is hindered by the complexity of sediment transport and hydrodynamics, and limited access to the detailed local forcing that drives fast scale processes. Modern remote sensing systems provide an efficient, economical means to collect data within these regions. A solar-powered digital camera installation is used to capture the coast's evolution, and machine learning algorithms are implemented to extract the shoreline and estimate the daily mean intertidal coastal profile. Methods in nonlinear time series forecasting and genetic programming applied to these data corroborate that coastal morphology at these scales is predominately driven by nonlinear internal dynamics, which partially mask external forcing signatures. Results indicate that these forecasting techniques achieve nontrivial predictive skill for spatiotemporal forecast of the upper coastline profile (as much as 43% of variance in data explained for one day predictions). This analysis provides evidence that societally relevant coastline forecasts can be achieved without knowing the forcing environment or the underlying dynamical equations that govern coastline evolution. PMID- 26520083 TI - On the dynamics of ocean ambient noise: Two decades later. AB - Two decades ago, it was shown that ambient noise exhibits low dimensional chaotic behavior. Recent new techniques in nonlinear science can effectively detect the underlying dynamics in noisy time series. In this paper, the presence of low dimensional deterministic dynamics in ambient noise is investigated using diverse nonlinear techniques, including correlation dimension, Lyapunov exponent, nonlinear prediction, and entropy based methods. The consistent interpretation of different methods demonstrates that ambient noise can be best modeled as nonlinear stochastic dynamics, thus rejecting the hypothesis of low dimensional chaotic behavior. The ambient noise data utilized in this study are of duration 60 s measured at South China Sea. PMID- 26520084 TI - Sequential memory: Binding dynamics. AB - Temporal order memories are critical for everyday animal and human functioning. Experiments and our own experience show that the binding or association of various features of an event together and the maintaining of multimodality events in sequential order are the key components of any sequential memories-episodic, semantic, working, etc. We study a robustness of binding sequential dynamics based on our previously introduced model in the form of generalized Lotka Volterra equations. In the phase space of the model, there exists a multi dimensional binding heteroclinic network consisting of saddle equilibrium points and heteroclinic trajectories joining them. We prove here the robustness of the binding sequential dynamics, i.e., the feasibility phenomenon for coupled heteroclinic networks: for each collection of successive heteroclinic trajectories inside the unified networks, there is an open set of initial points such that the trajectory going through each of them follows the prescribed collection staying in a small neighborhood of it. We show also that the symbolic complexity function of the system restricted to this neighborhood is a polynomial of degree L - 1, where L is the number of modalities. PMID- 26520085 TI - Spatial discordance and phase reversals during alternate pacing in discrete-time kinematic and cardiomyocyte ionic models. AB - Alternans, a beat-to-beat alternation in the cardiac action potential duration (APD), is a dynamical instability linked with the initiation of arrhythmias and sudden cardiac death, and arises via a period-doubling bifurcation when myocytes are stimulated at fast rates. In this study, we analyze the stability of a propagating electrical wave in a one-dimensional cardiac myocyte model in response to an arrhythmogenic rhythm known as alternate pacing. Using a discrete time kinematic model and complex frequency (Z) domain analysis, we derive analytical expressions to predict phase reversals and spatial discordance in the interbeat interval (IBI) and APD, which, importantly, cannot be predicted with a model that neglects the influence of cell coupling on repolarization. We identify key dimensionless parameters that determine the transition from spatial concordance to discordance. Finally, we show that the theoretical predictions agree closely with numerical simulations of an ionic myocyte model, over a wide range of parameters, including variable IBI, altered ionic current gating, and reduced cell coupling. We demonstrate a novel approach to predict instability in cardiac tissue during alternate pacing and further illustrate how this approach can be generalized to more detail models of myocyte dynamics. PMID- 26520086 TI - Suppression of seizures based on the multi-coupled neural mass model. AB - Epilepsy is one of the most common serious neurological disorders, which affects approximately 1% of population in the world. In order to effectively control the seizures, we propose a novel control methodology, which combines the feedback linearization control (FLC) with the underlying mechanism of epilepsy, to achieve the suppression of seizures. The three coupled neural mass model is constructed to study the property of the electroencephalographs (EEGs). Meanwhile, with the model we research on the propagation of epileptiform waves and the synchronization of populations, which are taken as the foundation of our control method. Results show that the proposed approach not only yields excellent performances in clamping the pathological spiking patterns to the reference signals derived under the normal state but also achieves the normalization of the pathological parameter, where the parameters are estimated from EEGs with Unscented Kalman Filter. The specific contribution of this paper is to treat the epilepsy from its pathogenesis with the FLC, which provides critical theoretical basis for the clinical treatment of neurological disorders. PMID- 26520087 TI - Dispersal-induced synchrony, temporal stability, and clustering in a mean-field coupled Rosenzweig-MacArthur model. AB - In spatial ecology, dispersal among a set of spatially separated habitats, named as metapopulation, preserves the diversity and persistence by interconnecting the local populations. Understanding the effects of several variants of dispersion in metapopulation dynamics and to identify the factors which promote population synchrony and population stability are important in ecology. In this paper, we consider the mean-field dispersion among the habitats in a network and study the collective dynamics of the spatially extended system. Using the Rosenzweig MacArthur model for individual patches, we show that the population synchrony and temporal stability, which are believed to be of conflicting outcomes of dispersion, can be simultaneously achieved by oscillation quenching mechanisms. Particularly, we explore the more natural coupling configuration where the rates of dispersal of different habitats are disparate. We show that asymmetry in dispersal rate plays a crucial role in determining inhomogeneity in an otherwise homogeneous metapopulation. We further identify an unusual emergent state in the network, namely, a multi-branch clustered inhomogeneous steady state, which arises due to the intrinsic parameter mismatch among the patches. We believe that the present study will shed light on the cooperative behavior of spatially structured ecosystems. PMID- 26520088 TI - Supertransmission channel for an intrinsic localized mode in a one-dimensional nonlinear physical lattice. AB - It is well known that a moving intrinsic localized mode (ILM) in a nonlinear physical lattice looses energy because of the resonance between it and the underlying small amplitude plane wave spectrum. By exploring the Fourier transform (FT) properties of the nonlinear force of a running ILM in a driven and damped 1D nonlinear lattice, as described by a 2D wavenumber and frequency map, we quantify the magnitude of the resonance where the small amplitude normal mode dispersion curve and the FT amplitude components of the ILM intersect. We show that for a traveling ILM characterized by a specific frequency and wavenumber, either inside or outside the plane wave spectrum, and for situations where both onsite and intersite nonlinearity occur, either of the hard or soft type, the strength of this resonance depends on the specific mix of the two nonlinearities. Examples are presented demonstrating that by engineering this mix the resonance can be greatly reduced. The end result is a supertransmission channel for either a driven or undriven ILM in a nonintegrable, nonlinear yet physical lattice. PMID- 26520089 TI - Reconstruction of chaotic saddles by classification of unstable periodic orbits: Kuramoto-Sivashinsky equation. AB - The unstable periodic orbits (UPOs) embedded in a chaotic attractor after an attractor merging crisis (MC) are classified into three subsets, and employed to reconstruct chaotic saddles in the Kuramoto-Sivashinsky equation. It is shown that in the post-MC regime, the two chaotic saddles evolved from the two coexisting chaotic attractors before crisis can be reconstructed from the UPOs embedded in the pre-MC chaotic attractors. The reconstruction also involves the detection of the mediating UPO responsible for the crisis, and the UPOs created after crisis that fill the gap regions of the chaotic saddles. We show that the gap UPOs originate from saddle-node, period-doubling, and pitchfork bifurcations inside the periodic windows in the post-MC chaotic region of the bifurcation diagram. The chaotic attractor in the post-MC regime is found to be the closure of gap UPOs. PMID- 26520090 TI - Phase synchronization in the cochlea at transition from mechanical waves to electrical spikes. AB - Measured auditory nervous spikes often show synchronization, phase-locking, or entrainment (P. Cariani, Neural Plast. 6(4), 142-172 (1999) and Kumaresana et al., J. Acoust. Soc. Am. 133(6), 4290-4310 (2013). Physiologically synchronization is found in the anteroventral cochlear nucleus (Joris et al., J. Neurophysiol. 71(3), 1022-1036 (1994)) or in the trapezoid body also between critical bandwidths (Louage et al., Auditory Signal Processing: Physiology, Psychoacoustics, and Models (Springer, New York, 2004), pp. 100-106). The effect is an enhancement of pitch detection, spatial localization, or speech intelligibility. To investigate the presence of synchronization already in the cochlea, in the present paper, a finite-difference time-domain model of the cochlea is implemented with conditions for spike excitation caused by mechanical basilar membrane displacement. This model shows synchronization already in the cochlea at the transition from mechanical waves to nerve spike excitation. Using a sound as model input consisting of ten harmonic overtones with random phase relations, the output spikes are strongly phase aligned after this transition. When using a two-sinusoidal complex as input, and altering the phase relations between the two sinusoidals, the output spikes show the higher sinusoidal shifting the phase of the lower one in its direction in a systematic way. Therefore, already during the transition from mechanical to electrical excitation within the cochlea, synchronization appears to be improving perception of pitch, speech, or localization. PMID- 26520091 TI - Smoothing tautologies, hidden dynamics, and sigmoid asymptotics for piecewise smooth systems. AB - Switches in real systems take many forms, such as impacts, electronic relays, mitosis, and the implementation of decisions or control strategies. To understand what is lost, and what can be retained, when we model a switch as an instantaneous event, requires a consideration of so-called hidden terms. These are asymptotically vanishing outside the switch, but can be encoded in the form of nonlinear switching terms. A general expression for the switch can be developed in the form of a series of sigmoid functions. We review the key steps in extending Filippov's method of sliding modes to such systems. We show how even slight nonlinear effects can hugely alter the behaviour of an electronic control circuit, and lead to "hidden" attractors inside the switching surface. PMID- 26520092 TI - Periodicity, chaos, and multiple attractors in a memristor-based Shinriki's circuit. AB - In this contribution, a novel memristor-based oscillator, obtained from Shinriki's circuit by substituting the nonlinear positive conductance with a first order memristive diode bridge, is introduced. The model is described by a continuous time four-dimensional autonomous system with smooth nonlinearities. The basic dynamical properties of the system are investigated including equilibria and stability, phase portraits, frequency spectra, bifurcation diagrams, and Lyapunov exponents' spectrum. It is found that in addition to the classical period-doubling and symmetry restoring crisis scenarios reported in the original circuit, the memristor-based oscillator experiences the unusual and striking feature of multiple attractors (i.e., coexistence of a pair of asymmetric periodic attractors with a pair of asymmetric chaotic ones) over a broad range of circuit parameters. Results of theoretical analyses are verified by laboratory experimental measurements. PMID- 26520093 TI - Elimination of a spiral wave pinned at an obstacle by a train of plane waves: Effect of diffusion between obstacles and surrounding media. AB - In excitable media such as cardiac tissue and Belousov-Zhabotinsky reaction medium, spiral waves tend to anchor (pin) to local heterogeneities. In general, such pinned waves are difficult to eliminate and may progress to spatio-temporal chaos. Heterogeneities can be classified as either the absence or presence of diffusive interaction with the surrounding medium. In this study, we investigated the difference in the unpinning of spiral waves from obstacles with and without diffusive interaction, and found a profound difference. The pacing period required for unpinning at fixed obstacle size is larger in case of diffusive obstacles. Further, we deduced a generic theoretical framework that can predict the minimal unpinning period. Our results explain the difference in pacing periods between for the obstacles with and without diffusive interaction, and the difference is interpreted in terms of the local decrease of spiral wave velocity close to the obstacle boundary caused in the case of diffusive interaction. PMID- 26520094 TI - A new reduced-order observer for the synchronization of nonlinear chaotic systems: An application to secure communications. AB - This paper deals with the master-slave synchronization scheme for partially known nonlinear chaotic systems, where the unknown dynamics is considered as the master system and we propose the slave system structure which estimates the unknown states. It introduced a new reduced order observer, using the concept of Algebraic Observability; we applied the results to a Sundarapandian chaotic system, and by means of some numerical simulations we show the effectiveness of the suggested approach. Finally, the proposed observer is utilized for encryption, where encryption key is the master system and decryption key is the slave system. PMID- 26520096 TI - Preliminary results of lab-scale investigations of products of incomplete combustion during incineration of primary and mixed digested sludge. AB - Separation between primary and secondary sludge treatment could be a valuable solution for sludge management. According to this approach, secondary sludge can be conveniently used in agriculture while primary sludge could be easily dried and incinerated. It follows that some concern may arise from incinerating primary sludge with respect to the current practice to incinerate mixed digested sludge. Incineration of primary and mixed digested municipal sludge was investigated with a lab-scale equipment in terms of emissions of products of incomplete combustion (PICs) during incineration failure modes. PICs can be grouped in three sub categories, namely aliphatic hydrocarbons (alkanes and alkenes), compounds with a single aromatic ring, and polycyclic aromatic hydrocarbons (PAHs). After-burning temperature was the most important parameter to be controlled in order to minimize emissions of alkanes and alkenes. As for mono-aromatic compounds, benzene and toluene are the most thermally resistant compounds, and in some cases, an after-burning temperature of 1100 degrees C was not enough to get the complete destruction of benzene leading to a residual emission of 18 mg/kgsludge. PAHs showed an opposite trend with respect to aliphatic and mono-aromatic hydrocarbons being the thermal failure mode the main responsible of PIC emissions. A proper oxygen concentration is more important than elevated temperature thus reflecting the high thermal stability of PAHs. Overall, obtained results, even though obtained under flameless conditions that are different from those of the industrial plants, demonstrated that separation of primary and secondary sludge does not pose any drawbacks or concern regarding primary sludge being disposed of by incineration even though it is more contaminated than mixed digested sludge in terms of organic pollutants. PMID- 26520095 TI - Cytosolic phospholipase A2 plays a crucial role in ROS/NO signaling during microglial activation through the lipoxygenase pathway. AB - BACKGROUND: Oxidative stress and inflammation are important factors contributing to the pathophysiology of numerous neurological disorders, including Alzheimer's disease, Parkinson's disease, acute stroke, and infections of the brain. There is well-established evidence that proinflammatory cytokines and glutamate, as well as reactive oxygen species (ROS) and nitric oxide (NO), are produced upon microglia activation, and these are important factors contributing to inflammatory responses and cytotoxic damage to surrounding neurons and neighboring cells. Microglial cells express relatively high levels of cytosolic phospholipase A2 (cPLA2), an enzyme known to regulate membrane phospholipid homeostasis and release of arachidonic acid (AA) for synthesis of eicosanoids. The goal for this study is to elucidate the role of cPLA2IV in mediating the oxidative and inflammatory responses in microglial cells. METHODS: Experiments involved primary microglia cells isolated from transgenic mice deficient in cPLA2alpha or iPLA2beta, as well as murine immortalized BV-2 microglial cells. Inhibitors of cPLA2/iPLA2/cyclooxygenase (COX)/lipoxygenase (LOX) were used in BV 2 microglial cell line. siRNA transfection was employed to knockdown cPLA2 expression in BV-2 cells. Griess reaction protocol was used to determine NO concentration, and CM-H2DCF-DA was used to detect ROS production in primary microglia and BV-2 cells. WST-1 assay was used to assess cell viability. Western blotting was used to assess protein expression levels. Immunocytochemical staining for phalloidin against F-actin was used to demonstrate cell morphology. RESULTS: In both primary and BV-2 microglial cells, stimulation with lipopolysaccharide (LPS) or interferon gamma (IFNgamma) resulted in a time dependent increase in phosphorylation of cPLA2 together with ERK1/2. In BV-2 cells, LPS- and IFNgamma-induced ROS and NO production was inhibited by arachidonyl trifluoromethyl ketone (AACOCF3) and pyrrophenone as well as RNA interference, but not BEL, suggesting a link between cPLA2, and not iPLA2, on LPS/IFNgamma-induced nitrosative and oxidative stress in microglial cells. Primary microglial cells isolated from cPLA2alpha-deficient mice generated significantly less NO and ROS as compared with the wild-type mice. Microglia isolated from iPLA2beta-deficient mice did not show a decrease in LPS-induced NO and ROS production. LPS/IFNgamma induced morphological changes in primary microglia, and these changes were mitigated by AACOCF3. Interestingly, despite that LPS and IFNgamma induced an increase in phospho-cPLA2 and prostaglandin E2 (PGE2) release, LPS- and IFNgamma-induced NO and ROS production were not altered by the COX-1/2 inhibitor but were suppressed by the LOX-12 and LOX-15 inhibitors instead. CONCLUSIONS: In summary, the results in this study demonstrated the role of cPLA2 in microglial activation with metabolic links to oxidative and inflammatory responses, and this was in part regulated by the AA metabolic pathways, namely the LOXs. Further studies with targeted inhibition of cPLA2/LOX in microglia during neuroinflammatory conditions can be valuable to investigate the therapeutic potential in ameliorating neurological disease pathology. PMID- 26520097 TI - Impact of temperature on the aging mechanisms of arsenic in soils: fractionation and bioaccessibility. AB - The present study focused on the influence of temperature variation on the aging mechanisms of arsenic in soils. The results showed that higher temperature aggravated the decrease of more mobilizable fractions and the increase of less mobilizable or immobilizable fractions in soils over time. During the aging process, the redistribution of both carbonate-bound fraction and specifically sorbed and organic-bound fraction in soils occurred at various temperatures, and the higher temperature accelerated the redistribution of specifically sorbed and organic-bound fraction. The aging processes of arsenic in soils at different temperatures were characterized by several stages, and the aging processes were not complete within 180 days. Arsenic bioaccessibility in soils decreased significantly by the aging, and the decrease was intensified by the higher temperature. In terms of arsenic bioaccessibility, higher temperature accelerated the aging process of arsenic in soils remarkably. PMID- 26520098 TI - Angiosuppressive properties of marine-derived compounds-a mini review. AB - Angiogenesis, formation of new blood vessels from preexisting one, is a critical step of tumorgenesis of solid tumors. Therefore, antiangiogenic therapy is one of the promising approaches to control tumor growth. In the past 20 years, a lot of compounds have been tested for their antiangiogenic properties. Bevacizumab, Avastin(r), the first antiangiogenic drug approved by the US FDA, has been widely used in clinic for treating cancer. Indeed, many synthetic compounds are highly toxic and exert side effects even though they are effective in inhibiting neovessel formation and cancer cell growth. Using natural compounds or their derivatives is one of the ways to solve these problems. Sinomenine and ginsenosides are common antiangiogenic and anticancer compounds that are extracted from herbal medicines. Recent findings suggested that marine algae derived natural pigments also possess similar activities. It has been reported that fucoxanthin from Undaria pinnatifida, Siphonaxanthin from Codium fragile, can inhibit angiogenesis and cancer growth effectively. In conclusion, natural compounds derived from marine algae could provide a novel and safe source for new drug development in anticancer and antiangiogenic properties in the future. PMID- 26520099 TI - Effects of sulfate and selenite on mercury methylation in a mercury-contaminated rice paddy soil under anoxic conditions. AB - Biogeochemical cycling of sulfur and selenium (Se) could play an important role in methylmercury (MeHg) dynamics in soil, while their potential effects on MeHg production in rice paddy soil are less understood. The main objective of this study was to explore the effects of sulfate and selenite on net MeHg production in contaminated rice paddy soil, characterized with massive MeHg production and thus MeHg accumulation in rice. A series of microcosm incubation experiments were conducted using a contaminated paddy soil amended with sulfate and/or selenite, in which sulfate-reducing bacteria were mainly responsible for MeHg production. Our results demonstrated that sulfate addition reduced solid and dissolved MeHg levels in soils by <=18 and <=25 %, respectively. Compared to sulfate, selenite was more effective in inhibiting net MeHg production, and the inhibitory effect depended largely on amended selenite doses. Moreover, sulfate input played a dual role in affecting Hg-Se interactions in soil, which could be explained by the dynamics of sulfate under anoxic conditions. Therefore, the effects of sulfate and selenium input should be carefully considered when assessing risk of Hg in anoxic environments (e.g., rice paddy field and wetland). PMID- 26520100 TI - Impact of treated urban wastewater for reuse in agriculture on crop response and soil ecotoxicity. AB - The scarcity of freshwater resources is a serious problem in arid regions, such as Tunisia, and marginal quality water is gradually being used in agriculture. This study aims to study the impact of treated urban wastewater for reuse in agriculture on the health of soil and food crops. The key findings are that the effluents of Sfax wastewater treatment plant (WWTP) did not meet the relevant guidelines, therefore emitting a range of organic (e.g., up to 90 mg L(-1) COD and 30 mg L(-1) BOD5) and inorganic pollutants (e.g., up to 0.5 mg L(-1) Cu and 0.1 mg L(-1) Cd) in the receiving aquatic environments. Greenhouse experiments examining the effects of wastewater reuse on food plants such as tomato, lettuce, and radish showed that the treated effluent adversely affected plant growth, photosynthesis, and antioxidant enzyme contents. However, the pollution burden and biological effects on plants were substantially reduced by using a 50 % dilution of treated sewage effluent, suggesting the potential of reusing treated effluent in agriculture so long as appropriate monitoring and control is in place. PMID- 26520101 TI - Calcium-dependent protein kinase (CDPK) and CDPK-related kinase (CRK) gene families in tomato: genome-wide identification and functional analyses in disease resistance. AB - Calcium-dependent protein kinases (CDPKs) and CDPK-related kinases (CRKs) play multiple roles in plant. Nevertheless, genome-wide identification of these two families is limited to several plant species, and role of CRKs in disease resistance remains unclear. In this study, we identified the CDPK and CRK gene families in genome of the economically important crop tomato (Solanum lycopersicum L.) and analyzed their function in resistance to various pathogens. Twenty-nine CDPK and six CRK genes were identified in tomato genome. Both SlCDPK and SlCRK proteins harbored an STKc_CAMK type protein kinase domain, while only SlCDPKs contained EF-hand type Ca(2+) binding domain(s). Phylogenetic analysis revealed that plant CRK family diverged early from CDPKs, and shared a common ancestor gene with subgroup IV CDPKs. Subgroup IV SlCDPK proteins were basic and their genes contained 11 introns, which were distinguished from other subgroups but similar to CRKs. Subgroup I SlCDPKs generally did not carry an N-terminal myristoylation motif while those of the remaining subgroups and SlCRKs universally did. SlCDPK and SlCRK genes were differently responsive to pathogenic stimuli. Furthermore, silencing analyses demonstrated that SlCDPK18 and SlCDPK10 positively regulated nonhost resistance to Xanthomonas oryzae pv. oryzae and host resistance to Pseudomonas syringae pv. tomato (Pst) DC3000, respectively, while SlCRK6 positively regulated resistance to both Pst DC3000 and Sclerotinia sclerotiorum in tomato. In conclusion, CRKs apparently evolved from CDPK lineage, SlCDPK and SlCRK genes regulate a wide range of resistance and SlCRK6 is the first CRK gene proved to function in plant disease resistance. PMID- 26520102 TI - The ABC transporter ABCG29 is involved in H2O2 tolerance and biocontrol traits in the fungus Clonostachys rosea. AB - For successful biocontrol interactions, biological control organisms must tolerate toxic metabolites produced by themselves or plant pathogens during mycoparasitic/antagonistic interactions, by host plant during colonization of the plant, and xenobiotics present in the environment. ATP-binding cassette (ABC) transporters can play a significant role in tolerance of toxic compounds by mediating active transport across the cellular membrane. This paper reports on functional characterization of an ABC transporter ABCG29 in the biocontrol fungus Clonostachys rosea strain IK726. Gene expression analysis showed induced expression of abcG29 during exposure to the Fusarium spp. mycotoxin zearalenone (ZEA) and the fungicides Cantus, Chipco Green and Apron. Expression of abcG29 in C. rosea was significantly higher during C. rosea-C. rosea (Cr-Cr) interaction or in exposure to C. rosea culture filtrate for 2 h, compared to interaction with Fusarium graminearum or 2 h exposure to F. graminearum culture filtrate. In contrast with gene expression data, DeltaabcG29 strains did not display reduced tolerance towards ZEA, fungicides or chemical agents known for inducing oxidative, cell wall or osmotic stress, compared to C. rosea WT. The exception was a significant reduction in tolerance to H2O2 (10 mM) in DeltaabcG29 strains when conidia were used as an inoculum. The antagonistic ability of DeltaabcG29 strains towards F. graminearum, Fusarium oxysporum or Botrytis cinerea in dual plate assays were not different compared with WT. However, in biocontrol assays DeltaabcG29 strains displayed reduced ability to protect Arabidopsis thaliana leaves from B. cinerea, and barley seedling from F. graminearum as measured by an A. thaliana detached leaf assay and a barley foot rot disease assay, respectively. These data show that the ABCG29 is dispensable for ZEA and fungicides tolerance, and antagonism but not H2O2 tolerance and biocontrol effects in C. rosea. PMID- 26520103 TI - RNA-seq transcriptome analysis of extensor digitorum longus and soleus muscles in large white pigs. AB - Skeletal muscle fibers are mainly categorized into red and white fiber types, and the ratio of red/white fibers within muscle mass plays a crucial role in meat quality such as tenderness and flavor. To better understand the molecular difference between the two muscle fibers, this study takes advantage of RNA-seq to compare differences in the transcriptome between extensor digitorum longus (EDL; white fiber) and soleus (Sol; red fiber) muscles of large white pigs. In total, 89,658,562 and 46,723,568 raw reads from EDL and Sol were generated, respectively. Comparison between the two transcriptomes revealed 561 differentially expressed genes, with 408 displaying higher and 153 lower levels of expression in Sol. Quantitative real-time polymerase chain reaction validated the differential expression of nine genes. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis discovered several differentially enriched biological functions and processes of the two muscles. Moreover, transcriptome comparison between EDL and Sol identified many muscle-related genes (CSRP3, ACTN2, MYL1, and MYH6) and pathways related to myofiber formation, such as focal adhesion, tight junction formation, extracellular matrix (ECM)-receptor pathway, calcium signaling, and Wnt signaling. In addition, 58,362 and 58,359 single nucleotide polymorphisms were identified in EDL and Sol, respectively, and the sequence of 9069 genes was refined at the 5', 3' or both ends. Numerous novel transcripts and alternatively spliced RNAs were also identified. Our transcriptome analysis constitutes valuable sequence resource for uncovering important genes and pathways involved in muscle fiber type determination, and might help further our understanding of the molecular mechanisms in different types of muscle. PMID- 26520104 TI - The Parent Participation Engagement Measure (PPEM): Reliability and Validity in Child and Adolescent Community Mental Health Services. AB - Parent participation in community-based child mental health services is an important yet understudied process associated with treatment effectiveness. This paper describes the development and psychometrics of the Parent Participation Engagement Measure in a sample of 1374 parents and 563 youth receiving publicly funded mental health services. Analyses indicated excellent internal consistency, and model fit indices/factor loadings supported a one-factor model. Convergent and discriminant validity were supported, although some coefficients were modest in magnitude. Psychometric results were consistent for Caucasian versus Hispanic, parent versus youth, and English versus Spanish-language respondents. The clinical and research utility of this measure are discussed. PMID- 26520108 TI - Erratum to: Stress In An Oncologist's Life: Present But Not Insurmountable : (Students Should Not Be Discouraged Choosing Oncology as Their Future Specialisation). PMID- 26520106 TI - RPA homologs and ssDNA processing during meiotic recombination. AB - Meiotic homologous recombination is a specialized process that involves homologous chromosome pairing and strand exchange to guarantee proper chromosome segregation and genetic diversity. The formation and repair of DNA double-strand breaks (DSBs) during meiotic recombination differs from those during mitotic recombination in that the homologous chromosome rather than the sister chromatid is the preferred repair template. The processing of single-stranded DNA (ssDNA) formed on intermediate recombination structures is central to driving the specific outcomes of DSB repair during meiosis. Replication protein A (RPA) is the main ssDNA-binding protein complex involved in DNA metabolism. However, the existence of RPA orthologs in plants and the recent discovery of meiosis specific with OB domains (MEIOB), a widely conserved meiosis-specific RPA1 paralog, strongly suggest that multiple RPA complexes evolved and specialized to subdivide their roles during DNA metabolism. Here we review ssDNA formation and maturation during mitotic and meiotic recombination underlying the meiotic specific features. We describe and discuss the existence and properties of MEIOB and multiple RPA subunits in plants and highlight how they can provide meiosis specific fates to ssDNA processing during homologous recombination. Understanding the functions of these RPA homologs and how they interact with the canonical RPA subunits is of major interest in the fields of meiosis and DNA repair. PMID- 26520107 TI - High-resolution in situ hybridization analysis on the chromosomal interval 61C7 61C8 of Drosophila melanogaster reveals interbands as open chromatin domains. AB - Eukaryotic chromatin is organized in contiguous domains that differ in protein binding, histone modifications, transcriptional activity, and in their degree of compaction. Genome-wide comparisons suggest that, overall, the chromatin organization is similar in different cells within an organism. Here, we compare the structure and activity of the 61C7-61C8 interval in polytene and diploid cells of Drosophila. By in situ hybridization on polytene chromosomes combined with high-resolution microscopy, we mapped the boundaries of the 61C7-8 interband and of the 61C7 and C8 band regions, respectively. Our results demonstrate that the 61C7-8 interband is significantly larger than estimated previously. This interband extends over 20 kbp and is in the range of the flanking band domains. It contains several active genes and therefore can be considered as an open chromatin domain. Comparing the 61C7-8 structure of Drosophila S2 cells and polytene salivary gland cells by ChIP for chromatin protein binding and histone modifications, we observe a highly consistent domain structure for the proximal 13 kbp of the domain in both cell types. However, the distal 7 kbp of the open domain differs in protein binding and histone modification between both tissues. The domain contains four protein-coding genes in the proximal part and two noncoding transcripts in the distal part. The differential transcriptional activity of one of the noncoding transcripts correlates with the observed differences in the chromatin structure between both tissues. The significance of our findings for the organization and structure of open chromatin domains will be discussed. PMID- 26520109 TI - Assessment of the Intestinal Barrier with Five Different Permeability Tests in Healthy C57BL/6J and BALB/cJ Mice. AB - BACKGROUND: Intestinal permeability is thought to be of major relevance for digestive and nutrition-related diseases, and therefore has been studied in numerous mouse models of disease. However, it is unclear which tools are the preferable ones, and how normal values should be defined. AIMS: To compare different in vivo permeability tests in healthy mice of commonly used genetic backgrounds. METHODS: We assessed the intestinal barrier in male and female C57BL/6J and BALB/cJ mice of different ages, using four orally administered permeability markers, FITC-dextran 4000 (FITC-D4000) and ovalbumin (OVA) measured in plasma, and polyethylene glycol (PEG) and lactulose/mannitol (Lac/Man) measured in urine, and by assessing lipopolysaccharide (LPS) in portal vein plasma. RESULTS: After gavage, FITC-D4000, OVA, Lac/Man, and PEG400, but not PEG4000, were detectable in plasma or urine. Female mice tended to have a higher permeability according to the FITC-D4000, OVA, and PEG400 tests, but the Lac/Man ratio was higher in males. No significant differences between the two mouse strains of young and old mice were observed except for mannitol recovery, which was higher in BALB/cJ mice compared to C57BL/6J mice (p < 0.05). Virtually no LPS was detected in healthy mice. For all markers, normal values have been defined based on 5th-95th percentile ranges of our data. CONCLUSION: Selected oral permeability tests, such as FITC-D4000, OVA, PEG400, and Lac/Man, as well as LPS measurements in portal vein plasma, could be suitable for the evaluation of the intestinal barrier in mice, if used in a standardized way. PMID- 26520110 TI - Regenerating Reputations: Are Wnt and Myc the Good Guys After All? PMID- 26520111 TI - Hint1 Up-Regulates IkappaBalpha by Targeting the beta-TrCP Subunit of SCF E3 Ligase in Human Hepatocellular Carcinoma Cells. AB - BACKGROUND AND AIM: There is increasing evidence that histidine triad nucleotide binding protein 1 (HINT1) is a novel tumor suppressor. In the present study, we investigated the mechanism by which HINT1 promotes the stability of inhibitor of NF-kappaB alpha (IkappaBalpha) in the cytoplasm of hepatocellular carcinoma (HCC) cells, which was observed in our previous study (Wang et al. in Int J Cancer 124:1526-1534, 2009). METHODS: We examined HINT1 and IkappaBalpha expression in HCC cell lines and determined the effect of HINT1 overexpression and knockdown on IkappaBalpha protein and mRNA expression in these cell lines. Then, ubiquitination assays were performed to investigate the effects of HINT1 expression plasmid transfection on IkappaBalpha ubiquitination. Next, the interaction between HINT1 and beta-TrCP was investigated in immunoprecipitation and immunofluorescence assays. RESULTS: Our data showed that increased HINT1 expression in HepG2 and SMMC7702 cells markedly increased IkappaBalpha protein levels, while decreased HINT1 expression markedly decreased them. Overexpression or knockdown of HINT1 did not alter the transcription of IkappaBalpha, but HINT1 inhibited proteasomal IkappaBalpha degradation and reduced its ubiquitination levels. This inhibition might occur because HINT1 is a component of the SCF(beta TrCP) E3 ligase, which is responsible for IkappaBalpha ubiquitination and degradation. CONCLUSION: This study provides new evidence that HINT1 is a regulator of IkappaBalpha through SCF(beta-TrCP) E3 ligase. These findings help to clarify the mechanism underlying the anticancer effects of HINT1. PMID- 26520112 TI - Insights into the sequence parameters for halophilic adaptation. AB - The sequence parameters for halophilic adaptation are still not fully understood. To understand the molecular basis of protein hypersaline adaptation, a detailed analysis is carried out, and investigated the likely association of protein sequence attributes to halophilic adaptation. A two-stage strategy is implemented, where in the first stage a supervised machine learning classifier is build, giving an overall accuracy of 86 % on stratified tenfold cross validation and 90 % on blind testing set, which are better than the previously reported results. The second stage consists of statistical analysis of sequence features and possible extraction of halophilic molecular signatures. The results of this study showed that, halophilic proteins are characterized by lower average charge, lower K content, and lower S content. A statistically significant preference/avoidance list of sequence parameters is also reported giving insights into the molecular basis of halophilic adaptation. D, Q, E, H, P, T, V are significantly preferred while N, C, I, K, M, F, S are significantly avoided. Among amino acid physicochemical groups, small, polar, charged, acidic and hydrophilic groups are preferred over other groups. The halophilic proteins also showed a preference for higher average flexibility, higher average polarity and avoidance for higher average positive charge, average bulkiness and average hydrophobicity. Some interesting trends observed in dipeptide counts are also reported. Further a systematic statistical comparison is undertaken for gaining insights into the sequence feature distribution in different residue structural states. The current analysis may facilitate the understanding of the mechanism of halophilic adaptation clearer, which can be further used for rational design of halophilic proteins. PMID- 26520113 TI - Erratum to: Bridging the genotyping gap: using genotyping by sequencing (GBS) to add high-density SNP markers and new value to traditional bi-parental mapping and breeding populations. PMID- 26520114 TI - Genetic mapping of common bunt resistance and plant height QTL in wheat. AB - KEY MESSAGE: Breeding for field resistance to common bunt in wheat will need to account for multiple genes and epistatic and QTL by environment interactions. Loci associated with quantitative resistance to common bunt are co-localized with other beneficial traits including plant height and rust resistance. ABSTRACT: Common bunt, also known as stinking smut, is caused by seed borne fungi Tilletia tritici (Bjerk.) Wint. [syn. Tilletia caries (DC.) Tul.] and Tilletia laevis Kuhn [syn. Tilletia foetida (Wallr.) Liro.]. Common bunt is known to cause grain yield and quality losses in wheat due to bunt ball formation and infestation of the grain. The objectives of this research were to identify and map quantitative trait loci (QTL) for common bunt resistance, to study the epistatic interactions between the identified QTL, and investigate the co-localization of bunt resistance with plant height. A population of 261 doubled haploid lines from the cross Carberry/AC Cadillac and checks were genotyped with polymorphic genome wide microsatellite and DArT((r)) markers. The lines were grown in 2011, 2012, and 2013 in separate nurseries for common bunt incidence and height evaluation. AC Cadillac contributed a QTL (QCbt.spa-6D) for common bunt resistance on chromosome 6D at markers XwPt-1695, XwPt-672044, and XwPt-5114. Carberry contributed QTL for bunt resistance on chromosomes 1B (QCbt.spa-1B at XwPt743523) 4B (QCbt.spa-4B at XwPt-744434-Xwmc617), 4D (QCbt.spa-4D at XwPt-9747), 5B (QCbt.spa-5B at XtPt 3719) and 7D (QCbt.spa-7D at Xwmc273). Significant epistatic interactions were identified for percent bunt incidence between QCbt.spa-1B * QCbt.spa-4B and QCbt.spa-1B * QCbt.spa-6D, and QTL by environment interaction between QCbt.spa-1B * QCbt.spa-6D. Plant height QTL were found on chromosomes 4B (QPh.spa-4B) and 6D (QPh.spa-6D) that co-located with bunt resistance QTL. The identification of previously unreported common bunt resistance QTL (on chromosomes 4B, 4D and 7D), and new understanding of QTL * QTL interactions will facilitate marker-assisted breeding for common bunt resistance. PMID- 26520115 TI - Regulation of TGF-beta Receptors. AB - In cells responding to extracellular polypeptide ligands, regulatory mechanisms at the level of cell surface receptors are increasingly seen to define the nature of the ligand-induced signaling responses. Processes that govern the levels of receptors at the plasma membrane, including posttranslational modifications, are crucial to ensure receptor function and specify the downstream signals. Indeed, extracellular posttranslational modifications of the receptors help define stability and ligand binding, while intracellular modifications mediate interactions with signaling mediators and accessory proteins that help define the nature of the signaling response. The use of various molecular biology and biochemistry techniques, based on chemical crosslinking, e.g., biotin or radioactive labeling, immunofluorescence to label membrane receptors and flow cytometry, allows for quantification of changes of cell surface receptor presentation. Here, we discuss recent progress in our understanding of the regulation of TGF-beta receptors, i.e., the type I (TbetaRI) and type II (TbetaRII) TGF-beta receptors, and describe basic methods to identify and quantify TGF-beta cell surface receptors. PMID- 26520116 TI - Determining TGF-beta Receptor Levels in the Cell Membrane. AB - Transforming growth factor-beta (TGF-beta) is a pleiotropic cytokine that signals via transmembrane TGF-beta type I and type II serine/threonine kinases receptors, i.e., TbetaRI and TbetaRII. Upon TGF-beta-induced receptor complex formation, the TbetaRII kinase phosphorylates TbetaRI. Subsequently, the activated TbetaRI induces the phosphorylation of receptor regulated SMAD2 and SMAD3, which can form heteromeric complexes with Smad4. These heteromeric SMAD complexes accumulate in the nucleus, where they regulate target gene expression. The stability and membrane localization of TbetaRI is an important determinant to control the intensity and duration of TGF-beta signaling. TbetaRI is targeted for poly ubiquitylation-mediated proteasomal degradation by the SMAD7-SMURF E3 ligase complex. We recently identified another important regulatory factor that controls TbetaRI levels in the cell membrane. As a strong inducer of TGF-beta signaling, ubiquitin-specific protease (USP) 4 was found to directly interact with TbetaRI and act as a deubiquitylating enzyme, thereby stabilizing TbetaRI levels at the plasma membrane. This chapter introduces methods for examining cell membrane receptor (TbetaRI) levels. PMID- 26520117 TI - Posttranslational Modifications of TGF-beta Receptors. AB - TGF-beta is a prototype of the TGF-beta cytokine superfamily and exerts multiple regulatory effects on cell activities. It signals through two types of membrane bound serine/threonine kinase receptors. Upon TGF-beta binding, the type II receptor TbetaRII recruits the type I receptor TbetaRI and form a functional heterocomplex. TbetaRII trans-phosphorylates the GS region of TbetaRI, thus triggering its kinase activity. Activated TbetaRI proceeds to activate downstream Smad2/3. Signal intensity and duration through the availability, activity and destiny of TGF-beta receptors are finely controlled by multiple posttranslational modifications such as phosphorylation, ubiquitination, and neddylation. This chapter introduces methods for examination of these modifications of TGF-beta receptors. PMID- 26520119 TI - Phosphorylation of Smads by Intracellular Kinases. AB - Smad proteins transduce the TGF-beta family signal at the cell surface into gene regulation in the nucleus. In addition to being phosphorylated by the TGF-beta family receptors, Smads are phosphorylated by a variety of intracellular kinases. The most studied are by cyclin-dependent kinases, the MAP kinase family members, and GSK-3. Phosphorylation by these kinases regulates Smad activities, leading to various biological effects. This chapter describes the methods for analyzing Smad phosphorylation by these kinases. PMID- 26520118 TI - Production, Isolation, and Structural Analysis of Ligands and Receptors of the TGF-beta Superfamily. AB - The ability to understand the molecular mechanisms by which secreted signaling proteins of the TGF-beta superfamily assemble their cell surface receptors into complexes to initiate downstream signaling is dependent upon the ability to determine atomic-resolution structures of the signaling proteins, the ectodomains of the receptors, and the complexes that they form. The structures determined to date have revealed major differences in the overall architecture of the signaling complexes formed by the TGF-betas and BMPs, which has provided insights as to how they have evolved to fulfill their distinct functions. Such studies, have however, only been applied to a few members of the TGF-beta superfamily, which is largely due to the difficulty of obtaining milligram-scale quantities of highly homogenous preparations of the disulfide-rich signaling proteins and receptor ectodomains of the superfamily. Here we describe methods used to produce signaling proteins and receptor ectodomains of the TGF-beta superfamily using bacterial and mammalian expression systems and procedures to purify them to homogeneity. PMID- 26520120 TI - Analysis of Smad Phosphatase Activity In Vitro. AB - Phosphorylation of Smad1/5/8 at the C-terminal SXS motif by BMP type I receptors is one of the most critical events in BMP signaling. Conversely, protein phosphatases that dephosphorylate phospho-Smad1/5/8 can consequently prevent or terminate BMP signaling. PPM1H is an undercharacterized phosphatase in the PPM family. We recently demonstrated that PPM1H can dephosphorylate Smad1 in the cytoplasm and block BMP signaling responses in cellular assays. Here we describe in vitro method showing that PPM1H is a bona fide phosphatase for Smad1/5/8. PPM1H is produced as GST fusion protein in E. coli, and purified against glutathione sepharose beads. Bacterially purified recombinant PPM1H possesses phosphatase activity toward artificial substrate para-nitrophenyl phosphate (pNPP). Recombinant PPM1H also dephosphorylates immuno-purified phosphorylated Smad1 in test tubes. These direct in vitro phosphatase assays provide convincing evidence demonstrating the role of PPM1H as a specific phosphatase for P-Smad1. PMID- 26520121 TI - Three-dimensional Mammary Epithelial Cell Morphogenesis Model for Analysis of TGFbeta Signaling. AB - Culturing mammary epithelial cells in laminin-rich extracellular matrices (three dimensional or 3D culture) offers significant advantages over that in the conventional two-dimensional (2D) tissue culture system in that it takes into considetation the impact of extracellular matrix (ECM) microenvironment on the proliferation, survival, and differentiation of mammary epithelial cells. When grown in the 3D culture, untransformed mammary epithelial cells undergo morphogenesis to form a multicellular and polarized acini-like structure that functionally mimics the differentiated alveoli in the pregnancy mammary gland. This process is subjected to regulation by many growth factors and cytokines. The transforming growth factor-beta (TGFbeta) is a multipotent cytokine that regulates multiple aspects of development and tumorigenesis. In addition to its effects on epithelial cell proliferation, survival, and differentiation, it is also a potent regulator of the cell-matrix interaction. Thus, the 3D culture model may recapitulate the complex in vivo epithelial cell microenvironment and allow us to fully evaluate the role of TGFbeta signaling in multiple aspects of normal and cancerous cell behavior. In this chapter we provide detailed protocols for growing mammary epithelial cells in the 3D Matrigel for analysis of signaling pathways. PMID- 26520122 TI - TGF-beta Signaling in Stem Cell Regulation. AB - The transforming growth factor-beta (TGF-beta) family of cytokines, including TGF beta, bone morphogenic proteins (BMPs), and activin/nodal, is a group of crucial morphogens in embryonic development, and plays key roles in modulating stem/progenitor cell fate. TGF-beta signaling is essential in maintaining the pluripotency of human pluripotent stem cells (hPSCs), including both human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), and its modulation can direct lineage-specific differentiation. Recent studies also demonstrate TGF-beta signaling negatively regulates reprogramming and inhibition of TGF-beta signaling can enhance reprogramming through facilitating mesenchymal-to-epithelial transition (MET). This chapter introduces methods of modulating somatic cell reprogramming to iPSCs and neural induction from hPSCs through modulating TGF-beta signaling by chemical approaches. PMID- 26520123 TI - Analysis of Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor beta. AB - In recent years, the importance of the cell biological process of epithelial mesenchymal transition (EMT) has been established via an exponentially growing number of reports. EMT has been documented during embryonic development, tissue fibrosis, and cancer progression in vitro, in animal models in vivo and in human specimens. EMT relates to many molecular and cellular alterations that occur when epithelial cells undergo a switch in differentiation that generates mesenchymal like cells with newly acquired migratory and invasive properties. In addition, EMT relates to a nuclear reprogramming similar to the one occurring in the generation of induced pluripotent stem cells. Via such a process, EMT is gradually established to promote the generation and maintenance of adult tissue stem cells which under disease states such as cancer, are known as cancer stem cells. EMT is induced by developmental growth factors, oncogenes, radiation, and hypoxia. A prominent growth factor that causes EMT is transforming growth factor beta (TGF-beta).A series of molecular and cellular techniques can be applied to define and characterize the state of EMT in diverse biological samples. These methods range from DNA and RNA-based techniques that measure the expression of key EMT regulators and markers of epithelial or mesenchymal differentiation to functional assays of cell mobility, invasiveness and in vitro stemness. This chapter focuses on EMT induced by TGF-beta and provides authoritative protocols and relevant reagents and citations of key publications aiming at assisting newcomers that enter this prolific area of biomedical sciences, and offering a useful reference tool to pioneers and aficionados of the field. PMID- 26520124 TI - In Vitro Th Differentiation Protocol. AB - CD4(+) T cells play central roles in adaptive immunity, driving appropriate immune responses to invading pathogens of diverse types. Four major CD4(+) T cell subsets, Th1, Th2, Th17, and Treg cells are differentiated from naive CD4(+) T cells upon ligation of their T cell receptors with antigens, depending on the cytokines they receive. Th1 cells, which are induced by IL-12 and IFN-gamma, mediate host defense against intracellular pathogens by exclusively expressing IFN-gamma. Th2 cells, which are induced by IL4, secrete IL-4, IL-5, and IL-13, and protect hosts from helminths. IL-6 plus TGF-beta induces Th17 cells, another Th subset identified relatively recently, express IL-17 and play important roles in the eradication of extracellular bacteria and fungi. Treg cells, which play central roles in immune suppression, are composed of either thymus-derived Treg cells (tTreg cells), which are directly developed from CD4-single positive (CD4 SP) cells in the thymus, or peripherally derived Treg cells (pTreg cells), which are induced by TGF-beta plus IL-2 from naive CD4(+) T cells. Although the regulated induction of Th cells results in proper eradication of pathogens, their excess activation results in various immune-associated diseases. For example, aberrant activation of Th1 and Th17 has been implicated in autoimmune diseases, excess Th2 activity causes atopic diseases, and impaired function of Treg cells due to abrogation of Foxp3 has been shown to cause fatal inflammatory disorders both in human and in mouse. The methods for in vitro differentiation of each Th subset described above are presented here. We hope these methods will facilitate understanding of differentiation and function of CD4(+) T cells and pathogenesis of various inflammatory diseases. PMID- 26520125 TI - Interrogating TGF-beta Function and Regulation in Endothelial Cells. AB - Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine with important roles in embryogenesis and maintaining tissue homeostasis during adult life. There are three isoforms of TGF-beta, i.e., TGF-beta1, -beta2, and -beta3, which signal by binding to a complex of transmembrane type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. In most cell types TGF-beta signals via TGF-beta type II receptor (TbetaRII) and TbetaRI, also termed activin receptor-like kinase 5 (ALK5). In endothelial cells, TGF-beta signals via ALK5 and ALK1. These two type I receptors mediate opposite cellular response for TGF-beta. The co-receptor endoglin, highly expressed on proliferating endothelial cells, facilitates TGF-beta/ALK1 and inhibits TGF beta/ALK5 signaling. Knockout of TGF-beta receptors in mice all result in embryonic lethality during midgestation from defects in angiogenesis, illustrating the pivotal role of TGF-beta in this process. This chapter introduces methods for examining the function and regulation of TGF-beta in angiogenesis in in vitro assays using cultured endothelial cells and ex vivo metatarsal explants. PMID- 26520126 TI - Isolation and Manipulation of Adipogenic Cells to Assess TGF-beta Superfamily Functions. AB - A variety of TGF-beta superfamily members affect adipocyte differentiation and function with consequential effects on energy metabolism. There has been a growing interest in this area because of the apparent influence of the BMP subgroup on brown adipose characteristics and potential application to the treatment of human obesity. In this chapter we describe methods that are useful in allowing one to assess the roles of specific members of the superfamily on adipocyte differentiation and mature adipocyte function, including the isolation and differentiation of mouse embryo fibroblasts (MEFs) to examine cell autonomous effects and the efficient transfection of two commonly used (but difficult to transfect) adipogenic cell lines, C3H/10T1/2 and 3T3-L1. PMID- 26520127 TI - Imaging TGFbeta Signaling in Mouse Models of Cancer Metastasis. AB - Metastatic spread of cancer cells from the primary tumors to distant vital organs, such as lung, liver, brain, and bone, is responsible for the majority of cancer-related deaths. Development of metastatic lesions is critically dependent on the interaction of tumor cells with the stromal microenvironment. As a multifunctional paracrine signaling factor that is abundantly produced by both tumor and stromal cells, TGFbeta has been well established as an important mediator of tumor-stromal interaction during cancer metastasis. Imaging the in vivo dynamic of TGFbeta signaling activity during cancer metastasis is critical for understanding the pathogenesis of the disease, and for the development of effective anti-metastasis treatments. In this chapter, I describe several xenograft methods to introduce human breast cancer cells into nude mice in order to generate spontaneous and experimental metastases, as well as the luciferase based bioluminescence imaging method for quantitative imaging analysis of TGFbeta signaling in tumor cells during metastasis. PMID- 26520128 TI - Generation and Characterization of Smad7 Conditional Knockout Mice. AB - Smad7 is an important negative modulator that regulates the duration and strength of TGF-beta signaling. Dysregulation of Smad7 is associated with the pathogenesis of many human diseases. Various mouse models are developed to facilitate addressing the physiological functions of Smad7. We have recently demonstrated that loss of Smad7 function by deletion in its MH2 domain leads to multiple cardiac defects and aggravates ethanol-induced liver injury. Here, we describe the procedure to construct and characterize the Smad7 conditional knockout mice. PMID- 26520129 TI - Monitoring Smad Activity In Vivo Using the Xenopus Model System. AB - The embryo of the African clawed frog Xenopus laevis plays a central role in the field of cell and developmental biology. One of the strengths of Xenopus as model system lies in the high degree of conservation between amphibians and mammals in the molecular mechanisms controlling tissue patterning and differentiation. As such, many signaling cascades were first investigated in frog embryos and then confirmed in mouse and/or human cells. The TGF-beta signaling cascade greatly benefited from this model system. Here we review the overall logic and experimental planning for studying Smad activity in vivo in the context of Xenopus embryonic development, and provide a guide for the interpretation of the results. PMID- 26520130 TI - Animal Cap Assay for TGF-beta Signaling. AB - TGF-beta signals regulate a variety of processes during early vertebrate development, from stem cell maintenance and differentiation to tissue patterning and organogenesis. Detailed understanding of how this signaling pathway operates and what genes control activities of the signaling components of the pathway is therefore important for us to comprehend temporal- and tissue-specific TGF-beta functions in vertebrate embryogenesis. Xenopus model system has been employed extensively in research on TGF-beta signals, and much insight about TGF-beta signaling mechanisms has been gained from these studies. Besides using whole embryos, explants from the ectodermal region of Xenopus, also known as animal caps, are used widely in investigations of the activities of an array of signal transducers as well as regulators of the pathway. This chapter introduces methods for dissection of animal caps and analyses of TGF-beta signaling effects on animal caps. PMID- 26520131 TI - Detection of Smad Signaling in Zebrafish Embryos. AB - Nodal and BMPs play critical roles in germ layer induction and patterning in early zebrafish embryos. Smad2/3 and Smad1/5/8 are intracellular effectors of Nodal and BMPs, respectively. These Smads regulate, in cooperation with other factors, transcription of hundreds of target genes in the nucleus. The activity and stability of Smads are regulated by phosphorylation modifications. To better understand the regulatory network of Smads-mediated signaling and its biological implications, it is necessary to monitor the signaling activity in an in vivo model system. In this chapter, we describe the methods used in zebrafish embryos for dissecting Smads signaling, including TGF-beta/Nodal- and BMP-responsive luciferase reporter assays, Western blotting for Smads, co-immunoprecipitation for Smads and their interacting proteins, chromatin-immunoprecipitation for identification of Smad2-binding sites, and immunostaining for detection of active Smad1/5/8. PMID- 26520132 TI - Role of TGF-beta Signaling in Coupling Bone Remodeling. AB - TGF-beta signaling plays a key role in the temporal and spatial regulation of bone remodeling. During osteoclast bone resorption, TGF-beta is released from the bone matrix and activated. Active TGF-beta recruits mesenchymal stem cells to the bone resorption pit through the SMAD signaling pathway. Mesenchymal stem cells undergo osteoblast differentiation and deposit new bone filling in the resorption pit and maintaining the structural integrity of the skeleton. Thus, TGF-beta signaling plays a key role in the coupling process and disruptions to the TGF beta signaling pathway lead to loss of skeletal integrity. This chapter describes methods on how to quantitate bone matrix TGF-beta and assess its role in mesenchymal stem cell migration both in vitro and in vivo. PMID- 26520133 TI - Studying the Functions of TGF-beta Signaling in the Ovary. AB - In mammals, ovulation is a multistep physiological process that includes preovulatory follicle growth, oocyte meiotic maturation, cumulus-oocyte complex (COC) expansion, follicle rupture, and luteinization. TGF-beta signaling pathway has multiple functions in mammalian ovary, as its complexity in ovarian function has been demonstrated by mouse models with knockouts of TGF-beta receptors and SMADs. We describe the protocol that we use to study functions of TGF-beta signaling pathway in follicle development and ovulation. Because total knockout of TGF-beta pathway components often causes embryonic lethality, which prevents further investigation of these genes in ovarian functions, people have generated ovarian cell type-specific knockout mouse strains for TGF-beta signaling pathway genes. These mouse models are also described. PMID- 26520134 TI - Quantitative Real-Time PCR Analysis of MicroRNAs and Their Precursors Regulated by TGF-beta Signaling. AB - The signaling pathway of TGF-beta and its family member BMP has been implicated in vascular development and maintenance of homeostasis by modulating expression of small noncoding microRNAs (miRNAs). MiRNAs repress target genes, which play a critical role in regulating vascular smooth muscle cell (VSMC) growth, phenotype, and function. To understand the mechanisms by which specific miRNAs control the TGF-beta and BMP signaling pathway in VSMC, it is essential to quantitate levels of specific miRNAs and their precursors whose expression are controlled by TGF beta/BMP signaling. Here, we describe a real-time quantization method for accurate and sensitive detection of miRNAs and their precursors, such as primary transcripts of miRNAs (pri-miRNAs) and precursor miRNAs (pre-miRNAs). This method requires two steps; synthesis of single-stranded complementary DNAs (cDNAs) from total RNA samples and quantization of specific pri-, pre-, or mature miRNAs by quantitative polymerase chain reaction (PCR) using a real-time PCR machine. PMID- 26520135 TI - TGF-beta-Regulated MicroRNAs and Their Function in Cancer Biology. AB - The transforming growth factor-beta (TGF-beta) is known to regulate a large number of biological processes and is involved in various aspects of tumor development. Recent studies have shown that the biogenesis of miRNAs can be regulated by TGF-beta signaling directly via Smad-dependent mechanisms and/or other unknown mechanisms, which may induce autoregulatory feedback loops in response to the activation of TGF-beta signaling, influencing the fate of tumor cells. In this chapter, we summarize the currently described mechanisms underlying TGF-beta's regulation of miRNA biogenesis, and the functional role of TGF-beta-regulated miRNAs in tumor initiation, epithelial-mesenchymal transition, and tumor microenvironment modulation. Finally, we introduce methods to study TGF beta-regulated miRNAs and their functions in tumor progression and metastasis using an example of publication from our lab demonstrating the presence of a TGF beta-miR-34a-CCL22 signaling axis, which serves as a potent etiological pathway for the development of hepatocellular carcinoma venous metastases. PMID- 26520136 TI - Epigenomic Regulation of Smad1 Signaling During Cellular Senescence Induced by Ras Activation. AB - Epigenomic modification plays important roles in regulating gene expression during development, differentiation, and cellular senescence. When oncogenes are activated, cells fall into stable growth arrest to block cellular proliferation, which is called oncogene-induced senescence. We recently identified through genome-wide analyses that Bmp2-Smad1 signal and its regulation by harmonized epigenomic alteration play an important role in Ras-induced senescence of mouse embryonic fibroblasts. We describe in this chapter the methods for analyses of epigenomic alteration and Smad1 targets on genome-wide scale. PMID- 26520137 TI - The Role of Ubiquitination to Determine Non-Smad Signaling Responses. AB - Ubiquitination is a posttranslational modification of proteins which acts as a key regulator of their function as well as fate. We have recently reported transforming growth factor beta (TGFbeta)-induced activation of non-Smad signaling responses through a specific Lys63-linked polyubiquitination of TGFbeta type I receptor and TGFbeta-associated kinase 1 (TAK1) that are utilized to specify cellular responses in cancer cells. This chapter gives a brief introduction of the biological importance of ubiquitination of proteins, the methods we have used for detecting new partners in the TGFbeta signaling pathway and for performing ubiquitination assays. PMID- 26520138 TI - Genome-Wide RNAi Screening to Dissect the TGF-beta Signal Transduction Pathway. AB - The transforming growth factor-beta (TGF-beta) family of cytokines figures prominently in regulation of embryonic development and adult tissue homeostasis from Drosophila to mammals. Genetic defects affecting TGF-beta signaling underlie developmental disorders and diseases such as cancer in human. Therefore, delineating the molecular mechanism by which TGF-beta regulates cell biology is critical for understanding normal biology and disease mechanisms. Forward genetic screens in model organisms and biochemical approaches in mammalian tissue culture were instrumental in initial characterization of the TGF-beta signal transduction pathway. With complete sequence information of the genomes and the advent of RNA interference (RNAi) technology, genome-wide RNAi screening emerged as a powerful functional genomics approach to systematically delineate molecular components of signal transduction pathways. Here, we describe a protocol for image-based whole genome RNAi screening aimed at identifying molecules required for TGF-beta signaling into the nucleus. Using this protocol we examined >90 % of annotated Drosophila open reading frames (ORF) individually and successfully uncovered several novel factors serving critical roles in the TGF-beta pathway. Thus cell based high-throughput functional genomics can uncover new mechanistic insights on signaling pathways beyond what the classical genetics had revealed. PMID- 26520139 TI - Measuring TGF-beta Ligand Dynamics in Culture Medium. AB - TGF-beta plays an important role in a myriad of cell activities including differentiation, proliferation, and growth arrest. These effects are influenced by the concentration of TGF-beta in the surrounding milieu, which is interpreted by mammalian cells and subsequently translated into meaningful signals that guide their proliferation, survival, or death. To predict cellular responses to TGF beta signaling based on molecular mechanisms, it is important to consider how cells respond to different ligand doses and how variations in ligand exposure impact Smad signaling dynamics and subsequent gene expression. Here we describe methods to measure TGF-beta concentration in the environment and approaches to perturb cellular TGF-beta exposure to gain a quantitative understanding of signaling dynamics of this pathway. PMID- 26520140 TI - Periodontal disease and chronic kidney disease among Aboriginal adults; an RCT. AB - BACKGROUND: This study will assess measures of vascular health and inflammation in Aboriginal Australian adults with chronic kidney disease (CKD), and determine if intensive periodontal intervention improves cardiovascular health, progression of renal disease and periodontal health over a 24-month follow-up. METHODS: The study will be a randomised controlled trial. All participants will receive the periodontal intervention benefits, with the delayed intervention group receiving periodontal treatment 24 months following baseline. Inclusion criteria include being an Aboriginal Australian, having CKD (a. on dialysis; b. eGFR levels of < 60 mls/min/1.73 m(2) (CKD Stages 3 to 5); c. ACR >= 30 mg/mmol irrespective of eGFR (CKD Stages 1 and 2); d. diabetes plus albuminuria (ACR >= 3 mg/mmol) irrespective of eGFR), having moderate or severe periodontal disease, having at least 12 teeth, and living in Central Australia for the 2-year study duration. The intervention involves intensive removal of dental plaque biofilms by scaling, root-planing and removal of teeth that cannot be saved. The intervention will occur in three visits; baseline, 3-month and 6-month follow-up. The primary outcome will be changes in carotid intima-media thickness (cIMT). Secondary outcomes will include progression of CKD or death as a consequence of CKD/cardiovascular disease. Progression of CKD will be defined by time to the development of the first of: (1) new development of macroalbuminuria; (2) 30 % loss of baseline eGFR; (3) progression to end stage kidney disease defined by eGFR < 15 mLs/min/1.73 m(2); (4) progression to end stage kidney disease defined by commencement of renal replacement therapy. A sample size of 472 is necessary to detect a difference in cIMT of 0.026 mm (SD 0.09) at the significance criterion of 0.05 and a power of 0.80. Allowing for 20 % attrition, 592 participants are necessary at baseline, rounded to 600 for convenience. DISCUSSION: This will be the first RCT evaluating the effect of periodontal therapy on progression of CKD and cardiovascular disease among Aboriginal patients with CKD. Demonstration of a significant attenuation of CKD progression and cardiovascular disease has the potential to inform clinicians of an important, new and widely available strategy for reducing CKD progression and cardiovascular disease for Australia's most disadvantaged population. TRIAL REGISTRATION: This trial is registered with the Australian New Zealand Clinical Trial Registry ANZCTR12614001183673. PMID- 26520141 TI - Investigation of the presence and antinociceptive function of muscarinic acetylcholine receptors in the African naked mole-rat (Heterocephalus glaber). AB - The present study investigated the cholinergic system in the African naked mole rat (Heterocephalus glaber) with focus on the muscarinic acetylcholine receptor subtypes M1 and M4. The protein sequences for the subtypes m 1-5 of the naked mole-rat were compared to that of the house mouse (Mus musculus) using basic local alignment search tool (BLAST). The presence and function of M1 and M4 was investigated in vivo, using the formalin test with the muscarinic receptor agonists xanomeline and VU0152100. Spinal cord tissue from the naked mole-rat was used for receptor saturation binding studies with [(3)H]-N-methylscopolamine. The BLAST test revealed 95 % protein sequence homology showing the naked mole-rat to have the genetic potential to express all five muscarinic acetylcholine receptor subtypes. A significant reduction in pain behavior was demonstrated after administration of 8.4 mg/kg in the formalin test. Administration of 50 mg/kg VU0152100 resulted in a non-significant tendency towards antinociception. The antinociceptive effects were reversed by the muscarinic acetylcholine receptor antagonist atropine. Binding studies indicated presence of muscarinic acetylcholine receptors with a radioligand affinity comparable to that reported in mice. In conclusion, muscarinic acetylcholine receptor subtypes are present in the naked mole-rat and contribute to antinociception in the naked mole-rat. PMID- 26520142 TI - Challenges and Opportunities in the Management of Cardiovascular Risk Factors in Youth With Type 1 Diabetes: Lifestyle and Beyond. AB - Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in persons with type 1 diabetes (T1D). Specific risk factors associated with diabetes, such as hyperglycemia and kidney disease, have been demonstrated to increase the incidence and progression of CVD. Nevertheless, few data exist on the effects of traditional risk factors such as dyslipidemia, obesity, and hypertension on CVD risk in youth with T1D. Improvements in understanding and approaches to the evaluation and management of CVD risk factors, specifically for young persons with T1D, are desirable. Recent advances in noninvasive techniques to detect early vascular damage, such as the evaluation of endothelial dysfunction and aortic or carotid intima-media thickness, provide new tools to evaluate the progression of CVD in childhood. In the present review, current CVD risk factor management, challenges, and potential therapeutic interventions in youth with T1D are described. PMID- 26520143 TI - Over-expression of Sirt1 contributes to chemoresistance and indicates poor prognosis in serous epithelial ovarian cancer (EOC). AB - Ovarian cancer is the most lethal malignancy in female patients, and chemoresistance is the major contribution to low over survival rate. We aim to investigate the correction between Sirt1 expression and chemoresistance in serous epithelial ovarian cancer (EOC) and prognosis significance of Sirt1. Immunochemistry was used to determine the location pattern and expression of Sirt1 in a total of 63 serous EOC patients (28 cases of chemoresistance patients and 35 chemosensitive).The relationship between Sirt1 expression and clinicopathological features of serous EOC was analyzed. Univariate analysis and multifactor logistic regression analysis were applied to investigate risk factor for chemoresistance. Cox proportional hazards regression model and Kaplan-Meier survival analysis were applied to determine the prognosis factor and survival time. Immunohistochemistry proved that over-expression of nuclear Sirt1 was related to chemoresistance (P = 0.039). Multivariate logistic regression analysis proved that the nuclear expression of Sirt1 (P = 0.018) and the lymph node metastasis (P = 0.037) was independent risk factors for chemoresistance in serous epithelial ovarian cancer. Multivariate Cox regression result indicated that expression of Sirt1 (P = 0.026, RR 2.434, 95 % CI 1.109-5.339) and stage (P = 0.005, RR 2.366, 95 % CI 1.288-4.345) was independent prognostic factors. Kaplan Meier analysis showed that the survival rate is significantly decreased in the Sirt1 highly expressed group. Western blot result showed that the protein level of Sirt1 was significantly higher in chemoresistant group compared with in sensitive group. In conclusion, our results proved that over-expression of Sirt1 could play an important role in chemoresistance of serous EOC and could be a prognosis indicator for the patient's survival outcome. PMID- 26520144 TI - Comparison of efficacy of neoadjuvant chemotherapy FEC 100 and Docetaxel 75 versus AC and Docetaxel in locally advanced breast cancer: a randomized clinical study. AB - The aim of the study was to assess and compare the clinical and pathological response and the toxicity profile between neoadjuvant chemotherapy FEC followed by docetaxel versus AC followed by docetaxel in locally advanced breast cancer patients. Between June 2013 and June 2014, 148 patients diagnosed with LABC were randomized into two groups with 74 in each group. Group 1 received AC (adriamycin 60 mg/m(2), cyclophosphamide 600 mg/m(2)) followed by docetaxel 100 mg/m(2) with primary GCSF prophylaxis and group 2 received FEC (5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), cyclophosphamide 500 mg/m(2)) followed by docetaxel 75 mg/m(2). MRM/BCS was performed for all patients after NACT and assessed for pathological response. Toxicity profile was assessed according to CTCAE version 4. All baseline parameters were equally matched between the two regimens. 90 % of patients completed NACT and underwent surgery. pCR rates were 31 % in group 1 and 34 % in group 2 without any difference. Any grade of hand-foot syndrome was significantly high in group 1 as compared to group 2. Grade 3 and grade 4 neutropenia and febrile neutropenia were significantly high in group 1 as compared to group 2. Median follow-up was 13.7 months (range, 2.9-25 months). There was no difference in the 2-year PFS between group 1 and group 2 (70.9 vs. 73.8 %, respectively) and OS (87.8 vs. 91.8 %, respectively) in our study population. Chemotherapy with FEC followed by docetaxel can be considered as an optimal neoadjuvant regimen in LABC as compared to AC followed by docetaxel. PMID- 26520145 TI - Atypical Neural Activity in Males But Not Females with Autism Spectrum Disorder. AB - The medial prefrontal cortex (mPFC) and the right temporo-parietal junction (rTPj) are highly involved in social understanding, a core area of impairment in autism spectrum disorder (ASD). We used fMRI to investigate sex differences in the neural correlates of social understanding in 27 high-functioning adults with ASD and 23 matched controls. There were no differences in neural activity in the mPFC or rTPj between groups during social processing. Whole brain analysis revealed decreased activity in the posterior superior temporal sulcus in males with ASD compared to control males while processing social information. This pattern was not observed in the female sub-sample. The current study indicates that sex mediates the neurobiology of ASD, particularly with respect to processing social information. PMID- 26520146 TI - Age-Related Differences in Response to Music-Evoked Emotion Among Children and Adolescents with Autism Spectrum Disorders. AB - While research regarding emotion recognition in ASD has focused primarily on social cues, musical stimuli also elicit strong emotional responses. This study extends and expands the few previous studies of response to music in ASD, measuring both psychophysiological and behavioral responses in younger children (ages 8-11) as well as older adolescents (ages 16-18). Compared to controls, the ASD group demonstrated reduced skin conductance response to music-evoked emotion. Younger groups, regardless of diagnosis, showed greater physiological reactivity to scary stimuli than to other emotions. There was a significant interaction of age group and diagnostic group in identifying scary music stimuli, possibly evidencing disrupted developmental trajectories in ASD for integrating physiological and cognitive cues that may underlie symptoms of anxiety. PMID- 26520147 TI - Altered Gesture and Speech Production in ASD Detract from In-Person Communicative Quality. AB - This study disentangled the influences of language and social processing on communication in autism spectrum disorder (ASD) by examining whether gesture and speech production differs as a function of social context. The results indicate that, unlike other adolescents, adolescents with ASD did not increase their coherency and engagement in the presence of a visible listener, and that greater coherency and engagement were related to lesser social and communicative impairments. Additionally, the results indicated that adolescents with ASD produced sparser speech and fewer gestures conveying supplementary information, and that both of these effects increased in the presence of a visible listener. Together, these findings suggest that interpersonal communication deficits in ASD are driven more strongly by social processing than language processing. PMID- 26520148 TI - Improving Empathic Communication Skills in Adults with Autism Spectrum Disorder. AB - The literature suggests that many individuals diagnosed with Autism Spectrum Disorder (ASD) experience challenges with recognizing and describing emotions in others, which may result in difficulties with the verbal expression of empathy during communication. Thus, there is a need for intervention techniques targeting this area. Using a multiple baseline across participants design, this study examined the effectiveness of a video-feedback intervention with a visual framework component to improve verbal empathetic statements and questions during conversation for adults with ASD. Following intervention, all participants improved in verbal expression of empathetic statements and empathetic questions during conversation with generalization and maintenance of gains. Furthermore, supplemental assessments indicated that each participant improved in their general level of empathy and confidence in communication skills. PMID- 26520149 TI - Brief Report: Non-right-Handedness Within the Autism Spectrum Disorder. AB - A larger distribution of left-handedness in the population of Autism Spectrum Disorder has been repeatedly reported. Despite of this, the sample sizes in the individual study's are too small for any generalization to be made. Using both description-based and citation-based searches, the present review combines the individual results in order to examine whether non-right-handedness is a general trait of the autism spectrum disorder. With a relatively large combined sample size (N = 497), it can be concluded that the distribution of non-right-handedness is significantly greater within the autism spectrum disorder population, compared with the population in general. PMID- 26520151 TI - Four Ways to Oligonucleotides Without Phosphoimidazolides. AB - Emergence of the very first RNA or RNA-like oligomers from simple nucleotide precursors is one of the most intriguing questions of the origin of life research. In the current paper, we analyse the mechanism of four non-enzymatic template-free scenarios suggested for the oligomerization of chemically non modified cyclic and acyclic nucleotides in the literature. We show that amines may have a twofold role in these syntheses: due to their high affinity to bind protons they may activate the phosphorus of the phosphate group via proton transfer reactions, or indirectly they may serve as charge compensating species and influence the self-assembling of nucleotides to supramolecular architectures compatible with the oligomerization reactions. Effect of cations and pH on the reactions is also discussed. PMID- 26520150 TI - A study on beta-defensin-2 and histatin-5 as a diagnostic marker of early childhood caries progression. AB - BACKGROUND: Recently, a continuous growth of interest has been observed in antimicrobial peptides (AMPs) in the light of an alarming increase in resistance of bacteria and fungi against antibiotics. AMPs are used as biomarkers in diagnosis and monitoring of oral cavity pathologies. Therefore, the determination of specific protein profiles in children diagnosed with early childhood caries (ECC) might be a basis for effective screening tests and specialized examinations which may enable progression of disease. METHODS: The objective of the studies was to determine the role of histatin-5 and beta-defensing-2 as a diagnostic marker of early childhood caries progression. In this work, results of concentration determination of two salivary proteins (histatin-5 and beta defensin-2) were presented. In addition, bacterial profiles from dental plaque in various stages of ECC and control were marked. The assessment of alteration in the concentration of these two proteins in a study group of children with various stages of ECC and a control group consisting of children with no symptoms was performed by enzyme-linked immunosorbent assays. RESULTS: The statistical analysis showed a significant increase in the concentration of histatin-5 and beta-defensin-2 in the study group compared to the control group and correlated with the progression of the disease. CONCLUSIONS: The confirmation of concentration changes in these proteins during the progression of dental caries may discover valuable disease progression biomarkers. PMID- 26520152 TI - Provider Opinions Regarding the Development of a Stigma-Reduction Intervention Tailored for Providers. AB - Interventions involving contact with a person who has recovered from mental illness are most effective at reducing stigma. This study sought input from health care providers to inform the design of a contact intervention intended to reduce provider stigma toward persons with serious mental illness. Using a purposive sampling strategy, data were collected from providers at five Veterans Affairs hospitals in the southeastern United States. Seven focus groups were conducted, and 83 health care providers participated. A semistructured interview guide was used to elicit providers' opinions about the target group of a contact intervention for providers, what providers would consider a credible contact, the preferred format for delivery, the usefulness of potentially tailoring the intervention to a specific facility, and how to measure change in clinical behaviors. Focus group data were analyzed using rapid data analysis techniques. Participants uniformly recommended a broad target audience for the stigma reduction intervention, including all primary care and specialist providers. They suggested that the person providing the "lived experience" for the contact intervention should be either a health care provider or a patient with serious mental illness. Face-to-face presentation was favored, but video presentation was considered more feasible. Participants stated that information about local disparities in care rendered to patients with or without mental illness would convince providers of how stigma may be a contributing factor to these disparities. Multiple training opportunities were favored, while mandatory training was disliked. Standard stigma-reduction interventions with subgroups of the general public (e.g., providers) may need to be modified for optimum subgroup effectiveness. PMID- 26520153 TI - Pediatric Return Appointment Adherence for Child Welfare-Involved Children in Los Angeles California. AB - OBJECTIVES: This study of primarily Latino caregivers and Latino child welfare involved children had the following aims: (1) explore the return appointment adherence patterns at a pediatric medical clinic; and (2) determine the relationship of adherence to return appointments and caregiver, child, and clinic variables. METHODS: The sample consisted of caregivers of child welfare-involved children who were asked to make a pediatric outpatient clinic return appointment (N = 87). Predictors included caregiver demographics, child medical diagnoses and age, and clinic/convenience factors including distance from the clinic to caregiver's home, days until the return appointment, reminder telephone call, Latino provider, and additional specialty appointment. Predictors were examined using chi(2) and t tests of significance. RESULTS: Thirty-nine percent of all caregivers were nonadherent in returning for pediatric appointments. When return appointments were scheduled longer after the initial appointment, caregivers were less likely to bring children back for medical care. CONCLUSIONS: The 39 % missed return appointment rate in this study is higher than other similar pediatric populations. Better coordination between pediatricians and caregivers in partnership with child welfare case workers is needed to ensure consistent follow up regarding health problems, especially when appointments are not scheduled soon after the initial appointment. PMID- 26520154 TI - Association Between Maternal Postpartum Depression and Unintentional Injury Among 4-Month-Old Infants in Japan. AB - OBJECTIVES: Unintentional injury among infants is a major public health issue; however, the relationship between unintentional infant injury and postpartum depression remains unclear. In this study, we aim to investigate the association between the two. METHODS: We administered an original questionnaire to mothers participating in a 3- or 4-month health check-up program (target n = 9707). This questionnaire assessed infant health, including types of unintentional injury experiences used in previous study, and maternal mental health such as postpartum depression, by the validated screening tool, the Edinburgh Postnatal Depression Scale (EPDS). Associations between infant injury and postpartum depression were assessed using logistic regression adjusted for covariates, including parental, infant, and household characteristics. RESULTS: In total, 6534 women responded to the questionnaire with valid answers on the EPDS (valid response rate, 67 %). Of the sample, 9.8 % of infants experienced unintentional injury (fall: 5.6 %; near drowning: 1.2 %), and 9.5 % of mothers had postpartum depression (EPDS score of 9+). After adjusting for covariates, postpartum depression was significantly positively associated with any unintentional injury (odds ratio [OR] 1.59, 95 % confidence interval [CI] 1.24-2.04), and falls (OR 1.41, 95 % CI 1.02-1.95), although near-drowning was not significantly associated. CONCLUSION: Postpartum depression might be a risk factor for unintentional injury of infants aged up to 4 months. Further prospective studies are needed to confirm the association between postpartum depression and unintentional injury of infants. PMID- 26520155 TI - Factors Influencing Exclusive Breastfeeding in Early Infancy: A Prospective Study in North Central Nigeria. AB - PURPOSE: To determine the association between prenatal exclusive breastfeeding intentions and exclusive breastfeeding (EBF) and explore other factors associated with EBF until 3 months postpartum among mothers residing in suburban parts of the Federal Capital Territory, Abuja Nigeria. DESCRIPTION: This longitudinal observational study involved the recruitment of 210 pregnant women who were prospectively followed until 3 months postpartum. Participants were recruited from antenatal clinics attached to four separate public secondary health facilities located in the suburban parts of Abuja. Cox regression hazards model was used to determine the risk of EBF cessation at 3 months postpartum. ASSESSMENT: Over 70.0 % of women had strong intention to exclusively breastfeed. The risk of exclusive breastfeeding cessation was significantly lower in women with strong exclusive breastfeeding intentions (HR 0.87, 95 % CI 0.8-0.95). Other risk factors for cessation of exclusive breastfeeding were pre-lacteal feed administration (HR 2.93 95 % CI 1.49-5.77) and mode of delivery (HR 0.17 95 % CI 0.04-0.67). Higher maternal age (>=35 years), religion (Muslim) and having an unplanned pregnancy lowered the likelihood of having a strong intention to exclusively breastfeed an infant. CONCLUSIONS: Prenatal exclusive breastfeeding intention was a strong predictor of exclusive breastfeeding. Intentions to EBF were further explained by maternal characteristics. Effective promotion of exclusive breastfeeding during prenatal period should also target factors influencing breastfeeding intentions. Additional research is warranted into the influence of maternal attitudes and self-efficacy about breastfeeding on breastfeeding intentions and practice. PMID- 26520156 TI - Maternal Alcohol Consumption During the Perinatal and Early Parenting Period: A Longitudinal Analysis. AB - OBJECTIVES: Despite potential health risks for women and children, one in five women report alcohol use during pregnancy and a significant proportion of those who quit during pregnancy return to drinking post-delivery. This study seeks to understand the longitudinal patterns of alcohol consumption before, during pregnancy and post-delivery, and the role of maternal characteristics for purposes of informing prevention design. METHODS: General growth mixture models were used to describe the average developmental patterns of maternal weekly drinking quantity at six time points, from preconception through child entering kindergarten, as well as heterogeneity in these patterns among 9100 mothers from the Early Childhood Longitudinal Study representing the 2001 US national birth cohort. RESULTS: Four distinct classes of mothers were defined by their longitudinal alcohol consumption patterns: Low Probability Drinkers (50.3 %), Escalating Risk Drinkers (12.0 %), Escalating Low Risk Drinkers (27.4 %), and Early Parenting Quitters (10.2 %). Heterogeneous covariate associations were observed. For example, mothers who gave birth after age 36 were twice as likely to be Escalating Risk Drinkers and Escalating Low Risk Drinkers (vs Low Probability Drinkers), but not more likely to be Early Parenting Quitters, when compared to mothers who gave birth between the ages of 26 and 35. CONCLUSIONS FOR PRACTICE: There is significant heterogeneity in maternal longitudinal alcohol use patterns during the perinatal period. Baseline maternal characteristics and behavior associated with these heterogeneous patterns provide valuable tools to identify potential risky drinkers during this critical time period and may be synthesized to tailor pre- and postnatal clinical counseling protocols. PMID- 26520157 TI - State Medicaid Eligibility Criteria and Unmet Preventive Dental Care Need for CSHCN. AB - OBJECTIVE: To determine if Medicaid eligibility is associated with unmet preventive dental care need for Medicaid-enrolled CSHCN. METHODS: We analyzed the 2009-2010 National Survey of CSHCN and focused on Medicaid-enrolled children ages 3-17. The outcome measure was parent-reported unmet need for preventive dental care. The predictor variable was state Medicaid eligibility criteria, categorized as broad [>250 % Federal Poverty Level (FPL)], moderate (200-249 % FPL), and narrow (<200 % FPL). Multiple variable multilevel logistic regression models estimated the association between state-level eligibility criteria and variability in unmet need. RESULTS: The multilevel models indicated no significant association between Medicaid eligibility criteria and unmet preventive dental care need. CSHCN with more severe chronic health conditions had significantly greater odds of unmet need (OR 1.52; 95 % CI 1.28, 1.82) and CSHCN with a medical home had significantly lower odds (OR 0.61; 95 % CI 0.50, 0.75). CONCLUSIONS FOR PRACTICE: There is significant state variability in unmet need for preventive dental care for Medicaid-enrolled CSHCN. Broadening Medicaid eligibility criteria alone is not likely to address the preventive dental care needs of CSHCN, which has policy implications for improving oral health disparities for publicly-insured CSHCN. PMID- 26520158 TI - Reach Out and Read is Feasible and Effective for Adolescent Mothers: A Pilot Study. AB - OBJECTIVES: The Reach Out and Read program (ROaR) is associated with increased parent-child book reading and improved language development in children. Though children of adolescent parents may have an elevated risk of language delay, ROaR has never been specifically studied among adolescent-headed families. This pilot evaluated the feasibility and effectiveness of ROaR among adolescent mothers and their children. METHODS: This randomized controlled pilot followed thirty adolescent mothers with children aged 6-20 months in a teen-tot clinic in downtown Toronto. At each of three consecutive well child checkups, intervention families received a new children's book, reading-related anticipatory guidance customized to the mother's developmental stage, counselling from a librarian, and a public library card. Control families received routine care. At baseline and study completion, all mothers completed a survey on family reading patterns and the Beck Depression Inventory-Revised (BDI-IA). RESULTS: Though regression models were not statistically significant, bivariate analyses at study completion revealed that intervention mothers were significantly more likely than controls to report reading as one of the child's favorite activities (29 vs 0 %) and had significantly lower maternal depression scores (7.0 vs 12.5; >=10 = clinically significant depression). Trends for all other variables, including time spent reading together and maternal enjoyment of reading, were also in the direction of benefit. This program was implemented at minimal cost and adopted permanently following study completion. CONCLUSIONS: This feasible and developmentally appropriate intervention shows promise in promoting shared book reading and reducing maternal depression within adolescent-headed families, warranting investigation with larger trials. PMID- 26520159 TI - Hepatitis C Seroprevalence Among HIV-Infected Childbearing Women in New York State in 2006. AB - OBJECTIVE: To identify factors associated with maternal hepatitis C virus (HCV) seroprevalence and transmission of HCV as identified by qualitative HCV ribonucleic acid (RNA) in the infants of human immunodeficiency virus (HIV) infected women delivering in New York State (NYS) in 2006. STUDY DESIGN: In this retrospective cohort study of HIV-exposed infants born in NYS, leftover infant plasma from HIV diagnostic testing was de-identified and tested for HCV. If HCV antibodies were detected, a second specimen collected when the infant was >2 months old was tested for HCV qualitative RNA. Multivariate logistic regression was used to identify factors associated with HCV seropositivity. RESULTS: In a final sample of 553 live birth events with perinatal HIV exposure, 21 (3.8 %) of tested infant specimens had HCV antibodies indicative of maternal HCV seropositivity. Maternal age at delivery of >35 years, Hispanic ethnicity, white race and injection drug use (IDU) were significantly associated with HCV seropositivity in multivariate analysis. No cases of HCV vertical transmission were identified among HCV exposed infant specimens. CONCLUSIONS: This statewide population-based study of HIV-infected childbearing women shows HCV seroprevalence of 3.8 %. Maternal age of >35 years and IDU are the strongest predictors of HCV seropositivity. Although no viral transmission was documented, more comprehensive longitudinal testing would be required to conclude that HCV transmission did not occur. PMID- 26520160 TI - Employing a Multi-level Approach to Recruit a Representative Sample of Women with Recent Gestational Diabetes Mellitus into a Randomized Lifestyle Intervention Trial. AB - OBJECTIVE: The postpartum period is a window of opportunity for diabetes prevention in women with recent gestational diabetes (GDM), but recruitment for clinical trials during this period of life is a major challenge. METHODS: We adapted a social-ecologic model to develop a multi-level recruitment strategy at the macro (high or institutional level), meso (mid or provider level), and micro (individual) levels. Our goal was to recruit 100 women with recent GDM into the Balance after Baby randomized controlled trial over a 17-month period. Participants were asked to attend three in-person study visits at 6 weeks, 6, and 12 months postpartum. They were randomized into a control arm or a web-based intervention arm at the end of the baseline visit at six weeks postpartum. At the end of the recruitment period, we compared population characteristics of our enrolled subjects to the entire population of women with GDM delivering at Brigham and Women's Hospital (BWH). RESULTS: We successfully recruited 107 of 156 (69 %) women assessed for eligibility, with the majority (92) recruited during pregnancy at a mean 30 (SD +/- 5) weeks of gestation, and 15 recruited postpartum, at a mean 2 (SD +/- 3) weeks postpartum. 78 subjects attended the initial baseline visit, and 75 subjects were randomized into the trial at a mean 7 (SD +/- 2) weeks postpartum. The recruited subjects were similar in age and race/ethnicity to the total population of 538 GDM deliveries at BWH over the 17 month recruitment period. CONCLUSIONS: Our multilevel approach allowed us to successfully meet our recruitment goal and recruit a representative sample of women with recent GDM. We believe that our most successful strategies included using a dedicated in-person recruiter, integrating recruitment into clinical flow, allowing for flexibility in recruitment, minimizing barriers to participation, and using an opt-out strategy with providers. Although the majority of women were recruited while pregnant, women recruited in the early postpartum period were more likely to present for the first study visit. Given the increased challenges of recruiting postpartum women with GDM into research studies, we believe our findings will be useful to other investigators seeking to study this population. PMID- 26520161 TI - Do Children with Autism Overutilize the Emergency Department? Examining Visit Urgency and Subsequent Hospital Admissions. AB - BACKGROUND: Children with autism spectrum disorders (ASD) are more likely to have difficulties accessing health care compared to other children with special health care needs. National data based on parent report indicate that children with ASD are overutilizing emergency department (ED) services, but data on actual ED use has been limited to children with psychiatric diagnoses. This study examined factors associated with ED utilization (rate, urgency, and hospital admissions) among children with ASD compared to those without ASD. METHODS: Data from an urban, tertiary children's hospital level 1 trauma center were examined retrospectively 2006-2009. Anderson's model of health services utilization served as the study framework. The NYU ED algorithm was used to predict nonurgent visits. Multivariate linear and logistic regression analyses were performed on the rate, urgency, and subsequent hospital admissions of these ED visits. RESULTS: There were 115,443 children 2-21 years old, accounting for a total of 157,902 visits. The top three reasons for visiting the ED for children with and without ASD were acute upper respiratory infections, viral infections and otitis media. Children with ASD had on average 0.26 more ED visits annually than children without ASD (p < 0.01) and were 2.6 % points more likely to have nonurgent visits; p < 0.01). Their visits were also less likely to result in hospital admissions (OR 0. 61; p < 0.01). CONCLUSIONS: Examination of predisposing, enabling, and reinforcing factors suggest that children with ASD were more likely to visit the ED and for nonurgent reasons. PMID- 26520163 TI - Impact of New Treatments on Hospitalisation, Surgery, Infection, and Mortality in IBD: a Focus Paper by the Epidemiology Committee of ECCO. AB - The medical management of inflammatory bowel disease has changed considerably over time with wider use of immunosuppressant therapy and the introduction of biological therapy. To what extent this change of medical paradigms has influenced and modified the disease course is incompletely known. To address this issue, an extensive review of the literature has been carried out on time trends of hospitalization, surgery, infections, cancer, and mortality rates in inflammatory bowel disease [IBD] patients. Preference was given to population based studies but, when data from these sources were limited, large cohort studies and randomised controlled trials were also considered. In general, data on hospitalisation rates are strikingly heterogeneous and conflicting. In contrast, the consistent drop in surgery/colectomy rates suggests that the growing use of immunosuppressants and biological agents has had a positive impact on the course of IBD. Most clinical trial data indicate that the risk of serious infections is not increased in patients treated with anti-tumour necrosis factor alpha [TNFalpha] agents, but a different picture emerges from cohort studies. The use of thiopurines increases the risk for non-melanoma skin cancers and to a lesser extent for lymphoma and cervical cancer [absolute risk: low], whereas no clear increase in the cancer risk has been reported for anti-TNF agents. Finally, the majority of studies reported in the literature do not reveal any increase in mortality with immunosuppressant therapy or biologicals/anti-TNF agents. PMID- 26520162 TI - The Temporal Evolution of Histological Abnormalities in Microscopic Colitis. AB - BACKGROUND AND AIMS: Microscopic colitis (MC) is a common cause of chronic watery diarrhoea but long-term follow-up data are sparse. METHODS: We performed a retrospective review of health records and all pathology reports in a regional cohort of patients with MC to describe the change in pre- and post-diagnostic colon biopsies. RESULTS: MC was diagnosed in 468 patients with collagenous colitis (CC), 361 with lymphocytic colitis (LC) and 226 with incomplete MC (MCi). The 2014 incidence of CC, LC and MCi was 14.5, 14.9 and 5 per 10(5). Biopsies from both right and left colon were obtained in 237 (51%) patients with CC, 200 (55%) with LC and 107 (47%) with MCi. The diagnostic sensitivities of both left- and right-sided biopsies for MC were high and did not differ. Pre-diagnostic biopsies were obtained in 150 patients and lamina propria inflammation was described in 59, 47 and 43% of patients with a diagnosis of CC, LC and MCi respectively within 1 year, while histology was normal in 16, 13 and 21%. Post diagnostic biopsies were obtained in 283 patients. MC persisted for up to one year in 77% with CC, 64% with LC and 45% with MCi, of whom 6, 9 and 18% respectively changed to a different MC subgroup. CONCLUSIONS: Colonic biopsies obtained prior to the MC diagnosis often revealed increased lamina propria inflammation. The pathological changes of CC and LC are more persistent than those of MCi. Biopsies from the descending or sigmoid colon are sufficient to elucidate whether a patient with chronic watery diarrhoea has MC. PMID- 26520164 TI - Timing of Thiopurine or Anti-TNF Initiation Is Associated with the Risk of Major Abdominal Surgery in Crohn's Disease: A Retrospective Cohort Study. AB - INTRODUCTION: Early stages of Crohn's disease [CD] are predominantly inflammatory and early treatment could be useful to change the natural history of CD. We aimed to evaluate the impact of early treatment in our cohort of CD patients. METHODS: We retrospectively reviewed clinical records of all CD patients at our centre who have received immunomodulators. Time from diagnosis to first CD-related major abdominal surgery or end of follow-up was considered. Dates of diagnosis, of starting immunomodulators (thiopurines / anti-tumour necrosis factor [TNF]), and of the first CD-related surgery when appropriate were collected. RESULTS: Of 422 patients who received thiopurines, 189 operated patients started thiopurines after a median of 117 months (interquartile range [IQR] 44-196) since diagnosis; non-operated patients, after a median of 30 months [IQR 6-128], p < 0,005. Odds ratio [OR] for surgery was 1.006 (95% confidence interval [CI]1.004-1008) for each month of delay in starting thiopurines. Among 272 patients who received anti TNFs, 137 operated patients started anti-TNFs after a median of 166 months [IQR 90-233] since diagnosis; non-operated patients after a median of 59 months [IQR 14-162]; p < 0,005. OR for surgery was 1.008 [95% CI 1.005-1.010] for each month of delay in starting anti-TNFs. Among 467 patients who received thiopurines and/or anti-TNF, 210 operated patients started any immunomodulator after a median of 120 months [IQR 48-197] since diagnosis and non-operated patients after a median of 30 months [IQR 6-126], p < 0,005. OR for surgery was 1.008 [95% CI 1.005-1.010] for each month of delay in starting immunomodulators. CONCLUSIONS: In our experience, time between diagnosis and thiopurine or anti-TNF initiation was associated with the risk of major abdominal surgery in Crohn's disease. PMID- 26520165 TI - An energy-saving nonlinear position control strategy for electro-hydraulic servo systems. AB - The electro-hydraulic servo system (EHSS) demonstrates numerous advantages in size and performance compared to other actuation methods. Oftentimes, its utilization in industrial and machinery settings is limited by its inferior efficiency. In this paper, a nonlinear backstepping control algorithm with an energy-saving approach is proposed for position control in the EHSS. To achieve improved efficiency, two control valves including a proportional directional valve (PDV) and a proportional relief valve (PRV) are used to achieve the control objectives. To design the control algorithm, the state space model equations of the system are transformed to their normal form and the control law through the PDV is designed using a backstepping approach for position tracking. Then, another nonlinear set of laws is derived to achieve energy-saving through the PRV input. This control design method, based on the normal form representation, imposes internal dynamics on the closed-loop system. The stability of the internal dynamics is analyzed in special cases of operation. Experimental results verify that both tracking and energy-saving objectives are satisfied for the closed-loop system. PMID- 26520166 TI - Abnormal repolarization dynamics in a patient with KCNE1(G38S) who presented with torsades de pointes. AB - Risk of G38S, major KCNE1 polymorphism [KCNE1(G38S)], for long QT syndrome (LQTS) remains unclear. A 72-year-old woman was admitted with recurrent torsades de pointes (TdP). She had remarkable QT prolongation (corrected QT interval 568 ms) under conditions of hypokalemia and hypomagnesemia. After correction of this electrolytic imbalance, TdP was suppressed and metoprolol was started. The QT-RR slope in 24-hour Holter electrocardiogram was steep and this enhanced bradycardia dependent QT prolongation was similar to that in LQTS. She carried KCNE1(G38S). Patients with KCNE1(G38S) could have similar potential risk of ventricular arrhythmia as with LQTS. Analysis of QT-RR relationship could also evaluate the latent arrhythmogenicity of KCNE1(G38S). PMID- 26520167 TI - Cannabis induced asystole. AB - Cannabis or marijuana is the most used recreational, and until recently illegal, drug in the United States. Although cannabis has medicinal use, its consumption has been linked to motor vehicle accidents in dose dependent fashion. Marijuana and other cannabinoids produce a multitude of effects on the human body that may result in these motor vehicle accidents. Some of the effects that marijuana has been known to cause include altered sensorium, diminished reflexes, and increased vagal tone. We present a case of cannabis induced asystole from hypervagotonia. PMID- 26520168 TI - Validation of continuous QTc measurement in critically ill patients. AB - INTRODUCTION: Prolongation of the corrected QT interval (QTc) can lead to torsades de pointes. This study is designed to determine the validity of the continuous QTc (cQTc) measurement in critically ill patients. METHODS: In a retrospective cohort study, QTc analysis was performed with manual measurements on a single selected lead from a 12-lead ECG and cQTc measurement obtained at the same time. In addition, automated QTc measurement from the 12-lead ECG was also included in the study. Validation was performed by calculating intraclass correlation coefficient (ICC), Pearson's correlation and Bland-Altman plot. RESULTS: 119 patients with QRS<120 ms were included with a mean cQTc of 468 ms (standard deviation (SD) 37) and mean manually measured QTc of 449 ms (SD 41) (p<0.001). Pearson's correlation was 0.65 (p<0.01), ICC was 0.65 (95% CI: 0.53 0.74). Bland-Altman plot shows a mean difference of 19.5 ms (limits of agreement (LOA) -44.6 to 83.7). For cQTc compared to automated QTc from the 12-lead ECG the intraclass correlation coefficient was 0.77 (95% CI: 0.68-0.83, p<0.001) and the Bland-Altman plot shows a mean difference of 7.8 ms (LOA -40.2 to 55.8). CONCLUSION: cQTc measurement in critically ill patients with a QRS duration shorter than 120 ms shows an acceptable accuracy to be used in routine care. PMID- 26520169 TI - Effect of Vitreomacular Adhesion on Treatment Outcomes in the Ranibizumab for Edema of the Macula in Diabetes (READ-3) Study. AB - PURPOSE: To assess the role of vitreomacular adhesion (VMA) in visual and anatomic outcomes in patients with diabetic macular edema (DME). DESIGN: Retrospective cohort study. PARTICIPANTS: Data from patients enrolled in the Ranibizumab for Edema of the Macula in Diabetes: Protocol 3 with High Dose (READ 3) study were analyzed. METHODS: In the READ-3 study, patients with DME received monthly intravitreal injections of either 0.5 or 2.0 mg ranibizumab. Optical coherence tomography images from patients who completed the month 6 visit of the study were analyzed at the baseline visit to identify the presence (VMA+) or absence (VMA-) of VMA. Patients with any degree of vitreomacular traction were excluded from the analysis. Two independent graders graded all images. Vitreomacular adhesion was classified by size of adhesion into either focal (<1500 MUm) or broad (>=1500 MUm). MAIN OUTCOME MEASURES: Mean changes in best corrected visual acuity (BCVA) and central retinal thickness (CRT) at month 6 and incidence of posterior vitreous detachment (PVD). RESULTS: One hundred fifty-two eyes (152 patients) were randomized in the READ-3 study. One hundred twenty-four eyes (124 patients) were eligible for the study based on study criteria. Twenty eight eyes did not meet study criteria and were excluded from the study. At baseline, 26 patients were classified as VMA+ and 98 patients were classified as VMA-. The distribution of the 2 doses of ranibizumab (0.5 and 2.0 mg) in the 2 groups was similar. At month 6, the mean improvement in BCVA was 11.31+/-6.67 and 6.86+/-7.58 letters in the VMA+ and VMA- groups, respectively (P = 0.007). Mean improvement in CRT was -173.81+/-132.31 and -161.84+/-131.34 MUm in the VMA+ and VMA- groups, respectively (P = 0.681). At month 6, among the 26 VMA+ eyes (at baseline), 7 eyes demonstrated PVD, 17 eyes showed no change in VMA status, and 2 eyes were not gradable and were excluded. CONCLUSIONS: Diabetic macular edema patients with VMA have a greater potential for improvement in visual outcomes with anti-vascular endothelial growth factor therapy. Therefore, the presence of VMA should not preclude patients with DME from receiving treatment. PMID- 26520170 TI - Periocular Skin Cancer in Solid Organ Transplant Recipients. AB - PURPOSE: To determine the proportion of solid organ transplant recipients developing periocular nonmelanoma skin cancer and to describe the morbidity of these cancers in transplant recipients. DESIGN: Cohort study. PARTICIPANTS: Consecutive patients undergoing solid organ transplantation at the Cleveland Clinic between 1990 and 2008. METHODS: The charts of all patients receiving a solid organ transplant from 1990-2008 evaluated in the dermatology department for a subsequent biopsy-proven head and neck malignancy through April 2015 were reviewed. Patients with a periocular region nonmelanoma skin cancer (NMSC) or a nonperiocular NMSC causing a complication requiring eyelid surgery were included. Charts were reviewed for demographic data; transplant date, type, and source; immunosuppressive agents received at diagnosis; and type of NMSC, number of nonperiocular NMSCs, ophthalmologic findings, and periocular sequelae after the repair. MAIN OUTCOME MEASURES: Primary outcome measures included the type, location, final defect size, tumor-node-metastasis classification, presence of perineural invasion, and reconstruction technique(s) used for each periocular NMSC. Secondary outcome measures included the type and treatment of ocular sequelae due to nonperiocular facial NMSC. RESULTS: A total of 3489 patients underwent solid organ transplantation between 1990 and 2008. Of these, 420 patients were evaluated in the dermatology clinic for biopsy-proven NMSC of the head and neck during the study period, and 11 patients (15 malignancies) met inclusion criteria. Nine patients developed 12 periocular malignancies and 3 patients required eyelid surgery for facial malignancies outside the periocular zone. All 11 patients developed a squamous cell carcinoma (14 malignancies), and 1 patient (1 malignancy) also developed a periocular basal cell carcinoma. There was orbital invasion in 4 cases and paranasal and/or cavernous sinus invasion in 3 cases. Two patients underwent exenteration. Seven cases required reconstruction with a free flap or graft. Periocular sequelae included lower eyelid ectropion (6 malignancies), dry eye and/or exposure symptoms (8 malignancies), unilateral vision loss (3 malignancies), and facial nerve paresis (5 malignancies). CONCLUSIONS: Squamous cell carcinoma affecting the periocular region represents a risk of solid organ transplantation and may produce significant ocular morbidity, including the need for major eyelid reconstruction, globe loss, and disfiguring surgery. PMID- 26520172 TI - [Guidelines for clinical practice: Post-partum--Method and organization]. PMID- 26520171 TI - Topical Fluorometholone Protects the Ocular Surface of Dry Eye Patients from Desiccating Stress: A Randomized Controlled Clinical Trial. AB - PURPOSE: To assess the efficacy of topical 0.1% fluorometholone in dry eye disease (DED) patients for ameliorating the worsening of the ocular surface when exposed to adverse environments. DESIGN: Single-center, double-masked, randomized, vehicle-controlled clinical trial. PARTICIPANTS: Forty-one patients showing moderate to severe DED. METHODS: Patients randomly received 1 drop 4 times daily of either topical 0.1% fluorometholone (FML group) or topical polyvinyl alcohol (PA group) for 22 days. Corneal and conjunctival staining, conjunctival hyperemia, tear film breakup time (TBUT), tear osmolarity, and the Symptom Assessment in Dry Eye (SANDE) questionnaire scores were determined at baseline. Variables were reassessed on day 21 before and after undergoing a 2 hour controlled adverse environment exposure and again on day 22. MAIN OUTCOMES MEASURES: Percentage of patients showing an increase 1 point or more in corneal staining and a reduction of 2 points or more (0-10 scale) in SANDE score, after the controlled adverse environment exposure and 24 hours later. RESULTS: After 21 days of treatment, the FML group showed greater improvements in corneal and conjunctival staining, hyperemia, and TBUT than the PA group (P<=0.03). After the adverse exposure, the percentage of patients having a 1-grade or more increase in corneal staining was significantly (P = 0.03) higher in the PA group (63.1% vs. 23.8%, respectively). Additionally, the FML group showed no significant changes in corneal staining (mean, 0.86; 95% confidence interval [CI], 0.47-1.25; vs. mean, 1.05; 95% CI, 0.59-1.51, for visit 2 and 3, respectively), conjunctival staining (mean, 0.95; 95% CI, 0.54-1.37 vs. mean, 1.19; 95% CI, 0.75-1.63), and hyperemia (mean, 0.71; 95% CI, 0.41-1.02 vs. 1.14; 95% CI, 0.71-1.58) after the exposure, whereas for the PA group, there was significant worsening (P<=0.009) in these variables (corneal staining: mean, 1.95; 95% CI, 1.57-2.33 vs. mean, 2.58; 95% CI, 2.17-2.98; conjunctival staining: mean, 1.68; 95% CI, 1.29-2.08 vs. mean, 2.47; 95% CI, 2.07-2.88; hyperemia: mean, 1.95; 95% CI, 1.63-2.26 vs. mean, 2.84; 95% CI, 2.62-3.07). CONCLUSIONS: Three-week topical 0.1% fluorometholone therapy is effective not only in reducing ocular surface signs in DED patients, but also especially in preventing exacerbation caused by exposure to a desiccating stress. PMID- 26520173 TI - [How to avoid the complications associated with hysterectomy: Place of subtotal hysterectomy, prevention of venous thromboembolism risk and preoperative treatment: Guidelines]. AB - OBJECTIVE: The National College of French gynecologists and obstetricians (CNGOF) decided to issue recommendations for clinical practice concerning the prevention of complications due to hysterectomy for benign disease. METHODS: Review of the English and French literature until May 2015 about complications with hysterectomy for benign gynaecological disease, excluding cancer. The following topics are covered in this article: prevention of venous thromboembolism risk, preoperative treatment that reduce the frequency of laparotomic hysterectomy and real interest of subtotal hysterectomy. RESULTS: For the prevention of venous thromboembolism risk we advise to follow the recommendations of the SFAR. In case of hysterectomy for benign indication for which a median laparotomy is envisaged, given the volume of the uterus, it is recommended to prescribe GnRH agonists and then reassess the surgical approach (grade B). We do not observe significative differences regarding the sexual quality of life for laparotomic subtotal hysterectomy versus laparotomic total hysterectomy (EL1). We do not observe significative differences regarding the sexual quality of life for laparoscopic subtotal hysterectomy versus laparoscopic total hysterectomy (EL1). Subtotal hysterectomy is not associated with a significant improvement in the sexual quality of life (EL1). Subtotal hysterectomy is not associated with a decreased prevalence of intraoperative Hemorrhagic or visceral complications (EL3) or to a reduction in transfusions (EL2). It is not recommended to perform subtotal hysterectomy to reduce the risk of complications per or postoperative (grade B). PMID- 26520174 TI - Novel and selective acetylcholinesterase inhibitors for Tetranychus cinnabarinus (Acari: Tetranychidae). AB - The carmine spider mite, Tetranychus cinnabarinus (Acari: Tetranychidae), is an economically important and extremely polyphagous herbivorous pest, with the title of "resistance champion" among arthropods. Anticholinesterase insecticides such as organophosphate and carbamate account for more than one-third of global insecticide sales. The non-target toxicity and resistance problem of organophosphate and carbamate have become of growing concern, which may be due to the fact that they target the ubiquitous catalytic serine residue of acetylcholinesterase (AChE) in mammals, birds, and beneficial insects. In this study, the structural differences between T. cinnabarinus AChE and human AChE, at or near the catalytic pocket, were illustrated. From the SPECS chemical lead compound database, 55 AChE inhibitor candidates were screened for high affinity for T. cinnabarinus AChE, but low affinity for human AChE, using the DOCK 6 and AutoDock Vina software. Three of the fifty-five candidates had inhibitory activity greater than that of the reversible AChE inhibitor eserine, with no observed inhibitory activities against human AChE. Two of the three had toxicity to T. cinnabarinus comparable to that of natural insecticidal pyrethrins. However, their potency is low compared with that of etoxazole, and further work is needed to optimize their potency. The selectivity of the three compounds over human and mite AChE may be due to their interaction with the mite-specific residues, as analyzed by Cyscore. The three compounds are potential lead compounds for development of novel acaricides against T. cinnabarinus with reduced toxicity to non-target species and a low propensity for resistance. PMID- 26520176 TI - A new compartmental model of Mycobacterium avium subsp. paratuberculosis infection dynamics in cattle. AB - Models of Mycobacterium avium subsp. paratuberculosis (MAP), a chronic infectious agent of cattle, are used to identify effective control programs. However, new biological findings show that adult infections occur and that infected animals can be separated into 2 paths: animals that will become high-shedding and, eventually, experience clinical disease (high-path); and animals that will shed only small quantities of MAP and will remain subclinical (low-path). Longitudinal data analysis found that high-path animals progress more quickly than previously believed. A standard model of MAP transmission in dairy herds was modified to include adult low-path infections and 2 infection pathways for infected calves. Analysis of this model showed that adult infection may play an important role in MAP dynamics on a dairy farm, and that the increased rate of progression for high path animals influences both the prevalence and the persistence of MAP on a dairy farm. This new model will be able to determine the effectiveness of MAP control programs more accurately than previous models. PMID- 26520175 TI - Summary of the 2014 Alcohol and Immunology Research Interest Group (AIRIG) meeting. AB - On November 21, 2014 the 19th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held at Loyola University Chicago Health Sciences Campus in Maywood, Illinois. The meeting focused broadly on inflammatory cell signaling responses in the context of alcohol and alcohol-use disorders, and was divided into four plenary sessions focusing on the gut and liver, lung infections, general systemic effects of alcohol, and neuro-inflammation. One common theme among many talks was the differential roles of macrophages following both chronic and acute alcohol intoxication. Macrophages were shown to play significant roles in regulating inflammation, oxidative stress, and viral infection following alcohol exposure in the liver, lungs, adipose tissue, and brain. Other work examined the role of alcohol on disease progression in a variety of pathologies including psoriasis, advanced stage lung disease, and cancer. PMID- 26520177 TI - A comparison of West Nile virus surveillance using survival analyses of dead corvid and mosquito pool data in Ontario, 2002-2008. AB - The aim of this study was to improve understanding of the relative performance of the use of dead wild corvids and mosquito pools infected with West Nile virus (WNv) in surveillance for WNv activity in the environment. To this end, all records on dead corvid submissions and mosquito pools tested in Public Health Units (PHUs) in Ontario, from 2002 to 2008, were explored. Survival analyses were employed using the first-WNv-positive cases detected each year for each PHU, and censored observations for PHUs which did not detect WNv during a given year using each data source (504 observations). Survival analyses were employed to compare the number of surveillance weeks before WNv was detected by either data source, and the influence of temporal, geographic and sociodemographic factors on these data. The outcome measurement for the final accelerated failure time (AFT) model with log-logistic distribution was a time ratio, which represents the ratio of the survival time of one group relative to another. Dead corvid surveillance was faster at detecting WNv than testing mosquito pools during the early years of WNv incursion into Ontario, while mosquito testing found WNv more quickly later in the study period. There was also regional variation in time-to-detection of WNv, by modality, as well as for various types of urban/rural settings. In comparison to mosquito surveillance, West Nile virus was detected more quickly using dead corvid surveillance in sparsely populated regions. These areas may benefit from collection of dead corvids to optimize detection and direct early surveillance efforts. When we compared the time-to-detection of WNv using dead corvids and the onset of human cases in PHUs, we found that dead corvid surveillance was predictive of West Nile activity in health units that reported human cases during the first 3 years of the incursion into Ontario. PMID- 26520178 TI - Psychometric Validation of the 14 items ChronIc Venous Insufficiency Quality of Life Questionnaire (CIVIQ-14): Confirmatory Factor Analysis. AB - OBJECTIVES: The study aim was to confirm the factorial structure of the short (14 item) version of the ChronIc Venous Insufficiency quality of life Questionnaire (CIVIQ-14) using the Vein Consult Program (VCP) results. METHODS: The international VCP study sought to evaluate the impact of chronic venous disease (CVD) on health care costs and quality of life (QoL). The factorial structure of the CIVIQ-14 was evaluated using two methods: exploratory factor analysis (EFA) to calculate the probabilities of items and dimensions remaining stable and to study the dimensionality of the scale using explained variance criteria, followed by confirmatory factor analysis (CFA) to confirm the original three dimensional structure and investigate alternative models that may have arisen from the dimensionality analysis. We also used the VCP results to evaluate the psychometric properties of the questionnaire and conducted subgroup analyses on countries with validated translations. RESULTS: A total of 47,149 questionnaires from 17 countries were available in the VCP. EFA revealed both items and dimensions as 100% stable. Dimensionality analysis showed that a two factor approach could be considered. CFA revealed the CIVIQ-14 three dimensional structure to be acceptable while rejecting the two dimensional model. Psychometric analysis confirmed the construct validity, internal consistency, and known groups validity of the CIVIQ-14. The results of subgroup analyses were consistent with those of the primary analysis. CONCLUSIONS: CFA of VCP data supported the factorial structure of the CIVIQ-14. The analysis corroborates the wide use of CIVIQ-14 as a valid instrument for reporting QoL in CVD patients. PMID- 26520179 TI - Commentary on 'Endovascular Versus Open Repair as Primary Strategy for Ruptured Abdominal Aortic Aneurysm: A National Population-based Study'. PMID- 26520180 TI - Compression of the Internal Carotid Artery by Turning the Head to the Left. PMID- 26520181 TI - Analysis of Moms Across America report suggesting bioaccumulation of glyphosate in U.S. mother's breast milk: Implausibility based on inconsistency with available body of glyphosate animal toxicokinetic, human biomonitoring, and physico-chemical data. AB - The non-peer-reviewed biomonitoring report published online by Moms Across America (MAA; Honeycutt and Rowlands, 2014) does not support the conclusion that glyphosate concentrations detected in a limited number of urine samples from women, men and children, or breast milk from nursing mothers, pose a health risk to the public, including nursing children. Systemically absorbed doses of glyphosate estimated from the MAA urine biomonitoring data and from other published biomonitoring studies indicate that daily glyphosate doses are substantially below health protective reference standards (ADIs; RfDs) established by regulatory agencies. The MAA report also suggested that detection of relatively high glyphosate concentrations in breast milk in 3 of 10 sampled women raised a concern for bioaccumulation in breast milk. However, the breast milk concentrations reported by MAA are highly implausible when considered in context to low daily systemic doses of glyphosate estimated from human urine biomonitoring data, and also are inconsistent with animal toxicokinetic data demonstrating no evidence of retention in tissues or milk after single- or multiple-dose glyphosate treatment. In addition, toxicokinetic studies in lactating goats have shown that glyphosate does not partition into milk at concentrations greater than blood, and that only a very small percentage of the total administered dose (<0.03%) is ultimately excreted into milk. The toxicokinetic studies also indicate that human glyphosate exposures estimated from urine biomonitoring fall thousands-of-fold short of external doses capable of producing blood concentrations sufficient to result in the breast milk concentrations described in the MAA report. Finally, in contrast to highly lipophilic compounds with bioaccumulation potential in breast milk, the physico chemical properties of glyphosate indicate that it is highly hydrophilic (ionized) at physiological pH and unlikely to preferentially distribute into breast milk. PMID- 26520182 TI - Human health risk characterization of petroleum coke calcining facility emissions. AB - Calcining processes including handling and storage of raw petroleum coke may result in Particulate Matter (PM) and gaseous emissions. Concerns have been raised over the potential association between particulate and aerosol pollution and adverse respiratory health effects including decrements in lung function. This risk characterization evaluated the exposure concentrations of ambient air pollutants including PM10 and gaseous pollutants from a petroleum coke calciner facility. The ambient air pollutant levels were collected through monitors installed at multiple locations in the vicinity of the facility. The measured and modeled particulate levels in ambient air from the calciner facility were compared to standards protective of public health. The results indicated that exposure levels were, on occasions at sites farther from the facility, higher than the public health limit of 150 MUg/m(3) 24-h average for PM10. However, the carbon fraction demonstrated that the contribution from the calciner facility was de minimis. Exposure levels of the modeled SO2, CO, NOx and PM10 concentrations were also below public health air quality standards. These results demonstrate that emissions from calcining processes involving petroleum coke, at facilities that are well controlled, are below regulatory standards and are not expected to produce a public health risk. PMID- 26520183 TI - Orally administered glycidol and its fatty acid esters as well as 3-MCPD fatty acid esters are metabolized to 3-MCPD in the F344 rat. AB - IARC has classified glycidol and 3-monochloropropane-1,2-diol (3-MCPD) as group 2A and 2B, respectively. Their esters are generated in foodstuffs during processing and there are concerns that they may be hydrolyzed to the carcinogenic forms in vivo. Thus, we conducted two studies. In the first, we administered glycidol and 3-MCPD and associated esters (glycidol oleate: GO, glycidol linoleate: GL, 3-MCPD dipalmitate: CDP, 3-MCPD monopalmitate: CMP, 3-MCPD dioleate: CDO) to male F344 rats by single oral gavage. After 30 min, 3-MCPD was detected in serum from all groups. Glycidol was detected in serum from the rats given glycidol or GL and CDP and CDO in serum from rats given these compounds. In the second, we examined if metabolism occurs on simple reaction with rat intestinal contents (gastric, duodenal and cecal contents) from male F344 gpt delta rats. Newly produced 3-MCPD was detected in all gut contents incubated with the three 3-MCPD fatty acid esters and in gastric and duodenal contents incubated with glycidol and in duodenal and cecal contents incubated with GO. Although our observation was performed at 1 time point, the results showed that not only 3 MCPD esters but also glycidol and glycidol esters are metabolized into 3-MCPD in the rat. PMID- 26520184 TI - The nuclear aryl hydocarbon receptor is involved in regulation of DNA repair and cell survival following treatment with ionizing radiation. AB - In the present study, we explored the role of the aryl hydrocarbon receptor (AhR) for gamma-H2AX associated DNA repair in response to treatment with ionizing radiation. Ionizing radiation was able to stabilize AhR protein and to induce a nuclear translocation in a similar way as described for exposure to aromatic hydrocarbons. A comparable AhR protein stabilization was obtained by treatment with hydroxyl-nonenal-generated by radiation-induced lipid peroxidation. AhR knockdown resulted in significant radio-sensitization of both A549- and HaCaT cells. Under these conditions an increased amount of residual gamma-H2AX foci and a delayed decline of gamma-H2AX foci was observed. Knockdown of the co-activator ARNT, which is essential for transcriptional activation of AhR target genes, reduced AhR-dependent CYP1A expression in response to irradiation, but was without effect on the amount of residual gamma-H2AX foci. Nuclear AhR was found in complex with gamma-H2AX, DNA-PK, ATM and Lamin A. AhR and gamma-H2AX form together nuclear foci, which disappear during DNA repair. Presence of nuclear AhR protein is associated with ATM activation and chromatin relaxation indicated by acetylation of histone H3. Taken together, we could show, that beyond the function as a transcription factor the nuclear AhR is involved in the regulation of DNA repair. Reduction of nuclear AhR inhibits DNA-double stand repair and radiosensitizes cells. First hints for its molecular mechanism suggest a role during ATM activation and chromatin relaxation, both essential for DNA repair. PMID- 26520185 TI - Calcitriol inhibits bleomycin-induced early pulmonary inflammatory response and epithelial-mesenchymal transition in mice. AB - Early pulmonary inflammation and epithelial-mesenchymal transition (EMT) play important roles during lung fibrosis. Increasing evidence demonstrates that calcitriol, the active form of vitamin D3, has anti-inflammatory activities. The aim of this study was to investigate the effects of calcitriol on bleomycin (BLM) induced early pulmonary inflammation and subsequent EMT. Mice were intratracheally injected with BLM (3.0mg/kg). In three calcitriol+BLM groups, mice were intraperitoneal (i.p.) injected with different doses of calcitriol (0.2, 1.0 or 5.0 MUg/kg) daily, beginning at 48 h before BLM injection. Twenty four hours, seven and fourteen days after BLM injection, pulmonary inflammation and EMT were evaluated. As expected, BLM-induced infiltration of inflammatory cells in the lungs was attenuated by calcitriol. BLM-induced pulmonary inflammatory cytokines were repressed by calcitriol. Moreover, BLM-induced nuclear translocation of nuclear factor kappa B (NF-kappaB) p65 was blocked by calcitriol. In addition, BLM-induced phosphorylation of pulmonary p38 MAPK and protein kinase B (Akt) was inhibited by calcitriol. Further analysis showed that BLM-induced alpha-smooth muscle actin (alpha-SMA), a marker for EMT in the lungs, was significantly attenuated by calcitriol. BLM-induced transforming growth factor-beta 1 (TGF-beta1) up-regulation and Smad phosphorylation were attenuated by calcitriol. In conclusion, calcitriol inhibits BLM-induced early pulmonary inflammation and subsequent EMT. PMID- 26520186 TI - Is there a specific phenotype associated with the different subtypes of KRAS mutations in patients with advanced non-small-cell lung cancers? AB - OBJECTIVES: KRAS mutations occur in 20 to 25% of non-small-cell lung cancers (NSCLC) and seem to predict a poor prognosis. There is heterogeneousness in the frequency and spectrum of KRAS mutations, which can be categorized in transitions and transversions. We wondered if subtypes of KRAS mutation were associated with specific clinical phenotypes and specific survival. MATERIALS AND METHODS: Between July 2007 and May 2012, patients with advanced NSCLC and KRAS mutation diagnosed in two university hospitals were included. Clinical and histological characteristics, therapeutics and survival data were collected. RESULTS: Among 635 patients screened for KRAS mutations, 90 were found to be mutated and were included. Median age was 59 years (range: 54-69). Most were males (60%), current or former smokers (63% and 33%, respectively) and had an adenocarcinoma (ADC) (80%). Eighty patients were stage IV and 10 were stage IIIB. Eighty percent of the KRAS mutations were transversions and 20% were transitions. In uni- and multivariate analyses, there was a trend for fewer smokers among patients with transitions than among those with transversions (Odds Ratio [OR]=0.28, 95% CI [0.079-0.999], p=0.05). No significant difference was noted between transitions and transversions for other clinical characteristics. Patients with transitions had more frequently squamous-cell carcinoma (SCC) compared to those with transversions, who had more frequently adenocarcinomas (OR=16.7, 95% CI [2.76 100.8], p=0.002). Seventy-nine patients (86%) had received first-line chemotherapy. No significant difference was seen for disease-control rate, median progression-free survival or overall survival between transitions and transversions. CONCLUSION: A higher proportion of non-smokers and SCC subtypes were observed in the transitions compared to transversions. This confirms the heterogeneity of KRAS mutations and could suggest to expand KRAS testing in SCC to assess impact of RAS in SCC, which remains poorly investigated. PMID- 26520187 TI - When is surgery indicated for small-cell lung cancer? AB - Small-cell lung cancer (SCLC) comprises 13-20% of all lung cancers but is the fifth leading cause of cancer death worldwide. SCLC prognosis remains poor despite improvements in diagnosis and therapy over the last 30 years. Current treatment is systemic chemotherapy, flanked by thoracic irradiation for limited stage disease; however, about two-thirds of patients are diagnosed with extensive stage disease when thoracic irradiation is not worthwhile. Randomized trials on surgical resection in patients with limited stage disease conducted in the pre PET era, when both staging and treatment were inadequate, did not support a role for surgery in disease management. However recent retrospective and population based studies indicate that outcomes after surgery in patients with very early SCLC are comparable to those in patients with non-SCLC, and that survival is better than in SCLC patients not given surgery. CT screening identifies SCLC at an earlier stage - with better survival - than usual care, and offers the hope that more SCLC patients may become long-term survivors. However, cases must be exhaustively staged to identify those likely to benefit from surgery. Finding a specific SCLC marker to facilitate early diagnosis remains a priority. PMID- 26520188 TI - We're in this together: Patients', caregivers' and health care providers' illness perceptions about non-small-cell lung cancer (NSCLC). AB - This study reviews empirical studies in the area of illness perceptions in patients with non-small-cell lung cancer (NSCLC). Beliefs about the illness and its consequences, including its medical management, are part of the review. Also, the relatively small research area of perceptions and views about patients with NSCLC of caregivers and health care providers is reviewed. Given our earlier review of the topic in this Journal [5], we now report on papers published after that 2011 publication. 38 papers were identified, a quite major increase in published research compared to the 15 papers in our previous publication (2011 and earlier). Most papers report on psychosocial concepts that determine responses to the illness and its treatment. Increasingly, reactions of caregivers and health care providers are studied. These last two categories of respondents perceive the psychosocial consequences of NSCLC as more severe than the patients themselves. Psychosocial variables appear to be stronger predictors of psychological distress and reduced quality of life than sociodemographic or clinical variables. These results are instrumental in the developing field of psychosocial interventions for patients with non-small-cell lung cancer and their caregivers, which may also be helpful for health care providers. Suggestions for research and clinical implications are presented. PMID- 26520189 TI - [How to improve practices and interventions for work integration of people with schizophrenia in France?]. AB - Getting and keeping a job are not only one of the criteria of recovery from schizophrenia, but are also one of its main means. Indeed, recovery is partly defined by the ability to work. Despite the lack of data in France about employment of people with schizophrenia, it is widely acknowledged that the employment rate of people with schizophrenia remains quite low, and frequently it is only an employment in sheltered workshops, not on the regular work market. International research data show that it is possible to improve significantly this employment rate, with an appropriate support, that is precisely defined by the current researches, and that is quickly spreading in most developed countries. The aim of this paper is to present, on the basis of a broad current literature review, the key predictive factors of the return to work for people with schizophrenia, and the strategies to optimize vocational services. It will appear that there are several ways to improve practices and interventions in France to support work integration. To begin with individual factors of work integration, dependant on each person, the clinical state and the cognitive skills (in a broad sense, including social cognition and metacognition) are to be taken into account, and optimized by means of the association of a finely tuned pharmacological treatment and psychosocial interventions such as cognitive remediation adjusted to the person's specific needs. The other main kind of factors is environmental factors, particularly the kind of vocational support, which turns out to have a major impact not only on job acquisition, but importantly also on job tenure. The most effective vocational services are based on the "Place and train" model, and even more precisely on the Individual Placement and Support (IPS) model, that allows to the majority of people with a severe mental illness (more than 50%) to obtain a competitive employment after 6 to 18 months of individualized support. This approach is now widely recommended as "an evidence-based practice" of rehabilitation. It is important to promote in France the development of this kind of practice, already implemented as an experiment by few militant and involved associations. This development remains in France slow and delayed (compared to the practices in the other European countries) because of the lack of public funding. It implies an evolution of the social and medico-social practices, taking into account current research data, and assessing the outcomes of their practices in order to improve them. The employment specialist (sometimes called also the "job coach") turns out to play a key role, emphasized by current research, implying, among many other tasks, to coordinate the net of people supporting the work integration, including the clinical team, the employer and the colleagues of the workplace. PMID- 26520190 TI - [In Process Citation]. PMID- 26520191 TI - [Functional and motor gastrointestinal disorders]. AB - This article discusses the most interesting studies on functional and motor gastrointestinal disorders presented at Digestive Diseases Week (DDW), 2015. Researchers are still seeking biomarkers for irritable bowel syndrome and have presented new data. One study confirmed that the use of low-dose antidepressants has an antinociceptive effect without altering the psychological features of patients with functional dyspepsia. A contribution that could have immediate application is the use of transcutaneous electroacupuncture, which has demonstrated effectiveness in controlling nausea in patients with gastroparesis. New data have come to light on the importance of diet in irritable bowel syndrome, although the effectiveness of a low-FODMAP diet seems to be losing momentum with time. Multiple data were presented on the long-term efficacy of rifaximin therapy in patients with irritable bowel syndrome and diarrhoea. In addition, among other contributions, and more as a curiosity, a study evaluated the effect of histamine in the diet of patients with irritable bowel syndrome. PMID- 26520192 TI - [Treatment of inflammatory bowel diseases]. AB - In addition to immunosuppressive drugs and anti-TNF, there are a number of new options in the treatment of inflammatory bowel diseases. Vedolizumab has been approved by the FDA and EMA and has demonstrated utility both in the treatment of ulcerative colitis (UC) and Crohn's disease (CD), even in anti-TNF refractory patients. Other monoclonal antibodies with different targets such as PF-005447659 (antiMAd-CAM1), ustekinumab (anti-IL23/IL12) or MEDI2070 (anti-IL23) have shown promising results in distinct clinical scenarios. Mongersen (antisense oligonucleotide anti-Smad7) and oznimod (an SP-1 modulator) are new alternatives with proven efficacy in clinical trials in CD and UC, respectively. Some data suggest that faecal microbiota transplantation could be efficacious in individual patients, although controlled data do not show clear differences with placebo. Autologous stem-cell transplantation has shown long-term efficacy in "ultra refractory" CD. The number of possible treatments is constantly increasing, and future research should focus both on the selection of the most appropriate treatment for any given patient and on comparative trials between options. PMID- 26520193 TI - [Natural history, complications, safety and pregnancy in inflammatory bowel disease]. AB - Numerous studies were presented in Digestive Disease Week 2015 (DDW 2015) on the natural history, complications, and safety of treatments in inflammatory bowel disease (IBD), as well as novel findings on fertility, pregnancy, and breastfeeding. The present article reviews presentations on the natural history of IBD, the risk of complications and their prevention, treatment safety, aspects related to fertility, pregnancy, and breastfeeding, as well as the risk of cancer and its association with IBD and with drugs used in its treatment. In the next few years, more data will become available on treatment safety and the possible complications that can develop in IBD patients due to the disease itself and the drugs employed in its treatment, which will allow measures to be adopted to improve prognosis. PMID- 26520194 TI - [Epidemiology, follow-up, monitoring and other aspects of inflammatory bowel disease]. AB - There are no important new data on the aetiology of inflammatory bowel disease. However, some new data were presented on the possible importance of certain nutrients or drugs in the genesis of the disease, as well as other data related to genetic features and their relationship with the microbiota. A highly interesting study suggested the strong potential of serological studies in predicting the course of Crohn's disease. The value of magnetic resonance imaging and the potential of low-radiation-dose tomography were reaffirmed in the monitoring and follow-up of patients and their treatments. Studies also confirmed the utility confirmed of new (and more comfortable) methods of home measurement of faecal calprotectin levels. In individualized therapy, attempts are being made to increase the practical application of new results on anti-TNF levels and their antibodies, for example, by identifying the utility of non-trough levels. We believe that the results presented on the impact of the disease on patients themselves were especially important, from their own perspective and in diverse setting. This impact is important both for patients (not only because of the repercussions of the disease on their quality of life but also on their mental health, disability, stress, and financial situation, etc.) and for their families. Finally, interesting results were presented of well-performed studies on colorectal cancer prevention in inflammatory bowel disease. These results confirm chromoendoscopy as a key technique but suggest that technological advances could change this situation, thus simplifying prevention. PMID- 26520195 TI - [Helicobacter pylori-associated diseases]. AB - This article summarizes the main conclusions of the studies presented at Digestive Disease Week this year (2015) related to Helicobacter pylori infection. Despite the undeniable widespread reduction in the prevalence of H. pylori infection, developing countries continue to have substantial infection rates. The prevalence of clarithromycin, metronidazole and quinolone resistance is markedly higher in most countries and continues to rise. Although H. pylori eradication reduces the incidence of gastric adenocarcinoma, it does not completely prevent its development; the presence of precancerous lesions--intestinal atrophy and metaplasia--is associated with a higher risk of developing this neoplasm, despite H. pylori eradication. The use of molecular diagnostic methods (polymerase chain reaction) in faecal samples could allow non-invasive evaluation of the antibiotic susceptibility of H. pylori. The effectiveness of standard triple therapy is clearly insufficient and continues to decrease. The effectiveness of sequential therapy in recent studies is lower than initially described and consequently this treatment cannot be recommended in clinical practice. Concomitant therapy is more effective and simpler than sequential therapy. In penicillin-allergic patients, quadruple therapy with bismuth is the treatment of choice in our environment. After the failure of standard triple therapy, second-line therapy with levofloxacin is effective and, moreover, is simpler and better tolerated than quadruple therapy with bismuth. Quadruple therapy with a proton pump inhibitor, bismuth, levofloxacin and amoxicillin is an effective (>= 90% eradication), simple and safe second-line therapy if triple or quadruple therapy without bismuth (sequential or concomitant) fails to eradicate the infection. The new generation quinolones, such as moxifloxacin or sitafloxacin, could be useful in second- or third-line rescue eradication therapy. Even after the failure of 3 eradication treatments, a fourth empirical rescue therapy (with rifabutin) can be effective. The management of H. pylori infection by European gastroenterologists is widely heterogeneous, and their eradication rates are generally unacceptable. In addition, there is a clear discrepancy between consensus document recommendations and clinical practice in primary care. The incidence of H. pylori reinfection is very low in the most developed regions, but is high in developing countries. PMID- 26520196 TI - [Oesophageal diseases: gastroesophageal reflux disease, Barrett's disease, achalasia and eosinophilic oesophagitis]. AB - The most important novel findings presented on oesophageal disease in DDW 2015 were the following: 1) GERD: a) hypervigilance seems to be a key pathogenic factor in reflux symptoms refractory to PPI; b) post-reflux swallowing-induced peristaltic waves could be an excellent diagnostic criterion for GERD; c) laryngeal pH-metry is not useful in the diagnosis of extra-oesophageal symptoms; d) the recommendation of weight loss adequately recorded in the clinical reports of patients with GERD and obesity or overweight is an excellent quality indicator and is associated with better outcomes. 2) Barrett's oesophagus: a) persistent low-grade dysplasia in more than one endoscopy and a diagnosis of "indefinite for dysplasia" are associated with a high risk of neoplastic progression; b) narrow band imaging allows areas of dysplasia on Barrett's oesophagus to be identified with high sensitivity and specificity; c) initial endoscopy fails to identify a high percentage of advanced neoplasms in Barrett's oesophagus. Early re-endoscopy should be considered; d) endoscopists specialized in Barret's oesophagus obtain a much higher yield in the diagnosis of advanced lesions. Patients at high risk men, older patients, smokers and those with long-segment Barrett's oesophagus could benefit from follow-up in a referral center. 3) Achalasia: POEM seems safe and effective, independently from patient characteristics (age, comorbidity) and the technical variations used. 4) Eosinophilic esophagitis: topical budesonide and exclusion diets are reasonably effective in PPI non-responders. PMID- 26520197 TI - [Gastrointestinal bleeding]. AB - In the Digestive Disease Week in 2015 there have been some new contributions in the field of gastrointestinal bleeding that deserve to be highlighted. Treatment of celecoxib with a proton pump inhibitor is safer than treatment with nonselective NSAID and a proton pump inhibitor in high risk gastrointestinal and cardiovascular patients who mostly also take acetylsalicylic acid. Several studies confirm the need to restart the antiplatelet or anticoagulant therapy at an early stage after a gastrointestinal hemorrhage. The need for urgent endoscopy before 6-12 h after the onset of upper gastrointestinal bleeding episode may be beneficial in patients with hemodynamic instability and high risk for comorbidity. It is confirmed that in Western but not in Japanese populations, gastrointestinal bleeding episodes admitted to hospital during weekend days are associated with a worse prognosis associated with delays in the clinical management of the events. The strategy of a restrictive policy on blood transfusions during an upper GI bleeding event has been challenged. Several studies have shown the benefit of identifying the bleeding vessel in non varicose underlying gastric lesions by Doppler ultrasound which allows direct endoscopic therapy in the patient with upper GI bleeding. Finally, it has been reported that lower gastrointestinal bleeding diverticula band ligation or hemoclipping are both safe and have the same long-term outcomes. PMID- 26520198 TI - [Colorectal cancer screening]. AB - Colorectal cancer is one of malignancies showing the greatest benefit from preventive measures, especially screening or secondary prevention. Several screening strategies are available with demonstrated efficacy and efficiency. The most widely used are the faecal occult blood test in countries with population based screening programmes, and colonoscopy in those conducting opportunistic screening. The present article reviews the most important presentations on colorectal cancer screening at the annual congress of the American Gastroenterological Association held in Washington in 2015, with special emphasis on the medium-term results of faecal occult blood testing strategies and determining factors and on strategies to reduce the development of interval cancer after colonoscopy. PMID- 26520199 TI - [Colonoscopy in the screening, follow-up and treatment of colorectal cancer and precursor lesions]. AB - Endoscopic polypectomy reduces the incidence of colorectal cancer and mortality due to this disease. Interval cancer is the marker par excellence of the effectiveness and quality of screening and surveillance programs. Interval cancer is defined as colorectal cancer appearing after a negative screening or surveillance test (whether colonoscopy or another type of test) for colorectal cancer and before the recommended date of the following screening test. It has been estimated that up to 75% of interval colorectal cancers may be due to poor endoscopic technique. Therefore, to reduce mortality from this disease, diagnostic and therapeutic colonoscopy must be carried out with high quality standards. In the latest congress of the American Gastroenterological Association, presentations were given on studies designed to analyse interval cancer and its possible causes, as well as to evaluate endoscopic techniques that could improve detection of polyps or optimize their complete resection. Likewise, strategies have begun to be evaluated that would allow rationalization of efforts and resources to achieve screening of the maximum number of individuals, with high quality standards, but without completely overloading the healthcare system. Finally, the congress also devoted substantial space to presentations on the management of post-polypectomy complications and large polyps. PMID- 26520200 TI - [New advances in hereditary colorectal cancer]. AB - Colorectal cancer is the most frequent malignancy in both sexes in Spain. Between 20% and 25% of affected individuals have a family history of the disease, and 5% to 6% have a germ mutation, i.e. the disease develops in the context of a hereditary syndrome. The importance of identifying patients with hereditary syndromes predisposing them to colorectal cancer lies in the possibility of applying preventive measures, screening, and more appropriate management of both patients and their families. The present article outlines the most important studies presented at the congress of the American Gastroenterological Association. PMID- 26520201 TI - [Latest advances in chronic pancreatitis]. AB - This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the early diagnosis of the disease, the treatment of symptoms and complications, mainly pain and pancreatic exocrine insufficiency, and the diagnosis and therapy of autoimmune pancreatitis. The multimodal dynamic endoscopic ultrasound-guided secretin-stimulated evaluation of the pancreas provides relevant morphological and functional information for the diagnosis of chronic pancreatitis at early stages. Extracorporeal shock wave lithotripsy in patients with calcifying pancreatitis and endoscopic pancreatic stent placement are effective alternatives for pain therapy in patients with chronic pancreatitis. Presence of pancreatic exocrine insufficiency in patients with chronic pancreatitis is associated with a significantly increase of mortality rate. Despite that, pancreatic enzyme replacement therapy is not prescribed in the majority of patients with pancreatic exocrine insufficiency, or it is prescribed at a low dose. The newly developed and commercialized needles for endoscopic ultrasound-guided pancreatic biopsy are effective in retrieving appropriate tissue samples for the histological diagnosis of autoimmune pancreatitis. Maintenance therapy with azathioprine is effective and safe to prevent relapses in patients with autoimmune pancreatitis. PMID- 26520202 TI - [Latest advances in pancreatic tumours]. AB - Pancreatic cancer continues to have an extremely poor prognosis. There have been hardly any therapeutic advances in the last few years and consequently attention is focussed on early diagnosis. In this regard, endoscopic ultrasonography and several associated techniques, such as electrography or the use of intravenous contrast agents, continue to be the cornerstone of differential diagnosis. In the latest Digestive Diseases Week, numerous presentations were made on cystic pancreatic tumours, especially intraductal papillary mucinous tumours, with their well-known potential for malignant transformation. In addition to the problems of the preoperative characterization of these entities, by both endoscopic ultrasound cytological evaluation--even with the presence of an on-site pathologist--and by intracystic markers, the role of other techniques was also mentioned, such as confocal laser endomicroscopy or the use of intravenous contrast agents to characterize the wall nodule. There were numerous studies on the natural history of intraductal papillary mucinous tumours, which mainly supported the increasingly conservative approach adopted by the recent Fukuoka international guidelines. Certain aspects were highlighted, such as comorbidities, when considering surgery, or the growth rate of the tumour. In treatment, endoscopic ultrasound-guided injection of gemcitabine and paclitaxel, without the need for alcohol as an ablative treatment of mucinous cystic tumours, is gaining ground in specific cases. PMID- 26520203 TI - [Latest advances in acute pancreatitis]. AB - The present article analyses the main presentations on acute pancreatitis at Digestive Disease Week 2015. Arterial pseudoaneurysm is an uncommon complication of acute pancreatitis (incidence 0.7%) and mortality from this cause is currently anecdotal. Diabetes mellitus has little impact on the clinical course of acute pancreatitis, unlike cirrhosis, which doubles the risk of mortality. Intake of unsaturated fat could be associated with an increased severity of acute pancreatitis and is a confounding factor in studies evaluating the relationship between obesity and morbidity and mortality. PET-CT (positron emission tomography computed tomography) could be a non-invasive tool to detect infection of collections in acute pancreatitis. Peripancreatic fat necrosis is less frequent than pancreatic fat necrosis and is associated with a better clinical course. If the clinical course is poor, increasing the calibre of the percutaneous drains used in the treatment of infected necrosis can avoid surgery in 20% of patients. The use of low molecular-weight heparin in moderate or severe pancreatitis could be associated with a better clinical course, specifically with a lower incidence of necrosis. In acute recurrent pancreatitis, simvastatin is a promising drug for prophylaxis of new episodes of acute pancreatitis. Nutritional support through a nasogastric tube does not improve clinical course compared with oral nutrition. PMID- 26520204 TI - Procedural and biophysical indicators of durable pulmonary vein isolation during cryoballoon ablation of atrial fibrillation. AB - BACKGROUND: Limited data exist on procedural and biophysical indicators of pulmonary vein (PV) isolation durability after the cryoballoon ablation of atrial fibrillation (AF). OBJECTIVE: The aim of this study was to investigate the procedural and biophysical characteristics associated with late PV reconnection (PVR) and durable PV isolation (PVI) after cryoablation using the currently available second-generation cryoballoon. METHODS: Data from 435 PVs targeted in 112 consecutive patients who underwent a repeat procedure 14 +/- 3 months after an index cryoablation of AF were examined. RESULTS: Altogether, 111 PVs (25.5%) in 71 patients (63.4%) demonstrated PVR, whereas 324 PVs (74.5%) exhibited PVI. The number and duration of cryoballoon applications did not differ between PVR and PVI. However, the time to PV isolation (time to effect) was considerably shorter (39.1 +/- 11.7 seconds vs 67.6 +/- 19.7 seconds; P < .001), the balloon temperature at time to effect was significantly warmer (-32.1 degrees C +/- 7.8 degrees C vs -39.4 degrees C +/- 5.8 degrees C; P < .001), the balloon nadir temperature was slightly cooler (-48.7 degrees C +/- 4.6 degrees C vs -47.8 degrees C +/- 2.9 degrees C; P = .034), and the total thaw time (56.5 +/- 25.4 seconds vs 34.8 +/- 9.1 seconds; P < .001) and interval thaw times at 0 degrees C (iTT0; 14.8 +/- 10.9 seconds vs 7.1 +/- 2.0 seconds; P < .001) and 15 degrees C (54.2 +/- 25.4 seconds vs 33.3 +/- 9.1 seconds; P < .001) were notably longer with PVI than with PVR. However, only a time to effect of <=60 seconds and an iTT0 of >=10 seconds emerged as significant predictors of PV isolation durability. Consequently, in a multivariate model, presence of both criteria predicted <1% and their mere absence ~75% likelihood of PVR. CONCLUSION: A time to effect of <=60 seconds and an iTT0 of >=10 seconds significantly predict PV isolation durability after the cryoballoon ablation of AF. If both criteria are met, the likelihood of PV reconnection may be exceedingly low. PMID- 26520205 TI - Reply to the Editor- Clinical Benefit of Contact Force-Sensing Catheters in Ablation of Atrial Fibrillation: Meta-analysis to Dig for Truth or Bias? PMID- 26520206 TI - To the Editor- Clinical benefit of contact force-sensing catheters in the ablation of atrial fibrillation: Meta-analysis to dig for truth or bias? PMID- 26520207 TI - Interatrial block and atrial arrhythmias in centenarians: Prevalence, associations, and clinical implications. AB - BACKGROUND: Data are lacking on the characteristics of atrial activity in centenarians, including interatrial block (IAB). OBJECTIVE: The aim of this study was to describe the prevalence of IAB and auricular arrhythmias in subjects older than 100 years and to elucidate their clinical implications. METHODS: We studied 80 centenarians (mean age 101.4 +/- 1.5 years; 21 men) with follow-ups of 6-34 months. Of these 80 centenarians, 71 subjects (88.8%) underwent echocardiography. The control group comprised 269 septuagenarians. RESULTS: A total of 23 subjects (28.8%) had normal P wave, 16 (20%) had partial IAB, 21 (26%) had advanced IAB, and 20 (25.0%) had atrial fibrillation/flutter. The IAB groups exhibited premature atrial beats more frequently than did the normal P wave group (35.1% vs 17.4%; P < .001); also, other measurements in the IAB groups frequently fell between values observed in the normal P wave and the atrial fibrillation/flutter groups. These measurements included sex preponderance, mental status and dementia, perceived health status, significant mitral regurgitation, and mortality. The IAB group had a higher previous stroke rate (24.3%) than did other groups. Compared with septuagenarians, centenarians less frequently presented a normal P wave (28.8% vs 53.5%) and more frequently presented advanced IAB (26.3% vs 8.2%), atrial fibrillation/flutter (25.0% vs 10.0%), and premature atrial beats (28.3 vs 7.0%) (P < .01). CONCLUSION: Relatively few centenarians (<30%) had a normal P wave, and nearly half had IAB. Our data suggested that IAB, particularly advanced IAB, is a pre-atrial fibrillation condition associated with premature atrial beats. Atrial arrhythmias and IAB occurred more frequently in centenarians than in septuagenarians. PMID- 26520208 TI - Parental stress management using relaxation techniques in a neonatal intensive care unit: A randomised controlled trial. AB - OBJECTIVE: The objective of this study was to investigate the effect of relaxation techniques on the stress/anxiety of parents with hospitalised premature infants, three months following discharge from the neonatal intensive care unit. STUDY DESIGN: A randomised controlled trial was conducted in the neonatal intensive care unit of a tertiary maternity hospital including 59 parents, who were randomised into two groups: 31 in the intervention group and 28 in the control group. Parents in the intervention group practiced three different relaxation techniques, in addition to undergoing the same information-based training courses as did the parents of the control group. DATA COLLECTION: Data were collected 10-15 days post delivery and three months post discharge. The assessment measures included the Perceived Stress Scale, the State and Trait Anxiety Inventory 1 and 2 and salivary cortisol levels. RESULTS: The psychometric assessment at baseline was comparable between the two groups. The intervention group showed a significant reduction in trait anxiety (p=0.02) compared with the control group three months post discharge. The perceived stress decreased in both groups (p=0.699). No difference in salivary cortisol levels was detected. The multivariate analysis revealed that higher initial stress levels (p<0.001) and university/college education (p=0.003) were associated with higher parental stress, whereas moderate-to-high income satisfaction was associated with lower parental stress (p=0.003). CONCLUSION: Further long-term follow-up of families with a neonatal intensive care unit experience could assess more delayed effects of stress management by relaxation techniques. PMID- 26520209 TI - The impact of interventional nephrologists on the growth of a peritoneal dialysis program: Long-term, single-center experience. AB - Peritoneal dialysis (PD) is an underutilized form of renal replacement therapy. Although a variety of factors have been deemed responsible, timely insertion of a PD catheter may also be a contributory factor. Furthermore, a good catheter implantation technique is important to allow for effective peritoneal access function and long-term technique survival. Studies regarding results obtained by nephrologists in comparison with surgeons have been limited to small single center experiences. Thus, the objective of this study was to explore the impact of the peritoneal dialysis (PD) catheter insertion by nephrologists compared to surgeons on early catheter complications and on technique survival. We also examine whether PD catheter insertion by nephrologists has a positive impact on the growth in the number of patients using PD. We performed 313 consecutive procedures: 192 catheter insertions and 121 catheter removal from January 1, 2006 to December 31, 2013. The main reasons for catheter removal were: renal transplantation, 52 (43%) follow of transfer to HD, 48 (40%) and catheter malfunction, 16 (13%). The patients were mostly male (63.4%) with the mean age of 50.8+/-15.1 years and 23.8 were diabetics. We only observed seven (2.5%) early complications (<4 weeks) associated to peritoneal catheter surgery (3 peritonitis episodes, 2 hemoperitoneum episodes, one complicated hernia and one omental entrapment). There were not significant differences in surgery-related complications in both periods. The penetration ratio of PD after 2006 was 117% higher compared with procedures performing before this date. In conclusions, we have demonstrated a positive impact on the growth of the PD population when catheter insertion is performed by nephrologists with a minimal incidence of complications associated. PMID- 26520211 TI - The impact of research assessments on midwifery. PMID- 26520210 TI - Colony size-frequency distribution of pocilloporid juvenile corals along a natural environmental gradient in the Red Sea. AB - Coral colony size-frequency distributions can be used to assess population responses to local environmental conditions and disturbances. In this study, we surveyed juvenile pocilloporids, herbivorous fish densities, and algal cover in the central and southern Saudi Arabian Red Sea. We sampled nine reefs with different disturbance histories along a north-south natural gradient of physicochemical conditions (higher salinity and wider temperature fluctuations in the north, and higher turbidity and productivity in the south). Since coral populations with negatively skewed size-frequency distributions have been associated with unfavorable environmental conditions, we expected to find more negative distributions in the southern Red Sea, where corals are potentially experiencing suboptimal conditions. Although juvenile coral and parrotfish densities differed significantly between the two regions, mean colony size and size-frequency distributions did not. Results suggest that pocilloporid colony size-frequency distribution may not be an accurate indicator of differences in biological or oceanographic conditions in the Red Sea. PMID- 26520212 TI - The viewing room: A lens for developing ethical comportment. AB - Healthcare is dynamic and complex, and against this background, nursing students must negotiate the transition from lay person to healthcare professional. Diverse life experiences and learning styles can further complicate this journey of transformation. The contemporary role of the nurse includes caring for and making clinical decisions about patients based on ethical principles. Learning about and integrating ethical comportment as part of the transformative journey requires nurse educators to create and implement learning experiences that challenge nursing students to think deeply and broadly about the experiences they encounter, to question their previous assumptions and prejudices, to consider the world of healthcare through a new lens, and to reflect on and learn from the process. The judicious use of film has the potential to assist students to recognize and develop ethical comportment as they prepare for real-world clinical practice experiences. In this paper, we present three film exemplars and related teaching strategies designed to facilitate transformative learning and development of ethical comportment. PMID- 26520213 TI - The effect of high-fidelity simulation on knowledge and confidence in critical care training: An integrative review. AB - Patient outcomes in critical care have long been linked to provider experience, but with older providers retiring, it is becoming difficult to maintain a high level of experience among the ICU staff. Innovative training methods that improve providers' knowledge and confidence may be able to make up for deficiencies in clinical experience. High-fidelity simulation training mimics clinical experience and has been extensively studied in the training of procedural skills, but what is the effect of this type of training on knowledge and confidence? To answer this question, we conducted a review of the literature for studies examining the effect of simulation training on knowledge and confidence among critical care providers. Seventeen papers were identified that met the inclusion criteria and a systematic approach was used to review the papers and synthesize the data. All 17 studies demonstrated an improvement in knowledge and while only 13 of the included studies examined the effect on provider confidence, all found an improvement. We conclude that high-fidelity simulation is a useful tool for improving knowledge and confidence among critical care providers and merits consideration for inclusion in critical care training programs. PMID- 26520214 TI - Candesartan ameliorates impaired fear extinction induced by innate immune activation. AB - Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 MUg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 MUg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 MUg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 MUg/kg) which impaired locomotion without affecting extinction. In addition, 15 h after an injection of 250 MUg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD. PMID- 26520215 TI - EurEAs_Gplex--A new SNaPshot assay for continental population discrimination and gender identification. AB - Assays that allow analysis of the biogeographic origin of biological samples in a standard forensic laboratory have to target a small number of highly differentiating markers. Such markers should be easy to multiplex and the assay must perform well in the degraded and scarce biological material. SNPs localized in the genome regions, which in the past were subjected to differential selective pressure in various populations, are the most widely used markers in the studies of biogeographic affiliation. SNPs reflecting biogeographic differences not related to any phenotypic traits are not sufficiently explored. The goal of our study was to identify a small set of SNPs not related to any known pigmentation/phenotype-specific genes, which would allow efficient discrimination between populations of Europe and East Asia. The selection of SNPs was based on the comparative analysis of representative European and Chinese/Japanese samples (B-lymphocyte cell lines), genotyped using the Infinium HumanOmniExpressExome microarray (Illumina). The classifier, consisting of 24 unlinked SNPs (24-SNP classifier), was selected. The performance of a 14-SNP subset of this classifier (14-SNP subclassifier) was tested using genotype data from several populations. The 14-SNP subclassifier differentiated East Asians, Europeans and Africans with ~100% accuracy; Palestinians, representative of the Middle East, clustered with Europeans, while Amerindians and Pakistani were placed between East Asian and European populations. Based on these results, we have developed a SNaPshot assay (EurEAs_Gplex) for genotyping SNPs from the 14-SNP subclassifier, combined with an additional marker for gender identification. Forensic utility of the EurEAs_Gplex was verified using degraded and low quantity DNA samples. The performance of the EurEAs_Gplex was satisfactory when using degraded DNA; tests using low quantity DNA samples revealed a previously not described source of genotyping errors, potentially important for any SNaPshot-based assays. PMID- 26520216 TI - Acceptance and Commitment Therapy in the Treatment of Alcohol Use Disorder and Comorbid Affective Disorder: A Pilot Matched Control Trial. AB - This study examined whether acceptance and commitment therapy (ACT) enhances treatment as usual (TAU) in improving treatment outcomes in patients with alcohol use disorder (AUD) and comorbid affective disorder. Fifty-two participants were included in the study, of whom 26 were patients with AUD and either depression or bipolar disorder treated with ACT group therapy in parallel with TAU (inpatient integrated treatment) and 26 were matched controls who had received TAU alone. Drinking and craving outcomes were total alcohol abstinence, cumulative abstinence duration (CAD) and Obsessive Compulsive Drinking Scale (OCDS) scores at 3 and 6 months postintervention. Affective and anxiety outcomes were Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Young Mania Rating Scale (YMRS) scores at these follow-ups. Baseline demographic and clinical characteristics were similar in both groups. Retention rates were high: 100% of the ACT group were followed up at 3 and 6 months; 92.3% and 84.6% of the TAU alone group were followed up at 3 and 6 months, respectively. Patients in the ACT group reported significantly higher CAD at 3 and 6 months, significantly lower BDI and BAI scores at 3 and 6 months, and significantly lower OCDS scores at 3 months, than those who received only TAU. No other significant differences in treatment outcomes were found between the groups. ACT provides added benefit to TAU in improving drinking, craving, depression and anxiety outcomes in patients with AUD and comorbid affective disorder. Most treatment improvements were sustained over a 6-month follow-up period. PMID- 26520217 TI - Internet-Based Exposure and Behavioral Activation for Complicated Grief and Rumination: A Randomized Controlled Trial. AB - This study examined the effectiveness and feasibility of therapist-guided Internet-delivered exposure (EX) and behavioral activation (BA) for complicated grief and rumination. Forty-seven bereaved individuals with elevated levels of complicated grief and grief rumination were randomly assigned to three conditions: EX (N=18), BA (N=17), or a waiting-list (N=12). Treatment groups received 6 homework assignments over 6 to 8weeks. Intention-to-treat analyses showed that EX reduced complicated grief, posttraumatic stress, depression, grief rumination, and brooding levels relative to the control group at posttreatment (d=0.7-1.2). BA lowered complicated grief, posttraumatic stress, and grief rumination levels at posttreatment (d=0.8-0.9). At 3-month follow-up, effects of EX were maintained on complicated grief and grief rumination (d=0.6-1.2), and for BA on complicated grief, posttraumatic stress, and grief rumination (d=0.8-0.9). EX reduced depression more strongly than BA (d=0.6). Completers analyses corroborated results for EX, and partially those for BA, but no group differences were detected. BA suffered from high dropout (59%), relative to EX (33%) and the waiting-list (17%). Feasibility appeared higher for EX than BA. Results supported potential applicability of online exposure but not behavioral activation to decrease complicated grief and rumination. PMID- 26520218 TI - Enhancing Father Engagement and Interparental Teamwork in an Evidence-Based Parenting Intervention: A Randomized-Controlled Trial of Outcomes and Processes. AB - This study examined the outcomes and process in a positive parenting program adapted to enhance father engagement and teamwork. A randomized control trial of the Group Triple P Program with additional father-relevant content was conducted with 42 families of children with conduct problems aged between 3 to 8years. Families were allocated to either the intervention or waitlist condition. Assessments of child behavior, self- and partner-reported parenting, and the interparental relationship were conducted at T1 (pre), T2 (post), and T3 (6-month follow-up). Observations were used to examine fathers' and mothers' unique and shared contributions to group process during participation in parenting group sessions. Following program completion (T2) intervention group fathers and mothers reported significantly fewer child behavior problems, dysfunctional parenting practices, and interparental conflict about child-rearing than waitlist parents. Intervention group mothers also reported increased parenting confidence and rated their partners as showing significantly fewer dysfunctional parenting practices. Intervention effects were maintained at 6-month follow-up. Observational data showed that fathers and mothers made similar contributions during the group sessions. The most frequent types of contributions were asking questions and sharing information with other parents about implementing parenting strategies. The key differences between parents were fathers' more frequent use of humor and mothers' more frequent sharing of personal stories and reporting co parenting cooperation. The levels of session attendance and program satisfaction were high for both fathers and mothers. Findings highlight the potential benefits of efforts to engage both fathers and mothers for program adherence, satisfaction, and effectiveness. PMID- 26520219 TI - Treatment Outcome and Predictors of Internet Guided Self-Help for Obsessive Compulsive Disorder. AB - Internet-guided self-help (iGSH) has amassed significant empirical support for a variety of psychiatric conditions; however, it is not known who responds best to these treatments. This open trial examined the clinical outcomes and predictors of a 17-week iGSH program for obsessive-compulsive disorder (OCD). Therapist support was provided either in person or by phone 9 times for an average of 13minutes per session. Twenty-four patients initiated treatment, and 17 of these (70.8%) completed. Results of the intent-to-treat sample indicated statistically significant improvements at posttreatment with large treatment effects for OCD symptoms as assessed by the Yale Brown Obsessive-Compulsive Scale (d=0.87), and small to moderate improvements in depression (d=0.19), functioning (d=0.53), and quality of life (d=-0.18). These outcomes were largely maintained over a 6-month follow-up. Readiness to reduce avoidance of OCD triggers and attendance to therapist sessions were moderately associated with posttreatment response, and correctly classified the responder status (defined as clinically significant change) of nearly 9 out of 10 patients at posttreatment. These same variables did not predict responder status at 6-month follow-up. These results lend further empirical support to iGSH as a treatment for OCD and provide direction on the development of predictor models to identify patients who are and are not likely to acutely respond to iGSH. PMID- 26520220 TI - Long-Term Outcome of Cognitive Behavior Therapy for Body Dysmorphic Disorder: A Naturalistic Case Series of 1 to 4 Years After a Controlled Trial. AB - There is some evidence for the efficacy of cognitive behavior therapy (CBT) for body dysmorphic disorder (BDD) after 1 to 6months but none in the long term. The aim of this study was to follow up the participants in a randomized controlled trial of CBT versus anxiety management to determine whether or not the treatment gains were maintained over time. Thirty of the original 39 participants who had CBT were followed up over 1 to 4years and assessed using a number of clinician and self-report measures, which included the primary outcome measure of the Yale Brown Obsessive Compulsive Scale modified for BDD. Outcome scores generally maintained over time from end of treatment to long-term follow-up. There was a slight deterioration from n=20 (51.3%) to n=18 (46.2%) who met improvement criteria at long-term follow-up. Eleven (28.2%) were in full remission and 22 (56.4%) were in partial remission. The gains made were generally maintained at long-term follow-up. However, there were a significant number of participants who maintained chronic symptoms after treatment and may need a longer-term or more complex intervention and active medication management. PMID- 26520221 TI - Psychometric Properties of a Self-Report Instrument for the Assessment of Tic Severity in Adults With Tic Disorders. AB - The gold-standard measure of tic severity in tic disorders (TD), the Yale Global Tic Severity Scale (YGTSS), is a semistructured clinician-administered interview that can be time consuming and requires highly trained interviewers. Moreover, the YGTSS does not provide information regarding frequency and intensity of specific tics because all motor and all vocal tics are rated as a group. The aim of the present study is to describe and test the Adult Tic Questionnaire (ATQ), a measure for the assessment of tic severity in adults, and to report its preliminary psychometric properties. The ATQ is a brief self-report questionnaire that provides information regarding frequency, intensity, and severity of 27 specific tics. In addition, the ATQ produces total frequency, intensity, and severity scores for vocal and motor tics, as well as a global total tic severity score. Results showed that the ATQ demonstrated very good internal consistency and temporal stability. The total, vocal, and motor tic severity scales of the ATQ showed strong correlation with corresponding subscales of the YGTSS, indicating strong convergent validity. Weak correlations with measures of severity of obsessive-compulsive disorder and attention deficit/hyperactivity disorder, indicated strong discriminant validity. The ATQ, a promising measure for the assessment of tic severity in adults with TD, may be a valuable supplement to the current recommended assessment battery for TD. Furthermore, the ATQ enables clinicians and researchers to track changes in the frequency and intensity of specific tics, which is important given their complex and dynamic nature. PMID- 26520222 TI - Genetic Correlates of Maladaptive Beliefs: COMT VAL(158)MET and Irrational Cognitions Linked Depending on Distress. AB - Maladaptive/irrational beliefs are significant cognitive vulnerability mechanisms in psychopathology. They are more likely to be associated with a genetic vulnerability marker under conditions of emotional distress when irrational beliefs are more salient. Therefore, in the current study we investigated the COMT Val(158)Met gene variation in relation to irrational beliefs, assuming this relationship depended on the level of emotional distress. Two hundred and sixty seven genotyped volunteers were assessed for core/general maladaptive beliefs, as well as trait emotional distress. We focused on context-independent measures of irrational beliefs and emotional distress in the absence of a stressor. As expected, the relationship between COMT Val(158)Met and irrational beliefs depended on the level of emotional distress (f(2)=.314). The COMT Val(158)Met irrationality association was significant only when individuals fell in the average to above average range of emotional distress. Furthermore, within this range the Met allele seemed to relate to higher irrational beliefs. These results were significant for overall irrational beliefs and its subtypes, but not for rational beliefs, the functional counterpart of irrationality. In light of the study's limitations, the results should be considered as preliminary. If replicable, these findings have potential implications for therapygenetics, changing the view that COMT Val(158)Met might be of greater relevance when treatment modality does not rely on cognitive variables. PMID- 26520223 TI - A Tutorial on Computing Bayes Factors for Single-Subject Designs. AB - When researchers are interested in the effect of certain interventions on certain individuals, single-subject studies are often performed. In their most simple form, such single-subject studies require that a subject is measured on relevant criterion variables several times before an intervention and several times during or after the intervention. Scores from the two phases are then compared in order to investigate the intervention effect. Since observed scores typically consist of a mixture of true scores and random measurement error, simply looking at the difference in scores can be misleading. Hence, de Vries & Morey (2013) developed models and hypothesis tests for single-subject data, quantifying the evidence in data for the size and presence of an intervention effect. In this paper we give a non-technical overview of the models and hypothesis tests and show how they can be applied on real data using the BayesSingleSub R package, with the aid of an empirical data set. PMID- 26520224 TI - Nonsuicidal Self-Injury and Suicidal Self-Injury: A Taxometric Investigation. AB - The present research examined the latent structure of self-injurious behavior (SIB) to determine whether suicidal self-injury (SSI) and nonsuicidal self-injury (NSSI) reflect categorically distinct types of SIB or dimensional variations of the same construct. Participants consisted of 1,525 female undergraduates across several universities in the United States who completed the Survey of College Mental Health and Well Being and endorsed a history of SIB. Empirically derived indicators representing intent to die, suicidal history, frequency of SIB, severity of SIB, and number of methods of SIB were submitted to three mathematically independent taxometric procedures. Results of multiple consistency tests converged to indicate that the latent structure of SIB is continuous, with individuals who engage in SSI and NSSI differing in degree rather than kind. The implications of these dimensional findings for the theoretical conceptualization, assessment, and treatment of SIB are discussed. PMID- 26520226 TI - Developing Partnerships in the Provision of Youth Mental Health Services and Clinical Education: A School-Based Cognitive Behavioral Intervention Targeting Anxiety Symptoms in Children. AB - Clinical scientists are calling for strong partnerships in the provision of evidence-based treatments for child mental health problems in real-world contexts. In the present study, we describe the implementation of a cognitive behavioral intervention (CBI) to address grade 5 children's anxiety symptoms. The CBI arose from a long-standing partnership between University and Education Department stakeholders. The partnership integrates school-based, evidence informed treatment delivery with clinical education, and also supports a school based psychology clinic to provide assessment and treatment services to children attending schools within the catchment area and clinical training for university graduate students. Children in the active condition (N=74) completed the CBI during regular class time, while children in the control condition (N=77) received the standard classroom curriculum. Children's anxiety and depressive symptoms, threat interpretation biases (perceived danger and coping ability), and perceptions of their social skills were assessed before and after condition. Children in the active condition reported significant improvements in self reported anxiety symptoms, and perceptions of their social skills and coping ability, whereas no significant differences were observed for children in the control condition from pre- to post-assessment. For a subset of children assessed 12 months after the CBI (n=76), symptom improvement remained stable over time and estimates of danger and coping ability showed even greater improvement. Results demonstrate the value of strong stakeholder partnerships in innovative youth mental health services, positive child outcomes, and clinical education. PMID- 26520225 TI - Manipulating Attention to Nonemotional Distractors Influences State Anxiety: A Proof-of-Concept Study in Low- and High-Anxious College Students. AB - Anxious individuals have difficulty inhibiting attention to salient, but nonemotional, distracting stimuli. The exact nature of this relationship remains unclear, however. In the present study, we tested the hypothesis that increasing attention to salient, but nonemotional, distracting stimuli would lead to increases in state anxiety by manipulating attentional strategies during a visual search task. We randomly assigned students low and high in trait anxiety to either a 1-session singleton detection training group or a feature search group. Singleton detection training increases distraction by salient, nonemotional stimuli whereas feature search training protects attention against distracting stimuli. Findings revealed that singleton detection training not only increased distraction by salient, nonemotional stimuli but also increased state anxiety. Moreover, this increase in state anxiety was most pronounced among high trait anxious individuals. In contrast, feature search training protected attention against distracting stimuli and against increases in state anxiety, particularly in the high trait-anxious individuals. Together, the current findings provide initial support for the notion that distraction by salient, nonemotional stimuli can increase state anxiety levels. Furthermore, these results suggest that individuals already vulnerable to experience anxiety are most likely to be affected by distraction by salient, nonemotional stimuli, and that training anxious individuals to focus on specific shape features may be a viable attention modification intervention. PMID- 26520227 TI - Mindfulness Therapy for Maladaptive Interpersonal Dependency: A Preliminary Randomized Controlled Trial. AB - Existing treatments for maladaptive interpersonal dependency and dependent personality disorder do not meet basic scientific standards for effectiveness. The present investigation tested the efficacy of a mindfulness-based approach: mindfulness therapy for maladaptive interpersonal dependency (MT-MID). Forty eight participants who reported consistently high levels of maladaptive dependency (i.e., scored higher than 1 standard deviation above the mean on the Interpersonal Dependency Inventory at two separate assessments) were randomized to either 5 sessions of MT-MID or a minimal contact control. Five self-reported outcomes (mindfulness, maladaptive interpersonal dependency, helplessness, fears of negative evaluation, and excessive reassurance seeking) were assessed at pretreatment, posttreatment, and a 4-week follow-up. Intent-to-treat analyses indicated that MT-MID yielded greater improvements than the control on all 5 outcomes at posttreatment (median d=1.61) and follow-up (median d=1.51). Participants assigned to MT-MID were more likely than control participants to meet criteria for clinically significant change at posttreatment (56.5% vs. 0%) and follow-up (42.9% vs. 0%). There was also evidence that increases in mindfulness mediated the dependency-related improvements. These results provide preliminary support for the efficacy of a mindfulness-based approach for treating the symptoms of maladaptive dependency. PMID- 26520228 TI - Johrei Effects on Water: A Pilot Study by Counting Drops. AB - BACKGROUND: Water is a key ingredient in the creation and sustainment of life. Moreover, water may be a key vehicle in the processes of energy healing, such as in the preparation of homeopathic remedies and spiritual treatments. Given these properties, the purpose of this study was to investigate whether the application of Johrei to water could lead to significant changes in the hydrodynamic behaviour of the fluid. METHODS: Four regular Johrei practitioners (P1, P2, P3 and P4) were selected for this study. Dripping water produced at the tip of a capillary was used as the hydrodynamic behaviour model. This behaviour was modelled mathematically, and tuning parameters phi4 and tau were used to assess significant differences in the dripping water samples that were subjected to Johrei compared with the samples that were not so treated. The tuning parameters were obtained using the Levenberg-Marquardt fitting algorithm. The data sets for each Johrei practitioner and the control experiment were analysed using ANOVA and a paired t-test. RESULTS: The mathematical model exhibited an excellent fit to our data, generating correlation coefficients (r) greater than or equal to 0.999. Significant differences were observed in both tau (P1 and P2, P < 0.05 and P < 0.01, respectively) and phi4 (P2, P < 0.01). As expected, no significant difference for the control experiment (without Johrei) was observed. CONCLUSIONS: Our results indicated a statistically significant change in the hydrodynamic behaviour of water correlated with Johrei treatment for 50% of the participating Johrei practitioners. PMID- 26520229 TI - Enzymatic diagnosis of Fabry disease using a fluorometric assay on dried blood spots: An alternative methodology. AB - Fabry disease (FD, OMIM#301500) is an X-linked lysosomal storage disorder caused by the functional deficiency of alpha-galactosidase A, a lysosomal enzyme. A method to screen for FD in large populations has been developed using a fluorometric assay of alpha-galactosidase A activity in dried blood spots (DBS) on filter paper. However, results can be influenced by quenching of fluorescence by haemoglobin which, together with small sample size, may result in a low light emission signal. An alternative, simple and sensitive fluorometric assay was developed for the determination of alpha-galactosidase A activity in DBS. The assay uses 4-methylumbelliferyl-alpha-d-galactose as an artificial substrate. To minimize the risk of false-positives, zinc sulfate was used for protein precipitation to stop the enzymatic reaction and eliminate interfering species (hemoglobin). Samples from 209 individuals (60 hemizygotes, 68 heterozygotes, and 81 controls) were tested to establish reference values for the assay. The mean alpha-galactosidase A activity of the 81 controls was 9.1 +/- 3.3 MUmol h(-1) L( 1) (mean +/- SD). All 60 hemizygotes affected with FD had AGAL activities below 1.7 MUmol h(-1) L(-1) (0.2 +/- 0.3 MUmol h(-1) L(-1)). For the 68 heterozygous females, AGAL activity ranged from 0 to 12.6 MUmol h(-1) L(-1) (3.5 +/- 2.7 MUmol h(-1) L(-1)). Two-thirds of the female patients could be identified using the enzymatic assay and a cut-off level of 40% of the median control value (<3.4 MUmol h(-1) L(-1)). Our fluorometric assay using zinc sulfate protein precipitation was shown to have similar sensitivity and robustness while reducing the risk of false positive results due to quenching of 4-MU fluorescence by haemoglobin. PMID- 26520230 TI - Clinical outcomes in patients with ST-segment elevation myocardial infarction treated with everolimus-eluting stents versus bare-metal stents (EXAMINATION): 5 year results of a randomised trial. AB - BACKGROUND: Data for the safety and efficacy of new-generation drug-eluting stents at long-term follow-up, and specifically in patients with ST-segment elevation myocardial infarction, are scarce. In the EXAMINATION trial, we compared everolimus-eluting stents (EES) with bare-metal stents (BMS) in an all comer population with ST-segment elevation myocardial infarction. In this study, we assessed the 5-year outcomes of the population in the EXAMINATION trial. METHODS: In the multicentre EXAMINATION trial, done in Italy, Spain, and the Netherlands, patients with ST-segment elevation myocardial infarction were randomly assigned in a 1:1 ratio to receive EES or BMS. The random allocation schedule was computer-generated and central randomisation (by telephone) was used to allocate patients in blocks of four or six, stratified by centre. Patients were masked to treatment assignment. At 5 years, we assessed the combined patient oriented outcome of all-cause death, any myocardial infarction, or any revascularisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00828087. FINDINGS: 1498 patients were randomly assigned to receive either EES (n=751) or BMS (n=747). At 5 years, complete clinical follow-up data were obtained for 731 patients treated with EES and 727 treated with BMS (97% of both groups). The patient-oriented endpoint occurred in 159 (21%) patients in the EES group versus 192 (26%) in the BMS group (hazard ratio 0.80, 95% CI 0.65-0.98; p=0.033). This difference was mainly driven by a reduced rate of all-cause mortality (65 [9%] vs 88 [12%]; 0.72, 0.52-0.10; p=0.047). INTERPRETATION: Our findings should be taken as a point of reference for the assessment of new bioresorbable polymer-based metallic stents or bioresorbable scaffolds in patients with ST-segment elevation myocardial infarction. FUNDING: Spanish Heart Foundation. PMID- 26520232 TI - Long-term EXAMINATION of drug-eluting stents in acute myocardial infarction. PMID- 26520233 TI - [Peritonitis in pediatric patients receiving peritoneal dialysis]. AB - BACKGROUND: Peritonitis on catheter of dialysis represents the most frequent complication of the peritoneal dialysis (PD) in the pediatric population. It remains a significant cause of morbidity and mortality. In this study, we investigated the risk factors for peritonitis in children. METHODS: In this study, we retrospectively collected the records of 85 patients who were treated with PD within the past ten years in the service of pediatrics of the University Hospital Charles-Nicolle of Tunis. RESULTS: Peritonitis rate was 0.75 episode per patient-year. Notably, peritonitis caused by Gram-positive organisms were more common. Analysis of infection risk revealed three significant independent factors: the poor weight (P=0.0045), the non-automated PD (P=0.02) and the short delay from catheter insertion to starting PD (P=0.02). The early onset peritonitis was significantly associated with frequent peritonitis episodes (P=0.0008). The mean duration between the first and second episode of peritonitis was significantly shorter than between PD commencement and the first episode of peritonitis. We revealed a significant association between Gram-negative peritonitis and the presence of ureterostomy (0.018) and between Gram-positive peritonitis and the presence of exit-site and tunnel infections (0.02). Transition to permanent hemodialysis was needed in many children but no death occurred in patients with peritonitis. CONCLUSION: Considering the important incidence of peritonitis in our patients, it is imperative to establish a targeted primary prevention. Nutritional care must be provided to children to avoid poor weight. The automated dialysis has to be the modality of choice. PMID- 26520231 TI - The World report on ageing and health: a policy framework for healthy ageing. AB - Although populations around the world are rapidly ageing, evidence that increasing longevity is being accompanied by an extended period of good health is scarce. A coherent and focused public health response that spans multiple sectors and stakeholders is urgently needed. To guide this global response, WHO has released the first World report on ageing and health, reviewing current knowledge and gaps and providing a public health framework for action. The report is built around a redefinition of healthy ageing that centres on the notion of functional ability: the combination of the intrinsic capacity of the individual, relevant environmental characteristics, and the interactions between the individual and these characteristics. This Health Policy highlights key findings and recommendations from the report. PMID- 26520234 TI - Diversity of Enterocytozoon bieneusi genotypes among small rodents in southwestern Poland. AB - Diversity of Enterocytozoon bieneusi genotypes in wild small rodent populations still remains incomplete and only few molecular studies have been conducted among these hosts. Therefore, the aim of this study was to determine whether small rodents, i.e., Apodemus agrarius, Apodemus flavicollis, Mus musculus and Myodes glareolus act as hosts of E. bieneusi and can play an important role in spore spreading in the environment of south-western Poland. Molecular analyses were conducted to determine pathogen genotypes. A total of 191 fecal and 251 spleen samples collected from 311 rodent individuals were examined for the occurrence of E. bieneusi by PCR amplifying ITS gene. The overall prevalence of E. bieneusi in rodent samples was 38.9%. The nucleotide sequences of ITS region of E. bieneusi revealed the presence a total of 12 genotypes with two being already known, i.e., D and gorilla 1 genotypes. The remaining ten are novel genotypes (WR1-WR10) which segregated into three groups in a neighbor joining phylogeny. This study reports for the first time E. bieneusi occurrence in wild living rodents in Poland and shows extensive genetic diversity within E. bieneusi isolates of rodent origin. PMID- 26520235 TI - Impact of the automatic rounding-off function of the computerized physician order entry system on the ordering time and dose dispersion of chemotherapeutic drugs in regimens for hematologic malignancies. AB - INTRODUCTION: EGMAIN-GX is the computerized physician order entry system used in Japan. The automatic rounding-off of the calculated dose of chemotherapeutic drugs is an update in version 4, compared to version 2. We conducted a comparative study between EGMAIN-GX versions 2 and 4 to estimate the effect of the automatic rounding-off function on ordering time and dose dispersion. METHODS: Twelve hematologists ordered 5 predefined chemotherapeutic regimens most commonly used in treating hematologic malignancies, twice for each regimen. RESULTS: EGMAIN-GX version 4 significantly reduced ordering times compared to version 2 (635s vs. 259s, p<0.01). EGMAIN-GX version 4 also yielded a significantly higher ratio of actual to ideal doses of chemotherapeutic drugs than did version 2 (1.0097 and 0.9997, respectively; p<0.01) and a lower standard deviation (0.0275 and 0.0290, respectively). CONCLUSIONS: The automatic rounding off function could decrease the ordering time and dose dispersion of chemotherapeutic drugs. PMID- 26520236 TI - Reformatted 3D airway imaging in patients with airway obstruction and micrognathia. AB - PURPOSE: Mandibular distraction osteogenesis (MDO) is an effective treatment for patients with micrognathia and severe recurrent airway obstruction (Denny, 2004; Denny and Amm, 2005; Denny, 2009; Cicchetti et al., 2012; Flores et al., 2014). However the efficacy of the procedure is based on selecting the appropriate patient. Presence of central apnea or airway obstruction anywhere other than the tongue base will make MDO futile. The availability of three dimensional reformatting of the airway has greatly improved the accuracy of correct patient selection, providing a powerful tool to further characterize the pathology in these patients. METHODS: We conducted a retrospective review of the last thirty patients with micrognathia and severe recurrent airway obstruction seen in consult by the senior author for potential role of surgery in their management. RESULTS: Twenty-one patients met our inclusion criteria, with fourteen treated appropriately with MDO. The remaining patients had findings on the 3D airway CT scans with other anatomic causes of obstruction making them inappropriate candidates for mandibular distraction osteogenesis. CONCLUSIONS: The use of three dimensional formatting of the airway from CT scans obtained using low dose protocols has improved the accuracy of evaluation and treatment of Pierre Robin patients. Most valuable is the non-invasive identification of airway abnormalities that would make mandibular distraction osteogenesis ineffective in correcting the airway obstruction. PMID- 26520238 TI - Behavioral and biochemical adjustments of the zebrafish Danio rerio exposed to the beta-blocker propranolol. AB - Propranolol (PROP) is a beta-blocker prescribed mainly to treat human cardiovascular diseases and as a result of its wide usage and persistence, it is reported in aquatic environments. This study examined whether PROP alters developmental patterns and catecholamine (CA)-regulated processes in the zebrafish (Danio rerio) and if exposure during early life alters the stress response and behaviors of adults. The calculated 48h larva LC50 was 21.6mg/L, well above reported environmental levels (0.01-0.59MUg/L). Stressed and PROP exposed adult zebrafish had reduced testosterone and estradiol levels and exhibited behaviors indicating less anxiety than control fish. Furthermore, adults previously PROP-exposed as embryos/larvae had decreased growth in terms of body length and mass. Finally, these adults showed increased cholesterol and a dose-dependent decrease in testosterone levels compared with unexposed zebrafish. Thus PROP-exposure of zebrafish embryos/larvae alters developmental patterns and CA-regulated processes that may affect normal behaviors and responses to stressors, and at least some of these changes persist in the adult zebrafish. PMID- 26520237 TI - Personal support networks, social capital, and risk of relapse among individuals treated for substance use issues. AB - BACKGROUND: The success of treatment for substance use issues varies with personal and social factors, including the composition and structure of the individual's personal support network. This paper describes the personal support networks and social capital of a sample of Italian adults after long-term residential therapeutic treatment for substance use issues, and analyses network correlates of post-treatment substance use (relapse). METHODS: Using a social network analysis approach, data were obtained from structured interviews (90-120 min long) with 80 former clients of a large non-governmental therapeutic treatment agency in Italy providing voluntary residential treatments and rehabilitation services for substance use issues. Participants had concluded the program at least six months prior. Data were collected on socio-demographic variables, addiction history, current drug use status (drug-free or relapsed), and the composition and structure of personal support networks. Factors related to risk of relapse were assessed using bivariate and multivariate logistic regression models. RESULTS: A main goal of this study was to identify differences between the support network profiles of drug free and relapsed participants. Drug free participants had larger, less dense, more heterogeneous and reciprocal support networks, and more brokerage social capital than relapsed participants. Additionally, a lower risk of relapse was associated with higher socio-economic status, being married/cohabiting, and having network members with higher socio economic status, who have greater occupational heterogeneity, and reciprocate support. CONCLUSIONS: Post-treatment relapse was found to be negatively associated with the socioeconomic status and occupational heterogeneity of ego's support network, reciprocity in the ties between ego and network members, and a support network in which the members are relatively loosely connected with one another (i.e., ego possesses "brokerage social capital"). These findings suggest the incorporation into therapeutic programming of interventions that address those aspects of clients' personal support networks. PMID- 26520239 TI - Molecular Histochemistry Identifies Peptidomic Organization and Reorganization Along Striatal Projection Units. AB - Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) (MALDI-IMS) provides a technical means for simultaneous analysis of precise anatomic localization and regulation of peptides. We explored the technical capability of matrix-assisted laser desorption ionization mass spectrometry for characterization of peptidomic regulation by an addictive substance along two distinct projection systems in the mouse striatum. The spatial expression patterns of substance P and proenkephalin, marker neuropeptides of two distinct striatal projection neurons, were negatively correlated at baseline. We detected 768 mass/charge (m/z) peaks whose expression levels were mostly negatively and positively correlated with expression levels of substance P and proenkephalin A (amino acids 218-228), respectively, within the dorsal striatum. After nicotine administration, there was a positive shift in correlation of mass/charge peak expression levels with substance P and proenkephalin A (218-228). Our exploratory analyses demonstrate the technical capacity of MALDI-IMS for comprehensive identification of peptidomic regulation patterns along histochemically distinguishable striatal projection pathways. PMID- 26520241 TI - Influence of charge exchange in acidic aqueous and alcoholic titania dispersions on viscosity. AB - Charging effects resulting from adsorption of acid, acid anions, and protons on titania (anatase) surfaces in anhydrous or mixed alcohol-water dispersions is summarized. The suddenly enhanced conductivity as compared to titania-free solutions has previously been modeled and explained as surface-induced electrolytic dissociation (SIED) of weak acids. This model and recently published results identifying concurrent surface-induced liquid (solvent) dissociation (SILD) are evaluated with experimentally determined conductivity and pH of solutions, zeta-potential of particles, and viscosity of dispersions. Titania (0 25wt%)-alcohol (methanol, ethanol, and propanol) dispersions mixed with (0 100wt%) water were acidified with oxalic, phosphoric, and sulfuric acids. It was found that the experimental results could in many cases be condensed to master curves representing extensive experimental results. These curves reveal that major properties of the systems appear within three concentration regions were different mechanisms (SILD, surface-induced liquid dissociation; SIAD, surface induced acid dissociation) and charge rearrangement were found to be simultaneously active. In particular, zeta-potential - pH and viscosity - pH curves are in acidified non-polar solvents mirror images to those dependencies observed in aqueous dispersions to which hydroxyl is added. The results suggest that multiple dispersion and adsorption equilibria should be considered in order to characterize the presented exceptionally extensive and complex experimental results. PMID- 26520240 TI - Enhancement of Psychosocial Treatment With D-Cycloserine: Models, Moderators, and Future Directions. AB - Advances in the understanding of the neurobiology of fear extinction have resulted in the development of d-cycloserine (DCS), a partial glutamatergic N methyl-D-aspartate agonist, as an augmentation strategy for exposure treatment. We review a decade of research that has focused on the efficacy of DCS for augmenting the mechanisms (e.g., fear extinction) and outcome of exposure treatment across the anxiety disorders. Following a series of small-scale studies offering strong support for this clinical application, more recent larger-scale studies have yielded mixed results, with some showing weak or no effects. We discuss possible explanations for the mixed findings, pointing to both patient and session (i.e., learning experiences) characteristics as possible moderators of efficacy, and offer directions for future research in this area. We also review recent studies that have aimed to extend the work on DCS augmentation of exposure therapy for the anxiety disorders to DCS enhancement of learning-based interventions for addiction, anorexia nervosa, schizophrenia, and depression. Here, we attend to both DCS effects on facilitating therapeutic outcomes and additional therapeutic mechanisms beyond fear extinction (e.g., appetitive extinction, hippocampal-dependent learning). PMID- 26520242 TI - Ionic liquids for nano- and microstructures preparation. Part 2: Application in synthesis. AB - Ionic liquids (ILs) are widely applied to prepare metal nanoparticles and 3D semiconductor microparticles. Generally, they serve as a structuring agent or reaction medium (solvent), however it was also demonstrated that ILs can play a role of a co-solvent, metal precursor, reducing as well as surface modifying agent. The crucial role and possible types of interactions between ILs and growing particles have been presented in the Part 1 of this review paper. Part 2 of the paper gives a comprehensive overview of recent experimental studies dealing with application of ionic liquids for preparation of metal and semiconductor based nano- and microparticles. A wide spectrum of preparation routes using ionic liquids is presented, including precipitation, sol-gel technique, hydrothermal method, nanocasting and ray-mediated methods (microwave, ultrasound, UV-radiation and gamma-radiation). It was found that ionic liquids formed of a 1-butyl-3-methylimidazolium [BMIM] combined with tetrafluoroborate [BF4], hexafluorophosphate [PF6], and bis(trifluoromethanesulfonyl)imide [Tf2N] are the most often used ILs in the synthesis of nano- and microparticles, due to their low melting temperature, low viscosity and good transportation properties. Nevertheless, examples of other IL classes with intrinsic nanoparticles stabilizing abilities such as phosphonium and ammonium derivatives are also presented. Experimental data revealed that structure of ILs (both anion and cation type) affects the size and shape of formed metal particles, and in some cases may even determine possibility of particles formation. The nature of the metal precursor determines its affinity to polar or nonpolar domains of ionic liquid, and therefore, the size of the nanoparticles depends on the size of these regions. Ability of ionic liquids to form varied extended interactions with particle precursor as well as other compounds presented in the reaction media (water, organic solvents etc.) provides nano- and microstructures with different morphologies (0D nanoparticles, 1D nanowires, rods, 2D layers, sheets, and 3D features of molecules). ILs interact efficiently with microwave irradiation, thus even small amount of IL can be employed to increase the dielectric constant of nonpolar solvents used in the synthesis. Thus, combining the advantages of ionic liquids and ray-mediated methods resulted in the development of new ionic liquid assisted synthesis routes. One of the recently proposed approaches of semiconductor particles preparation is based on the adsorption of semiconductor precursor molecules at the surface of micelles built of ionic liquid molecules playing a role of a soft template for growing microparticles. PMID- 26520244 TI - Regulatory controversy on the pediatric ventricular assist device trial in Japan. PMID- 26520243 TI - Near-infrared light activated delivery platform for cancer therapy. AB - Cancer treatment using conventional drug delivery platforms may lead to fatal damage to normal cells. Among various intelligent delivery platforms, photoresponsive delivery platforms are becoming popular, as light can be easily focused and tuned in terms of power intensity, wavelength, and irradiation time, allowing remote and precise control over therapeutic payload release both spatially and temporally. This unprecedented controlled delivery manner is important to improve therapeutic efficacy while minimizing side effects. However, most of the existing photoactive delivery platforms require UV/visible excitation to initiate their function, which suffers from phototoxicity and low level of tissue penetration limiting their practical applications in biomedicine. With the advanced optical property of converting near infrared (NIR) excitation to localized UV/visible emission, upconversion nanoparticles (UCNPs) have emerged as a promising photoactive delivery platform that provides practical applications for remote spatially and temporally controlled release of therapeutic payload molecules using low phototoxic and high tissue penetration NIR light as the excitation source. This article reviews the state-of-the-art design, synthesis and therapeutic molecular payload encapsulation strategies of UCNP-based photoactive delivery platforms for cancer therapy. Challenges and promises for engineering of advanced delivery platforms are also highlighted. PMID- 26520245 TI - Impact of increased time at the highest urgency category on heart transplant outcomes for candidates with ventricular assist devices. AB - BACKGROUND: Ventricular assist devices (VADs) have improved survival among end stage heart disease patients. Since 2002, heart transplant candidates with VADs have been afforded 30 days of elective time at the highest urgency category (Status 1A) under Organ Procurement and Transplantation Network (OPTN) policy. We aimed to determine the effect of increasing elective time at the highest urgency category for heart transplant candidates with VADs. This analysis was requested by OPTN during its evaluation of heart allocation policy. METHODS: We simulated several allocation schemes wherein elective Status 1A time was increased to 45, 60, and 90 days; results were compared with a baseline simulation of 30 days and with the actual observed heart transplant waiting list cohort. RESULTS: The simulations showed that increasing elective Status 1A time for candidates with VADs did not substantially change waiting list mortality overall or for sub groups of concern, which were candidates with VADs listed at a lower-urgency category (Status 1B), those with with VAD complications, total artificial heart, or intraaortic balloon pump support; or those with extracorporeal membrane oxygenation. Across the different time allowances, the average post-transplant death rate remained stable. It also remained stable for recipients previously listed as Status 1A or 1B categories for VAD and for recipients with VAD complications or an intraaortic balloon pump at transplant, on extracorporeal membrane oxygenation, and those without devices. CONCLUSIONS: Our results suggest that increasing time in the highest urgency category for candidates with VADs would not improve waiting list mortality or post-transplant outcomes for heart transplant candidates overall. PMID- 26520246 TI - The use of circulating donor specific antibody to predict biopsy diagnosis of antibody-mediated rejection and to provide prognostic value after heart transplantation in children. AB - BACKGROUND: Antibody-mediated rejection (AMR) is a significant cause of mortality after heart transplantation (HT). Although the presence of donor specific antibody (DSA) is a risk factor for developing AMR, serial DSA testing is not widely performed. We aimed to investigate the predictive values and prognostic implications of circulating DSA using endomyocardial biopsy as the gold standard for AMR diagnosis in pediatric recipients of HT. METHODS: We performed a retrospective study in pediatric recipients of HT followed during the period 2009 2013 with at least 1 biopsy paired with DSA testing. Positive DSA was defined at mean fluorescent intensity (MFI) >=2,000 using single antigen bead testing. Statistical analyses included 2 * 2 contingency tables, receiver operating characteristic analysis for optimal MFI cutoffs, Spearman correlation of MFI strength to AMR grade, and Kaplan-Meier analysis of event-free survival. RESULTS: Of 66 children included, 27 (41%) had >=1 DSA positive test. DSA testing had a sensitivity of 92.6%, specificity of 62.2%, positive predictive value of 24.0%, and negative predictive value of 98.5% for biopsy diagnosis of AMR at our institution. There was a statistically significant correlation between higher MFI and higher AMR grade. Patients with positive DSA and AMR had similar survival early after DSA detection but trended toward lower cardiovascular event-free survival later compared with patients without DSA and a negative biopsy. CONCLUSIONS: The results of DSA testing in this cohort showed excellent sensitivity and negative predictive value for biopsy-diagnosed AMR, suggesting that DSA testing may aid in the non-invasive prediction of AMR absence in HT. The correlation of DSA MFI strength with higher AMR biopsy grade and the trend toward differences in longer term cardiovascular outcomes provide evidence for routine DSA monitoring after pediatric HT. PMID- 26520247 TI - Seventh INTERMACS annual report: 15,000 patients and counting. AB - The seventh annual report of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) summarizes the first 9 years of patient enrollment. The Registry includes >15,000 patients from 158 participating hospitals. Trends in device strategy, patient profile at implant and survival are presented. Risk factors for mortality with continuous-flow pumps are updated, and the major causes/modes of death are presented. The adverse event burden is compared between eras, and health-related quality of life is reviewed. A detailed analysis of outcomes after mechanical circulatory support for ambulatory heart failure is presented. Recent summary data from PediMACS and MedaMACS is included. With the current continuous-flow devices, survival at 1 and 2 years is 80% and 70%, respectively. PMID- 26520248 TI - Mechanical circulatory support and simultaneous heart-kidney transplantation: An outcome analysis. AB - BACKGROUND: Single-donor simultaneous heart-kidney transplantation (SHKT) can significantly improve the survival of those with advanced heart failure and advanced renal insufficiency. Data on pre-transplant use of mechanical circulatory support (MCS) devices and outcomes after SHKT are limited and conflicting. METHODS: Using the United Network for Organ Sharing registry data, we evaluated 749 adults undergoing SHKT after January 1, 2000. Patients were categorized into the following groups according to their type of pre-transplant MCS device: none (n = 568), pulsatile-flow left (n = 28), continuous-flow left (n = 68), temporary (n = 12), biventricular (n = 19), total artificial heart (n = 20), and unknown (n = 34). Regression analyses were performed to assess the association between types of MCS and post-transplant outcomes. RESULTS: Pre transplant MCS was not associated with in-hospital mortality (univariate odds ratio [OR], 1.57; 95% confidence interval [CI], 0.82-2.97; p = 0.170) or post discharge mortality (univariate hazard ratio, 0.92; 95% CI, 0.58-1.47; p = 0.733). Patients supported with pre-transplant temporary MCS devices were more likely to suffer from serious complications (composite of cardiac or non-cardiac surgeries, stroke, any drug-treated infection, and permanent pacemaker; multivariable adjusted OR, 10.0; 95% CI, 2.77-36.0; p < 0.001) after SHKT. Pre transplant MCS did not increase risk of post-transplant dialysis (multivariable adjusted OR, 1.19; 95% CI, 0.81-1.75; p = 0.375) or cardiac rejection (univariate OR, 0.71; 95% CI, 0.34-1.51; p = 0.382), and did not prolong the length of hospital stay (>= 4 weeks; multivariable adjusted OR, 1.05; 95% CI, 0.69-1.59; p = 0.832). Post-transplant dialysis status was a major determinant of adverse in hospital (multivariable adjusted OR, 6.17; 95% CI, 3.14-12.1; p < 0.001) and post discharge (multivariable adjusted hazard ratio, 1.56; 95% CI, 1.02-2.39; p = 0.041) mortality after SHKT. CONCLUSIONS: In the current transplant era, survival after SHKT in patients with pre-transplant MCS was equivalent to that of conventional SHKT. Pre-transplant dialysis, and not MCS status, determined the need for post-SHKT dialysis, which in-turn was a major risk factor for in hospital and long-term mortality. PMID- 26520249 TI - Mild cognitive decline. A position statement of the Cognitive Decline Group of the European Innovation Partnership for Active and Healthy Ageing (EIPAHA). AB - INTRODUCTION: Mild cognitive impairment (MCI) is a term used to describe a level of decline in cognition which is seen as an intermediate stage between normal ageing and dementia, and which many consider to be a prodromal stage of neurodegeneration that may become dementia. That is, it is perceived as a high risk level of cognitive change. The increasing burden of dementia in our society, but also our increasing understanding of its risk factors and potential interventions, require diligent management of MCI in order to find strategies that produce effective prevention of dementia. AIM: To update knowledge regarding mild cognitive impairment, and to bring together and appraise evidence about the main features of clinical interest: definitions, prevalence and stability, risk factors, screening, and management and intervention. METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSION: MCI describes a level of impairment in which deteriorating cognitive functions still allow for reasonable independent living, including some compensatory strategies. While there is evidence for some early risk factors, there is still a need to more precisely delineate and distinguish early manifestations of frank dementia from cognitive impairment that is less likely to progress to dementia, and furthermore to develop improved prospective evidence for positive response to intervention. An important limitation derives from the scarcity of studies that take MCI as an endpoint. Strategies for effective management suffer from the same limitation, since most studies have focused on dementia. Behavioural changes may represent the most cost-effective approach. PMID- 26520250 TI - A new index to assess chemicals increasing the greenhouse effect based on their toxicity to algae. AB - CO2, as the typical greenhouse gas causing the greenhouse effect, is a major global environmental problem and has attracted increasing attention from governments. Using algae to eliminate CO2, which has been proposed as an effective way to reduce the greenhouse effect in the past decades, can be disturbed by a growing number of artificial chemicals. Thus, seven types of chemicals and Selenastrum capricornutum (algae) were examined in this study, and the good consistency between the toxicity of artificial chemicals to algae and the disturbance of carbon fixation by the chemicals was revealed. This consistency showed that the disturbance of an increasing number of artificial chemicals to the carbon fixation of algae might be a "malware" worsening the global greenhouse effect. Therefore, this study proposes an original, promising index to assess the risk of deepening the greenhouse effect by artificial chemicals before they are produced and marketed. PMID- 26520251 TI - Quantum-dots-encoded-microbeads based molecularly imprinted polymer. AB - Quantum dots encoded microbeads have various advantages such as large surface area, superb optical properties and the ability of multiplexing. Molecularly imprinted polymer that can mimic the natural recognition entities has high affinity and selectivity for the specific analyte. Here, the concept of utilizing the quantum dots encoded microbeads as the supporting material and the polydopamine as the functional monomer to form the core-shell molecular imprinted polymer was proposed for the first time. The resulted imprinted polymer can provide various merits: polymerization can complete in aqueous environment; fabrication procedure is facile and universal; the obvious economic advantage; the thickness of the imprinting layer is highly controllable; polydopamine coating can improve the biocompatibility of the quantum dot encoded microbeads. The rabbit IgG binding and flow cytometer experiment result showed the distinct advantages of this strategy: cost-saving, facile and fast preparation procedure. Most importantly, the ability for the multichannel detection, which makes the imprinted polydopamine modified encoded-beads very attractive in protein pre concentration, recognition, separation and biosensing. PMID- 26520252 TI - Preparation of hemoglobin (Hb) imprinted polymer by Hb catalyzed eATRP and its application in biosensor. AB - Molecularly imprinted polymer (MIP) was prepared on the surface of Au electrode by electrochemically mediated atom transfer radical polymerization (eATRP) with hemoglobin (Hb) both as catalyst and template molecule. Firstly, the condition for eATRP such as the potential, time and Hb concentration were selected and determined to be -0.51 V, 120 min and 20mg/mL, respectively. Further, the electrode modified with MIP (MIP/Au) was carefully examined by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and scanning electron microscope (SEM). Finally, the MIP/Au electrode was used as a biosensor and successfully applied for the determination of Hb by differential pulse voltammetry (DPV) measurement. The results of experiments showed that the proposed biosensor displayed a broader linear range and a lower detection limit for Hb determination when it was compared to those Hb sensors based on MIP. The linear range was from 1.0 * 10(-10) to 1.0 * 10(1)mg/L with a detection limit of 7.8 * 10(-11)mg/L (S/N=3.3). In a word, the work of this paper established a useful way for the preparation and application of biosensor based on protein imprinted polymers. PMID- 26520253 TI - Ultrasensitive, passive and wearable sensors for monitoring human muscle motion and physiological signals. AB - Flexible sensors have attracted more and more attention as a fundamental part of anthropomorphic robot research, medical diagnosis and physical health monitoring. Here, we constructed an ultrasensitive and passive flexible sensor with the advantages of low cost, lightness and wearability, electric safety and reliability. The fundamental mechanism of the sensor is based on triboelectric effect inducing electrostatic charges on the surfaces between two different materials. Just like a plate capacitor, current will be generated while the distance or size of the parallel capacitors changes caused by the small mechanical disturbance upon it and therefore the output current/voltage will be produced. Typically, the passive sensor unambiguously monitors muscle motions including hand motion from stretch-clench-stretch, mouth motion from open-bite open, blink and respiration. Moreover, this sensor records the details of the consecutive phases in a cardiac cycle of the apex cardiogram, and identify the peaks including percussion wave, tidal wave and diastolic wave of the radial pulse wave. To record subtle human physiological signals including radial pulsilogram and apex cardiogram with excellent signal/noise ratio, stability and reproducibility, the sensor shows great potential in the applications of medical diagnosis and daily health monitoring. PMID- 26520254 TI - Cytotoxic effects of neem oil in the midgut of the predator Ceraeochrysa claveri. AB - Studies of morphological and ultrastructural alterations in target organs have been useful for evaluating the sublethal effects of biopesticides regarded as safe for non-target organisms in ecotoxicological analyses. One of the most widely used biopesticides is neem oil, and its safety and compatibility with natural enemies have been further clarified through bioassays performed to analyze the effects of indirect exposure by the intake of poisoned prey. Thus, this study examined the cellular response of midgut epithelial cells of the adult lacewing, Ceraeochrysa claveri, to neem oil exposure via intake of neem oil contaminated prey during the larval stage. C. claveri larvae were fed Diatraea saccharalis eggs treated with neem oil at concentrations of 0.5%, 1% and 2% throughout the larval stage. The adult females obtained from these treatments were used at two ages (newly emerged and at the start of oviposition) in morphological and ultrastructural analyses. Neem oil was found to cause pronounced cytotoxic effects in the adult midgut, such as cell dilation, emission of cytoplasmic protrusions, cell lysis, loss of integrity of the cell cortex, dilation of cisternae of the rough endoplasmic reticulum, swollen mitochondria, vesiculated appearance of the Golgi complex and dilated invaginations of the basal labyrinth. Epithelial cells responded to those injuries with various cytoprotective and detoxification mechanisms, including increases in cell proliferation, the number of calcium-containing cytoplasmic granules, and HSP 70 expression, autophagic processes and the development of smooth endoplasmic reticulum, but these mechanisms were insufficient for recovery from all of the cellular damage to the midgut. This study demonstrates that neem oil exposure impairs the midgut by causing sublethal effects that may affect the physiological functions of this organ, indicating the importance of studies of different life stages of this species and similar species to evaluate the safe and compatible integrated use of biopesticides. PMID- 26520255 TI - Diagenetic history of lower Pliocene rhodoliths of the Azores Archipelago (NE Atlantic): Application of cathodoluminescence techniques. AB - The diagenetic history of calcareous fossils is required for their application as palaeoenvironmental indicators. In this study, cathodoluminescence-microscopy (CL microscopy) and back scatter electron image-energy dispersive X-ray spectroscopy (BSE-EDS microscopy) were applied to Pliocene rhodoliths from the Azores Archipelago (NE Atlantic) in order to gain additional insight regarding the trace element content distribution throughout the algae thalli, and to ascertain palaeoenvironmental interpretations. Two types of luminescence were obtained: (1) high and (2) low luminescence. Rhodoliths with high luminescence are related with high concentrations of Mn(2+) in seawater and low luminescence rhodoliths are related with low concentrations of Mn(2+) in seawater. When the rhodoliths were deposited at about 4.0-4.5 Ma, the shoreline configuration of Santa Maria Island was much different than today. The influence of volcanic activity due to the extrusion of lavas and associated products and/or the presence of active shallow water hydrothermal vents, was reflected in the sea water chemistry, with penecontemporaneous palaeoshores of the island featuring a high sea water concentration of Mn(2+), which mirrored on the rhodolith Mn(2+) high concentration. By contrast, rhodoliths located about 2.8 and 2.9 km from the shore, in areas with low seawater Mn(2+) concentration, had low luminescence, reflecting the low Mn(2+) concentration in seawater. Rhodoliths chemical data and the geological history of the island proved to be congruent with the palaeogeographical reconstruction of Santa Maria Island at the time of the formation of the rhodoliths. PMID- 26520256 TI - Chronic motivational state interacts with task reward structure in dynamic decision-making. AB - Research distinguishes between a habitual, model-free system motivated toward immediately rewarding actions, and a goal-directed, model-based system motivated toward actions that improve future state. We examined the balance of processing in these two systems during state-based decision-making. We tested a regulatory fit hypothesis (Maddox & Markman, 2010) that predicts that global trait motivation affects the balance of habitual- vs. goal-directed processing but only through its interaction with the task framing as gain-maximization or loss minimization. We found support for the hypothesis that a match between an individual's chronic motivational state and the task framing enhances goal directed processing, and thus state-based decision-making. Specifically, chronic promotion-focused individuals under gain-maximization and chronic prevention focused individuals under loss-minimization both showed enhanced state-based decision-making. Computational modeling indicates that individuals in a match between global chronic motivational state and local task reward structure engaged more goal-directed processing, whereas those in a mismatch engaged more habitual processing. PMID- 26520257 TI - Simultaneous determination of 3-O-acetyloleanolic acid and oleanolic acid in rat plasma using liquid chromatography coupled to tandem mass spectrometry. AB - 3-O-Acetyloleanolic acid (OAA) is a triterpenoid compound, and exerts an apoptosis in cancer cell lines, an inhibition of both atopic and allergic contact dermatitis in murine model, and a suppression of inflammatory bone loss in mice. OAA can be converted into oleanolic acid (OA) by hydrolysis in vivo, and OA exhibits several pharmacological effects as well. A liquid chromatographic method using tandem mass spectrometry (MS/MS) was developed for the simultaneous determination of OAA and OA in rat plasma. After liquid-liquid extraction with ethylacetate, both substances were chromatographed on a reversed phase column with a mobile phase of 0.1% formic acid aqueous solution and acetonitrile (1:9, v/v). The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods. This analytical method was successfully applied to monitor plasma concentrations of both substances over time following an intravenous administration of OAA in rats. PMID- 26520258 TI - Energy flux parametrization as an opportunity to get Urban Heat Island insights: The case of Athens, Greece (Thermopolis 2009 Campaign). AB - Energy flux parameterization was effected for the city of Athens, Greece, by utilizing two approaches, the Local-Scale Urban Meteorological Parameterization Scheme (LUMPS) and the Bulk Approach (BA). In situ acquired data are used to validate the algorithms of these schemes and derive coefficients applicable to the study area. Model results from these corrected algorithms are compared with literature results for coefficients applicable to other cities and their varying construction materials. Asphalt and concrete surfaces, canyons and anthropogenic heat releases were found to be the key characteristics of the city center that sustain the elevated surface and air temperatures, under hot, sunny and dry weather, during the Mediterranean summer. A relationship between storage heat flux plus anthropogenic energy flux and temperatures (surface and lower atmosphere) is presented, that results in understanding of the interplay between temperatures, anthropogenic energy releases and the city characteristics under the Urban Heat Island conditions. PMID- 26520259 TI - Spatial and temporal distributions of aerosol concentrations and depositions in Asia during the year 2010. AB - Aerosol Modeling System (AMS) that is consisted of the Asian Dust Aerosol Model2 (ADAM2) and the Community Multi-scale Air Quality (CMAQ) modeling system has been employed to document the spatial distributions of the monthly and the annual averaged concentration of both the Asian dust (AD) aerosol and the anthropogenic aerosol (AA), and their total depositions in the Asian region for the year 2010. It is found that the annual mean surface aerosol (PM10) concentrations in the Asian region affect in a wide region as a complex mixture of AA and AD aerosols; they are predominated by the AD aerosol in the AD source region of northern China and Mongolia with a maximum concentration exceeding 300 MUg m(-3); AAs are predominated in the high pollutant emission regions of southern and eastern China and northern India with a maximum concentration exceeding 110 MUg m(-3); while the mixture of AA and AD aerosols is dominated in the downwind regions extending from the Yellow Sea to the Northwest Pacific Ocean. It is also found that the annual total deposition of aerosols in the model domain is found to be 485 Tg (372 Tg by AD aerosol and 113 Tg by AA), of which 66% (319 Tg) is contributed by the dry deposition (305 Tg by AD aerosol and 14 Tg by AA) and 34% (166 Tg) by the wet deposition (66 Tg by AD aerosol and 100 Tg by AA), suggesting about 77% of the annual total deposition being contributed by the AD aerosol mainly through the dry deposition process and 24% of it by AA through the wet deposition process. The monthly mean aerosol concentration and the monthly total deposition show a significant seasonal variation with high in winter and spring, and low in summer. PMID- 26520260 TI - Effects of diphenyl diselenide on growth, oxidative damage, and antioxidant response in silver catfish. AB - The aim of this study was to evaluate the effects of dietary diphenyl diselenide [(PhSe)2] at different concentrations (1.5, 3.0, and 5.0 mg/kg) on growth, oxidative damage and antioxidant parameters in silver catfish after 30 and 60 days. Fish fed with 5.0 mg/kg of (PhSe)2 experienced a significant decrease in weight, length, and condition factor after 30 days and these parameters increased after 60 days. Thiobarbituric acid reactive substances (TBARS) and protein carbonyl (PC) decreased in the liver of silver catfish supplemented with (PhSe)2 after 30 days at all concentrations, while after 60 days these parameters decreased in liver, gills, brain, and muscle. Supplementation with (PhSe)2 induced a decrease in catalase (CAT) activity from liver only after 60 days of feeding. Superoxide dismutase (SOD) decreased at 5.0 mg/kg after 30 and 60 days and glutathione peroxidase (GPx) was enhanced at 1.5 and 3.0 mg/kg after 30 and 60 days. Silver catfish supplemented for 30 days showed a significant increase in liver glutathione S-transferase (GST) at 3.0 mg/kg, while after 60 days GST activity increased in liver at 1.5, 3.0, and 5.0 mg/kg and in gills at 3.0 and 5.0 mg/kg of (PhSe)2. After 30 days, non-protein thiols (NPSH) did not change, while after 60 days NPSH increased in liver, gills, brain, and muscle. In addition, ascorbic acid (AA) levels after 30 days increased in liver at three concentrations and in gills and muscle at 1.5 mg/kg, while after 60 days, AA increased at all concentrations in all and tissues tested. Thus, diet supplemented with (PhSe)2 for 60 days could be more effective for silver catfish. Although the concentration of 5.0 mg/kg showed decreased growth parameters, concentrations of 1.5 and 3.0 mg/kg, in general, decreased oxidative damage and increased antioxidant defenses. PMID- 26520261 TI - The relationship between economic growth, energy consumption, and CO2 emissions: Empirical evidence from China. AB - Following several decades of rapid economic growth, China has become the largest energy consumer and the greatest emitter of CO2 in the world. Given the complex development situation faced by contemporary China, Chinese policymakers now confront the dual challenge of reducing energy use while continuing to foster economic growth. This study posits that a better understanding of the relationship between economic growth, energy consumption, and CO2 emissions is necessary, in order for the Chinese government to develop the energy saving and emission reduction strategies for addressing the impacts of climate change. This paper investigates the cointegrating, temporally dynamic, and casual relationships that exist between economic growth, energy consumption, and CO2 emissions in China, using data for the period 1990-2012. The study develops a comprehensive conceptual framework in order to perform this analysis. The results of cointegration tests suggest the existence of long-run cointegrating relationship among the variables, albeit with short dynamic adjustment mechanisms, indicating that the proportion of disequilibrium errors that can be adjusted in the next period will account for only a fraction of the changes. Further, impulse response analysis (which describes the reaction of any variable as a function of time in response to external shocks) found that the impact of a shock in CO2 emissions on economic growth or energy consumption was only marginally significant. Finally, Granger casual relationships were found to exist between economic growth, energy consumption, and CO2 emissions; specifically, a bi-directional causal relationship between economic growth and energy consumption was identified, and a unidirectional causal relationship was found to exist from energy consumption to CO2 emissions. The findings have significant implications for both academics and practitioners, warning of the need to develop and implement long-term energy and economic policies in order to effectively address greenhouse effects in China, thereby setting the nation on a low-carbon growth path. PMID- 26520262 TI - Assessing irrigated agriculture's surface water and groundwater consumption by combining satellite remote sensing and hydrologic modelling. AB - Globally, irrigation accounts for more than two thirds of freshwater demand. Recent regional and global assessments indicate that groundwater extraction (GWE) for irrigation has increased more rapidly than surface water extraction (SWE), potentially resulting in groundwater depletion. Irrigated agriculture in semi arid and arid regions is usually from a combination of stored surface water and groundwater. This paper assesses the usefulness of remotely-sensed (RS) derived information on both irrigation dynamics and rates of actual evapotranspiration which are both input to a river-reach water balance model in order to quantify irrigation water use and water provenance (either surface water or groundwater). The assessment is implemented for the water-years 2004/05-2010/11 in five reaches of the Murray-Darling Basin (Australia); a heavily regulated basin with large irrigated areas and periodic droughts and floods. Irrigated area and water use are identified each water-year (from July to June) through a Random Forest model which uses RS vegetation phenology and actual evapotranspiration as predicting variables. Both irrigated areas and actual evapotranspiration from irrigated areas were compared against published estimates of irrigated areas and total water extraction (SWE+GWE).The river-reach model determines the irrigated area that can be serviced with stored surface water (SWE), and the remainder area (as determined by the Random Forest Model) is assumed to be supplemented by groundwater (GWE). Model results were evaluated against observed SWE and GWE. The modelled SWE generally captures the observed interannual patterns and to some extent the magnitudes, with Pearson's correlation coefficients >0.8 and normalised root-mean-square-error<30%. In terms of magnitude, the results were as accurate as or better than those of more traditional (i.e., using areas that fluctuate based on water resource availability and prescribed crop factors) irrigation modelling. The RS irrigated areas and actual evapotranspiration can be used to: (i) understand irrigation dynamics, (ii) constrain irrigation models in data scarce regions, as well as (iii) pinpointing areas that require better ground-based monitoring. PMID- 26520263 TI - Restoring fish ecological quality in estuaries: Implication of interactive and cumulative effects among anthropogenic stressors. AB - Estuaries are subjected to multiple anthropogenic stressors, which have additive, antagonistic or synergistic effects. Current challenges include the use of large databases of biological monitoring surveys (e.g. the European Water Framework Directive) to help environmental managers prioritizing restoration measures. This study investigated the impact of nine stressor categories on the fish ecological status derived from 90 estuaries of the North East Atlantic countries. We used a random forest model to: 1) detect the dominant stressors and their non-linear effects; 2) evaluate the ecological benefits expected from reducing pressure from stressors; and 3) investigate the interactions among stressors. Results showed that largest restoration benefits were expected when mitigating water pollution and oxygen depletion. Non-additive effects represented half of pairwise interactions among stressors, and antagonisms were the most common. Dredged sediments, flow changes and oxygen depletion were predominantly implicated in non additive interactions, whereas the remainder stressors often showed additive impacts. The prevalence of interactive impacts reflects a complex scenario for estuaries management; hence, we proposed a step-by-step restoration scheme focusing on the mitigation of stressors providing the maximum of restoration benefits under a multi-stress context. PMID- 26520264 TI - Moss bag biomonitoring of airborne toxic element decrease on a small scale: A street study in Belgrade, Serbia. AB - A database of potentially hazardous substances, necessary for estimating the exposure of humans to air pollutants, may be deficient because of a limited number of regulatory monitoring stations. This study was inspired by undeniably harmful effects of human long-term exposure to intense traffic emissions in urban area. Moss bag biomonitors were used to characterize spatial variation of airborne toxic elements near crossroads and two- and one-lane streets. The Sphagnum girgensohnii and Hypnum cupressiforme moss bags were exposed for 10 weeks to 48 sampling sites across Belgrade (Serbia) during the summer of 2014. In addition, oven-drying pretreatment of the moss bags was tested. During the experimental period, traffic flows were estimated at each site by counting the number of vehicles during the rush hours. The concentrations of 39 elements were determined in the moss samples. There was no significant difference between the results obtained for nontreated and oven-dried moss bags. For the majority of elements, the moss bags identified a common pattern of decrease in the concentration from crossroads to two- and one-lane streets. The exposed moss bags were enriched with Sb, Cu and Cr. The correlation coefficients (r=0.65-0.70) between the moss concentrations of Cr, Cu, Fe and Sb and the site-counted traffic flows also confirmed a dependence of the airborne element content on traffic emissions. A strong correlation with traffic flows makes Sb, Cu and Cr reliable traffic tracers. PMID- 26520265 TI - Recent DDT and PCB contamination in the sediment and biota of the Como Bay (Lake Como, Italy). AB - Due to its peculiar geographical and morphological characteristics, Lake Como (Northern Italy) represents an interesting study-case for investigating the sub basin scale circulation of persistent organic pollutants (POPs) that, despite being banned since the 1970s, have reached surprisingly high concentrations in some southern alpine lakes as a consequence of their release from melting glaciers in recent years. In particular, the Como Bay, which is located in the city of Como, seems noteworthy because its waters have a longer residence time than the other areas of the lake. The analyses of the historical concentration of PCBs, pp'DDT and its metabolites in a sediment core sampled from the Como Bay covering a time-period from their ban to recent times, showed that the DDTs have never experienced a significant (p < 0.05) decrease over time, with concentrations of the most abundant homologue, pp'DDE, ranging from 27 to 75 ng g(-1) d.w. Conversely PCBs significantly (p < 0.05) decreased towards recent times, reaching concentrations around 80 ng g(-1) d.w. The contribution of high altitude and local sources was recorded also in the food web: both zooplankton and the zooplanktivorous fish agone were mainly contaminated by pp'DDE (81.4 ng g(-1) w.w. and 534.6 ng g(-1) w.w. respectively) and by the PCB metabolite hexa CB (449.7 ng g(-1) w.w. and 1672.1 ng g(-1) w.w. respectively). The DDT concentrations in the agone (sampled during the years 2006-2009) never exceeded the limits for human consumption in Italy, while concentrations of six selected PCBs exceeded human health advisory recommendations in one of the fish samples analysed, when it was approximately two times higher than the recommended value of 125 ng g(-1) w.w. PMID- 26520266 TI - A review on current knowledge and future prospects of organohalogen contaminants (OHCs) in Asian birds. AB - The release of harmful chemicals in the Asian environment has recently increased dramatically due to rising industrial and agricultural activities. About 60% of the global human population is currently living on the Asian continent and may thus be exposed to a large range of different chemicals. Different classes of organohalogen chemicals have indeed been reported in various environmental compartments from Asia including humans and wildlife, but this issue has received less attention in birds. In this article, we reviewed the available literature on levels of legacy persistent organic pollutants (POPs) and various flame retardants (FRs) in Asian avifauna to analyze the existing pool of knowledge as well as to identify the gaps that should be addressed in future research. Furthermore, we discussed the variation in levels of organohalogens based on differences in regions, trophic level, dietary sources and migratory behaviors of species including distribution patterns in different tissues of birds. Although the mass of published literature is very low and even absent in many important regions of Asia, we deduced from the reported studies that levels of almost all classes of organohalogens (OHCs) including FRs were highest in East Asian countries such as Japan, China and South Korea, except for HCHs that were found at maximum levels in birds of South India. Concentrations (ng/g LW) of different OHCs in Asian birds ranged between 2% of the samples included: insecticides thiamethoxam (46%), bifenthrin (28%), clothianidin (24%), chlorpyrifos (17%), imidacloprid (13%), fipronil desulfinyl (7%; degradate); fungicides azoxystrobin (17%), pyraclostrobin (11%), fluxapyroxad (9%), and propiconazole (9%); herbicides atrazine (19%) and metolachlor (9%). Concentrations ranged from 1 to 310 ng/g for individual pesticides. Pesticides were detected in samples collected from both grasslands and wheat fields; the location of the sample and the surrounding land cover at the 1000 m radius influenced the pesticides detected but because of a small number of temporally comparable samples, correlations between pesticide concentration and land cover were not significant. The results show native bees collected in an agricultural landscape are exposed to multiple pesticides, these results can direct future research on routes/timing of pesticide exposure and the design of future conservation efforts for pollinators. PMID- 26520271 TI - Multiple factors drive regional agricultural abandonment. AB - An understanding of land-use change and its drivers in agroecosystems is important when developing adaptations to future environmental and socioeconomic pressures. Agricultural abandonment occurs worldwide with multiple potentially positive and negative consequences; however, the main factors causing agricultural abandonment in a country i.e., at the macro scale, have not been identified. We hypothesized that socio-environmental factors driving agricultural abandonment could be summarized comprehensively into two, namely "natural" and "social", and the relative importance of these differs among regions. To test this postulate, we analyzed the factors currently leading to agricultural abandonment considering ten natural environment variables (e.g., temperature) and five social variables (e.g., number of farmers) using the random forest machine learning method after dividing Japan into eight regions. Our results showed that agricultural abandonment was driven by various socio-environmental factors, and the main factors leading to agricultural abandonment differed among regions, especially in Hokkaido in northern Japan. Hokkaido has a relatively large area of concentrated farmland, and abandonment might have resulted from the effectiveness of cultivation under specific climate factors, whereas the other regions have relatively small areas of farmland with many elderly part-time farmers. In such regions, abandonment might have been caused by the decreasing numbers of potential farmers. Thus, two different drivers of agricultural abandonment were found: inefficient cultivation and decreasing numbers of farmers. Therefore, agricultural abandonment cannot be prevented by adopting a single method or policy. Agricultural abandonment is a significant problem not only for food production but also for several ecosystem services. Governments and decision makers should develop effective strategies to prevent further abandonment to ensure sustainable future management of agro-ecosystems. PMID- 26520272 TI - Analyzing sites of OH radical attack (ring vs. side chain) in oxidation of substituted benzenes via dual stable isotope analysis (delta(13)C and delta(2)H). AB - OH radicals generated by the photolysis of H2O2 can degrade aromatic contaminants by either attacking the aromatic ring to form phenolic products or oxidizing the substituent. We characterized these competing pathways by analyzing the carbon and hydrogen isotope fractionation (epsilonC and epsilonH) of various substituted benzenes. For benzene and halobenzenes that only undergo ring addition, low values of epsilonC (-0.70/00 to -1.00/00) were observed compared with theoretical values (-7.20/00 to -80/00), possibly owing to masking effect caused by pre equilibrium between the substrate and OH radical preceding the rate-limiting step. In contrast, the addition of OH radicals to nitrobenzene ring showed a higher epsilonC (-3.90/00), probably due to the lower reactivity. Xylene isomers, anisole, aniline, N,N-dimethylaniline, and benzonitrile yielded normal epsilonH values (-2.80/00 to -290/00) indicating the occurrence of side-chain reactions, in contrast to the inverse epsilonH (11.70/00 to 300/00) observed for ring addition due to an sp(2) to sp(3) hybridization change at the reacting carbon. Inverse epsilonH values for toluene (140/00) and ethylbenzene (300/00) were observed despite the formation of side-chain oxidation products, suggesting that ring addition has a larger contribution to isotope fractionation. Dual element isotope slopes (?delta(2)H/?delta(13)C) therefore allow identification of significant degradation pathways of aromatic compounds by photochemically induced OH radicals. Issues that should be addressed in future studies include quantitative determination of the contribution of each competing pathway to the observed isotope fractionation and characterization of physical processes preceding the reaction that could affect isotope fractionation. PMID- 26520273 TI - A multiple lines of evidence approach for the ecological risk assessment of an accidental bitumen release from a steam assisted gravity drainage (SAGD) well in the Athabasca oil sands region. AB - To assess the ecological impacts of two independent accidental bitumen releases from two steam assisted gravity drainage (SAGD) wells in the Athabasca oil sands region, a multiple lines of evidence (LOE) approach was developed. Following the release in 2010, action was taken to minimize environmental impact, including the selective removal of the most highly impacted vegetation and the use of oil socks to minimize possible runoff. An ecological risk assessment (ERA) was then conducted based on reported concentrations of bitumen related contaminants in soil, vegetation, and water. Results of biological assessments conducted at the site were also included in the risk characterization. Overall, the conclusion of the ERA was that the likelihood of long-term adverse health effects to ecological receptors in the area was negligible. To provide evidence for this conclusion, a small mammal sampling plan targeting Southern red-back voles (Myodes gapperi) was carried out at two sites and two relevant reference areas. Voles were readily collected at all locations and no statistically significant differences in morphometric measurements (i.e., body mass, length, foot length, and adjusted liver weight) were found between animals collected from impact zones of varying levels of coverage. Additionally, no trends corresponding with bitumen coverage were observed with respect to metal body burden in voles for metals that were previously identified in the source bitumen. Hepatic ethoxyresorufin-O-deethylase (EROD) activity was statistically significantly elevated in voles collected from the high impact zones of sites compared to those collected from the reference areas, a finding that is indicative of continued exposure to contaminants. However, this increase in EROD was not correlated with any observable adverse population-wide biological outcomes. Therefore the biological sampling program supported the conclusion of the initial ERA and supported the hypothesis of no significant long-term population-wide ecological impact of the accidental bitumen releases. PMID- 26520274 TI - The impact of commercially treated oil and gas produced water discharges on bromide concentrations and modeled brominated trihalomethane disinfection byproducts at two downstream municipal drinking water plants in the upper Allegheny River, Pennsylvania, USA. AB - In 2010, a dramatic increase in the levels of total trihalomethane (THM) and the relative proportion of brominated species was observed in finished water at several Pennsylvania water utilities (PDW) using the Allegheny River as their raw water supply. An increase in bromide (Br(-)) concentrations in the Allegheny River was implicated to be the cause of the elevated water disinfection byproducts. This study focused on quantifying the contribution of Br(-) from a commercial wastewater treatment facility (CWTF) that solely treats wastes from oil and gas producers and discharges into the upper reaches of the Allegheny River, and impacts on two downstream PDWs. In 2012, automated daily integrated samples were collected on the Allegheny River at six sites during three seasonal two-week sampling campaigns to characterize Br(-) concentrations and river dispersion characteristics during periods of high and low river discharges. The CWTF discharges resulted in significant increases in Br(-) compared to upstream baseline values in PDW raw drinking water intakes during periods of low river discharge. During high river discharge, the assimilative dilution capacity of the river resulted in lower absolute halide concentrations, but significant elevations Br(-) concentrations were still observed at the nearest downstream PDW intake over baseline river levels. On days with active CWTF effluent discharge the magnitude of bromide impact increased by 39 ppb (53%) and 7 ppb (22%) for low and high river discharge campaigns, respectively. Despite a declining trend in Allegheny River Br(-) (2009-2014), significant impacts from CWTF and coal-fired power plant discharges to Br(-) concentrations during the low river discharge regime at downstream PDW intakes was observed, resulting in small modeled increases in total THM (3%), and estimated positive shifts (41-47%) to more toxic brominated THM analogs. The lack of available coincident measurements of THM, precursors, and physical parameters limited the interpretation of historical trends. PMID- 26520275 TI - Water footprints of products of oil palm plantations and palm oil mills in Thailand. AB - The water footprint (WF) of fresh fruit bunches (FFBs) from oil palm plantations and crude palm oil (CPO) from palm oil mills in southern and eastern Thailand were determined over 25 years. Climatic conditions, soil characteristics, and the characteristics of oil palm growth were considered. The WF of FFBs was 1063 m(3)/ton (t) on average. Green, blue, and grey waters comprised of 68, 18, and 14% of total WF, respectively. The oil palm plantations in Thailand required smaller amounts of indirect blue water. The average WF for producing a ton of CPO of seven mills was 5083 m(3). Most of the waters used in the mills originated from indirect green, blue and grey waters from the plantations. The direct blue water used in the mills had less impact on the total WF, lower than 1% of the total WF. Average percentages of green, blue, and grey waters of 69, 16, and 15% of total WF were determined for the mills, respectively. The water deprivation of the FFBs and CPO ranged from 0.73-12.9 and 3.44-58.3 m(3)H2Oeq/t, respectively. In 2013, the CPO production in Thailand including green, blue, and grey waters from plantation and blue water from mills required 11,343 million m(3) water. If the oil palm variety Suratthani 7 is used in the plantation, it would increase the yield from 15.2 to 22.8 t FFBs/ha-year and decrease the WF to 888 m(3)/t FFBs. The average value of the oil extraction rate (OER) of mills was 18.1%. With an increase in the OER of 1%, a reduction of the WF of 250 m(3)/t CPO or 5.1% of total WF could be obtained. PMID- 26520276 TI - Long term supervision as a crucial ingredient of all anticoagulant therapy. PMID- 26520277 TI - Future trends and inequalities in premature coronary deaths in England: Modelling study. AB - BACKGROUND: Coronary heart disease (CHD) is a major cause of premature mortality, particularly in deprived groups. Might recent declines in overall mortality obscure different rates of decline among social strata, creating potentially misleading views on inequalities? METHODS: We used a Bayesian analysis of an age period-cohort model for the English population. We projected age-specific premature CHD mortality (ages 35-74) by gender and area-based deprivation status for the period 2007-2035, using 1982-2006 as the input. Deprivation status was measured by Index of Multiple Deprivation quintiles, which aggregate seven types of deprivation, including health and income. We analysed inequality in premature CHD mortality. We investigated the annual changes in inequality and the contributions of changes in each IMDQ to the overall annual changes, using both absolute (probability) and relative (logit) scales. We quantified inequality using the statistical variance in the probability of premature death among deprivation quintiles. RESULTS: The overall premature CHD mortality trends conceal marked heterogeneities. Our models predict more rapid declines in premature CHD mortality for the most affluent quintiles than for the most deprived (annualized rate of decline 2006-2025, 7.5% [95% Credible Interval 4.3 10.5%] versus 5.4% [2.2-8.7%] for men, and 6.3% [3.0-9.9%] versus 5.9% [1.5 10.8%] for women). For men, the posterior probability that the rate of decline is greater for the most affluent was 82%. Variance in premature CHD mortality across deprivation quintiles was projected to decrease by approximately 81% [28-95%] among men and by 89% [30-99%] among women. This decrease was particularly driven by the most deprived groups due to their higher premature death rates. However, relative inequality was projected to rise by 93% among men [81-125%] and rise by 13% [-25-58%] among women. These increases are also mostly influenced by the most deprived, reflecting their slower declines in premature deaths. CONCLUSIONS: Overall, premature coronary death rates in England continue to decline steeply. Absolute inequalities are decreasing, reflecting declines in the high premature mortality in deprived groups. However, relative inequalities are projected to widen further, reflecting slower mortality declines in the most deprived groups. More aggressive and progressive prevention policies are urgently needed. PMID- 26520278 TI - Healing after coronary artery dissection: The effect of a drug coated balloon angioplasty in a bifurcation lesion. A lesson from intravascular ultrasound analysis. PMID- 26520279 TI - Pulse wave velocity measurements in moderate to severe chronic obstructive pulmonary disease: A test-retest reliability study. PMID- 26520280 TI - An unusual indication of heart transplantation. PMID- 26520281 TI - Burden of arrhythmias in patients with multiple myeloma. PMID- 26520283 TI - Jet pumps for thermoacoustic applications: Design guidelines based on a numerical parameter study. AB - The oscillatory flow through tapered cylindrical tube sections (jet pumps) is characterized by a numerical parameter study. The shape of a jet pump results in asymmetric hydrodynamic end effects which cause a time-averaged pressure drop to occur under oscillatory flow conditions. Hence, jet pumps are used as streaming suppressors in closed-loop thermoacoustic devices. A two-dimensional axisymmetric computational fluid dynamics model is used to calculate the performance of a large number of conical jet pump geometries in terms of time-averaged pressure drop and acoustic power dissipation. The investigated geometrical parameters include the jet pump length, taper angle, waist diameter, and waist curvature. In correspondence with previous work, four flow regimes are observed which characterize the jet pump performance and dimensionless parameters are introduced to scale the performance of the various jet pump geometries. The simulation results are compared to an existing quasi-steady theory and it is shown that this theory is only applicable in a small operation region. Based on the scaling parameters, an optimum operation region is defined and design guidelines are proposed which can be directly used for future jet pump design. PMID- 26520282 TI - Chanarin-Dorfman syndrome: A case report and review of the literature. AB - Chanarin-Dorfman syndrome, a "neutral lipid storage disease with ichthyosis," is a multisystem inherited metabolic disorder associated with congenital ichthyosis and accumulation of lipid droplets in various types of cells. CASE REPORT: A 3 year-old male presented to the Pediatric Hepatology Unit, Cairo University Children's Hospital, Cairo, Egypt, with accidentally discovered hepatomegaly. He had generalised ichthyosis with dark skin pigmentation and bilateral ectropion. Abdominal examination revealed generalised abdominal distention with firm nontender hepatomegaly. His liver functions were deranged. Blood film showed many vacuolated neutrophils. Serum triglyceride and creatine kinase levels were elevated. Abdominal ultrasound showed a moderately enlarged liver with a bright echo pattern. Liver biopsy revealed marked diffuse macrovesicular fatty changes. The diagnosis of Chanarin-Dorfman Syndrome was made based on the dermatological, haematological, and liver biopsy findings. PMID- 26520284 TI - Multiple and single snapshot compressive beamforming. AB - For a sound field observed on a sensor array, compressive sensing (CS) reconstructs the direction of arrival (DOA) of multiple sources using a sparsity constraint. The DOA estimation is posed as an underdetermined problem by expressing the acoustic pressure at each sensor as a phase-lagged superposition of source amplitudes at all hypothetical DOAs. Regularizing with an l1-norm constraint renders the problem solvable with convex optimization, and promoting sparsity gives high-resolution DOA maps. Here the sparse source distribution is derived using maximum a posteriori estimates for both single and multiple snapshots. CS does not require inversion of the data covariance matrix and thus works well even for a single snapshot where it gives higher resolution than conventional beamforming. For multiple snapshots, CS outperforms conventional high-resolution methods even with coherent arrivals and at low signal-to-noise ratio. The superior resolution of CS is demonstrated with vertical array data from the SWellEx96 experiment for coherent multi-paths. PMID- 26520285 TI - A test of deep water Rytov theory at 284 Hz and 107 km in the Philippine Sea. AB - Predictions of log-amplitude variance are compared against sample log-amplitude variances reported by White, Andrew, Mercer, Worcester, Dzieciuch, and Colosi [J. Acoust. Soc. Am. 134, 3347-3358 (2013)] for measurements acquired during the 2009 Philippine Sea experiment and associated Monte Carlo computations. The predictions here utilize the theory of Munk and Zachariasen [J. Acoust. Soc. Am. 59, 818-838 (1976)]. The scattering mechanism is the Garrett-Munk internal wave spectrum scaled by metrics based on measured environmental profiles. The transmitter was at 1000 m depth and the receivers at nominal range 107 km and depths 600-1600 m. The signal was a broadband m-sequence centered at 284 Hz. Four classes of propagation paths are examined: the first class has a single upper turning point at about 60 m depth; the second and third classes each have two upper turning points at roughly 250 m; the fourth class has three upper turning points at about 450 m. Log-amplitude variance for all paths is predicted to be 0.04-0.09, well within the regime of validity of either Born or Rytov scattering. The predictions are roughly consistent with the measured and Monte Carlo log amplitude variances, although biased slightly low. Paths turning in the extreme upper ocean (near the mixed layer) seem to incorporate additional scattering mechanisms not included in the original theory. PMID- 26520286 TI - Characterization of immersed transversely isotropic rods by inversion of acoustic scattering data. AB - An ultrasonic technique is proposed for measurement of the elastic constants of a transversely isotropic cylindrical sample. This technique can measure all five elastic constants of a transversely isotropic rod or fiber nondestructively. The immersed rod is insonified first by a normally incident, and then by an obliquely incident, ultrasonic wave and the backscattered pressure amplitude spectra, form functions, are measured. The elastic constants of the transversely isotropic cylindrical sample are then extracted from these form functions by an inversion process. The inversion process is based on a genetic algorithm and matches a theoretical model to the measured form functions at resonance points. The proposed approach is simple and very accurate. PMID- 26520287 TI - Arctic underwater noise transients from sea ice deformation: Characteristics, annual time series, and forcing in Beaufort Sea. AB - A 13-month time series of Arctic Ocean noise from the marginal ice zone of the Eastern Beaufort Sea is analyzed to detect under-ice acoustic transients isolated from ambient noise with a dedicated algorithm. Noise transients due to ice cracking, fracturing, shearing, and ridging are sorted out into three categories: broadband impulses, frequency modulated (FM) tones, and high-frequency broadband noise. Their temporal and acoustic characteristics over the 8-month ice covered period, from November 2005 to mid-June 2006, are presented and their generation mechanisms are discussed. Correlations analyses showed that the occurrence of these ice transients responded to large-scale ice motion and deformation rates forced by meteorological events, often leading to opening of large-scale leads at main discontinuities in the ice cover. Such a sequence, resulting in the opening of a large lead, hundreds by tens of kilometers in size, along the margin of landfast ice and multiyear ice plume in the Beaufort-Chukchi seas is detailed. These ice transients largely contribute to the soundscape properties of the Arctic Ocean, for both its ambient and total noise components. Some FM tonal transients can be confounded with marine mammal songs, especially when they are repeated, with periods similar to wind generated waves. PMID- 26520288 TI - Description and clustering of echolocation signals of Commerson's dolphins (Cephalorhynchus commersonii) in Bahia San Julian, Argentina. AB - Commerson's dolphins (Cephalorhynchus commersonii) inhabit coastal waters of Southern South America and Kerguelen Islands. Limited information exists about the acoustic repertoire of this species in the wild. Here, echolocation signals from free-ranging Commerson's dolphins were recorded in Bahia San Julian, Argentina. Signal parameters were calculated and a cluster analysis was made on 3180 regular clicks. Three clusters were obtained based on peak frequency (129, 137, and 173 kHz) and 3 dB bandwidth (8, 6, and 5 kHz). The 428 buzz clicks were analyzed separately. They consisted of clicks emitted with a median inter-click interval of 3.5 ms, peak frequency at 131 kHz, 3 dB bandwidth of 9 kHz, 10 dB bandwidth of 18 kHz, and duration of 56 MUs. Buzz clicks were significantly shorter and with a lower peak frequency and a broader bandwidth than most of the regular clicks. This study provided the first description of different echolocation signals, including on- and off-axis signals, recorded from Commerson's dolphins in the wild, most likely as a result of animals at several distances and orientations to the recording device. This information could be useful while doing passive acoustic monitoring. PMID- 26520289 TI - The effects of noise on key workplace skills. AB - This study explored the effect on memory and psychomotor performance of wideband noise (simulated in-cabin aircraft noise) at 75 dBA, which is similar to that experienced during the cruise phase of a commercial flight. The results from the tests were compared to the effects of a widely known and common metric on the same skills, namely, blood alcohol concentration (BAC). All 32 participants, half non-native English speakers, completed three different tests (recognition memory, working memory, and reaction time) presented in counterbalanced order, either in the presence of noise, with or without noise attenuation headphones, and without noise but with a BAC of 0.05 or 0.10. Simulated aircraft noise was found to affect recognition memory but not working memory or reaction time. These effects were more pronounced for non-native speakers and reflected performance similar to that for BAC of 0.05 or 0.10. PMID- 26520290 TI - On the use of evanescent plane waves for low-frequency energy transmission across material interfaces. AB - The transmission of airborne sound into high-impedance media is of interest in several applications. For example, sonic booms in the atmosphere may impact marine life when incident on the ocean surface, or affect the integrity of existing structures when incident on the ground. Transmission across high impedance-difference interfaces is generally limited by reflection and refraction at the surface, and by the critical angle criterion. However, spatially decaying incident waves, i.e., inhomogeneous or evanescent plane waves, may transmit energy above the critical angle, unlike homogeneous plane waves. The introduction of a decaying component to the incident trace wavenumber creates a nonzero propagating component of the transmitted normal wavenumber, so energy can be transmitted across the interface. A model of evanescent plane waves and their transmission across fluid-fluid and fluid-solid interfaces is developed here. Results are presented for both air-water and air-solid interfaces. The effects of the incident wave parameters (including the frequency, decay rate, and incidence angle) and the interfacial properties are investigated. Conditions for which there is no reflection at the air-solid interface, due to impedance matching between the incident and transmitted waves, are also considered and are found to yield substantial transmission increases over homogeneous incident waves. PMID- 26520291 TI - The precedence effect with increased lag level. AB - When a pair of sounds arrive from different directions with a sufficiently short delay between them, listeners hear a perceptually fused image with a perceived location that is dominated by the first arriving sound. This is called the precedence effect. To test the limits of this phenomenon, 200-ms noise stimuli were presented over headphones to model a temporally overlapping direct sound (lead) with a single reflection (lag) at inter-stimulus intervals (ISIs) of 0-5 ms. Lag intensity exceeded that of the lead by 0-10 dB. Results for 16 listeners show that lateralization shifted from the position of the lead towards the lag as lag level increased. Response variability also increased with lag level. An oscillatory pattern emerged across ISIs as lag level increased, to a degree that varied greatly between listeners. Analysis of modeled binaural cues suggests that these oscillatory patterns are correlated with ILDs produced by the physical interference of lead and lag during the ongoing portion of the stimulus, especially in the 764-Hz frequency band. Different listeners apparently weighted cues from the onset versus ongoing portions of the stimulus differently, as evidenced by the varying degree of influence the ongoing ILD cues had on listeners' perceived lateralization. PMID- 26520292 TI - The relationship between aircraft noise exposure and day-use visitor survey responses in backcountry areas of national parks. AB - To evaluate the relationship between aircraft noise exposure and the quality of national park visitor experience, more than 4600 visitor surveys were collected at seven backcountry sites in four U.S. national parks simultaneously with calibrated sound level measurements. Multilevel logistic regression was used to estimate parameters describing the relationship among visitor responses, aircraft noise dose metrics, and mediator variables. For the regression models, survey responses were converted to three dichotomous variables, representing visitors who did or did not experience slightly or more, moderately or more, or very or more annoyance or interference with natural quiet from aircraft noise. Models with the most predictive power included noise dose metrics of sound exposure level, percent time aircraft were audible, and percentage energy due to helicopters and fixed-wing propeller aircraft. These models also included mediator variables: visitor ratings of the "importance of calmness, peace and tranquility," visitor group composition (adults or both adults and children), first visit to the site, previously taken an air tour, and participation in bird watching or interpretive talks. The results complement and extend previous research conducted in frontcountry areas and will inform evaluations of air tour noise effects on visitors to national parks and remote wilderness sites. PMID- 26520293 TI - Fast computation of seabed spherical-wave reflection coefficients in geoacoustic inversion. AB - This paper develops a fast numerical approach to computing spherical-wave reflection coefficients (SWRCs) for layered seabeds, which provides substantial savings in computation time when used as the forward model for geoacoustic inversion of broadband seabed reflectivity data. The approach exploits the Sommerfeld-integral representation of SWRCs as the Hankel transform of a function proportional to the plane-wave reflection coefficient (PWRC), and applies Levin integration to the rapidly oscillating integrand cast as the product of a (pre computed) media-independent matrix and a vector involving PWRCs at a sparse sampling of integration angles. Compared to conventional Simpson's rule integration for computation of the SWRC, the Levin integration yields speed-up factors of an order of magnitude or more. Further, it results in reduced memory requirements for storage of pre-computed quantities, a desirable property when a graphics processing unit (GPU) is used for parallel computation of SWRCs. The paper applies trans-dimensional Bayesian inversion to investigate the impact of forward modeling in terms of PWRCs and SWRCs on the estimation of geoacoustic parameters and uncertainties. Model comparisons are quantified in simulated- and measured-data inversions by comparing the estimated geoacoustic parameters to the true parameters or core measurements, respectively, and by calculating the deviance information criterion for model selection. PMID- 26520294 TI - Automatic transcription of Turkish microtonal music. AB - Automatic music transcription, a central topic in music signal analysis, is typically limited to equal-tempered music and evaluated on a quartertone tolerance level. A system is proposed to automatically transcribe microtonal and heterophonic music as applied to the makam music of Turkey. Specific traits of this music that deviate from properties targeted by current transcription tools are discussed, and a collection of instrumental and vocal recordings is compiled, along with aligned microtonal reference pitch annotations. An existing multi pitch detection algorithm is adapted for transcribing music with 20 cent resolution, and a method for converting a multi-pitch heterophonic output into a single melodic line is proposed. Evaluation metrics for transcribing microtonal music are applied, which use various levels of tolerance for inaccuracies with respect to frequency and time. Results show that the system is able to transcribe microtonal instrumental music at 20 cent resolution with an F-measure of 56.7%, outperforming state-of-the-art methods for the same task. Case studies on transcribed recordings are provided, to demonstrate the shortcomings and the strengths of the proposed method. PMID- 26520295 TI - Erratum: Stimulus ratio dependence of low-frequency distortion-product otoacoustic emissions in humans [J. Acoust. Soc. Am. 137(2), 679-689 (2015)]. PMID- 26520296 TI - The relationship between speech segment duration and vowel centralization in a group of older speakers. AB - This study examined the relationship between average vowel duration and spectral vowel quality across a group of 149 New Zealand English speakers aged 65 to 90 yr. The primary intent was to determine whether participants who had a natural tendency to speak slowly would also produce more spectrally distinct vowel segments. As a secondary aim, this study investigated whether advancing age exhibited a measurable effect on vowel quality and vowel durations within the group. In examining vowel quality, both flexible and static formant extraction points were compared. Two formant measurements, from selected [a:], [ i:], and [ o:] vowels, were extracted from a standard passage and used to calculate two measurements of vowel space area (VSA) for each speaker. Average vowel duration was calculated from segments across the passage. The study found a statistically significant relationship between speakers' average vowel durations and VSA measurements indicating that, on average, speakers with slower speech rates produced more acoustically distinct speech segments. As expected, increases in average vowel duration were found with advancing age. However, speakers' formant values remained unchanged. It is suggested that the use of a habitually slower speaking rate may assist speakers in maintaining acoustically distinct vowels. PMID- 26520297 TI - Optimal design of modal beamformers for circular arrays. AB - An approach to optimal design of circular harmonics based modal beamformers for circular arrays is presented. Theoretical analysis shows the equivalence between the element-space and circular-harmonics-domain beamformers. By deriving the expression for the signal and noise covariance matrices, array manifold, and the array response in terms of the circular-harmonics-domain beamforming weights, the weights design problem is formulated as one of minimum variance distortionless response beamforming in the circular harmonics domain. It is found that the well known phase-mode beamformer for circular arrays can be viewed as an ideal minimum variance distortionless response beamformer against the planarly isotropic noise in the circular harmonics domain. This interesting result is useful for analyzing and evaluating the performance of the phase-mode circular arrays. In this circular-harmonics-domain beamformer, additional constraints can be imposed to improve its robustness and control the sidelobes, which is important in practical applications. The developed approach can include both the delay-and-sum and phase mode beamformers as special cases, which leads to very flexible designs. Simulation and experimental results show excellent performance of the proposed beamforming approach. PMID- 26520298 TI - Eigenvector pruning method for high resolution beamforming. AB - This paper introduces an eigenvector pruning algorithm for the estimation of the signal-plus-interference eigenspace, required as a preliminary step to subspace beamforming. The proposed method considers large-aperture passive array configurations operating in environments with multiple maneuvering targets in background noise, in which the available data for estimation of sample covariances and eigenvectors are limited. Based on statistical properties of scalar products between deterministic and complex random vectors, this work defines a statistically justified threshold to identify target-related features embedded in the sample eigenvectors, leading to an estimator for the signal bearing eigenspace. It is shown that data projection into this signal subspace results in sharpening of beamforming outputs corresponding to closely spaced targets and provides better target separation compared to current subspace beamformers. In addition, the proposed threshold gives the user control over the worst-case scenario for the number of false detections by the beamformer. Simulated data are used to quantify the performance of the subspace estimator according to the distance between estimated and true signal subspaces. Beamforming resolution using the proposed method is analyzed with simulated data corresponding to a horizontal line array, as well as experimental data from the Shallow Water Array Performance experiment. PMID- 26520300 TI - Observations of backscatter from sand and gravel seafloors between 170 and 250 kHz. AB - Interpreting observations of frequency-dependence in backscatter from the seafloor offers many challenges, either because multiple frequencies are used for different observations that will later be merged or simply because seafloor scattering models are not well-understood above 100 kHz. Hindering the understanding of these observations is the paucity of reported, calibrated acoustic measurements above 100 kHz. This manuscript seeks to help elucidate the linkages between seafloor properties and frequency-dependent seafloor backscatter by describing observations of backscatter collected from sand, gravel, and bedrock seafloors at frequencies between 170 and 250 kHz and at a grazing angle of 45 degrees . Overall, the frequency dependence appeared weak for all seafloor types, with a slight increase in seafloor scattering strength with increasing frequency for an area with unimodal, very poorly to moderately well sorted, slightly granular to granular medium sand with significant amounts of shell debris and a slight decrease in all other locations. PMID- 26520301 TI - Resource Paper: Sonoluminescence. AB - Sonoluminescence is the production of electromagnetic radiation, much of it in the form of visible light, that is emitted from a gas-filled cavity that has grown and collapsed under the influence of a varying pressure field. This resource paper provides a guide to the literature of sonoluminescence, from its early history to the present. PMID- 26520302 TI - On cross-language consonant identification in second language noise. AB - Speech perception in everyday conditions is highly affected by the presence of noise of a different nature. The presence of overlapping speakers is considered an especially challenging scenario, as it introduces both energetic and informational masking. The efficacy of the masking also depends on the familiarity with the language of both the target and masking stimuli. This work analyses consonant identification by non-native English speakers in N-talker natural babble noise and babble-modulated noise, by varying the number of talkers in the babble. In particular, only English consonants that are also present in all the native languages of the subjects are used. As the subjects are familiar with the consonants used, this study can be considered a step towards a deeper analysis on perception of first language speech in the presence of second language maskers. PMID- 26520303 TI - Lateralization of noise bursts in interaurally correlated or uncorrelated background noise using interaural level differences. AB - The interaural level difference (ILD) of a lateralized target source may be effectively reduced when the target is presented together with background noise containing zero ILD. It is not certain whether listeners perceive a position congruent with the reduced ILD or the actual target ILD in a lateralization task. Two sets of behavioral experiments revealed that many listeners perceived a position at or even larger than that corresponding to the presented target ILD when a temporal onset/offset asynchrony between the broadband target and the broadband background noise was present. When no temporal asynchrony was present, however, the perceived lateral position indicated a dependency on the coherence of the background noise for several listeners. With interaurally correlated background noise, listeners reported a reduced ILD resulting from the combined target and background noise stimulus. In contrast, several of the listeners made a reasonable estimate of the position corresponding to the target ILD for interaurally uncorrelated, broadband, background noise. No obvious difference in performance was seen between low- or high-frequency stimuli. Extension of a weighting template to the output of a standard equalization-cancellation model was shown to remove a lateral bias on the predicted target ILD resulting from the presence of background noise. Provided that an appropriate weighting template is applied based on knowledge of the background noise coherence, good prediction of the behavioral data is possible. PMID- 26520304 TI - Linearized two-hydrophone localization of a pulsed acoustic source in the presence of refraction: Theory and simulations. AB - This paper develops an efficient three-dimensional localization method for transient acoustic sources, with uncertainty estimation, based on time differences between direct and surface-reflected arrivals at two hydrophones. The localization method accounts for refraction caused by a depth-dependent sound speed profile using a ray-theoretic approach for calculating eigenray travel times and partial derivatives. Further, the method provides localization error estimates accounting for uncertainties of the arrival times and hydrophone locations, as well as for depth-dependent uncertainties in the sound-speed profile. In the first of two steps, source depth and range to each hydrophone are estimated using an iterative, linearized Gauss-Markov inversion scheme. In the second step, the estimated source ranges are combined with the hydrophone locations to obtain the source location in the horizontal. Localization performance is analyzed in a simulation study, and the linearized localization estimates and uncertainties are validated by comparison with a fully nonlinear (but numerically intensive) Markov-chain Monte Carlo inversion. PMID- 26520305 TI - Room acoustical parameters of two electronically connected rooms. AB - The acoustical properties of two rooms that are one-way connected electroacoustically, e.g., in a telephone/video conference, can be analyzed through the total impulse response from a source in one room to the receiver in the other room. The total impulse response is a convolution of the two involved room impulse responses, and such a model is analyzed in this paper. The room impulse response model used here facilitates convolution analysis as the model is quite simple and composed of two terms only, a direct sound term and an exponentially decaying random Gaussian noise term. Analytical expressions have been derived for the energy decay function, leading to estimates of room acoustical parameters like clarity and the modulation transfer functions for such convolved impulse responses. Background noise expressions are also introduced to allow signal-to-noise ratio studies. Estimates of acoustic parameter values have been compared with measurements to evaluate the model used and verify the results achieved. PMID- 26520307 TI - Modeling the effects of linear shallow-water internal waves on horizontal array coherence. AB - The coherence length of a horizontal array is the maximum separation between two points where coherent processing gives useful gain when a distant source is at broadside. In shallow water, the coherence length is limited by the environmental variability caused by several relevant oceanographic processes. In the present study, a statistical model is developed that quantifies how one oceanographic process, linear internal waves, affects the coherence length. A key input to the ocean sub-model is the vertically integrated energy density of the internal wave field. The acoustic sub-model is based on the adiabatic normal mode approximation and so should be reasonable for frequencies under 1 kHz. Numerical calculations using environmental data from the Shallow Water 2006 Experiment (SW06) show how the coherence length of individual modes varies with consequent effects on array coherence. The coherence length is shown to be a strong function of where the source and array are positioned in the water column. For a bottom-mounted array above a moderately lossy seabed, the model predicts a coherence length that depends only weakly on range, an effect observed in field experiments. PMID- 26520306 TI - Reflectance measurement validation using acoustic horns. AB - Variability in wideband acoustic reflectance (and absorbance) measurements adversely affects the clinical utility of reflectance for diagnosis of middle-ear disorders. A reflectance standard would encourage consistency across different measurement systems and help identify calibration related issues. Theoretical equations exist for the reflectance of finite-length exponential, conical, and parabolic acoustic horns. Reflectance measurements were repeatedly made in each of these three horn shapes and the results were compared to the corresponding theoretical reflectance. A method is described of adjusting acoustic impedance measurements to compensate for spreading of the wave front that propagates from the small diameter sound port of the probe to the larger diameter of the acoustic cavity. Agreement between measured and theoretical reflectance was less than 1 dB at most frequencies in the range from 0.2 to 10 kHz. Pearson correlation coefficients were greater than 0.95 between measured and theoretical time-domain reflectance within the flare region of the horns. The agreement suggests that the distributed reflectance of acoustic horns may be useful for validating reflectance measurements made in human ear canals; however, refinements to reflectance measurement methods may still be needed. PMID- 26520308 TI - A more stable transition matrix for acoustic target scattering by elongated objects. AB - The transition (T) matrix of Waterman has been very useful for computing fast, accurate acoustic scattering predictions for axisymmetric elastic objects, but this technique is usually limited to fairly smooth objects that are not too aspherical unless complex basis functions or stabilization schemes are used. To ease this limitation, a spherical-basis formulation adapted from approaches proposed recently by Waterman [J. Acoust. Soc. Am. 125(1), 42-51 (2009)] and Doicu, Eremin, and Wriedt [Acoustic and Electromagnetic Scattering Analysis Using Discrete Sources (Academic, London, 2000)] is suggested. This is implemented by simply transforming the high-order outgoing spherical basis functions within standard T-matrix formulations to low-order functions distributed along the object's symmetry axis. A free-field T matrix is produced in a nonstandard form, but computations with it become much more stable for elongated aspherical elastic shapes. Some advantages of this approach over the approaches of Waterman and Doicu, Eremin, and Wriedt are noted, and sample calculations for a 10:1 Al prolate spheroid and a 10:1 Al superspheroid of order 10 are given to demonstrate the enhanced stability. PMID- 26520309 TI - Impedance measurement techniques for one-port and two-port networks. AB - A microphone array impedance matrix measurement technique is presented for linear and passive acoustic two-port networks. Two impedance tubes fitted with three non uniformly spaced microphones are required in the measurement. The non-uniform spacing is intended to avoid ill-posedness problems in calculating two plane-wave components traveling in opposite directions. Based on the one-port measurement, acoustic two-port networks modeled with the source and the load connected are examined. Three experimental procedures, the two-load measurement method (TLMM), the reciprocal-constrained method (RCM), and the reciprocity-symmetry-constrained method (RSCM), are developed to measure the acoustic impedance matrix. Experiments are conducted for several acoustic two-port systems to verify the proposed techniques. The results demonstrate the efficacy of the three experimental procedures when applied to symmetrical and reciprocal systems. For asymmetrical systems, the TLMM and RCM are preferred over the RSCM for measuring the impedance matrix. On top of that, the non-uniform array in conjunction with TLMM is extended to a general electroacoustic two-port system, which can be regarded as a unique contribution of the present work. PMID- 26520310 TI - Wind noise within and across behind-the-ear and miniature behind-the-ear hearing aids. AB - Previous studies investigated wind noise with Behind-The-Ear (BTE) hearing aids, but not the more common mini-BTE style of device, which typically has a smaller shell and microphones located more deeply behind the pinna. The current study investigated wind-noise levels across one BTE and two mini-BTE devices, and between the front and rear omni-directional microphones within devices. Levels were measured at two wind speeds (3 and 6 m/s) and 36 wind azimuths (10 degrees increments). The pattern of wind-noise level versus azimuth was similar across mini-BTE devices, and differed for the BTE device. However, mean levels were markedly different across mini-BTE devices, and could be higher, lower, or similar to those of the BTE device. For within-device level differences, the pattern and mean across azimuth were similar across mini-BTE devices, and differed for the BTE device. Wind noise had the potential to slightly or severely reduce speech intelligibility at 3 or 6 m/s, respectively, across all devices. PMID- 26520311 TI - Effects of instructed timing and tempo on snare drum sound in drum kit performance. AB - This paper reports on an experiment investigating the expressive means with which performers of groove-based musics signal the intended timing of a rhythmic event. Ten expert drummers were instructed to perform a rock pattern in three different tempi and three different timing styles: "laid-back," "on-the-beat," and "pushed." The results show that there were systematic differences in the intensity and timbre (i.e., sound-pressure level, temporal centroid, and spectral centroid) of series of snare strokes played with these different timing styles at the individual level. A common pattern was found across subjects concerning the effect of instructed timing on sound-pressure level: a majority of the drummers played laid-back strokes louder than on-the-beat strokes. Furthermore, when the tempo increased, there was a general increase in sound-pressure level and a decrease in spectral centroid across subjects. The results show that both temporal and sound-related features are important in order to indicate that a rhythmic event has been played intentionally early, late, or on-the-beat, and provide insight into the ways in which musicians communicate at the microrhythmic level in groove-based musics. PMID- 26520312 TI - Oestreicher and elastography. AB - A sphere moving back and forth in tissue generates the kinds of complex displacement fields that are used in elastography. The analytical solution of Hans Oestreicher for this phenomenon [(1951). J. Acoust. Soc. Am. 23, 704-714] gives an understanding of the transverse and longitudinal, fast and slow waves that are generated. The results suggest several ways to determine the absorption coefficients of tissues, which together with phase velocity permit the computation of both the real shear modulus and the shear viscosity as functions of frequency. PMID- 26520313 TI - Finite element modelling of elastic wave scattering within a polycrystalline material in two and three dimensions. AB - Finite element modelling is a promising tool for further progressing the development of ultrasonic non-destructive evaluation of polycrystalline materials. Yet its widespread adoption has been held back due to a high computational cost, which has restricted current works to relatively small models and to two dimensions. However, the emergence of sufficiently powerful computing, such as highly efficient solutions on graphics processors, is enabling a step improvement in possibilities. This article aims to realise those capabilities to simulate ultrasonic scattering of longitudinal waves in an equiaxed polycrystalline material in both two (2D) and three dimensions (3D). The modelling relies on an established Voronoi approach to randomly generate a representative grain morphology. It is shown that both 2D and 3D numerical data show good agreement across a range of scattering regimes in comparison to well established theoretical predictions for attenuation and phase velocity. In addition, 2D parametric studies illustrate the mesh sampling requirements for two different types of mesh to ensure modelling accuracy and present useful guidelines for future works. Modelling limitations are also shown. It is found that 2D models reduce the scattering mechanism in the Rayleigh regime. PMID- 26520314 TI - Sound quality indicators for urban places in Paris cross-validated by Milan data. AB - A specific smartphone application was developed to collect perceptive and acoustic data in Paris. About 3400 questionnaires were analyzed, regarding the global sound environment characterization, the perceived loudness of some emergent sources and the presence time ratio of sources that do not emerge from the background. Sound pressure level was recorded each second from the mobile phone's microphone during a 10-min period. The aim of this study is to propose indicators of urban sound quality based on linear regressions with perceptive variables. A cross validation of the quality models extracted from Paris data was carried out by conducting the same survey in Milan. The proposed sound quality general model is correlated with the real perceived sound quality (72%). Another model without visual amenity and familiarity is 58% correlated with perceived sound quality. In order to improve the sound quality indicator, a site classification was performed by Kohonen's Artificial Neural Network algorithm, and seven specific class models were developed. These specific models attribute more importance on source events and are slightly closer to the individual data than the global model. In general, the Parisian models underestimate the sound quality of Milan environments assessed by Italian people. PMID- 26520317 TI - Explaining the Railsback stretch in terms of the inharmonicity of piano tones and sensory dissonance. AB - The perceptual results of Plomp and Levelt [J. Acoust. Soc. Am. 38, 548-560 (1965)] for the sensory dissonance of a pair of pure tones are used to estimate the dissonance of pairs of piano tones. By using the spectra of tones measured for a real piano, the effect of the inharmonicity of the tones is included. This leads to a prediction for how the tuning of this piano should deviate from an ideal equal tempered scale so as to give the smallest sensory dissonance and hence give the most pleasing tuning. The results agree with the well known "Railsback stretch," the average tuning curve produced by skilled piano technicians. The authors' analysis thus gives a quantitative explanation of the magnitude of the Railsback stretch in terms of the human perception of dissonance. PMID- 26520316 TI - Cochlear implant users' spectral ripple resolution. AB - This study revisits the issue of the spectral ripple resolution abilities of cochlear implant (CI) users. The spectral ripple resolution of recently implanted CI recipients (implanted during the last 10 years) were compared to those of CI recipients implanted 15 to 20 years ago, as well as those of normal-hearing and hearing-impaired listeners from previously published data from Henry, Turner, and Behrens [J. Acoust. Soc. Am. 118, 1111-1121 (2005)]. More recently, implanted CI recipients showed significantly better spectral ripple resolution. There is no significant difference in spectral ripple resolution for these recently implanted subjects compared to hearing-impaired (acoustic) listeners. The more recently implanted CI users had significantly better pre-operative speech perception than previously reported CI users. These better pre-operative speech perception scores in CI users from the current study may be related to better performance on the spectral ripple discrimination task; however, other possible factors such as improvements in internal and external devices cannot be excluded. PMID- 26520318 TI - Source level estimates for sei whale (Balaenoptera borealis) vocalizations off the Azores. AB - Sei whale calls have been documented on very few occasions and never in the Azores Archipelago, an area transited by this species during their migration to northern latitudes in spring and early summer. Using a combination of video range tracking (VRT) and acoustic methods, vocalizations are described from an encounter with two sei whales in April 2012 off Pico Island, Azores. Recordings analyzed post-survey revealed 53 low frequency downsweep calls with average maximum frequencies of 100 Hz [standard deviation (SD = 14 Hz)] down to 37 Hz (SD = 8 Hz) over 1.21 s (SD = 0.33 s). Apparent source levels of 177 dB (SD = 5 dB) root-mean-square (rms) re 1 MUPa were recorded. Vocalizations were attributed to the pair of sei whales encountered using a combination of the VRT data and differences in arrival time of calls at the hydrophones. These calls are similar to those reported from sei whales off New England and similar to those recorded off Hawaii. The growing body of acoustic data on sei whale vocalizations may contribute to the understanding of this species' distribution and population identity; key information is needed to guide future conservation efforts for this species. PMID- 26520319 TI - Influences of word predictability and type of masker noise on intelligibility of sung text in live concerts. AB - Vocal music is often intended to convey meaning, but how effectively this is achieved is poorly understood. This study systematically assessed the influence of three non-phonetic factors on the intelligibility of sung words in six public concerts in different venues: word predictability from sentence context, type of masker noise (spoken babble, sung vowels, [?(w)]), and signal-to-noise ratio (SNR). Stimuli were sung live by a professional a cappella ensemble with one male singing target sentences and five others (two female) producing the masker sounds. The concert audiences (N = 319) reported the final word of each sentence using a handheld voting device, from four phonetically- and semantically controlled written alternatives projected onto a screen after the sentence was sung. Although overall accuracy differed between performances, intelligibility patterns were robust across concerts. They included predicted main effects of masker noise type ([?(w)] masking least disruptive, babble most), SNR (high > low), semantic predictability (high > low), listener age (young > old), and listener language status (native > non-native), and some strong interactions. These results suggest that, despite acoustic differences between sung and spoken words and the unusual and varied experimental venues, key findings from traditional speech research apply to sung words, given appropriate musical composition. PMID- 26520320 TI - Reproduction of nearby sources by imposing true interaural differences on a sound field control approach. AB - In anechoic conditions, the Interaural Level Difference (ILD) is the most significant auditory cue to judge the distance to a sound source located within 1 m of the listener's head. This is due to the unique characteristics of a point source in its near field, which result in exceptionally high, distance dependent ILDs. When reproducing the sound field of sources located near the head with line or circular arrays of loudspeakers, the reproduced ILDs are generally lower than expected, due to physical limitations. This study presents an approach that combines a sound field reproduction method, known as Pressure Matching (PM), and a binaural control technique. While PM aims at reproducing the incident sound field, the objective of the binaural control technique is to ensure a correct reproduction of interaural differences. The combination of these two approaches gives rise to the following features: (i) an accurate reproduction of ILDs is achieved at the head positions considered by the method, (ii) the ILD variations in the vicinity of those positions are smoothed, thus lowering the ILD error, and (iii) the true wavefront is preserved. Given the properties of the presented method, intended distance and directional perception is expected. PMID- 26520321 TI - On the inadvisability of using single parameter impedance models for representing the acoustical properties of ground surfaces. AB - Although semi-empirical one parameter models are used widely for representing outdoor ground impedance, they are not physically admissible. Even when corrected to satisfy a passivity condition in respect of surface impedance they do not satisfy the condition that the real part of complex density must be greater than zero. Comparison of predictions with frequency-domain data for short range propagation have indicated that physically admissible models provide superior overall agreement. A two parameter variable porosity model yields better agreement for many grassland surfaces and a two parameter version of the slit pore microstructural impedance model yields better agreement with data obtained over low flow resistivity surfaces such as forest floors and gravel. Impedance models and conditions for physical admissibility are summarised. In addition to those examined previously, the slit pore model is shown to be physically admissible. After providing further examples of the better agreement with short range data that can be achieved using two parameter models, it is shown that differences between frequency domain predictions at longer ranges using physically admissible models rather than one parameter models are significantly greater than those resulting from short range spatial variability and comparable with seasonal variability over grassland. PMID- 26520322 TI - Experimental and numerical investigations of resonant acoustic waves in near critical carbon dioxide. AB - Flow and transport induced by resonant acoustic waves in a near-critical fluid filled cylindrical enclosure is investigated both experimentally and numerically. Supercritical carbon dioxide (near the critical or the pseudo-critical states) in a confined resonator is subjected to acoustic field created by an electro mechanical acoustic transducer and the induced pressure waves are measured by a fast response pressure field microphone. The frequency of the acoustic transducer is chosen such that the lowest acoustic mode propagates along the enclosure. For numerical simulations, a real-fluid computational fluid dynamics model representing the thermo-physical and transport properties of the supercritical fluid is considered. The simulated acoustic field in the resonator is compared with measurements. The formation of acoustic streaming structures in the highly compressible medium is revealed by time-averaging the numerical solutions over a given period. Due to diverging thermo-physical properties of supercritical fluid near the critical point, large scale oscillations are generated even for small sound field intensity. The strength of the acoustic wave field is found to be in direct relation with the thermodynamic state of the fluid. The effects of near critical property variations and the operating pressure on the formation process of the streaming structures are also investigated. Irregular streaming patterns with significantly higher streaming velocities are observed for near-pseudo critical states at operating pressures close to the critical pressure. However, these structures quickly re-orient to the typical Rayleigh streaming patterns with the increase operating pressure. PMID- 26520323 TI - Erratum: Prediction of a body's structural impedance and scattering properties using correlation of random noise [J. Acoust. Soc. Am. 134, 4401-4411 (2013)]. PMID- 26520324 TI - Comparison of glottal flow rate characteristics based on experimental and computational data. AB - In a recent computational model, Farahani and Zhang [J. Acoust. Soc. Am. 136, EL369-EL375 (2014)] concluded that intraglottal vortices did not affect the closing mechanism of the folds. In order to determine the validity of any model that addresses the issue of vortex significance, it is important that the results of the computational model are comparable to experimental results. The results of Farahani and Zhang's model are inconsistent with data published for experimental models, which may challenge the validity of their conclusions. PMID- 26520325 TI - Auditory brainstem responses of Japanese house bats (Pipistrellus abramus) after exposure to broadband ultrasonic noise. AB - Echolocating bats forage and navigate within an intense soundscape containing their own sonar sounds as well as sounds from other bats. To determine how the bat's auditory system copes with these high noise levels, auditory brainstem responses (ABR) were measured in the Japanese house bat, Pipistrellus abramus, before and after exposure to ultrasonic noise (30 min duration). Noise spectral content (10-80 kHz) and level (90 dB sound pressure level) are within the ranges these bats experience in their natural environment. ABR thresholds to test frequencies of 20, 40, and 80 kHz did not vary significantly between pre-exposure and post-exposure times of 0 and 30 min. Amplitudes and latencies of the P3 wave at suprathreshold were not significantly affected by noise exposure. These data show that the bat's hearing is not compromised when exposed to background sounds similar in wideband frequency content and sound level to what the animal encounters naturally. These results provide a baseline for examining how the bat's auditory system deals with other intense sounds, such as those emitted by anthropogenic sources or those producing temporary threshold shifts in other mammals. PMID- 26520326 TI - Listening efficiency during lessons under various types of noise. AB - Pupils inside primary school classrooms can be exposed to extraneous noise, impairing their performance in the speech reception process. The different noises show a peculiar impact, depending on their level, spectral content and temporal fine structure. In order to understand how the disturbance is built up over time, in this work a large data set was analyzed, detailing the changes of pupils' performance as the lesson progresses from the start to the end. Several types of noise are considered (traffic, tapping and activity noise) and the analysis concerns III to V graders of the Italian primary school (8 to 10 year old pupils). By using as indicators the intelligibility scores, the response time and their ratio, the so-called "listening efficiency," several findings are achieved. Pupils respond differently to each noise during the course of the lesson. In the better listening conditions, the performance in the speech reception worsens under traffic and babble noise whereas an opposite trend is found under tapping noise. On the contrary adaptation is observed in the worse listening conditions for the traffic noise alone. Moreover, indications are achieved that the age proficiency may affect differently babble noise compared to traffic and tapping noise. PMID- 26520328 TI - The effect of different open plan and enclosed classroom acoustic conditions on speech perception in Kindergarten children. AB - Open plan classrooms, where several classes are in the same room, have recently re-emerged in Australian primary schools. This paper explores how the acoustics of four Kindergarten classrooms [an enclosed classroom (25 children), double classroom (44 children), fully open plan triple classroom (91 children), and a semi-open plan K-6 "21st century learning space" (205 children)] affect speech perception. Twenty-two to 23 5-6-year-old children in each classroom participated in an online four-picture choice speech perception test while adjacent classes engaged in quiet versus noisy activities. The noise levels recorded during the test were higher the larger the classroom, except in the noisy condition for the K-6 classroom, possibly due to acoustic treatments. Linear mixed effects models revealed children's performance accuracy and speed decreased as noise level increased. Additionally, children's speech perception abilities decreased the further away they were seated from the loudspeaker in noise levels above 50 dBA. These results suggest that fully open plan classrooms are not appropriate learning environments for critical listening activities with young children due to their high intrusive noise levels which negatively affect speech perception. If open plan classrooms are desired, they need to be acoustically designed to be appropriate for critical listening activities. PMID- 26520327 TI - Effect of intervening tissues on ultrasonic backscatter measurements of bone: An in vitro study. AB - Ultrasonic backscatter techniques are being developed to diagnose osteoporosis. Tissues that lie between the transducer and the ultrasonically interrogated region of bone may produce errors in backscatter measurements. The goal of this study is to investigate the effects of intervening tissues on ultrasonic backscatter measurements of bone. Measurements were performed on 24 cube shaped specimens of human cancellous bone using a 5 MHz transducer. Measurements were repeated after adding a 1 mm thick plate of cortical bone to simulate the bone cortex and a 3 cm thick phantom to simulate soft tissue at the hip. Signals were analyzed to determine three apparent backscatter parameters (apparent integrated backscatter, frequency slope of apparent backscatter, and frequency intercept of apparent backscatter) and three backscatter difference parameters [normalized mean backscatter difference (nMBD), normalized slope of the backscatter difference, and normalized intercept of the backscatter difference]. The apparent backscatter parameters were impacted significantly by the presence of intervening tissues. In contrast, the backscatter difference parameters were not affected by intervening tissues. However, only one backscatter difference parameter, nMBD, demonstrated a strong correlation with bone mineral density. Thus, among the six parameters tested, nMBD may be the best choice for in vivo backscatter measurements of bone when intervening tissues are present. PMID- 26520330 TI - Three-dimensional tracking of Cuvier's beaked whales' echolocation sounds using nested hydrophone arrays. AB - Cuvier's beaked whales (Ziphius cavirostris) were tracked using two volumetric small-aperture (~1 m element spacing) hydrophone arrays, embedded into a large aperture (~1 km element spacing) seafloor hydrophone array of five nodes. This array design can reduce the minimum number of nodes that are needed to record the arrival of a strongly directional echolocation sound from 5 to 2, while providing enough time-differences of arrivals for a three-dimensional localization without depending on any additional information such as multipath arrivals. To illustrate the capabilities of this technique, six encounters of up to three Cuvier's beaked whales were tracked over a two-month recording period within an area of 20 km(2) in the Southern California Bight. Encounter periods ranged from 11 min to 33 min. Cuvier's beaked whales were found to reduce the time interval between echolocation clicks while alternating between two inter-click-interval regimes during their descent towards the seafloor. Maximum peak-to-peak source levels of 179 and 224 dB re 1 MUPa @ 1 m were estimated for buzz sounds and on-axis echolocation clicks (directivity index = 30 dB), respectively. Source energy spectra of the on-axis clicks show significant frequency components between 70 and 90 kHz, in addition to their typically noted FM upsweep at 40-60 kHz. PMID- 26520329 TI - Comparing the information conveyed by envelope modulation for speech intelligibility, speech quality, and music quality. AB - This paper uses mutual information to quantify the relationship between envelope modulation fidelity and perceptual responses. Data from several previous experiments that measured speech intelligibility, speech quality, and music quality are evaluated for normal-hearing and hearing-impaired listeners. A model of the auditory periphery is used to generate envelope signals, and envelope modulation fidelity is calculated using the normalized cross-covariance of the degraded signal envelope with that of a reference signal. Two procedures are used to describe the envelope modulation: (1) modulation within each auditory frequency band and (2) spectro-temporal processing that analyzes the modulation of spectral ripple components fit to successive short-time spectra. The results indicate that low modulation rates provide the highest information for intelligibility, while high modulation rates provide the highest information for speech and music quality. The low-to-mid auditory frequencies are most important for intelligibility, while mid frequencies are most important for speech quality and high frequencies are most important for music quality. Differences between the spectral ripple components used for the spectro-temporal analysis were not significant in five of the six experimental conditions evaluated. The results indicate that different modulation-rate and auditory-frequency weights may be appropriate for indices designed to predict different types of perceptual relationships. PMID- 26520331 TI - Spinner dolphin whistle in the Southwest Atlantic Ocean: Is there a geographic variation? AB - Acoustic parameters for the spinner dolphins' bioacoustic sounds have previously been described. However, the dolphins in the Southwest Atlantic Ocean were only recently studied near the Fernando de Noronha Archipelago. Therefore, to contribute to additional knowledge of this cosmopolitan species, this study compares previous results with a Brazilian recording. Despite statistically significant differences, the mean value comparison indicated that Hawaiian and Southwest Atlantic Ocean spinners emit similar whistles. The fact that geographical isolation does not lead the dissemblance nor the similarity of the acoustic variations in this species raises the possibility of other factors influencing those emissions. Here those differences and similarities are discussed, thereby contributing to an understanding of how distinct populations and/or species communicate through different ocean basins. PMID- 26520332 TI - Characterization of material properties of soft solid thin layers with acoustic radiation force and wave propagation. AB - Evaluation of tissue engineering constructs is performed by a series of different tests. In many cases it is important to match the mechanical properties of these constructs to those of native tissues. However, many mechanical testing methods are destructive in nature which increases cost for evaluation because of the need for additional samples reserved for these assessments. A wave propagation method is proposed for characterizing the shear elasticity of thin layers bounded by a rigid substrate and fluid-loading, similar to the configuration for many tissue engineering applications. An analytic wave propagation model was derived for this configuration and compared against finite element model simulations and numerical solutions from the software package Disperse. The results from the different models found very good agreement. Experiments were performed in tissue-mimicking gelatin phantoms with thicknesses of 1 and 4 mm and found that the wave propagation method could resolve the shear modulus with very good accuracy, no more than 4.10% error. This method could be used in tissue engineering applications to monitor tissue engineering construct maturation with a nondestructive wave propagation method to evaluate the shear modulus of a material. PMID- 26520333 TI - Hearing thresholds of a harbor porpoise (Phocoena phocoena) for narrow-band sweeps. AB - The hearing sensitivity of a 2-yr-old male harbor porpoise was measured using a standard psycho-acoustic technique under low ambient noise conditions. Auditory sensitivity was measured for narrow-band 1 s sweeps (center frequencies: 0.125 150 kHz). The audiogram was U-shaped; range of best hearing (within 10 dB of maximum sensitivity) was from 13 to ~140 kHz. Maximum sensitivity (threshold: ~39 dB re 1 MUPa) occurred at 125 kHz at the peak frequency of echolocation pulses produced by harbor porpoises. Reduced sensitivity occurred at 32 and 63 kHz. Sensitivity fell by ~10 dB per octave below 16 kHz and declined sharply above 125 kHz. Apart from this individual's ca. 10 dB higher sensitivity at 0.250 kHz, ca. 10 dB lower sensitivity at 32 kHz, and ca. 59 dB lower sensitivity at 150 kHz, his audiogram is similar to that of two harbor porpoises tested previously with a similar psycho-acoustic technique. PMID- 26520334 TI - Extraction of the envelope from impulse responses using pre-processed energy detection for early decay estimation. AB - The Schroeder's backward integration method and its applications have been widely studied in the literature; some papers analyze the performance of the method, some others suggest various enhancement techniques. In spite of these findings, there exist several cases where the energy decay curve extracted using the classical backward integration method and the parameters computed from it seem not always representative of the phenomenon under study. Among them, the cases where the early decay is dependent on strong, distinct reflections occurring just after the direct wave, as in most Italian opera houses. Other cases are measured impulse responses with a very low signal-to-noise ratio or missing the direct wave. In the literature, alternatives to the Schroeder's method have been proposed, ranging from Hilbert transform to non-linear processing techniques. In this work a method for the extraction of the envelope based on pre-processed energy detection for early decay estimation is proposed. It is shown that it returns an envelope well matching the first part of the decay even in non-linear cases, returning detailed information on the first part of the decay. The performance of the proposed method is presented and discussed for some exemplary impulse responses measured in historical opera houses. A preliminary study on the perceptive relevance of the method is finally presented. PMID- 26520335 TI - The perception of complex pitch in cochlear implants: A comparison of monopolar and tripolar stimulation. AB - Cochlear implant listeners typically perform poorly in tasks of complex pitch perception (e.g., musical pitch and voice pitch). One explanation is that wide current spread during implant activation creates channel interactions that may interfere with perception of temporal fundamental frequency information contained in the amplitude modulations within channels. Current focusing using a tripolar mode of stimulation has been proposed as a way of reducing channel interactions, minimising spread of excitation and potentially improving place and temporal pitch cues. The present study evaluated the effect of mode in a group of cochlear implant listeners on a pitch ranking task using male and female singing voices separated by either a half or a quarter octave. Results were variable across participants, but on average, pitch ranking was at chance level when the pitches were a quarter octave apart and improved when the difference was a half octave. No advantage was observed for tripolar over monopolar mode at either pitch interval, suggesting that previously published psychophysical advantages for focused modes may not translate into improvements in complex pitch ranking. Evaluation of the spectral centroid of the stimulation pattern, plus a lack of significant difference between male and female voices, suggested that participants may have had difficulty in accessing temporal pitch cues in either mode. PMID- 26520336 TI - Underwater sound transmission through arrays of disk cavities in a soft elastic medium. AB - Scattering from a cavity in a soft elastic medium, such as silicone rubber, resembles scattering from an underwater bubble in that low-frequency monopole resonance is obtainable in both cases. Arrays of cavities can therefore be used to reduce underwater sound transmission using thin layers and low void fractions. This article examines the role of cavity shape by microfabricating arrays of disk shaped air cavities into single and multiple layers of polydimethylsiloxane. Comparison is made with the case of equivalent volume cylinders which approximate spheres. Measurements of ultrasonic underwater sound transmission are compared with finite element modeling predictions. The disks provide a deeper transmission minimum at a lower frequency owing to the drum-type breathing resonance. The resonance of a single disk cavity in an unbounded medium is also calculated and compared with a derived estimate of the natural frequency of the drum mode. Variation of transmission is determined as a function of disk tilt angle, lattice constant, and layer thickness. A modeled transmission loss of 18 dB can be obtained at a wavelength about 20 times the three-layer thickness, and thinner results (wavelength/thickness ~ 240) are possible for the same loss with a single layer depending on allowable hydrostatic pressure. PMID- 26520337 TI - Sonodynamic action of hypocrellin B on biofilm-producing Staphylococcus epidermidis in planktonic condition. AB - Staphylococcus epidermidis is an opportunistic pathogen causing biofilm associated infections. To investigate sonodynamic action of hypocrellin B on biofilm-producing Staphylococcus epidermidis in planktonic culture, a biofilm producing strain Staphylococcus epidermidis (ATCC 35984) was incubated with hypocrellin B and then exposed to ultrasound at intensity (ISATA) of 1.56 W/cm(2) with a frequency of 1 MHz in continuous mode for 5 min. After sonodynamic treatment of hypocrellin B, the bacterial growth was measured using the colony counting method. Bacterial membrane integrity was investigated using a flow cytometry with propidium iodide staining. Intracellular reactive oxygen species (ROS) level was measured using a flow cytometry with DCFH-DA staining. The results showed that sonodynamic action of hypocrellin B significantly induced survival reduction of Staphylococcus epidermidis in a hypocrellin B dose dependent manner, and a 4-log reduction was observed after the combined treatment of hypcorellin B (40 MUM) and ultrasound sonication with the intensity of 1.56 W/cm(2) for 5 min. Bacterial membrane integrity was notably damaged and the level of intracellular ROS level was remarkably increased after sonodynamic treatment. The findings demonstrated that sonodynamic action of hypocrellin B had significant antibacterial activity on biofilm-producing Staphylococcus epidermidis in planktonic condition probably through increasing intracellular ROS level to cause damage to bacterial membrane integrity. PMID- 26520338 TI - Physics underlying the physiology of the ear. PMID- 26520339 TI - An investigation of prior knowledge in Automatic Music Transcription systems. AB - Automatic transcription of music is a long-studied research field with many operational systems available commercially. In this paper, a generic transcription system able to host various prior knowledge parameters has been developed, followed by an in-depth investigation of their impact on music transcription. Explicit links between musical knowledge and algorithmic formalism have been made. Musical knowledge covers classes of timbre, musicology, and playing style of an instrument repertoire. An evaluation sound corpus gathering musical pieces played by human performers from three different instrument repertoires, namely, classical piano, steel-string acoustic guitar, and the marovany zither from Madagascar, has been developed. The different components of musical knowledge have been successively incorporated in a complete transcription system, consisting mainly of a Probabilistic Latent Component Analysis algorithm post-processed with a Hidden Markov Model, and their impact on transcription results have been comparatively evaluated. PMID- 26520340 TI - The significance of the evanescent spectrum in structure-waveguide interaction problems. AB - Modal decomposition is often applied in elastodynamics and acoustics for the solution of problems related to propagation of mechanical disturbances in waveguides. One of the key elements of this method is the solution of an eigenvalue problem for obtaining the roots of the dispersion equation, which signify the wavenumbers of the waves that may exist in the system. For non dissipative media, the wavenumber spectrum consists of a finite number of real roots supplemented by infinitely many imaginary and complex ones. The former refer to the propagating modes in the medium, whereas the latter constitute the so-called evanescent spectrum. This study investigates the significance of the evanescent spectrum in structure-waveguide interaction problems. Two cases are analysed, namely, a beam in contact with a fluid layer and a cylindrical shell interacting with an acousto-elastic waveguide. The first case allows the introduction of a modal decomposition method and the establishment of appropriate criteria for the truncation of the modal expansions in a simple mathematical framework. The second case describes structure-borne wave radiation in an offshore environment during the installation of a pile with an impact hammer-a problem that has raised serious concerns in recent years due to the associated underwater noise pollution. PMID- 26520341 TI - The influence of hearing-aid compression on forward-masked thresholds for adults with hearing loss. AB - This paper describes forward-masked thresholds for adults with hearing loss. Previous research has demonstrated that the loss of cochlear compression contributes to deficits in this measure of temporal resolution. Cochlear compression can be mimicked with fast-acting compression where the normal dynamic range is mapped to the impaired dynamic range. To test the hypothesis that fast acting compression will most-closely approximate the normal ability to perceive forward-masked pure-tones, forward-masked thresholds were measured for two groups of adults (normal hearing, hearing loss). Adults with normal hearing were tested without amplification. Adults with hearing loss were tested with three different compression speeds and two different prescriptive procedures using a hearing-aid simulator. The two prescriptive procedures differed in the extent to which the normal dynamic range was mapped onto the impaired dynamic range. When using a faster compression speed with the prescriptive procedure that best restored the lost dynamic range, forward-masked thresholds for the listeners with hearing loss approximated those observed for the listeners with normal hearing. PMID- 26520342 TI - Sound propagation in dilute suspensions of spheres: Analytical comparison between coupled phase model and multiple scattering theory. AB - Sound propagation in dilute suspensions of small spheres is studied using two models: a hydrodynamic model based on the coupled phase equations and an acoustic model based on the ECAH (ECAH: Epstein-Carhart-Allegra-Hawley) multiple scattering theory. The aim is to compare both models through the study of three fundamental kinds of particles: rigid particles, elastic spheres, and viscous droplets. The hydrodynamic model is based on a Rayleigh-Plesset-like equation generalized to elastic spheres and viscous droplets. The hydrodynamic forces for elastic spheres are introduced by analogy with those of droplets. The ECAH theory is also modified in order to take into account the velocity of rigid particles. Analytical calculations performed for long wavelength, low dilution, and weak absorption in the ambient fluid show that both models are strictly equivalent for the three kinds of particles studied. The analytical calculations show that dilatational and translational mechanisms are modeled in the same way by both models. The effective parameters of dilute suspensions are also calculated. PMID- 26520343 TI - Stress-dependent second-order grain statistics of polycrystals. AB - In this article, the second-order statistics of the elastic moduli of randomly oriented grains in a polycrystal are derived for the case when an initial stress is present. The initial stress can be either residual stress or stresses generated from external loading. The initial stress is shown to increase or decrease the variability of the grain's elastic moduli from the average elastic moduli of the polycrystal. This variation in the elastic properties of the individual grains causes acoustic scattering phenomenon in polycrystalline materials to become stress-dependent. The influence of the initial stress on scattering is shown to be greater than the influence on acoustic phase velocities, which defines the acoustoelastic effect. This work helps the development of scattering based tools for the nondestructive analysis of material stresses in polycrystals. PMID- 26520344 TI - Calculation of an axial temperature distribution using the reflection coefficient of an acoustic wave. AB - This work verifies the idea that in principle it is possible to reconstruct axial temperature distribution of fluid employing reflection or transmission of acoustic waves. It is assumed that the fluid is dissipationless and its density and speed of sound vary along the wave propagation direction because of the fluid temperature distribution. A numerical algorithm is proposed allowing for calculation of the temperature distribution on the basis of known frequency characteristics of reflection coefficient modulus. Functionality of the algorithm is illustrated on a few examples, its properties are discussed. PMID- 26520345 TI - Numerical analysis of three-dimensional acoustic propagation in the Catoche Tongue. AB - Analysis of modeled time series data is presented to provide insight into propagation physics of horizontally refracted sound in the Catoche Tongue region of the Gulf of Mexico. The analysis is motivated by the observation of out-of plane arrivals in measured time series data. In particular, the extended duration of the refracted arrivals is shown to be caused by interaction with multiple locations along the steep sides of the Tongue. Comparison of the modeled time series is made to previous work by Sturm [J. Acoust. Soc. Am. 117(3), 1058-1079 (2005)], who examined the frequency dependence of out-of-plane modal arrivals for the wedge-shaped ocean. PMID- 26520346 TI - Modeling explosion generated Scholte waves in sandy sediments with power law dependent shear wave speed. AB - Experimental measurements of Scholte waves from underwater explosions collected off the coast of Virginia Beach, VA in shallow water are presented. It is shown here that the dispersion of these explosion-generated Scholte waves traveling in the sandy seabed can be modeled using a power-law dependent shear wave speed profile and an empirical source model that determines the pressure time-series at 1 m from the source as a function of TNT-equivalent charge weight. PMID- 26520347 TI - Optimized extraction of coherent arrivals from ambient noise correlations in a rapidly fluctuating medium. AB - Ambient noise correlations can be used to estimate Green's functions for passive monitoring purposes. However, this method traditionally relies on sufficient time averaging of the noise-correlations to extract coherent arrivals (i.e., Green's function estimates), and is thus limited by rapid environmental fluctuations occurring on short time scales while the averaging takes place. This letter demonstrates with simulation and data that the use of a stochastic search algorithm to correct and track these rapid environmental fluctuations can significantly reduce the required averaging time to extract coherent arrivals from noise correlations in a fluctuating medium. PMID- 26520348 TI - A real-time articulatory visual feedback approach with target presentation for second language pronunciation learning. AB - Articulatory information can support learning or remediating pronunciation of a second language (L2). This paper describes an electromagnetic articulometer-based visual-feedback approach using an articulatory target presented in real-time to facilitate L2 pronunciation learning. This approach trains learners to adjust articulatory positions to match targets for a L2 vowel estimated from productions of vowels that overlap in both L1 and L2. Training of Japanese learners for the American English vowel /ae/ that included visual training improved its pronunciation regardless of whether audio training was also included. Articulatory visual feedback is shown to be an effective method for facilitating L2 pronunciation learning. PMID- 26520349 TI - Temporal characteristics of Punjabi word-medial singletons and geminates. AB - Many studies have investigated the temporal characteristics of the word-medial singletons and geminates in Indo-Aryan languages. However, little is known about the acoustic cues distinguishing between the word-medial singletons and geminates of Punjabi. The present study examines the temporal characteristics of Punjabi word-medial singleton and geminate stops in a C1V1C2V2 template. The results from five Punjabi speakers showed that, unlike previous studies of Indo-Aryan languages, the durations of C2 and V2 are the most important acoustic correlates of singleton and geminate stops in Punjabi. These findings therefore point towards the cross-linguistic differences in the acoustic correlates of singletons and geminates. PMID- 26520350 TI - Audio-vocal responses elicited in adult cochlear implant users. AB - Auditory deprivation experienced prior to receiving a cochlear implant could compromise neural connections that allow for modulation of vocalization using auditory feedback. In this report, pitch-shift stimuli were presented to adult cochlear implant users to test whether compensatory motor changes in vocal F0 could be elicited. In five of six participants, rapid adjustments in vocal F0 were detected following the stimuli, which resemble the cortically mediated pitch shift responses observed in typical hearing individuals. These findings suggest that cochlear implants can convey vocal F0 shifts to the auditory pathway that might benefit audio-vocal monitoring. PMID- 26520351 TI - Reciprocal measurement of acoustic feedback paths in hearing aids. AB - A reciprocal measurement procedure to measure the acoustic feedback path in hearing aids is investigated. The advantage of the reciprocal measurement compared to the direct measurement is a significantly reduced sound pressure in the ear. The direct and reciprocal measurements are compared using measurements on a dummy head with adjustable ear canals, different earmolds, and variations in the outer sound field. The results show that the reciprocal measurement procedure can be used to obtain plausible feedback paths, while reducing the sound pressure in the ear canal by 30 to 40 dB. PMID- 26520352 TI - Intrinsic fundamental frequency of vowels is moderated by regional dialect. AB - There has been a long-standing debate whether the intrinsic fundamental frequency (IF0) of vowels is an automatic consequence of articulation or whether it is independently controlled by speakers to perceptually enhance vowel contrasts along the height dimension. This paper provides evidence from regional variation in American English that IF0 difference between high and low vowels is, in part, controlled and varies across dialects. The sources of this F0 control are socio cultural and cannot be attributed to differences in the vowel inventory size. The socially motivated enhancement was found only in prosodically prominent contexts. PMID- 26520353 TI - Aging effect on Mandarin Chinese vowel and tone identification. AB - Mandarin Chinese speech sounds (vowels * tones) were presented to younger and older Chinese-native speakers with normal hearing. For the identification of vowel-plus-tone, vowel-only, and tone-only, younger listeners significantly outperformed older listeners. The tone 3 identification scores correlated significantly with the age of older listeners. Moreover, for older listeners, the identification rate of vowel-plus-tone was significantly lower than that of vowel only and tone-only, whereas for younger listeners, there was no difference among the three identification scores. Therefore, aging negatively affected Mandarin vowel and tone perception, especially when listeners needed to process both phonemic and tonal information. PMID- 26520354 TI - Investigating the emotional response to room acoustics: A functional magnetic resonance imaging study. AB - While previous research has demonstrated the powerful influence of pleasant and unpleasant music on emotions, the present study utilizes functional magnetic resonance imaging (fMRI) to assess the positive and negative emotional responses as demonstrated in the brain when listening to music convolved with varying room acoustic conditions. During fMRI scans, subjects rated auralizations created in a simulated concert hall with varying reverberation times. The analysis detected activations in the dorsal striatum, a region associated with anticipation of reward, for two individuals for the highest rated stimulus, though no activations were found for regions associated with negative emotions in any subject. PMID- 26520355 TI - Hemispherical breathing mode speaker using a dielectric elastomer actuator. AB - Although indoor acoustic characteristics should ideally be assessed by measuring the reverberation time using a point sound source, a regular polyhedron loudspeaker, which has multiple loudspeakers on a chassis, is typically used. However, such a configuration is not a point sound source if the size of the loudspeaker is large relative to the target sound field. This study investigates a small lightweight loudspeaker using a dielectric elastomer actuator vibrating in the breathing mode (the pulsating mode such as the expansion and contraction of a balloon). Acoustic testing with regard to repeatability, sound pressure, vibration mode profiles, and acoustic radiation patterns indicate that dielectric elastomer loudspeakers may be feasible. PMID- 26520356 TI - On the resolution of phonological constraints in spoken production: Acoustic and response time evidence. AB - This study examines the production of words the pronunciation of which depends on the phonological context. Participants produced adjective-noun phrases starting with the French determiner un. The pronunciation of this determiner requires a liaison consonant before vowels. Naming latencies and determiner acoustic durations were shorter when the adjective and the noun both started with vowels or both with consonants, than when they had different onsets. These results suggest that the liaison process is not governed by the application of a local contextual phonological rule; they rather favor the hypothesis that pronunciation variants with and without the liaison consonant are stored in memory. PMID- 26520357 TI - Suppression of harmonics in a model of thermoacoustic refrigerator based on an acoustic metamaterial. AB - A model of thermoacoustic refrigerator on the basis of an acoustic metamaterial is presented, in which an array of side pipes is adopted to suppress harmonic waves in the thermoacoustic resonator. The array of side pipes traps the acoustic waves with Fabry-Perot resonant frequencies and induces narrow forbidden bands of transmission. When the resonant frequency of the thermoacoustic refrigerator is chosen as the operating frequency, the harmonic wave can be exactly located in the forbidden band by properly adapting the structural parameters of the system. Therefore, the component of the harmonic wave in the thermoacoustic resonator can be efficiently suppressed. PMID- 26520358 TI - The role of prosody in infants' early syntactic analysis and grammatical categorization. AB - This study tested the hypothesis that phrasal prosody assists early syntactic acquisition. Stimulus-sentences consisting of French determiners and pseudo lexical-words were ambiguous between two syntactic structures, e.g., [[TonDet felliAdj craleN]NP [vurV laDet gosineN]VP] versus [[TonDet felliN]NP [craleV vurPrep laDet gosineN]VP], which had distinct prosodic cues. French-learning 20 month-olds were familiarized with the sentences either in the prosody of one structure, or the other structure. All infants were tested with Det + N (e.g., LeDet craleN) versus Pron + V (e.g., TuPron cralesV) trials containing non familiarized functors. Infants perceived the test-stimuli according to the familiarized structure. They used prosody to categorize words and interpret adjacent and non-adjacent syntactic dependencies. PMID- 26520359 TI - Re: "is the inverse association between selenium and bladder cancer due to confounding by smoking?". PMID- 26520360 TI - Odds per adjusted standard deviation: comparing strengths of associations for risk factors measured on different scales and across diseases and populations. AB - How can the "strengths" of risk factors, in the sense of how well they discriminate cases from controls, be compared when they are measured on different scales such as continuous, binary, and integer? Given that risk estimates take into account other fitted and design-related factors-and that is how risk gradients are interpreted-so should the presentation of risk gradients. Therefore, for each risk factor X0, I propose using appropriate regression techniques to derive from appropriate population data the best fitting relationship between the mean of X0 and all the other covariates fitted in the model or adjusted for by design (X1, X2, ... , Xn). The odds per adjusted standard deviation (OPERA) presents the risk association for X0 in terms of the change in risk per s = standard deviation of X0 adjusted for X1, X2, ... , Xn, rather than the unadjusted standard deviation of X0 itself. If the increased risk is relative risk (RR)-fold over A adjusted standard deviations, then OPERA = exp[ln(RR)/A] = RR(s). This unifying approach is illustrated by considering breast cancer and published risk estimates. OPERA estimates are by definition independent and can be used to compare the predictive strengths of risk factors across diseases and populations. PMID- 26520361 TI - Migrant mortality in Qatar. PMID- 26520362 TI - Effects of ligation of lateral intermuscular septum perforating vessels on blood supply to the femur. AB - INTRODUCTION: With a subvastus approach to the femur, the vessels that perforate the lateral intermuscular septum (LISP-vessels) must be ligated. The effect on the blood supply to the femur remains unclear. The purpose of the current study was to investigate the effect of ligation of the LISP-Vessels on the blood supply and to examine the anatomy of the LISP-vessels and the anastomoses around the femur. MATERIALS: In six human cadavers the LISP vessels were ligated by a lateral subvastus approach on one side. The contralateral side served as control group. After bilateral injection of different coloured silicon dyes into the lateral and medial circumflex femoral artery (green), deep femoral artery (red) and the superficial femoral artery (blue) dissection was performed bilaterally. The arterial perfusion on both sides was compared and the anatomy of the LISP vessels studied. RESULTS: The medullary perfusion of the femur was not altered by the ligation of the LISP vessels. It did also not lead to a decrease in periosteal vessel filling. The LISP vessels were shown to be a part of a complex and rich anastomotic network and play an important role in the perfusion of the femur and quadriceps muscle group. The ligature could be compensated for by this anastomotic network. Branches to the periosteum separate from the LISP vessels immediately after perforating the lateral intermuscular septum. The linea aspera turned out to be an important area for the femoral blood supply. DISCUSSION AND CONCLUSIONS: Exposure of the femur through a lateral subvastus approach with ligation of LISP vessels causes a certain degree of soft tissue trauma. However, by using a gentle surgical technique the periostal perfusion of the femur can be preserved by a potent anastomotic network after ligation of the LISP vessels if they are not ligated to close to the lateral intermuscular septum and the linea aspera is not unnecessarily exposed. PMID- 26520363 TI - Outcomes of war related femoral neck fractures. AB - INTRODUCTION: In the civilian trauma literature, femoral neck fractures in young adults are considered an orthopedic 'urgency'. To our knowledge, there have been no studies looking at the outcomes of these injuries in the combat setting. The purpose of this study is to determine the outcomes of war related femoral neck fractures; the rates avascular necrosis associated with these injuries as well as the effect time to fixation has on the development of avascular necrosis. METHODS: We performed a retrospective review of 21 patients who sustained combat related femoral neck fractures from October 2001 through October 2013. We collected demographic data, time to fixation, time to union, incidence of avascular necrosis, as well as complications and final recreational activity status. RESULTS: Our study included 21 males (100%). The average length of follow up was 19.0 (2.7-62.3) months, and the average length of radiographic follow up was 21.4 months. The average age was 25.2 (21-36) years. Displaced fractures were sustained in 71.4% of patients and 95.2% had a Pauwels' type 3 fracture. 56.9% had initial reduction and fixation within 24h of injury. Percutaneous screw fixation and dynamic hip screws were definitive fixation in 57.1% and 23.8% of patients, respectively, while the remainder had a cephalomedullary device or a salvage procedure. The average time to union was 5.5 months. There was 1 case of nonunion and 1 case of delayed union. Three of the patients (16.7%) developed avascular necrosis of the femoral head, 2 of which were initially reduced within 24h of injury. There were no statistically significant differences between time to fixation, type of reduction, or presence of displacement as a predictor of the development of avascular necrosis. DISCUSSION: We found a high rate of displaced and high Pauwels' angle fractures, consistent with the high-energy injury mechanisms. With nearly a two-year average radiographic follow-up, the incidence of avascular necrosis was 16.7%, despite only half of our patients receiving initial reduction within 24h of injury. Urgent reduction and fixation continues to be of utmost importance to decrease the risk of femoral head avascular necrosis. PMID- 26520364 TI - A combined posterior reversed L-shaped and anterolateral approach for two column tibial plateau fractures in Caucasians: A technical note. AB - OBJECTIVE: Open reduction and internal fixation of two column posterior and lateral tibial plateau fractures through a combined posterior reversed L-shaped and anterolateral approach in floating position in Caucasians. INDICATIONS: Two column posterior and lateral tibial plateau fractures. CONTRAINDICATIONS: Tibial plateau fractures that do not involve the posterior and lateral column. SURGICAL TECHNIQUE: The patient is positioned in floating position, a reversed L-shaped skin incision is made, the posterior column after lateral retraction of the medial head of the gastrocnemius muscle is exposed, and the posterior fragments are reduced and fixed. Subsequently, flexion and varus stress on the knee is applied, an anterolateral skin incision is made, the lateral column is exposed, and the lateral fragments are reduced and fixed. CONCLUSION: Despite a different physique as Asians, a combined posterior reversed L-shaped and anterolateral approach in a floating position for the surgical treatment of two column posterior and lateral tibial plateau fractures is technically possible in Caucasians. In our experience, this combined approach is an excellent strategy in most patients for surgical treatment of two column posterior and lateral column fractures. PMID- 26520365 TI - Preface. PMID- 26520366 TI - Marked contribution of alternative end-joining to chromosome-translocation formation by stochastically induced DNA double-strand-breaks in G2-phase human cells. AB - Ionizing radiation (IR) induces double strand breaks (DSBs) in cellular DNA, which if not repaired correctly can cause chromosome translocations leading to cell death or cancer. Incorrect joining of DNA ends generating chromosome translocations can be catalyzed either by the dominant DNA-PKcs-dependent, classical non-homologous end-joining (c-NHEJ), or by an alternative end-joining (alt-EJ) process, functioning as backup to abrogated c-NHEJ, or homologous recombination repair. Alt-EJ operates with slower kinetics as compared to c-NHEJ and generates larger alterations at the junctions; it is also considered crucial to chromosome translocation-formation. A recent report posits that this view only holds for rodent cells and that in human cells c-NHEJ is the main mechanism of chromosome translocation formation. Since this report uses designer nucleases that induce DSBs with unique characteristics in specific genomic locations and PCR to detect translocations, we revisit the issue using stochastically distributed DSBs induced in the human genome by IR during the G2-phase of the cell cycle. For visualization and analysis of chromosome translocations, which manifest as chromatid translocations in cells irradiated in G2, we employ classical cytogenetics. In wild-type cells, we observe a significant contribution of alt-EJ to translocation formation, as demonstrated by a yield-reduction after treatment with inhibitors of Parp, or of DNA ligases 1 and 3 (Lig1, Lig3). Notably, a nearly fourfold increase in translocation formation is seen in c-NHEJ mutants with defects in DNA ligase 4 (Lig4) that remain largely sensitive to inhibitors of Parp, and of Lig1/Lig3. We conclude that similar to rodent cells, chromosome translocation formation from randomly induced DSBs in human cells largely relies on alt-EJ. We discuss DSB localization in the genome, characteristics of the DSB and the cell cycle as potential causes of the divergent results generated with IR and designer nucleases. PMID- 26520367 TI - Activation of the Fanconi anemia/BRCA pathway at low doses of ionization radiation. AB - Fanconi anemia (FA) is a rare, clinically heterogeneous autosomal recessive or X linked genetic disease characterized by chromosome fragility, congenital malformations and cancer susceptibility. FA patients are usually radiosensitive when exposed to radiotherapy but the role of the FA in response to ionizing radiation (IR) is controversial. Here we have investigated IR-induced activation of the FA pathway by systematically analyzing monoubiquitination of the central protein FANCD2 and subsequent recruitment to stalled replication forks in primary fibroblasts. We developed an immunolabelling method to simultaneously visualize IR-induced FANCD2 and gammaH2AX foci in S-phase. We observed FANCD2 foci formation in a subset of IR-induced gammaH2AX foci in S-phase cells. This was observed at doses of IR ranging from 0.1 to 5.0Gy in a dose dependent non threshold fashion. Our results indicate that minimum doses of IR can produce replication fork stalling and FA pathway activation during S-phase in primary cells. PMID- 26520368 TI - Cytogenetic evidence that DNA topoisomerase II is not involved in radiation induced chromsome-type aberrations. AB - ICRF-187 (CardioxaneTM, Chiron) is a catalytic inhibitor of DNA topoisomerase II (Topo II), proposed to act by blocking Topo II-mediated DNA cleavage without stabilizing DNA-Topo II-"cleavable complexes". In this study ICRF-187 was used to evaluate the potential involvement of DNA topoisomerase II in the formation of the radiation-induced chromosome-type aberrations in the G0 phase of the cell cycle in human lymphocytes from three healthy male donors. This is based on many evidences that DNA topoisomerases are involved in DNA recombination, mainly of illegitimate type (non-homologous) both in vitro and in vivo. The results obtained clearly indicated that ICRF-187 did not induce per se any chromosomal damage. When challenged with the non-catalytic Topo II poison VP-16 (etoposide), which acts by stabilizing the "cleavable complex" generating "protein concealed" DSB's and thus chromosomal aberrations, it completely abolished the significant induction of chromosome-type aberrations and formation of dicentric chromosomes. This indicates that ICRF-187 acts effectively as catalytic inhibitor of Topo II. On the other hand, when X-ray treatments were challenged with ICRF-187 using experimental conditions as for VP-16 treatments, no modification of the incidence of chromosome-type aberrations and dicentric chromosomes was observed. On this basis, we conclude that Topo II is not involved in the formation of X-ray-induced chromosome-type aberrations and dicentric chromosomes in human lymphocytes in the G0 phase of the cell cycle. PMID- 26520369 TI - APE1/REF-1 down-regulation enhances the cytotoxic effects of temozolomide in a resistant glioblastoma cell line. AB - Temozolomide (TMZ) is widely used for patients with glioblastoma (GBM); however, tumor cells frequently exhibit drug-resistance. Base excision repair (BER) has been identified as a possible mediator of TMZ resistance, and an attractive approach to sensitizing cells to chemotherapy. Human apurinic/apyrimidinic endonuclease/redox factor-1 (APE1) is an essential enzyme with a role in the BER pathway by repairing abasic sites, and it also acts as a reduction factor, maintaining transcription factors in an active reduced state. Thus, we aimed to investigate whether the down-regulation of APE1 expression by siRNA can interfere with the resistance of GBM to TMZ, being evaluated by several cellular and molecular parameters. We demonstrated that APE1 knockdown associated with TMZ treatment efficiently reduced cell proliferation and clonogenic survival of resistant cells (T98G), which appears to be a consequence of increased DNA damage, S-phase arrest, and H2AX phosphorylation, resulting in apoptosis induction. On the contrary, for those assays, the sensitization effects of APE1 silencing plus TMZ treatment did not occur in the TMZ-sensitive cell line (U87MG). Interestingly, TMZ-treatment and APE1 knockdown significantly reduced cell invasion in both cell lines, but TMZ alone did not reduce the invasion capacity of U87MG cells, as observed for T98G. We also found that VEGF expression was down-regulated by TMZ treatment in T98G cells, regardless of APE1 knockdown, but U87MG showed a different response, since APE1 silencing counteracted VEGF induction promoted by TMZ, suggesting that the APE1-redox function may play an indirect role, depending on the cell line. The present results support the contribution of BER in the GBM resistance to TMZ, with a greater effect in TMZ resistant, compared with TMZ-sensitive cells, emphasizing that APE1 can be a promising target for modifying TMZ tolerance. Furthermore, genetic characteristics of tumor cells should be considered as critical information to select an appropriate therapeutic strategy. PMID- 26520371 TI - Determination of the relative biological effectiveness and oxygen enhancement ratio for micronuclei formation using high-LET radiation in solid tumor cells: An in vitro and in vivo study. AB - We determined the relative biological effectiveness (RBE) and oxygen enhancement ratio (OER) of micronuclei (MN) formation in clamped (hypoxic) and non-clamped (normoxic) solid tumors in mice legs following exposure to X-rays and heavy ions. Single-cell suspensions (aerobic) of non-irradiated tumors were prepared in parallel and used directly to determine the radiation response for aerobic cells. Squamous cell carcinoma (SCCVII) cells were transplanted into the right hind legs of syngeneic C3H/He male mice. Irradiation doses with either X-rays or heavy ions at a dose-averaged LET (linear energy transfer) of 14-192keV/MUm were delivered to 5-mm diameter tumors and aerobic single-cells in sample-tubes. After irradiation, the tumors were excised and trypsinized to observe MN in single cells. The single-cell suspensions were used for MN formation assays. The RBE values increased with increasing LET. The maximum RBE values for the three different oxygen conditions; hypoxic tumor, normoxic tumor, and aerobic cells, were 8.18, 5.30, and 3.76 at an LET of 192keV/MUm, respectively. After X irradiation, the OERh/n values (hypoxic tumor/normoxic tumor) were lower than the OERh/a (hypoxic tumor/aerobic cells), and were 1.73 and 2.58, respectively. We found that the OER for the in vivo studies were smaller in comparison to that for the in vitro studies. Both of the OER values at 192keV/MUm were small in comparison to those of the X-ray irradiated samples. The OERh/n and OERh/a values at 192keV/MUm were 1.12 and 1.19, respectively. Our results suggest that high LET radiation has a large biological effect even if a solid tumor includes substantial numbers of hypoxic cells. To conclude, we found that the RBE values under each oxygen state for non-MN fraction increased with increasing LET and that the OER values for both tumors in vivo and cells in vitro decreased with increasing LET. PMID- 26520370 TI - Sub-micrometer 20MeV protons or 45MeV lithium spot irradiation enhances yields of dicentric chromosomes due to clustering of DNA double-strand breaks. AB - In conventional experiments on biological effects of radiation types of diverse quality, micrometer-scale double-strand break (DSB) clustering is inherently interlinked with clustering of energy deposition events on nanometer scale relevant for DSB induction. Due to this limitation, the role of the micrometer and nanometer scales in diverse biological endpoints cannot be fully separated. To address this issue, hybrid human-hamster AL cells have been irradiated with 45MeV (60keV/MUm) lithium ions or 20MeV (2.6keV/MUm) protons quasi-homogeneously distributed or focused to 0.5*1MUm(2) spots on regular matrix patterns (point distances up to 10.6*10.6MUm), with pre-defined particle numbers per spot to provide the same mean dose of 1.7Gy. The yields of dicentrics and their distribution among cells have been scored. In parallel, track-structure based simulations of DSB induction and chromosome aberration formation with PARTRAC have been performed. The results show that the sub-micrometer beam focusing does not enhance DSB yields, but significantly affects the DSB distribution within the nucleus and increases the chance to form DSB pairs in close proximity, which may lead to increased yields of chromosome aberrations. Indeed, the experiments show that focusing 20 lithium ions or 451 protons per spot on a 10.6MUm grid induces two or three times more dicentrics, respectively, than a quasi-homogenous irradiation. The simulations reproduce the data in part, but in part suggest more complex behavior such as saturation or overkill not seen in the experiments. The direct experimental demonstration that sub-micrometer clustering of DSB plays a critical role in the induction of dicentrics improves the knowledge on the mechanisms by which these lethal lesions arise, and indicates how the assumptions of the biophysical model could be improved. It also provides a better understanding of the increased biological effectiveness of high-LET radiation. PMID- 26520372 TI - Influence of radiation quality on mouse chromosome 2 deletions in radiation induced acute myeloid leukaemia. AB - Leukaemia is the prevailing neoplastic disorder of the hematopoietic system. Epidemiological analyses of the survivors of the Japanese atomic bombings show that exposure to ionising radiation (IR) can cause leukaemia. Although a clear association between radiation exposure and leukaemia development is acknowledged, the underlying mechanisms remain incompletely understood. A hemizygous deletion on mouse chromosome 2 (del2) is a common feature in several mouse strains susceptible to radiation-induced acute myeloid leukaemia (rAML). The deletion is an early event detectable 24h after exposure in bone marrow cells. Ultimately, 15 25% of exposed animals develop AML with 80-90% of cases carrying del2. Molecular mapping of leukaemic cell genomes identified a minimal deleted region (MDR) on chromosome 2 (chr2) in which a tumour suppressor gene, Sfpi1 is located, encoding the transcription factor PU.1, essential in haematopoiesis. The remaining copy of Sfpi1 has a point mutation in the coding sequence for the DNA-binding domain of the protein in 70% of rAML, which alters a single CpG sequence in the codon for arginine residue R235. In order to identify chr2 deletions and Sfpi.1/PU.1 loss, we performed array comparative genomic hybridization (aCGH) on a unique panel of 79rAMLs. Using a custom made CGH array specifically designed for mouse chr2, we analysed at unprecedentedly high resolution (1.4M array- 148bp resolution) the size of the MDR in low LET and high-LET induced rAMLs (32 X-ray- and 47 neutron induced). Sequencing of Sfpi1/PU.1DNA binding domain identified the presence of R235 point mutations, showing no influence of radiation quality on R235 type or frequency. We identified for the first time rAML cases with complex del2 in a subset of neutron-induced AMLs. This study allowed us to re-define the MDR to a much smaller 5.5Mb region (still including Sfpi1/PU.1), identical regardless of radiation quality. PMID- 26520373 TI - mBAND and mFISH analysis of chromosomal aberrations and breakpoint distribution in chromosome 1 of AG01522 human fibroblasts that were exposed to radiation of different qualities. AB - High-resolution multicolour banding FISH (mBAND) and multiplex FISH (mFISH) were used to analyse the aberrations of chromosome 1 in irradiated-AG01522 human primary fibroblasts. The cells were exposed to 1Gy of a panel of radiation of different qualities, such as X-rays, low-energy protons (28keV/MUm), helium-ions (62keV/MUm) and carbon-ions (96 and 252keV/MUm). mBAND and mFISH analysis in calyculin-A G2-condensed chromosome spreads allowed us to detect intra- and interchromosome aberrations involving chromosome 1, including simple and complex type exchanges, inversions (both para- and pericentric ones), deletions and rings. The data indicate that the induction of chromosomal exchanges was influenced by both Linear energy transfer (LET) and particle types. Moreover, the complex-to-simple exchanges ratio (C-ratio) and interchromosome to intrachromosome exchanges ratio (F-ratio) were evaluated by mFISH and mBAND techniques, respectively. Our results indicate that the C-ratio is a more reliable marker of radiation quality, with values that increased linearly in an LET-dependent manner. In addition, by means of mBAND analysis, the distribution of radiation-induced breakpoints along chromosome 1 was analyzed and compared with the expected distributions of the breaks. The expected values were calculated assuming a random distribution of the breakpoints. The data indicate that, irrespective of the radiation that was used, the breakpoints were non randomly distributed along chromosome 1. In particular, breaks in the pericentromeric region were encountered at a higher frequency than expected. A deeper analysis revealed that breaks were not located in the constitutive heterochromatin (G-bands 1p11/1q11 and 1q12), but rather in a region comprised between 1p11.2 and 1p22.1, which includes G-light and G-dark bands. PMID- 26520374 TI - Chromosome aberrations induced by the Auger electron emitter (125)I. AB - DNA-associated Auger electron emitters (AEE) cause cellular damage leading to high-LET type cell survival curves indicating an enhanced relative biological effectiveness. Double strand breaks (DSBs) induced by Iodine-125-deoxyuridine ((125)I-UdR) decays are claimed to be very complex. To elucidate the assumed genotoxic potential of (125)I-UdR, chromatid aberrations were analysed in exposed human peripheral blood lymphocytes (PBL). PBL were stimulated with medium containing phytohaemagglutinin (PHA). After 24h, cultures were labelled with (125)I-UdR for 18h (activity concentration 1-45 kBq) during the S-phase. Following standard cytogenetic procedure, at least 100 metaphases were analysed microscopically for each activity concentration. Cell death was measured by apoptosis assay using flow cytometry. Radiation doses were determined by using point kernel calculations. After 18h labelling with (125)I-UdR the cell cycle distribution is severely disturbed. About 40% of PBL are fully labelled and 20% show a moderate labelling of (125)I-UdR, whereas 40% of cells remain un-labelled. The dose-response relationship fits to a polynomial curve in the low dose range, whereas a linear fit supplies a better estimation in the high dose range. Even the lowest dose of 0.2Gy leads to a 13-fold increase of aberrations compared to the controls. On average every fifth (125)I-decay produces a single chromatid aberration in PBL. Additionally, a dose-dependent increase of cell death is observed. (125)I-UdR has a very strong genotoxic capacity in human PBL, even at 0.2Gy. Efficiently labelled cells displaying a prolonged cell cycle compared to moderately labelled cells and cell death contribute substantially to the desynchronisation of the cell cycle. Our data, showing for the first time, that one (125)I-decay induces ~ 0.2 chromatid aberrations, are in very good accordance to DSB data, stating that ~0.26 DSB are induced per decay, indicating that it takes on average 250 decays to induce one chromosome aberration (CA). [Corrected] PMID- 26520375 TI - Low concentrations of caffeine induce asymmetric cell division as observed in vitro by means of the CBMN-assay and iFISH. AB - The dual role of caffeine as a chromosomal damage inducer and G2/M-checkpoint abrogator is well known but it is observed mainly at relatively high concentrations. At low concentrations, caffeine enhances the cytogenetic effects of several carcinogens and its intake during pregnancy has been recently reported to cause adverse birth outcomes. Interestingly, a threshold below which this association is not apparent was not identified. Since chromosomal abnormalities and aneuploidy are the major genetic etiologies of spontaneous abortions and adverse birth outcomes, we re-evaluate here the effects of caffeine at the cytogenetic level and propose a model for the mechanisms involved. Our hypothesis is that low caffeine concentrations affect DNA replication and cause chromosomal aberrations and asymmetric cell divisions not easily detected at metaphase since damaged cells are delayed during their G2/M-phase transition and the low caffeine concentrations cannot abrogate the G2-checkpoint. To test this hypothesis, caffeine-induced chromatid breaks and micronuclei in peripheral blood lymphocytes (PBLs) were evaluated in vitro after low caffeine concentration exposures, followed by a short treatment with 4mM of caffeine to abrogate the G2-checkpoint. The results show a statistically significant increase in chromatid breaks at caffeine concentrations >=1mM. When caffeine was applied for G2/M-checkpoint abrogation, a statistically significant increase in chromatid breaks, compared to an active checkpoint, was only observed at 4mM of caffeine. The potential of low concentrations to induce asymmetric cell divisions was tested by applying a methodology combining the cytochalasin-B mediated cytokinesis-block micronucleus assay (CBMN) with interphase FISH (iFISH), using selected centromeric probes. Interestingly, low caffeine concentrations induce a dose dependent aneuploidy through asymmetric cell divisions, which are caused by misalignment of chromosomes through a mechanism unrelated to the formation of chromatid breaks. The cytogenetic approach used, combining CBMN with iFISH, is proposed as a valuable tool to test chemically induced asymmetric cell divisions. PMID- 26520376 TI - The micronucleus assay in mammalian cells in vitro to assess health benefits of various phytochemicals. AB - We evaluated the protective effects of Gentiana lutea extracts (GLEx) and 6 Gingerol (6-G) on clastogenicity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 7,12-dimethylbenz(alpha) anthracene (DMBA) in vitro on HepG2 cells using the frequencies of induced micronuclei (MN) as the end point. Pre-, post- and simultaneous treatments with GLEx or 6-G and the carcinogens were carried out. Both GLEx post- and simultaneous treatments reduced the frequencies of MN induced by MNNG and DMBA. Probably this effect is due to an increase of cytostasis and a physico-chemical interaction between GLEx and DMBA under simultaneous treatment. Pre- and simultaneous treatments with 6-G significantly reduced the yield of MNNG induced micronuclei without affecting % of cytostasis. Simultaneous treatment with 6-G plus DMBA resulted in reduction in the frequency of MN and an increase in cytotoxicity compared to sample treated alone with DMBA, whereas a post treatment, caused a significant decrease in the yield of MN compared with DMBA alone without any cytotoxic effect. These results are compared with our earlier data obtained in the same system with other phytochemicals. It is concluded that for a critical evaluation of the protective effects of phytochemicals, both the influence on the induced MN and induced cytostasis have to be considered. PMID- 26520377 TI - Plumbagin alters telomere dynamics, induces DNA damage and cell death in human brain tumour cells. AB - Natural plant products may possess much potential in palliative therapy and supportive strategies of current cancer treatments with lesser cytotoxicity to normal cells compared to conventional chemotherapy. In the current study, anti cancer properties of plumbagin, a plant-derived naphthoquinone, on brain cancer cells were determined. Plumbagin treatment resulted in the induction of DNA damage, cell cycle arrest and apoptosis, followed by suppression of the colony forming ability of the brain tumour cells. These effects were substantiated by upregulation of PTEN, TNFRSF1A and downregulation of E2F1 genes, along with a drop in MDM2, cyclin B1, survivin and BCL2 protein expression. Plumbagin induced elevated levels of caspase-3/7 activity as well. For the first time, we show here that plumbagin inhibits telomerase in brain tumour cells and results in telomere shortening following chronic long-term treatment. This observation implies considerable cytotoxicity of plumbagin towards cancer cells with higher telomerase activity. Collectively, our findings suggest plumbagin as a potential chemotherapeutic phytochemical in brain tumour treatment modalities. PMID- 26520378 TI - Modulation of radiation-induced cytogenetic damage in human peripheral blood lymphocytes by hypothermia. AB - PURPOSE: Recent studies have shown that low temperature (hypothermia) at exposure can act in a radio-protective manner at the level of cytogenetic damage. The mechanisms of this phenomenon are not understood, but it was suggested to be due to hypothermia-induced perturbations of the cell cycle. The purpose of the present study was to detect whether a reduced frequency of micronuclei is observed in peripheral blood lymphocytes (PBL) irradiated at low temperature and harvested sequentially at 3 time points. Additionally, the level of apoptosis was estimated by microscopic analysis of the MN slides. MATERIALS AND METHODS: Experiments were carried out with blood drawn from three donors at the Stockholm University and from three donors at the Jan Kochanowski University. Prior to irradiation, blood samples were incubated for 20min and irradiated at the respective temperature (0 degrees C and 37 degrees C) with gamma rays. Whole blood cultures were set up, cytochalasin B was added after 44h of irradiation and the samples were harvested after 72, 96 and 120h of incubation time. RESULTS AND CONCLUSIONS: The frequency of micronuclei was markedly lower in PBL harvested at 72h, 96h and 120h following irradiation at 0 degrees C as compared to 37 degrees C. This indicates that the temperature effect observed in peripheral blood lymphocytes after irradiation is not related to a temporary perturbation of the cell cycle. Also, it is not due to selective elimination of damaged cells by apoptosis. PMID- 26520379 TI - Evolution of the Health Canada astronaut biodosimetry program with a view toward international harmonization. AB - Biodosimetry of astronaut lymphocyte samples, taken prior to- and post-flight, provides an important in vivo measurement of radiation-induced damage incurred during space flight which can be included in the medical records of the astronauts. Health Canada has been developing their astronaut biodosimetry program since 2007 and since then has analyzed data from 7 astronauts. While multiple cytogenetic endpoints may be analyzed for the astronauts, the Fluorescent in situ hybridization (FISH) assay is considered to be key for detecting long-lasting stable damage. It is believed that this long-lasting damage is most likely to lead to an increased risk to the health of the astronauts during long-term flights (lasting 6 months or more). The complexity of damage that results from protracted, non-homogeneous radiation exposure, like that found in the space environment, requires a detailed scoring schematic to capture as much information as possible. To that end, this paper outlines the efforts to harmonize the manner in which Health Canada's FISH data are recorded to better facilitate the comparison of results with other international biodosimetry programs. PMID- 26520380 TI - Triage biodosimetry using centromeric/telomeric PNA probes and Giemsa staining to score dicentrics or excess fragments in non-stimulated lymphocyte prematurely condensed chromosomes. AB - The frequency of dicentric chromosomes in human peripheral blood lymphocytes at metaphase is considered as the "gold-standard" method for biological dosimetry and, presently, it is the most widely used for dose assessment. Yet, it needs lymphocyte stimulation and a 2-day culture, failing the requirement of rapid dose estimation, which is a high priority in radiation emergency medicine and triage biodosimetry. In the present work, we assess the applicability of cell fusion mediated premature chromosome condensation (PCC) methodology, which enables the analysis of radiation-induced chromosomal aberrations directly in non-stimulated G0-lymphocytes, without the 2-day culture delay. Despite its advantages, quantification of an exposure by means of the PCC-method is not currently widely used, mainly because Giemsa-staining of interphase G0-lymphocyte chromosomes facilitates the analysis of fragments and rings, but not of dicentrics. To overcome this shortcoming, the PCC-method is combined with fluorescence in situ hybridization (FISH), using simultaneously centromeric/telomeric peptide nucleic acid (PNA)-probes. This new approach enables an accurate analysis of dicentric and centric ring chromosomes, which are formed within 8h post irradiation and will, therefore, be present in the blood sample by the time it arrives for dose estimation. For triage biodosimetry, a dose response curve for up to 10Gy was constructed and compared to that obtained using conventional metaphase analysis with Giemsa or centromeric/telomeric PNA-probes in metaphase. Since FISH is labor intensive, a simple PCC-method scoring Giemsa-stained fragments in excess of 46 was also assessed as an even more rapid approach for triage biodosimetry. First, we studied the rejoining kinetics of fragments and constructed a dose-response curve for 24h repair time. Then, its applicability was assessed for four different doses and compared with the PCC-method using centromeric/telomeric PNA probes, through the evaluation of speed of analysis and minimum number of cells required for dose estimation and categorization of exposed individuals. PMID- 26520381 TI - Standards in biological dosimetry: A requirement to perform an appropriate dose assessment. AB - Every year, many countries perform a significant number of investigations based on biological radiation dose assessment to check suspected or true overexposure by irradiation of radiation workers and individuals of the general population. The scoring of dicentrics in peripheral blood lymphocytes has gradually become the "gold standard" for the biodosimetry-based assessment of accidental situations. Nevertheless, other "classical" biodosimetric methods such as micronuclei, prematurely condensed chromosomes (PCC) and FISH translocations are relevant in some exposure situations, also for surveillance of groups of populations at risk. Historical international intercomparison studies have shown discrepancies among dose-effect curves used to estimate doses from blood samples irradiated between 0 and 4Gy. Recent experimental work performed by the biological dosimetry laboratory of the French Institute for Radiation Protection and Nuclear Safety (IRSN) has shown the impact of some blood harvesting parameters on the mitotic index, and consequently on the quality of dose assessment. Therefore, it was relevant to define the best Quality Assurance (QA) and Quality Control (QC) criteria to harmonize protocols among biodosimetry laboratories. Complementary with several editions of an IAEA technical manual, ISO standards were written with the view of considering the most used chromosome aberrations assays: dicentrics and micronuclei. An important feature of these standards is to address the organization of population triage and laboratories networking that would be required in case of a large nuclear event or malicious act involving radioactive material. These ISO standards are relevant and helpful to implement a coordinated response of several biodosimetry networks in Europe, Japan, Canada, and to support European programs such as MULTIBIODOSE and RENEB. A new important ISO standard on the use of FISH translocations in retrospective dosimetry is now being drafted. PMID- 26520382 TI - Global quantification of gammaH2AX as a triage tool for the rapid estimation of received dose in the event of accidental radiation exposure. AB - The phosphorylation of the H2AX histone to form gammaH2AX foci has been shown to be an accurate biomarker of ionizing radiation exposure. It is well established that there is a one-to-one correlation between the number of gammaH2AX foci and radiation-induced double strand breaks in cellular DNA, which can be translated to the received dose. However, manual counting of foci is time-consuming, and cannot accommodate high throughput analysis required to obtain rapid results for medical triage purposes in the case of large-scale accidental exposure. Furthermore, the accuracy of gammaH2AX measurements could potentially be compromised by delays between the time of exposure and analysis of results, as well as inter-cellular and inter-individual variability of this biological response. To evaluate more rapid approaches of quantifying gammaH2AX for use in an emergency situation, and to determine the impact of inter-individual variability, we compared two methods of global gammaH2AX fluorescence quantification (low magnification immunofluorescence microscopy and flow cytometry) to the well-established gammaH2AX foci scoring method in human primary fibroblasts. All three approaches were well correlated, indicating that global gammaH2AX fluorescence measurements are suitable for dose estimation. For rapid triage in an emergency situation, we propose the use of flow cytometry, as it is more highly correlated with foci scoring and because of the speed and ease of the method. Dose response curves (0.25-6Gy) using flow cytometry measurements showed that inter-individual variability in global gammaH2AX fluorescence is statistically insignificant at 4h post-irradiation. Based on these data, we propose calibration curves that can be applied to populations exposed to moderate radiation doses to estimate individual received doses, independent of individual radiosensitivity, at this specific time point post-irradiation using human fibroblasts and lymphocytes. Furthermore, we define three triage categories that could facilitate immediate and follow-up care in the case of a radiological accident. PMID- 26520383 TI - High-throughput sample processing and sample management; the functional evolution of classical cytogenetic assay towards automation. AB - High-throughput individual diagnostic dose assessment is essential for medical management of radiation-exposed subjects after a mass casualty. Cytogenetic assays such as the Dicentric Chromosome Assay (DCA) are recognized as the gold standard by international regulatory authorities. DCA is a multi-step and multi day bioassay. DCA, as described in the IAEA manual, can be used to assess dose up to 4-6 weeks post-exposure quite accurately but throughput is still a major issue and automation is very essential. The throughput is limited, both in terms of sample preparation as well as analysis of chromosome aberrations. Thus, there is a need to design and develop novel solutions that could utilize extensive laboratory automation for sample preparation, and bioinformatics approaches for chromosome-aberration analysis to overcome throughput issues. We have transitioned the bench-based cytogenetic DCA to a coherent process performing high-throughput automated biodosimetry for individual dose assessment ensuring quality control (QC) and quality assurance (QA) aspects in accordance with international harmonized protocols. A Laboratory Information Management System (LIMS) is designed, implemented and adapted to manage increased sample processing capacity, develop and maintain standard operating procedures (SOP) for robotic instruments, avoid data transcription errors during processing, and automate analysis of chromosome-aberrations using an image analysis platform. Our efforts described in this paper intend to bridge the current technological gaps and enhance the potential application of DCA for a dose-based stratification of subjects following a mass casualty. This paper describes one such potential integrated automated laboratory system and functional evolution of the classical DCA towards increasing critically needed throughput. PMID- 26520384 TI - Growth Differentiation Factor-15 (GDF-15) is a potential marker of radiation response and radiation sensitivity. AB - We have investigated the importance of GDF-15 (secreted cytokine belonging to the TGF-beta superfamily) in low and high dose radiation-induced cellular responses. A telomerase immortalized human fibroblast cell line (F11hT) was used in the experiments. A lentiviral system encoding small hairpin RNAs (shRNA) was used to establish GDF-15 silenced cells. Secreted GDF-15 levels were measured in culture medium by ELISA. Cell cycle analysis was performed by flow cytometry. The experiments demonstrated that in irradiated human fibroblasts GDF-15 expression increased with dose starting from 100mGy. Elevated GDF-15 expression was not detected in bystander cells. The potential role of GDF-15 in radiation response was investigated by silencing GDF-15 in immortalized human fibroblasts with five different shRNA encoded in lentiviral vectors. Cell lines with considerably reduced GDF-15 levels presented increased radiation sensitivity, while a cell line with elevated GDF-15 was more radiation resistant than wild type cells. We have investigated how the reduced GDF-15 levels alter the response of several known radiation inducible genes. In F11hT-shGDF-15 cells the basal expression level of CDKN1A was unaltered relative to F11hT cells, while GADD45A and TGF beta1 mRNA levels were slightly higher, and TP53INP1 was considerably reduced. The radiation-induced expression of TP53INP1 was lower in the silenced than in wild type fibroblast cells. Cell cycle analysis indicated that radiation-induced early G2/M arrest was abrogated in GDF-15 silenced cells. Moreover, radiation induced bystander effect was less pronounced in GDF-15 silenced fibroblasts. In conclusion, the results suggest that GDF-15 works as a radiation inducible radiation resistance increasing factor in normal human fibroblast cells, acts by regulating the radiation-induced transcription of several genes and might serve as a radiation-induced early biomarker in exposed cells. PMID- 26520385 TI - Biological effects of in vitro THz radiation exposure in human foetal fibroblasts. AB - In recent years, terahertz (THz) radiation has been widely used in a variety of applications: medical, security, telecommunications and military areas. However, few data are available on the biological effects of this type of electromagnetic radiation and the reported results, using different genetic or cellular assays, are quite discordant. This multidisciplinary study focuses on potential genotoxic and cytotoxic effects, evaluated by several end-points, associated with THz radiation. For this purpose, in vitro exposure of human foetal fibroblasts to low frequency THz radiation (0.1-0.15THz) was performed using a Compact Free Electron Laser. We did not observe an induction of DNA damage evaluated by Comet assay, phosphorylation of H2AX histone or telomere length modulation. In addiction, no induction of apoptosis or changes in pro-survival signalling proteins were detected. Moreover, our results indicated an increase in the total number of micronuclei and centromere positive micronuclei induction evaluated by CREST analysis, indicating that THz radiation could induce aneugenic rather than clastogenic effects, probably leading to chromosome loss. Furthermore, an increase of actin polymerization observed by ultrastructural analysis after THz irradiation, supports the hypothesis that an abnormal assembly of spindle proteins could lead to the observed chromosomal malsegregation. PMID- 26520386 TI - Investigation of micronucleus induction in MTH1 knockdown cells exposed to UVA, UVB or UVC. AB - The longer wave parts of UVR can increase the production of reactive oxygen species (ROS) which can oxidize nucleotides in the DNA or in the nucleotide pool leading to mutations. Oxidized bases in the DNA are repaired mainly by the DNA base excision repair system and incorporation of oxidized nucleotides into newly synthesized DNA can be prevented by the enzyme MTH1. Here we hypothesize that the formation of several oxidized base damages (from pool and DNA) in close proximity, would cause a high number of base excision repair events, leading to DNA double strand breaks (DSB) and therefore giving rise to cytogenetic damage. If this hypothesis is true, cells with low levels of MTH1 will show higher cytogenetic damage after the longer wave parts of UVR. We analyzed micronuclei induction (MN) as an endpoint for cytogenetic damage in the human lymphoblastoid cell line, TK6, with a normal and a reduced level of MTH1 exposed to UVR. The results indicate a higher level of micronuclei at all incubation times after exposure to the longer wave parts of UVR. There is no significant difference between wildtype and MTH1-knockdown TK6 cells, indicating that MTH1 has no protective role in UVR-induced cytogenetic damage. This indicates that DSBs induced by UV arise from damage forms by direct interaction of UV or ROS with the DNA rather than through oxidation of dNTP. PMID- 26520387 TI - Alternative end-joining repair pathways are the ultimate backup for abrogated classical non-homologous end-joining and homologous recombination repair: Implications for the formation of chromosome translocations. AB - DNA double strand breaks (DSB) are the most deleterious lesions for the integrity of the genome, as their misrepair can lead to the formation of chromosome translocations. Cells have evolved two main repair pathways to suppress the formation of these genotoxic lesions: homology-dependent, error-free homologous recombination repair (HRR), and potentially error-prone, classical, DNA-PK dependent non-homologous end-joining (c-NHEJ). The most salient feature of c NHEJ, speed, will largely suppress chromosome translocation formation, while sequence alterations at the junction remain possible. It is now widely accepted that when c-NHEJ is inactivated, globally or locally, an alternative form of end joining (alt-EJ) removes DSBs. Alt-EJ operates with speed and fidelity markedly lower than c-NHEJ, causing thus with higher probability chromosome translocations, and generating more extensive sequence alterations at the junction. Our working hypothesis is that alt-EJ operates as a backup to c-NHEJ. Recent results show that alt-EJ can also backup abrogated HRR in G2 phase cells, again at the cost of elevated formation of chromosome translocations. These observations raise alt-EJ to a global rescuing mechanism operating on ends that have lost their chromatin context in ways that compromise processing by HRR or c NHEJ. While responsible for eliminating from the genome highly cytotoxic DNA ends, alt-EJ provides this function at the price of increased translocation formation. Here, we analyze recent literature on the mechanisms of chromosome translocation formation and propose a functional hierarchy among DSB processing pathways that makes alt-EJ the global backup pathway. We discuss possible ramifications of this model in cellular DSB management and pathway choice, and analyze its implications in radiation carcinogenesis and the design of novel therapeutic approaches. PMID- 26520388 TI - Chromosomal instability--mechanisms and consequences. AB - Chromosomal instability is defined as a state of numerical and/or structural chromosomal anomalies in cells. Numerous studies have documented the incidence of chromosomal instability, which acutely or chronically may lead to accelerated ageing (tissue-wide or even organismal), cancer or other genetic disorders. Potential mechanisms leading to the generation of chromosome-genome instability include erroneous/inefficient DNA repair, chromosome segregation defects, spindle assembly defects, DNA replication stress, telomere shortening/dysfunction - to name a few. Understanding the cellular and molecular mechanisms for chromosomal instability in various human cells and tissues will be useful in elucidating the cause for many age associated diseases including cancer. This approach holds a great promise for the cytogenetic assays not only for prognosis but also for diagnostic purposes in clinical settings. In this review, a multi-dimensional approach has been attempted to portray the complexity behind the incidence of chromosome-genome instability including evolutionary implications at the species level for some of the mechanisms of chromosomal instability. PMID- 26520389 TI - Stress induced by premature chromatin condensation triggers chromosome shattering and chromothripsis at DNA sites still replicating in micronuclei or multinucleate cells when primary nuclei enter mitosis. AB - Combination of next-generation DNA sequencing, single nucleotide polymorphism array analyses and bioinformatics has revealed the striking phenomenon of chromothripsis, described as complex genomic rearrangements acquired in a single catastrophic event affecting one or a few chromosomes. Via an unproven mechanism, it is postulated that mechanical stress causes chromosome shattering into small lengths of DNA, which are then randomly reassembled by DNA repair machinery. Chromothripsis is currently examined as an alternative mechanism of oncogenesis, in contrast to the present paradigm that considers a stepwise development of cancer. While evidence for the mechanism(s) underlying chromosome shattering during cancer development remains elusive, a number of hypotheses have been proposed to explain chromothripsis, including ionizing radiation, DNA replication stress, breakage-fusion-bridge cycles, micronuclei formation and premature chromosome compaction. In the present work, we provide experimental evidence on the mechanistic basis of chromothripsis and on how chromosomes can get locally shattered in a single catastrophic event. Considering the dynamic nature of chromatin nucleoprotein complex, capable of rapid unfolding, disassembling, assembling and refolding, we first show that chromatin condensation at repairing or replicating DNA sites induces the mechanical stress needed for chromosome shattering to ensue. Premature chromosome condensation is then used to visualize the dynamic nature of interphase chromatin and demonstrate that such mechanical stress and chromosome shattering can also occur in chromosomes within micronuclei or asynchronous multinucleate cells when primary nuclei enter mitosis. Following an aberrant mitosis, chromosomes could find themselves in the wrong place at the wrong time so that they may undergo massive DNA breakage and rearrangement in a single catastrophic event. Specifically, our results support the hypothesis that premature chromosome condensation induces mechanical stress and triggers shattering and chromothripsis in chromosomes or chromosome arms still undergoing DNA replication or repair in micronuclei or asynchronous multinucleate cells, when primary nuclei enter mitosis. PMID- 26520390 TI - Editorial. AB - Cancer is a multifaceted disease and research over decades has sequentially broadened our understanding of the mechanisms which underlie its development, progression and resistance against wide ranging molecular therapeutics. Data obtained through in-vitro studies and xenografted mice based investigations clearly suggested that inactivation of tumor suppressor genes, overexpression of oncogenes, imbalance of pro- and anti-apoptotic proteins, loss of apoptosis, dysregulation of spatio-temporally controlled intracellular signaling cascades, epithelial to mesenchymal transition, intra-tumor heterogeneity are significantly involved in regulation of different steps of cancer. Recently emerging information is also shedding light on considerable role of microRNAs in cancer and we have seen an exponential growth in the list of tumor suppressor and oncogenic miRNAs. Amirkhah et al, described how miRNAs regulated resistance mechanisms against different therapeutics in colorectal cancer. Nosheen Masood and Muhammad Zahid Qureshi emphasized on intricate interplay between Notch signaling and different miRNAs in head and neck cancer. Gasparri et al discussed new frontiers in therapeutic targets in ovarian cancer with spotlight on PARP inhibitors. Notch mediated intracellular signaling in esophageal cancer was comprehensively explained by Wang et al. Resistance mechanisms against TRAIL based therapeutics were described in detail by Limami et al. The authors gave opinion about different approaches which have been tested in preclinical trials to overcome resistance against TRAIL. Mansoor et al reported that GG genotype in death receptor 4 played protective role however, CC genotype had a causative role in colorectal cancer in Pakistani population. Larger pool of patients, sporadic mutations, expression studies will further demystify the association. Hsu et al, extensively described various strategies focusing on how post-translationally modifiable histones can be targeted for cancer treatment. Attar et al provided detailed information related to Viscum album against different cancers. Ahmadi et al studied network structure information and biological data on miRNA-and transcription factor-based gene regulation. Apoptotic cell death is a key mechanism frequently inactivated in cancer cells and different strategies have been used to re-activate/functionalize apoptotic pathway in drug resistant phenotype. We have attempted to present most recent landmarks set in cancer biology and therapeutics. Sarkar et al review summarized multifunctional roles of ASPP (apoptosis stimulating proteins of p53) family in cancer. Smina et al reported that Hesperetin, a flavonoid effectively induced apoptosis in skin cancer cell line. Chong et al experimentally verified that lipid accumulation may not only induce pro-inflammatory responses in hepatocytes but also activate CSC like properties of hepatoma cells through NFkappaB activation. The present thematic issue brings to limelight most recent advancements in constantly developing field of molecular oncology. PMID- 26520391 TI - Receptome: Interactions between three pain-related receptors or the "Triumvirate" of cannabinoid, opioid and TRPV1 receptors. AB - A growing amount of data demonstrates the interactions between cannabinoid, opioid and the transient receptor potential (TRP) vanilloid type 1 (TRPV1) receptors. These interactions can be bidirectional, inhibitory or excitatory, acute or chronic in their nature, and arise both at the molecular level (structurally and functionally) and in physiological processes, such as pain modulation or perception. The interactions of these three pain-related receptors may also reserve important and new therapeutic applications for the treatment of chronic pain or inflammation. In this review, we summarize the main findings on the interactions between the cannabinoid, opioid and the TRPV1 receptor regarding to pain modulation. PMID- 26520392 TI - Antinociceptive effects of fisetin against diabetic neuropathic pain in mice: Engagement of antioxidant mechanisms and spinal GABAA receptors. AB - Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Fisetin, a naturally occurring flavonoid, has been reported to exert antidepressant-like effect in previous studies. As antidepressant drugs are employed clinically to treat neuropathic pain, this work aimed to investigate whether fisetin possess beneficial effect on diabetic neuropathic pain and explore the mechanism(s). We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (200mg/kg), and von Frey test or Hargreaves test was used to assess mechanical allodynia or thermal hyperalgesia, respectively. Chronic treatment of diabetic mice with fisetin not only ameliorated the established symptoms of thermal hyperalgesia and mechanical allodynia, but also arrested the development of neuropathic pain when given at low doses. Although chronic fisetin administration did not impact on the symptom of hyperglycemia in diabetic mice, it reduced exacerbated oxidative stress in tissues of spinal cord, dorsal root ganglion (DRG) and sciatic verve. Furthermore, the analgesic actions of fisetin were abolished by repetitive co treatment with the reactive oxygen species (ROS) donor tert-butyl hydroperoxide (t-BOOH), but potentiated by the ROS scavenger phenyl-N-tert-butylnitrone (PBN). Finally, acute blockade of spinal GABAA receptors by bicuculline totally counteracted such fisetin analgesia. These findings indicate that chronic fisetin treatment can delay or correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the present fisetin analgesia may be associated with its antioxidant activity, and spinal GABAA receptors are likely rendered as downstream targets. PMID- 26520393 TI - Beyond recidivism: changes in health and social service involvement following exposure to drug treatment court. AB - BACKGROUND: The majority of Drug Treatment Court (DTC) research has examined the impact of DTCs on criminal recidivism. Comparatively little research has addressed the association between DTC participation and engagement with community based health and social services. The present study investigated changes in participant involvement with outpatient healthcare and income assistance within a DTC cohort. We hypothesized that involvement with community-based (outpatient) health and social services would increase post-DTC participation, and that service levels would be higher among program graduates and offenders with histories of co-occurring mental and substance use disorders. METHODS: Participants were 631 offenders at the DTC in Vancouver, Canada (DTCV). Administrative data representing hospital, outpatient medical care, and income assistance were examined one-year pre/post program to assess differences over time. Generalized estimating equations were used to investigate the association between changes in service use and program involvement. We also examined the relationship between level of service use and offender characteristics. RESULTS: Members of the cohort were disproportionately Aboriginal (33 %), had been sentenced 2.7 times in the 2 years preceding their index offence, and 50 % had been diagnosed with a non substance-related mental disorder in the five years preceding the index offence. The mean number of outpatient services post DTCV was 51, and the mean amount of social assistance paid was $5,897. Outpatient service use increased following exposure to DTCV (Adjusted Rate Ratio (ARR) = 1.45) and was significantly higher among women (ARR = 1.47), program graduation (ARR = 1.23), and those previously diagnosed with concurrent substance use and mental disorders (ARR = 4.92). Overall, hospital admissions did not increase post program, although rates were significantly higher among women (ARR = 1.76) and those with concurrent disorders (ARR = 2.71). Income assistance increased significantly post program (ARR = 1.16), and was significantly higher among women (ARR = 1.03), and those diagnosed with substance use disorders (ARR = 1.42) and concurrent disorders (ARR = 1.72). CONCLUSIONS: These findings suggest that the DTCV was a catalyst for increased participant engagement with community health and social supports, and that rates of service use were consistently higher among women and individuals with concurrent disorders. Research is needed to investigate the potential link between health and social support and reductions in recidivism associated with DTCs. PMID- 26520395 TI - Human herpesvirus type 8 in tuberculosis patients with effusion. AB - BACKGROUND: Many patients with tuberculosis (TB) are seropositive for human herpesvirus type 8 (HHV-8), and many patients with primary effusion lymphoma have high levels of HHV-8 DNA in their effusions. However, the status of HHV-8 in the effusions of patients with TB remains unclear. METHODS: Blood samples were collected from 129 patients with pulmonary TB and 129 age- and sex-matched healthy controls. Forty of the TB patients had pleural or peritoneal effusions, and 38 of these effusions were available. Both blood and effusion samples were analyzed for lymphocyte and monocyte counts and/or HHV-8 antibodies and DNA. RESULTS: TB patients with or without effusions had significantly greater HHV-8 seropositivity (p = 0.009) and titers of HHV-8 antibodies (p = 0.005) than healthy controls. The seropositivity and blood titers of HHV-8 antibodies were similar in TB patients with and without effusions. Among TB patients with effusions, similar percentages had seropositive plasma and seropositive effusions. Plasma samples of 6 TB patients, but none of the healthy controls, were positive for HHV-8 DNA (p = 0.03). TB patients with or without effusions had lower blood lymphocyte counts and higher blood monocyte counts than healthy controls (p < 0.0001 for both). TB patients with effusions had significantly lower blood lymphocyte counts than those without effusions (p = 0.035). CONCLUSIONS: HHV-8 had similar seroprevalence in TB patients with and without effusions. However, TB patients with effusions had lower blood lymphocyte counts than those without effusions. PMID- 26520394 TI - SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation. AB - BACKGROUND: Amyotrophic Lateral Sclerosis is characterized by a focal onset of symptoms followed by a progressive spread of pathology that has been likened to transmission of infectious prions. Cell-to-cell transmission of SOD1 protein aggregates is dependent on fluid-phase endocytosis pathways, although the precise molecular mechanisms remain to be elucidated. RESULTS: We demonstrate in this paper that SOD1 aggregates interact with the cell surface triggering activation of Rac1 and subsequent membrane ruffling permitting aggregate uptake via stimulated macropinocytosis. In addition, other protein aggregates, including those associated with neurodegenerative diseases (TDP-43, Httex146Q, alpha synuclein) also trigger membrane ruffling to gain entry into the cell. Aggregates are able to rupture unstructured macropinosomes to enter the cytosol allowing propagation of aggregation to proceed. CONCLUSION: Thus, we conclude that in addition to basic proteostasis mechanisms, pathways involved in the activation of macropinocytosis are key determinants in the spread of pathology in these misfolding diseases. PMID- 26520396 TI - Predictive factors for ovarian response in a corifollitropin alfa/GnRH antagonist protocol for controlled ovarian stimulation in IVF/ICSI cycles. AB - BACKGROUND: This secondary analysis aimed to identify predictors of low (<6 oocytes retrieved) and high ovarian response (>18 oocytes retrieved) in IVF patients undergoing controlled ovarian stimulation with corifollitropin alfa in a gonadotropin-releasing hormone (GnRH) antagonist protocol. METHODS: Statistical model building for high and low ovarian response was based on the 150 MUg corifollitropin alfa treatment group of the Pursue trial in infertile women aged 35-42 years (n = 694). RESULTS: Multivariable logistic regression models were constructed in a stepwise fashion (P <0.05 for entry). 14.1 % of subjects were high ovarian responders and 23.2 % were low ovarian responders. The regression model for high ovarian response included four independent predictors: higher anti Mullerian hormone (AMH) and antral follicle count (AFC) increased the risk, and higher follicle-stimulating hormone (FSH) levels and advancing age decreased the risk of high ovarian response. The regression model for low ovarian response also included four independent predictors: advancing age increased the risk, and higher AMH, higher AFC and longer menstrual cycle length decreased the risk of low ovarian response. CONCLUSIONS: AMH, AFC and age predicted both high and low ovarian responses, FSH predicted high ovarian response, and menstrual cycle length predicted low ovarian response in a corifollitropin alfa/GnRH antagonist protocol. TRIAL REGISTRATION NUMBER: NCT01144416 , Protocol P06029. PMID- 26520397 TI - Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma. AB - BACKGROUND: Despite advances in therapeutics, outcomes for hepatocellular carcinoma (HCC) remain poor and there is an urgent need for efficacious systemic therapy. Unfortunately, drugs that are successful in preclinical studies often fail in the clinical setting, and we hypothesize that this is due to functional differences between primary tumors and commonly used preclinical models. In this study, we attempt to answer this question by comparing tumor morphology and gene expression profiles between primary tumors, xenografts and HCC cell lines. METHODS: Hep G2 cell lines and tumor cells from patient tumor explants were subcutaneously (ectopically) injected into the flank and orthotopically into liver parenchyma of Mus Musculus SCID mice. The mice were euthanized after two weeks. RNA was extracted from the tumors, and gene expression profiling was performed using the Gene Chip Human Genome U133 Plus 2.0. Principal component analyses (PCA) and construction of dendrograms were conducted using Partek genomics suite. RESULTS: PCA showed that the commonly used HepG2 cell line model and its xenograft counterparts were vastly different from all fresh primary tumors. Expression profiles of primary tumors were also significantly divergent from their counterpart patient-derived xenograft (PDX) models, regardless of the site of implantation. Xenografts from the same primary tumors were more likely to cluster together regardless of site of implantation, although heat maps showed distinct differences in gene expression profiles between orthotopic and ectopic models. CONCLUSIONS: The data presented here challenges the utility of routinely used preclinical models. Models using HepG2 were vastly different from primary tumors and PDXs, suggesting that this is not clinically representative. Surprisingly, site of implantation (orthotopic versus ectopic) resulted in limited impact on gene expression profiles, and in both scenarios xenografts differed significantly from the original primary tumors, challenging the long held notion that orthotopic PDX model is the gold standard preclinical model for HCC. PMID- 26520398 TI - Effects of combining robot-assisted therapy with neuromuscular electrical stimulation on motor impairment, motor and daily function, and quality of life in patients with chronic stroke: a double-blinded randomized controlled trial. AB - BACKGROUND: Robot-assisted therapy (RT) is a widely used intervention approach to enhance motor recovery in patients after stroke, but its effects on functional improvement remained uncertain. Neuromuscular electrical stimulation (NMES) is one potential adjuvant intervention approach to RT that could directly activate the stimulated muscles and improve functional use of the paretic hand. METHODS: This was a randomized, double-blind, sham-controlled study. Thirty-nine individuals with chronic stroke were randomly assigned to the RT combined with NMES (RT + ES) or to RT with sham stimulation (RT + Sham) groups. The participants completed the intervention 90 to 100 minutes/day, 5 days/week for 4 weeks. The outcome measures included the upper extremity Fugl-Meyer Assessment (UE-FMA), modified Ashworth scale (MAS), Wolf Motor Function Test (WMFT), Motor Activity Log (MAL), and Stroke Impact Scale 3.0 (SIS). All outcome measures were assessed before and after intervention, and the UE-FMA, MAL, and SIS were reassessed at 3 months of follow-up. RESULTS: Compared with the RT + Sham group, the RT + ES group demonstrated greater improvements in wrist flexor MAS score, WMFT quality of movement, and the hand function domain of the SIS. For other outcome measures, both groups improved significantly after the interventions, but no group differences were found. CONCLUSION: RT + ES induced significant benefits in reducing wrist flexor spasticity and in hand movement quality in patients with chronic stroke. TRIAL REGISTRATION: ClinicalTrials.gov. NCT01655446. PMID- 26520400 TI - Enhanced in vitro osteogenic differentiation of human fetal MSCs attached to 3D microcarriers versus harvested from 2D monolayers. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are of great interest in bone regenerative medicine due to their osteogenic potential and trophic effects. However, challenges to large-scale production of MSCs can hinder the translation of MSC therapies. 3D Microcarrier (MC)-based MSC culture presents a scalable and cost-effective alternative to conventional methods of expansion in 2D monolayers. Furthermore, biodegradable MCs may allow for MC-bound MSC delivery without enzymatic harvest for selected applications such as bone healing. However, the effects of cell expansion on microcarriers and enzymatic cell harvest on MSC phenotype and osteogenic differential potential are not well understood. In this study, we characterized human fetal MSCs (hfMSCs) after expansion in 3D microcarrier spinner or 2D monolayer cultures. Following expansion, we compared osteogenic differentiation of cultures seeded with 3D MC-harvested, 3D MC-bound and conventional 2D monolayer (MNL)-harvested cells when cultured in osteogenic induction media on collagen-coated plates. RESULTS: Fetal MSCs expanded on both 3D agitated Microcarriers (MC) and 2D Plastic static monolayer (MNL) cultures express high levels of MSC surface markers. MC-harvested hfMSCs displayed higher expression of early osteogenic genes but slower mineralization kinetics compared to MNL-harvested MSCs during osteogenic induction. However, in the comparison between MC-bound and MC-harvested hfMSCs, osteogenic genes were upregulated and mineralization kinetics was accelerated in the former condition. Importantly, 3D MC-bound hfMSCs expressed higher levels of osteogenic genes and displayed either higher or equivalent levels of mineralization, depending on the cell line, compared to the classical monolayer cultures use in the literature (MNL-harvested hfMSCs). CONCLUSION: Beyond the processing and scalability advantages of the microcarrier culture, hfMSCs attached to MCs undergo robust osteogenic differentiation and mineralization compared to enzymatically harvested cells. Thus biodegradable/biocompatible MCs which can potentially be used for cell expansion as well as a scaffold for direct in vivo delivery of cells may have advantages over the current methods of monolayer-expansion and delivery post harvest for bone regeneration applications. PMID- 26520399 TI - Pax6 is required intrinsically by thalamic progenitors for the normal molecular patterning of thalamic neurons but not the growth and guidance of their axons. AB - BACKGROUND: In mouse embryos, the Pax6 transcription factor is expressed in the progenitors of thalamic neurons but not in thalamic neurons themselves. Its null mutation causes early mis-patterning of thalamic progenitors. It is known that thalamic neurons generated by Pax6 (-/-) progenitors do not develop their normal connections with the cortex, but it is not clear why. We investigated the extent to which defects intrinsic to the thalamus are responsible. RESULTS: We first confirmed that, in constitutive Pax6 (-/-) mutants, the axons of thalamic neurons fail to enter the telencephalon and, instead, many of them take an abnormal path to the hypothalamus, whose expression of Slits would normally repel them. We found that thalamic neurons show reduced expression of the Slit receptor Robo2 in Pax6 (-/-) mutants, which might enhance the ability of their axons to enter the hypothalamus. Remarkably, however, in chimeras comprising a mixture of Pax6 (-/-) and Pax6 (+/+) cells, Pax6 (-/-) thalamic neurons are able to generate axons that exit the diencephalon, take normal trajectories through the telencephalon and avoid the hypothalamus. This occurs despite abnormalities in their molecular patterning (they express Nkx2.2, unlike normal thalamic neurons) and their reduced expression of Robo2. In conditional mutants, acute deletion of Pax6 from the forebrain at the time when thalamic axons are starting to grow does not prevent the development of the thalamocortical tract, suggesting that earlier extra-thalamic patterning and /or morphological defects are the main cause of thalamocortical tract failure in Pax6 (-/-) constitutive mutants. CONCLUSIONS: Our results indicate that Pax6 is required by thalamic progenitors for the normal molecular patterning of the thalamic neurons that they generate but thalamic neurons do not need normal Pax6-dependent patterning to become competent to grow axons that can be guided appropriately. PMID- 26520401 TI - A randomized trial of the efficacy of artesunate and three quinine regimens in the treatment of severe malaria in children at the Ebolowa Regional Hospital, Cameroon. AB - BACKGROUND: Severe malaria is a medical emergency with high mortality in children below 5 years of age especially in sub-Saharan Africa. Recently, quinine has been replaced by artesunate as the first-line drug in the treatment of severe malaria in Cameroon. No local data are yet available on the efficacy of artesunate with respect to the different quinine regimens used in this setting. This study was undertaken at the Ebolowa Regional Hospital (ERH), which is located in a region of perennial transmission of malaria. METHODS: This was a randomized, open-label trial in children aged 3 months to 15 years, admitted in the hospital with severe malaria due to Plasmodium falciparum confirmed on microscopy after informed parental consent. Patients were randomized into four groups. Group 1 (ARTES) received parenteral artesunate at 2.4 mg/kg at H0, H12, H24 and then once daily; Group 2 (QLD) received a loading dose of quinine base at 16.6 mg/kg followed 8 hours later by an eight-hourly maintenance dose of 8.3 mg/kg quinine base; Group 3 (QNLD3) received 8.3 mg/kg quinine base every 8 hours; and, Group 4 (QNLD2) received 12.5 mg/kg quinine base every 12 h. All patients invariably received a minimum of 24 h parenteral treatment, then, oral drugs were prescribed. The endpoints were fever clearance time, time to sit unsupported, time to eat, parasite clearance time, and parasitaemia reduction rate at H24. Survival analysis was used to compare the outcomes. RESULTS: One-hundred and sixteen patients completed the study: 29 in ARTES arm, 28 in QLD arm, 30 in QNLD3 arm, and 29 in QNLD2 arm. There was no major differences in baseline characteristics in the treatment groups. On analysis of endpoints, fever clearance time and parasite clearance time were significantly shorter for artesunate-treated patients than for quinine-treated patients. Parasitaemia reduction rate at H24 was also significantly higher for artesunate. Time to sit unsupported and time to eat were shorter with artesunate, but the difference was not statistically significant. CONCLUSION: Artesunate is more effective than quinine in the treatment of severe malaria in Cameroonian children. PMID- 26520402 TI - Predictive validity of two process-of-care quality measures for residential substance use disorder treatment. AB - BACKGROUND: In order to monitor and ultimately improve the quality of addiction treatment, professional societies, health care systems, and addiction treatment programs must establish clinical practice standards and then operationalize these standards into reliable, valid, and feasible quality measures. Before being implemented, quality measures should undergo tests of validity, including predictive validity. Predictive validity refers to the association between process-of-care quality measures and subsequent patient outcomes. This study evaluated the predictive validity of two process quality measures of residential substance use disorder (SUD) treatment. METHODS: Washington Circle (WC) Continuity of Care quality measure is the proportion of patients having an outpatient SUD treatment encounter within 14 days after discharge from residential SUD treatment. The Early Discharge measure is the proportion of patients admitted to residential SUD treatment who discharged within 1 week of admission. The predictive validity of these process measures was evaluated in US Veterans Health Administration patients for whom utilization-based outcome and 2 year mortality data were available. Propensity score-weighted, mixed effects regression adjusted for pre-index imbalances between patients who did and did not meet the measures' criteria and clustering of patients within facilities. RESULTS: For the WC Continuity of Care measure, 76 % of 10,064 patients had a follow-up visit within 14 days of discharge. In propensity score-weighted models, patients who had a follow-up visit had a lower 2-year mortality rate [odds ratio (OR) = 0.77, p = 0.008], but no difference in subsequent detoxification episodes relative to patients without a follow-up visit. For the Early Discharge measure, 9.6 % of 10,176 discharged early and had significantly higher 2-year mortality (OR = 1.49, p < 0.001) and more subsequent detoxification episodes. CONCLUSIONS: These two measures of residential SUD treatment quality have strong associations with 2-year mortality and the Early Discharge measure is also associated with more subsequent detoxification episodes. These results provide initial support for the predictive validity of residential SUD treatment quality measures and represent the first time that any SUD quality measure has been shown to predict subsequent mortality. PMID- 26520404 TI - Acetazolamide Use in an Ultra-Runner: A Complicated Treatment Consideration for AMS. PMID- 26520403 TI - Critical analysis of a simplified Fuhrman grading scheme for prediction of cancer specific mortality in patients with clear cell renal cell carcinoma--Impact on prognosis. AB - INTRODUCTION AND OBJECTIVES: The traditional 4-tiered Fuhrman grading system (FGS) is widely accepted as histopathological classification for clear cell renal cell carcinoma (ccRCC) and has shown prognostic value. As intra- and inter observer agreement are sub-optimal, simplified 2- or 3-tiered FGSs have been proposed. We aimed to validate these simplified 2- or 3-tiered FGSs for prediction of cancer-specific mortality (CSM) in a large study population from 2 European tertiary care centers. METHODS: We identified and followed-up 2415 patients with ccRCC who underwent radical or partial nephrectomy in 2 European tertiary care centers. Univariable and multivariable analyses and prognostic accuracy analyses were performed to evaluate the ability of several simplified FGSs (i.e. grades I + II vs., grades III + IV, grades I + II vs. grade III and grade IV) to predict CSM. RESULTS: Independent predictor status in multivariate analyses was proved for the simplified 2-tiered FGS (high-grade vs. low-grade), for the simplified 3-tiered FGS (grades I + II vs. grade III and grade IV) as well as for the traditional 4-tiered FGS. The prognostic accuracy of multivariable models of 77% was identical for all tested models. Prognostic accuracy of the model without FG was 75%. CONCLUSIONS: A simplified 2- or 3 tiered FGS could predict CSM as accurate as the traditional 4-tiered FGS in a large European study population. Application of new simplified 2- or 3-tiered FGS may reduce inter-observer-variability and facilitate clinical practice without compromising the ability to predict CSM in ccRCC patients after radical or partial nephrectomy. PMID- 26520405 TI - The plasticizer BBP selectively inhibits epigenetic regulator sirtuins. AB - The plasticizer benzyl butyl phthalate (BBP) is a well-known endocrine disruptor. Widespread human exposure to phthalates has raised substantial public concern due to its detrimental health effects. However, molecular mechanisms of the phthalates effect require elucidation. In this study, we analyzed: 1) the binding interaction of several phthalates and persistent organic pollutants with epigenetic regulator sirtuins and 2) the effect of BBP on the sirtuins in HepG2 cells. AutoDock molecular docking analysis showed that BBP binds to Sirt1 and Sirt3 proteins similarly to the native ligands with shortest binding free energies (DeltaGb) of -7.35 and -8.3 kcal/mol, respectively; and inhibition constants (Ki) of 4.07 MUM and 0.82 MUM, respectively. Furthermore, BBP was superimposed onto the co-crystallized ligands within the least root-mean-square deviation (RMSD) of 0.96A and 1.55A for Sirt1 and Sirt3, respectively, and bound into the sites with a sufficient number of hydrogen bonds, implying the best fit compared to other sirtuins. In HepG2 cells, BBP significantly down-regulated Sirt1 and Sirt3 (p<0.05) gene expression at a concentration as low as 10nM; other sirtuins remained unaffected. Consistent with decreased gene expression, Sirt1 and Sirt3 protein levels were significantly decreased at 48 h (p<0.05). In addition, mitochondrial biogenesis regulators PGC-1alpha, NRF-1, and NRF-2, were decreased (p<0.05). SiRNA studies showed that BBP did not regulate PGC-1alpha via sirtuin and BBP requires sirtuin's presence to regulate NRF-1 or NRF-2. BBP significantly increased ROS production (p<0.05) and ROS may be chiefly regulated by NRF-1 and NRF-2 in HepG2 cells under Sirt1 and Sirt3 silenced condition. This is the first report to demonstrate that BBP selectively disrupts specific sirtuins in HepG2 cells. In conclusion, our study suggests that BBP can impair two vital epigenetic regulators and mitochondrial biogenesis regulators in liver cells. PMID- 26520406 TI - Bioactivity of noble metal nanoparticles decorated with biopolymers and their application in drug delivery. AB - The unique properties of nanomaterials can be applied to solve different problems including new ways of drug delivery. Noble metal nanoparticles are most promising because they have been used for medicinal purposes since ancient time. It is evident from the past studies that the metallic nanoparticles are much more effective against various microorganisms when compared to their conventional counterparts. However, decoration of such nanoparticles with biomaterials add more advantages to their antimicrobial activity. Decoration of metal nanoparticles with biopolymers is a quite new area of research. Studies performed hitherto shown that nanoparticles of noble metals like silver, gold and platinum demonstrated better antibacterial, antifungal and antiviral activities when conjugated with biopolymers. The development of such technology has potential to develop materials that are more effective in the field of health science. Considering the importance and uniqueness of this concept, the present review aims to discuss the use of biopolymer-decorated metal nanoparticles for combating various diseases caused by microbial pathogens. Moreover, the nanotoxicity aspect has also been discussed. PMID- 26520407 TI - In vitro and in vivo performance of dexamethasone loaded PLGA microspheres prepared using polymer blends. AB - The foreign body reaction is the major cause of the dysfunction and relatively short lifetime associated with implanted glucose biosensors. An effective strategy to maintain sensor functionality is to apply biocompatible coatings that elute drug to counter the negative tissue reactions. This has been achieved using dexamethasone releasing poly(lactic-co-glycolic acid) (PLGA) microspheres embedded in a polyvinyl alcohol (PVA) hydrogel coating. Accordingly, the biosensor lifetime relies on the duration and dose of drug release from the coating. To achieve long-term drug release mixed populations of microspheres have been used. In the current study, microspheres were prepared by blending low (25KDa) and high (113KDa) molecular weight PLGA at different mass ratios to overcome problems associated with mixing multiple populations of microspheres. "Real-time" in vitro studies demonstrated dexamethasone release for approximately 5 months. An accelerated method with discriminatory ability was developed to shorten drug release to less than 2 weeks. An in vivo pharmacodynamics study demonstrated efficacy against the foreign body reaction for 4.5 months. Such composite coatings composed of PLGA microspheres prepared using polymer blends could potentially be used to ensure long-term performance of glucose sensors. PMID- 26520408 TI - Additive manufacturing of scaffolds with dexamethasone controlled release for enhanced bone regeneration. AB - The adoption of additive manufacturing in tissue engineering and regenerative medicine (TERM) strategies greatly relies on the development of novel 3D printable materials with advanced properties. In this work we have developed a material for bone TERM applications with tunable bioerosion rate and dexamethasone release profile which can be further employed in fused deposition modelling (the most common and accessible 3D printing technology in the market). The developed material consisted of a blend of poly-epsilon-caprolactone (PCL) and poloxamine (Tetronic(r)) and was processed into a ready-to-use filament form by means of a simplified melt-based methodology, therefore eliminating the utilization of solvents. 3D scaffolds composed of various blend formulations were additively manufactured and analyzed revealing blend ratio-specific degradation rates and dexamethasone release profiles. Furthermore, in vitro culture studies revealed a similar blend ratio-specific trend concerning the osteoinductive activity of the fabricated scaffolds when these were seeded and cultured with human mesenchymal stem cells. The developed material enables to specifically address different regenerative requirements found in various tissue defects. The versatility of such strategy is further increased by the ability of additive manufacturing to accurately fabricate implants matching any given defect geometry. PMID- 26520409 TI - Recent advances in superparamagnetic iron oxide nanoparticles (SPIONs) for in vitro and in vivo cancer nanotheranostics. AB - Recently superparamagnetic iron oxide nanoparticles (SPIONs) have been extensively used in cancer therapy and diagnosis (theranostics) via magnetic targeting, magnetic resonance imaging, etc. due to their remarkable magnetic properties, chemical stability, and biocompatibility. However, the magnetic properties of SPIONs are influenced by various physicochemical and synthesis parameters. So, this review mainly focuses on the influence of spin canting effects, introduced by the variations in size, shape, and organic/inorganic surface coatings, on the magnetic properties of SPIONs. This review also describes the several predominant chemical synthesis procedures and role of the synthesis parameters for monitoring the size, shape, crystallinity and composition of the SPIONs. Moreover, this review discusses about the latest developments of the inorganic materials and organic polymers for encapsulation of the SPIONs. Finally, the most recent advancements of the SPIONs and their nanopackages in combination with other imaging/therapeutic agents have been comprehensively discussed for their effective usage as in vitro and in vivo theranostic agents in cancer treatments. PMID- 26520411 TI - Embracing complexity. PMID- 26520410 TI - [Treatment of postoperative cystoid macular edema (Irvine-Gass syndrome) with dexamethasone 0.7 mg intravitreal implant]. AB - PURPOSE: To evaluate the efficacy of dexamethasone 0.7 mg intravitreal implant in patients with postoperative cystoid macular edema. MATERIALS AND METHODS: Fourteen patients' charts with postoperative cystoid macular edema were retrospectively reviewed. The main outcome measures were best-corrected visual acuity (BCVA) and mean central retinal thickness (CRT). RESULTS: Patients' mean age was 72.1 years old. Five patients were diabetic. All patients had previously been treated with non-steroidal anti-inflammatory drops. Four patients had received a previous treatment with intravitreal ranibizumab. The mean follow-up period was 8.7 months. Mean BCVA before intravitreal dexamethasone was 0.72 logMAR. After injection, it improved to 0.50 at month 1, was 0.47 at month 3, and 0.60 logMAR at month 12. The pre-injection mean CRT was 598 MUm. It improved to 286 MUm at month 1, 338 MUm at month 3, and was 441 MUm at month 12. Eight patients received 2 intravitreal injections of dexamethasone. Five patients presented with elevated intraocular pressure during follow-up, which was treated with drops. CONCLUSIONS: Intravitreal dexamethasone injection improved visual acuity and macular thickness at month 1 and month 3 in patients with postoperative cystoid macular edema. A second injection was necessary after a mean period of 5 months. PMID- 26520412 TI - Prognostic value of a previous medical or surgical admission in outpatients with symptomatic pulmonary embolism. AB - OBJECTIVE: To determine whether an earlier medical (MA) or surgical (SA) admission in the previous three months is a factor associated with mortality at 30 days in outpatients with acute symptomatic pulmonary embolism. METHOD: Observational, retrospective cohort study on adult patients diagnosed with acute symptomatic pulmonary embolism in a tertiary hospital over a period of 6 years. RESULTS: The study included 870 patients with a mean age of 72.7 years: 10.6% (92) had a prior MA, 4.9% (43) had a SA and 12.9% (112) died within the first 30 days. The MA group showed a higher frequency of simplified Pulmonary Embolism Severity Index (PESI) of high risk (>=1) (MA 90.2% vs SA 65.1% vs no prior admission 67.0%; p<0.001) and mortality at 30 days (MA 20.7% vs SA 7.0% vs no prior admission 12.9%; p=0.038). The logistic regression analysis demonstrated that a simplified PESI>=1 was the only independent risk factor for mortality at 30 days. CONCLUSIONS: The severity of the acute episode, as assessed by the simplified PESI scale, is independently associated with mortality at 30 days in outpatients with acute symptomatic pulmonary embolism. An earlier MA in the previous 3 months usually involves greater severity in the acute episode. PMID- 26520413 TI - The effect of prebiotic supplementation with inulin on cardiometabolic health: Rationale, design, and methods of a controlled feeding efficacy trial in adults at risk of type 2 diabetes. AB - Prediabetes is associated with low-grade chronic inflammation that increases the risk for developing type 2 diabetes (T2D) and cardiovascular disease (CVD). An elevated lipopolysaccharide concentration, associated with dysbiosis of the intestinal microbiota, has been implicated in the development of both T2D and CVD. Selective modulation of the intestinal microbiota with prebiotics reduces intestinal permeability and endotoxin concentrations, inflammation, and metabolic dysfunction in rodents. The effect of prebiotic supplementation on cardio metabolic function in humans at risk for T2D is not known. The primary aim of this trial is to determine the influence of prebiotic supplementation with inulin on insulin sensitivity and skeletal muscle metabolic flexibility in adults at risk for T2D. We hypothesize that prebiotic supplementation with inulin will improve insulin sensitivity and skeletal muscle metabolic flexibility. We will randomize 48 adults (40-75 yrs) with prediabetes or a score >= 5 on the American Diabetes Association (ADA) risk screener to 6 weeks of prebiotic supplementation with inulin (10 g/day) or placebo. Subjects will be provided with all food for the duration of the study, to avoid potential confounding through differences in dietary intake between individuals. Intestinal permeability, serum endotoxin concentrations, insulin sensitivity, skeletal muscle metabolic flexibility, endothelial function, arterial stiffness, and fecal bacterial composition will be measured at baseline and following treatment. The identification of prebiotic supplementation with inulin as an efficacious strategy for reducing cardio metabolic risk in individuals at risk of T2D could impact clinical practice by informing dietary recommendations and increasing acceptance of prebiotics by the scientific and medical community. PMID- 26520414 TI - [Pharmacist perception of the use of analgesics and their practice on mild moderate pain. DOLOR-OFF survey]. AB - OBJECTIVE: To examine the use of analgesics, from the perspective of the pharmacist community, and pharmaceutical practice in mild-moderate pain. DESIGN: A cross-sectional, observational study was performed between April and September 2013. SETTING: 696 community pharmacies in 20 Spanish provinces. PARTICIPANTS: Community pharmacists with a minimum professional experience of one year. MAIN MEASUREMENTS: Characterisation of the demand for analgesics, analgesic users, and pharmaceutical intervention for mild-moderate pain from the perspective of the pharmaceutical community. RESULTS: The main reason why a patient with mild moderate pain visits a pharmacy is to receive a drug with prescription (45.5%), and the most common condition is headache (35.2%). Ibuprofen and paracetamol are the most commonly used drugs for mild-moderate pain. More than one-third (38.9%) of pharmacists follow a protocol for counselling. A correlation was found between the pharmacist's professional experience and the application of counselling process (Fisher P<.05). Some 87.8% of pharmacists checked two indicators from the dispensing service, and only 1.3% did not check any. Referral to a physician was made by 14.8% of pharmacists, with the main reason being the detection of alarm indicators. CONCLUSIONS: Protocols need to be designed and adapted to the characteristics of the 3 profiles identified, in order to increase the efficiency of pharmaceutical services in mild-moderate pain relief. Practical and specific training in pain are required to implement services to ensure the correct and systemic use of analgesics and positive clinical outcomes. PMID- 26520415 TI - Stool DNA Testing for Screening Detection of Colorectal Neoplasia in Alaska Native People. AB - OBJECTIVE: To assess the accuracy of a multitarget stool DNA test (MT-sDNA) compared with fecal immunochemical testing for hemoglobin (FIT) for detection of screening-relevant colorectal neoplasia (SRN) in Alaska Native people, who have among the world's highest rates of colorectal cancer (CRC) and limited access to conventional screening approaches. PATIENTS AND METHODS: We performed a prospective, cross-sectional study of asymptomatic Alaska Native adults aged 40 85 years and older undergoing screening or surveillance colonoscopy between February 6, 2012, and August 7, 2014. RESULTS: Among 868 enrolled participants, 661 completed the study (403 [61%] women). Overall, SRN detection by MT-sDNA (49%) was superior to that by FIT (28%; P<.001); in the screening group, SRN detection rates were 50% and 31%, respectively (P=.01). Multitarget stool DNA testing detected 62% of adenomas 2 cm or larger vs 29% by FIT (P=.05). Sensitivity by MT-sDNA increased with adenoma size (to 80% for lesions >=3 cm; P=.01 for trend) and substantially exceeded FIT sensitivity at all adenoma sizes. For sessile serrated polyps larger than 1 cm (n=9), detection was 67% by MT-sDNA vs 11% by FIT (P=.07). For CRC (n=10), detection was 100% by MT-sDNA vs 80% by FIT (P=.48). Specificities were 93% and 96%, respectively (P=.03). CONCLUSION: The sensitivity of MT-sDNA for cancer and larger polyps was high and significantly greater than that of FIT for polyps of any size, while specificity was slightly higher with FIT. These findings could translate into high cumulative neoplasm detection rates on serial testing within a screening program. The MT sDNA represents a potential strategy to expand CRC screening and reduce CRC incidence and mortality, especially where access to endoscopy is limited. PMID- 26520416 TI - MMP-7 is a highly specific negative marker for benign and malignant mesothelial cells in serous effusions. AB - The aim of this study was to analyze the diagnostic role of MMP-7 in effusion cytology. Effusions (n = 356), consisting of 307 carcinomas (184 ovarian, 55 breast, 32 lung, 36 carcinomas of other origin) and 49 malignant mesotheliomas, were analyzed for MMP-7 expression using immunohistochemistry. MMP-7 was expressed in 124/307 (40%) carcinomas and was uniformly absent in malignant mesotheliomas (0/49; 0%; P < .001). Reactive mesothelial cells were similarly MMP 7 negative in all carcinoma specimens. In carcinomas, expression was most frequent in tumors of ovarian and other female genital (cervical and endometrial) origin (P < .001). The sensitivity and specificity of this marker in the differential diagnosis between high-grade serous carcinoma and malignant mesothelioma were 46% and 100%, respectively. In conclusion, MMP-7 expression is highly specific, though only of moderate sensitivity, for the diagnosis of carcinoma in the differential diagnosis from both benign and malignant mesothelial cells. PMID- 26520417 TI - The diagnostic utility of reduced immunohistochemical expression of SMARCB1 in synovial sarcomas: a validation study. AB - Synovial sarcoma is a malignant mesenchymal neoplasm of uncertain histogenesis, characterized by a specific SS18-SSX fusion. The diagnosis of synovial sarcoma can be challenging based on morphology and conventional immunohistochemistry alone, and identification of the fusion gene by molecular genetics may be necessary for diagnosis. Several recent studies have demonstrated the diagnostic utility of the reduced expression of SMARCB1 in synovial sarcomas as measured using immunohistochemistry. Therefore, we undertook a validation study using synovial sarcomas and other spindle or round cell tumors that could enter differential diagnosis of monophasic or poorly differentiated synovial sarcomas. Among 36 synovial sarcomas that were successfully evaluated, the expression of SMARCB1 was diffusely reduced in 33 cases (92%) at variable degrees. In contrast, the expression of SMARCB1 was not reduced in any of the 93 evaluable non-synovial sarcoma tumors (5 thymomas, 5 sarcomatoid mesotheliomas, 10 schwannomas, 9 mesenchymal chondrosarcomas, 20 solitary fibrous tumors, 19 Ewing sarcomas, and 25 malignant peripheral nerve sheath tumors). A few schwannomas and malignant peripheral nerve sheath tumors showed mosaic or complete loss of SMARCB1 expression. Reduced expression of SMARCB1 immunoreactivity was therefore found to be highly sensitive and specific for synovial sarcoma, and can be useful for rapidly and accurately confirming the diagnosis of synovial sarcoma. This reduction in SMARCB1 expression likely reflects the BAF47 ejection mechanism of the SS18-SSX fusion product and can therefore be viewed as an indirect visualization of this fusion product. PMID- 26520418 TI - Are clinicopathological features of colorectal cancers with methylation in half of CpG island methylator phenotype panel markers different from those of CpG island methylator phenotype-high colorectal cancers? AB - CpG island methylator phenotype (CIMP)-high (CIMP-H) colorectal cancer (CRC) is defined when a tumor shows methylation at greater than or equal to 60% of CIMP panel markers. Although CRCs with methylation at 50% of panel markers are classified as CIMP-low/CIMP-0 tumors, little is known regarding the clinicopathological and molecular features of CRCs with methylation at 4/8 panel markers (4/8 methylated markers) and whether they are akin to CIMP-H or CIMP low/CIMP-0 CRCs in terms of their clinicopathological or molecular features. A total of 1164 cases of surgically resected CRC were analyzed for their methylation status in 8 CIMP panel markers, and the frequencies of various clinicopathological and molecular features were compared between CRCs with 0/8, 1/8 to 3/8, 4/8, and 5/8 to 8/8 methylated markers. CRCs with 4/8 methylated markers were closer to CRCs with 5/8 to 8/8 methylated markers in terms of sex distribution, mucin production, serration, nodal metastasis, CK7 expression, CK20 loss, and CDX2 loss frequencies and overall survival rate. CRCs with methylation at 4/8 markers were closer to CRCs with 1/8 to 3/8 methylated markers in terms of less frequent right colon location and poor differentiation. CRCs with 4/8 methylated markers showed the shortest overall survival time compared with CRCs with 0/8, 1/8 to 3/8, 4/8, or 5/8 to 8/8 methylated markers. In terms of clinicopathological and molecular features, CRCs with 4/8 methylated markers appeared to be closer to CIMP-H than to CIMP-low/CIMP-0 and would thus be better classified as CIMP-H if the CRCs require classification into either CIMP-H or CIMP-low/CIMP-0. PMID- 26520420 TI - Validation of next-generation sequencing for comprehensive chromosome screening of embryos. AB - Massively parallel genome sequencing, also known as next-generation sequencing (NGS), is the latest approach for preimplantation genetic diagnosis. The purpose of this study was to determine whether NGS can accurately detect aneuploidy in human embryos. Low coverage genome sequencing was applied to trophectoderm biopsies of embryos at the blastocyst stage of development. Sensitivity and specificity of NGS was determined by comparison of results with a previously validated platform, array-comparative genomic hybridization (aCGH). In total, 156 samples (116 were blindly assessed) were tested: 40 samples were re-biopsies of blastocysts where the original biopsy specimen was previously tested for aCGH; four samples were re-biopsies of single blastomeres from embryos previously biopsied at the cleavage stage and tested using aCGH; 18 samples were single cells derived from well-characterized cell lines; 94 samples were whole-genome amplification products from embryo biopsies taken from previous preimplantation genetic screening cycles analysed using aCGH. Per embryo, NGS sensitivity was 100% (no false negatives), and 100% specificity (no false positives). Per chromosome, NGS concordance was 99.20%. With more improvement, NGS will allow the simultaneous diagnosis of single gene disorders and aneuploidy, and may have the potential to provide more detailed insight into other aspects of embryo viability. PMID- 26520419 TI - Significance of a minor high-grade component in a low-grade noninvasive papillary urothelial carcinoma of bladder. AB - To assess the clinicopathological features and prognostic significance of the presence of 5% or less high-grade component in otherwise low-grade noninvasive bladder urothelial carcinoma, referred to as mixed-grade (MG) urothelial carcinoma, we reviewed all archival cases with such diagnosis between 2005 and 2014. Clinicopathological and outcome parameters were compared to those in our previously reported low- and high-grade noninvasive bladder urothelial carcinoma cohorts (LGUC and HGUC, respectively). The study included 31 MG urothelial carcinomas. Mean patient age was 67.6 years, and mean follow-up was 39.7 months. Intravesical treatment was administered in 15 patients (48.4%). Recurrence occurred in 14 cases (45.2%): 10 as LGUC and 4 as HGUC; there was no stage progression. Mean time to progression was 9 months (5-17 months), and there was no death of disease. MG urothelial carcinoma stage progression and dead of disease rates were comparable to that of LGUC. MG urothelial carcinoma stage progression was significantly lower than that of HGUC, P = .002, using Pearson chi(2) test. MG urothelial carcinoma patients with no intravesical treatment had higher incidence rate of grade progression (25%) compared to LGUC patients (7.9%); however, the difference was not statistically significant. MG urothelial carcinoma had a prognosis closer to "pure" LGUC than "pure" HGUC. Untreated MG urothelial carcinoma may have a higher rate of grade progression than LGUC, although more data are needed before this issue can be definitively addressed. Until such data are available, it is reasonable to keep MG urothelial carcinoma as a distinct grade category with potential management implications. PMID- 26520421 TI - Recovery of Renal Function after Prolonged Anuria in Acute Suprarenal Aortic Occlusion. AB - Acute suprarenal aortic occlusion is a rare but often catastrophic event. Despite immediate treatment, mortality and morbidity are high. We present a case of acute suprarenal aortic occlusion presenting with renal failure and dyspnea but without lower limb ischemia. Diagnosis was initially not taken in consideration. The patient required hemodialysis and temporary mechanical ventilation. After 13 days, an abdominal ultrasound was performed which revealed thrombosis of the suprarenal abdominal aorta. Suprarenal aortic thrombectomy was performed followed by aortobi-iliac bypass grafting. Diuresis returned 4 hr after surgery, and the patient fully recovered. Thorough review of the literature revealed only 8 cases of acute suprarenal aortic occlusion. Only 3 patients survived. To our knowledge, this is the first reported case of acute suprarenal occlusion, in which renal function could be restored after a 14-day period of anuria. The case illustrates that in select cases with prolonged acute renal failure aortorenal revascularization can be performed successfully. PMID- 26520422 TI - Thoracic Aortic Pseudoaneurysm after Esophageal Perforation and Mediastinitis Caused by Accidental Ingestion of a Mutton Bone: A Case Report on Staged Endoscopic and Endovascular Treatments. AB - BACKGROUND: Esophageal perforation involving the thoracic aorta is a rare but potentially life-threatening event. Esophageal wall dehiscence, aortoesophageal fistula, mycotic aneurysms, or mediastinitis may complicate this challenging condition, and a multidisciplinary approach is mandatory. Aggressive endoscopic and medical therapy followed by thoracic endovascular aneurysm repair (TEVAR) may be a valuable approach to reduce the mortality rate of this catastrophic event. CASE REPORT: A 79-year-old man presented at the emergency department with a 2-day history of worsening dysphagia and fever, suddenly appeared after consuming mutton meat. Esophagogastroduodenoscopy and computed tomography (CT) scan at admission showed a bone fragment penetrating the esophagus very close to the thoracic aorta, associated with signs of mild mediastinitis. After endoscopic removal of the bone, an esophageal fistula occurred. A conservative approach by means of endoscopic clipping of the esophageal perforation, nasojejunal tube for enteral nutrition and broad spectrum antibiotic therapy was preferred at this stage. Control chest X-ray with oral water-soluble contrast (Gastrografin) and repeat CT at 10- and 20-day follow-up showed a complete resolution of the esophageal fistula and mediastinitis. On the other hand, an increase of the aortic pseudoaneurysm was noted. This was treated by means of TEVAR. Subsequent clinical evolution was uneventful, and the patient was discharged in optimal clinical conditions with a 4-week course of home antibiotic therapy. The 6-month follow-up was uneventful. CONCLUSIONS: Foreign body esophageal perforation causing mediastinitis and aortic pseudoaneurysm is a very rare and challenging situation that requires a strict follow-up and an intensive multidisciplinary approach. A staged approach, first by endoscopy followed by endovascular treatment, may be safe and effective in selected patients. PMID- 26520423 TI - Transient Ischemic Attacks of Spinal Cord due to Abdominal Aortic Aneurysm Thrombus. AB - Thrombosis due to abdominal aortic aneurysm is a rare condition that causes high mortality. Transient ischemic attack of the spinal cord can occur as a result of trash emboli from thrombus in abdominal aortic aneurysm. This condition generally occurs during operation of abdominal aortic aneurysm; very rarely, it can also be seen in laminated abdominal aortic aneurysm. Here, we present a case of a patient presenting with bilateral lower extremity paralysis resulting from transient ischemic attack of the spinal cord due to infrarenal abdominal aortic aneurysm. PMID- 26520424 TI - Unusual Open Surgical Repair of a Type IB Endoleak and a Giant Symptomatic Aortic Aneurysm following Stent Grafting for Type B Aortic Dissection. AB - Treatment of type IB endoleak after thoracic endovascular aortic repair (TEVAR) for post-dissection aortic aneurysm usually includes attempts of endovascular interventions using coils or plugs to occlude the false lumen or placement of a distal fenestrated endograft. Open conversion usually requires deep hypothermia and circulatory arrest with the associated increased mortality and complications. We present a case of a young patient with a 90 mm descending thoracic aneurysm caused by a chronic type B aortic dissection. A type II endoleak after TEVAR was successfully treated with left subclavian artery transposition. The patient had a rapidly increasing aortic aneurysm with a persistent type IB endoleak in spite of placement of an Amplatzer plug into the false lumen of the dissection. He developed progressive acute compression of the main stem bronchi by the aneurysm sac and his dyspnea worsened by an acute pulmonary embolism treated with anticoagulation. Adequate oxygenation could only be achieved with mechanical ventilation using a double-lumen endobronchial tube. A left thoracotomy was performed and the type IB endoleak was treated with bending of the distal aorta around the stent graft with a Dacron graft sleeve. Aortic clamping and circulatory support devices were avoided. The sac of the aneurysm was opened, a giant hematoma was evacuated, and aneurysmorrhaphy was performed to cover the stent graft. There was no residual endoleak and the bronchi were decompressed. The patient recovered after prolonged hospitalization and he was discharged home in good condition 24 days after admission. He returned to his normal activities and is asymptomatic 5 months later. Computed tomographic angiography showed decreased aneurysm sac, no evidence of endoleak, no residual pulmonary embolus, and no bronchial compression. PMID- 26520425 TI - Primary Open Stenting to Simplify Distal Anastomosis on Heavily Calcified Artery: The POSE Technique. AB - Despite improvements in surgical techniques, performing distal anastomosis on a heavily calcified artery (HCA) remains technically challenging. Clamping lesions and arterial wall trauma while suturing can lead to immediate or delayed arterial dissection and thrombosis. These issues are generally overcome by performing an extensive search for supple arterial zones, using sutureless techniques with covered stent-grafts and/or stenting the anastomosis under fluoroscopic guidance after unclamping. We describe a technique intended to simplify open surgical procedures on HCA. It consists of primary open stenting followed by localized endarterectomy (namely, the primary open stenting followed by localized endarterectomy [POSE] technique) to secure a distal anastomosis on an HCA. So far, we have successfully used the POSE technique in 24 patients but the durability of the technique remains to be determined. PMID- 26520426 TI - Aortic Dissection as a Cause of Pulsus Bisferiens: A Case Report and Review. AB - We present a case of a 62-year-old woman who developed an aortic dissection after aortic valve replacement for aortic stenosis and supracoronary replacement of the ascending aorta for aneurysmal dilation. Dynamic compression of the distal aorta by the dissection flap was identified with the detection of abnormal continuous wave Doppler signals heard while performing ankle-brachial indices. Duplex ultrasound (US) and Doppler spectral waveforms confirmed dynamic compression of the distal aorta with each cardiac cycle. We review some of the characteristics of continuous wave Doppler signals, specifically discussing the distinguishing characteristics of pulsus bisferiens, and the use of duplex US in imaging the distal aorta. PMID- 26520427 TI - Short-term uvb-irradiation leads to putative limbal stem cell damage and niche cell-mediated upregulation of macrophage recruiting cytokines. AB - Ultraviolet light B (UVB)-irradiation is linked to various ocular pathologies such as limbal stem cell defects in pterygium. Despite the large circumstantial evidence linking UVB irradiation and limbal epithelial stem cell damage, the precise molecular responses of limbal stem cells to UVB irradiation are unclear. Here the effect of UVB irradiation on the putative stem cell phenotype, limbal niche cells and the subsequent effects on corneal (lymph)angiogenic privilege were investigated. Primary human limbal epithelial stem cells and fibroblasts were irradiated with 0.02 J/cm(2) of UVB, a low dose corresponding to 3 min of solar irradiation. UVB irradiation caused significant reduction of limbal epithelial and limbal fibroblast proliferation for 24 h, but apoptosis of limbal epithelial stem cells only. Moreover, UVB induced stem-like character loss of limbal epithelial cells, as their colony forming efficiency and putative stem cell marker expression significantly decreased. Interestingly, limbal epithelial cells co-cultured with UVB-irradiated limbal fibroblasts also exhibited loss of stem cell character and decrease of colony forming efficiency. Conditioned media from limbal epithelial cells inhibited lymphatic endothelial cell proliferation and tube network complexity; however this effect diminished following UVB irradiation. In contrast, pro-inflammatory and macrophage-recruiting cytokines such as TNFalpha, IFNgamma and MCP1 were significantly upregulated following cell irradiation of limbal fibroblasts. These data demonstrate the key role of the limbal stem cell niche in response to UVB and subsequent (lymph)angiogenic and inflammatory events. These data suggest that the known pro(lymph)angiogenic effect of UVB irradiation in pterygium is not linked to a direct up-regulation of pro-angiogenic cytokines, but rather to indirect macrophage-recruiting cytokines being upregulated after UVB irradiation. PMID- 26520428 TI - Osteoclast-Like Giant Cell Carcinoma Hidden by a Bladder Stone in a Patient With Neurogenic Bladder. PMID- 26520429 TI - A Cross-Sectional Investigation of Fatigue, Mucositis, Hand-Foot Syndrome and Dysgeusia in Advanced Renal Cell Carcinoma Treatment: Final Results From the FAMOUS Study. AB - Treatment of metastatic renal cell carcinoma can be associated with adverse symptoms. The perception of fatigue, mucositis, hand-foot syndrome, and dysgeusia, and quality of life (QOL) was assessed in 63 oncologists and their patients receiving first-line treatment. Physicians underestimated the severity of the symptoms and the severity correlated with a lower QOL. A consistent assessment of symptoms in routine practice might improve QOL, adherence to treatment, and outcome. BACKGROUND: The management of symptoms associated with treatment of metastatic renal cell carcinoma (mRCC) is crucial to ensure treatment adherence and outcome. The perception of symptoms can vary between the treating physician and patient, leading to assumptions and subsequent changes in treatment, potentially affecting treatment effectiveness. The aim of the present cross-sectional study was to evaluate the perception of the common symptoms of fatigue, mucositis, hand-foot syndrome, and dysgeusia in patients with mRCC receiving systemic therapies in routine practice. PATIENTS AND METHODS: German patients receiving first-line systemic treatment for mRCC and their physicians were independently queried about the incidence and severity of fatigue, mucositis, hand-foot syndrome, and dysgeusia. Patients also completed the Functional Assessment of Cancer Therapy-General questionnaire to assess their quality of life (QOL). The effect of the 4 symptoms on QOL was analyzed using linear regression modeling. RESULTS: A total of 63 matching questionnaires were completed by both physicians and patients with first-line treatment. The incidence and severity of symptoms differed between the patients and physicians. Patients rated the severity of symptoms significantly higher than did the physicians. A greater severity of symptoms correlated with a lower QOL. In multivariate regression analysis, fatigue adversely affected overall QOL. CONCLUSION: Physicians underestimated the severity of common symptoms in patients with mRCC. The incorporation of patient-reported outcome measures into routine practice might increase awareness of patients' overall QOL and thereby potentially improve treatment adherence. A thorough evaluation of fatigue, its potential underlying causes, and active measures to manage fatigue could potentially improve patients' QOL. PMID- 26520430 TI - A Single-Institution Retrospective Study of Jugular Foramen Schwannoma Management: Radical Resection Versus Subtotal Intracranial Resection Through a Retrosigmoid Suboccipital Approach Followed by Radiosurgery. AB - BACKGROUND: Despite advances in skull base surgery, achieving effective surgical management of jugular foramen schwannomas (JFSs) that avoids postoperative cranial nerve (CN) deficits remains a challenge. Subtotal resection followed by radiosurgery (rather than radical resection) is increasingly being viewed as a better treatment strategy. Here, an institutional database was retrospectively analyzed for outcomes after surgical treatment of JFSs to evaluate the optimal strategy for managing JFSs. METHODS: Twenty-two patients with JFSs were operated on by either radical resection (n = 13) or conservative resection plus radiosurgery (n = 9). These 2 different groups were compared in terms of early (<=4 weeks after surgery) and late postoperative functional outcome and oncologic control. RESULTS: No deaths occurred in either group, but there were 3 surgery related complications in the radical resection group. Postoperative CN deficits and additional procedures related to CN morbidity were generally higher in the radical resection group, but the differences were not statistically significant. The conservative surgery group showed a statistically significant improvement in the level of dysphagia and dysphagia-related functional state in the late postoperative period. There was 1 case of recurrence after radical resection over a mean follow-up period of 73 months. All tumors in the conservative surgery group were controlled over a mean period of 34 months. CONCLUSIONS: Our results suggest that conservative resection of JFSs via a familiar intracranial approach plus radiosurgery may be an effective surgical alternative for improving functional outcome with adequate oncologic control. PMID- 26520431 TI - Fistula and Infratentorial Location, Characteristics That Contribute to Cerebral Arteriovenous Malformations, Lead to the Formation of Associated Aneurysms in Patients. AB - OBJECTIVE: Because the formation of associated aneurysms (AAs) related to the characteristics of cerebral artriovenous malformations (cAVMs) is poorly recognized, the purpose of this study was to identify the responsible characteristics of cAVMs related to the formation of AAs and to identify patients with responsible characteristics related to the formation of AAs through the analysis of the outcomes of these patients after treatment. METHODS: This study was performed to analyze the baseline characteristics of patients with cAVMs and AAs. The recurrent AA and residual size of cAVMs were used to evaluate the outcomes of patients after treatment. At the same time, the ROC curve was measured to gauge the relationship between the residual size of cAVMs and recurrent AAs in eligible patients. RESULTS: Fifty (15.0%) patients with cAVMs and AA were confirmed; these patients had twice the hazard of hemorrhage as patients with only isolated cAVMs. An infratentorial location (P < 0.001) and fistula (P = 0.002) were independent predictors of the formation of AAs. After a mean 22.7 months follow-up, 2 patients developed recurrent AAs, and the annual recurrence rate for patients with responsible characteristics was 17.6%, but for all patients was 7.2%. The ROC curve showed that patients, specifically patients with responsible characteristics, the residual size of the cAVM was closely related to recurrent AA (area = 0.89, 95% confidence interval 0.81-0.97, P = 0.023, cut-off value = 82.5%). CONCLUSIONS: Patients with cAVMs and AA who harbor a fistula or an infratentorial location tend to form AAs. To prevent recurrent AAs and decrease the subsequent risk of hemorrhage, complete obliteration of cAVMs or retrograding over 80% size of cAVMs is recommended. PMID- 26520432 TI - Intraoperative Subcortical Fiber Mapping with Subcortico-Cortical Evoked Potentials. AB - OBJECTIVE: During brain surgery, there are difficulties associated with identifying subcortical fibers with no clear landmarks. We evaluated the usefulness of cortical evoked potentials with subcortical stimuli (subcortico cortical evoked potential [SCEP]) in identifying subcortical fibers intraoperatively. METHODS: We used SCEP to identify the pyramidal tract in 4 patients, arcuate fasciculus in 1 patient, and both in 2 patients during surgical procedures. After resection, a 1 * 4-electrode plate was placed on the floor of the removal cavity and 1-Hz alternating electrical stimuli were delivered to this electrode. A 4 * 5 recording electrode plate was placed on the central cortical areas to map the pyramidal tract and temporoparietal cortical areas for the arcuate fasciculus. SCEPs were obtained by averaging electrocorticograms time locked to the stimulus onset. RESULTS: The subcortical stimulation within 15 mm of the target fiber induced cortical evoked potentials in the corresponding areas, whereas the stimulation apart from 20 mm did not. Five patients showed transient worsening of neurologic symptoms after surgery. However, all patients recovered. CONCLUSIONS: SCEP was useful for identifying subcortical fibers and confirmed the preservation of these fibers. This technique is expected to contribute to the effectiveness and safety of resective surgery in patients with lesions close to eloquent areas. PMID- 26520434 TI - Clinical significance of ureteral stent removal by flexible cystoscopy on pain and satisfaction in young males: a prospective randomised control trial. AB - The cystoscopic removal of ureteral stents causes discomfort and pain, especially in young male patients. We aimed to evaluate the usefulness of ureteral stent removal by flexible cystoscopy on pain and satisfaction in young males. In total, 104 patients undergoing ureteroscopic removal of stones with indwelling of ureteral stent (May 2013-July 2015) were randomised to receive a ureteral stent removal by either rigid cystoscopy (group 1) or flexible cystoscopy (group 2). Visual analogue scale (VAS) pain score and satisfaction scale score were assessed immediately after stent removal. All patients were males and the mean age was 22.72 +/- 2.49 years. Group 2 showed significantly lower VAS pain score (p < 0.001) and higher satisfaction scale score (p < 0.001) than group 1. Ureteral stent removal by flexible cystoscopy may offer advantages on pain and satisfaction to young male patients. PMID- 26520433 TI - A Perspective on Roles Played by Innate and Adaptive Immunity in the Pathobiology of Neurodegenerative Disorders. AB - Aberrant innate and adaptive immune responses are neurodegenerative disease effectors. Disease is heralded by a generalized, but subtle immune activation orchestrated by the release of extracellular prion-like aggregated and oxidized or otherwise modified proteins. These are responsible for an inflammatory neurotoxic cascade. The perpetrators of such events include effector T cells and activated microglia. What ensues are Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis and stroke with changed frequencies of effector T cell and reduced numbers or function of regulatory lymphocytes. The control of such immune responses could lead to new therapeutic strategies and the means to effectively combat a composite of diseases that have quite limited therapeutic options. PMID- 26520435 TI - Effects of habitat on mercury concentrations in fish: a case study of Nile perch (Lates niloticus) in Lake Nabugabo, Uganda. AB - This study focused on variation in fish mercury (Hg) concentrations in 185 Nile perch (Lates niloticus) samples collected across four different habitat types in Lake Nabugabo, Uganda, a tropical lake located proximate to Lake Victoria. We quantified the stomach contents of Nile perch using the % index of relative importance, as well as, nitrogen and carbon isotopic concentrations to assess the role of diet and trophic level on Hg concentrations. In each habitat, we also evaluated a suite of chemical and physical characteristics that are commonly associated with variation in Hg bioavailability in temperate systems. Using linear mixed models and ANOVA, we demonstrate that habitat of capture is an important predictor of Hg concentrations in Nile perch from Lake Nabugabo and that the relationship between habitat and Hg is size and diet dependent. Nile perch diet as well as dissolved oxygen concentration and pH were also correlated with observed differences in fish Hg. Overall, Hg concentrations in Nile perch were all well below the WHO/FAO recommended guideline of 500 ng/g (mean 13.6 +/- 0.4 ng/g wet weight; range 4.9 and 29.3 ng/g wet weight). This work contributes to a growing awareness of intra-lake divergence in Nile perch, as well as, divergence in Hg concentrations between varying aquatic habitat types, particularly wetlands. PMID- 26520436 TI - Copper toxicity in a natural reference soil: ecotoxicological data for the derivation of preliminary soil screening values. AB - The risk assessment of contaminated soils is conventionally done with the support of soil screening values (SSVs). Since SSVs are still unavailable for many European countries, including Portugal, standardized toxicity tests are urgently claimed for their derivation. Hence, this work aimed the generation of toxicity values for copper (Cu) in a natural reference soil (PTRS1) targeting different terrestrial species, endpoints and soil functions, as to derive a preliminary Cu SSV. For this, the Assessment Factor approach was applied, which allowed calculating predicted no effect concentrations (PNEC) for Cu that will be the basis for SSV proposal. In order to increase the reliability of the PNEC, and hence of the SSV, a lab/field factor was applied to correct the toxicity values used for PNEC determination. Cu affected urease, cellulase and nitrogen mineralization activities. The EC50 values calculated for the invertebrates reproduction were 130.9, 165.1 and 191.6 mg Cu Kg(-1) soildw for Eisenia andrei, Enchytraeus crypticus and Folsomia candida, respectively. Cu inhibited seed germination mainly for Lactuca sativa, whilst it was toxic for the growth of different plant species (EC50s between 89 and 290.5 mg Cu Kg(-1) soildw). Based on the outcomes gathered, we proposed SSVs for Cu ranging between 26.3 and 31.8 mg Kg(-1) soildw, which is above the background values reported and below all the EC20s recorded for the species and endpoints herein analyzed. Overall, this work describes a procedure that could be easily followed by other European countries wishing to derive SSVs adjusted to their soils. PMID- 26520437 TI - Neurobehavioral Effects from Developmental Methamphetamine Exposure. AB - Intrauterine methamphetamine exposure adversely affects the neurofunctional profile of exposed children, leading to a variety of higher order cognitive deficits, such as decreased attention, reduced working-memory capability, behavioral dysregulation, and spatial memory impairments (Kiblawi et al. in J Dev Behav Pediatr 34:31-37, 2013; Piper et al. in Pharmacol Biochem Behav 98:432-439 2011; Roussotte et al. in Neuroimage 54:3067-3075, 2011; Twomey et al. in Am J Orthopsychiatry 83:64-72, 2013). In animal models of developmental methamphetamine, both neuroanatomical and behavioral outcomes critically depend on the timing of methamphetamine administration. Methamphetamine exposure during the third trimester human equivalent period of brain development results in well defined and persistent wayfinding and spatial navigation deficits in rodents (Vorhees et al. in Neurotoxicol Teratol 27:117-134, 2005, Vorhees et al. in Int J Dev Neurosci 26:599-610, 2008; Vorhees et al. in Int J Dev Neurosci 27:289-298, 2009; Williams et al. in Psychopharmacology (Berl) 168:329-338, 2003b), whereas drug delivery during the first and second trimester equivalents produces no such effect (Acuff-Smith et al. in Neurotoxicol Teratol 18:199-215, 1996; Schutova et al. in Physiol Res 58:741-750, 2009a; Slamberova et al. in Naunyn Schmiedebergs Arch Pharmacol 380:109-114, 2009, Slamberova et al. in Physiol Res 63:S547-S558, 2014b). In this review, we examine the impact of developmental methamphetamine on emerging neural circuitry, neurotransmission, receptor changes, and behavioral outcomes in animal models. The review is organized by type of effects and timing of drug exposure (prenatal only, pre- and neonatal, and neonatal only). The findings elucidate functional patterns of interconnected brain structures (e.g., frontal cortex and striatum) and neurotransmitters (e.g., dopamine and serotonin) involved in methamphetamine-induced developmental neurotoxicity. PMID- 26520438 TI - Atypical Kawasaki disease presenting as a retropharyngeal abscess. PMID- 26520439 TI - Solitary circumscribed neuroma of the larynx. PMID- 26520440 TI - W346 inhibits cell growth, invasion, induces cycle arrest and potentiates apoptosis in human gastric cancer cells in vitro through the NF-kappaB signaling pathway. AB - The therapeutic agent selectively killing cancer cells is urgently needed for gastric cancer treatment. Curcumin has been investigated for its effect on the cancer treatment because of its significant therapeutic potential and safety profile. A synthetic unsymmetry mono-carbonyl compound termed W346 was developed from curcumin. In this study, we investigated the potential antineoplastic effect and mechanism of W346 against human gastric cancer cells. W346 suppressed the proliferation and invasion, blocked cell cycle arrest at G2/M phase, and increased apoptosis in gastric cancer cells, and it presented obviously improved anticancer activity than curcumin. Moreover, W346 effectively inhibited tumor necrosis factor (TNF-alpha)-induced NF-kappaB activation by suppressing IKK phosphorylation, inhibiting IkappaB-alpha degradation, and restraining the accumulation of NF-kappaB subunit p65 nuclear translocation. W346 also affected NF-kappaB-regulated downstream products involved in cycle arrest and apoptosis. In a word, W346 exhibited significantly improved anti-gastric cancer activity over curcumin by targeting NF-kappaB signaling pathway, and it is likely to be a promising starting point for the development of curcumin-based therapeutic agent. PMID- 26520441 TI - Reciprocal expression of p-AMPKa and p-S6 is strongly associated with the prognosis of gastric cancer. AB - Activation of AMP-activated protein kinase (AMPK) suppressed mammalian target of rapamycin (mTOR) pathway, resulting in impaired cancer cell proliferation. Two cohorts (50 and 1072 cases) of patients with resected gastric adenocarcinoma were enrolled in the study. Immunohistochemical staining for p-AMPKa, p-ACC, p-mTOR, p S6, and p-4EBP1 was performed on the 50-patient cohort. Tissue microarray blocks containing samples from 1072 patients of Chinese ethnicity were used for the immunohistochemical detection of p-AMPKa and p-S6 levels. p-AMPK and p-ACC were frequently inactivated in both cohorts of gastric cancer samples, while p-mTOR, p S6, and p-4EBP1 were frequently activated in the small cohort of gastric cancer. However, only levels of p-AMPKa and p-S6 were associated with the overall survival of gastric cancer patients. In the larger 1072-patient cohort, downregulation of p-AMPKa and upregulation of p-S6 were associated with tumor progression and were independent predictors of survival after resection of primary gastric cancer. Therefore, reciprocal expression of p-AMPKa and p-S6 may be promising prognostic biomarkers in patients with gastric cancer. PMID- 26520442 TI - HNF1beta drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC). AB - Chemoresistance to platinum-based antineoplastic agents is a consistent feature among ovarian carcinomas; however, whereas high-grade serous carcinoma (OSC) acquires resistance during chemotherapy, ovarian clear cell carcinoma (OCCC) is intrinsically resistant. The main objective of this study was to explore, in vitro and in vivo, if hepatocyte nuclear factor 1beta (HNF1beta) and glutaminolysis contribute for the resistance of OCCC to carboplatin through the intrinsically increased GSH bioavailability. To disclose the role of HNF1beta, experiments were also performed in an OSC cell line, which does not express HNF1beta. Metabolic profiles, GSH quantification, HNF1beta, and gamma glutamylcysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) expression, cell cycle, and death were assessed in ES2 cell line (OCCC) and OVCAR3 cell line (OSC); HNF1beta knockdown was performed in ES2 and murine model of subcutaneous and peritoneal OCCC tumors was established to test buthionine sulphoxamine (BSO), as a sensitizer to carboplatin. Glutaminolysis is activated in ES2 and OVCAR3, though ES2 exclusively synthesizes amino acids and GSH. ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH production by BSO sensitizes ES2 to carboplatin. HNF1beta regulates the expression of GCLC, but not GCLM, and consequently GSH production in ES2. In vivo, BSO prior to carboplatin reduces dramatically subcutaneous tumor size and GSH levels, as well as peritoneal dissemination. Our study discloses HNF1beta as the mediator of intrinsic OCCC chemoresistance and sheds a light to re-explore a cancer adjuvant therapeutic approach using BSO to overcome the lack of efficient therapy in OCCC. PMID- 26520444 TI - Baerveldt tube implantation following failed deep sclerectomy versus repeat deep sclerectomy. AB - PURPOSE: To compare the surgical outcomes of repeat deep sclerectomy (DS) and the Baerveldt glaucoma implant (BGI) in eyes with failed primary deep sclerectomy. DESIGN: A retrospective comparative case-control study. METHODS: Fifty-eight eyes of 56 glaucoma patients with previously failed DS underwent BGI (group BGI) and 58 eyes of 55 patients underwent repeat DS (group DS) at a tertiary referral centre. Visual acuity, intraocular pressure (IOP), number of glaucoma medications, surgical failure rates and complication rates were compared between groups. Surgical failure was defined as loss of IOP control, loss of light perception, or need for further glaucoma surgery. RESULTS: Baseline demographics were similar between groups. Preoperatively, median IOP was lower in the DS than the BGI group (19 mmHg versus 21 mmHg, p = 0.10). Postoperatively at year 1, median IOP was significantly higher in the DS than BGI group (14 mmHg versus 11 mmHg, p = 0.02). There were no differences between the DS and BGI groups in mean number of medications preoperatively (2.3 versus 2.6) or postoperatively (1.3 versus 1.1). Complication rates were significantly higher in the DS group [41 % (n = 24) versus 14 % (n = 8); p = 0.01]. The failure rate at 1 year was higher in eyes with repeat DS than in eyes with BGI (30 vs. 21 %, respectively; p = 0.07). CONCLUSIONS: Baerveldt implants were more effective in lowering IOP and resulted in significantly fewer complications than repeat deep sclerectomy in eyes with previously failed deep sclerectomy. PMID- 26520443 TI - miR-449a enhances radiosensitivity through modulating pRb/E2F1 in prostate cancer cells. AB - miR-449a, a novel tumor suppressor, is deregulated in various malignancies, including prostate cancer. Overexpression of miR-449a induces cell cycle arrest, apoptosis, and senescence, but its role in response to ionizing radiation and underlying molecular mechanism are still unknown. Here, we report that miR-449a enhances radiation-induced G2/M phase arrest and apoptosis through modulating pRb/E2F1 and sensitizes prostate cancer cells to X-ray radiation. In wild-type Rb PC-3 cells, overexpression of miR-449a enhances radiation-induced G2/M arrest and apoptosis and promotes the sensitivity to X-ray radiation. While mutant Rb DU-145 cells are resistant to the X-ray radiation despite in the presence of miR-449a. The cell cycle distribution of DU-145 cells is not significantly altered by miR 449a in the response to ionizing radiation. Furthermore, elevated miR-449a downregulates cell cycle regulator CDC25A and oncogene HDAC1. By targeting genes involved in controlling pRb/E2F1 activity, miR-449a regulates cell cycle progression and apoptosis and consequently enhances the radiosensitivity of PC-3 cells. Thus, miR-449a, as a miRNA component of the Rb pathway, promotes the radiosensitivity of PC-3 cells through regulating pRb/E2F1. PMID- 26520445 TI - Long-term results of ab externo trabeculotomy for glaucoma secondary to chronic uveitis. AB - PURPOSE: To present the long-term results of ab externo trabeculotomy in the management of glaucoma secondary to chronic uveitis. METHODS: In this retrospective single-centre case series, medical records of patients with glaucoma secondary to chronic uveitis, who underwent ab externo trabeculotomy, were evaluated. Two definitions of success were used: intraocular pressure (IOP) 6 <= IOP <= 21 mmHg (success 1) or 6 <= IOP <= 21 mmHg and at least 25 % reduction from baseline (success 2). Success was complete when no additional medication was required or qualified when additional medication or cycloablative procedures were required to achieve the specific IOP definition. RESULTS: Twenty two eyes of 18 patients were included. After 3 years, median IOP decreased from 27 mmHg [range 17-43 mmHg, mean 27.5 mmHg, 95 % confidence interval of the mean (CI) 24.5-30.5 mmHg] to 15 mmHg (range 9-19 mmHg, mean 14.5 mmHg, CI 13-16.1 mmHg). Complete and qualified success 1 was 23 and 45 % after 3 years, respectively. For success 2, the rates were 23 and 32 %, respectively. Hyphema was the most common complication, which resolved completely within 1 month after surgery without further intervention. CONCLUSION: Trabeculotomy ab externo was moderately successful in glaucoma secondary to chronic uveitis after 3 years. No sight-threatening complications were observed during the follow-up period. PMID- 26520446 TI - Dysregulated Blood Pressure: Can Regulating Emotions Help? AB - Despite having identified key physiological and behavioral risk factors, the prevalence of hypertension continues to rise, affecting two thirds of American adults 60 years or older. An important condition in its own right, hypertension is also a leading risk factor for cardiovascular diseases; thus, identifying additional modifiable determinants remains a public health priority. Psychological states and negative emotions more specifically have been proposed as risk factors, but the research findings are inconsistent. Additional prospective studies have recently been published increasing the availability of longitudinal data. The aim of this literature review is to evaluate these findings focusing on those from the last 3 years. We synthesize current research on whether negative (e.g., depression, anxiety) or positive (e.g., optimism) emotion-related factors are associated with high blood pressure onset. We discuss discrepant findings and propose considering emotion regulation as a novel approach to explain inconsistencies. Finally, we provide thoughts on future research directions. PMID- 26520447 TI - Advanced oxidation protein products induce chondrocyte apoptosis via receptor for advanced glycation end products-mediated, redox-dependent intrinsic apoptosis pathway. AB - Pro-inflammatory cytokine-induced chondrocyte apoptosis is a primary cause of cartilage destruction in the progression of rheumatoid arthritis (RA). Advanced oxidation protein products (AOPPs), a novel pro-inflammatory mediator, have been confirmed to accumulate in patients with RA. However, the effect of AOPPs accumulation on chondrocyte apoptosis and the associated cellular mechanisms remains unclear. The present study demonstrated that the plasma formation of AOPPs was enhanced in RA rats compared with normal. Then, chondrocyte were treated with AOPPs-modified rat serum albumin (AOPPs-RSA) in vitro. Exposure of chondrocyte to AOPPs activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and increased expression of NADPH oxidase subunits, which was mediated by receptor for advanced glycation end products (RAGE), but not scavenger receptor CD36. Moreover, AOPPs challenge triggered NADPH oxidase dependent ROS generation which induced mitochondrial dysfunction and endoplasmic reticulum stress resulted in activation of caspase family that eventually lead to apoptosis. Lastly, blockade of RAGE, instead of CD36, largely attenuated these signals. Our study demonstrated first time that AOPPs induce chondrocyte apoptosis via RAGE-mediated and redox-dependent intrinsic apoptosis pathway in vitro. These data implicates that AOPPs may represent a novel pathogenic factor that contributes to RA progression. Targeting AOPPs-triggered cellular mechanisms might emerge as a promising therapeutic option for patients with RA. PMID- 26520448 TI - Latent dimensions of posttraumatic stress disorder and their relations with alcohol use disorder. AB - PURPOSE: The objective of this study was to evaluate the relationship between factors of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) using confirmatory factor analysis (CFA) in order to further our understanding of the substantial comorbidity between these two disorders. METHODS: CFA was used to examine which factors of PTSD's dysphoria model were most related to AUD in a military sample. Ohio National Guard soldiers with a history of overseas deployment participated in the survey (n = 1215). Participants completed the PTSD Checklist and a 12-item survey from the National Survey on Drug Use used to diagnosis AUD. RESULTS: The results of the CFA indicated that a combined model of PTSD's four factors and a single AUD factor fit the data very well. Correlations between PTSD's factors and a latent AUD factor ranged from correlation coefficients of 0.258-0.285, with PTSD's dysphoria factor demonstrating the strongest correlation. However, Wald tests of parameter constraints revealed that AUD was not more correlated with PTSD's dysphoria than other PTSD factors. CONCLUSIONS: All four factors of PTSD's dysphoria model demonstrate comparable correlations with AUD. The role of dysphoria to the construct of PTSD is discussed. PMID- 26520449 TI - Biological and psychosocial risk factors for psychotic major depression. AB - AIMS: Few studies have investigated risk factors for psychotic major depression (PMD). We aimed to investigate the biological and psychosocial risk factors associated with PMD compared with other psychotic disorders. METHODS: Based on the aetiology and ethnicity in schizophrenia and other psychoses (AESOP) study, we used a case-control study to identify and recruit, at baseline and 10-year follow-up, all first episode cases of psychosis, presenting for the first time to specialist mental health services in defined catchment areas in the UK. Population-based controls were recruited from the same areas. Data were collected on: sociodemographics; social isolation; childhood adversity; life events; minor physical anomalies; and neurological soft signs. RESULTS: Living alone (aOR = 2.26, CI = 1.21-4.23), basic level qualification (aOR = 2.89, CI = 1.08-7.74), being unemployed (aOR = 2.12, CI = 1.13-3.96), having contact with friends less than monthly (aOR = 4.24, CI = 1.62-11.14), having no close confidants (aOR = 4.71, CI = 2.08-10.68), having experienced childhood adversity (aOR = 2.57, CI = 1.02-6.44), family history of mental illness (aOR = 10.68, CI = 5.06-22.52), family history of psychosis (aOR = 12.85, CI = 5.24-31.51), and having more neurological soft signs (aOR = 1.15, CI = 1.07-1.24) were all associated with a follow-up diagnosis of PMD and schizophrenia. Few variables associated with PMD were also associated with a diagnosis of bipolar disorder. Minor physical anomalies were associated with a follow-up diagnosis of schizophrenia and bipolar disorder, but not PMD. CONCLUSIONS: Risk factors associated with PMD appear to overlap with those for schizophrenia, but less so for bipolar disorder. Future work on the differential aetiology of PMD, from other psychoses is needed to find the 'specifier' between PMD and other psychoses. Future research on aetiology in PMD, and perhaps other psychoses, should account for diagnostic change. PMID- 26520450 TI - Numerical simulation of pressure therapy glove by using Finite Element Method. AB - Pressure therapy garments apply pressure to suppress the growth and flatten hypertrophic scars caused by serious burns. The amount of pressure given by the pressure garments is critical to the treatment adherence and outcomes. In the present study, a biomechanical model for simulating the pressure magnitudes and distribution over hand dorsum given by a pressure glove was developed by using finite element method. In this model, the shape geometry of the hand, the mechanical properties of the glove and human body tissues were incorporated in the numerical stress analyses. The geometry of the hand was obtained by a 3D laser scanner. The material properties of two warp knitted fabrics were considered in the glove fabric model that developed from the glove production pattern with 10% size reduction in circumferential dimensions. The glove was regarded an isotropic elastic shell and the hand was assumed to be a homogeneous, isotropic and linearly elastic body. A glove wearing process was carried in the finite element analysis and the surface-to-surface contact pressure between hand and glove fabric was hence obtained. Through validation, the simulated contact pressure showed a good agreement with the experimental interface pressure measurement. The simulation model can be used to predict and visualise the pressure distribution exerted by a pressure therapy glove onto hand dorsum. It can provide information for optimising the material mechanical properties in pressure garment design and development, give a clue to understand the mechanisms of pressure action on hypertrophic scars and ultimately improve the medical functions of pressure garment. PMID- 26520451 TI - Structural Basis for Differences in Dynamics Induced by Leu Versus Ile Residues in the CD Loop of Kir Channels. AB - The effect of the conserved Leu/Ile site in the CD loop on the gating dynamics of Kir channels and corresponding micro-structural mechanism remains unclear. Molecular dynamics simulations were performed to investigate the structural mechanism of chicken Kir2.2. Compared to WT, the I223L mutant channel bound to PIP2 more strongly, was activated more rapidly, and maintained the activation state more stably after PIP2 dissociation. Cellular electrophysiology assays of mouse Kir2.1 and human Kir2.2 indicated that, consistent with simulations, the Leu residue increased the channel responses to PIP2 through increased binding affinity and faster activation kinetics, and the deactivation kinetics decreased upon PIP2 inhibition. The Ile residue induced the opposite responses. This difference was attributed to the distinct hydrophobic side chain symmetries of Leu and Ile; switching between these residues caused the interaction network to redistribute and offered effective conformation transduction in the Leu systems, which had more rigid and independent subunits. PMID- 26520453 TI - Single-nucleotide polymorphism rs 175080 in the MLH3 gene and its relation to male infertility. AB - PURPOSE: MLH3, a MutL homolog protein in mammals playing a role in DNA mismatch repair, is associated with spermatogenesis and male infertility. The purpose of the present study was to investigate the association of the single-nucleotide polymorphism (SNP), rs 175080 in the MLH3 gene, with sperm parameters in a Greek population. METHODS: The study included 300 men of couples undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) treatments (years 2011-2013). Genomic DNA was extracted from 300 peripheral blood samples, and conventional quantitative real-time PCR was performed for genotyping. Of them, 122 were from men used as "controls" and 178 from men used as "cases." Allocation to the two groups was based on sperm concentrations (>=15 and <15 million/ml, respectively). Serum FSH, LH, estradiol, testosterone, and prolactin concentrations as well as sperm parameters were compared between three genotypes (GG, GA, and AA). Furthermore, the frequencies of these three genotypes were compared between "cases" and "controls." RESULTS: Anthropometric parameters and hormonal values did not differ significantly between the three genotypes. Significantly lower sperm concentrations were found in men with the AA genotype as compared to men with the GG and GA genotypes (p < 0.001). The AA genotype had the lower progressive motility values as compared to the other two genotypes (p < 0.05). Also, there was a significantly different distribution of the frequencies of the three genotypes between "cases" and "controls" (p < 0.001). CONCLUSIONS: It is suggested that the studied SNP in the MLH3 gene may be linked to oligozoospermia in Caucasian men of a certain area. PMID- 26520452 TI - Neuroprotective Effects of a PSD-95 Inhibitor in Neonatal Hypoxic-Ischemic Brain Injury. AB - The postsynaptic density-95 inhibitor NA-1 uncouples NMDA glutamate receptors from downstream neurotoxic signaling pathways without affecting normal glutamate receptor function. NA-1 attenuates NMDA receptor-mediated neuronal cell death after stroke in multiple models and species. However, its efficacy in providing neuroprotection in models of neonatal hypoxic-ischemic brain injury has not yet been tested. In this study, a modified version of the Rice-Vannucci method for the induction of neonatal hypoxic-ischemic brain injury was performed on postnatal day 7 mouse pups. Animals received a single dose of NA-1 intraperitoneally either before or after right common carotid artery occlusion. All experiments were performed in a blinded manner. Infarct volumes were measured 1 and 7 days after the injury, while behavioral tests were conducted 1, 3, and 7 days after injury. Administration of NA-1 before right common carotid artery occlusion or immediately after ischemia significantly reduced infarct volume and improved neurobehavioral outcomes 1, 3, and 7 days post-injury. The neuroprotection and improvement in neurobehavioral outcomes conferred by NA-1 in this mouse neonatal hypoxic-ischemic injury model imply that NA-1 will be effective in reducing neonatal stroke damage and thus could potentially serve as a therapeutic drug for prevention or treatment of neonatal stroke. PMID- 26520455 TI - The adapted American Academy of Sleep Medicine sleep scoring criteria in one month old infants: A means to improve comparability? AB - OBJECTIVE: The lack of standards induces variability in the sleep staging of infants less than two months of age. We evaluated the feasibility of the 2012 AASM sleep scoring rules for healthy one month old infants. METHODS: 84 polysomnographies were scored into sleep stages with the adapted AASM criteria. The acquired sleep parameters were compared with the parameters in the literature. In addition the effect of age on sleep was studied. RESULTS: The two independent scorers achieved substantial agreement by using the adapted AASM criteria. The infants' sleep parameters showed marked variability. The amount of active sleep was 36.7% (mean, range 21.3-54.1%), quiet sleep 41.5% (30.3-57.7%) and indeterminate sleep 21.6% (9.7-36.0%). With age sleep became more continuous, but the sleep stage percentages did not change. Our sleep parameters differed clearly from the parameters presented in the literature. CONCLUSIONS: The adapted scoring rules were reproducible. This encourages their use in clinical practice, as no uniform recommendations exist. SIGNIFICANCE: Normal values are essential in pediatric sleep medicine and the individual variability in the sleep parameters of healthy infants advocates the standardisation of scoring methods. Here we present sleep stage normative values for one month old infants based on the AASM scoring criteria. PMID- 26520456 TI - What is the concordance between the seizure onset zone and the irritative zone? A SEEG quantified study. AB - OBJECTIVE: In focal epilepsies, the accurate delineation of the epileptogenic network is a fundamental step before surgery. For years, the relationship between the interictal epileptic spikes (defining the "irritative zone", IZ) and the sites of seizure initiation (SOZ) has been a matter of debate. METHODS: Our goal was to investigate from intracerebral recordings (stereoelectroencephalography, SEEG) the distribution of interictal epileptic spikes (based on a spike frequency index, SI) and the topography of the SOZ (based on the Epileptogenicity Index, EI) in patients having focal neocortical epilepsies. Thirty-one patients were studied. A total of 539 brain regions were quantified in term of both spike generation (SI) and seizure initiation (EI). RESULTS: We found a 56% (18/32) rate of agreement between maximal EI and maximal SI values. When considering separately patients with focal cortical dysplasia (FCD), the proportion of patients with good concordance was ~75% (15/20), whereas it was only 33% (4/12) in the non FCD group. CONCLUSIONS: Our results show that a significant part of patients have some dissociation between regions showing pronounced spiking activity and those showing high epileptogenicity. e is clinically important. SIGNIFICANCE: For patients with these dissociations, other markers than spiking frequency remain to be investigated. In the FCD group, the good concordance between SI and EI confirms that the mapping of the irritative zone is clinically important. PMID- 26520457 TI - Examining mixing methods in an evaluation of a smoking cessation program. AB - Three different methods were used in an evaluation of a smoking cessation study: surveys, focus groups, and phenomenological interviews. The results of each method were analyzed separately and then combined using both a pragmatic and dialectic stance to examine the effects of different approaches to mixing methods. Results show that the further apart the methods are philosophically, the more diverse the findings. Comparisons of decision maker opinions and costs of the different methods are provided along with recommendations for evaluators' uses of different methods. PMID- 26520458 TI - Increased risk of bladder cancer in critical areas at high pressure of pollution of the Campania region in Italy: A systematic review. AB - During the past three decades, large areas of the Naples and the Caserta provinces of the Campania region in Italy have been extensively contaminated by the widespread burial and open-air dumping and incineration of industrial toxic waste. On the basis of the finding that the incidence of bladder cancer appears remarkably high in the Naples province with respect to the rest of Europe and of a potential causative role of environmental contaminants, we sought associations between exposure to toxic agents and increased mortality/incidence of bladder cancer by performing a systematic search of epidemiology and human biomonitoring studies conducted in the provinces of Naples and Caserta. The data show that the incidence of bladder cancer is higher than expected on the basis of regional data in the province of Naples and in certain areas of the province of Caserta, even after accounting for social deprivation, with two clusters of increased mortality rate located in the north-western part of Naples province and in the south eastern part of the Caserta province. The biomonitoring studies conducted focused on the levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs), which are generated by the uncontrolled combustion of refuse abandoned in the territory and have been shown to enter the food chain. While the average values of PCDD/F and PCBs reported in blood serum and human milk of the area population are in accordance with those expected on the basis of studies conducted at a national and international level, five municipalities assessed in the province of Naples, that is Brusciano, Caivano, Giugliano, Mugnano, and Qualiano-Villaricca were clearly characterized by the presence of arsenic, with 62% samples showing serum arsenic levels higher than the 95th percentile of the national distribution. The potential negative synergism of social deprivation, environmental pressure and arsenic contamination may account for the higher than expected bladder cancer incidence and mortality in certain areas of the Campania region and remains to be elucidated via the conduction of ad hoc population-based studies. PMID- 26520459 TI - Paranasal sinus cancer. AB - Paranasal sinus cancers are rare diseases, accounting for about 5% of all head and neck malignancies. The variety of histological types and the overlapping pathological features with other entities constitute difficulties in pathologic interpretation, often requiring a skilled interpretation or a second opinion. Treatment of locally advanced disease relies on surgery and radiation therapy for operable disease, with a possible role for systemic treatment in selected histologies within a multimodal approach; unresectable paranasal sinus cancers are generally treated with a combination of radiotherapy and chemotherapy. The employment of high conformal radiation techniques, such as Intensity Modulated Radiation Therapy orcharged particle therapy, proton or carbon ion therapy may improve outcome and reduce late effects. Surgical treatment has evolved due to the progressive application of transnasal endoscopic techniques for naso ethmoidal malignancies and due to innovative reconstructive techniques after resection of cancers of the maxillary sinus. Because of the rarity and complexity of this disease, multicenter trials represent an urgent need to improve prognosis and to reduce treatment-related effects. PMID- 26520461 TI - Neuroendocrine dysfunction and insomniain in mild traumatic brain injury patients. AB - Mild traumatic brain injury (mTBI) has been a growing public health concern in the worldwide. To investigate the subjective and objective characteristics of insomnia following mTBI and the association between insomnia and hypothalamic pituitary-adrenal (HPA) function of mTBI patients, 59 patients with mTBI (mTBI group) were compared with 50 healthy participants (control group) in the present study. The subjective and objective measures of insomnia were respectively obtained from Pittsburgh Sleep Quality (PSQI) and polysomnography (PSG). HPA function was measured with low-dose short synacthen test (LDSST). According to the comparative and correlation analysis of the two groups, for PSQI, the scores of sleep syndrome, sleep latency, sleep efficiency, overall sleep quality and daytime dysfunction of mTBI patients were all higher, however only sleep efficiency and daytime dysfunction of mTBI patients were related with peak cortisol on lDSST; while for PSG, sleep efficiency (SE) was lower and wake after sleep onset (WASO) was longer in mTBI patients, moreover SE and WASO of mTBI patients were correlated with peak cortisol on LDSTT; for HPA function indexes, only peak cortisol on LDSST was lower in mTBI patients. These findings suggested that mTBI patients experienced more serious subjective insomnia symptoms than objective measurement, which were associated with HPA dysfunction. This study may contribute to identifying better treatment for mTBI patients with insomnia. PMID- 26520462 TI - Biomarkers of Renal Function in Type 2 Diabetic Patients with Cognitive Impairment. AB - Kidney disease is associated with cognitive impairment in studies of nondiabetic adults. We examined the cross-sectional relation between three measures of renal function and cognitive impairment (CI) in type 2 diabetic patients. A total of 357 patients with type 2 diabetes were prospectively enrolled. There were 108 patients with CI and 249 patients without CI (control). We calculated the urinary albumin/creatinine ratio (UACR) from morning spot urine and the estimated glomerular filtration rate (eGFR) in serum samples. Serum Cystatin C (Cys C) was measured with an automated particle-enhanced turbidimetric immunoassay. UACR and Cystatin C levels were significantly higher in patients with CI than those without CI (P<0.001), and the eGFR was lower in patients with CI than those without (P=0.003). A logistic regression analysis indicates that kidney impairment biomarkers levels were significantly associated with an increased risk of CI after adjustment for age and gender. The OR of each kidney biomarker (eGFR, UACR, Cystatin C) for CI status was 1.78 (0.89-3.27), 2.36 (1.29-4.42), and 2.77 (1.36-5.97), respectively. Among three kidney biomarkers (eGFR, UACR, Cystatin C), only elevated serum Cystatin C was associated with increased risk of CI in type 2 diabetic patients, with an OR of 1.42 (1.25-4.24) after additional adjustment for duration of diabetes, hypertension, hyperlipidemia, hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein (Hs-CRP), intima-media thickness (IMT), ankle brachial index (ABI), and brachial-ankle pulse wave velocity (ba PWV). Furthermore, combination of conventional risk factors and Cystatin C levels exhibited a fair diagnostic value for CI, with an area under the curve (AUC) of 0.91. Among three kidney impairment biomarkers (eGFR, UACR, Cystatin C), only elevated serum Cystatin C was associated with increased risk of CI in type 2 diabetic patients, independent of conventional risk factors. Furthermore, Cystatin C may be a better marker for CI than eGFR and UACR, and exhibited diagnostic value. PMID- 26520460 TI - The contribution of TRPC1, TRPC3, TRPC5 and TRPC6 to touch and hearing. AB - Transient receptor potential channels have diverse roles in mechanosensation. Evidence is accumulating that members of the canonical subfamily of TRP channels (TRPC) are involved in touch and hearing. Characteristic features of TRP channels include their high structural homology and their propensity to form heteromeric complexes which suggests potential functional redundancy. We previously showed that TRPC3 and TRPC6 double knockout animals have deficits in light touch and hearing whilst single knockouts were apparently normal. We have extended these studies to analyse deficits in global quadruple TRPC1, 3, 5 and 6 null mutant mice. We examined both touch and hearing in behavioural and electrophysiological assays, and provide evidence that the quadruple knockout mice have larger deficits than the TRPC3 TRPC6 double knockouts. Mechano-electrical transducer currents of cochlear outer hair cells were however normal. This suggests that TRPC1, TRPC3, TRPC5 and TRPC6 channels contribute to cutaneous and auditory mechanosensation in a combinatorial manner, but have no direct role in cochlear mechanotransduction. PMID- 26520463 TI - Role of the NMDA receptor GluN2D subunit in the expression of ketamine-induced behavioral sensitization and region-specific activation of neuronal nitric oxide synthase. AB - The present study aimed to investigate the involvement of the NMDA receptor (NMDAR) and/or nitric oxide (NO) pathway in ketamine-induced behavioral sensitization. Mice received repeated subcutaneous administration of ketamine (25mg/kg), once daily or once weekly for a total of five doses. Even three administrations of ketamine, daily or weekly, induced a rapid increase in locomotor activity in wild-type (WT), but not in GluN2D knockout (GluN2D-KO) mice. Furthermore, for WT mice receiving daily ketamine, elevated locomotor activity was maintained after a 1-month withdrawal period; however, this was not the case when ketamine was administered weekly. The effect of acute ketamine on nNOS activities was estimated with nicotinamide adenine dinucleotide hydrogen phosphate-diaphorase (NADPH-d) histochemistry. Ketamine rapidly increased the number of NADPH-d activated cells and strongly stained dendrites in the dorsal striatum and prefrontal cortex of WT mice, but not GluN2D-KO mice. These results suggest that ketamine-induced locomotor sensitization and nNOS activation in the frontal cortex-striatum neuronal circuit are positively correlated and that the NMDAR GluN2D subunit plays an important role in the acquisition and maintenance of ketamine-induced behavioral sensitization. PMID- 26520464 TI - Estrogen protects against dopamine neuron toxicity in primary mesencephalic cultures through an indirect P13K/Akt mediated astrocyte pathway. AB - Astrocytes regulate neuronal homeostasis and have been implicated in affecting the viability and functioning of surrounding neurons under stressed and injured conditions. Previous data from our lab suggests indirect actions of estrogen through ERalpha in neighboring astroglia to protect dopamine neurons against 1 methyl-4-phenylpyridinium (MPP(+)) toxicity in mouse mesencephalic cultures. We further evaluate estrogen signaling in astrocytes and the mechanism of estrogen's indirect neuroprotective effects on dopamine neurons. Primary mesencephalic cultures pre-treated with 17beta-estradiol and the membrane impermeable estrogen, E2-BSA, were both neuroprotective against MPP(+) -induced dopamine neuron toxicity, suggesting membrane-initiated neuroprotection. ERalpha was found in the plasma membrane of astrocyte cultures and colocalized with the lipid raft marker, flotillin-1. A 17beta-estradiol time course revealed a significant increase in Akt, which was inhibited by the PI3 kinase inhibitor, LY294004. Estrogen conditioned media collected from pure astrocyte cultures rescued glial deficient mesencephalic cultures from MPP(+). This indirect estrogen-mediated neuroprotective effect in mesencephalic cultures was significantly reduced when PI3 kinase signaling in astrocytes was blocked prior to collecting estrogen conditioned media using the irreversible PI3 kinase inhibitor, Wortmannin. Estrogen signaling via astrocytes is rapidly initiated at the membrane level and requires PI3 kinase signaling in order to protect primary mesencephalic dopamine neurons from MPP(+) neurotoxicity. PMID- 26520466 TI - The alpha1 adrenoceptors in ventrolateral orbital cortex contribute to the expression of morphine-induced behavioral sensitization in rats. AB - The aim of the present study was to investigate the effect of microinjection of benoxathian, selective alpha1 adrenoceptor antagonist, into the ventrolateral orbital cortex (VLO) on morphine-induced behavioral sensitization and its underlying molecular mechanism in rats. A single morphine treatment protocol was used in establishing the behavioral sensitization model. The effect of bilateral intra-VLO benoxathian injection on locomotor activity was examined and the protein expression levels of alpha1 adrenoceptors and activation of extracellular signal-regulated kinase (ERK) in the VLO were detected after locomotor test. The results showed that a single injection of morphine could induce behavioral sensitization by a low challenge dosage of morphine after a 7-days drug free period. Benoxathian significantly suppressed the expression but not the development of morphine-induced behavioral sensitization. Morphine treatment significantly elicited ERK phosphorylation and downregulated the expression level of alpha1 adrenoceptors in the VLO. In addition, intra-VLO benoxathian injection enhanced the expression levels of alpha1 adrenoceptors and phosphorylated ERK. These results suggest that alpha1 adrenoceptors in the VLO are involved in regulating the expression of morphine-induced behavioral sensitization. The effect of decreased locomotor activity by blocking alpha1 adrenoceptors might be associated with activation of ERK in the VLO. PMID- 26520465 TI - Magnetic resonance T2 relaxation time at 7 Tesla associated with amyloid beta pathology and age in a double-transgenic mouse model of Alzheimer's disease. AB - The aim of this study was to better understand the effect of amyloid-beta plaques on magnetic resonance T2 relaxation time. We investigated these changes associated with age in an APP/PS1 mouse model of AD at 7 Tesla, combined with histology. Ten double-transgenic AD and ten wild type (WT) female mice (aged 12 20 months) were used in a cross-sectional study. Mean T2 values and standard deviations were calculated for each Regions of interest (ROIs) on T2 map. Immunohistochemistry for amyloid plaques and fluorescence staining with thioflavine S were performed of brain sections after imaging. The results showed that mean T2 values of the hippocampus, cortex, corpus callosum, and thalamus of older mice were significantly lower than of the younger. Compared to WT mice, the T2 values of the hippocampus, corpus callosum, and thalamus in younger AD mice were significantly greater, while the T2 values of the hippocampus and cortex in older AD mice were significantly less. Abeta-40 immunohistochemistry and thioflavine S stainging were positive in the matched region both for younger and older AD mice, while neither Abeta-40 nor thioflavine S were observed in WT mice. These findings suggest that regional T2 values of AD mice may decrease with age, and changes in T2 values in AD mice may be influenced by many factors besides amyloid-beta plaque accumulation. Furthermore, they support that the standard deviation of the mean T2 value should be considered as well as the mean. PMID- 26520468 TI - Effect of protein corona magnetite nanoparticles derived from bread in vitro digestion on Caco-2 cells morphology and uptake. AB - Nanoparticles (NPs) in biological fluids immediately interact with proteins forming a biomolecular corona (PC) that imparts their biological identity. While several studies on the formation of the PC in human plasma have been reported, the PC of orally administrated NPs has been less investigated, mostly in the presence of a food matrix. In fact, food matrixes when digested are subject of several dynamic changes that will certainly affect the PC formed on the NPs. The lack of studies on this topic is clearly related to the difficulty in isolating representative PC NPs from such a complex environment. In this work magnetite NPs were added to in vitro simulated digestion simultaneously with bread and PC NPs were isolated after gastric and duodenal phases by sucrose gradient ultracentrifugation (UC). The PC NPs were characterized in terms of size and protein composition. Translocation studies were then performed on Caco-2 monolayers in a serum free environment and cell morphology was characterized by confocal microscopy. PC NPs isolated from gastric and duodenal phases were different in size, surface charge and protein corona composition. NP cellular uptake was enhanced by the digestive PC inducing morphology changes in the cell monolayer. Overall, in this work we were able to isolate PC NPs from digested fluids in the presence of a food matrix and study their biological response on Caco-2 cells. PMID- 26520469 TI - Fungal weathering of asbestos in semi arid regions of India. AB - The science of Geomicrobiology, which deals with mineral- microbe interaction in nature contributes effectively to three important processes namely- mineral and metal bioremediation, biomining and soil mineral formation by microbes. Bioremediation one of the important process of the above, degrades or transforms hazardous contaminants to less toxic compounds. Several groups of fungi have proved highly efficient in this aspect, with asbestos being one such toxic entity in the environment on which their activity was studied. The present investigation uses the same tool as a device for detoxifying asbestos, a potent carcinogenic entity; with fungal isolates native to the asbestos mines of Rajasthan, India, being investigated for the first time. The cellular mechanism of asbestos toxicity is mainly attributed to the presence of iron in its chemical composition which catalyzes generation of free radicals leading to oxidation of biomolecules. The two dominant novel species found therein, identified as Aspergillus tubingenesis and Coemansia reversa have proved capable of actively removing iron from asbestos fibers as studied by scanning electron microscopy- electron diffraction X-ray (SEM-EDX) analysis. This probably could lead to a reduction in toxicity of asbestos, due to reduced iron concentration as reported in related studies. Many fungi are known to release iron chelating compounds, siderophores, which could be instrumental in the study. The findings related to two new fungal species being added to the list of earlier identified fungal bioremediators of asbestos, widens the prospect of using bioremediation as an effective tool for asbestos detoxification. PMID- 26520467 TI - Assessment of pro-apoptotic activity of doxorubicin-transferrin conjugate in cells derived from human solid tumors. AB - Conjugates of anthracyclines are a new possibility for anticancer agent delivery, which seems to be a very promising alternative to the currently used cancer treatment strategies. In our study, we investigated the ability of a doxorubicin transferrin (DOX-TRF) conjugate to induce cell death in two solid tumor cell lines: non-small cell lung cancer (A549) and hepatocellular liver carcinoma (HepG2). The observed effects of the DOX-TRF conjugate on these cell cultures were compared with those of free doxorubicin (DOX), a widely used antineoplastic therapeutic agent. Our results provided direct evidence that the investigated conjugate is considerably more cytotoxic to the examined human cancer cell lines than is DOX alone. Moreover, we confirmed that the antitumor efficacy of DOX-TRF conjugate is related to its apoptosis-inducing ability, which was shown during measurements of typical features of programmed cell death. In solid tumor cell lines, the DOX-TRF conjugate induced changes in cellular morphology, mitochondrial membrane potential and caspases-3 and -9 activities. Furthermore, all of the analyzed hallmarks of apoptosis were confirmed by the oligonucleosomal DNA fragmentation assay and by a real-time PCR quantitative study, which displayed the superiority of the conjugate-induced programmed cell death over free drug-triggered cell death. PMID- 26520470 TI - [Can we enhance the one-day part in breast conservative surgery?]. AB - INTRODUCTION: French national guidelines lead us to increase the part of one-day breast cancer conservative surgery. Our objective was to check if we can enhance our outpatient part and to identify solutions to improve our practices. METHODS: From 01/01/2013 to 31/12/2014, we conducted a monocentric and retrospective register about all cases of breast conservative surgery (infiltrating or in situ carcinoma, atypical hyperplasia). The collected data were: patients' sociodemographic characteristics, modality of hospitalization, surgical characteristics, preoperative exams organization, complications and reasons for an absence of surgery planned in one-day modality. We compared the two groups (one-day and standard hospitalization). RESULTS: We reported 324 surgeries of which 50.3% planned in one-day mode. The outpatient part increased from 39.8% in 2013 to 60.8% in 2014. There was no difference for postoperative complications between the two groups. We found a higher rate of outpatient for sentinel node axillary dissection in 2014 (65% versus 37% in 2013). We reported a rate of axillary dissection in one-day mode of 20%, of which 15% were drained. The proportion of patients unplanned in one-day mode without contraindications was reduced from 81% in 2013 to 57% for 2014. DISCUSSION: Increasing our outpatient part in breast conservative surgery was possible. There are still efforts to do to reach the national goals of one-day conservative breast cancer surgery, especially for the organizational aspects that remains the main obstruction. The implementation of pathways specifically for outpatient in and out of the hospital could be an interesting solution. PMID- 26520471 TI - Outcomes of Cardiac Surgery in Patients With Previous Solid Organ Transplantation (Kidney, Liver, and Pancreas). AB - A growing number of solid organ transplant survivors require surgery for cardiac disease. We examined the effect of having a previous transplant on outcomes after cardiac surgery in these patients from a population-based perspective. Of 1,709,735 patients who underwent coronary artery bypass grafting, valve, or thoracic aorta surgery from 2004 to 2008 in the Nationwide Inpatient Sample, 3,535 patients (0.21%) had a previous organ transplant (2,712 kidney, 738 liver, 300 pancreas). Multivariate logistic regression analysis and propensity score matching were used to determine the effect of a previous solid organ transplant on outcomes. In-hospital mortality rate was 7% for patients who underwent transplantation versus 4% for patients who did not undergo transplantation (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.16 to 2.38). Patients who underwent transplantation were at an increased risk for acute renal failure (OR 1.62, CI 1.36 to 1.94) and blood transfusions (OR 1.63, CI 1.36 to 1.95). Median length of stay was longer (10 vs 9 days), with greater median total charges ($111,362 vs $102,221; both p <0.001). Occurrence of stroke, gastrointestinal complication, infection, and pneumonia was similar between groups. In conclusion, previous solid organ transplantation is an incremental risk factor for postoperative mortality after cardiac surgery. Renal protective strategies and bleeding control should be stressed to mitigate complications. PMID- 26520472 TI - Variation in assessment and standard setting practices across UK undergraduate medicine and the need for a benchmark. AB - OBJECTIVES: The principal aim of this study is to provide an account of variation in UK undergraduate medical assessment styles and corresponding standard setting approaches with a view to highlighting the importance of a UK national licensing exam in recognizing a common standard. METHODS: Using a secure online survey system, response data were collected during the period 13 - 30 January 2014 from selected specialists in medical education assessment, who served as representatives for their respective medical schools. RESULTS: Assessment styles and corresponding choices of standard setting methods vary markedly across UK medical schools. While there is considerable consensus on the application of compensatory approaches, individual schools display their own nuances through use of hybrid assessment and standard setting styles, uptake of less popular standard setting techniques and divided views on norm referencing. CONCLUSIONS: The extent of variation in assessment and standard setting practices across UK medical schools validates the concern that there is a lack of evidence that UK medical students achieve a common standard on graduation. A national licensing exam is therefore a viable option for benchmarking the performance of all UK undergraduate medical students. PMID- 26520473 TI - What matters for working fathers? Job characteristics, work-family conflict and enrichment, and fathers' postpartum mental health in an Australian cohort. AB - One in ten fathers experience mental health difficulties in the first year postpartum. Unsupportive job conditions that exacerbate work-family conflict are a potential risk to fathers' mental health given that most new fathers (95%) combine parenting with paid work. However, few studies have examined work-family conflict and mental health for postpartum fathers specifically. The aim of the present study was to identify the particular work characteristics (e.g., work hours per week, job quality) associated with work-family conflict and enrichment, and fathers' mental health in the postpartum period. Survey data from 3243 fathers of infants (aged 6-12 months) participating in the Longitudinal Study of Australian Children were analysed via path analysis, considering key confounders (age, education, income, maternal employment, maternal mental health and relationship quality). Long and inflexible work hours, night shift, job insecurity, a lack of autonomy and more children in the household were associated with increased work-family conflict, and this was in turn associated with increased distress. Job security, autonomy, and being in a more prestigious occupation were positively associated with work-family enrichment and better mental health. These findings from a nationally representative sample of Australian fathers contribute novel evidence that employment characteristics, via work-family conflict and work-family enrichment, are key determinants of fathers' postnatal mental health, independent from established risk factors. Findings will inform the provision of specific 'family-friendly' conditions protective for fathers during this critical stage in the family life-cycle, with implications for their wellbeing and that of their families. PMID- 26520474 TI - Spectrophotometric study on the proton transfer reaction between 2-amino-4 methylpyridine with 2,6-dichloro-4-nitrophenol in methanol, acetonitrile and the binary mixture 50% methanol+50% acetonitrile. AB - Proton transfer reaction between 2-amino-4-methylpyridine (2AMP) as the proton acceptor with 2,6-dichloro-4-nitrophenol (DCNP) as the proton donor has been investigated spectrophotometrically in methanol (MeOH), acetonitrile (AN) and a binary mixture composed of 50% MeOH and 50% AN (AN-Me). The composition of the complex has been investigated utilizing Job(')s and photometric titration methods to be 1:1. Minimum-maximum absorbance equation has been applied to estimate the formation constant of the proton transfer reaction (K(PT)) where it reached high values in the investigated solvent confirming its high stability. The formation constant recorded higher value in AN compared with MeOH and mixture of AN-Me. Based on the formation of stable proton transfer complex, a sensitive spectrophotometric method was suggested for quantitative determination of 2AMP. The Lambert-Beer(')s law was obeyed in the concentration range 0.5-8 MUg mL(-1) with small values of limits of detection and quantification. The solid complex between 2AMP with DCNP has been synthesized and characterized by elemental analysis to be 1:1 in concordant with the molecular stoichiometry in solution. Further analysis of the solid complex was carried out using infrared and (1)H NMR spectroscopy. PMID- 26520475 TI - Optimization, isotherm, kinetic and thermodynamic studies of Pb(II) ions adsorption onto N-maleated chitosan-immobilized TiO2 nanoparticles from aqueous media. AB - Chitosan, CS was chemically engineered by maleic anhydride via simple protocol to produce N-maleated chitosan, MCS which immobilized on anatase TiO2 to synthesize novel eco-friendly nanosorbent (51+/-3.8 nm), MCS@TiO2 for cost-effective and efficient removal of Pb(II) ions from aqueous media. The chemical structure, surface properties and morphology of MCS@TiO2 were recognized by FTIR, (1)H NMR, XRD, TEM, DLS and zeta-potential techniques. The relations between %removal of Pb(II) and different analytical parameters such as solution acidity (pH), MCS@TiO2 dosage, time of contact and initial Pb(II) concentration were optimized using response surface methodology (RSM) and Box-Behnken design (BBD) statistical procedures. The fitting of the experimental data to four different isotherm models at optimized conditions was carried out by various statistical treatments including the correlation coefficient (r), coefficient of determination (r(2)) and non-linear Chi-square (chi(2)) test analyses which all confirm the suitability of Langmuir model to explain the adsorption isotherm data. Also, statistics predicted that the pseudo-second-order model is the optimum kinetic model among four applied kinetic models to closely describe the rate equation of the adsorption process. Thermodynamics viewed the adsorption as endothermic and feasible physical process. EDTA could release the sorbed Pb(II) ions from MCS@TiO2 with a recovery above 92% after three sorption-desorption cycles. The novel synthesized nanosorbent is evidenced to be an excellent solid phase extractor for Pb(II) ions from wastewaters. PMID- 26520476 TI - Development of new portable miniaturize solid phase microextraction of silver APDC complex using micropipette tip in-syringe system couple with electrothermal atomic absorption spectrometry. AB - An innovative and simple miniaturized solid phase microextraction (M-SPME) method, was developed for preconcentration and determination of silver(I) in the fresh and waste water samples. For M-SPME, a micropipette tip packed with activated carbon cloth (ACC) as sorbent, in a syringe system. The size, morphology and elemental composition of ACC before and after adsorption of analyte have been characterized by scanning electron microscopy and energy dispersive spectroscopy. The sample solution treated with a complexing reagent, ammonium pyrrolidine dithiocarbamate (APDC), was drawn into the syringe filled with ACC and dispensed manually for 2 to 10 aspirating/dispensing cycle. Then the Ag- complex sorbed on the ACC in micropipette was quantitatively eluted by drawing and dispensing of different concentrations of acids for 2 to 5 aspirating/dispensing cycles. The extracted Ag ions with modifier were injected directly into the electrothermal atomic absorption spectrometry for analysis. The influence of different variables on the extraction efficiency, including the concentration of ligand, pH, sample volume, eluent type, concentration and volume was investigated. Validity and accuracy of the developed method was checked by the standard addition method. Reliability of the proposed methodology was checked by the relative standard deviation (%RSD), which was found to be <5%. Under the optimized experimental variables, the limits of detection (LOD) and enhancement factors (EF), were obtained to be 0.86 ng L(-1) and 120, respectively. The proposed method was successfully applied for the determination of trace levels of silver ions in fresh and waste water samples. PMID- 26520477 TI - A new series of two-photon blue/violet fluorescent trans-alkenes: Green synthesis and optical properties. AB - A new series of trans-alkenes (3a-3e) containing different electron-donating groups were synthesized by the solvent-free Horner-Wadsworth-Emmons reaction, and characterized by infrared, hydrogen nuclear magnetic resonance, mass spectrometry and elemental analysis. Their UV-visible absorption, one-photon excited fluorescence, two-photon absorption, and two-photon excited fluorescence were systematically investigated in different solvents. Experimental results show different trends in linear and nonlinear optical properties with different donor units. 3a with triphenylamine donor exhibits the best optical properties. It emits strong blue up-converted fluorescence, and the two-photon absorption cross section can be as large as 218 GM in DCM. PMID- 26520478 TI - Ethyl-3H analogues of plant natural products: Biologically active proxy radioligands via vinyl group tritiation. AB - Methods are presented to tritiate the plant natural product analogues dihydrocolforsin and dihydroquinidine. PMID- 26520479 TI - Newborn hearing screening: Prevalence and medical and paramedical treatment of bilateral hearing loss in a neonatal series in the Ile-de-France region of France. AB - OBJECTIVES: We report results for newborn hearing screening in a cohort of children born in the Ile-de-France region of France, as part of a national screening program set up by the French national health insurance agency. MATERIALS AND METHODS: A prospective study was performed on neonates undergoing hearing screening by automated auditory brainstem response at 35 dB in maternity departments between 2005 and 2011. In case of positive findings, a further check was performed; if this was also positive in one or both ears, the child was referred to the diagnostic center. RESULTS: The study recruited 27,885 births; 96% of neonates were tested. Retest was positive in 0.84% of cases. Bilateral hearing loss was diagnosed in 0.63% of infants. Fifty-nine percent of these had >= 1 risk factor. Hearing normalized by end of follow-up in 25% of cases. Hearing loss was moderate in 59% of hearing-impaired children, severe in 12% and profound in 29%. Mean age at hearing aid fitting ranged from 4 months in profound hearing loss to 11.4 months in moderate hearing loss. In children receiving a cochlear implant, mean age at implantation was 14 months. CONCLUSION: Newborn hearing screening is now public policy. It is effective in terms of exhaustiveness, age at diagnosis and early management. Caution is appropriate in the treatment of moderate hearing loss. In case of moderate hearing loss associated with otitis media serosa, transtympanic aerators should be suggested as of the age of 6 months to enable hearing threshold measurement. Hearing aid fitting can then be considered around 9 months of age if hearing has not improved. PMID- 26520480 TI - Substernal goiter: Experience with 50 cases. AB - INTRODUCTION: Goiter is localized or generalized thyroid hypertrophy. It is usually cervical, but may show intra-thoracic development beyond the thoracic inlet and down to the mediastinum: i.e., substernal goiter. The purpose of this study was to analyze the epidemiological, clinical and paraclinical profile of substernal goiter and the difficulties of management. MATERIAL AND METHODS: A retrospective study included 50 cases from our ENT department. RESULTS: Mean age was 47 years, with a sex ratio of 0.06. Clinical symptomatology was dominated by medial anterior cervical swelling. Compression signs were observed in 26 patients, and cervical lymph nodes in 3. Mean time to consultation was 7 years. Fiberoptic endoscopy found vocal cord palsy in 3 patients. Cervical ultrasonography was the first-line diagnostic test. Cervical-thoracic CT scan was requested in 45 patients to study thoracic extension and the relation of the thyroid mass with the supra-aortic vascular axes. Treatment systematically comprised total thyroidectomy on a cervical approach. There were 6 cases of malignancy. DISCUSSION-CONCLUSION: Substernal goitre is fairly frequent. Despite particularities, an exclusively cervical approach is sufficient in a large majority of cases. The substernal nature of the goitre did not have major impact on postoperative complications. PMID- 26520481 TI - Self- and parental assessment of quality of life in child cochlear implant bearers. AB - OBJECTIVES: The aim of this study was to assess quality of life in children fitted with cochlear implants, using combined self- and parental assessment. MATERIALS AND METHODS: Thirty-two children, aged 6 to 17 years, with prelingual hearing loss and receiving cochlear implants at a mean age of 22 months, were included along with their families. The KIDSCREEN-27 questionnaire was implemented, in face-to-face interview, in its parents and children-adolescents versions, with 27 items covering physical well-being ("physical activities and health"), psychological well-being ("general mood and feelings about yourself"), autonomy & parents ("family and free time"), peers & social support ("friends") and school environment ("school and learning"). Parent and child responses were compared with a general population database, and pairwise. RESULTS: Global scores were compared against the general population on Cohen d effect-size. For child self-assessment, the results were: physical well-being, 72.81 (d=0); psychological well-being, 78.13 (d=-0.4); autonomy & parents, 63.84 (d=-0.2); peers & social support, 61.72 (d=-0.4); and school environment 73.83 (d=0). For parent assessment, the respective results were 62.66 (d=-0.8), 74.89 (d=-0.3), 57.37 (d=-1.2), 51.56 (d=-0.8), and 68.95 (d=-0.4). Half of the children could not answer the questionnaire, mainly due to associated disability. Schooling and language performance were poorer in non-respondent than respondent children. Quality of life was comparable between implanted and non-implanted children: Cohen d, 0 to 0.4. Early cochlear implantation in children with pre-lingual hearting loss provides quality of life comparable to that of the general population. PMID- 26520482 TI - Comparison of Mosquito Magnet and Biogents Sentinel Traps for Operational Surveillance of Container-Inhabiting Aedes (Diptera: Culicidae) Species. AB - Container-inhabiting Aedes are among the most medically important mosquito vectors of diseases. They also impact health and quality of life by their persistent and severe biting. Monitoring of container-inhabiting Aedes species is challenging due to the need for specialized traps and lures. Biogents Sentinel (BGS) trap has become a standard for Aedes albopictus (Skuse) surveillance; however, it has substantial problems with durability, quality of construction, and sample exposure to the elements. The goal of this study was to develop a methodology for collecting medically important container-inhabiting Aedes species in numbers sufficient for population trend analysis, control efficacy studies, and pathogen testing. Mosquito Magnets (MM) baited with BG lure and R-octenol were selected as the most practical alternative to BGS, collecting significantly more Ae. albopictus (32.1 +/- 0.7 vs. 5.6 +/- 0.1), Aedes japonicus (Theobald) (10.1 +/- 0.4 vs. 1.2 +/- 0.02), and Aedes triseriatus (Say) (0.9 +/- 0.04 vs. 0.04 +/- 0.004) females on average per trapping under a variety of weather conditions. MM can be particularly useful for long-term surveillance or when large numbers of specimens are required for pathogen isolation, such as at the sites with suspected dengue or chikungunya transmission. PMID- 26520483 TI - Investigation of the relationship between anxiety and heart rate variability in fibromyalgia: A new quantitative approach to evaluate anxiety level in fibromyalgia syndrome. AB - BACKGROUND: Fibromyalgia syndrome (FMS) is identified by widespread musculoskeletal pain, sleep disturbance, nonrestorative sleep, fatigue, morning stiffness and anxiety. Anxiety is very common in Fibromyalgia and generally leads to a misdiagnosis. Self-rated Beck Anxiety Inventory (BAI) and doctor-rated Hamilton Anxiety Inventory (HAM-A) are frequently used by specialists to determine anxiety that accompanies fibromyalgia. However, these semi-quantitative anxiety tests are still subjective as the tests are scored using doctor-rated or self-rated scales. METHOD: In this study, we investigated the relationship between heart rate variability (HRV) frequency subbands and anxiety tests. The study was conducted with 56 FMS patients and 34 healthy controls. BAI and HAM-A test scores were determined for each participant. ECG signals were then recruited and 71 HRV subbands were obtained from these ECG signals using Wavelet Packet Transform (WPT). The subbands and anxiety tests scores were analyzed and compared using multilayer perceptron neural networks (MLPNN). RESULTS: The results show that a HRV high frequency (HF) subband in the range of 0.15235Hz to 0.40235Hz, is correlated with BAI scores and another HRV HF subband, frequency range of 0.15235Hz to 0.28907Hz is correlated with HAM-A scores. The overall accuracy is 91.11% for HAM-A and 90% for BAI with MLPNN analysis. CONCLUSION: Doctor-rated or self-rated anxiety tests should be supported with quantitative and more objective methods. Our results show that the HRV parameters will be able to support the anxiety tests in the clinical evaluation of fibromyalgia. In other words, HRV parameters can potentially be used as an auxiliary diagnostic method in conjunction with anxiety tests. PMID- 26520484 TI - Regularized logistic regression with adjusted adaptive elastic net for gene selection in high dimensional cancer classification. AB - Cancer classification and gene selection in high-dimensional data have been popular research topics in genetics and molecular biology. Recently, adaptive regularized logistic regression using the elastic net regularization, which is called the adaptive elastic net, has been successfully applied in high dimensional cancer classification to tackle both estimating the gene coefficients and performing gene selection simultaneously. The adaptive elastic net originally used elastic net estimates as the initial weight, however, using this weight may not be preferable for certain reasons: First, the elastic net estimator is biased in selecting genes. Second, it does not perform well when the pairwise correlations between variables are not high. Adjusted adaptive regularized logistic regression (AAElastic) is proposed to address these issues and encourage grouping effects simultaneously. The real data results indicate that AAElastic is significantly consistent in selecting genes compared to the other three competitor regularization methods. Additionally, the classification performance of AAElastic is comparable to the adaptive elastic net and better than other regularization methods. Thus, we can conclude that AAElastic is a reliable adaptive regularized logistic regression method in the field of high-dimensional cancer classification. PMID- 26520485 TI - Toward standardized quantitative image quality (IQ) assessment in computed tomography (CT): A comprehensive framework for automated and comparative IQ analysis based on ICRU Report 87. AB - PURPOSE: Based on the guidelines from "Report 87: Radiation Dose and Image quality Assessment in Computed Tomography" of the International Commission on Radiation Units and Measurements (ICRU), a software framework for automated quantitative image quality analysis was developed and its usability for a variety of scientific questions demonstrated. METHODS: The extendable framework currently implements the calculation of the recommended Fourier image quality (IQ) metrics modulation transfer function (MTF) and noise-power spectrum (NPS), and additional IQ quantities such as noise magnitude, CT number accuracy, uniformity across the field-of-view, contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) of simulated lesions for a commercially available cone-beam phantom. Sample image data were acquired with different scan and reconstruction settings on CT systems from different manufacturers. RESULTS: Spatial resolution is analyzed in terms of edge-spread function, line-spread-function, and MTF. 3D NPS is calculated according to ICRU Report 87, and condensed to 2D and radially averaged 1D representations. Noise magnitude, CT numbers, and uniformity of these quantities are assessed on large samples of ROIs. Low-contrast resolution (CNR, SNR) is quantitatively evaluated as a function of lesion contrast and diameter. Simultaneous automated processing of several image datasets allows for straightforward comparative assessment. CONCLUSIONS: The presented framework enables systematic, reproducible, automated and time-efficient quantitative IQ analysis. Consistent application of the ICRU guidelines facilitates standardization of quantitative assessment not only for routine quality assurance, but for a number of research questions, e.g. the comparison of different scanner models or acquisition protocols, and the evaluation of new technology or reconstruction methods. PMID- 26520487 TI - [Severe low growth and 2q37 syndrome]. PMID- 26520486 TI - [Non-pharmacological analgesia in spanish neonatal units]. PMID- 26520488 TI - [Medication errors in a neonatal unit: One of the main adverse events]. AB - INTRODUCTION: Neonatal units are one of the hospital areas most exposed to the committing of treatment errors. A medication error (ME) is defined as the avoidable incident secondary to drug misuse that causes or may cause harm to the patient. The aim of this paper is to present the incidence of ME (including feeding) reported in our neonatal unit and its characteristics and possible causal factors. A list of the strategies implemented for prevention is presented. MATERIAL AND METHODS: An analysis was performed on the ME declared in a neonatal unit. RESULTS: A total of 511 MEs have been reported over a period of seven years in the neonatal unit. The incidence in the critical care unit was 32.2 per 1000 hospital days or 20 per 100 patients, of which 0.22 per 1000 days had serious repercussions. The ME reported were, 39.5% prescribing errors, 68.1% administration errors, 0.6% were adverse drug reactions. Around two-thirds (65.4%) were produced by drugs, with 17% being intercepted. The large majority (89.4%) had no impact on the patient, but 0.6% caused permanent damage or death. Nurses reported 65.4% of MEs. The most commonly implicated causal factor was distraction (59%). Simple corrective action (alerts), and intermediate (protocols, clinical sessions and courses) and complex actions (causal analysis, monograph) were performed. CONCLUSIONS: It is essential to determine the current state of ME, in order to establish preventive measures and, together with teamwork and good practices, promote a climate of safety. PMID- 26520489 TI - [Meningoencephalitis as a presentation form of Behcet]. PMID- 26520490 TI - Anaerobic digestion of fines from recovered paper processing - Influence of fiber source, lignin and ash content on biogas potential. AB - Fines concentration harms paper machine runability and output quality in recovered paper processing, hence, their extraction would be fundamentally beneficial. In this study, separated fines from an industrial recycled fiber pulp (RFP) were characterized and evaluated for their potential biogas yields with a focus on understanding the role of varying lignin and ash contents. Further, these results were compared with biogas yields from conventional chemical and mechanical pulps. Overall, methane yields of fines from mechanical pulps (21 28mL/gVS) and RFP (127mL/gVS) are relatively low compared to the high methane yields of 375mL/gVS from the chemical pulp fines. However, it was shown that the high ash content in RFP fines (up to 50%) did not negatively influence overall yield, rather, it was the presence of slowly biodegrading lignin-rich fiber fines. PMID- 26520491 TI - Integrating particle physical geometry into composting degradation kinetics. AB - The study was carried out to integrate physical geometry of compost particle with degradation kinetics to model biological reactions, which revealing additional dynamic approaches. A sphere and its circumscribing cube were used to represent compost particles. An inner sphere, representing anaerobic zone, was introduced to describe variations of substrate volume without sufficient oxygen supply. Degradation of soluble substrates and hydrolysis of insoluble substrates were associated with the particle geometry. Transportation of soluble substrates produced from hydrolysis was expressed using Fick's law. Through the integration of degradation kinetics with geometry models, degradation models could describe varying volume of composting materials involving aerobic or anaerobic digestion and transportation of soluble substrates in a unit compost particle. PMID- 26520492 TI - Local equilibrium and the second law of thermodynamics for irreversible systems with thermodynamic inertia. AB - Validity of local equilibrium has been questioned for non-equilibrium systems which are characterized by delayed response. In particular, for systems with non zero thermodynamic inertia, the assumption of local equilibrium leads to negative values of the entropy production, which is in contradiction with the second law of thermodynamics. In this paper, we address this question by suggesting a variational formulation of irreversible evolution of a system with non-zero thermodynamic inertia. We introduce the Lagrangian, which depends on the properties of the normal and the so-called "mirror-image" systems. We show that the standard evolution equations, in particular, the Maxwell-Cattaneo-Vernotte equation, can be derived from the variational procedure without going beyond the assumption of local equilibrium. We also argue that the second law of thermodynamics in non-equilibrium should be understood as a consequence of the variational procedure and the property of local equilibrium. For systems with instantaneous response this leads to the standard requirement of the local instantaneous entropy production being always positive. However, if a system is characterized by delayed response, the formulation of the second law of thermodynamics should be altered. In particular, the quantity, which is always positive, is not the instantaneous entropy production, but the entropy production averaged over a proper time interval. PMID- 26520493 TI - Range of applicability of modified Fick-Jacobs equation in two dimensions. AB - Axial diffusion in a two-dimensional channel of smoothly varying geometry can be approximately described as one-dimensional diffusion in the entropy potential with position-dependent effective diffusivity by means of the modified Fick Jacobs equation. In this paper, Brownian dynamics simulations are used to study the range of applicability of such a description, as well as the accuracy of the expressions for the effective diffusivity proposed by different researchers. PMID- 26520494 TI - Approximating electronically excited states with equation-of-motion linear coupled-cluster theory. AB - A new perturbative approach to canonical equation-of-motion coupled-cluster theory is presented using coupled-cluster perturbation theory. A second-order Moller-Plesset partitioning of the Hamiltonian is used to obtain the well known equation-of-motion many-body perturbation theory equations and two new equation of-motion methods based on the linear coupled-cluster doubles and linear coupled cluster singles and doubles wavefunctions. These new methods are benchmarked against very accurate theoretical and experimental spectra from 25 small organic molecules. It is found that the proposed methods have excellent agreement with canonical equation-of-motion coupled-cluster singles and doubles state for state orderings and relative excited state energies as well as acceptable quantitative agreement for absolute excitation energies compared with the best estimate theory and experimental spectra. PMID- 26520495 TI - Examining the impact of harmonic correlation on vibrational frequencies calculated in localized coordinates. AB - Carefully choosing a set of optimized coordinates for performing vibrational frequency calculations can significantly reduce the anharmonic correlation energy from the self-consistent field treatment of molecular vibrations. However, moving away from normal coordinates also introduces an additional source of correlation energy arising from mode-coupling at the harmonic level. The impact of this new component of the vibrational energy is examined for a range of molecules, and a method is proposed for correcting the resulting self-consistent field frequencies by adding the full coupling energy from connected pairs of harmonic and pseudoharmonic modes, termed vibrational self-consistent field (harmonic correlation). This approach is found to lift the vibrational degeneracies arising from coordinate optimization and provides better agreement with experimental and benchmark frequencies than uncorrected vibrational self-consistent field theory without relying on traditional correlated methods. PMID- 26520496 TI - Observations on variational and projector Monte Carlo methods. AB - Variational Monte Carlo and various projector Monte Carlo (PMC) methods are presented in a unified manner. Similarities and differences between the methods and choices made in designing the methods are discussed. Both methods where the Monte Carlo walk is performed in a discrete space and methods where it is performed in a continuous space are considered. It is pointed out that the usual prescription for importance sampling may not be advantageous depending on the particular quantum Monte Carlo method used and the observables of interest, so alternate prescriptions are presented. The nature of the sign problem is discussed for various versions of PMC methods. A prescription for an exact PMC method in real space, i.e., a method that does not make a fixed-node or similar approximation and does not have a finite basis error, is presented. This method is likely to be practical for systems with a small number of electrons. Approximate PMC methods that are applicable to larger systems and go beyond the fixed-node approximation are also discussed. PMID- 26520497 TI - Orthogonality of embedded wave functions for different states in frozen-density embedding theory. AB - Other than lowest-energy stationary embedded wave functions obtained in Frozen Density Embedding Theory (FDET) [T. A. Wesolowski, Phys. Rev. A 77, 012504 (2008)] can be associated with electronic excited states but they can be mutually non-orthogonal. Although this does not violate any physical principles--embedded wave functions are only auxiliary objects used to obtain stationary densities- working with orthogonal functions has many practical advantages. In the present work, we show numerically that excitation energies obtained using conventional FDET calculations (allowing for non-orthogonality) can be obtained using embedded wave functions which are strictly orthogonal. The used method preserves the mathematical structure of FDET and self-consistency between energy, embedded wave function, and the embedding potential (they are connected through the Euler Lagrange equations). The orthogonality is built-in through the linearization in the embedded density of the relevant components of the total energy functional. Moreover, we show formally that the differences between the expectation values of the embedded Hamiltonian are equal to the excitation energies, which is the exact result within linearized FDET. Linearized FDET is shown to be a robust approximation for a large class of reference densities. PMID- 26520498 TI - Non-linear non-local molecular electrodynamics with nano-optical fields. AB - The interaction of optical fields sculpted on the nano-scale with matter may not be described by the dipole approximation since the fields may vary appreciably across the molecular length scale. Rather than incrementally adding higher multipoles, it is advantageous and more physically transparent to describe the optical process using non-local response functions that intrinsically include all multipoles. We present a semi-classical approach for calculating non-local response functions based on the minimal coupling Hamiltonian. The first, second, and third order response functions are expressed in terms of correlation functions of the charge and the current densities. This approach is based on the gauge invariant current rather than the polarization, and on the vector potential rather than the electric and magnetic fields. PMID- 26520499 TI - Imaginary time density-density correlations for two-dimensional electron gases at high density. AB - We evaluate imaginary time density-density correlation functions for two dimensional homogeneous electron gases of up to 42 particles in the continuum using the phaseless auxiliary field quantum Monte Carlo method. We use periodic boundary conditions and up to 300 plane waves as basis set elements. We show that such methodology, once equipped with suitable numerical stabilization techniques necessary to deal with exponentials, products, and inversions of large matrices, gives access to the calculation of imaginary time correlation functions for medium-sized systems. We discuss the numerical stabilization techniques and the computational complexity of the methodology and we present the limitations related to the size of the systems on a quantitative basis. We perform the inverse Laplace transform of the obtained density-density correlation functions, assessing the ability of the phaseless auxiliary field quantum Monte Carlo method to evaluate dynamical properties of medium-sized homogeneous fermion systems. PMID- 26520500 TI - Determining the pivotal plane of fluid lipid membranes in simulations. AB - Each leaflet of a curved lipid membrane contains a surface at which the area strain vanishes, the so-called pivotal plane. Its distance z0 from the bilayer's midplane arises in numerous contexts, for instance the connection between monolayer and bilayer moduli, stress-profile moments, or area-difference elasticity theories. Here, we propose two precise methods for determining the location of the pivotal plane in computer simulations, both of which rely on monitoring the lipid imbalance across a curved bilayer. The first method considers the ratio of lipid number between the two leaflets of cylindrical or spherical vesicles; it hence requires lipid flip-flop for equilibration. The second method looks at the leaflet difference across local sections cut out from a buckled membrane; this observable equilibrates even in the absence of flip flop. We apply our methods to two different coarse-grained lipid models, the generic three-bead solvent-free Cooke model and a ten-bead representation of dimyristoylphosphocholine with the explicit solvent MARTINI model. The Cooke model is amenable to both methods and gives results that agree at the percent level. Using it, we also show that the pivotal plane moves outward as lipid curvature becomes more positive. The MARTINI model can only be analyzed with the buckling method; the obtained value z0 = 0.850(11) nm lies about 0.4 nm inwards of the glycerol backbone and is hence unexpectedly small. We attribute this to limitations of the coarse-grained description, suggesting that the location of the pivotal plane might be a good indicator for how well lipid models capture the microscopic origins of curvature elasticity. Finally, we also show that the pivotal plane position itself moves as the membrane is bent. The leading correction is linear in curvature, dependent on the Poisson ratio, and can matter when analyzing experimental results obtained from highly curved inverse hexagonal phases. PMID- 26520501 TI - Time dependent semiclassical tunneling through one dimensional barriers using only real valued trajectories. AB - The time independent semiclassical treatment of barrier tunneling has been understood for a very long time. Several semiclassical approaches to time dependent tunneling through barriers have also been presented. These typically involve trajectories for which the position variable is a complex function of time. In this paper, a method is presented that uses only real valued trajectories, thus avoiding the complications that can arise when complex trajectories are employed. This is accomplished by expressing the time dependent wave packet as an integration over momentum. The action function in the exponent in this expression is expanded to second order in the momentum. The expansion is around the momentum, p0(*) , at which the derivative of the real part of the action is zero. The resulting Gaussian integral is then taken. The stationary phase approximation requires that the derivative of the full action is zero at the expansion point, and this leads to a complex initial momentum and complex tunneling trajectories. The "pseudo-stationary phase" approximation employed in this work results in real values for the initial momentum and real valued trajectories. The transmission probabilities obtained are found to be in good agreement with exact quantum results. PMID- 26520502 TI - Vibrational solvatochromism. III. Rigorous treatment of the dispersion interaction contribution. AB - A rigorous first principles theory of vibrational solvatochromism including the intermolecular dispersion interaction, which is based on the effective fragment potential method, is developed. The present theory is an extended version of our previous vibrational solvatochromism model that took into account the Coulomb, exchange-repulsion, and induction interactions. We show that the frequency shifts of the amide I mode of N-methylacetamide in H2O and CDCl3, when combined with molecular dynamics simulations, can be quantitatively reproduced by the theory, which indicates that the dispersion interaction contribution to the vibrational frequency shift is not always negligibly small. Nonetheless, the reason that the purely Coulombic interaction model for vibrational solvatochromism works well for describing amide I mode frequency shifts in polar solvents is because the electrostatic contribution is strong and highly sensitive to the relative orientation of surrounding solvent molecules, which is in stark contrast with polarization, dispersion, and exchange-repulsion contributions. It is believed that the theory presented and discussed here will be of great use in quantitatively describing vibrational solvatochromism and electrochromism of infrared probes in not just polar solvent environments but also in biopolymers such as proteins. PMID- 26520503 TI - H4: A challenging system for natural orbital functional approximations. AB - The correct description of nondynamic correlation by electronic structure methods not belonging to the multireference family is a challenging issue. The transition of D(2h) to D(4h) symmetry in H4 molecule is among the most simple archetypal examples to illustrate the consequences of missing nondynamic correlation effects. The resurgence of interest in density matrix functional methods has brought several new methods including the family of Piris Natural Orbital Functionals (PNOF). In this work, we compare PNOF5 and PNOF6, which include nondynamic electron correlation effects to some extent, with other standard ab initio methods in the H4 D(4h)/D(2h) potential energy surface (PES). Thus far, the wrongful behavior of single-reference methods at the D(2h)-D(4h) transition of H4 has been attributed to wrong account of nondynamic correlation effects, whereas in geminal-based approaches, it has been assigned to a wrong coupling of spins and the localized nature of the orbitals. We will show that actually interpair nondynamic correlation is the key to a cusp-free qualitatively correct description of H4 PES. By introducing interpair nondynamic correlation, PNOF6 is shown to avoid cusps and provide the correct smooth PES features at distances close to the equilibrium, total and local spin properties along with the correct electron delocalization, as reflected by natural orbitals and multicenter delocalization indices. PMID- 26520504 TI - Proton-detected 3D (1)H/(13)C/(1)H correlation experiment for structural analysis in rigid solids under ultrafast-MAS above 60 kHz. AB - A proton-detected 3D (1)H/(13)C/(1)H chemical shift correlation experiment is proposed for the assignment of chemical shift resonances, identification of (13)C (1)H connectivities, and proximities of (13)C-(1)H and (1)H-(1)H nuclei under ultrafast magic-angle-spinning (ultrafast-MAS) conditions. Ultrafast-MAS is used to suppress all anisotropic interactions including (1)H-(1)H dipolar couplings, while the finite-pulse radio frequency driven dipolar recoupling (fp-RFDR) pulse sequence is used to recouple dipolar couplings among protons and the insensitive nuclei enhanced by polarization transfer technique is used to transfer magnetization between heteronuclear spins. The 3D experiment eliminates signals from non-carbon-bonded protons and non-proton-bonded carbons to enhance spectral resolution. The 2D (F1/F3) (1)H/(1)H and 2D (13)C/(1)H (F2/F3) chemical shift correlation spectra extracted from the 3D spectrum enable the identification of (1)H-(1)H proximity and (13)C-(1)H connectivity. In addition, the 2D (F1/F2) (1)H/(13)C chemical shift correlation spectrum, incorporated with proton magnetization exchange via the fp-RFDR recoupling of (1)H-(1)H dipolar couplings, enables the measurement of proximities between (13)C and even the remote non carbon-bonded protons. The 3D experiment also gives three-spin proximities of (1)H-(1)H-(13)C chains. Experimental results obtained from powder samples of L alanine and L-histidine ? H2O ? HCl demonstrate the efficiency of the 3D experiment. PMID- 26520505 TI - Analyzing the special PFG signal attenuation behavior of intermolecular MQC via the effective phase shift diffusion equation method. AB - Inter-molecular multiple quantum coherence (iMQC) has important applications in NMR and MRI. However, the current theoretical methods still have some difficulties in analyzing the behavior of iMQC signal attenuation of pulsed field gradient diffusion experiments. In this paper, the iMQC diffusion experiments were analyzed by an effective phase shift diffusion equation (EPSDE) method, which is based on the idea that the accumulating phase shift (APS) can be viewed as the result of a diffusion process in virtual phase space (VPS) with effective diffusion coefficient K(2)(t) D (rad(2)/s) where K(t)=?0 (t)gammag(t')dt' is a wavenumber and D is the physical diffusion coefficient of the spin carrier in the real space. The term K(t(tot)) z1 needs to be added to the APS when K(t(tot)) is not zero. Most of the time, K(t(tot)) equals zero. However, in iMQC experiments, the condition K(t(tot)) equaling zero or being non-zero for each spin depends on the gradient pulse setting. The signal attenuations of these two types of iMQC, zero or non-zero K(t(tot)), were analyzed in detail for free and restricted diffusions, which shows that there are significant differences between these two types of iMQC. Particularly, if an apparent diffusion coefficient D(app) is used to analyze the signal attenuation, it equals nD for zero K(t(tot)) which agrees with current theoretical and experimental reports, while for non-zero K(t(tot)), it equals (2n - 1) D which agrees with experimental results from the literature; there are no similar theoretical results reported for comparison. The result that D(app) equals (2n - 1) D is important because the higher value of D(app) means that non-zero K(t(tot)) iMQC can potentially provide more contrast and measure slower diffusion rates than zero K(t(tot)) iMQC. The EPSDE method provides a new way to analyze iMQC diffusion experiments. PMID- 26520506 TI - Resolving molecular vibronic structure using high-sensitivity two-dimensional electronic spectroscopy. AB - Coherent multidimensional optical spectroscopy is an emerging technique for resolving structure and ultrafast dynamics of molecules, proteins, semiconductors, and other materials. A current challenge is the quality of kinetics that are examined as a function of waiting time. Inspired by noise suppression methods of transient absorption, here we incorporate shot-by-shot acquisitions and balanced detection into coherent multidimensional optical spectroscopy. We demonstrate that implementing noise-suppression methods in two dimensional electronic spectroscopy not only improves the quality of features in individual spectra but also increases the sensitivity to ultrafast time-dependent changes in the spectral features. Measurements on cresyl violet perchlorate are consistent with the vibronic pattern predicted by theoretical models of a highly displaced harmonic oscillator. The noise-suppression methods should benefit research into coherent electronic dynamics, and they can be adapted to multidimensional spectroscopies across the infrared and ultraviolet frequency ranges. PMID- 26520507 TI - Electronic structure of NSO(-) and SNO(-) anions: Stability, electron affinity, and spectroscopic properties. AB - The low-energy electronic states of NSO anion and its SNO isomeric form for the singlet, triplet, and quintet spin multiplicities have been investigated by accurate ab initio approaches and large atomic basis sets. One-dimensional cuts of the three-dimensional potential energy surfaces (PESs) along selected interatomic distances and bending angles for these states have been calculated to assess the formation and stability of NSO(-) and SNO(-) in the gas phase. Results show that these anions have two low-energy states (X(1)A(') and 1(3)A") that are bound and stable with respect to electron detachment. Owing to the energetic position of the dissociating asymptotes of the neutral and anionic species, several electronic excited states are suggested to be stable with respect to the electron autodetachment process in the long-range parts of the potentials before reaching the molecular region. The nature of the PESs in these regions and their implications and effects on the formation of SNO(-) from atomic and molecular fragments are discussed. This information is essential for a better understanding of the potential role of these species in diverse media. PMID- 26520508 TI - Single impacts of keV fullerene ions on free standing graphene: Emission of ions and electrons from confined volume. AB - We present the first data from individual C60 impacting one to four layer graphene at 25 and 50 keV. Negative secondary ions and electrons emitted in transmission were recorded separately from each impact. The yields for C(n)(-) clusters are above 10% for n <= 4, they oscillate with electron affinities and decrease exponentially with n. The result can be explained with the aid of MD simulation as a post-collision process where sufficient vibrational energy is accumulated around the rim of the impact hole for sputtering of carbon clusters. The ionization probability can be estimated by comparing experimental yields of C(n)(-) with those of C(n)(0) from MD simulation, where it increases exponentially with n. The ionization probability can be approximated with ejecta from a thermally excited (3700 K) rim damped by cluster fragmentation and electron detachment. The experimental electron probability distributions are Poisson-like. On average, three electrons of thermal energies are emitted per impact. The thermal excitation model invoked for C(n)(-) emission can also explain the emission of electrons. The interaction of C60 with graphene is fundamentally different from impacts on 3D targets. A key characteristic is the high degree of ionization of the ejecta. PMID- 26520509 TI - Interpretation of the photoelectron, ultraviolet, and vacuum ultraviolet photoabsorption spectra of bromobenzene by ab initio configuration interaction and DFT computations. AB - New photoelectron, ultraviolet (UV), and vacuum UV (VUV) spectra have been obtained for bromobenzene by synchrotron study with higher sensitivity and resolution than previous work. This, together with use of ab initio calculations with both configuration interaction and time dependent density functional theoretical methods, has led to major advances in interpretation. The VUV spectrum has led to identification of a considerable number of Rydberg states for the first time. The Franck-Condon (FC) analyses including both hot and cold bands lead to identification of the vibrational structure of both ionic and electronically excited states including two Rydberg states. The UV onset has been interpreted in some detail, and an interpretation based on the superposition of FC and Herzberg-Teller contributions has been performed. In a similar way, the 6 eV absorption band which is poorly resolved is analysed in terms of the presence of two pipi* states of (1)A1 (higher oscillator strength) and (1)B2 (lower oscillator strength) symmetries, respectively. The detailed analysis of the vibrational structure of the 2(2)B1 ionic state is particularly challenging, and the best interpretation is based on equation-of-motion-coupled cluster with singles and doubles computations. A number of equilibrium structures of the ionic and singlet excited states show that the molecular structure is less subject to variation than corresponding studies for iodobenzene. The equilibrium structures of the 3b13s and 6b23s (valence shell numbering) Rydberg states have been obtained and compared with the corresponding ionic limit structures. PMID- 26520510 TI - Mid-infrared signatures of hydroxyl containing water clusters: Infrared laser Stark spectroscopy of OH-H2O and OH(D2O)n (n = 1-3). AB - Small water clusters containing a single hydroxyl radical are synthesized in liquid helium droplets. The OH-H2O and OH(D2O)n clusters (n = 1-3) are probed with infrared laser spectroscopy in the vicinity of the hydroxyl radical OH stretch vibration. Experimental band origins are qualitatively consistent with ab initio calculations of the global minimum structures; however, frequency shifts from isolated OH are significantly over-predicted by both B3LYP and MP2 methods. An effective Hamiltonian that accounts for partial quenching of electronic angular momentum is used to analyze Stark spectra of the OH-H2O and OH-D2O binary complexes, revealing a 3.70(5) D permanent electric dipole moment. Computations of the dipole moment are in good agreement with experiment when large-amplitude vibrational averaging is taken into account. Polarization spectroscopy is employed to characterize two vibrational bands assigned to OH(D2O)2, revealing two nearly isoenergetic cyclic isomers that differ in the orientation of the non hydrogen-bonded deuterium atoms relative to the plane of the three oxygen atoms. The dipole moments for these clusters are determined to be approximately 2.5 and 1.8 D for "up-up" and "up-down" structures, respectively. Hydroxyl stretching bands of larger clusters containing three or more D2O molecules are observed shifted approximately 300 cm(-1) to the red of the isolated OH radical. Pressure dependence studies and ab initio calculations imply the presence of multiple cyclic isomers of OH(D2O)3. PMID- 26520511 TI - Roto-translational states of the interstitial molecular hydrogen in silicon: A theoretical study. AB - A theoretical study of the interstitial molecular hydrogen in the silicon single crystal is reported. H2 and Si have been approximated as a rigid object and a static matrix, respectively. A five-dimensional numerical-analytical representation of an ab initio potential energy surface of the system has been constructed. This representation has been used to calculate rotational, translational, and roto-translational energy levels of the interstitial hydrogen, where three levels of theory, 2D, 3D, and 5D were considered. The potential energy surface, the band structure of energy levels, and the roto-translational states obtained are presented together with the symmetry analysis of the roto translational wavefunctions. PMID- 26520512 TI - The stereo-dynamics of collisional autoionization of ammonia by helium and neon metastable excited atoms through molecular beam experiments. AB - A combined analysis of both new (energy spectra of emitted electrons) and previously published (ionization cross sections) experimental data, measured under the same conditions and concerning electronically excited lighter noble gas -NH3 collisional autoionization processes, is carried out. Such an analysis, performed by exploiting a formulation of the full potential energy surface both in the real and imaginary parts, provides direct information on energetics, structure, and lifetime of the intermediate collision complex over all the configuration space. The marked anisotropy in the attraction of the real part, driving the approach of reagents, and the selective role of the imaginary component, associated to the charge transfer coupling between entrance and exit channels, suggests that reactive events occur almost exclusively in the molecular hemisphere containing the nitrogen lone pair. Crucial details on the stereo dynamics of elementary collisional autoionization processes are then obtained, in which the open shell nature of the disclosed ionic core of metastable atom plays a crucial role. The same analysis also suggests that the strength of the attraction and the anisotropy of the interaction increases regularly along the series Ne*((3)P), He*((3)S), He*((1)S)-NH3. These findings can be ascribed to the strong rise of the metastable atom electronic polarizability (deformability) along the series. The obtained results can stimulate state of the art ab initio calculations focused on specific features of the transition state (energetics, structure, lifetime, etc.) which can be crucial for a further improvement of the adopted treatment and to better understand the nature of the leading interaction components which are the same responsible for the formation of the intermolecular halogen and hydrogen bond. PMID- 26520513 TI - Observation of hydroxymethyl hydroperoxide in a reaction system containing CH2OO and water vapor through pure rotational spectroscopy. AB - Pure rotational transitions of hydroxymethyl hydroperoxide (HMHP) were observed in the discharged plasma of a CH2I2/O2/water gas mixture, where the water complex with the simplest Criegee intermediate CH2OO has been identified [M. Nakajima and Y. Endo, J. Chem. Phys. 140, 134302 (2014)]. Isotope experiments using heavy water support that the currently observed HMHP molecule was produced by the reaction of CH2OO with water vapor. The observed species was identified as the most stable conformer with the help of quantum chemical calculations. We also clarified that productions of formic acid and dioxirane are promoted by the existence of water vapor in the discharged reaction system. PMID- 26520514 TI - Experimental quantification of decoherence via the Loschmidt echo in a many spin system with scaled dipolar Hamiltonians. AB - We performed Loschmidt echo nuclear magnetic resonance experiments to study decoherence under a scaled dipolar Hamiltonian by means of a symmetrical time reversal pulse sequence denominated Proportionally Refocused Loschmidt (PRL) echo. The many-spin system represented by the protons in polycrystalline adamantane evolves through two steps of evolution characterized by the secular part of the dipolar Hamiltonian, scaled down with a factor |k| and opposite signs. The scaling factor can be varied continuously from 0 to 1/2, giving access to a range of complexity in the dynamics. The experimental results for the Loschmidt echoes showed a spreading of the decay rates that correlate directly to the scaling factors |k|, giving evidence that the decoherence is partially governed by the coherent dynamics. The average Hamiltonian theory was applied to give an insight into the spin dynamics during the pulse sequence. The calculations were performed for every single radio frequency block in contrast to the most widely used form. The first order of the average Hamiltonian numerically computed for an 8-spin system showed decay rates that progressively decrease as the secular dipolar Hamiltonian becomes weaker. Notably, the first order Hamiltonian term neglected by conventional calculations yielded an explanation for the ordering of the experimental decoherence rates. However, there is a strong overall decoherence observed in the experiments which is not reflected by the theoretical results. The fact that the non-inverted terms do not account for this effect is a challenging topic. A number of experiments to further explore the relation of the complete Hamiltonian with this dominant decoherence rate are proposed. PMID- 26520515 TI - Photodissociation of the carbon monoxide dication in the (3)Sigma(-) manifold: Quantum control simulation towards the C(2+) + O channel. AB - The photodissociation and laser assisted dissociation of the carbon monoxide dication X(3)Pi CO(2+) into the (3)Sigma(-) states are investigated. Ab initio electronic structure calculations of the adiabatic potential energy curves, radial nonadiabatic couplings, and dipole moments for the X (3)Pi state are performed for 13 excited (3)Sigma(-) states of CO(2+). The photodissociation cross section, calculated by time-dependent methods, shows that the C(+) + O(+) channels dominate the process in the studied energy range. The carbon monoxide dication CO(2+) is an interesting candidate for control because it can be produced in a single, long lived, v = 0 vibrational state due to the instability of all the other excited vibrational states of the ground (3)Pi electronic state. In a spectral range of about 25 eV, perpendicular transition dipoles couple this (3)Pi state to a manifold of (3)Sigma(-) excited states leading to numerous C(+) + O(+) channels and a single C(2+) + O channel. This unique channel is used as target for control calculations using local control theory. We illustrate the efficiency of this method in order to find a tailored electric field driving the photodissociation in a manifold of strongly interacting electronic states. The selected local pulses are then concatenated in a sequence inspired by the "laser distillation" strategy. Finally, the local pulse is compared with optimal control theory. PMID- 26520516 TI - Expansion Hamiltonian model for a diatomic molecule adsorbed on a surface: Vibrational states of the CO/Cu(100) system including surface vibrations. AB - Molecular-surface studies are often done by assuming a corrugated, static (i.e., rigid) surface. To be able to investigate the effects that vibrations of surface atoms may have on spectra and cross sections, an expansion Hamiltonian model is proposed on the basis of the recently reported [R. Marquardt et al., J. Chem. Phys. 132, 074108 (2010)] SAP potential energy surface (PES), which was built for the CO/Cu(100) system with a rigid surface. In contrast to other molecule-surface coupling models, such as the modified surface oscillator model, the coupling between the adsorbed molecule and the surface atoms is already included in the present expansion SAP-PES model, in which a Taylor expansion around the equilibrium positions of the surface atoms is performed. To test the quality of the Taylor expansion, a direct model, that is avoiding the expansion, is also studied. The latter, however, requests that there is only one movable surface atom included. On the basis of the present expansion and direct models, the effects of a moving top copper atom (the one to which CO is bound) on the energy levels of a bound CO/Cu(100) system are studied. For this purpose, the multiconfiguration time-dependent Hartree calculations are carried out to obtain the vibrational fundamentals and overtones of the CO/Cu(100) system including a movable top copper atom. In order to interpret the results, a simple model consisting of two coupled harmonic oscillators is introduced. From these calculations, the vibrational levels of the CO/Cu(100) system as function of the frequency of the top copper atom are discussed. PMID- 26520517 TI - Absolute NMR shielding scales and nuclear spin-rotation constants in (175)LuX and (197)AuX (X = (19)F, (35)Cl, (79)Br and (127)I). AB - We present nuclear spin-rotation constants, absolute nuclear magnetic resonance (NMR) shielding constants, and shielding spans of all the nuclei in (175)LuX and (197)AuX (X = (19)F, (35)Cl, (79)Br, (127)I), calculated using coupled-cluster singles-and-doubles with a perturbative triples (CCSD(T)) correction theory, four component relativistic density functional theory (relativistic DFT), and non relativistic DFT. The total nuclear spin-rotation constants determined by adding the relativistic corrections obtained from DFT calculations to the CCSD(T) values are in general in agreement with available experimental data, indicating that the computational approach followed in this study allows us to predict reliable results for the unknown spin-rotation constants in these molecules. The total NMR absolute shielding constants are determined for all the nuclei following the same approach as that applied for the nuclear spin-rotation constants. In most of the molecules, relativistic effects significantly change the computed shielding constants, demonstrating that straightforward application of the non-relativistic formula relating the electronic contribution to the nuclear spin-rotation constants and the paramagnetic contribution to the shielding constants does not yield correct results. We also analyze the origin of the unusually large absolute shielding constant and its relativistic correction of gold in AuF compared to the other gold monohalides. PMID- 26520518 TI - Effects of spin-orbit coupling on laser cooling of BeI and MgI. AB - We present the ab initio study of spin-orbit coupling effects on laser cooling of BeI and MgI molecules. Potential energy curves for the X(2)Sigma(+)(1/2), A(2)Pi(1/2,3/2), and 2(2)Pi(3/2,1/2) states are calculated using multi-reference configuration interaction method plus Davidson corrections. Spectroscopic parameters of BeI and MgI are in excellent agreement with available experimental and theoretical values. The A(2)Pi(3/2) state of MgI is a repulsive state. It is an unsuitable scheme for the A(2)Pi(3/2)(upsilon')<- X(2)Sigma(+)(1/2) (upsilon") transition for laser cooling of MgI. Highly diagonally distributed Franck-Condon factors f00 for the A(2)Pi(1/2,3/2) (upsilon' = 0) <- X(2)Sigma(+)(1/2) (upsilon" = 0) transitions and suitable radiative lifetimes tau for the A(2)Pi(1/2,3/2) (upsilon' = 0) of BeI and MgI are obtained. Three laser wavelength drives are required for the A(2)Pi(1/2,3/2)(upsilon')<-X(2)Sigma(+)(1/2) (upsilon") transitions of BeI and MgI. The proposed cooling wavelengths of BeI and MgI are both in the violet region. The results imply the feasibility of laser cooling of BeI and MgI, and that laser cooling of BeI is more possible. PMID- 26520519 TI - Nanocluster ionization energies and work function of aluminum, and their temperature dependence. AB - Ionization threshold energies of Al(n) (n = 32-95) nanoclusters are determined by laser ionization of free neutral metal clusters thermalized to several temperatures in the range from 65 K to 230 K. The photoion yield curves of cold clusters follow a quadratic energy dependence above threshold, in agreement with the Fowler law of surface photoemission. Accurate data collection and analysis procedures make it possible to resolve very small (few parts in a thousand) temperature-induced shifts in the ionization energies. Extrapolation of the data to the bulk limit enables a determination of the thermal shift of the polycrystalline metal work function, found to be in excellent agreement with theoretical prediction based on the influence of thermal expansion. Small clusters display somewhat larger thermal shifts, reflecting their greater susceptibility to thermal expansion. Ionization studies of free size-resolved nanoclusters facilitate understanding of the interplay of surface, electronic, and lattice properties under contamination-free conditions. PMID- 26520520 TI - Interaction of a pseudo-pi C-C bond with cuprous and argentous chlorides: Cyclopropane?CuCl and cyclopropane?AgCl investigated by rotational spectroscopy and ab initio calculations. AB - Strongly bound complexes (CH2)3?MCl (M = Cu or Ag), formed by non-covalent interaction of cyclopropane and either cuprous chloride or argentous chloride, have been generated in the gas phase by means of the laser ablation of either copper or silver metal in the presence of supersonically expanded pulses of a gas mixture containing small amounts of cyclopropane and carbon tetrachloride in a large excess of argon. The rotational spectra of the complexes so formed were detected with a chirped-pulse, Fourier transform microwave spectrometer and analysed to give rotational constants and Cu and Cl nuclear quadrupole coupling constants for eight isotopologues of each of (CH2)3?CuCl and (CH2)3?AgCl. The geometry of each of these complexes was established unambiguously to have C(2v) symmetry, with the three C atoms coplanar, and with the MCl molecule lying along a median of the cyclopropane C3 triangle. This median coincides with the principal inertia axis a in each of the two complexes (CH2)3?MCl. The M atom interacts with the pseudo-pi bond linking the pair of equivalent carbon atoms (F)C (F = front) nearest to it, so that M forms a non-covalent bond to one C-C edge of the cyclopropane molecule. The (CH2)3?MCl complexes have similar angular geometries to those of the hydrogen- and halogen-bonded analogues (CH2)3?HCl and (CH2)3?ClF, respectively. Quantitative details of the geometries were determined by interpretation of the observed rotational constants and gave results in good agreement with those from ab initio calculations carried out at the CCSD(T)(F12*)/aug-cc-pVTZ-F12 level of theory. Interesting geometrical features are the lengthening of the (F)C-(F)C bond and the shrinkage of the two equivalent (B)C-(F)C (B = back) bonds relative to the C-C bond in cyclopropane itself. The expansions of the (F)C-(F)C bond are 0.1024(9) A and 0.0727(17) A in (CH2)3?CuCl and (CH2)3?AgCl, respectively, according to the determined r0 geometries. The C-C bond lengthening is in each case about four times that observed by similar methods in the corresponding complexes of MCl with ethyne and ethene, even though the cyclopropane complexes are more weakly bound than their ethyne and ethene analogues. Reasons for the larger increase in r(CC) in the pseudo-pi complexes are discussed. PMID- 26520521 TI - Revisiting the glass transition and dynamics of supercooled benzene by calorimetric studies. AB - The glass transition and dynamics of benzene are studied in binary mixtures of benzene with five glass forming liquids, which can be divided into three groups: (a) o-terphenyl and m-xylene, (b) N-butyl methacrylate, and (c) N,N dimethylpropionamide and N,N-diethylformamide to represent the weak, moderate, and strong interactions with benzene. The enthalpies of mixing, DeltaH(mix), for the benzene mixtures are measured to show positive or negative signs, with which the validity of the extrapolations of the glass transition temperature T(g) to the benzene-rich regions is examined. The extrapolations for the T(g) data in the mixtures are found to converge around the point of 142 K, producing T(g) of pure benzene. The fragility m of benzene is also evaluated by extrapolating the results of the mixtures, and a fragility m ~ 80 is yielded. The obtained T(g) and m values for benzene allow for the construction of the activation plot in the deeply supercooled region. The poor glass formability of benzene is found to result from the high melting point, which in turn leads to low viscosity in the supercooled liquid. PMID- 26520522 TI - A molecular dynamics simulations study on the relations between dynamical heterogeneity, structural relaxation, and self-diffusion in viscous liquids. AB - We perform molecular dynamics simulations for viscous liquids to study the relations between dynamical heterogeneity, structural (alpha) relaxation, and self-diffusion. For atomistic models of supercooled water, polymer melts, and an ionic liquid, we characterize the space-time characteristics of dynamical heterogeneity by the degree of deviations from Gaussian displacement statistics (alpha2), the size of clusters comprising highly mobile particles (S(w)), and the length of strings consisting of cooperatively moving particles (L(w)). Comparison of our findings with previous simulation results for a large variety of viscous liquids, ranging from monoatomic liquids to silica melt, reveals a nearly universal decoupling between the time scales of maximum non-Gaussian parameter (tau(alpha2)) and the time constant of the alpha relaxation (tau(alpha)) upon cooling, explicitly, tau(alpha2) ?tau(alpha)(3/4). Such uniform relation was not observed between the peak times of S(w) or L(w) and tau(alpha). On the other hand, the temperature-dependent time scale of maximum string length (tau(L)) follows the inverse of the self-diffusion coefficient (D) for various systems at sufficiently low temperatures, i.e., tau(L) ? D(-1). These observations are discussed in view of a breakdown of the Stokes-Einstein relation for the studied systems. It is found that the degree of deviation from this relation is correlated with the stretching of the alpha relaxation. PMID- 26520523 TI - Mechanism of abnormally slow crystal growth of CuZr alloy. AB - Crystal growth of the glass-forming CuZr alloy is shown to be abnormally slow, which suggests a new method to identify the good glass-forming alloys. The crystal growth of elemental Cu, Pd and binary NiAl, CuZr alloys is systematically studied with the aid of molecular dynamics simulations. The temperature dependence of the growth velocity indicates the different growth mechanisms between the elemental and the alloy systems. The high-speed growth featuring the elemental metals is dominated by the non-activated collision between liquid-like atoms and interface, and the low-speed growth for NiAl and CuZr is determined by the diffusion across the interface. We find that, in contrast to Cu, Pd, and NiAl, a strong stress layering arisen from the density and the local order layering forms in front of the liquid-crystal interface of CuZr alloy, which causes a slow diffusion zone. The formation of the slow diffusion zone suppresses the interface moving, resulting in much small growth velocity of CuZr alloy. We provide a direct evidence of this explanation by applying the compressive stress normal to the interface. The compression is shown to boost the stress layering in CuZr significantly, correspondingly enhancing the slow diffusion zone, and eventually slowing down the crystal growth of CuZr alloy immediately. In contrast, the growth of Cu, Pd, and NiAl is increased by the compression because the low diffusion zones in them are never well developed. PMID- 26520524 TI - Correlation between supercooled liquid relaxation and glass Poisson's ratio. AB - We report on a correlation between the supercooled liquid (SL) relaxation and glass Poisson's ratio (v) by comparing the activation energy ratio (r) of the alpha and the slow beta relaxations and the v values for both metallic and nonmetallic glasses. Poisson's ratio v generally increases with an increase in the ratio r and this relation can be described by the empirical function v = 0.5 A*exp(-B*r), where A and B are constants. This correlation might imply that glass plasticity is associated with the competition between the alpha and the slow beta relaxations in SLs. The underlying physics of this correlation lies in the heredity of the structural heterogeneity from liquid to glass. This work gives insights into both the microscopic mechanism of glass deformation through the SL dynamics and the complex structural evolution during liquid-glass transition. PMID- 26520525 TI - Unique effects of thermal and pressure histories on glass hardness: Structural and topological origin. AB - The properties of glass are determined not only by temperature, pressure, and composition, but also by their complete thermal and pressure histories. Here, we show that glasses of identical composition produced through thermal annealing and through quenching from elevated pressure can result in samples with identical density and mean interatomic distances, yet different bond angle distributions, medium-range structures, and, thus, macroscopic properties. We demonstrate that hardness is higher when the density increase is obtained through thermal annealing rather than through pressure-quenching. Molecular dynamics simulations reveal that this arises because pressure-quenching has a larger effect on medium range order, while annealing has a larger effect on short-range structures (sharper bond angle distribution), which ultimately determine hardness according to bond constraint theory. Our work could open a new avenue towards industrially useful glasses that are identical in terms of composition and density, but with differences in thermodynamic, mechanical, and rheological properties due to unique structural characteristics. PMID- 26520526 TI - A comparative study of ibuprofen and ketoprofen glass-forming liquids by molecular dynamics simulations. AB - In this paper, structural and dynamical properties of ibuprofen and ketoprofen glass-forming liquids have been investigated by means of molecular dynamics simulations. Molecular mobility of both materials is analyzed with respect to the different inter-molecular linear/cyclic hydrogen bonding associations. For ibuprofen, the dominant organization is found to be composed of small hydrogen bonding aggregates corresponding to cyclic dimers through the carboxyl group. For ketoprofen, the propensity of cyclic dimers is significantly reduced by the formation of hydrogen bonds with the ketone oxygen of the molecule altering the hydrogen bond (HB) associating structures that can be formed and thus molecular dynamics. The issue of the presence/absence of the peculiar low frequency Debye type process in dielectric relaxation spectroscopy (DRS) data in these materials is addressed. Results obtained from simulations confirm that the Debye process originates from the internal cis-trans conversion of the -COOH carboxyl group. It is shown that the specific intermolecular HB structures associated to a given profen control the main dynamical features of this conversion, in particular its separation from the alpha-process, which make it detectable or not from DRS. For ibuprofen, the possible role of the -CCCO torsion motion, more "local" than the COOH motion since it is less influenced by the intermolecular HBs, is suggested in the microscopic origin of the quite intense secondary gamma-relaxation process detected from DRS. PMID- 26520527 TI - First-principles equation of state and electronic properties of warm dense oxygen. AB - We perform all-electron path integral Monte Carlo (PIMC) and density functional theory molecular dynamics (DFT-MD) calculations to explore warm dense matter states of oxygen. Our simulations cover a wide density-temperature range of 1-100 g cm(-3) and 10(4)-10(9) K. By combining results from PIMC and DFT-MD, we are able to compute pressures and internal energies from first-principles at all temperatures and provide a coherent equation of state. We compare our first principles calculations with analytic equations of state, which tend to agree for temperatures above 8 * 10(6) K. Pair-correlation functions and the electronic density of states reveal an evolving plasma structure and ionization process that is driven by temperature and density. As we increase the density at constant temperature, we find that the ionization fraction of the 1s state decreases while the other electronic states move towards the continuum. Finally, the computed shock Hugoniot curves show an increase in compression as the first and second shells are ionized. PMID- 26520528 TI - Mechanisms for pressure-induced crystal-crystal transition, amorphization, and devitrification of SnI4. AB - The pressure-induced amorphization and subsequent recrystallization of SnI4 have been investigated using first principles molecular dynamics calculations together with high-pressure (119)Sn nuclear resonant inelastic x-ray scattering measurements. Above ~8 GPa, we observe a transformation from an ambient crystalline phase to an intermediate crystal structure and a subsequent recrystallization into a cubic phase at ~64 GPa. The crystalline-to-amorphous transition was identified on the basis of elastic compatibility criteria. The measured tin vibrational density of states shows large amplitude librations of SnI4 under ambient conditions. Although high pressure structures of SnI4 were thought to be determined by random packing of equal-sized spheres, we detected electron charge transfer in each phase. This charge transfer results in a crystal structure packing determined by larger than expected iodine atoms. PMID- 26520529 TI - Free-energy coarse-grained potential for C60. AB - We propose a new deformable free energy method for generating a free-energy coarse-graining potential for C60. Potentials generated from this approach exhibit a strong temperature dependence and produce excellent agreement with benchmark fully atomistic molecular dynamics simulations. Parameter sets for analytical fits to this potential are provided at four different temperatures. PMID- 26520530 TI - Far tails of the density of states in amorphous organic semiconductors. AB - Far tails of the density of state (DOS) are calculated for the simple models of organic amorphous material, the model of dipolar glass and model of quadrupolar glass. It was found that in both models far tails are non-Gaussian. In the dipolar glass model, the DOS is symmetric around zero energy, while for the model of quadrupolar glass, the DOS is generally asymmetric and its asymmetry is directly related to the particular geometry of quadrupoles. Far tails of the DOS are relevant for the quasi-equilibrium transport of the charge carriers at low temperature. Asymmetry of DOS in quadrupolar glasses means a principal inequivalence of the random energy landscape for the transport of electrons and holes. Possible effect of the non-Gaussian shape of the far tails of the DOS on the temperature dependence of carrier drift mobility is discussed. PMID- 26520531 TI - Soret, thermodiffusion, and mean diffusion coefficients of the ternary mixture n dodecane+isobutylbenzene+1,2,3,4-tetrahydronaphthalene. AB - We have investigated thermodiffusion in ternary mixtures of dodecane (nC12), isobutylbenzene (IBB), and 1,2,3,4-tetrahydronaphthalene (THN) by means of two color optical beam deflection over the entire ternary composition space. The Soret and the thermodiffusion coefficients S(T,i)'(c1,c2) and D(T,i)'(c1,c2), respectively, have been determined for all three components i and fitted by smooth approximating polynomials in the independent concentrations c1 (nC12) and c2 (THN). Both the Soret and the thermodiffusion coefficient are negative for nC12 and positive for THN over all compositions. In case of IBB, they change sign, being negative for THN-rich and positive for nC12-rich mixtures. Both the positive and negative signs and the sign change are in agreement with qualitative predictions based on the recently introduced thermophobicity concept [S. Hartmann et al., Phys. Rev. Lett. 109, 065901 (2012); J. Chem. Phys. 141, 134503 (2014)]. For isothermal diffusion, a mean diffusion coefficient D but neither the diffusion matrix nor its eigenvalues could be determined. PMID- 26520533 TI - Bonding and structure in dense multi-component molecular mixtures. AB - We have performed finite-temperature density functional theory molecular dynamics simulations on dense methane, ammonia, and water mixtures (CH4:NH3:H2O) for various compositions and temperatures (2000 K <= T <= 10,000 K) that span a set of possible conditions in the interiors of ice-giant exoplanets. The equation-of state, pair distribution functions, and bond autocorrelation functions (BACF) were used to probe the structure and dynamics of these complex fluids. In particular, an improvement to the choice of the cutoff in the BACF was developed that allowed analysis refinements for density and temperature effects. We note the relative changes in the nature of these systems engendered by variations in the concentration ratios. A basic tenet emerges from all these comparisons that varying the relative amounts of the three heavy components (C,N,O) can effect considerable changes in the nature of the fluid and may in turn have ramifications for the structure and composition of various planetary layers. PMID- 26520532 TI - Excess entropy and crystallization in Stillinger-Weber and Lennard-Jones fluids. AB - Molecular dynamics simulations are used to contrast the supercooling and crystallization behaviour of monatomic liquids that exemplify the transition from simple to anomalous, tetrahedral liquids. As examples of simple fluids, we use the Lennard-Jones (LJ) liquid and a pair-dominated Stillinger-Weber liquid (SW16). As examples of tetrahedral, water-like fluids, we use the Stillinger Weber model with variable tetrahedrality parameterized for germanium (SW20), silicon (SW21), and water (SW(23.15) or mW model). The thermodynamic response functions show clear qualitative differences between simple and water-like liquids. For simple liquids, the compressibility and the heat capacity remain small on isobaric cooling. The tetrahedral liquids in contrast show a very sharp rise in these two response functions as the lower limit of liquid-phase stability is reached. While the thermal expansivity decreases with temperature but never crosses zero in simple liquids, in all three tetrahedral liquids at the studied pressure, there is a temperature of maximum density below which thermal expansivity is negative. In contrast to the thermodynamic response functions, the excess entropy on isobaric cooling does not show qualitatively different features for simple and water-like liquids; however, the slope and curvature of the entropy-temperature plots reflect the heat capacity trends. Two trajectory-based computational estimation methods for the entropy and the heat capacity are compared for possible structural insights into supercooling, with the entropy obtained from thermodynamic integration. The two-phase thermodynamic estimator for the excess entropy proves to be fairly accurate in comparison to the excess entropy values obtained by thermodynamic integration, for all five Lennard-Jones and Stillinger-Weber liquids. The entropy estimator based on the multiparticle correlation expansion that accounts for both pair and triplet correlations, denoted by S(trip), is also studied. S(trip) is a good entropy estimator for liquids where pair and triplet correlations are important such as Ge and Si, but loses accuracy for purely pair-dominated liquids, like LJ fluid, or near the crystallization temperature (T(thr)). Since local tetrahedral order is compatible with both liquid and crystalline states, the reorganisation of tetrahedral liquids is accompanied by a clear rise in the pair, triplet, and thermodynamic contributions to the heat capacity, resulting in the heat capacity anomaly. In contrast, the pair-dominated liquids show increasing dominance of triplet correlations on approaching crystallization but no sharp rise in either the pair or thermodynamic heat capacities. PMID- 26520534 TI - Explicit expressions of self-diffusion coefficient, shear viscosity, and the Stokes-Einstein relation for binary mixtures of Lennard-Jones liquids. AB - Explicit expressions of the self-diffusion coefficient, D(i), and shear viscosity, eta(sv), are presented for Lennard-Jones (LJ) binary mixtures in the liquid states along the saturated vapor line. The variables necessary for the expressions were derived from dimensional analysis of the properties: atomic mass, number density, packing fraction, temperature, and the size and energy parameters used in the LJ potential. The unknown dependence of the properties on each variable was determined by molecular dynamics (MD) calculations for an equimolar mixture of Ar and Kr at the temperature of 140 K and density of 1676 kg m(-3). The scaling equations obtained by multiplying all the single-variable dependences can well express D(i) and eta(sv) evaluated by the MD simulation for a whole range of compositions and temperatures without any significant coupling between the variables. The equation for Di can also explain the dual atomic-mass dependence, i.e., the average-mass and the individual-mass dependence; the latter accounts for the "isotope effect" on Di. The Stokes-Einstein (SE) relation obtained from these equations is fully consistent with the SE relation for pure LJ liquids and that for infinitely dilute solutions. The main differences from the original SE relation are the presence of dependence on the individual mass and on the individual energy parameter. In addition, the packing-fraction dependence turned out to bridge another gap between the present and original SE relations as well as unifying the SE relation between pure liquids and infinitely dilute solutions. PMID- 26520535 TI - Tensorial analysis of Eshelby stresses in 3D supercooled liquids. AB - It was recently proposed that the local rearrangements governing relaxation in supercooled liquids impress on the liquid medium long-ranged (Eshelby) stress fluctuations that accumulate over time. From this viewpoint, events must be characterized by elastic dipoles, which are second order tensors, and Eshelby fields are expected to show up in stress and stress increment correlations, which are fourth order tensor fields. We construct here an analytical framework that permits analyzing such tensorial correlations in isotropic media in view of accessing Eshelby fields. Two spherical bases are introduced, which correspond to Cartesian and spherical coordinates for tensors. We show how they can be used to decompose stress correlations and thus test such properties as isotropy and power law scalings. Eshelby fields and the predicted stress correlations in an infinite medium are shown to belong to an algebra that can conveniently be described using the spherical tensor bases. Using this formalism, we demonstrate that the inherent stress field of 3D supercooled liquids is power law correlated and carries the signature of Eshelby fields, thus supporting the idea that relaxation events give rise to Eshelby stresses that accumulate over time. PMID- 26520536 TI - Understanding the sensitivity of nucleation free energies: The role of supersaturation and temperature. AB - Simulations are used to investigate the vapor-to-liquid nucleation of water for several different force fields at various sets of physical conditions. The nucleation free energy barrier is found to be extremely sensitive to the force field at the same absolute conditions. However, when the results are compared at the same supersaturation and reduced temperature or the same metastability parameter and reduced temperature, then the differences in the nucleation free energies of the different models are dramatically reduced. This finding suggests that comparisons of experimental data and computational predictions are most meaningful at the same relative conditions and emphasizes the importance of knowing the phase diagram of a given computational model, but such information is usually not available for models where the interaction energy is determined directly from electronic structure calculations. PMID- 26520537 TI - Influence of dimensionality and interface type on optical and electronic properties of CdS/ZnS core-shell nanocrystals--A first-principles study. AB - Semiconducting nanocrystals (NCs) have become one of the leading materials in a variety of applications, mainly due to their size tunable band gap and high intensity emission. Their photoluminescence (PL) properties can be notably improved by capping the nanocrystals with a shell of another semiconductor, making core-shell structures. We focus our study on the CdS/ZnS core-shell nanocrystals that are closely related to extensively studied CdSe/CdS NCs, albeit exhibiting rather different photoluminescence properties. We employ density functional theory to investigate the changes in the electronic and optical properties of these nanocrystals with size, core/shell ratio, and interface structure between the core and the shell. We have found that both the lowest unoccupied eigenstate (LUES) and the highest occupied eigenstate (HOES) wavefunction (WF) are localized in the core of the NCs, with the distribution of the LUES WF being more sensitive to the size and the core/shell ratio. We show that the radiative lifetimes are increasing, and the Coulomb interaction energies decrease with increasing NC size. Furthermore, we investigated the electronic and optical properties of the NCs with different interfaces between the core and the shell and different core types. We find that the different interfaces and core types have rather small influence on the band gaps and the absorption indexes, as well as on the confinement of the HOES and LUES WFs. Also the radiative lifetimes are found to be only slightly influenced by the different structural models. In addition, we compare these results with the previous results for CdSe/CdS NCs, reflecting the different PL properties of these two types of NCs. We argue that the difference in their Coulomb interaction energies is one of the main reasons for their distinct PL properties. PMID- 26520538 TI - Thin film lubrication of hexadecane confined by iron and iron oxide surfaces: A crucial role of surface structure. AB - A comparative analysis of thin film lubrication of hexadecane between different iron and its oxide surfaces has been carried out using classical molecular dynamic simulation. An ab initio force-field, COMPASS, was applied for n hexadecane using explicit atom model. An effective potential derived from density functional theory calculation was utilized for the interfacial interaction between hexadecane and the tribo-surfaces. A quantitative surface parameterization was introduced to investigate the influence of surface properties on the structure, rheological properties, and tribological performance of the lubricant. The results show that although the wall-fluid attraction of hexadecane on pure iron surfaces is significantly stronger than its oxides, there is a considerable reduction of shear stress of confined n-hexadecane film between Fe(100) and Fe(110) surfaces compared with FeO(110), FeO(111), Fe2O3(001), and Fe2O3(012). It was found that, in thin film lubrication of hexadecane between smooth iron and iron oxide surfaces, the surface corrugation plays a role more important than the wall-fluid adhesion strength. PMID- 26520539 TI - A three dimensional integral equation approach for fluids under confinement: Argon in zeolites. AB - In this work, we explore the ability of an inhomogeneous integral equation approach to provide a full three dimensional description of simple fluids under conditions of confinement in porous media. Explicitly, we will consider the case of argon adsorbed into silicalite-1, silicalite-2, and an all-silica analogue of faujasite, with a porous structure composed of linear (and zig-zag in the case of silicalite-1) channels of 5-8 A diameter. The equation is based on the three dimensional Ornstein-Zernike approximation proposed by Beglov and Roux [J. Chem. Phys. 103, 360 (1995)] in combination with the use of an approximate fluid-fluid direct correlation function furnished by the replica Ornstein-Zernike equation with a hypernetted chain closure. Comparison with the results of grand canonical Monte Carlo/molecular dynamics simulations evidences that the theory provides an accurate description for the three dimensional density distribution of the adsorbed fluid, both at the level of density profiles and bidimensional density maps across representative sections of the porous material. In the case of very tight confinement (silicalite-1 and silicalite-2), solutions at low temperatures could not be found due to convergence difficulties, but for faujasite, which presents substantially larger channels, temperatures as low as 77 K are accessible to the integral equation. The overall results indicate that the theoretical approximation can be an excellent tool to characterize the microscopic adsorption behavior of porous materials. PMID- 26520540 TI - Trapping and desorption of complex organic molecules in water at 20 K. AB - The formation, chemical, and thermal processing of complex organic molecules (COMs) is currently a topic of much interest in interstellar chemistry. The isomers glycolaldehyde, methyl formate, and acetic acid are particularly important because of their role as pre-biotic species. It is becoming increasingly clear that many COMs are formed within interstellar ices which are dominated by water. Hence, the interaction of these species with water ice is crucially important in dictating their behaviour. Here, we present the first detailed comparative study of the adsorption and thermal processing of glycolaldehyde, methyl formate, and acetic acid adsorbed on and in water ices at astrophysically relevant temperatures (20 K). We show that the functional group of the isomer dictates the strength of interaction with water ice, and hence the resulting desorption and trapping behaviour. Furthermore, the strength of this interaction directly affects the crystallization of water, which in turn affects the desorption behaviour. Our detailed coverage and composition dependent data allow us to categorize the desorption behaviour of the three isomers on the basis of the strength of intermolecular and intramolecular interactions, as well as the natural sublimation temperature of the molecule. This categorization is extended to other C, H, and O containing molecules in order to predict and describe the desorption behaviour of COMs from interstellar ices. PMID- 26520541 TI - Quantum and classical dynamics of water dissociation on Ni(111): A test of the site-averaging model in dissociative chemisorption of polyatomic molecules. AB - Recently, we reported the first highly accurate nine-dimensional global potential energy surface (PES) for water interacting with a rigid Ni(111) surface, built on a large number of density functional theory points [B. Jiang and H. Guo, Phys. Rev. Lett. 114, 166101 (2015)]. Here, we investigate site-specific reaction probabilities on this PES using a quasi-seven-dimensional quantum dynamical model. It is shown that the site-specific reactivity is largely controlled by the topography of the PES instead of the barrier height alone, underscoring the importance of multidimensional dynamics. In addition, the full-dimensional dissociation probability is estimated by averaging fixed-site reaction probabilities with appropriate weights. To validate this model and gain insights into the dynamics, additional quasi-classical trajectory calculations in both full and reduced dimensions have also been performed and important dynamical factors such as the steering effect are discussed. PMID- 26520542 TI - Adsorption and diffusion of Ru adatoms on Ru(0001)-supported graphene: Large scale first-principles calculations. AB - Large-scale first-principles density functional theory calculations are performed to investigate the adsorption and diffusion of Ru adatoms on monolayer graphene (G) supported on Ru(0001). The G sheet exhibits a periodic moire-cell superstructure due to lattice mismatch. Within a moire cell, there are three distinct regions: fcc, hcp, and mound, in which the C6-ring center is above a fcc site, a hcp site, and a surface Ru atom of Ru(0001), respectively. The adsorption energy of a Ru adatom is evaluated at specific sites in these distinct regions. We find the strongest binding at an adsorption site above a C atom in the fcc region, next strongest in the hcp region, then the fcc-hcp boundary (ridge) between these regions, and the weakest binding in the mound region. Behavior is similar to that observed from small-unit-cell calculations of Habenicht et al. [Top. Catal. 57, 69 (2014)], which differ from previous large-scale calculations. We determine the minimum-energy path for local diffusion near the center of the fcc region and obtain a local diffusion barrier of ~0.48 eV. We also estimate a significantly lower local diffusion barrier in the ridge region. These barriers and information on the adsorption energy variation facilitate development of a realistic model for the global potential energy surface for Ru adatoms. This in turn enables simulation studies elucidating diffusion-mediated directed-assembly of Ru nanoclusters during deposition of Ru on G/Ru(0001). PMID- 26520543 TI - Thermally driven smoothening of molecular thin films: Structural transitions in n alkane layers studied in real-time. AB - We use thermal annealing to improve smoothness and to increase the lateral size of crystalline islands of n-tetratetracontane (TTC, C44H90) films. With in situ x ray diffraction, we find an optimum temperature range leading to improved texture and crystallinity while avoiding an irreversible phase transition that reduces crystallinity again. We employ real-time optical phase contrast microscopy with sub-nm height resolution to track the diffusion of TTC across monomolecular step edges which causes the unusual smoothing of a molecular thin film during annealing. We show that the lateral island sizes increase by more than one order of magnitude from 0.5 MUm to 10 MUm. This desirable behavior of 2d-Ostwald ripening and smoothing is in contrast to many other organic molecular films where annealing leads to dewetting, roughening, and a pronounced 3d morphology. We rationalize the smoothing behavior with the highly anisotropic attachment energies and low surface energies for TTC. The results are technically relevant for the use of TTC as passivation layer and as gate dielectric in organic field effect transistors. PMID- 26520544 TI - Kinetic analysis of interaction between N atoms and O-covered Ru(0001). AB - Eley-Rideal (ER) reactions involving neutral atoms heavier than hydrogen reacting with adsorbed atoms of similar mass were first observed in recent molecular beam experiments by Zaharia et al. [Phys. Rev. Lett. 113, 053201 (2014)]. Through analysis of two types of measurements, they obtained different estimations for the N-O ER reaction cross section, one of which is unexpectedly high. This was qualitatively accounted for by invoking a secondary effect whereby the presence of N adatoms on the surface acted to "shield" O adatoms from prompt recombinative desorption. We apply a rate equation model that includes two ER processes involving different adsorbed species (N-Oad and N-Nad) and an N-adsorption process to the full-beam exposure subset of the experimental data in order to study the reaction kinetics. Values for the individual reaction cross sections are derived. The measured N2 response can be well described by the model, but it is insufficient to completely describe the NO response. Modeling of different exposures is used to evaluate the qualitative picture presented by Zaharia et al. PMID- 26520545 TI - Kinetics of protein adsorption on gold nanoparticle with variable protein structure and nanoparticle size. AB - The spontaneous protein adsorption on nanomaterial surfaces and the formation of a protein corona around nanoparticles are poorly understood physical phenomena, with high biological relevance. The complexity arises mainly due to the poor knowledge of the structural orientation of the adsorbed proteins onto the nanoparticle surface and difficulties in correlating the protein nanoparticle interaction to the protein corona in real time scale. Here, we provide quantitative insights into the kinetics, number, and binding orientation of a few common blood proteins when they interact with citrate and cetyltriethylammoniumbromide stabilized spherical gold nanoparticles with variable sizes. The kinetics of the protein adsorption was studied experimentally by monitoring the change in hydrodynamic diameter and zeta potential of the nanoparticle-protein complex. To understand the competitive binding of human serum albumin and hemoglobin, time dependent fluorescence quenching was studied using dual fluorophore tags. We have performed molecular docking of three different proteins--human serum albumin, bovine serum albumin, and hemoglobin--on different nanoparticle surfaces to elucidate the possible structural orientation of the adsorbed protein. Our data show that the growth kinetics of a protein corona is exclusively dependent on both protein structure and surface chemistry of the nanoparticles. The study quantitatively suggests that a general physical law of protein adsorption is unlikely to exist as the interaction is unique and specific for a given pair. PMID- 26520546 TI - Many-body ab initio diffusion quantum Monte Carlo applied to the strongly correlated oxide NiO. AB - We present a many-body diffusion quantum Monte Carlo (DMC) study of the bulk and defect properties of NiO. We find excellent agreement with experimental values, within 0.3%, 0.6%, and 3.5% for the lattice constant, cohesive energy, and bulk modulus, respectively. The quasiparticle bandgap was also computed, and the DMC result of 4.72 (0.17) eV compares well with the experimental value of 4.3 eV. Furthermore, DMC calculations of excited states at the L, Z, and the gamma point of the Brillouin zone reveal a flat upper valence band for NiO, in good agreement with Angle Resolved Photoemission Spectroscopy results. To study defect properties, we evaluated the formation energies of the neutral and charged vacancies of oxygen and nickel in NiO. A formation energy of 7.2 (0.15) eV was found for the oxygen vacancy under oxygen rich conditions. For the Ni vacancy, we obtained a formation energy of 3.2 (0.15) eV under Ni rich conditions. These results confirm that NiO occurs as a p-type material with the dominant intrinsic vacancy defect being Ni vacancy. PMID- 26520547 TI - The influence of surface preparation on low temperature HfO2 ALD on InGaAs (001) and (110) surfaces. AB - Current logic devices rely on 3D architectures, such as the tri-gate field effect transistor (finFET), which utilize the (001) and (110) crystal faces simultaneously thus requiring passivation methods for the (110) face in order to ensure a pristine 3D surface prior to further processing. Scanning tunneling microscopy (STM), x-ray photoelectron spectroscopy (XPS), and correlated electrical measurement on MOSCAPs were utilized to compare the effects of a previously developed in situ pre-atomic layer deposition (ALD) surface clean on the InGaAs (001) and (110) surfaces. Ex situ wet cleans are very effective on the (001) surface but not the (110) surface. Capacitance voltage indicated the (001) surface with no buffered oxide etch had a higher C(max) hypothesized to be a result of poor nucleation of HfO2 on the native oxide. An in situ pre-ALD surface clean employing both atomic H and trimethylaluminum (TMA) pre-pulsing, developed by Chobpattana et al. and Carter et al. for the (001) surface, was demonstrated to be effective on the (110) surface for producing low D(it) high C(ox) MOSCAPs. Including TMA in the pre-ALD surface clean resulted in reduction of the magnitude of the interface state capacitance. The XPS studies show the role of atomic H pre pulsing is to remove both carbon and oxygen while STM shows the role of TMA pre pulsing is to eliminate H induced etching. Devices fabricated at 120 degrees C and 300 degrees C were compared. PMID- 26520548 TI - The length distribution of frangible biofilaments. AB - A number of different proteins possess the ability to polymerize into filamentous structures. Certain classes of such assemblies can have key functional roles in the cell, such as providing the structural basis for the cytoskeleton in the case of actin and tubulin, while others are implicated in the development of many pathological conditions, including Alzheimer's and Parkinson's diseases. In general, the fragmentation of such structures changes the total number of filament ends, which act as growth sites, and hence is a key feature of the dynamics of filamentous growth phenomena. In this paper, we present an analytical study of the master equation of breakable filament assembly and derive closed form expressions for the time evolution of the filament length distribution for both open and closed systems with infinite and finite monomer supply, respectively. We use this theoretical framework to analyse experimental data for length distributions of insulin amyloid fibrils and show that our theory allows insights into the microscopic mechanisms of biofilament assembly to be obtained beyond those available from the conventional analysis of filament mass only. PMID- 26520549 TI - Rupture of DNA aptamer: New insights from simulations. AB - Base-pockets (non-complementary base-pairs) in a double-stranded DNA play a crucial role in biological processes. Because of thermal fluctuations, it can lower the stability of DNA, whereas, in case of DNA aptamer, small molecules, e.g., adenosinemonophosphate and adenosinetriphosphate, form additional hydrogen bonds with base-pockets termed as "binding-pockets," which enhance the stability. Using the Langevin dynamics simulations of coarse grained model of DNA followed by atomistic simulations, we investigated the influence of base-pocket and binding-pocket on the stability of DNA aptamer. Striking differences have been reported here for the separation induced by temperature and force, which require further investigation by single molecule experiments. PMID- 26520550 TI - Determination of the effective diffusivity of water in a poly (methyl methacrylate) membrane containing carbon nanotubes using kinetic Monte Carlo simulations. AB - A kinetic Monte Carlo (kMC) simulation algorithm is developed for computing the effective diffusivity of water molecules in a poly(methyl methacrylate) (PMMA) matrix containing carbon nanotubes (CNTs) at several loadings. The simulations are conducted on a cubic lattice to the bonds of which rate constants are assigned governing the elementary jump events of water molecules from one lattice site to another. Lattice sites belonging to PMMA domains of the membrane are assigned different rates than lattice sites belonging to CNT domains. Values of these two rate constants are extracted from available numerical data for water diffusivity within a PMMA matrix and a CNT pre-computed on the basis of independent atomistic molecular dynamics simulations, which show that water diffusivity in CNTs is 3 orders of magnitude faster than in PMMA. Our discrete space, continuum-time kMC simulation results for several PMMA-CNT nanocomposite membranes (characterized by different values of CNT length L and diameter D and by different loadings of the matrix in CNTs) demonstrate that the overall or effective diffusivity, D(eff), of water in the entire polymeric membrane is of the same order of magnitude as its diffusivity in PMMA domains and increases only linearly with the concentration C (vol. %) in nanotubes. For a constant value of the concentration C, D(eff) is found to vary practically linearly also with the CNT aspect ratio L/D. The kMC data allow us to propose a simple bilinear expression for D(eff) as a function of C and L/D that can describe the numerical data for water mobility in the membrane extremely accurately. Additional simulations with two different CNT configurations (completely random versus aligned) show that CNT orientation in the polymeric matrix has only a minor effect on D(eff) (as long as CNTs do not fully penetrate the membrane). We have also extensively analyzed and quantified sublinear (anomalous) diffusive phenomena over small to moderate times and correlated them with the time needed for penetrant water molecules to explore the available large, fast-diffusing CNT pores before Fickian diffusion is reached. PMID- 26520551 TI - Pair interactions in polyelectrolyte-nanoparticle systems: Influence of dielectric inhomogeneities and the partial dissociation of polymers and nanoparticles. AB - We study the effective pair interactions between two charged spherical particles in polyelectrolyte solutions using polymer self-consistent field theory. In a recent study [V. Pryamitsyn and V. Ganesan, Macromolecules 47, 6095 (2015)], we considered a model in which the particles possess fixed charge density, the polymers contain a prespecified amount of dissociated charges and, the dielectric constant of the solution was assumed to be homogeneous in space and independent of the polymer concentration. In this article, we present results extending our earlier model to study situations in which either or both the particle and the polymers possess partially dissociable groups. Additionally, we also consider the case when the dielectric constant of the solution depends on the local concentration of the polymers and when the particle's dielectric constant is lower than that of the solvent. For each case, we quantify the polymer-mediated interactions between the particles as a function of the polymer concentrations and the degree of dissociation of the polymer and particles. Consistent with the results of our previous study, we observe that the polymer-mediated interparticle interactions consist of a short-range attraction and a long-range repulsion. The partial dissociablity of the polymer and particles was seen to have a strong influence on the strength of the repulsive portion of the interactions. Rendering the dielectric permittivity to be inhomogeneous has an even stronger effect on the repulsive interactions and results in changes to the qualitative nature of interactions in some parametric ranges. PMID- 26520552 TI - On the stability of a quasicrystal and its crystalline approximant in a system of hard disks with a soft corona. AB - Using computer simulations, we study the phase behavior of a model system of colloidal hard disks with a diameter sigma and a soft corona of width 1.4sigma. The particles interact with a hard core and a repulsive square-shoulder potential. We calculate the free energy of the random-tiling quasicrystal and its crystalline approximants using the Frenkel-Ladd method. We explicitly account for the configurational entropy associated with the number of distinct configurations of the random-tiling quasicrystal. We map out the phase diagram and find that the random tiling dodecagonal quasicrystal is stabilised by entropy at finite temperatures with respect to the crystalline approximants that we considered, and its stability region seems to extend to zero temperature as the energies of the defect-free quasicrystal and the crystalline approximants are equal within our statistical accuracy. PMID- 26520553 TI - On the hydrodynamics of swimming enzymes. AB - Several recent experiments suggest that rather generally the diffusion of enzymes may be augmented through their activity. We demonstrate that such swimming motility can emerge from the interplay between the enzyme energy landscape and the hydrodynamic coupling of the enzyme to its environment. Swimming thus occurs during the transit time of a transient allosteric change. We estimate the velocity during the transition. The analysis of such a swimming motion suggests the final stroke size is limited by the hydrodynamic size of the enzyme. This limit is quite a bit smaller than the values that can be inferred from the recent experiments. We also show that one proposed explanation of the experiments based on reaction heat effects can be ruled out using an extended hydrodynamic analysis. These results lead us to propose an alternate explanation of the fluorescence correlation measurements. PMID- 26520554 TI - Modelling DNA origami self-assembly at the domain level. AB - We present a modelling framework, and basic model parameterization, for the study of DNA origami folding at the level of DNA domains. Our approach is explicitly kinetic and does not assume a specific folding pathway. The binding of each staple is associated with a free-energy change that depends on staple sequence, the possibility of coaxial stacking with neighbouring domains, and the entropic cost of constraining the scaffold by inserting staple crossovers. A rigorous thermodynamic model is difficult to implement as a result of the complex, multiply connected geometry of the scaffold: we present a solution to this problem for planar origami. Coaxial stacking of helices and entropic terms, particularly when loop closure exponents are taken to be larger than those for ideal chains, introduce interactions between staples. These cooperative interactions lead to the prediction of sharp assembly transitions with notable hysteresis that are consistent with experimental observations. We show that the model reproduces the experimentally observed consequences of reducing staple concentration, accelerated cooling, and absent staples. We also present a simpler methodology that gives consistent results and can be used to study a wider range of systems including non-planar origami. PMID- 26520555 TI - Chiral effects on helicity studied via the energy landscape of short (D, L) alanine peptides. AB - The homochirality of natural amino acids facilitates the formation of regular secondary structures such as alpha-helices and beta-sheets. Here, we study the relationship between chirality and backbone structure for the example of hexa alanine. The most stable stereoisomers are identified through global optimisation. Further, the energy landscape, a database of connected low-energy local minima and transition points, is constructed for various neutral and zwitterionic stereoisomers of hexa-alanine. Three order parameters for partial helicity are applied and metric disconnectivity graphs are presented with partial helicity as a metric. We also apply the Zimm-Bragg model to derive average partial helicities for Ace-(L-Ala)6-NHMe, Ace-(D-Ala-L-Ala)3-NHMe, and Ace-(L Ala)3-(D-Ala)3-NHMe from the database of local minima and compare with previous studies. PMID- 26520556 TI - Note: Cold spectra of the electronic transition A(2)Sigma(+)-X(2)Pi of N2O(+) radical: High resolution analysis of the bands 000-100, 100-100, and 001-101. AB - In this note, three vibrational bands of the electronic transition A(2)Sigma(+) X(2)Pi of the N2O(+) radical (000-100, 100-100, and 001-101) were theoretically analysed. Starting from Hamiltonian models proposed for this kind of molecule, their parameters were calculated using a Levenberg-Marquardt fit procedure in order to reduce the root mean square deviation from the experimental transitions below to 0.01 cm(-1). The main objective of this work is to obtain new and reliable values for rotational constant B" and the spin-orbit interaction parameter A of the analysed vibrational levels of the X(2)Pi electronic state of this molecule. PMID- 26520557 TI - Note: The effect of viscosity on the rate of diffusion-limited association of nanoparticles. AB - In the treatments of diffusion-limited association of suspended nanoparticles, their diffusion coefficients are usually considered to be constant and equal to those given by conventional hydrodynamics for diffusion of single nanoparticles. In reality, according to hydrodynamics, these coefficients depend, however, on the distance between nanoparticles. I show how this dependence can influence the association rate. PMID- 26520558 TI - Comment on "A novel and facile decay path of Criegee intermediates by intramolecular insertion reactions via roaming transition states" [J. Chem. Phys. 142, 124312 (2015)]. AB - We discuss the recent report of a roaming type mechanism for the decomposition of the Criegee intermediate. We show that the predicted barrier height for this new pathway is too low by ~30 kcal/mol owing to an inconsistent use of spin restricted and spin-unrestricted calculations. As a result, this new pathway is not expected to compete significantly with the well-known dioxirane pathways for the decomposition of the Criegee intermediate. PMID- 26520559 TI - Erratum: "Double-walled carbon nanotube array for CO2 and SO2 adsorption" [J. Chem. Phys. 143, 124701 (2015)]. PMID- 26520562 TI - Albumin and depression in elderly stroke survivors: An observational cohort study. AB - BACKGROUND/OBJECTIVES: Post-stroke depression affects approximately one third of stroke survivors. In non-stroke affected populations, depressive symptomatology is associated with hypoalbuminemia. This is also common among stroke survivors and associated with poor outcome and increased mortality. The role of stroke associated hypoalbuminemia in post-stroke depression is not clear. We aimed to explore the relationship between serum albumin and post-stroke depression, as measured 20 months post-stroke. SUBJECTS/METHODS: Observational cohort study of elderly Swedish patients drawn from the 'Gothenburg 70+ Stroke Study' (n=149) and assessed at 20 months after stroke onset. Serum albumin was drawn from venous blood and analysed with gas chromatography/mass spectrometry. Depressive symptomatology was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and functional impairment was assessed using the Barthel Index. RESULTS: Analysis of covariance analysis showed that serum albumin levels were associated with depressive symptoms at 20 months after stroke. Multivariate analysis of covariance showed that disability scores at 3 days were associated with depressive symptoms at 20 months after stroke and after accounting for the age covariate. Stroke survivors were not clinically deficient in serum albumin. CONCLUSIONS: Low serum albumin appears to be associated with depressive symptoms in elderly individuals long term post-stroke. PMID- 26520563 TI - Assessment of Retrograde Coronary Venous Infusion of Mesenchymal Stem Cells Combined with Basic Fibroblast Growth Factor in Canine Myocardial Infarction Using Strain Values Derived from Speckle-Tracking Echocardiography. AB - Speckle-tracking echocardiography was used to assess retrograde coronary venous infusion of mesenchymal stem cells (MSCs) combined with basic fibroblast growth factor (bFGF) in a canine model of acute myocardial infarction (AMI). AMI was induced by ligation of the left anterior descending coronary artery. Coronary venous retroperfusion was performed at 1 wk after AMI. Twenty-eight animals were randomized into four groups: saline, bFGF+saline, saline+MSCs and bFGF+MSCs. Echocardiography was performed before AMI, at 7 d post-AMI and 40 d after retroperfusion. Apoptotic cardiomyocytes in the border zone of the ischemic region were evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling. Vascular endothelial growth factor and factor VIII concentrations were measured by western blotting. The left ventricular end-systolic volume increased significantly, whereas the left ventricular ejection fraction and global and segmental strain values decreased significantly after AMI. After retroperfusion, the strain values of the infarct zone, but not conventional echocardiographic parameters, were significantly different between control and bFGF+MSC groups. Cardiomyocyte apoptosis decreased, whereas vascular endothelial growth factor and factor VIII concentrations were higher in the bFGF+MSC, bFGF and MSC groups. Cardiomyocyte apoptosis was well correlated with the strain values. Although retrograde coronary venous infusion of bFGF and MSCs promoted neo-vascularization of the infarcted myocardium and inhibited apoptosis, there was only a slight strain improvement without a substantial increase in global cardiac functions. PMID- 26520564 TI - Prescription drug misuse and suicidal ideation: Findings from the National Survey on Drug Use and Health. AB - OBJECTIVE: Suicide is one of the leading causes of injury-related mortality in the United States and prior research has identified alcohol and other drug use as a major risk factor. In recent years, prescription drug misuse has become a serious public health issue; however, very little research examines the relationship between prescription drug misuse and suicide or suicidal ideation. METHODS: Using data from the National Survey on Drug Use and Health, the current research examines the relationship between prescription drug misuse and suicidal ideation among adults. Suicidal ideation was measured by asking respondents if they seriously thought about killing themselves in the past 12 months. Prescription drug misuse was defined as use without a prescription or solely for the feeling or experience caused by the drug in the past 12 months. Several multivariable logistic regression models were estimated. RESULTS: Findings show that respondents who report prescription drug misuse in the past year, specifically pain relievers, are more likely to report that they had seriously though about killing themselves. CONCLUSIONS: The current research fills an important gap in the literature by examining the relationship between prescription drug misuse and suicidal ideation. Consistent with the extant literature, prescription drug misuse is significantly associated with suicidal ideation among adults. PMID- 26520565 TI - The evolution of dwarf shrubs in alpine environments: a case study of Alchemilla in Africa. AB - BACKGROUND AND AIMS: Alpine and arctic environments worldwide, including high mountains, are dominated by short-stature woody plants (dwarf shrubs). This conspicuous life form asserts considerable influence on local environmental conditions above the treeline, creating its own microhabitat. This study reconstructs the evolution of dwarf shrubs in Alchemilla in the African tropical alpine environment, where they represent one of the largest clades and are among the most common and abundant plants. METHODS: Different phylogenetic inference methods were used with plastid and nuclear DNA sequence markers, molecular dating (BEAST and RelTime), analyses of diversification rate shifts (MEDUSA and BAMM) and ancestral character and area reconstructions (Mesquite). KEY RESULTS: It is inferred that African Alchemilla species originated following long-distance dispersal to tropical East Africa, but that the evolution of dwarf shrubs occurred in Ethiopia and in tropical East Africa independently. Establishing a timeframe is challenging given inconsistencies in age estimates, but it seems likely that they originated in the Pleistocene, or at the earliest in the late Miocene. The adaptation to alpine-like environments in the form of dwarf shrubs has apparently not led to enhanced diversification rates. Ancestral reconstructions indicate reversals in Alchemilla from plants with a woody base to entirely herbaceous forms, a transition that is rarely reported in angiosperms. CONCLUSIONS: Alchemilla is a clear example of in situ tropical alpine speciation. The dwarf shrub life form typical of African Alchemilla has evolved twice independently, further indicating its selective advantage in these harsh environments. However, it has not influenced diversification, which, although recent, was not rapid. PMID- 26520566 TI - Effects of intracellular products of Bacillus subtilis VSG1 and Lactobacillus plantarum VSG3 on cytokine responses in the head kidney macrophages of Labeo rohita. AB - The efficiency of intracellular products (ICPs) of the probiotics Bacillus subtilis VSG1 and Lactobacillus plantarum VSG3 in stimulating cytokine responses in the head kidney (HK) macrophages of Labeo rohita was investigated. The HK macrophages were incubated with ICPs and lipopolysaccharide (LPS), and the responses of cytokine genes, namely interleukin-10 (IL-10), IL-1beta, IL-12p35, IL-12p40, IL-18, tumour necrosis factor-alpha (TNF-alpha), nuclear factor kappa B (NF-kappaB), cyclo-oxygenase-2 (COX-2), interferon-1 (IFN-1), and IFN-gamma were assessed by quantitative real-time PCR (qRT-PCR) at 2, 6, 12, 24, and 48 h post stimulation (hps). Among the proinflammatory cytokines, a strong increase in the gene expression of IL-1beta and TNF-alpha was displayed mainly at 2-6 hps with ICPs, as compared to that of the positive control (LPS) or the negative control (PBS) (P < 0.05). However, COX-2 and NF-kappaB showed higher expression at 2 and 24 hps, and 6-24 hps with ICPs, respectively. Antiviral cytokines IFN-1 and IFN gamma displayed strong expressions (P < 0.05) at 6-12 hps, and 12-24 hps with ICPs, respectively. Upregulation of the anti-inflammatory cytokine, IL-10, was recorded at 6-24 hps with ICPs, as compared to that controls. Expressions of cell mediated immune factor genes (IL-12p35, IL-12p40, and IL-18) were also significantly upregulated at different time points, except 48 hps, in HK macrophages stimulated with ICPs. Furthermore, enhanced cellular (phagocytic activity and nitroblue tetrazolium assay) and humoral (lysozyme) immune parameters in stimulated cells confirmed the induction of the inflammatory response. Therefore, the results of this in vitro study indicate that the ICPs of B. subtilis VSG1 or L. plantarum VSG3 have great potential for stimulating the cytokine responses in fish, and are thereby potential immunostimulants to fish. Further studies could be conducted to explore its suitability as an adjuvant vaccine in aquaculture. PMID- 26520567 TI - Prevalence and correlates of diagnosed and undiagnosed type 2 diabetes mellitus and pre-diabetes in older adults: Findings from the Irish Longitudinal Study on Ageing (TILDA). AB - AIMS: The prevalence of type 2 diabetes and pre-diabetes has increased rapidly in recent decades and this trend will continue as the global population ages. This study investigates the prevalence of, and factors associated with, diagnosed and undiagnosed type 2 diabetes mellitus and pre-diabetes in older adults in Ireland. METHODS: Cross-sectional data from 5377 men and women aged 50 and over from Wave 1 of the Irish Longitudinal Study on Ageing (TILDA) was analysed. Diagnosed diabetes was defined using self-reported doctors' diagnosis and medications data. Glycated haemoglobin (HbA1c) analysis was used to identify undiagnosed and pre diabetes. Age and sex-specific prevalence estimates were generated. Logistic regression was used to investigate the association between diabetes classification and the demographic, health and lifestyle characteristics of the population. RESULTS: The prevalence of diagnosed and undiagnosed type 2 diabetes was 8.6% (95% confidence interval (CI): 7.6-9.5%) and 0.9% (95% CI: 0.6-1.1%) respectively. Diabetes was more prevalent in men than women and increased with age. The prevalence of pre-diabetes was 5.5% (95% CI: 4.8-6.3%) and increased with age. Diabetes and pre-diabetes were independently associated with male sex, central obesity and a history of hypertension, while undiagnosed diabetes was associated with geographic location and medical costs cover. CONCLUSION: Despite high rates of obesity and other undiagnosed health conditions, the prevalence of undiagnosed and pre-diabetes is relatively low in community-dwelling older adults in Ireland. Addressing lifestyle factors in this population may help to further reduce the prevalence of pre-diabetes and improve outcomes for those with a previous diagnosis. PMID- 26520568 TI - Intracranial control after Cyberknife radiosurgery to the resection bed for large brain metastases. AB - BACKGROUND: Stereotactic radiosurgery (SRS) is an alternative to post-operative whole brain radiation therapy (WBRT) following resection of brain metastases. At our institution, CyberKnife (CK) is considered for local treatment of large cavities >=2 cm. In this study, we aimed to evaluate patterns of failure and characterize patients best suited to treatment with this approach. METHODS: We retrospectively reviewed 30 patients treated with CK to 33 resection cavities >=2 cm between 2011 and 2014. Patterns of intracranial failure were analyzed in 26 patients with post-treatment imaging. Survival was estimated by the Kaplan-Meier method and prognostic factors examined with log-rank test and Cox proportional hazards model. RESULTS: The most frequent histologies were lung (43 %) and breast (20 %). Median treatment volume was 25.1 cm(3) (range 4.7-90.9 cm(3)) and median maximal postoperative cavity diameter was 3.8 cm (range 2.8-6.7). The most common treatment was 30 Gy in 5 fractions prescribed to the 75 % isodose line. Median follow up for the entire cohort was 9.5 months (range 1.0-34.3). Local failure developed in 7 treated cavities (24 %). Neither cavity volume nor CK treatment volume was associated with local failure. Distant brain failure occurred in 20 cases (62 %) at a median of 4.2 months. There were increased rates of distant failure in patients who initially presented with synchronous metastases (p = 0.02). Leptomeningeal carcinomatosis (LMC) developed in 9 cases, (34 %). Salvage WBRT was performed in 5 cases (17 %) at a median of 5.2 months from CK. Median overall survival was 10.1 months from treatment. CONCLUSIONS: This study suggests that adjuvant CK is a reasonable strategy to achieve local control in large resection cavities. Patients with synchronous metastases at the time of CK may be at higher risk for distant brain failure. The majority of cases were spared or delayed WBRT with the use of local CK therapy. PMID- 26520569 TI - Statins induce insulin-degrading enzyme secretion from astrocytes via an autophagy-based unconventional secretory pathway. AB - BACKGROUND: Insulin degrading enzyme (IDE) is a major protease of amyloid beta peptide (Abeta), a prominent toxic protein in Alzheimer's disease (AD) pathogenesis. Previous studies suggested that statins promote IDE secretion; however, the underlying mechanism is unknown, as IDE has no signal sequence. RESULTS: In this study, we found that simvastatin (0.2 MUM for 12 h) induced the degradation of extracellular Abeta40, which depended on IDE secretion from primary astrocytes. In addition, simvastatin increased IDE secretion from astrocytes in a time- and dose-dependent manner. Moreover, simvastatin-mediated IDE secretion was mediated by an autophagy-based unconventional secretory pathway, and autophagic flux regulated simvastatin-mediated IDE secretion. Finally, simvastatin activated autophagy via the LKB1-AMPK-mTOR signaling pathway in astrocytes. CONCLUSIONS: These results demonstrate a novel pathway for statin mediated IDE secretion from astrocytes. Modulation of this pathway could provide a potential therapeutic target for treatment of Abeta pathology by enhancing extracellular clearance of Abeta. PMID- 26520570 TI - Population attributable risks of oral cavity cancer to behavioral and medical risk factors in France: results of a large population-based case-control study, the ICARE study. AB - BACKGROUND: Population attributable risks (PARs) are useful tool to estimate the burden of risk factors in cancer incidence. Few studies estimated the PARs of oral cavity cancer to tobacco smoking alone, alcohol drinking alone and their joint consumption but none performed analysis stratified by subsite, gender or age. Among the suspected risk factors of oral cavity cancer, only PAR to a family history of head and neck cancer was reported in two studies. The purpose of this study was to estimate in France the PARs of oral cavity cancer to several recognized and suspected risk factors, overall and by subsite, gender and age. METHODS: We analysed data from 689 oral cavity cancer cases and 3481 controls included in a population-based case-control study, the ICARE study. Unconditional logistic regression models were used to estimate odds ratios (ORs), PARs and 95% confidence intervals (95% CI). RESULTS: The PARs were 0.3% (95% CI -3.9%; +3.9%) for alcohol alone, 12.7% (6.9%-18.0%) for tobacco alone and 69.9% (64.4%-74.7%) for their joint consumption. PAR to combined alcohol and tobacco consumption was 74% (66.5%-79.9%) in men and 45.4% (32.7%-55.6%) in women. Among suspected risk factors, body mass index 2 years before the interview <25 kg.m(-2), never tea drinking and family history of head and neck cancer explained 35.3% (25.7% 43.6%), 30.3% (14.4%-43.3%) and 5.8% (0.6%-10.8%) of cancer burden, respectively. About 93% (88.3%-95.6%) of oral cavity cancers were explained by all risk factors, 94.3% (88.4%-97.2%) in men and only 74.1% (47.0%-87.3%) in women. CONCLUSION: Our study emphasizes the role of combined tobacco and alcohol consumption in the oral cavity cancer burden in France and gives an indication of the proportion of cases attributable to other risk factors. Most of oral cavity cancers are attributable to concurrent smoking and drinking and would be potentially preventable through smoking or drinking cessation. If the majority of cases are explained by recognized or suspected risk factors in men, a substantial number of cancers in women are probably due to still unexplored factors that remain to be clarified by future studies. PMID- 26520571 TI - Increased pericardial fat accumulation is associated with increased intramyocardial lipid content and duration of highly active antiretroviral therapy exposure in patients infected with human immunodeficiency virus: a 3T cardiovascular magnetic resonance feasibility study. AB - BACKGROUND: The aim of the current study was to examine whether the use of highly active antiretroviral therapy (HAART) in patients with HIV is associated with changes in pericardial fat and myocardial lipid content measured by cardiovascular magnetic resonance (CMR). METHODS: In this prospective case control study, we compared 27 HIV seropositive (+) male subjects receiving HAART to 22 control male subjects without HIV matched for age, ethnicity and body mass index. All participants underwent CMR imaging for determination of pericardial fat [as volume at the level of the origin of the left main coronary artery (LM) and at the right ventricular free wall] and magnetic resonance spectroscopy (MRS) for evaluation of intramyocardial lipid content (% of fat to water in a single voxel at the interventricular septum). All measurements were made by two experienced readers blinded to the clinical history of the study participants. Two-sample t-test, Spearman's correlation coefficient or Pearson's correlation coefficient and multivariable logistic regression were used for statistical analysis. RESULTS: Pericardial fat volume at the level of LM origin was higher in HIV (+) subjects (33.4 cm(3) vs. 27.4 cm(3), p = 0.03). On multivariable analysis adjusted for age, Framingham risk score (FRS) and waist/hip ratio, pericardial fat remained significantly associated to HIV-status (OR 1.09, p = 0.047). For both HIV (+) and HIV (-) subjects, pericardial fat volume showed strong correlation with intramyocardial lipid content (r = 0.58, p < 0.0001) and FRS (r = 0.53, p = 0.0002). Among HIV (+) subjects, pericardial fat was significantly higher in patients with lipo-accumulation (37 cm(3) vs. 27.1 cm(3), p = 0.03) and showed significant correlation with duration of both HIV infection (r = 0.5, p = 0.01) and HAART (r = 0.46, p = 0.02). CONCLUSIONS: Pericardial fat content is increased in HIV (+) subjects on chronic HAART (>5 years), who demonstrate HAART related lipo-accumulation and prolonged HIV duration of infection. Further investigation is warranted to determine whether increased pericardial fat is associated with higher cardiovascular risk leading to premature cardiovascular events in this patient population. PMID- 26520572 TI - Rationale and design of a randomized study of short-term food and cash assistance to improve adherence to antiretroviral therapy among food insecure HIV-infected adults in Tanzania. AB - BACKGROUND: Food insecurity is an important barrier to retention in care and adherence to antiretroviral therapy (ART) among people living with HIV infection (PLHIV). However, there is a lack of rigorous evidence about how to improve food security and HIV-related clinical outcomes. To address this gap, this randomized trial will evaluate three delivery models for short-term food and nutrition support for food insecure PLHIV in Shinyanga, Tanzania: nutrition assessment and counseling (NAC) alone, NAC plus food assistance, and NAC plus cash transfers. METHODS/DESIGN: At three HIV care and treatment sites, 788 participants will be randomized into one of three study arms in a 3:3:1 ratio, stratified by site: NAC plus food assistance, NAC plus cash transfer, and NAC only. Eligible participants are: 1) at least 18 years of age; 2) living with HIV infection; 3) initiated ART in the past 90 days; and 4) food insecure, as measured with the Household Hunger Scale. PLHIV who are severely malnourished (body mass index (BMI) < 16 kg/m(2)) will be excluded. Participants randomized to receive food or cash transfers are eligible to receive assistance for up to six months, conditional on attending regularly scheduled visits with their HIV care provider. Participants will be followed for 12 months: the initial 6-month intervention period and then for another 6 months post-intervention. The primary outcome is ART adherence measured with the medication possession ratio. Secondary outcomes include 1) retention in care; 2) nutritional indicators including changes in food security, BMI, and weight gain; 3) viral suppression and self-reported ART adherence; and 4) participation in the labor force. DISCUSSION: This rigorously designed trial will inform policy decisions regarding supportive strategies for food insecure PLHIV in the early stages of treatment. The study will measure outcomes immediately after the period of support ends as well as 6 months later, providing information on the duration of the interventions' effect. The comparison of food to cash transfers will better inform policies favoring cash assistance or will provide rationale for the continued investment in food and nutrition interventions for PLHIV. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01957917. PMID- 26520573 TI - Self-Reported Prevalence of Alcohol Screening Among U.S. Adults. AB - INTRODUCTION: The U.S. Preventive Services Task Force recommends for adults alcohol screening and brief behavioral counseling interventions in primary care settings. However, there is a paucity of population-based data on the prevalence of alcohol screening. This study examines adherence to this U.S. Preventive Services Task Force recommendation by estimating the prevalence of alcohol screening by demographic characteristics and binge drinking. METHODS: A cross sectional analysis was conducted in 2013 and 2014 on data from the 2013 fall wave of the ConsumerStyles survey. ConsumerStyles is drawn from an Internet panel randomly recruited by probability-based sampling to be representative of the U.S. POPULATION: Data from 2,592 adult respondents who visited primary care physicians in the last year were analyzed to determine the prevalence of alcohol screening. RESULTS: Only 24.7% of respondents reported receiving alcohol screening. The prevalence of screening was similar among women (24.9%) and men (24.5%). Black non-Hispanics reported a significantly lower prevalence of screening than white non-Hispanics (16.2% vs 26.9%, prevalence ratio=0.60, 95% CI=0.40, 0.90). College graduates reported a significantly higher prevalence of screening than respondents with a high school degree or less (28.1% vs 20.8%, prevalence ratio=1.35, 95% CI=1.08, 1.69). CONCLUSIONS: Only about one in four respondents who visited a primary care physician in the last year reported being screened for alcohol misuse. Therefore, many men and women who misuse alcohol are unlikely to be identified. Increased screening may help reduce alcohol misuse and related negative health outcomes. PMID- 26520574 TI - Validation of a wireless dry electrode system for electroencephalography. AB - BACKGROUND: Electroencephalography (EEG) is a widely used neuroimaging technique with applications in healthcare, research, assessment, treatment, and neurorehabilitation. Conventional EEG systems require extensive setup time, expensive equipment, and expertise to utilize and therefore are often limited to clinical or laboratory settings. Technological advancements have made it possible to develop wireless EEG systems with dry electrodes to reduce many of these barriers. However, due to the lack of homogeneity in hardware, electrode evaluation, and methodological procedures the clinical acceptance of these systems has been limited. METHODS: In this investigation the validity of a wireless dry electrode system compared to a conventional wet electrode system was assessed, while addressing methodological limitations. In Experiment 1, the signal output of both EEG systems was examined at Fz, C3, Cz, C4, and Pz using a conductive head model and generated test signals at 2.5 Hz, 10 Hz, and 39 Hz. In Experiment 2, two-minutes of eyes-closed and eyes-open EEG data was recorded simultaneously with both devices from the adjacent electrode sites in a sample of healthy adults. RESULTS: Between group effects and frequency*device and electrode*device interactions were assessed using a mixed ANOVA for the simulated and in vivo signal output, producing no significant effects . Bivariate correlation coefficients were calculated to assess the relationship between electrode pairs during the simultaneous in vivo recordings, indicating a significant positive relationship (all p's < .05) and larger correlation coefficients (r > +/- 0.5) between the dry and wet electrode signal amplitude were observed for theta, alpha, beta 1, beta 2, beta 3, and gamma in both the eyes-closed and eyes-open conditions. CONCLUSIONS: This report demonstrates preliminary but compelling evidence that EEG data recorded from the wireless dry electrode system is comparable to data recorded from a conventional system. Small correlation values in delta activity were discussed in relation to minor differences in hardware filter settings, variation in electrode placement, and participant artifacts observer during the simultaneous EEG recordings. Study limitations and impact of this research on neurorehabilitation were discussed. PMID- 26520575 TI - Investigation of the mechanisms of Angelica dahurica root extract-induced vasorelaxation in isolated rat aortic rings. AB - BACKGROUND: The root of Angelica dahurica Bentham et Hooker (Umbelliferae) has been used as a traditional medicine for colds, headache, dizziness, toothache, supraorbital pain, nasal congestion, acne, ulcer, carbuncle, and rheumatism in China, Japan, and Korea. Interestingly, it has been used in the treatment of vascular diseases including hypertension. The aim of this study was to provide pharmacological evidence for the anti-hypertensive effect of A. dahurica by investigating the mechanism underlying its vasorelaxant effect. METHODS: The vasorelaxant effects of a 70% methanol extract of the A. dahurica root (ADE) on rat thoracic aorta and its underlying mechanisms were assessed. Isolated rat aortic rings were suspended in organ chambers containing 10 ml Krebs-Henseleit (K H) solution and placed between 2 tungsten stirrups and connected to an isometric force transducer. Changes in tension were recorded via isometric transducers connected to a data acquisition system. RESULTS: ADE causes concentration dependent relaxation in both endothelium-intact and endothelium-denuded aortic rings precontracted with phenylephrine (PE; 1 MUM) or potassium (KCl; 60 mM) in K H solution. And pre-treatment with ADE (1 mg/ml) inhibited calcium-induced vasocontraction of aortic rings induced by PE or KCl. However, ADE pre-treatment did not affect the contraction induced by PE or caffeine in Ca(2+)-free K-H solution. CONCLUSIONS: These results suggested that the ADE has vasorelaxant effect and the vasorelaxant activity is mediated by endothelium-independent pathway that includes the blockade of extracellular calcium influx through the receptor-operated Ca(2+) channel and voltage-dependent calcium channel pathways. PMID- 26520577 TI - Diurnal variation of CD63 expression on activated blood basophils: a pilot study. PMID- 26520576 TI - Trypanosoma cruzi Discret Typing Units (TcII and TcVI) in samples of patients from two municipalities of the Jequitinhonha Valley, MG, Brazil, using two molecular typing strategies. AB - BACKGROUND: Trypanosoma cruzi is classified into six discrete taxonomic units (DTUs). For this classification, different biological markers and classification criteria have been used. The objective was to identify the genetic profile of T. cruzi samples isolated from patients of two municipalities of Jequitinhonha Valley, MG, Brazil. METHODS: Molecular characterization was performed using two different criteria for T. cruzi typing to characterize 63 T. cruzi samples isolated from chronic Chagas disease patients. The characterizations followed two distinct methodologies. Additionally, the RAPD technique was used to evaluate the existence of genetic intragroup variability. RESULTS: The first methodology identified 89% of the samples as TcII, but it was not possible to define the genetic identity of seven isolates. The results obtained with the second methodology corroborated the classification as TcII of the same samples and defined the classification of the other seven as TcVI. RAPD analysis showed lower intra-group variability in TcII. CONCLUSIONS: The results confirmed the preliminary data obtained in other municipalities of the Jequitinhonha Valley, showing a predominance of TcII, similar to that verified in northeast/south axis of Brazil and the first detection of TcVI in the study region. The second protocol was more simple and reliable to identify samples of hybrid character. PMID- 26520578 TI - Venom allergy testing: is a graded approach necessary? AB - BACKGROUND: Many institutions recommend a stepwise approach to intradermal testing for venom allergy. This is costly and uncomfortable for the patient. The rationale for this approach is the risk of potential adverse reactions to testing with the maximal dose alone. OBJECTIVE: To evaluate the safety of a single-step approach to venom allergy testing. METHODS: The authors retrospectively reviewed the charts of 300 consecutive patients with suspected hymenoptera venom allergy based on history who underwent venom allergy testing in a single allergist's clinic where a single-step protocol had been adopted. All patients had positive skin test reaction to at least 1 hymenoptera venom. Charts were reviewed for testing protocol used, results of testing, and reported immediate and delayed adverse reactions to testing. RESULTS: All patients underwent testing with an identical single-step protocol with an intradermal dose of 0.02 mL of a 1.0 MUg/mL concentration of each of the 5 commercially available vespid and bee venoms. Only 1 patient reported an adverse reaction to testing, which was delayed until the morning after his visit. There were no immediate adverse reactions. The patient who had the delayed reaction was successfully started on venom immunotherapy subsequent to his reaction. CONCLUSION: A single-step venom allergy intradermal testing protocol with a 1.0-MUg/mL concentration of commercially available extracts is a safe option, which, if adopted into practice, could lead to more streamlined care for patients and cost savings for the medical system. PMID- 26520579 TI - Evaluation of breath alcohol levels after fluticasone nasal spray. PMID- 26520580 TI - Influence of water storage on fatigue strength of self-etch adhesives. AB - OBJECTIVES: The purpose of this study was to determine enamel and dentin bond durability after long-term water storage using self-etch adhesives. METHODS: Two single step self-etch adhesives (SU, Scotchbond Universal and GB, G-aenial Bond) and a two-step self-etch adhesive (OX, OptiBond XTR) were used. The shear bond strength (SBS) and shear fatigue strength (FS) of the enamel and dentin were obtained with and without phosphoric acid pre-etching prior to application of the adhesives. The specimens were stored in distilled water at 37 degrees C for 24 h, 6 months, and one year. A staircase method was used to determine the FS using a frequency of 10 Hz for 50,000 cycles or until failure occurred. RESULTS: The SBS and FS of enamel bonds were significantly higher with pre-etching, when compared to no pre-etching for the same water storage period. The FS of dentin bonds with pre-etching tended to decrease relative to no pre-etching at the same storage period. For the one year storage period, SU and GB with pre-etching showed significantly lower FS values than the groups without pre-etching. CONCLUSIONS: The influence of water storage on FS of the self-etch adhesives was dependent on the adhesive material, storage period and phosphoric acid pre etching of the bonding site. CLINICAL SIGNIFICANCE: Phosphoric acid pre-etching of enamel improves the effectiveness of self-etch adhesive systems. Inadvertent contact of phosphoric acid on dentin appears to reduce the ability of self-etch adhesives to effectively bond resin composite materials. PMID- 26520581 TI - [A rare cause of cervical swelling in a child: Solitary plexiform neurofibroma]. AB - Plexiform neurofibroma is a rare benign tumor of the peripheral tissue cells developed in the perineurium. Often considered pathognomonic of neurofibromatosis type 1 (NF1 or von Recklinghausen disease), it can be solitary without NF1, especially in children. The diagnosis is essentially pathological and treatment is primarily surgical to avoid malignant degeneration. We report on a case of cervical solitary plexiform neurofibroma discovered in a 9-year-old child. PMID- 26520582 TI - Untangling the effects of tinnitus and hypersensitivity to sound (hyperacusis) in the gap detection test. AB - In recent years, there has been increasing use of the gap detection reflex test to demonstrate induction of tinnitus in animals. Animals with tinnitus show weakened gap detection ability for background noise that matches the pitch of the tinnitus. The usual explanation is that the tinnitus 'fills in the gap'. It has recently been shown, however, that tinnitus is commonly associated with hyperacusis-like enhancements of the acoustic startle response, a change which might potentially alter responses in the gap detection test. We hypothesized that such enhancements could lead to an apparent reduction of gap suppression, resembling that caused by tinnitus, by altering responses to the startle stimulus or the background noise. To test this hypothesis, we compared gap detection abilities in 3 subsets of noise-exposed animals with those in unexposed controls. The results showed that exposed animals demonstrated altered gap detection abilities, but these alterations were sometimes explained as consequences of hyper-responsiveness to either the startle stimulus or to the background noise. Two of the three subsets of animals studied, however, displayed weakened gap detection abilities that could not be explained by enhanced responses to these stimuli or by reduced sound sensitivity or a reduction of temporal processing speed, consistent with the induction of tinnitus. These results demonstrate that not only hearing loss but also changes in sensitivity to background noise or to startle stimuli are potential confounds that, when present, can underlie changes in gap detection irrespective of tinnitus. We discuss how such confounds can be recognized and how they can be avoided. PMID- 26520583 TI - The hidden dysfunction of otolithic organs in patients with profound sensorineural hearing loss. AB - OBJECTIVE: To define the profiles of ocular and cervical vestibular-evoked myogenic potentials (oVEMP and cVEMP, respectively) in patients with profound sensorineural hearing loss (PSHL). METHODS: Twenty-nine patients with PSHL and 20 healthy volunteers were investigated. The patients' medical records were collected and analyzed. The ACS-evoked oVEMPs and cVEMPs and caloric test were tested and analyzed. RESULTS: The oVEMP and cVEMP response rates in the patients with PSHL were 38.9% and 44.4%, respectively, and these values were significantly less than those in the healthy volunteers (both were 100%). Regarding the oVEMPs, significantly higher threshold (p < 0.001) and smaller amplitude (p = 0.022) were observed in the patients. Regarding the cVEMPs, a significant elevation in the threshold (p < 0.001) and a decrease in the amplitude (p = 0.024) were observed, and marked reductions in the P1 (p = 0.002) and N1 latencies (p = 0.001) were observed in the patients. Regarding the caloric test, the ratio of semicircular canal dysfunction in patients with PSHL was significantly higher than that in healthy volunteers (p < 0.001). However, neither the patients nor the doctors noticed balance problems or the loss of otolithic function in the summaries of the medical records of all 29 of the patients. CONCLUSION: The utricular and saccular dysfunction that can be concealed in patients with PSHL can be observed in oVEMPs and cVEMPs. Otolithic function should receive attention in the diagnosis and treatment of PSHL. VEMPs have special value for the observation of hidden dysfunctions of the otolithic organs of patients with PSHL. PMID- 26520584 TI - Immune defense is the primary function associated with the differentially expressed genes in the cochlea following acoustic trauma. AB - Our previous RNA-sequencing analysis of the rat cochlear genes identified multiple biological processes and molecular pathways in the cochlear response to acoustic overstimulation. However, the biological processes and molecular pathways that are common to other species have not been documented. The identification of these common stress processes is pivotal for a better understanding of the essential response of the cochlea to acoustic injury. Here, we compared the RNA-sequencing data collected from mice and rats that sustained a similar, but not identical, acoustic injury. The transcriptome analysis of cochlear genes identified the differentially expressed genes in the mouse and rat samples. Bioinformatics analysis revealed a marked similarity in the changes in the biological processes between the two species, although the differentially expressed genes did not overlap well. The common processes associated with the differentially expressed genes are primarily associated with immunity and inflammation, which include the immune response, response to wounding, the defense response, chemotaxis and inflammatory responses. Moreover, analysis of the molecular pathways showed considerable overlap between the two species. The common pathways include cytokine-cytokine receptor interactions, the chemokine signaling pathway, the Toll-like receptor signaling pathway, and the NOD-like receptor signaling pathway. Further analysis of the transcriptional regulators revealed common upstream regulators of the differentially expressed genes, and these upstream regulators are also functionally related to the immune and inflammatory responses. These results suggest that the immune and inflammatory responses are the essential responses to acoustic overstimulation in the cochlea. PMID- 26520585 TI - Animal models of tinnitus. AB - Presented is a thematic review of animal tinnitus models from a functional perspective. Chronic tinnitus is a persistent subjective sound sensation, emergent typically after hearing loss. Although the sensation is experientially simple, it appears to have central a nervous system substrate of unexpected complexity that includes areas outside of those classically defined as auditory. Over the past 27 years animal models have significantly contributed to understanding tinnitus' complex neurophysiology. In that time, a diversity of models have been developed, each with its own strengths and limitations. None has clearly become a standard. Animal models trace their origin to the 1988 experiments of Jastreboff and colleagues. All subsequent models derive some of their features from those experiments. Common features include behavior-dependent psychophysical determination, acoustic conditions that contrast objective sound and silence, and inclusion of at least one normal-hearing control group. In the present review, animal models have been categorized as either interrogative or reflexive. Interrogative models use emitted behavior under voluntary control to indicate hearing. An example would be pressing a lever to obtain food in the presence of a particular sound. In this type of model animals are interrogated about their auditory sensations, analogous to asking a patient, "What do you hear?" These models require at least some training and motivation management, and reflect the perception of tinnitus. Reflexive models, in contrast, employ acoustic modulation of an auditory reflex, such as the acoustic startle response. An unexpected loud sound will elicit a reflexive motor response from many species, including humans. Although involuntary, acoustic startle can be modified by a lower-level preceding event, including a silent sound gap. Sound-gap modulation of acoustic startle appears to discriminate tinnitus in animals as well as humans, and requires no training or motivational manipulation, but its sensitivity, reliability, mechanism, and optimal implementation are incompletely understood. While to date animal models have significantly expanded the neuroscience of tinnitus, they have been limited to examining sensory features. In the human condition, emotional and cognitive factors are also important. It is not clear that the emotional features of tinnitus can be further understood using animal models, but models may be applied to examine cognitive factors. A recently developed model is described that reveals an interaction between tinnitus and auditory attention. This research suggests that effective tinnitus therapy could rely on modifying attention to the sensation rather than modifying the sensation itself. This article is part of a Special Issue entitled . PMID- 26520586 TI - Sugar activation and glycosylation in Plasmodium. AB - Glycoconjugates are important mediators of host-pathogen interactions and are usually very abundant in the surface of many protozoan parasites. However, in the particular case of Plasmodium species, previous works show that glycosylphosphatidylinositol anchor modifications, and to an unknown extent, a severely truncated N-glycosylation are the only glycosylation processes taking place in the parasite. Nevertheless, a detailed analysis of the parasite genome and the recent identification of the sugar nucleotide precursors biosynthesized by Plasmodium falciparum support a picture in which several overlooked, albeit not very prominent glycosylations may be occurring during the parasite life cycle. In this work, the authors review recent developments in the characterization of the biosynthesis of glycosylation precursors in the parasite, focusing on the outline of the possible fates of these precursors. PMID- 26520587 TI - Beneficial reward-to-risk action of glucosamine during pathogenesis of osteoarthritis. AB - OBJECTIVE: Glucosamine is widely used to improve the symptoms and to delay the structural progression of osteoarthritis. However, its efficacy in osteoarthritis has been controversial and its underlying mechanism of action remains unclear. The aim of this study was to investigate the effects of glucosamine and the underlying mechanisms in human chondrocytes. METHODS: Chondrocytes from normal human articular cartilage were treated with glucosamine (10-100 mM). Subsequently, cell death was analyzed by Annexin V staining and FACS and mitochondrial function was studied by measuring the mitopotential. Peroxisomal function was analyzed by BODIPY staining, and gene expression of PMP70 and acyl CoA oxidase 1, by real-time PCR. Total lipids were analyzed by gas chromatography/mass spectrometry. Autophagy activation was determined by western blotting of beclin and light chain 3B. Autophagosome formation was analyzed by introduction of green fluorescent protein (GFP) LC3, and pexophagy was determined by introduction of mRFP-EGFP-SKL plasmids. RESULTS: Treatment of chondrocytes with glucosamine exerts exposure time-dependent dual effects on apoptosis/autophagy. Short time exposure of glucosamine to chondrocytes activated autophagy, pexophagy, and peroxidation. On the other hand, long time exposure of glucosamine had opposite effects, namely accumulation of very long chain fatty acids and peroxisomal dysfunction. CONCLUSION: We highlight the dual role of glucosamine in apoptosis/autophagy in human chondrocytes depending on exposure time. Although further research is required to fully understand the dual effects of glucosamine, dosage and duration of glucosamine treatment are clear contributing factors towards the line of beneficial reward-to-risk action. PMID- 26520588 TI - A new successful approach to combating vancomycin-resistant enterococcus. PMID- 26520589 TI - Temporal trend in the incidence of pertussis and exposures among healthcare workers: descriptive report from a tertiary care hospital for children in Singapore. PMID- 26520590 TI - Microbiology service centralization: a step too far. PMID- 26520591 TI - The white coat, microbiology service centralization, and combined infection training: what is happening to infection prevention and control? PMID- 26520592 TI - Hygienic interventions to decrease deep sternal wound infections following coronary artery bypass grafting. AB - BACKGROUND: The department of Cardiothoracic Surgery at Uppsala University Hospital has 25 beds in one to four patient rooms and an operating suite consisting of five operating rooms with ultraclean air. Around 700 open heart (250 isolated coronary artery bypass grafting, CABG) operations are performed annually. In 2009, the numbers of deep sternal wound infections (DSWIs) increased to unacceptable rates despite existing hygienic guidelines. AIM: To show how root cause analysis (RCA) followed by quality improvement interventions reduced the rate of DSWI after CABG surgery. METHODS: Only isolated CABG patients requiring surgical revision due to DSWI were included. Swabs and tissue biopsies were taken during surgical revision and analysed with standard methods. DSWIs were registered prospectively according to US Centers for Disease Control and Prevention definitions. RCA for infection was performed between September 2009 and April 2010. Interventions based on results of the RCA and on nationally recommended practices were concluded in April 2010, and thought to have taken full effect by July 1st, 2010. Air was actively sampled at <=0.5m from the sternal incision. FINDINGS: DSWI incidence rates per CABG operations decreased from 5.1% pre intervention to 0.9% post intervention. Wound cultures pre intervention grew Staphylococcus aureus 27.1% and coagulase negative staphylococcus (CoNS) 47.1%, post intervention S. aureus 23.1% and CoNS 30.8%. Air counts did not exceed 5cfu/m(3). CONCLUSION: When the aetiology of an error is multifactorial, RCA engaging both the medical professions and the infection control team is a potential tool to map causes leading to adverse events such as healthcare-associated infections. A systematic quality improvement intervention based on the RCA may reduce the number of deep sternal wound infections after CABG surgery. PMID- 26520593 TI - Analysis of norovirus outbreaks reveals the need for timely and extended microbiological testing. AB - BACKGROUND: Norovirus outbreaks in hospitals remain a substantial threat despite many recommendations for prevention published recently. AIM: To analyse the factors contributing to onset of a norovirus outbreak in hospitals in order to identify new prevention options. METHODS: Data from 71 norovirus outbreaks occurring in five German hospitals between 2002 and 2012 were analysed focusing on the start conditions: the weekday of outbreak, the time span between the first symptomatic cases and the outbreak onset date, the timing of a positive norovirus test result in an outbreak, and presence of concomitant Clostridium difficile infections. FINDINGS: In 68 (96%) outbreaks index cases were identifiable. In 30 of 44 (68%) outbreaks the index case patient acquired norovirus infection in hospital. In 20% of all outbreaks, the index case was a staff member. Nine outbreaks were caused by not isolating contact patients during the incubation time after their exposure to a symptomatic case. Case numbers in norovirus outbreaks were lower when the norovirus test results were available before the outbreak onset (P = 0.028). In 30 of 46 (64%) norovirus outbreaks, C. difficile toxin tests were positive in up to ten patients. Co-infection or subsequent infection with norovirus and C. difficile in single patients occurred in nine (20%) outbreaks. CONCLUSION: Future prevention strategies should focus not only on patients but also on staff. Constant surveillance for new cases of diarrhoea and vomiting and timely adherence to contact precautions for all exposed persons is crucial in outbreak control, as is the need for extended microbiological testing. PMID- 26520594 TI - First outbreak of linezolid-resistant vancomycin-resistant Enterococcus faecium in an Irish hospital, February to September 2014. AB - An outbreak of linezolid-resistant vancomycin-resistant Enterococcus faecium (LRVREfm) occurred in the hepatology ward of a tertiary referral hospital in Ireland between February and September 2014. LRVREfm was isolated from 15 patients; pulsed-field gel electrophoresis confirmed spread of a single clone. This is the first report of an outbreak of linezolid-resistant vancomycin resistant enterococcus in Ireland. PMID- 26520595 TI - Combined infection training - should we be concerned about its impact on infection prevention and control training of microbiologists in the UK? PMID- 26520596 TI - Thermal Bowel Injury During Difficult Laparoscopic Myomectomy. PMID- 26520597 TI - The CROWN Initiative: Journal Editors Invite Researchers to Develop Core Outcomes in Women's Health. PMID- 26520598 TI - Restricting ankle motion via orthotic bracing reduces toe clearance when walking over obstacles. AB - BACKGROUND: When trans-tibial amputees cross obstacles leading with their prosthesis, foot clearance is achieved using compensatory swing-phase kinematics. Such compensation would suggest able-bodied individuals normally use swing-phase ankle dorsiflexion to attain adequate obstacle clearance; however, direct evidence of such contribution is equivocal. This study determined the contribution of sagittal plane ankle motion in achieving lead-limb clearance during obstacle negotiation. METHODS: Twelve male able-bodied individuals (ages 18-30) completed obstacle crossing trials while walking on a flat surface. Lead limb (right) ankle motion was manipulated using a knee-ankle-foot orthosis. Trials were completed with the ankle restricted at a neutral angle or unrestricted (allowing ~+/-15 degrees plantar/dorsiflexion). FINDINGS: Restricted ankle motion caused significant increase in trail-limb foot placement distance before the obstacle (p=0.005); significant decrease in vertical toe clearance (p<0.003), vertical heel clearance (p=0.045), and lead-limb foot placement distance after the obstacle (p=0.045); but no significant changes in knee angle at instant of crossing or in average walking speed. INTERPRETATION: The shifts in foot placements altered the part of swing that the lead-limb was in when the foot crossed the obstacle, which led to a decrease in clearance. These adaptations may have been due to being unable to dorsiflex the ankle to 'lift' the toes in mid-swing or to plantarflex the ankle during initial contact following crossing, which changed how the lead-limb was to be loaded. These findings suggest individuals using ankle bracing or those with ankle arthrodesis, will have reduced gait safety when negotiating obstacles. PMID- 26520599 TI - Measuring emotion regulation and emotional expression in breast cancer patients: A systematic review. AB - The important role of emotion regulation and expression in adaptation to breast cancer is now widely recognized. Studies have shown that optimal emotion regulation strategies, including less constrained emotional expression, are associated with better adaptation. Our objective was to systematically review measures used to assess the way women with breast cancer regulate their emotions. This systematic review was conducted in accordance with PRISMA guidelines. Nine different databases were searched. Data were independently extracted and assessed by two researchers. English-language articles that used at least one instrument to measure strategies to regulate emotions in women with breast cancer were included. Of 679 abstracts identified 59 studies were deemed eligible for inclusion. Studies were coded regarding their objectives, methods, and results. We identified 16 instruments used to measure strategies of emotion regulation and expression. The most frequently employed instrument was the Courtauld Emotional Control Scale. Few psychometric proprieties other than internal consistency were reported for most instruments. Many studies did not include important information regarding descriptive characteristics and psychometric properties of the instruments used. The instruments used tap different aspects of emotion regulation. Specific instruments should be explored further with regard to content, validity, and reliability in the context of breast cancer. PMID- 26520600 TI - [Sexual intercourse debut and associated factors in Mexican students aged 14-19 years in public schools]. AB - OBJECTIVE: To estimate the mean age of sexual intercourse debut (SID) and associated family and individual factors in 14-19-year-olds of both sexes in the 32 states of Mexico in 2007. METHODS: A cross-sectional study was conducted of a representative sample of 9,893 students aged between 14 and 19 years old. The data were collected through a self-administered, anonymous and voluntary questionnaire. Logistic regression models were used to estimate odds ratios (OR) with 95% confidence intervals (95%CI) by category: no SID, SID at 10-15 years and SID at 16-19 years. RESULTS: The national mean age of SID was 16 years, being 15 years for boys (95%CI: 15.88-16.11) and 16 years for girls (95%CI: 15.26-15.42). Factors associated with SID in boys were disadvantaged socioeconomic level (OR=0.66; 95%CI: 0.46-0.94), living with parents (OR=0.65; 95%CI: 0.56-0.75), less offensive communication between parents and boys/girls (OR=0.66; 95%CI: 0.57 0.77), and high social self-esteem (OR=1.68; 95%CI: 1.35-1.77). Factors associated with SID in girls were traditional gender beliefs (OR=0.49; 95%CI: 0.32-0.74), high depressive symptoms (OR=1.88; 95%CI: 1.19-2.99), and high family self-esteem (OR= 0.50; 95%CI: 0.38-0.65). CONCLUSIONS: In Mexico, SID occurred early in boys. In addition, the findings of this study show that in Mexico, the age of SID and associated factors differ in boys and girls. The age of SID is strongly influenced by gender and cultural beliefs. PMID- 26520601 TI - Immune parameters differentiating active from latent tuberculosis infection in humans. AB - Tuberculosis remains a highly prevalent infectious disease worldwide. Identification of the immune parameters that differentiate active disease from latent infection will facilitate the development of efficient control measures as well as new diagnostic modalities for tuberculosis. Here, we investigated the cytokine production profiles of monocytes and CD4(+) T lymphocytes upon encountering mycobacterial antigens. In addition, cytokines and lipid mediators with immune-modulating activities were examined in plasma samples ex vivo. Comparison of these parameters in active tuberculosis patients and healthy subjects with latent infection revealed that, active tuberculosis was associated with diminished Th1-type cytokine secretion from CD4(+) T cells and less augmented inflammatory cytokine secretion from monocytes induced by IFN-gamma than that in latent tuberculosis infection. In addition, a higher plasma concentration of lipoxin A4 and lower ratio of prostaglandin E2 to lipoxin A4 were observed in active cases than in latent infections. These findings have implications for preparing new therapeutic strategies and for differential diagnosis of the two types of tuberculosis infection. PMID- 26520602 TI - [Adrenal pheochromocytoma producing vasoactive intestinal peptide]. PMID- 26520603 TI - [Fast-growing tumor in the chest]. PMID- 26520604 TI - [Cyclosporin-induced thrombotic thrombocytopenic purpura. Report of three cases]. PMID- 26520605 TI - [Transitory rectangular alopecia after endovascular procedure]. PMID- 26520606 TI - [Respiratory failure caused by amyloid myopathy]. PMID- 26520607 TI - [Reply]. PMID- 26520608 TI - [Neonatal lupus syndrome induced by anti-ribonucleoprotein antibodies]. PMID- 26520609 TI - [Early screening and brief intervention in alcohol misuse to improve the treatment of hypertension in primary care]. PMID- 26520610 TI - [Guidelines for the prevention and control of tuberculosis in health care workers]. AB - Tuberculosis remains one of the communicable diseases that cause increased morbidity and mortality worldwide. With an incidence rate of 13,04 per 100,000 population, Spain ranks third among the most affected European countries. These data show a tendency to decrease meaning that it may go unnoticed with the potential to miss the appropriate preventive measures in a suspected case. In centers where patients are treated with tuberculosis, health care worker presents risk of transmission. This risk is higher in some areas or work units. The Occupational health physicians' services, which monitorize the health of health care workers, use different strategies in order to prevent and detect tuberculosis infection. The national guidelines include the tuberculin skin test as a screening test for tuberculosis infection with mention of new diagnostic tests based on the in vitro detection of gamma interferon (IGRA) for certain cases. The purpose of this guide is to establish common criteria for IGRA tests, as a supplementary aid to the tuberculin skin test in health care workers, from the evidence available today. Recommendations for its use have been adapted to the different situations faced by the professionals involved in monitoring the health of health workers. PMID- 26520611 TI - [Infectious arthritis with osteomyelitis due to Scedosporium prolificans in an immunocompetent patient]. PMID- 26520612 TI - [Growth hormone treatment in 2 patients with 22q11.21 deletion syndrome]. PMID- 26520613 TI - [Euthyroid sick syndrome as a risk factor for mortality in critically ill patients]. PMID- 26520614 TI - [Forensic autopsy and clinical autopsy]. PMID- 26520615 TI - A new detailed map of total phosphorus stocks in Australian soil. AB - Accurate data are needed to effectively monitor environmental condition, and develop sound policies to plan for the future. Globally, current estimates of soil total phosphorus (P) stocks are very uncertain because they are derived from sparse data, with large gaps over many areas of the Earth. Here, we derive spatially explicit estimates, and their uncertainty, of the distribution and stock of total P in Australian soil. Data from several sources were harmonized to produce the most comprehensive inventory of total P in soil of the continent. They were used to produce fine spatial resolution continental maps of total P in six depth layers by combining the bootstrap, a decision tree with piecewise regression on environmental variables and geostatistical modelling of residuals. Values of percent total P were predicted at the nodes of a 3-arcsecond (approximately 90 m) grid and mapped together with their uncertainties. We combined these predictions with those for bulk density and mapped the total soil P stock in the 0-30 cm layer over the whole of Australia. The average amount of P in Australian topsoil is estimated to be 0.98 t ha(-1) with 90% confidence limits of 0.2 and 4.2 t ha(-1). The total stock of P in the 0-30 cm layer of soil for the continent is 0.91 Gt with 90% confidence limits of 0.19 and 3.9 Gt. The estimates are the most reliable approximation of the stock of total P in Australian soil to date. They could help improve ecological models, guide the formulation of policy around food and water security, biodiversity and conservation, inform future sampling for inventory, guide the design of monitoring networks, and provide a benchmark against which to assess the impact of changes in land cover, land use and management and climate on soil P stocks and water quality in Australia. PMID- 26520616 TI - Neurodegenerative changes and apoptosis induced by intrauterine and extrauterine exposure of radiofrequency radiation. AB - Adverse health effects of radiofrequency radiation (RFR) on the ongoing developmental stages of children from conception to childhood are scientifically anticipated subject. This study was performed to identify the effects of global system for mobile communications (GSM) modulated mobile phone like RFR in 1800MHz frequency on oxidative DNA damage and lipid peroxidation beside the apoptotic cell formation, using histopathological and immunohistochemical methods in the brain tissue of 1-month-old male and female New Zealand White rabbits that were exposed to these fields at their mother's womb and after the birth. Oxidative DNA damage and lipid peroxidation levels were investigated by measuring the 8-hydroxy 2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) levels, respectively. Histopathological changes were observed using by hematoxylin and eosin (HE) staining. Apoptotic cells were detected in the examined organs by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. For both male and female infants; 8-OHdG levels increased in the group exposed to RFR in both intrauterine and extrauterine periods compared to the infants that were never exposed to RFR and the ones were exposed when they reached one month of age (p<0.05). MDA results were different for male and female rabbits. There was no difference between all female infant groups (p>0.05), while only intrauterine exposure significantly causes MDA level increase for the male infants. HE staining revealed mild lessions in neuronal necrobiosis in brain tissues of female rabbits that had only intaruterine exposure and male rabbits had only extrauterine exposure. Gliosis were mildly positive in brain tissues of rabbits that are exposed only intrauterine period, also the group exposed both intrauterine and extrauterine periods. However, there was no apoptotic change detected by TUNEL staining in the brain tissues of all groups. PMID- 26520617 TI - Oxidative stress of brain and liver is increased by Wi-Fi (2.45GHz) exposure of rats during pregnancy and the development of newborns. AB - An excessive production of reactive oxygen substances (ROS) and reduced antioxidant defence systems resulting from electromagnetic radiation (EMR) exposure may lead to oxidative brain and liver damage and degradation of membranes during pregnancy and development of rat pups. We aimed to investigate the effects of Wi-Fi-induced EMR on the brain and liver antioxidant redox systems in the rat during pregnancy and development. Sixteen pregnant rats and their 48 newborns were equally divided into control and EMR groups. The EMR groups were exposed to 2.45GHz EMR (1h/day for 5 days/week) from pregnancy to 3 weeks of age. Brain cortex and liver samples were taken from the newborns between the first and third weeks. In the EMR groups, lipid peroxidation levels in the brain and liver were increased following EMR exposure; however, the glutathione peroxidase (GSH Px) activity, and vitamin A, vitamin E and beta-carotene concentrations were decreased in the brain and liver. Glutathione (GSH) and vitamin C concentrations in the brain were also lower in the EMR groups than in the controls; however, their concentrations did not change in the liver. In conclusion, Wi-Fi-induced oxidative stress in the brain and liver of developing rats was the result of reduced GSH-Px, GSH and antioxidant vitamin concentrations. Moreover, the brain seemed to be more sensitive to oxidative injury compared to the liver in the development of newborns. PMID- 26520618 TI - Sex disparity in childhood and young adult acute myeloid leukemia (AML) survival: Evidence from US population data. AB - Sex variation has been persistently investigated in studies concerning acute myeloid leukemia (AML) survival outcomes but has not been fully explored among pediatric and young adult AML patients. We detected sex difference in the survival of AML patients diagnosed at ages 0-24 years and explored distinct effects of sex across subgroups of age at diagnosis, race-ethnicity and AML subtypes utilizing the United States Surveillance Epidemiology and End Results (SEER) population based dataset of 4865 patients diagnosed with AML between 1973 and 2012. Kaplan-Meier survival function, propensity scores and stratified Cox proportional hazards regression were used for data analyses. After controlling for other prognostic factors, females showed a significant survival advantage over their male counterparts, adjusted hazard ratio (aHR, 95% confidence interval (CI): 1.09, 1.00-1.18). Compared to females, male patients had substantially increased risk of mortality in the following subgroups of: ages 20-24 years at diagnosis (aHR1.30), Caucasian (1.14), acute promyelocytic leukemia (APL) (1.35), acute erythroid leukemia (AEL) (1.39), AML with inv(16)(p13.1q22) (2.57), AML with minimum differentiation (1.47); and had substantially decreased aHR in AML t(9;11)(p22;q23) (0.57) and AML with maturation (0.82). Overall, females demonstrated increased survival over males and this disparity was considerably large in patients ages 20-24 years at diagnosis, Caucasians, and in AML subtypes of AML inv(16), APL and AEL. In contrast, males with AML t(9;11)(p22;q23), AML with maturation and age at diagnosis of 10-14 years showed survival benefit. Further investigations are needed to detect the biological processes influencing the mechanisms of these interactions. PMID- 26520619 TI - Prevalence of hypercalcemia of malignancy among cancer patients in the UK: analysis of the Clinical Practice Research Datalink database. AB - BACKGROUND: The reported proportion of cancer patients who experience hypercalcemia of malignancy (HCM) ranges between 3% and 30%. HCM can be observed with any type of tumor and occurs most commonly in lung cancer, breast cancer and multiple myeloma. While HCM is a potentially fatal condition, the prevalence of HCM is not well defined. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we identified adult cancer patients with recorded corrected serum calcium (CSC). Hypercalcemic patients (CSC >= 10.8 mg/dL) were classified into 4 CSC levels. We estimated annual prevalence of HCM overall, stratified by cancer type, and in patients with stage IV cancer. RESULTS: Among 37,442 cancer patients in 2003-2012 the prevalence of grade 1 HCM increased from 0.13% to 0.45% and the prevalence of HCM overall (grade 1 or higher) increased from 0.20% to 0.67% over the study period. Prevalence estimates varied across cancer type and were highest for lung cancer, multiple myeloma and patients with stage IV cancer. CONCLUSION: We provide the first systematic analysis using a UK population-based data source to estimate number of cancer patients affected with HCM by grade. The increase in HCM prevalence over the 10-year study period is likely due to the increased recording of laboratory values, particularly comparing more recent data to 2003. Our findings suggest that HCM in general is not a common condition. PMID- 26520620 TI - Black:White disparities in lung cancer mortality in the 50 largest cities in the United States. AB - INTRODUCTION: This paper presents race-specific lung cancer mortality rates and the corresponding rate ratios for the 50 largest U.S. cities for the 5-year intervals 1990-1994 and 2005-2009. METHODS: The 50 largest cities in the U.S. were the units of analysis. Numerator data were abstracted from national death files where the cause was malignant neoplasms of trachea, bronchus, and lung (lung cancer) (ICD-9=162 and ICD-10=C33-C34). Population-based denominators were obtained from the U.S. Census Bureau for 1990, 2000, and 2010. To measure the racial disparity, we calculated non-Hispanic Black:non-Hispanic White rate ratios (RRs) and confidence intervals for each 5-year period. We calculated correlation coefficients for 12 ecological variables and the RRs. RESULTS: At the final time point (2005-2009), 15RRs were less than 1, but only 8 significantly so while 29RRs were greater than 1, 16 of them significantly so. Of the 45 cities included in the analysis, 21 saw an increase in the Black:White RR between the first and second time points. Measures of socioeconomic status (SES) and inequalities therein were found to be associated with the RRs. CONCLUSION: This analysis revealed large disparities in Black:White lung cancer mortality in the U.S. and many of its largest cities during the period 1990-2009. The data demonstrate considerable variation in the degree of disparity across cities, even among cities within the same state. These data can inform and motivate local health officials to implement targeted prevention and treatment strategies where they are needed most, ultimately contributing to a reduction in the disparity in lung cancer mortality rates. PMID- 26520621 TI - Higher prevalence of oral human papillomavirus infection in HIV-positive than HIV negative Thai men and women. AB - OBJECTIVE: This study was designed to investigate the prevalence of oral human papillomavirus (HPV) infection among HIV-positive and HIV-negative Thai men and women. METHODS: Participants including men who have sex with men (MSM) and heterosexual women were enrolled at the Thai Red Cross Anonymous Clinic in Bangkok. History taking and oral examination were performed by three independent dentists after calibration. HPV infection was evaluated from oral rinse with mouthwash collected at the time of examination. HPV typing was performed by PCR and nucleic acid hybridization to detect thirty-seven HPV DNA genotypes using Linear Array((r)) HPV Genotyping Test (Roche Molecular System, Inc.). RESULTS: 244 subjects were enrolled in the study, consisted of 187 HIV-positive (51.9% women and 48.1% MSM) and 57 HIV-negative (21.0% women and 79.0% MSM) Thai subjects. The prevalence of oral HPV infection was 17.2% in HIV-positive subjects whereas only 5.3% of HIV-negative cases had HPV detected in their oral rinses (p=0.0346). Among HIV positive subjects, MSM had higher chance of having HPV infection than females (25% vs. 9.4%, p=0.0074). CONCLUSIONS: HIV-positive Thai MSM and women had higher prevalence of oral HPV infection than those without HIV. PMID- 26520622 TI - Preserved global histone H4 acetylation linked to ETV6-RUNX1 fusion and PAX5 deletions is associated with favorable outcome in pediatric B-cell progenitor acute lymphoblastic leukemia. AB - Epigenetic dysregulation is a hallmark of cancer executed by a number of complex processes the most important of which converge on DNA methylation and histone protein modifications. Epigenetic marks are potentially reversible and thus promising drug targets. In the setting of acute lymphoblastic leukemia (ALL) they have been associated with clinicopathological features including risk of relapse or molecular subgroups of the disease. Here, using immunocytochemistry of bone marrow smears from diagnosis, we studied global histone H4 acetylation, whose loss was previously linked to treatment failure in adults with ALL, in pediatric patients. We demonstrate that preserved global histone H4 acetylation is significantly associated with favorable outcome (RFS, EFS, OS) in children with B cell progenitor (BCP) ALL, recapitulating the findings from adult populations. Further, for the first time we demonstrate differential histone H4 acetylation in molecular subclasses of BCP-ALL including cases with ETV6-RUNX1 fusion gene or PAX5 deletion or deletions in genes linked to B cell development. We conclude global histone H4 acetylation is a prognostic marker and a potential therapeutic target in ALL. PMID- 26520624 TI - Lamotrigine effects on breastfed infants. AB - Lamotrigine is a safe anti-epileptic drug among pregnant and lactating women. Some concerns exist regarding the safety of lamotrigine during breastfeeding and related neonatal complications. In this brief review, this matter was evaluated and discussed. In this review study, the medical literature available in search databases such as Embase, Scopus, PubMed, and Medline and even also local medical search engines were evaluated. The results indicated that lamotrigine is a safe anti-epileptic drug for breastfeeding women with rare and usually mild adverse effects among neonates exposed to high milk concentration of this drug and its metabolites. However, close periodical monitoring for infants whose mothers are utilizing lamotrigine is recommended to decrease the probability of severe side effects among them. PMID- 26520623 TI - Impact of telomere length on survival in classic and variant hairy cell leukemia. AB - Telomeres, which protect the ends of chromosomes, are shortened in several hematologic malignancies, often with adverse prognostic implications, but their effect on prognosis of classic and variant hairy cell leukemia (HCL and HCLv) has not been reported. HCL/HCLv genomic DNA from 46 patients was studied by PCR to determine the ratio of telomere to single copy gene number (T/S). T/S was unrelated to diagnosis of HCL or HCLv (p=0.27), but shorter T/S was associated with unmutated immunoglobulin rearrangements (p=0.033) and age above the median at diagnosis (p=0.017). Low T/S was associated with shorter overall survival from diagnosis (OS), particularly T/S <0.655 (p=0.0064, adjusted p=0.019). Shorter OS was also associated with presence of unmutated (p<0.0001) or IGHV4-34+ (p<0.0001) rearrangements, or increasing age (p=0.0002). Multivariable analysis with Cox modeling showed that short T/S along with either unmutated or IGHV4-34+ rearrangements remained associated with reduced OS (p=0.0071, p=0.0024, respectively) after age adjustment. While T/S is relatively long in HCL and the disease usually indolent with excellent survival, shortened telomeres in HCL/HCLv are associated with decreased survival. Shortened T/S could represent a risk factor needing further investigation/intervention to determine if non chemotherapy treatment options, in addition to or instead of chemotherapy, might be particularly useful. PMID- 26520625 TI - Elevated serum levels of pregnancy-associated plasma protein-A in type 2 diabetics compared to healthy controls: associations with subclinical atherosclerosis parameters. AB - Type 2 diabetes mellitus is associated with increased inflammation and accelerated atherosclerosis. The association of the pro-inflammatory and potentially pro-atherosclerotic molecule, pregnancy associated plasma protein-A (PAPP-A) with diabetes and vascular diseases remains to be further established. A total of 107 patients with type 2 diabetes and 101 healthy controls participated in this study. Serum levels of PAPP-A was measured by Enzyme-linked Immunosorbent Assay (ELISA). We also evaluated the lipid profile, aortic augmentation index, coronary calcium score, ankle brachial index, flow mediated dilation, and carotid intima media thickness. Serum level of PAPP-A was significantly higher in patients with diabetes compared to controls (P<0.001). In the multivariable regression analysis, PAPP-A was positively correlated with diabetes (P<0.001), aortic augmentation index (P=0.021) and was negatively associated with coronary calcification (P=0.050). In conclusion, serum levels of PAPP-A were significantly higher in diabetics compared to healthy controls and correlated with aortic augmentation index and coronary calcification. Our study results suggest that PAPP-A can be a marker of subclinical atherosclerosis in patients with diabetes. PMID- 26520626 TI - Growth inhibition of MDA-MB-231 cell line by peptides designed based on uPA. AB - Interaction between urokinase-type plasminogen activator (uPA) and its receptor (uPAR) plays an important role in the progression of numerous cancer types including breast cancer by promoting tumor initiating, proliferation, invasion and metastasis. Hence, disruption of this interaction inhibits their downstream cascades and subsequently tumor growth. For this, we created two series of 8 and 10 amino acids linear peptides, derived from uPA binding region to target uPAR and studied the inhibition of proliferation in MDA-MB-231 cell line. Results revealed that all of the 10-mer peptides inhibited breast cancer cell proliferation significantly with maximum 40% inhibition of 103 peptides. Meanwhile, none of the 8-mer peptides showed significant toxicity. Current results indicate that the linear 10-mer peptides which mimic a small part of a sequence of a binding domain of uPA to uPAR could be exploited to design a novel class of anti-cancer agents. PMID- 26520627 TI - Diagnostic value of IL-6, CRP, WBC, and absolute neutrophil count to predict serious bacterial infection in febrile infants. AB - Since clinical manifestations of most febrile infants younger than three months old are nonspecific, differentiation of Serious Bacterial Infection (SBI) from self-limiting viral illness is a significant challenge for pediatricians. This study was performed to assess the diagnostic value of white blood cell count (WBC), Absolute Neutrophil Count (ANC), Interleukin -6 (IL-6) and C-reactive protein (CRP) level to predict SBI in febrile infants younger than three months old who were hospitalized. This was a diagnostic test validation study. In this prospective study, 195 febrile infants admitted to 17 Shahrivar Hospital underwent a full sepsis workup including blood, urine, cerebrospinal fluid cultures and chest radiography. WBC count, ANC and CRP and Il-6 level were measured in all patients. Serum IL-6 concentration was measured by Enzyme-linked Immunosorbent Assay test. Then diagnostic, values of these tests for predicting SBI was compared with each other. Of total cases, 112 (57.4%) infants were male. SBI was diagnosed in 29 (14.9%) patients. The most common type of SBI was Urinary Tract Infection (UTI). Serum IL-6 (320pg/dl) had sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 79/1%, 91.6%,75.4%, 60.3%, respectively and for CRP (3 10mg/l) values were 81.6%, 89.8%, 78.2%, and 52%,respectively. The predictive values of CRP and IL-6 were higher than WBC and ANC. IL-6 and CRP are more valid and better diagnostic markers for predicting SBI than WBC count and ANC. CRP level seems to be an accessible and cost-effective marker for early diagnosis of SBI. Since by no marker we can totally rule out SBI in febrile infants < three months of age, it is recommended to administer systemic antibiotics until culture results become available. PMID- 26520628 TI - The effects of two different breastfeeding workshops on improving knowledge, attitude, and practice of participants:a comparative study. AB - Health professionals play crucial roles on the self-confidence of nursing mothers and their knowledge of breastfeeding. The aim of this study was a comparison of two different breastfeeding workshops on participants' knowledge, attitude, practice (KAP) and related factors. A cross-sectional study took place in Fetal and neonatal Research Centre (2011- 2012). The intervention composed of two different training courses in breastfeeding. Two workshops were held during three days in two parts: lectures and practical. Each speech regarded the most important aspects of breastfeeding. In training part, a breastfeeding consultant managed the practical exercises. In the second workshop the lecturers used different methods (didactic, strategies to enhance active involvement, educational devices and so on). A questionnaire was used to evaluate participants' KAP before and after each workshop. Among 40 participants in the first workshop, the average age was 37.78 years old, 32 were midwives-nurses and 8 were GPs-residents. Twenty six had children from which 19 breastfed successfully. Of 27 participants in a second workshop with an average age of 38.59 years, 19 were midwifes-nurses. Fourteen reported having children from which 11 breastfed successfully. Our data showed that both workshops improved participants' KAP scores significantly. No significant differences were seen between two groups' attitude before workshops (P. Value =0.093) but this difference, after the workshop was noticeable (P. Value =0.000). The pertained background factors in changing KAP were: having children, successful breastfeeding experience and age (P. Value< 0.05). In-service breastfeeding training program improves KAP; however, the interactive, practical method is much more effective in changing attitudes of participants. PMID- 26520629 TI - Criteria for evidence-based practice in Iranian traditional medicine. AB - The major difference between Iranian traditional medicine and allopathic medicine is in the application of evidence and documents. In this study, criteria for evidence-based practice in Iranian traditional medicine and its rules of practice were studied. The experts' views were investigated through in- depth, semi-structured interviews and the results were categorized into four main categories including Designing clinical questions/clinical question-based search, critical appraisal, resource search criteria and clinical prescription appraisal. Although the application of evidence in Iranian traditional medicine follows Evidence Based Medicine (EBM) principles but it benefits from its own rules, regulations, and criteria that are compatible with EBM. PMID- 26520630 TI - Changes in leukocyte subpopulations with decline in glomerular filtration rate in patients with type 2 diabetes. AB - Recent studies suggested the role of white blood cells (WBCs) in the pathogenesis and complications of type 2 diabetes. Increased WBC counts predict mortality in patients with chronic kidney disease (CKD). In this study alterations in WBC subpopulations in diabetic patients with non-dialysis dependent CKD are investigated. This was a cross-sectional study on 376 participants, including 272 diabetic patients and 104 healthy controls. Total and differential WBC counts were compared among diabetics with CKD, diabetics without CKD and controls. Among patients with type 2 diabetes, there was no significant difference in total WBC count between those with and without CKD. Diabetic patients with CKD had higher neutrophil, monocyte and eosinophil and lower lymphocyte count compared with both diabetic patients without CKD and healthy controls. Except for monocytes, a significant association was observed between GFR and differential WBC counts, which persisted after adjustment for conventional diabetes riskfactors (R2=0.272, P < 0.001 for regression model). Neutrophil/lymphocyte ratio was the best predictor ofGFR in total study population (beta= -1.995 +/- 0.45, P<0.001). Changes in WBC subpopulations are present even before significant alterations in total WBC count. Immune system dysfunction needs special consideration in diabetic patients with CKD. PMID- 26520632 TI - Unstimulated salivary p53 in patients with oral lichen planus and squamous cell carcinoma. AB - Unstimulated whole salivary p53 was evaluated in non-involved subjects, in patients suffering from oral lichen planus (OLP) and squamous cell carcinoma (SCC). A total of 34 patients with OLP, 24 patients suffering from oral SCC and 41 non-involved participants were enrolled. The unstimulated whole saliva p53 level was assayed by ELISA. Data was analyzed by ANOVA followed by the Tukey post hoc test. Saliva p53 concentration in patients with SCC (5.36+/-1.08) was significantly higher than in healthy participants (0.41+/-0.04) and in patients suffering from OLP (0.94+/-0.31). This study could not confirm the precancerous nature of OLP based on the relatively low p53 expressions in comparison to SCC. PMID- 26520631 TI - Work-related musculoskeletal disorders in truck drivers and official workers. AB - Work-related musculoskeletal disorders (WMSDs) are common among drivers and official workers. Musculoskeletal disorders are frequent causes of absenteeism in many countries. The aim of this study was to determine the prevalence of musculoskeletal disorders and risk factors associated with these symptoms. A total of 346 workers and truck drivers were participated in this case-control study. All the participants were interviewed using a self- administered questionnaire containing demographic data and a Nordic questionnaire about presence site and characteristics of pain. Then the data were gathered, and the prevalence of the mentioned parameters and the relationship between variables in the questionnaire were analyzed statistically. The results of this study revealed that 78.6% out of truck drivers and 55.5% out of official workers had musculoskeletal disorders in on-year and there was a significant difference between two groups in this regard (P<0.001). On the whole, the most common symptoms were neck 47 (27.2%), followed by lumbar pain 42 (24.3%) in truck drivers and knee 63 (36.4%) and lumbar symptom 21 (12.1%) in one-year in official workers. In this study, musculoskeletal disorders showed statistically significant association with work duration, age and BMI (P<0.001). Within the limits of this study, it can be concluded that the musculoskeletal troubles have a high frequency among the drivers and official workers. Both groups usually remain on a prolonged uncomfortable postures and high static muscle load which may imply a risk for development of the troubles. PMID- 26520633 TI - Huge dissected ascending aorta associated with pseudo aneurysm and aortic coarctation feridoun. AB - We report a unique case of chronic dissection of the ascending aorta complicated with huge and thrombotic pseudoaneurysm in a patient with coarctation of descending aorta. Preoperative investigations such as transesophageal echocardiography (TEE) confirmed the diagnosis of dissection. Intraoperative findings included a12 cm eccentric bulge of the right lateral side of dilated the ascending aorta filled with the clot and a circular shaped intimal tear communicating with an extended hematoma and dissection of the media layer. The rarity of the report is an association of the chronic dissection with huge pseudoaneurysm and coarctation. The patient underwent staged repair of an aneurysm and coarctation and had an uneventful postoperative recovery period. PMID- 26520635 TI - Different femoral fixation techniques in reconstruction of anterior cruciate ligament. PMID- 26520634 TI - Primary retroperitoneal hydatid cyst: a rare case report. AB - Hydatid disease is a parasitic tapeworm infestation that usually involves liver and lungs. Primary retroperitoneal hydatid without liver and lung involvement is very rare. Surgery is the principle method of treatment for large retroperitoneal hydatid, whenever feasible. We report a case of primary retroperitoneal hydatid cyst in 29-year-old male patient. PMID- 26520636 TI - Ethnicity or cultural group identity of pregnant women in Sydney, Australia: Is country of birth a reliable proxy measure? AB - BACKGROUND: Australia has one of the most ethnically and culturally diverse maternal populations in the world. Routinely few variables are recorded in clinical data or health research to capture this diversity. This paper explores how pregnant women, Australian-born and overseas-born, respond to survey questions on ethnicity or cultural group identity, and whether country of birth is a reliable proxy measure. METHODS: As part of a larger study, pregnant women attending public antenatal clinics in Sydney, Australia, completed a survey about their knowledge and expectations of pregnancy duration. The survey included two questions on country of birth, and identification with an ethnicity or cultural group. Country of birth data were analysed using frequency tabulations. Responses to ethnicity or cultural group were analysed using inductive coding to identify thematic categories. RESULTS: Among the 762 with 75 individual cultural groups or ethnicities and 68 countries of birth reported. For Australian-born women (n=293), 23% identified with a cultural group or ethnicity, and 77% did not. For overseas-born women (n=469), 44% identified with a cultural group or ethnicity and 56% did not. Responses were coded under five thematic categories. CONCLUSIONS: Ethnicity and cultural group identity are complex concepts; women across and within countries of birth identified differently, indicating country of birth is not a reliable measure. To better understand the identities of the women receiving maternity care, midwives, clinicians and researchers have an ethical responsibility to challenge practices that quantify cultural group or ethnicity, or use country of birth as a convenient proxy measure. PMID- 26520637 TI - Epilepsy, excess deaths and years of life lost from external causes. AB - We systematically quantified excess mortality in epilepsy patients by cause of death using the population-attributable fraction and epilepsy-attributable years of potential life lost (YPLL) by age 75 years at ages 15 and over. We updated and undertook a re-review of mortality studies from our previous systematic review following PRISMA guidelines to identify cohort studies of general epilepsy populations reporting a relative risk (RR) of death by cause relative to the background rates in the population. Studies on epilepsy prevalence were identified through published reviews. Country-specific mortality figures were obtained from the WHO World Mortality Database. We performed a pooled analysis with the DerSimonian-Laird random effects method. In countries with very high Human Development Indices, epilepsy contributed to 0.5-1.1 % of all deaths in the total population. Among external causes, suicides (RR 2.9, 95 % confidence interval 2.2-3.8; I(2) 52 %) were the major contributor to YPLL, corresponding to 6.7 % and 4.2 % of excess YPLL due to epilepsy in the United States (US) and in the United Kingdom (UK) in 2010, with 541 (346-792) and 44 (28-65) excess suicide cases, respectively. Fatal accidental falls were more common, with 813 (610-1064) and 95 (71-125) excess deaths in the US and in the UK, but these caused only 2.0 % of excess YPLL as they occurred in older age groups. Suicides were the most important external cause of death in epilepsy patients in terms of excess YPLL, whereas other external causes were either more common in older ages or caused less excess deaths. PMID- 26520638 TI - The French CONSTANCES population-based cohort: design, inclusion and follow-up. AB - The CONSTANCES general-purpose cohort is intended to serve as an epidemiological research infrastructure accessible to the epidemiologic research community with a focus on occupational and social factors, and on chronic diseases and aging. CONSTANCES will also provide useful public health information to the public health authorities since it was designed as a large representative sample of the general French adult population. CONSTANCES is designed as a randomly selected representative sample of French adults aged 18-69 years at inception; 200,000 subjects will be included over a five-year period. At inclusion, the selected subjects are invited to complete questionnaires and to attend a Health Screening Center (HSC) for a comprehensive health examination. A biobank will be set up. The follow-up includes a yearly self-administered questionnaire, and a periodic visit to an HSC. Social and health data are collected from the French national databases. Data collected for participants include social and demographic characteristics, socioeconomic status, life events, behaviors, and occupational factors. The health data cover a wide spectrum: self-reported health scales, reported prevalent and incident diseases, long-term chronic diseases and hospitalizations, sick-leaves, handicaps, limitations, disabilities and injuries, healthcare utilization and services provided, and causes of death. To take into account non-participation at inclusion and attrition throughout the longitudinal follow-up, a cohort of non-participants was set up and will be followed through the same national databases as participants. Inclusion begun at the end of 2012 and more than 82,000 were already included by September 2015. A public call for nested research projects was launched. PMID- 26520639 TI - Childhood cancer and residential exposure to highways: a nationwide cohort study. AB - Children living near highways are exposed to higher concentrations of traffic related carcinogenic pollutants. Several studies reported an increased risk of childhood cancer associated with traffic exposure, but the published evidence is inconclusive. We investigated whether cancer risk is associated with proximity of residence to highways in a nation-wide cohort study including all children aged <16 years from Swiss national censuses in 1990 and 2000. Cancer incidence was investigated in time to event analyses (1990-2008) using Cox proportional hazards models and incidence density analyses (1985-2008) using Poisson regression. Adjustments were made for socio-economic factors, ionising background radiation and electromagnetic fields. In time to event analysis based on 532 cases the adjusted hazard ratio for leukaemia comparing children living <100 m from a highway with unexposed children (>=500 m) was 1.43 (95 % CI 0.79, 2.61). Results were similar in incidence density analysis including 1367 leukaemia cases (incidence rate ratio (IRR) 1.57; 95 % CI 1.09, 2.25). Associations were similar for acute lymphoblastic leukaemia (IRR 1.64; 95 % CI 1.10, 2.43) and stronger for leukaemia in children aged <5 years (IRR 1.92; 95 % CI 1.22, 3.04). Little evidence of association was found for other tumours. Our study suggests that young children living close to highways are at increased risk of developing leukaemia. PMID- 26520640 TI - Survival but not brain metastasis response relates to lung cancer mutation status after radiosurgery. AB - We prospectively addressed whether EGFR and KRAS mutations, EML4-ALK, ROS1 and RET rearrangements, or wild-type (WT), affects radiosurgery outcomes and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Of 326 patients with BM treated in 2012-2014 with Gamma Knife radiosurgery (GKRS), 112 NSCLC patients received GKRS as their initial intracranial treatment. OS, intracranial progression-free survival, and time to intracranial failure were determined. Univariate and multivariate analysis were performed to determine factors affecting OS. Toxicity of treatment was evaluated. Median follow-up was 9 months. Patients with EGFR mutant BM had improved survival compared to WT. Median time to development of BM was higher in EGFR mutant patients, but this difference was not significant (2.2 vs 0.9 months; p = 0.2). Median time to distant brain failure was independent of EGFR mutation status. Karnofsky performance status (KPS), non-squamous histopathology, targeted therapy, systemic disease control, EGFR mutation, and low tumor volume were predictive of increased OS on univariate analysis. KPS (p = 0.001) and non squamous histopathology (p = 0.03) continued to be significant on multivariate analysis. Patients with EGFR mutant BM underwent salvage treatment more often than those without (p = 0.04). Treatment-related toxicity was no different in patients treated with GKRS combined with targeted therapies versus GKRS alone (5 vs 7%, p = 0.7). Patients with EGFR mutant BM had improved survival compared to a WT cohort. Intracranial disease control following radiosurgery was similar for all tumor subtypes. Radiosurgery is effective for BM and concurrent treatment with targeted therapy appears to be safe. PMID- 26520641 TI - Efficacy and Safety of 308-nm Monochromatic Excimer Lamp Versus Other Phototherapy Devices for Vitiligo: A Systematic Review with Meta-Analysis. AB - BACKGROUND: Various phototherapy methods are used to treat vitiligo; however, the recent emergence of new devices has heightened debate concerning the best treatment method. OBJECTIVE: We aimed to systematically review and meta-analyze published data comparing the efficacy and adverse effects of monochromatic excimer lamps versus excimer laser and narrowband ultraviolet B (NB-UVB) in treating vitiligo. METHODS: A systematic search of PubMed, EMBASE, LILACS, Cochrane Central Register of Controlled Trials (CENTRAL), and clinical trials registries identified randomized controlled trials that included vitiligo patients, regardless of age, sex, or study language. We evaluated studies comparing excimer lamps with excimer laser or NB-UVB phototherapy. RESULTS: The review included six studies (411 patients, 764 lesions). No study found significantly different efficacy between excimer lamps and excimer laser using the outcomes of >=50% repigmentation [risk ratio (RR) = 0.97, 95% confidence interval (CI) 0.84-1.11] and >=75% repigmentation (RR = 0.96, 95% CI 0.71-1.30). Likewise, no study found significant differences between excimer lamps and NB-UVB (RR = 1.14, 95% CI 0.88-1.48 for >=50% repigmentation; RR = 1.81, 95% CI 0.11 29.52 for >=75% repigmentation). Adverse effects were mild, including pruritus, burning sensation, and dryness, none of which interrupted treatment. CONCLUSIONS: To our knowledge, this is the first systematic review of the efficacy and safety of excimer lamp treatment for vitiligo. Excimer lamps, excimer laser, and NB-UVB are all safe and effective in repigmentation of vitiligo lesions. Safety, effectiveness, and cost are considerations when choosing treatment. PROSPERO REGISTRATION NUMBER: CRD42014015237. PMID- 26520642 TI - Plagiarism Allegations Account for Most Retractions in Major Latin American/Caribbean Databases. AB - This study focuses on retraction notices from two major Latin American/Caribbean indexing databases: SciELO and LILACS. SciELO includes open scientific journals published mostly in Latin America/the Caribbean, from which 10 % are also indexed by Thomson Reuters Web of Knowledge Journal of Citation Reports (JCR). LILACS has a similar geographical coverage and includes dissertations and conference/symposia proceedings, but it is limited to publications in the health sciences. A search for retraction notices was performed in these two databases using the keywords "retracted", "retraction" "withdrawal", "withdrawn", "removed" and "redress". Documents were manually checked to identify those that actually referred to retractions, which were then analyzed and categorized according to the reasons alleged in the notices. Dates of publication/retraction and time to retraction were also recorded. Searching procedures were performed between June and December 2014. Thirty-one retraction notices were identified, fifteen of which were in JCR-indexed journals. "Plagiarism" was alleged in six retractions of this group. Among the non-JCR journals, retraction reasons were alleged in fourteen cases, twelve of which were attributed to "plagiarism". The proportion of retracted articles for the SciELO database was approximately 0.005 %. The reasons alleged in retraction notices may be used as signposts to inform discussions in Latin America on plagiarism and research integrity. At the international level, these results suggest that the correction of the literature is becoming global and is not limited to mainstream international publications. PMID- 26520643 TI - Context- and dose-dependent modulatory effects of naringenin on survival and development of Drosophila melanogaster. AB - Naringenin, the predominant bioflavonoid found in grapefruit and tomato has diverse bioactive properties that encompass anti-carcinogenic, anti-inflammatory, anti-atherogenic, anti-estrogenic, anti-hyperlipidemic and anti-hyperglycemic characteristics. Naringenin has not been explored for its pro-longevity traits in fruit flies. Therefore, the current study explores its influence on longevity, fecundity, feeding rate, larval development, resistance to starvation stress and body weight in male and female wild-type Drosophila melanogaster Canton-S flies. Flies were fed with normal and high fat diets respectively. The results implied hormetic effects of naringenin on longevity and development in flies. In flies fed with standard and high fat diets, lower concentrations of naringenin (200 and 400 uM) augmented mean lifespan while higher concentrations (600 and 800 uM) were consistently lethal. However, enhanced longevity seen at 400 uM of naringenin was at the expense of reduced fecundity and food intake in flies. Larvae reared on standard diet having 200 uM of naringenin exhibited elevated pupation and emergence as flies. Eclosion time was hastened in larvae reared on standard diet having 200 uM of naringenin. Female flies fed with a standard diet having 200 and 400 uM of naringenin were more resistant to starvation stress. Reduction in body weight was observed in male and female flies fed with a high fat diet supplemented with 200 and 400 uM of naringenin respectively. Collectively, the results elucidated a context- and dose-dependent hormetic efficacy of naringenin that varied with gender, diet and stage of lifecycle in flies. PMID- 26520644 TI - Preoperative NSAIDs, non-acute onset and long-standing symptoms predict inferior outcome at long-term follow-up after rotator cuff repair. AB - PURPOSE: To evaluate mid- to long-term results after arthroscopic rotator cuff repair and to explore possible predictors of inferior outcome. METHODS: Patients treated for full-thickness supraspinatus and/or infraspinatus tears from 2004 to 2008, using a uniform single-row arthroscopic technique, were included in the study. Pre- and post-operative QuickDASH were used as the primary outcome measure, and VAS of pain, function and satisfaction were also collected. An additional questionnaire explored demographic and preoperative factors like onset and duration of symptoms, preoperative treatment and smoking habits. RESULTS: One hundred and forty-seven patients (82 %) were available at 6-9 years after surgery. All outcomes improved significantly from the preoperative values. A total of 8 % of patients had undergone additional surgery to the same shoulder during the follow-up period. Long-standing symptoms (>12 months) (P < 0.01), non acute onset of symptoms (P < 0.01) and preoperative use of NSAIDs (P = 0.01) were correlated with inferior outcome at follow-up. No other factors investigated (i.e. gender, age, smoking and steroid injections) were found to affect the primary outcome (QuickDASH). CONCLUSION: The current study is one of few reports of mid- to long-term outcomes after arthroscopic single-row repair of full thickness rotator cuff tears. Global improvement in symptoms and function was found between the preoperative and the 6-9 years evaluation, and the technique therefore seems like a viable approach for treating tears of the supra- and the infraspinatus tendon. Several predictors of inferior long-term outcome after rotator cuff repair were, however, identified: preoperative use of NSAIDs, long standing symptoms before surgery and non-acute onset of shoulder symptoms. In light of the current findings, accurate diagnosis and prompt treatment seem important in optimizing outcomes after rotator cuff surgery. LEVEL OF EVIDENCE: IV. PMID- 26520645 TI - Absorbable and non-absorbable suture fixation results in similar outcomes for tibial eminence fractures in children and adolescents. AB - PURPOSE: To evaluate efficacy and safety of extraphyseal tibial eminence avulsion fracture repair with absorbable sutures and a distal bone bridge fixation in comparison to previously described technique with non-absorbable sutures and distal screw fixation. METHODS: In a physeal-sparing technique, tibial eminence fractures (n = 25; McKeever type II/III n = 11/14) were either treated in group A (n = 15, follow-up 28.1 months) using an absorbable suture fixed over a bone bridge or in group B (n = 10, follow-up 47.4 months) with a non-absorbable suture wrapped around an extraarticular tibial screw. IKDC and Lysholm scores were assessed, and the difference between the surgical and contralateral knee in anteroposterior (AP) translation, measured with a Rolimeter. RESULTS: There was no significant difference between group A and group B in IKDC and Lysholm scores with 90.1 points +/- 10.2 and 94.1 points +/- 8.1, respectively (n.s.). AP translation did not differ between groups (n.s.). Eight of ten screws in group B had to be removed in a second intervention. A total of four arthrofibroses were counted (three in group A). CONCLUSION: Extraphyseal tibial eminence repair with absorbable sutures and a distal bone bridge fixation results in similar rates of radiographic and clinical healing at 3 months after surgery as non-absorbable sutures tied around a screw, while avoiding the need for hardware removal. The minimal invasive technique to fix an eminence fracture without any permanent sutures or hardware is advantageous for children. To our knowledge, this is the first study that compares non-absorbable with absorbable sutures for a physeal sparing technique. LEVEL OF EVIDENCE: III. PMID- 26520646 TI - Medial compartment knee osteoarthritis: age-stratified cost-effectiveness of total knee arthroplasty, unicompartmental knee arthroplasty, and high tibial osteotomy. AB - PURPOSE: To compare the age-based cost-effectiveness of total knee arthroplasty (TKA), unicompartmental knee arthroplasty (UKA), and high tibial osteotomy (HTO) for the treatment of medial compartment knee osteoarthritis (MCOA). METHODS: A Markov model was used to simulate theoretical cohorts of patients 40, 50, 60, and 70 years of age undergoing primary TKA, UKA, or HTO. Costs and outcomes associated with initial and subsequent interventions were estimated by following these virtual cohorts over a 10-year period. Revision and mortality rates, costs, and functional outcome data were estimated from a systematic review of the literature. Probabilistic analysis was conducted to accommodate these parameters' inherent uncertainty, and both discrete and probabilistic sensitivity analyses were utilized to assess the robustness of the model's outputs to changes in key variables. RESULTS: HTO was most likely to be cost-effective in cohorts under 60, and UKA most likely in those 60 and over. Probabilistic results did not indicate one intervention to be significantly more cost-effective than another. The model was exquisitely sensitive to changes in utility (functional outcome), somewhat sensitive to changes in cost, and least sensitive to changes in 10-year revision risk. CONCLUSIONS: HTO may be the most cost-effective option when treating MCOA in younger patients, while UKA may be preferred in older patients. Functional utility is the primary driver of the cost-effectiveness of these interventions. For the clinician, this study supports HTO as a competitive treatment option in young patient populations. It also validates each one of the three interventions considered as potentially optimal, depending heavily on patient preferences and functional utility derived over time. PMID- 26520647 TI - Temporal averaging across multiple response options: insight into the mechanisms underlying integration. AB - Rats trained on a dual-duration, dual-modality peak-interval procedure (e.g., tone = 10 s/light = 20 s) often show unimodal response distributions with peaks that fall in between the anchor durations when both cues are presented as a simultaneous compound. Two hypotheses can explain this finding. According to the averaging hypothesis, rats integrate the anchor durations into an average during compound trials, with each duration being weighted by its respective reinforcement probability. According to the simultaneous temporal processing hypothesis, rats time both durations veridically and simultaneously during compound trials and respond continuously across both durations, thereby producing a unimodal response distribution with a peak falling in between the anchor durations. In the present compounding experiment, rats were trained to associate a tone and light with two different durations (e.g., 5 and 20 s, respectively). However, in contrast to previous experiments, each cue was also associated with a distinct response requirement (e.g., left nosepoke for tone/right nosepoke for light). On the majority of compound trials, responding on a given nosepoke fell close to its respective duration, but was shifted in the direction of the other cue's duration, suggesting rats timed an average of the two durations. However, more weight appeared to be given to the duration associated with the manipulandum on which the rat responded, rather than the duration associated with a higher reinforcement probability as predicted by the averaging hypothesis. Group differences were also observed, with rats trained to associate the tone and light with the short and long durations, respectively, being more likely to show these shifts than the counterbalanced modality-duration group (i.e., light-short/tone long). This parallels group differences observed in past studies and suggest that cue weighting in response to stimulus compounds is influenced by the modality duration relationship of the anchor cues. The current results suggest that temporal averaging is a more flexible process than previously theorized and provide novel insight into the mechanisms that affect cue weighting. PMID- 26520648 TI - Effects of environmental enrichment on cognitive performance of pigs in a spatial holeboard discrimination task. AB - This study investigated the effects of environmental enrichment on the cognitive performance of female conventional farm (growing) pigs in a spatial holeboard task. Ten pairs of littermates matched for weight were used. From each litter, one piglet was randomly assigned to a barren environment; the other was assigned to an enriched environment from 4 weeks of age. The enriched environment was double the size of the barren environment, had a floor covered with straw, a rooting area filled with peat, and one of the four different enrichment toys which were exchanged daily. Starting at 11 weeks of age, all pigs were tested in a spatial holeboard discrimination task in which 4 out of 16 holes were baited. Furthermore, basal salivary cortisol levels of all pigs were determined after the end of all testing. All pigs were able to acquire the pattern of baited holes (acquisition phase, 40 trials) and the diagonally mirrored pattern (reversal phase, 20 trials). During the acquisition phase, the reference memory performance of the enriched-housed pigs was better than that of their barren-housed littermates, i.e. they reduced visits to the unbaited set of holes. During the reversal phase, enriched-housed pigs had a better general working memory performance than the barren-housed pigs as indicated by reduced revisits to holes already visited during a trial, irrespective of whether they were of the baited or the unbaited set. The enriched-housed pigs also searched for the hidden bait faster during both phases. The environments did not affect basal salivary cortisol levels. In conclusion, environmental enrichment slightly improved the cognitive performance of pigs in a spatial learning task. We hypothesise that the long period of habituation to and testing in the holeboard acted as enrichment that partially reduced the effects of barren housing. PMID- 26520649 TI - Respiratory syncytial virus infection in infants with acute leukemia: a retrospective survey of the Japanese Pediatric Leukemia/Lymphoma Study Group. AB - Respiratory syncytial virus (RSV) can cause life-threatening complications of lower respiratory tract infection (LRTI) in young children with malignancies, but reports remain limited. We performed a retrospective nationwide survey to clarify the current status of RSV disease among infants with hematological malignancies. Clinical course, treatment, and outcome of patients with hematological malignancies who suffered from RSV infections at the age of <24 months during anti-tumor therapy from April 2006 to March 2009 were investigated by sending a questionnaire to all member institutions of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG). Twelve patients with acute leukemia were identified as having experienced RSV disease. The primary diseases were acute myeloid leukemia (n = 8) and acute lymphoblastic leukemia (n = 4). RSV infection occurred pre- or during induction therapy (n = 8) and during consolidation therapy (n = 4). Eight patients developed LRTI, four of whom had severe pneumonia or acute respiratory distress syndrome; these four patients died despite receiving intensive care. In our survey, the prognosis of RSV disease in pediatric hematological malignancies was poor, and progression of LRTI in particular was associated with high mortality. In the absence of RSV-specific therapy, effective prevention and treatment strategies for severe RSV disease must be investigated. PMID- 26520650 TI - Clinical usefulness of WT1 mRNA expression in bone marrow detected by a new WT1 mRNA assay kit for monitoring acute myeloid leukemia: a comparison with expression of WT1 mRNA in peripheral blood. AB - We have previously shown the clinical usefulness of Wilms' tumor 1 gene (WT1) mRNA expression in peripheral blood (PB) as a minimal residual disease (MRD) monitoring marker in 191 acute myeloid leukemia (AML) patients using the WT1 mRNA assay kit "Otsuka" (Otsuka Pharmaceutical Co., Ltd.; "former kit"). In contrast, the usefulness of WT1 mRNA expression in bone marrow (BM) has been investigated in only a limited number of subjects using former kit. Following that previous study, a next-generation kit, WT1 mRNA assay kit II "Otsuka" (Otsuka Pharmaceutical Co., Ltd.; "new kit") has been newly developed. In the present study, we aimed to evaluate the performance of the new kit and to investigate the clinical usefulness of WT1 mRNA expression in BM. The PB and BM were collected on the same day from 164 blood disease patients, including 118 AML patients. WT1 mRNA expression was determined using the new and former kits and the values obtained were compared. The performance of new kit was shown to be equivalent to that of former kit. As reported in PB, WT1 mRNA expression in BM was found to be a useful marker for monitoring disease status as well as for a diagnosis of early stage relapse in AML patients. PMID- 26520651 TI - Immunohistochemical examination of cholecystokinin and gastrin receptors (CCK 2/gastrin-R) expression in normal and exocrine cancerous human pancreatic tissues. AB - OBJECTIVE: Evaluating tissue samples of normal and exocrine cancerous human pancreas on the expression of CCK2/gastrin receptor. We performed an immunohistochemical protocol that allows efficient detection of this receptor in formalin-fixed, paraffin-embedded human tissues. METHODS: Twenty (20) paraffin blocks of pancreatic tissue sections were collected from the Departments of pathology, Central University Hospital of Sidi-bel-Abbes City (Western Algeria) for the period 2004-2013; ten (10) of them were normal pancreatic samples; and ten (10) cancerous pancreatic sections. The samples were studied using an immunohistochemical protocol for CCK-2/gastrin receptors. RESULTS: Our immunohistochemical analysis revealed that CCK-2/gastrin receptors were expressed in both normal and malignant pancreatic cells but with different immunoreactivity levels and different immunostaining intensity i.e., CCK-2/gastrin receptors were highly expressed within the cytoplasmic area of cancerous cells; 40% of the samples had an immunoreactivity (IR) of (+++) and 60% (++++); the immunostaining was as well very intense since we reported a dark brown staining of the malignant cells. However; in normal pancreatic tissues; CCK-2/gastrin receptors IR levels were very low; 80% of the samples had an IR of (+); and 20% had (++) and the immunostaining was less intense; we noted a light brown staining of few normal pancreatic cells. CONCLUSION: The gastrointestinal peptides CCK could be very interesting targets for exocrine pancreatic cancer therapies; thus further surveys such as western blotting and RTPCR could indentify CCK-2/gastrin receptors as a helpful biomarker for exocrine pancreatic cancer diagnosis and treatment. PMID- 26520652 TI - Surgical and oncological impact of main pancreatic duct spread in invasive ductal adenocarcinoma: A clinicopathological study of 184 resected cases. AB - BACKGROUND/OBJECTIVES: This study examined main pancreatic ductal spread in invasive ductal adenocarcinoma (IDC) of the pancreas. METHODS: Data from IDC patients who underwent radical surgery from 1990 to 2013 in our hospital were examined retrospectively. Incidence of intraductal spread of pancreatic cancer (IS), distance from the tumor edge, direction of IS and clinicopathological factors associated with the presence of IS were retrospectively examined with data from IDC patients who underwent radical surgery. RESULTS: Among 260 IDC patients who underwent surgery, 184 eligible cases, IS was identified in 42 patients (22.8%) and mean length of IS was 18.7 +/- 21.6 mm. Mean distances on the ampullary and distal sides of IS were 11.1 mm and 11.6 mm. IS was significantly more frequent in localized tumors (UICC T1-2 vs. 3-4, p = 0.007), with tumor diameter <=2 cm (p = 0.034) and in cases with scarce microscopic perineural invasion (p = 0.047). Among patients who underwent pancreaticoduodenectomy and distal pancreatectomy, IS presence (11.6 vs. 21.8%), mean distance to the contralateral side (11.4 vs. 11.6 mm), and IS >= 2 cm (3.3 vs. 4.7%) showed no significant differences. Overall survival did not differ significantly between IS-positive and -negative patients in the full analysis set or propensity score-matched patients (42 matched pairs). CONCLUSIONS: In setting resectional margins at 2 cm, a small proportion of cases (3.8%) showed positive surgical margins. Localized tumor (UICC: T1-2, or <2 cm in diameter) requires more care with surgical margins, warranting intraoperative frozen sections. PMID- 26520653 TI - Preservation of native esophagus in infants with pure esophageal atresia has good long-term outcomes despite significant postoperative morbidity. AB - PURPOSE: To evaluate long-term outcomes of pure esophageal atresia (EA) repair with preservation of native esophagus. METHODS: Infants with pure EA treated at our institution (2000-2010) and with minimum 5-year follow-up were reviewed (REB:1000046653). Data analysed included demographics, management and outcomes and are reported as mean +/- SD/median (range). RESULTS: Of 185 infants with EA, 12 (7 %) had pure EA (gestational age: 36 +/- 2.4 weeks, birth weight: 2353 +/- 675 g). Ten had associated anomalies, including trisomy-21 (n = 2) and duodenal atresia (n = 1). SURGERY: 1 patient (short gap) underwent primary thoracoscopic anastomosis, 11 had gastrostomy (Stamm, n = 5; image-guided, n = 6) as initial procedure. At definitive repair (age: 128 +/- 91 days; weight 5.5 +/- 2.3 kg): ten had primary anastomosis and 1 had Collis gastroplasty. No patient had esophageal replacement surgery. OUTCOMES: three patients had gastrostomy dehiscence requiring re-operation. At post-operative esophagram, seven had anastomotic leak successfully treated conservatively. Seven patients developed strictures requiring balloon dilatations (median two dilatations, range 1-10), six received antireflux surgery. At 7-year follow-up (range 5-15 years), all patients had the gastrostomy closed and were on full oral feeds. CONCLUSIONS: The management of pure EA continues to be challenging. The preservation of native esophagus is possible with significant morbidity. The long-term outcomes are favourable. PMID- 26520655 TI - The significance of social determinants of health on the outcome of surgical neonates in a third world setting. AB - PURPOSE: We aimed to determine whether the outcome of general surgery neonates, cared for within our unit, was influenced by socio-economic status as measured by a selection of social variables [primary caregiver's education level, primary caregiver's age, and living standards measure (LSM)] and to determine the rate for each of the three levels of the outcome measure (i.e., good outcome, poor outcome, and deceased). METHODS: A consecutive sampling strategy was used, including all subjects in our neonatal data base with major surgical diagnoses operated on between 1 July 2010 and 31 August 2011. The primary caregiver of each patient was questioned with respect to the variables and these results were analysed along with clinical information from patient records. Multinomial logistic regression was used to answer both objectives. RESULTS: The final multinomial logistic model is highly significant and includes only LSM as a predictor variable. As LSM increases by one level, the risk of experiencing a poor outcome decreases by 82 % as compared to those patients experiencing a good outcome. As LSM increases by one level, the risk of neonatal death also decreases by 88 % as compared to those patients experiencing a good outcome. CONCLUSION: This study shows that the probability of a neonate having a good outcome increases with increasing LSM. PMID- 26520654 TI - The rising incidence of pediatric empyema with fistula. AB - PURPOSE: The incidence and etiology of empyema with fistula (EWF) in children is unknown. We analyzed a national database to define the epidemiology and diagnoses associated with this condition. METHODS: Discharge data from the Kids' Inpatient Database were reviewed for EWF (ICD-9 diagnosis code 510.0) in children <=18 years from 2000 to 2012. Patient characteristics, institutional data, and accompanying conditions were evaluated. Weighted national estimates were calculated and incidence compared across years (2000, 2003, 2006, 2009) using the Rao-Scott Chi Square. RESULTS: From 2000 to 2012, 908 children were hospitalized with EWF. Age distribution was bimodal. Common primary diagnoses related to the hospitalization were pneumonia/pulmonary abscess (31.2 %) and EWF (19.3 %). Manipulation of the pleural space (e.g. decortication, drainage) comprised 45.0 % of procedures. Incidence rates of EWF increased (Rao Scott Adjusted Chi Square: 16.13, p < 0.01) over the study period. Although not statistically significant, median length of stay and age of diagnosis decreased and increased, respectively. CONCLUSION: This first, national pediatric EWF study reveals rising incidence during the years 2000-2009. Despite limitations in ICD-9 coding, concomitant primary diagnoses and procedures suggest bronchopleural fistulae likely represent the vast majority of cases in this cohort. Multi-institutional studies are needed to confirm etiology and characterize outcome of EWF. PMID- 26520656 TI - Comprehensive assessment of prognosis after laparoscopic portoenterostomy for biliary atresia. AB - PURPOSE: Total bilirubin (T-bil) is used universally for monitoring post portoenterostomy (PE) biliary atresia (BA) patients although other biochemical markers [BM; AST/ALT and platelet count (PC)] are also prognostic. We compared open PE (OPE) with laparoscopic PE (LPE) using T-bil, AST/ALT, and PC (3BM) as more comprehensive indicators of postoperative clinical status. METHODS: Subjects were 31 PE cases (LPE: n = 17; OPE: n = 14). BA classification was type III (n = 16), type II (n = 1) in LPE and type III (n = 12), type I (n = 1), type II (n = 1) in OPE. RESULTS: Mean ages and weights at PE were similar: 65.5 days, 4.4 kg (LPE) versus 69.3 days, 4.1 kg (OPE); and mean follow-up was 2.5 years for both LPE and OPE. Jaundice clearance (T-bil <=1.2 mg/dL) was achieved in 16/17 (94.1 %) after LPE versus 10/14 (71.4 %) after OPE (p = NS), but 3BM were closer to normal after OPE. At the time of review, 13/17 LPE cases (76.5 %) were alive with native livers and 4/17 had received LTx (23.5 %) and 10/14 OPE cases (71.4 %) were alive with native livers and 4/14 had received LTx (28.6 %). CONCLUSIONS: Although JC was better after LPE, 3BM were better after OPE. Further follow-up will prove the comprehensive prognostic value of 3BM. PMID- 26520657 TI - Transcriptional and Chromatin Regulation during Fasting - The Genomic Era. AB - An elaborate metabolic response to fasting is orchestrated by the liver and is heavily reliant on transcriptional regulation. In response to hormones (glucagon, glucocorticoids) many transcription factors (TFs) are activated and regulate various genes involved in metabolic pathways aimed at restoring homeostasis: gluconeogenesis, fatty acid oxidation, ketogenesis, and amino acid shuttling. We summarize recent discoveries regarding fasting-related TFs with an emphasis on genome-wide binding patterns. Collectively, the findings we discuss reveal a large degree of cooperation between TFs during fasting that occurs at motif-rich DNA sites bound by a combination of TFs. These new findings implicate transcriptional and chromatin regulation as major determinants of the response to fasting and unravels the complex, multi-TF nature of this response. PMID- 26520659 TI - Enemy-free space promotes maintenance of host races in an aphid species. AB - The enormous biodiversity of herbivorous insects may arise from ecological speciation via continuous host-plant switches. Whether such switches are successful depends on the trade-off between different selection pressures that act on herbivores. Decreased herbivore performance due to suboptimal nutrition might be compensated for by a reduced natural enemy pressure. As a consequence, an "enemy-free space" on a certain plant might facilitate host-plant switches and maintain biotypes. To test this hypothesis, we used the pea aphid (Acyrthosiphon pisum) complex, which consists of at least 11 genetically distinct host races that are native to specific legume host plants but can all develop on the universal host plant Vicia faba. Three A. pisum host races native to Trifolium pratense, Pisum sativum, and Medicago sativa were investigated in experiments on their respective host plants and on the universal host plant V. faba. We found that hoverflies preferred to oviposit on P. sativum and the universal host V. faba. Since feeding by hoverfly larvae suppressed aphid population growth on these host plants, the native hosts M. sativa and T. pratense provided enemy-free space for the respective A. pisum races. Mobile predators, such as ants and ladybird beetles, preferred Pisum race aphids on V. faba over P. sativum. Thus, all three of the native host plants studied supply enemy-free space for A. pisum compared to the universal host V. faba. Reducing encounters between aphid races on V. faba would reduce gene flow among them and could contribute to maintaining the host races. PMID- 26520660 TI - Synthesis of cynaropicrin-d(4). AB - Cynaropicrin is a guaianolide sesquiterpene lactone, which has potent in vitro and in vivo inhibitory activity against Trypanosoma brucei, the protozoan parasite that causes human African trypanosomiasis (HAT; sleeping sickness). Herein, we describe the synthesis of cynaropicrin's deuterated derivative, cynaropicrin-d4, by the replacement of the side chain of natural cynaropicrin. The synthesized cynaropicrin-d4 could be employed as an internal standard for liquid chromatography-mass spectrometry (LC-MS) analysis, in the pharmacokinetic study of cynaropicrin. This could potentially advance the study of this therapeutic lead. PMID- 26520658 TI - Metabolic Enzymes Enjoying New Partnerships as RNA-Binding Proteins. AB - In the past century, few areas of biology advanced as much as our understanding of the pathways of intermediary metabolism. Initially considered unimportant in terms of gene regulation, crucial cellular fate changes, cell differentiation, or malignant transformation are now known to involve 'metabolic remodeling' with profound changes in the expression of many metabolic enzyme genes. This review focuses on the recent identification of RNA-binding activity of numerous metabolic enzymes. We discuss possible roles of this unexpected second activity in feedback gene regulation ('moonlighting') and/or in the control of enzymatic function. We also consider how metabolism-driven post-translational modifications could regulate enzyme-RNA interactions. Thus, RNA emerges as a new partner of metabolic enzymes with far-reaching possible consequences to be unraveled in the future. PMID- 26520661 TI - 1,3-Disubstituted and 1,3,3-trisubstituted adamantyl-ureas with isoxazole as soluble epoxide hydrolase inhibitors. AB - Adamantyl ureas are good soluble epoxide hydrolase (sEH) inhibitors; however they have limited solubility and rapid metabolism, thus limiting their usefulness in some therapeutic indications. Herein, we test the hypothesis that nodal substitution on the adamantane will help solubilize and stabilize the compounds. A series of compounds containing adamantane derivatives and isoxazole functional groups were developed. Overall, the presence of methyl on the nodal positions of adamantane yields higher water solubility than previously reported urea-based sEH inhibitors while maintaining high inhibition potency. However, it did not improve microsomal stability. PMID- 26520662 TI - Interaction of carbonic anhydrase isozymes I, II, and IX with some pyridine and phenol hydrazinecarbothioamide derivatives. AB - A series of hydrazinecarbothioamide derivatives incorporating ethyl, phenyl, tolyl, benzyl, and allyl moieties were prepared and tested as possible inhibitors of three members of the pH regulatory enzyme family, carbonic anhydrase (CA; EC 4.2.1.1). The inhibitory and activatory potencies of the compounds against the cytosolic human isoforms hCA I and hCA II and the transmembrane, tumor-associated hCA IX were analyzed by a hydrase assay with CO2 as substrate, and the inhibition constants (KI) were calculated. Most compounds investigated here exhibited nanomolar or low micromolar inhibition constants against the three isoenzymes. KI values were in the range of 34.1-871 nM for hCA I and compounds 5-10 showed interesting activation of the hCA II with KA value of 0.81-12.5 MUM. Compounds 11 16 exhibited moderate inhibition effects on hCA IX in the range of 0.317-1.245 MUM but they were less effective for hCA II. Tested compounds were also investigated using in silico applications at the binding pockets of these three targets. The different mechanisms of inhibition by these tested compounds as compared to sulfonamides, and their diverse inhibition profile for these mammalian isozymes, makes this class of derivatives of great interest for the design of novel CA inhibitors. PMID- 26520663 TI - New INH-pyrazole analogs: Design, synthesis and evaluation of antitubercular and antibacterial activity. AB - With the aim of developing promising antitubercular and antibacterial leads, we have designed and synthesized a new series of isonicotinohydrazide based pyrazole derivatives (5a-r). All new derivatives (4a-b and 5a-r) were screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) strain. Four compounds 5j, 5k, 5l and 4b emerged as promising antitubercular agents with MIC of ?4.9 MUM which is much lower than the MIC of the first line antitubercular drug, ethambutol. The 3-chlorophenyl substituent at position-3 of the pyrazole ring enhanced the antiTB activity of the molecules. Three derivatives 5b, 5k and 4b exhibited promising antibacterial activity against the tested bacterial strains. The active molecules were nontoxic to normal Vero cells and showed high selectivity index (>160). The structure and antitubercular activity relationship was further supported by in silico molecular docking study of the active compounds against enoyl acyl carrier protein reductase (InhA) enzyme of M. tuberculosis. PMID- 26520664 TI - Solid-phase synthesis and in vitro biological activity of a Thr4->Ser4 analog of daptomycin. AB - Daptomycin is a Ca(+2)-dependent cyclic lipodepsipeptide antibiotic used clinically to treat serious infections caused by Gram-positive bacteria. The recent appearance of daptomycin-resistant strains, daptomycin's lack of activity in the presence of lung surfactant, and its incompletely understood mechanism of action underscores the need for establishing detailed structure-activity relationships. Here we report a solid-phase synthesis of a daptomycin analog in which Thr4, 3-MeGlu12 and Kyn13 in daptomycin were replaced with Ser, Glu and Trp residues, respectively (Dap-S4-E12-W13). The Thr4 to Ser4 substitution was detrimental to activity, as Dap-S4-E12-W13 was at least 20-fold less active at physiological Ca(+2) concentration than Dap-E12-W13. Much of its activity could be recovered at high (100 mM) Ca(+2) concentration, suggesting that the residue at position 4 affects Ca(+2) binding and, consequently, biological activity. PMID- 26520665 TI - Synthesis and biological evaluation of polyalthic acid derivatives for the treatment of neglected diseases. AB - Polyalthic acid is a naturally occurring diterpene found in copaiba oil, one of the most popular natural medicines in the Amazon. Based on the reported antileishmanial activity of copaiba oil, a series of amides and diols derivatives of polyalthic acid were synthesized and tested against Leishmania donovani and Trypanosoma brucei. Polyalthic acid was active in both assays with IC50 ranging from 3.87 to 8.68 MUg/mL. The compound with best antileishmanial activity was 2 h (IC50=3.84 MUg/mL) and compound 2c showed the best antitrypanosomal activity with an IC50 of 2.54 MUg/mL. PMID- 26520667 TI - Resection of supernumerary intrathoracic rib using robotic-assisted video assisted thoracoscopic surgery. AB - A supernumerary intrathoracic rib is a very rare congenital thoracic abnormality that is typically a benign incidental finding. However, in rare cases, they may cause pain, pneumothorax, and injury to surrounding viscus. We report a case of a supernumerary intrathoracic rib causing increasing chest pain diagnosed by computed tomography using three-dimensional reconstructions. The patient underwent robotic-assisted video-assisted thoracoscopic resection of the intrathoracic rib located in her left thorax. The rib was resected without complication, and the patient was discharged from the telemetry unit on post operative day two. Upon discharge, there was complete resolution of her preoperative symptoms. PMID- 26520666 TI - Oxytocin opposes effects of bacterial endotoxin on ER-stress signaling in Caco2BB gut cells. AB - BACKGROUND: The neuropeptide neuromodulator and hormone oxytocin (OT) activates signaling pathways involved in mRNA translation in response to endoplasmic reticulum stress and reduces inflammation associated with experimental colitis in rats. The anti-inflammatory effects of OT may serve a vital role in the development, survival and function of newborn-type enterocytes during microbial gut colonization, which coincides with the milk suckling period when OT receptor expression peaks in the gut. Furthermore, mice deficient in the OT receptor have abnormal gut structure and function, underscoring OT's developmental importance. METHODS: We tested the effect of OT upon lipopolysaccharide (LPS)-induced markers of the inflammatory response in Caco2BB gut cells in vitro using automated immunocapillary electrophoresis. RESULTS: We demonstrate that OT suppresses NF kappaB signaling and presumably inflammatory transcriptional programs, which are unleashed by LPS through the modulation of IkappaB. We show that OT counteracts LPS-elicited silencing of the unfolded protein response, a pathway limiting endoplasmic reticulum stress by suppressing protein translation. OT selectively activates dsRNA-activated kinase (PKR), X-box binding protein 1 (XBP1), immunoglobulin binding protein (BiP), A20 (TNFalpha-induced protein 3) and inositol requiring enzyme 1a (IRE1a). OT inactivates eukaryotic translation initiation factor 2a (eIF2a) without significant activation of protein kinase RNA like endoplasmic reticulum kinase (PERK). CONCLUSIONS: Mild, preemptive stimulation of endoplasmic reticulum stress sensors by OT may precondition newborn enterocytes to resist apoptosis associated with inflammation and may support their differentiation and development by modulating cellular metabolism. GENERAL SIGNIFICANCE: OT may protect enterocytes and other cell types, such as neurons, from stress-related complications during postnatal development. PMID- 26520668 TI - Norwegian Cancer Genomics Consortium: a platform for research on personalized cancer medicine in a public health system. PMID- 26520669 TI - Regulation of CD8+ T-cell cytotoxicity in HIV-1 infection. AB - Understanding the mechanisms involved in cellular immune responses against control of human immunodeficiency virus (HIV) infection is key to development of effective immunotherapeutic strategies against viral proliferation. Clear insights into the regulation of cytotoxic CD8+ T cells is crucial to development of effective immunotherapeutic strategies due to their unique ability to eliminate virus-infected cells during the course of infection. Here, we reviewed the roles of transcription factors, co-inhibitory molecules and regulatory cytokines following HIV infection and their potential significance in regulating the cytotoxic potentials of CD8+ T cells. PMID- 26520670 TI - Waterborne toxicity and diet-related effects of fungicides in the key leaf shredder Gammarus fossarum (Crustacea: Amphipoda). AB - Animals involved in leaf litter breakdown (i.e., shredders) play a central role in detritus-based stream food webs, while their fitness and functioning can be impaired by anthropogenic stressors. Particularly fungicides can affect shredders via both waterborne exposure and their diet, namely due to co-ingestion of adsorbed fungicides and shifts in the leaf-associated fungal community, on which shredders' nutrition heavily relies. To understand the relevance of these effect pathways, we used a full 2*2-factorial test design: the leaf material serving as food was microbially colonized for 12 days either in a fungicide-free control or exposed to a mixture of five current-use fungicides (sum concentration of 62.5MUg/L). Similarly, the amphipod shredder Gammarus fossarum was subjected to the same treatments but for 24 days. Waterborne exposure reduced leaf consumption by ~20%, which did not fully explain the reduction in feces production (~30%), indicating an enhanced utilization of food to compensate for detoxification mechanisms. This may also explain the reduced feces production (~10%) of gammarids feeding on fungicide-exposed leaves. The reduction may, however, also be caused by a decreased nutritious quality of the leaves indicated by a reduced species richness (~40%) of leaf-associated fungi. However, compensation for these effects by Gammarus was seemingly incomplete, since both waterborne exposure and the consumption of the fungicide-affected diet drastically reduced gammarid growth (~110% and ~40%, respectively). Our results thus indicate that fungicide mixtures have the potential for detrimental implications in aquatic ecosystem functioning by affecting shredders via both effect pathways. PMID- 26520671 TI - Reply. PMID- 26520672 TI - Prevention of Cystoid Macular Edema After Cataract Surgery in Non-Diabetic and Diabetic Patients: A Systematic Review and Meta-Analysis. PMID- 26520673 TI - Comparison of Lateral Rectus Muscle Re-recession and Medial Rectus Muscle Resection for Treatment of Postoperative Exotropia. PMID- 26520674 TI - Transvaginal Surgical Management of Cesarean Scar Pregnancy II (CSP-II): An Analysis of 25 Cases. AB - BACKGROUND: The aim of this study was to investigate the feasibility and clinical value of transvaginal surgical treatment for cesarean scar pregnancy (CSP-II). MATERIAL AND METHODS: This study was a retrospective analysis of 25 CSP-II patients who received transvaginal surgical treatments. These patients were admitted in our hospital between January 2010 and June 2012. RESULTS: All surgical treatments were successful without overt complications. The average operation time was 61.5 minutes, the average intraoperative blood loss was 60.5 ml, the average hospital stay was 9.4 days and the average time that blood beta human chorionic gonadotropin (beta-HCG) returned to normal range was 15 days. In all 25 patients, the cesarean scar mass located at the anterior wall of the lower uterine segment disappeared by B-ultrasound examination within 1 or 2 weeks after surgery. Postoperatively, the normal menstrual period started again with an average time of 28.9 days. No menstruation-related abnormalities, such as menstrual dripping or an abnormal amount of blood, were reported after surgery. CONCLUSIONS: Transvaginal surgery for CSP-II is a novel surgical approach. It has several advantages, including a thorough one-time treatment lesion clearance, short operation time, minimized trauma, minimal intraoperative blood loss, quick reduction of blood beta-HCG, and rapid menstruation recovery. It is a simple and feasible surgical approach of great clinical value and few treatment-related complications. PMID- 26520675 TI - Thebesian vessels are coronary vein-cameral connections and vessels of Wearn are coronary artery-cameral connections. PMID- 26520677 TI - Knockout of GH3 genes in the moss Physcomitrella patens leads to increased IAA levels at elevated temperature and in darkness. AB - Two proteins of the GRETCHEN HAGEN3 (GH3) family of acyl acid amido synthetases from the moss Physcomitrella patens conjugate indole-3-acetic acid (IAA) to a series of amino acids. The possible function of altered auxin levels in the moss in response to two different growth perturbations, elevated temperatures and darkness, was analyzed using a) the recently described double knockout lines in both P. patens GH3 genes (GH3-doKO) and b) a previously characterized line harboring an auxin-inducible soybean GH3 promoter::reporter fused to beta glucuronidase (G1-GUS). The GUS activity as marker of the auxin response increased at higher temperatures and after cultivation in the darkness for a period of up to four weeks. Generally, the double knockout plants grew more slowly than the wild type (WT). The altered growth conditions influenced the phenotypes of the double knockout lines differently from that of WT moss. Higher temperatures negatively affected GH3-doKO plants compared to WT which was shown by stronger loss of chlorophyll. On the other hand, a positive effect was found on the concentrations of free IAA which increased at 28 degrees C in the GH3 doKO lines compared to WT plants. A different factor, namely darkness vs. a light/dark cycle caused the adverse phenotype concerning chlorophyll concentrations. Mutant moss plants showed higher chlorophyll concentrations than WT and these correlated with higher free IAA in the plant population that was classified as green. Our data show that growth perturbations result in higher free IAA levels in the GH3-doKO mutants, but in one case - growth in darkness - the mutants could cope better with the condition, whereas at elevated temperatures the mutants were more sensitive than WT. Thus, GH3 function in P. patens WT could lie in the regulation of IAA concentrations under unfavorable environmental conditions. PMID- 26520678 TI - Cs-miR156 is involved in the nitrogen form regulation of catechins accumulation in tea plant (Camellia sinensis L.). AB - The nitrogen source affects the growth of tea plants and regulates the accumulation of catechins in the leaves. In this report, we assessed the influences of NH4(+) and NO3(-) on plant growth, catechins accumulation and associated gene expression. Compared with the preferential nitrogen source NH4(+), when NO3(-) was supplied as the sole nitrogen source, tea plants showed similar symptoms with the nitrogen-free treatments and showed lower nitrogen, free amino acid accumulation, chlorophyll content and biomass gain, indicating NO3(-) was not efficiently used by these plants. However, the total shoot catechins content was significantly higher for NO3(-) treatments than that for NH4(+) treatment or combined NH4(+)+NO3(-) treatment, suggesting that, in addition to its influence on plant growth, the nitrogen form regulated the accumulation of catechins in tea. The expression of catechins biosynthesis related genes was associated with the regulation of catechins accumulation and composition changes mediated by nitrogen form. PAL, CHS, CHI, and DFR genes exhibited higher expression levels in plants supplied with NO3(-), in which the transcript level of DFR in the shoots was significantly correlated with the catechins content. In the end, we identified a new function for the Cs-miR156, which was drastically induced through NH4(+). Moreover, a potential mechanism of the Cs-miR156 pathway in regulating catechins biosynthesis in tea plants has been suggested, with particular respect to nitrogen forms. Cs-miR156 might repress the expression of the target gene SPL to regulate the DFR gene, which plays a vital role in catechins biosynthesis. PMID- 26520679 TI - Applications of polyetheretherketone (PEEK) in oral implantology and prosthodontics. AB - PURPOSE: Polyetheretherketone (PEEK) is a polymer that has many potential uses in dentistry. The aim of this review was to summarize the outcome of research conducted on the material for dental applications. In addition, future prospects of PEEK in the field of clinical dentistry have been highlighted. STUDY SELECTION: An electronic search was carried out via the PubMed (Medline) database using keywords 'polyetheretherketone', 'dental' and 'dentistry' in combination. Original research papers published in English language in last fifteen year were considered. The studies relevant to our review were critically analyzed and summarized. RESULTS: PEEK has been explored for a number of applications for clinical dentistry. For example, PEEK dental implants have exhibited lesser stress shielding compared to titanium dental implants due to closer match of mechanical properties of PEEK and bone. PEEK is a promising material for a number of removable and fixed prosthesis. Furthermore, recent studies have focused improving the bioactivity of PEEK implants at the nanoscale. CONCLUSION: Considering mechanical and physical properties similar to bone, PEEK can be used in many areas of dentistry. Improving the bioactivity of PEEK dental implants without compromising their mechanical properties is a major challenge. Further modifications and improving the material properties may increase its applications in clinical dentistry. PMID- 26520680 TI - Dissociable routes for personal and interpersonal visual enhancement of touch. AB - Seeing a hand can enhance tactile acuity on the hand, even when tactile stimulation is not visible. This visual enhancement of touch (VET) occurs both when participants see their own hand (personal VET), and when they see another person's hand (interpersonal VET). Interpersonal VET occurs irrespective of where the viewed hand appears, while personal VET is eliminated when visual and proprioceptive signals about the location of one's own hand are incongruent. This suggests that the neural mechanisms for VET may differ according to ownership of the seen hand. We used continuous theta-burst transcranial magnetic stimulation (TMS) to disrupt either the human ventral intraparietal area (hVIP), which integrates tactile, proprioceptive, and visual information about one's own body, or the extrastriate body area (EBA), which processes visual body information irrespective of ownership. Participants then judged the orientation of tactile gratings applied to their hand while viewing images of their own hand, another person's hand, or a non-body object on a screen placed over their actual hand. Disrupting the hVIP attenuated personal VET but did not affect interpersonal VET, suggesting the hVIP is only involved in VET when one's own hand is seen. Disrupting the EBA reduced both personal and interpersonal VET, suggesting it is common to both routes. PMID- 26520681 TI - Perceiving numbers does not cause automatic shifts of spatial attention. AB - It is frequently assumed that the brain codes number magnitudes according to an inherent left-to-right spatial organization. In support of this hypothesis it has been reported that in humans, perceiving small numbers induces automatic shifts of attention toward the left side of space whereas perceiving large numbers automatically shifts attention to the right side of space (i.e., Attentional SNARC: Att-SNARC; Fischer, Castel, Dodd, & Pratt, 2003). Nonetheless, the Att SNARC has been often not replicated and its reliability never tested. To ascertain whether the mere perception of numbers causes shifts of spatial attention or whether number-space interaction takes place at a different stage of cognitive processing, we re-assessed the consistency and reliability of the Att SNARC and investigated its role in the production of SNARC effects in Parity Judgement (PJ) and Magnitude Comparison (MC) tasks. In a first study in 60 participants, we found no Att-SNARC, despite finding strong PJ- and MC-SNARC effects. No correlation was present between the Att-SNARC and the SNARC. Split half tests showed no reliability of the Att-SNARC and high reliability of the PJ- and MC-SNARC. In a second study, we re-assessed the Att-SNARC and tested its direct influence on a MC-SNARC task with laterally presented targets. No Att SNARC and no influence of the Att-SNARC on the MC-SNARC were found. Also in this case, the SNARC was reliable whereas the Att-SNARC task was not. Finally, in a third study we observed a significant Att-SNARC when participants were asked to recall the position occupied on a ruler by the numbers presented in each trial: however the Att-SNARC task was not reliable. These results show that perceiving numbers does not cause automatic shifts of spatial attention and that whenever present, these shifts do not modulate the SNARC. The same results suggest that numbers have no inherent mental left-to-right organization and that, whenever present, this organization can have both response-related and strategically driven memory-related origins. Nonetheless, response-related factors generate more reliable and stable spatial representations of numbers. PMID- 26520683 TI - Application of Prussian blue nanoparticles for the radioactive Cs decontamination in Fukushima region. AB - Cs decontamination efficiencies of the composites of iron hexacyanoferrate nanoparticles were investigated in comparison with commercial Prussian blue and natural zeolite. In pure water solution, the adsorption rate varied with sizes. In ash extract, where Cs adsorbing ability of zeolite was sharply dropped due to its poor selectivity, the impact of coexisting ions was negligible for FeHCF. FeHCF-n11, having the finest primary and secondary particle size, resulted the highest distribution coefficient, which was comparable to the high efficiency analogues, CoHCF or NiHCF. This observation suggested the possibility of preparing the high performance FeHCF by particle size and composition adjustment. FeHCF nanoparticle in bead form was tested for the removal of radioactive Cs in pilot scale. Due to larger secondary particle size, pronounced effect of solution temperature on the Cs adsorption kinetics on FeHCF bead was observed. Adjusting the mass of the adsorbent for the given solution temperature is recommended for achieving high decontamination rate. PMID- 26520682 TI - Crosstalk between stem cell and cell cycle machineries. AB - Pluripotent stem cells, defined by an unlimited self-renewal capacity and an undifferentiated state, are best typified by embryonic stem cells. These cells have a unique cell cycle compared to somatic cells as defined by a rapid progression through the cell cycle and a minimal time spent in G1. Recent reports indicate that pluripotency and cell cycle regulation are mechanistically linked. In this review, we discuss the reciprocal co-regulation of these processes, how this co-regulation may prevent differentiation, and how cellular reprogramming can re-establish the unique cell cycle regulation in induced pluripotent stem cells. PMID- 26520684 TI - Variability of radon and thoron equilibrium factors in indoor environment of Garhwal Himalaya. AB - The measurements of radon, thoron and their progeny concentrations have been carried out in the dwellings of Uttarkashi and Tehri districts of Garhwal Himalaya, India using LR-115 detector based pin-hole dosimeter and DRPS/DTPS techniques. The equilibrium factors for radon, thoron and their progeny were calculated by using the values measured with these techniques. The average values of equilibrium factor between radon and its progeny have been found to be 0.44, 0.39, 0.39 and 0.28 for rainy, autumn, winter and summer seasons, respectively. For thoron and its progeny, the average values of equilibrium factor have been found to be 0.04, 0.04, 0.04 and 0.03 for rainy, autumn, winter and summer seasons, respectively. The equilibrium factor between radon and its progeny has been found to be dependent on the seasonal changes. However, the equilibrium factor for thoron and progeny has been found to be same for rainy, autumn and winter seasons but slightly different for summer season. The annual average equilibrium factors for radon and thoron have been found to vary from 0.23 to 0.80 with an average of 0.42 and from 0.01 to 0.29 with an average of 0.07, respectively. The detailed discussion of the measurement techniques and the explanation for the results obtained is given in the paper. PMID- 26520686 TI - Salivary cortisol in early psychosis: New findings and meta-analysis. AB - BACKGROUND: Schizophrenia is a multifactorial disorder and environmental risk factors for it might contribute to hypothalamo-pituitary-adrenal axis (HPA) dysregulation. While increased cortisol levels have been reported in schizophrenia, as well as in early psychosis (compared to healthy controls), a crucial unresolved issue is whether elevated cortisol levels could be related to the distress of an emerging illness, rather than being specific to psychosis. Here, we report new findings from the first French cohort of young help-seekers (ICAAR) including ultra-high risk subjects (UHR), first-episode of psychosis (FEP) and non at-risk help seekers controls (HSC), followed by a meta-analysis of all available reports on salivary basal cortisol levels in early psychosis (UHR and FEP). METHODS: In the ICAAR study, 169 individuals (15-30 years old) had their basal cortisol levels sampled and they were categorized (at baseline) as either UHR, FEP, or HSC using the criteria of the Comprehensive Assessment of At Risk Mental States (CAARMS). The three groups were compared at baseline, and the UHR and HSC individuals were also included in a one-year longitudinal follow-up. UHRs who converted to psychosis at the follow up (UHR-P) were compared to non converters (UHR-NP). We also performed a meta-analysis from case-control studies with basal salivary measures of cortisol, drawing from a systematic bibliographic search using the keywords 'cortisol', 'glucocorticoid', 'HPA' with 'UHR', 'CHR', 'at-risk mental state', 'schizotypal ', 'prodromal schizophrenia', 'first-episode psychosis', 'first episode schizophrenia', 'newly diagnosed schizophrenia', 'recent onset schizophrenia' [in Medline, Web of Knowledge (WOS), EBSCO], followed by a systematic screening of the resulting articles. RESULTS: Basal cortisol levels were not significantly different between UHR, FEP, and HSC controls in the ICAAR cohort. Interestingly, initial cortisol levels were correlated with positive symptoms at the one year follow-up in the ICAAR cohort. The meta-analysis revealed a significant elevation of the salivary basal cortisol levels in UHR individuals compared to controls (8 studies--1060 individuals), but not between FEP and controls (6 studies--441 individuals). Indirect comparison of salivary basal cortisol levels between UHR and FEP did not yield significant differences. Finally, no differences were detected between the baseline cortisol of UHR-P and UHR-NP (4 studies--301 individuals). CONCLUSION: The meta-analysis (including new data) indicates that basal cortisol levels were increased in UHR compared to controls, but FEP levels were not different from UHR or controls. Many confounding factors could decrease the effect size in FEP especially medication intake. Taken together with our new results (which made use of help seeker controls, and not merely healthy controls), the findings indicate that basal cortisol levels may not be a reliable biomarker for early psychosis. Further studies are needed to clarify the precise role of the HPA axis in psychotic conversion. PMID- 26520685 TI - Association of HPA axis hormones with copeptin after psychological stress differs by sex. AB - INTRODUCTION: Copeptin levels are elevated in severe medical conditions, an effect that is attributed to elevated arginine vasopressin (AVP) levels in response to physiological stress, resulting in activation of hypothalamus pituitary-adrenal (HPA) axis. In the current study, we wanted to determine if copeptin is responsive to psychological stress, correlates with cortisol and adrenocorticotropin hormone (ACTH), and if associations differed by sex. MATERIALS AND METHODS: In a cross-sectional study that included 100 healthy men (41%) and women (59%) (aged 18-30 years; mean 24.6 +/- 3 years), who underwent the Trier Social Stress Test (TSST), we examined the association between percent change (peak-baseline/baseline) in copeptin levels and percent change in log ACTH and cortisol. Three baselines samples were drawn followed by blood sampling at 20, 35, 50, 65 and 85 min after TSST. RESULTS: There was a significant positive association between the percent change in copeptin and the percent change in log transformed salivary cortisol (beta-coefficient=0.95; p=0.02). The association between percent change in copeptin and log-transformed serum cortisol was not statistically significant in the overall population. There was a trend for a non significant association between percent change in copeptin and percent change in log-transformed ACTH (beta-coefficient=1.14; p=0.06). In males, there was a significant positive association between the percent change in copeptin levels and log-transformed salivary (beta-coefficient=1.33, p=0.016) and serum cortisol (beta-coefficient=0.69, p=0.01), whereas in women there was no statistically significant association. CONCLUSIONS: We found a significant positive association between percent change in copeptin and percent change in salivary and serum cortisol among males only. PMID- 26520687 TI - Oxidative DNA damage is associated with inflammatory response, insulin resistance and microvascular complications in type 2 diabetes. AB - Urinary markers of nucleic acid oxidation may be useful biomarkers in diabetes. It has been demonstrated that T2DM patients have an increased level of oxidative DNA damage; however, it is unclear whether increased DNA damage may be related to a greater degree of inflammation and insulin resistance. Thus, the aim of this present study was to investigate the relation of the impact of oxidative DNA damage, assessed by urinary 8-OHdG, on the levels of inflammatory cytokines, as well as insulin resistance. In addition, we also investigated the diagnostic ability of urinary 8-OHdG in the identification of microvascular complications in T2DM.A case-control study, enrolling 22 healthy controls and 54 subjects with T2DM, was performed to evaluate the relation between oxidative DNA damage and interleukin-6 (IL-6), IL-1,tumor necrosis factor-alpha (TNF-alpha), IL-10, and Homeostasis Model Assessment (HOMA-IR) index. T2DM patients presented higher urinary 8-OHdG, IL-6, IL-1, TNF-alpha levels and HOMA-IR, and lower IL-10 levels than control subjects. Moreover, urinary 8-OHdG levels were significantly higher in the group T2DM with microvascular complications when compared to the without complications. The areas under the curve for urinary 8-OHdG and urinary albumin were, respectively, 0.836 (P<0.001) and 0.786 (P=0.002). Thus, urinary 8-OHdG has a slightly higher ability to discriminate microvascular complications in T2DM compared with urinary albumin. It was also demonstrated that T2DM patients with higher median of urinary 8-OHdG had significantly elevated levels of IL-6, TNF alpha and HOMA-IR, and decreased IL-10 levels. Our findings showed that T2DM patients with higher urinary 8-OHdG levels showed a greater inflammatory degree and higher insulin resistance. It is possible to speculate that T2DM patients present a cascade of events as increasing metabolic abnormalities such as insulin resistance and inflammatory activation, as well as increased ROS generation factors that may contribute directly to greater oxidative DNA damage. PMID- 26520688 TI - Acanthopanax trifoliatus inhibits lipopolysaccharide-induced inflammatory response in vitro and in vivo. AB - Acanthopanax trifoliatus is a well-known herb that is used for the treatment of bruising, neuralgia, impotence, and gout in Taiwan. This herb exhibits multifunctional activities, including anticancer, anti-inflammation, and antioxidant effects. This paper investigated the in vitro and in vivo anti inflammatory effect of A. trifoliatus. High-performance liquid chromatography analysis established the fingerprint chromatogram of the ethyl acetate fraction of A. trifoliatus (EAAT). The anti-inflammatory effect of EAAT was detected using lipopolysaccharide (LPS) stimulation of the mouse macrophage cell line RAW264.7 in vitro and LPS-induced lung injury in vivo. The effects of EAAT on LPS-induced production of inflammatory mediators in RAW264.7 murine macrophages and the mouse model were measured using enzyme-linked immunosorbent assay and Western blot. EAAT attenuated the production of LPS-induced nitric oxide (NO), tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), and IL-6 in vitro and in vivo. Pretreatment with EAAT markedly reduced LPS-induced histological alterations in lung tissues. Furthermore, EAAT significantly reduced the number of total cells and protein concentration levels in the bronchoalveolar lavage fluid. Western blotting test results revealed that EAAT blocked protein expression of inducible NO synthase, cyclooxygenase-2, phosphorylation of Nuclear factor-kappa-B Inhibitor alpha (IkappaB-alpha) protein, and mitogen-activated protein kinases in LPS-stimulated RAW264.7 cells as well as LPS-induced lung injury. This study suggests that A. trifoliatus may be a potential therapeutic candidate for the treatment of inflammatory diseases. PMID- 26520689 TI - EphA2 modulates radiosensitive of hepatocellular carcinoma cells via p38/mitogen activated protein kinase-mediated signal pathways. AB - This experiment was conducted to investigate the role of EPH receptor A2 (EphA2) in the modulation of radiosensitivity of hepatic cellular cancer (HCC) cells and to determine whether p38/mitogen-activated protein kinase (p38MAPK) signaling mediated EphA2 function in this respect. The protein expressions of EphA2 and phosphorylated p38MAPK were tested in HCC and normal hepatic tissues. In HCC 97H cells, EphA2 was overexpressed and knocked out by transfection with EphA2 expression vector and EphA2-ShRNA, respectively, prior to cell exposure to low dose irradiation. Significantly upregulated EphA2 and phosphorylated p38MAPK were observed in HCC tissues, compared with those in normal hepatic tissues. Low-dose irradiation (1 Gy) only caused minor damage to HCC 97H cells, as assessed by alterations in cell viability, apoptosis rate, and cell healing capacity (p = 0.072, p = 0.078, and p = 0.069 respectively). However, EphA2 knock-out in HCC 97H cells induced significant reduction in cell viability and cell healing capacity after these cells were subjected to low-dose irradiation. Apoptosis rate underwent dramatic increase (p < 0.01). By contrast, EphA2 overexpression in HCC 97H cells reversed these effects and enhanced cell colony formation rate, thus displaying remarkable attenuation of radiosensitivity of HCC 97H cells. Further, SB203580, a specific inhibitor of p38MAPK, was added to HCC 97H cells over expressing EphA2. The effect of EphA2 overexpression on the radiosensitivity of HCC 97H cells was abrogated. Thus, the present study indicates that EphA2 have the ability to negatively regulate the radiosensitivity of HCC 97H cells, which mainly depends on 38MAPK-mediated signal pathways. PMID- 26520690 TI - Pregnancy-associated plasma protein A gene polymorphism in pregnant women with preeclampsia and intrauterine growth restriction. AB - Preeclampsia (PE) and intrauterine growth restriction (IUGR) are still among the most commonly researched titles in perinatology. To shed light on their etiology, new prevention and treatment strategies are the major targets of studies. In this study, we aimed to investigate the relation between gene polymorphism of one of the products of trophoblasts, pregnancy-associated plasma protein A (PAPP-A) and PE/IUGR.A total of 147 women (IUGR, n = 61; PE, n = 47; IUGR + PE, n = 37; eclampsia, n = 2) were compared with 103 controls with respect to the sequencing of exon 14 of the PAPP-A gene to detect (rs7020782) polymorphism. Genotypes "AA" and "CC" were given in the event of A or C allele homozygosity and "AC" in A and C allele heterozygosity. Our findings revealed that the rate of AA, CC homozygotes, and AC heterozygotes did not differ between groups. Moreover, there was no difference in the distribution of PAPP-A genotypes among the patients with IUGR, PE, IUGR + PE, or eclampsia. Finally, birth weight, rate of the presence of proteinuria, and total protein excretion on 24-hour urine were similar in the subgroups of AA, AC, and CC genotypes in the study group. Our study demonstrated no association between PAPP-A gene rs7020782 polymorphism and PE/IUGR. PMID- 26520691 TI - Prognostic factors in Taiwanese patients with penile-invasive squamous cell carcinoma. AB - In Taiwanese patients, carcinoma of the penis is an uncommon disease. We retrospectively reviewed potential prognostic factors in Taiwanese patients with invasive-penile squamous cell carcinoma (SCC). From 1997 to 2009, 52 patients were enrolled. The median patient age at diagnosis was 66.5 years and the peak incident occurred during the 6(th) and 7(th) decades of life. Thirteen patients (25%) died of penile cancer, with a mean follow-up time of 45 months (interquartile range: 15-64 months). The 5-year cumulative cancer-specific survival rate was 81%, with 100% for those with Stage I, 90% for those with Stage II, 60% for those with Stage III, and 14% for those with Stage IV. Eleven variables, including grade, tumor, node, metastasis (TNM) stage, involvement of corpus spongiosum or corpora cavernosa, lymphovascular or perineural invasion, lymphadenectomy, and palpable lymph node, with p < 0.05 using univariate analysis were chosen for multivariate regression analysis. Three of these potential prognostic factors, including histological grade, distant metastasis, and lymphovascular invasion, remained statistically significant. Our study is the first report using the latest TNM classification (2009) to determine these potential predictors with penile SCC in Taiwan. PMID- 26520692 TI - Midterm renal functions following acute renal infarction. AB - The aim of this study was to explore clinical features of renal infarction (RI) that may have a role in diagnosis and treatment in our patient cohort and provide data on midterm renal functions. Medical records of patients with diagnosis of acute RI, established by contrast enhanced computed tomography (CT) and at least 1 year follow-up data, who were hospitalized in our clinic between 1998 and 2012 were retrospectively reviewed; including descriptive data, clinical signs and symptoms, etiologic factors, laboratory findings, and prescribed treatments. Patients with solitary infarct were treated with acetylsalicylic acid (ASA) only, whereas patients with atrial fibrillation (AF) or multiple or global infarct were treated with anticoagulants. Estimated Glomerular Filtration Rate (eGFR) referring to renal functions was determined by the Modification of Diet in Renal Disease (MDRD) formula. Twenty-seven renal units of 23 patients with acute RI were identified. The mean age was 59.7 +/- 15.7 years. Fourteen patients (60.8%) with RI had atrial fibrillation (AF) as an etiologic factor of which four had concomitant mesenteric ischemia at diagnosis. At presentation, 20 patients (86.9%) had elevated serum lactate dehydrogenase (LDH), 18 patients (78.2%) had leukocytosis, and 16 patients (69.5%) had microscopic hematuria. Two patients with concomitant mesenteric ischemia and AF passed away during follow up. Mean eGFR was 70.8 +/- 23.2 mL/min/1.73 m(2) at admission and increased to 82.3 +/- 23.4 mL/min/1.73 m(2) at 1 year follow up. RI should be considered in patients with persistent flank or abdominal pain, particularly if they are at high risk of thromboembolism. Antiplatelet and/or anticoagulant drugs are both effective treatment options according to the amplitude of the infarct for preserving kidney functions. PMID- 26520693 TI - Rivaroxaban in preventing venous thromboembolism after arthroplastic surgery in Taiwan. AB - Venous thromboembolism (VTE) is one of the severe complications of total hip arthroplasty (THA) and total knee arthroplasty (TKA). The incidence of VTE could be reduced if preventive antithrombotic medicines are used; however, the incidence of bleeding may increase. Rivaroxaban is a factor Xa inhibitor that prevents VTE after THA or TKA. This study is designed to confirm the efficacy and safety of rivaroxaban in Taiwan. This is a retrospective database study based on the data of 6996 patients provided by the Taiwan National Health Insurance Research Database from 2008 to 2012. The data included the number of prescription, the cost of prescription, and case number for patients treated with antithrombotic agents for the prevention or treatment of joint arthroplasty complications (including THA, TKA, partial hip arthroplasty, revision THA and TKA), and the incidence of thrombosis and hemorrhage from year 2008 to 2012. The overall postoperative VTE rate was 0.49%. Compared with other antithrombotic drugs, rivaroxaban and heparin analogs can reduce the percentage of thrombosis. We also found that the expenditure and hospitalization was less in the rivaroxaban group than in the heparin analogs group. Because some benefits of rivaroxaban were found in our study, further cost-effective and drug safety studies are warranted. It is important to consider the cost-effective principle for the use of antithrombotic drugs in preventing thromboembolic complications after total joint arthroplasty. PMID- 26520694 TI - Use of the Burch-Schneider cage and structural allografts in complex acetabular deficiency: 3- to 10-year follow up. AB - This study aimed to evaluate retrospectively the clinical outcomes and complications of structural allografts and Burch-Schneider antiprotrusio cages to treat severe acetabular defects in revision total hip arthroplasty (THA). Between July 2003 and December 2010, 29 patients (representing 31 hips) underwent revision THA using structural allografts and Burch-Schneider cages for acetabular reconstruction. The patients had a mean age of 59 years (range, 37-79 years). Seventeen hips had a Paprosky IIIA defect, 12 hips had a IIIB defect, and two hips had a pelvic discontinuity (PD) acetabular defect. After a mean follow up of 5.5 years (range, 3.0-10.5 years), all patients, except for two patients with recurrent infections, significantly improved, based on the mean Harris hip score (30 points vs. 67 points, p < 0.001) and the Western Ontario and McMaster Universities Arthritis index (WOMAC) score (65 points vs. 32 points, p < 0.001). Using re-revision surgery as the endpoint, the cage had a survival rate of 76% [95%, confidence interval (CI), 67.4-84.6%] at 5 years and 57% (95% CI, 39.3 74.7%) at 10 years. Other complications included hip dislocation [3 (9.7%) hips]; deep infection [3 (9.7%) hips]; and sciatic nerve impingement, vesicle-acetabular fistula, and leg lengthening [1 (3.2%) hip]. There was a trend toward a higher failure rate in hips with four revisions, compared to hips with three revisions or fewer (p = 0.055). Three hips with a failed cage underwent re-revision surgery using a standard noncemented acetabular component. In conclusion, a structural allograft with Burch-Schneider antiprotrusio cage for complex acetabular defect is a technique-demanding procedure with a 5-year survival rate of 76%. Even with failed cage reconstruction, re-revision surgery with a noncemented acetabular component may be feasible once the allograft has healed. PMID- 26520695 TI - Sarcoidosis and Sjogren's syndrome: Mimicry or coexistence? PMID- 26520696 TI - Accessory conduction pathway ablated by myocarditis in a patient with Wolff Parkinson-White syndrome. PMID- 26520697 TI - Preventable transfers in pediatric trauma: A 10-year experience at a level I pediatric trauma center. AB - BACKGROUND: Injured children are often treated at one facility then transferred to another that specializes in pediatric trauma care. The purpose of this study was to identify and characterize potentially preventable transfers (PT) to a freestanding level-I pediatric trauma center. METHODS: Children with traumatic injuries transferred between 2003 and 2013 were retrospectively analyzed. A PT was defined as a child who was discharged within 36hours of arrival without surgical intervention or advanced imaging studies. RESULTS: During this period, 6380 children were transferred, with head injury being the most common injury. 61% had CT imaging performed before transfer. The mean age was 6.9years, mean injury severity score (ISS) 10.4, and median transfer distance 37miles. 27% of these transfers were classified as PT. Air transport was used in 15% at mean charge of $18,574. 29% were discharged from the emergency department. When compared, PTs were younger (6.0 vs. 7.2years, p<0.001), with lower median ISS (5 vs. 9, p<0.001), shorter median LOS (15 vs. 43.6hours, p<0.001), and less PICU admissions (6% vs. 34%, p<0.001). CONCLUSION: A significant number of pediatric trauma transfers can be classified as preventable. Reducing preventable transfers could offer opportunities for improving value in a trauma care system. PMID- 26520698 TI - Mediastinal tumor resection via open or video-assisted surgery in 31 pediatric cases: Experiences at a single institution. AB - BACKGROUND: Video-assisted thoracic surgery (VATS) has been increasingly used for the diagnosis and treatment of thoracic diseases. Pediatric mediastinal tumors are often difficult to resect because of their proximity to important organs. For this reason, VATS is not established as a standard surgical approach for such tumors. We compared the efficacy and safety of mediastinal tumor resection in children using open thoracotomy (OT) and VATS. METHODS: A total of 31 children underwent mediastinal tumor resection (21 by VATS and 10 by OT). These nonrandomized approaches were retrospectively compared for incidence of operative complications, morbidity, and mortality. RESULTS: Tumor sizes and operation times were similar between groups. However, the VATS group required significantly fewer blood transfusions and shorter durations of thoracic drainage and hospital stays (p<0.05). Complications greater than grade 2 on the Clavien-Dindo classification occurred in four patients treated by VATS and OT. No delayed effects were noted in the survivors of either group. A patient with clear cell sarcoma of the kidney who underwent OT relapsed and died. CONCLUSION: Although complication rates were similar between the two approaches, VATS was suggested as less invasive because of fewer blood transfusions required, and shorter thoracic drainage and hospital stay durations. PMID- 26520699 TI - Fetal and neonatal presentation of OEIS complex. AB - OEIS complex is a rare entity comprising a combination of omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects. We present a case that demonstrates the imaging features of OEIS complex, which also has the rare diagnosis of a terminal myelocystocele, across multiple imaging modalities both prenatally and postnatally. A prenatal diagnosis of OEIS complex allowed for appropriate planned multidisciplinary management of this patient. PMID- 26520700 TI - Usefulness of the CPG in the management of severe S. aureus infections. PMID- 26520701 TI - Infantile tumoral calcinosis of the cervical spine presenting as torticollis. AB - The computed tomography (CT) and MRI findings of infantile tumoral calcinosis and the utility of image-guided biopsy are demonstrated. A 5-month old presented with torticollis and a calcified cervical spinal mass. The radiologic appearance suggested a malignant neoplasm, prompting CT-guided biopsy, which diagnosed tumoral calcinosis. We hope to increase awareness of this entity and describe image-guided biopsy as a way to avoid morbidity associated with open biopsy. PMID- 26520702 TI - Magnetic resonance imaging findings of undifferentiated carcinoma with osteoclast like giant cells of pancreas. AB - Undifferentiated carcinoma with osteoclast-like giant cells is a rare pancreatic and periampullary neoplasm with less than 50 cases reported in the literature. Pathologically, this tumor mimics a giant cell tumor in bones. We report a case of undifferentiated carcinoma with osteoclast-like giant cells in a 55-year-old man presenting as a pancreatic mass with associated regional and distant lymphadenopathy. On T1- and T2-weighted images, the mass shows dark signal intensity which was atypical for a pancreatic adenocarcinoma. PMID- 26520704 TI - Maintaining a Healthy Balance: Targeting TERT to Stem Benign Prostatic Hyperplasia. PMID- 26520703 TI - Intermittent Versus Continuous Androgen Deprivation Therapy in Patients with Relapsing or Locally Advanced Prostate Cancer: A Phase 3b Randomised Study (ICELAND). AB - BACKGROUND: Intermittent androgen deprivation (IAD) has received increasing attention; however, the current literature is still limited, especially in nonmetastatic prostate cancer (PCa), and the relative efficacy and safety benefits of IAD versus continuous androgen deprivation (CAD) remain unclear. OBJECTIVE: To add to the knowledge base regarding efficacy and potential benefits, including reduced side effects and improved quality of life (QoL), of IAD versus CAD in patients with nonmetastatic relapsing or locally advanced PCa. DESIGN, SETTING, AND PARTICIPANTS: A 42-mo phase 3b open-label randomised study in 933 patients from 20 European countries. INTERVENTION: Following a 6-mo induction with leuprorelin acetate (Eligard) 22.5mg 3-mo depot, patients were randomised to CAD or IAD with leuprorelin for 36 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was time to prostate-specific antigen (PSA) progression while receiving luteinising hormone-releasing hormone agonist, defined as three consecutive increasing PSA values >= 4 ng/ml >= 2 wk apart. Secondary end points included PSA progression-free survival (PFS), overall survival (OS), testosterone levels, performance status, and QoL. RESULTS AND LIMITATIONS: A total of 933 patients entered the induction phase; 701 were randomised. The median number of injections administered after randomisation was 12 (range: 1-12) for the CAD group and 3 (range: 1-10) for the IAD group. There were no statistically significant or clinically relevant differences between the groups for time to PSA progression, PSA PFS, OS, mean PSA levels over time, or QoL. A similar number of adverse events was observed in each group; the most common were hot flushes and hypertension. Study limitations include the open label design and absence of formal testosterone recovery assessment. CONCLUSIONS: IAD and CAD demonstrated similar efficacy, tolerability, and QoL in men with nonmetastatic PCa. The principal benefit of IAD compared with CAD is a potential cost reduction with comparable OS rates. There are no apparent QoL benefits. PATIENT SUMMARY: This randomised trial showed that both intermittent and continuous hormone therapy had similar efficacy, tolerability, and quality-of life profiles in patients with relapsing M0 or locally advanced prostate cancer. Intermittent therapy may be a valid option for selected patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00378690. PMID- 26520705 TI - Point/Counterpoint. Spontaneous tumors in pets are an excellent translational model for human cancers. PMID- 26520706 TI - Early detection of chemotherapy-refractory patients by monitoring textural alterations in diffuse optical spectroscopic images. AB - PURPOSE: Changes in textural characteristics of diffuse optical spectroscopic (DOS) functional images, accompanied by alterations in their mean values, are demonstrated here for the first time as early surrogates of ultimate treatment response in locally advanced breast cancer (LABC) patients receiving neoadjuvant chemotherapy (NAC). NAC, as a standard component of treatment for LABC patient, induces measurable heterogeneous changes in tumor metabolism which were evaluated using DOS-based metabolic maps. This study characterizes such inhomogeneous nature of response development, by determining alterations in textural properties of DOS images apparent at early stages of therapy, followed later by gross changes in mean values of these functional metabolic maps. METHODS: Twelve LABC patients undergoing NAC were scanned before and at four times after treatment initiation, and tomographic DOS images were reconstructed at each time. Ultimate responses of patients were determined clinically and pathologically, based on a reduction in tumor size and assessment of residual tumor cellularity. The mean value parameters and textural features were extracted from volumetric DOS images for several functional and metabolic parameters prior to the treatment initiation. Changes in these DOS-based biomarkers were also monitored over the course of treatment. The measured biomarkers were applied to differentiate patient responses noninvasively and compared to clinical and pathologic responses. RESULTS: Responding and nonresponding patients demonstrated different changes in DOS-based textural and mean-value parameters during chemotherapy. Whereas none of the biomarkers measured prior the start of therapy demonstrated a significant difference between the two patient populations, statistically significant differences were observed at week one after treatment initiation using the relative change in contrast/homogeneity of seven functional maps (0.001=0.13 mmol/kg at 1.5 T and >=0.16 mmol/kg at 3 T, the RSST1-signal time course in macrovessels and brain tissue with Gd-DOTA impermeable vasculature reaches a steady state at maximum amplitude for about 8 s. In macrovessels, a BVf of 100% was obtained validating cerebral microvascular BVf quantification (3.5%-4.5% in gray matter and 1.5%-2.0% in white matter). In tumor tissue, a continuously increasing signal is detected, necessitating signal modeling for tumor BVf calculation. CONCLUSIONS: Using approved doses of Gd-DOTA, the steady state RSST1-signal in brain tissue is reached during the first pass and corresponds to the BVf. The first-pass duration is sufficient to allow accurate BVf quantification. The RSST1 method is appropriate for serial clinical studies since it allows fast and straightforward BVf quantification without arterial input function determination. This quantitative MRI method is particularly useful to assess the efficacy of antiangiogenic agents. PMID- 26520729 TI - Evaluation of the OSC-TV iterative reconstruction algorithm for cone-beam optical CT. AB - PURPOSE: The present work evaluates an iterative reconstruction approach, namely, the ordered subsets convex (OSC) algorithm with regularization via total variation (TV) minimization in the field of cone-beam optical computed tomography (optical CT). One of the uses of optical CT is gel-based 3D dosimetry for radiation therapy, where it is employed to map dose distributions in radiosensitive gels. Model-based iterative reconstruction may improve optical CT image quality and contribute to a wider use of optical CT in clinical gel dosimetry. METHODS: This algorithm was evaluated using experimental data acquired by a cone-beam optical CT system, as well as complementary numerical simulations. A fast GPU implementation of OSC-TV was used to achieve reconstruction times comparable to those of conventional filtered backprojection. Images obtained via OSC-TV were compared with the corresponding filtered backprojections. Spatial resolution and uniformity phantoms were scanned and respective reconstructions were subject to evaluation of the modulation transfer function, image uniformity, and accuracy. The artifacts due to refraction and total signal loss from opaque objects were also studied. RESULTS: The cone-beam optical CT data reconstructions showed that OSC-TV outperforms filtered backprojection in terms of image quality, thanks to a model-based simulation of the photon attenuation process. It was shown to significantly improve the image spatial resolution and reduce image noise. The accuracy of the estimation of linear attenuation coefficients remained similar to that obtained via filtered backprojection. Certain image artifacts due to opaque objects were reduced. Nevertheless, the common artifact due to the gel container walls could not be eliminated. CONCLUSIONS: The use of iterative reconstruction improves cone-beam optical CT image quality in many ways. The comparisons between OSC-TV and filtered backprojection presented in this paper demonstrate that OSC-TV can potentially improve the rendering of spatial features and reduce cone-beam optical CT artifacts. PMID- 26520730 TI - A framework for quantification and visualization of segmentation accuracy and variability in 3D lateral ventricle ultrasound images of preterm neonates. AB - PURPOSE: Intraventricular hemorrhage (IVH) is a major cause of brain injury in preterm neonates. Three dimensional ultrasound (US) imaging systems have been developed to visualize 3D anatomical structure of preterm neonatal intracranial ventricular system with IVH and ventricular dilation. To allow quantitative analysis, the ventricle system is required to be segmented accurately and efficiently from 3D US images. Although semiautomatic segmentation algorithms have been developed, local segmentation accuracy and variability associated with these algorithms should be evaluated statistically before they can be applied in clinical settings. This work proposes a statistical framework to quantify the local accuracy and variability and performs statistical tests to identify locations where the semiautomatically segmented surfaces are significantly different from manually segmented surfaces. METHODS: Three dimensional lateral ventricle US images of preterm neonates were each segmented six times manually and using a semiautomated segmentation algorithm. The local difference between manually and algorithmically segmented surfaces as well as the segmentation variability for each method was computed and superimposed on the ventricular surface of each subject. To summarize the segmentation performance for a whole group of subjects, the subject-specific local difference and standard deviation maps were registered onto a 3D template ventricular surface using a nonrigid registration algorithm. Pointwise, intersubject average accuracy and pooled variability for the whole group of subjects can be computed and visualized on the template surface, providing a summary of performance of the segmentation algorithm for the whole group of ventricles with highly variable geometry. In addition to pointwise statistical analysis performed on the template surface, statistical conclusion regarding the accuracy of the segmentation algorithm was made for subregions and the whole ventricle with the spatial correlation of pointwise accuracy taken into account. RESULTS: Ten 3D US images were involved in this study. Pointwise local difference, DeltaS, its absolute value |DeltaS| as well as the standard deviations of the manual and algorithm segmentations were computed and superimposed on the each ventricle surface. Regions with lower segmentation accuracy and higher segmentation variability can be identified from these maps, and the localized information was applied to improve the accuracy of the algorithm. Intersubject average DeltaS and |DeltaS| as well as pooled standard deviations was computed on the template surface. Intersubject average DeltaS and |DeltaS| indicated that the algorithm underestimated regions in the neighborhood of the tips of anterior, inferior, and posterior horns. Intersubject pooled standard deviations indicated that manual segmentation had a higher segmentation variability than algorithm segmentation over the whole ventricle. Statistical analysis on the template surface showed that there was significant difference between algorithm and manual methods for segmenting the right lateral ventricle but not for the left lateral ventricle. CONCLUSIONS: A framework was proposed for evaluating, visualizing, and summarizing the local accuracy and variability of a segmentation algorithm. This framework can be used for improving the accuracy of segmentation algorithms, as well as providing useful feedback to improve the manual segmentation performance. More importantly, this framework can be applied for longitudinal monitoring of local ventricular changes of neonates with IVH. PMID- 26520732 TI - Degradation of proton depth dose distributions attributable to microstructures in lung-equivalent material. AB - PURPOSE: The purpose of the work reported here was to investigate the influence of sub-millimeter size heterogeneities on the degradation of the distal edges of proton beams and to validate Monte Carlo (MC) methods' ability to correctly predict such degradation. METHODS: A custom-designed high-resolution plastic phantom approximating highly heterogeneous, lung-like structures was employed in measurements and in Monte Carlo simulations to evaluate the degradation of proton Bragg curves penetrating heterogeneous media. RESULTS: Significant differences in distal falloff widths and in peak dose values were observed in the measured and the Monte Carlo simulated curves compared to pristine proton Bragg curves. Furthermore, differences between simulations of beams penetrating CT images of the phantom did not agree well with the corresponding experimental differences. The distal falloff widths in CT image-based geometries were underestimated by up to 0.2 cm in water (corresponding to 0.8-1.4 cm in lung tissue), and the peak dose values of pristine proton beams were overestimated by as much as ~35% compared to measured curves or depth-dose curves simulated on the basis of true geometry. The authors demonstrate that these discrepancies were caused by the limited spatial resolution of CT images that served as a basis for dose calculations and lead to underestimation of the impact of the fine structure of tissue heterogeneities. A convolution model was successfully applied to mitigate the underestimation. CONCLUSIONS: The results of this study justify further development of models to better represent heterogeneity effects in soft-tissue geometries, such as lung, and to correct systematic underestimation of the degradation of the distal edge of proton doses. PMID- 26520731 TI - Enhanced resting-state dynamics of the hemoglobin signal as a novel biomarker for detection of breast cancer. AB - PURPOSE: The work presented here demonstrates an application of diffuse optical tomography (DOT) to the problem of breast-cancer diagnosis. The potential for using spatial and temporal variability measures of the hemoglobin signal to identify useful biomarkers was studied. METHODS: DOT imaging data were collected using two instrumentation platforms the authors developed, which were suitable for exploring tissue dynamics while performing a simultaneous bilateral exam. For each component of the hemoglobin signal (e.g., total, oxygenated), the image time series was reduced to eight scalar metrics that were affected by one or more dynamic properties of the breast microvasculature (e.g., average amplitude, amplitude heterogeneity, strength of spatial coordination). Receiver-operator characteristic (ROC) analyses, comparing groups of subjects with breast cancer to various control groups (i.e., all noncancer subjects, only those with diagnosed benign breast pathology, and only those with no known breast pathology), were performed to evaluate the effect of cancer on the magnitudes of the metrics and of their interbreast differences and ratios. RESULTS: For women with known breast cancer, simultaneous bilateral DOT breast measures reveal a marked increase in the resting-state amplitude of the vasomotor response in the hemoglobin signal for the affected breast, compared to the contralateral, noncancer breast. Reconstructed 3D spatial maps of observed dynamics also show that this behavior extends well beyond the tumor border. In an effort to identify biomarkers that have the potential to support clinical aims, a group of scalar quantities extracted from the time series measures was systematically examined. This analysis showed that many of the quantities obtained by computing paired responses from the bilateral scans (e.g., interbreast differences, ratios) reveal statistically significant differences between the cancer-positive and -negative subject groups, while the corresponding measures derived from individual breast scans do not. ROC analyses yield area-under-curve values in the 77%-87% range, depending on the metric, with sensitivity and specificity values ranging from 66% to 91%. An interesting result is the initially unexpected finding that the hemodynamic-image metrics are only weakly dependent on the tumor burden, implying that the DOT technique employed is sensitive to tumor-induced changes in the vascular dynamics of the surrounding breast tissue as well. Computational modeling studies serve to identify which properties of the vasomotor response (e.g., average amplitude, amplitude heterogeneity, and phase heterogeneity) principally determine the values of the metrics and their codependences. Findings from the modeling studies also serve to clarify the influence of spatial-response heterogeneity and of system-design limitations, and they reveal the impact that a complex dependence of metric values on the modeled behaviors has on the success in distinguishing between cancer-positive and -negative subjects. CONCLUSIONS: The authors identified promising hemoglobin-based biomarkers for breast cancer from measures of the resting-state dynamics of the vascular bed. A notable feature of these biomarkers is that their spatial extent encompasses a large fraction of the breast volume, which is mainly independent of tumor size. Tumor induced induction of nitric oxide synthesis, a well-established concomitant of many breast cancers, is offered as a plausible biological causal factor for the reported findings. PMID- 26520733 TI - Simultaneous 3D-2D image registration and C-arm calibration: Application to endovascular image-guided interventions. AB - PURPOSE: Three-dimensional to two-dimensional (3D-2D) image registration is a key to fusion and simultaneous visualization of valuable information contained in 3D pre-interventional and 2D intra-interventional images with the final goal of image guidance of a procedure. In this paper, the authors focus on 3D-2D image registration within the context of intracranial endovascular image-guided interventions (EIGIs), where the 3D and 2D images are generally acquired with the same C-arm system. The accuracy and robustness of any 3D-2D registration method, to be used in a clinical setting, is influenced by (1) the method itself, (2) uncertainty of initial pose of the 3D image from which registration starts, (3) uncertainty of C-arm's geometry and pose, and (4) the number of 2D intra interventional images used for registration, which is generally one and at most two. The study of these influences requires rigorous and objective validation of any 3D-2D registration method against a highly accurate reference or "gold standard" registration, performed on clinical image datasets acquired in the context of the intervention. METHODS: The registration process is split into two sequential, i.e., initial and final, registration stages. The initial stage is either machine-based or template matching. The latter aims to reduce possibly large in-plane translation errors by matching a projection of the 3D vessel model and 2D image. In the final registration stage, four state-of-the-art intrinsic image-based 3D-2D registration methods, which involve simultaneous refinement of rigid-body and C-arm parameters, are evaluated. For objective validation, the authors acquired an image database of 15 patients undergoing cerebral EIGI, for which accurate gold standard registrations were established by fiducial marker coregistration. RESULTS: Based on target registration error, the obtained success rates of 3D to a single 2D image registration after initial machine-based and template matching and final registration involving C-arm calibration were 36%, 73%, and 93%, respectively, while registration accuracy of 0.59 mm was the best after final registration. By compensating in-plane translation errors by initial template matching, the success rates achieved after the final stage improved consistently for all methods, especially if C-arm calibration was performed simultaneously with the 3D-2D image registration. CONCLUSIONS: Because the tested methods perform simultaneous C-arm calibration and 3D-2D registration based solely on anatomical information, they have a high potential for automation and thus for an immediate integration into current interventional workflow. One of the authors' main contributions is also comprehensive and representative validation performed under realistic conditions as encountered during cerebral EIGI. PMID- 26520734 TI - Collision prediction software for radiotherapy treatments. AB - PURPOSE: This work presents a method of collision predictions for external beam radiotherapy using surface imaging. The present methodology focuses on collision prediction during treatment simulation to evaluate the clearance of a patient's treatment position and allow for its modification if necessary. METHODS: A Kinect camera (Microsoft, Redmond, WA) is used to scan the patient and immobilization devices in the treatment position at the simulator. The surface is reconstructed using the skanect software (Occipital, Inc., San Francisco, CA). The treatment isocenter is marked using simulated orthogonal lasers projected on the surface scan. The point cloud of this surface is then shifted to isocenter and converted from Cartesian to cylindrical coordinates. A slab models the treatment couch. A cylinder with a radius equal to the normal distance from isocenter to the collimator plate, and a height defined by the collimator diameter is used to estimate collisions. Points within the cylinder clear through a full gantry rotation with the treatment couch at 0 degrees , while points outside of it collide. The angles of collision are reported. This methodology was experimentally verified using a mannequin positioned in an alpha cradle with both arms up. A planning CT scan of the mannequin was performed, two isocenters were marked in pinnacle, and this information was exported to AlignRT (VisionRT, London, UK)--a surface imaging system for patient positioning. This was used to ensure accurate positioning of the mannequin in the treatment room, when available. Collision calculations were performed for the two treatment isocenters and the results compared to the collisions detected the room. The accuracy of the Kinect-Skanect surface was evaluated by comparing it to the external surface of the planning CT scan. RESULTS: Experimental verification results showed that the predicted angles of collision matched those recorded in the room within 0.5 degrees , in most cases (largest deviation -1.2 degrees ). The accuracy study for the Kinect-Skanect surface showed an average discrepancy between the CT external contour and the surface scan of 2.2 mm. CONCLUSIONS: This methodology provides fast and reliable collision predictions using surface imaging. The use of the Kinect-Skanect system allows for a comprehensive modeling of the patient topography including all the relevant anatomy and immobilization devices that may lead to collisions. The use of this tool at the treatment simulation stage may allow therapists to evaluate the clearance of a patient's treatment position and optimize it before the planning CT scan is performed. This can allow for safer treatments for the patients due to better collision predictions and improved clinical workflow by minimizing replanning and resimulations due to unforeseen clearance issues. PMID- 26520735 TI - The development and verification of a highly accurate collision prediction model for automated noncoplanar plan delivery. AB - PURPOSE: Significant dosimetric benefits had been previously demonstrated in highly noncoplanar treatment plans. In this study, the authors developed and verified an individualized collision model for the purpose of delivering highly noncoplanar radiotherapy and tested the feasibility of total delivery automation with Varian TrueBeam developer mode. METHODS: A hand-held 3D scanner was used to capture the surfaces of an anthropomorphic phantom and a human subject, which were positioned with a computer-aided design model of a TrueBeam machine to create a detailed virtual geometrical collision model. The collision model included gantry, collimator, and couch motion degrees of freedom. The accuracy of the 3D scanner was validated by scanning a rigid cubical phantom with known dimensions. The collision model was then validated by generating 300 linear accelerator orientations corresponding to 300 gantry-to-couch and gantry-to phantom distances, and comparing the corresponding distance measurements to their corresponding models. The linear accelerator orientations reflected uniformly sampled noncoplanar beam angles to the head, lung, and prostate. The distance discrepancies between measurements on the physical and virtual systems were used to estimate treatment-site-specific safety buffer distances with 0.1%, 0.01%, and 0.001% probability of collision between the gantry and couch or phantom. Plans containing 20 noncoplanar beams to the brain, lung, and prostate optimized via an in-house noncoplanar radiotherapy platform were converted into XML script for automated delivery and the entire delivery was recorded and timed to demonstrate the feasibility of automated delivery. RESULTS: The 3D scanner measured the dimension of the 14 cm cubic phantom within 0.5 mm. The maximal absolute discrepancy between machine and model measurements for gantry-to-couch and gantry to-phantom was 0.95 and 2.97 cm, respectively. The reduced accuracy of gantry-to phantom measurements was attributed to phantom setup errors due to the slightly deformable and flexible phantom extremities. The estimated site-specific safety buffer distance with 0.001% probability of collision for (gantry-to-couch, gantry to-phantom) was (1.23 cm, 3.35 cm), (1.01 cm, 3.99 cm), and (2.19 cm, 5.73 cm) for treatment to the head, lung, and prostate, respectively. Automated delivery to all three treatment sites was completed in 15 min and collision free using a digital Linac. CONCLUSIONS: An individualized collision prediction model for the purpose of noncoplanar beam delivery was developed and verified. With the model, the study has demonstrated the feasibility of predicting deliverable beams for an individual patient and then guiding fully automated noncoplanar treatment delivery. This work motivates development of clinical workflows and quality assurance procedures to allow more extensive use and automation of noncoplanar beam geometries. PMID- 26520736 TI - Correction of quantification errors in pelvic and spinal lesions caused by ignoring higher photon attenuation of bone in [18F]NaF PET/MR. AB - PURPOSE: MR-based attenuation correction (MRAC) in routine clinical whole-body positron emission tomography and magnetic resonance imaging (PET/MRI) is based on tissue type segmentation. Due to lack of MR signal in cortical bone and the varying signal of spongeous bone, standard whole-body segmentation-based MRAC ignores the higher attenuation of bone compared to the one of soft tissue (MRACnobone). The authors aim to quantify and reduce the bias introduced by MRACnobone in the standard uptake value (SUV) of spinal and pelvic lesions in 20 PET/MRI examinations with [18F]NaF. METHODS: The authors reconstructed 20 PET/MR [18F]NaF patient data sets acquired with a Philips Ingenuity TF PET/MRI. The PET raw data were reconstructed with two different attenuation images. First, the authors used the vendor-provided MRAC algorithm that ignores the higher attenuation of bone to reconstruct PETnobone. Second, the authors used a threshold-based algorithm developed in their group to automatically segment bone structures in the [18F]NaF PET images. Subsequently, an attenuation coefficient of 0.11 cm(-1) was assigned to the segmented bone regions in the MRI-based attenuation image (MRACbone) which was used to reconstruct PETbone. The automatic bone segmentation algorithm was validated in six PET/CT [18F]NaF examinations. Relative SUVmean and SUVmax differences between PETbone and PETnobone of 8 pelvic and 41 spinal lesions, and of other regions such as lung, liver, and bladder, were calculated. By varying the assigned bone attenuation coefficient from 0.11 to 0.13 cm(-1), the authors investigated its influence on the reconstructed SUVs of the lesions. RESULTS: The comparison of [18F]NaF-based and CT-based bone segmentation in the six PET/CT patients showed a Dice similarity of 0.7 with a true positive rate of 0.72 and a false discovery rate of 0.33. The [18F]NaF-based bone segmentation worked well in the pelvis and spine. However, it showed artifacts in the skull and in the extremities. The analysis of the 20 [18F]NaF PET/MRI examinations revealed relative SUVmax differences between PETnobone and PETbone of (-8.8%+/-2.7%, p=0.01) and (-8.1%+/-1.9%, p=2.4*10(-8)) in pelvic and spinal lesions, respectively. A maximum SUVmax underestimation of -13.7% was found in lesion in the third cervical spine. The averaged SUVmean differences in volumes of interests in lung, liver, and bladder were below 3%. The average SUVmax differences in pelvic and spinal lesions increased from -9% to -18% and 8% to -17%, respectively, when increasing the assigned bone attenuation coefficient from 0.11 to 0.13 cm(-1). CONCLUSIONS: The developed automatic [18F]NaF PET-based bone segmentation allows to include higher bone attenuation in whole-body MRAC and thus improves quantification accuracy for pelvic and spinal lesions in [18F]NaF PET/MRI examinations. In nonbone structures (e.g., lung, liver, and bladder), MRACnobone yields clinically acceptable accuracy. PMID- 26520737 TI - Lung deformations and radiation-induced regional lung collapse in patients treated with stereotactic body radiation therapy. AB - PURPOSE: To differentiate radiation-induced fibrosis from regional lung collapse outside of the high dose region in patients treated with stereotactic body radiation therapy (SBRT) for lung tumors. METHODS: Lung deformation maps were computed from pre-treatment and post-treatment computed tomography (CT) scans using a point-to-point translation method. Fifty anatomical landmarks inside the lung (vessel or airway branches) were matched on planning and follow-up scans for the computation process. Two methods using the deformation maps were developed to differentiate regional lung collapse from fibrosis: vector field and Jacobian methods. A total of 40 planning and follow-ups CT scans were analyzed for 20 lung SBRT patients. RESULTS: Regional lung collapse was detected in 15 patients (75%) using the vector field method, in ten patients (50%) using the Jacobian method, and in 12 patients (60%) by radiologists. In terms of sensitivity and specificity the Jacobian method performed better. Only weak correlations were observed between the dose to the proximal airways and the occurrence of regional lung collapse. CONCLUSIONS: The authors presented and evaluated two novel methods using anatomical lung deformations to investigate lung collapse and fibrosis caused by SBRT treatment. Differentiation of these distinct physiological mechanisms beyond what is usually labeled "fibrosis" is necessary for accurate modeling of lung SBRT-induced injuries. With the help of better models, it becomes possible to expand the therapeutic benefits of SBRT to a larger population of lung patients with large or centrally located tumors that were previously considered ineligible. PMID- 26520738 TI - Technical Report: TG-142 compliant and comprehensive quality assurance tests for respiratory gating. AB - PURPOSE: To develop and establish a comprehensive gating commissioning and quality assurance procedure in compliance with TG-142. METHODS: Eight Varian TrueBeam Linacs were used for this study. Gating commissioning included an end-to end test and baseline establishment. The end-to-end test was performed using a CIRS dynamic thoracic phantom with a moving cylinder inside the lung, which was used for carrying both optically simulated luminescence detectors (OSLDs) and Gafchromic EBT2 films while the target is moving, for a point dose check and 2D profile check. In addition, baselines were established for beam-on temporal delay and calibration of the surrogate, for both megavoltage (MV) and kilovoltage (kV) beams. A motion simulation device (MotionSim) was used to provide periodic motion on a platform, in synchronizing with a surrogate motion. The overall accuracy and uncertainties were analyzed and compared. RESULTS: The OSLD readings were within 5% compared to the planned dose (within measurement uncertainty) for both phase and amplitude gated deliveries. Film results showed less than 3% agreement to the predicted dose with a standard sinusoid motion. The gate-on temporal accuracy was averaged at 139+/-10 ms for MV beams and 92+/-11 ms for kV beams. The temporal delay of the surrogate motion depends on the motion speed and was averaged at 54.6+/-3.1 ms for slow, 24.9+/-2.9 ms for intermediate, and 23.0+/-20.1 ms for fast speed. CONCLUSIONS: A comprehensive gating commissioning procedure was introduced for verifying the output accuracy and establishing the temporal accuracy baselines with respiratory gating. The baselines are needed for routine quality assurance tests, as suggested by TG-142. PMID- 26520739 TI - Luminescence imaging of water during proton-beam irradiation for range estimation. AB - PURPOSE: Proton therapy has the ability to selectively deliver a dose to the target tumor, so the dose distribution should be accurately measured by a precise and efficient method. The authors found that luminescence was emitted from water during proton irradiation and conjectured that this phenomenon could be used for estimating the dose distribution. METHODS: To achieve more accurate dose distribution, the authors set water phantoms on a table with a spot scanning proton therapy system and measured the luminescence images of these phantoms with a high-sensitivity, cooled charge coupled device camera during proton-beam irradiation. The authors imaged the phantoms of pure water, fluorescein solution, and an acrylic block. RESULTS: The luminescence images of water phantoms taken during proton-beam irradiation showed clear Bragg peaks, and the measured proton ranges from the images were almost the same as those obtained with an ionization chamber. Furthermore, the image of the pure-water phantom showed almost the same distribution as the tap-water phantom, indicating that the luminescence image was not related to impurities in the water. The luminescence image of the fluorescein solution had ~3 times higher intensity than water, with the same proton range as that of water. The luminescence image of the acrylic phantom had a 14.5% shorter proton range than that of water; the proton range in the acrylic phantom generally matched the calculated value. The luminescence images of the tap-water phantom during proton irradiation could be obtained in less than 2 s. CONCLUSIONS: Luminescence imaging during proton-beam irradiation is promising as an effective method for range estimation in proton therapy. PMID- 26520740 TI - Technical Note: Immunohistochemical evaluation of mouse brain irradiation targeting accuracy with 3D-printed immobilization device. AB - PURPOSE: Small animal immobilization devices facilitate positioning of animals for reproducible imaging and accurate focal radiation therapy. In this study, the authors demonstrate the use of three-dimensional (3D) printing technology to fabricate a custom-designed mouse head restraint. The authors evaluate the accuracy of this device for the purpose of mouse brain irradiation. METHODS: A mouse head holder was designed for a microCT couch using cad software and printed in an acrylic based material. Ten mice received half-brain radiation while positioned in the 3D-printed head holder. Animal placement was achieved using on board image guidance and computerized asymmetric collimators. To evaluate the precision of beam localization for half-brain irradiation, mice were sacrificed approximately 30 min after treatment and brain sections were stained for gamma H2AX, a marker for DNA breaks. The distance and angle of the gamma-H2AX radiation beam border to longitudinal fissure were measured on histological samples. Animals were monitored for any possible trauma from the device. RESULTS: Visualization of the radiation beam on ex vivo brain sections with gamma-H2AX immunohistochemical staining showed a sharp radiation field within the tissue. Measurements showed a mean irradiation targeting error of 0.14+/-0.09 mm (standard deviation). Rotation between the beam axis and mouse head was 1.2 degrees +/-1.0 degrees (standard deviation). The immobilization device was easily adjusted to accommodate different sizes of mice. No signs of trauma to the mice were observed from the use of tooth block and ear bars. CONCLUSIONS: The authors designed and built a novel 3D-printed mouse head holder with many desired features for accurate and reproducible radiation targeting. The 3D printing technology was found to be practical and economical for producing a small animal imaging and radiation restraint device and allows for customization for study specific needs. PMID- 26520741 TI - Spherical grating based x-ray Talbot interferometry. AB - PURPOSE: Grating interferometry is a state-of-the-art x-ray imaging approach, which can acquire information on x-ray attenuation, phase shift, and small-angle scattering simultaneously. Phase-contrast imaging and dark-field imaging are very sensitive to microstructural variation and offers superior contrast resolution for biological soft tissues. However, a common x-ray tube is a point-like source. As a result, the popular planar grating imaging configuration seriously restricts the flux of photons and decreases the visibility of signals, yielding a limited field of view. The purpose of this study is to extend the planar x-ray grating imaging theory and methods to a spherical grating scheme for a wider range of preclinical and clinical applications. METHODS: A spherical grating matches the wave front of a point x-ray source very well, allowing the perpendicular incidence of x-rays on the grating to achieve a higher visibility over a larger field of view than the planer grating counterpart. A theoretical analysis of the Talbot effect for spherical grating imaging is proposed to establish a basic foundation for x-ray spherical gratings interferometry. An efficient method of spherical grating imaging is also presented to extract attenuation, differential phase, and dark-field images in the x-ray spherical grating interferometer. RESULTS: Talbot self-imaging with spherical gratings is analyzed based on the Rayleigh-Sommerfeld diffraction formula, featuring a periodic angular distribution in a polar coordinate system. The Talbot distance is derived to reveal the Talbot self-imaging pattern. Numerical simulation results show the self-imaging phenomenon of a spherical grating interferometer, which is in agreement with the theoretical prediction. CONCLUSIONS: X-ray Talbot interferometry with spherical gratings has a significant practical promise. Relative to planar grating imaging, spherical grating based x-ray Talbot interferometry has a larger field of view and improves both signal visibility and dose utilization for pre-clinical and clinical applications. PMID- 26520743 TI - The influence of neutron contamination on dosimetry in external photon beam radiotherapy. AB - PURPOSE: Photon fields with energies above ~7 MeV are contaminated by neutrons due to photonuclear reactions. Their influence on dosimetry-although considered to be very low-is widely unexplored. METHODS: In this work, Monte Carlo based investigations into this issue performed with fluka and egsnrc are presented. A typical Linac head in 18 MV-X mode was modeled equivalently within both codes. egsnrc was used for the photon and fluka for the neutron production and transport simulation. Water depth dose profiles and the response of different detectors (Farmer chamber, TLD-100, TLD-600H, and TLD-700H chip) in five representative depths were simulated and the neutrons' impact (neutron absorbed dose relative to photon absorbed dose) was calculated. To take account of the neutrons' influence, a theoretically required correction factor was defined and calculated for five representative water depths. RESULTS: The neutrons' impact on the absorbed dose to water was found to be below 0.1% for all depths and their impact on the response of the Farmer chamber and the TLD-700H chip was found to be even less. For the TLD-100 and the TLD-600H chip it was found to be up to 0.3% and 0.7%, respectively. The theoretical correction factors to be applied to absorbed dose to water values measured with these four detectors in a depth different from the reference/calibration depth were calculated and found to be below 0.05% for the Farmer chamber and the TLD-700H chip, but up to 0.15% and 0.35% for the TLD-100 and TLD-600H chips, respectively. In thermoluminescence dosimetry the neutrons' influence (and therefore the additional inaccuracy in measurement) was found to be higher for TLD materials whose 6Li fraction is high, such as TLD-100 and TLD 600H, resulting from the thermal neutron capture reaction on 6Li. CONCLUSIONS: The impact of photoneutrons on the absorbed dose to water and on the response of a typical ionization chamber as well as three different types of TLD chips was quantified and was as expected found to be very low relative to that of the primary photons. For most practical reasons the neutrons' influence on dosimetry might be neglected while for absolute precise thermoluminescence dosimetry in high energy photon fields, the use of TLD-700H (<0.03% 6Li) instead of the commonly used TLD-100 (7.4% 6Li) or even the extra neutron sensitive TLD-600H is recommended (95.6% 6Li) due to the additional inaccuracy in measurement for TLD materials with a high 6Li fraction. PMID- 26520742 TI - Computer-aided breast MR image feature analysis for prediction of tumor response to chemotherapy. AB - PURPOSE: To identify a new clinical marker based on quantitative kinetic image features analysis and assess its feasibility to predict tumor response to neoadjuvant chemotherapy. METHODS: The authors assembled a dataset involving breast MR images acquired from 68 cancer patients before undergoing neoadjuvant chemotherapy. Among them, 25 patients had complete response (CR) and 43 had partial and nonresponse (NR) to chemotherapy based on the response evaluation criteria in solid tumors. The authors developed a computer-aided detection scheme to segment breast areas and tumors depicted on the breast MR images and computed a total of 39 kinetic image features from both tumor and background parenchymal enhancement regions. The authors then applied and tested two approaches to classify between CR and NR cases. The first one analyzed each individual feature and applied a simple feature fusion method that combines classification results from multiple features. The second approach tested an attribute selected classifier that integrates an artificial neural network (ANN) with a wrapper subset evaluator, which was optimized using a leave-one-case-out validation method. RESULTS: In the pool of 39 features, 10 yielded relatively higher classification performance with the areas under receiver operating characteristic curves (AUCs) ranging from 0.61 to 0.78 to classify between CR and NR cases. Using a feature fusion method, the maximum AUC=0.85+/-0.05. Using the ANN-based classifier, AUC value significantly increased to 0.96+/-0.03 (p<0.01). CONCLUSIONS: This study demonstrated that quantitative analysis of kinetic image features computed from breast MR images acquired prechemotherapy has potential to generate a useful clinical marker in predicting tumor response to chemotherapy. PMID- 26520744 TI - Multigrid reconstruction with block-iterative updates for breast tomosynthesis. AB - PURPOSE: The authors wish to evaluate the possible advantages of using a multigrid approach to maximum-a-posteriori reconstruction in digital breast tomosynthesis together with block-iterative updates in the form of either plane by-plane updates or ordered subsets. METHODS: The authors previously developed a penalized maximum likelihood reconstruction algorithm with resolution model dedicated to breast tomosynthesis [K. Michielsen et al., "Patchwork reconstruction with resolution modeling for digital breast tomosynthesis," Med. Phys. 40, 031105 (10pp.) (2013)]. This algorithm was extended with ordered subsets and multigrid updates, and the effects on the convergence and on limited angle artifact appearance were evaluated on a mathematical phantom and patient data. To ensure a fair comparison, the analysis was performed at the same computational cost for all methods. To assess convergence and artifact creation in the phantom reconstructions, the authors looked at posterior likelihood, sum of squared residuals, contrast of identical calcifications at different positions, and the standard deviation between the contrasts of these calcifications. For the patient cases, the authors calculated posterior likelihood, measured the signal difference to noise ratio of subtle microcalcifications, and visually evaluated the reconstructions. RESULTS: The authors selected multigrid sequences scoring in the best 10% of the four evaluated parameters, except for the reconstructions with subsets where a low standard deviation of the contrast was incompatible with the three other parameters. In further evaluation of phantom reconstructions from noisy data and patient data, the authors found improved convergence and a reduction in artifacts for our chosen multigrid reconstructions compared to the single grid reconstructions with equivalent computational cost, although there was a diminishing return for an increasing number of subsets. CONCLUSIONS: Multigrid reconstruction improves upon reconstruction with a fixed grid when evaluated at a fixed computational cost. For multigrid reconstruction, using plane-by-plane updates or applying ordered subsets resulted in similar performance. PMID- 26520745 TI - Improved quality of intrafraction kilovoltage images by triggered readout of unexposed frames. AB - PURPOSE: The gantry-mounted kilovoltage (kV) imager of modern linear accelerators can be used for real-time tumor localization during radiation treatment delivery. However, the kV image quality often suffers from cross-scatter from the megavoltage (MV) treatment beam. This study investigates readout of unexposed kV frames as a means to improve the kV image quality in a series of experiments and a theoretical model of the observed image quality improvements. METHODS: A series of fluoroscopic images were acquired of a solid water phantom with an embedded gold marker and an air cavity with and without simultaneous radiation of the phantom with a 6 MV beam delivered perpendicular to the kV beam with 300 and 600 monitor units per minute (MU/min). An in-house built device triggered readout of zero, one, or multiple unexposed frames between the kV exposures. The unexposed frames contained part of the MV scatter, consequently reducing the amount of MV scatter accumulated in the exposed frames. The image quality with and without unexposed frame readout was quantified as the contrast-to-noise ratio (CNR) of the gold marker and air cavity for a range of imaging frequencies from 1 to 15 Hz. To gain more insight into the observed CNR changes, the image lag of the kV imager was measured and used as input in a simple model that describes the CNR with unexposed frame readout in terms of the contrast, kV noise, and MV noise measured without readout of unexposed frames. RESULTS: Without readout of unexposed kV frames, the quality of intratreatment kV images decreased dramatically with reduced kV frequencies due to MV scatter. The gold marker was only visible for imaging frequencies>=3 Hz at 300 MU/min and >=5 Hz for 600 MU/min. Visibility of the air cavity required even higher imaging frequencies. Readout of multiple unexposed frames ensured visibility of both structures at all imaging frequencies and a CNR that was independent of the kV frame rate. The image lag was 12.2%, 2.2%, and 0.9% in the first, second, and third frame after an exposure. The CNR model predicted the CNR with triggered image readout with a mean absolute error of 2.0% for the gold marker. CONCLUSIONS: A device that triggers readout of unexposed frames during kV fluoroscopy was built and shown to greatly improve the quality of intratreatment kV images. A simple theoretical model successfully described the CNR improvements with the device. PMID- 26520746 TI - Technical Note: MR-visualization of interventional devices using transient field alterations and balanced steady-state free precession imaging. AB - PURPOSE: In interventional magnetic resonance imaging, instruments can be equipped with conducting wires for visualization by current application. The potential of sequence triggered application of transient direct currents in balanced steady-state free precession (bSSFP) imaging is demonstrated. METHODS: A conductor and a modified catheter were examined in water phantoms and in an ex vivo porcine liver. The current was switched by a trigger pulse in the bSSFP sequence in an interval between radiofrequency pulse and signal acquisition. Magnitude and phase images were recorded. Regions with transient field alterations were evaluated by a postprocessing algorithm. A phase mask was computed and overlaid with the magnitude image. RESULTS: Transient field alterations caused continuous phase shifts, which were separated by the postprocessing algorithm from phase jumps due to persistent field alterations. The overlaid images revealed the position of the conductor. The modified catheter generated visible phase offset in all orientations toward the static magnetic field and could be unambiguously localized in the ex vivo porcine liver. CONCLUSIONS: The application of a sequence triggered, direct current in combination with phase imaging allows conspicuous localization of interventional devices with a bSSFP sequence. PMID- 26520747 TI - A continuous surface reconstruction method on point cloud captured from a 3D surface photogrammetry system. AB - PURPOSE: To accurately and efficiently reconstruct a continuous surface from noisy point clouds captured by a surface photogrammetry system (VisionRT). METHODS: The authors have developed a level-set based surface reconstruction method on point clouds captured by a surface photogrammetry system (VisionRT). The proposed method reconstructs an implicit and continuous representation of the underlying patient surface by optimizing a regularized fitting energy, offering extra robustness to noise and missing measurements. By contrast to explicit/discrete meshing-type schemes, their continuous representation is particularly advantageous for subsequent surface registration and motion tracking by eliminating the need for maintaining explicit point correspondences as in discrete models. The authors solve the proposed method with an efficient narrowband evolving scheme. The authors evaluated the proposed method on both phantom and human subject data with two sets of complementary experiments. In the first set of experiment, the authors generated a series of surfaces each with different black patches placed on one chest phantom. The resulting VisionRT measurements from the patched area had different degree of noise and missing levels, since VisionRT has difficulties in detecting dark surfaces. The authors applied the proposed method to point clouds acquired under these different configurations, and quantitatively evaluated reconstructed surfaces by comparing against a high-quality reference surface with respect to root mean squared error (RMSE). In the second set of experiment, the authors applied their method to 100 clinical point clouds acquired from one human subject. In the absence of ground truth, the authors qualitatively validated reconstructed surfaces by comparing the local geometry, specifically mean curvature distributions, against that of the surface extracted from a high-quality CT obtained from the same patient. RESULTS: On phantom point clouds, their method achieved submillimeter reconstruction RMSE under different configurations, demonstrating quantitatively the faith of the proposed method in preserving local structural properties of the underlying surface in the presence of noise and missing measurements, and its robustness toward variations of such characteristics. On point clouds from the human subject, the proposed method successfully reconstructed all patient surfaces, filling regions where raw point coordinate readings were missing. Within two comparable regions of interest in the chest area, similar mean curvature distributions were acquired from both their reconstructed surface and CT surface, with mean and standard deviation of (MUrecon=-2.7*10(-3) mm(-1), sigmarecon=7.0*10(-3) mm(-1)) and (MUCT=-2.5*10(-3) mm(-1), sigmaCT=5.3*10(-3) mm(-1)), respectively. The agreement of local geometry properties between the reconstructed surfaces and the CT surface demonstrated the ability of the proposed method in faithfully representing the underlying patient surface. CONCLUSIONS: The authors have integrated and developed an accurate level-set based continuous surface reconstruction method on point clouds acquired by a 3D surface photogrammetry system. The proposed method has generated a continuous representation of the underlying phantom and patient surfaces with good robustness against noise and missing measurements. It serves as an important first step for further development of motion tracking methods during radiotherapy. PMID- 26520748 TI - Technical Note: Phantom study to evaluate the dose and image quality effects of a computed tomography organ-based tube current modulation technique. AB - PURPOSE: This technical note quantifies the dose and image quality performance of a clinically available organ-dose-based tube current modulation (ODM) technique, using experimental and simulation phantom studies. The investigated ODM implementation reduces the tube current for the anterior source positions, without increasing current for posterior positions, although such an approach was also evaluated for comparison. METHODS: Axial CT scans at 120 kV were performed on head and chest phantoms on an ODM-equipped scanner (Optima CT660, GE Healthcare, Chalfont St. Giles, England). Dosimeters quantified dose to breast, lung, heart, spine, eye lens, and brain regions for ODM and 3D-modulation (SmartmA) settings. Monte Carlo simulations, validated with experimental data, were performed on 28 voxelized head phantoms and 10 chest phantoms to quantify organ dose and noise standard deviation. The dose and noise effects of increasing the posterior tube current were also investigated. RESULTS: ODM reduced the dose for all experimental dosimeters with respect to SmartmA, with average dose reductions across dosimeters of 31% (breast), 21% (lung), 24% (heart), 6% (spine), 19% (eye lens), and 11% (brain), with similar results for the simulation validation study. In the phantom library study, the average dose reduction across all phantoms was 34% (breast), 20% (lung), 8% (spine), 20% (eye lens), and 8% (brain). ODM increased the noise standard deviation in reconstructed images by 6% 20%, with generally greater noise increases in anterior regions. Increasing the posterior tube current provided similar dose reduction as ODM for breast and eye lens, increased dose to the spine, with noise effects ranging from 2% noise reduction to 16% noise increase. At noise equal to SmartmA, ODM increased the estimated effective dose by 4% and 8% for chest and head scans, respectively. Increasing the posterior tube current further increased the effective dose by 15% (chest) and 18% (head) relative to SmartmA. CONCLUSIONS: ODM reduced dose in all experimental and simulation studies over a range of phantoms, while increasing noise. The results suggest a net dose/noise benefit for breast and eye lens for all studied phantoms, negligible lung dose effects for two phantoms, increased lung dose and/or noise for eight phantoms, and increased dose and/or noise for brain and spine for all studied phantoms compared to the reference protocol. PMID- 26520749 TI - Multihelix rotating shield brachytherapy for cervical cancer. AB - PURPOSE: To present a novel brachytherapy technique, called multihelix rotating shield brachytherapy (H-RSBT), for the precise angular and linear positioning of a partial shield in a curved applicator. H-RSBT mechanically enables the dose delivery using only linear translational motion of the radiation source/shield combination. The previously proposed approach of serial rotating shield brachytherapy (S-RSBT), in which the partial shield is rotated to several angular positions at each source dwell position [W. Yang et al., "Rotating-shield brachytherapy for cervical cancer," Phys. Med. Biol. 58, 3931-3941 (2013)], is mechanically challenging to implement in a curved applicator, and H-RSBT is proposed as a feasible solution. METHODS: A Henschke-type applicator, designed for an electronic brachytherapy source (Xoft AxxentTM) and a 0.5 mm thick tungsten partial shield with 180 degrees or 45 degrees azimuthal emission angles and 116 degrees asymmetric zenith angle, is proposed. The interior wall of the applicator contains six evenly spaced helical keyways that rigidly define the emission direction of the partial radiation shield as a function of depth in the applicator. The shield contains three uniformly distributed protruding keys on its exterior wall and is attached to the source such that it rotates freely, thus longitudinal translational motion of the source is transferred to rotational motion of the shield. S-RSBT and H-RSBT treatment plans with 180 degrees and 45 degrees azimuthal emission angles were generated for five cervical cancer patients with a diverse range of high-risk target volume (HR-CTV) shapes and applicator positions. For each patient, the total number of emission angles was held nearly constant for S-RSBT and H-RSBT by using dwell positions separated by 5 and 1.7 mm, respectively, and emission directions separated by 22.5 degrees and 60 degrees , respectively. Treatment delivery time and tumor coverage (D90 of HR-CTV) were the two metrics used as the basis for evaluation and comparison. For all the generated treatment plans, the D90 of the HR-CTV in units of equivalent dose in 2 Gy fractions (EQD2) was escalated until the D2cc (minimum dose to hottest 2 cm3) tolerance of either the bladder (90 Gy3), rectum (75 Gy3), or sigmoid colon (75 Gy3) was reached. RESULTS: Treatment time changed for H-RSBT versus S-RSBT by -7.62% to 1.17% with an average change of -2.8%, thus H-RSBT treatments times tended to be shorter than for S-RSBT. The HR-CTV D90 also changed by -2.7% to 2.38% with an average of -0.65%. CONCLUSIONS: H-RSBT is a mechanically feasible delivery technique for use in the curved applicators needed for cervical cancer brachytherapy. S-RSBT and H-RSBT were clinically equivalent for all patients considered, with the H-RSBT technique tending to require less time for delivery. PMID- 26520750 TI - Comparison of organ-at-risk sparing and plan robustness for spot-scanning proton therapy and volumetric modulated arc photon therapy in head-and-neck cancer. AB - PURPOSE: Proton radiotherapy for head-and-neck cancer (HNC) aims to improve organ at-risk (OAR) sparing over photon radiotherapy. However, it may be less robust for setup and range uncertainties. The authors investigated OAR sparing and plan robustness for spot-scanning proton planning techniques and compared these with volumetric modulated arc therapy (VMAT) photon plans. METHODS: Ten HNC patients were replanned using two arc VMAT (RapidArc) and spot-scanning proton techniques. OARs to be spared included the contra- and ipsilateral parotid and submandibular glands and individual swallowing muscles. Proton plans were made using Multifield Optimization (MFO, using three, five, and seven fields) and Single-field Optimization (SFO, using three fields). OAR sparing was evaluated using mean dose to composite salivary glands (CompSal) and composite swallowing muscles (CompSwal). Plan robustness was determined for setup and range uncertainties (+/ 3 mm for setup, +/-3% HU) evaluating V95% and V107% for clinical target volumes. RESULTS: Averaged over all patients CompSal/CompSwal mean doses were lower for the three-field MFO plans (14.6/16.4 Gy) compared to the three-field SFO plans (20.0/23.7 Gy) and VMAT plans (23.0/25.3 Gy). Using more than three fields resulted in differences in OAR sparing of less than 1.5 Gy between plans. SFO plans were significantly more robust than MFO plans. VMAT plans were the most robust. CONCLUSIONS: MFO plans had improved OAR sparing but were less robust than SFO and VMAT plans, while SFO plans were more robust than MFO plans but resulted in less OAR sparing. Robustness of the MFO plans did not increase with more fields. PMID- 26520751 TI - Multipinhole SPECT helical scan parameters and imaging volume. AB - PURPOSE: The authors developed SPECT imaging capability on an animal PET scanner using a multiple-pinhole collimator and step-and-shoot helical data acquisition protocols. The objective of this work was to determine the preferred helical scan parameters, i.e., the angular and axial step sizes, and the imaging volume, that provide optimal imaging performance. METHODS: The authors studied nine helical scan protocols formed by permuting three rotational and three axial step sizes. These step sizes were chosen around the reference values analytically calculated from the estimated spatial resolution of the SPECT system and the Nyquist sampling theorem. The nine helical protocols were evaluated by two figures-of merit: the sampling completeness percentage (SCP) and the root-mean-square (RMS) resolution. SCP was an analytically calculated numerical index based on projection sampling. RMS resolution was derived from the reconstructed images of a sphere-grid phantom. RESULTS: The RMS resolution results show that (1) the start and end pinhole planes of the helical scheme determine the axial extent of the effective field of view (EFOV), and (2) the diameter of the transverse EFOV is adequately calculated from the geometry of the pinhole opening, since the peripheral region beyond EFOV would introduce projection multiplexing and consequent effects. The RMS resolution results of the nine helical scan schemes show optimal resolution is achieved when the axial step size is the half, and the angular step size is about twice the corresponding values derived from the Nyquist theorem. The SCP results agree in general with that of RMS resolution but are less critical in assessing the effects of helical parameters and EFOV. CONCLUSIONS: The authors quantitatively validated the effective FOV of multiple pinhole helical scan protocols and proposed a simple method to calculate optimal helical scan parameters. PMID- 26520752 TI - A pencil beam approach to proton computed tomography. AB - PURPOSE: A new approach to proton computed tomography (pCT) is presented. In this approach, protons are not tracked one-by-one but a beam of particles is considered instead. The elements of the pCT reconstruction problem (residual energy and path) are redefined on the basis of this new approach. An analytical image reconstruction algorithm applicable to this scenario is also proposed. METHODS: The pencil beam (PB) and its propagation in matter were modeled by making use of the generalization of the Fermi-Eyges theory to account for multiple Coulomb scattering (MCS). This model was integrated into the pCT reconstruction problem, allowing the definition of the mean beam path concept similar to the most likely path (MLP) used in the single-particle approach. A numerical validation of the model was performed. The algorithm of filtered backprojection along MLPs was adapted to the beam-by-beam approach. The acquisition of a perfect proton scan was simulated and the data were used to reconstruct images of the relative stopping power of the phantom with the single proton and beam-by-beam approaches. The resulting images were compared in a qualitative way. RESULTS: The parameters of the modeled PB (mean and spread) were compared to Monte Carlo results in order to validate the model. For a water target, good agreement was found for the mean value of the distributions. As far as the spread is concerned, depth-dependent discrepancies as large as 2%-3% were found. For a heterogeneous phantom, discrepancies in the distribution spread ranged from 6% to 8%. The image reconstructed with the beam-by-beam approach showed a high level of noise compared to the one reconstructed with the classical approach. CONCLUSIONS: The PB approach to proton imaging may allow technical challenges imposed by the current proton-by-proton method to be overcome. In this framework, an analytical algorithm is proposed. Further work will involve a detailed study of the performances and limitations of this approach in terms of image quality. The paper shows how to account for the MCS in the reconstruction step with this new approach when an analytical reconstruction algorithm is used. PMID- 26520753 TI - Analytic image reconstruction from partial data for a single-scan cone-beam CT with scatter correction. AB - PURPOSE: A beam-blocker composed of multiple strips is a useful gadget for scatter correction and/or for dose reduction in cone-beam CT (CBCT). However, the use of such a beam-blocker would yield cone-beam data that can be challenging for accurate image reconstruction from a single scan in the filtered-backprojection framework. The focus of the work was to develop an analytic image reconstruction method for CBCT that can be directly applied to partially blocked cone-beam data in conjunction with the scatter correction. METHODS: The authors developed a rebinned backprojection-filteration (BPF) algorithm for reconstructing images from the partially blocked cone-beam data in a circular scan. The authors also proposed a beam-blocking geometry considering data redundancy such that an efficient scatter estimate can be acquired and sufficient data for BPF image reconstruction can be secured at the same time from a single scan without using any blocker motion. Additionally, scatter correction method and noise reduction scheme have been developed. The authors have performed both simulation and experimental studies to validate the rebinned BPF algorithm for image reconstruction from partially blocked cone-beam data. Quantitative evaluations of the reconstructed image quality were performed in the experimental studies. RESULTS: The simulation study revealed that the developed reconstruction algorithm successfully reconstructs the images from the partial cone-beam data. In the experimental study, the proposed method effectively corrected for the scatter in each projection and reconstructed scatter-corrected images from a single scan. Reduction of cupping artifacts and an enhancement of the image contrast have been demonstrated. The image contrast has increased by a factor of about 2, and the image accuracy in terms of root-mean-square-error with respect to the fan-beam CT image has increased by more than 30%. CONCLUSIONS: The authors have successfully demonstrated that the proposed scanning method and image reconstruction algorithm can effectively estimate the scatter in cone-beam projections and produce tomographic images of nearly scatter-free quality. The authors believe that the proposed method would provide a fast and efficient CBCT scanning option to various applications particularly including head-and-neck scan. PMID- 26520754 TI - A novel approach to background subtraction in contrast-enhanced dual-energy digital mammography with commercially available mammography devices: Polychromaticity correction. AB - PURPOSE: Contrast-enhanced digital mammography is an image subtraction technique that is able to improve the detectability of lesions in dense breasts. One of the main sources of error, when the technique is performed by means of commercial mammography devices, is represented by the intrinsic polychromaticity of the x ray beams. The aim of the work is to propose an iterative procedure, which only assumes the knowledge of a small set of universal quantities, to take into account the polychromaticity and correct the subtraction results accordingly. METHODS: In order to verify the procedure, it has been applied to an analytical simulation of a target containing a contrast medium and to actual radiographs of a breast phantom containing cavities filled with a solution of the same medium. RESULTS: The reconstructed densities of contrast medium were compared, showing very good agreement between the theoretical predictions and the experimental results already after the first iteration. Furthermore, the convergence of the iterative procedure was studied, showing that only a small number of iterations is necessary to reach limiting values. CONCLUSIONS: The proposed procedure represents an efficient solution to the polychromaticity issue, qualifying therefore as a viable alternative to inverse-map functions. PMID- 26520755 TI - Development of a dual phantom technique for measuring the fast neutron component of dose in boron neutron capture therapy. AB - PURPOSE: Research and development of various accelerator-based irradiation systems for boron neutron capture therapy (BNCT) is underway throughout the world. Many of these systems are nearing or have started clinical trials. Before the start of treatment with BNCT, the relative biological effectiveness (RBE) for the fast neutrons (over 10 keV) incident to the irradiation field must be estimated. Measurements of RBE are typically performed by biological experiments with a phantom. Although the dose deposition due to secondary gamma rays is dominant, the relative contributions of thermal neutrons (below 0.5 eV) and fast neutrons are virtually equivalent under typical irradiation conditions in a water and/or acrylic phantom. Uniform contributions to the dose deposited from thermal and fast neutrons are based in part on relatively inaccurate dose information for fast neutrons. This study sought to improve the accuracy in the dose estimation for fast neutrons by using two phantoms made of different materials in which the dose components can be separated according to differences in the interaction cross sections. The development of a "dual phantom technique" for measuring the fast neutron component of dose is reported. METHODS: One phantom was filled with pure water. The other phantom was filled with a water solution of lithium hydroxide (LiOH) capitalizing on the absorbing characteristics of lithium-6 (Li 6) for thermal neutrons. Monte Carlo simulations were used to determine the ideal mixing ratio of Li-6 in LiOH solution. Changes in the depth dose distributions for each respective dose component along the central beam axis were used to assess the LiOH concentration at the 0, 0.001, 0.01, 0.1, 1, and 10 wt. % levels. Simulations were also performed with the phantom filled with 10 wt. % 6LiOH solution for 95%-enriched Li-6. A phantom was constructed containing 10 wt. % 6LiOH solution based on the simulation results. Experimental characterization of the depth dose distributions of the neutron and gamma-ray components along the central axis was performed at Heavy Water Neutron Irradiation Facility installed at Kyoto University Reactor using activation foils and thermoluminescent dosimeters, respectively. RESULTS: Simulation results demonstrated that the absorbing effect for thermal neutrons occurred when the LiOH concentration was over 1%. The most effective Li-6 concentration was determined to be enriched 6LiOH with a solubility approaching its upper limit. Experiments confirmed that the thermal neutron flux and secondary gamma-ray dose rate decreased substantially; however, the fast neutron flux and primary gamma-ray dose rate were hardly affected in the 10%-6LiOH phantom. It was confirmed that the dose contribution of fast neutrons is improved from approximately 10% in the pure water phantom to approximately 50% in the 10%-6LiOH phantom. CONCLUSIONS: The dual phantom technique using the combination of a pure water phantom and a 10% 6LiOH phantom developed in this work provides an effective method for dose estimation of the fast neutron component in BNCT. Improvement in the accuracy achieved with the proposed technique results in improved RBE estimation for biological experiments and clinical practice. PMID- 26520756 TI - Ongoing quality control in digital radiography: Report of AAPM Imaging Physics Committee Task Group 151. AB - Quality control (QC) in medical imaging is an ongoing process and not just a series of infrequent evaluations of medical imaging equipment. The QC process involves designing and implementing a QC program, collecting and analyzing data, investigating results that are outside the acceptance levels for the QC program, and taking corrective action to bring these results back to an acceptable level. The QC process involves key personnel in the imaging department, including the radiologist, radiologic technologist, and the qualified medical physicist (QMP). The QMP performs detailed equipment evaluations and helps with oversight of the QC program, the radiologic technologist is responsible for the day-to-day operation of the QC program. The continued need for ongoing QC in digital radiography has been highlighted in the scientific literature. The charge of this task group was to recommend consistency tests designed to be performed by a medical physicist or a radiologic technologist under the direction of a medical physicist to identify problems with an imaging system that need further evaluation by a medical physicist, including a fault tree to define actions that need to be taken when certain fault conditions are identified. The focus of this final report is the ongoing QC process, including rejected image analysis, exposure analysis, and artifact identification. These QC tasks are vital for the optimal operation of a department performing digital radiography. PMID- 26520757 TI - A feasibility study: Selection of a personalized radiotherapy fractionation schedule using spatiotemporal optimization. AB - PURPOSE: To investigate the impact of using spatiotemporal optimization, i.e., intensity-modulated spatial optimization followed by fractionation schedule optimization, to select the patient-specific fractionation schedule that maximizes the tumor biologically equivalent dose (BED) under dose constraints for multiple organs-at-risk (OARs). METHODS: Spatiotemporal optimization was applied to a variety of lung tumors in a phantom geometry using a range of tumor sizes and locations. The optimal fractionation schedule for a patient using the linear quadratic cell survival model depends on the tumor and OAR sensitivity to fraction size (alpha/beta), the effective tumor doubling time (Td), and the size and location of tumor target relative to one or more OARs (dose distribution). The authors used a spatiotemporal optimization method to identify the optimal number of fractions N that maximizes the 3D tumor BED distribution for 16 lung phantom cases. The selection of the optimal fractionation schedule used equivalent (30-fraction) OAR constraints for the heart (Dmean<=45 Gy), lungs (Dmean<=20 Gy), cord (Dmax<=45 Gy), esophagus (Dmax<=63 Gy), and unspecified tissues (D05<=60 Gy). To assess plan quality, the authors compared the minimum, mean, maximum, and D95 of tumor BED, as well as the equivalent uniform dose (EUD) for optimized plans to conventional intensity-modulated radiation therapy plans prescribing 60 Gy in 30 fractions. A sensitivity analysis was performed to assess the effects of Td (3-100 days), tumor lag-time (Tk=0-10 days), and the size of tumors on optimal fractionation schedule. RESULTS: Using an alpha/beta ratio of 10 Gy, the average values of tumor max, min, mean BED, and D95 were up to 19%, 21%, 20%, and 19% larger than those from conventional prescription, depending on Td and Tk used. Tumor EUD was up to 17% larger than the conventional prescription. For fast proliferating tumors with Td less than 10 days, there was no significant increase in tumor BED but the treatment course could be shortened without a loss in tumor BED. The improvement in the tumor mean BED was more pronounced with smaller tumors (p-value=0.08). CONCLUSIONS: Spatiotemporal optimization of patient plans has the potential to significantly improve local tumor control (larger BED/EUD) of patients with a favorable geometry, such as smaller tumors with larger distances between the tumor target and nearby OAR. In patients with a less favorable geometry and for fast growing tumors, plans optimized using spatiotemporal optimization and conventional (spatial-only) optimization are equivalent (negligible differences in tumor BED/EUD). However, spatiotemporal optimization yields shorter treatment courses than conventional spatial-only optimization. Personalized, spatiotemporal optimization of treatment schedules can increase patient convenience and help with the efficient allocation of clinical resources. Spatiotemporal optimization can also help identify a subset of patients that might benefit from nonconventional (large dose per fraction) treatments that are ineligible for the current practice of stereotactic body radiation therapy. PMID- 26520758 TI - Collimator design for a multipinhole brain SPECT insert for MRI. AB - PURPOSE: Brain single photon emission computed tomography (SPECT) imaging is an important clinical tool, with unique tracers for studying neurological diseases. Nowadays, most commercial SPECT systems are combined with x-ray computed tomography (CT) in so-called SPECT/CT systems to obtain an anatomical background for the functional information. However, while CT images have a high spatial resolution, they have a low soft-tissue contrast, which is an important disadvantage for brain imaging. Magnetic resonance imaging (MRI), on the other hand, has a very high soft-tissue contrast and does not involve extra ionizing radiation. Therefore, the authors designed a brain SPECT insert that can operate inside a clinical MRI. METHODS: The authors designed and simulated a compact stationary multipinhole SPECT insert based on digital silicon photomultiplier detector modules, which have shown to be MR-compatible and have an excellent intrinsic resolution (0.5 mm) when combined with a monolithic 2 mm thick LYSO crystal. First, the authors optimized the different parameters of the SPECT system to maximize sensitivity for a given target resolution of 7.2 mm in the center of the field-of-view, given the spatial constraints of the MR system. Second, the authors performed noiseless simulations of two multipinhole configurations to evaluate sampling and reconstructed resolution. Finally, the authors performed Monte Carlo simulations and compared the SPECT insert with a clinical system with ultrahigh-resolution (UHR) fan beam collimators, based on contrast-to-noise ratio and a visual comparison of a Hoffman phantom with a 9 mm cold lesion. RESULTS: The optimization resulted in a stationary multipinhole system with a collimator radius of 150.2 mm and a detector radius of 172.67 mm, which corresponds to four rings of 34 diSPM detector modules. This allows the authors to include eight rings of 24 pinholes, which results in a system volume sensitivity of 395 cps/MBq. Noiseless simulations show sufficient axial sampling (in a Defrise phantom) and a reconstructed resolution of 5.0 mm (in a cold-rod phantom). The authors compared the 24-pinhole setup with a 34-pinhole system (with the same detector radius but a collimator radius of 156.63 mm) and found that 34 pinholes result in better uniformity but a worse reconstruction of the cold-rod phantom. The authors also compared the 24-pinhole system with a clinical triple-head UHR fan beam system based on contrast-to-noise ratio and found that the 24-pinhole setup performs better for the 6 mm hot and the 16 mm cold lesions and worse for the 8 and 10 mm hot lesions. Finally, the authors reconstructed noisy projection data of a Hoffman phantom with a 9 mm cold lesion and found that the lesion was slightly better visible on the multipinhole image compared to the fan beam image. CONCLUSIONS: The authors have optimized a stationary multipinhole SPECT insert for MRI and showed the feasibility of doing brain SPECT imaging inside a MRI with an image quality similar to the best clinical SPECT systems available. PMID- 26520759 TI - Sensitivity estimation in time-of-flight list-mode positron emission tomography. AB - PURPOSE: An accurate quantification of the images in positron emission tomography (PET) requires knowing the actual sensitivity at each voxel, which represents the probability that a positron emitted in that voxel is finally detected as a coincidence of two gamma rays in a pair of detectors in the PET scanner. This sensitivity depends on the characteristics of the acquisition, as it is affected by the attenuation of the annihilation gamma rays in the body, and possible variations of the sensitivity of the scanner detectors. In this work, the authors propose a new approach to handle time-of-flight (TOF) list-mode PET data, which allows performing either or both, a self-attenuation correction, and self normalization correction based on emission data only. METHODS: The authors derive the theory using a fully Bayesian statistical model of complete data. The authors perform an initial evaluation of algorithms derived from that theory and proposed in this work using numerical 2D list-mode simulations with different TOF resolutions and total number of detected coincidences. Effects of randoms and scatter are not simulated. RESULTS: The authors found that proposed algorithms successfully correct for unknown attenuation and scanner normalization for simulated 2D list-mode TOF-PET data. CONCLUSIONS: A new method is presented that can be used for corrections for attenuation and normalization (sensitivity) using TOF list-mode data. PMID- 26520760 TI - Evaluation of the local dose enhancement in the combination of proton therapy and nanoparticles. AB - PURPOSE: The outcome of radiotherapy can be further improved by combining irradiation with dose enhancers such as high-Z nanoparticles. Since 2004, spectacular results have been obtained when low-energy x-ray irradiations have been combined with nanoparticles. Recently, the same combination has been explored in hadron therapy. In vitro studies have shown a significant amplification of the biological damage in tumor cells charged with nanoparticles and irradiated with fast ions. This has been attributed to the increase in the ionizations and electron emissions induced by the incident ions or the electrons in the secondary tracks on the high-Z atoms, resulting in a local energy deposition enhancement. However, this subject is still a matter of controversy. Within this context, the main goal of the authors' work was to provide new insights into the dose enhancement effects of nanoparticles in proton therapy. METHODS: For this purpose, Monte Carlo calculations (gate/geant4 code) were performed. In particular, the geant4-DNA toolkit, which allows the modeling of early biological damages induced by ionizing radiation at the DNA scale, was used. The nanometric radial energy distributions around the nanoparticle were studied, and the processes (such as Auger deexcitation or dissociative electron attachment) participating in the dose deposition of proton therapy treatments in the presence of nanoparticles were evaluated. It has been reported that the architecture of Monte Carlo calculations plays a crucial role in the assessment of nanoparticle dose enhancement and that it may introduce a bias in the results or amplify the possible final dose enhancement. Thus, a dosimetric study of different cases was performed, considering Au and Gd nanoparticles, several nanoparticle sizes (from 4 to 50 nm), and several beam configurations (source nanoparticle distances and source sizes). RESULTS: This Monte Carlo study shows the influence of the simulations' parameters on the local dose enhancement and how more realistic configurations lead to a negligible increase of local energy deposition. The obtained dose enhancement factor was up to 1.7 when the source was located at the nanoparticle surface. This dose enhancement was reduced when the source was located at further distances (i.e., in more realistic situations). Additionally, no significant increase in the dissociative electron attachment processes was observed. CONCLUSIONS: The authors' results indicate that physical effects play a minor role in the amplification of damage, as a very low dose enhancement or increase of dissociative electron attachment processes is observed when the authors get closer to more realistic simulations. Thus, other effects, such as biological or chemical processes, may be mainly responsible for the enhanced radiosensibilization observed in biological studies. However, more biological studies are needed to verify this hypothesis. PMID- 26520761 TI - Ultrasonic tracking of shear waves using a particle filter. AB - PURPOSE: This paper discusses an application of particle filtering for estimating shear wave velocity in tissue using ultrasound elastography data. Shear wave velocity estimates are of significant clinical value as they help differentiate stiffer areas from softer areas which is an indicator of potential pathology. METHODS: Radio-frequency ultrasound echo signals are used for tracking axial displacements and obtaining the time-to-peak displacement at different lateral locations. These time-to-peak data are usually very noisy and cannot be used directly for computing velocity. In this paper, the denoising problem is tackled using a hidden Markov model with the hidden states being the unknown (noiseless) time-to-peak values. A particle filter is then used for smoothing out the time-to peak curve to obtain a fit that is optimal in a minimum mean squared error sense. RESULTS: Simulation results from synthetic data and finite element modeling suggest that the particle filter provides lower mean squared reconstruction error with smaller variance as compared to standard filtering methods, while preserving sharp boundary detail. Results from phantom experiments show that the shear wave velocity estimates in the stiff regions of the phantoms were within 20% of those obtained from a commercial ultrasound scanner and agree with estimates obtained using a standard method using least-squares fit. Estimates of area obtained from the particle filtered shear wave velocity maps were within 10% of those obtained from B-mode ultrasound images. CONCLUSIONS: The particle filtering approach can be used for producing visually appealing SWV reconstructions by effectively delineating various areas of the phantom with good image quality properties comparable to existing techniques. PMID- 26520762 TI - Evaluation of tumor-derived MRI-texture features for discrimination of molecular subtypes and prediction of 12-month survival status in glioblastoma. AB - PURPOSE: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain cancer. Four molecular subtypes of GBM have been described but can only be determined by an invasive brain biopsy. The goal of this study is to evaluate the utility of texture features extracted from magnetic resonance imaging (MRI) scans as a potential noninvasive method to characterize molecular subtypes of GBM and to predict 12-month overall survival status for GBM patients. METHODS: The authors manually segmented the tumor regions from postcontrast T1 weighted and T2 fluid-attenuated inversion recovery (FLAIR) MRI scans of 82 patients with de novo GBM. For each patient, the authors extracted five sets of computer-extracted texture features, namely, 48 segmentation-based fractal texture analysis (SFTA) features, 576 histogram of oriented gradients (HOGs) features, 44 run-length matrix (RLM) features, 256 local binary patterns features, and 52 Haralick features, from the tumor slice corresponding to the maximum tumor area in axial, sagittal, and coronal planes, respectively. The authors used an ensemble classifier called random forest on each feature family to predict GBM molecular subtypes and 12-month survival status (a dichotomized version of overall survival at the 12-month time point indicating if the patient was alive or not at 12 months). The performance of the prediction was quantified and compared using receiver operating characteristic (ROC) curves. RESULTS: With the appropriate combination of texture feature set, image plane (axial, coronal, or sagittal), and MRI sequence, the area under ROC curve values for predicting different molecular subtypes and 12-month survival status are 0.72 for classical (with Haralick features on T1 postcontrast axial scan), 0.70 for mesenchymal (with HOG features on T2 FLAIR axial scan), 0.75 for neural (with RLM features on T2 FLAIR axial scan), 0.82 for proneural (with SFTA features on T1 postcontrast coronal scan), and 0.69 for 12-month survival status (with SFTA features on T1 postcontrast coronal scan). CONCLUSIONS: The authors evaluated the performance of five types of texture features in predicting GBM molecular subtypes and 12-month survival status. The authors' results show that texture features are predictive of molecular subtypes and survival status in GBM. These results indicate the feasibility of using tumor-derived imaging features to guide genomically informed interventions without the need for invasive biopsies. PMID- 26520763 TI - Image-derived and arterial blood sampled input functions for quantitative PET imaging of the angiotensin II subtype 1 receptor in the kidney. AB - PURPOSE: The radioligand 11C-KR31173 has been introduced for positron emission tomography (PET) imaging of the angiotensin II subtype 1 receptor in the kidney in vivo. To study the biokinetics of 11C-KR31173 with a compartmental model, the input function is needed. Collection and analysis of arterial blood samples are the established approach to obtain the input function but they are not feasible in patients with renal diseases. The goal of this study was to develop a quantitative technique that can provide an accurate image-derived input function (ID-IF) to replace the conventional invasive arterial sampling and test the method in pigs with the goal of translation into human studies. METHODS: The experimental animals were injected with [11C]KR31173 and scanned up to 90 min with dynamic PET. Arterial blood samples were collected for the artery derived input function (AD-IF) and used as a gold standard for ID-IF. Before PET, magnetic resonance angiography of the kidneys was obtained to provide the anatomical information required for derivation of the recovery coefficients in the abdominal aorta, a requirement for partial volume correction of the ID-IF. Different image reconstruction methods, filtered back projection (FBP) and ordered subset expectation maximization (OS-EM), were investigated for the best trade-off between bias and variance of the ID-IF. The effects of kidney uptakes on the quantitative accuracy of ID-IF were also studied. Biological variables such as red blood cell binding and radioligand metabolism were also taken into consideration. A single blood sample was used for calibration in the later phase of the input function. RESULTS: In the first 2 min after injection, the OS-EM based ID-IF was found to be biased, and the bias was found to be induced by the kidney uptake. No such bias was found with the FBP based image reconstruction method. However, the OS-EM based image reconstruction was found to reduce variance in the subsequent phase of the ID-IF. The combined use of FBP and OS-EM resulted in reduced bias and noise. After performing all the necessary corrections, the areas under the curves (AUCs) of the AD-IF were close to that of the AD-IF (average AUC ratio=1+/-0.08) during the early phase. When applied in a two-tissue-compartmental kinetic model, the average difference between the estimated model parameters from ID-IF and AD-IF was 10% which was within the error of the estimation method. CONCLUSIONS: The bias of radioligand concentration in the aorta from the OS-EM image reconstruction is significantly affected by radioligand uptake in the adjacent kidney and cannot be neglected for quantitative evaluation. With careful calibrations and corrections, the ID-IF derived from quantitative dynamic PET images can be used as the input function of the compartmental model to quantify the renal kinetics of 11C-KR31173 in experimental animals and the authors intend to evaluate this method in future human studies. PMID- 26520764 TI - A round-robin gamma stereotactic radiosurgery dosimetry interinstitution comparison of calibration protocols. AB - PURPOSE: Absorbed dose calibration for gamma stereotactic radiosurgery is challenging due to the unique geometric conditions, dosimetry characteristics, and nonstandard field size of these devices. Members of the American Association of Physicists in Medicine (AAPM) Task Group 178 on Gamma Stereotactic Radiosurgery Dosimetry and Quality Assurance have participated in a round-robin exchange of calibrated measurement instrumentation and phantoms exploring two approved and two proposed calibration protocols or formalisms on ten gamma radiosurgery units. The objectives of this study were to benchmark and compare new formalisms to existing calibration methods, while maintaining traceability to U.S. primary dosimetry calibration laboratory standards. METHODS: Nine institutions made measurements using ten gamma stereotactic radiosurgery units in three different 160 mm diameter spherical phantoms [acrylonitrile butadiene styrene (ABS) plastic, Solid Water, and liquid water] and in air using a positioning jig. Two calibrated miniature ionization chambers and one calibrated electrometer were circulated for all measurements. Reference dose-rates at the phantom center were determined using the well-established AAPM TG-21 or TG-51 dose calibration protocols and using two proposed dose calibration protocols/formalisms: an in-air protocol and a formalism proposed by the International Atomic Energy Agency (IAEA) working group for small and nonstandard radiation fields. Each institution's results were normalized to the dose-rate determined at that institution using the TG-21 protocol in the ABS phantom. RESULTS: Percentages of dose-rates within 1.5% of the reference dose-rate (TG 21+ABS phantom) for the eight chamber-protocol-phantom combinations were the following: 88% for TG-21, 70% for TG-51, 93% for the new IAEA nonstandard-field formalism, and 65% for the new in-air protocol. Averages and standard deviations for dose-rates over all measurements relative to the TG-21+ABS dose-rate were 0.999+/-0.009 (TG-21), 0.991+/-0.013 (TG-51), 1.000+/-0.009 (IAEA), and 1.009+/ 0.012 (in-air). There were no statistically significant differences (i.e., p>0.05) between the two ionization chambers for the TG-21 protocol applied to all dosimetry phantoms. The mean results using the TG-51 protocol were notably lower than those for the other dosimetry protocols, with a standard deviation 2-3 times larger. The in-air protocol was not statistically different from TG-21 for the A16 chamber in the liquid water or ABS phantoms (p=0.300 and p=0.135) but was statistically different from TG-21 for the PTW chamber in all phantoms (p=0.006 for Solid Water, 0.014 for liquid water, and 0.020 for ABS). Results of IAEA formalism were statistically different from TG-21 results only for the combination of the A16 chamber with the liquid water phantom (p=0.017). In the latter case, dose-rates measured with the two protocols differed by only 0.4%. For other phantom-ionization-chamber combinations, the new IAEA formalism was not statistically different from TG-21. CONCLUSIONS: Although further investigation is needed to validate the new protocols for other ionization chambers, these results can serve as a reference to quantitatively compare different calibration protocols and ionization chambers if a particular method is chosen by a professional society to serve as a standardized calibration protocol. PMID- 26520765 TI - Optimization of an on-board imaging system for extremely rapid radiation therapy. AB - PURPOSE: Next-generation extremely rapid radiation therapy systems could mitigate the need for motion management, improve patient comfort during the treatment, and increase patient throughput for cost effectiveness. Such systems require an on board imaging system that is competitively priced, fast, and of sufficiently high quality to allow good registration between the image taken on the day of treatment and the image taken the day of treatment planning. In this study, three different detectors for a custom on-board CT system were investigated to select the best design for integration with an extremely rapid radiation therapy system. METHODS: Three different CT detectors are proposed: low-resolution (all 4*4 mm pixels), medium-resolution (a combination of 4*4 mm pixels and 2*2 mm pixels), and high-resolution (all 1*1 mm pixels). An in-house program was used to generate projection images of a numerical anthropomorphic phantom and to reconstruct the projections into CT datasets, henceforth called "realistic" images. Scatter was calculated using a separate Monte Carlo simulation, and the model included an antiscatter grid and bowtie filter. Diagnostic-quality images of the phantom were generated to represent the patient scan at the time of treatment planning. Commercial deformable registration software was used to register the diagnostic quality scan to images produced by the various on-board detector configurations. The deformation fields were compared against a "gold standard" deformation field generated by registering initial and deformed images of the numerical phantoms that were used to make the diagnostic and treatment-day images. Registrations of on-board imaging system data were judged by the amount their deformation fields differed from the corresponding gold standard deformation fields--the smaller the difference, the better the system. To evaluate the registrations, the pointwise distance between gold standard and realistic registration deformation fields was computed. RESULTS: By most global metrics (e.g., mean, median, and maximum pointwise distance), the high-resolution detector had the best performance but the medium-resolution detector was comparable. For all medium- and high resolution detector registrations, mean error between the realistic and gold standard deformation fields was less than 4 mm. By pointwise metrics (e.g., tracking a small lesion), the high- and medium-resolution detectors performed similarly. For these detectors, the smallest error between the realistic and gold standard registrations was 0.6 mm and the largest error was 3.6 mm. CONCLUSIONS: The medium-resolution CT detector was selected as the best for an extremely rapid radiation therapy system. In essentially all test cases, data from this detector produced a significantly better registration than data from the low-resolution detector and a comparable registration to data from the high-resolution detector. The medium-resolution detector provides an appropriate compromise between registration accuracy and system cost. PMID- 26520766 TI - Erratum: "Modeling respiratory motion for reducing motion artifacts in 4D CT images" [Med. Phys. 40, 041716 (13pp.) (2013)]. PMID- 26520767 TI - Erratum: "Analytic variance estimates of Swank and Fano factors" [Med. Phys. 41, 072102 (5pp.) (2014)]. PMID- 26520769 TI - Resting-state functional MRI and [18F]-FDG PET demonstrate differences in neuronal activity between commonly used mouse strains. AB - The existence of numerous interesting mouse models of neurological disorders enables the investigation of causal relations between pathological events and the effect of treatment regimes. However, mouse models of a specific neurological disease are often generated using different background strains, which raises the question whether the observed effects are specific to pathology or depend on the used strain. This study used two independent in vivo functional imaging techniques to evaluate whether mouse strain differences exist in functional connectivity (FC) and brain glucose metabolism i.e. indirect measures of neuronal activity. For this purpose, C57BL/6, BALB/C and SJL mice (N=15/group, male) were evaluated using resting-state functional MRI (rsfMRI) and static [18F] fluorodeoxyglucose Positron Emission Tomography ([18F]-FDG PET). RsfMRI and [18F] FDG PET data were analyzed with independent component analysis (ICA). FC was quantified by calculating the mean network-specific FC strength and [18F]-FDG uptake was quantified by calculating the mean network-specific standard uptake value corrected for plasma glucose levels and body weight (SUVglu). The ICA results showed spatially similar neurological components in the rsfMRI and [18F] FDG PET data, suggesting that patterns of metabolic covariance in the mouse brain reflect FC networks. Comparing FC and [18F]-FDG data showed that strain-dependent differences in brain activity exist for several brain networks i.e. the frontal, cingulate, (hypo)thalamus, striatum, and sensorimotor networks. The results of this study have implications for the interpretation of in vivo functional imaging data in mouse models of neurological disorders generated on different background strains. PMID- 26520770 TI - Using executive control training to suppress amygdala reactivity to aversive information. AB - The ability to regulate emotions is essential for adaptive behavior. This ability is suggested to be mediated by the connectivity between prefrontal brain regions and the amygdala. Yet, it is still unknown whether the ability to regulate emotions can be trained by using a non-emotional procedure, such as the recruitment of executive control (EC). Participants who were trained using a high frequent executive control (EC) task (80% incongruent trials) showed reduced amygdala reactivity and behavioral interference of aversive pictures. These effects were observed only following multiple-session training and not following one training session. In addition, they were not observed for participants exposed to low-frequent EC training (20% incongruent trials). Resting-state functional connectivity analysis revealed a marginally significant interaction between training group and change in the connectivity between the amygdala and the right inferior frontal gyrus (IFG). Amygdala-IFG connectivity was significantly increased following the training only in the high-frequent EC training group. These findings are the first to show that non-emotional training can induce changes in amygdala reactivity to aversive information and alter amygdala-prefrontal connectivity. PMID- 26520771 TI - Three-dimensional localization of cortical electrodes in deep brain stimulation surgery from intraoperative fluoroscopy. AB - Electrophysiological recordings from subdural electrocorticography (ECoG) electrodes implanted temporarily during deep brain stimulation (DBS) surgeries offer a unique opportunity to record cortical activity for research purposes. The optimal utilization of this important research method relies on accurate and robust localization of ECoG electrodes, and intraoperative fluoroscopy is often the only imaging modality available to visualize electrode locations. However, the localization of a three-dimensional electrode position using a two dimensional fluoroscopic image is problematic due to the lost dimension orthogonal to the fluoroscopic image, a parallax distortion implicit to fluoroscopy, and variability of visible skull contour among fluoroscopic images. Here, we present a method to project electrodes visible on the fluoroscopic image onto a reconstructed cortical surface by leveraging numerous common landmarks to translate, rotate, and scale coregistered computed tomography (CT) and magnetic resonance imaging (MRI) reconstructed surfaces in order to recreate the coordinate framework in which the fluoroscopic image was acquired, while accounting for parallax distortion. Validation of this approach demonstrated high precision with an average total Euclidian distance between three independent reviewers of 1.65+/-0.68mm across 8 patients and 82 electrodes. Spatial accuracy was confirmed by correspondence between recorded neural activity over sensorimotor cortex during hand movement. This semi-automated interface reliably estimates the location of temporarily implanted subdural ECoG electrodes visible on intraoperative fluoroscopy to a cortical surface. PMID- 26520772 TI - Visualization of perivascular spaces in the human brain at 7T: sequence optimization and morphology characterization. AB - Noninvasive imaging of perivascular spaces (PVSs) may provide useful insights into their role in normal brain physiology and diseases. Fast MRI sequences with sub-millimeter spatial resolutions and high contrast-to-noise ratio (CNR) are required for accurate delineation of PVS in human. To achieve the optimal condition for PVS imaging at 7T, we carried out detailed simulation and experimental studies to characterize the dependence of CNR on imaging sequences (T1 versus T2-weighted) and sequence parameters. In addition, PVSs were segmented semi-automatically, which revealed much larger numbers of PVSs in young healthy subjects (age 21-37years) than previously reported. To the best of our knowledge, our study provides, for the first time, detailed length, volume, and diameter distributions of PVS in the white matter and subcortical nuclei, which can serve as a reference for future studies of PVS abnormalities under diseased conditions. PMID- 26520773 TI - Age differences in brain systems supporting transient and sustained processes involved in prospective memory and working memory. AB - In prospective memory (PM), an intention to act in response to an external event is formed, retained, and at a later stage, when the event occurs, the relevant action is performed. PM typically shows a decline in late adulthood, which might affect functions of daily living. The neural correlates of this decline are not well understood. Here, 15 young (6 female; age range=23-30years) and 16 older adults (5 female; age range=64-74years) were scanned with fMRI to examine age related differences in brain activation associated with event-based PM using a task that facilitated the separation of transient and sustained components of PM. We show that older adults had reduced performance in conditions with high demands on prospective and working memory, while no age-difference was observed in low demanding tasks. Across age groups, PM task performance activated separate sets of brain regions for transient and sustained responses. Age-differences in transient activation were found in fronto-striatal and MTL regions, with young adults showing more activation than older adults. Increased activation in young, compared to older adults, was also found for sustained PM activation in the IFG. These results provide new evidence that PM relies on dissociable transient and sustained cognitive processes, and that age-related deficits in PM can be explained by an inability to recruit PM-related brain networks in old age. PMID- 26520774 TI - Neural signals encoding shifts in beliefs. AB - Dopamine is implicated in a diverse range of cognitive functions including cognitive flexibility, task switching, signalling novel or unexpected stimuli as well as advance information. There is also longstanding line of thought that links dopamine with belief formation and, crucially, aberrant belief formation in psychosis. Integrating these strands of evidence would suggest that dopamine plays a central role in belief updating and more specifically in encoding of meaningful information content in observations. The precise nature of this relationship has remained unclear. To directly address this question we developed a paradigm that allowed us to decompose two distinct types of information content, information-theoretic surprise that reflects the unexpectedness of an observation, and epistemic value that induces shifts in beliefs or, more formally, Bayesian surprise. Using functional magnetic-resonance imaging in humans we show that dopamine-rich midbrain regions encode shifts in beliefs whereas surprise is encoded in prefrontal regions, including the pre supplementary motor area and dorsal cingulate cortex. By linking putative dopaminergic activity to belief updating these data provide a link to false belief formation that characterises hyperdopaminergic states associated with idiopathic and drug induced psychosis. PMID- 26520776 TI - [Outpatient thoracoscopic resection of lung nodules within a fast-track recovery program]. AB - INTRODUCTION: The objectives of outpatient surgery are to reduce the risks related to the hospitalization, to improve the postoperative recovery and to optimize contact with family physicians. The objective of this work is to present the first unit of outpatient pulmonary surgery and to report the results of the resections of pulmonary nodules in outpatient surgery in the setting of early discharge. METHODS: The indications for the resection of nodules were discussed in a multidisciplinary thoracic oncology meeting. The patients underwent resection of one or more lung nodules by thoracoscopy after verification that they met the anaesthetic and surgical criteria for ambulatory surgery. We analyzed the characteristics of the population, the duration of surgery, the type of resection, the time of the chest drain removal and the postoperative follow up. RESULTS: Between November 2013 and December 2014, 51 patients underwent sub lobar pulmonary resections. Among them 7 patients (4 men and 3 women), with an average age of 57.6 years (39-64) and histories of malignant tumor, underwent 7 atypical resections and two segmentectomies in outpatient surgery (3 patients had two resections). The average operating time was 53.75min (30-90). The chest drain was removed before the third hour in 8 cases and on the third day in one case. The average tumor diameter was 10.375mm (6-23). The histology revealed a metastasis of colorectal carcinoma in 4 cases, a metastasis of a renal carcinoma in 1 case, an in situ adenocarcinoma in 1 case and a benign tumor in 3 cases. Neither recurrence nor complication was observed during an average follow-up of 6 months. CONCLUSION: Thanks to a protocol of early mobilisation and discharge included in a well established clinical care pathway, thoracoscopic resection of lung nodules is feasible, with safety in properly selected and prepared patients in outpatient surgery. PMID- 26520777 TI - [A new cause of drug-induced cough: The dipeptidyl peptidase-IV inhibitors]. PMID- 26520775 TI - The impact of quality assurance assessment on diffusion tensor imaging outcomes in a large-scale population-based cohort. AB - BACKGROUND: Diffusion tensor imaging (DTI) is applied in investigation of brain biomarkers for neurodevelopmental and neurodegenerative disorders. However, the quality of DTI measurements, like other neuroimaging techniques, is susceptible to several confounding factors (e.g., motion, eddy currents), which have only recently come under scrutiny. These confounds are especially relevant in adolescent samples where data quality may be compromised in ways that confound interpretation of maturation parameters. The current study aims to leverage DTI data from the Philadelphia Neurodevelopmental Cohort (PNC), a sample of 1601 youths with ages of 8-21 who underwent neuroimaging, to: 1) establish quality assurance (QA) metrics for the automatic identification of poor DTI image quality; 2) examine the performance of these QA measures in an external validation sample; 3) document the influence of data quality on developmental patterns of typical DTI metrics. METHODS: All diffusion-weighted images were acquired on the same scanner. Visual QA was performed on all subjects completing DTI; images were manually categorized as Poor, Good, or Excellent. Four image quality metrics were automatically computed and used to predict manual QA status: Mean voxel intensity outlier count (MEANVOX), Maximum voxel intensity outlier count (MAXVOX), mean relative motion (MOTION) and temporal signal-to-noise ratio (TSNR). Classification accuracy for each metric was calculated as the area under the receiver-operating characteristic curve (AUC). A threshold was generated for each measure that best differentiated visual QA status and applied in a validation sample. The effects of data quality on sensitivity to expected age effects in this developmental sample were then investigated using the traditional MRI diffusion metrics: fractional anisotropy (FA) and mean diffusivity (MD). Finally, our method of QA is compared with DTIPrep. RESULTS: TSNR (AUC=0.94) best differentiated Poor data from Good and Excellent data. MAXVOX (AUC=0.88) best differentiated Good from Excellent DTI data. At the optimal threshold, 88% of Poor data and 91% Good/Excellent data were correctly identified. Use of these thresholds on a validation dataset (n=374) indicated high accuracy. In the validation sample 83% of Poor data and 94% of Excellent data was identified using thresholds derived from the training sample. Both FA and MD were affected by the inclusion of poor data in an analysis of an age, sex and race matched comparison sample. In addition, we show that the inclusion of poor data results in significant attenuation of the correlation between diffusion metrics (FA and MD) and age during a critical neurodevelopmental period. We find higher correspondence between our QA method and DTIPrep for Poor data, but we find our method to be more robust for apparently high-quality images. CONCLUSION: Automated QA of DTI can facilitate large-scale, high-throughput quality assurance by reliably identifying both scanner and subject induced imaging artifacts. The results present a practical example of the confounding effects of artifacts on DTI analysis in a large population-based sample, and suggest that estimates of data quality should not only be reported but also accounted for in data analysis, especially in studies of development. PMID- 26520778 TI - [Noninvasive ventilation during pulmonary rehabilitation in COPD patients]. AB - INTRODUCTION: Pulmonary rehabilitation is currently the gold standard treatment for patients with chronic obstructive pulmonary disease (COPD). However, the workload achieved may be insufficient to obtain physiological benefits because of the restricted respiratory capacity. BACKGROUND: In patients with COPD, changes in flow as well as biomechanical factors (distension) compromise respiratory adaptation to exertion. Some studies have shown that noninvasive ventilation (NIV) during exercise has a positive effect on respiratory muscle workload, physiological parameters and perceived exertion. However the evidence remains insufficient regarding the effects of the NIV during comprehensive pulmonary rehabilitation programs. OBJECTIVES: The identification of criteria which determine responsive patients is necessary in order to reduce human and time costs and to optimize the use of NIV during exercise. CONCLUSIONS: NIV is used during training to overcome dyspnoea and to increase muscle workload. Further studies are needed to verify the effectiveness of NIV in pulmonary rehabilitation. PMID- 26520779 TI - [KRAS and bronchial adenocarcinoma. Between disappointments and hopes]. AB - A better understanding of oncogenesis and the development of targeted therapies have led to improved outcomes in the treatment of lung cancer. KRAS mutation has the potential to drive the oncogenesis of almost one third of lung adenocarcinomas but it leads to a highly complex proliferation signal involving multiple signaling pathways, explaining the disappointing results of various inhibition strategies of K-ras or its effectors. Nevertheless, recent data suggest different roles of distinct KRAS mutation subtypes and KRAS interactions with new genes in the field of synthetic lethality mechanisms open the way to new therapeutic possibilities. This review aims to provide an overview of: 1) epidemiological data and particularly the prognostic impact of KRAS mutations in non-small cell lung cancer, 2) the results of different drugs either being tested in humans or sources of hope. PMID- 26520780 TI - Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients. AB - BACKGROUND: Dexamethasone (DXM) is commonly used in the management of cerebral edema in patients diagnosed with glioblastoma multiforme (GBM). Bevacizumab (BEV) is FDA-approved for the progression or recurrence of GBM but has not been shown to improve survival when given for newly diagnosed patients concurrently with radiation (RT) and temozolomide (TMZ). Both DXM and BEV reduce cerebral edema, however, DXM has been shown to induce cytokine cascades which could interfere with cytotoxic therapy. We investigated whether DXM would reduce survival of GBM patients in the setting of concurrent TMZ and BEV administration. METHODS: We reviewed the treatment of all 73 patients with GBM who received definitive therapy at our institution from 2005 to 2013 with RT (60 Gy) delivered with concurrent daily TMZ (75 mg/m(2)). Of these, 34 patients also were treated with concurrent BEV (10 mg/kg every two weeks). Patients received adjuvant therapy (TMZ or TMZ/Bev) until either progression, discontinuation due to toxicity, or 12 months after radiation completion. All patients who had GBM progression with TMZ were offered BEV for salvage therapy, with 19 (56 %) receiving BEV. RESULTS: With a median follow-up of 15.6 months, 67 (91.8 %) patients were deceased. The OS for the entire cohort was 15.9 months, while the PFS was 7.7 months. The extent of resection was a prognostic indicator for OS (p = .0044). The median survival following gross tumor resection (GTR) was 22.5 months, subtotal resection (STR) was 14.9 months, and biopsy was 12.1 months. The addition of BEV to TMZ with RT was borderline significantly associated with increased PFS (9.4 vs. 5.1 months, p = 0.0574) although was not significantly associated with OS (18.1 vs. 15.3 months respectively, p = 0.3064). In patients receiving TMZ, DXM use concurrent with RT was a poor prognostic indicator of both OS (12.7 vs. 22.6 months, p = 0.003) and PFS (3.6 vs. 8.4 months, p <0.0001). DXM did not reduce OS in patients who received TMZ and BEV concurrently with RT (22.9 vs 22.8 months, p = 0.4818). On multivariable analysis, DXM use predicted an unfavorable OS hazard ratio (HR) = 1.72, p = 0.045). CONCLUSIONS: Our results with TMZ, BEV, and RT are similar to previous studies in terms of PFS and OS. DXM use during RT with concurrent TMZ correlated with reduced OS and PFS unless BEV was administered. PMID- 26520781 TI - Effect of floor type on the performance, physiological and behavioural responses of finishing beef steers. AB - BACKGROUND: The study objective was to investigate the effect of bare concrete slats (Control), two types of mats [(Easyfix mats (mat 1) and Irish Custom Extruder mats (mat 2)] fitted on top of concrete slats, and wood-chip to simulate deep bedding (wood-chip placed on top of a plastic membrane overlying the concrete slats) on performance, physiological and behavioral responses of finishing beef steers. One-hundred and forty-four finishing steers (503 kg; standard deviation 51.8 kg) were randomly assigned according to their breed (124 Continental cross and 20 Holstein-Friesian) and body weight to one of four treatments for 148 days. All steers were subjected to the same weighing, blood sampling (jugular venipuncture), dirt and hoof scoring pre study (day 0) and on days 23, 45, 65, 86, 107, 128 and 148 of the study. Cameras were fitted over each pen for 72 h recording over five periods and subsequent 10 min sampling scans were analysed. RESULTS: Live weight gain and carcass characteristics were similar among treatments. The number of lesions on the hooves of the animals was greater (P < 0.05) on mats 1 and 2 and wood-chip treatments compared with the animals on the slats. Dirt scores were similar for the mat and slat treatments while the wood-chip treatment had greater dirt scores. Animals housed on either slats or wood-chip had similar lying times. The percent of animals lying was greater for animals housed on mat 1 and mat 2 compared with those housed on concrete slats and wood chips. Physiological variables showed no significant difference among treatments. CONCLUSIONS: In this exploratory study, the performance or welfare of steers was not adversely affected by slats, differing mat types or wood-chip as underfoot material. PMID- 26520782 TI - Gadolinium free cardiovascular magnetic resonance with 2-point Cine balanced steady state free precession. AB - BACKGROUND: Cardiovascular magnetic resonance (CMR) of ventricular structure and function is widely performed using cine balanced steady state free precession (bSSFP) MRI. The bSSFP signal of myocardium is weighted by magnetization transfer (MT) and T1/T2-relaxation times. In edematous and fibrotic tissues, increased T2 and reduced MT lead to increased signal intensity on images acquired with high excitation flip angles. We hypothesized that acquisition of two differentially MT weighted bSSFP images (termed 2-point bSSFP) can identify tissue that would enhance with gadolinium similar to standard of care late gadolinium enhancement (LGE). METHODS: Cine bSSFP images (flip angles of 5 degrees and 45 degrees ) and native-T1 and T2 maps were acquired in one mid-ventricular slice in 47 patients referred for CMR and 10 healthy controls. Afterwards, LGE images and post contrast T1 maps were acquired and gadolinium partition coefficient (GPC) was calculated. Maps of DeltaS/So were calculated as (S45-S5)/S5*100 (%), where Sflip_angle is the voxel signal intensity. RESULTS: Twenty three patients demonstrated areas of myocardial hyper-enhancement with LGE. In enhanced regions, DeltaS/So, native-T1, T2, and GPC were heightened (p < 0.05 vs. non-enhanced tissues). DeltaS/So, native-T1, and T2 all demonstrated association with GPC, however the association was strongest for DeltaS/So. Bland-Altman analysis revealed a slight bias towards larger volume of enhancement with DeltaS/So compared to LGE, and similar transmurality. Subjective analysis with 2-blinded expert readers revealed agreement between DeltaS/So and LGE of 73.4 %, with false positive detection of 16.7 % and false negative detection of 15.2 %. CONCLUSIONS: Gadolinium free 2-point bSSFP identified tissue that enhances at LGE with strong association to GPC. Our results suggest that with further development, MT weighted CMR could be used similar to LGE for diagnostic imaging. PMID- 26520783 TI - Association of advanced airway device with chest compression fraction during out of-hospital cardiopulmonary arrest. AB - BACKGROUND: Select Emergency Medical Services (EMS) practitioners substitute endotracheal intubation (ETI) with supraglottic airway (SGA) insertion to minimize CPR chest compression interruptions, but the resulting effects upon chest compression fraction (CCF) are unknown. We sought to determine the differences in CCF between adult out-of-hospital cardiac arrest (OHCA) receiving ETI and those receiving SGA. METHODS: We studied adult, non-traumatic OHCA patients enrolled in the Resuscitation Outcomes Consortium (ROC) Prehospital Resuscitation using an Impedance valve and an Early vs. Delayed analysis (PRIMED) trial. Chest compressions were measured using compression or thoracic impedance sensors. We limited the analysis to those receiving ETI or SGA (Combitube, King Laryngeal Tube, or Laryngeal Mask Airway) and >2min of chest compression data before and after airway insertion. We compared CCF between ETI and SGA before and after airway insertion, adjusting for age, sex, witnessed arrest, bystander CPR, shockable initial rhythm, public location, PRIMED trial arm, and regional ROC center. We also compared the change in CCF for each airway technique. RESULTS: Of 14,955 patients enrolled in the ROC PRIMED trial, we analyzed 2767 cases, including 2051 ETI, 671 SGA, and 45 both. Among subjects in this investigation the mean age was 66.4 years with a male predominace, 46% with witnessed event, 37% receiving bystander CPR, and 22% presenting with an initially shockable rhythm. Pre- and post-airway CCF was higher for SGA than ETI (SGA pre-airway CCF 73.2% [95%CI: 71.6-74.7%] vs. ETI 70.6% [95%CI: 69.7-71.5%]; post-airway 76.7% [95%CI: 75.2-78.1%] vs. 72.4% [95%CI: 71.5-73.3%]). After adjusting for potential confounders, these significant changes persisted (pre-airway difference 2.2% favoring SGA, p-value=0.046; post-airway 3.4% favoring SGA, p=0.001). CONCLUSION: In patients with OHCA, we detected a slightly higher rate of CCF in patients for whom a SGA was inserted, both before and after insertion. However, the actual differences were so small, that in the context of this observational, secondary analysis, it is unclear if this represents a clinically significant difference. PMID- 26520785 TI - 9 + 0 and 9 + 2 cilia are randomly dispersed in the mouse node. AB - The initial determination of left-right asymmetry is an essential process in embryonic development. In mouse embryo, cilia in the node play an important role generating the nodal flow that subsequently triggers left-right determination in the embryo. Although nodal cilia have historically been thought to have a 9 + 0 axonemal configuration, the existence of 9 + 2 cilia has been reported so far. Because the distribution of those two types of cilia within the node has not yet been reported, we assessed the arrangement of 9 + 0 and 9 + 2 cilia in the node. In this study, we concluded that most of the nodal cilia were 9 + 0 in structure and there were much fewer 9 + 2 cilia than 9 + 0 cilia. Furthermore, the two types of cilia were randomly distributed in the node with no regularity. In addition, we studied the embryonic origin of the crown cells surrounding the node to better understand their identity. PMID- 26520786 TI - Quantitative determination of occupation sites of trace Co substituted for multiple Fe sites in M-type hexagonal ferrite using statistical beam-rocking TEM EDXS analysis. AB - The occupation sites and the occupancies of trace dopants in La/Co co-doped Sr-M type ferrite, SrFe12O19, were quantitatively and precisely determined by beam rocking energy-dispersive X-ray spectroscopy (EDXS) on the basis of electron channeling effects. Because the Co atoms, in particular, should be partially substituted for the five crystallographically inequivalent sites, which could be key parameters in improving the magneto-crystalline anisotropy, it is difficult yet intriguing to discover their occupation sites and occupancies without using the methods of large-scale facilities, such as neutron diffraction and synchrotron radiation. In the present study, we tackled this problem by applying an extended statistical atom location by channeling enhanced microanalysis method, using conventional transmission electron microscopy, EDXS and dynamical electron elastic/inelastic scattering theories. The results show that the key occupation sites of Co were the 2a, 4f1 and 12k sites. The quantified occupancies of Co were consistent with those of the previous study, which involved a combination of neutron diffraction and extended X-ray absorption fine structure analysis, as well as energetics considerations based on by first-principles calculations. PMID- 26520784 TI - Two promising future developments of cryo-EM: capturing short-lived states and mapping a continuum of states of a macromolecule. AB - The capabilities and application range of cryogenic electron microscopy (cryo-EM) method have expanded vastly in the last two years, thanks to the advances provided by direct detection devices and computational classification tools. We take this review as an opportunity to sketch out promising developments of cryo EM in two important directions: (i) imaging of short-lived states (10-1000 ms) of biological molecules by using time-resolved cryo-EM, particularly the mixing spraying method and (ii) recovering an entire continuum of coexisting states from the same sample by employing a computational technique called manifold embedding. It is tempting to think of combining these two methods, to elucidate the way the states of a molecular machine such as the ribosome branch and unfold. This idea awaits further developments of both methods, particularly by increasing the data yield of the time-resolved cryo-EM method and by developing the manifold embedding technique into a user-friendly workbench. PMID- 26520787 TI - Effects of isoconcentration surface threshold values on the characteristics of needle-shaped precipitates in atom probe tomography data from an aged Al-Mg-Si alloy. AB - Needle-shaped precipitates in an aged Al-0.62Mg-0.93Si (mass%) alloy were identified using a compositional threshold method, an isoconcentration surface, in atom probe tomography (APT). The influence of thresholds on the morphological and compositional characteristics of the precipitates was investigated. Utilizing optimum parameters for the concentration space, a reliable number density of the precipitates is obtained without dependence on the elemental concentration threshold in comparison with evaluation by transmission electron microscopy (TEM). It is suggested that careful selection of the concentration space in APT can lead to a reasonable average Mg/Si ratio for the precipitates. It was found that the maximum length and maximum diameter of the precipitates are affected by the elemental concentration threshold. Adjustment of the concentration threshold gives better agreement with the precipitate dimensions measured by TEM. PMID- 26520788 TI - Repurposing Vitamin D as an Anticancer Drug. PMID- 26520789 TI - Breast cancer metastasis suppressor 1 (BRMS1) attenuates TGF-beta1-induced breast cancer cell aggressiveness through downregulating HIF-1alpha expression. AB - BACKGROUND: Cancer metastasis is a multi-step event including epithelial-to mesenchymal transition (EMT). Breast cancer metastasis suppressor 1 (BRMS1) is a novel metastasis suppressor protein without anti-proliferating activity. However, a detailed underlying mechanism by which BRMS1 attenuates cancer cell EMT and invasion remained to be answered. In the present study, we report an additional mechanism by which BRMS1 attenuates Transforming growth factor-beta1 (TGF-beta1) induced breast cancer cell EMT and invasion. METHODS: Experimental analysis involving chromosome immunoprecipitation (ChIP) and luciferase reporter assays were used to validate hypoxia inducible factor-1alpha (HIF-1alpha) as a transcriptional regulator of TWIST1 and Snail. Quantitative RT-PCR was used to analyze transcript expression. Immunoblotting and immunofluorescence were used to analyze protein expression. Matrigel-coated in vitro invasion insert was used to analyze cancer cell invasion. RESULTS: BRMS1 strongly inhibited TGF-beta1-induced breast cancer cell EMT and invasion. Unexpectedly, we observed that BRMS1 downregulates not only TWIST1 but also Snail expression, thereby inhibiting breast cancer cell invasion. In addition, we provide evidence that HIF-1alpha is required for Snail and TWIST1 expression. Further, BRMS1 reduced TGF-beta1 induced HIF-1alpha transcript expression through inactivation of nuclear factor kappaB (NF-kappaB). CONCLUSION: Collectively, the present study demonstrates a mechanical cascade of BRMS1 suppressing cancer cell invasion through downregulating HIF-1alpha transcript and consequently reducing Snail and TWIST1 expression. PMID- 26520790 TI - A systematic review of medicinal plants used for weight loss in Brazil: Is there potential for obesity treatment? AB - ETHNOPHARMACOLOGICAL RELEVANCE: Obesity is a pandemic disease and its prevalence is still increasing. Moreover, it has important costs to public health. In Brazil, many plants are used for weight loss by overweight or obese people, but there is a lack of scientific basis for this practice. Many ethnobotanical studies aiming to characterize this usage have been published, but they are still limited by the region considered and the diversity of the popular knowledge. AIM OF THE STUDY: The present study was undertaken to systematically review the ethnobotanical surveys regarding the species utilized to reduce body weight in overweight or obese people in Brazil. METHODS: Ethnobotanical surveys related to this usage and performed in Brazilian regions were systematically found in MEDLINE, LILACS and Scopus. RESULTS: Thirty-three studies were included in this review. Fifty species were popularly utilized to lose weight. The most cited species were Baccharis trimera (Less.) DC, Annona muricata L. and Hancornia speciosa Gomes. Camellia sinensis (L.) Kuntze and Hibiscus sabdariffa L. were also cited and are supported by either animal or human investigations that indicate some beneficial activity against obesity. However, for the majority of species cited in the included studies, there is no scientific basis that assures the biological effects of this usage. Many studies have demonstrated important effects of these plants on glycemia, serum lipid levels or body weight control in non-obese conditions, which is not sufficient to recommend the use of these plants to reduce body weight in overweight or obese people. CONCLUSIONS: Although many plants are popularly used to reduce weight in overweight or obese people in Brazil, there is little scientific evidence corroborating its usage. Based on the ethnobotanical data presented, this review indicates the plants that should be considered for scientifically controlled studies devoted to investigating their effects on obesity. PMID- 26520791 TI - Risk factors for severe hand foot mouth disease in Singapore: a case control study. AB - BACKGROUND: Hand foot mouth disease (HFMD) is a common childhood infection that can potentially lead to serious complications. The aim of this study is to identify risk factors of acquiring severe HFMD in our population. METHODS: We performed a case control study using patients admitted to our hospital from August 2004 to July 2014. Cases were patients with severe HFMD disease while controls were age-matched patients obtained from the same year, in a 2:1 ratio. Data comprising demographic characteristics, clinical symptoms and signs, and lab findings were collected. Conditional univariable logistic regression was performed to determine risk factors for severe disease. RESULTS: A total of 24 cases of severe HFMD were identified and matched with 48 controls. Seventeen (70.8%) cases had central nervous system complications. Seven (29.2%) had cardiovascular complications without evidence of myocarditis. One patient died of encephalitis. The overall mortality of severe disease is 4%. Evidence of hypoperfusion, seizure, altered mentation, meningeal irritation, tachycardia, tachypnea, raised absolute neutrophil count and EV-A71 (Enterovirus A71) positivity were significantly associated with a severe course of HFMD. CONCLUSION: In managing children with HFMD, physicians should consider these factors to help identify patients at risk for severe disease. PMID- 26520793 TI - Inhibitory effect of herbal medicines and their trapping abilities against methylglyoxal-derived advanced glycation end-products. AB - BACKGROUND: Methylglyoxal (MG) is one of the most reactive glycating agents, which result the formation of advanced glycation end-products (AGEs) that have been implicated in the progression of age-related diseases. Inhibition of MG induced AGE formation is the imperative approach for alleviating diabetic complications. The objective of this study was to investigate the MG-trapping abilities of herbal medicines and their inhibitory activities on the formation of MG-derived AGEs. METHODS: The aqueous extract of herbal medicines was measured for the content of total phenolic compounds and the antioxidant activity by Folin Ciocalteu assay and the 1,1-diphenyl 2-picrylhydrazyl (DPPH) radical scavenging activity, respectively. The extracts were investigated the MG-trapping ability by high performance liquid chromatography (HPLC). The extracts were incubated with BSA and MG at 37 degrees C for 1 day. The formation of MG-derived AGEs was measured. RESULTS: Total phenolic compounds of eleven herbal medicines showed marked variations, ranging from 12.16 to 272.36 mg gallic acid equivalents/g extract. All extracts (1 mg/mL) markedly exhibited the DPPH radical scavenging activity (0.31-73.52%) and the MG-trapping abilities (13.97-58.97%). In addition, they also inhibited the formation of MG-derived AGEs by 4.01-79.98%. The results demonstrated that Rhinacanthus nasutus, Syzygium aromaticum, and Phyllanthus amarus were the potent inhibitors against the formation of MG-derived AGEs. The positive correlations between the contents of phenolics and % MG trapping (r = 0.912, p < 0.01) and % inhibition of MG-derived AGEs (r = 0.716, p < 0.01) were observed in the study. Furthermore, there was a moderate positive correlation between % MG trapping and % inhibition of MG-derived AGEs (r =0.584, p < 0.01). CONCLUSIONS: Rhinacanthus nasutus, Syzygium aromaticum, and Phyllanthus amarus could reduce the formation of MG-derived AGEs through their MG-trapping abilities. These findings are relevant for focusing on potential herbal medicines to prevent or ameliorate AGE-mediated diabetic complications. PMID- 26520794 TI - Prevalence of intestinal helminth infection among school children in Maksegnit and Enfranz Towns, northwestern Ethiopia, with emphasis on Schistosoma mansoni infection. AB - BACKGROUND: Schistosomiasis is endemic in Ethiopia and previously unknown transmission foci have been reported from time to time in different parts of the country. Further surveys are required in areas where endemicity of the disease is not known to cover them with control program if transmission is taking place. This study, therefore, aims to assess the magnitude of schistosomiasis mansoni and soil-transmitted helminthiasis in Maksegnit and Enfranz Towns, northwestern Ethiopia. METHODS: Cross-sectional parasitological and malacological surveys were conducted in three schools found in Maksegnit and Enfranz Towns. Stool specimens were collected from 550 randomly selected school children (age range 5 to 17 years) and processed for microscopic examination using Kato-Katz method (single smear per stool sample). Malacological survey was conducted in Gumara and Garno Rivers found in the study areas. Biomphalaria pfeifferi snails collected from the two rivers were individually exposed to artificial light in order to induce cercarial shedding. Laboratory-bred Swiss albino mice were exposed to the cercariae and definite identification of the schistosome species was made based on morphology. RESULTS: The overall prevalence of S. mansoni infection was found to be 49%; however, it varied by schools, with Selam having 60.7%, and Maksegnit Number 1 and 2 having 45.8 and 39.6%, respectively. The respective mean intensity of S. mansoni infection among school children in Selam, Maksegnit Number 1 and Maksegnit Number 2 Schools were 243, 194 and 183 eggs per gram of stool (epg). In all the study areas there was no difference in prevalence of S. mansoni infection in relation to age, however, the prevalence varied by sex, with males having highest prevalence (54.5% vs 44.1%) (p = 0.012). Adult S. mansoni worms were harvested from mice exposed to cercariae shed from B. pfeifferi on the 6(th) week post-exposure. The prevalence of Ascaris lumbricoides single infection was 16.5% while its co-infection with S. mansoni was 18.2%. CONCLUSION: Infections of young children, findings of schistosome infected snails, establishment of mice infection and harvesting adult worms from the lab-bred mice confirm that autochthonous transmission is taking place in the study areas. Hence, preventive chemotherapy with praziquantel should be put in place, complemented with other measures such as provision of sanitary facilities and health education, to control morbidity and transmission of schistosomiasis and soil-transmitted helminthiasis in the study areas. PMID- 26520795 TI - Reduced deformability of parasitized red blood cells as a biomarker for anti malarial drug efficacy. AB - BACKGROUND: Malaria remains a challenging and fatal infectious disease in developing nations and the urgency for the development of new drugs is even greater due to the rapid spread of anti-malarial drug resistance. While numerous parasite genetic, protein and metabolite biomarkers have been proposed for testing emerging anti-malarial compounds, they do not universally correspond with drug efficacy. The biophysical character of parasitized cells is a compelling alternative to these conventional biomarkers because parasitized erythrocytes become specifically rigidified and this effect is potentiated by anti-malarial compounds, such as chloroquine and artesunate. This biophysical biomarker is particularly relevant because of the mechanistic link between cell deformability and enhanced splenic clearance of parasitized erythrocytes. METHODS: Recently a microfluidic mechanism, called the multiplexed fluidic plunger that provides sensitive and rapid measurement of single red blood cell deformability was developed. Here it was systematically used to evaluate the deformability changes of late-stage trophozoite-infected red blood cells (iRBCs) after treatment with established clinical and pre-clinical anti-malarial compounds. RESULTS: It was found that rapid and specific iRBC rigidification was a universal outcome of all but one of these drug treatments. The greatest change in iRBC rigidity was observed for (+)-SJ733 and NITD246 spiroindolone compounds, which target the Plasmodium falciparum cation-transporting ATPase ATP4. As a proof-of-principle, compounds of the bisindole alkaloid class were screened, where cladoniamide A was identified based on rigidification of iRBCs and was found to have previously unreported anti-malarial activity with an IC50 lower than chloroquine. CONCLUSION: These results demonstrate that rigidification of iRBCs may be used as a biomarker for anti-malarial drug efficacy, as well as for new drug screening. The novel anti-malarial properties of cladoniamide A were revealed in a proof-of principle drug screen. PMID- 26520792 TI - Pathobiology of tobacco smoking and neurovascular disorders: untied strings and alternative products. AB - Tobacco smoke (TS) is the leading cause of preventable deaths worldwide. In addition to a host of well characterized diseases including chronic obstructive pulmonary disease, oral and peripheral cancers and cardiovascular complications, epidemiological evidence suggests that chronic smokers are at equal risk to develop neurological and neurovascular complications such as multiple sclerosis, Alzheimer's disease, stroke, vascular dementia and small vessel ischemic disease (SVID). Unfortunately, few direct neurotoxicology studies of tobacco smoking and its pathogenic pathways have been produced so far. A major link between TS and CNS disorders is the blood-brain barrier (BBB). In this review article, we summarize the current understanding of the toxicological impact of TS on BBB physiology and function and major compensatory mechanisms such as nrf2- ARE signaling and anti-inflammatory pathways activated by TS. In the same context, we discuss the controversial role of antioxidant supplementation as a prophylactic and/or therapeutic approach in delaying or decreasing the disease complications in smokers. Further, we cover a number of toxicological studies associated with "reduced exposure" cigarette products including electronic cigarettes. Finally, we provide insights on possible avenues for future research including mechanistic studies using direct inhalation rodent models. PMID- 26520796 TI - Phenotypic variability confirmed by nuclear ribosomal DNA suggests a possible natural hybrid zone of Triatoma brasiliensis species complex. AB - Triatoma brasiliensis macromelasoma occurs in Pernambuco state, Brazil, which is situated between the distribution areas of Triatoma brasiliensis brasiliensis (north) and Triatoma juazeirensis (south). T. b. macromelasoma displays greater variations in its chromatic phenotype than either T. b. brasiliensis or T. juazeirensis, and patterns reminiscent of one or the other. Experimental crosses from each of these members of the T. brasiliensis species complex generated fertile offspring suggesting that viable hybrids could be present in nature, despite their significant genetic distances. Considering the geographical position of occurrence of the T. b. macromelasoma (in Pernambuco) it was proposed to be an area capable of supporting natural hybridization between T. b. brasiliensis and T. juazeirensis. Since phenotypic variability is expected, this study investigated the existence of intermediate chromatic phenotypes for T. b. macromelasoma in various locations in areas between the T. b. brasiliensis and T. juazeirensis occurrences. Thirteen different color patterns were for the first time characterized and nine of those displayed intermediate phenotypes. Molecular analysis performed using ribosomal DNA intergenic region, grouped all within the T. brasiliensis complex. The intermediate chromatic phenotypes, molecular analysis and experimental crosses all support the distinction of a zone of hybridization that gave rise to the T. b. macromelasoma through homoploidal evolution. PMID- 26520797 TI - Type-specific PCR assays for Babesia bovis msa-1 genotypes in Asia: Revisiting the genetic diversity in Sri Lanka, Mongolia, and Vietnam. AB - Babesia bovis is the most virulent Babesia organism, resulting in a high mortality rate in cattle. The genetic diversity of B. bovis merozoite surface antigens (MSAs), such as MSA-1, MSA-2b, and MSA-2c, might be linked to altered immune profiles in the host animals. The present study aimed to develop type specific PCR assays for Asian msa-1 genotypes, thereby re-analyzing the genetic diversity of msa-1 in Sri Lanka, Mongolia, and Vietnam. Specific primers were designed for nine Asian msa-1 genotypes, which had been detected based on the phylogeny constructed using msa-1 gene sequences retrieved from the GenBank database. Specificity of the type-specific PCR assays was confirmed using plasmids containing the inserts of msa-1 gene fragments that represent Asian genotypes. Furthermore, no amplicons were observed by these PCR assays when DNA samples of Babesia bigemina, Babesia ovata, Theileria annulata, Theileria orientalis, Trypanosoma evansi, Trypanosoma theileri, Anaplasma marginale, and Anaplasma bovis, and non-infected bovine blood were analyzed. In total, 109 B. bovis-positive blood DNA samples sourced from Sri Lanka (44 cattle), Mongolia (26 cattle), and Vietnam (23 cattle and 16 water buffaloes) were then screened by the type-specific PCR assays. The sequences derived from all of the PCR amplicons were phylogenetically analyzed. Out of 109 DNA samples, 23 (20 from cattle and 3 from water buffaloes) were positive for at least one genotype. In agreement with previous studies, five and four different genotypes were detected among the DNA samples from Sri Lanka and Vietnam, respectively. In contrast, four genotypes, including three novel genotypes, were detected from Mongolia. Five DNA samples were found to be co-infected with multiple genotypes. The sequences of the PCR amplicons clustered phylogenetically within the corresponding clades. These findings indicated that the type-specific PCR assays described herein are useful for the determination of genotypic diversity of the B. bovis msa-1 gene in Asia. PMID- 26520798 TI - Mechanical compression during repeated sustained isometric muscle contractions and hyperemic recovery in healthy young males. AB - BACKGROUND: An elevated intramuscular pressure during a single forearm isometric muscle contraction may restrict muscle hyperemia. However, during repeated isometric exercise, it is unclear to what extent mechanical compression and muscle vasodilatation contribute to the magnitude and time course of beat-to-beat limb hemodynamics, due to alterations in leg vascular conductance (LVC). METHODS: In eight healthy male subjects, the time course of both beat-to-beat leg blood flow (LBF) and LVC in the femoral artery was determined between repeated 10-s isometric thigh muscle contractions and 10-s muscle relaxation (a duty cycle of 20 s) for steady-state 120 s at five target workloads (10, 30, 50, 70, and 90% of maximum voluntary contraction (MVC)). The ratio of restricted LBF due to mechanical compression across workloads was determined by the formula (relaxation LBF--contraction LBF)/relaxation LBF (%). RESULTS: The exercise protocol was performed completely by all subjects (<= 50% MVC), seven subjects (<= 70% MVC), and two subjects (<= 90% MVC). During a 10-s isometric muscle contraction, the time course in both beat-to-beat LBF and LVC displayed a fitting curve with an exponential increase (P < 0.001, r (2) >= 0.956) at each workload but no significant difference in mean LBF across workloads and pre-exercise. During a 10 s muscle relaxation, the time course in both beat-to-beat LBF and LVC increased as a function of workload, followed by a linear decline (P < 0.001, r (2) >= 0.889), that was workload-dependent, resulting in mean LBF increasing linearly across workloads (P < 0.01, r (2) = 0.984). The ratio of restricted LBF can be described as a single exponential decay with an increase in workload, which has inflection point distinctions between 30 and 50% MVC. CONCLUSIONS: In a 20-s duty cycle of steady-state repeated isometric muscle contractions, the post contraction hyperemia (magnitude of both LBF and LVC) during muscle relaxation was in proportion to the workload, which is in agreement with previous findings. Furthermore, time-dependent beat-to-beat muscle vasodilatation was seen, but not restricted, during isometric muscle contractions through all target workloads. Additionally, the relative contribution of mechanical obstruction and vasodilatation to the hyperemia observed in the repeated isometric exercise protocol was non-linear with regard to workload. In combination with repeated isometric exercise, the findings could potentially prove to be useful indicators of circulatory adjustment by mechanical compression for muscle-related disease. PMID- 26520799 TI - Unmeasured Confounders and Predictive Models: What's Your C-Statistic? PMID- 26520800 TI - [Three years after reaching the indexing in PubMed]. PMID- 26520801 TI - Type III Secretion: Building and Operating a Remarkable Nanomachine. AB - The Type III secretion system (T3SS) is a protein export pathway that is widespread in Gram-negative bacteria and delivers effector proteins directly into eukaryotic cells. At its core lie the injectisome (a sophisticated transmembrane secretion apparatus) and a complex network of specialized chaperones that target secretory proteins to the antechamber of the injectisome. The assembly of the system, and the subsequent secretion of proteins through it, undergo fine-tuned, hierarchical regulation. Here, we present the current understanding of the injectisome assembly process, secretion hierarchy, and the role of chaperones. We discuss these events in light of available structural and biochemical dissection and propose future directions essential to revealing mechanistic insight into this fascinating nanomachine. PMID- 26520802 TI - Mitochondrial Proteins Moonlighting in the Nucleus. AB - Mitochondria function as cellular energy generators, producing the fuel required to drive biological processes. The response of cells to mitochondrial activity or dysfunction regulates their survival, growth, proliferation, and differentiation. Several proteins that contain mitochondrial-targeting sequences (MTS) also reside in the nucleus and there is increasing evidence that the nuclear translocation of mitochondrial proteins represents a novel pathway by which mitochondria signal their status to the cell. Here, we discuss the different mechanisms that control the dual mitochondrial and nuclear localisation of proteins and propose that these nuclear moonlighters represent a widespread regulatory circuit to maintain mitochondrial homeostasis. PMID- 26520803 TI - PIK-ing the right gene for polymicrogyria. PMID- 26520805 TI - Leptin as a potential mediator of both physiologic and behavioral determinants of reductions in activity-related energy expenditure during weight loss. PMID- 26520804 TI - Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study. AB - BACKGROUND: Bilateral perisylvian polymicrogyria (BPP), the most common form of regional polymicrogyria, causes the congenital bilateral perisylvian syndrome, featuring oromotor dysfunction, cognitive impairment, and epilepsy. The causes of BPP are heterogeneous, but only a few genetic causes have been reported. The aim of this study was to identify additional genetic causes of BPP and characterise their frequency in this population. METHODS: Children (aged <=18 years) with polymicrogyria were enrolled into our research programme from July, 1980, to October, 2015, at two centres (Florence, Italy, and Seattle, WA, USA). We obtained samples (blood and saliva) throughout this period at both centres and did whole-exome sequencing on DNA from eight trios (two parents and one affected child) with BPP in 2014. After the identification of mosaic PIK3R2 mutations in two of these eight children, we performed targeted screening of PIK3R2 by two methods in a cohort of 118 children with BPP. First, we performed targeted sequencing of the entire PIK3R2 gene by single molecule molecular inversion probes (smMIPs) on 38 patients with BPP with normal to large head size. Second, we did amplicon sequencing of the recurrent PIK3R2 mutation (Gly373Arg) in 80 children with various types of polymicrogyria including BPP. One additional patient had clinical whole-exome sequencing done independently, and was included in this study because of the phenotypic similarity to our cohort. FINDINGS: We identified a mosaic mutation (Gly373Arg) in a regulatory subunit of the PI3K-AKT mTOR pathway, PIK3R2, in two children with BPP. Of the 38 patients with BPP and normal to large head size who underwent targeted next-generation sequencing by smMIPs, we identified constitutional and mosaic PIK3R2 mutations in 17 additional children. In parallel, one patient had the recurrent PIK3R2 mutation identified by clinical whole-exome sequencing. Seven of these 20 patients had BPP alone, and 13 had BPP in association with features of the megalencephaly-polymicrogyria polydactyly-hydrocephalus (MPPH) syndrome. 19 patients had the same mutation (Gly373Arg), and one had a nearby missense mutation (Lys376Glu). Mutations were constitutional in 12 patients and mosaic in eight patients. In patients with mosaic mutations, we noted substantial variation in alternate (mutant) allele levels, ranging from ten (3%) of 377 reads to 39 (37%) of 106 reads, equivalent to 5-73% of cells analysed. Levels of mosaicism varied from undetectable to 37 (17%) of 216 reads in blood-derived DNA compared with 2030 (29%) of 6889 reads to 275 (43%) of 634 reads in saliva-derived DNA. INTERPRETATION: Constitutional and mosaic mutations in the PIK3R2 gene are associated with developmental brain disorders ranging from BPP with a normal head size to the MPPH syndrome. The phenotypic variability and low-level mosaicism, which challenge conventional molecular methods, have important implications for genetic testing and counselling. FUNDING: US National Institutes of Health. PMID- 26520806 TI - Editorial Comment. PMID- 26520807 TI - The molecular mechanism behind reactive aldehyde action on transmembrane translocations of proton and potassium ions. AB - Membrane transporters are involved in enormous number of physiological and pathological processes. Under oxidative stress they become targets for reactive oxygen species and its derivatives which cause protein damage and/or influence protein function(s). The molecular mechanisms of this interaction are poorly understood. Here we describe a novel lipid-mediated mechanism by which biologically important reactive aldehydes (RAs; 4-hydroxy-2-nonenal, 4-hydroxy-2 hexenal and 4-oxo-2-nonenal) modify the activity of several membrane transporters. We revealed that investigated RAs covalently modify the membrane lipid phosphatidylethanolamine (PE), that lead to the formation of different membrane active adducts. Molecular dynamic simulations suggested that anchoring of PE-RA adducts in the lipid headgroup region is primarily responsible for changes in the lipid membrane properties, such as membrane order parameter, boundary potential and membrane curvature. These caused the alteration of transport activity of mitochondrial uncoupling protein 1, potassium carrier valinomycin and ionophore CCCP. In contrast, neither direct protein modification by RAs as previously shown for cytosolic proteins, nor its insertion into membrane bilayers influenced the studied transporters. Our results explain the diversity of aldehyde action on cell proteins and open a new field in the investigation of lipid-mediated effects of biologically important RAs on membrane receptors, channels and transporters. PMID- 26520809 TI - Localization of ginsenosides in Panax ginseng with different age by matrix assisted laser-desorption/ionization time-of-flight mass spectrometry imaging. AB - The root of Panax ginseng C.A. Mey. (P. ginseng) is one of the most popular traditional Chinese medicines, with ginsenosides as its main bioactive components. Because different ginsenosides have varied pharmacological effects, extraction and separation of ginsenosides are usually required for the investigation of pharmacological effects of different ginsenosides. However, the contents of ginsenosides vary with the ages and tissues of P. ginseng root. In this research, an efficient method to explore the distribution of ginsenosides and differentiate P. ginseng roots with different ages was developed based on matrix assisted laser desorption/ionization time-of-flight mass spectrometry imaging (MALDI-TOF-MSI). After a simple sample preparation, there were 18 peaks corresponding to 31 ginsenosides with distinct localization in the mass range of m/z 700-1400 identified by MALDI-TOF-MSI and MALDI-TOF-MS/MS. All the three types of ginsenosides were successfully detected and visualized in images, which could be correlated with anatomical features. The P. ginseng at the ages of 2, 4 and 6 could be differentiated finely through the principal component analysis of data collected from the cork based on the ion images but not data from the whole tissue. The experimental result implies that the established method for the direct analysis of metabolites in plant tissues has high potential for the rapid identification of metabolites and analysis of their localizations in medicinal herbs. Furthermore, this technique also provides valuable information for the component-specific extraction and pharmacological research of herbs. PMID- 26520810 TI - Comparison of the characteristics and mechanisms of Hg(II) sorption by biochars and activated carbon. AB - Two biochars were produced from bagasse and hickory chips (referred to as BB and HCB, respectively) and evaluated for their sorption ability of Hg(II) in aqueous solution. A commercial activated carbon (AC) which is commonly used for Hg(II) removal was included for comparison. Both biochars showed higher sorption capacities than AC, following the trend of BB>HCB>AC. The sorption of Hg(II) by BB and AC was mainly attributed to the formation of (COO)2Hg(II) and (O)2Hg(II). As a result, the adsorption capacity of Hg(II) by BB decreased 17.6% and 37.6% after COOH and OH were blocked, respectively and that of Hg(II) by AC decreased 6.63% and 62.2% for COOH and OH hindered, respectively. However, blocking the function groups had little effect on the Hg removal by HCB since sorption of Hg(II) by HCB was mainly resulted from the pi electrons of CC and CO induced Hg pi binding. Further X-ray photoelectron spectroscopy analysis indicated the possibility of reduction of the Hg(II) to Hg(I) by phenol groups or pi electrons during the removal of Hg(II) by both biochars. In conclusion, biochar is more effective than activated carbon in removing Hg(II) and there exists a high potential that biochar can be a substitute of activated carbon for removal of Hg(II) from wastewater. PMID- 26520811 TI - Hydrophobic-hydrophilic post-cross-linked polystyrene/poly (methyl acryloyl diethylenetriamine) interpenetrating polymer networks and its adsorption properties. AB - In this study, we developed an effective approach for increasing the equilibrium adsorption capacity of the interpenetrating polymer networks (IPNs) toward polar aromatic compounds. For this purpose, a novel post-cross-linked polystyrene/poly (methyl acryloyl diethylenetriamine) (CMPS_pc/PMADETA) IPNs was synthesized and its adsorption was evaluated from aqueous solution using p-hydroxybenzoic acid as the adsorbate. CMPS_pc/PMADETA IPNs possessed a relatively high Brunauer-Emmett Teller (BET) surface area and hydrophobic networks as well as hydrophilic networks, inducing a much enhanced adsorption toward p-hydroxybenzoic acid. The equilibrium adsorption capacity of p-hydroxybenzoic acid on CMPS_pc/PMADETA IPNs was remarkably larger than that on its precursors and the equilibrium data were correlated better by Sips model than the Langmuir and Freundlich models. Furthermore, the adsorption was a fast process, and the micropore diffusion model characterized the kinetic data very well. At a feed concentration of 1060.8mg/L and a flow rate of 10.8BV/h, the dynamic adsorption capacity was calculated to be 200.8mg/mL wet resin. PMID- 26520812 TI - Controlled optical properties of water-soluble CdTe nanocrystals via anion exchange. AB - We report a study on anion exchange reaction of CdTe nanocrystals with S(2-) in aqueous solution under ambient condition. We found that the optical properties of CdTe nanocrystals can be well tuned by controlling the reaction conditions, in which the reaction temperature is crucially important. At low reaction temperature, the product nanocrystals showed blue-shifts in both absorption and PL spectra, while the photoluminescence quantum yield (PLQY) was significantly enhanced. When anion exchanges were carried out at higher reaction temperature, on the other hand, obvious red shifts in absorption and PL spectra accompanied by a fast increase followed by gradual decrease in PLQY were observed. On variation of S(2-) concentration, it was found that the overall kinetics of Te(2-) for S(2 ) exchanges depends also on [S(2-)] when anion exchanges were performed at higher temperature. A possible mechanism for anion exchanges in CdTe NCs was proposed. PMID- 26520813 TI - Highly selective Pt/ordered mesoporous TiO2-SiO2 catalysts for hydrogenation of cinnamaldehyde: The promoting role of Ti(2.). AB - A highly selective and stable catalyst based on Pt nanoparticles confined in Mesoporous TiO2-SiO2 frameworks were prepared and employed for selective hydrogenation of cinnamaldehyde to cinnamyl alcohol. The as-prepared Pt/MesoTiO2 SiO2-M catalyst displayed excellent selectivity to cinnamyl alcohol (around 91%) at nearly complete conversion. Ti(2+) and stronger metal-support interaction (SMSI) played key roles on the adsorption behavior of cinnamaldehyde and activation of CO bonds. The existence of amorphous SiO2 and mixed TiO2 phases (anatase and rutile) was helpful for the formation of Ti(2+) sites and SMSI. The electron-enriched Pt surfaces and the formed Pt-TiOx system benefited the enhanced activity and selectivity. PMID- 26520814 TI - Structural characteristics of oil-poor dilutable fish oil omega-3 microemulsions for ophthalmic applications. AB - Docosahexaenoic acid (DHA) promotes synthesis of anti-inflammatory prostaglandins and relief of dry eye symptoms. However, topical ophthalmic application of DHA is difficult because of its lipophilic property. Therefore, it is important to develop aqueous-based formulation with enhanced capabilities. Novel, unique water dilutable microemulsions (MEs) were constructed to allow loading of naturally occurring rigid long-chain triglyceride of DHA (TG-DHA). The TG-DHA serves as solubilizate and as the oil phase, therefore preparation is poor in oil. The structural transformations of MEs upon water dilution were studied by SAXS, viscosity, electrical conductivity, self-diffusion NMR, DSC, cryo-TEM, and DLS techniques. At low water content a new type of water-in-oil (W/O) structure is formed. The glycerol/water phase hydrates the headgroups of surfactants, and the oil solvates their tails, forming "ill-defined bicontinuous domains". Upon further water dilution more structured bicontinuous domains of high viscosity are formed. After additional dilution, the mesophases invert to oil-in-water (O/W) droplets of ~8nm. In the structures composed of up to 25wt% water, the TG-DHA spaces and de-entangles the surfactant tails. Once the bicontinuous structures are formed, the surfactants and TG-DHA content decrease and their interfacial layer shrinks, leading to entanglement and buildup of viscous non-Newtonian mesophase. Above 70wt% water TG-DHA is embedded in the core of the O/W droplets, and its effect on the droplets' structure is minimal. This new dilutable ill defined microemulsion can be a potential delivery vehicle for ophthalmic TG-DHA transport. PMID- 26520815 TI - Synthesis and characterization of low molecular weight polyethyleneimine terminated Poly(beta-amino ester) for highly efficient gene delivery of minicircle DNA. AB - Gene therapy has held great promise for treating specific acquired and inherited diseases. However, the lack of safe and efficient gene delivery systems remains as the major challenge. Poly(beta-amino ester)s (PBAEs) have attracted much attention due to their outstanding properties in biosafety, DNA delivery efficiency and convenience in synthesis. In this paper, we reported the further enhancement of the PBAE functions by increasing its positive charge through conjugating with low molecular weight polyethylenimine (LPEI). The resulted LPEI PBAE polymer was able to condense minicircle DNA (mcDNA) forming nanoparticles with a diameter of 50-200nm. Furthermore, as compared to parental PBAE and a commercial transfection reagent very common in laboratory application, the LPEI PBAE demonstrated significantly higher transfection efficiency with little cytotoxicity. These results suggested LPEI-PBAEs are worthy of further optimization for gene therapy applications. PMID- 26520816 TI - Pd-Pt alloys nanowires as support-less electrocatalyst with high synergistic enhancement in efficiency for methanol oxidation in acidic medium. AB - In a facile approach, Pd73Pt27 alloy nanowires (NWs) with large aspect ratios were synthesized in high yield by using sacrificial templates. Unlike majority of processes, our synthesis was carried out in aqueous solution with no intermittent separating stages for the products, while maintaining the NW morphology up to ~30% of Pt. Upon evaporation of their dispersion, the NWs transform into a stable porous membrane due to self-entanglement and can be directly lifted and employed for electrocatalytic applications without external catalyst supports. We show that the NW membranes exhibit efficient electrocatalytic performance for methanol oxidation reaction (MOR) with 10 times higher mass activity and 4.4 times higher specific activity in acidic media as compared to commercial Pt catalysts. The membrane electrocatalysts is robust and exhibited very good stability with retention of ~70% mass-activity after 4000 potential cycles. Since Pd was found to be inert towards MOR in acidic medium, our investigation provides a direct estimate of synergistic enhancement of efficiency. Over 10 times increment of mass activity appears to be significantly higher than previous investigations in various other reaction media. PMID- 26520808 TI - Antioxidant therapy for treatment of inflammatory bowel disease: Does it work? AB - Oxidative stress (OS) is considered as one of the etiologic factors involved in several signals and symptoms of inflammatory bowel diseases (IBD) that include diarrhea, toxic megacolon and abdominal pain. This systematic review discusses approaches, challenges and perspectives into the use of nontraditional antioxidant therapy on IBD, including natural and synthetic compounds in both human and animal models. One hundred and thirty four papers were identified, of which only four were evaluated in humans. Some of the challenges identified in this review can shed light on this fact: lack of standardization of OS biomarkers, absence of safety data and clinical trials for the chemicals and biological molecules, as well as the fact that most of the compounds were not repeatedly tested in several situations, including acute and chronic colitis. This review hopes to stimulate researchers to become more involved in this fruitful area, to warrant investigation of novel, alternative and efficacious antioxidant-based therapies. PMID- 26520817 TI - alpha-Fe2O3 nanosheet-assembled hierarchical hollow mesoporous microspheres: Microwave-assisted solvothermal synthesis and application in photocatalysis. AB - alpha-Fe2O3 nanosheet-assembled hierarchical hollow mesoporous microspheres (HHMSs) were prepared by thermal transformation of nanosheet-assembled hierarchical hollow mesoporous microspheres of a precursor. The precursor was rapidly synthesized using FeCl3.6H2O as the iron source, ethanolamine (EA) as the alkali source, and ethylene glycol (EG) as the solvent by the microwave-assisted solvothermal method. The samples were characterized by X-ray powder diffraction (XRD), thermogravimetric (TG) analysis, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM) and nitrogen adsorption-desorption isotherm. The effects of the microwave solvothermal temperature and EA amount on the morphology of the precursor were investigated. The as-prepared alpha-Fe2O3 HHMSs exhibit a good photocatalytic activity for the degradation of salicylic acid, and are promising for the application in wastewater treatment. PMID- 26520818 TI - Removal of Pb(II) from water by the activated carbon modified by nitric acid under microwave heating. AB - The rice husk based activated carbon (RH-AC) was treated by nitric acid under microwave heating, in order to improve its capability for the removal of heavy metal ions from water. The optimal conditions for the modification of RH-AC (M-RH AC) were determined by means of orthogonal array experimental design, giving those as the concentration of nitric acid of 8mol/L, modification time of 15min, modification temperature of 130 degrees C and microwave power of 800W. The characteristics of the M-RH-AC and RH-AC were examined by BET, XRD, Raman spectrum, pH titration, zeta potential, Boehm titration and FTIR analysis. The M RH-AC has lower pore surface area, smaller crystallite, lower pHIEP and more oxygen-containing functional groups than the RH-AC. Removal capacity of Pb(II) ions by the M-RH-AC and RH-AC from water solution was estimated concerning the influence of contact time, pH value, and initial concentration. The equilibrium time of Pb(II) removal was found to be around 90min after modification process. Two kinetic models are adopted to describe the possible Pb(II) adsorption mechanism, finding that the adsorption rate of Pb(II) ions by the M-RH-AC is larger than that of RH-AC. PMID- 26520819 TI - Effect of molecular exchange on water droplet size analysis in W/O emulsions as determined by diffusion NMR. AB - Using NMR diffusometry, the diffusion of water and tetramethylammonium chloride was recorded in order to determine the water droplet size distribution in W/O emulsions. This study aimed at evaluating the effect of extradroplet diffusion of water on the estimated droplet size distribution upon comparison to the real droplet size distribution. The latter originated from the diffusion behavior of the tetramethylammonium cation (TMA+), which is known to have a much lower permeability through the oil phase as compared to water. Whereas both low resolution and high-resolution pulsed field gradient NMR revealed that the water droplet size overestimation could be reduced selecting either a lower measurement temperature during diffusion analysis, or a smaller diffusion delay value Delta, still comparison to TMA+ diffusion indicated that artefacts were unavoidable even at low Delta and temperature. In order to correct for this extradroplet water diffusion phenomenon, different data analysis methods were evaluated. The previously described Pfeuffer exchange model could only partly compensate for the effect of extradroplet diffusion on the water droplet size determination. On the other hand, accurate water droplet size analysis results were obtained by correcting the experimentally determined diffusion distances based on Einstein's diffusion law. As such, reliable data could be obtained by low resolution NMR based on water diffusion at or even above room temperature. PMID- 26520821 TI - Novel Bi2MoO6/TiO2 heterostructure microspheres for degradation of benzene series compound under visible light irradiation. AB - Novel Bi2MoO6/TiO2 heterostructure microspheres were successfully synthesized via a facile solvothermal method. Their morphology, structure and photocatalytic performance in the degradation of phenol and nitrobenzene were characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, electrochemical impedance spectra, UV-vis absorption spectroscopy and total organic carbon analyser, respectively. The results show that the Bi2MoO6/TiO2 heterostructures exhibit excellent photocatalytic performance with maximum phenol and nitrobenzene degradation rates of 96% and 94% and corresponding mineralization rates of 66% and 61% in 300min under visible light irradiation, respectively. The improved photocatalytic performance is mainly ascribed to the reduced electron-hole pair recombination with the introduction of TiO2. PMID- 26520820 TI - Varying the counter ion changes the kinetics, but not the final structure of colloidal gels. AB - We show that, while the gelation of colloidal silica proceeds much faster in the presence of added KCl than NaCl, the final gels are very similar in structure and properties. We have studied the gelation process by visual inspection and by small angle X-ray scattering for a range of salt and silica particle concentrations. The characteristic times of the early aggregation process and the formation of a stress-bearing structure with both salts are shown to collapse onto master curves with single multiplicative constants, linked to the stability ratio of the colloidal suspensions. The influence of the salt type and concentration is confirmed to be mainly kinetic, as the static structure factors and viscoelastic moduli of the gels are shown to be equivalent at normalized times. While there is strong variation in the kinetics, the structure and properties of the gel at long-times are shown to be mainly controlled by the concentration of particles, and hardly influenced by the type or the concentration of salt. This suggests that the differences between gels generated by different salts are only transient in time. PMID- 26520822 TI - A comprehensive investigation on adsorption of Ca (II), Cr (III) and Mg (II) ions by 3D porous nickel films. AB - The present study reports the removal of Ca (II), Cr (III), Mg (II) ions from aqueous solution using 3D-porous nickel films (3DNFs) as a novel adsorbent material prepared by hydrogen bubble dynamic template (HBDT) method at room temperature. The structure morphology and the phase constitution of 3DNFs were characterized by FESEM, EDS and XRD. Adsorption process of Ca (II), Cr (III), Mg (II) ions was fast as the equilibrium was established within 30min, and the maximum adsorption at equilibrium was 44.1mg/g, 46.4mg/g and 32.7mg/g, respectively. The adsorption kinetics well fitted using a pseudo second-order kinetic model. The adsorption isotherm data of all the three metals fit well the Langmuir and Freundlich adsorption isotherm model. It was found out that kinetics of adsorption varies with initial concentration of metal ions. Thermodynamic parameters (i.e., the standard Gibbs free energies (DeltaG), enthalpy change (DeltaH), standard entropy change (DeltaS)) were also evaluated. Thermodynamic analysis indicated that a high temperature is favored for the adsorption of metal ions by 3DNFs. These results suggest that 3DNFs have good potential application in effective adsorption of metal ions with satisfactory results. PMID- 26520823 TI - Urease immobilized polymer hydrogel: Long-term stability and enhancement of enzymatic activity. AB - A method has been developed in which an enzyme namely urease was immobilized inside hydrogel matrix to study the stability and enzymatic activity in room temperature (~27-30 degrees C). This urease coupled hydrogel (UCG) was obtained by amine-acid coupling reaction and this procedure is such that it ensured the wider opening of mobile flap of enzyme active site. A systematic comparison of urea-urease assay and the detailed kinetic data clearly revealed that the urease shows activity for more than a month when stored at ~27-30 degrees C in case of UCG whereas it becomes inactive in case of free urease (enzyme in buffer solution). The aqueous microenvironment inside the hydrogel, unusual morphological features and thermal behaviour were believed to be the reasons for unexpected behaviour. UCG displayed enzyme activity at basic pH and up to 60 degrees C. UCG showed significant enhancement in activity against thermal degradation compared to free urease. In summary, this method is a suitable process to stabilize the biomacromolecules in standard room temperature for many practical uses. PMID- 26520824 TI - Surfactant-free alternative fuel: Phase behavior and diffusion properties. AB - Phase behavior of the three components, 1-propanol, water and oil is studied at 10, 25, and 40 degrees C. Biodiesel, limonene and diesel are used as oil phases. NMR self-diffusion measurements are performed to investigate the microstructure of the one-phase regions. Tie lines in the two-phase regions are determined both by proton NMR analysis and compared with theoretical calculations. NMR self diffusion results for the different components in these systems do not show any sign of confinement or obstructions, demonstrating these mixtures to be structureless solutions. A good agreement between the experimental and calculated phase behavior is obtained. The determined tie lines in the two-phase regions show higher affinity of 1-propanol to water than to oil. PMID- 26520825 TI - Tuning the surface enhanced Raman scattering and catalytic activities of gold nanorods by controlled coating of platinum. AB - Galvanic replacement of silver (Ag) by platinum (Pt) on bi-metallic nanorods (NRs) having gold (Au) core and silver shell (Au@Ag) resulted in discontinuous coating of Pt over Au (Au@Pt-DC) NRs. However, a novel method has been developed in this work for the preparation of Au NRs having smooth and continuous coating of Pt (Au@Pt-C NRs) using galvanic replacement reaction of Au@Ag NRs in presence of sulphuric acid. Selective blocking by the bisulfate ions that are adsorbed on Pt surface, preventing Pt on Pt deposition seems to be the mechanism of formation of Au@Pt-C NRs. Effect of the nature of Pt shell (i.e. whether continuous or discontinuous) on SERS activity of the NRs was investigated with methylene blue (MB) as a reporter molecule. The specific enhancement of the Raman signals were in the order Au@ Pt-C NRs 0.05) in body ash and protein content and in the specific activity of phosphatase alkaline and amylase in the digestive tract of all the fishes. V. proomii and B. mojavensis persisted in the fish intestine and in the feed in high numbers during the feeding period (group 1: 5.8 * 10(4) CFU/ml, group 2: 9.6 * 10(4) CFU/ml, and group 3: 9.8 * 10(4) CFU/ml day 60). The two probiotics V. proomii and B. mojavensis were adequate for improved growth performance and survival and for healthy gut microenvironment of the host. PMID- 26520834 TI - New insight into the catalytic properties of rice sucrose synthase. AB - Sucrose synthase (SuS), which catalyzes the reversible conversion of sucrose and uridine diphosphate (UDP) into fructose and UDP-glucose, is a key enzyme in sucrose metabolism in higher plants. SuS belongs to family 4 of the glycosyltransferases (GT4) and contains an E-X7-E motif that is conserved in members of GT4 and two other GT families. To gain insight into the roles of this motif in rice sucrose synthase 3 (RSuS3), the two conserved glutamate residues (E678 and E686) in this motif and a phenylalanine residue (F680) that resides between the two glutamate residues were changed by site-directed mutagenesis. All mutant proteins maintained their tetrameric conformation. The mutants E686D and F680Y retained partial enzymatic activity and the mutants E678D, E678Q, F680S, and E686Q were inactive. Substrate binding assays indicated that UDP and fructose, respectively, were the leading substrates in the sucrose degradation and synthesis reactions of RSuS3. Mutations on E678, F680, and E686 affected the binding of fructose, but not of UDP. The results indicated that E678, F680, and E686 in the E-X7-E motif of RSuS3 are essential for the activity of the enzyme and the sequential binding of substrates. The sequential binding of the substrates implied that the reaction catalyzed by RSuS can be controlled by the availability of fructose and UDP, depending on the metabolic status of a tissue. PMID- 26520836 TI - A Review of "The New Drug Reimbursement Game: A Regulator's Guide to Playing and Winning". PMID- 26520835 TI - L-Galactono-1,4-lactone dehydrogenase is an assembly factor of the membrane arm of mitochondrial complex I in Arabidopsis. AB - L-Galactono-1,4-lactone dehydrogenase (GLDH) catalyses the last enzymatic step of the ascorbate biosynthetic pathway in plants. GLDH is localised to mitochondria and several reports have shown that GLDH is associated with complex I of the respiratory chain. In a gldh knock-out mutant, complex I is not detectable, suggesting that GLDH is essential for complex I assembly or stability. GLDH has not been identified as a genuine complex I subunit, instead, it is present in a smaller, lowly abundant version of complex I called complex I*. In addition, GLDH activity has also been detected in smaller protein complexes within mitochondria membranes. Here, we investigated the role of GLDH during complex I assembly. We identified GLDH in complexes co-localising with some complex I assembly intermediates. Using a mutant that accumulates complex I assembly intermediates, we confirmed that GLDH is associated with the complex I assembly intermediates of 400 and 450 kDa. In addition, we detected accumulation of the 200 kDa complex I assembly intermediate in the gldh mutant. Taken together, our data suggest that GLDH is an assembly factor of the membrane arm of complex I. This function appears to be independent of the role of GLDH in ascorbate synthesis, as evidenced by the ascorbate-deficient mutant vtc2-1 accumulating wild-type levels of complex I. Therefore, we propose that GLDH is a dual-function protein that has a second, non-enzymatic function in complex I assembly as a plant-specific assembly factor. We propose an updated model for complex I assembly that includes complex I* as an assembly intermediate. PMID- 26520837 TI - Influence of endurance running on calcaneal bone stiffness in male and female runners. AB - PURPOSE: The aim of this investigation was to determine the influence of endurance running on calcaneus bone stiffness in male and female runners. METHODS: A total of 122 marathoners (longer distance runners, men = 101; women = 21) and 81 half-marathon and 10-km runners (shorter distance runners; men = 48; women = 33), competing in an international running event, underwent an ultrasonographic assessment of the right and left calcaneus. Calcaneus bone stiffness was estimated using the measurements of the speed of sound (SOS) and broadband ultrasound attenuation (BUA). Seventy-five age-matched sedentary people served as the control group. RESULTS: Male and female longer distance runners and shorter distance runners presented higher values than sedentary counterparts in SOS (P < 0.05), and calcaneus stiffness (P < 0.05). Although there were no significant differences between longer distance and shorter distance runners in the ultrasonographic variables, longer distance runners presented greater effects size in SOS (1.00 vs. 0.93 males; 1.10 vs. 0.77 females), BUA (0.62 vs. 0.25 males; 0.89 vs. 0.20 females) and calcaneus stiffness (0.88 vs. 0.66 males; 1.20 vs. 0.60 females) than shorter distance endurance runners. CONCLUSION: Calcaneus bone stiffness was higher in all endurance runners compared to a sedentary control population. The volume of ground reaction forces which occur during endurance running might induce the adaptation of the calcaneus bone. PMID- 26520838 TI - Point Mutation Ile137-Met Near Surface Conferred Psychrophilic Behaviour and Improved Catalytic Efficiency to Bacillus Lipase of 1.4 Subfamily. AB - Bacillus lipolytic enzymes of subfamily 1.4 are industrially attractive because of its alkaline optimum pH and broad substrate specificity. The activity and stability of these enzymes for a limited temperature range (30-50 degrees C) need attention for its industrial application. In the present study, Bacillus subtilis LipJ was rationally designed for low-temperature adaptation. Small amino acids with lower volume and without side chain branches have high occurrence among psychrophilic proteins. Met residue is reported to be preferred for cold adaptation as it is thermolabile in nature and undergoes oxidation at high temperature. Therefore, the Ile137 residue, three residues downstream the catalytic residue Asp133, was substituted by Met. Biochemical study demonstrated that variant Ile137Met was optimally active at 20 degrees C whereas parent enzyme was most active at 37 degrees C. The variant retained 70-80% relative activity at 10 degrees C where parent enzyme demonstrated low activity. Ile137Met was observed to be unstable at and above 30 degrees C. Kinetic study demonstrated increased K m and k cat values for variant referring improved catalytic efficiency but poor substrate affinity. Homolog modelling predicted lowered number of weak interactions by substituted Met137 as molecular basis of increased flexibility of variant. Hence, increased structure flexibility might be responsible for poor substrate affinity but increased molecular motion for higher catalysis at cold. PMID- 26520839 TI - Repair of a traumatic cloaca after obstetric anal sphincter injury. AB - INTRODUCTION AND HYPOTHESIS: Unsuccessful primary repair of fourth-degree obstetric trauma can lead to permanent communication between the rectum and the vagina, which, in association with full-thickness anal sphincter defects, is characterized by complete fecal incontinence and severe impairment of quality of life. The aim of this video is to serve as a tutorial for repair. METHODS: A 27 year-old woman who developed a full-thickness recto-vaginal defect extended from the perineum to the upper third of the vagina has been managed through layered surgical repair without flaps. RESULTS: Anatomy and fecal continence have been completely restored by a follow-up of 24 months. CONCLUSION: The procedure described in this video has been shown to be effective and safe. PMID- 26520840 TI - Detection of cerebrospinal fluid tumor cells and its clinical relevance in leptomeningeal metastasis of breast cancer. AB - Circulating tumor cells are commonly observed in the peripheral blood of advanced breast cancer patients. We tested the feasibility of tumor cell detection in the cerebrospinal fluid (CSF) and studied its clinical relevance in leptomeningeal metastasis (LM) of breast cancer. CSF samples were collected from 38 metastatic breast cancer patients known or suspected to have LM. Control CSF samples were collected from 14 individuals without solid tumor malignancy. We used a modified CellSearchTM assay and an alternative EPCAM-based method involving immunomagnetic enrichment followed by flow cytometry (IE/FC) to enumerate CSF tumor cells (CSFTCs). CSFTCs were assayed at time of LM diagnosis and over the course of LM directed therapy. We analyzed a total of 102 CSF samples with modified CellSearchTM. The CSFTC counts were strongly correlated with the corresponding IE/FC results (Pearson's r = 0.94). Twenty-eight out of 30 samples in which malignant cells were identified by CSF cytology were CSFTC-positive by modified CellSearchTM. Baseline CSFTC levels from 21 patients eventually diagnosed with LM were significantly higher than the controls (p = 0.0202), whereas 13 patients deemed not to have LM showed CSFTC results indistinguishable from the controls. In patients with serial samples, it was possible to monitor CSFTC levels as a potential biomarker of treatment response. CSFTC detection using a modified CellSearchTM assay demonstrated high sensitivity in detecting malignant cells in CSF and may be a promising method for diagnosing LM and monitoring LM during treatment. PMID- 26520841 TI - Design of new phenothiazine-thiadiazole hybrids via molecular hybridization approach for the development of potent antitubercular agents. AB - A new library of phenothiazine and 1,3,4-thiadiazole hybrid derivatives (5a-u) was designed based on the molecular hybridization approach and the molecules were synthesized in excellent yields using a facile single-step chloro-amine coupling reaction between 2-chloro-1-(10H-phenothiazin-10-yl)ethanones and 2-amino-5 subsituted-1,3,4-thiadiazoles. The compounds were evaluated for their in vitro inhibition activity against Mycobacterium tuberculosis H37Rv (MTB). Compounds 5 g and 5 n were emerged as the most active compounds of the series with MIC of 0.8 MUg/mL (~ 1.9 MUM). Also, compounds 5a, 5b, 5c, 5e, 5l and 5m (MIC = 1.6 MUg/mL), and compounds 5j, 5k and 5o (MIC = 3.125 MUg/mL) showed significant inhibition activity. The structure-activity relationship demonstrated that an alkyl (methyl/n-propyl) or substituted (4-methyl/4-Cl/4-F) phenyl groups on the 1,3,4 thiadiazole ring enhance the inhibition activity of the compounds. The cytotoxicity study revealed that none of the active molecules are toxic to a normal Vero cell line thus proving the lack of general cellular toxicity. Further, the active molecules were subjected to molecular docking studies with target enzymes InhA and CYP121. PMID- 26520842 TI - Synthesis of functionalized new conjugates of batracylin with tuftsin/retro tuftsin derivatives and their biological evaluation. AB - New batracylin conjugates with tuftsin/retro-tuftsin derivatives were designed and synthesized using T3P as a coupling agent. The conjugates possess an amide bond formed between the carboxyl group of heterocyclic molecule and the N-termini of the tuftsin/retro-tuftsin chain. The in vitro cytotoxic activity of the new analogues and their precursors was evaluated using a series of human and murine tumor cells. BAT conjugates containing retro-tuftsin with branched side aminoacid chain, in particular with leucine or isoleucine, were about 10-fold more cytotoxic toward two human tumor cell lines (lung adenocarcinoma (A549) and myeloblastic leukemia (HL-60)). These compounds showed about 10-fold increased cytotoxicity against the two types of tumor cells compared to parent BAT. We have not observed important differences in the mechanism of action between BAT and its cytotoxic tuftsin/retro-tuftsin conjugates. We propose that high biological activity of the most active BAT conjugates is a result of their greatly increased intracellular accumulation. PMID- 26520843 TI - Hemichorea-hemiballismus in patients with non-ketotic hyperglycemia. PMID- 26520844 TI - Wall thickening pattern in atherosclerotic basilar artery stenosis. AB - Our aim was to investigate wall thickening (WT) pattern of atherosclerotic basilar artery stenosis with three-dimensional volumetric isotropic turbo spin echo acquisition (3D VISTA), and the relationship with clinical characteristics. Twenty consecutive patients with atherosclerotic basilar artery stenosis were prospectively enrolled. All cross-sectional slices on VISTA images of basilar arteries were assessed, and classified as eccentric or concentric WT. Clinical characteristics and degree of stenosis were compared between the patients with different wall WT pattern. Wall abnormalities were identified in 568 cross sectional slices in basilar arteries of 20 patients including eccentric WT in 497 (87.5 %) slices, and concentric WT in 71 (12.5 %) slices. In 11 of 20 patients, all the cross-sectional slices (293 slices) showed eccentric WT. In 9 of 20 patients, the cross-sectional slices (275 slices) showed both eccentric WT (204 slices, 74.2 %) and concentric WT (71 slices, 25.8 %). No lesion showed only concentric WT. At the slices of maximum luminal narrowing sites, only one patient showed concentric WT. Symptomatic stenosis was more common in the patients with mixed WT (eccentric and concentric), compared to patients with only eccentric WT (100 vs 54.5 %, p = 0.038). Atherosclerotic basilar artery stenosis could show both eccentric and concentric WT based on each slice analysis. Concentric WT was found in near half of the patients, but tended to locate in minimal slices. No lesion was entirely concentric. Lesions with mixed WT (concentric and eccentric) might represent advanced atherosclerosis with high risk of ischemic event. PMID- 26520845 TI - Comparison of VerifyNow P2Y12 and thrombelastography for assessing clopidogrel response in stroke patients in China. AB - Poor response to clopidogrel is often associated with recurrent ischemic events, and reliable platelet function tests are needed to identify clopidogrel low response (CLR). The aim of the study was to compare the consistency of VerifyNow P2Y12 and thrombelastography (TEG) in acute ischemic stroke patients treated with clopidogrel. Patients hospitalized in Changhai Hospital from August 2012 to September 2013 and assigned to treatment with a daily 75-mg dose of clopidogrel. The blood samples were taken on the 5-7th day to assess the capability of VerifyNow P2Y12 and TEG for evaluation of clopidogrel response, and all instrument parameters were used to perform correlation analysis. Patients with CLR were detected by using the methods and criteria published earlier (PRU >= 230 assayed by VerifyNow P2Y12 or TEG-Inhib% <=30 % measured by TEG). Totally 58 patients were enrolled for the study and there were wide varieties in parameters of VerifyNow P2Y12 and TEG. Results showed a total of 17 and 9 patients, respectively, identified as CLR assessed by VerifyNow P2Y12 and TEG, but only three patients were detected to be clopidogrel low responders with both tests. The kappa consistency analysis showed poor consistency between VerifyNow P2Y12 and TEG results in terms of CLR (Kappa = -0.0349, p = 0.7730). Linear regression also demonstrated poor correlation between VerifyNow-PRU/VerifyNow-Inhib% and TEG Inhib% (p = 0.07901 and p = 0.3788, respectively). Our study demonstrated that there was poor correlation between VerifyNow P2Y12 and TEG results, and VerifyNow P2Y12 showed a larger proportion of CLR than TEG. PMID- 26520846 TI - Parkinson's Disease Sleep Scale 2: application in an Italian population. AB - Sleep disturbances and nocturnal disabilities are common in Parkinson's Disease (PD). The PD sleep scale, second version (PDSS-2), has been proposed as a helpful tool for measuring sleep disorders in PD. We aimed to validate the Italian version of the PDSS-2. One hundred and twenty-three consecutive PD outpatients (76 males) were evaluated by means of PDSS-2, Epworth Sleepiness Scale, Hamilton Depression Rating Scale, Parkinson's Disease Quality of Life Questionnaire (self administered scales), Unified Parkinson's Disease Rating (motor section) and Hoehn and Yahr Scales, and Mini Mental State Examination. PDSS-2 internal consistency was satisfactory (Cronbach's alpha: 0.77) with significant item to total score correlation and high intra-class correlation coefficient for test retest reliability (0.943). Total PDSS-2 score was correlated with the scores on all other clinical scales. The factor analysis identified five factors, related to five areas of nocturnal disturbances, similarly as the original PDSS-2. The five factors mainly reflected: (1) nocturnal movement-related problems, (2) quality of sleep, (3) dreaming distress, (4) fragmentation of sleep and (5) insomnia symptoms. The PDSS-2 scale has confirmed its usefulness in evaluating sleep problems in Italian PD patients. PMID- 26520847 TI - Alcohol consumption among first-time mothers and the risk of preterm birth: a cohort study. AB - PURPOSE: Our aim was to explore the association between alcohol consumption, before and during pregnancy, and the risk of preterm birth among 46,252 primiparous mothers. METHODS: We obtained information on alcohol consumption from questionnaire responses at pregnancy week 15 from the prospective, observational Norwegian Mother and Child Cohort Study. Data on preterm birth, categorized as delivery before gestation week 37, were retrieved from the Medical Birth Registry of Norway. RESULTS: Among the participants, 91% consumed alcohol before pregnancy and fewer than 20% reported consuming alcohol during pregnancy. The adjusted odds ratio (aOR) for preterm birth associated with prepregnancy alcohol consumption was 0.81 (95% confidence interval [CI], 0.70-0.95). We did not find a risk reduction for overall drinking during pregnancy, aOR = 1.03 (95% CI, 0.90-1.19). However, dose-response analyses showed tendencies toward adverse effects when drinking 1-3 times per month during the first 15 weeks of pregnancy, aOR = 1.51 (95% CI, 1.14-2.00). CONCLUSIONS: We did not find any effects of alcohol consumption during pregnancy, whereas pre-pregnancy drinking was associated with reduced risk of preterm birth. Residual confounding may have influenced the risk estimates, especially before pregnancy, as nondrinkers have lower socioeconomic status and well-being than drinkers. PMID- 26520848 TI - Emergency department quality and safety indicators in resource-limited settings: an environmental survey. AB - BACKGROUND: As global emergency care grows, practical and effective performance measures are needed to ensure high quality care. Our objective was to systematically catalog and classify metrics that have been used to measure the quality of emergency care in resource-limited settings. METHODS: We searched MEDLINE, Embase, CINAHL, and the gray literature using standardized terms. The references of included articles were also reviewed. Two researchers screened titles and abstracts for relevance; full text was then reviewed by three researchers. A structured data extraction tool was used to identify and classify metrics into one of six Institute of Medicine (IOM) quality domains (safe, timely, efficient, effective, equitable, patient-centered) and one of three of Donabedian's structure/process/outcome categories. A fourth expert reviewer blinded to the initial classifications re-classified all indicators, with a weighted kappa of 0.89. RESULTS: A total of 1705 articles were screened, 95 received full text review, and 34 met inclusion criteria. One hundred eighty unique metrics were identified, predominantly process (57 %) and structure measures (27 %); 16 % of metrics were related to outcomes. Most metrics evaluated the effectiveness (52 %) and timeliness (28 %) of care, with few addressing the patient centeredness (11 %), safety (4 %), resource-efficiency (3 %), or equitability (1 %) of care. CONCLUSIONS: The published quality metrics in emergency care in resource-limited settings primarily focus on the effectiveness and timeliness of care. As global emergency care is built and strengthened, outcome-based measures and those focused on the safety, efficiency, and equitability of care need to be developed and studied to improve quality of care and resource utilization. PMID- 26520849 TI - Perineural capsaicin induces the uptake and transganglionic transport of choleratoxin B subunit by nociceptive C-fiber primary afferent neurons. AB - The distribution of spinal primary afferent terminals labeled transganglionically with the choleratoxin B subunit (CTB) or its conjugates changes profoundly after perineural treatment with capsaicin. Injection of CTB conjugated with horseradish peroxidase (HRP) into an intact nerve labels somatotopically related areas in the ipsilateral dorsal horn with the exceptions of the marginal zone and the substantia gelatinosa, whereas injection of this tracer into a capsaicin pretreated nerve also results in massive labeling of these most superficial layers of the dorsal horn. The present study was initiated to clarify the role of C-fiber primary afferent neurons in this phenomenon. In L5 dorsal root ganglia, analysis of the size frequency distribution of neurons labeled after injection of CTB-HRP into the ipsilateral sciatic nerve treated previously with capsaicin or resiniferatoxin revealed a significant increase in the proportion of small neurons. In the spinal dorsal horn, capsaicin or resiniferatoxin pretreatment resulted in intense CTB-HRP labeling of the marginal zone and the substantia gelatinosa. Electron microscopic histochemistry disclosed a dramatic, ~10-fold increase in the proportion of CTB-HRP-labeled unmyelinated dorsal root axons following perineural capsaicin or resiniferatoxin. The present results indicate that CTB-HRP labeling of C-fiber dorsal root ganglion neurons and their central terminals after perineural treatment with vanilloid compounds may be explained by their phenotypic switch rather than a sprouting response of thick myelinated spinal afferents which, in an intact nerve, can be labeled selectively with CTB HRP. The findings also suggest a role for GM1 ganglioside in the modulation of nociceptor function and pain. PMID- 26520850 TI - Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1. AB - The electromechanical delay during muscle contraction and relaxation can be partitioned into mainly electrochemical and mainly mechanical components by an EMG, mechanomyographic, and force combined approach. Component duration and measurement reliability were investigated during contraction and relaxation in a group of patients with myotonic dystrophy type 1 (DM1, n = 13) and in healthy controls (n = 13). EMG, mechanomyogram, and force were recorded in DM1 and in age and body-matched controls from tibialis anterior (distal muscle) and vastus lateralis (proximal muscle) muscles during maximum voluntary and electrically evoked isometric contractions. The electrochemical and mechanical components of the electromechanical delay during muscle contraction and relaxation were calculated off-line. Maximum strength was significantly lower in DM1 than in controls under both experimental conditions. All electrochemical and mechanical components were significantly longer in DM1 in both muscles. Measurement reliability was very high in both DM1 and controls. The high reliability of the measurements and the differences between DM1 patients and controls suggest that the EMG, mechanomyographic, and force combined approach could be utilized as a valid tool to assess the level of neuromuscular dysfunction in this pathology, and to follow the efficacy of pharmacological or non-pharmacological interventions. PMID- 26520852 TI - Interaction of BODIPY Dyes with the Blood Plasma Proteins. AB - Photophysical properties of several BODIPY-based fluorescent dyes were investigated in systems containing blood plasma biomolecules and in model system containing bovine serum albumin in terms of electronic absorption and fluorescence spectroscopy. The interaction between the investigated dyes and protein plasma components changes spectral characteristics of the dyes and leads to bathochromic and hypochromic absorption spectra shifts accompanied by changing of fluorescence intensity. The mechanism of fluorescence changing was defined in the terms of Stern-Volmer theory. It was shown that the static factor of molecular dye-biopolymers complex formation prevails at plasma protein concentration up to 1 g/l, while the higher viscosity range is characterized mainly by nonspecific fluorophore interactions. The increase of fluorescent characteristics of phenyl-substituted BODIPY in the presence of proteins caused by resonance energy transfer and change of physicochemical properties of the molecular environment of the fluorophore was shown for the first time. PMID- 26520851 TI - Adherence to the DASH diet in relation to psychological profile of Iranian adults. AB - INTRODUCTION: Although empirically derived dietary patterns have been examined in relation to depression, limited data are available linking theory-based dietary patterns and psychological health. OBJECTIVE: We aimed to investigate the association between adherence to DASH-style diet and psychological health among Iranian adults. METHODS: This cross-sectional study was done among 3846 general public adults in Isfahan, Iran. Dietary assessment was conducted using a validated 106-item dish-based semiquantitative food frequency questionnaire. To investigate participants' adherence to DASH-style diet, we created DASH score based on earlier publications focusing on eight components (fruits, vegetables, nuts and legumes, dairy products, grains, sweetened beverages and sweets, sodium, and red and processed meats). Participants were classified into three categories based on their DASH score [low (<=40), moderate (41-50), and high adherence (>=51)]. This categorization, instead of distribution-based classification, was used due to low adherence to the DASH dietary pattern in the study population. Psychological health was examined by means of validated Hospital Anxiety and Depression Scale and General Health Questionnaire. Depression, anxiety, and psychological distress were defined based on standard criteria. RESULTS: We found that moderate adherence to DASH-style diet was associated with lower odds of depression (OR 0.73; 95 % CI 0.59-0.90, P trend = 0.63) compared with those with the lowest adherence. In our stratified analyses, these associations remained significant for women (0.70; 0.54-0.91) and for normal-weight participants (0.70; 0.52-0.92). Moreover, after controlling for potential confounders, an inverse association was observed between high adherence to DASH-style diet and anxiety in normal-weight participants (0.61; 0.37-0.98). Such associations were also seen between moderate adherence to DASH-eating style and anxiety in overweight or obese individuals (0.63; 0.42-0.95). We failed to find any significant association between consumption of DASH-style diet and psychological distress. CONCLUSION: We found an inverse association between moderate adherence to DASH dietary pattern and depression. Further prospective studies are required to confirm these findings. PMID- 26520853 TI - catRAPID signature: identification of ribonucleoproteins and RNA-binding regions. AB - MOTIVATION: Recent technological advances revealed that an unexpected large number of proteins interact with transcripts even if the RNA-binding domains are not annotated. We introduce catRAPID signature to identify ribonucleoproteins based on physico-chemical features instead of sequence similarity searches. The algorithm, trained on human proteins and tested on model organisms, calculates the overall RNA-binding propensity followed by the prediction of RNA-binding regions. catRAPID signature outperforms other algorithms in the identification of RNA-binding proteins and detection of non-classical RNA-binding regions. Results are visualized on a webpage and can be downloaded or forwarded to catRAPID omics for predictions of RNA targets. AVAILABILITY AND IMPLEMENTATION: catRAPID signature can be accessed at http://s.tartaglialab.com/new_submission/signature CONTACT: gian.tartaglia@crg.es or gian@tartaglialab.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26520854 TI - Enumeration and extension of non-equivalent deterministic update schedules in Boolean networks. AB - MOTIVATION: Boolean networks (BNs) are commonly used to model genetic regulatory networks (GRNs). Due to the sensibility of the dynamical behavior to changes in the updating scheme (order in which the nodes of a network update their state values), it is increasingly common to use different updating rules in the modeling of GRNs to better capture an observed biological phenomenon and thus to obtain more realistic models.In Aracena et al. equivalence classes of deterministic update schedules in BNs, that yield exactly the same dynamical behavior of the network, were defined according to a certain label function on the arcs of the interaction digraph defined for each scheme. Thus, the interaction digraph so labeled (update digraphs) encode the non-equivalent schemes. RESULTS: We address the problem of enumerating all non-equivalent deterministic update schedules of a given BN. First, we show that it is an intractable problem in general. To solve it, we first construct an algorithm that determines the set of update digraphs of a BN. For that, we use divide and conquer methodology based on the structural characteristics of the interaction digraph. Next, for each update digraph we determine a scheme associated. This algorithm also works in the case where there is a partial knowledge about the relative order of the updating of the states of the nodes. We exhibit some examples of how the algorithm works on some GRNs published in the literature. AVAILABILITY AND IMPLEMENTATION: An executable file of the UpdateLabel algorithm made in Java and the files with the outputs of the algorithms used with the GRNs are available at: www.inf.udec.cl/ ~lilian/UDE/ CONTACT: lilisalinas@udec.cl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26520856 TI - Are genetic variations the most important risk factors for development of hepatocellular carcinoma? PMID- 26520855 TI - The discordant method: a novel approach for differential correlation. AB - MOTIVATION: Current differential correlation methods are designed to determine molecular feature pairs that have the largest magnitude of difference between correlation coefficients. These methods do not easily capture molecular feature pairs that experience no correlation in one group but correlation in another, which may reflect certain types of biological interactions. We have developed a tool, the Discordant method, which categorizes the correlation types for each group to make this possible. RESULTS: We compare the Discordant method to existing approaches using simulations and two biological datasets with different types of -omics data. In contrast to other methods, Discordant identifies phenotype-related features at a similar or higher rate while maintaining reasonable computational tractability and usability. AVAILABILITY AND IMPLEMENTATION: R code and sample data are available at https://github.com/siskac/discordant CONTACT: katerina.kechris@ucdenver.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26520857 TI - Stochastic analysis of the extra clustering model for animal grouping. AB - We consider the extra clustering model which was introduced by Durand et al. (J Theor Biol 249(2):262-270, 2007) in order to describe the grouping of social animals and to test whether genetic relatedness is the main driving force behind the group formation process. Durand and Francois (J Math Biol 60(3):451-468, 2010) provided a first stochastic analysis of this model by deriving (amongst other things) asymptotic expansions for the mean value of the number of groups. In this paper, we will give a much finer analysis of the number of groups. More precisely, we will derive asymptotic expansions for all higher moments and give a complete characterization of the possible limit laws. In the most interesting case (neutral model), we will prove a central limit theorem with a surprising normalization. In the remaining cases, the limit law will be either a mixture of a discrete and continuous law or a discrete law. Our results show that, except of in degenerate cases, strong concentration around the mean value takes place only for the neutral model, whereas in the remaining cases there is also mass concentration away from the mean. PMID- 26520858 TI - Paracetamol overdose: relevance of recent evidence for managing patients in Sri Lanka. PMID- 26520859 TI - Development and validation of an Enzyme Linked Immunosorbent Assay (ELISA) test for the diagnosis of toxoplasmosis in Sri Lanka. AB - INTRODUCTION: ELISA is the most widely used form of diagnosis for toxoplasmosis. Several commercial kits are currently used in Sri Lanka. However, these kits are not affordable in resource-limited settings. Objectives Aim of this study was to develop a cost effective in-house ELISA for the detection of Toxoplasma antibody and to estimate the diagnostic accuracy compared to a commercial kit. METHODS: Vero cell lines were inoculated with tachyzoites and harvested after 2-6 days and sonicated to obtain somatic antigen. The antigen was used as coating material in ELISA to detect antibodies against T. gondii in patient sera. Hundred and three patients' sera were analysed by in-house ELISA and kit ELISA. Optical density (OD) values were analysed statistically. Toxoplasma IgG avidity test was used to determine the chronic and acute phase of infection. RESULTS: The optimum working dilutions for antigen was 0.846 MUg/ml and for serum 1 in 100. The optimal cut off values for the in-house ELISA within the range 0.85 to 0.98 at which the sensitivity was 95.3% and specificity was 98.3. The OD values of in-house ELISA were compared with OD values of kit ELISA and the results showed strong correlation between the two tests. CONCLUSIONS: The results of our study demonstrated that our in-house ELISA for detection of T. gondii antibody was as sensitive and specific as the commercial kit used in this study. Thus, the in house ELISA is a useful, costeffective tool for diagnostic and screening purposes. PMID- 26520860 TI - Road rage in Sri Lanka: prevalence and psychiatric distress. AB - INTRODUCTION: Road traffic accidents are a major public health concern in Sri Lanka. Aggressive and reckless driving is an important contributor to the high rate of road traffic accidents. OBJECTIVE: We studied prevalence, nature, determinants and associated psychiatric morbidity of road rage among motorists in Sri Lanka. Methods Data were gathered from 238 randomly selected motorists in Sri Lanka using a modified questionnaire regarding road rage and the 6-item version of Kessler's psychological distress scale. RESULTS: While 98.7% participants reported being victims of road rage, 85.3% were involved in offending behaviour. However actual physical assault (0.8%) and damage to vehicles (2.5%) were rare. Male gender, young age, increased traffic density and driving a three-wheeler or bus were associated with daily road rage victimisation and perpetration. Psychiatric distress was associated with being a victim of road rage. CONCLUSIONS: High prevalence of road rage in Sri Lanka and significant psychiatric distress associated with it indicate the necessity of interventions at least for target groups. PMID- 26520861 TI - Musculoskeletal symptoms, skin disorders and visual impairment among fishermen in the Divisional Secretariat Division of Kalpitiya. AB - INTRODUCTION: To describe musculoskeletal symptoms, skin disorders and visual impairment among fishermen in the Divisional Secretariat Division of Kalpitiya. METHODS: This was a community based descriptive cross sectional study conducted from August to October 2011. The sample consisted of 465 fishermen with >= 6 months experience in fishing selected using the cluster sampling technique. An interviewer administered questionnaire and a record sheet were used for data collection. Prevalence of the above conditions with 95% confidence Intervals (CI) were calculated. Chi square test was applied for the investigation of the factors associated with the above conditions. RESULTS: The prevalence of musculoskeletal symptoms was 61% (95% CI: 56.6%-65.4%). The commonest symptom was back pain (37.6%). The prevalence of skin disorders was 24% (95% CI: 20.1-27.8) and visual symptoms were 38.9% (95% CI: 34.5%-43.3%). The prevalence of visual impairment of either eye was 24.3% (95% CI: 20.3%- 28.3%) low vision of either eye 22.4% (95% CI: 18.6%- 26.2%) and blindness of either eye was 1.9% (95% CI: 1.1-2.7). The prevalence of visual impairment of better eye was 16% (95% CI: 12.7-19.3), low vision of better eye 15% (95% CI: 12-18.3) and blindness of better eye were 0.9% (95% CI: 0.05-1.75). The prevalence of musculoskeletal symptoms, skin disorders or visual impairment did not vary according to service duration in the fishing industry, number of days spent in the boat for a trip or type of boat. CONCLUSIONS: Prevalence of musculoskeletal and skin disorders and visual impairment were relatively higher among the fishermen. PMID- 26520862 TI - Overweight, obesity and chronic complications of diabetes mellitus in patients attending Diabetic Centre, Teaching Hospital, Jaffna, Sri Lanka. AB - INTRODUCTION: To find out the association of Body Mass Index (BMI) with chronic complications of diabetes mellitus. METHODS: A descriptive study was carried out on 8401 diabetic patients registered in the Diabetic Centre, Teaching Hospital of Jaffna, Sri Lanka from May 2009 to November 2013. BMI was categorised according to WHO Southeast Asia classification. Complications were identified from the summary sheets. Retinopathy was assessed with retinal images, peripheral neuropathy was assessed clinically with monofilament and biothesometer in selected patients. Nephropathy was assessed with urine microalbumin. Ischaemic heart disease, peripheral vascular disease and cerebrovascular accidents were assessed from medical records. RESULTS: Of the 8401 patients 51.1% were males and 48.9% were females. The mean age of males was 61.49 years and females 60.42 years. The mean BMI was 23.70 kg/m2. There was no significant difference in BMI according to gender. According to BMI 7.4% were underweight (BMI<18.5 kg/m2), 38.3% were normal weight, 20.5% were overweight and 33.8% were obese. Rate of complications were ischaemic heart disease 21.1%, cerebrovascular accidents 3.9%, retinopathy 12.0%, peripheral neuropathy 34.1% and nephropathy 39.5%. There was no significant difference in complication rates according to BMI categories except for hypertension. CONCLUSIONS: BMI was not associated with complications of diabetes. There was association between hypertension and BMI. PMID- 26520863 TI - An ecological study for Sri Lanka about health effects of coconut. AB - An ecological correlation study was conducted to determine the association between consumption of coconut products and cardiovascular disease (CVD) deaths in Sri Lanka. Data on coconut consumption patterns from 1961 to 2006 were abstracted from the FAO database, and mortality data from reports of the Department of Census and Statistics, and UN databases. Correlational and regression analyses were carried out. There was no increase in the per capita consumption of coconut products from 1961 to 2006 (range 54.1-76.2kg/ capita/year). The CVD death rates and the proportionate mortality rate due to CVD increased from 1961 to 2006. CVD death rates were significantly associated with per capita GDP, percentage of urban population, and elderly dependency ratio but not consumption of coconut products after adjusting for the other variables (R2=0.94). The results do not provide evidence at the population level that consumption of coconut products increases mortality due to cardiovascular diseases. PMID- 26520864 TI - Concordance between measured and estimated appendicular muscle mass in adult females. AB - This study assessed the accuracy of a selected formula used to estimate the appendicular muscle mass (AMM) which is linked with many clinical outcomes. A group of community-dwelling adult women (n=80) had their AMM measured using dual energy x-ray absorptiometry (DXA). The same was estimated using a formula already published {Skeletal muscle mass = (0.244 * BW in kg) + (7.80 * Ht in meters) + (6.6 * Sex) - (0.098 * Age) + race - 3.3} (sex=0 for female and 1 for male, race =-1.2 for Asian, 1.4 for African American and 0 for White and Hispanic).The two datasets were compared for accuracy and precision. Mean AMM measured by DXA and estimated by the formula were very close (14.8 and 14.5 kg) and the difference ranged from -1.2 to 3.6 kg. Correlation between the two datasets was high (r=0.92) and the Bland-Altman plot showed an acceptable measurement agreement between the two methods. Results were independent of age and BMI. The formula used in this analysis gave an accurate estimation of the absolute AMM in women included in this study. PMID- 26520865 TI - Comparison of risk factors, severity and outcome between lacunar and non-lacunar stroke in a tertiary care center in Sri Lanka: a descriptive study. AB - This study compares demography, risk factors and outcome of lacunar (LAC) and non lacunar (non-LAC) strokes from the prospective hospital based stroke registry at Colombo South Teaching Hospital from 1st March 2012 to 30th June 2013. Data on admission, discharge and at 28 days after discharge were analysed. There were 229 ischaemic stroke (IS) patients. Average age was 65.7 years (SD 12.2, range 34-94) and 116 (50.7%) were males. LAC (n=130, 56.8%) were common than non-LAC (n=99, 43.2%). There were 75 (64.7%) males and 55 (48.7%) females in the LAC group (adjusted OR 2.1, 95% CI 1.08-4.29). Atrial fibrillation was less frequent among LAC stroke (OR 0.3, 95% CI 0.09-0.99). Hypertension, diabetes, smoking, dyslipidaemia did not differ in the two groups. Lower NIHSS (5.34 Vs 6.6, p= 0.053), higher GCS (14.7 Vs 13.3, p=0.001) were seen in LAC. Disability (MRS, Barthel index) on discharge, at 28 days and mortality during hospital stay and within 28 days was lower in the LAC group (p <0.001). PMID- 26520866 TI - Prevalence and risk factors of diabetes mellitus among adults in Jaffna District. AB - A cross sectional descriptive study was carried out to determine the prevalence and risk factors of diabetes mellitus among adults in Jaffna District. Multistage stratified cluster sampling technique was employed to select 544 participants. An interviewer administrated questionnaire was used. Anthropometric and blood pressure (BP) measurements were recorded and biochemical parameters were analysed. Response rate was 95.3%. Of them, 224 (43.8%) were male. The prevalence of diabetes mellitus was 16.4% (95% CI: 13.3- 19.9); in males 19.6% (95% CI: 14.6 25.4) and in females 13.9% (95% CI: 10.1-18.5). Of the diabetics, 27.4% were previously undiagnosed. In the final multivariable model, participants with family history of diabetes were 3.5 times (p<0.001) more likely and those with high waist hip ratio were 2 times (p=0.009) more likely to develop diabetes mellitus. PMID- 26520867 TI - Laparoscopic excision of caesarean scar ectopic pregnancy. PMID- 26520868 TI - Takotsubo cardiomyopathy after an emotional outburst. PMID- 26520869 TI - Necrotizing fascitis of the axila. PMID- 26520870 TI - Perspectives on the profession. AB - In his presidential address to the Southwestern Surgical Congress, he examines surgery as a profession from three different perspectives: his experience as a patient, a surgeon, and a photographer. He uses photography to illustrate the importance of perspective and illumination. He respectfully suggests that we should consciously choose to reframe the profession from a different perspective that accurately reflects its beauty. He also advises that we take effort to shine a gentle, soft light on the profession, a light that will reveal the beauty, the true beauty, of the profession. And finally, he submits that it is our responsibility to consciously and faithfully maintain and defend the profession from enemies inside and outside its borders. PMID- 26520871 TI - Outcomes of primary fascial closure after open abdomen for nontrauma emergency general surgery patients. AB - BACKGROUND: Emergency general surgery patients are increasingly being managed with an open abdomen (OA). Factors associated with complications after primary fascial closure (PFC) are unknown. METHODS: Demographic and operative variables for all emergency general surgery patients managed with OA at an academic medical center were prospectively examined from June to December 2013. Primary outcome was complication requiring reoperation. RESULTS: Of 58 patients, 37 managed with OA achieved PFC. Of these, 14 needed re-exploration for dehiscence, compartment syndrome, infection, or other. Complications after PFC were not associated with age, type of operative intervention, time to closure, re-explorations, comorbidities, or mortality. Complications correlated with higher body mass index (P = .02), skin closure (P = .04), plasma infusion (P = .01), and less intraoperative bleeding (P = .05). Deep surgical site infection correlated with fascial dehiscence (P = .02). CONCLUSIONS: Reoperation after PFC was more likely in obese and nonhemorrhagic patients. Recognition of these factors and strategies to reduce surgical site infection may improve outcomes. PMID- 26520872 TI - A systematic review and meta-analysis of mesh vs suture cruroplasty in laparoscopic large hiatal hernia repair. AB - BACKGROUND: Equipoise exists regarding whether mesh cruroplasty during laparoscopic large hiatal hernia repair improves symptomatic outcomes compared with suture repair. DATA SOURCE: Systematic literature review (MEDLINE and EMBASE) identified 13 studies (1,194 patients; 521 suture and 673 mesh) comparing mesh versus suture cruroplasty during laparoscopic repair of large hiatal hernia. We abstracted data regarding symptom assessment, objective recurrence, and reoperation and performed meta-analysis. CONCLUSIONS: The majority of studies reported significant symptom improvement. Data were insufficient to evaluate symptomatic versus asymptomatic recurrence. Time to evaluation was skewed toward longer follow-up after suture cruroplasty. Odds of recurrence (odds ratio .51, 95% confidence interval .30 to .87; overall P = .014) but not need for reoperation (odds ratio .42, 95% confidence interval .13 to 1.37; overall P = .149) were less after mesh cruroplasty. Quality of evidence supporting routine use of mesh cruroplasty is low. Mesh should be used at surgeon discretion until additional studies evaluating symptomatic outcomes, quality of life, and long term recurrence are available. PMID- 26520873 TI - Of duty hour violations and shift work: changing the educational paradigm. AB - BACKGROUND: Successful surgical education balances learning opportunities with Accreditation Council on Graduate Medical Education (ACGME) duty hour requirements. We instituted a night shift system and hypothesized that implementation would decrease duty hour violations while maintaining quality education. METHODS: A system of alternating teams working 12-hour shifts was instituted and was assessed via an electronic survey distributed at 2, 6, and 12 months after implementation. Resident duty hour violations and resident case volume were evaluated for 1 year before and 2 years after implementation of the night shift system. RESULTS: Survey data revealed a decrease in the perception that residents had problems meeting duty hour restrictions from 44% to 14% at 12 months (P = .012). Total violations increased 26% in the 1st year, subsequently decreasing by 62%, with shift length violations decreasing by 90%. Resident availability for didactics was improved, and average operative cases per academic year increased by 65%. CONCLUSIONS: Night shift systems are feasible and help meet duty hour requirements. Our program decreased violations while increasing operative volume and didactic time. PMID- 26520874 TI - Differentiation of ductal carcinoma in-situ from benign micro-calcifications by dedicated breast computed tomography. AB - PURPOSE: Compare conspicuity of ductal carcinoma in-situ (DCIS) to benign calcifications on unenhanced (bCT), contrast-enhanced dedicated breast CT (CEbCT) and mammography (DM). METHODS AND MATERIALS: The institutional review board approved this HIPAA-compliant study. 42 women with Breast Imaging Reporting and Data System 4 or 5 category micro-calcifications had breast CT before biopsy. Three subjects with invasive disease at surgery were excluded. Two breast radiologists independently compared lesion conspicuity scores (CS) for CEbCT, to bCT and DM. Enhancement was measured in Hounsfield units (HU). Mean CS +/- standard deviations are shown. Receiver operating characteristic analysis (ROC) measured radiologists' discrimination performance by comparing CS to enhancement alone. Statistical measurements were made using ANOVA F-test, Wilcoxon rank-sum test and robust linear regression analyses. RESULTS: 39 lesions (17 DCIS, 22 benign) were analyzed. DCIS (8.5 +/- 0.9, n=17) was more conspicuous than benign micro-calcifications (3.6 +/- 2.9, n=22; p<0.0001) on CEbCT. DCIS was equally conspicuous on CEbCT and DM (8.5 +/- 0.9, 8.7 +/- 0.8, n=17; p=0.85) and more conspicuous when compared to bCT (5.3 +/- 2.6, n=17; p<0.001). All DCIS enhanced; mean enhancement (90HU +/- 53HU, n=17) was higher compared to benign lesions (33 +/- 30HU, n=22) (p<0.0001). ROC analysis of the radiologists' CS showed high discrimination performance (AUC=0.94) compared to enhancement alone (AUC=0.85) (p<0.026). CONCLUSION: DCIS is more conspicuous than benign micro-calcifications on CEbCT. DCIS visualization on CEbCT is equal to mammography but improved compared to bCT. Radiologists' discrimination performance using CEBCT is significantly higher than enhancement values alone. CEbCT may have an advantage over mammography by reducing false positive examinations when calcifications are analyzed. PMID- 26520875 TI - Fibroid morcellation: a shared clinical decision tool for mode of hysterectomy. AB - OBJECTIVE: To compare risks and benefits of laparoscopic hysterectomy with morcellation versus abdominal hysterectomy without morcellation for large fibroids. STUDY DESIGN: We developed a shared clinical decision tool to communicate risks and benefits of laparoscopic versus abdominal hysterectomy to patients with large fibroids as mandated by the FDA. The decision tool was designed to serve as a framework for providers to counsel patients about mode of hysterectomy to facilitate shared decision-making between patient and provider. Risks and benefits were estimated from the literature, including surgical complications (venous thromboembolism, small bowel obstruction, adhesions, hernia, surgical site infections, and transfusions), uterine sarcoma risks, and quality-of-life endpoints. The shared clinical decision tool was applied to a hypothetical population of 20,000 patients with large uterine fibroids, of which 10,000 underwent laparoscopic hysterectomies and 10,000 had abdominal hysterectomies. RESULTS: Abdominal hysterectomy would result in 50.1% more adhesions, 10.7% more hernias, 4.8% more surgical site infections, 2.8% more bowel obstructions, and 2% more venous thromboembolisms compared to laparoscopic hysterectomy. Abdominal hysterectomy would also result in longer hospital stays (2 days), slower return to work (13.6 days), greater postoperative day 3 narcotic requirements (48%), and lower SF-36 quality-of-life scores (50.4 points lower). 0.28% of fibroid hysterectomy patients would have unsuspected uterine sarcomas. Among these patients, laparoscopic hysterectomy with morcellation would have a 27% reduction in 5-year overall survival rates and a 28.8 month shorter recurrence-free survival period. CONCLUSION: Some evidence suggests laparoscopic hysterectomy with morcellation may result in increased risk of cancer dissemination with worse survival outcomes among uterine sarcoma patients compared to abdominal hysterectomy without morcellation, however, the current data is limited and the exact risks associated specifically with electromechanical morcellation are not conclusive. Data also supports abdominal hysterectomy would lead to a net detriment in other outcomes, with greater risks of venous thromboembolism, obstruction, hernia, adhesions, infection, and blood loss compared to laparoscopic hysterectomy. This shared clinical decision tool may aid the patient and physician in determining an optimal mode of hysterectomy for large uterine fibroids while taking account of risks and benefits as mandated by the FDA. PMID- 26520876 TI - Interleukin-33 acts as a transcriptional repressor and extracellular cytokine in fibroblast-like synoviocytes in patients with rheumatoid arthritis. AB - The present study aimed to assess the functions of interleukin (IL)-33 in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). Enzyme-linked immunosorbent assays (ELISAs) were used to quantify interleukin (IL)-33 in plasma obtained from patients with RA and osteoarthritis (OA). To evaluate functions of intracellular IL-33, levels of inflammatory mediators and matric metalloproteinases (MMPs) were measured in RA FLS transfected with IL-33 small- interfering RNA (siRNA) or plasmids, and changes in the expression and regulation of nuclear factor kappaB (NF-kappaB) were determined using western blotting and reporter gene assays. In addition, to examine the extracellular effects of IL-33, IP10 and receptor activator of NF-kappaB ligand (RANKL) mRNA levels were measured after treatment with IL-33 and blocking antibodies to ST2, the IL-33 receptor. To evaluate whether extracellular IL-33 regulated osteoclastogenesis, human CD14(+) monocytes cocultured with IL-33-stimulated FLS were stained with tartrate-resistant acid phosphatase (TRAP). IL-33 levels were higher in plasma obtained from patients with RA than in those obtained from patients with OA. The expression levels of IL-33 were elevated in RA FLS that had been stimulated with poly I:C, IL-1beta, and tumor necrosis factor (TNF)-alpha. Silencing of IL-33 increased the levels of pro-inflammatory molecules and MMPs, promoted inhibitor of kappaB (IkappaBalpha) degradation, and increased NF-kappaB activity; these effects were reversed in IL-33 plasmid-transfected FLS. Stimulation with exogenous IL-33 increased RANKL and IP-10 mRNA expression. These increases were blocked by anti-ST2 treatment. Furthermore, we confirmed that extracellular IL-33 stimulated the formation of TRAP(+) multinucleated osteoclasts through RA FLS. These results suggested that intracellular IL-33 acted as a transcriptional repressor of NF-kappaB, which may provide negative feedback against inflammatory responses, whereas, extracellular IL-33 functioned as an activator of osteoclastogenesis. Therefore, increased plasma IL-33 levels in patients with RA could be a possible biomarker to reflect the potential risks of bone erosion. PMID- 26520878 TI - Psychosocial factors associated with in postsurgical prognosis of temporal lobe epilepsy related to hippocampal sclerosis. AB - We examined the long-term psychosocial trajectory in a consecutive and homogeneous series of 120 patients followed up for five years after corticoamygdalohippocampectomy (CAH). Evaluation of psychosocial variables at baseline and at five-year follow-up were compared. After five years of CAH, a significant improvement in educational level (p=0.004) and employment status (p<0.001) was observed, although retirement (p<0.001) and divorce (p=0.021) rates increased. In a long-term follow-up, a tendency to have similar QOL profile was observed between Engel classes IA and IB (p>0.05). A more favorable surgical outcome (Engel IA) was related to better psychiatric status (p=0.012). Poor psychosocial adjustment before surgery was the most important predictor of QOL outcome (p<0.05). Patients' trajectory after surgical treatment showed positive effects mainly in those with better seizure outcome. Our results emphasized the influence regarding baseline psychosocial functioning on postoperative psychosocial adjustment. Furthermore, many psychosocial gains and difficulties after surgery may be similar in developing and developed countries. PMID- 26520877 TI - Chemokine and cytokine levels in inflammatory bowel disease patients. AB - Crohn's disease (CD) and ulcerative colitis (UC), two forms of inflammatory bowel disease (IBD), are chronic, relapsing, and tissue destructive lesions that are accompanied by the uncontrolled activation of effector immune cells in the mucosa. Recent estimates indicate that there are 1.3 million annual cases of IBD in the United States, 50% of which consists of CD and 50% of UC. Chemokines and cytokines play a pivotal role in the regulation of mucosal inflammation by promoting leukocyte migration to sites of inflammation ultimately leading to tissue damage and destruction. In recent years, experimental studies in rodents have led to a better understanding of the role played by these inflammatory mediators in the development and progression of colitis. However, the clinical literature on IBD remains limited. Therefore, the aim of this study was to evaluate systemic concentrations of key chemokines and cytokines in forty-two IBD patients with a range of disease activity compared to levels found in ten healthy donors. We found a significant increase in an array of chemokines including macrophage migration factor (MIF), CCL25, CCL23, CXCL5, CXCL13, CXCL10, CXCL11, MCP1, and CCL21 in IBD patients as compared to normal healthy donors (P<0.05). Further, we also report increases in the inflammatory cytokines IL-16, IFN-gamma, IL-1beta and TNF-alpha in IBD patients when compared to healthy donors (P<0.05). These data clearly indicate an increase in circulating levels of specific chemokines and cytokines that are known to modulate systemic level through immune cells results in affecting local intestinal inflammation and tissue damage in IBD patients. Blockade of these inflammatory mediators should be explored as a mechanism to alleviate or even reverse symptoms of IBD. PMID- 26520879 TI - Children with new onset seizures: A prospective study of parent variables, child behavior problems, and seizure occurrence. AB - OBJECTIVE: Parent variables (stigma, mood, unmet needs for information and support, and worry) are associated with behavioral difficulties in children with seizures; however, it is not known how this relationship is influenced by additional seizures. This study followed children (ages 4-14 years) and their parents over a 24-month period (with data collected at baseline and 6, 12, and 24 months) and investigated the effect of an additional seizure on the relationship between parenting variables and child behavior difficulties. METHODS: The sample was parents of 196 children (104 girls and 92 boys) with a first seizure within the past 6 weeks. Child mean age at baseline was 8 years, 3 months (SD 3 years). Data were analyzed using t-tests, chi-square tests, and repeated measures analyses of covariance. RESULTS: Relationships between parent variables, additional seizures, and child behavior problems were consistent across time. Several associations between parent variables and child behavior problems were stronger in the additional seizure group than in the no additional seizure group. CONCLUSIONS: Findings suggest that interventions that assist families to respond constructively to the reactions of others regarding their child's seizure condition and to address their needs for information and support could help families of children with continuing seizures to have an improved quality of life. PMID- 26520880 TI - The attentional networks in benign epilepsy with centrotemporal spikes. AB - Benign epilepsy affecting children with normal mental development often occurs at a particular age, responds well to medication, and could be resolved completely by puberty. Although several studies have shown neuropsychological disabilities of children with benign epilepsy with centrotemporal spikes (BECTS), there is no clear evidence about the impairment of attentional systems and the comorbidity of attentional problems. Our research was based on the attention network model and assessed the characteristics of three anatomically defined subnetworks (alerting, orienting, and executive control) of 90 children with BECTS and 90 healthy children. All the subjects enrolled in the study participated in the attention network test (ANT) with assessment of both the reaction time (RT) and accuracy of the test. The results indicated that the performance of healthy controls was significantly better in orienting of attentional system (P<0.001) and the accuracy of attention network test (P<0.001), compared with that of children affected by BECTS. The grand mean effect (higher score worse) was significantly higher (P<0.001) in the patient group than that in the control group. The multiple linear regression analysis revealed a positive correlation between the age of onset and the accuracy of attention network test results, and a negative correlation between the age of onset and the results of grand mean effect. A negative correlation was observed between spike index (SI) of the non-REM sleep stage and the accuracy of attention network test results. We found no relationship between the grand mean effect and clinical factors such as gender, duration of clinical course, duration of seizures, total number of seizures, severity of seizures (seizure frequency), hemispheric lateralization of electroencephalograph (EEG), and the awake SI. Furthermore, no relationship was observed between the clinical factors and the accuracy of the test results. The findings showed that BECTS is associated with impaired attentional networks, and impairments are greater at younger ages of onset. PMID- 26520881 TI - "I don't want them to look at me and think of my illness, I just want them to look at me and see me": Child perspectives on the challenges associated with disclosing an epilepsy diagnosis to others. AB - OBJECTIVES: Disclosure of a concealable stigmatized identity, such as epilepsy, to those external to the nuclear family can be complex. Among children living with epilepsy (CWE), diagnosis disclosure has been identified as a quality-of life issue and a source of psychosocial distress. Despite this, limited empirical evidence exists regarding the disclosure experiences of CWE. This study aimed to identify the contextual factors that act as challenges for CWE when disclosing their epilepsy diagnosis to others external to the nuclear family. METHOD: This qualitative exploratory study consisted of individual interviews with 29 CWE (aged 6-16 years; mean age=11.17 years; S.D.=2.85). Participants were recruited from a tertiary referral unit in the neurology department of a pediatric hospital and through a national epilepsy association. Interviews were audiotaped and transcribed verbatim. Data were thematically analyzed. FINDINGS: The five main challenges to epilepsy diagnosis disclosure for children were: 1) CWE's desire for normalcy, 2) out of sight but in the mind, 3) contending with negative responses to disclosure, 4) the complexity of epilepsy, and 5) self and others' perceptions of epilepsy. DISCUSSION: These findings provide valuable insight into the factors that present difficulties and impede epilepsy diagnosis disclosure among CWE. Such knowledge is important in informing engagements between health care professionals (HCPs) and CWE. In particular, HCPs should remain cognisant of the challenges CWE face as they: (i) strive for normalcy and (ii) grapple with comprehending their complex neurological condition. Tackling such disclosure challenges could serve to enhance life quality, improve CWE's openness with others about epilepsy, and consequently work toward reducing epilepsy-related misconceptions and stigma. PMID- 26520882 TI - Ictal movements mimicking Islamic praying rituals: localizing value in a series of 12 patients. AB - The aim of this study was to determine the lateralizing value of the ictal praying gesture and of ictal religious speech in patients who are candidates for epilepsy surgery. We retrospectively searched video/EEG data of 1430 patients who were evaluated at an epilepsy center from 1999 to 2014. Twelve patients were found to have demonstrated ictal praying during their complex partial seizures. Among all patients, the ictal focus was in the right temporal region. Ictal behavior simulating prayer, which includes both hands as in the Islamic ritual tradition is a rare automatism that lateralizes the ictal focus. PMID- 26520883 TI - Gene expression profiling of bone marrow-derived stromal cells seeded onto a sandblasted, large-grit, acid-etched-treated titanium implant surface: The role of the Wnt pathway. AB - OBJECTIVE: The physical and chemical characteristics of the titanium implant surface have been shown to influence dental implant fixation. However, the underlying mechanism by which sandblasted, large-grit, acid-etched (SLA) treatment affects osseointegration remains elusive. METHODS: In the present study, the involved target genes and pathways for SLA treatment, which is an extensively used implant surface modification on improving osseointegration, were identified by in vitro microarray and bioinformatics analyses. RESULTS: A total of 19 genes were differentially expressed after SLA treatment, which included Apc2, Fzd1, Frzb, Wnt16, Fzd2, Plau, Wnt5b, Wnt5a, Lrp6, Wnt9a, Sfrp4, Prkch, Calcoco1, Ccnd1, Wif1, Fzd4, Myc, LRP5, and Lect2. Interaction pathway analyses showed that the Wnt pathway was the most relevant signal after SLA treatment. To ensure the reliability of microarray data, LRP5 was shown to positively regulate osteogenic commitment, extracellular matrix synthesis, and mineralization for BMMSCs seeded onto an SLA-treated titanium surface. However, with LRP5 shRNA treatment, the reduction in calcium deposition in the SLA-treated group was more severe than that observed in cells seeded onto SLA-untreated titanium surface, suggesting that the function of LRP5 was reinforced in the SLA-treated group. In addition, the present study demonstrated that the beta-catenin/LRP5 pathway was responsible for the enhanced osteogenic responses of BMMSCs on SLA-treated titanium surface. CONCLUSIONS: The findings of the present study serve as an initial step towards understanding the mechanism underlying SLA treatment in osseointegration. PMID- 26520884 TI - A survey of the criteria for prescribing in cases of borderline refractive errors. AB - PURPOSE: This research investigated the reported optometric prescribing criteria of Israeli optometrists. METHODS: An online questionnaire based on previous studies was distributed via email and social networking sites to optometrists in Israel. The questionnaire surveyed the level of refractive error at which respondents would prescribe for different types of refractive error at various ages with and without symptoms. RESULTS: 124 responses were obtained, yielding a response rate of approximately 12-22%, 92% of whom had trained in Israel. For all refractive errors, the presence of symptoms strongly influenced prescribing criteria. For example, for 10-20 year old patients the degree of hyperopia for which 50% of practitioners would prescribe is +0.75 D in the presence of symptoms but twice this value (+1.50 D) in the absence of symptoms. As might be expected, optometrists prescribed at lower degrees of hyperopia for older compared with younger patients. There was a trend for more experienced practitioners to be less likely to prescribe for lower degrees of myopia and presbyopia. Practitioner gender, country of training, the type of practice environment, and financial incentives were not strongly related to prescribing criteria. CONCLUSIONS: The prescribing criteria found in this study are broadly comparable with those in previous studies and with published prescribing guidelines. Subtle indications suggest that optometrists may become more conservative in their prescribing criteria with experience. PMID- 26520885 TI - Synthesis of 4-thiazolidinone analogs as potent in vitro anti-urease agents. AB - 4-Thiazolidinone analogs 1-20 were synthesized, characterized by (1)H NMR and EI MS and investigated for urease inhibitory activity. All twenty (20) analogs exhibited varied degree of urease inhibitory potential with IC50 values 1.73 69.65MUM, if compared with standard thiourea having IC50 value of 21.25+/ 0.15MUM. Among the series, eight derivatives 3, 6, 8, 10, 15, 17, 19, and 20 showed outstanding urease inhibitory potential with IC50 values of 9.34+/-0.02, 14.62+/-0.03, 8.43+/-0.01, 7.3+/-0.04, 2.31+/-0.002, 5.75+/-0.003, 8.81+/-0.005, and 1.73+/-0.001MUM, respectively, which is better than the standard thiourea. The remaining analogs showed good to excellent urease inhibition. The binding interactions of these compounds were confirmed through molecular docking studies. PMID- 26520886 TI - Femoro-tibial knee osteoarthritis: One or two X-rays? Results from a population based study. AB - OBJECTIVE: Our objective was to compare the use of both anteroposterior (AP) extended-knee X-ray and semi-flexed X-ray (current gold standard) versus the use of semi-flexed X-ray alone to detect femoro-tibial osteoarthritis (OA). METHODS: Individuals 40 to 75 years of age with symptomatic hip and/or knee OA (Kellgren/Lawrence [KL] score>=2) were recruited using a multiregional prevalence survey in France. Both AP and schuss X-rays were performed and read; two years later, the same examiner, blinded to the results of the first reading, performed a second reading of the schuss X-ray. We compared the KL stages of each knee and analyzed osteophyte detection and localization, joint space narrowing (JSN), and the relationship to obesity. RESULTS: The analysis included 350 participants with OA of various stages. Comparing the two readings showed that a higher proportion of patients had KL>=2 when the two X-ray views were combined (right knee: P<0.0001; left knee: P<0.001). There were no differences when using the schuss X ray alone versus in combination with an AP X-ray in terms of detecting JSN, osteophytes. A comparison of schuss X-ray alone versus AP X-ray alone demonstrated the superiority of the schuss view for evaluating JSN (P=0.0001 and P=0.0001) and no difference in osteophyte detection. CONCLUSION: Our study shows that the schuss view alone was sufficient for detecting knee osteophytes and JSN. Using one X-ray rather than two will reduce medical costs and irradiation burden. Using two views seems preferable for epidemiological studies. PMID- 26520887 TI - The role of vascular peroxidase 1 in ox-LDL-induced vascular smooth muscle cell calcification. AB - Reactive oxygen species (ROS)-induced osteogenic differentiation of vascular smooth muscle cells (VSMCs) is associated with the pathogenesis of vascular calcification. Vascular peroxidase 1 (VPO1), a peroxidase in the cardiovascular system, utilizes the hydrogen peroxide (H2O2) produced by co-expressed NADPH oxidases to produce hypochlorous acid (HOCl) and catalyze peroxidative reactions. The aim of this study was to determine whether VPO1 plays a role in the osteogenic differentiation of VSMCs in the setting of the vascular calcification induced by oxidized low-density lipoprotein (ox-LDL). In cultured primary rat VSMCs, we observed that the expression of VPO1 was significantly increased in combination with increases in calcification, as demonstrated via increased mineralization, as well as increased alkaline phosphatase (ALP) activity and up regulated runt-related transcription factor 2 (Runx2) expression in ox-LDL treated cells. Ox-LDL-induced VSMC calcification and Runx2 expression were both inhibited by knockdown of VPO1 using a small interfering RNA or by an NADPH oxidase inhibitor. Moreover, the knockdown of VPO1 in VSMCs suppressed the production of HOCl and the phosphorylation of AKT, ERK and P38 MAPK. Furthermore, HOCl treatment facilitated the phosphorylation of AKT, ERK1/2 and P38 MAPK and the expression of Runx2, whereas LY294002 (a specific inhibitor of PI3K), U0126 (a specific inhibitor of ERK1/2) and SB203580 (a specific inhibitor of P38 MAPK) significantly attenuated the HOCl-induced up-regulation of Runx2. Collectively, these results demonstrated that VPO1 promotes ox-LDL-induced VSMC calcification via the VPO1/HOCl/PI3K/AKT, ERK1/2, and P38 MAPK/Runx2 signaling pathways. PMID- 26520889 TI - Vascular health toolbox for spinal cord injury: Recommendations for clinical practice. AB - Over the last half century, the life expectancy for persons with spinal cord injury has increased drastically. Associated with the increased life expectancy, renal, metabolic and respiratory complications have given way to cardiovascular disease as the leading cause of death. Therefore, it is imperative that clinicians have at their disposal non-invasive and practical techniques for tracking cardiovascular disease risk amongst individual patients. This review provides an overview of non-invasive, widely available, and relatively inexpensive technologies for assessing cardiovascular health in persons with spinal cord injury. These technologies include ultrasound, pulse wave velocity and pulse wave analysis. A number of assessments can be conducted using these technologies, which confer acceptable reliability and validity, and are relatively simple to administer. Assessment recommendations for use in clinical practice are provided, and there is sufficient evidence to encourage the use of these techniques as a component of routine serial assessments. PMID- 26520888 TI - The effects of exercise on the lipoprotein subclass profile: A meta-analysis of 10 interventions. AB - OBJECTIVE: The goal was to examine lipoprotein subclass responses to regular exercise as measured in 10 exercise interventions derived from six cohorts. METHODS: Nuclear magnetic resonance spectroscopy was used to quantify average particle size, total and subclass concentrations of very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein particles (VLDL-P, LDL-P, and HDL-P, respectively) before and after an exercise intervention in 1555 adults from six studies, encompassing 10 distinct exercise programs: APOE (N = 106), DREW (N = 385), GERS (N = 79), HERITAGE (N = 715), STRRIDE I (N = 168) and II (N = 102). Random-effects meta-analyses were performed to evaluate the overall estimate of mean change across the unadjusted and adjusted mean change values from each exercise group. RESULTS: Meta-analysis of unadjusted data showed that regular exercise induced significant decreases in the concentration of large VLDL P, small LDL-P, and medium HDL-P and mean VLDL-P size, with significant increases in the concentration of large LDL-P and large HDL-P and mean LDL-P size. These changes remained significant in meta-analysis with adjustment for age, sex, race, baseline body mass index, and baseline trait value. CONCLUSIONS: Despite differences in exercise programs and study populations, regular exercise produced putatively beneficial changes in the lipoprotein subclass profile across 10 exercise interventions. Further research is needed to examine how exercise induced changes in lipoprotein subclasses may be associated with (concomitant changes in) cardiovascular disease risk. PMID- 26520890 TI - Soluble endoglin, hypercholesterolemia and endothelial dysfunction. AB - A soluble form of endoglin (sEng) is known to be an extracellular domain of the full-length membrane endoglin, which is elevated during various pathological conditions related to vascular endothelium. In the current review, we tried to summarize a possible role of soluble endoglin in cardiovascular pathologies, focusing on its relation to endothelial dysfunction and cholesterol levels. We discussed sEng as a proposed biomarker of cardiovascular disease progression, cardiovascular disease treatment and endothelial dysfunction. We also addressed a potential interaction of sEng with TGF-beta/eNOS or BMP-9 signaling. We suggest soluble endoglin levels to be monitored, because they reflect the progression/treatment efficacy of cardiovascular diseases related to endothelial dysfunction and hypercholesterolemia. A possible role of soluble endoglin as an inducer of endothelial dysfunction however remains to be elucidated. PMID- 26520891 TI - Impact of atorvastatin or rosuvastatin co-administration on platelet reactivity in patients treated with dual antiplatelet therapy. AB - BACKGROUND: Residual high-on treatment platelet reactivity (HRPR) still represents a challenging matter in patients with coronary artery disease. Drug-to drug interaction has been suggested between some statin and antiplatelet agents, despite their co-administration is mandatory in patients after an acute cardiovascular event or coronary stenting. Therefore, the aim of the current study was to investigate any impact of rosuvastatin or atorvastatin co administration on platelet reactivity in patients receiving dual antiplatelet therapy (DAPT). METHODS: Our population is represented by patients on DAPT (ASA and either clopidogrel 75 mg or ticagrelor 90 mg b.i.d) after an ACS or percutaneous revascularization, and receiving rosuvastatin or atorvastatin. Platelet function was assessed by Multiplate Impedance Aggregometry (Roche Diagnostics AG). RESULTS: We included a total of 374 patients, 240 (64.2%) receiving atorvastatin, 134 (35.8%) rosuvastatin. Rosuvastatin treated patients were more often using beta-blockers (p = 0.05), diuretics (p = 0.04) and displayed higher HDL (p < 0.001) and lower LDL cholesterol (p < 0.001). The prevalence of HRPR for ASA was low, with no difference according to statin type (0.8% vs 1.5%, p = 0.62, adjusted OR[95%CI] = 2[0.23-16.6], p = 0.52). Concerning ADP-antagonists, in the 163 patients treated with clopidogrel, rosuvastatin co administration was associated with a significantly increased rate of HRPR (55.6%vs 32%, p = 0.01, adjusted OR[95%CI] = 2.69[1.22-5.96], p = 0.015) with higher ADP-mediated platelet reactivity (p = 0.01) and TRAP-test results (p = 0.04). On the contrary, in the 211 ticagrelor treated patients, statin type did not affect mean platelet reactivity or the prevalence of HRPR with ticagrelor (10.5% vs 11.2%, p = 0.99, adjusted OR[95%CI] = 0.86[0.34-2.22], p = 0.76) CONCLUSIONS: Among patients receiving DAPT, rosuvastatin but not atorvastatin is associated with an increased rate of HRPR for clopidogrel, without any influence on the antiplatelet effect of ASA or ticagrelor. Therefore, cautiousness should be exerted for clopidogrel and rosuvastatin therapeutic association. PMID- 26520892 TI - Low circulating vitamin D levels are associated with increased arterial stiffness in prediabetic subjects identified according to HbA1c. AB - BACKGROUND AND AIMS: We investigated serum -hydroxyvitamin D levels [25(OH)D] and their correlation with early markers of cardiovascular disease in subjects with pre-diabetes. We particularly focused on individuals identified only by glycated hemoglobin A1c (HbA1c 5.7-6.4%) according to the American Diabetes Association criteria but who were normotolerant (NT) after oral glucose tolerance test (OGTT) and had normal fasting glucose (NFG). METHODS: 25(OH)D levels, HbA1c, OGTT, arterial stiffness and intima-media thickness (IMT) were evaluated in 286 subjects without history of diabetes. Subjects were stratified into four groups: controls with HbA1c <5.7%, NFG and NT; prediabetic patients with pre-diabetes according to only HbA1c (HbA1c 5.7-6.4% and NFG/NT); subjects with impaired fasting glucose and impaired glucose tolerance (IFG/IGT); new onset type 2 diabetes (HbA1c >= 6.5%). RESULTS: Subjects with NFG/NT and HbA1c 5.7-6.4% (n = 83) showed lower 25(OH)D levels compared with controls (n = 80) (21.7 [15.8-31.1] vs 23.1 [17.1-29.7] ng/mL, P = 0.009); these values were similar to those of the IFG/IGT group and were higher but not significantly different from subjects with new onset type 2 diabetes. After multiple regression analyses, only HbA1c and BMI were independently associated with 25(OH)D levels. Age, HbA1c and 25(OH)D were the major determinants of Augmentation Index. No independent association between 25(OH)D and IMT was found. CONCLUSIONS: Subjects with pre-diabetes (HbA1c 5.7 6.4% and NFG/NT) had significantly reduced 25(OH)D levels compared with controls. Reduction of 25(OH)D levels is inversely associated with arterial stiffness independently of classical risk factors and inflammatory markers. Based on these data, subjects with NFG and NT are not a homogeneous population of patients, and they present different cardiovascular and glycometabolic risks. Our data suggest considering HbA1c as a reliable marker of cardiovascular and metabolic risk independent of fasting and post-load glycemia. PMID- 26520893 TI - Hepatic ABCG5/G8 overexpression substantially increases biliary cholesterol secretion but does not impact in vivo macrophage-to-feces RCT. AB - BACKGROUND AND AIMS: Biliary cholesterol secretion is important for reverse cholesterol transport (RCT). ABCG5/G8 contribute most cholesterol mass secretion into bile. We investigated the impact of hepatic ABCG5/G8 on cholesterol metabolism and RCT. METHODS: Biliary and fecal sterol excretion (FSE) as well as RCT were determined using wild-type controls, Abcg8 knockout mice, Abcg8 knockouts with adenovirus-mediated hepatocyte-specific Abcg8 reinstitution and hepatic Abcg5/g8 overexpression in wild-types. RESULTS: In Abcg8 knockouts, biliary cholesterol secretion was decreased by 75% (p < 0.001), while mass FSE and RCT were unchanged. Hepatic reinstitution of Abcg8 increased biliary cholesterol secretion 5-fold (p < 0.001) without changing FSE or overall RCT. Overexpression of both ABCG5/G8 elevated biliary cholesterol secretion 5-fold and doubled FSE (p < 0.001) without affecting overall RCT. CONCLUSIONS: ABCG5/G8 mediate mass biliary cholesterol secretion but not from a RCT-relevant pool. Intervention strategies aiming at increasing hepatic Abcg5/g8 expression for enhancing RCT are not likely to be successful. PMID- 26520894 TI - Mesoglycan improves vascular reactivity and insulin sensitivity in patients with metabolic syndrome. AB - OBJECTIVES: The aim of this study was to evaluate the acute and chronic effects of mesoglycan on the endothelial function and arterial elastic properties in patients with metabolic syndrome (MetS). BACKGROUND: MetS is defined by a clustering of vascular risk factors that demand both pharmacologic and non pharmacologic interventions, including body weight reductions and physical activity. The correction of endothelial dysfunction and arterial wall distensibility associated with MetS have lately received increasing interest. METHODS: Thirty consecutive ambulatory patients affected by MetS were 2:1 randomized in a double-blind fashion to receive mesoglycan or placebo, respectively. In the first phase of the study, we evaluated the acute effects of a single i.m. administration of mesoglycan (60 mg) or placebo on vascular reactivity, as assessed by brachial flow-mediated dilation (FMD). Then, patients were chronically treated with mesoglycan per os (50 mg twice a day) or placebo for 90 days. At the end of this period, vascular reactivity and the arterial wall elastic properties were evaluated. RESULTS: In the mesoglycan group, FMD increased above baseline after acute administration, with a maximum increment of 52% after 2 h. FMD was also significantly greater than baseline after 90 days of chronic treatment. In the placebo group, FMD was unaffected by both acute and chronic mesoglycan administration. Moreover, after 90 days of mesoglycan treatment, a marked improvement in arterial distensibility and compliance was detected and arterial stiffness reduced significantly. CONCLUSIONS: This small, preliminary study shows that mesoglycan exerts relevant effects on vascular physiology, both in an acute setting as well as after prolonged, three-month treatment, in patients affected by metabolic syndrome. PMID- 26520895 TI - Long-term prognostic value of IgM antibodies against phosphorylcholine for adverse cardiovascular events in patients with stable coronary heart disease. AB - BACKGROUND: Low concentrations of IgM-phosphorylcholine autoantibodies (IgM-anti PC) have been shown to be associated with increased risk of incident cardiovascular disease (CVD) events and total mortality in patients suffering from an acute coronary syndrome. We assessed whether IgM-anti-PC concentrations add prognostic information for cardiovascular risk in patients with known stable coronary artery disease (CAD). METHODS: IgM-anti-PC concentrations were measured in serum obtained from 1062 patients with clinically manifest stable CAD at baseline. The relation of IgM-anti PC concentrations with CVD events during long term follow-up was assessed by the Kaplan-Meier and life table method and quantified by means of the log-rank test. Then, Cox proportional hazards regression analysis was performed to assess the independent association of IgM anti-PC concentration with risk of secondary CVD events after adjustment for established and emerging risk factors. RESULTS: In n = 1062 patients with stable CAD only very low IgM anti-PC serum concentrations were associated with increased risk for future fatal and non-fatal coronary events (n = 201 during median of 10 years of follow-up). Among patients with IgM anti-PC concentrations in the lowest decile, the partly adjusted hazard ratio for fatal and non-fatal coronary events was 1.60 (95% confidence interval (CI) 1.01-2.55) compared to the top quartile and 1.94 (95%-CI 1.18-3.18) after adjustment for multiple covariates. CONCLUSION: In patients with stable CAD, very low concentrations of IgM anti-PC are associated with increased risk for fatal and non-fatal future coronary events and thus may add prognostic information to traditional cardiovascular risk factors among these patients. PMID- 26520896 TI - IFN-gamma-producing Th17 cells bias by HMGB1-T-bet/RUNX3 axis might contribute to progression of coronary artery atherosclerosis. AB - BACKGROUND: IFN-gamma-producing Th17 cells have been implicated in autoimmune disorders, but their properties in humans are known only partially. The molecular mechanisms and external factors that govern IFN-gamma-producing Th17-cell bias are incompletely understood. The present work was to clarify whether (i) IFN gamma-producing Th17 cells are present in the peripheral circulation of patients with coronary atherosclerosis (CA); (ii) high mobility group box (HMGB)1 in circulation is associated with IFN-gamma-producing Th17-cell bias. METHODS: Thirty-six patients (17 females and 19 males; 45-84 years) diagnosed as having atherosclerosis after coronary angiography for suspected or known CA were included the study cohort. Samples of peripheral blood were collected from healthy volunteers and patients, and classical tests (flow cytometry, RT-qPCR) were used to measure blood components. RESULTS AND CONCLUSION: Our results clearly demonstrated that HMGB1 were up-regulated in different progressive CA patients: 5.38 +/- 1.48 ng/ml, 6.30 +/- 1.53 ng/ml and 5.86 +/- 1.12 ng/ml vs1.45 +/- 0.65 ng/ml for only atherosclerotic plaque (AP), atherosclerotic plaque and some plaque rupture, no thrombosis (PR), plaque rupture and accompanying thrombosis (TH) and volunteers, respectively, p < 0.05. The frequency of IFN gamma-producing Th17 cells was 2.33 +/- 0.58%, 1.93 +/- 0.2% and 2.21 +/- 0.65% vs 0.38 +/- 0.21% for AP, PR, TH and volunteers, p < 0.05, respectively. Furthermore, HMGB1 contributed to IFN-gamma-producing Th17-cell bias by controlling expression of T-bet and RUNX3. We demonstrated, for the first time, that HMGB1 is a potential inducer of IFN-gamma-producing Th17-cell bias, and that IFN-gamma-producing Th17 cells might be one of the pathogenic factors in atherosclerosis. PMID- 26520897 TI - LR11/SorLA links triglyceride-rich lipoproteins to risk of developing cardiovascular disease in FH patients. AB - OBJECTIVE: Familial Hypercholesterolemia (FH) is associated with an increased risk of cardiovascular disease (CVD). However, whether an individual heterozygous FH patient will develop CVD depends on other genetic- and environmental risk factors as well. LDL receptor-related protein with 11 ligand binding repeat (LR11) and its soluble form (sLR11) play a role in the progression of atherosclerosis. We investigated the involvement of LR11 and sLR11 in CVD development in FH patients and in LDLR deficient (Ldlr(-/-)) mice. APPROACH AND RESULTS: In statin-treated asymptomatic male heterozygous FH subjects, plasma sLR11 levels correlated with carotid intima-media thickness. Increased plasma sLR11 levels were found in Ldlr(-/-) and also in wild-type mice exclusively after high-fat feeding. Hepatic LR11 mRNA levels, however, were higher in chow-fed Ldlr(-/-) in comparison with wild-type mice and were further increased after a high fat diet. Similar results were obtained with Apoe(-/-) mice, but not with wild-type mice. LR11 mRNA and protein levels and release of sLR11 from cultured HepG2 and aortic smooth muscle cells were upregulated by postprandial triglyceride-rich lipoproteins (TGRL). Overexpression of human LR11 in CHO cells resulted in increased binding and association of 12I-labeled TGRL, but not of 12I labeled LDL. CONCLUSION: Our data strongly suggest an involvement of LR11 in mediating the harmful effects of a high-fat diet on CVD progression. Elevated sLR11 levels may increase the CVD risk especially in subjects with delayed clearance of triglyceride-rich remnants, such as in FH patients. PMID- 26520898 TI - Irisin protects against endothelial injury and ameliorates atherosclerosis in apolipoprotein E-Null diabetic mice. AB - OBJECTIVE: The circulating irisin increases energy expenditure and improves insulin resistance in mice and humans. The improvement of insulin resistance ameliorates atherosclerosis. Therefore, we hypothesized that irisin alleviates atherosclerosis in diabetes. METHODS: Endothelial function was measured by acetylcholine-induced endothelium-dependent vasodilation using aortic rings in apolipoprotein E-Null (apoE(-/-)) streptozotocin-induced diabetic mice. Atherosclerotic lesion was evaluated by plaque area and inflammatory response in aortas. In addition, the endothelium-protective effects of irisin were also further investigated in primary human umbilical vein endothelial cells (HUVECs) in vitro. RESULTS: The in vivo experiments showed that irisin treatment significantly improved endothelial dysfunction, decreased endothelial apoptosis, and predominantly decreased atherosclerotic plaque area of both en face and cross sections when compared with normal saline-treated diabetic mice. Moreover, the infiltrating macrophages and T lymphocytes within plaque and the mRNA expression levels of inflammatory cytokines in aortas were also significantly reduced by irisin treatment in mice. The in vitro experiments revealed that irisin inhibited high glucose-induced apoptosis, oxidative stress and increased antioxidant enzymes expression in HUVECs, and pretreatment with LY294002, l-NAME, AMPK-siRNA or eNOS-siRNA, attenuated the protection of irisin on HUVECs apoptosis induced by high glucose. In addition, the in vivo and in vitro experiments showed that irisin increased the phosphorylation of AMPK, Akt and eNOS in aortas and cultured HUVECs. CONCLUSIONS: The present study indicates that systemic administration of irisin may be protected against endothelial injury and ameliorated atherosclerosis in apoE(-/-) diabetic mice. The endothelium-protective action of irisin was through activation of AMPK-PI3K-Akt-eNOS signaling pathway. Irisin could be therapeutic for atherosclerotic vascular diseases in diabetes. PMID- 26520899 TI - Berberine, a plant alkaloid with lipid- and glucose-lowering properties: From in vitro evidence to clinical studies. AB - Berberine (BBR) is an isoquinoline plant alkaloid endowed with several pharmacological activities, including anti-microbial, glucose- and cholesterol lowering, anti-tumoral and immunomodulatory properties. The main mechanism by which BBR exerts a protective role in atherosclerosis relates to its cholesterol lowering activity. BBR significantly increases hepatic low density lipoprotein receptor (LDLR) expression and reduces the expression and secretion of the LDLR modulator proprotein convertase subtilisin/kexin type 9 (PCSK9). In addition to this, several other atheroprotective effects have been ascribed to BBR, including anti-inflammatory and anti-oxidant properties, inhibition of vascular smooth muscle cell proliferation and improvement of endothelial dysfunction. BBR also increases glucose utilization in adipocytes and myocytes, while decreases glucose absorption in intestinal cells, resulting in a net hypoglycemic effect. In hypercholesterolemic animals, BBR significantly decreases LDL-C and total cholesterol (TC) levels and reduces aortic lesions, an effect similar to that of statins. In diabetic animals, BBR significantly reduces glucose levels, improves glucose tolerance, reduces body weight gain and adipose tissue mass. Several clinical studies have also tested the efficacy of BBR in humans. In hypercholesterolemic subjects, BBR induces a significant reduction of TC, triglycerides and LDL-C levels and a significant increase of HDL-C levels, without major adverse effects. BBR also reduces glycemia and plasma cholesterol in diabetic patients, improves lipid and glucose profile and decreases body mass index and waist circumference in subjects with metabolic syndrome. These findings, together with the good tolerability, suggest that BBR administration might be considered a potential therapeutic approach for the treatment of hypercholesterolemia or diabetes. Given the level of evidence available to date well-designed randomized controlled trials to test safety and efficacy of BBR are warranted. PMID- 26520900 TI - Associations of non-invasive measures of arterial structure and function, and traditional indicators of cardiovascular risk in adults with cerebral palsy. AB - BACKGROUND: Persons with cerebral palsy (CP) have mobility limitations and may be at increased risk for cardiovascular disease (CVD). AIMS: To determine the feasibility of assessing novel CVD risk indicators and to identify predictors of CVD risk in a clinic-based group of adults with CP. METHODS: In an observational study, we examined 42 adults with CP (mean age 33.5 +/- 12.3 yr). Traditional (resting blood pressure, smoking status and lipids) and novel CVD risk indicators (endothelial function, arterial stiffness, and carotid wall thickness) were assessed. RESULTS: Measures of endothelial function and central arterial stiffness were conducted in 100% and 83% of participants, respectively. Age was the strongest independent predictor of vascular health (cIMT, Age, R square = 0.576, p = 0.001). CONCLUSION: Non-invasive measures of arterial structure and function are feasible to assess and may assist in the prediction of CVD risk in adults with CP. PMID- 26520901 TI - Impact of carotid atherosclerosis loci on cardiovascular events. AB - BACKGROUND: Genome-wide association studies (GWAS) have identified six single nucleotide polymorphisms (SNPs) related to carotid intima media thickness (cIMT) or plaque. However, whether these loci relate to other vascular diseases and subsequent vascular events is unclear. METHODS AND RESULTS: We tested six SNPs (rs4888378, rs11781551, rs445925, rs6601530, rs17398575 and rs1878406) for association with subclinical atherosclerotic measures (cIMT, plaque presence and ankle-brachial index), as well as ischemic stroke, abdominal aortic aneurysm, peripheral or coronary artery disease (CAD) in the Second Manifestations of ARTerial disease (SMART) cohort. Four SNPs were associated with cIMT and two with plaque (p < 0.05). One SNP was also significantly associated to CAD (rs1878406, OR = 1.24, 95% CI = 1.08-1.42, p = 2 * 10(-3)). A genetic risk score (GRS) based on the cIMT-related SNPs was associated to increased risk of cIMT itself (p = 1 * 10(-3)), but not to other secondary outcomes or vascular events during follow-up (p = 0.86). CONCLUSIONS: In addition to replicating previously published associations for cIMT, we confirmed a nominally significant effect between the GRS and cIMT. PMID- 26520902 TI - The association of pulmonary function with carotid atherosclerosis in older Chinese: Guangzhou Biobank Cohort Study-CVD Subcohort. AB - BACKGROUND: Evidence describing the association between pulmonary function and carotid atherosclerosis has been inconclusive and the role of smoking in this association is unclear. We therefore examined this association in the Guangzhou Biobank Cohort Study-CVD Subcohort. METHODS: Common carotid artery (CCA) intima media thickness (IMT) and carotid plaques were measured by B-mode ultrasonography and lung function by spirometry using a turbine flowmeter. Chronic obstructive pulmonary disease (COPD) was defined as the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) of less than 0.70. Predicted FEV1 and FVC were derived using equations for Chinese. RESULTS: Of 1625 participants aged 50 + years, 382 (23.5%) had evidence of carotid plaque. The mean CCA-IMT was higher in those with COPD than those without (0.82 +/- 0.29 mm versus 0.76 +/- 0.31 mm, P = 0.02). We found no evidence that the association of pulmonary function with CCA-IMT varied by smoking status (P values interaction: 0.23-0.83). After adjustment for a wide range of potential confounders, the increased risks of thickened CCA-IMT (CCA-IMT >=1.0 mm) in those with COPD became marginally nonsignificant (adjusted odds ratio (OR) 1.45, 95% confidence interval (CI) 0.91 2.29; P = 0.12). Compared to those in the highest tertile, participants in the lowest tertile of FEV1 observed to predicted ratio had increased risk of thickened CCA-IMT (adjusted OR 2.18, 95% CI 1.42-3.34) and carotid plaque (adjusted OR 1.50, 95% CI 1.08-2.09), while participants in the lowest tertile of FVC observed to predicted ratio had increased risk of thickened CCA-IMT (adjusted OR 2.29, 95% CI 1.46-3.58), but the adjusted OR for carotid plaque was marginally nonsignificant (adjusted OR 1.29, 95% CI 0.93-1.80; P = 0.13). CONCLUSION: Independent of smoking status, poor pulmonary function was dose-dependently associated with carotid atherosclerosis in older Chinese. (281 words). PMID- 26520903 TI - Alpha1beta1 and integrin-linked kinase interact and modulate angiotensin II effects in vascular smooth muscle cells. AB - The effects of angiotensin II (Ang II) on vascular smooth muscle cells (VSMC) are modulated by reactive oxygen species (ROS) and also involve integrin engagement. However, the potential link between alpha1beta1 integrin signaling with NOX system and their combined contribution to Ang II effects on VSMC have not been investigated. We aimed to elucidate the moslecular mechanisms underlying the activation of these two pathways in Ang II effects on VSMC. Ang II-induced VSMC migration (2-fold increase) and proliferation (2.5-fold increase) is modulated by alpha1beta1 integrin, being inhibited by obtustatin, a specific alpha1beta1 integrin blocker. Ang II also stimulates ROS production in VSMC (140%) that is NOX1 dependent, being completely inhibited in NOX1 silenced cells. The ROS production develops in two peaks, and the second peak is maintained by NOX2 activation. Apocynin and obtustatin inhibit the NOX2-associated second peak, but not the first peak of ROS production, which is related to NOX1 activation. Corroborating the involvement of alpha1beta1 integrin, the pretreatment of VSMC with obtustatin impaired Ang II-induced FAK phosphorylation, AKT activation, p21 degradation and the increase of ILK expression. Silencing of ILK blocked cell migration, AKT phosphorylation and the second peak of ROS, but partially inhibits (70%) VSMC proliferation induced by Ang II. The data demonstrate a novel role for NOX2 in Ang II effects on VSMC, and suggest alpha1beta1 integrin and ILK as target molecules to the development of more effective therapeutic interventions in cardiovascular diseases. PMID- 26520904 TI - Longitudinal changes of the serum calcium levels and accelerated progression of arterial stiffness with age. AB - BACKGROUND AND AIMS: The progression of arterial stiffness is accelerated by aging, although the underlying mechanisms have not yet been clarified. This prospective observational study was conducted to clarify whether longitudinal changes in the serum calcium/phosphate levels are associated with the accelerated progression of arterial stiffness with age. METHODS: In a cohort of employees at a construction company (1507 middle-aged Japanese men), the serum calcium/phosphate levels and brachial-ankle pulse wave velocity (baPWV) were measured at the start and at the end of a 3-year study period. RESULTS: A general linear model multivariate analysis revealed a significant interaction of the 2 factors {age and longitudinal changes of the serum calcium levels (delCa) during the follow-up period} on the longitudinal changes of the baPWV during the study period (delPWV). The delCa was significantly correlated with the delPWV even after adjustments for covariates in subjects aged >=48 years. The delPWV in subjects aged >=48 years with the delCa in the upper tertile (69 +/- 137 cm/s) was significantly larger than that in the other groups even after adjustments for covariates (e.g., del PWV in subjects aged <48 years with the delCa in the lower tertile = 1 +/- 94 cm/s) (p < 0.01). CONCLUSIONS: The association between the arterial stiffness and serum calcium levels differed with age. Pathophysiological abnormalities related to increased serum calcium levels appeared to be associated with accelerated progression of arterial stiffness with age. PMID- 26520905 TI - Lean mass, and not fat mass, is an independent determinant of carotid intima media thickness in obese subjects. AB - BACKGROUND AND AIMS: Obesity is an important determinant of increased cardiovascular risk. Increased fat mass has been assumed to constitute the main prominent contributor to changes in carotid intima-media thickness (c-IMT). METHODS: In 421 consecutive subjects (301 women), c-IMT was evaluated ultrasonographically in 6 independent territories and body composition was assessed by dual-energy X-ray absorptiometry. RESULTS: c-IMT was positively associated with lean body mass in both men (r = 0.328, p = <0.0001) and women (r = 0.268 p = <0.0001) and increased across lean mass quartiles (p = <0.0001 for linear-trend ANOVA). Stepwise linear regression analysis showed that age and lean mass (but not fat mass or traditional cardiovascular risk factors) contributed to 46.2% of c-IMT variance in men (p = <0.0001). Even within obese men, lean mass was an independent contributor to c-IMT variance. Among women, age, lean mass and ultrasensitive CRP levels contributed independently to 47.7% of c-IMT variance (p < 0.0001). CONCLUSIONS: Lean mass, and not fat mass, might contribute to increase c-IMT in obese patients independently of classical atherosclerotic risk factors. These data reinforce the concept that the increase in metabolically fat-free mass that accompanies the body weight enlargement is closely related to the raise in blood pressure. PMID- 26520907 TI - Subclinical carotid artery atherosclerosis and performance on cognitive tests in middle-aged adults: Baseline results from the ELSA-Brasil. AB - BACKGROUND AND AIMS: Carotid artery intima-media thickness (CIMT) may be used as a biomarker for early cognitive impairment. However, the results of the association between CIMT and cognitive function in middle-aged subjects are mixed. We aimed to investigate this association in a large Brazilian sample with no history of stroke at baseline. Additionally, we tested the effect of interactions between CIMT and cardiovascular risk factors on cognitive performance. METHODS: In this cross-sectional study, cognition was evaluated using the delayed word recall (DWRT), the category fluency, and the trail making tests (TMT). CIMT was measured at the common carotid artery. The association between CIMT and cognitive tests was investigated using linear regression models, adjusted for an extensive set of possible confounding variables. We also included interaction terms with selected risk factors. RESULTS: The mean age of the 8208 participants was 49.6 +/- 7.3 years, 44% were male, and 56% White. Increase in CIMT was associated with worse performance on the DWRT (beta = -0.433, 95%CI = 0.724;-0.142, p = 0.004). We found effect modification of the association between cognitive function and CMIT by self-reported heart failure and alcohol intake. Participants had worse performance in the TMT if they had greater CIMT and current alcohol use (p < 0.0001). The interaction between CIMT and heart failure on TMT performance was not significant after adjustment for multiple comparisons (p = 0.07). CONCLUSIONS: In this sample of middle-aged adults, CIMT was inversely associated with memory function. Additionally, the presence of alcohol use resulted in a stronger association of CIMT with worse performance on an executive function test. PMID- 26520906 TI - miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice. AB - RATIONALE: Recently, there has been significant interest in the therapeutic administration of miRNA mimics and inhibitors to treat cardiovascular disease. In particular, miR-27b has emerged as a regulatory hub in cholesterol and lipid metabolism and potential therapeutic target for treating atherosclerosis. Despite this, the impact of miR-27b on lipid levels in vivo remains to be determined. As such, here we set out to further characterize the role of miR-27b in regulating cholesterol metabolism in vitro and to determine the effect of miR-27b overexpression and inhibition on circulating and hepatic lipids in mice. METHODS AND RESULTS: Our results identify miR-27b as an important regulator of LDLR activity in human and mouse hepatic cells through direct targeting of LDLR and LDLRAP1. In addition, we report that modulation of miR-27b expression affects ABCA1 protein levels and cellular cholesterol efflux to ApoA1 in human hepatic Huh7 cells. Overexpression of pre-miR-27b in the livers of wild-type mice using AAV8 vectors increased pre-miR-27b levels 50-fold and reduced hepatic ABCA1 and LDLR expression by 50% and 20%, respectively, without changing circulating and hepatic cholesterol and triglycerides. To determine the effect of endogenous miR 27b on circulating lipids, wild-type mice were fed a Western diet for one month and injected with 5 mg/kg of LNA control or LNA anti-miR-27b oligonucleotides. Following two weeks of treatment, the expression of ABCA1 and LDLR were increased by 10-20% in the liver, demonstrating effective inhibition of miR-27b function. Intriguingly, no differences in circulating and hepatic lipids were observed between treatment groups. CONCLUSIONS: The results presented here provide evidence that short-term modulation of miR-27b expression in wild-type mice regulates hepatic LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels. PMID- 26520908 TI - Symptoms associated with button batteries injuries in children: An epidemiological review. AB - OBJECTIVES: To provide an epidemiological framework of symptoms related to Foreign Body (FB) injuries due to Button Battery (BB). METHODS: Data on BB ingestion/inhalation have been obtained from the ButtonBatteryDB. The ButtonBatteryDB is a database collecting information on BB injuries in children (0-18 years of age). Data on 348 BB injures have been derived from the Registry of Foreign Body Injuries "Susy Safe" (269 cases) and from published scientific literature reporting case reports of FB injuries (79 cases). RESULTS: Most of injured children were male and BBs were found more often in the mouth/esophagus/stomach (ICD935) and in the nose (ICD932). Analyzing symptoms related to BB located in the esophagus/mouth/stomach, we found that children had higher probability of experiencing dysphagia (30.19%, 95% C.I. 17.83-42.55), fever and cough (26.42%, 95% C.I. 14.55-38.28), compared to the other symptoms. Referring to the probability that symptoms occurred simultaneously, fever and cough are more likely (3.72%, 95% C.I. 1.0-6-43) to jointly showing up in children with BB in mouth/esophagus/stomach (ICD935), followed by fever and dysphagia (2.66%, 95% C.I. 0.36-4.96) and by fever and irritability/crying, fever and drooling, dysphagia and irritability/crying (2.13% C.I. 0.00-4.19, 95% C.I.) CONCLUSIONS: These findings provide new insight in clinical presentation of BB injuries: the identification of unique patterns of symptoms related to BB injuries is useful to perform an early diagnosis (and to guarantee a prompt medical reaction), also when the injury is un-witnessed. PMID- 26520909 TI - The effect of early auditory experience on the spatial listening skills of children with bilateral cochlear implants. AB - OBJECTIVES: Both electrophysiological and behavioural studies suggest that auditory deprivation during the first months and years of life can impair listening skills. Electrophysiological studies indicate that 31/2 years may be a critical age for the development of symmetrical cortical responses in children using bilateral cochlear implants. This study aimed to examine the effect of auditory experience during the first 31/2 years of life on the behavioural spatial listening abilities of children using bilateral cochlear implants, with reference to normally hearing children. Data collected during research and routine clinical testing were pooled to compare the listening skills of children with bilateral cochlear implants and different periods of auditory deprivation. METHODS: Children aged 4-17 years with bilateral cochlear implants were classified into three groups. Children born profoundly deaf were in the congenital early bilateral group (received bilateral cochlear implants aged <=31/2 years, n=28) or congenital late bilateral group (received first implant aged <=31/2 years and second aged >31/2 years, n=38). Children with some bilateral acoustic hearing until the age of 31/2 years, who subsequently became profoundly deaf and received bilateral cochlear implants, were in the acquired/progressive group (n=16). There were 32 children in the normally hearing group. Children completed tests of sound-source localization and spatial release from masking (a measure of the ability to use both ears to understand speech in noise). RESULTS: The acquired/progressive group localized more accurately than both groups of congenitally deaf children (p<0.05). All three groups of children with cochlear implants showed similar spatial release from masking. The normally hearing group localized more accurately than all groups with bilateral cochlear implants and displayed more spatial release from masking than the congenitally deaf groups on average (p<0.05). CONCLUSION: Children with bilateral cochlear implants and early experience of acoustic hearing showed more accurate localization skills, on average, than children born profoundly deaf. PMID- 26520910 TI - Surgery for velopharyngeal insufficiency: The outcomes of the University Hospitals Leuven. AB - OBJECTIVES: We reviewed the outcomes of patients who underwent a velopharyngoplasty and subsequent speech therapy for velopharyngeal insufficiency (VPI) to determine possible prognostic variables. METHODS: During the period 2002 2010, 91 patients with VPI underwent a velopharyngoplasty (either the Honig velopharyngoplasty, the modified Honig velopharyngoplasty or the Hynes pharyngoplasty). Of these, 62 had complete data for long-term evaluation of speech outcome and analysis of variables potentially influencing this outcome. Speech outcome was assessed using five criteria that were evaluated pre- and postoperatively: hypernasality, nasal emission, facial grimacing, retro articulation and glottal stops. The former two variables were transformed into a semi-objective nasality index (NI), the latter three variables were assembled to form a subjective articulation index (AI). Prognostic variables for outcome that were studied included age at velopharyngoplasty, associated 22q11.2 deletion syndrome, intervention type, primary or secondary surgery and pre-intervention speech therapy. RESULTS: Before surgery, based on the NI, 15 patients had mild VPI and 44 patients had moderate to severe VPI. Postoperatively at 12 months, 46 patients had a good speech outcome (normal or mild VPI), 13 patients had moderate VPI and no more severe VPI was observed. The overall success rate of 78% after one year increased to 90% in the long-term (median 27 months) with further speech therapy. Patients without the diagnosis of 22q11.2 deletion syndrome had better speech outcomes than patients with the syndrome. No statistically significant effect of the age at velopharyngoplasty on speech outcome was found. No cases of sleep apnea syndrome were reported. CONCLUSIONS: Our protocol of patient tailored surgical interventions and further postoperative speech therapy results in good speech outcomes, with no or only mild remaining VPI for the majority of patients. The correction of VPI is more difficult for the subgroup of patients with 22q11.2 deletion syndrome. PMID- 26520911 TI - Congenital anomalies of the incudostapedial joint. AB - OBJECTIVE: To describe congenital anomalies of the incudostapedial joint (ISJ) and to discuss the possible unique embryogenesis of the ISJ based on the two anomalies that were encountered. SETTING: Tertiary care medical center. SUBJECTS AND METHODS: Retrospective review of the medical records of all patients with ISJ anomalies. RESULTS: Four patients presented with congenital hearing loss. Upon further workup, we observed a preserved incudostapedial joint (ISJ) with deficiencies of the incus and stapes in three cases. Our fourth case demonstrated the inverse pattern of the congenital anomalies in which the ISJ was missing with an intact proximal incus and stapes crura. Three patients opted for surgical intervention with improvement in hearing. One case preferred hearing amplification over surgery. CONCLUSION: Isolated ISJ malformations are uncommon potential causes of congenital conductive hearing loss. Although numerous patterns of ossicular anomalies have been reported in the literature, our case series is the first to demonstrate both the absence of the ISJ in one patient and the presence of the ISJ in the presence of missing stapes crura and incus body in other patients. Though limited by the small number of cases, the inverse relationship of the single case compared to the three other cases, suggests a possible independent embryological development pathway for the ISJ. Therefore, an embryological explanation of the defects should be considered. Additionally, surgical intervention can improve hearing outcomes for patients with isolated ISJ anomalies. PMID- 26520912 TI - The effective quadriceps and patellar tendon moment arms relative to the tibiofemoral finite helical axis. AB - The moment arm is a crucial parameter for understanding musculoskeletal dynamics as it defines how linear muscle force is transformed into a moment. Yet, for the quadriceps tendon this parameter cannot be directly calculated, as the patella creates a dynamic fulcrum. Thus, the effective quadriceps moment arm (EQma) was developed to define the quadriceps force to tibial moment relationship. In vivo data in regards to the EQma are lacking and the critical question of how patellofemoral kinematics may influence the EQma remains unresolved. Therefore, the purpose of this study was to quantify the in vivo EQma during a knee extension exercise in asymptomatic controls and to correlate the EQma with sagittal plane patellofemoral kinematics. While subjects (30F/10M, 26.5+/-5.6 years, 167.5+/-10.2 cm, 62.6+/-10.7 kg) cyclically flexed-extended their knees within the MR scanner, dynamic cine-phase contrast and cine MR images were acquired. From these data, patellofemoral kinematics, the ratio of the patellar tendon to quadriceps force, the patellar tendon moment arm, and the EQma were quantified. The EQma trended upwards (32.9-45.5 mm (females) and 31.5-47.1 mm (males)) as the knee angle decreased (50-10 degrees ). The quadriceps had a mechanical advantage (ratio of patellar to quadriceps tendon forces >1.0) for knee angles <=20 degrees . The EQma did not correlate with sagittal plane patellofemoral kinematics. As this is the first study to characterize the EQma in vivo during dynamic volitional activity, in a large group of asymptomatic controls, it can serve as a foundation for future knee joint models and to explore how pathological conditions affect the EQma. PMID- 26520914 TI - Meal-Skipping Behaviors and Body Fat in 6-Year-Old Children. AB - OBJECTIVE: To assess the prospective associations of breakfast, lunch, and dinner skipping at age 4 years with body fat (ie, percent fat mass, body mass index [BMI], and weight status) at age 6 years. STUDY DESIGN: Data were analyzed from 5913 children participating in the Generation R Study, a population-based prospective cohort study in Rotterdam, The Netherlands. Meal-skipping behaviors were assessed through parent-report questionnaires. Children's weight and height were objectively measured and converted to BMI SDSs. Weight status (ie, overweight or normal weight) was defined according to age- and sex-specific cutoff points. At age 6 years, percent fat mass was assessed by dual-energy X-ray absorptiometry. Linear and logistic regression analyses were performed, adjusting for covariates and BMI at age 4 years. RESULTS: Breakfast skipping at age 4 years was associated with a higher percent fat mass at age 6 years (beta = 1.38; 95% CI, 0.36-2.40). No associations were found with BMI or weight status. Furthermore, no associations were found between lunch and dinner skipping at age 4 years and body fat at age 6 years. CONCLUSION: Breakfast skipping at age 4 years is associated with a higher percent fat mass at age 6 years. Further prospective studies, including intervention studies, are warranted to extend the evidence base on the directionality and causality of this association. PMID- 26520913 TI - Leaf biomechanical properties in Arabidopsis thaliana polysaccharide mutants affect drought survival. AB - Individual sugars are the building blocks of cell wall polysaccharides, which in turn comprise a plant's overall architectural structure. But which sugars play the most prominent role in maintaining a plant's mechanical stability during large cellular deformations induced by drought? We investigated the individual contributions of several genes that are involved in the synthesis of monosaccharides which are important for cell wall structure. We then measured drought tolerance and mechanical integrity during simulated drought in Arabidopsis thaliana. To assess mechanical properties, we designed a small-scale tensile tester for measuring failure strain, ultimate tensile stress, work to failure, toughness, and elastic modulus of 6-week-old leaves in both hydrated and drought-simulated states. Col-0 mutants used in this study include those deficient in lignin, cellulose, components of hemicellulose such as xylose and fucose, the pectic components arabinose and rhamnose, as well as mutants with enhanced arabinose and total pectin content. We found that drought tolerance is correlated to the mechanical and architectural stability of leaves as they experience dehydration. Of the mutants, S096418 with mutations for reduced xylose and galactose was the least drought tolerant, while the arabinose-altered CS8578 mutants were the least affected by water loss. There were also notable correlations between drought tolerance and mechanical properties in the diminished rhamnose mutant, CS8575 and the dehydrogenase-disrupted S120106. Our findings suggest that components of hemicellulose and pectins affect leaf biomechanical properties and may play an important role in the ability of this model system to survive drought. PMID- 26520915 TI - Eczema Is Associated with Childhood Speech Disorder: A Retrospective Analysis from the National Survey of Children's Health and the National Health Interview Survey. AB - OBJECTIVE: To determine if eczema is associated with an increased risk of a speech disorder. STUDY DESIGN: We analyzed data on 354,416 children and adolescents from 19 US population-based cohorts: the 2003-2004 and 2007-2008 National Survey of Children's Health and 1997-2013 National Health Interview Survey, each prospective, questionnaire-based cohorts. RESULTS: In multivariate survey logistic regression models adjusting for sociodemographics and comorbid allergic disease, eczema was significantly associated with higher odds of speech disorder in 12 of 19 cohorts (P < .05). The pooled prevalence of speech disorder in children with eczema was 4.7% (95% CI 4.5%-5.0%) compared with 2.2% (95% CI 2.2%-2.3%) in children without eczema. In pooled multivariate analysis, eczema was associated with increased odds of speech disorder (aOR [95% CI] 1.81 [1.57 2.05], P < .001). In a single study assessing eczema severity, mild (1.36 [1.02 1.81], P = .03) and severe eczema (3.56 [1.70-7.48], P < .001) were associated with higher odds of speech disorder. History of eczema was associated with moderate (2.35 [1.34-4.10], P = .003) and severe (2.28 [1.11-4.72], P = .03) speech disorder. Finally, significant interactions were found, such that children with both eczema and attention deficit disorder with or without hyperactivity or sleep disturbance had vastly increased risk of speech disorders than either by itself. CONCLUSIONS: Pediatric eczema may be associated with increased risk of speech disorder. Further, prospective studies are needed to characterize the exact nature of this association. PMID- 26520916 TI - Factors Associated with Respiratory Illness in Children and Young Adults with Cerebral Palsy. AB - OBJECTIVE: To describe associations between respiratory illness and its potential predictors in children and young adults with cerebral palsy (CP). STUDY DESIGN: Cross-sectional survey of self- and caregiver-reported respiratory symptoms for individuals aged up to 26 years with CP. Respiratory illness was indicated by 2 outcomes: (1) >=1 respiratory hospitalizations in the past year; and (2) >=2 courses of antibiotics for respiratory symptoms in the past year. ORs were calculated using univariate and multivariate logistic regression. RESULTS: There were 551 participants, aged 1-26 years, distributed across all gross motor function classification scale (GMFCS) levels. In univariate analyses, factors significantly associated with respiratory hospitalizations were weekly respiratory symptoms (OR 2.31, 95% CI 1.78-3.00), respiratory symptoms during meals (OR 3.23, 95% CI 1.50-5.80), gastroesophageal reflux (OR 3.01, 95% CI 1.71 5.31), coughing or choking on saliva (OR 4.36, 95% CI 2.38-8.01), current asthma (OR 3.56, 95% CI 1.97-6.42), age (0-3 years) (OR 3.24, 95% CI 1.19-8.80, compared with 13-17 years), seizures (OR 3.45, 95% CI 1.96-6.08), and scoliosis (OR 2.14, 95% CI 1.16-3.97). Nonambulatory individuals (GMFCS IV-V) were at significantly increased risk of hospitalizations only if they had food modifications and/or nasogastric or gastrostomy tube feeds (OR 5.36, 95% CI 2.89-9.96, compared with GMFCS I-III with no food modifications and no tube). All factors, except seizures and scoliosis, were significantly associated with multiple courses of antibiotics in univariate analyses. CONCLUSIONS: Oromotor dysfunction is strongly associated with respiratory illness in patients with CP. PMID- 26520917 TI - To the limit of extreme malnutrition. AB - Extreme malnutrition with body mass index (BMI) as low as 10 kg/m(2) is not uncommon in anorexia nervosa, with survival enabled through complex metabolic adaptations. In contrast, outcomes from hunger strikes and famines are usually fatal after weight loss to about 40% below expected body weight, corresponding to BMI 12 to 13 kg/m(2) in adults. Thus, many years of adaptation in adolescent onset anorexia nervosa, supported by supplements of vitamins and treatment of intercurrent diseases, may allow survival at a much lower BMI. However, in the literature only a few cases of survival in patients with BMI <9 kg/m(2) have been described. We report on the case of a 29-y-old woman who was successfully treated in a specialized unit. She had a BMI of 7.8 kg/m(2). To our knowledge, this level of extreme malnutrition has not previously been reported. The present case emphasizes the importance of adherence to guidelines to decrease refeeding complications. PMID- 26520918 TI - Ghrelin and GHS-R in the rat gastric mucosa: Are they involved in regulation of growth during early weaning? AB - OBJECTIVES: Based on previous evidence showing that early weaning disturbs the ontogenesis of rat gastric glands, which are the major site of ghrelin synthesis, we investigated the distribution of ghrelin and its receptor (GHS-R) in the rat gastric epithelium during postnatal development and evaluated the effects of early weaning on their levels. Additionally, we studied the contribution of ghrelin to gastric growth during the abrupt nutrient transition. METHODS: Wistar rats were submitted to early weaning at 15 d and suckling counterparts were taken as controls. RESULTS: By running quantitative reverse transcription polymerase chain reaction, immunoblots, and immunohistochemistry, we detected a variation of ghrelin levels and an increase of expression and number of immunolabeled cells, 3 d after treatment (P < 0.05). Through confocal microscopy, we identified GHS-R in the neck region of the gland and did not observe changes in protein levels. Growth was evaluated after ghrelin antagonist ([D-Lys-3]-GHRP-6) administration, which reduced DNA synthesis index in early-weaned rats (P < 0.05) as determined by bromodeoxyuridine incorporation. CONCLUSION: The present study demonstrated that ghrelin and GHS-R are distributed in gastric mucosa during the postnatal development, indicating that they can signal and function in epithelial cells. We concluded that early weaning increased ghrelin levels in the stomach, and it takes part of cell proliferation control that is essential for stomach growth. Therefore, among the many effects previously described for early weaning, this abrupt nutrient transition also changed ghrelin levels, which might represent an additional element in the complex mechanism that coordinates stomach development. PMID- 26520919 TI - Testing times. PMID- 26520920 TI - NtRTI sparing in patients at risk of bone disease. PMID- 26520921 TI - Contraceptive implants and efavirenz-based ART: friend or foe? PMID- 26520922 TI - Male partner recruitment in Malawi's option B+ programme. PMID- 26520923 TI - Insights into HIV treatment in Latin America and the Caribbean. PMID- 26520924 TI - Are randomised controlled trials always required? PMID- 26520925 TI - Join us at The Lancet Clinic. PMID- 26520927 TI - Pregnancy rates in HIV-positive women using contraceptives and efavirenz-based or nevirapine-based antiretroviral therapy in Kenya: a retrospective cohort study. AB - BACKGROUND: Concerns have been raised about efavirenz reducing the effectiveness of contraceptive implants. We aimed to establish whether pregnancy rates differ between HIV-positive women who use various contraceptive methods and either efavirenz-based or nevirapine-based antiretroviral therapy (ART) regimens. METHODS: We did this retrospective cohort study of HIV-positive women aged 15-45 years enrolled in 19 HIV care facilities supported by Family AIDS Care and Education Services in western Kenya between Jan 1, 2011, and Dec 31, 2013. Our primary outcome was incident pregnancy diagnosed clinically. The primary exposure was a combination of contraceptive method and efavirenz-based or nevirapine-based ART regimen. We used Poisson models, adjusting for repeated measures, and demographic, behavioural, and clinical factors, to compare pregnancy rates among women receiving different contraceptive and ART combinations. FINDINGS: 24,560 women contributed 37,635 years of follow-up with 3337 incident pregnancies. In women using implants, adjusted pregnancy incidence was 1.1 per 100 person-years (95% CI 0.72-1.5) for nevirapine-based ART users and 3.3 per 100 person-years (1.8-4.8) for efavirenz-based ART users (adjusted incidence rate ratio [IRR] 3.0, 95% CI 1.3-4.6). In women using depot medroxyprogesterone acetate, adjusted pregnancy incidence was 4.5 per 100 person-years (95% CI 3.7-5.2) for nevirapine based ART users and 5.4 per 100 person-years (4.0-6.8) for efavirenz-based ART users (adjusted IRR 1.2, 95% CI 0.91-1.5). Women using other contraceptive methods, except for intrauterine devices and permanent methods, had 3.1-4.1 higher rates of pregnancy than did those using implants, with 1.6-2.8 higher rates in women using efavirenz-based ART. INTERPRETATION: Although HIV-positive women using implants and efavirenz-based ART had a three-times higher risk of contraceptive failure than did those using nevirapine-based ART, these women still had lower contraceptive failure rates than did those receiving all other contraceptive methods except for intrauterine devices and permanent methods. Guidelines for contraceptive and ART combinations should balance the failure rates for each contraceptive method and ART regimen combination against the high effectiveness of implants. FUNDING: None. PMID- 26520928 TI - Recruiting male partners for couple HIV testing and counselling in Malawi's option B+ programme: an unblinded randomised controlled trial. AB - BACKGROUND: Couples HIV testing and counselling (CHTC) is encouraged but is not widely done in sub-Saharan Africa. We aimed to compare two strategies for recruiting male partners for CHTC in Malawi's option B+ prevention of mother-to child transmission programme: invitation only versus invitation plus tracing and postulated that invitation plus tracing would be more effective. METHODS: We did an unblinded, randomised, controlled trial assessing uptake of CHTC in the antenatal unit at Bwaila District Hospital, a maternity hospital in Lilongwe, Malawi. Women were eligible if they were pregnant, had just tested HIV-positive and therefore could initiate antiretroviral therapy, had not yet had CHTC, were older than 18 years or 16-17 years and married, reported a male sex partner in Lilongwe, and intended to remain in Lilongwe for at least 1 month. Women were randomly assigned (1:1) to either the invitation only group or the invitation plus tracing group with block randomisation (block size=4). In the invitation only group, women were provided with an invitation for male partners to present to the antenatal clinic. In the invitation plus tracing group, women were provided with the same invitation, and partners were traced if they did not present. When couples presented they were offered pregnancy information and CHTC. Women were asked to attend a follow-up visit 1 month after enrolment to assess social harms and sexual behaviour. The primary outcome was the proportion of couples who presented to the clinic together and received CHTC during the study period and was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, number NCT02139176. FINDINGS: Between March 4, 2014, and Oct 3, 2014, 200 HIV-positive pregnant women were enrolled and randomly assigned to either the invitation only group (n=100) or the invitation plus tracing group (n=100). 74 couples in the invitation plus tracing group and 52 in the invitation only group presented to the clinic and had CHTC (risk difference 22%, 95% CI 9-35; p=0.001) during the 10 month study period. Of 181 women with follow-up data, two reported union dissolution, one reported emotional distress, and none reported intimate partner violence. One male partner, when traced, was confused about which of his sex partners was enrolled in the study. No other adverse events were reported. INTERPRETATION: An invitation plus tracing strategy was highly effective at increasing CHTC uptake. Invitation plus tracing with CHTC could have many substantial benefits if brought to scale. FUNDING: National Institutes of Health. PMID- 26520930 TI - Importance and proper use of fatty acid levels in vascular events. PMID- 26520929 TI - Incidence of virological failure and major regimen change of initial combination antiretroviral therapy in the Latin America and the Caribbean: an observational cohort study. AB - BACKGROUND: Access to combination antiretroviral therapy (ART) is expanding in Latin America (Mexico, Central America, and South America) and the Caribbean. We assessed the incidence of and factors associated with regimen failure and regimen change of initial ART in this region. METHODS: This observational cohort study included antiretroviral-naive adults starting ART from 2000 to 2014 at sites in seven countries throughout Latin America and the Caribbean. Primary outcomes were time from ART initiation until virological failure, major regimen modification, and a composite endpoint of the first of virological failure or major regimen modification. Cumulative incidence of the primary outcomes was estimated with death considered a competing event. FINDINGS: 14,027 patients starting ART were followed up for a median of 3.9 years (2.0-6.5): 8374 (60%) men, median age 37 years (IQR 30-44), median CD4 count 156 cells per MUL (61-253), median plasma HIV RNA 5.0 log10 copies per mL (4.4-5.4), and 3567 (28%) had clinical AIDS. 1719 (12%) patients had virological failure and 1955 (14%) had a major regimen change. Excluding the site in Haiti, which did not regularly measure HIV RNA, cumulative incidence of virological failure was 7.8% (95% CI 7.2-8.5) 1 year after ART initiation, 19.2% (18.2-20.2) at 3 years, and 25.8% (24.6-27.0) at 5 years; cumulative incidence of major regimen change was 5.9% (5.3-6.4) at 1 year, 12.7% (11.9-13.5) at 3 years, and 18.2% (17.2-19.2) at 5 years. Incidence of major regimen change at the site in Haiti was 10.7% (95% CI 9.7-11.6) at 5 years. Virological failure was associated with younger age (adjusted hazard ratio [HR] 2.03, 95% CI 1.68-2.44, for 20 years vs 40 years), infection through injection drug use (vs infection through heterosexual sex; 1.60, 1.02-2.52), and initiation in earlier calendar years (1.28, 1.13-1.46, for 2002 vs 2006), but was not significantly associated with boosted protease inhibitor-based regimens (vs non nucleoside reverse transcriptase inhibitor; 1.17, 1.00-1.36). INTERPRETATION: Incidence of virological failure in Latin America and the Caribbean was generally lower than that reported in North America or Europe. Our results suggest the need to design strategies to reduce failure and major regimen change in young patients and those with a history of injection drug use. FUNDING: US National Institutes of Health. PMID- 26520932 TI - Contributed Review: Application of voice coil motors in high-precision positioning stages with large travel ranges. AB - Recent interest in high-precision positioning stages with large travel ranges has sparked renewed attention to the development of voice coil motors (VCMs). Due to their large output force, VCMs can actuate more complicated flexure structures, eliminate rail friction, and improve positioning speed. The VCM structure is both compact and flexible; hence, it is convenient to design VCMs for a variety of stage structures. Furthermore, VCMs combined with other actuators are able to achieve large travel ranges with high precision. In this paper, we summarize the principles and control methods of a typical VCM, and we analyze its properties, including thrust force, acceleration, and response time. We then present recent research on high-precision VCM positioning stages with large travel ranges. PMID- 26520931 TI - Molecular and antigenic characterization of bovine Coronavirus circulating in Argentinean cattle during 1994-2010. AB - Bovine coronavirus (BCoV) is an important viral pathogen associated with neonatal calf diarrhea. Our aim was to investigate the incidence of BCoV in diarrhea outbreaks in beef and dairy herds from Argentina during 1994-2010. A total of 5.365 fecal samples from diarrheic calves were screened for BCoV diagnosis by ELISA. The virus was detected in 1.71% (92/5365) of the samples corresponding to 5.95% (63/1058) of the diarrhea cases in 239 beef and 324 dairy farms. The detection rate of BCoV was significantly higher in dairy than in beef herds: 12.13% (29/239) vs. 4.32% (14/324) respectively. Phylogenetic analysis of the hypervariable S1 region of seven representative samples (from different husbandry systems, farm locations and years of sampling) indicated that BCoV strains circulating in Argentinean beef and dairy herds formed a cluster distinct from other geographical regions. Interestingly, Argentinean strains are distantly related (at both the nucleotide and amino acid levels) with the Mebus historic reference BCoV strain included in the vaccines currently available in Argentina. However, Mebus-induced antibodies were capable of neutralizing the BCoV Arg95, a field strain adapted to grow in vitro, and vice versa, indicating that both strains belong to the same CoV serotype reported in cattle. This work represents the first large survey describing BCoV circulation in Argentinean cattle. PMID- 26520933 TI - Contributed Review: Absolute spectral radiance calibration of fiber-optic shock temperature pyrometers using a coiled-coil irradiance standard lamp. AB - We describe an accurate and precise calibration procedure for multichannel optical pyrometers such as the 6-channel, 3-ns temporal resolution instrument used in the Caltech experimental geophysics laboratory. We begin with a review of calibration sources for shock temperatures in the 3000-30,000 K range. High power, coiled tungsten halogen standards of spectral irradiance appear to be the only practical alternative to NIST-traceable tungsten ribbon lamps, which are no longer available with large enough calibrated area. However, non-uniform radiance complicates the use of such coiled lamps for reliable and reproducible calibration of pyrometers that employ imaging or relay optics. Careful analysis of documented methods of shock pyrometer calibration to coiled irradiance standard lamps shows that only one technique, not directly applicable in our case, is free of major radiometric errors. We provide a detailed description of the modified Caltech pyrometer instrument and a procedure for its absolute spectral radiance calibration, accurate to +/-5%. We employ a designated central area of a 0.7* demagnified image of a coiled-coil tungsten halogen lamp filament, cross-calibrated against a NIST-traceable tungsten ribbon lamp. We give the results of the cross-calibration along with descriptions of the optical arrangement, data acquisition, and processing. We describe a procedure to characterize the difference between the static and dynamic response of amplified photodetectors, allowing time-dependent photodiode correction factors for spectral radiance histories from shock experiments. We validate correct operation of the modified Caltech pyrometer with actual shock temperature experiments on single-crystal NaCl and MgO and obtain very good agreement with the literature data for these substances. We conclude with a summary of the most essential requirements for error-free calibration of a fiber-optic shock-temperature pyrometer using a high-power coiled tungsten halogen irradiance standard lamp. PMID- 26520934 TI - A trap-based pulsed positron beam optimised for positronium laser spectroscopy. AB - We describe a pulsed positron beam that is optimised for positronium (Ps) laser spectroscopy experiments. The system is based on a two-stage Surko-type buffer gas trap that produces 4 ns wide pulses containing up to 5 * 10(5) positrons at a rate of 0.5-10 Hz. By implanting positrons from the trap into a suitable target material, a dilute positronium gas with an initial density of the order of 10(7) cm(-3) is created in vacuum. This is then probed with pulsed (ns) laser systems, where various Ps-laser interactions have been observed via changes in Ps annihilation rates using a fast gamma ray detector. We demonstrate the capabilities of the apparatus and detection methodology via the observation of Rydberg positronium atoms with principal quantum numbers ranging from 11 to 22 and the Stark broadening of the n = 2 -> 11 transition in electric fields. PMID- 26520935 TI - Creation of cold nitric oxide by extraction of the cold fraction of a thermal distribution. AB - We describe a device using the Stark effect to extract the cold fraction of nitric oxide molecules from a warmer thermal distribution. Room temperature NO is cryogenically cooled to 72-82 K and injected into a straight, hexapole guide that uses the Stark effect. By blocking line-of-sight trajectories from the input to the output, primarily the slowest molecules are guided around the obstruction and are transferred into a new chamber. We measure the temperature distribution using a field-stabilized Rydberg time-of-flight technique. A superposition of molecular Rydberg states is excited, sufficiently increasing the lifetime of the excited state for a time-of-flight measurement for cold molecular samples. We produce a continuous source of nitric oxide with temperatures ranging from 7 to 20 K in the lowest ro-vibrational state. The output temperature is controlled by the initial temperature distribution and the guide voltage. PMID- 26520936 TI - High-resolution setup for measuring wavelength sensitivity of photoyellowing of translucent materials. AB - Polystyrene and many other materials turn yellow when exposed to ultraviolet (UV) radiation. All photodegradation mechanisms including photoyellowing are functions of the exposure wavelength, which can be described with an action spectrum. In this work, a new high-resolution transmittance measurement setup based on lasers has been developed for measuring color changes, such as the photoyellowing of translucent materials aged with a spectrograph. The measurement setup includes 14 power-stabilized laser lines between 325 nm and 933 nm wavelengths, of which one at a time is directed on to the aged sample. The power transmitted through the sample is measured with a silicon detector utilizing an integrating sphere. The sample is mounted on a high-resolution XY translation stage. Measurement at various locations aged with different wavelengths of exposure radiation gives the transmittance data required for acquiring the action spectrum. The combination of a UV spectrograph and the new high-resolution transmittance measurement setup enables a novel method for studying the UV-induced ageing of translucent materials with a spectral resolution of 3-8 nm, limited by the adjustable spectral bandwidth range of the spectrograph. These achievements form a significant improvement over earlier methods. PMID- 26520937 TI - Extending the applicability of an open-ring trap to perform experiments with a single laser-cooled ion. AB - A special ion trap was initially built up to perform beta-nu correlation experiments with radioactive ions. The trap geometry is also well suited to perform experiments with laser-cooled ions, serving for the development of a new type of Penning trap, in the framework of the project TRAPSENSOR at the University of Granada. The goal of this project is to use a single (40)Ca(+) ion as detector for single-ion mass spectrometry. Within this project and without any modification to the initial electrode configuration, it was possible to perform Doppler cooling on (40)Ca(+) ions, starting from large clouds and reaching single ion sensitivity. This new feature of the trap might be important also for other experiments with ions produced at radioactive ion beam facilities. In this publication, the trap and the laser system will be described, together with their performance with respect to laser cooling applied to large ion clouds down to a single ion. PMID- 26520938 TI - A dead-zone free 4He atomic magnetometer with intensity-modulated linearly polarized light and a liquid crystal polarization rotator. AB - We demonstrate an all-optical (4)He atomic magnetometer experimental scheme based on an original Bell-Bloom configuration. A single intensity-modulated linearly polarized laser beam is used both for generating spin polarization within a single (4)He vapor and probing the spin precessing under a static magnetic field. The transmitted light signal from the vapor is then phase-sensitively detected at the modulation frequency and its harmonics, which lead to the atomic magnetic resonance signals. Based on this structure, a liquid crystal is added in our magnetometer system and constitutes a polarization rotator. By controlling the voltage applied on the liquid crystal, the light linear polarization vector can be kept perpendicular with the ambient magnetic field direction, which in turn provides the maximum resonance signal amplitude. Moreover, the system exhibits a magnetic-field noise floor of about 2pT/?Hz, which is not degraded due to the presence of the liquid crystal and varying magnetic field direction. The experiment results prove that our method can eliminate the dead-zone effect, improve the system spatial isotropy, and thus be suitable in mobile applications. PMID- 26520939 TI - Higher certainty of the laser-induced damage threshold test with a redistributing data treatment. AB - As a consequence of its statistical nature, the measurement of the laser-induced damage threshold holds always risks to over- or underestimate the real threshold value. As one of the established measurement procedures, the results of S-on-1 (and 1-on-1) tests outlined in the corresponding ISO standard 21 254 depend on the amount of data points and their distribution over the fluence scale. With the limited space on a test sample as well as the requirements on test site separation and beam sizes, the amount of data from one test is restricted. This paper reports on a way to treat damage test data in order to reduce the statistical error and therefore measurement uncertainty. Three simple assumptions allow for the assignment of one data point to multiple data bins and therefore virtually increase the available data base. PMID- 26520926 TI - Bone mineral density and inflammatory and bone biomarkers after darunavir ritonavir combined with either raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial. AB - BACKGROUND: Osteopenia, osteoporosis, and low bone mineral density are frequent in patients with HIV. We assessed the 96 week loss of bone mineral density associated with a nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI)-sparing regimen. METHODS: Antiretroviral-naive adults with HIV were enrolled in 78 clinical sites in 15 European countries into a randomised (1:1), open-label, non-inferiority trial (NEAT001/ANRS143) assessing the efficacy and safety of darunavir (800 mg once per day) and ritonavir (100 mg once per day) plus either raltegravir (400 mg twice per day; NtRTI-sparing regimen) or tenofovir (245 mg once per day) and emtricitabine (200 mg once per day; standard regimen). For this bone-health substudy, 20 of the original sites in six countries participated, and any patient enrolled at one of these sites who met the following criteria was eligible: plasma viral loads greater than 1000 HIV RNA copies per mL and CD4 cell counts of fewer than 500 cells per MUL, except in those with symptomatic HIV infection. Exclusion criteria included treatment for malignant disease, testing positive for hepatitis B virus surface antigen, pregnancy, creatinine clearance less than 60 mL per min, treatment for osteoporosis, systemic steroids, or oestrogen-replacement therapy. The two primary endpoints were the mean percentage changes in lumbar spine and total hip bone mineral density at week 48, assessed by dual energy x-ray absorptiometry (DXA) scans. We did the analysis with an intention-to-treat-exposed approach with antiretroviral modifications ignored. The parent trial is registered with ClinicalTrials.gov, number NCT01066962, and is closed to new participants. FINDINGS: Between Aug 2, 2010, and April 18, 2011, we recruited 146 patients to the substudy, 70 assigned to the NtRTI-sparing regimen and 76 to the standard regimen. DXA data were available for 129, 121 and 107 patients at baseline, 48 and 96 weeks respectively. At week 48, the mean percentage loss in bone mineral density in the lumbar spine was greater in the standard group than in the NtRTI sparing group (mean percentage change -2.49% vs -1.00%, mean percentage difference -1.49, 95% CI -2.94 to -0.04; p=0.046). Total hip bone mineral density loss was similarly greater at week 48 in the standard group than in the NtRTI sparing group (mean percentage change -3.30% vs -0.73%; mean percentage difference -2.57, 95% CI -3.75 to -1.35; p<0.0001). Seven new fractures occurred during the trial (two in the NtRTI-sparing group and five in the standard group). INTERPRETATION: A raltegravir-based regimen was associated with significantly less loss of bone mineral density than a standard regimen containing tenofovir disoproxil fumarate, and might be a treatment option for patients at high risk of osteopenia or osteoporosis who are not suitable for NtRTIs such as abacavir or tenofovir alafenamide. FUNDING: The European Union Sixth Framework Programme, Inserm-ANRS, Ministerio de Sanidad y Asuntos Sociales de Espana, Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories. PMID- 26520940 TI - A decade-spanning high-resolution asynchronous optical sampling terahertz time domain and frequency comb spectrometer. AB - We present the design and capabilities of a high-resolution, decade-spanning ASynchronous OPtical Sampling (ASOPS)-based TeraHertz Time-Domain Spectroscopy (THz-TDS) instrument. Our system employs dual mode-locked femtosecond Ti:Sapphire oscillators with repetition rates offset locked at 100 Hz via a Phase-Locked Loop (PLL) operating at the 60th harmonic of the ~80 MHz oscillator repetition rates. The respective time delays of the individual laser pulses are scanned across a 12.5 ns window in a laboratory scan time of 10 ms, supporting a time delay resolution as fine as 15.6 fs. The repetition rate of the pump oscillator is synchronized to a Rb frequency standard via a PLL operating at the 12th harmonic of the oscillator repetition rate, achieving milliHertz (mHz) stability. We characterize the timing jitter of the system using an air-spaced etalon, an optical cross correlator, and the phase noise spectrum of the PLL. Spectroscopic applications of ASOPS-THz-TDS are demonstrated by measuring water vapor absorption lines from 0.55 to 3.35 THz and acetonitrile absorption lines from 0.13 to 1.39 THz in a short pathlength gas cell. With 70 min of data acquisition, a 50 dB signal-to-noise ratio is achieved. The achieved root-mean-square deviation is 14.6 MHz, with a mean deviation of 11.6 MHz, for the measured water line center frequencies as compared to the JPL molecular spectroscopy database. Further, with the same instrument and data acquisition hardware, we use the ability to control the repetition rate of the pump oscillator to enable THz frequency comb spectroscopy (THz-FCS). Here, a frequency comb with a tooth width of 5 MHz is generated and used to fully resolve the pure rotational spectrum of acetonitrile with Doppler-limited precision. The oscillator repetition rate stability achieved by our PLL lock circuits enables sub-MHz tooth width generation, if desired. This instrument provides unprecedented decade-spanning, tunable resolution, from 80 MHz down to sub-MHz, and heralds a new generation of gas-phase spectroscopic tools in the THz region. PMID- 26520941 TI - Surface microstructure profilometry based on laser confocal feedback. AB - We demonstrate a surface microstructure profile measurement method, which utilizes the positioning ability of confocal technology and the high sensitivity of frequency-shift feedback of a microchip laser. The surface profile is measured by combination of the amplitude and phase information of the feedback light reflected by the sample. The amplitude information is used for coarse measurement and to determine the integral number of half lasing wavelengths contained in the sample profile variation. The phase information is used for fine measurement and to determine the fractional number. The measurement realizes both a large axial measuring range of tens of microns and a high axial resolution of ~2 nm. Meanwhile, a heterodyne phase measurement approach is introduced to compensate for environmental disturbance and to realize high axial resolution measurement under common room conditions. The surface profile of a grating is measured and proves the feasibility of the method. PMID- 26520942 TI - Femtosecond optical Kerr effect setup with signal "live view" for measurements in the solid, liquid, and gas phases. AB - We present the experimental setup constructed in our laboratory for measurement of the femtosecond optical Kerr effect. The setup allows measurements with high temporal resolution and acquisition speed. The high signal to noise ratio is obtained with use of a homemade balanced detector. Due to the high acquisition speed and good signal to noise ratio, it is possible to have a "live view" of the signal and to easily tune the sample position and orientation before the measurement. We show the example results obtained in the solid, liquid, and the gas phases and we use them in order to check on the precision of our setup. As the samples we have used a YAG crystal, liquid acetone, and atmospheric air. In the latter two cases, a good agreement with the literature data has been found. The measurements in the gas phase confirm that our setup, although utilizing low energy pulses from the sapphire oscillator, is able to acquire high quality rotational signal in a low density sample. PMID- 26520943 TI - Investigation of different magnetic field configurations using an electrical, modular Zeeman slower. AB - We present a method of constructing an automatically reconfigurable, modular, electronic Zeeman slower, which is remotely controlled. This setup is used to investigate the ability of different magnetic field profiles to slow thermal atoms to the capture velocity of a magneto-optical-trap. We show that a simple numerical optimization process yields better results than the commonly used approach for deciding on the appropriate field and comes close to the optimum field, found by utilizing a fast feedback loop which uses a genetic algorithm. Our new numerical method is easily adaptable to a variety of existing slower designs and may be beneficial where feedback is unavailable. PMID- 26520944 TI - Deceleration, precooling, and multi-pass stopping of highly charged ions in Be+ Coulomb crystals. AB - Preparing highly charged ions (HCIs) in a cold and strongly localized state is of particular interest for frequency metrology and tests of possible spatial and temporal variations of the fine structure constant. Our versatile preparation technique is based on the generic modular combination of a pulsed ion source with a cryogenic linear Paul trap. Both instruments are connected by a compact beamline with deceleration and precooling properties. We present its design and commissioning experiments regarding these two functionalities. A pulsed buncher tube allows for the deceleration and longitudinal phase-space compression of the ion pulses. External injection of slow HCIs, specifically Ar(13+), into the linear Paul trap and their subsequent retrapping in the absence of sympathetic cooling is demonstrated. The latter proved to be a necessary prerequisite for the multi-pass stopping of HCIs in continuously laser-cooled Be(+) Coulomb crystals. PMID- 26520945 TI - New two-dimensional space-resolving flux detection technique for measurement of hohlraum inner radiation in Shenguang-III prototype. AB - The space-resolving measurement of X-ray flux from a specific area (laser spot, re-emitting wall, or capsule) inside the hohlraum is an ongoing and critical problem in indirectly driven inertial-confinement fusion experiments. In this work, we developed a new two-dimensional space-resolving flux detection technique to measure the X-ray flux from specific areas inside the hohlraum by using the time- and space-resolving flux detector (SRFD). In two typical hohlraum experiments conducted at the Shenguang-III prototype laser facility, the X-ray flux and radiation temperature from an area 0.2 mm in diameter inside the hohlraum were measured through the laser entrance hole (LEH). The different flux intensities and radiation temperatures detected using the SRFD from the inner area of the LEH were compared with the result measured using the flat-response X ray detector from the entire LEH. This comparison was also analyzed theoretically. The inner area detected using the SRFD was found to be the re emitting wall area alone. This important improvement in space-resolving X-ray flux measurement will enhance the current X-ray flux space characterization techniques, thereby furthering the quantitative understanding of X-ray flux space behavior in the hohlraum. PMID- 26520946 TI - Three-dimensional imaging of carbonyl sulfide and ethyl iodide photodissociation using the pixel imaging mass spectrometry camera. AB - The Pixel Imaging Mass Spectrometry (PImMS) camera is used in proof-of-principle three-dimensional imaging experiments on the photodissociation of carbonyl sulfide and ethyl iodide at wavelengths around 230 nm and 245 nm, respectively. Coupling the PImMS camera with DC-sliced velocity-map imaging allows the complete three-dimensional Newton sphere of photofragment ions to be recorded on each laser pump-probe cycle with a timing precision of 12.5 ns, yielding velocity resolutions along the time-of-flight axis of around 6%-9% in the applications presented. PMID- 26520947 TI - Effect of thermionic cathode heating current self-magnetic field on gaseous plasma generator characteristics. AB - The performance capabilities of the PINK, a plasma generator with a thermionic cathode mounted in the cavity of a hollow cathode, depending for its operation on a non-self-sustained low-pressure gas discharge have been investigated. It has been shown that when a single-filament tungsten cathode 2 mm in diameter is used and the peak filament current is equal to or higher than 100 A, the self-magnetic field of the filament current significantly affects the discharge current and voltage waveforms. This effect is due to changes in the time and space distributions of the emission current density from the hot cathode. When the electron mean free path is close to the characteristic dimensions of the thermionic cathode, the synthesized plasma density distribution is nonuniform and the cathode is etched nonuniformly. The cathode lifetime in this case is 8-12 h. Using a cathode consisting of several parallel-connected tungsten filaments ~0.8 mm in diameter moderates the effect of the self-magnetic field of the filament current and nearly doubles the cathode lifetime. The use of this type of cathode together with a discharge igniting electrode reduces the minimum operating pressure in the plasma generator to about one third of that required for the generator operation with a single-filament cathode (to 0.04 Pa). PMID- 26520948 TI - Radio-frequency ion deflector for mass separation. AB - Electrostatic cylindrical deflectors act as energy analyzer for ion beams. In this article, we present that by imposing of a radio-frequency modulation on the deflecting electric field, the ion transmission becomes mass dependent. By the choice of the appropriate frequency, amplitude, and phase, the deflector can be used as mass filter. The basic concept of the new instrument as well as simple mathematic relations are described. These calculations and further numerical simulations show that a mass sensitivity is achievable. Furthermore, we demonstrate the proof-of-principle in experimental measurements, compare the results to those of from a 1 m linear time-of-flight spectrometer, and comment on the mass resolution of the method. Finally, some potential applications are indicated. PMID- 26520949 TI - Fast ion energy distribution from third harmonic radio frequency heating measured with a single crystal diamond detector at the Joint European Torus. AB - Neutron spectroscopy measurements with a single crystal diamond detector have been carried out at JET, for the first time in an experiment aimed at accelerating deuterons to MeV energies with radio frequency heating at the third harmonic. Data are interpreted by means of the expected response function of the detector and are used to extract parameters of the highly non-Maxwellian distribution function generated in this scenario. A comparison with observations using a time of flight and liquid scintillator neutron spectrometers is also presented. The results demonstrate the capability of diamond detectors to contribute to fast ion physics studies at JET and are of more general relevance in view of the application of such detectors for spectroscopy measurements in the neutron camera of next step tokamak devices. PMID- 26520950 TI - Enhanced electron yield from laser-driven wakefield acceleration in high-Z gas jets. AB - An investigation of the electron beam yield (charge) form helium, nitrogen, and neon gas jet plasmas in a typical laser-plasma wakefield acceleration experiment is carried out. The charge measurement is made by imaging the electron beam intensity profile on a fluorescent screen into a charge coupled device which was cross-calibrated with an integrated current transformer. The dependence of electron beam charge on the laser and plasma conditions for the aforementioned gases are studied. We found that laser-driven wakefield acceleration in low Z-gas jet targets usually generates high-quality and well-collimated electron beams with modest yields at the level of 10-100 pC. On the other hand, filamentary electron beams which are observed from high-Z gases at higher densities reached much higher yields. Evidences for cluster formation were clearly observed in the nitrogen gas jet target, where we received the highest electron beam charge of ~1.7 nC. Those intense electron beams will be beneficial for the applications on the generation of bright X-rays, gamma rays radiations, and energetic positrons via the bremsstrahlung or inverse-scattering processes. PMID- 26520951 TI - Influence of lithium coating on the optics of Doppler backscatter system. AB - This paper presents the first investigation of the effect of lithium coating on the optics of Doppler backscattering. A liquid lithium limiter has been applied in the Experimental Advanced Superconducting Tokamak (EAST), and a Doppler backscattering has been installed in the EAST. A parabolic mirror and a flat mirror located in the vacuum vessel are polluted by lithium. An identical optical system of the Doppler backscattering is set up in laboratory. The power distributions of the emission beam after the two mirrors with and without lithium coating (cleaned before and after), are measured at three different distances under four incident frequencies. The results demonstrate that the influence of the lithium coating on the power distributions are very slight, and the Doppler backscattering can work normally under the dosage of lithium during the 2014 EAST campaign. PMID- 26520952 TI - Design and installation of a ferromagnetic wall in tokamak geometry. AB - Low-activation ferritic steels are leading material candidates for use in next generation fusion development experiments such as a prospective component test facility and DEMO power reactor. Understanding the interaction of plasmas with a ferromagnetic wall will provide crucial physics for these facilities. In order to study ferromagnetic effects in toroidal geometry, a ferritic wall upgrade was designed and installed in the High Beta Tokamak-Extended Pulse (HBT-EP). Several material options were investigated based on conductivity, magnetic permeability, vacuum compatibility, and other criteria, and the material of choice (high-cobalt steel) is characterized. Installation was accomplished quickly, with minimal impact on existing diagnostics and overall machine performance, and initial results demonstrate the effects of the ferritic wall on plasma stability. PMID- 26520953 TI - Continuous wave cavity ring-down spectroscopy for velocity distribution measurements in plasma. AB - We report the development of a continuous wave cavity ring-down spectroscopic (CW CRDS) diagnostic for real-time, in situ measurement of velocity distribution functions of ions and neutral atoms in plasma. This apparatus is less complex than conventional CW-CRDS systems. We provide a detailed description of the CW CRDS apparatus as well as measurements of argon ions and neutrals in a high density (10(9) cm(-3) < plasma density <10(13) cm(-3)) plasma. The CW-CRDS measurements are validated through comparison with laser induced fluorescence measurements of the same absorbing states of the ions and neutrals. PMID- 26520954 TI - Halo current diagnostic system of experimental advanced superconducting tokamak. AB - The design, calibration, and installation of disruption halo current sensors for the Experimental Advanced Superconducting Tokamak are described in this article. All the sensors are Rogowski coils that surround conducting structures, and all the signals are analog integrated. Coils with two different cross-section sizes have been fabricated, and their mutual inductances are calibrated. Sensors have been installed to measure halo currents in several different parts of both the upper divertor (tungsten) and lower divertor (graphite) at several toroidal locations. Initial measurements from disruptions show that the halo current diagnostics are working well. PMID- 26520955 TI - Development of a tunable Fabry-Perot etalon-based near-infrared interference spectrometer for measurement of the HeI 23S-23P spectral line shape in magnetically confined torus plasmas. AB - In magnetically confined torus plasmas, the local emission intensity, temperature, and flow velocity of atoms in the inboard and outboard scrape-off layers can be separately measured by a passive emission spectroscopy assisted by observation of the Zeeman splitting in their spectral line shape. To utilize this technique, a near-infrared interference spectrometer optimized for the observation of the helium 2(3)S-2(3)P transition spectral line (wavelength 1083 nm) has been developed. The applicability of the technique to actual torus devices is elucidated by calculating the spectral line shapes expected to be observed in LHD and QUEST (Q-shu University Experiment with Steady State Spherical Tokamak). In addition, the Zeeman effect on the spectral line shape is measured using a glow-discharge tube installed in a superconducting magnet. PMID- 26520956 TI - Investigations of a high current linear aperture radial multichannel pseudospark switch. AB - In this paper, a high current linear aperture radial multichannel Pseudospark switch (LARM-PSS) is reported which has been analyzed for its high current characteristics. In order to enhance hold-off voltage and support hollow cathode effect for the ignition of the discharge in this configuration, the field penetration analysis through circular and linear apertures of the electrodes has been carried out. The linear apertures in the electrodes increase the current handling capacity than that of circular aperture electrodes without significant compromise of the hold-off capacity. The developed LARM-PSS switch is capable to hold voltage up to 25 kV at gas pressure between 10 and 50 Pa for hydrogen. The switch has been operated using a 800 nF capacitor bank and conducted an effective charge up to 1.5 C with peak switch current ~20 kA at applied voltage 19 kV. PMID- 26520957 TI - Spatial calibration of a tokamak neutral beam diagnostic using in situ neutral beam emission. AB - Neutral beam injection is used in tokamaks to heat, apply torque, drive non inductive current, and diagnose plasmas. Neutral beam diagnostics need accurate spatial calibrations to benefit from the measurement localization provided by the neutral beam. A new technique has been developed that uses in situ measurements of neutral beam emission to determine the spatial location of the beam and the associated diagnostic views. This technique was developed to improve the charge exchange recombination (CER) diagnostic at the DIII-D tokamak and uses measurements of the Doppler shift and Stark splitting of neutral beam emission made by that diagnostic. These measurements contain information about the geometric relation between the diagnostic views and the neutral beams when they are injecting power. This information is combined with standard spatial calibration measurements to create an integrated spatial calibration that provides a more complete description of the neutral beam-CER system. The integrated spatial calibration results are very similar to the standard calibration results and derived quantities from CER measurements are unchanged within their measurement errors. The methods developed to perform the integrated spatial calibration could be useful for tokamaks with limited physical access. PMID- 26520958 TI - Experimental determination of some equilibrium parameter of Damavand tokamak by magnetic probe measurements for representing a physical model for plasma vertical movement. AB - This investigation is about plasma modeling for the control of vertical instabilities in Damavand tokamak. This model is based on online magnetic measurement. The algebraic equation defining the vertical position in this model is based on instantaneous force-balance. Two parameters in this equation, including decay index, n, and lambda, Lambda, have been considered as functions of time-varying poloidal field coil currents and plasma current. Then these functions have been used in a code generated for modeling the open loop response of plasma. The main restriction of the suitability analysis of the model is that the experiments always have to be performed in the presence of a control loop for stabilizing vertical position. As a result, open loop response of the system has been identified from closed loop experimental data by nonlinear neural network identification method. The results of comparison of physical model with identified open loop response from closed loop experiments show root mean square error percentage less than 10%. The results are satisfying that the physical model is useful as a Damavand tokamak vertical movement simulator. PMID- 26520959 TI - Use of a priori spectral information in the measurement of x-ray flux with filtered diode arrays. AB - Filtered x-ray diode (XRD) arrays are often used to measure x-ray spectra vs. time from spectrally continuous x-ray sources such as hohlraums. A priori models of the incident x-ray spectrum enable a more accurate unfolding of the x-ray flux as compared to the standard technique of modifying a thermal Planckian with spectral peaks or dips at the response energy of each filtered XRD channel. A model x-ray spectrum consisting of a thermal Planckian, a Gaussian at higher energy, and (in some cases) a high energy background provides an excellent fit to XRD-array measurements of x-ray emission from laser heated hohlraums. If high resolution measurements of part of the x-ray emission spectrum are available, that information can be included in the a priori model. In cases where the x-ray emission spectrum is not Planckian, candidate x-ray spectra can be allowed or excluded by fitting them to measured XRD voltages. Examples are presented from the filtered XRD arrays, named Dante, at the National Ignition Facility and the Laboratory for Laser Energetics. PMID- 26520960 TI - High bandwidth deflection readout for atomic force microscopes. AB - This contribution presents the systematic design of a high bandwidth deflection readout mechanism for atomic force microscopes. The widely used optical beam deflection method is revised by adding a focusing lens between the cantilever and the quadrant photodetector (QPD). This allows the utilization of QPDs with a small active area resulting in an increased detection bandwidth due to the reduced junction capacitance. Furthermore the additional lens can compensate a cross talk between a compensating z-movement of the cantilever and the deflection readout. Scaling effects are analyzed to get the optimal spot size for the given geometry of the QPD. The laser power is tuned to maximize the signal to noise ratio without limiting the bandwidth by local saturation effects. The systematic approach results in a measured -3 dB detection bandwidth of 64.5 MHz at a deflection noise density of 62fm/?Hz. PMID- 26520961 TI - Sub-50 nm metrology on extreme ultra violet chemically amplified resist--A systematic assessment. AB - With lithographic patterning dimensions decreasing well below 50 nm, it is of high importance to understand metrology at such small scales. This paper presents results obtained from dense arrays of contact holes (CHs) with various Critical Dimension (CD) between 15 and 50 nm, as patterned in a chemically amplified resist using an ASML EUV scanner and measured at ASML and TNO. To determine the differences between various (local) CD metrology techniques, we conducted an experiment using optical scatterometry, CD-Scanning Electron Microscopy (CD-SEM), Helium ion Microscopy (HIM), and Atomic Force Microscopy (AFM). CD-SEM requires advanced beam scan strategies to mitigate sample charging; the other tools did not need that. We discuss the observed main similarities and differences between the various techniques. To this end, we assessed the spatial frequency content in the raw images for SEM, HIM, and AFM. HIM and AFM resolve the highest spatial frequencies, which are attributed to the more localized probe-sample interaction for these techniques. Furthermore, the SEM, HIM, and AFM waveforms are analyzed in detail. All techniques show good mutual correlation, albeit the reported CD values systematically differ significantly. HIM systematically reports a 25% higher CD uniformity number than CD-SEM for the same arrays of CHs, probably because HIM has a higher resolution than the CD-SEM used in this assessment. A significant speed boost for HIM and AFM is required before these techniques are to serve the demanding industrial metrology applications like optical critical dimension and CD-SEM do nowadays. PMID- 26520962 TI - Autopilot for frequency-modulation atomic force microscopy. AB - One of the most challenging aspects of operating an atomic force microscope (AFM) is finding optimal feedback parameters. This statement applies particularly to frequency-modulation AFM (FM-AFM), which utilizes three feedback loops to control the cantilever excitation amplitude, cantilever excitation frequency, and z-piezo extension. These loops are regulated by a set of feedback parameters, tuned by the user to optimize stability, sensitivity, and noise in the imaging process. Optimization of these parameters is difficult due to the coupling between the frequency and z-piezo feedback loops by the non-linear tip-sample interaction. Four proportional-integral (PI) parameters and two lock-in parameters regulating these loops require simultaneous optimization in the presence of a varying unknown tip-sample coupling. Presently, this optimization is done manually in a tedious process of trial and error. Here, we report on the development and implementation of an algorithm that computes the control parameters automatically. The algorithm reads the unperturbed cantilever resonance frequency, its quality factor, and the z-piezo driving signal power spectral density. It analyzes the poles and zeros of the total closed loop transfer function, extracts the unknown tip-sample transfer function, and finds four PI parameters and two lock-in parameters for the frequency and z-piezo control loops that optimize the bandwidth and step response of the total system. Implementation of the algorithm in a home-built AFM shows that the calculated parameters are consistently excellent and rarely require further tweaking by the user. The new algorithm saves the precious time of experienced users, facilitates utilization of FM-AFM by casual users, and removes the main hurdle on the way to fully automated FM-AFM. PMID- 26520963 TI - Spherical quartz crystals investigated with synchrotron radiation. AB - The quality of x-ray spectra and images obtained from plasmas with spherically bent crystals depends in part on the crystal's x-ray diffraction across the entire crystal surface. We employ the energy selectivity and high intensity of synchrotron radiation to examine typical spherical crystals from alpha-quartz for their diffraction quality, in a perpendicular geometry that is particularly convenient to examine sagittal focusing. The crystal's local diffraction is not ideal: the most noticeable problems come from isolated regions that so far have failed to correlate with visible imperfections. Excluding diffraction from such problem spots has little effect on the focus beyond a decrease in background. PMID- 26520964 TI - Background oriented schlieren in a density stratified fluid. AB - Non-intrusive quantitative fluid density measurement methods are essential in the stratified flow experiments. Digital imaging leads to synthetic schlieren methods in which the variations of the index of refraction are reconstructed computationally. In this study, an extension to one of these methods, called background oriented schlieren, is proposed. The extension enables an accurate reconstruction of the density field in stratified liquid experiments. Typically, the experiments are performed by the light source, background pattern, and the camera positioned on the opposite sides of a transparent vessel. The multimedia imaging through air-glass-water-glass-air leads to an additional aberration that destroys the reconstruction. A two-step calibration and image remapping transform are the key components that correct the images through the stratified media and provide a non-intrusive full-field density measurements of transparent liquids. PMID- 26520965 TI - Simultaneous dynamic electrical and structural measurements of functional materials. AB - A new materials characterization system developed at the XMaS beamline, located at the European Synchrotron Radiation Facility in France, is presented. We show that this new capability allows to measure the atomic structural evolution (crystallography) of piezoelectric materials whilst simultaneously measuring the overall strain characteristics and electrical response to dynamically (ac) applied external stimuli. PMID- 26520966 TI - A finger-like hardness tester based on the contact electromechanical impedance of a piezoelectric bimorph cantilever. AB - We proposed a finger-like hardness tester based on the electromechanical impedance of a piezoelectric bimorph cantilever. A Vickers indenter was fabricated to the free end of the bimorph to contact the sample. The contact force was monitored by a strain gauge and the contact area was obtained by tracking the bimorph's resonance frequency. The bimorph-sample contact system was modeled by the electromechanical equivalent circuit method. Verification experiments on standard hardness samples were conducted and the measured hardness values agreed well with those given by a conventional Vickers hardness tester. Further hardness measurement on a gear wheel showed that the proposed hardness tester is very adaptive and can be used for inner surface testing or in situ testing, where other hardness testers may not be applicable. The proposed hardness tester can be regarded as an improved ultrasonic hardness tester. PMID- 26520967 TI - Direct measurements of the magnetic entropy change. AB - An experimental device that can accurately measure the magnetic entropy change, Deltas, as a function of temperature, T, and magnetic field, H, is presented. The magnetic field source is in this case a set of counter-rotating concentric Halbach-type magnets, which produce a highly homogeneous applied field with constant orientation. The field may be varied from 0 to 1.5 T in a continuous way. The temperature stability of the system is controlled to within +/-10 mK and the standard range for the current setup is from 230 K to 330 K. The device is under high vacuum and we show that thermal losses to the ambient are negligible in terms of the calorimetric determination of the magnetic entropy change, while the losses cannot be ignored when correcting for the actual sample temperature. We apply the device to two different types of samples; one is commercial grade Gd, i.e., a pure second-order phase transition material, while the other is Gd5Si2Ge2, a first order magnetic phase transition material. We demonstrate the device's ability to fully capture the thermal hysteresis of the latter sample by following appropriate thermal resetting scheme and magnetic resetting scheme. PMID- 26520968 TI - A device for the application of uniaxial strain to single crystal samples for use in synchrotron radiation experiments. AB - We present the design, construction, and testing of a straining device compatible with many different synchrotron radiation techniques, in a wide range of experimental environments (including low temperature, high field and ultra-high vacuum). The device has been tested by X-ray diffraction on single crystal samples of quasi-one-dimensional Cs2Mo6Se6 and K2Mo6Se6, in which microscopic strains up to a Deltac/c = 0.12% +/- 0.01% change in the c lattice parameters have been achieved. We have also used the device in an inelastic X-ray scattering experiment, to probe the strain-dependent speed of sound nu along the c axis. A reduction Deltanu/nu of up to -3.8% was obtained at a strain of Deltac/c = 0.25% in K2Mo6Se6. PMID- 26520969 TI - A reactor for high-throughput high-pressure nuclear magnetic resonance spectroscopy. AB - The design of a reactor for operando nuclear magnetic resonance (NMR) monitoring of high-pressure gas-liquid reactions is described. The Wisconsin High Pressure NMR Reactor (WiHP-NMRR) design comprises four modules: a sapphire NMR tube with titanium tube holder rated for pressures as high as 1000 psig (68 atm) and temperatures ranging from -90 to 90 degrees C, a gas circulation system that maintains equilibrium concentrations of dissolved gases during gas-consuming or gas-releasing reactions, a liquid injection apparatus that is capable of adding measured amounts of solutions to the reactor under high pressure conditions, and a rapid wash system that enables the reactor to be cleaned without removal from the NMR instrument. The WiHP-NMRR is compatible with commercial 10 mm NMR probes. Reactions performed in the WiHP-NMRR yield high quality, information-rich, and multinuclear NMR data over the entire reaction time course with rapid experimental turnaround. PMID- 26520970 TI - A structurally decoupled mechanism for measuring wrist torque in three degrees of freedom. AB - The wrist joint is a critical part of the human body for movement. Measuring the torque of the wrist with three degrees of freedom (DOFs) is important in some fields, including rehabilitation, biomechanics, ergonomics, and human-machine interfacing. However, the particular structure of the wrist joint makes it difficult to measure the torque in all three directions simultaneously. This work develops a structurally decoupled instrument for measuring and improving the measurement accuracy of 3-DOF wrist torque during isometric contraction. Three single-axis torque sensors were embedded in a customized mechanical structure. The dimensions and components of the instrument were designed based on requirement of manufacturability. A prototype of the instrument was machined, assembled, integrated, and tested. The results show that the structurally decoupled mechanism is feasible for acquiring wrist torque data in three directions either independently or simultaneously. As a case study, we use the device to measure wrist torques concurrently with electromyography signal acquisition in preparation for simultaneous and proportional myoelectric control of prostheses. PMID- 26520972 TI - Generation of flat-top pulsed magnetic fields with feedback control approach. AB - We describe the construction of a simple, compact, and cost-effective feedback system that produces flat-top field profiles in pulsed magnetic fields. This system is designed for use in conjunction with a typical capacitor-bank driven pulsed magnet and was tested using a 60-T pulsed magnet. With the developed feedback controller, we have demonstrated flat-top magnetic fields as high as 60.64 T with an excellent field stability of +/-0.005 T. The result indicates that the flat-top pulsed magnetic field produced features high field stability and an accessible field strength. These features make this system useful for improving the resolution of data with signal averaging. PMID- 26520971 TI - A novel polydimethylsiloxane microfluidic viscometer fabricated using microwire molding. AB - We present a new economical microfluidic viscometer to measure the viscosity of biological fluids, using sample volumes of less than 200 MUl. It is fabricated using a microwire-molding technique, making it easier and cheaper to produce than existing viscometers. The viscometer is based on laminar flow inside a polydimethylsiloxane microchip. The velocity of the sample flow inside the capillary was monitored with a camera, and the movement of the liquid column was determined by a Matlab video-processing program. The device was calibrated using deionized water, which is a Newtonian fluid, at 20 degrees C. The viscometer provides accurate measurements of viscosity for values as small as 0.69 mPa s. The viscosity of water at different temperatures was measured, showing more than 98% agreement with the values provided by the National Institute of Standards and Technology. Various samples including a series of glycerol solutions, phosphate buffered saline, alcohol, and cell media were also tested, and the measured viscosities were compared with those from a traditional glass capillary viscometer. The results show good agreement between the two methods, with an average relative error of less than 1%. Furthermore, the viscosities of several cell suspensions were measured, showing a relative standard deviation of less than 1.5%. The microchip viscometer is economical and is shown to be accurate, which is very important for the simulation and control of lab-on-a-chip experiments. PMID- 26520973 TI - The design and implementation of a multi-waveform radar echo simulator. AB - Radar simulator is an effective tool for performance assessment of radar systems by accurately reproducing echo signals from complicated environment. This paper presents a design of fast multi-waveform radar echo generation based on deconvolution method. First, scene information is retrieved from outfield data based on improved conjugate gradient algorithm. Then, the new radar echoes are generated through convolution of new transmitted signal and restored scene information. A fast and area-efficient field programmable gate array realization is provided to meet the real-time requirement of radar echo simulation. Finally, a series of experiments are performed to evaluate the effectiveness of proposed radar simulation instrument. PMID- 26520974 TI - Preliminary experimental investigation of a complex dual-band high power microwave source. AB - In order to promote the power conversion efficiency of a magnetically insulated transmission line oscillator (MILO) and obtain microwaves in dual bands, an axially extracted C-band virtual cathode oscillator (VCO) with multiple resonant cavities is introduced to partially utilize the load current of an S-band MILO. The formed novel dual-band high power microwave source called MILO and VCO is investigated with simulation and experimentally. A dual-band radiation antenna is designed to effectively radiate microwaves generated by the MILO and the VCO, respectively, while avoiding them being influenced by the microwave reflection and diffraction. The preliminary experimental results measured by the dual-band diagnostic system show that both the MILO and the VCO operate normally under repeated shots. A microwave of 2.1 GHz, 1.70 GW is generated from the MILO and a 0.37 GW microwave at frequencies of 4.1 GHz and 3.8 GHz is generated from the VCO under the condition of about 440 kV and 35 kA. Compared with a single MILO (10.6%), a MILO and VCO achieves higher total power and efficiency (13.4%) in both S and C bands, indicating that the load current of the MILO partially couples into the beam-wave interaction in the VCO and then contributes to the output microwaves. However, more works are needed regarding the spectrum purification of the VCO and promotion of the output power of both the MILO and the VCO. PMID- 26520975 TI - Theory and experiment research for ultra-low frequency maglev vibration sensor. AB - A new maglev sensor is proposed to measure ultra-low frequency (ULF) vibration, which uses hybrid-magnet levitation structure with electromagnets and permanent magnets as the supporting component, rather than the conventional spring structure of magnetoelectric vibration sensor. Since the lower measurement limit needs to be reduced, the equivalent bearing stiffness coefficient and the equivalent damping coefficient are adjusted by the sensitivity unit structure of the sensor and the closed-loop control system, which realizes both the closed loop control and the solving algorithms. A simple sensor experimental platform is then assembled based on a digital hardware system, and experimental results demonstrate that the lower measurement limit of the sensor is increased to 0.2 Hz under these experimental conditions, indicating promising results of the maglev sensor for ULF vibration measurements. PMID- 26520976 TI - A three-axis SQUID-based absolute vector magnetometer. AB - We report on the development of a three-axis absolute vector magnetometer suited for mobile operation in the Earth's magnetic field. It is based on low critical temperature dc superconducting quantum interference devices (LTS dc SQUIDs) with sub-micrometer sized cross-type Josephson junctions and exhibits a white noise level of about 10 fT/Hz(1/2). The width of superconducting strip lines is restricted to less than 6 MUm in order to avoid flux trapping during cool-down in magnetically unshielded environment. The long-term stability of the flux-to voltage transfer coefficients of the SQUID electronics is investigated in detail and a method is presented to significantly increase their reproducibility. We further demonstrate the long-term operation of the setup in a magnetic field varying by about 200 MUT amplitude without the need for recalibration. PMID- 26520977 TI - A generalized analytical compliance model for cartwheel flexure hinges. AB - Normal cartwheel flexure hinge (NCFH) typically consists of two flexible springs crossing at their mid points. These have been used in compliant mechanism applications owing to the large motion range of such hinges. In this paper, a novel generalized cartwheel flexure hinge (GCFH) is proposed by modifying spring number and varying the angle between two springs on the basis of the NCFH. A 6 degrees of freedom (6-DOF) compliance model of the GCFH was derived. Validity of this model was demonstrated using finite element analysis simulation and experimental results on a GCFH with 3 pairs of springs and 70 degrees angle. According to the model, influence of distribution and shape parameters of GCFH on performance was analyzed. Characteristics such as compliance, off-axis/axis compliance ratio, motion precision, and capacity of rotation were determined. Results show that the GCFH can achieve improved performance compared to NCFH with optimized GCFH parameters. PMID- 26520978 TI - Cryocooled terahertz photoconductive detector system with background-limited performance in 1.5-4 THz frequency range. AB - We describe a 4-K-cryocooled dual-band terahertz (THz) photoconductive detector system with background-limited performance. The detector system comprises two THz photoconductive detectors covering a response in a wide frequency range from 1.5 to 4 THz, low noise amplifiers, optical low-pass filters to eliminate input radiation of higher frequencies, and a mechanical 4 K Gifford-McMahon refrigerator that provides practical and convenient operation without a liquid He container. The electrical and optical performances of the THz detector system were evaluated at a detector temperature of 4 K under 300 K background radiation. We proved that the detector system can achieve background-limited noise equivalent-power on the order of 10(-14) W/Hz(1/2) in the frequency range from 1.5 to 4 THz even if the vibration noise of the mechanical refrigerator is present. PMID- 26520979 TI - Versatile setup for optical spectroscopy under high pressure and low temperature. AB - We present an optical setup for spectroscopic measurements in the infrared and of Raman shift under high pressure and at low temperature. Using a membrane-driven diamond anvil cell, the pressure can be tuned in situ up to 20 GPa and the temperatures ranges from room temperature down to 18 K in transmission mode and 13 K in reflection mode. In transmission, the setup is entirely working under vacuum to reduce the water absorption features and obtain a higher spectral stability. Since the infrared throughput obtained with a thermal source is limited, the use of a synchrotron source allowed to enhance the performance, as illustrated with results obtained with various materials. The analysis of the reflectivity is adapted so that it benefits from ambient pressure data and produces quantitative optical conductivity curves that can be easily compared to the results at ambient pressure. PMID- 26520980 TI - Versatile magnetometer assembly for characterizing magnetic properties of nanoparticles. AB - We constructed a versatile magnetometer assembly for characterizing iron oxide nanoparticles. The magnetometer can be operated at room temperature or inside a cryocooler at temperatures as low as 6 K. The magnetometer's sensor can be easily exchanged and different detection electronics can be used. We tested the assembly with a non-cryogenic commercial Hall sensor and a benchtop multimeter in a four wire resistance measurement scheme. A magnetic moment sensitivity of 8.5 * 10(-8) Am(2) was obtained with this configuration. To illustrate the capability of the assembly, we synthesized iron oxide nanoparticles coated with different amounts of a triblock copolymer, Pluronic F-127, and characterized their magnetic properties. We determined that the polymer coating does not affect the magnetization of the particles at room temperature and demonstrates that it is possible to estimate the average size of coating layers from measurements of the magnetic field of the sample. PMID- 26520981 TI - Nonlinear stability research on the hydraulic system of double-side rolling shear. AB - This paper researches the stability of the nonlinear system taking the hydraulic system of double-side rolling shear as an example. The hydraulic system of double side rolling shear uses unsymmetrical electro-hydraulic proportional servo valve to control the cylinder with single piston rod, which can make best use of the space and reduce reversing shock. It is a typical nonlinear structure. The nonlinear state-space equations of the unsymmetrical valve controlling cylinder system are built first, and the second Lyapunov method is used to evaluate its stability. Second, the software AMEsim is applied to simulate the nonlinear system, and the results indicate that the system is stable. At last, the experimental results show that the system unsymmetrical valve controlling the cylinder with single piston rod is stable and conforms to what is deduced by theoretical analysis and simulation. The construction and application of Lyapunov function not only provide the theoretical basis for using of unsymmetrical valve controlling cylinder with single piston rod but also develop a new thought for nonlinear stability evaluation. PMID- 26520982 TI - A compact E * B filter: A multi-collector cycloidal focusing mass spectrometer. AB - A compact E * B mass spectrometer is presented. The mass spectrometer presented is termed a "perfect focus" mass spectrometer as the resolution of the device is independent of both the initial direction and energy of the ions (spatial and energy independent). The mass spectrometer is small in size (~10.7 in.(3)) and weight (~2 kg), making it an attractive candidate for portability when using small, permanent magnets. A multi-collector Faraday cup design allows for the detection of multiple ion beams in discrete collectors simultaneously; providing the opportunity for isotope ratio monitoring. The mass resolution of the device is around 400 through narrow collector slits and the sensitivity of the device follows expected theoretical calculations of the ion current produced in the electron impact ion source. Example mass spectra obtained from the cycloidal focusing mass spectrometer are presented as well as information on mass discrimination based on instrumental parameters and isotope ratio monitoring of certain ion signals in separate Faraday cups. PMID- 26520983 TI - A method to analyze molecular tagging velocimetry data using the Hough transform. AB - The development of a method to analyze molecular tagging velocimetry data based on the Hough transform is presented. This method, based on line fitting, parameterizes the grid lines "written" into a flowfield. Initial proof-of principle illustration of this method was performed to obtain two-component velocity measurements in the wake of a cylinder in a Mach 4.6 flow, using a data set derived from computational fluid dynamics simulations. The Hough transform is attractive for molecular tagging velocimetry applications since it is capable of discriminating spurious features that can have a biasing effect in the fitting process. Assessment of the precision and accuracy of the method were also performed to show the dependence on analysis window size and signal-to-noise levels. The accuracy of this Hough transform-based method to quantify intersection displacements was determined to be comparable to cross-correlation methods. The employed line parameterization avoids the assumption of linearity in the vicinity of each intersection, which is important in the limit of drastic grid deformations resulting from large velocity gradients common in high-speed flow applications. This Hough transform method has the potential to enable the direct and spatially accurate measurement of local vorticity, which is important in applications involving turbulent flowfields. Finally, two-component velocity determinations using the Hough transform from experimentally obtained images are presented, demonstrating the feasibility of the proposed analysis method. PMID- 26520984 TI - Feasibility study of monitoring of plasma etching chamber conditions using superimposed high-frequency signals on rf power transmission line. AB - An in situ monitoring system that can detect changes in the conditions of a plasma etching chamber has been developed. In the system, low-intensity high frequency signals are superimposed on the rf power transmission line used for generating plasma. The system measures reflected high-frequency signals and detects the change in their frequency characteristics. The results indicate that the system detects the changes in the conditions in etching chambers caused by the changes in the electrode gap and the inner wall condition and demonstrate the effectiveness of the system. The system can easily be retrofitted to mass production equipment and it can be used with or without plasma discharge. Therefore, our system is suitable for in situ monitoring of mass-production plasma etching chambers. The system is expected to contribute to development of predictive maintenance, which monitors films deposited on the inner wall of the chamber and prevents equipment faults caused by misalignment of chamber parts in mass-production equipment. PMID- 26520985 TI - High-temperature apparatus for chaotic mixing of natural silicate melts. AB - A unique high-temperature apparatus was developed to trigger chaotic mixing at high-temperature (up to 1800 degrees C). This new apparatus, which we term Chaotic Magma Mixing Apparatus (COMMA), is designed to carry out experiments with high-temperature and high-viscosity (up to 10(6) Pa s) natural silicate melts. This instrument allows us to follow in time and space the evolution of the mixing process and the associated modulation of chemical composition. This is essential to understand the dynamics of magma mixing and related chemical exchanges. The COMMA device is tested by mixing natural melts from Aeolian Islands (Italy). The experiment was performed at 1180 degrees C using shoshonite and rhyolite melts, resulting in a viscosity ratio of more than three orders of magnitude. This viscosity ratio is close to the maximum possible ratio of viscosity between high temperature natural silicate melts. Results indicate that the generated mixing structures are topologically identical to those observed in natural volcanic rocks highlighting the enormous potential of the COMMA to replicate, as a first approximation, the same mixing patterns observed in the natural environment. COMMA can be used to investigate in detail the space and time development of magma mixing providing information about this fundamental petrological and volcanological process that would be impossible to investigate by direct observations. Among the potentials of this new experimental device is the construction of empirical relationships relating the mixing time, obtained through experimental time series, and chemical exchanges between the melts to constrain the mixing-to-eruption time of volcanic systems, a fundamental topic in volcanic hazard assessment. PMID- 26520986 TI - An atmospheric pressure high-temperature laminar flow reactor for investigation of combustion and related gas phase reaction systems. AB - A new high-temperature flow reactor experiment utilizing the powerful molecular beam mass spectrometry (MBMS) technique for detailed observation of gas phase kinetics in reacting flows is presented. The reactor design provides a consequent extension of the experimental portfolio of validation experiments for combustion reaction kinetics. Temperatures up to 1800 K are applicable by three individually controlled temperature zones with this atmospheric pressure flow reactor. Detailed speciation data are obtained using the sensitive MBMS technique, providing in situ access to almost all chemical species involved in the combustion process, including highly reactive species such as radicals. Strategies for quantifying the experimental data are presented alongside a careful analysis of the characterization of the experimental boundary conditions to enable precise numeric reproduction of the experimental results. The general capabilities of this new analytical tool for the investigation of reacting flows are demonstrated for a selected range of conditions, fuels, and applications. A detailed dataset for the well-known gaseous fuels, methane and ethylene, is provided and used to verify the experimental approach. Furthermore, application for liquid fuels and fuel components important for technical combustors like gas turbines and engines is demonstrated. Besides the detailed investigation of novel fuels and fuel components, the wide range of operation conditions gives access to extended combustion topics, such as super rich conditions at high temperature important for gasification processes, or the peroxy chemistry governing the low temperature oxidation regime. These demonstrations are accompanied by a first kinetic modeling approach, examining the opportunities for model validation purposes. PMID- 26520987 TI - Research of weak pulsed magnetic field system derived from the time, displacement, and static magnetic field. AB - The accurate measurement of dynamic characteristics in weak magnetic sensors is urgently required as a greater number of applications for these devices are found. In this paper, a novel weak pulsed magnetic field system is presented. The underlying principle is to drive a permanent magnet passing another magnet rapidly, producing a pulsed weak magnetic field. The magnitude of the field can be adjusted by changing the velocity and distance between the two magnets. The standard value of the pulsed dynamic magnetic field can be traced back to the accurate measurement of time, displacement, and static magnetic field. In this study a detailed procedure for producing a pulse magnetic field system using the above method is outlined after which a theoretical analysis of the permanent magnet movement is discussed. Using the described apparatus a milli-second level pulse-width with a milli-Tesla magnetic field magnitude is used to study the dynamic characteristics of a giant magnetoresistance sensor. We conclude by suggesting possible improvements to the described apparatus. PMID- 26520988 TI - A temperature oscillation instrument to determine pyroelectric properties of materials at low frequencies: Towards elimination of lock-in methods. AB - Pyroelectric properties of materials can be accurately determined by applying a new digital signal processing method on the discrete sampled data obtained with a temperature oscillation technique. The pyroelectric coefficient is calculated from the component of the generated current 90 degrees out of phase with respect to the sinusoidal temperature wave. The novelty of the proposed approach lies in the signal analysis procedure which implements a simple Fast Fourier transform that filters residual noise through convolution, and calculates the phase difference between the peaks of the temperature and current waves. The new idea requires relatively simple hardware and enables very accurate measurement of the pyroelectric coefficient of materials at ultra low frequencies, 1-250 mHz, without using costly lock-in amplifiers. PMID- 26520989 TI - A novel flexure-based vertical nanopositioning stage with large travel range. AB - This paper presents the design of a novel flexure-based vertical (or Z-axis) nanopositioning stage driven by a piezoelectric actuator (PZT), which is capable of executing large travel range. The proposed stage consists mainly of a hybrid displacement amplification mechanism (DAM), a motion guiding mechanism, and a decoupling mechanism. The hybrid DAM with amplification ratio of 12.1 is developed to transfer the transverse motion of the PZT actuator into the vertical motion. The motion guiding mechanism is introduced to avoid cross coupling at the output end. The decoupling mechanism can significantly reduce the cross coupling at the driving end to protect the PZT. The stiffness and dynamics of the proposed stage are improved by these mechanisms. Analytical modeling and finite element analysis (FEA) are then adopted to optimize dimensions of the stage. Finally, a prototype of the stage is fabricated and tested for verification. The results of static and dynamic tests show that the proposed stage is capable of vertical travel range of 214 MUm with resolution of 8 nm, and the first two resonance frequencies are 205 Hz and 1206 Hz, respectively. Cross coupling tests under various lateral loads (0 g-1000 g) show that the maximum variances of the lateral and angular cross couplings are less than 0.78 MUm and 95 MUrad, respectively, indicating good decoupling capability. In addition, the low-profile structure of the stage is well suited to be used in limited vertical space. PMID- 26520990 TI - Mimicking Martian dust: An in-vacuum dust deposition system for testing the ultraviolet sensors on the Curiosity rover. AB - We have designed and developed an in-vacuum dust deposition system specifically conceived to simulate and study the effect of accumulation of Martian dust on the electronic instruments of scientific planetary exploration missions. We have used this device to characterize the dust effect on the UV sensor of the Rover Environmental Monitoring Station in the Mars science Laboratory mission of NASA in similar conditions to those found on Mars surface. The UV sensor includes six photodiodes for measuring the radiation in all UV wavelengths (direct incidence and reflected); it is placed on the body of Curiosity rover and it is severely affected by the dust deposited on it. Our experimental setup can help to estimate the duration of reliable reading of this instrument during operation. We have used an analogous of the Martian dust in chemical composition (magnetic species), color, and density, which has been characterized by X-ray spectroscopy. To ensure a Brownian motion of the dust during its fall and a homogeneous coverage on the instrumentation, the operating conditions of the vacuum vessel, determined by partial pressures and temperature, have to be modified to account for the different gravities of Mars with respect to Earth. We propose that our designed device and operational protocol can be of interest to test optoelectronic instrumentation affected by the opacity of dust, as can be the degradation of UV photodiodes in planetary exploration. PMID- 26520991 TI - A servo controlled gradient loading triaxial model test system for deep-buried cavern. AB - A servo controlled gradient loading model test system is developed to simulate the gradient geostress in deep-buried cavern. This system consists of the gradient loading apparatus, the digital servo control device, and the measurement system. Among them, the gradient loading apparatus is the main component which is used for exerting load onto the model. This loading apparatus is placed inside the counterforce wall/beam and is divided to several different loading zones, with each loading zone independently controlled. This design enables the gradient loading. Hence, the "real" geostress field surrounding the deep-buried cavern can be simulated. The loading or unloading process can be controlled by the human computer interaction machines, i.e., the digital servo control system. It realizes the automation and visualization of model loading/unloading. In addition, this digital servo could control and regulate hydraulic loading instantaneously, which stabilizes the geostress onto the model over a long term. During the loading procedure, the collision between two adjacent loading platens is also eliminated by developing a guide frame. This collision phenomenon is induced by the volume shrinkage of the model when compressed in true 3D state. In addition, several accurate measurements, including the optical and grating-based method, are adopted to monitor the small deformation of the model. Hence, the distortion of the model could be accurately measured. In order to validate the performance of this innovative model test system, a 3D geomechanical test was conducted on a simulated deep-buried underground reservoir. The result shows that the radial convergence increases rapidly with the release of the stress in the reservoir. Moreover, the deformation increases with the increase of the gas production rate. This observation is consistence with field observation in petroleum engineering. The system is therefore capable of testing deep-buried engineering structures. PMID- 26520992 TI - Compact test apparatus for evaluation of flow erosion of marine coatings. AB - An apparatus designed and manufactured for evaluation of flow erosion of coatings or layers is presented in this paper. The setup was primarily designed for coatings intended to perform in dynamic marine environments but can be also used for evaluation using fresh water. The concept is based on an in-line flow test cell and modular design allowing good flexibility of varying testing parameters. The flow rate that can be achieved depends on the flow cell geometry and can reach 28 km/h (15 kn) with the presented setup. Temperature may be adjusted between 15 and 35 degrees C. Particle and metal ion filters are parts of this setup. The dimensions of the apparatus including all components do not exceed 2 m * 2 m * 2 m. The use of the apparatus is illustrated with the results of evaluation of self-polishing anti-fouling coatings and model, silicon wafer grafted layers. PMID- 26520993 TI - Sub-micro-Newton resolution thrust balance. AB - Herein is described a sensitive vacuum balance for measuring the thrust produced by small (~0.5 kg) thrusters typically employed in microsat station-keeping. The balance is based on a torsion design but incorporates jewel-pivot bearings instead of the more typical torsion spring bearings. Novel tilt control allows maintenance of true verticality of the bearing axis even while under vacuum. The low moment of inertia design allows it to measure small thrusts from high-voltage devices without direct wire conductor connections. Calibration by several means is described including use of a previously calibrated dielectric barrier discharge thruster. PMID- 26520994 TI - Fatigue reliability based optimal design of planar compliant micropositioning stages. AB - Conventional compliant micropositioning stages are usually developed based on static strength and deterministic methods, which may lead to either unsafe or excessive designs. This paper presents a fatigue reliability analysis and optimal design of a three-degree-of-freedom (3 DOF) flexure-based micropositioning stage. Kinematic, modal, static, and fatigue stress modelling of the stage were conducted using the finite element method. The maximum equivalent fatigue stress in the hinges was derived using sequential quadratic programming. The fatigue strength of the hinges was obtained by considering various influencing factors. On this basis, the fatigue reliability of the hinges was analysed using the stress-strength interference method. Fatigue-reliability-based optimal design of the stage was then conducted using the genetic algorithm and MATLAB. To make fatigue life testing easier, a 1 DOF stage was then optimized and manufactured. Experimental results demonstrate the validity of the approach. PMID- 26520995 TI - Kinematic analysis of in situ measurement during chemical mechanical planarization process. AB - Chemical mechanical planarization (CMP) is the most widely used planarization technique in semiconductor manufacturing presently. With the aid of in situ measurement technology, CMP tools can achieve good performance and stable productivity. However, the in situ measurement has remained unexplored from a kinematic standpoint. The available related resources for the kinematic analysis are very limited due to the complexity and technical secret. In this paper, a comprehensive kinematic analysis of in situ measurement is provided, including the analysis model, the measurement trajectory, and the measurement time of each zone of wafer surface during the practical CMP process. In addition, a lot of numerical calculations are performed to study the influences of main parameters on the measurement trajectory and the measurement velocity variation of the probe during the measurement process. All the efforts are expected to improve the in situ measurement system and promote the advancement in CMP control system. PMID- 26520996 TI - High temperature setup for measurements of Seebeck coefficient and electrical resistivity of thin films using inductive heating. AB - We have developed an automated setup for simultaneous measurement of Seebeck coefficient S(T) and electrical resistivity rho(T) of thin film samples from room temperature to ~650 degrees C. S and rho are extracted from current-voltage (I V) measurements obtained using a semiconductor parameter analyzer and temperature measurements obtained using commercial thermocouples. The slope and the x-axis intercept of the I-V characteristics represent the sample conductance G and the Seebeck voltage, respectively. The measured G(T) can be scaled to rho(T) by the geometry factor obtained from the room temperature resistivity measurement of the film. The setup uses resistive or inductive heating to control the temperature and temperature gradient on the sample. Inductive heating is achieved with steel plates that surround the test area and a water cooled copper pipe coil underneath that generates an AC magnetic field. The measurements can be performed using resistive heating only or inductive heating only, or a combination of both depending on the desired heating ranges. Inductive heating provides a more uniform heating of the test area, does not require contacts to the sample holder, can be used up to the Curie temperature of the particular magnetic material, and the temperature gradients can be adjusted by the relative positions of the coil and sample. Example results obtained for low doped single-crystal silicon with inductive heating only and with resistive heating only are presented. PMID- 26520997 TI - A one-dimensional ion beam figuring system for x-ray mirror fabrication. AB - We report on the development of a one-dimensional Ion Beam Figuring (IBF) system for x-ray mirror polishing. Ion beam figuring provides a highly deterministic method for the final precision figuring of optical components with advantages over conventional methods. The system is based on a state of the art sputtering deposition system outfitted with a gridded radio frequency inductive coupled plasma ion beam source equipped with ion optics and dedicated slit developed specifically for this application. The production of an IBF system able to produce an elongated removal function rather than circular is presented in this paper, where we describe in detail the technical aspect and present the first obtained results. PMID- 26520998 TI - Note: Small anaerobic chamber for optical spectroscopy. AB - The study of oxygen-sensitive biological samples requires an effective control of the atmosphere in which they are housed. In this aim however, no commercial anaerobic chamber is adequate to solely enclose the sample and small enough to fit in a compact spectroscopic system with which analysis can be performed. Furthermore, spectroscopic analysis requires the probe beam to pass through the whole chamber, introducing a requirement for adequate windows. In response to these challenges, we present a 1 l anaerobic chamber that is suitable for broad band spectroscopic analysis. This chamber has the advantage of (1) providing access, via a septum, to the sample and (2) allows the sample position to be adjusted while keeping the chamber fixed and hermetic during the experiment. PMID- 26520999 TI - Note: Ion-induced secondary electron emission from oxidized metal surfaces measured in a particle beam reactor. AB - The secondary electron emission of metals induced by slow ions is characterized in a beam chamber by means of two coaxial semi-cylindrical electrodes with different apertures. The voltages of the outer electrode (screening), inner electrode (collector), and sample holder (target) were set independently in order to measure the effective yield of potential and kinetic electron emissions during ion bombardment. Aluminum samples were exposed to quantified beams of argon ions up to 2000 eV and to oxygen atoms and molecules in order to mimic the plasma surface interactions on metallic targets during reactive sputtering. The variation of electron emission yield was correlated to the ion energy and to the oxidation state of Al surfaces. This system provides reliable measurements of the electron yields in real time and is of great utility to explore the fundamental surface processes during target poisoning occurring in reactive magnetron sputtering applications. PMID- 26521000 TI - Note: Dissolved hydrogen detection in power transformer oil based on chemically etched fiber Bragg grating. AB - A fiber Bragg grating (FBG) sensor based on chemically etched cladding to detect dissolved hydrogen is proposed and studied in this paper. Low hydrogen concentration tests have been carried out in mixed gases and transformer oil to investigate the repeatability and sensitivity. Moreover, to estimate the influence of etched cladding thickness, a physical model of FBG-based hydrogen sensor is analyzed. Experimental results prove that thin cladding chemically etched by HF acid solution improves the response to hydrogen detection in oil effectively. At last, the sensitivity of FBG sensor chemically etched 16 MUm could be as high as 0.060 pm/(MUl/l), increased by more than 30% in comparison to un-etched FBG. PMID- 26521001 TI - Note: Void effects on eddy current distortion in two-phase liquid metal. AB - A model based on the first order perturbation expansion of magnetic flux in a two phase liquid metal flow has been developed for low magnetic Reynolds number Rem. This model takes into account the distortion of the induced eddy currents due to the presence of void in the conducting medium. Specific experiments with an eddy current flow meter have been realized for two periodic void distributions. The results have shown, in agreement with the model, that the effects of velocity and void on the emf modulation are decoupled. The magnitude of the void fraction and the void spatial frequency can be determined from the spectral density of the demodulated emf. PMID- 26521002 TI - Note: Fabrication of a fast-response and user-friendly environmental chamber for atomic force microscopes. AB - The atomic force microscope is one of the most widespread tools in science, but many suppliers do not provide a competitive solution to make experiments in controlled atmospheres. Here, we provide a solution to this problem by fabricating a fast-response and user-friendly environmental chamber. We corroborate the correct functioning of the chamber by studying the formation of local anodic oxidation on a silicon sample (biased under opposite polarities), an effect that can be suppressed by measuring in a dry nitrogen atmosphere. The usefulness of this chamber goes beyond the example here presented, and it could be used in many other fields of science, including physics, mechanics, microelectronics, nanotechnology, medicine, and biology. PMID- 26521003 TI - Note: Vibration suppression using tunable vibration absorber based on stiffness variable magneto-rheological gel. AB - This paper proposes a novel adaptive tunable vibration absorber (TVA) based on a smart material the magnetorheological gel (MRG) to achieve a wide range of tonal vibration suppression on the primary system to protect any connected sensitive device. The vibration suppression performance of the MRG TVA was analyzed by conducting a modal test of the primary system under different magnetic fields. The experiment verified that the proposed MRG TVA can be controlled to produce 379% of stiffness change or 115% of tuning frequency under just 200 mT magnetic field. The proposed MRG TVA was found to possess a wider tuning frequency range than the TVA based on other smart material such as magnetorheological elastomer. PMID- 26521004 TI - Note: Model identification and analysis of bivalent analyte surface plasmon resonance data. AB - Surface plasmon resonance (SPR) is a widely used, affinity based, label-free biophysical technique to investigate biomolecular interactions. The extraction of rate constants requires accurate identification of the particular binding model. The bivalent analyte model involves coupled non-linear differential equations. No clear procedure to identify the bivalent analyte mechanism has been established. In this report, we propose a unique signature for the bivalent analyte model. This signature can be used to distinguish the bivalent analyte model from other biphasic models. The proposed method is demonstrated using experimentally measured SPR sensorgrams. PMID- 26521005 TI - Note: Design of a full photon-timing recorder down to 1-ns resolution for fluorescence fluctuation measurements. AB - A photon timing recorder was realized in a field programmable gate array to capture all timing data of photons on multiple channels with down to a 1-ns resolution and to transfer all data to a host computer in real-time through universal serial bus with more than 10 M events/s transfer rate. The main concept is that photon time series can be regarded as a serial communication data stream. This recorder was successfully applied for simultaneous measurements of fluorescence fluctuation and lifetime of near-infrared dyes in solution. This design is not only limited to the fluorescence fluctuation measurement but also applicable to any kind of photon counting experiments in a nanosecond time range because of the simple and easily modifiable design. PMID- 26521006 TI - Note: A rectangular pulse generator for 50 kV voltage, 0.8 ns rise time, and 10 ns pulse width based on polymer-film switch. AB - In this article, we describe a rectangular pulse generator, consisting of a polymer-film switch, a tri-plate transmission line, and parallel post-shaped ceramic resistor load, for 50-kV voltage, 0.8-ns rise time, and 10-ns width. The switch and resistors are arranged in atmospheric air and the transmission line can work in atmospheric air or in transformer oil to change the pulse width from 6.7 ns to 10 ns. The fast switching and low-inductance characteristics of the polymer-film switch ensure the fast rising wavefront of <1 ns. This generator can be applied in the calibration of nanosecond voltage dividers and used for electromagnetic pulse tests as a fast-rising current injection source. PMID- 26521007 TI - Note: Reliable, robust measurement system for trace moisture in gas at parts-per trillion levels using cavity ring-down spectroscopy. AB - We report a simple, robust cavity ring-down spectroscopy system to reliably measure trace moisture in gases at parts-per-trillion (ppt) levels. The performance of the system was evaluated on the basis of experiments performed in a manner traceable to the International System of Units. The obtained result was in good agreement with the primary trace-moisture standard at 12 nmol/mol (12 ppb) in N2 in amount-of-substance fraction. Measurement capability of residual moisture in high-purity dry N2 at ~130 pmol/mol (130 ppt) was demonstrated, and background noise of 5.3 * 10(-12) cm(-1) was attained, corresponding to a minimum detectable H2O of 5 pmol/mol (5 ppt). PMID- 26521008 TI - Note: Non-invasive optical method for rapid determination of alignment degree of oriented nanofibrous layers. AB - This paper presents a rapid non-destructive method that provides information on the anisotropic internal structure of nanofibrous layers. A laser beam of a wavelength of 632.8 nm is directed at and passes through a nanofibrous layer prepared by electrostatic spinning. Information about the structural arrangement of nanofibers in the layer is directly visible in the form of a diffraction image formed on a projection screen or obtained from measured intensities of the laser beam passing through the sample which are determined by the dependency of the angle of the main direction of polarization of the laser beam on the axis of alignment of nanofibers in the sample. Both optical methods were verified on Polyvinyl alcohol (PVA) nanofibrous layers (fiber diameter of 470 nm) with random, single-axis aligned and crossed structures. The obtained results match the results of commonly used methods which apply the analysis of electron microscope images. The presented simple method not only allows samples to be analysed much more rapidly and without damaging them but it also makes possible the analysis of much larger areas, up to several square millimetres, at the same time. PMID- 26521009 TI - Note: Effective anvil size for transverse delamination test of rare-earth Ba2Cu3Oy coated conductor tapes. AB - In coated conductor (CC) tapes used in magnet and coil applications, delamination due to excessive transverse tensile stresses is still one of the major issues that need considerations. Recently, several methods in evaluating the delamination strength of CC tapes are being used. In the case of anvil test, size of the anvils will be an important factor considering its applications (i.e., superconducting coil impregnation). In this study, delamination strength of CC tape was examined using different upper anvil sizes and their effects were discussed. Finally, reasonable sizes of upper anvil to be used were proposed considering the application conditions. PMID- 26521011 TI - Fibulin-3 fragments are prognostic biomarkers of osteoarthritis incidence in overweight and obese women. AB - OBJECTIVE: To determine the association between three fibulin-3 peptides and the incidence of radiographic and clinical knee osteoarthritis (OA). DESIGN: Women between 50 and 60 years, with a BMI >=27 kg/m(2), free of knee OA, were recruited. Using binary logistic regression, the association between baseline concentration of serum fibulin (Fib)3-1, Fib3-2 and Fib3-3 and incidence of clinical and radiographic knee OA after 30 months of follow-up was evaluated. RESULTS: Baseline and follow-up measurements were available for 241 women with a mean age of 55.9 +/- 3.2 years and mean BMI of 31.7 +/- 3.6 kg/m(2). None of the concentrations of the three Fib3 epitopes were associated with the incidence of medial or lateral joint space narrowing (JSN) >=1.0 mm or the incidence of Kellgren & Lawrence (K&L) grade >=2 after 30 months. All three Fib3 epitopes were associated with the incidence of the clinical and radiographic ACR-criteria and Fib3-1 and Fib3-3 also with chronic pain at follow-up. When adjusted for the other Fib3 peptide concentrations, only Fib3-1 was significantly associated to the incidence of the American College of Rheumatology (ACR)-criteria (OR 3.2 [1.2 8.7]) and chronic pain at follow-up (OR 3.0 [1.2-7.7]). CONCLUSIONS: Baseline fibulin-3 concentrations are associated with the incidence of clinical knee OA among middle-aged overweight and obese women. Therewith, they meet the criteria of a prognostic biomarker according to the BIPED biomarker classification for OA. Further validation of the fibulin-3 epitopes seems warranted in order to better distinguish subgroups of individuals at increased risk for knee OA development. PMID- 26521012 TI - Residual hip dysplasia at 1 year after treatment for neonatal hip instability is not related to degenerative joint disease in young adulthood: a 21-year follow-up study including dGEMRIC. AB - OBJECTIVE: Developmental dysplasia of the hip (DDH) is associated with an increased risk of early hip osteoarthritis (OA). We aimed to examine the outcome at the completion of growth in a cohort of children who had residual acetabular dysplasia at age 1 year following early treatment for neonatal instability of the hip (NIH). DESIGN: We examined 21 of 30 subjects who had been treated with the von Rosen splint neonatally for NIH and had residual acetabular dysplasia at age 1 year. Mean follow-up time was 21 years (range 17-24). Signs of OA and acetabular dysplasia were assessed by radiography. Cartilage quality was assessed by delayed Gadolinium Enhanced Magnetic Resonance Imaging of Cartilage (dGEMRIC), a tool for molecular imaging of cartilage quality, at 1.5 T. Patient reported outcome (PRO) was assessed by the 12-item WOMAC score. RESULTS: No study participant had radiographic OA (defined as Kellgren-Lawrence grade >=2) or minimum joint space width (JSW) <=2 mm. The mean dGEMRIC index was 630 ms (95% CI: 600-666, range: 516-825) suggesting good cartilage quality. The mean 12-item WOMAC score was 1.2. Two of three radiographic measurements of DDH correlated positively to the dGEMRIC index. CONCLUSIONS: Children treated neonatally for NIH have good hip function and no signs of cartilage degeneration at 21-year follow up, despite residual dysplasia at age 1 year. Unexpectedly, radiographic signs of dysplasia were associated with better cartilage quality, as assessed with dGEMRIC. This may indicate cartilage adaptation to increased mechanical stress in mild hip dysplasia. PMID- 26521013 TI - Australian diagnosis related groups: Drivers of complexity adjustment. AB - BACKGROUND: In undertaking a major revision to the Australian Refined Diagnosis Related Group (ARDRG) classification, we set out to contrast Australia's approach to using data on additional (not principal) diagnoses with major international approaches in splitting base or Adjacent Diagnosis Related Groups (ADRGs). METHODS: Comparative policy analysis/narrative review of peer-reviewed and grey literature on international approaches to use of additional (secondary) diagnoses in the development of Australian and international DRG systems. ANALYSIS: European and US approaches to characterise complexity of inpatient care are well documented, providing useful points of comparison with Australia's. Australia, with good data sources, has continued to refine its national DRG classification using increasingly sophisticated approaches. Hospital funders in Australia and in other systems are often under pressure from provider groups to expand classifications to reflect clinical complexity. DRG development in most healthcare systems reviewed here reflects four critical factors: these socio political factors, the quality and depth of the coded data available to characterise the mix of cases in a healthcare system, the size of the underlying population, and the intended scope and use of the classification. Australia's relatively small national population has constrained the size of its DRG classifications, and development has been concentrated on inpatient care in public hospitals. DISCUSSION AND CONCLUSIONS: Development of casemix classifications in health care is driven by both technical and socio-political factors. Use of additional diagnoses to adjust for patient complexity and cost needs to respond to these in each casemix application. PMID- 26521014 TI - Clinical effects of buprenorphine on open field behaviour and gait symmetry in healthy and lame weaned piglets. AB - Lameness in pigs decreases animal welfare and economic profit for the farmer. An important reason for impaired welfare in lame animals is pain due to lameness. No direct measurement of pain is possible in animals, and methods to indirectly detect and quantify the amount of pain an animal is experiencing are urgently needed. In this study, two methods to assess pain associated with lameness in pigs were evaluated to determine if they were sensitive enough to detect a lameness reduction as an effect of an experimental analgesic medication. Asymmetry associated with lameness was objectively quantified using pressure mat kinetic parameters: peak vertical force (PVF), load rate (LR), vertical impulse (VI) and peak vertical pressure (PVP). Locomotor activity was assessed in an open field test. A dose of 0.04 mg/kg buprenorphine, a strong analgesic, was used to treat 10 lame pigs, while eight other lame pigs, treated with physiological saline solution, served as controls. Buprenorphine decreased lameness-associated asymmetry for pressure mat LR (P = 0.002), VI (P = 0.003) and PVP (P = 0.001) and increased activity of the lame pigs in the open field (P = 0.023), while saline treated animals did not show any changes in asymmetry and became less active in the open field (P <0.001). It was concluded that measurement of gait asymmetry by pressure mat analysis and locomotor activity in an open field test are both sensitive enough to detect the analgesic effects of buprenorphine when used to treat moderate to severe clinical pain in a relatively small group of affected pigs. The methods used in this study may also provide promising additional tools for future research into early pain recognition and lameness treatment in pigs. PMID- 26521015 TI - A broad scope knowledge based model for optimization of VMAT in esophageal cancer: validation and assessment of plan quality among different treatment centers. AB - BACKGROUND: To evaluate the performance of a broad scope model-based optimisation process for volumetric modulated arc therapy applied to esophageal cancer. METHODS AND MATERIALS: A set of 70 previously treated patients in two different institutions, were selected to train a model for the prediction of dose-volume constraints. The model was built with a broad-scope purpose, aiming to be effective for different dose prescriptions and tumour localisations. It was validated on three groups of patients from the same institution and from another clinic not providing patients for the training phase. Comparison of the automated plans was done against reference cases given by the clinically accepted plans. RESULTS: Quantitative improvements (statistically significant for the majority of the analysed dose-volume parameters) were observed between the benchmark and the test plans. Of 624 dose-volume objectives assessed for plan evaluation, in 21 cases (3.3 %) the reference plans failed to respect the constraints while the model-based plans succeeded. Only in 3 cases (<0.5 %) the reference plans passed the criteria while the model-based failed. In 5.3 % of the cases both groups of plans failed and in the remaining cases both passed the tests. CONCLUSIONS: Plans were optimised using a broad scope knowledge-based model to determine the dose volume constraints. The results showed dosimetric improvements when compared to the benchmark data. Particularly the plans optimised for patients from the third centre, not participating to the training, resulted in superior quality. The data suggests that the new engine is reliable and could encourage its application to clinical practice. PMID- 26521016 TI - VPS35-deficiency results in an impaired AMPA receptor trafficking and decreased dendritic spine maturation. AB - BACKGROUND: Vacuolar protein sorting 35 (VPS35), a key component of retromer, plays an important role in endosome-to-Golgi retrieval of membrane proteins. Dysfunction of VPS35/retromer is a risk factor for neurodegenerative disorders, including AD (Alzheimer's disease) and PD (Parkinson's disease). However, exactly how VPS35-deficiency contributes to AD or PD pathogenesis remains poorly understood. RESULTS: We found that VPS35-deficiency impaired dendritic spine maturation and decreased glutamatergic transmission. AMPA receptors, GluA1 and GluA2, are significantly reduced in purified synaptosomal and PSD fractions from VPS35-deficient brain. The surface levels of AMPA receptors are also decreased in VPS35-deficient neurons. Additionally, VPS35 interacted with AMPA-type receptors, GluA1 and GluA2. Overexpression of GluA2, but not GluA1, could partially restore the spine maturation deficit in VPS35-deficient neurons. CONCLUSIONS: These results provide evidence for VPS35's function in promoting spine maturation, which is likely through increasing AMPA receptor targeting to the postsynaptic membrane. Perturbation of such a VPS35/retromer function may contribute to the impaired glutamatergic transmission and pathogenesis of neurodegenerative disorders, such as AD and PD. PMID- 26521017 TI - Impairment of PI3K/AKT and WNT/beta-catenin pathways in bone marrow mesenchymal stem cells isolated from patients with myelodysplastic syndromes. AB - Bone marrow mesenchymal stem cells (BM-MSCs) exhibit multiple abnormalities in myelodysplastic syndromes (MDS), including impaired proliferative and clonogenic capacity, altered morphology, increased senescence, impaired immunoregulatory properties, and reduced hematopoietic support capacity. Common signaling pathways, such as PI3K/AKT and WNT/beta-catenin, regulate multiple MSC properties, including proliferation, differentiation, and cell-cell interaction. Here, with polymerase chain reaction arrays, we investigated the expression of 84 genes belonging to the PI3K/AKT signaling pathways in BM-MSCs isolated from patients with MDS, acute myeloid leukemia, and therapy-related myeloid neoplasms, using as a control BM-MSCs isolated from patients with untreated early-stage lymphomas without BM involvement. Statistically significant downregulation of GSK3beta, SOS1, RASA1, and MTCP1 gene expression was observed in BM-MSCs isolated from patients with de novo MDS, as compared with controls. Moreover, expression of the GSK3beta protein was reduced in MDS-derived MSCs, and was associated with concomitant reduction of phosphorylation at Ser-9. The role of GSK3beta in the downstream WNT/beta-catenin signaling pathway was assessed. We investigated beta catenin protein levels and expression of 84 genes belonging to the WNT target gene pathway using PCR arrays in MDS BM-MSCs, as compared with control BM-MSCs. GSK3beta impairment translated into decreased beta-catenin protein levels and downregulation of several WNT/beta-catenin target genes (SOX9, EGR1, WISP1). These findings suggest that deregulation of genes involved in the PI3K/AKT and WNT signaling pathways may contribute to the phenotypical abnormalities of MDS BM MSCs. PMID- 26521018 TI - The nod-like receptor, Nlrp12, plays an anti-inflammatory role in experimental autoimmune encephalomyelitis. AB - BACKGROUND: Multiple sclerosis (MS) is an organ-specific autoimmune disease resulting in demyelinating plaques throughout the central nervous system. In MS, the exact role of microglia remains unknown. On one hand, they can present antigens, skew T cell responses, and upregulate the expression of pro inflammatory molecules. On the other hand, microglia may express anti inflammatory molecules and inhibit inflammation. Microglia express a wide variety of immune receptors such as nod-like receptors (NLRs). NLRs are intracellular receptors capable of regulating both innate and adaptive immune responses. Among NLRs, Nlrp12 is largely expressed in cells of myeloid origins. It plays a role in immune inflammatory responses by negatively regulating the nuclear factor-kappa B (NF-kappaB) pathway. Thus, we hypothesize that Nlrp12 suppresses inflammation and ameliorates the course of MS. METHODS: We used experimental autoimmune encephalomyelitis (EAE), a well-characterized mouse model of MS. EAE was induced in wild-type (WT) and Nlrp12 (-/-) mice with myelin oligodendrocyte glycoprotein (MOG):complete Freud's adjuvant (CFA). The spinal cords of healthy and immunized mice were extracted for immunofluorescence and pro-inflammatory gene analysis. Primary murine cortical microglia cell cultures of WT and Nlrp12 (-/-) were prepared with cortices of 1-day-old pups. The cells were stimulated with lipopolysaccharide (LPS) and analyzed for the expression of pro-inflammatory genes as well as pro-inflammatory molecule secretions. RESULTS: Over the course of 9 weeks, the Nlrp12 (-/-) mice demonstrated increased severity in the disease state, where they developed the disease earlier and reached significantly higher clinical scores compared to the WT mice. The spinal cords of immunized WT mice relative to healthy WT mice revealed a significant increase in Nlrp12 messenger ribonucleic acid (mRNA) expression at 1, 3, and 5 weeks post injection. A significant increase in the expression of pro-inflammatory genes Ccr5, Cox2, and IL-1beta was found in the spinal cords of the Nlrp12 (-/-) mice relative to the WT mice (P < 0.05). A significant increase in the level of gliosis was observed in the spinal cords of the Nlrp12 (-/-) mice compared to the WT mice after 9 weeks of disease (P < 0.05). Primary Nlrp12 (-/-) microglia cells demonstrated a significant increase in inducible nitric oxide synthase (iNOS) expression (P < 0.05) and secreted significantly (P < 0.05) more tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), and nitric oxide (NO). CONCLUSION: Nlrp12 plays a protective role by suppressing inflammation during the development of EAE. The absence of Nlrp12 results in an increased inflammatory response. PMID- 26521019 TI - Treatment of early non-response in patients with schizophrenia: assessing the efficacy of antipsychotic dose escalation. AB - BACKGROUND: Early non-response to antipsychotic treatment in patients with schizophrenia has been shown in multiple studies to predict poor response at short-term trial endpoint. Therefore, strategies to address the challenge of non improvement early in the course of treatment are needed. A novel trial design was developed to assess the potential utility of antipsychotic dose escalation in patients with an inadequate initial treatment response. This design was embedded in a study intended to assess the efficacy of low dose lurasidone in patients with schizophrenia. The purpose of this report is to describe the background, rationale and design of this study that included a novel method for the assessment of the potential for dose-response in early non-responding patients with schizophrenia. METHODS/DESIGN: In this 6-week, international, multicenter, double-blind trial, eligible adults with acute schizophrenia were randomized to receive fixed doses of lurasidone 20 mg/day, 80 mg/day (active control), or placebo in a 1:2:1 ratio. Patients initially randomized to lurasidone 80 mg/day who did not have a Positive and Negative Syndrome Scale total score improvement >= 20% at Week 2 were re-randomized on a 1:1 basis to receive either lurasidone 80 mg/day or lurasidone 160 mg/day for the remainder of the trial. All other groups remained on their initially assigned treatment. The formal primary objective of the study was to evaluate the efficacy of low-dose lurasidone (20 mg/day) compared to placebo; secondary objectives included evaluating the efficacy of lurasidone 80 mg/day versus 160 mg/day in early non-responders, and evaluating the efficacy of lurasidone in all subjects initially randomized to 80 mg/day versus placebo. DISCUSSION: Since a lack of early improvement predicts poor response to short-term antipsychotic treatment in patients with schizophrenia, several treatment strategies have been proposed to enhance treatment outcome in early non-responders. A novel clinical trial design involving a placebo arm and re-randomization of early non-responders to increased or maintained antipsychotic dose was developed. The study design described in this report provides a robust method to assess the value of antipsychotic dose escalation in patients with schizophrenia who demonstrate poor initial treatment response. TRIAL REGISTRATION: ClinicalTrials.gov NCT01821378; initial registration March 22, 2013. PMID- 26521020 TI - Violacein induces apoptosis in human breast cancer cells through up regulation of BAX, p53 and down regulation of MDM2. AB - We aimed to explore the anticancer potential of violacein and its time, dose dependent mechanism of action in human MCF-7 breast cancer cells. We observed, violacein inhibit MCF-7 cells viability in a time and dose-dependent manner, IC50 value was 4.5 MUM in 24 h, 1.7 MUM in 48 h and 0.51 MUM in 72 h. Violacein triggered generation of intra cellular ROS even from the lower doses, significant ROS production was observed from 0.25, 0.45 MUM dose range and it is relative to higher doses. Further we fixed 0.45 MUM and 4.5 MUM as an experimental dose for relative dose dependent analysis. In nuclear staining, after 48 h 0.45 MUM dose showed characteristic apoptotic morphological changes such as, 59% of cells in apoptosis and 11% of cells in necrotic stage, also in 72 h we found 68% in apoptosis and 12% in necrotic stage. However, 4.5 MUM (IC50) dose of violacein, 78% of cells became apoptotic and 21% in necrotic after 48 h; but in 72 h only 61% cells are in apoptotic, necrosis was increased to 38%. Violacein increased both mitochondrial and extra mitochondrial apoptotic pathway related gene expressions; it was confirmed by increased CYP1A, GPX, GSK3beta and TNF-alpha gene. Further, 0.45 and 4.5 MUM of violacein increased apoptotic genes, such as Bax, p53, caspase 3, Fas, FADD and markedly reduced Bcl-2 and MDM2 expression levels to two fold when compared to control. In addition violacein upregulated poly ADP-ribose polymerase (PARP), CDKN1A and caspase-9 significantly (p<=0.05) when compared to control. Relative quantification of caspase-8 was differently expressed; there were no changes in 0.45 MUM, but in 4.5 MUM we found two fold increased caspase-8 expression. In conclusion, lower dose of violacein treatment induced apoptosis in human breast cancer MCF-7 cells through TNF-alpha and p53 dependent mitochondrial pathways. PMID- 26521021 TI - Differential associations of cardiovascular disease risk factors with relative wealth in urban-dwelling South Africans. AB - BACKGROUND: To examine the associations of cardiovascular disease risk factors (CVDRF) with wealth, defined by the asset index, in 25- to 74-year-old black Africans in Cape Town. METHODS: Assets, including consumer durable goods, and CVDRF were determined in a randomly selected cross-sectional sample. A principal component analysis of the pooled data, based on assets that defined wealth, was used to develop an asset index. Ordinal logistic regression analyses assessed the independent associations of CVDRF with wealth tertiles. RESULTS: Among the 1099 participants, the least poor compared with the poorest tertile had significantly higher prevalence of diabetes (16.3 versus 9.6%), hypercholesterolaemia (33.9 versus 21.4%), obesity (45.4 versus 26.3%) and fat intake >=30% of diet (44.2 versus 29.3%). Daily smoking was highest in the poorest (35.8%) versus the least poor (26.4%). Psychosocial stress (low sense of coherence or locus of control) was significantly higher in poorer participants. In the regression analyses, wealth was associated with male gender [odds ratio (OR): 1.89, 95% confidence interval (CI): 1.37-2.60], urbanization (OR: 1.02, 95% CI: 1.01-1.02), high fat intake, obesity and hypercholesterolaemia. Daily smoking, problematic alcohol use (OR: 0.70, 95% CI: 0.52-0.94) and psychosocial stress were inversely related to wealth. CONCLUSIONS: Differential distribution of CVDRF by wealth mandates incorporating equity components when developing tailored interventions. PMID- 26521022 TI - The Role of Parental Misperception of Child's Body Weight in Childhood Obesity. AB - To investigate the accuracy of parental perceptions of their child's weight status and also the relationship between parental perceptions and the prevalence of childhood obesity in Mississippi. DESIGN AND METHODS: Data from multi-year surveys (2009-2012) with random samples of public school parents (N=14,808). Descriptive statistics and multiple logistic regression were conducted with quantitative data to examine the relationship between parental perception and childhood obesity. RESULTS: More than 2 out of 5 parents misperceived the weight status of their child (k-12). The greatest difference occurred with kindergartners, 83.9% of parents categorized them as "healthy", when only 28.3% actually were. Parents who misperceived their child's weight were almost 12 times more likely of having an obese child. CONCLUSIONS: Only half of the children in this study had a healthy weight (54.5%). Health care providers, nutritionists, social workers, teachers, and school health councils could play an important role in educating parents and children on how to recognize an unhealthy weight. PRACTICE IMPLICATIONS: The strongest predictor of childhood obesity was parental misperception of their child's weight status. PMID- 26521024 TI - "Are we forgetting the smallest, sub 10 nm combustion generated particles?". AB - Although mass emissions of combustion-generated particulate matter have been substantially reduced by new combustion technology, there is still a great concern about the emissions of huge numbers of sub-10 nm particles with insignificant mass. These particles have up to orders of magnitude higher surface area to mass ratios compared to larger particles, have surfaces covered with adsorbed volatile and semi-volatile organic species or even are constituted by such species. Currently there is only very little information available on exposure and related health effects specific for smaller particles and first evidences for long-term health effects has only been recently published. However, the fact that these nanoparticles are not easily measured at the exhausts and in the atmosphere and that their biological activity is obscure does not mean that we can overlook them. There is an urgent need to develop i) reliable methods to measure sub-10 nm particles at the exhaust and in the atmosphere and ii) a robust correlation between the chemical structure of the molecules making up combustion generated nanoparticles and health burden of new combustion technologies. Our attention has to turn to this new class of combustion-generated nanoparticles, which might be the future major constituents of air pollution. PMID- 26521023 TI - Vitamin D and respiratory tract infections in childhood. AB - BACKGROUND: Respiratory tract infections (RTIs) remain among of the most important causes of morbidity and mortality among children. Several studies have associated vitamin D deficiency with an increased risk of RTIs, and vitamin D supplementation has been proposed as a possible preventive measure against RTIs in children. The main aim of this review is to summarize the current evidence from the literature about the link between vitamin D and RTIs in children. DISCUSSION: Several recent studies have shown that vitamin D has different immunomodulatory properties associated with the risk of RTIs in childhood. In this regard, it is very important to understand the definition of deficiency and insufficiency of vitamin D and when and how to treat this condition. Unfortunately, there is no consensus, although a level of at least 10 ng/mL 25 hydroxycholecalciferol (25[OH]D) is thought to be necessary to promote bone mineralization and calcium homeostasis, and a concentration between 20 ng/mL and 50 ng/mL is considered adequate to provide an immunomodulatory effect. Available data support a role for vitamin D deficiency in the risk of pediatric tuberculosis, recurrent acute otitis media, and severe bronchiolitis, whereas further studies are needed to confirm an association in children with recurrent pharyngotonsillitis, acute rhinosinusitis and community-acquired pneumonia. CONCLUSIONS: Maintenance of adequate vitamin D status may be an effective and inexpensive prophylactic method against some RTIs, but the supplementation regimen has not been clearly defined. Further clinical trials are needed to determine the 25(OH)D concentrations associated with an increased risk of RTIs and optimal vitamin D supplementation regimen according to the type of RTI while also taking into consideration vitamin D receptor polymorphisms. PMID- 26521025 TI - Transcriptome sequencing reveals thousands of novel long non-coding RNAs in B cell lymphoma. AB - BACKGROUND: Gene profiling of diffuse large B cell lymphoma (DLBCL) has revealed broad gene expression deregulation compared to normal B cells. While many studies have interrogated well known and annotated genes in DLBCL, none have yet performed a systematic analysis to uncover novel unannotated long non-coding RNAs (lncRNA) in DLBCL. In this study we sought to uncover these lncRNAs by examining RNA-seq data from primary DLBCL tumors and performed supporting analysis to identify potential role of these lncRNAs in DLBCL. METHODS: We performed a systematic analysis of novel lncRNAs from the poly-adenylated transcriptome of 116 primary DLBCL samples. RNA-seq data were processed using de novo transcript assembly pipeline to discover novel lncRNAs in DLBCL. Systematic functional, mutational, cross-species, and co-expression analyses using numerous bioinformatics tools and statistical analysis were performed to characterize these novel lncRNAs. RESULTS: We identified 2,632 novel, multi-exonic lncRNAs expressed in more than one tumor, two-thirds of which are not expressed in normal B cells. Long read single molecule sequencing supports the splicing structure of many of these lncRNAs. More than one-third of novel lncRNAs are differentially expressed between the two major DLBCL subtypes, ABC and GCB. Novel lncRNAs are enriched at DLBCL super-enhancers, with a fraction of them conserved between human and dog lymphomas. We see transposable elements (TE) overlap in the exonic regions; particularly significant in the last exon of the novel lncRNAs suggest potential usage of cryptic TE polyadenylation signals. We identified highly co expressed protein coding genes for at least 88 % of the novel lncRNAs. Functional enrichment analysis of co-expressed genes predicts a potential function for about half of novel lncRNAs. Finally, systematic structural analysis of candidate point mutations (SNVs) suggests that such mutations frequently stabilize lncRNA structures instead of destabilizing them. CONCLUSIONS: Discovery of these 2,632 novel lncRNAs in DLBCL significantly expands the lymphoma transcriptome and our analysis identifies potential roles of these lncRNAs in lymphomagenesis and/or tumor maintenance. For further studies, these novel lncRNAs also provide an abundant source of new targets for antisense oligonucleotide pharmacology, including shared targets between human and dog lymphomas. PMID- 26521026 TI - The interplay between academic performance and quality of life among preclinical students. AB - BACKGROUND: The high academic performance of medical students greatly influences their professional competence in long term career. Meanwhile, medical students greatly demand procuring a good quality of life that can help them sustain their medical career. This study examines validity and reliability of the tool among preclinical students and testifies the influence of their scholastic performance along with gender and academic year on their quality of life. METHODS: A cross sectional study was conducted by distributing World Health Organization Quality of Life, WHOQOL-BREF, survey among medical students of year one to three at Alfaisal University. For validity, item discriminate validity(IDV) and confirmatory factor analysis were measured and for reliability, Cronbach's alpha test and internal item consistency(IIC) were examined. The association of GPA, gender and academic year with all major domains was drawn using Pearson's correlation, independent samples t-test and one-way ANOVA, respectively. RESULTS: A total of 335 preclinical students have responded to this questionnaire. The construct has demonstrated an adequate validity and good reliability. The high academic performance of students positively correlated with physical (r = 0.23, p < 0.001), psychological health (r = 0.29, p < 0.001), social relations (r = 0.11, p = 0.03) and environment (r = 0.23, p < 0.001). Male student scored higher than female peers in physical and psychological health. DISCUSSION: This study has identified a direct relationship between the academic performance of preclinical students and their quality of life. CONCLUSION: The WHOQOL-BREF is a valid and reliable tool among preclinical students and the positive direction of high academic performance with greater QOL suggests that academic achievers procure higher satisfaction and poor achievers need a special attention for the improvement of their quality of life. PMID- 26521027 TI - The role of income inequality and social policies on income-related health inequalities in Europe. AB - INTRODUCTION: The aim of the paper is to examine the role of income inequality and redistribution for income-related health inequalities in Europe. This paper contributes in two ways to the literature on macro determinants of socio-economic inequalities in health. First, it widens the distinctive focus of the research field on welfare state regimes to quantifiable measures such as social policy indicators. Second, looking at income differences completes studies on socio economic health inequalities, which often analyse health inequalities based on educational differences. METHODS: Using data from the European Values Study (2008/2009), 42 European countries are available for analysis. Country characteristics are derived from SWIID, Eurostat, and ILO and include indicators for income inequality, social policies, and economic performance. The data is analysed by using a two-step hierarchical estimation approach: At the first step the individual level-the effect of household income on self-assessed health is extracted and introduced as an indicator measuring income-related health inequalities at the second step, the country-level. RESULTS: Individual-level analyses reveal that income-related health inequalities exist all across Europe. Results from country-level analyses show that higher income inequality is significantly positively related to higher health inequalities while social policies do not show significant relations. Nevertheless, the results show the expected negative association between social policies and health inequalities. Economic performance also has a reducing influence on health inequalities. In all models, income inequality was the dominating explanatory effect for health inequalities. CONCLUSIONS: The analyses indicate that income inequality has more impact on health inequalities than social policies. On the contrary, social policies seemed to matter to all individuals regardless of socio-economic position since it is significantly positively linked to overall population health. Even though social policies are not significantly related to health inequalities, the power of public redistribution to impact health inequalities should not be downplayed. Social policies as a way of public redistribution are a possible instrument to reduce income inequalities which would in turn lead to a reduction in health inequalities. PMID- 26521028 TI - Academic authorship guidelines for capstone and dissertation work. PMID- 26521029 TI - Galantamine attenuates amyloid-beta deposition and astrocyte activation in APP/PS1 transgenic mice. AB - While galantamine may not provide a cure for Alzheimer's disease (AD), it decelerates the progression and provides symptomatic relief for this disorder. The aim of this study was to investigate the effect of chronic galantamine treatment on cognitive performance, Abeta deposition and astrocyte activation in the transgenic APP/PS1 mouse model of AD. Galantamine (5mg/kg, i.p.) or 0.9% saline was administrated twice daily for eight weeks in 10-month-old APP/PS1 mice. In addition a separate group of 10-month old male C57BL/6 wild type mice was included as a reference control. Compared with saline treated APP/PS1 mice, galantamine treated mice exhibited significantly improved escape latencies on Days 6 and 7 of testing (p<0.05) and significantly decreased numbers of platform crossings (p<0.01) as assessed in the Morris water maze. Galantamine reduced the total area of amyloid load within the hippocampus of transgenic APP/PS1 mice, inhibited astrocyte activation as assessed by immunohistochemistry and decreased intracellular TNF-alpha and IL-6 expression as determined by immunofluorescence. Galantamine failed to alter hippocampal levels of TNF-alpha and IL-6 as assayed by ELISA. Galantamine may be involved in modifying AD pathophysiological mechanisms by alleviating Abeta deposition and neuroinflammation. The results from this study provide new evidence for use of galantamine in the treatment of AD. PMID- 26521030 TI - Computational proteomics: Integrating mass spectral data into a biological context. PMID- 26521032 TI - Predictors of violence against children in Tamil families in northern Sri Lanka. AB - Children living in post-conflict settings are not only at high risk of developing war-related psychopathology but also of experiencing maltreatment within their families. However, little is known about the mechanisms of the relationship between war and family violence. In order to investigate the variables associated with the experience and perpetration of child maltreatment, we conducted a two generational study with Tamil families in the North of Sri Lanka, a region affected by war and Tsunami. We interviewed children and the corresponding family dyads and triads with 359 children, 122 mothers, and 88 fathers on the basis of standardized questionnaires to assess their exposure to adverse life experiences and mental health symptoms. Using multivariate regression analyses, we found that the strongest predictors for children's report of victimization were children's exposure to mass trauma and child psychopathology. Mothers' experiences of mass trauma, family violence and partner violence were each significantly related to mother-reported maternal perpetration as well as child-reported victimization. Likewise, all types of traumatic events reported by fathers were significantly related to child-reported victimization and father-reported perpetration. Fathers' alcohol use was the strongest predictor of father-reported paternal perpetration. These findings provide further support for the transmission of mass trauma into family violence, and emphasize the role of child psychopathology as well as alcohol consumption in this relationship. PMID- 26521031 TI - Optimizing the calculation of DM,CO and VC via the single breath single oxygen tension DLCO/NO method. AB - Alveolar-capillary membrane conductance (D(M,CO)) and pulmonary-capillary blood volume (V(C)) are calculated via lung diffusing capacity for carbon monoxide (DL(CO)) and nitric oxide (DL(NO)) using the single breath, single oxygen tension (single-FiO2) method. However, two calculation parameters, the reaction rate of carbon monoxide with blood (theta(CO)) and the D(M,NO)/D(M,CO) ratio (alpha ratio), are controversial. This study systematically determined optimal theta(CO) and alpha-ratio values to be used in the single-FiO2 method that yielded the most similar D(M,CO) and V(C) values compared to the 'gold-standard' multiple-FiO2 method. Eleven healthy subjects performed single breath DL(CO)/DL(NO) maneuvers at rest and during exercise. D(M,CO) and V(C) were calculated via the single-FiO2 and multiple-FiO2 methods by implementing seven theta(CO) equations and a range of previously reported alpha-ratios. The RP theta(CO) equation (Reeves, R.B., Park, H.K., 1992. Respiration Physiology 88 1-21) and an alpha-ratio of 4.0-4.4 yielded DM,CO and VC values that were most similar between methods. The RP theta(CO) equation and an experimental alpha-ratio should be used in future studies. PMID- 26521033 TI - Integrated systematic review on educational strategies that promote academic success and resilience in undergraduate indigenous students. AB - BACKGROUND: Despite numerous recommendations by governments, researchers, and education policymakers the recruitment, retention and success of undergraduate indigenous students in higher education is not commensurate of the wider student population. There is minimal evidence of valuing indigenous worldviews and perspectives in curricula, and effectiveness of educational strategies to strengthen indigenous student success rates in completing undergraduate studies. OBJECTIVES: To conduct an integrative systematic review of educational strategies to promote academic success and resilience in undergraduate indigenous students. METHODS: Major databases of Scopus, ProQuest, Informit and Web of Science were searched. Inclusion criteria were peer reviewed research articles from scholarly journals that referenced indigenous, aboriginal, First Nation or Maori students in undergraduate programs in higher education. The search was limited to English language and studies conducted from 1995 to 2014. RESULTS: The search yielded 156 research papers which reduced to 16 papers that met the inclusion criteria. The included papers were critiqued from a standpoint theory approach that reflects feminism, cultural respect, and humanism. Much of the literature describes issues, and provides qualitative analyses of experiences, but empirical evaluations of interventions are rare. CONCLUSIONS: There was a gap in current research evaluating strategies to improve indigenous student success and resilience. Key strategies for indigenous student success are multi-faceted, layered support, underpinned by the principles of respect, relationships, and responsibility. Implications for nursing and midwifery education, research and health care practice are outlined. PMID- 26521034 TI - Development and evaluation of a simulation exercise to prepare midwifery students for neonatal resuscitation. AB - BACKGROUND: Simulation provides opportunities for midwifery students to enhance their performance in emergency situations. Neonatal resuscitation is one such emergency and its management is a major concern for midwifery students. OBJECTIVES: This project aimed to develop and evaluate a simulation exercise, for neonatal resuscitation, for 3rd year midwifery students. DESIGN: A quantitative survey design was employed using questions from two previously validated questionnaires: (1.) Student Satisfaction and Self-Confidence in Learning and (2.) the Clinical Teamwork Scale (CTS). SETTING: Australian university. PARTICIPANTS: 40 final year midwifery students were invited to participate and 36 agreed to take part in the project. RESULTS: In pre-simulation questionnaires, students reported low levels of confidence in initiating care of an infant requiring resuscitation. Most anticipated that the simulation exercise would be useful to better prepare them respond to a neonatal emergency. Post-simulation questionnaires reported an increase in student confidence, with 30 of 36 students agreeing/ strongly agreeing that their confidence levels had improved. Nonetheless, an unexpected number of students reported a lack of familiarity with the equipment. CONCLUSIONS: The single simulation exercise evaluated in this project resulted in improved student confidence and greater knowledge and skills in neonatal resuscitation. However, deficits in handling emergency equipment, and in understanding the role of the student midwife/midwife in neonatal resuscitation, were also noted. For the future, the development and evaluation of a programme of simulation exercises, over a longer period, is warranted. This approach may reduce stress and better address student learning needs. PMID- 26521035 TI - Medication competency of nurses according to theoretical and drug calculation online exams: A descriptive correlational study. AB - BACKGROUND: Medication administration is an important task of registered nurses. According to previous studies, nurses lack theoretical knowledge and drug calculation skills and knowledge-based mistakes do occur in clinical practice. Finnish health care organizations started to develop a systematic verification processes for medication competence at the end of the last decade. No studies have yet been made of nurses' theoretical knowledge and drug calculation skills according to these online exams. OBJECTIVES: The aim of this study was to describe the medication competence of Finnish nurses according to theoretical and drug calculation exams. DESIGN: A descriptive correlation design was adopted. Participants and settings All nurses who participated in the online exam in three Finnish hospitals between 1.1.2009 and 31.05.2014 were selected to the study (n=2479). METHODS: Quantitative methods like Pearson's chi-squared tests, analysis of variance (ANOVA) with post hoc Tukey tests and Pearson's correlation coefficient were used to test the existence of relationships between dependent and independent variables. RESULTS: The majority of nurses mastered the theoretical knowledge needed in medication administration, but 5% of the nurses struggled with passing the drug calculation exam. Theoretical knowledge and drug calculation skills were better in acute care units than in the other units and younger nurses achieved better results in both exams than their older colleagues. CONCLUSION: The differences found in this study were statistically significant, but not high. Nevertheless, even the tiniest deficiency in theoretical knowledge and drug calculation skills should be focused on. It is important to identify the nurses who struggle in the exams and to plan targeted educational interventions for supporting them. The next step is to study if verification of medication competence has an effect on patient safety. PMID- 26521036 TI - A Phase II Trial of Erlotinib and Concurrent Palliative Thoracic Radiation for Patients With Non-Small-Cell Lung Cancer. AB - BACKGROUND: The downstream signaling pathways of the epidermal growth factor receptor might influence radiation resistance. Data from preclinical work support the hypothesis that erlotinib concurrent with radiation therapy (RT) might increase cancer cell killing. The present trial was designed to examine the efficacy and toxicity of combined erlotinib and palliative chest thoracic RT in non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with newly diagnosed stage III-IV (American Joint Committee on Cancer, version 6) or recurrent NSCLC received 3 weeks of erlotinib at a dose of 150 mg daily, starting 1 week before palliative thoracic RT to 30 Gy in 10 fractions within 2 weeks. The primary outcome was a change in the quality of life, as measured by the Lung Cancer Symptom Scale (LCSS) question on the "symptoms of lung cancer" from baseline to 4 weeks after treatment. RESULTS: A total of 40 patients were recruited from 2 institutions. Of the 40 patients, 22 (55%) were men, with an average age of 71 years, and 60% had stage IV disease. A total of 26 patients (65%) completed the full course of erlotinib, and 35 (88%) completed the planned RT. Twenty-five patients (62.5%) reported LCSS scores at 4 weeks after treatment, with an average change (improvement) of -12.5 U (95% confidence interval, -23.0 to -1.9; 2P = .023). This was less than the a priori hypothesis of a change of 17.5 U. The median overall and progression-free survival was 5.2 and 3.2 months, respectively. CONCLUSION: The present single-arm, phase II trial did not demonstrate additional symptomatic benefit from concurrent erlotinib therapy with standard palliative thoracic RT for patients with locally advanced or metastatic NSCLC. PMID- 26521037 TI - Roles of aromatic side chains and template effects of the hydrophobic cavity of a self-assembled peptide nanoarchitecture for anisotropic growth of gold nanocrystals. AB - Gold nanocrystals are promising as catalysts and for use in sensing/imaging systems, photonic/plasmonic devices, electronics, drug delivery systems, and for photothermal therapy due to their unique physical, chemical, and biocompatible properties. The use of various organic templates allows control of the size, shape, structure, surface modification and topology of gold nanocrystals; in particular, currently the synthesis of gold nanorods requires a cytotoxic surfactant to control morphology. To control the shape of gold nanocrystals, we previously demonstrated the de novo design and synthesis of a beta-sheet-forming nonapeptide (RU006: Ac-AIAKAXKIA-NH2, X=L-2-naphthylalanine, Nal) and the fabrication of gold nanocrystals by mixing RU006 and HAuCl4 in water. The reaction afforded ultrathin gold nanoribbons 50-100 nm wide, several nanometers high, and microns long. To understand the mechanism underlying gold nanoribbon formation by the RU006 system, we here report (i) the effects of replacement of the Nal aromatic side chain in the RU006 sequence with other aromatic moieties, (ii) the electrochemical properties of aromatic side chains in the de novo designed template peptides to estimate the redox potential and number of electrons participating in the gold crystallization process, and (iii) the stoichiometry of the RU006 system for gold nanoribbon synthesis. Interestingly, RU006 bearing a naphthalene moiety (oxidation peak potential of 1.50 V vs Ag/Ag(+)) and an analog [Ant(6)]-RU006 bearing a bulky anthracene moiety (oxidation peak potential of 1.05 V vs Ag/Ag(+)) allowed the growth of anisotropic (ribbon-like) and isotropic (round) gold nanocrystals, respectively. This trend in morphology of gold nanocrystals was attributed to spatially arranged hydrophobic cavities sufficiently large to accommodate the gold precursor and to allow directed crystal growth driven by cross-linking reactions among the naphthalene rings. Support for this mechanism was obtained by decreasing the mole fraction of [Ant(6)]-RU006 against the total concentration of [Ant(6)]-RU006 and [Phe(6)]-RU006: absorption spectra similar to that for RU006 were obtained. Differences in the redox properties of the anthracene and naphthalene moieties scarcely affected morphology. We propose that construction of an appropriate hydrophobic cavity is important for templating gold nanocrystal architectures by peptide self-assembly. This mechanism would be applicable for developing simple, low toxicity, mild synthetic methods for constructing metallic nanomaterials for therapeutic use. PMID- 26521038 TI - Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians. AB - BACKGROUND: Caspase recruitment domain-containing protein 9 (CARD9) deficiency is an autosomal recessive primary immunodeficiency conferring human susceptibility to invasive fungal disease, including spontaneous central nervous system candidiasis (sCNSc). However, clinical characterization of sCNSc is variable, hindering its recognition. Furthermore, an in-depth understanding of the bases for this susceptibility has remained elusive. OBJECTIVES: We sought to comprehensively characterize sCNSc and to dissect the mechanisms by which a hypomorphic CARD9 mutation causes susceptibility to Candida species. METHODS: We describe the clinical and radiologic findings of sCNSc caused by CARD9 deficiency in a French-Canadian cohort. We performed genetic, cellular, and molecular analyses to further decipher its pathophysiology. RESULTS: In our French-Canadian series (n = 4) sCNSc had onset in adulthood (median, 38 years) and was often misinterpreted radiologically as brain malignancies; 1 patient had additional novel features (eg, endophthalmitis and osteomyelitis). CARD9 deficiency resulted from a hypomorphic p.Y91H mutation and allelic imbalance established in this population through founder effects. We demonstrate a consistent cellular phenotype of impaired GM-CSF responses. The ability of CARD9 to complex with B cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is intact in our series, arguing against its involvement in susceptibility to fungi. Instead, we show that the p.Y91H mutation impairs the ability of CARD9 to complex with Ras protein-specific guanine nucleotide-releasing factor 1 (RASGRF1), leading to impaired activation of nuclear factor kappaB and extracellular signal-regulated kinase (ERK) in monocytes and subsequent GM-CSF responses. Successful treatment of a second patient with adjunctive GM-CSF bolsters the clinical relevance of these findings. CONCLUSIONS: Hypomorphic CARD9 deficiency caused by p.Y91H results in adult-onset disease with variable penetrance and expressivity. Our findings establish the CARD9/RASGRF1/ERK/GM-CSF axis as critical to the pathophysiology of sCNSc. PMID- 26521039 TI - Association of periostin expression with eosinophilic inflammation in nasal polyps. PMID- 26521040 TI - Defective nuclear entry of hydrolases prevents neutrophil extracellular trap formation in patients with chronic granulomatous disease. PMID- 26521041 TI - Household almond and peanut consumption is related to the development of sensitization in young children. PMID- 26521042 TI - A histamine-independent itch pathway is required for allergic ocular itch. PMID- 26521044 TI - TRAF2-mediated Lys63-linked ubiquitination of DUSP14/MKP6 is essential for its phosphatase activity. AB - Dual-specificity phosphatase 14 (DUSP14, also known as MKP6) is a MAP kinase phosphatase that dephosphorylates JNK, ERK, and p38 in vitro. We recently reported that DUSP14 negatively regulates T-cell activation and immune responses by interfering activation of TAB1-TAK1 complex. However, the molecular mechanism that regulates the phosphatase activity of DUSP14 remains unclear. Here, we report the post-translational modification of DUSP14 by ubiquitination. Mass spectrometry and mutational analyses identified that DUSP14 was Lys63-linked ubiquitinated at lysine 103 residue. Furthermore, DUSP14 inducibly interacted with the E3 ligase TRAF2 during T-cell receptor (TCR) signaling; TRAF2 shRNA knockdown reduced the DUSP14 ubiquitination. We also show that ubiquitination of DUSP14 was required for its phosphatase activity during TCR signaling. Together, these findings reveal a novel mechanism by which TRAF2 mediates Lys63-linked ubiquitination of DUSP14, leading to DUSP14 activation in T cells. PMID- 26521043 TI - Clinical correlates of lung ventilation defects in asthmatic children. AB - BACKGROUND: Lung ventilation defects identified by using hyperpolarized 3-helium gas ((3)He) lung magnetic resonance imaging (MRI) are prevalent in asthmatic patients, but the clinical importance of ventilation defects is poorly understood. OBJECTIVES: We sought to correlate the lung defect volume quantified by using (3)He MRI with clinical features in children with mild and severe asthma. METHODS: Thirty-one children with asthma (median age, 10 years; age range, 3-17 years) underwent detailed characterization and (3)He lung MRI. Quantification of the (3)He signal defined ventilation defect and hypoventilated, ventilated, and well-ventilated volumes. RESULTS: The ventilation defect to total lung volume fraction ranged from 0.1% to 11.6%. Children with ventilation defect percentages in the upper tercile were more likely to have severe asthma than children in the lower terciles (P = .005). The ventilation defect percentage correlated (P < .05 for all) positively with the inhaled corticosteroid dose, total number of controller medications, and total blood eosinophil counts and negatively with the Asthma Control Test score, FEV1 (percent predicted), FEV1/forced vital capacity ratio (percent predicted), and forced expiratory flow rate from 25% to 75% of expired volume (percent predicted). CONCLUSION: The lung defect volume percentage measured by using (3)He MRI correlates with several clinical features of asthma, including severity, symptom score, medication requirement, airway physiology, and atopic markers. PMID- 26521045 TI - Nuclear spheres modulate the expression of BEST1 and GADD45G. AB - Nuclear spheres are composed of FE65, TIP60, BLM and other yet unknown proteins. The amyloid precursor protein plays a central role for the generation of these highly toxic aggregates in the nucleus of cells. Thus, nuclear spheres might play a crucial role in Alzheimer's disease (AD). However, studies are hampered by the elevated cell death, once spheres are generated. In this work, we established for the first time a stable nuclear sphere model based on the inductive expression of FE65 and TIP60 following Doxycycline stimulation. We studied hitherto controversially discussed target genes, give clues for the reason of controversy, and moreover report new highly reliable targets bestrophin 1 and growth arrest and DNA-damage-inducible protein gamma. qPCR studies further revealed that the regulation of these targets strongly depends on the generation of nuclear spheres, but not on the induction of FE65 or TIP60 alone. As the bestrophin 1 ion channel was recently described to be involved in the abnormal release of GABA, our study might reveal the missing link between AD associated neurotransmitter changes and the amyloid precursor protein. PMID- 26521047 TI - Music, empathy and cultural understanding: The need for developmental research: Comment on "Music, empathy and cultural understanding" by E. Clarke et al. PMID- 26521046 TI - The Breast Cancer Susceptibility Gene Product (gamma-Synuclein) Alters Cell Behavior through its [corrected] Interaction with Phospholipase Cbeta. AB - The breast cancer susceptibility gene protein, also known as gamma-synuclein, is highly expressed in human breast cancer in a stage-specific manner, with highest expression in late stage cancer. In model systems, gamma-synuclein binds phospholipase Cbeta2 which is regulated by Galphaq to generate intracellular Ca(2+) signals. PLCbeta2, which is also absent in normal tissue but highly expressed in breast cancer, is additionally regulated by Rac to promote migration pathways. We have found that gamma-synuclein binds to the same region of PLCbeta2 as Galphaq. Using cells that mimic stage 4 breast cancer (MDA MB 231), we show that down-regulation of gamma-synuclein reduces the protein level of PLCbeta but increases the transcript level over 40 fold. gamma-Synuclein down-regulation also promotes the interaction between Galphaq and PLCbeta resulting in a stronger Ca(2+) response to Galphaq agonists. The ability of gamma-synuclein to interfere with Galphaq-PLCbeta interactions allows more PLCbeta to colocalize with Rac impacting Rac-mediated pathways that may give rise to cancerous phenotypes. PMID- 26521048 TI - Music as a way of knowing: Comment on "Music, empathy, and cultural understanding" by E. Clarke et al. PMID- 26521049 TI - Connecting human behavior and infectious disease spreading: Comment on "Coupled disease-behavior dynamics on complex networks: A review" by Wang et al. PMID- 26521050 TI - Rapid whole genome sequencing and precision neonatology. AB - Traditionally, genetic testing has been too slow or perceived to be impractical to initial management of the critically ill neonate. Technological advances have led to the ability to sequence and interpret the entire genome of a neonate in as little as 26 h. As the cost and speed of testing decreases, the utility of whole genome sequencing (WGS) of neonates for acute and latent genetic illness increases. Analyzing the entire genome allows for concomitant evaluation of the currently identified 5588 single gene diseases. When applied to a select population of ill infants in a level IV neonatal intensive care unit, WGS yielded a diagnosis of a causative genetic disease in 57% of patients. These diagnoses may lead to clinical management changes ranging from transition to palliative care for uniformly lethal conditions for alteration or initiation of medical or surgical therapy to improve outcomes in others. Thus, institution of 2-day WGS at time of acute presentation opens the possibility of early implementation of precision medicine. This implementation may create opportunities for early interventional, frequently novel or off-label therapies that may alter disease trajectory in infants with what would otherwise be fatal disease. Widespread deployment of rapid WGS and precision medicine will raise ethical issues pertaining to interpretation of variants of unknown significance, discovery of incidental findings related to adult onset conditions and carrier status, and implementation of medical therapies for which little is known in terms of risks and benefits. Despite these challenges, precision neonatology has significant potential both to decrease infant mortality related to genetic diseases with onset in newborns and to facilitate parental decision making regarding transition to palliative care. PMID- 26521051 TI - FKBP5 polymorphisms moderate the influence of adverse life events on the risk of anxiety and depressive disorders in preschool children. AB - FKBP5 is thought to be involved in the pathogenesis of stress-related disorders. Studies have shown that FKBP5 genotypes moderate the risk of post-traumatic stress disorder and depression in traumatized adults. We aimed to replicate this finding in a sample of preschool children. Parents of preschoolers (N = 186) were interviewed using the Preschool Age Psychiatric Assessment (PAPA) to evaluate the presence of anxiety and depressive disorders and to quantify the child's exposure to adverse events. All FKBP5 polymorphisms showed significant interactions with mild to moderate life events, but not with severe life events, in predicting the risk of anxiety and/or depressive disorders (p = 0.003-0.019). Children who experienced a high number of mild to moderate life events had a higher risk of developing an anxiety and/or depressive disorder if they were carriers of the minor allele compared to major allele homozygotes. Results indicate that genetic variation in FKBP5 influences the risk of anxiety and/or depressive disorders in preschool age by altering the sensitivity to the deleterious effects of mild to moderate adverse events. In case of severe life events, the FKBP5 genotype does not seem to play a role, suggesting that severe life events might influence directly the risk of anxiety and/or depressive disorders independent of an FKBP5 genotype-dependent vulnerability. PMID- 26521052 TI - How to use and interpret hormone ratios. AB - Hormone ratios have become increasingly popular throughout the neuroendocrine literature since they offer a straightforward way to simultaneously analyze the effects of two interdependent hormones. However, the analysis of ratios is associated with statistical and interpretational concerns which have not been sufficiently considered in the context of endocrine research. The aim of this article, therefore, is to demonstrate and discuss these issues, and to suggest suitable ways to address them. In a first step, we use exemplary testosterone and cortisol data to illustrate that one major concern of ratios lies in their distribution and inherent asymmetry. As a consequence, results of parametric statistical analyses are affected by the ultimately arbitrary decision of which way around the ratio is computed (i.e., A/B or B/A). We suggest the use of non parametric methods as well as the log-transformation of hormone ratios as appropriate methods to deal with these statistical problems. However, in a second step, we also discuss the complicated interpretation of ratios, and propose moderation analysis as an alternative and oftentimes more insightful approach to ratio analysis. In conclusion, we suggest that researchers carefully consider which statistical approach is best suited to investigate reciprocal hormone effects. With regard to the hormone ratio method, further research is needed to specify what exactly this index reflects on the biological level and in which cases it is a meaningful variable to analyze. PMID- 26521053 TI - Coinfection of Trypanosoma cruzi and Mycobacterium tuberculosis in a patient from Colombia. PMID- 26521054 TI - "I just have to move on": Women's coping experiences and reflections following their first year after primary breast cancer surgery. AB - PURPOSE: The purpose of this qualitative follow-up study was to describe women's individual coping experiences and reflections following their first year after primary breast cancer surgery. METHODS: Using a qualitative descriptive design, we collected data through individual interviews with ten women at a Norwegian university hospital between August 2007 and April 2008. We employed Kvale's method of qualitative meaning condensation analysis. RESULTS: Themes identified were: existential concerns and finding meaning, ways of thinking and feeling about the disease, taking action, and returning to normal life. Most women experienced an increased appreciation of life and greater confidence in themselves, were more caring and compassionate towards others, and focused more on their life priorities. Their family and close relationships became more important. They accepted their situation and made the best of it. Positive thinking, physical activity, self-care, nature, hobbies and work helped. Generally, they were optimistic despite a fear of cancer recurrence and uncertainty about their future. The women wanted to return to a "normal" and healthy life by distancing themselves from both the cancer environment and information about cancer. CONCLUSION: Uncertainty and anxiety about a potential future cancer relapse was a major undercurrent one year following surgery. Our findings emphasize the richness in these women's coping strategies, their different coping profiles and different needs, as well as some general adaptive strategies, which all fluctuated over time. Not all managed to cope equally well. Through awareness of these women's individual experiences and coping strategies, healthcare professionals can enhance these women's coping endeavours. PMID- 26521055 TI - Liver glycogen in type 2 diabetic mice is randomly branched as enlarged aggregates with blunted glucose release. AB - Glycogen is a vital highly branched polymer of glucose that is essential for blood glucose homeostasis. In this article, the structure of liver glycogen from mice is investigated with respect to size distributions, degradation kinetics, and branching structure, complemented by a comparison of normal and diabetic liver glycogen. This is done to screen for differences that may result from disease. Glycogen alpha-particle (diameter ~ 150 nm) and beta-particle (diameter ~ 25 nm) size distributions are reported, along with in vitro gamma-amylase degradation experiments, and a small angle X-ray scattering analysis of mouse beta-particles. Type 2 diabetic liver glycogen upon extraction was found to be present as large loosely bound, aggregates, not present in normal livers. Liver glycogen was found to aggregate in vitro over a period of 20 h, and particle size is shown to be related to rate of glucose release, allowing a structure-function relationship to be inferred for the tissue specific distribution of particle types. Application of branching theories to small angle X-ray scattering data for mouse beta-particles revealed these particles to be randomly branched polymers, not fractal polymers. Together, this article shows that type 2 diabetic liver glycogen is present as large aggregates in mice, which may contribute to the inflexibility of interconversion between glucose and glycogen in type 2 diabetes, and further that glycogen particles are randomly branched with a size that is related to the rate of glucose release. PMID- 26521056 TI - Reduction of enterotoxin induced fluid accumulation in ileal loops of neonatal calves with anti-F5 fimbriae recombinant antibody. AB - Neonatal calf colibacillosis caused by enterotoxigenic Escherichia coli (ETEC) is an economically significant problem in most parts of the world. The most common ETEC found in calves express the F5 (K99) fimbriae, which are necessary for the attachment of the bacteria to the ganglioside receptors on enterocytes. It is known that prevention of ETEC F5(+) adhesion to its ganglioside receptors with specific antibodies protects calves from colibacillosis. Previously we have described the development and characterization of a mouse recombinant antibody fragment (moRAb) that prevents F5 fimbrial protein induced agglutination of horse red blood cells (HRBC), which exhibit the same gangloside receptor for F5 fimbriae. Here we demonstrate that this recombinant antibody fragment inhibits in vitro the attachment of ETEC F5(+) bacteria to HRBC as well as isolated calf enterocytes, and in vivo it decreases fluid accumulation in intestinal loops of calves. Thus, correct oral administration of this anti-F5 moRAb may serve as an immunoprophylactic for cost effective control of colibacillosis in calves. PMID- 26521057 TI - Patient Involvement in the Design of a Patient-Centered Clinical Trial to Promote Adherence to Supplemental Oxygen Therapy in COPD. AB - BACKGROUND: Patients are increasingly viewed as key stakeholders who can contribute in meaningful ways to clinical research and are emphasized in research funded by the Patient-Centered Outcomes Research Institute (PCORI). We are not aware of other peer-reviewed publications that report methods and outcomes of patient engagement to refine study design for a PCORI-sponsored clinical effectiveness trial. OBJECTIVE: The aim of this report was to describe the process and outcomes of involving patients in the design of a clinical trial to promote adherence to supplemental oxygen therapy among patients with chronic obstructive pulmonary disease. METHODS: In-person focus groups and individual discussions via telephone and email were used to elicit feedback to refine the intervention and clarify outcomes of highest importance to patients. RESULTS: A total of 25 patients and five caregivers provided feedback. Their feedback has informed decisions regarding the length of intervention sessions (20 min and in some cases longer was acceptable), the importance of including caregivers, and discussion topics (e.g., social discomfort about using oxygen in public, identifying personally relevant reasons to use oxygen, pulmonary rehabilitation). Multiple outcomes were rated as highly important to patients (physical function, fatigue, sleep, anxiety, depression, and ability to participate in social roles and activities), and the outcome that was ranked as most important varied by individual. Therefore, multiple patient-reported outcomes will be used as endpoints for the clinical trial. CONCLUSIONS: Patient involvement led to refinements of the intervention and clinical trial endpoints to better address the expressed needs and concerns of patients and caregivers. PMID- 26521058 TI - Analysis of the Role of Insulin Signaling in Bone Turnover Induced by Fluoride. AB - The role of insulin signaling on the mechanism underlying fluoride induced osteopathology was studied. We analyzed the expression of genes related with bone turnover and insulin signaling in rats treated by varying dose of fluoride with or without streptozotocin (STZ) in vivo. Furthermore, insulin receptor (InR) expression in MC3T3-E1 cells (pre-osteoblast cell line) was interfered with small interfering RNA (siRNA), and genes related with osteoblastic and osteoclastic differentiation were investigated in cells exposed to fluoride in vitro for 2 days. The in vivo study indicated the possible role of insulin in bone lesion induced by excessive amount of fluoride. Fluoride activated the InR and Insulin like growth factor 1 (IGF1) signaling, which were involved in the mechanism underlying fluoride induced bone turnover. The TGFbeta1 and Wnt10/beta-catenin pathway took part in the mechanism of bone lesion induced by fluoride, and insulin probably modulated the TGFbeta1 and beta-catenin to exert action on bone turnover during the development of bone lesion. The in vitro study showed the concomitant decrease of OPG, osterix and OCN with inhibition of InR expression in osteoblast, and three genes still was low in cells co-treated with fluoride and InR siRNA, which suggested that fluoride probably stimulated the expression of OPG, osterix and OCN through InR signaling. In conclusion, insulin played the important role in bone lesion induced by excessive amount of fluoride through mediating InR receptor signaling, and IGF1 signaling probably exerted action on bone turnover caused by overdose of fluoride. PMID- 26521059 TI - Quercetin Modulates the Effects of Chromium Exposure on Learning, Memory and Antioxidant Enzyme Activity in F1 Generation Mice. AB - In the present study, we investigated whether chromium (Cr) administered to the dams (F0) during lactation period could affect memory and oxidative stress in F1 generation mice in their adulthood and whether quercetin could modulate these effects. Morris water maze (MWM) was used to test for spatial memory. Passive avoidance task and elevated plus maze were used to test for acquisition and retention memory. Oxidative stress was evaluated by measuring glutathione-S transferase (GST), catalase activity and malonaldehyde (MDA) levels in the brain tissue. The results of MWM showed that the animals in the Cr-treated group compared to control have better spatial memory that was further enhanced when Cr was administered along with quercetin (50 mg/kg). The elevated plus maze test also showed the Cr-treated group to improve acquisition as well as retention memory compared to control. Co-treatment with quercetin (all doses) also exhibited enhanced acquisition and retention memory compared to control. The passive avoidance task demonstrated no significant improvement in memory in the Cr-treated mice but co-treatment with quercetin (100 mg/kg) showed improved acquisition memory compared to control which was significantly better than the animals treated with chromium alone. GST activity was significantly increased in the Cr-treated animals, and this was further increased in groups treated with Cr and quercetin (all doses). Chromium when administered alone and in combination with quercetin (all doses) significantly reduced MDA levels. However, Cr treatment did not show significant change in catalase activity. Nevertheless, co treatment with quercetin (25 and 50 mg/kg) resulted in significant decrease in catalase activity. Thus, our study demonstrates that Cr exposure during lactation could be beneficial for pups with respect to augmentation of cognitive function and reduction of oxidative stress. Quercetin could probably enhance this effect to some extent. PMID- 26521060 TI - Screening of Blood Levels of Mercury, Cadmium, and Copper in Pregnant Women in Dakahlia, Egypt: New Attention to an Old Problem. AB - Heavy metals toxicity is a prevalent health problem particularly in developing countries. Mercury and cadmium are toxic elements that have no physiologic functions in human body. They should not be present in the human body by any concentration. Copper, on the other hand, is one of the elements that are essential for normal cell functions and a deficiency as well as an excess of which can cause adverse health effects. To test blood levels of mercury, cadmium, and copper in pregnant women in Dakahlia, Egypt. Using atomic absorption spectrophotometry, blood levels of cadmium, mercury, and copper were measured in 150 pregnant women attending to the antenatal care in Mansoura University Hospital in Dakahlia governorate, Egypt. The mean +/- SD of blood mercury, cadmium, and copper levels were found to be far from their levels in the population surveys carried in developed countries like United States of America (USA) and Canada. Heavy metal intoxication and accumulation is a major health hazard. Developing countries, including Egypt, still lack many of the regulatory policies and legislations to control sources of pollution exposure. This should be dealt with in order to solve this problem and limit its health consequences. PMID- 26521061 TI - New ASCO/CAP guideline recommendations for HER2 testing increase the proportion of reflex in situ hybridization tests and of HER2 positive breast cancers. AB - Accurate determination of tumour human epidermal growth factor receptor type 2 (HER2) status is critical for optimal treatment of breast cancer. In October 2013, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) issued joint updated guideline recommendations for HER2 testing in breast cancer, with a revised algorithm for interpretation of immunohistochemistry (IHC) and in situ hybridisation (ISH) results. This study investigates the impact on HER2 IHC categorisation, implication for reflex ISH testing and potential for identification of false negative IHC. HER2 IHC preparations on 251 invasive breast tumours, originally reported according to 2007 guidelines, were re-scored using 2013 guidelines and the diagnostic categories compared. The results of ISH testing on a separate cohort of 32 breast tumours reported as HER2 IHC 2+ following the introduction of the 2013 guidelines, that would have been designated 1+ according to 2007, were reviewed. Application of 2013 guidelines resulted in a decrease in tumours classified as HER2 negative (83/251 vs 144/251) and a comparable increase in those classified as equivocal (2+) (139/251 vs 80/251). Relatively few tumours were re-classified as positive (29/251 vs 27/251). Furthermore, 3/32 breast cancer cases (HER2 IHC 2+ as per 2013 guidelines, 1+ using 2007 guidelines) were HER2 ISH positive. Application of the 2013 guidelines increases the HER2 IHC equivocal (2+) category and requirement for reflex ISH testing. The reduced threshold for ISH testing identifies some patients with HER2 positive breast cancer whose tumours would have been categorised as HER2 negative according to the 2007 guidelines. PMID- 26521062 TI - Diffuse invasive breast carcinoma of no special type. AB - Diffuse invasive breast carcinomas are rare tumors associated with unfavorable prognostic parameters. This growth pattern is often related to invasive lobular cancer (ILC). Diffuse ductal breast carcinoma of no special type (NST) is largely under-recognized in the literature. We identified 70 diffuse invasive breast carcinomas in a consecutive series of 1249 invasive tumors. Based on morphology and E-cadherin expression, 15/70 were NST and 55/70 were ILC. Subgroups differed in mammographic appearance, as more NST tumors than ILCs formed stellate masses (53 vs. 18 %, p = 0.000436) while ILCs displayed more architectural distortion. NST tumors were significantly more often radiologically extensive than ILCs (80 vs. 38 %, p = 0.0042987). Subgroups did not differ significantly in disease extent on histology, lymph node status, progesterone receptor status, and molecular phenotype, with a difference of borderline statistical significance in estrogen receptor status (87 vs. 100 %, p = 0.0434783). Significantly more NST tumors were HER2 positive (27 vs. 4 %, p = 0.0050463) and showed high Ki67 proliferation index (60 vs. 25 %, p = 0.0121808). The most striking differences occurred in the histology grade of the in situ (high grade in 53 vs. 4 %) and invasive (high grade in 27 vs. 2 %) tumor components and in the distribution of the in situ component (diffuse in 73 vs. 11 %). We conclude that diffuse invasive breast carcinomas of NST comprise a small subgroup of breast carcinomas. Most of these cancers are non-high grade and of luminal phenotype, but extensive and lymph node positive with worse prognostic parameters than diffuse ILC. PMID- 26521063 TI - Papillary thyroid carcinoma with extensive squamous dedifferentiation metastatic to the lung: BRAF mutational analysis as a useful tool to rule out tumor to tumor metastasis. AB - Tumors containing elements of both papillary thyroid carcinoma (PTC) and squamous cell carcinoma (SCC) are rare but well documented. When they present initially as metastatic disease in an organ that can harbor a primary SCC, the possibility of a tumor to tumor metastasis (TTM) must be considered. The aim of this case study is to illustrate how BRAF mutational analysis can be used to help differentiate between these two diagnoses. We report a 63-year-old male with a longstanding history of PTC metastatic to the brain and lymph nodes who presented to our institution with a right lower lobe lung mass after a 2-year recurrence-free interval. Histopathologic and immunohistochemical analysis revealed a composite neoplasm with distinct elements of both PTC and SCC. We performed BRAF (V600E) (c.1799 T > A) mutational analysis to help elucidate the origin of each component. This is the first time that BRAF sequencing has been used to discriminate between dedifferentiated PTC and TTM, to the best of our knowledge. In the context of metastatic PTC with SCC dedifferentiation, the presence of the identical BRAF (V600E) (c.1799 T > A) mutation in both components might help rule out tumor to tumor metastasis. PMID- 26521064 TI - Editorial Commentary: The emerging role of epigenetics in atrial fibrillation. PMID- 26521065 TI - Investigation of the links between heterocyst and biohydrogen production by diazotrophic cyanobacterium A. variabilis ATCC 29413. AB - This work investigates the effect of heterocyst toward biohydrogen production by A. variabilis. The heterocyst frequency was artificially promoted by adding an amino acid analog, in this case DL-7-azatryptophan into the growth medium. The frequency of heterocyst differentiation was found to be proportional to the concentration of azatryptophan (0-25 uM) in the medium. Conversely, the growth and nitrogenase activity were gradually suppressed. In addition, there was also a distinct shortening of the cells filaments and detachment of heterocyst from the vegetative cells. Analysis on the hydrogen production performance revealed that both the frequency and distribution of heterocyst in the filaments affected the rate of hydrogen production. The highest hydrogen production rate and yield (41 umol H2 mg chl a(-1) h(-1) and 97 mL H2 mg chl a(-1), respectively) were achieved by cells previously grown in 15 uM of azatryptophan with 14.5 % of heterocyst frequency. The existence of more isolated heterocyst has been shown to cause a relative loss in nitrogenase activity thus lowering the hydrogen production rate. PMID- 26521066 TI - The feasibility of sub-millisievert coronary CT angiography with low tube voltage, prospective ECG gating, and a knowledge-based iterative model reconstruction algorithm. AB - We evaluated the feasibility of sub-millisievert (mSv) coronary CT angiography (CCTA) using low tube voltage, prospective ECG gating, and a knowledge-based iterative model reconstruction algorithm. Twenty-four non-obese healthy subjects (M:F 13:11; mean age 50.2 +/- 7.8 years) were enrolled. Three sets of CT images were reconstructed using three different reconstruction methods: filtered back projection (FBP), iterative reconstruction (IR), and knowledge-based iterative model reconstruction (IMR). The scanning parameters were as follows: step-and shoot axial scanning, 80 kVp, and 200 mAs. On the three sets of CT images, the attenuation and image noise values were measured at the aortic root. The signal to-noise ratio (SNR) and the contrast-to-noise ratio (CNR) were calculated at the proximal right coronary artery and the left main coronary artery. The qualitative image quality of the CCTA with IMR was assessed using a 4-point grading scale (grade 1, poor; grade 4, excellent). The mean radiation dose of the CCTA was 0.89 +/- 0.09 mSv. The attenuation values with IMR were not different from those of other reconstruction methods. The image noise with IMR was significantly lower than with IR and FBP. Compared to FBP, the noise reduction rate of IMR was 69 %. The SNR and CNR of CCTA with IMR were significantly higher than with FBP or IR. On the qualitative analysis with IMR, all included segments were diagnostic (grades 2, 3, and 4), and the mean image quality score was 3.6 +/- 0.6. In conclusion, CCTA with low tube voltage, prospective ECG gating, and an IMR algorithm might be a feasible method that allows for sub-millisievert radiation doses and good image quality when used with non-obese subjects. PMID- 26521068 TI - Developmental minocycline treatment reverses the effects of neonatal immune activation on anxiety- and depression-like behaviors, hippocampal inflammation, and HPA axis activity in adult mice. AB - Neonatal infection is associated with increased lifetime risk for neuropsychiatric disorders including anxiety and depression, with evidence showing that dysregulation of the hypothalamic-pituitary-adrenal-(HPA)-axis system may be partly responsible. Preclinical and clinical studies demonstrate that minocycline exhibits antidepressant effects through inhibition of microglial activation and anti-inflammatory actions, and of interest is that recent studies suggest that minocycline alleviates the behavioral abnormalities induced by early life insults. The current study was designed to determine if developmental minocycline treatment attenuates the neonatal immune activation-induced anxiety- and depression-like symptoms and HPA-axis-dysregulation later in life. To this end, neonatal mice were treated to either lipopolysaccharide or saline on postnatal days (PND) 3-5, then dams during lactation (PND 6-20) and male offspring during adolescence (PND 21-40) received oral administration of minocycline or water via regular drinking bottles. Anxiety- and depression-like behaviors, HPA-axis-reactivity (corticosterone), and hippocampal inflammation (TNF-alpha and IL-1beta) after exposure to stress were evaluated. The results indicated that neonatal immune activation resulted in increased anxiety and depression-like symptoms, HPA-axis-hyperactivity, and elevated the levels of TNF alpha and IL-1beta in the hippocampus in response to stress in adulthood. Interestingly, developmental minocycline treatment significantly reduced the abnormalities induced by neonatal inflammation in adult mice. In addition, minocycline, regardless of postnatal inflammation, did not have any detrimental effects on the above measured parameters. Considering that minocycline is currently under exploration as an alternative or adjunctive therapy for reducing the symptoms of neurological disorders, our findings suggest that minocycline during development can decrease the behavioral abnormalities induced by early life inflammation in adulthood. PMID- 26521067 TI - Morphine-induced antinociception and reward in "humanized" mice expressing the mu opioid receptor A118G polymorphism. AB - The rewarding and antinociceptive effects of opioids are mediated through the mu opioid receptor. The A118G single nucleotide polymorphism in this receptor has been implicated in drug addiction and differences in pain response. Clinical and preclinical studies have found that the G allele is associated with increased heroin reward and self-administration, elevated post-operative pain, and reduced analgesic responsiveness to opioids. Male and female mice homozygous for the "humanized" 118AA or 118GG alleles were evaluated to test the hypothesis that 118GG mice are less sensitive to the rewarding and antinociceptive effects of morphine. We found that 118AA and 118GG mice of both genders developed conditioned place preference for morphine. All mice developed tolerance to the antinociceptive and hypothermic effects of morphine. However, morphine tolerance was not different between AA and GG mice. We also examined sensitivity to the antinociceptive and hypothermic effects of cumulative morphine doses. We found that 118GG mice show reduced hypothermic and antinociceptive responses on the hotplate for 10mg/kg morphine. Finally, we examined basal pain response and morphine-induced antinociception in the formalin test for inflammatory pain. We found no gender or genotype differences in either basal pain response or morphine induced antinociception in the formalin test. Our data suggests that homozygous expression of the GG allele in mice blunts morphine-induced hypothermia and hotplate antinociception but does not alter morphine CPP, morphine tolerance, or basal inflammatory pain response. PMID- 26521069 TI - Contraception counseling for young breast cancer patients: A practical needs assessment and a survey among medical oncologists. AB - BACKGROUND/METHODS: We analyzed an unselected, consecutive cohort of young breast cancer (BC) patients (<=40 years, n = 100) with regard to the contraceptive methods used at the time of diagnosis. Based on this data, we assessed the individual need for contraceptive counseling before cancer therapy. Secondly, in a study-specific self-report questionnaire, we surveyed 101 medical oncologists with the aim of evaluating attitudes towards contraception and how young patients are being counseled in the practical clinical setting. RESULTS: In 62% of our cohort of young BC patients, we identified situations in which contraceptive counseling was necessary at the time of BC diagnosis. The patients did not use contraception or used an ineffective method (TIER III/IV, 42%), or were using hormonal methods (12%) or IUDs (8%). Almost all respondents of the survey (99%) stated that contraception is an important aspect in the surveillance of young BC patients and the vast majority (90%) discussed this item before starting therapy. Only 20% of the respondents reported that they a) inform the patients that reliable contraception is necessary before starting therapy, b) ask whether contraceptive methods are used during ongoing therapy, and c) regularly refer their patients to specialist counseling by a gynecologist. CONCLUSIONS: A large proportion of young women require contraceptive counseling after newly diagnosed BC. Oncologists should be aware that the use of reliable contraceptive methods should not only be discussed before starting therapy, but also during ongoing therapy. Oncologists should consider actively referring their young patients to gynecologists to ensure proper contraceptive counseling. PMID- 26521071 TI - Hematopoietic stem and multipotent progenitor cells produce IL-17, IL-21 and other cytokines in response to TLR signals associated with late apoptotic products and augment memory Th17 and Tc17 cells in the bone marrow of normal and lupus mice. AB - We studied effects of early and late apoptotic (necroptotic) cell products, related damage associated alarmins and TLR agonists, on hematopoietic stem and progenitor cells (HSPC). Surprisingly, normal HSPC themselves produced IL-17 and IL-21 after 11/2days of stimulation, and the best stimulators were TLR 7/8 agonist; HMGB1-DNA; TLR 9 agonist, and necroptotic B cells. The stimulated HSPC expressed additional cytokines/mediators, directly causing rapid expansion of IL 17(+) memory CD4 T (Th17), and CD8 T (Tc17) cells, and antigen-experienced IL 17(+) T cells with "naive" phenotype. In lupus marrow, HSPC were spontaneously pre-stimulated by endogenous signals to produce IL-17 and IL-21. In contrast to HSPC, megakaryocyte progenitors (MKP) did not produce IL-17, and unlike HSPC, they could process and present particulate apoptotic autoantigens to augment autoimmune memory Th17 response. Thus abnormally stimulated primitive hematopoietic progenitors augment expansion of IL-17 producing immune and autoimmune memory T cells in the bone marrow, which may affect central tolerance. PMID- 26521073 TI - Structural and Functional Magnetic Resonance Imaging of the Cerebellum: Considerations for Assessing Cerebellar Ataxias. AB - Magnetic resonance imaging (MRI) of the brain is of high interest for diagnosing and understanding degenerative ataxias. Here, we present state-of-the-art MRI methods to characterize structural alterations of the cerebellum and introduce initial experiments to show abnormalities in the cerebellar nuclei. Clinically, T1-weighted MR images are used to assess atrophy of the cerebellar cortex, the brainstem, and the spinal cord, whereas T2-weighted and PD-weighted images are typically employed to depict potential white matter lesions that may be associated with certain types of ataxias. More recently, attention has also focused on the characterization of the cerebellar nuclei, which are discernible on spatially highly resolved iron-sensitive MR images due to their relatively high iron content, including T2 (*)-weighted images, susceptibility-weighted images (SWI), effective transverse relaxation rate (R2 (*)) maps, and quantitative susceptibility maps (QSM). Among these iron-sensitive techniques, QSM reveals the best contrast between cerebellar nuclei and their surroundings. In particular, the gyrification of the dentate nuclei is prominently depicted, even at the clinically widely available field strength of 3 T. The linear relationship between magnetic susceptibility and local iron content allows for determination of iron deposition in cerebellar nuclei non-invasively. The increased signal-to-noise ratio of ultrahigh-field MRI (B0 >= 7 T) and advances in spatial normalization methods enable functional MRI (fMRI) at the level of the cerebellar cortex and cerebellar nuclei. Data from initial fMRI studies are presented in three common forms of hereditary ataxias (Friedreich's ataxia, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6). Characteristic changes in the fMRI signal are discussed in the light of histopathological data and current knowledge of the underlying physiology of the fMRI signal in the cerebellum. PMID- 26521072 TI - Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation. AB - The functional dynamics and cellular sources of oxidative stress are central to understanding MS pathogenesis but remain elusive, due to the lack of appropriate detection methods. Here we employ NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX enzymes) in vivo to identify inflammatory monocytes, activated microglia, and astrocytes expressing NOX1 as major cellular sources of oxidative stress in the central nervous system of mice affected by experimental autoimmune encephalomyelitis (EAE). This directly affects neuronal function in vivo, indicated by sustained elevated neuronal calcium. The systemic involvement of oxidative stress is mirrored by overactivation of NOX enzymes in peripheral CD11b(+) cells in later phases of both MS and EAE. This effect is antagonized by systemic intake of the NOX inhibitor and anti-oxidant epigallocatechin-3-gallate. Together, this persistent hyper-activation of oxidative enzymes suggests an "oxidative stress memory" both in the periphery and CNS compartments, in chronic neuroinflammation. PMID- 26521075 TI - To delegate or not to delegate: A review of control frameworks for autonomous cars. AB - There have been significant advances in technology and automated systems that will eventually see the use of autonomous cars as commonplace on our roads. Various systems are already available that provide the driver with different levels of decision support. This paper highlights the key human factors issues associated with the interaction between the user and an autonomous system, including assistive decision support and the delegation of authority to the automobile. The level of support offered to the driver can range from traditional automated assistance, to system generated guidance that offers advice for the driver to act upon, and even more direct action that is initiated by the system itself without driver intervention. In many of these instances the role of the driver is slowly moving towards a supervisory role within a complex system rather than one of direct control of the vehicle. Different paradigms of interaction are considered and focus is placed on the partnership that takes place between the driver and the vehicle. Drawing on the wealth of knowledge that exists within the aviation domain and research literature that examines technology partnerships within the cockpit, this paper considers important factors that will assist the automotive community to understand the underlying issues of the human and their interaction within complex systems. PMID- 26521074 TI - Linking Essential Tremor to the Cerebellum: Clinical Evidence. AB - Essential tremor (ET) might be a family of diseases unified by the presence of kinetic tremor, but also showing etiological, pathological, and clinical heterogeneity. In this review, we will describe the most significant clinical evidence, which suggests that ET is linked to the cerebellum. Data for this review were identified by searching PUBMED (January 1966 to May 2015) crossing the terms "essential tremor" (ET) and "cerebellum," which yielded 201 entries, 11 of which included the term "cerebellum" in the article title. This was supplemented by articles in the author's files that pertained to this topic. The wide spectrum of clinical features of ET that suggest that it originates as a cerebellar or cerebellar outflow problem include the presence of intentional tremor, gait and balance abnormalities, subtle features of dysarthria, and oculomotor abnormalities, as well as deficits in eye-hand coordination, motor learning deficits, incoordination during spiral drawing task, abnormalities in motor timing and visual reaction time, impairment of social abilities, improvement in tremor after cerebellar stroke, efficacy of deep brain stimulation (which blocks cerebellar outflow), and cognitive dysfunction. It is unlikely, however, that cerebellar dysfunction, per se, fully explains ET-associated dementia, because the cognitive deficits that have been described in patients with cerebellar lesions are generally mild. Overall, a variety of clinical findings suggest that in at least a sizable proportion of patients with ET, there is an underlying abnormality of the cerebellum and/or its pathways. PMID- 26521076 TI - Communicating hydrocephalus, a long-term complication of dural tear during lumbar spine surgery. AB - PURPOSE: Iatrogenic dural tears during lumbar spine surgery are not uncommon and may have multiple long-term sequelae if not managed promptly and definitively. Sequelae include pseudomeningocoeles due to a persistent cerebrospinal fluid leak, which may result in a subarachnoid hemorrhage or subdural hematoma. These, in turn, can lead to adult communicating hydrocephalus. The purpose of this study is to describe a case of an intraoperative iatrogenic dural tear leading to the formation of a pseudomeningocoele and progressing to hydrocephalus. METHODS: We present a case of a 62-year-old female who had an iatrogenic dural tear during a lumbar decompression and instrumented fusion. Attempts at closure were unsuccessful, which led to the formation of a pseudomeningocoele and an ascending subdural hygroma, progressing into a communicating hydrocephalus which was treated with a ventriculoperitoneal shunt. RESULTS: Imaging studies and clinical follow up after the incidental durotomy demonstrate complications arising from the persistent cerebrospinal fluid leak, beginning with the formation of the pseudomeningocoele and progression to hydrocephalus. Based on these imaging studies, it was possible to illustrate the development of each of the complications. CONCLUSION: The need for prompt recognition and proper management of iatrogenic dural tears are emphasized in order to avoid future complications that may arise from inadequate or proper treatment. PMID- 26521077 TI - Subtotal Cholecystectomy-"Fenestrating" vs "Reconstituting" Subtypes and the Prevention of Bile Duct Injury: Definition of the Optimal Procedure in Difficult Operative Conditions. AB - Less than complete cholecystectomy has been advocated for difficult operative conditions for more than 100 years. These operations are called partial or subtotal cholecystectomy, but the terms are poorly defined and do not stipulate whether a remnant gallbladder is created. This article briefly reviews the history and development of the procedures and introduces new terms to clarify the field. The term partial is discarded, and subtotal cholecystectomies are divided into "fenestrating" and "reconstituting" types. Subtotal reconstituting cholecystectomy closes off the lower end of the gallbladder, reducing the incidence of postoperative fistula, but creates a remnant gallbladder, which may result in recurrence of symptomatic cholecystolithiasis. Subtotal fenestrating cholecystectomy does not occlude the gallbladder, but may suture the cystic duct internally. It has a higher incidence of postoperative biliary fistula, but does not appear to be associated with recurrent cholecystolithiasis. Laparoscopic subtotal cholecystectomy has advantages but may require advanced laparoscopic skills. PMID- 26521078 TI - Right hemisphere grey matter structure and language outcomes in chronic left hemisphere stroke. AB - The neural mechanisms underlying recovery of language after left hemisphere stroke remain elusive. Although older evidence suggested that right hemisphere language homologues compensate for damage in left hemisphere language areas, the current prevailing theory suggests that right hemisphere engagement is ineffective or even maladaptive. Using a novel combination of support vector regression-based lesion-symptom mapping and voxel-based morphometry, we aimed to determine whether local grey matter volume in the right hemisphere independently contributes to aphasia outcomes after chronic left hemisphere stroke. Thirty-two left hemisphere stroke survivors with aphasia underwent language assessment with the Western Aphasia Battery-Revised and tests of other cognitive domains. High resolution T1-weighted images were obtained in aphasia patients and 30 demographically matched healthy controls. Support vector regression-based multivariate lesion-symptom mapping was used to identify critical language areas in the left hemisphere and then to quantify each stroke survivor's lesion burden in these areas. After controlling for these direct effects of the stroke on language, voxel-based morphometry was then used to determine whether local grey matter volumes in the right hemisphere explained additional variance in language outcomes. In brain areas in which grey matter volumes related to language outcomes, we then compared grey matter volumes in patients and healthy controls to assess post-stroke plasticity. Lesion-symptom mapping showed that specific left hemisphere regions related to different language abilities. After controlling for lesion burden in these areas, lesion size, and demographic factors, grey matter volumes in parts of the right temporoparietal cortex positively related to spontaneous speech, naming, and repetition scores. Examining whether domain general cognitive functions might explain these relationships, partial correlations demonstrated that grey matter volumes in these clusters related to verbal working memory capacity, but not other cognitive functions. Further, grey matter volumes in these areas were greater in stroke survivors than healthy control subjects. To confirm this result, 10 chronic left hemisphere stroke survivors with no history of aphasia were identified. Grey matter volumes in right temporoparietal clusters were greater in stroke survivors with aphasia compared to those without history of aphasia. These findings suggest that the grey matter structure of right hemisphere posterior dorsal stream language homologues independently contributes to language production abilities in chronic left hemisphere stroke, and that these areas may undergo hypertrophy after a stroke causing aphasia. PMID- 26521080 TI - Matrix metalloproteinase genes on chromosome 11q22 and risk of carpal tunnel syndrome. AB - Involvement of tendons and/or connective tissue structures in the aetiology of idiopathic carpal tunnel syndrome (CTS) has been proposed. DNA sequence variants within genes encoding structural components of the collagen fibril, the basic structural unit of connective tissue, have been shown to associate with modulating CTS risk. The matrix metalloproteinases (MMPs) play an important role in connective tissue remodelling. Variants within the MMP10, MMP1, MMP3 and MMP12 gene cluster on chromosome 11q22 have been associated with connective tissue injuries. The aim of this study was to investigate whether variants within these MMP genes are associated with CTS. Ninety-seven, self-reported Coloured participants with a history of CTS release surgery and 131 appropriately matched controls were genotyped for MMP10 rs486055 (C/T), MMP1 rs1799750 (G/GG), MMP3 rs679620 (A/G) or MMP12 rs2276109 (A/G) variants. A Pearson's Chi-squared test or a Fisher's exact test was used to determine any significant differences between the genotype distributions or any other categorical data of the groups. An analysis of variance (ANOVA) was used to detect any significant differences between CTS and control groups for continuous data. There were no independent associations between any of the investigated MMP variants and CTS. There were also no significant differences in the relative distributions of the constructed MMP inferred haplotypes between CTS and CON groups. The MMP variants previously associated with other connective tissue injuries were not associated with CTS in this population. These findings do not exclude the possibility that other variants within this locus or other MMP genes are associated with CTS. PMID- 26521081 TI - Cross-cultural validation of the paediatric Gait, Arms, Legs, Spine (pGALS) tool for the screening of musculoskeletal disorders in Mexican children. AB - The aim of this study was to validate the paediatric Gait, Arms, Legs, Spine (pGALS) tool for Mexican Spanish to screen Mexican paediatric population for musculoskeletal (MSK) disorders. A cross-sectional study was performed in the Paediatric Hospital of the Mexican Social Security Institute in Guadalajara, Jalisco. The validation included children and adolescents aged 6-16 years, 87 patients with musculoskeletal disorders and 88 controls without musculoskeletal disorders. The cross-cultural validation followed the current published guidelines. The average pGALS administration time was 2.9 min (SD 0.54). The internal consistency score (Cronbach's alpha) was 0.90 (0.89 for inflammatory and 0.77 for non-inflammatory disorders) for MSK disorders, with a sensitivity of 97 % (95 % CI 92-99 %), a specificity of 93 % (95 % CI 86-97 %), a LR+ of 14.3, and a ROC curve of 0.95 (95 % CI 0.92-0.98 %). The inflammatory disorders group had a sensitivity of 97 % (95 % CI 86-99 %), a specificity of 93 % (95 % CI 86-97 %), a LR+ of 14.2, and a ROC curve of 0.95 % (95 % CI 0.91-0.99 %). The non inflammatory disorders group had a sensitivity of 98 % (95 % CI 89-99 %), a specificity of 93 % (95 % CI 86-97 %), and a LR+ of 14.37, with a ROC curve of 0.95 % (95 % CI 0.92-0.98 %). pGALS is a valid screening tool, fast, easy to administer, and useful for detecting musculoskeletal disorders in Mexican children and adolescents. PMID- 26521079 TI - Focal bone involvement in inflammatory arthritis: the role of IL17. AB - Conditions such as rheumatoid arthritis (RA) and spondyloarthritis (SpA, such as psoriatic arthritis, PsA, and ankylosing spondylitis, AS) are characterized by an imbalance between osteoclast (OC) bone resorption and osteoblast (OB) bone formation. The two conditions present substantial differences in bone involvement, which is probably related to the different expression of IL17 and TNFalpha, two cytokines that strongly promote osteoclastogenesis and focal bone erosions. TNFalpha is the major inflammatory cytokine in RA. It acts by both triggering OC bone erosion via the RANK-RANKL system, and suppressing OB bone formation through the overexpression of DKK1, a powerful inhibitor of the WNT bone anabolic signaling pathway. Differing from TNFalpha, IL17 promotes also osteogenesis, particularly at inflamed sites undergoing mechanical stress, such as entheses. Therefore, in RA, where overexpression of TNFalpha is higher than IL17, OC bone resorption largely prevails upon bone formation. In PsA and AS, the prevailing inflammatory cytokine is IL17, which promotes also osteogenesis. Given the prevalent involvement of entheses poor of OC, excess bone formation may even prevail over excess bone resorption. The results of clinical trials support the different pathophysiology of bone involvement in chronic arthritis. Inflammation control through anti-TNFalpha agents has not resulted in incomparable effects on radiographic progression and excess bone formation in both AS and PsA. Clinical trials investigating IL17 inhibitors, such as secukinumab, in patients with psoriatic disease are underway. The preliminary results on inflammation and symptoms appear positive, while long-term studies are required to demonstrate an effect on excess bone formation. PMID- 26521084 TI - A review of reproductive toxicity of microcystins. AB - Animal studies provide strong evidence of positive associations between microcystins (MCs) exposure and reproductive toxicity, representing a threat to human reproductive health and the biodiversity of wild life. This paper reviews current knowledge of the reproductive toxicity of MCs, with regard to mammals, fishes, amphibians, and birds, mostly in males. Toxicity of MCs is primarily governed by the inhibition of protein phosphatases 1 and 2A (PP1 and PP2A) and disturbance of cellular phosphorylation balance. MCs exposure is related to excessive production of reactive oxygen species (ROS) and oxidative stress, leading to cytoskeleton disruption, mitochondria dysfunction, endoplasmic reticulum (ER) stress, and DNA damage. MCs induce cell apoptosis mediated by the mitochondrial and ROS and ER pathways. Through PP1/2A inhibition and oxidative stress, MCs lead to differential expression/activity of transcriptional factors and proteins involved in the pathways of cellular differentiation, proliferation, and tumor promotion. MC-induced DNA damage is also involved in carcinogenicity. Apart from a direct effect on testes and ovaries, MCs indirectly affect sex hormones by damaging the hypothalamic-pituitary-gonad (HPG) axis and liver. Parental exposure to MCs may result in hepatotoxicity and neurotoxicity of offspring. We also summarize the current research gaps which should be addressed by further studies. PMID- 26521082 TI - Brain glucose metabolism during hypoglycemia in type 1 diabetes: insights from functional and metabolic neuroimaging studies. AB - Hypoglycemia is the most frequent complication of insulin therapy in patients with type 1 diabetes. Since the brain is reliant on circulating glucose as its main source of energy, hypoglycemia poses a threat for normal brain function. Paradoxically, although hypoglycemia commonly induces immediate decline in cognitive function, long-lasting changes in brain structure and cognitive function are uncommon in patients with type 1 diabetes. In fact, recurrent hypoglycemia initiates a process of habituation that suppresses hormonal responses to and impairs awareness of subsequent hypoglycemia, which has been attributed to adaptations in the brain. These observations sparked great scientific interest into the brain's handling of glucose during (recurrent) hypoglycemia. Various neuroimaging techniques have been employed to study brain (glucose) metabolism, including PET, fMRI, MRS and ASL. This review discusses what is currently known about cerebral metabolism during hypoglycemia, and how findings obtained by functional and metabolic neuroimaging techniques contributed to this knowledge. PMID- 26521083 TI - Xeroderma pigmentosum group C sensor: unprecedented recognition strategy and tight spatiotemporal regulation. AB - The cellular defense system known as global-genome nucleotide excision repair (GG NER) safeguards genome stability by eliminating a plethora of structurally unrelated DNA adducts inflicted by chemical carcinogens, ultraviolet (UV) radiation or endogenous metabolic by-products. Xeroderma pigmentosum group C (XPC) protein provides the promiscuous damage sensor that initiates this versatile NER reaction through the sequential recruitment of DNA helicases and endonucleases, which in turn recognize and excise insulting base adducts. As a DNA damage sensor, XPC protein is very unique in that it (a) displays an extremely wide substrate range, (b) localizes DNA lesions by an entirely indirect readout strategy, (c) recruits not only NER factors but also multiple repair players, (d) interacts avidly with undamaged DNA, (e) also interrogates nucleosome-wrapped DNA irrespective of chromatin compaction and (f) additionally functions beyond repair as a co-activator of RNA polymerase II-mediated transcription. Many recent reports highlighted the complexity of a post translational circuit that uses polypeptide modifiers to regulate the spatiotemporal activity of this multiuse sensor during the UV damage response in human skin. A newly emerging concept is that stringent regulation of the diverse XPC functions is needed to prioritize DNA repair while avoiding the futile processing of undamaged genes or silent genomic sequences. PMID- 26521085 TI - Decellularization of porcine articular cartilage explants and their subsequent repopulation with human chondroprogenitor cells. AB - Engineering tissues with comparable structure, composition and mechanical functionality to native articular cartilage remains a challenge. One possible solution would be to decellularize xenogeneic articular cartilage in such a way that the structure of the tissue is maintained, and to then repopulate this decellularized matrix with human chondroprogenitor cells that will facilitate the reconstitution, maintenance and eventual turnover of the construct following implantation. The overall objective of this study was to develop a protocol to efficiently decellularize porcine articular cartilage grafts and to identify a methodology to subsequently repopulate such explants with human chondroprogenitor cells. To this end, channels were first introduced into cylindrical articular cartilage explants, which were then decellularized with a combination of various chemical reagents including sodium dodecyl sulfate (SDS) and nucleases. The decellularization protocol resulted in a ~90% reduction in porcine DNA content, with little observed effect on the collagen content and the collagen architecture of the tissue, although a near-complete removal of sulfated glycosaminoglycans (sGAG) and a related reduction in tissue compressive properties was observed. The introduction of channels did not have any detrimental effect on the biochemical or the mechanical properties of the decellularized tissue. Next, decellularized cartilage explants with or without channels were seeded with human infrapatellar fat pad derived stem cells (FPSCs) and cultured chondrogenically under either static or rotational conditions for 10 days. Both channeled and non-channeled explants supported the viability, proliferation and chondrogenic differentiation of FPSCs. The addition of channels facilitated cell migration and subsequent deposition of cartilage-specific matrix into more central regions of these explants. The application of rotational culture appeared to promote a less proliferative cellular phenotype and led to an increase in sGAG synthesis within the explants. Rotational culture also appeared to promote higher cell viability and led to a more even distribution of cells within the channels of decellularized explants. To conclude, this study describes an effective protocol for the decellularization of porcine articular cartilage grafts and a novel methodology for the partial recellularization of such explants with human stem cells. Decellularized soft tissue explants that maintain their native collagen architecture may represent promising scaffolds for musculoskeletal tissue engineering applications. PMID- 26521086 TI - Depressive symptoms and cognitive decline: A longitudinal analysis of potentially modifiable risk factors in community dwelling older adults. AB - BACKGROUND: Depressive symptoms have been associated with increased risk of cognitive decline in later life. There are no interventions proven to reduce risk of cognitive decline in older adults with depression, and it is unclear how these effects are mediated. We aim to determine what mediates the relationship between depressive symptoms and cognitive decline in later life. METHODS: Seven thousand six hundred and sixty six community dwelling older adults (age >= 50) from the English Longitudinal study of Ageing (ELSA) underwent clinical assessment. Inflammation was assessed with C Reactive Protein and depressive symptoms were assessed with the 8-item version of the Center for Epidemiologic Studies (CESD) scale. RESULTS: Five thousand, five hundred and ninety (73.5%) had a follow-up cognitive assessment after a median of 47 months. Depressive symptoms were independently associated with cognitive decline (B=0.09, p<0.001). Low physical activity, inflammation, metabolic syndrome and vascular risk factors were associated with elevated depressive symptoms. Low physical activity (z=2.16, p=0.03) and inflammation (z=2.3, p=0.02) mediated the relationship between depressive symptoms and cognitive decline while hypertension, diabetes and smoking also contributed. LIMITATIONS: This is an observational study with a limited duration of follow up. Not all variables related to cognitive decline were accounted for in this analysis. CONCLUSIONS: The relationship between depressive symptoms and cognitive decline in later life appears to be mediated by low physical activity, increased inflammation and vascular risk factors that may be amenable to modification. PMID- 26521087 TI - Lower [3H]LY341495 binding to mGlu2/3 receptors in the anterior cingulate of subjects with major depressive disorder but not bipolar disorder or schizophrenia. AB - INTRODUCTION: The glutamatergic system has recently been implicated in the pathogenesis and treatment of major depressive disorders(MDD) and mGlu2/3 receptors play an important role in regulating glutamatergic tone. We therefore measured cortical levels of mGlu2/3 to determine if they were changed in MDD. METHODS: Binding parameters for [(3)H]LY341495 (mGlu2/3 antagonist) were determined to allow optimized in situ binding with autoradiography to be completed using a number of CNS regions. Subsequently, density of [(3)H]LY341495 binding was measured in BA24(anterior cingulate cortex), BA17(visual cortex) and BA46(dorsolateral prefrontal cortex) from subjects with MDD, Bipolar Disorder(BPD), Schizophrenia(SCZ), and controls, as well as rats treated with imipramine (20mg/kg), fluoxetine (10mg/kg), or vehicle. RESULTS: mGlu2/3 are widely expressed throughout the brain with high levels observed in cortex. [(3)H]LY341495 binding was significantly lower in BA24 from subjects with MDD (mean +/- SEM=141.3 +/- 14.65 fmol/ETE) relative to controls (184.9 +/- 7.76 fmol/ETE; Cohen's d=1.005, p<0.05). There were no other differences with diagnoses, and chronic antidepressant treatment in rats had minimal effect on binding. LIMITATIONS: Using this approach we are unable to determine whether the change represents fluctuations in mGlu2, mGlu3, or both. Moreover, using postmortem tissue we are unable to dissociate the irrevocable confound of suicidality upon binding levels. CONCLUSION: We have demonstrated lower [(3)H]LY341495 binding levels in MDD in BA24-a brain region implicated in depression. Moreover we show that the lower levels are unlikely to be the result of antidepressant treatment. These data suggest that levels of either mGlu2 and/or mGlu3 are affected in the aetiology of MDD. PMID- 26521089 TI - Studies on the optimum conditions using acid-washed zero-valent iron/aluminum mixtures in permeable reactive barriers for the removal of different heavy metal ions from wastewater. AB - The method of permeable reactive barriers (PRBs) is considered as one of the most practicable approaches in treating heavy metals contaminated surface and groundwater. The mixture of acid-washed zero-valent iron (ZVI) and zero-valent aluminum (ZVAl) as reactive medium in PRBs to treat heavy metal wastewater containing Cr(VI), Cd(2+), Ni(2+), Cu(2+), and Zn(2+) was investigated. The performance of column filled with the mixture of acid-washed ZVI and ZVAl was much better than the column filled with ZVI or ZVAl alone. At initial pH 5.4 and flow rates of 1.0 mL/min, the time that the removal efficiencies of Cr(VI), Cd(2+), Ni(2+), Cu(2+), and Zn(2+) were all above 99.5% can keep about 300 h using 80 g/40 g acid-washed ZVI/ZVAl when treating wastewater containing each heavy metal ions (Cr(VI), Cd(2+), Ni(2+), Cu(2+), and Zn(2+)) concentration of 20.0 mg/L. Scanning electron microscopy (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) were used to characterize ZVI/ZVAl before and after reaction and the reaction mechanism of the heavy metal ions with ZVI/ZVAl was discussed. PMID- 26521088 TI - World Health Organization cardiovascular risk stratification and target organ damage. AB - BACKGROUND: Prediction charts allow treatment to be targeted according to simple markers of cardiovascular risk; many algorithms do not recommend screening asymptomatic target organ damage which could change dramatically the assessment. OBJECTIVE: To demonstrate that target organ damage is present in low cardiovascular risk hypertensive patients and it is more frequent and severe as global cardiovascular risk increases. METHODS: Consecutive hypertensive patients treated at a single Latin American center. Cardiovascular risk stratified according to 2013 WHO/ISH risk prediction chart America B. Left ventricular mass assessed by Devereux method, left ventricular hypertrophy considered >95g/m(2) in women and >115g/m(2) in men. Transmitral diastolic peak early flow velocity to average septal/lateral peak early diastolic relaxation velocity (E/e' ratio) measured cut off value >13. Systolic function assessed by tissue Doppler average interventricular septum/lateral wall mitral annulus rate systolic excursion (s wave). RESULTS: A total of 292 patients were included of whom 159 patients (54.5%) had cardiovascular risk of <10%, 90 (30.8%) had cardiovascular risk of 10 20% and 43 (14.7%) had cardiovascular risk of >20%. Left ventricular hypertrophy was detected in 17.6% low risk patients, 27.8% in medium risk and 23.3% in high risk (p<0.05), abnormal E/e' ratio was found in 13.8%, 31.1% and 27.9%, respectively (p<0.05). Mean s wave was 8.03+8, 8.1+9 and 8.7+1cm/s for low, intermediate and high risk patients, respectively (p<0.025). CONCLUSIONS: Target organ damage is more frequent and severe in high risk; one over four subjects was misclassified due to the presence of asymptomatic target organ damage. PMID- 26521090 TI - Environmental assessment of heavy metal transport and transformation in the Hangzhou Bay, China. AB - The environmental impact of heavy metal (Cu, Cd, Zn, Pb, Ni, (90)Sr and (137)Cs) transport and transformation in the Hangzhou Bay (China) was assessed through a comprehensive model that integrates hydrodynamics, sediment and heavy metal transport. A mechanistic surface complexation model was used to estimate the adsorption and desorption of heavy metal by suspended sediment under different aqueous chemistry conditions. The dynamics of metal exchange to and from the seabed was also assessed. The primary processes regulating heavy metal distribution, i.e., convection-diffusion, adsorption-desorption, sedimentation resuspension, as well as other physical and chemical processes related to mass exchange between adjacent sediment layers, were considered in detail. The accidental discharge of (137)Cs was simulated as an example and results showed that (137)Cs transported along the coast driven by tidal flow. Most (137)Cs distributed near the outfall and accumulated in the seabed sediment. The proposed model can be a useful tool for predicting heavy metal transport and fate and provide a theoretical basis to guide field sampling, assessment of risks and the design of remediation strategies. PMID- 26521091 TI - Ultrasound-assisted heterogeneous Fenton-like degradation of tetracycline over a magnetite catalyst. AB - The degradation of tetracycline over Fe3O4 catalyst was studied by using a coupled ultrasound/heterogeneous Fenton process. The effects of some key reaction parameters, the evolution of toxicity, and the reaction mechanism were investigated. Experimental results showed that the stability of catalyst was significantly improved when ultrasound was employed. Under optimal conditions, 93.6% of tetracycline was removed after 60 min of treatment. The removal efficiency of the total organic carbon (TOC) at 60 min was 31.8%. The surface hydroxyl radicals were identified as the major reactive species during the oxidation process. Toxicity tests with Daphnia magna indicated that the toxicity of the solution increased during the first 60 min and then decreased as the oxidation proceeded. PMID- 26521092 TI - Selecting boundary conditions in physiological strain analysis of the femur: Balanced loads, inertia relief method and follower load. AB - Selection of boundary constraints may influence amount and distribution of loads. The purpose of this study is to analyze the potential of inertia relief and follower load to maintain the effects of musculoskeletal loads even under large deflections in patient specific finite element models of intact or fractured bone compared to empiric boundary constraints which have been shown to lead to physiological displacements and surface strains. The goal is to elucidate the use of boundary conditions in strain analyses of bones. Finite element models of the intact femur and a model of clinically relevant fracture stabilization by locking plate fixation were analyzed with normal walking loading conditions for different boundary conditions, specifically re-balanced loading, inertia relief and follower load. Peak principal cortex surface strains for different boundary conditions are consistent (maximum deviation 13.7%) except for inertia relief without force balancing (maximum deviation 108.4%). Influence of follower load on displacements increases with higher deflection in fracture model (from 3% to 7% for force balanced model). For load balanced models, follower load had only minor influence, though the effect increases strongly with higher deflection. Conventional constraints of fixed nodes in space should be carefully reconsidered because their type and position are challenging to justify and for their potential to introduce relevant non-physiological reaction forces. Inertia relief provides an alternative method which yields physiological strain results. PMID- 26521093 TI - Reversible and irreversible sorption of perfluorinated compounds (PFCs) by sediments of an urban reservoir. AB - Uncertainty about the extent to which contaminant sorption by suspended solids and bed sediments is irreversible is a major impediment for modeling and managing the water quality of surface water resources. This study examined reversible and irreversible sorption of several perfluorinated compounds (PFCs) to bed sediments from an urban reservoir. PFCs investigated include C4, C6, C8, C9 and C10 perfluoroalkanoate homologues (PFBA, PFHxA, PFOA, PFNA and PFDA, respectively) and perfluorooctane and hexane sulfonate (PFOS and PFHxS, respectively). Although sorption branches of the PFOS, PFNA and PFDA isotherms were nearly linear (implying a partitioning-like process), desorption experiments indicated that a fraction of the sorbed PFCs were entrapped and resistant to desorption. The hysteretic desorption branches were approximately linear. Irreversibility increased with chain length and was nearly complete for PFDA (thermodynamic irreversibility index (TII) 0.98). For the weakly sorbing PFOA and PFHxS, sorption was largely reversible. Data suggest that (1) for the strongly sorbing PFCs, e.g. PFNA, PFDA and PFOS, bed sediments acted predominantly as irreversible sinks, (2) aqueous concentrations of the moderately sorbing PFCs (PFOA and PFHxS) are buffered by reversibly sorbing suspended solids, and (3) the short-chain PFCs (PFBA and PFHxA) are not significantly sorbed and therefore not expected to be significantly influenced by sediment transport. Situations in which highly contaminated particles entering relatively clean water bodies, equilibrium is approached from the reverse (desorption) direction. For irreversibly sorbed contaminants field-based K(D) values will be higher than the K(D) values derived from laboratory sorption data obtained from forward sorption experiments. PMID- 26521094 TI - Curcumin as an Adjunct Drug for Infectious Diseases. AB - Curcumin, by virtue of its ability to function as an immunomodulator, has the potential to serve as an adjunct drug to treat infectious diseases and provide long-term protection. The current need is to establish clinical trials with curcumin as an adjunct drug against specific infectious diseases. PMID- 26521095 TI - Comparison of antioxidant activities of different parts from snow chrysanthemum (Coreopsis tinctoria Nutt.) and identification of their natural antioxidants using high performance liquid chromatography coupled with diode array detection and mass spectrometry and 2,2'-azinobis(3-ethylbenzthiazoline-sulfonic acid)diammonium salt-based assay. AB - Snow chrysanthemum (Coreopsis tinctoria Nutt.), a world-widely well-known flower tea material, has attracted more and more attention because of its beneficial health effects such as antioxidant activity and special flavor. In this study, a high performance liquid chromatography coupled with diode array detection and mass spectrometry (HPLC-DAD-MS) and 2,2'-azinobis(3-ethylbenzthiazoline-sulfonic acid)diammonium salt (ABTS) based assay was employed for comparison and identification of antioxidants in different samples of snow chrysanthemum. The results showed that snow chrysanthemum flowers possessed the highest while stems presented the lowest antioxidant capacities. Fourteen detected peaks with antioxidant activity were temporarily identified as 3,4',5,6,7 pentahydroxyflavanone-O-hexoside, chlorogenic acid, 2R-3',4',8 trihydroxyflavanone-7-O-glucoside, flavanomarein, flavanocorepsin, flavanokanin, quercetagitin-7-O-glucoside, 3',5,5',7-tetrahydroxyflavanone-O-hexoside, marein, maritimein, 1,3-dicaffeoylquinic acid, coreopsin, okanin and acetyl-marein by comparing their UV spectra, retention times and MS data with standards or literature data. Antioxidants existed in snow chrysanthemum are quite different from those reported in Chrysanthemum morifolium, a well-known traditional beverage in China, which indicated that snow chrysanthemum may be a promising herbal tea material with obvious antioxidant activity. PMID- 26521096 TI - Quantitative structure-property relationship analysis for the retention index of fragrance-like compounds on a polar stationary phase. AB - A quantitative structure-property relationship (QSPR) was developed for modeling the retention index of 1184 flavor and fragrance compounds measured using a Carbowax 20M glass capillary gas chromatography column. The 4885 molecular descriptors were calculated using Dragon software, and then were simultaneously analyzed through multivariable linear regression analysis using the replacement method (RM) variable subset selection technique. We proceeded in three steps, the first one by considering all descriptor blocks, the second one by excluding conformational descriptor blocks, and the last one by analyzing only 3D descriptor families. The models were validated through an external test set of compounds. Cross-validation methods such as leave-one-out and leave-many-out were applied, together with Y-randomization and applicability domain analysis. The developed model was used to estimate the I of a set of 22 molecules. The results clearly suggest that 3D-descriptors do not offer relevant information for modeling the retention index, while a topological index such as the Randic-like index from reciprocal squared distance matrix has a high relevance for this purpose. PMID- 26521097 TI - Tissue-engineered bone treating simple bone cyst--a new strategy. AB - BACKGROUND: The pathological fracture is a most important complication during bone cyst and can be prevented by early focus clearance and bone grafting. Tissue engineered bone (TEB) with outstanding osteogenesis is a better choice for bone repair. Here, we firstly reported that TEB was used to heal bone cyst. MATERIALS AND METHODS: The clinical data were collected from 23 patients who received bone defect repair separately with TEB or allogeneic bone (Allo-B) after erasion during 2004-2008. Allo-B had been as a control. The healing time and healing quality, the incidence of complications, the safety, and the bone grafting failure rate were compared. RESULTS: In TEB group, the follow-up time was 28 +/- 15.48 months; nine cases were confirmed healed (3.45 +/- 2.01 months), one case was cyst healing with defect, and one case had relapse. In Allo-B, 12 patients were followed up for 28.58 +/- 20.44 months; seven cases were confirmed healed (6.75 +/- 3.31 mo), four cases were cyst healing with defect, and one case had relapse. After operation, no statistically significant differences in bone healing and incidence of complications were observed between two groups, but the difference in bone healing time was statistically significant (P < 0.05). There was no else tumorigenesis in both groups. CONCLUSIONS: In treating simple bone cyst, Allo-B and TEB have considerable efficacy and safety; TEB is superior to Allo-B in respect of healing time; there is no rejection after TEB grafting but certain rejection after Allo-B grafting. PMID- 26521098 TI - CDP-choline modulates matrix metalloproteinases in rat sciatic injury. AB - BACKGROUND: CDP-choline (cytidine-5'-diphosphocholine) improves functional recovery, promotes nerve regeneration, and decreases perineural scarring in rat peripheral nerve injury. The aim of the present study was to investigate the mechanism of action of CDP-choline with regard to matrix metalloproteinase (MMP) activity in the rat-transected sciatic nerve injury model. MATERIALS AND METHODS: Male Wistar rats were randomized into Sham, Saline, and CDP-choline groups. Rats in Sham group received Sham surgery, whereas rats in Saline and CDP-choline groups underwent right sciatic nerve transection followed by immediate primary saturation and injected intraperitoneally with 0.9% NaCl (1 mL/kg) and CDP choline (600 MUg/kg), respectively. Sciatic nerve samples were obtained 1, 3, and 7 d after the surgery and analyzed for levels and activities of MMP-2 and MMP-9, levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) and TIMP-3, and axonal regeneration. RESULTS: CDP-choline treatment decreased the levels and activities of MMP-2 and MMP-9, whereas increasing levels of TIMP-1 and TIMP-3 significantly on the third and seventh day after injury compared to Saline group. In addition, CDP-choline administration resulted in new axon formation and formation and advancement of myelination on newly formed islets (compartments) of axonal regrowth. CONCLUSIONS: Our data show, for the first time, that CDP-choline modulates MMP activity and promotes the expression of TIMPs to stimulate axonal regeneration. These data help to explain one mechanism by which CDP-choline provides neuroprotection in peripheral nerve injury. PMID- 26521099 TI - Murine colitis treated with multitargeted tyrosine kinase inhibitors. AB - BACKGROUND: Angiogenesis, a known pathogenic component of neoplastic and nonneoplastic diseases, serves as a therapeutic target. Vascular endothelial growth factor (VEGF) and angiogenesis are clinically elevated in inflammatory bowel disease. By targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) with receptor tyrosine kinase inhibitors in a murine model of colitis, we hypothesize that angiogenesis will be suppressed and disease severity improved. METHODS AND METHODS: Sorafenib, sunitinib, and axitinib were administered by oral gavage in a murine model of dextran sodium sulfate (DSS) colitis. Inflammation score, microvessel density (MVD), and gene expression of VEGF, VEGFR, platelet-derived growth factor, PDGFR, Ang-2, and epidermal growth factor receptor was assessed. RESULTS: Inflammation and MVD were elevated in groups receiving DSS, but were similar between DSS-only and treatment cohorts. Unexpected weight loss was present in the gavaged groups versus DSS only. In treated groups, VEGFR was significantly decreased (P = 0.002) and VEGF gene expression trended down (P = 0.213) versus DSS only. Neither the platelet-derived growth factor/PDGFR pathway nor the alternative pathways, Ang-2 and epidermal growth factor receptor, were significantly changed from DSS control in treatment cohorts. CONCLUSIONS: This study confirms the association between inflammation and MVD. Antiangiogenic receptor tyrosine kinase inhibitors suppressed the VEGF/VEGFR pathway but the expected decrease in colonic MVD did not follow, suggesting possible involvement of other angiogenic pathway(s). In the DSS model of colitis, vehicle selection and mouse strain can impact disease response. PMID- 26521100 TI - Effects of CYP2C19 allelic variants on inhibition of platelet aggregation and major adverse cardiovascular events in Japanese patients with acute coronary syndrome: The PRASFIT-ACS study. AB - BACKGROUND: We examined the effects of cytochrome P450 2C19 (CYP2C19) polymorphisms on the efficacy and safety of prasugrel and clopidogrel in a post hoc analysis of the PRASugrel compared with clopidogrel For Japanese patIenTs with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) (PRASFIT-ACS) study. METHODS: Japanese ACS patients undergoing PCI were randomized (double-blind) to receive prasugrel (loading/maintenance dose: 20/3.75mg) or clopidogrel (300/75mg) plus aspirin for 24-48 weeks. Pharmacogenomic analyses were conducted in 773/1363 patients. P2Y12 reaction units (PRU) were determined using the VerifyNow((r)) P2Y12 assay (Accumetrics, San Diego, CA, USA). CYP2C19 genotypes were classified as extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM). RESULTS: Overall, 39.2% and 60.8% of patients in the prasugrel group and 35.2% and 64.8% of patients in the clopidogrel group were classified as EM and IM+PM, respectively. Among EM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group at 2-4 and 5-12h after the loading dose, but was similar in both groups from week 4 onwards. Among IM+PM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group throughout the study. Among EM patients, the incidence of major adverse cardiovascular events (MACE) at 24 weeks was 11.8% in the prasugrel group and 11.9% in the clopidogrel group [hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.50-1.96]. Among IM+PM patients, the incidence of MACE was 9.3% in the prasugrel group and 12.5% in the clopidogrel group (HR: 0.78, 95% CI: 0.45-1.35). The incidences of major, minor, and clinically relevant bleeding were similar between the two groups for each genotype. CONCLUSIONS: Prasugrel showed more consistent antiplatelet effects than clopidogrel in Japanese ACS patients irrespective of the CYP2C19 phenotype. PMID- 26521101 TI - Targeting airway mucus hypersecretion in chronic obstructive pulmonary disease. PMID- 26521102 TI - Comorbidity in chronic obstructive pulmonary disease. AB - Patients with chronic obstructive pulmonary diseases (COPD) often experience comorbid conditions. The most common comorbidities that have been associated with COPD include cardiovascular diseases, lung cancer, metabolic disorder, osteoporosis, anxiety and depression, skeletal muscle dysfunction, cachexia, gastrointestinal diseases, and other respiratory conditions. Not only are comorbidities common but they also considerably influence disease prognosis and patients' health status, and are associated with poor clinical outcomes. However, perusal of literature indicates that little has been done so far to effectively assess, manage, and treat comorbidities in patients with COPD. The aim of this review is to comprehensively narrate the comorbid conditions that often coexist with COPD, along with their reported prevalence and their significant impacts in the disease management of COPD. A perspective on integrated disease management approaches for COPD is also discussed. PMID- 26521103 TI - The chronic obstructive pulmonary disease comorbidity spectrum in Japan differs from that in western countries. AB - Patients with Chronic Obstructive Pulmonary Disease (COPD) frequently suffer from various comorbidities, such as cardiovascular disease, osteoporosis, depression, malnutrition, metabolic syndrome, diabetes, and lung cancer. These comorbidities have a significant impact on disease severity and survival. In fact, guidelines from both the Global Initiative for Chronic Obstructive Lung Disease and the Japanese Respiratory Society recommend that physicians take comorbidities into account when they evaluate COPD severity. These guidelines also emphasize the importance of managing comorbidities alongside airway obstruction in COPD. The mechanisms by which the many COPD-related comorbidities develop are still unclear. Aging and smoking are well-established as major factors. However, systemic inflammation may also contribute to the disease process. Having developed from the classical theory to differentiate COPD patients into "pink puffers" and "blue bloaters", COPD is now generally considered as a heterogeneous condition. On this point, we have noticed that the characteristics of Japanese COPD patients tend to differ from those of Westerners. Specifically, Japanese patients tend to be older, to have lower body mass index, to suffer from emphysema-dominant lung disease, and to experience exacerbations less frequently. The comorbidity spectrum of Japanese COPD patients also seems to differ from that of Westerners. For instance, in Japanese patients, cardiovascular disease and metabolic syndrome are less prevalent, whereas osteoporosis and malnutrition are more frequent. In order to treat Japanese COPD patients optimally, we must pay particular attention to their unique demographics and comorbidity spectrum, which contrast with those of Western COPD patients. PMID- 26521104 TI - Risk factors for acute exacerbation of idiopathic pulmonary fibrosis--Extended analysis of pirfenidone trial in Japan. AB - BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a lifethreatening event and one of the important endpoints in clinical trials involving IPF. Despite this, there has been little evaluation of the potential risk factors for AE-IPF in clinical trials. We evaluated the risk factors for AE IPF in a phase III clinical trial of pirfenidone in Japanese IPF patients. METHODS: The study population comprised 267 patients. The effects of various baseline characteristics as possible risk factors for AE-IPF during the study, as well as those of a >=10% decline in percent vital capacity (%VC) within 6 months, were evaluated using Cox's proportional hazard model. The >=10% decline in %VC was calculated in two ways: (1) an absolute decline (e.g. from 60% predicted to 50%); and (2) a relative decline (e.g. from 60% predicted to 54%). RESULTS: Over 52 weeks, 14 patients experienced AE-IPF. Univariate analysis using Cox's proportional hazards model showed that both relative and absolute >=10% decline in %VC within 6 months were significant risk factors for AE-IPF. Stepwise multivariate analysis demonstrated that absolute or relative decline in both %VC and alveolar to arterial oxygen pressure difference (AaDO2) were significant risk factors for AE. The model using absolute decline [Hazard Ration (HR)=7.405, p=0.0007] and baseline AaDO2 (HR=1.063, p=0.0266) had a better fit than the model using relative decline and baseline AaDO2. CONCLUSIONS: Rapid %VC decline (>=10% within 6 months), and high baseline AaDO2, may be risk factors for AE-IPF. PMID- 26521105 TI - Efficacy of pirfenidone and disease severity of idiopathic pulmonary fibrosis: Extended analysis of phase III trial in Japan. AB - BACKGROUND: A phase III clinical trial of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) in Japan has revealed that pirfenidone attenuated the decline in vital capacity (VC) and improved progression-free survival (PFS). We conducted an extended analysis of the pirfenidone trial to investigate its efficacy with respect to IPF severity in the trial population. METHODS: Patients in the phase III trial were stratified by baseline pulmonary functions including %VC predicted, %diffusion capacity for carbon monoxide predicted, and oxygen saturation by pulse oximetry on exertion and were categorized into mild, moderate, and severe groups of functional impairment. The efficacy of pirfenidone for VC and PFS over 52 weeks was compared among the three sub-populations. RESULTS: Of 264 patients, 102 (39%), 90 (34%), and 72 patients (27%) were classified as having mild, moderate, and severe grades of functional impairment, respectively. This classification was associated with arterial oxygen partial pressure at rest and degree of dyspnea at baseline. While pirfenidone attenuated VC decline at all grades of severity, covariance analysis revealed pirfenidone to have better efficacy in the sub-population with mild-grade IPF. Mixed model repeated measures analysis confirmed that pirfenidone markedly attenuated VC decline in patients with mild-grade IPF compared to its effects in patients with moderate or severe IPF. Pirfenidone also improved PFS markedly in patients with mild-grade IPF. CONCLUSION: This extended analysis suggested that pirfenidone exerted better therapeutic effects in patients with milder IPF. Further analysis with a larger population is needed to confirm these results. PMID- 26521107 TI - Promising effect of chemotherapy with bevacizumab for patients with pulmonary pleomorphic carcinoma: Two case reports and a literature review. AB - Pulmonary pleomorphic carcinoma (PPC) is a rare disease with a poor prognosis. Chemotherapy regimens used to date have not been effective against PPC; thus, a new treatment strategy is needed. Here, we report two patients with PPC who were effectively treated with a chemotherapy regimen including bevacizumab. Both patients received carboplatin/paclitaxel/bevacizumab and showed a partial response. As patients with PPC have been reported to show high expression of vascular endothelial growth factor (VEGF), the tumor specimens from the presented patients also showed high expression of VEGF. Therefore, a chemotherapy regimen including a VEGF inhibitor such as bevacizumab is a promising treatment for patients with PPC. PMID- 26521106 TI - Cyclosporine A combined with low-dose corticosteroid treatment in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: It has been reported that cyclosporine A (CYA) treatment may benefit idiopathic pulmonary fibrosis (IPF) patients. We conducted a randomized, controlled trial at 27 centers across Japan to evaluate the efficacy and safety of CYA with low-dose corticosteroids (CS) for IPF treatment. We compared these findings with others obtained using cyclophosphamide (CPA) combined with low-dose CS: the current standard therapy for IPF. METHODS: The study involved patients between 50 and 74 years of age with well-defined IPF. The primary endpoint was a change in forced vital capacity (FVC) between baseline and 48 weeks. RESULTS: We started this trial in May 2005 and ended it in December 2008. Ninety-nine patients were enrolled in the study. There was no significant difference between the CYA and CPA groups with regard to the change in FVC between baseline and 48 weeks (-0.078L and -0.087L, respectively). Neither did the two groups differ significantly with regard to the incidence rates of several adverse events. CONCLUSIONS: This clinical trial revealed no significant differences between the CYA group and the CPA group with regard to either safety data or the primary endpoint. However, the trial should be regarded as inconclusive because of its small sample size. There was a trend toward a reduction in FVC decline per year when the trial groups were compared with the placebo groups of previous studies, despite patients in this study having severely impaired lung function. Both therapies were well tolerated and lacked serious adverse effects. PMID- 26521108 TI - Comparison of PAVMs associated or not associated with hereditary hemorrhagic telangiectasia in the Japanese population. PMID- 26521109 TI - GBM surgery in the elderly-time to be more aggressive? PMID- 26521110 TI - Administration and Burden of Subcutaneous Immunotherapy for Allergic Rhinitis in U.S. and Canadian Clinical Practice. AB - BACKGROUND: Allergy immunotherapy (AIT) is the only available treatment that alters the natural course of allergies and has possible disease-modifying effects. AIT is administered primarily via subcutaneous injection delivered in a physician's office. Few studies have been conducted in the United States or Canada to evaluate the costs of subcutaneous immunotherapy (SCIT). OBJECTIVES: To (a) describe SCIT administration processes, resources, and costs and (b) characterize the patient population receiving SCIT. METHODS: A multisite, prospective, observational time and motion study was conducted. Injection and wait times were collected by a third-party observer on 1 visit for each patient. Extract preparation processes were also observed. Site staff reported on treatment protocols, administrative time, supplies, and patient medical history. Patients responded to questionnaires on demographics, reasons for treatment, medication use, productivity, and travel time. Costs were estimated by applying unit costs to the time observations and the patient- and staff-reported data. RESULTS: A total of 670 SCIT patients were enrolled at 6 sites in the United States and 6 sites in Canada. Average age in the United States was 41 years (SD = 18) and 44 years (15) in Canada, with 10% of the patients aged >= 65 years. Annual incomes were over $100,000 for 40% of U.S. patients and 30% of Canadian patients. U.S. patients had over 4 times as many different allergens in their SCIT treatments as Canadian patients, with a mean of 18 versus 4. The most common reasons reported for starting SCIT was a "desire to cure allergies once and for all" (73%) and that "symptoms are not improved by allergy medications" (60%). Percentages of patients taking allergy medications in the 4 weeks prior to observation were 86% in the United States and 66% in Canada: antihistamines 75% United States, 54% Canada; inhaled corticosteroids 32% United States, 22% Canada. The predominant comorbidity was asthma, 43% United States, 24% Canada. Site protocols for build-up treatment phases were 1 to 2 injections per week for an average of 25 weeks (range 12-52). Maintenance phases were 1 injection every 3 to 4 weeks for an average of 4 years (range 2.5-5). Eight of the sites had total mean staff times per injection visit of 7 to 22 minutes; 1 site averaged fewer minutes, and 3 sites averaged more. Total direct medical costs were an average of $30 for Canadian patients per visit and $32 per visit for U.S. patients, half accounted for by the cost of the extract. Pre- and postinjection administrative tasks were the second largest driver of direct costs. Total injection visit related time for patients, including round-trip travel time, averaged about 80 minutes per visit in the United States and in Canada. CONCLUSIONS: Analyses revealed substantial variation in SCIT regimens among sites, but the sites had commonalities in the injection process components. SCIT requires patient commitment to a long-term treatment regimen involving numerous clinic visits and resources for administration. PMID- 26521111 TI - Potential Health Implications of Medication Therapy Management Eligibility Criteria in the Patient Protection and Affordable Care Act Across Racial and Ethnic Groups. AB - BACKGROUND: The Medicare Prescription Drug, Improvement, and Modernization Act requires Part D plans to establish programs to provide medication therapy management (MTM) services starting from 2006. MTM services have been found to improve patient outcomes from pharmacotherapy, reduce emergency room visits and hospitalizations, and reduce health care costs in a cost-effective fashion. However, previous research found that non-Hispanic blacks (blacks) and Hispanics may be less likely to be eligible for MTM services than non-Hispanic whites (whites) among the Medicare population, according to current Medicare MTM eligibility criteria. This finding is because Medicare MTM eligibility criteria are predominantly based on medication use and costs, and blacks and Hispanics tend to use fewer prescription medications and incur lower prescription medication costs. The Patient Protection and Affordable Care Act (PPACA) laid out a set of MTM eligibility criteria for eligible entities to target patients for MTM services: "(1) take 4 or more prescribed medications ...; (2) take any 'high risk' medications; (3) have 2 or more chronic diseases ... or (4) have undergone a transition of care, or other factors ... that are likely to create a high risk of medication-related problems." OBJECTIVES: To (a) examine racial/ethnic disparities in meeting the eligibility criteria for MTM services in PPACA among the Medicare population and (b) determine whether there would be greater disparities in health and economic outcomes among MTM-ineligible than MTM eligible groups. METHODS: This was a retrospective cross-sectional analysis of the Medicare Current Beneficiaries Survey (2007-2008). To determine medication characteristics, the U.S. Food and Drug Administration's Electronic Orange Book was also used. Proportions of the population eligible for MTM services based on PPACA MTM eligibility criteria were compared across racial and ethnic groups using a chi-square test; a logistic regression model was used to adjust for population sociodemographic and health characteristics. Health and economic outcomes examined included health status (self-perceived good health status, number of chronic diseases, activities of daily living [ADLs], and instrumental activities of daily living [IADLs]), health services utilization and costs (physician visits, emergency room visits, and total health care costs), and medication use patterns (generic dispensing ratio). To determine difference in disparities across MTM eligibility categories, difference-in-differences regressions of various functional forms were employed, depending on the nature of the dependent variables. Interaction terms between the dummy variables for minority groups (e.g., blacks or Hispanics) and MTM eligibility were included to test whether disparity patterns varied between MTM-ineligible and MTM-eligible individuals. RESULTS: The sample consisted of 12,966 Medicare beneficiaries, of which 11,161 were white, 930 were black, and 875 were Hispanic. Of the study sample, 9,992 whites (86.4%), 825 blacks (86.3%), and 733 Hispanics (80.6%) were eligible for MTM. The difference between whites and Hispanics was significant (P less than 0.050), and the difference between whites and blacks was not significant (P greater than 0.050). In multivariate analyses, significant disparity in eligibility for MTM services was found only between Hispanics and whites (odds ratio [OR] = 0.59; 95% CI = 0.43-0.82) but not between blacks and whites (OR = 0.78; 95% CI = 0.55-1.09). Disparities were greater among the MTM ineligible than the MTM-eligible populations in self-perceived health status, ADLs, and IADLs for both blacks and Hispanics compared with whites. When analyzing the number of chronic conditions, the number and costs of physician visits, and total health care costs, the authors of this study found lower racial and ethnic disparities among the ineligible population than the eligible population. CONCLUSIONS: Hispanics are significantly less likely than whites to qualify for MTM among the Medicare population, according to MTM eligibility criteria stipulated in the PPACA. PPACA MTM eligibility criteria may aggravate existing racial and ethnic disparities in health status but may remediate racial and ethnic disparities in health services utilization. Alternative MTM eligibility criteria other than PPACA MTM eligibility criteria may be needed to improve the efficiency and equity of access to Medicare Part D MTM programs. PMID- 26521112 TI - Patient Outcomes in a Medicaid Managed Care Lock-In Program. AB - BACKGROUND: Prescription drug abuse is a growing epidemic in the United States, and opioids are among the most commonly abused and misused controlled substances. Managed care organizations can use pharmacy lock-in programs to limit patients' access to opioids by requiring that they receive all scripts from 1 prescriber, potentially reducing inappropriate use. OBJECTIVE: To evaluate opioid use patterns among patients in a Medicaid managed care lock-in program limiting opioid coverage to prescriptions written by assigned prescribers. METHODS: This retrospective cohort study included all patients enrolled in the lock-in program at Blue Care Network (BCN) of Michigan Medicaid managed care from March 2008 through May 2013, with outcomes assessed through August 2013. BCN medical and pharmacy claims, the Michigan Automated Prescription System, and Blue Cross Complete Controlled Substance Committee reports were used to assess outcomes at 6, 12, 24, and 36 months after enrollment. Patients were defined as "stable" if they exclusively filled opioid prescriptions from assigned prescribers or received treatment for opioid dependence and "unstable" if they purchased prescription opioids with cash or submitted opioid claims not prescribed by assigned providers. RESULTS: Of the 59 patients enrolled in the program, over half (55.9%) dropped BCN coverage, and 1 died while enrolled. The proportion of patients who dropped coverage fell as time in the program increased, from 29% in the first 6 months to 11% semiannually after 24 months. Among those who remained enrolled, the proportion of stable patients increased from 31% at 6 months to 78% at 36 months. The small sample size did not permit formal statistical analysis. CONCLUSIONS: The finding that most patients exited the program by dropping coverage was an unintended consequence meriting further investigation. Conversely, the finding that patients who remained enrolled largely achieved desired outcomes indicates that this program played an important role in addressing opioid abuse. PMID- 26521113 TI - Use of ICS/LABA on Asthma Exacerbation Risk in Patients Within a Medical Group. AB - BACKGROUND: Asthma medication ratio (AMR) >= 0.5 has been shown to predict asthma exacerbations. This study explores the impact of increasing or decreasing inhaled corticosteroid/long-acting beta-agonist (ICS/LABA) use over a 7-year period on achieving an AMR of >= 0.5. OBJECTIVES: To (a) assess the impact of increasing use of ICS/LABAs on changes in a modified AMR (mAMR) and (b) examine asthma risk over time as measured by an mAMR over a 7-year period, adjusting for differences in baseline characteristics. METHODS: This is a retrospective, observational study using pharmacy and medical claims from a medical group from January 1, 2003, to December 31, 2010. All patients with >= 1 asthma diagnosis (ICD-9-CM, 493.xx) with >= 1 inhaled asthma medication dispensed in each year of eligibility were included. The mAMR = total ICS controllers dispensed/(total ICS controllers dispensed + albuterol dispensed). The proportion of ICS/LABA use was determined as the number of ICS/LABA canisters dispensed/(total of ICS/LABA + ICS dispensed). Generalized linear mixed models were used to assess the effect of incremental change in ICS/LABA use on mAMR over 7 years, adjusting for differences in resource utilization, time, and asthma medication use. RESULTS: Nine hundred ninety patients (mean age [+/- SD] 34.7 years [+/- 18.2], 61.7% female) met all criteria. Overall, mean mAMR increased over time, while mean albuterol use decreased over time. Adjusting for covariates, we found that a 10% increase in ICS/LABA use was associated with a 9% increase (adjusted OR = 1.09, 95% CI = 1.06-1.12) in the likelihood of achieving an mAMR >= 0.5, while a 50% increase in ICS/LABA use was associated with a 53% increase (OR = 1.53, 95% CI = 1.31-1.80) in the likelihood of achieving an mAMR >= 0.5. CONCLUSIONS: Increase in ICS/LABA use over time in a population of asthma patients was significantly associated with a higher likelihood of achieving an mAMR >= 0.5. PMID- 26521114 TI - Analysis of National Drug Code Identifiers in Ambulatory E-Prescribing. AB - BACKGROUND: Communication of an accurate and interpretable drug identifier between prescriber and pharmacist is critically important for realizing the potential benefits of electronic prescribing (e-prescribing) while minimizing its risk. The National Drug Code (NDC) is the most commonly used codified drug identifier in ambulatory care e-prescribing, but concerns have been raised regarding its use for this purpose. OBJECTIVES: To (a) assess the frequency of NDC identifier transmission in ambulatory e-prescribing; (b) characterize the type of NDC identifier transmitted (representative, repackaged, obsolete, private label, and unit dose); and (c) assess the level of agreement between drug descriptions corresponding to NDC identifiers in electronic prescriptions (e prescriptions) and the free-text drug descriptions that were entered by prescribers. METHODS: We analyzed a sample of 49,997 e-prescriptions that were transmitted by ambulatory care prescribers to outlets of a national retail drugstore chain during a single day in April 2014. The First Databank MedKnowledge drug database was used as the primary reference data base to assess the frequency and types of NDC numbers in the e-prescription messages. The FDA's Comprehensive NDC Standard Product Labeling Data Elements File and the National Library of Medicine's RxNorm data file were used as secondary and tertiary references, respectively, to identify NDC numbers that could not be located in the primary reference file. Three experienced reviewers compared the free-text drug description that had been entered by the prescriber with the drug description corresponding to the NDC number from 1 of the 3 reference database files to identify discrepancies. Two licensed pharmacists with residency training and ambulatory care experience served as final adjudicators. RESULTS: A total of 42,602 e-prescriptions contained a value in the NDC field, of which 42,335 (84.71%) were found in 1 of the 3 study reference databases and were thus considered to be valid NDC numbers. A total of 28,172 (67.70%) e-prescriptions in the sample were found to contain a representative NDC number, according to the definition used by the National Council for Prescription Drug Programs (NCPDP). The remaining e-prescriptions consisted of 4 subtypes of unrepresentative NDC numbers. In 41,298 (97.55%) e-prescriptions that contained an NDC number, the drug description associated with the number from 1 of the 3 data source files pointed to the identical semantic drug concept as the free-text drug description that had been entered by the prescriber. However, in 87 (0.21%) e-prescriptions, the free-text drug descriptions and the drug description associated with the NDC number pointed to completely different semantic drug concepts. CONCLUSIONS: We found the use of NDC identifiers in our sample of e-prescriptions to be relatively high. However, approximately one-third consisted of unrepresentative NDC numbers (obsolete, repackaged, unit dose, or private label) that have the potential to create workflow disruptions at the dispensing pharmacy. Most disturbing was our finding that more than 2 out of every 1,000 e-prescriptions in our sample contained a free-text drug description that pointed to a completely different drug concept than that associated with its NDC value. Our study suggests the need for e-prescribing technology vendors to maintain accurate and up-to-date drug database files within their systems and to conduct regular validation checks to ensure that the drug descriptions associated with the NDC identifier and the free-text drug description that is sent in the e-prescription message point to the same drug concept. The FDA may need to consider a more active role in ensuring the accuracy of NDC assignment by drug manufacturers. PMID- 26521115 TI - A Call for Appropriate Evidence and Outcomes-Based Use and Measurement of Anticoagulation for Atrial Fibrillation: Moving the Population Towards Improved Health Via Multiple Stakeholders. AB - A multidimensional approach involving consideration of available resources, individual patient characteristics, patient preferences, and cost of treatment is often required to optimize clinical decision making in the management of atrial fibrillation (AF). In order to bring together varying perspectives on effective tactics and to formulate innovative strategies to improve the management of AF, a think tank consortium of advisors was assembled from across the spectrum of health care stakeholders. Focus groups were conducted and facilitated by a moderator and a notetaker. Participants were asked to comment on preliminary data for the increased prevalence of AF, patterns of treatment, impact of adherence with anticoagulants on clinical and economic outcomes, and opportunities for optimizing treatment.Several recommendations to reach short- and long-term goals in improving AF management emerged from the focus group discussions. These recommendations specifically targeted 3 stakeholder groups--patients/caregivers, physicians, and payers--and addressed the need for better understanding of determinants of undertreatment and nonadherence for those on anticoagulation therapy. Recommendations included the use of real-world data studies to understand regional and demographic patterns of treatment and outcomes, the development of an enhanced national quality standard for anticoagulation, and engaging patients in shared decision making to optimize satisfaction with treatment. Actionable strategies were presented to address gaps related to anticoagulation management. Balancing new anticoagulants' higher prescription costs and safety concerns with their superior effectiveness and convenience of administration for at-risk individuals would require a concerted effort involving patients and their caregivers, physicians, and payers. PMID- 26521116 TI - Hospital Admissions, Costs, and 30-Day Readmissions Among Newly Diagnosed Nonvalvular Atrial Fibrillation Patients Treated with Dabigatran Etexilate or Warfarin. AB - BACKGROUND: Oral anticoagulation such as warfarin and dabigatran is indicated for atrial fibrillation (AF) patients at risk of ischemic stroke. Dabigatran etexilate was developed to address the limitations of warfarin, including the need for regular blood monitoring, which has the potential to lead to higher health care resource use, particularly in hospitalized patients. OBJECTIVE: To evaluate whether hospitalization cost, length of hospital stay (LOS), likelihood of readmission within 30 days, and cost of readmissions differed across inpatient encounters among nonvalvular atrial fibrillation (NVAF) patients that were newly diagnosed and newly treated with either dabigatran or warfarin. METHODS: A retrospective cohort study was conducted using IMS Health's Charge Detail Master (CDM) database. Hospitalizations were identified based on a primary or secondary AF diagnosis, dabigatran or warfarin use, and a discharge date from January 2011 through March 2012. The identified patients without valvular procedures and transient AF were required to have a minimum of 12 months of pharmacy and private practitioner records prior to the inpatient encounter to ensure that they were newly treated on dabigatran or warfarin. Propensity score matching was used to balance baseline characteristics between treatment cohorts. Outcomes assessed were LOS, 30-day readmissions, and costs. Because individual patients could have more than 1 hospital observation, generalized estimating equations (GEE) with a gamma distribution (log link) were used for the analysis of continuous outcome measures (e.g., LOS and costs) and a binominal distribution for dichotomous outcomes (hospital readmissions). RESULTS: Two cohorts were propensity score matched (1:2) on demographic and clinical characteristics. The dabigatran cohort included 646 hospitalizations, and the warfarin cohort included 1,292 hospitalizations. Hospitalizations were on average 13% shorter (4.8 vs. 5.5 days, P less than 0.001) and cost 12% less ($14,794 vs. $16,826, P = 0.007) when dabigatran was used versus warfarin. No differences in 30-day readmissions were observed. CONCLUSIONS: Hospital encounters among newly diagnosed NVAF patients during which warfarin was initiated had longer lengths of stay and incurred higher costs than those during which dabigatran was initiated. PMID- 26521117 TI - Adherence to a Novel Oral Anticoagulant Among Patients with Atrial Fibrillation. AB - BACKGROUND: Dabigatran is a direct thrombin inhibitor approved by the FDA in October 2010 for the treatment of nonvalvular atrial fibrillation. Little is known regarding patient adherence to this therapy. OBJECTIVE: To examine adherence and persistence to dabigatran among adults with atrial fibrillation. METHODS: We used IMS Health's LifeLink Health Plan Claims Database from 2010 to 2012 to identify patients with atrial fibrillation who were new users of dabigatran. We derived adherence and persistence for continuously enrolled patients at 6 months, 9 months, and 12 months of follow-up. We measured adherence using the medication possession ratio (MPR), defined as individuals with MPRs of 0.80 or greater as adherent, and examined persistence by identifying individuals with gaps in drug possession of 60 days or greater. RESULTS: Of 5,951 adults with atrial fibrillation who were new users of dabigatran, 49% had prevalent atrial fibrillation and at least 6 months of continuous follow-up. Of these, 89% used dabigatran as the only oral anticoagulant, whereas the remainder filled prescriptions for at least 1 other oral anticoagulant during the follow-up period. Among those using dabigatran alone (n = 2,713), the mean MPR was 0.73 (standard error = 0.30), 41% were nonadherent with therapy, and 32% had gaps of 60 days or greater. Among those observed for 9 (or 12) months who used dabigatran alone, rates of nonadherence were 47% (49%), whereas 48% (49%) discontinued therapy during follow-up. Rates of adherence and persistence were similar for patients with incident atrial fibrillation. CONCLUSIONS: Nonadherence to dabigatran was common among patients with atrial fibrillation. Future studies are needed to understand the reasons for nonadherence. PMID- 26521118 TI - An Assessment of the AGA and CCFA Quality Indicators in a Sample of Patients Diagnosed with Inflammatory Bowel Disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a chronic relapsing disease characterized by activation of the mucosal immune system and inflammation of the gastrointestinal tract. Management of IBD places a significant burden on the health care system because of the complexity of treatment, variability in patient outcomes, and chronic nature of the disease. OBJECTIVE: To investigate the American Gastroenterological Association (AGA) and Crohn's and Colitis Foundation of America's (CCFA) quality measurement sets in a sample of IBD patients. METHODS: Fourteen quality measures were restated for application to a claims database and calculated using Optum Clinformatics DataMart database. Selected measures were calculated over calendar year 2011. RESULTS: Performance measures ranged from 0.4% for AGA measure 9, prophylaxis for venous thromboembolism, to 66.9% for AGA measure 8, testing for Clostridium difficile. CCFA outcome measures ranged from 0.6% qualifying for CCFA O10, report of fecal incontinence, to 32.9% for CCFA O1, prednisone usage. In addition to Clostridium difficile testing, the use of appropriate corticosteroid-sparing therapy (51.1%) and testing for latent tuberculosis before initiating anti-tumor necrosis factor therapy (45.0%) were the highest achieved measures. CONCLUSIONS: This is the first examination of IBD quality measures using administrative claims. Rates of achievement across measures were variable and likely affected by the ability to calculate certain measures with claims data. Future studies should further examine measurement of IBD quality indicators in claims data to assess the validity of claims-based analyses and to ascertain whether measure attainment translates into better overall health or IBD-related outcomes. PMID- 26521119 TI - Prescribing Patterns for Outpatient Treatment of Constipation, Irritable Bowel Syndrome-Related Constipation, and Opioid-Induced Constipation: A Retrospective Cross-Sectional Study. AB - BACKGROUND: Despite national recommendations for treatment of constipation, prescribing patterns for treatment are inconsistent, and health care utilization has increased. OBJECTIVE: To identify patterns in pharmacologic and nonpharmacologic treatment of constipation and associations between treatment and other variables across age groups. METHODS: This was a retrospective cross sectional study that used the National Ambulatory Medical Care Survey (NAMCS) to compare prescribing from 2000 to 2004 and from 2005 to 2009. Treatment patterns for constipation, irritable bowel syndrome-related constipation (IBS-C), and opioid-induced constipation were considered. RESULTS: From 2000 to 2009, there were 89.6 million office visits related to constipation: 63.4 million for constipation alone, 28.2 million for IBS-C alone, and 3.7 million for opioid induced constipation. For constipation, there was an overall decrease in the prescription of combination therapy (17% vs. 11%, P less than 0.05); an increase in the prescription of medication monotherapy (21% vs. 29%, P less than 0.05); decreases in the use of lubricants (9% vs. 2%, P less than 0.05) and saline (7% vs. 1%, P less than 0.001) among patients aged less than 18 years; a decrease in combination therapy (31% vs. 17%, P less than 0.05); and age group differences in the prescription of specific medications. For IBS-C and opioid-induced constipation, there were no changes in major treatment category or specific medication. Age, gender, race, ethnicity, payer source, physician specialty, and region were all found to be associated with treatment choice. CONCLUSIONS: Health care utilization for constipation increased, and prescribing patterns shifted significantly from 2000 to 2009 for constipation and IBS-C. Patterns in treatment were significantly influenced by many factors, including age, gender, and race. Changes in treatment categories over time included a decrease in combination therapy for patients aged less than 18 years and an increase in medication monotherapy for all ages, which are in contrast to national recommendations. PMID- 26521120 TI - Adherence and Persistence Among Chronic Myeloid Leukemia Patients During Second Line Tyrosine Kinase Inhibitor Treatment. AB - In a study published last year in the October 2014 issue of the Journal of Managed Care Specialty Pharmacy, Trivedi et al. compared treatment patterns of dasatinib and nilotinib as second-line tyrosine kinase inhibitors (TKI) therapy in chronic myeloid leukemia (CML) patients during the first year of treatment.1 Trivedi et al. concluded that among second-line TKI-treated patients, dasatinib patients had significantly higher adherence and lower discontinuation rates compared with those receiving nilotinib. We feel that although the study presents results that are of particular interest to the CML community, certain aspects of the study design raise questions, and the conclusions need to be cautiously considered, since they appear not to be fully substantiated by some of the presented results. PMID- 26521121 TI - A Portable Device as Sleep-Screening Tool in the Identification of Obstructive Sleep Apnea in Chronic Heart Failure: Which Value Should We Consider as Cutoff? PMID- 26521122 TI - A novel approach to optimize workflow in grid-based teleradiology applications. AB - BACKGROUND AND OBJECTIVE: This study proposes an infrastructure with a reporting workflow optimization algorithm (RWOA) in order to interconnect facilities, reporting units and radiologists on a single access interface, to increase the efficiency of the reporting process by decreasing the medical report turnaround time and to increase the quality of medical reports by determining the optimum match between the inspection and radiologist in terms of subspecialty, workload and response time. METHODS: Workflow centric network architecture with an enhanced caching, querying and retrieving mechanism is implemented by seamlessly integrating Grid Agent and Grid Manager to conventional digital radiology systems. The inspection and radiologist attributes are modelled using a hierarchical ontology structure. Attribute preferences rated by radiologists and technical experts are formed into reciprocal matrixes and weights for entities are calculated utilizing Analytic Hierarchy Process (AHP). The assignment alternatives are processed by relation-based semantic matching (RBSM) and Integer Linear Programming (ILP). RESULTS: The results are evaluated based on both real case applications and simulated process data in terms of subspecialty, response time and workload success rates. Results obtained using simulated data are compared with the outcomes obtained by applying Round Robin, Shortest Queue and Random distribution policies. The proposed algorithm is also applied to a real case teleradiology application process data where medical reporting workflow was performed based on manual assignments by the chief radiologist for 6225 inspections. CONCLUSIONS: RBSM gives the highest subspecialty success rate and integrating ILP with RBSM ratings as RWOA provides a better response time and workload distribution success rate. RWOA based image delivery also prevents bandwidth, storage or hardware related stuck and latencies. When compared with a real case teleradiology application where inspection assignments were performed manually, the proposed solution was found to increase the experience success rate by 13.25%, workload success rate by 63.76% and response time success rate by 120%. The total response time in the real case application data was improved by 22.39%. PMID- 26521123 TI - Evaluation and management of vestibular migraine in children: Experience from a pediatric vestibular clinic. AB - OBJECTIVE: Epidemiologic studies have shown Vestibular migraine (VM) to be the most common cause of vertigo in children, but little is known about the typical presentation and response to treatment of this disorder in the pediatric population. The aim of this study was to evaluate the diagnostic features and response to therapy of VM in children managed at a pediatric vestibular clinic. METHODS: Twenty-eight patients <=18 years old with a diagnosis of VM were identified from 208 patients seen at the Balance and Vestibular Program at Boston Children's Hospital from July 2012-July 2014, after excluding 12 patients with a history of major otologic or neurologic surgery, recent concussion, or additional vestibular disorders. Patients' electronic medical records and testing results were retrospectively reviewed. RESULTS: Patients ranged in age from 9 to 18 years old (mean 14.48). All included patients met criteria for definite (n = 25) or probable (n = 3) VM as defined by the International Classification of Headache Disorders. Rotary chair (n = 17), caloric (n = 8), cervical vestibular evoked myogenic potential (n = 16), and video head impulse (n = 3) tests were normal. Medications effectively reduced reported vestibular symptoms in 88% of those treated with tricyclics (n = 8), 86% of those treated with cyprohepatadine (n = 7), 80% of those treated with topiramate (n = 5), 80% of those treated with triptans (n = 10), and 25% of those treated with gabapentin (n = 4). CONCLUSIONS: Vestibular migraine is a common cause of vertigo in the pediatric population that is frequently responsive to medical therapy. PMID- 26521124 TI - Pharmacophore modeling, virtual screening, molecular docking studies and density functional theory approaches to identify novel ketohexokinase (KHK) inhibitors. AB - Fructose catabolism starts with phosphorylation of d-fructose to fructose 1 phosphate, which is performed by ketohexokinase (KHK). Fructose metabolism may be the key to understand the long-term consumption of fructose in human's obesity, diabetes and metabolic states in western populations. The inhibition of KHK has medicinally potential roles in fructose metabolism and the metabolic syndrome. To identify the essential chemical features for KHK inhibition, a three-dimensional (3D) chemical-feature-based QSAR pharmacophore model was developed for the first time by using Discovery Studio v2.5 (DS). The best pharmacophore hypothesis (Hypo1) consisting two hydrogen bond donor, two hydrophobic features and has exhibited high correlation co-efficient (0.97), cost difference (76.1) and low RMS (0.66) value. The robustness and predictability of Hypo1 was validated by fisher's randomization method, test set, and the decoy set. Subsequently, chemical databases like NCI, Chembridge and Maybridge were screened for validated Hypo1. The screened compounds were further analyzed by applying drug-like filters such as Lipinski's rule of five, ADME properties, and molecular docking studies. Further, the highest occupied molecular orbital, lowest unoccupied molecular orbital and energy gap values were calculated for the hits compounds using density functional theory. Finally, 3 hit compounds were selected based on their good molecular interactions with key amino acids in the KHK active site, GOLD fitness score, and lowest energy gaps. PMID- 26521125 TI - Simultaneous resection of bilateral anomalous systemic supply to the basal segments of the lungs: a case report. AB - BACKGROUND: Anomalous systemic arterial supply to the normal basal lung segments is a sequestration spectrum variant (Pryce type 1) that is distinguished from pulmonary sequestration by normal bronchopulmonary and parenchymal tissues. CASE PRESENTATION: A 33-year-old Japanese man was referred to our hospital because of an abnormal pulmonary shadow. Computed tomography showed two aberrant arteries arising from the descending aorta and running into the lower lung lobes on each side, without any bronchial anomaly. He was diagnosed with bilateral anomalous systemic supply to the basal segments. A left thoracotomy was performed and the aberrant arteries were ligated and dissected at their origin followed by left basal segmentectomy. Simultaneous right S10 segmentectomy was performed under video-assisted thoracic surgery. CONCLUSION: Although bilateral anomalous systemic arterial supply to the basal segments is extremely rare, knowledge of this anomaly should allow for a definitive diagnosis and appropriate therapy. PMID- 26521126 TI - Ubiquilin-2 drives NF-kappaB activity and cytosolic TDP-43 aggregation in neuronal cells. AB - BACKGROUND: Mutations in the gene encoding Ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). UBQLN2 plays a central role in ubiquitin proteasome system (UPS) and UBQLN2 mutants can form cytoplasmic aggregates in vitro and in vivo. RESULTS: Here, we report that overexpression of WT or mutant UBQLN2 species enhanced nuclear factor kappaB (NF kappaB) activation in Neuro2A cells. The inhibition of NF-kappaB stress-mediated activation with SB203580, a p38 MAPK inhibitor, demonstrated a role for MAPK in NF-kappaB activation by UBQLN2 species. Live cell imaging and microscopy showed that UBQLN2 aggregates are dynamic structures that promote cytoplasmic accumulation of TAR DNA-binding protein (TDP-43), a major component of ALS inclusion bodies. Furthermore, up-regulation of UBQLN2 species in neurons caused an ER-stress response and increased their vulnerability to death by toxic mediator TNF-alpha. Withaferin A, a known NF-kappaB inhibitor, reduced mortality of Neuro2A cells overexpressing UBQLN2 species. CONCLUSIONS: These results suggest that UBQLN2 dysregulation in neurons can drive NF-kappaB activation and cytosolic TDP-43 aggregation, supporting the concept of pathway convergence in ALS pathogenesis. These Ubiquilin-2 pathogenic pathways might represent suitable therapeutic targets for future ALS treatment. PMID- 26521127 TI - Microbial terroir and food innovation: The case of yeast biodiversity in wine. AB - Saccharomyces and non-Saccharomyces represents a heterogeneous class in the grape/must/wine environments including several yeast genera (e.g., Saccharomyces, Hanseniaspora, Pichia, Candida, Metschnikowia, Kluyveromyces, Zygosaccharomyces, Torulaspora, Dekkera and Schizosaccharomyces) and species. Since, each species may differently contribute to the improvement/depreciation of wine qualities, it appears clear the reason why species belong to non-Saccharomyces are also considered a biotechnological resource in wine fermentation. Here, we briefly review the oenological significance of this specific part of microbiota associated with grapes/musts/wine. Moreover, the diversity of cultivable non Saccharomyces genera and their contribute to typical wines fermentations will be discussed. PMID- 26521128 TI - The Effect of Patella Eversion on Clinical Outcome Measures in Simultaneous Bilateral Total Knee Arthroplasty: A Prospective Randomized Controlled Trial. AB - BACKGROUND: During total knee arthroplasty (TKA), surgical exposure requires mobilization technique of the patella. With this trial, we intended to investigate the effect of patella eversion on clinical outcome measures in simultaneous bilateral TKA. METHODS: We prospectively enrolled 44 patients (88 knees) from April 2008 to June 20l4.One knee was operated with patella eversion (group A) and the other with patella lateral retraction (group B) randomly. Follow-up results, including the operation time, complications, and the time of achieving straight leg raise (SLR) and 90 degrees knee flexion, were recorded. The data of range of motion (ROM) and Visual Analogue Scale score were collected separately at 7 days, 3 months, 6 months, and 1 year postoperatively. RESULTS: The time of achieving SLR was 2.7 +/- 0.8 days in group A and 2.1 +/- 0.7 DAYS in group B, which were significantly different (P = .032). Significant difference was found on active and passive ROM during the follow-up times between groups A and B, except the passive ROM at 6 months postoperatively. No significant difference was found on operation time, complications, patella baja or tilt, time of achieving 90 degrees knee flexion, and Visual Analogue Scale score during the follow-up times. CONCLUSIONS: Patellar eversion was adverse to the early knee function recovery after TKA; it would delay the time of achieving SLR and decrease the passive and active ROM. In addition, more carefully and scientifically designed randomized controlled trials are still required to further prove the claim. PMID- 26521129 TI - Is Preoperative Nasal Povidone-Iodine as Efficient and Cost-Effective as Standard Methicillin-Resistant Staphylococcus aureus Screening Protocol in Total Joint Arthroplasty? AB - The purpose of this study was to compare nasal povidone-iodine swab for total joint arthroplasty patients to methicillin-resistant Staphylococcus aureus (MRSA) screening on the incidence of 90-day postoperative surgical site infections in total knee and hip arthroplasties as well as the cost-effectiveness. This is a single-center retrospective review of primary or revision total knee or hip arthroplasty patients. There were 849 patients screened for MRSA and 1004 patients in the nasal swab groups, both with an infection rate of 0.8%. The mean cost for the nasal swab was $27.21 (SD, 0), significantly different (P <= .01) than the mean cost for MRSA screens, $121.16 (SD, 26.18). There were significant cost savings with no difference in infection rates; therefore, nasal povidone iodine swab antiseptic is financially and clinically successful. PMID- 26521130 TI - Validation of Synovial Aspiration in Girdlestone Hips for Detection of Infection Persistence in Patients Undergoing 2-Stage Revision Total Hip Arthroplasty. AB - BACKGROUND: The aim of this study was to assess the diagnostic performance of synovial aspiration in Girdlestone hips, without a Polymethylmethacrylate (PMMA) spacer, for the detection of infection persistence before total hip arthroplasty (THA) reimplantation. METHODS: Seventy-four patients undergoing stage revision THA surgery were included in this retrospective cohort study. Both synovial cultures and serum C-reactive protein values were acquired before explantation of the THA and of the Girdlestone hip before reimplantation. RESULTS: The diagnostic performance of the synovial aspiration of the Girdlestone hip achieved a sensitivity of only 13% and a specificity of 98%. The determination of the serum C-reactive protein value for Girdlestone hips achieved a sensitivity of 95% and a specificity of only 20%. CONCLUSIONS: Our data show that the Girdlestone aspiration can neither reliably confirm nor exclude a persistence of infection. PMID- 26521131 TI - Expanded Gram-Negative Antimicrobial Prophylaxis Reduces Surgical Site Infections in Hip Arthroplasty. AB - BACKGROUND: A first-generation cephalosporin is the recommended antibiotic prophylaxis for implants. However, this standard does not address the increasing prevalence and virulence of gram-negative pathogens infecting patients. We found that gram-negative bacilli caused 30% of our surgical site infections (SSIs) following hip procedures, whereas only 10% of knee SSIs were caused by gram negative bacilli. To address this, we instituted Expanded Gram-Negative Antimicrobial Prophylaxis (EGNAP) for our hip arthroplasty patients. The purpose of this study is to measure the effect of EGNAP on the SSI rates following primary total hip arthroplasty. METHODS: The study consisted of 10,084 total patients. Before July 2012, all patients were administered 1 g of cefazolin. After July 2012, our protocol was adjusted by adding the EGNAP with either gentamicin or aztreonam to hip patients (group 1) and not to the knee arthroplasty patients (group 2). RESULTS: Group 1 consisted of the 5389 primary hip arthroplasty patients. Of these patients, 4122 (before July 2012) did not receive weight-based high-dose gentamicin and 1267 (after July 2012) did. Before the introduction of EGNAP, group 1 SSI rate was 1.19% (49/4122). After July 2012 when EGNAP was added, the overall group 1 SSI rate decreased to 0.55% (7/1267) (P = .05). During the study period, there was not a significant difference in SSI rate of knee arthroplasty (group 2): 1.08% vs 1.02% (P = .999). CONCLUSIONS: The addition of EGNAP for hip arthroplasty is a safe and effective method to decrease SSIs. LEVEL OF EVIDENCE: III. Case-control study. PMID- 26521133 TI - Tobacco use and household expenditures on food, education, and healthcare in low- and middle-income countries: a multilevel analysis. AB - BACKGROUND: The majority of one billion smokers worldwide live in low- and middle income countries (LMICs) and the highest proportion of smokers in most of these countries belong to the lower socioeconomic groups. This study aimed to investigate the associations between tobacco use within households and expenditures on food, education, and healthcare in LMICs. METHODS: Using data from the World Health Survey, this cross-sectional study included a sample of 53,625 adult males aged <60 years from 40 LMICs. Multilevel, mixed-effects linear regression was used to determine the association between current tobacco use status of the main income provider (daily; occasional; no use) and three categories of (logged) household expenditures: food, education, and healthcare; controlling for age, level of education, household wealth quintile, marital status, urban-rural setting, country-level income group, and region. RESULTS: In the preferred random-slope models that controlled for covariates, daily tobacco use was associated with lower household expenditures on education and healthcare by 8.0% (95% confidence interval: -12.8 to -3.2%) and 5.5% (-10.7 to -0.3%), respectively. The association between tobacco use and food expenditure was inconsistent across models. CONCLUSIONS: Tobacco use in LMICs may have a negative influence on investment in human capital development. Addressing the tobacco use problem in LMICs could benefit not only the health and economic well-being of smokers and their immediate families but also long-run economic development at a societal level. PMID- 26521132 TI - IL-4/10 prevents stress vulnerability following imipramine discontinuation. AB - BACKGROUND: Identifying stress vulnerability after antidepressant discontinuation may be useful in treating relapses in depression. Previous studies have suggested significant effects of the immune system as well as the central nervous system (CNS) on progression and induction of major depression. In the present study, we hypothesized that the factors that are not rescued by a tricyclic antidepressant imipramine may be associated with stress vulnerability and relapses in depression. METHODS: To address this issue, mice were exposed to 2 h of restraint stress for 21 consecutive days (chronic restraint stress (CRS)) with or without co-treatment of imipramine. These groups were exposed to an electronic foot shock (FS) as additional stress after imipramine washout. Main targets of stress and antidepressants were analyzed in the hippocampus, lymph node, and serum after a series of depression-like behavior analysis. RESULTS: In this study, we found for the first time that mice exposed to CRS with a tricyclic antidepressant imipramine co-treatment, which did not show depressive-like behaviors, were vulnerable to subsequent stressful stimuli compared to the non-stressed mice after imipramine washout. CRS mice with imipramine co-treatment did not show any difference in BDNF, serotonin receptors, pro-inflammatory cytokines, or kynurenine pathway in the hippocampus compared to the controls. However, peripheral IL-4, IL-10, and alternatively activated microglial phenotypes in the hippocampus were not restored with sustained reduction in CRS mice despite chronic imipramine administration. Supplementing recombinant IL-4 and IL-10 in co Imi+CRS mice prevented the stress vulnerability on additional stress and restored factors related to alternatively activated microglia (M2) in the hippocampus. CONCLUSION: Thus, our results suggest that the reduced IL-4 and IL-10 levels in serum with hippocampal M2 markers may be involved in the stress vulnerability after imipramine discontinuation, and the restoration and modulation of these factors may be useful to some forms of depression-associated conditions. PMID- 26521134 TI - Visually guided targeting enhances bilateral force variability in healthy older adults. AB - This study observed the effect of visual feedback on between-limb force variability relationships in young and older adults. Abduction force was examined in healthy young (n = 15, 25 +/- 4 years) and older adults (n = 18, 71 +/- 6 years) during simultaneous isometric contractions of both index fingers. Target forces ranged from 5% to 30% maximum voluntary contraction (MVC), where force variability and first dorsal interosseus activity were measured while (1) subjects viewed visual targets for both index fingers, (2) a visual target was provided for the dominant index finger only, and (3) visual targets were removed for both index fingers during bilateral isometric contractions. When subjects were provided with bilateral visual feedback during simultaneous contractions at low forces (5% and 10% MVC), older adults produced greater force variability than younger subjects (p = 0.002). However, when bilateral visual feedback was removed, age-related differences in variability were no longer present. Between limb force variability differences existed at higher force outputs (20% and 30% MVC) when visual feedback was removed for the nondominant limb during bilateral isometric index finger abduction (p = 0.002). The control of bilateral force variability is compromised in older adults when visuomotor processes are engaged. However, age-related differences in force variability are abolished when no task related visual feedback is available, and isometric contractions are based on internally guided feedback. PMID- 26521136 TI - Haemophilus influenzae LicB contributes to lung damage in an aged mice co infection model. AB - Phosphorylcholine (ChoP) decoration of lipopolysaccharides is an important virulence strategy adopted by Haemophilus influenzae to establish a niche on the mucosal surface and to promote adherence to the host cells. The incorporation of ChoP on the LPS surface involves the lic1 operon, which consists of the licA, licB, licC, and licD genes. Among which, licB is a choline transporter gene required for acquisition of choline from environmental sources. In this study, we investigated the pathogenesis of the licB gene in an aged mice infection model. Due to immediate clearance of H. influenzae upon infection in mice, we employed influenza A virus and H. influenzae co-infection model. Our data showed that in the co-infection model, the secondary bacterial infection with a very low H. influenzae concentration of 100 colony forming unit is lethal to the aged mice. Although we did not observe any differences in weight loss between parent and licB mutant strains during the course of infection, a significant reduction of lung tissue damage was observed in the licB mutant infected aged mice. These results suggest that the licB gene is a virulence factor during H. influenzae infection in the lung in aged mice, possibly due to the increased binding to the host cell receptor via ChoP expression on the bacterial surface. In addition, when aged mice and mature mice were compared in the challenge experiments, we did not observe any protective immunity in the co-infection model suggesting the detrimental effects of the secondary bacterial infection on the aged mice in contrast to obvious immune-protections observed in the mature mice. The results of our experiments also implied that the co-infection model with influenza A virus and H. influenzae may be employed as a model system to study H. influenzae pathogenesis in vivo in aged mice. PMID- 26521137 TI - A mutant of the nematophagous fungus Paecilomyces lilacinus (Thom) is a novel biocontrol agent for Sclerotinia sclerotiorum. AB - Sclerotinia sclerotiorum causes severe stem rot and yield loss in oilseed rape (Brassica napus L.) and other crops worldwide. Extensive studies have been conducted on Paecilomyces lilacinus as a nematophagous bioagent. However, no reports stated the effect of P. lilacinus as a biocontrol agent against oilseed rape rot S. sclerotiorum. This study describes such effect in lab and field trials using the new transformant pt361 derived from the wild strain P. lilacinus 36-1. Unlike the wild-type strain, the mutant pt361 showed high antagonistic effect against S. Sclerotiorum A. Under lab conditions, the pt361 inhibited (65%) radial mycelial growth of S. sclerotiorum in dual culture test producing 5.9 mm inhibition zone IZ in front of the S. sclerotiorum colony. Moreover, the cell free filtrate of pt361 culture showed strong inhibitory effects (60.3-100%) on mycelial growth of S. sclerotiorum. In leaf detached assay, pt361 significantly (p < 0.05) inhibited (40.4-97.9%) the extension of the leaf spots caused by S. sclerotiorum A at all tested concentrations. The genomic DNA sequences of the inserted T-DNA flanking obtained from pt361 strain was cloned, verified as a glycoside hydrolase 31 family by homologous analysis with other fungal strains, and named PGH31 (2556bp). Secondary structure prediction showed a domain (Glycoside hydrolase31). Three years field trial confirmed that the cell-free filtrates or spores suspension of pt361 achieved significant (p < 0.05) suppression of oilseed rape stem rot, promoted growth and increased yield compared to the control and exceeded, at dose 100%, the action of the fungicide procymidone((r)). In conclusion, the mutant pt361 of P. lilacinus is a novel and promising biocontrol agent against oilseed rape Sclerotinia stem rot. PMID- 26521135 TI - Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging. AB - Leading a mentally stimulating life may build up a reserve of neural and mental resources that preserve cognitive abilities in late life. Recent autopsy evidence links neuronal density in the locus coeruleus (LC), the brain's main source of norepinephrine, to slower cognitive decline before death, inspiring the idea that the noradrenergic system is a key component of reserve (Robertson, I. H. 2013. A noradrenergic theory of cognitive reserve: implications for Alzheimer's disease. Neurobiol. Aging. 34, 298-308). Here, we tested this hypothesis using neuromelanin-sensitive magnetic resonance imaging to visualize and measure LC signal intensity in healthy younger and older adults. Established proxies of reserve, including education, occupational attainment, and verbal intelligence, were linearly correlated with LC signal intensity in both age groups. Results indicated that LC signal intensity was significantly higher in older than younger adults and significantly lower in women than in men. Consistent with the LC reserve hypothesis, both verbal intelligence and a composite reserve score were positively associated with LC signal intensity in older adults. LC signal intensity was also more strongly associated with attentional shifting ability in older adults with lower cognitive reserve. Together these findings link in vivo estimates of LC neuromelanin signal intensity to cognitive reserve in normal aging. PMID- 26521138 TI - Streptococcus pneumoniae and Haemophilus influenzae in paediatric meningitis patients at Goroka General Hospital, Papua New Guinea: serotype distribution and antimicrobial susceptibility in the pre-vaccine era. AB - BACKGROUND: Bacterial meningitis remains an important infection globally, with the greatest burden in children in low-income settings, including Papua New Guinea (PNG). We present serotype, antimicrobial susceptibility and outcome data from paediatric meningitis patients prior to introduction of Haemophilus influenzae type b (Hib) and pneumococcal conjugate vaccines (PCVs) in PNG, providing a baseline for evaluation of immunisation programs. METHODS: Cerebrospinal fluid (CSF) was collected from children admitted to Goroka General Hospital with suspected meningitis between 1996 and 2005. Culture and sensitivity was conducted, and pneumococci and H. influenzae were serotyped. Laboratory findings were linked to clinical outcomes. RESULTS: We enrolled 1884 children. A recognised pathogen was identified in 375 children (19.9%). Streptococcus pneumoniae (n = 180) and Hib (n = 153) accounted for 88.8% of pathogens isolated. 24 different pneumococcal serogroups were identified; non-PCV types 2, 24 and 46 accounted for 31.6% of pneumococcal meningitis. 10- and 13-valent PCVs would cover 44.1% and 45.4% of pneumococcal meningitis respectively. Pneumococcal isolates were commonly resistant to penicillin (21.5%) and 23% of Hib isolates were simultaneously resistant to ampicillin, co-trimoxazole and chloramphenicol. The case fatality rate in patients with a recognised bacterial pathogen was 13.4% compared to 8.5% in culture-negative patients. CONCLUSIONS: If implemented in routine expanded programme of immunisation (EPI) with high coverage, current PCVs could prevent almost half of pneumococcal meningitis cases. Given the diversity of circulating serotypes in PNG serotype replacement is of concern. Ongoing surveillance is imperative to monitor the impact of vaccines. In the longer term vaccines providing broader protection against pneumococcal meningitis will be needed. PMID- 26521139 TI - Assessing particle and fiber toxicology in the respiratory system: the stereology toolbox. AB - The inhalation of airborne particles can lead to pathological changes in the respiratory tract. For this reason, toxicology studies on effects of inhalable particles and fibers often include an assessment of histopathological alterations in the upper respiratory tract, the trachea and/or the lungs. Conventional pathological evaluations are usually performed by scoring histological lesions in order to obtain "quantitative" information and an estimation of the severity of the lesion. This approach not only comprises a potential subjective bias, depending on the examiner's judgment, but also conveys the risk that mild alterations escape the investigator's eye. The most accurate way of obtaining unbiased quantitative information about three-dimensional (3D) features of tissues, cells, or organelles from two-dimensional physical or optical sections is by means of stereology, the gold standard of image-based morphometry. Nevertheless, it can be challenging to express histopathological changes by morphometric parameters such as volume, surface, length or number only. In this review we therefore provide an overview on different histopathological lesions in the respiratory tract associated with particle and fiber toxicology and on how to apply stereological methods in order to correctly quantify and interpret histological lesions in the respiratory tract. The article further aims at pointing out common pitfalls in quantitative histopathology and at providing some suggestions on how respiratory toxicology can be improved by stereology. Thus, we hope that this article will stimulate scientists in particle and fiber toxicology research to implement stereological techniques in their studies, thereby promoting an unbiased 3D assessment of pathological lesions associated with particle exposure. PMID- 26521140 TI - Retrospective case-series of Paecilomyces lilacinus ocular mycoses in Queensland, Australia. AB - BACKGROUND: The purpose of this study was to report: (1) the varying presentation of Paecilomyces ocular infections arising in Queensland; (2) the significance of immunosuppression as a primary determinant of disease; (3) the outcomes of voriconazole use; and (4) the ongoing need for both surgical and medical management of this devastating fungal infection. METHODS: A retrospective case series of 21 culture proven individuals participated in this series and were identified via a review of the pathology reporting system utilized in the Queensland public health system. All culture proven individuals were subjected to a systematic chart review. RESULTS: The primary risk factor for Paecilomyces lilacinus infection is immunosuppression with 81.25 % of individuals being on some form of immunosuppression (i.e. systemic or topical). Of the cases 71.43 % had an intact epithelial surface at the time of diagnosis, and 76 % had no previous ocular history. The final visual outcomes were nine cases with HM vision or worse, three cases with 6/48-6/60 vision, three cases 6/12-6/24, and six cases with 6/12 vision or better. Despite voriconazole use rates of greater than 80 %, protracted and poor treatment outcomes continue to be commonplace. CONCLUSIONS: Paecilomyces lilacinus is a filamentous fungus that has a predilection for immunosuppressed individuals. Despite in vitro and case reports demonstrating the effectiveness of voriconazole poor outcomes continue to be seen. PMID- 26521142 TI - The research process from ideas to implementation. PMID- 26521141 TI - Roflumilast partially reverses smoke-induced mucociliary dysfunction. AB - BACKGROUND: Phosphodiesterases (PDEs) break down cAMP, thereby regulating intracellular cAMP concentrations and diffusion. Since PDE4 predominates in airway epithelial cells, PDE4 inhibitors can stimulate Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by increasing cAMP. Tobacco smoking and COPD are associated with decreased CFTR function and impaired mucociliary clearance (MCC). However, the effects of the PDE4 inhibitor roflumilast on smoke induced mucociliary dysfunction have not been fully explored. METHODS: Primary normal human bronchial epithelial cells (NHBE) from non-smokers, cultured at the air-liquid interface (ALI) were used for most experiments. Cultures were exposed to cigarette smoke in a Vitrocell VC-10 smoking robot. To evaluate the effect of roflumilast on intracellular cAMP concentrations, fluorescence resonance energy transfer (FRET) between CFP- and YFP-tagged protein kinase A (PKA) subunits was recorded. Airway surface liquid (ASL) was measured using light refraction scanning and ciliary beat frequency (CBF) employing infrared differential interference contrast microscopy. Chloride conductance was measured in Ussing chambers and CFTR expression was quantified with qPCR. RESULTS: While treatment with 100 nM roflumilast had little effect alone, it increased intracellular cAMP upon stimulation with forskolin and albuterol in cultures exposed to cigarette smoke and in control conditions. cAMP baselines were lower in smoke-exposed cells. Roflumilast prolonged cAMP increases in smoke-exposed and control cultures. Smoke-induced reduction in functional, albuterol-mediated chloride conductance through CFTR was improved by roflumilast. ASL volumes also increased in smoke-exposed cultures in the presence of roflumilast while it did not in its absence. Cigarette smoke exposure decreased CBF, an effect rescued with roflumilast, particularly when used together with the long-acting beta-mimetic formoterol. Roflumilast also enhanced forskolin-induced CBF stimulation in ASL volume supplemented smoked and control cells, confirming the direct stimulatory effect of rising cAMP on ciliary function. In active smokers, CFTR mRNA expression was increased compared to non-smokers and ex-smokers. Roflumilast also increased CFTR mRNA levels in cigarette-smoke exposed cell cultures. CONCLUSIONS: Our results show that roflumilast can rescue smoke-induced mucociliary dysfunction by reversing decreased CFTR activity, augmenting ASL volume, and stimulating CBF, the latter particularly in combination with formoterol. As expected, CFTR mRNA expression was not indicative of apical CFTR function. PMID- 26521143 TI - A retrospective outcomes study examining the effect of interactive metronome on hand function. AB - INTRODUCTION: Interactive Metronome (IM, The Interactive Metronome Company, Sunrise, Florida, USA) is a computer-based modality marketed to rehabilitation professionals who want to improve outcomes in areas of coordination, motor skills, self-regulation behaviors, and cognitive skills. PURPOSE: This retrospective study examined the efficacy of IM training on improving timing skills, hand function, and parental report of self-regulatory behaviors. METHODS: Forty eight children with mixed motor and cognitive diagnoses completed an average of 14 one-hour training sessions over an average of 8.5 weeks in an outpatient setting. Each child was assessed before and after training with the Interactive Metronome Long Form Assessment, the Jebsen Taylor Test of Hand Function, and a parent questionnaire. RESULTS: All three measures improved with statistical significance despite participants having no direct skill training. CONCLUSION: These results suggest an intimate relationship between cognition and motor skills that has potential therapeutic value. LEVEL OF EVIDENCE: Level 4, Retrospective Case Series. PMID- 26521144 TI - Cross-national comparison of socioeconomic inequalities in obesity in the United States and Canada. AB - INTRODUCTION: Prior cross-national studies of socioeconomic inequalities in obesity have only compared summary indices of inequality but not specific, policy relevant dimensions of inequality: (a) shape of the socioeconomic gradient in obesity, (b) magnitude of differentials in obesity across socioeconomic levels and, (c) level of obesity at any given socioeconomic level. We use unique data on two highly comparable societies - U.S. and Canada - to contrast each of these inequality dimensions. METHODS: Data came from the 2002/2003 Joint Canada/U.S. Survey of Health. We calculated adjusted prevalence ratios (APRs) for obesity (compared to normal weight) by income quintile and education group separately for both nations and, between Canadians and Americans in the same income or education group. RESULTS: In the U.S., every socioeconomic group except the college educated had significant excess prevalence of obesity. By contrast in Canada, only those with less than high school were worse off, suggesting that the shape of the socioeconomic gradient differs in the two countries. U.S. differentials between socioeconomic levels were also larger than in Canada (e.g., PR quintile 1 compared to quintile 5 was 1.82 in the U.S. [95 % CI: 1.52-2.19] but 1.45 in Canada [95 % CI: 1.10-1.91]). At the lower end of the socioeconomic gradient, obesity was more prevalent in the U.S. than in Canada. CONCLUSIONS: Our results suggest there is variation between U.S. and Canada in different dimensions of socioeconomic inequalities in obesity. Future research should examine a broader set of nations and test whether specific policies or environmental exposures can explain these differences. PMID- 26521145 TI - Effects of photodynamic therapy mediated by nanoemulsion containing chloro aluminum phthalocyanine: a histologic and immunohistochemical study in human gingiva. AB - BACKGROUND: Photodynamic therapy (PDT) uses photosensitizing agents, which are delivered in target cells, followed by local application of visible light in specific wavelengths. This reaction produce reactive oxygen species able to induce cell death by apoptosis or necrosis, injured to the local vasculature, and exert important effects on the immune system. OBJECTIVE: The present work evaluated the clinical findings, histomorphological alterations and immunodetection of VEGF after PDT using chloro-aluminum phthalocyanine (AlClPc) entrapped in a lipid nanoemulsion in a split-mouth clinical trial. MATERIAL AND METHODS: Eight healthy volunteers with clinical indication for extraction were included in the study. Seven days before the extraction 40 ul of nanoemulsion AlClPc 5MUM was injected into gingival tissue followed by irradiation with diode laser, the contralateral side was used as control. Tissue specimens were removed seven days after the PDT and divided into two groups (test and control groups) for histological and immunohistochemical analysis. Patients were monitored at days, 0, 7, 14 and 30 to assess adverse effects of the therapy. RESULTS: The therapy was well tolerated by all patients. Adverse effects were short-time and completely reversible. Areas of edema, vascular congestion, and intense vascularization were viewed in gingival samples that received PDT. Additionally, dystrophic calcification was observed in subepithelial region. VEGF showed moderate to strong immunostaining in specimens subjected to PDT. CONCLUSIONS: Taken together, the results showed that the protocol used in this study mediated by nanoemulsion containing AlClPc is safe for clinical application in gingival tissue and suggests that VEGF is increased after PDT. PMID- 26521146 TI - Biochemical characterization of a novel carboxypeptidase inhibitor from a variety of Andean potatoes. AB - Natural protease inhibitors of metallocarboxypeptidases are rarely reported. In this work, the cloning, expression and characterization of a proteinaceous inhibitor of the A/B-type metallocarboxypeptidases, naturally occurring in tubers of Solanum tuberosum, subsp. andigenum cv. Imilla morada, are described. The obtained cDNA encoded a polypeptide of 80 residues, which displayed the features of metallocarboxypeptidase inhibitor precursors from the Potato Carboxypeptidase Inhibitor (PCI) family. The mature polypeptide (39 residues) was named imaPCI and in comparison with the prototype molecule of the family (PCI from S. tuberosum subsp. tuberosum), its sequence showed one difference at its N-terminus and another three located at the secondary binding site, a region described to contribute to the stabilization of the complex inhibitor-target enzyme. In order to gain insights into the relevance of the secondary binding site in nature, a recombinant form of imaPCI (rimaPCI) having only differences at the secondary binding site with respect to recombinant PCI (rPCI) was cloned and expressed in Escherichia coli. The rimaPCI exhibited a molecular mass of 4234.8Da by MALDI TOF/MS. It displayed potent inhibitory activity towards A/B-type carboxypeptidases (with a Ki in the nanomolar range), albeit 2-4-fold lower inhibitory capacity compared to its counterpart rPCI. This result is in agreement with our bioinformatic analysis, which showed that the main interaction established between the secondary binding site of rPCI and the bovine carboxypeptidase A is likely lost in the case of rimaPCI. These observations reinforce the importance of the secondary binding site of PCI-family members on inhibitory effects towards A/B-type metallocarboxypeptidases. Furthermore, as a simple proof of concept of its applicability in biotechnology and biomedicine, the ability of rimaPCI to protect human epidermal growth factor from C-terminal cleavage and inactivation by carboxypeptidases A and B was demonstrated. PMID- 26521147 TI - Microbiomes of Endodontic-Periodontal Lesions before and after Chemomechanical Preparation. AB - INTRODUCTION: This study was conducted to evaluate the microbiomes of endodontic periodontal lesions before and after chemomechanical preparation (CMP). METHODS: Clinical samples were taken from 15 root canals (RCs) with necrotic pulp tissues and from their associated periodontal pockets (PPs) (n = 15) of teeth with endodontic-periodontal lesions before and after CMP. The Human Oral Microbe Identification using Next Generation Sequencing (NGS) protocol and viable culture were used to analyze samples from RCs and PPs. The Mann-Whitney U test and Benjamini-Hochberg corrections were performed to correlate the clinical and radiographic findings with microbial findings (P < .05). RESULTS: Bacteria were detected in 100% of the samples in both sites (15/15) using NGS. Firmicutes was the most predominant phylum in both sites using both methods. The most frequently detected species in the RCs before and after CMP using NGS were Enterococcus faecalis, Parvimonas micra, Mogibacterium timidum, Filifactor alocis, and Fretibacterium fastidiosum. The species most frequently detected in the PPs before and after CMP using NGS were P. micra, E. faecalis, Streptococcus constellatus, Eubacterium brachy, Tannerella forsythia, and F. alocis. Associations were found between periapical lesions <= 2 mm and Desulfobulbus sp oral taxon 041 and with periodontal pockets >= 6 mm and Dialister invisius and Peptostreptococcus stomatis (all P < .05, found in the RCs before CMP). CONCLUSIONS: It is concluded that the microbial community present in combined endodontic-periodontal lesions is complex and more diverse than previously reported. It is important to note that bacteria do survive in some root canals after CMP. Finally, the similarity between the microbiota of both sites, before and after CMP, suggests there may be a pathway of infection between the pulp and periodontium. PMID- 26521148 TI - Evaluation of Periapical Lesions and Their Association with Maxillary Sinus Abnormalities on Cone-beam Computed Tomographic Images. AB - INTRODUCTION: Periapical inflammation is often responsible for distinct maxillary sinus (MS) changes. This retrospective, cross-sectional study evaluated the association between the clinical characteristics of periapical lesions (presence, size, and distance) in maxillary posterior teeth and the presence of sinus abnormalities by evaluating cone-beam computed tomographic (CBCT) images obtained from an archived collection. Apart from sex, no other patient information was available. METHODS: The study sample was composed of CBCT images of 143 MSs of patients with at least 1 maxillary posterior tooth with a periapical lesion and 178 MSs of patients without periapical radiolucent lesions. Sinus abnormalities were classified as mucosal thickening, sinus polyp, antral pseudocyst, nonspecific opacification, periostitis, and antral calcification; periapical radiolucent areas were classified using the CBCT periapical index, and the distance between the periapical lesion edge and the MS floor was measured. Data were analyzed using chi-square tests at a level of significance set at alpha = 0.05. RESULTS: Most sinus abnormalities were associated with at least 1 maxillary posterior tooth with a periapical lesion (P > .05). The most frequent sinus abnormality in the presence of a periapical lesion was mucosal thickening. All teeth with a CBCT periapical index score of 5 were associated with sinus abnormalities. The highest frequency of abnormalities was found when the radiolucent area was subjacent to the sinus floor. CONCLUSIONS: Maxillary posterior teeth with periapical radiolucent lesions had the highest frequency of sinus abnormalities. The size of a periapical lesion was not associated with the frequency of sinus abnormalities. A close spatial relationship between periapical lesions and sinuses resulted most frequently in sinus abnormalities. PMID- 26521149 TI - Leptin dose-dependently decreases atherosclerosis by attenuation of hypercholesterolemia and induction of adiponectin. AB - OBJECTIVES: Conflicting evidence concerning leptin in atherosclerosis has been published. Furthermore, dose-dependent effects of leptin on atherogenesis have not been studied. METHODS: Leptin-deficient low-density lipoprotein receptor (LDLR) knockout (LDLR(-/-);ob/ob) mice were treated with saline, 0.1, 0.5, or 3.0mg/kg body weight (BW)/d recombinant leptin over 12weeks starting at 8weeks of age. Aortic root and brachiocephalic artery (BCA) atherosclerotic lesions were analyzed by oil red O staining. Furthermore, glucose homeostasis, lipid metabolism, and liver function including tissue studies were assessed in all animals. RESULTS: Leptin treatment dose-dependently decreased BW in LDLR(-/ );ob/ob mice as compared to saline. Mice in the 0.1 and 0.5mg/kgBW/d groups remained heavier (i.e. subphysiological leptin dose) and in the 3.0mg/kgBW/d group had similar weight (i.e. physiological leptin dose) as compared to non leptin-deficient LDLR(-/-) animals. Recombinant leptin dose-dependently reduced plaque area in the aortic root and the BCA by 36% and 58%, respectively. Leptin mediated reductions of plasma total and LDL-cholesterol (Chol) remained independent predictors for aortic root plaque area. Chol content in liver, as well as hepatic expression of key lipid and proinflammatory genes, were dose dependently regulated by leptin. Furthermore, leptin treatment increased circulating levels and adipose tissue mRNA expression of the adipokine adiponectin. CONCLUSIONS: Leptin administration within the subphysiological to physiological range diminishes atherosclerotic lesions. Leptin appears to mediate its antiatherogenic effects indirectly through reduction of hypercholesterolemia and liver steatosis, as well as upregulation of insulin-sensitizing and atheroprotective adiponectin. PMID- 26521150 TI - Spontaneous hypertension occurs with adipose tissue dysfunction in perilipin-1 null mice. AB - Perilipin-1 (Plin1) coats lipid droplets exclusively in adipocytes and regulates two principle functions of adipose tissue, triglyceride storage and hydrolysis, which are disrupted upon Plin1 deficiency. In the present study, we investigated the alterations in systemic metabolites and hormones, vascular function and adipose function in spontaneous hypertensive mice lacking perilipin-1 (Plin1-/-). Plin1-/- mice developed spontaneous hypertension without obvious alterations in systemic metabolites and hormones. Plin1 expressed only in adipose cells but not in vascular cells, so its ablation would have no direct effect in situ on blood vessels. Instead, Plin1-/- mice showed dysfunctions of perivascular adipose tissue (PVAT), a fat depot that anatomically surrounds systemic arteries and has an anticontractile effect. In Plin1-/- mice, aortic and mesenteric PVAT were reduced in mass and adipocyte derived relaxing factor secretion, but increased in basal lipolysis, angiotensin II secretion, macrophage infiltration and oxidative stress. Such multiple culprits impaired the anticontractile effect of PVAT to promote vasoconstriction of aortic and mesenteric arteries of Plin1-/- mice. Furthermore, arterial vessels of Plin1-/- mice showed increasing angiotensin II receptor type 1, monocyte chemotactic protein-1 and interlukin-6 expression, structural damage of endothelial and smooth muscle cells, along with impaired endothelium-dependent relaxation. Hypertension in Plin1-/- mice might occur as a deleterious consequence of PVAT dysfunction. This finding provides the direct evidence that links dysfunctional PVAT to vascular dysfunction and hypertension, particularly in pathophysiological states. This hypertensive mouse model might mimic and explain the hypertension occurring in patients with adipose tissue dysfunction, particularly with Plin1 mutations. PMID- 26521151 TI - Attenuation of functional hyperemia to visual stimulation in mild Alzheimer's disease and its sensitivity to cholinesterase inhibition. AB - Despite the growing recognition of the significance of cerebrovascular impairment in the etiology and progression of Alzheimer's disease (AD), the early stage brain vascular dysfunction and its sensitivity to pharmacological interventions is still not fully characterized. Due to the early and aggressive treatment of probable AD with cholinesterase inhibitors (ChEI), which in and of themselves have direct effects on brain vasculature, the vast majority of hemodynamic measurements in early AD subjects reported hitherto have consequently been made only after the start of treatment, complicating the disentanglement of disease- vs. treatment-related effects on the cerebral vasculature. To address this gap, we used pseudo continuous arterial spin labeling MRI to measure resting perfusion and visual stimulation elicited changes in cerebral blood flow (CBF) and blood oxygenation dependent (BOLD) fMRI signal in a cohort of mild AD patients immediately prior to, 6months post, and 12months post commencement of open label cholinesterase inhibitor treatment. Although patients exhibited no gray matter atrophy prior to treatment and their resting perfusion was not distinguishable from that in age, education and gender-matched controls, the patients' visual stimulation-elicited changes in BOLD fMRI and blood flow were decreased by 10+/ 4% (BOLD) and 23+/-2% (CBF), relative to those in controls. Induction of cholinesterase inhibition treatment was associated with a further, 7+/-2% reduction in patients' CBF response to visual stimulation, but it stabilized, at this new lower level, over the follow-up period. Likewise, MMSE scores remained stable during the treatment; furthermore, higher MMSE scores were associated with higher perfusion responses to visual stimulation. This study represents the initial step in disentangling the effects of AD pathology from those of the first line treatment with cholinesterase inhibitors on cerebral hemodynamics and supports the use of arterial spin labeling MRI for quantitative evaluation of the brain vascular function in mild Alzheimer's disease. The findings provide evidence of a pronounced deficit in the visual cortex hyperemia despite the relative sparing of visual function in early stage AD, its reduction with ChEI treatment induction, and its stabilization in the first year of cholinesterase inhibition treatment. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID- 26521152 TI - More genes, more problems? Benefits and risks of multiplex genetic testing. PMID- 26521153 TI - 3-phase dual-energy CT scan as a feasible salvage imaging modality for the identification of non-localizing parathyroid adenomas: a prospective study. AB - OBJECTIVES: Accurate pre-operative imaging of parathyroid adenomas (PAs) is essential for successful minimally invasive surgery; however, rates of non localizing PAs can be as high as 18 %. Multiphasic dual-energy CT (DECT) has the potential to increase accuracy of PA detection by enabling creation of paired material maps and spectral tissue characterization. This study prospectively evaluated the utility of 3-phase DECT for PA identification in patients with failed localizatio n via standard imaging. METHODS: Patients with primary hyperparathyroidism and non-localizing PAs underwent a 3 phase post-contrast DECT scan acquired at 25, 55, and 85 s. The scans were prospectively evaluated by two head and neck radiologists. Pre-operative localization was compared to intraoperative localization and final histopathology. A post-hoc DECT spectral density characterization was performed on pathologically-proven PAs. RESULTS: Out of 29 patients with primary hyperparathyroidism and non-localized PAs, DECT identified candidates in 26. Of the 23 patients who underwent parathyroidectomy, DECT provided precise anatomic localization in 20 patients (PPV = 87.0%), one with multi-gland disease. The virtual unenhanced images were not found to be useful for diagnosis but successful diagnosis was made without an unenhanced phase regardless. Spectral analysis demonstrated a distinct spectral Hounsfield attenuation curve for PAs compared to lymph nodes on arterial phase images. CONCLUSION: 3-phase DECT without an unenhanced phase is a feasible salvage imaging modality for previously non-localizing parathyroid adenomas. Optimal interpretation is achieved based on a combination of perfusion characteristics and other morphologic features. Advanced spectral DECT analysis has the potential for further increasing accuracy of PA identification in the future. PMID- 26521156 TI - Some Comments on Infection Prophylaxis. PMID- 26521154 TI - Epidemiological characterization of diabetic patients on therapy with continuous subcutaneous insulin infusion and continuous glucose monitoring in real time. AB - OBJECTIVE: To describe baseline characteristics of diabetic patients who were started on insulin pump and real time continuous glucose monitor (CSII-rtCGM) in a specialized center in Medellin, Colombia. MATERIALS AND METHODS: All patients with diabetes with complete data who were started on CSII-rtCGM between February 2010 and May 2014 were included. This is a descriptive analysis of the sociodemographic and clinical characteristics. RESULTS: 141 of 174 patients attending the clinic were included. 90,1% had type 1diabetes (T1D). The average age of T1D patients at the beginning of therapy was 31,4 years (SD 14,1). 75.8% of patients had normal weight (BMI<25), 21.0% were overweight (BMI 25-30) and 2,3% were obese (BMI>30). The median duration of T1D was 13 years (P25-P75=10.7 22.0). 14,2% of the patients were admitted at least once in the year preceding the start of CSII-rtCGM because of diabetes related complications. Mean A1c was 8.6%+/-1.46%. The main reasons for starting CSII-rtCGM were: poor glycemic control (50.2%); frequent hypoglycemia, nocturnal hypoglycemia, hypoglycemia related to exercise, asymptomatic hypoglycemia (30.2%); severe hypoglycemia (16.44%) and dawn phenomena (3.1%). CONCLUSION: Baseline characteristics of patients included in this study who were started on CSII-rtCGM are similar to those reported in the literature. The Clinic starts CSII-rtCGM mainly in T1D patients with poor glycemic control, frequent or severe hypoglycemia despite being on basal/bolus therapy. PMID- 26521155 TI - Metabolic control after years of completing a clinical trial on sensor-augmented pump therapy. AB - BACKGROUND: Sensor-augmented pump (SAP) therapy has been shown to be effective and safe for improving metabolic control in patients with type 1 diabetes mellitus (T1DM) in a number of trials. Our objective was to assess glycemic control in a group of T1DM patients on insulin pump or SAP therapy after years of participating in the SWITCH (Sensing With Insulin pump Therapy To Control HbA1c) trial and their return to routine medical monitoring. METHODS: A retrospective, observational study of 20 patients who participated in the SWITCH trial at our hospital from 2008 to 2010. HbA1c values were compared at the start, during (at the end of the periods with/without SAP use - Sensor On/Sensor Off period respectively - of the cross-over design), and 3 years after study completion. HbA1c values of patients who continued SAP therapy (n=6) or only used insulin pump (n=14) were also compared. RESULTS: Twenty patients with T1DM (44.4+/-9.3 years, 60% women, baseline HbA1c level 8.43+/-0.55%) were enrolled into the SWITCH study). Three years after study completion, HbA1c level was 7.79+/-0.77 in patients on pump alone, with no significant change from the value at the end of the Off period of the study (7.85+/-0.57%; p=0.961). As compared to the end of the On period, HbA1c worsened less in patients who remained on SAP than in those on pump alone (0.18+/-0.42 vs. 0.55+/-0.71%; p=0.171), despite the fact that levels were similar at study start (8.41+/-0.60 vs. 8.47+/-0.45; p=0.831) and at the end of the On period (7.24+/-0.48 vs. 7.38+/-0.61; p=0.566). Frequency of CGM use in patients who continued SAP therapy was high (61.2% of the time in the last 3 months). CONCLUSIONS: Our study suggests that the additional benefit of SAP therapy achieved in a clinical trial may persist in the long term in routine clinical care of patients with T1DM. PMID- 26521157 TI - Treatment of vertebral compression fractures with the cranio-caudal expandable implant SpineJack(r): Technical note and outcomes in 77 consecutive patients. AB - In vertebral compression fractures, the potential of kyphoplasty for restoring vertebral height is limited by the loss of restored height that occurs when the balloon is deflated and removed. SpineJack((r)) is also inserted percutaneously but is then left within the vertebral body after its expansion to reduce the fracture, thus avoiding loss of correction before the injection of cement. SpineJack((r)) was used in 77 patients to treat 83 recent VCFs (55.4% at L1-L2) due to trauma (59.7%) or osteoporosis (40.3%). Three (3.9%) complications were recorded, but none was related to SpineJack((r)): there was one case each of symptomatic cement leakage along a secondary pedicular fracture line; infection; and incipient device migration at the beginning of the learning curve. The rate of adjacent fractures was only 2.6%. The 5-year outcomes demonstrate that SpineJack((r)) provides both immediate and long-term benefits in terms of pain relief, functional recovery, and maintenance of vertebral height restoration. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 26521158 TI - Muscle activity of leg muscles during unipedal stance on therapy devices with different stability properties. AB - OBJECTIVES: To test the hypotheses that less stable therapy devices require greater muscle activity and that lower leg muscles will have greater increases in muscle activity with less stable therapy devices than upper leg muscles. DESIGN: Cross-sectional laboratory study. SETTING: Laboratory setting. PARTICIPANTS: Twenty-five healthy subjects. MAIN OUTCOME MEASURES: Electromyographic activity of four lower (gastrocnemius medialis, soleus, tibialis anterior, peroneus longus) and four upper leg muscles (vastus medialis and lateralis, biceps femoris, semitendinosus) during unipedal quiet barefoot stance on the dominant leg on a flat rigid surface and on five therapy devices with varying stability properties. RESULTS: Muscle activity during unipedal stance differed significantly between therapy devices (P < 0.001). The order from lowest to highest relative muscle activity matched the order from most to least stable therapy device. There was no significant interaction between muscle location (lower versus upper leg) and therapy device (P = 0.985). Magnitudes of additional relative muscle activity for the respective therapy devices differed substantially among lower extremity muscles. CONCLUSIONS: The therapy devices offer a progressive increase in training intensity, and thus may be useful for incremental training programs in physiotherapeutic practice and sports training programs. PMID- 26521159 TI - Asymptomatic ureteral rupture secondary to chronic urinary retention from massive prostatic enlargement. AB - Non-traumatic ureteral rupture has been reported more frequently, resulting from increased intraluminal pressures from distal urinary tract obstruction. We report the case of a 77-year-old man presenting with chronic urinary retention secondary to massive prostatic enlargement through acute kidney injury. Ultrasound scan detected a shallow left perinephric fluid collection with a possible bladder mass, demonstrated on flexible cystoscopy to be a massive median lobe of prostate. Computed tomography confirmed extravasation of urine from the left proximal ureter. In the absence of specific symptoms, the patient had successful conservative management with antibiotics and urinary catheterization for his acute episode, although declined further surgical intervention. PMID- 26521160 TI - Nonunion of the tibial facture as a consequence of posterior tibial artery pseudoaneurysm. AB - Pseudoaneurysm of the posterior tibial artery (PTA) is uncommon, and they mainly occur following high-velocity trauma, open fractures and can be iatrogenic in nature. To the best of our knowledge, this is the first reported and successfully treated case of PTA pseudoaneurysm identified as a consequence of tibia fracture nonunion in an otherwise healthy young individual 6 months following the original incident with a novel intraoperative technique. PMID- 26521161 TI - Rotation flap to cover a large defect on the dorsum of the hand. AB - The unique requirements of soft tissue coverage of the hand offer a challenge for the surgeon dealing with such defects. Local excision of such lesions may end in a defect that is not amenable to primary closure. Management of such defects requires the application of a graft or flap. We describe the application of a rotation flap for closure of a large defect on the dorsum of the hand following excision of a keratoacanthoma. The rotation flap offers repair with local skin of similar colour, texture and thickness. The end results were excellent both functionally and cosmetically. PMID- 26521162 TI - A simple approach to atom probe sample preparation by using shadow masks. AB - Here, we present a new method that utilises shadow masks in a broad ion beam system to prepare atom probe samples. It is particularly suited to non-conductors and materials with surface layers such as surface oxides, implanted layers or thin films. This new approach bypasses the focused ion beam (FIB) lift-out step, increasing the sample throughput, dramatically reducing the required FIB beam time and decreasing the complexity of sample preparation. PMID- 26521163 TI - Synchronizing atomic force microscopy force mode and fluorescence microscopy in real time for immune cell stimulation and activation studies. AB - A method is presented for combining atomic force microscopy (AFM) force mode and fluorescence microscopy in order to (a) mechanically stimulate immune cells while recording the subsequent activation under the form of calcium pulses, and (b) observe the mechanical response of a cell upon photoactivation of a small G protein, namely Rac. Using commercial set-ups and a robust signal coupling the fluorescence excitation light and the cantilever bending, the applied force and activation signals were very easily synchronized. This approach allows to control the entire mechanical history of a single cell up to its activation and response down to a few hundreds of milliseconds, and can be extended with very minimal adaptations to other cellular systems where mechanotransduction is studied, using either purely mechanical stimuli or via a surface bound specific ligand. PMID- 26521164 TI - Functional extension of high-speed AFM for wider biological applications. AB - High-speed atomic force microscopy (HS-AFM) has been established and used, which can visualize biomolecules in dynamic action at high spatiotemporal resolution without disturbing their function. Various studies conducted in the past few years have demonstrated that the dynamic structure and action of biomolecules revealed with HS-AFM can provide greater insights than ever before into how the molecules function. However, this microscopy has still limitations in some regards. Recently, efforts have been carried out to overcome some of the limitations. As a result, it has now become possible to visualize dynamic processes occurring even on live cells and perform simultaneous observations of topographic and fluorescent images at a high rate. In this review, we focus on technical developments for expanding the range of objects and phenomena observable by HS-AFM as well as for granting multiple functionalities to HS-AFM. PMID- 26521165 TI - Why Principal Component Analysis of STEM spectrum-images results in "abstract", uninterpretable loadings? AB - Principal Component Analysis (PCA) can improve dramatically the treatment of large STEM spectrum-images by finding the directions (loadings) of highest data variance in the factor space and projecting the data on these directions. Loadings typically do not show clear physical meanings, thus the interpretation of PCA results is difficult. This work investigates the potential reasons for appearing such counterintuitive PCA outputs. The following reasons are identified: (i) missing the step of centering the data in the PCA pre-treatment, (ii) complexity of data variations inconsistent with the orthogonality restrictions of PCA, (iii) non-linearity caused either by chemical variations or by the peculiarities of the spectra formation, and (iv) inaccuracy in extracting major PCA components. In many cases, the PCA treatment can be altered in such a way that the intuitively clear loadings are delivered. PMID- 26521166 TI - The provision of workplace accommodations following cancer: survivor, provider, and employer perspectives. AB - PURPOSE: With improvements in screening, diagnosis, and treatment, the number of persons surviving cancer and staying at or returning to work is increasing. While workplace accommodations optimize workers' abilities to participate in the workforce, there has been little in-depth investigation of the types of accommodations reported to have been provided to cancer survivors and the processes relevant to ensuring their successful implementation. METHODS: We employed an exploratory qualitative method and conducted 40 semi-structured interviews with three groups: (i) cancers survivors (n = 16), (ii) health/vocational service providers (n = 16), and (iii) employer representatives (n = 8) to explore return to work and accommodation processes, successes, and challenges. An inductive thematic analysis approach was used to analyze the data. RESULTS: Four types of accommodations were recommended: (1) graduated return to work plans and flexible scheduling, (2) modification of work duties and performance expectations, (3) retraining and supports at the workplace, and (4) modification of the physical work environment and/or the provision of adaptive aids/technologies. Processes relevant to ensuring effective accommodations included: (1) developing knowledge about accommodations, (2) employer's ability to accommodate, (3) negotiating reasonable accommodations, (4) customizing accommodations, and (5) implementing and monitoring accommodation plans. Accommodation challenges included: (1) survivors' fears requesting accommodations, (2) developing clear and specific accommodations, (3) difficult to accommodate jobs, and (4) workplace challenges, including strained pre-cancer workplace relationships, insufficient/inflexible workplace policies, employer concerns regarding productivity and precedent setting, and limited modified duties. CONCLUSIONS: Accommodations need to be customized and clearly linked to survivors' specific job demands, work context, and available workplace supports. Survivors need to feel comfortable disclosing the need for accommodations. Ongoing communication and monitoring are required to ensure accommodations are implemented and changes made to the return to work plan as required. IMPLICATIONS FOR CANCER SURVIVORS: The provision of appropriate workplace accommodations can enhance survivors' abilities to stay or return to work. PMID- 26521167 TI - Thrombolysis, Complete Recanalization, Diffusion Reversal, and Luxury Perfusion in Hyperacute Stroke. AB - A 59-year old man was admitted to our stroke care unit 1.8 hours after onset of cardioembolic stroke. Administration of issue-plasminogen activator achieved complete recanalization, and his lesion on diffusion-weighted imaging (DWI) disappeared and single photon emission computed tomography showed luxury perfusion. DWI reversal and luxury perfusion were sometimes observed in hyperacute stroke patients, especially timely reperfusion was achieved. However, the relationships between DWI reversal and luxury perfusion were not well known. Transient DWI reversal may be associated with luxury perfusion in patients treated with t-PA, via early complete recanalization achieved by thrombolysis. PMID- 26521168 TI - Gender Differences in Fibrin Polymerization and Lysability of Fibrin in Patients with Atrial Fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia for both men and women. The embolic cardiovascular events represent serious complications of AF, and apparently women are affected more seriously than men. Little is known about prothrombotic factors and possible gender differences. The present study aimed to characterize fibrin polymerization, fibrinolysis, and fibrin fiber properties in men and in women with AF. MATERIALS AND METHODS: Forty six female and 101 male patients with AF and without previous stroke were included. Polymerization kinetics, lysis of preformed clot, and fibrin fiber properties were determined by turbidimetric methods. RESULTS: Women were slightly older than men (P < .01), and the male group had a higher systolic blood pressure (P < .01) and a higher incidence of peripheral arterial disease (P < .01) than the female group. Compared with men, women had a higher Vmax during fibrin polymerization (P < .04) and a lower lysability of fibrin, when recombinant tissue plasminogen activator (rt-PA) was added during clot formation (P < .01), while external lysis (rt-PA added after clot formation), plasma fibrinolytic activity, d-dimer, and fibrin fiber properties did not differ between men and women. A significantly higher number of men received acetylsalicylic acid (ASA) compared with women (P < .004). Subgroup analyses on subjects not receiving ASA demonstrated that women still had higher Vmax (P < .04) and a lower rt-PA-induced fibrinolysis (P < .03). CONCLUSION: Women with AF have a higher velocity of lateral aggregation of fibrin fiber protofibrils and a lower lysis of fibrin clots than men. PMID- 26521169 TI - Dilated Virchow-Robin Spaces in First-Ever Lacunar Stroke Patients: Topography and Clinical Correlations. AB - BACKGROUND AND PURPOSE: Dilated Virchow-Robin spaces (dVRSs) were regarded as a phenotype of cerebral small-vessel disease (SVD). However, the clinical correlations of dVRS were still unclear. In this study, we aimed to investigate the topography and clinical correlations of dVRS in first-ever lacunar stroke patients. METHODS: Patients with first-ever lacunar stroke were recruited and had magnetic resonance scans to identify the presence and degree of dVRS in the basal ganglia (BG-dVRS), dVRS in the central semiovale (CSO-dVRS), leukoaraiosis, and silent brain infarction (SBI). The neurological deficits after stroke onset and functional outcome after 1 year were evaluated using National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale, respectively. Clinical and radiological features were compared between patients with high and low degrees of dVRS, and between patients with favorable and unfavorable outcomes. Logistic regression models were constructed to identify the risk factors of unfavorable outcome. RESULTS: The NIHSS scores were not statistically different between patients with high and low degrees of dVRS. More patients with high degrees of BG dVRS had unfavorable outcomes than those with low degrees of BG-dVRS. Logistic regression showed that the degrees of BG-dVRS, leukoaraiosis, and SBIs were not independent risk factors for the unfavorable outcome, whereas the total burden of SVD was an independent risk factor for the unfavorable outcome. CONCLUSION: The degrees of either BG-dVRS or CSO-dVRS were not associated with the severity of first lacunar stroke. BG-dVRS was related to the unfavorable 1-year outcome. This association might be based on the total severity of SVD. PMID- 26521171 TI - Delay discounting of hypothetical monetary rewards with decoys. AB - The current research attempted to decrease individuals' rates of delay discounting by introducing decoys that are similar but inferior to delayed rewards. Two experiments in the current study compared patterns of delay discounting generated by repeated choices between two hypothetical monetary rewards in the absence or presence of a decoy. Binary questionnaires (i.e., decoy absent) included questions with two options: a smaller-sooner (SS) reward and a larger-later (LL) reward. Trinary questionnaires (i.e., decoy present) included questions with three options: an SS reward, an LL reward, and a decoy. If an option is at least as rewarding on every dimension of value as an alternative and the option is more rewarding than an alternative on at least one dimension, then the option is considered to dominate the alternative (Wedell, 1991). The first experiment assessed the influence of decoys dominated by LL rewards (LL(-) decoys), which were constructed to be similar (on the dimension of amount) but inferior (on the dimension of delay) to LL rewards. The second experiment examined the effects of counterbalancing the order of binary and trinary questionnaires. In the first experiment, participants discounted to a lesser degree when LL(-) decoys were present as compared to when they were absent. In the second experiment, participants only discounted to a lesser degree on trinary questionnaires with LL(-) decoys when they had not previously completed binary questionnaires. Patterns of discounting generated by binary questionnaires were similar to those generated by trinary questionnaires when decoys are present; however, the degree to which individuals discounted delayed rewards was affected by the number of and type of options that were available. The current results join previous evidence suggesting that rates of delay discounting are sensitive to a variety of contextual influences. PMID- 26521170 TI - Impairment of ATP hydrolysis decreases adenosine A1 receptor tonus favoring cholinergic nerve hyperactivity in the obstructed human urinary bladder. AB - This study was designed to investigate whether reduced adenosine formation linked to deficits in extracellular ATP hydrolysis by NTPDases contributes to detrusor neuromodulatory changes associated with bladder outlet obstruction in men with benign prostatic hyperplasia (BPH). The kinetics of ATP catabolism and adenosine formation as well as the role of P1 receptor agonists on muscle tension and nerve evoked [(3)H]ACh release were evaluated in mucosal-denuded detrusor strips from BPH patients (n = 31) and control organ donors (n = 23). The neurogenic release of ATP and [(3)H]ACh was higher (P < 0.05) in detrusor strips from BPH patients. The extracellular hydrolysis of ATP and, subsequent, adenosine formation was slower (t (1/2) 73 vs. 36 min, P < 0.05) in BPH detrusor strips. The A(1) receptor-mediated inhibition of evoked [(3)H]ACh release by adenosine (100 MUM), NECA (1 MUM), and R-PIA (0.3 MUM) was enhanced in BPH bladders. Relaxation of detrusor contractions induced by acetylcholine required 30-fold higher concentrations of adenosine. Despite VAChT-positive cholinergic nerves exhibiting higher A(1) immunoreactivity in BPH bladders, the endogenous adenosine tonus revealed by adenosine deaminase is missing. Restoration of A1 inhibition was achieved by favoring (1) ATP hydrolysis with apyrase (2 U mL(-1)) or (2) extracellular adenosine accumulation with dipyridamole or EHNA, as these drugs inhibit adenosine uptake and deamination, respectively. In conclusion, reduced ATP hydrolysis leads to deficient adenosine formation and A(1) receptor-mediated inhibition of cholinergic nerve activity in the obstructed human bladder. Thus, we propose that pharmacological manipulation of endogenous adenosine levels and/or A(1) receptor activation might be useful to control bladder overactivity in BPH patients. PMID- 26521172 TI - Budget Impact Analysis of Using Dihydroartemisinin-Piperaquine to Treat Uncomplicated Malaria in Children in Tanzania. AB - BACKGROUND AND OBJECTIVE: Dihydroartemisinin-piperaquine (DhP) is a very cost effective anti-malarial drug. The aim of this study was to predict the budget impact of using DhP as a first- or second-line drug to treat uncomplicated malaria in children in Tanzania. METHODS: A dynamic Markov decision model was developed based on clinical and epidemiological data to estimate annual cases of malaria in children aged under 5 years. The model was used to predict the budget impact of introducing DhP as the first- or second-line anti-malarial drug, from the perspective of the National Malaria Control Program in 2014; thus, only the cost of drugs and diagnostics were considered. Probabilistic sensitivity analysis was performed to explore overall uncertainties in input parameters. RESULTS: The model predicts that the policy that uses artemether-lumefantrine (AL) and DhP as the first- and second-line drugs (AL + DhP), respectively, will save about $US64,423 per year, while achieving a 3% reduction in the number of malaria cases, compared with that of AL + quinine. However, the policy that uses DhP as the first-line drug (DhP + AL) will consume an additional $US780,180 per year, while achieving a further 5% reduction in the number of malaria cases, compared with that of AL + DhP. CONCLUSION: The use of DhP as the second-line drug to treat uncomplicated malaria in children in Tanzania is slightly cost saving. However, the policy that uses DhP as the first-line drug is somewhat more expensive but with more health benefits. PMID- 26521173 TI - Inflatable bouncer-related injuries to children: increasing phenomenon in pediatric emergency department, 2002-2013. AB - A sharp uptrend in emergency department (ED) visits for injuries associated with inflatable bouncers (IBs) has been observed recently. The aim of this study is to describe the epidemiology and features of injuries resulting from the use of IBs at an Italian pediatric ED. We collected data of 521 children from GIPSE (regional software for management of admission at ED) in the period of 2002-2013. The injuries were slightly more frequent in males than females (52.4 vs 47.6 %). Preschooler children were the most commonly injured (45.7 %). The occurrence of injuries increased by year (eight cases in 2002 and 90 cases in 2013), and a seasonal variability was reported (207 cases in the period of April-June). The most common body region injured was the upper extremity (52.4 %). Children with fractures were 126 times more likely to have injured the upper extremity rather than other body regions compared with patients with no fracture (p < 0.05). Humerus and radius/ulna fractures occurred most commonly in preschooler children (p < 0.05). Fractures were 43 times more likely to be hospitalized than children with no fracture (p < 0.05). CONCLUSION: Injuries associated with IBs increased over time. Preschooler children were most injured, and this means there is insufficient adherence to existing recommendations concerning an age limit. WHAT IS KNOWN: * Along with the skyrocketing popularity of IBs among children, the number of children presenting to ED with injuries from these plays has also been increasing at an alarming rate; * The European literature about this phenomenon is scarce and no specific legislations exist for safety of these devises in European Union (EU). What is New: * This is the first study in EU that examines trends for pediatric inflatable bouncer-related injuries at ED over an 11-year period. * Although American Academy of Pediatrics recommends restrictions of attendance to IBs under 6 years old, injuries and fractures continue to occur more frequently under this age. PMID- 26521174 TI - GABA(A) Receptors in the Central Nucleus of the Amygdala Are Involved in Pain- and Itch-Related Responses. AB - Itch and pain are unpleasant sensations that distress many patients with disease. However, most studies have focused on the neural mechanisms of pain, and much less effort has been devoted to itch. It has been reported that itch and pain might share a common pathway, and gamma-aminobutyric acid type A (GABA(A)) receptors in the central nucleus of the amygdala (CeA) are involved in pain modulation. However, the contribution of GABAA receptors in the CeA to the modulation of itch remains poorly understood. Herein, we report that bilateral intra-CeA microinjection of a selective GABAA receptor agonist muscimol hydrochloride (Mus; 50 ng per side), but not a selective GABAA receptor antagonist bicuculline (Bic; 20 ng per side) or vehicle, showed significant analgesic effects, reflected by an increase in tail-flick latency and a decrease in allyl isothiocyanate (mustard oil)-evoked ipsilateral forelimb wipes. More importantly, rats subjected to intra-CeA infusion of Bic showed a significantly greater number of scratching bouts and time in acute and chronic pruritus animal models than control rats. Conversely, intra-CeA infusion of Mus in animal models dramatically decreased the number of scratching bouts and time compared with control rats. In addition, intra-CeA infusion of Bic or Mus at the current dose had no obvious effects on other behaviors including locomotor activity and spontaneous facial grooming in rats subjected to cheek microinjection of 5 hydroxytryptamine. Taken together, these results indicate that the GABA(A) receptor-mediated inhibitory system in the CeA is involved in itch modulation as well as is known in pain control. PERSPECTIVE: Itch, especially chronic itch, remains a challenge in clinic. Results of this study showed that the GABAA receptors in the CeA play an important role in itch modulation, which might help us to better understand the mechanisms of itch and subsequently develop novel mechanisms-based strategies to treat chronic itch in clinic. PMID- 26521175 TI - Determination of nine sensitizing disperse dyes in activated sludge by ultrasound assisted liquid-liquid extraction-ultra-performance liquid chromatography electrospray ionization-tandem mass spectrometry. AB - A method was developed on the basis of ultrasound-assisted liquid-liquid extraction ultra-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (ULLE-UPLC-ESI-MS/MS) to determine nine sensitizing disperse dyes in activated sludge. The samples were extracted using ULLE and separated through UPLC on an ACQUITY UPLCTM BEH C18 column with a gradient elution program of acetonitrile and acidified water (containing 2% acetonitrile, 0.2% formic acid, and 0.005 mol/L ammonium; pH 2.7) as the mobile phase. The samples were then identified and quantified through UPLC-ESI-MS/MS in a positive mode and multiple reaction monitoring. Results showed good linearity (10-1000 MUg/L, 0.9934-0.9998), detection limit (0.08-2.17 MUg/L), and quantification limit (0.27-7.38 MUg/L) for the nine sensitizing disperse dyes, with recoveries ranging from 65.0 to 111.3%. The proposed method was applied to detect and determine the concentration of sensitizing disperse dyes in sludge samples obtained from various sewage treatment plants (six dyeing enterprises and one dye manufacturer). Three sensitizing disperse dyes were identified, and the lowest concentration detected was 10 MUg/kg. PMID- 26521176 TI - Aptamer-based fluorescent screening assay for acetamiprid via inner filter effect of gold nanoparticles on the fluorescence of CdTe quantum dots. AB - This paper reports a novel aptamer-based fluorescent detection method for small molecules represented by acetamiprid based on the specific binding of aptamers with acetamiprid, and the inner filter effect (IFE) of gold nanoparticles (AuNPs) on the fluorescence of CdTe quantum dots (CdTe QDs). When CdTe QDs were mixed with AuNPs, the fluorescence of CdTe QDs was significantly quenched via IFE. The IFE efficiency could be readily modulated by the absorption and the aggregation state of AuNPs. The presence of salt could easily induce the aggregation of AuNPs, resulting in the fluorescence recovery of the quenched QDs. Acetamiprid binding aptamer (ABA) could adsorb on the negatively charged AuNPs through the coordination interaction to protect AuNPs from salt-induced aggregation, so the fluorescence of CdTe QDs would be quenched by the IFE of AuNPs. However, the specific binding of ABA with acetamiprid could release the ABA from the surfaces of AuNPs and decrease the salt tolerance of AuNPs, so the IFE-decreased fluorescence of CdTe QDs was regained with the presence of acetamiprid, and the fluorescence enhancement efficiency was driven by the concentration of acetamiprid. Based on this principle, the aptamer-based fluorescent method for acetamiprid has been established and optimized. The assay exhibited excellent selectivity towards acetamiprid over its analogues and other pesticides which may coexist with acetamiprid. Under the optimum experiment conditions, the established method could be applied for the determination of acetamiprid with a wide linear range from 0.05 to 1.0 MUM, and a low detection limit of 7.29 nM (3sigma). Furthermore, this IFE-based method has been successfully utilized to detect acetamiprid in six types of vegetables, and the results were in full agreement with those from HPLC and LC-MS. The proposed method displays remarkable advantages of high sensitivity, rapid analysis, excellent selectivity, and would be suitable for the practical application of target screening in real samples. PMID- 26521177 TI - A nanoaggregate-on-mirror platform for molecular and biomolecular detection by surface-enhanced Raman spectroscopy. AB - A nanoaggregate-on-mirror (NAOM) structure has been developed for molecular and biomolecular detection using surface-enhanced Raman spectroscopy (SERS). The smooth surface of the gold mirror allows for simple and homogeneous functionalization, while the introduction of the nanoaggregates enhances the Raman signal of the molecule(s) in the vicinity of the aggregate-mirror junction. This is evidenced by functionalizing the gold mirror with 4-nitrothiophenol, and the further addition of gold nanoaggregates promotes local SERS activity only in the areas with the nanoaggregates. The application of the NAOM platform for biomolecular detection is highlighted using glucose and H2O2 as molecules of interest. In both cases, the gold mirror is functionalized with 4 mercaptophenylboronic acid (4-MPBA). Upon exposure to glucose, the boronic acid moiety of 4-MPBA forms a cyclic boronate ester. Once the nanoaggregates are added to the surface, detection of glucose is possible without the use of an enzyme. This method of indirect detection provides a limit of detection of 0.05 mM, along with a linear range of detection from 0.1 to 15 mM for glucose, encompassing the physiological range of blood glucose concentration. The detection of H2O2 is achieved with optical inspection and SERS. The H2O2 interferes with the coating of the gold mirror, enabling qualitative detection by visual inspection. Simultaneously, the H2O2 reacts with the boronic acid to form a phenol, a change that is detected by SERS. PMID- 26521178 TI - Evaluation of drug incorporation into hair segments and nails by enantiomeric analysis following controlled single MDMA intakes. AB - Incorporation rates of the enantiomers of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA) into hair and nails were investigated after controlled administration. Fifteen subjects without MDMA use received two doses of 125 mg of MDMA. Hair, nail scrapings, and nail clippings were collected 9-77 days after the last administration (median 20 days). Hair samples were analyzed in segments of 1- to 2-cm length. After chiral derivatization with N-(2,4-dinitro-5-fluorophenyl)-L-valinamide, MDMA and MDA diastereomers were analyzed by liquid chromatography-tandem mass spectrometry. Highest concentrations in hair segments corresponded to the time of MDMA intake. They ranged from 101 to 3200 pg/mg and 71 to 860 pg/mg for R- and S-MDMA, and from 3.2 to 116 pg/mg and 4.4 to 108 pg/mg for R- and S-MDA, respectively. MDMA and MDA concentrations in nail scrapings and clippings were significantly lower than in hair samples. There was no significant difference between enantiomeric ratios of R/S-MDMA and R/S-MDA in hair and nail samples (medians 2.2-2.4 for MDMA and 0.85-0.95 for MDA). Metabolite ratios of MDA to MDMA were in the same range in hair and nail samples (medians 0.044-0.055). Our study demonstrates that administration of two representative doses of MDMA was detected in the hair segments corresponding to the time of intake based on average hair growth rates. MDMA was detected in all nail samples regardless of time passed after intake. Comparable R/S ratios in hair and nail samples may indicate that incorporation mechanisms into both matrices are comparable. PMID- 26521179 TI - Assessment of the real-time PCR and different digital PCR platforms for DNA quantification. AB - Digital PCR (dPCR) is beginning to supersede real-time PCR (qPCR) for quantification of nucleic acids in many different applications. Several analytical properties of the two most commonly used dPCR platforms, namely the QX100 system (Bio-Rad) and the 12.765 array of the Biomark system (Fluidigm), have already been evaluated and compared with those of qPCR. However, to the best of our knowledge, direct comparison between the three of these platforms using the same DNA material has not been done, and the 37 K array on the Biomark system has also not been evaluated in terms of linearity, analytical sensitivity and limit of quantification. Here, a first assessment of qPCR, the QX100 system and both arrays of the Biomark system was performed with plasmid and genomic DNA from human cytomegalovirus. With use of PCR components that alter the efficiency of qPCR, each dPCR platform demonstrated consistent copy-number estimations, which indicates the high resilience of dPCR. Two approaches, one considering the total reaction volume and the other considering the effective reaction size, were used to assess linearity, analytical sensitivity and variability. When the total reaction volume was considered, the best performance was observed with qPCR, followed by the QX100 system and the Biomark system. In contrast, when the effective reaction size was considered, all three platforms showed almost equal limits of detection and variability. Although dPCR might not always be more appropriate than qPCR for quantification of low copy numbers, dPCR is a suitable method for robust and reproducible quantification of viral DNA, and a promising technology for the higher-order reference measurement method. PMID- 26521180 TI - Determination of immunosuppressive drugs in human urine and serum by surface assisted laser desorption/ionization mass spectrometry with dispersive liquid liquid microextraction. AB - A rapid and sensitive method for the determination of immunosuppressive drugs through surface-assisted laser desorption/ionization mass spectrometric detection (SALDI/MS) was developed. Colloidal Pd and alpha-cyano-4-hydroxycinnamic acid (CHCA) were used as the SALDI co-matrix. To eliminate interference and enhance the sensitivity, dispersive liquid-liquid microextraction (DLLME) was employed to extract the immunosuppressive drugs from the aqueous solutions. Under optimal extraction and detection conditions, calibration curves for cyclosporine and everolimus in aqueous solutions were linear over a concentration range from 0.01 to 1.20 MUM. For sirolimus, the linear concentration range of the calibration curve was from 0.05 to 2.00 MUM. The limits of detection (LODs) were calculated to be 3, 3, and 14 nM for cyclosporine, everolimus, and sirolimus, respectively. The enrichment factors of DLLME were calculated to be 108, 122, and 101 for cyclosporine, everolimus, and sirolimus, respectively. This novel method was successfully applied for the determination of immunosuppressive drugs in human urine and serum samples. PMID- 26521181 TI - Paper-capillary spray for direct mass spectrometry analysis of biofluid samples. AB - Paper spray has been developed as an ambient ionization method for direct analysis of biological samples using mass spectrometry. While distinct advantages of paper spray have been demonstrated, especially for quantitative analysis and design of disposable sample cartridges, the need for improvement has also been recognized, especially for the use with miniature mass spectrometers. In this study, we made an improvement to the sampling and ionization by adding a capillary emitter to the paper substrate to produce a paper-capillary spray, which has been shown to have significant, positive impact on the sensitivity and reproducibility for direct mass spectrometry analysis. The paper-capillary devices were fabricated and the effects of the geometry, the treatment of the capillary emitters, as well as the sample disposition methods were characterized. The method's analytical performance was also characterized for analysis of therapeutic drugs in blood samples. Quantitation of cotinine in blood using a commercial triple quadrupole and sitagliptin (Januvia(r)) in blood using a desktop Mini 12 ion trap mass spectrometer was also demonstrated. PMID- 26521182 TI - Rationale and Design of a Randomized Controlled Trial Evaluating Whole Muscle Exercise Training Effects in Outpatients with Pulmonary Arterial Hypertension (WHOLEi+12). AB - BACKGROUND AND AIMS: Physical exercise is an important component in the management of pulmonary artery hypertension (PAH). The aim of this randomized controlled trial (RCT) is to determine the effects of an 8-week intervention combining muscle resistance, aerobic and inspiratory pressure load exercises in PAH outpatients. METHODS: The RCT will be conducted from September 2015 to September 2016 following the recommendations of the Consolidated Standards of Reported Trials (CONSORT), with a total sample size of n >= 48 (>=24 participants/group). We will determine the effects of the intervention on: (i) skeletal-muscle power and mass (primary end points); and (ii) NT-proBNP, cardiopulmonary exercise testing variables (VO2peak, ventilatory equivalent for CO2 at the anaerobic threshold (VE/VCO2 at the AT), end-tidal pressure of CO2 at the anaerobic threshold (PETCO2 at the AT), 6-min walking distance (6MWD), maximal inspiratory pressure (PImax), health-related quality of life (HRQoL), objectively-assessed spontaneous levels of physical activity, and safety (secondary end points). CONCLUSIONS AND PERSPECTIVES: This trial will provide insight into biological mechanisms of the disease and indicate the potential benefits of exercise in PAH outpatients, particularly on muscle power. PMID- 26521183 TI - Electric Eels Concentrate Their Electric Field to Induce Involuntary Fatigue in Struggling Prey. AB - Nature is replete with predator venoms that immobilize prey by targeting ion channels. Electric eels (Electrophorus electricus) take a different tactic to accomplish the same end. Striking eels emit electricity in volleys of 1 ms, high voltage pulses. Each pulse is capable of activating prey motor neuron efferents, and hence muscles. In a typical attack, eel discharges cause brief, immobilizing tetanus, allowing eels to swallow small prey almost immediately. Here I show that when eels struggle with large prey or fish held precariously, they commonly curl to bring their own tail to the opposite side of prey, sandwiching it between the two poles of their powerful electric organ. They then deliver volleys of high voltage pulses. Shortly thereafter, eels juggle prey into a favorable position for swallowing. Recordings from electrodes placed within prey items show that this curling behavior at least doubles the field strength within shocked prey, most likely ensuring reliable activation of the majority of prey motor neurons. Simulated pulse trains, or pulses from an eel-triggered stimulator, applied to a prey muscle preparations result in profound muscle fatigue and loss of contractile force. Consistent with this result, video recordings show that formerly struggling prey are temporarily immobile after this form of attack, allowing the manipulation of prey that might otherwise escape. These results reveal a unique use of electric organs to a unique end; eels superimpose electric fields from two poles, ensuring maximal remote activation of prey efferents that blocks subsequent prey movement by inducing involuntary muscle fatigue. PMID- 26521184 TI - Detection of cervical lesions by multivariate analysis of diffuse reflectance spectra: a clinical study. AB - Diffuse reflectance (DR) spectroscopy is a non-invasive, real-time, and cost effective tool for early detection of malignant changes in squamous epithelial tissues. The present study aims to evaluate the diagnostic power of diffuse reflectance spectroscopy for non-invasive discrimination of cervical lesions in vivo. A clinical trial was carried out on 48 sites in 34 patients by recording DR spectra using a point-monitoring device with white light illumination. The acquired data were analyzed and classified using multivariate statistical analysis based on principal component analysis (PCA) and linear discriminant analysis (LDA). Diagnostic accuracies were validated using random number generators. The receiver operating characteristic (ROC) curves were plotted for evaluating the discriminating power of the proposed statistical technique. An algorithm was developed and used to classify non-diseased (normal) from diseased sites (abnormal) with a sensitivity of 72 % and specificity of 87 %. While low grade squamous intraepithelial lesion (LSIL) could be discriminated from normal with a sensitivity of 56 % and specificity of 80 %, and high-grade squamous intraepithelial lesion (HSIL) from normal with a sensitivity of 89 % and specificity of 97 %, LSIL could be discriminated from HSIL with 100 % sensitivity and specificity. The areas under the ROC curves were 0.993 (95 % confidence interval (CI) 0.0 to 1) and 1 (95 % CI 1) for the discrimination of HSIL from normal and HSIL from LSIL, respectively. The results of the study show that DR spectroscopy could be used along with multivariate analytical techniques as a non invasive technique to monitor cervical disease status in real time. PMID- 26521185 TI - Benefits of sinogram-affirmed iterative reconstruction in 0.4 mSv ultra-low-dose CT of the upper abdomen following transarterial chemoembolisation: comparison to low-dose and standard-dose CT and filtered back projection technique. AB - AIM: To evaluate the advantage of sinogram-affirmed iterative reconstruction (SIR) compared to filtered back projection (FBP) in upper abdomen computed tomography (CT) after transarterial chemoembolisation (TACE) at different tube currents. MATERIALS AND METHODS: The study was approved by the institutional review board. Written informed consent was obtained from all patients. Post-TACE CT was performed with different tube currents successively varied in four steps (180, 90, 45 and 23 mAs) with 40 patients per group (mean age: 60+/-12 years, range: 23-85 years, sex: 70 female, 90 male). The data were reconstructed with standard FBP and five different SIR strengths. Image quality was independently rated by two readers on a five-point scale. High (Lipiodol-to-liver) as well as low (liver-to-fat) contrast-to-noise ratios (CNRs) were intra-individually compared within one dose to determine the optimal strength (S1-S5) and inter individually between different doses to determine the possibility of dose reduction using the Kruskal-Wallis test. RESULTS: Subjective image quality and objective CNR analysis were concordant: intra-individually, SIR was significantly (p<0.001) superior to FBP. Inter-individually, regarding different doses (180 versus 23 ref mAs), there was no significant (p=1.00) difference when using S5 SIR at 23 mAs instead of FBP. CONCLUSION: SIR allows for an 88% dose reduction from 3.43 to 0.4 mSv in unenhanced CT of the liver following TACE without subjective or objective loss in image quality. PMID- 26521186 TI - Volumetric Arterial Spin-labeled Perfusion Imaging of the Kidneys with a Three dimensional Fast Spin Echo Acquisition. AB - RATIONALE AND OBJECTIVES: Renal perfusion measurements using noninvasive arterial spin-labeled (ASL) magnetic resonance imaging techniques are gaining interest. Currently, focus has been on perfusion in the context of renal transplant. Our objectives were to explore the use of ASL in patients with renal cancer, and to evaluate three-dimensional (3D) fast spin echo (FSE) acquisition, a robust volumetric imaging method for abdominal applications. We evaluate 3D ASL perfusion magnetic resonance imaging in the kidneys compared to two-dimensional (2D) ASL in patients and healthy subjects. MATERIALS AND METHODS: Isotropic resolution (2.6 * 2.6 * 2.8 mm(3)) 3D ASL using segmented FSE was compared to 2D single-shot FSE. ASL used pseudo-continuous labeling, suppression of background signal, and synchronized breathing. Quantitative perfusion values and signal-to noise ratio (SNR) were compared between 3D and 2D ASL in four healthy volunteers and semiquantitative assessments were made by four radiologists in four patients with known renal masses (primary renal cell carcinoma). RESULTS: Renal cortex perfusion in healthy subjects was 284 +/- 21 mL/100 g/min, with test-retest repeatability of 8.8%. No significant differences were found between the quantitative perfusion value and SNR in volunteers between 3D ASL and 2D ASL, or in 3D ASL with synchronized or free breathing. In patients, semiquantitative assessment by radiologists showed no significant difference in image quality between 2D ASL and 3D ASL. In one case, 2D ASL missed a high perfusion focus in a mass that was seen by 3D ASL. CONCLUSIONS: 3D ASL renal perfusion imaging provides isotropic-resolution images, with comparable quantitative perfusion values and image SNR in similar imaging time to single-slice 2D ASL. PMID- 26521187 TI - Middle ear function in sinonasal polyposis. AB - Nasal airway patency has long been considered a major factor in ear health. The aim of this study was to determine the effect of sinonasal polyposis on middle ear and eustachian tube (ET) functionality. Forty-four individuals with polyposis, 23 with non-polyposis nasal obstruction, and 23 healthy controls were enrolled. Demographic, clinical and imaging data of all participants were collected and ET function tests and audiologic tests were performed. Hearing loss (p = 0.02), flat tympanogram (p = 0.02), disturbed Toynbee and Valsalva tests (p = 0.01), and the prevalence of allergy (p = 0.04) and purulent nasal discharge (p < 0.001) were significantly higher in the polyposis group than the other groups. Regression analysis revealed that infection and allergy have more important roles in ET function than the nasal obstruction. Polyposis could impede ET function; however, it is probably not because of its obstructive nature, but because of the associated increased risk of infection. PMID- 26521188 TI - Tympanomastoid cholesterol granuloma: radiological and intraoperative findings of blood source connection. AB - The hypothesis that the close contiguity between the cholesterol granulomas and some rich blood sources provided the trigger to the aggressive nature of tympanomastoid cholesterol granulomas has been recently reported. To corroborate this new etiopathogenetic theory we retrospectively reviewed a series of 14 patients with primary middle ear and mastoid cholesterol granulomas and investigated the temporal bone marrow invasion and its hematopoietic potentialities and a possible cholesterol granulomas contiguity with relevant vascular structures such as the carotid artery, sigmoid jugular system, mastoid or dural vein. Eight cases did not show radiological sign of bone marrow invasion or hematopoietic potentialities visible in MRI. Besides no intraoperative vascular connections that could explain an initial bleeding source were found. Cholesterol granulomas bone marrow invasion was present in six patients. A bone marrow hematopoietic potentiality was showed in four of these patients, whereas, an evident anatomical contiguity of the cholesterol granuloma with some important temporal bone vascular structures was visible in five cases. Analysis of cardiovascular risk factors showed that four patients presented one or more of the risk factors analysed. PMID- 26521189 TI - Phosphodiesterase 4D gene polymorphisms in sudden sensorineural hearing loss. AB - The phosphodiesterase 4D (PDE4D) gene has been reported as a risk gene for ischemic stroke. The vascular factors are between the hypothesized etiologies of sudden sensorineural hearing loss (SSNHL), and this genetic effect might be attributed for its role in SSNHL. We hypothesized that genetic variants of the PDE4D gene are associated with susceptibility to SSNHL. We conducted a case control study with 362 SSNHL cases and 209 controls. Three single nucleotide polymorphisms (SNPs) were selected. The genotypes were determined using TaqMan technology. Hardy-Weinberg equilibrium (HWE) was tested for each SNP, and genetic effects were evaluated according to three inheritance modes. We carried out sex specific analysis to analyze the overall data. All three SNPs were in HWE. When subjects were stratified by sex, the genetic effect was only evident in females but not in males. The TT genotype of rs702553 exhibited an adjusted odds ratio (OR) of 3.83 (95 % confidence interval = 1.46-11.18) (p = 0.006) in female SSNHL. The TT genotype of SNP rs702553 was associated with female SSNHL under the recessive model (p = 0.004, OR 3.70). In multivariate logistic regression analysis, TT genotype of rs702553 was significantly associated with female SSNHL (p = 0.0043, OR 3.70). These results suggest that PDE4D gene polymorphisms influence the susceptibility for the development of SSNHL in the southern Taiwanese female population. PMID- 26521190 TI - Hypertonic Saline in Conjunction with High-Dose Furosemide Improves Dose-Response Curves in Worsening Refractory Congestive Heart Failure. AB - INTRODUCTION: Diuretic responsiveness in patients with chronic heart failure (CHF) is better assessed by urine production per unit diuretic dose than by the absolute urine output or diuretic dose. Diuretic resistance arises over time when the plateau rate of sodium and water excretion is reached prior to optimal fluid elimination and may be overcome when hypertonic saline solution (HSS) is added to high doses of furosemide. METHODS: Forty-two consecutively hospitalized patients with refractory CHF were randomized in a 1:1:1 ratio to furosemide doses (125 mg, 250 mg, 500 mg) so that all patients received intravenous furosemide diluted in 150 ml of normal saline (0.9%) in the first step (0-24 h) and the same furosemide dose diluted in 150 ml of HSS (1.4%) in the next step (24-48 h) as to obtain 3 groups as follows: Fourteen patients receiving 125 mg (group 1), fourteen patients receiving 250 mg (group 2), and fourteen patients receiving 500 mg (group 3) of furosemide. Urine samples of all patients were collected at 30, 60, and 90 min, and 3, 4, 5, 6, 8, and 24 h after infusion. Diuresis, sodium excretion, osmolality, and furosemide concentration were evaluated for each urine sample. RESULTS: After randomization, 40 patients completed the study. Two patients, one in group 2 and one in group 3 dropped out. Patients in group 1 (125 mg furosemide) had a mean age of 77 +/- 17 years, 43% were male, 6 (43%) had heart failure with a preserved ejection fraction (HFpEF), and 64% were in New York Heart Association (NYHA) class IV; the mean age of patients in group 2 (250 mg furosemide) was 80 +/- 8.1 years, 15% were male, 5 (38%) had HFpEF, and 84% were in NYHA class IV; and the mean age of patients in group 3 (500 mg furosemide) was 73 +/- 12 years, 54% were male, 6 (46%) had HFpEF, and 69% were in NYHA class IV. HSS added to furosemide increased total urine output, sodium excretion, urinary osmolality, and furosemide urine delivery in all patients and at all time points. The percentage increase was 18,14, and 14% for urine output; 29, 24, and 16% for total sodium excretion; 45, 34, and 20% for urinary osmolarity; and 27, 36, and 32% for total furosemide excretion in groups 1, 2, and 3, respectively. These findings were translated in an improvement in the furosemide dose-response curves in these patients. CONCLUSION: These results may serve as new pathophysiological basis for HSS use in the treatment of refractory CHF. PMID- 26521191 TI - Cardiac and Hemodynamic Benefits: Mode of Action of Ivabradine in Heart Failure. AB - Heart failure has seen a number of therapeutic advances in recent years. Despite this, heart failure is still related to increasing rates of morbidity, repeated hospitalizations, and mortality. Ivabradine is a recent treatment option for heart failure. It has a mode of action that includes reduction in heart rate, and leads to improvement in outcomes related to heart failure mortality and morbidity, as demonstrated by the results of the SHIFT trial in patients with systolic heart failure, functional classes II and III on the New York Heart Association classification, and left ventricular ejection fraction <= 35%. These results are intriguing since many heart failure drugs reduce heart rate without such benefits, or with quite different effects, making it more difficult to understand the novelty of ivabradine in this setting. Many of the drugs used in heart failure modify heart rate, but most have other pathophysiological effects beyond their chronotropic action, which affect their efficacy in preventing morbidity and mortality outcomes. For instance, heart rate reduction at rest or exercise with ivabradine prolongs diastolic perfusion time, improves coronary blood flow, and increases exercise capacity. Another major difference is the increase in stroke volume observed with ivabradine, which may underlie its beneficial cardiac effects. Finally, there is mounting evidence from both preclinical and clinical studies that ivabradine has an anti-remodeling effect, improving left ventricular structures and functions. All together, these mechanisms have a positive impact on the prognosis of ivabradine-treated patients with heart failure, making a compelling argument for use of ivabradine in combination with other treatments. PMID- 26521192 TI - Hampton's hump in a patient with endocarditis and septic emboli. AB - We discuss a case of a 20-year-old woman presenting with chest pain found to have a Hampton's hump on chest x-ray and corresponding wedge infarct on computed tomographic scan. Contrary to our suspicion that this febrile and tachycardic patient had a pulmonary embolism, she was later determined to have a septic embolus secondary to endocarditis. We highlight the difficulties in diagnosing certain cases of endocarditis in the emergency department, as well as the difficulties in distinguishing septic emboli from pulmonary emboli,especially with plain radiographs. PMID- 26521193 TI - A patient with clear consciousness even with a glucose level of 5 mg/dL (0.2 mmol/L). AB - A 74-year-old man noted dysarthria and right hemiparesis. His history included a gastric ulcer 2 years previously, and he had gradually lost 10 kg over a 2-year period due to appetite loss. He daily consumed 120 mg of alcohol. Upon arrival, he had clear consciousness and stable vital signs. He was malnourished. Neurologic findings included a positive finding of Barre sign in the right hand and dysarthria. A venous blood gas analysis demonstrated the following: pH 7.059; PCO2, 21.5 mm Hg; PO2, 59.1 mm Hg; HCO(3-), 5.8 mmol/L; base excess, -22.7 mmol/L; lactate,17 mmol/L; and glucose, 4 mg/dL. After the administration of an infusion of thiamine and glucose, his abnormal neurologic findings subsided completely. Head magnetic resonance image (MRI; diffusion weighted image) disclosed 3 spotty, high-intensity signals in the brain. The main results of biochemical analyses of the blood collected on arrival were as follows: hemoglobin, 5.5 g/dL; glucose, 5 mg/dL; aspartate aminotransferase, 89 IU/L. He was admitted for further examination and was diagnosed as having alcoholic ketoacidosis with hypoglycemic encephalopathy and anemia due to colon cancer. PMID- 26521194 TI - Self-assessment of hunger among ED patients with abdominal pain: lack of association with disease severity. PMID- 26521195 TI - Acute pancreatitis with normal amylase and lipase--an ED dilemma. PMID- 26521196 TI - Intratendinous rupture of the supraspinatus: anatomical and functional results of 24 operative cases. AB - INTRODUCTION: The aim was to describe the natural history of intratendinous partial rotator cuff tears as well as the anatomical and clinical results of surgical treatment of a cohort of 24 patients. PATIENTS AND METHODS: There were 14 men and 10 women with a mean age of 50 years. The right shoulder was involved in 17 cases. For 16 cases, a progressive history of shoulder pain was reported. Pre-operatively, a painful and positive Jobe's sign was observed in only 13 cases. Pre-operative mean absolute constant score was 63.52 points. Based on standard MRI, intratendinous lesions were diagnosed on the coronal view with hyper-signal within the tendon in the T2 FatSat sequence. No fatty infiltration was noted. Fourteen open and 10 arthroscopic repairs were performed. RESULTS: Patients were reviewed with clinical assessment and MRI. The final Constant score was 81.3 points with a mean gain of 18.5 points. Patients were back to work after a mean of 5.8 months and to sports after 6 months. The mean subjective result was of 8.9/10. Three cases of reflex sympathetic dystrophy were observed. DISCUSSION: Intratendinous tears of the supraspinatus tendon are rare and difficult to diagnose. Diagnosis relies on MRI (T2 FatSat). Trauma is not usually described. Chronic calcifying tendonitis may also contribute to the development of such tears. There is no associated fatty infiltration of the muscle. The Jobe's test is frequently painful or positive. Arthroscopic resection of the tendon insertion with reinsertion to the greater tuberosity seems to be the optimal treatment. LEVEL OF EVIDENCE: Retrospective study, IV. PMID- 26521197 TI - Risk factors for re-fracture in children with diaphyseal fracture of the forearm treated with elastic stable intramedullary nailing. AB - A retrospective study aims to investigate predisposing factors leading to re fracture in patients with nails still in place and to identify potential correlations between nail size-to-medullary canal diameter ratio and re-fracture, working to the hypothesis that a higher ratio correlates with a higher risk of re fracture. Rates of re-fracture with nail still in place after forearm elastic stable intramedullary nailing are higher in younger pediatric patients. Re fractures occurred at a mean age of 6.7 years (range 5-8.7). While the role of body frame and bone medullary diameter remains unclear, there are grounds for adjusting treatment strategy for age, weight and bone medullary diameter to achieve effective outcome. History of previous forearm fracture and open treatment may also be further risk factors. PMID- 26521198 TI - Cribiform variant of papillary thyroid cancer and familial adenomatous polyposis. AB - BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome characterised by the progressive development of multiple colorectal adenomatous polyps and an increased incidence of colorectal carcinoma. It is often accompanied by other benign or malignant extracolonic manifestations, including gastric and duodenal tumours, osteomas, desmoid tumours, retinal pigmentation, and thyroid and adrenocortical tumours METHODS AND RESULTS: We report the case of a 42-year-old white female with FAP who was referred to our Endocrine Surgery Unit for surgery because of a palpable mass in the left side of the neck. An ultrasound-guided fine needle aspiration biopsy showed a cribriform morular variant (CMV) of papillary thyroid carcinoma (PTC). The incidence, clinical presentation, histology and treatment options for this rare histological subtype are discussed. CONCLUSIONS: The diagnosis of CMV of PTC is very strongly related to the FAP syndrome and must be suspected when a thyroid node appears in FAP patients. Likewise, any patient without known FAP who presents this histology in a surgically biopsied or resected thyroid node should undergo total colonoscopy for screening of colonic polyposis and genetic study of the APC gene sequence. PMID- 26521199 TI - Endovascular retrieval of an irrigation cannula from the thoracic aorta following cardiac surgery: A case report. AB - INTRODUCTION: Endovascular techniques to retrieve intravascular foreign bodies are a necessary component of the Vascular surgeon's skill set. We report the successful retrieval of an embolized irrigation cannula from the thoracic aorta following aortic valve replacement. PRESENTATION OF CASE: The patient is an 81 year old male who underwent coronary artery bypass grafting and aortic valve replacement. Prior to closure, the aortotomy was irrigated with heparinized saline using a syringe with an olive tip irrigation cannula. When the syringe was handed back to the nursing staff, the tip was noted to be missing but could not be found. Prior to closure of the sternum, the field was searched again for the tip and thus the chest was closed. The missing instrument then prompted an intraoperative chest radiograph that demonstrated a metal irrigation cannula superimposed on the cardiac silhouette. Additionally, a transesophageal echocardiogram was performed, which demonstrated the irrigation cannula within the descending thoracic aorta. Right common femoral artery was accessed and a thoracic aortogram was performed demonstrating the cannula to be lodged in the descending thoracic aorta. Intravascular ultrasound (IVUS) was performed to exclude an aortic abnormality preventing the caudad migration of the cannula. No aortic pathology was identified. A tri-lobed snare was used to grasp the cannula at its tip and withdrawn into the right external iliac artery. The cannula was successfully removed through a transverse arteriotomy in the distal right external iliac artery. The patient's postoperative course was uneventful. CONCLUSION: Endovascular retrieval of intravascular foreign bodies is minimally invasive, relatively simple, and carries minimal morbidity compared to conventional open surgical techniques. This unusual case demonstrates the importance of a working knowledge of techniques and instruments requisite for retrieval of intravascular foreign bodies. PMID- 26521200 TI - Parapharyngeal abscess following use of a laryngeal mask airway during open revision septorhinoplasty. AB - INTRODUCTION: A laryngeal mask airway (LMA) is an established safe tool to support the airway during surgery under general anesthetic. It is commonly used both in North America and abroad. Complications with this device are rare. PRESENTATION OF CASE: A 50-year old female developed a parapharyngeal neck abscess following an uneventful septorhinoplasty during use of an LMA Classic. The patient had symptoms of pain and difficulty swallowing. CT revealed extensive soft tissue edema and swelling in the right and posterior neck involving the right parapharyngeal space, right parotid space, minimal involvement of the right submandibular space, and extending across the retropharyngeal space. The abscess was incised and drained with an open approach, combined with laryngoscopy to evaluate the site of the infection at the right pyriform fossa. The patient fully recovered following discharge. DISCUSSION: Despite the rare incidence of LMA injuries, early recognition of parapharyngeal neck abscesses can initiate early treatment and prevention of spread to retropharyngeal space where airway obstruction and emergent complications may occur. CONCLUSION: Laryngeal mask airways have a high rate of success and low rate of complications. In this reported case, pressure necrosis from over-inflation of the LMA is thought to have perforated the right pyriform fossa. The perforation created a communication into the parapharyngeal space causing infection. We report this case to highlight the importance of identifying possible complications associated with a routine method of airway management during shared airway surgeries. PMID- 26521201 TI - Sporadic diffuse segmental interstitial cell of Cajal hyperplasia harbouring two gastric gastrointestinal stromal tumours (GIST) mimicking hereditary GIST syndromes. AB - INTRODUCTION: Gastrointestinal stromal tumours (GISTs) are thought to derive from or differentiate towards the interstitial cells of Cajal (ICC) as most demonstrate a similar immunoprofile: CD117+, CD34+ and DOG1+. ICC hyperplasia refers to KIT-expressing microscopic spindle cell proliferations involving the myenteric plexus. CASE REPORT: 74 year-old male presented with a 5-year history of heartburn and dysphagia. Imaging revealed a 4cm GIST in the gastric fundus. Pathology of the resected specimen revealed diffuse segmental ICC hyperplasia harbouring two macroscopic GISTs and a 'tumorlet'. A mutation in c-KIT exon 11 was detected in both the solid and the diffuse components. DISCUSSION: ICC hyperplasia can occur either as a sporadic focal lesion or in a syndromic setting, known to predispose to multiple GIST tumours at different sites. The majority of cases of sporadic ICC hyperplasia previously reported were of localised type. The hereditary form is mostly caused by germline mutations in c KIT and PDGFRA or in patients with NF-1 andpresents as a diffuse hyperplasia, usually with a confluent, nodular or multifocal growth pattern. CONCLUSION: We describe a diffuse form of sporadic ICC hyperplasia harbouring multifocal GISTs, mimicking diffuse ICC hyperplasia in hereditary GIST syndromes. Detection of somatic c-KIT exon 11 mutation ruled out a hereditary disorder. PMID- 26521202 TI - Pharmacologic analyses of four chicken melanocortin-4 receptor mutations. AB - The melanocortin-4 receptor (MC4R) is a critical regulator of mammalian food intake and energy expenditure, with receptor activation resulting in decreased food intake and increased energy expenditure. Recently, studies on role of MC4R in regulation of food intake have been extended to other species, such as chicken. Functional study of mutant MC4Rs is important in proving the causal link between MC4R mutation and production traits. Herein, we cloned chicken MC4R (cMC4R) complementary DNA and generated 4 mutant cMC4Rs (Q18H, G21R, S76L, and L299P) by site-directed mutagenesis and measured their expression by flow cytometry. Pharmacologic characteristics were analyzed with binding and signaling assays using 3 agonists. We showed that G21R had decreased cell surface and total expression (P < 0.05), whereas the other 3 mutants had similar total and cell surface expression levels as wild-type cMC4R. The 4 mutants had either decreased (Q18H, G21R, S76L; P < 0.05) or no (L299P) binding to radiolabeled [Nle(4), D Phe(7)]-alpha-melanocyte-stimulating hormone (MSH). In signaling assays, Q18H was constitutively active. Q18H, G21R, and S76L had decreased responses to alpha-MSH stimulation (P < 0.05). L299P had decreased basal and ligand-stimulated signaling (P < 0.01). Nle(4), D-Phe(7)-MSH was the most potent agonist for cMC4R and therefore would be better suited for further in vivo studies. We conclude that the cloned cMC4R was a functional receptor and provided detailed functional data for these mutations, contributing to a better understanding of cMC4R variants associated with production traits. PMID- 26521203 TI - Insulin: pancreatic secretion and adipocyte regulation. AB - Insulin is the primary acute anabolic coordinator of nutrient partitioning. Hyperglycemia is the main stimulant of insulin secretion, but other nutrients such as specific amino acids, fatty acids, and ketoacids can potentiate pancreatic insulin release. Incretins are intestinal hormones with insulinotropic activity and are secreted in response to food ingestion, thus integrating diet chemical composition with the regulation of insulin release. In addition, prolactin is required for proper islet development, and it stimulates beta-cell proliferation. Counterintuitively, bacterial components appear to signal insulin secretion. In vivo lipopolysaccharide infusion acutely increases circulating insulin, which is paradoxical as endotoxemia is a potent catabolic condition. Insulin is a potent anabolic orchestrator of nutrient partitioning, and this is particularly true in adipocytes. Insulin dictates lipid accretion in a dose dependent manner during preadipocyte development in adipose tissue-derived stromal vascular cell culture. However, in vivo studies focused on insulin's role in regulating adipose tissue metabolism from growing, and market weight pigs are sometimes inconsistent, and this variability appears to be animal, age and depot dependent. Additionally, porcine adipose tissue synthesizes and secretes a number of adipokines (leptin, adiponectin, and so forth) that directly or indirectly influence insulin action. Therefore, because insulin has an enormous impact on agriculturally important phenotypes, it is critical to have a better understanding of how insulin homeostasis is governed. PMID- 26521204 TI - The role of sirtuins in aging and age-related diseases. AB - Sirtuins, initially described as histone deacetylases and gene silencers in yeast, are now known to have much more functions and to be much more abundant in living organisms. Sirtuins gained much attention when they were first acknowledged to be responsible for some beneficial and longevity-promoting effects of calorie restriction in many species of animals - from fruit flies to mammals. In this paper, we discuss some detailed molecular mechanisms of inducing these effects, and wonder if they could be possibly mimicked without actually applying calorie restriction, through induction of sirtuin activity. It is known now that sirtuins, when adjusting the pattern of cellular metabolism to nutrient availability, can regulate many metabolic functions significant from the standpoint of aging research - including DNA repair, genome stability, inflammatory response, apoptosis, cell cycle, and mitochondrial functions. While carrying out these regulations, sirtuins cooperate with many transcription factors, including PGC-1a, NFKB, p53 and FoxO. This paper contains some considerations about possible use of facilitating activity of the sirtuins in prevention of aging, metabolic syndrome, chronic inflammation, and other diseases. PMID- 26521205 TI - Pyrazinamide resistance in Mycobacterium tuberculosis: Review and update. AB - The global control and management of tuberculosis (TB) is faced with the formidable challenge of worsening scenarios of drug-resistant disease. Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of TB. It plays a key role in reducing TB relapse rates, shortening the course of the disease treatment from 9-12 months to 6 months, and the treatment of patients infected with bacillary strains that are resistant to at least isoniazid and rifampicin. Additionally, it is the only first-line anti-TB drug most likely to be maintained in all new regimens, which are aimed at reducing the treatment period of susceptible, multi-drug resistant and extensively drug-resistant TB. It has a preferential sterilizing activity against non-replicating persister bacilli with low metabolism at acid pH in vitro or in vivo during active inflammation where other drugs may not act so well. PZA seem to have a non-specific cellular target and instead, exerts its anti-mycobacterial effect by disrupting the membrane energetics, the trans-translation process, acidification of the cytoplasm and perhaps coenzyme A synthesis, which is required for survival of Mycobacterium tuberculosis (MTB) persisters. Indeed, the emergence of MTB strains resistant to PZA represents an important clinical and public health problem. The essential role of PZA in TB treatment underlines the need for accurate and rapid detection of its resistance. This article presents an updated review of the molecular mechanisms of drug action and resistance in MTB against PZA, commenting on the several research gaps and proposed drug targets for PZA. PMID- 26521206 TI - Reduction of ceramide de novo synthesis in solid tissues changes sphingolipid levels in rat plasma, erythrocytes and platelets. AB - PURPOSE: De novo sphingolipid synthesis does not occur in plasma, erythrocytes and platelets. The purpose of the study was to examine the effect of inhibition of sphingolipid synthesis in solid tissues on the level of the following bioactive sphingolipids: sphinganine, ceramide, sphingosine and sphingosine 1 phosphate in plasma, erythrocytes and platelets. MATERIAL/METHODS: The experiments were carried out on male Wistar rats. Myriocin was used to inhibit serine palmitoyltransferase activity (the enzyme catalyzes the first step of ceramide de novo synthesis) and nicotinic acid was used to reduce the concentration of plasma free fatty acids (a substrate for the de novo ceramide synthesis). The sphingolipids were quantified by means of liquid chromatography/mass spectrometry. RESULTS: Myriocin reduced the level of each compound in plasma. It reduced the level of sphinganine, sphingosine-1-phosphate and total ceramide and elevated the level of sphingosine in erythrocytes. In platelets, myriocin reduced the total level of ceramide. Nicotinic acid reduced the plasma level of sphinganine, sphingosine and total ceramide. It increased the level of sphingosine-1-phosphate in erythrocytes. In platelets, nicotinioc acid increased the level of sphinganine and sphingosine and reduced the level of sphingosine-1-phosphate and total ceramide. CONCLUSIONS: Inhibition of serine palmitoyltransferase activity in solid tissues and reduction in plasma free fatty acids concentration affects sphingolipid level in plasma, erythrocytes and platelets. The changes in erythrocytes and platelets depend both on the cell type and the sphingolipid studied and only partially follow the changes in the plasma. PMID- 26521207 TI - Structure-based de novo design, molecular docking and molecular dynamics of primaquine analogues acting as quinone reductase II inhibitors. AB - Primaquine is a traditional antimalarial drug with low parasitic resistance and generally good acceptance at higher doses, which has been used for over 60 years in malaria treatment. However, several limitations related to its hematotoxicity have been reported. It is believed that this toxicity comes from the hydroxylation of the C-5 and C-6 positions of its 8-aminoquinoline ring before binding to the molecular target: the quinone reductase II (NQO2) human protein. In this study we propose primaquine derivatives, with substitution at position C 6 of the 8-aminoquinoline ring, planned to have better binding to NQO2, compared to primaquine, but with a reduced toxicity related to the C-5 position being possible to be oxidized. On this sense the proposed analogues were suggested in order to reduce or inhibit hydroxylation and further oxidation to hemotoxic metabolites. Five C-6 substituted primaquine analogues were selected by de novo design and further submitted to docking and molecular dynamics simulations. Our results suggest that all analogues bind better to NQO2 than primaquine and may become better antimalarials. However, the analogues 3 and 4 are predicted to have a better activity/toxicity balance. PMID- 26521208 TI - Vienna Soil-Organic-Matter Modeler--Generating condensed-phase models of humic substances. AB - Humic substances are ubiquitous in the environment and have manifold functions. While their composition is well known, information on the chemical structure and three-dimensional conformation is scarce. Here we describe the Vienna Soil Organic-Matter Modeler, which is an online tool to generate condensed phase computer models of humic substances (http://somm.boku.ac.at). Many different models can be created that reflect the diversity in composition and conformations of the constituting molecules. To exemplify the modeler, 18 different models are generated based on two experimentally determined compositions, to explicitly study the effect of varying e.g. the amount of water molecules in the models or the pH. Molecular dynamics simulations were performed on the models, which were subsequently analyzed in terms of structure, interactions and dynamics, linking macroscopic observables to the microscopic composition of the systems. We are convinced that this new tool opens the way for a wide range of in silico studies on soil organic matter. PMID- 26521209 TI - Cytokinin profiles in ex vitro acclimatized Eucomis autumnalis plants pre-treated with smoke-derived karrikinolide. AB - KEY MESSAGE: The current evidence of regulatory effect of smoke-water (SW) and karrikinolide (KAR(1)) on the concentrations of endogenous cytokinins in plants partly explain the basis for their growth stimulatory activity. Karrikinolide (KAR1) which is derived from smoke-water (SW) is involved in some physiological aspects in the life-cycle of plants. This suggests a potential influence on the endogenous pool (quantity and quality) of phytohormones such as cytokinins (CKs). In the current study, the effect of SW (1:500; 1:1000; 1:1500 v/v dilutions) and KAR1 (10(-7); 10(-8); 10(-9) M) applied during micropropagation of Eucomis autumnalis subspecies autumnalis on the ex vitro growth and CKs after 4 months post-flask duration was evaluated. The interactions of SW and KAR(1) with benzyladenine (BA), alpha-naphthaleneacetic acid (NAA) or BA+NAA were also assessed. Plants treated with SW (1:500) and KAR1 (10(-8) M) demonstrated superior growth in terms of the rooting, leaf and bulb sizes and fresh biomass than the control and plants treated with BA and BA+NAA. However, plant growth was generally inhibited with either SW (1:500) or KAR1 (10(-8) M) and BA when compared to BA (alone) treatment. Relative to NAA treatment, the presence of KAR(1) (10(-7) M) with NAA significantly increased the leaf area and fresh biomass. Both SW and KAR1-treated plants accumulated more total CKs, mainly isoprenoid-type than the control and NAA-treated plants. The highest CK content was also accumulated in SW (1:500) with BA+NAA treatments. Similar stimulatory effects were observed with increasing concentrations of KAR(1) and BA. The current findings establish that SW and KAR1 exert significant influence on the endogenous CK pools. However, the better growth of plants treated with SW and KAR1 treatments was not exclusively related to the endogenous CKs. PMID- 26521210 TI - Level of tissue differentiation influences the activation of a heat-inducible flower-specific system for genetic containment in poplar (Populus tremula L.). AB - KEY MESSAGE: Differentiation level but not transgene copy number influenced activation of a gene containment system in poplar. Heat treatments promoted CRE gene body methylation. The flower-specific transgene deletion was confirmed. Gene flow between genetic modified trees and their wild relatives is still motive of concern. Therefore, approaches for gene containment are required. In this study, we designed a novel strategy for achieving an inducible and flower-specific transgene removal from poplar trees but still expressing the transgene in the plant body. Hence, pollen carrying transgenes could be used for breeding purposes under controlled conditions in a first phase, and in the second phase genetic modified poplars developing transgene-free pollen grains could be released. This approach is based on the recombination systems CRE/loxP and FLP/frt. Both gene constructs contained a heat-inducible CRE/loxP-based spacer sequence for in vivo assembling of the flower-specific FLP/frt system. This allowed inducible activation of gene containment. The FLP/frt system was under the regulation of a flower-specific promoter, either CGPDHC or PTD. Our results confirmed complete CRE/loxP-based in vivo assembling of the flower-specific transgene excision system after heat treatment in all cells for up to 30 % of regenerants derived from undifferentiated tissue cultures. Degradation of HSP::CRE/loxP spacer after recombination but also persistence as extrachromosomal DNA circles were detected in sub-lines obtained after heat treatments. Furthermore, heat treatment promoted methylation of the CRE gene body. A lower methylation level was detected at CpG sites in transgenic sub-lines showing complete CRE/loxP recombination and persistence of CRE/loxP spacer, compared to sub-lines with incomplete recombination. However, our results suggest that low methylation might be necessary but not sufficient for recombination. The flower-specific FLP/frt-based transgene deletion was confirmed in 6.3 % of flowers. PMID- 26521211 TI - Enhancement of alpha-linolenic acid content in transgenic tobacco seeds by targeting a plastidial omega-3 fatty acid desaturase (fad7) gene of Sesamum indicum to ER. AB - KEY MESSAGE: Expression of sesame plastidial FAD7 desaturase modified with the endoplasmic reticulum targeting and retention signals, enhances the alpha linolenic acid accumulation in seeds of Nicotiana tabacum. In plants, plastidial omega-3 fatty acid desaturase-7 (FAD7) catalyzes the formation of C16 and C18 trienoic fatty acids using organellar glycerolipids and participate in the membrane lipid formation. The plastidial omega-3 desaturases (FAD7) share high sequence homology with the microsomal omega-3 desaturases (FAD3) at the amino acid level except the N-terminal organelle transit peptide. In the present study, the predicted N-terminal plastidial signal peptide of fad7 gene was replaced by the endoplasmic reticulum signal peptide and an endoplasmic reticulum retention signal was placed at the C-terminal. The expression of the modified sesame omega 3 desaturase increases the alpha-linolenic acid content in the range of 4.78-6.77 % in the seeds of transgenic tobacco plants with concomitant decrease in linoleic acid content. The results suggested the potential of the engineered plastidial omega-3 desaturase from sesame to influence the profile of alpha-linolenic acid in tobacco plant by shifting the carbon flux from linoleic acid, and thus it can be used in suitable genetic engineering strategy to increase the alpha-linolenic acid content in sesame and other vegetable oils. PMID- 26521213 TI - Dual use of electronic and tobacco cigarettes among adolescents: a cross sectional study in Poland. AB - OBJECTIVES: Electronic cigarettes (e-cigarettes) are gaining in popularity among youth. While these products may be beneficial in adult smokers, the effect on young users of electronic and tobacco cigarettes (dual users) is unknown. The objective of this study was to assess the frequency of dual use among adolescents and to compare tobacco cigarette consumption among dual and exclusive tobacco cigarette users. METHODS: A cross-sectional survey of a sample of 2213 Polish students aged 16-18 conducted between December 2013 and February 2014. RESULTS: Overall, 21.8 % of students were dual users. Dual users were more likely to smoke tobacco cigarettes on a daily basis [adjusted odds ratio, AOR 3.54 (95 % CI 2.34 5.36) and less likely to smoke fewer cigarettes per day (AOR 0.27 (95 % CI 0.12 0.57)] than exclusive tobacco cigarette users. CONCLUSIONS: The frequency of dual use was higher than exclusive use of a single product among Polish adolescents. Young dual users do not smoke a lower number of tobacco cigarettes per day than exclusive tobacco cigarette users. PMID- 26521212 TI - Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study. AB - Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics. PMID- 26521214 TI - Reciprocal regulation of p53 and NF-kappaB by diacylglycerol kinase zeta. AB - Diacylglycerol kinase (DGK) participates in lipid mediated-signal transduction. It phosphorylates diacylglycerol (DG) to phosphatidic acid (PA), thereby regulating the balanced control of these second messenger actions. Previous reports have described that one DGK family, DGKzeta, is closely involved in stress responses under various conditions. Cellular stress response, a physiological process enabling cells to cope with an altered environment, is finely tuned through various signaling cascades and their molecular crosstalk. The major components of stress response are p53 and NF-kappaB. p53 generally serves as a proapoptotic transcriptional factor, whereas NF-kappaB promotes resistance to programmed cell death under most circumstances. Recent studies have suggested that DGKzeta facilitates p53 degradation in cytoplasm through ubiquitin proteasome system and that DGKzeta deletion upregulates p53 protein levels under basal and DNA-damage conditions. Counter-intuitively, however, DGKzeta deletion suppresses p53 transcriptional activity despite increased p53 levels. In contrast, DGKzeta knockdown engenders enhancement of NF-kappaB pathway in response to cytokines such as TNF-alpha and IL-1beta. In response to these cytokines, DGKzeta downregulation accelerates phosphorylation of the p65 subunit and its nuclear translocation, thereby enhancing NF-kappaB transcriptional activity. Furthermore, DGKzeta deficiency is shown to promote increased association of p65 subunit with the transcriptional cofactor CBP. It is particularly interesting that this association is observed even under basal conditions in the absence of stimulation. These findings suggest that DGKzeta plays a role in sequestration of the limiting pool of CBP/p300 between the NF kappaB p65 subunit and p53, and that DGKzeta downregulation shifts CBP/p300 toward the NF-kappaB subunit to regulate reciprocally antagonistic phenotypes of these transcription factors. PMID- 26521215 TI - Low back pain misdiagnosis or missed diagnosis: Core principles. AB - Consensus guidelines for the management of low back pain recommend that the clinician use contemporary best practice for assessment and treatment, consider biopsychosocial factors and, if chronic, use a multimodal and multi-disciplinary approach. Where guidelines are not followed and basic assessment is inadequate the diagnosis may be compromised and the sequelae of errors compounded. Factors such as a lack of knowledge or recognition of the common structure specific pain referral patterns, poor clinical reasoning, inappropriate referral and predilection for popular management approaches also contribute to mis-diagnosis and mis-management. This report describes two cases of chronic low back pain with lengthy histories of multiple failed interventions to highlight the consequences of focussing on a singular approach to the exclusion of evidence based pathways and the resulting risk of a missed diagnosis. The eventual management to mitigate these problems is reported with the aid of low back pain outcome measures, computer-aided combined movement examination, disability and pain questionnaires and health quality of life surveys. PMID- 26521217 TI - Hydrogen production from the dissolution of nano zero valent iron and its effect on anaerobic digestion. AB - Nano zero valent iron (NZVI) has shown inhibition on methanogenesis in anaerobic digestion due to its reductive decomposition of cell membrane. The inhibition was accompanied by the accumulation of hydrogen gas due to rapid NZVI dissolution. It is not clear whether and how rapid hydrogen release from NZVI dissolution directly affects anaerobic digestion. In this study, the hydrogen release kinetics from NZVI (average size = 55 +/- 11 nm) dissolution in deionized water under anaerobic conditions was first evaluated. The first-order NZVI dissolution rate constant was 2.62 +/- 0.26 h(-1) with its half-life of 0.26 +/- 0.03 h. Two sets of anaerobic digestion experiments (i.e., in the presence of glucose or without any substrate but at different anaerobic sludge concentrations) were performed to study the impact of H2 release from rapid NZVI dissolution, in which H2 was generated in a separate water bottle containing NZVI (i.e., ex situ H2 or externally supplied from NZVI dissolution) before hydrogen gas was introduced to anaerobic digestion. The results showed that the H2 partial pressure in the headspace of the digestion bottle reached as high as 0.27 atm due to rapid NZVI dissolution, resulting in temporary inhibition of methane production. Nevertheless, the 5-d cumulative methane volume in the group with ex situ H2 production due to NZVI dissolution was actually higher than that of control, suggesting NZVI inhibition on methanogenesis is solely due to the reductive decomposition of cell membrane after direct contact with NZVI. PMID- 26521216 TI - Biomonitoring of human exposures to chlorinated derivatives and structural analogs of bisphenol A. AB - The high reactivity of bisphenol A (BPA) with disinfectant chlorine is evident in the instantaneous formation of chlorinated BPA derivatives (ClxBPA) in various environmental media that show increased estrogen-activity when compared with that of BPA. The documented health risks associated with BPA exposures have led to the gradual market entry of BPA structural analogs, such as bisphenol S (BPS), bisphenol F (BPF), bisphenol B (BPB), etc. A suite of exposure sources to ClxBPA and BPA analogs in the domestic environment is anticipated to drive the nature and range of halogenated BPA derivatives that can form when residual BPA comes in contact with disinfectant in tap water and/or consumer products. The primary objective of this review was to survey all available studies reporting biomonitoring protocols of ClxBPA and structural BPA analogs (BPS, BPF, BPB, etc.) in human matrices. Focus was paid on describing the analytical methodologies practiced for the analysis of ClxBPA and BPA analogs using hyphenated chromatography and mass spectrometry techniques, because current methodologies for human matrices are complex. During the last decade, an increasing number of ecotoxicological, cell-culture and animal-based and human studies dealing with ClxBPA exposure sources and routes of exposure, metabolism and toxicity have been published. Up to date findings indicated the association of ClxBPA with metabolic conditions, such as obesity, lipid accumulation, and type 2 diabetes mellitus, particularly in in-vitro and in-vivo studies. We critically discuss the limitations, research needs and future opportunities linked with the inclusion of ClxBPA and BPA analogs into exposure assessment protocols of relevant epidemiological studies. PMID- 26521218 TI - Oxidation of organic contaminants by manganese oxide geomedia for passive urban stormwater treatment systems. AB - To advance cost-effective strategies for removing trace organic contaminants from urban runoff, the feasibility of using manganese oxides as a geomedia amendment in engineered stormwater infiltration systems to oxidize organic contaminants was evaluated. Ten representative organic chemicals that have previously been detected in urban stormwater were evaluated for reactivity in batch experiments with birnessite. With respect to reactivity, contaminants could be classified as: highly reactive (e.g., bisphenol A), moderately reactive (e.g., diuron) and unreactive (e.g., tris(2-chloro-1-propyl)phosphate). Bisphenol A and diuron reacted with birnessite to produce a suite of products, including ring-cleavage products for bisphenol A and partially dechlorinated products for diuron. Columns packed with manganese oxide-coated sand were used evaluate design parameters for an engineered infiltration system, including necessary contact times for effective treatment, as well as the impacts of stormwater matrix variables, such as solution pH, concentration of natural organic matter and major anions and cations. The manganese oxide geomedia exhibited decreased reactivity when organic contaminants were oxidized, especially in the presence of divalent cations, bicarbonate, and natural organic matter. Under typical conditions, the manganese oxides are expected to retain their reactivity for 25 years. PMID- 26521219 TI - Correlation and prediction of adsorption capacity and affinity of aromatic compounds on carbon nanotubes. AB - Adsorption of 22 nonpolar and polar aromatic compounds on 10 carbon nanotubes (CNTs) with various diameters, lengths and surface oxygen-containing group contents was investigated to develop predictive correlations for adsorption, using the isotherm fitting of Polanyi theory-based Dubinin-Ashtakhov (DA) model. Adsorption capacity of aromatic compounds on CNTs is negatively correlated with melting points of aromatic compounds, and surface oxygen-containing group contents and surface area ratios of mesopores to total pores of CNTs, but positively correlated with total surface area of CNTs. Adsorption affinity is positively correlated with solvatochromic parameters of aromatic compounds, independent of tube lengths and surface oxygen-containing group contents of CNTs, but negatively correlated with surface area ratios of mesopores to total pores of CNTs. The correlations of adsorption capacity and adsorption affinity with properties of both aromatic compounds and CNTs clearly have physical significance, can be used successfully with DA model to predict adsorption of aromatic compounds on CNTs from the well-known physiochemical properties of aromatic compounds (i.e., solvatochromic parameters, melting points) and CNTs (i.e., surface area and total acidic group contents), and thus can facilitate the environmental application of CNTs as sorbents and environmental risk assessment of both aromatic contaminants and CNTs. PMID- 26521220 TI - Coagulant recovery and reuse for drinking water treatment. AB - Coagulant recovery and reuse from waterworks sludge has the potential to significantly reduce waste disposal and chemicals usage for water treatment. Drinking water regulations demand purification of recovered coagulant before they can be safely reused, due to the risk of disinfection by-product precursors being recovered from waterworks sludge alongside coagulant metals. While several full scale separation technologies have proven effective for coagulant purification, none have matched virgin coagulant treatment performance. This study examines the individual and successive separation performance of several novel and existing ferric coagulant recovery purification technologies to attain virgin coagulant purity levels. The new suggested approach of alkali extraction of dissolved organic compounds (DOC) from waterworks sludge prior to acidic solubilisation of ferric coagulants provided the same 14:1 selectivity ratio (874 mg/L Fe vs. 61 mg/L DOC) to the more established size separation using ultrafiltration (1285 mg/L Fe vs. 91 mg/L DOC). Cation exchange Donnan membranes were also examined: while highly selective (2555 mg/L Fe vs. 29 mg/L DOC, 88:1 selectivity), the low pH of the recovered ferric solution impaired subsequent treatment performance. The application of powdered activated carbon (PAC) to ultrafiltration or alkali pre-treated sludge, dosed at 80 mg/mg DOC, reduced recovered ferric DOC contamination to <1 mg/L but in practice, this option would incur significant costs. The treatment performance of the purified recovered coagulants was compared to that of virgin reagent with reference to key water quality parameters. Several PAC-polished recovered coagulants provided the same or improved DOC and turbidity removal as virgin coagulant, as well as demonstrating the potential to reduce disinfection byproducts and regulated metals to levels comparable to that attained from virgin material. PMID- 26521221 TI - Transesophageal echocardiography to diagnose anomalous right coronary artery type R2A in dogs. AB - OBJECTIVES: To assess the feasibility of transesophageal echocardiography (TEE) as an alternative to angiography for the diagnosis of R2A coronary artery (CA) abnormalities. ANIMALS: Twenty-two dogs with a diagnosis of type R2A CA anomaly were reviewed/analyzed. METHODS: A retrospective study of case records. Transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), angiography, and follow-up investigations of pulmonic stenosis (PS) with R2A CA were carried out to compare different diagnostic methods. RESULTS: Based on the TTE morphology, PS with an aberrant CA was suspected in all dogs (n = 22) and later confirmed by angiography in 18 cases (18/22), and necropsy in two cases (2/22). In 12 cases (12/22), TEE and angiography were both performed and confirmed the diagnosis of an R2A anomaly. Two cases (2/22) were diagnosed only with TEE. CONCLUSIONS: Transesophageal echocardiography may be considered an effective tool to diagnose CA abnormalities, in particular when TTE is inconclusive. Transesophageal echocardiography offers detailed and easily reproducible views of coronary ostia, and the spatial relationship between the right common CA and the great arteries. Although it is not possible to define the course of the more distal coronary branches, TEE has proven reliable in recognizing those elements that can constitute a risk for the execution of a balloon valvuloplasty (BV). Therefore, TEE can be used to confirm this type of CA anomaly and prevent a BV, which is contraindicated in these cases. In addition, TEE avoids any further vascular access, radiation exposure, and contrast medium injection. PMID- 26521222 TI - Aortic chondroid neoplasia in two Labrador Retriever dogs. AB - In the same week, two Labrador Retriever dogs presented to The Ohio State University Veterinary Medical Center for cardiac evaluation. The presenting signs in both dogs included: weight loss, weakness, lethargy, and decreased femoral pulses. The first dog presented in cardiogenic shock and biventricular congestive heart failure, which initially responded to treatment; however, the dog was euthanized due to deteriorating clinical condition. In contrast, the second dog had a milder clinical course without signs of congestive heart failure, and remained stable over the 2-month period of clinical evaluation prior to euthanasia. Echocardiographic evaluation revealed a dilated cardiomyopathy phenotype in the first dog, while a space-occupying intraluminal mass originating at the aortic valve with preserved left ventricular systolic function was observed in the second dog. At autopsy, each dog had a large obstructive luminal mass affecting the ascending aorta and arch. Histopathology revealed that the mass in the first dog was consistent with a benign chondroma, while in the second dog the morphologic characteristics, mitotic activity, and infiltrative growth justified a diagnosis of chondrosarcoma. This report presents the contrasting clinical disease progression and findings in two dogs with aortic neoplasia, with a proposed pathogenesis of cardiac failure secondary to aortic neoplasia. PMID- 26521223 TI - The effectiveness of a program of physical activity and diet to modify cardiovascular risk factors in patients with severe mental illness after 3-month follow-up: CAPiCOR randomized clinical trial. AB - BACKGROUND: The aim of this randomized clinical trial follow-up at three months was to evaluate the effectiveness of an educational intervention with a focus on diet and physical activity (PA) to change the amount of PA, body mass index (BMI) and the waist circumference (WC) in patients with severe mental illness. METHODS: We recruited 332 outpatients with severe mental disorders undergoing treatment with antipsychotic medication from Mental Healthcare Centers of Barcelona. They were randomly assigned to an intervention or a control group. The patients in the intervention group participated in a group PA and diet educational program. The blinded measurements at 0 and 3 months were: the level of PA (IPAQ questionnaire), BMI, WC, blood pressure, dietary habits (PREDIMED questionnaire), quality of life (SF-36 questionnaire) and laboratory parameters (cholesterol, triglycerides, glucose). RESULTS: The average age was 46.7 years and 55% were males. Schizophrenia had been diagnosed in 67.1% of them. At 3 months, the average weekly walking METs rose significantly in the IG 266.05 METs (95%CI: 16.86 to 515.25; P=0.036). The total MET average also rose although not significantly: 191.38 METs (95%CI: 1.38 to 381.38; P=0.086). However, the BMI decreased significantly more in the CG, by 0.26kg/m(2) (95%CI: 0.02 to 0.51; P=0.038), than in the IG. There were no significant differences in the WC. CONCLUSIONS: The short-term results suggest that the intervention increases the level of PA, but does not improve physical or laboratory parameters. TRIAL REGISTRATION: Clinicaltrials.gov NCT01729650 (effectiveness of a physical activity and diet program in patients with psychotic disorder [CAPiCOR]). PMID- 26521224 TI - Seasonal variations of respiratory viruses and etiology of human rhinovirus infection in children. AB - BACKGROUND: Using the polymerase chain reaction (PCR) method it is possible to detect uncultivable viruses and discover multiple viral infections. However, the clinical importance of these findings in relation to symptoms is not known. OBJECTIVES: The seasonal fluctuations of respiratory viruses and the clinical outcomes of single infections and dual infections were investigated. STUDY DESIGN: Nasal aspirate samples were obtained from outpatients and inpatients of a children's hospital and these samples were subjected to real-time PCR to detect 16 respiratory viruses. Seasonal variations of the 16 viruses and the clinical outcomes such as wheezing, the need for oxygenation and prolonged hospitalization of patients with single viral infections and multiple infections were determined for the 5 most often detected viruses. RESULTS: Among 512 specimens analyzed, one or more viruses were detected in 424 (83%) specimens. Two or more viruses were detected in 160 samples (31% of all samples). The epidemic peaks of the viruses did not coincide with each other. Rhinoviruses were the most frequently detected viruses and their coinfection rates were also higher. However, the disease severity in the lower respiratory tract did not differ in most respiratory viral infections regardless of whether there was single infection or dual infection with a rhinovirus and other respiratory virus. CONCLUSIONS: Seasonal distribution was seen for each virus. There were no significant differences in clinical symptoms in the children studied. Because the infection of rhinoviruses is the common occurrence in children, it is hypothesized that the factors related to disease severity are mainly the underlying conditions of the children. PMID- 26521225 TI - Acute hepatitis E virus in pregnant women in Israel and in other industrialized countries. AB - BACKGROUND AND OBJECTIVES: Acute hepatitis E virus (HEV) is the most common etiology of viral hepatitis in adults in developing countries. HEV is rare in industrialized countries but its incidence is rising both in returning travelers and through autochthonous infection. In developing countries HEV is associated with a high rate of fulminant hepatitis and mortality during pregnancy and contributes to poor obstetric and fetal outcomes. There are no reliable data on the outcome of HEV during pregnancy in industrialized countries. STUDY DESIGN: A retrospective analysis of acute HEV cases diagnosed in Israel were examined. The clinical course of the disease among pregnant women was retrieved. A systematic review of the literature was performed for cases of HEV and pregnancy, originating or treated in industrialized countries RESULTS: Between the years 1993-2013, 68 cases of acute HEV were diagnosed in Israel, including 9 pregnant women (13%). An additional 6 reported cases were found from a literature search. From the 15 women (10 autochthonous cases and 5 imported cases), the outcome was favorable in 10 cases, however, 5 cases (33%) resulted in fulminant hepatitis and two women underwent an urgent liver transplantation. No fatality occurred in the mothers and all babies were born alive and healthy. DISCUSSION: This is the first case series of acute HEV infection in pregnant women in industrialized countries. Acute HEV infection poses a significant risk in pregnancy, irrespective of patients' country of origin. In contrast to reports from developing countries, all babies and mothers survived. PMID- 26521226 TI - Live adenovirus types 4 and 7 not detected in the blood of vaccine recipients. PMID- 26521227 TI - Viral excretion and antibody titers in children infected with hepatitis A virus from an orphanage in western India. AB - BACKGROUND: Hepatitis A is endemic in India and mainly causes sporadic infections. However, children in childcare centers, schools and orphanages are vulnerable to common-source outbreaks as they have naive hosts. OBJECTIVES: To investigate hepatitis A outbreak in an orphanage from Pune, India. STUDY DESIGN: Monitoring of virus excretion and anti-HAV antibody levels in hepatitis A virus (HAV) infected children. RESULTS: The orphanage housed 93 children of the age 1 month-6.5 years. Analysis of the collected serum (n=78) and stool samples (n=63) revealed 20 children to be either positive for anti-HAV IgM antibodies or excreting HAV, 14 being symptomatic and 6 asymptomatic, while 32 were already anti-HAV IgG positive either due to past HAV exposure (n=7, mean log antibody titers: 2.96) or maternal antibodies (n=25, mean log antibody titers: 1.13). Serum samples, taken 4 weeks apart, did not show any significant difference in the IgM and IgG antibody levels either. However, virus excretion decreased significantly after 15 days in symptomatic children (mean log HAV RNA copies/ml 1.03+0.30), while asymptomatic children continued to excrete higher viral loads, at constant levels (mean log HAV RNA copies/ml 2.33+0.33), for up to 90 days. CONCLUSIONS: Though virus excretion continued up to 90 days in all HAV infected children, asymptomatic children excreted higher viral loads for longer period and hence can contribute significantly in person-to-person virus transmission. All children should be vaccinated in such set ups. PMID- 26521228 TI - Flexible combination of multiple diagnostic biomarkers to improve diagnostic accuracy. AB - BACKGROUND: In medical research, it is common to collect information of multiple continuous biomarkers to improve the accuracy of diagnostic tests. Combining the measurements of these biomarkers into one single score is a popular practice to integrate the collected information, where the accuracy of the resultant diagnostic test is usually improved. To measure the accuracy of a diagnostic test, the Youden index has been widely used in literature. Various parametric and nonparametric methods have been proposed to linearly combine biomarkers so that the corresponding Youden index can be optimized. Yet there seems to be little justification of enforcing such a linear combination. METHODS: This paper proposes a flexible approach that allows both linear and nonlinear combinations of biomarkers. The proposed approach formulates the problem in a large margin classification framework, where the combination function is embedded in a flexible reproducing kernel Hilbert space. RESULTS: Advantages of the proposed approach are demonstrated in a variety of simulated experiments as well as a real application to a liver disorder study. CONCLUSION: Linear combination of multiple diagnostic biomarkers are widely used without proper justification. Additional research on flexible framework allowing both linear and nonlinear combinations is in need. PMID- 26521229 TI - Midterm results of mitral valve repair with lifting annuloplasty strip for acute phase infective endocarditis. AB - BACKGROUND: Mitral valve repair is favored over replacement due to superior outcomes. However, extensive infective endocarditis (IE) often has been considered unreconstructable. We retrospectively analyzed the mid-term outcomes of an individualized repair approach using a lifting annuloplasty strip. METHODS: Between December 2007 and March 2014, 27 consecutive patients with acute single mitral valve IE (age 43 +/- 16 years, 11 men) underwent lifting mitral annuloplasty (LMA) with a strip (Mitracon(r) strip, 28 mm in 4, 32 mm in 10, and 34 mm in 13). Blood culture was positive in 70 % (Streptococcus 10, Staphylococcus 4, HACEK 3, Enterococcus 1, Gram negative bacilli 1). One case (4 %) had a previously repaired mitral valve-the repair was redone. Via right thoracotomy (74 %) or median sternotomy (26 %), repair was performed by removal of vegetation and resection of infected tissue, the defect typically then being repaired using a bovine pericardial patch (81 %). Artificial chordae were formed in 5 patients. Nine (33 %) of them had posterior leaflet augmentation (PLA) to get sufficient coaptation height. Clinical and echocardiographic follow-up were performed. RESULTS: Compared with preoperative ones, postoperative echocardiograms revealed decreases of left ventricular (LV) end-diastolic dimensions (57.2 +/- 6.3 versus, 45.4 +/- 6.2, or 44.8 +/- 4.1 mm, all p < 0.01). The LV ejection fraction decreased immediately, but recovered (64.4 +/- 9.6 % vs. 54.5 +/- 9.8 %, or 65.2 +/- 6.1 %, p = 0.002, p = 1.000, respectively). The latest follow-up echocardiograms (median 28 months) universally showed no or minimal regurgitation, with a preserved mitral valve opening area (2.27 +/- 0.48 cm(2)). During the clinical follow-up (median, 54 months), one (3.7 %) death was observed (in-hospital, due to biliary sepsis and pneumonia). There was no reoperation or major cardiovascular event. The 5 year survival rate was 96.3 %. CONCLUSIONS: The repair technique of LMA and/or PLA in patients with IE achieved good structural and functional outcomes as well as an excellent 5 year survival rate. An individualized repair approach should be recommended in patients with acute phase IE. PMID- 26521230 TI - Monitoring of in-hospital cardiac arrest events with the focus on Automated External Defibrillators--a retrospective observational study. AB - BACKGROUND: Patients with cardiac arrest have lower survival rates, when resuscitation performance is low. In In-hospital settings the first responders on scene are usually nursing staff without rhythm analysing skills. In such cases Automated External Defibrillators (AED) might help guiding resuscitation performance. At the Wuerzburg University Hospital (Germany) an AED-program was initiated in 2007. Aim of the presented study was to monitor the impact of Automated External Defibrillators on the management of in-hospital cardiac arrest events. METHODS: The data acquisition was part of a continuous quality improvement process of the Wuerzburg University Hospital. For analysing the CPR performance, the chest compression rate (CCR), compression depth (CCD), the no flow fraction (NFF), time interval from AED-activation to the first compression (TtC), the time interval from AED-activation to the first shock (TtS) and the post schock pause (TtCS) were determined by AED captured data. A questionnaire was completed by the first responders. RESULTS: From 2010 to 2012 there were 359 emergency calls. From these 53 were cardiac arrests with an AED-application. Complete data were available in 46 cases. The TtC was 34 (32-52) seconds (median and IQR).The TtS was 30 (28-32) seconds (median and IQR). The TtCS was 4 (3-6) seconds (median and IQR). The CCD was 5.5 +/- 1 cm while the CCR was 107 +/- 11/min. The NFF was calculated as 41 %. ROSC was achieved in 21 patients (45 %), 8 patients (17 %) died on scene and 17 patients (37 %) were transferred under ongoing CPR to an Intensive Care Unit (ICU). CONCLUSION: The TtS and TtC indicate that there is an AED-user dependent time loss. These time intervals can be markedly reduced, when the user is trained to interrupt the AED's "chain of advices" by placing the electrode-paddles immediately on the patient's thorax. At this time the AED switches directly to the analysing mode. Intensive training and adaption of the training contents is needed to optimize the handling of the AED in order to maximize its advantages and to minimize its disadvantages. PMID- 26521231 TI - Prevalence and care-seeking for chronic diseases among Syrian refugees in Jordan. AB - BACKGROUND: There are currently more people displaced by conflict than at any time since World War II. The profile of displaced populations has evolved with displacement increasingly occurring in urban and middle-income settings. Consequently, an epidemiological shift away from communicable diseases that have historically characterized refugee populations has occurred. The high prevalence of non-communicable diseases (NCDs) poses a challenge to in terms of provision of appropriate secondary and tertiary services, continuity of care, access to medications, and costs. In light of the increasing burden of NCDs faced by refugees, we undertook this study to characterize the prevalence of NCDs and better understand issues related to care-seeking for NCDs among Syrian refugees in non-camp settings in Jordan. METHODS: A cross-sectional survey of 1550 refugees was conducted using a multi-stage cluster design with probability proportional to size sampling to obtain a nationally representative sample of Syrian refugees outside of camps. To obtain information on chronic conditions, respondents were asked a series of questions about hypertension, cardiovascular disease, diabetes, chronic respiratory disease, and arthritis. Differences by care-seeking for these conditions were examined using chi-square and t-test methods and characteristics of interest were included in the adjusted logistic regression model. RESULTS: Among adults, hypertension prevalence was the highest (9.7%, CI: 8.8-10.6), followed by arthritis (6.8%, CI: 5.9-7.6), diabetes (5.3%, CI: 4.6-6.0), chronic respiratory diseases (3.1%, CI: 2.4-3.8), and cardiovascular disease (3.7%, CI: 3.2, 4.3). Of the 1363 NCD cases, 84.7% (CI: 81.6-87.3) received care in Jordan; of the five NCDs assessed, arthritis cases had the lowest rates of care seeking at 65%, (CI:0-88, p = 0.005). Individuals from households in which the head completed post-secondary and primary education, respectively, had 89% (CI: 22-98) and 88% (CI: 13-98) lower odds of seeking care than those with no education (p = 0.028 and p = 0.037, respectively). Refugees in North Jordan were most likely to seek care for their condition; refugees in Central Jordan had 68% (CI: 1-90) lower odds of care-seeking than those in the North (p = 0.047). CONCLUSION: More than half of Syrian refugee households in Jordan reported a member with a NCD. A significant minority did not receive care, citing cost as the primary barrier. As funding limitations persist, identifying the means to maintain and improve access to NCD care for Syrian refugees in Jordan is essential. PMID- 26521232 TI - Next-generation sequencing identifies altered whole blood microRNAs in neuromyelitis optica spectrum disorder which may permit discrimination from multiple sclerosis. AB - BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) have a similar clinical phenotype but represent distinct diseases, requiring different therapies. MicroRNAs (miRNAs) are short non-coding RNAs whose expression profiles can serve as diagnostic biomarkers and which may be involved in the pathophysiology of neuroinflammatory diseases. Here, we analyzed miRNA profiles in serum and whole blood of patients with NMOSD and clinically isolated syndrome (CIS)/relapsing-remitting MS (RRMS) as well as healthy controls by next generation sequencing (NGS). METHODS: MiRNA expression profiles were determined by NGS in sera of patients with aquaporin-4 antibody-positive NMOSD (n = 20), CIS/RRMS (n = 20), and healthy controls (n = 20) and in whole blood of patients with NMOSD (n = 11), CIS/RRMS (n = 60), and healthy controls (n = 43). Differentially expressed miRNAs were calculated by analysis of variance and t tests. All significance values were corrected for multiple testing. Selected miRNAs were validated in whole blood of patients with NMOSD (n = 18) and CIS/RRMS (n = 19) by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: None of 261 miRNAs detected in serum but 178 of 416 miRNAs detected in whole blood showed significantly different expression levels among the three groups. Pairwise comparisons revealed 115 (NMOSD vs. CIS/RRMS), 141 (NMOSD vs. healthy controls), and 44 (CIS/RRMS vs. healthy controls) miRNAs in whole blood with significantly different expression levels. qRT-PCR confirmed different expression levels in whole blood of patients with NMOSD and CIS/RRMS for 9 out of 10 exemplarily chosen miRNAs. In silico enrichment analysis demonstrated an accumulation of altered miRNAs in NMOSD in particular in CD15(+) cells (i.e., neutrophils and eosinophils). CONCLUSIONS: This study identifies a set of miRNAs in whole blood, which may have the potential to discriminate NMOSD from CIS/RRMS and healthy controls. In contrast, miRNA profiles in serum do not appear to be promising diagnostic biomarkers for NMOSD. Enrichment of altered miRNAs in CD15(+) neutrophils and eosinophils, which were previously implicated in the pathophysiology of NMOSD, suggests that miRNAs could be involved in the regulation of these cells in NMOSD. PMID- 26521233 TI - KRAS G12D mosaic mutation in a Chinese linear nevus sebaceous syndrome infant. AB - BACKGROUND: Linear nevus sebaceous syndrome (LNSS) is a multisystem disorder that includes nevus sebaceous and central nervous system, ocular and skeletal anomalies. We report the first case of a KRAS G12D mosaic mutation in a patient diagnosed with LNSS. CASE PRESENTATION: A 3-month-old female with a clinical diagnosis of LNSS presented with intermittent epilepsy. Her mother carefully collected a skin lesion sample from scratched-off scurf obtained from the patient's nails. DNA was extracted, and long-range PCR was performed to amplify the KRAS gene, which was then analyzed by next-generation sequencing. The results revealed the presence of a low-level heterozygous mutation in the KRAS gene (c.35C>T; p.G12D, 5 %). CONCLUSIONS: These findings suggest that the KRAS somatic mosaic mutation in this patient may have caused her skin and eye lesions and epilepsy. With this correct diagnosis, the infant can be effectively treated. PMID- 26521234 TI - Protective role of silymarin in a mouse model of renal Ischemia-Reperfusion injury. AB - BACKGROUND: We investigated the mechanism of action of silymarin in a mouse model of renal ischemia-reperfusion injury (I/R) to ascertain its role in the treatment of I/R injury. METHODS: Twenty-four C57BL/6 male mice were divided randomly into three groups: control (sham); ischemia-reperfusion (I/R); silymarin + ischemia reperfusion (silymarin + I/R). In sham mice, an abdominal incision was made, followed by dissection of the bilateral renal pedicle, with no further cross clamping of arteries. Silymarin + I/R mice were administered 100 mg/kg silymarin daily for 7 consecutive days before surgery, whereas I/R mice were administered (i.g.) 0.9 % saline + 0.1 % (v/v) ethanol daily for 7 consecutive days before surgery. Silymarin + I/R and I/R mice were subjected to renal ischemia to induce acute kidney injury after 45-min clamping of bilateral renal arteries. Serum levels of creatinine and blood urea nitrogen levels were measured. Periodic acid Schiff (PAS) staining was undertaken to detect damaged renal tissue. Myeloperoxidase (MPO) activity and immunofluorescent detection of CD68 expression was undertaken for each group. Levels of inflammatory cytokines secreted by renal tissue were monitored by ELISA. Apoptosis was detected by TUNEL staining. Expression of cleaved-caspase-3, Bcl-2 and Bax was detected by western blotting. RESULTS: Serum creatinine and blood urea nitrogen levels were elevated in silymarin + I/R and I/R groups compared with sham mice (p < 0.05), whereas those in the I/R group were significantly higher than in the silymarin + I/R group (p < 0.05). Number of damaged renal tubule cells and apoptotic cells in sham and silymarin + I/R groups was significantly lower than in I/R mice. MPO activity and secretion of inflammatory cytokines in silymarin + I/R and I/R groups was reduced (p < 0.05), and CD68 expression in silymarin + I/R mice was lower than in I/R mice (p < 0.05). Expression of cleaved-caspase-3 and Bax in the I/R group was significantly higher than in sham mice, whereas Bcl-2 expression was lower than in silymarin + I/R mice (p < 0.05). CONCLUSIONS: Silymarin can inhibit renal I/R injury by inhibiting release of inflammatory factors and regulating apoptosis. PMID- 26521235 TI - Meningitis caused by Pasteurella multocida in a dog owner without a dog bite: clonal lineage identification by MALDI-TOF mass spectrometry. AB - BACKGROUND: Pasteurella multocida meningitis in an immunocompetent patient is rare and commonly occurs after animal bite. To our knowledge, only 48 cases have been reported in the literature since 1989. P. multocida meningitis is commonly linked to animal contagion. Here we report on a new case of P. multocida meningitis in an immunocompetent patient who is a dog owner without a dog bite. We used the matrix-assisted laser desorption/ionization-time of flight (MALDI TOF) mass spectrometry to investigate the clonal lineage between animal and human isolates. CASE PRESENTATION: In our case, a 25-year-old immunocompetent French Caucasian woman with nothing notable in her medical history was admitted for meningitis caused by P. multocida. Clonal lineage of P. multocida strains from cerebrospinal fluid and blood culture and her dog's oral cavity has been recognized by MALDI-TOF mass spectrometry dendrograms and clustering of the 21 P. multocida isolates in our centres. She was treated by a combination of intravenous ceftriaxone (2 g/day) and oral levofloxacin (1 g/day). She was discharged on the 6th day of admission. The antimicrobial therapy was conducted for 15 days. The dog was treated by clavulanic-acid amoxicillin for 3 weeks by the veterinarian. The evolution of the patient at the 5th month after the end of the antimicrobial therapy was normal without any neurological after-effects. CONCLUSION: The meningitis caused by P. multocida could be considered a cause of human meningitis in dog lovers without an animal bite. MALDI-TOF mass spectrometry should be considered as it is an accurate tool to identify clonal lineage between animal and human isolates. PMID- 26521236 TI - Factors associated with no apparent coronary artery disease in patients with type 2 diabetes mellitus for more than 10 years of duration: a case control study. AB - BACKGROUND: Type 2 diabetes mellitus is an important risk factor in the development of coronary artery disease (CAD) and is often associated with severe disease. However, this risk is not uniform, some patients remain free of CAD even after many years of treatment for diabetes. The present study was aimed to identify the factors that are associated with a favorable CAD profile. METHODS: A case-control study of 76 patients with type 2 diabetes mellitus who were on treatment for more than 10 years duration and undergoing a coronary angiogram for the evaluation of clinically suspected CAD at a tertiary care hospital were recruited for the study. The presence and absence of significant CAD was determined after a coronary angiogram. Clinical history, and anthropometric and biochemical parameters were analyzed. Insulin resistance was determined by the Homeostasis Model Assessment. Multiple logistic regressions were done to find out the factors associated for a favorable CAD profile. RESULTS: The difference in HOMA-IR (2.37 +/- 0.69 VS 3.77 +/- 1.64, p < 0.001) and urine microalbumin (24.15 +/- 32.16 VS 82.72 +/- 117.70, p = 0.004) were found to be statistically significant among those who did not have CAD when compared to those who had CAD. The difference in lipid profile, HbA1C, fasting blood sugar, BMI, waist hip ratio, waist and hip circumference was not significant. The adjusted odds ratio for insulin resistance less than 2.5 (OR 9.09, 95 % CI 1.91-41.83, p = 0.005), females (OR 7.91, 95% CI 1.55-40.38, p = 0.013) and microalbumin <20 mg/l (OR 4.57, 95% CI 1.17-17.85, p = 0.029) were independently associated with normal coronaries. The adjusted odds ratio for lipid profile, BMI, blood pressure and HbA1C were not significant. CONCLUSIONS: HOMA-IR less than 2.5, microalbuminuria less than 20 mg/l and females are the factors appear to be associated with no apparent CAD. PMID- 26521237 TI - Barriers in household access to medicines for chronic conditions in three Latin American countries. AB - BACKGROUND: Access to medicines is one of the major challenges in health policy. The high out-of-pocket expenditures on medicines in the Latin American and Caribbean (LAC) region represents important barrier to affordable access to care for NCDs. This paper aim to identify key barriers in access to medicines for household members with a diagnosed chronic condition in three Central America countries. METHODS: This was a cross-sectional analytic study, based on data from three household surveys using a common methodology. We examined associated factors to: (1) seeking care for chronic illness from a trained clinician in the formal health system, and (2) obtaining all medicines sought for the chronic conditions reported. RESULTS: A chronic condition was reported in 29.8 % (827) of 2761 households - 47.0, 30.7 and 11.8 % in Nicaragua, Honduras and Guatemala, respectively. The three main chronic conditions reported were hypertension, arthritis, and diabetes. Seeking care in the formal health system ranged from 73.4 % in Nicaragua to 83.1 % in Honduras, while full access to medicines varied from 71.6 % in Guatemala to 88.0 % in Honduras. The main associated factors of seeking care in the formal health system were geographic location, household head gender, Spanish literacy, patient age, perceived health status, perceived quality of public sector care, household economic level, and having health insurance. Seeking care in the formal health system was the main bivariate associated factor of obtaining full access to medicines (OR: 4.3 95 % CI 2.6 - 7.0). The odds of full access to medicines were significantly higher when the household head was older than 65 years, medicines were obtained for free, households had higher socioeconomic status, and health care was sought in the private sector. CONCLUSIONS: The nature of the health system plays an important role in access to medicines. Access is better when public facilities are available and function effectively, or when private sector care is affordable. Thus, understanding how people seek care in a given setting and strengthening key health system components will be important strategies to improve access to medicines, especially for populations at high risk of poor access. PMID- 26521238 TI - Changes of lung tumour volume on CT - prediction of the reliability of assessments. AB - BACKGROUND: For oncological evaluations, quantitative radiology gives clinicians significant insight into patients' response to therapy. In regard to the Response Evaluation Criteria in Solid Tumours (RECIST), the classification of disease evolution partly consists in applying thresholds to the measurement of the relative change of tumour. In the case of tumour volumetry, response thresholds have not yet been established. This study proposes and validates a model for calculating thresholds for the detection of minimal tumour change when using the volume of pulmonary lesions on CT as imaging biomarker. METHODS: Our work is based on the reliability analysis of tumour volume measurements documented by the Quantitative Imaging Biomarker Alliance. Statistics of measurements were entered into a multi-parametric mathematical model of the relative changes derived from the Geary-Hinkley transformation. The consistency of the model was tested by comparing modelled thresholds against Monte Carlo simulations of tumour volume measurements with additive random error. The model has been validated by repeating measurements on real patient follow ups. RESULTS: For unchanged tumour volume, relying on a normal distribution of error, the agreement between model and simulations featured a type I error of 5.25%. Thus, we established that a threshold of 35% of volume reduction corresponds to a partial response (PR) and a 55% volume increase corresponds to progressive disease (PD). Changes between -35 and +55% are categorized as stable disease (SD). Tested on real clinical data, 97.1% [95.7; 98.0] of assessments fall into the range of variability predicted by our model of confidence interval. CONCLUSIONS: Our study indicates that the Geary Hinkley model, using published statistics, is appropriate to predict response thresholds for the volume of pulmonary lesions on CT. PMID- 26521239 TI - New Developments in the Genetics of Hypertension: What Should Clinicians Know? AB - It has long been known that genetic factors play a major role in determining an individual's propensity to hypertension. In recent years, there has been major progress towards realizing the goal of identifying the specific genetic factors that lead to alterations in blood pressure. Of particular note, new genes regulating renal sodium handling and aldosterone regulation have been discovered via the study of rare Mendelian disorders. Similarly, a number of large genome wide association studies have been completed, which have added to our understanding as well. Here, recent progress in the genetics of hypertension will be reviewed, with an emphasis towards highlighting specific areas where clinical practice has already or will soon be affected. PMID- 26521240 TI - Bringing nitrilase sequences from databases to life: the search for novel substrate specificities with a focus on dinitriles. AB - The aim of this study was to discover new nitrilases with useful activities, especially towards dinitriles that are precursors of high-value cyano acids. Genes coding for putative nitrilases of different origins (fungal, plant, or bacterial) with moderate similarities to known nitrilases were selected by mining the GenBank database, synthesized artificially and expressed in Escherichia coli. The enzymes were purified, examined for their substrate specificities, and classified into subtypes (aromatic nitrilase, arylacetonitrilase, aliphatic nitrilase, cyanide hydratase) which were largely in accordance with those predicted from bioinformatic analysis. The catalytic potential of the nitrilases for dinitriles was examined with cyanophenyl acetonitriles, phenylenediacetonitriles, and fumaronitrile. The nitrilase activities and selectivities for dinitriles and the reaction products (cyano acid, cyano amide, diacid) depended on the enzyme subtype. At a preparative scale, all the examined dinitriles were hydrolyzed into cyano acids and fumaronitrile was converted to cyano amide using E. coli cells producing arylacetonitrilases and an aromatic nitrilase, respectively. PMID- 26521241 TI - Glyphosate acetylation as a specific trait of Achromobacter sp. Kg 16 physiology. AB - The growth parameters of Achromobacter sp. Kg 16 (VKM B-2534 D), such as biomass and maximum specific growth rate, depended only on the source of phosphorus in the medium, but not on the carbon source or the presence of growth factors. With glyphosate as a sole phosphorus source, they were still 40-50 % lower than in media supplemented with orthophosphate or other organophosphonate methylphosphonic acid. At the first time process of glyphosate acetylation and accumulation of acetylglyphosate in culture medium were revealed in this strain. Acetylglyphosate isolated from cultural liquid was identified by mass spectroscopy; its mass spectrum fully corresponded with that of chemically synthesized acetylglyphosate. Even poorer growth was observed in media with acetylglyphosate: although the strain was able to utilize this compound as a sole source of phosphorus, the maximum biomass was still 58-70 % lower than with glyphosate. The presence of acetylglyphosate in culture medium could also hinder the utilization of glyphosate as a phosphorus source. Therefore, the acetylation of glyphosate may be a specific feature of Achromobacter sp. Kg 16 responsible for its poor growth on this compound. PMID- 26521242 TI - Bioconversion of methanol to value-added mevalonate by engineered Methylobacterium extorquens AM1 containing an optimized mevalonate pathway. AB - Methylotrophic biosynthesis using methanol as a feedstock is a promising and attractive method to solve the over-dependence of the bioindustry on sugar feedstocks derived from grains that are used for food. In this study, we introduced and engineered the mevalonate pathway into Methylobacterium extorquens AM1 to achieve high mevalonate production from methanol, which could be a platform for terpenoid synthesis. We first constructed a natural operon (MVE) harboring the mvaS and mvaE genes from Enterococcus faecalis as well as an artificial operon (MVH) harboring the hmgcs1 gene from Blattella germanica and the tchmgr gene from Trypanosoma cruzi that encoded enzymes with the highest reported activities. We achieved mevalonate titers of 56 and 66 mg/L, respectively, in flask cultivation. Introduction of the phaA gene from Ralstonia eutropha into the operon MVH increased the mevalonate titer to 180 mg/L, 3.2-fold higher than that of the natural operon MVE. Further modification of the expression level of the phaA gene by regulating the strength of the ribosomal binding site resulted in an additional 20 % increase in mevalonate production to 215 mg/L. A fed-batch fermentation of the best-engineered strain yielded a mevalonate titer of 2.22 g/L, which was equivalent to an overall yield and productivity of 28.4 mg mevalonate/g methanol and 7.16 mg/L/h, respectively. The production of mevalonate from methanol, which is the initial, but critical step linking methanol with valuable terpenoids via methylotrophic biosynthesis, represents a proof of concept for pathway engineering in M. extorquens AM1. PMID- 26521243 TI - Enhanced succinic acid production in Aspergillus saccharolyticus by heterologous expression of fumarate reductase from Trypanosoma brucei. AB - Aspergillus saccharolyticus exhibits great potential as a cell factory for industrial production of dicarboxylic acids. In the analysis of the organic acid profile, A. saccharolyticus was cultivated in an acid production medium using two different pH conditions. The specific activities of the enzymes, pyruvate carboxylase (PYC), malate dehydrogenase (MDH), and fumarase (FUM), involved in the reductive tricarboxylic acid (rTCA) branch, were examined and compared in cells harvested from the acid production medium and a complete medium. The results showed that ambient pH had a significant impact on the pattern and the amount of organic acids produced by A. saccharolyticus. The wild-type strain produced higher amount of malic acid and succinic acid in the pH buffered condition (pH 6.5) compared with the pH non-buffered condition. The enzyme assays showed that the rTCA branch was active in the acid production medium as well as the complete medium, but the measured enzyme activities were different depending on the media. Furthermore, a soluble NADH-dependent fumarate reductase gene (frd) from Trypanosoma brucei was inserted and expressed in A. saccharolyticus. The expression of the frd gene led to an enhanced production of succinic acid in frd transformants compared with the wild-type in both pH buffered and pH non-buffered conditions with highest amount produced in the pH buffered condition (16.2 +/- 0.5 g/L). This study demonstrates the feasibility of increasing succinic acid production through the cytosolic reductive pathway by genetic engineering in A. saccharolyticus. PMID- 26521245 TI - Genetically engineered Pseudomonas putida X3 strain and its potential ability to bioremediate soil microcosms contaminated with methyl parathion and cadmium. AB - A multifunctional Pseudomonas putida X3 strain was successfully engineered by introducing methyl parathion (MP)-degrading gene and enhanced green fluorescent protein (EGFP) gene in P. putida X4 (CCTCC: 209319). In liquid cultures, the engineered X3 strain utilized MP as sole carbon source for growth and degraded 100 mg L(-1) of MP within 24 h; however, this strain did not further metabolize p nitrophenol (PNP), an intermediate metabolite of MP. No discrepancy in minimum inhibitory concentrations (MICs) to cadmium (Cd), copper (Cu), zinc (Zn), and cobalt (Co) was observed between the engineered X3 strain and its host strain. The inoculated X3 strain accelerated MP degradation in different polluted soil microcosms with 100 mg MP kg(-1) dry soil and/or 5 mg Cd kg(-1) dry soil; MP was completely eliminated within 40 h. However, the presence of Cd in the early stage of remediation slightly delayed MP degradation. The application of X3 strain in Cd-contaminated soil strongly affected the distribution of Cd fractions and immobilized Cd by reducing bioavailable Cd concentrations with lower soluble/exchangeable Cd and organic-bound Cd. The inoculated X3 strain also colonized and proliferated in various contaminated microcosms. Our results suggested that the engineered X3 strain is a potential bioremediation agent showing competitive advantage in complex contaminated environments. PMID- 26521244 TI - Transcription factor-based biosensors in biotechnology: current state and future prospects. AB - Living organisms have evolved a plethora of sensing systems for the intra- and extracellular detection of small molecules, ions or physical parameters. Several recent studies have demonstrated that these principles can be exploited to devise synthetic regulatory circuits for metabolic engineering strategies. In this context, transcription factors (TFs) controlling microbial physiology at the level of transcription play a major role in biosensor design, since they can be implemented in synthetic circuits controlling gene expression in dependency of, for example, small molecule production. Here, we review recent progress on the utilization of TF-based biosensors in microbial biotechnology highlighting different areas of application. Recent advances in metabolic engineering reveal TF-based sensors to be versatile tools for strain and enzyme development using high-throughput (HT) screening strategies and adaptive laboratory evolution, the optimization of heterologous pathways via the implementation of dynamic control circuits and for the monitoring of single-cell productivity in live cell imaging studies. These examples underline the immense potential of TF-based biosensor circuits but also identify limitations and room for further optimization. PMID- 26521246 TI - Entomotoxic and nematotoxic lectins and protease inhibitors from fungal fruiting bodies. AB - Fruiting bodies or sporocarps of dikaryotic (ascomycetous and basidiomycetous) fungi, commonly referred to as mushrooms, are often rich in entomotoxic and nematotoxic proteins that include lectins and protease inhibitors. These protein toxins are thought to act as effectors of an innate defense system of mushrooms against animal predators including fungivorous insects and nematodes. In this review, we summarize current knowledge about the structures, target molecules, and regulation of the biosynthesis of the best characterized representatives of these fungal defense proteins, including galectins, beta-trefoil-type lectins, actinoporin-type lectins, beta-propeller-type lectins and beta-trefoil-type chimerolectins, as well as mycospin and mycocypin families of protease inhibitors. We also present an overview of the phylogenetic distribution of these proteins among a selection of fungal genomes and draw some conclusions about their evolution and physiological function. Finally, we present an outlook for future research directions in this field and their potential applications in medicine and crop protection. PMID- 26521247 TI - Inverse metabolic engineering based on transient acclimation of yeast improves acid-containing xylose fermentation and tolerance to formic and acetic acids. AB - Improving the production of ethanol from xylose is an important goal in metabolic engineering of Saccharomyces cerevisiae. Furthermore, S. cerevisiae must produce ethanol in the presence of weak acids (formate and acetate) generated during pre treatment of lignocellulosic biomass. In this study, weak acid-containing xylose fermentation was significantly improved using cells that were acclimated to the weak acids during pre-cultivation. Transcriptome analyses showed that levels of transcripts for transcriptional/translational machinery-related genes (RTC3 and ANB1) were enhanced by formate and acetate acclimation. Recombinant yeast strains overexpressing RTC3 and ANB1 demonstrated improved ethanol production from xylose in the presence of the weak acids, along with improved tolerance to the acids. Novel metabolic engineering strategy based on the combination of short-term acclimation and system-wide analysis was developed, which can develop stress tolerant strains in a short period of time, although conventional evolutionary engineering approach has required long periods of time to isolate inhibitor adapted strains. PMID- 26521248 TI - Multi-parameter flow cytometry as a process analytical technology (PAT) approach for the assessment of bacterial ghost production. AB - Flow cytometry (FCM) is a tool for the analysis of single-cell properties in a cell suspension. In this contribution, we present an improved FCM method for the assessment of E-lysis in Enterobacteriaceae. The result of the E-lysis process is empty bacterial envelopes-called bacterial ghosts (BGs)-that constitute potential products in the pharmaceutical field. BGs have reduced light scattering properties when compared with intact cells. In combination with viability information obtained from staining samples with the membrane potential-sensitive fluorescent dye bis-(1,3-dibutylarbituric acid) trimethine oxonol (DiBAC4(3)), the presented method allows to differentiate between populations of viable cells, dead cells, and BGs. Using a second fluorescent dye RH414 as a membrane marker, non-cellular background was excluded from the data which greatly improved the quality of the results. Using true volumetric absolute counting, the FCM data correlated well with cell count data obtained from colony-forming units (CFU) for viable populations. Applicability of the method to several Enterobacteriaceae (different Escherichia coli strains, Salmonella typhimurium, Shigella flexneri 2a) could be shown. The method was validated as a resilient process analytical technology (PAT) tool for the assessment of E-lysis and for particle counting during 20-l batch processes for the production of Escherichia coli Nissle 1917 BGs. PMID- 26521249 TI - Integration of bacterial expansin-like proteins into cellulosome promotes the cellulose degradation. AB - Cellulosomes are multi-enzyme complexes assembled by cellulases and hemicellulases through dockerin-cohesin interactions, which are the most efficient system for the degradation of lignocellulosic resources in nature. Recent genomic analysis of a cellulosome-producing anaerobe Clostridium clariflavum DSM 19732 revealed that two expansin-like proteins, Clocl_1298 and Clocl_1862, contain a dockerin module, which suggests that they are components of the cellulosome. Bacterial expansin-like proteins do not have hydrolytic activities, but can facilitate the degradation of cellulosic biomass via synergistic effects with cellulases. In this study, the synergistic effect of the expansin-like proteins with both native and designer cellulosomes was investigated. The free expansin-like proteins, including expansin-like domains of Clocl_1298 and Clocl_1862, as well as a well-studied bacterial expansin-like protein BsEXLX1 from Bacillus subtilis, promoted the cellulose degradation by native cellulosomes, indicating the cellulosomal expansin-like proteins have the synergistic function. When they were integrated into a trivalent designer cellulosome, the synergistic effect was further amplified. The sequence and structure analyses indicated that these cellulosomal expansin-like proteins share the conserved functional mechanism with other bacterial expansin-like proteins. These results indicated that non-catalytic expansin-like proteins in the cellulosome can enhance the activity of the cellulosome in lignocellulose degradation. The involvement of functional expansin-like proteins in the cellulosome also implies new physiological functions of bacterial expansin-like proteins and cellulosomes. PMID- 26521250 TI - Assessment of bacterial and fungal (hemi)cellulose-degrading enzymes in saccharification of ammonia fibre expansion-pretreated Arundo donax. AB - This study reports enzymatic hydrolysis of the biomass of the giant reed (Arundo donax L.) after ammonia fibre expansion (AFEX) pretreatment. In particular, the capacity of the arabinofuranosidase from the fungus Pleurotus ostreatus recombinantly expressed in Pichia pastoris rPoAbf, its evolved mutant rPoAbf F435Y/Y446F and the endo-cellulase from Streptomyces sp. G12 CelStrep recombinantly expressed in Escherichia coli to enhance the hydrolysis of AFEX treated A. donax was investigated, using the corn stover as reference feedstock. The investigated enzymes were assayed using a mixture of purified cellulases (CBHI, CBHII, EGI and betaG), endoxylanases (LX3, LX4) and accessory hemicellulases (LarbF and LbetaX) as reference enzyme mixture and substituting EGI with rCelStrep and LarbF with rPoAbf or rPoAbf F435Y/Y446F. The use of rPoAbf F435Y/Y446F in the substitution of LarbF led to improvements in sugar conversion, giving a glucan, xylan and arabinan conversion after 72 h of around 62, 63 and 80 %, respectively, similar or higher than those (44, 66 and 55 %) achieved by 72 h hydrolysis with commercial enzymes Novozymes Cellic(r), Ctec3 and Htec3. The enzymes rPoAbf, rPoAbf F435Y/Y446F and rCelStrep were also investigated for their effect on hydrolysis of AFEX-pretreated A. donax by addition to commercial enzyme mixture Novozymes Cellic(r), Ctec3 and Htec3, and it was shown that the addition of rPoAbf and its evolved mutant rPoAbf F435Y/Y446F enhanced both xylan and arabinan conversions, which achieved 80 % after 6 days of saccharification with rPoAbf F435Y/Y446F. PMID- 26521251 TI - Identification and engineering of regulation-related genes toward improved kasugamycin production. AB - Kasugamycin, produced by Streptomyces kasugaensis and Streptomyces microaureus, is an important amino-glycoside family antibiotic and widely used for veterinary and agricultural applications. In the left flanking region of the previously reported kasugamycin gene cluster, four additional genes (two-component system kasW and kasX, MerR-family kasV, and isoprenylcysteine carboxyl methyltransferase kasS) were identified both in the low-yielding S. kasugaensis BCRC12349 and high yielding S. microaureus XM301. Deletion of regulatory gene kasT abolished kasugamycin production, and its overexpression in BCRC12349 resulted in an increased titer by 186 %. Deletion of kasW, kasX, kasV, and kasS improved kasugamycin production by 12, 19, 194, and 22 %, respectively. qRT-PCR analysis demonstrated that the transcription of kas genes was significantly increased in all the four mutants. Similar gene inactivation was performed in the high yielding strain S. microaureus XM301. As expected, the deletion of kasW/X resulted in a 58 % increase of the yield from 6 to 9.5 g/L. However, the deletion of kasV and over-expression of kasT had no obvious effect, and the disruption of kasS surprisingly decreased kasugamycin production. In addition, trans complementation of the kasS mutant with a TTA codon-mutated kasS increased the kasugamycin yield by 20 %. A much higher transcription of kas genes was detected in the high-yielding XM301 than in the low-yielding BCRC12349, which may partially account for the discrepancy of gene inactivation effects between them. Our work not only generated engineered strains with improved kasugamycin yield, but also pointed out that different strategies on manipulating regulatory-related genes should be considered for low-yielding or high-yielding strains. PMID- 26521252 TI - Erythropoietin Protects Rat Brain Injury from Carbon Monoxide Poisoning by Inhibiting Toll-Like Receptor 4/NF-kappa B-Dependent Inflammatory Responses. AB - Inflammatory responses play critical roles in carbon monoxide (CO) poisoning induced cerebral injury. The present study investigated whether erythropoietin (EPO) modulates the toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF kappaB) inflammatory signaling pathways in brain injury after acute CO poisoning. EPO (2500 and 5000 U/kg) was injected subcutaneously twice a day after acute CO poisoning for 2 days. At 48 h after treatment, the expression levels of TLR4 and NF-kappaB as well as the levels of inflammatory cytokines in the hippocampal tissues were measured. Our results showed that CO poisoning induced a significant upregulation of TLR4, NF-kappaB, and inflammatory cytokines in the injured rat hippocampal tissues. Treatment with EPO remarkably suppressed the gene and protein expression levels of TLR4 and NF-kappaB, as well as the concentrations of TNF-alpha, IL-1beta, and IL-6 in the hippocampal tissues. EPO treatment ameliorated CO poisoning-induced histological edema and neuronal necrosis. These results suggested that EPO protected against CO poisoning-induced brain damage by inhibiting the TLR4-NF-kappaB inflammatory signaling pathway. PMID- 26521253 TI - Gastrointestinal symptoms negatively impact on sleep quality among obese individuals: a population-based study. AB - BACKGROUND: Reduced sleep quality has been linked to obesity; however, no studies have assessed the impact of gastrointestinal (GI) symptoms on sleep quality among obese individuals. This study aims to determine the role of gastrointestinal symptoms on sleep among obese individuals in a community-based sample. METHODS: A validated questionnaire was sent to 5000 randomly selected subjects in Western Sydney, Australia. Assessed were five GI symptoms that might wake individuals from sleep (abdominal pain, diarrhea, chest pain, acid regurgitation, and heartburn). Sleep quality was measured using the validated Pittsburgh Sleep Quality Index (PSQI). Additional measures included socioeconomic status (SES) and body mass index (BMI). RESULTS: The response rate was 60 %. There were 647 (25.13 %) obese individuals. Prevalence estimates for general quality of sleep were reported as very good (18.51 %), fairly good (53.19 %), fairly bad (20.68 %), and very bad (7.62 %). Obese individuals reported less hours of actual sleep than nonobese individuals (OR = 0.87; 95 % CI 0.81-0.94). Quality of sleep was worse for obese compared to nonobese individuals (OR = 1.25; 95 % CI 1.12-1.40). Univariate analysis found that all GI symptoms were more likely to wake obese people from their sleep; however, only two GI symptoms (chest pain: OR = 1.60; 95 % CI 1.25-2.04) and (acid regurgitation: OR = 1.27; 95 % CI 1.05-1.53) were independent predictors of sleep disturbance. CONCLUSIONS: Gastrointestinal symptoms did not predict waking in nonobese individuals. Chest pain and acid regurgitation are major GI symptoms associated with waking obese individuals from sleep. Overall, obese individuals have a worse quality of sleep compared to nonobese individuals. PMID- 26521254 TI - Encapsulating peritoneal sclerosis in an Italian center: thirty year experience. AB - BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare but life threatening complication of peritoneal dialysis (PD). Its incidence and prevalence are still not clearly defined. No data exist on the prevalence of EPS in Italy. OBJECTIVES: To evaluate the incidence and prevalence of EPS, and identify potential factors useful for prevention or early diagnosis of EPS. METHODS: A retrospective study in patients starting PD between 1979 and 2013 in one Italian center. Data on demographics, occurrence of EPS, time on PD, peritoneal equilibration test, and therapy for EPS were gathered. RESULTS: EPS occurred in 26/920 patients with a prevalence of 2.8 % and incidence of 1/105 patient-years. The prevalence increased with the time spent on PD: 0.4 % for PD duration <2 years, 3 % (2-4 years), 4 % (4-6 years), 6 % (6-8 years), 8 % (8-10 years), 18 % (10-12 years), 75 % (12-14 years), 67 % (>14 years). EPS prevalence was not higher in PD patients transplanted: 5/172 (2.9 %); only two of them (1.2 %) were diagnosed while with a functioning graft. In only one patient (0.6 %) was the diagnosis made during hemodialysis; the other 23 were diagnosed while still on PD. Mortality due to EPS was 38.5 %, and was associated with PD duration. Therapy with steroids reduced mortality [hazard ratio 0.047 (95 % CI: 0.008 0.273); p < 0.001]. CONCLUSIONS: In our experience the prevalence of EPS is low, but increases progressively with the duration of PD. The transfer to hemodialysis or transplantation does not appear to be a key factor for EPS. Therapy with steroids significantly improves the outcome. PMID- 26521255 TI - Low-Dose Endothelial Monocyte-Activating Polypeptide-II Increases Blood-Tumor Barrier Permeability by Activating the RhoA/ROCK/PI3K Signaling Pathway. AB - Previous studies have demonstrated that low-dose endothelial monocyte-activating polypeptide-II (EMAP-II) can increase blood-tumor barrier (BTB) permeability via both paracellular and transcellular pathways. In addition, we revealed that the RhoA/Rho kinase (ROCK) signaling pathway is involved in EMAP-II-induced BTB opening. This study further investigated the exact mechanisms by which the RhoA/ROCK signaling pathway affects EMAP-II-induced BTB hyperpermeability. In an in vitro BTB model, low-dose EMAP-II significantly activated phosphatidylinositol 3-kinase (PI3K) in rat brain microvascular endothelial cells (RBMECs) at 0.75 h. Pretreatment with RhoA inhibitor C3 exoenzyme or ROCK inhibitor Y-27632 completely blocked EMAP-II-induced activation of PI3K. PKC-alpha/beta inhibitor GO6976 pretreatment caused no change in EMAP-II-induced activation of PI3K. Besides, pretreatment with LY294002, a specific inhibitor of PI3K, did not affect EMAP-II-induced activation of PKC-alpha/beta. Furthermore, LY294002 pretreatment significantly diminished EMAP-II-induced changes in BTB permeability, phosphorylation of myosin light chain and cofilin, expression and distribution of tight junction-associated protein ZO-1, and actin cytoskeleton arrangement in RBMECs. In summary, this study demonstrates that low-dose EMAP-II can increase BTB permeability by activating the RhoA/ROCK/PI3K signaling pathway. PMID- 26521256 TI - Unique intravascular tumor microenvironment predicting recurrence of lung squamous cell carcinoma. AB - PURPOSE: Histological vascular invasion (VI) by tumors is a risk factor for recurrence after surgical resection. However, VI features vary histologically. The aim of this study was to identify characteristic VI features that are associated with recurrence in squamous cell carcinoma (SCC) of the lung. METHODS: We enrolled 149 patients with pathological stage I primary lung SCC in this study and examined whether the presence, frequency, and size of VI were associated with recurrence. We also evaluated immunophenotypes of carcinoma cells and stromal cells within VI areas. RESULTS: Of the 149 patients, 58 had tumors with VI. The presence of VI was significantly correlated with shorter recurrence-free survival (RFS) (P = 0.018). Although VI frequency was not associated with RFS, larger VI size (>425 um) was significantly correlated with shorter RFS (P = 0.003). Carcinoma cells within larger VI areas expressed significantly higher levels of podoplanin, cancer stem cell marker (P = 0.039); higher numbers of CD34(+) microvessels (P = 0.009), CD204(+) macrophages (P = 0.026), and alpha-SMA(+) myofibroblasts (P = 0.056) were present within larger VI areas than within smaller VI ones. CONCLUSIONS: Our results indicate that larger VI areas are a predictor for recurrence in lung SCC; also, within the larger blood vessel, cancer stem cells and abundant stromal cells can create a more favorable microenvironment for tumor metastasis. PMID- 26521257 TI - Treatment results of alternating chemoradiotherapy followed by proton beam therapy boost combined with intra-arterial infusion chemotherapy for stage III IVB tongue cancer. AB - PURPOSE: Proton beam therapy (PBT), compared with conventional radiotherapy, can deliver high-dose radiation to a tumor, while minimizing doses delivered to surrounding normal tissues. The better dose distribution of PBT may contribute to the improvement in local control rate and reduction in late adverse events. We evaluated therapeutic results and toxicities of PBT combined with selective intra arterial infusion chemotherapy (PBT-IACT) in patients with stage III-IVB squamous cell carcinoma of the tongue. MATERIALS AND METHODS: After 2 systemic chemotherapy courses and whole-neck irradiation (36 Gy in 20 fractions), we administered concurrent chemoradiotherapy comprising PBT for the primary tumor [28.6-33 Gy(RBE) in 13-15 fractions] and for the metastatic neck lymph node [33 39.6 Gy(RBE) in 15-18 fractions] with weekly retrograde intra-arterial chemotherapy by continuous infusion of cisplatin with sodium thiosulfate. RESULTS: Between February 2009 and September 2012, 33 patients were enrolled. The median follow-up duration was 43 months. The 3-year overall survival, progression free survival, local control rate, and regional control rate for the neck were 87.0, 74.1, 86.6, and 83.9 %, respectively. Major acute toxicities >grade 3 included mucositis in 26 cases (79 %), neutropenia in 17 cases (51 %), and dermatitis in 11 cases (33 %). Late grade 2 osteoradionecrosis was observed in 1 case (3 %). CONCLUSIONS: PBT-IACT for stage III-IVB tongue cancer has an acceptable toxicity profile and showed good treatment results. This protocol should be considered as a treatment option for locally advanced tongue cancer. PMID- 26521258 TI - A possible influence of age on absorption and elimination of adalimumab in focal segmental glomerulosclerosis (FSGS). PMID- 26521259 TI - Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients. AB - PURPOSE: The once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure. METHODS: Stable liver transplant patients receiving once daily tacrolimus (N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available (N = 49), and demographic factors, CYP3A4*22 and CYP3A5*3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients. RESULTS: Pharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had an average 1.7 fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed an average 1.3 fold higher clearance compared with non-carriers. CYP3A4*22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration. CONCLUSIONS: Both donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4*22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure. PMID- 26521261 TI - Diagnosis of acute cholecystitis: why do patients get multiple studies? AB - The aim of this study is to establish factors affecting total number of imaging studies performed for acute cholecystitis (AC) prior to surgery. The study included subjects with cholecystectomy and pathologic diagnosis of AC 1/1/05 1/1/14 and imaging studies (computed tomography (CT), ultrasound (US), and/or cholescintigraphy) within 7 days of surgery. The subjects were separated into groups based on modality of the first study. For each subject, report of the first study was reviewed for report's confidence in diagnosis of AC (scored 1-5 on Likert scale: 5 = definitely AC, 1 = definitely no AC), recommendation of additional study, clinical history concerning for AC (history of right upper quadrant pain, cholelithiasis, and/or "rule out AC"). There were 219, 339, and 38 subjects in CT, US, and cholescintigraphy groups, respectively, with mean confidence scores of 3.7 (+/- 1.2), 3.7 (+/- 1.1), and 4.7 (+/- 0.9), respectively (p < 0.001). Prior to surgery, only one study was performed in 21.9 % (48/219) of CT group, 70.2 % (238/339) of US group, and 71.1 % (27/38) of cholescintigraphy group (p < 0.0001). Compared to the US group, the odds of undergoing additional study were 11.8 times higher (p < 0.001) in CT group and 1.7 times higher (p = 0.229) in cholescintigraphy group, adjusting for age, sex, time interval between first study and the surgery, confidence score, recommendation of follow-up study, and clinical history concerning for AC. Patients with AC and CT as the first study are more likely to undergo additional imaging studies prior to surgery as compared to US or cholescintigraphy. PMID- 26521260 TI - Prenatal Depressive Symptoms and Toddler Behavior Problems: The Role of Maternal Sensitivity and Child Sex. AB - Increasing evidence suggests that maternal depression during pregnancy is associated with child behavioral outcomes even after accounting for later maternal depression. The purpose of this study was to examine various mechanisms, including maternal sensitivity, neonatal problems, and concurrent maternal depression, that might explain the association between prenatal maternal depressive symptoms and toddler behavior problems. Young, low income, African American mothers (n = 196) were interviewed during pregnancy and at 24-months postpartum, medical records were collected at the birth, and mother-child interactions were video-recorded at 24 months. Path analyses revealed that the association between prenatal depression and toddler behavior problems was mediated by maternal sensitivity and maternal depressive symptoms at 24 months. No evidence was found for a mediating effect of neonatal problems. Path models examining sex differences suggested that different mediating factors may be important for boys and girls, with boys being particularly susceptible to the effects of maternal sensitivity. PMID- 26521263 TI - Very late scaffold thrombosis of everolimus-eluting bioresorbable scaffold following implantation in STEMI after discontinuation of dual antiplatelet therapy. AB - A 42-year-old male with a history of smoking and dyslipidemia was admitted due to ST-elevation myocardial infarction. Coronary angiography showed severe stenosis in proximal right coronary artery (RCA) and total occlusion in mid RCA. Absorb everolimus-eluting bioresorbable scaffolds were deployed in mid and proximal RCA. The patient was discharged with dual anti-platelet therapy. Patient was admitted 15-months later due to acute coronary syndrome with scaffold thrombosis. Both aspirin and clopidogrel had been discontinued 1 month prior to the second event because of general malaise. Therefore, either aspirin or clopidogrel should have been continued even after 1 year following stent implantation. PMID- 26521264 TI - Postoperative acute cerebellar swelling after pineal surgery: pathogenesis and treatment. PMID- 26521265 TI - Avoidance of postoperative acute cerebellar swelling after pineal tumor surgery. PMID- 26521266 TI - Prior Image Constrained Compressed Sensing Metal Artifact Reduction (PICCS-MAR): 2D and 3D Image Quality Improvement with Hip Prostheses at CT Colonography. AB - PURPOSE: To assess the effect of the prior-image-constrained-compressed-sensing based metal-artefact-reduction (PICCS-MAR) algorithm on streak artefact reduction and 2D and 3D-image quality improvement in patients with total hip arthroplasty (THA) undergoing CT colonography (CTC). MATERIALS AND METHODS: PICCS-MAR was applied to filtered-back-projection (FBP)-reconstructed DICOM CTC-images in 52 patients with THA (unilateral, n = 30; bilateral, n = 22). For FBP and PICCS-MAR series, ROI-measurements of CT-numbers were obtained at predefined levels for fat, muscle, air, and the most severe artefact. Two radiologists independently reviewed 2D and 3D CTC-images and graded artefacts and image quality using a five point-scale (1 = severe streak/no-diagnostic confidence, 5 = no streak/excellent image-quality, high-confidence). Results were compared using paired and unpaired t-tests and Wilcoxon signed-rank and Mann-Whitney-tests. RESULTS: Streak artefacts and image quality scores for FBP versus PICCS-MAR 2D-images (median: 1 vs. 3 and 2 vs. 3, respectively) and 3D images (median: 2 vs. 4 and 3 vs. 4, respectively) showed significant improvement after PICCS-MAR (all P < 0.001). PICCS-MAR significantly improved the accuracy of mean CT numbers for fat, muscle and the area with the most severe artefact (all P < 0.001). CONCLUSIONS: PICCS MAR substantially reduces streak artefacts related to THA on DICOM images, thereby enhancing visualization of anatomy on 2D and 3D CTC images and increasing diagnostic confidence. KEY POINTS: * PICCS-MAR significantly reduces streak artefacts associated with total hip arthroplasty on 2D and 3D CTC. * PICCS-MAR significantly improves 2D and 3D CTC image quality and diagnostic confidence. * PICCS-MAR can be applied retrospectively to DICOM images from single-kVp CT. PMID- 26521267 TI - Chemical composition and antimicrobial activity of honeybee (Apis mellifera ligustica) propolis from subtropical eastern Australia. AB - Propolis is a material manufactured by bees and contains beeswax, bee salivary secretions and plant resins. Propolis preparations have been used for millennia by humans in food, cosmetics and medicines due to its antibacterial effects. Within the hive, propolis plays an important role in bees' health, with much of its bioactivity largely dependent on the plant resins the bees select for its production. Few chemical studies are available on the chemistry of propolis produced by Australian honeybees (Apis mellifera, Apidae). This study aimed to determine the chemical composition as well as in vitro antimicrobial effects of propolis harvested from honeybees in subtropical eastern Australia. Honeybee propolis was produced using plastic frames and multiple beehives in two subtropical sites in eastern Australia. Methanolic extracts of propolis were analysed by liquid chromatography with ultraviolet detection and high-resolution mass spectrometry (ultra-high-pressure liquid chromatography (UHPLC)-UV-high resolution tandem mass spectrometry (HR-MS/MS)) and by gas chromatography mass spectrometry (GC-MS). The resulting chemical data were dereplicated for compound characterisation. The two crude extracts in abs. ethanol were tested in vitro by the agar diffusion and broth dilution methods, using a phenol standard solution as the positive control and abs. ethanol as the negative control. Chemical constituents were identified to be pentacyclic triterpenoids and C-prenylated flavonoids, including Abyssinoflavanone VII, Propolin C and Nymphaeol C. The two propolis crude extracts showed bactericidal effects at the minimal inhibitory concentrations of 0.37-2.04 mg mL(-1) against Staphylococcus aureus ATCC 25923. However, the extracts were inactive against Klebsiella pneumoniae ATCC 13883 and Candida albicans ATCC 10231. The antistaphylococcal potential of propolis was discussed, also in relation to honeybees' health, as it warrants further investigations on the social and individual immunities of Australian honeybees. PMID- 26521268 TI - Successful Retreatment of Chronic HCV Genotype-1 Infection With Ledipasvir and Sofosbuvir After Initial Short Course Therapy With Direct-Acting Antiviral Regimens. AB - BACKGROUND: The optimal retreatment strategy for chronic hepatitis C virus (HCV) patients who fail directly-acting antiviral agent (DAA)-based treatment is unknown. In this study, we assessed the efficacy and safety of ledipasvir (LDV) and sofosbuvir (SOF) for 12 weeks in HCV genotype-1 (GT-1) patients who failed LDV/SOF-containing therapy. METHODS: In this single-center, open-label, phase 2a trial, 34 participants with HCV (GT-1) and early-stage liver fibrosis who previously failed 4-6 weeks of LDV/SOF with GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks. The primary endpoint was HCV viral load below the lower limit of quantification 12 weeks after completion of therapy (sustained virological response [SVR]12). Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial relapse, prior to retreatment, and at second relapse with Illumina next-generation sequencing technology. RESULTS: Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 * 10(6) IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85%) had NS5A-resistant variants. The SVR12 rate was 91% (31/34; intention to treat, ITT) after retreatment. One patient relapsed. CONCLUSIONS: In patients who previously failed short-course combination DAA therapy, we demonstrate a high SVR rate in response to 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants. CLINICAL TRIALS REGISTRATION: NCT01805882. PMID- 26521270 TI - The quest for the grail: multidimensional efforts for understanding and targeting severe asthma. PMID- 26521269 TI - Combined Quitline Counseling and Text Messaging for Smoking Cessation: A Quasi Experimental Evaluation. AB - INTRODUCTION: This study seeks to determine whether comprehensive quitline services combined with text messaging improve smoking cessation rates beyond those achieved by offering comprehensive quitline services alone. METHODS: The study sample consisted of callers to the Alere Wellbeing, Inc, commercial quitline in 2012. A quasi-experimental design was implemented using propensity score matching to create the intervention and control groups. The intervention group consisted of those who were offered and accepted a text message intervention in addition to usual quitline services, while the control group consisted of those who were not offered the text message intervention. Analyses utilized baseline data collected at intake, program use data (eg, call history and text message use), and reports of smoking behaviors and program satisfaction collected 6 months after intake. RESULTS: Similar rates of 7-day abstinence were reported regardless of whether participants received combined multi-call quitline services plus text messaging (25.3%) or multi-call quitline services in isolation (25.5%), though those who received combined services reported higher treatment satisfaction (P < .05). Among those who received combined services, the number of text messages sent to the text message program predicted 7-day abstinence such that those who sent more text messages were less likely to report 7-day abstinence. CONCLUSIONS: Text messaging may not confer additional benefits over and above those received through multi-modal, multi-call quitline programs. Future research should investigate whether text messaging programs improve quit rates when combined with less intensive services such as single-call phone counseling. IMPLICATIONS: While the impact of quitline and text messaging services for smoking cessation have been examined in isolation, no study has explored the impact of combined services on smoking outcomes. This study examines the role of text messaging in combination with comprehensive quitline services including multi-call phone counseling, access to an interactive website and nicotine replacement therapy. PMID- 26521271 TI - Weaning from inhaled corticosteroids in COPD: the evidence. PMID- 26521272 TI - Knowing when to stop: inhaled corticosteroids and COPD. PMID- 26521273 TI - Targeted therapy for lung cancer. PMID- 26521274 TI - Lung allograft loss: naming helps seeing... and vice versa! PMID- 26521275 TI - Gaining insights into pulmonary hypertension in respiratory diseases. PMID- 26521276 TI - Completely scoobied: the confusing world of temperature and pollution effects on sleep apnoea. PMID- 26521277 TI - Eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome): where are we now? PMID- 26521278 TI - Should the treatment of advanced lepidic adenocarcinoma be adapted to the pathological subtype? PMID- 26521279 TI - Asthma education: an essential component in asthma management. PMID- 26521280 TI - Pneumococcal conjugate vaccine for adults: "It's tough to make predictions, ...". PMID- 26521281 TI - A message from the ERS President and the ERS Secretary for EU Affairs. PMID- 26521282 TI - Lung cancer screening white paper: a slippery step forward? PMID- 26521283 TI - Lung cancer screening white paper: a slippery step forward? PMID- 26521284 TI - COPD (confusion over proper diagnosis) in the zone of maximum uncertainty. PMID- 26521285 TI - COPD (confusion over proper diagnosis) in the zone of maximum uncertainty. PMID- 26521286 TI - We must join forces in the battle against COPD. PMID- 26521287 TI - We must join forces in the battle against COPD. PMID- 26521288 TI - The Rotterdam study: why fall in COPD? PMID- 26521289 TI - The Rotterdam study: why fall in COPD? PMID- 26521290 TI - "Echocardiographic abnormalities in patients with COPD at their first hospital admission." Xavier Freixa, Karina Portillo, Carles Pare, Judith Garcia-Aymerich, Federico P. Gomez, Marta Benet, Josep Roca, Eva Farrero, Jaume Ferrer, Carlos Fernandez-Palomeque, Josep M. Anto and Joan Albert Barbera, on behalf of the PAC COPD Study Investigators. Eur Respir J 2013; 41: 784-791. PMID- 26521292 TI - Non-documented but induced supraventricular tachycardia: a new challenge or a new light? PMID- 26521293 TI - Non-documented but induced supraventricular tachycardia: a new challenge or a new light?--author's reply. PMID- 26521294 TI - TIGIT-positive circulating follicular helper T cells and sickle cell alloimmunization. PMID- 26521295 TI - The origin of relapse in pediatric T-cell acute lymphoblastic leukemia. PMID- 26521297 TI - Complement inhibitors to treat IgM-mediated autoimmune hemolysis. AB - Complement activation in autoimmune hemolytic anemia may exacerbate extravascular hemolysis and may occasionally result in intravascular hemolysis. IgM autoantibodies as characteristically found in cold autoantibody autoimmune hemolytic anemia, in cold agglutinin disease but also in a considerable percentage of patients with warm autoantibodies are very likely to activate complement in vivo. Therapy of IgM-mediated autoimmune hemolytic anemia mainly aims to decrease autoantibody production. However, most of these treatments require time to become effective and will not stop immediate ongoing complement mediated hemolysis nor prevent hemolysis of transfused red blood cells. Therefore pharmacological inhibition of the complement system might be a suitable approach to halt or at least attenuate ongoing hemolysis and improve the recovery of red blood cell transfusion in autoimmune hemolytic anemia. In recent years, several complement inhibitors have become available in the clinic, some of them with proven efficacy in autoimmune hemolytic anemia. In the present review, we give a short introduction on the pathogenesis of autoimmune hemolytic anemia, followed by an overview on the complement system with a special focus on its regulation. Finally, we will discuss complement inhibitors with regard to their potential efficacy to halt or attenuate hemolysis in complement-mediated autoimmune hemolytic anemia. PMID- 26521296 TI - A hostel for the hostile: the bone marrow niche in hematologic neoplasms. AB - Our understanding of the biology of the normal hematopoietic stem cell niche has increased steadily due to improved murine models and sophisticated imaging tools. Less well understood, but of growing interest, is the interaction between cells in the bone marrow during the initiation, maintenance and treatment of hematologic neoplasms. This review summarizes the emerging concepts of the normal and leukemic hematopoietic bone marrow niche. Furthermore, it reviews current models of how the microenvironment of the bone marrow may contribute to or be modified by leukemogenesis. Finally, it provides the rationale for a "two pronged" approach, directly targeting cancer cells themselves while also targeting the bone microenvironment to make it inhospitable to malignant cells and, ultimately, eradicating cancer stem-like cells. PMID- 26521298 TI - Comment on "Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial". PMID- 26521299 TI - Response to comment by P. Vassilakopoulos and colleagues. PMID- 26521300 TI - IL-28B down-regulates regulatory T cells but does not improve the protective immunity following tuberculosis subunit vaccine immunization. AB - Regulatory T cells (Tregs), which could be down-regulated by IL-28B, were reported to suppress T-cell-mediated immunity. The aim of this study was to investigate the role of IL-28B on the immune responses and protective efficacy of a tuberculosis (TB) subunit vaccine. First, a recombinant adenoviral vector expressing mouse IL-28B (rAd-mIL-28B) was constructed; then C57BL/6 mice were immunized with subunit vaccine ESAT6-Ag85B-Mpt64(190-198)-Mtb8.4-HspX (EAMMH) and rAd-mIL-28B together thrice or primed with Mycobacterium bovis bacillus Calmette Gue'rin (BCG) and boosted by EAMMH and rAd-mIL-28B twice. At last the immune responses were evaluated, and the mice primed with BCG and boosted by subunit vaccines were challenged with virulent Mycobacterium tuberculosis H37Rv to evaluate the protective efficacy. The results showed that rAd-mIL-28B treatment significantly down-regulated the frequency of Tregs at 4 weeks after the last immunization but did not increase the Th1-type immune responses. Moreover, in the regimen of BCG priming and EAMMH boosting, rAd-mIL-28B treatment did not increase the antigen-specific cellular and humoral immune responses, and consequently did not reduce the bacteria load following H37Rv challenge. Instead, it induced more serious pathology reaction. In conclusion, IL-28B down-regulates Tregs following EAMMH vaccination but does not improve the protective immune responses. PMID- 26521301 TI - Multilayered temporal modeling for the clinical domain. AB - OBJECTIVE: To develop an open-source temporal relation discovery system for the clinical domain. The system is capable of automatically inferring temporal relations between events and time expressions using a multilayered modeling strategy. It can operate at different levels of granularity--from rough temporality expressed as event relations to the document creation time (DCT) to temporal containment to fine-grained classic Allen-style relations. MATERIALS AND METHODS: We evaluated our systems on 2 clinical corpora. One is a subset of the Temporal Histories of Your Medical Events (THYME) corpus, which was used in SemEval 2015 Task 6: Clinical TempEval. The other is the 2012 Informatics for Integrating Biology and the Bedside (i2b2) challenge corpus. We designed multiple supervised machine learning models to compute the DCT relation and within sentence temporal relations. For the i2b2 data, we also developed models and rule based methods to recognize cross-sentence temporal relations. We used the official evaluation scripts of both challenges to make our results comparable with results of other participating systems. In addition, we conducted a feature ablation study to find out the contribution of various features to the system's performance. RESULTS: Our system achieved state-of-the-art performance on the Clinical TempEval corpus and was on par with the best systems on the i2b2 2012 corpus. Particularly, on the Clinical TempEval corpus, our system established a new F1 score benchmark, statistically significant as compared to the baseline and the best participating system. CONCLUSION: Presented here is the first open source clinical temporal relation discovery system. It was built using a multilayered temporal modeling strategy and achieved top performance in 2 major shared tasks. PMID- 26521303 TI - Maternal and neonatal tetanus elimination: validation survey in 4 States and 2 union territories in India, May 2015. PMID- 26521302 TI - Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine. AB - The antitumor agent lonidamine (LND; 1-(2,4-dichlorobenzyl)-1H-indazole-3 carboxylic acid) is known to interfere with energy-yielding processes in cancer cells. However, the effect of LND on central energy metabolism has never been fully characterized. In this study, we report that a significant amount of succinate is accumulated in LND-treated cells. LND inhibits the formation of fumarate and malate and suppresses succinate-induced respiration of isolated mitochondria. Utilizing biochemical assays, we determined that LND inhibits the succinate-ubiquinone reductase activity of respiratory complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through complex II, which reduced the viability of the DB-1 melanoma cell line. The ability of LND to promote cell death was potentiated by its suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. Using stable isotope tracers in combination with isotopologue analysis, we showed that LND increased glutaminolysis but decreased reductive carboxylation of glutamine-derived alpha-ketoglutarate. Our findings on the previously uncharacterized effects of LND may provide potential combinational therapeutic approaches for targeting cancer metabolism. PMID- 26521305 TI - [Not Available]. PMID- 26521304 TI - [Let's banish pain in pediatrics procedures]. PMID- 26521306 TI - [Not Available]. PMID- 26521307 TI - [In Process Citation]. PMID- 26521308 TI - [Certain theoretical-methodological problems of forensic medical expertise of the blast injury]. AB - This article is devoted to the analysis of the theoretical problems facing forensic medical expertise of the blast injury. The original notions of the blast, injurious blast factors, and their traumatic consequences are proposed together with the classification of the blasts and their injurious factors. The principal lines of the further research on the forensic medical aspects of the blast injury are formulated. PMID- 26521309 TI - [The comprehensive approach to ensure the quality of forensic medical examination of a cadaver]. AB - The objective of the present work was to estimate the effectiveness of the comprehensive monitoring system designed to enhance the quality of forensic medical expertise for determining the cause of death in the hanging cases. It was shown that the practical application of the algorithmization and automated quality control system improves the effectiveness of forensic medical examination of the cadavers in the hanging cases. The system performs the control, directing, and teaching functions. Moreover, it allows to estimate the completeness of the examination of the cadaver. PMID- 26521310 TI - [The possibilities for the medical assessment of the injuries inflicted by the darts fired from the pneumatic rifles]. AB - This article reports the results of analysis of the data borrowed from the special literature. They demonstrate the absence of objective forensic medical evidence needed to diagnose injuries to the human body and clothes inflicted by the darts fired from the pneumatic rifles. Meanwhile, the use of the darts differing in the design parameters has the significant influence on the morphological features of the resulting injuries. The knowledge of the dart characteristics creates the prerequisites for the differentiation between the injuries caused by these missile weapons and other metallic objects. PMID- 26521311 TI - [Forensic medical expertise of sudden cardiac death from alcoholic cardiomyopathy in the subjects having a low ethanol concentration in the blood and urine]. AB - The objective of the present study was to evaluate the cases of sudden cardiac death from alcoholic cardiomyopathy of the subjects having a low ethanol concentration in the blood and urine; the second objective was the statistical analysis of the data thus obtained. It was shown that sudden cardiac death from alcoholic cardiomyopathy occurs in the men more frequently than in the women despite rather low ethanol levels in the blood and urine of both genders or even in the cases of complete absence of ethanol in these fluids. It is concluded that ethanol concentration in the blood and urine of the subjects who died from the alcohol-induced heart injury depends on their age and sex. PMID- 26521312 TI - [The main principles underlying the pathologo-anatomical diagnostics and coding of the causes of death from tuberculosis]. AB - The objective of the present study was to universalize the approaches to pathologoanatomical diagnostics and coding of the causes of death from tuberculosis and other diseases. We undertook the analysis of 409 medical death certificates of the subjects who died from tuberculosis in Moscow during 2013. It revealed the main errors of pathologoanatomical diagnostics and formulation of the respective medical documentation. The recommendations are proposed for pathologoanatomical diagnostics of tuberculosis, completion of medical death certificates, and formulation of the conclusions of the causes of death. It was shown that tuberculosis should be regarded either as the main independent disease or one of the components of the combined pathology in the structure of pathologoanatomical diagnosis. The diagnosis must reflect the form of the disease, its localization, the extension of the pathological process, phases of the clinical course, and the results of bacteriological studies. Only one form of tuberculosis should be indicated with the emphasis on its chronic or destructive character. The fatal complications of a single form of tuberculosis may differ. The categorization of a "minor" form as the "major" disease is the serious error even if it is confirmed by the results of the bacteriological study. Such nosological forms as acute coronary heart disease, urgent surgical pathology, etc. in the combined "major" disease must be indicated in the first place, even in the presence of progressive tuberculosis. It is concluded that the pathologoanatomical diagnosis structure must include the comparison of the clinical and morphological data, correct assessment of the activity and the extension of the tuberculosis process, its role in tanatogenesis, and the significance of tuberculosis compared with the concomitant diseases. PMID- 26521313 TI - [The possibilities for the use of unusual personality traits in the examination of the skeletonized corpses with the long prescription of burying]. AB - The objective of the present study was to develop the method for the detection and identification of the traces of the previous diseases on the skeletonized and mummified corpses with the purpose of discovery of the new specific traits making possible the personality identification and substantiation of the search of their localization at the burial places depending on the prescription of burying. It was shown that the identification of the corpses under conditions of their complete skeletonization should be based not only on the general (sex, age, height) but also the specific (congenital malformations, post-traumatic and pathological changes of the bones) traits. The biological structures making possible the personality identification are described, such as the mineralized (petrified) fibrous capsules of the hepatic echinoccocus vesicles, the primary lung tuberculosis complex, and postoperative scar ossificates of the abdominal white tine. Some data on the lifetime of bone remains in the ground and the duration of their possible skeletonization are presented together with the description of the method for the use of this information with a view to the personality identification of the unknown corpse. PMID- 26521314 TI - [The possibilities and limitations of the methods for the personality identification from the voice and sounding speech characteristics]. AB - This paper is designed to report the results of the comparative analysis of the methods currently employed in the government-controlled and private agencies of forensic medical expertise for the personality identification based on the voice and sounding speech recorded on the phonograms. PMID- 26521315 TI - [The reconstruction of the human body length from the wrist size]. AB - The objective of the present study was to develop the regression models for the reconstruction of the human body length from the wrist size taking into consideration the availability of the results of the measurements of the palm fragments or the wrist undergoing muscular contracture. The study included 106 Caucasoid subjects (41 men and 65 women) at the age varying from 18 to 76 years. The following parameters were measured: body length, wrist length, the length of the fingers and phalanges on the back of the hand, palmar length and width, ulnar edge size of the palm. It was shown that the selected longitudinal dimensions of the palm and fingers can be used to estimate the body length as accurately as from the wrist length. The high prognostic value of ulnar edge size of the palm was documented which allows this characteristic to be used in the cases of partial palm destruction or in the wrist with pronounced flexion contracture of the fingers. The most exact equations are those derived from the combination of the results of the measurement of the fingers and the ulnar edge size of the palm. Less accurate equations are based on the palmar dimensions alone and on the total wrist size with the exception of the equation for the wrist length with regard to the subject's sex. The gender information needs to be taken into account if the wrist is preserved to the extent that only the length of the palm and of the IV and V fingers can be measured or if the wrist is sufficiently long and wide (short and wide) and the gender is supposed to be masculine. In contrast, this information should be disregarded if the wrist is long and narrow (short and narrow) and the gender is supposedly feminine. PMID- 26521316 TI - [Metabolism of designer drugs. Piperazine derivatives]. AB - The present review is focused on the specific features of metabolism of designer drugs based on piperazine derivatives. Selected physicochemical properties of the key metabolites of these compounds are described with special reference to their effect on the behavior of these drugs in the human organism.. Recommendations on the analysis of the markers and methods of sample preparation for the identification of the main psychoactive piperazine derivatives are proposed. PMID- 26521317 TI - [G.I. Arkhangel'sky and M.N Shmelev, the editors of the first Russian forensic medical periodical]. PMID- 26521318 TI - [Evgeniy Stepanovich Mishin (on the occasion of his 70th birthday anniversary)]. PMID- 26521319 TI - [Aleksandr Sergeevich Semenov (on the occasion of his 60th birthday anniversary)]. PMID- 26521320 TI - Dentistry's Demise is not Inevitable. PMID- 26521321 TI - The 2015 Legislative Session. Disasters Averted and Big Gains Made. PMID- 26521322 TI - Cautionary Tale. PMID- 26521323 TI - Wisdom. AB - Restorative dentists are often faced with the challenge of weighing best practice treatment plans against the treatment requests of their patients. I believe we all must ask ourselves prior to performing any dental procedure, "How do I know this restoration will be successful, given the multitude of physiological, pathological and anatomical limitations that can affect the prognosis?" There is no restorative dental procedure that is free of risk. The purpose of this article is to examine an interesting and somewhat controversial restorative case that illuminates perception and judgment and the consequences of risk assessment. PMID- 26521324 TI - Workshop Focuses on Improving Children's Dental Health. PMID- 26521325 TI - Rheumatoid Arthritis and Periodontal Disease. An Update. AB - A review of the epidemiological, pathological and immunological relationships between two chronic inflammatory diseases: rheumatoid arthritis (RA) and periodontal disease (PD). RA is a chronic inflammatory disease of the joints, characterized by loss of connective tissue and mineralized structures, the so called "synovial membrane." Periodontitis is the inflammatory destruction of the periodontal attachment and alveolar bone. While the etiology of these two diseases may differ, the underlying pathogenic mechanisms are similar. And it is possible that individuals manifesting both PD and RA may suffer from a unifying underlying systemic deregulation of the inflammatory response. There is an overproduction of a variety of cytokines and MMPs that appears to be common in both diseases. Oral health parameters should be more closely monitored in patients with RA, an autoimmune disease. Data suggest that periodontal therapies combined with routine RA treatments further improve RA status. Interventions to prevent, minimize or treat periodontitis in arthritis patients will definitely promise a better quality of life for these patients. PMID- 26521326 TI - Epithelial and Fibrous Hyperplasia: An Oral Manifestation of Tuberous Sclerosis Complex. A Case Study. AB - The authors present a case study of a 13-year-old female with a past medical history of tuberous sclerosis complex (TSC), an autosomal dominant disorder. It usually presents with a triad of epilepsy, mental deficiency and facial angiofibromas that are often distributed around the nose, cheek and chin, and are frequently shaped like butterfly wings. In addition, oral manifestations include gingival enlargement and developmental enamel pitting on the facial aspect of the anterior permanent dentition in 50% to 100% of patients. The patient's chief complaint was gingival enlargement and gingival bleeding. The histology of the excised gingival tissue revealed epithelial and fibrous hyperplasia, consistent with TSC. PMID- 26521327 TI - Ortho-Perio Interrelationship. Treatment Challenges. AB - It is an undisputed fact that sound periodontal health is a prerequisite for successful orthodontic therapy. Various complex dental problems necessitate a multidisciplinary approach; there cannot be a better example than an ortho-perio interaction. Certain periodontal treatment modalities need to be undertaken before commencing orthodontic treatment. And some periodontal procedures are required after active orthodontic treatment. The aim of this article is to familiarize clinicians in the field of both periodontics and orthodontics with the precautions and clinical techniques necessary to preserve the integrity of already compromised periodontium. PMID- 26521328 TI - Methadone Maintenance Therapy and the Dental Patient. AB - Methadone is a Schedule II drug best known for its use in the treatment of opioid dependence. Dental providers should be aware of the oral and systemic effects of methadone. In patients undergoing methadone maintenance therapy, there is a higher incidence of rampant caries, xerostomia, bruxism and poor oral hygiene. A review of the pharmacology, systemic effects, drug interactions and oral manifestations is presented, as well as possible modifications to treatment and specific considerations in dental therapies. PMID- 26521329 TI - Differential Diagnosis of a Periapical Radiolucent Lesion. A Case Report and Review of the Literature. AB - This article demonstrates a methodological approach to diagnosing a periapical radiolucency that could not be diagnosed using only basic clinical and radiographic findings. The patient was a 59-year-old Hispanic female with a small tender mass on the lower gingiva associated with tooth #25. Radiographic appearance demonstrated a well-defined radiolucent lesion at the apices of the mandibular incisors. The patient had no significant medical history. Cone-beam computed tomography (CBCT) showed bony expansion of the buccal plate. Differential diagnosis included non-endodontic unilocular radiolucent lesions in the anterior mandibular region. Biopsy findings were consistent with periapical cemento-osseous dysplasia (PCOD). In conclusion, clinical appearance of PCOD varies from non-expansile and asymptomatic to being expansile and sometimes symptomatic. In the latter cases, it may be necessary to use additional diagnostic tools to confirm the diagnosis. PMID- 26521330 TI - Plasma Cell Gingivitis: An Occasional Case Report. AB - Plasma cell gingivitis, an infrequently observed oral condition, has been clinically characterized by diffuse gingival enlargement, erythema and sometimes desquamation. These lesions are usually asymptomatic, but invariably the patient will complain of a burning sensation in the gingiva and bleeding from the mouth. The diagnosis requires hematological screening in addition to clinical and histopathological examinations. This case report outlines one such case of plasma cell gingivitis in a 15-year-old female caused by use of an herbal, homemade toothpowder. The case presented here highlights the adverse effects and irrational use of herbal agents in dentifrices. At the same time, it emphasizes the need for comprehensive history taking, careful clinical examination and appropriate diagnostic tests in order to arrive at a definitive diagnosis and treatment plan for gingival conditions that are refractory to conventional therapy and to exclude certain malignancies and oral manifestations of systemic diseases. PMID- 26521331 TI - NYU Bluestone Center Receives Award to Study Oral Cancer Pain. PMID- 26521332 TI - Treating my Granddaughters. PMID- 26521333 TI - '21st Century Cures' Isn't a Cure for Everything. PMID- 26521334 TI - The new ERA of mega-plans. PMID- 26521335 TI - The ACA as a Survivor. PMID- 26521336 TI - For Narrow Networks, Fresh Scrutiny: Can They Pass the Adequacy Test? PMID- 26521337 TI - In a Crowded Market for Renal Cell Carcinoma Treatments, 2 Trials Take Aim at a Common Enemy. PMID- 26521338 TI - First Million-Dollar Syringe Could Be a Sight for Sore Eyes. PMID- 26521339 TI - Cost Differences Between Open and Minimally Invasive Surgery. AB - PURPOSE: To analyze the cost difference between minimally invasive surgery (MIS) and open surgery from a commercial payer perspective for colectomy, ventral hernia repair, thoracic resection (resection of the lung), and hysterectomy. DESIGN: A retrospective claims data analysis was conducted using the 2011 and 2012 Truven Health Analytics MarketScan Commercial Claims and Encounter Database. Study eligibility criteria included age 18-64 years, pharmacy coverage, >= 1 month of eligibility in 2012, and a claim coded with 1 of the 4 surgical procedures of interest; the index year was 2012. METHODOLOGY: Average allowed facility and professional costs were calculated during inpatient stay (or day of surgery for outpatient hysterectomy) and the 30 days after discharge for MIS vs open surgery. Cost difference was compared after adjusting for presence of cancer, geographic region, and risk profile (age, gender, and comorbidities). RESULTS: In total, 46,386 cases in the 2012 MarketScan database represented one of the surgeries of interest. The difference in average allowed surgical procedure cost (facility and professional) between open surgery vs adjusted MIS was $10,204 for colectomy; $3,721, ventral hernia repair; $12,989, thoracic resection; and $1,174, noncancer hysterectomy (P < .001 for all comparisons).The difference in average allowed cost in the 30 days after surgery between open surgery vs adjusted MIS was $1,494 for colectomy, $1,320 for ventral hernia repair, negative $711 for thoracic resection, and negative $425 for noncancer hysterectomy (P < .001 for all comparisons, except P = .487 for thoracic resection). CONCLUSION: MIS was associated with statistically significantly lower costs than open surgery for all 4 analyzed surgeries. PMID- 26521340 TI - CDHP offerings tied to fate of the Cadillac Tax. PMID- 26521342 TI - Validity of cervical auscultation in the screening for aspiration. AB - INTRODUCTION: Cervical auscultation could improve the performance of bedside swallowing test to predict aspiration, especially silent aspiration. The aim of this study is to compare the predictive values of bedside swallowing test performed with and without cervical auscultation by logopedist students who had intensive training on cervical auscultation. MATERIALS AND METHODS: 64 patients were included in the study. They all underwent swallowing test alone, combined swallowing test and cervical auscultation, and videofluoroscopic swallowing study as defined gold standard. Two logopedist students, at the end of their training, performed the auscultation and noted their results. RESULTS: 128 tests were performed, 96% of the tests were judged positive for aspiration. When comparing the results of the two different clinical tests, the detection of clinical signs is not improved by the addition of auscultation. Using a penetration aspiration scale threshold >5, the area under the curve measured for the swallowing test alone was significantly higher than that measured for the combined tests (p = 0.03) (0.66 for the swallowing test alone (95% CI between 0.49 and 0.83), and 0.50 for the combined tests (95% CI between 0.31 and 0.69). CONCLUSION: This study showed no advantage in performing cervical auscultation with bedside swallowing test. Cervical auscultation seems to hamper the assessment, mainly the perception of wet voice and laryngeal motion. These results are compatible with literature but need further confirmation using studies performed with trained logopedists. PMID- 26521343 TI - Iatrogenic scarring of the vocal folds after phonosurgery for benign lesions. A descriptive study of 108 patients. AB - OBJECTIVES: Patients with iatrogenic scarring of the vocal folds can present with a spectrum of dysphonia ranging from slight hoarseness to very severe dysphonia. In this paper we will describe the clinical and stroboscopic presentation of VFIS, and discuss the possibility of identifying the factors favouring such lesions. STUDY DESIGN: A retrospective chart review from 2002 to 2011. METHODS: A retrospective chart analysis of patients complaining of no improvement in (or worsening of) the quality of their voices after primary phono-surgery for benign lesions of the vocal folds. RESULTS: Our series consisted of 108 patients (107 women and 1 man) with a mean age of 38.1. The initial complaint was always of no improvement in (or worsening of) voice quality more than three months after phonosurgery for benign vocal fold lesions. The overall grade of dysphonia according to Hirano's scale was 1.79 (n = 84). Voice evaluation showed forced phonation in 29% of the patients, sharp breaks or irregular vibration in 31%. The appearance of the larynx in normal and stroboscopic light is presented. The results of this study do not allow the factors favouring the occurrence of iatrogenic scars to be formally identified since in 75% of cases, the diagnosis of the initial lesion or the operative procedure used was unknown. However, the link between the initial lesion, the operating technique and the occurrence of scarring is discussed for the remaining 25%. PMID- 26521344 TI - [F0 characteristics in Parkinsonian speech: Contrast between the effect of hypodopaminergy due to Parkinson's disease and that of the therapeutic delivery of L-Dopa]. AB - Voice and speech impairments are frequent in Parkinson's disease, particularly when the disease is at an advanced stage. These impairments affect spoken communication and may become a serious disability for someone with Parkinson's disease. Many studies based on auditory-perceptual or acoustic methods have been carried out to characterize dysarthria. The heterogeneity of evaluation methods and experimental bias however make results difficult to understand. For instance, in terms of phonatory impairments and with regard to F0, results are contradictory: PD speech may be characterized by either higher F0 or lower F0 compared to control subjects, or there may be no difference at all between the two population. In this study, we aim to provide a conceptual and methodological framework which allows for interpreting the results obtained from 44 speakers (29 PD and 15 control subjects) in relation to physiological (gender, age, PD subjects' pharmacologic state) and linguistic (speech production tasks) constraints. For the present corpus, we did not observe any F0 mean difference between the two groups. Our results however reveal a significant increase in F0 mean in PD subjects under L-dopa. We assume a double and opposite effect on F0 mean during drug withdrawal: low sub-glottal pressure, due to PD, results in a decrease in F0, while laryngeal rigidity leads to an increase in F0. These two effects thus mutually annihilate. Under L-Dopa, however, the drug effect increases sub-glottal pressure, which combined with an increase in F0 due to rigidity, leads to a global increase in F0. PMID- 26521345 TI - [Prosody and reading: Temporal and melodic characteristics in the dyslexic child in reading and narration]. AB - Dyslexia is widely associated to a massive phonological awareness deficit. This deficit leads to difficulties in grapheme to phoneme conversions in reading and difficulties in words and sentences productions. The origin of the phonological deficit is partially explained by the magnocellular, cerebellar and articulatory theories. Recently, an increasing number of studies demonstrated the relationship between prosody and reading and, more specifically, the potential key role of suprasegmental phonology in the healthy development of phonological representations. The aim of this study is to explore part of prosodic features in dyslexics and normal developing children in reading and narration tasks, in French. We examined reading accuracy, reading rate, pauses frequency and duration, inter-pausal units (IPUs) duration and instantaneous variations of F0. Results show correct decoding skills for all subjects but a lack of automation of this procedure for dyslexics. Differences in pauses frequency and duration, IPUS duration and F0 variations observed between dyslexics and controls confirm the link between prosodic reading and automaticity. The longer pause duration in narrative form a temporal feature of dyslexic's production. This temporal characteristic reflects the cognitive cost done by a speech generation task involving lexical selection, syntactic planning and articulatory programming processes. This result is a first step towards evidence of a suprasegmental phonological deficit in spoken language that could be an early marker of later reading difficulties. PMID- 26521346 TI - [Study of tongue pressure on the hard palate during exercises of swallowing rehabilitation]. AB - INTRODUCTION: The exercises performed during the reeducation of swallowing seek to improve forces of propulsion of the bolus and airway protection during the course of swallowing. The objective of this study was to objectify the effect of pronunciation praxis of posterior phonemes /aka/ and /akra/, and swallowing maneuvers (super-supraglottic swallow with or without superimposed effort swallowing effort) on the time of the oral swallowing. MATERIALS AND METHODS: Four healthy volunteers participated in the experiment. They are called "experts" because they have a good knowledge of physiology and rehabilitation of swallowing. The dynamic palatography setup measured continuously the different pressures from the tongue on the hard palate through three force sensors arranged in a sagittal plane during the implementation of articulatory and swallowing tasks. RESULTS: Articulatory praxis created significant pressure on the posterior sensor for 2 of the 4 subjects. All the swallowing maneuvers increased the contact pressure and the contact duration compared to the control swallowing for the anterior and posterior pressure sensor. A large inter-individual variability was found. CONCLUSION: The complexity of instruction, the inter-individual variability in their performance, and the non-invasive nature of the instrument make the dynamic palatography a potentially useful tool in routine practice of swallowing reeducation. PMID- 26521347 TI - [Multidisciplinary daytime hospitalisation for swallowing disorders: Its value and limitations. Our practice in the University Hospital of Tours]. AB - Swallowing disorders are in many cases serious and complex. Their management needs to be considered from several perspectives. Multidisciplinary daytime hospitalisation (MDH) for swallowing disorders is an appropriate solution for many patients: a single day is sufficient for a complete check-up and the initiation of a therapeutic programme. A Ministerial Direction (15 June 2010), the content of which is discussed in this article, lays out the conditions of this approach. Our institution (Regional University Hospital of Tours) has substantial experience of MDH for swallowing disorders and here we take a look at the organisational, human, medical, and financial aspects of this activity. PMID- 26521348 TI - Early evaluation of voice quality in glottic cancer (T1, T2) following curative radiotherapy. AB - BACKGROUND: This is prospective study analyzing the subjective and objective quality of voice and voice related quality of life in patients of early glottic cancer (T1, T2 disease) before and after receiving curative radiotherapy. METHODS: Fifteen patients of early glottic carcinoma (T1, T2) underwent voice assessment using multidimensional voice protocol based on recommendation by European Laryngological Society which included Perceptual analysis of voice by speech therapist and otolaryngologist, acoustic analysis; aerodynamic efficiency analysis-Maximum phonation time; patient's self perception of voice analysis- Voice handicap index; and videolaryngostroboscopy. Assessment was done prior to commencement of radiation therapy and at 1 month and 3 months following radio- therapy. RESULTS: There was significant improvement in majority of the voice parameters post radiotherapy. Perceptual analysis showed significant improvement in GRBAS score following radiotherapy. Perturbation measures (jitter, shimmer, SNR, HNR) showed improvement post radiotherapy though remained inferior compared to controls. Mean fundamental frequency (Mean F0) and habitual frequency (habitual F0) decreased post radiotherapy. Intensity of voice increased following radiotherapy which was statistically significant (p < 0.05). There was significant improvement in the patient's perception of their quality of voice and voice related quality of life post radiotherapy. Maximum phonation time showed statistically significant improvement post-radiotherapy. Perceptual analysis of voice by professional observer correlated well with patients self perception of his own voice. CONCLUSION: Voice quality improves following radiotherapy but not all the patients regain normal voice. Improvement in voice quality improves quality of life of patients shown by improved voice handicap index. PMID- 26521349 TI - [Transgender voice and communication treatment: Review of the literature]. AB - Transgender persons constitute a small but growing population in ENT department: as a matter of fact, many voice parameters significantly contribute to the perception of gender (fundamental frequency, supraglottic resonance patterns, etc.). The persons involved in transition processes may therefore aim at changing their own voice properties, either by means of speech therapy or by medical intervention (hormonotherapy and/or surgery). The current voice assessment and outcome measures for this population before and after treatment are nevertheless still lacking validity. A well-accepted general framework including self perception, subjective assessment of the practitioner and objective measures is not well documented. This review is therefore meant as a contribution to the development of a state of the art in the field. PMID- 26521350 TI - [A rare and unusual cause of dysphonia: The leech]. AB - We report a case of dysphonia associated with intermittent episodes of hemoptysis low abundance in a patient aged 32, clinical examination is normal, nasofibroscopie objective a leech at the laryngeal orifice, extracted by direct laryngoscopy in emergency. PMID- 26521351 TI - [A single appointment with a speech therapist can release a patient, even from a long-term aphonic status! Three clinical cases]. AB - Those three clinical cases involved aphonic female patients without any laryngeal disorders for their ENTs. 1) The first one had been out of work since 11/2 year because of her aphonia. She was still suffering from it in spite of a weekly speech therapy session and a monthly psychotherapy appointment. 2) The second patient had been aphonic for 3 weeks. Three different ENTs had renewed her prescription of work stoppage, even with normal laryngeal exam. 3) The third had lost her singing voicing ability during a performance in a national festival of songs and had to cancel the followings events. Even if all of them were waiting for a "miracle pill" they recorded their training session and left this single phoniatrician appointment with their restored voicing ability. PMID- 26521353 TI - Sentinel lymph node biopsy in head and neck melanoma: A single institution analysis. AB - INTRODUCTION: The aim of our study was to analyze a series of patients from our institution who underwent surgery for head and neck cutaneous melanoma and who received sentinel lymph node biopsy (SLNB). MATERIAL AND METHODS: A single-center observational cohort of 120 head and neck melanoma patients was investigated from 2002 to 2011. RESULTS: Among the 107 patients (89.2%) with lymph node identified during lymphoscintigraphy, at least one node was collected and analyzed in 96 patients (90.6%). A positive sentinel lymph node was found in 9.4% of patients. Our data showed higher failure rate of lymphoscintigraphic identification (11.7%), lower rate of SLN positivity (9.4%), and higher false-negative rate of SLNB (24.1%) than the usualfigures established for malignant melanomas in other locations. After a mean follow-up of 38.1 months, the disease-free survival (DFS) rate in the positive SLN group was 53% vs 75% for the negative SLN after 2 years of follow-up and 53% vs 48% after 5 years (p = 0.44). CONCLUSION: The complexity of lymphatic drainage and the anatomy of the cervical region probably accounts for a specificities which result in a lower predictive value of SLNB in head and neck melanoma than in MM in other locations. PMID- 26521354 TI - Predictive factors for surgical site infection in head and neck cancer surgery: A case-control study. AB - Surgical Site Infection (SSI) after head and neck cancer surgery may be life threatening and induces increasing in healthcare cost. The objective of this present study was to identify predictive factors associated to surgical site infection in head and neck cancer surgery. Numerous predictive factors were analyzed with univariate case-control method, then with multivariate method. This retrospective study included 71 patients who have been hospitalized in our department during 2010 for a head and neck cancer surgery. The incidence of surgical site infection was 15.5%. The T3-T4 stages were identified as an independent predictive factor (p = 0.04). Our study does not find other predictive factor for a SSI. The NNIS index (National Nosocomial Infections Surveillance), used by the Center for disease control and prevention as predictive factor, was not valid in our study. A specific predictive index should include the tumor stage for Head and Neck Cancer surgery and should be taken into account for the management of a preventive antibiotic treatment. PMID- 26521355 TI - [Role of positron emission tomography and CT with 18F-FDG PET-CT in follow-up of patients treated for head and neck squamous cell carcinoma]. AB - The authors in this article, made from a review of the scientific literature (PubMed search engine), indicate the current position of positron emission tomography with 18F-fluro-2-deoxy-D-glucose coupled computed tomography (PET-CT) in the early and late post-treatment follow up of squamous cell carcinomas of the upper aerodigestive tract. The aim of this follow up is twofold: Early detection of locoregional progressive evolution or metastatic progression and search for a possible second metachronous cancer in patients at risk. PMID- 26521356 TI - [Morbidity of neck dissection submuscular recess (sublevel IIb) in head and neck cancer]. AB - OBJECTIVES: The impact of neck dissection on quality of life has often been considered less important than the oncological control. Dissection of level IIb doesn't improve oncologic control everytime, knowing that an injury of the spinal nerve can occur. The aim of our study was to assess the impact of neck dissection including level IIb on shoulder function and quality of life in N0 patients. MATERIALS AND METHODS: Fifteen patients with squamous cell carcinoma of the upper aerodigestive tract, clinical and radiological NO, were included. They were assessed by validated scales (QLQ-C30, H&N35 and DASH) and they underwent an examination of the shoulder. RESULTS: Almost half of the patients had pain in the shoulder. The functional scale score QLQ-C30 was statistically more altered (49.7%) than that of patients with cancer in general (74.9%, p = 0.00016) and of the general population 60 to 69 years (85.4%, p = 0). CONCLUSION: The results of our study underscore the morbidity on shoulder function after neck dissection. These findings, combined with the low prevalence of occult lymph node metastases in level IIb among T1-T2 patients, must question the systematic inclusion of this level in neck dissection. PMID- 26521357 TI - [Chyle leak after cervical surgery: Meta analysis--Management strategy]. AB - OBJECTIVE: Chyle fistula is a known complication in cervical surgery. It can lead to a postoperative lymphorrhea. There is no consensus on its management. The aim of this work is to propose a management strategy for postoperative chyle leak. MATERIALS AND METHODS: A literature review was conducted using PubMed database. RESULTS: Six prospectives articles were included. The enteral diet allowed a success in 57% of cases, and in these cases a lymph flow less than 580 mL/day. Parenteral nutrition was effective when the flow was less than 1050 mL/day. Reoperation was performed in case of failure of the nutritional treatments. CONCLUSION: Several therapeutics are available. From this meta-analysis, we developed a management strategy. We initiate an enteral diet when lymph flow is less than 500 mL/ day. Parenteral nutrition is used if the flow rate is between 500 and 1000 mL/day or in case of inefficiency of enteral diet during 10 days. Finally, revision surgery is necessary when the flow is greater than 1000 mL/day or when parenteral nutrition was ineffective in 10 days. PMID- 26521358 TI - [Free nonvascularized bone graft evolution after mandibular resections: 45 cases report]. AB - The resection of mandibular benign tumors often require reconstruction. The purpose of our study is to present the middle and long-term results of 45 patients, treated by free no-vascularized bone graft after resection of benign tumors, dominated by the ameloblastoma. The PSIM type III hemimandibulectomy was the most frequent (58%). A combined approach was necessary in the majority of cases. The immediate reconstruction by corticospongeal iliac grafts fixed by screws plaques with intermaxillary blockage was the most used technique (95%). The mean follow was 4.5 years. The evolution was marked by good osteointegration of the graft, with good functional and morphologic results in 40%. The infection and bone resorption represented the major complications and were interrelated, so the infection was noted in 9 cases. The bone resorption hampered the evolution with a bad functional and morphological result in 4 cases (9%). PMID- 26521359 TI - [Sinonasal polyposis associated with a deficiency subclass immunoglobulin G: Place of substitution immunoglobulins]. AB - PURPOSE: To study the effect of the introduction of a substitution by intravenous Immunoglobulins (Ig IV) at patients with immunoglobulins G (IgG) subclasses deficiency and nasal polyposis. MATERIAL AND METHODS: Prospective study concerning five patients with IgG subclasses deficiency and nasal polyposis treated by Ig IV. Rhinologic, otologic and pulmonary symptoms, exacerbations of nasal polyposis, chronic otitis and asthma as well as the number of antibiotics and corticoids treatments were counted during the Ig IV substitution. OBJECTIVES: To study the association between IgIV substitution and the number of exacerbations of nasal polyposis, chronic otitis, asthma and the number of antibiotics and corticoids treatments in patients with IgG subclasses deficiency and nasal polyposis. RESULTS: Five patients with a IgG subclass deficiency and nasal polyposis were substituted. The number of antibiotics and corticoids cures increased at one patient and remained stable at four others. The number of sinus, ear and lung infections as well as the global rhinologic score of symptoms and the endoscopic stage of the nasal polyposis remained stable. In the absence of efficiency of the treatment, this one was interrupted at the end of 6 months for patients n degrees 1 and n degrees 3, 24 months for patient n degrees 4 and 42 months for patient n degrees 5. CONCLUSION: The current study failed to highlight clinical improvement in patients wih IgG subclasses deficiency and nasal polyposis treated by Ig IV. A previous study had not allowed to find a link between IgG subclasses deficiency and severity of nasal polyposis, what seems to be confirmed by the absence of improvement brought during the substitution of this deficit in the current study. PMID- 26521360 TI - [Lipoma of the floor of the mouth: Case report and literature review]. AB - Lipoma of the floor of the mouth is a benign and uncommun lesion in this location. It may be isolated or associated with multiple forms or a specific clinical entity. The symptoms are nonspecific and dependent on the volume of the lipoma. It is characterized by a very slow evolution and may reach large dimensions. The treatment is surgical. The histopathological study identifies the variety of the lipoma. Recurrences are rare if the excision is complete and may be seen in specific forms (infiltrative lipoma and spindle cell lipoma). PMID- 26521362 TI - [Pathophysiology, assessment and treatment of laryngopharyngeal reflux]. AB - Laryngopharyngeal reflux is a prevalent, yet incompletely understood, ENT disorder accounting for 8 to 10% of patients consulting ENT. This clinical entity, increasingly considered as different from gastroesophageal reflux disease, may greatly affect the quality of life of patients through vocal and digestive symptoms. Debate persists concerning pathophysiology, diagnosis, and treatment. The aim of this review is to study the current literature about the pathophysiology, diagnosis, treatment, and the outcomes in the follow-up. PMID- 26521363 TI - Evaluation of the presence of the 35delG mutation in patients with severe to profound hearing loss based on ethnicity. AB - INTRODUCTION: The 35delG mutation in the connexin 26 gene is the most common mutation that generates deafness, but its frequency in different countries is strongly based on its ethnicity. Brazilians belong to different ethnic groups. OBJECTIVES: To report the frequency of homo and heterozygosis 35delG mutation in a population with severe to profound bilateral sensorineural deafness, and separate them by ethnicity. METHODS: 100 individuals were studied with severe to profound hearing loss, with no other etiology found, and tested for 35delG mutation. The group presented the following ethnicity distribution: 25% Blacks; 30% Latin Europeans; 26.2% Blacks/Latin Europeans and 2.3% native. RESULTS: The 35delG mutation was found in 20% of patients: 15% were heterozygous and 5% homozygous. All homozygous were of Latin European origin. CONCLUSION: Ethnicity shows marked determination of the presence of the 35delG mutation, and it was only found in homozygosis in the group of Latin Europeans. PMID- 26521364 TI - Cochlear implantation in patients with chronic otitis media and radical mastoidectomy: A single-stage procedure. AB - BACKGROUND: We conducted a retrospective case review of patients with mastoid cavity and active or inactive chronic otitis media (COM) who underwent cochlear implantation and ear obliteration in a single-stage procedure. The objectives of this review are to assess the rates of complications and postoperative infections and to evaluate post-implantation audiologic performance. MATERIALS AND METHODS: All patients with COM and mastoid cavity, associated or not with active disease, who undergo cochlear implantation and obliteration of the ear as a single-stage procedure from November 2004 to April 2013, were included in the review. All the complications were recorded. Open-set sentence scores were used to evaluate the audiologic gain after implantation. RESULTS: Twenty-seven patients were included in our review: Ten with active COM and seventeen with inactive COM. Overall, nine patients (9/27) presented post-operative complications (7/9 were minor): three were amongst active COM patients (30%) as compared to six amongst inactive COM patients (35%), which included the two major complications. A mean gain of 55.9% on open-set sentence scores was obtained after cochlear implantation. DISCUSSION: We found that complications rate of the one-stage cochlear implantation was higher in patients with COM than in global implant population, but most complications were minors and there was no statistical difference between active and inactive COM. In addition, these patients had audiologic scores similar to those found in patients with normal temporal bone anatomy. CONCLUSION: Cochlear implantation performed as a one-stage procedure could be considered as an option of treatment to avoid staging in patients with active and inactive COM. Although these patients need a regular follow-up, they present good post-implantation audiometric scores. PMID- 26521365 TI - [Characteristics of the male facelift]. AB - Male face lifting is the cosmetic surgery which has witnessed the greatest rise in demand in recent years. A result of social evolution and development of non surgical techniques for facial rejuvenation, this intervention represents a real challenge for the surgeon who operates mainly on women. Man has specific characteristics which include differences in the aging process, and a multitude of anatomical and psychosocial factors that will require adjustments in the patient's overall care. Indeed, the adaptation of the conventional technique of the female facelift would lead to an unnatural result, not satisfactory for the patient. To best meet the demands of the male patient, the surgeon must take into account the male facial characteristics in order to optimize the results. PMID- 26521366 TI - Herniation of the temporomandibular joint into the external auditory canal: Our review of 13 cases. AB - Symptomatic dehiscence of the anterior wall of the external auditory canal is only occasionally encountered during otologic surgery. OBJECTIVE: To propose a technical answer for the reconstruction of anterior wall defects based on the size of the dehiscence. MATERIAL AND METHODS: Retrospective study of 13 cases of dehiscence of the anterior wall (9 male and 4 female patients between 30 and 66 years) operated between 1998 and 2010. The pathologies at the cause of the dehiscence were cholesteatoma (2 cases), chronic otitis externa (3 cases), congenital dehiscence (1 case), 5 cases which appeared after a surgery mainly for exostosis (3 of them previously operated in another center) and 2 cases of accidental breach during canal calibration. The size of the defect measured during surgery was "small" (< 4 mm diameter) in 2 cases, "medium" (between 4 and 8 mm) in 8 cases and "large" in 3 (> 8 mm). The reconstruction was performed in 7 cases through the EAC and in 6 cases an anterior approach of the anterior wall of the EAC was used. In all cases, we could insert a graft anteriorly and this was held in place by the pressure exerted by the temporomandibular joint. Bone pate and temporalis fascia with in most cases a piece of cortical bone graft was used in all cases. RESULTS: The follow up period ranged from 6 to 24 months. In 10 cases the anatomical result was perfect (in 3 cases we encountered some minor complications but with no clinical consequences). In the other three cases there was one with persistent inflammation of the external auditory canal, one case of recurrence of the lateralization of the tympanic membrane and one case which required a revision surgery. CONCLUSION: The reconstruction and the approach are done according to the size of the defect, whether small, medium or large. Complications and revision surgeries have been minimal. PMID- 26521367 TI - Respiratory epithelial adenomatoid hamartomas and olfactory function. AB - INTRODUCTION: Respiratory epithelial adenomatoid hamartoma can occur alone or associated with several diseases with very different pathological processes. Our hypothesis is that REAH is a non-specific reaction of the nose when olfaction is impaired. MATERIAL AND METHOD: This is a retrospective study including all patients with HERA operated in an academic ENT department. Data analysis focused on the pre and post-operative olfaction, corticosteroids consumption, histological results of the polyps, the evolution of the disease allowing a comparison of HERA with or without polyps and comparison of data literature. RESULTS: 28 patients suffered from REAH of which 18 are associated with polyps. Nineteen patients had inflammatory disease with a 9 year interval between initial diagnosis and surgery of REAH. Olfactory function was improved after surgery (p < 0.01). The cell content of the polyps showed eosinophilic infiltration in 8 patients which 6 were correlated with inflammatory disease. Lymphoplasmacytic infiltration was present in 10 patients which 8 were correlated with inflammatory disease. Nasal corticosteroid consumption decreased after surgery (p < 0.02). The mean follow-up after surgery was 34 +/- 43 months. Polyp recurrence rate was 11% (3 patients), and 0% for REAH. CONCLUSION: In most cases, olfactory function, cellular infiltration and polyp recurrence rate are not correlated with the pathophysiological inflammatory processes that coincides with REAH. Therefore, the co-existence of nasal polyposis with REAH is probably overestimated. PMID- 26521368 TI - Correlation between the rate of asymmetry volume of maxillary sinuses and clinical symptomatology in the silent sinus syndrome: A retrospective study about 13 cases. AB - OBJECTIVES: The "silent sinus syndrome" (SSS) also known as imploding antrum syndrome or chronic maxillary sinus atelectasis consists of painless enophthalmos and inward retraction of the ipsilateral maxillary sinus walls. The aims of the present study were: i) to look for a correlation between the level of volume asymmetry of the maxillary sinuses and the presence of ophthalmological and rhinosinusitis signs, ii) to determine the benefits of a middle meatal antrostomy in SSS cases, and iii) to evaluate the preventive role of neuronavigation surgery in the morbidity of this specific surgery. MATERIALS AND METHODS: We retrospectively analyzed the data of 13 patients operated on for a SSS by middle meatal antrostomy, with the aid of neuronavigation in 7 cases. The median follow up was 30 months. No reconstruction of the orbital floor was performed. Morphometric analysis and modeling of the sinus volume from the preoperative CT scanners were performed to assess the impact of the loss of sinus volume on the symptoms. RESULTS: all patients displayed a retraction of the orbital floor. There was a significant correlation between the magnitude of the decrease in sinus volume and clinical manifestations. Surgical treatment allowed rhinosinusitis symptom disappearance in 53% of patients. Ophthalmological symptoms did not decrease, but stayed stable after the surgical treatment. When neuronavigation surgery was performed, no complications were observed. CONCLUSION: SSS symptoms correlated with the reduction of volume of the maxillary sinuses. This measure may be related to the severity of the disease. The middle meatal antrostomy seemed sufficient to stop the evolution of the SSS, avoiding the occurrence of severe enophthalmos. Neuronavigation surgery helped preventing serious eye complications. PMID- 26521369 TI - [Unusual location of pleomorphic adenoma: A series of 7 cases]. AB - INTRODUCTION: The pleomorphic adenoma is a benign tumor of the salivary glands. Its location outside the main salivary glands defines the pleomorphic adenoma of atypical location. The aim of this study is to analyze the clinical, diagnostical and therapeutical features of this tumor at atypical locations through seven observations. PATIENTS AND METHODS: This work is a retrospective study. It has for objective to present 7 cases of pleomorphic adenoma developed on minor salivary glands diagnosed in Otolaryngology Head and Neck surgery department in Mohammed VI University hospital, between December 2003 and December 2010. RESULTS: We had 3 cases of pleomorphic adenoma of the hard palate and 1 case of each soft palate, superior lip, lower eyelid and nasal septum. The sex ratio woman/ man was 133. The symptomatology was variable according to the location of the tumor. The tumoral syndrome was constant. The diagnosis of pleomorphic adenoma was suspected at the clinical stage in 3 cases of palatal location. The CT scan was performed for all patients except in 2 cases of the tumor of the lip and the eyelid. We did not realize a magnetic resonance imaging nor of a fine needle aspiration to our patients. The preoperative biopsy was realized to 5 patients. The treatment consisted of a wide surgical excision of the tumor. The mean follow up of 3 years showed no signs of recurrence nor of malignant transformation. DISCUSSION/CONCLUSION: The pleomorphic adenoma of atypical location is rare. The clinical presentation is variable according to the tumor site and volume. The treatment is surgical. It is based on the early and complete excision of the tumor. The histo-pathological diagnosis is made. The diagnosis differential is with malignant tumors arising on minor salivary glands. The prognosis is favorable. Nevertheless, regular and prolonged follow-up of the patients is important to watch for complications. PMID- 26521370 TI - [Malignant melanoma of the mandibular gingiva]. AB - INTRODUCTION: The oral melanoma (OM) account for 1% of all melanomas. The prognosis is poor despite an adequate locoregional control of the disease. OBSERVATION: A 47 year old women consulted for a blackish lesion of the mandibular gingiva next to tooth 37. Intraoral examination showed a dark pigmented lesion on the lingual side of the left mandibular molar region, extending from tooth 37 to the trine retro left molar. The biopsy confirmed the diagnosis of mucosal nodular melanoma. A wide surgical excision without ipsilateral neck dissection was performed. The treatment was completed by 30 Gy external beam radiotherapy, the patient died 18 months after the first consultation. DISCUSSION: Oral melanomas have a poor prognosis probably because they are generally detected late. The most common sites for oral melanomas are the palate and maxillary gingival, malignant melanoma of the mandibular gingiva is extremely rare. About 30% of OM is preceded by areas of oral pigmentation for several months or years. The prognosis is poor with a 5% to 20% five-year survival rate. PMID- 26521371 TI - Cholesteatoma behind a normal tympanic membrane after trauma (Blast). AB - OBJECTIVES: One of theories concerning the origins of cholesteatoma, is the barotraumatic etiology. It suggests blast perforation of the tympanic membrane, and secondary implantation of epithelium in the tympanic cavity, as a cause of middle ear cholesteatoma. We report a case of cholesteatoma after spontaneous healing of a tympanic membrane perforation by blast, and revue the literature about this etiology of cholesteatoma. CASE REPORT: We report the case of a 38 year-old man with a history of bilateral blast injury trauma 4 years earlier. The blast caused a bilateral tympanic perforation. The right tympanic membrane healed spontaneously and a left tympanic perforation remained. A cholesteatoma was encountered on the right side, behind a scared tympanic membrane, during preoperative imaging study for surgery for the left side. The literature describes an incidence of 3 to 12% cholesteatoma after blast injury, rarely behind a closed tympanic membrane. We discuss the best imaging methods to detect cholesteatoma in these cases. CONCLUSIONS: After a blast injury, a cholesteatoma may arise behind a spontaneously healed tympanic membrane. For this reason, spontaneous healing of the perforation does not mean the end of the follow-up. It is essential to plan a follow-up with imaging test one year after the blast trauma. We consider that in cases of traumatic tympanic membrane perforations due to blast injury with spontaneous healing of the perforation, HRCT scan offers a better diagnostic performance and a higher spatial resolution for cholesteatoma detection (as it relates to an aerated mastoid and tympanic cavity) than DW MRI. Furthermore, it is available in the great majority of health centers. PMID- 26521372 TI - Bilateral facial nerve schwannoma: A case report. AB - Facial nerve schwannoma (FNS) is an uncommon disease, bilateral FNS are exceptional. We describe a case of a 23-year-old man who presented a bilateral 3rd segment facial nerve schwannoma, without neurofibromatosis disease. We discuss the clinical presentation, radiologic findings and management of this case. Facial nerve schwannoma can present in various ways. The imaging appearance of FNS is more varied than originally described. Our case demonstrates an uncommon presentation of a relatively rare tumor in which the tumor has been respected. During this time, the tumor may be followed by radiologic imaging. PMID- 26521373 TI - [Myringoplasties for anterior tympanic perforations: Our surgical technique]. AB - Anterior tympanic perforations are actually the most difficult to close and a number of different techniques exist. This article represents the author's surgical procedure for type I tympanoplasties (myringoplasties) for this kind of perforation using the tragal cartilage and the perichondrium after preparation (revival, cleaning) of the perforation edge with a laser. This technique does not use a skin incision of external auditory meatus, when this one is large. PMID- 26521374 TI - Total ossicular reconstruction: The "mushroom technique". AB - OBJECTIVE: The "Mushroom technique" is introduced in this paper as an alternative technique to reconstruct the total ossicular chain by using autologous grafts where it is not possible to use the patient's ossicles, and to seal a peri lymphatic fistula (PLF) if present. MATERIALS AND METHODS: This non randomized retrospective study covers 18 patients aged between 26 and 72 years, operated between January 2006 and March 2012 by the same surgeon using a retro-auricular approach. There were 13 males and 5 females, 12 right ears and 6 left ears. The three ossicles were damaged in 18 patients, a PLF was associated in 3 cases, and a tympanum perforation was present in 2 ears. Postoperative follow-up period was a minimum of 6 months and up to 6.5 years. The origin of 18 patient's disease was; post traumatic in 11 patients and post removal cholesteatoma in 7 patients. The "mushroom technique" was performed for all patients. The average Air Bone Gap (ABG) of each patient was calculated (frequencies 500, 1000, 2000 and 4000 Hz) both pre and 6 months postoperatively. RESULTS: There were no extrusion of the composite graft. In the three cases of PLF; the leak was sealed. And in the two ears with tympanum perforation; the perforation was closed. The average post operative ABG is 25 dB while it was 45 dB before surgery. Average gain is 20 dB. Non sensorineural hearing loss ocurred. CONCLUSION: This technique has several advantages: The mounting footplate-fascia-connective tissue-bone-cartilage perichondrium-tympanum is solid and long lasting, the rate of leak closure in case of PLF is improved; This technique closes the leak, the hearing results are satisfactory, the cost of autograft is null and the tolerance is excellent. On the other hand, it might be time consuming since it is a delicate looking procedure. PMID- 26521375 TI - [Reconstruction of bone defects in the earcanal with hydroxyapatite]. AB - Traditional reconstruction methods of osseous defects within the tympanic frame, most often being the atticotomy, within the framework of chronic otitis media surgery, still do not produce stable or definitive results, usually due to displacement or partial lyse of the transplanted material (cartilage, bone ...). The reconstruction procedure with the aid of hydroxyapatite cement as presented by the authors, allows for a complete, stable and definitive reconstruction. PMID- 26521376 TI - Health Care Reform in Latin America and Implications for the Hospital Sector. PMID- 26521377 TI - PAHO'S Strategy for Universal Access to Health and Universal Health Coverage: implications for health services and hospitals in LAC. AB - Moving towards Universal Access to Health and Universal Health Coverage (UAH/UHC) is an imperative task on the health agenda for the Americas. The Directing Council of the Pan American Health Organization (PAHO) recently approved resolution CD53.R14, titled Strategy for Universal Access to Health and Universal Health Coverage. From the perspective of the Region of the Americas, UAH/UHC "imply that all people and communities have access, without any kind of discrimination, to comprehensive, appropriate and timely, quality health services determined at the national level according to needs, as well as access to safe, affordable, effective, quality medicines, while ensuring that the use of these services does not expose users to financial hardship, especially groups in conditions of vulnerability". PAHO's strategic approach to UAH/UHC sets out four specific lines of action toward effective universal health systems. The first strategic line proposes: a) implementation of integrated health services delivery networks (IHDSNs) based on primary health care as the key strategy for reorganizing, redefining and improving healthcare services in general and the role of hospitals in particular; and b) increasing the response capacity of the first level of care. An important debate initiated in 2011 among hospital and healthcare managers in the region tried to redefine the role of hospitals in the context of IHSDNs and the emerging UAH/UHC movement. The debates resulted in agreements around three main propositions: 1) IHSDNs cannot be envisioned without hospitals; 2) The status-quo and current hospital organizational culture makes IHSDNs inviable; and 3) Without IHSDNs, hospitals will not be sustainable. This process, that predates the approval of PAHO's UAH/UHC resolution, now becomes more relevant with the recognition that UAH/UHC cannot be attained without a profound change in healthcare service and particularly in hospitals. In this context, a set of challenges both for hospitals and for the first level of care based on the experience of hospital and healthcare services managers and the vision they have for hospitals in IHSDNs is presented. PMID- 26521378 TI - Private hospitals in Latin America - An investor's perspective. AB - Private hospitals are expanding in Latin America, but the industry is less developed in this region than in some other emerging markets. Groups of hospitals are emerging in countries such as Brazil, Mexico, Colombia and Peru. However, they haven't reached the size of hospital groups in Malaysia, India and South Africa. They also remain domestically focused, while companies from the aforementioned three emerging markets outside Latin America have expanded to multiple other countries and have listed on stock exchanges to access more capital to finance their expansion. It is very likely that these trends seen in other emerging markets will manifest in Latin America as it continues to develop. PMID- 26521379 TI - Argentina. A country of contrast and paradox. AB - In Argentina, health is not considered a state policy, and it does not benefit from effective action in all areas of government. The budget is essentially used up by structural costs, and despite having made progress in some areas such as vaccinations, there is little impact on the community as a whole from the promotion of health and the prevention of prevalent chronic illnesses linked to metabolism and lifestyle. The biggest health expenditure is private, including so called "out-of-pocked spending," which leads to inequality, with over 40% of the population without explicit health coverage. In the national systems, coverage is linked to formal employment and Obras Sociales and is essentially managed by trade unions. Social determinants therefore continue leading to illness, which the health system then attempts to cure at enormous human and financial cost. Recommendations of international bodies (PAHO, WHO, FLH, IHF) stress the importance of organizing state and private RISS, but very little has been done in this regard. Right to healthcare is already required, but it's a long way form being sufficient. The whole population needs to be provided explicit and effective universal health coverage, in order to ensure healthcare and equality, and organize healthcare networks which make awareness, promotion, prevention, and rehabilitation more effective for all, using existing, high-level structural and human resources. PMID- 26521380 TI - Hospital 360 degrees . AB - There are forces that are greater than the individual performance of each hospital institution and of the health system structural of each country. The world is changing and to face up to the future in the best possible way, we need to understand how contexts and emerging trends link up and how they affect the hospital sector. The Columbian Association of Hospitals and Clinics, ACHC, has thus come up with the Hospital 360 degrees concept which uses hospitals capable of anticipating changing contexts by means of the transition between present and future and takes on board the experience of global, socio-economic, demographic, political, environmental and technological fields as its model. Hospital 360 degrees is an invitation to reinvent processes and institution themselves allowing them to adapt and incorporate a high degree of functional flexibility. Hospital 360 degrees purses goals of efficiency, effectiveness and relevance, but also of impact and sustainability, and is coherent with the internal needs of hospital institutions and society for long-term benefits. PMID- 26521381 TI - Operating private hospitals in Mexico. AB - Mexico is one of the richest countries in Latin America and over the last several decades there have been many changes in the healthcare delivery systems, from universal healthcare coverage for all Mexicans to the fast paced expansion of private healthcare. Like many countries, Mexico has both private and public health systems and hospital administrators are facing challenges on multiple fronts in addition to facing exciting new opportunities. In this article you will get a bird's eye view of this ever changing panorama. How the new growing middle class consumerism has impacted physicians, health insurance and private healthcare industry. PMID- 26521382 TI - Brazil's Mixed Public and Private Hospital System. AB - Brazil's hospital sector is vibrant and growing. Under the 1988 Brazilian constitution all citizens have the right to health care, anticipating the global commitment to Universal Health Care. Brazil's public sector prides itself on having one of the world's largest single payer health care systems, but complementing that is a significant and larger private sector that is seeing big increase in investment, utilization and prices. This article outlines the structure of the hospital system and analyzes the nature and direction of private health sector expansion. Twenty-six percent of Brazilians have private health insurance and although coverage is concentrated in the urban areas of the Southeastern part of the country, it is growing across the nation. The disease burden shift to chronic diseases affects the nature of demand and the directly affects overall health care costs, which are rising rapidly outstripping national inflation by a factor of 3. Increasingly costs will have to be brought under control to maintain the viability of the private sector. Adaption of integrated care networks and strengthening of the public reimbursement system represent important areas for improvement. PMID- 26521383 TI - Challenges and Perspectives for Tertiary Level Hospitals in Bolivia: The case of Santa Cruz de La Sierra Department. AB - Current legislation transferred public tertiary hospitals in Bolivia from the Municipalities to the Regional Level. However, the Regional Governments are experiencing technical and financial constraints to reform infrastructure, modernize equipment and introduce reforms to allow better governance, management and sustainability of these hospitals. This articles summarizes the recent experience of the Government of Santa Cruz de la Sierra in Bolivia where five tertiary hospitals and blood bank (most of them in precarious working conditions) has been transferred in 2012 from the Municipal Government of Santa Cruz (the capital) to the Regional Government of Santa Cruz. To face the challenges, the Regional Government of Santa Cruz implement several improvements, such as contract new clinical and administrative personal, increases hospital budgetary autonomy, outsource hospitals' auxiliary services, take measures to eliminate waiting lists and make several new investments to modernize and equip the hospitals. The World Bank was contracted to evaluated the future financial sustainability of these investments and to advice the Government to propose changes to increase the hospitals' management performance. The article describes the remaining challenges in these hospitals and the proposals from the World Bank Study. In the area of quality of care, the main challenge is to improve client satisfaction and continuous outcomes monitoring and evaluation according quality standards. In the area of financing, the challenge is how to assure the sustainability of these hospitals with the current level of health financing and the insufficient financial transfers from the National Government. In the area of Governance, reforms to streamline and simplify internal processes need to be introduced in order to establish mechanisms to increase transparency and accountability, allowing the hospital to have a good administration and adequate participation of the main actors in the guidance of the institution. PMID- 26521384 TI - Solving a Health Information Management Problem. An international success story. AB - The management of health care delivery requires the availability of effective 'information management' tools based on e-technologies [eHealth]. In developed economies many of these 'tools' are readily available whereas in Low and Middle Income Countries (LMIC) there is limited access to eHealth technologies and this has been defined as the "digital divide". This paper provides a short introduction to the fundamental understanding of what is meant by information management in health care and how it applies to all social economies. The core of the paper describes the successful implementation of appropriate information management tools in a resource poor environment to manage the HIV/AIDS epidemic and other disease states, in sub-Saharan Africa and how the system has evolved to become the largest open source eHealth project in the world and become the health information infrastructure for several national eHealth economies. The system is known as Open MRS [www.openmrs.org). The continuing successful evolution of the OpenMRS project has permitted its key implementers to define core factors that are the foundations for successful eHealth projects. PMID- 26521385 TI - The Pursuit of Nursing Excellence. PMID- 26521386 TI - Leaislative Update--Many Unanswered Questions. PMID- 26521387 TI - ANA Recap--Congratulations Are in Order! PMID- 26521388 TI - Speaking Up About Nursing with a Disability. PMID- 26521389 TI - Providing Culturally Sensitive Care to NC's Montagnards. PMID- 26521390 TI - Attitude is Everything--It's Not About Me!! PMID- 26521391 TI - Hypertension Self-Management Support in Primary Care: A DNP Quality Improvement Project and a Charge for Leadership and Advocacy with the Million Hearts. PMID- 26521392 TI - North Carolina Chiefs of the United States Army Nurse Corps. PMID- 26521393 TI - In Your Corner--Evolving Healthcare Landscape. PMID- 26521394 TI - Suburban Plane Crash. Family considerations shape care when a small craft lands in a yard. PMID- 26521395 TI - How to Master Decision-Making. EMS leaders need to learn to slow down when it comes to making their mind up. PMID- 26521396 TI - The Hub of the Wheel: How FD CARES Is Cutting 9-1-1 & Hospital Use. How EMT-level program is data-driven and designed for replicability. PMID- 26521397 TI - Community Paramedics Go Live in California. The state's 12 pilot projects launched this summer. PMID- 26521398 TI - Differential Diagnosis: Bell's Palsy vs. Stroke. They can look similar, but it's important to tell them apart. PMID- 26521399 TI - How to Break the 9-1-1 Language Barrier. Services are available to help providers communicate with patients who don't speak English. AB - America's multiethnic composition can create havoc in answering emergency calls and translating patient information on scene. It is incumbent upon EMS services to have a translation strategy and protocol in place to mitigate delays in providing emergency care. While digital translation programs may be of assistance, exercise caution in ensuring information is accurately downloaded to obtain an accurate translation. PMID- 26521400 TI - 20 Years at EMS World: A tribute to Editorial Director Nancy Perry. PMID- 26521401 TI - A Profound Impact. After a serious ambulance crash, an EMS community emerges stronger. PMID- 26521402 TI - A National Perspective on Ambulance Crashes and Safety. Guidance from the National Highway Traffic Safety Administration on ambulance safety for patients and providers. PMID- 26521404 TI - [2015: And now that?]. PMID- 26521403 TI - Who's Responsible? You are, without allowances for inconvenience, distraction or fatigue. PMID- 26521405 TI - [NURSING CARE FOR A PATIENT UNDERGONE ENDONASAL ENDOSCOPIC APPROACH PITUITARY SURGERY]. AB - The pituitary gland is an endocrine gland that releases different hormones responsible for controlling the production of hormones in other glands, and maintaining the body's homeostasis. This tiny gland is located in a bone cavity known as the sellaturcica. Anomalous growth of some cells produces pituitary adenomas, which represent between 10 and 15% of intracranial tumors. In the majority of cases, the cause is unknown, but they are usually benign tumors with a slow growth rate. Due to the wide range of functions of the pituitary gland, it can present a wide variety of symptoms which tend to present once the adenoma has reached a certain size. The most commonly used currently access to the pituitary gland is the transphenoidal endoscopic approach. We present here the case of a 28 year old man diagnosed with a non-functioning pituitary macroadenoma, describing the health education, monitoring and emotional support provided during his hospital stay and the recommendations made on his discharge from hospital. It is important to emphasise the role of nursing in order to avoid complications and ensure that care is adapted to the needs of the individual at all times. PMID- 26521406 TI - [TUBERCULOSIS INFECTION PREVALENCE AMONG NURSING DEGREE STUDENTS IN LA RIOJA UNIVERSITY]. AB - INTRODUCTION: Tuberculosis (TB) is a disease of contagious and infectious character that has harassed humanity throughout its history. Many studies say that health professionals and health degrees students as degree in nursing are exposed to a higher risk of transmission of TB to deal with patients who suffer from this disease in their jobs. OBJECTIVES: Knowing the risk of acquiring infection by M. tuberculosis among students of the degree in nursing (GUE) from the University of La Rioja (UR); contrasting outcomes as they have made their formative period of clinical practice in hospitals or not. MEHODOLOGY: Observational study, descriptive, transversal and cutting, for which has been taken a representative sample of 106 students who carried an epidemiological clinical questionnaire. After, according to criteria of participation and under informed consent, has been practiced them tuberculin test to see if they are infected or not causing by the tuberculosis bacillus. RESULTs: The final sample was 85 people, which were highly represented by women, whose average age was between 20 and 23 years old. The reading of the PT was managed to do in 28 from 37 students from 1st grade (75.7 %) and 45 from 48 students from 4th grade (93.75 %). The other participants not attended appointment agreed with them to perform reading, which accounted for 14.1% of abstention in the second part of the study. Response to the tuberculin globally compared, without taking into account other variables, didn't show differences in distribution between 1st and 4th grade students. The percentage of positive PT was 0 % between 1st grade students, while in 4th grade the percentage of infected with M. tuberculosis amounted to 2.22 %. The average size of indurdtions was 1.03 mm (+/-1.87) in students of 1st grade and 1.46 mm (+/-2.98) in the 4th grade, so that difference is not significant. The number of confirmed contacts with TB patients, or their samples, was more often in 4th grade students than 1st grade students (52 % vs. 18 %, respectively). From 19 people who had vaccine scar of bacillus Calmette-Guerin (BCG), 14 of them (73.68 %) showed some kind of reactivity to tuberculin. The prevalence of TB infection was very low among the students of GUE from UR (0.01). CONCLUSIONS: The results aren't as expected, as was conceived one higher prevalence of infection among students more involved in health care. The fact that the results do not match those obtained in similar studies may be due to that they have been made in countries with the highest prevalence of the disease (Latin America). On the other hand it is considered that the low prevalence of tuberculous infection among students of the UR is the right preventive measures developed by institutions which develop clinical practices. Also a suitable training and awareness of students about how to prevent the spread of disease influences the good results obtained. Also, the low prevalence of tuberculous infection could be due to an insufficient time of exposure of these students in the health field to become infected. PMID- 26521407 TI - [NURSING DIAGNOSIS PROPOSAL FOR GENDER VIOLENCE SYNDROME IN NANDA-I TAXONOMY]. AB - Gender-based violence is a widespread and muted problem in public health that particularly affects millions of women worldwide. The situation being relegated to the private sphere is difficult to know the exact number of women who suffer and causes much of the morbidity and the mortality of women. However, at some point in their lives women visit health services and health professionals, especially nursing, is supposed to be the first to detect cases of abuse. The need to include gender-based violence as a nursing diagnosis is evident because nursing diagnoses names health problems which nurses can approach independently. We have conducted a literature search in order to propose violence as nursing diagnosis to NANDA-I, in order to recognize that this is really a serious health problem and that nursing has an important role in detecting and monitoring of women victims of violence. The aim of this paper is to describe the development phases of <> as a proposal for inclusion in the NANDA-I taxonomy. PMID- 26521408 TI - [CARE NURSE AT REFRACTORY SPIRITUAL SUFFERING USING TAXONOMY NANDA-NOC-NIC]. AB - This paper introduces the concept of refractory spiritual suffering in the terminal patient, the factors that influence it, the possibility of their assessment and care approach emphasizing the role of nurse care to despair for identification and relief through the use of taxonomy NANDA-NOC-NIC (NNN). We conclude that it is necessary to incorporate into the care routine screening of spiritual suffering, assessment, prevention and interdisciplinary care. When direct care nursing developed aimed at improving levels of hope that the patient achieves his spiritual suffering terminal decline. In refractory spiritual suffering is necessary to consider the option of palliative sedation in which nurses have a crucial role both in their valuation for the indication and in the administration and evaluation of its therapeutic effects. PMID- 26521409 TI - [A MODEL OF COMPREHENSIVE CARE FOR COMPLEX CHRONIC PATIENT. EXPERIENCE OF A TERRITORY]. AB - INTRODUCTION: The Increase in life expectancy has brought an increase in chronic diseases. The evolution of chronic disease is the cause of several organic and systemic dysfunctions, leading to physical and mental limitations that determine the need for some aid to perform basic vital tasks. Primary health care has a key role in the monitoring of fragility, chronicity, and complexity of population. However, in order to address properly high complexity diseases it is necessary to know and coordinate the different resources existing inside the territory. THE DEVELOPMENT OF THE MODEL FOR ACTION: THE IMPLEMENTATIONS OF A FUNCTIONAL UNIT. The Primary Health Care must ensure equity, accessibility, longitudinally, and continuity of care, bearing in mind that health outcomes must be optimal. There are several health care providers in the Delta del Llobregat SAP, so it was implemented a strategic plan focused on the coordination and/or the reconciliation of all the devices involved in the assistance in order to provide comprehensive attention to the patient. The patients included in this program were to be identified as CCP (Complex chronic Patient), in an evolved and tributary phase of intensive follow-up. CONCLUSIONS. The identification ofpatients listed as CCP and at clinical risk allows a comprehensive monitoring in order to prevent exacerbations and overuse of unscheduled hospital resources. PMID- 26521411 TI - [Interview with Mercedes Montiu Ferro, president of the 26th National Conference of Nurse Managers, Nursing Supervision]. PMID- 26521410 TI - [NURSES' SAFETY BRIEFING FOR PATIENT HANDOFF IN THE ICU]. AB - HYPOTHESIS AND MAIN GOALS: Safety Briefing improves the effectiveness of the information exchange process of patient handoffs and strengthens the safety culture. The goal was to design a Safety Briefing for standardizing the exchange process of sensible information at the patient handoffs in an intensive care unit (ICU). The subsidiary goals were: evaluate the impact on the safety culture and the communication between professionals, describe the methodology for filling the information into the Briefing for every shift and collect and discuss the professional's opinions about the use of it. METHODS: This is a prospective intervention study. We designed a Briefing and it was introduced into the nurses' patient handoffs for a period of six months. Surveys before and after the introduction of the Briefing were conducted to evaluate the impact of the Safety Briefing on the nurses' safety culture and information exchange. A total of 23 nurses participated in the experiment. The presented results have been analyzed with Chi-squared and Fisher's tests. RESULTS: Nurses reported a change in the quality of oral communications. The proposed Briefing was used on the 80.2 % of the patient handoffs. Most of the subjects evaluating the proposed Briefing considered that its usage not only speeded up the information exchange process, but also improved the quality of the information. CONCLUSIONS: The change of the nurses' perceptions in the quality of the oral communications when using the Briefing, the elevated number of information exchanges carried out with the proposed tool and the good reviews received from the nursery team, give us a conclusion that the Safety Briefing is an effective tool for information exchange which can also improve the critical patient's safety. However, there is still no conclusive evidence of improvement regarding to safety culture or general oral communication. PMID- 26521412 TI - [Interview with Jose Manuel Pena Martin, Chairman of the Organizing Committee of the 31st. National Conference of Nursing in Trauma and Orthopaedic Surgery]. PMID- 26521413 TI - Medical Retainer Agreements Are Not Insurance Products. PMID- 26521414 TI - Introducing ... Doctor Rose Ramirez. PMID- 26521415 TI - Be Cybersecure: Protect Patient Records, Avoid Fines, and Safeguard Your Reputation. PMID- 26521416 TI - ICD-10 Implementation: Making the Best of Transition. PMID- 26521417 TI - Analysis of EHR Contributing Factors in Medical Professional Liability Claims. PMID- 26521418 TI - Measuring the Impact of New Policies on Immunization Waiver Rates. PMID- 26521420 TI - Honoring the Past and Looking to the Future. PMID- 26521419 TI - Five ways to be a Tax Efficient Investor.. PMID- 26521421 TI - What Starts Here Changes the World. PMID- 26521422 TI - [Ebola lessons]. PMID- 26521423 TI - [COMPREHENSIVE CARE IN THE LAST DAYS AND HOURS OF LIFE]. AB - This article identifies the most significant elements of the process of nurse attention to the last days and hours of life in the context of a disease previously diagnosed like a terminal situation. For this object, we have reviewed the main clinical guidelines on comprehensive care and, especially, the guideline that was designed by the Saint John of God Hospital in Seville. We conclude that it is necessary to know how to identify the phase of agony to apply, therefore a default care plan that, allows to respond customized to the specific needs that occur in the last hours of the life of a terminal patient. A continued and coordinated interprofessional assistance to patient and family following standardized standards allows achieving a peaceful death and free from avoidable suffering. PMID- 26521424 TI - [NURSING RESEARCH VISIBILITY: DATABASES AND IMPACT FACTOR]. AB - Nowadays, mainly as a result of the implementation of processes of accreditation of the teaching and research activity, there is discussion about the publication in journals of nursing according to the impact factor or their indexing in certain databases, basic criteria for obtaining favorable evaluations in these processes promoted by quality agencies. To response to this problem we are going to analyze conceptually the current methodological support on which is based the analysis of the scientific quality of the research in our discipline, as well as the impact on its visibility and development. PMID- 26521425 TI - [BURNOUT SYNDROME AND STRESS OF NURSING STAFF IN A OURENSE HOSPITAL]. AB - OBJECTIVE: Set up the stress prevalence and burnout syndrome in different units of nursing staff of the Complexo Hospitalario Universitario de Ourense (CHUOU) and analyse which factors cause it. MATERIALS AND METHODS: It has been designed a transversal, descriptive study by performing three assessment instruments: questionnaire of social-demographic variables; Maslach Burnout Inventory (MBI), and Nursing Stress Scale (NSS), to a 117 nursing staff of CHUOU as population. The average age was 39.23 years old and 83.8% were women. RESULTS: The average scoring in the emotional exhaustion dimension was 24.44, in the component of depersonalization was 7.58, and in the personal accomplishment was 34.50. Moreover, 89.7% suffer stress related with work environment. The average score in the dimension of emotional exhaustion was 24.44, the depersonalization of 7.58 and the personal accomplishment of 34.50. The 89.7% suffered from work-related stress. CONCLUSIONS: Nursing staff present high burnout syndrome and stress. It has been observed a higher vulnerability to the syndrome from subjects with temporary contract and rotary shift. There has been statistically significant differences in young nursing staff and less career seniority, whom present hiqher stress levels. PMID- 26521426 TI - [INTERVENTIONS FOR PREVENTION AND MANAGEMENT OF CHILD AND YOUTH OBESITY]. AB - OBJECTIVE: To determine the current epidemiological situation, prevention and management of child and youth obesity based on the best scientific evidence available. METHODOLOGY: Literature search in PubMed, Cochrane, Science Direct, ENFISPO, Lilacs and SciELO, selecting articles about child and youth obesity, its prevention and treatment. RESULTS: Child and youth obesity is a multifactorial chronic disease that it has been increasing, tending to stay in adolescence and adulthood with greater intensity than more early starts. The data vary from country to country, although most articles are governed by body mass index (BMI). Pediatric overweight is defined by a BMI percentiles located between 91-98 and obesity by a percentile equal or greater than 99. Its prevalence varies according to time, geography, age, gender and race. The prevalence rates of obesity in Spain are one of the highest around the world. The overweight prevalence is lower slightly and there is no difference in gender. Its implications include the metabolic syndrome and diabetes mellitus II. Unanimously, the combination of interventions on life and dietary habits and physical activity is important for the management of obesity and overweight. CONCLUSION: Currently, the obesity management requires a generalized approach, with changes in lifestyle, diet and physical activity. The best solution for reducing this epidemic lies in prevention rather than treatment. PMID- 26521427 TI - [SAFETY AND EFFICACY OF INFLUENZA VACCINE IN PREGNANCY]. AB - Only 22.7% of pregnant women are immunized against the flu virus, by the popular belief that the vaccine can cause the onset of the disease or other complications. OBJECTIVE: To review the scientific evidence regarding the safety and efficacy of influenza vaccines in pregnant women. METHODOLOGY: Literature review of the scientific literature. RESULTS: Pregnant women and the fetus can have complications if they contract the flu. The influenza vaccine in pregnant women is effective in reducing flu boxes during pregnancy, and it is not observed any increase in adverse effects of the vaccine in mothers or children, compared with non pregnant women. CONCLUSIONS: Vaccination is safe for pregnant women and fetus and is well tolerated. Therefore, vaccination is the safest and most effective method to prevent infection in any trimester. PMID- 26521428 TI - [WATSON'S MODEL OF CARING FOR A NEW PARADIGM IN NURSING CARE]. AB - Due to the fact that caring is the essence and main role of nurses, we make an historical perspective to place ourselves on the current moment. We also debate the need for adequate care, and therefore, teaching and research to a model that could give properly answers to every health/disease process. For this purpose, it is briefly described the historical stages of nursing and the situation of a man who suffers from fibromyalgia to contrast it with Jean Watson model care, the paradigm of transformation and knowledge associated to critical thinking. PMID- 26521429 TI - [CONTROL OF FETAL WELL-BEING: BIOPHYSICS INTRAPARTUM MONITORING]. AB - This article presents an update on the control of the intrapartum fetal wellbeing including the following aspects: methods of monitoring the fetal heart rate and the uterine dynamic and uterine contraction parameters. Moreover, the assessment of intrapartum CTG records is described by analyzing the fetal heart rate in relation to uterine contractions. The different types of fetal heart rate decelerations: early late and variable, its clinical significance and the guidelines to follow in each one of them are evaluated. Finally, the parameters that make up a normal CTG registration are defined. PMID- 26521430 TI - [Health education: nutrition in the elderly]. PMID- 26521431 TI - [Research progress in the study of protective effect of tanshinone IIA on cerebral ischemic stroke]. AB - Danshen is one of the traditional Chinese herbal medicines and nas a long history or being used clinically in the treatment of cardiovascular and cerebrovascular conditions such as coronary heart disease and angina pectoris. Tanshinone IIA is a derivative of phenanthrene-quinone isolated from Danshen. It has been reported to be the major bioactive compound of Danshen and has diverse biological effects. Recent studies demonstrated that tanshinone IIA had neuroprotective effects on experimental ischemic stroke through its antiinflammatory, anti-oxidant, anti apoptosis effects and its inhibitory effect on excitatory amino acid toxicity. In this review, we summarized all the recent progresses on the protective effect of tanshinone IIA on cerebral ischemic stroke. Hopefully, this article will throw some light on further study and application of tanshinone IIA. PMID- 26521432 TI - [Progress in the study of small molecule inhibitors of HSP90]. AB - HSP90, which is the biomarker of cell stress and endogenous protective protein, functions as a molecular chaperone. Many client proteins of HSP90, including EGFR, Met, Raf-1, IKK and p53, play important roles in the occurrence and development of tumor. Binding of HSP90 inhibitors triggers the deactivation of HSP90, resulting in client protein degradation, and hence inhibits the tumor growth by blocking multiple targets involved in signaling of tumor proliferation. This review summarizes recent development of small molecule inhibitors bound to N terminal of HSP90. PMID- 26521433 TI - [Research progress of the drug delivery system of antitumor platinum drugs with macrocyclic compounds]. AB - Platinum-based anticancer drugs have been becoming one of the most effective drugs for clinical treatment of malignant tumors for its unique mechanism of action and broad range of anticancer spectrum. But, there are still several problems such as side effects, drug resistance/cross resistance and no-specific targeting, becoming obstacles to restrict its expanding of clinical application. In recent years, supramolecular chemistry drug delivery systems have been gradually concerned for their favorable safety and low toxicity. Supramolecular macrocycles-platinum complexes increased the water solubility, stability and safety of traditional platinum drugs, and have become hot focus of developing novel platinum-based anticancer drugs because of its potential targeting of tumor tissues/organs. This article concentrates in the research progress of the new drug delivery system between platinum-based anticancer drugs with three generations of macrocycles: crown ether, cyclodextrin, cucurbituril and calixarene. PMID- 26521434 TI - [Progress in study of selective ERbeta ligands]. AB - Estrogen receptors (ERs) are members of nuclear receptors and related to several diseases such as cancer, inflammation and osteoporosis. ERs have two forms, ERalpha and ERbeta, which have different functions and organism distributions. Compounds selectively targeting ERbeta can regulate important physiological functions and avoid the side effects caused by targeting ERalpha. Therefore, selective ERbeta ligands have received considerable research interest in recent years. In this article, different kinds of selective ERbeta ligands were summarized and their structure-activity relationships were also analyzed. PMID- 26521435 TI - [Recent advances in the quantification of drug metabolizing enzymes and transporters by proteomic approach]. AB - With the advance of drug development and research techniques, the drug metabolic processes and mechanism can be more deeply achieved. As the drug metabolism and pharmacokinetics process are mediated by drug metabolizing enzymes and transporters, study of drug metabolizing enzymes and transporters has become an important part for drug development. The traditional immunoassays with low sensitivity and poor specificity can not reflect the accurate expression level of drug metabolizing enzymes and transporters. We now give a brief review on the quantitative study of drug metabolizing enzymes and transporters by mass spectrometry-based proteomic approach. PMID- 26521436 TI - [Research progress of lactoferrin as drug carriers]. AB - Lactoferrin (Lf) is one of the food protein belonged to the innate immune system. Apart from its main biological function of binding and transport of iron ions, lactoferrin also has many other functions and properties such as antibacterial, antiviral, antiparasitic, catalytic, anti-cancer, anti-allergic and radioprotecting. Lf is usually used as additives of food and cosmetics. The research of lactoferrin has been increasingly reported, and the application of lactoferrin as a drug carrier has drawn extensive attention over the recent year. In this paper, researches of lactoferrin as drug carriers are classified and summarized in brain targeting, liver tumor targeting, lung tumor targeting and oral delivery systems according to their different characteristics. PMID- 26521437 TI - [The effects of compound CX09040 on the inhibition of PTP1B and protection of pancreatic beta cells]. AB - To investigate the effects of 2-(4-methoxycarbonyl-2 tetradecyloxyphenyl)carbamoylbenzoic acid (CX09040) on protecting pancreatic beta cells, the beta cell dysfunction model mice were induced by injection of alloxan into the caudal vein of ICR mice, and were treated with compound CX09040. Liraglutide was used as the positive control drug. The amount and the size of islets observed in pathological sections were calculated to evaluate the beta cell mass; the glucose stimulated insulin secretion (GSIS) test was applied to estimate the beta cell secretary function; the oral glucose tolerance test (OGTT) was taken to observe the glucose metabolism in mice; the expressions of protein in pancreas were detected by Western blotting. The effects on the target protein tyrosine phosphatase 1B (PTP1B) were assessed by the PTP1B activities of both recombinant protein and the intracellular enzyme, and by the PTP1B expression in the pancreas of mice, separately. As the results, with the treatment of CX09040 in alloxan-induced beta cell dysfunction mice, the islet amount (P<0.05) and size (P<0.05) increased significantly, the changes of serum insulin in GSIS (P<0.01) and the values of acute insulin response (AIR, P<0.01) were enhanced, compared to those in model group; the impaired glucose tolerance was also ameliorated by CX09040 with the decrease of the values of area under curve (AUC, P<0.01). The activation of the signaling pathways related to beta cell proliferation was enhanced by increasing the levels of p-Akt/Akt (P<0.01), p-FoxO1/FoxOl (P<0.001) and PDX-1 (P<0.01). The effects of CX09040 on PTP1B were observed by inhibiting the recombinant hPTP1B activity with IC50 value of 2.78x 10(-7) mol.L-1, reducing the intracellular PTP1B activity of 72.8% (P<0.001), suppressing the PTP1B expression (P<0.001) and up-regulating p-IRbeta/IRbeta (P<0.01) in pancreas of the beta cell dysfunction mice, separately. In conclusion, compound CX09040 showed significant protection effects against the dysfunction of beta cell of mice by enlarging the pancreatic beta cell mass and increasing the glucose induced insulin secretion; its major mechanism may be the inhibition on target PTP1B and the succedent up-regulation of beta cell proliferation. PMID- 26521438 TI - [Central-adenosine A1 receptor involved in the thermal regulation effect of YZG 330, a N6-substituted adenosine derivative, in mice]. AB - Adenosine receptors (AR) play an important role in the regulation processes for body temperature and vigilance states. During our previous studies, we noticed that aminophylline (a non-selective, blood-brain-barrier penetrably AR antagonist) could attenuate the effects of YZG-330 [(2R,3S,4R,5R)-2 (hydroxymethyl-5-(6-(((R)-1-phenylpropyl)amino)-9H-purin-9-yl)tetrahydrofuran-3, 4-diol] on lowering the body temperature. Hereby, we focused ourselves on the character of thermal regulation effect of YZG-330 in mice and tried to specify the receptor subtype via giving typical adenosine receptor antagonists. The results showed that both of the magnitude and lasting time of the effect that YZG 330 played on decreasing body temperature are in a dose-dependent manner: within the next 3 hour after intragastric administration (ig) of 0.25, 1 or 4 mg . kg-1 YZG-330, the extreme values on body temperature decreasing were (1.2 +/- 0.3) degrees C, (3.6 +/- 0.4) degrees C (P<0.001) and (7.4+/-0.5) degrees C (P<0.001), separately; whereas the duration that body temperature below 34 degrees C were 0, (10+/-5) and (153+/-4) min, separately. Adenosine A1 receptor (A1R) antagonist (DPCPX) could effectively reverse YZG-330's effect on decreasing body temperature, with intraperitoneal administration of DPCPX (5 mg . kg-1) 20 min prior than YZG-330 (4 mg.kg-1, ig), the extreme value on body temperature decreasing was (3.5 +/- 0.7) degrees C (P<0.001), the duration that body temperature below 34 degrees C was (8+/-6) min (P<0.001). However, adenosine A2a receptor antagonist, SCH-58261, did not show any influence on the effects of YZG 330 at all. Combined with the fact that 8-SPT (a non-selective, blood-brain barrier impenetrably AR antagonist) did not reverse the effect of YZG-330, we come to the conclusion that central-adenosine A, receptor plays a significant role on the thermal regulation effect of YZG-330. PMID- 26521439 TI - [Neuroprotective effect screening and the mechanism of 10 kinds of coumarin derivatives]. AB - The study reports the detection of neuroprotective effect of 10 kinds of coumarin derivatives and explores their possible mechanism. MTT method was used to screen the neuroprotective effect of 10 coumarin derivatives on neurotoxic agents (Abeta25-35 and rotenone) or OGD (oxygen-glucose deprivation). A compound with better protective effect was obtained. Then the effect of this compound on neurotoxic agents on PC12 was detected by the morphological observation. Furthermore, the effect of compound 3 on microglia with lipopolysaccharide (LPS) induced inflammation was detected. And the inflammatory factor was tested. Finally, direct free radical scavenging ability was detected. Compound 3 was found to be the best compound through three neurons toxic models. Not only compound 3 ameliorated cell viability reduced by three neurons toxic models, but also significantly inhibited the production of inflammatory factor (TNF-alpha and IL-1beta). And its free radical scavenging ability is very good, especially the effect on superoxide anion, which is comparable with vitamin C. The significant scavenging effect of compound 3 on superoxide anion might be the mechanism of the neuroprotection. Compound 3 as a potential neural cell protective agent merits further investigation. PMID- 26521440 TI - [Inhibitory effect of kaempferol on inflammatory response of lipopolysaccharide stimulated human mast cells]. AB - This study is to investigate the inhibitory effect of kaempferol on inflammatory response of lipopolysaccharide(LPS)-stimulated HMC-1 mast cells. The cytotoxicity of kaempferol to HMC-1 mast cells were analyzed by using MTT assay and then the administration concentrations of kaempferol were established. Histamine, IL-6, IL 8, IL-1beta and TNF-alpha were measured using ELISA assay in activated HMC-1 mast cells after incubation with various concentrations of kaempferol (10, 20 and 40 umol.L-1). Western blot was used to test the protein expression of p-IKKbeta, IkappaBalpha, p-IkappaBalpha and nucleus NF-kappaB of LPS-induced HMC-1 mast cells after incubation with different concentrations of kaempferol. The optimal concentrations of kaempferol were defined as the range from 5 umol.L-1 to 40 umol.L-1. Kaempferol significantly decreased the release of histamine, IL-6, IL 8, IL-1beta and TNF-alpha of activated HMC-1 mast cells (P<0.01). After incubation with kaempferol, the protein expression of p-IKKbeta, p-IKBa and nucleus NF-kappaB (p65) markedly reduced in LPS-stimulated HMC-1 mast cells (P<0.01). Taken together, we concluded that kaempferol markedly inhibit mast cell mediated inflammatory response. At the same time, kaempferol can inhibit the activation of IKKbeta, block the phosphorylation of IkappaBalpha, prevent NF-KB entering into the nucleus, and then decrease the release of inflammatory mediators. PMID- 26521441 TI - [Metabolomics study of doxorubicin induced hepatotoxicity]. AB - To reveal the underlying mechanism of doxorubicin induced hepatotoxicity, an NMR based metabolomic approach combined with multivariate statistical analysis was used to observe its metabolic alternations of rat liver. Sixteen differential metabolites between model rats and normal rats were characterized as potential pathological biomarkers related to doxorubicin induced hepatotoxicity. Six pathways, including phenylalanine, tyrosine and tryptophan biosynthesis, valine, leucine and isoleucine biosynthesis, phenylalanine metabolism, glycine, serine and threonine metabolism, alanine, aspartate and glutamate metabolism, and tyrosine metabolism were regarded as the targeted metabolic pathways according to Metabolic Pathway Analysis (MetPA). The results suggested that the metabolic perturbations in rats with doxorubicin induced hepatotoxicity were mainly involved in amino acid metabolism, lipid pathways, purine metabolism, energy metabolism, dysfunction of biotransformation and oxidative stress. The investigation revealed the effects of doxorubicin on liver in a holistic metabolic way, which laid a foundation for further studies on its toxicity mechanism. PMID- 26521442 TI - [Quantification of sitagliptin in human plasma and urine by LC-MS/MS method and its application]. AB - A rapid and sensitive liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method for quantification of sitagliptin in human plasma and urine had been developed. This method was applied to the pharmacokinetics study of sitagliptin tablet after single- and multiple-dosing in Chinese population. Plasma samples were prepared by a liquid-liquid extracted method, and urine samples were diluted. Compounds were analyzed by multiple reaction monitoring (MRM) mode with a electrospray ionization (ESI) interface. Mobile phase consisted of methanol and water (85 : 15, v/v). The linear concentration range of calibration curve was 0.5-1 000 ng.mL-1. and 0.2-100 ug.mL , intra-run/between run accuracy was 98.98%-103.69% and 97.63%-102.29%, intra-run/between-run precision was <5.51% and 4.26% for plasma and urine sample, respectively. The stability of sitagliptin stock solution was tested for 55 days at -30 degrees C. Sitagliptin was stable when stored under the following conditions: 24 hours in the autosampler after sample preparation; 24 hours at room temperature, after 3 freeze and thaw cycles (from -30 degrees C to room temperature), 40 days at -30 degrees C for plasma and urine samples. The absolute recovery in plasma was 71.1%, and no matrix effect was founded. This method was proved simple, specific, sensitive, rapid and suitable for pharmacokinetics study of sitagliptin in human being. PMID- 26521443 TI - [Design, synthesis and evaluation of new L-proline derivatives as acetylcholinesterase inhibitors]. AB - In this paper, fourteen new L-proline derivatives were designed and synthesized, and their acetlcholinesterase (AChE) inhibitory activities were also investigated in vitro. New L-proline derivatives were prepared from substituted 2-bromo-1 acetophenones through four-step reaction; and their bioactivities as AChE inhibitors were measured by Ellman spectrophotometry. The results showed that the target compounds had a certain AChE inhibitory activity to in vitro. The bioactivity of compound 8b was the best of them, and its IC50 value was 5.45 umol.L-1, which was better than that of rivastigmine. So the acetylcholinesterase inhibitory activities of new L-proline derivatives were worth to be further studied. PMID- 26521444 TI - [Design, synthesis and biological evaluation of the novel trehalose derivatives]. AB - Using brartemicin as the leading compound, fifteen novel trehalose derivatives were designed and synthesized, and the structures were determined by 11H NMR, MS and element analysis. Inhibitory effects of the target compounds on the proliferation of A549, HepG2 and HUVEC cells were detectec by MTT assay. The abilities of adhesion, invasion and migration of A549 and HepG2 cells inhibited by the synthesized compounds were evaluated through Matrigel experiment and Transwell assay. The results showed that, the target compounds had no significant cytotoxicity (compared with the control, P>0.05) to A549, HepG2 and HUVEC cells at the dose range of 1-32 umol.L-1. At the above dose range, the inhibitory effects of A549 cells adhesion, invasion and migration and HepG2 cells adhesion and invasion by compounds 79 and 82 are better than brartemicin. PMID- 26521445 TI - [HPLC enantioseparation, absolute configuration determination and anti-HIV-1 activity of (+/-)-F18 enantiomers]. AB - Racemic (+/-)-F18 (10-chloromethyl-11-demethyl-12-oxo-calanolide A), an analog of nature product (+)-calanolide A, is a new anti-HIV-1 nonnucleoside reverse transcript inhibitor (NNRTI). A successful enantioseparation of (+/-)-F18 offering (R)-F18 and (S)-F18 was achieved by a chiral stationary phase prepared HPLC. Their absolute configurations were determined by measurement of their electronic circular dichroisms combined with modem quantum-chemical calculations. Further investigation revealed that (R)-F18 and (S)-F18 shared a similar anti-HIV activities, however, (R)-F18 was more potent than (S)-F18 against wild-type virus, K101E mutation and P225H mutation pseudoviruses. PMID- 26521446 TI - [Design, synthesis and biological evaluation of novel 3-(2-oxo-2-substituted acetamido)benzamides as PARP-1 inhibitors]. AB - Poly(ADP-ribose)polymerase-1 (PARP-1) plays a significant role in the DNA repair process by catalyzing the transfer of ADP-ribose from NAD+ to its receptors. It is a promising anticancer drug target and many PARP-1 inhibitors have been developed and used in the clinical trial. In this work, a series of 3-(2-oxo-2 substituted acetamido)benzamides have been synthesized and their inhibitory activities against PARP-1 were evaluated. Of all the tested compounds, six compounds displayed inhibitory activities with IC50 values ranging from 0.23 to 5.78 umol.L-1 . The binding pose of compound 5a was predicted using molecular docking to facilitate further structural modification. PMID- 26521447 TI - [A new cyclic diarylheptanoid from the bark of Myrica rubra]. AB - To study the chemical constituents from the bark of Myrica rubra, fourteen compounds were isolated from the methanolic extract using various chromatographic techniques, including silica gel, Sephadex LH-20 and preparative HPLC. Their structures were identified on the basis of chemical properties and spectroscopic data, as 3, 5-dimethoxy-4-hydroxymyricanol (1), myricanol (2), myricanone (3), myricanol 11-sulfate (4), myricitrin (5), quercetin (6), quercetin-3-rhamnoside (7), tamarixol (8), uvaol (9), ursolic acid (10), taraxerol (11), myricadiol (12), beta-sitosterol (13) and beta-daucosterol (14). Among them, compound 1 is a new compound, named as 3, 5-dimethoxy-4-hydroxymyricanol, compounds 8, 9 were isolated from the genus Myrica for the first time. PMID- 26521448 TI - [Establishment and application of HPLC-QAMS for quality evaluation of Chuanxiong Rhizoma]. AB - A quantitative analysis method of multi-components with a single marker (QAMS) for simultaneous determination of six marker compounds (one from phenolic acids and five from phthalides) in Chuanxiong Rhizoma was established by applying HPLC and using butylidenephthalide as the internal reference substance. And also the feasibility and accuracy of the established method for quality evaluation and application of Chuanxiong Rhizoma were investigated and validated. The analysis was performed with the mobile phase consisting of acetonitrile - 0.2% aqueous formic acid. The flow rate was 1.0 mL . min-1 and the column temperature was maintained at 30 degrees C. The detection wavelengths were set at 252 nm (for ferulic acid, Z-ligustilide, and butylidenephthalide) and 266 nm (for senkyunolide I, senkyunolide A, and coniferyl ferulate), separately, and 20 uL was injected for analysis with gradient elution. The results showed that there were no significant differences observed between the HPLC-QAMS method and the external standard method (RSD <5%). The relative correction factors were credible (RSD < 5%) in changed chromatographic conditions. The established HPLC-QAMS method can be accurately used for simultaneously evaluating and controlling the quality of Chuanxiong Rhizoma with multi-components. PMID- 26521449 TI - [Rapid N-glycosylation profiling of glycoprotein based on ultrafiltration devices]. AB - With development of bio-technique, more and more proteins were applied as clinical approaches. However, the protein homogeneity, especially the N glycosylation limited the further research and application of these protein drugs. The analysis method for N-glycans is believed to be critical in protein drugs development. To enhance the N-glycans isolation efficiency and accelerate the pretreatment, a new strategy was built on ultrafiltration-devices. New methods increased the isolation efficiency of N-glycans containing N acetylglucosa mine with 10%-20%. The degrading of N-glycans containing sialic acids was also minimized with this method. 20%-100% more N-glycans with sialic acids were isolated. The pretreatment was finished within 30 min. Coupled with HPLC-HRMS, an effective and reliable strategy designed for protein drugs N glycans analysis were developed. PMID- 26521450 TI - [The construction of cell-penetrating peptide R8 and pH sensitive cleavable polyethylene glycols co-modified liposomes]. AB - The purpose of the study is to construct R8 peptide (RRRRRRRR) and pH sensitive polyethylene glycols (PEG) co-modified liposomes (Cl-Lip) and utilize them in breast cancer treatment. The co-modified liposomes were prepared with soybean phospholipid, cholesterol, DSPE-PEG2K-R8 and PEG5K-Hz-PE (pH sensitive PEG). The size and zeta potential of Cl-Lip were also characterized. The in vitro experiment demonstrated that the Cl-Lip had high serum stability in 50% fetal bovine serum. The cellular uptake of Cl-Lip under different pre-incubated conditions was evaluated on 4T1 cells. And the endocytosis pathway, lysosome escape ability and tumor spheroid penetration ability were also evaluated. The results showed the particle size of the Cl-Lip was (110.4 +/- 5.2) nm, PDI of the Cl-Lip was 0.207 +/- 0.039 and zeta potential of the Cl-Lip was (-3.46 +/- 0.05) mV. The cellular uptake of Cl-Lip on 4T1 cells was pH sensitive, as the cellular uptake of Cl-Lip pre-incubated in pH 6.0 was higher than that of pH 7.4 under each time point. The main endocytosis pathways of Cl-Lip under pH 6.0 were micropinocytosis and energy-dependent pathway. At the same time, the Cl-Lip with pre-incubation in pH 6.0 had high lysosome escape ability and high tumor spheroid penetration ability. All the above results demonstrated that the Cl-Lip we constructed had high pH sensitivity and is a promising drug delivery system. PMID- 26521451 TI - [Quantitative structure characteristics and fractal dimension of Chinese medicine granules measured by synchrotron radiation X-ray computed micro tomography]. AB - The shape and structure of granules are controlled by the granulation process, which is one of the main factors to determine the nature of the solid dosage forms. In this article, three kinds of granules of a traditional Chinese medicine for improving appetite and promoting digestion, namely, Jianwei Granules, were prepared using granulation technologies as pendular granulation, high speed stirring granulation, and fluidized bed granulation and the powder properties of them were investigated. Meanwhile, synchrotron radiation X-ray computed micro tomography (SR-uCT) was applied to quantitatively determine the irregular internal structures of the granules. The three-dimensional (3D) structure models were obtained by 3D reconstruction, which were more accurately to characterize the three-dimensional structures of the particles through the quantitative data. The models were also used to quantitatively compare the structural differences of granules prepared by different granulation processes with the same formula, so as to characterize how the production process plays a role in the pharmaceutical behaviors of the granules. To focus on the irregularity of the particle structure, the box counting method was used to calculate the fractal dimensions of the granules. The results showed that the fractal dimension is more sensitive to reflect the minor differences in the structure features than the conventional parameters, and capable to specifically distinct granules in structure. It is proved that the fractal dimension could quantitatively characterize the structural information of irregular granules. It is the first time suggested by our research that the fractal dimension difference (Df,c) between two fractal dimension parameters, namely, the volume matrix fractal dimension and the surface matrix fractal dimension, is a new index to characterize granules with irregular structures and evaluate the effects of production processes on the structures of granules as a new indicator for the granulating process control and optimization. PMID- 26521452 TI - [Preparation and evaluation of risperidone-loaded microsphere/sucrose acetate isobutyrate in situ forming complex depot with double diffusion barriers]. AB - In the present study, a risperidone loaded microsphere/sucrose acetate isobutyrate (SAIB) in situ forming complex depot was designed to reduce the burst release of SAIB in situ forming depot and to continuously release risperidone for a long-term period without lagime. The model drug risperidone (Ris) was first encapsulated into microspheres and then the Ris-microspheres were embedded into SAIB depot to reduce the amount of dissolved drug in the depot. The effects of different types of microsphere matrix, including chitosan and poly(lactide coglycolide) (PLGA), matrix/Ris ratios in microspheres and morphology of microspheres on the drug release behavior of complex depot were investigated. In comparison with the Ris-loaded SAIB depot (Ris-SAIB), the complex depot containing chitosan microspheres (in which chitosan/Ris = 1 : 1, w/w) (Ris-Cm SAIB) decreased the burst release from 12.16% to 5.80%. However, increased drug release rate after 4 days was observed in Ris-Cm-SAIB, which was caused by the high penetration of the medium to Ris-Cm-SAIB due to the hydrophilie of chitosan. By encapsulation of risperidone in PLGA microspheres, most drugs can be prevented from dissolving in the depot and meanwhile the hydrophobic PLGA can reduce the media penetration effect on the depot. The complex depot containing PLGA microspheres (in which PLGA/ drug=4 : 2, w/w) (Ris-Pm-SAIB) showed a significant effectiveness on reducing the burst release both in vitro and in vivo whereby only 0.64% drug was released on the first day in vitro and a low AUC0-4d value [(105.2+/- 24.4) ng.mL-1.d] was detected over the first 4 days in vivo. In addition, drug release from Ris-Pm-SAIB can be modified by varying the morphology of microspheres. The porous PLGA microspheres could be prepared by adding medium chain triglyceride (MCT) in the organic phase which served as pore agents during the preparation of PLGA microspheres. The complex depot containing porous PLGA microspheres (which were prepared by co-encapsulation of 20% MCT) (Ris-PPm-SAIB) exhibited a slightly increased AUC0-4d of (194.6+/-15.8) ng.mL-1d and high plasma concentration levels from 4 to 78 days [Cs(4-78d)=(7.8+/-1.2) ng.mL-1]. The plasma concentration on 78 day C78d was (9.0 2.5) ng.mL-1 which was higher than that of Ris-Pm-SAIB [C78d= (1.6 +/- 0.6) ng.mL-1]. In comparison with Ris-Pm SAIB, the AUC4-78d of Ris-PPm-SAIB increased from (379.0+/-114.3) ng.mL-1.d to (465.0 +/-149.2) ng.mL-1.d, indicating sufficient drug release from the Ris-PPm SAIB. These results demonstrate that the risperidone loaded porous PLGA microsphere/SAIB in situ forming complex depot could not only efficiently reduce the burst release of SAIB depot both in vitro and in vivo, but also release the drug sufficiently in vivo, and be capable to continuously release the drug for 78 days. PMID- 26521453 TI - [Identification of medicinal plant Dendrobium based on the chloroplast psbK-psbI intergenic spacer]. AB - In this paper, the chloroplast psbK-psbI intergenic spacers of 18 species of Dendrobium and their adulterants were amplified and sequenced, and then the sequence characteristics were analyzed. The sequence lengths of chloroplast psbK psbI regions of Dendrobium ranged from 474 to 513 bp and the GC contents were 25.4%-27.6%. The variable sites were 71 while the informative sites were 46. The inter-specific genetic distances calculated by Kimura 2-parameter (K2P) of Dendrobium were 0.006 1-0.058 1, with an average of 0.028 4. The K2P genetic distances between Dendrobium species and Bulbophyllum odoratissimum were 0.093 2 0.120 4. The NJ tree showed that the Dendrobium species can be easily differentiated from each other and 6 samples of the inspected Dendrobium species were identified successfully through sequencing the psbK-psbI intergenic spacer. Therefore, the chloroplast psbK-psbI intergenic spacer can be used as a candidate marker to identify Dendrobium species and its adulterants. PMID- 26521454 TI - [The in vitro dissolution of total composition of the tablet of rhizomes of Ligusticum chuanxiong components and in vitro-in vivo correlation by the method of area under the absorbance-wavelength curve]. AB - To discuss the availability of evaluation on the dissolution studies of the multicomponents in traditional Chinese medicine, the in vitro dissolution of total composition of the tablet of rhizomes of Ligusticum chuanxiong components and its correlation with the in vivo were studied by the method of area under the absorbance-wavelength curve (AUAWC). Taken the tablet of rhizomes of Ligusticum chuanxiong components which is composed of sodium ferulate and ligustrazine hydrochloride as subject model, the dissolution tests were carried out with basket method. The plasma concentrations of tablets in different rats were determined by AUAWC at different interval times. The in vivo absorption percentage was calculated by Wagner-Nelson equation to evaluate the in vitro and in vivo correlation. According to the results, the cumulative dissolution in vitro of total composition of tablets of rhizomes of Ligusticum chuanxiong components at 60 min was 90.65% in water by AUAWC. The in vivo pharmacokinetics is fitted with an one-compartment model. The linear equation based on the cumulative dissolution rate (fr) and absorption percentage (fa) at 5, 10, 20, 30 and 60 min was fa = 0.819 7 fr+0.183 and the correlation coefficient was 0.959 5, which showed a good correlation between the in vitro dissolution and the in vivo absorption percentage. The method of AUAWC can be used accurately, feasibly and conveniently to evaluate the in vitro and in vivo correlation of total composition of tablets of rhizomes of Ligusticum chuanxiong components, which will provide better guidance to study the in vitro and in vivo correlation of sustained release preparation etc under complex system of traditional Chinese medicine in the future. PMID- 26521455 TI - [EFFICIENCY "SLEEVE" GASTRECTOMY IN TREATMENT OF OBESITY]. AB - The possible mechanisms of clinical efficacy "sleeve" gastrectomy in patients with obe- sity were analysed. The metabolic effect transactions associated not only with reducing the volume of the stomach, but the acceleration passage of gastric contents of the tube and the small intestinp_ PMID- 26521456 TI - [INFULGAN-OPTIMAL ANALGETIC DRUG FOR USE IN LAPAROSCOPIC SURGERY]. AB - The experience of the application of 78 patients after various laparoscopic procedures was generalized. As perioperative anesthesia drug Infulgan (production of corporation "Jury-Farm") was applyed. Appointment of Infulgan in standard dose ensured the achievement expressed analgesic effect, reducing the volume of injected opioids and frequency of adverse reactions. PMID- 26521457 TI - [RENTGENOENDOSCOPIC INTERVENTIONS FOR BILIARY OBSTRUCTION OF NON-TUMOR GENESIS]. AB - We analyzed the immediate and long-term results of endoscopic diagnostic and therapeutic interventions in patients on the non-tumor obstruction of the bile ducts. Application of the developed diagnostic algorithm using ultrasound, fistulocholangiography, computer and magnetic resonance imaging, endoscopic retrograde cholangiopancreatography, diagnostic endoscopic papillosphincterotomy, instrumental revision of bile ducts, transduodenal holedohoscopy provided sensitive diagnostic reasons of non-tumor biliary obstruction to (94.2 +/- 1.7)%. Optimization of treatment strategy developed with the introduction of the clinic endobiliary endoscopic intervention has achieved positive results in 83.7% of patients, reducing the morbidity of 1.7%, mortality--0.9%. PMID- 26521458 TI - [CREATING A CROSS-TUNNEL UNDER OSTIUM OF MAIN HEPATIC VEINS AND PIGGY BACK FUND LIVER ABLATE TUMOR THROMBUS FROM THE INFERIOR VENA CAVA]. AB - The analysis of the effectiveness of a new method of thrombectomy, including the formation of cross-tunnel under the ostium of the main hepatic veins by removing tumor thrombus of the inferior vena cava (IVC). Successfully perform a piggy back manage to mobilize the liver in 12 (80%) patients, a tunnel formed in 4 (50%). Duration pigg back stage liver mobilization much higher than the formation of the tunnel. Forming tunnel cross recommended conditions when the IVC portion covered retrohepatic liver less than 1/2 of a circle or when the surgeon is sure to Derform manipulation capabilities. PMID- 26521459 TI - [TREATMENT OF ACUTE CALCULOUS CHOLECYSTITIS: "EARLY" OR "PLANNED" LAPAROSCOPIC CHOLECYSTECTMIVY]. AB - The comparative analysis of results of surgical treatment of 82 patients with acute cholecystitis, which made "early" (ELCE) or "planned" (PLCE) laparoscopic cholecystectomy (LCE) in the surgical department for the period from 2012 to 2014. The analysis showed that LCE can be set in any time from the beginning of acute cholecystitis. However, priority should be given ELCE, providing significant reduction in duration of treatment of patients in hospitals and is more cost effective. PMID- 26521460 TI - [PREVENTION AND CORRECTION OF PULMONARY COMPLICATIONS FOR SEVERE ACUTE PANCREATITIS]. AB - Increased of proinflammatory cytokines levels, including interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) on severe acute pancreatitis causes vasodilatation, increased permeability of the wall, accumulation of fluid in lung tissue and pleural sinuses. Transudate from acute parapancreatyc clusters of hot liquid and abdomen falls into the chest cavity through microscopic defects in the diaphragm due to the formation of pathological pleural-peritoneal connections or the relevant pressure gradient between the abdominal and pleural cavities. Remediation and removal of acute parapancreatyc clusters combined with the use of a multicomponent drug infusion therapy Cytoflavin provide a reduction in the frequency of pulmonary complications of acute pancreatitis from 48.3 to 31.0%. Use of the drug Cytoflavin reduces the severity of endogenous intoxication and mortality from acute lung injury from 12.9 to 6.1%. PMID- 26521461 TI - [IMMUNOHISTOCHEMICAL AND CYTOLOGICAL ASSESSMENT OF LOCAL INFLAMMATORY REACTION IN THE EARLY POSTOPERATIVE PERIOD IN PATIENTS UNDERGOING SURGERY FOR COMPLEX FORMS OF ACUTE PARAPROCTITIS]. AB - The optimal time to fulfill the second (plastic) phase delayed early radical surgery in patients over the complicated forms of acute paraproctitis. On the 7th day after the opening of an abscess in a smear from the surface layer of the wound inflammatory regenerative cytogram type was observed in 66.8% of patients, early regenerative type--at 33.2%. On the 10th day was observed regenerative cytogram type. The dynamics of the concentration of cytokines in wound fluid on the 7th day showed a favorable course of wound healing process, without increasing the levels of proinflammatory cytokines, which allowed to perform the second stage of early delayed surgery in 7-10 days. PMID- 26521462 TI - [THE EXPRESSION OF TLR-4 GENE MONONUCLEAR CELLS PERIPHERAL BLOOO IN PATIENTS BY HIGH RISK OF PURULENT-INFLAMMATORY COMPLICATIONS AFTER SURGERY FOR ACUTE DISEASES OF THE ABDOMINAL ORGANS]. AB - The specified level of gene expression TLR-4 in peripheral blood mononuclear cells in 77 patients operated on acute diseases of the abdominal organs in the 1st and the 4th day after surgery was determined. Established dynamic changes of gene expression TLR-4. Adverse course early postoperative period in patients initially high and medium risk of purulent-septic complications was accompanied by activation of gene expression TLR-4 in peripheral blood mononuclear cells. PMID- 26521463 TI - [VIABILITY OF MYOCAROIUM AS RISK FACTOR FOR MORTALITY IN EARLY AND LATE PERIOD AFTER BYPASS SURGERY OF CORONARY ARTERIES IN PATIENTS WITH CORONARY HEART DISEASE AND SEVERE LEFT VENTRICULAR DYSFUNCTION]. AB - In coronary heart disease and low ejection fraction of the left ventricle (LV) in patients after coronary artery bypass surgery tend mortality and complication rate higher than preserved LV systolic function. Significant preoperative predictors of early mortality and remote in these patients, and the incidence of complications in the early postoperative period were reveald. PMID- 26521464 TI - [FEATURES ROTATIONAL MOTION OF LEFT VENTRICULAR WALLS IN PATIENTS WITH AORTAL STENOSIS]. AB - The features of the rotational movement of the left ventricle (LV) walls in patients with aortal stenosis (AS) were studied. In normal and AS rotation basal and apical parts of the LV walls occurs in mutually antithetical ways: basal rotate clockwise, apical-counterclockwise. Increased systolic pressure gradient with AS to (103.5 +/- 21.3) mm Hg accompanied by a compensatory increase in the LV myocardium before curling (33.1 +/- 5.1). Increased performance twisting LV myocardium at AS is due to the increase of rotation as the basal and apical parts of its walls. Thus, an increase in the twisting AS provides overcoming severe obstruction of the affected aortic valve, and is a compensatory factor in maintaining normal cardiac output for a long time. PMID- 26521465 TI - [SURGICAL TREATMENT OF VARICOSE DISEASE, COMPLICATED BY VARICOTHROMBOPHLEBITIS, COMBINED WITH TROPHIC ULCERS]. AB - The comparative analysis of treatment results of 40 patients over the varicose disease of the lower extremities, complicated varicothrombophlebitis, in conjunction with trophic ulcers was conducted. In 22 (55%) patients (I group) performed radical surgery with minimally invasive techniques, in 18 (45%) patients (11 group)--crossectomy followed by conservative therapy. The active tactics and radical surgery varicose disease of the lower extremities, trophic ulcers, and complicated by the varicothrombophlebitis, have led to effective results and improve of patients quality of life. PMID- 26521466 TI - [EXPERIENCE OF SEVERE CHRONIC VENOUS INSUFFICIENCY OF THE LOWER EXTREMITIES TREATMENT]. AB - The results of treatment of 246 patients on different forms of chronic venous insufficiency of the lower extremities were presented. The leading diagnostic criterion when choosing tactics consider patients ultrasound duplex scanning with color mapping. Patients in the presence of large ulcers basic treatment is autodermoplasty. The complex treatment include pharmacotherapy, the use of elastic compression hosiery. PMID- 26521467 TI - [COMPARISON OF INTRAOPERATIVE SCLEROOBLITERATION AND ECHOSCLEROOBLITERATION EFFICIENCY OF VARICOSE DISEASES OF THE LOWER EXTREMITIES C6 CLASS IN PATIENTS BY TYPE II DIABETES MELLITUS]. AB - The experience of surgical treatment of 50 patients for varicose disease of lower extremities, complicated by trophic ulcers, in the presence of diabetes mellitus type II were analysed. During surgery in patients of the 1st group performed a combined phlebectomy, group 2--scleroobliteration and echoscleroobliteration. Using fleboscleroobliteration method helped reduce the frequency of early postoperative complications in (6.5 +/- 1.3) times. PMID- 26521468 TI - [APPLICATIONS ENDOVASCULAR HEMOSTASIS TREATMENT OF PULMONARY HEMORRHAGE]. AB - Rentgenoendovascular embolization of bronchial arteries was performed in 222 patients about pulmonary hemorrhage (PH) of different nature. Resistant hemostasis was achieved in 198 (89.9%) patients. The possibility of endovascular hemostasis in patients in advanced lung cancer complicated by PH. Hemostasis was ineffective in 24 (10.8%) patients. Died 5 (2.2%) patients due to unresectable lung cancer. The reasons for ineffective hemostasis were analysed. PMID- 26521469 TI - [BRAF-STATUS OF PAPILLARY THYROID CARCINOMAS AND STRATEGY OF SURGICAL TREATMENT]. AB - Analyzed the presence of BRAF V600E mutation in the focal thyroid gland in the preoperative diagnosis of papillary carcinoma (PC). Molecular genetic testing conducted on puncture aspirates from 26 patients before surgery. The diagnosis was verified according to the morphological investigations. Mutations in BRAF V600E detected only in patients with the thyroid PC. Thus, the definition of BRAF V600E mutation may be a marker in the preoperative diagnosis of thyroid PC. Analyzed the presence of BRAF V600E mutation in the focal thyroid gland in the preoperative diagnosis of papillary carcinoma (PC). Molecular genetic testing conducted on puncture aspirates from 26 patients before surgery. The diagnosis was verified according to the morphological investigations. Mutations in BRAF V600E detected only in patients with the thyroid PC. Thus, the definition of BRAF V600E mutation may be a marker in the preoperative diagnosis of thyroid PC. PMID- 26521470 TI - [BODY SUPPORT ROLE NUTRITIONAL VICTIMS WITH BURN INJURIES IN THE STAGE SEPTICOTOXEMIA]. AB - The analysis of the treatment results of burn victims septicotoxemia of 120 injured persons in the area of thermal lesions 40-70% of the body surface. The dynamics of the clinical course of burn disease influenced by nutritional support with solutions of amino acids (AA) Aminosol and Aminosol-neo. Patients performed enteral, parenteral and mixed food. Parenteral nutrition improves the quality and results of treatment in stage burn septicotoxemia, contributes to an earlier elimination syndrome hipermetabolizm-hiperkatabolizm and readiness wounds to the plastic skin renewal and better engraftment of transplanted grafts of skin, reducing the frequency of complications and duration of hospitalization. PMID- 26521472 TI - [STRATEGY OF ANTIBACTERIAL THERAPY OF SEPSIS. PART I]. PMID- 26521471 TI - [NEUROBLASTOMA IN PEDIATRIC PATIENTS]. AB - Neuroblastoma the most common malignant tumor of childhood, which is often localized in the retroperitoneal space, mainly in the adrenal glands, paravertebral retroperitoneal space, at rare in the posterior mediastinum, in the neck, presacral area. First symptoms of neuroblastoma are nonspecific, mimic various diseases. In the following clinical manifestations depend on the localization of the tumor, stage presence and location of metastases. In the diagnosis of neuroblastoma using ultrasonography and computed tomography. Of the 26 children whose neuroblastoma detected in different periods have died 12. Radical removal of the tumor only effective the first year of life. Chemotherapy is effective in 50% of operated children. PMID- 26521473 TI - [PROPHYLACTIC METHOD FOR POSTOPERATIVE TROCAR HERNIAS OCCURRENCE AFTER LAPAROSCOPIC CHOLECYSTECTOMY]. PMID- 26521474 TI - [FULL CROSS GAP PANCREAS WITH CLOSED ABDOMINAL TRAUMA]. PMID- 26521475 TI - [VACUUM THERAPY OF INFECTED WOUNDS IN LAPAROSTOMY IN ABDOMINAL SURGERY]. PMID- 26521476 TI - [EFFICACY OF ELECTROWELDING TECHNOLOGY IN ELECTIVE AND URGENT ABDOMINAL SURGERY]. PMID- 26521477 TI - [EMPIRIC ANTIBACTERIAL THERAPY IN SURGICAL TREATMENT OF DIABETIC FOOT SYNDROME]. PMID- 26521478 TI - [Realistic dopamine--the study progress of Parkinson's disease]. PMID- 26521479 TI - [Research Progress of Pathogenesis and Treatment of Parkinsons Disease]. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease. The most prominent pathological features are the loss of dopaminergic neurons in the substantia nigra pars compacta and the deposition of intraneuronal inclusions named Lewy bodies in most cases. The most prominent symptom of PD is the impairment of motor behavior due to the loss of dopaminergic neurons and the consequent loss of the dopamine signaling in the basal ganglia. So DA replacement (including L-dopa, the gold standard treatment) still remains to be the best treatment for the disease due to its ability of relieving most of the motor symptoms. Growing evidence suggests that a combination of environmental, genetic factors and aging may contribute to PD. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and excitability toxicity contribute to the pathogensis of PD. Currently available treatments for PD, including drug therapy, surgical treatment, cell and tissue transplantation and gene therapy, but their efficacy was unsatisfactory. Here we review the most recent findings and developments about pathogenesis and treatment of PD, and hope to offer some clues for clinical drug development and novel alternative therapies. PMID- 26521480 TI - [The "Yin/Yang" Functional Features of Neurotrophic Factors]. AB - Neurotrophic factor is a kind of protein family that plays an important role in the nutrition, support and differentiation to central neurons as well as synaptic plasticity. Growing evidences have revealed that pro-forms of various neurotrophic factors, which are generated in process of protein synthesis and might exert opposite roles involving in inducement of neuronal apoptosis and implication in pathogenesis of neurodegenerative diseases. This paper reviews "Yin/Yang" features of neurotrophic factors in the anabolism, receptor regulation, functional aspects, and their related role in pathogenesis of neurodegenerative diseases. It is hopefully to provide new idea on understanding and investigation of the neurotrophic factors regarding on their functional, pathological and potential therapeutic significance. PMID- 26521481 TI - [The Function of Neuroinflammation in Parkinson Disease]. AB - Parkinson disease (PD) is the second most common neurodegenerative disorder, characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN). The pathology of PD remains unclear. Recent findings suggests neuroinflammation plays a critical role in PD. Occurrence of neuroinflammation, including microglia and astrocyte activation, T lymphocyte infiltration and blood brain barrier disruption, has been identified in PD. However, the mechanism of neuroinflammation regulation in PD is not fully deciphered. In this review, we focus on the cutting edge in researches of neuroinflammation in PD, which may provide us new ideas in prevention and recovery of PD. PMID- 26521482 TI - [The Role of Iron and Alpha-synuclein Interacting in Parkinson's Disease]. AB - Both iron and alpha-synuclein accumulation are one of hallmarks of Parkinson's disease (PD). Alpha-synuclein aggregation is often accompanied by abnormal accumulation of iron, indicating that there is a certain link between iron and alpha-synuclein aggregation. Iron promotes alpha-synuclein aggregation by increasing its synthesis and decreasing its degradation. Also, alpha-synuclein regulates iron metabolism through its ferrireductase activity. In this review, we will describe the roles of iron and alpha-synuclein in PD pathogenesis, and the mechanisms of iron and alpha-synuclein interaction. PMID- 26521483 TI - [Parkinson Disease With Rapid Eye Movement Sleep Behavior Disorder]. AB - Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by lack of muscle atonia during REM sleep and enactment of dream content. RBD is associated with Parkinson disease (PD) and has high incidence in PD patients. PD patient with RBD mainly presents rigid type, has longer disease duration, more severe motor and non-motor symptoms and poorer activity of daily living and life quality. The pathophysiological mechanisms of RBD may be related to dysfunctions of pontine tegmentum, locus coeruleus/sub-locus coeruleus complex and related projections. The diagnosis of RBD depends on clinical histories and video polysomnography (v-PSG). Besides treatment for PD, protective measures have to be taken for patients and their sleep partners. If abnormal behaviors during sleep cause distress and danger,patients should be given drug therapy. PMID- 26521484 TI - [Clinical Features and Pathogenic Mechanisms of Parkinson Disease With Pure Apathy]. AB - Parkinson disease (PD) is a common neurodegenerative disease characterized by classical motor symptoms, including static tremor, bradykinesia, rigidity and postural and gait abnormalities. Besides, recent studies have found a variety of non-motor symptoms, including neuropsychiatric symptoms, sleep disorders, abnormal sensory and autonomic dysfunctions, etc. PD with pure apathy, referring to apathy without dementia and depression, is correlated with motor symptoms and other non-motor symptoms, and greatly reduces the activity of daily living and the quality of life for PD patients. The pathogenesis of PD with pure apathy involves the mechanisms of neuroanatomy, neuropathology, neurological biochemistry and neuroinflammation. This paper will introduce the clinical features and pathogenic mechanisms of PD with pure apathy. PMID- 26521485 TI - [Mouse models of polycystic ovary syndrome]. PMID- 26521486 TI - [Alternative splicing in the bile acids metabolism and regulation]. PMID- 26521487 TI - [Ca2(+)-signaling regulates cell death: the mechanisms]. PMID- 26521488 TI - [The function of 3beta-hydroxysteroid dehydrogenase in steroidogenesis tissues]. PMID- 26521489 TI - [The role of peroxisome proliferator-activated receptors in the pathogenesis of nonalcoholic fatty liver disease]. PMID- 26521490 TI - [MicroRNAs and diabetic nephropathy]. PMID- 26521491 TI - [Progress in the development of diabetes mellitus and its complications: the role of ALDH2]. PMID- 26521492 TI - [Ion channels play a role on cell proliferation and osteogenic differentiation of MSCs]. PMID- 26521493 TI - [Posttranslational modification and expression regulation of aquporin AQP2]. PMID- 26521494 TI - Reflections on Clinical Simulation: The Past, Present, and Future. PMID- 26521495 TI - A Systematic Review of the Literature Related to the NLN/Jeffries Simulation Framework. AB - AIM: The purpose of this manuscript it to disseminate findings from a systematic review of the literature related to the NLN/Jeffries Simulation Framework. BACKGROUND: This review was initiated by the National League for Nursing to illuminate what is currently known about best simulation practices, research to support these practices, and priorities for future research. It is part of a larger project aimed at further developing the NLN/Jeffries Simulation Framework. METHOD: Searches using CINAHL, the journal Simulation in Healthcare, and reference lists from key documents yielded 1,533 relevant publications for the period January 2000 to September 2014. RESULTS: The final review of the literature includes 153 studies. Three themes, along with key issues, gaps, and best practices supported by the literature, were identified. CONCLUSION: This systematic review provides empirical support for the major components of the NLN/Jeffries Simulation Framework and contributes to its further development. PMID- 26521496 TI - NLN Jeffries Simulation Theory: Brief Narrative Description. PMID- 26521497 TI - INACSL Standards of Best Practice for Simulation: Past, Present, and Future. AB - AIM: To describe the historical evolution of the International Nursing Association for Clinical Simulation and Learning's (INACSL) Standards of Best Practice: Simulation. BACKGROUND: The establishment of simulation standards began as a concerted effort by the INACSL Board of Directors in 2010 to provide best practices to design, conduct, and evaluate simulation activities in order to advance the science of simulation as a teaching methodology. METHOD: A comprehensive review of the evolution of INACSL Standards of Best Practice: Simulation was conducted using journal publications, the INACSL website, INACSL member survey, and reports from members of the INACSL Standards Committee. RESULTS: The initial seven standards, published in 2011, were reviewed and revised in 2013. Two new standards were published in 2015. The standards will continue to evolve as the science of simulation advances. CONCLUSION: As the use of simulation-based experiences increases, the INACSL Standards of Best Practice: Simulation are foundational to standardizing language, behaviors, and curricular design for facilitators and learners. PMID- 26521498 TI - The National League for Nursing Project to Explore the Use of Simulation for High Stakes Assessment: Process, Outcomes, and Recommendations. AB - AIM: This project was designed to explore the feasibility of using simulation for high-stakes assessment in pre-licensure RN programs. METHOD: A think tank of experts recommended simulation scenarios suitable for assessing students at the end of their program. Two teams were formed: one to design the simulations, the other to develop the evaluation plan. Scenarios were piloted and refined, then sent to schools across the country. Student performances on video recordings were scored by raters. RESULTS: Essential elements of simulation design, implementation, evaluation tools, and processes were found. CONCLUSION: Well designed and facilitated scenarios, delivered in the controlled environment of the simulation center, can be a reliable and valid tool for evaluating the clinical skills of students. PMID- 26521499 TI - Enhancing Clinical Reasoning Through Simulation Debriefing: A Multisite Study. AB - AIM: The aim of this research was to replicate Dreifuerst's 2012 findings of enhanced clinical reasoning scores using a structured debriefing: Debriefing for Meaningful Learning (DML). BACKGROUND: The direct effect of debriefing on clinical reasoning is not well studied. The nursing education literature supports debriefing as a reflective dialogue necessary to enhance clinical reasoning. METHOD: A quasi-experimental, pretest-posttest, repeated measure research design was used to evaluate nursing students' clinical reasoning using the Health Sciences Reasoning Test (HSRT). RESULTS: The change in HSRT mean scores was determined to be significant for the intervention group at the .05 level and insignificant for the control group. The change in HSRT mean scores between the intervention and control groups was determined to be significant at the .10 level. CONCLUSION: Nursing students who had the DML debriefing scored significantly higher in their clinical reasoning than nursing students who had usual and customary debriefing. PMID- 26521500 TI - Psychometric Testing of a Simulation Rubric for Measuring Interprofessional Communication. AB - AIM: The aim of this study was to establish psychometric testing of the Indiana University Simulation Integration Rubric (IUSIR), a tool for measuring interprofessional communication in simulations. BACKGROUND: Educators engage in a wide variety of activities to promote interprofessional education, with many of these activities involving simulation. As interprofessional education evolves, tools are needed to measure the effectiveness of interventions. METHOD: A sample of 229 pre-licensure bachelor of science in nursing students and 66 pre-licensure first- and second-year medical students was evaluated using the IUSIR. Cronbach's alpha, inter-item and inter-total correlations, and interrater agreement were used to evaluate reliability of the tool. An ANOVA to test for difference between the two levels of students was used to establish validity. RESULTS: Reliability and validity were supported for all individual items for nursing and medical students, and for all team items CONCLUSION: The IUSIR is a reliable and valid measure for interprofessional communication. PMID- 26521501 TI - Updating the Simulation Effectiveness Tool: Item Modifications and Reevaluation of Psychometric Properties. AB - AIM: This study evaluated the psychometric properties of the modified Simulation Effectiveness Tool (SET), the SET-M. BACKGROUND: The SET, developed in 2005, was updated to be consistent with INACSL Standards of Best Practice, QSEN practices, and American Association of Colleges of Nursing baccalaureate essentials. METHOD: Undergraduate nursing students from two nursing programs, one with multiple campuses, completed the SET-M following completion of a simulated clinical experience; 1,288 students took part in the study. RESULTS: Exploratory factor analysis was completed using unweighted least squares. Four subscales were identified with acceptable internal consistency: Prebriefing (alpha = .833), Learning (alpha = .852), Confidence (alpha = .913), and Debriefing (alpha = .908). CONCLUSION: Revisions made to modify the SET to current standards of simulation practice have resulted in the SET-M, which has been shown to be a valid and reliable method of evaluating students' perceptions of the effectiveness of learning in the simulation environment. PMID- 26521502 TI - Effectiveness of Simulation Preparation on Novice Nurses' Competence and Self Efficacy in a Multiple-Patient Simulation. AB - This study examined the influence of three simulation preparation methods (expert modeling/intervention, voice-over PowerPoint/active control, and reading assignments/passive control) on improving novice nurses' competence and self efficacy for providing care to multiple simulated patients. Both competence and self-efficacy were measured at baseline and following a five-week intervention. Twenty senior pre-licensure nursing students participated in the trial. One-way ANOVAs and parametric/nonparametric correlations were used. Voice-over PowerPoint and expert modeling resulted in greater improvements in self-efficacy compared with traditional reading assignments as simulation preparation. However, there was no relationship between change in competence and self-efficacy over time. PMID- 26521503 TI - Integrating Simulation into a Reflection-Centered Graduate Psychiatric/Mental Health Nursing Curriculum. AB - The purpose of this qualitative study was to explore reflections of student learning following a simulation experience integrated into a psychiatric/mental health nurse practitioner course. As the demand for clinical placement sites increases and availability of preceptors declines, students require experiences that will prepare them for competent patient care. This experiential learning activity was grounded in reflection-centered pedagogy, utilizing standardized patients. Three main themes emerged from the data: importance of feedback, insight gained, and improved confidence. Findings suggest that simulation is a promising approach to promote the development of competencies in graduate nursing education. PMID- 26521504 TI - Do You Hear What I Hear? The Impact of a Hearing Voices Simulation on Affective Domain Attributes in Nursing Students. AB - Affective domain teaching and learning can facilitate the reduction of stigmatization of clients with mental illness in nursing students. Experiential learning activities such as simulation are regarded as an effective method for facilitating student learning in the affective domain. The project reported here measured the impact of a simulation experience, "Hearing Voices Which Are Distressing," on attitudes, values, and beliefs of accelerated baccalaureate students caring for clients with mental illness who experienced hearing voices. PMID- 26521505 TI - Assessment of APRN Student Competency Using Simulation: A Pilot Study. AB - Assessment and evaluation of competency for advanced practice registered nurses (APRNs) is a challenge facing educators, regulators, and consumers of health care. The purpose of this study was to determine the effectiveness of using simulation to assess and evaluate APRN student competence in managing complex cases. Students were videotaped in the simulation laboratory at four separate intervals; two independent reviewers used the APRN Competency Evaluation Tool to review the simulation. Results showed statistically significant improvement in all categories of evaluation following increased exposure to simulation of complex cases. Student competence increased for managing complex patients, use of evidence-based guidelines, patient safety, leadership, prioritization, delegation, collaboration, communication, and professionalism. PMID- 26521506 TI - Fostering Learning Through Interprofessional Virtual Reality Simulation Development. AB - This article presents a unique strategy for improving didactic learning and clinical skill while simultaneously fostering interprofessional collaboration and communication. Senior-level nursing students collaborated with students enrolled in the Department of Interactive Media Studies to design a virtual reality simulation based upon disaster management and triage techniques. Collaborative creation of the simulation proved to be a strategy for enhancing students' knowledge of and skill in disaster management and triage while impacting attitudes about interprofessional communication and teamwork. PMID- 26521507 TI - Seeing Through Google Glass: Using an Innovative Technology to Improve Medication Safety Behaviors in Undergraduate Nursing Students. AB - Addressing safe medication administration skills and behaviors is integrated throughout many nursing curricula using high-fidelity simulation. Simulation allows students to practice on electronic manikins in a safe environment, allowing for independent, critical thinking as medications are administered. However, the restricted physical environment, often behind a one-way mirror, inhibits faculty from observing the processes students use to calculate or reference medication dosages. This article describes the errors in medication administration identified through use of Google Glass, an innovative technology that allows video recording from the student's perspective. PMID- 26521508 TI - Developing a Theory-Based Simulation Educator Resource. AB - The NLN Leadership Development Program for Simulation Educators 2014 faculty development group identified a lack of a common language/terminology to outline the progression of expertise of simulation educators. The group analyzed Benner's novice-to-expert model and applied its levels of experience to simulation educator growth. It established common operational categories of faculty development and used them to organize resources that support progression toward expertise. The resulting theory-based Simulator Educator Toolkit outlines levels of ability and provides quality resources to meet the diverse needs of simulation educators and team members. PMID- 26521509 TI - Connected Care Quotient (CCQ) and the Future of Nursing. PMID- 26521510 TI - NLN, in Collaboration with INACSL, Releases A Vision for Debriefing Across the Curriculum. PMID- 26521511 TI - HETEROLOGOUS EXPRESSION OF TOXOPLASMA GONDII DENSE GRANULE PROTEIN 2 AND 5. AB - Toxoplasmosis is a foodborne disease caused by Toxoplasma gondii, an obligate intracellular parasite. The parasite remains protected within a parasitophorous vacuole (PV), a specialized compartment formed within the infected host cell during and after invasion. Dense granules (GRA) are T. gondii specialized secretory organelles involved in PV development. GRA2 contributes to the formation of intravacuolar network in the PV, allowing nutrients transportation to nourish the parasites. GRA5 helps to inhibit apoptosis of the infected cells thereby protecting the parasites. As such, these two essential antigens have been selected as the target subjects. Heterologous expression in E. coli BL21 pLysS (DE3) of GRA2 and GRA5 fragment was achieved by transfecting with recombinant expression GRA2- and GRA5-pRSET B plasmid, respectively. His-tagged recombinant proteins were affinity purified using a Nickel-nitrilotriacetic acid column. The identities of recombinant rGRA2 (30 kDa) and 5 (20 kDa) proteins were confirmed by western blotting using immune serum from a patient with toxoplasmosis and by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. The purified T. gondii antigens provide candidates for future development of diagnostic kits of human infection as well as vaccines. PMID- 26521512 TI - SEROPREVALENCE OF TOXOPLASMA GONDII IN RODENTS FROM VARIOUS LOCATIONS IN PENINSULAR MALAYSIA. AB - Numerous studies have reported the prevalence of toxoplasmosis among Malaysians and various domestic animals; but there is paucity of information on its prevalence among rodents which could potentially contribute to the transmission of Toxoplasma gondii in both domestic and sylvatic fauna. Five hundred twenty-six rodents were captured from six locations in Malaysia and identified to species. Serum samples were collected from these rodents and tested for T.gondii antibodies using an immunofluorescent antibody test (IFAT). T.gondii antibodies were found in 5.9% (31/526) of the tested samples. Most of the positive antibodies were from commensal rats: Rattus exulans (9/64, 14.0%), Rattus argentiventer (2/8, 25%), Rattus rattus diardii (10/166, 6.0%) and Rattus tiomanicus (6/215, 2.7%). Only two of the forest rats were positive: Maxomys rajah (1/9, 11.1%) and Rattus bowersi (1/12, 8.3%). Eighteen point one percent of ground squirrels (Tupaia glis) tested (2/11) were positive for antibodies. The highest antibodies titer (1:1024) was found in Rattus exulans followed by T.glis (1:256). Sabak Bernam, Selangor had the highest prevalence (10.8%) followed by Baling, Kedah (5.0%) and Bagan Terap, Selangor (4.0%). None of the serum samples of rodents collected from Gua Musang, Kelantan; Jasin, Malacca; or Labis, Johor were positive. Our study reports for the first time the serologic prevalence of T.gondii antibodies among rodents in Peninsular Malaysia. Further studies are needed to confirm T.gondii infection among wild rodents, such as a bioassay, to assess their potential role in transmission of the parasite. PMID- 26521513 TI - TREMATODE INFECTION OF FRESHWATER SNAIL, FAMILY BITHYNIIDAE IN THAILAND. AB - Opisthorchis viverrini is restricted to and requires for its aquatic life cycle only Bithynia snail as first intermediate host but many species of cyprinid fish as second intermediate hosts. A survey in Thailand of trematode infection in freshwater snails of the family Bithyniidae carried out during October 2008 - July 2009 found a total of 5,492 snails, classified into ten species distributed in various geographic areas. Bithyniafuniculata and Gabbia pygmaea were localized to the north, B. s. goniomphalos, Wattebledia siamensis and W. crosseana to northeast and B. s. siamensis, Hydrobioides nassa and G. wykoffi to central region. W. baschi and G. erawanensis was found only in the south and Erawan waterfall, Kanchanaburi Province, respectively. Trematode infection rate was 3.15%. Cercariae were identified as belonging to six types, namely, amartae , monostome, mutabile, O. viverrini, virgulate, and unknown. The prevalence of cercarial infection in B. s. goniomphalos of amartae, mutabile, O. viverrini, virgulate, and unknown type cercaria was 0.55%, 0.74%, 1.07%, 2.87%, and 0.37%, respectively, and in B. s. siamensis monostome (1.10%) and virgulate (0.55%). Only virgulate cercariae were shed from W. crosseana (3.85%) and W. siamensis (5.19%). Cercariae of the unknown type were found in G. wykoffi (1.69%). No infection of O. viverrini cercariae was detected in the other species. PMID- 26521514 TI - BIONOMICS AND ECOLOGY OF ANOPHELES LITORALIS ON BONGAO ISLAND, TAWI-TAWI PROVINCE, PHILIPPINES: IMPLICATIONS FOR VECTOR CONTROL. AB - Entomological surveys were conducted to identify Anopheles malaria vector species, their feeding and resting behaviors, and characterization of larval habitats on Bongao Island, Tawi-tawi Province, in July and November, 2007. Survey parameters included all-evening human-landing collections (HLC), evening buffalo baited trap (BBT) collections, daytime indoor and outdoor adult resting collections, adult female age-grading, identification of natural Plasmodium infections in mosquitoes, larval habitat identification and physical/biological characterization, and adult insecticide susceptibility assays. Both surveys revealed the predominant and putative malaria vector species on Bongao Island is Anopheles litoralis. Anophelesflavirostris was collected on only one occasion. The HLC during the July survey produced approximately 4 mosquitoes/human/night (mhn). The November survey yielded 1.27 mhn due, in part, to inclement weather conditions during time of sampling. Anopheles litoralis host seeking behavior occurred throughout the evening (06:00 PM - 06:00 AM) with peak biting between 10:00 PM and 04:00 AM. This species exhibited stronger zoophilic behavior based on comparison of HLC and BBT data. HLC showed a slightly greater exophagic (outdoor) behavior (1.4:1 ratio). During the July collection, an older adult population was present (75% parous) compared to the lower numbers of An. litoralis dissected in November (25% parous). Albeit a small sample size (n=19), 10.5% of An. litoralis dissected contained midgut oocysts of Plasmodium. Daytime adult resting harborages included biotic and abiotic sites in and around partially shaded, brackish water habitats where immature stages were common. Anopheles litoralis was found susceptible to pirimiphos-methyl and four different synthetic pyrethroids. This survey provides further epidemiological evidence of the importance of An. litoralis in malaria transmission on Bongao Island, and presumably throughout much of the Sulu Archipelago in the southern Philippines. Published observations of this species remain very limited and further investigations on the bionomics and epidemiological importance of this species are needed. Both ecological and human factors in malaria transmission are presented with implications for improved control of An. litoralis and prevention of infection. PMID- 26521515 TI - DISTRIBUTION OF PHLEBOTOMINE SAND FLIES (DIPTERA:PSYCHODIDAE) IN LIMESTONE CAVES, KHAO PATHAWI, UTHAI THANI PROVINCE, THAILAND. AB - This study investigated the species composition and density of the sand flies found inside four limestone caves at Khao Pathawi, Thap Than District, Uthai Thani Province. Sand flies were collected using Centers for Disease Control (CDC) light traps from October 2012 to September 2013. The sand flies were captured between 06:00 PM - 06:00 AM. A total of 11,817 sand flies were collected with a male:female ratio of 1.0:1.2 (5,325:6,492). The specimens were identified as eight species belonging to three genera Phlebotomus, Sergentomyia, Chinius, and comprised of S. anodontis, P. argentipes, P. stantoni, S. barraudi, S. silvatica, S. gemmea, S. indica, and C. barbazani. Sergentomyia anodontis (55.0%) was the predominant species followed by P. argentipes (33.6%) and others. Five species of sand fly were found throughout the year in this area: P. argentipes, P. stantoni, S. anodontis, S. barraudi and S. gemmea. The highest average density of sand flies was found in Ratree cave (35.0 sand flies per trap per night) and lowest in Bandai cave (29.0 sand flies per trap per night). The population of sand fly fluctuated from the highest peak in December (28.5%) to the lowest peak in May (2.3%). The distribution of sand fly species in attraction areas is important for the control program of infection risk of leishmaniasis. PMID- 26521516 TI - EPIDEMIOLOGY OF ROTAVIRUS DIARRHEA AMONG CHILDREN AGED LESS THAN 5 YEARS IN RURAL SOUTHERN ETHIOPIA. AB - The objective of this study was to determine the epidemiological and clinical features of rotavirus infection among children aged less than 5 years in rural southern Ethiopia. We conducted a hospital-based, prospective study among children aged less than 5 years with acute diarrhea and moderate to severe dehydration attending the outpatient department of Gambo Rural Hospital, Ethiopia during September-November 2012. Three hundred fourteen children were included in the study, of whom 137 (43.6%) had rotavirus infection. The average age of children with rotavirus infection was lower than those without it [odds ratio (OR): 0.94]. Finding severe dehydration on skin pinch test (adjusted OR: 3.76) and having diarrhea for !3 days (adjusted OR: 2.50) were associated with rotavirus infection. The mortality rate was 4.4% among rotavirus infection children and 0% among non-rotavirus diarrhea cases (p=0.006). Rotavirus infection should be suspected in children with severe dehydration on a skin pinch test and among those presenting with diarrhea for 3 days in rural southern Ethiopia. PMID- 26521517 TI - A PREGNANT WOMAN WITH AVIAN INFLUENZA A (H7N9) VIRUS PNEUMONIA AND ARDS MANAGED WITH EXTRACORPOREAL MEMBRANE OXYGENATION. AB - We report a case of H7N9 avian influenza pneumonia in a pregnant woman who developed acute respiratory distress syndrome (ARDS) managed with extracorporeal membrane oxygenation (ECMO). A 29-year-old, 27 week pregnant woman developed rapidly progressive pneumonia with bilateral infiltrates on chest x-ray and was confirmed to have influenza A (H7N9) infection. Her condition deteriorated and she developed ARDS which was managed with veno-venous extracorporeal membrane oxygenation (V-V ECMO) and treated with antimicrobials. Her clinical symptoms and oxygenation gradually improved and the ECMO was discontinued on the 19t day. Unfortunately, she suddenly died a few days later, due to a presumed pulmonary embolism. Based on our experience, ECMO may be useful to manage pneumonia due to H7N9 avian influenza and ARDS in pregnant women. PMID- 26521518 TI - RISK FACTORS FOR SEVERE HAND, FOOT AND MOUTH DISEASE. AB - We studied risk factors associated with severe hand, foot and mouth disease (HFMD) caused by enteroviruses among patients aged less than 15 years admitted to King Narai Hospital, Lopburi, Thailand during 2011-2013. Cases were divided into either mild or severe. Severe cases were those with encephalitis, meningitis, myocarditis, pneumonia, pulmonary edema or respiratory failure. Risk factors for severe infection were evaluated using univariate and multivariate logistic regression analysis. One hundred eighteen patients met the case definition of HFMD. Of these, 95 (80.5%) were classified as mild cases, and 23 (19.5%) as severe cases; there were 5 deaths (4.2%). Of the 23 severe cases, 9 were infected with coxsackievirus A16 (CA16), 8 with enterovirus 71 (EV71) and 4 with both EV71 and CA16. The most common presentations among the severe caseswere: seizures (74%), pneumonia (39%), encephalitis (39%), and meningitis (13%). The clinical manifestations significantly related to severe HFMD on univariate analysis were highest body temperature 39.00C, duration of fever 23 days, absence of skin lesions, diarrhea, dyspnea, seizures and hyperglycemia. The clinical manifestations significantly related to severe HFMD on both univariate and multivariate analyses were age less than 1 year, absence of oral lesions and drowsiness/lethargy. Clinicians should be aware of these factors. Early recognition of severe cases is important to increase the rates of successful outcomes and reduce mortality. PMID- 26521519 TI - ZIKA VIRUS INFECTION IN AUSTRALIA FOLLOWING A MONKEY BITE IN INDONESIA. AB - A traveller returning to Australia developed Zika virus infection, with fever, rash and conjunctivitis, with onset five days after a monkey bite in Bali, Indonesia. Flavivirus RNA detected on PCR from a nasopharyngeal swab was sequenced and identified as Zika virus. Although mosquito-borne transmission is also possible, we propose the bite as a plausible route of transmission. The literature for non-vector transmissions of Zika virus and other flaviviruses is reviewed. PMID- 26521520 TI - STAPHYLOCOCCUS AUREUS AND STREPTOCOCCUS PNEUMONIAE PREVALENCE AMONG ELDERLY ADULTS IN JAKARTA, INDONESIA. AB - We studied Staphylococcus aureus and Streptococcus pneumoniae carriage among elderly adults in Jakarta, Indonesia. Nasopharyngeal swabs were collected from 149 adults aged 60-97 years. Both S. aureus and S. pneumoniae were identified by conventional and molecular methods. Methicillin-resistant Staphylococcus aureus (MSRA) was determined by PCR and antibiotic susceptibility using the disk diffusion method. Pneumococcal serotyping was performed with sequential multiplex PCR. We found S. aureus and S. pneumoniae present in 42 and 4 elderly adults respectively, and MRSA prevalence of 6%. Serotypes 3, 6A/B, 15B/C and 35F were identified among the four pneumococcal isolates. The majority of S. aureus isolates were susceptible to chloramphenicol (93%) and sulfamethoxazole/trimethoprim (93%), followed by gentamicin (88%), erythromycin (83%), penicillin (79%) and tetracycline (74%). Thus S. aureus prevalence is higher than that of S. pneumoniae, and a high frequency of MRSA carried by elderly adults in Jakarta, Indonesia. PMID- 26521521 TI - ANTI-STAPHYLOCOCCAL ACTIVITY OF MELALEUCA HONEY. AB - Honey is well-known for its antioxidant properties due to the presence of phytochemical compounds, which are also involved in antibacterial activities. In this study, properties (total phenolic compounds, flavonoids, free radical scavenging activity, ferric reducing-antioxidant power, reducing sugar content, and pH) of Malaysian Melaleuca honey were investigated for their antistaphylococcal activity, against both methicillin-sensitive (MSSA) and resistant (MRSA) Staphylococcus aureus strains using a hole-in-plate diffusion method. The outcome revealed there is a significant positive correlation between the antistaphylococcal activity and increase in honey concentration [20%-80% (v/v) in distilled water], which also correlated with each of the above mentioned parameter in honey, except for pH value that shows negative correlation. Furthermore, there was no difference in susceptibility to Melaleuca honey between MSSA and MRSA strains. Thus, in addition to being an antioxidant product, Melaleuca honey has a potential as a natural antistaphylococcal agent. PMID- 26521522 TI - MICROBIAL CONTAMINATION OF STREET VENDED FOODS FROM A UNIVERSITY CAMPUS IN BANGLADESH. AB - The microbiological quality of street vended food samples from Dhaka, Bangladesh was evaluated. The objective of the study was to identify the presence of common pathogens (Escherichia coli, Shigella spp, Salmonella and Vibrio spp) and to describe the molecular characterization of E coli, a commonly found pathogen in various street foods. Fifty food samples were collected from fixed and mobile vendors from two sampling locations (Mohakhali and Aftabnagar) in Dhaka city, Bangladesh. The tested samples included deep fried and fried snacks; quick lunch items; pickles; fruit chutney; baked items; spicy, sour and hot snacks etc: Juices, tamarind water and plain drinking water were also tested. Sterile polythene bags were used for collecting 200 g of each category of samples. They were tested for the presence of microorganisms following conventional microbiological processes. Biochemical tests followed by serology were done for the confirmation of Shigella and Salmonella. Serological reaction was carried out for confirmation of Vibrio spp. DNA was isolated for the molecular characterization to detect the pathogenic E. coli by polymerase chain reaction (PCR). Out of 50 food samples, six (12%) were confirmed to contain different species of E. coli and Shigella. Molecular characterization of E. coli revealed that three samples were contaminated with enteroaggregative E. coli (EAEC) and one was contaminated with enterotoxigenic E. coli (ETEC). Shigellaflexneri X variant was detected in one food item and Shigella flexneri 2a was found in drinking water. All these enteric pathogens could be the potential cause for foodborne illnesses. PMID- 26521523 TI - TRANSMISSION AND RISK FACTORS FOR LATENT TUBERCULOSIS INFECTIONS AMONG INDEX CASE MATCHED HOUSEHOLD CONTACTS. AB - An understanding of the risk factors associated with acquiring and transmitting Mycobacterium tuberculosis (MTB) is required for controlling tuberculosis (TB). We aimed to determine the risk factors and transmission factors for latent tuberculosis infection (LTBI) in northeastern Thailand. Household contact persons (n = 70) and matched index patients with pulmonary TB (n = 42) who presented to Srinagarind Hospital, Khon Kaen, Thailand were interviewed from September 1, 2012 to March 31, 2014. LTBI was determined by positive results on both a tuberculin skin test and the QuantiFERON-TB Gold In-Tube test. Multivariate analysis of host and environmental risk factors was performed. Among contact persons, being aged 20 years (adjusted OR=14.0; 95% CI: 1.2-159.5), having a family relationship with a TB subject such as being a spouse or parent (adjusted OR=24.9; 95% CI: 2.4 263.9) and exposure to a TB subject for 5 hours/day (adjusted OR=9.2; 95% CI: 1.4 58.1) were risk factors for LTBI. Having a high bacillary load (adjusted OR=2; 95% CI: 1.26-3.17) or a moderate bacillary load (adjusted OR=1.39; 95% CI: 1.04 1.84) among TB subjects correlated with increased transmissibility compared to having a low bacillary load. The type of dwelling and density of household members were not found to be risk factors for LTBI in our study. We conclude being aged 20 years and having a relationship with a TB patient as a spouse or parent were risk factors for acquiring LTBI, and having a higher bacillary load was a risk factor for transmitting TB. Keywords: latent tuberculosis infection, transmission factor, risk factor, Mycobacterium tuberculosis, interferon-gamma release assay, Thailand PMID- 26521524 TI - DIFFERENCES IN CLINICAL MANIFESTATIONS AND PLEURAL FLUID CHARATERISTICS BETWEEN TUBERCULOUS AND MALIGNANT PLEURAL EFFUSIONS. AB - Tuberculous and malignant pleural effusions share similar clinical and radiographic findings and both may produce lymphocytic-predominant exudative effusions. This study aimed to determine distinguishing clinical features between the two diseases. We conducted a retrospective study among 47 patients with tuberculous pleural effusions (TBPE) and 73 with malignant pleural effusions (MPE). Demographic data, clinical features, pleural fluid characteristics, and radiographic findings were obtained for each patient and the 2 groups were compared. Sixty-nine (57.5%) patients were males. The mean (+/- SD, range) age was 60.2 (+/- 16.9, 19-94) years. Mean (+/- SD) symptom duration was 31.6 (+/- 51.6) days. Univariate analysis identified 20 clinical, pleural fluid and radiological differences between the two groups. Multivariate logistic regression analysis revealed 3 independent predictors of TBPE: fever (OR=8.2; 95% CI: 1.9 - 35.9; p=0.005), having a non-serosanguinous effusion (OR=6.1; 95% CI: 1.1 - 33.6; p=0.038), and a fluid adenosine deaminase level > 30 U/I (OR=86.7; 95% CI: 4.3 - 1735; p=0.004). Fever, non-serosanguinous pleural effusions and high adenosine deaminase levels were suggestive of a TBPE and could be clinically useful when evaluating a pleural effusion of unknown etiology. PMID- 26521525 TI - TRADITIONAL CARDIOVASCULAR RISK-FACTORS AMONG HEALTHCARE WORKERS IN KELANTAN, MALAYSIA. AB - We conducted a cross sectional study of cardiovascular risk factors among healthcare workers at four government hospitals in Kelantan, Malaysia. We randomly selected 330 subjects fulfilling the following study criteria: those who had been working for at least one year at that health facility, Malaysians citizens and those with some form of direct contact with patients. We conducted an interview, obtained physical measurements, a fasting blood sugar and fasting lipid profiles among 308 subjects. The mean age of the subjects was 43.5 years, 82% were female; 30.8%, 14.3%, 10.4%, 1.3% and 1.6% of the subjects had dyslipidemia, hypertension, diabetes mellitus, a history of stroke and a history of ischemic heart disease, respectively. Forty-two percent of subjects had at least one medical condition. The mean body mass index (BMI) was 27.0 kg/M2 (SD=4.8) and 24.3% had a BMI > or =30 kg/M2. The mean systolic and diastolic blood pressures were 121.5 mmHg (SD=14.0) and 76.5 mmHg (SD=9.7), respectively and the mean waist-hip ratio was 0.84 (SD=0.1). The mean fasting blood sugar, total cholesterol, triglyceride, high density lipoprotein and low density lipoprotein were 5.8 mmol/l (SD=2.4), 5.5 mmol/l (SD=1.0), 1.4 mmol/l (SD=0.9), 1.5 mmol/l (SD=0.3) and 3.5 mmol/l (SD=0.9), respectively. Our study population had a smaller proportion of hypertension than that of the general Malaysian population. They had higher fasting total cholesterol, slightly lower fasting blood sugar, with a large proportion of them, obese and had diabetes. Immediate intervention is needed to reduce the traditional cardiovascular risk factors in this population. Keywords: cardiovascular risk factors, health care workers, Malaysia PMID- 26521526 TI - KNOWLEDGE, ATTITUDE AND PERCEPTION OF PARENTS ON THE USE OF COUGH AND COLD MEDICATIONS IN CHILDREN. AB - This study investigated the knowledge, attitude and perception of parents on the use of cough and cold medications in children. Questionnaires were distributed to parents of children aged < or =6 years in selected kindergartens. The overall knowledge of the parents (n=248) was satisfactory with a mean score of 5.87 +/- 1.70 (from a total of 10) and the overall attitude was positive with a mean score of 41.15 +/- 6.72 (from a total of 50). Ten percent of parents admitted administering cough and cold medications in children aged <2 years. Age of the parents, education level and monthly income were found to significantly influence knowledge level (p<0.05). Spearman's rank-order correlation between knowledge and attitude scores showed a statistically significant positive linear relationship (r(s), = 0.290, p<0.05). The study provides some insights into the use of cough and cold medications in children from the parents' perspectives. PMID- 26521527 TI - FACTORS ASSOCIATED WITH PREGNANCY AMONG UNMARRIED WOMEN IN MALAYSIA. AB - Pregnancy among unmarried women may have negative social and health implications in Malaysia. The number of pregnancies among unmarried women has increased in Malaysia, but the socio-demographic profile of these women is unclear. This study aims to evaluate the characteristics of unmarried pregnant women and the factors associated with unmarried pregnancies among young women in Malaysia. We conducted a cross sectional study at six hospitals and six women's shelters in Peninsular Malaysia during 2011-2012. Unmarried pregnant women were compared with married pregnant women. Participants were interviewed using a structured questionnaire asking for socio-demographic data, family background, risky sexual behavior, social support and pregnancy details. A total of 484 women (239 unmarried and 245 married) were included in the study. Most unmarried subjects were adolescents, from urban areas, from a low socioeconomic group, and lived with parents prior to pregnancy. Age (OR=0.67; 95% CI: 0.61-0.74), studying status (OR=17.33; 95% CI: 2.65-113.19), alcohol use (OR=40.46; 95% CI: 2.51-652.38) exposure to pornographic material (OR=13.48; 95% CI: 3.24-56.01), contraceptive use (OR=0.20; 95% CI: 0.08-0.51), and social support (OR=0.90; 95% CI: 0.86-0.94) were all associated with unmarried pregnancy. These factors need to be considered when.designing an intervention program. PMID- 26521529 TI - Finding Value. PMID- 26521528 TI - EFFECT OF ADDING TRICALCIUM PHOSPHATE TO FLUORIDE MOUTHRINSE ON MICROHARDNESS OF DEMINERALIZED PRIMARY HUMAN TOOTH. AB - The purpose of the present study was to evaluate the effect of fluoride mouthrinse containing tricalcium phosphate on microhardness of demineralized primary enamel. Thirty-six sound primary incisors were immersed in a demineralizing solution (pH 4.4) for 96 hours at 37 degrees C to create artificial caries-like lesions. After artificial caries formation, the specimens were randomly divided into 3 groups (with 12 specimens in each group): Group A: deionized water; Group B: 0.05% NaF plus 20 ppm tricalcium phosphate mouthrinse and Group C: 0.05% NaF mouthrinse. All the specimens were immersed for 1 minute at 37 degrees C three times per day for 7 days in the respective mouthrinse among pH cycling. The surface microhardness was examined using a Vickers hardness tester (100 grams for 15 seconds) at baseline, before and after the pH-cycling procedure. Data were analyzed using one-way ANOVA and Tukey's multiple comparison tests with a significance level of 0.05. After treatment, Group Ahad a significantly lower surface microhardness value than the other two groups (p=0.000); however, there was no significant difference between Groups B and C (p=0.728). We concluded fluoride mouthrinse containing tricalcium phosphate and fluoride mouthrinse have similar remineralizing effects on microhardness of demineralized primary teeth. PMID- 26521530 TI - Too Many Vaccines? PMID- 26521531 TI - The Interstate Medical Licensure Compact. A Pathway to Expediting Medical Licenses for Physicians. PMID- 26521532 TI - Smartphone Mobile Applications to Enhance Diagnosis of Skin Cancer: A Guide for the Rural Practitioner. AB - Primary care physicians occupy a vital position to impact many devastating conditions, especially those dependent upon early diagnosis, such as skin cancer. Skin cancer is the most common cancer in the United States and despite improvements in skin cancer therapy, patients with a delay in diagnosis and advanced disease continue to have a grave prognosis. Due to a variety of barriers, advanced stages of skin cancer are more prominent in rural populations. In order to improve early diagnosis four things are paramount: increased patient participation in prevention methods, establishment of screening guidelines, increased diagnostic accuracy of malignant lesions, and easier access to dermatologists. Recent expansion in smartphone mobile application technology offers simple ways for rural practitioners to address these problems. More than 100,000 health related applications are currently available, with over 200 covering dermatology. This review will evaluate the newest and most useful of those applications offered to enhance the prevention and early diagnosis of skin cancer, particularly in the rural population. PMID- 26521533 TI - The Tri-State Experience. Outcome Analysis of Patients with Triple Negative Breast Cancer Treated at Marshall University. AB - Breast cancer is the most frequently diagnosed malignancy in women in the United States. It is the second most common malignancy to cause death, with approximately 39,000 women dying of breast cancer in the United States in 2013. Triple negative breast cancer is defined as the absence of estrogen, progesterone and human epidermal growth factor receptor 2 receptors. It has been associated with a higher incidence in African American women, a younger age and a more advanced stage at diagnosis, and an inferior overall survival. To recognize the differences of our West Virginia community population when compared to the national average, we conducted a retrospective review of all patients diagnosed with breast cancer from 2000-2012. PMID- 26521534 TI - Unilateral Forehead Paralysis Following Operative Repair of Facial Trauma: A Case Study and Review of the Literature. AB - The temporal branch of the facial nerve is a commonly injured nerve during facial trauma due to its superficial course over the zygomatic arch, and is a commonly damaged nerve during facial surgery. We report a case of trauma to the left temporal fossa, and subsequent unilateral forehead paralysis. Early exploration revealed external suture compression as the origin of his paralysis. Removal of the suture led to complete resolution of the neurological deficit. The differential diagnosis did not include the possibility of the compression of the nerve by a suture, however the decision for early exploration led to a full recovery. PMID- 26521535 TI - Trends in Lung Cancer Molecular Testing. AB - Molecular testing of non-small cell lung carcinomas (NSCLCC) with adenocarcinoma features has become commonplace with the development and use of targeted treatments for these malignancies. Prior to treating these tumors with targeted drug regimens, testing for specific mutations is usually required to determine the potential response of the tumor to the therapeutic agents. This case review describes a patient with lung cancer showing a specific gene mutation who benefitted from targeted treatment. Also reviewed are the current standards of care and trends in the molecular testing of NSCLC with adenocarcinoma features and possible future molecular targets. PMID- 26521536 TI - Food Safety During Power Outages. PMID- 26521537 TI - Multi-hospital Community NICU Quality Improvement Improves Survival of ELBW Infants. AB - Quality improvement or high reliability in medicine is an evolving science where we seek to integrate evidence-based medicine, structural resources, process management, leadership models, culture, and education. Newborn Associates is a community-based neonatology practice that staffs and manages neonatal intensive care units (NICU's) at Central Mississippi Medical Center, Mississippi Baptist Medical Center, River Oaks Hospital, St Dominic's Hospital and Woman's Hospital within the Jackson, Mississippi, metropolitan area. These hospitals participate in the Vermont-Oxford Neonatal Network (VON), which is a voluntary national network of about 1000 NICU groups that submit data allowing them to benchmark their patient outcome. This network currently holds data on 1.5 million infants. Participation may also include the Newborn Improvement Quality Collaborative (NICQ) which is an intensive quality improvement program where 40-60 of the almost 1000 VON centers participate each year or the iNICQ, which is an internet based collaborative involving about 150 centers per year. From 2008-2009, our group concentrated efforts on quality improvement which included consolidating resources of three corporately managed hospitals to allow focused care of babies under 800-1000 grams at a single center, expanding participation in the VON NICQ to include all physicians and centers, and establishing a group QI focused committee aimed at sharing practice bundles and adopting quality improvement methodology. The goal of this article is to report the impact of these QI activities on survival of the smallest preterm infants who weigh less than 1500 grams at birth. Two epochs were compared: 2006-2009, and 2010-2013. 551 VLBW (< 1 500 grams) infants from epoch I were compared to 583 VLBW infants from epoch 2. Mortality in this group decreased from 18% to 11.1% (OR 0.62,95% CI 0.44-0.88). Mortality in the 501-750 grams birth weight category decreased from 45.7% to 18% (OR 0.39,95% CI 0.21-0.74). Improved survival was noted in all centers over the time period. These findings suggest that a physician-driven, multidisciplinary, individualized and multifactorial quality improvement effort can positively impact the care of extremely preterm infants in the community NICU setting. PMID- 26521538 TI - Tuberculosis Containment among the Homeless in Metropolitan Jackson, Mississippi. AB - IMPORTANCE: Preventing tuberculosis among the homeless has emerged as an especially difficult challenge. OBJECTIVES: We assessed a 2008-2009 tuberculosis (TB) outbreak ad subsequent prevention strategies among homeless persons in metropolitan Jackson, Hinds County, Mississippi. DESIGN, SETTING AND PARTICIPANTS: We compared data about cases and subclinical TB infections (LTBI) among homeless persons during the outbreak and post-outbreak years, interviewed involved homeless persons, compiled observations from visits to Jackson homeless shelters and conducted literature reviews on homelessness and infectious diseases. We reviewed homeless shelter TB prevention methods adopted by other municipalities, guidelines developed by the Centers for Disease Control and Prevention (CDC), and recommendations from other official and ad hoc groups and considered their applicability to metropolitan Jackson. MAIN OUTCOMES AND MEASURES: The Mississippi State Department of Health TB Program assisted by the CDC and other agencies, contained the Jackson-area outbreak by the end of 2009 as reflected by progressively lower TB rates among homeless persons thereafter. However, some follow-up activities and enforcement of shelter preventive measures have not been consistently maintained. Resources to prevent further outbreaks continue to be inadequate, and over-reliance on private organizations has continued. In the process, appreciation of the dynamic interaction enhancing TB risk among the homeless and incarcerated persons has emerged. RESULTS: Major outbreak contributors were lack of periodic TB screening among homeless shelter clients, preventive treatment compliance and follow-up difficulties among those with subclinical tuberculosis infections, interrupted preventive measures among infected persons incarcerated in local correctional facilities who disproportionately re-join Jackson's homeless community when released, inadequate attention to shelter environmental preventive strategies such as ultraviolet light germicidal irradiators and proper air-exchange/ventilation, costs of isolation housing for homeless people with full-blown tuberculosis (especially those co-infected with HIV and other infections and those with alcohol and/or other chemical dependencies), lack of adequate transportation which impacts access to evaluation and care, lack of mandated ongoing training among shelter and correctional facility staff, and inadequate attention to the societal problem of homelessness itself. CONCLUSIONS: Sustained adherence to local shelter and correctional facility TB prevention measures based on standards and policies proved effective in other settings is most crucial. These include requirements for periodic tuberculosis prevention and awareness training for shelter and correctional facility staff, ongoing tuberculosis screening and follow-up among homeless shelter clients and inmates of local correctional facilities, and attention to shelter and correctional facility environmental sanitation, proper ventilation, ultraviolet light fixtures and capacity/bed alignment standards. PMID- 26521539 TI - Straight from the Horse's Mouth. PMID- 26521540 TI - Top Ten Facts You Need to Know about the Treatment of Venous Thromboembolism. PMID- 26521541 TI - The Official Address of the 147th President. PMID- 26521543 TI - Telemedicine and Rural Communities. PMID- 26521542 TI - The Future of Population Health in Mississippi. PMID- 26521544 TI - Stress responses of starry flounder, Platichthys stellatus (Pallas) following water temperature rise. AB - Stress responses of starry flounder, Platichthys stellatus (Pallas) following water temperature rise were investigated to establish the influence of ambient temperature on this species. The physiological indicators of stress were plasma cortisol, glucose, aspartate aminotransferase, alanine aminotransferase, sodium, chloride, osmolality and triiodothyronine (T3). No significant difference in plasma parameters were observed among the experimental groups of 15 degrees C, 18 degrees C and 21 degrees C. Level of plasma cortisol (49.0-95.0 ng ml(-1)) and glucose (56.1-58.1 mg dl(-1)) of starry flounders kept at 24 degrees C-27 degrees C were significantly higher than those (cortisol: 20.4-23.6 ng ml(-1), glucose: 40.6-47.1 mg dl(-1)) observed in the 15 degrees C-21 degrees C groups. Changes in aspartate aminotransferase and alanine aminotransferase following water temperature rise showed a similar pattern to plasma cortisol and glucose. Starry flounders exposed to 27 degrees C exhibited higher plasma sodium (164.7 mmol l( 1)), chloride (147.6 mmol l(-1)), and osmolality (450.7 mOsm kg(-1)) than those (sodium: 154.0-158.7 mmol l(-1), chloride: 139.1-140.4 mmol l(-1), osmolality: 375.1-383.8 mOsm kg(-1)) fish exposed to 15-21 degrees C. Though plasma T3 (29.4 ng ml(-1)) of starry flounder increased at 24 degrees C, this hormone was significantly lower (19.3 ng ml(-1)) in fish kept at 27 degrees C than those (24.6 ng ml(-1)) the fish at 15 degrees C. This phenomenon seems to be directly associated with long-term fasting. Accordingly, the results suggested that starry flounders got stressed with osmoregulatory disturbances above 24 degrees C. PMID- 26521545 TI - Population distribution and genetic relatedness in Indian Fusarium udum isolates based on ribosomal internal transcribe spacer and elongation factor. AB - With the objective to study the geographical distribution pattern and pathotype classification, isolates from 12 major pigeonpea growing states of India were examined at morphological and molecular levels. Two DNA based internal transcribe spacer (ITS) region derived primers FDP 3 (ITS1/ITS2), FDP 25 (mRNA, LOC100383610) and two elongation factors FDP 4 (F98-BKR5) and FDP 29 (M9968PY) were employed to genetically differentiate the isolates. As a result, each marker system gave an average of 3 alleles/marker. The higher efficiency of ITS over EF 1alpha marker was revealed using detailed comparative analysis that included various parameters like gene diversity index, effective marker ratio, and marker index. Neighbour Joining tree analysis grouped the isolates into three major clusters and showed narrow existence of genetic divergence. Combination of genotyping data with pathological measurements indicates dominance of variant 1 in the Central zone, South zone and North East Plain Zone, while North East Plain Zone and North West Plain Zone were largely dominated by variants 2 and 1, with strong possibility of evolving other variants. The present study would help in identifying specific isolate and patterns of its distribution in various pigeonpea growing regions thereby enhancing the scope for precise resistance breeding for crop improvement. PMID- 26521546 TI - Performance and cost evaluation of constructed wetland for domestic waste water treatment. AB - Root zone treatment through constructed wetlands is an engineered method of purifying wastewater. The aim of the present research was to study the potential of wetland plants Phragmites and Typha in treatment of wastewater and to compare the cost of constructed wetlands with that of conventional treatment systems. A pilot wetland unit of size 2x1x0.9 m was constructed in the campus. 3x3 rows of plants were transplanted into the pilot unit and subjected to wastewater from the hostels and other campus buildings. The raw wastewater and treated wastewater were collected periodically and tested for Total nitrogen (TN),Total Phosphorous (TP), Biological Oxygen Demand (BOD), Chemical Oxygen Demand (COD). It was observed that this pilot unit reduced the concentrations of TN, TP, BOD and COD by 76, 73, 83 and 86%, respectively, on an average. Root zone system achieved standards for tertiary treatment with low operating costs, low maintenance costs, enhance the landscape, provide a natural habitat for birds, and did not emit any odour. PMID- 26521547 TI - Analysis of release cutting effects on increment and growth in Oriental beech (Fagus orientalis Lipsky) stand. AB - In the present study, the effects of release cuttings on stand structures and increment and growth relations were investigated in afforested oriental beech (Fagus orientalis Lipsky) stands. To maximize spatial variation in dataset, stratified random sampling was used to layout transects. 24 sampling plots were determined which reflects average characteristics of actual stand structure. 8 sampling plots were selected from unthinned stands, 8 sampling plots were selected from lightly thinned (19% of the total basal area removed) stand and 8 sampling plots were selected from heavily thinned (40% of the total basal area removed) stand. Light thinning was done in the year 2008 and heavy thinning in 2009. Stem analyses were carried out and pre- and post-treatment height, diameter, basal area and volume increments were examined according to thinning intensities. Obtained results showed that removal of 40% of the basal area does not contribute to stand increment and growth more positively than those in stands treated by removal of 19% of the basal area. Expected increase in height and diameter increment did not occurr post-treatment in 2008 and 2009. However, in only lightly thinned stands mean basal area increment increased after treatment. Release cuttings in beech stand needs to be practiced at least twice every 5 to 6 years, provided that peculiar characteristics of every habitat are considered. PMID- 26521548 TI - Decolourization of azo, heterocyclic and reactive dyes using spent mycelium substrate of Hypsizygus ulmarius. AB - Cultivation of Hypsizygus ulmarius to generate spent mycelium substrate (SMS) for dye decolourization gave better yield, biological efficiency, fruitwidth and moisture content (145 gm, 33%, 4 cm, 91%) on paddy straw as compared to coconut husk (59 gm, 21%, 3 cm, 90%). Solid-phase decolourization of Congo red (Azo dye) and Methylene blue (Heterocyclic dye) showed that maximum decolourization (3.31), measured as Decolourization Index, occurred at dye concentration of 25 mg l(-1), while in Solochrome black (Reactive dye), it was at 100 mg l(-1) (1.7). Time taken for maximum decolourization was 10 days in Congo red and Solochrome black; 20 days in Methylene blue. Decolourization Index was maximum in Methylene blue (3.1), followed by Congo red (1.9) and Solochrome black (1.2). Liquid-phase decolourization of Methylene blue and Solochrome black showed that maximum decolourization (62.5%) measured as percent decolourization occurred at 25 mg l( 1), while it was at 50 mg l(-1) (36%) for Congo red. Time taken for maximum decolourization for all three dyes was 10 days. During this period, the percent decolourization was maximum in Methylene blue (91.3%), followed by Solochrome black (82.2%) and Congo red (79.7%). Decolourization potential in solid-phase was observed till 100 mg l(-1) and day 25 for all the three dyes, however, in liquid phase it was observed till 50 mg I(-1) and day 20 for Congo red, 75 mg l(-1) and day 10 for Solochrome black, 100 mg I(-1) and day 20 for Methylene blue. Maximum laccase was produced on day 25 during decolourization of 25 mg I(-1) Congo red, while maximum Manganese peroxidase was noted on day 20 at 50 mg l(-1) Congo red. PMID- 26521549 TI - Pumping bottom water to prevent Korean red tide damage caused by Cochlodinium polykrikoides Margalef. AB - Cochlodinium polykrikoides Margalef produces annual massive blooms in Korean coastal waters which cause great damage to aquaculture and fisheries. Although various methods have been developed to remove the red tide of C. polykrikoides, release of yellow loess has been regarded as the most desirable technique for mitigation for over 10 years. Each August, strong irradiation generates water column stratification separating warm surface from colder bottom waters. Water from a distance of 0 (St. 1), 5 (St. 2), 10 (St. 3), and 15 m (St. 4) was pumped by running a pump for 0, 10, 30 and 90 min and characterized water temperature, salinity collected, suspended solids, Chl-a, and phytoplankton including C. polykrikoides. After running for 30 min, was temperature and salinity in surface water was similar to those of bottom water, and water column stratification completely reversed after 90 min. Likewise, suspended solids, Chl-a, and total phytoplankton cell density decreased after 30 min, but C. polykrikoides did not show strong removal because of low cell density during sampling. However, the number of C. polykrikoides was significantly diluted (80%) after 90 min. These results suggested that pumping device was as an environmentally-friendly method convenient to be install in fish cages and effective to remove C. polykrikoides stratified water column conditions. PMID- 26521550 TI - Influence of organic wastes on the biology of epigeic earthworm, Perionyx excavatus during different seasons. AB - Epigeic earthworm, Perionyx excavatus were cultured on a variety of organic wastes amended with cattle manure in different seasons to know the influence of different organic waste-diets and seasonal environmental factors on life activities of epigeic earthworm, Perionyx excavatus. Results showed that growth and reproductive strategies of P. excavatus varied with different organic waste diets and seasons. Growth, maturity and reproduction of worms in all waste-diets were significantly more during monsoon followed by winter and summer seasons. All agricultural and garden organic wastes served as a source of balanced diet for this worm during all three seasons. Further, mixed organic waste and soft (straw based) wastes appeared more congenial for overall life activities of this worm than that of hard (pod-based) wastes (P < 0.001, P < 0.05). PMID- 26521551 TI - Characterization of biosurfactants from indigenous soil bacteria recovered from oil contaminated sites. AB - Three bacterial isolates (G1, G2 and G3) characterized as Pseudomonas plecoglossicida, Lysinibacillus fusiformis and Bacillus safensis were recovered from contaminated soil of oil refinery. These bacterial isolates produced biosurfactants in MSM medium in stationary phase. Biosurfactants were characterized on the basis of their emulsifying properties with petrol, diesel, mobil oil and petrol engine oil. Reduction in surface tension (below 40 mN m(-1)) and blood hemolysis were also included in biosurfactants characterization. Emulsification indices of G1, G2 and G3 were in the range of 98.82, 23.53 and 58.82 for petrol; 29.411,1.05 and 70.588 for diesel; 35.31, 2.93 and 17.60 for mobil oil and 35.284, 58.82 and 17.647 for petrol engine oil respectively. Dry weight of the extracted biosurfactant was 4.6, 1.4 and 2.4 g I(-1) for G1, G2 and G3 respectively. Structural analysis of the biosurfactants by Fourier Transform Infrared Spectroscopy (FTIR) revealed significant differences in the bonding pattern of individual biosurfactant. PMID- 26521552 TI - Adsorption, desorption and mobility of cyfluthrin in three Malaysian tropical soils of different textures. AB - The sorption and desorption of cyfluthrin mixture isomers were determined using batch equilibration method and mobility was studied under laboratory conditions, using packed soil column. The soil types used in the study were clayey, clay loam and sandy clay loam obtained from three tomato farms in Cameron Highlands. A low Freundlich adsorption distribution coefficient K(ads(f)) for cyfluthrin was observed for clayey, clay loam and sandy clay loam soils (95.69, 21.64 and 8.99 l/kg, respectively). Results showed that cyfluthrin had high Freundlich organic matter (OM) distribution coefficient K(oc) values of 5799, 2278 and 1635 lkg(-1) for clayey, clay loam and sandy clay loam soils, respectively. These values indicate that cyfluthrin is considered immobile in Malaysian soils with different textures, based on the value of K(oc) by McCall. Adsorption of cyfluthrin was significantly (P < 0.05) affected with soil pH, fertilizer NPK, organic matter content and temperature. It was observed that approximately 95.8%, 93.8% and 91.8% of the adsorbed cyfluthrin remained sorbed after four successive rinses for clayey, clay loam and sandy clay loam soils. Soil column test showed that cyfluthrin was not detected in leachate. Cyfluthrin was detected in topsoil and its concentration decreased with depth. The downward movement of cyfluthrin in sandy clay loam soil was more than that in clay loam and clayey soils. Approximately, 80.9%, 77.8% and 67.3% cyfluthrin was observed at the depth of 0-5 cm (rainfall 350 mm) for clayey, clay loam and sandy clay loam soils respectively. Mobility of cyfluthrin showed that the percentage of cyfluthrin leached into soil was not affected by the amount of rainfall. The result clearly showed that cyfluthrin molecules were bound strongly to all the three Malaysian soil types. PMID- 26521553 TI - PCR- RFLP based bacterial diversity analysis of a municipal sewage treatment plant. AB - Bacterial diversity of sewage soil is an essential study to discover novel bacterial species involved in biodegradation. Restriction Fragment Length Polymorphism is one of the most useful molecular technique for diversity analysis in terms of cost effectiveness and reliability. The present study focuses on bacterial diversity of municipal sewage treatment plant in Chennai, Tamil Nadu, India through metagenomic approach. A 16S r DNA clone library was constructed from metagenomic DNA of sewage soil. 200 clones from the library were subjected to colony PCR and RFLP analysis. Upon RFLP analysis, 16 different Operational Taxonomic Units (OTU's) were obtained and a single clone from each OTU was subjected to sequencing. Phylogenetic analysis of sequences revealed the presence of five different groups of bacteria namely Proteobacteria (56%), Actinobacteria (7%), Firmicutes (5%), Bacteroidetes (17%) and Plancomycetes (7%). Three novel and uncultured groups of bacteria (8%) were also discovered. Most of the organisms identified through this study were reported to be efficient degraders of hydrocarbons, aromatic compounds and heavy metals, thereby promoting biodegradation of polluted environment. PMID- 26521554 TI - Ethyl methane sulphonate induced genetic variability and heritability in macrosperma and microsperma lentils. AB - Dry and healthy seeds of two lentil cultivars, LH90-54 (macrosperma) and LH89-48 (microsperma) were treated with three doses of ethyl methane sulphonate (0.1, 0.2 and 0.4 %). In both the cultivars, all the M, plants with sufficient seed from each treatment and control were taken to raise independent M2 plant progenies. Wider range of means in both positive and negative directions along with overall positive shift in mean for all the polygenic traits, except pod-initiation height and 100-seed weight, were observed in different treatments in M2 generation. In both the cultivars, medium dose induced highest amount of variation. The estimates of variance, GCV and PCV for different polygenic traits increased significantly over control values in all the treatments of both the cultivars. Higher estimates of heritability and genetic advance in M2 population indicated tremendous scope for the improvement of seed yield and its component traits through selection in the mutagenized material. PMID- 26521555 TI - Variation and inheritance pattern in cone and seed characteristics of Scots pine (Pinus sylvestris L.) for evaluation of genetic diversity. AB - Scots pine (Pinus sylvestris L.) is one of the most common and important forest tree species in Turkey due to usefulness of its wood to many commercial uses. This species is classified as one of the economically important tree species for Turkish Forestry in the "National Tree Breeding and Seed Production Program". The objective of the present study was to investigate variation and inheritance pattern in cone and seed characteristics of Scots pine and to evaluate variation in cone and seed characters within and among clones and grafts. The results showed that maximum CV among the clones was found for SWe (21.95), FS (16.99) and CWe (16.88). According to the results of SAS, variation between the clones is averaged at 19.2% and variation within the clones is averaged at 24.4 %. Variation between the clones ranged from 3.6% (SW) to 34.5% (TC) and variation within the clones ranged from 12.3% (SW) to 38.1% (WL). For CW, AL, AW, WW and TC, genetic variation among clones was higher than within clones. When the results of study like compared with results obtained from natural populations, it was seen that genetic variability in seed orchard which was subjected to study was quite low. This case may have dangerous results for the future of forests. PMID- 26521556 TI - Pollination ecology and reproductive biology of Canarium strictum Roxb. from evergreen forests of Central Western Ghats, India. AB - Pollination and reproductive biology of a dioecious tree Canarium strictum Roxb. (Burseraceae) was extensively studied within the Agumbe forest range of Western Ghats, Karnataka to identify primary pollen vectors and to enumerate interrelationship with the pollinators. The study also investigated phenology, floral biology, pollen production, pollen viability, stigma receptivity and nectar production. Trees produced functionally unisexual flowers with white petals, organized densely on inflorescences. Staminate flowers produced high percentage of viable pollen and relatively abundant nectar (15.75 MUl) as a reward to the pollinators, while pistillate flowers produced only nectar (12 MUl). Successful fruit set with wind pollination was facilitated by synchronization of flowering male and female trees, long term receptivity of stigma in female flowers and extended lifespan of flowers. The highest mean percent of fruit set with hand cross-pollination (MU = 91.06) suggests the influence of local male tree density, as well as, frequency and abundance of pollinator community on fruit set by open pollination. PMID- 26521557 TI - Evaluation of antisecretory, gastroprotective and in-vitro antacid capacity of Fumaria indica in rats. AB - Fumaria indica is used for its anthelmintic, antidyspeptic, cholagogue, diaphoretic, diuretic, laxative, stomachic, tonic properties and claimed to possess various properties for the ailments of blood, skin, gastrointestinal systems and central nervous system. The present study was undertaken to evaluate antisecretory, gastroprotective and in-vitro antacid capacity of ethanol extract from F. indica in rats. Evaluation of F. indica extract as antisecretory was carried out by pyloric ligation induced ulcer model. The gastroprotective effect was carried out by absolute ethanol induced ulcer model. Integrity of gastric mucosa was evaluated by estimation of GSH and gastric mucus level. The in-vitro antacid capacity was evaluated by titration method. Ethanol extract of F. indica at 200 mg kg(-1), orally showed inhibition of secretion in pyloric ligation model. GSH level (1.67 MUg mg(-1) protein), gastricwall mucus (240.76 MUg g(-1) wet glandular tissue) and percentage protection (77.59%) of ulcer were significantly (P < 0.05) increased in absolute ethanol induced ulcer model. The in-vitro antacid capacity of ethanol extract of F. indica was compared with the standard. Conclusively, it appears that F. indica possess antisecretory (inhibition of acid secretion), gastroprotective (potentiation of defensive factors) and in-vitro antacid activity. PMID- 26521558 TI - Study on preparation of water hyacinth-based activated carbon for pulp and paper mill wastewater treatment. AB - Mulberry pulp and paper mills produce high chemical- and organic matter containing waste water in Thailand. Many of the mills are not equipped with wastewater treatment unit; their untreated effluent is directly discharged into recipient water resources. The effluent constituents are well recognized as acute and chronic pollutants that are hazardous to the environment. The present study aimed to investigate the utilization of an activated carbon from a low-cost material and to examine its adsorption performance using batch and fixed-bed adsorption. Water hyacinth was used as a raw material for activated carbon production via a chemical activation method. The results showed that water hyacinth-based activated carbon (WHAC) provided a high surface area of 912-1,066 m2g(-1) and exhibited micropore structure. Based on the Freundlich fit, the maximum adsorption capacity of COD and color was 4.52 mgg(-1) and 13.57 Pt-Cog( 1), respectively. The fixed bed adsorption provided maximum removal efficiency of 91.70 and 92.62% for COD and color, respectively. A continuous adsorption data agreed well with the Thomas kinetic model. In summary, water hyacinth can be used as a low-cost material for activated carbon production with high removal efficiency of COD and color for pulp and paper mill wastewater treatment. PMID- 26521559 TI - Optimization of culture parameters for tannery effluent bioremediation by Bacillus gala ctosidilyticus APBS5-3. AB - Wastewaters produced by tanneries contain high concentration of hexavalent chromium [Cr(VI)] and organic pollutants. In the presentwork, tannery effluent remediation ability of a chromium resistant Bacillus galactosidilyticus strain APBS5-3, isolated from tannery effluent enriched soil, was evaluated. This strain was found to be resistant up to 800 ppm Cr(VI). Optimization of pH, carbon source, nitrogen source, inoculum concentration, agitation rate and incubation temperature was performed for efficient bioremediation of tannery effluent. Highest reduction of COD and Cr(VI) was found to be 63.1 and 41.8%, respectively and final O.D. (at 600 nm) and pH were found to be 1.222 and 8.54, respectively after 72 hr under optimized conditions. PMID- 26521560 TI - Physico-chemical qualities of water in high altitude rice fish farming system of Ziro valley, Arunachal Pradesh, India. AB - Water in rice fields of mountain valley of Ziro, Arunachal Pradesh was investigated for physico-chemical characterization during rice fish farming season (Kharif) of 2013. Water temperature, dissolved oxygen, biological oxygen demand, free carbon dioxide, nitrate-nitrogen, phosphate-phosphorus, chloride, total hardness, calcium hardness, alkalinity, pH, total dissolved solids, specific conductivity and water depth were studied. This study revealed that the physical parameters of water in rice fields like water temperature, pH, total dissolved solids, specific conductivity and water depth were 23.5-31.3 degrees C, 5.9-6.9, 250.34-370.5 mgl(-1), 437.75-660.33 MUScm(-1) and 3.72-16.9 cm respectively. The chemical features like dissolved oxygen, biological oxygen demand, free CO2, nitrate-nitrogen, phosphate-phosphorus, chloride, total hardness Ca hardness, alkalinity were 2.4-12.9 mgl(-1), 1.5-11.1 mgl(-1), 9.7 23.35 mgl(-1), 1.28-3.9 mgl(-1), 0.005-0.539 mgl(-1), 16.6-46.8 mgl(-1), 13.9 34.5 mgl(-1), 9.6-13.53 mgl(-1) and 23.16-43.34 mgl(-1) respectively. On the other hand, investigation on planktonic life forms indicated the presence of 13.5x10(3)-84.9x10(3) indl(-1)" and 1.23x10(3)-4.86x10(3) indl(-1) phytoplankton and zooplankton respectively during the Kharif season. The above physiochemical parameters were found to be conducive for raising fish as companion crop of rice due to occurrence of diversified planktonic life forms in underneath water. PMID- 26521561 TI - Distribution of heavy metals in internal organs and tissues of Korean molluscan shellfish and potential risk to human health. AB - Molluscan shellfish (gastropods and bivalves) were collected from major fish markets on the Korean coast and analyzed for mercury by direct Hg analyzer and for other metals, such as cadmium, lead, chromium, silver, nickel, copper and zinc, using inductively coupled plasma mass spectrometry. Distribution of heavy metals in muscles, internal organs and whole tissues were determined and a potential risk assessment was conducted to evaluate their hazard for human consumption. Heavy metals were accumulated significantly higher (P < 0.05) in internal organs than in muscles for all species. The mean Cd level, which had the highest level of three hazardous metals (Cd, Pb, and Hg) in all internal-organ samples were above the regulatory limit of Korea and the mean level in whole tissue samples of the selected gastropod species, bay scallop and comb pen shell, exceeded the limit (except in a few cases). The sum of the estimated dietary intake of Cd, Pb and Hg for each part of all tested species accounted for 1.59 16.94, 0.02-0.36, and 0.07-0.16% respectively, of the provisional tolerable daily intake adopted by the Joint FAO/WHO Expert Committee on Food Additives. The hazard index for each part of gastropods and bivalves was below 1.0, however, the maximum HI for internal organs of all analysed species was quite high (0.71). These results suggest that consumption of flesh after removing the internal organs of some molluscan shellfish (all gastropod species, bay scallop and comb pen shell) is a suitable way for reducing Cd exposure. PMID- 26521562 TI - Molecular and functional diversity of PGPR fluorescent Pseudomonads based on 16S rDNA-RFLP and RAPD markers. AB - The genetic and functional diversity of plant growth promoting rhizobacterial (PGPR) fluorescent pseudomonads associated with chickpea (Cicer arietinum L.) rhizosphere was analyzed. In total, 34 isolates along with two reference isolates were screened for various plant growth promoting traits (phosphorous solubilization, ACC deaminase, HCN, IAA and siderophore productions) and antagonist activity against four fungal phytopathogens and three bacterial pathogens. Most of the isolates, that showed PGPR activity, also showed antagonistic activity against all the three fungal pathogens. The genetic relationship was assessed by using random amplification of polymorphic DNA (RAPD) and PCR-restriction fragment length polymorphism (16S rDNA-RFLP). Relationship between both the markers was analyzed based on mantel test and a negative correlation was observed. The study concluded that PGPR traits appeared to be strain specific rather than specific to any phylogenetic group. The study also reported that 16S rDNA based profiling differentiated PGPR fluorescent Pseudomonas on the basis of location rather than biological trait. RAPD profiling could be useful to differentiate among the closely related isolates. The genetic and functional diversity of fluorescent pseudomonads, associated with the chickpea rhizosphere, has useful ecological role and potential utilization in sustainable agriculture. PMID- 26521563 TI - Phytoremediation potential of Cd and Zn by wetland plants, Colocasia esculenta L. Schott., Cyperus malaccensis Lam. and Typha angustifolia L. grown in hydroponics. AB - Cadmium and zinc phytoremediation potential of wetland plants, Colocasia esculenta, Cyperus malaccensis, and Typha angustifolia, was investigated. Plants were grown for 15 days in nutrient solutions containing various concentrations of Cd (0, 5, 10, 20, 50 mg l(-1)) and Zn (0, 10, 20, 50, 100 mg l(-1)). T angustifolia was tolerant to both metals as indicated by high RGR when grown in 50 mg I(-1) Cd and 100 mg I(-1) Zn solutions. All these plants accumulated more metals in their underground parts and > 100 mg kg(-1) in their aboveground with TF values < 1. Only C. esculenta could be considered a Zn hyperaccumulator because it could concentrate > 10,000 mg kg(-1) in its aboveground parts with TF > 1. T angustifolia exhibited highest biomass production and highest Cd and Zn uptake, confirming that this plant is a suitable candidate for treating of Cd contaminated soil/sediments. PMID- 26521564 TI - Allometry, condition index and secondary production in bivalve Barbatia decussata on rocky intertidal shores in the Northern Persian Gulf, Iran. AB - Biological parameters including allometry, condition index and secondary production were estimated for Barbatia decussata on rocky intertidal shores in the northern Persian Gulf (Iran) between August 2011 to September 2012. Relationship between shell dimensions (length, height, width, hinge) as well as relationship between shell length and weight (total wet weight, tissue wet weight, tissue dry weight, tissue ash free dry weight, shell dry weight, shell ash free dry weight) were estimated with b (equilibrium constant) values ranging from 3.023 to 3.347 (3.180 +/- 0.120). The b value between shell length and total wet weight was 3.181, indicating positive allometric growth pattern. Relationships between shell length-total wet weight (TLW), shell length-tissue wet weight (WW), shell length-tissue dry weight (DW), shell length-tissue ash free dry weight (AFDW), shell length-shell dry weight (sDW) and shell length shell ash free dry weight (sAFDW) were 0.0001xSL(3.181), 0.000015SL(3.347), 0.000006SL(3.169), 0.000004SL(3.234), 0.000074SL(3.150) and 0.000004SL(3.023), respectively. The condition index varied from 13.80 to 20.26 increasing from January 2012 to August 2012. Annual production, mean biomass and production to biomass ratio (P/ ) were 6.31 (g AFDWm(-2) year(-1)), 5.52 (g AFDWm(-2)) and 1.14 year(-1) respectively. PMID- 26521565 TI - Population genetic structure of Indian shad, Tenualosa ilisha inferred from variation in mitochondrial DNA sequences. AB - Indian shad, Tenualosa ilisha, is a commercially important anadromous fish representing major catch in Indo-pacific region. The present study evaluated partial Cytochrome b (Cyt b) gene sequence of mtDNA in T. ilisha for determining genetic variation from Bay of Bengal and Arabian Sea origins. The genomic DNA extracted from T. ilisha samples representing two distant rivers in the Indian subcontinent, the Bhagirathi (lower stretch of Ganges) and the Tapi was analyzed. Sequencing of 307 bp mtDNA Cytochrome b gene fragment revealed the presence of 5 haplotypes, with high haplotype diversity (Hd) of 0.9048 with variance 0.103 and low nucleotide diversity (pi) of 0.14301. Three population specific haplotypes were observed in river Ganga and two haplotypes in river Tapi. Neighbour-joining tree based on Cytochrome b gene sequences of T. ilisha showed that population from Bay of Bengal and Arabian Sea origins belonged to two distinct clusters. PMID- 26521566 TI - Forest structure and litter production of naturally re-generated white mangrove Avicennia marina in sub-tropical estuarine coast. AB - The present work deals with plant structure, phenology, litter production and decomposition of mangrove Avicennia marina in the newly re-generated mangrove forest in sub-tropical coast. The natural generation in this accreted coastal land of mono-specific A. marina forest stand was prominent, with 45% seedlings and 32% saplings. Peak flowering and fruiting were noticed in May and August, respectively. Reproductive components contribute countable percent into the total litter production during the peak flowering (60%) and fruiting (86%) season. The percentage of leaf litter fall fluctuated throughout the year and contributed 13 99% (73% in average) of the total litter production of 11.53 tones ha(-1)'yr(-1). The total litter production differed with season and influenced by local climate, pore water salinity and phenology of the mangrove. The naturally generated young (7 years) A. marina with 1.8 m height produced more leaf litter as compared to similar tree height elsewhere. Decomposition rate was related to season, with higher litter loss during rainy season which could help cycling nutrients and support estuarine food web by supplying organic matter into the sub-tropical coastal environment. PMID- 26521567 TI - Influence of diesel contamination in soil on growth and dry matter partitioning of Lactuca sativa and Ipomoea batatas. AB - Phytotoxic effect of diesel contaminated soil was investigated on growth and dry matter partitioning in Lactuca sativa and Ipomoea batatas in greenhouse pot experiment at two concentration range (0-30 ml and 0-6 ml diesel kg(-1) soil) for 14 weeks. The results indicated thatwhole plant biomass, stem length, root length, number of leaves and leaf chlorophyll in two plants were negatively correlated with increasing diesel concentrations. The critical concentration of diesel associated with 10% decrease in plant growth was 0.33 ml for lettuce and 1.50 ml for sweet potato. Thus, growth of lettuce in diesel contaminated soil was more sensitive than sweet potato. The pattern of dry matter partitioning between root and shoot in both plants were similar. In 0-6 ml diesel contamination range, allocation of dry matter to shoot system was favoured resulting in high shoot: root ratio of 4.54 and 12.91 for lettuce and sweet potato respectively. However, in 0-30 ml diesel contamination range, allocation of dry matter to root was favoured, which may have been an adaptive mechanism in which the root system was used for storage in addition to increasing the capacity for foraging for mineral nutrients and water. Although lettuce accumulated more metals in its tissue than sweet potato, the tissue mineral nutrients in both species did not vary to great extent. The critical diesel concentration for toxicity suggested that the cause of mortality and poor growth of sweet potato and lettuce grown in diesel contaminated soil was due to presence of hydrocarbons in diesel. PMID- 26521568 TI - Application of response surface methodology for optimising caffeine-degrading parameters by Leifsonia sp. strain SIU. AB - Caffeine is an important naturally occurring compound which can be degraded by bacteria. Previously, Leifsonia sp. strain SIU capable of degrading caffeine was isolated from agricultural soil. Plackett-Burman design was used to screen significant parameters that affect the rate of caffeine degradation. After the design was applied, response surface methodology (RSM) through Central Composite Design (CCD) was used to study significant parameters further, in order to get the most superior degradation conditions. The optimum concentrations of carbon source (sucrose), nitrogen source (NH4Cl), pH and initial caffeine concentration was found to be 5.0 gl(-1), 0.4 gl(-1), 6.0 and 375 ppm respectively. Second order polynomial regression model accurately showed interpretation of experimental data with an R2 value of 0.9989, Adjusted (Adj) R2, Predicted (Pred) R2 and F values of 0.9939, 0.9225 and 88.77 respectively. PMID- 26521569 TI - [Neonatal hypoxic ischemic encephalopathy treated with acupuncture combined with acupoint injection: a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical efficacy difference in the treatment of neonatal hypoxic ischemic encephalopathy (NHIE) between the combined therapy of acupuncture land acupoint injection of nerve growth fac-tor (NGF) and the combined therapy of the intravenous drop of citicoline sodium and intramuscular injection of NGF. METHODS: Sixty-one cases of NHIE were randomized into an observation group (32 cases) and a control group (29 cases). In the observation group, acupuncture combined with acupint injection of NGF was adopted. The acupoints were Baihui (GV 20), Dazhui (GV 14) and Fengfu (GV 16), 0. 5 mL each acupoint, once a day. In the control group, the intravenous drop of citicoline sodium and intramuscular injection of NGF were used. The, treatment of 7 days made one session and 3 sessions were required. Separately, in 7, 14 and 21 days of treatment, the clinical efficacy, behavior nerve determination score and adverse reaction were observed in the two groups. RESULTS: In 7, 14 and 21 days of treatment, the total effective rates were 50. 0% (16/32), 68. 8% (22/32) and 78. 1% (25/32) in the observation group and were 69. 0% (20/29), 72. 4% (21/29) and 82. 8% (24/29) in the control group. The result in the control group was better than that in the observation group in the 7 days (P< 0. 05). The behavior determination scores in 7, 14 and 21 days were all improved obviously as compared with those before treatment in the two groups (P<0. 05, P<0. 01). The score in the control group was better than that in the, observation group in the 7 days (P<0. 05). The differences were not significant in the scores between the two groups in 14 and 21 days (both P>0. 05). The incidence of adverse reaction in the observation group was lower than that in, the control group [14. 3% (5/35) vs 31. 4% (11/35), P<0. 05] and the severity was mild. CONCLUSION: In the treatment of NHIE with the combined therapy of acupuncture and acupint injection, the overall efficacy in 1 week; is inferior to that of the combined therapy of the intravenous drop of citicoline sodium and intramuscular injection of NGF. But the efficacy is improved gradually along with the treatment progression and the adverse reaction is less. PMID- 26521570 TI - [Warming acupuncture combined with facial moving cupping for 28 cases of intractable facial paralysis]. PMID- 26521572 TI - [Clinical efficacy on mental retardation in the children treated with JIN's three scalp needling therapy and the training for cognitive and perceptual disturbance]. AB - OBJECTIVE: To explore the impacts on the cognitive level of the children with mental retardation (MR) treated with JIN's three scalp needling therapy and the training for cognitive and perceptual disturbance so as to seek the more effective therapeutic method for the treatment of MR in children. Methods Sixty six MR children were randomized into a head-point needle-retaining therapy + training group (group A) and a training after acupuncture group (group B). Seven cases and 12 cases were dropped in the two groups respectively. Twenty-six cases accomplished the treatment in the group A and 21 cases in the group B. In the group A, the points on the head were stimulated and the needles were retained (30 min after the general acupuncture, the needles on the body points were removed; and those on the head points were retained for 1 h, including Sishenzhen, Naosanzhen, Zhisanzhen and Niesanzhen). Simultaneously, the training for the cognitive perceptual disturbance was combined. In the group B, 1 h after needle retaining at the body points and head points, all the needles were removed; the training for the cognitive perceptual disturbance was followed. The treatment was given once a day, and the treatment for 3 months was required. Before and after treatment, the Wechsler intelligence scale for children (WISC) was used for evaluation and observation of verbal intelligence quotient (VIQ) , performance intelligence quotient (PIQ) and full-scale intelligence quotient (TFIQ) and score changes of 11 items such as information, picture vocabu; lary, arithmetic, picture generalization, comprehension, etc. RESULTS: After treatment, FIQ, VIQ and PIQ scores were different significantly as compared with those before treatment (all P<0. 01). In the group A, the results of picture vocabulary, animal egg laying, maze, block design and geometric figure were all improved significantly (all P<0. 05). In the group B, the results of information, comprehension, block design and geometric figure were all improved significantly (all P<0. 05). After treatment, concerning the value difference in FIQ and PIQ of the two groups; the changes in the group A were more significant (both P<0. 01). After treatment, the results of picture vocabulary and maze were improved significantly in the group A as compared with the group B (both P<. 01). The IQ categories changed apparently after treatment in the two groups, toward the higher level in tendency generally, but without significant difference (both P>0. 05). CONCLUSION: The simultaneous treatment with head point retaining of JIN's three needling therapy and the training for cognitive and perceptual disturbance obviously improves children patients' verbal comprehension, expression ability, hand-eye coordination ability, attention, logical reasoning ability and visual perception. The efficacy is better than that in the treatment of the training after acupuncture. PMID- 26521571 TI - [Clinical observation of sleeping disorder in children with encephalopathy treated with acupuncture at head points and seed-pressure at ear points]. AB - OBJECTIVE: To compare the difference of clinical efficacy on sleeping disorder in the children with encephalopathy between the combined therapy of acupuncture at head points and seed-pressure at ear points and the simple acupuncture at head points. METHODS: Thirty cases of sleeping disorder induced by encephalopathy werei randomized into an observation group and a control group, 15 cases in each one. In the observation group, the combined therapy of acupuncture at head points and seed-pressure at ear points was adopted. The head points in cluded Sishencong (EX-HN 1), Shenting (GV 24) and Benshen (GB 13). The ear points were the positive reactive sites in the cymba and cavum conchae. In the control group, acupuncture was applied simply to the acupoints on the head. The treatment was given once on every Tuesday and Friday a week separately, 30 min each time. Totally, 16 treatments were required. Children's sleeping habit questionnaire (CSHQ) was used to observe the sleep improvements and the efficacy in the patients of the two groups. RESULTS: In the observation group, the results of sleep resistance, sleep anxiety, night sleep wake, parasomnias, sleep dyspnea, daytime somnolence and the total score after treatment were all improved apparently as compared with those before treatment (all P<0. 05). In the control group, the results of night sleep wake, parasomnias, daytime somnolence and the total score after treatment were improved apparently than those before treatment (all P<0. 05). In the observation group, the results of sleep resistance, sleep dyspnea and the total score after treatment were better than those in the control group (all P<0. 05) and the scores of sleep anxiety and daytime somnolence in the control group were better than those in the observation group after treatment (both P<0. 05). CONCLUSION: The combined therapy of acupuncture at head points and seed-pressure at the positive reactive sites in the cymba and cavum conchae achieves the superior efficacy on sleep resistance and sleep dyspnea as compared with the simple acupuncture. The efficacy of simple acupuncture is more satisfactory on sleep anxiety and daytime somnolence. PMID- 26521573 TI - [Case of depression]. PMID- 26521574 TI - [Magnetic resonance spectroscopic study of memory impairment after cerebral infarction treated with electroacupuncture]. AB - OBJECTIVE: To study the impacts of electroacupuncture (EA) on memory impairment after cerebral infarction through the observation of hydrogen proton magnetic resonance spectroscopy (1H-MRS) of brain tissue metabolites in the patients of cerebral infarction. METHODS: Sixty cases of memory impairment after cerebral infarction were randomized into an observation group and a control group, 30 cases in each one. The conventional rehabilitation training and medication were applied to all the patients. In the observation group, beside the basic treatment, EA was applied to bilateral Ezhongxian (MS 1), Dingzhongxian (MS 5), Dingniehouxiexian (MS 7), Hegu (LI 4), Taichong (LR 3), Zusanli (ST 36), Taixi (KI 3), Xuanzhong (GB 39) and Fengchi (GB 20). The treatment was given once a day, 5 times a week, for 8 weeks. The clinical memory scale was used for the score evaluation before and after treatment in all the patients. The magnetic resonance image (MRI) and 1H-MRS scanning were applied to the head. The ratio of N-acetyl aspartate (NAA) and creatine (Cr) and the ratio of choline (Cho) and Cr were determined in the foci of cerebral infarction. RESULTS: Eight weeks later, the scores of clinical memory scale were all increased after treatment as compared with those before treatment in the two group (all P<0. 01). The ratio of NAA and Cr was increased as compared with that before treatment (P<0. 05); the ratio of Cho and Cr was reduced as compared with that before treatment (P<0. 05). The changes in the observation group were more obvious than those in the control group (all P<0. 05). CONCLUSION: On the basis of the conventional medication and rehabilitation training, EA improves the metabolism of brain tissue and memory function of the patients. The efficacy of this therapy is better than that of medication combined with rehabilitation training. PMID- 26521575 TI - [Clinical study of post-stroke speech apraxia treated with scalp electric acupuncture under anatomic orientation and rehabilitation training]. AB - OBJECTIVE: To compare the differences in the clinical efficacy on post-stroke speech disorder between scalp electric acupuncture (EA) under anatomic orientation combined with rehabilitation training and simple rehabilitation training. METHODS: Sixty patients of post-stroke speech apraxia were randomized into an observation group and a control group, 30 cases in each one. In the observation group, under anatomic orientation, the scalp EA was adopted to the dominant hemisphere Broca area on the left cerebrum. Additionally, the speech rehabilitation training was combined. In the control group, the speech rehabilitation training was simply,used. The treatment lasted for 4 weeks totally. The speech movement program module in the psychological language assessment and treatment system of Chinese aphasia was used for the evident of efficacy assessment. The scores of counting, singing scale, repeating phonetic alphabet, repeating monosyllable and repeating disyllable were observed in the patients of the two groups. The assessment was done separately on the day of grouping and 4 weeks after treatment. RESULTS: In 4 weeks of treatment, the scores of counting, singing scale, repeating phonetic alphabet, repeating monosyllable and repeating disyllable were all improved as compared with those before treatment in the two groups (all P<0. 001). The results in the observation group were better than those in the control group (all P< 0. 05). The total effective rate was 100. 0% (30/30) in the observation group, superior apparently to 53. 3% (16/30) in the control group (P<0. 001). CONCLUSION: The scalp EA under anatomic orientation combined with' speech rehabilitation training obviously improves speech apraxia in stroke patients so that the speech disorder cani be relieved. The efficacy is better than that in simple rehabilitation training. PMID- 26521576 TI - [Copracrasia treated with acupuncture and moxibustion: a randomized controlled trial]. AB - OBJECTIVE: To explore the clinical efficacy and safety of acupuncture and moxibustion for copracrasia. METHODS: By prospective live randomized controlled trial, 40 cases with copracrasia were randomly divided into an acupuncture moxibustion group and a medication group, 20 cases in each one. In the acupuncture-moxibustion group, acupuncture was applied at Ciliao (BL 32), Changqiang (GV 1) and Tianshu (ST 25) and mild moxibustion was used at Qihai (CV 6). Treatment was given for 12 weeks and 32 times, 3 times a week in the front 8 weeks, 2 times a week in the latter 4 weeks. In the medication group, conventional symptomatic treatment, support therapy, and complications preventing and treating were adopted for 12 weeks. Anal incontinence score (Vaizey incontinence score), effective rate and self-rating score for satisfaction were observed before and after treatment and in the follow-up period. RESULTS: After 12 weeks' treatment in the two groups, Vaizey incontinence' scores were both decreased (both P<0. 05), and after treatment and in the follow-up period the scores in the acupuncture-moxibustion group were lower than those in the corresponding period in the medication group (both P< 0. 05). The effective rate of the acupuncture-moxibustion group was 80. 0% (16/20), which was statistically different from 50. 0% (10/20) in the medication group (P<0. 05). The effective rate in the follow-up period of the acupuncture-moxibustion group was 90. 0% (18/20) and it was not statistically different from 80. 0% (16/20) in the medication group (P>0. 05). The self-rating scores for satisfaction in the acupuncture-moxibustion group were superior to those in the medication group after treatment and in the follow-up period (both P< 0. 05). CONCLUSION: Acupuncture and moxibustion could improve copracrasia and the acupuncture moxibustion rules and characteristics for the disorder should be paid attention to in the further research. PMID- 26521577 TI - [Clinical efficacy on neurogenic bladder after spinal cord injury treated with rehabilitation training and acupuncture-moxibustion]. AB - OBJECTIVE: To compare the differences in the clinical efficacy on neurogenic bladder after spinal cord injury (SCD between the matrix needling technique combined with rehabilitation training and rehabilitation training in the patients. METHODS: Sixty patients of SCI neurogenic bladder were randomized into an observation group (29 cases) and a control group (31 cases). In the control group, the conventional rehabilitation therapy, the intermittent catheterization and bladder function training were adopted, once every day, for 4 weeks totally. In the observation group, on the basic treatment of the rehabilitation as the control group, the matrix needling technique and acupuncture at sanyin points were applied. The treatment of 8 days made one session, at the interval of 2 days, continuously for 3 sessions, meaning 4 weeks totally. The bladder function score, residual urine volume and bladder capacity were compared before and after treatment in the two groups. RESULTS: The bladder function score was reduced after treatment as compared with that before treatment in either group (both P<0. 05). The score in the observation group was lower than that in the control group after treatment (P<0. 05). No matter which spinal segment was injured, the residual urine volume after treatment was reduced as compared with that before treatment and the bladder capacity was increased (P<0. 05). The residual urine volume in the observation group was less than that in the control group after treatment and the bladder capacity was more increased (P< 0. 05). CONCLUSION: The conventional rehabilitation program in combination with the matrix needling technique and acupuncture at sanyin points achieve the significant efficacy on SCI neurogenic bladder. PMID- 26521578 TI - [Ginger-partitioned moxibustion for 60 cases of chronic cough caused by exogenous diseases]. PMID- 26521579 TI - [Case of pancreatic cancer]. PMID- 26521580 TI - [Case of chronic diarrhea]. PMID- 26521581 TI - [Efficacy of acupuncture on pain after replantation of severed finger]. AB - OBJECTIVE: To observe the efficacy of acupuncture on pain after replantation of severed finger. METHODS: A total of 80 patients who underwent replantation of severed finger were randomly divided into an observation group and a control group, 40 cases in each one. The patients in the control group were treated with postoperative routine care of hand surgery, while patients in the observation group, based on the regular treatment, were treated with acupuncture within first 72 h of surgery. The health side of Yanglingquan (GB 34), Xuehai (SP 10), Hegu (LI 4), Houxi (SI 3) were selected and the needles were retained for 30 min. The acupuncture was given for 6 times. The evaluation was performed by using visual analogue scale (VAS) 2 h, 4 h, 6 h, 12 h, 24 h, 48 h and 72 h after surgery. The use of analgesics after surgery was recorded in the two groups, and the blood supply and survival rate of severed finger were evaluated. RESULTS: Compared between the two groups, the VAS 4 h, 6 h, 12 h, 24 h and 48 h after surgery in the observation group was lower than that in the control group (all P<0. 05); the use frequency of analgesics in the observation group was lower than that in the control group (P<0. 05); the abnormality rate of blood supply in the observation group was lower than that in the control group (P<0. 05). CONCLUSION: Acupuncture can significantly relieve postoperative pain of replantation of severed finger, and reduce the occurrence rate of abnormal blood supply, which is worthy of clinical promotion. PMID- 26521582 TI - [Clinical observation of Erlong Xizhu acupuncture for retinitis pigmentosa]. AB - OBJECTIVE: To explore the clinical effect of Erlong Xizhu acupuncture for retinitis pigmentosa. Methods Sixty patients with retinitis pigmentosa were randomly divided into an Erlong Xizhu acupuncture group and a conventional acupuncture group, 30 cases in each one. In the conventional acupuncture group, Tongziliao (GB 1), Sizhukong (TE 23), Taiyang (EX-HN 5) were acupunctured as the main acupoints by uniform reinforcing-reducing manipulation; acupoints based on syndrome differentiation were coordinated by acupuncture manipulation of reinforcing deficiency and reducing excess. The treatment in the Erlong Xizhu acupuncture group was the same as that in the conventional group, except acupuncture manipulation at the main acupoints replaced by Erlong Xizhu acupuncture. In the two groups, treatment was given once a day, 10 days as one session and there were 2 days at the interval between sessions. The change of the vision and visual field and the efficacy were observed after 3 sessions in the two groups. RESULTS: The total effective rate on enhancing the vision of patients in the Erlong Xizhu acupuncture group was 93. 10% (54/58), which was superior to 81. 36% (48/59) in the conventional acupuncture group (P<0. 01). And the effective rate on improving the visual field was 91. 38% (53/58) in the Erlong Xizhu acupuncture group, which was better than 83. 05% (49/59) in the conventional acupuncture group (P<0. 01). On the comprehensive effect, the effective rate was 90. 00% (27/30) in the Erlong Xizhu acupuncture group, which was better than 63. 34% (19/30) in the conventional acupuncture group (P<0. 05). CONCLUSION: The clinical effect of Erlong Xizhu acupuncture is superior to that of conventional acupuncture for retinitis pigmentosa and it is worthy of promoting. PMID- 26521583 TI - [Ginger-salt-partitioned moxibustion at Shenque (CV 8) for 19 cases of urine incontinence after stroke]. PMID- 26521585 TI - [Brief on the standardization of the practitioner's posture in acupuncture operation]. AB - To discuss the standardization of the practitioner's posture in acupuncture operation. Based on the relevant discussion on 'way to holding needle' recorded in Lingshu (Miraculous Pivot) and in association with the clinical acupuncture practice, it was required to standardize the practitioner's posture in acupuncture operation in reference to Lingshu (Miraculous Pivot). The standard standing posture of the practitioner is the precondition of acupuncture operation; the standard holding needle with the puncture hand is the key to the exercise of acupuncture technique and the regular standing orientation is the need of acupuncture operation. The three aspects are complemented each other, which is the coordinative procedure in acupuncture operation and enable the practitioner's high concentration with the body, qi and mind involved. PMID- 26521584 TI - [Effects of moxa smoke with different concentrations on expression of SOD and MDA in lung and serum of rats]. AB - OBJECTIVE: To observe the effects of intervention of moxa smoke with different concentrations on superoxide dismutase (SOD) and malondialdehyde (MDA) in serum and lung of male rats, so as to explore the safety concentration of moxa smoke. METHODS: A total of 32 Wistar male rats were randomly divided into a control group, a low-concentration group, a moderate-concentration group and a high concentration group, 8 rats in each one. All the rats were exposed in the full automatic toxicant exposure cabinet, and the overshadow of moxa smoke was set at 0%, 10%, 40% and 70%, respectively. Each rat was exposed for 20 min per day. After 26 weeks, the activities of SOD and content of MDA in serum, lung organ and bronchoalveolar lavage fluid were tested. RESULTS: Compared with the control group, the activities of serum SOD in the high-concentration group were reduced (P< 0. 05), but those in the low-concentration group and moderate-concentration group were not significantly different (both P>0. 05). Compared with the control group, the content of serum MDA in the low-concentration group, moderate concentration group and high-concentration group was increased insignificantly (all P>0. 05). There were no significant differences regarding activities of SOD and content of MDA in lung organ and bronchoalveolar lavage fluid among each moxa smoke group (all P>0. 05). CONCLUSION: There is no obvious toxic reaction in the low-concentration group and moderate-concentration group; in the high concentration group the antioxidant ability is damaged due to long-term exposure. PMID- 26521586 TI - [Guan's tongue acupuncture for 20 cases of burning mouth syndrome]. PMID- 26521587 TI - [Effects of electroacupuncture on the expression of related protein mRNA in the striatum in rats with Parkinson's disease]. AB - OBJECTIVE: To explore action mechanism of electroacupuncture (EA) on treatment of Parkinson's disease (PD). METHODS: A total of 40 healthy male SD rats were randomly divided into a normal group, a sham operation group, a model group and an EA group, 10 rats in each group. PD rat model was duplicated by micro injection of 6-hydroxyl dopamine into right striatum of rats, and the rats in the sham operation group were treated with micro injection of 0. 9% NaCl. Rats in the normal group, model group and the sham operation group received no treatment; rats in the EA group were treated by EA at "Fengfu" (GV 16) and "Taichong" (LR 3) with continuous wave, 2 Hz in frequency, 1 mA in intensity for 30 min. The treatment was given once a day for total 2 weeks. Behavioral test was used to evaluate rotational behavior changes of PD rats. RT-PCR method was applied to detect the expression of GFAP (glial fiber acidic protein) mRNA and Cx43 (connexin 43) mRNA in the striatum. RESULTS: The difference of rotational behavior was not significant before and after treatment in the model group (P>0. 05), while that in the EA group was significant (P<0. 01). The expression of GFAP mRNA and Cx43 mRNA in the model group was significantly higher than that in the normal group and sham operation group (all P<0. 01); after EA treatment, the expression of GFAP mRNA and Cx43 mRNA in the EA group was lower significantly than that in the model group (both P<0. 01). CONCLUSION: The action mechanism of EA for prevention and treatment of Parkinson' s disease may be associated with inhibiting the activation of astrocytes. PMID- 26521588 TI - [Effects of moxibustion with seed-sized moxa cone at "Ganshu" (BL 18) on liver function in rats with precancerous lesion of hepatic cellular cancer]. AB - OBJECTIVE: To explore the effects of moxibustion with seed-sized moxa cone at "Ganshu" (BL 18) on liver furiction and morphology in rat with precancerous lesion of hepatic cellular cancer MCC). METHODS: A total of 60 male Wistar rats were randomly divided into a normal group (10 rats), a model group (20 rats), a 20-day treatment group (15 rats) and a 40-day treatment group (15 rats). HCC model was established by intraperitoneal injection of diethylnitrosamine (DEN). Rats in the normal group received no treatment. Rats in the model group were treated with fixation. Rats in the 20-day treatment group and 40-day treatment group were treated by moxibustion with seed-sized moxa cone at "Ganshu" (BL 18), once every other day, for 20 days and 40 days, respectively. Blood sample in each group was collected 1 d before model establishment, 20 d, 40 d and 84 d after model establishment. Chemical method was applied to test the activity of ALT (alamine aminotransferase), AST (aspartate transaminase) and GGT (glutamyl transpeptidase); at the end of model establishment, all the rats were sacrificed to observe the liver morphology changes. RESULTS: After the first therapeutic course, the. content of ALT and AST in the 20-day treatment group was significantly lower than that in the model group (all P<0. 05); after the second therapeutic course, the content of ALT, AST and GGT in the 40-day treatment group was insignificantly lower than that in the model group (all P>0. 05). Under light microscope, the slice of liver tissue indicated that primary tumor was induced in the model group, and the tumor cells were stained and irregular; the cytoplasm in the 20-day treatment group was even, and the tumor cells were few with several nodules alone. In the 40-day treatment group the liver morphology was normal and the staining was even; the tumor cells were few without nodules or a few. Conclusion Moxibustion with seed-sized moxa cone at "Ganshu" (BL 18) could reduce the serum content of ALT, AST and GGT in rats with HCC, which could protect the liver and: delay the DEN-induced precancerous lesion on some levels. PMID- 26521589 TI - [Impacts on oxidative stress in the patients with cardiac valve replacement treated with electroacupuncture at Neiguan (PC 6)]. AB - OBJECTIVE: To observe the myocardial protective effect of electroacupuncture (EA) at Neiguan (PC 6) in the patients with valve replacement via extracorporeal circulation. METHODS: Fifty patients of rheumatic cardiac disease planned for valve replacement were graded as II or III level according to America Society of Anesthesiologists (ASA) and were randomized into an observation group and a control group, 25 cases in each one. The same anesthesia and valve replacement via extracorporeal circulation were adopted in the patients of the two groups. In the observation group, 30 min before operation, EA was used to stimulate bilateral Neiguan (PC 6) till the end of operation. The venous blood was collected at 5 time points separately, named before aorta blockage (T1), 15 min after aorta open (T2), 30 min after aorta open (T3), 6 h after opening (T4) and 24 h after opening (T5). The concentrations of malondial dehyde (MDA), superoxide dismutase (SOD) and cardiac troponin 1 (cTnI) were determined in serum. The heart re-beating and the total dosage of vasoactive drugs after operation were recorded. RESULTS: Compared with those before aorta blockage, MDA and cTnI at each time point of aorta open were all apparently increased in the patients of the two groups (all P<0. 05), and SOD was reduced apparently (P<0. 05). Compared with the control group, at the time points from T3 to T5 , MDA and cTnL were lower apparently in the observation group as compared with those in the control group (all P<0. 05) and SOD was higher than that in the control group (P<0. 05). The dosage of vasoactive drugs was reduced apparently (P<. 05). CONCLUSION: EA at Neiguan (PC 6) alleviates oxidative stress injury and has the protective effect on ischemic reperfusion myocardium. PMID- 26521590 TI - [Aging law on anti-hypertensive effect of scrapping therapy on primary hypertension]. AB - OBJECTIVE: To observe the aging law on anti-hypertensive effect of scrapping therapy on primary hypertension so as to provide the reference evidence for the best treatment frequency of scrapping therapy. METHODS: Eighty-nine patients of primary hypertension complied with inclusive criteria were treated with scrapping therapy according to syndrome differentiation. The stimulated sites included the courses of the governor vessel and the bladder meridian on the neck and back region, the line from Quchi (LI 11) to Shousanli (LI 10) and that from Zusanli (ST 36) to Fenglong (ST 40). The strong stimulation for reducing attempt was applied to the case of excessi syndrome, determined by subcutaneous capillary rupture and subcutaneous blood stasis. The mild stimulation for reinforcing attempt was applied to the case of deficiency syndrome, determined by subcutaneous capillary hyperemia and skin flush. Each site was scrapped for 10 times, about 5 cm in width, for 15 min. One scrapping treatment was required. The blood pressure was taken as the observation index separately, named 2:00 pm, 2:30 pm, 3:00 pm, 3:30 pm, 4:00 pm, 5:00 pm, 6:00 pm and 8:00 pm one day before scrapping, the time before scrapping in the afternoon on the day of treatment, the moment (2:00 pm), 2:30 pm, 3:00 pm; 3:30 pm, 4:00 pm, 5:00 pm, 6:00 pm and 8:00 pm after scrapping, in 24 h and 48 h after scrapping. RESULTS: (1) After one scrapping, the blood pressure was reduced to be (137. 51+/-10. 24)/(81. 06+/-10. 56) mmHg half a hour after scrapping from (149. 00+/-10. 19)/(85. 30+/-10. 96) mmHg (1mmHg~0. 133 kPa) before scrapping (P<0. 01). (2) The differences were significant in blood pressure at each time point after scrapping as compared with that before scrapping (all P<0. 01). (3) Through nonlinear regression analysis, the systolic blood pressure after scrapping was increased up to 140 mmHg in 47. 2 h after scrapping. CONCLUSION: Scrapping therapy achieves the apparent immediate anti-hypertensive effect on primary hypertension. It is suitable to apply scrapping treatment once every other day. PMID- 26521591 TI - [Acupuncture and tuina clinical thoughts of "treating the back from abdomen" for low back pain]. AB - In clinical treatment, it is found that certain patients always have some positive reaction points those are relevant with low back pain in the abdomen area. When the simple treatment on the low back is ineffective, the efficacy could be significantly improved if acupuncture or tuina is performed at the abdomen areas, which is called "regulating yin to treat yang", or "treating the back from abdomen". In this paper, with the diagnosis and treatment method of "treating the back from abdomen" for low back pain as principal line, the detailed manipulation is explained for low back pain that is induced by TCM meridian diseases or modern anatomy, which could open the methods for clinical treatment of low back pain and enrich the therapeutic options. PMID- 26521592 TI - [Case of Huntington disease]. PMID- 26521593 TI - [Analysis on the factors that cause the difference of acupoints synergy effect]. AB - Based on traditional acupuncture theory and modern researches, the factors that cause the difference of acupoints synergy effect are summarized and analyzed. It is found that the factors include the specificity of acupoint, the interaction of acupoints, the pathway of acupuncture signal, the body condition level, acupuncture manipulation, etc. It is believed that the specificity of acupoint is the key factor to determine the difference of acupoints synergy effect. Interaction of acupoints may be related to the pathway of selected acupuncture signal, which is an important factor in difference of acupoints synergy effect. The body condition level and acupuncture manipulation are internal and external factor to influence acupoints synergy effect, respectively. PMID- 26521594 TI - [Brief discussion on "Sanli acupoint for du-fu diseases"]. AB - The connotations of "du-fu" and "Sanli" in "Sanli acupoint for du-fu diseases" are discussed in this paper, which can provide theoretical foundation for the clinical application of "Sanli acupoint for du-fu diseases". Based on ancient literature combined with related theories in the Huangdi Neijing (Yellow Emperor's Canon of Internal Classic), a deep discussion is performed through the relationship between Zusanli (ST 36) and stomach, indication and mechanism of Zusanli (ST 36) on du-fu diseases and comparison between Zusanli (ST 36) and Shousanli (LI 10). It is believed that "du" should be pronounced as "du", meaning stomach, and it indicates that Zusanli (ST 36) is closely related to stomach and spleen when it is used for du-fu diseases; "fu" means abdomen area, including liver-gallbladder, spleen, stomach-intestine, kidney, uterus, triple energizer; "sanli' means exclusively the acupoint of Zusanli (ST 36). PMID- 26521595 TI - [Acupuncture technique of "five elements motion and six kinds of qi"]. AB - The origin and development of "five elements motion and six kinds of qi" acupuncture technique are reviewed, and acupuncture for treatment and prevention of disorders of "five elements motion and six kinds of qi" is summarized. Also its principle is analyzed. Problems such as the inconformity of acupoint selection, lack of systematic theory are discussed. It is pointed out that, instead of indiscriminate copy, treatment should be based on the observation of the transportation and transformation of qi; it is suggested that the classics should be inherited and innovated, combining the tradition with contemporary, and according to a sixty-year cycle, the acupuncture technique of "five elements motion and six kinds of qi" can be improved systematically for promotion and application. PMID- 26521596 TI - [Case of failed lumbar surgery syndrome]. PMID- 26521597 TI - [Classification and characteristic of the acupuncture medical literature during the period of the Republic of China]. AB - The acupuncture medical literature during the Republic of China is divided into four categories, including theoretical literature, acupuncture channels and acupoints drawing literature, translations, and teaching materials and medical cases. It is found that the theoretical literature focuses on inheriting the traditional theories as well as combining traditional Chinese and Western medicine. The drawings are becoming more and more precise, and in these drawing works anatomy begins to appear at that time. Translations are the achievements of communication between TCM and Western medicine, which promote the scientization of acupuncture greatly. Teaching materials are also influenced by Western medicine, presenting a rough frame of modern acupuncture disciplinary system. As important clinic data, medical cases have great clinical value. Overall, acupuncture medical literature during the Republic of China is widely published, which is influenced greatly by the Western medicine and presents a significant tendency of scientization. PMID- 26521598 TI - [Analysis on the academic cultivation of young TCM scholars based on Professor LIU Zhicheng's academic track]. AB - In view of the public academic papers of Professor LIU Zhicheng, his academic track is analyzed, including validating effect, exploring mechanism, improving efficacy, expanding disease variety, deepening mechanism, optimizing program and seeking breakthrough. On this basis, combined with the self-character of TCM, the potential path for the academic cultivation of young scholars is refined: focusing on clinical practice, confirming clinical efficacy, deepening mechanism exploration, improving clinical therapeutic effect, optimizing clinical program, extending clinical disease spectrum, inheriting, seeking, breaking through, innovating, expecting and topping over. It is believed that during the academic cultivation, the importance is to form the stable research direction and continuity, organize research team, absorb actively new knowledge and thoughts, and adopt multidisciplinary cross and coordination so as to achieve the greater success ultimately. PMID- 26521599 TI - [Standardizing the manipulation procedure of acupuncture-moxibustion, reinforcing the training of' clinical skill: learning experience of Acupuncture-moxibustion Clinical Skills Training: Chapter of Commonly Used Needling and Moxibustion Techniques]. AB - The book Acupuncture-moxibustion Clinical Skills Training is one of "Twelfth Five Year Plan" in novative teaching materials, which is published by People's Medical Publishing House. Through learning the first half of the book commonly used needling and moxibustion techniques, it is realized that the selection of book content is reasonable and much attention is paid to needling and moxibustion techniques; the chapter arrangement is well-organized, and the form is novel, which is concise and intuitive; for every technique, great attention is paid to standardize the manipulation procedure and clarify the technique key, simultaneously the safety of acupuncture and moxibustion is also emphasized. The characteristics of the book, including innovativeness, practicability, are highlighted, and it greatly helps to improve students' clinical skills and examination ability. PMID- 26521600 TI - [Blood letting therapy in ear apex for 17 cases of iritis]. PMID- 26521601 TI - [Development and application of new temperature control moxibustion device]. AB - To develop a new temperature control moxibustion device so as to improve the clinical therapeutic effect of moxibustion. According to the thermal effect of moxibustion, with the designs such as the modern electronic equipment (temperature control system) adopted and in combination of smoke filtration device and oxygen mask device, a new temperature control moxibustion device was developed. The new temperature control moxibustion device may achieve the automatic regulation of temperature and distance and avoid the pollution and irritation of smoke and flavor, etc. As a result, the traditional moxibustion therapy can better play its efficacy and display its safety and convenience in practice. PMID- 26521602 TI - [Case of thrombocytosis associated with leukocytosis]. PMID- 26521603 TI - [Research progress of acupuncture for cerebral ischemia reperfusion injury in recent 10 years]. AB - By searching relevant data from the PubMed database, Chinese National Knowledge Infrastructure (CNKI) database and Wanfang database, a comprehensive analysis and review regarding acupuncture for cerebral ischemia reperfusion injury (CIRI) in recent 10 years were performed. The results showed that acupuncture could inhibit the inflammatory reaction, reduce oxidative stress injury, restrain brain edema formation, inhibit apoptosis, promote neural and vascular regeneration, etc. Acupuncture methods used included electroacupuncture, scalp acupuncture, eye acupuncture and "consciousness-restoring resuscitation needling", etc. The existing problem was that the intervention action of acupuncture was mainly focused on inhibiting inflammatory reaction and oxidative stress injury, and the study on apoptosis and neural and vascular regeneration was needed. It is suggested that from the aspect of multiple target points, the intervention mechanism of acupuncture for CIRI should be systemically studied in the future, which could provide new idea for clinical diagnosis and treatment on ischemic cerebrovascular diseases. PMID- 26521604 TI - Diabetes quiz. How much do you know about diabetes and heart disease? PMID- 26521605 TI - Baking and cooking with sugar substitutes. PMID- 26521606 TI - Fear of fat. A fresh look at an old enemy. PMID- 26521607 TI - The Book of Adjustments. PMID- 26521608 TI - More than skin deep. Proper care, awareness crucial to maintaining healthy skin. PMID- 26521609 TI - Celiac. Diabetes' Sometimes Sidekick. PMID- 26521611 TI - ODA Past President Perspective: Dr. Bill Brewer ODA President 1990-91. PMID- 26521610 TI - It's a Hard Life, Being a Dentist. PMID- 26521612 TI - Yes, I am the Dentist! PMID- 26521613 TI - A Survey of Artificial Pharmaceutical 'Stones'--Part 1. PMID- 26521614 TI - Representing pharmacy: The Pharmaceutical Society of Great Britain's first Diploma. PMID- 26521615 TI - Drug shortages in World War I: How German pharmacy survived the years of crisis. PMID- 26521616 TI - Thomas Skinner: A Pioneer in Homeopathic Pharmacy. PMID- 26521617 TI - A Survey of Artificial Pharmaceutical 'Stones'--Part 2. PMID- 26521618 TI - Peganum Oil in Iranian Traditional Pharmacy. PMID- 26521619 TI - Intranasal hypnotic drugs used in Iranian Traditional Medicine (ITM). PMID- 26521620 TI - Extemporaneous Preparations from the Past. PMID- 26521621 TI - The Anglo-American Pharmaceutical Company Limited. PMID- 26521622 TI - Grounded, Rooted and Flourishing: AHNA Financial Health 2015. PMID- 26521623 TI - Bringing Nurse Coaching to a Cardiovascular Health Clinic. PMID- 26521624 TI - Nurse Coaching Through a Nursing Lens: The Theory of Integrative Nurse Coaching. PMID- 26521625 TI - Transpersonal Coaching. AB - These are just a few of many stories shared by patients who have benefited from transpersonal coaching. This practice blends well with holistic nursing and can be easily applied to a variety of situations and healthcare settings. When a holistic nurse works from the assumption that the transpersonal aspect of human nature is an objective fact, it is possible to help patients gain access to their transpersonal nature and thereby experience new feelings and insights. The insights usually come in the form of images and energies and provide the personality with a greater sense of wholeness and courage. PMID- 26521626 TI - Nurse Coaching Is Not What I Do: It Informs Who I Am. PMID- 26521627 TI - The Nuances of Cultural Diversity in Coaching. PMID- 26521628 TI - Facilitate. Empower. Transform. Get Nationally Certified as a Nurse Coach. PMID- 26521629 TI - Sometimes All Roads DO Lead Home: Reflections on the AHNA 35th Conference. PMID- 26521630 TI - The Healthy Nurse: Holistic Nurses Leading the Way to Wellness. PMID- 26521631 TI - Would Congress still fund the ESRD Program today? PMID- 26521632 TI - Physician practice mergers in nephrology. PMID- 26521633 TI - Nursing homes: The new frontier. AB - As the population continues to age, we will see a larger percentage of end-stage CKD patients in nursing homes, both skilled and long-term facilities. This is a fragile population and will take buy-in from all practitioners to care for them. Even with the dietitian to manage a complicated and detailed menu, the social worker to manage the transportation and multiple issues with equipment, the therapy staff to protect against loss of ADLs, the recreational therapist to protect against loss of cognitive function and the medical staff (APs, nursing, physicians), this population will continue to present both challenges and opportunities. PMID- 26521634 TI - Reducing dialysis catheters: A smart approach to quality care. PMID- 26521635 TI - How Sutter Health Built a Shared Services Organization Focused on the Future. PMID- 26521636 TI - Reimbursement Benchmarking: Weighted Averages and the Importance of Codes. PMID- 26521637 TI - ROI Beyond the Dollar: A Strategic Approach to Patient Payment Programs. PMID- 26521638 TI - What's Really Driving Your Denial Rate? PMID- 26521639 TI - Five years later, hospitals still struggle with readmissions. AB - Despite the huge focus on reducing 30-day readmission rates, a majority of hospitals are still getting penalized. But, in many cases, the penalties may be too small to justify big expenditures for new programs and staff. Case management leaders should work with the hospital administration to redesign the way that care is delivered in order to succeed as the healthcare market changes. Hospitals need to have a handle on their own readmission data including number of patients readmitted within 7, 14, and 30 days, the top 10 conditions of readmitted patients, and where readmitted patients went after their initial discharge. Case managers should take the time to thoroughly assess patients for healthcare literacy, social issues, family support, and educate them on their conditions, their prognosis, and palliative and hospice care if appropriate. PMID- 26521640 TI - Take time to base the discharge plan on patients' individual challenges. PMID- 26521641 TI - Team approach to readmission reductions pays off. AB - Our Lady of the Lake Regional Medical Center has avoided readmission penalties for Medicare patients by launching a series of initiatives that tailor interventions to the individual patient. Members of the multidisciplinary team communicate throughout the day during morning rounds and daily huddles, and share information on patients and their caregivers that the case manager can use to develop a discharge plan. Care navigators in some areas provide extra assistance and post-discharge follow-up for patients who need it. Every patient gets at least one follow-up phone call after discharge. PMID- 26521642 TI - Targeting low literacy patients pays off for health system. AB - Ochsner Health, with headquarters in New Orleans, targets patients with low health literacy, along with other readmission reduction programs. When patients are readmitted, the case managers administer the Rapid Estimate of Adult Literacy in Medicine (REALM) tool, developed by the Agency for Healthcare Research and Quality (AHRQ) to identify patients who need extra help in understanding their discharge instructions. When case managers make post-discharge follow-up calls to at-risk patients, they ask a series of questions that determine if the patient can understand written instructions. - The staff uses pictographs and videos to educate patients identified as having low literacy and make sure the caregivers understand the discharge instructions. PMID- 26521643 TI - Following last year's misfire, EH programs may get more pushback, questions about flu shots. PMID- 26521644 TI - Moving Forward--One Voice. PMID- 26521645 TI - Role of the compression screw in the dynamic hip-screw system: A finite-element study. AB - The dynamic hip-screw (DHS) system is a common implant for fixation of proximal femur fractures. During assembly, it has been recommended to remove the compression screw after initial compression has been obtained; however, related complications had been reported. So far, the role of compression screw in the reconstructed stability of hip fractures as well as the mechanical strength of the DHS system has rarely been mentioned. This study investigated the function of this screw in the DHS system during fracture healing. Based on the FE method, six numerical models of proximal femur were employed to analyze the mechanical response of a DHS implant with various fracture types and different fixation strategies (with or without a compression screw). The displacement of the femur head and peak von Mises stress were selected as indices of the stability of a fractured femur stabilized by a DHS device and of the risk of implant failure, respectively. Our results showed that a retained compression screw increased reconstructed structural stiffness, reducing the displacement of the femur head. This screw also helped to lessen mechanical failure of side plate by reducing the peak von Mises stress around the connection between the barrel and side plate. Both findings were evident in the proximal femur fracture involving the intertrochanteric part, and even more obvious in the setting of bony defects. Thus, we recommend the maintenance of compression screw in the DHS system while treating the intertrochanteric fracture, particularly in cases with bony defects. PMID- 26521646 TI - [Groupe pour la recherche et l'enseignement en pneumo-infectiologie (GREPI): The ball is rolling...]. PMID- 26521647 TI - A guide to performing a peer review of randomised controlled trials. AB - Peer review of journal articles is an important step in the research process. Editors rely on the expertise of peer reviewers to properly assess submissions. Yet, peer review quality varies widely and few receive training or guidance in how to approach the task. This paper describes some of the main steps that peer reviewers in general and, in particular, those performing reviewes of randomised controlled trials (RCT), can use when carrying out a review. It can be helpful to begin with a brief read to acquaint yourself with the study, followed by a detailed read and a careful check for flaws. These can be divided into 'major' (problems that must be resolved before publication can be considered) and 'minor' (suggested improvements that are discretionary) flaws. Being aware of the appropriate reporting checklist for the study being reviewed (such as CONSORT and its extensions for RCTs) can also be valuable. Competing interests or prejudices might corrode the review, so ensuring transparency about them is important. Finally, ensuring that the paper's strengths are acknowledged along with a dissection of the weaknesses provides balance and perspective to both authors and editors. Helpful reviews are constructive and improve the quality of the paper. The proper conduct of a peer review is the responsibility of all who accept the role. PMID- 26521648 TI - Marine Bi-, Bis-, and Trisindole Alkaloids. AB - This chapter, covering the chemistry literature up until June 2013 and comprising 142 references, records the chemical structures of 130 bi-, bis-, and trisindole alkaloids isolated from a plethora of marine phyla including bacteria, algae, bryozoans, sponges, mollusks, hard corals, and ascidians. While the vast majority of bisindoles have been isolated from marine sponges, biindoles are more commonly found in red algae species than sponges. Trisindoles are far less common than bisindoles in the marine environment and have been limited to two species of sponge and a single species of marine microbe. Antimicrobial activity and cytotoxicity dominate the bioactivities explored for selected members of this family of alkaloids. Synthetic approaches to 28 natural products are presented in 33 schemes, and in the absence of any in vivo biosynthetic studies, the putative biosyntheses of eight bisindole metabolites are presented. PMID- 26521649 TI - The Chemistry of Hapalindoles, Fischerindoles, Ambiguines, and Welwitindolinones. AB - Isolated from diverse cyanobacteria, the hapalindole family of indole alkaloids comprises over 80 interrelated natural products. The family is further divided into several subclasses including the hapalindoles, fischerindoles, ambiguines, and welwitindolinones, each sharing one or more of the many common structural motifs, including an indole or oxindole core, a highly functionalized cyclohexane unit fused to the indole at C-3, and the uncommon isonitrile or isothiocyanate functionalities. Reported here is a comprehensive review covering the isolation of all currently known hapalindole-type alkaloids, the biological activity for several members of the family, and the proposed biosyntheses that give rise to the intricate structural diversity within the family. Finally, the major thrust of this chapter is a comprehensive outline of decades of cutting edge synthetic chemistry toward these complex alkaloids. To date, only a small fraction of the hapalindole-type alkaloids have yielded to chemical synthesis, yet the strategies and methodologies developed showcase the state of the art in synthetic chemistry and provide access to new compounds that can be evaluated for their biological activities. PMID- 26521650 TI - The Hasubanan and Acutumine Alkaloids. AB - Research in the hasubanan and acutumine alkaloid fields up to 1970 was discussed under "morphine alkaloids" in Volume 13 of this chapter. Advances in the field of hasubanan alkaloids from 1971 to 1975 were reviewed in Volume 16 and from 1976 to 1986 in Volume 33. This chapter extends the information in the three preceding reviews to hasubanan alkaloid literature published from 1987 to June 2013. This chapter covers acutumine alkaloid literature since (-)-acutumine (3) was isolated in 1929. This chapter includes occurrence and physical constants, new alkaloids, synthesis, biosynthesis, and pharmacology. Section 1 introduces the foremost alkaloids, (-)-hasubanonine (1) and (-)-acutumine (3), and the numbering systems of the hasubanan (2) and acutumine (4) skeletons. Section 2 details the occurrence and physical constants of 29 new hasubanan and 15 acutumine alkaloids. The isolation and structural determination of these new alkaloids are described in Section 3. Section 4 summarizes total syntheses and synthetic studies toward hasubanan and acutumine alkaloids. Completed syntheses of the hasubanan alkaloids (+)-cepharamine (ent-71), (-)-hasubanonine (1), (-)-runanine (8), (-)-delavayine (6), (+)-periglaucine B (19), and (-)-8-demethoxyrunanine (12) are reviewed. Completed syntheses of (-)-acutumine (3) and (-)-dechloroacutumine (52) are also described. Section 5 details biosyntheses of (-)-acutumine (3) advanced by Barton, Wipf, and Sugimoto. Section 6 summarizes pharmacological studies of hasubanan and acutumine alkaloids. Opioid receptor affinity, anti-HBV activity, and antimicrobial activity of hasubanan alkaloids are reported. Antiamnesic properties, cytotoxicity, and anti-HBV activity of acutumine alkaloids are described. PMID- 26521651 TI - The Saraine Alkaloids. AB - Saraines have been isolated by the group of Cimino from the marine sponge Reniera sarai collected in the Bay of Naples. These alkaloids can be classified into two categories, depending on the type of their structure. Saraines 1-3 and isosaraines 1-3 are characterized by a trans-2-oxoquinolizidine moiety bound directly to a tetrahydropyridine ring, both nuclei being also linked by two alkyl chains of different lengths. On the other hand, saraines A-C and misenine present a diazatricyclic central core, showing an unusual interaction between an aldehyde and a tertiary amine and giving them a zwitterionic character, and flanked with two chains forming macrocycles. In a first part of the chapter, the isolation, spectral data, and structure elucidation of saraines are presented. Biological properties and biogenetic proposals concerning these compounds are then described. The most important part is devoted to synthetic approaches and total synthesis of saraine A. PMID- 26521652 TI - Preface. PMID- 26521653 TI - Contribution of Electrochemistry to the Biomedical and Pharmaceutical Analytical Sciences. AB - All analytical techniques have experienced major progress since the last ten years and electroanalysis is also involved in this trend. The unique characteristics of phenomena occurring at the electrode-solution interface along with the variety of electrochemical methods currently available allow for a broad spectrum of applications. Potentiometric, conductometric, voltammetric and amperometric methods are briefly reviewed with a critical view in terms of performance of the developed instrumentation with special emphasis on pharmaceutical and biomedical applications. PMID- 26521654 TI - Characterization and Antioxidant Activity of Quercetin/Methyl-beta-Cyclodextrin Complexes. AB - Quercetin (Qu), a polyphenolic flavonoid, is one of the most effective plant originated antioxidants. Despite the potential use of Qu in clinical trials, low water solubility, stability problems and the scarcity of cellular bioavailability limit its applications. The purpose of this study was to enhance aqueous solubility, dissolution rate and antioxidant activity of Qu by complexation with Methyl-beta- cyclodextrin (M-beta-CD). Analyses results showed that the aqueous solubility, dissolution rate and antioxidant activity of the complex were increased 254-fold, ~3-fold and 10% respectively compared to the pure Qu. Complexes were prepared by freeze-drying and evaporation method. The characteristics of the complexes were evaluated by DSC, XRD, (1)H-NMR, FT-IR, SEM, encapsulation efficacy, in-vitro dissolution rate analyses. Antioxidant activity studies on complexes carried out with DPPH tests. Analyses results showed that the formation of the complexes resulted in enhanced solubility with increased its antioxidant activity of Qu. PMID- 26521655 TI - Newest Strategies in the Search for Bioactive Saponins from the Tropical Plant Biodiversity. AB - This review will focus on newest results leading to the discovery of new bioactive saponins by using a combination of successive advanced procedures in extraction, isolation, structure elucidation and bioassays. Microwave- and ultrasonic-assisted extractions, two recent advanced methods have been increasingly used in the last decade. Then, a multistep purification procedure was achieved by flash chromatography, vacuum liquid chromatography, low, medium- and high-pressure liquid chromatography on silica gel and reversed-phase silica gel RP-18 (VLC, LPLC, MPLC, HPLC). These successive chromatographic steps have been implemented in the author's laboratory in order to avoid the time-consuming traditional partitions between butanol and water, dialysis procedures or precipitations in diethyl/ether. The structural elucidation of complex saponins possessing from 5 to 8 sugar units is performed by a combination of extensive spectroscopic techniques including 1D- and 2D-NMR experiments (1H, 13C, DEPT, COSY, NOESY, TOCSY, HSQC, HMBC) and mass spectrometry (FAB-MS HRESIMS). The bioassays have been mainly carried out in the field of cancerology and inflammation, two closely related areas, and also in the field of immunology with recent literature results on Quillaja saponins in order to explore some structure/activity relationships. The more recent results of the author's laboratory will be presented with examples of saponins from the tropical plant biodiversity (Pittosporaceae, Polygalaceae, Mimosaceae, Sapindaceae, Apiaceae, Dioscoreaceae, and Asparagaceae). Furthermore, some new trends reported in the literature will be briefly reviewed concerning dereplication, and metabolomic approachs which are currently of considerable importance in the field of natural product discovery. PMID- 26521656 TI - Ofloxacin Loaded Electrospun Fibers for Ocular Drug Delivery: Effect of Formulation Variables on Fiber Morphology and Drug Release. AB - Ofloxacin (OFL) loaded poly(epsilon-caprolactone) (PCL) and PCL: poly(butylene succinate) PBS fibers as a drug delivery system in the treatment of ocular infections were prepared by electrospinning. In particular, the effect of some formulation variables including polymer:drug ratio (9:1, 8:2 and 7:3 w/w), solvent systems like dichloromethane (DCM), N,N-dimethylformamide (DMF), N,Ndimethylacetamide (DMAc) and dimethylsulfoxide (DMSO), polymer blends of PCL:PBS at 80:20, 60:40 and 40:60 ratios on fiber morphology, fiber size were investigated. The morphology and diameter of the electrospun fibers were investigated by scanning electron microscopy (SEM) images also the thermal properties were evaluated by differential scanning calorimetry (DSC). The drug release behaviour from fibers and in vitro antibacterial activity were also studied. It was noticed that the average fiber diameter decreased with decreasing polymer amount in initial composition meanwhile the release of drug increased with increasing amount of drug in formulations. Solvent system of DCM:DMF at 80:20 ratio improved fiber morphology and resulted in a reduction in fiber diameter. It was found that smooth surface, flexible fibers with uniform morphology were obtained with 80:20 ratio of PCL:PBS compositions. All fibers showed a burst release of OFL. The initial amount of the released OFL was found to vary as a function of PCL:OFL ratio and polymer composition in the fiber. The microbiological activity of optimized formulation was evaluated using P. aeruginosa, S. epidermidis, S. Aureus and E. coli strains and the results of this study clearly demonstrated that freely released OFL from fibers inhibited the growth of the tested bacteria. The process of electrospinning had no adverse effect on the activity of incorporated drug in fibers. PMID- 26521657 TI - Notch signaling in prostate cancer: refining a therapeutic opportunity. AB - Notch is an evolutionarily conserved signaling pathway that plays a critical role in specifying cell fate and regulating tissue homeostasis and carcinogenesis. Studies using organ cultures and genetically engineered mouse models have demonstrated that Notch signaling regulates prostate development and homeostasis. However, the role of the Notch signaling pathway in prostate cancer remains inconclusive. Many published studies have documented consistent deregulation of major Notch signaling components in human prostate cancer cell lines, mouse models for prostate cancers, and human prostate cancer specimens at both the mRNA and the protein levels. However, functional studies in human cancer cells by modulation of Notch pathway elements suggest both tumor suppressive and oncogenic roles of Notch. These controversies may originate from our inadequate understanding of the regulation of Notch signaling under versatile genetic contexts, and reflect the multifaceted and pleiotropic roles of Notch in regulating different aspects of prostate cancer cell biology, such as proliferation, metastasis, and chemo-resistance. Future comprehensive studies using various mouse models for prostate cancer may help clarify the role of Notch signaling in prostate cancer and provide a solid basis for determining whether and how Notch should be employed as a therapeutic target for prostate cancer. PMID- 26521659 TI - Adherence to antiepileptic drugs in children with epilepsy in a Scottish population cohort. AB - AIM: To measure the adherence to antiepileptic drugs (AED) in a population cohort of children with epilepsy and to study the relationship between adherence and a series of clinical variables. METHOD: A population-based study of children (<16y) with epilepsy on AED treatment from the Tayside region of Scotland during two epochs of 12 months each. A clinical database was constructed using hospital records and linked to a community dispensing pharmacy database to calculate an Adherence Index. The principal outcome measure was the measurement of population based adherence to AEDs. Secondary outcome measures were the association of adherence with the clinical characteristics of the population. RESULTS: The median age of study group was 10 years and the median duration of epilepsy was 4 years. Only 30.9% of the total 320 children adhered to recommended AED treatment (Adherence Index >90%) across a year of treatment. Twenty-five percent of children had an Adherence Index of less than 50%. Adherence declined with increasing age. There was no significant correlation between adherence and other clinical characteristics studied (sex, duration of epilepsy, other comorbid health problems, other regular medications, and seizure frequency). INTERPRETATION: Our data shows adherence to AED treatment is poor in children with epilepsy. PMID- 26521660 TI - Prospective evaluation of patient satisfaction after the use of brachytherapy specific educational materials for cervical cancer. AB - BACKGROUND: Cervical cancer patients are faced with an enormous amount of medical information in a complex oncology field with sophisticated treatments including brachytherapy. We investigated the use of enhanced vs. standard brachytherapy specific educational materials on patient-reported satisfaction during the informed consent process for intracavitary high-dose-rate brachytherapy. METHODS AND MATERIALS: A single-institution, prospective, randomized trial was performed to study patient-reported satisfaction with novel educational materials for high dose-rate brachytherapy in women undergoing definitive radiation for cervical cancer. RESULTS: Fourteen women receiving informed consent with a customized educational booklet were randomized between no further intervention and take-home educational materials. The weighted average for 10 of 11 survey questions was higher in the intervention arm but ranged between 4 (agree) and 5 (strongly agree) for all questions in both arms. The mean weighted patient satisfaction scores +/- standard deviations in the control arm and the intervention arms were 54.3 +/- 6.4 and 57.5 +/- 2.7, respectively (p = 0.26). CONCLUSIONS: Knowledge acquisition is presumed to be part of the coping process for women facing increased stress during a cancer diagnosis. A brachytherapy-specific, visual, patient-educational booklet and take-home materials used to supplement the informed consent process for high-dose-rate brachytherapy resulted in high levels of patient-reported satisfaction among women treated with cervical cancer. PMID- 26521658 TI - Controlling the transcription levels of argGH redistributed L-arginine metabolic flux in N-acetylglutamate kinase and ArgR-deregulated Corynebacterium crenatum. AB - Corynebacterium crenatum SYPA5-5, an L-arginine high-producer obtained through multiple mutation-screening steps, had been deregulated by the repression of ArgR that inhibits L-arginine biosynthesis at genetic level. Further study indicated that feedback inhibition of SYPA5-5 N-acetylglutamate kinase (CcNAGK) by L arginine, as another rate-limiting step, could be deregulated by introducing point mutations. Here, we introduced two of the positive mutations (H268N or R209A) of CcNAGK into the chromosome of SYPA5-5, however, resulting in accumulation of large amounts of the intermediates (L-citrulline and L-ornithine) and decreased production of L-arginine. Genetic and enzymatic levels analysis involved in L-arginine biosynthetic pathway of recombinants SYPA5-5-NAGKH268N (H 7) and SYPA5-5-NAGKR209A (R-8) showed that the transcription levels of argGH decreased accompanied with the reduction of argininosuccinate synthase and argininosuccinase activities, respectively, which led to the metabolic obstacle from L-citrulline to L-arginine. Co-expression of argGH with exogenous plasmid in H-7 and R-8 removed this bottleneck and increased L-arginine productivity remarkably. Compared with SYPA5-5, fermentation period of H-7/pDXW-10-argGH (H-7 GH) reduced to 16 h; meanwhile, the L-arginine productivity improved about 63.6%. Fed-batch fermentation of H-7-GH in 10 L bioreactor produced 389.9 mM L-arginine with the productivity of 5.42 mM h(-1). These results indicated that controlling the transcription of argGH was a key factor for regulating the metabolic flux toward L-arginine biosynthesis after deregulating the repression of ArgR and feedback inhibition of CcNAGK, and therefore functioned as another regulatory mode for L-arginine production. Thus, deregulating all these three regulatory modes was a powerful strategy to construct L-arginine high-producing C. crenatum. PMID- 26521661 TI - Bladder distension improves the dosimetry of organs at risk during intracavitary cervical high-dose-rate brachytherapy. AB - PURPOSE: To evaluate dose-volume histograms (DVHs) and dose-surface histograms (DSHs) to analyze bladder distension during cervical brachytherapy. METHODS: Twenty brachytherapy fractions from five cervical cancer patients were selected. For each fraction, empty and full (200cc of contrasted saline) bladder simulation CT scans existed, one of which was used to plan treatment. An alternative plan was then created with the unused scan. DVH for each fraction was generated for the bladder, rectum, sigmoid colon, and small bowel. Mean DVH dose, D0.1cc, and D2cc were calculated for each organ at risk. Plans were then exported to a MATLAB based program to generate a DSH. RESULTS: Full bladder plans showed no difference in bladder D2cc or D0.1cc compared with empty bladder plans; however, bladder mean DVH dose and DSH dose were both significantly reduced. Full bladder plans showed a significant reduction in small intestine D2cc from 2.81 Gy to 1.83 Gy and reduction in D0.1cc from 4.07 Gy to 2.57 Gy (p < 0.05); similarly, sigmoid D2cc was significantly reduced from 4.24 Gy to 3.87 Gy (p < 0.05) and D0.1cc was reduced from 6.12 Gy to 5.61 Gy (p < 0.05) in full bladder plans. Both small intestine and sigmoid also showed reduced mean DVH and DSH dose in full bladder plans. The rectum showed no significant difference in D2cc, D0.1cc, mean DVH, or DSH dose between plans. CONCLUSIONS: Bladder distension during cervical brachytherapy significantly reduced dose in all DVH and DSH parameters for sigmoid and small intestine with no change in bladder parameters. It reduces dose to organ at risk, but the correlation to toxicity requires further investigation. PMID- 26521662 TI - [Editorial and scientific excellence of biomedical journals: Is the impact factor everything?]. PMID- 26521663 TI - Intake of dietary antioxidants is inversely associated with biomarkers of oxidative stress among men with prostate cancer. AB - Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer-related mortality among men in the USA. Growing evidence suggests that oxidative stress is involved in the development and progression of prostate cancer. In this study, the association between antioxidants from diet and supplements and biomarkers of oxidative stress in blood (n 278), urine (n 298) and prostate tissue (n 55) were determined among men from the North Carolina Louisiana Prostate Cancer Project. The association between antioxidant intake and oxidative stress biomarkers in blood and urine was determined using linear regression, adjusting for age, race, prostate cancer aggressiveness and smoking status. Greater antioxidant intake was found to be associated with lower urinary 8-isoprostane concentrations, with a 10% increase in antioxidant intake corresponding to an unadjusted 1.1% decrease in urinary 8-isoprostane levels (95% CI -1.7, -0.3%; P value<0.01) and an adjusted 0.6% decrease (95% CI -1.4, 0.2%; P value=0.16). In benign prostate tissue, thioredoxin 1 was inversely associated with antioxidant intake (P=0.02). No significant associations were found for other blood or urinary biomarkers or for malignant prostate tissue. These results indicate that antioxidant intake may be associated with less oxidative stress among men diagnosed with prostate cancer. PMID- 26521664 TI - Is there a differential conversion of artesunate to dihydroartemisinin in pregnant vs. post-partum patients with malaria after oral artesunate dosing? PMID- 26521665 TI - Chaos control via feeding switching in an omnivory system. AB - Tanabe and Namba (Ecology, 86, 3411-3414) studied a three species Lotka-Volterra model with omnivory and explored that omnivory can create chaos. It is well documented that predator switching is a similar biological phenomenon to omnivory and likely to occur simultaneously. In the present paper, the tri-trophic Lotka Volterra food web model with omnivory and predator switching is re-investigated. We observe that if we incorporate predator switching in the system and the intensity of predator switching increases above a threshold value, then the system will be stable from chaotic dynamics. To study the global dynamics of the system extensive numerical simulations are performed. Our analytical and numerical results suggest that predator switching mechanism enhances the stability and the persistence of a food chain system. PMID- 26521666 TI - Introduction: Communicating Reproduction. AB - Communication should be central to histories of reproduction, because it has structured how people do and do not reproduce. Yet communication has been so pervasive, and so various, that it is often taken for granted and the historical specificities overlooked. Making communication a frame for histories of reproduction can draw a fragmented field together, including by putting the promotion of esoteric ideas on a par with other practical activities. Paying communication close attention can revitalize the history of reproduction over the long term by highlighting continuities as well as the complex connections between new technologies and new approaches. Themes such as the power of storytelling, the claiming and challenging of expertise, and relations between knowledge and ignorance, secrecy and propriety also invite further study. PMID- 26521667 TI - Performative Rituals for Conception and Childbirth in England, 900-1500. AB - This study proposes that performative rituals-that is, verbal and physical acts that reiterate prior uses-enabled medieval women and men to negotiate the dangers and difficulties of conception and childbirth. It analyzes the rituals implicated in charms, prayers, amulets, and prayer rolls and traces the circulation of such rituals within medieval English society. Manuscript records from the Anglo-Saxon period to the late Middle Ages offer evidence of the interaction of oral and written means of communicating these rituals. Certain rituals were long-lived, though variants were introduced over time that reflected changing religious attitudes and the involvement of various interested parties, including local healers, doctors, and medical practitioners, as well as monks, friars, and users of vernacular remedy books. Although many of those who recommended or provided assistance through performative rituals were males, the practices often devolved upon women themselves, and their female companions or attendants. PMID- 26521668 TI - Reading and Hearing The Womans Booke in Early Modern England. AB - This essay takes seriously Thomas Raynalde's advice in The Womans Booke that women might read this work aloud. The evidence I use to sketch the scene of reading includes Raynalde's advice to readers in his long prologue, and also the kind of reading practice that his own writing represents. But I also go outside the text, considering what we know about the experience of listening to a book, and emphasizing the link between this practice and rhetorical education. I also examine the evidence left behind by two male readers: William Ward, who marked his copy of the 1565 edition privately, and Edward Poeton of Petworth, who represented instead a semipublic or shared reading: the evaluation of The Womans Booke and other books of generation by a Midwife and her Deputy in a fictional dialogue "The Midwives Deputie" (ca. 1630s). PMID- 26521669 TI - "Your Whole Effort Has Been to Create Desire": Reproducing Knowledge and Evading Censorship in the Nineteenth- Century Subscription Press. AB - Historians once regarded the passage of the Comstock Laws in 1873 as a death knell for the public discourse on gender, sex, and reproduction that thrived in the early nineteenth-century United States, but this view has given way to a more complex appreciation of the strategies available to actors seeking knowledge about the body. I examine some of these strategies in late-century health and hygiene manuals. Although certain discourses about sex became closed off, others persisted and evolved in the interstices of Comstock's regulatory state. Readers' demand for information did not abate in 1873; savvy publishers found different ways to meet it, utilizing suggestion, allusion, and nontextual cues from which active readers could extract useful knowledge. A once-public debate about the morality, effectiveness, and appropriate use of contraception had become coded in the pages of health and hygiene manuals, pointing readers to the burgeoning mass market for contraceptive devices as a locus of reproductive control. PMID- 26521670 TI - The Making of a Best-Selling Book on Reproduction: Lennart Nilsson's A Child Is Born. AB - This article examines the 1965 first edition of Swedish photographer Lennart Nilsson's Ett barn blir till (A Child Is Born) by placing the book back in the historical context in which it was produced, marketed, and reviewed. In particular it shows how medicine and the media in Sweden were intertwined in the process of incorporating Nilsson's photographs of aborted embryos and fetuses into a best-selling book on the origin and development of human life. Nilsson's work is related to other books in the same genre as well as the popular picture magazines of the time, in order to highlight how it aspired to offer something new. It is argued that a number of commercial and other interests were involved and that an immense effort went into not only making and promoting the book but also trying to control the meaning of the images. PMID- 26521671 TI - Communicating a New Consciousness: Countercultural Print and the Home Birth Movement in the 1970s. AB - This essay analyzes the production of three influential home birth texts of the 1970s written by self-proclaimed lay midwives that helped to fuel and sustain a movement in alternative birth practices. As part of a countercultural lifestyle print culture, early "how-to" books (Raven Lang's The Birth Book, Ina May Gaskin's Spiritual Midwifery) provided readers with vivid images and accounts in stark contrast to those of the sterile hospital delivery room. By the end of the decade, Rahima Baldwin's more mainstream guidebook, Special Delivery, indicated an interest in translating home birth to a wider audience who did not necessarily identify as "countercultural." Lay midwives who were authors of radical print texts in the 1970s played an important role in reshaping expectations about the birth experience, suggesting a need to rethink how we define the counterculture and its legacies. PMID- 26521672 TI - American Association for the History of Medicine: Report of the Eighty-Eighth Annual Meeting. PMID- 26521675 TI - NEFI: Network Extraction From Images. AB - Networks are amongst the central building blocks of many systems. Given a graph of a network, methods from graph theory enable a precise investigation of its properties. Software for the analysis of graphs is widely available and has been applied to study various types of networks. In some applications, graph acquisition is relatively simple. However, for many networks data collection relies on images where graph extraction requires domain-specific solutions. Here we introduce NEFI, a tool that extracts graphs from images of networks originating in various domains. Regarding previous work on graph extraction, theoretical results are fully accessible only to an expert audience and ready-to use implementations for non-experts are rarely available or insufficiently documented. NEFI provides a novel platform allowing practitioners to easily extract graphs from images by combining basic tools from image processing, computer vision and graph theory. Thus, NEFI constitutes an alternative to tedious manual graph extraction and special purpose tools. We anticipate NEFI to enable time-efficient collection of large datasets. The analysis of these novel datasets may open up the possibility to gain new insights into the structure and function of various networks. NEFI is open source and available at http://nefi.mpi-inf.mpg.de. PMID- 26521676 TI - Alcohol level and injury severity: is the floppy patient myth true? AB - BACKGROUND: The impact of inebriation on severity of injury is unclear. The few studies to date on this topic are limited to a particular mechanism of injury (MOI), injury pattern, or blood alcohol level (BAL). Therefore, we sought to determine the impact of BAL on injury pattern and severity across all MOI. We hypothesize that there is no relationship between BAL and injury severity when controlling for MOI. MATERIALS AND METHODS: After institutional review board approval, a retrospective study was performed at an adult trauma center from January 1, 2012-December 31, 2012. All MOI were included. Injury severity was assessed using the injury severity score (ISS). Chi square and analysis of variance were used to examine the relationship between BAL, injury pattern, and ISS within each MOI. Multivariate regression analysis examined the BAL-ISS association adjusting for MOI, gender, and age. RESULTS: Of 1397 patients, the mean age was 44 +/- 19, ISS was 7.5 +/- 6.8, BAL was 93 +/- 130 mg/dL, and 70% were male. Rib fracture (P = 0.002) and hemothorax and/or pneumothorax (P = 0.0009) were negatively associated with BAL, whereas concussion and soft tissue injury had a positive association with BAL (P < 0.0001). An increasing BAL had a negative correlation with ISS after fall from standing (P < 0.001), whereas bicycle collisions had a positive association (P = 0.027). Across all MOI, there was no significant association between BAL and ISS. CONCLUSIONS: BAL is associated with ISS, in specific MOI; however, across all MOI, there was no significant association between BAL and ISS. Inebriated patients should be triaged with the same clinical index of suspicion for injury as sober patients. PMID- 26521677 TI - Brain tissue oxygen evaluation by wireless near-infrared spectroscopy. AB - BACKGROUND: Monitoring the partial pressure of oxygen in brain tissue (PbtO2) is an important tool for traumatic brain injury (TBI) but is invasive and inconvenient for real time monitoring. Near-infrared spectroscopy (NIRS), which can monitor hemoglobin parameters in the brain tissue, has been used widely as a noninvasive tool for assessing cerebral ischemia and hypoxia. Therefore, it may have the potential as a noninvasive tool for estimating the change of PbtO2. In this study, a novel wireless NIRS system was designed to monitor hemoglobin parameters of rat brains under different impact strengths and was used to estimate the change of PbtO2 noninvasively in TBI. MATERIALS AND METHODS: The proposed wireless NIRS system and a PbtO2 monitoring system were used to monitor the oxygenation of rat brains under different impact strengths. Rats were randomly assigned to four different impact strength groups (sham, 1.6 atm, 2.0 atm, and 2.4 atm; n = 6 per group), and the relationships of concentration changes in oxyhemoglobin (HbO2), deoxyhemoglobin (HbR), and total hemoglobin (HbT), and PbtO2 during and after TBI with different impact strengths were investigated. Triphenyltetrazolium chloride (TTC) staining was also used to evaluate infarction volume. RESULTS: Concentration changes in HbO2, HbR, and HbT dropped immediately after the impact, increased gradually, and then became stable. Changes in PbtO2 had a similar tendency with the hemoglobin parameters. There was significant correlation between changes in PbtO2 and HbO2 (correlation = 0.76) but not with changes in HbR (correlation = 0.06). In triphenyltetrazolium chloride staining, the infarction volume was highly but negatively associated with oxygen-related parameters like PbtO2 and HbO2. CONCLUSIONS: Changes in HbO2 under TBI was highly and positively correlated with changes in PbtO2. By using the relative changes in HbO2 as a reference parameter, the proposed wireless NIRS system may be developed as a noninvasive tool for estimating the change of PbtO2 in brain tissue after TBI. PMID- 26521678 TI - Reduction of alpha,beta-Unsaturated Ketones by Old Yellow Enzymes: Mechanistic Insights from Quantum Mechanics/Molecular Mechanics Calculations. AB - Enoate reductases catalyze the reduction of activated C?C bonds with high enantioselectivity. The oxidative half-reaction, which involves the addition of a hydride and a proton to opposite faces of the C?C bond, has been studied for the first time by hybrid quantum mechanics/molecular mechanics (QM/MM). The reduction of 2-cyclohexen-1-one by YqjM from Bacillus subtilis was selected as the model system. Two-dimensional QM/MM (B3LYP-D/OPLS2005) reaction pathways suggest that the hydride and proton are added as distinct steps, with the former step preceding the latter. Furthermore, we present interesting insights into the reactivity of this enzyme, including the weak binding of the substrate in the active site, the role of the two active site histidine residues for polarization of the substrate C?O bond, structural details of the transition states to hydride and proton transfer, and the role of Tyr196 as proton donor. The information presented here will be useful for the future design of enantioselective YqjM mutants for other substrates. PMID- 26521679 TI - Impact of vitamin C on the cardiometabolic and inflammatory profiles of mice lacking a functional Werner syndrome protein helicase. AB - Werner syndrome (WS) is a premature aging disorder caused by mutations in a DNA helicase/exonuclease. Mice lacking the helicase domain of this protein exhibit metabolic abnormalities that are reversed by vitamin C. In this study, we used a targeted metabolomic approach to identify serum metabolites significantly altered in young mutant mice treated with or without vitamin C. We also measured several serum inflammatory and cardiometabolic factors. We show that young mutant mice exhibit an increase in serum hydroxyproline and plasminogen activator inhibitor-1 (PAI-1), markers of cardiovascular diseases and inflammation, before they exhibit morphological anomalies in different tissues. We also observed an increase in three very long chain lysophosphatidylcholines underlying peroxisome perturbation. Vitamin C reversed the concentrations of these metabolites and PAI 1 to wild type values. Transcriptomic analyses on the liver of mutant mice revealed a decrease in the expression of genes involved in fatty acid degradation compared to wild type animals. Vitamin C treatment increased the expression of genes involved in glutathione metabolism and the synthesis of unsaturated fatty acids in these mice. These results show that changes at the transcriptomic level concord with the alterations of several serum metabolites in these mice. Finally, we found that a mislocalization of the Wrn mutant protein in the liver endoplasmic reticulum fraction increased oxidative stress in that cellular compartment. Vitamin C reversed this oxidative stress. To conclude, this study provides novel potential predictive cardiometabolic biomarkers in WS that will allow the assessment of the impact of vitamin C on patients with WS. PMID- 26521680 TI - Chemical-Free Technique to Study the Ultrastructure of Primary Cilium. AB - A primary cilium is a hair-like structure with a width of approximately 200 nm. Over the past few decades, the main challenge in the study of the ultrastructure of cilia has been the high sensitivity of cilia to chemical fixation, which is required for many imaging techniques. In this report, we demonstrate a combined high-pressure freezing (HPF) and freeze-fracture transmission electron microscopy (FFTEM) technique to examine the ultrastructure of a cilium. Our objective is to develop an optimal high-resolution imaging approach that preserves cilia structures in their best natural form without alteration of cilia morphology by chemical fixation interference. Our results showed that a cilium has a swelling like structure (termed bulb), which was previously considered a fixation artifact. The intramembrane particles observed via HPF/FFTEM indicated the presence of integral membrane proteins and soluble matrix proteins along the ciliary bulb, which is part of an integral structure within the ciliary membrane. We propose that HPF/FFTEM is an important and more suitable chemical-free method to study the ultrastructure of primary cilia. PMID- 26521681 TI - [Isolated auditory hallucination in prepubertal children: Diagnostic framework and predictive value]. AB - Isolated auditory hallucination is a common symptom, probably underdiagnosed, in prepubertal children. There is currently no consensus to guide the care for such manifestations; however, they are often painful for the patients. The literature emphasizes the unspecific and transnosographic aspect of this symptom. The most common symptom is having one's name called by voices, which often remains without predictive value, associated with anxiety disorders. However, isolated auditory hallucination is a useful clinical source to detect an underlying psychiatric disorder, especially when symptoms are complex, severe, or persistent. Although medical follow-up is always necessary, psychological follow-up can sometimes be beneficial, but medication should not be used before a 6-month observation and limited to cases that reveal an underlying pathology. PMID- 26521682 TI - [Type 1 xanthinuria: Report on three cases]. AB - Type 1 xanthinuria is a rare cause of urolithiasis due to xanthine dehydrogenase deficiency. Pediatric cases are exceptional. Through the genetic analysis of two cases, we discovered three mutations responsible for a loss of enzyme activity. The first one had a C.3536T>C missense mutation in the XDH gene and the other one was heterozygous for two mutations c.700+1G>T and c.31778_82delTCAT. We review the diagnostic methods, possible complications, and preventive measures for stone formation. PMID- 26521683 TI - A novel method for quantitative analysis of acetylacetone and ethyl acetoacetate by fluorine-19 nuclear magnetic spectroscopy. AB - A new method utilization of NMR spectra was developed for structural and quantitative analysis of enol forms of acetylacetone and ethyl acetoacetate. Acetylacetone and ethyl acetoacetate were determined by (19) F NMR upon derivatisation with r-fluorobenzoyl chloride. The base-catalyzed derivatives of acetylacetone and ethyl acetoacetate reaction with r-fluorobenzoyl chloride were analyzed by (1) H and (13) C NMR spectroscopies. E and Z configurations of acetylacetone and ethyl acetoacetate were separated and purified by thin layer chromatography. In addition, the ability of (19) F NMR for quantitative analysis of acetylacetone by integration of the appropriate signals of the derivatives were tested and compared. The results further testified the enol forms of acetylacetone and ethyl acetoacetate and the feasibility of (19) F NMR method. This method can be potentially used to characterize E and Z isomers and quantitatively analyze E/Z ratio of beta-diketone and beta-ketoester homologues. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26521684 TI - Electrochemical Biosensor Based on Nanoporous Au/CoO Core-Shell Material with Synergistic Catalysis. AB - An ultrathin CoO layer is deposited on the skeleton surfaces of a nanoporous gold (NPG) film by using atomic layer deposition, creating a flexible electrode. Detailed characterization demonstrates the superior performance of the flexible NPG/CoO hybrids for electrochemical catalysis. The NPG/CoO hybrid not only achieves high catalytic activity for glucose oxidation and H2O2 reduction, but also exhibits a linear dependence of the electrical signal on the concentration of glucose and H2O2 molecules in the electrolyte. Meanwhile, the sensitivity for H2O2 reduction can be as high as 62.5 MUA mm(-1) cm(-2) with linear dependence on the concentration in the range of 0.1-92.9 mm. The high sensitivity is proposed to result from the synergistic effect of Au and CoO at the interfaces, and the high conductivity of the gold skeleton with a large surface area. The superior electrochemical performance of this hybrid electrode is promising for future potential applications in various transitional-metal-oxide-based electrochemical electrodes. PMID- 26521686 TI - RadPath: A Web-based System for Integrating and Correlating Radiology and Pathology Findings During Cancer Diagnosis. AB - RATIONALE AND OBJECTIVES: The current paradigm of cancer diagnosis involves uncoordinated communication of findings from radiology and pathology to downstream physicians. Discordance between these findings can require additional time from downstream users to resolve, or given incorrect resolution, may adversely impact treatment decisions. To mitigate this problem, we developed a web-based system, called RadPath, for correlating and integrating radiology and pathology reporting. MATERIALS AND METHODS: RadPath includes interfaces to our institution's clinical information systems, which are used to retrieve reports, images, and test results that are structured into an interactive compendium for a diagnostic patient case. The system includes an editing interface for physicians, allowing for the inclusion of additional clinical data, as well as the ability to retrospectively correlate and contextualize imaging findings following pathology diagnosis. RESULTS: During pilot deployment and testing over the course of 1 year, physicians at our institution have completed 60 RadPath cases, requiring an average of 128 seconds from a radiologist and an average of 93 seconds from a pathologist per case. Several technical and workflow challenges were encountered during development, including interfacing with diverse clinical information systems, automatically structuring report contents, and determining the appropriate physicians to create RadPath summaries. Reaction to RadPath has been positive, with users valuing the system's ability to consolidate diagnostic information. CONCLUSIONS: With the increasing complexity of medicine and the movement toward team-based disease management, there is a need for improved clinical communication and information exchange. RadPath provides a platform for generating coherent and correlated diagnostic summaries in cancer diagnosis with minimal additional effort from physicians. PMID- 26521685 TI - Novel High Content Screen Detects Compounds That Promote Neurite Regeneration from Cochlear Spiral Ganglion Neurons. AB - The bipolar spiral ganglion neurons (SGN) carry sound information from cochlear hair cells to the brain. After noise, antibiotic or toxic insult to the cochlea, damage to SGN and/or hair cells causes hearing impairment. Damage ranges from fiber and synapse degeneration to dysfunction and loss of cells. New interventions to regenerate peripheral nerve fibers could help reestablish transfer of auditory information from surviving or regenerated hair cells or improve results from cochlear implants, but the biochemical mechanisms to target are largely unknown. Presently, no drugs exist that are FDA approved to stimulate the regeneration of SGN nerve fibers. We designed an original phenotypic assay to screen 440 compounds of the NIH Clinical Collection directly on dissociated mouse spiral ganglia. The assay detected one compound, cerivastatin, that increased the length of regenerating neurites. The effect, mimicked by other statins at different optimal concentrations, was blocked by geranylgeraniol. These results demonstrate the utility of screening small compound libraries on mixed cultures of dissociated primary ganglia. The success of this screen narrows down a moderately sized library to a single compound which can be elevated to in-depth in vivo studies, and highlights a potential new molecular pathway for targeting of hearing loss drugs. PMID- 26521687 TI - Breast Density Estimation with Fully Automated Volumetric Method: Comparison to Radiologists' Assessment by BI-RADS Categories. AB - RATIONALE AND OBJECTIVES: The objective of our study was to calculate mammographic breast density with a fully automated volumetric breast density measurement method and to compare it to breast imaging reporting and data system (BI-RADS) breast density categories assigned by two radiologists. MATERIALS AND METHODS: A total of 476 full-field digital mammography examinations with standard mediolateral oblique and craniocaudal views were evaluated by two blinded radiologists and BI-RADS density categories were assigned. Using a fully automated software, mean fibroglandular tissue volume, mean breast volume, and mean volumetric breast density were calculated. Based on percentage volumetric breast density, a volumetric density grade was assigned from 1 to 4. RESULTS: The weighted overall kappa was 0.895 (almost perfect agreement) for the two radiologists' BI-RADS density estimates. A statistically significant difference was seen in mean volumetric breast density among the BI-RADS density categories. With increased BI-RADS density category, increase in mean volumetric breast density was also seen (P < 0.001). A significant positive correlation was found between BI-RADS categories and volumetric density grading by fully automated software (rho = 0.728, P < 0.001 for first radiologist and rho = 0.725, P < 0.001 for second radiologist). Pairwise estimates of the weighted kappa between Volpara density grade and BI-RADS density category by two observers showed fair agreement (kappa = 0.398 and 0.388, respectively). CONCLUSIONS: In our study, a good correlation was seen between density grading using fully automated volumetric method and density grading using BI-RADS density categories assigned by the two radiologists. Thus, the fully automated volumetric method may be used to quantify breast density on routine mammography. PMID- 26521688 TI - Predicting High Imaging Utilization Based on Initial Radiology Reports: A Feasibility Study of Machine Learning. AB - RATIONALE AND OBJECTIVES: Imaging utilization has significantly increased over the last two decades, and is only recently showing signs of moderating. To help healthcare providers identify patients at risk for high imaging utilization, we developed a prediction model to recognize high imaging utilizers based on their initial imaging reports. MATERIALS AND METHODS: The prediction model uses a machine learning text classification framework. In this study, we used radiology reports from 18,384 patients with at least one abdomen computed tomography study in their imaging record at Stanford Health Care as the training set. We modeled the radiology reports in a vector space and trained a support vector machine classifier for this prediction task. We evaluated our model on a separate test set of 4791 patients. In addition to high prediction accuracy, in our method, we aimed at achieving high specificity to identify patients at high risk for high imaging utilization. RESULTS: Our results (accuracy: 94.0%, sensitivity: 74.4%, specificity: 97.9%, positive predictive value: 87.3%, negative predictive value: 95.1%) show that a prediction model can enable healthcare providers to identify in advance patients who are likely to be high utilizers of imaging services. CONCLUSIONS: Machine learning classifiers developed from narrative radiology reports are feasible methods to predict imaging utilization. Such systems can be used to identify high utilizers, inform future image ordering behavior, and encourage judicious use of imaging. PMID- 26521689 TI - PET/MRI: Emerging Clinical Applications in Oncology. AB - Positron emission tomography (PET), commonly performed in conjunction with computed tomography (CT), has revolutionized oncologic imaging. PET/CT has become the standard of care for the initial staging and assessment of treatment response for many different malignancies. Despite this success, PET/CT is often supplemented by magnetic resonance imaging (MRI), which offers superior soft tissue contrast and a means of assessing cellular density with diffusion-weighted imaging. Consequently, PET/MRI, the newest clinical hybrid imaging modality, has the potential to provide added value over PET/CT or MRI alone. The purpose of this article is to provide a comprehensive review of the current body of literature pertaining to the clinical performance of PET/MRI, with the aim of summarizing current evidence and identifying gaps in knowledge to direct clinical expansion and future research. Multiple example cases are also provided to illustrate the central findings of these publications. PMID- 26521690 TI - Notching early repolarization pattern in inferior leads increases risk of ventricular tachyarrhythmias in patients with acute myocardial infarction: a meta analysis. AB - The aim of this of this meta-analysis was to examine the potential association between certain early repolarization (ER) characteristics and ventricular tachyarrhythmias (VTAs) in patients with acute myocardial infarction (AMI). We searched PubMed, Embase and Web of Science databases for records published until December 2014. Of the 658 initially identified records, 7 studies with a total of 1,565 patients (299 with ER and 1,266 without ER) were finally analyzed. Overall, patients with ER displayed a higher risk of VTAs following AMI compared to patients without ER [odds ratio (OR): 3.75, 95% CI: 2.62-5.37, p < 0.00001]. Subgroup analyses showed that the diagnosis of ER prior to AMI onset is a better predictor of VTAs (OR: 5.70, p < 0.00001) compared to those diagnosed after AMI onset (OR: 2.60, p = 0.00001). Remarkably, a notching morphology was a significant predictor of VTAs compared to slurring morphology (OR: 3.85, p = 0.002). Finally, an inferior ER location (OR: 8.85, p < 0.00001) was significantly associated with increased risk of VTAs in AMI patients. In conclusion, our meta-analysis suggests that ER pattern is associated with greater risk of VTAs in patients with AMI. A notched ER pattern located in inferior leads confers the highest risk for VTAs in AMI. PMID- 26521692 TI - Optimal strategies to consider when peer reviewing a systematic review and meta analysis. AB - Systematic reviews are popular. A recent estimate indicates that 11 new systematic reviews are published daily. Nevertheless, evidence indicates that the quality of reporting of systematic reviews is not optimal. One likely reason is that the authors' reports have received inadequate peer review. There are now many different types of systematic reviews and peer reviewing them can be enhanced by using a reporting guideline to supplement whatever template the journal editors have asked you, as a peer reviewer, to use. Additionally, keeping up with the current literature, whether as a content expert or being aware of advances in systematic review methods is likely be make for a more comprehensive and effective peer review. Providing a brief summary of what the systematic review has reported is an important first step in the peer review process (and not performed frequently enough). At its core, it provides the authors with some sense of what the peer reviewer believes was performed (Methods) and found (Results). Importantly, it also provides clarity regarding any potential problems in the methods, including statistical approaches for meta-analysis, results, and interpretation of the systematic review, for which the peer reviewer can seek explanations from the authors; these clarifications are best presented as questions to the authors. PMID- 26521691 TI - Interferon gamma boosts the nucleotide oligomerization domain 2-mediated signaling pathway in human dendritic cells in an X-linked inhibitor of apoptosis protein and mammalian target of rapamycin-dependent manner. AB - The cytoplasmic nucleotide oligomerization domain 2 (NOD2) receptor recognizes the bacterial cell wall component muramyl dipeptide (MDP). NOD2 ligation initiates the nuclear factor kappa B and the mitogen-activated protein kinase cascades. However, administering MDP alone is insufficient to elicit strong cytokine responses in various immune cells, including dendritic cells (DCs). Because the simultaneous presence of various microbial products and cytokines in inflamed tissues modulates DC function, we initiated this study to examine how interferon gamma (IFNgamma), a central modulator of inflammation, affects the NOD2-mediated signaling pathway in human conventional DCs (cDCs). Synergistic stimulation of DCs with MDP and IFNgamma increased the expression of CD40, CD80, CD83, CD86, and human leukocyte antigen DQ proteins and significantly elevated the production of pro-inflammatory cytokines IL-1beta, IL-6, IL-12, and tumour necrosis factor (TNF), as well as anti-inflammatory cytokine IL-10. Furthermore, the simultaneous presence of MDP and IFNgamma was necessary to decrease IkBalpha protein levels. By investigating various mechanisms implicated in MDP- and IFNgamma-mediated signaling pathways, we revealed that the increased production of pro-inflammatory cytokines is highly dependent on the X-linked inhibitor of apoptosis protein (XIAP) but not on cellular IAP1 and IAP2. We also found that the NOD2 signaling pathway is regulated by the mammalian target of rapamycin (mTOR) but is not affected by phosphatidylinositol-3 kinase or signal transducer and activator of transcription 1 inhibition. Our results demonstrate, for the first time, that IFNgamma positively affects NOD2-mediated signaling in human cDCs, in a manner considerably dependent on XIAP and partially dependent on mTOR. PMID- 26521693 TI - Passband switchable microwave photonic multiband filter. AB - A reconfigurable microwave photonic (MWP) multiband filter with selectable and switchable passbands is proposed and experimentally demonstrated, with a maximum of 12 simultaneous passbands evenly distributed from 0 to 10 GHz. The scheme is based on the generation of tunable optical comb lines using a two-stage Lyot loop filter, such that various filter tap spacings and spectral combinations are obtained for the configuration of the MWP filter. Through polarization state adjustment inside the Lyot loop filter, an optical frequency comb with 12 different comb spacings is achieved, which corresponds to a MWP filter with 12 selectable passbands. Center frequencies of the filter passbands are switchable, while the number of simultaneous passbands is tunable from 1 to 12. Furthermore, the MWP multiband filter can either work as an all-block, single-band or multiband filter with various passband combinations, which provide exceptional operation flexibility. All the passbands have over 30 dB sidelobe suppression and 3-dB bandwidth of 200 MHz, providing good filter selectivity. PMID- 26521694 TI - Identification of novel candidate plasma metabolite biomarkers for distinguishing serous ovarian carcinoma and benign serous ovarian tumors. AB - OBJECTIVE: Serous ovarian carcinoma (OC) represents a leading cause of cancer related death among U.S. women. Non-invasive tools have recently emerged for discriminating benign from malignant ovarian masses, but evaluation remains ongoing, without widespread implementation. In the last decade, metabolomics has matured into a new avenue for cancer biomarker development. Here, we sought to identify novel plasma metabolite biomarkers to distinguish serous ovarian carcinoma and benign serous ovarian tumor. METHODS: Using liquid chromatography mass spectrometry, we conducted global and targeted metabolite profiling of plasma isolated at the time of surgery from 50 serous OC cases and 50 serous benign controls. RESULTS: Global lipidomics analysis identified 34 metabolites (of 372 assessed) differing significantly (P<0.05) between cases and controls in both training and testing sets, with 17 candidates satisfying FDR q<0.05, and two reaching Bonferroni significance. Targeted profiling of ~150 aqueous metabolites identified a single amino acid, alanine, as differentially abundant (P<0.05). A multivariate classification model built using the top four lipid metabolites achieved an estimated AUC of 0.85 (SD=0.07) based on Monte Carlo cross validation. Evaluation of a hybrid model incorporating both CA125 and lipid metabolites was suggestive of increased classification accuracy (AUC=0.91, SD=0.05) relative to CA125 alone (AUC=0.87, SD=0.07), particularly at high fixed levels of sensitivity, without reaching significance. CONCLUSIONS: Our results provide insight into metabolic changes potentially correlated with the presence of serous OC versus benign ovarian tumor and suggest that plasma metabolites may help differentiate these two conditions. PMID- 26521695 TI - A new insertion/deletion fragment polymorphism of inhibin-alpha gene associated with follicular cysts in Large White sows. AB - Ovarian follicular cysts are anovulatory follicular structures that lead to infertility. Hormones play key roles in the formation and persistence of cysts. Inhibins are heterodimeric gonadal glycoprotein hormones that belong to the transforming growth factor-beta superfamily. These hormones suppress the secretion of follicle-stimulating hormone. In this report, partial fragment of inhibin-alpha (INHA) subunit gene of Large White pig was detected from the genomic DNA by polymerase chain reaction. The sequence showed a 283 bp fragment insertion/deletion (I/D) polymorphism in INHA subunit gene. A total of 49 Large White sows with cystic follicles and 152 normal sows were screened for this polymorphism. The relationship of INHA I/D polymorphisms with follicular cysts was investigated. The distribution of I/D was significantly different between cystic and normal sows, thereby suggesting that the INHA subunit gene might be a potential biological marker for breeding programs in pig. PMID- 26521696 TI - The evolutionary landscape of intergenic trans-splicing events in insects. AB - To explore the landscape of intergenic trans-splicing events and characterize their functions and evolutionary dynamics, we conduct a mega-data study of a phylogeny containing eight species across five orders of class Insecta, a model system spanning 400 million years of evolution. A total of 1,627 trans-splicing events involving 2,199 genes are identified, accounting for 1.58% of the total genes. Homology analysis reveals that mod(mdg4)-like trans-splicing is the only conserved event that is consistently observed in multiple species across two orders, which represents a unique case of functional diversification involving trans-splicing. Thus, evolutionarily its potential for generating proteins with novel function is not broadly utilized by insects. Furthermore, 146 non-mod trans spliced transcripts are found to resemble canonical genes from different species. Trans-splicing preserving the function of 'breakup' genes may serve as a general mechanism for relaxing the constraints on gene structure, with profound implications for the evolution of genes and genomes. PMID- 26521697 TI - Concentrated fed-batch cell culture increases manufacturing capacity without additional volumetric capacity. AB - Biomanufacturing factories of the future are transitioning from large, single product facilities toward smaller, multi-product, flexible facilities. Flexible capacity allows companies to adapt to ever-changing pipeline and market demands. Concentrated fed-batch (CFB) cell culture enables flexible manufacturing capacity with limited volumetric capacity; it intensifies cell culture titers such that the output of a smaller facility can rival that of a larger facility. We tested this hypothesis at bench scale by developing a feeding strategy for CFB and applying it to two cell lines. CFB improved cell line A output by 105% and cell line B output by 70% compared to traditional fed-batch (TFB) processes. CFB did not greatly change cell line A product quality, but it improved cell line B charge heterogeneity, suggesting that CFB has both process and product quality benefits. We projected CFB output gains in the context of a 2000-L small-scale facility, but the output was lower than that of a 15,000-L large-scale TFB facility. CFB's high cell mass also complicated operations, eroded volumetric productivity, and showed our current processes require significant improvements in specific productivity in order to realize their full potential and savings in manufacturing. Thus, improving specific productivity can resolve CFB's cost, scale-up, and operability challenges. PMID- 26521698 TI - Complete genome sequence of Microbacterium sp. CGR1, bacterium tolerant to wide abiotic conditions isolated from the Atacama Desert. AB - Microbacterium sp. CGR1 (RGM2230) is an isolate from the Atacama Desert that displays a wide pH, salinity and temperature tolerance. This strain exhibits riboflavin overproducer features and traits for developing an environmental arsenic biosensor. Here, we report the complete genome sequence of this strain, which represents the first genome of the genus Microbacterium sequenced and assembled in a single contig. The genome contains 3,634,864bp, 3299 protein coding genes, 45 tRNAs, six copies of 5S-16S-23S rRNA and a high genome average GC-content of 68.04%. PMID- 26521699 TI - Terminal decontamination of the Royal Free London's high-level isolation unit after a case of Ebola virus disease using hydrogen peroxide vapor. AB - We report the decontamination of the high-level isolation unit at the Royal Free London after the discharge of a patient with Ebola virus disease, who was repatriated from West Africa. Hydrogen peroxide vapor (HPV) was used to decontaminate the patient care isolators and the rooms housing them. HPV decontamination was completed without incident and allowed the unit to be returned to service more quickly than the previous protocol of using formaldehyde. PMID- 26521700 TI - Extra length of stay and costs because of health care-associated infections at a German university hospital. AB - BACKGROUND: Health care-associated infections (HAIs) can be associated with increased health care costs. We examined extra length of hospital stay (LOS) and associated per diem costs attributable to HAIs in a large academic medical center. METHODS: Data for analysis were acquired in a preinterventional phase of a prospective cohort study (ALERTS) conducted over 12 months in 27 general and 4 intensive care units at Jena University Hospital. HAIs were identified among patients hospitalized for >=48 hours with at least 1 risk factor for HAI and new antimicrobial therapy; the diagnosis was confirmed by U.S. Centers for Disease Control and Prevention criteria. Extra LOS was estimated by multistate modeling, and associated extra costs were based on average per diem costs for clinical units sampled. RESULTS: Of a total of 22,613 patients hospitalized for >=48 hours, 893 (3.95%) experienced 1,212 episodes of HAI during 12 months. The associated mean extra LOS +/- SEM in general units was 8.45 +/- 0.80 days per case and 8.09 +/- 0.91 days for patients treated in both general and intensive care units. Additional costs attributable to HAIs were ?5,823-?11,840 ($7,453 $15,155) per infected patient. CONCLUSION: HAIs generated substantial extra costs by prolonging hospitalization. Potential clinical and financial savings may be realized by implementing effective infection prevention programs. PMID- 26521701 TI - Nosocomial transmission of Ebola virus disease on pediatric and maternity wards: Bombali and Tonkolili, Sierra Leone, 2014. AB - BACKGROUND: In the largest Ebola virus disease (EVD) outbreak in history, nosocomial transmission of EVD increased spread of the disease. We report on 2 instances in Sierra Leone where patients unknowingly infected with EVD were admitted to a general hospital ward (1 pediatric ward and 1 maternity ward), exposing health care workers, caregivers, and other patients to EVD. Both patients died on the general wards, and were later confirmed as being infected with EVD. We initiated contact tracing and assessed risk factors for secondary infections to guide containment recommendations. METHODS: We reviewed medical records to establish the index patients' symptom onset. Health care workers, patients, and caregivers were interviewed to determine exposures and personal protective equipment (PPE) use. Contacts were monitored daily for EVD symptoms. Those who experienced EVD symptoms were isolated and tested. RESULTS: Eighty-two contacts were identified: 64 health care workers, 7 caregivers, 4 patients, 4 newborns, and 3 children of patients. Seven contacts became symptomatic and tested positive for EVD: 2 health care workers (1 nurse and 1 hospital cleaner), 2 caregivers, 2 newborns, and 1 patient. The infected nurse placed an intravenous catheter in the pediatric index patient with only short gloves PPE and the hospital cleaner cleaned the operating room of the maternity ward index patient wearing short gloves PPE. The maternity ward index patient's caregiver and newborn were exposed to her body fluids. The infected patient and her newborn shared the ward and latrine with the maternity ward index patient. Hospital staff members did not use adequate PPE. Caregivers were not offered PPE. CONCLUSIONS: Delayed recognition of EVD and inadequate PPE likely led to exposures and secondary infections. Earlier recognition of EVD and adequate PPE might have reduced direct contact with body fluids. Limiting nonhealth-care worker contact, improving access to PPE, and enhancing screening methods for pregnant women, children, and inpatients may help decrease EVD transmission in general health care settings. PMID- 26521702 TI - Influence of a total joint infection control bundle on surgical site infection rates. AB - Quality improvement initiatives combined with pulsed xenon ultraviolet room disinfection were implemented to reduce surgical site infections (SSIs) in patients undergoing total joint procedures. After 12 months, knee SSIs were reduced from 4 to 0 (P = .03) and hip SSIs were reduced from 3 to 0 (P = .15) for a combined prevention of 7 SSIs (P = .01) and a savings of $290,990. PMID- 26521703 TI - A bundle that includes active surveillance, contact precaution for carriers, and cefazolin-based antimicrobial prophylaxis prevents methicillin-resistant Staphylococcus aureus infections in clean orthopedic surgery. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of orthopedic surgical site infections (SSIs). The aim of this study was to evaluate the effect of a bundle approach in the prevention of orthopedic MRSA SSIs. MATERIAL AND METHODS: MRSA active surveillance and decolonization were performed preoperatively at our institution from July 2004 until 2007. In January 2008, a bundle approach comprising contact precautions for MRSA-positive patients and cefazolin-based antimicrobial prophylaxis (AMP) stewardship was implemented. Data on the prevalence of MRSA SSIs, antimicrobial use density, duration of AMP, and the use of an alcohol antiseptic agent (L/1,000 patient-days) were evaluated during 2 periods: July 2004-December 2007 (period A) and January 2008-December 2012 (period B). RESULTS AND DISCUSSION: The MRSA SSI rate during period B (0.97%; 19 out of 1,966) was significantly lower than that during period A (2.17%; 29 out of 1,333; P = .003). The infection rate correlated negatively with both the cefazolin antimicrobial use density (r = -0.76; P = .0002) and the use of an alcohol antiseptic agent (r = -0.68; P = .002). CONCLUSIONS: An infection prevention bundle consisting of contact precautions for carriers and AMP stewardship in addition to active surveillance was associated with a significant decrease in the incidence of orthopedic MRSA SSIs. PMID- 26521704 TI - Environmental persistence of OXA-48-producing Klebsiella pneumoniae in a French intensive care unit. AB - The spread of carbapenemase-producing Gram-negative rods is an emerging global problem. This study describes the epidemiologic features of an outbreak caused by an environmental reservoir of OXA-48-producing Klebsiella pneumoniae caused by persistence of the bacteria during 20 months in an intensive care unit in France. This report emphasizes the importance of early environmental screening to interrupt the transmission of carbapenemase-producingEnterobacteriaceae. PMID- 26521705 TI - Turn-On Near-Infrared Fluorescent Sensor for Selectively Imaging Serotonin. AB - A molecular imaging tool that provides for the direct visualization of serotonin would significantly aid in the investigation of neuropsychiatric disorders that are attributed to its neuronal dysregulation. Here, the design, synthesis, and evaluation of NeuroSensor 715 (NS715) is presented. NS715 is the first molecular sensor that exhibits a turn-on near-infrared fluorescence response toward serotonin. Density functional theory calculations facilitated the design of a fluorophore based on a coumarin-3-aldehyde scaffold that derives from an electron rich 1,2,3,4-tetrahydroquinoxaline framework, which provides appropriate energetics to prevent the hydroxyindole moiety of serotonin from quenching its fluorescence emission. Spectroscopic studies revealed that NS715 produces an 8 fold fluorescence enhancement toward serotonin with an emission maximum at 715 nm. Accompanying binding studies indicated NS715 displays a 19-fold selective affinity for serotonin and a modest affinity for catecholamines over other primary-amine neurotransmitters. The utility of NS715 toward neuroimaging applications was validated by selectively labeling and directly imaging norepinephrine within secretory vesicles using live chromaffin cells, which serve as a model system for specialized neurons that synthesize, package, and release only a single, unique type of neurotransmitter. In addition, NS715 effectively differentiated between cell populations that express distinct neurotransmitter phenotypes. PMID- 26521706 TI - Resource specialists lead local insect community turnover associated with temperature - analysis of an 18-year full-seasonal record of moths and beetles. AB - Insect responses to recent climate change are well documented, but the role of resource specialization in determining species vulnerability remains poorly understood. Uncovering local ecological effects of temperature change with high quality, standardized data provides an important first opportunity for predictions about responses of resource specialists, and long-term time series are essential in revealing these responses. Here, we investigate temperature related changes in local insect communities, using a sampling site with more than a quarter-million records from two decades (1992-2009) of full-season, quantitative light trapping of 1543 species of moths and beetles. We investigated annual as well as long-term changes in fauna composition, abundance and phenology in a climate-related context using species temperature affinities and local temperature data. Finally, we explored these local changes in the context of dietary specialization. Across both moths and beetles, temperature affinity of specialists increased through net gain of hot-dwelling species and net loss of cold-dwelling species. The climate-related composition of generalists remained constant over time. We observed an increase in species richness of both groups. Furthermore, we observed divergent phenological responses between cold- and hot dwelling species, advancing and delaying their relative abundance, respectively. Phenological advances were particularly pronounced in cold-adapted specialists. Our results suggest an important role of resource specialization in explaining the compositional and phenological responses of insect communities to local temperature increases. We propose that resource specialists in particular are affected by local temperature increase, leading to the distinct temperature mediated turnover seen for this group. We suggest that the observed increase in species number could have been facilitated by dissimilar utilization of an expanded growing season by cold- and hot-adapted species, as indicated by their oppositely directed phenological responses. An especially pronounced advancement of cold-adapted specialists suggests that such phenological advances might help minimize further temperature-induced loss of resource specialists. Although limited to a single study site, our results suggest several local changes in the insect fauna in concordance with expected change of larger-scale temperature increases. PMID- 26521708 TI - The knockdown of each component of the cysteine proteinase-adhesin complex of Entamoeba histolytica (EhCPADH) affects the expression of the other complex element as well as the in vitro and in vivo virulence. AB - Entamoeba histolytica is the protozoan parasite causative of human amoebiasis, disease responsible for 40 000-100 000 deaths annually. The cysteine proteinase adhesin complex of this parasite (EhCPADH) is a heterodimeric protein formed by a cysteine protease (EhCP112) and an adhesin (EhADH) that plays an important role in the cytopathic mechanism of this parasite. The coding genes for EhCP112 and EhADH are adjacent in the E. histolytica genome, suggesting that their expression may be co-regulated, but this hypothesis has not yet been confirmed. Here, we performed the knockdown of EhCP112 and EhADH using gene-specific short-hairpin RNAs (shRNA), and the effect of these knockdowns on the expression of both complex components as well as on the in vitro and in vivo virulence was analysed. Results showed that the knockdown of one of the EhCPADH components produced a simultaneous downregulation of the other protein. Accordingly, a concomitant reduction in the overall expression of the complex was observed. The downregulation of each component also produced a significant decrease in the in vitro and in vivo virulence of trophozoites. These results demonstrated that the expression of EhCP112 and EhADH is co-regulated and confirmed that the EhCPADH complex plays an important role in E. histolytica virulence. PMID- 26521707 TI - Chronic lung infection by Pseudomonas aeruginosa biofilm is cured by L-Methionine in combination with antibiotic therapy. AB - Bacterial biofilms are associated with 80-90% of infections. Within the biofilm, bacteria are refractile to antibiotics, requiring concentrations >1,000 times the minimum inhibitory concentration. Proteins, carbohydrates and DNA are the major components of biofilm matrix. Pseudomonas aeruginosa (PA) biofilms, which are majorly associated with chronic lung infection, contain extracellular DNA (eDNA) as a major component. Herein, we report for the first time that L-Methionine (L Met) at 0.5 MUM inhibits Pseudomonas aeruginosa (PA) biofilm formation and disassembles established PA biofilm by inducing DNase expression. Four DNase genes (sbcB, endA, eddB and recJ) were highly up-regulated upon L-Met treatment along with increased DNase activity in the culture supernatant. Since eDNA plays a major role in establishing and maintaining the PA biofilm, DNase activity is effective in disrupting the biofilm. Upon treatment with L-Met, the otherwise recalcitrant PA biofilm now shows susceptibility to ciprofloxacin. This was reflected in vivo, in the murine chronic PA lung infection model. Mice treated with L-Met responded better to antibiotic treatment, leading to enhanced survival as compared to mice treated with ciprofloxacin alone. These results clearly demonstrate that L-Met can be used along with antibiotic as an effective therapeutic against chronic PA biofilm infection. PMID- 26521709 TI - Non-periodic outbreaks of recurrent epidemics and its network modelling. AB - The study of recurrent epidemic outbreaks has been attracting great attention for decades, but its underlying mechanism is still under debate. Based on a large number of real data from different cities, we find that besides the seasonal periodic outbreaks of influenza, there are also non-periodic outbreaks, i.e. non seasonal or non-annual behaviors. To understand how the non-periodicity shows up, we present a network model of SIRS epidemic with both time-dependent infection rate and a small possibility of persistent epidemic seeds, representing the influences from the larger annual variation of environment and the infection generated spontaneously in nature, respectively. Our numerical simulations reveal that the model can reproduce the non-periodic outbreaks of recurrent epidemics with the main features of real influenza data. Further, we find that the recurrent outbreaks of epidemic depend not only on the infection rate but also on the density of susceptible agents, indicating that they are both the necessary conditions for the recurrent epidemic patterns with non-periodicity. A theoretical analysis based on Markov dynamics is presented to explain the numerical results. This finding may be of significance to the control of recurrent epidemics. PMID- 26521710 TI - Can problematic fibroepithelial lesions be accurately classified on core needle biopsies? AB - Fibroepithelial lesions (FEL) of the breast are notoriously difficult to classify on core needle biopsies. The goal of this study was to evaluate interobserver variability and accuracy of subclassifying difficult FELs into fibroadenoma (FA) and phyllodes tumors (PTs). We identified 50 breast core needle biopsies, initially diagnosed generically as FEL, with subsequent excision and final diagnosis of either FA or benign PT. Five surgical pathologists from one institution independently reviewed these in 3 rounds. The pathologists were blinded to the final excisional diagnosis. Two diagnostic categories were allowed: FA and PT. A set of histologic criteria was provided including the presence of subepithelial condensation, stromal heterogeneity, overgrowth, pleomorphism, fragmentation, cellularity, adipose tissue entrapment, and mitotic count and asked to review the slides for the second round. A third round of interpretations was conducted after each criterion was defined. Interobserver agreement for the diagnosis and each criterion was evaluated using the kappa level of agreement. Accuracy of ratings to final diagnosis was calculated using Wilcoxon signed-rank test. kappa Values for interobserver agreement were fair for the first and second rounds varying from 0.20 to 0.22, respectively. This increased to 0.27 in round 3. When considering each category, the kappa value varied from 0.26 to 0.29 for FA and 0.28 to 0.14 for PT. Overall, there was fair agreement between the pathologists in all categories. The rate of correctly diagnosed cases ranged from 40% in the first round, to 48% in the second round, to 67% in round 3. Overall the pathologists performed better in identifying FA than PT. The accuracy of interpretations was significantly different between the first (40%), second (48%), and third rounds (67%). PMID- 26521711 TI - Electroblotting from Polyacrylamide Gels. AB - Transferring proteins from polyacrylamide gels onto retentive membranes is now primarily used for immunoblotting. A second application that was quite common up to about a decade ago was electroblotting of proteins for N-terminal and internal sequencing using Edman chemistry. This unit contains procedures for electroblotting proteins from polyacrylamide gels onto a variety of membranes, including polyvinylidene difluoride (PVDF) and nitrocellulose. In addition to the commonly used tank or wet transfer system, protocols are provided for electroblotting using semidry and dry systems. This unit also describes procedures for eluting proteins from membranes using detergents or acidic extraction with organic solvents for specialized applications. PMID- 26521712 TI - Electron Microscopy and Image Processing: Essential Tools for Structural Analysis of Macromolecules. AB - Macromolecular electron microscopy typically depicts the structures of macromolecular complexes ranging from ~200 kDa to hundreds of MDa. The amount of specimen required, a few micrograms, is typically 100 to 1000 times less than needed for X-ray crystallography or nuclear magnetic resonance spectroscopy. Micrographs of frozen-hydrated (cryogenic) specimens portray native structures, but the original images are noisy. Computational averaging reduces noise, and three-dimensional reconstructions are calculated by combining different views of free-standing particles ("single-particle analysis"). Electron crystallography is used to characterize two-dimensional arrays of membrane proteins and very small three-dimensional crystals. Under favorable circumstances, near-atomic resolutions are achieved. For structures at somewhat lower resolution, pseudo atomic models are obtained by fitting high-resolution components into the density. Time-resolved experiments describe dynamic processes. Electron tomography allows reconstruction of pleiomorphic complexes and subcellular structures and modeling of macromolecules in their cellular context. Significant information is also obtained from metal-coated and dehydrated specimens. PMID- 26521713 TI - The Isotope-Coded Affinity Tag Method for Quantitative Protein Profile Comparison and Relative Quantitation of Cysteine Redox Modifications. AB - The isotope-coded affinity tag (ICAT) technique has been applied to measure pairwise changes in protein expression through differential stable isotopic labeling of proteins or peptides followed by identification and quantification using a mass spectrometer. Changes in protein expression are observed when the identical peptide from each of two biological conditions is identified and a difference is detected in the measurements comparing the peptide labeled with the heavy isotope to the one with a normal isotopic distribution. This approach allows the simultaneous comparison of the expression of many proteins between two different biological states (e.g., yeast grown on galactose versus glucose, or normal versus cancer cells). Due to the cysteine-specificity of the ICAT reagents, the ICAT technique has also been applied to perform relative quantitation of cysteine redox modifications such as oxidation and nitrosylation. This unit describes both protein quantitation and profiling of cysteine redox modifications using the ICAT technique. PMID- 26521714 TI - Large-Scale Identification of the Arginine Methylome by Mass Spectrometry. AB - The attachment of one or more methylation groups to the side chain of arginine residues is a regulatory mechanism for cellular proteins. Recent advances in mass spectrometry-based characterization allow comprehensive identification of arginine methylation sites by peptide-level enrichment strategies. Described in this unit is a 4-day protocol for enrichment of arginine-methylated peptides and subsequent identification of thousands of distinct sites by mass spectrometry. Specifically, the protocol explains step-by-step sample preparation, enrichment using commercially available antibodies, prefractionation using strong cation exchange, and identification using liquid chromatography coupled to tandem mass spectrometry. A strategy for relative quantification is described using stable isotope labeling by amino acids in cell culture (SILAC). Approaches for analysis of arginine methylation site occupancy are also discussed. Collectively, the unit describes the essential parameters required for a successful and comprehensive experiment detailing the arginine methylome. PMID- 26521715 TI - Evaluation of Photoreceptors in Bietti Crystalline Dystrophy with CYP4V2 Mutations Using Adaptive Optics Scanning Laser Ophthalmoscopy. AB - PURPOSE: To evaluate photoreceptors in Bietti crystalline dystrophy patients with CYP4V2 mutations using high-resolution images of the macula obtained with adaptive optics scanning laser ophthalmoscopy (AO-SLO). DESIGN: Prospective observational case series with comparison to healthy controls. METHODS: Seven eyes of 7 Bietti crystalline dystrophy patients with CYP4V2 mutations and 12 normal eyes of 12 age- and axial length-matched healthy volunteers were studied. All participants underwent ophthalmologic examinations and AO-SLO assessments. All patients underwent spectral-domain optical coherence tomography, fundus autofluorescence, Humphrey field analysis, and electroretinography. AO-SLO images were analyzed 0.5 mm and 1.0 mm from the center of the fovea in the superior, inferior, nasal, and temporal quadrants. RESULTS: Mean +/- standard deviation cone density (cells/mm(2)) 0.5 mm from the center of the fovea was 17,209 +/- 2276 in patients and 20 493 +/- 2758 in controls, which was statistically different (P = .001); however, mean cone density 1.0 mm from the center of the fovea was 15 685 +/- 2302 in patients and 15 705 +/- 1848 in controls, which was not statistically different (P = .20). There was no correlation between cone density and mean deviation measured using a Humphrey field analysis or visual acuity in patients. CONCLUSIONS: In Bietti crystalline dystrophy patients with CYP4V2 mutations, cone density remained for visual dysfunction by evaluation using high-resolution AO-SLO. These findings support the theory that disorder of the retinal pigment epithelium and the photoreceptors in the patients are the primary and secondary pathologic changes, respectively. This is consistent with results from previous basic studies. PMID- 26521716 TI - Idiopathic Enlargement of the Extraocular Muscles in Young Patients: A Case Series. AB - PURPOSE: To describe a case series of enlarged extraocular muscles in young patients. DESIGN: Retrospective interventional case series. METHODS: Study involves 6 young patients who presented with atypical restrictive strabismus and reduced eye movements. Examination, neuroimaging, biochemistry results, and biopsy results are presented. The surgeries are described, and the follow-up over 1-20 years is presented. RESULTS: All 6 patients had enlarged extraocular muscles that caused restrictive strabismus. The patients had no significant medical history. There was no identifiable underlying pathology on biochemistry tests or muscle biopsy. Three of the patients required multiple surgeries. CONCLUSION: Atypical presentations of strabismus should be investigated for systemic conditions. Neuroimaging of the orbit and brain and a biopsy of the affected muscles should be considered. The patients should be counseled that multiple surgeries may be necessary to improve the strabismus, and it is unlikely that orthotropia will be attained. PMID- 26521717 TI - Outcomes of Laparoscopic Partial Nephrectomy in Patients Continuing Aspirin Therapy. AB - PURPOSE: A clinical dilemma surrounds the use of aspirin therapy during laparoscopic partial nephrectomy. Despite reduced cardiac morbidity with perioperative aspirin use, fear of bleeding related complications often prompts discontinuation of therapy before surgery. We evaluate perioperative outcomes among patients continuing aspirin and those in whom treatment is stopped preoperatively. MATERIALS AND METHODS: A total of 430 consecutive cases of laparoscopic partial nephrectomy performed between January 2012 and October 2014 were reviewed. Patients on chronic aspirin therapy were stratified into on aspirin and off aspirin groups based on perioperative status of aspirin use. Primary end points evaluated included estimated intraoperative blood loss and incidence of bleeding related complications, major postoperative complications, and thromboembolic events. Secondary outcomes included operative time, transfusion rate, length of hospital stay, rehospitalization rate and surgical margin status. RESULTS: Among 101 (23.4%) patients on chronic aspirin therapy, antiplatelet treatment was continued in 17 (16.8%). Bleeding developed in 1 patient in the on aspirin group postoperatively and required angioembolization. Conversely 1 myocardial infarction was observed in the off aspirin cohort. There was no significant difference in the incidence of major postoperative complications, intraoperative blood loss, transfusion rate, length of hospital stay and rehospitalization rate. Operative time was increased with continued aspirin use (181 vs 136 minutes, p=0.01). CONCLUSIONS: Laparoscopic partial nephrectomy is safe and effective in patients on chronic antiplatelet therapy who require perioperative aspirin for cardioprotection. Larger, prospective studies are necessary to discern the true cardiovascular benefit derived from continued aspirin therapy as well as better characterize associated bleeding risk. PMID- 26521718 TI - Final Pathological Stage after Neoadjuvant Chemotherapy and Radical Cystectomy for Bladder Cancer-Does pT0 Predict Better Survival than pTa/Tis/T1? AB - PURPOSE: We assessed survival dependent on pathological response after neoadjuvant chemotherapy in a large multicenter patient cohort, with a particular focus on the difference between the absence of residual cancer (pT0) and the presence of only nonmuscle invasive residual cancer (pTa, pTis, pT1). MATERIALS AND METHODS: We retrospectively reviewed records of patients with urothelial cancer who received neoadjuvant chemotherapy and underwent radical cystectomy at 19 contributing institutions from 2000 to 2013. Patients with cT2-4aN0M0 and eventual pN0 disease were selected for this analysis. Estimated overall survival was compared between patients with pT0 and pTa/Tis/T1 disease. A multivariable Cox proportional hazards regression model for overall survival was generated to evaluate hazard ratios for variables of interest. RESULTS: Of 1,543 patients treated with neoadjuvant chemotherapy and radical cystectomy during the study period 257 had pT0N0 and 207 had pTa/Tis/T1N0 disease. The Kaplan-Meier mean estimates of overall survival for pT0 and pTa/Tis/T1 cases were 186.7 months (95% CI 145.9-227.6, median 241.1) and 138 months (95% CI 118.2-157.8, median 187.4), respectively (p=0.58). In the Cox proportional hazards regression model for overall survival pTa/Tis/T1N0 status (HR 0.36, 95% CI 0.23-0.67) and pT0N0 status (HR 0.28, 95% CI 0.17-0.47) compared to pT2N0 pathology, positive surgical margin (HR 1.75, 95% CI 1.07-2.86), and receiving a methotrexate, vinblastine, doxorubicin and cisplatin regimen compared to an "other" regimen (HR 0.45, 95% CI 0.27-0.76) were predictors of overall survival. CONCLUSIONS: pTa/Tis/T1N0 and pT0N0 stage on the final cystectomy specimen are strong predictors of survival in patients treated with neoadjuvant chemotherapy and radical cystectomy. We did not discern a statistically significant difference in overall survival when comparing these 2 end points. PMID- 26521720 TI - Sleep Duration and the Risk of Mortality From Stroke in Japan: The Takayama Cohort Study. AB - BACKGROUND: Few studies have assessed the associations between sleep duration and stroke subtypes. We examined whether sleep duration is associated with mortality from total stroke, ischemic stroke, and hemorrhagic stroke in a population-based cohort of Japanese men and women. METHODS: Subjects included 12 875 men and 15 021 women aged 35 years or older in 1992, who were followed until 2008. The outcome variable was stroke death (ischemic stroke, hemorrhagic stroke, and total stroke). RESULTS: During follow-up, 611 stroke deaths (354 from ischemic stroke, 217 from hemorrhagic stroke, and 40 from undetermined stroke) were identified. Compared with 7 h of sleep, >=9 h of sleep was significantly associated with an increased risk of total stroke and ischemic stroke mortality after controlling for covariates. Hazard ratios (HRs) and 95% confidence intervals (CIs) were 1.51 (95% CI, 1.16-1.97) and 1.65 (95% CI, 1.16-2.35) for total stroke mortality and ischemic stroke mortality, respectively. Short sleep duration (<=6 h of sleep) was associated with a decreased risk of mortality from total stroke (HR 0.77; 95% CI, 0.59-1.01), although this association was of borderline significance (P = 0.06). The trends for total stroke and ischemic stroke mortality were also significant (P < 0.0001 and P = 0.0002, respectively). There was a significant risk reduction of hemorrhagic stroke mortality for <=6 h of sleep as compared with 7 h of sleep (HR 0.64; 95% CI, 0.42-0.98; P for trend = 0.08). The risk reduction was pronounced for men (HR 0.31; 95% CI, 0.16-0.64). CONCLUSIONS: Data suggest that longer sleep duration is associated with increased mortality from total and ischemic stroke. Short sleep duration may be associated with a decreased risk of mortality from hemorrhagic stroke in men. PMID- 26521719 TI - First in Human Clinical Trial of Ultrasonic Propulsion of Kidney Stones. AB - PURPOSE: Ultrasonic propulsion is a new technology using focused ultrasound energy applied transcutaneously to reposition kidney stones. We report what are to our knowledge the findings from the first human investigational trial of ultrasonic propulsion toward the applications of expelling small stones and dislodging large obstructing stones. MATERIALS AND METHODS: Subjects underwent ultrasonic propulsion while awake without sedation in clinic, or during ureteroscopy while anesthetized. Ultrasound and a pain questionnaire were completed before, during and after propulsion. The primary outcome was to reposition stones in the collecting system. Secondary outcomes included safety, controllable movement of stones and movement of stones less than 5 mm and 5 mm or greater. Adverse events were assessed weekly for 3 weeks. RESULTS: Kidney stones were repositioned in 14 of 15 subjects. Of the 43 targets 28 (65%) showed some level of movement while 13 (30%) were displaced greater than 3 mm to a new location. Discomfort during the procedure was rare, mild, brief and self-limited. Stones were moved in a controlled direction with more than 30 fragments passed by 4 of the 6 subjects who had previously undergone a lithotripsy procedure. The largest stone moved was 10 mm. One patient experienced pain relief during treatment of a large stone at the ureteropelvic junction. In 4 subjects a seemingly large stone was determined to be a cluster of small passable stones after they were moved. CONCLUSIONS: Ultrasonic propulsion was able to successfully reposition stones and facilitate the passage of fragments in humans. No adverse events were associated with the investigational procedure. PMID- 26521722 TI - Enantioselective hydrogenation of cyclic imines catalysed by Noyori-Ikariya half sandwich complexes and their analogues. AB - A method for enantioselective hydrogenation of cyclic imines with gaseous hydrogen has been developed. Easily accessible Noyori-Ikariya Ru(II) and Rh(III) complexes can be used directly without an inert atmosphere. Substrate activation has been achieved by trifluoroacetic acid. A new hydroxyl-functionalized complex is reported, showing high activity in transfer hydrogenation. PMID- 26521721 TI - Sleep problems and associated comorbidities among adults with Down syndrome. AB - BACKGROUND: Sleep problems, including sleep apnoea and behavioural sleep disturbances, are common among adults with Down syndrome (DS). Despite a preliminary understanding of potential medical and behavioural comorbidities of these sleep problems among children with DS, little is known about comorbid conditions associated with these sleep problems among adults with DS. Understanding causes and sequelae of sleep problems in this ageing population is essential to providing quality health screening and treatment. The current study examines the physical health problems, mental health conditions, functional abilities and behavioural problems associated with sleep apnoea and behavioural sleep disturbances among adults with DS. METHOD: Family caregivers participated in clinical interviews and completed questionnaires, providing reports regarding 75 adults with DS. Caregivers reported on sleep problems, physical and mental health conditions, daily living skills and behaviours regarding their ageing family member with DS. RESULTS: Sleep apnoea was associated with more common other respiratory concerns, and more frequent visits to physicians, but not with some expected medical comorbidities (cardiac). Behavioural sleep disturbances (delayed sleep onset, night-time awakenings and morning awakenings) were associated with poorer health, more frequent overnight hospital and emergency department visits, more common cardiac conditions, less common thyroid condition, more common mental health conditions (anxiety, depression and dementia) and a higher rate of daytime behaviour problems. CONCLUSION: The study findings suggest that there are differential correlates for the various sleep problems in adults with DS, which warrant attention when screening for medical and mental health comorbidities, assessing behavioural problems and in treatment planning for ageing adults with DS. PMID- 26521723 TI - Fuzzy model-based observers for fault detection in CSTR. AB - Under the vast variety of fuzzy model-based observers reported in the literature, what would be the properone to be used for fault detection in a class of chemical reactor? In this study four fuzzy model-based observers for sensor fault detection of a Continuous Stirred Tank Reactor were designed and compared. The designs include (i) a Luenberger fuzzy observer, (ii) a Luenberger fuzzy observer with sliding modes, (iii) a Walcott-Zak fuzzy observer, and (iv) an Utkin fuzzy observer. A negative, an oscillating fault signal, and a bounded random noise signal with a maximum value of +/-0.4 were used to evaluate and compare the performance of the fuzzy observers. The Utkin fuzzy observer showed the best performance under the tested conditions. PMID- 26521724 TI - Decentralized PID controller for TITO systems using characteristic ratio assignment with an experimental application. AB - This paper presents a decentralized PID controller design method for two input two output (TITO) systems with time delay using characteristic ratio assignment (CRA) method. The ability of CRA method to design controller for desired transient response has been explored for TITO systems. The design methodology uses an ideal decoupler to reduce the interaction. Each decoupled subsystem is reduced to first order plus dead time (FOPDT) model to design independent diagonal controllers. Based on specified overshoot and settling time, the controller parameters are computed using CRA method. To verify performance of the proposed controller, two benchmark simulation examples are presented. To demonstrate applicability of the proposed controller, experimentation is performed on real life interacting coupled tank level system. PMID- 26521725 TI - An indirect adaptive neural control of a visual-based quadrotor robot for pursuing a moving target. AB - This paper aims to use a visual-based control mechanism to control a quadrotor type aerial robot which is in pursuit of a moving target. The nonlinear nature of a quadrotor, on the one hand, and the difficulty of obtaining an exact model for it, on the other hand, constitute two serious challenges in designing a controller for this UAV. A potential solution for such problems is the use of intelligent control methods such as those that rely on artificial neural networks and other similar approaches. In addition to the two mentioned problems, another problem that emerges due to the moving nature of a target is the uncertainty that exists in the target image. By employing an artificial neural network with a Radial Basis Function (RBF) an indirect adaptive neural controller has been designed for a quadrotor robot in search of a moving target. The results of the simulation for different paths show that the quadrotor has efficiently tracked the moving target. PMID- 26521726 TI - Lifelong leukocyte telomere dynamics and survival in a free-living mammal. AB - Telomeres play a fundamental role in the maintenance of genomic integrity at a cellular level, and average leukocyte telomere length (LTL) has been proposed as a biomarker of organismal aging. However, studies tracking LTL across the entire life course of individuals are lacking. Here, we examined lifelong patterns of variation in LTL among four birth cohorts of female Soay sheep (Ovis aries) that were longitudinally monitored and sampled from birth to death. Over the first 4 months of life, there was within-individual loss of LTL, consistent with findings in the human and primate literature, but there was little evidence of consistent LTL loss associated with age after this point. Overall, we observed only weak evidence of individual consistency in LTL across years and over the entire lifespan: Within-individual variation was considerable, and birth cohorts differed markedly in their telomere dynamics. Despite the high levels of LTL variation within the lifetimes of individuals, there remained significant associations between LTL and longevity. Detailed analysis of the longitudinal data set showed that this association was driven by improved survival of individuals with longer LTL over the first 2 years of life. There was no evidence that LTL predicted survival in later adulthood. Our data provide the first evidence from a mammal that LTL can predict mortality and lifespan under natural conditions, and also highlight the potentially dynamic nature of LTL within the lifetimes of individuals experiencing a complex and highly variable environment. PMID- 26521727 TI - Inflammation in osteoarthritis: changing views. PMID- 26521728 TI - Inflammation in joint injury and post-traumatic osteoarthritis. AB - Inflammation is a variable feature of osteoarthritis (OA), associated with joint symptoms and progression of disease. Signs of inflammation can be observed in joint fluids and tissues from patients with joint injuries at risk for development of post-traumatic osteoarthritis (PTOA). Furthermore, inflammatory mechanisms are hypothesized to contribute to the risk of OA development and progression after injury. Animal models of PTOA have been instrumental in understanding factors and mechanisms involved in chronic progressive cartilage degradation observed after a predisposing injury. Specific aspects of inflammation observed in humans, including cytokine and chemokine production, synovial reaction, cellular infiltration and inflammatory pathway activation, are also observed in models of PTOA. Many of these models are now being utilized to understand the impact of post-injury inflammatory response on PTOA development and progression, including risk of progressive cartilage degeneration and development of chronic symptoms post-injury. As evidenced from these models, a vigorous inflammatory response occurs very early after joint injury but is then sustained at a lower level at the later phases. This early inflammatory response contributes to the development of PTOA features including cartilage erosion and is potentially modifiable, but specific mediators may also play a role in tissue repair. Although the optimal approach and timing of anti-inflammatory interventions after joint injury are yet to be determined, this body of work should provide hope for the future of disease modification tin PTOA. PMID- 26521730 TI - Differential expression of interleukin-17 and interleukin-22 in inflamed and non inflamed synovium from osteoarthritis patients. AB - OBJECTIVE: Synovitis associated with osteoarthritis (OA) is directly responsible for several clinical symptoms and reflects OA's structural progression. This study sought to analyze the expression of proinflammatory mediations, including Interleukin (IL)-17 and IL-22, which play key roles in regulating inflammatory processes, in inflamed and non-inflamed areas of osteoarthritic synovium. METHODS: Synovium from knees of 32 OA patients were collected at surgery. Macroscopic evaluation of inflammation enabled inflamed and non-inflamed areas to be separated. Samples were incubated to obtain tissue-conditioned media. Quantitative mRNA expression of proinflammatory mediators was analyzed by RT-PCR and protein levels by ELISA and gelatin zymography. Immunohistochemistry and histology were performed. RESULTS: Inflamed synovium were characterized by increased leukocyte infiltration and a higher vessel-to-tissue area ratio than non-inflamed tissues. Macrophages, T and B lymphocytes, and some neutrophils were found only in the inflamed tissue, and only in the subintimal layer. Levels of proinflammatory cytokines and MMP-9 were significantly higher in tissue conditioned media from inflamed than non-inflamed tissues. Inflamed areas were associated with higher expression of IL-17 and IL-22, both correlated with the combined release of IL-6, IL-23, and TGFbeta1. CONCLUSION: Our results showed that inflammatory cytokines, including IL-17 and IL-22, are expressed at higher levels by inflamed OA synovium and suggest IL-22 involvement in OA pathophysiology. This study will help identify new therapeutic strategies for OA, especially the targeting of IL-22 to decrease inflammation. PMID- 26521731 TI - Arthritic and non-arthritic synovial fluids modulate IL10 and IL1RA gene expression in differentially activated primary human monocytes. AB - OBJECTIVE: Synovitis with an increased presence of macrophages is observed in osteoarthritis (OA) and rheumatoid arthritis (RA). Given the important role of macrophages in arthritis, we investigated the influence of OA and RA synovial fluid (SF) on primary human monocytes (Mo), their lineage precursors. METHOD: Adherent monocytes without any stimulation (Mo(-)) or stimulated with IFN-gamma and TNF-alpha (Mo(IFN-gamma/TNF-alpha)) or IL-4 (Mo(IL-4)) were exposed to SF from 6 donors without any known joint disease (SF-Ctrl), 10 OA donors (SF-OA), and 10 RA donors (SF-RA). The transcriptional expression of IL6, IL1B, TNFA, IL10, CCL18, CD206, and IL1RA was analyzed. RESULTS: Mo(-) exposed to SF-RA had a lower expression of IL10 and a higher expression of IL1RA than when exposed to SF Ctrl. Mo(IL-4) exposed to SF-RA had a lower expression of IL10 and CCL18 than when exposed to SF-Ctrl and Mo(IFN-gamma/TNF-alpha) were not affected by SF-RA. Mo exposed to SF-OA also expressed less IL10, but only upon stimulation with IL 4, and expressed more IL1RA than when exposed to SF-Ctrl in any condition. CONCLUSION: A lower expression of IL10 may be regarded as a response to less inflammatory conditions since IL10 expression is higher in response to IFN gamma/TNF-alpha stimulation, probably as a feedback mechanism. Therefore, the lower expression of IL10 and the higher expression of IL1RA in Mo exposed to arthritic than to non-arthritic SF suggest that arthritic SF is mainly reducing the inflammatory responses in Mo. This may mimic the response of monocytes/macrophages recruited to the joint, where feedback mechanisms counteract pro-inflammatory processes. PMID- 26521729 TI - Inflammation and intracellular metabolism: new targets in OA. AB - Articular cartilage degeneration is hallmark of osteoarthritis (OA). Low-grade chronic inflammation in the joint can promote OA progression. Emerging evidence indicates that bioenergy sensors couple metabolism with inflammation to switch physiological and clinical phenotypes. Changes in cellular bioenergy metabolism can reprogram inflammatory responses, and inflammation can disturb cellular energy balance and increase cell stress. AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) are two critical bioenergy sensors that regulate energy balance at both cellular and whole-body levels. Dysregulation of AMPK and SIRT1 has been implicated in diverse human diseases and aging. This review reveals recent findings on the role of AMPK and SIRT1 in joint tissue homeostasis and OA, with a focus on how AMPK and SIRT1 in articular chondrocytes modulate intracellular energy metabolism during stress responses (e.g., inflammatory responses) and how these changes dictate specific effector functions, and discusses translational significance of AMPK and SIRT1 as new therapeutic targets for OA. PMID- 26521732 TI - Multicolor flow cytometry-based cellular phenotyping identifies osteoprogenitors and inflammatory cells in the osteoarthritic subchondral bone marrow compartment. AB - PURPOSE: The cellular component of subchondral bone is thought to be responsible for aberrant bone remodeling in osteoarthritis (OA). Direct phenotypical analysis of the cellular compartment is critical to better understand the OA disease process. This study provides proof-of-principle for flow cytometry-based phenotyping of isolated subchondral trabecular bone (STB) marrow cells without prior use of cell culture techniques. METHODS: Tibial plateaus were obtained from OA patients undergoing total knee arthroplasty. Subchondral bone chips were digested with collagenase IA and single cell suspensions were directly phenotyped using flow cytometry. Cells were analyzed for the expression of alkaline phosphatase (ALP) as osteoblast/osteoprogenitor marker and monocyte/macrophage markers (CD14, CD68, HLA-DR, CD115). RESULTS: MTT staining revealed abundant viable cells in the bone marrow compartment of STB prior to digestion, which were efficiently released by collagenase. Within the CD45-negative cell fraction, approximately 20% of the cells were positive for the early osteoblast/osteoprogenitor marker ALP. Within the CD45+ hematopoietic cell fraction, the majority of cells were of monocytic origin (>80%) displaying strong surface expression of CD14. Discreet macrophage populations (CD14+/HLA-DR+/CD68+) and putative osteoclast progenitors (CD45+/HLA-DR-/CD115+) were unequivocally identified. Osteoblast, macrophage and osteoclast progenitor presence in the subchondral bone unit (SBU) was confirmed by (immuno)histochemical staining for osteocalcin, CD68 and tartrate-resistant acid phosphatase, respectively. CONCLUSIONS: Flow cytometric analysis is a valuable methodology to study the cellular compartment of STB marrow. This method provides a proof of principle that the whole resident cell population can be directly phenotypically characterized without the prior use of cell culture techniques. PMID- 26521733 TI - Deficiency of hyaluronan synthase 1 (Has1) results in chronic joint inflammation and widespread intra-articular fibrosis in a murine model of knee joint cartilage damage. AB - OBJECTIVE: Articular cartilage defects commonly result from traumatic injury and predispose to degenerative joint diseases. To test the hypothesis that aberrant healing responses and chronic inflammation lead to osteoarthritis (OA), we examined spatiotemporal changes in joint tissues after cartilage injury in murine knees. Since intra-articular injection of hyaluronan (HA) can attenuate injury induced osteoarthritis in wild-type (WT) mice, we investigated a role for HA in the response to cartilage injury in mice lacking HA synthase 1 (Has1(-/-)). DESIGN: Femoral groove cartilage of WT and Has1(-/-) mice was debrided to generate a non-bleeding wound. Macroscopic imaging, histology, and gene expression were used to evaluate naive, sham-operated, and injured joints. RESULTS: Acute responses (1-2 weeks) in injured joints from WT mice included synovial hyperplasia with HA deposition and joint-wide increases in expression of genes associated with inflammation, fibrosis, and extracellular matrix (ECM) production. By 4 weeks, some resurfacing of damaged cartilage occurred, and early cell responses were normalized. Cartilage damage in Has1(-/-) mice also induced early responses; however, at 4 weeks, inflammation and fibrosis genes remained elevated with widespread cartilage degeneration and fibrotic scarring in the synovium and joint capsule. CONCLUSIONS: We conclude that the ineffective repair of injured cartilage in Has1(-/-) joints can be at least partly explained by the markedly enhanced expression of particular genes in pathways linked to ECM turnover, IL-17/IL-6 cytokine signaling, and apoptosis. Notably, Has1 ablation does not alter gross HA content in the ECM, suggesting that HAS1 has a unique function in the metabolism of inflammatory HA matrices. PMID- 26521735 TI - Associations of markers of matrix metabolism, inflammation markers, and adipokines with superior cam deformity of the hip and their relation with future hip osteoarthritis. AB - OBJECTIVE: First, to study how markers of matrix metabolism, inflammation markers, and adipokines relate to (superior) cam deformity and (possible) cam impingement of the hip. Second, to investigate whether they can identify subjects with cam deformity that are at risk of future hip osteoarthritis (OA). METHOD: In a cohort of 1002 subjects (CHECK), (superior) cam deformity was defined by an alpha angle >60 degrees on anteroposterior pelvic radiographs and (possible) cam impingement by a cam deformity together with internal hip rotation <=20 degrees . Hip OA at 5-year follow-up was defined by Kellgren and Lawrence grade >=2 or total hip replacement. RESULTS: Subjects with (superior) cam deformity and (possible) cam impingement showed lower levels of bone turnover markers (uCTX-I, uNTX-I, sPINP, sOC) than those without. Cam deformity was positively associated with future hip OA, but associations were weaker at high levels of bone turnover. sCOMP and sHA levels were higher in subjects with cam deformity, while other cartilage and synovium markers were not. Some markers of inflammation (pLeptin, pAdiponectin, and erythrocyte sedimentation rate) were lower in presence of cam deformity and cam impingement, but high-sensitivity C-reactive protein was not. Most associations depended largely on gender differences. CONCLUSION: Bone metabolism may be relevant in the pathogenesis of (superior) cam deformity and in the development of (superior) cam deformity into hip OA. Subjects with cam deformity and cam impingement surprisingly showed lower levels of inflammation markers and adipokines. Associations of cartilage turnover markers with cam deformity and cam impingement were less obvious. PMID- 26521734 TI - Inflammatory biomarkers in osteoarthritis. AB - Osteoarthritis (OA) is highly prevalent and a leading cause of disability worldwide. Despite the global burden of OA, diagnostic tests and treatments for the molecular or early subclinical stages are still not available for clinical use. In recent years, there has been a large shift in the understanding of OA as a "wear and tear" disease to an inflammatory disease. This has been demonstrated through various studies using MRI, ultrasound, histochemistry, and biomarkers. It would of great value to be able to readily identify subclinical and/or sub-acute inflammation, particularly in such a way as to be appropriate for a clinical setting. Here we review several types of biomarkers associated with OA in human studies that point to a role of inflammation in OA. PMID- 26521736 TI - Interleukin-6 and tumor necrosis factor alpha in synovial fluid are associated with progression of radiographic knee osteoarthritis in subjects with previous meniscectomy. AB - OBJECTIVE: To explore potential associations between proinflammatory cytokines in synovial fluid and progression of osteoarthritis (OA) in meniscectomized subjects. DESIGN: We studied 132 subjects on average 18 years after meniscectomy, with a second examination 4-10 years later. We measured concentrations of interleukin (IL)-6, -8 and tumor necrosis factor (TNF)-alpha by multiplex immunoassay, graded radiographic features of tibiofemoral and patellofemoral OA according to the Osteoarthritis Research Society International (OARSI) atlas, scored patient-reported outcomes using the Knee Injury and Osteoarthritis Outcome Score (KOOS), and used logistic regression (adjusted for age, gender, body mass index, and time between examinations) for assessment of associations. RESULTS: Higher first examination concentrations of IL-6 and TNF-alpha were associated with increased risk for subsequent osteophyte progression (odds ratios (OR); 95% confidence intervals 1.05; 1.00-1.09 and 1.35; 1.03-1.75). Higher second examination concentrations of TNF-alpha were associated with having progressed in loss of joint space (OR 1.70; 1.15-2.52) or having worsened in the activity of daily living subscale of KOOS (OR 1.50; 1.07-2.09) in the preceding years. Subjects with increasing concentrations of IL-6 or TNF-alpha between examinations were five times more likely to have progressed in joint space narrowing between the same examinations, as compared to those with stable or decreasing concentrations (OR 5.17; 1.54-17.32 and 5.01; 1.32-18.92). CONCLUSIONS: In subjects with previous meniscectomy, higher or over time increasing synovial fluid levels of IL-6 and TNF-alpha seems to be associated with increased risk for progression of radiographic OA. PMID- 26521738 TI - Ultrasound detected inflammation is associated with the development of new bone erosions in hand osteoarthritis: a longitudinal study over 3.9 years. AB - OBJECTIVE: To evaluate the association between ultrasound (US) detected inflammation at baseline and the subsequent development of new bone erosions at follow-up in patients with hand osteoarthritis (HOA). METHOD: 32 of the 35 (10 controls, 12 patients with non erosive HOA (non-EHOA), 13 with EHOA subjects originally studied were re-evaluated 3.9 years after the initial study, by means of standard radiography and US examination. Kellgren-Lawrence (K-L) and Kallman scores were utilized to evaluate 576 interphalangeal (IP) joints. US detected synovial inflammation features were scored as present/absent. US detected bone erosions were also investigated. The association between synovial inflammation features at baseline and the development of new bone erosions was evaluated using the generalized linear mixed model (GLMM) after adjustment for patient effect, age, gender, body mass index. RESULTS: In HOA patients, radiographic scores worsened and bone erosions progressed. In HOA patients similar percentages of joints with Power Doppler Signal (PDS) and gray scale (GS) synovitis were found comparing baseline and follow-up examinations, whilst a significant increase was found in the joints with effusions. Only a minority of joints were positive on both occasions (between 2 and 6 %), the majority fluctuated between positive and negative and vice versa. PDS positivity was associated with new radiographic central erosions and US-detected bone erosions, whereas GS synovitis and effusion were not. CONCLUSIONS: Radiographic scores and bone erosions increased over a period of about 4 years. Synovial inflammation as detected by PDS was associated with the appearance of new bone erosions. PMID- 26521737 TI - Plasma levels of interleukin-1 receptor antagonist (IL1Ra) predict radiographic progression of symptomatic knee osteoarthritis. AB - OBJECTIVE: Pro- and anti-inflammatory mediators, such as IL-1beta and IL1Ra, are produced by joint tissues in osteoarthritis (OA), where they may contribute to pathogenesis. We examined whether inflammatory events occurring within joints are reflected in plasma of patients with symptomatic knee osteoarthritis (SKOA). DESIGN: 111 SKOA subjects with medial disease completed a 24-month prospective study of clinical and radiographic progression, with clinical assessment and specimen collection at 6-month intervals. The plasma biochemical marker IL1Ra was assessed at baseline and 18 months; other plasma biochemical markers were assessed only at 18 months, including IL-1beta, TNFalpha, VEGF, IL-6, IL-6Ralpha, IL-17A, IL-17A/F, IL-17F, CRP, sTNF-RII, and MMP-2. RESULTS: In cross-sectional studies, WOMAC (total, pain, function) and plasma IL1Ra were modestly associated with radiographic severity after adjustment for age, gender and body mass index (BMI). In addition, elevation of plasma IL1Ra predicted joint space narrowing (JSN) at 24 months. BMI did associate with progression in some but not all analyses. Causal graph analysis indicated a positive association of IL1Ra with JSN; an interaction between IL1Ra and BMI suggested either that BMI influences IL1Ra or that a hidden confounder influences both BMI and IL1Ra. Other protein biomarkers examined in this study did not associate with radiographic progression or severity. CONCLUSIONS: Plasma levels of IL1Ra were modestly associated with the severity and progression of SKOA in a causal fashion, independent of other risk factors. The findings may be useful in the search for prognostic biomarkers and development of disease-modifying OA drugs. PMID- 26521739 TI - The role of inflammation-related genes in osteoarthritis. AB - In this review article we examine the role of inflammation-related genes in osteoarthritis (OA) from the perspective of genetics, epigenetics and gene expression. There have been great strides in such genomic analyses of OA in recent years thanks to the study of adequately powered patient cohorts, the detailed analysis of candidate genes, and the application of genome-wide approaches. These have led to some unexpected and therefore exciting discoveries, implicating pathways that would not necessarily have been predicted to have a role in this common arthritis. Inflammatory-related genes sit firmly in the candidate camp based on prior observations that the OA disease process can have an inflammatory component. What is clear from the genetic studies published to date is that there is no compelling evidence that DNA variation in inflammatory genes is an OA risk factor. This conclusion may of course change as ever more powerful association studies are conducted. There is, however, compelling evidence that epigenetic effects involving inflammatory genes are a component of OA and that alteration in the expression of these genes is also highly relevant to the disease process. We may in fact be close to demonstrating, at the genomic level, a clear separation of OA patients into those in whom inflammation is a key driver of the disease and those in whom it is not. This has obvious implications for the design of trials of novel OA interventions and may also guide the intelligent re-purposing of anti-inflammatory therapies. PMID- 26521740 TI - Human genome-wide expression analysis reorients the study of inflammatory mediators and biomechanics in osteoarthritis. AB - A major objective of this article is to examine the research implications of recently available genome-wide expression profiles of cartilage from human osteoarthritis (OA) joints. We propose that, when viewed in the light of extensive earlier work, this novel data provides a unique opportunity to reorient the design of experimental systems toward clinical relevance. Specifically, in the area of cartilage explant biology, this will require a fresh evaluation of existing paradigms, so as to optimize the choices of tissue source, cytokine/growth factor/nutrient addition, and biomechanical environment for discovery. Within this context, we firstly discuss the literature on the nature and role of potential catabolic mediators in OA pathology, including data from human OA cartilage, animal models of OA, and ex vivo studies. Secondly, due to the number and breadth of studies on IL-1beta in this area, a major focus of the article is a critical analysis of the design and interpretation of cartilage studies where IL-1beta has been used as a model cytokine. Thirdly, the article provides a data-driven perspective (including genome-wide analysis of clinical samples, studies on mutant mice, and clinical trials), which concludes that IL 1beta should be replaced by soluble mediators such as IL-17 or TGF-beta1, which are much more likely to mimic the disease in OA model systems. We also discuss the evidence that changes in early OA can be attributed to the activity of such soluble mediators, whereas late-stage disease results more from a chronic biomechanical effect on the matrix and cells of the remaining cartilage and on other local mediator-secreting cells. Lastly, an updated protocol for in vitro studies with cartilage explants and chondrocytes (including the use of specific gene expression arrays) is provided to motivate more disease-relevant studies on the interplay of cytokines, growth factors, and biomechanics on cellular behavior. PMID- 26521741 TI - Epigenetic regulation of interleukin-8, an inflammatory chemokine, in osteoarthritis. AB - OBJECTIVE: To determine whether altered IL8 methylation status is associated with increased expression of IL8 in human osteoarthritic (OA) chondrocytes. METHODS: IL8 expression levels and the percentage CpG methylation in human chondrocytes were quantified by qRT-PCR and pyrosequencing in OA patients and in non-OA osteoporotic controls. The effect of CpG methylation on IL8 promoter activity was determined using a CpG-free vector; co-transfections with expression vectors encoding nuclear factor-kappa B (NF-kappaB), AP-1 and C/EBP were subsequently undertaken to analyse for IL8 promoter activity in response to changes in methylation status. RESULTS: IL8 expression in OA patients was 37-fold higher than in osteoporotic controls. Three CpG sites in the IL8 promoter were significantly demethylated in OA patients. Multiple regression analysis revealed that the degree of methylation of the CpG site located at -116-bp was the strongest predictor of IL8 expression. In vitro DNA methylation was noted to decrease IL8 promoter basal activity. Furthermore, NF-kappaB, AP-1 and C/EBP strongly enhanced IL8 promoter activity whilst DNA methylation inhibited the effects of these three transcription factors. CONCLUSIONS: The present study demonstrates the key role of DNA methylation status on the expression of IL8 in human chondrocytes. We demonstrate a quantitative relationship between percentage methylation and gene expression within clinical samples. These studies provide direct evidence linking the activation of IL8, DNA demethylation and the induction of the OA process with important therapeutic implications therein for patients with this debilitating disease. PMID- 26521742 TI - Aging-related inflammation in osteoarthritis. AB - It is well accepted that aging is an important contributing factor to the development of osteoarthritis (OA). The mechanisms responsible appear to be multifactorial and may include an age-related pro-inflammatory state that has been termed "inflamm-aging." Age-related inflammation can be both systemic and local. Systemic inflammation can be promoted by aging changes in adipose tissue that result in increased production of cytokines such as interleukin (IL)-6 and tumor necrosis factor-alpha (TNFalpha). Numerous studies have shown an age related increase in blood levels of IL-6 that has been associated with decreased physical function and frailty. Importantly, higher levels of IL-6 have been associated with an increased risk of knee OA progression. However, knockout of IL 6 in male mice resulted in worse age-related OA rather than less OA. Joint tissue cells, including chondrocytes and meniscal cells, as well as the neighboring infrapatellar fat in the knee joint, can be a local source of inflammatory mediators that increase with age and contribute to OA. An increased production of pro-inflammatory mediators that include cytokines and chemokines, as well as matrix-degrading enzymes important in joint tissue destruction, can be the result of cell senescence and the development of the senescence-associated secretory phenotype (SASP). Further studies are needed to better understand the basis for inflamm-aging and its role in OA with the hope that this work will lead to new interventions targeting inflammation to reduce not only joint tissue destruction but also pain and disability in older adults with OA. PMID- 26521743 TI - IL-1beta mediates MMP secretion and IL-1beta neosynthesis via upregulation of p22(phox) and NOX4 activity in human articular chondrocytes. AB - OBJECTIVES: Osteoarthritis (OA) is characterized by a progressive alteration of the biochemical properties of the articular cartilage. Inflammation plays a major role in OA, particularly through the cytokine Interleukine-1beta, promoting reactive oxygen species (ROS) generation and matrix metalloproteinases (MMP) synthesis by the chondrocytes, orchestrating matrix proteolysis. NADPH oxidases (NOX) are membrane enzymes dedicated to the production of ROS. Role of oxidative stress is well established in OA; however, contribution of NOX in this process is still poorly documented. In this study, we addressed the role of NOX in primary human articular chondrocytes (HAC) upon inflammatory conditions--namely IL-1beta and OA. DESIGN: HAC were collected from patients undergoing hip surgery. Chondrocytes were treated with IL-1beta and NOX inhibitors Diphenylene Iodonium, GKT136901, Tiron and Heme oxygenase-1 before MMP expression and NOX activity assessment. Finally, NOX4 expression was compared between OA and non OA parts of hip cartilage (n = 14). RESULTS: This study establishes for the first time in human that NOX4 is the main NOX isoform expressed in chondrocytes. We found a significant upregulation of NOX4 mRNA in OA chondrocytes. Expression of NOX4/p22(phox) as well as ROS production is enhanced by IL-1beta. On the other hand, the use of NOX4 inhibitors decreased IL-1beta-induced collagenase synthesis by chondrocytes. Moreover, our study support the existence of a redox dependant loop sustaining pro-catabolic pathways induced by IL-1beta. CONCLUSIONS: This study points out NOX4 as a new putative target in OA and suggests that NOX targeted therapies could be of interest for the causal treatment of the pathology. PMID- 26521745 TI - Relationship between inflammation, the gut microbiota, and metabolic osteoarthritis development: studies in a rat model. AB - Osteoarthritis (OA) may result from intrinsic inflammation related to metabolic disturbance. Obesity-associated inflammation is triggered by lipopolysaccharide (LPS) derived from the gut microbiota. However, the relationship between gut microbiota, LPS, inflammation, and OA remain unclear. OBJECTIVE: To evaluate the associations between gut microbiota, systemic LPS levels, serum and local inflammatory profiles, and joint damage in a high fat/high sucrose diet induced obese rat model. METHODS: 32 rats were randomized to a high fat/high sucrose diet (diet-induced obese (DIO), 40% fat, 45% sucrose, n = 21) or chow diet group (12% fat, 3.7% sucrose n = 11) for 28 weeks. After a 12-week obesity induction period, DIO animals were stratified into Obesity Prone (DIO-P, top 33% by change in body mass, n = 7), and Obesity Resistant groups (DIO-R, bottom 33%, n = 7). At sacrifice, joints were scored using a Modified Mankin Criteria. Blood and synovial fluid analytes, serum LPS, and fecal gut microbiota were analyzed. RESULTS: DIO animals had greater Modified Mankin scores than chow animals (P = 0.002). There was a significant relationship (r = 0.604, p = 0.001) between body fat, but not body mass, and Modified Mankin score. Eighteen synovial fluid and four serum analytes were increased in DIO animals. DIO serum LPS levels were increased compared to chow (P = 0.031). Together, Lactobacillus species (spp.) and Methanobrevibacter spp. abundance had a strong predictive relationship with Modified Mankin Score (r(2) = 0.5, P < 0.001). CONCLUSIONS: Increased OA in DIO animals is associated with greater body fat, not body mass. The link between gut microbiota and adiposity-derived inflammation and metabolic OA warrants further investigation. PMID- 26521744 TI - Catabolic cytokines disrupt the circadian clock and the expression of clock controlled genes in cartilage via an NFkB-dependent pathway. AB - OBJECTIVE: To define how the catabolic cytokines (Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFalpha)) affect the circadian clock mechanism and the expression of clock-controlled catabolic genes within cartilage, and to identify the downstream pathways linking the cytokines to the molecular clock within chondrocytes. METHODS: Ex vivo cartilage explants were isolated from the Cry1-luc or PER2::LUC clock reporter mice. Clock gene dynamics were monitored in real-time by bioluminescence photon counting. Gene expression changes were studied by qRT PCR. Functional luc assays were used to study the function of the core Clock/BMAL1 complex in SW-1353 cells. NFkB pathway inhibitor and fluorescence live-imaging of cartilage were performed to study the underlying mechanisms. RESULTS: Exposure to IL-1beta severely disrupted circadian gene expression rhythms in cartilage. This effect was reversed by an anti-inflammatory drug dexamethasone, but not by other clock synchronizing agents. Circadian disruption mediated by IL-1beta was accompanied by disregulated expression of endogenous clock genes and clock-controlled catabolic pathways. Mechanistically, NFkB signalling was involved in the effect of IL-1beta on the cartilage clock in part through functional interference with the core Clock/BMAL1 complex. In contrast, TNFalpha had little impact on the circadian rhythm and clock gene expression in cartilage. CONCLUSION: In our experimental system (young healthy mouse cartilage), we demonstrate that IL-1beta (but not TNFalpha) abolishes circadian rhythms in Cry1-luc and PER2::LUC gene expression. These data implicate disruption of the chondrocyte clock as a novel aspect of the catabolic responses of cartilage to pro-inflammatory cytokines, and provide an additional mechanism for how chronic joint inflammation may contribute to osteoarthritis (OA). PMID- 26521747 TI - Excitatory amino acid glutamate: role in peripheral nociceptive transduction and inflammation in experimental and clinical osteoarthritis. AB - Although a large proportion of patients with osteoarthritis (OA) show inflammation in their affected joints, the pathological role of inflammation in the development and progression of OA has yet to be clarified. Glutamate is considered an excitatory amino acid (EAA) neurotransmitter in the mammalian central nervous system (CNS). There are cellular membrane glutamate receptors and transporters for signal input modulation and termination as well as vesicular glutamate transporters (VGLUTs) for signal output through exocytotic release. Glutamate been shown to mediate intercellular communications in bone cells in a manner similar to synaptic transmission within the CNS. Glutamate-mediated events may also contribute to the pathogenesis and ongoing processes of peripheral nociceptive transduction and inflammation of experimental arthritis models as well as human arthritic conditions. This review will discuss the differential roles of glutamate signaling and blockade in peripheral neuronal and non-neuronal joint tissues, including bone remodeling systems and their potentials to impact OA-related inflammation and progression. This will serve to identify several potential targets to direct novel therapies for OA. Future studies will further elucidate the role of glutamate in the development and progression of OA, as well as its association with the clinical features of the disease. PMID- 26521746 TI - Intra-articular nerve growth factor regulates development, but not maintenance, of injury-induced facet joint pain & spinal neuronal hypersensitivity. AB - OBJECTIVE: The objective of the current study is to define whether intra articular nerve growth factor (NGF), an inflammatory mediator that contributes to osteoarthritic pain, is necessary and sufficient for the development or maintenance of injury-induced facet joint pain and its concomitant spinal neuronal hyperexcitability. METHOD: Male Holtzman rats underwent painful cervical facet joint distraction (FJD) or sham procedures. Mechanical hyperalgesia was assessed in the forepaws, and NGF expression was quantified in the C6/C7 facet joint. An anti-NGF antibody was administered intra-articularly in additional rats immediately or 1 day following facet distraction or sham procedures to block intra-articular NGF and test its contribution to initiation and/or maintenance of facet joint pain and spinal neuronal hyperexcitability. NGF was injected into the bilateral C6/C7 facet joints in separate rats to determine if NGF alone is sufficient to induce these behavioral and neuronal responses. RESULTS: NGF expression increases in the cervical facet joint in association with behavioral sensitivity after that joint's mechanical injury. Intra-articular application of anti-NGF immediately after a joint distraction prevents the development of both injury-induced pain and hyperexcitability of spinal neurons. Yet, intra-articular anti-NGF applied after pain has developed does not attenuate either behavioral or neuronal hyperexcitability. Intra-articular NGF administered to the facet in naive rats also induces behavioral hypersensitivity and spinal neuronal hyperexcitability. CONCLUSION: Findings demonstrate that NGF in the facet joint contributes to the development of injury-induced joint pain. Localized blocking of NGF signaling in the joint may provide potential treatment for joint pain. PMID- 26521748 TI - Monosodium iodoacetate-induced inflammation and joint pain are reduced in TRPA1 deficient mice--potential role of TRPA1 in osteoarthritis. AB - OBJECTIVES: Intra-articularly injected monosodium iodoacetate (MIA) induces joint pathology mimicking osteoarthritis (OA) and it is a widely used experimental model of OA. MIA induces acute inflammation, cartilage degradation and joint pain. Transient Receptor Potential Ankyrin 1 (TRPA1) is an ion channel known to mediate nociception and neurogenic inflammation. Here, we tested the hypothesis that TRPA1 would be involved in the development of MIA-induced acute inflammation, cartilage changes and joint pain. METHODS: The effects of pharmacological blockade (by TCS 5861528) and genetic depletion of TRPA1 were studied in MIA-induced acute paw inflammation. Cartilage changes (histological scoring) and joint pain (weight-bearing test) in MIA-induced experimental OA were compared between wild type and TRPA1 deficient mice. The effects of MIA were also studied in primary human OA chondrocytes and in mouse cartilage. RESULTS: MIA evoked acute inflammation, degenerative cartilage changes and joint pain in wild type mice. Interestingly, these responses were attenuated in TRPA1 deficient animals. MIA-induced paw inflammation was associated with increased tissue levels of substance P; and the inflammatory edema was reduced by pretreatment with catalase, with the TRPA1 antagonist TCS 5861528 and with the neurokinin 1 receptor antagonist L703,606. In chondrocytes, MIA enhanced interleukin-1 induced cyclooxygenase-2 (COX-2) expression, an effect that was blunted by pharmacological inhibition and genetic depletion of TRPA1. CONCLUSIONS: TRPA1 was found to mediate acute inflammation and the development of degenerative cartilage changes and joint pain in MIA-induced experimental OA in the mouse. The results reveal TRPA1 as a potential mediator and drug target in OA. PMID- 26521749 TI - Mesenchymal stem cells for the management of inflammation in osteoarthritis: state of the art and perspectives. AB - Osteoarthritis (OA) is the most common form of degenerative arthritis, mainly characterized by the degradation of articular cartilage and associated with subchondral bone lesions. Novel therapeutic approaches for OA include cell-based therapies that have become thriving areas of research and development. In this context, mesenchymal stem or stromal cells (MSCs) have gained much interest based on their trophic and immunomodulatory properties that can help tissue repair/regeneration. The present review article discusses the interest of using MSCs in cell-therapy approaches with a focus on the mechanisms by which MSCs might exhibit a therapeutic potential in OA. Special attention is given to the anti-inflammatory function of MSCs and on miRNA modulation in OA for possible future innovative strategies. The paper also presents the current data on the undergoing MSCs-based clinical trials in OA. PMID- 26521750 TI - Early intervention with Interleukin-1 Receptor Antagonist Protein modulates catabolic microRNA and mRNA expression in cartilage after impact injury. AB - OBJECTIVE: The purpose of this controlled laboratory study was to determine the efficacy of Interleukin-1 Receptor Antagonist Protein (IRAP) treatment as an early intervention strategy by examining the changes in microRNA and mRNA expression in cartilage in an ex-vivo porcine knee joint impact model. METHODS: Custom impact device was used to create replicable injury ex-vivo to intact porcine knee joint. Injury was caused by dropping a 10 kg weight one time from 1 m directly above the knee in extension. One hour after impact 20 MUg/ml IRAP solution was intra-articularly injected. At 8 h post-injury, cartilage samples were harvested for cell viability and genetic expression analysis. Genetic expression of miR-27b, miR-140, miR-125b, ADAMTS-4, ADAMTS-5, MMP-3, IL-1beta, and TNF-alpha were analyzed by RT-PCR. Cell viability image analysis was performed using ImageJ software. Groups were compared by analysis of variance (ANOVA) followed by Tukey's post-hoc test. A P-value <0.05 was considered significant. RESULTS: At 8 h after IRAP treatment, expressions of ADAMTS-4, ADAMTS-5, MMP-3, IL-1beta, and TNF-alpha in cartilage were significantly down regulated from injury group (all P < 0.001). MiR-140, miR-125b, and miR-27b expressions were significantly up-regulated after treatment as compared to control and injury groups (all P < 0.001). CONCLUSION: This study demonstrates that IRAP treatment administered during acute phase of cartilage impact injury increases expression levels of miR-140, miR-125b, and miR-27b in cartilage, indicating increased inhibition of their respective matrix-degrading enzymes. Clinically, these findings support the potential of IRAP treatment as an early intervention strategy for the prevention of cartilage degeneration after impact injury. PMID- 26521751 TI - Lack of anti-inflammatory and anti-catabolic effects on basal inflamed osteoarthritic chondrocytes or synoviocytes by adipose stem cell-conditioned medium. AB - OBJECTIVE: To define whether good manufacturing practice (GMP)-clinical grade adipose stem cell (ASC)-derived conditioned medium (CM) is as effective as GMP ASC in modulating inflammatory and catabolic factors released by both osteoarthritis (OA) chondrocytes or synoviocytes. METHODS: OA chondrocytes and synoviocytes were treated with ASC-CM or co-cultured with ASC. Inflammatory factors (IL6, CXCL1/GROalpha,CXCL8/IL8, CCL2/MCP-1, CCL3/MIP-1alpha and CCL5/RANTES) and proteinases, such as metalloproteinase (MMP13), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS4, ADAMTS5) and their tissue metalloproteinase inhibitors (TIMP1, TIMP3) were evaluated by qRT-PCR or immunoassays. The involvement of prostaglandin E2 (PGE2) was also analyzed. RESULTS: Most ASC-CM ratios tested did not decrease IL6, CCL2/MCP-1, CCL3/MIP1 alpha, CCL5/RANTES on basal inflamed chondrocytes or synoviocytes in contrast to what we found using ASC in co-culture. CXCL8/IL8 and CXCL1/GROalpha were not decreased by ASC-CM on synoviocytes but were only partially reduced on chondrocytes. Moreover, ASC-CM was less efficient both on basal inflamed OA chondrocytes and synoviocytes in reducing proteinases, such as MMP13, ADAMTS4, ADAMTS5 and increasing TIMP1 and TIMP3 compared to ASC in co-culture. The different ratios of ASC-CM contain lower amounts of PGE2 which were not sufficient to reduce inflammatory factors. CONCLUSIONS: These data show that ASC CM has a limited ability to decrease inflammatory and proteinases factors produced by OA chondrocytes or synoviocytes. ASC-CM is not sufficient to recapitulate the beneficial effect demonstrated using ASC in co-culture with inflamed OA chondrocytes and synoviocytes and shows that their use in clinical trials is fundamental to counteract OA progression. PMID- 26521752 TI - Evaluation of corneal biomechanical properties using an ocular response analyser to examine aphakic and pseudophakic patients after congenital cataract surgery. AB - PURPOSE: We evaluated corneal biomechanical properties in aphakic and pseudophakic patients after congenital cataract surgery and compared the data with those of age-matched normal subjects. METHODS: We included 43 eyes of 43 aphakic or pseudophakic patients treated via congenital cataract surgery. As controls, 42 healthy age- and sex-matched subjects were enrolled. After a complete ophthalmic examination, central corneal thickness (CCT) and intraocular pressure (IOP) were determined. Corneal hysteresis (CH), corneal resistance factor (CRF), corneal-compensated IOP (IOPcc) and Goldmann-correlated IOP (IOPg) were recorded using an ocular response analyser. RESULTS: In the study group, 18 eyes were aphakic and 25 eyes pseudophakic. We found a significant difference in CCT between the aphakic, pseudophakic and control groups (p < 0.001). No significant among-group differences were detected in CH or CRF (p > 0.05). We found significant differences in IOPcc, IOPg and IOP measured with Goldmann applanation tonometry (IOPGAT ) between the study and control groups (p < 0.001). In contrast, we found no significant differences within the two study groups in terms of these three IOP values (p > 0.05). CONCLUSION: Although CCT increased after congenital cataract surgery, corneal biomechanical parameters, including CH and the CRF, were not affected by such surgery. Determination of the IOPcc did not provide any additional information on true IOP, which was independent of CCT in both aphakic and pseudophakic patients after congenital cataract surgery. PMID- 26521753 TI - Factors associated with the internal jugular venous approach for MelodyTM Transcatheter Pulmonary Valve implantation. AB - BACKGROUND: Transcatheter pulmonary valve implantation is usually performed from a femoral venous - transfemoral - approach, but this may not be the optimal vascular access option in some patients. This study aimed to determine which group of patients might benefit from an internal jugular - transjugular - approach for transcatheter pulmonary valve implantation. METHODS: This multicentre retrospective study included all patients who underwent attempted transcatheter pulmonary valve placement in the right ventricular outflow tract between April 2010 and June 2012 at two large congenital heart centres. Patients were divided into two groups based on venous access site - transfemoral or transjugular. Patient characteristics, procedural outcomes, and complications were compared between groups. RESULTS: Of 81 patients meeting the inclusion criteria (median age 16.4 years), the transjugular approach was used in 14 patients (17%). The transjugular group was younger (median age 11.9 versus 17.3 years), had lower body surface area (mean 1.33 versus 1.61 m2), more often had moderate or greater tricuspid regurgitation (29% versus 7%), and had a higher ratio of right ventricle-to-systemic systolic pressure (mean 82.4 versus 64.7). Patients requiring a transjugular approach after an unsuccessful transfemoral approach had longer fluoroscopic times and procedure duration. CONCLUSIONS: The transjugular approach for transcatheter pulmonary valve implantation is used infrequently but is more often used in younger and smaller patients. Technical limitations from a transfemoral approach may be anticipated if there is moderate or greater tricuspid regurgitation or higher right ventricular pressures. In these patients, a transjugular approach should be considered early. PMID- 26521754 TI - An open randomized controlled clinical trial to evaluate ridge preservation and repair using SocketKAP(TM) and SocketKAGE(TM) : part 1-three-dimensional volumetric soft tissue analysis of study casts. AB - OBJECTIVES: The aims of this study were to evaluate (i) the efficacy of ridge preservation and repair involving SocketKAP(TM) and SocketKAGE(TM) devices following tooth removal; and (ii) ridge contour changes at 6 months post extraction in intact sockets and sockets with dehiscence defects. MATERIAL AND METHODS: Thirty-six patients required a total of 61 teeth to be extracted. Five cohorts were established with groups A-C involving intact sockets and groups D and E involving facial dehiscence: (A) Negative Control; (B) SocketKAP(TM) alone; (C) Anorganic Bovine Bone Mineral (ABBM) + SocketKAP(TM) ; (D) Negative Control; and (E) ABBM + SocketKAP(TM) + SocketKAGE(TM) . Preoperative CBCT and laser scanned casts were obtained. Teeth segmented from preoperative CBCT were merged with study cast images to allow for digital removal of teeth from the casts. Volumetric measurements of ridge contour were performed. Images of preoperative and 6 months post-operative casts were superimposed to measure ridge contour changes. RESULTS: Post-extraction contour loss occurred in all sockets primarily in the crestal 3 mm but was also detected up to 6 mm from alveolar crest. For intact sockets, SocketKAP(TM) or SocketKAP(TM) + ABBM interventions led to greater percentages of remaining ridge contour when compared to controls. A significant difference favoring SocketKAP(TM) + SocketKAGE(TM) + ABBM treatment was observed for sockets with facial dehiscence when compared to controls. CONCLUSION: SocketKAP(TM) , with or without ABBM, significantly limited post extraction ridge contour loss in intact sockets. In the absence of a group treated with only the SocketKAGE(TM) , it is not possible to determine its efficacy, although the combination of SocketKAGE(TM) + SocketKAP(TM) + ABBM was effective in limiting post-extraction ridge contour loss in sockets with dehiscence defects. PMID- 26521755 TI - Three-dimensional regional displacement after surgical-orthodontic correction of Class III malocclusion. AB - OBJECTIVES: To investigate how displacements of maxillo-mandibular structures are associated with each other at splint removal and 1 year post-surgery following 1 jaw and 2-jaw surgeries for correction of Class III malocclusion. SETTING AND SAMPLE POPULATION: Fifty patients who underwent surgical correction with maxillary advancement only (n = 25) or combined with mandibular setback (n = 25) were prospectively enrolled in this study. METHODS: Cone-beam computed tomographies were taken pre-surgery, at splint removal and at 1 year post surgery. Three-dimensional cranial base superimpositions and shape correspondence were used to measure the outcomes from pre-surgery to splint removal (surgical changes) and splint removal to 1 year post-surgery (post-surgical adaptations). Pearson's correlation coefficients were used to evaluate the association between the regional displacements. RESULTS: Both surgery groups presented mandibular clockwise rotation with surgery and post-surgical adaptive counterclockwise rotation. In patients treated with maxillary advancement only, the surgical changes of the maxilla were significantly correlated with chin changes. The amount and direction of chin autorotation were significantly correlated with right and left ramus autorotation. Right and left condylar displacements were significantly correlated. One year post-surgery, adaptive displacements and bone remodeling of both rami were correlated with the chin and condylar changes. For the 2-jaw group, the few correlations between the positional and remodeling changes in the anatomic regions of interest observed due to the surgery were different than those observed after post-surgical adaptations, suggesting that these changes occurred independently. CONCLUSION: Our results indicate that surgical displacements and post-surgical adaptations are often correlated in one jaw surgery and are, in general, independent in two-jaw surgery. PMID- 26521756 TI - Is carbamazepine a human teratogen? AB - The foetal outcomes of 2,635 pregnancies recorded in the Australian Pregnancy Register were studied. In at least the initial 4months of 515 pregnancies, there had been no intrauterine exposure to antiepileptic drugs, though the women involved in 264 of these pregnancies took antiepileptic drugs in later pregnancies. Compared with these 515 drug-unexposed pregnancies, foetal malformations risks were increased more than five-fold in association with valproate monotherapy, and more than doubled in association with carbamazepine monotherapy (p<0.05). There were no statistically significant increases in malformation rates associated with other more commonly used antiepileptic drugs, while the malformation risk in relation to levetiracetam exposure was lower than that in the drug-unexposed pregnancies. The published literature has rather consistently shown raised malformation rates associated with carbamazepine monotherapy, though only once was it statistically significant. There now appears to be enough evidence to make it likely that carbamazepine possesses some teratogenic capacity. This makes it unwise to employ the malformation rate associated with carbamazepine monotherapy as a comparator when assessing the foetal hazards from exposure to newer antiepileptic drugs. Levetiracetam may prove a better comparator if adequate untreated control material is unobtainable. PMID- 26521757 TI - Motor neurone disease in Lancashire and South Cumbria in North West England and an 8 year experience with enteral nutrition. AB - Motor neurone disease (MND) is a fatal neurodegenerative disease of unknown aetiology. Malnutrition is a common occurrence and an independent risk factor for worse prognosis. However, it remains unclear whether provision of enteral nutrition (EN) through a gastrostomy tube offers any survival advantage. Our aim was to describe the demographic and clinical characteristics of MND in Lancashire and South Cumbria in North West England and the impact of EN on survival in the 8 year period of 2005-2012. Four hundred and seven patients with MND were identified through the Preston MND care and research centre registry giving a crude incidence rate of 3.15/100,000. Three hundred and forty patients with adequate information were included in the final analysis of whom 53.2% were male. The presentation was limb/spinal in 62.1% and bulbar in 37.9% of patients, bulbar onset being more common in elderly females. Mean age of onset was 67.28 years (standard deviation 11.06; range 22.78-93.06). Median survival was 1.98 years (range 1.18-3.05). Ninety-one patients received EN of whom 67% had bulbar onset disease. EN was not associated with a statistically significant survival advantage except for the subgroup who received EN more than 500 days after symptom onset. In conclusion, the early requirement for EN may indicate a prognostically less favourable subgroup. PMID- 26521758 TI - Pharmacology of the cell/matrix form of adhesion. AB - Cell adhesions are heterogeneous processes including two main forms, CAM and cell/matrix forms. Both these forms induce the interaction among cells and with the extracellular matrix, and the generation of intracellular signals. The signaling of the two adhesion forms include, at the cell surface, involvement of distinct integrins, necessary for intracellular cascade activation. I will focus on the cell/integrin form based on two specific integrins, alpha5beta1 (the most important) and alphavbeta3, activated by the preferential binding of fibronectin, a unique extracellular matrix protein. Such binding induces local assembly of stratified adhesion complexes containing protein kinases, that trigger the intracellular signaling cascades (Akt, ERK and others); proteins that sustain mechanical processes; and proteins associated with the cytoskeleton. In view of its role in several diseases, from cancers to the eye macular-degeneration; from brain neurodegeneration to fibroses, the pharmacological interest for the cell/integrin adhesion has grown, and presumably will further grow in the near future. The agents identified and developed for therapy include antibodies, many peptides and chemical drugs against alpha5beta1 integrin; drugs against fibronectin and metalloproteinases 2/9, responsible of the latter enzyme proteolysis; anti-kinase and anti-cascade drugs, some of which targeted to the activation of transcription factors and/or their transfer to the nucleus, with repression or activation of gene expression. A new perspective, based on the investigation of both animal models and human patients, includes factors active on the cell/matrix and CAM adhesions, considered separately or coordinately in distinct therapeutic approaches, integrated or not with classical chemotherapic treatments. PMID- 26521760 TI - Socioeconomic status and cardiovascular health in the changing world. PMID- 26521759 TI - Sarcolipin is a novel regulator of muscle metabolism and obesity. AB - Obesity is increasing at an alarming rate, both in adults and adolescents, across the globe due to increased consumption of caloric rich diet. Obesity and its associated complications appear to be major contributing factors not only to diabetes/heart disease but also to cancer, and neurological diseases causing a huge burden on the health care system. To date, there are no effective treatments to reduce weight gain, other than caloric restriction and exercise which are often difficult to enforce. There are very few drugs available for treating obesity and those that are available only reduce obesity by ~ 10%. Identifying mechanisms to increase energy expenditure, on top of the increase elicited by exercise, would be more beneficial to control weight gain. The purpose of this review is to highlight the role of sarcolipin (SLN), a regulator of SERCA pump, in muscle thermogenesis and metabolism. We will further discuss if enhancing SLN activity could be an effective mechanism to increase energy expenditure and control weight gain. We will also discuss the merits of adaptive thermogenesis in muscle and brown fat as potential mechanisms to increase energy expenditure during caloric overload. That said, there is still a great need for further research into the mechanism of diet induced thermogenesis and its relevance to overall metabolism and obesity. PMID- 26521761 TI - EuroSCORE II, is its predictive capacity influenced by the patient's risk profile. PMID- 26521762 TI - Can ivabradine reduce NT-proBNP and improve outcomes in systolic heart failure? PMID- 26521763 TI - When prevention is a risk. More is not always better. PMID- 26521764 TI - Using the rd1 mouse to understand functional and anatomical retinal remodelling and treatment implications in retinitis pigmentosa: A review. AB - Retinitis Pigmentosa (RP) reflects a range of inherited retinal disorders which involve photoreceptor degeneration and retinal pigmented epithelium dysfunction. Despite the multitude of genetic mutations being associated with the RP phenotype, the clinical and functional manifestations of the disease remain the same: nyctalopia, visual field constriction (tunnel vision), photopsias and pigment proliferation. In this review, we describe the typical clinical phenotype of human RP and review the anatomical and functional remodelling which occurs in RP determined from studies in the rd/rd (rd1) mouse. We also review studies that report a slowing down or show an acceleration of retinal degeneration and finally we provide insights on the impact retinal remodelling may have in vision restoration strategies. PMID- 26521765 TI - Long time remodeling during retinal degeneration evaluated by optical coherence tomography, immunocytochemistry and fundus autofluorescence. AB - PURPOSE: To characterize the relationship between fundus autofluorescence (FAF), Optical Coherence Tomography (OCT) and immunohistochemistry (IHC) over the course of chronic retinal degeneration in the P23H rat. METHODS: Homozygous albino P23H rats, Sprague-Dawley (SD) rats as controls and pigmented Long Evans (LE) rats were used. A Spectralis HRA OCT system was used for scanning laser ophthalmoscopy (SLO) imaging OCT and angiography. To determine FAF, fluorescence was excited using diode laser at 488 nm. A fast retina map OCT was performed using the optic nerve as a landmark. IHC was performed to correlate with the findings of OCT and FAF changes. RESULTS: During the course of retinal degeneration, the FAF pattern evolved from some spotting at 2 months old to a mosaic of hyperfluorescent dots in rats 6 months and older. Retinal thicknesses progressively diminished over the course of the disease. At later stages of degeneration, OCT documented changes in the retinal layers, however, IHC better identified the cell loss and remodeling changes. Angiography revealed attenuation of the retinal vascular plexus with time. CONCLUSION: We provide for the first time a detailed long-term analysis of the course of retinal degeneration in P23H rats using a combination of SLO and OCT imaging, angiography, FAF and IHC. Although, the application of noninvasive methods enables longitudinal studies and will decrease the number of animals needed for a study, IHC is still an essential tool to identify retinal changes at the cellular level. PMID- 26521766 TI - Cost Accounting as a Tool for Increasing Cost Transparency in Selective Hepatic Transarterial Chemoembolization. AB - PURPOSE: To increase cost transparency and uncover potential areas for savings in patients receiving selective transarterial chemoembolization at a tertiary care academic center. MATERIALS AND METHODS: The hospital cost accounting system charge master sheet for direct and total costs associated with selective transarterial chemoembolization in fiscal years 2013 and 2014 was queried for each of the four highest volume interventional radiologists at a single institution. There were 517 cases (range, 83-150 per physician) performed; direct costs incurred relating to care before, during, and after the procedure with respect to labor, supply, and equipment fees were calculated. RESULTS: A median of 48 activity codes were charged per selective transarterial chemoembolization from five cost centers, represented by the angiography suite, units for care before and after the procedure, pharmacy, and observation floors. The average direct cost of selective transarterial chemoembolization did not significantly differ among operators at $9,126.94, $8,768.77, $9,027.33, and $8,909.75 (P = .31). Intraprocedural costs accounted for 82.8% of total direct costs and provided the greatest degree in cost variability ($7,268.47-$7,691.27). The differences in intraprocedural expense among providers were not statistically significant (P = .09), even when separated into more specific procedure-related labor and supply costs. CONCLUSIONS: Cost accounting systems could effectively be interrogated as a method for calculating direct costs associated with selective transarterial chemoembolization. The greatest source of expenditure and variability in cost among providers was shown to be intraprocedural labor and supplies, although the effect did not appear to be operator dependent. PMID- 26521767 TI - A time-efficient web-based teaching tool to improve medical knowledge and decrease ABIM failure rate in select residents. AB - AIM: The American Board of Internal Medicine (ABIM) exam's pass rate is considered a quality measure of a residency program, yet few interventions have shown benefit in reducing the failure rate. We developed a web-based Directed Reading (DR) program with an aim to increase medical knowledge and reduce ABIM exam failure rate. METHODS: Internal medicine residents at our academic medical center with In-Training Examination (ITE) scores <= 35 th percentile from 2007 to 2013 were enrolled in DR. The program matches residents to reading assignments based on their own ITE-failed educational objectives and provides direct electronic feedback from their teaching physicians. ABIM exam pass rates were analyzed across various groups between 2002 and 2013 to examine the effect of the DR program on residents with ITE scores <= 35 percentile pre- (2002-2006) and post-intervention (2007-2013). A time commitment survey was also given to physicians and DR residents at the end of the study. RESULTS: Residents who never scored <= 35 percentile on ITE were the most likely to pass the ABIM exam on first attempt regardless of time period. For those who ever scored <= 35 percentile on ITE, 91.9% of residents who participated in DR passed the ABIM exam on first attempt vs 85.2% of their counterparts pre-intervention (p < 0.001). This showed an improvement in ABIM exam pass rate for this subset of residents after introduction of the DR program. The time survey showed that faculty used an average of 40+/-18 min per week to participate in DR and residents required an average of 25 min to search/read about the objective and 20 min to write a response. CONCLUSIONS: Although residents who ever scored <= 35 percentile on ITE were more likely to fail ABIM exam on first attempt, those who participated in the DR program were less likely to fail than the historical control counterparts. The web-based teaching method required little time commitment by faculty. PMID- 26521768 TI - Chronic fatigue syndrome: what is it and how to treat? PMID- 26521769 TI - Can neuroimaging be used to predict the onset of psychosis? AB - The onset of psychotic disorders is preceded by a high-risk phase characterised by attenuated or brief psychotic symptoms and a marked decline in functioning. About a third of individuals presenting with these features develop a psychotic disorder within 3 years. A fundamental challenge in the clinical management of this population is that it is not possible to predict whether an individual at high risk will go on to develop psychosis on the basis of their presenting features. Consequently, preventive interventions that might reduce the risk of progression to psychosis cannot be selectively offered to those patients for whom they would be most useful. However, neuroimaging investigation suggests that the structure, function, and chemistry of the brain in high-risk individuals who become psychotic differ from those in individuals who do not become psychotic. In this Personal View, we review these findings and discuss the main challenges for translating them into clinical practice. The development of techniques that allow clinicians to tailor interventions to the level of risk is a major translational goal for research in this field. PMID- 26521770 TI - Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial. AB - BACKGROUND: The PACE trial found that, when added to specialist medical care (SMC), cognitive behavioural therapy (CBT), or graded exercise therapy (GET) were superior to adaptive pacing therapy (APT) or SMC alone in improving fatigue and physical functioning in people with chronic fatigue syndrome 1 year after randomisation. In this pre-specified follow-up study, we aimed to assess additional treatments received after the trial and investigate long-term outcomes (at least 2 years after randomisation) within and between original treatment groups in those originally included in the PACE trial. METHODS: The PACE trial was a parallel-group randomised controlled trial of patients meeting Oxford criteria for chronic fatigue syndrome who were recruited from six secondary care clinics in the UK between March 18, 2005, and Nov 28, 2008. Participants were randomly allocated to receive SMC alone or plus APT, CBT, or GET. Primary outcomes (were fatigue measured with Chalder fatigue questionnaire score and physical functioning with short form-36 subscale score, assessed 1 year after randomisation. In this long-term follow-up, we sent postal questionnaires to assess treatment received after the trial and outcomes a minimum of 2 years after randomisation. We assessed long-term differences in outcomes within and between originally randomised groups. The PACE trial is registered at http://isrctn.org, number ISRCTN54285094. FINDINGS: Between May 8, 2008, and April 26, 2011, 481 (75%) participants from the PACE trial returned questionnaires. Median time from randomisation to return of long-term follow-up assessment was 31 months (IQR 30 32; range 24-53). 210 (44%) participants received additional treatment (mostly CBT or GET) after the trial; with participants originally assigned to SMC alone (73 [63%] of 115) or APT (60 [50%] of 119) more likely to seek treatment than those originally assigned to GET (41 [32%] of 127) or CBT (36 [31%] of 118; p<0.0001). Improvements in fatigue and physical functioning reported by participants originally assigned to CBT and GET were maintained (within-group comparison of fatigue and physical functioning, respectively, at long-term follow up as compared with 1 year: CBT -2.2 [95% CI -3.7 to -0.6], 3.3 [0.02 to 6.7]; GET -1.3 [-2.7 to 0.1], 0.5 [-2.7 to 3.6]). Participants allocated to APT and to SMC alone in the trial improved over the follow-up period compared with 1 year (fatigue and physical functioning, respectively: APT -3.0 [-4.4 to -1.6], 8.5 [4.5 to 12.5]; SMC -3.9 [-5.3 to -2.6], 7.1 [4.0 to 10.3]). There was little evidence of differences in outcomes between the randomised treatment groups at long-term follow-up. INTERPRETATION: The beneficial effects of CBT and GET seen at 1 year were maintained at long-term follow-up a median of 2.5 years after randomisation. Outcomes with SMC alone or APT improved from the 1 year outcome and were similar to CBT and GET at long-term follow-up, but these data should be interpreted in the context of additional therapies having being given according to physician choice and patient preference after the 1 year trial final assessment. Future research should identify predictors of response to CBT and GET and also develop better treatments for those who respond to neither. FUNDING: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions, National Institute for Health Research (NIHR), NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust, King's College London. PMID- 26521771 TI - AMPK Function in Aging Process. AB - Aging involves the progressive deterioration of physiological functions, diminishing the individual's capacity for survival. Indeed, aging is the main risk factor for cancer, diabetes, cardiovascular disorders and neurodegenerative diseases. The discovery that the rate of aging is controlled by conserved genetic and biochemical pathways represented an unprecedented advance in aging research. The AMPK protein is a metabolic sensor that acts as a qualified cellular housekeeper, as well as controlling energy homeostasis and resistance to stress. Thus, the correct regulation of this factor enhances health and survival. In this manuscript we will review the molecular pathways regulated by AMPK that are related to the aging process, paying special attention to mitochondrial dysfunction, metabolic deregulation, cell senescence and autophagy. PMID- 26521772 TI - Editorial: New Therapies, Markers and Therapeutic Targets in HCV Chronic Infection and HCV Extrahepatic Manifestations. AB - More than 180 millions of subjects in the world are infected by Hepatitis C Virus (HCV), and about 20% of them with HCV chronic infection progress to cirrhosis. Furthermore, numerous HCV extrahepatic manifestations have been reported in up to 74% of patients, as mixed cryoglobulinemia, lymphomas, rheumatic disorders, autoimmune thyroiditis, hypothyroidism, papillary thyroid cancer, and type 2 diabetes. Advances in understanding the HCV life cycle, and the inflammatory processes (involving a complex network of cytokines and chemokines) associated with HCV chronic infection, have led to substantial advancements in therapy. The combination of ribavirin and PEGylated interferon-alpha was the standard of therapy for HCV chronically infected patients in the last decades. However, interferon has limited effectiveness and is associated with severe adverse effects. Recently, direct-acting antivirals (DAAs) that act as inhibitors of N5SA, or polymerase, or protease have been shown to result in shorter duration of therapy, better efficacy and tolerance, with respect to ribavirin and PEGylated interferon-alpha. Circulating CXCL10 levels, and the interleukin(IL)-28B gene polymorphisms, are associated with the success of the therapy both with DAAs or ribavirin and PEGylated interferon-alpha. New DAAs targeting the HCV at various molecular levels have been developed to eradicate HCV. Moving to interferonfree therapies should offer new treatments for resistant HCV genotypes, and for ineligible patients or patients failing to respond to prior therapies. Many efforts have been made to understand the factors that are involved with clearance of HCV to personalize the therapy for each patient, with the aim to reduce side effects, increasing the sustained virologic response rate, and to prevent the progression of the disease. PMID- 26521773 TI - Chemical Structure Similarity Search for Ligand-based Virtual Screening: Methods and Computational Resources. AB - For many years the assumption that "Chemical compounds with similar structures may have similar activities" has been a foundation for lead identification. The similarity can be computed based upon topological, steric, electronic, and/or physical properties. The chemical structure similarity search differs from the chemical substructure search in that the former requires assessment of the properties of each compound and thus no filter can be applied for skipping structures before they are assessed to accelerate the computation. The latter can be accelerated by pre-screening compounds and omitting those that miss one (or more) specified fragments from the query. Moreover, three-dimensional similarity search requires superimposing many conformation pairs for each compound in the library. This makes 3-D similarity search algorithms time-consuming, and in general requires high performance computing (HPC) resources. This review will summarize recent progress in the techniques for HPC-supported two and three dimensional chemical structure similarity search algorithms, and their applications in ligand-based virtual screening. PMID- 26521774 TI - Multi-Target Mining of Alzheimer Disease Proteome with Hansch's QSBR-Perturbation Theory and Experimental-Theoretic Study of New Thiophene Isosters of Rasagiline. AB - Hansch's model is a classic approach to Quantitative Structure-Binding Relationships (QSBR) problems in Pharmacology and Medicinal Chemistry. Hansch QSAR equations are used as input parameters of electronic structure and lipophilicity. In this work, we perform a review on Hansch's analysis. We also developed a new type of PT-QSBR Hansch's model based on Perturbation Theory (PT) and QSBR approach for a large number of drugs reported in CheMBL. The targets are proteins expressed by the Hippocampus region of the brain of Alzheimer Disease (AD) patients. The model predicted correctly 49312 out of 53783 negative perturbations (Specificity = 91.7%) and 16197 out of 21245 positive perturbations (Sensitivity = 76.2%) in training series. The model also predicted correctly 49312/53783 (91.7%) and 16197/21245 (76.2%) negative or positive perturbations in external validation series. We applied our model in theoretical-experimental studies of organic synthesis, pharmacological assay, and prediction of unmeasured results for a series of compounds similar to Rasagiline (compound of reference) with potential neuroprotection effect. PMID- 26521776 TI - Postoperative Approach for Crohn's Disease: The Right Therapy to the Right Patient. AB - BACKGROUND: Recurrence is a common event after surgical resections secondary to Crohn's disease (CD). Endoscopic signs of inflammation, defined as postoperative endoscopic recurrence (PER) occur in up to 90% of the patients after one year. PER precedes clinical recurrence and further need for reoperations due to consequent bowel damage. Therefore, controlling inflammation after surgery in a preventive way is essential for disease control. OBJECTIVE: to review data regarding PER in CD, and demonstrate algorithms for its management after surgery. RESULTS: There is no fixed strategy to prevent recurrence after surgery in CD. There are several risk factors that must be taken into consideration to guide physicians to choose the best therapeutic agents and strategies in this scenario. In this review, the authors describe in details the stratification based on risk factors, the therapeutic agents mostly used to prevent recurrence and discuss the several options for the postoperative management in CD. CONCLUSIONS: No fixed strategy is recommended after surgical resections in CD. Thus, the need for a personalized approach for each patient is emphasized, in accordance with several conditions and variables. PMID- 26521777 TI - Trends in Nanomaterials and Processing for Drug Delivery of Polyphenols in the Treatment of Cancer and Other Therapies. AB - For decades polyphenols have been considered to be sound, naturally occurring therapeutic compounds. While there are several polyphenols with special applications used in the treatment of cancer and other diseases, they need a specific carrier in order to reach the cells targeted for treatment. Recently, a number of new technologies have been developed on a nanoscale, such as nanoparticles, nanocapsules and nanofibers that can provide targeted delivery of polyphenols for medical purposes. This work summarizes the current trends in nanoscale delivery technology for polyphenols in cancer treatment and outlines its capabilities and the significant improvements that have been made. Special emphasis is given to the materials and to the manufacturing processes used to produce these kinds of drug delivery system nanostructures. PMID- 26521778 TI - Innovations in Orthopedics and Traumatology in China. PMID- 26521775 TI - Adenosine Monophosphate-activated Protein Kinase (AMPK) Activators For the Prevention, Treatment and Potential Reversal of Pathological Pain. AB - Pathological pain is an enormous medical problem that places a significant burden on patients and can result from an injury that has long since healed or be due to an unidentifiable cause. Although treatments exist, they often either lack efficacy or have intolerable side effects. More importantly, they do not reverse the changes in the nervous system mediating pathological pain, and thus symptoms often return when therapies are discontinued. Consequently, novel therapies are urgently needed that have both improved efficacy and disease-modifying properties. Here we highlight an emerging target for novel pain therapies, adenosine monophosphate-activated protein kinase (AMPK). AMPK is capable of regulating a variety of cellular processes including protein translation, activity of other kinases, and mitochondrial metabolism, many of which are thought to contribute to pathological pain. Consistent with these properties, preclinical studies show positive, and in some cases disease-modifying effects of either pharmacological activation or genetic regulation of AMPK in models of nerve injury, chemotherapy-induced peripheral neuropathy (CIPN), postsurgical pain, inflammatory pain, and diabetic neuropathy. Given the AMPK-activating ability of metformin, a widely prescribed and well-tolerated drug, these preclinical studies provide a strong rationale for both retrospective and prospective human pain trials with this drug. They also argue for the development of novel AMPK activators, whether orthosteric, allosteric, or modulators of events upstream of the kinase. Together, this review will present the case for AMPK as a novel therapeutic target for pain and will discuss future challenges in the path toward development of AMPK-based pain therapeutics. PMID- 26521779 TI - Prevalence of Nontraumatic Osteonecrosis of the Femoral Head and its Associated Risk Factors in the Chinese Population: Results from a Nationally Representative Survey. AB - BACKGROUND: Nontraumatic osteonecrosis of the femoral head (NONFH) is a debilitating disease that represents a significant financial burden for both individuals and healthcare systems. Despite its significance, however, its prevalence in the Chinese general population remains unknown. This study aimed to investigate the prevalence of NONFH and its associated risk factors in the Chinese population. METHODS: A nationally representative survey of 30,030 respondents was undertaken from June 2012 to August 2013. All participants underwent a questionnaire investigation, physical examination of hip, and bilateral hip joint X-ray and/or magnetic resonance imaging examination. Blood samples were taken after overnight fasting to test serum total cholesterol, triglyceride, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels. We then used multivariate logistic regression analysis to investigate the associations between various metabolic, demographic, and lifestyle-related variables and NONFH. RESULTS: NONFH was diagnosed in 218 subjects (0.725%) and the estimated NONFH cases were 8.12 million among Chinese people aged 15 years and over. The prevalence of NONFH was significantly higher in males than in females (1.02% vs. 0.51%, chi2 = 24.997, P < 0.001). Among NONFH patients, North residents were subjected to higher prevalence of NONFH than that of South residents (0.85% vs. 0.61%, chi 2 = 5.847, P = 0.016). Our multivariate regression analysis showed that high blood levels of triglycerides, total cholesterol, LDL-cholesterol, and non-HDL-cholesterol, male, urban residence, family history of osteonecrosis of the femoral head, heavy smoking, alcohol abuse and glucocorticoid intake, overweight, and obesity were all significantly associated with an increased risk of NONFH. CONCLUSIONS: Our findings highlight that NONFH is a significant public health challenge in China and underscore the need for policy measures on the national level. Furthermore, NONFH shares a number of risk factors with atherosclerosis. PMID- 26521780 TI - Surgical Fixation of Fourth and Fifth Metacarpal Shaft Fractures with Flexible Intramedullary Absorbable Rods: Early Clinical Outcomes and Implications. AB - BACKGROUND: To avoid the irritation of tendons and soft tissues as well as hardware-related problems, we designed an intramedullary fixation with bioabsorbable rods for the treatment of the metacarpal shaft fractures. METHODS: Five patients with nine shaft fractures of the fourth and fifth metacarpi were treated with intramedullary absorbable implants and followed up with an average of 4.2 months postoperatively. RESULTS: At final follow-up, all patients achieved fracture union with no signs of inflammatory or subcutaneous effusion. There was no shortening, angulatory, or rotatory deformity. There was almost full active extension range of motion (ROM) of the metacarpophalangeal joints while the active flexion ROM of these joints was 80.7 +/- 9.6 degrees . Compared with the contralateral hand, the grip strength of the injured hand was 94.0 +/- 9.6%. X rays showed that the arch of the second to fifth metacarpal heads was smooth. There were no intramedullary lytic changes and soft tissue swellings. CONCLUSION: The intramedullary absorbable implants are a safe, simple, and practical treatment for fourth and fifth metacarpal fractures with good early clinical outcomes and no significant complications. PMID- 26521781 TI - Four Methods for Calculating Blood-loss after Total Knee Arthroplasty. AB - BACKGROUND: Currently, various calculation methods for evaluating blood-loss in patients with total knee arthroplasty (TKA) are applied in clinical practice. However, different methods may yield different results. The purpose of this study was to determine the most reliable method for calculating blood-loss after primary TKA. METHODS: We compared blood-loss in 245 patients who underwent primary unilateral TKA from February 2010 to August 2011. We calculated blood loss using four methods: Gross equation, hemoglobin (Hb) balance, the Orthopedic Surgery Transfusion Hemoglobin European Overview (OSTHEO) formula, and Hb dilution. We determined Pearson's correlation coefficients for the four methods. RESULTS: There were large differences in the calculated blood-loss obtained by the four methods. In descending order of combined correlation coefficient based on calculated blood-loss, the methods were Hb-balance, OSTHEO formula, Hb dilution, and Gross equation. CONCLUSIONS: The Hb-balance method may be the most reliable method of estimating blood-loss after TKA. PMID- 26521782 TI - Clinical Outcomes and Risks of Single-stage Bilateral Unicompartmental Knee Arthroplasty via Oxford Phase III. AB - BACKGROUND: Osteoarthritis often affects the joint bilaterally, and the single stage (SS) unicompartmental knee arthroplasty (UKA) is advantageous in terms of a single anesthesia administration, a short hospital stay, lower medical costs, and enhanced patient convenience. However, the complication risk of SS UKA continues to be debated. The aim of this article was to evaluate the clinical effectiveness, complications, and functional recovery of SS and two-stage (TS) UKA. METHODS: From January 2008 to December 2013, we compared a series of 36 SS UKA with 45 TS UKA for osteoarthritis. The mean age was 65.4 years (range: 55-75 years). The mean body mass index was 25.2 kg/m 2 (range: 22-29 kg/m 2 ). The pre- and post-operative Oxford Knee Scores (OKSs), complications, operative times, tourniquet times, the amount of drainage, and hemoglobin (Hb) were evaluated. The Chi-square test, Fisher's exact test, and paired and grouped t-tests were used in this study. RESULTS: The mean follow-up was 50 months. No complications of death, fat embolism, deep vein thrombosis, and prosthetic infection were reported. Patients who underwent SS UKA had a shorter cumulative anesthesia time (113.5 vs. 133.0 min, P < 0.01). There were no significant variations between the values of the mean tourniquet time, the amount of drainage, pre- and post-operative Hb in the different groups. No patient required a blood transfusion. No statistical differences were found in the complications between two groups (P > 0.05). At the final follow-up, the mean OKS improved from 39.48 +/- 5.69 to 18.83 +/- 3.82 (P < 0.01), with no statistical differences between the two groups (P > 0.05). Patients who underwent SS UKA had a faster recovery. CONCLUSIONS: The single staged UKA offers the benefits of a single anesthesia administration, reduced total anesthetic time, decreased overall rehabilitation time, and absence of an increase in perioperative mortality or complications compared with the TS bilateral UKA. PMID- 26521783 TI - Effect of Joint Line Elevation after Posterior-stabilized and Cruciate-retaining Total Knee Arthroplasty on Clinical Function and Kinematics. AB - BACKGROUND: Joint line (JL) is a very important factor for total knee arthroplasty (TKA) to restore. The objective of this study was to evaluate the early clinical and kinematic results of TKAs with posterior-stabilized (PS) or cruciate retaining (CR) implants in which the JL was elevated postoperatively. METHODS: Data were collected from patients who underwent TKA in our department between April 2011 and April 2014. The patients were divided into two groups based on the prosthesis they received (PS or CR). At 1-year postoperatively, clinical outcomes were evaluated by the American Knee Society (AKS) knee score, AKS function score, and patella score. In vivo kinematic analysis after TKA was performed on all patients and a previously validated three-dimensional to two dimensional image registration technique was used to obtain the kinematic data. Anteroposterior (AP) translation of the medial and lateral femoral condyles, and axial rotation relative to the tibial plateau, were analyzed. The data were assessed using the Mann-Whitney test. RESULTS: At time of follow-up, there were differences in the AKS knee scores (P = 0.005), AKS function scores (P = 0.025), patella scores (P = 0.015), and postoperative range of motions (P = 0.004) between the PS group and the CR group. In the PS group, the magnitude of AP translation for the medial and lateral condyle was 4.9 +/- 3.0 mm and 12.8 +/- 3.3 mm, respectively. Axial rotation of the tibial component relative to the femoral component was 12.9 +/- 4.5 degrees . In the CR group, the magnitude of AP translation for the medial and lateral condyle was 4.3 +/- 3.5 mm and 7.9 +/- 4.2 mm, respectively. The axial rotation was 6.7 +/- 5.9 degrees . There were statistically different between PS group and CR group in kinematics postoperatively. CONCLUSION: Our results demonstrate that postoperative JL elevation had more adverse effects on the clinical and kinematic outcomes of CR TKAs than PS TKAs. PMID- 26521784 TI - Finite Element Analysis of Mobile-bearing Unicompartmental Knee Arthroplasty: The Influence of Tibial Component Coronal Alignment. AB - BACKGROUND: Controversies about the rational positioning of the tibial component in unicompartmental knee arthroplasty (UKA) still exist. Previous finite element (FE) studies were rare, and the results varied. This FE study aimed to analyze the influence of the tibial component coronal alignment on knee biomechanics in mobile-bearing UKA and find a ration range of inclination angles. METHODS: A three-dimensional FE model of the intact knee was constructed from image data of one normal subject. A 1000 N compressive load was applied to the intact knee model for validating. Then a set of eleven UKA FE models was developed with the coronal inclination angles of the tibial tray ranging from 10 degrees valgus to 10 degrees varus. Tibial bone stresses and strains, contact pressures and load distribution in all UKA models were calculated and analyzed under the unified loading and boundary conditions. RESULTS: Load distribution, contact pressures, and contact areas in intact knee model were validated. In UKA models, von Mises stress and compressive strain at proximal medial cortical bone increased significantly as the tibial tray was in valgus inclination >4 degrees , which may increase the risk of residual pain. Compressive strains at tibial keel slot were above the high threshold with varus inclination >4 degrees , which may result in greater risk of component migration. Tibial bone resection corner acted as a strain-raiser regardless of the inclination angles. Compressive strains at the resected surface slightly changed with the varying inclinations and were not supposed to induce bone resorption and component loosening. Contact pressures and load percentage in lateral compartment increased with the more varus inclination, which may lead to osteoarthritis progression. CONCLUSIONS: Static knee biomechanics after UKA can be greatly affected by tibial component coronal alignment. A range from 4 degrees valgus to 4 degrees varus inclination of tibial component can be recommended in mobile-bearing UKA. PMID- 26521785 TI - Dynamic Alterations in Microarchitecture, Mineralization and Mechanical Property of Subchondral Bone in Rat Medial Meniscal Tear Model of Osteoarthritis. AB - BACKGROUND: The properties of subchondral bone influence the integrity of articular cartilage in the pathogenesis of osteoarthritis (OA). However, the characteristics of subchondral bone alterations remain unresolved. The present study aimed to observe the dynamic alterations in the microarchitecture, mineralization, and mechanical properties of subchondral bone during the progression of OA. METHODS: A medial meniscal tear (MMT) operation was performed in 128 adult Sprague Dawley rats to induce OA. At 2, 4, 8, and 12 weeks following the MMT operation, cartilage degeneration was evaluated using toluidine blue O staining, whereas changes in the microarchitecture indices and tissue mineral density (TMD), mineral-to-collagen ratio, and intrinsic mechanical properties of subchondral bone plates (BPs) and trabecular bones (Tbs) were measured using micro-computed tomography scanning, confocal Raman microspectroscopy and nanoindentation testing, respectively. RESULTS: Cartilage degeneration occurred and worsened progressively from 2 to 12 weeks after OA induction. Microarchitecture analysis revealed that the subchondral bone shifted from bone resorption early (reduced trabecular BV/TV, trabecular number, connectivity density and trabecular thickness [Tb.Th], and increased trabecular spacing (Tb.Sp) at 2 and 4 weeks) to bone accretion late (increased BV/TV, Tb.Th and thickness of subchondral bone plate, and reduced Tb.Sp at 8 and 12 weeks). The TMD of both the BP and Tb displayed no significant changes at 2 and 4 weeks but decreased at 8 and 12 weeks. The mineral-to-collagen ratio showed a significant decrease from 4 weeks for the Tb and from 8 weeks for the BP after OA induction. Both the elastic modulus and hardness of the Tb showed a significant decrease from 4 weeks after OA induction. The BP showed a significant decrease in its elastic modulus from 8 weeks and its hardness from 4 weeks. CONCLUSION: The microarchitecture, mineralization and mechanical properties of subchondral bone changed in a time-dependent manner as OA progressed. PMID- 26521786 TI - A Cross-sectional Study Assessing Predictors of Essential Medicines Prescribing Behavior Based on Information-motivation-behavioral Skills Model among County Hospitals in Anhui, China. AB - BACKGROUND: The self-consciousness and practicality of preferentially prescribed essential medicines (EMs) are not high enough in county hospitals. The purposes of this study were to use the information-motivation-behavioral skills (IMB) model to identify the predictors of essential medicines prescribing behavior (EMPB) among doctors and to examine the association between demographic variables, IMB, and EMPB. METHODS: A cross-sectional study was carried out to assess predictive relationships among demographic variables and IMB model variables using an anonymous questionnaire administered in nine county hospitals of Anhui province. A structural equation model was constructed for the IMB model to test the instruments using analysis of moment structures 17.0. RESULTS: A total of 732 participants completed the survey. The average age of the participants was 37.7 +/- 8.9 years old (range: 22-67 years old). The correct rate of information was 90.64%. The average scores of the motivation and behavioral skills were 45.46 +/- 7.34 (hundred mark system: 75.77) and 19.92 +/- 3.44 (hundred mark system: 79.68), respectively. Approximately half (50.8%) of respondents reported that the proportion of EM prescription was below 60%. The final revised model indicated a good fit to the data (chi2 /df = 4.146, goodness of fit index = 0.948, comparative fit index = 0.938, root mean square error of approximation = 0.066). More work experience (beta = 0.153, P < 0.001) and behavioral skills (beta = 0.449, P < 0.001) predicted more EMPB. Higher income predicted less information (beta = -0.197, P < 0.001) and motivation (beta = 0.204, P < 0.001). Behavioral skills were positively predicted by information (beta = 0.135, P < 0.001) and motivation (beta = 0.742, P < 0.001). CONCLUSION: The present study predicted some factors of EMPB, and specified the relationships among the model variables. The utilization rate of EM was not high enough. Motivation and behavior skills were crucial factors affecting EMPB. The influence of demographic variables, such as income and work experience, on EMPB should be fully appreciated. Comprehensive intervention measures should be implemented from multiple perspectives. PMID- 26521787 TI - A Comparison of Brain Death Criteria between China and the United States. AB - BACKGROUND: Criteria for determining brain death (BD) vary between China and the United States. We reported the results of an investigation designed to compare procedures to determine BD in two countries. METHODS: The latest criteria in the United states were published in 2010. The latest criteria in China were published in 2009. We used these two types of BD criteria to evaluate patients who were considered to be BD. The time, cost, and accuracy of the diagnosis were compared. RESULTS: From January 1, 2012 to October 8, 2013, there were 37 patients which were applied for BD evaluation in the Neurological Intensive Care Unit of Beijing Tiantan Hospital. The cause of coma were known as subarachnoid hemorrhage (18 patients, 48.6%), intracerebral hemorrhage (8 patients, 21.6%), cerebral ischemia (9 patients, 24.3%), brain stem tumor (1 patient, 2.7%), and intracranial infection (1 patient, 2.7%). The clinical examinations were done for all of the patients except 1 patient who had low blood pressure. Three patients had brainstem reflexes that were excluded from BD. Twenty-five patients had apnea tests, and 20 tests were completed that were all positive. Confirmatory tests were completed differently: Transcranial Doppler (30 patients, positive rate 86.7%), electroencephalogram (25 patients, positive rate 100%), and somatosensory evoked potential (16 patients, positive rate 100%). Thirty-three patients were diagnosed BD by criteria of the United States. Only 9 patients were diagnosed BD by Chinese criteria. The use of time and money in the USA criteria was obviously fewer than those in Chinese criteria (P = 0.000). CONCLUSION: Compared with BD criteria of the United States, Chinese criteria were stricter, lower positive rate, more cost in money and time, and more reliable by families and doctors. PMID- 26521788 TI - Hereditary Transthyretin Amyloidosis in Eight Chinese Families. AB - BACKGROUND: Mutations of transthyretin (TTR) cause the most common type of autosomal-dominant hereditary systemic amyloidosis, which occurs worldwide. To date, more and more mutations in the TTR gene have been reported. Some variations in the clinical presentation are often observed in patients with the same mutation or the patients in the same family. The purpose of this study was to find out the clinicopathologic and genetic features of Chinese patients with hereditary TTR amyloidosis. METHODS: Clinical and necessary examination materials were collected from nine patients of eight families with hereditary TTR amyloidosis at Peking University First Hospital from January 2007 to November 2014. Sural nerve biopsies were taken for eight patients and skin biopsies were taken in the calf/upper arm for two patients, for light and electron microscopy examination. The TTR genes from the nine patients were analyzed. RESULTS: The onset age varied from 23 to 68 years. The main manifestations were paresthesia, proximal and/or distal weakness, autonomic dysfunction, cardiomyopathy, vitreous opacity, hearing loss, and glossohypertrophia. Nerve biopsy demonstrated severe loss of myelinated fibers in seven cases and amyloid deposits in three. One patient had skin amyloid deposits which were revealed from electron microscopic examination. Genetic analysis showed six kinds of mutations of TTR gene, including Val30Met, Phe33Leu, Ala36Pro, Val30Ala, Phe33Val, and Glu42Gly in exon 2. CONCLUSIONS: Since the pathological examinations of sural nerve were negative for amyloid deposition in most patients, the screening for TTR mutations should be performed in all the adult patients, who are clinically suspected with hereditary TTR amyloidosis. PMID- 26521789 TI - Investigation of Urination Disorder in Parkinson's disease. AB - BACKGROUND: Urination disorders are common in Parkinson's disease (PD) and respond poorly to medication. This study aimed to analyze the risk factors for urination disorders in PD. METHODS: Ninety-one patients with PD (aged 34-83 years old) were recruited. Patients were assessed with the Unified PD Rating Scale (UPDRS), Hoehn and Yahr stage, Pittsburgh Sleep Quality Index (PSQI), Hamilton Depression Rating Scale (HAMD), and Hamilton Anxiety Scale (HAMA). Micturition number was recorded, and Type B ultrasound was used to evaluate residual urine. Statistics was performed using binary logistic regression, bivariate correlations, and Chi-square and t-tests. RESULTS: Of 91 patients, urinary dysfunction occurred in 55.0%. Among these, 49.5% suffered with nocturia, 47.3% with pollakiuria. Nocturia number had a positive linear relationship with HAMA score (odds ratio [OR] = 0.340, P = 0.001), HAMD score (OR = 0.323, P = 0.002), duration of L-dopa medication (OR = 0.328, P = 0.001), dose of L-dopa (OR = 0.273, P = 0.009), UPDRS-II (OR = 0.402, P = 0.000), UPDRS-III score (OR = 0.291, P = 0.005), and PSQI score (OR = 0.249, P = 0.017). Micturition number over 24 h was positively associated with HAMA (OR = 0.303, P = 0.004) and UPDRS-II scores (OR = 0.306, P = 0.003). Of patients with residual urine, 79.3% had a volume of residual urine <50 ml. Residual urine was present in 44.4% of the patients with nocturia, 46.5% of the patients with pollakiuria, and 80.0% of the patients with dysuria. More men than women had residual urine (35.2% male vs. 13.3% female; P = 0.002). CONCLUSIONS: Nocturia and pollakiuria were common micturition symptoms in our participants with PD. Nocturia was associated with depression, anxiety, sleep problems, and severity of PD. Pollakiuria was associated with anxiety and severity of PD. Male patients were more prone to residual urine and pollakiuria. PMID- 26521790 TI - Expression of Innate Immunity Genes in Epithelial Cells of Hypertrophic Adenoids with and without Pediatric Chronic Rhinosinusitis: A Preliminary Report. AB - BACKGROUND: Adenoid hypertrophy (AH) is associated with pediatric chronic rhinosinusitis (pCRS), but its role in the inflammatory process of pCRS is unclear. It is thought that innate immunity gene expression is disrupted in the epithelium of patients with chronic rhinosinusitis (CRS), including antimicrobial peptides and pattern recognition receptors (PRRs). The aim of this preliminary study was to detect the expression of innate immunity genes in epithelial cells of hypertrophic adenoids with and without pCRS to better understand their role in pCRS. METHODS: Nine pCRS patients and nine simple AH patients undergoing adenoidectomy were recruited for the study. Adenoidal epithelium was isolated, and real-time quantitative polymerase chain reaction (RT-qPCR) was employed to measure relative expression levels of the following messenger RNAs in hypertrophic adenoid epithelial cells of pediatric patients with and without CRS: Human beta-defensin (HBD) 2 and 3, surfactant protein (SP)-A and D, toll-like receptors 1-10, nucleotide-binding oligomerization domain (NOD)-like receptors NOD 1, NOD 2, and NACHT, LRR and PYD domains-containing protein 3, retinoic acid induced gene 1, melanoma differentiation-associated gene 5, and nuclear factor kappaB (NF-kappaB). RT-qPCR data from two groups were analyzed by independent sample t-tests and Mann-Whitney U-tests. RESULTS: The relative expression of SP-D in adenoidal epithelium of pCRS group was significantly lower than that in AH group (pCRS 0.73 +/- 0.10 vs. AH 1.21 +/- 0.15; P = 0.0173, t = 2.654). The relative expression levels of all tested PRRs and NF-kappaB, as well as HBD-2, HBD-3, and SP-A, showed no statistically significant differences in isolated adenoidal epithelium between pCRS group and AH group. CONCLUSIONS: Down-regulated SP-D levels in adenoidal epithelium may contribute to the development of pCRS. PRRs, however, are unlikely to play a significant role in the inflammatory process of pCRS. PMID- 26521791 TI - Asynchronization in Changes of Electrophysiology and Pathology of Spinal Cord Motor Neurons in Rats Following Middle Cerebral Artery Occlusion. AB - BACKGROUND: Motor dysfunction is common in stroke patients. Clinical electrophysiological studies suggest that transsynaptic degeneration occurred in the lower motor neurons, while pathological evidence is lacked. This study aimed to combine the electrophysiological and pathological results to prove the existence of transsynaptic degeneration in the motor system after stroke. METHODS: Modified neurologic severity score, electrophysiological, and pathological assessments were evaluated in rats before middle cerebral artery occlusion (MCAO), and at 24 hours, 7 days, and 14 days after MCAO. Paired and independent-sample t-tests were applied to assess the changes of electrophysiological and pathological data. RESULTS: Compound motor action potential amplitude in the paretic side was significantly lower than the nonparetic side at both 24 hours (61.9 +/- 10.4 vs. 66.6 +/- 8.9, P < 0.05) and 7 days (60.9 +/- 8.4 vs. 67.3 +/- 9.6, P < 0.05) after MCAO. Motor unit number estimation of the paretic side was significantly less than the nonparetic side (379.0 +/- 84.6 vs. 445.0 +/- 89.5, P < 0.05) at 7 days after MCAO. Until 14 days after stroke, the pathological loss of motor neurons was detected. Motor neurons in 14-day MCAO group were significantly decreased, compared with control group (5.3 +/- 0.7 vs. 7.3 +/- 1.8, P < 0.05). CONCLUSIONS: Both electrophysiological and pathological studies showed transsynaptic degeneration after stroke. This study identified the asynchronization in changes of electrophysiology and pathology. The abnormal physiological changes and function impairment can be detected in the early stage and recovered quickly, while the pathological loss of motor neuron can be detected only in a later stage. PMID- 26521792 TI - Expression of Brain-derived Neurotrophic Factor and Tyrosine Kinase B in Cerebellum of Poststroke Depression Rat Model. AB - BACKGROUND: The pathophysiology of poststroke depression (PSD) remains elusive because of its proposed multifactorial nature. Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology of depression and PSD. And the cerebellar dysfunction may be important in the etiology of depression; it is not clear whether it also has a major effect on the risk of PSD. This study aimed to explore the expression of BDNF and high-affinity receptors tyrosine kinase B (TrkB) in the cerebellum of rats with PSD. METHODS: The rat models with focal cerebral ischemic were made using a thread embolization method. PSD rat models were established with comprehensive separate breeding and unpredicted chronic mild stress (UCMS) on this basis. A normal control group, depression group, and a stroke group were used to compare with the PSD group. Thirteen rats were used in each group. Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) for detecting the expression of BDNF and TrkB protein and mRNA in the cerebellum were used at the 29 th day following the UCMS. RESULTS: Compared with the normal control group and the stroke group, the number of BDNF immunoreactive (IR) positive neurons was less in the PSD group (P < 0.05). Furthermore, the number of TrkB IR positive cells was significantly less in the PSD group than that in the normal control group (P < 0.05). The gene expression of BDNF and TrkB in the cerebellum of PSD rats also decreased compared to the normal control group (P < 0.05). CONCLUSIONS: These findings suggested a possible association between expression of BDNF and TrkB in the cerebellum and the pathogenesis of PSD. PMID- 26521793 TI - Oenanthe Javanica Extract Protects Against Experimentally Induced Ischemic Neuronal Damage via its Antioxidant Effects. AB - BACKGROUND: Water dropwort (Oenanthe javanica) as a popular traditional medicine in Asia shows various biological properties including antioxidant activity. In this study, we firstly examined the neuroprotective effect of Oenanthe javanica extract (OJE) in the hippocampal cornus ammonis 1 region (CA1 region) of the gerbil subjected to transient cerebral ischemia. METHODS: Gerbils were established by the occlusion of common carotid arteries for 5 min. The neuroprotective effect of OJE was estimated by cresyl violet staining. In addition, 4 antioxidants (copper, zinc superoxide dismutase [SOD], manganese SOD, catalase, and glutathione peroxidase) immunoreactivities were investigated by immunohistochemistry. RESULTS: Pyramidal neurons in the CA1 region showed neuronal death at 5 days postischemia; at this point in time, all antioxidants immunoreactivities disappeared in CA1 pyramidal neurons and showed in many nonpyramidal cells. Treatment with 200 mg/kg, not 100 mg/kg, OJE protected CA1 pyramidal neurons from ischemic damage. In addition, 200 mg/kg OJE treatment increased or maintained antioxidants immunoreactivities. Especially, among the antioxidants, glutathione peroxidase immunoreactivity was effectively increased in the CA1 pyramidal neurons of the OJE-treated sham-operated and ischemia operated groups. CONCLUSION: Our present results indicate that treatment with OJE can protect neurons from transient ischemic damage and that the neuroprotective effect may be closely associated with increased or maintained intracellular antioxidant enzymes by OJE. PMID- 26521794 TI - Caffeine Suppresses Apoptosis of Bladder Cancer RT4 Cells in Response to Ionizing Radiation by Inhibiting Ataxia Telangiectasia Mutated-Chk2-p53 Axis. AB - BACKGROUND: Caffeine suppresses ataxia telangiectasia and Rad3 related and ataxia telangiectasia mutated (ATM) activities; ATM is the major kinase for DNA damage detection. This study aimed to investigate the effects of caffeine on DNA damage responses in cells from the bladder cancer cell line RT4 those were exposed to ionizing radiation (IR). METHODS: Immunofluorescent staining was performed to investigate changes in the proteins involved in DNA damage responses with or without caffeine. A mouse xenograft model was used to study the effects of caffeine on the DNA damage responses. Western blotting was used to investigate the effects of caffeine pretreatment on the ATM-Chk2-p53-Puma axis, while real time polymerase chain reaction (RT-PCR) assessed changes in messenger RNA levels of p53 and downstream targets responding to IR. Finally, terminal deoxynucleotidyl transferase-dUTP nick end labeling assay. Western blotting and colony formation assay were used to measure the effects of caffeine on radiation related apoptosis. All of the data were analyzed with a two-tailed Student's t test. RESULTS: Immunofluorescent staining showed that caffeine pretreatment profoundly suppressed the formation of gammaH2AXand p53-binding protein 1 foci in RT4 cells in response to irradiation. Cellular and animal experiments suggested that this suppression was mediated by suppression of the ATM-Chk2-p53-Puma DNA damage-signaling axis. RT-PCR indicated caffeine also attenuated transactivation of p53 and p53-inducible genes. The colony formation assay revealed that caffeine displayed radioprotective effects on RT4 cells in response to low-dose radiation compared to the radiosensitization effects on T24 cells. CONCLUSION: Caffeine may inhibit IR-related apoptosis of bladder cancer RT4 cells by suppressing activation of the ATM-Chk2-p53-Puma axis. PMID- 26521795 TI - The Treatment of Mid-shaft Clavicle Fractures. AB - OBJECTIVE: Through reviewing the relevant literature from the past decades, to summarize the assessment and management of fractures of the clavicle, and provide an overview of the clinical results of a range of treatment options. DATA SOURCES: The data analyzed in this review are mainly from articles included in PubMed and EMBASE, published from 1960 to 2015. STUDY SELECTION: Studies involving assessment of fractures of the clavicle were reviewed. Further literatures were gathered regarding the conservative and surgical treatment of these fractures, including the methods of fixation and the surgical approaches used. Both conservative and surgical treatments were then compared and contrasted. RESULTS: Through retrieving and reading the abstract, a total of 42 representative articles were selected, which covered all aspects of the conservative treatment and surgical treatment, and compared the advantages and disadvantages of different treatment options. CONCLUSIONS: Although the majority of recent data suggest that surgery may be more appropriate as it improves functional outcome and reduces the risk of complications, we recommend that the treatment should be individually assessed. PMID- 26521797 TI - Comparison of Elastic Properties of Bilateral Carotid Arteries in Relation to Site of Acute Ischemic Stroke Using Velocity Vector Imaging. PMID- 26521796 TI - Advanced Chronic Obstructive Pulmonary Disease: Innovative and Integrated Management Approaches. PMID- 26521798 TI - Rapid Identification of Mycobacterium Leprae by Polymerase Chain Reaction restriction Fragment Length Polymorphism Analysis of the Heat Shock Protein 65 Gene from Skin Specimens. PMID- 26521799 TI - Lessons Learned from a Case with Valgus Deformity of the Knee Following Partial Removal of Lateral Discoid Meniscus. PMID- 26521800 TI - Apparently Recovering Breath Function in Brain Death. PMID- 26521801 TI - Potential Effect of Preoperative Immunotherapy on Anesthesia of Patients with Anti-N-methyl-D-aspartate Receptor Encephalitis. PMID- 26521802 TI - Corrigendum: Prevalence and Risk Factors of Atrial Fibrillation in Chinese Elderly: Results from the Chinese Longitudinal Healthy Longevity Survey. PMID- 26521803 TI - Investigating Conservative Therapy of Cervical Radiculopathy by a Delphi Technique. PMID- 26521804 TI - Severe Acute Respiratory Distress Syndrome after Bilateral Total Knee Replacement. PMID- 26521805 TI - Phenylalanine Hydroxylase Deficiency and Citrin Deficiency in a Chinese Infant. PMID- 26521806 TI - Retrograde Duodenoduodenal Intussusception: An Uncommon Complication of Peptic Ulcer. PMID- 26521807 TI - Corrigendum: Comparison of C50 for Propofol-remifentanil Target-controlled Infusion and Bispectral Index at Loss of Consciousness and Response to Painful Stimulus in Elderly and Young Patients. PMID- 26521808 TI - How to spot a statistical problem: advice for a non-statistical reviewer. AB - Statistical analyses presented in general medical journals are becoming increasingly sophisticated. BMC Medicine relies on subject reviewers to indicate when a statistical review is required. We consider this policy and provide guidance on when to recommend a manuscript for statistical evaluation. Indicators for statistical review include insufficient detail in methods or results, some common statistical issues and interpretation not based on the presented evidence. Reviewers are required to ensure that the manuscript is methodologically sound and clearly written. Within that context, they are expected to provide constructive feedback and opinion on the statistical design, analysis, presentation and interpretation. If reviewers lack the appropriate background to positively confirm the appropriateness of any of the manuscript's statistical aspects, they are encouraged to recommend it for expert statistical review. PMID- 26521809 TI - Trans-octadecenoic Acid Positional Isomers Have Different Accumulation and Catabolism Properties in Mice. AB - Trans fatty acids (TFA) are considered risk factors for cardiovascular disease (CVD), while the details of distribution and metabolism of the individual isomers are not clear. Here we investigated the accumulation and catabolic rate of TFA positional isomers of octadecenoic acid (18:1) in mice. ICR mice were fed deuterium- and [1-(13)C] stable isotope-labeled trans-9-18:1 (9t-18:1*), trans-10 18:1 (10t-18:1*), or trans-11-18:1 (11t-18:1*) for 2 or 4 weeks, or a TFA mixture (9t-18:1*, 10t-18:1*, and 11t-18:1*) for 3 weeks. Analysis of whole-body tissues by gas chromatography-chemical ionization mass spectrometry revealed the highest 9t-18:1* levels in the heart. Significant differences in the accumulation of the respective trans-18:1 were observed in the heart and erythrocytes, where 9t- > 11t- > 10t-18:1*, but no significant difference was observed in the liver or white adipose tissue (WAT). Mice fed on 11t-18:1 demonstrated accumulation of endogenously synthesized conjugated linoleic acid in the liver, WAT, and heart, but any other metabolites were not found in other groups. Furthermore, we analyzed catabolic rates of single-dose-administered trans-18:1* isomers into [(13)C]-labeled CO2 using isotope-ratio mass spectrometry, and the 10t 18:1*catabolic rate was significantly higher than those of 9t- and 11t-18:1*. We found that the accumulation and catabolism of trans-18:1 positional isomers varied in these mice. Differential accumulation in tissues suggests that individual TFA positional isomers may play different roles in human health. PMID- 26521810 TI - Synthesis, Surface Active Properties and Cytotoxicity of Sodium N-Acyl Prolines. AB - Sodium N-acyl prolines (NaNAPro) were synthesized using mixture of fatty acids obtained from coconut, palm, karanja, Sterculia foetida and high oleic sunflower oils via Schotten-Baumann reaction in 58-75% yields to study the synergetic effect of mixture of hydrophobic fatty acyl functionalities like saturation, unsaturation and cyclopropene fatty acids with different chain lengths and aliphatic hetero cyclic proline head group on their surface and cytotoxicity activities. The products were characterized by chromatographic and spectral techniques. The synthesized products were evaluated for their surface active properties such as surface tension, wetting power, foaming characteristics, emulsion stability, calcium tolerance, critical micelle concentration (CMC) and thermodynamic properties. The results revealed that all the products exhibited superior surface active properties like CMC, calcium tolerance and emulsion stability as compared to the standard surfactant, sodium lauryl sulphate (SLS). In addition, palm, Sterculia foetida and high oleic sunflower fatty N-acyl prolines exhibited promising cytotoxicity against different tumor cell lines. PMID- 26521811 TI - Inhibitory Effect of Oleic Acid on Octanoylated Ghrelin Production. AB - Ghrelin is a growth hormone-releasing peptide that also displays orexigenic activity. Since serine-3 acylation with octanoylate (octanoylation) is essential for the orexigenic activity of ghrelin, suppression of octanoylation could lead to amelioration or prevention of obesity. To enable the exploration of inhibitors of octanoylated ghrelin production, we developed a cell-based assay system using AGS-GHRL8 cells, in which octanoylated ghrelin concentration increases in the presence of octanoic acid. Using this assay system, we investigated whether fatty acids contained in foods or oils, such as acetic acid, stearic acid, oleic acid, linoleic acid, and alpha-linolenic acid, have inhibitory effects on octanoylated ghrelin production. Acetic acid did not suppress the increase in octanoylated ghrelin production in AGS-GHRL8 cells, which was induced by the addition of octanoic acid. However, stearic acid, oleic acid, linoleic acid, and alpha linolenic acid significantly suppressed octanoylated ghrelin production, with the effect of oleic acid being the strongest. Additionally, oleic acid decreased the serum concentration of octanoylated ghrelin in mice. The serum concentration of des-acyl ghrelin (without acyl modification) was also decreased, but the decrease was smaller than that of octanoylated ghrelin. Decreased octanoylated ghrelin production likely resulted from post-translational ghrelin processing, as there were no significant differences in gene expression in the stomach between oleic acid-treated mice and controls. These results suggest that oleic acid is a potential inhibitor of octanoylated ghrelin production and that our assay system is a valuable tool for screening compounds with suppressive effects on octanoylated ghrelin production. PMID- 26521812 TI - Enzymatic Analysis of Positional Fatty Acid Distributions in Triacylglycerols by 1(3)-Selective Transesterification with Candida antarctica Lipase B: a Collaborative Study. AB - The positional distributions of fatty acids (FAs) in fats and oils are principally analyzed by selectively transesterifying the target triacylglycerols (TAGs) at the 1(3) position using Pseudozyma (Candida) antarctica lipase, followed by recovering the resulting 2-monoacylglycerols (MAGs) by chromatography. FA compositions were measured by gas chromatography (GC) after methylating target TAGs and 2-MAGs. The method was collaboratively evaluated by 12 laboratories by analyzing the positional FA distributions in soybean, palm, and sardine oils. The maximum reproducibility relative standard deviations for the major FAs and those at the sn-2 positions of soybean, palm, and sardine oils were 4.41% and 3.92% (18:3n-3), 4.48% and 3.82% (18:0), and 8.93 and 8.24% (14:0), respectively. The values at the sn-2 position were always low. Therefore, these results indicated that the variations were mainly caused by the FA analysis procedure, i.e., the methylation and GC analyses, rather than the enzymatic transesterification and chromatography utilized to prepare 2-MAGs from the target oil. PMID- 26521813 TI - Production of Structured Triacylglycerols Containing Palmitic Acids at sn-2 Position and Docosahexaenoic Acids at sn-1, 3 Positions. AB - Docosahexaenoic acid supplementation has been shown well-established health benefits that justify their use as functional ingredients in healthy foods and nutraceutical products. Structured triacylglycerols rich in 1,3-docosahexenoyl-2 palmitoyl-sn-glycerol were produced from algal oil (Schizochytrium sp) which was prepared by a two-step process. Novozym 435 lipase was used to produce tripalmitin. Tripalmitin was then used to produce the final structured triacylglycerol (STAG) through interesterification reactions using Lipozyme RM IM. The optimum conditions for the enzymatic reaction were a mole ratio of tripalmitin/fatty acid ethyl esters 1:9, 60 degrees C, 10% enzyme load (wt % of substrates), 10 h; the enzymatic product contained 51.6% palmitic acid (PA), 30.13% docosahexaenoic acid (DHA, C22:6 n-3) and 5.33% docosapentanoic acid (DPA, C22:5 n-3), 12.15% oleic acid (OLA). This STAG can be used as a functional ingredient in dietary supplementation to provide the benefits of DHA. PMID- 26521814 TI - Evaluation of the Key Odorants in Volatile Oils from Tubers of Apios americana Medikus. AB - This study was investigated the chemical composition of volatile oils and aroma evaluation from the tubers of Apios americana Medikus. Theses volatile oils were obtained by the hydrodistillation (HD) and the solvent-assisted flavor evaporation (SAFE) methods. These oils were analyzed by Gas chromatography (GC), GC-mass spectrometry (GC-MS), GC-olfactometry (GC-O), aroma extract dilution analysis (AEDA) and odor activity values (OAV) for the first time. The major compounds in the HD oil were palmitic acid (36.5%), linoleic acid (10.5%) and nonadecanol (5.7%). Meanwhile, in the SAFE oil, the major compounds were 4 hydroxy-4-methyl-2-pentanone (34.2%), hexanal (11.0%) and hexanol (7.9%). Through aroma evaluation, 20 (HD) and 14 (SAFE) aroma-active compounds were identified by GC-O. As a result, the most intense aroma-active compounds in both extraction methods were 1-octen-3-ol and hexanal, both of which showed high odor activity values (OAV). PMID- 26521815 TI - Controversies in medical publishing; messages from New Delhi. PMID- 26521816 TI - Friedrich Berthold Reinke (1862-1919): brilliant yet troubled anatomist of the vocal fold. AB - Reinke's space is a critical laryngeal structure, and the eponym remains in current use in both clinical and research settings. However, little is known about the life of the German anatomist Friedrich Berthold Reinke. His name is missing from the otolaryngological histories, despite his work on the structure he described being responsible for a fundamental advance in our understanding of the larynx. Although brilliant, Reinke was described as impetuous and coarse by his colleagues, resulting in his academic career being cut short. Reinke's relative anonymity is thought to derive from the fact that he never defined himself as a laryngologist. Without question, Reinke's observations of the human vocal fold are substantive contributions, without which modern laryngology could not have evolved. This article aimed to summarise this brilliant yet troubled man's life and achievements, allowing appreciation for his singular genius and fundamental contribution to laryngology. PMID- 26521817 TI - Outcome evaluation of clarithromycin, metronidazole and lansoprazole regimens in Helicobacter pylori positive or negative children with resistant otitis media with effusion. AB - OBJECTIVE: To compare the efficacy of two treatment regimens among Helicobacter pylori stool antigen positive children suffering from resistant otitis media with effusion. METHODS: The study comprised 258 children with bilateral otitis media with effusion; 134 were positive for H pylori stool antigen, and were equally and randomly allocated to the control group or study group. The control group received standard otitis media with effusion therapy (amoxicillin and clavulanate), while the study group received standard H pylori triple therapy (clarithromycin, metronidazole and lansoprazole). RESULTS: In the control group, there was a marked clinical response to treatment in 33 of the 67 children (49.3 per cent). In the study group, there was a marked response in a significantly higher number of children (46 out of 67, 68.7 per cent). The 124 H pylori stool antigen negative children not included in the 2 aforementioned groups received amoxicillin and clavulanate, and a marked response in symptoms was evident in 98 of these children (79 per cent). CONCLUSION: H pylori infection may lead to resistance to traditional otitis media with effusion treatment in some cases. H pylori eradication is associated with a high cure rate. PMID- 26521818 TI - Host gut microorganisms' cues mediate orientation behaviour in the larva of the parasitoid Mallophora ruficauda. AB - The robber fly Mallophora ruficauda is one of the most important apicultural pests in the Pampas region of Argentina. This species is a parasitoid of scarab beetle larvae. Females lay eggs away from the host, and the larvae perform active search behaviour toward Cyclocephala signaticollis third instar larvae, parasitoid's preferred host. This behaviour is mediated by host-related chemical cues produced in hosts' fermentation chamber. Also, C. signaticollis larvae are attracted to fermentation chamber extracts. As scarab larvae have microbe-rich fermentation chamber, it has been suggested that microorganisms could be involved in the production of these semiochemicals. The aims of this work were first to ascertain the presence of microorganisms in the fermentation chamber of C. signaticollis larvae and second to determine the role of microorganisms in the orientation response of parasitoid and host larvae. We found that microorganisms free C. signaticollis larvae showed deterioration in their development and did not produce the attractive semiochemicals. Therefore, we isolated fermentation chamber microorganisms of host larvae by means of different cultures media, and then, assayed different microorganisms' stimuli by binary choice tests. We were able to isolate microorganisms and determine that M. ruficauda larvae are attracted to semiochemicals from protein degradation in the fermentation chamber. However, C. signaticollis larvae were not attracted to any semiochemicals associated with microorganisms' activity in the fermentation chamber. Although we were unable to elucidate the exact role of gut microorganisms in host behaviour, we discuss their relevance in parasitoid host-seeking behaviour and host conspecific interaction in M. ruficauda-C. signaticollis system. PMID- 26521819 TI - Development of a versatile in vitro method for understanding the migration of Fasciola hepatica newly excysted juveniles. AB - Fasciola hepatica is a parasitic trematode that causes serious losses to livestock producers, and also zoonotic disease. The limitations of chemotherapy for the control of fasciolosis have led to significant interest in the development of vaccines to protect cattle and sheep from infection. However, relatively few studies have concentrated on the mechanisms of invasion of the gut by newly excysted juvenile liver flukes (NEJ) and the host response triggered by this event. The aim of this work was to develop an in vitro model to study invasion by NEJ, while also reducing the requirement for challenge infections of experimental animals. Fasciola hepatica metacercariae were excysted in vitro and placed into compartments containing rat distal jejunal sheets. Variations in incubation medium, chamber size and incubation temperature were used to identify optimal conditions for NEJ migration across the gut. Histological examination showed increased migration until 120 min post-incubation. The use of RPMI, without gassing at 39 degrees C, as the incubation medium was found to be optimal, with 40.5% of NEJ migrating after 150 min. This study describes a readily-reproducible method for studying the migration of F. hepatica NEJ within the definitive host. It will be useful for identifying potential drug and vaccine targets. PMID- 26521820 TI - Irsogladine Maleate Prevents Colitis in Interleukin-10 Gene-Deficient Mice by Reducing Interleukin-12 and -23 Production. AB - Irsogladine maleate (2,4-diamino-6-[2,5-dichlorophenyl]-s-triazine maleate; IM), an anti-peptic ulcer drug, may have a protective effect on the gastrointestinal mucosa. This study investigated the effects of IM on spontaneous colitis in interleukin-10 gene-deficient (IL-10(-/-)) mice. Five-week-old IL-10(-/-) mice were fed a control diet or one containing 100 ppm of IM for 10 weeks. Colonic tissues were evaluated morphologically and histologically. J774A.1 murine monocyte/macrophage cells were incubated with IM after lipopolysaccharide stimulation. mRNA expression was assessed by quantitative polymerase chain reaction (PCR) and protein concentration by enzyme-linked immunosorbent assay (ELISA). Colonic length, weight, and histological scores clearly demonstrated that spontaneous colitis was prevented in IL-10(-/-) mice fed a diet containing IM compared with those fed control diet. Levels of tumor necrosis factor-alpha (TNF-alpha) (-2.5-fold), IL-1beta (-5.4), interferon-gamma (IFN-gamma) (-4.5), IL 17 (-113.0), IL-12p35 (-21.0), IL-12p40 (-3.4), and IL-23p19 (-4.2) mRNA expression were significantly decreased in the colonic tissues of IM-treated animals, suggesting that oral treatment with IM suppressed the T-helper (Th)1/Th17 immune response in the colonic mucosa. An in vitro study using monocyte/macrophage cells to clarify the pharmacological action of IM indicated that IL-12p40 and IL-23p19 mRNA expression levels were dose-dependently decreased by IM treatment. ELISA showed that IL-12p40 and IL-23 protein secretion were significantly decreased by IM in a dose-dependent manner. Oral treatment with IM prevented spontaneous colitis in IL-10(-/-) mice by suppressing the colonic mucosal Th1/Th17 immune response through inhibition of IL-12 and -23 production in monocyte/macrophage cells. PMID- 26521821 TI - Association between Selective Serotonin Reuptake Inhibitor Therapy and Suicidality: Analysis of U.S. Food and Drug Administration Adverse Event Reporting System Data. AB - Selective serotonin reuptake inhibitors (SSRIs) are prescribed for the treatment of depression worldwide. SSRIs are suspected to increase the risk of suicidal ideation and behavior (suicidality) in children, adolescents, and young adults. We examined the association between SSRI therapy and suicidality by applying a logistic regression model to age-stratified data from the Food and Drug Administration (FDA) Adverse Event Reporting System database. We attempted to mitigate the effect of patient-related factors by data subsetting. We selected case reports for SSRIs as referred to in the World Health Organization Anatomical Therapeutic Chemical classification code N06AB. The association between SSRIs and "suicidal events" or "self-harm events" was calculated as a reporting odds ratio (ROR) and adjusted for covariates by logistic regression. For subjects <18 years old (y.o.) the adjusted RORs (95% confidence interval) of SSRI therapy with suicidal events were 9.58 (8.97-10.23) in the whole data analysis and 4.64 (4.15 5.19) in the subset analysis; those with self-harm events were 31.40 (27.71 35.58) and 16.31 (13.12-20.29), respectively. Although the adjusted RORs were lower in the subset analyses than in the whole data analyses, both analyses indicated associations between SSRI treatment and suicidal and self-harm events. In both analyses these associations were stronger in the <18 y.o. group than other age groups. Children and adolescents should be closely monitored for the occurrence of suicidality when they are prescribed SSRIs. In addition, we found that data subsetting might mitigate the effect of an intrinsic risk among patients taking the suspected drug. PMID- 26521822 TI - New Approach for Setting a Management Criterion in Microbiological Monitoring Using Rapid Microbiological Methods. AB - The application of rapid microbiological methods (RMM) to bacterial monitoring in pharmaceutical manufacturing processes is now a key topic, since timely microbiological data are critical for product release, continuous process improvement and quality control. An automated, highly sensitive detection system has been developed which can measure the amount of ATP in a sample in 2 h with one hundredfold more sensitive than the conventional ATP method. One of the major subjects for adoption and implementation of RMM is how to set the criterion value for practical microbial control. This value was conventionally been set by experimental rule and indicated as the number of colonies counted after incubation in a particular medium. We have adopted a new approach to set a criterion value which enables assessment in whether the status of the object is normal or not. By setting this criterion value, it is possible to conduct the microbiological control with the intended probability of false-positive and false negative. In this approach the probability distribution model of the measurement value of each object in a normal status has been established by performing repetitive measurement of each object. We have suggested and verified the probability distribution form of the ATP measurement value using measurement data of the standard bacterial solution of Staphylococcus aureus. The theoretical value of the model was in good agreement with the actual measured value. The results suggest it is possible to set an applicable management criterion value using this model and to conduct new microbiological monitoring using RMM. PMID- 26521823 TI - Effects of 1alpha,25-Dihydroxyvitamin D3 on Intestinal Absorption and Disposition of Adefovir Dipivoxil and Its Metabolite, Adefovir, in Rats. AB - The aim of this study was to investigate the effect of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), an active form of vitamin D, on the oral absorption and disposition of adefovir dipivoxil (P-glycoprotein (P-gp) substrate) and its major active metabolite, adefovir (multidrug resistance-associated protein 4 (Mrp4) substrate), in rats. The pharmacokinetics of intravenous adefovir and oral adefovir dipivoxil was evaluated in control and 1,25(OH)2D3-treated rats. The intestinal absorption of adefovir dipivoxil was investigated through an in situ closed loop study, and the tissue distribution of adefovir after oral administration of adefovir dipivoxil was evaluated in the two groups. There was no significant difference in pharmacokinetic parameters of intravenous adefovir between the two groups. Importantly, the total area under the plasma concentration-time curve from time zero to time infinity (AUC), peak plasma concentration (Cmax) and extent of absolute oral bioavailability (F) of adefovir after oral administration of adefovir dipivoxil were significantly higher in 1,25(OH)2D3-treated rats than in control rats. In the in situ closed loop study, there was no significant difference in the remaining fraction of adefovir dipivoxil in the duodenum, jejunum and ileum loops between the two groups. In the tissue distribution study after oral administration of adefovir dipivoxil, the tissue-to-plasma partition coefficients of adefovir in the liver, brain, kidney, and intestine were significantly lower in the 1,25(OH)2D3-treated rats than in control rats. The present study indicates that 1,25(OH)2D3 treatment can enhance the oral absorption of adefovir dipivoxil, likely via the induction of basolateral Mrp4 function in rat intestine. However, the impact of 1,25(OH)2D3 treatment on the pharmacokinetics of intravenous adefovir was limited. These results could lead to further studies in clinically significant P-gp and/or MRP4 mediated 1,25(OH)2D3-drug interactions. PMID- 26521824 TI - Investigation of Antiulcer and Antioxidant Activity of Juniperus phoenicea L. (1753) Essential Oil in an Experimental Rat Model. AB - Juniperus phoenicea is a tree of the Cupressaceae family that is popularly known in the south of Tunisia because of its wide application in herbal medicine, including the use of its leaves to treat many diseases such as diarrhea, rheumatism, and intestinal disorders. The aim of this study was to evaluate the ulceroprotective and antioxidant activity of essential oil extracted from the leaves of J. phoenicea (EOJp) against hydrogen chloride (HCl)/ethanol-induced ulcers in rats. The antiulcer activities of 50, 75 and 100 mg/kg body weight (b.w.) EOJp were investigated on 0.3 M HCl/ethanol-induced ulcers in rats. The essential oil yield was 0.69% with 48 compounds; alpha-pinene was the principal component (20.24%). In vivo pretreatment with EOJp given orally provided dose dependent protection against HCl/ethanol-induced gastric ulcers in rats. Furthermore, pretreatment with EOJp significantly decreased malondialdehyde (MDA) content and increased the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). The activity of the antiulcerogenic EOJp could be from synergistic antioxidant and anti-secretory effects. Oral use of EOJp has excellent preventive effects on induced gastric ulcers comparable to those of the proton pump inhibitor (PPI) omeprazole. PMID- 26521825 TI - Pancreatic Changes in Nerve Growth Factor/TrkA Associated with Insulin Secretion in Cerebral Ischemia. AB - Regulation of blood glucose levels as a therapeutic strategy for cerebral ischemia plays an important role in suppressing neuronal damage. In particular, suppression of post-ischemic glucose intolerance improves cerebral ischemia. We have reported that cerebral ischemia induces glucose intolerance and an increase in plasma insulin levels. However, the mechanism of insulin secretion after cerebral ischemia is unclear. Nerve growth factor (NGF), a member of the neurotrophin family, has high affinity for tropomyosin-related kinase A (TrkA). NGF/TrkA signaling is associated with neuronal survival, differentiation, and function. Recently, NGF/TrkA signaling has been reported to be associated with insulin synthesis and secretion. In the present study, we evaluated the insulin content and expression of NGF/TrkA by immunofluorescence and Western blotting after middle cerebral artery occlusion (MCAO) as a cerebral ischemia model. At 6, 12, and 24 h after MCAO, insulin contents were increased in MCAO mice. The expression of NGF was increased at 6, 12, and 24 h, whereas the expression of TrkA tended to decrease in pancreas after MCAO. These results suggest that NGF/TrkA signaling is an important factor in cerebral ischemia-induced insulin synthesis and secretion in the pancreas. PMID- 26521826 TI - Pemetrexed-Induced Rash May Be Prevented by Supplementary Corticosteroids. AB - Pemetrexed, a chemotherapeutic drug, is highly active in non-small cell lung cancer and malignant pleural mesothelioma. Unfortunately, rashes are more commonly associated with pemetrexed than other chemotherapies, and it is recommended that patients receive corticosteroids (8 mg/d of dexamethasone) for 3 d, including the day of pemetrexed administration (day 1). However, the efficacy of corticosteroids in this context has not been fully verified. In this retrospective study, we evaluated the medical records of 78 patients who received pemetrexed between April 2009 and March 2014, to confirm whether supplementary corticosteroids prevented rash development. The incidence of rash was lower in the 47 patients who received supplementary corticosteroids (after day 1) compared with the incidence among the 31 patients who did not receive supplementary corticosteroids (19.1% vs. 38.7%). The average cutoff dosage of supplementary corticosteroids on day 2 and day 3 was 1.5 mg/d of dexamethasone, as calculated using the receiver operating characteristic curve, and the odds ratio was 0.33 (95% confidence interval: 0.12-0.94). Administration of >=1.5 mg of corticosteroids on day 2 and day 3 significantly reduced the severity of the rash compared to no supplementary treatment (grades 2/3, 13.3% vs. 33.3%, p<0.05). However, increasing the dose of corticosteroids had no additional effect on rash development. These results suggest that >=1.5 mg of supplementary dexamethasone on day 2 and day 3 (in addition to day 1) may be necessary for preventing pemetrexed-induced rash, but high doses of dexamethasone (e.g., 8 mg/d) are unnecessary. PMID- 26521827 TI - Characterization of Perivascular Nerve Distribution in Rat Mesenteric Small Arteries. AB - The distribution pattern of perivascular nerves in some branches of rat mesenteric arteries was studied. Mesenteric arteries isolated from 8-week-old Wistar rats were divided into the 1st-, 2nd-, and 3rd-order branches. The distribution of perivascular nerves in each branch was immunohistochemically evaluated using antibodies against neuropeptide Y (NPY), tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), substance P (SP), and neuronal nitric oxide synthase (nNOS). The density of NPY-, TH-, CGRP-, and SP-like immunoreactive (LI) nerves in the 2nd and 3rd branches was significantly greater than that in the 1st branch, and a negative relationship was found between nerve density and arterial diameter, except for TH-LI nerves. The density of NPY- and TH-LI nerves in all branches, which was similar, was greater than that of CGRP- (except for NPY-LI nerves in the 1st branch), SP-, or nNOS-LI nerves. Double immunostaining revealed that TH-LI nerves made contact with nNOS-LI, CGRP-LI, and SP-LI nerves and that CGRP-LI nerves made contact with TH-, NPY-, or nNOS-LI nerves, while TH-LI and CGRP-LI nerves nearly merged with NPY-LI and SP-LI nerves, respectively. These results suggest that the each branch of mesenteric arteries is densely innervated by vasoconstrictor nerves containing NPY, TH, and vasodilator CGRP nerves. They also suggest that the intense density of perivascular nerves in the 2nd and 3rd branches may contribute to maintaining vascular tone. PMID- 26521828 TI - Protective Effects of Everolimus against N-Methyl-D-aspartic Acid-Induced Retinal Damage in Rats. AB - We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-D-aspartic acid (NMDA)-induced retinal neurotoxicity, but the mechanism underlying this protection is not fully understood. The present study aimed to examine the effects of everolimus, another inhibitor of mTOR, on neuronal cell loss and inflammation in a rat model of NMDA induced retinal neurotoxicity, and to determine whether the extracellular signal regulated kinase (ERK) pathway contributes to the protective effect of everolimus. Intravitreal injection of NMDA (200 nmol) resulted in (1) cell loss in the ganglion cell layer, (2) increase in the numbers of CD45-positive leukocytes and Iba1-positive microglia, and (3) phosphorylation of ribosomal protein S6 (pS6), a downstream indicator of mTOR activity. Simultaneous injection of everolimus with NMDA significantly attenuated these NMDA-induced responses. The neuroprotective effect of everolimus was almost completely prevented by the mitogen-activated protein kinase/ERK kinase inhibitor U0126 (1 nmol). NMDA increased the level of phosphorylated ERK (pERK) in Muller cells, and increase in pERK levels was also observed after co-injection of NMDA and everolimus. These results suggest that everolimus has a neuroprotective effect against NMDA-induced retinal neurotoxicity, an effect that seems to be mediated partly by activation of the ERK pathway in Muller cells. PMID- 26521829 TI - Quantification of Sorafenib in Human Serum by Competitive Enzyme-Linked Immunosorbent Assay. AB - The multikinase inhibitor sorafenib has been used in the treatment of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma. Here we have demonstrated the production of the first specific antibody against sorafenib. Anti-sorafenib serum was obtained by immunizing mice with an antigen conjugated with bovine serum albumin and carboxylic modified 4-(4 aminophenoxy)-N-methyl-2-pyridinecarboxamide (AMPC) using the N-succinimidyl ester method. Enzyme labeling of sorafenib with horseradish peroxidase was similarly performed using carboxylic modified AMPC. A simple competitive enzyme linked immunosorbent assay (ELISA) for sorafenib was developed using the principle of direct competition between sorafenib and the enzyme marker for anti sorafenib antibody, which had been adsorbed by the plastic surface of a microtiter plate. Serum sorafenib concentrations lower than 0.04 ug/mL were reproducibly measurable using the ELISA. This ELISA was specific to sorafenib and showed very slight cross-reactivity (2.5%) with a major metabolite, sorafenib N oxide. The values of serum sorafenib levels from 32 patients measured by this ELISA were comparable with those measured by HPLC, and there was a strong correlation between the values determined by the two methods (Y=1.016X-0.137, r=0.979). The specificity and sensitivity of the ELISA for sorafenib should provide a valuable new tool for use in therapeutic drug monitoring and pharmacokinetic studies of sorafenib. PMID- 26521830 TI - Effects of Various 5,7-Dihydroxyflavone Analogs on Adipogenesis in 3T3-L1 Cells. AB - We studied the effects of twelve 5,7-dihydroxyflavone analogs on adipogenesis in 3T3-L1 cells. Among the compounds, luteolin, diosmetin, and chrysoeriol partly inhibited adipogenesis by blocking the accumulation of triacylglycerol in the cells. Conversely, tricetin facilitated triacylglycerol accumulation in the cells. The induction of lipogenesis or lipolysis may depend on the number and bonding position of hydroxyl or methoxy groups on the B ring of 5,7 dihydroxyflavone. The mRNA expression levels of adipogenic and lipogenic genes were suppressed by luteolin treatment in the cells, while the mRNA levels of lipolytic genes were not affected. However, the expression levels of the adipogenic, lipogenic, and lipolytic genes, except for adipocyte protein 2 (aP2), were not affected by the addition of tricetin. Moreover, luteolin suppressed glucose transporter type 4 (GLUT4) gene and protein levels. These results indicate that luteolin decreased triacylglycerol levels in 3T3-L1 cells during adipogenesis through the suppression of adipogenic/lipogenic and GLUT4 genes and GLUT4 protein. PMID- 26521831 TI - Relaxation Induced by Atrial Natriuretic Peptide Is Impaired in Carotid but Not Renal Arteries from Spontaneously Hypertensive Rats Due to Reduced BKCa Channel Activity. AB - Atrial natriuretic peptide (ANP) plays an important role in vascular functions such as blood pressure regulation and relaxant activity. Individual vascular beds exhibit differences in vascular reactivity to various ligands, however, the difference in responsiveness to ANP between carotid and renal arteries and the molecular mechanisms of its vasorelaxant activity in a pathophysiological state, including hypertension, remain unclear. We therefore investigated this issue by exposing carotid and renal artery rings obtained from spontaneously hypertensive rats (SHR) to ANP. In the SHR artery (vs. control WKY artery), the ANP-induced relaxations were reduced in carotid artery but not renal artery. Acetylcholine induced relaxations were reduced in both arteries in SHR (vs. WKY). Sodium nitroprusside-induced relaxation was similar in both arteries between the groups. In carotid arteries, the ANP-induced relaxation was not affected by endothelial denudation or by treatment with inhibitors of nitric oxide synthase, cyclooxygenase, the voltage-dependent potassium channel, or ATP-sensitive potassium channel in arteries from both SHR and WKY. In the carotid artery from WKY but not SHR, the ANP-induced relaxation was significantly reduced by inhibition of the large-conductance calcium-activated potassium channel (BKCa). The BKCa activator-induced relaxation was reduced in the SHR artery (vs. WKY). These results suggest that ANP-induced relaxation is impaired in the carotid artery from SHR and this impairment may be at least in part due to the reduction of BKCa activity rather than endothelial components. PMID- 26521832 TI - Orthovanadate-Induced Vasoconstriction of Rat Mesenteric Arteries Is Mediated by Rho Kinase-Dependent Inhibition of Myosin Light Chain Phosphatase. AB - Orthovanadate (OVA), a protein tyrosine phosphatase inhibitor, induces vasoconstriction in a Rho kinase-dependent manner. The aim of this study was to determine the mechanism underlying OVA-induced vasoconstriction of rat mesenteric arteries. OVA-induced constriction of mesenteric arterial rings treated with N(G) nitro-L-arginine methyl ester (L-NAME, 0.1 mM), a nitric oxide synthase inhibitor, was significantly blocked by the Rho kinase inhibitor Y-27632 (R-(+) trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide, 10 uM), extracellular signal-regulated kinase 1 and 2 (Erk1/2) inhibitor FR180204 (5-(2 phenyl-pyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-3-ylamine, 10 uM), Erk1/2 kinase (MEK) inhibitor PD98059 (2'-amino-3'-methoxyflavone, 10 uM), epidermal growth factor receptor (EGFR) inhibitor AG1478 (4-(3-chloroanilino)-6,7 dimethoxyquinazoline, 10 uM), and Src inhibitor PP2 (4-amino-3-(4-chlorophenyl)-1 (t-butyl)-1H-pyrazolo[3,4-d]pyrimidine, 3 uM). However, the myosin light chain kinase inhibitor ML-7 (1-(5-iodonaphthalene-1-sulfonyl)-homopiperazine, 10 uM) did not affect OVA-induced constriction. Phosphorylation of myosin phosphatase target subunit 1 (MYPT1, an index of Rho kinase activity) was abrogated by inhibitors of Src, EGFR MEK, Erk1/2, and Rho kinase. OVA-stimulated Erk1/2 phosphorylation was blocked by inhibitors of EGFR, Src, MEK, and Erk1/2 but not affected by an inhibitor of Rho kinase. OVA-induced Src phosphorylation was abrogated by an Src inhibitor but not affected by inhibitors of EGFR, MEK, Erk1/2, and Rho kinase. In addition, the metalloproteinase inhibitor TAPI-0 (N (R)-[2-(hydroxyaminocarbonyl)methyl]-4-methylpentanoyl-L-naphthylalanyl-L-alanine amide, 10 uM) and an inhibitor of heparin/epidermal growth factor binding (CRM 197, 10 ug/mL) did not affect OVA-induced contraction of rat mesenteric arterial rings. These results suggest that OVA induces vasoconstriction in rat mesenteric arteries via Src, EGFR, MEK, and Erk1/2 activation, leading to the inactivation of myosin light chain phosphatase through phosphorylation of MYPT1. PMID- 26521833 TI - Pharmacokinetics of Prophylactic Ampicillin-Sulbactam and Dosing Optimization in Patients Undergoing Cardiovascular Surgery with Cardiopulmonary Bypass. AB - Antibiotic concentrations must be maintained at an adequate level throughout cardiovascular surgery to prevent surgical site infection. This study aimed to determine the most appropriate timing for intraoperative repeated dosing of ampicillin-sulbactam, a commonly used antibiotic prophylaxis regimen, to maintain adequate concentrations throughout the course of cardiovascular surgery with cardiopulmonary bypass (CPB). The total plasma concentrations of ampicillin were monitored in 8 patients after ampicillin (1 g)-sulbactam (0.5 g) administration via initial intravenous infusion and subsequent CPB priming. Pharmacokinetic parameters were estimated and used to predict the free plasma concentrations of ampicillin. The mean values for the volume of distribution, elimination rate constant, elimination half-life, and total clearance of ampicillin were 15.8+/ 4.1 L, 0.505+/-0.186 h(-1), 1.52+/-0.47 h, and 7.72+/-2.72 L/h, respectively. When ampicillin (1 g)-sulbactam (0.5 g) was intravenously administered every 3, 4, 6, and 12 h after the start of CPB, the predicted free trough plasma concentrations of ampicillin were 15.20, 8.25, 2.74, and 0.13 ug/mL, respectively. Therefore, an every-6-h regimen was needed to maintain the free ampicillin concentration at more than 2 ug/mL during cardiovascular surgery with CPB. We suggest that the dose and dosing interval for ampicillin-sulbactam should be adjusted to optimize the efficacy and safety of treatment, according to the minimum inhibitory concentrations for methicillin-sensitive Staphylococcus aureus isolates at each institution. REGISTRATION NUMBER: UMIN000007356. PMID- 26521834 TI - Affinity Selection of Peptide Binders with Magnetic Beads via Organic Phase Separation (MOPS). AB - We describe a new method for affinity selection of peptide binders for soluble protein targets using magnetic beads via organic phase separation (MOPS) from a phage display library. As a model target molecule, a mouse monoclonal antibody against human integrin alpha9beta1 (Y9A2) immobilized onto protein G magnetic beads was incubated with a 15-mer or 20-mer random peptide phage-display library. The suspensions containing the phage-magnetic beads conjugates were then transferred onto the organic phase and centrifuged in order to recover the Y9A2 bound phage immobilized on the protein G magnetic beads in the lower organic phase. After three rounds of biopanning, we were able to isolate specific phage clones that could not be obtained by the conventional approach. Furthermore, this new approach was found to be highly effective for isolating phage-binders for Fc fusion constructs; indeed, enrichment of specific phage-binders was observed after only the first panning cycle. Thus, MOPS can improve the selection of specific phage-binders for soluble protein targets mainly due to the removal of non-specific binders. PMID- 26521835 TI - Hypercapnia-Induced Changes in Cerebral Blood Flow Against the Background of Experimental Cerebral Circulatory Failure. AB - The peculiarities of hypercapnia-induced blood circulatory changes in the local cortical and subcortical regions of the brain and the character of disturbances of the adequate (vasodilator) responses to CO2 were examined on rabbits with experimental chronic cerebral circulatory failure. The study revealed moderation of local vasodilator effect of CO2 and reversal of the circulatory reactions to CO2 manifested in a decrease of local blood fl ow instead of its elevation. The data argue for individual use of carbogen therapy in relation to initial state of the functional organism systems. PMID- 26521836 TI - Abnormal heart rate recovery and deficient chronotropic response after submaximal exercise in young Marfan syndrome patients. AB - BACKGROUND: Marfan syndrome patients present important cardiac structural changes, ventricular dysfunction, and electrocardiographic changes. An abnormal heart rate response during or after exercise is an independent predictor of mortality and autonomic dysfunction. The aim of the present study was to compare heart rate recovery and chronotropic response obtained by cardiac reserve in patients with Marfan syndrome subjected to submaximal exercise. METHODS: A total of 12 patients on beta-blocker therapy and 13 off beta-blocker therapy were compared with 12 healthy controls. They were subjected to submaximal exercise with lactate measurements. The heart rate recovery was obtained in the first minute of recovery and corrected for cardiac reserve and peak lactate concentration. RESULTS: Peak heart rate (141+/-16 versus 155+/-17 versus 174+/-8 bpm; p=0.001), heart rate reserve (58.7+/-9.4 versus 67.6+/-14.3 versus 82.6+/ 4.8 bpm; p=0.001), heart rate recovery (22+/-6 versus 22+/-8 versus 34+/-9 bpm; p=0.001), and heart rate recovery/lactate (3+/-1 versus 3+/-1 versus 5+/-1 bpm/mmol/L; p=0.003) were different between Marfan groups and controls, respectively. All the patients with Marfan syndrome had heart rate recovery values below the mean observed in the control group. The absolute values of heart rate recovery were strongly correlated with the heart rate reserve (r=0.76; p=0.001). CONCLUSION: Marfan syndrome patients have reduced heart rate recovery and chronotropic deficit after submaximal exercise, and the chronotropic deficit is a strong determinant of heart rate recovery. These changes are suggestive of autonomic dysfunction. PMID- 26521837 TI - Oral cavity infections: why should cardiologists care about them? PMID- 26521838 TI - Emergency echocardiography to guide therapy in a patient with Takotsubo cardiomyopathy complicated with dynamic left ventricular outflow tract obstruction. PMID- 26521839 TI - [Asymptomatic tumour or abnormal tricuspidal ring structure: role of echocardiography and magnetic resonance imaging]. PMID- 26521840 TI - Image integration of cine-angiography with 3D electroanatomical mapping. Atrial flutter ablation with CARTO UniVuTM module support. PMID- 26521841 TI - Low symptomatic malignant cardiac arrhythmia in a patient with lamin-related congenital muscular dystrophy. PMID- 26521842 TI - [Type 2 diabetes prevention. Experts' Group position paper endorsed by the Polish Cardiac Society Working Group on Cardiovascular Pharmacotherapy]. AB - Type 2 diabetes is responsible for approximately 90% of all diabetes worldwide and it is a global public health problem. This is a chronic, progressive, metabolic disease characterised by hyperglycaemia, which leads to microangiopathic and macroangiopathic complications. Subjects with type 2 diabetes have increased mortality and a reduced life expectancy compared with those without diabetes. Strong evidence supports the fact that identification of type 2 diabetes risk factors and early intervention influencing the modifiable ones can reduce incidence rate of diabetes and prevalence of its complications. There are many advantages of such interventions for patients (prolonged life expectancy, improvement of life quality) and for the whole society (reduction of the costs). Therefore the guidelines for the prevention of type 2 diabetes are needed. Experts of the Polish Cardiac Society Working Group on Cardiovascular Pharmacotherapy reviewed recently published clinical studies regarding the prevention of type 2 diabetes and prepared their recommendations. The guidelines are designed to assist clinicians and other healthcare workers to make evidence based management decisions. The strategies are grouped broadly into interventions that aim to change lifestyle through physical activity and diet, interventions based on drug administration (pharmacotherapy) and surgical interventions. PMID- 26521843 TI - [A new version of cardiovascular risk assessment system and risk charts calibrated for Polish population]. PMID- 26521844 TI - Alignment of classification paradigms for communication abilities in children with cerebral palsy. AB - AIM: We examined three communication ability classification paradigms for children with cerebral palsy (CP): the Communication Function Classification System (CFCS), the Viking Speech Scale (VSS), and the Speech Language Profile Groups (SLPG). Questions addressed interjudge reliability, whether the VSS and the CFCS captured impairments in speech and language, and whether there were differences in speech intelligibility among levels within each classification paradigm. METHOD: Eighty children (42 males, 38 females) with a range of types and severity levels of CP participated (mean age 60mo, range 50-72mo [SD 5mo]). Two speech-language pathologists classified each child via parent-child interaction samples and previous experience with the children for the CFCS and VSS, and using quantitative speech and language assessment data for the SLPG. Intelligibility scores were obtained using standard clinical intelligibility measurement. RESULTS: Kappa values were 0.67 (95% confidence interval [CI] 0.55 0.79) for the CFCS, 0.82 (95% CI 0.72-0.92) for the VSS, and 0.95 (95% CI 0.72 0.92) for the SLPG. Descriptively, reliability within levels of each paradigm varied, with the lowest agreement occurring within the CFCS at levels II (42%), III (40%), and IV (61%). Neither the CFCS nor the VSS were sensitive to language impairments captured by the SLPG. Significant differences in speech intelligibility were found among levels for all classification paradigms. INTERPRETATION: Multiple tools are necessary to understand speech, language, and communication profiles in children with CP. Characterization of abilities at all levels of the International Classification of Functioning, Disability and Health will advance our understanding of the ways that speech, language, and communication abilities present in children with CP. PMID- 26521845 TI - Flightless I is a key regulator of the fibroproliferative process in hypertrophic scarring and a target for a novel antiscarring therapy. AB - BACKGROUND: Hypertrophic scarring carries a large burden of disease, including disfigurement, pain and disability. There is currently no effective medical treatment to reduce or prevent hypertrophic scarring. Flightless I (Flii), a member of the gelsolin family of actin remodelling proteins, is an important negative regulator of wound repair. OBJECTIVES: The objective of this study was to investigate the role of Flii as a potential regulator of hypertrophic scarring. METHODS: Using human skin samples and an animal model of bleomycin induced hypertrophic scarring in mice that overexpress or have reduced expression of Flii, we investigated its effect on dermal fibrosis and hypertrophic scarring. RESULTS: Flii expression was increased in human burns and hypertrophic scars. A similar increase in Flii was observed in hypertrophic scars formed in mice post treatment with bleomycin. However, Flii-deficient (Flii(+/-) ) mice had reduced scarring in response to bleomycin evidenced by decreased dermal thickness, smaller cross-sectional scar areas, fewer myofibroblasts and a decreased collagen I/III ratio. In contrast, bleomycin-treated Flii-overexpressing mice (Flii(Tg/Tg) ) showed increased scar dermal thickness, larger cross-sectional scar areas, more myofibroblasts and an increased collagen I/III ratio. Injecting developing scars with a Flii neutralizing antibody led to a significant reduction in the size of the scars and a reduction in the collagen I/III ratio. CONCLUSIONS: This study identifies Flii as a profibrotic agent that contributes to excessive scar formation. Reducing its activity using neutralizing antibodies is a promising approach for reducing hypertrophic scarring. PMID- 26521846 TI - Total Synthesis of Gymnocin-A. AB - A convergent total synthesis of cytotoxic marine natural polycyclic ether, gymnocin-A (1), is described. The synthesis features three iterations of an oxiranyl anion strategy, involving base-mediated cycloetherification, ring expansion, and reductive etherification, for the construction of the FGH fragment and for its coupling with the ABC and KLMN fragments. PMID- 26521847 TI - SAMDI Mass Spectrometry-Enabled High-Throughput Optimization of a Traceless Petasis Reaction. AB - Development of the self-assembled monolayer/MALDI mass spectrometry (SAMDI) platform to enable a high-throughput optimization of a traceless Petasis reaction is described. More than 1800 unique reactions were conducted simultaneously on an array of self-assembled monolayers of alkanethiolates on gold to arrive at optimized conditions, which were then successfully transferred to the solution phase. The utility of this reaction was validated by the efficient synthesis of a variety of di- and trisubstituted allenes. PMID- 26521848 TI - Massive hyperhomocysteinaemia as a complication of nitrous oxide inhalation. PMID- 26521849 TI - Development of Suppositories Containing Flutamide-Loaded Alginate-Tamarind Microparticles for Rectal Administration: In Vitro and in Vivo Studies. AB - In the present work the absorption of flutamide from suppositories containing hydrophilic tamarind alginate microparticles after rectal administration in rats was investigated with the purpose of enhancing bioavailability and to avoid hepatic toxicity. Microparticles were developed by ionic gelation method and optimized using one factorial design of response surface methodology. The optimized batch of microparticles had tamarind gum-sodium alginate (1 : 3) ratio and showed entrapment efficiency 94.969% and mucoadhesion strength 94.646% with desirability of 0.961. Suppositories loaded with microparticles were developed by fusion method using poloxamer 407 and poloxamer 188 in combination as suppository base. Kinetic analysis of the release data of microparticle-loaded suppositories showed time-independent release of drug. Higher values of 'n' (>0.89) represent Super Case II-type drug release. The pharmacokinetics of flutamide from flutamide tamarind alginate microparticle-loaded suppository were compared with oral suspension. Cmax of microparticle-loaded suppository was significantly larger than that of oral suspension (1.711 and 0.859 ug/mL, respectively). PMID- 26521850 TI - Screening and Characterization of Hydrate Forms of T-3256336, a Novel Inhibitor of Apoptosis (IAP) Protein Antagonist. AB - Different crystal packing of hydrates from anhydrate crystals leads to different physical properties, such as solubility and stability. Investigation of the potential of varied hydrate formation, and understanding the stability in an anhydrous/hydrate system, are crucial to prevent an undesired transition during the manufacturing process and storage. Only one anhydrous form of T-3256336, a novel inhibitor of apoptosis (IAP) protein antagonist, was discovered during synthesis, and no hydrate form has been identified. In this study, we conducted hydrate screening such as dynamic water vapor sorption/desorption (DVS), and the slurry experiment, and characterized the solid-state properties of anhydrous/hydrate forms to determine the most desirable crystalline form for development. New hydrate forms, both mono-hydrate and hemi-hydrate forms, were discovered as a result of this hydrate screening. The characterization of two new hydrate forms was conducted, and the anhydrous form was determined to be the most desirable development form of T-3256336 in terms of solid-state stability. In addition, the stability of the anhydrous form was investigated using the water content and temperature controlled slurry experiment to obtain the desirable crystal form in the crystallization process. The water content regions of the stable phase of the desired form, the anhydrous form, were identified for the cooling crystallization process. PMID- 26521851 TI - Antioxidant Activity of Novel Fused Heterocyclic Compounds Derived from Tetrahydropyrimidine Derivative. AB - 6-(Benzo[d][1,3]dioxol-5-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5 carbonitrile has been utilized for synthesis of the fused heterocyclic compounds namely thiazolopyrimidines, tetrazolopyrimidine, pyrimidoquinazoline, pyrimidothiazolopyrimidine, pyrimidothiazolotriazine and pyrrolothiazolopyrimidine derivatives. The newly synthesized compounds were characterized by IR, (1)H-NMR, (13)C-NMR, and mass spectral data. Antioxidant activities of all synthesized compounds were investigated. PMID- 26521852 TI - Synthesis and Biological Evaluation of Curcuminoid Derivatives. AB - Many curcuminoid derivatives have been reported to have multiple biological activities. The aim of this study was to improve the biological activity of curcuminoids by synthesizing 16 new derivatives which combined cinnamic acids with curcuminoids, and we also analyzed the structure-activity relationship of the new compounds. Almost all the new compounds showed encouraging activity, especially compound 7g. It had much better antioxidant activity than curcuminoids and Vitamin C (VC), and also had the most significant antibacterial activity, which was 5-folder better than ampicillin (one of the best marketed antibiotics) with a minimum inhibitory concentration (MIC) of 0.5 ug/mL against Gram-positive cocci (Staphylococcus aureus and Streptococcus viridans) as well as Escherichia coli and 0.6 ug/mL against Enterobacter cloacae. Compound 7g also showed the greatest anticancer activity with a much lower IC50, which was 0.51 uM against MCF-7, 0.58 uM against HepG-2, 0.63 uM against LX-2, and 0.79 uM against 3T3. The results suggest that these compounds have promising potential as candidates for the treatment of cancer and thus further studies are warranted. PMID- 26521853 TI - Novel Tranylcypromine/Hydroxylcinnamic Acid Hybrids as Lysine-Specific Demethylase 1 Inhibitors with Potent Antitumor Activity. AB - Novel tranylcypromine/hydroxylcinnamic acid hybrids 15a, b, and 19a-l were designed and synthesized by connecting tranylcypromine with hydroxylcinnamic acid, and their biological activities were evaluated. The in vitro assay of their inhibitory activities against lysine-specific demethylase 1 (LSD1) showed that most of the target compounds displayed high potency with IC50 values ranging from submicromolar to single-digit micromolar levels. In particular, compound 19l had robust, selective LSD1 inhibitory activity, which was obviously higher than the inhibitory activity against homologues monoamine oxidase-A (MAO-A) and MAO-B, respectively. Furthermore, the most potent compound 19l selectively inhibited cancer cell but not nontumor colon cell proliferation in vitro. In addition, compound 19l also dose-dependently increased the expression of H3K4me2 at the cellular level. Our findings suggest that tranylcypromine/hydroxylcinnamic acid hybrids as LSD1 inhibitors may hold great promise as therapeutic agents for the treatment of human cancers. PMID- 26521854 TI - Self-organizing Map Analysis for Understanding Comprehensive Relationships between Formulation Variables, State of Water, and the Physical Stability of Pharmaceutical Emulsions. AB - The physical stability of pharmaceutical emulsions is an important quality attribute to be considered. To obtain a better understanding of this issue, this study investigated the contribution of the state of water to the physical stability of pharmaceutical emulsions. The key technology to evaluate the state of water was magnetic resonance imaging (MRI). For sample preparation, model emulsions with different formulation variables (surfactant content, water content, and hydrophilic-lipophilic balance) were prepared. The T1 relaxation time, diffusion coefficient, and viscosity were measured as physical properties. The physical stability of the samples was evaluated using apparent diffusion coefficient maps acquired by MRI. Data analysis of the observed data was performed using the nonlinear response surface method and Kohonen's self organizing map (SOM). It was determined that, depending on the formulation variables, the state of water was substantially changed and it played a significant role in the physical stability. SOM analysis successfully classified the conditions of formulation variables into four distinct clusters in terms of the similarity of the physical properties of the resultant emulsions, and then clarified the characteristics of the stable emulsions. This study provided us with a comprehensive understanding of the formulation variables, physical properties, and stability concerning the preparation of the model emulsion. PMID- 26521855 TI - New NitroG-Grasp Molecules with Enhanced Capture Reactivity for 8-Nitroguanosine in the Aqueous Media. AB - 8-Nitroguanosine is formed by the nitration of guanosine, and has been conventionally classified as a genotoxic material. Recently, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) has become of great interest due to its biological role as an intracellular signaling molecule. In an attempt to develop recognition molecules for 8-nitroguanosine, we have determined a 1,3 diazaphenoxazine nucleoside derivative (nitroG-grasp) bearing a thiol group with a urea linker, which efficiently displaces the nitro group through the formation of multiple hydrogen-bonded complexes with 8-nitroguanosine. However, a drawback of this capture molecule was that the displacement efficiency was not sufficient to capture 8-nitroguanosine in water. Taking into account that both the flexibility of the linker and the pKa value of the thiol group are determinants of the reactivity, new nitroG-grasp molecules were designed to have a fixed linker structure with different pKa values. Compared to the previous nitroG grasp, the new compounds with the (2-aminophenyl)methanethiol or the propylene acetal of 3-amino-1-mercaptopropan-2-one unit have exhibited more than 10-100 times faster reactivity in the aqueous media. These compounds may be potential components to construct new nitroG-grasp molecules to capture 8-nitro-cGMP in the biological systems. PMID- 26521856 TI - Enhancement of TFO Triplex Formation by Conjugation with Pyrene via Click Chemistry. AB - This paper reports the preparation of 14-mer triplex-forming oligonucleotides (TFOs) containing a 2-O-methyl-1-beta-phenyl-alpha-propargyl-ribose unit, which was conjugated with azide-modified molecules via a click reaction. Modification of these TFOs with pyrene assisted triplex formation, improving the stability of the triplex DNA and the anti-proliferative effects against A549 cells. PMID- 26521857 TI - Novel Dammarane-Type Triterpene Saponins from Panax ginseng Root. AB - Four phytochemical constituents were isolated from Panax ginseng root by repeated column chromatography (CC), medium pressure liquid chromatography (MPLC), high speed counter current chromatography (HSCCC), and semi-preparative HPLC. Their structures were elucidated as the dammarane-type triterpene saponins ginsenoside Rg18 (1), 6-acetyl ginsenoside-Rg3 (2), ginsenoside-Rs11 (3), and ginsenoside-Re7 (4) based on spectral data. Compounds 1-4 from P. ginseng root were new compounds from nature. They showed good hydroxyl radical scavenging activity and anti bacterial activity against Escherichia coli and Staphylococcus aureus. However, they did not show any anti-inflammatory activity. In addition, they inhibited the growth of adenocarcinoma gastric stomach cells. Among them, ginsenoside-Rs11 (3) showed the best anti-oxidative, anti-bacterial, and anti-cancer activities. PMID- 26521858 TI - Synthesis and Antiviral Evaluation of Some C(3)-Symmetrical Trialkoxy-Substituted 1,3,5-Triazines and Their Molecular Geometry. AB - As one of our projects, we here report some new molecular modifications of 2,4,6 trichloro-1,3,5-triazine (TCTAZ: 1) to symmetrical 2,4,6-trialkoxy- or 2,4,6 triaryloxy-substituted 1,3,5-triazine (TAZ) molecules, as well as the results of anti-herpes simplex virus type 1 (anti-HSV-1) activity evaluation of synthesized 2,4,6-trisubstituted TAZ derivatives. Among the tested 2,4,6-trisubstituted TAZ derivatives, we reconfirmed that a C3-symmetrical TAZ derivative, 4e, shows the highest level of anti-HSV-1 activity with a good selectivity index. In this paper, we also report the results of the preparation of newly targeted TAZ derivatives and the structure-activity relationships (SARs) of these trialkoxy substituted TAZ derivatives and related compounds. The sugar recognition properties of C3-symmetrical TAZ derivative 4e are also described. PMID- 26521859 TI - Paratrimerins A and B, Two New Dimeric Monoterpene-Linked Coumarin Glycosides from the Roots and Stems of Paramignya trimera. AB - Two new dimeric monoterpene-linked coumarin glucosides, paratrimerins A (1) and B (2), and three known coumarins, 6-(6-hydroxy-3,7-dimethylocta-2,7-dienyl)-7 hydroxycoumarin (3), ostruthin (4), and ninhvanin (5), were isolated from the roots and stems of Paramignya trimera (OLIV.) GUILL. collected in Khanh Hoa province, Vietnam. Compound 1 comprises two 7-O-beta-D-glucopyranoside coumarins linked at positions 6,6' via a 1,3,4,4-tetrasubstituted cyclohexene containing a monoterpene bridge, whereas compound 2 is a beta-D-apiofuranosyl(1->6)-beta-D glucopyranosyl derivative of 1. The chemical structures of these compounds were determined by one dimensional (1D) and 2D-NMR and high resolution-electrospray ionization (HR-ESI)-MS spectroscopy. PMID- 26521860 TI - Ginseng Saponins in Different Parts of Panax vietnamensis. AB - Chemical and pharmacological studies of Panax vietnamensis (Vietnamese ginseng; VG) have been reported since its discovery in 1973. However, the content of each saponin in different parts of VG has not been reported. In this study, 17 ginsenosides in the different underground parts of P. vietnamensis were analyzed by HPLC/evaporative light scattering detector (ELSD). Their contents in the dried rhizome, radix, and fine roots were 195, 156, and 139 mg/g, respectively, which were extremely high compared to other Panax species. The content of protopanaxatriol (PPT)-type saponins were not much different among underground parts; however, the content of protopanaxadiol (PPD)- and ocotillol (OCT)-type saponins were greatly different. It is noteworthy that the ginsenoside pattern in the fine roots is different from other underground parts. In particular, despite the content of PPD-type saponins being the highest in the fine roots, which is similar to other Panax species, the total content of saponins was the lowest in the fine roots, which is different from other Panax species. The ratios of PPT : PPD : OCT-type saponins were 1 : 1.7 : 7.8, 1 : 1.6 : 5.5, and 1 : 4.8 : 3.3 for the rhizome, radix, and fine roots, respectively. OCT-type saponins accounted for 36-75% of total saponins and contributed mostly to the difference in the total saponin content of each part. PMID- 26521861 TI - Anticholinesterase and beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitory Compounds from the Heartwood of Juniperus chinensis. AB - Two new compounds (2, 3) and 20 known compounds (1, 4-22) were isolated from the heartwood of Juniperus chinensis LINNE (Cupressaceae), and their structures were elucidated as 9'-methoxycalocedrin (1); alpha-methyl artoflavanocoumarin (2); 5,7,4'-trihydroxy-2-styrylchromone (3); cedrol (4); widdrol (5); savinin (6); calocedrin (7); 10-oxowiddrol (8); 12-hydroxywiddrol (9); (+)-naringenin (10); vanillic acid methyl ester (11); (+)-taxifolin (12); (+)-aromadendrin (13); kaempferol (14); quercetin (15); (7S,8R)-dihydro-3'-hydroxy-8- hydroxymethyl-7-(4 hydroxy-3-methoxyphenyl)-1'-benzofuranpropanol (16); styraxlignolide C (17); protocatechuic acid (18); vanillic acid (19); (7R,8S)-dihydro-3'-methoxy-8 hydroxymethyl-7-(4-hydroxy-3-methoxyphenyl)-1'-benzofuranpropanol 4-O-beta-D glucopyranoside (20); (7S,8S)-dihydro-3'-hydroxy-8-hydroxymethyl-7-(4-hydroxy-3 methoxyphenyl)-1'-benzofuranpropanol 4-O-alpha-L-rhamnopyranoside (21); and (+) catechin (22) on the basis of spectroscopic evidence. The new compounds (2, 3) exhibited good inhibitory activities against beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), with IC50 values of 6.25, and 11.91 uM, respectively. PMID- 26521862 TI - Synthesis and Determination of Absolute Configuration of Lentztrehalose A. AB - The synthesis of lentztrehalose A, a naturally occurring trehalose derivative exhibiting various biological activities including autophagy-inducing activity, was achieved. The synthesis commenced with the selective protection of hydroxyl groups of commercially available trehalose, followed by the introduction of the side chain moiety by two methods: 1) prenylation and successive diastereoselective dihydroxylation; or 2) etherification by opening of the chiral epoxide. The present synthetic study clarified the unreported absolute configuration of the secondary alcohol part in the side chain portion. PMID- 26521863 TI - Sinorhizobium fredii HH103 bacteroids are not terminally differentiated and show altered O-antigen in nodules of the Inverted Repeat-Lacking Clade legume Glycyrrhiza uralensis. AB - In rhizobial species that nodulate inverted repeat-lacking clade (IRLC) legumes, such as the interaction between Sinorhizobium meliloti and Medicago, bacteroid differentiation is driven by an endoreduplication event that is induced by host nodule-specific cysteine rich (NCR) antimicrobial peptides and requires the participation of the bacterial protein BacA. We have studied bacteroid differentiation of Sinorhizobium fredii HH103 in three host plants: Glycine max, Cajanus cajan and the IRLC legume Glycyrrhiza uralensis. Flow cytometry, microscopy analyses and viability studies of bacteroids as well as confocal microscopy studies carried out in nodules showed that S. fredii HH103 bacteroids, regardless of the host plant, had deoxyribonucleic acid (DNA) contents, cellular sizes and survival rates similar to those of free-living bacteria. Contrary to S. meliloti, S. fredii HH103 showed little or no sensitivity to Medicago NCR247 and NCR335 peptides. Inactivation of S. fredii HH103 bacA neither affected symbiosis with Glycyrrhiza nor increased bacterial sensitivity to Medicago NCRs. Finally, HH103 bacteroids isolated from Glycyrrhiza, but not those isolated from Cajanus or Glycine, showed an altered lipopolysaccharide. Our studies indicate that, in contrast to the S. meliloti-Medicago model symbiosis, bacteroids in the S. fredii HH103-Glycyrrhiza symbiosis do not undergo NCR-induced and bacA-dependent terminal differentiation. PMID- 26521864 TI - Plasma thrombospondin-1 and clinical outcomes in traumatic brain injury. AB - OBJECTIVE: Thrombospondin-1 (TSP-1) acts as an anti-angiogenic factor, and its expression in rat brain is upregulated after intracerebral hemorrhage. The current study was designed to investigate the change of plasma TSP-1 levels and assess the prognostic predictive effect of plasma TSP-1 level and it is associated with head trauma severity in the patients with severe traumatic brain injury (STBI). MATERIALS AND METHODS: The plasma TSP-1 levels of 134 patients and 134 healthy controls were measured using enzyme-linked immunosorbent assay. The relationships between plasma TSP-1 levels and trauma severity reflected by Glasgow Coma Scale (GCS) scores as well as between plasma TSP-1 levels and short term and long-term clinical outcomes were analyzed using multivariate analysis. RESULTS: Plasma TSP-1 levels were statistically significantly higher in patients than in healthy controls. The multivariate analysis demonstrated close association of TSP-1 with GCS scores and also identified TSP-1 as an independent predictor for 1-week mortality, 6-month mortality, and 6-month unfavorable outcome. Plasma TSP-1 levels had high prognostic predictive value based on receiver operating characteristic curve. The difference between its prognostic predictive value and GCS scores was not statistically significant. CONCLUSIONS: Plasma TSP-1 levels are elevated and are highly associated with head trauma severity and short-term and long-term outcomes of STBI. TSP-1 may be a good prognostic biomarker of STBI. PMID- 26521866 TI - Needle size in intravitreal injections - pain evaluation of a randomized clinical trial. AB - PURPOSE: To evaluate the influence of the needle size used for intravitreal (IVT) injections on patients' pain experience in a randomized, double-armed, single blinded, clinical trial. METHODS: Patients included were randomized to have an IVT injection performed with a 27-gauge needle (group 1) or with a 30-gauge needle (group 2). The topical anaesthesia before the injection was standardized. Immediately after the injection, patients were asked to grade their pain using the visual analogue scale (VAS) and the Wong-Baker FACES scale. The main outcome measure was the pain score assessment. Cofactors analysed were patients' demographics (age and gender) and clinical characteristics (such as the number of previous IVT injections). In addition, scaled surgeon's questionnaires to assess the IVT injection procedure were evaluated. For statistical analysis, a regression model was used. RESULTS: The data of 208 patients (group 1: 104 patients; group 2: 104 patients) were analysed. There was no significant difference in the VAS pain scores (p > 0.18) and in the Wong-Baker pain scores (p > 0.59) between both treatment groups. Gender (p = 0.0288) and the number of previous IVT injections (p = 0.0028) significantly influenced the VAS pain scores (p < 0.05). Female patients and patients with a history of previous IVT injections had higher pain scores. The surgeon's questionnaire showed an overall preference towards the use of a 30-gauge needle for IVT injections. CONCLUSION: The use of a 30-gauge needle for IVT injections showed no significant effect in pain relief compared to the use of a 27-gauge needle. However, a 30-gauge needle was preferred by all surgeons. PMID- 26521865 TI - Literature review of visual representation of the results of benefit-risk assessments of medicinal products. AB - BACKGROUND: The PROTECT Benefit-Risk group is dedicated to research in methods for continuous benefit-risk monitoring of medicines, including the presentation of the results, with a particular emphasis on graphical methods. METHODS: A comprehensive review was performed to identify visuals used for medical risk and benefit-risk communication. The identified visual displays were grouped into visual types, and each visual type was appraised based on five criteria: intended audience, intended message, knowledge required to understand the visual, unintentional messages that may be derived from the visual and missing information that may be needed to understand the visual. RESULTS: Sixty-six examples of visual formats were identified from the literature and classified into 14 visual types. We found that there is not one single visual format that is consistently superior to others for the communication of benefit-risk information. In addition, we found that most of the drawbacks found in the visual formats could be considered general to visual communication, although some appear more relevant to specific formats and should be considered when creating visuals for different audiences depending on the exact message to be communicated. CONCLUSION: We have arrived at recommendations for the use of visual displays for benefit-risk communication. The recommendation refers to the creation of visuals. We outline four criteria to determine audience-visual compatibility and consider these to be a key task in creating any visual. Next we propose specific visual formats of interest, to be explored further for their ability to address nine different types of benefit-risk analysis information. PMID- 26521868 TI - Effects of metabolic syndrome on masseter muscle of male Wistar rats. AB - The aim of this study was to investigate the association between metabolic syndrome (MetS) and the metabolic indicators of masticatory muscles in an animal model. A total of 16 male Wistar rats were used. To induce MetS, 10 rats were fed with standard rat chow and 32% sucrose solution ad libitum for 16 wk. Six rats fed with standard rat chow and water ad libitum formed the control group. All rats were killed at week 16, and the right superficial masseter muscles were harvested. Metabolic indicators of masticatory muscle metabolism, including antioxidant enzyme activities, ion transport ATPase activities, and the levels of macro and trace elements, were determined in the muscles. Superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities were significantly decreased by 32%, 26%, 33%, and 16%, respectively, in the MetS group. Na(+) /K(+) -ATPase activity was significantly decreased in the MetS group by 54% compared with the control group. The levels of chromium and selenium were significantly decreased, and the level of copper was increased, in the MetS group compared with the control group. These results show that significant alterations occurred in antioxidant defense mechanisms, ion transport mechanisms, and trace element levels of masseter muscles in MetS. PMID- 26521867 TI - Regional metabolic heterogeneity of the hippocampus is nonuniformly impacted by age and caloric restriction. AB - The hippocampus is critical for cognition and memory formation and is vulnerable to age-related atrophy and loss of function. These phenotypes are attenuated by caloric restriction (CR), a dietary intervention that delays aging. Here, we show significant regional effects in hippocampal energy metabolism that are responsive to age and CR, implicating metabolic pathways in neuronal protection. In situ mitochondrial cytochrome c oxidase activity was region specific and lower in aged mice, and the impact of age was region specific. Multiphoton laser scanning microscopy revealed region- and age-specific differences in nicotinamide adenine dinucleotide (NAD)-derived metabolic cofactors. Age-related changes in metabolic parameters were temporally separated, with early and late events in the metabolic response to age. There was a significant regional impact of age to lower levels of PGC-1alpha, a master mitochondrial regulator. Rather than reversing the impact of age, CR induced a distinct metabolic state with decreased cytochrome c oxidase activity and increased levels of NAD(P)H. Levels of hippocampal PGC-1alpha were lower with CR, as were levels of GSK3beta, a key regulator of PGC-1alpha turnover and activity. Regional distribution and colocalization of PGC-1alpha and GSK3beta in mouse hippocampus was similar in monkeys. Furthermore, the impact of CR to lower levels of both PGC-1alpha and GSK3beta was also conserved. The studies presented here establish the hippocampus as a highly varied metabolic environment, reveal cell-type and regional specificity in the metabolic response to age and delayed aging by CR, and suggest that PGC-1alpha and GSK3beta play a role in implementing the neuroprotective program induced by CR. PMID- 26521869 TI - [Tremendous Human, Social, and Economic Losses Caused by Obstinate Application of the Failed Linear No-threshold Model]. AB - The linear no-threshold model (LNT) was recommended in 1956, with abandonment of the traditional threshold dose-response for genetic risk assessment. Adoption of LNT by the International Commission on Radiological Protection (ICRP) became the standard for radiation regulation worldwide. The ICRP recommends a dose limit of 1 mSv/year for the public, which is too low and which terrorizes innocent people. Indeed, LNT arose mainly from the lifespan survivor study (LSS) of atomic bomb survivors. The LSS, which asserts linear dose-response and no threshold, is challenged mainly on three points. 1) Radiation doses were underestimated by half because of disregard for major residual radiation, resulting in cancer risk overestimation. 2) The dose and dose-rate effectiveness factor (DDREF) of 2 is used, but the actual DDREF is estimated as 16, resulting in cancer risk overestimation by several times. 3) Adaptive response (hormesis) is observed in leukemia and solid cancer cases, consistently contradicting the linearity of LNT. Drastic reduction of cancer risk moves the dose-response curve close to the control line, allowing the setting of a threshold. Living organisms have been evolving for 3.8 billion years under radiation exposure, naturally acquiring various defense mechanisms such as DNA repair mechanisms, apoptosis, and immune response. The failure of LNT lies in the neglect of carcinogenesis and these biological mechanisms. Obstinate application of LNT continues to cause tremendous human, social, and economic losses. The 60-year-old LNT must be rejected to establish a new scientific knowledge-based system. PMID- 26521870 TI - [Basic Research on Neurotrophic Factors and Its Application to Medical Uses]. AB - The author has studied nerve growth factor (NGF) and its family of neurotrophic factors (neurotrophins) for over 40 years. During the first 20 years, my laboratory established a highly sensitive enzyme immunoassay for NGF and analyzed the regulatory mechanism of NGF synthesis in cultured primary cells. Fibroblast cells cultured from peripheral organs such as the heart and astrocytes from the brain produced a substantial amount of NGF in a growth-dependent manner. Furthermore, synthesis of NGF in these cells could be upregulated by catechol compounds including catecholamines. This observation might explain a physiological relation between the level of NGF mRNA and the density of innervation in the peripheral sympathetic nervous systems. Over the subsequent 20 years, my laboratory investigated the physiological functions of neurotrophic factors, including neurotrophins, during development or post-injury and found that brain-derived neurotrophic factor (BDNF) plays a role in the formation of the laminar structure of the cerebral cortex. In addition, my laboratory discovered that endogenous glial cell line-derived neurotrophic factor (GDNF) contributes to the amelioration of motor activity after spinal cord injury. Therefore we aimed to develop low-molecular weight compounds that generate neurotrophic factor-like intracellular signals to protect or ameliorate neurological/psychiatric diseases. 2-Decenoic acid derivatives and other similar molecules could protect or ameliorate in animal models of mood disorders such as depression and enhance recovery from spinal cord injury-induced motor paralysis. Compounds that can generate neurotrophin-like signals in neurons are expected to be developed as therapeutic drugs for certain neurological or psychiatric disorders. PMID- 26521871 TI - [Role of Monocarboxylate Transporter in Statin-induced Cytotoxicity]. AB - Although exercise and drug therapy are important to prevent progression of arteriosclerotic disease, exercise leads to an increase in muscular disorder induced by HMG-CoA reductase inhibitors (statins). Elucidation of this mechanism is needed to prevent the occurrence of muscular disorders. Since exercise induces expression of monocarboxylate transporter (MCT) 4, we focused on the association between MCT4 function and statin-induced muscle injury. First, we examined the transport of L-lactate via MCT4 using MCT4 cRNA-injected Xenopus laevis oocytes. L-lactate uptake by MCT4-expressing oocytes was markedly reduced by alkalizing the buffer pH and saturated at higher L-lactate concentrations. On the other hand, AMP-activated protein kinase (AMPK) and protein kinase C (PKC) are activated by exercise. We next examined whether AMPK and PKC activation affects the expression and function of MCT4 in rat skeletal muscle and RD cells as an in vitro skeletal muscle model. AMPK and PKC activation increased MCT4 expression level and lactate efflux by MCT4. Finally, we examined the association between MCT4 function and statin-induced cytotoxicity. Statins inhibited transport of L lactate via MCT4 in a concentration-dependent manner. Statin-induced cytotoxicity was associated with intracellular acidification and caspase-3/7 activation. On the other hand, bicarbonate suppressed statin-induced pH alteration, caspase activation, and morphological change. The results suggest that statin-induced muscle injury exacerbated by exercise is associated with intracellular acidification and that the effects of statins on L-lactate transport are mediated by MCT4. PMID- 26521872 TI - [Role of Human Orphan Esterases in Drug-induced Toxicity]. AB - Esterases hydrolyze compounds containing ester, amide, and thioester bonds, causing prodrug activation or detoxification. Among esterases, carboxylesterases have been studied in depth due to their ability to hydrolyze a variety of drugs. However, there are several drugs for which the involved esterase(s) is unknown. We found that flutamide, phenacetin, rifamycins (rifampicin, rifabutin, and rifapentine), and indiplon are hydrolyzed by arylacetamide deacetylase (AADAC), which is highly expressed in human liver and gastrointestinal tissues. Flutamide hydrolysis is considered associated with hepatotoxicity. Phenacetin, a prodrug of acetaminophen, was withdrawn due to side effects such as methemoglobinemia and renal failure. It was demonstrated in vitro and in vivo using mice that AADAC is responsible for phenacetin hydrolysis, which leads to methemoglobinemia. In addition, it was shown that AADAC-mediated hydrolysis attenuates the cytotoxicity of rifamycins. Thus AADAC plays critical roles in drug-induced toxicity. Another orphan esterase, alpha/beta hydrolase domain containing 10 (ABHD10), was found responsible for deglucuronidation of acyl-glucuronides including mycophenolic acid acyl-glucuronide and probenecid acyl-glucuronide. Because acyl-glucuronides appear associated with toxicity, ABHD10 would function as a detoxification enzyme. The roles of orphan esterases are becoming increasingly understood. Further studies will facilitate our knowledge of the pharmacologic and toxicological significance of orphan esterases in drug therapy. PMID- 26521873 TI - [Stereoselective Synthesis of Multi-substituted Fluoro-beta-lactams and Their Conversion to Fluorinated beta-Amino Acid Core]. AB - Multi-substituted beta-lactam compounds have not only attracted considerable interest as core structures of pharmaceutical compounds such as antibiotics but also have been used as building blocks for the construction of beta-amino acids. Electrophilic beta-lactams can be used to enhance essential biological activities. Furthermore, the ring-opening reactions of electrophilic beta-lactams can be used to provide facile access to beta-amino acids. The introduction of an electronegative fluorine atom to a beta-lactam ring to give the corresponding fluoro-beta-lactam can be used as an effective strategy for the preparation of electrophilic beta-lactams. In this review, we provide a summary of our recent research towards the direct functionalization of fluoro-beta-lactams. This review has been divided into four topics, including: 1) the alkylation and hydroxyalkylation of alpha-bromo-alpha-fluoro-beta-lactams (1); 2) the nickel catalyzed cross coupling reaction of 1; 3) the asymmetric synthesis of fluoro beta-lactams using chiral ligands; and 4) the utilization of fluoro-beta-lactams as highly electrophilic building blocks. PMID- 26521874 TI - [Multi-component Reactions Based on Formal [2+2] Reaction of Benzyne with Formamide]. AB - Arynes, such as benzyne, are highly strained and kinetically unstable intermediates that have been widely employed in organic synthesis. In particular, since the initial report regarding the in situ generation of arynes under neutral conditions from ortho-(trimethylsilyl)aryl triflates and fluoride ions in 1983, numerous nucleophilic additions to arynes have been utilized in the synthesis of carbocycles, heterocycles, and multi-substituted arenes. Recently, we reported the insertion of arynes into the pi-bond in formamides, as well as related cascade reactions. First, we synthesized salicylaldehydes and aminophenols via the insertion of arynes into the C=O bond of sterically less hindered N,N dimethylformamide (DMF). Notably, computational studies revealed the generation of unstable benzoxetene and ortho-quinone methide as reactive intermediates. We also studied multi-component coupling reactions leading to 2H-chromenes, coumarins, and xanthen-1-ones under mild conditions through the stepwise release of the strain energy in arynes. Furthermore, we studied the synthesis of O heterocycles such as dihydrobenzofuran, benzofuran, and 4H-chromene as an application of our method. In this review, we will describe these studies in detail. PMID- 26521875 TI - [Molecular and Neural Mechanisms for the Robustness of the Circadian Clock]. AB - The endogenous circadian clock drives robust oscillations in physiology and behavior, such as hormone secretions and sleep/wake cycles, with a period of about 24 h. We are rarely aware of this internal clock system because it is usually synchronized with environmental light-dark cycles. However, travelling rapidly across multiple time zones in a jet airplane suddenly makes us aware of the desynchrony between the body clock and external time, causing sleep disturbances and gastrointestinal problems. Although jet lag is recognized as a chronobiological problem, its specific molecular and neural mechanisms are poorly understood. To address this issue, we identified genes highly expressed in the suprachiasmatic nucleus of the anterior hypothalamus (SCN), the mammalian master clock that controls rhythmic behavior, then analyzed the behavior of knock-out mice for these genes under jet lag condition. We found that the circadian rhythms of locomotor activity and clock gene expression rapidly re-entrained to phase shifted light-dark cycles in mice genetically deficient in V1a and V1b receptors. Real-time imaging of cellular rhythms in the SCN suggested that interneuronal communication through V1a and V1b confers on the SCN an intrinsic resistance to external perturbation, enhancing the robustness of the SCN clockwork. Pharmacological blockade of V1a and V1b in the SCN of wild-type mice accelerated their recovery from jet lag symptoms, suggesting vasopressin signaling as a potential pharmaceutical intervention for the management of circadian rhythm misalignment. PMID- 26521876 TI - [In Vitro and in Vivo Assessments of Drug-induced Hepatotoxicity and Drug Metabolism in Humans]. AB - Drug-induced hepatotoxicity is of concern in drug discovery and development. Reactive metabolites generated by drug metabolizing enzymes in the liver contribute to the induction of hepatotoxicity. Therefore, drug-induced hepatotoxicity, drug metabolism, and pharmacokinetics were evaluated in vitro and in vivo in this pre-clinical study. First, hepatotoxicity was tested in vitro using three-dimensional hepatocyte cultures. Hepatocyte spheroids formed in the three-dimensional culture systems maintain various liver functions such as the expression of drug metabolizing enzymes. High dose exposure to acetaminophen (APAP) induces hepatotoxicity because of the formation of reactive metabolites by CYP. Using fluorescence imaging, we observed that cell viability and glutathione levels were reduced in hepatocyte spheroids exposed to APAP mediated by the metabolic activation of CYP. On the other hand, there are species differences in the expression of drug metabolizing enzymes and metabolite profiles between animals and humans. Therefore, chimeric mice transfected with human hepatocytes were used for the in vivo assessment of metabolic profiles in humans. We found that drug metabolism and pharmacokinetics mediated by CYP and non-CYP enzymes, such as UDP-glucuronosyltransferase and aldehyde oxidase, in chimeric mice with humanized liver were similar to those in humans. The combination of in vitro and in vivo assessments using spheroids and chimeric mice with humanized liver, respectively, during the screening of drug candidates may help to reveal hepatotoxicity induced by the formation of metabolites. PMID- 26521877 TI - [Structure and Function of a Novel Class of High Mannose-binding Proteins with Anti-viral or Anti-tumor Activity]. AB - The recently discovered high mannose (HM)-binding lectin family in lower organisms such as bacteria, cyanobacteria, and marine algae represents a novel class of anti-viral or anti-tumor compounds. This lectin family shows unique carbohydrate binding properties with exclusive high specificity for HM glycans with core trisaccharide comprising Manalpha(1-3)Manalpha(1-6)Man at the D2 arm. At low nanomolar levels, these lectins exhibit potent antiviral activity against HIV and influenza viruses through the recognition of HM glycans on virus spike glycoproteins. In addition, some of these lectins, such as bacterial PFL, show cytotoxicity for various cancer cells at low micromolar levels. Cell surface molecules to which PFL bound were identified as integrin alpha 2 and epidermal growth factor receptor (EGFR) by peptide mass finger printing with MALDI-TOF MS. Upon PFL binding, these molecules were rapidly internalized to cytoplasm. EGFR was time dependently degraded in the presence of PFL, and this process was largely responsible for autophagy. Furthermore, PFL sensitizes cancer cells to the EGFR kinase inhibitor, gefitinib. In vivo experiments showed that intratumoral injection of PFL significantly inhibited the growth of tumors in nude mice. PFL-mediated down regulation of integrin/EGFR ultimately contributed to the inhibition of tumor growth both in vitro and in vivo. Thus, the novel anti cancer mechanism of PFL suggests that this lectin is potentially useful as an anti-cancer drug or as an adjuvant for other drugs. This class of proteins will likely have beneficial impact as a tool for biochemical and biomedical research because of its unique carbohydrate specificity and various biological activities. PMID- 26521878 TI - [Development of Cyclodextrin-based Cancer Treatment]. AB - Drug delivery techniques to tumor cells have attracted considerable attention. For instance, folic acid (FA) as a tumor-targeting ligand is widely used because of overexpression of folate receptor-alpha (FR-alpha) in various kinds of epithelial tumor cells. On the other hand, methyl-beta-cyclodextrin (M-beta-CyD) is acknowledged to induce cell death through the extraction of cholesterol from lipid rafts. It was recently reported that intraperitoneal administration of M beta-CyD exerted antitumor activity in human tumor xenografted athymic nude mice. However, the cytotoxic activity of M-beta-CyD is known to lack tumor cell selectivity. Therefore in the present study, in an attempt to confer tumor cell selectivity to M-beta-CyD, we newly synthesized folate-appended M-beta-CyD (FA-M beta-CyD) and evaluated its potential as a novel antitumor agent. FA-M-beta-CyD showed potent antitumor activity in various FR-alpha-positive cells such as KB cells, Ihara cells, and M213 cells but not in FR-alpha-negative cells, A549 cells. FA-M-beta-CyD induced the formation of autophagic vacuoles in KB cells. In addition, the antitumor activity of FA-M-beta-CyD, but not M-beta-CyD, was inhibited by addition of the autophagy inhibitors chloroquine and bafilomycin A1 in KB cells. A single intravenous injection of FA-M-beta-CyD drastically inhibited tumor growth and significantly improved survival rate in Colon-26 cells allografted or M213 cells-xenografted mice. In conclusion, FA-M-beta-CyD has potential as a novel tumor-selective anticancer agent due to FR-alpha-mediated cellular uptake. The present results provide useful information for the design and development of novel antitumor drug carriers and antitumor drugs based on CyDs. PMID- 26521879 TI - [Structure-Function Analysis and Development of Inhibitors of Metallo-beta lactamases Conferring Drug Resistance in Bacteria]. AB - Metallo-beta-lactamases (MBLs) are di-Zn(II) metalloenzymes that efficiently hydrolyze most beta-lactam antibiotics used in clinical settings. Bacteria producing MBLs have been isolated from clinical settings and from natural environments such as rivers and soils, and are now recognized as a new potential threat to human health. No effective inhibitors are available for clinical use, making the treatment of infectious diseases caused by bacteria producing MBLs more difficult. IMP-1 is encoded on a plasmid which can be horizontally transferred between bacterial strains. Our studies on MBLs, and especially on IMP 1, focus on understanding the role of Zn(II) ion(s) in the hydrolysis of beta lactam antibiotics and on the detailed structure of the IMP-1 active site in order to develop efficient inhibitors. We investigated the role of the two Zn(II) ions in IMP-1 by kinetic, spectroscopic and thermodynamic analyses. The results revealed that the first Zn(II) ion is necessary for the hydrolysis of beta-lactam antibiotics while the second Zn(II) ion enhances enzyme activity and structural stability, thus helping the enzyme achieve maximum activity. The detailed structures of the IMP-1 active site were examined by X-ray crystallography. Thiol compounds for irreversibly inhibiting IMP-1 were developed and the binding mode of these inhibitors was investigated in detail. These findings will aid the design of inhibitors that target MBLs. PMID- 26521880 TI - [Evaluation of Detachment and Clinical Usability of Transdermal Fentanyl Patches in Healthy Volunteers]. AB - The dose of a transdermal fentanyl patch is proportional to its application site area. Therefore, the absorption of fentanyl may decrease if the patch detaches, leading to insufficient analgesia. Sixteen healthy volunteers were enrolled in a study to investigate the appropriate application sites and clinical utility of three transdermal fentanyl patches available in Japan. Three placebos, Fentanyl 1 day (Fentos; Fen), Fentanyl 3-day (Durotep; Dur), and Generic Fentanyl 3-day (HMT) were administered using a crossover study design. The placebos were applied to 11 different sites, including both sides of the upper arm, abdomen, back, thigh, chest, and the middle of the chest. We determined the patch detachment area and incidence of patch-induced itching every 24 h and evaluated differences between each application site using the Wilcoxon signed-rank test. Significant patch detachment was observed on the abdomen and upper arms with Fen, on the abdomen and chest with Dur, and on the chest with HMT compared with that at other sites (p<0.005). Although no significant difference in itching was observed between regions when administering Fen, itching significantly increased on the chest and back when using Dur and on the abdomen when using HMT as compared with that at other sites (p<0.05). Our results indicate that the three transdermal Fen patches exhibit different adhesive properties and local adverse events, indicating that the application site should be cautiously selected for each patch type. PMID- 26521881 TI - [Discussion on Partial Validation in Small Molecule Regulated Bioanalysis: Change in Analytical Instruments]. AB - In recent years, the necessity of a bioanalytical method validation has been discussed and guidance/guidelines have been released from regulatory agencies. However, none of these provides any details for partial validation (PV) in case of a partial change in the validated analytical method. Therefore eleven scientists have launched a discussion group (DG) with the approval of Japan Bioanalysis Forum (JBF), and have been discussing PV for chromatographic methods based on survey results of Japanese bioanalysts. This document reports the results of discussion on PV for a change of analytical instruments such as: 1) full system (limited to same manufacturer and model); 2) pump; 3) autosampler; and 4) mass spectrometer. The DG members agreed on an outline that validation items required for PV are as follows: calibration curve and reproducibility in case 1); calibration curve, reproducibility, and selectivity in case 2); calibration curve, reproducibility, and carryover in case 3); and nearly full validation items without recovery, dilution integrity, and stability in case 4), in consideration of instrument specification and characteristics of each analytical method. Note that this report does not represent a consensus of all the members of JBF, but is a recommendation from the DG members at this stage. Thus further thought is recommended for future discussions. PMID- 26521882 TI - Adaptive management of invasive pests in natural protected areas: the case of Matsucoccus feytaudi in Central Italy. AB - Invasive species are a significant threat to affected ecosystems, having serious environmental, economic and social impacts. The maritime pine bast scale, Matsucoccus feytaudi Ducasse (Hemiptera: Matsucoccidae), causes serious damage to Pinus pinaster forests in SE France, Corsica and Italy where it has been introduced. This study illustrates the adaptive management plan implemented in the Migliarino, San Rossore, Massaciuccoli Regional Natural Park in Tuscany, Italy, where M. feytaudi arrived in 2004, leading to the decay of local P. pinaster stands. The management programme, aimed at slowing the establishment and growth of M. feytaudi, was carried out in the main sector of the park, Tenuta di San Rossore, to retard the destruction of the P. pinaster coastal strip protecting the more internal woodland from sea salt and to allow replacement of P. pinaster trees with a more stable broad-leaved wood. The combined use of mass trapping and silvicultural interventions, applied in a targeted manner according to distribution maps of pest captures and damage, helped to delay forest destruction compared with a nearby unmanaged area of the park Tenuta di Tombolo. Although M. feytaudi continued to spread during the management period, the populations remained at low levels for 6 years, showing a marked increase in 2012. During this period, the P. pinaster stands were reduced from 320 to 249 ha. The final result of this ongoing gradual conversion process will be transformation of the P. pinaster forest into Holm oak woods and Mediterranean shrub land, while P. pinaster will survive as clusters or blocks of trees. PMID- 26521883 TI - Peer review: tips from field experts for junior reviewers. AB - This editorial introduces a series of tutorials by experts, who provide tips and advice for junior reviewers on how to conduct peer review based on specific study designs. The aim of these articles is to provide an easy-to-use, quick reference for those who are seeking more guidance on how to peer review biomedical research papers. Unlike previous tips and guides on peer review, this series is the first to provide advice from experts for those in their specific fields. PMID- 26521884 TI - A Pilot Study to Assess Adenosine 5'-triphosphate Metabolism in Red Blood Cells as a Drug Target for Potential Cardiovascular Protection. AB - OBJECTIVE: To study the effect of exercise preconditioning on adenosine 5'triphosphate (ATP) metabolism in red blood cells and cardiovascular protection against injury induced by isoproterenol in vivo. METHODS: Male Sprague Dawley rats (SDR) were each exercised on a treadmill for 15 minutes at 10 m/min and 10% grade (n = 7) (LowEx), or 14 m/min and 22% grade (n = 8) (VigEx). Two hours after the exercise, each rat received a single dose of isoproterenol (30 mg/kg) by subcutaneous (sc) injection. Two separate groups of SDR were used as control: One received no exercise (n = 10) (NoEx) and the other received no exercise and no isoproterenol (n = 11) (NoIso). Serial blood samples were collected over 5 hours for measurement of ATP and its catabolites by a validated HPLC. Hemodynamic recording was collected continuously for the duration of the experiment. Data were analysed using ANOVA and t-tests and difference considered significant at p < 0.05. RESULTS: Exercise pre-conditioning (both LowEx and VigEx) reduced mortality after isoproterenol from 50% to < 30% (p > 0.05). It attenuated the rebound in blood pressure significantly (p < 0.05 between NoEx vs VigEx), attenuated the increase of RBC adenosine 5'-monophosphate (AMP) concentrations induced by isoproterenol, and also decreased the breakdown of ATP to AMP in the RBC (p < 0.05 vs NoEx). CONCLUSION: Exercise pre-conditioning decreased the blood pressure rebound and also breakdown of ATP in RBC after isoproterenol which may be exploited further as a drug target for cardiovascular protection and prevention. PMID- 26521885 TI - Organ Preference of Cancer Metastasis and Metastasis-Related Cell Adhesion Molecules Including Carbohydrates. AB - This review starts on one of our special interests, the organ preference of metastasis. We examined data on 1,117 autopsy cases and found that the organ distribution of metastasis of cancers of the lung, pancreas, stomach, colon, rectum, uterine cervix, liver, bile duct, and esophagus involved the lung, liver, adrenal gland, bone/bone marrow, lymph node, and pleura/peritoneum. Cancers of the kidney, thyroid, ovary, choriocarcinoma, and breast, however, manifested different metastatic patterns. The distribution of leukemia and lymphoma metastases was quite different from that of epithelial cancers. On the basis of experimental studies, we believe that the anatomical-mechanical hypothesis should be replaced by the microinjury hypothesis, which suggests that tissue microinjury induced by temporal tumor cell embolization is crucial for successful metastasis. This hypothesis may actually reflect the so-called inflammatory oncotaxis concept. To clarify the mechanisms underlying metastasis, we developed an experimental model system of a rat hepatoma AH7974 that embraced substrate adhesiveness. This model did not prove a relationship between substrate-adhesion potential and metastatic lung-colonizing potential of tumor cells, but metastatic potential was correlated with the expression of the laminin carbohydrate that was recognized by Griffonia (Bandeiraea) simplicifolia isolectin G4. Therefore, we investigated the relationship between carbohydrate expression profiles and metastasis and prognosis. We indeed found an intimate relationship between the carbohydrate expression of cancer cells and the progression of malignant tumors, organ preference of metastasis, metastatic potential of tumor cells, and prognosis of patients. PMID- 26521886 TI - NxStage dialysis system-associated thrombocytopenia: a report of two cases. AB - Thrombocytopenia in hemodialysis patients has recently been reported to be commonly caused by electron-beam sterilization of dialysis filters. We report the occurrence of thrombocytopenia in the first two patients of a newly established home hemodialysis program. The 2 patients switched from conventional hemodialysis using polysulfone electron-beam sterilized dialyzers to a NxStage system, which uses gamma sterilized polyehersulfone dialyzers incorporated into a drop-in cartridge. The thrombocytopenia resolved after return to conventional dialysis in both patients and recurred upon rechallenge in the patient who opted to retry NxStage. This is the first report of thrombocytopenia with the NxStage system according to the authorsa?? knowledge. Dialysis-associated thrombocytopenia pathophysiology and clinical significance are not well understood and warrant additional investigations. PMID- 26521887 TI - Neutrophil-to-lymphocyte ratio and platelet-tolymphocyte ratio in evaluation of inflammation in end-stage renal disease. AB - OBJECTIVE: To evaluate the relationship between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and inflammation in end-stage renal disease (ESRD) patients on maintenance hemodialysis (HD). METHODS: 100 ESRD patients on maintenance HD (mean +/- SD age: 52.3 +/- 1.7 years, 52% were males) were included in this cross-sectional study. Data on patient demographics, dry weight, body mass index, duration of HD (months), etiology of ESRD, delivered dose of dialysis (spKt/V), complete blood count, blood biochemistry and inflammatory markers including hs-CRP (mg/L), TNF-alpha (pg/mL), NLR, and PLR were recorded in all patients and compared in patients with hs-CRP levels of <= 3 mg/L vs. > 3 mg/L. other study parameters were also recorded. RESULTS: Compared to patients with lower hs-CRP levels, patients with hs-CRP levels of > 3 mg/L had significantly higher values for NLR (3.7 +/- 0.2 vs. 2.7 +/- 0.2, p < 0.01) and PLR (150.7 +/- 6.9 vs. 111.8 +/- 7.0, p < 0.001). Both NLR and PLR were positively correlated with hs-CRP (r = 0.333, p = 0.01 and r = 0.262, p = 0.001, respectively) and negatively correlated with transferrin saturation (%) (r = 0.418, p = 0.001 and r = -0.309, p = 0.002, respectively). CONCLUSION: Our findings in a cohort of ESRD patients on maintenance HD revealed higher values for NLR and PLR in patients with higher levels of inflammation along with a significant positive correlation of both NLR and PLR with hs-CRP levels. Being a simple, relatively inexpensive and universally available method, whether or not calculation of NLR and PLR offers a plausible strategy in the evaluation of inflammation in ESRD patients in the clinical practice should be addressed in larger scale randomized and controlled studies. PMID- 26521888 TI - Tumor induced osteomalacia: associated with elevated circulating levels of fibroblast growth factor-7 in addition to fibroblast growth factor-23. AB - Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia, and osteomalacia. Fibroblast growth factor (FGF)-23, a phosphatonin i.e., phosphaturia-promoting hormone, is commonly implicated in the pathogenesis of TIO. However, very limited information is available about the circulating levels and clinical significance of other phosphatonins that are expressed by TIO-associated tumors. In addition, identification of the primary tumor constitutes a frequent major challenge in the management of TIO. Here, we report a patient with the clinical diagnosis of TIO with elevated blood levels of the phosphatonins FGF-23 and FGF-7; and extensive but unrewarding radiological search for the primary tumor. In selective venous sampling, both FGF-23 and FGF-7 displayed highest concentrations in the left femoral and iliac veins; although lateralization was much more pronounced for FGF 7 than FGF-23. This laboratory finding allowed us to focus on the left lower extremity as the likely location of the primary tumor. Our case is the first to show that FGF-7 can be analyzed in the circulation and used to assist in the diagnosis and localization of TIO-associated tumors. PMID- 26521889 TI - Cost-minimization analysis comparing intravenous immunoglobulin with plasma exchange in the management of patients with myasthenia gravis. AB - INTRODUCTION: Myasthenia gravis (MG) exacerbations may be treated with intravenous immunoglobulin (IVIg) or plasma exchange (PLEX), which have equivalent effectiveness. This cost-minimization analysis compared IVIg with PLEX for treatment of patients with MG exacerbation. METHODS: We combined the Ontario based health cost data with clinical data from a randomized clinical trial. Analyses were undertaken from the perspective of a public healthcare insurer and from the perspective of a tertiary university hospital payer. RESULTS: PLEX was less costly than IVIg among patients with a body mass index (BMI) > 15.7 kg/m(2) , from the perspective of the public healthcare insurer (P < 0.0001). However, PLEX was more costly than IVIg from the perspective of the hospital payer when the costs of blood products were excluded (P < 0.0001). CONCLUSIONS: PLEX can be considered a short-term cost-minimizing therapy when compared with IVIg for treatment of MG exacerbation among patients with BMI >15.7 kg/m(2) , from the perspective of a public healthcare insurer. Muscle Nerve 53: 872-876, 2016. PMID- 26521890 TI - Characterization of the Neospora caninum NcROP40 and NcROP2Fam-1 rhoptry proteins during the tachyzoite lytic cycle. AB - Virulence factors from the ROP2-family have been extensively studied in Toxoplasma gondii, but in the closely related Neospora caninum only NcROP2Fam-1 has been partially characterized to date. NcROP40 is a member of this family and was found to be more abundantly expressed in virulent isolates. Both NcROP2Fam-1 and NcROP40 were evaluated as vaccine candidates and exerted a synergistic effect in terms of protection against vertical transmission in mouse models, which suggests that they may be relevant for parasite pathogenicity. NcROP40 is localized in the rhoptry bulbs of tachyzoites and bradyzoites, but in contrast to NcROP2Fam-1, the protein does not associate with the parasitophorous vacuole membrane due to the lack of arginine-rich amphipathic helix in its sequence. Similarly to NcROP2Fam-1, NcROP40 mRNA levels are highly increased during tachyzoite egress and invasion. However, NcROP40 up-regulation does not appear to be linked to the mechanisms triggering egress. In contrast to NcROP2Fam-1, phosphorylation of NcROP40 was not observed during egress. Besides, NcROP40 secretion into the host cell was not successfully detected by immunofluorescence techniques. These findings indicate that NcROP40 and NcROP2Fam-1 carry out different functions, and highlight the need to elucidate the role of NcROP40 within the lytic cycle and to explain its relative abundance in tachyzoites. PMID- 26521891 TI - The Delphi consensus technique: oracle of gait analysis. PMID- 26521892 TI - Infective endocarditis: call for education of adults with CHD: review of the evidence. AB - Advanced surgical repair procedures have resulted in the increased survival rate to adulthood of patients with CHD. The resulting new chronic conditions population is greater than one million in the United States of America and >1.2 million in Europe. This review describes the risks and effects of infective endocarditis - a systemic infectious process with high morbidity and mortality - on this population and examines the evidence to determine whether greater patient education on recognition of symptoms and preventative measures is warranted. The literature search included the terms "infective endocarditis" and "adult congenital heart disease". Search refinement, the addition of articles cited by included articles, as well as addition of supporting articles, resulted in utilisation of 24 articles. Infective endocarditis, defined by the modified Duke Criteria, occurs at a significantly higher rate in the CHD population due to congenitally or surgically altered cardiac anatomies and placement of prosthetic valves. This literature review returned no studies in the past five years assessing knowledge of the definition, recognition of symptoms, and preventative measures of infective endocarditis in the adult CHD population. Existing data are more than 15 years old and show significant knowledge deficits. Studies have consistently shown the need for improved CHD patient knowledge with regard to infective endocarditis, and there is no recent evidence that these knowledge deficits have decreased. It is important to address and decrease knowledge deficits in order to improve patient outcomes and decrease healthcare utilisation and costs. PMID- 26521893 TI - [Fondaparinux in the treatment of acute coronary syndromes in Poland--from theory to practice. Experts' group position paper endorsed by the Polish Cardiac Society Working Group on Cardiovascular Pharmacotherapy]. PMID- 26521894 TI - Direct thioamination of arynes via reaction with sulfilimines and migratory N arylation. AB - A novel method for preparing a diverse range of o-sulfanylanilines is described. Direct thioamination of arynes with sulfilimines gives o-sulfanylanilines, involving C-N and C-S bond formations and migratory N-arylation. PMID- 26521895 TI - Tailoring Anisotropic Interactions between Soft Nanospheres Using Dense Arrays of Smectic Liquid Crystal Edge Dislocations. AB - We investigated composite films of gold nanoparticles (NPs)/liquid crystal (LC) defects as a model system to understand the key parameters, which allow for an accurate control of NP anisotropic self-assemblies using soft templates. We combined spectrophotometry, Raman spectroscopy, and grazing incidence small-angle X-ray scattering with calculations of dipole coupling models and soft sphere interactions. We demonstrate that dense arrays of elementary edge dislocations can strongly localize small NPs along the defect cores, resulting in formation of parallel chains of NPs. Furthermore, we show that within the dislocation cores the inter-NP distances can be tuned. This phenomenon appears to be driven by the competition between "soft (nano)sphere" attraction and LC-induced repulsion. We evidence two extreme regimes controlled by the solvent evaporation: (i) when the solvent evaporates abruptly, the spacing between neighboring NPs in the chains is dominated by van der Waals interactions between interdigitated capping ligands, leading to chains of close-packed NPs; (ii) when the solvent evaporates slowly, strong interdigitation between the is avoided, leading to a dominating LC-induced repulsion between NPs associated with the replacement of disordered cores by NPs. The templating of NPs by topological defects, beyond the technological inquiries, may enable creation, investigation, and manipulation of unique collective features for a wide range of nanomaterials. PMID- 26521896 TI - A severe and prolonged case of pemphigoid gestationis successfully treated with combination therapies. PMID- 26521897 TI - Haploidentical Related Peripheral Blood Stem Cell Transplantation as a Salvage Transplantation in Patients with Graft Failure. PMID- 26521898 TI - Successful Multidisciplinary Therapy for Small Cell Carcinomas Arising from the Extrahepatic Bile Duct. AB - A 74-year-old man was diagnosed with small cell carcinoma arising from the extrahepatic bile duct according to a histological examination of the biopsy specimen obtained during endoscopic retrograde cholangiopancreatography. Additionally, bulky hilar lymphadenopathy was observed, and the patient was treated with the combination of radiation and chemotherapy (cisplatin and irinotecan). Post-therapy, he underwent pancreaticoduodenectomy. The histological examination of the resected specimen revealed no residual cancer cells in the bile duct wall and a small amount of cancer cells in only a single lymph node. Due to this multidisciplinary therapy, the patient showed no signs of recurrence 12 months postoperatively. PMID- 26521899 TI - Coronary Subclavian Steal Syndrome Evaluated with Multimodality Imaging. AB - In patients with mammary-coronary bypass grafts, the presence of a subclavian artery stenosis proximal to the internal mammary artery may result in a condition termed coronary-subclavian steal syndrome of which the incidence varies between 0.07-3.4% among those requiring coronary grafts. We reported a patient with a history of the coronary artery bypass graft who presented with typical angina pectoris at rest that was exacerbated by selective exercise of the left upper extremity in whom occlusion of the left subclavian artery was demonstrated in this patient by 3D reconstruction of computed tomography angiography, a reversal blood flow in the left internal mammary artery-left anterior descending artery graft by Doppler ultrasonography, and a coronary angiography. PMID- 26521900 TI - Use of Coils and a Pulmonary Vasodilator to Reduce Pulmonary Hypertension in a Patient with Interstitial Pneumonia and Scleroderma. AB - Fistulas between systemic and pulmonary arteries are associated with various underlying etiologies and cause pulmonary hypertension (PH). Diagnosis of this condition requires several imaging studies and the exclusion of other possible causes of PH. We herein report a case of a patient with interstitial pneumonia and scleroderma. The imaging revealed multiple fistulas involving the inferior phrenic and left lower pulmonary arteries. The fistulas were closed using coils, but the PH remained presumably due to other undiagnosed fistulas. The improvement of symptoms following use of a supplementary pulmonary vasodilator provides the hope that the chosen treatment could be a viable alternative approach for other similar cases. PMID- 26521901 TI - Myocardial Injury without Electrocardiographic Changes after a Suicide Attempt by an Overdose of Glimepiride and Zolpidem: A Case Report and Literature Review. AB - A 40-year-old diabetic man was admitted to our hospital for poor glycemic control. During hospitalization, he took 42 mg glimepiride and 50 mg zolpidem as a suicide attempt. The following day, the creatine kinase-MB fraction and troponin I levels were elevated to 112 IU/L and 8.77 ng/mL, respectively, without any electrocardiographic abnormalities. The patient recovered completely without any complications. Four weeks later, coronary computed tomography angiography and myocardial perfusion scintigraphy revealed moderate one-vessel coronary disease without the evidence of myocardial ischemia or old infarction. Cardiac-specific markers must be considered in sulfonylurea-induced hypoglycemic patients, particularly when the patient is unconscious and does not exhibit any clinical manifestations. PMID- 26521902 TI - Successful Diagnosis of a Thymoma by Endobronchial Ultrasound-guided Transbronchial Needle Aspiration: A Report of Two Cases. AB - We herein report two cases of thymomas diagnosed by endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA). In both cases, the tumor was adjacent to the central airway. Therefore, we attempted to perform EBUS-TBNA in order to obtain specimens for a histopathological examination, which resulted in a diagnosis of thymoma. In one case, surgical resection was conducted and the histological evaluation of the resected specimen confirmed thymoma type AB, consistent with the histology from the EBUS-TBNA specimen. As a safe and minimally invasive procedure, EBUS-TBNA may be considered for the diagnosis of mediastinal tumors, including thymoma. PMID- 26521903 TI - A Rare Case of Pleomorphic Carcinoma of the Lung Harboring an Anaplastic Lymphoma Kinase (ALK) Rearrangement. AB - Molecular testing for anomalies, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase (ALK) rearrangement, is part of the current standard of care for non-small cell lung cancer, particularly adenocarcinoma. ALK rearrangement occurs most frequently in adenocarcinoma cells and rarely in non-adenocarcinoma cells. We herein report a rare case of pleomorphic lung carcinoma with ALK rearrangement in both its adenocarcinoma and spindle cell components. This case suggests the possibility of ALK rearrangement in pleomorphic carcinoma. PMID- 26521904 TI - Huge Pulmonary Arteriovenous Malformation, Venous Thromboembolism and Anticoagulation Treatment in a Patient with Hereditary Hemorrhagic Telangiectasia. AB - Hereditary hemorrhagic telangiectasia (HHT) usually presents in association with pulmonary arteriovenous malformations (PAVMs). In addition, the incidence of venous thromboembolism tends to be increased in these patients. A 74-year-old female with HHT presented with cyanosis and hypoxemia. Contrast-enhanced multislice computed tomography (MSCT) revealed two left PAVMs and one in the right upper lobe. Both left PAVMs were treated with embolotherapy. Follow-up MSCT revealed an incidental pulmonary embolism in the right pulmonary branches. Deep venous thrombosis was confirmed and anticoagulation was initiated. Follow-up MSCT revealed the resolution of thromboembolism. Finally, embolotherapy was performed. This case illustrates the chronic adaptation to hypoxemia and adds further evidence to the relative safety of anticoagulation treatment in these patients. PMID- 26521905 TI - Successful Engraftment and Durable Graft-versus-host Disease Control with Haploidentical Peripheral Blood and a Short-term Conditioning Regimen for Primary Graft Failure. AB - Primary graft failure occurred after cord blood transplantation for a patient with acute lymphoblastic leukemia. The second transplantation was performed using haploidentical peripheral blood. The conditioning regimen consisted of fludarabine (day -1; 30 mg/m(2)), cyclophosphamide (day -1; 2,000 mg/m(2)), and total body irradiation (day -1; 2 Gy). The immunosuppressants contained tacrolimus, prednisolone, and rabbit anti-thymocyte globulin (day -3 to -2; total dose: 3.75 mg/kg). The engraftment was confirmed on day 9. Both acute and chronic graft-versus-host disease were controllable. The present regimen appears to be suitable for immediate management, fast engraftment, and the durable control of complications. PMID- 26521906 TI - Diffuse Leukoencephalopathy Associated with Dialysis Disequilibrium Syndrome. AB - A 52-year-old woman, previously treated for gastric cancer, began hemodialysis (HD) to treat the onset of severe acidemia. After her initial HD sessions, she suffered from a prolonged coma for approximately ten days. Magnetic resonance imaging revealed diffuse leukoencephalopathy, with increased apparent diffusion coefficient. Magnetic resonance spectroscopy showed a reduction of the N acetylaspartate/creatine ratio. Her neuroimaging findings gradually resolved. Her transient cerebral white matter lesions were thought to be interstitial edema derived from dialysis disequilibrium syndrome (DDS), which might have been amplified by subclinical brain injury due to past chemotherapy. Her history of cancer chemotherapy may be a risk factor for an exacerbation of DDS. PMID- 26521907 TI - Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Negative Small Vessel Vasculitis: A Rare Cause of Pulmonary Renal Syndrome. AB - Pulmonary renal syndrome (PRS) is characterized by both diffuse alveolar haemorrhage and glomerulonephritis as pathological features. Several immunologic and non-immunologic mechanisms including anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis, anti-glomerular basement membrane disease, and systemic lupus erythematosus are commonly involved in the pathogenesis of the syndrome. We herein present a 60-year-old woman, non-smoker, who presented with fever, polyarthralgia, and the spreading of generalized purpuric rashes. The patient displayed rapid deterioration over the following two weeks marked by progressive declining renal function followed by haemoptysis. The patient was subsequently diagnosed with PRS, which was confirmed by the radiological evidence of alveolar haemorrhage and the histopathological evidence of pauci-immune glomerulonephritis. All immune markers including ANCA were negative. The patient was successfully treated with hemodialysis and immunosuppressive therapy. ANCA negative vasculitis is a rare entity and even more rare as an etiology of PRS. An early diagnosis of this disease and its timely intervention is crucial. PMID- 26521908 TI - Primary Gingival Tuberculosis Diagnosed Based on Genetic Identification. AB - A case of primary gingival tuberculosis in a 71-year-old Japanese woman is herein presented. A serous saliva culture was positive for tuberculosis, and we recognized that the origin of the tuberculosis infection was the gingiva based on the genetic identification in gingival biopsy tissue. The definitive diagnosis was facilitated by the genetic identification, a useful modern tool for diagnosing infectious diseases. The location and clinical presentation of this lesion were unusual, which underlines the importance of considering tuberculosis in the differential diagnosis of oral lesions that affect the gingiva. PMID- 26521909 TI - Neurosyphilis Is a Long-forgotten Disease but Still a Possible Etiology for Dementia. AB - We herein report a heterosexual Japanese man in his forties who had been suffering from advanced dementia and personality change for 4 years. Positive results of a serological test for syphilis, Treponema pallidum hemagglutination assay, and fluorescent treponemal antibody-absorption test of both serum and cerebral spinal fluid led to the diagnosis of neurosyphilis. Jarisch-Herxheimer reaction was seen shortly after the first dose of penicillin was administered to the patient. His cognitive function did not recover after treatment. The incidence of syphilis has been reported to be increasing. Neurosyphilis should not be overlooked as an etiology for progressive dementia even in this post antibiotic era. PMID- 26521910 TI - Actinomyces turicensis Bacteremia Secondary to Pyometra. AB - We herein present a rare case of Actinomyces turicensis bacteremia that was caused by pyometra. The patient was successfully treated with transvaginal drainage and antibiotic therapy. A literature review in MEDLINE showed that there have been only 8 previously reported cases of A. turicensis bacteremia. This infection frequently occurs in patients with visceral abscesses, and blood culture examinations usually reveal a polymicrobial pattern. However, the prognosis of such patients has been reported to generally be benign. Due to difficulties in performing bacterial identification and the wide-spectrum clinical pictures associated with this bacteremia, no comprehensive understanding of the clinical features of each Actinomyces species has yet been established. PMID- 26521911 TI - Unilateral Capecitabine-related Hand-foot Syndrome. PMID- 26521912 TI - Extrusion of Glue Cast after Sclerotherapy. PMID- 26521913 TI - Remarkable Adrenocortical Hyperplasia in Adrenocorticotropin-dependent Cushing's Syndrome. PMID- 26521914 TI - An Insulinoma Discovered in a Patient with Diffusely Calcified Chronic Pancreatitis. PMID- 26521915 TI - Air-fluid Levels in Lucite-ball Plombage for Pulmonary Tuberculosis. PMID- 26521916 TI - A Hypopharyngeal Lipoma Resulting in Obstructive Sleep Apnea. PMID- 26521917 TI - Gradually Enlarging Crazy-paving Appearance. PMID- 26521918 TI - Sporadic Inclusion Body Myositis Presenting with Beevor's Sign. PMID- 26521919 TI - A Wig Sign. PMID- 26521920 TI - A Rare Pubic Osteophyte Eroding into the Bladder. PMID- 26521921 TI - Superior Vena Cava Syndrome in a Uremic Patient. PMID- 26521923 TI - GRP78 knockdown does not affect cytotoxicity of cisplatin in ovarian cancer cells. PMID- 26521922 TI - The effects of a 2-h trial of high-flow oxygen by nasal cannula versus Venturi mask in immunocompromised patients with hypoxemic acute respiratory failure: a multicenter randomized trial. AB - INTRODUCTION: In immunocompromised patients, acute respiratory failure (ARF) is associated with high mortality, particularly when invasive mechanical ventilation (IMV) is required. In patients with severe hypoxemia, high-flow nasal oxygen (HFNO) therapy has been used as an alternative to delivery of oxygen via a Venturi mask. Our objective in the present study was to compare HFNO and Venturi mask oxygen in immunocompromised patients with ARF. METHODS: We conducted a multicenter, parallel-group randomized controlled trial in four intensive care units. Inclusion criteria were hypoxemic ARF and immunosuppression, defined as at least one of the following: solid or hematological malignancy, steroid or other immunosuppressant drug therapy, and HIV infection. Exclusion criteria were hypercapnia, previous IMV, and immediate need for IMV or noninvasive ventilation (NIV). Patients were randomized to 2 h of HFNO or Venturi mask oxygen. RESULTS: The primary endpoint was a need for IMV or NIV during the 2-h oxygen therapy period. Secondary endpoints were comfort, dyspnea, and thirst, as assessed hourly using a 0-10 visual analogue scale. We randomized 100 consecutive patients, including 84 with malignancies, to HFNO (n = 52) or Venturi mask oxygen (n = 48). During the 2-h study treatment period, 12 patients required IMV or NIV, and we found no significant difference between the two groups (15 % with HFNO and 8 % with the Venturi mask, P = 0.36). None of the secondary endpoints differed significantly between the two groups. CONCLUSIONS: In immunocompromised patients with hypoxemic ARF, a 2-h trial with HFNO improved neither mechanical ventilatory assistance nor patient comfort compared with oxygen delivered via a Venturi mask. However, the study was underpowered because of the low event rate and the one sided hypothesis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02424773 . Registered 20 April 2015. PMID- 26521924 TI - Gene regulatory biomarker identification for skin toxicities induced by EGFR inhibitor treatment. AB - 1 Federal Institute for Drugs and Medical Devices (BfArM), Research Division, Bonn, 2 Institute of Pharmacology of Natural Products and Clinical Pharmacology, 3 Department of Internal Medicine II, University of Ulm, Ulm, 4 Pneumology, Thoracic Oncology, Sleep- and Respiratory Critical Care Medicine, Clinics Kempten Oberallgau, Kempten, and 5 Department of Internal Medicine I, University of Ulm, Ulm, and 4 Department of Internal Medicine I, Martin Luther University Halle Wittenberg, Germany. PMID- 26521925 TI - Apoptosis-related biomarkers in patients with gynecological cancer. PMID- 26521926 TI - Treatment of a patient with severe hemorrhagic fever accompanied by infection with methicillinresistant Staphylococcus aureus, Acinetobacter baumannii, aspergillus and mucor: a case report. AB - A 40-year-old Korean man developed hemorrhagic fever in Xi'an, which is one of the main endemic areas for this illness in China. According to the local epidemiological situation, his condition could have been due to hantavirus infection, but this was not confirmed. He presented with the typical symptoms of hemorrhagic fever and rapidly progressed to a severe multisystem illness. The clinical situation deteriorated rapidly after admission, and he became coinfected with methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, aspergillus, and mucor. The patient was successfully treated with appropriate fluid infusion, hemodynamic support, continuous renal replacement therapy, liver protectants, and antibacterials. This case indicates that the choice of antimicrobials and the required dose are crucial issues, and that the vaccination campaign for hemorrhagic fever in Xi'an needs greater attention. PMID- 26521927 TI - Antipsychotic polypharmacy and quality of life in patients with schizophrenia treated in primary care in China. AB - OBJECTIVE: In China, maintenance treatment for clinically stable patients with schizophrenia is usually provided by primary care physicians, but their prescribing patterns have not been studied. This study examined the frequency as well as demographic and clinical correlates of antipsychotic polypharmacy (APP) and its impact on quality of life (QOL) in patients with schizophrenia treated in primary care in China. METHOD: A total of 623 community-dwelling patients from 18 randomly selected primary care services were interviewed. Patients' socio demographic and clinical characteristics, including number of hospitalizations, antipsychotic drug-induced side effects, and QOL were recorded using a standardized protocol and data collection procedure. RESULTS: The rate of APP prescription was 31% (193/623). Of the patients on APP, 89.6% received 2 antipsychotics, 10.4% received 3 or more antipsychotics. Clozapine (35.6%) was the most commonly prescribed second generation antipsychotic (SGA), while perphenazine (17.8%) was the most commonly prescribed first generation antipsychotic (FGA). Multiple logistic regression analyses revealed that patients on APP were more likely to receive SGAs and anticholinergics, had fewer hospitalizations, younger age of onset, and higher doses of antipsychotics. There were no significant differences between the two groups in any of the QOL domains. CONCLUSIONS: Approximately a third of Chinese patients with schizophrenia in primary care receive APP. Further examination of the rationale and appropriateness of APP and its alternatives is warranted. PMID- 26521928 TI - Efficient strategy for obtaining reliable pharmacokinetic parameters in population compartmental approaches. AB - OBJECTIVE: This study aimed to suggest efficient strategies for obtaining reliable pharmacokinetic (PK) parameters in population compartmental approach (PCA) a early-phase or resource-limited clinical trials with limited data. METHODS: This study employed plasma concentration of olanzapine, an antipsychotic drug, from a bioequivalence study. To assess bias and precision of PK parameters that were estimated from limited data, this study utilized simulations with the generation of small-size datasets (SSD) and minimal-sampling datasets (MSD) that consisted of limited volunteers and PK samplings per volunteer, respectively. RESULTS: Clearance (CL) estimates were the most robust, volume of the central (Vc) and peripheral compartment (Vp) were moderately affected, and absorption rate constant (Ka) and intercompartmental clearance (Q) were very sensitive with limited dataset. MSD had more impact on the bias and precision of PK parameter estimation than SSD. CONCLUSIONS: Performance of PK parameter estimation evaluated by bias and precision from simulation datasets was better in SSD than MSD. This finding implies that collecting more PK samplings is a more efficient strategy than recruiting more volunteers in order to obtain informative results in performing PCA. PMID- 26521929 TI - Correlation between N2 amplitude of multifocal ERGs and retinal sensitivity and retinal nerve fiber layer thickness in glaucomatous eyes. AB - PURPOSE: To determine whether there are significant correlations between the N2 amplitude of the multifocal electroretinograms (mfERGs) and the retinal sensitivity and retinal nerve fiber layer (RNFL) thickness in glaucomatous and normal eyes. METHODS: Thirty-eight glaucomatous and 11 normal eyes were studied. The mfERGs were elicited by red stimuli presented on a blue background. The responses from the central five elements within a 20 degrees stimulated area were analyzed. The retinal sensitivity was determined by Humphrey Field Analyzer and the RNFL thickness by spectral-domain optical coherence tomography. The correlations between the N2 amplitude and the retinal sensitivity and the RNFL thickness were calculated. RESULTS: The N2 amplitude was significantly smaller in the glaucomatous eyes than the normal eyes in all areas (P < 0.05). There was a significant correlation between the N2 amplitude and the retinal sensitivity (1/Lambert linear unit) of the HFA for the superior retina (r = 0.36, P = 0.01), for the central retina (r = 0.54, P < 0.0001), and for the inferior retina (r = 0.51, P = 0.0001). There were significant correlations between the N2 amplitude and the RNFL thicknesses in the superior retina (r = 0.49, P = 0.0003), the central retina (r = 0.79, P < 0.0001), and the inferior retina (r = 0.52, P = 0.0001) for both normal and glaucomatous eyes. CONCLUSIONS: These results indicate that the activity of the retinal ganglion cells contribute to the amplitude of the N2 of the mfERGs and thus can be used as an objective monitor of retinal ganglion cell function. PMID- 26521930 TI - Targeting IL-17 and IL-23 in Immune Mediated Renal Disease. AB - T helper (Th) cells belong to the adaptive immune system and provide an effective and antigen-specific means of host protection. Th17 cells are a subset of Th cells, characterized by the production of the inflammatory cytokines interleukin (IL)-17A (IL-17A) and IL-17F, which bind to a receptor complex comprised of IL 17RA and IL-17RC subunits. Th17 cells combat extracellular and fungal infections, but have been implicated in autoimmune diseases. In many autoimmune conditions, the dysregulated immune response involves several parts of the immune system, including autoantibodies, B and T cells. Targeted biological therapies are appealing, as they may prevent unwanted side effects in patients. There is evolving evidence that Th17 cells are important in the kidney, mediating injury in response to vascular or chemical insults to the renal tubules, and in autoimmune diseases of the glomerulus, either through a specific attack on the glomerular basement membrane or as part of a generalized systemic inflammatory disease. Therapies targeting IL-17A, IL-12p40 and IL-17RA are being explored in clinical trials or are being utilized in clinical practice for the treatment of other IL-17 mediated diseases, such as psoriasis. This review explores the current evidence that IL-17A and Th17 cells may be pathogenic in immune kidney disease, including anti-glomerular basement membrane disease, antineutrophil cytoplasmic antibody associated vasculitis and lupus nephritis, as well as in acute kidney injury. It will discuss the place that biological agents against IL 17A, IL-12p40 and IL-17RA may have in the treatment of these conditions. PMID- 26521931 TI - APIC's Strategic Partner Program and Productive Collaborations. PMID- 26521932 TI - Impact of Clostridium difficile-associated diarrhea on acute care length of stay, hospital costs, and readmission: A multicenter retrospective study of inpatients, 2009-2011. AB - BACKGROUND: The recent epidemiologic changes of Clostridium difficile-associated diarrhea (CDAD) have resulted in substantial economic burden to U.S. acute care hospitals. Past studies evaluating CDAD-attributable costs have been geographically and demographically limited. Here, we describe CDAD-attributable burden in inpatients, overall, and in vulnerable subpopulations from the Premier hospital database, a large, diverse cohort with a wide range of high-risk subgroups. METHODS: Discharges from the Premier database were retrospectively analyzed to assess length of stay (LOS), total inpatient costs, readmission, and inpatient mortality. RESULTS: Patients with CDAD had significantly worse outcomes than matched controls in terms of total LOS, rates of intensive care unit (ICU) admission, and inpatient mortality. After adjustment for risk factors, patients with CDAD had increased odds of inpatient mortality, total and ICU LOS, costs, and odds of 30-, 60- and 90-day all-cause readmission versus non-CDAD patients. CDAD-attributable costs were higher in all studied vulnerable subpopulations, which also had increased odds of 30-, 60- and 90-day all-cause readmission than those without CDAD. CONCLUSION: Given the significant economic impact CDAD has on hospitals, prevention of initial episodes and targeted therapy to prevent recurrences in vulnerable patients are essential to decrease the overall burden to hospitals. PMID- 26521933 TI - Social and political determinants of vaccine hesitancy: Lessons learned from the H1N1 pandemic of 2009-2010. AB - BACKGROUND: Public acceptance of vaccination programs is essential for vaccine preventable diseases. However, increasing sectors of the population have expressed hesitancy about participating in such programs, leading to the re emergence of vaccine preventable diseases. In this study we rely on a recreancy hypothesis to test the association between confidence in the government and local hospitals and the willingness to take the vaccine. METHODS: A secondary analysis of a survey that used a large sample of the U.S. population conducted in October 2009 was used (N = 968). RESULTS: The results indicate that 36.1% of the respondents expressed willingness to be vaccinated. Those with the greatest trust in the government were the most likely to be vaccinated (43.4%), and those least confident were the least willing (15.8%). From the ones reporting being confident in the local health system, 38.4% were willing to be vaccinated, and from those not confident, only 23.5% were willing to be vaccinated. CONCLUSION: The decision to get vaccinated in the midst of a contagious outbreak involves many considerations. Trust in the government's technical and organization skill to deal with the infectious outbreak along with trust in medical organizations predict the adoption of recommended protection measures. The results indicate that public compliance with vaccination plans in health crisis requires the development of social and institutional trust. PMID- 26521934 TI - The role of message strategy in improving hand hygiene compliance rates. AB - BACKGROUND: Despite increased attention to hand hygiene over the past decade compliance rates remain relatively low. Although there have been a number of improvements in the science of hand hygiene, very little attention has been devoted to the messages that promote it. METHOD: A total of 86 health care workers who are members of Association for Professionals in Infection Control and Epidemiology chapters participated in an online evaluation of 6 message strategies. The participants evaluated the strategies on ease of understanding, believability, and whether the message strategies were likely to lead to increased handwashing. RESULTS: Of the 6 strategies--ego, social, sensory, routine, acute need, and ration--the social strategy was rated the most likely to lead to action. The sensory strategy was seen as not only least likely but also counterproductive. CONCLUSIONS: ICPs should add a social message strategy to communication programs promoting hand hygiene. Although further testing is needed, ego, routine, and acute need strategies show promise for tapping into motivations that lead to improved compliance. PMID- 26521935 TI - Influence of multiple factors on the incidence of occupational blood and body fluid exposures in health care workers in Guizhou, China: A structural equation modeling approach. AB - BACKGROUND: We investigated the influence of multiple factors on the incidence of occupational blood and body fluid exposures (BBFEs) in health care workers (HCWs) in Guizhou, China, using structural equation modeling (SEM). METHODS: SEM tested in general hospitals was evaluated using survey data from a sample of 1,774 HCWs from 25 hospitals in Guizhou, China, between January and April 2014. RESULTS: The incidence of occupational BBFEs in HCWs was affected by HCWs' knowledge of safe work practices, HCWs' belief in their ability to use safe work practices, HCWs' use of safe work practices, the workplace safety environment, sufficiency of the controls implemented at health care facilities, and workloads. Knowledge of safe work practices had the most influence on the incidence of occupational BBFE in doctors and laboratory technicians. Ability to use safe work practices had the most influence on the incidence of occupational BBFEs in nurses. CONCLUSION: The workplace safety environment, sufficiency of controls implemented at health care facilities, HCWs' knowledge of safe work practices, HCWs' belief in their ability to use safe work practices, HCWs' use of safe work practices, and workload influence the incidence of occupational BBFEs in HCWs. PMID- 26521936 TI - Analysis of single root tip microbiomes suggests that distinctive bacterial communities are selected by Pinus sylvestris roots colonized by different ectomycorrhizal fungi. AB - Symbiotic ectomycorrhizal tree roots represent an important niche for interaction with bacteria since the fungi colonizing them have a large surface area and receive a direct supply of photosynthetically derived carbon. We examined individual root tips of Pinus sylvestris at defined time points between 5 days and 24 weeks, identified the dominant fungi colonizing each root tip using Sanger sequencing and the bacterial communities colonizing individual root tips by 454 pyrosequencing. Bacterial colonization was extremely dynamic with statistically significant variation in time and increasing species richness until week 16 (3477 operational taxonomic units). Bacterial community structure of roots colonized by Russula sp. 6 GJ-2013b, Piloderma spp., Meliniomyces variabilis and Paxillus involutus differed significantly at weeks 8 and 16 but diversity declined and significant differences were no longer apparent at week 24. The most common genera were Burkholderia, Sphingopyxsis, Dyella, Pseudomonas, Acinetobacter, Actinospica, Aquaspirillum, Acidobacter Gp1, Sphingomonas, Terriglobus, Enhydrobacter, Herbaspirillum and Bradyrhizobium. Many genera had high initial abundance at week 8, declining with time but Dyella and Terriglobus increased in abundance at later time points. In roots colonized by Piloderma spp. several other bacterial genera, such as Actinospica, Bradyrhizobium, Acidobacter Gp1 and Rhizomicrobium appeared to increase in abundance at later sampling points. PMID- 26521937 TI - WU-CRISPR: characteristics of functional guide RNAs for the CRISPR/Cas9 system. AB - The CRISPR/Cas9 system has been rapidly adopted for genome editing. However, one major issue with this system is the lack of robust bioinformatics tools for design of single guide RNA (sgRNA), which determines the efficacy and specificity of genome editing. To address this pressing need, we analyze CRISPR RNA-seq data and identify many novel features that are characteristic of highly potent sgRNAs. These features are used to develop a bioinformatics tool for genome-wide design of sgRNAs with improved efficiency. These sgRNAs as well as the design tool are freely accessible via a web server, WU-CRISPR ( http://crispr.wustl.edu ). PMID- 26521938 TI - KINFix--A formalin-free non-commercial fixative optimized for histological, immunohistochemical and molecular analyses of neurosurgical tissue specimens. AB - An optimal fixative should ideally combine the advantages of formalin fixation and freezing, allowing for good preservation of histology and molecular components, easy handling and storage, lack of toxicity, and low costs. Most of these criteria are fulfilled by ethanol-based solutions, and due to our good experience with the commercial RCL2 fixative, reflected by our published single center trial, we initiated a multicenter ring trial. However, during its course, RCL2 was discontinued on the market. Therefore, we created our own agent, KINFix, composed of the same main constituents as RCL2, and employed it in our laboratory with similar results. Here we present our evaluation of the three fixatives formalin, RCL2, and KINFix from the perspective of histopathology as well as nucleic acid and protein analyses in comparison to fresh frozen tissues together with the multicenter ring trial data for RCL2. We observe that RCL2 and KINFix offer comparable histomorphology and superior template for molecular analyses than formalin. Moreover, KINFix as freely available fixative might overcome some of the difficulties related to the commercial agents. Therefore, we conclude that KINFix might be an attractive complement to formalin in tissue processing and advocate its use in neuropathological practice. PMID- 26521939 TI - Isoforms, structures, and functions of versatile spectraplakin MACF1. AB - Spectraplakins are crucially important communicators, linking cytoskeletal components to each other and cellular junctions. Microtubule actin crosslinking factor 1 (MACF1), also known as actin crosslinking family 7 (ACF7), is a member of the spectraplakin family. It is expressed in numerous tissues and cells as one extensively studied spectraplakin. MACF1 has several isoforms with unique structures and well-known function to be able to crosslink F-actin and microtubules. MACF1 is one versatile spectraplakin with various functions in cell processes, embryo development, tissue-specific functions, and human diseases. The importance of MACF1 has become more apparent in recent years. Here, we summarize the current knowledge on the presence and function of MACF1 and provide perspectives on future research of MACF1 based on our studies and others. PMID- 26521940 TI - Hypoxic repression of CYP7A1 through a HIF-1alpha- and SHP-independent mechanism. AB - Liver cells experience hypoxic stress when drug-metabolizing enzymes excessively consume O2 for hydroxylation. Hypoxic stress changes the transcription of several genes by activating a heterodimeric transcription factor called hypoxia-inducible factor- 1alpha/beta (HIF-1alpha/beta). We found that hypoxic stress (0.1% O2) decreased the expression of cytochrome P450 7A1 (CYP7A1), a rate-limiting enzyme involved in bile acid biosynthesis. Chenodeoxycholic acid (CDCA), a major component of bile acids, represses CYP7A1 by activating a transcriptional repressor named small heterodimer partner (SHP). We observed that hypoxia decreased the levels of both CDCA and SHP, suggesting that hypoxia repressed CYP7A1 without inducing SHP. The finding that overexpression of HIF-1alpha increased the activity of the CYP7A1 promoter suggested that hypoxia decreased the expression of CYP7A1 in a HIF-1-independent manner. Thus, the results of this study suggested that hypoxia decreased the activity of CYP7A1 by limiting its substrate O2, and by decreasing the transcription of CYP7A1. [BMB Reports 2016; 49(3): 173-178]. PMID- 26521941 TI - miR-185 inhibits endoplasmic reticulum stress-induced apoptosis by targeting Na+/H+ exchanger-1 in the heart. AB - Prolonged ER stress (ERS) can be associated with the induction of apoptotic cell death in various heart diseases. In this study, we searched for microRNAs affecting ERS in the heart using in silico and in vitro methods. We found that miR-185 directly targets the 3'-untranslated region of Na+/H+ exchanger-1 (NHE 1), a protein involved in ERS. Cardiomyocyte ERS-triggered apoptosis induced by 100 ng/ml tunicamycin (TM) or 1 MUM thapsigargin (TG), ERS inducers, was significantly reduced by miR-185 overexpression. Protein expression of pro apoptotic markers such as CCAAT/enhancer-binding protein homologous protein (CHOP) and cleaved-caspase-3 was also markedly reduced by miR-185 in a dose dependent manner. Cariporide (20 MUM), a pharmacological inhibitor of NHE-1, also attenuated ERS-induced apoptosis in cardiomyocytes and CHOP protein expression, suggesting that NHE-1 plays an important role in ERS-associated apoptosis in cardiomyocytes. Collectively, the present results demonstrate that miR-185 is involved in cardio- protection against ERS-mediated apoptotic cell death. [BMB Reports 2016; 49(4): 208-213]. PMID- 26521942 TI - microRNA for determining the age-related myogenic capabilities of skeletal muscle. AB - Skeletal muscle exhibits a loss of muscle mass and function with age. Decreased regenerative potential of muscle stem/progenitor cells is a major underlying cause of sarcopenia. We analyzed microRNAs (miRNA) that are differentially expressed in young and old myoblasts, to identify novel intrinsic factors that play a degenerative role in aged skeletal muscle. miR-431, one of decreasing miRNAs in old myoblasts, improved the myogenic differentiation when overexpressed in old myoblast, but suppressed their myogenic capability in knockdowned young myoblasts. We found that miR-431 directly binds to 3'untranslated regions (UTR) of Smad4 mRNA, and decreases its expression. Given that SMAD4 is one of the downstream effectors of TGF-beta, a well-known degenerative signaling pathway in myogenesis, the decreased miR-431 in old myoblast causes SMAD4 elevation, thus resulting in defective myogenesis. Exogenous expression of miR-431 greatly improved the muscle regeneration in the cardiotoxin-injured hindlimb muscle of old mice by reducing SMAD4 levels. Since the miR-431 seed sequence is conserved in human SMAD4 3'UTR, miR-431 regulates the myogenic capacity of human skeletal myoblasts in the same manner. Our results suggest that age-associated miR-431 is required for the maintenance of the myogenic capability in myoblasts, thus underscoring its potential as a therapeutic target to slow down muscle aging. PMID- 26521943 TI - Identification of a novel compound (beta-sesquiphellandrene) from turmeric (Curcuma longa) with anticancer potential: comparison with curcumin. AB - Considering that as many as 80% of the anticancer drugs have their roots in natural products derived from traditional medicine, we examined compounds other than curcumin from turmeric (Curcuma longa) that could exhibit anticancer potential. Present study describes the isolation and characterization of another turmeric-derived compound, beta-sesquiphellandrene (SQP) that exhibits anticancer potential comparable to that of curcumin. We isolated several compounds from turmeric, including SQP, alpha-curcumene, ar-turmerone, alpha-turmerone, beta turmerone, and gamma-turmerone, only SQP was found to have antiproliferative effects comparable to those of curcumin in human leukemia, multiple myeloma, and colorectal cancer cells. While lack of the NF-kappaB-p65 protein had no effect on the activity of SQP, lung cancer cells that expressed p53 were more susceptible to the cytotoxic effect of SQP than were cells that lacked p53 expression. SQP was also found to be highly effective in suppressing cancer cell colony formation and inducing apoptosis, as shown by assays of intracellular esterase activity, plasma membrane integrity, and cell-cycle phase. SQP was found to induce cytochrome c release and activate caspases that lead to poly ADP ribose polymerase cleavage. SQP exposure was associated with downregulation of cell survival proteins such cFLIP, Bcl-xL, Bcl-2, c-IAP1, and survivin. Furthermore, SQP was found to be synergistic with the chemotherapeutic agents velcade, thalidomide and capecitabine. Overall, our results indicate that SQP has anticancer potential comparable to that of curcumin. PMID- 26521944 TI - Epigenetics in Brain Tumors: HDACs Take Center Stage. AB - Primary tumors of the brain account for 2 % of all cancers with malignant gliomas taking the lion's share with 70 %. Malignant gliomas (high grade gliomas WHO degrees III and degrees IV) belong to one of the most threatening tumor entities known with their disappointingly short median survival time of just 14 months despite maximum therapy according to current gold standards. Malignant gliomas secrete various factors, through which they adapt and manipulate the tumor microenvironment to their advantage. Epigenetic mechanisms operate on the tumor microenvironment by de- and methylation processes and imbalances between the histone deacetylases (HDAC) and histone acetylases (HAT). Many compounds have been discovered modulating epigenetically controlled signals. Recent studies indicate that xCT (system xc-, SLC7a11) and CD44 (H-CAM,ECM-III, HUTCH-1) functions as a bridge between these epigenetic regulatory mechanisms and the malignant glioma progression. The question that ensues is the extent to which therapeutic intervention on these signaling pathways would exert influence on the treatment of malignant gliomas as well as the extent to which manipulation of HDAC activity can sensitize tumor cells for chemotherapeutics through 'epigenetic priming'. Considering the current stagnation in the development of therapeutic options the need for new strategies in the treatment of gliomas has never been so urgent. Here, the possibility of pharmacological intervention on tumor-associated genes by epigenetic priming opens a novel path in combating primary brain tumors. PMID- 26521946 TI - Lipid mediator profile in vernix caseosa reflects skin barrier development. AB - Vernix caseosa (VC) is a protective layer that covers the skin of most human newborns. This study characterized the VC lipid mediator profile, and examined its relationship to gestational period, gender of the newborn and maternal lifestyle. VC collected at birth from 156 newborns within the ALADDIN birth cohort was analyzed and 3 different groups of lipid mediators (eicosanoids and related oxylipin analogs, endocannabinoids and sphingolipids) were screened using LC-MS/MS. A total of 54 compounds were detected in VC. A number of associations between lipid mediators and the gestational period were observed, including increases in the ceramide to sphingomyelin ratio as well as the endocannabinoids anandamide and 2-arachidonoylglycerol. Gender-specific differences in lipid mediator levels were observed for all 3 lipid classes. In addition, levels of the linoleic acid oxidation products 9(10)-epoxy-12Z-octadecenoic and 12(13)-epoxy-9Z octadecenoic acid (EpOMEs) as well as 12,13-dihydroxy-9Z-octadecenoic acid (DiHOME) were increased in VC of children from mothers with an anthroposophic lifestyle. Accordingly, VC was found to be rich in multiple classes of bioactive lipid mediators, which evidence lifestyle, gender and gestational week dependencies. Levels of lipid mediators in VC may therefore be useful as early stage non-invasive markers of the development of the skin as a protective barrier. PMID- 26521945 TI - Eicosanoids Derived From Arachidonic Acid and Their Family Prostaglandins and Cyclooxygenase in Psychiatric Disorders. AB - Arachidonic acid (AA)-derived lipid mediators are called eicosanoids. Eicosanoids have emerged as key regulators of a wide variety of physiological responses and pathological processes, and control important cellular processes. AA can be converted into biologically active compounds by metabolism by cyclooxygenases (COX). Beneficial effect of COX-2 inhibitor celecoxib add-on therapy has been reported in early stage of schizophrenia. Moreover, add-on treatment of celecoxib attenuated refractory depression and bipolar depression. Further, the COX/prostaglandin E pathway play an important role in synaptic plasticity and may be included in pathophysiology in autism spectrum disorders (ASD). In this regard, plasma transferrin, which is an iron mediator related to eicosanoid signaling, may be related to social impairment of ASD. COX-2 is typically induced by inflammatory stimuli in the majority of tissues, and the only isoform responsible for propagating the inflammatory response. Thus, COX-2 inhibitors considered as the best target for Alzheimer's disease. PMID- 26521947 TI - Inhibition of tribbles protein-1 attenuates radioresistance in human glioma cells. AB - Radiotherapy is one of the remedies in the treatment of glioma. The radioresistance is a major drawback, of which the mechanism is unclear. Tribble protein and histone deacetylase are involved in the cancer pathogenesis. This study aims to test a hypothesis that the histone deacetylase inhibitors attenuate the radioresistance in human glioma cells. In this study, human glioma cells were cultured. The cells were treated with irradiation with or without a histone deacetylase inhibitor, butyrate. Apoptosis of the glioma cells was assessed by flow cytometry. The results showed that human glioma cells expressed a low level of Trib1, which was significantly up regulated by exposure to small doses (2 Gy/day for 4 days) of irradiation. Trib1-deficient glioma cells showed an enhanced response to irradiation-induced apoptosis. Exposure to small doses of irradiation, Trib1 formed a complex with pHDAC1 (phosphor histone deacetylase-1) to inhibit p53 expression in glioma cells. The presence of HDAC1 inhibitor, butyrate or parthenolide, significantly enforced irradiation-induced glioma cell apoptosis. In conclusion, the Trib1 plays a critical role in the development of radioresistance of glioma cells. The data suggest that inhibition of Trib1 or HDAC1 has the potential to prevent or attenuate the radioresistance. PMID- 26521948 TI - Intergenerational Transmission of Maladaptive Parenting Strategies in Families of Adolescent Mothers: Effects from Grandmothers to Young Children. AB - The current longitudinal study examined the effect of the transmission of maladaptive parenting strategies from grandmothers to adolescent mothers on children's subsequent development. Mexican-origin adolescent mothers (N = 204) participated in home interviews when the adolescent's child (89 boys, 60 girls) was 2, 3, 4, and 5 years old. Grandmothers' psychological control toward the adolescent mother was positively related to adolescents' potential for abuse 1 year later, which was subsequently positively related to adolescents' punitive discipline toward their young child. In addition, adolescent mothers' punitive discipline subsequently predicted greater externalizing problems and less committed compliance among their children. Adolescent mothers' potential for abuse and punitive discipline mediated the effects of grandmothers' psychological control on children's externalizing problems. Finally, adolescent mothers' potential for abuse mediated the effect of grandmothers' psychological control on adolescent mothers' punitive discipline. Results highlight the salience of long term intergenerational effects of maladaptive parenting on children's behavior. PMID- 26521950 TI - Characterization of a Bacteriophage-Derived Murein Peptidase for Elimination of Antibiotic-Resistant Staphylococcus aureus. AB - Staphylococcus aureus is a major cause of infection in humans and animals, causing a wide variety of diseases, from local inflammations to fatal sepsis. The bacterium is commonly multi-drug resistant and thus many front-line antibiotics have been rendered ineffective for treating such infections. Research on murein/peptidoglycan hydrolases, derived from bacterial viruses (bacteriophages), has demonstrated that such proteins are attractive candidates for development as novel antibacterial agents for combatting Gram-positive pathogens. Here we review the research produced to-date on the bacteriophage-derived CHAPK murein peptidase. Initially, we sequenced and annotated the genome of anti staphylococcal bacteriophage K and cloned the gene for the bacteriophage endolysin, a murein hydrolase which plays a role in cell killing during the bacteriophage life cycle. An highly active domain of the enzyme, a cysteine, histidine-dependent amido hydrolase/peptidase (CHAPK), was cloned, overexpressed in E. coli and purified. This CHAPK enzyme was demonstrated to rapidly lyse several strains of methicillin resistant S. aureus and both disrupted and prevented the formation of a staphylococcal biofilm. The staphylolytic activity of the peptidase was demonstrated in vivo using a mouse model, without adverse effects on the animals. The crystal structure of the enzyme was elucidated, revealing a calcium ion close to the active site. Site-directed mutagenesis indicated that this calcium ion is involved in the catalytic mechanism of the enzyme. The crystal structure of this enzyme is a valuable source of information for efficient engineering of this and similar CHAP-domain-containing proteins. Overall, the data collected to date on CHAPK has demonstrated its strong potential as a novel therapeutic candidate for treatment of staphylococcal infections and has provided us with insight into the fundamental enzymatic mechanisms of CHAP domain-containing peptidoglycan hydrolases. PMID- 26521949 TI - Early life trauma is associated with decreased peripheral levels of thyroid hormone T3 in adolescents. AB - An adverse early life environment can induce changes on behavioral and metabolic responses later in life. Recent studies in rats showed that the quality of maternal care as measured by high levels of pup licking and grooming (LG) was associated with changes in the relationship between the precursor thyroid-hormone T4 and the more active T3. Here we investigated if early exposure to childhood abuse is associated with thyroid-hormone levels in human adolescents. Given the empirical evidence from animal models showing that good maternal care was associated with increased conversion of T4 to T3, we hypothesized that early adversity would be associated with a decreased peripheral conversion of T4 to T3. A sample of 80 adolescents (10-18 years) participated in this study. We used the Childhood Trauma Questionnaire to investigate early life stress. We calculate the body mass index (BMI) assessing weight and height and sexual maturation stage was determined by self-assessment. Blood samples were collected to measure T3 and T4 levels. ANCOVA were used to evaluate the influence of the Physical Abuse domain of the Childhood Trauma Questionnaire as the early life stress variable in T3 and T4 separately, adjusted for potential confounders such as pubertal status, gender, socioeconomic status and BMI. Early life trauma was associated with reduced T3 levels in adolescents, when adjusted for potential confounders (p=0.013), but not with peripheral T4 levels (p=0.625). We extended findings from animal models showing that adverse early experience persistently impacts on the individual's responses to stress, which is marked by an abnormal metabolism of thyroid hormones. Further studies are needed to further investigate the nature of such associations. PMID- 26521951 TI - Rescue of the activity of HNH nuclease mutants - towards controlled enzymes for gene therapy. AB - Artificial nucleases are designed for in vivo gene engineering, as the DNA cleavage performed at a specific target site enhances the effectiveness of the cell's DNA repair machinery. The therapeutic potential of the above phenomenon stems from the knowledge that (i) the shifted reading frame can be restored by non-homologous end-joining, or (ii) a DNA of erroneous sequence - causing a genetic disease - can be corrected by homologous recombination in the presence of a suitable DNA template. Besides the advantageous properties of the nowadays applied zinc finger nucleases, TALE nucleases and the CRISPR/Cas9 system, they possess a residual citotoxicity. This is related to offtarget cleavages, which could be prevented by the strict regulation of the enzymes. The studies on enzymes acting naturally in a controlled manner are beneficial to get better insight into their mechanism. Such enzymes or their appropriate domains may be the most promising alternatives to the presently applied ones. As an example, the DNA cleavage of the inactive HNH nuclease mutants is inducible in a multiple way. This property may be used for establishing a control mechanism and thus, in combination with specific DNA-binding domains they are good candidates for the catalytic site of artificial nucleases. Here we collect the results on the properties of the HNH nucleases that allow for their redesign into enzymes with possible therapeutic applications. PMID- 26521952 TI - Bacterial expression and/or solid phase peptide synthesis of 20-40 amino acid long polypeptides and miniproteins, the case study of Class B GPCR ligands. AB - By using two different synthetic techniques several polypeptides interacting with Class B type G-protein coupled receptors were prepared. These polypeptides of different lengths (20 <= amino acids <= 40), structural and aggregation properties, were prepared both by solid phase peptide synthesis (SPPS) and E.coli bacterial expression. Their purity, synthetic yields, by-products and (15)N/(13)Clabelling characteristics were compared as function of i) the applied method, ii) amino acid length and iii) folding propensities. Their tentative yields, costs and "environmental footprints" were analyzed and found as follows. For unlabelled and short polypeptides (n= 20 aa.) the method of choice is the less environmentally friendly however, quick and effective SPPS. If the polypeptide is (un)folded and/or has no aggregation propensity, then SPPS gives relatively good yield (e.g. 14 +/- 4%) and a pure product (>97%). For aggregating polypeptides production yields drop for both methods 4 +/- 2% (SPPS) and 2 +/- 1% (E. coli), respectively. For longer (n>= 30 aa.) macromolecules (e.g. miniproteins) bacterial expression efficacy gets higher. Moreover biotechnology is "greener", the resulting in raw material is purer (2.8 +/- 1.5 mg). All these advantages for at a lower cost: ~4 ?/aa. If isotopic labelling is needed for heteronuclear NMR measurements, bacterial expression is the sole option, due to the high cost of (15)N/(13)C labelled Fmoc(Boc)-L-aa-OH starting materials needed for SPPS. In E.coli uniformly double-labelled, pure polypeptides can be obtained for less than 5-700 ?/mg, regardless of the length of the polypeptide chain. Thus, chemists are encouraged to use E.coli expression systems when adequate to make not only proteins but polypeptides and miniproteins as well. PMID- 26521953 TI - Reactions of Dinuclear Platinum(II) Complexes with Peptides. AB - The present review article highlights recent findings in the reactions between different dinuclear Pt(II) complexes with peptides containing cysteine, methionine and histidine residues. The reactions of {trans-[Pt(NH3)2Cl]2(MU X)}(2+) and {trans-[Pt(NH3)2(H2O)]2(MU-X)}(4+) type complexes with different bridging ligands (X) (X = pyrazine, 4,4'-bipyridyl and 1,2-bis(4-pyridyl)ethane) with the tripeptide glutathione proceeded in two steps. In the first step, one water or chlorido ligand of the dinuclear Pt(II) complex was substituted by the sulfhydryl group of GSH, while in the second step, the remaining water or chlorido ligand from the dinuclear Pt(II)-peptide complex was replaced by the second molecule of glutathione, finally leading to the formation of the {trans [Pt(NH3)2(GS)]2(MU-X)}(2+) complex. It was shown that the bridging ligand had an important influence on the reactivity of these complexes with glutathione. No hydrolytic cleavage of any amide bond was observed in the reactions between these complexes and glutathione. However, in reactions performed in acidic media (2.0 < pH < 2.5) between dinuclear Pt(II) complexes with the general formulae {[Pt(L)(H2O)]2(MU-diazine)}(4+) (L is different bidentate coordinated diamine ligands and diazine is a pyrazine- or pyridazine-bridging ligand) and Nacetylated peptides containing L-methionine and L-histidine amino acids in the side chains (Ac-L-Met-Gly, Ac-L-His-Gly and Ac-L-Met-Gly-L-His-GlyNH2), regioselective cleavage of these peptides occurred. The mechanism of these hydrolytic reactions was discussed in relation to the structure of the diazine-bridged Pt(II) complex and the investigated peptides. A systematic summary of these results could contribute to the future design of new dinuclear Pt(II) complexes as potential reagents for regioselective cleavage of peptides and proteins. PMID- 26521954 TI - Pentameric models as alternative molecular targets for the design of new antiaggregant agents. AB - The structure-based drug design has been an extremely useful technique used for searching and developing of new therapeutic agents in various biological systems. In the case of AD, this approach has been difficult to implement. Among other several causes, the main problem might be the lack of a specific stable and reliable molecular target. In this paper the results obtained using a pentameric amyloid beta (Abeta) model as a molecular target are discussed. Our MD simulations have shown that this system is relatively structured and stable, displaying a lightly conformational flexibility during 2.0 MUs of simulation time. This study allowed us to distinguish characteristic structural features in specific regions of the pentamer which should be taken into account when choosing this model as a molecular target. This represents a clear advantage compared to the monomer or dimer models which are highly flexible structures with large numbers of possible conformers. Using this pentameric model we performed two types of studies usually carried out on a molecular target: a virtual screening and the design on structural basis of new mimetic peptides with antiaggregant properties. Our results indicate that this pentameric model might be a good molecular target for these particular studies of molecular modeling. Details about the predictive power of our virtual screening as well as about the molecular interactions that stabilize the mimetic peptide-pentamer Abeta complexes are discussed in this paper. PMID- 26521955 TI - Protein Folding and Misfolding, Endoplasmic Reticulum Stress in Neurodegenerative Diseases: in Trace of Novel Drug Targets. AB - Alzheimer's disease (AD) is characterized by severe cognitive impairment and memory loss. AD is classified both into the "protein conformational" and the "endoplasmic reticulum-mitochondria stress" disorders. AD is a very complex, multifactorial disease of heterogeneous genetic and environmental background. The amyloid hypothesis of AD cannot fully explain the various clinical forms of the disease. Protein folding and misfolding in the endoplasmic reticulum (ER), and accumulation of several misfolded proteins (beta-amyloid, Tau, alpha-synuclein, etc.) in ER and mitochondria (MT) may play a key role in the development of AD. Functional degradation of the synapse and the synapse holding neurites represents the first step in the pathogenesis of neurodegeneration. MT and ER are tightly coupled both physically and functionally with a special lipid raft called mitochondria-associated ER-membrane (MAM). MAM is crucial for Ca(2+) signalling and metabolic regulation of the cell. In turn, the impairment of ER-MT interplay is a common mechanism of different neurodegenerative diseases. In this review, we discuss recent findings focusing on the protein conformational and metabolic dysfunction, and the role of MAM and ER-MT crosstalk in neurodegeneration. PMID- 26521956 TI - On Spontaneously Pulsating Proline-Phenylalanine Peptide Microfibers. AB - Earlier, we have collected an experimental evidence showing that low molecular weight chiral carboxylic acids (amino acids included) can spontaneously undergo an oscillatory chiral conversion and an oscillatory condensation in abiotic aqueous and non-aqueous liquid systems, stored for certain amount of time under mild external conditions. These earlier findings are summarized in the introductory part of this study. In the second part, a preliminary report is given on spontaneous pulsation of peptide microfibers in the aged proline phenylalanine (Pro-Phe) solution in 70% aqueous acetonitrile. The experimental evidence originates from a number of advanced analytical techniques. In view of our earlier and present findings, a presumption is made that the mechanism of spontaneous pulsation (formation and decay) of Pro-Phe microfibers is directly related to the oscillatory chiral conversion and oscillatory peptidization. The entity of the discussed results pointing out to spontaneous and uncontrolled instability of peptide structures might be a bad prognostic for employing such structures in nanobiotechnology. PMID- 26521957 TI - Cellulose Template Assembled Synthetic Peptides as Molecular Receptors. AB - The relatively simple peptides assembled on the templates are excellent mimic of complex conformational and functional defined binding sites of proteins. The main benefit of experiments with artificial receptors arises from the relative simplicity of the interacting host-guest system allowing the understanding of the rules controlling the model process of the molecular recognition. Efficient modification of molecular receptors by using rational design of their structure or combinatorial methods is crucial for verification of any hypothesis concerning the binding forces or enhancing the binding properties. This approach is presenting promising strategy for understanding mode of action and the control of biological functions of proteins, for designing new pharmaceutically active compounds, new tools for medical diagnostic and molecular sensing. PMID- 26521958 TI - Advances in Peptide-based DNA/RNA-Intercalators. AB - Interactions between DNA/RNA and huge variety of peptides are quite common in nature, controlling vast number of processes. Also, there are several naturally occurring small molecules which contain peptide and DNA intercalator in structure, whereby their biological activity is based on synergistic interactions of both components; for instance bis-intercalator echinomycin. Versatility of synthetic approaches to short peptides allowed their usage as simple recognition units within the DNA or RNA grooves or as backbone carriers for variety of bioactive substituents attached to amino acid side chains, one of very popular examples being PNAs. Such peptide-backbones were also used for synthesis of novel intercalators and poly-intercalators, many of them showing intriguing novel DNA/RNA interacting properties. PMID- 26521959 TI - Analysis of Aged Human Serum Albumin Affinity for Doxazosin. AB - Structural changes of human serum albumin (HSA) caused by old age and coexisting diseases result in differences in the binding of doxazosin (DOX). DOX is a postsynaptic alpha1- adrenoreceptor antagonist used for treatment of hypertension and benign prostatic hyperplasia. In elderly people suffering from various renal or hepatic diseases the significant portion of N-form of human serum albumin (normal) is converted to A-form (aged). The differences in binding of doxazosin to N- and Aform of albumin are an important factor, which may determines therapeutic dosage and toxicity of the test drug. To indicate these differences, the technique of fluorescence spectroscopy was used. The association constant (Ka) obtained from fluorescence quenching demonstrated that doxazosin has higher affinity for AHSA than for HSA. In order to describe the cooperativity in binding process, the values of the Hill's coefficient has been analysed. For DOX-HSA system (lambdaex 295 nm) Hill's coefficient is close to 1 and it indicates that there is a single class of binding sites. For DOX-HSA (lambdaex 275 nm) and DOX AHSA (lambdaex 275 nm and lambdaex 295 nm) systems we observed positive cooperativity (nH>1). A greater red shift of fluorescence emission maximum of AHSA than HSA in the presence of DOX was observed. This suggests that the binding of DOX to AHSA was accompanied by a stronger increase in polarity around the fluorophores in comparison to HSA. The binding interaction between DOX and HSA has been also studied by molecular docking simulation. PMID- 26521960 TI - Advances in peptidic and peptidomimetic-based approaches to inhibit STAT signaling in human diseases. AB - STATs promote fundamental cellular processes, marking them as convergence points of many oncogenic and inflammatory pathways. Therefore, aberrant activation of STAT signaling is implicated in a plethora of human diseases, like cancer, inflammation and auto-immunity. Identification of STAT-specific inhibitors is the topic of great practical importance, and various inhibitory strategies are being pursued. An interesting approach includes peptides and peptide-like biopolymers, because they allow the manipulation of STAT signaling without the transfer of genetic material. Phosphopeptides and peptidomimetics directly target STATs by inhibiting dimerization. Despite that a large number of efficient peptide- based STAT3-specific inhibitors have been reported to date, none of them was able to meet the pharmacological requirements to serve as a potent anti-cancer drug. The existing limitations, like metabolic instability and poor cell permeability during in vivo tests, excluded these macromolecules from further clinical development. To overcome these liabilities, in the last five years many advances have been made to develop next generation STAT-specific inhibitors. Here we discuss the pitfalls of current STAT inhibitory strategies and review the progress on the development of peptide-like prodrugs directly targeting STATs. Novel strategies involve screening of high-complexity libraries of random peptides, as specific STAT3 or STAT5 DNA-binding inhibitors, to construct cell permeable peptide aptamers and aptides for cancer therapy. Another new direction is synthesis of negative dominant alpha-helical mimetics of the STAT3 N-domain, preventing oligomerization on DNA. Moreover, construction of phosphopeptide conjugates with molecules mediating cellular uptake offers new therapeutic possibilities in treatment of cancer, asthma and allergy. PMID- 26521961 TI - Challenges of using next generation sequencing in newborn screening. AB - Whole-genome and whole-exome sequencing for clinical applications is now an integral part of medical genetics practice. The term newborn screening refers to public health programs designed to screen newborns for various treatable metabolic conditions, by measuring levels of circulating blood metabolites. The availability and significant decrease in sequencing costs has raised the question of whether metabolic newborn screening should be replaced by whole-genome or whole-exome sequencing. While newborn genome sequencing can potentially increase the number of disorders identified by newborn screening, the generalization of its practice raises a number of important ethical issues. This short article argues that there are medical, psychological, ethical and economic reasons why widespread dissemination of newborn screening is still premature. PMID- 26521962 TI - Strongly polarizing weakly coupled (13)C nuclear spins with optically pumped nitrogen-vacancy center. AB - Enhancing the polarization of nuclear spins surrounding the nitrogen-vacancy (NV) center in diamond has recently attracted widespread attention due to its various applications. Here we present an analytical formula that not only provides a clear physical picture for the recently observed polarization reversal of strongly coupled(13)C nuclei over a narrow range of magnetic field [H. J. Wang et al., Nat. Commun. 4, 1940 (2013)], but also demonstrates the possibility to strongly polarize weakly coupled (13)C nuclei. This allows sensitive magnetic field control of the (13)C nuclear spin polarization for NMR applications and significant suppression of the (13)C nuclear spin noise to prolong the NV spin coherence time. PMID- 26521963 TI - A Quinoline-Based Ratiometric and Reversible Fluorescent Probe for Cadmium Imaging in Living Cells. AB - We report a novel ratiometric and reversible fluorescent probe for Cd(2+) detection utilizing a 6-(dimethylamino)quinaldine derivative as the fluorophore and a 2-hydrazinopyridine derivative as Cd(2+) chelator. This ratiometric fluorescent probe possesses favorable photophysical properties. It shows a large (55 nm) red-shift from 515 nm to 570 nm in the emission spectrum. Moreover, this probe also exhibits an excellent linear relationship of fluorescence intensity ratio (F570/F515) (R(2)=0.989) vs. Cd(2+) concentration in the range of 0-10 uM at physiological pH, which can serve as a "quantitative detecting" probe for Cd(2+). Utilizing this sensitive and selective probe, we have successfully detected Cd(2+) in living cells. PMID- 26521964 TI - The mGluR5 antagonist MPEP suppresses the expression and reinstatement, but not the acquisition, of the ethanol-conditioned place preference in mice. AB - The glutamatergic system may play a vital role in regulating neurobehavioral effects of various drugs of abuse. In the present study, we evaluated the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective antagonist of the type 5 metabotropic glutamate receptor (mGluR5) on the acquisition, expression and reinstatement of ethanol conditioned place preference (CPP). In the ethanol acquisition study, mice were conditioned with saline or ethanol (20% v/v, 2g/kg) on alternating days for 8 consecutive days and were given MPEP 10 min before ethanol conditioning. In another experiment, animals were conditioned with 2g/kg ethanol and MPEP was administered 10 min prior to the post-conditioning test. In a reinstatement study, following the extinction phase, animals were pretreated with MPEP 10 min prior to a priming injection of 1.0 g/kg ethanol. The mGluR5 antagonist MPEP significantly reduced the expression and the reinstatement in dose-dependent manner, but not acquisition of ethanol-induced CPP. These results indicate that mGluR5 may be involved in the expression and reinstatement of conditioned rewarding effects of ethanol, but not the acquisition of ethanol, which provide an evidence that mGluR5 blockade might make dissociable contributions during the training (acquisition phase), the performance of behavior (expression phase) and reinstatement. PMID- 26521965 TI - Knockout crickets for the study of learning and memory: Dopamine receptor Dop1 mediates aversive but not appetitive reinforcement in crickets. AB - Elucidation of reinforcement mechanisms in associative learning is an important subject in neuroscience. In mammals, dopamine neurons are thought to play critical roles in mediating both appetitive and aversive reinforcement. Our pharmacological studies suggested that octopamine and dopamine neurons mediate reward and punishment, respectively, in crickets, but recent studies in fruit flies concluded that dopamine neurons mediates both reward and punishment, via the type 1 dopamine receptor Dop1. To resolve the discrepancy between studies in different insect species, we produced Dop1 knockout crickets using the CRISPR/Cas9 system and found that they are defective in aversive learning with sodium chloride punishment but not appetitive learning with water or sucrose reward. The results suggest that dopamine and octopamine neurons mediate aversive and appetitive reinforcement, respectively, in crickets. We suggest unexpected diversity in neurotransmitters mediating appetitive reinforcement between crickets and fruit-flies, although the neurotransmitter mediating aversive reinforcement is conserved. This study demonstrates usefulness of the CRISPR/Cas9 system for producing knockout animals for the study of learning and memory. PMID- 26521966 TI - How much will the data allow us to know? PMID- 26521967 TI - Timing is everything. PMID- 26521968 TI - Symmetric Meso-Chloro-Substituted Pentamethine Cyanine Dyes Containing Benzothiazolyl/Benzoselenazolyl Chromophores Novel Synthetic Approach and Studies on Photophysical Properties upon Interaction with bio-Objects. AB - A series of symmetric pentamethine cyanine dyes derived from various N substituted benzothiazolium/benzoselenazolium salts, and a conjugated bis-aniline derivative containing a chlorine atom at meso-position with respect to the polymethine chain, were synthesized using a novel improved synthetic approach under mild conditions at room temperature. The reaction procedure was held by grinding the starting compounds for relative short times. The novel method is reliable and highly reproducible. Some photophysical characteristics were recorded in various solvents, including absorption, and fluorescence quantum yields using Cy-5 as a reference. Additional studies on interactions with several bio-objects such as liposomes, DNA, and proteins have been investigated in the present work. PMID- 26521969 TI - Factors Influencing Patients' Perspectives of Radiology Imaging Centers: Evaluation Using an Online Social Media Ratings Website. AB - PURPOSE: The goal of this study was to use patient reviews posted on Yelp.com, an online ratings website, to identify factors most commonly associated with positive versus negative patient perceptions of radiology imaging centers across the United States. METHODS: A total of 126 outpatient radiology centers from the 46 largest US cities were identified using Yelp.com; 1,009 patient reviews comprising 2,582 individual comments were evaluated. Comments were coded as pertaining to either the radiologist or other service items, and as expressing either a positive or negative opinion. Distribution of comments was compared with center ratings using Fisher's exact test. RESULTS: Overall, 14% of comments were radiologist related; 86% pertained to other aspects of service quality. Radiologist-related negative comments more frequent in low-performing centers (mean rating <=2 on 1-5 scale) than high-performing centers (rating >=4) pertained to imaging equipment (25% versus 7%), report content (25% versus 2%), and radiologist professionalism (25% versus 2%) (P < .010). Other service-related negative comments more frequent in low-performing centers pertained to receptionist professionalism (70% versus 21%), billing (65% versus 10%), wait times (60% versus 26%), technologist professionalism (55% versus 12%), scheduling (50% versus 17%), and physical office conditions (50% versus 5%) (P < .020). Positive comments more frequent in high-performing centers included technologist professionalism (98% versus 55%), receptionist professionalism (79% versus 50%), wait times (72% versus 40%), and physical office conditions (64% versus 25%) (P < .020). CONCLUSIONS: Patients' perception of radiology imaging centers is largely shaped by aspects of service quality. Schedulers, receptionists, technologists, and billers heavily influence patient satisfaction in radiology. Thus, radiologists must promote a service-oriented culture throughout their practice. PMID- 26521970 TI - An Abbreviated Protocol for High-Risk Screening Breast MRI Saves Time and Resources. AB - PURPOSE: To review the ability of an abbreviated, high-risk, screening, breast MRI protocol to detect cancer and save resources. METHODS: High-risk screening breast MR images were reviewed, from both an abbreviated protocol and a full diagnostic protocol. Differences in cancer detection, scanner utilization, interpretation times, and need for additional imaging were recorded in an integrated data form, and reviewed and compared. RESULTS: A total of 568 MRI cases were reviewed, with the abbreviated and full protocols. No difference was found in the number of cancers detected. Scan times were decreased by 18.8 minutes per case, for a total of 10,678 minutes (178 hours). Interpretation time, on average, was 1.55 minutes for the abbreviated protocol, compared with 6.43 minutes for the full protocol. Review of the full protocol led to a significant change in the final BI-RADS((r)) assessment in 12 of 568 (2.1%) cases. CONCLUSIONS: Abbreviated MRI is as effective as full-protocol MRI for demonstration of cancers in the high-risk screening setting, with only 12 (2.1%) cases recommended for additional MRI evaluation. The efficiency and resource savings of an abbreviated protocol would be significant, and would allow for opportunities to provide MRI for additional patients, as well as improved radiologist time management and workflow, with the potential to add real-time MRI interpretation or double reading. PMID- 26521972 TI - Quest for alternate personalized clinical source of MSCs: Advancing towards hiPSCs derived iMSCs. AB - The Human mesenchymal stromal/stem cells (MSCs) have been isolated from various tissue sources. Yet, the lack of a distinctive marker for identifying in vivo MSCs in their tissue niche has hampered the MSC's in vivo behavior tracking and compared that to the in vitro expanded cultures. In this review, we present a comprehensive report on MSCs history, isolation from assorted tissue sources, classification, long-term cultures for comprehensively characterized MSCs, immunomodulation, regenerative medical applications, iMSCs as a novel source of patient-specific iPSCs and scaleup strategies for translational applications. We have emphasized on prenatal tissue-derived MSCs and iMSCs derived from hiPSCs as an effective alternative to adult MSCs. We also highlight the urgent requirement to revisit the initial criteria laid down by International Society for Cellular Therapy (ISCT) and propose more stringent criteria to define, identify and exclusively characterize the MSCs derived from various tissue sources using advanced molecular tools; also more international workshops are necessary for delineating unique features of MSCs. Unless the proposed goal is achieved, it is extremely difficult to realize the full potential of MSCs in translational applications. Although numerous patients have been tested with MSCs to date, no immediate adverse outcomes or infusion-related toxicity has been reported, suggesting MSCs infusion to be safe. However, rare adverse event and late complications of the treatment may be detected in large cohorts of patients with long-term follow-up. PMID- 26521971 TI - Trends in Materials Science for Ligament Reconstruction. AB - The number of ligament injuries increases every year and concomitantly the need for materials or systems that can reconstruct the ligament. Limitations imposed by autografts and allografts in ligament reconstruction together with the advances in materials science and biology have attracted a lot of interest for developing systems and materials for ligament replacement or reconstruction. This review intends to synthesize the major steps taken in the development of polymer based materials for anterior cruciate ligament, their advantages and drawbacks and the results of different in vitro and in vivo tests. Until present, there is no successful polymer system for ligament reconstruction implanted in humans. The developing field of synthetic polymers for ligament reconstruction still has a lot of potential. In addition, several nano-structured materials, made of nanofibers or in the form of ceramic/polymeric nanocomposites, are attracting the interest of several groups due to their potential use as engineered scaffolds that mimic the native environment of cells, increasing the chances for tissue regeneration. Here, we review the last 15 years of literature in order to obtain a better understanding on the state-of-the-art that includes the usage of nano- and poly-meric materials for ligament reconstruction, and to draw perspectives on the future development of the field. PMID- 26521973 TI - Natural Polymer-Cell Bioconstructs for Bone Tissue Engineering. AB - The major goal of bone tissue engineering is to develop bioconstructs which substitute the functionality of damaged natural bone structures as much as possible if critical-sized defects occur. Scaffolds that mimic the structure and composition of bone tissue and cells play a pivotal role in bone tissue engineering applications. First, composition, properties and in vivo synthesis of bone tissue are presented for the understanding of bone formation. Second, potential sources of osteoprogenitor cells have been investigated for their capacity to induce bone repair and regeneration. Third, taking into account that the main property to qualify one scaffold as a future bioconstruct for bone tissue engineering is the biocompatibility, the assessments which prove it are reviewed in this paper. Forth, various types of natural polymer- based scaffolds consisting in proteins, polysaccharides, minerals, growth factors etc, are discussed, and interaction between scaffolds and cells which proved bone tissue engineering concept are highlighted. Finally, the future perspectives of natural polymer-based scaffolds for bone tissue engineering are considered. PMID- 26521974 TI - Cluster analysis of medical service resources at district hospitals in Taiwan, 2007-2011. AB - BACKGROUND: A vast amount of the annual/national budget has been spent on the National Health Insurance program in Taiwan. However, the market for district hospitals has become increasingly competitive, and district hospitals are under pressure to optimize the use of health service resources. Therefore, we employed a clustering method to explore variations in input and output service volumes, and investigate resource allocation and health care service efficiency in district hospitals. METHODS: Descriptive and cluster analyses were conducted to examine the district hospitals included in the Ministry of Health and Welfare database during 2007-2011. RESULTS: The results, according to the types of hospital ownership, suggested that the number of public hospitals has decreased and that of private hospitals increased; the largest increase in the number of district hospitals occurred when Taichung City was merged into Taichung County. The descriptive statistics from 2007 to 2011 indicated that 43% and 36.4% of the hospitals had 501-800 occupied beds and 101-200 physicians, respectively, and > 401 medical staff members. However, the number of outpatients and discharged patients exceeded 6001 and 90,001, respectively. In addition, the highest percentage of hospitals (43.9%) had 30,001-60,000 emergency department patients. In 2010, the number of patients varied widely, and the analysis of variance cluster results were nonsignificant (p > 0.05). CONCLUSION: District hospitals belonging to low-throughput and low-performance groups were encouraged to improve resource utilization for enhancing health care service efficiency. PMID- 26521975 TI - Self-reported pain management in hidradenitis suppurativa. PMID- 26521976 TI - Use of HCA in subproteome-immunization and screening of hybridoma supernatants to define distinct antibody binding patterns. AB - Understanding the properties and functions of complex biological systems depends upon knowing the proteins present and the interactions between them. Recent advances in mass spectrometry have given us greater insights into the participating proteomes, however, monoclonal antibodies remain key to understanding the structures, functions, locations and macromolecular interactions of the involved proteins. The traditional single immunogen method to produce monoclonal antibodies using hybridoma technology are time, resource and cost intensive, limiting the number of reagents that are available. Using a high content analysis screening approach, we have developed a method in which a complex mixture of proteins (e.g., subproteome) is used to generate a panel of monoclonal antibodies specific to a subproteome located in a defined subcellular compartment such as the nucleus. The immunofluorescent images in the primary hybridoma screen are analyzed using an automated processing approach and classified using a recursive partitioning forest classification model derived from images obtained from the Human Protein Atlas. Using an ammonium sulfate purified nuclear matrix fraction as an example of reverse proteomics, we identified 866 hybridoma supernatants with a positive immunofluorescent signal. Of those, 402 produced a nuclear signal from which patterns similar to known nuclear matrix associated proteins were identified. Detailed here is our method, the analysis techniques, and a discussion of the application to further in vivo antibody production. PMID- 26521977 TI - Preparation and characterization of aptamer-polyelectrolyte films and microcapsules for biosensing and delivery applications. AB - "Smart" materials are polymer systems that are able to change their physical or chemical properties in response to external stimuli in their environment. By adding a specific molecular recognition probe to a polymer, hybrid materials can be developed that retain the properties of the advanced polymer and gain the ability to respond to a specific molecular target. Aptamers are single-stranded oligonucleotides that are well-suited to serve as molecular recognition probes due to the specificity and affinity of their target recognition as well as their stability and ease of synthesis and labeling. In particular, their negatively charged backbone makes for their facile incorporation into polyelectrolyte-based materials. This article will provide a brief review of the currently reported biosensor and delivery platforms that have been reported employing aptamer polyelectrolyte materials, as well as a detailed description of the methods used to synthesize and study films and microcapsules containing small-molecule aptamer probes. PMID- 26521978 TI - Fluorescent whole-mount RNA in situ hybridization (F-WISH) in plant germ cells and the fertilized ovule. AB - First evidence on gene function and regulation is provided by the cellular expression pattern in complex tissues. However, to understand the activity of a specific gene, it is essential to analyze the regulatory network, which controls the spatio-temporal translation pattern during the entire life span of the transcribed mRNA. To explore mechanisms which control mRNA abundance and localization in space and time, it is necessary to visualize mRNAs quantitatively with a subcellular resolution, without sectioning the tissues. We have adapted and optimized a protocol for colorimetric whole-mount RNA in situ hybridization (WISH) using egg cell-specific digoxigenin (DIG) labeled probes (Hejatko et al., 2006) [1] on ovules and early seeds of Arabidopsis. Furthermore, we established a fluorescent whole-mount RNA in situ hybridization (F-WISH) protocol, which allows mRNA visualization on a subcellular level. The polar localized mRNA of SBT4.13, encoding a subtilase, was identified using this protocol. Both methods are described and discussed in detail. Additionally a (F)-WISH flow-chart is provided along with a troubleshooting table. PMID- 26521979 TI - Eye Movements Reveal Mental Looking Through Time. AB - People often make use of a spatial "mental time line" to represent events in time. We investigated whether the eyes follow such a mental time line during online language comprehension of sentences that refer to the past, present, and future. Participants' eye movements were measured on a blank screen while they listened to these sentences. Saccade direction revealed that the future is mapped higher up in space than the past. Moreover, fewer saccades were made when two events are simultaneously taking place at the present moment compared to two events that are happening in different points in time. This is the first evidence that oculomotor correlates reflect mental looking along an abstract invisible time line during online language comprehension about time. Our results support the idea that observing eye movements is likely to "detect" invisible spatial scaffoldings which are involved in cognitively processing abstract meaning, even when the abstract meaning lacks an explicit spatial correlate. Theoretical implications of these findings are discussed. PMID- 26521980 TI - Electrochemical immunosensor based on Pd-Au nanoparticles supported on functionalized PDDA-MWCNT nanocomposites for aflatoxin B1 detection. AB - This paper reports a label-free electrochemical immunosensor for the determination of aflatoxin B1 (AFB1), which is based on a gold electrode modified by a biocompatible film of carbon nanotubes/poly(diallyldimethylammoniumchloride)/Pd-Au nanoparticles (CNTs/PDDA/Pd Au). The nanocomposite was characterized by transmission electron microscopy and the electrochemical behavior of modified electrodes was investigated by cyclic voltammetry. The CNTs/PDDA/Pd-Au nanocomposites film showed good electron transfer ability, which ensured high sensitivity to detect AFB1 in a range from 0.05 to 25 ng mL(-1) with a detection limit of 0.03 ng mL(-1) obtained at 3sigma (where sigma is the standard deviation of the blank solution, n = 10). The proposed immunosensor provides a simple tool for AFB1 detection. This strategy can be extended to any other antigen detection by using the corresponding antibodies. PMID- 26521981 TI - Identification of peptide inhibitors of penicillinase using a phage display library. AB - There is a constant need to identify novel inhibitors to combat beta-lactamase mediated antibiotic resistance. In this study, we identify three penicillinase binding peptides, P1 (DHIHRSYRGEFD), P2 (NIYTTPWGSNWS), and P3 (SHSLPASADLRR), using a phage display library. Surface plasmon resonance (SPR) is utilized for quantitative determination and comparison of the binding specificity of selected peptides to penicillinase. An SPR biosensor functionalized with P3-GGGC (SHSLPASADLRRGGGC) is developed for detection of penicillinase with excellent sensitivity (15.8 RU nM(-1)) and binding affinity (KD = 0.56 nM). To determine if peptides can be good inhibitors for penicillinase, these peptides are mixed with penicillinase and their inhibition efficiency is determined by measuring the hydrolysis of substrate penicillin G using UV-vis spectrophotometry. Peptide P2 (NIYTTPWGSNWS) is found to be a promising penicillinase inhibitor with a Ki of 9.22 MUM and a Ki' of 33.12 MUM, suggesting that the inhibition mechanism is a mixed pattern. This peptide inhibitor (P2) can be used as a lead compound to identify more potent small molecule inhibitors for penicillinase. This study offers a potential approach to both detection of beta-lactamases and development of novel inhibitors of beta-lactamases. PMID- 26521982 TI - Risks of hypertension associated with cyclosporine, nonsteroidal anti inflammatory drugs, and systemic glucocorticoids in patients with psoriasis: a nationwide population-based nested case-control study in Taiwan. AB - PURPOSE: Patients with psoriasis and/or psoriatic arthritis (PsA) are known to have increased cardiovascular morbidity and mortality. Hypertension, an important risk factor for cardiovascular disease, is highly prevalent in patients with psoriasis and/or PsA. The effects of anti-psoriatic medications - including cyclosporine, nonsteroidal anti-inflammatory drugs, and glucocorticoids - on hypertension remain unclear. We examined whether such medication exposure was associated with hypertension in psoriasis patients. METHODS: This population based, nested case-control study analyzed data from an inception psoriasis cohort identified from Taiwan's National Health Insurance Research Database, 2000-2010. A total of 1530 patients with newly diagnosed hypertension and 4542 age- and gender-matched controls were included in the analysis. Conditional logistic regressions were applied to estimate the effects of drug of interest on hypertension. RESULTS: After adjusting for potential confounders, patients with current use of cyclosporine [odds ratio (OR) = 7.13; 95% confidence interval (CI) 1.85-27.49], nonsteroidal anti-inflammatory drugs (OR = 2.2; 95% CI 1.95-2.49), or systemic glucocorticoids (OR = 1.42; 95% CI 1.23-1.64) showed an increased risk of hypertension as compared to those not exposed to these drugs. Moreover, an increasing dose or combined use of nonsteroidal anti-inflammatory drugs and glucocorticoids was associated with increased hypertension risk. The risk of hypertension associated with glucocorticoids, or combined use was greatest among patients aged 49 years or less. CONCLUSIONS: The use of cyclosporine, nonsteroidal anti-inflammatory drugs, or glucocorticoid was associated with hypertension in patients with psoriasis and/or PsA. These study results inform physicians on the importance of early identification of hypertension during therapy with such medication. PMID- 26521983 TI - Pathogenesis of hepatic encephalopathy in cirrhosis: the concept of synergism revisited. AB - The concept of synergistic mechanisms as the pathophysiologic basis of hepatic encephalopathy started with the pioneering work of Les Zieve in Minneapolis some 60 years ago where synergistic actions of the liver-derived toxins ammonia, methanethiol, and octanoic acid were described. More recently, synergistic actions of ammonia and manganese, a toxic metal that is normally eliminated via the hepatobiliary route and shown to accumulate in brain in liver failure, on the glutamatergic neurotransmitter system were described. The current upsurge of interest in brain inflammation (neuroinflammation) in relation to the CNS complications of liver failure has added a third dimension to the synergy debate. The combined actions of ammonia, manganese and pro-inflammatory cytokines in brain in liver failure result in oxidative/nitrosative stress resulting from activation of glutamate (NMDA) receptors and consequent nitration of key brain proteins. One such protein, glutamine synthetase, the sole enzyme responsible for brain ammonia removal is nitrated and inactivated in brain in liver failure. Consequently, brain ammonia levels increase disproportionately resulting in alterations of brain excitability, impaired brain energy metabolism, encephalopathy and brain swelling. Experimental therapeutic approaches for which proof-of-principle has been established include the NMDA receptor antagonist memantine, N-acetyl cysteine (recently shown to have antioxidant properties at both hepatic and cerebral levels) and probiotics. PMID- 26521984 TI - Intranasal vaccination with killed Leishmania amazonensis promastigotes antigen (LaAg) associated with CAF01 adjuvant induces partial protection in BALB/c mice challenged with Leishmania (infantum) chagasi - CORRIGENDUM. PMID- 26521985 TI - 2-Hydroxy-4-Methylselenobutanoic Acid as New Organic Selenium Dietary Supplement to Produce Selenium-Enriched Eggs. AB - Food-based strategies need to be developed to improve the selenium (Se) status of individuals. The aim of this study was to evaluate the effects of a new organic Se [2-hydroxy-4-methylselenobutanoic acid (HMSeBA)] on selected performance criteria and Se deposition in egg of laying hens. Isa Brown laying hens, 18 weeks of age were randomly allocated to two dietary treatments and fed for 10 weeks. The hens were fed two corn-soybean meal-based diets comprising a control basal diet without Se supplementation and a test diet supplemented with Se at 0.2 mg/kg from HMSeBA. No difference was observed among dietary treatments on feed intake, egg weight and laying rate, whereas egg yolk fatty acid profile and vitamin E content were positively influenced by HMSeBA supplementation. Hens fed Se supplemented diet exhibited greater (P < 0.001) egg yolk total Se contents, which averaged 21.2 mg/100 g dry matter (DM) compared to control diet (11.7 mg/100 g DM). Our results suggested that HMSeBA as Se supplement influences positively egg yolk quality without affecting hens' productive traits. Moreover, HMSeBA offers an efficient alternative to fortify eggs with Se, which can consequently lead to greater supply of Se for humans. PMID- 26521986 TI - Potential role of FLT3-ligand in the angiogenic process of multiple myeloma. AB - The aim of the study was to evaluate serum levels of FLT3-ligand (FLT3-L), a soluble molecule in bone marrow (BM), participating actively in hematopoiesis, in relation with angiogenic factors in multiple myeloma (MM) patients. We measured, in 70 patients with active MM and in 38 of them who responded to conventional therapy, serum levels of FLT3-L, along with known angiogenic factors, such as VEGF, endoglin, TNF-alpha and HGF (with ELISA) and BM microvascular density (MVD), estimating the immunohistochemical expression of CD31. All pre-treatment values were higher in active MM patients compared to controls (p<0.001 for all cases), in parallel with both International Staging System and Durie-Salmon stages (p<0.001 for all cases). Moreover, levels of FLT3-L correlated positively with all soluble angiogenic factors, as well with MVD (p<0.0001 for all cases). Post-treatment values of FLT3-L decreased significantly in responders to therapy (p<0.001). The underlying relation of MM angiogenesis with FLT3-L may result from the fact that BM microvasculature is a major source of FLT3-L, both in BM niche and probably in peripheral blood. Our results suggest that serum levels of FLT3-L may be used as angiogenic marker in MM patients. PMID- 26521988 TI - Clinical activity of alvocidib (flavopiridol) in acute myeloid leukemia. AB - There have been minimal therapeutic advancements in acute myeloid leukemia (AML) over the past 4 decades and outcomes remain unsatisfactory. Alvocidib (formerly flavopiridol) is a multi-serine threonine cyclin-dependent kinase inhibitor with demonstrable in vitro and clinical activity in AML when combined in a timed sequential chemotherapy regimen, FLAM (alvocidib followed by cytarabine continuous infusion and mitoxantrone). FLAM has been evaluated in sequential phase 1 and phase 2 studies in 149 and 256 relapsed/refractory and newly diagnosed non-favorable risk AML patients, respectively, with encouraging findings in both patient populations warranting further investigation. This review highlights the mechanism of action of alvocidib, pre-clinical studies of alvocidib in AML, and the clinical trials evaluating alvocidib alone and in combination with cytotoxic agents (FLAM) in AML. PMID- 26521989 TI - Assessing the utility of geospatial technologies to investigate environmental change within lake systems. AB - Over 50% of the world's population live within 3 km of rivers and lakes highlighting the on-going importance of freshwater resources to human health and societal well-being. Whilst covering c. 3.5% of the Earth's non-glaciated land mass, trends in the environmental quality of the world's standing waters (natural lakes and reservoirs) are poorly understood, at least in comparison with rivers, and so evaluation of their current condition and sensitivity to change are global priorities. Here it is argued that a geospatial approach harnessing existing global datasets, along with new generation remote sensing products, offers the basis to characterise trajectories of change in lake properties e.g., water quality, physical structure, hydrological regime and ecological behaviour. This approach furthermore provides the evidence base to understand the relative importance of climatic forcing and/or changing catchment processes, e.g. land cover and soil moisture data, which coupled with climate data provide the basis to model regional water balance and runoff estimates over time. Using examples derived primarily from the Danube Basin but also other parts of the World, we demonstrate the power of the approach and its utility to assess the sensitivity of lake systems to environmental change, and hence better manage these key resources in the future. PMID- 26521987 TI - Polymorphisms within beta-catenin encoding gene affect multiple myeloma development and treatment. AB - Recent studies have suggested that cereblon (CRBN) is essential for the anti myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide, and that dysregulation of Wnt/beta-catenin pathway may be one of possible reasons of lenalidomide resistance. This prompted us to analyze the effect of polymorphisms within the genes coding for cereblon (CRBN (rs121918368 C>T)) and beta-catenin (CTNNB1 (rs4135385 A>G; rs4533622 A>C)). MM patients (n=142) and healthy individuals (n=123) were genotyped using the Light SNiP assays. The presence of the CTNNB1 (rs4533622) A allele was more frequently detected in patients presented with stage II-III disease according to International Staging System (63/82 vs. 26/44, p=0.043) and Durie-Salmon criteria (75/99 vs. 14/26, p=0.049). The CTNNB1 (rs4135385) AA homozygosity was more frequent among patients with better response to CTD, i.e., cyclophosphamide thalidomide-dexamethasone (18/23 vs. 32/60, p=0.047). Patients carrying the CTNNB1 (rs4533622) AA genotype were better responders to the first line therapy with thalidomide containing regimens (p<0.05). No significant association was observed between the effect of lenalidomide therapy and polymorphisms studied. However, the occurrence of neutropenia during lenalidomide therapy was more frequent among the CTNNB1 (rs4135385) AA carriers (p=0.019), while the CTNNB1 (rs4533622) AA homozygosity characterized patients with high grade (3-4) neutropenia (p=0.044). No association was found for the CRBN polymorphism. These results suggest that the CTNNB1 polymorphisms may affect the clinical course and response to chemotherapy in patients with multiple myeloma. PMID- 26521990 TI - A novel substance flow analysis model for analysing multi-year phosphorus flow at the regional scale. AB - Achieving sustainable management of phosphorus (P) is crucial for both global food security and global environmental protection. In order to formulate informed policy measures to overcome existing barriers of achieving sustainable P management, there is need for a sound understanding of the nature and magnitude of P flow through various systems at different geographical and temporal scales. So far, there is a limited understanding on the nature and magnitude of P flow over multiple years at the regional scale. In this study, we have developed a novel substance flow analysis (SFA) model in the MATLAB/Simulink(r) software platform that can be effectively utilized to analyse the nature and magnitude of multi-year P flow at the regional scale. The model is inclusive of all P flows and storage relating to all key systems, subsystems, processes or components, and the associated interactions of P flow required to represent a typical P flow system at the regional scale. In an annual time step, this model can analyse P flow and storage over as many as years required at a time, and therefore, can indicate the trends and changes in P flow and storage over many years, which is not offered by the existing regional scale SFA models of P. The model is flexible enough to allow any modification or the inclusion of any degree of complexity, and therefore, can be utilized for analysing P flow in any region around the world. The application of the model in the case of Gippsland region, Australia has revealed that the model generates essential information about the nature and magnitude of P flow at the regional scale which can be utilized for making improved management decisions towards attaining P sustainability. A systematic reliability check on the findings of model application also indicates that the model produces reliable results. PMID- 26521991 TI - Proximal femoral fractures and vascular injuries in adults: Incidence, aetiology and outcomes. AB - INTRODUCTION: Vascular injuries (VI) presenting during internal fixation (IF) of proximal femoral fractures (PFF) are potentially limb- and life-threatening. The purpose of this systematic review of the literature is to report on their incidence, associated complications and to give special emphasis in their prevention. MATERIALS AND METHODS: A comprehensive review of the literature was undertaken using the PRISMA guidelines with no language restriction. Case reports of VIPFF-IF and series of PFF-IF with cases of VI published between inception of journals to March 2015 were eligible for inclusion. Relevant information was divided in two parts. Part I included the analysis of cases of VIPFF-IF, with the objective of establishing the frequency of injury of each vessel, the types and mechanisms of injury, the diagnostic and therapeutic modalities, and the outcomes. Part II analysed series of PFF-IF, which included case(s) of VI for assessing the incidence of VIPFF-IF. RESULTS: Overall 160 articles with 182 cases of VIPFF-IF met the inclusion criteria. The injuries to extrapelvic vessels prevailed over those of intrapelvic vessels. There was a higher frequency of injury to the deep femoral artery and its branches in extrapelvic vessels and of external iliac artery and vein in intrapelvic vessels. The types of injury were: compression, intimal flap tear, disruption of the intimal layer with thrombosis, laceration with haemorrhage, and puncture or progressive erosion leading to a pseudoaneurysm (PSA) or arteriovenous fistula (AVF), with high prevalence for PSA, followed by lacerations. PSAs were more frequent in extrapelvic lesions and lacerations in the intrapelvic vessels. There were 7 non-iatrogenic injuries, produced by a displaced lesser trochanter fragment or other bone fragments, and 175 iatrogenic injuries (96.15%). The intrapelvic intraoperative protrusion of instruments or implants, or the post-operative migration of implants produced the injuries of intrapelvic vessels. For iatrogenic injuries of extrapelvic vessels the prevalent mechanism was a displaced lesser trochanter fragment, either intra- or postoperatively, followed by injuries by an overshot drill bit or a protruding screw; several other mechanisms completed the list. The clinical and radiological investigations were similar to those of VI elsewhere. VI occurred either at the time of fracture, during surgery or after it, early or late, weeks, months or even years after IF. The diagnostic and therapeutic modalities were most diverse, and the incidence of morbidity and mortality was 18.06%. The overall incidence of VIPFF-IF was 0.49%. CONCLUSION: The incidence of VIPFF-IF is low, though it will probably rise because of the increasing frequency of PFF. With few exceptions, these injuries, which are potentially limb and life-threatening, are iatrogenic, resulting of errors in IF, with different types of lesions to intra- and extrapelvic vessels running in close proximity to the bone. Although the surgeon should bear in mind this possibility and achieve early diagnosis and prompt accurate treatment, there is no consensus as to what is the best diagnostic or therapeutic modality. A precise diagnosis of the preoperative vascular status of the limb, monitoring of the displacement of the lesser trochanter fragment, careful and gentle reduction of the fracture, and precise handling of instruments and implant selection and placement during IF, are factors to consider in order to prevent this complication, which should never be underestimated. PMID- 26521992 TI - Pitfalls associated with open reduction and internal fixation of fractured ribs. AB - Rib fracture is exceedingly common and remains a leading cause of death in patients with chest injury. Probability of death increases by 19% with each broken rib, and the probability of death increases further with age. Treatment is centered on pain control and early mobilization to provide adequate pulmonary hygiene. Multimodality interventions, such as incentive spirometry, postural changes, and coughing, are pivotal in minimizing the risk of pneumonia and death. Recently, many studies have found mortality benefit to operation fixation (ORIF) of ribs in select patients. However, this procedure remains underutilized partly due to lack of familiarity with its technique and pitfalls by trauma surgeons, in particular. Whereas there are publications on operative technique, there are no studies describing pitfalls associated with this procedure. The purpose of this paper is to describe pitfalls on the technical aspects of ORIF of the ribs based on the medical literature where possible and based on our experience in instances where peer reviewed evidence is lacking. The paper is not meant to serve as a protocol for managing rib fractures. PMID- 26521993 TI - Comparative study of the effect of PTH (1-84) and strontium ranelate in an experimental model of atrophic nonunion. AB - This study aimed to set up an experimental model of long bone atrophic nonunion and to explore the potential role of PTH-1-84 (PTH 1-84) and strontium ranelate (SrR). A model of atrophic nonunion was created in Sprague-Dawley rats at the femoral midshaft level. The animals were randomised into four groups. Group A1: control rodents, fracture without bone gap; Group A2: rodents with subtraction osteotomy (non-union model control) treated with saline; Group B: rodents with subtraction osteotomy treated with human-PTH (PTH 1-84); and Group C: rodents with subtraction osteotomy treated with strontium ranelate (SrR). The groups were followed for 12 weeks. X-rays were be obtained at weeks 1, 6 and 12. After sacrificing the animals, we proceeded to the biomechanical study and four point bending tests to evaluate the resistance of the callus and histological study. In second phase, the expression of genes related to osteoblast function was analysed by reverse transcription-quantitative PCR in rats subjected to substraction osteotomy and treated for 2 weeks. The animals were randomised into three groups: Group A2: rodents treated with saline; Group B: rodents treated with PTH 1-84 and Group C: rodents treated with SrR. RESULTS: No significant histological differences were found between animals subjected to subtraction osteotomy and treated with either saline or PTH (p=0.628), but significant difference existed between animals receiving saline or SrR (p=0.005). There were no significant differences in X-ray score between the saline and PTH groups at either 6 or 12 weeks (p=0.33 and 0.36, respectively). On the other hand, better X-ray scores were found in the SrR group (p=0.047 and 0.006 in comparison with saline, at 6 and 12 weeks, respectively). In line with this, biomechanical tests revealed improved results in the SrR group. Gene expression analysis revealed a slightly decreased levels of DKK1, a Wnt pathway inhibitor, in rats treated with SrR. CONCLUSIONS: SrR increases has a beneficial effect in this atrophic non-union model in rats. This suggests that it might have a role may have important implications for the potential clinical role in the treatment of fracture nonunion. PMID- 26521994 TI - Long stem reverse shoulder arthroplasty and cerclage for treatment of complex long segment proximal humeral fractures with diaphyseal extension in patients more than 65 years old. AB - INTRODUCTION: Treatment of long segment proximal humeral fractures with extension below the surgical neck into the diaphysis remains a significant challenge for orthopaedic surgeons. The purpose of this paper was to evaluate the clinical and radiological outcomes following primary long-stem RSA with cerclage fixation for complex long segment proximal humeral fractures with diaphyseal extension in patients more than 65 years old. MATERIAL AND METHODS: Between February 2010 and March 2013, 22 patients who suffered a complex proximal humerus fracture with extended diaphyseal involvement underwent surgery with long-stem RSA and cerclages fixation. There were 17 female and 5 male patients, and the mean age was 77.2 years at time of surgery (range 65-84 years). All patients had a 3 or 4 part proximal humerus fracture or a two part fracture with a split of humeral head, with extension to the proximal diaphysis. Clinical and radiographic follow up was performed on all 22 patients at 6 weeks, at 3, 6, and 12 months postoperatively, and then at 2 years. Clinical evaluation consisted of the shoulder rating Constant scale. X ray evaluation was done to evaluate fracture healing and eventually humeral and glenoid component loosening or other complications. RESULTS: No infections were reported, neither other serious complications. Two patients developed a seroma and one patient developed chronic pain at that was treated with referral to pain management. No patients were lost at follow-up. At final follow-up, average active elevation was 132.5 degrees (range 100 degrees -140 degrees ), external rotation 30 degrees (range 55 degrees -10 degrees ). Average abduction was 120 degrees (range 90 degrees -135 degrees ). The mean adjusted Constant score was 72/100 (range 64-82). All fractures were healed within 3 months after surgery. No loosening of the humeral or glenoid components and no episodes of dislocation/instability were observed in this series. We did not observe scapular notching in any patient on the x-ray at most recent follow-up. CONCLUSION: Long-stem RSA with cerclages wire fixation represents a viable treatment option for complex long-segment displaced proximal humerus fractures with diaphyseal extension in patients older than 65 years. Our results suggest clinical outcomes at two years of follow up are satisfactory with an acceptable complication rate. PMID- 26521995 TI - Basal (18)F-FDG PET/CT as a predictive biomarker of tumor response for neoadjuvant therapy in breast cancer. AB - PURPOSE: To explore the relation between tumor kinetic assessed by (18)F-FDG PET and final neoadjuvant chemotherapy (NC) response within a molecular phenotype perspective. MATERIAL AND METHODS: Prospective study included 144 women with breast cancer. All patients underwent a dual-time point (18)F-FDG PET/CT previous to NC. The retention index (RI), between SUV-1 and SUV-2 was calculated. Molecular subtypes were re-grouped in low, intermediate and high-risk biological phenotypes. After NC, all residual primary tumor specimens were histopathologically classified in tumor regression grades (TRG) and response groups. The relation between SUV-1, SUV-2 and RI with the TRG and response groups was evaluated in all molecular subtypes and in accordance with the risk categories. RESULTS: Responder's lesions showed significant greater SUVmax compared to non-responders. The RI value did not show any significant relation with response. Attending to molecular phenotypes, statistical differences were observed with greater SUV for responders having high-risk molecular subtypes. CONCLUSION: Glycolytic tumor characteristics showed a significant correlation with NC response and dependence of risk phenotype. PMID- 26521996 TI - Is there any correlation between levels of serum ostepontin, CEA, and FDG uptake in lung cancer patients with bone metastasis? AB - OBJECTIVE: In this study, an evaluation was made of the relationship between the serum levels of carcinoembryonic antigen (CEA), osteopontin (OPN), and the semi quantitative parameters of 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in lung cancer patients with bone metastasis. MATERIAL AND METHODS: The evaluation included 42 non-small cell lung cancer (NSCLC) and 31 small cell lung cancer (SCLC) patients who were referred to our institution for staging by (18)F-FDG PET/CT. The biochemical parameters measured included CEA and OPN serum levels. RESULTS: Serum levels of OPN in NSCLC patients with and without bone metastasis were 21.20+/-4.97 ng/ml and 13.33+/-4.53 ng/ml, respectively (p<0.05). In SCLC patients with and without bone metastasis serum OPN levels were 23.95+/-4.78 ng/ml and 17.30+/-3.09 ng/ml, respectively (p<0.05). Serum levels of CEA in NSCLC patients with and without bone metastasis were 33.79+/-6.49 ng/ml and 11.74+/-2.96 ng/ml, respectively (p<0.05). In SCLC patients with and without bone metastasis serum levels of CEA were 28.93+/-4.59 ng/ml and 13.88+/-4.47 ng/ml, respectively (p<0.05). There were no correlations between primary tumor SUVmax, and serum levels of CEA and OPN. CONCLUSIONS: Bone metastasis can be detected in patients with lung cancer by measuring CEA and OPN levels. Increased levels of CEA and OPN levels may be considered an early warning sign in patients needing accurate imaging, as they are at higher risk of bone metastasis. PMID- 26521997 TI - Pulmonary talcosis caused by methadone misuse and mimicking primary lung cancer. FDG-PET/CT findings. PMID- 26521998 TI - Radioisotope synoviorthesis in paediatric and adolescent patients with haemophilia. AB - OBJECTIVE: To assess the outcome and adverse-effects of the radioisotope synoviorthesis in paediatric and adolescent patients with haemophilia. MATERIAL AND METHODS: Prospective study of historical cohort was conducted. A total of 20 consecutive haemophiliacs with a mean age of 13.1 years (range 4-17) were included with a mean follow-up of 64.9 months (range 18-109). The diagnosis of synovitis was established on the basis of clinical follow-up including radiological images (radiography and/or MRI). For evaluation, the classification proposed by Fernandez-Palazzi was used. INCLUSION CRITERIA: Patients aged less than 18 years old with haemophilia and more than one haemarthrosis in less than 3 months remaining a chronic synovitis despite prophylactic therapy intensification. EXCLUSION CRITERIA: Any contraindication for radionuclide synoviorthesis. Twenty-seven radioisotope synoviorthesis with (90)Y-citrate colloid and/or (186)Re-sulphide-colloid were done. The effectiveness of the procedure was assessed through pre and posttreatment clinical comparison at 6 months after radioisotope synoviorthesis. RESULTS: Nineteen of the 27 synoviorthesis (70.3%) had a good or excellent response and 8 joints (29.7%) had partial response. It was necessary to repeat the procedure in 3 joints in 3 different patients, obtaining in all cases a good or excellent response. We appreciated inflammatory reaction after procedure in 4 cases (14.8%), which improved with analgesics and nonsteroidal anti-inflamatory drugs. None of the patients presented malignant or premalignant lesions during the follow-up. CONCLUSION: The radionuclide synoviorthesis is a very effective procedure in paediatric and adolescent patients with hemophilia, being a minimally invasive procedure, easy to perform, safe and with minimal side effects. PMID- 26521999 TI - Assessment of treatment response with FDG PET/CT on a primary neuroendocrine tumor of vagina. PMID- 26522000 TI - BCGitis detected by (18)F-FDG PET/CT after treatment of bladder urothelial carcinoma. PMID- 26522001 TI - Paediatric grade-II lymphomatoid granulomatosis: (18)F-FDG PET/CT monitoring of disease activity. PMID- 26522002 TI - Bilateral symmetrical adrenal hypermetabolism on FDG PET/CT due to Cushing syndrome in well differentiated neuroendocrine carcinoma. AB - The (18)F-FDG PET/CT scan has been suggested for whole-body imaging to identify ectopic adrenocorticotrophic hormone secreting tumours, but there are some challenges involved. The case of a patient is presented, who was admitted with the pre-diagnosis of ectopic ACTH syndrome. On the CT, a nodular lesion was detected in the medial segment of the right lung. The FDG uptake of the lesion seemed to be increased visually, but was not pathological quantitatively (SUVmax: 1.8) on the PET/CT. There was also diffuse increased uptake (SUVmax: 14.2) in the enlarged adrenal glands. The lesion was reported as a possible malignant lesion with low FDG affinity, such as a low grade neuroendocrine tumour, while the diffuse enlarged adrenal glands with high uptake were interpreted as diffusely hyperplasic, due to Cushing's syndrome. The patient was treated with a surgical wedge resection. The histopathological diagnosis confirmed that the tumour was a grade 1 well-differentiated neuroendocrine carcinoma. PMID- 26522003 TI - Glycolytic activity in breast cancer using 18F-FDG PET/CT as prognostic predictor: A molecular phenotype approach. AB - AIM: To explore the relationship between basal (18)F-FDG uptake in breast tumors and survival in patients with breast cancer (BC) using a molecular phenotype approach. MATERIAL AND METHODS: This prospective and multicentre study included 193 women diagnosed with BC. All patients underwent an (18)F-FDG PET/CT prior to treatment. Maximum standardized uptake value (SUVmax) in tumor (T), lymph nodes (N), and the N/T index was obtained in all the cases. Metabolic stage was established. As regards biological prognostic parameters, tumors were classified into molecular sub-types and risk categories. Overall survival (OS) and disease free survival (DFS) were obtained. An analysis was performed on the relationship between semi-quantitative metabolic parameters with molecular phenotypes and risk categories. The effect of molecular sub-type and risk categories in prognosis was analyzed using Kaplan-Meier and univariate and multivariate tests. RESULTS: Statistical differences were found in both SUVT and SUVN, according to the molecular sub-types and risk classifications, with higher semi-quantitative values in more biologically aggressive tumors. No statistical differences were observed with respect to the N/T index. Kaplan-Meier analysis revealed that risk categories were significantly related to DFS and OS. In the multivariate analysis, metabolic stage and risk phenotype showed a significant association with DFS. CONCLUSION: High-risk phenotype category showed a worst prognosis with respect to the other categories with higher SUVmax in primary tumor and lymph nodes. PMID- 26522004 TI - Usefulness of (18)F-FDG PET/CT in recurrent basal cell carcinoma: Report of a case. AB - We analyze the case of a patient with left periorbital infiltrating basal cell carcinoma treated with surgical excision in October 2010. Surgery included orbital exenteration and reconstruction using skin graft and radiotherapy. In May 2013 a MR imaging showed a mass in the left orbital fossa, suggesting a recurrence in the graft. A basal cell carcinoma recurrence with perineural invasion was confirmed in the biopsy. On (18)F-FDG PET/CT performed, a hypermetabolic activity was observed in the left periorbital area with extension to surrounding sinus and bones. The use of (18)F-FDG PET/CT in patients with advanced basal cell carcinoma has not been fully explored due to the rarity of this entity. This case demonstrates the usefulness of this technique to determine the extent of non-melanocytic recurrent skin tumors, and its value in the staging and treatment control, supporting the incorporation of (18)F-FDG PET/CT in the management of advanced basal cell carcinoma. PMID- 26522005 TI - Brain FDG-PET showing striatal hypometabolism in a case of chorea-acanthocytosis. PMID- 26522006 TI - Integrated micro-optofluidic platform for real-time detection of airborne microorganisms. AB - We demonstrate an integrated micro-optofluidic platform for real-time, continuous detection and quantification of airborne microorganisms. Measurements of the fluorescence and light scattering from single particles in a microfluidic channel are used to determine the total particle number concentration and the microorganism number concentration in real-time. The system performance is examined by evaluating standard particle measurements with various sample flow rates and the ratios of fluorescent to non-fluorescent particles. To apply this method to real-time detection of airborne microorganisms, airborne Escherichia coli, Bacillus subtilis, and Staphylococcus epidermidis cells were introduced into the micro-optofluidic platform via bioaerosol generation, and a liquid-type particle collection setup was used. We demonstrate successful discrimination of SYTO82-dyed fluorescent bacterial cells from other residue particles in a continuous and real-time manner. In comparison with traditional microscopy cell counting and colony culture methods, this micro-optofluidic platform is not only more accurate in terms of the detection efficiency for airborne microorganisms but it also provides additional information on the total particle number concentration. PMID- 26522007 TI - Expression profiling of prostate cancer tissue delineates genes associated with recurrence after prostatectomy. AB - Prostate cancer is a leading cause of cancer death amongst males. The main clinical dilemma in treating prostate cancer is the high number of indolent cases that confer a significant risk of overtreatment. In this study, we have performed gene expression profiling of tumor tissue specimens from 36 patients with prostate cancer to identify transcripts that delineate aggressive and indolent cancer. Key genes were validated using previously published data and by tissue microarray analysis. Two molecular subgroups were identified with a significant overrepresentation of tumors from patients with biochemical recurrence in one of the groups. We successfully validated key transcripts association with recurrence using two publically available datasets totaling 669 patients. Twelve genes were found to be independent predictors of recurrence in multivariate logistical regression analysis. SFRP4 gene expression was consistently up regulated in patients with recurrence in all three datasets. Using an independent cohort of 536 prostate cancer patients we showed SFRP4 expression to be an independent predictor of recurrence after prostatectomy (HR = 1.35; p = 0.009). We identified SFRP4 to be associated with disease recurrence. Prospective studies are needed in order to assess the clinical usefulness of the identified key markers in this study. PMID- 26522008 TI - Characterization of Nucleic Acid Compaction with Histone-Mimic Nanoparticles through All-Atom Molecular Dynamics. AB - The development of nucleic acid (NA) based nanotechnology applications rely on the efficient packaging of DNA and RNA. However, the atomic details of NA nanoparticle binding remains to be comprehensively characterized. Here, we examined how nanoparticle and solvent properties affect NA compaction. Our large scale, all-atom simulations of ligand-functionalized gold nanoparticle (NP) binding to double stranded NAs as a function of NP charge and solution salt concentration reveal different responses of RNA and DNA to cationic NPs. We demonstrate that the ability of a nanoparticle to bend DNA is directly correlated with the NPs charge and ligand corona shape, where more than 50% charge neutralization and spherical shape of the NP ligand corona ensured the DNA compaction. However, NP with 100% charge neutralization is needed to bend DNA almost as efficiently as the histone octamer. For RNA in 0.1 M NaCl, even the most highly charged nanoparticles are not capable of causing bending due to charged ligand end groups binding internally to the major groove of RNA. We show that RNA compaction can only be achieved through a combination of highly charged nanoparticles with low salt concentration. Upon interactions with highly charged NPs, DNA bends through periodic variation in groove widths and depths, whereas RNA bends through expansion of the major groove. PMID- 26522010 TI - Two-dimensional polymers: concepts and perspectives. AB - Creation of polymers comprised of repeat units that can create topologically planar macromolecules (rather than linear) has been the topic of several recent studies in the field of synthetic polymer chemistry. Such novel macromolecules, known as 2D polymers, are the result of advanced synthetic methodology which allows creation of monolayer sheets with a periodic internal structure and functional groups placed at predetermined sites under mild conditions. Given the promising potentials of 2D polymers, this feature paper aims at discussing the concept of these novel macromolecules from a topological viewpoint in Section 1. This is followed by spotlighting the expected behavior of 2D polymers in the context of polymer physics (entropy elasticity, strength, percolation, and persistence) and polymer chemistry (copolymers and growth kinetics) in Section 2. Section 3 delineates synthetic and analytical matters associated with 2D polymers followed by a brief final section highlighting the potential of these sheet-like macromolecules for application purposes. We hope this article will trigger the interest of chemists, physicists and engineers to help develop this encouraging new class of materials further such that societally relevant applications will be accessible in the market soon. PMID- 26522009 TI - Predictive Factors for Positive Margin and the Surgical Learning Curve in Non Palpable Breast Cancer After Wire-Guided Localization - Prospective Study of 214 Consecutive Patients. AB - To investigate the most commonly used technique, the wire-guided localization (WGL) in non-palpable breast cancer. To analyze the effective factors on positive surgical margins in our practice and determine the surgical learning curve of this method. Prospective consecutive study was performed from January 2005 to December 2011. Inclusion criteria was a non-palpable breast lesion with malignancy on preoperative histology. All lesions were localized by ultrasound or stereotactic guided wire placement. Margins 1 mm or closer were accepted as positive margins which required re-excision. To determine the learning curve of WGL method we investigated the change in the reoperation rate after primary procedure performed by "high-volume" surgeon. Two hundred and fourteen consecutive patients were enrolled. In 23 patients (10.7%) reexcision was needed. Positive surgical margins were significantly influenced by the patient's age (p = 0.03), tumor volume (p < =0.001), proportion of tumor volume/specimen volume (p < 0.001), presence of DCIS (p < 0.001), multifocality (p = 0.03) and the learning curve (p = 0.006) with univariate analysis. Only the tumor volume, presence of DCIS and the learning curve were proved as independent prognostic factor for reoperation by multivariate analysis. The reoperation rate decreased below 20% after the fortieth operation. Results of our single institutional study suggest, that this localization technique can be performed safely with very good results after 40 procedures as a learning curve for surgeons. PMID- 26522011 TI - Transcriptomic response during phage infection of a marine cyanobacterium under phosphorus-limited conditions. AB - The transcriptomic responses of bacteria to environmental stresses have been studied extensively, yet we know little about how the stressed cells respond to bacteriophage infection. Here, we conducted the first whole transcriptome sequencing (RNA-seq) study of stressed bacteria to phage infection by infecting the marine picocyanobacterium Prochlorococcus NATL2A with cyanomyovirus P-SSM2 under P limitation, a strong selective force in the oceans. Transcripts of the P acquisition genes in the uninfected cells were enriched after P limitation, including the high-affinity phosphate-binding protein gene pstS. They were still enriched in the infected cells under P-limited conditions. In contrast, transcripts of adenosine triphosphate (ATP) synthase and ribosomal protein genes were depleted in the uninfected cells after P limitation but were enriched during phage infection of P-starved cells. Cyanophage P-SSM2 contains pstS, and pstS and its adjacent gene g247 of unknown function were the only phage genes that were enriched under P-limited conditions. We further found that the host pstS transcript number per cell decreased after infection, however, it was still much higher in the P-limited infected cells than that in the nutrient-replete cells. Moreover, phage pstS transcript number per cell was ~ 20 times higher than the host copy, which may help maintain the host phosphate uptake rate during infection. PMID- 26522012 TI - Conformational fluctuations of the AXH monomer of Ataxin-1. AB - In this paper, we report the results of molecular dynamics simulations of AXH monomer of Ataxin-1. The AXH domain plays a crucial role in Ataxin-1 aggregation, which accompanies the initiation and progression of Spinocerebellar ataxia type 1. Our simulations involving both classical and replica exchange molecular dynamics, followed by principal component analysis of the trajectories obtained, reveal substantial conformational fluctuations of the protein structure, especially in the N-terminal region. We show that these fluctuations can be generated by thermal noise since the free energy barriers between conformations are small enough for thermally stimulated transitions. In agreement with the previous experimental findings, our results can be considered as a basis for a future design of ataxin aggregation inhibitors that will require several key conformations identified in the present study as molecular targets for ligand binding. PMID- 26522013 TI - Sirtuin-2 mediates male specific neuronal injury following experimental cardiac arrest through activation of TRPM2 ion channels. AB - OBJECTIVE: Sirtuins (Sirt) are a class of deacetylase enzymes that play an important role in cell proliferation. Sirt2 activation produces O-acetylated ADPribose (OAADPr) which can act as a ligand for transient receptor potential cation channel, M2 (TRPM2). We tested the hypothesis that Sirt2 is activated following global cerebral ischemia and contributes to neuronal injury through activation of TRPM2. METHODS: Adult male and female mice (8-12 weeks old) C57Bl/6 and TRPM2 knock-out mice were subjected to 8 min of cardiac arrest followed by cardiopulmonary resuscitation (CA/CPR). The Sirt2 inhibitor AGK-2 was administered intravenously 30 min after resuscitation. Hippocampal CA1 injury was analyzed at 3 days after CA/CPR. Acute Sirt2 activity was analyzed at 3 and 24 h after CA/CPR. Long-term hippocampal function was assessed using slice electrophysiology 7 days after CA/CPR. RESULTS: AGK-2 significantly reduced CA1 injury in WT but not TRPM2 knock-out males and had no effect on CA1 injury in females. Elevated Sirt2 activity was observed in hippocampal tissue from males at 24 h after cardiac arrest and was reduced by AGK-2. In contrast, Sirt2 activity in females was increased at 3 but not 24 h. Finally, we observed long-term benefit of AGK-2 on hippocampal function, with a protection of long-term potentiation at CA1 synapses at 7 and 30 days after ischemia. CONCLUSIONS: In summary, we observed a male specific activation of Sirt2 that contributes to neuronal injury and functional deficits after ischemia specifically in males. These results are consistent with a role of Sirt2 in activating TRPM2 following global ischemia in a sex specific manner. These results support the growing body of literature showing that oxidative stress mechanisms predominate in males and converge on TRPM2 activation as a mediator of cell death. PMID- 26522014 TI - Saffron-Based Crocin Prevents Early Lesions of Liver Cancer: In vivo, In vitro and Network Analyses. AB - BACKGROUND: The angiogenesis inhibitor, sorafenib, remains the only available therapy of hepatocellular carcinoma (HCC). Only recently patents of VEGF receptors-3 inhibitors are developed. Thus, a novel approach against HCC is essential for a better therapeutic outcome. OBJECTIVE: The aims of this study were to examine the chemopreventive action of saffron's main biomolecule, crocin, against chemically-induced liver cancer in rats, and to explore the mechanisms by which crocin employs its anti-tumor effects. METHOD: We investigated the anti cancer effect of crocin on an experimental carcinogenesis model of liver cancer by studying the anti-oxidant, anti-inflammatory, anti-proliferation, pro apoptotic activities of crocin in vivo. In addition, we provided a network analysis of differentially expressed genes in tissues of animals pre-treated with crocin in comparison to induced-HCC animals' tissues. To further support our results, in vitro analysis was carried out. We assessed the effects of crocin on HepG2 cells viability by treating them with various concentrations of crocin; in addition, effects of crocin on cell cycle distribution of HepG2 cells were investigated. RESULTS: Findings reported herein demonstrated the anti proliferative and pro-apoptotic properties of crocin when administrated in induced- HCC model. Crocin exhibited anti-inflammatory properties where NF kappaB, among other inflammatory markers, was inhibited. In vitro analysis confirmed crocin's effect in HepG2 by arresting the cell cycle at S and G2/M phases, inducing apoptosis and down regulating inflammation. Network analysis identified NF-kappaB as a potential regulatory hub, and therefore, a candidate therapeutic drug target. CONCLUSION: Taken together, our findings introduce crocin as a candidate chemopreventive agent against HCC. PMID- 26522015 TI - Using metamaterial nanoengineering to triple the superconducting critical temperature of bulk aluminum. AB - Recent experiments have shown the viability of the metamaterial approach to dielectric response engineering for enhancing the transition temperature, Tc, of a superconductor. In this report, we demonstrate the use of Al2O3-coated aluminium nanoparticles to form the recently proposed epsilon near zero (ENZ) core-shell metamaterial superconductor with a Tc that is three times that of pure aluminium. IR reflectivity measurements confirm the predicted metamaterial modification of the dielectric function thus demonstrating the efficacy of the ENZ metamaterial approach to Tc engineering. The developed technology enables efficient nanofabrication of bulk aluminium-based metamaterial superconductors. These results open up numerous new possibilities of considerable Tc increase in other simple superconductors. PMID- 26522017 TI - Sellar Masses: An Epidemiological Study. AB - BACKGROUND: Sellar masses (SM) are mostly benign growths of pituitary or nonpituitary origin that are increasingly encountered in clinical practice. To date, no comprehensive population-based study has reported the epidemiology of SM from North America. AIM: To determine the epidemiology of SM in the province of Nova Scotia, Canada. METHODS: Data from all pituitary-related referrals within the province were prospectively collected in interlinked computerized registries starting in November 2005. We conducted a retrospective analysis on all patients with SM seen within the province between November 2005 and December 2013. RESULTS: A total of 1107 patients were identified, of which 1005 were alive and residing within the province. The mean age at presentation was 44.6+/-18 years, with an overall female preponderance (62%) and a population prevalence rate of 0.1%. Of patients with SM, 837 (83%) had pituitary adenomas and 168 (17%) had nonpituitary lesions. The relative prevalence and standardized incidence ratio, respectively, of various SM were: nonfunctioning adenomas (38.4%; 2.34), prolactinomas (34.3%; 2.22), Rathke's cyst (6.5%; 0.5), growth hormone-secreting adenomas (6.5%; 0.3), craniopharyngiomas (4.5%; 0.2), adrenocorticotropic hormone secreting adenomas (3.8%; 0.2), meningiomas (1.9%), and others (3.9%; 0.21). At presentation, 526 (52.3%) had masses >=1 cm, 318 (31.6%) at <1 cm, and 11 (1.1%) had functioning pituitary adenomas without discernible tumor, whereas tumor size data were unavailable in 150 (14.9%) patients. The specific pathologies and their most common presenting features were: nonfunctioning adenoma (incidental, headaches, and vision loss), prolactinomas (galactorrhea, menstrual irregularity, and headache), growth hormone-secreting adenomas (enlarging extremities and sweating), adrenocorticotropic hormone-secreting adenoma (easy bruising, muscle wasting, and weight gain) and nonpituitary lesions (incidental, headaches, and vision problems). Secondary hormonal deficiencies were common, ranging from 19.6% to 65.7%; secondary hypogonadism, hypothyroidism, and growth hormone deficiencies constituted the majority of these abnormalities. CONCLUSIONS: This is the largest North American study to date to assess the epidemiology of SM in a large stable population. Given their significant prevalence in the general population, more studies are needed to evaluate the natural history of these masses and to help allocate appropriate resources for their management. PMID- 26522016 TI - Surgical treatment for refractory epileptic spasms: The Detroit series. AB - OBJECTIVE: We reviewed our experience of surgery for epileptic spasms (ES) with or without history of infantile spasms. METHODS: Data were reviewed from 65 (33 male) patients with ES who underwent surgery between 1993 and 2014; palliative cases were excluded. RESULTS: Mean age at surgery was 5.1 (range 0.2-19) years, with mean postsurgical follow-up of 45.3 (6-120) months. Mean number of anticonvulsants used preoperatively was 4.2 (2-8), which decreased to 1.2 (0-4) postoperatively (p < 0.0001). Total hemispherectomy was the most commonly performed surgery (n = 20), followed by subtotal hemispherectomy (n = 17), multilobar resection (n = 13), lobectomy (n = 7), tuberectomy (n = 6), and lobectomy + tuberectomy (n = 2), with International League Against Epilepsy (ILAE) class I outcome in 20, 10, 7, 6, 3, and 0 patients, respectively (total 46/65 (71%); 22 off medication). Shorter duration of epilepsy (p = 0.022) and presence of magnetic resonance imaging (MRI) lesion (p = 0.026) were independently associated with class I outcome. Of 34 patients operated <3 years after seizure onset, 30 (88%) achieved class I outcome. Thirty-seven (79%) of 47 patients with lesional MRI had class-I outcome, whereas 9 (50%) of 18 with normal MRI had class I outcome. Positron emission tomography (PET) scan was abnormal in almost all patients [61 (97%) of 63 with lateralizing/localizing findings in 56 (92%) of 61 patients, thus helping in surgical decision making and guiding subdural grid placements, particularly in patients with nonlesional MRI. Fifteen patients had postoperative complications, mostly minor. SIGNIFICANCE: Curative epilepsy surgery in ES patients, with or without history of infantile spasms, is best accomplished at an early age and in those patients with lesional abnormalities on MRI with electroencephalography (EEG) concordance. Good outcomes can be achieved even when there is no MRI lesion but positive PET localization. PMID- 26522018 TI - Production of viable trout offspring derived from frozen whole fish. AB - Long-term preservation of fish fertility is essential for the conservation of endangered fishes. However, cryopreservation techniques for fish oocytes and embryos have not yet been developed. In the present study, functional eggs and sperm were derived from whole rainbow trout that had been frozen in a freezer and stored without the aid of exogenous cryoprotectants. Type A spermatogonia retrieved from frozen-thawed whole trout remained viable after freezing duration up to 1,113 days. Long-term-frozen trout spermatogonia that were intraperitoneally transplanted into triploid salmon hatchlings migrated toward the recipient gonads, where they were incorporated, and proliferated rapidly. Although all triploid recipients that did not undergo transplantation were functionally sterile, 2 of 12 female recipients and 4 of 13 male recipients reached sexual maturity. Eggs and sperm obtained from the salmon recipients were capable of producing donor-derived trout offspring. This methodology is thus a convenient emergency tool for the preservation of endangered fishes. PMID- 26522019 TI - New vistas in orthodontic research. PMID- 26522020 TI - The AJO-DO and the history of orthodontics. PMID- 26522021 TI - Back to the future. PMID- 26522022 TI - Where are we going? PMID- 26522023 TI - Reflections on the future. PMID- 26522024 TI - History of orthodontic education. PMID- 26522025 TI - The "quack" in the orthodontist. PMID- 26522027 TI - Ahead to basics. PMID- 26522028 TI - Anthony Gianelly: lecturer, researcher, author, and teacher. PMID- 26522029 TI - Shinjiro Takahashi and Fujio Miura: Leaders in orthodontic education and research in Japan. PMID- 26522030 TI - Multistranded wire bonded retainers: from start to success. AB - Fixed or bonded retainers are routinely placed at the end of orthodontic treatment. Wires of various types and sizes are available, and they can be bonded labially or lingually. This article presents the background for and evolution of multistranded fixed retainers and gives clinical recommendations for their use. Based on my over 20 years' experience, I recommend a 5-stranded 0.0215-in diameter wire. PMID- 26522031 TI - A century of influence: part 3. The modern era. AB - The story of orthodontics during the first 100 years of Journal publication can be told through the people who lived it. As part of the American Journal of Orthodontics and Dentofacial Orthopedics Centennial Celebration, we present 100 people who most influenced the specialty during the last 100 years. Part 3 concludes with "The Modern Era" and describes those born in 1920 or later. They came of age near or after the end of World War II. Proprietary orthodontic schools and preceptorship training were giving way to expanding postgraduate university programs. The graduates of these rigorous programs fanned out across the country, making orthodontic specialty education available to an ever-widening circle of students and orthodontic treatment to new generations of patients. PMID- 26522032 TI - Centennial inventory: the changing face of orthodontics. AB - The American Journal of Orthodontics and Dentofacial Orthopedics celebrates its centennial, safeguarded by the nearly 115-year-old American Association of Orthodontists. This journey witnessed the rise and demise of various developments, concepts, and procedures, while basic knowledge is still needed. Various periods can be defined in the past century, but the goals remain to obtain more accurate diagnosis through precise anatomic imaging, more controlled and faster tooth movement, more discreet appliances, and the balance of esthetics, function, and stability. The most recent technologic advances have buttressed these goals. Cone-beam computed tomography has brought 3-dimensional assessment to daily usage, albeit the original enthusiasm is tempered by the risk of additional radiation. Temporary anchorage devices or miniscrews have revolutionized orthodontic practice and loom as a solid cornerstone of orthodontic science. Decortication and microperforation promise to speed up tooth displacement by stimulating vascularization. The concept of the regional acceleratory phenomenon has touched upon even the timing of orthognathic surgery. The burden of esthetic appliances remains, with the demand for "cosmetic" appliances and clear aligners. Have these developments changed the face of orthodontics? Have we engaged in another turn wherein certain treatment modalities may fade, while others join mainstream applications? These questions are addressed in this essay on the challenges, promises, and limitations of current orthodontic technology, enhancement of biologic response, and personalized treatment approaches. PMID- 26522033 TI - How has our interest in the airway changed over 100 years? AB - Since the beginning of our specialty, our understanding of the link between function and facial growth and development has progressively improved. Today, we know that children with sleep-related breathing problems will often develop distinctive facial characteristics. In adults, sleep apnea can result in serious morbidity and mortality. Orthodontists can ask sleep-related questions in the health history to help identify sleep breathing disorders. Treating these patients presents unique opportunities for orthodontists to collaborate with other medical specialties to improve a patient's health and treatment outcome. Research presented in our Journal in the next century may shed new light that will help us better identify the problem and aid the specialty in developing more effective evidence-based treatment. Additional efforts are needed to understand the physiology, neurology, and genetics of sleep breathing disorders. PMID- 26522034 TI - Match or non-Match: at the crossroads. AB - INTRODUCTION: The National Matching Service provides an ethical and unbiased selection process between residency programs and candidates. Currently, 51 of the 66 accredited orthodontic residency programs in the United States participate in the matching service for orthodontic programs (the Match), and 15 do not. Our purpose was to identify the factors that contribute to an orthodontic residency program's decision to participate in the Match program or to refrain from doing so. METHODS: A survey was sent to 64 orthodontic programs regarding their perception of the Match. A qualitative content analysis of the survey responses was conducted. Common recurring themes were identified. Simple descriptive statistics were used to summarize the data. RESULTS: Fifty-six programs responded to the survey. Survey content analysis showed 2 prevailing themes: orthodontic programs participate in the Match because they believe it is a fair process, or they refrain from participating so that they can pressure selected candidates to accept positions early. CONCLUSIONS: Participation in the Match benefits candidates, schools, and orthodontic education in general. Candidates can interview at multiple schools and rank their choices without the pressure of early acceptance. Orthodontic programs are forced to compete for strong candidates; this ultimately strengthens the education their residents receive. The Match can accommodate complex requirements of different programs, including allowing them to recruit a certain mix or a diversity of students. We concluded that all orthodontic residency programs in the United States should participate in the Match. PMID- 26522035 TI - Comparison of patient acceptance of the Forsus Fatigue Resistant Device with and without mini-implant anchorage: a randomized controlled trial. AB - INTRODUCTION: The objective of this 2-arm parallel randomized controlled trial was to evaluate patient acceptance of the mini-implant anchored Forsus Fatigue Resistant Device (FFRD) (3M Unitek, Monrovia, Calif). METHODS: The study included 32 skeletal Class II girls. The eligibility criteria included a deficient mandible, a horizontal or neutral growth pattern, an increased overjet, and a full set of erupted permanent teeth. After the leveling and alignment stage, FFRDs and mini-implants were inserted; they were removed after the teeth reached an edge-to-edge incisor relationship. The patients were afterward asked to fill out assessment questionnaires regarding their experience with the FFRD. OUTCOMES: The primary outcome of this study was to assess patient acceptance of the appliance and satisfaction with the results. The secondary outcomes were interference with functional activities, noticeability by others, pain, swelling, gum problems caused by the appliance, and appliance breakage. RANDOMIZATION: Computer random sequence generation was done using block sizes of 6 and 4. Allocation concealment was achieved with sequentially numbered opaque sealed envelopes. BLINDING: Blinding of the clinicians and the patients to the intervention was impossible, but it was done for the outcome assessment and the statistician. RESULTS: The 32 patients were randomly allocated in a 1:1 ratio into 2 groups: 16 patients (mean age, 13.25 +/- 1.12 years) received the FFRD alone (FFRD group), and 16 patients (mean age, 13.07 +/- 1.41 years) had mini implants in conjunction with FFRDs (FMI group). No statistically significant differences were reported between the 2 groups regarding ease of appliance insertion, noticeability by others, pain, swelling, effects on eating and speech, and gum bleeding; 100% and 87.5% were satisfied with the results in the FFRD and FMI groups, respectively, with a ridit value of 0.57 (95% confidence interval, 0.43-0.71; P = 0.36). No serious harm was observed other than swelling of the cheeks, which occurred in 4 patients. CONCLUSIONS: There were no significant differences between the patients' acceptance of the FFRD and the mini-implant anchored FFRD. They were highly satisfied with the results. Neither group reported significant functional limitations. REGISTRATION: This trial was not registered. PROTOCOL: The protocol was not published before trial commencement. FUNDING: The study was self-funded by the authors. PMID- 26522036 TI - Experience and expertise regarding orthodontic management of childhood and adolescent cancer survivors. AB - INTRODUCTION: Great strides in pediatric cancer treatment are allowing hundreds of thousands of children to survive into adulthood. However, these treatments can be responsible for long-term medical and dental complications. The treatments may alter the patients' dental health and require modifications to standard orthodontic care. The aim of this study was to examine knowledge and clinical experience regarding orthodontic management of childhood cancer survivors. METHODS: A 12-question online survey consisting of 3 sections was sent to 2500 randomly selected members of the American Association of Orthodontists and all 2300 members of the Southern Association of Orthodontists. The first section consisted of questions about the respondents' practice characteristics, the second questioned how many survivor patients the respondent had treated, and the third included questions about specific (anonymous) patient experiences and treatment modifications. RESULTS AND CONCLUSIONS: There were 381 responses. The data from this study suggest a tendency for more experienced practitioners to have treated survivors of childhood cancer. Orthodontic education regarding the treatment of these patients is limited. Although most orthodontists reported having treated such patients, few had treated more than 10. There is a need for more information regarding dental complications of pediatric cancer treatment and for guidelines for the orthodontic treatment of these patients. PMID- 26522037 TI - "Why do you want your child to have braces?" Investigating the motivations of Hispanic/Latino and white parents. AB - INTRODUCTION: Many psychological, social, and cultural factors influence parents' motivation to seek orthodontic care for their children. In this study, we used Q methodology to identify and categorize shared motives and determine whether cultural differences exist between Hispanic/Latino (H/L) and non-Hispanic/Latino, white (W) parents. METHODS: The fundamental question posed to the parents was "Why do you want your child to have braces?" Q methodology involves 3 stages. (1) Interviews of H/L (n = 5) and W (n = 5) parents generated 35 statements that represented different motives to seek orthodontic care. (2) In the Q sort, 70 new parents (22 H/L, 48 W) ranked statements in order of relative importance using a forced distribution grid. (3) Factor analysis was performed separately for the H/L and W groups to uncover cultural differences. RESULTS: Four motivational profiles were described for both the H/L and W parents based on the significant factors identified in each group. More H/L parents (18 of 22 parents) than W parents (22 of 48 parents) were characterized by 1 of their group's 4 profiles. Comparisons of the motivational profiles across the groups showed 4 global themes: well-timed treatment that prevents future dental problems, parental responsibility, perceived benefits, and perceived need instilled by the dentist. CONCLUSIONS: Four global themes captured the motives of most parents seeking orthodontic treatment for their children. Understanding these global themes can help clinicians frame their treatment discussions with parents. PMID- 26522038 TI - Factors influencing molar relationship behavior in the mixed dentition. AB - INTRODUCTION: Our objectives were to compare different patterns of molar relationship changes from the mixed dentition to the permanent dentition and to discriminate the contributing dentoskeletal factors. METHODS: In this retrospective cohort study, we used a sample selected from 1212 untreated subjects who were longitudinally followed from the mixed to the permanent dentition. Eighty subjects (mean age, 8.69 years) had their right and left dental arch sides divided into 6 groups, according to molar relationship behavior: distal step kept in Class II (group 1A) or changed to Class I (group 1B); flush terminal plane kept in Class II (group 2A) or changed to Class I (group 2B); and mesial step kept in Class I (group 3A) or changed to Class III (group 3B). The groups were statistically evaluated at P <0.05. RESULTS: Class I and Class II defined by mesial and distal steps were stable. The flush terminal plane groups had a similar probability of maintaining the Class II relationship or changing to Class I. Groups 2A and 2B had significantly different changes in molar relationship, maxillary width, and mandibular skeletal traits as a whole. Class II maxillomandibular discrepancy, maxillary narrowing, and sagittal mandibular deficiency were the disadvantageous factors for favorable molar relationship adjustment. CONCLUSIONS: Mesial and distal steps produced stable molar relationships from the mixed to the permanent dentition. There were 2 distinct dentoskeletal parameters of subjects with flush terminal planes regarding transverse maxillary and sagittal mandibular dimensions that should be diagnosed early to define the prognosis for molar relationship adjustment and orthodontic treatment need. PMID- 26522039 TI - Prevalence and distribution of dental anomalies: a comparison between maxillary and mandibular tooth agenesis. AB - INTRODUCTION: The aim of this study was to compare the pattern and prevalence of associated dental anomalies between maxillary and mandibular tooth agenesis (hypodontia). METHODS: A sample of 3315 dental patients, aged 8.6 to 25.4 years, was surveyed for tooth agenesis (excluding third molars): 106 subjects were diagnosed with maxillary hypodontia (group 1) and 70 with mandibular hypodontia (group 2). Both groups were examined for the following dental anomalies: retained deciduous molars, infraocclusion of deciduous molars, impaction, microdontia of maxillary lateral incisors, supernumerary teeth, transposition, transmigration, and ectopic eruption of the permanent molars. For statistical testing, the chi square test (P <0.05) was used to compare the occurrences of these anomalies among the groups. RESULTS: We found that 77.5% of the patients in the mandibular hypodontia group had at least 1 dental anomaly compared with 49.5% in the maxillary hypodontia group (P <0.0001). The only dental anomaly with a significantly increased prevalence in the maxillary hypodontia group compared with the mandibular hypodontia group was microdontia of the maxillary lateral incisors (groups 1, 46.7%; group 2, 12.9%; P <0.0001). On the other hand, the prevalences of retained deciduous molars (group 1, 9.4%; group 2, 60.0%), infraoccluded deciduous molars (group 1, 0.9%; group 2, 7.1%), and impacted teeth (group 1, 22.6%; group 2, 38.6%) were significantly higher in the mandibular hypodontia group. The prevalences of supernumerary teeth, transposition, transmigration, and ectopic eruption of permanent molars were low and not significantly different between the groups. CONCLUSIONS: Tooth agenesis isolated to the maxilla is frequently associated with microdontia of the maxillary lateral incisors, whereas tooth agenesis isolated to the mandible is frequently associated with retained deciduous molars, infraoccluded deciduous molars, and impacted teeth. The results of this study may provide additional evidence supporting the field-specific genetic control theory for dental development in both jaws. PMID- 26522040 TI - Association between third molar agenesis and craniofacial structure development. AB - INTRODUCTION: The aim of this investigation was to study the relationship between third molar agenesis-including the number of ageneses-and craniofacial structure growth. METHODS: We reviewed 305 clinical histories of patients treated at the Orthodontics Unit of the Faculty of Medicine and Dentistry at the University of Valencia in Spain. This included radiographic records of optimal quality. Of these, 40 patients who had agenesis of at least 1 third molar were included in the study group. A control group was formed with another 40 patients with all 4 third molars present. For both groups, a further criterion for inclusion was cone beam computed tomography records. The cephalometric analysis was performed with NemoCeph 3D software (version 11.3.1.38; Nemotec, Madrid, Spain). RESULTS: The only significant differences between the 2 groups were in the total gonial angle and the upper gonial angle (P <=0.05), both of which were smaller in the study group. CONCLUSIONS: Third molar agenesis is associated with a reduction in Jarabak's gonial angle and upper gonial angle, characteristic of patients with a more horizontal or brachyfacial skeletal pattern. No significant differences were found in other measurements. PMID- 26522041 TI - Combined orthodontic-periodontal treatment in periodontal patients with anteriorly displaced incisors. AB - INTRODUCTION: Flared and elongated incisors are associated with different types of periodontal bone defects, usually horizontal. Combined orthodontic-periodontal treatment is being used in periodontal patients with anterior displacement of the incisors. The purpose of this study was to investigate the changes in periodontal health and the shape of bone defects in the incisors after such combined treatment. METHODS: Fourteen adults were included in the study. In total, 56 elongated maxillary incisors with horizontal bone defects received orthodontic periodontal treatment with circumferential supracrestal fibrotomy. To improve bone morphology, periodontal regenerative surgery and guided tissue regeneration were performed on the anterior teeth with angular bone defects after orthodontic treatment. Cone-beam computed tomography scans were taken before treatment (T0), at the end of the orthodontic intrusion (T1), and 6 months after the guided tissue regeneration surgery (T2). Probing pocket depth and clinical attachment loss were examined at T0, T1, and T2. The data were analyzed using paired t tests. RESULTS: From T0 to T1, clinical attachment loss decreased significantly by 0.29 mm (P <0.05). The distance from the cementoenamel junction to the marginal bone crest decreased by 0.66 mm (P <0.05). The labial side of alveolar bone thickness increased by 0.54 mm (P <0.05), and the lingual side of alveolar bone thickness decreased by 0.46 mm (P <0.05). The shape of the bone defect was changed from horizontal to vertical on some teeth. From T1 to T2, both probing pocket depth and clinical attachment loss improved significantly, and the radiographic examinations showed bone redepositions of 2.15 +/- 0.68 mm (P <0.05) vertically and 1.44 +/- 0.92 mm (P <0.05) horizontally. The distance from the most apical point of the bone defect to the cementoenamel junction after combined treatment decreased by 2.11 +/- 1.30 mm (P <0.05). CONCLUSIONS: Combined orthodontic-periodontal treatment improved the periodontal conditions of the defective bone sites. Bone morphology, altered by orthodontic intrusion with fibrotomy, can improve the results of subsequent guided tissue regeneration. PMID- 26522042 TI - Effect of light-curable fluoride varnish on enamel demineralization adjacent to orthodontic brackets: an in-vivo study. AB - INTRODUCTION: The purpose of this in-vivo study was to evaluate the effect of a single application of Clinpro XT (3M ESPE, Pymble, New South Wales, Australia), a light-curable fluoride varnish, on enamel demineralization adjacent to orthodontic brackets. METHODS: Thirty-eight patients (152 teeth) whose orthodontic treatment involved extraction of 4 first premolars were recruited. Two premolars each were assigned to the control group (no treatment) and the experimental group (received fluoride varnish application). The study was designed as a nonrandomized split-mouth study in which diagonally opposite quadrants received the same treatment. After the bonding procedures, a sectional T-loop was ligated into each bracket to serve as a site for plaque retention for enhanced demineralization. Clinpro XT was applied on the buccal surfaces adjacent to the brackets on all teeth in the experimental group only. Teeth in both groups were extracted after 15 days (n = 30), 30 days (n = 30), 45 days (n = 30), 90 days (n = 18), and 120 days (n = 18). Buccolingual sections were then evaluated under polarized light microscopy. After we excluded the dropouts, the mean depth of the demineralized enamel lesions was measured in final sample of 126 teeth. The Mann-Whitney test was used for comparison of the groups. RESULTS: In the control group, the depths of the demineralized enamel lesions increased from 30 to 120 days, whereas in the experimental group no sign of demineralization was noted throughout the observation period except for 3 teeth. Significant differences in the depths of demineralized lesions were found between the study groups. CONCLUSIONS: Clinpro XT light-curable fluoride varnish may be a reasonable alternative in the reduction of enamel demineralization around orthodontic brackets, especially in noncompliant and high-risk patients. PMID- 26522043 TI - Evaluation of the vertical accuracy of bracket placement with the Boone gauge. AB - INTRODUCTION: In this study, we aimed to evaluate the influence of clinical experience and the type of tooth (incisors, canines, and premolars) on the vertical accuracy of bracket placement with the Boone gauge. METHODS: For this analysis, 4 groups were defined. Group 1 was composed of undergraduate students from the dental school with no previous experience in bonding orthodontic attachments; group 2 was composed of graduate students in the dental school; group 3 consisted of orthodontists with a maximum of 5 years of clinical experience; and group 4 comprised orthodontists with more than 5 years of clinical experience. Each group included 6 participants. A typodont was simulated with a Class I crowded malocclusion that reproduced the same occlusal characteristics for all groups to be bonded. All participants were instructed to bond 0.022 * 0.028-in edgewise brackets on the labial surfaces of the maxillary and mandibular incisors, canines, and premolars at a height of 4 mm from the incisal edge or the labial cusp tip. After each bonding procedure, all teeth were photographed after being removed from the typodont and positioned in a stabilizing device adapted to a camera stand. RESULTS: The analyses of the variations showed that group 1 had the closest mean to 4 mm. However, this group also showed the greatest variance (0.433) (P <0.001). The smallest variations were observed in group 2 (variance, 0.093), followed by group 4 (variance, 0.094). The comparison of the means obtained in the groups of teeth at 4 mm demonstrated that the incisors showed a statistically significant difference (P <0.001), whereas canines (P = 0.133) and premolars (P = 0.913) did not. CONCLUSIONS: Operators are prone to fail in the placement of orthodontic attachments with the Boone gauge, despite their clinical experience in orthodontics. In the comparison of the groups of teeth, the incisors showed a statistically significant difference in relation to the height suggested for bracket placement with the Boone gauge. PMID- 26522044 TI - Satisfaction with orthognathic surgery of skeletal Class III patients. AB - INTRODUCTION: Class III relationships can be corrected with single-jaw or bimaxillary surgery. The purpose of this research was to assess patient satisfaction after bimaxillary surgery, compared with setback surgery alone, for Class III corrections. Identifying patients' relative levels of satisfaction will provide guidance for the selection of surgical options. METHODS: The cephalometric outcomes for 25 patients who underwent 2-jaw surgery were compared with the outcomes in 40 patients who had mandibular setback. Soft and hard tissue changes were evaluated using initial and postsurgical lateral cephalograms. The patients were asked to complete self-administered questionnaires after orthognathic treatment. Correlations between cephalometric improvement and patient satisfaction were evaluated. RESULTS: The patients in the 2-jaw group reported significantly higher satisfaction in the appearance of the mouth (P <0.05), smile (P <0.05), and treatment outcome (P <0.001). These item scores and the changes in ANB, ANS-M, and nasolabial angle showed strong correlations in the 2-jaw group and moderate correlations in the 1-jaw group. CONCLUSIONS: ANS-M and nasolabial angle should be considered in the conventional diagnosis of skeletal Class III orthognathic surgery to obtain adequate correction of facial esthetics and patient satisfaction. Esthetic needs contribute to surgical decisions when treating patients with skeletal Class III malocclusions and dentofacial deformities such as maxillary deficiency and long facial height that causes a turned-up upper lip. PMID- 26522045 TI - Increasing orthodontic and orthognathic surgery treatment efficiency with a modified surgery-first approach. AB - This case report describes the treatment of a 33-year-old white man who had a skeletal Class III and dental Class II subdivision malocclusion caused by a retrognathic maxilla, with severe maxillary crowding, a highly placed maxillary left canine, mild mandibular crowding, and a bilateral posterior crossbite. Treatment was performed with a modified surgery-first approach, which included a short presurgical alignment phase for the correction of the significant maxillary crowding while controlling the incisal angulation, followed by LeFort I maxillary advancement surgery. The short presurgical orthodontic phase aimed at eliminating the anterior dental interferences before the maxillary advancement, and the use of the inherent increased bone turnover in the postsurgical phase helped to reduce the total orthodontic treatment time to 12 months. Pleasing esthetic results and a good functional occlusion were achieved. PMID- 26522046 TI - Uprighting mesially impacted mandibular molars with 2 miniscrews. AB - Mesially tilted or impacted mandibular molars cause occlusal disharmony and periodontal problems. For proper restoration of the occlusion and to prevent further periodontal damage, uprighting of tilted molars is the recommended treatment option. Although several orthodontic methods including miniscrews have been proposed, most of them have innate limitations and problems such as the possibility of unwanted tooth movement. In this case series, we introduce a new system that uses 2 miniscrews with slots that can accommodate rectangular orthodontic wires to 3 dimensionally control the tilted molar in 3 patients. We also discuss the advantages and possible disadvantages of this new system. PMID- 26522048 TI - Analysis of variance. PMID- 26522047 TI - Fabrication of a resin appliance with alloy components using digital technology without an analog impression. AB - The aim of this study was to fabricate a resin appliance incorporating "wire" components without the use of an analog impression and dental casts using an intraoral scanner and computer technology to build the appliance. This unique alignment of technology offers an enormous reduction in the number of fabrication steps when compared with more traditional methods of manufacture. The prototype incorporated 2 Adams clasps and a fitted labial bow. The alloy components were built from cobalt-chromium in an initial powdered form using established digital technology methods and then inserted into a build of a resin base plate. This article reports the first known use of computer-aided design and additive manufacture to fabricate a resin and alloy appliance, and constitutes proof of the concept for such manufacturing. The original workflow described could be seen as an example for many other similar appliances, perhaps with active components. The scan data were imported into an appropriate specialized computer-aided design software, which was used in conjunction with a force feedback (haptic) interface. The appliance designs were then exported as stereolithography files and transferred to an additive manufacturing machine for fabrication. The results showed that the applied techniques may provide new manufacturing and design opportunities in orthodontics and highlights the need for intraoral-specific additive manufacture materials to be produced and tested for biocompatibility compliance. In a trial, the retainer was fitted orally and judged acceptable by the clinician according to the typical criteria when placing such appliances in situ. PMID- 26522049 TI - microRNAs for peripheral blood fraction identification: Origin, pathways and forensic relevance. AB - microRNAs (miRNAs) are small non-coding RNAs, with a length of 18 to 24 nucleotides that play a regulatory role in several cellular processes. Since their discovery, they have been identified in cells, tissues, organs, and body fluids and their potential as molecular biomarkers for the diagnosis of various pathologic conditions has been explored. However, little is known about the origin of the extracellular miRNAs and what factors influence the levels of circulating miRNAs. This information could help the refinement of miRNAs as more effective biomarkers. Additionally, the identification of the origin of miRNAs may prove to be very useful in the association of particular miRNAs with specific pathologies. This review aims to gather information concerning the origin of miRNAs in plasma and serum, as well as to assess their potential to be use as biomarkers for these peripheral blood fractions. PMID- 26522050 TI - The proteins interacting with C-terminal of MU receptor are identified by bacterial two-hybrid system from brain cDNA library in morphine-dependent rats. AB - AIMS: Opioid addiction is associated with long-term adaptive changes in the brain that involve protein expression. The carboxyl-terminal of the MU opioid receptor (MOR-C) is important for receptor signal transduction under opioid treatment. However, the proteins that interact with MOR-C after chronic morphine exposure remain unknown. The brain cDNA library of chronic morphine treatment rats was screened using rat MOR-C to investigate the regulator of opioids dependence in the present study. MAIN METHODS: The brain cDNA library from chronic morphine dependent rats was constructed using the SMART (Switching Mechanism At 5' end of RNA Transcript) technique. Bacterial two-hybrid system was used to screening the rat MOR-C interacting proteins from the cDNA library. RT-qPCR and immunoblotting were used to determine the variation of MOR-C interacting proteins in rat brain after chronic morphine treatment. Column overlay assays, immunocytochemistry and coimmunoprecipitation were used to demonstrate the interaction of MOR-C and p75NTR-associated cell death executor (NADE). KEY FINDINGS: 21 positive proteins, including 19 known proteins were screened to interact with rat MOR-C. Expression of several of these proteins was altered in specific rat brain regions after chronic morphine treatment. Among these proteins, NADE was confirmed to interact with rat MOR-C by in vitro protein-protein binding and coimmunoprecipitation in Chinese hamster ovary (CHO) cells and rat brain with or without chronic morphine treatment. SIGNIFICANCE: Understanding the rat MOR-C interacting proteins and the proteins variation under chronic morphine treatment may be critical for determining the pathophysiological basis of opioid tolerance and addiction. PMID- 26522051 TI - Mechanical instability of monocrystalline and polycrystalline methane hydrates. AB - Despite observations of massive methane release and geohazards associated with gas hydrate instability in nature, as well as ductile flow accompanying hydrate dissociation in artificial polycrystalline methane hydrates in the laboratory, the destabilising mechanisms of gas hydrates under deformation and their grain boundary structures have not yet been elucidated at the molecular level. Here we report direct molecular dynamics simulations of the material instability of monocrystalline and polycrystalline methane hydrates under mechanical loading. The results show dislocation-free brittle failure in monocrystalline hydrates and an unexpected crossover from strengthening to weakening in polycrystals. Upon uniaxial depressurisation, strain-induced hydrate dissociation accompanied by grain-boundary decohesion and sliding destabilises the polycrystals. In contrast, upon compression, appreciable solid-state structural transformation dominates the response. These findings provide molecular insight not only into the metastable structures of grain boundaries, but also into unusual ductile flow with hydrate dissociation as observed during macroscopic compression experiments. PMID- 26522052 TI - Regioselective Isomerization of 2,3-Disubstituted Epoxides to Ketones: An Alternative to the Wacker Oxidation of Internal Alkenes. AB - We report an alternative pathway to the Wacker oxidation of internal olefins involving epoxidation of trans-alkenes followed by a mild and highly regioselective isomerization to give the major ketone isomers in 66-98% yield. Preliminary kinetics and isotope labeling studies suggest epoxide ring opening as the turnover limiting step in our proposed mechanism. A similar catalytic system was applied to the kinetic resolution of select trans-epoxides to give synthetically useful selectivity factors of 17-23 for benzyl-substituted substrates. PMID- 26522053 TI - Phase I lead-in and subsequent randomized trial assessing safety and modulation of regulatory T cell numbers following a maximally tolerated dose doxorubicin and metronomic dose cyclophosphamide combination chemotherapy protocol in tumour bearing dogs. AB - Maximally tolerated dose (MTD) and metronomic dose chemotherapeutic approaches alter the immune system and the angiogenic process in different yet potentially complementary ways. A combination of MTD doxorubicin (MTD-DOX) and metronomic cyclophosphamide (mCTX) protocol was evaluated for safety and effect on circulating regulatory T (Treg) cells. We found that mCTX can be safely administered with MTD-DOX in tumour-bearing dogs. Both combination DOX/mCTX and single-agent DOX resulted in significant depletions of circulating lymphocytes throughout the chemotherapy cycle without apparent selectivity for Tregs. The indiscriminant lymphocyte depletions were similar between dogs randomized to receive DOX and dogs randomized to receive DOX/mCTX, suggesting this effect is because of DOX alone. These findings may have implications as to the therapeutic benefit (or lack thereof) of concurrent combination MTD and metronomic protocols. Future investigations are required to determine the effects and indeed the efficacy of concurrent versus sequential applications of MTD and metronomic chemotherapy protocols. PMID- 26522054 TI - Biosimilars for psoriasis: preclinical analytical assessment to determine similarity. AB - Biosimilars, sometimes called 'generic biologics', are no longer a vision for the future but a present-day reality. Drug manufacturers and regulatory authorities are charged with ensuring that these products are safe and effective. Because biologically produced medications are large, complex proteins, many factors affect the quality of the end product, including glycosylation and presence of impurities, and thus many factors need to be compared between an emerging biosimilar and its originator biologic. Indeed, preclinical analytical assessments to determine similarity to an originator biologic are critical and are considered to be the foundation for regulatory approval of biosimilars. Here, the science behind the preclinical development of biosimilars is discussed by members of the International Psoriasis Council, and suggestions are put forth to try to ensure that future biosimilars are produced in a high quality and standardized manner. PMID- 26522055 TI - Lamina cribrosa defects in eyes with glaucomatous disc haemorrhage. AB - PURPOSE: To investigate the frequency of focal abnormalities of the lamina cribrosa (LC) in eyes with glaucomatous disc haemorrhage (DH) using swept-source optical coherence tomography (SS-OCT). METHODS: We analysed 72 glaucomatous eyes with DH (72 subjects) detected by masked grading of stereophotographs along with 63 glaucomatous eyes without DH (63 subjects) consecutively recruited from the cohort of DH Study from Seoul National University Hospital. All of the subjects underwent stereoscopic optic disc photography and in vivo SS-OCT LC imaging based on a customized optic disc scanning protocol (Topcon, Inc., Tokyo, Japan). Two masked graders evaluated each eye's serial en face images for focal LC defects. En face image/optic disc photograph overlay images were evaluated to determine the relationship between the respective focal LC defect and DH locations. RESULTS: Among the eyes with DH, the proportion with >=1 LC defect was 80.6% (58 of 72 eyes), significantly higher than that for eyes without DH (39.7%, 25 of 63 eyes; p < 0.001). In the 58 eyes with DH and >=1 LC defect, the location of the focal LC defect corresponded with that of the RNFL defect in 47 eyes (81.0%), and the location of the focal LC defect corresponded with the DH in 36 eyes (62.1%). CONCLUSIONS: Focal LC defects are more frequently visible in eyes with glaucomatous DH than in eyes without DH. DH and LC defects, moreover, are often spatially correlated. These findings suggest that DH is associated with focal abnormalities of the LC. PMID- 26522056 TI - Stomach nematodes of three sympatric species of anatid birds off the coast of Patagonia. AB - The present study focuses on the nematode community in the stomachs of three sympatric anatid bird species from the Central Patagonian coast, Argentina. The bird species include the Chubut steamer duck, Tachyeres leucocephalus, the crested duck, Lophonetta specularioides, and the black-necked swan, Cygnus melancoryphus. Up to 138 nematodes representing five species were recovered from 10 of the 13 ducks examined, with an overall prevalence of 77% and a mean intensity of 13.8. Nematodes isolated from the gizzard were Streptocara formosensis and Sciadiocara legendrei (Acuariidae) in T. leucocephalus, and Epomidiostomum vogelsangi (Amidostomatidae) in C. melancoryphus, whereas Echinuria uncinata (Acuariidae) and Tetrameres (Petrowimeres) fissispina (Tetrameriidae) were found in the proventiculus of L. specularioides. In particular, S. legendrei was registered for the first time in South America and T. leucocephalus, whereas T. fissispina represents a new record in Argentina and L. specularioides. Moreover, E. vogelsangi and E. uncinata were isolated in Patagonia for the first time. The birds studied herein are sympatric in their distribution, and two of them are syntopic breeders; however, they were infected with different parasite species. This situation could be partially due to their diet or their seasonal movements, or a combination of both. Despite the low number of hosts examined, this work enhances our knowledge about parasites from a frequently occurring group of birds on the Patagonian coast, a subject that has not been studied extensively in South America. PMID- 26522057 TI - Cycling Exercise with Electrical Stimulation of Antagonist Muscles Increases Plasma Growth Hormone and IL-6. AB - Performing aerobics and resistance exercise at exactly the same time has not been available although combining both types of exercise in one training program has been attempted. The hybrid training system (HTS) is a resistance exercise that combines voluntary concentric muscle contractions with electrically stimulated eccentric muscle contractions. We devised an exercise technique using HTS on a cycle ergometer (HCE). Growth hormone (GH) and lactate are indicators of adequate training intensity. Interleukin-6 (IL-6) reflects enhancing lipid metabolism. The purpose of this study was to show that HCE provides sufficient exercise to stimulate the secretion of GH, lactate and IL-6. We compared an HCE test with cycle ergometer alone (CE). Ten healthy male subjects performed HCE and CE tests for 30 minutes each. The workload of both tests was set the same at 40% of each subject's peak oxygen uptake. For HCE, 2-minute HTS and 1-minute rest intervals were repeated. GH, lactate, and IL-6 were evaluated before and immediately after exercise, and at 15, 30 and 60 minutes. GH and lactate increased immediately after HCE. Moreover, the degree of the increases in GH after HCE (0 and 15 minutes) was higher than that after CE. IL-6 increased after HCE at 30 min, and the rate of change was higher than for CE. These results showed that HCE was more efficient in stimulating acute increases in GH, lactate and IL-6 than CE at the same workload. We may be able to combine electrically stimulated resistance exercise with aerobic exercise using HCE. PMID- 26522058 TI - Phase II study of computed tomography-guided (125)I-seed implantation plus chemotherapy for locally recurrent rectal cancer. AB - BACKGROUND AND PURPOSE: This trial evaluated the efficacy and safety of CT guided (125)I-seed implantation (CTII) plus chemotherapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment for locally recurrent rectal cancer (LRRC). MATERIAL AND METHODS: Patients with LRRC who received one prior chemotherapy regimen were enrolled and divided randomly assigned to FOLFORI alone (Arm A) and FOLFORI plus CTII (Arm B). The primary endpoint was local control time (LCT). Overall survival (OS) and treatment related adverse events (TRAEs) were also observed. RESULTS: Fifty-seven patients were enrolled from October 2008 and December 2014. Twenty-seven were assigned into Arm A and 30 into Arm B. The overall response rate of locally recurrent tumor was improved to 100% in Arm B versus 29.6% in Arm A (P<0.001). A significant longer LCT was observed in Arm A (P<0.001); median LCT was 12 months in Arm B versus 4 months in Arm A. A borderline significant improvement in OS was also observed in Arm B (P=0.0464); median OS was 25 months in Arm B versus 19 months in Arm A. For patients without distant metastases, median OS was 37 months in Arm B versus 21 months in Arm A (P=0.0101). For patients with (neo)adjuvant radiotherapy (ART), a longer LCT and OS were also found in Arm B (P<0.001 and P=0.0217, respectively). TRAEs were not serious generally. There was no statistically significant difference in treatment related toxicity between Arm A and B both for all patients and patients receiving ART. CONCLUSIONS: CTII plus FOLFIRI improves the LCT with tolerable toxicities as a second-line treatment in patients with local recurrent rectal cancer, and is helpful to prolong the OS, particularly in patients without distant metastases or with a history of radiotherapy. PMID- 26522059 TI - Palliative radiotherapy fractionation schedules prescribed are dependent on the distance a patient travels to receive treatment. AB - This study assessed the impact of the distance a patient travelled to the treatment centre on the use of single fraction RT for bone metastases. There was significant variability in the prescription of SFRT by distance at which the patient lives from a cancer centre (p<0.001). PMID- 26522060 TI - Dose-surface maps identifying local dose-effects for acute gastrointestinal toxicity after radiotherapy for prostate cancer. AB - BACKGROUND AND PURPOSE: We evaluated dose distributions in the anorectum and its relation to acute gastrointestinal toxicities using dose surface maps in an image guided (IG) IMRT and 3D-conformal radiotherapy (3D-CRT) population. MATERIAL AND METHODS: For patients treated to 78 Gy with IG-IMRT (n=260) or 3D-CRT (n=215), for whom acute toxicity data were available, three types of surface maps were calculated: (1) total anorectum using regular intervals along a central axis with perpendicular slices, (2) the rectum next to the prostate, and (3) the anal canal (horizontal slicing). For each toxicity, an average dose map was calculated for patients with and without the toxicity and subsequently dose difference maps were constructed, 3D-CRT and IG-IMRT separately. P-values were based on permutation tests. RESULTS: Dose distributions in patients with grade ?2 acute proctitis were significantly different from dose distributions in patients without toxicity, for IG-IMRT and 3D-CRT. At the cranial and posterior rectal site, in areas receiving moderate dose levels (~25-50 Gy), dose differences up to 10 Gy were identified for IG-IMRT. For pain, cramps, incontinence, diarrhea and mucus loss significant differences were found as well. CONCLUSIONS: We demonstrated significant relationships between acute rectal toxicity and local dose distributions. This may serve as a basis for subsequent dose-effect modeling in IG-IMRT, and improved dose constraints in current clinical practice. PMID- 26522061 TI - Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. AB - PURPOSE: The purpose of this study was to compare outcomes with Hodgkin lymphoma (HL) patients receiving IMRT (intensity-modulated radiation therapy), versus those receiving 2D/3D-CRT (3-dimensional conformal RT) in a large observational cohort. PATIENTS AND METHODS: We evaluated patients diagnosed with stage I-IV HL from 1998 to 2011 from the National Cancer Database (NCDB). The association between IMRT use vs. 2D/3D-CRT, co-variables, and outcome was assessed in a Cox proportional hazards model. Propensity score (PS) matching was performed to balance known confounding factors. Survival was estimated using the Kaplan-Meier method. RESULTS: Of the 76,672 patients with HL within the NCDB, 12,393 patients with stage I-IV HL received RT (median dose=30.6 Gy) and were eligible for this study, and 6013 patients analyzed for overall survival. The cohort had a median follow-up of 6.2 years and median age of 37 years (range: 18-90). The RT modalities used were: 2D/3D-CRT (n=11,491, 92.7%) or IMRT (n=902, 7.3%). Patients were more likely to receive IMRT if they were of male gender, early stage, no "B" symptoms, and treated at comprehensive cancer programs (all p<0.05). During this time period, there was a significant decrease in use of 2D/3D-CRT from 100% to 81.5%, with a subsequent increase in IMRT utilization from 0% to 18.5%. Five-year overall survival for patients receiving 2D/3D-CRT (n=5844) was 89.9% versus 95.2% for those receiving IMRT (n=169; HR=0.45; 95% CI, 0.23-0.91, p=0.02). After PS matching based on clinicopathologic characteristics, IMRT use remained associated with improved overall survival (HR=0.40; 95% CI, 0.16-0.97, p=0.04). CONCLUSIONS: Our study reveals that HL patients receiving modern RT techniques were associated with an improvement in overall survival. This may have been related to patient selection, access to improved staging and management, or improvements in treatment technology. This represents the only study examining survival outcomes of advanced RT modalities, which may be considered on a case-by-case basis for highly selected patients with HL. PMID- 26522062 TI - Toll-like receptor 4-induced endoplasmic reticulum stress contributes to impairment of vasodilator action of insulin. AB - Impairment of vasodilator action of insulin is associated with endothelial dysfunction and insulin resistance. Activation of Toll-like receptor 4 (TLR4) induces proinflammatory response and endoplasmic reticulum (ER) stress. Saturated fatty acids (SFA) activate TLR4, which induces ER stress and endothelial dysfunction. Therefore, we determined whether TLR4-mediated ER stress is an obligatory step mediating SFA-induced endothelial dysfunction. Palmitate stimulated proinflammatory responses and ER stress, and this was suppressed by knockdown of TLR4 in primary human aortic endothelial cells (HAEC). Next, we examined the role of TLR4 in vasodilatory responses in intact vessels isolated from wild-type (WT, C57BL/6) and TLR4-KO mice after feeding high-fat (HFD) or normal chow diet (NCD) for 12 wk. Arterioles isolated from HFD WT mice exhibited impaired insulin-stimulated vasodilation compared with arterioles isolated from NCD WT mice. Deficiency of TLR4 was protective from HFD-induced impairment of insulin-stimulated vasodilation. There were no differences in acetylcholine (Ach) or sodium nitroprusside (SNP)-stimulated vasodilation between the two groups. Furthermore, we examined whether ER stress is involved in SFA-induced impairment of vasodilator actions of insulin. Infusion of palmitate showed the impairment of vasodilatory response to insulin, which was ameliorated by coinfusion with tauroursodeoxycholic acid (TUDCA), an ER stress suppressor. Taken together, the results suggest that TLR4-induced ER stress may be an obligatory step mediating the SFA-mediated endothelial dysfunction. PMID- 26522063 TI - Interspinous process stabilization with Rocker via unilateral approach versus X Stop via bilateral approach for lumbar spinal stenosis: a comparative study. AB - BACKGROUND: Rocker is a novel interspinous process stabilization (IPS) that can be installed via unilateral approach by virtue of its unique design. This controlled study compared the clinical outcome of Rocker versus X-Stop to access the feasibility and validity of the novel IPS. METHODS: From March 2011 to September 2012, 32 patients treated with Rocker and 30 patients treated with X Stop were enrolled in this study. The primary clinical outcome measure was Oswestry Disability Index (ODI) score. The secondary clinical outcome measure was Japanese orthopaedics association (JOA) score. Disc height index (DHI) and foraminal height index (FHI) were measured for postoperative radiographic evaluation. Implant failures were also recorded. RESULTS: There were 55 patients with complete data during 24 months follow-up. Among the 55 patients, 38 patients underwent IPS in combination with microdecompression. At the final follow-up, 49 patients achieved a minimal clinical important difference (>= 8 points ODI improvement). The mean operative time was 53.6 min (range, 30 to 90 min) in Rocker group and 63.1 min (range, 30 to 100 min) in X-Stop group. The average blood loss was 111 ml (range, 50 to 400 ml) in Rocker group and 138 ml (range, 50 to 350 ml) in X-Stop group. ODI score were significantly improved from preoperative 46.8 +/- 9.2 to 12.2 +/- 2.6 at 24 months follow-up in the Rocker group and from preoperative 45.8 +/- 9.8 to 11.8 +/- 2.4 at 24 months follow-up in the X-Stop group. JOA score also improved significantly in both groups. The radiographic parameters of DHI and FHI in both groups increased immediately postoperatively, however, the improvements seemed to revert toward initial value during follow-up. Two patients in Rocker group demonstrated implant dislocation within one week postoperatively and one patient in X-Stop group demonstrated implant migration at two months postoperatively. CONCLUSIONS: Preliminary clinical and radiographic outcome was similar between Rocker and X-Stop group. For patients of lumbar spinal stenosis with unilateral nerve root involved or mild-to-moderate central canal stenosis, Rocker offers a new alternative with less damage. PMID- 26522064 TI - Next generation sequencing technologies in cancer diagnostics and therapeutics: A mini review. AB - The development of advanced molecular technologies has ushered in the era of 'omics' science, including transcriptomics, proteomics, and genomics. Genomics, or whole genome approach, has become the most comprehensive investigative method to identify new gene mutations, signal pathways and drug targets for cancers. The purpose of this review is to summarize current second generation sequencing techniques in applied genomics, and to analyze the advantages and/or problems associated with each of the various sequencing platforms. Our understanding of molecular factors associated with tumorigenesis is no longer limited to the mutation of well-known cancer related genes, but may involve a broader range of factors involved in tumor development, including novel somatic mutations, gene fusions, long non-coding RNAs, microRNAs, copy number variations, methylation, and genomic structural variations. Furthermore, these new methods are not limited to analyses of single genetic or epigenetic factor, but offer comprehensive molecule profiling as a more critical and powerful approach to decoding the mystery of tumor development and identifying more reliable cancer biomarkers. PMID- 26522065 TI - Effect of Tongxinluo on nerve regeneration in mice with diabetic peripheral neuropathy. AB - Diabetic peripheral neuropathy (DPN) is a common complication of diabetes. This study aims to investigate the effects of Tongxinluo on the nerve regeneration in diabetic peripheral neuropathy mice. Forty Specefic Pathogen Free (SPF) male KK/Upj—Ay mice were divided into diabetes group, diabetes with high dose Tongxinluo (4g/kg) (D+H), diabetes with mid dose Tongxinluo (2g/kg) (D+M), and diabetes with low dose Tongxinluo (1g/kg) (D+L) groups. Fasting blood glucose (FPG), heat pain threshold, motor nerve conduction velocity (MNCV), insulin—like growth factor—1 (IGF1), activator protein 1 (c—fos), nerve growth factor (NGF), and basic fibroblast growth factor (BFGF) were measured. Results indicated that FPG of diabetes group was significantly higher than that of control group. Heat pain threshold and MNCV were significantly lowered in diabetes group. Expression levels of IGF1, NGF and BFGF were significantly lower than that of control, whereas c—fos expression was significantly higher than that of control group. Tongxinluo treatment (D+M and D+H) significantly up—regulated heat pain threshold, MNCV, and IGF1, NGF and BFGF expression, but decreased c—fos expresson when compared to that of diabetes group. In conclusion, Tongxinluo can ameliorate diabetic peripheral neuropathy, improve MNCV, and promote nerve regeneration. The underlying mechanism needs to be further elucidated. PMID- 26522066 TI - Comparison and improvement in primary airway fibroblast culture across different mammalian species. AB - This study aims to establish rabbit, rat and human models of primary airway fibroblasts, improve existing culture methods of human, and provide alternatives to benign airway stenosis in vitro. We used conventional "tissue adherent method" to culture airway primary fibroblasts extracted from New Zealand rabbits, Sprague—Dawley (SD) rats and human subjects. To improve quality of this culture, we combined the "tissue adherent method" with " trypsinization", and compared the success rate of the two approaches. Cultures were examined using an inverted microscope, following hematoxylin—eosin and immunohistochemical staining. The different species were identified based on the total number of chromosomes. We successfully cultured primary airway fibroblasts isolated from three species. Human airway primary fibroblasts are more difficult to culture. The efficiency of culture is low, when using the "tissue adherent method". However, the rate of successful culture is improved when combined with the "trypsinization", and by using the "serum adherent, organizing tablet" technology. In conclusion, we demonstrate that primary airway fibroblasts from three mammalian species can be cultured successfully in vitro, for a reliable cellular model of benign airway stenosis. Culturing human primary airway fibroblasts is technically more challenging than the other two species. It is necessary to improve it. PMID- 26522067 TI - Toxicological effects of benzo[a]pyrene on DNA methylation of whole genome in ICR mice. AB - It has been well known that alterations in DNA methylation - an important regulator of gene transcription - lead to cancer. Therefore a change in the level of DNA methylation of whole genome has been considered as a biomarker of carcinogenesis. Previously, a large number of experimental results in genetic toxicology have showed that benzo[a]pyrene could cause DNA mutation and fragmentation. However, there was little to no studies on alterations in DNA methylation of genome directly result from exposure to benzo[a]pyrene. In this paper, possible mechanisms of alterations in whole genomic DNA methylation by benzo[a]pyrene were investigated using ICR mice after benzo[a]pyrene exposure. The blood, liver, pancreas, skin, lung and bladder of ICR mice were removed and checked after a fixed time interval (6 hours) of benzo[a]pyrene exposure, and whole genomic DNA methylation level was determined by high performance liquid chromatography (HPLC). The results exhibited tissue specificity, that is, the level of whole genomic DNA methylation decreases significantly in blood and liver, rather than pancreas, lung, skin and bladder of ICR mice. This study investigated the direct relationship between aberrant DNA methylation level and benzo[a]pyrene exposure, which might be helpful to clarify the toxicological mechanism of benzo[a]pyrene in epigenetic perspectives. PMID- 26522068 TI - Alternate documentation of illegible signatures Centers for Medicare and Medicaid Service guidance. PMID- 26522069 TI - Geriatric trauma: An opportunity for proactive palliative care. PMID- 26522070 TI - Targeted delivery of CCR2 antagonist to activated pulmonary endothelium prevents metastasis. AB - Enhanced levels of the inflammatory chemokine CCL2 are known to correlate with increased tumorigenesis and metastases, and thereby poor prognosis for cancer patients. The CCL2-CCR2 chemokine axis was shown to facilitate the metastatic initiation through the recruitment of inflammatory monocytes and the activation of endothelial cells at metastatic sites. Both steps are required for efficient cancer cell trans-endothelial migration and seeding in the targeted tissue. The translation of preclinical evidence proved to be challenging due to systemic effects of chemokine inhibition and limited target specificity. Here we tested an approach of a targeted delivery of the CCR2 antagonist Teijin Compound 1 to metastatic sites. VCAM-1 binding peptide tagged liposomes carrying the CCR2 antagonist enabled a specific delivery to cancer cell-activated endothelium. The subsequent binding of target-sensitive liposomes triggered the release of the Teijin Compound 1 and thereby local inhibition of CCR2 in the lungs. Blocking of CCR2 resulted in reduced induction of the lungs vascular permeability, and thereby reduced tumor cell extravasation. However, the recruitment of inflammatory monocytes to the pre-metastatic lungs remained unaltered. Endothelial VCAM-1 targeted delivery of the CCR2 antagonist resulted in inhibition of pulmonary metastases both in a murine (MC-38GFP cells) and a human xenograft (patient-derived cells) model. Thus, timely- and spatially-defined inhibition of CCR2 signaling represents a potential therapeutic approach for treatment of metastasis without affecting homeostatic functions. PMID- 26522071 TI - Bacteriomimetic invasin-functionalized nanocarriers for intracellular delivery. AB - Intracellular bacteria invade mammalian cells to establish an infectious niche. The current work models adhesion and subsequent internalization strategy of pathogenic bacteria into mammalian cells to design a bacteriomimetic bioinvasive delivery system. We report on the surface functionalization of liposomes with a C terminal fragment of invasin (InvA497), an invasion factor in the outer membrane of Yersinia pseudotuberculosis. InvA497-functionalized liposomes adhere to mammalian epithelial HEp-2 cell line at different infection stages with a significantly higher efficiency than liposomes functionalized with bovine serum albumin. Covalent attachment of InvA497 results in higher cellular adhesion than liposomes with physically adsorbed InvA497 with non-specific surface protein alignment. Uptake studies in HEp-2 cells indicate active internalization of InvA497-functionalized liposomes via beta1-integrin receptor-mediated uptake mechanism mimicking the natural invasion strategy of Y. pseudotuberculosis. Uptake studies in Caco-2 cells at different polarization states demonstrate specific targeting of the InvA497-functionalized liposomes to less polarized cells reflecting the status of inflamed cells. Moreover, when loaded with the anti-infective agent gentamicin and applied to HEp-2 cells infected with Y. pseudotuberculosis, InvA497-functionalized liposomes are able to significantly reduce the infection load relative to non-functionalized drug-loaded liposomes. This indicates a promising application of such a bacteriomimetic system for drug delivery to intracellular compartments. PMID- 26522072 TI - 70-kDa heat shock protein coated magnetic nanocarriers as a nanovaccine for induction of anti-tumor immune response in experimental glioma. AB - Nanovaccines based on superparamagnetic iron oxide nanoparticles (SPIONs) provide a novel approach to induce the humoral and cell-based immune system to fight cancer. Herein, we increased the immunostimulatory capacity of SPIONs by coating them with recombinant heat shock protein 70 (Hsp70) which is known to chaperone antigenic peptides. After binding, Hsp70-SPIONs deliver immunogenic peptides from tumor lysates to dendritis cells (DCs) and thus stimulate a tumor-specific, CD8+ cytotoxic T cell response. We could show that binding activity of Hsp70-SPIONs to the substrate-binding domain (SBD) is highly dependent on the ATPase activity of its nucleotide-binding domain NBD), as shown by (31)P NMR spectroscopy. Immunization of C6 glioma-bearing rats with DCs pulsed with Hsp70-SPIONs and tumor lysates resulted in a delayed tumor progression (as measured by MRI) and an increased overall survival. In parallel an increased IFNgamma secretion were detected in the serum of these animals and immunohistological analysis of subsequent cryosections of the glioma revealed an enhanced infiltration of memory CD45RO+ and cytotoxic CD8+ T cells. Taken together the study demonstrates that magnetic nanocarriers such as SPIONs coated with Hsp70 can be applied as a platform for boosting anti-cancer immune responses. PMID- 26522073 TI - Benefit of endovascular stenting for aortic coarctation on systemic hypertension in adults. AB - BACKGROUND: Endovascular stenting is a recognised treatment strategy for aortic coarctation (CoA) in adults. We assessed systemic hypertension control and the need for antihypertensive therapy after CoA stenting in adults. METHODS: Data were collected prospectively on 54 patients (36 men; mean age: 34 +/- 16 years) who underwent endovascular stenting for CoA over a 7-year period. Five patients were excluded as they did not attend follow-up appointments. Patients underwent clinical examination, including right arm systolic blood pressure (SBP) and 24 hour ambulatory blood pressure monitoring at baseline, 6-12 weeks and 9-12 months. RESULTS: There was a significant fall in mean peak-to-peak systolic gradient (PG) across the CoA after stenting (26 +/- 11 mmHg vs. 5 +/- 4 mmHg; P<0.01). There were successive reductions in right arm SBP and ambulatory SBP at baseline, 6-12 weeks and 9-12 months post-procedure (right arm: 155 +/- 18 mmHg vs. 137 +/- 17 mmHg vs. 142 +/- 16 mmHg, respectively; all P-values <0.01; ambulatory: 142 +/- 14 mmHg vs. 132 +/- 16 mmHg vs. 131 +/- 15 mmHg, respectively; all P-values <0.01). Twenty-four patients had severe CoA (PG >25 mmHg before stenting); baseline SBP was significantly higher in severe versus non severe patients (160 mmHg vs. 148 mmHg; P=0.02). The absolute reduction in PG after stenting was significantly higher in the severe group (31 +/- 7 mmHg vs. 14 +/- 5 mmHg; P<0.0001), but there was no significant difference in SBP between groups at 6-12 weeks (141 mmHg vs. 135 mmHg; P=0.21) or 9-12 months (139 mmHg vs. 139 mmHg; P=0.96). CONCLUSION: Endovascular stenting of CoA results in a significant reduction in SBP at 6-12 weeks, which is sustained at 9-12 months, with similar outcomes in severe and non-severe CoA groups. PMID- 26522074 TI - Innovation in obsessive compulsive disorder: A commentary. AB - As noted in this commentary, the research in this special issue presents several conceptual and methodological innovations that advance out understanding of obsessions and compulsions. The issue spans a broad range of topics from basic psychological processes such as selfhood themes, perceptions of internal states, and preference for visual symmetry to new insights into compulsions and other forms of neutralization to promising treatment approaches for special OCD symptom presentations. The implications of this research for understanding vulnerability to OCD and the role of compulsions are discussed and three methodological challenges are highlighted that require further attention by OCD researchers. PMID- 26522075 TI - Distinct inflammatory and cytopathic characteristics of Escherichia coli isolates from inflammatory bowel disease patients. AB - Escherichia coli (E. coli) may be implicated in the pathogenesis of inflammatory bowel disease (IBD), as implied from a higher prevalence of mucosa-associated E. coli in the gut of IBD-affected individuals. However, it is unclear whether different non-diarrheagenic E. coli spp. segregate from each other in their ability to promote intestinal inflammation. Herein we compared the inflammation inducing properties of non-diarrheagenic LF82, 691-04A, E. coli Nissle 1917 (ECN) and eleven new intestinal isolates from different locations in five IBD patients and one healthy control. Viable E. coli were cultured with human monocyte-derived dendritic cells (moDCs) and monolayers of intestinal epithelial cells (IECs), followed by analysis of secreted cytokines, intracellular levels of reactive oxygen species and cellular death. The IBD-associated E. coli LF82 induced the same dose-dependent inflammatory cytokine profile as ECN and ten of the new E. coli isolates displayed as high level IL-12p70, IL-1beta, IL-23 and TNF-alpha from moDCs irrespective of their site of isolation (ileum/colon/faeces), disease origin (diseased/non-diseased) or known virulence factors. Contrarily, 691-04A and one new IBD E. coli isolate induced a different cellular phenotype with enhanced killing of moDCs and IECs, coupled to elevated IL-18. The cytopathic nature of 691-04A and one other IBD E. coli isolate suggests that colonization with specific non-diarrheagenic E. coli could promote intestinal barrier leakage and profound intestinal inflammation, while LF82, ECN and the remaining non diarrheagenic E. coli isolates hold notorious pro-inflammatory characteristics that can progress inflammation in case of intestinal barrier leakage. PMID- 26522076 TI - Controlling bacterial infections by inhibiting proton-dependent processes. AB - Bacterial resistance to antibiotics is recognized as one of the greatest threats in modern healthcare, taking a staggering toll worldwide. New approaches for controlling bacterial infections must be designed, eventually combining multiple strategies for complimentary therapies. This review explores an old/new paradigm for multi-targeted antibacterial therapy, focused at disturbing bacterial cytoplasmic membrane functions at sub minimal inhibitory concentrations, namely through superficial physical alterations of the bilayer, thereby perturbing transmembrane signals transduction. Such a paradigm may have the advantage of fighting the infection while avoiding many of the known resistance mechanisms. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. PMID- 26522077 TI - The biophysical properties of ethanolamine plasmalogens revealed by atomistic molecular dynamics simulations. AB - Given the importance of plasmalogens in cellular membranes and neurodegenerative diseases, a better understanding of how plasmalogens affect the lipid membrane properties is needed. Here we carried out molecular dynamics simulations to study a lipid membrane comprised of ethanolamine plasmalogens (PE-plasmalogens). We compared the results to the PE-diacyl counterpart and palmitoyl-oleyl phosphatidylcholine (POPC) bilayers. Results show that PE-plasmalogens form more compressed, thicker, and rigid lipid bilayers in comparison with the PE-diacyl and POPC membranes. The results also point out that the vinyl-ether linkage increases the ordering of sn-1 chain substantially and the ordering of the sn-2 chain to a minor extent. Further, the vinyl-ether linkage changes the orientation of the lipid head group, but it does not cause changes in the head group and glycerol backbone tilt angles with respect to the bilayer normal. The vinyl-ether linkage also packs the proximal regions of the sn-1 and sn-2 chains more closely together which also decreases the distance between the rest of the sn-1 and sn-2 chains. PMID- 26522078 TI - Modified inoculation and disease assessment methods reveal host specificity in Erwinia tracheiphila-Cucurbitaceae interactions. AB - We conducted a greenhouse trial to determine specific compatible interactions between Erwinia tracheiphila strains and cucurbit host species. Using a modified inoculation system, E. tracheiphila strains HCa1-5N, UnisCu1-1N, and MISpSq-N were inoculated to cucumber (Cucumis sativus) cv. 'Sweet Burpless', melon (Cucumis melo) cv. 'Athena Hybrid', and squash (Cucubita pepo) cv. 'Early Summer Crookneck'. We observed symptoms and disease progression for 30 days; recorded the number of days to wilting of the inoculated leaf (DWIL), days to wilting of the whole plant (DWWP), and days to death of the plant (DDP). We found significant interactions between host cultivar and pathogen strains, which imply host specificity. Pathogen strains HCa1-5N and UnisCu1-1N isolated from Cucumis species exhibited more virulence in cucumber and melon than in squash, while the reverse was true for strain MISpSq-N, an isolate from Cucurbita spp. Our observations confirm a previous finding that E. tracheiphila strains isolated from Cucumis species were more virulent on Cucumis hosts and those from Cucubita were more virulent on Cucubita hosts. This confirmation helps in better understanding the pathosystem and provides baseline information for the subsequent development of new disease management strategies for bacterial wilt. We also demonstrated the efficiency of our modified inoculation and disease scoring methods. PMID- 26522079 TI - Obesity Leads to Tissue, but not Serum Vitamin A Deficiency. AB - Obesity negatively affects multiple metabolic pathways, but little is known about the impact of obesity on vitamin A (VA)[retinol (ROL)], a nutrient that regulates expression of genes in numerous pathways essential for human development and health. We demonstrate that obese mice, generated from a high fat diet (HFD) or by genetic mutations (i.e., ob/ob; db/db), have greatly reduced ROL levels in multiple organs, including liver, lungs, pancreas, and kidneys, even though their diets have adequate VA. However, obese mice exhibit elevated serum VA. Organs from obese mice show impaired VA transcriptional signaling, including reductions in retinoic acid receptor (RARalpha, RARbeta2 and RARgamma) mRNAs and lower intracellular ROL binding protein Crbp1 (RBP1) levels in VA-storing stellate cells. Reductions in organ VA signaling in obese mice correlate with increasing adiposity and fatty liver (steatosis), while with weight loss VA levels and signaling normalize. Consistent with our findings in obese mice, we show that increasing severity of fatty liver disease in humans correlates with reductions in hepatic VA, VA transcriptional signaling, and Crbp1 levels in VA storing stellate cells. Thus, obesity causes a "silent" VA deficiency marked by reductions in VA levels and signaling in multiple organs, but not detected by serum VA. PMID- 26522080 TI - The effects of gamma rays on the regeneration of hair follicles are carried over to later hair cycles. AB - PURPOSE: The purpose of this study was to determine whether the effects of gamma rays on the regeneration of hair follicles are carried over to later hair cycles. MATERIALS AND METHODS: The whole bodies of C57BL/10JHir mice in the 1st telogen phase were irradiated with (60)Co gamma-rays. Mice were examined for the effects on hair follicles, including their number, morphology and pigmentation in the 3rd anagen phase. Effects of gamma-rays on hair follicle stem cells were investigated by the indirect immunolabeling of keratin 15 (K15). RESULTS: Decreased hair follicle density and induction of curved hair follicles were observed in the dermis of irradiated skin. In addition, white hair and hypopigmented hair bulbs were found. The number of K15-positive hair follicle stem cells in the hair bulge region of irradiated skin appeared to decrease slightly but not significantly. CONCLUSIONS: These results suggest that the effects of gamma-rays are carried over to a later hair cycle to affect the number, structure and pigmentation of hair follicles in the 3rd anagen phase when stem cells and committed progenitors for keratinocytes and melanocytes are irradiated in the 1st telogen phase. PMID- 26522081 TI - The effects of different levels of calcium supplementation on the bone mineral status of postpartum lactating Chinese women: a 12-month randomised, double blinded, controlled trial. AB - Increasing dietary Ca intake may prevent the excessive mobilisation of bone mineral in nursing mothers. We aimed to investigate whether higher Ca intake could positively modulate the bone mineral changes in Chinese postpartum lactating women. The study was a 12-month randomised, double-blinded, parallel group trial conducted over 12 months. A total of 150 postpartum women were randomly selected to receive either 40 g of milk powder containing 300 mg of Ca and 5 MUg of vitamin D (Low-Ca group) or same milk powder additionally fortified with 300 mg of Ca (Mid-Ca group) or 600 mg of Ca (High-Ca group). Bone mineral density (BMD) for the whole body, the lumbar spine, the total left hip and its sub-regions was measured using dual-energy X-ray absorptiometry. A total of 102 subjects completed the whole trial. The duration of total lactating time was 7.9 (SD 2.8) months on average. The intention-to-treat analysis yielded the following mean percentage changes in BMD for the whole body, the lumbar spine and the total left hip, respectively: -0.93 (SD 1.97), 2.11 (SD 4.90) and -1.60 (SD 2.65)% for the Low-Ca group; -0.56 (SD 1.89), 2.21 (SD 3.77) and -1.43 (SD 2.30)% for the Mid-Ca group; and -0.44 (SD 1.67), 2.32 (SD 4.66) and -0.95 (SD 4.08)% for the High-Ca group. The differences between the groups were not statistically significant (P: 0.5-0.9). The results of the complete case analysis were similar. In sum, we found no significant differences in the bone mineral changes from baseline to 12 months in postpartum lactating women consuming milk powder fortified with different levels of Ca. PMID- 26522082 TI - Superior Optical Properties of Perovskite Nanocrystals as Single Photon Emitters. AB - The power conversion efficiency of photovoltaic devices based on semiconductor perovskites has reached ~20% after just several years of research efforts. With concomitant discoveries of other promising applications in lasers, light-emitting diodes, and photodetectors, it is natural to anticipate what further excitement these exotic perovskites could bring about. Here we report on the observation of single photon emission from single CsPbBr3 perovskite nanocrystals (NCs) synthesized from a facile colloidal approach. Compared with traditional metal chalcogenide NCs, these CsPbBr3 NCs exhibit nearly 2 orders of magnitude increase in their absorption cross sections at similar emission colors. Moreover, the radiative lifetime of CsPbBr3 NCs is greatly shortened at both room and cryogenic temperatures to favor an extremely fast output of single photons. The above superior optical properties have paved the way toward quantum-light applications of perovskite NCs in various quantum information processing schemes. PMID- 26522084 TI - CD4+ T cells, but not non-classical monocytes, are dispensable for the development of chronic lymphocytic leukemia in the TCL1-tg murine model. PMID- 26522083 TI - Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia. AB - DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients. PMID- 26522087 TI - Treatment of Mild Gastrointestinal Disorders with a Herbal Combination: Results of a Non-interventional Study with Gastritol(r) Liquid. AB - A combination of extracts from chamomile, silverweed, licorice, angelica, blessed thistle and wormwood, Gastritol((r)) Liquid, is registered for the use of indigestion and gastrointestinal spasmodic complaints. To gain data on the experience in practice, a non-interventional open study was conducted in ambulatory patients including diabetics which were treated for 2 weeks. The efficacy of treatment was assessed by medical examination and evaluation of typical symptoms by patients. A total of 149 patients was enrolled, 90 without and 59 with diabetes. The treatment led to relevant improvements in all symptoms in both study groups. The most notable improvements were seen for the symptoms vomiting (-66.7%; diabetics: -63.9%) and retching (-52.2%; diabetics: -53.6%). An overall improvement was rated by about 90% in both study groups. In seven patients adverse events had been reported (5 times temporary nausea after intake, one time gastric spasm and one time oral burning sensation), all of them of mild nature. The global tolerability was assessed as good or very good in more than 80% by practitioners and patients. Under the conditions of this open study method Gastritol((r)) Liquid had been shown to be safe and effective in the treatment of mild gastrointestinal disorders, including diabetic patients. PMID- 26522085 TI - Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo. AB - Chronic lymphocytic leukemia (CLL) is characterized by apoptosis resistance and a dysfunctional immune system. Previous reports suggested a potential role of myeloid cells in mediating these defects. However, the composition and function of CLL-associated myeloid cells have not been thoroughly investigated in vivo. Using the EMU-TCL1 mouse model, we observed severe skewing of myeloid cell populations with CLL development. Monocytes and M2-like macrophages infiltrated the peritoneal cavity of leukemic mice. Monocytes also accumulated in the spleen in a CCR2-dependent manner, and were severely skewed toward Ly6C(low) patrolling or nonclassical phenotype. In addition, the percentage of MHC-II(hi) dendritic cells and macrophages significantly dropped in the spleen. Gene expression profiling of CLL-associated monocytes revealed aberrantly high PD-L1 expression and secretion of multiple inflammatory and immunosuppressive cytokines like interleukin-10, tumor necrosis factor-alpha and CXCL9. In vivo myeloid cell depletion using liposomal Clodronate resulted in a significant control of CLL development accompanied by a pronounced repair of innate immune cell phenotypes and a partial resolution of systemic inflammation. In addition, CLL-associated skewing of T cells toward antigen-experienced phenotypes was repaired. The presented data suggest that targeting nonmalignant myeloid cells might serve as a novel immunotherapeutical strategy for CLL. PMID- 26522086 TI - Species, Abundance and Function of Ammonia-oxidizing Archaea in Inland Waters across China. AB - Ammonia oxidation is the first step in nitrification and was thought to be performed solely by specialized bacteria. The discovery of ammonia-oxidizing archaea (AOA) changed this view. We examined the large scale and spatio-temporal occurrence, abundance and role of AOA throughout Chinese inland waters (n = 28). Molecular survey showed that AOA was ubiquitous in inland waters. The existence of AOA in extreme acidic, alkaline, hot, cold, eutrophic and oligotrophic environments expanded the tolerance limits of AOA, especially their known temperature tolerance to -25 degrees C, and substrate load to 42.04 mM. There were spatio-temporal divergences of AOA community structure in inland waters, and the diversity of AOA in inland water ecosystems was high with 34 observed species level operational taxonomic units (OTUs; based on a 15% cutoff) distributed widely in group I.1b, I.1a, and I.1a-associated. The abundance of AOA was quite high (8.5 * 10(4) to 8.5 * 10(9) copies g(-1)), and AOA outnumbered ammonia oxidizing bacteria (AOB) in the inland waters where little human activities were involved. On the whole AOB predominate the ammonia oxidation rate over AOA in inland water ecosystems, and AOA play an indispensable role in global nitrogen cycle considering that AOA occupy a broader habitat range than AOB, especially in extreme environments. PMID- 26522088 TI - Interactions of a potent cyclic peptide inhibitor with the light chain of botulinum neurotoxin A: Insights from X-ray crystallography. AB - The seven antigenically distinct serotypes (A-G) of botulinum neurotoxin (BoNT) are responsible for the deadly disease botulism. BoNT serotype A (BoNT/A) exerts its lethal action by cleaving the SNARE protein SNAP-25, leading to inhibition of neurotransmitter release, flaccid paralysis and autonomic dysfunction. BoNTs are dichain proteins consisting of a ~ 100 kDa heavy chain and a ~ 50 kDa light chain; the former is responsible for neurospecific binding, internalization and translocation, and the latter for cleavage of neuronal SNARE proteins. Because of their extreme toxicity and history of weaponization, the BoNTs are regarded as potential biowarfare/bioterrorism agents. No post-symptomatic therapeutic interventions are available for BoNT intoxication other than intensive care; therefore it is imperative to develop specific antidotes against this neurotoxin. To this end, a cyclic peptide inhibitor (CPI-1) was evaluated in a FRET assay for its ability to inhibit BoNT/A light chain (Balc). CPI was found to be highly potent, exhibiting a Ki of 12.3 nM with full-length Balc448 and 39.2 nM using a truncated crystallizable form of the light chain (Balc424). Cocrystallization studies revealed that in the Balc424-CPI-1 complex, the inhibitor adopts a helical conformation, occupies a high percentage of the active site cavity and interacts in an amphipathic manner with critical active site residues. The data suggest that CPI-1 prevents SNAP-25 from accessing the Balc active site by blocking both the substrate binding path at the surface and the Zn(2+) binding region involved in catalysis. This differs from linear peptide inhibitors described to date which block only the latter. PMID- 26522089 TI - Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization. AB - Whole-cell high-throughput screening of a diverse SoftFocus library against Mycobacterium tuberculosis (Mtb) generated a novel aminopyrazolo[1,5-a]pyrimidine hit series. The synthesis and structure activity relationship studies identified compounds with potent antimycobacterial activity. The SAR of over 140 compounds shows that the 2-pyridylmethylamine moiety at the C-7 position of the pyrazolopyrimidine scaffold was important for Mtb activity, whereas the C-3 position offered a higher degree of flexibility. The series was also profiled for in vitro cytotoxicity and microsomal metabolic stability as well as physicochemical properties. Consequently liabilities to be addressed in a future lead optimization campaign have been identified. PMID- 26522091 TI - Facilitators and barriers in the collaboration between the primary care and the sport sector in order to promote physical activity: A systematic literature review. AB - INTRODUCTION: The aim of this review was to identify collaborative initiatives between the primary care and the sport sector in order to promote physical activity (PA), and barriers and facilitators in these initiatives. METHOD: Pubmed, SportDiscus, Web of Science, and SOCindex were systematically searched for publications published between 2000 and June 2014. Publications reporting on collaboration between the primary care and the sport sector to promote PA were included. Publications reporting on non-empirical data were excluded, except for study protocols. RESULTS: The search process yielded 1352 publications. After selection, 40 publications were included. Twenty-eight different initiatives were divided into four forms of collaboration, and two approaches to promote PA were distinguished with different kinds of facilitators and barriers. In the referral of patients, sport professionals' lack of medical knowledge, and health professionals' lack of time, were seen as barriers. In networks to organize activities to promote PA among the community, different shared interests and different cultures were seen as barriers. CONCLUSION: This review showed that performance of intersectoral collaboration and the collaboration between both sectors are still unexplored. This review provides a first step towards an insight into collaboration and factors that facilitate or hinder collaboration between these sectors. PMID- 26522093 TI - Influence of school community and fitness on prevalence of overweight in Australian school children. AB - The study objectives were (1) to determine the variation in prevalence of overweight between school communities, (2) to evaluate the relationship between cardiorespiratory fitness and the probability of being overweight among different school communities, and (3) to test whether this relationship varies between school communities. Using a repeated cross-sectional design, data from 31,424 (15,298 girls, 16,126 boys) Australian school children who had objective assessments of body composition and physical performance were used. Ninety-one schools located across 5 states and territories were included. Independent samples were taken across 12 school years (2000-2011). Analysis used generalised linear mixed models in R with a two-level hierarchical structure-children, nested within school communities. Predictor variables considered were: level 1-gender, age, cardiorespiratory fitness and year of measurement; level 2-school community. A total of 24.6% of the children were overweight and 69% were of low fitness. Variation in the prevalence of overweight between school communities was significant, ranging from 19% to 34%. The probability of being overweight was negatively associated with increasing cardiorespiratory fitness. The relationship was steepest at low fitness and varied markedly between school communities. Children of low fitness had probabilities of being overweight ranging between 26% and 75% depending on school community, whereas those of high fitness had probabilities of <2%. Our findings suggest that most might be gained from a public health perspective by focusing intervention on the least fit children in the worst-performing communities. PMID- 26522094 TI - Transition and Damping of Collective Modes in a Trapped Fermi Gas between BCS and Unitary Limits near the Phase Transition. AB - We investigate the transition and damping of low-energy collective modes in a trapped unitary Fermi gas by solving the Boltzmann-Vlasov kinetic equation in a scaled form, which is combined with both the T-matrix fluctuation theory in normal phase and the mean-field theory in order phase. In order to connect the microscopic and kinetic descriptions of many-body Feshbach scattering, we adopt a phenomenological two-fluid physical approach, and derive the coupling constants in the order phase. By solving the Boltzmann-Vlasov steady-state equation in a variational form, we calculate two viscous relaxation rates with the collision probabilities of fermion's scattering including fermions in the normal fluid and fermion pairs in the superfluid. Additionally, by considering the pairing and depairing of fermions, we get results of the frequency and damping of collective modes versus temperature and s-wave scattering length. Our theoretical results are in a remarkable agreement with the experimental data, particularly for the sharp transition between collisionless and hydrodynamic behaviour and strong damping between BCS and unitary limits near the phase transition. The sharp transition originates from the maximum of viscous relaxation rate caused by fermion-fermion pair collision at the phase transition point when the fermion depair, while the strong damping due to the fast varying of the frequency of collective modes from BCS limit to unitary limit. PMID- 26522095 TI - Liver disease in pregnancy. AB - Deranged liver function tests are encountered in 3% of pregnancies. The potential causes are classified as those unique to and those just incidental to pregnancy. Pregnancy-related diseases are the most frequent causes of liver dysfunction during pregnancy and exhibit a trimester-specific occurrence during pregnancy. Differentiation of liver dysfunction as that related to and just incidental to pregnancy is the key to management, especially when liver dysfunction is encountered after 28 weeks of pregnancy. It can be judged from the fact that delivery remains the cornerstone of management of pregnancy-related diseases except hyperemesis gravidarum. This is an overview of the causes of liver dysfunction during pregnancy; an update on the underlying mechanisms of their occurrence, especially liver diseases unique to pregnancy; and a methodological approach to their diagnosis and management. PMID- 26522092 TI - From fatalism to mitigation: A conceptual framework for mitigating fetal programming of chronic disease by maternal obesity. AB - Prenatal development is recognized as a critical period in the etiology of obesity and cardiometabolic disease. Potential strategies to reduce maternal obesity-induced risk later in life have been largely overlooked. In this paper, we first propose a conceptual framework for the role of public health and preventive medicine in mitigating the effects of fetal programming. Second, we review a small but growing body of research (through August 2015) that examines interactive effects of maternal obesity and two public health foci - diet and physical activity - in the offspring. Results of the review support the hypothesis that diet and physical activity after early life can attenuate disease susceptibility induced by maternal obesity, but human evidence is scant. Based on the review, we identify major gaps relevant for prevention research, such as characterizing the type and dose response of dietary and physical activity exposures that modify the adverse effects of maternal obesity in the offspring. Third, we discuss potential implications of interactions between maternal obesity and postnatal dietary and physical activity exposures for interventions to mitigate maternal obesity-induced risk among children. Our conceptual framework, evidence review, and future research directions offer a platform to develop, test, and implement fetal programming mitigation strategies for the current and future generations of children. PMID- 26522096 TI - Medical treatment for heavy menstrual bleeding. AB - Heavy menstrual bleeding, or menorrhagia, is subjectively defined as a "complaint of a large amount of bleeding during menstrual cycles that occurs over several consecutive cycles" and is objectively defined as menstrual blood loss of more than 80 mL per cycle that is associated with an anemia status (defined as a hemoglobin level of <10 g/dL). During their reproductive age, more than 30% of women will complain of or experience a heavy amount of bleeding, which leads to a debilitating health outcome, including significantly reduced health-related quality of life, and a considerable economic burden on the health care system. Although surgical treatment might be the most important definite treatment, especially hysterectomy for those women who have finished bearing children, the uterus is still regarded as the regulator and controller of important physiological functions, a sexual organ, a source of energy and vitality, and a maintainer of youth and attractiveness. This has resulted in a modern trend in which women may reconsider the possibility of organ preservation. For women who wish to retain the uterus, medical treatment may be one of the best alternatives. In this review, recent trends in the management of women with heavy menstrual bleeding are discussed. PMID- 26522097 TI - Management of type II unruptured cesarean scar pregnancy: Comparison of gestational mass excision and uterine artery embolization combined with methotrexate. AB - OBJECTIVE: This research was carried out to investigate the effectiveness, rationality, and safety of laparotomy management compared with uterine artery embolization (UAE) combined with methotrexate (MTX) for the treatment of deep implantation cesarean scar pregnancy (CSP II). MATERIALS AND METHODS: Data from 29 patients seen between June 2008 and February 2012 were retrospectively analyzed. The patients were divided into the surgery group and the UAE combined with MTX group according to the treatment they received. We compared the clinical characteristics and treatment outcomes between the two groups. RESULTS: The patients' clinical characteristics did not differ between the surgery group and the UAE combined with MTX group. However, the mean blood loss was decreased in the surgery group compared with the UAE combined with MTX group (90 +/- 4.5 mL vs. 286 +/- 5.2 mL, p < 0.05). No patients required blood transfusion in the surgery group, whereas two patients in the UAE combined with MTX group received blood transfusions. The length of time for the serum beta human chorionic gonadotropin (beta-HCG) level to normalize, the time required for the disappearance of the gestational mass, and the duration of hospital stay were significantly less in the surgery group than in the UAE combined with MTX group (13.7 +/- 1.0 days vs. 40.7 +/- 1.7 days, 7.1 +/- 1.3 days vs. 135.4 +/- 6.7 days, and 11.0 +/- 1.2 days vs. 41.4 +/- 3.2 days, respectively; p < 0.01). Although the treatment success rate did not differ significantly between the two groups, the success rate was 100% for the surgery group and 73% for the UAE combined with MTX group. CONCLUSION: Surgical treatment can remove gestational masses and allow wound repair. Moreover, laparotomy is available in almost all hospitals. Thus, surgery can be an effective and reasonable treatment for CSP II. PMID- 26522098 TI - Temporary prophylactic intravascular balloon occlusion of the common iliac arteries before cesarean hysterectomy for controlling operative blood loss in abnormal placentation. AB - OBJECTIVES: The purpose of this study was to investigate the efficacy and safety of temporary prophylactic intravascular balloon occlusion of the common iliac arteries (CIA) before planned cesarean hysterectomy for controlling operative blood loss in abnormal placentation. MATERIALS AND METHODS: A retrospective study of 13 pregnant women at risk for placenta accreta identified using sequential obstetric ultrasonography and magnetic resonance imaging from January 2007 to December 2009 was performed. Temporary prophylactic intravascular balloon catheterization of the bilateral CIA before cesarean hysterectomy was performed by interventional radiologists. The maximum duration of occlusion time of CIA must not exceed 60 minutes. The primary outcome for this study included estimated blood loss and secondary outcomes included the development of thromboembolism, disseminated intravascular coagulation and surgical complications. RESULTS: Among these 13 patients, the mean age of the patients was 32.8 +/- 0.7 years (range 29 37 years). The mean gestational age at cesarean hysterectomy was 32.2 +/- 0.9 weeks (range 28-36 weeks), and the mean intraoperative blood loss was 1902.3 +/- 578.8 mL (range 500-8000 mL). Operative bleeding was controlled by conservative treatment without additional surgery in two cases. Importantly, two patients (15.8%) had severe complications possibly related to the interventional procedure. One patient was noted to have a popliteal artery thrombosis. A second patient had an external iliac artery thrombosis with 80-90% occlusion. Both patients required antithrombotic treatment without sequelae. CONCLUSION: With limited experience in this small series, we observed a statistically significant reduction in operative blood loss after the use of temporary prophylactic balloon occlusion of the CIA technique compared with historical controls of similar demographic characteristics previously published (1902.3 +/- 578.8 mL, range 500 8000 mL vs. 4445.7 +/- 996.48 mL, range 1040-15,000 mL, p = 0.0402). Additionally, two patients had arterial thrombosis. These preliminary findings are based on a small number of patients, and therefore further investigation is needed to determine the effectiveness and safety of this new technique. PMID- 26522099 TI - Proteomic profiling reveals alpha1-antitrypsin, alpha1-microglobulin, and clusterin as preeclampsia-related serum proteins in pregnant women. AB - OBJECTIVE: Preeclampsia is a major cause of mortality in pregnant women but the underlying mechanism remains unclear to date. In this study, we attempted to identify candidate proteins that might be associated with preeclampsia in pregnant women by means of proteomics tools. MATERIALS AND METHODS: Differentially expressed proteins in serum samples obtained from pregnant women with severe preeclampsia (n = 8) and control participants (n = 8) were identified using two-dimensional gel electrophoresis (2-DE) followed by peptide mass fingerprinting using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS). Additional serum samples from 50 normal and 41 pregnant women with severe preeclampsia were analyzed by immunoassay for validation. RESULTS: Ten protein spots were found to be upregulated significantly in women with severe preeclampsia. These protein spots had the peptide mass fingerprints matched to alpha1-antitrypsin, alpha1-microglobulin, clusterin, and haptoglobin. Immunoassays in an independent series of serum samples showed that serum alpha1-antitrypsin, alpha1-microglobulin, and clusterin levels of severe preeclampsia patients (n = 41) were significantly higher than those in the normal participants (n = 50; alpha1-antitrypsin 295.95 +/- 50.94 mg/dL vs. 259.31 +/- 33.90 mg/dL, p = 0.02; alpha1-microglobulin 0.029 +/- 0.004 mg/mL vs. 0.020 +/- 0.004 mg/mL, p < 0.0001; clusterin 77.6 +/- 16.15 MUg/dL vs. 67.6 +/- 15.87 MUg/dL, p < 0.05). CONCLUSION: Identification of these proteins by proteomics analysis enables further understanding of the pathophysiology of preeclampsia. Further studies are warranted to investigate the role of these biomarkers in prediction of this disease. PMID- 26522100 TI - Establishment of human-embryonic-stem-cell line from mosaic trisomy 9 embryo. AB - OBJECTIVE: Human-embryonic-stem-cell (hESC) lines derived from chromosomally or genetically abnormal embryos obtained following preimplantation genetic diagnosis are valuable in investigating genetic disorders. MATERIALS AND METHODS: In this study, a new hESC line, Center of Clinical Reproductive Medicine 8 (CCRM8) was established by isolation, culture, and passaging of the inner cell mass of mosaic trisomy 9 embryos. RESULTS: A karyotype analysis showed that the hESC line possessed a euploid (46 chromosomes). The undifferentiated hESCs exhibited long term proliferation capacity and expressed typical markers of OCT4, TRA-1-60, and TRA-1-81. In vitro embryoid-body (EB) formation, differentiation, and in vivo teratoma production confirmed the pluripotency of the hESC line. The data represented here are the first detailed report on the characterization and differentiation of one Chinese hESC line generated from mosaic trisomy 9 embryos. CONCLUSION: Our study showed that chromosomally aberrant embryos could generate a normal hESC line, which would be useful in investigating gene function and embryo development. PMID- 26522101 TI - Decreasing trend of hysterectomy in Taiwan: A population-based study, 1997-2010. AB - OBJECTIVE: Gynecologists in Taiwan are lacking a comprehensive picture of the changes in clinical practice and indications of hysterectomy over a long period of time. The aims of this study were to examine the national trends in the utilization of hysterectomy and to explore changes in its utilization rate over a 14-year period from 1997 to 2010. MATERIALS AND METHODS: We conducted a population-based trend analysis using the claims data from the Taiwan's National Health Insurance program. RESULTS: We identified a total of 341,993 women aged 20 years or older who underwent hysterectomy between 1997 and 2010. The total number of hysterectomies increased from 22,961 in 1997 to 27,757 cases in 1999, followed by a decline to 22,351 in 2010. Overall, 5406 fewer hysterectomies (-19.5%) were performed in 2010 when compared with those performed in 1999. The number of hysterectomies performed decreased from 1997 to 2010 for precancerous lesions ( 55.6%), chronic pelvic pain (-35.2%), uterine leiomyoma (-13.1%), and uterine prolapse (-7.2%). However, the utilization of hysterectomy increased for endometriosis (+76.3%) and gynecologic cancer (+22.7%) during the same time frame. CONCLUSION: The clinical utilization and primary indications of hysterectomy changed substantially in Taiwan from 1997 to 2010. The continued monitoring of changes in hysterectomy rates will be critical for understanding the appropriate indications for hysterectomy and oophorectomy, the emergence of alternative managements for uterine disorders, and future trends in women's reproductive health. PMID- 26522102 TI - Pelvic reconstruction improves pelvic floor strength in pelvic organ prolapse patients. AB - OBJECTIVE: To evaluate pelvic floor muscle strength after the modified pelvic reconstruction procedure for pelvic organ prolapse (POP). MATERIALS AND METHODS: Patients were assigned to two groups consisting of 37 patients diagnosed with POP and undergoing modified pelvic reconstruction (reconstruction group), and 30 patients admitted to our hospital during the same period for other surgical indications (control group). Vaginal palpation of pelvic floor muscle strength was performed according to the modified Oxford grading system before operating on the two groups and again in the 3(rd) month following surgery for the reconstruction group. A comparative study was performed to evaluate the differences between the two groups and the improvement of pelvic floor muscle strength in the reconstruction group. RESULTS: The pelvic floor muscle strength was significantly improved postoperatively when compared with preoperative results in the reconstruction group (t = -17.478, p < 0.001). However, pre- and postoperative muscle strength in the reconstruction group was significantly lower relative to the control group, respectively (chi(2) = 63.293, p < 0.001; chi(2) = 31.550, p < 0.001). CONCLUSION: The modified pelvic reconstruction procedure could improve pelvic floor muscle strength in POP patients, which remains lower when compared with the normal population. Pelvic floor muscle strength should be included in the assessment of surgical outcomes in POP. PMID- 26522103 TI - Decreased endometrial vascularity and receptivity in unexplained recurrent miscarriage patients during midluteal and early pregnancy phases. AB - OBJECTIVE: To evaluate the predictive value of three-dimensional (3D)-power Doppler sonography on recurrent miscarriage. MATERIALS AND METHODS: The study patients were divided into a recurrent miscarriage group (30 cases) and a normal pregnancy group (21 cases). Measurement of endometrial thickness was performed using two-dimensional transvaginal ultrasound in the midluteal phase. The endometrial volume, vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) in midluteal and placenta volume, as well as the VI, FI, and VFI of early pregnancy were measured using Virtual Organ Computer aided Analysis of 3D-power Doppler ultrasound. RESULTS: Endometrial thickness, endometrial volume, endometrial vascular data, VI, FI, and VFI of the midluteal phase were lower in the recurrent miscarriage group compared with the normal pregnancy group (p < 0.05). Placental volume, VI, and VFI during early pregnancy were lower in the miscarriage group compared with the normal pregnancy group (p < 0.05). There was no significant change in FI between the recurrent miscarriage and control groups during early pregnancy (p > 0.05). The predictive accuracy of endometrial thickness, endometrial volume, VI, FI, and VFI in the midluteal phase, and placenta volume, VI, FI, and VFI in early pregnancy as measured by the receiver operating characteristic curve to predict miscarriage before 12 gestational weeks in participants was 0.681, 0.876, 0.770, 0.720, 0.879, 0.771, 0.907, 0.592, respectively. CONCLUSION: The 3D-power Doppler ultrasound is a more comprehensive and sensitive method for evaluating endometrial receptivity. Endometrial volume, VI, FI, and VFI in the midluteal phase, as well as VI in early pregnancy, can be considered as predictive factors for recurrent miscarriage. PMID- 26522104 TI - Maternal mosaicism of sex chromosome causes discordant sex chromosomal aneuploidies associated with noninvasive prenatal testing. AB - OBJECTIVE: To investigate the clinical efficiency of noninvasive prenatal test (NIPT) identifying fetal chromosomal aneuploidies. MATERIALS AND METHODS: In the present study, 917 women with high-risk pregnancies were invited to participate in an NIPT trial based on an Illumina HiSeq massively parallel sequencing platform. Abnormal cases in NIPT were validated by karyotyping and fluorescence in situ hybridization (FISH) analysis. All of the participants' infants were examined clinically and followed up for at least 6 months. RESULTS: A total of 35 (3.82%) high-risk pregnancies were detected with abnormal results in NIPT, which included 25 cases (2.73%) of trisomy 21 (Tri21), four cases (0.44%) of trisomy 18 (Tri18), four cases (0.44%) of Turner syndrome (45, X), one cases (0.11%) of Klinefelter's syndrome (47, XXY), and one cases (0.11%) with lower X chromosome concentration. Further validation indicated that one case of Tri18 and the case with lower X chromosome concentration were false positive results (0.22%) in NIPT. Furthermore, it was found that the false positive case with lower X chromosome concentration in NIPT was caused by maternal sex chromosomal mosaicism (45, X and 46, XX). CONCLUSION: Our findings indicated that maternal mosaicism of sex chromosome could cause discordant sex chromosomal aneuploidies associated with NIPT. We highly recommended that maternal karyotype should be confirmed for the cases with abnormal results in NIPT. PMID- 26522105 TI - Outcome of ovarian preservation during surgical treatment for endometrial cancer: A Taiwanese Gynecologic Oncology Group study. AB - OBJECTIVE: The goal of this study was to investigate the impact of ovarian preservation on the survival of women with early-stage endometrial cancer, particularly young women. MATERIALS AND METHODS: A study cohort of 64 patients with histologically confirmed early-stage endometrial cancer was retrospectively collected from 10 member hospitals of the Taiwanese Gynecologic Oncology Group between 1998 and 2009. Survivorship and overall survival were compared between these two groups using a log-rank test. RESULTS: All patients who underwent surgery were adult women with a mean age of 40.4 +/- 9.2 years (range 24-63 years). Ovary-preserving surgery was performed in 38 (59.4%) patients who desired to preserve their ovaries, incidentally in 19 (29.7%) patients with a preoperative diagnosis other than endometrial carcinoma, and in seven patients (10.9%) with unknown reasons. The 5-year recurrence-free survival rate was 98.3% with a median follow up of 44.6 months (range 1.0-126.9 months). Eight patients required adjuvant treatment (12.5%); one patient had documented local recurrence (1.6%); and no metachronous ovarian malignancy occurred during follow up. CONCLUSION: Preservation of bilateral ovaries does not increase cancer-related mortality. A more conservative approach to surgical staging may be considered in premenopausal women with early-stage endometrial cancer without risk factors. PMID- 26522106 TI - Is intravesical instillation of hyaluronic acid and chondroitin sulfate useful in preventing recurrent bacterial cystitis? A multicenter case control analysis. AB - OBJECTIVE: Urinary tract infections (UTIs) are common in the female population and, over a lifetime, about half of women have at least one episode of UTI requiring antibiotic therapy. The aim of the current study was to compare two different strategies for preventing recurrent bacterial cystitis: intravesical instillation of hyaluronic acid (HA) plus chondroitin sulfate (CS), and antibiotic prophylaxis with sulfamethoxazole plus trimethoprim. MATERIALS AND METHODS: This was a retrospective review of two different cohorts of women affected by recurrent bacterial cystitis. Cases (experimental group) were women who received intravesical instillations of a sterile solution of high concentration of HA + CS in 50 mL water with calcium chloride every week during the 1(st) month and then once monthly for 4 months. The control group included women who received traditional therapy for recurrent cystitis based on daily antibiotic prophylaxis using sulfamethoxazole 200 mg plus trimethoprim 40 mg for 6 weeks. RESULTS: Ninety-eight and 76 patients were treated with experimental and control treatments, respectively. At 12 months after treatment, 69 and 109 UTIs were detected in the experimental and control groups, respectively. The proportion of patients free from UTIs was significantly higher in the experimental than in the control group (36.7% vs. 21.0%; p = 0.03). Experimental treatment was well tolerated and none of the patients stopped it. CONCLUSION: The intravesical instillation of HA + CS is more effective than long-term antibiotic prophylaxis for preventing recurrent bacterial cystitis. PMID- 26522107 TI - Ectopic pregnancy following in vitro fertilization with embryo transfer: A single center experience during 15 years. AB - OBJECTIVE: Ectopic pregnancy is an obstetrical disease that is potentially associated with maternal death in the first trimester. It is one of the well known complications following in vitro fertilization (IVF) with embryo transfer (ET). The incidence of ectopic pregnancy is estimated to be 2.1-8.6% of clinical pregnancy after IVF-ET, which is higher than natural conceptions (incidence rate 2%). This study aimed to re-evaluate the ectopic pregnancy rate in patients undergoing IVF-ET and to investigate the effects of embryo stage and frozen thawed blastocyst transfer and ET during full bladder distention on ectopic pregnancy rate. MATERIALS AND METHODS: This retrospective study reviewed women who achieved a clinical pregnancy after IVF-ET at the Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital between 1999 and 2013. We compared ectopic pregnancy rate following Day 3 ET with Day 5 ET, and after fresh ET with thawed ET. Besides, multivariate analysis was used to clarify the factors affecting ectopic pregnancy after IVF-ET. RESULTS: Of the total 1213 clinical pregnancies after fresh ET, 18 (1.5%) were verified as ectopic, which is similar to the rate following natural conception. The ectopic pregnancy rates were similar for Day 3 (1.2%) and Day 5 (1.7%) ETs. The incidence of ectopic pregnancy in thawed ET cycles (0.6%) was not significantly reduced than fresh ET cycles (1.5%). Tubal ET (TET) and ET under full bladder distention had a significant effect on ectopic pregnancy. CONCLUSION: Thawed ET was not associated with a lower incidence of ectopic pregnancy than fresh ET, and embryo stage did not affect the rate of ectopic pregnancy. In addition, TET and ET under conditions of full bladder distention may increase the ectopic pregnancy rate. PMID- 26522108 TI - Methylenetetrahydrofolate reductase gene polymorphism in endometrial cancer: A systematic review and meta-analysis. AB - OBJECTIVE: We conducted a meta-analysis of case-controlled prospective or retrospective studies to assess the effect of MTHFR polymorphisms on the risk of developing endometrial cancer. MATERIALS AND METHODS: PubMed, Cochrane, EMBASE, and ISI Web of Knowledge were searched (up to March 2014) for prospective or retrospective case-controlled studies that investigated the association of three MTHFR polymorphisms (rs180113 [C677T], rs1801131 [A1289C], and rs2274976 [G1793A]) with endometrial cancer. RESULTS: The patient population included subjects from three separate countries: China, Spain, and the USA. Only one study reported quantitative findings for MTHFR G1793A and, consequently, this polymorphism was not evaluated in our analysis. There were no significant associations of any MTHFR C677T or MTHFR A1298C alleles or genotypes with endometrial cancer (all p > 0.300). CONCLUSION: This meta-analysis does not support the association of endometrial cancer with two common MTHFR polymorphisms from this patient population. PMID- 26522109 TI - Reproductive outcomes after previous cesarean scar pregnancy: Follow up of 189 women. AB - OBJECTIVE: To investigate the reproductive and pregnancy outcomes of women after previous Cesarean Scar Pregnancy. MATERIALS AND METHODS: From January 2009 to December 2013, a total of 214 patients with CSP received surgical evacuation treatment by means of dilation and suction evacuation and local resection of the ectopic gestational mass. A telephone follow-up was conducted every year after CSP treatment. The follow-up was ended on December 2014. RESULTS: Twenty-five patients were lost to follow-up due to loss of contacts. The previous medical records of the remaining 189 women were reviewed. Fifty-eight women wished to give birth again. However, 48 (82.8%, 48/58) of them stopped the attempts to get pregnant because they were afraid of recurrent CSP and the high risk of uterine rupture during the subsequent pregnancy. The other 10 women spontaneously attempted to get pregnant again, among whom 6 (60%, 6/10) succeeded with the birth of 7 healthy babies. A total of 32 women conceived again, either in plan or by chance. Five women (15.6%, 5/32) experiencing recurrent CSP. CONCLUSION: Even though our result did not necessarily represent the true recurrence rate, our study provided some evidence about the likelihood of fertility and recurrence risk for future pregnancies after previous CSP. PMID- 26522110 TI - Frequency of postnatal hydronephrosis in infants with a renal anterior-posterior pelvic diameter > 4 mm on midtrimester ultrasound. AB - OBJECTIVE: To examine the association of antenatal renal pelvic dilatation observed on midtrimester ultrasound screening with the presence of hydronephrosis in newborn infants. MATERIALS AND METHODS: The records of patients who received fetal ultrasound examination at 18-28 weeks' gestation from May 2008 to March 2012 were retrospectively reviewed. A fetal renal pelvic anterior-posterior (AP) diameter > 4 mm was considered abnormal and <= 4 mm was considered normal. On postnatal ultrasound, a renal pelvic AP diameter > 3 mm was considered to indicate hydronephrosis and <= 3 mm was considered normal. The association of postnatal hydronephrosis with prenatal pelvic AP diameter was determined using binary logistic regression analysis. RESULTS: The study comprised 1310 newborn infants: 684 (52.2%) male and 626 (47.8%) female. Multivariate analysis showed a right or left prenatal AP renal pelvic diameter > 4 mm was associated with a higher risk of postnatal hydronephrosis compared with a right and left prenatal AP renal pelvic diameter <= 4 mm. Boys had a higher risk for postnatal hydronephrosis than girls (odds ratio = 2.42, p < 0.05). CONCLUSION: An antenatal renal pelvic AP diameter > 4 mm on midtrimester ultrasound is predictive of postnatal hydronephrosis. PMID- 26522111 TI - Detection of human papillomavirus in squamous cell carcinoma arising from dermoid cysts. AB - OBJECTIVE: Primary squamous cell carcinoma (SCC) of the ovary in humans is rare. Most cases represent a malignant transformation of ovarian teratoma, Brenner tumor, or endometriosis. The etiology of this cancer remains largely unknown. Human papillomavirus (HPV) infection is a critical factor that induces tumor formation, particularly cervical cancer. Therefore, this study aimed to evaluate the association of HPV with malignant transformation of mature cystic teratoma (MCT) into SCC of the ovary. MATERIALS AND METHODS: The samples included four formalin-fixed paraffin-embedded SCC-MCT tissues and their adjacent tissues from the cervix to the ovaries, 12 cases of benign teratoma ovarian tissues (dermoid tissues), and 11 cases of benign nonteratoma ovarian tissues (nondermoid tissues). The two squamous carcinoma tissues of the cervix were used as control samples. HPV was detected by immunohistochemistry (IHC) with anti-HPV capsid or E6 (HPV type 16/18) antibodies and in situ hybridization (ISH) with three sets of genotyping probes, HPV types 6/11, 16/18, and 31/33. RESULTS: IHC revealed HPV infection associated with the four cases of SCC-MCT and the two cases of control cervical cancer samples. Importantly, HPV was also detected in adjacent reproductive tissues of the SCC-MCT cases, which suggested that the viral particles might spread in an ascending route through the fallopian tubes, endometrium, endocervix, and cervix to the ovaries. ISH revealed HPV type 16/18 in all SCC-MCT cases and HPV type 31/33 in two, with no HPV type 6/11 in any SCC MCT cases. However, compared with the SCC-MCT cases, the lower detection rates of HPV in dermoid cysts and nondermoid tissues suggested that HPV might not be associated with normal ovarian tissues or benign ovarian teratomas. CONCLUSION: Our data suggest that high-risk HPV infection might be a causal factor that induces malignant transformation of MCT into SCC of the ovary, although further investigation is still required. PMID- 26522112 TI - The influence of female age on the cumulative live-birth rate of fresh cycles and subsequent frozen cycles using vitrified blastocysts in hyper-responders. AB - OBJECTIVE: The aim of this research was to study the influence of female age on the cumulative live-birth rate of fresh and subsequent frozen cycles using vitrified blastocysts of the same cohort in hyper-responders. MATERIALS AND METHODS: This was a retrospective study of 1137 infertile women undergoing their first in vitro fertilization treatment between 2006 and 2013. The main outcome measure was cumulative live births among the fresh and all vitrified blastocyst transfers combined after the same stimulation cycle. The results were also analyzed according to age (i.e., <35 years, 35-39 years, and >= 40 years). RESULTS: The mean number of retrieved oocytes was 19.9 +/- 8.5 oocytes. The cumulative pregnancy rate was 89.2% and the cumulative live-birth rate was 73.3%. The cumulative live-birth rate declined from 73.9% for women younger than 35 years old to 67.3% for women 35-39 years old to 57.9% for women 40 years or older. CONCLUSION: Combined fresh and vitrified blastocyst transfer cycles can result in a high cumulative live-birth rate. The cumulative live-birth rates among older women are lower than the rates among younger women when autologous oocytes are used. PMID- 26522113 TI - Quantitative DNA methylation analysis of selected genes in endometrial carcinogenesis. AB - OBJECTIVE: Most endometrial carcinomas appear to develop from precursors (e.g., endometrial hyperplasia) that progress for several years. Patients who are ultimately diagnosed with carcinoma often present clinically with complaints of abnormal vaginal bleeding years before diagnosis, which offers an opportunity for early diagnosis and curative treatment. The analysis of DNA methylation may be used as a method for detecting endometrial cancer (EC). To test the potential clinical application of this method, we used quantitative methylation analysis of five genes in a full spectrum of endometrial lesions. MATERIALS AND METHODS: This hospital-based, prospective, case-controlled study was conducted on 68 patients, which included patients who had a normal endometrium (n = 18), hyperplasia of the endometrium (n = 24), and EC (n = 26). Methylation levels of the following genes were determined by using real-time methylation-specific polymerase chain reaction (PCR) amplification: zinc finger protein 177 (ZNF177), collagen type XIV alpha1 (COL14A1), dihydropyrimidinase-like 4 (DPYSL4), homeobox A9 (HOXA9), transmembrane protein with epidermal growth factor-like and two follistatin-like domains 2 (TMEFF2). The methylation index (MI) cutoff values for the different diagnoses were determined to test the sensitivity and specificity of the method and to generate the receiver operating characteristic (ROC) curves. The Mann Whitney U test was used to test between-group differences in the MI. RESULTS: The MI of the five genes was significantly higher in EC than the MIs in specimens of hyperplasia of endometrium and normal appearance (p < 0.001). The ROC analysis demonstrated that the sensitivity, specificity, and accuracy for detecting EC were 92.3%, 94.4%, and 95.1%, respectively, for ZNF177; 92.3%, 94.4%, and 95.7%, respectively, for COL14A1; 80.8%, 94.4%, and 81.4%, respectively, for HOXA9; 65.4%, 94.4%, and 89.5%, respectively, for TMEFF2; and 61.5%, 94.4%, and 63.3%, respectively, for DPYSL4. The combined testing of ZNF177 and COL14A1 had the best specificity (100%), but compromised sensitivity (88.5%). CONCLUSION: Promoter methylation of ZNF177, COL14A1, HOXA9, DPYSL4, and TMEFF2 genes is a frequent epigenetic event in EC. Furthermore, the epigenetic hypermethylation of TMEFF2 may be a valuable marker for identifying undetected EC within endometrial hyperplasia. PMID- 26522114 TI - Fetoscopic laser coagulation of intertwin anastomoses reduces discordant placental autophagic activities in discordant twin growth. AB - OBJECTIVES: To investigate placental autophagic activity in cases of twin-twin transfusion syndrome (TTTS) after successful laser therapy and to evaluate the effect of intertwin anastomoses on discordant placenta autophagic activity in monochorionic twins with one twin exhibiting selective intrauterine growth restriction. MATERIALS AND METHODS: Placenta samples were prospectively obtained from 11 cases of successful TTTS post-laser therapy with two living babies. Among these infants, five infants had selective intrauterine growth restriction (sIUGR), based on the definition of a birth weight below the 10(th) percentile. After protein extraction, western blot tests were used to determine the amount of placenta microtubule-associated protein 1A/1B-light chain 3 (LC3)-II protein in the two individual placenta territories of the twin pair. The LC3-II protein fold change ratio (FCR) in a twin pair was defined as the LC3-II protein fold value over beta-actin of the smaller twin divided by the LC3-II protein fold value over beta-actin of the larger twin. RESULTS: The LC3-II FCRs were not significantly different between TTTS with sIUGR and TTTS without sIUGR, after successful laser therapy. CONCLUSION: The discordance of placenta autophagic activity in the monochorionic twin with sIUGR was reduced after laser coagulation of the intertwin anastomoses, which may result from the effect of correction of the discordant intertwin placenta perfusion. PMID- 26522115 TI - A gonadotropin releasing hormone agonist trigger of ovulation with aggressive luteal phase support for patients at risk of ovarian hyperstimulation syndrome undergoing controlled ovarian hyperstimulation. AB - OBJECTIVE: The aim of this study was to determine the efficacy and safety of luteal phase support using human chorionic gonadotropin (hCG) in cycles that are triggered with a gonadotropin-releasing hormone (GnRH) agonist in a moderate-to high risk population undergoing a GnRH antagonist protocol. MATERIALS AND METHODS: We retrospectively reviewed the charts of patients undergoing an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle with a GnRH antagonist protocol from September 2011 to August 2012. The patients were defined as at high risk for ovarian hyperstimulation syndrome (OHSS) in terms of anti-Mullerian hormone (AMH) and antral follicle counts (AFCs). The patients were divided into two groups depending on whether ovulation was triggered with hCG or a GnRH agonist. Modified luteal support was provided for the cycles triggered by the GnRH agonist via low dose hCG (1500~5000 IU). For the cycles that were triggered by hCG, urinary hCG (5000 IU) following two doses of recombinant hCG (250 MUg) were administered. The primary outcomes of this study were the clinical pregnancy rate and the OHSS rate of the two groups. The secondary outcomes were the number of oocytes retrieved and the number of good quality embryos obtained. RESULTS: The study group and the control group were similar in terms of the primary and secondary outcome measures. CONCLUSION: Aggressive luteal support with low dose hCG following a GnRH agonist trigger can result in a comparable pregnancy rate to that with the use of a traditional hCG ovulation trigger. However, OHSS can still occur in patients with risk factors. Therefore, other OHSS prevention strategies should be considered. PMID- 26522116 TI - Interphase fluorescence in situ hybridization assisting in prenatal counseling for amniocentesis karyotyping-detected fetal mosaicism. AB - OBJECTIVE: To evaluate how interphase fluorescence in situ hybridization (FISH) played a role in genetic counseling when encountering prenatally detected fetal mosaicism cases. MATERIALS AND METHODS: We retrospectively reviewed 17 cases of amniotic fluid specimens diagnosed with Level III chromosome mosaicism using in situ coverslip culture method. Among them, seven received additional interphase FISH tests; five were related to autosomal mosaicism and two others were due to sex chromosomes. RESULTS: In the autosome group, one couple chose to terminate the pregnancy due to a high percentage of trisomy 21 cells (48.1%) shown on interphase FISH; in the gonosome group, one case chose termination as FISH exhibited as high as 80% of XXYY cells. CONCLUSION: Performing interphase FISH on uncultured amniocytes for cases detected with mosaicism by traditional amniotic fluid culture provided quick confirmation of the karyotyping results; additionally, obtaining information about the extent of the abnormality involved using interphase FISH could also play a role in counseling patients on the decision making concerning the future of their pregnancies. PMID- 26522117 TI - Prenatal diagnosis and array comparative genomic hybridization characterization of interstitial deletions of 8q23.3-q24.11 and 8q24.13 associated with Langer Giedion syndrome, Cornelia de Lange syndrome and haploinsufficiency of TRPS1, RAD21 and EXT1. AB - OBJECTIVE: The aim of this research was to present prenatal diagnosis of Langer Giedion syndrome (LGS/TRPS type II) and Cornelia de Lange syndrome-4 (CDLS4). MATERIALS AND METHODS: A 36-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Conventional cytogenetic analysis of amniocentesis revealed an interstitial deletion of chromosome 8q or del(8)(q23.3q24.13). Level II prenatal ultrasound examination revealed craniofacial dysmorphism. The pregnancy was terminated, and a malformed fetus was delivered with characteristic craniofacial dysmorphism of LGS/TRPS type II and CDLS4. Whole-genome array comparative genomic hybridization (aCGH) on the DNA extracted from cultured amniocytes was performed. RESULTS: The analysis by aCGH revealed a result of arr 8q23.3q24.11 (116,087,006-118,969,399)*1, 8q24.13 (123,086,851-124,470,847)*1 (NCBI build 37) with a 2.88-Mb deletion of 8q23.3 q24.11 encompassing six OMIM genes, TRPS1, EIF3H, RAD21, SLC30A8, MED30, and EXT1, and a 1.383-Mb deletion of 8q24.13 encompassing four OMIM genes, ZHX2, DERL1, ZHX1, and ATAD2. CONCLUSION: In the present case, the conventional cytogenetic analysis of cultured amniocytes revealed del(8)(q23.3q24.13), whereas aCGH analysis of cultured amniocytes showed the deletions of 8q23.3-q24.11 and 8q24.13 with the presence of the segment 8q24.12. Therefore, aCGH provides the advantage of better understanding of the nature of interstitial deletion and genotype-phenotype correlation in this case. PMID- 26522118 TI - Maternal and fetal outcomes in pregnant women with Takayasu aortoarteritis: Does optimally timed intervention in women with renal artery involvement improve pregnancy outcome? AB - OBJECTIVE: Takayasu aortoarteritis (TA) is common in the Southeast Asian and Indian subcontinent regions with a female-to-male ratio of 8:1. Age at diagnosis is < 30 years in 90% of the cases. Because the disease is common in women of child-bearing age, management of pregnancy in these patients becomes an important issue. The purpose of this study is to evaluate the maternal and fetal outcomes in pregnancies with TA and also to evaluate whether early intervention for renal artery involvement is associated with improved outcomes. MATERIALS AND METHODS: We collected data of 12 patients with 18 pregnancies prospectively from 2006 to 2012. The patients were divided into three groups and their outcomes were noted: (1) without renal artery involvement; (2) with renal artery involvement without intervention; and (3) with renal artery involvement for which intervention has been done. RESULTS: Body mass index of patients was between 18.5 kg/m(2) and 23.2 kg/m(2). Renal artery involvement and hypertension were seen in four patients. One patient had percutaneous transluminal balloon angioplasty and another had renal artery stenting. In patients without renal artery involvement, gestational hypertension was seen in 50%, pre-eclampsia in 10%, abortion in 10%, and intrauterine growth restriction (IUGR) in 40% of pregnancies. In patients with renal artery involvement without intervention, gestational hypertension was seen in 90%, pre-eclampsia in 20%, abortion in 60%, preterm in 20%, IUGR in 20%, fetal demise in 20%, and neonatal death in 20% of pregnancies. In patients with renal artery involvement for which intervention has been carried out, gestational hypertension was seen in 66%, and abortion and IUGR were seen in 33% of pregnancies. CONCLUSION: Patients with renovascular involvement without intervention are at high risk of having maternal and fetal complications. Early intervention prior to conception in these women is recommended to prevent pregnancy complications. PMID- 26522119 TI - Malignant presentation of uterine lymphangioleiomyomatosis. AB - OBJECTIVE: The main aim of this case report was to present the method of diagnosis, management, and the 12-year-follow-up of a patient diagnosed with primary uterine lymphangioleiomyomatosis (LAM). CASE REPORT: A 47-year-old woman was admitted to the Department of Thoracosurgery due to pulmonary lesions suspected to be metastatic. The potential primary site of the neoplasm was not identified by previous imaging studies and specialist counseling. The patient had a history of total abdominal hysterectomy without ovaries due to a uterine tumor recognized as cellular leiomyoma and left salpingo-oophorectomy due to a solid ovarian tumor also recognized as leiomyoma. She had previously undergone the removal of a left kidney angiomyolipoma. After histopathological examination of the pulmonary lesions and repeated evaluation of the ovarian and uterine tumors, the diagnosis of primary uterine LAM with metastases to the ovary and the lungs was established. Although new metastatic lesions occurred, the patient remained in good condition during the 12-year-follow-up. CONCLUSION: The history of our patient and review of the literature suggest that although uterine LAM presents malignant features (i.e., metastasis), the disease is long lasting and the patient can be in good condition for a number of years. PMID- 26522120 TI - Hysteroscopic fetoscopy: A role as virtuopsy for parents who refuse full autopsy? A case of facial clefting, proboscis, and limb deformities. AB - OBJECTIVE: To describe the value of hysteroscopic fetoscopy (virtuopsy) at the time of uterine suction in a case of early diagnosis of congenital anomalies in parents refusing conventional full autopsy examination. CASE REPORT: First trimester ultrasound diagnosis of proboscis, median cleft lip and palate and limb deformities. Chorionic villus sampling demonstrated normal karyotype. Parents refused medical induction of termination of pregnancy with subsequent conventional autopsy. At this stage, hysteroscopic fetoscopy was consented and carried out under local anesthesia prior to uterine evacuation. CONCLUSION: Hysteroscopic fetoscopy (virtuopsy) proved to be a valuable complementary diagnostic investigation and enhanced the parental bonding process concerning the fetal phenotype. Notwithstanding, the woman declared an acceptable compliance during the procedure. In selected cases, virtuopsy may be a valid option in confirming early prenatal ultrasound diagnosis in parents refusing conventional autopsy or when full postmortem examination may not be clinically indicated or warranted. PMID- 26522121 TI - In vitro fertilization complicated by rupture of tubo-ovarian abscess during pregnancy. AB - OBJECTIVE: Pelvic abscess during pregnancy is an uncommon complication, but can lead to adverse perinatal outcomes during pregnancy. CASE REPORT: We present a patient who developed rupture of a tubo-ovarian abscess during pregnancy following in vitro fertilization and embryo transfer. Thirty-eight reported cases are reviewed, and transvaginal oocyte retrieval, genital tract infections, endometrioma, and previous pelvic surgery are considered as risk factors for pelvic abscess during pregnancy. CONCLUSION: Prolonging gestational duration when an infection situation is allowed is the principle of treatment. PMID- 26522122 TI - Experience of successful treatment of patients with metronidazole-resistant Trichomonas vaginalis with zinc sulfate: A case series. AB - OBJECTIVE: There are no universally successful guidelines for the treatment of metronidazole-resistant vaginal trichomoniasis. This is distressing for patients and frustrating for physicians. We therefore decided to evaluate whether zinc sulfate douche is effective in treating vaginal trichomoniasis, because the compound is a natural antimicrobial chemical defense in humans. CASE REPORTS: In our retrospective case review, eight cases of metronidazole-resistant trichomoniasis were treated with 1% zinc sulfate douche with or without tinidazole between 2005 and 2012. Except for one patient who was pregnant, seven patients were successfully treated and were negative for microscopic findings with no clinical symptoms at follow up. CONCLUSION: Although the exact role of zinc sulfate in metronidazole-resistant trichomoniasis is not clear, our patients experienced a therapeutic effect with zinc sulfate douche treatment. We therefore recommend zinc sulfate douche as an option for the treatment of metronidazole resistant vaginal trichomoniasis. PMID- 26522123 TI - Epithelioid trophoblastic tumor. AB - OBJECTIVE: To describe a case of epithelioid trophoblastic tumor (ETT) in a postmenopausal woman, which had several peculiar features that differentiate it from previously reported ETTs. CASE REPORT: ETT of the uterus is a rare form of trophoblastic tumor with only 100 cases distinguished until now. Our case differs from the previously reported ones due to its several exceptional features. Our patient had no history of trophoblastic or gynecological disease; is postmenopausal; had endocervical extension from the beginning; recurrences and metastasis at follow up; and had a high Ki-67 index and a normal beta-human chorionic gonadotropin value. CONCLUSION: Because precise differential diagnosis will alter the therapeutic approach and prognosis, it is necessary for treating physicians to be aware of these unusual presentations. PMID- 26522124 TI - Systemic embolic events with nonbacterial thrombotic endocarditis as manifestations of recurrent ovarian clear cell carcinoma. AB - OBJECTIVE: To present a rare case of recurrent ovarian clear cell carcinoma (OCCC) with systemic embolic events. CASE REPORT: A 60-year-old woman with a history of OCCC presented with an acute ischemic stroke. Magnetic resonance imaging showed multifocal, bilateral infarctions over the cerebrum and cerebellum. An echocardiogram revealed vegetation growth in the mitral and tricuspid valves and showed no evidence of atrial fibrillation. The serological studies for stroke were negative for all assessed parameters (normal values of protein C, protein S, antithrombin III, and lupus anticoagulant antibodies). Computed tomography of the abdomen and pelvis revealed bilateral renal and splenic infarctions, as well as enlarged pelvic lymph nodes due to a recurrent ovarian neoplasm. We diagnosed the patient with nonbacterial thrombotic endocarditis (NBTE) based on serial negative blood cultures and sterile vegetation of the surgical specimen. CONCLUSION: NBTE should be considered among the possible causes of multifocal embolic infarctions and as an early manifestation of recurrent OCCC. Anticoagulant therapy is the mainstay of treatment, and dual anticoagulation therapies are necessary to reduce the risk of recurrent thromboembolism. PMID- 26522125 TI - Management of pancreatic ectopic pregnancy. PMID- 26522126 TI - Aortic Curvature Instead of Angulation Allows Improved Estimation of the True Aorto-iliac Trajectory. AB - OBJECTIVE: Supra- and infrarenal aortic neck angulation have been associated with complications after endovascular aortic aneurysm repair. However, a uniform angulation measurement method is lacking and the concept of angulation suggests a triangular oversimplification of the aortic anatomy. (Semi-)automated calculation of curvature along the center luminal line describes the actual trajectory of the aorta. This study proposes a methodology for calculating aortic (neck) curvature and suggests an additional method based on available tools in current workstations: curvature by digital calipers (CDC). METHODS: Proprietary custom software was developed for automatic calculation of the severity and location of the largest supra- and infrarenal curvature over the center luminal line. Twenty four patients with severe supra- or infrarenal angulations (>=45 degrees ) and 11 patients with small to moderate angulations (<45 degrees ) were included. Both CDC and angulation were measured by two independent observers on the pre- and postoperative computed tomographic angiography scans. The relationships between actual curvature and CDC and angulation were visualized and tested with Pearson's correlation coefficient. The CDC was also fully automatically calculated with proprietary custom software. The difference between manual and automatic determination of CDC was tested with a paired Student t test. A p-value was considered significant when two-tailed alpha < .05. RESULTS: The correlation between actual curvature and manual CDC is strong (.586-.962) and even stronger for automatic CDC (.865-.961). The correlation between actual curvature and angulation is much lower (.410-.737). Flow direction angulation values overestimate CDC measurements by 60%, with larger variance. No significant difference was found in automatically calculated CDC values and manually measured CDC values. CONCLUSION: Curvature calculation of the aortic neck improves determination of the true aortic trajectory. Automatic calculation of the actual curvature is preferable, but measurement or calculation of the curvature by digital calipers is a valid alternative if actual curvature is not at hand. PMID- 26522127 TI - Spin-dependent transport properties of Fe3O4/MoS2/Fe3O4 junctions. AB - Magnetite is a half-metal with a high Curie temperature of 858 K, making it a promising candidate for magnetic tunnel junctions (MTJs). Yet, initial efforts to exploit its half metallic nature in Fe3O4/MgO/Fe3O4 MTJ structures have been far from promising. Finding suitable barrier layer materials, which keep the half metallic nature of Fe3O4 at the interface between Fe3O4 layers and barrier layer, is one of main challenges in this field. Two-dimensional (2D) materials may be good candidates for this purpose. Molybdenum disulfide (MoS2) is a transition metal dichalcogenide (TMD) semiconductor with distinctive electronic, optical, and catalytic properties. Here, we show based on the first principle calculations that Fe3O4 keeps a nearly fully spin polarized electron band at the interface between MoS2 and Fe3O4. We also present the first attempt to fabricate the Fe3O4/MoS2/Fe3O4 MTJs. A clear tunneling magnetoresistance (TMR) signal was observed below 200 K. Thus, our experimental and theoretical studies indicate that MoS2 can be a good barrier material for Fe3O4 based MTJs. Our calculations also indicate that junctions incorporating monolayer or bilayer MoS2 are metallic. PMID- 26522128 TI - Can the Acoustic Analysis of Expressive Prosody Discriminate Schizophrenia? AB - Emotional states, attitudes and intentions are often conveyed by modulations in the tone of voice. Impaired recognition of emotions from a tone of voice (receptive prosody) has been described as characteristic symptoms of schizophrenia. However, the ability to express non-verbal information in speech (expressive prosody) has been understudied. This paper describes a useful technique for quantifying the degree of expressive prosody deficits in schizophrenia, using a semi-automatic method, and evaluates this method's ability to discriminate between patient and control groups. Forty-five medicated patients with a diagnosis of schizophrenia were matched with thirty-five healthy comparison subjects. Production of expressive prosodic speech was analyzed using variation in fundamental frequency (F0) measures on an emotionally neutral reading task. Results revealed that patients with schizophrenia exhibited significantly more pauses (p < .001), were slower (p < .001), and showed less pitch variability in speech (p < .05) and fewer variations in syllable timing (p < .001) than control subjects. These features have been associated with "flat" speech prosody. Signal processing algorithms applied to speech were shown to be capable of discriminating between patients and controls with an accuracy of 93.8%. These speech parameters may have a diagnostic and prognosis value and therefore could be used as a dependent measure in clinical trials. PMID- 26522130 TI - The role of FSCN1 in migration and invasion of pituitary adenomas. AB - The prediction of invasion or malignant behavior in PAs remains challenging. FSCN1, an actin-bundling protein, is associated with increased risk of mortality and metastasis in various cancer types. The objective of the study was to evaluate the expression of FSCN1 in 312 PAs cases, and to analyze its association with clinicopathologic features and invasion of PAs, thus serving as a promoter of cancer invasion. In non-function PAs (NFPA), FSCN1 nuclear-positive cases were 53/97 in the invasive group (IPA), and 21/115 in the noninvasive group (nIPA) (x(2) = 30.65, p = 0.004). FSCN1 cytoplasm-positive cases were 36/97 in IPA, and 8/107 in nIPA (x(2) = 29.09, p = 0.000). In growth hormone adenomas (GHomas), FSCN1 nuclear-positive were 10/13 in IPA, and 3/37 in nIPA (x(2) = 23.67, p = 0.000). FSCN1 cytoplasm-positive were 8/13 in IPA, and 2/37 in nIPA (Table 3 x(2) = 18.94, p = 0.000). Overall, a significant difference was found between FSCN1 expression and tumor size (x(2) = 46.21, p = 0.000), not age (x(2) = 2.09, p = 0.148). In the high FSCN1 expression group, 27/137 cases (19.7%) had tumor recurrence, and 10/175 cases (5.7%) in low FSCN1 level (x(2) = 14.40 p = 0.000). Reduction of FSCN1 suppressed the invasion level of GH3 cells through transwells test. In addition, reduction of FSCN1 can obviously down-regulate the level of Notch1 and DLL3. Our data may help in deciding whether FSCN1 can be a predictor for invasion and recurrence of PAs. PMID- 26522129 TI - The different ecological niches of enterotoxigenic Escherichia coli. AB - Enterotoxigenic Escherichia coli (ETEC) is a water and food-borne pathogen that infects the small intestine of the human gut and causes diarrhoea. Enterotoxigenic E. coli adheres to the epithelium by means of colonization factors and secretes two enterotoxins, the heat labile toxin and/or the heat stable toxin that both deregulate ion channels and cause secretory diarrhoea. Enterotoxigenic E. coli as all E. coli, is a versatile organism able to survive and grow in different environments. During transmission and infection, ETEC is exposed to various environmental cues that have an impact on survivability and virulence. The ability to cope with exposure to different stressful habitats is probably shaping the pool of virulent ETEC strains that cause both endemic and epidemic infections. This review will focus on the ecology of ETEC in its different habitats and interactions with other organisms as well as abiotic factors. PMID- 26522131 TI - Exercise-induced lactate accumulation regulates intramuscular triglyceride metabolism via transforming growth factor-beta1 mediated pathways. AB - The mechanism regulating the utilization of intramuscular triacylglycerol (IMTG) during high-intensity interval training (HIIT) and post-exercise recovery period remains elusive. In this study, the acute and long-term effects of HIIT on transforming growth factor beta 1 (TGF-beta1) abundance in rat skeletal muscle and role of lactate and TGF-beta1 in IMTG lipolysis during post-exercise recovery period were examined. TGF-beta1 and Adipose triacylglycerol lipase (ATGL) abundance as well as total lipase activity in the gastrocnemius muscle significantly increased to a maximum value 10 h after acute bout of HIIT. Inhibition of TGF-beta1 signaling by intramuscular injection of SB431542 30 min prior to the acute exercise attenuated ATGL abundance and total lipase activity in the gastrocnemius muscle in response to acute exercise. Intramuscular acute injection of lactate increased TGF-beta1 and ATGL abundance in the gastrocnemius muscle and there were a significant increase in Muscle TGF-beta1 and ATGL abundance after 5 weeks of HIIT/lactate treatment. These results indicate that exercise-induced lactate accumulation regulates intramuscular triglyceride metabolism via transforming growth factor-beta1 mediated pathways during post exercise recovery from strenuous exercise. PMID- 26522132 TI - Protein Kinase C Delta restrains growth in ACTH-secreting pituitary adenoma cells. AB - Protein Kinase C Delta (PRKCD) has been highlighted among disrupted pathways in corticotroph adenomas. PRKCD is expressed at low level in human corticotroph adenomas and controls cell cycle in vitro. Therefore, PRKCD may play an important role in the development/progression of corticotroph adenomas, warranting further studies to understand the role of PRKCD and related pathways in restraining pituitary cell growth. We evaluated PRKCD role in influencing cell behavior in terms of cell viability, hormone expression and protein expression profile, by silencing PRKCD in AtT-20/D16v-F2 cells. PRKCD silencing increases cell viability, enhances hormone expression and induces morphological changes associated with deregulation of adhesion molecules. PRKCD silencing is associated with an increase in Epithelial Growth Factor Receptor (EGFR) expression, a marker of tumor aggressive behavior, and sensitivity to anti-EGFR molecules. PRKCD might restrain corticotroph adenoma cells from acquiring an aggressive behavior, candidating PRKCD as a possible molecular target for the treatment of corticotroph adenomas. PMID- 26522134 TI - Clostridium difficile secreted Pro-Pro endopeptidase PPEP-1 (ZMP1/CD2830) modulates adhesion through cleavage of the collagen binding protein CD2831. AB - The Clostridium difficile cd2830 gene product is a secreted metalloprotease, named Pro-Pro endopeptidase (PPEP-1). PPEP-1 cleaves C. difficile cell surface proteins (e.g. CD2831). Here, we confirmed that PPEP-1 has a unique preference for prolines surrounding the scissile bond. Moreover, we show that it exhibits a high preference for an asparagine at the P2 position and hydrophobic residues at the P3 position. Using a PPEP-1 knockout C. difficile strain, we demonstrate that the removal of the collagen binding protein CD2831 is fully attributable to PPEP 1 activity. The PPEP-1 knockout strain demonstrated higher affinity for collagen type I with attenuated virulence in hamsters. PMID- 26522133 TI - Role of 3'-5'-cyclic adenosine monophosphate on the epidermal growth factor dependent survival in mammary epithelial cells. AB - Epidermal growth factor (EGF) has been suggested to play a key role in the maintenance of epithelial cell survival during lactation. Previously, we demonstrated that EGF dependent activation of PI3K pathway prevents apoptosis in confluent murine HC11 cells cultured under low nutrient conditions. The EGF protective effect is associated with increased levels of the antiapoptotic protein Bcl-XL. Here, we identify the EGF-dependent mechanism involved in cell survival that converges in the regulation of bcl-X expression by activated CREB. EGF induces Bcl-XL expression through activation of a unique bcl-X promoter, the P1; being not only the PI3K/AKT signaling pathway but also the increase in cAMP levels and the concomitant PKA/CREB activation necessary for both bcl-XL upregulation and apoptosis avoidance. Results presented in this work suggest the existence of a novel connection between the EGF receptor and the adenylate cyclase that would have an impact in preventing apoptosis under low nutrient conditions. PMID- 26522135 TI - Traditional Chinese medicine therapy improves the survival of systemic lupus erythematosus patients. AB - OBJECTIVE: No previous studies have evaluated the effect of traditional Chinese medicine (TCM) treatment on the survival of patients with systemic lupus erythematosus (SLE). Hence, in this study, we determined whether TCM treatment affects the survival of SLE patients. METHODS: This nationwide population-based retrospective cohort study assessed 23,084 patients newly diagnosed with SLE between 1999 and 2009, using the database of the Taiwan National Health Insurance program. RESULTS: Among these patients, 9267 (40.15%) used TCM for SLE treatment and exhibited a significantly decreased risk of death [hazard ratio (HR) = 0.73; 95% confidence interval (CI): 0.68-0.78], with multivariate adjustment, compared with those without TCM use. A similar significant protective effect of TCM use was found across various subgroups of comorbidities. TCM use 1 year before diagnosis also reduced the risk of death. Our study findings indicated that Zhi Bo Di Huang Wan (HR = 0.54; 95% CI: 0.32-0.91), Jia Wei Xiao Yao San (HR = 0.35; 95% CI: 0.16-0.73), Liu Wei Di Huang Wan (HR = 0.51; 95% CI: 0.28-0.93), Gan Lu Yin (HR = 0.40; 95% CI: 0.17-0.96), and Yin Qiao San (HR = 0.22; 95% CI: 0.05 0.86) were the most effective TCM agents that improved survival. CONCLUSIONS: This nationwide retrospective cohort study provided information that combined therapy with TCM may improve the survival in SLE patients. This study also suggests that TCM may be used as an integral element of effective therapy for SLE. PMID- 26522136 TI - Systematic analysis of the quality of the scientific evidence and conflicts of interest in osteoarthritis of the hip and knee practice guidelines. AB - OBJECTIVE: To determine the validity of the hip and knee osteoarthritis guidelines. METHODS: A systematic search of PubMed using a combination of Mesh and text terms with limitations to guidelines was performed to identify hip and knee osteoarthritis guidelines. The study was performed from April 17, 2014 to October 1, 2014. Guidelines were reviewed for graded levels of evidence, methods used to grade the evidence, and disclosures of conflicts of interest. Additionally, guidelines were also assessed for key quality measures using the AGREE II system for assessing the quality of guidelines. RESULTS: A total of 13 guidelines relevant to the diagnosis and/or treatment of hip/knee osteoarthritis was identified. The 180 recommendations reviewed were supported by 231 pieces of evidence. In total, 35% (n = 80; range: 0-26) were supported by level A evidence, 15% (n = 35; range: 0-10) were by level B, and 50% (n = 116; range: 0-62) were by level C. Median age of the guidelines was 4 years (+/-4.8; range: 0-16) with no comments on planned updates. In total, 31% of the guidelines included patients in the development process. Only one guideline incorporated cost consideration, and only 15% of the guidelines addressed the surgical management of osteoarthritis. Additionally, 46% of guidelines did not comment on conflicts of interest (COI). When present, there was an average 29.8 COI. Notably, 82% of the COI were monetary support/consulting. CONCLUSIONS: In total, 50% of the hip/knee osteoarthritis guideline recommendations are based on lower quality evidence. Nearly half the guidelines fail to disclose relevant COI and when disclosed, multiple potential COI are present. Future hip/knee osteoarthritis guideline development committees should strive to improve the transparency and quality of evidence used to formulate practice guidelines. PMID- 26522137 TI - Healthy lifestyle habits for patients with systemic lupus erythematosus: A systemic review. AB - OBJECTIVES: To assess the effects of lifestyle habits on the disease activity and damage, the occurrence of flares and quality of life of people with systemic lupus erythematosus (SLE). METHODS: A systematic literature review was performed. MEDLINE, EMBASE, and SCI/SSCI were searched. Experimental and observational studies evaluating the effect of lifestyles for SLE patients were included. Two independent reviewers selected studies and extracted relevant data. Critical appraisal of the studies was assessed following SIGN criteria. RESULTS: Eligibility criteria were met by 21 studies, five analyzed the effect of tobacco consumption, nine the effect of physical exercise and seven the effect of diet. Three studies on tobacco observed an association with increased SLE activity and the onset of cutaneous damage. The studies on physical exercise, of heterogeneous quality, reported that aerobic activity is safe for SLE patients, leading to an increase of tolerance to exercise, physical and functional capacity for those with moderate or low activity. A reduction in fatigue, anxiety and depression, as well as improved quality of life, is also suggested though evidence for these outcomes is limited. Better-quality studies on diet analyzed the effect of polyunsaturated fatty acids on disease activity. Three of the four randomized placebo-controlled trials revealed a positive effect both on overall SLE indices and individual symptoms that affect patients. CONCLUSIONS: Tobacco smoking increases the risk of skin damage and disease activity in patients with SLE. A diet rich in polyunsaturated fatty acids, avoiding a sedentary lifestyle and supervised exercise should be recommended for patients with stable SLE. PMID- 26522138 TI - 25-Hydroxyvitamin D and osteoarthritis: A meta-analysis including new data. AB - OBJECTIVES: To study the relationship between 25-hydroxy (OH) vitamin D serum levels and osteoarthritis (OA) of the knee, hip, and hand in a meta-analysis, with updated and expanded results of our previous study. METHODS: Pubmed was searched from February 1975 to December 2014 for articles assessing the relationship between vitamin D levels and OA. In our meta-analysis, 6 cross sectional and 6 longitudinal studies were included. The number of subjects in these studies ranged from 99 to 1248 subjects. The latter 1248 subjects (58% women) were drawn from the Rotterdam Study, a prospective population-based cohort study of the elderly. At baseline, 25(OH) vitamin D serum levels were measured and prevalent OA of knees, hips and hands was scored by the Kellgren-Lawrence grading system. After a mean follow-up time was 8.4 years, incidence and progression of OA were assessed. RESULTS: No clear association between vitamin serum levels and prevalent, incident or progressive knee, hip or hand OA was observed. The quality of most studies was low, and the results were conflicting. Meta-analysis of 3 cross-sectional studies on vitamin D levels and knee joint space narrowing (JSN) showed an increased risk of prevalent JSN with decreasing vitamin D levels (OR = 1.52, 95% CI: 1.15-2.01). The association observed in the meta-analysis of 3 studies on low vitamin D levels and incident and progressive knee OA was not significant (OR = 1.37, 95% CI: 0.97-1.92); however, when considering solely progressive knee OA, the risk was significantly increased (OR = 2.40, 95% CI: 1.22-4.72). CONCLUSIONS: Epidemiological studies do not provide evidence of an independent association between 25(OH) vitamin D serum levels with hip or hand OA. When analyzing subgroups of knee OA, significant associations of low vitamin D levels with prevalent knee JSN and with progressive knee OA were observed. Overall, the results of this study do not support the advice to supplement vitamin D to prevent the onset or worsening of osteoarthritis, except perhaps for progressive knee OA. PMID- 26522139 TI - Imaging as a potential outcome measure in gout studies: A systematic literature review. AB - OBJECTIVE: Despite major progress in the imaging of gout, it is unclear which domains these techniques can evaluate and whether imaging modalities have the potential to provide valid outcome measures. The aim of this study was to assess the use of imaging instruments in gout according to the Outcomes in Rheumatology Clinical Trials (OMERACT) filter to inform the development of imaging as an outcome measure. METHODS: A systematic literature search of imaging modalities for gout was undertaken. Articles were assessed by two reviewers to identify imaging domains and summarize information according to the OMERACT filter. RESULTS: The search identified 78 articles (one abstract). Modalities included were conventional radiography (CR) (16 articles), ultrasound (US) (29), conventional computed tomography (CT) (11), dual energy computed tomography (DECT) (20), and magnetic resonance imaging (MRI) (16). Three domains were identified as follows: urate deposition, joint damage, and inflammation. Although sufficient data were available to assess feasibility, validity, and reliability, comprehensive assessment of discrimination was not possible due to the paucity of prospective imaging studies. CR is widely accessible, inexpensive with a validated damage scoring system. US and MRI offer radiation-free methods of evaluating urate deposition, damage and inflammation, but may be limited by accessibility. DECT provides excellent definition of urate deposition and bone damage, but has restricted availability and requires radiation. CONCLUSIONS: Imaging methods can detect urate deposition, damage, and inflammation in gout. More than one modality may be required depending on the domains and therapeutic agent of interest. No single imaging method currently fulfils all aspects of the OMERACT filter for any domain. PMID- 26522140 TI - A randomized clinical trial of preoperative versus postoperative misoprostol in elective cesarean delivery. AB - OBJECTIVE: To determine the optimum time for misoprostol administration to minimize blood loss during and after elective cesarean delivery. METHODS: A randomized clinical trial was conducted at Mansoura University Hospital, Egypt, between January 1, 2013, and December 31, 2014. Eligible participants had full term pregnancies, were scheduled to have a cesarean, and had normal fetal heart tracing. Patients were randomly allocated into two equal groups using computer generated tables and sealed opaque envelopes. Misoprostol (400MUg, given rectally) was given either before (group 1) or after (group 2) surgery. Patients, investigators, and data analysts were not masked to group assignment. The primary outcome was blood loss. RESULTS: A total of 348 women were included (174 in each group). Blood loss was significantly lower in group 1 than in group 2 (570+/-240 vs 844+/-270mL; P<0.001). The frequency of maternal and neonatal adverse events did not differ between the groups. CONCLUSION: Preoperative misoprostol (400MUg, given rectally) reduces blood loss to a greater extent than does postoperative misoprostol during elective cesarean delivery. The frequency of complications was not affected by time of administration. PMID- 26522142 TI - Three Dimensional Hybrids of Vertical Graphene-nanosheet Sandwiched by Ag nanoparticles for Enhanced Surface Selectively Catalytic Reactions. AB - Three dimensional (3D) plasmonic nanostructure is perfect for the surface enhanced Raman scattering (SERS) and also very suitable for surface catalytic reaction, but how to design and fabricate is still a robust task. Here, we show a 3D plasmonic nanohybrid of vertical graphene-nanosheet sandwiched by Ag nanoparticles on the silicon nanocone array substrate for enhanced surface catalytic reaction. By SERS detection, we find that this hierarchical nanohybrid structure is highly efficient in the enhancement of catalytic reaction, even at a very low concentration of 10(-11) M, which is far better than previous reports by four orders of magnitude. A strong electric field enhancement produced in the 3D framework nanohybrids of graphene nanosheet/Ag-nanoparticles is responsible for this great enhancement of catalytic reaction, due to larger electron collective oscillation in the composite system. Especially the oxygen adsorbed on the graphene and Ag nanoparticles can be excited to triplet excited states, and the electrons on the graphene and the nanoparticles can be effectively transferred to the oxygen, which plays very important role in molecular catalytic reactions. Our results demonstrate the contribution of graphene in plasmon-driven catalytic reactions, revealing a co-driven reaction process.This excellent SERS substrate can be used for future plasmon and graphene co-catalytic surface catalytic reactions, graphene-based surface plasmon sensors and so on. PMID- 26522141 TI - Validating Appetite Assessment Tools Among Patients Receiving Hemodialysis. AB - OBJECTIVE: To test the performance of appetite assessment tools among patients receiving hemodialysis (HD). DESIGN: Cross-sectional. SUBJECTS: Two hundred twenty-one patients receiving HD enrolled in seven dialysis facilities in Northern California. INTERVENTION: We assessed 5 appetite assessment tools (self assessment of appetite, subjective assessment of appetite, visual analog scale [VAS], Functional Assessment of Anorexia/Cachexia Therapy [FAACT] score, and the Anorexia Questionnaire [AQ]). MAIN OUTCOME MEASURES: Reported food intake, normalized protein catabolic rate, and change in body weight were used as criterion measures, and we assessed associations among the appetite tools and biomarkers associated with nutrition and inflammation. Patients were asked to report their appetite and the percentage of food eaten (from 0% to 100%) during the last meal compared to usual intake. RESULTS: Fifty-eight (26%) patients reported food intake <= 50% (defined as poor appetite). The prevalence of anorexia was 12% by self-assessment of appetite, 6% by subjective assessment of appetite, 24% by VAS, 17% by FAACT score, and 12% by AQ. All the tools were significantly associated with food intake <= 50% (P < .001), except self assessment of appetite. The FAACT score and the VAS had the strongest association with food intake <= 50% (C-statistic 0.80 and 0.76). Patients with food intake <= 50% reported weight loss more frequently than patients without low intake (36% vs 22%) and weight gain less frequently (19% vs 35%; P = .03). Normalized protein catabolic rate was lower among anorexic patients based on the VAS (1.1 +/- 0.3 vs 1.2 +/- 0.3, P = .03). Ln interleukin-6 correlated inversely with food intake (P = .03), but neither interleukin-6 nor C-reactive protein correlated with any of the appetite tools. Furthermore, only the self-assessment of appetite was significantly associated with serum albumin (P = .02), prealbumin (P = .02) and adiponectin concentrations (P = .03). CONCLUSIONS: Alternative appetite assessment tools yielded widely different estimates of the prevalence of anorexia in HD. When considering self-reported food intake as the criterion standard for anorexia, the FAACT score and VAS discriminated patients reasonably well. PMID- 26522143 TI - Production of bioactive recombinant rat soluble receptor for advanced glycation end products (rrsRAGE) in Pichia pastoris. AB - Soluble receptor for advanced glycation end products (sRAGE), a natural inhibitor of RAGE, is considered to be a putative therapeutic molecule for a variety of diseases and a biomarker for certain conditions. To further study the function of sRAGE, recombinant rat sRAGE (rrsRAGE) was expressed and produced in a eukaryotic system. The open reading frame of rat sRAGE was cloned downstream of the methanol inducible alcohol oxidase promoter of pPICZalphaA vector, and Pichia pastoris strain X-33 was used as the host strain. The expression of rrsRAGE was achieved by fermentation in a 15-L bioreactor and the resulting fermentation broth was subjected to purification on a cation exchange chromatography column. The purification of rrsRAGE reached 95% after size exclusion chromatography(SEC). The bioactivity of the purified protein was confirmed in a SH-SY5Y cell proliferation assay. The biological function of the purified rrsRAGE protein rat CCl4-induced model was then examined. Treatment with rrsRAGE resulted in significantly lower liver fibrosis and lower serum level of ALT, suggesting that sRAGE prevent liver from injury and fibrosis. In conclusion, we achieved high-efficiency production of bioactive rrsRAGE in P. pastoris. PMID- 26522144 TI - Expression of NUCB2/nesfatin-1 in the taste buds of rats. AB - Nesfatin-1, an anorexigenic peptide derived from nucleobindin 2 (NUCB2), is closely involved in feeding behavior, glycometabolism, and satiety regulation. Some studies show that NUCB2/nesfatin-1 is highly expressed and interacts with many appetite-regulating peptides that are co-expressed in the gastrointestinal tract. However, it remains unclear whether nesfatin-1 is expressed and interacts similarly in taste buds. Glucagon-like peptide-1 (GLP-1), a well-known appetite down-regulating peptide, is associated with changes in the expression of nesfatin 1. Therefore, we measured the expression of the NUCB2 gene and the distribution of nesfatin-1-immunoreactive cells and investigated whether these variables change in taste buds of circumvallate papillae (CV) from rats with type 2 diabetes (T2DM) after treatment with liraglutide, a GLP-1 receptor agonist. The results showed that nesfatin-1 immunoreactive cells were localized in the taste buds of rat CV. Quantitative RT-PCR showed a significantly lower expression of NUCB2 mRNA in the taste buds of diabetic control rats (T2DM-C) than in those of the normal control group (NC) and a higher level of NUCB2 in the liraglutide treated group (T2DM + LIR) than either the T2DM-C or the NC groups. Changes in the expression of NUCB2 in the rat hypothalamus were opposite to those in CV taste buds. In summary, we found that rat CV taste buds express NUCB2/nesfatin-1, and that this expression decreases significantly in T2DM and increases after treatment with liraglutide in rat CV. This indicates that nesfatin-1 could be an important factor in the regulation of gustatory function, feeding and perhaps energy homeostasis. PMID- 26522145 TI - Age Differences in Reaction Times and a Neurophysiological Marker of Cholinergic Activity. AB - RESUME La deterioration du systeme cholinergique lors du vieillissement normal semble contribuer au declin de l'attention avec l'age. Nous avons examine l'effet potentiel de l'age sur la performance au " Attention Network Test " (ANT) ainsi que sur la variabilite intra-individuelle dans la vitesse des reponses a une tache go/no-go et a une tache de temps de reaction (TR) a choix multiples chez un groupe de jeunes adultes et de personnes agees en sante. Nous avons ensuite examine si un marqueur neurophysiologique de l'activite cholinergique derive de la stimulation magnetique transcranienne (i.e., inhibition afferente a courte latence; IACL) etait associe a la performance. Les personnes agees montraient un ralentissement au ANT ainsi qu'une plus grande variabilite intra-individuelle que les jeunes adultes a la tache de TR a choix multiples, mais il n'y avait pas de difference liee a l'age dans les scores refletant les reseaux attentionnels du ANT (vigilance, orientation aux stimuli et controle executif). Les niveaux de IACL etaient diminues chez les personnes agees, mais ils n'etaient pas associes a la performance. Il est possible que des relations entre le marqueur de l'activite cholinergique et l'attention emergent seulement en cas de deficits de neurotransmission severes. D'autres mecanismes corticaux pourraient aussi etre plus fortement associes aux fonctions liees a l'attention. PMID- 26522146 TI - Cellular distributions of monocarboxylate transporters: a review. AB - Lactate and ketone bodies play important roles as alternative energy substrates, especially in conditions with a decreased utility of glucose. Short-chain fatty acids (acetate, propionate, and butyrate), produced by bacterial fermentation, supply most of the energy substrates in ruminants such as the cow and sheep. These monocarboxylates are transfered through the plasma membrane by proton coupled monocarboxylate transporters (MCTs) and sodium-coupled MCTs (SMCTs). To reveal the metabolism and functional significance of monocarboxylates, the cellular localization of MCTs and SMCTs together with the expressed intensities holds great importance. This paper reviews the immunohistochemical localization of SMCTs and major MCT subtypes throughout the mammalian body. MCTs and SMCTs display a selective membrane-bound localization with porality. In contrast to the limited expression of SMCTs in the intestine and kidney, MCTs display a broader distribution pattern than GLUTs. The brain, kidney, placenta, and male genital tract express multiple subtypes of the MCT family. Determination of the cellular localization of MCTs is most controversial in the brain, possibly due to regional differences and the transcriptional modification of MCT proteins. Information on the localization of MCTs and SMCTs aids in understanding the nutrient absorption and metabolism throughout the mammalian body. In some cases, the body may use monocarboxylates as signal molecules, like hormones. PMID- 26522147 TI - A role of CD36 in the perception of an oxidised phospholipid species in mice. AB - CD36 is a broadly expressed transmembrane protein that engages multiple ligands, including polar lipids. This protein is thought to even contribute to the chemosensory detection of long-chain fatty acids in the oral cavity of rodents. In this study, we assessed whether animals consciously perceive a ligand of CD36, 1-(palmitoyl)-2-(5-keto-6-octanedioyl)phosphatidylcholine (KOdiA-PC), and if so, whether CD36 is involved in sensing the oxidised phospholipid species. We found that mice avoided or hesitated to ingest fluids containing KOdiA-PC, suggesting a conscious perception of the lipid in the animals. We assessed the involvement and role of CD36 in the KOdiA-PC perception by comparing the behavioural responses of wild-type and CD36-deficient mice to the test fluids, and provided evidence that the protein could play a role in sensing a lower level of the lipid. We also found that transection of the olfactory nerve of wild-type mice resulted in an inability to perceive KOdiA-PC, suggesting the significance of olfactory system in the lipid sensing. Our findings, coupled with the recent finding of CD36 expression in the mouse olfactory epithelium, led us to predict that the site of CD36 action in the KOdiA-PC sensing plausibly lies within the nasal cavity of the animal. PMID- 26522148 TI - Characteristics of podocyte injury in malignant hypertensive nephropathy of rats (MSHRSP/Kpo strain). AB - Proteinuria is not only a hallmark of renal complication in malignant hypertension, but is also a major deteriorating factor for the progression to end stage renal disease. Podocyte injury plays a crucial role in the renal damage associated with hypertensive nephropathy, but the underlying mechanism remains unclear. Malignant stroke-prone spontaneously hypertensive rats (MSHRSP/Kpo) represent an original and useful model of human malignant hypertension. In this study, we disclosed the glomerular injuries in the MSHRSP/Kpo. MSHRSP/Kpo exhibited elevated blood pressure at 6 weeks along with renal dysfunction and proteinuria. Histological analysis of the MSHRSP/Kpo glomeruli revealed a severe atrophy, but no change was found in the podocyte number. The expression levels of podocyte-specific proteins, nephrin, podocin, and synaptopodin were decreased in the MSHRSP/Kpo glomeruli, though another podocyte-specific protein, CD2AP, in the MSHRSP/Kpo glomeruli exhibited a similar extent of staining as in normotensive WKY/Kpo rats. Furthermore, desmin was not markedly detected in the WKY/Kpo glomeruli, but was strongly positive in MSHRSP/Kpo. By electron microscopy, well formed foot processes (FP) were replaced by effacement in MSHRSP/Kpo. An original malignant hypertension strain MSHRSP/Kpo exhibits podocyte injuries associated with the decrease of some podocyte-specific proteins and the upregulation of desmin, along with FP effacement and proteinuria. PMID- 26522149 TI - Genetic background-dependent diversity in renal failure caused by the tensin2 gene deficiency in the mouse. AB - Tensin2 (Tns2) is thought to be a component of the cytoskeletal structures linking actin filaments with focal adhesions and is known to play a role as an intracellular signal transduction mediator through integrin in podocytes, although the mechanism by which it functions remains unclear. A Tns2-null mutation (nph) leads to massive albuminuria following podocyte foot process effacement in the ICGN mice, the origin of the mutation, and the DBA/2J (D2) mice, but not in the C57BL/6J (B6) mice or 129(+Ter)/SvJcl (129T) mice. Elucidating the reasons for these differences in diverse genetic backgrounds could help in unraveling Tns2 function in podocytes. We produced congenic mice in which Tns2(nph) was introgressed into a FVB/NJ background (FVB-Tns2(nph)), and evaluated the progression of kidney disease. FVB-Tns2(nph) mice developed albuminuria, renal fibrosis and renal anemia as seen in ICGN mice. The FVB Tns2(nph) mice demonstrated podocyte foot process alteration under an electron microscope by as early as 4 weeks of age. This revealed that FVB strain is susceptible to Tns2-deficiency. PMID- 26522150 TI - Three-dimensional microanatomy of the pericapillary mesangial tissues in the renal glomerulus: Comparative observations in four vertebrate classes. AB - The renal glomeruli in lower vertebrates display mesangium-like cells and matrices interposed between the capillary endothelium and the basement membrane, while those in mammals reportedly lack such interpositions except in pathological conditions. By combined scanning and transmission electron microscopic observations, the pericapillary mesangial tissues were comparatively analyzed in four vertebrate classes: mammals (rats and rabbits), reptiles (green iguanas), amphibians (bullfrogs), and teleosts (carps). The observations discriminated three types of pericapillary interposition. The first, acellular interpositions, occurred universally, with mammalians displaying rudimental ones. This tissue type corresponded with extracellular matrices held in subendothelial grooves which were supported by fine endothelial projections anchored to the basement membrane. In lower vertebrates these grooves constituted an anastomosed system of subendothelial channels that communicated with the mesangial region, to favor cleaning of the glomerular filter. The second, compound type was specific to reptiles and amphibians, affecting the entire capillary circumference in the latter. In this tissue type, fine mesangial processes--which accompanied considerable amounts of fibrillar matrices--were loosely associated with the endothelial bases, indicating their possible nature as a kind of myofibroblast. Occurrence of the third, cellular interpositions was confined to small incidental loci in mammalian and teleost glomeruli. This tissue type was mostly occupied by thick processes or main bodies of the mesangial cells that tightly interlocked their short marginal microvilli with corresponding indentations on the endothelial bases. PMID- 26522151 TI - Brazilian propolis extract increases leptin expression in mouse adipocytes. AB - We investigated the anti-obesity effects of Brazilian green propolis ethanol extract using a mouse model of obesity. Repeated intraperitoneal injection of propolis (100 mg/kg twice a week) caused feeding suppression in C57BL/6 mice, whereas this treatment had negligible effects on C57BL/6 ob/ob mice. Since C57BL/6 ob/ob mice have a missense mutation in the Lep gene, leptin is likely to contribute to the propolis-induced feeding suppression. We found that propolis treatment indeed clearly increased leptin mRNA production in the visceral adipose tissues. Moreover, propolis extract directly elevated leptin expression in differentiated 3T3-L1 adipocytes. Artepillin C, an important organic compound found in Brazilian green propolis, failed to induce leptin mRNA in 3T3-L1 cells. Compounds other than artepillin C in Brazilian propolis must thus cause leptin induction in adipocytes, possibly resulting in the suppression of feeding and obesity. PMID- 26522153 TI - Latin America: rising to the challenge of cancer control. PMID- 26522152 TI - Toward rational thermostabilization of Aspergillus oryzae cutinase: Insights into catalytic and structural stability. AB - Cutinases are powerful hydrolases that can cleave ester bonds of polyesters such as poly(ethylene terephthalate) (PET), opening up new options for enzymatic routes for polymer recycling and surface modification reactions. Cutinase from Aspergillus oryzae (AoC) is promising owing to the presence of an extended groove near the catalytic triad which is important for the orientation of polymeric chains. However, the catalytic efficiency of AoC on rigid polymers like PET is limited by its low thermostability; as it is essential to work at or over the glass transition temperature (Tg) of PET, that is, 70 degrees C. Consequently, in this study we worked toward the thermostabilization of AoC. Use of Rosetta computational protein design software in conjunction with rational design led to a 6 degrees C improvement in the thermal unfolding temperature (Tm) and a 10 fold increase in the half-life of the enzyme activity at 60 degrees C. Surprisingly, thermostabilization did not improve the rate or temperature optimum of enzyme activity. Three notable findings are presented as steps toward designing more thermophilic cutinase: (a) surface salt bridge optimization produced enthalpic stabilization, (b) mutations to proline reduced the entropy loss upon folding, and (c) the lack of a correlative increase in the temperature optimum of catalytic activity with thermodynamic stability suggests that the active site is locally denatured at a temperature below the Tm of the global structure. PMID- 26522154 TI - Cancer registration and information systems in Latin America. PMID- 26522155 TI - Developments in paediatric care in Latin America. PMID- 26522156 TI - Cancer control in the English-speaking Caribbean. PMID- 26522157 TI - Progress and remaining challenges for cancer control in Latin America and the Caribbean. AB - Cancer is one of the leading causes of mortality worldwide, and an increasing threat in low-income and middle-income countries. Our findings in the 2013 Commission in The Lancet Oncology showed several discrepancies between the cancer landscape in Latin America and more developed countries. We reported that funding for health care was a small percentage of national gross domestic product and the percentage of health-care funds diverted to cancer care was even lower. Funds, insurance coverage, doctors, health-care workers, resources, and equipment were also very inequitably distributed between and within countries. We reported that a scarcity of cancer registries hampered the design of credible cancer plans, including initiatives for primary prevention. When we were commissioned by The Lancet Oncology to write an update to our report, we were sceptical that we would uncover much change. To our surprise and gratification much progress has been made in this short time. We are pleased to highlight structural reforms in health care systems, new programmes for disenfranchised populations, expansion of cancer registries and cancer plans, and implementation of policies to improve primary cancer prevention. PMID- 26522159 TI - Detection and characterization of integrative and conjugative elements (ICEs) positive Vibrio cholerae isolates from aquacultured shrimp and the environment in Shanghai, China. AB - Increasing industrialization and use of antimicrobial agents in aquaculture production, have led to heavy metals and multidrug resistant (MDR) pathogens becoming serious problems. These resistances are conferred in two ways: intrinsic and transfer via conjugation, or transformation by the major transmission mediators. Integrative and conjugative elements (ICEs) are one of the major mediators; however, few studies on ICEs of environmental origin have been reported in Asia. Herein, we determined the prevalence, antimicrobial susceptibility, heavy metal resistance and genotypes of 126 strains of Vibrio cholerae isolated from aquatic products and the environment in Shanghai, China. 92.3% of isolates were ICEs-positive from aquaculture water and 89.3% of isolates from shrimp showed MDR. Tracing the V. cholerae genotypes, showed no significant relevance of genotype among the antimicrobial resistance strains bearing the ICEs or not. Thus, in aquaculture, ICEs are not the major transmission mediators of resistance to antibiotics or heavy metals. PMID- 26522158 TI - Mechanistic basis of Nek7 activation through Nek9 binding and induced dimerization. AB - Mitotic spindle assembly requires the regulated activities of protein kinases such as Nek7 and Nek9. Nek7 is autoinhibited by the protrusion of Tyr97 into the active site and activated by the Nek9 non-catalytic C-terminal domain (CTD). CTD binding apparently releases autoinhibition because mutation of Tyr97 to phenylalanine increases Nek7 activity independently of Nek9. Here we find that self-association of the Nek9-CTD is needed for Nek7 activation. We map the minimal Nek7 binding region of Nek9 to residues 810-828. A crystal structure of Nek7(Y97F) bound to Nek9(810-828) reveals a binding site on the C-lobe of the Nek7 kinase domain. Nek7(Y97F) crystallizes as a back-to-back dimer between kinase domain N-lobes, in which the specific contacts within the interface are coupled to the conformation of residue 97. Hence, we propose that the Nek9-CTD activates Nek7 through promoting back-to-back dimerization that releases the autoinhibitory tyrosine residue, a mechanism conserved in unrelated kinase families. PMID- 26522160 TI - Bioremediation strategies of hydrocarbons and microbial diversity in the Trindade Island shoreline--Brazil. AB - This study analyzed the microbial diversity colonizing the surface of an oil sample during its contact with water, off the Trindade Island coast and simulated the efficiency of eight different bioremediation strategies for this environment. The diversity analysis was performed using acrylic coupons that served as the support for an oil inclusion at sea. The coupons were sampled over 30 days, and T RFLP multiplex was employed to access the diversity of fungi, Bacteria and Archaea present on the oil surface. The bioremediation strategies were simulated in a respirometer. The results showed that the bacterial domain was the most dominant in oil colonization and that the richness of the species attached to the oil gradually increases with the exposure time of the coupons. The combination of biostimulation and bioaugmentation with a native population was proven to be an effective strategy for the remediation of oil off the Trindade Island shoreline. PMID- 26522161 TI - Estimating the willingness to pay to protect coral reefs from potential damage caused by climate change--The evidence from Taiwan. AB - Coral reefs constitute the most biologically productive and diverse ecosystem, and provide various goods and services including those related to fisheries, marine tourism, coastal protection, and medicine. However, they are sensitive to climate change and rising temperatures. Taiwan is located in the central part of the world's distribution of coral reefs and has about one third of the coral species in the world. This study estimates the welfare losses associated with the potential damage to coral reefs in Taiwan caused by climate change. The contingent valuation method adopted includes a pre-survey, a face-to-face formal survey, and photo illustrations used to obtain reliable data. Average annual personal willingness to pay is found to be around US$35.75 resulting in a total annual willingness to pay of around US$0.43 billion. These high values demonstrate that coral reefs in Taiwan deserve to be well preserved, which would require a dedicated agency and ocean reserves. PMID- 26522162 TI - Number of bacteria decomposing organic phosphorus compounds and phosphatase activity in the sand of two marine beaches differing in the level of anthropopressure. AB - Number of heterotrophic bacteria ability to decompose organic phosphorus compounds and the level of phosphatase activity in the sand of two marine beaches (southern coast of the Baltic Sea) differing in the level of anthropopressure were studied. The study showed that the number of bacteria and level phosphatase activity were higher in the sand of the beach subjected to stronger anthropopressure. In both studied beaches bacteria hydrolysing DNA were the most numerous (92.7-302.8 CFU.g(-1) d.w.). The least numerous were phytin (26.0.10(3) CFU.g(-1) d.w.) and phenolphthalein diphosphate (11.1.10(3) CFU.g(-1) d.w.) decomposing bacteria. Number of bacteria able to attack tested organic phosphorus compounds were the most numerous in dry zones (10.77-739.92 CFU.g(-1) d.w.) then wet zones (3.34-218.15 CFU.g(-1) d.w.). In both studied beaches bacteria hydrolysing organic phosphorus compounds and phosphatase activity generally were more numerous in surface sand layer. Seasonal variation in the occurrence of bacteria in both studied beaches was observed. PMID- 26522163 TI - A fish-based index for assessing the ecological status of Polish transitional and coastal waters. AB - Fish assemblages are considered indicators of aquatic ecosystem quality. Based on how fish communities respond to anthropogenic pressures, we developed a multimetric fish index for evaluating the health of both coastal and transitional waters. Fish data were collected along the Polish coast in the years 2011, 2013 and 2014 using different types of gear. Redundancy analysis showed that the most important environmental factor affecting fish community was salinity. Responses to anthropogenic disturbances of 20 candidate metrics were tested by generalized linear models, taking into account salinity, sampling protocol and the proxy of human pressures described by the Baltic Sea Impact Index (BSII). Five selected metrics were combined in a Multimetric Index, which showed negative significant correlation with BSII. The index presented herein appeared to be a good tool for assessing the ecological state of highly impacted Polish transitional and coastal areas and complies with the Water Framework Directive requirements. PMID- 26522164 TI - East Asian seas: A hot spot of pelagic microplastics. AB - To investigate concentrations of pelagic micro- (<5mm in size) and mesoplastics (>5mm) in the East Asian seas around Japan, field surveys using two vessels were conducted concurrently in summer 2014. The total particle count (pieces km(-2)) was computed based on observed concentrations (pieces m(-3)) of small plastic fragments (both micro- and mesoplastics) collected using neuston nets. The total particle count of microplastics within the study area was 1,720,000 pieces km( 2), 16 times greater than in the North Pacific and 27 times greater than in the world oceans. The proportion of mesoplastics increased upstream of the northeastward ocean currents, such that the small plastic fragments collected in the present surveys were considered to have originated in the Yellow Sea and East China Sea southwest of the study area. PMID- 26522165 TI - Hydrodynamic evaluation of long term impacts of climate change and coastal effluents in the Arabian Gulf. AB - A comprehensive basin wide hydrodynamic evaluation has been carried out to assess the long term impacts of climate change and coastal effluents on the salinity and seawater temperature of the Arabian Gulf (AG) using Delft3D-Flow model. The long term impacts of climate change scenarios A2 and B1 of the IPCC-AR4 on the AG hydrodynamics were evaluated. Using the current capacity and production rates of coastal desalination, power, and refinery plants, two projection scenarios until the year 2080 with 30 year intervals were developed namely the realistic and the optimistic discharge scenarios. Simulations of the individual climate change scenarios ascertained overall increase of the AG salinity and temperature and decrease of precipitation. The changes varied spatially with different scenarios as per the depth, proximity to exchange with ocean water, flushing, vertical mixing, and flow restriction. The individual tested scenarios of coastal projected discharges showed significant effects but within 10-20 km from the outfalls. PMID- 26522166 TI - Dissecting the Molecular Roles of Histone Chaperones in Histone Acetylation by Type B Histone Acetyltransferases (HAT-B). AB - The HAT-B enzyme complex is responsible for acetylating newly synthesized histone H4 on lysines K5 and K12. HAT-B is a multisubunit complex composed of the histone acetyltransferase 1 (Hat1) catalytic subunit and the Hat2 (rbap46) histone chaperone. Hat1 is predominantly localized in the nucleus as a member of a trimeric NuB4 complex containing Hat1, Hat2, and a histone H3-H4 specific histone chaperone called Hif1 (NASP). In addition to Hif1 and Hat2, Hat1 interacts with Asf1 (anti-silencing function 1), a histone chaperone that has been reported to be involved in both replication-dependent and -independent chromatin assembly. To elucidate the molecular roles of the Hif1 and Asf1 histone chaperones in HAT-B histone binding and acetyltransferase activity, we have characterized the stoichiometry and binding mode of Hif1 and Asf1 to HAT-B and the effect of this binding on the enzymatic activity of HAT-B. We find that Hif1 and Asf1 bind through different modes and independently to HAT-B, whereby Hif1 binds directly to Hat2, and Asf1 is only capable of interactions with HAT-B through contacts with histones H3-H4. We also demonstrate that HAT-B is significantly more active against an intact H3-H4 heterodimer over a histone H4 peptide, independent of either Hif1 or Asf1 binding. Mutational studies further demonstrate that HAT-B binding to the histone tail regions is not sufficient for this enhanced activity. Based on these data, we propose a model for HAT-B/histone chaperone assembly and acetylation of H3-H4 complexes. PMID- 26522167 TI - Estimation of kinetic parameters of transcription from temporal single-RNA measurements. AB - Gene expression dynamics in prokaryotes is largely controlled by the multi-step process of transcription initiation whose kinetics is subject to regulation. Since the number and duration of these steps cannot be currently measured in vivo, we propose a novel method for estimating them from time series of RNA numbers in individual cells. We demonstrate the method's applicability on measurements of fluorescence-tagged RNA molecules in Escherichia coli cells, and compare with a previous method. We show that the results of the two methods agree for equal data. We also show that, when incorporating additional data, the new method produces significantly different estimates, which are in closer agreement with qPCR measurements. Unlike the previous method, the new method requires no preprocessing of the RNA numbers, using maximal information from the RNA time series. In addition, it can use data outside of the observed RNA productions. Overall, the new method characterizes the transcription initiation process with enhanced detail. PMID- 26522168 TI - Decadal trends of the upper ocean salinity in the tropical Indo-Pacific since mid 1990s. AB - A contrasting trend pattern of sea surface salinity (SSS) between the western tropical Pacific (WTP) and the southeastern tropical Indian Ocean (SETIO) is observed during 2004-2013, with significant salinity increase in the WTP and freshening in the SETIO. In this study, we show that increased precipitation around the Maritime Continent (MC), decreased precipitation in the western central tropical Pacific, and ocean advection processes contribute to the salinity trends in the region. From a longer historical record, these salinity trends started in the mid-1990s, a few years before the Global Warming Hiatus from 1998 to present. The salinity trends are associated a strengthening trend of the Walker Circulation over the tropical Indo-Pacific, which have reversed the long-term salinity changes in the tropical Indo-Pacific as a consequence of global warming. Understanding decadal variations of SSS in the tropical Indo Pacific will better inform on how the tropical hydrological cycle will be affected by the natural variability and a warming climate. PMID- 26522169 TI - The Effectiveness of Group-based Self-management Programmes to Improve Physical and Psychological Outcomes in Patients with Cancer: a Systematic Review and Meta analysis of Randomised Controlled Trials. AB - The purpose of this study was to determine if patients with cancer who participate in group-based self-management programmes have better physical and psychological outcomes than patients with cancer who do not participate in group based self-management programmes. A literature search was conducted in Ovid MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL, Web of Science and ProQUEST using the terms 'self-management' OR 'self-care' AND 'cancer' OR 'neoplasm'. Randomised controlled trials comparing outcomes for people with cancer participating in group-based self-management programmes with those not participating in these programmes were selected after screening by two reviewers. Initial searches yielded 563 articles. Two reviewers independently extracted data using piloted forms and assessed risk of bias using Cochrane's tool. Standard mean differences were calculated for continuous outcomes. The percentage of variability due to heterogeneity was assessed using I(2). A subgroup analysis was carried out where possible. Six trials were included in the review after 141 full-text articles were screened. Group-based self-management programmes were found to improve physical function [standard mean difference (95% confidence interval) = 0.34 (0.02, 0.65), P = 0.04]. No significant results were found between groups for quality of life [0.48 (-0.16, 1.11), P = 0.14] and physical activity level [0.21 (-0.07, 0.5), P = 0.15] outcomes. Group-based self-management programmes for individuals with cancer resulted in improvements in physical outcomes. However, considerable heterogeneity was found between the included studies and the quality of evidence was very low for all main outcomes. Therefore the results should be viewed with caution. PMID- 26522171 TI - K-12 School Food Service Staff Training Interventions: A Review of the Literature. AB - BACKGROUND: School food service professionals are vital to implementing national nutrition standards in school meal programs. Appropriate and effective training for these professionals may be one key to producing healthful meals that students are excited to eat and also meet United States Department of Agriculture (USDA) nutrient guidelines. A systematic literature review was conducted to understand the scope of interventions conducted with food service staff. METHODS: PubMed, Web of Knowledge, and Science Direct databases were searched for articles detailing school food service training interventions in K-12 school settings within the United States. RESULTS: Of 2341 articles retrieved, 17 articles describing 14 food service training interventions met the inclusion criteria. While food service staff training was an important component of many comprehensive school health and school meal interventions, there were few studies that specifically addressed school food service staff trainings. Although some best practices can be concluded from the current literature, major gaps in knowledge about effective school food service training interventions and validated research tools remain. CONCLUSIONS: As new professional standards are mandated by the USDA, a more thorough evaluation and understanding of best practices is vital to maximize the effectiveness of food service staff training. PMID- 26522170 TI - Trypanosome RNA editing: the complexity of getting U in and taking U out. AB - RNA editing, which adds sequence information to RNAs post-transcriptionally, is a widespread phenomenon throughout eukaryotes. The most complex form of this process is the uridine (U) insertion/deletion editing that occurs in the mitochondria of kinetoplastid protists. RNA editing in these flagellates is specified by trans-acting guide RNAs and entails the insertion of hundreds and deletion of dozens of U residues from mitochondrial RNAs to produce mature, translatable mRNAs. An emerging model indicates that the machinery required for trypanosome RNA editing is much more complicated than previously appreciated. A family of RNA editing core complexes (RECCs), which contain the required enzymes and several structural proteins, catalyze cycles of U insertion and deletion. A second, dynamic multiprotein complex, the Mitochondrial RNA Binding 1 (MRB1) complex, has recently come to light as another essential component of the trypanosome RNA editing machinery. MRB1 likely serves as the platform for kinetoplastid RNA editing, and plays critical roles in RNA utilization and editing processivity. MRB1 also appears to act as a hub for coordination of RNA editing with additional mitochondrial RNA processing events. This review highlights the current knowledge regarding the complex molecular machinery involved in trypanosome RNA editing. WIREs RNA 2016, 7:33-51. doi: 10.1002/wrna.1313 For further resources related to this article, please visit the WIREs website. PMID- 26522172 TI - Association Between Bullying Victimization and Health Risk Behaviors Among High School Students in the United States. AB - BACKGROUND: Childhood exposure to adverse experiences has been associated with adult asthma, smoking, sexually transmitted disease, obesity, substance use, depression, and sleep disturbances. Conceptualizing bullying as an adverse childhood experience, 2011 Youth Risk Behavior Survey (YRBS) data were used to examine the relationship between in-person and electronic bullying victimization among US high school students and health risk behaviors and conditions related to violence, substance use, sexual risk, overweight and physical activity, sleep, and asthma. METHODS: Data were from the 2011 national YRBS among students who answered questions about in-person and electronic bullying (N = 13,846). The YRBS is a biennial, nationally representative survey of students in grades 9-12 (overall response rate = 71%). Logistic regression analyses, stratified by sex and controlling for race/ethnicity and grade, examined the association between bullying victimization and health risk behaviors or conditions. RESULTS: Rates of victimization varied; 9.4% of students reported being bullied in-person and electronically, 10.8% only bullied in-person, 6.8% only electronically bullied, and 73.0% uninvolved. Bullying was associated with nearly all health risk behaviors and conditions studied. CONCLUSION: Assessing the broad functioning and behaviors of victims of bullying could enable educators and health practitioners to intervene early and promote the long-term health of youth. PMID- 26522173 TI - Multilevel Factor Structure and Concurrent Validity of the Teacher Version of the Authoritative School Climate Survey. AB - BACKGROUND: School climate is well recognized as an important influence on student behavior and adjustment to school, but there is a need for theory-guided measures that make use of teacher perspectives. Authoritative school climate theory hypothesizes that a positive school climate is characterized by high levels of disciplinary structure and student support. METHODS: A teacher version of the Authoritative School Climate Survey (ASCS) was administered to a statewide sample of 9099 7th- and 8th-grade teachers from 366 schools. The study used exploratory and multilevel confirmatory factor analyses (MCFA) that accounted for the nested data structure and allowed for the modeling of the factor structures at 2 levels. RESULTS: Multilevel confirmatory factor analyses conducted on both an exploratory (N = 4422) and a confirmatory sample (N = 4677) showed good support for the factor structures investigated. Factor correlations at 2 levels indicated that schools with greater levels of disciplinary structure and student support had higher student engagement, less teasing and bullying, and lower student aggression toward teachers. CONCLUSIONS: The teacher version of the ASCS can be used to assess 2 key domains of school climate and associated measures of student engagement and aggression toward peers and teachers. PMID- 26522174 TI - Associations of Truancy, Perceived School Performance, and Mental Health With Alcohol Consumption Among Adolescents. AB - BACKGROUND: This study examined associations of truancy, perceived school performance, and mental health with adolescents' week, weekend, and binge drinking. METHODS: A cross-sectional study was conducted among 1167 secondary school students of Dutch ethnicity (mean age, 15.9 years, SD = 0.69). Alcohol consumption, truancy, perceived school performance, and mental health status were assessed with self-report questionnaires. Ordinal regression analyses were performed to assess the associations. RESULTS: Truancy (odds ratio [OR] = 2.53; 95% confidence interval [CI], 1.70-3.77) and poorer mental health (OR = 1.04; 95% CI, 1.02-1.07) were associated with binge drinking more often. Truancy (OR = 1.89; 95% CI, 1.14-3.16) and poorer mental health (OR = 1.06; 95% CI, 1.02-1.09) were also associated with drinking (more) alcohol on week days. Furthermore, truancy (OR = 2.60; 95% CI, 1.76-3.83) and having an average (OR = 1.81; 95% CI, 1.19-2.77) or less than average (OR = 3.65; 95% CI, 1.93-6.90) perceived school performance were associated with drinking (more) alcohol on the weekend. CONCLUSIONS: Findings of this study suggest that adolescents who are truant and/or have a poor mental health status are at increased risk of binge and week drinking. Furthermore, adolescents who are truant and/or have an average or less than average perceived school performance are at increased risk of weekend drinking. PMID- 26522175 TI - Twelve-Month Effects of the COPE Healthy Lifestyles TEEN Program on Overweight and Depressive Symptoms in High School Adolescents. AB - BACKGROUND: We evaluated the 12-month effects of the COPE (Creating Opportunities for Personal Empowerment) Healthy Lifestyles TEEN (Thinking, Emotions, Exercise, Nutrition) program versus an attention control program (Healthy Teens) on overweight/obesity and depressive symptoms in high school adolescents. METHODS: A cluster randomized controlled trial was conducted. Participants were 779 culturally diverse adolescents in the US Southwest. COPE is a cognitive behavioral skills-building intervention with 20 min of physical activity integrated into a health course and taught by teachers once a week for 15 weeks. Outcome measures included body mass index (BMI) and depressive symptoms. RESULTS: COPE teens had a significantly lower BMI at 12 months (F(1,698) = 11.22, p = .001) than Healthy Teens (24.95 versus 25.48). There was a significant decrease in the proportion of overweight and obese COPE teens from baseline to 12 months (chi(2) = 5.40, p = .02) as compared with Healthy Teens. For youth who began the study with extremely elevated depressive symptoms, COPE teens had significantly lower depression at 12 months compared with Healthy Teens (COPE M = 42.39; Healthy Teens M = 57.90); (F(1 ,12) = 5.78, p = .03). CONCLUSIONS: COPE can improve long-term physical and mental health outcomes in teens. PMID- 26522176 TI - A Multilevel Study on Ethnic and Socioeconomic School Stratification and Health Related Behaviors Among Students in Stockholm. AB - BACKGROUND: This study examines the extent to which high alcohol consumption, drug use, and delinquency vary between schools with different socioeconomic characteristics, over and above the pupil's own sociodemographic background. METHODS: Analyses are based on data on 5484 ninth-grade students distributed over 93 schools in Stockholm, from the 2010 Stockholm School Survey. School-level information was retrieved from the Swedish National Agency for Education. School disadvantage was determined by combining information on the level of education among parents and the share of pupils with a nonnative background, 2 aspects that have been shown to be central to school segregation in Sweden. RESULTS: Results indicate significant school-to-school differences in relation to all outcomes. The risk for high alcohol consumption and drug use is greater in more advantaged school settings, adjusting for individual characteristics, whereas the opposite is true in relation to criminal behavior. The school's level of collective efficacy also seems to play an important, albeit not mediating, role. CONCLUSIONS: Regardless of an adolescent's own background, the risk of having adverse health behaviors is higher at certain schools compared to others. However, school socioeconomic factors do not influence health behaviors consistently; instead, it seems as if the association varies depending on the behavior under study. PMID- 26522177 TI - Physical Activity Intensity, Lesson Context, and Teacher Interactions During an Unstructured Afterschool Physical Activity Program. AB - BACKGROUND: Afterschool programs are promising arenas to improve youth physical activity (PA) levels. During the school year for 2012-2013, 5 elementary schools from a low-socioeconomic status (SES) school district in southern Colorado participated in evaluation of the afterschool program entitled Keep It Moving! (KIM). METHODS: In this cross-sectional analysis we sought to evaluate the relationships among participant PA, teacher interaction, and lesson context during an unstructured afterschool PA program. Participants were third-fifth grade students enrolled in the KIM program at the 5 participating elementary schools and were assessed utilizing accelerometers and direct observation with the System for Observing Fitness Instruction Time (SOFIT). RESULTS: Program participants wore the accelerometer 37.1 +/- 5.4 min session(-1). Approximately half of the time was spent in light PA (LPA) and 15.7 +/- 5.3 min session(-1) in moderate to vigorous PA (MVPA). Game play was positively associated with LPA and negatively associated with MVPA. When teachers did not promote PA with students there was a positive association with sedentary activity (SA) and a negative association with MVPA. CONCLUSIONS: Lesson context and teacher interactions may be important factors associated with PA intensity of afterschool PA programming. Future research should address whether structured PA curricula may improve quality of afterschool PA programming. PMID- 26522178 TI - Comparing School-Based Teen Pregnancy Prevention Programming: Mixed Outcomes in an At-Risk State. AB - BACKGROUND: The purpose of this study is to compare the effectiveness of a national comprehensive teen pregnancy prevention (TPP) intervention to a national abstinence-only TPP intervention on middle school students' knowledge, attitudes, and behaviors related to teen sexual behaviors in a state with high teen birth rates. METHODS: Pre- and post-intervention data were collected annually (2005 2010) from seventh-grade students to evaluate school-based TPP programs that implemented a comprehensive (N = 3244) or abstinence-only (N = 3172) intervention. Chi-square and t tests, logistic regressions, and hierarchical multiple regressions examined relationships between sexuality-related behavioral intentions, knowledge, and attitudes. RESULTS: Students in both interventions reported significant (p < .05) improvements post-intervention. Youth in the comprehensive TPP intervention were more likely (p < .05) to have significantly improved their attitudes (odds ratios [ORs] = 1.35, 1.83, 1.23) and behavior regarding abstinence decisions in the past 3 months (OR = 1.39). The interventions' improvements in attitudes were more explanatory for behavioral intentions for students in the abstinence-only intervention than for students in the comprehensive TPP intervention. CONCLUSIONS: The mixed results suggest the comprehensive TPP intervention was only slightly more effective than the abstinence intervention, but that changing student attitudes and perceptions may be a key component of more effective TPP interventions. PMID- 26522179 TI - Phenotype of 53 Chinese individuals with nicastrin gene mutations in association with familial hidradenitis suppurativa (acne inversa). PMID- 26522180 TI - Alignment of Gold Nanoparticle-Decorated DNA Origami Nanotubes: Substrate Prepatterning versus Molecular Combing. AB - DNA origami has become an established technique for designing well-defined nanostructures with any desired shape and for the controlled arrangement of functional nanostructures with few nanometer resolution. These unique features make DNA origami nanostructures promising candidates for use as scaffolds in nanoelectronics and nanophotonics device fabrication. Consequently, a number of studies have shown the precise organization of metallic nanoparticles on various DNA origami shapes. In this work, we fabricated large arrays of aligned DNA origami decorated with a high density of gold nanoparticles (AuNPs). To this end, we first demonstrate the high-yield assembly of high-density AuNP arrangements on DNA origami adsorbed to Si surfaces with few unbound background nanoparticles by carefully controlling the concentrations of MgCl2 and AuNPs in the hybridization buffer and the hybridization time. Then, we evaluate two methods, i.e., hybridization to prealigned DNA origami and molecular combing in a receding meniscus, with respect to their potential to yield large arrays of aligned AuNP decorated DNA origami nanotubes. Because of the comparatively low MgCl2 concentration required for the efficient immobilization of the AuNPs, the prealigned DNA origami become mobile and displaced from their original positions, thereby decreasing the alignment yield. This increased mobility, on the other hand, makes the adsorbed origami susceptible to molecular combing, and a total alignment yield of 86% is obtained in this way. PMID- 26522182 TI - Bronchoscopy in panendoscopy: review and assessment. AB - OBJECTIVE: To determine the utility of bronchoscopy to identify synchronous primaries in head and neck cancer patients. STUDY DESIGN: Case series with chart review. METHOD: The charts of all patients undergoing bronchoscopy between January 2008 and December 2013 were reviewed. Only those undergoing bronchoscopy as part of panendoscopy for head and neck cancer were included. Operative reports, pathology reports and discharge summaries were reviewed for operative findings, complications and length of hospital stay. RESULTS: A total of 404 charts were reviewed and 168 were included in the study. No synchronous primaries were identified. Bronchoscopy changed clinical management in one patient. There were no complications from bronchoscopy. CONCLUSION: Bronchoscopy is a safe and well-tolerated procedure commonly performed in the investigation of head and neck cancer patients, but it adds little additional useful clinical information. Routine performance of bronchoscopy in this setting should be weighed against its added costs, and tailored to the individual patient. PMID- 26522181 TI - Doxorubicin-induced necrosis is mediated by poly-(ADP-ribose) polymerase 1 (PARP1) but is independent of p53. AB - Necrosis, unregulated cell death, is characterized by plasma membrane rupture as well as nuclear and cellular swelling. However, it has recently been reported that necrosis is a regulated form of cell death mediated by poly-(ADP-ribose) polymerase 1 (PARP1). PARP1 is thought to mediate necrosis by inducing DNA damage, although this remains unconfirmed. In this study, we examined the mechanisms of PARP1-mediated necrosis following doxorubicin (DOX)-induced DNA damage in human kidney proximal tubular (HK-2) cells. DOX initiated DNA damage response (DDR) and upregulated PARP1 and p53 expression, resulting in morphological changes similar to those observed during necrosis. Additionally, DOX induced mitochondrial hyper-activation, as evidenced by increased mitochondrial respiration and cytosolic ATP (cATP) production. However, DOX affected mitochondrial mass. DOX-induced DNA damage, cytosolic reactive oxygen species (cROS) generation, and mitochondrial hyper-activation decreased in cells with inhibited PARP1 expression, while generation of nitric oxide (NO) and mitochondrial ROS (mROS) remained unaffected. Moreover, DOX-induced DNA damage, cell cycle changes, and oxidative stress were not affected by p53 inhibition. These findings suggest that DNA damage induced necrosis through a PARP1-dependent and p53-independent pathway. PMID- 26522183 TI - Bullying and school transition: Context or development? AB - The relative impact of school transition versus development on peer victimization and bullying perpetration were examined in a natural experiment involving 698 students where half transitioned into middle school from Grade 5 to Grade 6 and the other half remained in their elementary school over the same period. Results indicated that, on average, peer victimization decreased over the transition period while bullying perpetration remained stable for the whole sample. Multilevel modeling was used to investigate the effects of school transition and sex on changes in victimization and perpetration. Results indicated that the effect of transition status on changes in peer victimization was moderated by sex. Middle school transition status predicted decreases in peer victimization for girls, but not for boys, who transitioned. However, school transition status and participants' sex (and their interaction) did not predict changes in perpetration over time. Our findings indicate that changes in student involvement with peer victimization are better understood as a contextual rather than a typical developmental process, whereas bullying perpetration may be better understood as developmental. PMID- 26522185 TI - Editorial - Health Systems of Asia: Equity, Governance and Social Impact. PMID- 26522184 TI - A "methyl extension" strategy for polyketide natural product linker site validation and its application to dictyostatin. AB - An approach to the validation of linker strategies for polyketide natural products with few or no obvious handles for linker attachment, and its application to dictyostatin, are described. Analogues in which the C(6)- and C(12)-methyl groups were replaced by 4-azidobutyl groups were prepared and shown to retain the low nanomolar potency of dictyostatin. Further, conjugation of the C(6) analogue with a cyclooctyne resulted in only minor attenuations in potency. Together, these results shed light on the binding of dictyostatin to beta tubulin, establish a validated linker strategy for dictyostatin, and set the stage for the synthesis and study of dictyostatin conjugates. PMID- 26522186 TI - Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants. AB - Early-onset Alzheimer's disease (EOAD) accounts for 1%-2% of all Alzheimer's disease (AD) subjects, with large variation in the reported genetic contribution of known dementia genes. In this pilot study, we genetically characterized a German EOAD cohort (23 subjects) by whole-exome sequencing, capturing variants in all recognized AD and frontotemporal dementia genes. After variant filtering, we identified 7 events of altogether 6 different rare variants in 6 subjects, including 4 novel variants. Four of the 6 variants, observed in 5 different index subjects (5/23 = 22%), were considered to be possibly pathogenic. These included 2 presenilin 2 (PSEN2) variants (p.N141I-previously denoted as a Volga German variant, observed in 2 index subjects; and p.L238P), 1 amyloid precursor protein (p.I716M), and 1 presenilin 1 (DeltaE9). Using a control exome data set of 96 ethnically matched neurodegenerative disease controls (Parkinson's disease), we identified only 1 variant (PSEN2 p.T18M) (1%), demonstrating a significantly higher mutational burden in the EOAD group (p > 0.0001). Our findings demonstrate a substantial frequency of variants in dementia genes in EOAD, including several seemingly "sporadic" subjects. This indicates that heritability in EOAD might be higher than assumed. The finding of 3 subjects carrying potential pathogenic PSEN2 variants suggests that, in specific populations PSEN2 variants might be as frequent as (or more frequent than) presenilin 1, for example, in German populations which are influenced by Volga German heritage. Variants in AD genes were also associated with rare phenotypes such as frontal AD or primary progressive aphasia, demonstrating the need to screen AD genes in frontotemporal dementia-like phenotypes. PMID- 26522187 TI - A Rare Haemoglobin Variant Identified as K Woolwich in a Pakistani Male. AB - Haemoglobin (Hb) K Woolwich is a rare Hb variant which was first described in a family from West Indies and its occurrence was later reported mainly in Black families from many African countries. We report a case of a young male who came for evaluation of anemia. His complete blood count showed hypochromic, microcytic anemia and his serum ferritin was low. Hb electrophoresis done as part of initial workup showed an abnormal band which moved faster than HbA. For further evaluation, Hb analysis by high performance liquid chromatography was subsequently performed and revealed Hb K Woolwich. This is a rare Hb variant recognized in Pakistani population for the first time through careful interpretation of the chromatographic behavior of the Hb. PMID- 26522188 TI - Neuromyelitis Optica (NMO) with Abdominal Tuberculosis (TB). AB - Neuromyelitis Optica (NMO), previously regarded as a form of multiple sclerosis, is defined by Gault and Devic, as a retrobulbar neuritis or papillitis accompanied by acute myelitis and occasionally other neurological symptom or signs not restricted to the spinal cord or optic nerves. With the diagnosis of specific antibodies, probable role of humoral immunity supports its pathogenesis. Only a few cases of NMO have been reported in association with pulmonary tuberculosis (TB). Here we report a case of young girl with acute onset paraplegia diagnosed to have NMO, who later on during hospital stay developed ascites which cultured positive for Mycobacterium tuberculosis. This association of abdominal TB with NMO is under-reported in literature. PMID- 26522189 TI - Co-existent Ascariasis and Multiloculated Tuberculous Pleurisy Treated with Intrapleural Streptokinase. AB - This case describes a young male with pleuro-pulmonary tuberculosis having one week history of fever and hemoptysis along with a multiloculated right sided exudative lymphocytic pleural effusion. His pulmonary diagnostic confusion was due to passage of adult Ascaris lumbricoides per orally but that was found to be of intestinal origin. Pleural tissue histopathology revealed necrotizing granulomatous inflammation and right upper lobe bronchial washings were positive for acid fast bacilli. His multiloculated pleural effusion was successfully resolved with intrapleural streptokinase injections via a 10 French pleural catheter. Treatment with class-I anti-tuberculous drugs led to complete clearance of remaining pleuro-pulmonary shadowing. PMID- 26522190 TI - Dengue Hemorrhagic Fever Complicated by Intercostal Artery Hemorrhage. AB - Hemorrhagic manifestations are fairly common in Dengue hemorrhagic fever and are associated with increased mortality. During last few decades there have been increasing reports of Dengue infection with unusual manifestations. Here we present a case of dengue hemorrhagic fever complicated by spontaneous rupture of an intercostal artery leading to a large hematoma which was treated successfully with angio-embolization. To the authors' knowledge this is a first case of dengue hemorrhagic fever complicated by spontaneous intercostal artery hemorrhage. PMID- 26522191 TI - Giant Pleomorphic Adenoma of the Parotid Gland. AB - Salivary gland tumours are a relatively rare entity. Pleomorphic adenoma is the most common amongst these, comprising 60 - 70% of all parotid tumours. Pleomorphic adenomas are benign and tend to increase in size slowly. Here we are presenting a case of giant pleomorphic adenoma of the parotid, being the largest in size to be excised in Pakistan in recorded literature measuring 24 x 22 x 12 cm and weighing 1.8 kgs. Superficial parotidectomy was done with an excellent cosmetic outcome. PMID- 26522192 TI - Amyloidosis with Multiple Myeloma Presenting with Acromegalic Features. AB - Amyloidosis and multiple myeloma are included in the same spectrum of clonal plasma cell disorders. Amyloidosis can present with localized deposits or manifest as systemic disease involving multiple organs. Here we are reporting a case of an elderly female, having amyloidosis leading to facial disfigurement and neuropathy for many years and then presenting with concomitant multiple myeloma as an incidental diagnosis with no typical symptoms related to it at all. PMID- 26522193 TI - An Unusual Cause of Right Iliac Fossa Pain: Caecal Diverticulum Perforation. AB - Caecal diverticulum perforation is a rare condition. It mimics acute appendicitis and is seldom suspected pre-operatively. Commonly it is discovered during exploration. Ultrasonography and computed tomography are helpful in the diagnosis of the condition. There is controversy regarding the surgical treatment. We are presenting the case of a 44-year male who underwent exploration for suspected acute appendicitis but was found to have a perforated solitary caecal diverticulum. Patient underwent diverticulectomy and made an uneventful recovery. PMID- 26522194 TI - Sildenafil in Cystic Hygroma. AB - Cystic hygroma is a benign congenital malformation of the lymphatic system. Most of the cystic hygromas are found in the neck; other rare locations include axilla, mediastinum, and limbs. Symptoms range from mere presence of lesions to gross morbidity secondary to compression of adjacent organs, infection, hemorrhage etc. Treatment is primarily aimed at complete surgical resection. Other treatment modalities include sclerotherapy, radiotherapy and laser ablation as well as medical therapy with sirolimus but recurrence rate is high. We present a neonate with right sided cystic hygroma whose lesion settled completely with sildenafil. PMID- 26522195 TI - Laparoscopic Adrenalectomy for Ovarian Metastasis and Underlying Horse Shoe Kidney. AB - Adrenal metastasis from ovarian malignancy is extremely rare. Very few cases in literature have reported surgical removal of isolated adrenal metastasis in patients with ovarian carcinoma. Presence of horse shoe kidney can impose technical challenges in patients planned for laparoscopic adrenalectomy. A52 years female with high grade serous carcinoma ovary, horse shoe kidney and previous history of two laparotomies for primary malignancy developed adrenal metastasis 3 years after diagnosis of the primary lesion. She underwent laparoscopic left adrenalectomy in right lateral position. She was discharged on the second postoperative day. Laparoscopic adrenalectomy for ovarian metastasis in a patient with horse shoe kidney has not been reported before. Surgical resection of solitary adrenal metastasis offers survival benefit and laparoscopic resection should always be a treatment option in these patients. PMID- 26522196 TI - Ultrasound Diagnosis of Penile Fracture. AB - A rare but possibly underreported urological emergency is penile fracture which results from tear in the tunica albuginea of the penis. The proposed etiology is forceful manipulation of an erect penis or secondary to blunt trauma. We would like to report a case of young patient presenting with large penile shaft hematoma and deformity. The patient did not provide obvious history of trauma or sexual intercourse. The ultrasound of penis was performed which suggested the diagnosis of penile fracture and ultrasound findings were correlated with peroperative findings. PMID- 26522197 TI - Aleukemic Myeloid Sarcoma of the Breast. AB - Myeloid sarcoma is a solid collection of leukemic blast cells outside bone marrow. It is seen infrequently in association with overt Acute Myeloid Leukemia (AML), however, it invariably transforms into this aggressive condition. A28-year woman presented with a lump in left breast for last 2 years. Morphological and immunophenotypic results of breast mass were consistent with myeloid sarcoma. Bone marrow aspirate and biopsy were normal, however, patient died after one and a half years of diagnosis. Myeloid sarcoma at any extramedullary site heralds development of overt acute myeloid leukemia and should be appropriately managed at the time of diagnosis. PMID- 26522198 TI - Fraser Syndrome. AB - Fraser's Syndrome (FS) is a rare autosomal recessive disorder with a spectrum of malformations. The most consistent features are Cryptophthalmos (CO), syndactyly, genitourinary tract abnormalities, laryngeal and tracheal anomalies, craniofacial dysmorphism, malformations of the ear and nose, orofacial clefting and musculoskeletal defects. FS is genetically heterogeneous; so far mutations in FRAS1, FREM2 and GRIP1 genes have been linked to FS. FS can be diagnosed on clinical examination, pre-natal ultrasound or perinatal autopsy. We present a case of a 3 months old child born to consanguineous healthy parents with bilateral complete CO, unilateral microphthalmia, hypertelorism, syndactyly (hands and feet bilaterally), ambiguous genitalia with cryptorchidism and an umbilical hernia. We also present the criteria for diagnosing FS and the significant features on pre-natal ultrasonography. Around 200 case reports of patients with FS and CO have been published. To our knowledge, this is the first reported case of FS in Pakistan. PMID- 26522200 TI - Oral Leiomyoma in Retromolar Trigone. AB - Leiomyoma is benign tumour arising from smooth muscle that occurs between 40 and 49 years of age. Leiomyomas are a rare entity in the oral cavity and if present they are usually localized on tongue, lips and palate. Leiomyoma appears to be well-defined mass, with slow growth. The treatment is surgical excision. We report a 10-year girl child, with a lump in the right retromolar trigone region intraorally. Excisional biopsy performed under general anaesthesia revealed the specimen to be a leiomyoma. The low incidence of this pathology, the age of the patient and the location are unusual. PMID- 26522199 TI - Oral Manifestations of Osteopetrosis. AB - Osteopetrosis is a hereditary disorder of bone characterized by sclerosis of bone and decreased marrow spaces. Due to depressed marrow function, this disorder can cause anemia, hepatosplenomegaly, recurrent infections and osteomyelitis of jaw. Excessive bone deposition in skull base leads to narrowing of foramina and cranial nerve compression. Bone marrow transplantation is the only curative treatment. Other treatments, like interferon gamma, corticosteroids, parathormone and erythropoietin are also used for management. Transfusion of blood, debridement of wound and antibiotics is used to manage complications. Due to its rarity, it is always difficult to diagnose osteopetrosis. Proper diagnosis and treatment decreases the long-term sequelae of the disease. PMID- 26522201 TI - Post-Traumatic Bilateral Facial Paralysis Associated with Temporal Bone Fracture. AB - Bilateral traumatic facial paralysis is a very rare clinical condition. Loss of taste sensation, associated with bilateral traumatic paralysis, is even rarer and has not been well described in the literature. In this report, a 23-year old male, who developed bilateral facial paralysis with loss of taste sensation and hearing impairment, following a motor vehicle accident, is presented. He had initially presented with unconsciousness for about 2 hours after he sustained closed head injury after a motor vehicle accident. Initial Computed Tomography (CT) scans revealed a small epidural hematoma, right temporal bone fracture and air densities around the basal cistern. On the 4th day after trauma, he was noted to have incomplete closure of both eyes and was feeling difficulty with chewing and drooling of saliva. Electrodiagnostic testing confirmed the diagnosis of bilateral facial paralysis-House-Brackmann (HB) grade V. Electroneuronography (ENoG) showed degeneration of 90% nerve fibres bilaterally. The high-resolution CT scans showed bilateral temporal bone fractures. At 3 months of follow-up, the patient had partial recovery of facial nerve function bilaterally and improvement in HB classification to grade III and ENoG of 60% was observed. PMID- 26522202 TI - Celiac Crisis in Refractory Celiac Disease Type I with Neurological Manifestations: A Diagnostic Dilemma. AB - Celiac crisis is a life-threatening condition in which patients have profuse diarrhea and severe metabolic disturbances. Refractory Celiac Disease (RCD) is a rare condition defined as persistence of symptoms despite being on Gluten Free Diet (GFD) for 6 months. Neurological involvement in Celiac Disease (CD) is seen in around 8 - 10% of adult patients; however, it is rare in children. Herein we present a case of an adolescent presenting with neurological symptoms and celiac crisis and diagnosed as RCD, type 1. He was treated with high dose steroids. This case underscores the need to consider RCD in patients presenting in celiac crisis and showing no improvement on GFD. PMID- 26522203 TI - Symptomatic Early Congenital Syphilis: A Common but Forgotten Disease. AB - Congenital syphilis is a severe, disabling infection often with grave consequences seen in infants. It occurs due to the transmission of the disease from an infected mother to the unborn infant through the placenta. Congenital syphilis can involve any organ system and present with various symptoms. However, early diagnosis of congenital syphilis is difficult because more than half of the affected infants are asymptomatic, and the signs in symptomatic infants may be subtle and nonspecific. The continuing prevalence of this disease reveals the failure of control measures established for its prevention. Here we report a case of a one-month infant who presented with skin rash. The report stresses upon the importance of implementing the World Health Organization's recommendation that all pregnant women should be screened for syphilis in the first antenatal visit in the first trimester and again in the late pregnancy. PMID- 26522204 TI - Isolated Penile Fournier's Gangrene Presenting with Glans Penis Involvement. AB - Fournier's Gangrene (FG) is a type of necrotizing infection or gangrene usually affecting the perineum. Penile gangrene is a rare disease because of rich collateral circulation and blood flow in the perineum and lower abdomen. We report an unusual and rare presentation of FG with isolated glans penis necrosis in a 62-year-old man. The patient underwent subtotal penectomy and closure of the wound with penile skin flap after covering the spongious tissue with dartos fascial flap enclosing the urethra. The recovery phase was uneventful and the patient had no urinating symptoms during follow-up. PMID- 26522206 TI - Special Supplement of Case Reports. PMID- 26522205 TI - Successful Repair of a Pseudoaneurysm of Renal Allograft Artery. AB - Aneurysm of renal artery is a rare vascular complication after renal transplantation. A 60 years man showed an aneurysm of the renal artery in the transplanted kidney was an incidental finding on routine abdominal ultrasound. The function of the allograft was stable. A magnetic resonance angiogram confirmed the diagnosis. Considering a very high risk of rupture due to its size (6.0 x 4.9 x 4.7 cm), and the organ being his only functional kidney, it was decided to perform an open surgical repair. Midline laparotomy was performed, allograft was mobilised, the aneurysm was resected and dacron patch arterioplasty was done. The patient had an uneventful recovery and his renal function returned to pre-operative levels by the fifth postoperative day. The patient was discharged home with regular monthly follow-up for 6 months. PMID- 26522207 TI - Septic Shock Due to Biliary Stones in a Postcholecystectomy Patient. AB - Septic shock leading to multi-organ failure is not uncommon. Early diagnosis to confirm the source is the distinctive attribute of sepsis management guidelines. Cholangitis as the source of sepsis can become a diagnostic dilemma in patients who have had cholecystectomy in the past. CT abdomen should be the investigation of choice in this group of patients. This report describes two postcholecystectomy patients who presented with septic shock secondary to biliary stones. The source of septic shock in both patients were biliary stones was confirmed with abdominal CT. Ultrasound abdomen failed to report biliary stones in these patients. Both improved on percutaneous transhepatic biliary drainage. PMID- 26522208 TI - Neurofibromatosis: Challenge for Anaesthetist. AB - Neurofibromatosis type 1 (NF-1) is an autosomal dominant neurocutaneous syndrome which is characterized by formation of neurofibromas all over the skin and various other body systems. The anaesthetic management of these patients requires attention to all possible abnormalities and associated disturbances to prevent any peri-operative complication. NF-1-associated complications of the musculoskeletal, respiratory, cardiovascular, central nervous, and gastrointestinal and genitourinary systems present with various degrees of considerations for anaesthesiologists. While evaluating and managing these patients for surgical procedures. NF-1 or von Recklinghausen disease, is an autosomal dominant disease with incidence of approximately 1/3000 births. Gastrointestinal (GI) neoplasms are present in about 2 - 25% of patients of NF-1. In these patients, neurofibromas are the most frequently (52%) diagnosed benign neoplasms. Patients with NF-1 and GI symptoms are at risk for gastrointestinal neoplasms; symptomatic patients are likely to experience significant morbidity. This report describes the anaesthetic of a patient with NF-1 and gastric outlet obstruction. PMID- 26522209 TI - Acquired Tracheo-oesophageal Fistula: A Challenging Complication of Tracheostomy. AB - Acquired tracheo-oesophageal fistula (TEF) after tracheostomy is a life threatening complication and can occur in about 1% of cases of tracheostomy. Percutaneous tracheostomy was performed in intensive care unit on a 40 years male patient for long-term mechanical ventilation. Subsequently patient developed TEF as the complication of tracheostomy. He was initially managed with endoscopically inserted self expanding plastic stent but later on required surgery for definitive repair. The problems associated with acquired TEF and its management are discussed hereby. PMID- 26522210 TI - Percutaneous Coronary Intervention Under Cover of Left Ventricular Assist Device (Impella 2.5). AB - Impella 2.5 is a temporary left ventricular assist device that is being increasingly used in high risk Percutaneous Coronary intervention (PCI). It reduces the cardiac workload and provides assistance to myocardium and vital organs in states of severe left ventricular dysfunction and cardiogenic shock. We report the first case of successful percutaneous coronary stenting performed in a high risk patient using impella 2.5. A 65-year old diabetic and hypertensive male with a known double vessel coronary artery disease and a reduced left ventricular function (ejection fraction, 20%) was admitted with intractable angina. He was on optimal medical treatment for 2 months. His coronary angiogram done 2 months back had revealed double vessel coronary artery disease (subtotally occluded co dominant left circumflex and moderate 60% stenosis in left anterior descending artery and a normal co-dominant right coronary artery). He was considered a high risk both for Coronary Artery Bypass Graft (CABG) surgery and PCI due to co morbidities and reduced left ventricular function. As he had failed a trial of optimal medical therapy and the cardiac surgeon's reluctance for surgery, the patient and his family was counseled for high risk PCI with left ventricular assist device using the impella 2.5. PMID- 26522211 TI - Chemotherapy Induced Acute Pericarditis in a Child. AB - A9 years boy diagnosed with nasopharyngeal carcinoma was started on chemotherapy protocol including 5-fluorouracil. After 90 hours of 5-fluorouracil infusion, he developed severe retrosternal chest pain. Electrocardiography showed signs of acute pericarditis and was managed with ibuprofen and 5-fluorouracil was discontinued. The 5-fluorouracil rarely causes cardiac complications such as angina pectoris and pericarditis in adult patients. We report acute myopericarditis in a child caused by 5-fluorouracil, which is a very rare complication of 5-fluorouracil in pediatric age group. PMID- 26522212 TI - Dual Ectopy of Thyroid Tissue: Intratracheal and in Nasopharynx, Associated with Normally Located Thyroid. AB - Dual ectopic thyroid tissue associated with normally located thyroid, is a rare anomaly. We report a case of 42 years lady, who underwent left hemithyroidectomy for nodules in the left lobe of thyroid 15 years back. She presented with right side neck swelling and dyspnea for 6 months. Right hemithyroidectomy was done for multinodular goiter involving right lobe of thyroid. She developed stridor on the first postoperative day. CT scan and MRI showed intratracheal ectopic thyroid tissue. Ectopic thyroid tissue was removed by dividing cricoid cartilage, and trachea was repaired. Radio iodine scan after 6 weeks showed another ectopic thyroid tissue in nasopharynx. Patient refused for radio iodine ablation and, she was given thyroxin replacement. PMID- 26522213 TI - Laparoscopic Management of Primary Segmental Omental Infarction Mimicking Acute Appendicitis. AB - Primary Segmental Infarction (PSI) of the greater omentum is rare. It usually presents as acute appendicitis and the diagnosis is made per operatively. We report a case of 22 years male who presented with history and clinical features suggestive of acute appendicitis. Laparoscopic appendicectomy was planned but during diagnostic laparoscopic phase, omentum was found infarcted in the right lower abdomen and the appendix was normal. Laparoscopic omentectomy of the infarcted segment was done and the patient had smooth recovery. PMID- 26522214 TI - Parietolith: A Late Complication of Spilled Gallstones. AB - Sub-costal port site abscess and sinus formation secondary to spilled gallstones during laparoscopic cholecystectomy is extremely rare, however such complications at umbilical port site has been described in literature. We present one such case in an elderly diabetic female. Spilled stones migrating to the port site should be kept in mind in a patient presenting with chronic discharging sinus at any of the laparoscopic port sites after laparoscopic cholecystectomy. PMID- 26522215 TI - Hemoperitoneum Due to Warfarin Toxicity Presenting as Intestinal Obstruction. AB - The patients on anticoagulation therapy especially warfarin can develop gastrointestinal bleed, gum bleeding, hematuria or ecchymosis. Rarely do such patients present with hemoperitoneum producing symptoms. Hemoperitoneum can produce shock, cause compression symptoms or may even be fatal. Such patients can be managed conservatively or may need surgical exploration for ongoing bleeding or decompression. We had a patient taking warfarin who presented with hemoperitoneum producing intestinal symptoms. The patient was managed conservatively with fluid and blood product replacement and stopping warfarin. The benefits of thromboprophylaxis and the risks of bleeding should be carefully evaluated and the dose of warfarin carefully adjusted. PMID- 26522216 TI - Giant Bilateral Juvenile Fibroadenoma of the Breast in Prepubescent Girl. AB - Juvenile fibroadenoma accounts for 4% of the total fibroadenomas. Giant juvenile fibroadenoma is found in only 0.5% of all fibroadenomas. The authors report a 10 year girl presenting with progressive enlargement of both breasts for one year. Based on clinical findings and Fine Needle Aspiration Cytology (FNAC), a diagnosis of bilateral giant juvenile fibroadenomas of breast was made. She underwent bilateral lumpectomy with breast conservation and made uneventful postoperative recovery. PMID- 26522217 TI - Upshaw-Schulman Syndrome. AB - A13 years girl presented with history of sudden onset fits, altered sensorium and anuria for 2 days. There was also history of right sided weakness of the whole body. Past history revealed repeated episodes of similar complaints since early childhood. On the basis of history, physical examination and extensive investigations, patient was diagnosed as Upshaw-Schulman syndrome, a rare case of congenital Thrombotic Thrombocytopenic Purpura (TTP). She is now in remission and being maintained on twice weekly transfusions of Fresh Frozen Plasma (FFP). PMID- 26522218 TI - Bone health and its correlates in Korean prostate cancer patients receiving androgen deprivation therapy. AB - PURPOSE: This study aimed to examine bone health status, identify factors associated with bone mineral density (BMD), and determine potential risk factors for osteoporosis in Korean prostate cancer patients receiving androgen deprivation therapy (ADT). METHODS: Using a cross-sectional descriptive design, we recruited 139 men with prostate cancer receiving ADT at two university-based hospitals in South Korea. Participants completed a self-reported questionnaire and underwent dual energy X-ray absorptiometry testing. BMD (gm/cm(2)), bone health status (normal BMD, osteopenia, and osteoporosis), and lifestyle variables (physical activity, smoking, and alcohol consumption) were measured. RESULTS: The prevalence in our sample was 49.6% for osteopenia and 17.3% for osteoporosis. In multivariate linear regression analyses, BMD was positively associated with body mass index, number of comorbidities, and level of physical activity and negatively associated with being unemployed or retired, having a lower monthly income, and being treated with gonadotropin-releasing hormone therapy alone. In logistic regression analyses, potential risk factors for osteoporosis were low monthly income (OR = 4.33, p = 0.011), receipt of radiation therapy (OR = 4.69, p = 0.018), and lack of regular physical activity (OR = 2.63, p = 0.035). CONCLUSIONS: Our results suggest that a proportion of prostate cancer survivors who are receiving ADT warrant monitoring to prevent osteoporosis, particularly men of lower economic status and those having lower levels of physical activity. Nurses can play an important role in screening these high risk groups. PMID- 26522219 TI - The relationship between essential tremor and Parkinson's disease. AB - Essential tremor (ET) and Parkinson's disease (PD) are the two most common tremor disorders encountered in a movement disorders clinic. Although distinct clinical pathological entities, both disorders may share overlapping features in addition to rest and postural tremor, such as bradykinesia, rigidity, gait and balance impairment and some non-motor signs. A subset of patients may have a combination of long-standing ET with subsequent PD (ET-PD). There are several lines of evidence from clinical, epidemiologic, imaging, genetic and pathologic studies supporting a link between ET and PD, greater than by chance alone. In this review we will discuss the latest data supporting a relationship between ET and PD and the implications for possible pathogenic link and treatment. PMID- 26522220 TI - Current perspectives of molecular pathways involved in chronic inflammation mediated breast cancer. AB - Inflammation has multifaceted role in cancer progression including initiation, promotion and invasion by affecting the immune surveillance and associated signaling pathways. Inflammation facilitates the over-expression of cytokines, chemokines and growth factors involved in progression of different cancers including breast cancer progression. Deregulation of biological processes such as oxidative stress, angiogenesis, and autophagy elicit favorable immune response towards chronic inflammation. Apart from the role in carcinogenesis, chronic inflammation also favors the emergence of drug resistance clones by inducing the growth of breast cancer stem-like cells. Immunomodulation mediated by cytokines, chemokines and several other growth factors present in the tumor microenvironment regulate chronic inflammatory response and alter crosstalk among various signaling pathways such as NF-kappaB, Nrf-2, JAK-STAT, Akt and MAPKs involved in the progression of breast cancer. In this review, we focused on cellular and molecular processes involved in chronic inflammation, crosstalk among different signaling pathways and their association in breast cancer pathogenesis. PMID- 26522221 TI - Amyloid-beta peptide increases cell surface localization of alpha7 ACh receptor to protect neurons from amyloid beta-induced damage. AB - Amyloid-beta peptide 1-42 (Abeta1-42) reduced PC-12 cell viability in a concentration (1-10 MUM)- and treatment time (48-72 h)-dependent manner. Nicotine prevented Abeta1-42-induced PC-12 cell death, but conversely, the alpha7 ACh receptor antagonist alpha-bungarotoxin enhanced Abeta1-42-induced cell toxicity. Extracellularly applied Abeta1-42 significantly increased cell surface localization of alpha7 ACh receptor in PC-12 cells as compared with that for non treated control cells. Cell surface localization of alpha7 ACh receptor in the brain of 5xFAD mouse, an animal model of Alzheimer's disease (AD), apparently increased in an age (1-12 months)-dependent manner in association with increased accumulation of Abeta1-42 in the plasma membrane component. Taken together, these results indicate that Abeta1-42 promotes translocation of alpha7 ACh receptor towards the cell surface and that alpha7 ACh receptor rescues neuronal cells from Abeta1-42-induced damage. PMID- 26522222 TI - Sirtuin 1 participates in the process of age-related retinal degeneration. AB - BACKGROUND: The process of aging involves retinal cell damage that leads to visual dysfunction. Sirtuin (Sirt) 1 can prevent oxidative stress, DNA damage, and apoptosis. In the present study, we measured the expression of Sirt1 as a functional regulator in the retina during the aging process. METHODS: The visual function and Sirt1 expression in young (1 month) and old (19 months) Sprague Dawley (SD) rats. Electroretinogram (ERG) and real-time polymerase chain reaction (PCR) or Western blotting were performed. Resveratrol, an activator of Sirt1, was orally administered to SD rats at a dose of 5 mg/kg/day for 19 months. The expression of Sirt1, brain-derived neurotrophic factor (BDNF), and tropomyosin receptor kinase B (TrkB) was evaluated in the retinas of mice that did and did not receive resveratrol treatment. Apoptosis was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. RESULTS: With decreasing b-wave amplitude, the expression level of Sirt1 was significantly reduced in aged retinas compared to that in young retinas. After 19 months of treatment with resveratrol, the Sirt1 expression level and b-wave amplitude increased. In old rats treated with resveratrol, the expression levels of BDNF and TrkB were up-regulated. Compared to young retinas, the aged retinas exhibited higher apoptosis, but resveratrol delayed this process. CONCLUSIONS: Our data demonstrated a reduction of Sirt1 expression during the aging process of the retina, but enhancing Sirt1 expression reversed the degeneration of the retina. These results suggested that increasing Sirt1 expression may protect retinal neurons and visual function via regulating neurotrophin and its receptor. PMID- 26522223 TI - Elevated beta-catenin activity contributes to carboplatin resistance in A2780cp ovarian cancer cells. AB - Ovarian cancer is the fifth leading cause of cancer-related mortalities in women. Epithelial ovarian cancer (EOC) represents approximately 90% of all ovarian malignancies. Most EOC patients are diagnosed at advanced stages and current chemotherapy regimens are ineffective against advanced EOC due to the development of chemoresistance. It is important to better understand the molecular mechanisms underlying acquired resistance to effectively manage this disease. In this study, we examined the expression of the Wnt/beta-catenin signaling components in the paired cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) EOC cell lines. Our results showed that several negative regulators of Wnt signaling are downregulated, whereas a few Wnt ligands and known Wnt/beta-catenin target genes are upregulated in A2780cp cells compared to A2780s cells, suggesting that Wnt/beta-catenin signaling is more active in A2780cp cells. Further analysis revealed nuclear localization of beta-catenin and higher beta-catenin transcriptional activity in A2780cp cells compared to A2780s cells. Finally, we demonstrated that chemical inhibition of beta-catenin transcriptional activity by its inhibitor CCT036477 sensitized A2780cp cells to carboplatin, supporting a role for beta-catenin in carboplatin resistance in A2780cp cells. In conclusion, our data suggest that increased Wnt/beta-catenin signaling activity contributes to carboplatin resistance in A2780cp cells. PMID- 26522224 TI - Autophagy inhibition enhances silibinin-induced apoptosis by regulating reactive oxygen species production in human prostate cancer PC-3 cells. AB - Silibinin is a major bioactive component of silymarin and has anticancer effects on cancer cell line and has been used as a supportive therapy for chronic inflammatory liver condition. These anticancer effects of silibinin have been demonstrated both in vitro and in vivo cancer models. Although various evidences showed apoptosis signaling pathways by silibinin, there is no report to address the clearly mechanism of silibinin-induced autophagy in prostate cancer PC-3 cells. Our study showed that silibinin triggered autophagy through up-regulation of microtubule-associated protein 1 light chain 3 (LC3)-II, formation of acidic vesicular organelles (AVO) and punctuate of GFP-LC3, which was inhibited by 3 methyladenine (3-MA), an inhibitor of specific autophagy. In addition, silibinin induced autophagy through production of reactive oxygen species (ROS). Inhibition of ROS with diphenyleneiodonium (DPI), a ROS inhibitor, attenuated silibinin triggered autophagy. Inhibition of autophagy with 3-MA enhanced the silibinin induced apoptosis through the regulation of caspase-3 and PARP. These results suggested that silibinin induced autophagy by regulating ROS and its mechanism played a protective role against apoptosis in PC-3 cells. PMID- 26522225 TI - Inhibition of the 26S proteasome by peptide mimics of the coiled-coil region of its ATPase subunits. AB - Regulation of proteasomal degradation is an indispensable tool for biomedical studies. Thus, there is demand for novel proteasome inhibitors. Proteasomal degradation requires formation of coiled-coil structure by the N-terminal region of ATPase subunits of the proteasome cap. Here we show that peptides that mimic the N-terminal coiled-coil region of ATPase subunits interfere with proteasome function. These results suggest that coiled-coil peptides represent promising new proteasome inhibitors and that N-terminal coiled-coil regions of ATPase subunits are targets for proteasome inhibition. PMID- 26522226 TI - Up-regulation of epithelial Na(+) channel ENaC by human parvovirus B19 capsid protein VP1. AB - BACKGROUND: Clinical disorders caused by parvovirus B19 (B19V) infection include endothelial dysfunction with cardiac ischemia. The virus is effective in part by lysophosphatidylcholine-producing phospholipase A2 (PLA2) activity of B19V capsid protein VP1. Mechanisms compromising endothelial function include up-regulation of amiloride sensitive epithelial Na(+)-channel ENaC leading to endothelial cell stiffness. Regulators of ENaC include ubiquitin-ligase Nedd4-2. The present study explored whether VP1 modifies ENaC-activity. METHODS: cRNA encoding ENaC was injected into Xenopus oocytes without or with cRNA encoding VP1. Experiments were made with or without coexpression of Nedd4-2. ENaC activity was estimated from amiloride (50 MUM) sensitive current. RESULTS: Injection of cRNA encoding ENaC into Xenopus oocytes was followed by appearance of amiloride sensitive current, which was significantly enhanced by additional injection of cRNA encoding VP1, but not by additional injection of cRNA encoding PLA2-negative VP1 mutant (H153A). The effect of VP1 on ENaC was mimicked by treatment of ENaC expressing oocytes with lysophosphatidylcholine (1 MUg/ml). The effect of VP1 and lysophosphatidylcholine was not additive. ENaC activity was downregulated by Nedd4-2, an effect not reversed by VP1. CONCLUSIONS: The B19V capsid protein VP1 up-regulates ENaC, an effect at least partially due to phospholipase A2 (PLA) dependent formation of lysophosphatidylcholine. PMID- 26522227 TI - Identification of elevated urea as a severe, ubiquitous metabolic defect in the brain of patients with Huntington's disease. AB - Huntington's disease (HD) is a neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein through the lengthening of a polyglutamine tract and initiates a cascade that ultimately leads to dementia and premature death. However, neurodegeneration typically manifests in HD only in middle age, and processes linking the causative mutation to brain disease are poorly understood. Here, our objective was to elucidate further the processes that cause neurodegeneration in HD, by measuring levels of metabolites in brain regions known to undergo varying degrees of damage. We applied gas chromatography/mass spectrometry-based metabolomics in a case-control study of eleven brain regions in short post-mortem-delay human tissue from nine well characterized HD patients and nine controls. Unexpectedly, a single major abnormality was evident in all eleven brain regions studied across the forebrain, midbrain and hindbrain, namely marked elevation of urea, a metabolite formed in the urea cycle by arginase-mediated cleavage of arginine. Urea cycle activity localizes primarily in the liver, where it functions to incorporate protein derived amine-nitrogen into urea for recycling or urinary excretion. It also occurs in other cell-types, but systemic over-production of urea is not known in HD. These findings are consistent with impaired local urea regulation in brain, by up-regulation of synthesis and/or defective clearance. We hypothesize that defective brain urea metabolism could play a substantive role in the pathogenesis of neurodegeneration, perhaps via defects in osmoregulation or nitrogen metabolism. Brain urea metabolism is therefore a target for generating novel monitoring/imaging strategies and/or therapeutic interventions aimed at ameliorating the impact of HD in patients. PMID- 26522228 TI - Sampling frequency affects estimates of annual nitrous oxide fluxes. AB - Quantifying nitrous oxide (N2O) fluxes, a potent greenhouse gas, from soils is necessary to improve our knowledge of terrestrial N2O losses. Developing universal sampling frequencies for calculating annual N2O fluxes is difficult, as fluxes are renowned for their high temporal variability. We demonstrate daily sampling was largely required to achieve annual N2O fluxes within 10% of the 'best' estimate for 28 annual datasets collected from three continents- Australia, Europe and Asia. Decreasing the regularity of measurements either under- or overestimated annual N2O fluxes, with a maximum overestimation of 935%. Measurement frequency was lowered using a sampling strategy based on environmental factors known to affect temporal variability, but still required sampling more than once a week. Consequently, uncertainty in current global terrestrial N2O budgets associated with the upscaling of field-based datasets can be decreased significantly using adequate sampling frequencies. PMID- 26522229 TI - Effect of weight loss after bariatric surgery on kidney function in a multiethnic Asian population. AB - BACKGROUND: Current literature reports improvement in kidney function in obese patients after bariatric surgery in non-Asian centers. It is unclear how kidney function is affected by postoperative body composition changes in obese Asian patients. OBJECTIVES: To evaluate kidney function and its relationship to body composition in a multiethnic Asian population after bariatric surgery. SETTING: This study was performed in a university hospital. METHODS: Data of 68 obese patients who were followed for 1 year after surgery were retrieved from our university hospital clinical care database. Body composition was obtained by bioimpedance analysis. Kidney function was calculated as glomerular filtration rate (GFR) using the following formulas: (1) Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (estimated GFR [eGFR], mL/min/1.73 m(2)); (2) absolute GFR (aGFR, mL/min); and (3) lean weight-adjusted Cockcroft-Gault creatinine clearance (CG-LBW, mL/min). Patients were further examined by 2 subgroups: eGFR<90 and>90 mL/min/1.73 m(2). RESULTS: One year after surgery, body mass index (BMI) declined from 41.9+/-5.7 to 29.6+/-4.2 kg/m(2) (P<.001), body surface area (BSA) decreased from 2.15+/-0.23 to 1.86+/-0.18 m(2) (P<.001), and fat mass (FM) reduced from 45.8+/-9.4 to 25.6+/-10.5 kg (P<.001). There were significant differences in percentage excess weight loss (%EWL) among Chinese, Malays, Indians, and other ethnicities. Similar results were found with percentage fat mass loss (%FML). Changes in aGFR were associated with reductions in FM (P = .010), BSA (P = .049), and %EWL (P<.001). In the eGFR>90 subgroup, eGFR decreased from 143+/-22 to 122+/-19 mL/min/1.73 m(2). Conversely, in the eGFR<90 subgroup, eGFR had a trend of improvement from 69 to 79 mL/min/1.73 m(2). CONCLUSION: Changes in eGFR after bariatric surgery in the obese Asian patient are strongly associated with reduction in FM, BSA, and %EWL. More work is required to investigate if certain ethnicities have better postoperative renal profiles. PMID- 26522230 TI - Antiproliferative activity of goniothalamin enantiomers involves DNA damage, cell cycle arrest and apoptosis induction in MCF-7 and HB4a cells. AB - (R)-goniothalamin (R-GNT) is a styryl lactone that exhibits antiproliferative property against several tumor cell lines. (S)-goniothalamin (S-GNT) is the synthetic enantiomer of R-GNT, and their biological properties are poorly understood. The aim of this study was to evaluate the antiproliferative mechanisms of (R)-goniothalamin and (S)-goniothalamin in MCF-7 breast cancer cells and HB4a epithelial mammary cells. To determine the mechanisms of cell growth inhibition, we analyzed the ability of R-GNT and S-GNT to induce DNA damage, cell cycle arrest and apoptosis. Moreover, the gene expression of cell cycle components, including cyclin, CDKs and CKIs, as well as of genes involved in apoptosis and the DNA damage response were evaluated. The natural enantiomer R GNT proved more effective in both cell lines than did the synthetic enantiomer S GNT, inhibiting cell proliferation via cell cycle arrest and apoptosis induction, likely in response to DNA damage. The cell cycle inhibition caused by R-GNT was mediated through the upregulation of CIP/KIP cyclin-kinase inhibitors and through the downregulation of cyclins and CDKs. S-GNT, in turn, was able to cause G0/G1 cell cycle arrest and DNA damage in MCF-7 cells and apoptosis induction only in HB4a cells. Therefore, goniothalamin presents potent antiproliferative activity to breast cancer cells MCF-7. However, exposure to goniothalamin brings some undesirable effects to non-tumor cells HB4a, including genotoxicity and apoptosis induction. PMID- 26522231 TI - Effect of long-term coadministration of compound glycyrrhizin tablets on the pharmacokinetics of mycophenolic acid in rats. AB - 1. Mycophenolic acid (MPA), having high-protein affinity, is an immunodepressant and the genuine-active ingredient of enteric-coated mycophenolate sodium (EC-MPS) tablet that has been widely used in combination with tacrolimus or cyclosporine to prevent acute rejection after organ transplantation. Moreover, MPA mainly experiences glucuronidation and its metabolites are partly transported by multidrug resistance-associated protein (Mrp) 2 into bile then reforms MPA via enterohepatic circulation. 2. Glycyrrhizin (GL), having high-protein affinity, is the main active ingredient of compound glycyrrhizin tablet, which is often prescribed with EC-MPS, tacrolimus or cyclosporine to prevent drug-induced hepatitis. In addition, GL can inhibit Mrp2 and selectively induce CYP3A and UGTs; and it also undergoes enterohepatic circulation. 3. After 14 days of coadministration of compound GL tablets with the capsules of EC-MPS tablets, the AUC0-48 h of total and free MPA was dramatically increased, and the clearance of total and free MPA was apparently decreased. It would seem reasonable that our data appear to support further investigation of this drug-drug interactions in the clinic and more careful monitoring of drug levels as well as clinical effect and toxicity in patients receiving the combination of these two agents. PMID- 26522232 TI - DNA damage induces a meiotic arrest in mouse oocytes mediated by the spindle assembly checkpoint. AB - Extensive damage to maternal DNA during meiosis causes infertility, birth defects and abortions. However, it is unknown if fully grown oocytes have a mechanism to prevent the creation of DNA-damaged embryos. Here we show that DNA damage activates a pathway involving the spindle assembly checkpoint (SAC) in response to chemically induced double strand breaks, UVB and ionizing radiation. DNA damage can occur either before or after nuclear envelope breakdown, and provides an effective block to anaphase-promoting complex activity, and consequently the formation of mature eggs. This contrasts with somatic cells, where DNA damage fails to affect mitotic progression. However, it uncovers a second function for the meiotic SAC, which in the context of detecting microtubule-kinetochore errors has hitherto been labelled as weak or ineffectual in mammalian oocytes. We propose that its essential role in the detection of DNA damage sheds new light on its biological purpose in mammalian female meiosis. PMID- 26522234 TI - Treatment of the Mucocutaneous Manifestations of Hereditary Hemorrhagic Telangiectasia Using the Nd:YAG Laser (1064nm). PMID- 26522233 TI - Effect of bread gluten content on gastrointestinal function: a crossover MRI study on healthy humans. AB - Gluten is a crucial functional component of bread, but the effect of increasing gluten content on gastrointestinal (GI) function remains uncertain. Our aim was to investigate the effect of increasing gluten content on GI function and symptoms in healthy participants using the unique capabilities of MRI. A total of twelve healthy participants completed this randomised, mechanistic, open-label, three-way crossover study. On days 1 and 2 they consumed either gluten-free bread (GFB), or normal gluten content bread (NGCB) or added gluten content bread (AGCB). The same bread was consumed on day 3, and MRI scans were performed every 60 min from fasting baseline up to 360 min after eating. The appearance of the gastric chime in the images was assessed using a visual heterogeneity score. Gastric volumes, the small bowel water content (SBWC), colonic volumes and colonic gas content and GI symptoms were measured. Fasting transverse colonic volume after the 2-d preload was significantly higher after GFB compared with NGCB and AGCB with a dose-dependent response (289 (SEM 96) v. 212 (SEM 74) v. 179 (SEM 87) ml, respectively; P=0.02). The intragastric chyme heterogeneity score was higher for the bread with increased gluten (AGCB 6 (interquartile range (IQR) 0.5) compared with GFB 3 (IQR 0.5); P=0.003). However, gastric half-emptying time was not different between breads nor were study day GI symptoms, postprandial SBWC, colonic volume and gas content. This MRI study showed novel mechanistic insights in the GI responses to different breads, which are poorly understood notwithstanding the importance of this staple food. PMID- 26522235 TI - Adalimumab-Induced Pityriasis Lichenoides Chronica That Responded Well to Methotrexate in a Patient With Psoriasis. PMID- 26522236 TI - Basal Cell Carcinoma With a Cylindromatous Phenotype. PMID- 26522237 TI - TAKING THE PULSE OF PROLONGED EXPOSURE THERAPY: PHYSIOLOGICAL REACTIVITY TO TRAUMA IMAGERY AS AN OBJECTIVE MEASURE OF TREATMENT RESPONSE. AB - BACKGROUND: Physiological reactivity to trauma-related cues is a primary symptom of PTSD and can be assessed objectively using script-driven imagery paradigms. However, subjective self-reported symptom measures are the most common outcome indices utilized in PTSD treatment trials and clinic settings. We examined physiological reactivity during a short trauma imagery task as an objective index of response to PTSD treatment, optimized for use in routine clinical care settings. METHODS: Participants were 35 male combat veterans receiving prolonged exposure (PE) therapy in a Veterans Affairs outpatient clinic. In addition to traditional subjective self-reported and clinician-rated symptom measures, patients also completed a script-driven imagery task in which heart rate (HR) and skin conductance (SC) were recorded at three assessment points across treatment. We examined changes in subjective symptom measures and objective trauma-specific physiological reactivity over the course of PE, and investigated the association between pretreatment physiological reactivity and treatment response. RESULTS: Patients who completed PE showed significantly diminished HR and SC reactivity to trauma imagery across therapy. Additionally, individuals showing greater trauma specific HR reactivity at pretreatment showed greater reductions in subjectively reported PTSD symptoms at posttreatment. CONCLUSIONS: Findings support the utility of physiological reactivity during trauma imagery as an objective outcome measure that has the potential to be incorporated into evidence-based PTSD treatment in routine clinical settings, or prospective studies related to the individualization of care at pretreatment. PMID- 26522238 TI - Sufficiency and Necessity Assumptions in Causal Structure Induction. AB - Research on human causal induction has shown that people have general prior assumptions about causal strength and about how causes interact with the background. We propose that these prior assumptions about the parameters of causal systems do not only manifest themselves in estimations of causal strength or the selection of causes but also when deciding between alternative causal structures. In three experiments, we requested subjects to choose which of two observable variables was the cause and which the effect. We found strong evidence that learners have interindividually variable but intraindividually stable priors about causal parameters that express a preference for causal determinism (sufficiency or necessity; Experiment 1). These priors predict which structure subjects preferentially select. The priors can be manipulated experimentally (Experiment 2) and appear to be domain-general (Experiment 3). Heuristic strategies of structure induction are suggested that can be viewed as simplified implementations of the priors. PMID- 26522239 TI - Structural Elements and Cough Suppressing Activity of Polysaccharides from Zingiber officinale Rhizome. AB - Zingiber officinale is used for the management of fever, bronchial asthma and cough for thousands of years. While the link to a particular indication has been established in human, the active principle of the formulation remains unknown. Herein, we have investigated a water extracted polysaccharides (WEP) containing fraction from its rhizome. Utilizing a traditional aqueous extraction protocol and using chemical, chromatographic and spectroscopic methods a fraction containing a branched glucan and polygalaturonan in a ratio of 59:1 was characterized. This glucan, which has a molecular mass of 36 kDa, is made up of terminal-, (1,4)- and (1,4,6)-linked alpha-Glcp residues. Oral administration of WEP in doses of 25 and 50 mg/kg body weight significantly inhibited the number of citric acid-induced cough efforts in guinea pigs. It does not alter the specific airway smooth muscle reactivity significantly. Thus, traditional aqueous extraction method provides molecular entities, which induces antitussive activity without addiction. PMID- 26522241 TI - Nanobody-Based Electrochemical Immunoassay for Ultrasensitive Determination of Apolipoprotein-A1 Using Silver Nanoparticles Loaded Nanohydroxyapatite as Label. AB - Nanobodies (Nbs), derived from camelid heavy-chain antibodies, have distinct advantages over conventional antibodies in immunoassay. In this work, Nbs (Nb11 and Nb19) that can bind to different epitopes on apolipoprotein-A1 (Apo-A1) were screened out from an immunized Bactrian camel for the first time. Nb11 was used as capture antibody and fixed on gold nanoparticles (Au NPs) modified screen printed carbon electrode (SPCE). The silver nanoparticles loaded nanohydroxyapatite (Ag-nHAP) was used as signal tag to label secondary antibody Nb19. A sandwich-type immunological reaction occurred between Apo-A1 and the two Nbs, which brought the Ag-nHAP to the SPCE surface. After the Ag-nHAP were acidically dissolved in the microelectrolytic cell of the SPCE, stripping voltammetric measurement for the released silver ions was performed to obtain an amplified signal. The peak current values increased by the logarithmic values of Apo-A1 concentrations from 10(-4) to 50 ng mL(-1) under optimal conditions. The detection limit was calculated to be 0.02 pg mL(-1). This method was used for the serum samples analysis and achieved satisfactory results. The low cost and high sensitivity make the electrochemical immunosensor suitable for the Apo-A1 detection, which may find promising application in other fields. PMID- 26522240 TI - Cholesterol induces lipoprotein lipase expression in a tree shrew (Tupaia belangeri chinensis) model of non-alcoholic fatty liver disease. AB - Animal models are indispensible to investigate the pathogenesis and treatments of non-alcoholic fatty liver diseases (NAFLD). Altered cholesterol metabolism has been implicated into the pathogenesis of NAFLD. Here, using high fat, cholesterol and cholate diet (HFHC), we generated a novel tree shrew (Tupaia belangeri chinensis) model of NAFLD, which displayed dyslipidemia with increased levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-c) and high density lipoprotein-cholesterol (HDL-c), but decreased level of triglycerides (TG). Liver histopathology and genes expression indicated that HFHC diet successfully induced liver steatosis to inflammation and fibrosis progressively within 10 weeks. Moreover, HFHC induced the transcriptional expression of lipoprotein lipase (lpl) in the liver, but repressed the expression of LDL receptor, and the endogenous synthesis pathway and excretion of cholesterol. Notably, Poloxamer 407 (P-407) inhibition of LPL improved the severity of steatosis and reduced inflammation. These results illustrated that LPL plays an important role in cholesterol metabolism in NAFLD, and the tree shrew may be a valuable animal model for further research into NAFLD. PMID- 26522242 TI - Elasticity of polymeric nanocolloidal particles. AB - Softness is an essential mechanical feature of macromolecular particles such as polymer-grafted nanocolloids, polyelectrolyte networks, cross-linked microgels as well as block copolymer and dendrimer micelles. Elasticity of individual particles directly controls their swelling, wetting, and adsorption behaviour, their aggregation and self-assembly as well as structural and rheological properties of suspensions. Here we use numerical simulations and self-consistent field theory to study the deformation behaviour of a single spherical polymer brush upon diametral compression. We observe a universal response, which is rationalised using scaling arguments and interpreted in terms of two coarse grained models. At small and intermediate compressions the deformation can be accurately reproduced by modelling the brush as a liquid drop, whereas at large compressions the brush behaves as a soft ball. Applicable far beyond the pairwise additive small-strain regime, the models may be used to describe microelasticity of nanocolloids in severe confinement including dense disordered and crystalline phases. PMID- 26522243 TI - Sunitinib loaded chitosan nanoparticles formulation and its evaluation. AB - The nano-polymeric pharmaceutical excipient such as chitosan nanoparticles (CS NPs) were synthesized for formulating the anticancer drug Sunitinib (STB). The formulation was done through the simple ionic cross linking method. The prepared formulation was characterized by DLS, SEM, FT-IR and XRD. The DLS study reveals that the Sunitinib loaded chitosan nanoparticles (SNB-CS-NPs) were in the size range of < 200 nm. Encapsulation of Sunitinib and validation for the formulation was done using UV spectrophotometry. In vitro drug release and its cytotoxic studies were performed for STB-CS-NPs. This study implies the novel drug delivery system for Sunitinib for the effective sustained delivery. PMID- 26522244 TI - Cathepsin S of Sciaenops ocellatus: Identification, transcriptional expression and enzymatic activity. AB - Cathepsin S is a member of cysteine cathepsins and belongs to the cathepsin L like family. In mammals, it is known to participate in various physiological processes and host immune defense. In teleost fish, the function of cathepsin S is less investigated. In the present work, we characterized a cathepsin S homologue (SoCatS) from red drum (Sciaenops ocellatus), a commercially valuable fish in Chinese mariculture. Like all cathepsin S, SoCatS possesses a peptidase domain with four catalytically essential residues (Gln140, Cys146, His285, and Asn305) conserved in the cathepsin S of different organisms. SoCatS shares 60-90% overall sequence identities with known teleost cathepsin S. Phylogenetic profiling indicated that SoCatS is evolutionally close to the cathepsin S of other teleost fish, especially Miichthys miiuy, a member of Sciaenidae family like red drum. SoCatS expression was detected in various tissues and was enhanced by bacterial infection. Purified recombinant SoCatS exhibited apparent peptidase activity with maximum at 50 degrees C and pH 7.5. This activity depended on the catalytic residue Cys146 and was severely reduced by the cathepsin inhibitor E 64. Our results suggest that SoCatS functions as a cysteine protease which is probably involved in the antibacterial immunity of red drum. PMID- 26522245 TI - N-carboxyethyl chitosan fibers prepared as potential use in tissue engineering. AB - To improve the hydrophilicity of chitosan fiber, N-carboxyethyl chitosan fiber was prepared through Michael addition between chitosan fiber with acrylic acid. The structure was studied by (1)H NMR. The degree of N-substitution, measured via (1)H NMR, was easily varied from 0.10 to 0.51 by varying the molar ratio of acrylic acid to chitosan. Series of properties of N-carboxyethyl chitosan fiber including mechanical property, crystallinity, thermal property and in vitro degradation were investigated by Instron machine, X-ray diffraction and differential scanning calorimetry and thermogravimetric analysis, respectively. The results showed that, introducing the carboxyethyl group into the backbone chain of chitosan fiber destroyed the intra/intermolecular hydrogen bonding, leading to loss of the intra/intermolecular hydrogen bonding and improvement of hydrophilicity. Indirect cytotoxicity assessment of carboxyethyl chitosan fibers was investigated using a L929 cell line. And the obtained results clearly suggested that N-carboxyethyl chitosan fiber was nontoxic to L929 cells. The N carboxyethyl chitosan fibers are potential as tissue engineering scaffolds. PMID- 26522246 TI - Structural characterization and anti-tumor effects of an inulin-type fructan from Atractylodes chinensis. AB - A fructan (ACPS-1) with a molecular weight of 11.2 kDa was isolated from Atractylodes chinensis rhizome and characterized by chemical derivatization, HPLC, GC-MS, FT-IR, and NMR. Structural analyses revealed that ACPS-1 is predominately composed of fructose and a small amount of glucose and a polymerization degree of about 53. The fructan was deduced to be an inulin-type fructan containing a linear backbone composed of (2->1)-linked beta-d-Fruf residues. The in vitro antitumor activity of ACPS-1 was evaluated on four human cancer cell lines, including a cervical cancer cell line (Hela), two liver hepatocellular carcinoma cell lines (HepG2 and 7721), and an ovarian carcinoma cell line (Skov3). Results showed that ACPS-1 could significantly inhibit Hela, HepG2, and 7721 cell proliferation, especially HepG2, for which the fructan showed a proliferative inhibition rate as high as 87.40%. This result suggests that ACPS-1 may have anticancer potentiality against hepatocellular carcinoma and warrants further investigation. PMID- 26522247 TI - Anti-tumor and immunomodulatory activity of selenium (Se)-polysaccharide from Se enriched Grifola frondosa. AB - A polysaccharide termed Se-GP11 was extracted and purified from Se-enriched Grifola frondosa in our previous study. This study investigated the characterization, anti-tumor and immunomodulatory activity of Se-GP11. The results showed that Se-GP11 was composed of mannose, glucose and galactose with a molar ratio of 1:4.91:2.41. The weight-average molecular weight (Mw) and weight average mean square radius (Rw) of Se-GP11 in 0.1M sodium chloride solution were 3.3*10(4)Da and 32.8 nm. Se-GP11 existed as a globular conformation with random coil structure. Se-GP11 had no anti-tumor activity against HepG-2 cells in vitro, and it significantly inhibited the growth of Heps tumor in vivo. Se-GP11 increased the relatively thymus and spleen weights as well as serum necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) levels. In addition, Se-GP11 promoted the phagocytosis and NO production of RAW264.7 as compared with that of the normal control group. The results revealed that the Se-GP11 may exhibit the anti-tumor through improving immunologic function of the tumor bearing mice. PMID- 26522249 TI - Evaluation of a nutrient-based diet quality index in UK young children and investigation into the diet quality of consumers of formula and infant foods. AB - OBJECTIVE: To adapt and evaluate a nutrient-based diet quality index (PANDiet) for UK young children and to determine the nutritional adequacy of their diets according to consumption of young child formula (YCF) and commercial infant foods (CIF). DESIGN: Content and construct validity of the PANDiet were assessed by studying associations between the PANDiet and its components, energy intake, food intakes, and child and maternal characteristics. Four groups of children were defined according to their intake of YCF and CIF: (i) no consumption; (ii) consumption of YCF; (iii) consumption of CIF; and (iv) consumption of YCF and CIF. Child and maternal characteristics, PANDiet scores and food intakes of these four groups were compared. SETTING: Secondary analysis of data from the UK Diet and Nutrition Survey of Infants and Young Children (DNSIYC, 2011). SUBJECTS: Young children (n 1152) aged 12-18 months. RESULTS: The PANDiet was adapted to the UK based on twenty-five nutrients. A lower PANDiet score was linked to lower intakes of YCF, CIF, vegetables and fruits. Determinants of having a lower score were being older, having siblings and having a younger mother with a lower educational level. Compared with children consuming neither YCF nor CIF, PANDiet scores were higher in children consuming CIF (+1.4), children consuming YCF (+7.2) and children consuming YCF and CIF (+7.8; all P<0.001). CONCLUSIONS: The PANDiet is a valid indicator of the nutrient adequacy of the diet of UK young children. Consuming CIF was not found to be associated with lower nutritional adequacy whereas consuming YCF was associated with higher nutritional adequacy. PMID- 26522250 TI - Mapping of multi-elements during melting and solidification using synchrotron X rays and pixel-based spectroscopy. AB - A new synchrotron-based technique for elemental imaging that combines radiography and fluorescence spectroscopy has been developed and applied to study the spatial distribution of Ag, Zr and Mo in an Al alloy during heating and melting to 700, and then re-soldification. For the first time, multi-element distributions have been mapped independently and simultaneously, showing the dissolution of Ag- and Zr-rich particles during melting and the inter-dendritic segregation of Ag during re-solidification. The new technique is shown to have wide potential for metallurgical and materials science applications where the dynamics of elemental re-distribution and segregation in complex alloys is of importance. PMID- 26522251 TI - Can Macrosomia or Large for Gestational Age Be Predictive of Mucopolysaccharidosis Type I, II and VI? AB - BACKGROUND: The objective of the study was to compare mean values for birth body length and weight between patients with mucopolysaccharidosis (MPS) and the general population. METHODS: A retrospective analysis of birth anthropometric data was performed for patients (n = 103) with MPS I, II, and VI. Two-tailed t tests were used to compare mean values for body length and weight at birth between patients with MPS and the general population. RESULTS: Mean values for birth body length and weight for all studied groups were greater than in the general population. For body length the differences were statistically significant. When considered individually, 53% of patients were large for gestational age (LGA) and 30% were macrosomic. The highest percentage of LGA was observed in MPS II males and MPS VI females (55% and 56%, respectively), while the highest percentage of macrosomia was observed in MPS VI males (36%). CONCLUSION: At the time of birth, MPS patients were larger than those in the general population. High birth weight and/or LGA can be suggestive of MPS disease and should raise suspicion aiding early disease recognition. PMID- 26522252 TI - The Haplotype TGGAG in the ABCA3 Gene Increases the Risk of Respiratory Distress Syndrome in Preterm Infants in Southern China. AB - BACKGROUND: Rare mutations in the ATP-binding cassette (ABC) transporter A3 (ABCA3) gene are associated with neonatal respiratory distress syndrome (RDS). The contribution of common single nucleotide polymorphisms (SNPs) to preterm RDS differs between ethnicities and remains unclear in Chinese infants. This study evaluated whether common SNPs and consequent haplotypes increase susceptibility to RDS in a population of preterm infants from the Guangxi Zhuang Autonomous Region of China. METHODS: Using a tagging SNP (tSNP) strategy and real-time polymerase chain reaction, we genotyped four tSNPs (i.e., rs150929, rs4787273, rs11867129, and rs17135889) and one coding SNP (p.F353F) of the ABCA3 gene in preterm infants with RDS (n = 83) and without RDS (n = 83). We predicted the haplotypes. Minor allele frequencies (MAFs) and haplotype distributions were compared between the two groups. We analyzed correlations between the clinical data and the genotypes. RESULTS: Seven haplotypes existed at a frequency of 0.01 or greater. The haplotype TGGAG was significantly more frequent in RDS infants than in non-RDS infants (p = 0.026; odds ratio 3.41; 95% confidence interval 1.088-10.685). The MAF of rs17135889 SNP, a crucial SNP of the haplotype TGGAG located in the transcription factor binding site of ABCA3, was significantly higher in RDS infants (p < 0.05); however, the Bonferroni correction test showed no significant difference (p > 0.05). No significant correlation existed between the rs17135889 genotypes (AG/GG) and any clinical characteristic (e.g., oxygen supplementation duration and hospitalization, requirement for ventilation, bronchopulmonary dysplasia complications, and mortality rate). CONCLUSION: The TGGAG haplotype may be a risk factor for RDS in preterm infants in this Chinese population. Further study is needed with a larger sample size to verify the association between the rs17135889 SNP and increased risk of RDS in preterm infants, and to determine whether rs17135889 can be a reference in further population-based studies of ABCA3. PMID- 26522253 TI - Counseling patients with asthma and allergy about electronic cigarettes: an evidence-based approach. AB - OBJECTIVE: To provide an evidence-based review of common safety concerns and emerging potential benefits deriving from the regular use of electronic cigarettes (ECs) and thus improve counseling between physicians and their patients with asthma and allergy using or intending to use ECs. DATA SOURCES: Peer-reviewed articles from the National Center for Biotechnology Information's PubMed about ECs, risk reduction, and harm reversal were appraised. STUDY SELECTION: Keywords used in the search were smoking cessation, electronic cigarette, counseling, asthma, allergy, nicotine, tobacco harm reduction, and harm reversal. RESULTS: Vapor toxicology is far less problematic compared with combustible cigarettes, with exclusive EC users having substantial lower risk of exposure to tobacco smoke toxicants and carcinogens compared with cigarette smokers. Moreover, there is emerging evidence that switching to regular EC use could produce significant respiratory health gains. CONCLUSION: Inaccurate and inconsistent information about EC safety and efficacy, tobacco harm reduction, and nicotine toxicity is being offered to smokers and EC users. In particular, most health care professionals cannot communicate a clear and consistent message to their patients with respiratory problems and allergy who use or intend to use ECs. Therefore, it is important for the medical community to take an active role in considering all the pathways available to a smoking patient and recommend those that provide the greatest probability of eliminating exposure to tobacco smoke, including ECs. PMID- 26522254 TI - Does fractional exhaled nitric oxide vary by foreign-born status and years of US residence? PMID- 26522255 TI - Allergen stabilities and compatibilities in immunotherapy mixtures that contain cat, dog, dust mite, and cockroach extracts. AB - BACKGROUND: Indoor allergen mixtures that contain cat, dog, dust mite, and cockroach extracts are commonly used in allergy clinics for subcutaneous immunotherapy, but product-specific stabilities and mixing compatibilities in these complex patient formulas have not been determined. OBJECTIVES: To assess the recoveries of cat, dog epithelia, dog dander, dust mite Dermatophagoides farinae, and cockroach mix allergen activities in 5 component mixtures and 1:10 (vol/vol) dilutions stored for up to 12 months. METHODS: Concentrated stock mixtures, 10-fold dilutions of these mixtures in human serum albumin-saline diluent, and analogous single-extract controls were analyzed for major allergen concentrations (cat Fel d 1, dog dander Can f 1) and multiallergen IgE-binding potencies (dog epithelia, D farinae, cockroach mix) after storage for 3, 6, 9, and 12 months at 2 degrees C to 8 degrees C. RESULTS: The selected immunoassays were specific for individual target extracts in the 5-component mixtures and exhibited analytical sensitivities sufficient for evaluation of both the concentrated and diluted indoor allergen formulas. All control samples except diluted cockroach extract had near-complete stabilities during refrigerated storage. Mixtures that contained cat, dog epithelia, dog dander, and D farinae extracts exhibited favorable mixing compatibilities in 1:1 (vol/vol) concentrates (47.5% glycerin) and 1:10 (vol/vol) dilutions (4.75% glycerin), relative to corresponding control sample reactivities. Cockroach allergens in both 1:1 (vol/vol) and 1:10 (vol/vol) concentrations were stabilized significantly by mixing with the other 4 indoor allergen extracts. CONCLUSION: Extracts in mixtures that contained 5 common sources of indoor allergens possess favorable stabilities and mixing compatibilities and support the practice of combining these products in the same patient treatment formulations for subcutaneous immunotherapy. PMID- 26522256 TI - Relationship between maternal and child behaviors in pediatric food allergy--an exploratory study. PMID- 26522257 TI - The evolving story of human leukocyte antigen and the immunogenetics of peanut allergy. AB - OBJECTIVE: Peanut allergy (PA) clearly has a heritable component. Specific genetic contributions are unknown, but human leukocyte antigen (HLA) loci are obvious candidates. This review focuses on emerging studies of HLA associations with PA. DATA SOURCES: PubMed was searched with no time limitations using key terms human leukocyte antigen, HLA, MHC, peanut, peanut hypersensitivity, and peanut allergy. STUDY SELECTIONS: Qualifying studies were English-language reports of genetic analyses examining PA and HLA associations. RESULTS: Seven relevant citations were identified, which were published from 1996 to 2015. Early studies using candidate gene approaches found associations between PA and HLA-DR and -DQ alleles (HLA-DRB1*08 and DQB1*06:03P) when comparing subjects with peanut allergy with nonallergic unrelated control groups. No significant associations were found between siblings with and without peanut allergy. However, a recent large genomewide association study of patients with peanut allergy and their family members found 2 PA-associated single-nucleotide polymorphisms (rs9275596 and rs7192) mapping to regions involving the HLA-DR and HLA-DQ genes. Associations with differential DNA methylation partly mediated the associations between PA and single-nucleotide polymorphisms. CONCLUSION: Early studies using candidate gene approaches identified HLA associations with PA compared with the general population, suggesting a link with atopy but failing to identify a PA specific association. These studies had various limitations that included small samples. The most compelling evidence for a PA-specific HLA association comes from a genomewide association study, which examined the entire genome in large, well-defined, related cohorts. More research is needed to validate and replicate these findings, to perform fine genetic mapping of specific HLA loci, and to demonstrate underlying mechanisms of HLA contributions to PA. PMID- 26522258 TI - Additional provocation testing in patients with negative provocation test results with beta-lactam antibiotics. PMID- 26522259 TI - Carboxyamidotriazole inhibits oxidative phosphorylation in cancer cells and exerts synergistic anti-cancer effect with glycolysis inhibition. AB - Targeting cancer cell metabolism is a promising strategy against cancer. Here, we confirmed that the anti-cancer drug carboxyamidotriazole (CAI) inhibited mitochondrial respiration in cancer cells for the first time and found a way to enhance its anti-cancer activity by further disturbing the energy metabolism. CAI promoted glucose uptake and lactate production when incubated with cancer cells. The oxidative phosphorylation (OXPHOS) in cancer cells was inhibited by CAI, and the decrease in the activity of the respiratory chain complex I could be one explanation. The anti-cancer effect of CAI was greatly potentiated when being combined with 2-deoxyglucose (2-DG). The cancer cells treated with the combination of CAI and 2-DG were arrested in G2/M phase. The apoptosis and necrosis rates were also increased. In a mouse xenograft model, this combination was well tolerated and retarded the tumor growth. The impairment of cancer cell survival was associated with significant cellular ATP decrease, suggesting that the combination of CAI and 2-DG could be one of the strategies to cause dual inhibition of energy pathways, which might be an effective therapeutic approach for a broad spectrum of tumors. PMID- 26522260 TI - Real-Time Characterization of Diminutive Colorectal Polyp Histology Using Narrow Band Imaging: Implications for the Resect and Discard Strategy. AB - BACKGROUND & AIMS: Narrow-band imaging (NBI) allows real-time histologic classification of colorectal polyps. We investigated whether endoscopists without prior training in NBI can achieve the following thresholds recommended by the American Society for Gastrointestinal Endoscopy: for diminutive colorectal polyps characterized with high confidence, a >=90% negative predictive value for adenomas in the rectosigmoid and a >=90% agreement in surveillance intervals. METHODS: Twenty-six endoscopists from 2 tertiary care centers underwent standardized training in NBI interpretation. Endoscopists made real-time predictions of diminutive colorectal polyp histology and surveillance interval predictions based on NBI. Their performance was evaluated by comparing predicted with actual findings from histologic analysis. Multilevel logistic regression was used to assess predictors of performance. Cumulative summation analysis was used to characterize learning curves. RESULTS: The endoscopists performed 1451 colonoscopies and made 3012 diminutive polyp predictions (74.3% high confidence) using NBI. They made 898 immediate post-procedure surveillance interval predictions. An additional 505 surveillance intervals were determined with histology input. The overall negative predictive value for high-confidence characterizations in the rectosigmoid was 94.7% (95% confidence interval: 92.6% 96.8%) and the surveillance interval agreement was 91.2% (95% confidence interval: 89.7%-92.7%). Overall, 97.0% of surveillance interval predictions would have brought patients back on time or early. High-confidence characterization was the strongest predictor of accuracy (odds ratio = 3.42; 95% confidence interval: 2.72-4.29; P < .001). Performance improved over time, however, according to cumulative summation analysis, only 7 participants (26.9%) identified adenomas with sufficient sensitivity such that further auditing is not required. CONCLUSIONS: With standardized training, gastroenterologists without prior expertise in NBI were able to meet the negative predictive value and surveillance interval thresholds set forth by the American Society for Gastrointestinal Endoscopy. The majority of disagreement in surveillance interval brought patients back early. Performance improves with time, but most endoscopists will require ongoing auditing of performance. ClinicalTrials.gov ID NCT02441998. PMID- 26522261 TI - Association Between Response to Etrolizumab and Expression of Integrin alphaE and Granzyme A in Colon Biopsies of Patients With Ulcerative Colitis. AB - BACKGROUND & AIMS: Etrolizumab is a humanized monoclonal antibody against the beta7 integrin subunit that has shown efficacy vs placebo in patients with moderate to severely active ulcerative colitis (UC). Patients with colon tissues that expressed high levels of the integrin alphaE gene (ITGAE) appeared to have the best response. We compared differences in colonic expression of ITGAE and other genes between patients who achieved clinical remission with etrolizumab vs those who did. METHODS: We performed a retrospective analysis of data collected from 110 patients with UC who participated in a phase 2 placebo-controlled trial of etrolizumab, as well as from 21 patients with UC or without inflammatory bowel disease (controls) enrolled in an observational study at a separate site. Colon biopsies were collected from patients in both studies and analyzed by immunohistochemistry and gene expression profiling. Mononuclear cells were isolated and analyzed by flow cytometry. We identified biomarkers associated with response to etrolizumab. In the placebo-controlled trial, clinical remission was defined as total Mayo Clinic Score <=2, with no individual subscore >1, and mucosal healing was defined as endoscopic score <=1. RESULTS: Colon tissues collected at baseline from patients who had a clinical response to etrolizumab expressed higher levels of T-cell-associated genes than patients who did not respond (P < .05). Colonic CD4(+) integrin alphaE(+) cells from patients with UC expressed higher levels of granzyme A messenger RNA (GZMA mRNA) than CD4(+) alphaE(-) cells (P < .0001); granzyme A and integrin alphaE protein were detected in the same cells. Of patients receiving 100 mg etrolizumab, a higher proportion of those with high levels of GZMA mRNA (41%) or ITGAE mRNA (38%) than those with low levels of GZMA (6%) or ITGAE mRNA (13%) achieved clinical remission (P < .05) and mucosal healing (41% GZMA(high) vs 19% GZMA(low) and 44% ITGAE(high) vs 19% ITGAE(low)). Compared with ITGAE(low) and GZMA(low) patients, patients with ITGAE(high) and GZMA(high) had higher baseline numbers of epithelial crypt associated integrin alphaE(+) cells (P < .01 for both), but a smaller number of crypt-associated integrin alphaE(+) cells after etrolizumab treatment (P < .05 for both). After 10 weeks of etrolizumab treatment, expression of genes associated with T-cell activation and genes encoding inflammatory cytokines decreased by 40%-80% from baseline (P < .05) in patients with colon tissues expressing high levels of GZMA at baseline. CONCLUSIONS: Levels of GZMA and ITGAE mRNAs in colon tissues can identify patients with UC who are most likely to benefit from etrolizumab; expression levels decrease with etrolizumab administration in biomarker(high) patients. Larger, prospective studies of markers are needed to assess their clinical value. PMID- 26522262 TI - Aging of Liver Transplant Registrants and Recipients: Trends and Impact on Waitlist Outcomes, Post-Transplantation Outcomes, and Transplant-Related Survival Benefit. AB - BACKGROUND & AIMS: Epidemiologic factors have generated increased demand for liver transplantation among older patients. We aimed to describe trends in age among liver transplant registrants and recipients and the effect of age on waitlist and post-transplantation outcomes and on transplant-related survival benefit. METHODS: We obtained data from the United Network for Organ Sharing on adults who were listed for liver transplantation (N = 122,606) or underwent liver transplantation (N = 60,820) from 2002 to 2014 in the United States. Competing risks analysis was used to model waitlist outcomes and Cox proportional hazards analysis to model post-transplantation survival. These models were also used to estimate 5-year transplant-related survival benefit for different age groups, calculated as the difference between waitlist and post-transplantation life expectancy. RESULTS: Between 2002 and 2014, the mean age of liver transplant registrants increased from 51.2 to 55.7 years, with a more prominent increase in hepatitis C virus-positive (50.9-57.9 years) than hepatitis C virus-negative (51.3-54.3 years) registrants. The proportion of registrants aged >=60 years increased from 19% to 41%. In hepatitis C virus-negative patients, aging trends were driven by increasing proportions of patients with hepatocellular carcinoma or nonalcoholic steatohepatitis. Among transplant registrants, increasing age was associated with increasing mortality before transplantation and decreasing likelihood of transplantation. Among transplant recipients, increasing age was associated with increasing post-transplantation mortality. There was little difference in 5-year transplant-related survival benefit between different age groups who had the same Model for End-Stage Liver Disease score. CONCLUSIONS: Dramatic aging of liver transplant registrants and recipients occurred from 2002 to 2014, driven by aging of the hepatitis C virus-positive cohort and increased prevalence of nonalcoholic steatohepatitis and hepatocellular carcinoma. Increasing age does not affect transplant-related survival benefit substantially because age diminishes both post-transplantation survival and waitlist survival approximately equally. PMID- 26522263 TI - Automatic Voice Pathology Detection With Running Speech by Using Estimation of Auditory Spectrum and Cepstral Coefficients Based on the All-Pole Model. AB - BACKGROUND AND OBJECTIVE: Automatic voice pathology detection using sustained vowels has been widely explored. Because of the stationary nature of the speech waveform, pathology detection with a sustained vowel is a comparatively easier task than that using a running speech. Some disorder detection systems with running speech have also been developed, although most of them are based on a voice activity detection (VAD), that is, itself a challenging task. Pathology detection with running speech needs more investigation, and systems with good accuracy (ACC) are required. Furthermore, pathology classification systems with running speech have not received any attention from the research community. In this article, automatic pathology detection and classification systems are developed using text-dependent running speech without adding a VAD module. METHOD: A set of three psychophysics conditions of hearing (critical band spectral estimation, equal loudness hearing curve, and the intensity loudness power law of hearing) is used to estimate the auditory spectrum. The auditory spectrum and all-pole models of the auditory spectrums are computed and analyzed and used in a Gaussian mixture model for an automatic decision. RESULTS: In the experiments using the Massachusetts Eye & Ear Infirmary database, an ACC of 99.56% is obtained for pathology detection, and an ACC of 93.33% is obtained for the pathology classification system. The results of the proposed systems outperform the existing running-speech-based systems. DISCUSSION: The developed system can effectively be used in voice pathology detection and classification systems, and the proposed features can visually differentiate between normal and pathological samples. PMID- 26522264 TI - Saccharomyces eubayanus and Saccharomyces arboricola reside in North Island native New Zealand forests. AB - Saccharomyces is one of the best-studied microbial genera, but our understanding of the global distributions and evolutionary histories of its members is relatively poor. Recent studies have altered our view of Saccharomyces' origin, but a lack of sampling from the vast majority of the world precludes a holistic perspective. We evaluate alternate Gondwanan and Far East Asian hypotheses concerning the origin of these yeasts. Being part of Gondwana, and only colonized by humans in the last ~1000 years, New Zealand represents a unique environment for testing these ideas. Genotyping and ribosomal sequencing of samples from North Island native forest parks identified a widespread population of Saccharomyces. Whole genome sequencing identified the presence of S. arboricola and S. eubayanus in New Zealand, which is the first report of S. arboricola outside Far East Asia, and also expands S. eubayanus' known distribution to include the Oceanic region. Phylogenomic approaches place the S. arboricola population as significantly diverged from the only other sequenced Chinese isolate but indicate that S. eubayanus might be a recent migrant from South America. These data tend to support the Far East Asian origin of the Saccharomyces, but the history of this group is still far from clear. PMID- 26522265 TI - Summative assessment of clinical practice of student nurses: A review of the literature. AB - OBJECTIVES: To provide an overview of summative assessment of student nurses' practice currently in use. DESIGN: Narrative review and synthesis of qualitative and quantitative studies. DATA SOURCES: With the support of an information specialist, the data were collected from scientific databases which included CINAHL, PubMed, Medic, ISI Web of Science, Cochrane library and ERIC published from January 2000 to May 2014. Sources used in all of the included studies were also reviewed. REVIEW METHODS: 725 articles concerned with student nurse clinical practice assessment were identified. After inclusion and exclusion criteria, 23 articles were selected for critical review. RESULTS: Findings suggest that the assessment process of student nurses' clinical practice lacks consistency. It is open to the subjective bias of the assessor, and the quality of assessment varies greatly. Student nurses' clinical assessment was divided into 3 themes: acts performed before final assessment, the actual final assessment situation and the acts after the final assessment situation. Mentors and students need teachers to provide them with an orientation to the assessment process and the paperwork. Terminology on evaluation forms is sometimes so difficult to grasp that the mentors did not understand what they mean. There is no consensus about written assignments' ability to describe the students' skills. Mentors have timing problems to ensure relevant assessment of student nurses. At the final interview students normally self-assess their performance; the mentor assesses by interview and by written assignments whether the student has achieved the criteria, and the role of the teacher is to support the mentor and the student in appropriate assessment. The variety of patient treatment environments in which student nurses perform their clinical practice periods is challenging also for the assessment of student nurses' expertise. CONCLUSIONS: Mentors want clinical practice to be a positive experience for student nurses and it might lead mentors to give higher grades than what student nurses in fact deserve. It is very rare that student nurses fail their clinical practice. If the student nurse does not achieve the clinical competencies they are allowed to have extra time in clinical areas until they will be assessed as competent. Further research needs to be carried out to have more knowledge about the final assessment in the end of clinical practice. Through further research it will be possible to have better methods for high quality assessment processes and feedback to student nurses. Quality in assessment improves patient safety. PMID- 26522266 TI - Taxonomy of measurement properties: A response to the commentary by Mokkink et al. (2015). PMID- 26522267 TI - Differences in the mechanism of blood clot formation and nanostructure in infants and children compared with adults. AB - INTRODUCTION: Infants and children have a lower incidence of thrombosis compared with adults. Yet, the mechanism of blood clot formation and structure in infants and children, as the end product of coagulation, has not been studied. This study aimed to establish differences in the mechanism of thrombin generation, fibrin clot formation and response to thrombolysis in infants and children compared with adults. MATERIALS AND METHODS: We studied thrombin generation, fibrin clot formation, structure and fibrinolysis in healthy infants, children and adults. RESULTS: Younger populations had a decreased potential to generate thrombin, at a slower velocity compared with adults, correlating positively with age. Clot formation at venous shear rate was decreased in infants and children compared with adults, with increased time for fibrin formation, decreased fibrin formation velocity, resulting in decreased tendency for fibrin formation in younger populations. These differences were less pronounced at arterial shear rate. Studies of the fibrin clot structure in paediatric age groups showed a significantly larger pore size compared with adults, suggestive of a clot that is less resistant to fibrinolysis. The presence of tissue plasminogen activator (tPA) resulted in a significant decrease in the pore size of infants and children, but not in adults. CONCLUSIONS: This is the first study to suggest that the mechanism of blood clot formation and nanostructure, as well as response to thrombolytic therapy is different in infants and children compared with adults. PMID- 26522268 TI - A Study on Hereditary Thrombophilia and Stroke in a Cohort from Sri Lanka. AB - BACKGROUND: Thrombophilia is an enhanced tendency of arterial or venous blood clot formation. The frequently assessed hereditary thrombophilia mutations associated with stroke are methylenetetrahydrofolate reductase (MTHFR) c.677C>T, Factor V (F5) c.1691G>A (Leiden), and prothrombin (F2) c.20210G>A. The aim of this study was to describe the prevalence of the 3 mutations in ischemic stroke patients in Sri Lanka. METHODS: A database of clinical details and genetic test results of stroke patients referred for thrombophilia screening from June 2006 to April 2014 was maintained prospectively and analyzed retrospectively. RESULTS: A total of 400 ischemic stroke patients (319 arterial, 66 venous, and 15 location unreported) were screened for hereditary thrombophilia. Patients with the MTHFR c.677C>T, F5 c.1691G>A, and F2 c.20210G>A mutations were 17.3%, 3.3%, and .5% of the total cohort, respectively. F5 mutation was present in a statistically significant number of patients with venous thrombosis (P = .005) compared to patients with arterial thrombosis. The MTFHR and F2 mutations showed no such significant association. The mean age of patients with MTHFR, F5, and F2 mutations was 29 (+/-15), 34 (+/-11), and 38 (+/-5.6) years, respectively. CONCLUSION: MTHFR c.677C>T is the predominant mutation and the only mutation that had patients with the homozygous mutant genotype. Venous thrombosis showed a significant association with the F5 c.1691G>A mutation. PMID- 26522269 TI - Contributing Mechanisms of Aortic Atheroma in Ischemic Cerebrovascular Disease. AB - In recent years, the correlation between aortic atheroma (AA) and the occurrence and recurrence of ischemic cerebrovascular disease (ICVD) has attracted much attention, but the contributory mechanisms remain controversial. This review analyzes related research on the roles of AA in ICVD, and demonstrates the correlation between the formation and development of AA and abnormal metabolism, inflammation, hemodynamic changes, and other contributory factors. The presence of complex aortic plaque (CAP) in the ascending aorta and aortic arch increases the risk of cerebral embolism and degree of injury, while the association between CAP in the descending aorta and cerebral embolism remains ambiguous. AA also functions as an indicator of atherosclerosis burden as well as hypercoagulability, which may further increase the risk of ICVD. Further study on the relationship of AA to ICVD will improve diagnosis and treatment in clinical practice. PMID- 26522270 TI - NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment. AB - We report two brothers from a non-consanguineous Irish family presenting with a novel syndrome characterised by intellectual disability, facial dysmorphism, scoliosis and long QT. Their mother has a milder phenotype including long QT. X linked inheritance was suspected. Whole exome sequencing identified a novel missense variant (c.128 A > C; p.Tyr43Ser) in NAA10 (X chromosome) as the cause of the family's disorder. Sanger sequencing confirmed that the mutation arose de novo in the carrier mother. NAA10 encodes the catalytic subunit of the major human N-terminal acetylation complex NatA. In vitro assays for the p.Tyr43Ser mutant enzyme showed a significant decrease in catalytic activity and reduced stability compared to wild-type Naa10 protein. NAA10 has previously been associated with Ogden syndrome, Lenz microphthalmia syndrome and non-syndromic developmental delay. Our findings expand the clinical spectrum of NAA10 and suggest that the proposed correlation between mutant Naa10 enzyme activity and phenotype severity is more complex than anticipated; the p.Tyr43Ser mutant enzyme has less catalytic activity than the p.Ser37Pro mutant associated with lethal Ogden syndrome but results in a milder phenotype. Importantly, we highlight the need for cardiac assessment in males and females with NAA10 variants as both patients and carriers can have long QT. PMID- 26522271 TI - Effect of dapagliflozin on colon cancer cell [Rapid Communication]. AB - Dapagliflozin is a SGLT2 (Sodium/Glucose cotransporter 2) inhibitor that reduces circulating glucose levels in type 2 diabetic patients by blocking the SGLT2 dependent reabsorption of glucose in the kidney. Dapagliflozin is metabolized by UGT1A9 (UDP Glucuronosyltransferase 1 family, Polypeptidase A9), suppressing its SGLT2 inhibitor activity. However little information is available on whether dapagliflozin acts in the absence of dapagliflozin metabolism. Treatment with 0.5MUM dapagliflozin significantly reduced the number of HCT116 cells, which express SGLT2 but not UGT1A9. This was independent of SGLT2 inhibition, as the SGLT2 inhibitor phlorizin had no effect. Dapagliflozin also enhanced Erk phosphorylation but without changing levels of uncleaved and cleaved PPAR and uncleaved caspase-3, suggesting that the cause of the decrease in HCT116 cell number was apoptosis independent cell death. Taken together, these data indicate a new potential role for dapagliflozin as an anticancer reagent in tumor cell populations that do not express UGT1A9. PMID- 26522272 TI - Degludec is superior to glargine in terms of daily glycemic variability in people with type 1 diabetes mellitus. AB - To investigate the differences in glycemic variability between the long-acting insulins glargine and degludec using continuous glucose monitoring, we conducted an open-label, multicenter, prospective, observational study that enrolled 21 participants with type 1 diabetes mellitus currently receiving basal-bolus insulin therapy with glargine. To avoid the potential influence of diet and exercise on glycemic control, all participants were housed and monitored within the hospital for the duration of the study. Once glycemic control was achieved with glargine, glycemic variability was evaluated using continuous glucose monitoring for 3 days. Glargine was then replaced by degludec and glycemic variability again assessed via continuous glucose monitoring. The primary outcome measure of mean amplitude of glycemic excursions was significantly reduced with degludec (p = 0.028), as was area under the curve for daily blood glucose level <70 mg/dL (p = 0.046). The required insulin dose was reduced up to 25% in the degludec group, although 24-h mean glucose concentrations were not different between groups. In conclusion, once or twice daily glargine was successfully replaced by a daily injection of degludec. When replacing glargine with degludec, a lower dose should be utilized to avoid hypoglycemia. Degludec is an effective and promising long-acting insulin that reduced hypoglycemia and daily blood glucose variability in participants with type 1 diabetes. PMID- 26522273 TI - Helix 3 acts as a conformational hinge in Class A GPCR activation: An analysis of interhelical interaction energies in crystal structures. AB - A collection of crystal structures of rhodopsin, beta2-adrenergic and adenosine A2A receptors in active, intermediate and inactive states were selected for structural and energetic analyses to identify the changes involved in the activation/deactivation of Class A GPCRs. A set of helix interactions exclusive to either inactive or active/intermediate states were identified. The analysis of these interactions distinguished some local conformational changes involved in receptor activation, in particular, a packing between the intracellular domains of transmembrane helices H3 and H7 and a separation between those of H2 and H6. Also, differential movements of the extracellular and intracellular domains of these helices are apparent. Moreover, a segment of residues in helix H3, including residues L/I3.40 to L3.43, is identified as a key component of the activation mechanism, acting as a conformational hinge between extracellular and intracellular regions. Remarkably, the influence on the activation process of some glutamic and aspartic acidic residues and, as a consequence, the influence of variations on local pH is highlighted. Structural hypotheses that arose from the analysis of rhodopsin, beta2-adrenergic and adenosine A2A receptors were tested on the active and inactive M2 muscarinic acetylcholine receptor structures and further discussed in the context of the new mechanistic insights provided by the recently determined active and inactive crystal structures of the MU-opioid receptor. Overall, the structural and energetic analyses of the interhelical interactions present in this collection of Class A GPCRs suggests the existence of a common general activation mechanism featuring a chemical space useful for drug discovery exploration. PMID- 26522274 TI - Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed. AB - The discovery of genetic drivers of lung cancer in patient sub-groups has led to their use as predictive biomarkers and as targets for selective drug therapy. Some of the most important lung cancer drivers are mutations in the EGFR gene, for example, the exon 19 deletions and the L858R variant that confer sensitivity to the front line drugs erlotinib and gefitinib; the acquired T790M variants confer drug resistance and a poor prognosis. A challenge then in targeting EGFR is to produce drugs that inhibit both sensitising variants and resistance variants, leaving wild type protein in healthy cells unaffected. One such agent is AstraZeneca's "breakthrough" AZD9291 molecule that shows a 200-fold selectivity for T790M/L858R over wild type EGFR. Our X-ray crystal structure reveals the binding mode of AZD9291 to the kinase domain of wild type EGFR. PMID- 26522275 TI - Increased fractional anisotropy in cerebellum in obsessive-compulsive disorder. AB - BACKGROUND: Previous morphology and diffusion-imaging studies have suggested that structural changes in white matter is an important part of the pathophysiology of obsessive-compulsive disorder (OCD). However, different methodological approaches and the heterogeneity of patient samples question the validity of the findings. Materials and methods In total, 30 patients were matched for age and sex with 30 healthy controls. All participants underwent T1-weighted magnetic resonance imaging, diffusion tensor imaging and T2 fluid-attenuated inversion recovery. Voxel-based morphometry and tract-based spatial statistics were used to compare white matter volumes and diffusion tensor imaging between groups. These data were analysed correcting for the effects of multiple comparisons, age, sex, severity and duration of illness as nuisance covariates. White matter hyperintensities were manually identified. RESULTS: Increase in fractional anisotropy in cerebellum was the most prominent result. A decrease in fractional anisotrophy in patients comparable with previous studies was located in forceps minor. There were no differences in the white matter morphology or in the white matter hyperintensities between patients and healthy controls. CONCLUSION: Decrease in fractional anisotrophy in forceps minor and increase in cerebellum were found, and they were not due to neither white matter hyperintensities nor morphology of the white matter. Cerebellar hyperconnectivity could be an important part of OCD pathophysiology. PMID- 26522277 TI - Rothstein Roundtable Podcast-"Putting All of Our Eggs in One Basket: Human Movement System". PMID- 26522276 TI - Long-term changes in sleep duration, energy balance and risk of type 2 diabetes. AB - AIMS/HYPOTHESIS: Baseline sleep duration has a U-shaped relationship with type 2 diabetes, but little research examines the associated changes. We examined long term changes in sleep duration and concomitant changes in diet, physical activity, weight and subsequent diabetes. METHODS: The cohort includes 59,031 women aged 55-83 years in the Nurses' Health Study without diabetes in 2000. Change in sleep duration is the difference between self-reported 24 h sleep duration in 1986 and 2000. Diet, physical activity and covariates were updated every 2-4 years. Self-reported diabetes was confirmed via validated questionnaires. Cox regression models were adjusted for 1986 sleep duration and 1986 values of diabetes risk factors, including BMI, and subsequently for change in covariates from 1986 to 2000. RESULTS: We documented 3,513 incident diabetes cases through to 2012. Compared with no change, decreases in sleep duration were adversely associated with changes in diet quality and physical activity, while increases were associated with greater weight gain. After adjustment for 1986 covariates, HRs (95% CI) for <= -2, > -2 to < 0, > 0 to < 2 and >= 2 h/day changes in sleep duration (vs no change) were 1.09 (0.93, 1.28), 1.10 (1.001, 1.12), 1.09 (1.00, 1.18) and 1.30 (1.14, 1.46), respectively. Additional adjustment for diet and physical activity did not appreciably alter the results. Increases in sleep duration >= 2 h/day remained adversely associated with diabetes (HR [95% CI]: 1.15 [1.01, 1.30]) after adjustment for change in covariates, including BMI. CONCLUSIONS/INTERPRETATION: Increases in sleep duration among middle-aged and older women were modestly associated with risk of diabetes; changes in diet, physical activity and BMI did not explain associations. PMID- 26522278 TI - Modeling the influence of alternative forest management scenarios on wood production and carbon storage: A case study in the Mediterranean region. AB - Forest ecosystems are fundamental for the terrestrial biosphere as they deliver multiple essential ecosystem services (ES). In environmental management, understanding ES distribution and interactions and assessing the economic value of forest ES represent future challenges. In this study, we developed a spatially explicit method based on a multi-scale approach (MiMoSe-Multiscale Mapping of ecoSystem services) to assess the current and future potential of a given forest area to provide ES. To do this we modified and improved the InVEST model in order to adapt input data and simulations to the context of Mediterranean forest ecosystems. Specifically, we integrated a GIS-based model, scenario model, and economic valuation to investigate two ES (wood production and carbon sequestration) and their trade-offs in a test area located in Molise region (Central Italy). Spatial information and trade-off analyses were used to assess the influence of alternative forest management scenarios on investigated services. Scenario A was designed to describe the current Business as Usual approach. Two alternative scenarios were designed to describe management approaches oriented towards nature protection (scenario B) or wood production (scenario C) and compared to scenario A. Management scenarios were simulated at the scale of forest management units over a 20-year time period. Our results show that forest management influenced ES provision and associated benefits at the regional scale. In the test area, the Total Ecosystem Services Value of the investigated ES increases 85% in scenario B and decreases 82% in scenario C, when compared to scenario A. Our study contributes to the ongoing debate about trade offs and synergies between carbon sequestration and wood production benefits associated with socio-ecological systems. The MiMoSe approach can be replicated in other contexts with similar characteristics, thus providing a useful basis for the projection of benefits from forest ecosystems over the future. PMID- 26522279 TI - Influence of carbon dioxide on numbers of Culicoides midges collected with suction light traps in South Africa. AB - To implement risk management against diseases transmitted by species of Culicoides Latreille, 1809 (Diptera: Ceratopogonidae), it is essential to identify all potential vectors. Light traps are the most commonly used tool for the collection of Culicoides midges. Given the indiscriminate artificial attraction of light, traps will collect all night-flying insects rather than only livestock-associated Culicoides midges. Factors that may increase the efficacy of traps, especially for livestock-associated Culicoides midges, require investigation. In the present study, results obtained with Centers for Disease Control (CDC) and Onderstepoort light traps baited with carbon dioxide (CO2 ) were compared with those of unbaited controls. Comparisons were made using two replicates of a 4 * 4 randomized Latin square design. With both trap types, the mean numbers of Culicoides midges collected in 16 baited traps were higher than those caught in 16 unbaited traps. Although exceptionally low numbers were collected with the CDC traps, the increases in the numbers and frequency of collection of Culicoides imicola Kieffer, 1913 were more pronounced in the CDC traps compared with the Onderstepoort traps. These results indicate that the addition of CO2 may increase the efficiency of these traps for the collection of C. imicola and other livestock-associated Culicoides species. PMID- 26522283 TI - [Vaccines: building on scientific excellence and dispelling false myths]. AB - The EU and Italian institutions have recently reiterated their commitment to harmonize and implement vaccination policies as a fundamental strategy for public health. Nonetheless, vaccines are losing public confidence. False myths related to vaccine adverse reactions and commercial interests, combined with the recent judgements of the Court and the "Fluad(r) episode", are fuelling vaccine hesitancy. In such a context, a lively debate is ongoing in Italian scientific community. Aim of this contribution is to recall the available solid scientific evidence demonstrating that vaccines are among the most effective prevention tools ever invented and recall the economic data that support the cost effectiveness of the immunisation. As every other medicine, vaccines are registered after large and solid clinical trials have been conducted. Immunization schedules are proposed by experts in the field of clinical medicine, epidemiology and public health on the basis of the available scientific evidence, and then implemented by policy makers also taking into consideration resources allocation and financial sustainability. The false myth that vaccines are offered because of economic interests is to be dispelled;moreover, researchers, policy makers, scientific societies and the healthcare community at large should renew commitment to invest in health education and communication on vaccines, always disclosing potential conflicts of interests. PMID- 26522284 TI - Neovascularization of osteoporotic metaphyseal bone defects: A morphometric micro CT study. AB - PURPOSE: Neovascularization is essential for bone regeneration in fractures. This study aimed to investigate the microvascular morphology and distribution in the non-injured femur and the neovascularization of the metaphyseal critical size defect in a small animal model of osteoporosis. MATERIALS AND METHODS: Female rats (n=7) were ovariectomized (OVX) and received a multideficiency diet. Three months after OVX, a 5mm wedge shaped critical size defect was cut at the distal femoral metaphysis and stabilized with a T-shaped mini-plate. After six weeks, the animals were euthanized, and femora were removed and decalcified for micro-CT measurement of fracture neovascularization. RESULTS: No fracture healing was observed along the critical size defects. In the non-injured bone, micro-vessel distribution showed a specific pattern, thereby enabling a differentiation between epi-, meta- and diaphysis. Micro-CT based morphometry revealed a significant reduction of the vascular volume fraction as well as the vascular thickness (p<0.001) in the critical size defect compared to the intact contralateral femur. Blood volume related vascular surface (vascular surface/volume) increased significantly (p<0.001). Connectivity density and tissue volume related vascular surface (vascular surface density) did not change significantly. CONCLUSIONS: Micro-CT based vascular morphometry demonstrated differences between epi-, meta- and diaphysis in the non-injured bone as well as differences between the critical size defect and the non-injured metaphysis. As angiogenesis is a crucial prerequisite that precedes osteogenesis, our results may influence further evaluation of osteoconductive or osteogenic biomaterials in this small animal model of osteoporosis. PMID- 26522285 TI - p27(Kip1) and p21(Cip1)-independent proliferative inhibition of vascular smooth muscle cells cultured in type-I collagen matrix honeycombs. AB - The proliferation of vascular smooth muscle cells (SMCs) contributes to atherosclerotic plaque formation and restenosis. Cyclin-dependent kinase inhibitors, such as p27(Kip1) and p21(Cip1), are known to play significant roles in the control of the aberrant proliferation of SMCs. Primary cultured SMCs stop proliferating immediately when cultured in three-dimensional matrices of type-I collagen "honeycombs" structures. To clarify whether p27(Kip1) and p21(Cip1) are involved in the proliferative inhibition of SMCs cultured in honeycombs, the characteristics of SMCs derived from the aorta of both wild-type mice (p27[+/+] SMCs) and p27(Kip1) knockout mice (p27[-/-] SMCs) were investigated. Although the growth of p27(-/-) SMCs cultured on plates was faster than that of p27(+/+) SMCs, the number of both p27(+/+) and p27(-/-) SMCs did not change when they were cultured in honeycombs. p21(Cip1) expression was decreased but maintained in p27( /-) SMCs cultured on plates and in honeycombs. Knockdown of p21(Cip1) in p27(-/-) SMCs promoted proliferation on plates. On the contrary, p21(Cip1) knockdown had no effect on the proliferation of p27(-/-) SMCs cultured in honeycombs. In conclusion, p27(Kip1) and p21(Cip1) are insufficient for the proliferative inhibition of SMCs cultured in honeycombs. PMID- 26522286 TI - Dysregulated endocardial TGFbeta signaling and mesenchymal transformation result in heart outflow tract septation failure. AB - Heart outflow tract septation in mouse embryos carrying mutations in retinoic acid receptor genes fails with complete penetrance. In this mutant background, ectopic TGFbeta signaling in the distal outflow tract is responsible for septation failure, but it was uncertain what tissue was responsive to ectopic TGFbeta and why this response interfered with septation. By combining RAR gene mutation with tissue-specific Cre drivers and a conditional type II TGFbeta receptor (Tgfbr2) allele, we determined that ectopic activation of TGFbeta signaling in the endocardium is responsible for septation defects. Ectopic TGFbeta signaling results in ectopic mesenchymal transformation of the endocardium and thereby in improperly constituted distal OFT cushions. Our analysis highlights the interactions between myocardium, endocardium, and neural crest cells in outflow tract morphogenesis, and demonstrates the requirement for proper TGFbeta signaling in outflow tract cushion organization and septation. PMID- 26522287 TI - Molecular dynamics of water and monovalent-ions transportation mechanisms of pentameric sarcolipin. AB - The Sarcolipin (SLN) is a transmembrane protein that can form a self-assembled pentamer. In this work, the homology modeling and all-atom molecular dynamic (MD) simulation was performed to study the model of SLN pentamer in POPC (1-palmitoyl 2-oleoyl-sn-glycero-3-phosphocholine) membrane. The potential of mean force (PMF) was calculated for transmembrane transportation of Na(+), Cl(-) and water molecule along the pore channel of penta-SLN complex. The root mean square deviation (RMSD) of the SLN pentamer in POPC membrane showed that the stabilized SLN protein complex could exist in the membrane and that the Na(+) and Cl(-) could not permeate through the channel when the pore was under the vacuum state, but the water could permeate through from cytoplasm to lumen. Under the aqueous state, our simulation demonstrated that hydrated state of Na(+) and Cl(-) could pass through the channel. The PMF and radii of the pore showed that the channel had a gate at Leu(21) that is a key hydrophobicity residue in the channel. Our simulations help to clarify and to understand better the SLN pentamer channel that had a hydrophobic gate and could switch Na(+) and Cl(-) ion permeability by hydrated and vacuum states. PMID- 26522288 TI - [Respiratory assesment in people with spinal cord injury]. PMID- 26522289 TI - High-throughput 3D tracking of bacteria on a standard phase contrast microscope. AB - Bacteria employ diverse motility patterns in traversing complex three-dimensional (3D) natural habitats. 2D microscopy misses crucial features of 3D behaviour, but the applicability of existing 3D tracking techniques is constrained by their performance or ease of use. Here we present a simple, broadly applicable, high throughput 3D bacterial tracking method for use in standard phase contrast microscopy. Bacteria are localized at micron-scale resolution over a range of 350 * 300 * 200 MUm by maximizing image cross-correlations between their observed diffraction patterns and a reference library. We demonstrate the applicability of our technique to a range of bacterial species and exploit its high throughput to expose hidden contributions of bacterial individuality to population-level variability in motile behaviour. The simplicity of this powerful new tool for bacterial motility research renders 3D tracking accessible to a wider community and paves the way for investigations of bacterial motility in complex 3D environments. PMID- 26522290 TI - Is there a way out for the 2014 Ebola outbreak in Western Africa? AB - The 2014 Ebola outbreak in West Africa, primarily affecting Guinea, Sierra Leone, and Liberia, has exceeded all previous Ebola outbreaks in the number of cases and in international response. Although infections only occur frequently in Western Africa, the virus has the potential to spread globally and is classified as a category A pathogen that could be misused as a bioterrorism agent. This review aims (i) to discuss the latest data to aid our current recommendations for the prevention and control of the Ebola virus infection, (ii) to review its pathophysiology as well as offering insights on the most current data available about Ebola vaccine progress and potential use. PMID- 26522291 TI - Bithynia siamensis goniomphalos, the first intermediate host of Opisthorchis viverrini in Thailand. AB - Opisthorchiasis caused by Opisthorchis viverrini (O. viverrini) remains as medically important problem in Thailand especially in the north-eastern part. Infection with this parasite can lead to cholangiocarcinoma improvement. The highest prevalence of O. viverrini infection has been found in the Northeast Thailand and is associated with the high incidence rate of cholangiocarcinoma. To complete the life cycle of O. viverrini, the freshwater snails namely Bithynia funiculata, Bithynia siamensis siamensis and Bithynia siamensis goniomphalos (B. s. goniomphalos) are required to serve as the first intermediate host. Within these snails group, B. s. goniomphalos is distributed concisely in northeast Thailand and acts as the majority snail that transmitted the opisthorchiasis in this region. This study described the information of B. s. goniomphalos which research are needed for understanding the biology, distribution, transmission and factors influencing on the infection of the snail vector of this carcinogenic parasite. PMID- 26522292 TI - Is toxoplasmosis a potential risk factor for liver cirrhosis? AB - OBJECTIVE: To document Toxoplasma gondii (T. gondii) antibody status in patients with liver disease, blood samples were taken from 180 hepatic patients and 180 healthy controls. METHODS: Toxoplasma IgG antibody was detected using enzyme linked immunosorbent assay and histopathological assessment of liver biopsy METAVIR score was applied. RESULTS: Anti-T. gondii IgG antibodies were found in 32.8% of patients and in 22.2% of controls (P = 0.02). Toxoplasma seropositivity was significantly associated with lymphadenopathy, history of blood transfusion and reflex impairment in patients. Chronic hepatitis C virus (HCV) and chronic HCV-related cirrhosis groups compared to chronic HBV and chronic HBV-related cirrhosis groups expressed significantly higher prevalence of T. gondii seropositivity (odds ratio (OR) = 4; 95% confidence interval (CI): 1.3-12.6; P = 0.013, OR = 4.8; 95% CI: 1.5-14.9; P = 0.006, respectively). Within the chronic HCV group, T. gondii seropositivity significantly associated disease evolution as regards to METAVIR histopathological system for fibrosis and inflammation (OR = 19.4; 95% CI: 2.3-165.2; P = 0.0008, OR = 0.29; 95% CI: 0.1-0.8; P = 0.01, respectively). Albumin, international normalized ratio (INR) and platelets count were the laboratory parameters significantly altered in Toxoplasma-positive chronic HCV patients (P = 0.001, 0.03, 0.04, respectively). Child-Pugh scoring for cirrhosis in chronic HCV group placed the majority of seropositive patient in class C with significant statistical difference compared to Child A reference group (OR = 0.08; 95% CI: 0.01-0.5; P = 0.003). CONCLUSIONS: Toxoplasma seropositivity was high in patients with cirrhosis and associated higher grades of inflammation and necrosis signifying disease evolution, suggesting that cirrhotic patients may thus form a risk group for toxoplasmosis. PMID- 26522293 TI - Effects of Gastrodiae rhizoma on proliferation and differentiation of human embryonic neural stem cells. AB - OBJECTIVE: To investigate the effects of Gastrodiae rhizoma, a dried root of Gastrodia elata Blume, on proliferation and differentiation of human NSCs derived from embryonic stem cells. METHODS: A 70% ethanol extract of Gastrodiae rhizoma (EEGR) was estimated with 4-hydroxybenzyl alcohol as a representative constituent by HPLC. RESULTS: MTT assay showed that the treatment with EEGR increased the viability of NSCs in growth media. Compared to control, EEGR increased the number of dendrites and denritic spines extended from a differentiated NSC. Whereas EEGR decreased the mRNA expression of Nestin, it increased that of Tuj1 and MAP2 in NSCs grown in differentiation media. Immunocytochemical analysis using confocal microscopy also revealed the increased expression of MAP2 in dendrites of EEGR treated NSCs. Furthermore, EEGR decreased mRNA expression of Sox2 in NSCs grown even in growth media. CONCLUSIONS: In conclusion, our study demonstrates for the first time that EEGR induced proliferation and neuronal differentiation of NSCs, suggesting its potential benefits on NSC-based therapies and neuroregeneration in various neurodegenerative diseases and brain injuries. PMID- 26522294 TI - Potential of four marine-derived fungi extracts as anti-proliferative and cell death-inducing agents in seven human cancer cell lines. AB - OBJECTIVE: To evaluate the in vitro anticancer activity of crude ethyl acetate extracts of the culture of four marine-derived fungi Aspergillus similanensis KUFA 0013 (E1), Neosartorya paulistensis KUFC 7897 (E2), Neosartorya siamensis KUFA 0017 (E4) and Talaromyces trachyspermus KUFC 0021 (E3) on a panel of seven human cancer cell lines. METHODS: Effects on cell proliferation, induction of DNA damage and cell death were assessed by MTT and clonogenic assays, comet assay and nuclear condensation assay, respectively. RESULTS: The proliferation of HepG2, HCT116 and A375 cells decreased after incubation with the extracts E2 and E4. The anti-proliferative effect was confirmed by morphologic alterations and by clonogenic assay. Both extracts also induced cell death in HepG2 and HCT116 cells. Doxorubicin was used as a positive control and showed in vitro anticancer activity. CONCLUSIONS: This study demonstrated, for the first time, that extracts of Neosartorya paulistensis and Neosartorya siamensis have selective anti proliferative and cell death activities in HepG2, HCT16 and A375 cells. The bioactivity of these extracts suggests a potential for biotechnological applications and substantiates that both should be further considered for the elucidation of the molecular targets and signal transduction pathways involved. PMID- 26522295 TI - Regulatory effect of miRNA 320a on expression of aquaporin 4 in brain tissue of epileptic rats. AB - OBJECTIVE: To study the expression of miRNA 320a in the brain tissue of epileptic rats and analyze its effect on the expression of aquaporin 4 (AQP4). METHODS: All rats were performed with the intraperitoneal injection of lithium chloride (3 mmol/kg) and then the intraperitoneal injection of pilocarpine (30 mg/kg) 24 h later (injected twice) to prepare the epileptic model of Wistar rats. Rats in the control group were injected with the equal volume of normal saline. According to the Racine scale, rats with over stage 3 of epilepsy were chosen and the brain tissue was separated quickly and then stored at -80 degrees C. The immunohistochemistry was used to detect the expression of aquaporin in the brain tissue of epileptic model and the Real-time PCR was employed to determine the difference in the expression of miRNA 320a and AQP4 in the brain tissue of rats between the epileptic model group and control group. Five 5-day neonatal Wistar rats were chosen to collect the cerebral cortex and their primary astrocytes were separated and cultured. They were transfected with miRNA mimic and imitated to the endogenous miRNA 320a to up-regulate the expression of miRNA 320a. RESULTS: In the model group, the expression of AQP4 was significantly higher than the control group (P < 0.01). However, the expression of miRNA 320a in the model group was lower than control group (P < 0.05), which was negatively correlated to AQP4. In the primary astrocytes, the transfection of miRNA 320a mimic could significantly reduce the expression of AQP4, while its inhibitor could up regulate the expression of AQP4, which indicated that miRNA 320a could reduce the expression of AQP4. CONCLUSIONS: In the primary astrocytes of rats, the miRNA 320a could inhibit the expression of AQP4 and after adding the inhibitor of miRNA 320a, the expression of AQP4 was up-regulated. PMID- 26522296 TI - Effect of overexpression of hypoxia-inducible factor-1alpha induced by hyperoxia in vivo in LNCaP tumors on tumor growth rate. AB - OBJECTIVE: To study effect of overexpression of hypoxia-inducible factor-1alpha induced by hyperoxia in vivo in LNCaP tumors on tumor growth rate. METHODS: The prostate cancer LNCaP cells were inoculated in the abdomen of mice. All the mice were randomly placed in the gas chamber with different oxygen content. The groups were divided as follows: twelve mice in hypoxia group, sixteen mice in normoxia group, ten mice in hyperoxia group. After 28 d of treatment, the mice were weighed, the blood samples were taken from the left ventricle, and the tumor was isolated and weighed. Tumor growth, angiogenesis and vascularization, HIF-1alpha expression and intracellular signal transduction molecules expression in each group of xenografts were detected and analyzed by using Western blotting and immunofluorescence and determination of hemoglobin. RESULTS: Comparison of the growth of xenografts in each group showed that, the xenografts growth of hypoxia group was more quickly than that of normoxia group. The difference was statistically significant (P = 0.004). The difference in xenografts growth between hyperoxia group compared and normoxia group was not statistically significant (P > 0.05). The expressions of HIF-1alpha, VEGF and VEGF-R of xenografts in hyperoxia group were significantly higher than those of normoxia group (P < 0.05). The expression of HIF-1alpha of xenografts in hypoxia group and normoxia group were similar. The blood growth rate of xenografts in hypoxia group (170%) was significantly higher than that of normoxia group (40%) (P < 0.05). The expression of Nrf2 of xenografts in hyperoxia group was significantly higher than that of normoxia group (P < 0.05). CONCLUSIONS: When hyperoxia induces the overexpression of HIF-1alpha in LNCaP tumor, it will not affect tumor growth. It provides a new ideas and theoretical basis for the clinical treatment of prostate cancer. PMID- 26522297 TI - Effect of siRNA on Wisp-1 gene expression, proliferation, migration and adhesion of mouse hepatocellular carcinoma cells. AB - OBJECTIVE: To study the inhibition effect of siRNA on the expression of Wisp-1 gene in Hca-F of mouse hepatocellular carcinoma cells strain and also its effect on the proliferation, migration and adhesion of hepatocellular carcinoma cells. METHODS: Three expression vectors of siRNA were constructed. Lipo2000 was employed to transfect Hca-F cells and Western blot was used to detect the inhibition effect of siRNA on the expression of Wisp-1 gene. Afterward, CCK8 was adopted to detect the effect of Wisp-1 siRNA on the proliferation of Hca-F cells; Annexin V-FITC/PI double staining flow cytometry was used to detect the effect of Wisp-1 siRNA on the apoptosis of Hca-F cells; Transwell was used to detect the effect of Wisp-1 siRNA on the migration of Hca-F cells. The in vitro cell adhesion kit was used to detect of Wisp-1 siRNA on the change in the components of extracellular matrix to which Hca-F cells adhered. Western blot was used to detect the activation of protein kinase B (AKT)/glycogen synthase kinase-3beta pathway and the expression of downstream target protein p53 and matrix metalloproteinases-2. RESULTS: The siRNA showed interference effect on the expression of Wisp-1 gene. Compared with the control group, after being transfected to cells, Wisp-1 siRNA could significantly inhibit the proliferation, migration and adhesion of Hca-F cells and also promote the cell apoptosis, which was related to the down-regulated phosphorylation of AKT and glycogen synthase kinase-3beta and the expression of p53 and matrix metalloproteinases-2 (P < 0.05). CONCLUSIONS: The inhibition of Wisp-1 expression can reduce the proliferation, migration and adhesion of mouse hepatocellular carcinoma cells, which is related to the AKT/glycogen synthase kinase-3beta pathway. Wisp-1 gene may be the potential target to cure the hepatocellular carcinoma. PMID- 26522298 TI - Effect of microRNA-155 on angiogenesis after cerebral infarction of rats through AT1R/VEGFR2 pathway. AB - OBJECTIVE: To explore the function and mechanism of microRNA-155 to regulate the angiogenesis after the cerebral infarction of rats through the angiotensin II receptor 1 (AT1R)/vascular endothelial growth factor (VEGF) signaling pathway. METHODS: Female SD rats were chosen for the construction of cerebral infarction model of rats using the modified right middle cerebral artery occlusion. The real time PCR (RT-PCR) method was employed to detect the expression of microRNA-155 in each group at different time points after the cerebral infarction (1 h, l d, 3 d and 7 d). SD rats were randomly divided into four groups (n = 20 rats): sham operation group (Sham group), MACO group, MACO+microRNA-155 mimic group, and MACO+microRNA-155 inhibitor group. Sham group was given the free graft, while MACO+microRNA-155 mimic group and MACO+microRNA-155 inhibitor group were treated with microRNA-155 mimic and microRNA-155 inhibitor respectively. The Zea Longa 5 point scale was used to score the neurologic impairment of rats in each group; 2, 3, 5-triphenyl tetrazolium chloride staining to evaluate the volume of cerebral infarction of rats in each group; the immunohistochemistry to detect the expression of CD31; Western blot and RT-PCR to detect the expression of AT1R and VEGF receptor 2 (VEGFR2). RESULTS: The expression of microRNA-155 was increased in the cerebral ischemia tissue after the cerebral infarction. It was significantly increased at 1 d of ischemia and maintained at the high level for a long time. Rats in the Sham group had no symptom of neurologic impairment, while rats in the MACO group had the obvious neurologic impairment. After being treated with microRNA-155 inhibitor, the neural function of MACO rats had been improved, with the decreased area of cerebral infarction. But after being treated with microRNA-155 mimic, the neural function was further worsened, with the increased area of cerebral infarction. Results of immunohistochemical assay indicated that microRNA-155 inhibitor could up-regulate the expression of CD31, while microRNA 155 mimic could down-regulate the expression of CD31. The RT-PCR found that, after being treated with microRNA-155 inhibitor, MACO rats had the increased expression of AT1R and VEGFR2 messenger RNA (mRNA); but after being treated with microRNA-155 mimic, the expression of AT1R and VEGFR2 mRNA was decreased. Results of Western blot showed that, after being treated with microRNA-155 inhibitor, MACO rats had the increased expression of AT1R and VEGFR2 mRNA; but after being treated with microRNA-155 mimic, the expression of AT1R and VEGFR2 mRNA was decreased. CONCLUSIONS: The inhibition of microRNA-155 can improve the neurologic impairment of rats with the cerebral infarction, reduce the volume of cerebral infarction and effectively promote the angiogenesis in the region of ischemia, which may be mediated through AT1R/VEGFR2 pathway. PMID- 26522299 TI - Effect of preemptive local injection of ropivocaine with dexmedetomidine on mirror pain in rats and its mechanism. AB - OBJECTIVE: To observe the effect of preemptive local injection of ropivocaine with dexmedetomidine on activation of glial cells and on the mirror pain in rats and its mechanism. METHODS: A total of 48 adult male Sprague-Dawley rats (weighing 180 g-220 g) were included in the study and randomized into 3 groups, Group S, Group R, and Group RD1. A rat model of persistent postoperative pain evoked by skin/muscle incision and retraction was established in the three groups. Before procedures and nerve extraction, Group S (n = 16) was injected 0.9% saline locally; Group R (n = 16) was injected 0.5% ropivocaine locally, and Group RD1 (n = 16) was injected 0.5% ropivocaine in combined with 1 MUg dexmedetomidine locally. After the model being established in the three groups, 8 rats were used for behavior test until 28 d, and dorsal root ganglions (DRGs) of the other 8 rats were harvested on the 3rd day after surgery. Immunofluorescent and transmission electron microscopy were used to observe the activation of glial cells in DRG, and the behavior test results in the three groups were compared. RESULTS: The results showed that mechanical pain threshold in ipsilateral hind paws of the Group S, Group R, Group RD1 animals dropped to (3.640 +/- 1.963) g, (5.827 +/- 1.204) g, (7.482) +/- 1.412 g at 3 d respectively; while in contralateral paws dropped to (7.100 +/- 1.789) g, (17.687 +/- 1.112) g, (16.213 +/- 1.345) g on the 3 d respectively. Immunofluorescent showed that the glial cells were activated in bilateral side DRG after surgery in 3 groups, but ipsilateral paws expressed more active glial cells than contralateral paws. Transmission electron microscopy showed that mitochondria swelling/vacuolization and lysosomes were more obvious in ipsilateral paws than contralateral paws, but Group RD1 formula could reduce glial cells activity, mitochondria swelling/vacuolization and the amount of lysosomes. CONCLUSIONS: Local injection of ropivocaine and/or dexmedetomidine can effectively inhibit the activation of glial cells in DRG, mitigate the pathological changes of neuron in DRG and reduce mirror image pain. PMID- 26522300 TI - Effect of Rheum palmatum L. on NF-kappaB signaling pathway of mice with acute liver failure. AB - OBJECTIVE: To explore the regulation effect of Rheum palmatum (R. palmatum) L. on NF-kappaB signaling pathway of ALF mice. METHODS: The intraperitoneal injection of d-GalN/LPS was employed for the model building. Mice in the treatment group and positive control group were given the R. palmatum L. and bifendate before the model building. Mice in the normal group were given the intraperitoneal injection of equivalent normal saline for continuously 3 d. After 16 h of model building, the blood was collected from eyeballs of mice and then mice were executed. The measurement was performed on the content of ALT, AST, NO and Il-1beta in the serum of mice in each group, as well as the activity of Caspase 3 and Caspase 8 in the liver tissue. HE staining was employed to detect the pathological morphology of liver; and the western blot was used to detect the expression of iNOS, COX-2, Bax, Bcl-2, PCNA, NF-kappaB p65 and IkappaBalpha. RESULTS: The content of ALT, AST, NO and Il-1beta in the serum and the activity of Caspase 3 and Caspase 8 in the liver tissue were increased in the mice of ALF model group. Besides, the expression of iNOS, COX-2 and Bax was increased, the expression of Bcl-2 and PCNA was decreased, the phosphorylation of NF-kappaB p65 and IkappaBalpha was significant and the treatment group of R. palmatum L. could inhibit such change. CONCLUSIONS: Through NF-kappaB signaling pathway, the R. palmatum L. could reduce the content of enzyme of liver function and inflammation factor in the serum of ALF mice, regulate the expression of cell apoptosis related protein and improve the symptoms of ALF mice. PMID- 26522301 TI - Expression of HIP/PAP in hepatocellular carcinoma and effect of siRNA on migration and invasion in HCC cells. AB - OBJECTIVE: To investigate the expression of HIP/PAP in hepatocellular carcinoma (HCC) patients and explore its role in migration and invasion of HCC. METHODS: The expression of HIP/PAP in HCC tissue and corresponding adjacent noncancerous tissue was assessed by IHC, RT-PCR and Western blot. The correlation between clinicopathological features and HIP/PAP expression was analyzed. The role of HIP/PAP on invasion and migration of HCC cells was observed by RNA interference, wound healing and Transwell assay. RESULTS: Both mRNA and protein expression of HIP/PAP was upregulated in HCC tissues compared to tumor-adjacent tissue and correlated with poor tumor differentiation, advanced tumor stage and vascular invasion. HIP/PAP expression was also upregulated in HCC cells, and silencing its expression by specific siRNA could inhibit the invasion and migration of HCC cells. CONCLUSIONS: HIP/APA is overexpressed in HCC and contributes to the migration and invasion of HCC cells. PMID- 26522302 TI - Effect of HDAC-6 on PD cell induced by lactacystin. AB - OBJECTIVE: To explore the effects of histone deacetylase 6(HDAC-6) on the PD cell model induced by proteasome inhibitor lactacystin. METHODS: Human neuroblastoma SK-N-SH cells were cultured. The wild type pcDNA3.1-alpha-synuclein eukaryotic expression plasmid was transferred into the cells which then were divided into control group, group L, group T and group T+L. The cells of group L were added with 5 MUmol/L lactacystin dissolved indimethylsulfoxide (DMSO) to induce PD cell model with abnormal protein aggregation, the cells of control group were treated with 5 MUmol/L DMSO, the cells of group T were treated with 5 MUmol/L selective HDAC-6 inhibitor tubacin dissolved in DMSO, and the cells of group T+L were treated with 5 MUmol/L lactacystin and 10 MUmol/L tubacin dissolved in DMSO. The expression levels of alpha-synuclein oligomers, HSP-27 and HSP-70 were detected by Western blot and the cell survival rate of all the groups was detected by MTT colorimetric assay, and compared 24 h after the cells were treated. RESULTS: The expression levels of alpha-synuclein oligomers, HSP-27 and HSP-70 of the cells of group L were significantly higher than the control group, and the cell survival rate was significantly lower (P < 0.05); the expression level of alpha-synuclein oligomers of the cells of group T+L was significantly higher than group L, but the expression level of HSP-27 and HSP-70 were significantly lower, and so as the cell survival rate (P < 0.05); the differences of the expression level of alpha synuclein oligomers, HSP-27 and HSP-70 and the cell survival rate of the cells of group T and the control group were not statistically significant (P > 0.05). CONCLUSIONS: The expression level of alpha-synuclein oligomers can be improved and the cell survival rate can be reduced by the PD cell model induced by lactacystin and treated with selective HDAC-6 inhibitor tubacin, which means that alpha-synuclein oligomers of the PD cell model induced by lactacystin can be inhibited and the cell survival rate can be improved by HDAC-6, and the mechanism may be related to the increased of HSP-27 and HSP-70. PMID- 26522303 TI - Effect of Yaobitong capsule on histomorphology of dorsal root ganglion and on expression of p38mark phosphorylation in autologous nucleus pulposus transplantation model of rats. AB - OBJECTIVE: To discuss the effect of Yaobitong capsule on histomorphology of dorsal root ganglion and on expression of p38MARK phosphorylation in autologous nucleus pulposus transplantation model of rats. METHODS: A total of 60 SD rats were randomly divided into the blank group, model group and Yaobitong capsule group, with 20 rats in each group. The animal model of autologous nucleus pulposus transplantation around the lumbar nerve root was built. Three days after the modeling, rats were given the drugs for the first time, while rats in the model group were given the equivalent normal saline. After 30 d of continuous administration, samples were collected from rats. HE staining was performed on the dorsal root ganglion of L4 and L5 spinal cord of rats in each group and the expression of p38MARK phosphorylation was measured. All data were treated with the statistical analysis. RESULTS: The histological examination showed that the histomorphology of dorsal root ganglion in the Yaobitong capsule group was more significantly improved than the one in the model group, while the results of western blot showed that Yaobitong capsule could significantly inhibit the level of p38MAPK phosphorylation of dorsal root ganglion cells. CONCLUSIONS: Yaobitong capsule can improve the symptoms and nerve radiculopathy of autologous nucleus pulposus transplantation of rats and its mechanism may be associated with its inhibiting effect on the level of p38MAPK phosphorylation. PMID- 26522304 TI - Blood pH in coronary artery microthrombosis of rats. AB - OBJECTIVE: To study the mechanism and significance of pH change in the coronary artery microthrombosis of rats. METHODS: After the sodium laurate-induced model of coronary artery microthrombosis of rats was constructed, the vascular endothelial cells were separated and then cultured in the mediums with different pH values for 24 h. Enzyme linked immunosorbent assay was used to detect the content of von Willebrand factor (vWF) in the medium; while the real-time PCR and western blot assay were used to detect the expression of fibrinogen-like protein 2 (FGL2) at the mRNA and protein level. The comprehensive evaluation was performed to discuss the effect of pH change on the coronary artery microthrombosis of rats. RESULTS: The expression level of vWF detected by enzyme linked immunosorbent assay was 336.67 +/- 24.95, 311.33 +/- 14.98, 359.67 +/- 39.63, 354.67 +/- 49.01 and 332.00 +/- 33.42 (pg/mL) respectively; while the expression of vWF in the model group was 570.00 +/- 57.94, 524.67 +/- 57.94, 437.00 +/- 95.38, 415.33 +/- 44.38 and 444.67 +/- 74.31 respectively. Being cultured under the different pH values, the relative expression level of FGL2 mRNA in the model group was 7.93 +/- 0.93, 6.70 +/- 0.70, 5.03 +/- 0.32, 5.13 +/- 0.40 and 5.57 +/- 0.83 respectively. CONCLUSIONS: The coronary artery microthrombosis of rats can cause the high expression and secretion of vWF. Meanwhile, FGL2 is also up-regulated in the thrombosis and such up-regulation is more significant in the condition with low pH, which indicates that the low pH condition may be one of factors that contribute to the cardiovascular diseases. PMID- 26522305 TI - Expression of serum Dickkopf-1 in gastric cancer patients. AB - OBJECTIVE: To explore the expression and clinical significance of DKK-1 protein in patients with gastric cancers. METHODS: Enzyme linked immuno sorbent assay was used to detect expressions of serum DKK-1 protein in 90 cases of gastric cancers, 50 cases of gastric benign disease and 40 healthy cases. The dynamic change in serum DKK-1 protein of gastric cancer patients who accepted radical operation for a month was also observed. RESULTS: The expression of serum DKK-1 protein in gastric cancer groups was significantly higher than that in gastric benign group's (P < 0.01) and in health control (P < 0.01). Serum DKK-1 level was increased gradually along with the progress of the disease. Serum DKK-1 levels were significantly higher in patients at TNM staging III and IV than patients at TNM staging I and II. Level of serum DKK-1 was related to microvascular invasion, differentiation degree and infiltration depth. Level of serum DKK-1 was significantly reduced in patients after radical surgery (P < 0.01). CONCLUSIONS: The expression of serum DKK-1 protein in gastric cancer patients is increased. Level of serum DKK-1 is related to TNM staging, microvascular invasion, differentiation degree and infiltration depth. DKK-1 detection can be used as a reference index in monitoring gastric cancer progress and biological behavior. PMID- 26522306 TI - Therapeutic effect and mechanism of breviscapine on cisplatin-induced nephrotoxicity in mice. AB - OBJECTIVE: To observe the protective effect of breviscapine on mice with cisplatin-induced nephrotoxicity. METHODS: Mice were given a single injection of cisplatin (8 mg/kg, i.p.); then, breviscapine was given to mice at 25 mg/kg and 50 mg/kg doses, respectively, once a day for seven days. Renal tissue structure was observed after animals were sacrificed. Blood urea nitrogen (BUN), serum creatinine (Scr), lipid peroxide (MDA) and superoxide dismutase (SOD) serum levels were detected; and MDA, glutathione peroxidase, and SOD levels in the renal cortex were detected. RESULTS: Compared with the blank control group (BCG), the kidney pathological damage of mice in the model control group (MCG) was more severe. After applying different doses of breviscapine, different degrees of renal injury improvement appeared. Compared with the BCG, the serum levels of Scr and BUN in the MCG increased to (89.92 +/- 6.78) MUmoL/Land (15.32 +/- 4.53) mmoL/L. The differences were statistical significant (P < 0.01). Compared with the MCG, the serum levels of Scr and BUN in the Bre low-dose groups and Bre high dose groups decreased significantly (P < 0.05). Compared with the BCG, the MDA levels in serum and in the renal cortex in the MCG significantly increased, while the SOD levels significantly decreased. Both the differences were statistically significant (P < 0.01). In the Bre low-dose groups and Bre high-dose groups, MDA levels in serum and in the renal cortex significantly decreased, while SOD and glutathione peroxidase levels in the renal cortex significantly increased, compared with the MCG; and the differences were statistically significant (P < 0.05). CONCLUSIONS: Breviscapine can reduce cisplatin-induced renal toxicity in mice and it's possible through inhibition of renal tubule cell lipid peroxidation and reduces the nephrotoxicity of cisplatin. PMID- 26522307 TI - Fatal case of amoebic liver abscess in a child. AB - We reported a case of amoebic liver abscess (ALA) in a 6-year-old Malaysian boy who presented with fever, lethargy, diarrhoea and right hypochondriac pain. On admission he was diagnosed with perforated acute appendicitis and a laparotomy was done. After surgery he developed acute respiratory distress. Ultrasonography, chest X-Ray and CT scan revealed two ALAs in the posterior segment of right lobe of liver, pleural effusion and collapsed consolidation of lungs bilaterally. Percutaneous liver abscesses drainage was done and intravenous Metronidazole was started. PCR carried out on the pus from the abscess was positive for Entamoeba histolytica. Patient however succumbed to the infection one week after admission. PMID- 26522308 TI - Combination of antitumour necrosis factor-alpha and anti-interleukin-12/23 antibodies in refractory psoriasis and psoriatic arthritis: a long-term case series observational study. PMID- 26522309 TI - A membrane introduction mass spectrometer utilizing ion-molecule reactions for the on-line speciation and quantitation of volatile organic molecules. AB - RATIONALE: The ability of membrane introduction mass spectrometry to quantitatively resolve low molecular weight volatile organic compounds (VOCs) such as benzene, toluene, ethylbenzene and xylene (BTEX) using electron ionization (EI) can be compromised by isobaric interferences. This work focuses on reducing isobaric interferences with ion-molecule reactions in a portable quadrupole ion trap mass spectrometer for the analysis of VOCs. METHODS: EI was used to produce reagent ions from precursors (chloroform, methyl iodide, trichloroethylene or chlorobenzene) that were continually infused into the helium acceptor phase upstream of the membrane introduction mass spectrometry (MIMS) sampling interface. The reagent ions were selectively stored in the ion trap, and then allowed to react with target VOC analytes in air samples via ion-molecule reactions within the trap storage volume. A variety of reaction times were examined (50-5000 ms), and the resulting product ions were analyzed in positive ion mode. RESULTS: The detection limits achieved were comparable with those obtained using EI (low ppbv), and in some cases better than for EI coupled with tandem mass spectrometry (MS/MS). For the VOCs studied, isobaric interferences were greatly reduced or eliminated using chloroform as a reagent gas. The predominant ionization mechanism was via adduct formation, although charge transfer and hydride abstractions were also observed. An internal standard was shown to be effective at correcting for signal changes due to consumption of reagent ions when complex mixtures were sampled. CONCLUSIONS: Ion-molecule reactions were exploited to eliminate isobaric interferences that are often encountered in direct, real-time analysis strategies for atmospheric VOC mixtures. The use of a continuously infused internal standard will improve quantitative results in field applications where analyte concentration and sample complexity may be wide ranging. PMID- 26522310 TI - Use of advantageous, volatile matrices enabled by next-generation high-speed matrix-assisted laser desorption/ionization time-of-flight imaging employing a scanning laser beam. AB - RATIONALE: In mass spectrometry imaging (MSI) it is often desirable to analyse the same sample in both polarities to extract the most information. However, many matrices that produce high-quality spectra in matrix-assisted laser desorption/ionization (MALDI) are volatile, greatly limiting their use in long imaging experiments. We demonstrate that using a new high speed MALDI-MSI instrument, volatile matrices, including those that produce intense lipid signals in both positive and negative ion mode, can now be effectively used in MSI. METHODS: A prototype Bruker rapifleX MALDI TissuetyperTM time-of-flight (TOF) instrument was used for high-speed imaging. This allows acquisition rates up to 50 pixels/s made possible by use of a 10 kHz laser and two rotating mirrors that allow the laser beam to be moved over, and synchronised with, the rapidly moving sample. MSI experiments were performed on mouse brain sections using non-vacuum stable dithranol and 2,6-dihydroxyacetophenone (DHA) matrices with pixel sizes ranging from 10 * 10 um(2) to 50 * 50 um(2). RESULTS: Both DHA and dithranol produced rich, complementary lipid spectra in both positive and negative ion modes. Due to the rapid acquisition speed of the instrument, both matrices could be effectively used for MSI despite their volatility. For example, an entire mouse brain could be imaged consecutively in both positive and negative ion mode with 50 * 50 um(2) pixels in ~35 min. We demonstrate that these speeds make possible both faster and higher resolution imaging of biological tissues on practical timescales. CONCLUSIONS: These high acquisition speeds now make possible whole new classes of matrices that are unstable under high vacuum for MALDI-MSI studies. This provides researchers with far greater range and flexibility in choosing the best matrix for the given sample and analytes that they wish to detect. In addition, such instruments allow MSI to be performed at higher resolution across larger areas on practical time scales. PMID- 26522311 TI - Nitric oxide assisted C60 secondary ion mass spectrometry for molecular depth profiling of polyelectrolyte multilayers. AB - RATIONALE: Secondary ion mass spectrometry (SIMS) with polyatomic primary ions provides a successful tool for molecular depth profiling of polymer systems, relevant in many technological applications. Widespread C60 sources, however, cause in some polymers extensive damage with loss of molecular information along depth. We study a method, based on the use of a radical scavenger, for inhibiting ion-beam-induced reactions causing sample damage. METHODS: Layered polystyrene sulfonate and polyacrylic acid based polyelectrolyte films, behaving differently towards C60 beam-induced damage, were selected and prepared as model systems. They were depth profiled by means of time-of-flight (TOF)-SIMS in dual beam mode, using fullerene ions for sputtering. Nitric oxide was introduced into the analysis chamber as a radical scavenger. The effect of sample cooling combined with NO-dosing on the quality of depth profiles was explored. RESULTS: NO-dosing during C60-SIMS depth profiling of >1 micrometer-thick multilayered polyelectrolytes allows detection, along depth, of characteristic fragments from systems otherwise damaged by C60 bombardment, and increases sputtering yield by more than one order of magnitude. By contrast, NO has little influence on those layers that are well profiled with C60 alone. Such leveling effect, more pronounced at low temperature, leads to a dramatic improvement of profile quality, with a clear definition of interfaces. CONCLUSIONS: NO-dosing provides a tool for extending the applicability, in SIMS depth profiling, of the widely spread fullerene ion sources. In view of the acceptable erosion rates on inorganics, obtainable with C60, the method could be of relevance also in connection with the 3D-imaging of hybrid polymer/inorganic systems. PMID- 26522312 TI - Whole-cell-based identification of electrochemically active bacteria in microbial fuel cells by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - RATIONALE: Electrochemically active bacteria (EAB) that are capable of producing electricity from renewable biomass and organic wastes have been of particular interest in recent years. Methods for selective enrichment, accurate identification and easy acquisition of EAB fingerprints for phylogenetic characterization would facilitate utilization of these bioenergy-producing species in practical environmental engineering applications. METHODS: Electricigens/exoelectrogens were selectively enriched from domestic wastewater in a microbial fuel cell (MFC). Whole EAB cell-derived mass spectra were obtained with simple agar incubation for 24 h and subsequent release of proteins by 25% formic acid (FA) and ultrasonication. Mass fingerprints of EAB were obtained by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF-MS) and species-specific analyses were completed by using the Spectral ARchive and Microbial Identification System (SARAMIS). RESULTS: EAB could be discriminated by clustering of MALDI-TOF/TOF-MS results. Different species in mixtures originating from domestic sewage could be identified unambiguously at 99.90% confidence. Five species, namely Klebsiella oxytoca (K. oxytoca), Comamonas testosterone (C. testosterone), Pseudomonas putida (P. putida), Klebsiella pneumonia (K. pneumonia) and Raoultella ornithinolytica (R. ornithinolytica), that are known to be of clinical significance, were found to be enriched in MFCs and determined as high power-producing species. By using an agglomerative clustering algorithm to compute spectral similarity and diversity, a dendrogram was constructed to illustrate the phylogenetic relationships for EAB on the basis of mass spectral analyses. CONCLUSIONS: An integrated method based on MFC-enrichment, agar-cultivation and MALDI-TOF/TOF-MS identification of whole cell-extracted proteins has been proved to be a simple, rapid and reliable approach for rapid identification and routine inspection of EAB. Mixed phyla can be analyzed at species level to provide phylogenetic information on the highly efficient bacteria generating electricity from domestic wastewater. PMID- 26522313 TI - High-precision measurements of delta(17)O and (17) Oexcess of NBS19 and NBS18. AB - RATIONALE: Measurements of oxygen-17 excess ((17)Oexcess) in carbonates have become of great importance. However, to compare results obtained by different laboratories, it is necessary to normalize them to international standards. With this purpose in mind, we measured accurate and high precision delta(17)O and (17)Oexcess values for NBS19 and NBS18, two international standards, for which delta(18)O values are already widely used as the references for carbonates. METHODS: The measurements are based on isotopic exchange at steady state between O2 and CO2 over hot platinum sponge at 750 degrees C. Dual-inlet isotope ratio mass spectrometry (IRMS) measurements of the delta(17)O and delta(18)O values of this O2 allow delta(17)O values of CO2 to be obtained with very high precision (0.01 to 0.030/00) and, correspondingly, accurate (17)Oexcess values with a precision of 5 per meg. RESULTS: We measured, for the first time, the delta(17)O values and (17)Oexcess of CO2 liberated from NBS19 at 25 degrees C (39.196 +/- 0.026; 20.276 +/- 0.0150/00 and -227 +/- 4 per meg, respectively) and NBS18 (17.591 +/- 0.0410/00; 9.253 +/- 0.0180/00 and 3 +/- 5 per meg, respectively). The values are given versus VSMOW. CONCLUSIONS: Accurate values of delta(17)O and (17)Oexcess of the international standards NBS19-CO2 and NBS18-CO2 are now available. The new values should be used for normalization of measured oxygen isotope ratios of carbonates to allow meaningful comparison of results among different laboratories. PMID- 26522314 TI - Liquid chromatography/tandem mass spectrometry analysis of neonicotinoids in environmental water. AB - RATIONALE: Neonicotinoids (NNIs) are the fastest expanding group of pesticides in the world over the last two decades; however, they may be a significant contributing factor to bee mortality. The widespread use of NNIs makes it critical to monitor their residuals in the environment. Published methods for NNI analysis are mainly focused on agricultural and food products, and many of them only measured a portion of the commercially available NNIs. METHODS: Utilizing a biphenyl stationary-phase column, a sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed to determine eight NNIs, including acetamiprid, clothianidin, dinotefuran, flonicamid, imidacloprid, nitempyram, thiacloprid and thiamethoxam in environmental water. Two multiple reaction monitoring (MRM) transitions were monitored for each compound to ascertain true positive identification. Isotope-labelled NNIs, d3-acetamiprid, d3-clothianidin, d4-imidacloprid and d3-thiamethoxam, were used to compensate for extraction efficiency, matrix effects and instrument variability while monitoring real-time method performance. Target compounds in aqueous samples were analyzed by direct aqueous injection (DAI) or after solid-phase extraction (SPE). RESULTS: The method detection limits (MDLs) of NNIs in drinking water, surface water and groundwater were in the ranges of 50 to 190 and 2 to 7 ng/L for DAI and SPE procedures, respectively, and target compound recoveries ranged from 78 to 110%. The stability of target compounds in water samples and SPE extracts was also investigated for the first time to ensure accurate results. No obvious degradation was observed for target compounds within four weeks in either water samples or SPE extracts. CONCLUSIONS: The method developed for neonicotinoid pesticide analysis is very sensitive and efficient. It provides good flexibility to meet various environmental monitoring needs and is employed for an extensive study to determine the distribution of NNIs in Ontario's water. PMID- 26522315 TI - Comparison of delta(18)O and delta(13)C values between tree-ring whole wood and cellulose in five species growing under two different site conditions. AB - RATIONALE: We investigated the applicability of tree-ring whole-wood material for delta(18)O and delta(13)C analysis in comparison with the more time- and resource intensive use of cellulose, by considering possible variability between (i) five different tree species (Fagus sylvatica, Quercus robur, Picea abies, Abies alba, Pseudotsuga menziesii), (ii) two sites that differ in soil moisture, and (iii) climate conditions within a 10-year period. METHODS: Stem cores of 30 individual trees (n = 3 trees per each species and site) were sampled from two sites in south Germany (Bavaria), and tree rings within sapwood of the years 2001-2010 were separated. The delta(18)O and delta(13)C values from homogenized tree-ring whole wood and from extracted cellulose were measured by mass spectrometry. Species-specific offsets in isotope values were analyzed and the responses in isotopic signature to climate variability including a single drought event were compared between whole-wood and cellulose. RESULTS: A constant offset in delta(18)O values of ca 50/00 between wood and cellulose was observed for most species independent of site conditions, with a significant difference between beech and Douglas-fir, while inter-annual variability was only observed in oak. The offset in delta(13)C values ranged between 1.45 and 1.840/00 across species, sites and years. Both materials generally showed similar strength in responses to temperature, precipitation and soil water availability, particularly for conifers. Resistance to severe drought stress--partly more strongly reflected in the delta(13)C values of cellulose--was lower for conifers than for the deciduous species. CONCLUSIONS: Wood material from the sapwood of the studied tree species is as useful as cellulose for studying environmental effects on tree-ring delta(18)O and delta(13)C values at a short-term scale as considered in most ecophysiological studies. The more variable response of oak may require further investigations. PMID- 26522316 TI - Analysis of dye degradation products and assessment of the dye purity in dye sensitized solar cells. AB - RATIONALE: For commercialization of dye-sensitized solar cells (DSSCs), improvement of their long-term stability and efficiency is important. A key component in solar cells is the dye, its high purity and high stability. Here, methods for dye extraction and purification, and for determination of dye purity and dye degradation in DSSCs, were developed. METHODS: A method was developed for extraction of the dye Z907 from intact solar cells using a water/ethanol mixture containing tetrabutylammonium hydroxide. The N719 dye synthesized in our laboratory was purified by gel filtration on Sephadex LH20. These dyes, along with the dyes N3 and RuL2 (NC)2, were analyzed using nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography coupled to an electrospray ionization quadrupole-time-of-flight mass analyzer (LC/MS) operating in negative ionization mode. RESULTS: Purification of the synthesized N719 removed several impurities, including its undesired isomer with the thiocyanate ligand attached to ruthenium through sulfur instead of nitrogen. The dyes N719 and Z907 were successfully extracted from solar cells and together with N3 and RuL2 (NC)2 analyzed by LC/MS, although N719 isomerized almost immediately in basic aqueous solution. The [M-H](-1) ions were observed and the measured mass was within a +/ 6 ppm range from the exact mass. CONCLUSIONS: LC/MS in combination with NMR spectroscopy was shown to provide useful information on dye structure, purity, and on the efficiency of the purification methods. These methods allow for further studies of solar cell dyes, which may provide the detailed information needed for the improvement and eventual commercialization of the solar cell technology. PMID- 26522317 TI - Accuracy of delta(18)O isotope ratio measurements on the same sample by continuous-flow isotope-ratio mass spectrometry. AB - RATIONALE: The doubly labeled water method is considered the reference method to measure energy expenditure. Conventional mass spectrometry requires a separate aliquot of the same sample to be prepared and analyzed separately. With continuous-flow isotope-ratio mass spectrometry, the same sample could be analyzed sequentially for both (2)H and (18)O content and thus minimize sample requirement, reduce analytical cost, and avoid memory effect. METHODS: The (2)H contents of 197 urine samples collected from 22 doubly labeled water studies were determined using a Thermo Delta V Advantage continuous-flow isotope-ratio mass spectrometer. The (18)O content of these samples was measured either using a separate aliquot of the same sample using a VG Isogas gas-isotope-ratio mass spectrometer or using the same sample following the (2)H measurements on a Thermo Delta V continuous-flow isotope-ratio instrument. RESULTS: The delta(18)O values using the same aliquot of samples were accurate to 0.18 +/- 2.610/00 (mean difference +/- standard deviation (SD); 95% CI, -0.18 to 0.550/00; P = 0.33) compared with the values based on the standard conventional method. Bland and Altman pair-wise comparison also yielded a bias of 0.180/00 with a 95% limit of agreement between -4.94 and 5.300/00. CONCLUSIONS: The study demonstrated that continuous-flow isotope-ratio mass spectrometry is capable of producing accurate (18)O measurements on the same sample after (2)H measurements. The method greatly reduces the analytical cost and sample size requirement and could easily be adopted by any laboratories equipped with a continuous-flow isotope-ratio mass spectrometer. PMID- 26522318 TI - Enhanced electrospray ionization mass spectrometric detection of hexamethylene triperoxide diamine (HMTD) after oxidation to tetramethylene diperoxide diamine dialdehyde (TMDDD). AB - RATIONALE: Hexamethylene triperoxide diamine (HMTD) is one of the peroxide-based explosives that are difficult to detect using standard analytical methodologies. METHODS: It was analyzed by electrospray ionization mass spectrometry (ESI-MS) on a UPLC-TOF instrument. Alkali metal salts were used to promote the formation of ions. RESULTS: In the full scan positive ion mode a 3 ng (13 pmol) limit of detection was achieved if [HMTD + Me](+) ions (Me = Li, Na, K) were detected. It was found that HMTD easily undergoes oxidation to tetramethylene diperoxide diamine dialdehyde (TMDDD) in the source as well as in the samples. TMDDD can be detected as [TMDDD + Me](+) ions, but better ionization efficiency leads to the detection limit of TMDDD at the 2 pg (0.01 pmol) level. In butyl acetate the yield of oxidation of HMTD to TMDDD reaches 25% within 20 min at 120 degrees C, which offers a simple way of improving the detection limit of HMTD by two orders of magnitude. CONCLUSIONS: A simple procedure of detection of HMTD that matches the most sensitive methods available was developed. It uses standard equipment available in many laboratories. It was shown that the frequently reported [HMTD H](+) cation observed by various authors was in fact a misinterpretation of the results, and should be attributed to [TMDDD + H](+). PMID- 26522319 TI - Compound-specific stable isotope analysis of nitrogen-containing intact polar lipids. AB - RATIONALE: Compound-specific isotope analysis (CSIA) of nitrogen in amino acids has proven a valuable tool in many fields (e.g. ecology). Several intact polar lipids (IPLs) also contain nitrogen, and their nitrogen isotope ratios have the potential to elucidate food-web interactions or metabolic pathways. Here we have developed novel methodology for the determination of delta(15)N values of nitrogen-containing headgroups of IPLs using gas chromatography coupled with isotope-ratio mass spectrometry. METHODS: Intact polar lipids with nitrogen containing headgroups were hydrolyzed and the resulting compounds were derivatized by (1) acetylation with pivaloyl chloride for compounds with amine and hydroxyl groups or (2) esterification using acidified 2-propanol followed by acetylation with pivaloyl chloride for compounds with both carboxyl and amine groups. The delta(15)N values of the derivatives were subsequently determined using gas chromatography/combustion/isotope-ratio mass spectrometry. RESULTS: Intact polar lipids with ethanolamine and amino acid headgroups, such as phosphatidylethanolamine and phosphatidylserine, were successfully released from the IPLs and derivatized. Using commercially available pure compounds it was established that delta(15)N values of ethanolamine and glycine were not statistically different from the offline-determined values. Application of the technique to microbial cultures and a microbial mat showed that the method works well for the release and derivatization of the headgroup of phosphatidylethanolamine, a common IPL in bacteria. CONCLUSIONS: A method to enable CSIA of nitrogen of selected IPLs has been developed. The method is suitable for measuring natural stable nitrogen isotope ratios in microbial lipids, in particular phosphatidylethanolamine, and will be especially useful for tracing the fate of nitrogen in deliberate tracer experiments. PMID- 26522320 TI - Complexation of phosphates by 1,3-bis(3-(2-pyridylureido)propyl)-1,1,3,3 tetramethyldisiloxane. AB - RATIONALE: Compounds containing a urea or thiourea moiety form complexes with anions thanks to the ability to form quite strong hydrogen bonds. We have synthesized 1,3-bis(3-(2-pyridylureido)propyl)-1,1,3,3-tetramethyldisiloxane (1). Compound 1 contains two urea moieties connected by a long flexible linker; thus, it should be able to adopt a structure suitable for formation of quite stable complexes with anions. METHODS: The ability to form complexes of compound 1 with phosphates was tested by electrospray ionization mass spectrometry (ESI-MS). Full scan ESI mass spectra and collision-induced dissociation tandem mass (CID-MS/MS) spectra of the ions of interest were obtained on a quadrupole time-of-flight (QTOF) mass spectrometer. RESULTS: It has been found that compound 1 is not only much more prone to form complexes with the phosphate anion than with other inorganic anions, but it is also able to form complexes with organic phosphates, namely nucleotides and phospholipids. However, compound 1 is not able to form complexes with organic compounds not containing a phosphate group (e.g. nucleosides, sugars, glycerolipids). CONCLUSIONS: Compound 1 can be regarded as selective towards phosphate-containing organic compounds. Formation of such complexes may have some interesting applications for identification of organic phosphates in crude extracts from biological materials. PMID- 26522321 TI - Structural elucidation of metolachlor photoproducts by liquid chromatography/high resolution tandem mass spectrometry. AB - RATIONALE: Metolachlor is one of the most intensively used chloroacetanilide herbicides in agriculture. It has been detected in water; consequently, under UV visible irradiation, it can be transformed in degradation products (TPs). The structures of TPs were elucidated by liquid chromatography/high-resolution tandem mass spectrometry (LC/HR-MS/MS). The potential toxicities of these TPs were estimated by in silico tests. METHODS: Aqueous solutions of metolachlor were irradiated in a self-made reactor equipped with a mercury vapor lamp. Analyses were carried out using high-performance liquid chromatography coupled to quadrupole time-of-flight (QTOF) mass spectrometer. High-resolution m/z measurements, MS/MS and isotopic labeling experiments allowed structural elucidation of metolachlor TPs. Their toxicities were estimated in silico, using the T.E.S.T. RESULTS: Ten major metolachlor photoproducts were characterized by LC/MS/MS after irradiation of metolachlor in aqueous solution. Elucidation of their chemical structures was identified using high-resolution measurements and MS/MS experiments. They resulted from the combination of dehalogenation, hydroxylation and cyclisation processes. The potential oral rat lethal dose (LD50) was assessed with QSAR tests for metolachlor and each photoproduct. Results indicate that most of the TPs are much more toxic than metolachlor. CONCLUSIONS: UV-vis irradiation of metolachlor in aqueous solution leads to the formation of ten photoproducts. QSAR estimations show that the location of added hydroxyl group(s) is of key relevance as regards to biological activity and that routine water analysis should take into account the TPs are more toxic than the parent molecule. PMID- 26522322 TI - How enhanced molecular ions in Cold EI improve compound identification by the NIST library. AB - RATIONALE: Library-based compound identification with electron ionization (EI) mass spectrometry (MS) is a well-established identification method which provides the names and structures of sample compounds up to the isomer level. The library (such as NIST) search algorithm compares different EI mass spectra in the library's database with the measured EI mass spectrum, assigning each of them a similarity score called 'Match' and an overall identification probability. Cold EI, electron ionization of vibrationally cold molecules in supersonic molecular beams, provides mass spectra with all the standard EI fragment ions combined with enhanced Molecular Ions and high-mass fragments. As a result, Cold EI mass spectra differ from those provided by standard EI and tend to yield lower matching scores. However, in most cases, library identification actually improves with Cold EI, as library identification probabilities for the correct library mass spectra increase, despite the lower matching factors. METHODS: This research examined the way that enhanced molecular ion abundances affect library identification probability and the way that Cold EI mass spectra, which include enhanced molecular ions and high-mass fragment ions, typically improve library identification results. It involved several computer simulations, which incrementally modified the relative abundances of the various ions and analyzed the resulting mass spectra. RESULTS: The simulation results support previous measurements, showing that while enhanced molecular ion and high-mass fragment ions lower the matching factor of the correct library compound, the matching factors of the incorrect library candidates are lowered even more, resulting in a rise in the identification probability for the correct compound. CONCLUSIONS: This behavior which was previously observed by analyzing Cold EI mass spectra can be explained by the fact that high-mass ions, and especially the molecular ion, characterize a compound more than low-mass ions and therefore carries more weight in library search identification algorithms. These ions are uniquely abundant in Cold EI, which therefore enables enhanced compound characterization along with improved NIST library based identification. PMID- 26522323 TI - Phenyl group participation in rearrangements during collision-induced dissociation of deprotonated phenoxyacetic acid. AB - RATIONALE: The identification of trace constituents in biological and environmental samples is frequently based on the fragmentation patterns resulting from the collision-induced dissociation (CID) of gas-phase ions. Credible mechanistic characterization of fragmentation processes, including rearrangements, is required to make reliable assignments for structures of precursor and product ions. METHODS: Mass spectra were collected using both ion trap and triple quadrupole mass spectrometers operating in the negative ion mode. Precursor ion scans and CID of ions generated in-source were used to establish precursor-product ion relationships. Density functional theory (DFT) computations were performed at the MP2/6-311++G(2d,p)//B3LYP/6-31++G(2d,p) level of theory. RESULTS: Product ions at m/z 93 and 107 obtained upon CID of phenoxyacetate were attributed to phenoxide and o-methylphenoxide, respectively. An isotopic labeling experiment and computations showed that the phenoxide ion was formed by intramolecular displacement with formation of an alpha-lactone and also by a Smiles rearrangement. Rearrangement of phenoxyacetate via the ion-neutral complex formed in the alpha-lactone displacement pathway gave the isomeric o hydroxyphenylacetate ion which yielded o-methylphenoxide upon decarboxylation. Computations provided feasible energetics for these pathways. CONCLUSIONS: Previously unrecognized and energetically favorable rearrangements during the collision-induced fragmentation of phenoxyacetate have been characterized using isotopic labeling and DFT computations. Notably, the phenyl substituent plays an indispensable role in each rearrangement process resulting in multiple pathways for the fragmentation of phenoxyacetate. PMID- 26522324 TI - Elucidation of a side reaction occurring during nitroxide-mediated polymerization of cyclic ketene acetals by tandem mass spectrometric end-group analysis of aliphatic polyesters. AB - RATIONALE: In order to prevent side reactions while developing new polymerization processes, their mechanism has to be understood and one first key insight is the structure of the end-groups in polymeric by-products. The synthetic method scrutinized here is the nitroxide-mediated polymerization (NMP) of a cyclic ketene acetal, a promising alternative process to the production of polyesters. METHODS: Polymer end-group characterization was performed by mass spectrometry (MS), combining elemental composition information derived from accurate mass data in the MS mode with fragmentation features recorded in the MS/MS mode. Electrospray was used as the ionization method to ensure the integrity of original chain terminations and a quadrupole time-of-flight (QTOF) instrument was employed for high-resolution mass measurements in both MS and tandem mass spectrometry (MS/MS) modes. RESULTS: Occurrence of side reactions in the studied polymerization method, first evidenced by an unusual increase in dispersity with conversion, was confirmed in MS with the detection of two polymeric impurities in addition to the expected species. Fragmentation rules were first established for this new polyester family in order to derive useful structural information from MS/MS data. In addition to a usual NMP by-product, the initiating group of the second polymeric impurities revealed the degradation of the nitroxide moiety. CONCLUSIONS: Unambiguous MS/MS identification of end-groups in by-products sampled from the polymerization medium allowed an unusual side reaction to be identified during the NMP preparation of polyesters. On-going optimization of the polymerization method aims at preventing this undesired process. PMID- 26522325 TI - Can computational chemistry be used to predict CID fragmentation of anions? PMID- 26522326 TI - Electron-capture dissociation for investigating host/guest complexes of 18-crown 6-ether and peptides. PMID- 26522328 TI - An Upstream By-product from Ester Activation via NHC-Catalysis Catalyzes Downstream Sulfonyl Migration Reaction. AB - A sequential reaction combining N-heterocyclic carbene (NHC) and N hydroxyphthalimide (NHPI) catalysis allowed for the upstream by-product NHPI, which was generated in the NHC-catalyzed cycloaddition reaction, to act as the catalyst for a downstream nitrogen-to-carbon sulfonyl migration reaction. Enantiomeric excess of the major product in the cycloaddition reaction remained intact in the follow-up sulfonyl migration reaction. PMID- 26522327 TI - Deacetylation-mediated interaction of SIRT1-HMGB1 improves survival in a mouse model of endotoxemia. AB - Inflammatory signal-mediated release of high-mobility group box 1 (HMGB1) is a damage-associated molecular pattern or alarmin. The inflammatory functions of HMGB1 have been extensively investigated; however, less is known about the mechanisms controlling HMGB1 release. We show that SIRT1, the human homolog of the Saccharomyces cerevisiae protein silent information regulator 2, which is involved in cellular senescence and possibly the response to inflammation, forms a stable complex with HMGB1 in murine macrophage RAW264.7 cells. SIRT1 directly interacted with HMGB1 via its N-terminal lysine residues (28-30), and thereby inhibited HMGB1 release to improve survival in an experimental model of sepsis. By contrast, inflammatory stimuli such as lipopolysaccharide (LPS) and tumor necrosis factor-alpha promoted HMGB1 release by provoking its dissociation from SIRT1 dependent on acetylation, thereby increasing the association between HMGB1 and chromosome region maintenance 1, leading to HMGB1 translocation. In vivo infection with wild-type SIRT1 and HMGB1(K282930R), a hypo-acetylation mutant, improved survival (85.7%) during endotoxemia more than infection with wild-type SIRT1 and HMGB1-expressing adenovirus, indicating that the acetylation-dependent interaction between HMGB1 and SIRT1 is critical for LPS-induced lethality. Taken together, we propose that SIRT1 forms an anti-inflammatory complex with HMGB1, allowing cells to bypass the response to inflammation. PMID- 26522329 TI - Application of (13)C ramp CPMAS NMR with phase-adjusted spinning sidebands (PASS) for the quantitative estimation of carbon functional groups in natural organic matter. AB - The composition of carbon (C) functional groups in natural organic matter (NOM), such as dissolved organic matter, soil organic matter, and humic substances, is frequently estimated using solid-state (13)C NMR techniques. A problem associated with quantitative analysis using general cross polarization/magic angle spinning (CPMAS) spectra is the appearance of spinning side bands (SSBs) split from the original center peaks of sp (2) hybridized C species (i.e., aromatic and carbonyl C). Ramp CP/phase-adjusted side band suppressing (PASS) is a pulse sequence that integrates SSBs separately and quantitatively recovers them into their inherent center peaks. In the present study, the applicability of ramp CP/PASS to NOM analysis was compared with direct polarization (DPMAS), another quantitative method but one that requires a long operation time, and/or a ramp CP/total suppression side band (ramp CP/TOSS) technique, a popular but non-quantitative method for deleting SSBs. The test materials were six soil humic acid samples with various known degrees of aromaticity and two fulvic acids. There were no significant differences in the relative abundance of alkyl C, O-alkyl C, and aromatic C between the ramp CP/PASS and DPMAS methods, while the signal intensities corresponding to aromatic C in the ramp CP/TOSS spectra were consistently less than the values obtained in the ramp CP/PASS spectra. These results indicate that ramp CP/PASS can be used to accurately estimate the C composition of NOM samples. PMID- 26522330 TI - Mediated bioelectrochemical system for biosensing the cell viability of Staphylococcus aureus. AB - Staphylococcus aureus is one of the most dangerous human pathogens and is the cause of numerous illnesses ranging from moderate skin infections to life threatening diseases. Despite advances made in identifying microorganisms, rapid detection methods for the viability of bacteria are still missing. Here, we report a rapid electrochemical assay for cell viability combining the use of double redox mediators and multiwall carbon nanotubes-screen printed electrodes (MWCNTs-SPE), ferricyanide (FCN) and 2,6-dichlorophenolindophenol (DCIP), which served as electron shuttle to enable the bacterial-electrode communications. The current originating from the metabolically active cells was recorded for probing the activity of the intracellular redox centers. Blocking of the respiratory chain pathways with electron transfer inhibitors demonstrated the involvement of the electron transport chain in the reaction. A good correlation between the number of the metabolically active cells and the current was obtained. The proposed assay has been exploited for monitoring cell proliferation of S. aureus during the growth. The sensitivity of the detection method reached 0.1 OD600. Therefore, the technique described is promising for estimating the cell number, measuring the cell viability, and probing intracellular redox center(s). PMID- 26522331 TI - Multiple Effects of the Second Fluid on Suspension Viscosity. AB - Previous research has shown that adding a small amount of a second immiscible fluid to particulate suspension can result in a significant influence on viscosity. In this study, the effects of the second fluid addition over a small dosage range on the rheological properties of particle suspension were investigated. As the dosage of the second fluid was increased, the viscosity and yield stress initially decreased then increased and finally decreased again. The microstructure of the suspension was observed using a confocal laser scanning microscope (CLSM) and showed three different states with the increasing dosage of the second fluid: a dispersive sate, cluster state and cell state in sequence. The presence of these states interpreted the non-monotonic trend of viscosity and yield stress in the suspensions. PMID- 26522333 TI - Why germline variations in ALL can matter. PMID- 26522335 TI - Hypofractionation for prostate cancer and PROs. PMID- 26522332 TI - Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. AB - BACKGROUND: Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL. METHODS: Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude Children's Research Hospital front-line ALL trials. Patients were included in this study on the basis of their enrolment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterised bioinformatically and correlated with clinical and demographic features in children with ALL. FINDINGS: We identified a novel non-sense ETV6 variant (p.Arg359X) with a high penetrance in an index family. Subsequent targeted sequencing of ETV6 in 4405 childhood ALL cases identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1%). 15 (48%) of 31 ALL-related ETV6 variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukaemia diagnosis than those without (10.2 years [IQR 5.3-13.8] vs 4.7 years [3.0-8.7]; p=0.017). The hyperdiploid leukaemia karyotype was highly over represented in ALL cases harbouring germline ETV6 risk variants compared with the wild-type group (nine [64%] of 14 cases vs 538 [27%] of 2007 cases; p=0.0050). INTERPRETATION: Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants are needed. FUNDING: US National Institutes of Health and American Lebanese Syrian Associated Charities. PMID- 26522334 TI - Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. AB - BACKGROUND: Patient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial. METHODS: The CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b-T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923. FINDINGS: 2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50.0 months (IQR 38.4-64.2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0.59). We saw no differences between treatment groups in change of bowel bother score from baseline or pre-radiotherapy to 24 months. INTERPRETATION: The incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy. If efficacy outcomes from CHHiP show non-inferiority for hypofractionated treatments, these findings will add to the growing evidence for moderately hypofractionated radiotherapy schedules becoming the standard treatment for localised prostate cancer. FUNDING: Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network. PMID- 26522336 TI - Nedaplatin: a new platinum for squamous lung cancer? PMID- 26522338 TI - Ultrastructure and molecular phylogeny of Pleistophora hyphessobryconis (Microsporidia) infecting hybrid jundiara (Leiarius marmoratus * Pseudoplatystoma reticulatum) in a Brazilian aquaculture facility. AB - A microsporidian infecting the skeletal muscle of hybrid jundiara (Leiarius marmoratus * Pseudoplatystoma reticulatum) in a commercial aquaculture facility in Brazil is described. Affected fish exhibited massive infections in the skeletal muscle that were characterized by large opaque foci throughout the affected fillets. Histologically, skeletal muscle was replaced by inflammatory cells and masses of microsporidial developmental stages. Generally pyriform spores had a wrinkled bi-layer spore wall and measured 4.0 * 6.0 um. Multinucleate meronts surrounded by a simple plasma membrane were observed. The polar filament had an external membrane and a central electron dense mass. The development of sporoblasts within a sporophorous vesicle appeared synchronized. Ultrastructural observations and molecular analysis of 16S rDNA sequences revealed that the microsporidian was Pleistophora hyphessobryconis. This study is the first report of a P. hyphessobryconis infection in a non-ornamental fish. PMID- 26522337 TI - Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L): a randomised, open label, phase 3 trial. AB - BACKGROUND: The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1-2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival. METHODS: We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20-74 years, Eastern Cooperative Oncology Group performance status of 0-1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1:1) to 100 mg/m(2) nedaplatin and 60 mg/m(2) docetaxel intravenously, or 80 mg/m(2) cisplatin and 60 mg/m(2) docetaxel, every 3 weeks for four to six cycles (at the treating oncologist's discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants. FINDINGS: Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13.6 months, 95% CI 11.6-15.6) than in the cisplatin group (11.4 months,10.2-12.2; hazard ratio 0.81, 95% CI 0.65-1.02; p=0.037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively. INTERPRETATION: Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer. FUNDING: West Japan Oncology Group and Sanofi. PMID- 26522339 TI - Lipopolysaccharide and beta-1,3-glucan-binding protein (LGBP) bind to seaweed polysaccharides and activate the prophenoloxidase system in white shrimp Litopenaeus vannamei. AB - Lipopolysaccharide and beta-1,3-glucan-binding protein (LGBP), important pattern recognition proteins (PRPs), recognize lipopolysaccharide (LPS) and beta-1,3 glucan (betaG), known as pathogen-associated molecular patterns (PAMPs), and subsequently trigger innate immunity. Several seaweed polysaccharides and seaweed extracts increase immune parameters and resistance to pathogens. Here, we constructed the expression vector pET28b-LvLGBP and transferred it into Escherichia coli BL21 (DE3) for protein expression and to produce the recombinant protein LGBP (rLvLGBP) in white shrimp Litopenaeus vannamei. We examined the binding of rLvLGBP with seaweed-derived polysaccharides including alginate, carrageenan, fucoidan, laminarin, Gracilaria tenuistipitata extract (GTE), and Sargassum duplicatum extract (SDE), and examined the phenoloxidase activity of shrimp haemocytes incubated with a mixture of rLvLGBP and each polysaccharide. We also examined the binding of rLvLGBP with LPS and betaG, and the phenoloxidase activity of shrimp haemocytes incubated with a mixture of rLvLGBP and LPS (rLvLGBP-LPS) or a mixture of rLvLGBP and betaG (rLvLGBP-betaG). An ELISA binding assay indicated that rLvLGBP binds to LPS, betaG, alginate, carrageenan, fucoidan, laminarin, GTE, and SDE with dissociation constants of 0.1138-0.1770 MUM. Furthermore, our results also indicated that the phenoloxidase activity of shrimp haemocytes incubated with a mixture of rLvLGBP and LPS, betaG, alginate, carrageenan, fucoidan, laminarin, GTE, and SDE significantly increased by 328%, 172%, 200%, 213%, 197%, 194%, 191%, and 197%, respectively compared to controls (cacodylate buffer). We conclude that LvLGBP functions as a PRP, recognizes and binds to LPS, betaG, alginate, carrageenan, fucoidan, laminarin, GTE, and SDE, and subsequently leads to activating innate immunity in shrimp. PMID- 26522340 TI - Silkworm ferritin 1 heavy chain homolog is involved in defense against bacterial infection through regulation of haemolymph iron homeostasis. AB - Iron functions as a nutrient and a potential toxin in all organisms. It plays a key role in the interaction between microbes and their hosts as well. Microbial infection disrupts iron homeostasis in the host; meanwhile the host endeavors to keep the homeostasis through iron transport and storage. Transferrins and ferritins are the major iron-binding proteins that affect iron distribution in insects. In this study, we investigated a possible involvement of Bombyx mori ferritin 1 (BmFer1) heavy chain homolog in the defense against bacterial infection in the silkworm larvae. The BmFer1 mRNA abundance was up-regulated in hemocytes, but not in fat body, after Pseudomonas aeruginosa or Staphylococcus aureus infection. The infection resulted in elevated iron levels in the hemolymph. Injection of recombinant BmFer1 protein into hemocoel reduced the plasma iron level after infection, limited the bacterial growth in the hemolymph, and resulted in a lower mortality caused by infection. Our study indicated that B. mori ferritin-1 may restrict iron access of the invading bacteria to block their growth as a defense strategy. PMID- 26522341 TI - Cognitive Obstacles to Pro-Vaccination Beliefs. AB - Two frameworks--cultural attraction theory and epistemic vigilance--predict a cultural disadvantage for counter-intuitive beliefs. We review several cognitive mechanisms that conspire to render pro-vaccination beliefs counter-intuitive. Trust and argumentation can spread counter-intuitive beliefs, but only under some conditions. We discuss the hurdles that trust and argumentation face in the case of vaccination. PMID- 26522342 TI - Supraventricular Arrhythmias in Patients With Pulmonary Arterial Hypertension. AB - The onset of supraventricular arrhythmias (SVA) may be associated with clinical worsening in patients with pulmonary arterial hypertension (PAH). However, limited data have been reported, especially at long-term follow-up. Aim of this study was to investigate the incidence of SVA in our patients with PAH, the risk factors correlated to their onset and the prognostic impact. All consecutive patients with PAH without history of SVA were enrolled. Incidence of new SVA was investigated and also the risk factors for SVA. Primary end point of the study was the impact of SVA on a composite of all-cause mortality and re hospitalization, whereas mortality was the secondary end point. Seventy-seven patients were enrolled. No significant differences in the clinical or instrumental baseline characteristics between the 2 study groups were reported. During a median follow-up of 35 months (interquartile range 21.5 to 53.5), 17 (22%) patients experienced SVA. Development of SVA was associated with worsening of prognostic parameters at the follow-up: increasing of World Health Organization (WHO) functional class (p = 0.005) and N-terminal-pro-brain natriuretic peptide (NT-proBNP) (p = 0.018) and reduction of 6-minute walking distance (p = 0.048), tricuspid annular plane systolic excursion (TAPSE) (p = 0.041), and diffusing capacity of the lung for carbon monoxide (p = 0.025). The primary end point occurred in 13 patients (76%) in the SVA group and in 22 patients (37%) in the group without SVA (p = 0.004), whereas 9 patients (53%) among those with SVA died during the follow-up compared with 8 (13%) among those without (p = 0.001). At multivariate analysis, development of SVA was independently associated with an increased risk to meet the both primary (hazard ratio 2.13; 95% confidence interval 1.07 to 4.34; p = 0.031) and secondary (hazard ratio 4.1; 95% confidence interval 1.6 to 10.6; p = 0.004) end points. In conclusion, during the 3-year follow-up period, 1/3 of patients with PAH developed SVA, which was related to worsening of hemodynamic and functional parameter and independently predicted adverse prognosis. PMID- 26522343 TI - Thoracic Sympathectomy for Severe Refractory Multivessel Coronary Artery Spasm. AB - Coronary artery spasm is a rare but potentially fatal disease. Herein, we report a case of recurrent ST-segment myocardial infarctions and ventricular fibrillation complicating severe multivessel coronary artery spasm successfully treated with bilateral thoracic surgical sympathectomy. PMID- 26522344 TI - Multiple-micronutrient supplementation for women during pregnancy. AB - BACKGROUND: Multiple-micronutrient (MMN) deficiencies often coexist among women of reproductive age in low- to middle-income countries. They are exacerbated in pregnancy due to the increased demands, leading to potentially adverse effects on the mother and developing fetus. Though supplementation with MMNs has been recommended earlier because of the evidence of impact on pregnancy outcomes, a consensus is yet to be reached regarding the replacement of iron and folic acid supplementation with MMNs. Since the last update of this Cochrane review, evidence from a few large trials has recently been made available, the inclusion of which is critical to inform policy. OBJECTIVES: To evaluate the benefits of oral multiple-micronutrient supplementation during pregnancy on maternal, fetal and infant health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (11 March 2015) and reference lists of retrieved articles and key reviews. We also contacted experts in the field for additional and ongoing trials. SELECTION CRITERIA: All prospective randomised controlled trials evaluating MMN supplementation during pregnancy and its effects on the pregnancy outcome were eligible, irrespective of language or the publication status of the trials. We included cluster-randomised trials, but quasi-randomised trials were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: Nineteen trials (involving 138,538 women) were identified as eligible for inclusion in this review but only 17 trials (involving 137,791 women) contributed data to the review. Fifteen of these 17 trials were carried out in low and middle-income countries and compared MMN supplements with iron and folic acid versus iron with or without folic acid. Two trials carried out in the UK compared MMN with a placebo. MMN with iron and folic acid versus iron, with or without folic acid (15 trials): MMN resulted in a significant decrease in the number of newborn infants identified as low birthweight (LBW) (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.85 to 0.91; high-quality evidence) or small-for-gestational age (SGA) (average RR 0.90, 95% CI 0.83 to 0.97; moderate-quality evidence), and a reduced rate of stillbirth (RR 0.91, 95% CI 0.85 to 0.98; high-quality evidence). No significant differences were shown for other maternal and pregnancy outcomes: preterm births (RR 0.96, 95% CI 0.89 to 1.03; high-quality evidence), maternal anaemia in the third trimester (RR 0.97, 95% CI 0.86 to 1.10), miscarriage (RR 0.89, 95% CI 0.78 to 1.01), maternal mortality (RR 0.97, 95% CI 0.63 to 1.48), perinatal mortality (RR 0.97, 95% CI 0.84 to 1.12; high-quality evidence), neonatal mortality (RR 0.98, 95% CI 0.90 to 1.07; high -quality evidence), or risk of delivery via a caesarean section (RR 1.03; 95% CI 0.75 to 1.43).A number of prespecified, clinically important outcomes could not be assessed due to insufficient or non-available data. Single trials reported results for: very preterm birth < 34 weeks, macrosomia, side-effects of supplements, nutritional status of children, and congenital anomalies including neural tube defects and neurodevelopmental outcome: Bayley Scales of Infant Development (BSID) scores. None of these trials reported pre-eclampsia, placental abruption, premature rupture of membranes, cost of supplementation, and maternal well-being or satisfaction.When assessed according to GRADE criteria, the quality of evidence for the review's primary outcomes overall was good. Pooled results for primary outcomes were based on multiple trials with large sample sizes and precise estimates. The following outcomes were graded to be as of high quality: preterm birth, LBW, perinatal mortality, stillbirth and neonatal mortality. The outcome of SGA was graded to be of moderate quality, with evidence downgraded by one for funnel plot asymmetry and potential publication bias.We carried out sensitivity analysis excluding trials with high levels of sample attrition (> 20%); results were consistent with the main analysis. We explored heterogeneity through subgroup analysis by maternal height and body mass index (BMI), timing of supplementation and dose of iron. Subgroup differences were observed for maternal BMI and timing of supplementation for the outcome preterm birth, with significant findings among women with low BMI and with earlier initiation of supplementation in the prenatal period. Subgroup differences were also observed for maternal BMI, maternal height and dose of iron for the outcome SGA, indicating a significant impact among women with higher maternal BMI and height, and with MMN supplement containing 30 mg of iron versus control receiving 60 mg of iron. The findings between subgroups for other primary outcomes were inconclusive. MMN versus placebo (two trials): A single trial in the UK found no clear differences between groups for preterm birth, SGA, LBW or maternal anaemia in the third trimester. A second trial reported the number of women with pre-eclampsia; there was no evidence of a difference between groups. Other outcomes were not reported. AUTHORS' CONCLUSIONS: Our findings support the effect of MMN supplements with iron and folic acid in improving birth outcomes. The findings, consistently observed in several systematic evaluations of evidence, provide a strong basis to guide the replacement of iron and folic acid with MMN supplements containing iron and folic acid for pregnant women in developing countries where MMN deficiencies are common among women of reproductive age. Efforts should be focused on the integration of this intervention in maternal nutrition and antenatal care programs in developing countries. PMID- 26522345 TI - Optical Imaging of Nonuniform Ferroelectricity and Strain at the Diffraction Limit. AB - We have imaged optically the spatial distributions of ferroelectricity and piezoelectricity at the diffraction limit. Contributions to the birefringence from electro-optics--linked to ferroelectricity--as well as strain--arising from converse piezoelectric effects--have been recorded simultaneously in a BaTiO3 thin film. The concurrent recording of electro-optic and piezo-optic mappings revealed that, far from the ideal uniformity, the ferroelectric and piezoelectric responses were strikingly inhomogeneous, exhibiting significant fluctuations over the scale of the micrometer. The optical methods here described are appropriate to study the variations of these properties simultaneously, which are of great relevance when ferroelectrics are downscaled to small sizes for applications in data storage and processing. PMID- 26522346 TI - Experimental model of small subcortical infarcts in mice with long-lasting functional disabilities. AB - Small subcortical infarcts account for 25% of all ischemic strokes. Although once considered to be a small vessel disease with a favorable outcome, recent studies have reported relatively poor long-term prognoses following small subcortical infarcts. Limited pre-clinical modeling has hampered understanding of the etiology and development of treatments for this disease. Therefore, we attempted to develop a new experimental model of small subcortical infarcts in mice to investigate pathophysiological changes in the corticospinal tract and assess long term behavioral performance. The vasoconstrictor peptide, endothlin-1 (ET-1), in combination with the nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME), were injected into the internal capsule of mice. Histological and behavioral tests were performed 0-8 weeks after the injection. The ET-1/l-NAME injection resulted in severe neurological deficits that continued for up to 8 weeks. The loss of axons and myelin surrounded by reactive gliosis was identified in the region of the injection, in which the vasoconstriction of microvessels was also observed. Moreover, a tract-tracing study revealed an interruption in axonal flow at the internal capsule. The present model of small subcortical infarcts is unique and novel due to the reproduction of neurological deficits that continue for a long period, up to 8 weeks, as well as the use of mice as experimental animals. The reproducibility, simplicity, and easy adoptability make the present model highly appealing for use in further pre clinical studies on small subcortical infarcts. PMID- 26522347 TI - Lipophilic bioactive compounds in the oils recovered from cereal by-products. AB - BACKGROUND: The by-products of seven different cereal grains were investigated as a source of extractable oil, rich in lipophilic bioactive compounds. RESULTS: Oil yields (g kg(-1) DW) recovered from cereal by-products were as follows: 189 (rice bran) > 112 (wheat germ) > 74 (corn bran) > 58 (oat bran) > 41 (buckwheat bran) > 39 (spelt bran) > 33 (wheat bran) > 27 (rye bran). The main fatty acids identified in the studied oil samples were palmitic acid (11.39-17.23%), oleic acid (11.76-42.73%), linoleic acid (35.54-62.65%) and alpha-linolenic acid (1.05 9.46%). The range of total tocochromanols and phytosterols in the obtained oils was 0.369-3.763 and 1.19-35.24 g kg(-1) of oil, respectively. The oils recovered from buckwheat and corn bran, and wheat germ were dominated by tocopherols (99.9, 84.2 and 96.5%, respectively), whereas the oat, rice, rye, spelt, wheat bran oils were rich in tocotrienols (73.9, 79.6, 78.1, 90.6 and 73.8%, respectively). The campesterol and beta-sitosterol constituted 10.1-32.5 and 30.4-63.7%, respectively, of total phytosterols contents identified in all of the studied samples. CONCLUSION: The present study demonstrated that oils recovered from the cereal by-products are richer sources of bioactive compounds, compared with traditional oils. (c) 2015 Society of Chemical Industry. PMID- 26522348 TI - [Effects of different Toll-like receptor agonists on the function of T helper cells in mice]. AB - OBJECTIVE: To investigate the secretion of IL-12p40 and IL-6 by splenocytes, dendritic cells stimulated by different Toll-like receptor (TLR) agonists or in the sera of mice immunized with different TLR agonists, and evaluate the effects of different TLR agonists on the function of T helper (Th) cells, especially the differentiation of Th1 cells. METHODS: Supernatants of splenocytes and dendritic cells stimulated with different TLR agonists for 24 hours or sera of mice immunized with different TLR agonists at different time points were used to determine the levels of IL-12p40 and IL-6 by ELISA. CD4+ T cells isolated from the spleens of ovalbumin-T cell receptor (OVA-TCR) transgenic BALB/c (DO11.10) mice were co-cultured with antigen presenting cells (APCs) from congenic BALB/c mice at 1:3 ratio of T:APCs. Cultures were stimulated with OVA peptide or OVA peptide plus different doses of TLR agonists and the supernatants collected at different time points were assayed by ELISA for detecting IFN-gamma. RESULTS: Pam3CSK4, R848 and CpG oligodeoxynucleotide (ODN) promoted the production of IL 12p40 and IL-6 by splenocytes and dendritic cells obviously, and induced the expression of IFN-gamma in antigen specific CD4+ T cells in a time- and dose dependent manner. Monophosphoryl lipid A from Salmonella minnesota R595 lipopolysaccharide (MPLA-SM) induced low levels of cytokines by splenocytes and couldn't promote the production of IFN-gamma by antigen specific CD4+ T cells, but increased the expressions of IL-12p40 and IL-6 by DCs. All the sera of mice immunized with the four TLR agonists expressed high levels of IL-12p40 and IL-6. CONCLUSION: Splenocytes, DCs stimulated or sera of mice immunized with different TLR agonists produced different levels of cytokines, which could further affect the differentiation of Th1 cells. PMID- 26522349 TI - [Propionibacterium acnes induces the formation of granulomas via promoting Th1 and Th17 cell differentiation]. AB - OBJECTIVE: To investigate the immunostimulatory role of Propionibacterium acnes (P. acnes) in the differentiation of dendritic cell maturation and T helper (Th) subsets, and further explore the potential mechanism of its granuloma-inducing effect. METHODS: After the mouse bone marrow-derived dendritic cells (BMDCs) were stimulated by P. acnes, the expressions of co-stimulatory molecules CD40, CD80, CD86 and major histocompatibility complex II (MHCII) on BMDCs were detected by flow cytometry, the mRNA levels of inflammatory cytokines IL-12, IL-6 and IL-23 were measured by real-time quantitative PCR (qRT-PCR), and the protein concentrations of corresponding cytokines were analyzed by ELISA. Thereafter, BMDCs were cultured in the presence of P. acnes and CD4(+) T cells, and the percentages of Th1 and Th17 cells were detected by flow cytometry. In addition, murine model of liver granuloma was constructed by injecting heat-killed P. acnes through tail vein, and the mRNA levels of IL-17 and IFN-gamma were measured by qRT-PCR. RESULTS: P. acnes up-regulated the expressions of CD40, CD80, CD86 and MHCII on BMDCs, and the mRNA and protein levels of the IL-12, IL-6 and IL-23 cytokines were also higher on P. acnes-treated BMDCs compared with non-stimulated BMDCs. Furthermore, the percentages of Th1 and Th17 cells in the co-culture system increased. In addition, the mRNA levels of IL-17 and IFN-gamma were elevated obviously in the liver with abundant granulomas after P. acnes treatment. CONCLUSION: P. acnes could activate BMDCs, promote the differentiation of Th1 and Th17 cells, and further induce the formation of granulomas. PMID- 26522350 TI - [Protective effects of polydatin on HK-2 cells against oxygen-glucose deprivation/re-oxygenation-induced injury by regulating Sonic hedgehog through PI3K/Akt signaling pathway]. AB - OBJECTIVE: To explore the effects of polydatin on human kidney tubular epithelial cells (HK-2 cells) with oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced injury and potential mechanisms. METHODS: HK-2 cells were cultured under normal or OGD/R condition with different drug treatment methods, including 10, 20 and 40 MUmol/L polydatin, and 1 MUmol/L Wortmannin, a specific phosphatidylinositol 3 kinase (PI3K) inhibitor. MTT assay was used to detect the survival ability of cells in different groups. The contents of tumor necrosis factor alpha (TNF alpha) and interleukine 1beta (IL-1beta) in supernatant fluids of the cultured cells were examined by ELISA. And Western blotting was performed to determine the protein levels of total Akt (t-Akt), phospho-Akt (p-Akt) and Sonic hedgehog (Shh) in different groups. RESULTS: Polydatin significantly improved the viability of cells with OGD/R treatment, and apparently inhibited the secretion of TNF-alpha and IL-1beta induced by OGD/R. The inhibition of PI3K/Akt signaling pathway counteracted the anti-inflammation and pro-survival effects of polydatin and blocked the protein expression of Shh in HK-2 cells. The exogenous addition of human recombinant Shh protein not only improved the survival of cells with OGD/R treatment, but also inhibited the inflammation induced by OGD/R in HK-2 cells. CONCLUSION: Polydatin can exert protective effects on HK-2 cells with OGD/R through regulating the PI3K/Akt-dependent Shh pathway. PMID- 26522351 TI - [BAY11-7082 inhibits proliferation and promotes apoptosis in breast carcinoma MCF 7 cells by inhibiting phosphorylation of ATP citrate lyase]. AB - OBJECTIVE: To investigate the effect of NF-kappaB inhibitor BAY11-7082 on proliferation and apoptosis of breast carcinoma MCF-7 cells and the underlying mechanism. METHODS: MCF-7 cells in the logarithmic growth phase were divided into control group, 5 MUmol/L BAY11-7082 group and 10 MUmol/L LY294002 group. After the treatment of BAY11-7082 and LY294002, the protein levels of ATP citrate lyase (ACL), phosphated-ACL (p-ACL), phosphated-Akt (p-Akt) and phosphated nuclear factor kappaB (p-NF-kappaB) were determined by Western blotting. The proliferation of MCF-7 cells treated with BAY11-7082 or siACL were detected by CCK-8 assay. The apoptosis of MCF-7 cells treated with BAY11-7082 or siACL were observed by flow cytometry combined with annexin V-FITC/PI staining. RESULTS: The proliferation of MCF-7 cells was inhibited by BAY11-7082 in a dose-dependent manner. Compared with the control group, the expressions of p-ACL and p-NF-kappaB protein in MCF-7 cells treated with BAY11-7082 were lowered. The expressions of p ACL and p-NF-kappaB protein in MCF-7 cells treated with 10 MUmol/L LY294002 were also reduced significantly. The proliferation of MCF-7 cells treated with BAY11 7082 or siACL for 48 hours was inhibited and the apoptosis was promoted significantly, as shown by CCK-8 assay and flow cytometry. CONCLUSION: BAY11-7082 could inhibit the proliferation of MCF-7 breast carcinoma cells and promote the apoptosis by inhibiting the phosphorylation of ACL. PMID- 26522352 TI - [The myeloid cell leukemia-1 mRNA splicing mediated by epithelial splicing regulatory protein 1 (ESRP1) in glioma U251 cell lines]. AB - OBJECTIVE: To investigate the regulatory mechanism of myeloid cell leukemia-1 (MCL1) mRNA splicing mediated by epithelial splicing regulatory protein 1 (ESRP1) in glioma U251 cell lines. METHODS: Data mining was performed in glioma patient database to find out the key sites from MCL1 sequencing results. Exogenous ESRP1 was over-expressed in U251 cells via pcDNA-ESRP1 vector. The levels of different MCL1 isoforms were detected by reverse transcription PCR and Western blotting. RESULTS: The mRNA and protein level of endogenous ESRP1 was lower in U251 cells than in normal gliocytes. The level of MCL1 isoform 1 was higher, while isoform 2 and 3 were lower in U251 cells than in normal gliocytes. Furthermore, MCL1 isoform 1 was reduced and isoform 3 was up-regulated in U251 cells after ESRP1 over-expression. Isoform 2 was unchanged obviously. Finally, MCL1 with the deletion of 801G and 802A sites could not be correctly spliced by ESRP1 and no significant difference was seen in the expressions of isoform 1 and 3 in mutant MCL1. CONCLUSION: Repression of ESRP1 expression or mutation in its RNA recognized sites in tumor results in the abnormality of transcript splicing of oncogenes. PMID- 26522353 TI - [GoldMag particle-based chemiluminescence immunoassay for human high sensitive C reactive protein]. AB - OBJECTIVE: To develop a sensitive, accurate detection method for high sensitive C reactive protein (hsCRP). METHODS: With the GoldMag particle as the solid phase carrier, horseradish peroxidase (HRP)-lunimo-H2O2 as the chemiluminescence reaction system, we established a chemiluminescent immunoassay for hsCRP detection. Linear range, sensitivity, precision, accuracy and other indicators were evaluated. hsCRP level of 233 clinical human serum specimens were determined and compared by two different methods: the GoldMag particle-based magnetic chemiluminescence enzyme-linked immunoassay established in this study, and the commercialized scattering immunoturbidimetric assay from Germany SIEMENS. RESULTS: The chemiluminescent immunoassay for hsCRP based on GoldMag particle had a good linear relationship between 0.15 mg/L and 25 mg/L (R(2)=0.9937), with the detection limit of 0.076 mg/L. The intra-assay precision was less than 10.00% and the inter-assay precision was less than 15.00%. The average recovery rate for accuracy was 97.80%. In the contrast experiment of 233 clinical human serum specimens, the results obtained using the approach established in this study showed a high correlation and consistency with scattering immunoturbidimetric assay from Germany SIEMENS. CONCLUSION: GoldMag particle-based magnetic chemiluminescence enzyme-linked immunoassay for hsCRP has been successfully developed. PMID- 26522354 TI - [Dynamic changes and effect of primary cilia on adipogenesis during 3T3-L1 cell differentiation into adipocytes]. AB - OBJECTIVE: To investigate the dynamic changes and effect of primary cilia on adipogenesis during 3T3-L1 cell differentiation into adipocyte. METHODS: Chloral hydrate was applied to inhibit primary cilia on day 0 and 4 of 3T3-L1 cell differentiation into adipocyte. The expression levels of primary cilia key proteins like kinesin family member 3a (Kif3a), intraflagellar transport protein 88 (IFT88), acetylated alpha-tubulin (acAT) and adipogenic key protein peroxisome proliferator activated receptor gamma (PPARgamma) were detected by Western blotting. The number of primary cilia was analyzed by immunofluorescence assay. The promoter activity of PPARgamma gene was measured with dual-luciferase reporter assay system. The lipid accumulation was observed by oil red O staining. RESULTS: The levels of primary cilia key proteins, including Kif3a, IFT88, acAT, and the number of the primary cilia were higher on day 0 of cell differentiation, decreased on day 2, and then increased to the beginning levels on day 4, and significantly decreased again on day 8. Incubation with chloral hydrate on day 0 of differentiation significantly reduced the levels of Kif3a, IFT88, acAT proteins and the number of primary cilia, dramatically enhanced the promoter activity of PPARgamma gene, level of PPAR gamma protein and lipid accumulation. However, although primary cilia was significantly inhibited by the incubation with chloral hydrate on day 4 of differentiation, the promoter activity and protein expression of PPARgamma, lipid accumulation had no obvious changes compared with vehicle groups. CONCLUSION: Primary cilia presented a dynamic change during 3T3-L1 cell differentiation into adipocytes. Few primary cilia in the early differentiation led to significantly enhanced adipogenesis, but once the differentiation was under way, the decrease of primary cilia would not affect adipogenesis. PMID- 26522355 TI - [Mild hypothermia inhibits TLR4 activation and the expression of inflammatory cytokines induced by lipopolysaccharide in BV-2 mice microglias]. AB - OBJECTIVE: To investigate the impact of mild hypothermia on the lipopolysaccharide (LPS)-induced expressions of Toll-like receptor 4 (TLR4), nuclear factor kappaB (NF-kappaB) and downstream inflammatory cytokines in BV-2 microglias. METHODS: BV-2 cells cultured in vitro were divided into 33 Degrees Celsius-PBS, 33 Degrees Celsius-LPS, 37 Degrees Celsius-PBS and 37 Degrees Celsius-LPS groups. Real-time quantitative PCR was performed to detect the mRNA expressions of TLR4 and NF-kappaB in BV-2 cells, Western blotting was performed to detect the protein expressions of TLR4 and NF-kappaB in BV-2 cells, and ELISA to detect the levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) in the culture medium. RESULTS: After LPS stimulated BV-2 cells, TLR4 pathway protein exhibited the trend of increasing firstly and decreasing afterwards, while the expression of NF-kappaB protein in the pathway downstream continued to increase, and the release of inflammatory cytokines TNF-alpha and IL 1beta were significantly promoted. Mild hypothermia could significantly inhibit the transcription and expressions of TLR4 and NF-kappaB as well as the release of inflammatory cytokines. CONCLUSION: The mild hypothermia could inhibit the LPS/TLR4 pathway in BV-2 cells, and depress the expressions of TNF-alpha and IL 1beta. PMID- 26522356 TI - [C/EBPbeta promotes NF-kappaB-mediated invasion and migration of human renal carcinoma 786-O cells]. AB - OBJECTIVE: To explore the regulatory role of CCAAT/enhancer-binding protein beta (C/EBPbeta) in invasion and migration of 786-O human renal cancer cells. METHODS: C/EBPbeta adenoviral overexpression vector (pAd-C/EBPbeta) and C/EBPbeta siRNA were constructed and respectively transfered into 786-O cells. Wound healing and Transwell(TM) invasion methods were used to detect the invasion and migration of the cells. Laser scanning confocal microscopy was applied to determine the translocation of nuclear factor kappaB (NF-kappaB), the central regulator of epithelial-mesenchymal transition (EMT); Western blotting was performed to examine the levels of EMT key markers E-cadherin, vimentin and tenascin. RESULTS: When C/EBPbeta was overexpressed, invasion and migration of 786-O cells were enhanced, translocation of NF-kappaB increased, E-cadherin level was reduced, and vimentin and tenascin levels were elevated. When C/EBPbeta was knocked down, the results were completely opposite to those of C/EBPbeta overexpression: invasion and migration of 786-O cells were inhibited, translocation of NF-kappaB decreased, E-cadherin level was elevated, and vimentin and tenascin expressions were suppressed. Moreover, the above changes were not found in the cells that co treated with pAd-C/EBPbeta and C/EBPbeta siRNA. CONCLUSION: C/EBPbeta could promote the invasion and migration of human renal carcinoma 786-O cells, and had an inducing effect on nuclear translocation of NF-kappaB in 786-O cells. PMID- 26522357 TI - [Promoting effect of Fasudil on the proliferation and survival of bone marrow derived neural stem cells in vitro]. AB - OBJECTIVE: To explore the effect of Fasudil on the proliferation and survival of bone marrow-derived neural stem cells (BMNSCs) cultured in vitro. METHODS: BMNSCs were derived from C57BL/6 mice aged 3-4 weeks and induced to produce cell spheres in serum-free medium. The cells were detected by immunofluorescence staining with nestin antibody. The effect of Fasudil on the proliferation of BMNSCs was detected by 5, 6-carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling. BMNSCs were cultured under the inflammatory condition created by BV-2 microglia treated with lipopolysaccharide (LPS) and IFN-gamma. The mitochondrial membrane potential (MMP) and propidium iodide (PI) fluorescence value of BMNSCs were determined by flow cytometry to explore the protective effect of Fasudil on BMNSCs. RESULTS: Immunofluorescence staining verified that bone marrow-derived cell spheres were nestin-positive neural stem cells. The treatment of Fasudil significantly decreased the average fluorescence value of CFSE. BV-2 microglias treated with LPS and IFN-gamma released more inflammatory factors such as IL-6, TNF-alpha than PBS treated group. The inflammatory conditioned medium significantly decreased the MMP of BMNSCs and induced more cell death, while the treatment of Fasudil significantly restored the MMP of BMNSCs close to the normal value and reduced cell death in an obvious dose-dependent manner. CONCLUSION: Fasudil has significantly promoting effect on the proliferation and survival of BMNSCs in vitro. PMID- 26522358 TI - [The level of RORgammat increases in rat lung tissues of bronchiolitis caused by respiratory syncytial virus]. AB - OBJECTIVE: To study the level of retinoic acid receptor-related orphan receptor gammat (RORgammat) in rat lung tissues of bronchiolitis caused by respiratory syncytial virus (RSV) and its implication. METHODS: The rats were randomly divided into normal group and bronchiolitis group. After the model of bronchiolitis was established successfully by nasal dripping, the pathological changes of lung tissues were detected by HE staining; the plasma levels of interleukin 23 (IL-23), IL-17 were detected by ELISA; the level of RORgammat mRNA in lung tissues and peripheral blood mononuclear cells (PBMCs) were detected by real-time quantitative PCR; the level of RORgammat protein in lung tissues was examined by Western blotting. RESULTS: Compared with the normal group, the rats with bronchiolitis presented with pulmonary interstitial hyperemia and edema, more inflammatory cell infiltration, wider alveolar septa and bronchial collapse and deformation. Compared with the normal group, the level of RORgammat mRNA in the lung tissues and PBMCs increased in rats with bronchiolitis. The level of RORgammat protein in lung tissues and the plasma levels of IL-23 and IL -17 were higher in rats with bronchiolitis than in normal rats. CONCLUSION: The level of RORgammat was elevated in the lung tissues of rats with RSV-induced bronchiolitis. PMID- 26522359 TI - [Qibaipingfei Capsule down-regulate the levels of calcineurin and nuclear factor of activated T-cells isoform c3 (NFATc3) in chronic obstructive pulmonary disease]. AB - OBJECTIVE: To investigate the effect of Qibaipingfei Capsule (QPC) on the expressions of calcineurin (CaN) and nuclear factor of activated T-cells isoform c3 (NFATc3) of rat models with phlegm and blood stasis syndrome of chronic obstructive pulmonary disease (COPD), and to explore the possible mechanism underlying the intervention of QPC in pulmonary vascular remodeling of COPD. METHODS: Sixty male Sprague-Dawley (SD) rats were randomly divided into a normal group, a model group, a positive group of nifedipine, a high dose group, a middle dose group and a low dose group of QPC. The rat models with phlegm and blood stasis syndrome of COPD were established by compound methods of forced swimming, smoking and hypoxia. Then the pulmonary function and the pathological alterations of pulmonary vessels were observed. Furthermore, the mRNA and protein levels of CaN and NFATc3 in the lung tissues were determined by real-time quantitative PCR and Western blot analysis. RESULTS: Compared with the normal group, the forced expiratory volume at 0.3 second (FEV0.3), the forced vital capacity (FVC) and FEV0.3/FVC in the model group were significantly reduced, but compared with the model group, the values mentioned above were restored to different extents in the groups of nifedipine and QPC. The lung tissues of the model group showed the thickening of pulmonary vascular wall and the formation of compensating emphysema. The above pathological changes were relieved in all the treatment groups. Compared with the normal group, the expressions of CaN and NFATc3 in the model group were significantly up-regulated in transcription and translation levels. Compared with the model group, these expressions were down-regulated to various degrees in all the treatment groups. CONCLUSION: QPC can decrease the levels of CaN and NFATc3 in the lung tissues of COPD. PMID- 26522360 TI - [Chondrocytic biomimetic matrix materials-induced differentiation of rat bone marrow mesenchymal stem cells into chondrocyte-like cells in vitro]. AB - OBJECTIVE: To investigate the effect of chondrocytic biomimetic matrix scaffold materials containing type 2 collagen (Col2) hydrogel, chondroitin sulphate (CS) and (or) hyaluronic acid (HA) on chondrogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs) in vitro. METHODS: BMSCs were cultured in different groups as following: control, Col2, Col2-CS, Col2-HA, Col2-CS-HA. On day 7, 14, 21 and 28, cell proliferation and differentiation activities were determined using CCK-8 assay. The mRNA and protein expressions of Col2, sex determining region Y (SRY)-related high mobility group-box gene 9 (SOX9) and aggrecan were detected using reverse transcription PCR and immunofluorescence technique. RESULTS: CCK-8 assay indicated that chondrocytic biomimetic matrix scaffold materials based on Col2 could be used as good extracellular matrix for BMSCs culture in vitro. CS and HA increased the proliferation and differentiation activities. All the groups induced effectively BMSCs to differentiate into chondrocytes. Compared with the other groups, Col2-CS-HA-coated group up regulated the mRNA and protein expressions of Col2, SOX9 and aggrecan the most effectively. CONCLUSION: Chondrocytic biomimetic matrix scaffold materials based on Col2 could effectively induce rat BMSCs to differentiate into chondrocyte-like cells in vitro, and supplementation of the hydrogels with both CS and HA had the maximum efficacy. PMID- 26522361 TI - [A negative correlation between Drosha expression and gastric adenocarcinoma malignancy and invasion]. AB - OBJECTIVE: To investigate the role of Drosha expression in the progression of gastric adenocarcinoma and its impact on the invasive ability of SGC-7901 human gastric cancer cells. METHODS: Drosha expression was detected in 889 gastric carcinoma samples on tissue microarrays by immunohistochemistry staining and quantified by Image-Pro Plus software. Statistical analysis was used to evaluate the correlations between Drosha expression and the clinicopathological characteristics of the 889 tumor cases or the outcomes of 309 gastric adenocarcinoma patients. Drosha was knocked down in SGC-7901 cells by small interfering RNA (siRNA), and cell invasive ability was assessed by Transwell(TM) assay. RESULTS: Drosha expression was the highest in the well differentiated gastric adenocarcinoma (median absorbance, 0.4195), and the lowest in the poorly differentiated samples. Drosha expression was significantly related to Laren classification, tumor size, tumor invasion depth, lymph node metastasis, tumor pathological grade and stage. Patients in Drosha positive group had a higher survival rate than those in Drosha negative group. Silencing Drosha in SGC-7901 cells resulted in an enhanced cell invasion. CONCLUSION: Drosha expression was reduced gradually with the degrading histological differentiation of gastric adenocarcinoma, and the knock-down of Drosha expression could promote gastric adenocarcinoma cell invasion. PMID- 26522362 TI - [Increased expression URG11 in hepatocellular carcinoma tissues promotes the growth of hepatocellular carcinoma cells]. AB - OBJECTIVE: To detect the expression of upregulated gene 11 (URG11) in hepatocellular carcinoma (HCC) tissues and cell lines and study the effect of URG11 on HCC cell growth. METHODS: URG11 expression was detected through immunohistochemistry in normal liver tissues, HCC tissues, and matched adjacent non-cancer tissues. URG11 expression in HCC cell lines and control liver cell line was examined by reverse transcription PCR and western blotting. URG11 eukaryotic expression vector and siRNA vector were transfected into QZG cells and HCC cells. Growth of the transfected cells was investigated by MTT assay. Cell cycle was detected by flow cytometry. RESULTS: Positive rates of URG11 expression in HCC tissues was 62.35%, in adjacent non-tumor liver tissues was 69.41%, and in normal liver tissues was 18.5%. URG11 expression was higher significantly in HCC tissues as well as adjacent non-cancer tissues than in normal liver tissues. HCC cells were found to be with the highest URG11 expression, while QZG cells were with negative expression. After URG11 expression was upregulated in QZG cells, QZG cell growth was accelerated, while when URG11 was downregulated in HCC cells, HCC cell growth was suppressed. CONCLUSION: URG11 could promote HCC cell growth and proliferation. It might play an important role in HCC development. PMID- 26522363 TI - [Meta analysis of the changes of blood coagulation in patients with active ulcerative colitis]. AB - OBJECTIVE: To evaluate the changes of blood coagulation in patients with active ulcerative colitis. METHODS: We searched the PubMed, Medline, EMBASE, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), Wanfang Database for the Chinese or English literatures published until January 2015. The data that met the inclusion criteria were screened and evaluated. After evaluation, the eligible ones were subjected to Newcastle-Ottawa Scale (NOS) and meta analysis using the Stata12.0 software. RESULTS: A total of 28 case-control studies were recruited for the meta analysis. The analysis results showed that the levels of platelet (PLT), fibrinogen (FIB) and D-dimer significantly increased in active ulcerative colitis group compared with normal control group. The levels of mean platelet volume (MPV) and prothrombin time (PT) significantly decreased in active ulcerative colitis group compared with normal control group. Sensitivity analysis showed that the evaluation result was stable. Egger and Begg tests suggested no evidence of substantial publication bias except for the literatures about D-dimer. CONCLUSION: Abnormal blood coagulation indexes of active ulcerative colitis patients indicate there may be high coagulation state in ulcerative colitis. PMID- 26522364 TI - [Serum levels of B7-H3 and IFN-gamma in patients with hepatitis B and clinical implications]. AB - OBJECTIVE: To detect the serum levels of soluble B7-H3 (sB7-H3) and interferon gamma (IFN-gamma) in patients with hepatitis B and related clinical implications. METHODS: The levels of sB7-H3 and IFN-gamma were detected by ELISA in 87 cases of hepatitis B including 16 cases of acute hepatitis, 25 cases of chronic moderate to severe hepatitis, 24 cases of liver cirrhosis, 22 cases of decompensated cirrhosis, and 24 healthy subjects. Their correlations with the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alpha fetoprotein (AFP), white blood cells (WBCs), hepatitis virus B (HBV) DNA were analyzed statistically. RESULTS: The serum levels of sB7-H3 and IFN-gamma in patients with hepatitis B were (202.17 +/- 58.14) ng/mL and (3436.11 +/- 1605.01) pg/mL, respectively, which were significantly higher than those in the healthy subjects. SB7-H3 was closely related to IFN-gamma. AST, ALT, AFP, WBCs, and HBV DNA had no correlations with sB7-H3 and IFN-gamma. SB7-H3 was the highest in the patients with acute hepatitis, while IFN-gamma was the highest in the patients with chronic hepatitis B. CONCLUSION: The levels of sB7-H3 and IFN-gamma in the patients with hepatitis B are higher than those in the healthy subjects. Continuous monitoring of serum sB7-H3 and IFN-gamma may helpful in predicting disease outcomes for patients with hepatitis B. PMID- 26522365 TI - [Increased IL-19 level in peripheral blood of patients with allergic rhinitis is related with clinical severity]. AB - OBJECTIVE: To investigate the level of interleukin-19 (IL-19) in the peripheral blood of the patients with allergic rhinitis (AR) and reveal the possible role of IL-19 in the development of disease. METHODS: The levels of IL-19 mRNA and protein in the peripheral blood mononuclear cell (PBMCs) of AR patients and healthy controls were determined by real-time quantitative PCR (qRT-PCR) and ELISA. The clinical severity in AR group was evaluated by the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and the Visual Analog Scale (VAS) scores. Moreover, PBMCs from the AR group were stimulated by recombinant IL-19 or PBS, and then the frequency of Th2 cells, levels of GATA binding protein-3 (GATA-3) mRNA and IL-4 protein in PBMCs were detected by flow cytometry, qRT-PCR and ELISA, respectively. RESULTS: Compared with the control group, the level of IL-19 in the AR group was significantly elevated. In addition, RQLQ and VAS scores in the AR group were also significantly higher than those in the controls, and they were positively correlated with the levels of IL-19 in the AR group (rmRNA RQLQ=0.673, rmRNA-VAS=0.619, protein-RQLQ=0.669, protein-VAS=0.662, P<0.01). CONCLUSION: The level of IL-19 in the peripheral blood of AR patients increased and was related with the clinical severity of AR. PMID- 26522366 TI - [CXCR3 monoclonal antibody inhibits the proliferation and migration of MCF-7 cells and HepG2 cells in vitro]. AB - OBJECTIVE: To study the effects of chemokine (C-X-C motif) receptor 3 (CXCR3) monoclonal antibody (mAb) on the proliferation and migration of MCF-7 and HepG2 cells in vitro. METHODS: Ascites of CXCR3 mAb was prepared at first. MCF-7 and HepG2 cells with high expressions of CXCR3 were screened by flow cytometry. MTT assay was used to detect the effects of CXCR3 mAb on the proliferation of MCF-7 and HepG2 cells in vitro in the absence/presence of interferon-inducible T-cell alpha chemoattractant (I-TAC). TranswellTM assay was performed to investigate the effects of CXCR3 mAb on the migration of MCF-7 and HepG2 cells in vitro in the absence/presence of I-TAC. RESULTS: The expression rate of CXCR3 on MCF-7 and HepG2 cells were 83.5% and 96.2%, respectively. 50 mg/mL CXCR3 mAb significantly inhibited the proliferation and migration of MCF-7 and HepG2 cells, and also inhibited the promoting effect of I-TAC on the proliferation and migration of MCF 7 and HepG2 cells in vitro. CONCLUSION: CXCR3 mAb can significantly inhibit the proliferation and migration of the tumor cells highly expressing CXCR3 in vitro. PMID- 26522367 TI - [Preparation of monoclonal antibody against recombinant human interferon-beta1a]. AB - OBJECTIVE: To prepare the monoclonal antibody (mAb) against recombinant human interferon-beta1a (rhIFN-beta1a). METHODS: BALB/c mice were immunized with purified rhIFN-beta1a. The spleen lymphocyte cells from the one whose blood specific antibody titer exceeded 1:10 000 were fused with Sp2/0 cells. The fused cells went through HAT selection, serial dilution, and positive selection until stable hybridoma cell lines were obtained. The equilibrium dissociation constant (K(D)) of antibodies was calculated based on ELISA result. The cell line with the best KD value was cultured in a stirred-tank bioreactor with a fed-batch strategy to produce secreted anti-rhIFN-beta1a monoclonal antibody. The mAb released into the cell culture supernatant were purified by ultrafiltration and protein-G affinity chromatography. RESULTS: Thirteen hybridoma cell lines which stably produced anti-rhIFN-beta1a antibody were retrieved from standard hybridoma fusion and selection procedures. One of the 13 cell lines, 1E8 with the KD value of 4.6 * 10-9 mol/L was cultured and antibody titer in the cell culture supernatant reached 1:5000. The mAb with 90% purity was recovered from the two-steps purification. CONCLUSION: The anti-rhIFN-beta1a mAb with high purity has been successfully obtained. PMID- 26522368 TI - Evaluating the Use of Synthetic Replicas for SEM Identification of Bloodstains (with Emphasis on Archaeological and Ethnographic Artifacts). AB - Some archaeological or ethnographic specimens are unavailable for direct examination using a scanning electron microscope (SEM) due to methodological obstacles or legal issues. In order to assess the feasibility of using SEM synthetic replicas for the identification of bloodstains (BSs) via morphology of red blood cells (RBCs), three fragments of different natural raw material (inorganic, stone; plant, wood; animal, shell) were smeared with peripheral human blood. Afterwards, molds and casts of the bloodstained areas were made using vinyl polysiloxane (VPS) silicone impression and polyurethane (PU) resin casting material, respectively. Then, the original samples and the resulting casts were coated with gold and examined in secondary-electron mode using a high-vacuum SEM. Results suggest that PU resin casts obtained from VPS silicone molds can preserve RBC morphology in BSs, and consequently that synthetic replicas are feasible for SEM identification of BSs on cultural heritage specimens made of natural raw materials. Although the focus of this study was on BSs, the method reported in this paper may be applicable to organic residues other than blood, as well as to the surface of other specimens when, for any reason, the original is unavailable for an SEM. PMID- 26522369 TI - Monocyte-derived extracellular Nampt-dependent biosynthesis of NAD(+) protects the heart against pressure overload. AB - Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step in the salvage pathway for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, and thereby regulates the deacetylase activity of sirtuins. Here we show accommodative regulation of myocardial NAD(+) by monocyte-derived extracellular Nampt (eNampt), which is essential for hemodynamic compensation to pressure overload. Although intracellular Nampt (iNampt) expression was decreased in pressure-overloaded hearts, myocardial NAD(+) concentration and Sirt1 activity were preserved. In contrast, iNampt was up-regulated in spleen and monocytes, and circulating eNampt protein and nicotinamide mononucleotide (NMN), a key precursor of NAD(+), were significantly increased. Pharmacological inhibition of Nampt by FK866 or depletion of monocytes/macrophages by clodronate liposomes disrupted the homeostatic mechanism of myocardial NAD(+) levels and NAD(+)-dependent Sirt1 activity, leading to susceptibility to cardiomyocyte apoptosis and cardiac decompensation in pressure-overloaded mice. These biochemical and hemodynamic defects were prevented by systemic administration of NMN. Our studies uncover a crucial role of monocyte-derived eNampt in myocardial adaptation to pressure overload, and highlight a potential intervention controlling myocardial NAD(+) against heart failure. PMID- 26522370 TI - Incidence of gastric cancer after endoscopic resection of gastric adenoma. AB - BACKGROUND AND AIMS: The annual incidence of metachronous cancer after endoscopic resection (ER) of early gastric cancer (EGC) is approximately 3%. However, the incidence of gastric cancer after ER of a gastric adenoma is not known. The aim of this study was to determine whether the incidence of gastric cancer after ER of a gastric adenoma was different compared with that of metachronous cancer after ER of EGC. METHODS: We retrospectively analyzed data from patients who underwent ER for gastric neoplasia from January 2005 to August 2013. Enrolled patients were divided into 2 groups: patients with low-grade dysplasia were included in the adenoma group and patients with high-grade dysplasia or invasive neoplasia were included in the EGC group. The main outcome was the incidence of gastric cancer after ER. RESULTS: At a median follow-up of 28 months, gastric cancer newly developed in 13 adenoma patients (3.6%) and in 30 EGC patients (5.1%). The incidence rate of gastric cancer after ER was 14.4 cases per 1000 person-years in adenoma patients and 18.4 cases per 1000 person-years in EGC patients (P = .309 by the log-rank test). The hazard ratio of metachronous neoplasia in adenoma patients compared with EGC patients was 0.97 (95% confidence interval, 0.62-1.53). Metachronous tumors with invasion beyond the muscularis mucosa were more frequent in adenoma patients than in EGC patients (7/35 [20.0%] vs 3/63 [4.8%], P = .017). CONCLUSION: The incidence of gastric cancer after ER for gastric adenoma was not significantly different from that of EGC. If further prospective studies confirm these findings, careful endoscopic surveillance with the same level of intensity should be considered for both gastric adenoma and EGC patients after ER. PMID- 26522371 TI - Endoscopic intestinal bypass creation by using self-assembling magnets in a porcine model. AB - BACKGROUND AND AIMS: A purely endoluminal method of GI bypass would be desirable for the treatment of obstruction, obesity, or metabolic syndrome. We have developed a technology based on miniature self-assembling magnets that create large-caliber anastomoses (Incisionless Anastomosis System [IAS]). The aim of this study was to evaluate procedural characteristics of IAS deployment and long term anastomotic integrity and patency. METHODS: We performed a 3-month survival study of Yorkshire pigs (5 interventions, 3 controls). Intervention pigs underwent simultaneous enteroscopy/colonoscopy performed with the animals under intravenous sedation. The IAS magnets were deployed and coupled with reciprocal magnets under fluoroscopy. Every 3 to 6 days pigs underwent endoscopy until jejunocolonic anastomosis (dual-path bypass) creation and magnet expulsion. Necropsies and histological evaluation were performed. The primary endpoints were technical success; secondary endpoints of anastomosis integrity, patency, and histological characteristics were weight trends. RESULTS: Under intravenous sedation, endoscopic bypass creation by using IAS magnets was successfully performed in 5 of 5 pigs (100%). Given porcine anatomy, the easiest dual-path bypass to create was between the proximal jejunum and colon. The mean procedure time was 14.7 minutes. Patent, leak-free anastomoses formed by day 4. All IAS magnets were expelled by day 12. All anastomoses were fully patent at 3 months with a mean diameter of 3.5 cm. The mean 3-month weight was 45 kg in bypass pigs and 78 kg in controls (P = .01). At necropsy, adhesions were absent. Histology showed full re-epithelialization across the anastomosis without fibrosis or inflammation. CONCLUSION: Large-caliber, leak-free, foreign body-free endoscopic intestinal bypass by using IAS magnets can be safely and rapidly performed in the porcine by model using only intravenous sedation. PMID- 26522372 TI - Multicenter, prospective, crossover trial comparing the door-knocking method with the conventional method for EUS-FNA of solid pancreatic masses (with videos). AB - BACKGROUND AND AIMS: There are currently no prospective, controlled trials of needle puncture speed in EUS-guided FNA (EUS-FNA). In this study, we prospectively evaluated the accuracy of histological diagnosis and the tissue acquisition rate of EUS-FNA by using the door-knocking method (DKM) with a standard 22-gauge needle. METHODS: From November 2013 to August 2014, 82 patients who had solid pancreatic masses underwent EUS-FNA in which the conventional method (CM) and DKM with 2 respective passes in turn were used. The primary outcomes of this study were the accuracy of histological diagnosis and the rates of tissue acquisition in 2 FNA procedures by using these 2 methods. RESULTS: Although the successful tissue acquisition rate for histology was not significantly different with the DKM and CM (91.5% vs 89.0%, P = .37), the high cellularity tissue acquisition rate for histology with the DKM was significantly superior to that with the CM (54.9% vs 41.5%, P = .03). However, adequate quality rate and accuracy were not different in the DKM and CM (78.0% vs 80.5%, P = .42 and 76.8% vs 78.0%, P = .50, respectively). In the transgastric puncture group, although the adequate quality rate and accuracy were similar in the DKM and CM (84.1% vs 79.4%, P = .30 and 84.1% vs 76.2%, P = .11, respectively), the tissue acquisition rate tended to be higher with the DKM than the CM (93.7% vs 85.7%, P = .06). Moreover, the high cellularity tissue acquisition rate was significantly better with the DKM than the CM (63.5% vs 39.7%, P = .002). On the other hand, in the transduodenal puncture group, although the tissue acquisition rate was similar with the DKM and CM (84.2% vs 100%, P = .13), the adequate quality rate and accuracy were significantly lower with the DKM than with the CM (57.9% vs 84.2%, P = .03 and 52.6% vs 84.2%, P = .02, respectively). CONCLUSION: EUS-FNA by using a 22-gauge needle with the DKM did not improve the accuracy of histological diagnosis, but enabled acquisition of a larger amount of tissue specimen by using transgastric puncture. ( TRIAL REGISTRATION: http://www.umin.ac.jp/english/: UMIN000012127.). PMID- 26522373 TI - Active ocular vergence improves postural control in elderly as close viewing distance with or without a single cognitive task. AB - Performance of the vestibular, visual, and somatosensory systems decreases with age, reducing the capacity of postural control, and increasing the risk of falling. The purpose of this study is to measure the effects of vision, active vergence eye movements, viewing distance/vergence angle and a simple cognitive task on postural control during an upright stance, in completely autonomous elderly individuals. Participated in the study, 23 elderly subjects (73.4 +/- 6.8 years) who were enrolled in a center dedicated to the prevention of falling. Their body oscillations were measured with the DynaPort((r)) device, with three accelerometers, placed at the lumbosacral level, near the center of mass. The conditions were the following: eyes open fixating on LED at 20 cm or 150 cm (vergence angle 17.0 degrees and 2.3 degrees respectively) with or without additional cognitive tasks (counting down from one hundred), performing active vergence by alternating the fixation between the far and the near LED (convergence and divergence), eyes closed after having fixated the far LED. The results showed that the postural stability significantly decreased when fixating on the LED at a far distance (weak convergence angle) with or without cognitive tasks; active convergence-divergence between the LEDs improved the postural stability while eye closure decreased it. The privilege of proximity (with increased convergence at near), previously established with foot posturography, is shown here to be valid for accelerometry with the center of mass in elderly. Another major result is the beneficial contribution of active vergence eye movements to better postural stability. The results bring new perspectives for the role of eye movement training to preserve postural control and autonomy in elderly. PMID- 26522375 TI - Ultrasensitive Gold Nanostar-Polyaniline Composite for Ammonia Gas Sensing. AB - Gold in the form of bulk metal mostly does not react with gases or liquids at room temperature. On the other hand, nanoparticles of gold are very reactive and useful as catalysts. The reactivity of nanoparticles depends on the size and the morphology of the nanoparticles. Gold nanostars containing copper have rough surfaces and large numbers of active sites due to tips, sides, corners, and large surface area-to-volume ratios due to their branched morphology. Here the sensitivity of the gold nanostar-polyaniline composite (average size of nanostars ~170 nm) toward ammonia gas has been investigated. For 100 ppm ammonia, the sensitivity of the composite increased to 52% from a mere 7% value for pure polyaniline. The gold nanostar-polyaniline composite even showed a response time as short as 15 s at room temperature. The gold nanostars act as a catalyst in the nanocomposite. The stability and sensitivity at different concentrations and the selectivity for ammonia gas were also investigated. PMID- 26522374 TI - DNA methylation in Huntington's disease: Implications for transgenerational effects. AB - Huntington's disease (HD) is a devastating, neurodegenerative disorder caused by a CAG repeat mutation in the HTT gene. A growing body of evidence suggests that epigenetic modifications play a key role in HD pathogenesis. Expression of the disease protein, huntingtin, leads to extensive transcriptional dysregulation due to disruption of histone-modifying complexes and altered interactions with chromatin-related factors. Such epigenetic mechanisms also readily respond to environmental factors, which are now thought to influence the risk, onset and progression of neurodegenerative disorders, including HD. DNA methylation is an epigenetic modification that has been studied intensively, however, its role in HD is just emerging. In this review, DNA methylation differences associated with HD will be summarized, as well as the role of environmental factors to alter DNA methylation in a manner that could alter disease phenotypes. Further, transgenerational epigenetic inheritance will be discussed in the context of relevant environmental factors and their potential links to HD. The study of epigenetic states in HD presents an opportunity to gain new insights into risk factors and pathogenic mechanisms associated with HD, as well as to inform about treatment options. PMID- 26522376 TI - Adverse neurologic events in patients bridged with long-term mechanical circulatory support: A device-specific comparative analysis. AB - BACKGROUND: Neurologic complications are among the principal causes of morbidity and mortality after continuous-flow left ventricular assist device (CF-LVAD) implantation. The aim of this study was to describe a focused "real-world" multicenter comparison of neurologic outcomes between HeartMate II (HMII) and HeartWare HVAD CF-LVAD recipients. METHODS: Between March 2009 and October 2014, 497 patients underwent primary CF-LVAD implantation as a bridge to transplantation at centers included in the Mechanical Circulatory Support Research Network; 314 patients (63%) received HMII, and 183 patients (37%) received HVAD. Ischemic cerebrovascular accident, hemorrhagic cerebrovascular accident, and transient ischemic attack were the neurologic outcomes assessed. RESULTS: Median follow-up time for HMII recipients was 0.95 years (0.48, 1.85, range) and for HVAD recipients was 0.44 years (0.19, 0.97, range) (p < 0.001). HMII recipients had significantly fewer neurologic events per patient year for ischemic cerebrovascular accident (0.071) and transient ischemic attack (0.012) compared with HVAD recipients (0.157 and 0.072, respectively). Univariate analysis showed that 51 HMII recipients (16%) had any neurologic event, whereas 34 HVAD recipients (19%) had any neurologic event (p = 0.504). After adjusting for pre-specified covariates (device type, age, sex, atrial fibrillation, diabetes, and Interagency Registry for Mechanically Assisted Circulatory Support profile), multivariable analysis showed only advanced age was able to predict neurologic events (p = 0.02). Neurologic events were comparable between HMII and HVAD recipients after multivariable analysis. CONCLUSIONS: CF-LVAD placement incurs a low but significant risk of neurologic complications in patients receiving CF-LVADs as a bridge to transplantation. Advancing age is a risk factor for any adverse neurologic outcome. This multicenter analysis demonstrated comparable hazard of adverse neurologic events among patients implanted with HMII or HVAD. PMID- 26522378 TI - Safe site selection for chest drain insertion by trainee physicians - Implications for medical training and clinical practice. PMID- 26522377 TI - Troponin levels within the normal range and probability of inducible myocardial ischemia and coronary events in patients with acute chest pain. AB - BACKGROUND/OBJECTIVES: Patients with suspected acute coronary syndromes and negative cardiac troponin (cTn) levels are deemed at low risk. Our aim was to assess the effect of cTn levels on the frequency of inducible myocardial ischemia and subsequent coronary events in patients with acute chest pain and cTn levels within the normal range. METHODS: We evaluated 4474 patients with suspected acute coronary syndromes, nondiagnostic electrocardiograms and serial cTnI levels below the diagnostic threshold for myocardial necrosis using a conventional or a sensitive cTnI assay. The end points were the probability of inducible myocardial ischemia and coronary events (i.e., coronary death, myocardial infarction or coronary revascularization within 3 months). RESULTS: The probability of inducible myocardial ischemia was significantly higher in patients with detectable peak cTnI levels (25%) than in those with undetectable concentrations (14.6%, p<0.001). These results were consistent regardless of the type of cTnI assay, the type of stress testing modality, or the timing for cTnI measurement, and remained significant after multivariate adjustment (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.21-1.79, p<0.001). The rate of coronary events at 3 months was also significantly higher in patients with detectable cTnI levels (adjusted OR 2.08, 95% CI 1.64-2.64, p<0.001). CONCLUSIONS: Higher cTnI levels within the normal range were associated with a significantly increased probability of inducible myocardial ischemia and coronary events in patients with suspected acute coronary syndromes and seemingly negative cTnI. PMID- 26522379 TI - Bacterial isolates, antimicrobial susceptibility, and clinical characteristics of bacterial keratitis in dogs presenting to referral practice in Australia. AB - OBJECTIVE: To identify clinical characteristics, bacterial isolates, and their antimicrobial susceptibility patterns in a prospective study of dogs presenting with suspected bacterial keratitis to aid selection of appropriate therapy. ANIMALS: Seventy-one client-owned dogs presenting to two referral hospitals in Australia. PROCEDURE: Corneal swabs and clinical information were collected from dogs presenting with suspect bacterial keratitis from April 2012 to December 2014. Cytology and bacteriologic culture were performed on samples with in vitro antimicrobial susceptibility performed on bacterial isolates. RESULTS: Positive cultures were obtained from 42 of the 71 ulcers sampled (59%), with 45 bacteria isolated. The most commonly isolated bacteria were beta-hemolytic Streptococcus (14/45, 31%), Pseudomonas (14/45, 31%), and Staphylococcus species (8/45, 18%). beta-Hemolytic Streptococcus spp. were resistant to neomycin, polymyxin B, gentamicin, framycetin and fusidic acid and >80% were resistant to ciprofloxacin but remained susceptible to chloramphenicol and cephalexin. Pseudomonas aeruginosa isolates were resistant to chloramphenicol, cephalexin, and fusidic acid; however, >90% were susceptible to ciprofloxacin, polymyxin B, and gentamicin. Brachycephalic breed (34/42, 81%), previous ocular surgery (15/42, 36%), prior use of a topical corticosteroid (13/42, 31%), and concurrent ocular surface disease (10/42, 24%) were common in dogs with bacterial keratitis. CONCLUSION: Our study identified beta-hemolytic Streptococcus and Pseudomonas spp. as the most common bacterial pathogens in canine bacterial keratitis presenting for referral. Many cases exhibited clinical factors known to influence corneal integrity that may predispose them to ulceration and infection. Based on in vitro antimicrobial susceptibility patterns and clinical outcomes, monotherapy with a fluoroquinolone may be ineffective in ulcers caused by beta-hemolytic Streptococcus spp. PMID- 26522380 TI - Stress, depression, quality of life and salivary cortisol levels in community health agents. AB - OBJECTIVE: To determine the prevalence of and factors associated with depression and stress with perceived quality of life and the salivary cortisol levels in Community Health Agent (CHA). Materials and Methods Cross-sectional descriptive study of CHAs in Pelotas-RS, Brazil. Data collection, including sociodemographic information and factors related to work and health. Beck Depression Inventory (BDI) II was used to assess depressive symptoms, Inventory of Stress Symptoms Lipp (ISSL) was used for the analysis of stress and the WHOQOL-BREF was used to investigate quality of life. Salivary cortisol was quantified via ELISA test. RESULTS: The assessments showed that 71.0% are in a state of stress resistance, 30.5% were in the alert state of stress and 32.8% were in the stress state of exhaustion. Depressive episodes (BDI>=12) were observed in 28.2%. The environmental domain had the lowest score for quality of life. We observed significantly higher salivary cortisol levels in CHAs with less than 1 year of service and with the lowest quality of life scores in the environmental subsection. CONCLUSION: A high prevalence of stress and depression was observed in this sample of CHAs. In addition, the worst levels of quality of life were identified in the environmental subsection. Cortisol levels corroborate these findings regarding quality of life within the environmental domain and began working less than a year previously. PMID- 26522381 TI - Bilateral piriformis syndrome in two elite soccer players: Report of two cases. AB - Piriformis syndrome, a relatively rare condition, is described as entrapment of a sciatic nerve at the level of the piriformis muscle. There have been a few reports of bilateral piriformis syndrome in literature. In this study, we present bilateral piriformis syndrome in two professional soccer players from different teams who are symptom free at last follow-up after surgery. In both patients, resting EMG records were read normal, however EMG recording during the activity revealed prolonged H-reflexes. Both patients had no relief from conservative treatment and rehabilitation, therefore surgical treatment was performed. Preoperative mean visual analogue scale (VAS) value was 7, and decreased to 3 at the sixth month follow-up visit and at the longer term follow-up, mean 85months (74-96) it was valued at 1. Both soccer players returned to their active sports lives in the sixth postoperative month. According to Benson's functional evaluation scale, in long-term follow-up, there have been excellent results and both patients resumed their professional carrier for many years (mean 7 years). PMID- 26522382 TI - Comparison of intraoperative flat panel imaging and postoperative plain radiography for the detection of intraarticular screw displacement in volar distal radius plate ostheosynthesis. AB - OBJECTIVES: To investigate if intraoperative 3D flat panel imaging improves the detection of radiocarpal intraarticular screw misplacement (RCSM) in comparison to standard postoperative x-ray. METHODS: In a study on cadaver specimens, we evaluated the sensitivity and specificity to detect RCSM using X-ray, intraoperative 3D-fluoroscopy as well as the digital volume tomography. The gold standard reference was computed tomography. RESULTS: Sensitivity for the detection of RCSM for X-ray was 58% and specificity 88%. For DVT, the sensitivity to detect RCSM was 88% and the specificity 53%. For 3D-fluoroscopy, the sensitivity for RCSM was 68% and specificity 95%. When combining the methods, the best performance was found, when combining the two intraoperative imaging methods, with a resulting sensitivity of 88% and a specificity of 73%. CONCLUSIONS: Intraoperative 3D fluoroscopy and digital volume tomography appear to be at least as sensitive and specific to detect RCSM than the regular postoperative radiography in two planes. However, especially discrete screw misplacements can be missed with either method. LEVEL OF EVIDENCE: Level IV. Diagnostic device study. PMID- 26522383 TI - Cytoplasmic kinases downstream of GPR30 suppress gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone secretion from bovine anterior pituitary cells. AB - GPR30 is known as a membrane receptor for picomolar concentrations of estradiol. The GPR30-specific agonist G1 causes a rapid, non-genomic suppression of gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) secretion from bovine anterior pituitary (AP) cells. A few studies have recently clarified that protein kinase A (PKA) and phosphorylated extracellular signal-regulated kinase (pERK) might be involved in cytoplasmic signaling pathways of GPR30 in other cells. Therefore, we tested the hypothesis that PKA and ERK kinase (MEK) are important cytoplasmic mediators for GPR30-associated non-genomic suppression of GnRH-induced LH secretion from bovine AP cells. Bovine AP cells (n = 8) were cultured for 3 days under steroid-free conditions. The AP cells were previously treated for 30 min with one of the following: 5000 nM of PKA inhibitor (H89), 1000 nM of MEK inhibitor (U0126), or a combination of H89 and U0126. Next, the AP cells were treated with 0.01 nM estradiol for 5 min before GnRH stimulation. Estradiol treatment without inhibitor pretreatment significantly suppressed GnRH induced LH secretion (P < 0.01). In contrast, estradiol treatment after pretreatment with H89, U0126 or their combination had no suppressive effect on GnRH-induced LH secretion. The inhibitors also inhibited the G1 suppression of GnRH-induced LH secretion. Therefore, these data supported the hypothesis that PKA and MEK (thus, also pERK) are the intracellular mediators downstream of GPR30 that induce the non-genomic suppression of GnRH-induced LH secretion from bovine AP cells by estradiol or G1. PMID- 26522385 TI - Residual and ovicidal efficacy of essential oil-based formulations in vitro against the donkey chewing louse Bovicola ocellatus. AB - Essential oils have shown good experimental potential as novel veterinary ectoparasiticides. However, if they are to be used as veterinary products, they must be available in formulations that are suitable for practical application against specific ectoparasites. Here, the efficacies of formulations containing 5% (v/v) lavender or tea tree oil, in combination with two emulsifiers [a surfactant, 5% (w/v) N-lauroylsarcosine sodium salt (SLS), and a soluble polymer, 5% (w/v) polyvinylpyrrolidone (PVP)], with or without 10% coconut oil, were tested in contact bioassays against the donkey chewing louse Bovicola ocellatus (Piaget) (Phthiraptera: Trichodectidae). Residual activity was quantified in open and closed containers; ovicidal efficacy was also examined. Exposure to either of 5% (v/v) lavender or tea tree oils with SLS or PVP resulted in louse mortality of 100%, but when coconut oil was included as an excipient, significantly lower efficacy was recorded. However, the formulations became significantly less effective after 2 h in open containers and 40 h in closed containers. The results confirm that the residual activity of essential oils is relatively transitory and the addition of 10% coconut oil does not prolong the period of insecticidal activity by slowing essential oil evaporation. Too short a period of residual activity is likely to be a significant impediment to the effective practical use of essential oils. However, unlike many synthetic pediculicides, the essential oils tested here were highly ovicidal, which suggests that prolonged residual activity may not be essential to kill newly hatched nymphs after treatment. PMID- 26522386 TI - A Chemical Perspective on Microalgal-Microbial Interactions. AB - The exchange of chemical compounds is central to the interactions of microalgae with other microorganisms. Although foundational for many food webs, these interactions have been poorly studied compared with higher plant-microbe interactions. Emerging insights have begun to reveal how these interactions and the participating chemical compounds shape microbial communities and broadly impact biogeochemical processes. PMID- 26522384 TI - Decorin as a multivalent therapeutic agent against cancer. AB - Decorin is a prototypical small leucine-rich proteoglycan that epitomizes the multifunctional nature of this critical gene family. Soluble decorin engages multiple receptor tyrosine kinases within the target-rich environment of the tumor stroma and tumor parenchyma. Upon receptor binding, decorin initiates signaling pathways within endothelial cells downstream of VEGFR2 that ultimately culminate in a Peg3/Beclin 1/LC3-dependent autophagic program. Concomitant with autophagic induction, decorin blunts capillary morphogenesis and endothelial cell migration, thereby significantly compromising tumor angiogenesis. In parallel within the tumor proper, decorin binds multiple RTKs with high affinity, including Met, for a multitude of oncosuppressive functions including growth inhibition, tumor cell mitophagy, and angiostasis. Decorin is also pro inflammatory by modulating macrophage function and cytokine secretion. Decorin suppresses tumorigenic growth, angiogenesis, and prevents metastatic lesions in a variety of in vitro and in vivo tumor models. Therefore, decorin would be an ideal therapeutic candidate for combating solid malignancies. PMID- 26522387 TI - Generation of hypoxanthine phosphoribosyltransferase gene knockout rabbits by homologous recombination and gene trapping through somatic cell nuclear transfer. AB - The rabbit is a common animal model that has been employed in studies on various human disorders, and the generation of genetically modified rabbit lines is highly desirable. Female rabbits have been successfully cloned from cumulus cells, and the somatic cell nuclear transfer (SCNT) technology is well established. The present study generated hypoxanthine phosphoribosyltransferase (HPRT) gene knockout rabbits using recombinant adeno-associated virus-mediated homologous recombination and SCNT. Gene trap strategies were employed to enhance the gene targeting rates. The male and female gene knockout fibroblast cell lines were derived by different strategies. When male HPRT knockout cells were used for SCNT, no live rabbits were obtained. However, when female HPRT(+/-) cells were used for SCNT, live, healthy rabbits were generated. The cloned HPRT(+/-) rabbits were fertile at maturity. We demonstrate a new technique to produce gene-targeted rabbits. This approach may also be used in the genetic manipulation of different genes or in other species. PMID- 26522389 TI - Letter From the Editors. PMID- 26522390 TI - Pitfalls and Limitations of Radionuclide and Hybrid Imaging: Part 2. PMID- 26522388 TI - Farnesylated and methylated KRAS4b: high yield production of protein suitable for biophysical studies of prenylated protein-lipid interactions. AB - Prenylated proteins play key roles in several human diseases including cancer, atherosclerosis and Alzheimer's disease. KRAS4b, which is frequently mutated in pancreatic, colon and lung cancers, is processed by farnesylation, proteolytic cleavage and carboxymethylation at the C-terminus. Plasma membrane localization of KRAS4b requires this processing as does KRAS4b-dependent RAF kinase activation. Previous attempts to produce modified KRAS have relied on protein engineering approaches or in vitro farnesylation of bacterially expressed KRAS protein. The proteins produced by these methods do not accurately replicate the mature KRAS protein found in mammalian cells and the protein yield is typically low. We describe a protocol that yields 5-10 mg/L highly purified, farnesylated, and methylated KRAS4b from insect cells. Farnesylated and methylated KRAS4b is fully active in hydrolyzing GTP, binds RAF-RBD on lipid Nanodiscs and interacts with the known farnesyl-binding protein PDEdelta. PMID- 26522391 TI - Pitfalls and Artifacts in the Use of PET/CT in Oncology Imaging. AB - Accurate reporting of combined PET/CT imaging requires a thorough understanding of the normal and variant physiological distribution of tracers as well as common incidental findings and technical artifacts. We describe these pitfalls and artifacts, what action may help to mitigate them in clinical practice, and what further action may be appropriate. This review presents these in a region-based approach, in order to closely mimic clinical practice, and focuses on technical artifacts followed by a description of two commonly used oncologic tracers: FDG and choline. PMID- 26522392 TI - Pitfalls and Limitations of Radionuclide and Hybrid Imaging in Infection and Inflammation. AB - Both the referring clinician and the nuclear medicine specialist must be aware of the main known or potential pitfalls that can occur in infection and inflammation imaging. They must decide in consensus which tracer and which imaging protocol should be used for a specific indication. This article provides an overview of all the pitfalls and limitations of nuclear medicine techniques to image infections and inflammation. Both general pitfalls and pitfalls in specific clinical entities are discussed. PMID- 26522393 TI - Pitfalls and Limitations of Radionuclide Hepatobiliary and Gastrointestinal System Imaging. AB - Radionuclide imaging for the hepatobiliary and gastrointestinal system covers a wide range of different indications and imaging techniques. This wide variety allows the different functional assessments of both systems. Therefore, the understanding of each technique and its indications is essential. Cholescintigraphy is a well-established method in the assessment of acute and chronic cholecystitis. It also has a role in the detection of biliary atresia. The assessment of gastrointestinal transit is also well-established in radionuclide imaging for functional investigation of the gastrointestinal tract. Furthermore, detection of acute gastrointestinal bleeding with radionuclide imaging is also standard practice. This article aims to review the pitfalls and limitations in all of these areas. PMID- 26522394 TI - Technical Pitfalls and Limitations of SPECT/CT. AB - The synergy of functional and anatomic information in hybrid systems has undoubtedly enhanced the diagnostic potential of radionuclide imaging in recent years, contributing to the advancement of SPECT/CT in clinical practice. Since the introduction of commercial SPECT/CT in the late 1990 s, the field has seen rapid expansion and development toward multidetector CT subsystems, establishing the role of SPECT/CT as a routine imaging tool. It is, however, important to discuss possible challenges and technical limitations of such systems and how these influence imaging outcomes. In particular, the issues of patient motion and spatial misalignment of the SPECT and CT modalities, data corrections such as those for photon attenuation, and the choice of CT acquisition protocols in relation to radiation exposure are discussed in the article. PMID- 26522395 TI - Pitfalls and Limitations of PET/CT in Brain Imaging. AB - Neurologic applications were at the forefront of PET imaging when the technique was developed in the mid-1970s. Although oncologic indications have become prominent in terms of number of studies performed worldwide, neurology remains a major field in which functional imaging provides unique information, both for clinical and research purposes. The evaluation of glucose metabolism using FDG remains the most frequent exploration, but in recent years, alternative radiotracers have been developed, including fluorinated amino acid analogues for primary brain tumor imaging and fluorinated compounds for assessing the amyloid deposits in patients with suspected Alzheimer disease. As the brain is enclosed in the skull, which presents fixed landmarks, it is relatively easy to coregister images obtained with various cross-sectional imaging methods, either functional or anatomical, with a relatively high accuracy and robustness. Nevertheless, PET in neurology has fully benefited from the advent of hybrid imaging. Attenuation and scatter correction is now much faster and equally accurate, using CT as compared with the traditional transmission scan using an external radioactive source. The perfect coregistration with the CT data, which is now systematically performed, also provides its own set of valuable information, for instance regarding cerebral atrophy. However, hybrid imaging in neurology comes with pitfalls and limitations, in addition to those that are well known, for example, blood glucose levels or psychotropic drugs that greatly affect the physiological FDG uptake. Movements of the patient's head, either during the PET acquisition or between the PET and the CT acquisitions will generate artifacts that may be very subtle yet lead to erroneous interpretation of the study. Similarly, quantitative analysis, such as voxel-based analyses, may prove very helpful in improving the diagnostic accuracy and the reproducibility of the reading, but a wide variety of artifacts may also be introduced, and should therefore be identified and corrected. PMID- 26522396 TI - Pitfalls and Limitations in Simultaneous PET/MRI. AB - Simultaneous PET/MRI was introduced into the commercial market only a few years ago, and its availability is currently gaining momentum with the introduction of a second-generation PET/MRI system from an additional vendor. Furthermore, there is still an increasing interest in its potential in clinical and research applications. Despite very early technical infancy problems, which meanwhile have been solved, there are still different limitations that have to be worked around in daily routine responsibly by the physicists and physicians. This article gives an overview over the most common technical, logistical, and clinical limitations; artifacts; and pitfalls, without any claim for completeness. The readers will not only learn the background of the limitation but also partly learn about possible solutions. At the end of each paragraph, the readers will find a short summary for an easier overview of the topics discussed. PMID- 26522397 TI - Interesting Signs in Nuclear Medicine. AB - Classic radiological and nuclear medicine signs have been reported extensively because of a myriad of pathophysiological processes. When encountered, they aid in diagnosis of conditions and add confidence for the reader, at times even hinting at a specific diagnosis. The naming of signs is commonly associated with objects from everyday life to establish familiarity with visual findings. Association of signs and disease comes with regular practice and improves understanding of the image and its underlying cause. In this article, we have collated nuclear medicine signs reported in the literature since 1970. PMID- 26522398 TI - Unraveling cognitive traits using the Morris water maze unbiased strategy classification (MUST-C) algorithm. AB - The assessment of spatial cognitive learning in rodents is a central approach in neuroscience, as it enables one to assess and quantify the effects of treatments and genetic manipulations from a broad perspective. Although the Morris water maze (MWM) is a well-validated paradigm for testing spatial learning abilities, manual categorization of performance in the MWM into behavioral strategies is subject to individual interpretation, and thus to biases. Here we offer a support vector machine (SVM) - based, automated, MWM unbiased strategy classification (MUST-C) algorithm, as well as a cognitive score scale. This model was examined and validated by analyzing data obtained from five MWM experiments with changing platform sizes, revealing a limitation in the spatial capacity of the hippocampus. We have further employed this algorithm to extract novel mechanistic insights on the impact of members of the Toll-like receptor pathway on cognitive spatial learning and memory. The MUST-C algorithm can greatly benefit MWM users as it provides a standardized method of strategy classification as well as a cognitive scoring scale, which cannot be derived from typical analysis of MWM data. PMID- 26522399 TI - Electrical level of defects in single-layer two-dimensional TiO2. AB - The remarkable properties of graphene and transition metal dichalcogenides (TMDCs) have attracted increasing attention on two-dimensional materials, but the gate oxide, one of the key components of two-dimensional electronic devices, has rarely reported. We found the single-layer oxide can be used as the two dimensional gate oxide in 2D electronic structure, such as TiO2. However, the electrical performance is seriously influenced by the defects existing in the single-layer oxide. In this paper, a nondestructive and noncontact solution based on spectroscopic ellipsometry has been used to detect the defect states and energy level of single-layer TiO2 films. By fitting the Lorentz oscillator model, the results indicate the exact position of defect energy levels depends on the estimated band gap and the charge state of the point defects of TiO2. PMID- 26522400 TI - Predictors of medication adherence and persistence in Medicaid enrollees with developmental disabilities and type 2 diabetes. AB - BACKGROUND: The prevalence of diabetes mellitus is high among patients with developmental disabilities (cerebral palsy, autism, Down's syndrome and cognitive disabilities). OBJECTIVES: The purpose of this study was to examine the racial health disparities in medication adherence and medication persistence in developmentally disabled adults with type 2 diabetes enrolled in Medicaid. METHODS: This was a retrospective cohort study using the MarketScan((r)) Multi State Medicaid Database. Adults aged 18-64 years with a prior diagnosis of a developmental disability (cerebral palsy/autism/down's/cognitive disabilities) and a new diagnosis of type 2 diabetes enrolled in Medicaid from January 1, 2004 and December 31, 2006, were included. Adults were included if they had a continuous enrollment for at least 12 months and were excluded if they were dual eligible. Anti-diabetes medication adherence and diabetes medication persistence were measured using multivariate logistic regression and the Cox-proportional hazard regression, respectively. RESULTS: The study population comprised of 1529 patients. Although overall diabetes medication adherence in this population was optimal, African Americans had significantly lower odds (25%) of adhering to anti diabetes medications compared to Caucasians (OR = 0.75, 95% CI = 0.58-0.97, P < 0.05). Also, after controlling for other covariates, the rate of discontinuation was higher in African Americans compared to Caucasians (hazard ratio = 1.03, 95% CI = 0.91-1.18, P < 0.629). CONCLUSION: In this study, racial disparities were found in anti-diabetes medication adherence among Medicaid enrollees with developmental disabilities (DD). Studies conducted in the future should examine predictors that impact access to care, availability of primary and specialized care, social support as well as beliefs of racial minority populations with developmental disabilities and chronic conditions like diabetes to optimize medication use outcomes in this especially vulnerable population. PMID- 26522401 TI - [Not Available]. PMID- 26522402 TI - Changes in markers associated with dendritic cells driving the differentiation of either TH2 cells or regulatory T cells correlate with clinical benefit during allergen immunotherapy. AB - BACKGROUND: Regulatory dendritic cell (DC) markers, such as C1Q, are upregulated in PBMCs of patients with grass pollen allergy exhibiting clinical benefit during allergen immunotherapy (AIT). OBJECTIVES: We sought to define markers differentially expressed in human monocyte-derived DCs differentiated toward a proallergic (DCs driving the differentiation of TH2 cells [DC2s]) phenotype and investigate whether changes in such markers in the blood correlate with AIT efficacy. METHODS: Transcriptomes and proteomes of monocyte-derived DCs polarized toward DCs driving the differentiation of TH1 cells (DC1s), DC2s, or DCs driving the differentiation of regulatory T cells (DCreg cells) profiles were compared by using genome-wide cDNA microarrays and label-free quantitative proteomics, respectively. Markers differentially regulated in DC2s and DCreg cells were assessed by means of quantitative PCR in PBMCs from 80 patients with grass pollen allergy before and after 2 or 4 months of sublingual AIT in parallel with rhinoconjunctivitis symptom scores. RESULTS: We identified 20 and 26 new genes/proteins overexpressed in DC2s and DCreg cells, respectively. At an individual patient level, DC2-associated markers, such as CD141, GATA3, OX40 ligand, and receptor-interacting serine/threonine-protein kinase 4 (RIPK4), were downregulated after a 4-month sublingual AIT course concomitantly with an upregulation of DCreg cell-associated markers, including complement C1q subcomponent subunit A (C1QA), FcgammaRIIIA, ferritin light chain (FTL), and solute carrier organic anion transporter family member 2B1 (SLCO2B1), in the blood of clinical responders as opposed to nonresponders. Changes in such markers were better correlated with clinical benefit than alterations of allergen specific CD4(+) T-cell or IgG responses. CONCLUSIONS: A combination of 5 markers predominantly expressed by blood DCs (ie, C1Q and CD141) or shared with lymphoid cells (ie, FcgammaRIIIA, GATA3, and RIPK4) reflecting changes in the balance of regulatory/proallergic responses in peripheral blood can be used as early as after 2 months to monitor the early onset of AIT efficacy. PMID- 26522404 TI - Crystallography in the 21st century. PMID- 26522403 TI - Anti-IFN-gamma autoantibodies are strongly associated with HLA-DR*15:02/16:02 and HLA-DQ*05:01/05:02 across Southeast Asia. PMID- 26522405 TI - Complex modeling: a strategy and software program for combining multiple information sources to solve ill posed structure and nanostructure inverse problems. AB - A strategy is described for regularizing ill posed structure and nanostructure scattering inverse problems (i.e. structure solution) from complex material structures. This paper describes both the philosophy and strategy of the approach, and a software implementation, DiffPy Complex Modeling Infrastructure (DiffPy-CMI). PMID- 26522406 TI - Orbits of crystallographic embedding of non-crystallographic groups and applications to virology. AB - The architecture of infinite structures with non-crystallographic symmetries can be modelled via aperiodic tilings, but a systematic construction method for finite structures with non-crystallographic symmetry at different radial levels is still lacking. This paper presents a group theoretical method for the construction of finite nested point sets with non-crystallographic symmetry. Akin to the construction of quasicrystals, a non-crystallographic group G is embedded into the point group P of a higher-dimensional lattice and the chains of all G containing subgroups are constructed. The orbits of lattice points under such subgroups are determined, and it is shown that their projection into a lower dimensional G-invariant subspace consists of nested point sets with G-symmetry at each radial level. The number of different radial levels is bounded by the index of G in the subgroup of P. In the case of icosahedral symmetry, all subgroup chains are determined explicitly and it is illustrated that these point sets in projection provide blueprints that approximate the organization of simple viral capsids, encoding information on the structural organization of capsid proteins and the genomic material collectively, based on two case studies. Contrary to the affine extensions previously introduced, these orbits endow virus architecture with an underlying finite group structure, which lends itself better to the modelling of dynamic properties than its infinite-dimensional counterpart. PMID- 26522407 TI - Symmetries and color symmetries of a family of tilings with a singular point. AB - Tilings with a singular point are obtained by applying conformal maps on regular tilings of the Euclidean plane and their symmetries are determined. The resulting tilings are then symmetrically colored by applying the same conformal maps on colorings of regular tilings arising from sublattice colorings of the centers of the tiles. In addition, conditions are determined in order that the coloring of a tiling with singularity that is obtained in this manner is perfect. PMID- 26522408 TI - Uniqueness of the macromolecular crystallographic phase problem. AB - Uniqueness of the phase problem in macromolecular crystallography, and its relationship to the case of single particle imaging, is considered. The crystallographic problem is characterized by a constraint ratio that depends only on the size and symmetry of the molecule and the unit cell. The results are used to evaluate the effect of various real-space constraints. The case of an unknown molecular envelope is considered in detail. The results indicate the quite wide circumstances under which ab initio phasing should be possible. PMID- 26522409 TI - Periodic entanglement III: tangled degree-3 finite and layer net intergrowths from rare forests. AB - Entanglements of two-dimensional honeycomb nets are constructed from free tilings of the hyperbolic plane (H2) on triply periodic minimal surfaces. The 2-periodic nets that comprise the structures are guaranteed by considering regular, rare free tilings in H2. This paper catalogues an array of entanglements that are both beautiful and challenging for current classification techniques, including examples that are realized in metal-organic materials. The compactification of these structures to the genus-3 torus is considered as a preliminary method for generating entanglements of finite theta-graphs, potentially useful for gaining insight into the entanglement of the periodic structure. This work builds on previous structural enumerations given in Periodic entanglement Parts I and II [Evans et al. (2013). Acta Cryst. A69, 241-261; Evans et al. (2013). Acta Cryst. A69, 262-275]. PMID- 26522410 TI - Grazing-incidence small-angle X-ray scattering in a twofold rough-interface medium: a new theoretical approach using the q-eigenwave formalism. AB - Based on the rigorous Green function formalism to describe the grazing-incidence small-angle X-ray scattering (GISAXS) problem, a system of two linked integral equations is derived with respect to amplitudes of the reflected and transmitted plane q-eigenwaves (eigenstate functions) propagating through two homogeneous media separated from each other by a rough surface interface. To build up the coupled solutions of these basic equations beyond the perturbation theory constraint 2ksigmatheta0 < 1, a simple iteration procedure is proposed as opposed to the self-consistent wave approach [Chukhovskii (2011). Acta Cryst. A67, 200 209; Chukhovski (2012). Acta Cryst. A68, 505-512]. Using the first-order iteration, analytical expressions for the averaged specular and non-specular scattering intensity distributions have been obtained. These expressions are further analysed in terms of the GISAXS parameters {k, theta, theta0} and surface finish ones {sigma, l, h}, where theta and theta0 are the scattering and incidence angles of the X-rays, respectively, sigma is the root-mean-square roughness, l is the correlation length, h is the fractal surface model index, k = 2pi/lambda, and lambda is the X-ray wavelength. A direct way to determine the surface finish parameters from the experimental specular and diffuse scattering indicatrix scan data is discussed for an example of GISAXS measurements from rough surfaces of alpha-quartz and CdTe samples. PMID- 26522412 TI - [THE ELDERLY ASTHMA]. PMID- 26522413 TI - [BRONCHIAL ASTHMA AND LIFE ENVIRONMENT]. PMID- 26522414 TI - [SMOKING AND ADULT ASTHMA, COPD]. PMID- 26522415 TI - [SUBLINGUAL IMMUNOTHERAPY]. PMID- 26522416 TI - [A MULTICENTER STUDY ON CHILDHOOD ALLERGIC RHINITIS TREATMENT IN THE TOHOKU REGION]. AB - BACKGROUND: We performed a multicenter study in order to clarify the present conditions of the childhood allergic rhinitis treatment in many departments of otorhinolaryngology and pediatrics/internal medicine in the Tohoku region, northern Japan. METHODS: We performed a questionnaire survey about patient backgrounds, nasal symptoms, QOL disturbance, and treatment agents, for childhood allergic rhinitis patients under age 12. RESULTS: The total number of cases was 814, the mean age of the patients seen in pediatrics/internal medicine departments was significantly lower than that in otorhinolaryngology. The merger rate of bronchial asthma of the patients seen in pediatrics/internal medicine was significantly higher, and nasal symptoms and QOL disturbance of the patients seen in otorhinolaryngology were significantly more severe. For therapeutic agents, antihistamines were most prescribed, and the combination of LT receptor antagonist and intranasal steroids was used for the cases in which nasal symptoms were severe. The nasal symptoms in the combination group were significantly improved compared with the antihistamine monotherapy group. CONCLUSION: It was indicated that the combination therapy was useful in the severe cases of childhood allergic rhinitis. PMID- 26522417 TI - [OCULAR SYMPTOMS OF CEDAR POLLINOSIS IN OTOLARYNGOLOGY]. AB - BACKGROUND: Cedar pollinosis is a disease with various symptoms. Ocular symptoms as well as nasal symptoms appear frequently. However, there are only a few studies examined the incidence rate of ocular symptoms caused by cedar pollinosis. METHODS: Subjects consisted of 545 patients who have consulted our hospital and the affiliated hospitals without any previous treatment during the peak season for cedar pollen dispersal from 2009 to 2013. The patients were asked about their symptoms and quality of life (QOL) using the Japanese Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ). RESULTS: Of all the patients, 86% had ocular symptoms. Moreover, itchy eyes had the higher symptom prevalence than watery eyes. The nasal and ocular symptoms were correlated with each other; those patients with ocular symptoms had more severe nasal symptoms. CONCLUSIONS: This study showed that nasal symptoms in pollinosis patients with ocular symptoms were more likely to be severe than those in patients without ocular symptoms. PMID- 26522418 TI - [SAFETY AND EFFICACY OF ONE-YEAR RUSH SUBCUTANEOUS IMMUNOTHERAPY IN JAPANESE CHILDREN, USING HOUSE DUST EXTRACT]. AB - BACKGROUND: In recent years there have been few reports on the effects of immunotherapy on bronchial asthma (BA) and allergic rhinitis (AR) in Japanese children. OBJECTIVE: To investigate the safety and efficacy of house dust extract immunotherapy for one year. METHODS: Thirty-five children with AR and BA were subjected to rush immunotherapy with house dust extract. Systemic reactions were counted to evaluate safety. BA medication score and AR symptom-medication score were recorded. RESULTS: Three patients (8.3% of all patients) experienced 6 systemic reactions (0.15% of doses). BA medication score decreased from 567 to 325 (a reduction rate of 43%). AR symptom-medication score improved from 5.1 to 2.9 (a reduction rate of 43%). CONCLUSIONS: Rush immunotherapy with house dust extract is safe and effective for Japanese children. PMID- 26522419 TI - [SIX CASES OF WHEAT-DEPENDENT EXERCISE-INDUCED ANAPHYLAXIS IN CHILDREN]. AB - Wheat-dependent exercise-induced anaphylaxis (WDEIA) is often reported in adults for whom the specific IgE to omega-5 gliadin can be a useful diagnostic test. However, few cases of WDEIA in children have been reported. We herein report six cases (aged 7-16 years) of children with WDEIA, who had no clinical history of immediate-type wheat allergy but who were diagnosed by a wheat ingestion + exercise provocation test. The specific IgE to wheat ranged <0.35-3.49 (median 1.64) UA/ml. Skin prick tests using wheat extract were performed on 3 patients who showed either a negative or low specific IgE titer to wheat, and all of them resulted in negative findings. The specific IgE to omega-5 gliadin was below the detection limit in all cases. Aspirin-supplemented provocation tests were performed to 4 cases who had negative results in the wheat + exercise test. All of these resulted in a positive reaction, and two of them provoked the occurrence of anaphylactic shock, which was relieved by the intramuscular injection of adrenaline. WDEIA in children cannot be ruled out by serological tests alone. On the other hand, severe symptoms might be provoked by the provocation test. Therefore, a safe procedure is warranted for the diagnosis of WDEIA in children. PMID- 26522420 TI - [Lipoxin A4]. PMID- 26522421 TI - [alarmin]. PMID- 26522422 TI - [Chemokine receptors]. PMID- 26522423 TI - Functional cerebral blood volume mapping with simultaneous multi-slice acquisition. AB - The aim of this study is to overcome the current limits of brain coverage available with multi-slice echo planar imaging (EPI) for vascular space occupancy (VASO) mapping. By incorporating simultaneous multi-slice (SMS) EPI image acquisition into slice-saturation slab-inversion VASO (SS-SI VASO), many more slices can be acquired for non-invasive functional measurements of blood volume responses. Blood-volume-weighted VASO and gradient echo blood oxygenation level dependent (GE-BOLD) data were acquired in humans at 7T with a 32-channel head coil. SMS-VASO was applied in three scenarios: A) high-resolution acquisition of spatially distant brain areas in the visuo-motor network (V1/V5/M1/S1); B) high resolution acquisition of an imaging slab covering the entire M1/S1 hand regions; and C) low-resolution acquisition with near whole-brain coverage. The results show that the SMS-VASO sequence provided images enabling robust detection of blood volume changes in up to 20 slices with signal readout durations shorter than 150ms. High-resolution application of SMS-VASO revealed improved specificity of VASO to GM tissue without contamination from large draining veins compared to GE-BOLD in the visual cortex and in the sensory-motor cortex. It is concluded that VASO fMRI with SMS-EPI allows obtaining a reasonable three-dimensional coverage not achievable with standard VASO during the short time period when blood magnetization is approximately nulled. Due to the increased brain coverage and better spatial specificity to GM tissue of VASO compared to GE-BOLD signal, the proposed method may play an important role in high-resolution human fMRI at 7T. PMID- 26522424 TI - The Reference Ability Neural Network Study: Life-time stability of reference ability neural networks derived from task maps of young adults. AB - Analyses of large test batteries administered to individuals ranging from young to old have consistently yielded a set of latent variables representing reference abilities (RAs) that capture the majority of the variance in age-related cognitive change: Episodic Memory, Fluid Reasoning, Perceptual Processing Speed, and Vocabulary. In a previous paper (Stern et al., 2014), we introduced the Reference Ability Neural Network Study, which administers 12 cognitive neuroimaging tasks (3 for each RA) to healthy adults age 20-80 in order to derive unique neural networks underlying these 4 RAs and investigate how these networks may be affected by aging. We used a multivariate approach, linear indicator regression, to derive a unique covariance pattern or Reference Ability Neural Network (RANN) for each of the 4 RAs. The RANNs were derived from the neural task data of 64 younger adults of age 30 and below. We then prospectively applied the RANNs to fMRI data from the remaining sample of 227 adults of age 31 and above in order to classify each subject-task map into one of the 4 possible reference domains. Overall classification accuracy across subjects in the sample age 31 and above was 0.80+/-0.18. Classification accuracy by RA domain was also good, but variable; memory: 0.72+/-0.32; reasoning: 0.75+/-0.35; speed: 0.79+/-0.31; vocabulary: 0.94+/-0.16. Classification accuracy was not associated with cross sectional age, suggesting that these networks, and their specificity to the respective reference domain, might remain intact throughout the age range. Higher mean brain volume was correlated with increased overall classification accuracy; better overall performance on the tasks in the scanner was also associated with classification accuracy. For the RANN network scores, we observed for each RANN that a higher score was associated with a higher corresponding classification accuracy for that reference ability. Despite the absence of behavioral performance information in the derivation of these networks, we also observed some brain-behavioral correlations, notably for the fluid-reasoning network whose network score correlated with performance on the memory and fluid-reasoning tasks. While age did not influence the expression of this RANN, the slope of the association between network score and fluid-reasoning performance was negatively associated with higher ages. These results provide support for the hypothesis that a set of specific, age-invariant neural networks underlies these four RAs, and that these networks maintain their cognitive specificity and level of intensity across age. Activation common to all 12 tasks was identified as another activation pattern resulting from a mean-contrast Partial-Least-Squares technique. This common pattern did show associations with age and some subject demographics for some of the reference domains, lending support to the overall conclusion that aspects of neural processing that are specific to any cognitive reference ability stay constant across age, while aspects that are common to all reference abilities differ across age. PMID- 26522425 TI - fMRI study of olfaction in the olfactory bulb and high olfactory structures of rats: Insight into their roles in habituation. AB - Cerebral blood volume (CBV) fMRI with ultrasmall superparamagnetic iron oxide particles (USPIO) as a contrast agent was used to investigate olfactory processing in rats. fMRI data were acquired in sixteen 0.75-mm coronal slices covering the olfactory bulb (OB) and higher olfactory regions (HOR), including the anterior olfactory nucleus and piriform cortex. For each animal, multiple consecutive fMRI measurements were made during a 3-h experiment session, with each measurement consisting of a baseline period, an odorant stimulation period, and a recovery period. Two different stimulation paradigms with a stimulation period of 40s or 80s, respectively, were used to study olfactory processing. Odorant-induced CBV increases were robustly observed in the OB and HOR of each individual animal. Olfactory adaptation, which is characterized by an attenuation of responses to continuous exposure or repeated stimulations, has different characteristics in the OB and HOR. For adaptation to repeated stimuli, while it was observed in both the OB and HOR, CBV responses in the HOR were attenuated more significantly than responses in the OB. In contrast, within each continuous 40-s or 80-s odor exposure, CBV responses in the OB were stable and did not show adaptation, but the CBV responses in the HOR were state dependent, with no adaptation during initial exposures, but significant adaptation during following exposures. These results support previous reports that HOR plays a more significant role than OB in olfactory habituation. The technical approach presented in this study should enable more extensive fMRI studies of olfactory processing in rats. PMID- 26522427 TI - Design and conduct of a large obstetric or neonatal randomized controlled trial. AB - As event rates fall, if mortality and disability are to improve further there is increasing need for large, well-designed trials. These should enroll more patients, more rapidly and at lower cost, with better representation of infants at highest risk and greater integration with routine care. This may require simpler datasets, linkage with routinely collected data, and international collaboration. It may be helpful to draw attention to recent evidence that participation in Phase III randomized controlled trials (RCTs) is at least as safe as receiving established care. Nationally coordinated clinical research networks employing local research staff may be the single most effective strategy to integrate clinical trials into routine practice. Other goals are: international standardization of outcomes; consensus on composite endpoints, biomarkers, surrogates and measures of disability; greater efficiency through randomized factorial designs and cluster or cross-over cluster RCTs; and equipping parents as partners in all aspects of the conduct of RCTs and in implementing their results. PMID- 26522426 TI - Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism. AB - The tricarboxylic acid (TCA) cycle is a central metabolic pathway responsible for supplying reducing potential for oxidative phosphorylation and anabolic substrates for cell growth, repair and proliferation. As such it thought to be essential for cell proliferation and tissue homeostasis. However, since the initial report of an inactivating mutation in the TCA cycle enzyme complex, succinate dehydrogenase (SDH) in paraganglioma (PGL), it has become clear that some cells and tissues are not only able to survive with a truncated TCA cycle, but that they are also able of supporting proliferative phenotype observed in tumours. Here, we show that loss of SDH activity leads to changes in the metabolism of non-essential amino acids. In particular, we demonstrate that pyruvate carboxylase is essential to re-supply the depleted pool of aspartate in SDH-deficient cells. Our results demonstrate that the loss of SDH reduces the metabolic plasticity of cells, suggesting vulnerabilities that can be targeted therapeutically. PMID- 26522428 TI - Visualizing global properties of a molecular dynamics trajectory. AB - Molecular dynamics (MD) trajectories are very large data sets that contain substantial information about the dynamic behavior of a protein. Condensing these data into a form that can provide intuitively useful understanding of the molecular behavior during the trajectory is a substantial challenge that has received relatively little attention. Here, we introduce the sigma-r plot, a plot of the standard deviation of intermolecular distances as a function of that distance. This representation of global dynamics contains within a single, one dimensional plot, the average range of motion between pairs of atoms within a macromolecule. Comparison of sigma-r plots calculated from 10 ns trajectories of proteins representing the four major SCOP fold classes indicates diversity of dynamic behaviors which are recognizably different among the four classes. Differences in domain structure and molecular weight also produce recognizable features in sigma-r plots, reflective of differences in global dynamics. Plots generated from trajectories with progressively increasing simulation time reflect the increased sampling of the structural ensemble as a function of time. Single amino acid replacements can give rise to changes in global dynamics detectable through comparison of sigma-r plots. Dynamic behavior of substructures can be monitored by careful choice of interatomic vectors included in the calculation. These examples provide demonstrations of the utility of the sigma-r plot to provide a simple measure of the global dynamics of a macromolecule. PMID- 26522429 TI - Two-dimensional single-cell patterning with one cell per well driven by surface acoustic waves. AB - In single-cell analysis, cellular activity and parameters are assayed on an individual, rather than population-average basis. Essential to observing the activity of these cells over time is the ability to trap, pattern and retain them, for which previous single-cell-patterning work has principally made use of mechanical methods. While successful as a long-term cell-patterning strategy, these devices remain essentially single use. Here we introduce a new method for the patterning of multiple spatially separated single particles and cells using high-frequency acoustic fields with one cell per acoustic well. We characterize and demonstrate patterning for both a range of particle sizes and the capture and patterning of cells, including human lymphocytes and red blood cells infected by the malarial parasite Plasmodium falciparum. This ability is made possible by a hitherto unexplored regime where the acoustic wavelength is on the same order as the cell dimensions. PMID- 26522430 TI - Roles of the Androgen--Androgen Receptor System in Vascular Angiogenesis. AB - Although many clinical studies have shown that a low testosterone level is associated with cardiovascular diseases, the role of androgens in cardiovascular physiology and pathophysiology remains controversial. Androgens exert various actions in their target organs, and the androgen receptor (AR) is widely distributed in several tissues, including endothelial cells, smooth muscle cells, and fibroblasts, in the vascular system. Biological activities of androgens are predominantly mediated through the AR by the transcriptional control of target genes and interaction with multiple signaling pathways. To clarify the molecular mechanisms of androgens in cardiovascular disease, we examined a pathological model using AR knockout mice and showed that the androgen-AR system has protective effects on cardiovascular remodeling against cardiovascular stress. In this review, we focus on the role of the androgen-AR system in angiogenesis after ischemic stress. PMID- 26522431 TI - Effect of movement rate on corticokinematic coherence. AB - AIMS OF THE STUDY: This study investigates the effect of movement rate on the coupling between cortical magnetoencephalographic (MEG) signals and the kinematics of repetitive active finger movements, i.e., the corticokinematic coherence (CKC). MATERIAL AND METHODS: CKC was evaluated in ten right-handed healthy adults performing repetitive flexion-extension of the right-hand fingers in three different movement rate conditions: slow (~1 Hz, duration: 11 min), medium (~2 Hz, duration: 5 min) and fast (~3 Hz, duration: 3 min). Neuromagnetic signals were recorded with a whole-scalp-covering MEG (Elekta Oy) and index acceleration was monitored with a 3-axis accelerometer. Coherent sources were estimated on the time-course of the cross-correlogram using equivalent current dipole (ECD) modeling. RESULTS: Significant coherence was found at movement frequency or its first harmonics in all subjects and movement conditions. ECDs clustered at the primary sensorimotor cortex contralateral to hand movements. Movement rate had no effect on the coherence levels and the location of coherent sources. CONCLUSIONS: This study demonstrates that the movement rate does not affect coherence levels and CKC source location during active finger movements. This finding has direct implications for CKC functional mapping applications and studies investigating the pathophysiology of central nervous disorders affecting proprioceptive pathways. PMID- 26522432 TI - Reading simple and complex facial expressions in patients with major depressive disorder and anxiety disorders. AB - AIM: Decoding facial expression is important for psychological well-being. This study examined facial emotion recognition of simple/complex and pleasant/unpleasant emotions in patients with major depressive disorder (MDD) and anxiety disorders (AnD). METHODS: Patients with MDD (n = 37), AnD (n = 36) and healthy controls (HC) (n = 40) participated in this study. The recognition accuracy of emotional faces was calculated. RESULTS: Patients with MDD had significantly lower recognition accuracy compared to HC. Patients with MDD exhibited lower recognition accuracy for simple emotions compared to patients with AnD and HC, and lower accuracy for complex emotions compared only to HC. Patients with AnD and HC showed comparable recognition accuracy for simple emotions, which were lower than that of patients with MDD. However, in recognition accuracy of complex emotions, AnD was not significantly different from either MDD or HC. CONCLUSIONS: Patients with MDD and AnD have a distinctive difficulty with the recognition of facial expressions. The recognition of complex emotions in patients with MDD and AnD should be studied further. PMID- 26522433 TI - Biochemical and behavioral effects of PDE10A inhibitors: Relationship to target site occupancy. AB - Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [(3)H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [(3)H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (KD) of 0.15 nM and a functional selectivity of >100-fold over other PDE subtypes tested. Specific [(3)H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ~40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident. PMID- 26522434 TI - Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1 dependent, immunoregulatory signaling in dendritic cells. AB - Metabotropic glutamate receptor 4 (mGluR4) possesses immune modulatory properties in vivo, such that a positive allosteric modulator (PAM) of the receptor confers protection on mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE). ADX88178 is a newly-developed, one such mGluR4 modulator with high selectivity, potency, and optimized pharmacokinetics. Here we found that application of ADX88178 in the RR-EAE model system converted disease into a form of mild-yet chronic-neuroinflammation that remained stable for over two months after discontinuing drug treatment. In vitro, ADX88178 modulated the cytokine secretion profile of dendritic cells (DCs), increasing production of tolerogenic IL-10 and TGF-beta. The in vitro effects required activation of a Gi independent, alternative signaling pathway that involved phosphatidylinositol-3 kinase (PI3K), Src kinase, and the signaling activity of indoleamine 2,3 dioxygenase 1 (IDO1). A PI3K inhibitor as well as small interfering RNA targeting Ido1-but not pertussis toxin, which affects Gi protein-dependent responses abrogated the tolerogenic effects of ADX88178-conditioned DCs in vivo. Thus our data indicate that, in DCs, highly selective and potent mGluR4 PAMs such as ADX88178 may activate a Gi-independent, long-lived regulatory pathway that could be therapeutically exploited in chronic autoimmune diseases such as multiple sclerosis. PMID- 26522435 TI - 2-Cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride alters lipopolysaccharide-induced proinflammatory cytokines and neuronal morphology in mouse fetal brain. AB - It is well documented that a maternal immune response to infection during pregnancy can cause neurodevelopmental damage. We demonstrate in our current study that maternally administered 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride (KHG26377), a novel thiazole derivative, prevents fetal malformations and neurodevelopmental deficits in offspring by blocking lipopolysaccharide (LPS)-induced inflammation. Administration of KHG26377 effectively regulated LPS-induced inflammatory markers and mediators such as soluble intercellular adhesion molecule-1, se-Selectin, macrophage chemoattractant protein-1, and cytokine-induced neutrophil chemoattractant-1 in the maternal serum. Furthermore, maternally administered KHG26377 showed an inhibitory effect on the LPS-induced developmental toxicity by selectively suppressing the TNF-alpha level in maternal serum, amniotic fluid, placenta, fetal liver, and fetal brain as well as by suppression of LPS-induced nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and myelin basic protein (MBP) levels in the fetal brain. In addition, pretreatment of neuronal cells with KHG26377 effectively reestablished the cell body morphology and microtubule associated protein 2 (MAP2) staining compared to the LPS-treated group in cortex primary neuronal cultures. Although the clinical relevance of our findings remains to be determined, our results provide novel insights into KHG26377 as a possible therapeutic agent to protect fetuses against various inflammatory responses. PMID- 26522437 TI - Reflections on a pioneer in the field of diet, lipids and vascular disease. PMID- 26522436 TI - Incubation of cocaine-craving relates to glutamate over-flow within ventromedial prefrontal cortex. AB - Craving elicited by drug-associated cues intensifies across protracted drug abstinence - a phenomenon termed "incubation of craving" - and drug-craving in human addicts correlates with frontal cortical hyperactivity. Herein, we employed a rat model of cue-elicited cocaine-craving to test the hypothesis that the time dependent incubation of cue-elicited cocaine-craving is associated with adaptations in dopamine and glutamate neurotransmission within the ventromedial prefrontal cortex (vmPFC). Rats were trained to self-administer intravenous cocaine (6 h/day * 10 days) and underwent in vivo microdialysis procedures during 2 h-tests for cue-elicited cocaine-craving at either 3 or 30 days withdrawal. Controls rats were trained to either self-administer sucrose pellets or received no primary reinforcer. Cocaine-seeking rats exhibited a withdrawal-dependent increase and decrease, respectively, in cue-elicited glutamate and dopamine release. These patterns of neurochemical change were not observed in either control condition. Thus, cue-hypersensitivity of vmPFC glutamate terminals is a biochemical correlate of incubated cocaine-craving that may stem from dopamine dysregulation in this region. PMID- 26522438 TI - The impact of gestational hypercholesterolaemia on origins of disease. PMID- 26522439 TI - Speed kills in more ways than one: Methamphetamine and atherosclerosis. PMID- 26522440 TI - Flavanones and Chromones from Salicornia herbacea Mitigate Septic Lethality via Restoration of Vascular Barrier Integrity. AB - Salicornia herbacea is an annual halophytic glasswort that has been employed as a culinary vegetable, salad, and traditional medicinal resource. Chemical investigation of the aerial parts of S. herbacea led to the isolation of two new (1, 2) and known (3) flavanones as well as a new nature-derived (4) and two known chromone derivatives (5, 6). These purified compounds were evaluated for their suppressive potentials against the release of high-mobility group box 1 protein (HMGB1), which has captured attention as a viable target for alleviating serious septic manifestations or septicemia. The phenolic compounds improved the survival rates of cecal ligation and puncture operation (CLP) in murine models, simulating severe septic shock and its related complications, to 40-60%. These results collectively validate that flavanone- and chromone-based secondary metabolites may serve as prospective prodrugs or food additives that may be commercialized for the control of septic complications and lethality. PMID- 26522441 TI - A Novel 13-Segment Standardized Model for Assessment of Right Ventricular Function Using Two-Dimensional iRotate Echocardiography. AB - AIMS: The aim of this study was to evaluate the feasibility of transthoracic two dimensional (2D) iRotate, a new echo modality, to assess the whole right ventricle (RV) from a single transducer position based on anatomic landmarks. METHODS AND RESULTS: The anatomic landmarks were first defined based on three dimensional echocardiographic datasets using multiplane reconstruction analyses. Thereafter, we included 120 healthy subjects (51% male, age range 21-67 years). Using 2D iRotate, four views of the RV could be acquired based on these landmarks. The anterior, lateral, inferior wall (divided into three segments: basal-mid-apical), and right ventricular outflow tract (RVOT) anterior wall of the RV were determined. The feasibility of visualization of RV segments and tricuspid annular plane systolic excursion (TAPSE) and tissue Doppler imaging (TDI) measurements were assessed. To evaluate this model for diseased RVs, a small pilot study of 20 patients was performed. In 98% of healthy subjects and 100% of patients, iRotate mode was feasible to assess the RV from one single transducer position. In total, 86% and 95%, respectively, of the RV segments could be visualized. The visualization of the RVOT anterior wall was worse 23% and 75%, respectively. TAPSE and TDI measurements on all four views were feasible 93% and 92%, respectively, of the healthy subjects and in 100% of the patients. CONCLUSION: With 2D iRotate, a comprehensive evaluation of the entire normal and diseased RV is feasible from a fixed transducer position based on anatomic landmarks. This is less time-consuming than the multiview approach and enhances accuracy of RV evaluation. Imaging of the RVOT segment remains challenging. PMID- 26522442 TI - Cytochrome P450 125A4, the Third Cholesterol C-26 Hydroxylase from Mycobacterium smegmatis. AB - Mycobacterium tuberculosis (Mtb) and Mycobacterium smegmatis (Msmeg) can grow on cholesterol as the sole carbon source. In Mtb the utilization of cholesterol can be initiated by CYP125A1 or CYP142A1 and in Msmeg by the orthologous CYP125A3 and CYP142A2. Double knockout of the two enzymes in Mtb prevents its growth on cholesterol, but the double knockout of Msmeg is still able to grow, albeit at a slower rate. We report here that Msmeg has a third enzyme, CYP125A4, that also oxidizes cholesterol, although it has a much higher activity for the oxidation of 7alpha-hydroxycholesterol. The ability of Msmeg CYP125A4 (and Mtb CYP125A1) to oxidize 7alpha-hydroxycholesterol is due, at least in part, to the presence of a smaller amino acid side chain facing C-7 of the sterol substrate than in CYP125A3. The ability to oxidize 7-substituted steroids broadens the range of sterol carbon sources for growth, but even more importantly in Mtb, additional biological effects are possible due to the potent immunomodulatory activity of 7alpha,26-dihydroxycholesterol. PMID- 26522443 TI - Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases. AB - Nitric oxide (NO) is generated endogenously by NO synthases to regulate a number of physiological processes including cardiovascular and metabolic functions. A decrease in the production and bioavailability of NO is a hallmark of many major chronic diseases including hypertension, ischaemia-reperfusion injury, atherosclerosis and diabetes. This NO deficiency is mainly caused by dysfunctional NO synthases and increased scavenging of NO by the formation of reactive oxygen species. Inorganic nitrate and nitrite are emerging as substrates for in vivo NO synthase-independent formation of NO bioactivity. These anions are oxidation products of endogenous NO generation and are also present in the diet, with green leafy vegetables having a high nitrate content. The effects of nitrate and nitrite are diverse and include vasodilatation, improved endothelial function, enhanced mitochondrial efficiency and reduced generation of reactive oxygen species. Administration of nitrate or nitrite in animal models of cardiovascular disease shows promising results, and clinical trials are currently ongoing to investigate the therapeutic potential of nitrate and nitrite in hypertension, pulmonary hypertension, peripheral artery disease and myocardial infarction. In addition, the nutritional aspects of the nitrate-nitrite-NO pathway are interesting as diets suggested to protect against cardiovascular disease, such as the Mediterranean diet, are especially high in nitrate. Here, we discuss the potential therapeutic opportunities for nitrate and nitrite in prevention and treatment of cardiovascular and metabolic diseases. PMID- 26522445 TI - Structural Modifications of cis-Glycofused Benzopyran Compounds and Their Influence on the Binding to Amyloid-beta Peptide. AB - A small library of glycofused tricyclic compounds with a central pyran ring chemically modified in the position para to the ring oxygen has been synthesised. The influence of the chemical modification on the structural conformation of the compounds and on their ability to bind Abeta peptide has been evaluated respectively using molecular mechanics (MM) and molecular dynamics (MD) simulations, and STD NMR spectroscopy. The introduction of particularly polar/charged groups leads to the loss of binding ability, without a significant change in the conformation, whilst other substitutions does not significantly affect either the structural conformation or the binding. PMID- 26522444 TI - Long Non Coding RNA MALAT1 Promotes Tumor Growth and Metastasis by inducing Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma. AB - The prognosis of advanced oral squamous cell carcinoma (OSCC) patients remains dismal, and a better understanding of the underlying mechanisms is critical for identifying effective targets with therapeutic potential to improve the survival of patients with OSCC. This study aims to clarify the clinical and biological significance of metastasis-associated long non-coding RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in OSCC. We found that MALAT1 is overexpressed in OSCC tissues compared to normal oral mucosa by real-time PCR. MALAT1 served as a new prognostic factor in OSCC patients. When knockdown by small interfering RNA (siRNA) in OSCC cell lines TSCCA and Tca8113, MALAT1 was shown to be required for maintaining epithelial-mesenchymal transition (EMT) mediated cell migration and invasion. Western blot and immunofluorescence staining showed that MALAT1 knockdown significantly suppressed N-cadherin and Vimentin expression but induced E-cadherin expression in vitro. Meanwhile, both nucleus and cytoplasm levels of beta-catenin and NF-kappaB were attenuated, while elevated MALAT1 level triggered the expression of beta-catenin and NF-kappaB. More importantly, targeting MALAT1 inhibited TSCCA cell-induced xenograft tumor growth in vivo. Therefore, these findings provide mechanistic insight into the role of MALAT1 in regulating OSCC metastasis, suggesting that MALAT1 is an important prognostic factor and therapeutic target for OSCC. PMID- 26522446 TI - Sensitive electrochemical nonenzymatic glucose sensing based on anodized CuO nanowires on three-dimensional porous copper foam. AB - In this work, we proposed to utilize three-dimensional porous copper foam (CF) as conductive substrate and precursor of in-situ growth CuO nanowires (NWs) for fabricating electrochemical nonenzymatic glucose sensors. The CF supplied high surface area due to its unique three-dimensional porous foam structure, and thus resulted in high sensitivity for glucose detection. The CuO NWs/CF based nonenzymatic sensors presented reliable selectivity, good repeatability, reproducibility, and stability. In addition, the CuO NWs/CF based nonenzymatic sensors have been employed for practical applications, and the glucose concentration in human serum was measured to be 4.96 +/- 0.06 mM, agreed well with the value measured from the commercial available glucose sensor in hospital, and the glucose concentration in saliva was also estimated to be 0.91 +/- 0.04 mM, which indicated that the CuO NWs/CF owned the possibility for noninvasive glucose detection. The rational design of CuO NWs/CF provided an efficient strategy for fabricating of electrochemical nonenzymatic biosensors. PMID- 26522447 TI - CaseWorldTM: Interactive, media rich, multidisciplinary case based learning. AB - Nurse educators are challenged to keep up with highly specialised clinical practice, emerging research evidence, regulation requirements and rapidly changing information technology while teaching very large numbers of diverse students in a resource constrained environment. This complex setting provides the context for the CaseWorld project, which aims to simulate those aspects of clinical practice that can be represented by e-learning. This paper describes the development, implementation and evaluation of CaseWorld, a simulated learning environment that supports case based learning. CaseWorld provides nursing students with the opportunity to view unfolding authentic cases presented in a rich multimedia context. The first round of comprehensive summative evaluation of CaseWorld is discussed in the context of earlier formative evaluation, reference group input and strategies for integration of CaseWorld with subject content. This discussion highlights the unique approach taken in this project that involved simultaneous prototype development and large scale implementation, thereby necessitating strong emphasis on staff development, uptake and engagement. The lessons learned provide an interesting basis for further discussion of broad content sharing across disciplines and universities, and the contribution that local innovations can make to global education advancement. PMID- 26522448 TI - Ultrastructure of Sarcocystis bertrami sarcocysts from a naturally infected donkey (Equus asinus) from Egypt. AB - There is considerable confusion concerning Sarcocystis species in equids. Little is known of Sarcocystis infections in donkeys (Equus asinus). Here we describe the structure of Sarcocystis bertrami-like from the donkey by light microscopy (LM) and transmission electron microscopy (TEM). Nineteen sarcocysts from the tongue of a donkey from Egypt were studied both by LM and TEM. By LM, all sarcocysts had variably shaped and sized projections on the sarcocyst walls, giving it a thin-walled to thick-walled appearance, depending on individual sarcocyst and plane of section. By TEM, sarcocysts walls had villar protrusions (vp) of type 11. The sarcocyst wall had conical to slender vp, up to 6 um long and 1 um wide; the vp were folded over the sarcocyst wall. The total thickness of the sarcocyst wall with ground substance layer (gs) was 1-3 um. The vp had microtubules (mt) that originated deeper in the gs and continued up to the tip. The apical part of the vp had electron dense granules. The mt were configured into 3 types: a tuft of electron dense mt1 extending the entire length of the vp with a tuft of medium electron dense mt2 appearing in parallel, and fine mt3 present only in the villar tips. The gs was mainly smooth with few indistinct granules. All sarcocysts were mature and contained metrocytes and bradyzoites. Bradyzoites were approximately 11-15 * 2-3 um in size with typical organelles. PMID- 26522449 TI - The azetidine derivative, KHG26792 protects against ATP-induced activation of NFAT and MAPK pathways through P2X7 receptor in microglia. AB - Azetidine derivatives are of interest for drug development because they may be useful therapeutic agents. However, their mechanisms of action remain to be completely elucidated. Here, we have investigated the effects of 3-(naphthalen-2 yl(propoxy)methyl)azetidine hydrochloride (KHG26792) on ATP-induced activation of NFAT and MAPK through P2X7 receptor in the BV-2 mouse microglial cell line. KHG26792 decreased ATP-induced TNF-alpha release from BV-2 microglia by suppressing, at least partly, P2X7 receptor stimulation. KHG26792 also inhibited the ATP-induced increase in IL-6, PGE2, NO, ROS, CXCL2, and CCL3. ATP induced NFAT activation through P2X7 receptor, with KHG26792 reducing the ATP-induced NFAT activation. KHG26792 inhibited an ATP-induced increase in iNOS protein and ERK phosphorylation. KHG26792 prevented an ATP-induced increase in MMP-9 activity through the P2X7 receptor as a result of degradation of TIMP-1 by cathepsin B. Our data provide mechanistic insights into the role of KHG26792 in the inhibition of TNF-alpha produced via P2X7 receptor-mediated activation of NFAT and MAPK pathways in ATP-treated BV-2 cells. This study highlights the potential use of KHG26792 as a therapeutic agent for the many diseases of the CNS related to activated microglia. PMID- 26522450 TI - Neuroprotective effect of Valeriana wallichii rhizome extract against the neurotoxin MPTP in C57BL/6 mice. AB - Oxidative stress and inflammation are some of the contributing factors for dopaminergic neurodegeneration in Parkinson's disease (PD). Though Valeriana wallichii D.C. is known for its nervine activities its effect against PD is yet to be studied. This is the first report on the antioxidant and anti-inflammatory effect of V. wallichii rhizome extract (VWE) in MPTP induced PD mice. GC-MS analysis of VWE indicated the presence of phytoconstituents like isovaleric acid and acacetin. PD induced mice were treated orally with three different doses (50, 100 and 200mg/kg body weight (BW)) of VWE for 14 days and their behavioural changes were studied on days 0, 8, 13 and 21. The levels of striatal dopamine, mid brain tyrosine hydroxylase positive (TH(+)) cell count, TH protein expression, reactive oxygen species (ROS), lipid peroxidation (LPO), antioxidants and inflammatory cytokines were analysed. Mid brain glial fibrillary acidic protein (GFAP) expression was assessed by immunohistochemistry and western blotting. Also mid brain histopathological analysis was performed. VWE treatment significantly recuperated the altered behavioural test scores, striatal dopamine levels, mid brain TH(+) cell count and TH protein levels, increased GFAP expression and the histopathological changes observed in PD mice. Similarly, diminished levels of antioxidants, elevated levels of ROS, LPO and inflammatory cytokines were also significantly ameliorated following VWE treatment. The effective dose of VWE was found to be 200mg/kg BW. Conclusively, V. wallichii rhizome extract has the potential to mitigate oxidative stress and inflammatory damage in PD. PMID- 26522451 TI - Soluble receptors and hormone binding proteins: analytical approach and clinical relevance. PMID- 26522452 TI - The soluble leptin receptor. AB - The adipokine leptin realizes signal transduction via four different leptin receptor (OB-R) isoforms. The amount of functionally active OB-R, however, is affected by constitutive shedding of the extracellular domain. The product of the cleavage process, the so-called soluble leptin receptor (sOB-R), is the main binding protein for leptin in human blood and modulates its bioavailability. Concentrations of sOB-R are differentially regulated in metabolic disorders, such as type 1 diabetes mellitus or obesity, and can, therefore, enhance or reduce leptin sensitivity. Lipotoxicity and apoptosis increase OB-R cleavage via ADAM10 dependent mechanisms. In contrast, although increased sOB-R concentrations seem to directly inhibit leptin effects, reduced amounts of sOB-R may reflect decreased membrane expression of OB-R. These findings, in part, explain alterations of leptin sensitivity that are associated with changes in serum sOB-R concentrations seen in metabolic disorders. PMID- 26522453 TI - Growth hormone binding protein - physiological and analytical aspects. AB - A significant proportion of total circulating growth hormone (GH) is bound to a high affinity growth hormone binding protein (GHBP). Several low affinity binding proteins have also been described. Significant differences between species exist with respect to origin and regulation of GHBP, but generally it resembles the extracellular domain of the GH receptor. Concentrations are associated with GH status, body composition and other factors. Although the clinical relevance of GHBP is not fully understood it is suggested that concentrations indirectly reflect GH receptor status. This is supported by cases of Laron's syndrome where a molecular defect in the extracellular domain of the GH receptor is associated with low or unmeasurable GHBP concentrations. Methods to measure GHBP have evolved from chromatographic, activity based procedures to direct immunoassays. In clinical practice, measurement of GHBP can be helpful to differentiate between GH deficiency and GH insensitivity, particularly if GHBP is absent. PMID- 26522454 TI - Physiology and pathophysiology of IGFBP-1 and IGFBP-2 - consensus and dissent on metabolic control and malignant potential. AB - IGFBP-1 and IGFBP-2 are suppressed by growth hormone and therefore represent less prominent members of the IGFBP family when compared to IGFBP-3 that carries most of the IGFs during circulation under normal conditions in humans in vivo. As soon as the GH signal is decreased expression of IGF-I and IGFBP-3 is reduced. Under conditions of lowered suppression by GH the time seems come for IGFBP-1 and IGFBP 2. Both IGFBPs are potent effectors of growth and metabolism. Secretion of IGFBP 1 and IGFBP-2 is further suppressed by insulin and diminished with increasing obesity. Both IGFBP family members share the RGD sequence motif that mediates binding to integrins and is linked to PTEN/PI3K signalling. In mice, IGFBP-2 prevents age- and diet-dependent glucose insensitivity and blocks differentiation of preadipocytes. The latter function is modulated by two distinct heparin binding domains of IGFBP-2 which are lacking in IGFBP-1. IGFBP-2 is further regulated by leptin and has been demonstrated to affect insulin sensitivity and glucose tolerance, further supporting a particular role of IGFBP-2 in glucose and fat metabolism. Since IGFBP-2 is controlled by sex steroids as well, we devised a scheme to compare IGFBP effects in breast, ovarian and prostate cancer. While a positive association does not seem to exist with IGFBP-1 and risk of cancers within these reproductive tissues, a relationship between IGFBP-2 and breast cancer, ovarian cancer and prostate cancer does indeed appear to be present. To date, the specific roles of IGFBP-2 in estrogen signalling are unclear, though there is accumulating evidence for an effect of IGFBP-2 on PI3K signalling via PTEN, particularly in breast cancer. PMID- 26522455 TI - Insulin-like growth factor binding-protein-3 (IGFBP-3). AB - The IGF system comprises two IGFs (IGF-1, IGF-2), two IGF-receptors (IGF-R1, IGF R2), and six IGF binding proteins (IGFBPs) with a high affinity for IGFs. The IGFBPs, of which IGFBP-3 is the most abundant in postnatal blood, link with IGFs and prevent them from being degraded; they also facilitate IGF transport through body compartments. The interaction between IGFs and their specific receptors is partly regulated by structural modifications inherent to the IGFBPs. IGFBPs also have IGF-independent biological effects. Since serum IGFBP-3 is GH-dependent and correlates quantitatively with GH secretion, its measurement is useful in tests of abnormal GH secretion. Particularly during childhood, IGFBP-3 values play an important role in ascertaining alterations in GH secretion and action (i.e., primary IGF deficiency states). A new role for IGFBP-3 and other IGFBPs with natural or altered structures is likely to be established through current studies investigating their application in promoting apoptotic processes in malignancies. PMID- 26522456 TI - Insulin-like growth factor binding proteins 4-6. AB - Insulin-like growth factor binding proteins (IGFBPs) 4-6 have important roles as modulators of IGF actions. IGFBP-4 and IGFBP-6 predominantly inhibit IGF actions, whereas IGFBP-5 may enhance these actions under some circumstances. IGFBP-6 is unique among the IGFBPs for its marked IGF-II binding preference. IGFBPs 4-6 are found in the circulation as binary complexes with IGFs that can enter tissues. Additionally, about half of the circulating IGFBP-5 is found in ternary complexes with IGFs and an acid labile subunit; this high molecular complex cannot leave the circulation and acts as an IGF reservoir. IGFBPs 4-6 also have IGF independent actions. These IGFBPs are regulated in a cell-specific manner and their dysregulation may play a role in a range of diseases including cancer. However, there is no clear clinical indication for measuring serum levels of these IGFBPs at present. PMID- 26522457 TI - Soluble M6P/IGFIIR in the circulation. AB - Soluble M6P/IGFIIR has the potential to be a significant carrier of IGF-II and mannose 6-P proteins in the circulation and play an important role as an antagonist to the cellular receptor. Evidence suggests that soluble receptor plays a role in fetal and childhood growth by opposing the growth stimulatory effects of IGF-II. Maternal serum levels of M6P/IGFIIR are elevated in late pregnancy and the IGF-II:soluble M6P/IGFIIR ratio in cord blood correlates strongly with weight at birth and placental weight suggesting an important role in fetal growth and development. However, elevated soluble receptor levels may also be indicative of disease in later life, such as liver cirrhosis and some tumor types and may be a useful marker for monitoring treatment and progression of the disease. Further investigation of the regulation of this soluble receptor in health and disease is required to fully elucidate its role in the circulation. PMID- 26522459 TI - The biomarker sex hormone-binding globulin - from established applications to emerging trends in clinical medicine. AB - Sex hormone-binding globulin (SHBG) is a serum glycoprotein exhibiting the unique feature of binding sex steroids with high affinity and specificity. Its serum levels are regulated not only by androgens and estrogens but also by thyroid hormones and other metabolic factors. Several disease conditions are accompanied by altered SHBG levels such as hyper- and hypoandrogenism, thyroid disorders, pituitary diseases, liver disorders, and breast as well as prostate cancer. Additionally, several drugs and alcohol consumption influence serum concentrations of SHBG. In some cases, altered SHBG levels are a specific result of the underlying pathology. In others, they merely constitute an epiphenomenon, which still might offer the possibility of using serum measurements of SHBG as surrogate marker. This review article portrays the different disorders associated with altered SHBG levels and discusses the usefulness of SHBG as disease biomarker from a clinicians as well as from an endocrinological researchers point of view. PMID- 26522458 TI - Inherited defects of thyroxine-binding proteins. AB - Thyroid hormones (TH) are bound to three major serum transport proteins, thyroxine-binding globulin (TBG), transthyretin (TTR) and human serum albumin (HSA). TBG has the strongest affinity for TH, whereas HSA is the most abundant protein in plasma. Individuals harboring genetic variations in TH transport proteins present with altered thyroid function tests, but are clinically euthyroid and do not require treatment. Clinical awareness and early recognition of these conditions are important to prevent unnecessary therapy with possible untoward effects. This review summarizes the gene, molecular structure and properties of these TH transport proteins and provides an overview of their inherited abnormalities, clinical presentation, genetic background and pathophysiologic mechanisms. PMID- 26522460 TI - Corticosteroid-binding globulin: modulating mechanisms of bioavailability of cortisol and its clinical implications. AB - Corticosteroid-binding globulin (CBG) is the principal transport protein of glucocorticoids. Approximately 80-90% of serum cortisol binds to CBG with high affinity and only about 5% of cortisol remain unbound and is considered biologically active. CBG seems to modulate and influence the bioavailability of cortisol to local tissues. In this review, we will discuss physicochemical properties of CBG and structure of CBG in the mechanisms of binding and release of cortisol. This review describes several factors affecting CBG functions, such as genetic factors or temperature. Furthermore, clinical implications of CBG abnormalities and the measurement of CBG and its use for assessment of free cortisol levels are described in this review. PMID- 26522461 TI - Behind the scenes of vitamin D binding protein: more than vitamin D binding. AB - Although being discovered in 1959, the number of published papers in recent years reveals that vitamin D binding protein (DBP), a member of the albuminoid superfamily, is a hot research topic. Besides the three major phenotypes (DBP1F, DBP1S and DBP2), more than 120 unique variants have been described of this polymorphic protein. The presence of DBP has been demonstrated in different body fluids (serum, urine, breast milk, ascitic fluid, cerebrospinal fluid, saliva and seminal fluid) and organs (brain, heart, lungs, kidneys, placenta, spleen, testes and uterus). Although the major function is binding, solubilization and transport of vitamin D and its metabolites, the name of this glycoprotein hides numerous other important biological functions. In this review, we will focus on the analytical aspects of the determination of DBP and discuss in detail the multifunctional capacity [actin scavenging, binding of fatty acids, chemotaxis, binding of endotoxins, influence on T cell response and influence of vitamin D binding protein-macrophage activating factor (DBP-MAF) on bone metabolism and cancer] of this abundant plasma protein. PMID- 26522462 TI - The soluble interleukin-6 receptor and related proteins. AB - Interleukin-6 is a cytokine involved in the regulation of the immune system and the central nervous system. Interleukin-6 binds to an interleukin-6 receptor, and then associates with a dimer of the ubiquitously expressed gp130 receptor subunit, which initiates intracellular signaling. The interleukin-6 receptor is found in a soluble form, which is generated by proteolytic cleavage and also to a minor extent by translation from an alternatively spliced mRNA. The complex of interleukin-6 bound to the interleukin-6 receptor can stimulate cells, which only express gp130. Such cells are not responsive to interleukin-6 alone. We have for the first time identified the molecular basis of pro-and anti-inflammatory properties of interleukin-6 and we have defined the generation of the soluble IL 6R as a crucial point in the regulation between these two properties. Furthermore, we have deduced a therapeutic principle, which enables us to exclusively block the pro-inflammatory activities of this important cytokine. PMID- 26522463 TI - Beyond soluble transferrin receptor: old challenges and new horizons. AB - Disturbances of iron metabolism are a frequent challenge in outpatient and inpatient care. Although several established biomarkers are commonly used by clinicians for differential diagnosis, the discrimination between latent or classic iron deficiency, anaemia of chronic disease or a combination of functional iron deficiency (iron-restricted erythropoiesis) with anaemia of chronic disease in patients affected by inflammatory disease can be demanding. Soluble transferrin receptor (sTfR) is a cleaved monomer of transferrin receptor 1 and correlates positively with tissue iron deficiency as well as with stimulated erythropoiesis. The ratio between sTfR and ferritin in combination with reticulocyte haemoglobin content further helps to identify different states of iron deficiency. In this review, we will focus on biological aspects of iron metabolism and sTfR, established clinical applications and limitations of sTfR and derived indices, and prospects of future research and applications. PMID- 26522464 TI - Other miscellaneous hormone binding proteins: attempt at an epilogue. AB - An overview of the detection, mechanism of formation and clinical function of hormone binding proteins shedded from the membrane receptor and detected in the last twenty years is presented. The representatives of such binding proteins are restricted only to human soluble receptors that have been already detected in blood or other intravasal fluids such as soluble receptors for LH/hCG, prolactin, TSH, erythropoietin, insulin and IGF-I. The clinical or diagnostic significance of these putative-detectable or indeed circulating proteins often remains largely unclear. PMID- 26522465 TI - Anatomical study of the morphological continuity between iliotibial tract and the fibularis longus fascia. AB - PURPOSE: Recent research indicates that the skeletal muscles of the human body do not function as independent actuators. Instead, they seem to be linked by connective tissue forming myofascial chains. While the existence of such meridians has been demonstrated for the ventral and the dorsal side of the body, no data are available for morphological fusion of lateral muscles. This study aimed to provide evidence for the inferior part of the lateral myofascial chain. METHODS: Fourteen legs (7 embalmed cadavers, four ?, 86 +/- 7 years) were dissected to reveal a potential myofascial continuity between the fibularis longus muscle, more detailed, its fascia, and the iliotibial tract (ITT). Three investigators judged the general existence as well as the degree and characteristics of the continuity. If an anatomical continuity was evident, strain was applied to both structures in order to evaluate the tissues' ability for tensile transmission. RESULTS: An indirect connection between the iliotibial tract and the fascia of the fibularis longus muscle was found: in all examined legs, the ITT fused strongly with the crural fascia. The latter was hardly separable from the fibularis longus fascia. Application of strain to the ITT caused local movement in the crural fascia and the underlying fascia of the fibularis muscle. CONCLUSIONS: The iliotibial tract fuses firmly with the crural fascia and the degree of continuity suggests that moderate amounts of strain might be transmitted. However, biomechanical studies precisely quantifying this tensile transmission are warranted in order to estimate the relevance of the linkage for the locomotor system. PMID- 26522466 TI - Letter to the Editor. PMID- 26522467 TI - IL-1 Receptor Antagonist Inhibits Early Granulation Formation. AB - PURPOSE: Using a functional model of airway granulation tissue in laryngotracheal stenosis, we investigated changes in histopathology and inflammatory markers within granulation tissue in response to an interleukin-1 receptor antagonist (IL 1Ra). This study allows us to further delineate the immune response to wound healing and potentially identify treatment markers. METHODS: Laryngotracheal complexes (LTCs) of donor mice underwent direct airway injury. The LTCs were transplanted into subcutaneous tissue of recipient mice in 2 groups: IL-1Ra treated and untreated. The IL-1Ra-treated arm received daily intraperitoneal injections of IL-1Ra for 3 weeks. The LTCs were then harvested. Granulation formation was measured. The mRNA expression of transforming growth factor (TGF) beta and IL-1 was quantified using real-time reverse transcript polymerase chain reaction. RESULTS: There were statistically significant differences in lamina propria thickness. There were no statistically significant changes in mRNA expression of TGF-beta and IL-1beta between the treated and untreated specimens. CONCLUSIONS: Using a previously described murine model, we delineate inflammatory markers that can be targeted for potential therapy. While the levels of inflammatory markers do not change significantly, the lamina propria thickness shows that the effects of IL-1 have been inhibited. The early use of the IL-1Ra will inhibit the efficacy of IL-1 in the inflammatory cascade and can prevent early granulation formation. PMID- 26522468 TI - Surgeon Awareness of Operating Room Supply Costs. AB - BACKGROUND: The extent to which surgeons understand costs associated with expensive operative procedures remains unclear. The goal of the study was to better understand surgeon cost awareness of operating room supplies and implants. METHODS: This was a cross-sectional study of faculty (n = 24) and trainees (fellow and residents, n = 27) in the Department of Otolaryngology. Participants completed surveys to assess opinions on importance of cost and ease in accessing cost data and were asked to estimate the costs of operating room (OR) supplies and implants. Estimates within 20% of actual cost were considered correct. Analyses were stratified into faculty and trainee surgeons. RESULTS: Cost estimates varied widely, with a low percentage of correct estimations (25% for faculty, 12% for trainees). Surgeons tended to underestimate the cost of high cost items (55%) and overestimate the cost of low-cost items (77%). Attending surgeons were more accurate at correctly estimating costs within their own subspecialty (33% vs 16%, P < .001). Self-rated cost knowledge and years in practice did not correlate with cost accuracy (P < .05). CONCLUSIONS: A majority of surgeons were unable to correctly estimate the costs of items/implants used in their OR. An opportunity exists to improve the mechanisms by which cost data are fed back to physicians to help promote value-based decision making. PMID- 26522470 TI - Privacy Risks from Genomic Data-Sharing Beacons. AB - The human genetics community needs robust protocols that enable secure sharing of genomic data from participants in genetic research. Beacons are web servers that answer allele-presence queries--such as "Do you have a genome that has a specific nucleotide (e.g., A) at a specific genomic position (e.g., position 11,272 on chromosome 1)?"--with either "yes" or "no." Here, we show that individuals in a beacon are susceptible to re-identification even if the only data shared include presence or absence information about alleles in a beacon. Specifically, we propose a likelihood-ratio test of whether a given individual is present in a given genetic beacon. Our test is not dependent on allele frequencies and is the most powerful test for a specified false-positive rate. Through simulations, we showed that in a beacon with 1,000 individuals, re-identification is possible with just 5,000 queries. Relatives can also be identified in the beacon. Re identification is possible even in the presence of sequencing errors and variant calling differences. In a beacon constructed with 65 European individuals from the 1000 Genomes Project, we demonstrated that it is possible to detect membership in the beacon with just 250 SNPs. With just 1,000 SNP queries, we were able to detect the presence of an individual genome from the Personal Genome Project in an existing beacon. Our results show that beacons can disclose membership and implied phenotypic information about participants and do not protect privacy a priori. We discuss risk mitigation through policies and standards such as not allowing anonymous pings of genetic beacons and requiring minimum beacon sizes. PMID- 26522469 TI - Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26. AB - S-adenosylmethionine (SAM) is the predominant methyl group donor and has a large spectrum of target substrates. As such, it is essential for nearly all biological methylation reactions. SAM is synthesized by methionine adenosyltransferase from methionine and ATP in the cytoplasm and subsequently distributed throughout the different cellular compartments, including mitochondria, where methylation is mostly required for nucleic-acid modifications and respiratory-chain function. We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26. Clinical findings ranged from neonatal mortality resulting from respiratory insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and slowly progressive muscle weakness. We show that SLC25A26 mutations cause various mitochondrial defects, including those affecting RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid. PMID- 26522471 TI - Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2. AB - Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants. PMID- 26522473 TI - Combination antimicrobial susceptibility testing for acute exacerbations in chronic infection of Pseudomonas aeruginosa in cystic fibrosis. AB - BACKGROUND: Antibiotic therapy for acute pulmonary exacerbations in people with cystic fibrosis (CF) is usually chosen based on the results of antimicrobial susceptibility testing of individual drugs. Combination antimicrobial susceptibility testing assesses the efficacy of drug combinations including two or three antibiotics in vitro and can often demonstrate antimicrobial efficacy against bacterial isolates even when individual antibiotics have little or no effect. Therefore, choosing antibiotics based on combination antimicrobial susceptibility testing could potentially improve response to treatment in people with CF with acute exacerbations. This is an updated version of a previously published review. OBJECTIVES: To compare antibiotic therapy based on conventional antimicrobial susceptibility testing to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with CF and chronic infection with P. aeruginosa. SEARCH METHODS: We identified relevant trials from the Group's Cystic Fibrosis Trials Register.Latest search: 27 July 2015. SELECTION CRITERIA: Randomised and quasi randomised controlled trials of antibiotic therapy based on conventional antimicrobial susceptibility testing compared to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in CF due to chronic infection with P. aeruginosa. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed their quality and extracted data from eligible studies. Additionally, the authors contacted the study investigators to obtain further information. MAIN RESULTS: The search identified one study eligible for inclusion in the review. This study prospectively assessed whether the use of multiple combination bactericidal antibiotic testing (MCBT) improved clinical outcomes in participants with acute pulmonary exacerbations of CF who were infected with multiresistant bacteria. A total of 132 participants were randomised in the study. The study investigators provided data specific to the participants who were only infected with P. aeruginosa for the primary outcome: time until next pulmonary exacerbation. For "Time to next pulmonary exacerbation" in the participants specifically infected with only P. aeruginosa, the hazard ratio was 0.82, favouring the control group (95% CI 0.44 to 1.51) (P = 0.52). The data did not provide evidence that combination susceptibility testing was superior to conventional susceptibility testing. AUTHORS' CONCLUSIONS: The current evidence, limited to one study, shows that there is insufficient evidence to determine effect of choosing antibiotics based on combination antimicrobial susceptibility testing compared to choosing antibiotics based on conventional antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with CF with chronic P. aeruginosa infection. A large international and multicentre trial is needed to further investigate this issue.The only trial included in the review was published in 2005, and we have not identified any relevant trials up to September 2011. We therefore do not plan to update this review until new trials are published, although we will search the Group's Cystic Fibrosis Trials Register on a two-yearly cycle. PMID- 26522472 TI - Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer. AB - Cancer-predisposing genes associated with inherited cancer syndromes help explain mechanisms of sporadic carcinogenesis and often inform normal development. Cowden syndrome (CS) is an autosomal-dominant disorder characterized by high lifetime risks of epithelial cancers, such that ~50% of affected individuals are wild-type for known cancer-predisposing genes. Using whole-exome and Sanger sequencing of a multi-generation CS family affected by thyroid and other cancers, we identified a pathogenic missense heterozygous SEC23B variant (c.1781T>G [p.Val594Gly]) that segregates with the phenotype. We also found germline heterozygous SEC23B variants in 3/96 (3%) unrelated mutation-negative CS probands with thyroid cancer and in The Cancer Genome Atlas (TCGA), representing apparently sporadic cancers. We note that the TCGA thyroid cancer dataset is enriched with unique germline deleterious SEC23B variants associated with a significantly younger age of onset. SEC23B encodes Sec23 homolog B (S. cerevisiae), a component of coat protein complex II (COPII), which transports proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. Interestingly, germline homozygous or compound heterozygous SEC23B mutations cause an unrelated disorder, congenital dyserythropoietic anemia type II, and SEC23B-deficient mice suffer from secretory organ degeneration due to ER-stress-associated apoptosis. By characterizing the p.Val594Gly variant in a normal thyroid cell line, we show that it is a functional alteration that results in ER-stress-mediated cell-colony formation and survival, growth, and invasion, which reflect aspects of a cancer phenotype. Our findings suggest a different role for SEC23B, whereby germline heterozygous variants associate with cancer predisposition potentially mediated by ER stress "addiction." PMID- 26522474 TI - A zebrafish model of Poikiloderma with Neutropenia recapitulates the human syndrome hallmarks and traces back neutropenia to the myeloid progenitor. AB - Poikiloderma with Neutropenia (PN) is an autosomal recessive genodermatosis characterized by early-onset poikiloderma, pachyonychia, hyperkeratosis, bone anomalies and neutropenia, predisposing to myelodysplasia. The causative C16orf57/USB1 gene encodes a conserved phosphodiesterase that regulates the stability of spliceosomal U6-RNA. The involvement of USB1 in splicing has not yet allowed to unveil the pathogenesis of PN and how the gene defects impact on skin and bone tissues besides than on the haematological compartment. We established a zebrafish model of PN using a morpholino-knockdown approach with two different splicing morpholinos. Both usb1-depleted embryos displayed developmental abnormalities recapitulating the signs of the human syndrome. Besides the pigmentation and osteochondral defects, usb1-knockdown caused defects in circulation, manifested by a reduced number of circulating cells. The overall morphant phenotype was also obtained by co-injecting sub-phenotypic dosages of the two morpholinos and could be rescued by human USB1 RNA. Integrated in situ and real-time expression analyses of stage-specific markers highlighted defects of primitive haematopoiesis and traced back the dramatic reduction in neutrophil myeloperoxidase to the myeloid progenitors showing down-regulated pu.1 expression. Our vertebrate model of PN demonstrates the intrinsic requirement of usb1 in haematopoiesis and highlights PN as a disorder of myeloid progenitors associated with bone marrow dysfunction. PMID- 26522475 TI - Apocynin protects against ethanol-induced gastric ulcer in rats by attenuating the upregulation of NADPH oxidases 1 and 4. AB - Gastric ulcer is a common gastrointestinal disorder affecting many people all over the world. Absolute ethanol (5 ml/kg) was used to induce gastric ulceration in rats. Apocynin (50 mg/kg) was given orally one hour before the administration of absolute ethanol. Omeprazole (20 mg/kg) was used as a standard. Interestingly, apocynin pre-treatment provided 93.5% gastroprotection against ethanol-induced ulceration. Biochemically, gastric mucin content was significantly increased with apocynin pre-treatment. This finding was further supported by alcian blue staining of stomach sections obtained from the different treated groups. Also, gastric juice volume and acidity were significantly reduced. Apocynin significantly ameliorated ethanol-induced oxidative stress by replenishing reduced glutathione and superoxide dismutase levels as well as reducing elevated malondialdehyde levels in gastric tissues. Besides, ethanol-induced pro inflammatory response was significantly decreased by apocynin pre-treatment via reducing elevated levels of pro-inflammatory markers; interleukin-1beta, tumor necrosis factor-alpha, cyclooxygenase-2 and inducible nitric oxide synthase. Additionally, caspase-3 tissue level was significantly reduced in apocynin pre treated group. Interestingly, NADPH oxidase-1 (NOX-1) and NOX-4 up-regulation was shown to be partially involved in the pathogenesis of ethanol-induced gastric ulceration and was significantly reversed by apocynin pre-treatment. Gastroprotective properties of apocynin were confirmed by histopathological examination. It is worth mentioning that apocynin was superior in all aspects except gastric mucin content parameter where it was significantly increased by 13.5 folds in the omeprazole pre-treated group. This study was the first to show that apocynin is a promising gastroprotective agent against ethanol-induced gastric ulceration, partially via its anti-oxidant, anti-inflammatory, anti apoptotic effects as well as down-regulating NOX-1 and NOX-4 expression. PMID- 26522476 TI - Acetaminophen-induced liver injury: Implications for temporal homeostasis of lipid metabolism and eicosanoid signaling pathway. AB - Acetaminophen is a commonly used drug that induces serious hepatotoxicity when overdosed, leading to increased levels of serum aminotransferases. However, little knowledge exists linking acetaminophen to liver free fatty acids and the eicosanoid-mediated signaling pathway. To this end, adult NMRI mice injected with a dose of 400 mg/kg acetaminophen were monitored for one week post-treatment. Consistent changes were observed in serum transaminases, profile of hepatic free fatty acids, expression of cyclooxygenase, elongase, lipogenesis, and lipolysis genes; as well as in expression patterns of cyclooxygenase-1 and -2 in the liver. Both linoleic acid and arachidonic acid--substrates in eicosanoid biosynthesis- were significantly influenced by overdose, and the latter peaked first among the free fatty acids examined here. There was a close similarity between the temporal dynamics of linoleic acid and aspartate aminotransferases. Moreover, serum transaminases were reduced by cyclooxygenase-2 inhibitors, but not by cyclooxygenase-1 inhibitors. Our results hence attest to the hazard of acetaminophen overdose on the temporal homeostasis of hepatic concentrations of free fatty acids and expression of key genes underlying liver lipid metabolism. There is also evidence for activation of a cyclooxygenase-mediated signaling pathway, especially the cyclooxygenase 2-prostanoid pathway, during acetaminophen induced liver injury. Therefore, the results of the present study should provide valuable information to a wide audience, working to understand the health hazard of this drug and the implications of the eicosanoid signaling pathway in liver pathophysiology. PMID- 26522477 TI - The syntaxin protein (MoSyn8) mediates intracellular trafficking to regulate conidiogenesis and pathogenicity of rice blast fungus. AB - Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) mediate cellular membrane fusion and intracellular vesicle trafficking in eukaryotic cells, and are critical in the growth and development of pathogenic fungi such as Magnaporthe oryzae which causes rice blast. Rice blast is thought to involve distinct SNARE-mediated transport and secretion of fungal effector proteins into the host to modulate rice immunity. We have previously characterized two SNARE proteins, secretory protein (MoSec22) and vesicle associated membrane protein (MoVam7), as being important in cellular transport and pathogenicity. Here, we show that syntaxin 8 (MoSyn8), a Qc-SNARE protein homolog, also plays important roles in growth, conidiation, and pathogenicity. The MoSYN8 deletion mutant (?Mosyn8) mutant exhibits defects in endocytosis and F actin organization, appressorium turgor pressure generation, and host penetration. In addition, the ?Mosyn8 mutant cannot elaborate biotrophic invasion of the susceptible rice host, or secrete avirulence factors Avr-Pia (corresponding to the rice resistance gene Pia) and Avrpiz-t (the cognate Avr gene for the resistance gene Piz-t) proteins. Our study of MoSyn8 advances our understanding of SNARE proteins in effector secretion which underlies the normal physiology and pathogenicity of M. oryzae, and it sheds new light on the mechanism of the blight disease caused by M. oryzae. PMID- 26522479 TI - The patient safety climate in Danish hospital units. AB - INTRODUCTION: This study aimed to describe and analyse the patient safety climate in 15 Danish hospital units. METHODS: A cross-sectional study design was applied. Patient safety culture was measured by the Danish version of the Safety Attitude Questionnaire comprising six cultural subscales. Subscale results were calculated as the percentage responders with an individual scale score of 75 point or more (range: 0-100), equivalent to %-positive, and as mean scale scores. RESULTS: Out of 867 invited employees, 544 (63%) participated. No differences in %-positive were found between nurses and doctors, across age, gender or work experience (p > 0.05), but the difference between leaders and frontline staff was evident (p < 0.05). Perceptions varied more among individuals within the unit than between units within the hospital, and between hospitals. CONCLUSIONS: The results provide a snapshot of how staff perceives the culture. The level of %-positives per dimension is comparable with most international findings. The higher levels of leaders who perceive the culture as positive should be further investigated in larger samples. Generally, patient safety culture should be assessed at unit level; dimensional strengths and weaknesses as well as subgroup differences should be identified, and dialogue-based methods should be applied to uncover why the culture is perceived as it is. FUNDING: The TrygFonden provided financial support to the Danish Safer Hospital Programme, which funded this study. TRIAL REGISTRATION: not relevant. PMID- 26522478 TI - MRSA screening in emergency department detects a minority of MRSA carriers. AB - INTRODUCTION: Methicillin-resistant Staphylococcus areus (MRSA) is an emerging problem. The Danish Health and Medicines Authority (HMA) has developed a question based screening tool to identify patients with MRSA. The tool has three parts: questions on general risk situations, special risk situations and individual risk factors. The emergency departments (ED) play a key role in the prevention of in hospital spreading of MRSA. The aim of the present study was to estimate the prevalence of MRSA among all admitted ED patients to assess how many patients should be swab-tested for MRSA and isolated and to evaluate the ability of the HMA screening tool to detect MRSA. METHODS: Patients who were more than ten years old answered all the HMA questions on general and specific risk situations and individual risk factors for MRSA, and a swab was obtained for MRSA culture. RESULTS: A total of 1,945 patients were admitted and 73% participated. Indications for swab testing for MRSA were present in 8%. The general risk situation questions identified 3% for isolation due to suspicion of MRSA. A total of 11 patients had a positive MRSA swab culture (0.9%). Among the isolated patients, 3% had MRSA, 97% would have been isolated unnecessarily, while 91% of the MRSA patients would not have been isolated. The general risk situation questions had a sensitivity of 18-27% and the whole questionnaire had a sensitivity of 55% for the detection of MRSA patients. CONCLUSIONS: The majority of MRSA carriers who are acutely admitted to the ED will remain undetected. FUNDING: Hospital of Southern Jutland. TRIAL REGISTRATION: not relevant. PMID- 26522480 TI - Long-term outcomes after total thyroidectomy. AB - INTRODUCTION: The aim of this study was to assess the complication rates of total thyroidectomy in a regional hospital setting in Denmark for permanent hypoparathyroidism, recurrent laryngeal nerve palsy and post-operative bleeding. Furthermore, the long-term outcomes in the management of hypoparathyroidism were investigated. METHODS: This was a retrospective study of 114 consecutive patients undergoing total thyroidectomy due to benign thyroid disease. RESULTS: A total of 0.9% suffered from permanent recurrent laryngeal nerve palsy, whereas temporary nerve palsy was seen in 1.8%. Post-operative bleeding occurred in 5.4%. The frequencies of temporary and permanent post-operative hypocalcaemia were 22.8% and 17.4%, respectively. Autotransplantation of parathyroid tissue was performed in 23.7%. Unintentional parathyroidectomy occurred in 8.7%. Serum ionized calcium was significantly lower preoperatively in the group that developed hypocalcaemia (p = 0.03). CONCLUSIONS: The incidence of recurrent laryngeal nerve palsy was similar to that reported in other published studies. Post-operative bleeding was more common than in other studies. The high frequency of permanent post-operative hypocalcaemia is a cause for concern. We need to consider implementing a guideline to facilitate outfacing calcium and vitamin D supplements as an attempt to phase out was not attempted in all patients. FUNDING: not relevant. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency, but has not been registered due to its register-based design. PMID- 26522481 TI - Post-operative parathyroid hormone can be used as a predictor of normocalcaemia after total thyroidectomy. AB - INTRODUCTION: Development of hypocalcaemia is a serious complication to total thyroidectomy (TT). The measurement of intact plasma parathyroid hormone (iPTH) has been internationally described as a good predictor of hypocalcaemia. Despite this, consensus in the field has yet to be reached among clinicians. We aimed to evaluate if measurement of iPTH 24 hours post-operatively (24-iPTH) can identify patients who do not subsequently develop clinically significant hypocalcaemia (CSH), thereby allowing for early discharge after TT. METHODS: This was a historic cohort study of all patients who had a TT in the period from January 2013 to March 2014 at the Department of Oto-rhino-laryngology, Aarhus University Hospital, Denmark. Only patients with 24-iPTH measurements were included. Post operative treatment with calcium or activated vitamin D analogue was defined as CSH. Data were collected from medical records. RESULTS: A total of 69 patients were included, 80% were women, the median age was 47 and 83% had a malignant disease. A total of 35% developed CSH and the median hospitalisation period was four days. The sensitivity, specificity and positive predictive value of 24-iPTH >= 2.8 pmol/l to exclude CSH were 76%, 92% and 94%, respectively. In addition, we found that a body mass index > 25 kg/m(2) significantly increased the risk of developing CSH. CONCLUSIONS: The measurement of 24-iPTH >= 2.8 pmol/l can be used to predict patients who will not develop CSH after TT and allow for early discharge of more than 50% of the patients. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26522482 TI - The majority of participants with abnormal spirometry at walk-in consult their general practitioner as recommended. AB - INTRODUCTION: A number of studies inviting citizens to perform spirometry without need for a previous appointment have been performed to determine the need for general screening of the population for chronic obstructive pulmonary disease (COPD). Yet, no studies have examined how many of the participants follow the advice given to consult their general practitioner (GP) afterwards. METHODS: A walk-in spirometry was carried out on the island of Laesoe. All habitants above the age of 18 years were invited. In total, 142 were eligible for the study. Participants with an abnormal spirometry were recommended to consult their GP immediately, whereas smokers with symptoms, but with a normal spirometry, were recommended to consult their GP within a year for another spirometry. A follow-up was performed to investigate whether the participants had followed this advice. RESULTS: In total, 52% (74/142) of the participants were advised to contact their GP: 34 due to an abnormal spirometry and 40 due to smoking and respiratory symptoms. Among the participants with an abnormal spirometry, 79% saw their GP within three months, whereas 30% of the current smokers saw their GP within 9-15 months. Lung disease was diagnosed in 56% (19/34) of the participants who initially had an abnormal spirometry. CONCLUSIONS: Among the participants who had an abnormal spirometry at screening, 79% consulted their GP as recommended. Furthermore, 52% of the participants who had an abnormal spirometry were subsequently diagnosed with pulmonary disease by their GP. We conclude that walk in spirometry is a useful tool for early diagnosis of COPD. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26522483 TI - Management of cerebral palsy varies by healthcare region. AB - INTRODUCTION: Cerebral palsy (CP) is the most common type of motor disability in childhood. The aim of the present paper was to describe regional differences in the management of CP in school-aged children in Denmark. METHODS: This was a cross-sectional study based on the Danish Cerebral Palsy Registry. The parents of 462 children answered a questionnaire about their child's treatment and the family's characteristics. Descriptive and logistic regression analyses were performed for every treatment modality, stratified by the Gross Motor Function Classification System (GMFCS) level and adjusted for family and child characteristics. RESULTS: Significant regional differences were found regarding the provision of occupational therapy at all GMFCS levels, speech therapy at GMFCS levels II-V and orthopaedic surgery at GMFCS levels I and III-V. No regional differences were observed in the frequency of physiotherapy. We found no regional differences in the severity of disability. CONCLUSIONS: Regional differences in the management of CP cannot be explained by social differences or differences in the severity of the disability. FUNDING: This study was funded by the Research Foundation from the Central Denmark Region and the Department of Clinical Medicine at Aarhus University Hospital, the Augustinus Foundation, the Bevica Foundation, the Dagmar Marshalls Foundation, the Ludvig and Sara Elsass Foundation, and the Civil Engineer Frode V. Nyegaard's and his Wife's Foundation. TRIAL REGISTRATION: not relevant. PMID- 26522484 TI - Gestational trophoblastic diseases - clinical guidelines for diagnosis, treatment, follow-up, and counselling. AB - Hydatidiform mole is treated with surgical uterine evacuation with suction and blunt curettage (D). Medical uterine evacuation should not be used (C). On clinical suspicion of hydatidiform mole, one representative sample of the evacuated tissue is fixed for histopathologic investigation and one is forwarded unfixed for genetic analysis (D). Serum hCG is measured on suspicion of hydatidiform mole. At the time of the uterine evacuation, the initial hCG is measured (A). After a hydatidiform mole that is both triploid and partial, serum hCG is measured weekly until there are two consecutive undetectable values (< 1 or < 2), after which the patient can be discharged from follow-up (C). After a diploid hydatidiform mole, a complete mole, or a hydatidiform mole without valid ploidy determination, serum hCG is measured weekly until the value is undetectable (< 1 or < 2). If serum hCG is undetectable within 56 days after evacuation, the patient can be discharged from follow-up after an additional four monthly measurements. If serum hCG is first normalised after 56 days, the patient is follow-up with monthly serum hCG measurement for six months. Safe contraception should be used during the follow-up period (A). If hCG stagnates (less than 10% fall over three measurements), increases, or if hCG can be demonstrated for longer than 6 months, the patient by definition has persistent trophoblastic disease (PTD). A chest X-ray should be taken and a gynaecologic ultrasound scanning performed. The patient is referred to oncologic treatment (A). Uterine re-evacuation as a treatment for PTD can, in general, not be recommended because the rate of remission is low, and there is the risk of perforation of the uterus (C). In all following pregnancies, the woman is offered an early ultrasound scan, e.g. in gestational week eight (D). Eight weeks after termination of all future pregnancies, serum hCG is measured (D). In PTD and invasive hydatidiform mole, the primary treatment is MTX, either orally every third week or IV every week (B). In MTX-resistant PTD, IV act D is added (or replaces the MTX) (B). Third line chemotherapy is BEP or EP, alternatively EMA-CO (B). Choriocarcinoma is primarily treated with chemotherapy. Hysterectomy and/or resection of metastases are possible treatments (A). Placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT) are primarily treated with hysterectomy. In the case of disseminated disease, chemotherapy is considered (A). The risk of reoccurrence after trophoblastic disease treated with chemotherapy is approximately 3%. Most reoccurrences are seen within 12 months, and for this reason monitoring of hCG is recommended for one year, the first third months once or twice a month, thereafter every second to third month. Patients with PSTT and ETT are monitored with measurement of hCG throughout their lifetimes (C). In genetically verified twin pregnancy with hydatidiform mole and a living foetus, the pregnancy can continue if serum hCG is monitored and ultrasound scans regularly performed, and possible obstetric complications dealt with (C). In the case of recurrent hydatidiform mole and/or familial hydatidiform mole, patients should be referred to genetic workup and counselling (C). Women with a hereditary disposition to hydatidiform mole because of a mutation in NLRP7 should be informed of the possibility of becoming pregnant via egg donation (C). PMID- 26522485 TI - Course and cognitive outcome in major affective disorder. AB - Knowledge of the course and outcome of major affective illness has clinical as well as theoretical implications. In understanding the pathophysiology of the major affective disorders, an essential question in the interplay between biological, psychological and social factors is whether the individual is changed biologically by experiencing an affective episode or not. A biological change may be reflected in a changed risk of experiencing new episodes and changed chances of recovery from these episodes for the individual, and may possibly also be reflected in persisting altered cognitive function as an expression of brain function affected during a longer period. Previous studies of the course of affective episodes are flawed by a number of drawbacks such as various definitions of recovery and recurrence, various kinds of bias and confounders, low statistical power, and statistical analyses conducted without survival models and without paying attention to diagnostic instability or the individual heterogeneity of the course of episodes. Totally, these drawbacks and pitfalls affect the results of previous studies in unpredictable ways and make it hazardous to draw conclusions about the effect of prior affective episodes on the subsequent course of unipolar and bipolar disorder. The present thesis avoided most of these pitfalls or adjusted for them in analyses of hospital data from the Danish Psychiatric Central Register, collected nationwide from 1971 to 1993. Hospitalisation was used as an expression of an affective episode. On average, a progressive course with increasing risk of recurrence with every new episode was found for unipolar and bipolar affective disorders. Initially, the two types of disorders followed markedly different courses, but later in the course of the illness the risk of recurrence was the same for the two disorders. However, analyses with frailty models revealed that for unipolar men, this progressive course was due to a subgroup of patients who had a great liability to recurrence from the beginning of the illness, whereas the remainder of the unipolar men did not have a progressive course of episodes. Initially in the course of affective disorders, socio-demographic variables such as gender, age at onset, and marital status and co-morbidity with alcoholism acted as risk factors for further recurrence. Later, however, particularly variables related to the previous course of illness played a role. The chances of recovery from an episode were found not to change during the course of unipolar or bipolar disorder. In contrast, a review of studies from the era before active treatment revealed that the duration of untreated episodes seemed to increase during the course of illness. Further case register studies and a clinical follow-up study by the author showed in accordance with previous studies that unipolar and bipolar affective disorders seem to be associated with increased risk of developing cognitive impairment and dementia and that the risk seems to increase with the number and the frequency of affective episodes. Overall, the thesis illustrates: 1) that case register studies can supplement prospective clinical studies in longitudinal research of major affective disorders: 2) the importance of taking the number of episodes into account in the analyses of data: 3) that affective episodes persistently increase the liability to illness for the individual, and that a cerebral component seems to bee present in some patients with major affective disorder: 4) that the treatment methods used so far seem to prevent the progression in the duration of affective episodes but not the progression in the frequency of episodes. It seems that among the existing pathophysiological models the sensitisation and kindling paradigm is the one that fits these epidemiological data best. Studies for future epidemiological research on the course of affective disorder are suggested. PMID- 26522486 TI - Clinical outcomes after elective repair for small umbilical and epigastric hernias. AB - Repair for an umbilical or epigastric hernia is one of the most frequently conducted gastrointestinal surgical procedures. Al-though it is a minor procedure, there is no consensus on the optimal repair technique. The readmission rate is surprisingly high due to postoperative pain, wound-related complications, and long-term results in terms of recurrence and chronic pain is not well investigated. The overall objective of this thesis was to improve early and long term postoperative outcomes after repair for umbilical or epigastric hernias. The present thesis consisted of one RCT, one protocol article for a running RCT, and two register-based cohort studies. An abdominal binder had no analgesic effects or impact on seroma formation. We await early and late post-operative outcomes from a running RCT studying clinical effect of closing the hernia defect (inclusion is expected to end in October 2015). The two cohort studies included in the present theses found that mesh repair halved the long-term risk of recurrence compared with sutured repair. Mesh repair did not increase the risk of chronic pain or rate of reoperation for complications. PMID- 26522487 TI - Overweight, hypertension and cardiovascular disease: focus on adipocytokines, insulin, weight changes and natriuretic peptides. AB - BACKGROUND: Hypertension is one of the leading causes of cardiovascular disease (CVD) worldwide. Overweight and obesity are major risk factors for hypertension. The mechanisms linking these two diseases are incompletely understood, but abnormalities in several different pathways including insulin and glucose metabolism, inflammation, the sympathetic nervous system and the renin angiotensin-aldosterone system have been known for decades. Lately, the attention has shifted toward the endocrine function of adipose tissue, which among others secrete adiponectin, leptin and interleukin-6 (IL-6), which stimulates liver CRP production. These substances have all been regarded as candidate intermediates between adiposity and the development of hypertension. Furthermore, the so-called "natriuretic handicap" which characterizes obesity, has also attracted a great deal of attention as a possible pathway. Primary hypotheses: * The adipocytokines, adiponectin, leptin and CRP (used as a surrogate marker of IL-6) are independently associated with prevalent and incident hypertension. * Five year weight changes associate with BP alterations, even after adjustment for changes in lifestyle risk factors and serum insulin. * NT-proBNP (used as a surrogate marker of active BNP) is positively associated with prevalent hypertension, but negatively associated with incident hypertension. * The adipocytokines, adiponectin, leptin and CRP (used as a surrogate marker of IL-6), are independently associated with incident CVD. METHODS: The Inter99 study provided data for this thesis. In brief, Inter99 is a randomized, non pharmacological intervention study for the prevention of ischemic heart disease. The study included approximately 6,700 participants from the background population, who were thoroughly examined at baseline. Various measurements, including blood samples, were done at baseline and five-year follow-up. Data about cardiovascular events were gathered from national registers. RESULTS: Paper I: In the prevalent model including leptin, CRP, adiponectin, sex, age, lifestyle risk factors, lipids, insulin, haemoglobin A1c, and in the incident model which also included baseline heart rate and blood pressure, only leptin of the three candidate intermediates was significantly associated with both prevalent and incident hypertension. Paper II: Five-year weight changes were associated with blood pressure alterations and had a substantial impact on both fasting and two-hour post-glucose serum insulin levels. However, in multivariable regression analyses, additional adjustments for insulin values only attenuated the associations between weight changes and blood pressure minimally. Paper III: Higher serum concentrations of NT-proBNP associated with prevalent hypertension whereas lower concentrations associated with incident hypertension. Paper IV: Among 6,502 participants with a mean follow-up time of 11.4 years, 527 participants experienced one or multiple cardio-vascular events. Among adiponectin, leptin and CRP, only CRP were significantly positive associated with CVD in all models. CONCLUSIONS: Regarding the pathophysiology of overweight related hypertension and CVD, our results indicate that: * Leptin is possibly an independent risk factor for the development of hypertension. * Albeit weight loss improves insulin-profile, the effect of insulin on blood pressure changes seems minimal, indicating that insulin does not play a major direct role in the early development of hypertension. * A deficiency of the natriuretic peptides, resulting in reduced vasodilation and natriuresis, could be involved in the pathogenesis of hypertension in its early stages. * Since adjustment for CRP decreased the BMI-associated CVD risk markedly, our data indirectly suggest that IL-6 originating from fat tissue could play a role in overweight and obesity related cardiovascular disease. PMID- 26522488 TI - [Spanish Journal of Geriatrics and Gerentology: What type of journal do we want?]. PMID- 26522489 TI - [Post-stroke apathy]. AB - Apathy is a motivational disturbance that can be defined as a quantitative reduction of goal-directed behaviour. Patients present with loss of motivation, concern, interest, and emotional response, resulting in a loss of initiative, decreased interaction with their environment, and a reduced interest in social life. Apathy not only appears to be common in stroke patients, but it has also been related to a wide range of negative consequences for the patients and their caregivers, including poor functional recovery, loss of social independence, and caregiver distress. Clear definition and consensus diagnostic criteria for apathy are needed to accomplish an accurate assessment and an individualised treatment plan. Although there have been reports of successful behavioural therapy treatment of apathetic states, there is a paucity of controlled clinical trials on the efficacy of apathetic behaviours using pharmacotherapy. PMID- 26522490 TI - [Effect of high impact movements on body composition, strength and bone mineral density on women over 60 years]. AB - BACKGROUND: Osteoporosis is characterised by loss of bone mass and deterioration of bone tissue microarchitecture that leads to fragility related to the risk of fractures. The aim of the study is to analyse the effects of a training program based on explosive movements and impact, assessed in a swimming pool, on body composition, explosive strength and bone mineral density in women over 60 years old. MATERIAL AND METHODS: A total of 35 healthy physically active women (60+/ 4.19 years) were divided into a training pool group using multi jumps (JG) and a control group (CG). JG trained for 24 weeks, 3 times a week, an hour and a half per session. Body composition testing, explosive strength, and bone mineral density were assessed before and after the program. RESULTS: There were differences in the explosive force (JG vs CG=P<.05 to .001) and the estimated power (JG vs CG=P<.05 to .002) between JG vs CG, with significant increases in JG. There were no significant differences in the percentage of fat and lean mass, bone mineral density lumbar and femoral between groups, although slightly significant increases in bone mineral density lumbar and femoral could be seen in JG after program implementation (JG pre-test vs JG post- test=P<.05). CONCLUSIONS: The training program with impact and explosive movements assessed in a pool induces gains in muscle strength and power with slight adaptations in body mass index in women over 60 years. PMID- 26522491 TI - Implementation of NHS Health Checks in general practice: variation in delivery between practices and practitioners. AB - Aim To evaluate NHS Health Check implementation in terms of frequency of data recording, advice provided, referrals to community-based lifestyle support services, statin prescribing and new diagnoses, and to assess variation in these aspects between practices and health professionals involved in delivery. BACKGROUND: Most NHS Health Checks are delivered by general practices, but little detail is known about the extent of variation in how they are delivered in different practices and by different health professionals. METHODS: This was an observational study conducted in a purposively selected sample of 13 practices in Sefton, North West England. Practices used previously recorded information from their clinical management systems to identify patients with cardiovascular disease (CVD) risk ?20%, a potentially cost-effective approach. The evaluation was conducted during the first year of delivery in Sefton. Data were extracted from medical records of all patients identified, regardless of Health Check attendance. Findings Of the 2892 patients identified by the 13 practices, 1070 had received an NHS Health Check at the time of the study. Of these, only 936 (87.5%) had a recorded CVD risk score, with risk ?20% confirmed in 92.0%. Estimated risk category was correct in 456/677 (67.4%) of patients with estimated and actual risk scores. Significant variation was found between practices and health professionals in parameters recorded, tests requested, advice given and referrals for lifestyle support. Only 45.3% of patients had body mass index, smoking, alcohol, exercise, blood pressure and cholesterol all recorded. Lifestyle advice and referral into lifestyle services were documented in 80.6% and 6.4% of attenders, respectively, again with significant variation between practices and professionals. Statin prescribing rose in attenders from 19.6% to 34.6%. A similar proportion of attenders and non-attenders received new diagnoses. CONCLUSION: Effort is required to reduce variation in how practices deliver and follow-up NHS Health Checks, to ensure the consistency of the programme. PMID- 26522492 TI - The effects of a mid-morning snack and moderate-intensity exercise on acute appetite and energy intake in 12-14-year-old adolescents. AB - Energy intake (EI) and energy expenditure (EE) should not be considered independent entities, but more an inter-connected system. With increased physical activity and reduced snacking initiatives as prevalent Public Health measures, any changes to subsequent EI from these recommendations should be monitored. The aim of this study was to investigate changes in acute EI and appetite over four conditions: (1) a control condition with no snack and no exercise (CON); (2) a snack condition (+1 MJ; SK); (3) a moderate-intensity cycling exercise condition (-1 MJ; EX); and finally (4) both snack and exercise condition (+1 MJ, -1 MJ; EXSK). Acute changes in appetite (visual analogue scale) and lunchtime EI (ad libitum pizza meal) were recorded in twenty boys and eighteen girls (12-13 years). Lunch EI was not significantly different between conditions or sexes (P>0.05). Relative EI was calculated, where the energy manipulation (+1 MJ from the snack or -1 MJ from the exercise) was added to lunchtime EI. Relative EI indicated no significant differences between the sexes (P>0.05); however, in the EX condition, relative EI was significantly lower (P<0.001) compared with all other conditions. Appetite increased significantly over time (P<0.001) and was significantly higher in the CON and EX conditions compared with the SK and EXSK conditions. No significant sex differences were found between conditions. When aiming to evoke an acute energy deficit, increasing EE created a significantly larger relative energy deficit than the removal of the mid-morning snack. Sex was not a confounder to influence EI or appetite between any of the conditions. PMID- 26522493 TI - Quantum-electrodynamical birefringence vanishing in a thermal relativistic pair plasma. AB - Quantum electrodynamical (QED) birefringence in a thermal relativistic pair plasma with the presence of the strong crossed field: E0 ? B0, is proposed and investigated. We clarify the coupling relationship and competition between the QED effect and the plasma collective effect and find the critical condition that makes the birefringence vanish. In a relative weak electromagnetic field, the birefringence is dominated by the coupling of the QED-effect, the collective effect and the E0 * B0 drift effect. In a relative strong electromagnetic field, we obtain the formulations stating the competition between the QED effect and the collective effect and then the critical conditions so that they are canceled with each other and the birefringence vanishes. With our results, a new possible scheme is proposed to estimate the thickness of the magnetosphere in a millisecond pulsar and the plasma density of a pulsar, if the magnetic field is known beforehand. PMID- 26522494 TI - Two seconds is all it takes: European starlings (Sturnus vulgaris) increase levels of circulating glucocorticoids after witnessing a brief raptor attack. AB - Researchers typically study "acute" activation of the hypothalamic-pituitary adrenal (HPA) axis by measuring levels of circulating glucocorticoids in animals that have been exposed to a predator or a cue from a predator (e.g., odor), or have experienced a standardized capture-and-restraint protocol, all of which are many minutes in duration. However, exposure to predators in the "wild", either as the subject of an attack or as a witness to an attack, is generally much shorter as most depredation attempts upon free-living animals last <5s. Yet, whether a stimulus lasting only seconds can activate the HPA axis is unknown. To determine if a stimulus of a few seconds triggers a glucocorticoid response, we measured levels of corticosterone (CORT; the primary avian glucocorticoid) in wild-caught European starlings (Sturnus vulgaris) after they witnessed a brief (<2-8s) raptor attack upon a conspecific, a human "attack" (i.e., a researcher handling a conspecific), and an undisturbed control. Witnesses of a raptor attack responded with CORT levels comparable to that induced by a standardized capture-and restraint protocol. Glucocorticoid levels of individuals following the control treatment were similar to baseline levels, and those that witnessed a human "attack" had intermediate levels. Our results demonstrate that witnessing a predator attack of very brief duration triggers a profound adrenocortical stress response. Given the considerable evidence of a role for glucocorticoids in learning and memory, such a response may affect how individuals learn to recognize and appropriately react to predators. PMID- 26522495 TI - The feeding responses evoked by endogenous cholecystokinin are regulated by different gastrointestinal sites. AB - The current study tested the hypothesis that cholecystokinin (CCK) A receptor (CCKAR) in areas supplied by the celiac artery (CA), stomach and upper duodenum, and the cranial mesenteric artery (CMA), small and parts of the large intestine, is necessary for reduction of meal size, prolongation of the intermeal interval (time between first and second meal) and increased satiety ratio (intermeal interval/meal size or amount of food consumed during any given unit of time) by the non-nutrient stimulator of endogenous CCK release camostat. Consistent with our previous findings camostat reduced meal size, prolonged the intermeal interval and increased the satiety ratio. Here, we report that blocking CCKAR in the area supplied by the celiac artery attenuated reduction of meal size by camostat more so than the cranial mesenteric artery route. Blocking CCKAR in the area supplied by the cranial mesenteric artery attenuated prolongation of the intermeal interval length and increased satiety ratio by camostat more so than the celiac artery route. Blocking CCKAR in the areas supplied by the femoral artery (control) failed to alter the feeding responses evoked by camostat. These results support the hypothesis that CCKAR in the area supplied by the CA is necessary for reduction of meal size by camostat whereas CCKAR in the area supplied by the CMA is necessary for prolongation of the intermeal interval and increased satiety ratio by this substance. Our results demonstrate that meal size and intermeal interval length by camostat are regulated through different gastrointestinal sites. PMID- 26522496 TI - The contribution of the androgen receptor (AR) in human spatial learning and memory: A study in women with complete androgen insensitivity syndrome (CAIS). AB - Few studies have examined the impact of androgen insensitivity on human spatial learning and memory. In the present study, we tested 11 women with complete androgen insensitivity syndrome (CAIS), a rare genetic disorder characterized by complete absence of AR activity, and compared their performance against 20 comparison males and 19 comparison females on a virtual analog of the Morris Water Maze task. The results replicated a main sex effect showing that men relative to women were faster in finding the hidden platform and had reduced heading error. Furthermore, findings indicated that mean performance of women with CAIS was between control women and control men, though the differences were not statistically significant. Effect size estimates (and corresponding confidence intervals) of spatial learning trials showed little difference between women with CAIS and control women but CAIS women differed from men, but not women, on two variables, latency to find the platform and first-move latency. No differences between groups were present during visible platform trials or the probe trial, a measure of spatial memory. Moreover, groups also did not differ on estimates of IQ and variability of performance. The findings are discussed in relation to androgen insensitivity in human spatial learning and memory. PMID- 26522497 TI - The use of calorimetry in the biophysical characterization of small molecule alkaloids binding to RNA structures. AB - BACKGROUND: RNA has now emerged as a potential target for therapeutic intervention. RNA targeted drug design requires detailed thermodynamic characterization that provides new insights into the interactions and this together with structural data, may be used in rational drug design. The use of calorimetry to characterize small molecule-RNA interactions has emerged as a reliable and sensitive tool after the recent advancements in biocalorimetry. SCOPE OF THE REVIEW: This review summarizes the recent advancements in thermodynamic characterization of small molecules, particularly some natural alkaloids binding to various RNA structures. Thermodynamic characterization provides information that can supplement structural data leading to more effective drug development protocols. MAJOR CONCLUSIONS: This review provides a concise report on the use of isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC) techniques in characterizing small molecules, mostly alkaloids-RNA interactions with particular reference to binding of tRNA, single stranded RNA, double stranded RNA, poly(A), triplex RNA. GENERAL SIGNIFICANCE: It is now apparent that a combination of structural and thermodynamic data is essential for rational design of specific RNA targeted drugs. Recent advancements in biocalorimetry instrumentation have led to detailed understanding of the thermodynamics of small molecules binding to various RNA structures paving the path for the development of many new natural and synthetic molecules as specific binders to various RNA structures. RNA targeted drug design, that remained unexplored, will immensely benefit from the calorimetric studies leading to the development of effective drugs for many diseases. PMID- 26522498 TI - Brief reminiscence activities improve state well-being and self-concept in young adults: a randomised controlled experiment. AB - Reminiscence-based psychotherapies have been demonstrated to have robust effects on a range of therapeutic outcomes. However, little research has been conducted on the immediate effects of guided activities they are composed of, or how these might differ dependent on the type of reminiscence. The current study utilised a controlled experimental design, whereby 321 young adults (mean age = 25.5 years, SD = 3.0) were randomised to one of four conditions of online reminiscence activity: problem-solving (successful coping experiences), identity (self defining events contributing to a meaningful and continuous personal identity), bitterness revival (negative or adverse events), or a control condition (any memory from their past). Participants recalled autobiographical memories congruent with the condition, and answered questions to facilitate reflection on the memories. The results indicated that problem-solving and identity reminiscence activities caused significant improvements in self-esteem, meaning in life, self-efficacy and affect, whereas no effects were found in the bitterness revival and control conditions. Problem-solving reminiscence also caused a small effect in increasing perceptions of a life narrative/s. Differences between the conditions did not appear to be explained by the positive valence of memories. These results provide evidence for the specific effects of adaptive types of problem-solving and identity reminiscence in young adults. PMID- 26522499 TI - AIR: Advances in Respiration - Music therapy in the treatment of chronic pulmonary disease. AB - The aim of this randomized control study is to examine the effect of a multimodal psycho-music therapy intervention on respiratory symptoms, psychological well being and quality of life of patients with Chronic Obstructive Pulmonary Disease and other lung diseases as adjunct to Pulmonary Rehabilitation with a design of music therapy plus PR compared to Pulmonary Rehabilitation alone. Music therapy group treatment including music visualization, wind playing and singing was provided weekly. This was compared with standard care treatment. Adults ages 48 to 88 (mean 70.1) with moderate to severe GOLD stage II-IV lung disease as well as other diseases processes that lead to chronic airflow limitations were included (n = 98). Participants in both conditions were followed from baseline enrollment to six weeks post control/treatment. Outcome measures included the Beck Depression Inventory Scale 2nd edition-Fast Screen (BDI-FS), Chronic Respiratory Questionnaire Self-Reported (CRQ-SR), and Dyspnea Visual Analog Scale (VAS). Results showed improvement in symptoms of depression (LS mean -0.2) in the music therapy group with statistical divergence between groups (p = 0.007). The CRQ-SR demonstrated improvement in dyspnea (p = 0.01 LS mean 0.5) and mastery (p = 0.06 LS mean 0.5) in the music therapy group and fatigue (p = 0.01 LS mean 0.3). VAS demonstrated highly significant effect in the music therapy group between weeks 5 and 6 (p < 0.001). The findings of this study suggest that music therapy combined with standard PR may prove to be an effective modality in the management of pulmonary disease. PMID- 26522500 TI - Retrobulbar pigmented peripheral nerve sheath tumor in a dog. AB - A 1-year-old male castrated Pug was referred for unilateral exophthalmos unresponsive to oral antibiotic and anti-inflammatory therapy. Clinical findings included exophthalmos of the left eye with lateral strabismus, resistance to retropulsion, and an elevated nictitans. Hematologic and biochemical analyses were within normal limits. Findings following computed tomography (CT) of the head included an expansile retrobulbar soft tissue mass with bony lysis extending into the left nasal cavity and nasopharynx. Ultrasound-guided fine-needle aspirates and biopsy samples obtained via rhinoscopy were nondiagnostic. Palliative exenteration was elected; the patient was euthanized 13 weeks following exenteration due to development of neurologic signs and perceived poor quality of life. The histopathologic diagnosis was a malignant pigmented peripheral nerve sheath tumor. PMID- 26522501 TI - Tracing sources of Listeria contamination in traditional Italian cheese associated with a US outbreak: investigations in Italy. AB - In 2012 a US multistate outbreak of listeriosis was linked to ricotta salata imported from Italy, made from pasteurized sheep's milk. Sampling activities were conducted in Italy to trace the source of Listeria monocytogenes contamination. The cheese that caused the outbreak was produced in a plant in Apulia that processed semi-finished cheeses supplied by five plants in Sardinia. During an 'emergency sampling', 179 (23.6%) out of 758 end-products tested positive for L. monocytogenes, with concentrations from <10 c.f.u./g to 1.1 * 106 c.f.u./g. Positive processing environment samples were found in two out of four processing plants. A 'follow-up sampling' was conducted 8 months later, when environmental samples from three out of six plants tested positive for L. monocytogenes and for Listeria spp. PFGE subtyping showed 100% similarity between US clinical strains and isolates from ricotta salata, confirming the origin of the outbreak. The persistence of strains in environmental niches of processing plants was demonstrated, and is probably the cause of product contamination. Two PFGE profiles from clinical cases of listeriosis in Italy in 2011, stored in the MSS TESSy database, were found to have 100% similarity to one PFGE profile from a US clinical case associated with the consumption of ricotta salata, according to the US epidemiological investigation (sample C, pulsotype 17). However, they had 87% similarity to the only PFGE profile found both in the US clinical case and in 14 ricotta cheese samples collected during the emergency sampling (sample B, pulsotype 1). Sharing of molecular data and availability of common characterization protocols were key elements that connected the detection of the US outbreak to the investigation of the food source in Italy. Simultaneous surveillance systems at both food and human levels are a necessity for the efficient rapid discovery of the source of an outbreak of L. monocytogenes. PMID- 26522503 TI - Emergency laparoscopy: Role and implementation. AB - Laparoscopic surgery has emerged over the past two decades as the surgical approach of choice in the treatment of many digestive disorders. Laparoscopy has its place in the management of abdominal surgical emergencies since it provides the same benefits: less postoperative pain and shorter length of hospital stay when compared to laparotomy. However, its role in the management of abdominal emergencies has not yet been fully clarified. In this review, we focus on what has been validated concerning the role of emergency laparoscopy in the management of abdominal diseases. PMID- 26522504 TI - Can abdominal surgical emergencies be treated in an ambulatory setting? AB - INTRODUCTION: The performance of emergency abdominal surgery in an outpatient setting is increasingly the order of the day in France. This review evaluates the feasibility and reliability of ambulatory surgical treatment of the most common abdominal emergencies: appendectomy for acute appendicitis and cholecystectomy for acute complications of gallstone disease (acute cholecystitis and gallstone pancreatitis). METHODS: This study evaluates surgical procedures performed on an ambulatory basis according to the international definition (admission in the morning, discharge in the evening with a hospital stay of less than 12 hours). Just as for elective surgery, eligibility of patients for an ambulatory approach depends on the capacities of the surgical and anesthesia team: to manage the risks, particularly the risk of deferring surgery until the morning); to prevent or treat post-operative symptoms like pain, nausea, vomiting, re-ambulation in order to permit rapid post-operative discharge. RESULTS: Recent studies have shown that appendectomy for non-complicated acute appendicitis can be deferred for up to 12 hours without any increase in danger. Many other studies have shown that early discharge after appendectomy for acute non-complicated appendicitis is feasible and safe. Nonetheless, there is only one published series of truly ambulatory appendectomies. The results were excellent. Patients who presented in the afternoon were brought back for operation the following morning. The appropriate timing for performance of cholecystectomy in patients with acute calculous cholecystitis or gallstone pancreatitis has not been well defined, but is always somewhat delayed relative to the onset of symptoms. To minimize operative complications, cholecystectomy for acute calculous cholecystitis should probably be performed between 24 and 72 hours after diagnosis. Cholecystectomy for gallstone pancreatitis should probably not be delayed longer than a week; the need to keep the patient hospitalized during the interval has not been demonstrated. Early discharge after cholecystectomy was usually possible, even in series where acute cholecystitis was diagnosed intra-operatively. Cholecystectomy for acute cholecystitis and gallstone pancreatitis seems to be feasible but no reports specifically support this approach. CONCLUSIONS: Emergency abdominal surgery seems to be feasible on an ambulatory setting for non-complicated acute appendicitis, acute calculous cholecystitis and gallstone pancreatitis. Only a single French series on ambulatory appendectomy for acute appendicitis has been reported. PMID- 26522502 TI - Promoting multi-micronutrient powders (MNP) in Peru: acceptance by caregivers and role of health personnel. AB - Iron deficiency causes anaemia and other adverse effects on the nutritional status and development of millions of children. Multi-micronutrient powders (MNP) have been shown to reduce anaemia in young children. In Peru, 50% of children 6 36 months are anaemic. Since 2009, the government has started distributing MNP. This qualitative study explored the acceptability of MNP by caregivers and the role of health personnel (HP) in three regions (Apurimac, Ayacucho and Cajamarca), piloting the MNP programme between 2009 and 2011. Data collection consisted of interviews (35) and observations (13) with caregivers and HP (11). In Cajamarca, 16 families were visited three times in their homes to understand caregivers' use and difficulties. Results showed the critical role HP has in influencing caregiver understanding and use of the MNP, as well as the need for training to avoid confusing messages and provide counselling techniques that consider cultural sensitivity to optimize HP interactions with caregivers and adapt the recommendations for MNP use to local family feeding routines. There was greater acceptance of MNP by caregivers giving semi-solid foods (e.g. purees) to their children than those who served dilute preparations (e.g. soups). Acceptance was similar across regions, but there were some differences between urban and rural settings. Home visits were shown to be a key in improving the use of MNP by caregivers as misunderstandings on preparation, required consistency and optimum practices were common. These findings can contribute to strategies to enhance acceptability and use. KEY MESSAGES: Acceptance and use of multi-micronutrient powders (MNP) by caregivers greatly depend upon how it is presented, promoted and counselled by health personnel. Counselling for MNP use needs to consider and adapt to the local cultural context and incorporate family and child feeding routines. MNP are presented as part of appropriate feeding practices, encouraging caregivers to find simple and acceptable ways of giving semi-solid or solid foods with which to mix it. PMID- 26522505 TI - Emergency gastrointestinal surgery in the elderly. AB - The main problem in management of elderly patients who present to the emergency department with abdominal pain is related to difficulties in establishing a diagnosis, because of frequently impaired communication as well as to unusual clinical and laboratory presentations, resulting in delayed management. Early use of pertinent imaging may reduce this delay. Surgical procedures in the elderly do not differ from those in younger patients, but their associated morbidity is different. Assessing co-morbidities and patient frailty, as well as taking into consideration the diagnosis, patients' wishes and status should help in decision making. Therapeutic decisions should involve surgeons, anesthesiologists and geriatricians alike, both pre- and postoperatively, with the goal of optimizing patients' rehabilitation and offering good and appropriate care while ensuring the humane, social and financial aspects. PMID- 26522506 TI - Percutaneous transgluteal drainage of pelvic abscesses in interventional radiology: A safe alternative to surgery. AB - AIM: Interventional radiology plays an important role in the management of deep pelvic abscesses. Percutaneous drainage is currently considered as the first-line alternative to surgery. A transgluteal computed tomography (CT)-guided approach allows to access to deep infected collections avoiding many anatomical obstacles (vessels, nerves, bowel, bladder). The objective of this study was to assess the safety and efficacy of a transgluteal approach by reviewing our clinical experience. MATERIALS AND METHOD: We reviewed medical records of patients having undergone percutaneous CT-guided transgluteal drainage for deep pelvic abscesses. We focused on the duration of catheter drainage, the complications related to the procedures and the rate of complete resolution. RESULTS: Between 2005 and 2013, 39patients (27women and 12men; mean age: 52.5) underwent transgluteal approach CT guided percutaneous drainage of pelvis abscesses in our department. The origins of abscesses were postoperative complications in 34patients (87.2%) and infectious intra-abdominal disease in 5patients (12.8%). The mean duration of drainage was 8.3days (range: 3-33). Laboratory cultures were positive in 35patients (89.7%) and Escherichia coli was present in 71.4% of the positive samples. No major complication was observed. Drainage was successful in 38patients (97.4%). A transpiriformis approach was more significantly associated with intra-procedural pain (P=0.003). CONCLUSION: Percutaneous CT-guided drainage with a transgluteal approach is a safe, well-tolerated and effective alternative to surgery for deep pelvic abscesses. This approach should be considered as the first-line intention for the treatment of deep pelvic abscesses. PMID- 26522507 TI - Impaired female fertility in tubulointerstitial antigen-like 1-deficient mice. AB - Tubulointerstitial nephritis antigen-like 1 (Tinagl1, also known as adrenocortical zonation factor 1 [AZ-1] or lipocalin 7) is a matricellular protein. Previously, we demonstrated that Tinagl1 expression was restricted to extraembryonic regions during the postimplantation period and detected marked expression in mouse Reichert's membranes. In uteri, Tinagl1 is markedly expressed in the decidual endometrium during the postimplantation period, suggesting that it plays a physical and physiological role in embryo development and/or decidualization of the uterine endometrium during pregnancy. In the present study, in order to determine the role of Tinagl1 during embryonic development and pregnancy, we generated Tinagl1-deficient mice. Although Tinagl1(-/-) embryos were not lethal during development to term, homologous matings of Tinagl1(-/-) females and Tinagl1(-/-) males showed impaired fertility during pregnancy, including failure to carry pregnancy to term and perinatal lethality. To examine ovarian function, ovulation was induced with equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG); the number of ovulated oocytes did not differ between Tinagl1(-/-) and Tinagl1(flox/flox). In vitro fertilization followed by embryo culture also demonstrated the normal developmental potential of Tinagl1-null embryos during the preimplantation period. Our results demonstrate that Tinagl1 deficiency affects female mice and results in subfertility phenotypes, and they suggest that although the potential of Tinagl1( /-) oocytes is normal, Tinagl1 is related to fertility in adult females but is not essential for either fertilization or preimplantation development in vitro. PMID- 26522508 TI - Explicit and implicit tasks for assessing hedonic-versus nutrition-based attitudes towards food in French children. AB - Attitudes are important precursors of behaviours. This study aims to compare the food attitudes (i.e., hedonic- and nutrition-based) of children using both an implicit pairing task and an explicit forced-choice categorization task suitable for the cognitive abilities of 5- to 11-year-olds. A dominance of hedonically driven attitudes was expected for all ages in the pairing task, designed to elicit affective and spontaneous answers, whereas a progressive emergence of nutrition-based attitudes was expected in the categorization task, designed to involve deliberate analyses of the costs/benefits of foods. An additional exploratory goal was to evaluate differences in the attitudes of normal and overweight children in both tasks. Children from 3 school levels (n = 194; mean age = 8.03 years) were individually tested on computers in their schools. They performed a pairing task in which the tendencies to associate foods with nutritional vs. culinary contexts were assessed. Next, they were asked to categorize each food into one of the following four categories: "yummy", "yucky" (i.e., hedonic categories), "makes you strong", or"makes you fat" (i.e., nutritional categories). The hedonic/culinary pairs were very frequently selected (81% on average), and this frequency significantly increased through school levels. In contrast, in the categorization task, a significant increase in nutrition-driven categorizations with school level was observed. Additional analyses revealed no differences in the food attitudes between the normal and overweight children in the pairing task, and a tendency towards lower hedonic categorizations among the overweight children. Culinary associations can reflect cultural learning in the French context where food pleasure is dominant. In contrast, the progressive emergence of cognitively driven attitudes with age may reflect the cognitive development of children who are more reasonable and influenced by social norms. PMID- 26522510 TI - Differences in surrogate threshold effect estimates between original and simplified correlation-based validation approaches. AB - Surrogate endpoint validation has been well established by the meta-analytical correlation-based approach as outlined in the seminal work of Buyse et al. (Biostatistics, 2000). Surrogacy can be assumed if strong associations on individual and study levels can be demonstrated. Alternatively, if an effect on a true endpoint is to be predicted from a surrogate endpoint in a new study, the surrogate threshold effect (STE, Burzykowski and Buyse, Pharmaceutical Statistics, 2006) can be used. In practice, as individual patient data (IPD) are hard to obtain, some authors use only aggregate data and perform simplified regression analyses. We are interested in to what extent such simplified analyses are biased compared with the ones from a full model with IPD. To this end, we conduct a simulation study with IPD and compute STEs from full and simplified analyses for varying data situations in terms of number of studies, correlations, variances and so on. In the scenarios considered, we show that, for normally distributed patient data, STEs derived from ordinary (weighted) linear regression generally underestimate STEs derived from the original model, whereas meta regression often results in overestimation. Therefore, if individual data cannot be obtained, STEs from meta-regression may be used as conservative alternatives, but ordinary (weighted) linear regression should not be used for surrogate endpoint validation. PMID- 26522509 TI - Slowing down and taking a second look: Inhibitory deficits associated with binge eating are not food-specific. AB - Poor inhibitory control may contribute to the maintenance of binge eating (BE) among overweight and obese individuals. However, it is unknown whether deficits are general or specific to food (versus other attractive non-food stimuli), or whether observed deficits are attributable to increased depressive symptoms in BE groups. In the current study, we hypothesized that individuals with BE would display inhibitory control deficits, with more pronounced deficits occurring when food stimuli were used. Overweight or obese participants with (n = 25) and without (n = 65) BE completed a Stop Signal Task (SST) with distinct task blocks featuring food-specific stimuli, positive non-food stimuli, or neutral stimuli. The BE group exhibited poorer inhibitory control across SST stimuli types (p = .003, etap(2)=.10), but deficits did not differ by stimuli type (p = .68, etap(2) < .01). Including depression as a covariate did not significantly alter results. Results suggest individuals with BE display inhibitory control deficits compared to controls; however, deficits do not appear to be specific to stimuli type. Furthermore, inhibitory control deficits do not appear to be associated with mood disturbance in the BE group. Replication and further research is needed to guide treatment targets. PMID- 26522511 TI - Inferior PFC Subregions Have Broad Cognitive Roles. PMID- 26522512 TI - Fluoxetine regulates mTOR signalling in a region-dependent manner in depression like mice. AB - Previous studies have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway has an important role in ketamine-induced, rapid antidepressant effects despite the acute administration of fluoxetine not affecting mTOR phosphorylation in the brain. However, the effects of long-term fluoxetine treatment on mTOR modulation have not been assessed to date. In the present study, we examined whether fluoxetine, a type of commonly used antidepressant agent, alters mTOR signaling following chronic administration in different brain regions, including the frontal cortex, hippocampus, amygdala and hypothalamus. We also investigated whether fluoxetine enhanced synaptic protein levels in these regions via the activation of the mTOR signaling pathway and its downstream regulators, p70S6K and 4E-BP-1. The results indicated that chronic fluoxetine treatment attenuated the chronic, unpredictable, mild stress (CUMS)-induced mTOR phosphorylation reduction in the hippocampus and amygdala of mice but not in the frontal cortex or the hypothalamus. Moreover, the CUMS-decreased PSD-95 and synapsin I levels were reversed by fluoxetine, and these effects were blocked by rapamycin only in the hippocampus. In conclusion, our findings suggest that chronic treatment with fluoxetine can induce synaptic protein expression by activating the mTOR signaling pathway in a region-dependent manner and mainly in the hippocampus. PMID- 26522514 TI - 50th Anniversary Perspective on Volume 1: Morgan AD, Krovetz LJ, Schiebler GL, et al. Diagnosis and Palliative Surgery in Complete Transposition of the Great Vessels. Ann Thorac Surg 1965:1;711-22: Getting to the Switch: Perspectives of Pioneers. PMID- 26522513 TI - IL-10-producing CD4(+) T cells negatively regulate fucosylation of epithelial cells in the gut. AB - Fucosylated glycans on the surface of epithelial cells (ECs) regulate intestinal homeostasis by serving as attachment receptors and a nutrient source for some species of bacteria. We show here that epithelial fucosylation in the ileum is negatively regulated by IL-10-producing CD4(+) T cells. The number of fucosylated ECs was increased in the ileum of mice lacking T cells, especially those expressing alphabeta T cell receptor (TCR), CD4, and IL-10. No such effect was observed in mice lacking B cells. Adoptive transfer of alphabetaTCR(+) CD4(+) T cells from normal mice, but not IL-10-deficient mice, normalized fucosylation of ECs. These findings suggest that IL-10-producing CD4(+) T cells contribute to the maintenance of the function of ECs by regulating their fucosylation. PMID- 26522516 TI - 50th Anniversary Landmark Commentary on David TE, Bos J, Christakis GT, Brofman PR, Wong D, Feindel CM. Heart Valve Operations in Patients With Active Infective Endocarditis. Ann Thorac Surg 1990;49:701-5. PMID- 26522515 TI - 50th Anniversary Landmark Commentary on Orringer MB, Forastiere AA, Perez-Tamayo C, Urba S, Takasugi BJ, Bromberg J. Chemotherapy and Radiation Therapy Before Transhiatal Esophagectomy for Esophageal Carcinoma. Ann Thorac Surg 1990;49:348 55. PMID- 26522517 TI - 50th Anniversary Landmark Commentary on Cox JL, Boineau JP, Schuessler RB, Kater KM, Lappas DG. Five-Year Experience With the Maze Procedure for Atrial Fibrillation. Ann Thorac Surg 1993;56:814-24. PMID- 26522518 TI - A Multidisciplinary Approach to Ensure Scientific Integrity in Clinical Research. PMID- 26522519 TI - An Ecological View of Research Misconduct. PMID- 26522520 TI - How Expensive Is Sustained Moral Commitment? PMID- 26522521 TI - Addressing Scientific Integrity Through Education in the Responsible Conduct of Research. PMID- 26522522 TI - Open Data: Can It Prevent Research Fraud, Promote Reproducibility, and Enable Big Data Analytics In Clinical Research? PMID- 26522523 TI - Invited Commentary. PMID- 26522524 TI - Invited Commentary. PMID- 26522525 TI - Invited Commentary. PMID- 26522526 TI - Invited Commentary. PMID- 26522527 TI - Invited Commentary. PMID- 26522528 TI - Rare Cause of Recurrent Pneumonia in the Left Lower Lobe. AB - A 52-year-old male patient was hospitalized in our department with the diagnosis of recurrent pneumonia in the left lower lobe. The patient reported possible aspiration of plastic material about 10 years ago, although repeated bronchoscopies in an external hospital had not revealed any foreign body. A multiply folded 8-cm filing strip for a ring folder was detected and successfully removed together with granulation tissue by means of rigid bronchoscopy. PMID- 26522529 TI - Successful Singleton and Twin Pregnancies With the Nuss Bars in Place. AB - Pectus excavatum (PE) occurs less commonly in women, and the implications on a pregnancy after repair during the period when support bars are in place are unknown. We present 2 cases: 1 with a successful twin gestation and another with a successful singleton gestation. These women carried the pregnancies to term and delivered their infants with the Nuss bars in place. PMID- 26522530 TI - Percutaneous Sclerotherapy With OK-432 of a Cervicomediastinal Lymphangioma. AB - The present study reports a case of percutaneous sclerotherapy of a giant cystic cervicomediastinal lymphangioma using OK-432. To the best of our knowledge, percutaneous sclerotherapy of a mediastinal lymphangioma using OK 432 has not previously been reported in the English literature. PMID- 26522531 TI - Severe Mediastinitis and Pericarditis After Transbronchial Needle Aspiration. AB - Endobronchial ultrasonographically guided transbronchial needle aspiration (EBUS TBNA) is now widely performed for mediastinal lymph node staging of lung cancer. Although this procedure is less invasive than mediastinoscopy, some infectious complications have been reported. We report the successful use of pericardial and mediastinal drainage in a case of acute severe mediastinitis with pericarditis after EBUS-TBNA. PMID- 26522532 TI - Transapical Thoracic Endovascular Aortic Repair as a Bridge to Open Repair of an Infected Ascending Aortic Pseudoaneurysm. AB - Pseudoaneurysms of the ascending aorta pose a significant risk for free rupture during open aortic repair. This report describes the use of a modified thoracic aortic stent graft, delivered through transapical access, as a successful bridge to homograft replacement of the ascending aorta for the treatment of a mycotic ascending aortic pseudoaneurysm. PMID- 26522533 TI - Ventricular Tachycardia Rotating a Scar of a Total Right Ventricular Exclusion. AB - We describe a 15-year-old postoperative girl who underwent surgical 3-dimensional mapping and ablation of hemodynamically unstable ventricular tachycardia (VT) with an on-pump beating heart surgical technique. She had previously received a tricuspid valve closure, entire right ventricular free wall resection, and finally Fontan operation with an extracardiac conduit to treat a severe Ebstein's anomaly. Activation mapping revealed a VT rotating around a large right ventricular free wall incisional scar with a narrow conduction channel between the scar and a tricuspid annulus (TA). A linear radiofrequency ablation connecting the scar and the TA terminated the VT. PMID- 26522534 TI - Hybrid Repair of an Aortic Arch Aneurysm Using Double Parallel Grafts Perfused by Retrograde Flow in Endovascular Repair Combined With Left Subclavian Artery Surgical Bypass. AB - Despite its invasive nature, open surgical repair is still the first choice to treat aortic arch aneurysms. With the advancement of endovascular technology, thoracic endovascular aortic repair (TEVAR) has gained popularity in treating aortic aneurysms; however, blood flow preservation of the supra-arch branches remains a complicated challenge. This case report describes a hybrid procedure that successfully treated a patient with aortic arch aneurysm by combining the parallel grafts perfused by retrograde flow in the TEVAR procedure and a carotid subclavian artery bypass. PMID- 26522535 TI - A New Surgical Repair Technique for Ischemic Total Papillary Muscle Rupture. AB - Papillary muscle (PM) rupture is an emergency surgical condition that may occur after acute myocardial infarction. In patients with compete rupture of the PM, mitral valve replacement is preferred or recommended generally because of unstable vital signs or technical difficulties with successful repair, as compared with patients with partial PM rupture. This case report describes the successful repair of a complete anterolateral PM rupture by using the single PM formation technique with subsequent ring annuloplasty. PMID- 26522536 TI - Extensive Surgical Treatment of Primary Pulmonary Synovial Sarcoma After Recurrent Pneumothorax. AB - A 26-year-old woman with a history of right-sided recurrent pneumothorax and resection of pulmonary bullae, pleural abrasion, and talc pleurodesis underwent right-sided extensive pleural pneumonectomy for a monophasic primary pleural pulmonary synovial sarcoma (PPSS). The pathologic diagnosis was predominantly fusiform PPSS with R0 resection. Sixteen months after the operation, she is alive, without signs of new lesions. The extensive tumor resection can achieve a good result for controlling local disease. PMID- 26522537 TI - Asymptomatic Regional Thinning of Left Ventricle After Mitral Valve Replacement. AB - We report the successful repair of a rare case of regional thinning of the left ventricle after mitral valve replacement. An 80-year-old woman underwent prosthetic mitral valve replacement for mitral valve stenosis. Her postoperative course was uneventful; however, regional thinning of the left ventricular wall was detected on transthoracic echocardiography on postoperative day 7. We repaired the thinned area with a patch by using the felt sandwich technique. Postoperative echocardiography and computed tomography showed a successfully repaired left ventricular wall. PMID- 26522538 TI - Thoracoscopic Resection of Multiple Mullerian Cysts. AB - Mullerian cysts in the mediastinum were first described by Hattori in 2005 [1]. We report the first known case of multiple mullerian cysts in the thorax in a 35 year-old woman with cough and an abnormal chest roentgenogram. Multiple bilateral cysts were resected thoracoscopically. Histologic examination showed benign ciliated tubal epithelium that stained positive with immunohistochemical stains for estrogen receptor (ER), cancer antigen 125 (CA-125), Wilms' tumor protein 1 (WT-1), and paired box gene 8 (PAX8), confirming mullerian origin. We also review the embryogenesis and pathologic characteristics of mullerian cysts and the rare occurrence of their migration to the thorax. PMID- 26522539 TI - Simple and Useful Method to Minimize Tracheal Compression Resulting From Concave Sternum During Congenital Heart Surgery. AB - A 12-month-old boy weighing 5.2 kg underwent surgical repair for a ventricular septal defect (VSD) combined with airway obstruction resulting from pectus excavatum. His right atrium and left main bronchus were extremely compressed by the sternum. To repair the VSD, we performed a sternal closure for pectus excavatum that used a mesh-shaped bioresorbable device (Super Fixsorb MX40; Takiron Co, Ltd, Osaka, Japan) made of hydroxyapatite/poly-L-lactide composites. After the operation, the cardiac and tracheal compression caused by the sternum was alleviated. PMID- 26522540 TI - Good's Syndrome: Successful Management of Thymoma With Hypoimmunoglobulinemia. AB - We report a case of Good's syndrome managed with surgery and immunotherapy in a 58-year-old man who presented with a left arm skin infection and cough for 2 months. Imaging and laboratory studies revealed a large anterior mediastinal mass and panhypoimmunoglobulinemia, respectively. A biopsy was consistent with thymoma, and a diagnosis of Good's syndrome was established. Thymectomy was followed by intravenous immunoglobulin G and filgrastim with complete recovery through 9 months after discharge. Good's syndrome remains a rare entity often associated with poor prognosis. Adequate surgical resection remains key to outcomes, whereas immunotherapy aids in reducing postoperative complications and may improve survival. PMID- 26522541 TI - Patch Repair for a Subepicardial Aneurysm With an Approach From Inside the Heart. AB - We present a case of subepicardial aneurysm that developed as a complication of acute myocardial infarction. Although the patient had stable hemodynamics, the diameter of the aneurysm tended to increase over time; thus, an operation was performed. We thought that approaching the aneurysm from outside the heart would injure the papillary muscle or distort the left ventricle and exacerbate mitral regurgitation. Therefore, we performed patch repair using bovine pericardium and approached the aneurysm from inside the heart. This is the first case report of a subepicardial aneurysm that was approached and repaired from inside the heart. PMID- 26522542 TI - Treatment of Sternal Wound Infection Using a Free Myocutaneous Flap. AB - Deep sternal wound infections are potentially life-threatening complications after cardiac operations because they can spread into the mediastinum and cause postoperative morbidity and mortality. We present a 65-year-old man with a history of coronary artery bypass grafting. A large sternal defect was left after debridement. After brief vacuum-assisted closure (VAC), a free myocutaneous flap of the anterolateral thigh (ALT) was used to fill the dead space. At the 9-month follow-up, the wound had healed completely without tissue loss or complications, and the patient returned to normal life. This was a successful treatment of a deep sternal wound with free flap coverage. PMID- 26522543 TI - Large Percutaneous Tracheostomy-Induced Injury Repair by Thoracoscopic Approach. PMID- 26522544 TI - Anomalous Left Coronary Artery From Right Pulmonary Artery: Epicardial Imaging. PMID- 26522545 TI - Anomalous Pulmonary Arterial Supply to the Pulmonary Vein of the Right Lung: An Extremely Exceptional Case of Arterial Vein Fistulae. PMID- 26522546 TI - Modified Damus-Kaye-Stansel Procedure Subsequent to Pulmonary Artery Banding. AB - Both the Damus-Kaye-Stansel procedure and pulmonary artery banding provide an effective palliative technique in certain subsets of patients, but this combination of procedures is potentially hazardous in pulmonary valve geometry. This is a matter of vital concern, especially in patients whose pulmonary arteries have to work after operations as the major systemic output routes. In this report, we present a novel surgical modification that builds a systemic output route without causing valve deformities. PMID- 26522548 TI - Rectus-Sparing Technique for Driveline Insertion of Ventricular Assist Device. AB - We present a new technique for driveline insertion of the HeartWare ventricular assist device (HVAD) designed to preserve the integrity of the abdominal wall structure. Because of the size of the HVAD driveline connector (12 mm in diameter: triple the size of the driveline cable), the standard tunneling maneuver can result in tearing of the abdominal wall muscle layer, which is a primary mechanism to prevent ascending driveline infection. We find that our technique is particularly useful in children because their abdominal wall muscles are more fragile and thereby prone to accidental injury with blunt penetration when the standard technique is used. PMID- 26522547 TI - Modified Warden Procedure Using the Concept of Senning Operation: Repair Without Any Patch. AB - Various surgical techniques have been proposed to repair a partial anomalous pulmonary venous connection to the superior vena cava, such as the single-patch, the double-patch, and the caval division (Warden) techniques. The limited growth potential of the artificial patch, stenosis of the cavoatrial channel or rerouted pulmonary vein channel, and the risk of sinus node dysfunction were possible adverse events. We here describe a modified Warden procedure without any patch in a 6-month-old infant. Using the concept of the Senning atrial switch technique, the interatrial septum and the free wall of the right atrium were used to baffle the anomalous pulmonary vein into the left atrium. PMID- 26522549 TI - Complete Aortic Valve Cusp Replacement in the Pediatric Population Using Tissue Engineered Bovine Pericardium. AB - Three clinical cases of severe pediatric aortic valve defects undergoing complete aortic valve cusp replacement using tissue-engineered bovine pericardium are reported. All patients achieved excellent early results, and are being followed without complications. PMID- 26522550 TI - Invited Commentary. PMID- 26522551 TI - Jay Lloyd Ankeney, June 7, 1921-December 24, 2014. AB - Jay Ankeney, the 16th President of The Society of Thoracic Surgeons, was an early pioneer in adult and pediatric cardiac operations, a prescient advocate of off bypass coronary revascularization, and a strong champion of cardiothoracic recertification. He was among the first to endorse the need to provide practicing cardiothoracic surgeons the means for self-assessment and improvement. He led the development of Coordinating Committee for Continuing Education in Thoracic Surgery and inaugurated the self-education/self assessment syllabus for this purpose. Under his leadership he persuaded the vast majority of cardiothoracic surgeons to embrace recertification and by this means provide reassurance and accountability to their patients. PMID- 26522552 TI - Anterior Thoracoscopic Subcarinal Nodal Dissection: A Better Approach? PMID- 26522553 TI - Reply: To PMID 25841862. PMID- 26522554 TI - Reply: To PMID 25916873. PMID- 26522555 TI - Association Between Acute Kidney Injury and Hemodilution During Cardiopulmonary Bypass. PMID- 26522556 TI - Surgery Versus Radiation Therapy in Stage I Lung Cancer. PMID- 26522557 TI - Reply: To PMID 25661580. PMID- 26522558 TI - External Stenting of the Vein Grafts in Coronary Artery Operations: Limitations, Benefits, and Patients' Safety. PMID- 26522559 TI - Reply: To PMID 25886810. PMID- 26522560 TI - Perioperative Removal of Autologous Platelets. PMID- 26522561 TI - Reply: To PMID 25661906. PMID- 26522562 TI - Previous Information About Poland Syndrome Should Be Reviewed. PMID- 26522563 TI - Portland Protocol: Conclusions Are Not Justified by the Content of the Article. PMID- 26522564 TI - Reply: To PMID 25633462. PMID- 26522565 TI - Reply: To PMID 25442983. PMID- 26522566 TI - Surgical Training: Learning to Fly at "Top Gun" Level. PMID- 26522567 TI - Reply: To PMID 25595829. PMID- 26522568 TI - Reply: To PMID 25110334. PMID- 26522569 TI - Survival in Lung Transplantation. PMID- 26522570 TI - Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis: A Considered Opinion. PMID- 26522571 TI - Contemporary Bloodletting--An Opportunity for Collaboration With the Neonatal Intensive Care Unit. PMID- 26522572 TI - Does Visceral Pleural Invasion Affect Prognosis in Stage I Non-Small Cell Lung Cancer? PMID- 26522573 TI - Tracheoplasty With Use of an Intercostal Muscle Flap for Caustic Necrosis. AB - We report a case of intercostal muscle flap used in tracheobronchial reconstruction for extensive necrosis after burn lesions of the posterior wall. A 32-year-old man attempted suicide by ingestion of caustic material. He underwent emergency total esogastrectomy, tracheostomy, and feeding jejunostomy. Ten days later, endoscopy showed complete destruction of the membranous trachea, extending from the tracheostomy to the carina. Reconstruction was conducted with the patient under venovenous extracorporeal membrane oxygenation by use of a pedicled intercostal muscle flap. The patient was weaned from respiratory support on the 14th postoperative day. Examination of a biopsy specimen from the flap 7 months after tracheoplasty showed ciliated neoepithelium. PMID- 26522574 TI - An Incidentally Discovered Pedunculated Degenerative Cyst on the Aortic Valve. AB - We report the case of a pedunculated cystic mass on the aortic valve discovered in a patient presenting for a routine echocardiogram. The highly mobile nature of the mass warranted prompt surgical removal to prevent cardioembolic complications. The mass was preoperatively thought to be a papillary fibroelastoma. However, the patient's history, mass morphology, and histopathology pointed toward a simple degenerative cyst--previously unreported on the aortic valve. This report describes this rare finding, discusses relevant differential diagnoses, and underscores the importance of surgical intervention in such cases. PMID- 26522575 TI - Coronary Artery Fistula: Two Rare Cases. AB - Coronary artery fistula (CAF) is an incidental finding in up to 0.2% of cardiac catheterization studies and is a rare pathologic condition affecting up to 1% of the general population. We report two cases of CAF diagnosed by coronary angiography and managed by surgical ligation, with excellent postoperative outcome. Anatomic location, clinical presentation, investigation, and treatment of CAF are discussed. PMID- 26522576 TI - Transcatheter ACURATE-TA Aortic Valve Implantation in a Patient With a Previous Mechanical Mitral Valve. AB - Transcatheter aortic valve implantation (TAVI) in the presence of a mechanical mitral valve (MMV) prosthesis is still challenging because of the rigid mitral frame within the aortomitral curtain. Moreover, low-lying coronary ostia represent a hazardous problem of coronary obstruction, especially in narrow or porcelain aortic roots. The present case demonstrates the successful management of 2 challenging anatomical issues, the rigid cage of the MMV and the low-lying left main coronary ostium (LMCO), with the implantation of the ACURATE-TA bioprosthesis (Symetis SA, Ecublens, Switzerland). It also highlights the importance of having multiple TAVI devices in order to choose the ideal transcatheter aortic bioprosthesis to fit the unique anatomical presentation of the patient. PMID- 26522577 TI - Successful Operation for Thoracoabdominal Aortic Aneurysm in a 5-Year-Old Boy With Tuberous Sclerosis. AB - The association of abdominal aortic aneurysm (AAA) and tuberous sclerosis (TS) is rare. A 5-year-old boy was diagnosed with a 7-cm calcified thoracoabdominal aortic aneurysm (TAAA), and the clinical evaluation revealed TS. The patient underwent an open repair with a 14-mm polyester tube graft prosthesis. The pathologic examination showed nonspecific dystrophic changes with loss of elastin fibers in the media of the aorta. The graft was patent on computed tomographic angiography performed 1 month after the operation. Because of the high risk of rupture, early elective repair is suggested. PMID- 26522578 TI - Surgical and Anesthetic Management of a Mediastinal Fatty Tumor: Lipoblastoma. AB - Lipoblastoma is a rare fatty tumor that is diagnosed almost exclusively in children. Presentation often consists of respiratory symptoms; chest computed tomography shows a hypodense, low, attenuated mediastinal mass. Surgical approach and anesthetic management are dependent on the location of the tumor and the degree of airway compression; in most cases, a thoracotomy is performed, although a sternotomy is used in selected cases. Final diagnosis can be confirmed using molecular genetic analysis; a genetic hallmark of lipoblastoma is the rearrangement of chromosomal region 8q12 and the PLAG1 gene. Tumor recurrence is rare when a complete resection is performed. PMID- 26522579 TI - Hybrid Approach for Off-Pump Pulmonary Valve Replacement in Patients With a Dilated Right Ventricular Outflow Tract. AB - We describe a hybrid method for minimally invasive pulmonary valve replacement without the use of cardiopulmonary bypass in 3 patients with high surgical risk and dilated right ventricular outflow tracts incompatible with currently available transcatheter devices. This procedure entails surgical creation of a landing zone in the main pulmonary artery through an anterior thoracotomy, followed by transcatheter Melody valve pulmonary valve replacement. Particularly in high-risk patients, this approach may limit morbidity and mortality associated with traditional surgical pulmonary valve replacement. PMID- 26522580 TI - Gluteal Compartment Syndrome after Fenestrated Endovascular Aortic Aneurysm Repair. AB - We describe a case of gluteal compartment syndrome (GCS) after a 4-vessel fenestrated endovascular abdominal aortic aneurysm repair. The case highlights the need for a high index of suspicion for GCS as a differential diagnosis for spinal cord ischemia in patients developing perioperative lower limb neurologic deficit after extensive abdominal aortic stent-graft coverage. PMID- 26522581 TI - Plug the Hole--A Bailout Option for Acute Focal Aortic Rupture. AB - BACKGROUND: Focal aortic rupture may result from expanding aneurysms, penetrating aortic wall ulcerations, or virulent infections. An urgent repair of paravisceral focal aortic rupture is associated with high morbidity. A staged repair approach may provide an alternative option. CASE REPORT: A 64-year-old woman presented with acute focal rupture of the posterior paravisceral aortic wall and was progressing to hemorrhagic shock and mesenteric ischemia. Given the patient's dire condition, an endovascular approach was used to plug her focal aortic wall defect using a ventricular septal defect occluder device. Subsequently, the patient underwent resuscitation, stabilization, and operative exploration. Postoperatively, she recovered well from this staged approach. CONCLUSIONS: This case provides an example of a staged endovascular plugging of an acute paravisceral focal aortic rupture. In select cases, this type of repair strategy is feasible, until off-the-shelf endovascular repair options become a reality. PMID- 26522582 TI - A Novel Approach to Overcome Stent Strut Entrapment of the Distal Filter Retrieval Catheter during Vertebral Artery Stenting: The "Olive-Tipped" Technique. AB - We developed an "olive-tipped" technique for preventing the distal filter retrieval catheter from entrapment in the stent struts during retrieval procedures after stent deployment and which we used in 2 vertebral artery stenting cases. A new wire entry port was made in the catheter at the transition of larger and smaller lumen to permit passage of a low-profile balloon into the lumen of the retrieval catheter. When the balloon was inflated across the retrieval catheter tip, a smoother profile was created which eliminated the sharp step between the catheter tip and the filter wire. The retrieval catheter could then be advanced easily through the stent struts using this modified system. PMID- 26522583 TI - Misdiagnosis of a Patient with Internal Carotid Artery Fenestration: A Case Report and Literature Review. AB - BACKGROUND: Internal carotid artery fenestration is a rare congenital cerebrovascular condition and can be misdiagnosed as carotid artery dissection. CASE REPORT: A patient was initially misdiagnosed with carotid artery dissection. This initial diagnosis was made using a carotid vascular computed angiography and magnetic resonance angiography. A digital subtraction angiography examination revealed a fenestration in the terminal C1 segment of the right internal carotid artery. Previous literature related to carotid artery fenestration was reviewed and analyzed. CONCLUSIONS: Fenestration of the carotid artery combined with aneurysm at the external segment of the internal carotid artery or from the starting position of the carotid artery remains rare in elderly patients, can be misdiagnosed as artery dissection. PMID- 26522584 TI - Hemodynamic Conditions may Influence the Oversizing of Stent Grafts and the Postoperative Surveillance of Patients with Ruptured Abdominal Aortic Aneurysm Treated by EVAR. AB - BACKGROUND: To report the causes of second rupture in patients treated with a stent graft for ruptured abdominal aortic aneurysm (rAAA). CASE REPORT: A 69-year old man was admitted for abdominal pain and hypovolemic shock 22 months after endovascular exclusion of an rAAA with an aortomonoiliac stent graft and a crossover bypass despite normal duplex ultrasound and sac shrinkage at 1 year. During emergent laparotomy, a type IA endoleak was discovered and the aortomonoiliac stent graft was explanted. A Dacron bypass was interposed between the infrarenal aorta and the iliac extension stent graft. CONCLUSIONS: Considering the literature, this report has 3 implications for the endovascular treatment of rAAA. First, 30% oversizing is preferable to 15% when treating an rAAA assessed by computed tomography angiography (CTA) performed during permissive hypotension. Second, the surveillance program should rely on CTA and not on a duplex examination to detect any endoleaks or migration. Finally, partial stent graft explantation is a valid option for decreasing aortic clamping time. PMID- 26522585 TI - Eversion Subclavian Endarterectomy and Transposition for Coronary-Subclavian Steal Syndrome in a Patient with Refractory Angina Pectoris. AB - Late onset of angina pectoris associated with subclavian artery (SA) atherosclerotic occlusive disease is a rare and recognized cause of myocardial ischemia when the lesion is proximal to a left internal mammary artery (LIMA) to coronary bypass. The symptoms typically exacerbate by increasing the flow demand in the extremity; this phenomenon is known as late coronary-subclavian steal syndrome. We describe the case of a 66-year-old woman who underwent coronary artery bypass grafting from the LIMA to the left anterior descending coronary artery in 2000. Years later, she experienced refractory angina pectoris associated to an occlusive lesion in the proximal left SA. SA endarterectomy with eversion technique and subclavian-carotid transposition restored the antegrade flow with resolution of the symptomatology. PMID- 26522586 TI - Use of Aortic Occluders and Endovascular Plugs in a 2-step Hybrid Treatment of Secondary Aortoenteric Fistulas. AB - Aortoenteric fistula (AEF) is a dreadful complication of abdominal aortic surgery. Surgical treatment is associated to high mortality and requires urgent graft removal with extra-anatomic or in situ reconstruction. Other authors suggest the use of stent grafts, both as a stand-alone procedure or as a bridge solution before open repair. We reviewed the results of a cohort of patients that presented at our institution with an AEF and were treated with a novel 2-step endovascular-open surgical procedure. The first step consisted in immediate endovascular occlusion of the infrarenal graft with deployment, below the renal arteries, of an aortic occluder and/or endovascular plugs. After occlusion of the infrarenal graft, extra-anatomic reconstruction (axillofemoral bypass) was performed. The second step consisted in the removal of the infrarenal graft with aortic stump ligation and took place after a few days recovery to allow improvement of patients' condition. A total of 5 selected patients were treated. Endovascular aortic occlusion was achieved in all cases with the deployment of 1 (3 patients) or 2 (2 patients) devices. The mean interval between the first and the second step was 7 days (min 4-max 13). Complete removal of the aortic graft was possible in all patients. One patient died on the first postoperative day due to multiorgan failure (1 of 5, 20%). Mean survival after discharge was 24 months (min 6-max 36). One patient died at 6 months because of aortic stump blowout. In our initial experience, endovascular aortic occlusion seems an effective option to prevent fatal enteric bleeding and a valuable first-step treatment for selected cases of AEF. PMID- 26522587 TI - TEVAR for Flash Pulmonary Edema Secondary to Thoracic Aortic Aneurysm to Pulmonary Artery Fistula. AB - Enlarging aneurysms in the thoracic aorta frequently remain asymptomatic. Fistulization of thoracic aortic aneurysms (TAA) to adjacent structures or the presence of a patent ductus arteriosus and TAA may lead to irreversible cardiopulmonary sequelae. This article reports on a large aneurysm of the thoracic aorta with communication to the pulmonary artery causing pulmonary edema and cardiorespiratory failure. The communication was ultimately closed after thoracic endovascular aortic aneurysm repair allowing rapid symptom resolution. Early diagnosis and closure of such communication in the presence of TAA are critical for prevention of permanent cardiopulmonary damage. PMID- 26522588 TI - Combined Endovascular Embolization and Open Surgery for Splenic Artery Aneurysm with Arteriovenous Fistula. AB - Splenic artery aneurysm with arteriovenous fistula is extremely rare; however, it is clinically important because of the potential of aneurysm rupture and gastroesophageal variceal hemorrhage. Most previous cases were managed by surgery directly. We present a case which was successfully treated with combined endovascular embolization and open surgery. It may be a safe and effective approach to manage this entity. PMID- 26522589 TI - Bub1 is required for maintaining cancer stem cells in breast cancer cell lines. AB - Breast cancer is a leading cause of death among women worldwide due to therapeutic resistance and cancer recurrence. Cancer stem cells are believed to be responsible for resistance and recurrence. Many efforts to overcome resistance and recurrence by regulating cancer stem cells are ongoing. Bub1 (Budding uninhibited by benzimidazoles 1) is a mitotic checkpoint serine/threonine kinase that plays an important role in chromosome segregation. Bub1 expression is correlated with a poor clinical prognosis in patients with breast cancer. We identified that depleting Bub1 using shRNAs reduces cancer stem cell potential of the MDA-MB-231 breast cancer cell line, resulting in inhibited formation of xenografts in immunocompromised mice. These results suggest that Bub1 may be associated with cancer stem cell potential and could be a target for developing anti-breast cancer stem cell therapies. PMID- 26522590 TI - Ulinastatin- and thymosin alpha1-based immunomodulatory strategy for sepsis: A meta-analysis. AB - OBJECTIVE: This meta-analysis was performed to evaluate the efficacy of ulinastatin (UTI) and thymosin alpha1 (Talpha1) based immunomodulatory strategy in sepsis patients. METHODS: A systematic search was made of MEDLINE, Cochrane, ISI Web of Science and SCOPUS databases. Randomized clinical trials on treatment of sepsis with the combination of ulinastatin and Talpha1, compared with placebo, were reviewed. Studies were pooled to relative risk (RR) and weighted mean differences (WMD), with 95% confidence interval (CI). RESULTS: Six trials (enrolling 915 participants) met the inclusion criteria. Compared with placebo, the combination of ulinastatin and Talpha1 presented significant effects on 28 day all-cause mortality (RR 0.67; 95% CI 0.57 to 0.80), 90-day all-cause mortality (RR 0.75; 95% CI 0.61 to 0.93), TNF-alpha (WMD -73.86ng/L; 95% CI 91.00 to -56.73ng/L), IL-6 (WMD -55.04ng/L; 95% CI -61.22 to -48.85ng/L), and duration of mechanical ventilation (WMD -2.26days; 95% CI -2.79 to -1.73days). CONCLUSIONS: Immunomodulatory therapy that combines ulinastatin and Talpha1 significantly improves all-cause mortality, inflammatory mediators and duration of mechanical ventilation in subjects with sepsis. PMID- 26522591 TI - Cloning and characterization of tropomyosin from the mite Chortoglyphus arcuatus. AB - Tropomyosin is a pan-allergen that shares a high homology among species. It is involved in cross-reactivity among mites, crustaceans, mollusks and insects. The objectives were to express and purify recombinant tropomyosin from the storage mite Chortoglyphus arcuatus, and to investigate the homology and cross-reactivity with tropomyosin from other invertebrates. Recombinant C. arcuatus tropomyosin (r Cho a 10) was selected from a library by screening with a pool of patient sera. r Cho a 10 (UniProt: H2DFL1) was sequenced, expressed in Escherichia coli and purified by ion exchange and affinity chromatography. Polyclonal anti-tropomyosin antibodies were produced in mice. IgE recognition of r-Cho a 10 was checked by immunoblot. Immunoblot inhibition assays were used to identify the native tropomyosin in the complete extract from C. arcuatus and study cross-reactivity between r-Cho a 10 and Der p 10. Identification of tropomyosin in other allergenic sources was performed by immunoblot. r-Cho a 10 showed a high homology (54-96%) with other tropomyosins from different allergenic sources. IgE recognition was observed using a pool of sera from sensitized individuals. Tropomyosins from different extracts were identified not only in the whole C. arcuatus extract but also in Dermatophagoides pteronyssinus, shrimp, mussel, cockroach and Anisakis extracts with polyclonal alpha-Cho a 10. r-Cho a 10 completely inhibited the recognition of Der p 10. Recombinant C. arcuatus tropomyosin maintained its capacity to recognize IgE. r-Cho a 10 was used to prove cross-reactivity among tropomyosins from other invertebrate species, including mites. This is the first C. arcuatus allergen included in the WHO/IUIS (World Health Organization/International Union of Immunological Societies) Allergen Nomenclature database. PMID- 26522592 TI - Histone H3 Threonine Phosphorylation Regulates Asymmetric Histone Inheritance in the Drosophila Male Germline. AB - A long-standing question concerns how stem cells maintain their identity through multiple divisions. Previously, we reported that pre-existing and newly synthesized histone H3 are asymmetrically distributed during Drosophila male germline stem cell (GSC) asymmetric division. Here, we show that phosphorylation at threonine 3 of H3 (H3T3P) distinguishes pre-existing versus newly synthesized H3. Converting T3 to the unphosphorylatable residue alanine (H3T3A) or to the phosphomimetic aspartate (H3T3D) disrupts asymmetric H3 inheritance. Expression of H3T3A or H3T3D specifically in early-stage germline also leads to cellular defects, including GSC loss and germline tumors. Finally, compromising the activity of the H3T3 kinase Haspin enhances the H3T3A but suppresses the H3T3D phenotypes. These studies demonstrate that H3T3P distinguishes sister chromatids enriched with distinct pools of H3 in order to coordinate asymmetric segregation of "old" H3 into GSCs and that tight regulation of H3T3 phosphorylation is required for male germline activity. PMID- 26522593 TI - Relaxation of Loaded ESCRT-III Spiral Springs Drives Membrane Deformation. AB - ESCRT-III is required for lipid membrane remodeling in many cellular processes, from abscission to viral budding and multi-vesicular body biogenesis. However, how ESCRT-III polymerization generates membrane curvature remains debated. Here, we show that Snf7, the main component of ESCRT-III, polymerizes into spirals at the surface of lipid bilayers. When covering the entire membrane surface, these spirals stopped growing when densely packed: they had a polygonal shape, suggesting that lateral compression could deform them. We reasoned that Snf7 spirals could function as spiral springs. By measuring the polymerization energy and the rigidity of Snf7 filaments, we showed that they were deformed while growing in a confined area. Furthermore, we observed that the elastic expansion of compressed Snf7 spirals generated an area difference between the two sides of the membrane and thus curvature. This spring-like activity underlies the driving force by which ESCRT-III could mediate membrane deformation and fission. PMID- 26522594 TI - Surveillance and Processing of Foreign DNA by the Escherichia coli CRISPR-Cas System. AB - CRISPR-Cas adaptive immune systems protect bacteria and archaea against foreign genetic elements. In Escherichia coli, Cascade (CRISPR-associated complex for antiviral defense) is an RNA-guided surveillance complex that binds foreign DNA and recruits Cas3, a trans-acting nuclease helicase for target degradation. Here, we use single-molecule imaging to visualize Cascade and Cas3 binding to foreign DNA targets. Our analysis reveals two distinct pathways dictated by the presence or absence of a protospacer-adjacent motif (PAM). Binding to a protospacer flanked by a PAM recruits a nuclease-active Cas3 for degradation of short single stranded regions of target DNA, whereas PAM mutations elicit an alternative pathway that recruits a nuclease-inactive Cas3 through a mechanism that is dependent on the Cas1 and Cas2 proteins. These findings explain how target recognition by Cascade can elicit distinct outcomes and support a model for acquisition of new spacer sequences through a mechanism involving processive, ATP dependent Cas3 translocation along foreign DNA. PMID- 26522595 TI - Effect of Ocimum sanctum on Oral Cancer Cell Line: An in vitro Study. AB - BACKGROUND: Cancer till today remains the leading cause of death in both developed and developing countries. Plants have been beacon of therapeutic sources for curing diseases from times immemorial. Hence, the present study aimed at evaluating the antiproliferative activity of extract of Ocimum sanctum leaves on oral cancer cell line. OBJECTIVES: To evaluate the antiproliferative effect and to analyze dose dependent cytotoxic activity of aqueous extract of O. sanctum leaves on KB mouth cell line. To compare the effectiveness among different variety of O. sanctum. MATERIALS AND METHODS: KB cells (Mouth Epidermal Carcinoma Cells) were used for the present study. Aqueous and dry extract of O. sanctum with both dark (Krishna Tulsi) and light (Rama Tulsi) leaves were prepared in the institution. The antiproliferative and cytotoxic activity on KB cell line was evaluated by MTT assay. Statistical analysis with Mann-Whitney U-test and Wilcoxon matched pairs test was carried out. RESULTS: The aqueous extract of O. sanctum of both the leaves exhibited significant cytotoxic effect against oral cancer cell line. CONCLUSION: Aqueous extract of O. sanctum leaves was effective as an antiproliferative agent which caused apoptosis in oral cancer cell line. CLINICAL SIGNIFICANCE: Ocimum sanctum herb which is abundantly grown in India can be used for its anticancer properties for treating oral cancer. This will not only be cost-effective but will also have less or no side effects. PMID- 26522596 TI - Bioimpedance Assessment of Oral Squamous Cell Carcinoma with Clinicopathological Correlation. AB - AIM: Molecular alterations at membrane, cytosol and nuclear level in cancer cells/tissue show variations in bioimpedance measure. In the present study, bioimpedance assessment and comparison was investigated between oral squamous cell carcinoma (OSCC) and normal tissue. Study further involves clinicopathological correlation of bioimpedance values in OSCC. MATERIALS AND METHODS: The present study is comprised of 50 OSCC cases and 50 healthy control subjects. Four electrical properties of OSCC were measured: Impedance (Z); Phase angle (9); Real part of impedance (R); and Imaginary part of impedance (X) at six frequencies: 20 Hz; 50 kHz; 1.3 MHz; 2.5 MHz; 3.7 MHz; and 5 MHz with the amplitude of the applied voltage limited to 200 mV. RESULTS: The bioimpedance of OSCC as well as control group decreased as the measurement frequency increased from 20 Hz to 5 MHz. The bioimpedance of OSCC was generally smaller than that of control group. The mean bioimpedance of OSCC was found to be 4493 +/- 216.9 Omega and 370.0 +/- 26.45 Omega and that of control group was 15490 +/- 287.2 Omega and 817.1 +/- 7.227 Omega at frequencies of 20 Hz and 50 MHz respectively which is statistically significant (p < 0.0001). The values of phase angle, real and imaginary part of impedance of OSCC group were found to be significantly larger than that of control group (p < 0.0001) at 20 Hz and 50 MHz frequency. Impedance values of OSCC were seen to decrease from stages I to IV. Statistically significant differences in values of impedance were observed between stage I (4881 +/- 262.5 Omega) and IV (4500 +/- 181.6 Omega) (p = 0.0060) and also between stage I (4881 +/- 262.5 Omega) and III (4376 +/- 121.3 Omega) at frequency of 20 Hz (p-value 0.0005). Statistically significant differences in values of impedance were also observed between well differentiated (4557 +/- 260.8) and poorly differentiated OSCC (4347 +/- 76.12) (p = 0.0004) but only at 20 Hz frequency. CONCLUSION: Bioimpedance at a particular frequency showed significant alteration in OSCC tissue as compared to control. Hence, it can be potentially promising detection technique for OSCC. CLINICAL SIGNIFICANCE: It is a low-cost real time method, which requires little training, and hence can be easily used in primary care centers or in developing countries where multiple challenges limit national screening programs. PMID- 26522597 TI - Successful Management of Lip and Oral Venous Varices by Photocoagulation with Nd:YAG Laser. AB - AIM: This study assessed the effectiveness of photocoagulation with Nd:YAG laser in the treatment of lip and oral venous varices. MATERIALS AND METHODS: Sixteen consecutive patients (eight men and eight women, mean age 56 years) diagnosed as having either lip or oral venous varices, were examined and treated with a noncontact Nd:YAG laser. As lesions were small (less than 1 cm), round or oval in shape, flat, dark to blue in color and symptomless, patients sought for treatment either for esthetic reason, bleeding or cancerophobia-related concern. RESULTS: All but one lesion were successfully treated with only one irradiation exposure. Healing was completed in about 2 to 4 weeks; none of the patients experienced complications or recurrence. Pain was out of any major concern during immediate follow-up. CONCLUSION: Although photocoagulation with Nd:YAG laser did not outperform the effectiveness observed with diode laser (data shown in a previous study),(17) it proved to be safe and effective for the treatment of lip and oral varices, with consistent results. CLINICAL SIGNIFICANCE: Most of patients with oral and lip varices only need some clinical advice regarding the their nature of their lesions. Yet, for those who seek treatment for this conditions, the use Nd:YAG laser is an option as it yields satisfactory outcomes. PMID- 26522598 TI - Deoxyribonucleic Acid Probes Analyses for the Detection of Periodontal Pathogens. AB - BACKGROUND: In clinical microbiology several techniques have been used to identify bacteria. Recently, Deoxyribonucleic acid (DNA)-based techniques have been introduced to detect human microbial pathogens in periodontal diseases. Deoxyribonucleic acid probes can detect bacteria at a very low level if we compared with the culture methods. These probes have shown rapid and cost effective microbial diagnosis, good sensitivity and specificity for some periodontal pathogens in cases of severe periodontitis. MATERIALS AND METHODS: Eighty-five patients were recruited for the study. Twenty-one subjects ranging between 22 and 48 years of age fulfilled the inclusion and exclusion criteria. Seventy-eight samples became available for DNA probe analysis from the deepest pockets in each quadrant. RESULTS: All 21 patients showed positive results for Prevotella intermedia; also, Prevotella gingivalis was identified in 19 subjects, Aggregatibacter actinomycetemcomitans in 6 subjects. P. intermedia was diagnosed positive in 82% of the subgingival samples taken, 79% for P. gingivalis, and 23% for A. actinomycetemcomitans. CONCLUSION: This study shows a high frequency of putative periodontal pathogens by using DNA probe technology, which is semi quantitative in this study. Deoxyribonucleic acid probes can detect bacteria at very low level about 10(3) which is below the detection level of culture methods. The detection threshold of cultural methods. CLINICAL SIGNIFICANCE: The three types of bacteria can be detected rapidly with high sensitivity by using the DNA probe by general practitioners, and thus can help in the diagnosis process and the treatment. PMID- 26522599 TI - Sealing Ability of Four Calcium Containing Cements used for Repairing Furcal Perforations in Primary Molars: An in vitro study. AB - AIM: The aim of this study was to compare the sealing ability of mineral trioxide aggregate (MTA), Portland cement (PC), Biodentine(TM) and Tech biosealer in repairing furcal perforations in primary molars using the fluid-filtration technique. MATERIALS AND METHODS: Fifty freshly extracted maxillary second primary molars were sectioned horizontally at the furcation region to create dentin disks of 1.5 mm (+ 0.1 mm) thickness. Five disks were not perforated and served as negative controls. In the remaining 45 disks, furcation perforations were prepared. Five disks did not receive furcation repair and served as positive controls. The remaining 40 disks were then randomly divided into four equal groups (10 disks in each group). Perforations were repaired with: MTA, PC, Biodentine(TM) or Tech Biosealer. The sealing ability of the tested materials was evaluated by measuring microleakage for each disk after four different storage periods: 24-hour, 1-month, 6-month and 1-year storage using fluid-filtration. Comparisons between the four materials and the four time periods were done using the two-way analysis of variance and the Scheffe multiple comparisons test. RESULTS: There was no significant difference between the mean microleakage values obtained in the four tested materials after 24 hours, 1, 6 month and 1 year. However, microleakage values for each individual material were significantly higher at 24 hours than at the other time intervals. CONCLUSION: Mineral trioxide aggregate, PC, Biodentine(TM) and Tech biosealer showed similar capabilities in sealing the furcal perforations of the primary molars, where the sealing ability improved over time for each individual material. PMID- 26522600 TI - An Analysis of the Stress Induced in the Periodontal Ligament during Extrusion and Rotation Movements: A Finite Element Method Linear Study Part I. AB - BACKGROUND: Orthodontic tooth movement occurs due to various biomechanical changes in the periodontium. Forces within the optimal range yield maximum tooth movement with minimum deleterious effects. Among various types of tooth movements, extrusion and rotational movements are seen to be associated with the least amount of root resorption and have not been studied in detail. Therefore in this study, the stress patterns in the periodontal ligament (PDL) were evaluated with extrusion and rotational movements using the finite element method FEM. MATERIALS AND METHODS: A three-dimensional (3D) FEM model of the maxillary incisors was generated using SOLIDWORKS modeling software. Stresses in the PDL were evaluated with extrusive and rotational movements by a 3D FEM using ANSYS software with linear material properties. RESULTS: It was observed that with the application of extrusive load, the tensile stresses were seen at the apex, whereas the compressive stress was distributed at the cervical margin. With the application of rotational movements, maximum compressive stress was distributed at the apex and cervical third, whereas the tensile stress was distributed on cervical third of the PDL on the lingual surface. CONCLUSION: For extrusive movements, stress values over the periodontal ligament was within the range of optimal stress value as proposed by Lee, with a given force system by Profitt as optimum forces for orthodontic tooth movement using linear properties. During rotation there are stresses concentrated at the apex, hence due to the concentration of the compressive forces at the apex a clinician must avoid placing heavy stresses during tooth movement. PMID- 26522601 TI - Efficacy of Autofluorescence Imaging as an Adjunctive Technique for Examination and Detection of Oral Potentially Malignant Disorders: A Systematic Review. AB - BACKGROUND: Oral cancer is a serious global issue and early diagnosis of oral cancer is the key in reducing the high mortality rate. Autofluorescence properties of oral mucosa have been gaining interest in the field of early diagnosis of oral premalignant lesions. OBJECTIVE: The aim of the study was to evaluate the clinical usefulness of an autofluorescence based imaging system to detect oral premalignant and malignant lesions. MATERIALS AND METHODS: A systematic review of the English-language literature to evaluate the effectiveness of visually enhanced lesion scope (VELscope) published between 1966 and March, 2014 was undertaken. Data relating to study design, sampling and characteristics of the study group, interventions, and reported outcomes and diagnostic value of VELscope were abstracted from articles meeting inclusion and exclusion criteria. RESULTS: Eleven articles that met the inclusion criteria were included. In nine studies, all the lesions underwent histological assessment, whereas the remaining four studies only performed histological assessment on suspicious lesions. Visually enhanced lesion scope showed high sensitivity values in detecting oral premalignant and malignant lesions. However, most of the studies reported it inability in discriminating dysplasia cases from nondysplasia cases. CONCLUSION: There is insufficient evidence to support the use of VELscope in primary care setting, however, they may be useful in hands of a specialist. PMID- 26522602 TI - Prevalence and Possible Risk Factors of Peri-implantitis: A Concept Review. AB - AIM: The purpose of this review is to estimate the prevalence of peri implantitis, as well as to determine possible risk factors associated with its development in patients treated with oral implants. BACKGROUND: Although implant therapy has been identified as a successful and predictable treatment for partially and fully edentulous patients, complications and failures can occur. Peri-implantitis is considered a biologic complication that results in bone loss around implants and may lead to implant treatment failure. RESULTS: A great variation has been observed in the literature regarding the prevalence of peri implantitis according to the diagnostic criteria used to define peri-implantitis. The prevalence ranges from 4.7 to 43% at implant level, and from 8.9 to > 56% at patient level. Many risk factors that may lead to the establishment and progression of peri-implantitis have been suggested. There is strong evidence that presence and history of periodontitis are potential risk factors for peri implantitis. Cigarette smoking has not yet been conclusively established as a risk factor for peri-implantitis, although extra care should be taken with dental implant in smokers. Other risk factors, such as diabetes, genetic traits, implant surface roughness and presence of keratinized mucosa still require further investigation. CONCLUSION: Peri-implantitis is not an uncommon complication following implant therapy. A higher prevalence of peri-implantitis has been identified for patients with presence or history of periodontal disease and for smokers. Until now, a true risk factor for peri-implantitis has not been established. Supportive maintenance program is essential for the long-term success of treatments with oral implants. CLINICAL SIGNIFICANCE: The knowledge of the real impact of peri-implantitis on the outcome of treatments with oral implants as well as the identification of risk factors associated to this inflammatory condition are essential for the development of supportive maintenance programs and the establishment of prevention protocols. PMID- 26522603 TI - Orthodontic Extrusion as Treatment Option for Crown-Root Fracture: Literature Review with Systematic Criteria. AB - OBJECTIVE: To review the literature searching for a consensus for the choice of orthodontic extrusion as treatment for crown-root fracture. MATERIALS AND METHODS: An electronic search was performed in the databases PubMed, Cochrane Central Register of Controlled Trials and Scopus and a manual search of the Journal Dental Traumatology. RESULTS: Forty articles were found in PubMed and 38 in Scopus and after removal of duplicate sample 51 contained articles. Of these, 48 were excluded for not having orthodontic treatment, no follow-up or follow-up less than 6 months, or not report the presence of crown-root fracture. In manual search in Dental Traumatology 20 articles were found, but none of them met the prerequisites established. So, three articles formed the basis of the study. CONCLUSION: The choice of how to treat orthodontic extrusion of crown-root fracture was effective and stable, without root and periodontal changes. Factors, such as root formation and presence of pulp vitality were decisive for determining the stages of treatment, however, there is no consensus based on scientific evidence about these protocols. PMID- 26522604 TI - Quality of Life related to Eruption Hematoma in a Twenty Months Old Infant. AB - AIM: This paper describes a case of an eruption hematoma in a 20-month-old boy and the impact of this hematoma on the quality of life (QoL) related to oral health of this infant and his family. BACKGROUND: Eruption hematoma is a soft benign cyst that contains blood and overlie a tooth that are about to erupt. Oral health conditions can affect the QoL and bring psychological impacts. CASE REPORT: The proposed treatment was based on oral hygiene instruction, normal diet and massage on the lesion area. A weekly follow-up visits up to the spontaneous regression at the 6 weeks of the lesion was conducted. The impact on QoL was assessed though the Brazilian version of the early childhood Oral Health Impact Scale (B-ECOHIS) questionnaire before and after 2 months of the hematoma regression. CONCLUSION: The presence of eruption hematoma impacted, physically and emotionally, the QoL related to oral health of the child and his family, and this impact decreased when the eruption hematoma disappeared. CLINICAL SIGNIFICANCE: It is important the knowledge of the dentists about eruption cyst/hematoma to make the correct decisions to improve the QoL of their patients and families. PMID- 26522605 TI - Alveolar Ridge Augmentation using the Allograft Bone Shell Technique. AB - BACKGROUND: The loss of teeth, whether it is from trauma or pathology, is accompanied by a concomitant loss of the surrounding alveolar bone. Khoury introduced a new method for grafting ridge defects in 2007. This technique involved using thin cortical plates harvested from the ramus, and in a 'sandwich' type manner, interposed these bone plates with cancellous bone harvested from the same site. Although this has shown success, the technique suffers from similar disadvantages of most harvesting techniques, i.e. a need for a second surgical site, and donor site morbidity. In this case presentation, we report the use of an allograft bone plate in a similar manner as was previously described by Khoury, to reconstruction lost alveolar bone in order to facilitate the correct three dimensional (3D) placement of dental implants. CASE DESCRIPTION: A 53-year old female presented for the restoration of her missing dentition in her upper jaw. The cone bean computed tomography (CBCT) revealed a large horizontal bony defect in the region of the upper anterior teeth, with minimal remaining bone. Using bone fixation screws, the bone plates were fixed to the buccal defect and the space between the plate and the existing palatal bone wall was then filled using a combination of autograft bone scrapings and xenograft bone particles. Six months after the initial surgery, the grafted sites were surgically re-entered and showed a marked increase in ridge width. CONCLUSION: Evidence exists for the use of bone allografts for a variety of alveolar bone augmentation procedures. The case presented outlines another use for this versatile biomaterial. CLINICAL SIGNIFICANCE: Bone harvesting for large alveolar defects is invariably associated with increased morbidity and an increased risk of postoperative complications. The above technique described by the author, may be used as a suitable alternative to reconstruct these defects, without harvesting bone from a second surgical site. PMID- 26522606 TI - Nanorobots: Changing Trends in Cancer Therapy. PMID- 26522607 TI - Successfully Treated Isolated Posterior Spinal Artery Aneurysm Causing Intracranial Subarachnoid Hemorrhage: Case Report. AB - There are very few published reports of rupture of an isolated posterior spinal artery (PSA) aneurysm, and consequently the optimal therapeutic strategy is debatable. An 84-year-old man presented with sudden onset of restlessness and disorientation. Neuroradiological imaging showed an intracranial subarachnoid hemorrhage (SAH) with no visible intracranial vascular lesion. Spinal magnetic resonance imaging (MRI) detected a localized subarachnoid hematoma at Th10-11. Both contrast-enhanced spinal computed tomography and enhanced MRI and magnetic resonance angiography revealed an area of enhancement within the hematoma. Superselective angiography of the left Th12 intercostal artery demonstrated a faintly enhanced spot in the venous phase. Thirteen days after the onset of symptoms, a small fusiform aneurysm situated on the radiculopial artery was resected. The patient's postoperative course was uneventful and he was eventually discharged in an ambulatory condition. To our knowledge, this 84-year-old man is the oldest reported case of surgical management of a ruptured isolated PSA aneurysm. This case illustrates both the validity and efficacy of this therapeutic approach. PMID- 26522608 TI - Phylogenomic analyses of a Mediterranean earthworm family (Annelida: Hormogastridae). AB - Earthworm taxonomy and evolutionary biology remain a challenge because of their scarce distinct morphological characters of taxonomic value, the morphological convergence by adaptation to the uniformity of the soil where they inhabit, and their high plasticity when challenged with stressful or new environmental conditions. Here we present a phylogenomic study of the family Hormogastridae, representing also the first piece of work of this type within earthworms. We included seven transcriptomes of the group representing the main lineages as previously-described, analysed in a final matrix that includes twelve earthworms and eleven outgroups. While there is a high degree of gene conflict in the generated trees that obscure some of the internal relationships, the origin of the family is well resolved: the hormogastrid Hemigastrodrilus appears as the most ancestral group, followed by the ailoscolecid Ailoscolex, therefore rejecting the validity of the family Ailoscolecidae. Our results place the origin of hormogastrids in Southern France, as previously hypothesised. PMID- 26522609 TI - A multilocus assessment of nuclear and mitochondrial sequence data elucidates phylogenetic relationships among European spirlins (Alburnoides, Cyprinidae). AB - The phylogenetic relationships and taxonomy of the spirlins in the genus Alburnoides are examined by comparative sequencing analysis of mitochondrial and nuclear markers. Molecular analyses revealed 17 Eurasian lineages divided into two main clades, termed the Ponto-Caspian and European in accordance with the lineage distribution. The indel diagnostics of beta-actin and S7 markers and translation of cyt b to the amino acid chain were evaluated as a reliable identifying tool for most of the recognised lineages. Lineage richness is closely connected with the existence of known glacial refugia in most cases. The underestimation of species richness in the genus Alburnoides is confirmed: the genetic analyses support the validity of 11 morphologically accepted species; apart from them, four phylogenetic lineages requiring descriptions as separate species were revealed. The distribution area of the nominotypical species A. bipunctatus s. stricto is newly defined. Two diverging phylogenetic lineages, A. ohridanus, and A. prespensis complex, were observed in the Southeast Adriatic Freshwater Ecoregion, confirmed as a hotspot of endemic biodiversity. A. ohridanus demonstrates high divergence from the A. prespensis complex, represented by three similar mitochondrial lineages with the same nuclear haplotypes and sympatric occurrence. The range restricted endemism was confirmed for at least seven species. The Albanian river systems, as well as the wider Ponto-Caspian basin exhibit complications among definite species delineations and gaps in understanding of microevolutionary processes; these areas require further investigations. PMID- 26522610 TI - Visualizing the morphology of vortex lattice domains in a bulk type-II superconductor. AB - Alike materials in the solid state, the phase diagram of type-II superconductors exhibit crystalline, amorphous, liquid and spatially inhomogeneous phases. The multitude of different phases of vortex matter has thence proven to act as almost ideal model system for the study of both the underlying properties of superconductivity but also of general phenomena such as domain nucleation and morphology. Here we show how neutron grating interferometry yields detailed information on the vortex lattice and its domain structure in the intermediate mixed state of a type-II niobium superconductor. In particular, we identify the nucleation regions, how the intermediate mixed state expands, and where it finally evolves into the Shubnikov phase. Moreover, we complement the results obtained from neutron grating interferometry by small-angle neutron scattering that confirm the spatially resolved morphology found in the intermediate mixed state, and very small-angle neutron scattering that confirm the domain structure of the vortex lattice. PMID- 26522611 TI - Does the addition of time-lapse morphokinetics in the selection of embryos for transfer improve pregnancy rates? A randomized controlled trial. AB - OBJECTIVE: To determine if the addition of continuous morphokinetic data improves reproductive outcomes when all embryos are cultured in a closed system. DESIGN: Prospective, randomized, controlled study. SETTING: Single academic center. PATIENT(S): A total of 235 patients undergoing fresh autologous IVF cycles with at least four embryos, cultured in the Embryoscope: 116 patients randomized to conventional once-daily morphologic embryo screening (CS) and 119 to additional time-lapse kinetic monitoring (TLM) for selection. INTERVENTION(S): TLM versus CS. MAIN OUTCOME MEASURE(S): Intrauterine clinical pregnancy (CPR) and implantation (IR) rates. RESULT(S): CPR and IR were similar overall (TLM vs. CS, respectively: CPR 68% vs. 63%; IR 51% vs. 45%) and with blastocyst transfers (CPR 74% vs. 67%; IR 56% vs. 51%). CPR with day 5 transfer was threefold higher than day 3 transfer, but group (TLM vs. CS) was not a significant predictor of clinical pregnancy or implantation. Significantly more multinucleation was detected when CS embryos were retrospectively reviewed with the use of TLM (7.0% vs. 35.3%), and multinucleation was independently associated with decreased rates of implantation. Time to the start of blastulation of <100 hours after insemination and the morphokinetic scoring system used in the TLM group were independently associated with implantation. CONCLUSION(S): The addition of time lapse morphokinetic data did not significantly improve clinical reproductive outcomes in all patients and in those with blastocyst transfers. Absence of multinucleation, timing of blastulation, and morphokinetic score were found to be associated with blastocyst implantation rates. CLINICAL TRIAL REGISTRATION NUMBER: NCT02081859. PMID- 26522612 TI - Potentialities of steady-state and transient thermography in breast tumour depth detection: A numerical study. AB - Breast thermography still has inherent limitations that prevent it from being fully accepted as a breast screening modality in medicine. The main challenges of breast thermography are to reduce false positive results and to increase the sensitivity of a thermogram. Further, it is still difficult to obtain information about tumour parameters such as metabolic heat, tumour depth and diameter from a thermogram. However, infrared technology and image processing have advanced significantly and recent clinical studies have shown increased sensitivity of thermography in cancer diagnosis. The aim of this paper is to study numerically the possibilities of extracting information about the tumour depth from steady state thermography and transient thermography after cold stress with no need to use any specific inversion technique. Both methods are based on the numerical solution of Pennes bioheat equation for a simple three-dimensional breast model. The effectiveness of two approaches used for depth detection from steady state thermography is assessed. The effect of breast density on the steady state thermal contrast has also been studied. The use of a cold stress test and the recording of transient contrasts during rewarming were found to be potentially suitable for tumour depth detection during the rewarming process. Sensitivity to parameters such as cold stress temperature and cooling time is investigated using the numerical model and simulation results reveal two prominent depth-related characteristic times which do not strongly depend on the temperature of the cold stress or on the cooling period. PMID- 26522613 TI - Surface toughness of silicon nitride bioceramics: I, Raman spectroscopy-assisted micromechanics. AB - Indentation micro-fracture is revisited as a tool for evaluating the surface toughness of silicon nitride (Si3N4) bioceramics for artificial joint applications. Despite being unique and practical from an experimental perspective, a quantitative assessment of surface fracture toughness using this method is challenging. An improved method has been developed, consisting of coupling indentation with confocal (spatially resolved) Raman piezo-spectroscopy. Empowered by the Raman microprobe, the indentation micro-fracture method was found to be capable of providing reliable surface toughness measurements in silicon nitride biomaterials. In designing the microstructures of bioceramic bearing couples for improved tribological performance, surface toughness must be considered as a fundamentally different and distinct parameter from bulk toughness. The coupling of indention crack opening displacements (COD) with local stress field assessments by spectroscopy paves the way to reliably compare the structural properties of bioceramics and to quantitatively monitor their evolution during environmental exposure. PMID- 26522615 TI - Hematopoietic Support Capacity of Mesenchymal Stem Cells: Biology and Clinical Potential. AB - Mesenchymal stem cells (MSCs) play an important role in the physiology and homeostasis of the hematopoietic system. Because MSCs generate most of the stromal cells present in the bone marrow (BM), form part of the hematopoietic stem cell (HSC) niche, and produce various molecules regulating hematopoiesis, their hematopoiesis-supporting capacity has been demonstrated. In the last decade, BM-MSCs have been proposed to be useful in some ex vivo protocols for HSC expansion, with the aim of expanding their numbers for transplant purposes (HSC transplant, HSCT). Furthermore, application of MSCs has been proposed as an adjuvant cellular therapy for promoting rapid hematopoietic recovery in HSCT patients. Although the MSCs used in preliminary clinical trials have come from the BM, isolation of MSCs from far more accessible sources such as neonatal tissues has now been achieved, and these cells have been found to possess similar biological characteristics to those isolated from the BM. Therefore, such tissues are now considered as a potential alternative source of MSCs for clinical applications. In this review, we discuss current knowledge regarding the biological characteristics of MSCs as related to their capacity to support the formation of hematopoietic stem and progenitor cells. We also describe MSC manipulation for ex vivo HSC expansion protocols used for transplants and their clinical relevance for hematopoietic recovery in HSCT patients. PMID- 26522616 TI - Meta-analysis of colloids versus crystalloids in critically ill, trauma and surgical patients. AB - BACKGROUND: There is uncertainty regarding the safety of different volume replacement solutions. The aim of this study was systematically to review evidence of crystalloid versus colloid solutions, and to determine whether these results are influenced by trial design or clinical setting. METHODS: PubMed, Embase and the Cochrane Central Register of Controlled Trials were used to identify randomized clinical trials (RCTs) that compared crystalloids with colloids as volume replacement solutions in patients with traumatic injuries, those undergoing surgery and in critically ill patients. Adjusted odds ratios (ORs) for mortality and major morbidity including renal injury were pooled using fixed-effect and random-effects models. RESULTS: Some 59 RCTs involving 16 889 patients were included in the analysis. Forty-one studies (69 per cent) were found to have selection, detection or performance bias. Colloid administration did not lead to increased mortality (32 trials, 16 647 patients; OR 0.99, 95 per cent c.i. 0.92 to 1.06), but did increase the risk of developing acute kidney injury requiring renal replacement therapy (9 trials, 11 648 patients; OR 1.35, 1.17 to 1.57). Sensitivity analyses that excluded small and low-quality studies did not substantially alter these results. Subgroup analyses by type of colloid showed that increased mortality and renal replacement therapy were associated with use of pentastarch, and increased risk of renal injury and renal replacement therapy with use of tetrastarch. Subgroup analysis indicated that the risks of mortality and renal injury attributable to colloids were observed only in critically ill patients with sepsis. CONCLUSION: Current general restrictions on the use of colloid solutions are not supported by evidence. PMID- 26522614 TI - BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages. AB - The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential. PMID- 26522617 TI - Recommendation of Occupational Exposure Limits (2015-2016). PMID- 26522618 TI - Autobiographical memory dysfunctions in depressive disorders. AB - Autobiographical memory (AM) is a ubiquitous human experience that belongs to long-term declarative memory. It plays interpersonal and intrapsychic functions. The main aim of this study is to present results of contemporary research on AM in recurrent depressive disorders. The available research literature suggests that AM dysfunctions are a precursor and risk factor for recurrent depressive disorders and that they also appear to be a consequence of depressive symptoms in a bidirectional and interacting manner. These data suggest that AM might be a viable therapeutic target for cognitive remediation strategies, given the impact of cognition on diverse clinical outcomes. PMID- 26522619 TI - The neural basis of integrating pre- and post-response information for goal directed actions. AB - A fundamental prerequisite for goal-directed action is to encode the contingencies between responses (R) producing specific outcomes (O) in specific stimulus conditions (S). The present study aimed to characterize the functional neuroanatomy of different associational sub-components of such S-R-O contingencies during the first few trials of exposure. We devised a novel paradigm that was suited to distinguish BOLD activation patterns related to S-R, R-O, and the full S-R-O contingency. Different from previous studies our experimental design ensured that stimulus-related processes and outcome-related processes were maximally comparable, as both were learned incidentally and lacked intrinsic incentive value, and different from trial-and-error learning situations, outcomes did not serve a special role as performance feedback. We observed contingency-related dissociations between SMA, lateral OFC, and large parts of the reward system including central OFC, anterior striatum and midbrain areas. While the lateral OFC was involved in processing differential outcomes irrespective of a predictive stimulus context, the SMA was specifically engaged when differential outcomes could be predicted by the stimulus. By contrast, the activation pattern of reward system areas suggested that these regions serve a role in integrating non-incentive differential outcome information and incentive common outcome information. Together, these results support the notion that striatal and orbitofrontal regions are involved in outcome-related processes beyond trial-and-error S-R learning, that is, when outcomes are non-incentive and do not serve as reinforcing feedback that drives learning. Furthermore, our results clarify the role of the SMA in outcome-related processes thereby supporting current versions of ideomotor theory. PMID- 26522620 TI - Laterality and unilateral deafness: Patients with congenital right ear deafness do not develop atypical language dominance. AB - Auditory speech perception, speech production and reading lateralize to the left hemisphere in the majority of healthy right-handers. In this study, we investigated to what extent sensory input underlies the side of language dominance. We measured the lateralization of the three core subprocesses of language in patients who had profound hearing loss in the right ear from birth and in matched control subjects. They took part in a semantic decision listening task involving speech and sound stimuli (auditory perception), a word generation task (speech production) and a passive reading task (reading). The results show that a lack of sensory auditory input on the right side, which is strongly connected to the contralateral left hemisphere, does not lead to atypical lateralization of speech perception. Speech production and reading were also typically left lateralized in all but one patient, contradicting previous small scale studies. Other factors such as genetic constraints presumably overrule the role of sensory input in the development of (a)typical language lateralization. PMID- 26522621 TI - CEINMS: A toolbox to investigate the influence of different neural control solutions on the prediction of muscle excitation and joint moments during dynamic motor tasks. AB - Personalized neuromusculoskeletal (NMS) models can represent the neurological, physiological, and anatomical characteristics of an individual and can be used to estimate the forces generated inside the human body. Currently, publicly available software to calculate muscle forces are restricted to static and dynamic optimisation methods, or limited to isometric tasks only. We have created and made freely available for the research community the Calibrated EMG-Informed NMS Modelling Toolbox (CEINMS), an OpenSim plug-in that enables investigators to predict different neural control solutions for the same musculoskeletal geometry and measured movements. CEINMS comprises EMG-driven and EMG-informed algorithms that have been previously published and tested. It operates on dynamic skeletal models possessing any number of degrees of freedom and musculotendon units and can be calibrated to the individual to predict measured joint moments and EMG patterns. In this paper we describe the components of CEINMS and its integration with OpenSim. We then analyse how EMG-driven, EMG-assisted, and static optimisation neural control solutions affect the estimated joint moments, muscle forces, and muscle excitations, including muscle co-contraction. PMID- 26522622 TI - Finite element models predict the location of microdamage in cancellous bone following uniaxial loading. AB - High-resolution finite element models derived from micro-computed tomography images are often used to study the effects of trabecular microarchitecture and loading mode on tissue stress, but the degree to which existing finite element methods correctly predict the location of tissue failure is not well characterized. In the current study, we determined the relationship between the location of highly strained tissue, as determined from high-resolution finite element models, and the location of tissue microdamage, as determined from three dimensional fluoroscopy imaging, which was performed after the microdamage was generated in-vitro by mechanical testing. Fourteen specimens of human vertebral cancellous bone were assessed (8 male donors, 2 female donors, 47-78 years of age). Regions of stained microdamage, were 50-75% more likely to form in highly strained tissue (principal strains exceeding 0.4%) than elsewhere, and generally the locations of the regions of microdamage were significantly correlated (p<0.05) with the locations of highly strained tissue. This spatial correlation was stronger for the largest regions of microdamage (>=1,000,000MUm(3) in volume); 87% of large regions of microdamage were located near highly strained tissue. Together, these findings demonstrate that there is a strong correlation between regions of microdamage and regions of high strain in human cancellous bone, particularly for the biomechanically more important large instances of microdamage. PMID- 26522623 TI - A novel specimen-specific methodology to optimise the alignment of long bones for experimental testing. AB - The choice of coordinate system and alignment of bone will affect the quantification of mechanical properties obtained during in-vitro biomechanical testing. Where these are used in predictive models, such as finite element analysis, the fidelic description of these properties is paramount. Currently in bending and torsional tests, bones are aligned on a pre-defined fixed span based on the reference system marked out. However, large inter-specimen differences have been reported. This suggests a need for the development of a specimen specific alignment system for use in experimental work. Eleven ovine tibiae were used in this study and three-dimensional surface meshes were constructed from micro-Computed Tomography scan images. A novel, semi-automated algorithm was developed and applied to the surface meshes to align the whole bone based on its calculated principal directions. Thereafter, the code isolates the optimised location and length of each bone for experimental testing. This resulted in a lowering of the second moment of area about the chosen bending axis in the central region. More importantly, the optimisation method decreases the irregularity of the shape of the cross-sectional slices as the unbiased estimate of the population coefficient of variation of the second moment of area decreased from a range of (0.210-0.435) to (0.145-0.317) in the longitudinal direction, indicating a minimisation of the product moment, which causes eccentric loading. Thus, this methodology serves as an important pre-step to align the bone for mechanical tests or simulation work, is optimised for each specimen, ensures repeatability, and is general enough to be applied to any long bone. PMID- 26522624 TI - Efficient Expression and Crystallization System of Cancer-Associated Carbonic Anhydrase Isoform IX. AB - Human carbonic anhydrase IX (CA IX) is overexpressed in a number of solid tumors and is considered to be a marker for cellular hypoxia that it is not produced in most normal tissues. CA IX contributes to the acidification of the extracellular matrix, which, in turn, favors tumor growth and metastasis. Therefore, CA IX is considered to be a promising anti-cancer drug target. However, the ability to specifically target CA IX is challenging due to the fact that the human genome encodes 15 different carbonic anhydrase isoforms that have a high degree of homology. Furthermore, structure-based drug design of CA IX inhibitors so far has been largely unsuccessful due to technical difficulties regarding the expression and crystallization of the enzyme. Currently, only one baculovirus-produced CA IX structure in complex with a nonspecific CA inhibitor, acetazolamide, is available in Protein Data Bank. We have developed an efficient system for the production of the catalytic domain of CA IX in methylotrophic yeast Pichia pastoris. The produced protein can be easily crystallized in the presence of inhibitors, as we have demonstrated for several 2-thiophene-sulfonamide compounds. We have also observed significant differences in the binding mode of chemically identical compounds to CA IX and CA II, which can be further exploited in the design of CA IX-specific inhibitors. PMID- 26522625 TI - Preface. PMID- 26522626 TI - Efficacy and Safety of Transthoracic Echocardiography Alone in Transcatheter Closure of Secundum-Type Atrial Septal Defects in Adults. AB - BACKGROUND: On-site transthoracic echocardiography (TTE) to guide the transcutaneous closure of secundum-type atrial septal defects (ASDs) in the catheterization laboratory remains unclear, especially in adults. METHODS: Between 2005 and 2012, a total of 82 adults underwent transcutaneous closure of ASDs. The initial 15 cases underwent the procedure with both on-site transesophageal echocardiography (TEE) and TTE monitoring. Since January 2008, a total of 67 patients underwent on-site TTE alone to guide the procedure. RESULTS: Among the 82 adult patients who underwent a transcutaneous closure of the secundum-type ASD procedure, all had successful closure of the defects, and no periprocedural adverse complications occurred. No statistical significance was observed in the successful complete shunt closure rate between the TEE plus TTE and TTE groups during sequential follow-up (postprocedure 24 hour [87% vs. 92%],1 month [93% vs. 95%], 3 month [93% vs. 97%], and 12 month [93% vs. 97%], P > 0.05, respectively) nor was a significant difference observed between the two groups, including decreased right ventricular dimension (29.5 +/- 3.3 vs. 32.0 +/- 4.9 mm, 26.5 +/- 3.0 vs. 28.7 +/- 4.6 mm, 26.2 +/- 3.1 vs. 28.2 +/- 4.8 mm, and 25.6 +/- 2.8 vs. 27.7 +/- 4.7 mm, P > 0.05, respectively) or increased left ventricular end-diastolic dimension (41.1 +/- 2.0 vs. 42.6 +/- 3.0 mm, 44.3 +/- 2.7 vs. 45.5 +/- 3.1 mm, 44.2 +/- 2.8 vs. 45.4 +/- 3.1 mm, 44.9 +/- 2.7 vs. 45.8 +/- 2.6 mm, P > 0.05, respectively) before the procedure, and at the 3-, 6-, and 12-month follow-up evaluations. CONCLUSION: This study showed that TTE guidance alone may be considered efficacious and safe as TEE during a transcutaneous ASD occlusion procedure in select adults. PMID- 26522627 TI - Bioaccessible Porosity in Soil Aggregates and Implications for Biodegradation of High Molecular Weight Petroleum Compounds. AB - We evaluated the role of soil aggregate pore size on biodegradation of essentially insoluble petroleum hydrocarbons that are biodegraded primarily at the oil-water interface. The size and spatial distribution of pores in aggregates sampled from biodegradation experiments of a clayey, aggregated, hydrocarbon contaminated soil with relatively high bioremediation end point were characterized by image analyses of X-ray micro-CT scans and N2 adsorption. To determine the bioaccessible pore sizes, we performed separate experiments to assess the ability of hydrocarbon degrading bacteria isolated from the soil to pass through membranes with specific sized pores and to access hexadecane (model insoluble hydrocarbon). Hexadecane biodegradation occurred only when pores were 5 MUm or larger, and did not occur when pores were 3 MUm and smaller. In clayey aggregates, ~ 25% of the aggregate volume was attributed to pores larger than 4 MUm, which was comparable to that in aggregates from a sandy, hydrocarbon contaminated soil (~23%) scanned for comparison. The ratio of volumes of inaccessible pores (<4 MUm) to bioaccessible pores (>4 MUm) in the clayey aggregates was 0.32, whereas in the sandy aggregates it was approximately 10 times lower. The role of soil microstructure on attainable bioremediation end points could be qualitatively assessed in various soils by the aggregate characterization approach outlined herein. PMID- 26522628 TI - Quantum Oscillation Signatures of Pressure-induced Topological Phase Transition in BiTeI. AB - We report the pressure-induced topological quantum phase transition of BiTeI single crystals using Shubnikov-de Haas oscillations of bulk Fermi surfaces. The sizes of the inner and the outer FSs of the Rashba-split bands exhibit opposite pressure dependence up to P = 3.35 GPa, indicating pressure-tunable Rashba effect. Above a critical pressure P ~ 2 GPa, the Shubnikov-de Haas frequency for the inner Fermi surface increases unusually with pressure, and the Shubnikov-de Haas oscillations for the outer Fermi surface shows an abrupt phase shift. In comparison with band structure calculations, we find that these unusual behaviors originate from the Fermi surface shape change due to pressure-induced band inversion. These results clearly demonstrate that the topological quantum phase transition is intimately tied to the shape of bulk Fermi surfaces enclosing the time-reversal invariant momenta with band inversion. PMID- 26522629 TI - Cat and Mouse. PMID- 26522630 TI - Preparedness of Entering Pediatric Dentistry Residents: Advanced Pediatric Program Directors' and First-Year Residents' Perspectives. AB - For children to receive needed oral health care, adequate training at both the predoctoral and postdoctoral levels of dental education is required, but previous studies have found inadequacies in predoctoral education that lead to general dentists' unwillingness to treat certain young populations. As another way of assessing predoctoral preparation, the aim of this study was to determine the perspectives of first-year residents and pediatric program directors about residents' preparedness to enter advanced education programs in pediatric dentistry. Surveys were sent to all 74 U.S. program directors and 360 first-year residents. The survey focused on procedures related to prevention, behavior management, restorative procedures, pulp therapy, sedation, and surgery, as well as treating patients funded by Medicaid and with special health care needs. Among the first-year residents, 173 surveys were returned for a 48% response rate; 61 directors returned surveys for an 82% response rate. Only half of the residents (55%) reported feeling adequately prepared for their first year in residency; less than half cited adequate preparation to place stainless steel crowns (SSCs) (42%) and perform pulpotomies (45%). Far fewer felt adequately prepared to provide treatment for children six months to three years of age, including examinations (29%), infant oral exams (27%), and children with severe caries (37%). The program directors were even less positive about the adequacy of residents' preparation. Only 17% deemed them adequately prepared to place SSCs and 13% to perform pulpotomies. Approximately half reported their first-year residents were inadequately prepared to treat very young children and children with severe caries (55% each). This study found that the perceived inadequacy of predoctoral education in pediatric dentistry was consistent at both the learner and educator levels, supporting previous studies identifying inadequacies in this area. PMID- 26522631 TI - Educators' and Applicants' Views of the Postdoctoral Pediatric Dentistry Admission Process: A Qualitative Study. AB - The postdoctoral application and matching process in dental education is a high stakes and resource-intensive process for all involved. While programs seek the most qualified candidates, applicants strive to be competitive to increase their likelihood of being accepted to a desirable program. There are limited data regarding either subjective or objective factors underlying the complex interplay between programs and applicants. This qualitative study sought to provide insight into the stakeholders' experiences and views on the matching process. Telephone and in-person interviews were conducted with ten pediatric dentistry program directors and ten recent applicants to pediatric dentistry programs in the United States in 2013-14. Participants were selected to represent the geographic (five districts of the American Academy of Pediatric Dentistry) and institutional (hospital- or university-based) diversity of pediatric dentistry programs. Interviews were recorded and transcribed verbatim. Veracity and need for more information were the themes most often articulated by both groups. The program directors most valued teachability and self-motivation as desirable applicant characteristics. The applicants relied primarily on subjective sources to gather information about programs and prioritized location and financial factors as pivotal for their rankings. Both groups appreciated the uniformity of the current application process and highlighted several weaknesses and areas for improvement. These results shed light on the postdoctoral matching process in pediatric dentistry via a qualitative description of stakeholders' experiences and viewpoints. These insights can serve as a basis for improving and refining the matching process. PMID- 26522632 TI - Knowledge, Attitudes, and Practices of Pediatric Dentists Regarding Speech Evaluation of Patients: Implications for Dental Education. AB - The aim of this cross-sectional study was to determine pediatric dentists' attitudes about speech evaluation in the dental setting and assess their knowledge of speech development and pathology. In October 2013, members of the American Academy of Pediatric Dentistry were invited to participate in an electronic questionnaire. Categories of questions were demographics, attitudes and confidence in speech pathology, and theoretical and practical knowledge of speech development and speech pathology. Theoretical knowledge was assessed using questions about phonetics and speech milestones. Practical knowledge was determined with three 30-second interview-style video clips. A total of 539 responses were received for a response rate of 10.4%. The majority of respondents reported feeling that speech evaluation should be part of the pediatric dental visit (72.8%) and felt confident in their ability to detect speech issues (73.2%). However, they did poorly on the theoretical knowledge questions (41.9%) as well as the practical knowledge questions (8.5%). There was a statistically significant difference in theoretical score between gender and type of occupation (p<0.05). This difference was not observed when examining practical knowledge. This study suggests that although pediatric dentists are in an ideal position to aid in the detection of speech issues, they currently have insufficient training and knowledge to do so. PMID- 26522633 TI - Interprofessional Education in U.S. Dental Hygiene Programs: A National Survey. AB - Although there are many benefits of interprofessional health care, no previous research has sought to define the status of interprofessional education (IPE) in U.S. dental hygiene programs. The aims of this study were to assess how these programs engage in IPE, the challenges they encounter, and the value they place on IPE. Additionally, the study explored how program characteristics are related to IPE. Data were collected with a web-based survey sent to all 322 U.S. dental hygiene program directors (response rate: 33% of the 305 successfully contacted). The majority of the responding programs were located at institutions with nursing (90%) and other allied health programs (85%). They were likely to collaborate with nursing (50%), other allied health (44%), and dental assisting programs (41%), but were less likely to collaborate with dental schools (28%). IPE was most likely to occur in volunteer activities (68%), basic science courses (65%), and communication training/behavioral science courses (63%/59%). The most frequently reported challenges for IPE were schedule coordination (92%) and curriculum overload (76%). The majority of the respondents agreed that IPE was a priority for the dental hygiene profession in the U.S. (59%) and for the program directors personally (56%). Programs granting bachelor degrees were more likely to have IPE as a priority than programs that did not grant such degrees (scale of 1-5 with 5=most important: 3.81 vs. 2.88; p<0.01). The longer the students spent in the programs, the more those programs engaged in IPE (r=0.21; p<0.05). The data collected in this study can contribute to future efforts to help dental hygiene programs engage in meaningful IPE and contribute to developing interprofessional care in the U.S. health care system. PMID- 26522634 TI - Association Between Dental Student-Developed Exam Questions and Learning at Higher Cognitive Levels. AB - New dental accreditation standards emphasize that graduates must be competent in the use of critical thinking (a high cognitive-level skill). Despite this new standard, most written assessments in dental school courses are still based on low cognitive-level questions. The aim of this study was to determine if an exercise that allows students to collaboratively write exam questions would help cultivate higher cognitive levels of learning. To evaluate this exercise at one U.S. dental school, the cognitive level (according to Bloom's taxonomy) of multiple-choice exam questions and students' scores across two cohorts in a cariology course were compared. This evaluation took place using a control group in which questions were instructor-generated and an intervention group in which students worked in groups to develop questions. All students in one first-year class participated in the intervention group (n=104); all students in the first year class two years earlier served as the control group (n=106). Among students in the intervention group, the response rate to a post-intervention survey measuring students' attitudes about the experience was 70% (N=73). The results showed that the students generating their own assessments developed higher cognitive-level exam questions than the instructor-generated assessments. The intervention group (with student-generated assessments) also performed as well or better on tests compared to the control group (with instructor-generated assessments). In the intervention group survey, the vast majority of students agreed that the exercise was helpful for their overall learning experience, but working in teams was said to be the least valuable component of the activity for their learning. This study suggests that student-driven, collaborative assessments can be an important tool for building critical thinking skills in dental classrooms and that it may be worthwhile to expand this type of exercise into other courses. PMID- 26522635 TI - A One-Day Dental Faculty Workshop in Writing Multiple-Choice Questions: An Impact Evaluation. AB - Long training workshops on the writing of exam questions have been shown to be effective; however, the effectiveness of short workshops needs to be demonstrated. The aim of this study was to evaluate the impact of a one-day, seven-hour faculty development workshop at the College of Dentistry, King Saud University, Saudi Arabia, on the quality of multiple-choice questions (MCQs). Kirkpatrick's four-level evaluation model was used. Participants' satisfaction (Kirkpatrick's Level 1) was evaluated with a post-workshop questionnaire. A quasi experimental, randomized separate sample, pretest-posttest design was used to assess the learning effect (Kirkpatrick's Level 2). To evaluate transfer of learning to practice (Kirkpatrick's Level 3), MCQs created by ten faculty members as a result of the training were assessed. To assess Kirkpatrick's Level 4 regarding institutional change, interviews with three key leaders of the school were conducted, coded, and analyzed. A total of 72 course directors were invited to and attended some part of the workshop; all 52 who attended the entire workshop completed the satisfaction form; and 22 of the 36 participants in the experimental group completed the posttest. The results showed that all 52 participants were highly satisfied with the workshop, and significant positive changes were found in the faculty members' knowledge and the quality of their MCQs with effect sizes of 0.7 and 0.28, respectively. At the institutional level, the interviews demonstrated positive structural changes in the school's assessment system. Overall, this one-day item-writing faculty workshop resulted in positive changes at all four of Kirkpatrick's levels; these effects suggest that even a short training session can improve a dental school's assessment of its students. PMID- 26522636 TI - Item Analysis of Multiple-Choice Questions in Teaching Prosthodontics. AB - The aim of this study was to analyze multiple-choice questions used in teaching prosthodontics to dental students based on the items' distractor effectiveness and their difficulty and discrimination capacity. The overall goals were to assist the prosthodontics department in modifying its existing question bank and creating a set of prevalidated questions of known difficulty and discrimination capacity. The items selected for this study were from the three formative examinations in prosthodontics for fourth-year BDS students at Sinhgad Dental College and Hospital, Pune, Maharastra, India, during academic year 2011-12. As all the students' completed exams and scores were available, the task was to evaluate the efficacy of items already administered. Based on the item analysis of the questions, the following results were noted. None of the three examinations had items that were too difficult or defective. However, all three examinations had large percentages of easy items and many items had a low discrimination index. More than 60-70% of the items on all three examinations included ineffective distractors. All items therefore needed modifications based on their distractor effectiveness and difficulty and discrimination indices. After the study was completed, the results were discussed in a meeting with all teachers in the prosthodontics department and the test constructors, and suggestions were made with regard to improving the items for better evaluation of students. PMID- 26522638 TI - Correlation Between Students' Dental Admission Test Scores and Performance on a Dental School's Competency Exam. AB - The aim of this study was to investigate whether there was a statistically significant positive correlation between dental students' Dental Admission Test (DAT) scores, particularly on the Perceptual Ability Test (PAT), and their performance on a dental school's competency exam. Scores from the written and clinical competency exam administered in the fall quarter of the fourth year of the curriculum at Midwestern University College of Dental Medicine-Arizona were compared to DAT scores of all 216 members of the graduating classes of 2012 and 2013. It was hypothesized that students who performed highly on one or more sections of the DAT would perform highly on the competency exam. Backward stepwise regression analyses were used to analyze the data. The results showed that the PAT scores were most strongly correlated with the competency exam scores and were a positive predictor for all three clinical sections of the exam (operative dentistry, periodontics, and endodontics). Positive predictors for the written portion of the exam were total DAT score for patient assessment and treatment planning and the DAT reading comprehension score for prosthodontics; there were no predictors for periodontics. The total variance explained by the results ranged from 4% to 15%. While statistically significant relationships were found between the students' PAT scores and clinical performance, DAT scores explained relatively little variance in the competency exam scores. According to these findings, neither the PAT nor any of the DAT components contributed to predicting these students' clinical performance. PMID- 26522637 TI - Agreement Among Dental Students, Peer Assessors, and Tutor in Assessing Students' Competence in Preclinical Skills. AB - The aim of this study was to determine the level of agreement regarding assessments of competence among dental students, their student peers, and their clinical skills tutors in a preclinical skills program. In 2012-13 at the University of Edinburgh, second-year dental students learned to perform the following seven cavity preparations/restorations on primary and permanent Frasaco teeth: single-surface adhesive occlusal cavity; single-surface adhesive interproximal cavity; single-surface adhesive labial cavity; multi-surface adhesive cavity; multi-surface amalgam cavity; pre-formed metal crown preparation; and composite resin buildup of a fractured maxillary central incisor tooth. Each student, a randomly allocated student peer, and the clinical skills tutor used standardized descriptors to assign a competency grade to all the students' preparations/restorations. The grades were analyzed by chi-square analysis. Data were available for all 59 second-year students in the program. The results showed that both the students and their peers overestimated the students' competence compared to the tutor at the following levels: single-surface adhesive occlusal cavity (chi(2)=10.63, p=0.005); single-surface adhesive interproximal cavity (chi(2)=11.40, p=0.003); single-surface labial cavity (chi(2)=23.70, p=0.001); multi-surface adhesive cavity (chi(2)=12.56, p=0.002); multi-surface amalgam cavity (chi(2)=38.85, p=0.001); pre-formed metal crown preparation (chi(2)=40.41, p=0.001); and composite resin buildup (chi(2)=57.31, p=0.001). As expected, the lowest levels of agreement occurred on the most complicated procedures. These findings support the need for additional ways to help students better self-assess their work. PMID- 26522639 TI - Are All Dentiform Teeth with Simulated Caries the Same? A Six-Year Retrospective Study in Preclinical Operative Dentistry. AB - Dentiform teeth with simulated caries (DTSC), frequently used in preclinical courses, should show no variability in the amount of simulated caries from tooth to tooth. However, the level of caries variability among DTSC is currently unknown. The aim of this study was to assess the variation in simulated caries levels in one group of DTSC and determine whether variation among DTSC impacted the preclinical performance of dental students. In the study, 80 commercially available mandibular first molar DTSC with simulated mesio-occluso-distal caries were sectioned in coronal (n=40) and sagittal (n=40) planes where the caries depth/width was greatest. Section images were analyzed for variation in levels of simulated caries using image-processing software. Three years of practical performance data using DTSC were compared with three years of practical performance data using dentiform teeth without simulated caries, for a total of six years (students' performance on two exams, Practical 1 and Practical 2). The results showed that 70% of the coronally sectioned teeth had manufacturing defects that resulted in caries overextension at the dentino-enamel junctions (DEJs). Overextensions were found at the DEJ in 41.3% of the sagittally sectioned teeth. There was a statistically significant decrease in Practical 1 performance of the students who used DTSC as compared with students who used teeth without simulated caries (p=0.0001); there was no statistically significant difference on Practical 2 performance. Of the DTSC evaluated in this study, 56.6% contained manufacturing defects, and more than 80% were found to have excessive caries variation. Prediction of which DTSC will have caries overextension is not possible. Students preparing DTSC that contain caries overextension are therefore at increased risk of receiving undeserved negative summative assessment on practical examinations. PMID- 26522640 TI - The Role of Organizational Context in the Creation and Sustainability of Dental Faculty Development Initiatives. AB - Dental faculty development programs exist for a variety of reasons: to improve teaching skills, develop and reinforce relationships among colleagues and mentors, foster career development, and support curricular initiatives and institutional priorities. These activities impact individual faculty members as well as the institutions in which they work. Each institution has a distinct culture that should be acknowledged and understood alongside conventional outcome measures. As such, this article provides an expanded view of faculty development programming, associated educational activities, and related organizational changes at the College of Dentistry, New York University (NYU) since 2005. Contextual factors include the existence of an Office of Professional Development established in 1999, an Academy of Distinguished Educators founded in 2010, and other programs for present and future educators that support the college's educational mission. Outcomes include a comparison study of one program, the creation of new courses, the sustainability and expansion of existing programs, participants' retention rate, and an increase in awards and other educational accomplishments such as publication of abstracts, oral presentations, and related activities by NYU faculty at national forums in dental education. PMID- 26522642 TI - Development and Application of a New Learning Object for Teaching Operative Dentistry Using Augmented Reality. AB - Learning objects (LOs) associated with augmented reality have been used as attractive new technologic tools in the educational process. However, the acceptance of new LOs must be verified with the purpose of using these innovations in the learning process in general. The aim of this study was to develop a new LO and investigate the acceptance of gold onlay in teaching preparation design at a dental school in Brazil. Questionnaires were designed to assess, first, the users' computational ability and knowledge of computers (Q1) and, second, the users' acceptance of the new LO (Q2). For both questionnaires, the internal consistency index was calculated to determine whether the questions were measuring the same construct. The reliability of Q2 was measured with a retest procedure. The LO was tested by dental students (n=28), professors and postgraduate students in dentistry and prosthetics (n=30), and dentists participating in a continuing education or remedial course in dentistry and/or prosthetics (n=19). Analyses of internal consistency (Kappa coefficient and Cronbach's alpha) demonstrated a high degree of confidence in the questionnaires. Tests for simple linear regressions were conducted between the response variable (Q2) and the following explanative variables: the Q1 score, age, gender, and group. The results showed wide acceptance regardless of the subjects' computational ability (p=0.99; R2=0), gender (p=0.27; R2=1.6%), age (p=0.27; R2=0.1%), or group (p=0.53; R2=1.9%). The methodology used enabled the development of an LO with a high index of acceptance for all groups. PMID- 26522641 TI - Using a Simulated Infobutton Linked to an Evidence-Based Resource to Research Drug-Drug Interactions: A Pilot Study with Third-Year Dental Students. AB - Many health professions students and clinicians are using evidence-based databases that allow for quicker and more accurate clinical decisions. The aims of this pilot study were to compare third-year dental students' speed and accuracy in researching questions about drug-drug interactions (DDI) when using two different methods: a simulated infobutton linked to the evidence-based clinical decision support resource UpToDate versus traditional Internet resources accessed through a computer or smart device. Students researched two simulated cases during two sessions. In the first session, half the students used the infobutton, while the other half used traditional electronic tools only. In the second session, ten days later, a cross-over took place. The sessions were timed, and after researching the case, students answered three questions on the use of antibiotics, analgesics, and local anesthetics. Of the 50 students who volunteered for the study, two were excluded, and 44 participated in both sessions and the exam. The results showed that the students took a similar amount of time to identify DDI whether they used the infobutton (mean=286.5 seconds) or traditional tools (265.2 seconds); the difference was not statistically significant (p=0.429). Their scores using the two research methods were similar in all three content areas: antibiotics (p=0.797), analgesics (p=0.850), and local anesthetics (p=0.850). In a post-intervention survey, students were generally favorable about infobutton and UpToDate, reporting the tool was easy to use (62.5%), provided the answer they were looking for (53.1%), was fast (50%), and they would use it again (68.8%). This pilot study found that the time and accuracy of these students conducting DDI research with the infobutton and UpToDate were about the same as using traditional Internet resources. PMID- 26522643 TI - Development and Evaluation of an Endodontic Simulation Model for Dental Students. AB - The aims of this study were to develop an endodontic simulation model able to implement the electronic method of working length determination (electronic apex locators, EALs) in a dental school, to evaluate the practicality of this tool for dental students, and to compare the accuracy of working length measurements achieved by the EAL and the radiographic method. A new simulation model was constructed by embedding extracted human teeth in a self-cured resin, along with a conductive medium. After radiographic and electronic working length determinations, root canal instrumentation was performed by students at a dental school in Austria according to the working lengths obtained from the EAL. Subsequently, root apices (n=44) were longitudinally sectioned using a diamond coated bur. Measurements of the distance between the anatomical root apex (ARA) and the apical constriction (AC) as well as between ARA and the ascertained apical point of endodontic instrumentation were performed using digital photography and a 3D computer-assisted design software. The distance between ARA and the radiologic (ARA-R) or electrometric (ARA-EL) readings of the apical point of endodontic instrumentation was compared with the actual distance ARA-AC. The accuracy of both methods was determined. The difference between the actual distance ARA-AC and the targeted radiological distance was statistically significant (p=0.0001), as was the measured distance between ARA-R and ARA-EL (p=0.016). The electronic method seems to be more precisely referring to the AC (R(2)=0.0198) than the radiographic method (R(2)=0.0019). These results suggest that the endodontic simulation model described in this study can be successfully used in preclinical dental education. PMID- 26522644 TI - WITHDRAWN: International forum: WAA 2015 newsletter. AB - This article has been withdrawn at the request of the publisher. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26522645 TI - Unmethylated CpG motifs in Toxoplasma gondii DNA induce TLR9- and IFN-beta dependent expression of alpha-defensin-5 in intestinal epithelial cells. AB - The gut epithelial barrier is a strategic place to prevent, or at least to limit, parasite dissemination upon oral infection with Toxoplasma gondii. Innate immunity to this pathogen results from delicate interactions involving different components of the infecting agent and the host. We herein aimed to examine the molecular mechanism by which protozoan DNA boosts the production of alpha defensin-5 (DEFA-5), the main antimicrobial peptide at the target site of infection. The present study shows that DEFA-5 is rapidly upregulated in intestinal epithelial cells following intracellular Toll-like receptor 9 (TLR9) activation by unmethylated CpG motifs in DNA from T. gondii (CpG-DNA). Concomitantly, CpG-DNA purified from the pathogen markedly increased TLR9 mRNA expression levels in the Caco-2 cell line. We further verified that DEFA-5 production was dependent on interferon-beta released from these cells upon treatment with CpG-DNA prepared from tachyzoites. Our results suggest that, in protozoan DNA-stimulated intestinal epithelial cells, the TLR9/interferon beta/DEFA-5 pathway may initiate an innate anti-T. gondii response without the need of parasite invasion. These findings highlight the key role of the gut epithelium in Toxoplasma recognition and amplification of local host defence against this microbe, thereby contributing to gain insight into immunoprotective mechanisms and to improve therapeutic strategies. PMID- 26522646 TI - CD99 regulates CXCL12-induced chemotaxis of human plasma cells. AB - Migration of plasma cells (PCs) is crucial for the control of PC survival and antibody production and is controlled by chemokines, most importantly by CXCL12. This study investigated the role of CD99 in CXCL12-induced PC migration. Among B cell subsets in the tonsils, CD99 expression was highest in PCs. CD99 expression increased during in vitro differentiation of germinal center B cells and was highest in PCs. CD99 engagement reduced chemotactic migration of PCs toward CXCL12 and reduced extracellular signal-regulated kinase (ERK) activation by CXCL12. An ERK inhibitor reduced CXCL12-mediated chemotactic migration, which suggests that ERK has a critical role in migration. CD99 engagement did not influence apoptosis, differentiation, or antibody secretion of PCs. We propose a novel role of CD99 in PCs that suppresses ERK activation and chemotactic migration of these cells. PMID- 26522647 TI - The discovery of the blood-thymus barrier. AB - The blood-thymus barrier is a functional and selective barrier separating T lymphocytes from blood and cortical capillaries in the cortex of the thymus. The existence of this barrier was proposed for the first in time in 1961 by Marshall and White, and demonstrated in 1963 by Clark and Weiss. The most clear morphological evidence concerning the existence of the blood-thymus barrier may be attributed to the collaborative work published in 1972 by two scientists, Morris Karnovsky and Elio Raviola. Raviola and Karnovsky, using peroxidase as a permeability tracer, demonstrated that the venules at the cortico-medullary junction are the site of leakage for blood antigens, while the capillaries draining the cortex are largely impermeable. Other permeability studies have confirmed the existence of a blood-thymus barrier, which allow the access to low molecular weight tracers, while most exclude high molecular weight particles. PMID- 26522648 TI - [Minutes of the 3rd European Society for Therapeutic Radiology and Oncology (ESTRO) Forum. Barcelona (Spain), 24-28 April 2015]. PMID- 26522649 TI - Reply. PMID- 26522650 TI - Reply. PMID- 26522651 TI - Routine intracranial pressure monitoring in acute coma. AB - BACKGROUND: We know that the brain damage resulting from traumatic and other insults is not due solely to the direct consequences of the primary injury. A significant and potentially preventable contribution to the overall morbidity arises from secondary hypoxic-ischaemic damage. Brain swelling accompanied by raised intracranial pressure (ICP) prevents adequate cerebral perfusion with well oxygenated blood.Detection of raised ICP could be useful in alerting clinicians to the need to improve cerebral perfusion, with consequent reductions in brain injury. OBJECTIVES: To determine whether routine ICP monitoring in severe coma of any cause reduces the risk of all-cause mortality or severe disability at final follow-up. SEARCH METHODS: We searched the Cochrane Injuries Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL Plus, ISI Web of Science (SCI-EXPANDED & CPCI S), clinical trials registries and reference lists. We ran the most recent search on 22 May 2015. SELECTION CRITERIA: All randomised controlled studies of real time ICP monitoring by invasive or semi-invasive means in acute coma (traumatic or non-traumatic aetiology) versus clinical care without ICP monitoring (that is, guided only by clinical or radiological inference of the presence of raised ICP). DATA COLLECTION AND ANALYSIS: Two authors (ET and RF) worked independently to identify the one study that met inclusion criteria. JR and RF independently extracted data and assessed risk of bias. We contacted study authors for additional information, including details of methods and outcome data. MAIN RESULTS: One randomized controlled trial (RCT) meeting the selection criteria has been identified to date.The included study had 324 participants. We judged risk of bias to be low for all categories except blinding of participants and personnel, which is not feasible for this intervention. There were few missing data, and we analysed all on an intention-to-treat basis.Participants could be 13 years of age or older (mean age of sample 29; range 22 to 44), and all had severe traumatic brain injury, mostly due to traffic incidents. All were receiving care within intensive care units (ICUs) at one of six hospitals in either Bolivia or Ecuador. Investigators followed up 92% of participants for six months or until death. The trial excluded patients with a Glasgow Coma Score (GCS) less than three and fixed dilated pupils on admission on the basis that they had sustained brain injury of an unsalvageable severity.The study compared people managed using either an intracranial monitor or non-invasive monitoring (imaging and clinical examination) to identify potentially harmful raised intracranial pressure. Both study groups used imaging and clinical examination measures.Mortality at six months was 56/144 (39%) in the ICP-monitored group and 67/153 (44%) in the non invasive group.Unfavourable outcome (defined as death or moderate to severe disability at six months) as assessed by the extended Glasgow Outcome Scale (GOS E) was 80/144 (56%) in the ICP-monitored group and 93/153 (61%) in the non invasive group.Six percent of participants in the ICP monitoring group had complications related to the monitoring, none of which met criteria for being a serious adverse event. There were no complications relating to the non-invasive group.Other complications and adverse events were comparable between treatment groups, 70/157 (45%) in the ICP-monitored group and 76/167 (46%) in the non invasive group.Late mortality in both the monitored and non-invasive groups was high, with 35% of deaths occurring > 14 days after injury. The authors comment that this high late mortality may reflect inadequacies in post-ICU services for disabled survivors requiring specialist rehabilitation care. AUTHORS' CONCLUSIONS: The data from the single RCT studying the role of routine ICP monitoring in acute traumatic coma fails to provide evidence to support the intervention.Research in this area is complicated by the fact that RCTs necessarily assess the combined impact of measurement of ICP with the clinical management decisions made in light of this data. Future studies will need to assess the added value of ICP data alongside other information from the multimodal monitoring typically performed in intensive care unit settings. Additionally, even within traumatically acquired brain injury (TBI), there is great heterogeneity in mechanisms, distribution, location and magnitude of injury, and studies within more homogeneous subgroups are likely to be more informative. PMID- 26522653 TI - Physical realization of the Glauber quantum oscillator. AB - More than thirty years ago Glauber suggested that the link between the reversible microscopic and the irreversible macroscopic world can be formulated in physical terms through an inverted harmonic oscillator describing quantum amplifiers. Further theoretical studies have shown that the paradigm for irreversibility is indeed the reversed harmonic oscillator. As outlined by Glauber, providing experimental evidence of these idealized physical systems could open the way to a variety of fundamental studies, for example to simulate irreversible quantum dynamics and explain the arrow of time. However, supporting experimental evidence of reversed quantized oscillators is lacking. We report the direct observation of exploding n = 0 and n = 2 discrete states and Gamma0 and Gamma2 quantized decay rates of a reversed harmonic oscillator generated by an optical photothermal nonlinearity. Our results give experimental validation to the main prediction of irreversible quantum mechanics, that is, the existence of states with quantized decay rates. Our results also provide a novel perspective to optical shock-waves, potentially useful for applications as lasers, optical amplifiers, white-light and X-ray generation. PMID- 26522654 TI - Newborn screening for congenital hypothyroidism in Henan province, China. AB - BACKGROUND: Congenital hypothyroidism is the most common congenital endocrine disorder. The study aimed to determine the congenital hypothyroidism incidence by newborn screening programs in Henan Province, China. METHODS: The screening programs for congenital hypothyroidism are based on the measurement of TSH in dried blood spots. The TSH concentration was measured in the dry blood spot specimen using a DELFIA fluoroimmunoassay. The TSH cutoff concentration was 8mU/l. RESULTS: The total coverage and the incidence of congenital hypothyroidism were 24.85% (5,142,148/20,694,441) and 0.370/00 (1992/5,142,148), respectively. The coverage and the incidence of CH were only 0.58% (4526/784,580) and 0.220/00 (1/4526) in 1997, respectively. However, the coverage and the incidence of CH were increased to 74.67% (1,203,278/1,611,582) and 0.320/00 (389/1,203,278). There were no significant differences in the number of congenital hypothyroidism between males and females (P>0.05). The number of congenital hypothyroidism was increased year after year. CONCLUSIONS: The newborn screening program for CH is successful and quite effective. PMID- 26522652 TI - Stimulation of the wrist acupuncture point PC6 for preventing postoperative nausea and vomiting. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) are common complications following surgery and anaesthesia. Antiemetic drugs are only partially effective in preventing PONV. An alternative approach is to stimulate the PC6 acupoint on the wrist. This is an update of a Cochrane review first published in 2004, updated in 2009 and now in 2015. OBJECTIVES: To determine the effectiveness and safety of PC6 acupoint stimulation with or without antiemetic drug versus sham or antiemetic drug for the prevention of PONV in people undergoing surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library, Issue 12, 2014), MEDLINE (January 2008 to December 2014), EMBASE (January 2008 to December 2014), ISI Web of Science (January 2008 to December 2014), World Health Organization Clinical Trials Registry, ClinicalTrials.gov, and reference lists of articles to identify additional studies. We applied no language restrictions. SELECTION CRITERIA: All randomized trials of techniques that stimulated the PC6 acupoint compared with sham treatment or drug therapy, or combined PC6 acupoint and drug therapy compared to drug therapy, for the prevention of PONV. Interventions used in these trials included acupuncture, electro-acupuncture, transcutaneous electrical acupoint stimulation, transcutaneous nerve stimulation, laser stimulation, capsicum plaster, acu-stimulation device, and acupressure in people undergoing surgery. Primary outcomes were the incidences of nausea and vomiting after surgery. Secondary outcomes were the need for rescue antiemetic therapy and adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data and assessed the risk of bias domains for each trial. We used a random effects model and reported risk ratio (RR) with associated 95% confidence interval (95% CI). We used trial sequential analyses to help provide information on when we had reached firm evidence in cumulative meta-analyses of the primary outcomes, based on a 30% risk ratio reduction in PONV. MAIN RESULTS: We included 59 trials involving 7667 participants. We rated two trials at low risk of bias in all domains (selection, attrition, reporting, blinding and other). We rated 25 trials at high risk in one or more risk-of-bias domains. Compared with sham treatment, PC6 acupoint stimulation significantly reduced the incidence of nausea (RR 0.68, 95% CI 0.60 to 0.77; 40 trials, 4742 participants), vomiting (RR 0.60, 95% CI 0.51 to 0.71; 45 trials, 5147 participants) and the need for rescue antiemetics (RR 0.64, 95% CI 0.55 to 0.73; 39 trials, 4622 participants). As heterogeneity among trials was substantial and there were study limitations, we rated the quality of evidence as low. Using trial sequential analysis, the required information size and boundary for benefit were reached for both primary outcomes.PC6 acupoint stimulation was compared with six different types of antiemetic drugs (metoclopramide, cyclizine, prochlorperazine, droperidol. ondansetron and dexamethasone). There was no difference between PC6 acupoint stimulation and antiemetic drugs in the incidence of nausea (RR 0.91, 95% CI 0.75 to 1.10; 14 trials, 1332 participants), vomiting (RR 0.93, 95% CI 0.74 to 1.17; 19 trials, 1708 participants), or the need for rescue antiemetics (RR 0.87, 95% CI 0.65 to 1.16; 9 trials, 895 participants). We rated the quality of evidence as moderate, due to the study limitations. Using trial sequential analyses, the futility boundary was crossed before the required information size was surpassed for both primary outcomes.Compared to antiemetic drugs, the combination of PC6 acupoint stimulation and antiemetic therapy reduced the incidence of vomiting (RR 0.56, 95% CI 0.35 to 0.91; 9 trials, 687 participants) but not nausea (RR 0.79, 95% CI 0.55 to 1.13; 8 trials, 642 participants). We rated the quality of evidence as very low, due to substantial heterogeneity among trials, study limitations and imprecision. Using trial sequential analysis, none of the boundaries for benefit, harm or futility were crossed for PONV. The need for rescue antiemetic was lower in the combination PC6 acupoint stimulation and antiemetic group than the antiemetic group (RR 0.61, 95% CI 0.44 to 0.86; 5 trials, 419 participants).The side effects associated with PC6 acupoint stimulation were minor, transient and self-limiting (e.g. skin irritation, blistering, redness and pain) in 14 trials. Publication bias was not apparent in the contour-enhanced funnel plots. AUTHORS' CONCLUSIONS: There is low-quality evidence supporting the use of PC6 acupoint stimulation over sham. Compared to the last update in 2009, no further sham comparison trials are needed. We found that there is moderate-quality evidence showing no difference between PC6 acupoint stimulation and antiemetic drugs to prevent PONV. Further PC6 acupoint stimulation versus antiemetic trials are futile in showing a significant difference, which is a new finding in this update. There is inconclusive evidence supporting the use of a combined strategy of PC6 acupoint stimulation and antiemetic drug over drug prophylaxis, and further high-quality trials are needed. PMID- 26522655 TI - Association of bone-derived biomarkers with vascular calcification in chronic hemodialysis patients. AB - BACKGROUND: Abdominal aortic calcification (AAC) is commonly observed in chronic dialysis patients and is associated with cardiovascular and all-cause mortality. We investigated the factors associated with AAC and analyze the relationship between bone-derived biomarkers and AAC. METHODS: We enrolled 227 stable hemodialysis patients. Vascular calcifications were assessed using lateral lumbar radiography of the abdominal aorta. Demographic data were collected and serum levels of biochemical and bone-derived biomarkers, including sclerostin, Dickkopf 1 (DKK-1), and fibroblast growth factor 23 (FGF23), were measured. RESULTS: One hundred sixty-one patients (71.0%) had AAC. Patients with AAC score?13 were older, with higher body mass index (BMI), serum calcium, calcium phosphate product, high-sensitivity C-reactive protein (hsCRP), and FGF23 levels. Sclerostin and DKK-1 levels were inversely associated with AAC severity, and FGF23 was directly related to vascular calcification. Hypertension, vascular disease, hsCRP, FGF23, and sclerostin were independent AAC determinants. CONCLUSIONS: Chronic hemodialysis patients have a high prevalence of vascular calcifications. Levels of circulating sclerostin, DKK-1, and FGF23 were related to AAC severity. Sclerostin and FGF23 were independently associated with AAC. PMID- 26522656 TI - Corticosteroid-binding globulin cleavage is paradoxically reduced in alpha-1 antitrypsin deficiency: Implications for cortisol homeostasis. AB - High-affinity corticosteroid-binding globulin (haCBG) is cleaved by neutrophil elastase (NE) resulting in permanent transition to the low cortisol-binding affinity form (laCBG), thereby increasing cortisol availability at inflammatory sites. Alpha-1 antitrypsin (AAT) is the major inhibitor of NE. AAT deficiency (AATD) predisposes patients to early-onset emphysema due to increased proteolytic destruction from the inherent proteinase-antiproteinase imbalance. We hypothesized that AATD may result in increased CBG cleavage in vivo. We collected demographic data and blood samples from 10 patients with AATD and 28 healthy controls measuring total CBG and haCBG levels by parallel in-house ELISAs, as well as AAT, total and free cortisol levels. haCBG was higher (median [range]); 329 [210-551] vs. 250 [175-365] nmol/L; P<0.005, and laCBG lower; 174 [68-229] vs. 220 [119-348] nmol/L; P=0.016 in the AATD group, compared with controls. The ratio of haCBG:total CBG was also higher in AATD; 72 [53-83] vs. 54 [41-72] %; P=0.0001). There was a negative correlation between haCBG:total CBG and AAT levels (P<0.05, R=-0.64). Paradoxically, proteolytic cleavage of CBG was reduced in AATD, despite the recognized increase in NE activity. This implies that NE activity is not the mechanism for systemic CBG cleavage in basal, low inflammatory conditions. Relatively low levels of laCBG may have implications for cortisol action in AATD. PMID- 26522657 TI - Reference intervals of urinary acute kidney injury (AKI) markers [IGFBP7]?[TIMP2] in apparently healthy subjects and chronic comorbid subjects without AKI. AB - BACKGROUND: Insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) have demonstrated significantly improved diagnostic performance in assessing risk for acute kidney injury (AKI) compared with existing biomarkers. We present the findings of a multi-site trial to determine the reference intervals for these biomarkers in apparently healthy adults and those with stable chronic morbid conditions without AKI. METHODS: A urine specimen was collected from apparently healthy subjects (N=378) and subjects with at least one stable chronic morbidity (N=372). Specimens were kept frozen until analysis with the NephroCheck(r) Test (Astute Medical). The test is comprised of fluorescence immunoassays for IGFBP7 and TIMP-2 and is used with the Astute140(r) Meter which quantifies the concentration of each biomarker. The meter multiplies the concentrations of IGFBP7 and TIMP-2 and displays the result as a numerical value ([IGFBP7]?[TIMP-2]) expressed in (ng/ml)(2)/1000 which is called the AKIRiskTM Score. RESULTS: The reference intervals (inner 95%) for [IGFBP7]?[TIMP-2] in all subjects (N=750), apparently healthy subjects, and subjects with stable chronic morbidities were 0.04-2.22, 0.04-2.25, and 0.05-2.20 (ng/ml)(2)/1000 respectively. There was no statistical difference between reference intervals for apparently healthy and chronic stable morbid cohorts (p=0.42). CONCLUSIONS: Our investigation showed that urine [IGFBP7]?[TIMP-2] values were not elevated in patients with stable chronic morbidities who did not have AKI. PMID- 26522659 TI - Evaluation of sulfamethazine sorption and biodegradation by anaerobic granular sludge using batch experiments. AB - This study investigated the removal of the veterinary antimicrobial sulfamethazine (SMZ) using anaerobic granular sludge in batch tests. Adsorption and biodegradation were the main mechanisms involved, with adsorption being properly described by a pseudo-second-order model and a linear adsorption isotherm. The adsorption rate constant ranged from 0.00051 to 0.00587 L ug(-1) h( 1), whereas the SMZ partition coefficient was determined to be 0.0717 L g TVS( 1). Biodegradation depended on the presence of readily available organic matter, indicating the occurrence of cometabolism. The addition of exogenous COD to a 144 h batch run at the concentration level of 100 ug L(-1) increased the efficiency of SMZ removal from 57 to 84%. A two-compartment model was developed and fitted to the experimental results, which established the aqueous phase as the main bioavailable compartment. The results suggested that SMZ conversion in anaerobic reactors benefits from high influent dilution and an exogenous supply of organic matter. PMID- 26522660 TI - Mathematical model of organic substrate degradation in solid waste windrow composting. AB - Organic solid waste composting is a complex process that involves many coupled physical, chemical and biological mechanisms. To understand this complexity and to ease in planning, design and management of the composting plant, mathematical model for simulation is usually applied. The aim of this paper is to develop a mathematical model of organic substrate degradation and its performance evaluation in solid waste windrow composting system. The present model is a biomass-dependent model, considering biological growth processes under the limitation of moisture, oxygen and substrate contents, and temperature. The main output of this model is substrate content which was divided into two categories: slowly and rapidly degradable substrates. To validate the model, it was applied to a laboratory scale windrow composting of a mixture of wood chips and dog food. The wastes were filled into a cylindrical reactor of 6 cm diameter and 1 m height. The simulation program was run for 3 weeks with 1 s stepwise. The simulated results were in reasonably good agreement with the experimental results. The MC and temperature of model simulation were found to be matched with those of experiment, but limited for rapidly degradable substrates. Under anaerobic zone, the degradation of rapidly degradable substrate needs to be incorporated into the model to achieve full simulation of a long period static pile composting. This model is a useful tool to estimate the changes of substrate content during composting period, and acts as a basic model for further development of a sophisticated model. PMID- 26522661 TI - Effect of garlic on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled clinical trials. AB - OBJECTIVES: Garlic can play an essential role in the prevention of atherosclerosis, but the research addressing the effect of garlic on the concentration of lipoprotein(a) [Lp(a)] has not been fully demonstrated. The aim of this study was to assess the effect of garlic on plasma Lp(a) concentrations through systematic review of literature and meta-analysis of available randomized controlled trials. METHODS: The literature search included SCOPUS, PubMed Medline, ISI Web of Science, and Google Scholar databases up to March 10, 2015 to identify randomized controlled trials investigating the effect of garlic on plasma Lp(a) concentrations. Two independent reviewers extracted data on study characteristics, methods, and outcomes. Overall, the effect of garlic on plasma Lp(a) levels was reported in six trials. RESULTS: Meta-analysis did not suggest a significant alteration in plasma Lp(a) levels after garlic consumption (weighted mean difference [WMD] = 16.86%; 95% confidence interval, -4.59 to 38.31; P = 0.124). This result was robust in the leave-one-out sensitivity analysis. When the studies were categorized according to the duration of supplementation, there was no effect in the subgroup of trials lasting <=12 wk (WMD = 2.01%; 95% CI, 14.67 to 18.68; P = 0.813) but a significant elevation of plasma Lp(a) concentrations was found in trials lasting >12 wk (WMD = 54.59%; 95% CI, 30.47 78.71; P < 0.001). Random-effects meta-regression suggested an inverse association between the changes in plasma concentrations of Lp(a) and duration of supplementation (slope 1.71; 95% CI, 0.46-2.97; P = 0.007). CONCLUSIONS: The present meta-analysis did not suggest a significant effect of garlic supplementation on the reduction of Lp(a) levels. PMID- 26522658 TI - RDM4 modulates cold stress resistance in Arabidopsis partially through the CBF mediated pathway. AB - The C-REPEAT-BINDING FACTOR (CBF) pathway has important roles in plant responses to cold stress. How the CBF genes themselves are activated after cold acclimation remains poorly understood. In this study, we characterized cold tolerance of null mutant of RNA-DIRECTED DNA METHYLATION 4 (RDM4), which encodes a protein that associates with RNA polymerases Pol V and Pol II, and is required for RNA directed DNA methylation (RdDM) in Arabidopsis. The results showed that dysfunction of RDM4 reduced cold tolerance, as evidenced by decreased survival and increased electrolyte leakage. Mutation of RDM4 resulted in extensive transcriptomic reprogramming. CBFs and CBF regulon genes were down-regulated in rdm4 but not nrpe1 (the largest subunit of PolV) mutants, suggesting that the role of RDM4 in cold stress responses is independent of the RdDM pathway. Overexpression of RDM4 constitutively increased the expression of CBFs and regulon genes and decreased cold-induced membrane injury. A great proportion of genes affected by rdm4 overlapped with those affected by CBFs. Chromatin immunoprecipitation results suggested that RDM4 is important for Pol II occupancy at the promoters of CBF2 and CBF3. We present evidence of a considerable role for RDM4 in regulating gene expression at low temperature, including the CBF pathway in Arabidopsis. PMID- 26522662 TI - Methylmalonic acidemia with emergency hypertension. PMID- 26522663 TI - Animal models of pediatric chronic kidney disease. Is adenine intake an appropriate model? AB - Pediatric chronic kidney disease (CKD) has peculiar features. In particular, growth impairment is a major clinical manifestation of CKD that debuts in pediatric age because it presents in a large proportion of infants and children with CKD and has a profound impact on the self-esteem and social integration of the stunted patients. Several factors associated with CKD may lead to growth retardation by interfering with the normal physiology of growth plate, the organ where longitudinal growth rate takes place. The study of growth plate is hardly possible in humans and justifies the use of animal models. Young rats made uremic by 5/6 nephrectomy have been widely used as a model to investigate growth retardation in CKD. This article examines the characteristics of this model and analyzes the utilization of CKD induced by high adenine diet as an alternative research protocol. PMID- 26522664 TI - The contribution of school meals to energy and nutrient intake of Swedish children in relation to dietary guidelines. AB - BACKGROUND: In Sweden, school meals are served free of charge and Swedish law states that school meals must be nutritious. Nevertheless, data on children's energy and nutrient intake from school meals are scarce. OBJECTIVE: The aim was to describe the contribution of school meals to Swedish children's nutrient and energy intake during weekdays and compare this to the reference values based on the Nordic Nutrition Recommendations (NNR), which have been adopted as the official Swedish recommendations. DESIGN: A cross-sectional food consumption survey was performed on 1,840 Swedish children attending Grade 2 (mean age 8.6) and Grade 5 (mean age 11.7). The children's nutrient and energy intake was compared to the reference values based on the NNR. RESULTS: The mean intake from school meals of energy, carbohydrates, dietary fiber, polyunsaturated fatty acids (PUFA), and vitamins D and E did not reach the reference values and the intake of saturated fatty acids (SFA) and sodium exceeded the reference values in both age groups (significant differences, all p<=0.001). Additionally, the pupils in Grade 5 did not reach the reference values for folate, potassium, calcium, magnesium, iron, selenium, and zinc (significant differences, all p<=0.001). Standardized for energy, dietary fiber, PUFA, and vitamins D and E did not reach the reference values, whereas the reference values for SFA and sodium were exceeded in both age groups (significant differences, all p<=0.001). CONCLUSIONS: The study pointed to some central nutrients in need of improvement as regards school meals in Sweden, namely the quality of fat, dietary fiber, sodium, vitamin D, and iron. Some of these results may be attributed to the children not reporting eating the recommended number of calories, the children omitting some components of the meal, or underreporting, as a consequence of which the reference values for several nutrients were not met. PMID- 26522665 TI - Why are most EU pigs tail docked? Economic and ethical analysis of four pig housing and management scenarios in the light of EU legislation and animal welfare outcomes. AB - To limit tail biting incidence, most pig producers in Europe tail dock their piglets. This is despite EU Council Directive 2008/120/EC banning routine tail docking and allowing it only as a last resort. The paper aims to understand what it takes to fulfil the intentions of the Directive by examining economic results of four management and housing scenarios, and by discussing their consequences for animal welfare in the light of legal and ethical considerations. The four scenarios compared are: 'Standard Docked', a conventional housing scenario with tail docking meeting the recommendations for Danish production (0.7 m2/pig); 'Standard Undocked', which is the same as 'Standard Docked' but with no tail docking, 'Efficient Undocked' and 'Enhanced Undocked', which have increased solid floor area (0.9 and 1.0 m2/pig, respectively) provision of loose manipulable materials (100 and 200 g/straw per pig per day) and no tail docking. A decision tree model based on data from Danish and Finnish pig production suggests that Standard Docked provides the highest economic gross margin with the least tail biting. Given our assumptions, Enhanced Undocked is the least economic, although Efficient Undocked is better economically and both result in a lower incidence of tail biting than Standard Undocked but higher than Standard Docked. For a pig, being bitten is worse for welfare (repeated pain, risk of infections) than being docked, but to compare welfare consequences at a farm level means considering the number of affected pigs. Because of the high levels of biting in Standard Undocked, it has on average inferior welfare to Standard Docked, whereas the comparison of Standard Docked and Enhanced (or Efficient) Undocked is more difficult. In Enhanced (or Efficient) Undocked, more pigs than in Standard Docked suffer from being tail bitten, whereas all the pigs avoid the acute pain of docking endured by the pigs in Standard Docked. We illustrate and discuss this ethical balance using numbers derived from the above-mentioned data. We discuss our results in the light of the EU Directive and its adoption and enforcement by Member States. Widespread use of tail docking seems to be accepted, mainly because the alternative steps that producers are required to take before resorting to it are not specified in detail. By tail docking, producers are acting in their own best interests. We suggest that for the practice of tail docking to be terminated in a way that benefits animal welfare, changes in the way pigs are housed and managed may first be required. PMID- 26522666 TI - Evaluation of different methods to handle misreporting in obesity research: evidence from the Canadian national nutrition survey. AB - The association of dietary exposures with health outcomes may be attenuated or reversed as a result of energy intake (EI) misreporting. This study evaluated several methods for dealing with implausible recalls when analysing the association between dietary factors and obesity. We examined data from 16,187 Canadians aged >=12 years in the nationally representative Canadian Community Health Survey 2.2. Under- and over-reporting were defined as the ratio of EI:estimated energy requirement <0.7 and >1.42, respectively. Multinomial logistic regression-generalised logit model was conducted to test the utility of different methods for handling misreporting, including (a) adjusting for variables related to misreporting, (b) excluding misreported recalls, (c) adjusting for reporting groups (under-, plausible and over-reporters), (d) adjusting for propensity score and (e) stratifying the analyses by reporting groups. In the basic model, EI showed a negative association with overweight (OR 0.988; 95% CI 0.979, 0.998) and obesity (OR 0.989; 95% CI 0.977, 0.999). Similarly, the association between total energy density and overweight (OR 0.670; 95% CI 0.487, 0.923) and obesity (OR 0.709; 95% CI 0.495, 1.016) was inverse. Among all methods of handling misreporting, adjusting for the reporting status revealed the most satisfactory results, where a positive association between EI and overweight (OR 1.037; 95% CI 1.019, 1.055) and obesity (OR 1.109; 95% CI 1.082, 1.137) was observed (P<0.0001), as well as direct positive associations between energy density and percentage energy from solid fats and added sugars with obesity (P<0.05). The results of this study can help advance knowledge about the relationship between dietary variables and obesity and demonstrate to researchers and nutrition policy makers the importance of adjusting for recall plausibility in obesity research, which is highly relevant in light of global obesity epidemic. PMID- 26522667 TI - Effects of mesenchymal stromal cells on human myeloid dendritic cell differentiation and maturation in a humanized mouse model. AB - Mesenchymal stromal cells (MSCs) have shown promise as cellular therapy in allogeneic transplantation, although the precise mechanisms underlying their benefit in clinical trials are difficult to study. We previously demonstrated that MSCs exert immunoregulatory effects in mouse bone marrow-derived dendritic cell (DC) culture. Since mouse studies do not reliably reproduce human events, we used a humanized mouse model to study the immunomodulatory effects of human MSCs on human DC immunobiology. Humanized mice were established by injection of cord blood CD34(+) cells into NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl/SzJ) (NOD scid gamma, NSG) mice. Human cells were detected in the mouse bone marrow, blood, and spleen 12weeks after transplantation. Human DCs were differentiated from humanized mouse bone marrow cells during human MSC co-culture. MSCs inhibited DC differentiation and kept DCs in an immature state as demonstrated by phenotype and function. In conclusion, humanized mouse models represent a useful method to study the function of human MSCs on human DC immunobiology. PMID- 26522668 TI - Terahertz-induced acceleration of massive Dirac electrons in semimetal bismuth. AB - Dirac-like electrons in solid state have been of great interest since they exhibit many peculiar physical behaviors analogous to relativistic mechanics. Among them, carriers in graphene and surface states of topological insulators are known to behave as massless Dirac fermions with a conical band structure in the two-dimensional momentum space, whereas electrons in semimetal bismuth (Bi) are expected to behave as massive Dirac-like fermions in the three-dimensional momentum space, whose dynamics is of particular interest in comparison with that of the massless Dirac fermions. Here, we demonstrate that an intense terahertz electric field transient accelerates the massive Dirac-like fermions in Bi from classical Newtonian to the relativistic regime; the electrons are accelerated approaching the effective "speed of light" with the "relativistic" beta beta = 0.89 along the asymptotic linear band structure. As a result, the effective electron mass is enhanced by a factor of 2.4. PMID- 26522669 TI - TGIF function in oncogenic Wnt signaling. AB - Transforming growth-interacting factor (TGIF) has been implicated in the pathogenesis of many types of human cancer, but the underlying mechanisms remained mostly enigmatic. Our recent study has revealed that TGIF functions as a mediator of oncogenic Wnt/beta-catenin signaling. We found that TGIF can interact with and sequesters Axin1 and Axin2 into the nucleus, thereby culminating in disassembly of the beta-catenin-destruction complex and attendant accumulation of beta-catenin in the nucleus, where it activates expression of Wnt target genes, including TGIF itself. We have provided proof-of-concept evidences that high levels of TGIF expression correlate with poor prognosis in patients with triple negative breast cancer (TNBC), and that TGIF empowers Wnt-driven mammary tumorigenesis in vivo. Here, we will briefly summarize how TGIF influences Wnt signaling to promote tumorigenesis. PMID- 26522670 TI - Cyclo-oligomerization of 6,12-Diethynyl Indeno[1,2-b]fluorenes via Diradical Intermediates. AB - Indeno[1,2-b]fluorene derivatives with trimethylsilylethynyl substituents at the 6- and 12-positions were found to undergo cyclo-dimerization, cyclo trimerization, and higher oligomerizations at room temperature. The cyclic dimer features a novel double-decker motif, composed of two face-to-face stacked bis(propadienylide)dihydroindeno[1,2-b]fluorenes with a short centroid-to centroid distance of 3.50 A. The existence of a cyclic trimer and higher oligomers was confirmed by mass spectroscopy and gel permeation chromatography. The results clearly demonstrate the diradical feature of the indeno[1,2 b]fluorene moiety. PMID- 26522671 TI - Plants and other natural products used in the management of oral infections and improvement of oral health. AB - Challenges of resistance to synthetic antimicrobials have opened new vistas in the search for natural products. This article rigorously reviews plants and other natural products used in oral health: Punica granatum L. (pomegranate), Matricaria recutita L. (chamomile), Camellia sinensis (L.) Kuntze (green tea), chewing sticks made from Diospyros mespiliformis Hochst. ex A.D.C., Diospyros lycioides Desf., and Salvadora persica L. (miswak), honey and propolis from the manuka tree (Leptospermum scoparium J.R. Forst. & G. Forst.), rhein from Rheum rhabarbarum L. (rhubarb), dried fruits of Vitis vinifera L. (raisins), essential oils, probiotics and mushrooms. Further, the review highlights plants from Africa, Asia, Brazil, Mexico, Europe, and the Middle East. Some of the plants' antimicrobial properties and chemical principles have been elucidated. While the use of natural products for oral health is prominent in resource-poor settings, antimicrobial testing is mainly conducted in the following countries (in decreasing order of magnitude): India, South Africa, Brazil, Japan, France, Egypt, Iran, Mexico, Kenya, Switzerland, Nigeria, Australia, Uganda, and the United Kingdom. While the review exposes a dire gap for more studies on clinical efficacy and toxicity, the following emerging trend was noted: basic research on plants for oral health is mainly done in Brazil, Europe and Australia. Brazil, China, India and New Zealand generally conduct value addition of natural products for fortification of toothpastes. African countries focus on bioprospecting and primary production of raw plants and other natural products with antimicrobial efficacies. The Middle East and Egypt predominantly research on plants used as chewing sticks. More research and funding are needed in the field of natural products for oral health, especially in Africa where oral diseases are fuelled by human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). PMID- 26522672 TI - Accuracy of Prospective Predictions of 30-Day Hospital Readmission. AB - OBJECTIVE: This study examined how accurately inpatient case managers predicted 30-day readmission and whether objective patient characteristics improved prediction accuracy. METHODS: In this prospective study, inpatient case managers at a psychiatric hospital rated their concern (1, not concerned; 5, very concerned) about readmission after discharge of 282 privately insured patients. Sensitivity and specificity of the ratings were calculated. Logistic regression identified whether patient characteristics that could affect 30-day readmission improved prediction accuracy. RESULTS: Concern levels >=3 yielded 86% sensitivity, 37% specificity, and a positive predictive value (PPV) of 13%; levels >=4 yielded 39% sensitivity, 78% specificity, and a PPV of 17%. Concern level independently predicted readmission; appointments within seven days postdischarge further improved model accuracy (p=.03) (area under the curve=.67, 95% confidence interval=.58-.78). CONCLUSIONS: Although not highly accurate, case manager concern identified some patients at higher risk of 30-day readmission. Appointments within seven days of discharge improved prediction accuracy. PMID- 26522673 TI - Impact of Mental Health First Aid on Confidence Related to Mental Health Literacy: A National Study With a Focus on Race-Ethnicity. AB - OBJECTIVE: Low mental health literacy (MHL) is widespread in the general population and even more so among racial and ethnic minority groups. Mental Health First Aid (MHFA) aims to improve MHL. The objective of this study was to determine the impact of MHFA on perceptions of confidence about MHL in a large national sample and by racial and ethnic subgroup. METHODS: The self-perceived impact of MHFA on 36,263 people who completed the 12-hour training and a feedback form was examined. RESULTS: A multiple regression analysis showed that MHFA resulted in high ratings of confidence in being able to apply various skills and knowledge related to MHL. Perceived impact of MHFA training differed among some racial and ethnic groups, but the differences were small to trivial. CONCLUSIONS: Future research on MHFA should examine changes in MHL pre-post training and the extent to which perceived increases in MHL confidence among trainees translate into action. PMID- 26522674 TI - Improvement in Body Image, Perceived Health, and Health-Related Self-Efficacy Among People With Serious Mental Illness: The STRIDE Study. AB - OBJECTIVE: The authors examined secondary outcomes of STRIDE, a randomized controlled trial that tested a weight-loss and lifestyle intervention for individuals taking antipsychotic medications. METHODS: Hierarchical linear regression was used to explore the effects of the intervention and weight change at follow-up (six, 12, and 24 months) on body image, perceived health, and health related self-efficacy. RESULTS: Participants were 200 adults who were overweight and taking antipsychotic agents. Weight change * study arm interaction was associated with significant improvement in body image from baseline to six months. From baseline to 12 months, body image scores of intervention participants improved by 1.7 points more compared with scores of control participants; greater weight loss was associated with more improvement. Between baseline and 24 months, greater weight loss was associated with improvements in body image, perceived health, and health-related self-efficacy. CONCLUSIONS: Participation in STRIDE improved body image, and losing weight improved perceived health and health-related self-efficacy. PMID- 26522676 TI - Mental Health Service Utilization Among Natural Disaster Survivors With Perceived Need for Services. AB - OBJECTIVE: This study explored predisposing, illness-related, and enabling factors as predictors of mental health service use among disaster survivors with perceived need for services. METHODS: Participants (N=658) were part of a three wave, population-based study of Hurricane Ike survivors. At each wave, participants were asked whether they perceived having a need for mental health services, for example, information about stress reactions and medication for emotional problems. Those with perceived need were asked about use of eight services, such as a psychiatrist or physician, to address needs. Generalized estimating equations examined predisposing, illness-related, and enabling factors as predictors of service use among participants with perceived need (N=304). RESULTS: More general stressors (predisposing factor) and insurance coverage (enabling factor) predicted service use among participants with perceived need. CONCLUSIONS: The results suggest that expanded access to services that do not require insurance coverage could better address survivors' mental health needs after a disaster. PMID- 26522675 TI - Parents' Perceived Treatment Match and Treatment Retention Over 12 Months Among Youths in the LAMS Study. AB - OBJECTIVE: The goal of these analyses was to describe the 12-month prevalence of mental health services retention for youths ages six to 12 years and identify predictors of treatment retention. Data were from the Longitudinal Assessment of Manic Symptoms study. METHODS: In a longitudinal cohort study, 416 children and their parents completed measures of mental health services use and parents' perception of the services and participated in semistructured psychodiagnostic interviews during a baseline and 12-month assessment. Logistic regression analyses examined the effects on 12-month treatment retention of demographic and clinical variables and parents' perception of how well their children's treatment matched their needs. RESULTS: Sixty-nine percent of youths (N=289) continued to use services at 12 months. After the analyses controlled for other demographic and clinical factors, white race (p<.001) and greater functional impairment (p=.024) were associated with treatment retention; greater perceived treatment match at baseline significantly predicted retention above and beyond the effects of sociodemographic and clinical variables (p=.001). CONCLUSIONS: Parents' perceptions about appropriateness of treatment, white race, and functional impairment predicted 12-month treatment retention. PMID- 26522677 TI - The Social Determinants of Mental Health. AB - Ninety percent of the determinants of our health derive from our lifetime social and physical environment-not from the provision of health care. The author describes behaviors, such as poor eating, excessive drinking and abuse of drugs, smoking, and physical inactivity, and social factors, such as adverse childhood experiences, poor education, food insecurity, poor housing quality, unemployment, and discrimination, that contribute to ill health and early demise. Better health and mental health can be achieved by understanding and responding to these determinants of health. PMID- 26522678 TI - Information Sharing Across Institutions to Enhance Operations of Psychiatric Emergency Rooms in New York City. PMID- 26522679 TI - Clozapine for Schizophrenia: State Variation in Evidence-Based Practice. PMID- 26522680 TI - The Perfect Storm: Collision of the Business of Mental Health and the Implementation of Evidence-Based Practices. AB - Financing has been hypothesized to be an important driver of the implementation of evidence-based practices (EBPs), yet there has been little systematic investigation of financing as a factor in EBP implementation. This column presents findings from a qualitative study of the effects of financial factors on the implementation of EBPs in a large urban publicly funded mental health system. Interviews with 33 agency leaders and 16 policy makers identified financial distress in community mental health agencies, leading to concerns about complex and expensive implementation of EBPs. Stakeholders agreed that the cost of EBP implementation should be shared between the agencies and the system; however, the stakeholders did not agree on how EBPs should be financed. PMID- 26522681 TI - Anterior mitral annulus caseoma: as benign as posterior counterparts? AB - Mitral annular caseoma is a common incidental finding involving the posterior annulus. It has an innocent nature, with the exception of its endocarditic degeneration and/or a stenotic functional effect when exophytic. We report an exceptionally rare isolated anterior mitral annular caseoma involving also the anterior mitral leaflet and affecting its physiologic systolic movement, thus resulting in a restricting anterior leaflet motion responsible for mitral insufficiency. The case was successfully treated by complex mitral valve repair. PMID- 26522682 TI - Vitamin D deficiency impairs glucose-stimulated insulin secretion and increases insulin resistance by reducing PPAR-gamma expression in nonobese Type 2 diabetic rats. AB - Human studies have provided relatively strong associations of poor vitamin D status with Type 2 diabetes but do not explain the nature of the association. Here, we explored the physiological pathways that may explain how vitamin D status modulates energy, lipid and glucose metabolisms in nonobese Type 2 diabetic rats. Goto-Kakizaki (GK) rats were fed high-fat diets containing 25 (VD low), 1000 (VD-normal) or 10,000 (VD-high) cholecalciferol-IU/kg diet for 8 weeks. Energy expenditure, insulin resistance, insulin secretory capacity and lipid metabolism were measured. Serum 25-OH-D levels, an index of vitamin D status, increased dose dependently with dietary vitamin D. VD-low resulted in less fat oxidation without a significant difference in energy expenditure and less lean body mass in the abdomen and legs comparison to the VD-normal group. In comparison to VD-low, VD-normal had lower serum triglycerides and intracellular fat accumulation in the liver and skeletal muscles which was associated with down regulation of the mRNA expressions of sterol regulatory element binding protein 1c and fatty acid synthase and up-regulation of gene expressions of peroxisome proliferator-activated receptors (PPAR)-alpha and carnitine palmitoyltransferase 1. In euglycemic hyperinsulinemic clamp, whole-body and hepatic insulin resistance was exacerbated in the VD-low group but not in the VD-normal group, possibly through decreasing hepatic insulin signaling and PPAR-gamma expression in the adipocytes. In 3T3-L1 adipocytes 1,25-(OH)2-D (10 nM) increased triglyceride accumulation by elevating PPAR-gamma expression and treatment with a PPAR-gamma antagonist blocked the triglyceride deposition induced by 1,25-(OH)2-D treatment. VD-low impaired glucose-stimulated insulin secretion in hyperglycemic clamp and decreased beta-cell mass by decreasing beta-cell proliferation. In conclusion, vitamin D deficiency resulted in the dysregulation of glucose metabolism in GK rats by simultaneously increasing insulin resistance by decreasing adipose PPAR-gamma expression and deteriorating beta-cell function and mass. PMID- 26522684 TI - Penrose hypothesis and ethical implications. PMID- 26522685 TI - The effect of temperature on different Salmonella serotypes during warm seasons in a Mediterranean climate city, Adelaide, Australia. AB - Changing trends in foodborne disease are influenced by many factors, including temperature. Globally and in Australia, warmer ambient temperatures are projected to rise if climate change continues. Salmonella spp. are a temperature-sensitive pathogen and rising temperature can have a substantial effect on disease burden affecting human health. We examined the relationship between temperature and Salmonella spp. and serotype notifications in Adelaide, Australia. Time-series Poisson regression models were fit to estimate the effect of temperature during warmer months on Salmonella spp. and serotype cases notified from 1990 to 2012. Long-term trends, seasonality, autocorrelation and lagged effects were included in the statistical models. Daily Salmonella spp. counts increased by 1.3% [incidence rate ratio (IRR) 1.013, 95% confidence interval (CI) 1.008-1.019] per 1 degrees C rise in temperature in the warm season with greater increases observed in specific serotype and phage-type cases ranging from 3.4% (IRR 1.034, 95% CI 1.008-1.061) to 4.4% (IRR 1.044, 95% CI 1.024-1.064). We observed increased cases of S. Typhimurium PT9 and S. Typhimurium PT108 notifications above a threshold of 39 degrees C. This study has identified the impact of warm season temperature on different Salmonella spp. strains and confirms higher temperature has a greater effect on phage-type notifications. The findings will contribute targeted information for public health policy interventions, including food safety programmes during warmer weather. PMID- 26522687 TI - Expression of PCV2 antigen in the ovarian tissues of gilts. AB - The present study was performed to determine the expression of porcine circovirus type 2 (PCV2) antigen in the ovarian tissue of naturally infected gilts. Ovarian tissues were obtained from 11 culled gilts. The ovarian tissues sections were divided into two groups according to PCV2 DNA detection using PCR. PCV2 antigen was assessed in the paraffin embedded ovarian tissue sections by immunohistochemistry. A total of 2,131 ovarian follicles (i.e., 1,437 primordial, 133 primary, 353 secondary and 208 antral follicles), 66 atretic follicles and 131 corpora lutea were evaluated. It was found that PCV2 antigen was detected in 280 ovarian follicles (i.e., 239 primordial follicles, 12 primary follicles, 10 secondary follicles and 19 antral follicles), 1 atretic follicles and 3 corpora lutea (P<0.05). PCV2 antigen was detected in primordial follicles more often than in secondary follicles, atretic follicles and corpora lutea (P<0.05). The detection of PCV2 antigen was found mainly in oocytes. PCV2 antigen was found in both PCV2 DNA positive and negative ovarian tissues. It can be concluded that PCV2 antigen is expressed in all types of the ovarian follicles and corpora lutea. Further studies should be carried out to determine the influence of PCV2 on porcine ovarian function and oocyte quality. PMID- 26522686 TI - Partial costectomy for tracheal collapse and stenosis associated with perinatal rib fracture in three Japanese Black calves. AB - 2.3-month-old (Case 1), one-month-old (Case 2) and 6-month-old (Case 3), Japanese Black calves presented with mild to severe wheezing. All calves had histories of dystocia at birth with breech presentation. Physical examination, thoracic radiography, endoscopy or computed tomography indicated wheezing associated with tracheal collapse and stenosis caused by perinatal rib fractures. Partial resection of the fractured first and second ribs was performed on all calves. The respiration in Cases 1 and 2 immediately improved after the surgery, while Case 3 required two weeks to improve. Cases 1 and 3 grew up healthy and were sold at auction, but Case 2 had a recurrence of wheezing at three months post-discharge and showed growth retarding. Partial costectomy may be an effective solution for control of respiration, however, further cases are required to discuss the criteria for surgical management and to obtain favorable postoperative prognosis in calves with tracheal collapse and stenosis caused by perinatal rib fractures. PMID- 26522688 TI - Effects of aspirin on expression of iron transport and storage proteins in BV-2 microglial cells. AB - In the light of recent studies, we hypothesized that aspirin might have the functions to regulate the expression of iron transport proteins and then affect cellular iron levels. To test this hypothesis, we investigated the effects of aspirin on expression of iron uptake protein transferrin receptor 1 (TfR1), iron release protein ferroportin 1 (Fpn1) and iron storage protein ferritin using Western blot analysis and on tumor necrosis factor (TNF)-alphalpha, interleukin (IL)-6, interleukin (IL)-10 and hepcidin using quantitative real-time PCR in BV-2 microglial cells treated with lipopolysaccharides (LPS). We found that aspirin significantly down-regulated TfR1, while also up-regulated Fpn1 and ferritin expressions in BV-2 microglial cells in vitro. We also showed that TfR1 and Fpn1 expressions were significantly higher, while ferritin contents, IL-6, TNF-alpha and hepcidin mRNA levels were lower in cells treated with aspirin plus LPS than those in cells treated with LPS only. We concluded that aspirin has a negative effect on cell iron contents under 'normal' conditions and could partly reverse LPS-induced-disruption in cell iron balance under in vitro inflammatory conditions. Our findings also suggested that hepcidin might play a dominant role in the control of TfR1 expression by aspirin in the cells treated with LPS. PMID- 26522689 TI - Neuroprotection of Neuro2a cells and the cytokine suppressive and anti inflammatory mode of action of resveratrol in activated RAW264.7 macrophages and C8-B4 microglia. AB - Chronic inflammation is a hallmark of neurodegenerative disease and cytotoxic levels of nitric oxide (NO) and pro-inflammatory cytokines can initiate neuronal death pathways. A range of cellular assays were used to assess the anti inflammatory and neuroprotective action of resveratrol using murine microglial (C8-B4), macrophage (RAW264.7) and neuronal-like (Neuro2a) cell lines. We examined the release of NO by Griess assay and used a Bioplex array to measure a panel of pro- and anti-inflammatory cytokines and chemokines, in response to the inflammatory stimuli lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Resveratrol was a potent inhibitor of NO and cytokine release in activated macrophages and microglia. The activity of resveratrol increased marginally in potency with longer pre-incubation times in cell culture that was not due to cytotoxicity. Using an NO donor we show that resveratrol can protect Neuro2a cells from cytotoxic concentrations of NO. The protective effect of resveratrol from pro-inflammatory signalling in RAW264.7 cells was confirmed in co-culture experiments leading to increased survival of Neuro2a cells. Together our data are indicative of the potential neuroprotective effect of resveratrol during nitrosative stress and neuroinflammation. PMID- 26522690 TI - A sequential classification rule based on multiple quantitative tests in the absence of a gold standard. AB - In many medical applications, combining information from multiple biomarkers could yield a better diagnosis than any single one on its own. When there is a lack of a gold standard, an algorithm of classifying subjects into the case and non-case status is necessary for combining multiple markers. The aim of this paper is to develop a method to construct a composite test from multiple applicable tests and derive an optimal classification rule under the absence of a gold standard. Rather than combining the tests, we treat the tests as a sequence. This sequential composite test is based on a mixture of two multivariate normal latent models for the distribution of the test results in case and non-case groups, and the optimal classification rule is derived returning the greatest sensitivity at a given specificity. This method is applied to a real-data example and simulation studies have been carried out to assess the statistical properties and predictive accuracy of the proposed composite test. This method is also attainable to implement nonparametrically. PMID- 26522691 TI - Tissue Plasminogen Activator for preclinical stroke research: Neither "rat" nor "human" dose mimics clinical recanalization in a carotid occlusion model. AB - Tissue plasminogen activator (tPA) is the only approved thrombolytic therapy for acute ischemic stroke, yet many patients do not recanalize. Enhancing thrombolytic efficacy of tPA is a major focus of stroke research. Traditionally, a "rat dose" of 10 mg/kg has been used in rodent models. Recent studies suggested that the clinical "human" dose (0.9 mg/kg) may better mimic clinical recanalization. These studies only compared the rat and clinical doses, and so we aimed to test recanalization efficacy of multiple tPA doses ranging from 0.9 to 10 mg/kg in a model of endothelial injury and vessel stenosis. The common carotid artery of rats was crushed and stenosed to allow in-situ occlusive thrombus formation (Folt's model of 'physiological' thrombus). Intravenous tPA was administered 60 minutes post-occlusion (n = 6-7/group). Sustained recanalization rates were 0%, 17%, 67% and 71%, for 0.9, 1.8, 4.5, and 10 mg/kg, respectively. Median time to sustained recanalization onset decreased with increasing dosage. We conclude that 10 mg/kg of tPA is too effective, whereas 0.9 mg/kg is ineffective for lysis of occlusive thrombi formed in situ. Neither dose mimics clinical tPA responses. A dose of 2x the clinical dose is a more appropriate mimic of clinical tPA recanalization in this model. PMID- 26522692 TI - Research synthesis in veterinary science: Narrative reviews, systematic reviews and meta-analysis. AB - Reviews of the scientific literature are critically important for synthesizing the state of knowledge and are used extensively in teaching, clinical practice and public policy. Despite the importance of literature reviews, in veterinary science little attention has been paid to the science of research synthesis. In the same manner that diverse study designs address diverse research questions, different approaches to combining scientific literature serve different and valid purposes. However, and again reflective of the underlying primary research, the potential for bias in a review should also be considered when interpreting the results. This article introduces some basic concepts in research synthesis and discusses some of the basic forms of reviews including narrative reviews, systematic reviews and meta-analysis. Also discussed are potential sources of bias and design features that can be incorporated into reviews to either reduce, or at least acknowledge, the potential for bias. PMID- 26522693 TI - Induction chemotherapy for oral cavity cancer patients: Current status and future perspectives. AB - There is a lack of data from phase III randomized studies to support an ideal approach for locally advanced oral cavity cancer patients. In general, surgery, radiotherapy and chemotherapy are valid treatment options, and combined approach is usually indicated given poor clinical outcomes with single modality therapy. The aim of this study is to review the current status and future perspectives of induction chemotherapy for locally advanced oral cavity cancer patients. PMID- 26522694 TI - Status of and prospects for cancer vaccines against hepatocellular carcinoma in clinical trials. AB - Current therapies to treat advanced hepatocellular carcinoma (HCC) are not satisfactory because of the high rate of recurrence after treatment and because of severe complications after surgery. Cancer vaccines have been studied for decades to achieve effective, micro-invasive, long-lasting anti-tumor action. Cancer vaccines are designed to promote tumor-specific immune responses and increase specific cytotoxic CD8-positive T cells. This review summarizes 16 phase I clinical trials of cancer vaccines against HCC that have been conducted over the past 10 years. According to those trials, the Alpha fetoprotein (AFP), Glypican-3 (GPC3), and Multidrug resistance-associated protein 3 (MRP3) vaccines were well tolerated and safe. Some early clinical trials have shown that vaccination resulted in a large number of T cells activated by a specific tumor associated antigen in the circulation, but clinical outcomes were not satisfactory. This may be because targets for immunosuppressive agents have yet to be clearly determined in HCC. Therapeutic regimens that combine activative agents and suppressive agents may profoundly improve clinical outcomes for patients with HCC in the future. PMID- 26522695 TI - Insights into aureocin A70 regulation: participation of regulator AurR, alternative transcription factor sigma(B) and phage phi11 regulator cI. AB - Aureocin A70 is a four-component bacteriocin produced by Staphylococcus aureus A70. Its locus encompasses three transcriptional units coding for: (i) structural peptides (aurABCD), (ii) an ABC transporter (aurT) and (iii) the dedicated immunity protein and a putative transcriptional regulator (aurRI). The data provided here showed that AurR is an HTH-containing protein that reduces aureocin A70 production on solid medium, but not in broth. AurR seems to work similarly to LtnR and CylR2, repressors of lantibiotics lacticin 3147 and cytolysin, respectively. At least two other factors play a role in aureocin A70 production: (i) the alternative sigma(B) factor, as sigma(B)-defective cells produce more bacteriocin than the restored sigma(B+) cells, and (ii) the phi11 regulator cI, since a lysogenic strain for phi11 exhibited a significant reduction in aureocin A70 production on solid medium when compared with the non-lysogenic isogenic strain. Full aeration and ROS generation abolished the effect of the phage regulators on aureocin A70 production. Interestingly, the phi11 regulator cI seems to cooperate with AurR to abolish aureocin A70 production. This study therefore represents the first report showing that phage regulators may play a role in regulation of bacteriocin production. PMID- 26522696 TI - Breast cancer in thyroid cancer survivors: An analysis of the Surveillance, Epidemiology, and End Results-9 database. AB - BACKGROUND: We sought to further elucidate the increased risk for breast cancer among survivors of thyroid cancer. METHODS: Using the Surveillance, Epidemiology, and End Results-9 database, we conducted a retrospective cohort analysis on women >= 18 years of age with breast and thyroid cancer from 1973 to 2011. RESULTS: A total of 707,678 breast cancer patients and 53,853 thyroid cancer patients were included; 1,750 patients developed breast cancer after a preceding diagnosis of thyroid cancer (T1B). Age-specific risk for breast cancer was greater among thyroid cancer survivors. Incidence trends showed a significant age-time interaction and suggested a difference in thyroid cancer biology as well as a treatment effect. Compared with patients with thyroid cancer only, T1B patients were older with smaller cancers, had more follicular thyroid cancers, and fewer patients received radioactive iodine. T1B patients developed breast cancer earlier than the general population, had more estrogen receptor/progesterone receptor-positive and mixed invasive tumor histology, but smaller tumors, and there is no significant difference in the number of lymph nodes involved or radiation therapy. CONCLUSION: Thyroid cancer survivors are at greater risk for developing breast cancer than the general population. These patients develop breast cancer early, have more estrogen receptor/progesterone receptor-positive tumors, and have a greater incidence of mixed invasive cancer. Recognition of this association between thyroid and breast cancer should prompt vigilant screening in thyroid cancer survivors and further investigation into the relationship of these 2 diseases. PMID- 26522697 TI - Editorial: Translaryngeal vocal cord ultrasound: Ready for prime time. PMID- 26522698 TI - Discussion. PMID- 26522699 TI - Systemic differences in serum metabolome: a cross sectional comparison of women with localised and widespread pain and controls. AB - Chronic musculoskeletal pain exists either as localised to a single region or as widespread to multiple sites in several quadrants of the body. Prospective studies indicate that widespread pain could act as a far end of a continuum of musculoskeletal pain that started with chronic localised pain. The mechanism by which the transition from localised pain to widespread occurs is not clear, although many studies suggest it to be an altered metabolism. In this study, systemic metabolic differences between women with chronic localised neck-shoulder pain (NP), women with chronic widespread pain (CWP) and women who were healthy (CON) were assessed. Blood samples were analysed taking a metabolomics approach using gas chromatography mass spectrometry (GC-MS) and orthogonal partial least square discriminant analysis (OPLS-DA). The metabolomics analysis showed a clear systematic difference in the metabolic profiles between the subjects with NP and the CON but only a weak systematic difference between the subjects with CWP and the CON. This most likely reflects a difference in the portion of the metabolome influenced by the two pain conditions. In the NP group, the overall metabolic profile suggests that processes related to energy utilisation and lipid metabolism could be central aspects of mechanisms maintaining disorder. PMID- 26522701 TI - Interfacial effect on physical properties of composite media: Interfacial volume fraction with non-spherical hard-core-soft-shell-structured particles. AB - Interfaces are known to be crucial in a variety of fields and the interfacial volume fraction dramatically affects physical properties of composite media. However, it is an open problem with great significance how to determine the interfacial property in composite media with inclusions of complex geometry. By the stereological theory and the nearest-surface distribution functions, we first propose a theoretical framework to symmetrically present the interfacial volume fraction. In order to verify the interesting generalization, we simulate three phase composite media by employing hard-core-soft-shell structures composed of hard mono-/polydisperse non-spherical particles, soft interfaces, and matrix. We numerically derive the interfacial volume fraction by a Monte Carlo integration scheme. With the theoretical and numerical results, we find that the interfacial volume fraction is strongly dependent on the so-called geometric size factor and sphericity characterizing the geometric shape in spite of anisotropic particle types. As a significant interfacial property, the present theoretical contribution can be further drawn into predicting the effective transport properties of composite materials. PMID- 26522700 TI - Notch signaling in postnatal joint chondrocytes, but not subchondral osteoblasts, is required for articular cartilage and joint maintenance. AB - OBJECTIVE: Notch signaling has been identified as a critical regulator in cartilage development and joint maintenance, and loss of Notch signaling in all joint tissues results in an early and progressive osteoarthritis (OA)-like pathology. This study investigated the targeted cell population within the knee joint in which Notch signaling is required for normal cartilage and joint integrity. METHODS: Two loss-of-function mouse models were generated with tissue specific knockout of the core Notch signaling component, RBPjkappa. The AcanCre(ERT2) transgene specifically removed Rbpjkappa floxed alleles in postnatal joint chondrocytes, while the Col1Cre(2.3kb) transgene deleted Rbpjkappa in osteoblast populations, including subchondral osteoblasts. Mutant and control mice were analyzed via histology, immunohistochemistry (IHC), real time quantitative polymerase chain reaction (qPCR), X-ray, and microCT imaging at multiple time-points. RESULTS: Loss of Notch signaling in postnatal joint chondrocytes results in a progressive OA-like pathology, and triggered the recruitment of non-targeted fibrotic cells into the articular cartilage potentially due to mis-regulated chemokine expression from within the cartilage. Upon recruitment, these fibrotic cells produced degenerative enzymes that may lead to the observed cartilage degradation and contribute to a significant portion of the age-related OA-like pathology. On the contrary, loss of Notch signaling in subchondral osteoblasts did not affect normal cartilage development or joint maintenance. CONCLUSIONS: RBPjkappa-dependent Notch signaling in postnatal joint chondrocytes, but not subchondral osteoblasts, is required for articular cartilage and joint maintenance. PMID- 26522702 TI - OPTIXcell improves the postthaw quality and fertility of buffalo bull sperm. AB - The present study was conducted to compare the liposome-containing, animal protein-free, commercially available OPTIXcell extender with the Tris-citric-egg yolk extender for postthaw quality and fertility of buffalo semen. Semen was collected from five adult Nili-Ravi buffalo (Bubalus bubalis) bulls of similar age group with an artificial vagina (at 42 degrees C) for 3 weeks (replicates). Semen ejaculates from each buffalo bull were divided into two aliquots and diluted (at 37 degrees C having 50 * 10(6) spermatozoa/mL) in the OPTIXcell or Tris-citric-egg yolk (control) extender. Diluted semen was cooled to 4 degrees C in 2 hours, equilibrated for 4 hours, and filled in 0.5-mL straws. The semen straws were kept over liquid nitrogen vapors (5 cm) for 10 minutes. The straws were then plunged and stored in liquid nitrogen (-196 degrees C). After 24 hours of storage, the semen straws were thawed at 37 degrees C for 30 seconds to assess postthaw quality. Percentages of sperm motility, plasma membrane integrity, viability, and acrosomal integrity were improved (P < 0.05) in the OPTIXcell extender compared to the Tris-citric-egg yolk extender. Values for DNA integrity (%) did not differ in the OPTIXcell and Tris-citric-egg yolk extenders. The overall conception rate in buffaloes was improved (P < 0.05) with semen cryopreserved in the OPTIXcell extender (59.5%) compared to semen cryopreserved in the Tris-citric-egg yolk extender (41.5%). It is concluded that the liposome containing commercially available OPTIXcell extender is more efficient to conserve postthaw quality and resulted in higher fertility rate of buffalo in the field. PMID- 26522704 TI - Foreword. PMID- 26522703 TI - Combined use of progesterone inserts, ultrasongraphy, and GnRH to identify and resynchronize nonpregnant cows and heifers 21 days after timed artificial insemination. AB - The objective was to decrease the reinsemination interval (RI) when dairy cows and heifers are inseminated using all timed artificial insemination (TAI) programs. Holstein cows (n = 211) and heifers (n = 153) were randomly assigned to a control or 21-day Resynch (21dRES) at 13 days after TAI. Animals in 21dRES (n = 109 cows and 77 heifers) had a progesterone device inserted on Day 13 and removed on Day 20 after TAI and ovaries scanned by ultrasonography. Animals found not to have an active CL (<15 mm) or a CL that decreased 10 mm or greater from Days 13 to 20, and to have a follicle of 12 mm or greater received GnRH and TAI on Day 21. Pregnancy diagnosis was performed on Day 32. Nonpregnant control cows (n = 102) were resynchronized immediately using Ovsynch-56, and control heifers (n = 76) were resynchronized using 5-day Cosynch starting on Day 34; therefore, cows and heifers were reinseminated on Day 42. Nonpregnant 21dRES animals that had not been reinseminated on Day 21 were resynchronized concurrently with the control animals. Pregnancy per AI (PAI) for the initial TAI was similar (P = 0.80) for 21dRES and control cows (30.3% vs. 29.4%) and heifers (49.4% vs. 51.3%). Of the nonpregnant 21dRES animals, 33 of 76 cows (43.4%) and 22 of 39 heifers (56.4%) had been reinseminated on Day 21. Therefore, the RI was decreased by 9.9 days (33.3 +/- 1.0 vs. 43.2 +/- 1.0 days; P < 0.001) in 21dRES cows and by 12.2 days in 21dRES heifers (30.1 +/- 1.3 vs. 42.3 +/- 1.3 days; P < 0.001) compared with controls. The overall resynchronized PAI was similar for 21dRES cows compared with controls (31.6% vs. 25.0%; P = 0.23). The PAI was 24.2% for 21dRES cows reinseminated on Day 21 and 37.2% for 21dRES cows reinseminated on Day 42. The overall resynchronized PAI was increased for 21dRES heifers compared with controls (57.5% vs. 32.4%; P = 0.03) because 21dRES heifers reinseminated on Day 21 had similar PAI compared with controls (43.5% vs. 32.4%; P = 0.39), but PAI was increased for 21dRES heifers reinseminated on Day 42 compared with controls (76.5% vs. 32.4%; P = 0.003). Consequently, the proportion of animals pregnant from the initial and resynchronized TAI tended to be increased in 21dRES heifers (79.0% vs. 67.1%; P = 0.09). Cost per pregnancy was decreased for the 21dRES in heifers. In conclusion, 21dRES provided a useful method to decrease the RI in cows and heifers, and to increase PAI and decrease cost per pregnancy in heifers. PMID- 26522705 TI - Efficacy of Intracameral Moxifloxacin Endophthalmitis Prophylaxis at Aravind Eye Hospital. AB - PURPOSE: To compare the rate of postoperative endophthalmitis before and after initiation of intracameral (IC) moxifloxacin for endophthalmitis prophylaxis in patients undergoing cataract surgery. DESIGN: Retrospective, clinical registry. PARTICIPANTS: All charity and private patients (116 714 eyes) who underwent cataract surgery between February 15, 2014, and April 15, 2015, at the Madurai Aravind Eye Hospital were included. Group 1 consisted of 37 777 eyes of charity patients who did not receive IC moxifloxacin, group 2 consisted of 38 160 eyes of charity patients who received IC moxifloxacin prophylaxis, and group 3 consisted of 40 777 eyes of private patients who did not receive IC moxifloxacin. METHODS: The electronic health record data for each of the 3 groups were analyzed, and the postoperative endophthalmitis rates were statistically compared. The cost of endophthalmitis treatment (groups 1 and 2) and the cost of IC moxifloxacin prophylaxis (group 2) were calculated. MAIN OUTCOME MEASURES: Postoperative endophthalmitis rate before and after initiation of IC moxifloxacin endophthalmitis treatment cost. RESULTS: Manual, sutureless, small incision cataract surgery (M-SICS) accounted for approximately all of the 75 937 cataract surgeries in the charity population (97%), but only a minority of the 40 777 private surgeries (21% M-SICS; 79% phacoemulsification). Thirty eyes in group 1 (0.08%) and 6 eyes in group 2 (0.02%) were diagnosed with postoperative endophthalmitis (P < 0.0001). The group 3 endophthalmitis rate was 0.07% (29 eyes), which was also higher than the second group's rate (P < 0.0001). There were no adverse events attributed to IC moxifloxacin in group 2. The total cost of treating the 30 patients with endophthalmitis in group 1 was virtually identical to the total combined cost in group 2 of routine IC moxifloxacin prophylaxis and treatment of the 6 endophthalmitis cases. CONCLUSIONS: Routine IC moxifloxacin prophylaxis achieved a highly significant, 4-fold reduction in postoperative endophthalmitis in patients undergoing M-SICS. Compared with previous studies, having such a high volume of patients undergoing surgery during a relatively short 14-month time period strengthens the conclusion. This study provides further evidence that moxifloxacin is an effective IC prophylactic antibiotic and suggests that IC antibiotics should be considered for M-SICS and phacoemulsification. PMID- 26522706 TI - Diffuse Anterior Retinoblastoma with Globe Salvage and Visual Preservation in 3 Consecutive Cases. AB - PURPOSE: Diffuse anterior retinoblastoma is an exquisitely rare variant of retinoblastoma in which the tumor resides in the anterior segment of the eye, without apparent retinal involvement. Previously published cases have been managed with enucleation. We describe globe salvage and visual preservation in 3 consecutive cases using chemotherapy and radiotherapy. DESIGN: Retrospective case series. PARTICIPANTS: Three children with diffuse anterior retinoblastoma. METHODS: Plaque radiotherapy plus intravenous chemotherapy. MAIN OUTCOME MEASURES: Globe and vision preservation. RESULTS: The mean patient age at presentation elsewhere was 5.7 years (median, 7; range, 3-7 years). There were 2 white female patients and 1 African American male patient. The initial observation by parents/caregiver was reduced vision (n = 1), red eye (n = 1), or cloudy eye (n = 1), and the initial finding by physician was iris tumor (n = 2) or hyphema (n = 1). Referring diagnosis was iris melanoma (n = 1), infectious endotheliitis (n = 1), and possible tumor (nonspecified) (n = 1). At our evaluation, visual acuity was 20/50 to 20/60 (n = 2) and fix no follow (n = 1). In all cases, the opposite eye was normal. Mean intraocular pressure was 20 mm Hg (median, 16; range, 15-30 mmHg). Our examination revealed solid iris tumor (n = 3), ciliary body involvement (n = 2), and anterior chamber seeding (n = 3). In no case was there choroidal or retinal tumor, vitreous seed or subretinal seed, or extrascleral extension. Clear corneal fine-needle aspiration biopsy confirmed the diagnosis as retinoblastoma in each case. Treatment included plaque radiotherapy (n = 3) plus additional systemic chemotherapy (n = 2). At mean follow-up of 35 months (median, 34; range, 20-51 months), there has been no recurrence, extrascleral extension, enucleation, metastasis, or death. In all 3 cases, cataract surgery was necessary at a mean interval of 16 months after complete and stable regression of retinoblastoma. CONCLUSIONS: The rare diffuse anterior form of retinoblastoma can be managed with globe-salvaging alternatives and with visual preservation in selected cases. PMID- 26522713 TI - The Epileptic Genius: The Use of Dostoevsky as Example in the Medical Debate over the Pathology of Genius. AB - This paper examines how Fyodor Dostoevsky was used as an example in the debate over genius as a pathological phenomenon in nineteenth century medicine and criminal anthropology. When Dostoevsky's novels became known in Western Europe medical interest in the relation between genius and insanity reached its pinnacle. A known epileptic, Dostoevsky was exceptionally well suited to illustrate Cesare Lombroso's theory of genius as an epileptoid psychosis. Dostoevsky was also claimed as an example by the rivalling Lyon school, whose representatives argued that Dostoevsky's life and works demonstrate that genius is a higher form of health rather than a pathological deviation. PMID- 26522708 TI - Intravitreal Aflibercept for Macular Edema Following Branch Retinal Vein Occlusion: 52-Week Results of the VIBRANT Study. AB - PURPOSE: To determine week 52 efficacy and safety outcomes in eyes with macular edema after branch retinal vein occlusion (BRVO) treated with 2 mg intravitreal aflibercept injection (IAI) compared with grid laser. DESIGN: VIBRANT was a double-masked, randomized, phase 3 trial. PARTICIPANTS: Eyes randomized and treated in VIBRANT were followed to week 52. METHODS: In the IAI group, eyes received IAI every 4 weeks through week 24 and IAI every 8 weeks through week 48 with rescue grid laser if needed at week 36. In the grid laser group, all eyes received grid laser at baseline and, if prespecified rescue criteria were met, 1 additional laser from week 12 to 20 and IAI every 8 weeks after 3 monthly doses from week 24 onward (the laser/IAI group). MAIN OUTCOME MEASURES: The primary outcome measure was percentage of eyes with improvement from baseline best corrected visual acuity (BCVA) letter score >=15 at week 24. All outcome measures at week 52 were exploratory, and P values are considered nominal. RESULTS: The percentage of eyes with improvement from baseline letter score >=15 in the IAI and laser/IAI groups was 52.7% versus 26.7% (P = 0.0003) at week 24 and 57.1% versus 41.1% (P = 0.0296) at week 52. The corresponding mean change from baseline BCVA letter score was 17.0 versus 6.9 (P < 0.0001) at week 24 and 17.1 versus 12.2 (P = 0.0035) at week 52. The mean reduction from baseline central retinal thickness was 280.5 MUm versus 128.0 MUm (P < 0.0001) at week 24 and 283.9 MUm versus 249.3 MUm (P = 0.0218) at week 52. In the IAI group, 10.6% of eyes received rescue laser at week 36, and in the laser/IAI group, 80.7% received rescue IAI from week 24 to week 48. Traumatic cataract in 1 eye (1.1%) in the IAI group was the only ocular serious adverse event. CONCLUSIONS: After 6 monthly IAI, injections every 8 weeks maintained control of macular edema and visual benefits through week 52. In the laser group, rescue IAI given from week 24 onward resulted in substantial visual improvements at week 52. PMID- 26522707 TI - Delayed Rod-Mediated Dark Adaptation Is a Functional Biomarker for Incident Early Age-Related Macular Degeneration. AB - PURPOSE: To examine whether slowed rod-mediated dark adaptation (DA) in adults with normal macular health at baseline is associated with the incidence of age related macular degeneration (AMD) 3 years later. DESIGN: Prospective cohort. PARTICIPANTS: Adults aged >=60 years were recruited from primary care ophthalmology clinics. Both eyes were required to be step 1 (normal) on the Age Related Eye Disease Study 9-step AMD classification system based on color fundus photographs graded by experienced and masked evaluators. METHODS: Rod-mediated DA was assessed at baseline in 1 eye after a photobleach using a computerized dark adaptometer with targets centered at 5 degrees on the inferior vertical meridian. Speed of DA was characterized by the rod-intercept value, with abnormal DA defined as rod-intercept >=12.3 minutes. Demographic characteristics, best corrected visual acuity, and smoking status were also assessed. Log-binomial regression was used to calculate unadjusted and adjusted risk ratios (RRs) and associated 95% confidence intervals (CIs) for the association between baseline DA and incident AMD. MAIN OUTCOME MEASURES: Presence of AMD at the 3-year follow-up visit for the eye tested for DA at baseline. RESULTS: Both baseline and follow-up visits were completed by 325 persons (mean age, 67.8 years). At baseline, 263 participants had normal DA with mean rod-intercept of 9.1 (standard deviation [SD], 1.5), and 62 participants had abnormal DA with mean rod-intercept of 15.1 (SD, 4.0). After adjustment for age and smoking, those with abnormal DA in the tested eye at baseline were approximately 2 times more likely to have AMD in that eye (RR, 1.92; 95% CI, 1.03-3.62) by the time of the follow-up visit, compared with those who had normal DA at baseline. CONCLUSIONS: Delayed rod-mediated DA in older adults with normal macular health is associated with incident early AMD 3 years later, and thus is a functional biomarker for early disease. The biological relevance of this test is high, because it assesses translocation of vitamin A derivatives across the retinal pigment epithelium and Bruch's membrane, 2 tissues with prominent age- and AMD-related pathology. PMID- 26522719 TI - Oncofetal protein IGF2BP3 facilitates the activity of proto-oncogene protein eIF4E through the destabilization of EIF4E-BP2 mRNA. AB - RNA-binding proteins (RBPs) have important roles in tumorigenesis. Although IGF2BP3, an evolutionally conserved RBP, has been reported as a useful diagnostic marker for various cancers and has been considered a regulator of tumorigenesis, little is known of the function of IGF2BP3 because of lack of information regarding IGF2BP3 target mRNAs. Here, we report the identification of IGF2BP3 target mRNAs and IGF2BP3 function in cancer proliferation. We identified mRNAs with altered expression in IGF2BP3-depleted cells by massive sequencing analysis and IGF2BP3-binding RNAs by immunoprecipitation of IGF2BP3 followed by massive sequencing analysis, resulting in the identification of 110 candidates that are negatively regulated by IGF2BP3. We found that IGF2BP3 destabilized EIF4E-BP2 and MEIS3 mRNAs. Co-immunoprecipitation analysis revealed the interaction between IGF2BP3 and ribonucleases such as XRN2 and exosome component. The retarded proliferation of IGF2BP3-depleted cells was partially rescued by the depletion of EIF4E-BP2, which negatively regulates eukaryotic translation initiation factor 4E (eIF4E), an activator of translation and a well-known proto-oncogene. Consistent with this observation, IGF2BP3 depletion reduced phosphorylated eIF4E, the active form, and translational efficiency of eIF4E target transcripts. Reduction of phosphorylated eIF4E by IGF2BP3 depletion was rescued by EIF4E-BP2 depletion. At last, we found an inverse correlation between the expression level of IGF2BP3 and EIF4E-BP2 in human lung adenocarcinoma tissues. Together, these results suggest that IGF2BP3 promotes eIF4E-mediated translational activation through the reduction of EIF4E-BP2 via mRNA degradation, leading to enhanced cell proliferation. This is the first report demonstrating that IGF2BP3 is an RNA destabilizing factor. Notably, here we provide the first evidence for the functional linkage between two previously well-known cancer biomarkers, IGF2BP3 and eIF4E. PMID- 26522721 TI - ZFP521 contributes to pre-B-cell lymphomagenesis through modulation of the pre-B cell receptor signaling pathway. AB - ZFP521 was previously identified as a putative gene involved in induction of B cell lymphomagenesis. However, the contribution of ZFP521 to lymphomagenesis has not been confirmed. In this study, we sought to elucidate the role of ZFP521 in B cell lymphomagenesis. To this end, we used a retroviral insertion method to show that ZFP521 was a target of mutagenesis in pre-B-lymphoblastic lymphoma cells. The pre-B-cell receptor (pre-BCR) signaling molecules BLNK, BTK and BANK1 were positively regulated by the ZFP521 gene, leading to enhancement of the pre-BCR signaling pathway. In addition, c-myc and c-jun were upregulated following activation of ZFP521. Stimulation of pre-BCR signaling using anti-Vpreb antibodies caused aberrant upregulation of c-myc and c-jun and of Ccnd3, which encodes cyclin D3, thereby inducing the growth of pre-B cells. Stimulation with Vpreb affected the growth of pre-B cells, and addition of interleukin (IL)-7 receptor exerted competitive effects on pre-B-cell growth. Knockdown of BTK and BANK1, targets of ZFP521, suppressed the effects of Vpreb stimulation on cell growth. Furthermore, in human lymphoblastic lymphoma, analogous to pre-B-cell lymphoma in mice, the expression of ZNF521, the homolog of ZFP521 in humans, was upregulated. In conclusion, our data showed that the ZFP521 gene comprehensively induced pre-B-cell lymphomagenesis by modulating the pre-B-cell receptor signaling pathway. PMID- 26522722 TI - The Arkadia-ESRP2 axis suppresses tumor progression: analyses in clear-cell renal cell carcinoma. AB - Tumor-specific alternative splicing is implicated in the progression of cancer, including clear-cell renal cell carcinoma (ccRCC). Using ccRCC RNA sequencing data from The Cancer Genome Atlas, we found that epithelial splicing regulatory protein 2 (ESRP2), one of the key regulators of alternative splicing in epithelial cells, is expressed in ccRCC. ESRP2 mRNA expression did not correlate with the overall survival rate of ccRCC patients, but the expression of some ESRP target exons correlated with the good prognosis and with the expression of Arkadia (also known as RNF111) in ccRCC. Arkadia physically interacted with ESRP2, induced polyubiquitination and modulated its splicing function. Arkadia and ESRP2 suppressed ccRCC tumor growth in a coordinated manner. Lower expression of Arkadia correlated with advanced tumor stages and poor outcomes in ccRCC patients. This study thus reveals a novel tumor-suppressive role of the Arkadia ESRP2 axis in ccRCC. PMID- 26522720 TI - The NF-kappaB subunit c-Rel regulates Bach2 tumour suppressor expression in B cell lymphoma. AB - The REL gene, encoding the NF-kappaB subunit c-Rel, is frequently amplified in B cell lymphoma and functions as a tumour-promoting transcription factor. Here we report the surprising result that c-rel-/- mice display significantly earlier lymphomagenesis in the c-Myc driven, EMU-Myc model of B-cell lymphoma. c-Rel loss also led to earlier onset of disease in a separate TCL1-Tg-driven lymphoma model. Tumour reimplantation experiments indicated that this is an effect intrinsic to the EMU-Myc lymphoma cells but, counterintuitively, c-rel-/- EMU-Myc lymphoma cells were more sensitive to apoptotic stimuli. To learn more about why loss of c Rel led to earlier onset of disease, microarray gene expression analysis was performed on B cells from 4-week-old, wild-type and c-rel-/- EMU-Myc mice. Extensive changes in gene expression were not seen at this age, but among those transcripts significantly downregulated by the loss of c-Rel was the B-cell tumour suppressor BTB and CNC homology 2 (Bach2). Quantitative PCR and western blot analysis confirmed loss of Bach2 in c-Rel mutant EMU-Myc tumours at both 4 weeks and the terminal stages of disease. Moreover, Bach2 expression was also downregulated in c-rel-/- TCL1-Tg mice and RelA Thr505Ala mutant EMU-Myc mice. Analysis of wild-type EMU-Myc mice demonstrated that the population expressing low levels of Bach2 exhibited the earlier onset of lymphoma seen in c-rel-/- mice. Confirming the relevance of these findings to human disease, analysis of chromatin immunoprecipitation sequencing data revealed that Bach2 is a c-Rel and NF-kappaB target gene in transformed human B cells, whereas treatment of Burkitt's lymphoma cells with inhibitors of the NF-kappaB/IkappaB kinase pathway or deletion of c-Rel or RelA resulted in loss of Bach2 expression. These data reveal a surprising tumour suppressor role for c-Rel in lymphoma development explained by regulation of Bach2 expression, underlining the context-dependent complexity of NF-kappaB signalling in cancer. PMID- 26522723 TI - The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth. AB - Epidermal homeostasis depends on the coordinated control of keratinocyte cell cycle. Differentiation and the alteration of this balance can result in neoplastic development. Here we report on a novel DLX3-dependent network that constrains epidermal hyperplasia and squamous tumorigenesis. By integrating genetic and transcriptomic approaches, we demonstrate that DLX3 operates through a p53-regulated network. DLX3 and p53 physically interact on the p21 promoter to enhance p21 expression. Elevating DLX3 in keratinocytes produces a G1-S blockade associated with p53 signature transcriptional profiles. In contrast, DLX3 loss promotes a mitogenic phenotype associated with constitutive activation of ERK. DLX3 expression is lost in human skin cancers and is extinguished during progression of experimentally induced mouse squamous cell carcinoma (SCC). Reinstatement of DLX3 function is sufficient to attenuate the migration of SCC cells, leading to decreased wound closure. Our data establish the DLX3-p53 interplay as a major regulatory axis in epidermal differentiation and suggest that DLX3 is a modulator of skin carcinogenesis. PMID- 26522724 TI - Endothelin A receptor drives invadopodia function and cell motility through the beta-arrestin/PDZ-RhoGEF pathway in ovarian carcinoma. AB - The endothelin-1 (ET-1)/ET A receptor (ETAR) signalling pathway is a well established driver of epithelial ovarian cancer (EOC) progression. One key process promoted by ET-1 is tumor cell invasion, which requires the scaffolding functions of beta-arrestin-1 (beta-arr1) downstream of the receptor; however, the potential role of ET-1 in inducing invadopodia, which are crucial for cellular invasion and tumor metastasis, is completely unknown. We describe here that ET 1/ETAR, through beta-arr1, activates RhoA and RhoC GTPase and downstream ROCK (Rho-associated coiled coil-forming kinase) kinase activity, promoting actin based dynamic remodelling and enhanced cell invasion. This is accomplished by the direct interaction of beta-arr1 with PDZ-RhoGEF (postsynaptic density protein 95/disc-large/zonula occludens-RhoGEF). Interestingly, ETAR-mediated invasive properties are related to the regulation of invadopodia, as evaluated by colocalization of actin with cortactin, as well as with TKS5 and MT1-MMP (membrane type 1-matrix metalloproteinase) with areas of matrix degradation, and activation of cofilin pathway, which is crucial for regulating invadopodia activity. Depletion of PDZ-RhoGEF, or beta-arr1, or RhoC, as well as the treatment with the dual ET-1 receptor antagonist macitentan, significantly impairs invadopodia function, MMP activity and invasion, demonstrating that beta arr1/PDZ-RhoGEF interaction mediates ETAR-driven ROCK-LIMK-cofilin pathway through the control of RhoC activity. In vivo, macitentan is able to inhibit metastatic dissemination and cofilin phosphorylation. Collectively, our data unveil a noncanonical activation of the RhoC/ROCK pathway through the beta arr1/PDZ-RhoGEF complex as a regulator of ETAR-induced motility and metastasis, establishing ET-1 axis as a novel regulator of invadopodia protrusions through the RhoC/ROCK/LIMK/cofilin pathway during the initial steps of EOC invasion. PMID- 26522725 TI - Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF alpha-dependent necroptosis driven by RIP1 kinase and NF-kappaB. AB - Resistance towards the drug 5-fluorouracil (5-FU) is a key challenge in the adjuvant chemotherapy of colorectal cancer (CRC), and novel targeted approaches are required to improve the therapeutic outcome. Necroptosis is a recently discovered form of programmed cell death, which depends on receptor interacting protein 1 (RIP1) and particularly occurs under caspase-deficient conditions. The targeted induction of necroptosis represents a promising strategy to overcome apoptosis resistance in cancer. The aim of this study was to systematically explore the usage of pan-caspase inhibitors to sensitize resistant CRC cells for 5-FU. We found that pan-caspase inhibitors facilitated 5-FU-induced necroptosis, which was mediated by autocrine secretion of tumor necrosis factor alpha (TNF alpha). TNF-alpha production was driven by nuclear factor kappaB (NF-kappaB) and required RIP1 kinase. In vivo xenograft experiments showed that the novel pan caspase inhibitor IDN-7314 in combination with 5-FU synergistically blocked tumor growth. Ex vivo experiments with fresh human CRC tissue specimens further indicated that a subgroup of patients could benefit from combinatory treatment. Thereby, elevated levels of secreted TNF-alpha and expression of components of the necroptotic pathway might help to predict the sensitivity to pro-necroptotic therapies. Together, our results shed new light on the molecular regulation of necroptosis by NF-kappaB and RIP1. Moreover, we identify necroptotic cell death as an important effector mechanism of 5-FU-mediated anti-tumoral activity. On the basis of this study, we propose pan-caspase inhibitors as a novel approach in the adjuvant chemotherapy of CRC. PMID- 26522726 TI - mTORC1 directly phosphorylates and activates ERalpha upon estrogen stimulation. AB - Breast cancer is the leading cause of cancer-related deaths among women. Approximately 75% of breast cancers are estrogen receptor-alpha (ERalpha) positive, underscoring the dependence of cancer cells on estrogen for growth and survival. Patients treated with endocrine therapy often develop resistance, either de novo or acquired, which in some cases is caused by aberrations within the growth factor signaling pathways. The mechanistic target of rapamycin complex 1 (mTORC1) has emerged as a critical node in estrogenic signaling. We have previously shown that mTORC1 can phosphorylate and activate ERalpha on S167 via its effector-the 40S ribosomal S6 kinase 1 (S6K1). Presently, we have uncovered a direct link between mTORC1 and ERalpha. We found that ERalpha binds to regulatory associated protein of mTOR (Raptor) and causes it to translocate to the nucleus upon estrogen stimulation. In addition, we identified mTOR as the kinase that phosphorylates ERalpha on S104/106 and activates transcription of ER target genes. Our findings show a direct link between mTORC1 and ERalpha, which further implicates mTORC1 signaling in the pathogenesis of ER-positive breast cancer and provides rationale for FDA-approved use of mTORC1 inhibitors in combination with endocrine agents for treatment of this disease. PMID- 26522727 TI - Loss of ATF3 promotes hormone-induced prostate carcinogenesis and the emergence of CK5(+)CK8(+) epithelial cells. AB - Steroid sex hormones can induce prostate carcinogenesis, and are thought to contribute to the development of prostate cancer during aging. However, the mechanism for hormone-induced prostate carcinogenesis remains elusive. Here, we report that activating transcription factor 3 (ATF3)-a broad stress sensor suppressed hormone-induced prostate carcinogenesis in mice. Although implantation of testosterone and estradiol (T+E2) pellets for 2 months in wild-type mice rarely induced prostatic intraepithelial neoplasia (PIN) in dorsal prostates (one out of eight mice), the loss of ATF3 led to the appearance of not only PIN but also invasive lesions in almost all examined animals. The enhanced carcinogenic effects of hormones on ATF3-deficient prostates did not appear to be caused by a change in estrogen signaling, but were more likely a consequence of elevated androgen signaling that stimulated differentiation of prostatic basal cells into transformation-preferable luminal cells. Indeed, we found that hormone-induced lesions in ATF3-knockout mice often contained cells with both basal and luminal characteristics, such as p63(+) cells (a basal-cell marker) showing luminal-like morphology, or cells double-stained with basal (CK5(+)) and luminal (CK8(+)) markers. Consistent with these findings, low ATF3 expression was found to be a poor prognostic marker for prostate cancer in a cohort of 245 patients. Our results thus support that ATF3 is a tumor suppressor in prostate cancer. PMID- 26522728 TI - The MAP3K ZAK, a novel modulator of ERK-dependent migration, is upregulated in colorectal cancer. AB - Often described as a mediator of cell cycle arrest or as a pro-apoptotic factor in stressful conditions, the MAP3K ZAK (Sterile alpha motif and leucine zipper containing kinase) has also been proven to positively regulate epidermal growth factor receptor (EGFR) and WNT signaling pathways, cancer cell proliferation and cellular neoplastic transformation. Here, we show that both isoforms of ZAK, ZAK alpha and ZAK-beta are key factors in cancer cell migration. While ZAK depletion reduced cell motility of HeLa and HCT116 cells, its overexpression triggered the activation of all three mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and p38, as well as an increase in cell motion. On the contrary, the kinase-dead mutants, ZAK-alpha K45M and ZAK-beta K45M, were not able to provoke such events, and instead exerted a dominant-negative effect on MAPK activation and cell migration. Pharmacological inhibition of ZAK by nilotinib, preventing ZAK-autophosphorylation and thereby auto-activation, led to the same results. Activated by epidermal growth factor (EGF), we further showed that ZAK constitutes an essential element of the EGF/ERK dependent cell migration pathway. Using public transcriptomic databases and tissue microarrays, we finally established that, as strong factors of the EGFR signaling pathway, ZAK-alpha and/or ZAK-beta transcripts and protein(s) are frequently upregulated in colorectal adenoma and carcinoma patients. Notably, gene set enrichment analysis disclosed a significant correlation between ZAK+ colorectal premalignant lesions and gene sets belonging to the MAPK/ERK and motility-related signaling pathways of the reactome database, strongly suggesting that ZAK induces such pro-tumoral reaction cascades in human cancers. PMID- 26522730 TI - An Individual-Centered Framework For Unravelling Genotype-Phenotype Interactions. AB - A new framework in which the multiple levels of molecular variations contribute to phenotypic variations in a complex, nonlinear and interactive way, challenges the hierarchical nature of the relationships between the genotypic and phenotypic spaces. This individual-centered framework provides new insights on the evolutionary mechanisms involved in the production of phenotypes. We propose to move this research agenda forward by combining selection experiments and functional genetics. PMID- 26522729 TI - Interaction of MYC with host cell factor-1 is mediated by the evolutionarily conserved Myc box IV motif. AB - The MYC family of oncogenes encodes a set of three related transcription factors that are overexpressed in many human tumors and contribute to the cancer-related deaths of more than 70,000 Americans every year. MYC proteins drive tumorigenesis by interacting with co-factors that enable them to regulate the expression of thousands of genes linked to cell growth, proliferation, metabolism and genome stability. One effective way to identify critical co-factors required for MYC function has been to focus on sequence motifs within MYC that are conserved throughout evolution, on the assumption that their conservation is driven by protein-protein interactions that are vital for MYC activity. In addition to their DNA-binding domains, MYC proteins carry five regions of high sequence conservation known as Myc boxes (Mb). To date, four of the Mb motifs (MbI, MbII, MbIIIa and MbIIIb) have had a molecular function assigned to them, but the precise role of the remaining Mb, MbIV, and the reason for its preservation in vertebrate Myc proteins, is unknown. Here, we show that MbIV is required for the association of MYC with the abundant transcriptional coregulator host cell factor 1 (HCF-1). We show that the invariant core of MbIV resembles the tetrapeptide HCF binding motif (HBM) found in many HCF-interaction partners, and demonstrate that MYC interacts with HCF-1 in a manner indistinguishable from the prototypical HBM containing protein VP16. Finally, we show that rationalized point mutations in MYC that disrupt interaction with HCF-1 attenuate the ability of MYC to drive tumorigenesis in mice. Together, these data expose a molecular function for MbIV and indicate that HCF-1 is an important co-factor for MYC. PMID- 26522731 TI - Momentary fitting in a fluid environment: A grounded theory of triage nurse decision making. AB - BACKGROUND: Triage nurses control access to the Emergency Department (ED) and make decisions about patient acuity, patient priority, and placement of the patient in the ED. Understanding the processes and strategies that triage nurses use to make decisions is therefore vital for patient safety and the operation of the ED. The aim of the current study was to generate a substantive grounded theory (GT) of decision making by emergency triage Registered Nurses (RNs). METHOD: Data collection consisted of seven observations of the triage environment at three tertiary care hospitals where RNs conducted triage and twelve interviews with triage RNs. The data were analyzed by constant comparison in accordance with the classical GT method. RESULTS: In the resultant theory, Momentary Fitting in a Fluid Environment, triage is conceptualized as a process consisting of four categories, determining acuity, anticipating needs, managing space, and creating space. The findings indicate that triage RNs continually strive to achieve fit, while simultaneously considering the individual patient and the ED as a whole entity. CONCLUSION: Triage RNs require appropriately designed triage environments and computer technology that enable them to secure real time knowledge of the ED to maintain situation awareness. PMID- 26522732 TI - The journey should start at home! PMID- 26522733 TI - The association and prognostic relevance of cancerous inhibitor of protein phosphatase 2A and inflammation in tongue squamous cell carcinoma. AB - Cancerous inhibitor of protein phosphatase 2A (CIP2A) prevents proteolytic degradation of a universal transcription factor, c-Myc. Strong CIP2A expression associates with poor prognosis in early-stage tongue cancer and in other cancers. The aim of this study was to evaluate CIP2A and mucosal inflammation in tongue hyperplasia, in tongue cancer, and in its metastasis. Retrospective tongue and lymph node specimens (n = 105) were stained immunohistochemically with polyclonal antibody anti-CIP2A. CIP2A staining intensity and inflammation were assessed semi quantitatively with light microscopy. CIP2A was similarly detected in tongue cancer and tongue hyperplasia, whereas local inflammation was stronger in cancer (p = 0.000). CIP2A expression was increased in metastasized cancer compared to non-metastasized (p = 0.019). Markers for poorer survival were tumor size of >=20 mm, presence of metastasis and nodal CIP2A (p = 0.031, p = 0.000, p = 0.042). Cancer patients aged >=60 with increased inflammation predicted poor survival (p = 0.037). CIP2A and inflammation might play a role in progression of tongue cancer. PMID- 26522735 TI - Regenerative ophthalmology: Technologic and pharmacologic approaches to restoring sight via retinal prosthesis. AB - Retinal prosthesis technology can restore rudimentary form vision in patients with retinitis pigmentosa (RP) who have lost all eyesight. This continually advancing field within regenerative ophthalmology represents the merger of micro electromechanical systems technology with neurosensory retina. This man-machine interface is reliant upon the long-term health of a neurosensory retina undergoing progressive pathophysiologic changes. Pharmacologic approaches that address the pathophysiologic consequences of RP will likely play an important role for all regenerative treatment strategies. PMID- 26522734 TI - DNA damage-induced metaphase I arrest is mediated by the spindle assembly checkpoint and maternal age. AB - In mammalian oocytes DNA damage can cause chromosomal abnormalities that potentially lead to infertility and developmental disorders. However, there is little known about the response of oocytes to DNA damage. Here we find that oocytes with DNA damage arrest at metaphase of the first meiosis (MI). The MI arrest is induced by the spindle assembly checkpoint (SAC) because inhibiting the SAC overrides the DNA damage-induced MI arrest. Furthermore, this MI checkpoint is compromised in oocytes from aged mice. These data lead us to propose that the SAC is a major gatekeeper preventing the progression of oocytes harbouring DNA damage. The SAC therefore acts to integrate protection against both aneuploidy and DNA damage by preventing production of abnormal mature oocytes and subsequent embryos. Finally, we suggest escaping this DNA damage checkpoint in maternal ageing may be one of the causes of increased chromosome anomalies in oocytes and embryos from older mothers. PMID- 26522736 TI - Microphthalmia-associated transcription factor is expressed in projection neurons of the mouse olfactory bulb. AB - Microphthalmia-associated transcription factor (Mitf) is a key regulator for differentiation of the neural crest-derived melanocytes. Mitf consists of multiple isoforms, including melanocyte-specific Mitf-M and widely expressed Mitf A and Mitf-H. Mitf mRNAs are also expressed in the brain, although the identity of Mitf-expressing cells remains unknown. We therefore aimed to identify Mitf expressing cells in the brain. By the immunohistochemical analysis, we detected Mitf-expressing cells only in the olfactory bulb of the C57BL/6 mouse. The Mitf expressing cells were then identified as projection neurons, mitral cells and tufted cells, both of which receive the signal from the olfactory neurons and transmit the information to the olfactory cortex. Real-time RT-PCR analysis showed the expression level of Mitf-M mRNA was comparable to the expression levels of Mitf-A and Mitf-H mRNAs in the olfactory bulb. We then analyzed Mitf expressing neurons in the olfactory bulb of the homozygous black-eyed white (Mitf(mi-bw)) mouse that is characterized by the lack of melanocytes. Mitf was expressed in mitral cells and tufted cells in the olfactory bulb of the Mitf(mi bw) mouse, thereby excluding the contribution of melanocytes to the detected expression of Mitf-M. In conclusion, Mitf, including Mitf-M, is expressed in mitral cells and tufted cells of the olfactory bulb. PMID- 26522738 TI - Edaravone abrogates LPS-induced behavioral anomalies, neuroinflammation and PARP 1. AB - Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA nick-sensor enzyme that functions at the center of cellular stress response and affects the immune system at several key points, and thus modulates inflammatory diseases. Our previous study demonstrated that lipopolysaccharide (LPS)-induced depressive-like behavior in mice can be ameliorated by 3-aminobenzamide, which is a PARP-1 inhibitor. In the present study we've examined the effect of a free radical scavenger, edaravone pretreatment against LPS-induced anxiety and depressive-like behavior as well as various hippocampal biochemical parameters including PARP-1. Male Swiss albino mice were treated with edaravone (3 & 10mg/kgi.p.) once daily for 14days. On the 14th day 30min after edaravone treatment mice were challenged with LPS (1mg/kgi.p.). After 3h and 24h of LPS administration we've tested mice for anxiety and depressive-like behaviors respectively. Western blotting analysis of PARP-1 in hippocampus was carried out after 12h of LPS administration. Moreover, after 24h of LPS administration serum corticosterone, hippocampal BDNF, oxido nitrosative stress and pro-inflammatory cytokines were estimated by ELISA. Results showed that pretreatment of edaravone (10mg/kg) ameliorates LPS-induced anxiety and depressive-like behavior. Western blotting analysis showed that LPS induced anomalous expression of PARP-1 significantly reverses by the pretreatment of edaravone (10mg/kg). Biochemical analyses revealed that LPS significantly diminishes BDNF, increases pro-inflammatory cytokines and oxido-nitrosative stress in the hippocampus. However, pretreatment with edaravone (10mg/kg) prominently reversed all these biochemical alterations. Our study emphasized that edaravone pretreatment prevents LPS-induced anxiety and depressive-like behavior, mainly by impeding the inflammation, oxido-nitrosative stress and PARP-1 overexpression. PMID- 26522737 TI - Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea. AB - While chemotherapy-induced nausea and vomiting are clinically controlled in the acute (<24 h) phase following treatment, the anorexia, nausea, fatigue, and other illness-type behaviors during the delayed phase (>24 h) of chemotherapy are largely uncontrolled. As the hindbrain glucagon-like peptide-1 (GLP-1) system contributes to energy balance and mediates aversive and stressful stimuli, here we examine the hypothesis that hindbrain GLP-1 signaling mediates aspects of chemotherapy-induced nausea and reductions in feeding behavior in rats. Specifically, hindbrain GLP-1 receptor (GLP-1R) blockade, via 4th intracerebroventricular (ICV) exendin-(9-39) injections, attenuates the anorexia, body weight reduction, and pica (nausea-induced ingestion of kaolin clay) elicited by cisplatin chemotherapy during the delayed phase (48 h) of chemotherapy-induced nausea. Additionally, the present data provide evidence that the central GLP-1-producing preproglucagon neurons in the nucleus tractus solitarius (NTS) of the caudal brainstem are activated by cisplatin during the delayed phase of chemotherapy-induced nausea, as cisplatin led to a significant increase in c-Fos immunoreactivity in NTS GLP-1-immunoreactive neurons. These data support a growing body of literature suggesting that the central GLP-1 system may be a potential pharmaceutical target for adjunct anti-emetics used to treat the delayed-phase of nausea and emesis, anorexia, and body weight loss that accompany chemotherapy treatments. PMID- 26522739 TI - Are compression garments effective for the recovery of exercise-induced muscle damage? A systematic review with meta-analysis. AB - PURPOSE: The aim was to identify benefits of compression garments used for recovery of exercised-induced muscle damage. METHODS: Computer-based literature research was performed in September 2015 using four online databases: Medline (PubMed), Cochrane, WOS (Web Of Science) and Scopus. The analysis of risk of bias was completed in accordance with the Cochrane Collaboration Guidelines. Mean differences and 95% confidence intervals were calculated with Hedges' g for continuous outcomes. A random effect meta-analysis model was used. Systematic differences (heterogeneity) were assessed with I(2) statistic. RESULTS: Most results obtained had high heterogeneity, thus their interpretation should be careful. Our findings showed that creatine kinase (standard mean difference= 0.02, 9 studies) was unaffected when using compression garments for recovery purposes. In contrast, blood lactate concentration was increased (standard mean difference=0.98, 5 studies). Applying compression reduced lactate dehydrogenase (standard mean difference=-0.52, 2 studies), muscle swelling (standard mean difference=-0.73, 5 studies) and perceptual measurements (standard mean difference=-0.43, 15 studies). Analyses of power (standard mean difference=1.63, 5 studies) and strength (standard mean difference=1.18, 8 studies) indicate faster recovery of muscle function after exercise. CONCLUSIONS: These results suggest that the application of compression clothing may aid in the recovery of exercise induced muscle damage, although the findings need corroboration. PMID- 26522740 TI - Differential organization of male copulatory patterns in high- and low-yawning frequency sublines versus outbred Sprague-Dawley rats. AB - The temporal organization of masculine sexual behavior in rats is highly stereotyped; involving a sequence of mounts, intromissions and ejaculations. Sexual behavior has been described in exogamic and genetically manipulated rodent species. In this work, we compare the male sexual behavior of outbred Sprague Dawley (SD) to those of rats inbred for high (HY)- and low (LY)- spontaneous yawning frequency. In the first experiment, the percentage of inexperienced rats' ejaculatory behavior is significantly lower in the HY and LY respect to Sprague Dawley rats. The latency to ejaculate for inexperienced HY was shorter than the LY and SD rats. In the second experiment, we examined the differences between inbred sublines and Sprague-Dawley rats once the subjects had become sexually experienced after four copulatory sessions. HY rats still have slower proportion of ejaculators respect to LY and SD rats. Additionally, postejaculatory latencies were longer for HY rats, with longer intercopulatory intervals and higher number of copulatory bouts that delayed ejaculation. Both sublines show lower copulatory efficiency respect to SD rats. In conclusion, both sublines show alterations in the temporal organization of sexual motor pattern that are due at least partially to strong inbreeding process to select them. PMID- 26522741 TI - The role of the AMPA receptor and 5-HT(3) receptor on aggressive behavior and depressive-like symptoms in chronic social isolation-reared mice. AB - Chronic social isolation (SI)-reared mice exhibit aggressive and depressive-like behaviors. However, the pathophysiological changes caused by chronic SI remain unclear. The hypothalamus and amygdala have been suggested to be associated with the stress of SI. In addition to serotonin 3 (5-HT3) receptors, AMPA receptors have also been suggested to be involved in aggressive behavior and depressive like symptoms in animals. Therefore, we examined whether chronic SI affects AMPA and 5-HT3 receptor expression levels in these regions. A Western blot analysis revealed that after four weeks of SI, mice exhibited up-regulated AMPA receptor subunit (GluR1, GluR2) protein levels in the amygdala and down-regulated hypothalamic 5-HT3 receptor protein levels. The AMPA/kainate receptor antagonist NBQX (10 mg/kg; i.p.) attenuated SI-induced depressive-like symptoms but not aggressive behavior. Intra-amygdalar infusions of the selective AMPA receptor agonist (S)-AMPA (10 MUM) induced despair-like behavior, but not sucrose preference or aggressive behavior, in mice not reared in SI (naive mice). Alternatively, treatment with the 5-HT3 receptor agonist SR57227A (3.0 mg/kg; i.p.) decreased aggression levels. In addition, intra-hypothalamic infusions of the 5-HT3 receptor antagonist ondansetron (3 MUM) did not trigger aggressive behavior in naive mice; however, the administration of ondansetron (0.3 mg/kg; i.p.) increased aggression levels in two-week SI mice, which rarely exhibited the aggressive behavior. Moreover, ondansetron did not affect the depressive-like symptoms of the SI mice. These results suggest that SI-induced up-regulation of GluR1 and GluR2 subunits protein levels in the amygdalar region and down regulation of 5-HT3 receptor proteins level in the hypothalamic region are associated with the effect of AMPA receptor agonist and 5-HT3 receptor antagonist -induced aggressive behavior and depressive-like symptoms. PMID- 26522742 TI - Acute physical exercise under hypoxia improves sleep, mood and reaction time. AB - This study aimed to assess the effect of two sessions of acute physical exercise at 50% VO2peak performed under hypoxia (equivalent to an altitude of 4500 m for 28 h) on sleep, mood and reaction time. Forty healthy men were randomized into 4 groups: Normoxia (NG) (n = 10); Hypoxia (HG) (n = 10); Exercise under Normoxia (ENG) (n = 10); and Exercise under Hypoxia (EHG) (n = 10). All mood and reaction time assessments were performed 40 min after awakening. Sleep was reassessed on the first day at 14 h after the initiation of hypoxia; mood and reaction time were measured 28 h later. Two sessions of acute physical exercise at 50% VO2peak were performed for 60 min on the first and second days after 3 and 27 h, respectively, after starting to hypoxia. Improved sleep efficiency, stage N3 and REM sleep and reduced wake after sleep onset were observed under hypoxia after acute physical exercise. Tension, anger, depressed mood, vigor and reaction time scores improved after exercise under hypoxia. We conclude that hypoxia impairs sleep, reaction time and mood. Acute physical exercise at 50% VO2peak under hypoxia improves sleep efficiency, reversing the aspects that had been adversely affected under hypoxia, possibly contributing to improved mood and reaction time. PMID- 26522743 TI - Simultaneous extraction and determination of four different groups of pharmaceuticals in compost using optimized ultrasonic extraction and ultrahigh pressure liquid chromatography-mass spectrometry. AB - An analytical method for the simultaneous extraction and determination of four different groups of pharmaceuticals in compost from the biodegradation of biological infectious hazardous wastes (BIHW) was developed and successfully validated. Compost samples were spiked with known concentrations of the pharmaceuticals of interest. Ultrasonic extraction with an ethyl acetate and methanol solution (1:1) resulted to be effective for the extraction of eight target compounds. All the compounds were separated in a single gradient run by UHPLC using a Zorbax SB C18 Agilent (2.1*50mm, 1.8MUm) column. Analytes were detected and quantified via multiple reaction monitoring (MRM) using an AB SCIEX API-5000TM triple quadrupole with electrospray ionization (ESI) in positive mode. The optimum mobile phase consisted of ammonium formate (2mM, pH 3): MeOH (50:50). Recovery values of the ultrasonic extraction for all compounds were on the order of 87% to 113% with absolute deviations lower than 11%. The limits of detection and quantification for the eight pharmaceuticals were on the order of 0.66ngg(-1) and 2ngg(-1) respectively for all the pharmaceuticals analyzed. These values are lower than those values reported in the literature. Suitable level of linearity, acceptable limits of detection and quantification, good repeatability and inter day precision, non-ion interference, and low matrix effect resulted from the validation of the analytical method. Implementation of the analytical procedure proposed in this research will contribute in having shorter analysis time and lower costs when working with complex matrices such as compost. PMID- 26522744 TI - Insights on profiling of phorbol, deoxyphorbol, ingenol and jatrophane diterpene esters by high performance liquid chromatography coupled to multiple stage mass spectrometry. AB - This paper reports our effort to develop a comprehensive HPLC-MS(n)-based dereplication strategy for phorbol ester (PE), deoxyphorbol ester (dPE) and ingenol ester (IE) profiling in plant extracts. This strategy is composed of two sequential analysis exploiting specific hybrid triple quadrupole/linear ion trap instrument modes. A first run was performed using a multiple reaction monitoring (MRM) mode targeting fragmentation of PE and dPE/IE coupled with the acquisition of MS(2) spectrum for the ions at m/z 311 and m/z 313, respectively. A second run was then completed based on precursor ion scan mode (PIS) and automatic MS(2) acquisition for each quasimolecular ion. The developed approach was used to investigate ten Euphorbia extracts showing bioactivity against chikungunya virus replication. Experiments allowed partial annotation of three dPE/IE but no PE was detected. Results suggested that other types of diterpene esters displayed PE- and dPE/IE-like fragmentations. The study of jatrophane ester (JE) standards by CID fragmentation using low and high resolution mass spectrometry confirmed this hypothesis, highlighting challenges and difficulties of diterpene esters profiling within plant extracts. Nonetheless, the present LC-MS(n) method can be easily adapted to profile other types of diterpene esters. PMID- 26522745 TI - Simultaneous quantification of 21 water soluble vitamin circulating forms in human plasma by liquid chromatography-mass spectrometry. AB - This manuscript reports a validated analytical approach for the quantification of 21 water soluble vitamins and their main circulating forms in human plasma. Isotope dilution-based sample preparation consisted of protein precipitation using acidic methanol enriched with stable isotope labelled internal standards. Separation was achieved by reversed-phase liquid chromatography and detection performed by tandem mass spectrometry in positive electrospray ionization mode. Instrumental lower limits of detection and quantification reached <0.1-10nM and 0.2-25nM, respectively. Commercially available pooled human plasma was used to build matrix-matched calibration curves ranging 2-500, 5-1250, 20-5000 or 150 37500nM depending on the analyte. The overall performance of the method was considered adequate, with 2.8-20.9% and 5.2-20.0% intra and inter-day precision, respectively and averaged accuracy reaching 91-108%. Recovery experiments were also performed and reached in average 82%. This analytical approach was then applied for the quantification of circulating water soluble vitamins in human plasma single donor samples. The present report provides a sensitive and reliable approach for the quantification of water soluble vitamins and main circulating forms in human plasma. In the future, the application of this analytical approach will give more confidence to provide a comprehensive assessment of water soluble vitamins nutritional status and bioavailability studies in humans. PMID- 26522746 TI - A cadmium(II)-based metal-organic framework material for the dispersive solid phase extraction of polybrominated diphenyl ethers in environmental water samples. AB - In this study, a stable cadmium(II)-based metal-organic framework (MOF) material was designed and used as a sorbent for the dispersive solid-phase extraction (dSPE) of polybrominated diphenyl ethers (PBDEs) in environmental water samples. Gas chromatography coupled with triple quadrupole mass spectrometer (GC-MS/MS), working in the negative chemical ionization mode, was used to quantify the target analytes. Characterization of the material was performed by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), elementary analyses (EA) and thermogravimetric analyses (TGA). The synthesized rod shape MOF is on the micro level in size and has excellent chemical and solvent stability. The extraction conditions, including the extraction time, temperature and ionic strength, were examined systematically using response surface methodology (RSM). Under optimized conditions, the method that was developed showed an excellent extraction performance. Good linearity (R(2)>0.99) within the concentration range of 0.25-250ngL(-1) was obtained. Low limits of detection (0.08-0.15ngL(-1), signal-to-noise ratio=3:1) and good precision (relative standard deviation <12%, n=6) were achieved. The developed method was applied to analyze natural and spiked environmental water samples. PMID- 26522747 TI - Optimization of supercritical carbon dioxide extraction of essential oil from Dracocephalum kotschyi Boiss: An endangered medicinal plant in Iran. AB - Extraction of the essential oil from a medicinal plant called Dracocephalum kotschyi Boiss was performed by green technology of supercritical carbon dioxide (SC-CO2) extraction. A Taguchi orthogonal array design with an OA16 (4(5)) matrix was used to evaluate the effects of five extraction variables: pressure of 150 310bar, temperature of 40-60 degrees C, average particle size of 250-1000MUm, CO2 flow rate of 2-10ml/s and dynamic extraction time of 30-100min. The optimal conditions to obtain the maximum extraction yield were at 240bar, 60 degrees C, 500MUm, 10ml/s and 100min. The extraction yield under the above conditions was 2.72% (w/w) which is more than two times the maximum extraction yield that has been reported for this plant in the literature using traditional extraction techniques. Results from analysis of variance (ANOVA) indicated that the CO2 flow rate and the extraction time were the most significant factors on the extraction yield by percentage contribution of 44.27 and 28.86, respectively. Finally, the chemical composition of the essential oil was evaluated by using gas chromatography-mass spectroscopy (GC-MS). Citral, p-mentha-1,3,8-triene, D-3 carene and methyl geranate were the major components identified. PMID- 26522748 TI - Born-Oppenheimer and Renner-Teller Quantum Dynamics of CH(X(2)Pi) + D((2)S) Reactions on Three CHD Potential Surfaces. AB - The quantum dynamics of three CH(X(2)Pi) + D((2)S) reactions is studied by means of the coupled-channel time-dependent real-wavepacket (WP) and flux methods at collision energy Ecol <= 0.6 eV and on three potential energy surfaces (PESs): the Born-Oppenheimer (BO) ground PES X(3)A" and the excited ones a(1)A' and b(1)A", coupled by nonadiabatic (NA) Renner-Teller (RT) effects. This three-state model is suitable for obtaining initial-state-resolved observables, is based on a complete analysis of the correlation diagram of the lowest electronic states of the CHD intermediate and of their NA interactions, and neglects the smaller coupling effects due to the asymptotic electronic angular momenta that become important in state-to-state dynamics. WPs are propagated on each PES at total angular momentum values J <= 70, with CH in the two lowest vibrational states v0 and in the ground rotational state j0 = 1. Reaction probabilities are obtained for three possible final products (f): (dP) CH decay and C((3)P) + HD(X(1)Sigma(+)) formation that occurs on the uncoupled ground PES, (dD) CH decay and C((1)D) + HD(X(1)Sigma(+)) formation that depends on the RT-coupled singlet species, and (ex) exchange to CD(X(2)Pi) + H((2)S) available adiabatically from the X(3)A" PES and nonadiabatically from a(1)A' and b(1)A". Observable cross sections sigmaf,v0j0 and rate constants kf,v0j0 in the temperature range T = 100 2000 K are obtained for (dP), (dD), and (ex) channels. Comparing BO with RT probabilities, we show that NA effects are important at high J values for the (ex) channel at v0 = 1. Real time mechanisms on the three PESs show that RT couplings are opened after some time and clearly point out the formation of the product channels. Both cross sections and rate constants present the same sequence, for example sigmaex,11 > sigmadP,01 ~ sigmaex,01 > sigmadP,11 ? sigmadD,11 ? sigmadD,01, and the CH vibrational excitation enhances the total removal CH+D reactivity by a factor of ~1.7, mainly due to the increase of the (ex) channel contribution from ~47% at v0 = 0 to ~76% at v0 = 1. This fact implies a considerable vibrational enhancement of combustion processes at high temperature. In agreement with the probability results, the a(1)A'/b(1)A" RT coupling increases both sigmaex,11 and kex,11 up to ~30%. Moreover, including the three PESs in the dynamics simulation of CH+D increase by far the (ex)/(dP) branching ratio with respect to the CH + H' reaction. Thus, at room temperature, kdP,01 changes from 10.8 * 10(-11) to 3.4 * 10(-11) cm(3) s(-1) substituting H atom by D. PMID- 26522749 TI - The Role of Echocardiography in the Evaluation of Pulmonary Arterial Hypertension. AB - The evaluation of pulmonary arterial hypertension (PAH) requires a multimodality approach that combines invasive and noninvasive imaging studies to ensure accurate diagnosis and classification. Given the complexity of the hemodynamic relationships between the left heart, pulmonary circulation, and right heart, the diagnosis of PAH is often a challenging task. Right heart catheterization is the gold standard for diagnosis, providing the hemodynamic information that defines the disease. Nonetheless, echocardiography continues to be a valuable tool in the approach to the patient with suspected PAH. Echocardiographic assessment generates a wealth of information about the response of the right heart to elevated pulmonary pressures and provides essential diagnostic and prognostic data to the clinician. Numerous measurements can be used to identify alterations in right heart morphology, pressure, and function; although each variable in isolation may have little utility, meaningful information is revealed when multiple parameters are considered together. In this article, we will review the echocardiographic measurements employed in assessment of the right heart and seek to clarify the role of echocardiography in the diagnostic workup of PAH. PMID- 26522750 TI - Oocyte retrieval using the lateral recumbent position. PMID- 26522751 TI - Strong optomechanical interactions in a sliced photonic crystal nanobeam. AB - Coupling between mechanical and optical degrees of freedom is strongly enhanced by using subwavelength optical mode profiles. We realize an optomechanical system based on a sliced photonic crystal nanobeam, which combines such highly confined optical fields with a low-mass mechanical mode. Analyzing the transduction of motion and effects of radiation pressure we find the system exhibits a photon phonon coupling rate g0 /2pi ~ 11.5 MHz, exceeding previously reported values by an order of magnitude. We show that the large optomechanical interaction enables detecting thermal motion with detection noise below that at the standard quantum limit, even in broad bandwidth devices, important for both sensor applications as well as measurement-based quantum control. PMID- 26522752 TI - Immature platelet fraction in septic patients: clinical relevance of immature platelet fraction is limited to the sensitive and accurate discrimination of septic patients from non-septic patients, not to the discrimination of sepsis severity. AB - BACKGROUND: The immature platelet fraction (IPF) reflects the degree of reticulated platelets. We evaluated performances of IPF as a biomarker for the discrimination of septic patients from non-septic patients and sepsis severity. METHODS: Total 312 patients admitted between March and July 2013 were enrolled and samples were obtained at admission. Lactate (LA), procalcitonin (PCT), C reactive protein (CRP), immature granulocyte fraction (IG), immature reticulocyte fraction (IRF), and IPF were analyzed as sepsis biomarkers and their performances were compared. RESULTS: The performance of IPF (area under the curve [AUC]=0.868) in the discrimination of septic patients from non-septic patients was comparable to PCT/CRP/LA/IG (AUC=0.923/0.940/0.781/0.812, P=0.233/0.106/0.186/0.353, respectively), and was significantly better than the IRF (AUC=0.658, P=0.007). Sensitivity (89.8%, 95% confidence interval [CI] 84.9-99.8%) and accuracy (83.2%, 95% CI 78.8-90.0%) of IPF were the best among all biomarkers. The performance of IPF in discriminating septic patients from non-septic patients with local infection showed similar results. However, the IPF could not efficiently discriminate sepsis severity (AUC=0.599), similar to other biomarkers (AUC=0.519 0.752). CONCLUSIONS: The IPF possessed high sensitivity/accuracy in discriminating septic patients from non-septic patients, regardless of local infection status. However, the IPF did not efficiently discriminate sepsis severity. The clinical relevance of IPF as a sepsis biomarker is, therefore, limited to sensitive and accurate discrimination of septic patients from non septic patients, not discrimination of sepsis severity. PMID- 26522753 TI - Epidemiological study of erythromycin-resistant Streptococcus pyogenes from Korea and Japan by emm genotyping and multilocus sequence typing. AB - BACKGROUND: We determined the epidemiological characteristics of erythromycin (EM)-resistant Streptococcus pyogenes (group A streptococci, GAS) strains isolated from Korea and Japan, using emm genotyping and multilocus sequence typing (MLST). METHODS: Clinical isolates of GAS had been collected from 1992 to 2012 in Korea and from 2004 to 2009 in Japan. EM resistance was determined by the microdilution method, and resistance genotypes were assessed by PCR. The emm genotyping and MLST were performed by DNA sequencing. RESULTS: The emm genotypes and sequence types (STs) were concordant in 143 (85.1%) of 168 EM-resistant GAS strains from Korea. ST36/emm12 (35.1%), ST52/emm28 (22.6%), and ST49/emm75 (16.1%) were the most common types. Most of the ST36 (93.9%) and ST52 (95.8%) strains harbored erm(B), whereas strains ST49, ST42, and ST15 contained mef(A). The concordance between emm genotypes and STs was 41 (93.2%) among 44 EM resistant GAS strains from Japan. ST36/emm12 (34.1%), ST49/emm75 (18.2%), and ST28/emm1 (15.9%) were the major types. ST36 isolates harbored either erm(B) (56.3%) or mef(A) (37.5%), whereas isolates ST28, ST49, and ST38 carried only mef(A). The proportion of erm(B) and mef(A) was 66.1% and 33.3% in Korea and 22.7% and 68.2% in Japan, respectively. CONCLUSIONS: The common STs in Korea and Japan were ST36 and ST49, whereas ST52 was present only in Korea and ST28 only in Japan. Genotype erm(B) was predominant in Korea, whereas mef(A) was frequent in Japan. There were differences between Korea and Japan regarding the frequencies of emm genotypes, STs, and EM resistance genes among the EM-resistant GAS. PMID- 26522754 TI - Rapid detection of Pseudomonas aeruginosa and Acinetobacter baumannii Harboring bla(VIM-2), bla(IMP-1) and bla(OXA-23) genes by using loop-mediated isothermal amplification methods. AB - BACKGROUND: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) and Acinetobacter baumannii (CRAB) are the leading causes of nosocomial infections. A rapid and sensitive test to detect CRPA and CRAB is required for appropriate antibiotic treatment. We optimized a loop-mediated isothermal amplification (LAMP) assay to detect the presence of bla(VIM-2), bla(IMP-1), and bla(OXA-23), which are critical components for carbapenem resistance. METHODS: Two sets of primers, inner and outer primers, were manually designed as previously described. The LAMP buffer was optimized (at 2mM MgSO4) by testing different concentrations of MgSO4. The optimal reaction temperature and incubation time were determined by using a gradient thermocycler. Then, the optimized bla(VIM-2), bla(IMP-1), and bla(OXA 23) LAMP reactions were evaluated by using 120 P. aeruginosa and 99 A. baumannii clinical isolates. RESULTS: Only one strain of the 100 CRPA isolates harbored bla(IMP-1), whereas none of them harbored bla(VIM-2). These results indicate that the acquisition of bla(VIM-2) or bla(IMP-1) may not play a major role in carbapenem resistance in Korea. Fifty two strains of the 75 CRAB isolates contained bla(OXA-23), but none contained bla(VIM-2) and bla(IMP-1) alleles. CONCLUSIONS: Our results demonstrate the usefulness of LAMP for the diagnosis of CRPA and CRAB. PMID- 26522755 TI - Comparison of automated treponemal and nontreponemal test algorithms as first line syphilis screening assays. AB - BACKGROUND: Automated Mediace Treponema pallidum latex agglutination (TPLA) and Mediace rapid plasma reagin (RPR) assays are used by many laboratories for syphilis diagnosis. This study compared the results of the traditional syphilis screening algorithm and a reverse algorithm using automated Mediace RPR or Mediace TPLA as first-line screening assays in subjects undergoing a health checkup. METHODS: Samples from 24,681 persons were included in this study. We routinely performed Mediace RPR and Mediace TPLA simultaneously. Results were analyzed according to both the traditional algorithm and reverse algorithm. Samples with discordant results on the reverse algorithm (e.g., positive Mediace TPLA, negative Mediace RPR) were tested with Treponema pallidum particle agglutination (TPPA). RESULTS: Among the 24,681 samples, 30 (0.1%) were found positive by traditional screening, and 190 (0.8%) by reverse screening. The identified syphilis rate and overall false-positive rate according to the traditional algorithm were lower than those according to the reverse algorithm (0.07% and 0.05% vs. 0.64% and 0.13%, respectively). A total of 173 discordant samples were tested with TPPA by using the reverse algorithm, of which 140 (80.9%) were TPPA positive. CONCLUSIONS: Despite the increased false-positive results in populations with a low prevalence of syphilis, the reverse algorithm detected 140 samples with treponemal antibody that went undetected by the traditional algorithm. The reverse algorithm using Mediace TPLA as a screening test is more sensitive for the detection of syphilis. PMID- 26522756 TI - Basophil markers for identification and activation in the indirect basophil activation test by flow cytometry for diagnosis of autoimmune urticaria. AB - BACKGROUND: The indirect basophil activation test using flow cytometry is a promising tool for autoimmune urticaria diagnosis. We aimed to identify better donor basophils (from atopic vs. non-atopic donors and interleukin-3 primed vs. unprimed basophils) and improve basophil identification and activation markers (eotaxin CC chemokine receptor-3 [CCR3] vs. CD123 and CD63 vs. CD203c). METHODS: Donor basophils were obtained from non-atopic and atopic group O donors. Positive control sera were artificially prepared to simulate autoimmune urticaria patients' sera. Patient sera were obtained from nine children with chronic urticaria. Assay sensitivity was compared among each variation by using positive control sera (n=21), applying cutoff values defined from negative control sera (n=20). RESULTS: For basophil identification, a combination of CCR3 and CD123 markers revealed a higher correlation with automated complete blood count (r=0.530) compared with that observed using CD123 (r=0.498) or CCR3 alone (r=0.195). Three activation markers on the atopic donor basophils attained 100% assay sensitivity: CD203c on unprimed basophils, CD63+CD203+ or CD63 alone on primed basophils; however, these markers on the non-atopic donor basophils attained lower assay sensitivity. CONCLUSIONS: For basophil identification markers, a combination of CD123 and CCR3 is recommended, while CD123 alone may be used as an alternative. Donor basophils should be obtained from an atopic donor. For basophil activation markers, either CD203c alone on unprimed basophils or CD203c and CD63 on primed basophils are recommended, while CD63 alone on primed basophils may be used as an alternative. PMID- 26522757 TI - Frequency and pattern of noninfectious adverse transfusion reactions at a tertiary care hospital in Korea. AB - BACKGROUND: Although transfusion is a paramount life-saving therapy, there are multiple potential significant risks. Therefore, all adverse transfusion reaction (ATR) episodes require close monitoring. Using the computerized reporting system, we assessed the frequency and pattern of non-infectious ATRs. METHODS: We analyzed two-year transfusion data from electronic medical records retrospectively. From March 2013 to February 2015, 364,569 units of blood were transfused. Of them, 334,582 (91.8%) records were identified from electronic nursing records. For the confirmation of ATRs by blood bank physicians, patients' electronic medical records were further evaluated. RESULTS: According to the nursing records, the frequency of all possible transfusion-related events was 3.1%. After the blood bank physicians' review, the frequency was found to be 1.2%. The overall frequency of febrile non-hemolytic transfusion reactions (FNHTRs) to red blood cells (RBCs), platelet (PLT) components, and fresh frozen plasmas (FFPs) were 0.9%, 0.3%, and 0.2%, respectively, and allergic reactions represented 0.3% (RBCs), 0.9% (PLTs), and 0.9% (FFPs), respectively. The pre storage leukocyte reduction significantly decreased the frequency of FNHTRs during the transfusion of RBCs (P<0.01) or PLTs (Pfalling dots0.01). CONCLUSIONS: The frequency of FNHTRs, allergic reactions, and "no reactions" were 22.0%, 17.0%, and 60.7%, respectively. Leukocyte-reduction was associated with a lower rate of FNHTRs, but not with that of allergic reactions. The development of an effective electronic reporting system of ATRs is important in quantifying transfusion-related adverse events. This type of reporting system can also accurately identify the underlying problems and risk factors to further the quality of transfusion care for patients. PMID- 26522758 TI - Correlation between the CYP2C19 phenotype status and the results of three different platelet function tests in cardiovascular disease patients receiving antiplatelet therapy: an emphasis on newly introduced platelet function analyzer 200 P2Y test. AB - BACKGROUND: An association has been reported between CYP2C19 polymorphism and the altered antiplatelet activity of clopidogrel. We investigated this association using the newly introduced platelet function analyzer (PFA)-200 (INNOVANCE PFA 200 System; Siemens Healthcare, Germany) P2Y test. METHODS: Polymorphisms of CYP2C19*2, *3, *17 and the degree of inhibition of platelet function were determined in 83 patients. Three different platelet function tests were used to evaluate the degree of platelet inhibition and to check the association with genotype. RESULTS: The post-procedure PFA-200 values of extensive metabolizers (EM) patients (285.3+/-38.8) were higher than those of intermediate metabolizers (IM) and poor metabolizers (PM) patients (227.7+/-98.3 and 133.7+/-99.2, respectively; P=0.024). Light transmittance aggregometry (LTA) and the VerifyNow system showed that the post-procedure values for EM patients were lower than those of IM and PM patients (LTA: 24.4+/-15.7, 34.1+/-17.6, and 42.2+/-16.9, respectively, P<0.001; VerifyNow: 133.2+/-60.5, 171.5+/-42.6, and 218.7+/-59.3, respectively, P<0.001). The high residual platelet reactivity (HPR) rates were significantly different among the EM, IM, and PM groups using PFA-200 (PM:IM:EM=82.4:40.6:11.8, P<0.001). CONCLUSIONS: Approximately, 59.0% of Korean patients with cardiovascular disease receiving clopidogrel had CYP2C19 loss-of function genotypes classified as IM or PM, and the frequency was similar to the data from Asian people. The PFA-200, LTA, and VerifyNow platelet function tests revealed evidence of a significant association between the efficacy of clopidogrel and CYP2C19 genotypes. PMID- 26522759 TI - Efficiency of an automated reception and turnaround time management system for the phlebotomy room. AB - BACKGROUND: Recent advances in laboratory information systems have largely been focused on automation. However, the phlebotomy services have not been completely automated. To address this issue, we introduced an automated reception and turnaround time (TAT) management system, for the first time in Korea, whereby the patient's information is transmitted directly to the actual phlebotomy site and the TAT for each phlebotomy step can be monitored at a glance. METHODS: The GNT5 system (Energium Co., Ltd., Korea) was installed in June 2013. The automated reception and TAT management system has been in operation since February 2014. Integration of the automated reception machine with the GNT5 allowed for direct transmission of laboratory order information to the GNT5 without involving any manual reception step. We used the mean TAT from reception to actual phlebotomy as the parameter for evaluating the efficiency of our system. RESULTS: Mean TAT decreased from 5:45 min to 2:42 min after operationalization of the system. The mean number of patients in queue decreased from 2.9 to 1.0. Further, the number of cases taking more than five minutes from reception to phlebotomy, defined as the defect rate, decreased from 20.1% to 9.7%. CONCLUSIONS: The use of automated reception and TAT management system was associated with a decrease of overall TAT and an improved workflow at the phlebotomy room. PMID- 26522760 TI - Establishing reference intervals for sex hormones on the analytical platforms Advia Centaur and Immulite 2000XP. AB - Reliable reference intervals for sex hormones are indispensable in evaluations of the hypothalamo-pituitary-gonadal axis. This study established reference intervals for estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and prolactin with the immunoassay platforms Advia Centaur and Immulite 2000XP (Siemens Healthcare, Germany). We recruited healthy men (n=220), women in the follicular (n=139) or luteal (n=87) phases of the menstrual cycle, and postmenopausal women (n=103). Data was analyzed according to CLSI EP28-A3c guidelines. Although reference intervals established with both platforms showed good agreement with ranges quoted by the assay manufacturer, two discrepancies were noted. First, intervals for prolactin in women were influenced by hormonal status, and the partition analysis supported their separation into subgroups based on menstrual cycle. Second, the upper limit for estradiol in the follicular phase was nearly a half of that provided by the manufacturer. This discrepancy was attributed to the stringent definition of the follicular phase (consistently set at days 3-5 after menstruation onset). Our findings suggest that reference values for prolactin should both be gender specific and account for menstrual cycle phase. The results also emphasize that clear-cut selection criteria are required when assembling populations for establishing endocrine reference intervals. PMID- 26522761 TI - Identification of mucorales from clinical specimens: a 4-year experience in a single institution. AB - Mucormycosis, a fatal opportunistic infection in immunocompromised hosts, is caused by fungi belonging to the order Mucorales. Early diagnosis based on exact identification and multidisciplinary treatments is critical. However, identification of Mucorales fungi is difficult and often delayed, resulting in poor prognosis. This study aimed to compare the results of phenotypic and molecular identification of 12 Mucorales isolates collected from 4-yr-accumulated data. All isolates were identified on the basis of phenotypic characteristics such as growth rate, colony morphology, and reproductive structures. PCR and direct sequencing were performed to target internal transcribed spacer (ITS) and/or D1/D2 regions. Target DNA sequencing identified five Lichtheimia isolates, two Rhizopus microsporus isolates, two Rhizomucor pusillus isolates, one Cunninghamella bertholletiae isolate, one Mucor fragilis isolate, and one Syncephalastrum racemosum isolate. Five of the 12 (41.7%) isolates were incorrectly identified on the basis of phenotypic identification. DNA sequencing showed that of these five isolates, two were Lichtheimia isolates, one was Mucor isolate, one was Rhizomucor isolate, and one was Rhizopus microspores. All the isolates were identified at the species level by ITS and/or D1/D2 analyses. Phenotypic differentiation and identification of Mucorales is difficult because different Mucorales share similar morphology. Our results indicate that the molecular methods employed in this study are valuable for identifying Mucorales. PMID- 26522762 TI - A rare case of pediatric T lymphoblastic leukemia with t(11;17)(q23;q21) involving mixed-lineage leukemia gene rearrangement. PMID- 26522763 TI - Mutational analysis of SH2B3 in Korean patients with BCR-ABL1 negative myeloproliferative neoplasm. PMID- 26522765 TI - Role of sul2 gene linked to transposase in resistance to trimethoprim/sulfamethoxazole among Stenotrophomonas maltophilia isolates. PMID- 26522764 TI - Persistent Bordetella petrii infection related to bone fractures. PMID- 26522766 TI - Repeatability of QuantiFERON-TB gold in-tube assay results near cut-off points. PMID- 26522767 TI - A t(8;9)(p22;p24)/PCM1-JAK2 translocation in a patient with myeloproliferative neoplasm and myeloid sarcoma: first report in Korea. PMID- 26522768 TI - Bone marrow chimerism detection using next generation sequencing based on single nucleotide polymorphisms following liver transplantation: comparison with short tandem repeat-PCR. PMID- 26522769 TI - Antibody with an engineered Fc region as a therapeutic agent against dengue virus infection. AB - Antibody-dependent enhancement (ADE) of dengue virus (DENV) infectivity is thought to play a crucial role in severe dengue disease. It occurs when pre existing sub-neutralizing anti-DENV antibody (Ab) produced from a primary infection encounters a DENV serotype different from that of the initial infection and forms immune complexes, which enable the efficient infection of Fcgamma receptor-bearing cells. However, the exact role played by Abs during a secondary infection of patients remains unknown. We previously obtained a broadly cross reactive neutralizing IgG1 human monoclonal anti-DENV envelope (E) Ab (HuMAb) D23 1G7C2-IgG1 from a DENV-infected patient; however, D23-1G7C2-IgG1 had ADE activity. With the aim of being able to reduce the ADE activity, we exchanged the Fc region of D23-1G7C2 to generate Abs bearing each of the three other IgG subclasses (IgG2-4). In addition, N297A, a mutation known to reduce the affinity of the IgG1 Fc region for Fcgamma receptors, was introduced into D23-1G7C2-IgG1. Swapping D23-1G7C2-IgG1 to IgG2 or IgG4 subclasses reduced ADE activity in FcgammaRI and FcgammaRII-bearing THP-1 cells. By contrast, in FcgammaRII-bearing K562 cells, the change to IgG2 increased ADE activity. Introducing the N297A mutation into D23-1G7C2-IgG1 resulted in a marked reduction in ADE activity in both cell types. Compared to D23-1G7C2-IgG1, D23-1G7C2-IgG1-N297A was less protective in IFN-alpha/beta/gamma receptor knockout mice infected with a lethal dose of recombinant chimeric DENV, carrying prME of DENV-2 in Japanese encephalitis virus (80% vs. 40% survival, respectively). These observations provide valuable information regarding the use of recombinant Abs as therapeutics. PMID- 26522770 TI - Potent antiviral agents fail to elicit genetically-stable resistance mutations in either enterovirus 71 or Coxsackievirus A16. AB - Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) are the two major causative agents of hand, foot and mouth disease (HFMD), for which there are currently no licenced treatments. Here, the acquisition of resistance towards two novel capsid binding compounds, NLD and ALD, was studied and compared to the analogous compound GPP3. During serial passage, EV71 rapidly became resistant to each compound and mutations at residues I113 and V123 in VP1 were identified. A mutation at residue 113 was also identified in CVA16 after passage with GPP3. The mutations were associated with reduced thermostability and were rapidly lost in the absence of inhibitors. In silico modelling suggested that the mutations prevented the compounds from binding the VP1 pocket in the capsid. Although both viruses developed resistance to these potent pocket-binding compounds, the acquired mutations were associated with large fitness costs and reverted to WT phenotype and sequence rapidly in the absence of inhibitors. The most effective inhibitor, NLD, had a very large selectivity index, showing interesting pharmacological properties as a novel anti-EV71 agent. PMID- 26522771 TI - Pediatric renal abscesses: A contemporary series. AB - INTRODUCTION: Pediatric renal abscesses are an uncommon diagnosis, with a paucity of data comparing treatment modalities. Patient presentation ranges from persistent dull flank/abdominal pain with or without fevers, to those who are overtly ill, presenting with hemodynamic instability and bacteremia. Management for pediatric renal abscesses is typically based on results extrapolated from small series in adult cohorts, with conservative measures recommended when the lesion is <3 cm. OBJECTIVE: This study evaluated the presentation, management and outcomes of a contemporary cohort of pediatric patients with renal abscesses. STUDY DESIGN: A total of 16 consecutive pediatric patients with radiologically diagnosed intra-renal or peri-nephric abscesses from 1990 to 2012 were identified. Patients were identified by querying institutional records via ICD-9 and CPT codes referencing renal abscess. Charts were retrospectively reviewed to evaluate multiple clinical variables, including: presenting symptoms, size of abscess, management strategy and clinical outcomes. Clinical resolution was confirmed via repeat ultrasound or computed tomography. RESULTS: The median age at presentation was 13 years (range 1 month-18 years) and 13/16 patients (81%) were female. Abscess formation was secondary to: urinary tract infection in 13 (81%); hematogenous seeding from a skin infection in one (6%); and an unknown etiology in two (12%) patients. The most common organism identified on urine culture was Escherichia coli (10, 77%). Hematogenous seeding was confirmed in only one case, with Staphylococcus aureus growing on culture from both a cutaneous lesion and percutaneous drainage of the renal lesion. Overall, abscesses were a median of 2.2 cm (IQR 2, 3.7), with 13 (81%) successfully managed with conservative therapy, including intravenous antibiotics, with resolution on repeat imaging at a median of 21 days (range 6-55). For patients presenting with abscesses <=3 cm, conservative measures were employed in 10/11 cases, with 100% success rate. Three patients had larger abscesses (3.8, 4, and 10 cm), which resolved after treatment with percutaneous drainage. A voiding cystourethrogram was performed in 10 patients, with two (20%) detecting an abnormality (low-grade vesicoureteral reflux, which required no further intervention). CONCLUSIONS: Pediatric renal abscesses were most commonly small and secondary to an E. coli UTI. Most small (<=3 cm) renal abscesses resolved with conservative management. Percutaneous drainage should be considered for lesions >3 cm and in patients who remain persistently febrile, despite culture specific antibiotics, are immunocompromised or critically ill. PMID- 26522772 TI - H-RAS mutation is a key molecular feature of pediatric urothelial bladder cancer. A detailed report of three cases. AB - INTRODUCTION: Urothelial carcinoma (UC) of the bladder is a rare entity in the pediatric population, with an incidence of less than 0.4% in patients younger than 20 years. These patients overwhelmingly present with non-muscle-invasive low grade disease and an indolent behavior. OBJECTIVE: The aim was to determine the source of the different natural history between pediatric population and adults; we hypothesized that pediatric bladder cancer may stem from different molecular pathways. Our objective with this descriptive case series was to study the main genes involved in pediatric urothelial bladder carcinoma using immunohistochemical (IHC) and mutational analysis. By studying the genetic alterations and immunophenotype of the most commonly altered genes in bladder urothelial cancer in three pediatric tumors we could gain better understanding of the molecular pathogenesis in this rare disease. STUDY DESIGN: Formalin-fixed paraffin-embedded (FFPE) tissue slides of urothelial bladder tumors from three pediatric patients were retrospectively identified at Columbia University pathology archives (1990-2011) and re-evaluated. FGFR3, H-RAS, and PI3K hotspots mutational analyses were conducted by polymerase chain reaction amplification and Sanger sequencing from the FFPE tissue blocks. IHC analysis was conducted using antibodies against p53, PTEN, RB, EGFR, and HER2. Proliferative rate was assessed by Ki-67 expression. RESULTS: Two patients had low-grade Ta disease, whereas the other tumor was classified as a papillary urothelial neoplasm of low malignant potential. None of the lesions recurred. Notably, all specimens showed H-RAS G12V mutation, whereas they were characterized by wild-type FGFR3 and PI3K. Nuclear p53 was not detected, whereas PTEN and RB expression were maintained. EGFR was expressed in the three cases and HER2 was negative. The proliferation rate was very low in all cases. DISCUSSION: It is difficult to draw strong conclusions from the study of three tumors treated at the same institution and from the same referral population, and a multicentric study should be performed to confirm these preliminary results. However, we propose that H-RAS mutation analysis could be performed on urothelial bladder tumors of pediatric patients. The knowledge in the molecular basis of urothelial bladder tumors in children opens a promising field which could lead us to establish different guidelines for surveillance and follow-up of pediatric urothelial bladder cancer patients. CONCLUSION: Pediatric tumors are characterized by a consistent H-RAS mutation status, whereas FGFR3 and p53 pathways are not involved in this tumor initiation. These results may explain the few recurrences seen in this population. PMID- 26522773 TI - Fatal Theileria orientalis N2 genotype infection among Asian water buffaloes (Bubalus bubalis) in a commercial dairy farm in Kerala, India. AB - Fifteen dairy buffaloes of a farm in the state of Kerala, India developed fatal oriental theileriosis within 2 months of their procurement. Typical piroplasms of Theileria orientalis were observed in the erythrocytes of all affected animals by Giemsa-Leishman staining of blood smears. Case fatality rate was 87.5% (seven out of eight) in the clinically progressed cases. Therapeutic management with anti theilerial drugs buparvaquone and oxytetracycline led to recovery of seven other animals in less advanced stages of the disease. The aim of this study was to determine the reasons for increased virulence of this pathogen, hitherto considered to be benign. Acute haemolytic anaemia was the predominant haematological finding in the affected animals. Lymphocytic infiltration and degeneration of vital organs leading to functional derangement was the cause of the high mortality. Identification of T. orientalis was confirmed by polymerase chain reaction (PCR). DNA sequencing of the PCR products revealed close identity with already reported sequences of T. orientalis/buffeli N2 genotype. The sequences were deposited in GenBank with accession number KM609973 and KM043772. Rhipicephalus ticks, previously not reported as vectors for oriental theileriosis, were identified as the potential vectors. This is the first report of fatal oriental theileriosis in Asian water buffaloes. PMID- 26522774 TI - Awareness of racial/ethnic disparities in surgical outcomes and care: factors affecting acknowledgment and action. AB - BACKGROUND: Studies have demonstrated racial/ethnic disparities in surgical outcomes and care. Surgeon awareness and its association with institutional action remain unclear. The study sought to assess surgeons' awareness of racial/ethnic disparities, ascertain whether demographic and practice factors influence acknowledgement of disparities, and determine whether surgeons are seeking to mitigate disparities. METHODS: Anonymous online survey was administered to a random sample of American College of Surgeons (ACS) general surgeons (July 2013 to March 2014). Responses were weighted for nonresponse and risk-adjusted using logistic regression. RESULTS: 172 surgeons completed the survey. Levels of acknowledged disparities were low. Less than one half reported institutional efforts to address disparities, and less than one fourth had taken efforts to investigate disparities in their personal practice. Several respondent factors including Academic Medical Center affiliation, awareness of the ACS statement on optimal access, and year of medical school graduation significantly associated with expressed acknowledgment of disparities. CONCLUSIONS: Such associations speak to the need for continued efforts to promote enhanced provider awareness and participation. As the field of surgical disparities moves from understanding to action, we must acknowledge the contributing role that providers play. PMID- 26522775 TI - Patient safety: the what, how, and when. AB - Patient safety is a construct that implies behavior intended to minimize the risk of harm to patients through effectiveness and individual performance designed to avoid injuries to patients from the care that is intended to help them. The Accreditation Council for Graduate Medical Education has made patient safety a focused area in the new Clinical Learning Environment Review process. This lecture will focus on definitions of patient safety terminology; describe the culture of patient safety and a just culture; discuss what to report, who to report it too, and methods of conducting patient safety investigations. PMID- 26522776 TI - Trastuzumab resistance induces EMT to transform HER2(+) PTEN(-) to a triple negative breast cancer that requires unique treatment options. AB - Although trastuzumab is an effective treatment in early stage HER2(+) breast cancer the majority of advanced HER2(+) breast cancers develop trastuzumab resistance, especially in the 40% of breast cancers with loss of PTEN. However, HER2(+) breast cancer patients continue to receive trastuzumab regardless PTEN status and the consequence of therapy in these patients is unknown. We demonstrate that continued use of trastuzumab in HER2(+) cells with loss of PTEN induces the epithelial-mesenchymal transition (EMT) and transform HER2(+) to a triple negative breast cancer. These transformed cells exhibited mesenchymal morphology and gene expression markers, while parent HER2(+) cells showed epithelial morphology and markers. The transformed cells exhibited loss of dependence on ERBB family signaling (such as HER2, HER3, HER4, BTC, HRG, EGF) and reduced estrogen and progesterone receptors. Continued use of trastuzumab in HER2(+) PTEN(-) cells increased the frequency of cancer stem cells (CSCs) and metastasis potential. Strikingly, parental HER2(+) cells and transformed resistant cells respond to treatment differently. Transformed resistant cells were sensitive to chemical probe (sulforaphane) through inhibition of IL 6/STAT3/NF-kappaB positive feedback loop whereas parental HER2(+) cells did not respond. This data suggests that trastuzumab resistance in HER2(+) PTEN- breast cancer induces EMT and subtype switching, which requires unique treatment options. PMID- 26522777 TI - A threshold for concern? C-reactive protein levels following operatively managed neck of femur fractures can detect infectious complications with a simple formula. AB - INTRODUCTION: C-reactive protein (CRP) rises in response to multiple stimuli, including surgical procedures and infections. Deviations from the predicted CRP response to a given procedure may be an early indication of a postoperative complication. METHODS: Three hundred and fifty-four patients with an operatively managed neck of femur fracture admitted over a 1-year period to an NHS Hospital Trust were included. CRP values collected during the postoperative period were retrospectively examined, and objective evidence of postoperative complications was sought. Data analysis explored daily CRP thresholds that maximised sensitivity and specificity for the detection of patients with a postoperative complication. RESULTS: From the 5th to the 30th postoperative day, a CRP value in excess of the threshold defined by the formula 500/d (where d represents the number of postoperative days) retrospectively detected patients with a postoperative complication with a sensitivity of 0.97 and specificity of 0.82. Patients with a CRP value above the 500/d threshold during this period had a significantly increased 30-day mortality (10.0% vs. 3.9%, RR=2.74, p=0.03). CONCLUSION: Following operatively managed neck of femur fractures, a CRP value in excess of the threshold defined by the formula 500/d may indicate the presence of a postoperative complication and defines a group with increased mortality. In this context, a prompt wound review and septic screen could promote the early detection and management of infectious postoperative complications. PMID- 26522779 TI - The relative survival of composite free flaps in head and neck reconstruction. AB - Various composite free flaps are available for reconstruction of bony head and neck defects. The aim of this study was to compare the relative success of four different bony free flaps. One hundred and seventy-three microvascular composite free flap reconstructions for bony defects of the head and neck region, performed over the period April 2008 to April 2015, were reviewed retrospectively. The type of free flap, indication for free flap reconstruction, age at harvesting of the free flap, use of pre- or postoperative radiotherapy, and free flap failure were examined. For the 173 reconstructions performed, 84 fibula free flaps, 43 iliac crest free flaps, 32 scapula free flaps, and 14 osteocutaneous radial forearm free flaps were harvested. The mean age at time of harvesting was 40.7 years for the iliac crest, 57.3 years for the fibula, 64.3 years for the scapula, and 73.9 years for the osteocutaneous radial forearm free flap. No complete free flap failure was documented, nor was there any failure of bony segments. Three fibula flap skin paddles did not survive. No returns to theatre for salvage were required. This study showed no difference in the survival rates of these four types of composite free flap. PMID- 26522778 TI - Evaluation of HDL-modulating interventions for cardiovascular risk reduction using a systems pharmacology approach. AB - The recent failures of cholesteryl ester transport protein inhibitor drugs to decrease CVD risk, despite raising HDL cholesterol (HDL-C) levels, suggest that pharmacologic increases in HDL-C may not always reflect elevations in reverse cholesterol transport (RCT), the process by which HDL is believed to exert its beneficial effects. HDL-modulating therapies can affect HDL properties beyond total HDL-C, including particle numbers, size, and composition, and may contribute differently to RCT and CVD risk. The lack of validated easily measurable pharmacodynamic markers to link drug effects to RCT, and ultimately to CVD risk, complicates target and compound selection and evaluation. In this work, we use a systems pharmacology model to contextualize the roles of different HDL targets in cholesterol metabolism and provide quantitative links between HDL related measurements and the associated changes in RCT rate to support target and compound evaluation in drug development. By quantifying the amount of cholesterol removed from the periphery over the short-term, our simulations show the potential for infused HDL to treat acute CVD. For the primary prevention of CVD, our analysis suggests that the induction of ApoA-I synthesis may be a more viable approach, due to the long-term increase in RCT rate. PMID- 26522780 TI - Estimation of the width of free margin with a significant impact on local recurrence in surgical resection of oral squamous cell carcinoma. AB - The purpose of this study was to estimate the width of free margin with a significant impact on local recurrence in surgical resection of oral squamous cell carcinoma (OSCC). Clinical and pathological data of 127 consecutive patients who underwent radical resection of OSCC were analyzed retrospectively. The local control rate was compared between patients with clear, close, and involved surgical margins, changing the required width of free margin for the definition of 'close surgical margin' (from 1 to 5mm). If a free margin of within 1, 2, or 4mm was judged a close margin, the risk of local recurrence was significantly different among the patients with clear, close, and involved surgical margins. If the definition of close margin was within 5mm of the resection margin, the difference between clear and close margin did not reach statistical significance. The results of this study suggest that 5mm of clearance at the surgical resection margin should be the index of oncological surgery. More than 5mm of histological free margin around OSCC is not justified in terms of the risk management of local recurrence and the resultant morbidity. PMID- 26522781 TI - [Acceptability of the opportunistic search for human immunodeficiency virus infection by serology in patients recruited in Primary Care Centres in Spain]. AB - OBJECTIVE: To assess the acceptability of opportunistic search for human immunodeficiency virus (HIV). DESIGN: Cross-sectional, observational study. LOCATION: Primary Care Centres (PCC) of the Spanish National Health Care System. PARTICIPANTS: patients aged 18 to 65 years who had never been tested for HIV, and were having a blood test for other reasons. RECORDED VARIABLES: age, gender, stable partner, educational level, tobacco/alcohol use, reason for blood testing, acceptability of taking the HIV test, reasons for refusing to take the HIV test, and reasons for not having taken an HIV test previously. A descriptive, bivariate, multivariate (logistic regression) statistical analysis was performed. RESULTS: A total of 208 general practitioners (GPs) from 150 health care centres recruited 3,314 patients. Most (93.1%) of patients agreed to take the HIV test (95%CI: 92.2-93.9). Of these patients, 56.9% reported never having had an HIV test before because they considered not to be at risk of infection, whereas 34.8% reported never having been tested for HIV because their doctor had never offered it to them. Of the 6.9% who refused to take the HIV test, 73.9% considered that they were not at risk. According to the logistic regression analysis, acceptability was positively associated to age (higher among between 26 and 35 year olds, OR=1.79; 95%CI: 1.10-2.91) and non-smokers (OR=1.39; 95%CI: 1.01 1.93). Those living in towns with between 10,000 and 50,000 inhabitants showed less acceptance to the test (OR=0.57; 95%CI: 0.40-0.80). The HIV prevalence detected was 0.24% CONCLUSIONS: Acceptability of HIV testing is very high among patients having a blood test in primary care settings in Spain. Opportunistic search is cost-effective. PMID- 26522782 TI - [Primary care and mental health care collaboration in patients with depression: Evaluation of a pilot experience]. AB - OBJECTIVE: To implement and assess a collaborative experience between Primary Care (PC) and Mental Health (MH) in order to improve the care of patients with depression. DESIGN: Pilot collaborative project from a participatory action research approach during 2013. LOCATION: Basque Country. Osakidetza (Basque Health Service). Bizkaia and Gipuzkoa. PARTICIPANTS: The study included 207 professionals from general practice, nursing, psychiatry, psychiatric nursing, psychology and social work of 9 health centres and 6 mental health centres of Osakidetza. INTERVENTIONS: Shared design and development of four axes of intervention: 1) Communication and knowledge between PC and MH professionals, 2) Improvement of diagnostic coding and referral of patients, 3) Training programmes with meetings and common Clinical Practice Guidelines, and 4) Evaluation. MAIN MEASUREMENTS: Intervention and control questionnaires to professionals of the centres on the knowledge and satisfaction in the PC-MH relationship, joint training activities, and assessment of the experience. Osakidetza registers of prevalences, referrals and treatments. Follow-up meetings. RESULTS: Improvement in the 4 axes of intervention in the participant centres compared with the controls. Identification of factors to be considered in the development and sustainability of PC-MH collaborative care. CONCLUSIONS: The pilot experience confirms that collaborative projects promoted by PC and MH can improve depression care and the satisfaction of professionals. They are complex projects that need simultaneous interventions adjusted to the particularities of the health services. Multidisciplinary and continuous participation and management and information system support are necessary for their implementation. PMID- 26522783 TI - [Prevalence of non-vaccinable high risk genotypes of human papillomavirus in the Early Detection of Cervical Cancer Program in Cantabria]. AB - OBJECTIVE: To estimate the prevalence of infection with non-vaccinable high risk genotypes of human papillomavirus (HPV). DESIGN: Cross-sectional study. LOCATION: Seven randomly selected health centres in Cantabria (Northern Spain). PARTICIPANTS: All women with an evaluable vaginal smear (n=3,359) between 2010 and 2011. MAIN MEASURES: The variables collected were cytological diagnosis, PCR results, and family planning method. The vaginal smear results were classified with the Bethesda system. The classification by Munoz et al. was used for typing as oncogenic risk HPV. Proportions and odds ratio (OR) were estimated with corresponding confidence intervals at 95% (95% CI). RESULTS: The prevalence of HPV infection was 2.71% (95% CI: 2.15 to 3.27). The prevalence of high oncogenic risk HPV genotypes was 2.26%; (95% CI: 1.75 to 2.78). The most frequent genotype was 16 (28.89%). More than half of the women were positive for one of the non vaccinable high risk genotypes: 51 (18.89%) and 58 (13.33%) and 68 (12.22%) or 31 (11.11%). At least two non-vaccinable high-risk genotypes co-existed in 23.33% of women. Younger women (<=30 years) had twice the risk of any HPV infection: OR 2.01 (95% CI: 1.02 to 3.96); and were twice as likely to use condoms compared to hormonal contraceptives, OR 2.09 (95% CI: 1.64 to 2.67). CONCLUSIONS: According to the high percentage of non-vaccinable high oncogenic risk HPV types, there should be a re-think of the prevention strategy in the population, who may have a false sense of protection. PMID- 26522784 TI - [Intervention in the prescribing of the combination of an angiotensin converting enzyme inhibitor and an angiotensin-II receptor blocker]. PMID- 26522785 TI - [Repetition presyncopes in Bolivian woman]. PMID- 26522786 TI - Improving access to medicines for mental disorders in low-resource settings: some achievements but still a long road ahead. PMID- 26522787 TI - Morphological leaf variability in natural populations of Pistacia atlantica Desf. subsp. atlantica along climatic gradient: new features to update Pistacia atlantica subsp. atlantica key. AB - The effect of bioclimate range on the variation in Pistacia atlantica Desf. subsp. atlantica leaf morphology was studied on 16 sites in Northwest Algeria. The study examined biometrically mature leaves totaling 3520 compound leaves. Fifteen characters (10 quantitative and 5 qualitative) were assessed on each leaf. For each quantitative character, the nested analysis of variance (ANOVA) was used to examine relative magnitude of variation at each level of the nested hierarchy. The correlation between the climatic parameters and the leaf morphology was examined. The statistical analysis applied on the quantitative leaf characters showed highly significant variation at the within-site level and between-site variation. The correlation coefficient (r) showed also an important correlation between climatic parameters and leaf morphology. The results of this study exhibited several values reported for the first time on the species, such as the length and the width of the leaf (reaching up to 24.5 cm/21.9 cm), the number of leaflets (up to 18 leaflets/leaf), and the petiole length of the terminal leaflet (reaching up to 3.4 cm). The original findings of this study are used to update the P. atlantica subsp. atlantica identification key. PMID- 26522789 TI - Knock-down of synapsin alters cell excitability and action potential waveform by potentiating BK and voltage-gated Ca(2+) currents in Helix serotonergic neurons. AB - Synapsins (Syns) are an evolutionarily conserved family of presynaptic proteins crucial for the fine-tuning of synaptic function. A large amount of experimental evidences has shown that Syns are involved in the development of epileptic phenotypes and several mutations in Syn genes have been associated with epilepsy in humans and animal models. Syn mutations induce alterations in circuitry and neurotransmitter release, differentially affecting excitatory and inhibitory synapses, thus causing an excitation/inhibition imbalance in network excitability toward hyperexcitability that may be a determinant with regard to the development of epilepsy. Another approach to investigate epileptogenic mechanisms is to understand how silencing Syn affects the cellular behavior of single neurons and is associated with the hyperexcitable phenotypes observed in epilepsy. Here, we examined the functional effects of antisense-RNA inhibition of Syn expression on individually identified and isolated serotonergic cells of the Helix land snail. We found that Helix synapsin silencing increases cell excitability characterized by a slightly depolarized resting membrane potential, decreases the rheobase, reduces the threshold for action potential (AP) firing and increases the mean and instantaneous firing rates, with respect to control cells. The observed increase of Ca(2+) and BK currents in Syn-silenced cells seems to be related to changes in the shape of the AP waveform. These currents sustain the faster spiking in Syn deficient cells by increasing the after hyperpolarization and limiting the Na(+) and Ca(2+) channel inactivation during repetitive firing. This in turn speeds up the depolarization phase by reaching the AP threshold faster. Our results provide evidence that Syn silencing increases intrinsic cell excitability associated with increased Ca(2+) and Ca(2+)-dependent BK currents in the absence of excitatory or inhibitory inputs. PMID- 26522788 TI - Transfer of scarlet fever-associated elements into the group A Streptococcus M1T1 clone. AB - The group A Streptococcus (GAS) M1T1 clone emerged in the 1980s as a leading cause of epidemic invasive infections worldwide, including necrotizing fasciitis and toxic shock syndrome. Horizontal transfer of mobile genetic elements has played a central role in the evolution of the M1T1 clone, with bacteriophage encoded determinants DNase Sda1 and superantigen SpeA2 contributing to enhanced virulence and colonization respectively. Outbreaks of scarlet fever in Hong Kong and China in 2011, caused primarily by emm12 GAS, led to our investigation of the next most common cause of scarlet fever, emm1 GAS. Genomic analysis of 18 emm1 isolates from Hong Kong and 16 emm1 isolates from mainland China revealed the presence of mobile genetic elements associated with the expansion of emm12 scarlet fever clones in the M1T1 genomic background. These mobile genetic elements confer expression of superantigens SSA and SpeC, and resistance to tetracycline, erythromycin and clindamycin. Horizontal transfer of mobile DNA conferring multi-drug resistance and expression of a new superantigen repertoire in the M1T1 clone should trigger heightened public health awareness for the global dissemination of these genetic elements. PMID- 26522791 TI - Cyclopentadiene-Phosphine/Palladium-Catalyzed Synthesis of Indolizines from Pyrrole and 1,4-Dibromo-1,3-butadienes. AB - The cyclopentadiene-phosphine ligand (L1) and palladium were found to be an efficient catalyst system to activate the alpha-C(sp(2))-H bond of pyrrole and indole derivatives. Various alkenyl or aryl dibromides could be used to react with pyrrole and indole derivatives to afford multisubstituted indolizines in high yields. PMID- 26522790 TI - Tribolium castaneum defensins are primarily active against Gram-positive bacteria. AB - The red flour beetle Tribolium castaneum is a destructive insect pest of stored food and feed products, and a model organism for development, evolutionary biology and immunity. The insect innate immune system includes antimicrobial peptides (AMPs) with a wide spectrum of targets including viruses, bacteria, fungi and parasites. Defensins are an evolutionarily-conserved class of AMPs and a potential new source of antimicrobial agents. In this context, we report the antimicrobial activity, phylogenetic and structural properties of three T. castaneum defensins (Def1, Def2 and Def3) and their relevance in the immunity of T. castaneum against bacterial pathogens. All three recombinant defensins showed bactericidal activity against Micrococcus luteus and Bacillus thuringiensis serovar tolworthi, but only Def1 and Def2 showed a bacteriostatic effect against Staphylococcus epidermidis. None of the defensins showed activity against the Gram-negative bacteria Escherichia coli and Pseudomonas entomophila or against the yeast Saccharomyces cerevisiae. All three defensins were transcriptionally upregulated following a bacterial challenge, suggesting a key role in the immunity of T. castaneum against bacterial pathogens. Phylogenetic analysis showed that defensins from T. castaneum, mealworms, Udo longhorn beetle and houseflies cluster within a well-defined clade of insect defensins. We conclude that T. castaneum defensins are primarily active against Gram-positive bacteria and that other AMPs may play a more prominent role against Gram-negative species. PMID- 26522792 TI - Disorganized Systematic Reviews and Meta-analyses: Time to Systematize the Conduct and Publication of These Study Overviews? AB - The number of meta-analyses published annually has increased more than 20-fold between 1994 (n = 386) and 2014 (n = 8203). In examining how much of this increase in meta-analysis publication has genuinely represented novel contributions to clinical medicine and public health, it became clear that there was an abundance of redundant and disorganized meta-analyses, creating confusion and generating considerable debate. Ironically, meta-analyses, which should prevent redundant research, have become a victim of it. Recently, 17 meta analyses were published based on the results of only 3 randomized controlled trials that studied the role of transcatheter closure of patent foramen ovale for prevention of cryptogenic stroke. In our search of the published literature, we identified at least 10 topics that were the subject of 10 meta-analyses. In the context of overlapping meta-analyses, one questions what needs to be done to put this "runaway train" back on track. In this review we examine the practice of redundant meta-analyses and the reasons for its disturbing "popularity." The registration of systematic reviews should be mandatory in prospective registries, such as PROSPERO, and the PRISMA checklist should be updated to incorporate new evidence and mandate the reference of previously published reviews and rationale for any new study. PMID- 26522793 TI - Caring for 'Very Important Patients'--Ethical Dilemmas and Suggestions for Practical Management. AB - The care of Very Important Patients (VIPs) is different from other patients because they may receive greater access, attention, and resources from health care staff. Although the term VIP is used regularly in the medical literature and is implicitly understood, in practice it constitutes a wide and heterogeneous group of patients that have a strong effect on health care providers. We define a VIP as a very influential patient whose individual attributes and characteristics (eg, social status, occupation, position), coupled with their behavior, have the potential to significantly influence a clinician's judgment or behavior. Physicians, celebrities, the politically powerful, and philanthropists, may all become VIPs in the appropriate context. The quality of care may be inferior because health care professionals may deviate from standard practices when caring for them. Understanding the common features among what may otherwise be very different groups of patients can help health care providers manage ethical concerns when they arise. We use a series of vignettes to demonstrate how VIPs behavior and status can influence a clinician's judgment or actions. Appreciating the ethical principles in these varied circumstances provides health care professionals with the tools to manage ethical conflicts that arise in the care of VIPs. We conclude each vignette with guidance for how health care providers and administrators can manage the ethical concern. PMID- 26522795 TI - Top 10 Facts You Need to Know About Synthetic Cannabinoids: Not So Nice Spice. AB - In April and May 2015, the state of Mississippi experienced an unprecedented outbreak of severe reactions to the drug commonly referred to as "Spice." After numerous calls to the Poison Control Center, it became clear that health care providers were largely unfamiliar with the category of synthetic cannabinoids. This review article briefly highlights cannabinoid effects, chemical characteristics, and treatment for this often-dangerous category of drugs of abuse. PMID- 26522794 TI - Trends in Opioid Prescriptions Among Part D Medicare Recipients From 2007 to 2012. AB - BACKGROUND: There is growing concern about potential overuse of, and toxicity from, opioid analgesics. No nationally representative study has examined inter state variations in opioid use and impact of policy on opioid use among older adults. METHODS: We used national Medicare data from 2007-2012 to assess temporal and geographic trends in rates of opioid prescription and relationship to opioid toxicity and different state regulations in Part D Medicare recipients. We excluded those with a cancer diagnosis. Multilevel, multivariable regression analyses evaluated rates of prolonged prescriptions for schedule II, schedule III, and combination II/III opioid for each state, adjusting for patient characteristics. RESULTS: The percent of Part D recipients receiving prescriptions for combined schedule II/III opioid more than 90 days in a year increased from 4.62% in 2007 to 7.35% in 2012. Large variations existed among states in rates of opioid prescriptions: from 2.84% in New York to 10.93% in Utah, in 2012 data. The state variation was larger for schedule III than schedule II. Individual characteristics independently associated with prolonged use included older age, female gender, white race, low income, living in a lower education area, and comorbidity of drug abuse, rheumatoid arthritis, and depression. Only state law regulating pain clinic was associated with reduction of schedule II opioid prescriptions. Prolonged opioid prescription use increased the odds of opioid overdose-related emergency room visits or hospitalization by 60%. CONCLUSIONS: Analyses of Medicare Part D data demonstrated a substantial growth in opioid prescriptions from 2007 to 2011 and large variation in opioid prescriptions across states. PMID- 26522796 TI - The Fortress Becomes a Prison: Calcified Constrictive Pericarditis. PMID- 26522797 TI - Atherosclerotic Renal Artery Stenosis and Hypertension: Pragmatism, Pitfalls, and Perspectives. AB - For many years and even decades, a diagnostic work-up to look for a secondary form of hypertension, particularly of renovascular origin, has been a central tenet in medicine. Atherosclerotic renal artery stenosis is considered the most common cause of renovascular hypertension. However, advances in understanding the complex pathophysiology of this condition and the recently documented futility of renal revascularization bring into question whether atherosclerotic renal artery stenosis truly causes "renovascular hypertension." From a clinical point of view, a clear distinction should be made between hypertension associated with atherosclerotic renal artery stenosis and hypertension caused by renal artery stenosis-induced activation of the renin-angiotensin-aldosterone system. Most patients with atherosclerotic renal artery stenosis do not have a form of hypertension that is remediable or improved by angioplasty; to expose them to the cost, inconvenience, and risk of a diagnostic work-up add up to little more than a wild goose chase. However, with very few exceptions, medical therapy with antihypertensives and statins remains the cornerstone for the management of patients with atherosclerotic renal artery stenosis and hypertension. PMID- 26522798 TI - Top 10 Facts to Know About Inpatient Glycemic Control. AB - Uncontrolled hyperglycemia in hospitalized patients with or without a previous diagnosis of diabetes is associated with adverse outcomes and longer lengths of hospital stay. It is estimated that one-third of hospitalized patients will experience significant hyperglycemia, and the cost associated with hospitalization for patients with diabetes accounts for half of all health care expenditures for this disease. Optimizing glycemic control should be a priority for all health care providers in the inpatient setting. Appropriate management strategies should include identification of appropriate glycemic targets, prevention of hypoglycemia, initiation of appropriate basal-plus-bolus insulin regimens, and planning for the transition from inpatient to outpatient therapy before hospital discharge. PMID- 26522801 TI - Correction to Horgan et al. (2015). PMID- 26522799 TI - PBRNs or RBPNs or Both? PMID- 26522802 TI - PBRN Findings: Integrated Care for Individuals With Serious Mental Illnesses. PMID- 26522803 TI - Mental Health Laws Influence the Duration of Untreated Psychosis. PMID- 26522806 TI - Landfill area estimation based on integrated waste disposal options and solid waste forecasting using modified ANFIS model. AB - Solid waste prediction is crucial for sustainable solid waste management. The collection of accurate waste data records is challenging in developing countries. Solid waste generation is usually correlated with economic, demographic and social factors. However, these factors are not constant due to population and economic growth. The objective of this research is to minimize the land requirements for solid waste disposal for implementation of the Malaysian vision of waste disposal options. This goal has been previously achieved by integrating the solid waste forecasting model, waste composition and the Malaysian vision. The modified adaptive neural fuzzy inference system (MANFIS) was employed to develop a solid waste prediction model and search for the optimum input factors. The performance of the model was evaluated using the root mean square error (RMSE) and the coefficient of determination (R(2)). The model validation results are as follows: RMSE for training=0.2678, RMSE for testing=3.9860 and R(2)=0.99. Implementation of the Malaysian vision for waste disposal options can minimize the land requirements for waste disposal by up to 43%. PMID- 26522807 TI - Age-associated changes in long-chain fatty acid profile during healthy aging promote pro-inflammatory monocyte polarization via PPARgamma. AB - Differences in lipid metabolism associate with age-related disease development and lifespan. Inflammation is a common link between metabolic dysregulation and aging. Saturated fatty acids (FAs) initiate pro-inflammatory signalling from many cells including monocytes; however, no existing studies have quantified age associated changes in individual FAs in relation to inflammatory phenotype. Therefore, we have determined the plasma concentrations of distinct FAs by gas chromatography in 26 healthy younger individuals (age < 30 years) and 21 healthy FA individuals (age > 50 years). Linear mixed models were used to explore the association between circulating FAs, age and cytokines. We showed that plasma saturated, poly- and mono-unsaturated FAs increase with age. Circulating TNF alpha and IL-6 concentrations increased with age, whereas IL-10 and TGF-beta1 concentrations decreased. Oxidation of MitoSOX Red was higher in leucocytes from FA adults, and plasma oxidized glutathione concentrations were higher. There was significant colinearity between plasma saturated FAs, indicative of their metabolic relationships. Higher levels of the saturated FAs C18:0 and C24:0 were associated with lower TGF-beta1 concentrations, and higher C16:0 were associated with higher TNF-alpha concentrations. We further examined effects of the aging FA profile on monocyte polarization and metabolism in THP1 monocytes. Monocytes preincubated with C16:0 increased secretion of pro-inflammatory cytokines in response to phorbol myristate acetate-induced differentiation through ceramide dependent inhibition of PPARgamma activity. Conversely, C18:1 primed a pro resolving macrophage which was PPARgamma dependent and ceramide dependent and which required oxidative phosphorylation. These data suggest that a midlife adult FA profile impairs the switch from proinflammatory to lower energy, requiring anti-inflammatory macrophages through metabolic reprogramming. PMID- 26522808 TI - Comprehensive geriatric assessment in elderly patients with newly diagnosed aggressive non-Hodgkin lymphoma treated with multi-agent chemotherapy. AB - OBJECTIVES: The purpose of this prospective observational study is to evaluate the relation of the comprehensive geriatric assessment (CGA) to tolerability and survival of multi-agent chemotherapy for curative intent in elderly patients with aggressive non-Hodgkin lymphoma (NHL). MATERIALS AND METHODS: Patients who were 1) age >=65 years, 2) newly diagnosed aggressive NHL, and 3) treated with multi agent chemotherapy within 2 weeks from the time of diagnosis were enrolled from January 2011 to June 2014. Baseline clinical, laboratory, and CGA data being composed of Mini Nutritional Assessment-Short Form (MNA-SF), Korean version of Mini Mental Status Exam, Korean-Geriatric Depression Scale, and Groningen Frailty Index (GFI), were collected and analyzed for the relation to the outcome factors. RESULTS: Seventy patients were included; the median age was 73.5 years, 27 (38.6%) patients were Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or more, and half of the patients were high or high-intermediate risk by age-adjusted international prognostic index (aaIPI). Most patients received CHOP or CHOP-like chemotherapy. Factors affecting discontinuation of chemotherapy within 12 weeks were poor MNA-SF, poor GFI, poor PS, and presence of B symptom. Among those, poor MNA-SF was independent of other variables in multivariate analysis. Poor MNA-SF, bone marrow involvement, and baseline anemia of hemoglobin<10g /dL were found to be independent factors associated with inferior overall survival whereas aaIPI factors were not. CONCLUSION: MNA-SF predicted tolerability to multi-agents chemotherapy and overall survival in elderly patients with aggressive NHL who were treated with multi-agent chemotherapy. PMID- 26522809 TI - Serological survey of Borrelia infection of dogs in Sapporo, Japan, where Borrelia garinii infection was previously detected. AB - A serological survey of Borrelia infection of dogs was performed in Sapporo, Japan, where Borrelia garinii infection in dogs was detected in 2011. A total of 314 serum samples were collected from dogs that visited three animal hospitals in Sapporo from 2012 to 2014. The two-step evaluation method, involving screening ELISA followed by Western blot analysis, was used to detect antibodies against Borrelia species. A total of 34 samples were positive by ELISA. Among those 34 samples, 32 were positive for Borrelia spp. by Western blot. These findings suggest that the 32 dogs (10.2%) generated antibodies against Borrelia burgdorferi sensu lato, such as B. garinii or B. afzelii. Antibody positivity was 7.6% and 13.3% for dogs living in urban and rural areas, respectively. Dogs with a history of tick infestation showed a positive rate of 16.7%, which was higher, although not significantly, than the 6.7% among dogs without a history. PMID- 26522810 TI - Canine pyometra: a model for the analysis of serum CXCL8 in inflammation. AB - Interleukin-8 (IL-8 or CXCL8) is a highly selective pro-inflammatory chemokine, that is elevated in sera of humans and animals with various inflammatory diseases. CXCL8 is possibly involved in uncontrolled inflammation and the development of a systemic inflammatory response syndrome (SIRS) and sepsis. Nevertheless, its behavior and precise properties in the course of inflammation are not fully understood. Thus, we used naturally occurring canine pyometra as a model of inflammation, in order to examine the behavior of serum CXCL8 in relation to the disease intensity and commonly analyzed inflammatory mediators. Using a commercially available canine ELISA kit, a significant increase of CXCL8 was determined in the serum of 23 dogs with pyometra compared with 35 healthy dogs. Interestingly, serum CXCL8 did not increase in severely diseased patients and behaved contrary to white blood cells (WBC), neutrophils and C-reactive protein (CRP). The measurement of serum CXCL8 may provide valuable information about the extent of ongoing lesions and could be a useful complement for existing laboratory tests. PMID- 26522811 TI - The co-existence of a myxoid liposarcoma and leiomyoma in the same ovarian mass of a dog. AB - A 15-year-old, female mixed-breed dog presented with abdominal distention. An exploratory laparotomy revealed a large left ovarian mass (20 * 15 * 12 cm). Histopathological examination of the mass revealed a mixed myxoid liposarcoma and a well-differentiated leiomyoma. Four months after surgical removal of the mass, the dog died due to multiorgan metastasis. The metastasis was composed solely of the liposarcoma component. The liposarcoma component was Alcian Blue- and Oil red O-positive, and demonstrated immunoreactivity with S-100, adipophilin and vimentin. Electron microscopy revealed that the tumor cell cytoplasms were packed with lipid vacuoles and dilated rough endoplasmic reticulum. To our knowledge, this is the first report of myxoid liposarcoma and leiomyoma co-existing in a canine ovary. PMID- 26522812 TI - Acute and sub-chronic (28 days) oral toxicity evaluation of tincture Baccharis trimera (Less) Backer in male and female rodent animals. AB - The infusion of Baccharis trimera (Less) DC, popularly known as "carqueja" (broom), is popularly used in the treatment of hepatic and digestive problems. In this study, we evaluated the acute and sub-chronic oral toxicities of B. trimera tincture on male and female Wistar rats according to Organization for Economic Cooperation and Development (OECD, guidelines 423 e 407, respectively). The B. trimera tincture was administered by oral gavage in a single dose (2000 mg/kg) in doses of 100, 200 and 400 mg/kg daily for 28 days. Blood was collected to analyze hematological and biochemical parameters. Kidneys and liver were homogenized to determine lipid peroxidation and delta-aminolevulinate dehydratase (delta-ALA-D) and catalase (CAT) enzyme activities. In acute treatment, tincture did not induce any signs of toxicity or mortality. Daily oral administration produced no significant changes in the hematological and biochemical parameters, except for the hepatic enzymes alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) that showed a reduction in both sexes. Moreover, the B. trimera tincture did not increase lipid peroxidation or affected ALA-D and CAT activities. In conclusion, the tincture of B. trimera may be considered relatively safe in this protocol. PMID- 26522813 TI - Dissipation kinetics and residue of LH-2010A in cucumber and soil under greenhouse condition. AB - LH-2010A is a newly developed fungicide with novel mode of action in the treatment of cucurbit downy mildew. Dissipation kinetics and residue levels of LH 2010A in cucumber were investigated using a QuEChERS method with GC-ECD. Field trials were constructed at three different sites in China in 2013 and 2014. The average recoveries of LH-2010A in fortified samples were between 94.0 and 106.2% for cucumber and between 84.4% and 98.7% for soil, with relative standard deviations within 3%. The dissipation rate of LH-2010A residue was evaluated assuming a pseudo first-order kinetics. The half-lives of LH-2010A were 2.8-4.2 days and 6.3-9.4 days in cucumber and soil samples, respectively. The terminal residues in cucumber were 0.077-0.207 mg/kg and 0.109-0.307 mg/kg on the first day after spray at the recommended dosage and 1.5 times of the recommended dosage, respectively. Using this rapid and sensitive method, we determined the dissipation kinetics and residue level of HL-2010A in cucumber. The suggested MRL value of HL-2010A in cucumber is 0.5 mg/kg. The research would provide guidance for proper and safe use of this newly developed fungicide in cucumber in greenhouse ecosystems. PMID- 26522814 TI - On graphical tests for proportionality of hazards in two samples. AB - In this paper, we present a class of graphical tests of the proportional hazards hypothesis for two-sample censored survival data. The proposed tests are improvements over some existing tests based on asymptotic confidence bands of certain functions of the estimated cumulative hazard functions. The new methods are based on the comparison of unrestricted estimates of the said functions and their restricted versions under the hypothesis. They combine the rigour of analytical tests with the descriptive value of plots. Monte Carlo simulations suggest that the proposed asymptotic procedures have reasonable small sample properties. The power is much higher than existing graphical tests and comparable with existing analytical tests. The method is then illustrated through the analysis of a data set on bone marrow transplantation for Leukemia patients. PMID- 26522815 TI - Invisible Hyperbolic Metamaterial Nanotube at Visible Frequency. AB - Subwavelength-scale metal and dielectric nanostructures have served as important building blocks for electromagnetic metamaterials, providing unprecedented opportunities for manipulating the optical response of the matter. Recently, hyperbolic metamaterials have been drawing particular interest because of their unusual optical properties and functionalities, such as negative refraction and hyperlensing of light. Here, as a promising application of a hyperbolic metamaterial at visible frequency, we propose an invisible nanotube that consists of metal and dielectric alternating thin layers. The theoretical study of the light scattering of the layered nanotube reveals that almost-zero scattering can be achieved at a specific wavelength when the transverse-electric- or transverse magnetic-polarized light is incident to the nanotube. In addition, the layered nanotube can be described as a radial-anisotropic hyperbolic metamaterial nanotube. The low scattering occurs when the effective permittivity of the hyperbolic nanotube in the angular direction is near zero, and thus the invisibility of the layered nanotube can be efficiently obtained by analyzing the equivalent hyperbolic nanotube. Our new method to design and tune an invisible nanostructure represents a significant step toward the practical implementation of unique nanophotonic devices such as invisible photodetectors and low scattering near-field optical microscopes. PMID- 26522816 TI - Spontaneous Atraumatic Urinary Bladder Rupture Secondary to Alcohol Intoxication: A Case Report and Review of Literature. AB - BACKGROUND: Spontaneous rupture of the urinary bladder (SRUB) secondary to alcohol intoxication is an uncommon presentation with high morbidity and mortality. Herein, we reported a rare case of spontaneous atraumatic rupture of the urinary bladder due to alcohol intoxication. CASE REPORT: A 45-year-old Sri Lankan man presented with drowsiness, diffuse abdominal pain, vomiting with odor of alcohol, and urinary retention 24 hours prior to the index admission. CT cystogram confirmed the urinary bladder rupture at the dome, which was repaired through exploratory laparotomy. CONCLUSIONS: An SRUB patient with alcohol abuse often presents with non-specific symptoms due to absence of a traumatic event, which results in missed or delayed-diagnosis. Early diagnosis and management of SRUB is crucial for uneventful recovery. PMID- 26522817 TI - Improved protection against tuberculosis after boosting the BCG-primed mice with subunit Ag 85a delivered through intact skin with deformable vesicles. AB - To improve vaccination against tuberculosis (TBC) with Bacillus Calmette-Guerin (BCG), we introduce novel, non-invasive, secondary immunisations relying on epicutaneous (e.c.) applications of the TBC subunit antigen, Ag 85a, associated with deformable carrier vesicles. Immuno-boosting with such antigen-vesicles recruits more CD11c positive cells into the draining murine lymph nodes, and typically stimulates, especially the proximal, immune cells more than immunogen injections. Non-invasive antigen application also protects mice better against an infection with TBC. Subcutaneous injections of vesicular Ag 85a into BCG-primed mice mainly yield IgG1 and IgG2a, indicative of a mixed Th1 and Th2 response. Conversely, transcutaneous immuno-boosts of such mice with a deformable vesicle Ag 85a combination mainly generate serum IgA and IgG2a, indicative of an IgA facilitated, Th1-mediated, immune response. The Ag 85a specific antibody titres are generally low, but T lymphocytes also proliferate in the immunised mice. The new, partially non-invasive, vaccination method lowers the burden of pulmonary infection with M. tuberculosis. In mice immunised with Ag85a associated with deformable vesicles we measured 116* (e.c.) to 51* (s.c.) lower colony forming units number in spleen and 9* (e.c.) to 3* (s.c.) lower such number in lungs. PMID- 26522818 TI - Structural phase transitions in Bi2Se3 under high pressure. AB - Raman spectroscopy and angle dispersive X-ray diffraction (XRD) experiments of bismuth selenide (Bi2Se3) have been carried out to pressures of 35.6 and 81.2 GPa, respectively, to explore its pressure-induced phase transformation. The experiments indicate that a progressive structural evolution occurs from an ambient rhombohedra phase (Space group (SG): R-3m) to monoclinic phase (SG: C2/m) and eventually to a high pressure body-centered tetragonal phase (SG: I4/mmm). Evidenced by our XRD data up to 81.2 GPa, the Bi2Se3 crystallizes into body centered tetragonal structures rather than the recently reported disordered body centered cubic (BCC) phase. Furthermore, first principles theoretical calculations favor the viewpoint that the I4/mmm phase Bi2Se3 can be stabilized under high pressure (>30 GPa). Remarkably, the Raman spectra of Bi2Se3 from this work (two independent runs) are still Raman active up to ~35 GPa. It is worthy to note that the disordered BCC phase at 27.8 GPa is not observed here. The remarkable difference in atomic radii of Bi and Se in Bi2Se3 may explain why Bi2Se3 shows different structural behavior than isocompounds Bi2Te3 and Sb2Te3. PMID- 26522819 TI - Normalization of Left Ventricular Ejection Fraction and Incidence of Appropriate Antitachycardia Therapy in Patients With Implantable Cardioverter Defibrillator for Primary Prevention of Sudden Death. AB - BACKGROUND: Patients with severely depressed left ventricular ejection fractions (LVEFs) receive implantable cardioverter-defibrillators (ICDs) for the primary prevention of sudden death. In some patients, however, LVEF may improve or even normalize over time. Limited data are available on the incidence of appropriate antitachycardia therapy, including pacing and shock, in these patients. METHODS AND RESULTS: We retrospectively identified consecutive patients at our institution with an ICD for primary prevention who had LVEF measurement available at initial implantation and at the time of generator replacement. None of these patients had ever received appropriate antitachycardia therapy before generator replacement. The incidence of appropriate antitachycardia therapy after generator replacement was assessed. Of the 125 patients who received generator replacement, 53 (42%) received an ICD and 72 (58%) a cardiac resynchronization therapy defibrillator (CRT-D). Among them, 30 (21%) had LVEF normalized to >=50%, 25 (17%) had LVEF partially improved to 36%-49%, and 70 (63%) had LVEF that remained depressed at <=35%. During an overall follow-up period of 25 +/- 18 months, none of the individuals with normalized LVEF experienced appropriate antitachycardia therapy regardless of ICD or CRT-D. Meanwhile, 20% of patients with LVEF at 36% 49% and 14% of patients with LVEF at <=35% received appropriate ICD therapy. The omnibus P value for any differences among the 3 LVEF groups was 0.046 for the entire cohort, 0.01 for ICD, and 0.15 for CRT-D patients. CONCLUSIONS: These preliminary data suggest that patients with reduced LVEF and primary-prevention ICDs who normalize their LVEF over time may be at lower risk of appropriate antitachycardia therapy. PMID- 26522820 TI - Changing fluxes of carbon and other solutes from the Mekong River. AB - Rivers are an important aquatic conduit that connects terrestrial sources of dissolved inorganic carbon (DIC) and other elements with oceanic reservoirs. The Mekong River, one of the world's largest rivers, is firstly examined to explore inter-annual fluxes of dissolved and particulate constituents during 1923-2011 and their associated natural or anthropogenic controls. Over this period, inter annual fluxes of dissolved and particulate constituents decrease, while anthropogenic activities have doubled the relative abundance of SO4(2-), Cl(-) and Na(+). The estimated fluxes of solutes from the Mekong decrease as follows (Mt/y): TDS (40.4) > HCO3(-) (23.4) > Ca(2+) (6.4) > SO4(2-) (3.8) > Cl(-) (1.74)~Na(+) (1.7) ~ Si (1.67) > Mg(2+) (1.2) > K(+ 0.5). The runoff, land cover and lithological composition significantly contribute to dissolved and particulate yields globally. HCO3(-) and TDS yields are readily predicted by runoff and percent of carbonate, while TSS yield by runoff and population density. The Himalayan Rivers, including the Mekong, are a disproportionally high contributor to global riverine carbon and other solute budgets, and are of course underlined. The estimated global riverine HCO3(-) flux (Himalayan Rivers included) is 34,014 * 10(9) mol/y (0.41 Pg C/y), 3915 Mt/y for solute load, including HCO3(-), and 13,553 Mt/y for TSS. Thereby this study illustrates the importance of riverine solute delivery in global carbon cycling. PMID- 26522821 TI - [Fine particulate matter estimated by mathematical model and hospitalizations for pneumonia and asthma in children]. AB - OBJECTIVE: To estimate the association between exposure to fine particulate matter with an aerodynamic diameter <2.5 microns (PM2.5) and hospitalizations for pneumonia and asthma in children. METHODS: An ecological study of time series was performed, with daily indicators of hospitalization for pneumonia and asthma in children up to 10 years of age, living in Taubate (SP) and estimated concentrations of PM2.5, between August 2011 and July 2012. A generalized additive model of Poisson regression was used to estimate the relative risk, with lag zero up to five days after exposure; the single pollutant model was adjusted by the apparent temperature, as defined from the temperature and relative air humidity, seasonality and weekday. RESULTS: The values of the relative risks for hospitalization for pneumonia and asthma were significant for lag 0 (RR=1.051, 95%CI; 1.016 to 1.088); lag 2 (RR=1.066, 95%CI: 1.023 to 1.113); lag 3 (RR=1.053, 95%CI: 1.015 to 1.092); lag 4 (RR=1.043, 95%CI: 1.004 to 1.088) and lag 5 (RR=1.061, 95%CI: 1.018 to 1.106). The increase of 5mcg/m(3) in PM2.5 contributes to increase the relative risk for hospitalization from 20.3 to 38.4 percentage points; however, the reduction of 5MUg/m(3) in PM2.5 concentration results in 38 fewer hospital admissions. CONCLUSIONS: Exposure to PM2.5 was associated with hospitalizations for pneumonia and asthma in children younger than 10 years of age, showing the role of fine particulate matter in child health and providing subsidies for the implementation of preventive measures to decrease these outcomes. PMID- 26522822 TI - [Validation of questionnaires to assess quality of life related to fecal incontinence in children with anorectal malformations and Hirschsprung's disease]. AB - OBJECTIVE: Surgical treatment of anorectal malformations (ARMs) and Hirschsprung's disease (HD) leads to alterations in bowel habits and fecal incontinence, with consequent quality of life impairment. The objectives were to create and validate a Questionnaire for the Fecal Incontinence Index (FII) based on the Holschneider score, as well as a Questionnaire for the Assessment of Quality of Life Related to Fecal Incontinence in Children and Adolescents (QQVCFCA), based on the Fecal Incontinence Quality of Life. METHODS: The questionnaires were applied to 71 children submitted to surgical procedure, in two stages. Validity was tested by comparing the QQVCFCA and a generic quality of life questionnaire (SF-36), and between QQVCFCA and the FII. A group of 59 normal children was used as control. RESULTS: At two stages, 45.0% (32/71) and 42.8% (21/49) of the patients had fecal incontinence. It was observed that the QQVCFCA showed a significant correlation with the SF-36 and FII (Pearson's correlation 0.57), showing that the quality of life is directly proportional to improvement in fecal incontinence. Quality of life in patients with fecal incontinence is still globally impaired, when compared with control subjects (p<0.05, Student's t test). There were also significant differences between the results of children with ARMs and children with HD. CONCLUSIONS: QQVCFCA and FII are useful tools to assess the quality of life and fecal incontinence in these groups of children. Children with ARMs submitted to surgical procedure and HD have similar quality of life impairment. PMID- 26522824 TI - Theory-of-mind understanding and theory-of-mind use in unaffected first-degree relatives of schizophrenia and bipolar disorder. AB - We assessed theory of mind (ToM) in unaffected first-degree relatives (FDR) of patients with schizophrenia (SC) and bipolar disorder (BD) compared to healthy controls with a revised computerized referential communication task. Results showed that FDR of SC performed worse than FDR of BD and controls on a task requiring ToM-use, but not on a task requiring ToM-understanding. This indicates that deficient ToM-use, rather than ToM-understanding impairments, may represent a potential candidate endophenotype for schizophrenia. PMID- 26522823 TI - [Profile of patients with genitourinary anomalies treated in a clinical genetics service in the Brazilian unified health system]. AB - OBJECTIVE: To describe the profile of patients with genitourinary abnormalities treated at a tertiary hospital genetics service. METHODS: Cross-sectional study of 1,068 medical records of patients treated between April/2008 and August/2014. A total of 115 cases suggestive of genitourinary anomalies were selected, regardless of age. A standardized clinical protocol was used, as well as karyotype, hormone levels and genitourinary ultrasound for basic evaluation. Laparoscopy, gonadal biopsy and molecular studies were performed in specific cases. Patients with genitourinary malformations were classified as genitourinary anomalies (GUA), whereas the others, as sex differentiation disorders (SDD). Chi square, Fisher and Kruskal-Wallis tests were used for statistical analysis and comparison between groups. RESULTS: 80 subjects met the inclusion criteria, 91% with SDD and 9% with isolated/ syndromic GUA. The age was younger in the GUA group (p<0.02), but these groups did not differ regarding external and internal genitalia, as well as karyotype. Karyotype 46,XY was verified in 55% and chromosomal aberrations in 17.5% of cases. Ambiguous genitalia occurred in 45%, predominantly in 46,XX patients (p<0.006). Gonadal differentiation disorders accounted for 25% and congenital adrenal hyperplasia, for 17.5% of the sample. Consanguinity occurred in 16%, recurrence in 12%, lack of birth certificate in 20% and interrupted follow-up in 31% of cases. CONCLUSIONS: Patients with SDD predominated. Ambiguous genitalia and abnormal sexual differentiation were more frequent among infants and prepubertal individuals. Congenital adrenal hyperplasia was the most prevalent nosology. Younger patients were more common in the GUA group. Abandonment and lower frequency of birth certificate occurred in patients with ambiguous or malformed genitalia. These characteristics corroborate the literature and show the biopsychosocial impact of genitourinary anomalies. PMID- 26522825 TI - Predictors of suicide attempts after violent offences in schizophrenia spectrum disorders. AB - The aim of this survey was to identify predictors of suicide attempts that immediately followed a violent crime in patients with schizophrenia. Documentations of patients diagnosed with schizophrenia and released in a 10 years period from the National Institute of Forensic Psychiatry were reviewed. Twenty-six out of 223 patients attempted suicide after the violent crime. The young age of the victim, and living in partnership were those factors differentiating suicidal violent offenders from their non-suicidal counterparts. PMID- 26522826 TI - Erratum: Comparative transcriptomics reveals key differences in the response to milk oligosaccharides of infant gut-associated bifidobacteria. PMID- 26522827 TI - ERalpha36--Another piece of the estrogen puzzle. AB - Although the nuclear action of estrogen receptors (ER) is a well-known fact, evidence supporting membrane estrogen receptors is steadily accumulating. New ER variants of unrecognized function have been discovered. ERalpha is a product of the ESR1 gene. It serves not only as a template for the full-length 66kDa protein, but also for smaller isoforms which exist as independent receptors. The recently discovered ERalpha36 (36kDa), consisting of 310 amino acids of total 595 ERalpha66 protein residues, is an example of that group. The transcription initiation site is identified in the first intron of the ESR1 gene. C-Terminal 27 amino acids are encoded by previously unknown exon 9. The presence of this unique C-terminal sequence creates an opportunity for the production of selective antibodies. ERalpha36 has been shown to have a high affinity to the cell membrane and as much as 90% of the protein can be bound with it. Post-translational palmitoylation is suspected to play a crucial role in ERalpha36 anchoring to the cell membrane. In silico analysis suggests the existence of a potential transmembrane domain in ERalpha36. ERalpha36 was found in most cells of animals at various ages, but its exact physiological function remains to be fully elucidated. It seems that cells traditionally considered as being deprived of ER are able to respond to hormonal stimulation via the ERalpha36 receptor. Moreover, ERalpha36 displays unique pharmacological properties and its action may be behind antiestrogen resistance. The use of ERalpha36 in cancer diagnosis gives rise to great expectations. PMID- 26522828 TI - Adiposity, hypertension and weight management behaviours in Ghanaian type 2 diabetes mellitus patients aged 20-70 years. AB - OBJECTIVE: This study assessed the prevalence of general and abdominal obesity and hypertension as well the weight management behaviours of type 2 diabetes mellitus patients. METHODS: It included 378 diabetes patients seeking care from two hospitals in Ghana. Standard methods and tools were used to assess participants' weight, height, waist circumference (WC), blood pressure (BP) and fasting plasma glucose (FPG). Weight management behaviours were measured using a questionnaire. RESULTS: The prevalence of general obesity, abdominal obesity and hypertension was 20.1%, 46.6% and 67.7% respectively. Abdominal obesity was more likely in participants who: skipped breakfast, engaged in exercise to lose weight and were generally overweight/obese. General overweight and obesity was more likely in participants who: reported receipt of weight management counselling, engaged in exercise to lose weight, had a weight management plan/goal, and were abdominally obese. Hypertension was less likely in participants who had: no formal education, diabetes for >=5 years and modified their dietary habits to lose weight but more likely in those who skipped breakfast. CONCLUSION: Abdominal obesity, general overweight/obesity, and hypertension were frequent in this sample and were influenced by weight management behaviours. PMID- 26522829 TI - Low-level resistance and clonal diversity of Pseudomonas aeruginosa among chronically colonized cystic fibrosis patients. AB - A prospective study was conducted in Brazil to evaluate antimicrobial resistance patterns and molecular epidemiology of Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients with chronic lung infection. All isolates were obtained between May 2009 and June 2010 from 75 patients seen in four reference centers in Brazil: HCPA (20 patients) and HEOM (15 patients), located in southern and northeastern Brazil, respectively; IFF (20 patients) and HUPE (20 patients), both in southwestern Brazil. Antimicrobial susceptibility testing, PCR for detection of carpapenemases, and pulsed-field gel electrophoresis (PFGE) were performed in 274 isolates. A total of 224 PFGE types were identified and no clones were found circulating among the centers or within the same center. Despite the chronic infection, most patients were colonized by intermittent clones. Only three patients (4%) maintained the same clone during the study. The resistance rates were lower than 30% for the majority of antimicrobials tested in all centers and only 17% of isolates were multiresistant. Isolates (n = 54) with reduced susceptibility to imipenem and/or meropenem presented negative results for blaSPM-1, blaIMP-1, blaVIM , and blaKPC genes. Our results indicate an unexpected low level of antimicrobial resistance and a high genotypic diversity among P. aeruginosa from Brazilian chronic CF patients. PMID- 26522831 TI - Psychosocial job characteristics and psychological distress / well-being: the mediating role of personal goal facilitation. AB - OBJECTIVE: This study examined the mediating role of personal goal facilitation through work (PGFW), defined as perceptions of the extent to which one's job facilitates the attainment of one's personal goals, in the association between psychosocial job characteristics and psychological distress and job-related well being. MATERIAL AND METHODS: Questionnaire data from 217 nurses (84% female, with a mean age of 42.7 years, SD=7.2) were analyzed. Participants completed the following measures: the Leiden Quality of Work Questionnaire for Nurses, Workplace Goal Facilitation Inventory, Maslach Burnout Inventory-Human Services Survey, and Utrecht Work Engagement Scale (short version). A cross-sectional study design was applied. Hierarchical multiple regression analyses were conducted. RESULTS: The results indicated that unfavorable psychosocial job characteristics (high demands, low control, and low social support) were associated with lower PGFW. Furthermore, personal goal facilitation through work explained significant additional variance (from 2 to 11%) in psychological distress (somatic complaints and emotional exhaustion) and job-related well-being (personal accomplishment, job satisfaction, and work engagement), controlling for demographic indicators and psychosocial job characteristics. Finally, the results provided support for the mediating effects of PGFW between all psychosocial job characteristics and all outcomes, except in the case of depersonalization. CONCLUSIONS: This study suggests that hindered personal goal facilitation may be a mechanism through which psychosocial job characteristics have a negative impact on employees' well-being. PMID- 26522830 TI - Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing. AB - Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing. Targeted sequencing confirms allele segregation in six cases from four unrelated families. RNU4ATAC rare variants have been recently reported to cause microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all six of the Roifman Syndrome cases have one variant that overlaps MOPD1-implicated structural elements, while the other variant overlaps a highly conserved structural element not previously implicated in disease. RNA-seq analysis confirms extensive and specific defects of minor intron splicing. Available allele frequency data suggest that recessive genetic disorders caused by RNU4ATAC rare variants may be more prevalent than previously reported. PMID- 26522833 TI - Application of physiologically-based pharmacokinetic modeling to explore the role of kidney transporters in renal reabsorption of perfluorooctanoic acid in the rat. AB - Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been parameterized to specifically account for transporter mediated renal elimination. We developed a PBPK model for PFOA in male and female rats to explore the role of Oat1, Oat3, and Oatp1a1 in sex-specific renal reabsorption and excretion of PFOA. Descriptions of the kinetic behavior of these transporters were extrapolated from in vitro studies and the model was used to simulate time-course serum, liver, and urine data for intravenous (IV) and oral exposures in both sexes. Model predicted concentrations of PFOA in the liver, serum, and urine showed good agreement with experimental data for both male and female rats indicating that in vitro derived physiological descriptions of transporter-mediated renal reabsorption can successfully predict sex-dependent excretion of PFOA in the rat. This study supports the hypothesis that sex specific serum half-lives for PFOA are largely driven by expression of transporters in the kidney and contribute to the development of PBPK modeling as a tool for evaluating the role of transporters in renal clearance. PMID- 26522832 TI - Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE2 induced pain model. AB - Epoxyeicosatrienoic acids (EETs) are potent endogenous analgesic metabolites produced from arachidonic acid by cytochrome P450s (P450s). Metabolism of EETs by soluble epoxide hydrolase (sEH) reduces their activity, while their stabilization by sEH inhibition decreases both inflammatory and neuropathic pain. Here, we tested the complementary hypothesis that increasing the level of EETs through induction of P450s by omeprazole (OME), can influence pain related signaling by itself, and potentiate the anti-hyperalgesic effect of sEH inhibitor. Rats were treated with OME (100mg/kg/day, p.o., 7 days), sEH inhibitor TPPU (3mg/kg/day, p.o.) and OME (100mg/kg/day, p.o., 7 days)+TPPU (3mg/kg/day, p.o., last 3 days of OME dose) dissolved in vehicle PEG400, and their effect on hyperalgesia (increased sensitivity to pain) induced by PGE2 was monitored. While OME treatment by itself exhibited variable effects on PGE2 induced hyperalgesia, it strongly potentiated the effect of TPPU in the same assay. The significant decrease in pain with OME+TPPU treatment correlated with the increased levels of EETs in plasma and increased activities of P450 1A1 and P450 1A2 in liver microsomes. The results show that reducing catabolism of EETs with a sEH inhibitor yielded a stronger analgesic effect than increasing generation of EETs by OME, and combination of both yielded the strongest pain reducing effect under the condition of this study. PMID- 26522834 TI - Selenite exacerbates hepatic insulin resistance in mouse model of type 2 diabetes through oxidative stress-mediated JNK pathway. AB - Recent evidence suggests a potential pro-diabetic effect of selenite treatment in type 2 diabetics; however, the underlying mechanisms remain elusive. Here we investigated the effects and the underlying mechanisms of selenite treatment in a nongenetic mouse model of type 2 diabetes. High-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice were orally gavaged with selenite at 0.5 or 2.0mg/kg body weight/day or vehicle for 4 weeks. High-dose selenite treatment significantly elevated fasting plasma insulin levels and insulin resistance index, in parallel with impaired glucose tolerance, insulin tolerance and pyruvate tolerance. High-dose selenite treatment also attenuated hepatic IRS1/Akt/FoxO1 signaling and pyruvate kinase gene expressions, but elevated the gene expressions of phosphoenolpyruvate carboxyl kinase (PEPCK), glucose 6 phosphatase (G6Pase), peroxisomal proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) and selenoprotein P (SelP) in the liver. Furthermore, high-dose selenite treatment caused significant increases in MDA contents, protein carbonyl contents, and a decrease in GSH/GSSG ratio in the liver, concurrent with enhanced ASK1/MKK4/JNK signaling. Taken together, these findings suggest that high-dose selenite treatment exacerbates hepatic insulin resistance in mouse model of type 2 diabetes, at least in part through oxidative stress-mediated JNK pathway, providing new mechanistic insights into the pro diabetic effect of selenite in type 2 diabetes. PMID- 26522835 TI - Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A. AB - A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d6-BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d6-BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d6-BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species. PMID- 26522836 TI - Ultrafast Excited-State Dynamics of a Cyano-Substituted "Proton Sponge". AB - The dynamics of a substituted proton sponge-the 1,8-bis(dimethylamino)-4 cyanonaphthalene (DMAN-CN) molecule-was investigated after excitation in the S1 state. Experimental and theoretical information are reported. The former includes absorption, fluorescence, and time-resolved transient absorption spectra, which were recorded in solution. Real-time dynamics measurements were also performed on gas-phase isolated DMAN-CN. TD DFT/6-31G(d,p) level and CIS/6-31G(d,p) excited state calculations complement these results. This has allowed revisiting the energy transfer process between a locally excited (LE) and a charge transfer (CT) state, which is often invoked with this kind of molecule. PMID- 26522837 TI - Mechanistic Studies Lead to Dramatically Improved Reaction Conditions for the Cu Catalyzed Asymmetric Hydroamination of Olefins. AB - Enantioselective copper(I) hydride (CuH)-catalyzed hydroamination has undergone significant development over the past several years. To gain a general understanding of the factors governing these reactions, kinetic and spectroscopic studies were performed on the CuH-catalyzed hydroamination of styrene. Reaction profile analysis, rate order assessment, and Hammett studies indicate that the turnover-limiting step is regeneration of the CuH catalyst by reaction with a silane, with a phosphine-ligated copper(I) benzoate as the catalyst resting state. Spectroscopic, electrospray ionization mass spectrometry, and nonlinear effect studies are consistent with a monomeric active catalyst. With this insight, targeted reagent optimization led to the development of an optimized protocol with an operationally simple setup (ligated copper(II) precatalyst, open to air) and short reaction times (<30 min). This improved protocol is amenable to a diverse range of alkene and alkyne substrate classes. PMID- 26522838 TI - Electronic messaging support service programs improve adherence to lipid-lowering therapy among outpatients with coronary artery disease: an exploratory randomised control study. AB - AIMS AND OBJECTIVES: To compare drug adherence to lipid-lowering therapy among outpatients with coronary artery disease who received information via short message service, via short message service and Micro Letter, or via phone only. BACKGROUND: Messaging applications and short message service are commonly used internationally. However, little is known about how coronary artery disease outpatients in China may benefit from receiving health education through these technologies. DESIGN: Random sampling method. METHODS: Data were collected from March-December 2013. Subjects from Chengdu City, China, were randomised to three groups: short message service, short message service + Micro Letter, and phone (control). Appointment reminders and health information were delivered to patients in accordance with designations. After six months, adherence to statin prescriptions was compared among the groups by using the Morisky Medication Adherence Scale. Logistic regression analysis was applied to determine those independent variables that were related to adherence. RESULTS: The short message service and short message service + Micro Letter groups had better cumulative adherence (lower Morisky Medication Adherence Scale scores) after six months than phone group, and the short message service + Micro Letter group had better cumulative adherence (lower Morisky Medication Adherence Scale scores) than the short message service group. Female sex, older age and marriage show positive associations with adherence. CONCLUSIONS: Short message service and messaging applications, such as Micro Letter, are effective means of providing discharged patients with reminders and coronary artery disease-related health information. Implementation of a short message service + Micro Letter program can improve outpatient adherence to medication. RELEVANCE TO CLINICAL PRACTICE: This research offers useful information to help medical staff design effective interventions to improve medication compliance among coronary artery disease patients. PMID- 26522839 TI - Plastid control of abaxial-adaxial patterning. AB - Translational regulation, exerted by the cytosolic ribosome, has been shown to participate in the establishment of abaxial-adaxial polarity in Arabidopsis thaliana: many hypomorphic and null alleles of genes encoding proteins of the cytosolic ribosome enhance the leaf polarity defects of asymmetric leaves1 (as1) and as2 mutants. Here, we report the identification of the SCABRA1 (SCA1) nuclear gene, whose loss-of-function mutations also enhance the polarity defects of the as2 mutants. In striking contrast to other previously known enhancers of the phenotypes caused by the as1 and as2 mutations, we found that SCA1 encodes a plastid-type ribosomal protein that functions as a structural component of the 70S plastid ribosome and, therefore, its role in abaxial-adaxial patterning was not expected. PMID- 26522840 TI - Post-training gamma irradiation-enhanced contextual fear memory associated with reduced neuronal activation of the infralimbic cortex. AB - The brain might be exposed to irradiation under a variety of situations, including clinical treatments, nuclear accidents, dirty bomb scenarios, and military and space missions. Correctly recalling tasks learned prior to irradiation is important but little is known about post-learning effects of irradiation. It is not clear whether exposure to X-ray irradiation during memory consolidation, a few hours following training, is associated with altered contextual fear conditioning 24h after irradiation and which brain region(s) might be involved in these effects. Brain immunoreactivity patterns of the immediately early gene c-Fos, a marker of cellular activity was used to determine which brain areas might be altered in post-training irradiation memory retention tasks. In this study, we show that post-training gamma irradiation exposure (1 Gy) enhanced contextual fear memory 24h later and is associated with reduced cellular activation in the infralimbic cortex. Reduced GABA-ergic neurotransmission in parvalbumin-positive cells in the infralimbic cortex might play a role in this post-training radiation-enhanced contextual fear memory. PMID- 26522841 TI - Alteration of behavior and monoamine levels attributable to Lactobacillus plantarum PS128 in germ-free mice. AB - Probiotics, defined as live bacteria or bacterial products, confer a significant health benefit to the host, including amelioration of anxiety-like behavior and psychiatric illnesses. Here we administered Lactobacillus plantarum PS128 (PS128) to a germ-free (GF) mouse model to investigate the impact of the gut-brain axis on emotional behaviors. First, we demonstrated that chronic administration of live PS128 showed no adverse effects on physical health. Then, we found that administration of live PS128 significantly increased the total distance traveled in the open field test and decreased the time spent in the closed arm in the elevated plus maze test, whereas the administration of PS128 had no significant effects in the depression-like behaviors of GF mice. Also, chronic live PS128 ingestion significantly increased the levels of both serotonin and dopamine in the striatum, but not in the prefrontal cortex or hippocampus. These results suggest that the chronic administration of PS128 is safe and could induce changes in emotional behaviors. The behavioral changes are correlated with the increase in the monoamine neurotransmitters in the striatum. These findings suggest that daily intake of the L. plantarum strain PS128 could improve anxiety-like behaviors and may be helpful in ameliorating neuropsychiatric disorders. PMID- 26522843 TI - Chronic mild stress in submissive mice: Marked polydipsia and social avoidance without hedonic deficit in the sucrose preference test. AB - In the Chronic Mild Stress (CMS) protocol, rodents are exposed to unpredictable stressors to induce anxiety-like behavior and hedonic deficit in the Sucrose Preference test (SPT). Since CMS-induced anxiety- and anhedonic-like behavior may depend upon individual vulnerability to stress, we hypothesized that selectively bred Submissive (Sub) mice would exhibit heightened anxiety- and anhedonic-like behavior, in response to CMS exposure. We anticipated that the testing of Sub mice alongside their Wt counterparts in a battery of behavioral assays would identify parameters most sensitive to CMS effects. To test these assumptions, Sub mice and their outbred Sabra (Wt) counterparts underwent a five-week CMS-SPT regimen. CMS exposure led to reduced preference for sucrose (sucrose-sweetened water as percent of total intake) among both mouse strains (p<0.01 Wt; p<0.05 Sub). However, this effect was attributed to CMS-induced polydipsia, indicated by mice's increased water consumption, (p<0.01 Wt and Sub), without changes in sucrose intake. Furthermore, CMS-exposed Sub mice, but not Wt, demonstrated impaired social exploration in the Three Chamber test (p<0.05) and anxiety-like effects in the Elevated Plus Maze (p<0.05). Moreover, in a separate experiment, social isolation alone was sufficient to induce polydipsia in Sub mice, without affecting Wt mice's drinking behavior. The present findings suggest that the EPM and Three Chamber tests may be valuable complementary measures of CMS effects, alongside the Sucrose Preference test, and introduce the Sub mouse strain for use in study of susceptibility to stress. PMID- 26522844 TI - Prescribed Doses of Opioids in Long-Term Care Facilities. PMID- 26522842 TI - Differences in the performance of NK1R-/- ('knockout') and wildtype mice in the 5 Choice Continuous Performance Test. AB - Mice lacking functional NK1 (substance P-preferring) receptors typically display excessive inattentiveness (omission errors) and impulsivity (premature responses) when compared with wildtypes in the 5-Choice Serial Reaction-Time Test (5-CSRTT). These abnormal behaviours are analogous to those seen in humans suffering from Attention Deficit Hyperactivity Disorder (ADHD). Here we used the 5-Choice Continuous-Performance Test (5C-CPT) to ascertain whether NK1R-/- mice also display excessive false alarms (an inappropriate response to a 'no-go' signal), which is another form of impulsive behaviour. NK1R-/- mice completed more trials than wildtypes, confirming their ability to learn and carry out the task. At the start of Stage 1 of training, but not subsequently, they also scored more premature responses than wildtypes. When the mice were tested for the first time, neither false alarms nor premature responses was higher in NK1R-/- mice than wildtypes but, as in the 5-CSRTT, the latter behaviour was strongly dependent on time of day. NK1R-/- mice expressed excessive perseveration during all stages of the 5C-CPT. This behaviour is thought to reflect compulsive checking, which is common in ADHD patients. These findings point to differences in the 5-CSRTT and 5C-CPT protocols that could be important for distinguishing why the cognitive performance and response control of NK1R-/- mice differs from their wildtypes. The results further lead to the prediction that ADHD patients with polymorphism of the TACR1 gene (the human equivalent of Nk1r) would express more perseveration, but not false alarms, in Continuous Performance Tests when compared with other groups of subjects. PMID- 26522845 TI - The facts about myocardial infarction: There is more than meets the eye! PMID- 26522846 TI - A novel electroporation system for efficient molecular delivery into Chlamydomonas reinhardtii with a 3-dimensional microelectrode. AB - Electroporation is one of the most widely used transfection methods because of its high efficiency and convenience among the various transfection methods. Previous micro-electroporation systems have some drawbacks such as limitations in height and design, time-consuming and an expensive fabrication process due to technical constraints. This study fabricates a three dimensional microelectrode using the 3D printing technique. The interdigitated microstructure consisting of poly lactic acid was injected by a 3D printer and coated with silver and aluminum with a series of dip-coatings. With the same strength of electric field (V cm( 1)), a higher efficiency for molecular delivery and a higher cellular viability are achieved with the microelectrode than with a standard cuvette. In addition, this study investigates chemicophysical changes such as Joule heating and dissolved metal during electroporation and showed the micro-electroporation system had less chemicophysical changes. It was concluded that the proposed micro electroporation system will contribute to genetic engineering as a promising delivery tool, and this combination of 3D printing and electroporation has many potential applications for diverse designs or systems. PMID- 26522848 TI - cis-Regulatory control of the initial neurogenic pattern of onecut gene expression in the sea urchin embryo. AB - Specification of the ciliated band (CB) of echinoid embryos executes three spatial functions essential for postgastrular organization. These are establishment of a band about 5 cells wide which delimits and bounds other embryonic territories; definition of a neurogenic domain within this band; and generation within it of arrays of ciliary cells that bear the special long cilia from which the structure derives its name. In Strongylocentrotus purpuratus the spatial coordinates of the future ciliated band are initially and exactly determined by the disposition of a ring of cells that transcriptionally activate the onecut homeodomain regulatory gene, beginning in blastula stage, long before the appearance of the CB per se. Thus the cis-regulatory apparatus that governs onecut expression in the blastula directly reveals the genomic sequence code by which these aspects of the spatial organization of the embryo are initially determined. We screened the entire onecut locus and its flanking region for transcriptionally active cis-regulatory elements, and by means of BAC recombineered deletions identified three separated and required cis-regulatory modules that execute different functions. The operating logic of the crucial spatial control module accounting for the spectacularly precise and beautiful early onecut expression domain depends on spatial repression. Previously predicted oral ectoderm and aboral ectoderm repressors were identified by cis regulatory mutation as the products of goosecoid and irxa genes respectively, while the pan-ectodermal activator SoxB1 supplies a transcriptional driver function. PMID- 26522847 TI - Dephosphorylation of juxtamembrane serines and threonines of the NPR2 guanylyl cyclase is required for rapid resumption of oocyte meiosis in response to luteinizing hormone. AB - The meiotic cell cycle of mammalian oocytes starts during embryogenesis and then pauses until luteinizing hormone (LH) acts on the granulosa cells of the follicle surrounding the oocyte to restart the cell cycle. An essential event in this process is a decrease in cyclic GMP in the granulosa cells, and part of the cGMP decrease results from dephosphorylation and inactivation of the natriuretic peptide receptor 2 (NPR2) guanylyl cyclase, also known as guanylyl cyclase B. However, it is unknown whether NPR2 dephosphorylation is essential for LH-induced meiotic resumption. Here, we prevented NPR2 dephosphorylation by generating a mouse line in which the seven regulatory serines and threonines of NPR2 were changed to the phosphomimetic amino acid glutamate (Npr2-7E). Npr2-7E/7E follicles failed to show a decrease in enzyme activity in response to LH, and the cGMP decrease was attenuated; correspondingly, LH-induced meiotic resumption was delayed. Meiotic resumption in response to EGF receptor activation was likewise delayed, indicating that NPR2 dephosphorylation is a component of the pathway by which EGF receptor activation mediates LH signaling. We also found that most of the NPR2 protein in the follicle was present in the mural granulosa cells. These findings indicate that NPR2 dephosphorylation in the mural granulosa cells is essential for the normal progression of meiosis in response to LH and EGF receptor activation. In addition, these studies provide the first demonstration that a change in phosphorylation of a transmembrane guanylyl cyclase regulates a physiological process, a mechanism that may also control other developmental events. PMID- 26522849 TI - The mental health of male victims and their children affected by legal and administrative partner aggression. AB - The authors recently developed a psychometrically valid measure of legal and administrative (LA) intimate partner violence (IPV) victimization (Hines, Douglas, & Berger, 2014). The current article explores the impact of actual and threatened LA aggression on the mental health of male physical IPV victims and their children. In the current study, a sample of 611 men who sought help after experiencing physical IPV from their female partners completed a survey assessing the types and extent of IPV that occurred in their relationship, including LA aggression, their own mental health outcomes, and the mental health of their oldest child. A series of OLS regressions indicated that after controlling for covariates, actual LA aggression was associated with more symptoms of PTSD and depression in male victims, and that both threatened and actual LA aggression were associated with higher levels of affective and oppositional defiant symptoms in the men's school age children. The current findings suggest that it is important to screen couples for the presence of LA aggression and male partners and their children should be referred for mental health treatment if LA aggression is occurring in the relationship. Aggr. Behav. 42:346-361, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26522850 TI - Psychometric properties of the recovery measurement in homeless people with severe mental illness. AB - OBJECTIVE: The Recovery Assessment Scale (RAS) is one of the most widely used measurements of recovery in mental health research. To date, no data have been available concerning the psychometric characteristics of the RAS in homeless people with severe mental illness. The aim of this study was to provide new data regarding the psychometric properties of the RAS in homeless people with schizophrenia and bipolar disorder. METHODS: This multi-center study was conducted in 4 French cities. In addition to the RAS, data on sociodemographic information, disease severity using the Modified Colorado Symptom Index - MCSI, and the number of mental health comorbidities, care characteristics and quality of life (S-QoL-18) were collected. The RAS was tested for construct validity, reliability, external validity, sensitivity to change and acceptability. RESULTS: Six hundred fifty-eight homeless patients participated in this study. The five factor structure was confirmed by confirmatory factor analysis (RMSEA = 0.043, CFI = 0.95, NFI = 0.94 and SRMR = 0.063). The internal item consistency (from 0.40 to 0.80) and reliability (Cronbach's alpha from 0.79 to 0.87) were satisfactory for all dimensions. External validity testing revealed that the dimension scores were correlated significantly with the MCSI and S-QoL 18 scores. Significant associations with age, disease severity, psychiatric comorbidities and care characteristics showed good discriminant validity. The percentage of missing data (< 14.4%) and sensitivity to change were satisfactory. CONCLUSIONS: Our study demonstrated the satisfactory acceptability and psychometric properties of the RAS, supporting its use as a mean of recovery measurement for homeless patients. PMID- 26522851 TI - Diabetes and motor impairments. PMID- 26522852 TI - Inhibition of in vitro adhesion and virulence of Porphyromonas gingivalis by aqueous extract and polysaccharides from Rhododendron ferrugineum L. A new way for prophylaxis of periodontitis? AB - The effect of an aqueous extract from the leaves of Rhododendron ferrugineum (RF) was investigated for its capacity of inhibiting the adhesion of Porphyromonas gingivalis cells to epithelial buccal KB cells. RF was characterized by HPLC (12.1% taxifolin-3-O-beta-l-arabinopyranoside, 1.6% hyperoside, 0.9% isoquercitrin, 1.6% chlorogenic acid and a tannin content of 8.7%). Additionally raw polysaccharides (RPS) were obtained from the leaves of R. ferrugineum by aqueous extraction. RF and RPS interacted in a dose-dependent manner (max. 25% reduction at 1mg/ml each) with the adhesion of P. gingivalis by influencing bacterial outer membrane proteins. On protein level a time- and concentration dependent inhibition of Arg-gingipain activity by RF was observed, while the Lys gingipain activity remained unaltered. In addition, RF and RPS inhibited the bacterial hemagglutinin. RF affected the P. gingivalis adhesion also by interacting with KB cells in pre-incubation assays of the eukaryotic host cells, leading to reduced bacterial adhesion of about 75%. Gene expression analysis by RT-PCR indicated significant downregulation for arginine-specific gingipain rgpA by RF, while lysin-specific gingipain kgp and fimbrillinA fimA were strongly upregulated. Moreover, pre-incubation with RF abolished the P. gingivalis induced expression of IL-1beta, IL-6, IL-8 and TNFalpha in KB cells. Results of this study indicate that an aqueous extract from R. ferrugineum combines cytoprotective and antimicrobial effects by both downregulating the expression of pro-inflammatory genes and inhibiting the adhesion of P. gingivalis. Thus RF may be potential candidate for the development of an adjunctive antimicrobial approach in the prevention of periodontal diseases. PMID- 26522853 TI - ADAMs family and relatives in cardiovascular physiology and pathology. AB - A disintegrin and metalloproteinases (ADAMs) are a family of membrane-bound proteases. ADAM-TSs (ADAMs with thrombospondin domains) are a close relative of ADAMs that are present in soluble form in the extracellular space. Dysregulated production or function of these enzymes has been associated with pathologies such as cancer, asthma, Alzheimer's and cardiovascular diseases. ADAMs contribute to angiogenesis, hypertrophy and apoptosis in a stimulus- and cell type-dependent manner. Among the ADAMs identified so far (34 in mouse, 21 in human), ADAMs 8, 9, 10, 12, 17 and 19 have been shown to be involved in cardiovascular development or cardiomyopathies; and among the 19 ADAM-TSs, ADAM-TS1, 5, 7 and 9 are important in development of the cardiovascular system, while ADAM-TS13 can contribute to vascular disorders. Meanwhile, there remain a number of ADAMs and ADAM-TSs whose function in the cardiovascular system has not been yet explored. The current knowledge about the role of ADAMs and ADAM-TSs in the cardiovascular pathologies is still quite limited. The most detailed studies have been performed in other cell types (e.g. cancer cells) and organs (nervous system) which can provide valuable insight into the potential functions of ADAMs and ADAM-TSs, their mechanism of action and therapeutic potentials in cardiomyopathies. Here, we review what is currently known about the structure and function of ADAMs and ADAM TSs, and their roles in development, physiology and pathology of the cardiovascular system. PMID- 26522854 TI - Mechanism of bombesin-induced tonic contraction of the porcine lower esophageal sphincter. AB - Gastroesophageal reflux disease (GERD) is a disorder that is related to an incompetent lower esophageal sphincter (LES). Previous studies showed that bombesin could increase LES pressure in humans and opossums. The aim of the present study was to characterize the effects of bombesin on porcine LES contraction. We used the selective agonists, neuromedin B (NMB), gastrin releasing peptide (GRP), and [D-Tyr(6),Apa-4Cl(11),Phe(13),Nle(14)]bombesin-(6 14) (DTACPN-BN), as well as receptor antagonists of bombesin receptor subtype 2 (BB2), and 3 (BB3) for ex vivo contraction studies. Atropine, nifedipine, tetrodotoxin, and omega-conotoxin GVIA were used to explore the agonist-induced LES contraction mechanism. Reverse transcription polymerase chain reaction and immunohistochemistry were applied to detect bombesin receptor expression. Our results indicate that GRP and DTACPN-BN, but not NMB, induced tonic contractions of the porcine LES in a dose-dependent manner, and the contractions were inhibited with selective BB2 and BB3 antagonists. The GRP-induced contraction is mainly caused by L-type Ca(2+) channel-mediated Ca(2+) influx. However, DTACPN-BN induced contractions are associated with neuronal conduction. RT-PCR and immunohistochemistry revealed that BB2 and BB3 were expressed in the porcine LES. Bombesin-induced tonic contraction of the LES is mediated through BB2 and BB3. Bombesin, BB2, and BB3 agonists might have the potential to treat GERD. PMID- 26522855 TI - [Role of the stroma in the initiation and progression of tumors]. AB - In the last decade, growing attention was paid to the observation that tumors did not only consist of cancer cells, they are rather a complex tissue-like mixture of tumor and stromal cells, which are playing an important role in the course of the malignant disease. Their contribution is so essential that without them, tumors are not even able to grow. This short review summarizes how stromal cells can promote the cancerous transformation and early development of tumors, how chronic inflammation contributes to the progression of cancer and how the stroma takes part in the induction of angiogenesis. The main mechanisms by which tumors can escape the immune surveillance will be demonstrated as well as the complex contributions of stroma to the invasion, intravasation and metastasis of cancer cells. Finally, possible and promising therapies will be presented that aim at the stroma and its main effects on the progression of tumors. PMID- 26522856 TI - [Novel treatment options in relapsed and refracter Hodgkin lymphomas]. AB - INTRODUCTION: Hodgkin lymphoma is a curable lymphoma with an 80-90% long-term survival, however, 30% of the patients develop relapse. Only half of relapsed patients can be cured with autologous stem cell transplantation. AIM: The aim of the authors was to analyze survival rates and incidence of relapses among Hodgkin lymphoma patients who were treated between January 1, 1980 and December 31, 2014. Novel therapeutic options are also summarized. METHOD: Retrospective analysis of data was performed. RESULTS: A total of 715 patients were treated (382 men and 333 women; median age at the time of diagnosis was 38 years). During the studied period the frequency of relapsed patients was reduced from 24.87% to 8.04%. The numbers of autologous stem cell transplantations was increased among refracter/relapsed patients, and 75% of the patients underwent transplantation since 2000. The 5-year overall survival improved significantly (between 1980 and 1989 64.4%, between 1990 and 1999 82.4%, between 2000 and 2009 88.4%, and between 2010 and 2014 87.1%). Relapse-free survival did not change significantly. CONCLUSIONS: During the study period treatment outcomes improved. For relapsed/refractory Hodgkin lymphoma patients novel treatment options may offer better chance for cure. PMID- 26522857 TI - [Catch-22? Wide variety of phenotypes associated with the chromosome 22q11 deletion syndrome in two patients]. AB - The chromosome 22q11 deletion syndrome may present with a variety of phenotypes. Its symptoms generally include a characteristic facial dysmorphisms and multiplex developmental disorders. Fluorescence in situ hybridization is the current method of choice for the diagnosis if typical multiple defects and/or symptoms are present. The authors present the history of two patients who were followed-up for minor anomalies and various developmental disorders for several years in the genetic counseling office of the authors, but definitive diagnosis was not established. However, when DNA samples of the two patients were recently tested with array comparative genome hybridization, a diagnostic method which has already been used in their institute for several years, the results indicated deletion of the 11.2 region on the long arm of chromosome 22 in both patients. The authors draw attention to the incidence and wide phenotypic spectrum of the chromosome 22q11 deletion syndrome, and show that its identification can be aided with the novel molecular cytogenetic method available in their laboratory. PMID- 26522859 TI - Undergraduate obstetrics and gynecology medical education: why are we underrated and underappreciated? PMID- 26522860 TI - Reply. PMID- 26522861 TI - Impact of uterine closure on residual myometrial thickness after cesarean: a randomized controlled trial. AB - BACKGROUND: Incomplete healing of uterine scar after cesarean has been associated with adverse gynecological and obstetrical outcomes. Several studies reported that uterine closure at cesarean influences the healing of uterine scar and the risk of uterine rupture at subsequent pregnancies: the commonly used locked single-layer suture including the decidua being associated with a 4-fold increased risk of uterine rupture. However, data from randomized trials are lacking. OBJECTIVE: We sought to evaluate the impact of 3 techniques of uterine closure after cesarean delivery on uterine scar healing. STUDY DESIGN: This was a 3-arm 1:1:1 randomized study in women with singleton pregnancies undergoing elective primary cesarean delivery at >=38 weeks' gestation. Closure of the uterine scar was carried out by locked single layer including the decidua, double layer with locked first layer including the decidua, or double layer with unlocked first layer excluding the decidua. Primary outcome was residual myometrial thickness (RMT) at the site of the scar, measured by transvaginal ultrasound 6 months after delivery. Secondary outcome was the RMT as a percentage of the myometrial thickness above the scar (healing ratio). Intent-to-treat analyses using Student t test were performed to compare each double-layer technique to the single-layer closure, and P < .025 was considered significant. RESULTS: Complete follow-up was obtained from 73 (90%) of the 81 participants. Compared to single-layer closure, double-layer closure with unlocked first layer was associated with thicker RMT (3.8 +/- 1.6 mm vs 6.1 +/- 2.2 mm; P < .001) and greater healing ratio (54 +/- 20% vs 73 +/- 23%; P = .004). In contrast, double layer closure with locked first layer was not significantly different than single layer closure in either RMT (4.8 +/- 1.3; P = .032) or healing ratio (60 +/- 21%; P = .287). CONCLUSION: Double-layer closure with unlocked first layer is associated with better uterine scar healing than locked single layer. PMID- 26522862 TI - Prevalence of anal human papillomavirus infection and anal human papillomavirus related disorders in women: a systematic review. PMID- 26522863 TI - Design, synthesis, and characterization of BRC4 mutants based on the crystal structure of BRC4-RAD51(191-220). AB - Breast cancer susceptibility gene 2 (BRCA2)-a human tumor suppressor gene-is related to various malignancies such as breast and ovarian cancer. This gene can induce the key protein RAD51 recombinase, which is involved in homologous recombination with single-stranded DNA in the human body and can regulate RAD51 to complete the repair of damaged double-stranded DNA. Eight highly conserved BRC repeat motifs in BRCA2 protein serve as sites for the interaction between BRCA2 and RAD51. BRCA2 regulates RAD51 through these motifs. However, the mechanism of this interaction still requires further research. In this study, the BRC4 motif that demonstrated strong interaction with RAD51 was selected as template peptide. On the basis of known data regarding the crystal structure of the BRC4-RAD51(191 220) complex, a series of BRC4 mutants was designed using PyMOL software based on the sequence of BRC4, and polypeptides were synthesized by the Fmoc solid-phase method. After purification by reversed-phase high-performance liquid chromatography, the purity of the polypeptides reached >95 %. The primary determination of circular dichroism spectra showed that the polypeptides exhibited slight changes in secondary structure, which indicated that mutation on the non-conserved sites in BRC4 probably affected the interaction with BRC4. These findings will facilitate research on the interaction between targeting peptides and BRC4 mutants, as well the basic rules covering this interaction. PMID- 26522864 TI - Efficacy of an individualized social competence training for children with Oppositional Defiant Disorders/Conduct Disorders. AB - OBJECTIVES: Group-based Cognitive-Behavioral Therapy of children with aggressive behavior has resulted in significant reductions of behavior problems with small to medium effect sizes. We report the efficacy of an individualized Treatment Program for Children with Aggressive Behavior. METHOD: A within-subject design with two phases (waiting, treatment) was chosen. Sixty boys aged 6-12 years with peer-related aggressive behavior were included. The course of the outcome measures (growth rates) during a 6-week waiting phase was compared with those in the subsequent treatment phase (24 weekly child sessions together with an average of 8 parent contacts) by multilevel modeling. Primary outcome was peer-related aggressive behavior rated by parents. Further outcome measures included parent ratings and patient self-reports of aggressive and prosocial behavior. RESULTS: During the treatment, growth rates for all parent-rated outcome measures were significant (p < .001) and comparison with the waiting phase indicated a stronger decrease in aggressive behavior and a stronger increase in prosocial behavior. For all self-rated outcome measures, growth rates during the treatment were significant (p < .01), but comparison with the waiting phase indicated a stronger decrease only for disturbance of social interaction. CONCLUSIONS: The treatment program is an effective intervention for children with peer-related aggressive behavior. PMID- 26522865 TI - VALGENT: A protocol for clinical validation of human papillomavirus assays. AB - BACKGROUND: Testing for high-risk HPV is more effective in primary cervical cancer screening than the cytological examination of a Pap smear. Separate genotyping may be useful for triage in both HPV-based and cytology-based screening. Only clinically validated tests should be used in clinical practice. OBJECTIVES: VALGENT is a study framework for test comparison and validation of HPV assays in general and HPV genotyping tests in particular according to clinically relevant outcomes and for clinical applications endorsed by scientific evidence. STUDY DESIGN: VALGENT involves the collation of fresh or archived cervical cell specimen from women attending routine screening supplemented with cytologically abnormal samples. Multiple aliquots of residual material are sent from a central laboratory to participating laboratories for testing with novel HPV assays with limited, extended or full genotyping capacity. Outcomes are derived from screening and pathology registries. Each VALGENT panel includes an assay already validated for screening. A series of accuracy and concordance statistics were generated. RESULTS: Currently, two VALGENT study rounds, originated from laboratories in Antwerp (Belgium) and Edinburgh (Scotland), were completed. Two new assays (G5+/6+ PCR-LMNX and Xpert HPV) were validated for screening by showing similar accuracy for cervical precancer as the standard comparator test. For two other tests (BD Onclarity, PapilloCheck) validation was confirmed. Inter-test agreement was high although certain type-specific discordances were observed which warrant further analysis. CONCLUSION: VALGENT extends current guidelines for high-risk HPV test validation in cervical cancer screening and has produced a large study resource for test comparison. More robust procedures of sample selection and handling and integration with the global WHO reference laboratory network focusing on analytical accuracy, may result in the generation of an international standard and a formalized system for clinical validation of HPV assays and quality control in HPV-based screening. PMID- 26522866 TI - Genetic variants in the CPNE5 gene are associated with alcohol dependence and obesity in Caucasian populations. AB - Alcohol addiction may increase the risk of obesity due to shared genetic components. The Copine V (CPNE5) gene is involved in Ca(2+) binding and may play an important role in the development of the central nervous system. This study tested the genetic associations of 77 single-nucleotide polymorphisms (SNPs) within the CPNE5 gene with alcohol dependence (AD) and obesity using a Caucasian sample - The Study of Addiction - Genetics and Environment (SAGE) sample (1066 AD cases and 1278 non-AD controls, 422 obese cases and 1395 non-obese controls). The Marshfield sample (1442 obese cases and 2122 non-obese controls) was used for replication of obesity. Multiple logistic regression analysis was performed using the PLINK software. In the SAGE sample, we identified 10 SNPs associated with AD and 17 SNPs associated with obesity (p < 0.05). Interestingly, 6 SNPs (rs9986517, rs9470387, rs3213534, rs10456444, rs3752482, and rs9470386) were associated with both AD (OR = 0.77, 0.77, 0.83, 0.84, 0.79 and 1.14, respectively; p = 9.72 * 10( 5), 1.1 * 10(-4), 4.09 * 10(-3), 5.26 * 10(-3), 1.59 * 10(-2), and 3.81 * 10(-2), respectively) and obesity (OR = 0.77, 0.77, 0.78, 0.77, 0.68 and 1.18, respectively; p = 2.74 * 10(-3), 2.69 * 10(-3), 2.45 * 10(-3), 1.01 * 10(-3), 5.18 * 10(-3) and 3.85 * 10(-2), respectively). In the Marshfield sample, rs3752480 was associated with obesity (p = 0.0379). In addition, four SNPs (rs9986517, rs10456444, rs7763347 and rs4714010) showed associations with obesity in the meta-analysis using both samples (p = 0.00493, 0.0274, 0.00346, and 0.0141, respectively). These findings provide the first evidence of common genetic variants in the CPNE5 gene influencing both the AD and obesity; and will serve as a resource for replication in other populations. PMID- 26522867 TI - Hyperresponsivity and impaired prefrontal control of the mesolimbic reward system in schizophrenia. AB - Schizophrenia is characterized by substantial dysfunctions of reward processing, leading to detrimental consequences for decision-making. The neurotransmitter dopamine is responsible for the transmission of reward signals and also known to be involved in the mechanism of psychosis. Using functional magnetic resonance imaging (fMRI), sixteen medicated patients with schizophrenia and sixteen healthy controls performed the 'desire-reason dilemma' (DRD) paradigm. This paradigm allowed us to directly investigate reward-related brain activations depending on the interaction of bottom-up and top-down mechanisms, when a previously conditioned reward stimulus had to be rejected to achieve a superordinate long term goal. Both patients and controls showed significant activations in the mesolimbic reward system. In patients with schizophrenia, however, we found a significant hyperactivation of the left ventral striatum (vStr) when they were allowed to accept the conditioned reward stimuli, and a reduced top-down regulation of activation in the ventral striatum (vStr) and ventral tegmental area (VTA) while having to reject the immediate reward to pursue the superordinate task-goal. Moreover, while healthy subjects exhibited a negative functional coupling of the vStr with both the anteroventral prefrontal cortex (avPFC) and the ventromedial prefrontal cortex (VMPFC) in the dilemma situation, this functional coupling was significantly impaired in the patient group. These findings provide evidence for an increased ventral striatal activation to reward stimuli and an impaired top-down control of reward signals by prefrontal brain regions in schizophrenia. PMID- 26522868 TI - The impact of physical pain on suicidal thoughts and behaviors: Meta-analyses. AB - Although the relationship between physical pain and suicidal thoughts and behaviors has been explored in multiple epidemiologic and clinical studies, it is still far from being well understood. Consequently, we conducted a meta-analysis of studies comparing rates of suicidal thoughts and behaviors in individuals with and without physical pain. We searched MEDLINE and PsycINFO (May 2015) for studies comparing rates of current and lifetime suicidal thoughts and behaviors (death wish, suicide ideation, plan, attempt and death: DW, SI, SP, SA, SD) in individuals with any type of physical pain (headache, back, neck, chest, musculoskeletal, abdominal and pelvic pains, arthritis, fibromyalgia, medically unexplained pain, and other not specified pain) versus those without it. Data were analyzed with Cochrane Collaboration Review Manager Software (RevMan, version 5.3). We assessed the methodological quality of the studies with the STROBE statement. Of the 31 included studies, three focused on lifetime DW, twelve focused on current SI (six lifetime), six focused on current SP (two lifetime), nine focused on current SA (11 lifetime) and eight on SD. Individuals with physical pain were more likely to report lifetime DW (p = 0.0005), both current and lifetime SI (both p < 0.00001), SP (current: p = 0.0008; lifetime: p < 0.00001), and SA (current: p < 0.0001; lifetime: p < 0.00001). Moreover, they were more likely to report SD (p = 0.02). In all analyses, the between study heterogeneity was high. Moreover, the presence of publication bias has been detected in the main outcomes. Physical pain is a consistent risk factor for suicidal thoughts and behaviors. Further research is required to investigate the specific impact of: 1) chronic versus acute pain, 2) different types of pain (e.g., medically unexplained pain), and 3) risk factors for suicide in chronic pain patients. PMID- 26522869 TI - Amygdala response predicts trajectory of symptom reduction during Trauma-Focused Cognitive-Behavioral Therapy among adolescent girls with PTSD. AB - Trauma-Focused Cognitive-Behavioral Therapy (TF-CBT) is the gold standard treatment for pediatric PTSD. Nonetheless, clinical outcomes in TF-CBT are highly variable, indicating a need to identify reliable predictors that allow forecasting treatment response. Here, we test the hypothesis that functional neuroimaging correlates of emotion processing predict PTSD symptom reduction during Trauma-Focused Cognitive-Behavioral Therapy (TF-CBT) among adolescent girls with PTSD. Thirty-four adolescent girls with PTSD related to physical or sexual assault were enrolled in TF-CBT, delivered in an approximately 12 session format, in an open trial. Prior to treatment, they were engaged in an implicit threat processing task during 3T fMRI, during which they viewed faces depicting fearful or neutral expressions. Among adolescent girls completing TF-CBT (n = 23), slopes of PTSD symptom trajectories during TF-CBT were significantly related to pre-treatment degree of bilateral amygdala activation while viewing fearful vs neutral images. Adolescents with less symptom reduction were characterized by greater amygdala activation to both threat and neutral images (i.e., less threat safety discrimination), whereas adolescents with greater symptom reduction were characterized by amygdala activation only to threat images. These clinical outcome relationships with pre-treatment bilateral amygdala activation remained when controlling for possible confounding demographic or clinical variables (e.g., concurrent psychotropic medication, comorbid diagnoses). While limited by a lack of a control group, these preliminary results suggest that pre-treatment amygdala reactivity to fear stimuli, a component of neurocircuitry models of PTSD, positively predicts symptom reduction during TF-CBT among assaulted adolescent girls, providing support for an objective measure for forecasting treatment response in this vulnerable population. PMID- 26522870 TI - Prescription stimulant use is associated with earlier onset of psychosis. AB - A childhood history of attention deficit hyperactivity disorder (ADHD) is common in psychotic disorders, yet prescription stimulants may interact adversely with the physiology of these disorders. Specifically, exposure to stimulants leads to long-term increases in dopamine release. We therefore hypothesized that individuals with psychotic disorders previously exposed to prescription stimulants will have an earlier onset of psychosis. Age of onset of psychosis (AOP) was compared in individuals with and without prior exposure to prescription stimulants while controlling for potential confounding factors. In a sample of 205 patients recruited from an inpatient psychiatric unit, 40% (n = 82) reported use of stimulants prior to the onset of psychosis. Most participants were prescribed stimulants during childhood or adolescence for a diagnosis of ADHD. AOP was significantly earlier in those exposed to stimulants (20.5 vs. 24.6 years stimulants vs. no stimulants, p < 0.001). After controlling for gender, IQ, educational attainment, lifetime history of a cannabis use disorder or other drugs of abuse, and family history of a first-degree relative with psychosis, the association between stimulant exposure and earlier AOP remained significant. There was a significant gender * stimulant interaction with a greater reduction in AOP for females, whereas the smaller effect of stimulant use on AOP in males did not reach statistical significance. In conclusion, individuals with psychotic disorders exposed to prescription stimulants had an earlier onset of psychosis, and this relationship did not appear to be mediated by IQ or cannabis. PMID- 26522871 TI - Effects of structured exercise and pharmacotherapy vs. pharmacotherapy for adults with depressive symptoms: A randomized clinical trial. AB - OBJECTIVE: Physical exercise has been consistently documented as a complementary therapy in the treatment of depressive disorders. However, despite a higher prevalence among women compared to men, the trials developed in women are scarce. In addition, the optimal dosage of exercise capable of producing benefits that reduce depressive symptoms remains unclear. This clinical trial is designed to measure the effect of a structured physical exercise program as a complement to antidepressant medication in the treatment of women with depression. METHODS: From July 2013 to May 2014, we implemented a randomized controlled trial (HAPPY BRAIN study). A total of 26 women (aged 50.16 +/- 12.08) diagnosed with clinical depression were randomized either to a supervised aerobic exercise group (45-50 min/week three times a week for four months) plus pharmacotherapy (intervention group), or only antidepressant medication (control group). RESULTS: The exercise group presented a decrease in BDI-II and DASS-21 total score scales. Relatively to DASS-21, it showed a significant decrease in anxiety and stress. The exercise group when compared to a control group showed improvement in relation to physical functioning parameters between baseline and post-intervention. Moreover, anthropometric parameters presented only significant differences between groups in fat mass percentage. Nonetheless, no differences were found between groups in weight, body mass index, waist circumference, and self-esteem. CONCLUSION: Our results showed that supervised structured aerobic exercise training could be an effective adjuvant therapy for treating women with depression, reducing depressive symptomatology and improving physical fitness. A key factor of this improvement included strict control of exercise workload parameters and adjustment to each subject's capacity. In our study, due to the sample size there is an increase in the probability of type II errors. PMID- 26522872 TI - Epidemiology of psychiatric disability without posttraumatic stress disorder among U.S. Army and Marine Corps personnel evaluated for disability discharge. AB - Psychiatric disorders are a common reason for disability discharge from the U.S. military. Research on psychiatric disorders in military personnel evaluated for disability discharge has historically focused on posttraumatic stress disorder (PTSD), yet 40% of service members evaluated for a psychiatric-related disability do not have PTSD. This study's objective was to describe characteristics and correlates of disability in Army and Marine Corps personnel diagnosed with psychiatric disorders other than PTSD. In this cross-sectional study, the chi square and Wilcoxon-Mann-Whitney tests compared the distribution of demographic, disability and deployment characteristics between those evaluated for non-PTSD psychiatric disability (N = 9125) versus those evaluated for any other non psychiatric condition (N = 78,072). Multivariate logistic regression examined associations between disability retirement and demographic and disability characteristics. Results show a significantly higher prevalence of disability retirement, deployment, and comorbidity among Army and Marine Corps personnel evaluated for disability discharge related to a non-PTSD psychiatric disorder. Mood disorders, anxiety disorders and dementia were the most commonly evaluated psychiatric disorders. Characteristics associated with increased odds of non-PTSD psychiatric-related disability retirement includes being in the Marine Corps (OR = 1.24), being black (OR = 1.29) or other race (OR = 1.33), having a combat related condition (OR = 2.50), and older age. Service members evaluated for a non PTSD psychiatric disability have similar rates of disability retirement as those evaluated for PTSD, suggesting non-PTSD psychiatric disorders cause a severe and highly compensated disability. Additional research is needed describing the epidemiology of specific non-PTSD psychiatric disorders, such as depression, in service members evaluated for disability discharge. PMID- 26522873 TI - Engineering intracellular biomineralization and biosensing by a magnetic protein. AB - Remote measurement and manipulation of biological systems can be achieved using magnetic techniques, but a missing link is the availability of highly magnetic handles on cellular or molecular function. Here we address this need by using high-throughput genetic screening in yeast to select variants of the iron storage ferritin (Ft) that display enhanced iron accumulation under physiological conditions. Expression of Ft mutants selected from a library of 10(7) variants induces threefold greater cellular iron loading than mammalian heavy chain Ft, over fivefold higher contrast in magnetic resonance imaging, and robust retention on magnetic separation columns. Mechanistic studies of mutant Ft proteins indicate that improved magnetism arises in part from increased iron oxide nucleation efficiency. Molecular-level iron loading in engineered Ft enables detection of individual particles inside cells and facilitates creation of Ft based intracellular magnetic devices. We demonstrate construction of a magnetic sensor actuated by gene expression in yeast. PMID- 26522874 TI - Antihypertensive Medication: On the Right Path? Response. PMID- 26522875 TI - Vascular Healing Evaluated by Intravascular Ultrasound and Optical Coherence Tomography. PMID- 26522876 TI - Prospective Psychiatric Assessment of a Cohort of Spanish Heart Transplant Recipients. PMID- 26522877 TI - Selected Aspects of Mental Health of Elderly Patients with Chronic Back Pain Treated in Primary Care Centers. AB - BACKGROUND: Improvement of the effectiveness and efficiency of chronic back pain therapy is a continuing challenge on an international scale. The aim of the present study was to tentatively assess mental health of patients with chronic back pain treated in primary care centers. MATERIAL AND METHODS: The study enrolled 100 persons over 50 years of age. The back pain group consisted of 53 patients with chronic back pain and the control group consisted of 47 pain-free persons. The assessment of mental health used a Polish version of the international Goldberger's General Health Questionnaire (GHQ-28). ANOVA (1- and 2 factor) analysis of variance, Tukey's test, and Pearson's simple correlation were used to analyze the significance of differences, with the significance level set at alpha=0.05. RESULTS: All patients with chronic back pain, regardless of their age and gender, displayed poorer mental well-being compared to the control group: their overall score was higher by over 7 points than in persons without back pain (F1.96=14.8; p<0.001). Men with back pain were significantly more susceptible to depression than women (F2.96=5.5; p<0.05), compared to the control group. The duration of back pain also showed a significant (p<0.05) direct correlation with the overall mental health score from the questionnaire. Mental health was considerably poorer among patients occasionally (p<0.001) and regularly (p<0.05) consuming analgesics than among persons who did not do so. CONCLUSIONS: The study revealed that mental health was markedly poorer in patients with chronic back pain than in healthy controls. A preliminary assessment of aspects of mental health should be given more attention in the rehabilitation of patients with chronic back pain treated in primary care center outpatient clinics. PMID- 26522878 TI - Inter-nanocarrier and nanocarrier-to-cell transfer assays demonstrate the risk of an immediate unloading of dye from labeled lipid nanocapsules. AB - Release studies constitute a fundamental part of the nanovector characterization. However, it can be difficult to correctly assess the release of lipophilic compounds from lipid nanocarriers using conventional assays. Previously, we proposed a method including an extraction with oil to measure the loading stability of lipophilic dyes in lipid nanocapsules (LNCs). The method indicated a rapid release of Nile Red from LNCs, while the loading of lipophilic carbocyanine dyes remained stable. This method, although interesting for a rapid screening of the fluorescence labeling stability of nanocarriers, is far from what happens in vivo, where lipid acceptor phases are nanostructured. Here, lipophilic dye loading stability has been assessed, by monitoring dye transfer from LNCs toward stable colloidal lipid nanocompartments, i.e. non-loaded LNCs, using new methodology based on size exclusion chromatography (SEC) and Forster Resonance Energy Transfer (FRET). Dye transfer between LNCs and THP-1 cells (as model for circulating cells) has also been studied by FACS. The assays reveal an almost instantaneous transfer of Nile Red between LNCs, from LNCs to THP-1 cells, between THP-1 cells, and a reversal transfer from THP-1 cells to LNCs. On the contrary, there was no detectable transfer of the lipophilic carbocyanine dyes. Dye release was also analyzed using dialyses, which only revealed a very slow release of Nile Red from LNCs, demonstrating the weakness of membrane based assays for investigations of the lipophilic compound loading stability in lipid nanocarriers. These results highlight the importance of using relevant release assays, and the potential risk of an immediate unloading of lipophilic fluorescent dyes from lipid nanocarriers, in the presence of a lipid acceptor nanocompartment. Some misinterpretations of cellular trafficking and in vivo biodistribution of fluorescent nanoparticles should be avoided. PMID- 26522880 TI - Boulders on asteroid Toutatis as observed by Chang'e-2. AB - Boulders are ubiquitously found on the surfaces of small rocky bodies in the inner solar system and their spatial and size distributions give insight into the geological evolution and collisional history of the parent bodies. Using images acquired by the Chang'e-2 spacecraft, more than 200 boulders have been identified over the imaged area of the near-Earth asteroid Toutatis. The cumulative boulder size frequency distribution (SFD) shows a steep slope of -4.4 +/- 0.1, which is indicative of a high degree of fragmentation. Similar to Itokawa, Toutatis probably has a rubble-pile structure, as most boulders on its surface cannot solely be explained by impact cratering. The significantly steeper slope for Toutatis' boulder SFD compared to Itokawa may imply a different preservation state or diverse formation scenarios. In addition, the cumulative crater SFD has been used to estimate a surface crater retention age of approximately 1.6 +/- 0.3 Gyr. PMID- 26522879 TI - Recognition and management of hyperinsulinemic hypoglycemia after bariatric surgery. AB - Hyperinsulinemic hypoglycemia with neuroglycopenia is an increasingly recognized complication of Roux-en-Y gastric bypass (RYGB) due to the changes in gut hormonal milieu. Physicians should be aware of this complication to ensure timely and effective treatment of post-RYGB patients, who present to them with hypoglycemic symptoms. Possible causes of hypoglycemia in these patients include late dumping syndrome, nesidioblastosis and rarely insulinoma. Systematic evaluation including history, biochemical analysis, and diagnostic testing might help in distinguishing among these diagnoses. Continuous glucose monitoring is also a valuable tool, revealing the episodes in the natural environment and can also be used to monitor treatment success. Treatment should begin with strict low carbohydrate diet, followed by medication therapy. Therapy with diazoxide, acarbose, calcium channel blockers and octreotide have been proven to be beneficial, but the response apparently is highly variable. When other treatment options fail, surgical options can be considered. PMID- 26522881 TI - Objective criteria for acceptability and constancy tests of digital subtraction angiography. AB - PURPOSE: Demonstrate an objective procedure to quantify image quality in digital subtraction angiography (DSA) and suggest thresholds for acceptability and constancy tests. METHODS: Series of images were obtained in a DSA system simulating a small (paediatric) and a large patient using the dynamic phantom described in the IEC and DIN standards for acceptance tests of DSA equipment. Image quality was quantified using measurements of contrast-to-noise ratio (CNR). Overall scores combining the CNR of 10-100 mg/ml Iodine at a vascular diameter of 1-4 mm in a homogeneous background were defined. Phantom entrance surface air kerma (Ka,e) was measured with an ionisation chamber. RESULTS: The visibility of a low-contrast vessel in DSA images has been identified with a CNR value of 0.50 +/- 0.03. Despite using 14 times more Ka,e (8.85 vs 0.63 mGy/image), the protocol for large patients showed a decrease in the overall score CNRsum of 67% (4.21 +/- 0.06 vs 2.10 +/- 0.05). The uncertainty in the results of the objective method was below 5%. CONCLUSION: Objective evaluation of DSA images using CNR is feasible with dedicated phantom measurements. An objective methodology has been suggested for acceptance tests compliant with the IEC/DIN standards. The defined overall scores can serve to fix a reproducible baseline for constancy tests, as well as to study the device stability within one acquisition series and compare different imaging protocols. This work provides aspects that have not been included in the recent European guidelines on Criteria for Acceptability of Medical Radiological Equipment. PMID- 26522882 TI - Looking at the dark and bright sides of identity formation: New insights from adolescents and emerging adults in Japan. AB - The aim of the present study was to gain new insights into the dark and bright sides of identity formation with a sample of 1851 Japanese adolescents and emerging adults, applying a three-dimensional model of identity formation (i.e., commitment, in-depth exploration, and reconsideration of commitment). By means of cluster analysis, we identified five statuses that strongly resembled statues extracted in prior research with Western youth: achievement, foreclosure, moratorium, diffusion, and searching moratorium. We found that each status reported a distinct profile in terms of personality and psychosocial problems. Importantly, we found that the searching moratorium status was adaptive in adolescence but not in emerging adulthood. These results suggest that the five statuses are replicable in Japanese adolescents and emerging adults, and that the searching moratorium status presents a combination of the bright and dark sides whose prevalence varies with age. Clinical implications for identity research and intervention programs are discussed. PMID- 26522883 TI - Understanding identity integration: Theoretical, methodological, and applied issues. AB - Identity integration is one of the foundational theoretical concepts in Erikson's (1968) theory of lifespan development. However, the topic is understudied relative to its theoretical and practical importance. The extant research is limited in quantity and scope, and there is considerable heterogeneity in how identity integration is conceptualized and measured. Accordingly, the purpose of this paper is to 1) provide a conceptual discussion of different forms of identity integration 2) highlight the different methodological approaches represented in the literature, and 3) detail the implications of integration for psychological functioning. In particular, we provide a conceptual and methodological discussion of four forms of integration: two that are widely recognized, contextual integration and temporal integration, and two that have received less attention, ego integration and person-society integration. We see this paper as filling a need in the literature for those interested in how complex identity processes are related to psychological functioning. PMID- 26522884 TI - N-Lauroylation during the Expression of Recombinant N-Myristoylated Proteins: Implications and Solutions. AB - Incorporation of myristic acid onto the N terminus of a protein is a crucial modification that promotes membrane binding and correct localization of important components of signaling pathways. Recombinant expression of N-myristoylated proteins in Escherichia coli can be achieved by co-expressing yeast N myristoyltransferase and supplementing the growth medium with myristic acid. However, undesired incorporation of the 12-carbon fatty acid lauric acid can also occur (leading to heterogeneous samples), especially when the available carbon sources are scarce, as it is the case in minimal medium for the expression of isotopically enriched samples. By applying this method to the brain acid soluble protein 1 and the 1-185 N-terminal region of c-Src, we show the significant, and protein-specific, differences in the membrane binding properties of lauroylated and myristoylated forms. We also present a robust strategy for obtaining lauryl free samples of myristoylated proteins in both rich and minimal media. PMID- 26522886 TI - Mid-infrared ultrafast laser pulses induced third harmonic generation in nitrogen molecules on an excited state. AB - We report on generation of third harmonic from nitrogen molecules on the excited state with a weak driver laser pulse at a mid-infrared wavelength. The excited nitrogen molecules are generated using a circularly polarized intense femtosecond pulse which produces energetic electrons by photoionization to realize collisional excitation of nitrogen molecules. Furthermore, since the third harmonic is generated using a pump-probe scheme, it enables investigation of the excited-state dynamics of nitrogen molecules produced under different conditions. We also perform a comparative investigation in excited argon atoms, revealing different decay dynamics of the molecules and atoms from the excited states in femtosecond laser induced filaments. PMID- 26522885 TI - Benzyl alcohol protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes but causes mitochondrial dysfunction and cell death at higher doses. AB - Acetaminophen (APAP) hepatotoxicity is a serious public health problem in western countries. Current treatment options for APAP poisoning are limited and novel therapeutic intervention strategies are needed. A recent publication suggested that benzyl alcohol (BA) protects against APAP hepatotoxicity and could serve as a promising antidote for APAP poisoning. To assess the protective mechanisms of BA, C56Bl/6J mice were treated with 400 mg/kg APAP and/or 270 mg/kg BA. APAP alone caused extensive liver injury at 6 h and 24 h post-APAP. This injury was attenuated by BA co-treatment. Assessment of protein adduct formation demonstrated that BA inhibits APAP metabolic activation. In support of this, in vitro experiments also showed that BA dose-dependently inhibits cytochrome P450 activities. Correlating with the hepatoprotection of BA, APAP-induced oxidant stress and mitochondrial dysfunction were reduced. Similar results were obtained in primary mouse hepatocytes. Interestingly, BA alone caused mitochondrial membrane potential loss and cell toxicity at high doses, and its protective effect could not be reproduced in primary human hepatocytes (PHH). We conclude that BA protects against APAP hepatotoxicity mainly by inhibiting cytochrome P450 enzymes in mice. Considering its toxic effect and the loss of protection in PHH, BA is not a clinically useful treatment option for APAP overdose patient. PMID- 26522887 TI - Primary, large extra-axial chordoma in proximal tibia: a rare case report with literature review and diagnostic implications. AB - Primary extra-axial chordomas have been rarely documented, especially in the appendicular bones. Until now, nine such cases, objectively confirmed with positive brachyury immunostaining, have been reported. A 42-year-old male presented with pain in his right tibial tuberosity (shin) of 2-3 years duration without any associated swelling. He denied complaints related to any other lesion elsewhere in his body. Plain radiograph of his lower limbs revealed a large, eccentric, well-defined, lytic lesion containing internal septae with a narrow zone of transition and a sclerotic medullary border in the upper metaphysis of his right tibia, associated with a pathological fracture. There was no other lesion identified in his spine on radiographic imaging. Biopsy sections revealed a tumour composed of polygonal cells with moderate to abundant eosinophilic to vacuolated/'bubbly' cytoplasm (physaliphorous cells) arranged in lobules within a conspicuous myxoid matrix. By immunohistochemistry, tumour cells were diffusely positive for pan cytokeratin (AE1/AE3), epithelial membrane antigen (EMA), CK19, S100P, meso (HBME1) and Brachyury/T. Diagnosis of an a primary extra-axial chordoma was finally rendered. Subsequently, the patient underwent bone grafting from his iliac crest. The present case constitutes as the 11th documented case of an extra-axial, intraosseous chordoma and the 10th such case occurring in the appendicular bones. Literature review of similar cases; their diagnostic mimics along with diagnostic and therapeutic implications of such cases are discussed herewith. PMID- 26522888 TI - Differential effect of caffeine intake in subjects with genetic susceptibility to Parkinson's Disease. AB - We examined if caffeine intake has a differential effect in subjects with high and low genetic susceptibility to Parkinson's disease (PD), a common neurodegenerative disorder. A case control study involving 812 subjects consisting of PD and healthy controls were conducted. Caffeine intake assessed by a validated questionnaire and genotyping of PD gene risk variant (LRRK2 R1628P) was carried out. Compared to caffeine takers with the wild-type genotype (low genetic susceptibility), non-caffeine takers with R1628P variant (high genetic susceptibility) had a 15 times increased risk of developing PD (OR = 15.4, 95% CI = (1.94, 122), P = 0.01), whereas caffeine takers with R1628P (intermediate susceptibility) had a 3 times risk (OR = 3.07, 95% CI = (2.02, 4.66), P < 0.001). Caffeine intake would significantly reduce the risk of PD much more in those with high genetic susceptibility compared to those with low genetic susceptibility. PMID- 26522889 TI - Bridging the Gap between RF and Optical Patch Antenna Analysis via the Cavity Model. AB - Although optical antennas with a variety of shapes and for a variety of applications have been proposed and studied, they are still in their infancy compared to their radio frequency (rf) counterparts. Optical antennas have mainly utilized the geometrical attributes of rf antennas rather than the analysis tools that have been the source of intuition for antenna engineers in rf. This study intends to narrow the gap of experience and intuition in the design of optical patch antennas by introducing an easy-to-understand and easy-to-implement analysis tool in rf, namely, the cavity model, into the optical regime. The importance of this approach is not only its simplicity in understanding and implementation but also its applicability to a broad class of patch antennas and, more importantly, its ability to provide the intuition needed to predict the outcome without going through the trial-and-error simulations with no or little intuitive guidance by the user. PMID- 26522890 TI - [Current treatments for corneal neovascularization]. AB - The extension of blood vessels into the normally avascular stroma defines corneal neovascularization. Though this phenomenon, pathophysiological and clinical features are well characterized, therapeutic modalities have been hindered by a lack of safe, efficacious and non-controversial treatments. In this literature review, we focus on available therapeutic options in light of recent evidence provided by animal and clinical studies. First, this review will focus on pharmacological treatments that target angiogenesis. The low cost and market availability of bevacizumab make it the first anti-angiogenic therapy choice, and it has demonstrable efficacy in reducing corneal neovascularization when administered topically or subconjunctivally. However, novel anti-angiogenic molecules targeting the intracellular pathways of angiogenesis (siRNA, antisense oligonucleotides) provide a promising alternative. Laser therapy (direct photocoagulation or photo-dynamic therapy) and fine needle diathermy also find a place in the treatment of stabilized corneal neovascularization alone or in association with anti-angiogenic therapy. Additionally, ocular surface reconstruction using amniotic membrane graft or limbal stem cell transplantation is essential when corneal neovascularization is secondary to primary or acquired limbal deficiency. PMID- 26522891 TI - [Epidemiology and clinical characteristics of primary congenital glaucoma]. AB - INTRODUCTION: Primary congenital glaucoma (PCG) is a rare and sight threatening condition. Few large epidemiological studies are available in the literature concerning this condition. The purpose of the study was to evaluate the epidemiological and clinical characteristics of children affected by PCG. PATIENTS AND METHOD: Children affected by PCG, from 1 day to 3 years old at the time of diagnosis were retrospectively included between 1999 and 2014. The analysis concerned the pregnancy, family history, initial referral, clinical presentation with description of the classic findings in this condition, mean age at first consultation, duration of follow-up and presence of a delay in treatment, defined as a delay of over one month from the appearance of clinical signs until diagnosis. Two groups were defined according to age at appearance of the clinical signs: "early" group prior to 2 months old and "late" group beyond 2 months up until 3 years old. RESULTS: One hundred and forty-one eyes of 71 children were included, with 49.3% girls (n=35 children) and 50.7% boys (n=36 children) for a male:female ratio of 1.02. The "early" group included 50 children i.e. 70.3% of the population; the "late" group 21 children or 29.7% of the population. A first-degree family history of congenital glaucoma existed in 28% of cases (n=19). The average age at first consultation was 13.1 months for the entire population, and the mean duration of follow-up was 56.6 months. Involvement was bilateral in 99.3% of cases (n=70 children) and the most frequent clinical sign was buphthalmos in 64.5% of eyes (n=91 eyes). Treatment was delayed in 35.3% of cases (n=25 children). DISCUSSION AND CONCLUSION: This study is of particular relevance because it was performed over a long period and on a large population, considering the rare prevalence of the pathology, and has found epidemiological and clinical data comparable with those available in the literature for similar populations. PMID- 26522892 TI - [Corneal neovascularisation treatments compared: Subconjunctival bevacizumab injections and/or photodynamic therapy]. AB - PURPOSE: To evaluate and compare the efficacy of subconjunctival bevacizumab injections alone, photodynamic therapy alone and combined treatments for reduction of corneal neovascularization. METHODS: This study was conducted as a prospective case series. A total of seven eyes of 7 patients with corneal neovascularization caused by ocular surface disorders including fungal infectious keratitis and penetrating keratoplasty were included in the study. Patients were randomized into the three following groups: patients in group A received a single subconjunctival injection of 10mg (0.4mL) of bevacizumab, patients in group B were treated with photodynamic therapy with verteporfin (6mg/m(2)) to the neovascularized area and those in group C received a subconjunctival injection of bevacizumab and photodynamic therapy 7 days later. Morphological changes in neovascularization were evaluated over 6 months using slit-lamp biomicroscopy and digital corneal photography. A computer-assisted semi-automatic analysis of the area of corneal neovascularization was performed with Image J software. RESULTS: Recession of corneal vessels was observed in all eyes at 1 month post-treatment. The neovascularized surface area in all groups combined showed a decrease in the first month after treatment and this decrease continued up to the 6th month. The surface area of corneal neovascularization decreased by 34.05+/-8.28% in group A (subconjunctival injection of bevacizumab), by 42.06+/-28.36% in group B (photodynamic therapy with verteporfin) and by 51.67+/-18.93% in group C (combined subconjunctival injection of bevacizumab and photodynamic therapy). A combined treatment consisting of a subconjunctival injection followed by a PDT session 7 days later might be more effective for the treatment of corneal neovascularisation. No serious local or systemic adverse events were observed. CONCLUSIONS: Our medium-term results suggest that combined subconjunctival injection of bevacizumab and photodynamic therapy with verteporfin might be used safely and effectively to reduce corneal neovascularization surface. This combined therapy may show a tendency toward greater efficacy than the individual monotherapies. Controlled prospective randomized multicentric trials with a larger sample size are necessary to assess long-term efficacy and to confirm these results. PMID- 26522893 TI - Tityus serrulatus venom--A lethal cocktail. AB - Tityus serrulatus (Ts) is the main scorpion species of medical importance in Brazil. Ts venom is composed of several compounds such as mucus, inorganic salts, lipids, amines, nucleotides, enzymes, kallikrein inhibitor, natriuretic peptide, proteins with high molecular mass, peptides, free amino acids and neurotoxins. Neurotoxins are considered the most responsible for the envenoming syndrome due to their pharmacological action on ion channels such as voltage-gated sodium (Nav) and potassium (Kv) channels. The major goal of this review is to present important advances in Ts envenoming research, correlating both the crude Ts venom and isolated toxins with alterations observed in all human systems. The most remarkable event lies in the Ts induced massive releasing of neurotransmitters influencing, directly or indirectly, the entire body. Ts venom proved to extremely affect nervous and muscular systems, to modulate the immune system, to induce cardiac disorders, to cause pulmonary edema, to decrease urinary flow and to alter endocrine, exocrine, reproductive, integumentary, skeletal and digestive functions. Therefore, Ts venom possesses toxins affecting all anatomic systems, making it a lethal cocktail. However, its low lethality may be due to the low venom mass injected, to the different venom compositions, the body characteristics and health conditions of the victim and the local of Ts sting. Furthermore, we also described the different treatments employed during envenoming cases. In particular, throughout the review, an effort will be made to provide information from an extensive documented studies concerning Ts venom in vitro, in animals and in humans (a total of 151 references). PMID- 26522894 TI - Language sampling for children with and without cochlear implant: MLU, NDW, and NTW. AB - OBJECTIVES: Cochlear implants (CIs) can considerably improve the oral language of prelingual hearing-impaired children. However, because most studies have been performed with English speaking children, available information regarding Persian speaking children is scarce. Therefore, this study compared measures of lexical diversity (numbers of different words and total words), and syntactic complexity (mean length of utterance) in Persian-speaking children with and without CIs. METHODS: A cross-sectional study with 20 children with CIs and 20 typically developing children was conducted. To collect the data, the children's language samples were gathered via picture descriptions. The first 50 utterances were analyzed. RESULTS: All measures were significantly different between children with CIs and their typically developing age-matched peers, whereas no differences between children with CIs and their typically developing hearing age-matched peers were detected (p<0.05). CONCLUSIONS: CIs have been recognized to be one of the most beneficial rehabilitation prostheses because they help children to acquire speech and language abilities similar to their typically developing hearing age-matched peers. After implantation, the performance of children with CIs is similar to the performance of normal children with the same hearing experience. The duration of the hearing experience after the implantation is an important factor for determining the development of speech and language abilities. PMID- 26522895 TI - Development, validation and biomedical applications of stable-isotope dilution GC MS and GC-MS/MS techniques for circulating malondialdehyde (MDA) after pentafluorobenzyl bromide derivatization: MDA as a biomarker of oxidative stress and its relation to 15(S)-8-iso-prostaglandin F2alpha and nitric oxide (NO). AB - Malondialdehyde (MDA, CH2(CHO)2) is one of the best investigated and most frequently measured biomarkers of lipid peroxidation in biological fluids, a constituent of the so called thiobarbituric acid reactive substances (TBARS). The reaction of thiobarbituric acid with MDA and other carbonyl compounds is the basis for the batch TBARS assay, one of the most commonly and widely used assays of oxidative stress. Yet, the TBARS assay lacks specificity even if combined with HPLC separation prior to visible absorbance or fluorescence detection. In this article, we report highly specific and sensitive stable-isotope dilution GC-MS and GC-MS/MS methods for the quantitative determination of MDA in human plasma (0.1 mL). These methods utilize the acidity (pKa, 4.46) of the two methylene H protons of MDA in aqueous solution, which are as acidic as acetic acid. Endogenous MDA in native plasma and the externally added internal standard [1,3 (2)H2]-MDA (d2-MDA, CH2(CDO)2) are derivatized in aqueous acetone (400 MUL) with pentafluorobenzyl (PFB) bromide (10 MUL). The reaction products were identified as C(PFB)2(CHO)2 (molecular weight, 432) and C(PFB)2(CDO)2) (molecular weight, 434), respectively. After solvent extraction with toluene (1 mL) quantification is performed by selected-ion monitoring (SIM) in GC-MS and by selected-reaction monitoring (SRM) in GC-MS/MS in the electron-capture negative-ion chemical ionization (ECNICI) mode. In the SIM mode, the anions [M-PFB](-) at m/z 251 for MDA and m/z 253 for d2-MDA are detected. In the SRM mode, the mass transitions m/z 251 to m/z 175 for MDA and m/z 253 to m/z 177 for d2-MDA are monitored. The method was thoroughly validated in human plasma. Potential interfering substances including anticoagulants and commercially available monovettes commonly used for blood sampling were tested. The lowest MDA concentrations were measured in serum followed by heparinized and EDTA plasma. The GC-MS and GC-MS/MS methods were found to be specific, precise, accurate and sensitive. Thus, the LOD of the GC MS/MS method was determined to be 2 amol (2 * 10(-18)mol) MDA. The GC-MS/MS method is exceedingly useful in clinical settings. We report several biomedical applications and discuss the utility of circulating MDA as a biomarker of lipid peroxidation, especially in long-term clinical studies, and its relation to the F2-isoprostane 15(S)-8-iso-prostaglandin F2alpha and nitric oxide (NO). PMID- 26522896 TI - Ureteropelvic junction obstruction in children by polar vessels. Is laparoscopic vascular hitching procedure a good solution? Single center experience on 35 consecutive patients. AB - PURPOSE: We report the results of laparoscopic vascular hitching (LVH) in a series of children with ureteropelvic junction obstruction (UPJO) owing to aberrant lower polar crossing vessels (CV). Our aim is to confirm if LVH associated with intraoperative diuretic test (DT) represents a good procedure to treat extrinsic-UPJO by CV. In order to confirm the relief of the obstruction we suggest performing an intraoperative DT. MATERIALS AND METHODS: In our department from 2006 to 2014, 120 patients were treated for both extrinsic and intrinsic UPJO. 85 (30 females, 55 males) presented an intrinsic obstruction and underwent dismembered pyeloplasty (AHDP), 61 open, 16 laparoscopic, 8 retroperitoneoscopic. 35 (23 males, 12 females) were studied for a suspected extrinsic-UPJO: 30 were treated with LVH (modified Hellstrom vascular hitch). Intraoperative-DT was performed in all patients before and after vessel transpositions confirming the UPJO and eventual relief after the procedure. We included in the study only patients with suspicion of vascular extrinsic-UPJO. Average age at surgery was 7.5years. Symptoms of presentation were recurrent abdominal/flank pain and hematuria. All patients presented ultrasound (US) detection of hydronephrosis. Preoperative diagnostic studies include: US/doppler scan, MAG3 renogram, urography, functional magnetic resonance urography (fMRU) and CT scan. RESULTS: 28 out 35 patients had a correct preoperative diagnosis, and the remaining needed an intraoperative diagnosis confirmation. All 35 patients had an intraoperative DT: 30 patients underwent LVH (positive-DT); 3 patients (negative-DT) underwent laparoscopic-AHDP for intrinsic-UPJO; two with positive-DT and nonobstructive CV, had no surgical treatment. Median operating time was 95min; mean hospital stay was 4days. At 12-84months follow-up 29 patients remained symptoms-free, one needed after two years a laparoscopic-AHDP. CONCLUSIONS: According our experience, LVH associated with intraoperative-DT may be considered a safe procedure to treat extrinsic-UPJO by CV in carefully selected patients. In particular, the very low incidence of relapse suggest that in suspicion of extrinsic-UPJO, performing intraoperative-DT after CV transposition allows to exclude intrinsic-UPJO confirming that the LVH-procedure has relieved the pelvic obstruction, precluding the need for AHDP. PMID- 26522897 TI - Health-related quality of life experiences among children and adolescents born with esophageal atresia: Development of a condition-specific questionnaire for pediatric patients. AB - BACKGROUND/PURPOSE: The aims were to present the framework for the development a condition-specific health-related quality-of-life (HRQOL) questionnaire for children with esophageal atresia (EA) and to describe HRQOL experiences reported by children and by their parents. METHODS: Utilizing the well-established DISABKIDS methodology, standardized focus group discussions were held and transcribed. HRQOL experiences were identified, content analyzed and evaluated using descriptive statistics. RESULTS: 30 families (18 children 8-17years, 32 parents of children 2-17years) participated in ten focus group discussions. 1371 HRQOL experiences were identified referencing social, emotional and physical aspects of eating and drinking (n=368), relationships with other people (n=283), general life issues; physical activity, sleep and general health (n=202), communicative/interactive processes of one's health condition (n=161), body issues (n=109), bothersome symptoms (n=81), impact of health care use/medical treatment (n=78), confidence in oneself and in the future (n=65) and difficulties because of concomitant anomalies (n=24). A basis of two age-related HRQOL questionnaires for children with EA (2-7years, 8-17years) was subsequently constructed. CONCLUSIONS: EA interacts with various aspects of the child's life. In addition to HRQOL issues of eating and drinking, social dimensions like relationships and interactions with other people seem to be prominent condition specific HRQOL parameters. The settings for the development of the first condition-specific HRQOL questionnaires for patients with EA are established. PMID- 26522898 TI - Ultrasound guided percutaneous internal jugular vein access in neonatal intensive care unit patients. AB - BACKGROUND/PURPOSE: Internal jugular vein (IJV) access is commonly performed in neonates and infants with open cut-down method. We report the results of ultrasound guided percutaneous venous access in newborn patients in the neonatal intensive care unit (NICU). METHODS: We retrospectively examined the medical records of NICU patients who underwent therapeutic percutaneous IJV access under ultrasound guidance from October 2015 to May 2015. Under general anesthesia, IJV was punctured with a 21 gauge needle after identification by ultrasound. Catheter was inserted with Seldinger's technique. RESULTS: Twelve ultrasound-guided percutaneous IJV accesses were performed in eight patients and eleven cases were successful (91.6%). Procedure was performed at the median age of 4.5days (range 2days-47days). Median body weight was 3030g (range 1760g-4100g) and median operative time was 19minutes (range 8minutes-80minutes). Indications for central venous access were hyperammonemia caused by urea cycle defect (four patients) and mitochondrial disease (one patient), acute kidney injury (two patients), and congenital renal dysgenesis (one patient). Catheters were inserted in the right IJV in nine cases while two cases were done on the left IJV. All catheters functioned normally. Seven out of seven cases that were examined for venous patency by ultrasonography after catheter removal showed patent IJV. Among these seven cases, four reinsertions were attempted and successfully performed. There was one complication of hemopericardium with cardiac tamponade which is thought to be caused by direct injury from the guidewire. The patient underwent pericardiocentesis. CONCLUSION: Ultrasound guided IJV access in NICU patients can be performed safely and is associated with preserved venous patency after catheter removal. PMID- 26522899 TI - Predictors of Functional Outcome Following Stroke. AB - Predicting functional outcome in stroke is challenging to most clinicians, partly because of the complexity of the condition and also because of the lack of validated prognostic models. The strongest predictors of functional outcome are age and motor function at stroke onset. There is a growing literature on predicting recovery of upper limb after stroke; however, literature on prediction of language recovery remains sparse. This review covers the current status of predicting functional outcome after stroke focusing on recovery of activities of daily living, ambulation, upper limb use, and aphasia. Use of clinical factors, imaging, and neurophysiological measures are discussed. PMID- 26522901 TI - Hemiparetic Gait. AB - The most common pattern of walking impairment poststroke is hemiparetic gait, which is characterized by asymmetry associated with an extensor synergy pattern of hip extension and adduction, knee extension, and ankle plantar flexion and inversion. There are characteristic changes in the spatiotemporal, kinematic and kinetic parameters, and dynamic electromyography patterns in hemiparesis, which may be assessed most accurately in a motion studies laboratory. An understanding of normal human gait is necessary to assess the complex interplay of motor, sensory, and proprioceptive loss; spasticity; and/or ataxia on hemiparetic gait. PMID- 26522902 TI - Spasticity Management After Stroke. AB - Many poststroke survivors develop spasticity. Spasticity is usually associated with other neurologic impairments, in particular paresis, which complicate the evaluation of its consequences and of treatment outcomes. The diagnosis and the assessment of spasticity are based on clinical examination, in particular resistance to passive movement and abnormal involuntary muscle contraction. Nonpharmacologic and pharmacologic treatments are commonly combined to manage spasticity, based on prespecified goals. There is evidence supporting the effectiveness and safety of most medications commonly used to treat spasticity; however, more evidence is needed regarding functional outcomes and the impact of combining treatment modalities. PMID- 26522903 TI - Hemiplegic Shoulder Pain. AB - Hemiplegic shoulder pain is a common complaint for stroke survivors. Many pathologies are included in the diagnosis of hemiplegic shoulder pain, and many with shoulder pain have a multifactorial cause. This article provides rehabilitation specialists with an approach to evaluation and management of those with hemiplegic shoulder pain. PMID- 26522900 TI - Upper Limb Motor Impairment After Stroke. AB - Understanding poststroke upper limb impairment is essential to planning therapeutic efforts to restore function. However, determining which upper limb impairment to treat and how is complex because the impairments are not static and multiple impairments may be present simultaneously. How impairments contribute to upper limb dysfunction may be understood by examining them from the perspective of their functional consequences. There are 3 main functional consequences of impairments on upper limb function: (1) learned nonuse, (2) learned bad use, and (3) forgetting as determined by behavioral analysis of tasks. The impairments that contribute to each of these functional limitations are described. PMID- 26522904 TI - Poststroke Communication Disorders and Dysphagia. AB - Communication and swallowing disorders are common after stroke. Targeted surveillance followed by prompt evaluation and treatment is of paramount importance. The overall goals of rehabilitation for impaired swallowing and communication and swallowing deficits may differ based on the specific deficits caused by the stroke but the main goal is always to improve the patient's everyday interpersonal interactions and optimize participation in society. Fortunately, therapeutic or compensatory interventions can decrease the effects that communication and swallowing deficits have on the quality of life of stroke survivors. PMID- 26522905 TI - Neuropharmacology of Poststroke Motor and Speech Recovery. AB - Almost 7 million adult Americans have had a stroke. There is a growing need for more effective treatment options as add-ons to conventional therapies. This article summarizes the published literature for pharmacologic agents used for the enhancement of motor and speech recovery after stroke. Amphetamine, levodopa, selective serotonin reuptake inhibitors, and piracetam were the most commonly used drugs. Pharmacologic augmentation of stroke motor and speech recovery seems promising but systematic, adequately powered, randomized, and double-blind clinical trials are needed. At this point, the use of these pharmacologic agents is not supported by class I evidence. PMID- 26522906 TI - Robotic Therapy and the Paradox of the Diminishing Number of Degrees of Freedom. AB - There has been remarkable growth in the development and application of robotics to ameliorate or remediate impairment. This growth is associated with a) the understanding that plasticity is a fundamental property of the adult human brain and might be harnessed to remap or create new neural pathways and b) that robots that can safely interact with humans and assist human performance. This article discusses whether robotic therapy has achieved a level of maturity to justify its broad adoption as a rehabilitative tool. How to improve outcomes further and how to select degrees of freedom to optimize care to particular patients is also discussed. PMID- 26522907 TI - The Split-Belt Walking Paradigm: Exploring Motor Learning and Spatiotemporal Asymmetry Poststroke. AB - Although significant effort is concentrated toward gait retraining during stroke rehabilitation; 33% of community-dwelling individuals following stroke continue to demonstrate gait asymmetries following participation in conventional rehabilitation. Recent studies utilizing the split-belt treadmill indicate that subjects after stroke retain the ability to learn a novel locomotor pattern. Through the use of error augmentation, this locomotor pattern can provide a temporary improvement in symmetry, which can be exploited through repetitive task specific locomotor training. This article reviews findings from this experimental paradigm in chronic stroke survivors and discusses the future questions to be addressed in order to provide optimal rehabilitation interventions. PMID- 26522908 TI - Integrating Mental Practice with Task-specific Training and Behavioral Supports in Poststroke Rehabilitation: Evidence, Components, and Augmentative Opportunities. AB - Stroke remains a leading cause of death, with most survivors experiencing long term deficits in motor function. Upper extremity (UE) hemiparesis constitutes one of the most common and disabling poststroke impairments. Many contemporary rehabilitative methods target reacquisition of UE motor skills. One such intervention is mental practice (MP), which involves mental rehearsal without physical execution of the movement. MP has not been consistently integrated into clinical environments. This article discusses the scientific rationale for MPs, highlights evidence supporting their use, discusses components of the repetitive task-specific practice regimens accompanying MP, and discusses possible augmentative strategies and areas for research. PMID- 26522909 TI - Neuromuscular Electrical Stimulation for Motor Restoration in Hemiplegia. AB - This article reviews the most common therapeutic and neuroprosthetic applications of neuromuscular electrical stimulation (NMES) for upper and lower extremity stroke rehabilitation. Fundamental NMES principles and purposes in stroke rehabilitation are explained. NMES modalities used for upper and lower limb rehabilitation are described, and efficacy studies are summarized. The evidence for peripheral and central mechanisms of action is also summarized. PMID- 26522910 TI - Stroke Rehabilitation Using Virtual Environments. AB - This review covers the rationale, mechanisms, and availability of commercially available virtual environment-based interventions for stroke rehabilitation. It describes interventions for motor, speech, cognitive, and sensory dysfunction. Also discussed are the important features and mechanisms that allow virtual environments to facilitate motor relearning. A common challenge is the inability to translate success in small trials to efficacy in larger populations. The heterogeneity of stroke pathophysiology has been blamed, and experts advocate for the study of multimodal approaches. Therefore, this article also introduces a framework to help define new therapy combinations that may be necessary to address stroke heterogeneity. PMID- 26522913 TI - Stroke Rehabilitation. PMID- 26522911 TI - Tailoring Brain Stimulation to the Nature of Rehabilitative Therapies in Stroke: A Conceptual Framework Based on their Unique Mechanisms of Recovery. AB - Despite showing early promise, several recent clinical trials of noninvasive brain stimulation (NIBS) failed to augment rehabilitative outcomes of the paretic upper limb. This article addresses why pairing NIBS with unilateral approaches is weakly generalizable to patients in all ranges of impairments. The article also addresses whether alternate therapies are better suited for the more impaired patients, where they may be more feasible and offer neurophysiologic advantages not offered with unilateral therapies. The article concludes by providing insight on how to create NIBS paradigms that are tailored to distinctly augment the effects of therapies across patients with varying degrees of impairment. PMID- 26522914 TI - Companion animals and well-being in palliative care nursing: a literature review. AB - AIMS AND OBJECTIVES: To evaluate and critique current knowledge regarding the role of animals in palliative care. To explore the impact that animals may have on the well-being of individuals and to identify gaps in the evidence base. BACKGROUND: There is recognition that having a companion animal will affect patient experience. Similarly, there has been some previous exploration on the use of specific animal assisted therapies for patients with different healthcare needs. DESIGN: A literature review was conducted to identify published and unpublished research about companion animals or animal-assisted therapy in palliative and/or end-of-life care. The primary objective was to explore the impact of animals on well-being at the end of life. METHODS: A search for literature was carried out using a variety of databases and different combinations of search terms linked to animals in palliative care. Included works were critically appraised and thematically analysed. RESULTS: A limited range of literature was identified. From the small number of studies included in the review (n = 4), it appears that there is some evidence of animals (either companion animals or those used specifically to enhance care) having a positive impact on the patient experience. CONCLUSION: This study suggests that animals play a large part in the lives of people receiving palliative care. Using animals to support care may also offer some benefits to the patient experience. However, there appears to be a dearth of high-quality literature in this area. More research is therefore required. RELEVANCE TO CLINICAL PRACTICE: Nurses providing palliative care need to be aware of the part that a companion animal may play in the life of patients. There may also be the opportunity for nurses in some settings to integrate animal therapy into their provision of palliative care. PMID- 26522915 TI - Efficacy of two mouthwashes on 3-day supragingival plaque regrowth: a randomized crossover clinical trial. AB - BACKGROUND: The aim of this study was to evaluate the antiplaque effects of an alcohol-free essential oil (alcohol-free EO) mouthwash and an amine fluoride/stannous fluoride with zinc lactate (SnFl-Zn) mouthwash compared to a positive control of chlorhexidine (CHX) mouthwash, using an in vivo plaque regrowth model of 3 days. MATERIALS AND METHODS: The study was designed as a double-masked, randomized, crossover clinical trial, involving 20 volunteers to compare two different mouthwashes, using a 3-day plaque accumulation model. After receiving thorough professional prophylaxis at baseline, over the next 3 days, each volunteer refrained from all oral hygiene measures and performed two daily rinses with 20 ml of the test mouthwashes. A 0.20% CHX rinse served as a positive control. At the end of each experimental period, plaque was assessed, and the panellists completed a questionnaire. Each subject underwent a 14-day washout period, and then, there was another allocation. RESULTS: The SnFl-Zn mouthwash has shown a better inhibitory activity on plaque regrowth compared to the alcohol free EO mouthwash in the whole mouth (plaque index = 1.93 against 2.45, respectively), but there was less of an effect compared to the CHX group, with an overall plaque index of 1.41. The differences of 0.52 between alcohol-free EO and SnFl-Zn and between SnFl-Zn and CHX and of 0.96 between alcohol-free EO and CHX were all statistically significant (P < 0.001). CONCLUSION: The alcohol-free EO mouthwash seemed to have less of an inhibiting effect on plaque regrowth than the amine fluoride/SnFl-Zn mouthwash and the CHX control. PMID- 26522917 TI - Evaluation of the activity and substrate specificity of the human SENP family of SUMO proteases. AB - Protein modification with the small ubiquitin-like modifier (SUMO) is a reversible process regulating many central biological pathways. The reversibility of SUMOylation is ensured by SUMO proteases many of which belong to the sentrin/SUMO-specific protease (SENP) family. In recent years, many advances have been made in allocating SENPs to specific biological pathways. However, due to difficulties in obtaining recombinant full-length active SENPs for thorough enzymatic characterization, our knowledge on these proteases is still limited. In this work, we used in vitro synthesized full-length human SENPs to perform a side by-side comparison of their activities and substrate specificities. ProSUMO1/2/3, RanGAP1-SUMO1/2/3 and polySUMO2/3 chains were used as substrates in these analyses. We found that SENP1 is by far the most versatile and active SENP whereas SENP3 stands out as the least active of these enzymes. Finally, a comparison between the activities of full-length SENPs and their catalytic domains suggests that in some cases their non-catalytic regions influence their activity. PMID- 26522918 TI - Notch1 endocytosis is induced by ligand and is required for signal transduction. AB - The Notch signalling pathway is widely utilised during embryogenesis in situations where cell-cell interactions are important for cell fate specification and differentiation. DSL ligand endocytosis into the ligand-expressing cell is an important aspect of Notch signalling because it is thought to supply the force needed to separate the Notch heterodimer to initiate signal transduction. A functional role for receptor endocytosis during Notch signal transduction is more controversial. Here we have used live-cell imaging to examine trafficking of the Notch1 receptor in response to ligand binding. Contact with cells expressing ligands induced internalisation and intracellular trafficking of Notch1. Notch1 endocytosis was accompanied by transendocytosis of ligand into the Notch1 expressing signal-receiving cell. Ligand caused Notch1 endocytosis into SARA positive endosomes in a manner dependent on clathrin and dynamin function. Moreover, inhibition of endocytosis in the receptor-expressing cell impaired ligand-induced Notch1 signalling. Our findings resolve conflicting observations from mammalian and Drosophila studies by demonstrating that ligand-dependent activation of Notch1 signalling requires receptor endocytosis. Endocytosis of Notch1 may provide a force on the ligand:receptor complex that is important for potent signal transduction. PMID- 26522916 TI - Heterogeneity of miR-10b expression in circulating tumor cells. AB - Circulating tumor cells (CTCs) in the blood of cancer patients are recognized as important potential targets for future anticancer therapies. As mediators of metastatic spread, CTCs are also promising to be used as 'liquid biopsy' to aid clinical decision-making. Recent work has revealed potentially important genotypic and phenotypic heterogeneity within CTC populations, even within the same patient. MicroRNAs (miRNAs) are key regulators of gene expression and have emerged as potentially important diagnostic markers and targets for anti-cancer therapy. Here, we describe a robust in situ hybridization (ISH) protocol, incorporating the CellSearch((r)) CTC detection system, enabling clinical investigation of important miRNAs, such as miR-10b on a cell by cell basis. We also use this method to demonstrate heterogeneity of such as miR-10b on a cell-by cell basis. We also use this method to demonstrate heterogeneity of miR-10b in individual CTCs from breast, prostate and colorectal cancer patients. PMID- 26522919 TI - Representing energy efficiency diagnosis strategies in cognitive work analysis. AB - This article describes challenges encountered in applying Jens Rasmussen's Cognitive Work Analysis (CWA) framework to the practice of energy efficiency Monitoring & Targeting (M&T). Eight theoretic issues encountered in the analysis are described with respect to Rasmussen's work and the modeling solutions we adopted. We grappled with how to usefully apply Work Domain Analysis (WDA) to analyze categories of domains with secondary purposes and no ideal grain of decomposition. This difficulty encouraged us to pursue Control Task (ConTA) and Strategies (StrA) analysis, which are under-explored as bases for interface design. In ConTA we found M&T was best represented by two interlinked work functions; one controlling energy, the other maintaining knowledge representations. From StrA, we identified a popular representation-dependent strategy and inferred information required to diagnose faults in system performance and knowledge representation. This article presents and discusses excerpts from our analysis, and outlines their application to diagnosis support tools. PMID- 26522921 TI - Entitled vengeance: A meta-analysis relating narcissism to provoked aggression. AB - Narcissism has long been used to predict aggressive or vengeful responses to provocations from others. The strength of this relation can, however, vary widely from study to study. Narcissism and revenge were examined in 84 independent samples (N = 11297), along with the moderating role of sample type (i.e., child/adolescent, prisoner, undergraduate, or general samples), type of narcissism measure used (i.e., Narcissistic Personality Inventory, Psychological Entitlement Scale, Short D3, etc.), the nature of the provocation, and the type of provoked aggression examined. Narcissism was positively related to provoked aggression across studies (rho = .25), but that relation was stronger in child/adolescent samples (rho = .36) and when measures of entitlement or vulnerable narcissism were employed (rho = .29). Implications for practical research, as well as neglected areas of research on narcissism and provoked aggression are discussed. Aggr. Behav. 42:362-379, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26522920 TI - Evolving pneumococcal serotypes and sequence types in relation to high antibiotic stress and conditional pneumococcal immunization. AB - In Taiwan, beginning in 2013, the 13-valent pneumococcal conjugate vaccine (PCV13) was provided free of charge to children 2-5 years of age. In 2014, this was extended to children 1-5 years old. During 2012-2014, 953 cases of culture confirmed pneumococcal disease (CCPD), including 104 invasive pneumococcal disease (IPD), were prospectively identified and analyzed at a 3,700-bed hospital in Taiwan. From 2012 to 2014, the incidence per 10,000 admissions decreased from 26.7 to 20.4 for CCPD (P < 0.001) and from 3.2 to 1.9 for IPD (P < 0.05). Significant reduction of PCV13 serotypes was firstly noted in children in 2013 and extended to both paediatric and adult populations in 2014. Simultaneously, the incidence per 10,000 admissions of non-PCV13 serotypes increased from 6.1 in 2012 to 9.3 in 2014 (P < 0.005). The most prevalent non-PCV13 serotypes were 15A, 15B, and 23A, each containing a predominant clone, ST63(15A), ST83(15B), and ST338(23A). From 2012 to 2014, isolates with penicillin minimum inhibitory concentrations >2 mg/L decreased from 27.8% to 8.1% (P < 0.001) among all isolates. PCV13 immunization in young children demonstrated an early protective effect in all ages. However, in the elderly, the effect was compromised by an emergence of non-PCV13 serotypes. PMID- 26522922 TI - ESPEN guidelines on nutrition in dementia. AB - BACKGROUND: Older people suffering from dementia are at increased risk of malnutrition due to various nutritional problems, and the question arises which interventions are effective in maintaining adequate nutritional intake and nutritional status in the course of the disease. It is of further interest whether supplementation of energy and/or specific nutrients is able to prevent further cognitive decline or even correct cognitive impairment, and in which situations artificial nutritional support is justified. OBJECTIVE: It is the purpose of these guidelines to cover these issues with evidence-based recommendations. METHODS: The guidelines were developed by an international multidisciplinary working group in accordance with officially accepted standards. The GRADE system was used for assigning strength of evidence. Recommendations were discussed, submitted to Delphi rounds and accepted in an online survey among ESPEN members. RESULTS: 26 recommendations for nutritional care of older persons with dementia are given. In every person with dementia, screening for malnutrition and close monitoring of body weight are recommended. In all stages of the disease, oral nutrition may be supported by provision of adequate, attractive food in a pleasant environment, by adequate nursing support and elimination of potential causes of malnutrition. Supplementation of single nutrients is not recommended unless there is a sign of deficiency. Oral nutritional supplements are recommended to improve nutritional status but not to correct cognitive impairment or prevent cognitive decline. Artificial nutrition is suggested in patients with mild or moderate dementia for a limited period of time to overcome a crisis situation with markedly insufficient oral intake, if low nutritional intake is predominantly caused by a potentially reversible condition, but not in patients with severe dementia or in the terminal phase of life. CONCLUSION: Nutritional care and support should be an integral part of dementia management. In all stages of the disease, the decision for or against nutritional interventions should be made on an individual basis after carefully balancing expected benefit and potential burden, taking the (assumed) patient will and general prognosis into account. PMID- 26522924 TI - Opioid pathways activation mediates the activity of nicorandil in experimental models of nociceptive and inflammatory pain. AB - We have previously demonstrated that nicorandil inhibits the second phase of the nociceptive response induced by formaldehyde. In the present study, we evaluated the effects induced by nicorandil in other models of nociceptive and inflammatory pain in mice and also whether opioid pathways activation mediates its activity. As we have previously demonstrated, per os (p.o.) administration of nicorandil (50, 100 or 150mg/kg; -1h) inhibited the second phase of the nociceptive response induced by intraplantar (i.pl.) injection of formaldehyde. Nicorandil (50, 100 or 150mg/kg; p.o., -1h) also exhibited activity in models of inflammatory pain induced by i.pl. injection of carrageenan (300MUg) and nociceptive pain induced by exposure to noxious heat (50 degrees C). Intraperitoneal (i.p.) administration of the opioid antagonist naltrexone (1, 5 or 10mg/kg, -30min) attenuated or abolished the antinociceptive activity of nicorandil (100mg/kg, p.o.) in the three experimental pain models. In conclusion, we demonstrate that nicorandil exhibits activity in different models of nociceptive and inflammatory pain. The demonstration that the antinociceptive effect induced by nicorandil is markedly attenuated by an opioid antagonist provides solid information about an important mechanism mediating the activity of this antianginal drug. Altogether, our data suggest that the clinical pain relief induced by nicorandil in heart ischemic conditions may result from both vasodilation and intrinsic analgesic activity. PMID- 26522923 TI - Oral supplement enriched in HMB combined with pulmonary rehabilitation improves body composition and health related quality of life in patients with bronchiectasis (Prospective, Randomised Study). AB - BACKGROUND & AIMS: Pulmonary Rehabilitation (PR) is recommended for bronchiectasis but there is no data about its effect on body composition. The aim of this study is to assess the effect of Pulmonary Rehabilitation (PR) for 12 weeks in normally-nourished non-cystic-fibrosis bronchiectasis patients compared with the effect of PR plus a hyperproteic oral nutritional supplement enriched with beta-hydroxy-beta-methylbutyrate (HMB) on body composition, muscle strength, quality of life and serum biomarkers. METHODS: single center randomized controlled trial, parallel treatment design: Participants were randomly assigned to receive PR for 12 weeks or PR plus ONS (PRONS) (one can per day). Outcome assessments were performed at baseline, 12 weeks and 24 weeks: body composition (Dual-energy X-Ray Absorptiometry (DEXA), mid-arm muscle circumference (MAMC), phase angle by Bio-impedance), health related quality of life (Spanish QOL-B V3.0, Physical Functioning Scale), handgrip strength, diet questionnaire, and plasma levels of prealbumin, myostatin and somatomedin-c. RESULTS: Thirty patients were randomized (15 per group) without differences in clinical and respiratory variables. In the PRONS group bone mineral density (BMD), mean and maximum handgrip dynamometry, MAMC, QOLB and prealbumin were significantly increased from baseline at 12 and 24 weeks and Fat free Mass (FFM) and FFM index, at 12 weeks. In the PR group only mean handgrip dynamometry and prealbumin were significantly increased at 12 and 24 weeks. In both groups plasma myostatin was reduced at 12 weeks (without significant differences). CONCLUSION: The addition of a hyperproteic ONS enriched with HMB to Pulmonary Rehabilitation could improve body composition, BMD, muscle strength and health related quality of life in bronchiectasis patients. Clinical Trials Number NCT02048397. PMID- 26522925 TI - Compound C inhibits in vitro angiogenesis and ameliorates thrombin-induced endothelial barrier failure. AB - Compound C (comp. C) is a cell-permeable pyrrazolopyrimidine derivative and widely used as adenosine monophosphate-activated protein kinase (AMPK) inhibitor to characterise the role of AMPK in various physiological processes. However, its AMPK-independent effects have also been reported. In the present study we investigated the effects of moderate dose (1-10MUM) comp. C on endothelial cell (EC) proliferation, in vitro angiogenesis, and endothelial barrier function. Comp. C was unable to inhibit AMPK phosphorylation (activation) induced by metformin and A-769662 in ECs even at concentration of 10MUM. At lower concentration (1MUM), comp. C inhibited and potentiated the inhibitory effects of metformin and A-769662 on EC proliferation, migration, tube formation, and sprouting without inducing apoptosis. However, at higher concentration (10MUM), it strongly induced apoptosis as measured by enhanced caspase 3/7 activity. Moreover, comp. C antagonised thrombin-induced EC hyperpermeability accompanied by activation of Rac1 and strengthening of adherens junctions (AJs). This EC barrier protective effect was not affected by the presence of AMPK activators. The data of the present study demonstrate that long-term treatment of ECs with low concentration comp. C inhibits EC proliferation and angiogenesis without induction of apoptosis. While short-term incubation antagonises thrombin-induced EC hyperpermeability presumably via Rac1-dependent strengthening of AJs. Furthermore, higher concentration of comp. C (10MUM or above) is toxic for ECs and warns that this agent should be used with caution to demonstrate the AMPK mediated effects. PMID- 26522926 TI - Sparstolonin B inhibits lipopolysaccharide-induced inflammation in 3T3-L1 adipocytes. AB - Sparstolonin B (SsnB), an isocoumarin compound isolated from the tubers of both Sparganium stoloniferum and Scirpus yagara, has been reported to have anti inflammatory effects. However, whether SsnB has anti-inflammatory effects on LPS stimulated 3T3-L1 adipocytes remains unclear. In this study, we investigated the effects of SsnB on adipocyte inflammation in 3T3-L1 adipocytes and anti-obesity properties in high fat diet (HFD)-induced obese rats. 3T3-L1 adipocytes were pretreated with SsnB 1h before LPS treatment. The expression of MCP-1, IL-6, TNF alpha, and IL-10 were measured by qRT-PCR and ELISA. The expression of PPAR gamma, TLR4 and NF-kappaB were detected by western blotting. SsnB was administered to HFD-induced obese rats to confirm its effects in vivo. Our results showed that SsnB dose-dependently inhibited LPS-induced MCP-1, IL-6, and TNF-alpha production. SsnB was found to inhibit LPS-induced TLR4 expression and NF-kappaB activition. Furthermore, SsnB was found to activate PPAR-gamma and the inhibitory effects of SsnB on MCP-1, IL-6, and TNF-alpha production can be reversed by PPAR-gamma antagonist GW9662. In vivo, SsnB was found to reduce the body weight of rats fed with HFD. SsnB also inhibited the levels of serum triglyceride (TG) and cholesterol (TC) induced by HFD. In conclusion, the results suggested that SsnB could reduce HFD-induced obesity in rats and inhibited LPS induced cytokines production in 3T3-L1 adipocytes by activating PPAR-gamma. PMID- 26522927 TI - Cardio-protective effects of combined l-arginine and insulin: Mechanism and therapeutic actions in myocardial ischemia-reperfusion injury. AB - Reduced nitric oxide (NO) bioavailability plays a central role in the pathogenesis of myocardial ischemia-reperfusion injury (I-R), and reduced l arginine transport via cationic amino acid transporter-1 is a key contributor to the reduced NO levels. Insulin can increase NO levels by increasing the transport of its substrate l-arginine but insulin alone exerts minimal cardiac protection in I-R. We hypothesized that combined insulin and l-arginine may provide cardioprotective effects in the setting of myocardial I-R. The effect of supplemental insulin, l-arginine and the combination was examined in cardiomyocytes exposed to hypoxia/reoxygenation and in isolated perfused mouse hearts undergoing ischemia/reperfusion. When compared to controls, cardiomyocytes treated upon reoxygenation with 1nM insulin+1mM l-arginine exhibited significant (all P<0.05) improvements in NO generation and mitochondrial membrane potential, with a concomitant fall in reactive oxygen species production and LDH release. Insulin also increased l-arginine uptake following hypoxia-reoxygenation (P<0.05; n=4-6). In langendorff perfused isolated mouse hearts, combined l-arginine insulin treatment upon reperfusion significantly (all P<0.05; n=9-11) improved recovery of left ventricular developed pressure, rate pressure product and end diastolic pressure following ischemia, independent of any changes in post ischemic coronary flow, together with significantly lower LDH release. The observed improvements were greater than l-arginine or insulin treatment alone. In isolated cardiomyocytes (n=3-5), 1nM insulin caused cationic amino acid transporter-1 to redistribute to the cellular membrane from the cytosol and the effects of insulin on l-arginine uptake were partially dependent on the PI3K/Akt pathway. l-arginine-insulin treatment may be a novel strategy to ameliorate I-R injury. PMID- 26522928 TI - Berberine treatment prevents cardiac dysfunction and remodeling through activation of 5'-adenosine monophosphate-activated protein kinase in type 2 diabetic rats and in palmitate-induced hypertrophic H9c2 cells. AB - Diabetic cardiomyopathy is the major cause of death in type 2 diabetic patients. Berberine is an isoquinoline alkaloid extract from traditional chinese herbs and its hypoglycemic and hypolipidemic effects make it a promising drug for treatment of type 2 diabetes. We examined if berberine improved cardiac function and attenuated cardiac hypertrophy and fibrosis in high fat diet and streptozotocin induced-type 2 diabetic rats in vivo and reduced expression of hypertrophy markers in palmitate-induced hypertrophic H9c2 cells in vitro. Treatment of diabetic animals with berberine partially improved cardiac function and restored fasting blood insulin, fasting blood glucose, total cholesterol, and triglyceride levels to that of control. In addition, berberine treatment of diabetic animals increased cardiac 5'-adenosine monophosphate-activated protein kinase (AMPK) and protein kinase B (AKT) activation and reduced glycogen synthase kinase 3 beta (GSK3beta) activation compared to control. Palmitate incubation of H9c2 cells resulted in cellular hypertrophy and decreased expression of alpha-myosin heavy chain (alpha-MHC) and increased expression of beta-myosin heavy chain (beta-MHC) compared to controls. Berberine treatment of palmitate-incubated H9c2 cells reduced hypertrophy, increased alpha-MHC expression and decreased beta-MHC expression. In addition, berberine treatment of palmitate-incubated H9c2 cells increased AMPK and AKT activation and reduced GSK3beta activation. The presence of the AMPK inhibitor Compound C attenuated the effects of berberine. The results strongly indicate that berberine treatment may be protective against the development of diabetic cardiomyopathy. PMID- 26522929 TI - Opioid metabolism and clinical aspects. AB - Opioids are are commonly used for the management of acute and chronic pain. Opioids have different physicochemical and pharmacokinetic characteristics, which explain the profound changes in the clinical effect in several clinical conditions. Pharmacokinetics influences the opioid response affecting bioavailability, production of metabolites with residual clinical activity, and elimination. Generality of opioid metabolism and clinical implications for specific opioids in different clinical conditions were reviewed to bridge the gap between pharmacokinetics and clinical response. The knowledge of opioid metabolism is essential, particularly for older and complicated patients who receive multiple medications and may have impaired of renal and hepatic function. The recognition of possible metabolic problems and the consideration of adverse drug-drug interactions are fundamental to optimize the use of opioids in clinical practice. PMID- 26522930 TI - Hidradenitis suppurativa may not be associated with venous thromboembolia: Results from a large Danish cross-sectional study. PMID- 26522931 TI - The two parts of the blackcap song: Acoustic analysis and male responses to playbacks. AB - Bird songs are complex manifold acoustic signals serving two main functions: mate attraction and territorial defense. The way information is encoded in the song often reflects adaptation to proximate and ultimate constraints. Male blackcaps, Sylvia atricapilla, display versatile songs with two parts, a warble and a whistle, whose functions remain unclear. We showed that the two parts of songs differ in terms of intensity, frequency and temporal parameters. They also contain totally different sets of syllables. Furthermore, the warble is versatile whereas the whistle part shows syllable sharing between individuals leaving closeby. Altogether, the results of our analysis suggest that the two parts encode different information potentially directed to different audiences. In order to test the potential function of these two parts, we performed playback experiments by broadcasting entire songs and each part separately. Warble and whistle alone are sufficient to trigger male responses and males sing both parts in responses to all stimuli, showing that both parts of the song are used in male male competition. It is suggested that the segregation of information in the blackcap song could be related to public versus private communication, used in both intra- and intersexual contexts, rather than directed to male versus female audiences only. PMID- 26522932 TI - Cooperation improves the access of wild boars (Sus scrofa) to food sources. AB - Wild boar is a highly polycotous ungulate species, characterized by a complex and dynamical social organization based on the maintenance of long-term bonds between mother and daughters. The roots of this social organization have to be researched at the individual level, considering adaptations that improve fitness in hostile environments. We used information collected by camera-traps at artificial feeding sites, in two contrasting environments in Bulgaria (mountain habitat) and Italy (sub-Mediterranean habitat). We recorded 417 and 885 distinct groups on 7 and 11 foraging sites in Bulgaria and Italy, respectively. We computed (controlling for time range, study area and supplementary feeding site) an index of effective foraging time of the different social groups. We observed a positive and significant effect of the number of conspecifics of the same social group on the effective foraging time. The impact of the other social classes on effective foraging time is also positive, and males, yearlings, and juveniles benefited more from the presence of other social classes, while females were less affected. The access of the different social groups to foraging sites is not random. Males and yearlings play producers (i.e., search for food) and are prone to attend foraging sites before adult females and subadults, so attaining a larger foraging efficiency with respect to a situation where other groups are already present on the feeding site. Wild boars exhibit a more complex social organisation than previously believed, where cooperation prevails largely on competition. A rough division of labour is also present: yearlings, males, and juveniles use to play producers and assume a significant amount of risk determined by the presence of predators or hunters. PMID- 26522933 TI - Breaching the Barrier-The Nuclear Envelope in Virus Infection. AB - Many DNA and a few RNA viruses use the host cell nucleus for virion formation and/or genome replication. To this end, the nuclear envelope (NE) barrier has to be overcome for entry into and egress from the intranuclear replication compartment. Different virus families have devised ingenious ways of entering and leaving the nucleus usurping cellular transport pathways through the nuclear pore complex but also translocating directly through both membranes of the NE. This intriguing diversity in nuclear entry and egress of viruses also highlights different ways nucleocytoplasmic transport can occur. Thus, the study of interactions between viruses and the NE also helps to unravel hitherto unknown cellular pathways such as vesicular nucleocytoplasmic transfer. PMID- 26522934 TI - Conformational Transitions that Enable Histidine Kinase Autophosphorylation and Receptor Array Integration. AB - During bacterial chemotaxis, transmembrane chemoreceptor arrays regulate autophosphorylation of the dimeric histidine kinase CheA. The five domains of CheA (P1-P5) each play a specific role in coupling receptor stimulation to CheA activity. Biochemical and X-ray scattering studies of thermostable CheA from Thermotoga maritima determine that the His-containing substrate domain (P1) is sequestered by interactions that depend upon P1 of the adjacent subunit. Non hydrolyzable ATP analogs (but not ATP or ADP) release P1 from the protein core (domains P3P4P5) and increase its mobility. Detachment of both P1 domains or removal of one within a dimer increases net autophosphorylation substantially at physiological temperature (55 degrees C). However, nearly all activity is lost without the dimerization domain (P3). The linker length between P1 and P3 dictates intersubunit (trans) versus intrasubunit (cis) autophosphorylation, with the trans reaction requiring a minimum length of 47 residues. A new crystal structure of the most active dimerization-plus-kinase unit (P3P4) reveals trans directing interactions between the tether connecting P3 to P2-P1 and the adjacent ATP-binding (P4) domain. The orientation of P4 relative to P3 in the P3P4 structure supports a planar CheA conformation that is required by membrane array models, and it suggests that the ATP lid of CheA may be poised to interact with receptors and coupling proteins. Collectively, these data suggest that the P1 domains are restrained in the off-state as a result of cross-subunit interactions. Perturbations at the nucleotide-binding pocket increase P1 mobility and access of the substrate His to P4-bound ATP. PMID- 26522935 TI - The Kink Turn, a Key Architectural Element in RNA Structure. AB - Kink turns (k-turns) are widespread structural elements that introduce an axial bend into duplex RNA with an included angle of 50 degrees . These mediate key tertiary interactions and bind specific proteins including members of the L7Ae family. The standard k-turn comprises a three-nucleotide bulge followed by G.A and A.G pairs. The RNA kinks by an association of the two minor grooves, stabilized by the formation of a number of key cross-strand hydrogen bonds mostly involving the adenine bases of the G.A and A.G pairs. The k-turns may be divided into two conformational classes, depending on the receptor for one of these hydrogen bonds. k-turns become folded by one of three different processes. Some, but not all, k-turns become folded in the presence of metal ions. Whether or not a given k-turn is folded under these conditions is determined by its sequence. We present a set of rules for the prediction of folding properties and the structure adopted on local sequence. PMID- 26522936 TI - Solution NMR Studies of an Alternative Mode of Sin3 Engagement by the Sds3 Subunit in the Histone Deacetylase-Associated Sin3L/Rpd3L Corepressor Complex. AB - The Sds3 transcriptional corepressor facilitates the assembly of the 1- to 2-MDa histone deacetylase-associated Sin3L/Rpd3L complex by providing a crucial homodimerization activity. Sds3 engages the scaffolding protein Sin3A, via a bipartite motif within the Sin3 interaction domain (SID) comprising a helix and an extended segment. Here, we show that the SID samples two discrete, substantially populated conformations with lifetimes in the tens of milliseconds range. The two conformations differ via a translation of the main chain and the corresponding side chains in the 5- to 7-A range. Given the close proximity of the SID to other functional motifs in Sds3 at the sequence level, the conformational exchange has the potential to regulate these activities. PMID- 26522938 TI - Universal Stochastic Multiscale Image Fusion: An Example Application for Shale Rock. AB - Spatial data captured with sensors of different resolution would provide a maximum degree of information if the data were to be merged into a single image representing all scales. We develop a general solution for merging multiscale categorical spatial data into a single dataset using stochastic reconstructions with rescaled correlation functions. The versatility of the method is demonstrated by merging three images of shale rock representing macro, micro and nanoscale spatial information on mineral, organic matter and porosity distribution. Merging multiscale images of shale rock is pivotal to quantify more reliably petrophysical properties needed for production optimization and environmental impacts minimization. Images obtained by X-ray microtomography and scanning electron microscopy were fused into a single image with predefined resolution. The methodology is sufficiently generic for implementation of other stochastic reconstruction techniques, any number of scales, any number of material phases, and any number of images for a given scale. The methodology can be further used to assess effective properties of fused porous media images or to compress voluminous spatial datasets for efficient data storage. Practical applications are not limited to petroleum engineering or more broadly geosciences, but will also find their way in material sciences, climatology, and remote sensing. PMID- 26522939 TI - Overcoming drug resistance in HSV, CMV, HBV and HCV infection. AB - Although vaccination has provided as a very efficient preventive tool, antiviral therapy is still needed to control viral infections not avoidable by prophylaxis with vaccines; those caused by viruses for which a vaccine is available, but vaccination is not universally implemented or does not result in complete, long term protection; and in immunocompromised individuals with reduced immune control of viral replication. After more than 50 years of the first licensing for an antiherpetic drug, novel compounds for herpes-simplex viruses and human cytomegalovirus will open new strategies for better control and management of these two recurrent viral infections. Besides, the development and use of antiviral drugs for hepatitis viruses causing chronic liver disease has evolved from the unavailability of compounds targeting virus-specific pathways, to the generalization of different treatment regimes based on specific antiviral drugs, both for hepatitis B and C viruses. However, due to the nature of the viral genomes and their replication, in the face of the selective pressure imposed by antiviral drugs viral-resistant variants inevitably emerge, and specific strategies are needed to avoid, or reduce, their clinical and public health impact. PMID- 26522937 TI - Synthetic Ecology of Microbes: Mathematical Models and Applications. AB - As the indispensable role of natural microbial communities in many aspects of life on Earth is uncovered, the bottom-up engineering of synthetic microbial consortia with novel functions is becoming an attractive alternative to engineering single-species systems. Here, we summarize recent work on synthetic microbial communities with a particular emphasis on open challenges and opportunities in environmental sustainability and human health. We next provide a critical overview of mathematical approaches, ranging from phenomenological to mechanistic, to decipher the principles that govern the function, dynamics and evolution of microbial ecosystems. Finally, we present our outlook on key aspects of microbial ecosystems and synthetic ecology that require further developments, including the need for more efficient computational algorithms, a better integration of empirical methods and model-driven analysis, the importance of improving gene function annotation, and the value of a standardized library of well-characterized organisms to be used as building blocks of synthetic communities. PMID- 26522940 TI - Ipsilateral cortical motor desynchronisation is reduced in Benign Epilepsy with Centro-Temporal Spikes. AB - OBJECTIVE: Magnetoencephalography (MEG) and a simple motor paradigm were used to study induced sensorimotor responses and their relationship to motor skills in children diagnosed with Benign Epilepsy with Centro-Temporal Spikes (BECTS). METHODS: Twenty-one children with BECTS and 15 age-matched controls completed a finger abduction task in MEG; movement-related oscillatory responses were derived and contrasted between groups. A subset of children also completed psycho behavioural assessments. Regression analyses explored the relationship of MEG responses to manual dexterity performance, and dependence upon clinical characteristics. RESULTS: In children with BECTS, manual dexterity was below the population mean (p=.002) and three showed severe impairment. Our main significant finding was of reduced ipsilateral movement related beta desynchrony (MRBDi) in BECTS relative to the control group (p=.03) and predicted by epileptic seizure recency (p=.02), but not age, medication status, or duration of epilepsy. Laterality scores across the entire cohort indicated that less lateralised MRBD predicted better manual dexterity (p=.04). CONCLUSIONS: Altered movement-related oscillatory responses in ipsilateral motor cortex were associated with motor skill deficits in children with BECTS. These changes were more marked in those with more recent seizures. SIGNIFICANCE: These findings may reflect differences in inter-hemispheric interactions during motor control in BECTS. PMID- 26522941 TI - An evaluation of motor evoked potential surrogate endpoints during intracranial vascular procedures. AB - OBJECTIVE: MEPs are used as surrogate endpoints to predict the effectiveness of interventions, made in response to MEP deterioration, in avoiding new postoperative deficits. MEP performance in capturing intervention effects on these outcomes was investigated. METHODS: A meta-analysis of studies using MEPs during intracranial vascular surgeries between 2003 and 2014 was performed. MEP diagnostic performance and relative risk of new postoperative deficits for reversible compared with irreversible MEP changes were determined. Intervention efficacy in reversing MEP deterioration and postoperative outcomes was compared across studies. RESULTS: MEP diagnostic performance compared favorably with that of other tests used in medicine, with all likelihood ratios >10. The summary relative risk comparing reversible and irreversible changes was 0.40, indicating a 60% decrease in new deficits for reversible MEP changes. The proportion of MEP deteriorations which recovered was negatively correlated with the proportion of new postoperative deficits (r=-0.81, p<.005). CONCLUSIONS: The effectiveness of interventions in recovering an MEP decline was predictive of preserved neurologic status. MEPs are provisionally qualified as surrogate endpoints given potentially major harms to the patient if they are not used, compared to the minimal harms and costs associated with their use. SIGNIFICANCE: The performance of MEPs as substitute, or surrogate, endpoints during intracranial vascular surgeries for new deficits in motor strength in the immediate postoperative period was directly assessed for ten recent studies. PMID- 26522944 TI - How to perform low-dose computed tomography for renal colic in clinical practice. AB - Computed tomography (CT) has become the reference technique in medical imaging for renal colic, to diagnose, plan treatment and explore differential diagnosis. Its main limitation is the radiation dose, especially as urinary stone disease tends to relapse and mainly affects young people. It is therefore essential to reduce the CT radiation dose when renal colic is suspected. The goal of this review was twofold. First, we wanted to show how to use low-dose CT in patients with suspected renal colic in current clinical practice. Second, we wished to discuss the different ways of reducing CT radiation dose by considering both behavioral and technological factors. Among the behavioral factors, limiting the scan coverage area is a straightforward and effective way to reduce the dose. Improvement of technological factors relies mainly on using automatic tube current modulation, lowering the tube voltage and current as well using iterative reconstruction. PMID- 26522943 TI - Transmembrane protein sorting driven by membrane curvature. AB - The intricate structure of prokaryotic and eukaryotic cells depends on the ability to target proteins to specific cellular locations. In most cases, we have a poor understanding of the underlying mechanisms. A typical example is the assembly of bacterial chemoreceptors at cell poles. Here we show that the classical chemoreceptor TlpA of Bacillus subtilis does not localize according to the consensus stochastic nucleation mechanism but accumulates at strongly curved membrane areas generated during cell division. This preference was confirmed by accumulation at non-septal curved membranes. Localization appears to be an intrinsic property of the protein complex and does not rely on chemoreceptor clustering, as was previously shown for Escherichia coli. By constructing specific amino-acid substitutions, we demonstrate that the preference for strongly curved membranes arises from the curved shape of chemoreceptor trimer of dimers. These findings demonstrate that the intrinsic shape of transmembrane proteins can determine their cellular localization. PMID- 26522945 TI - Imaging of Von Meyenburg complexes. AB - Von Meyenburg complexes, or biliary hamartomas, are frequently incidentally detected. They are usually easy to characterize with magnetic resonance imaging. However, in some occasions they are difficult to differentiate from other liver lesions, in particular from small liver metastases. Von Meyenburg complexes are developmental malformations of the ductal plate. They can be found in association with Caroli disease and Caroli syndrome. Like other ductal plate malformations, Von Meyenburg complexes associated with cholangiocarcinoma have been described and their relationship has been established. This review provides an update on the etiopathogenesis of Von Meyenburg complexes, illustrates the imaging features on ultrasound, CT and MRI of this condition and discusses the most common diagnostic pitfalls. The relationships between Von Meyenburg complexes and the various ductal plate malformations and the most recent literature data regarding the relationships between Von Meyenburg complexes and cholangiocarcinoma are presented. PMID- 26522946 TI - The use of porcupine inhibitors to target Wnt-driven cancers. AB - Over the past decade, academic groups and pharmaceutical companies have uncovered several components and targets for intervention in the Wnt pathway. One approach is to block Wnt signalling through the use of orally bioavailable small molecules that prevent Wnt ligand secretion. In recent years, the membrane bound O-acyl transferase (MBOAT) porcupine (PORCN) has emerged as a molecular target of interest in the search for clinical options to treat Wnt-driven cancers. This review shall provide an overview of the reported small molecule inhibitors for PORCN and discuss the progress made in identifying human disease models that are responsive to PORCN inhibitors. PMID- 26522947 TI - Synthesis of biscoumarin and dihydropyran derivatives with promising antitumor and antibacterial activities. AB - Two series of biscoumarin (1-3) and dihydropyran (4-12) derivatives were successfully synthesized as new antitumor and antibacterial agents. The molecular structures of four representative compounds 2, 4, 7 and 10 were confirmed by single crystal X-ray diffraction study. The synthesized compounds (1-12) were evaluated for their antitumor activities against human intestinal epithelial adenocarcinoma cell line (HuTu80), mammary adenocarcinoma cell line (4T1) and pancreatic cancer cell line (PANC1) and antibacterial activities against one drug sensitive Staphylococcus aureus (S. aureus ATCC 29213) strain and three MRSA strains (MRSA XJ 75302, Mu50, USA 300 LAC). The further mechanism study demonstrated that the most potent compound 1 could obviously inhibit the proliferation of cancer cells via the mechanism to induce apoptosis. PMID- 26522948 TI - Potent complement C3a receptor agonists derived from oxazole amino acids: Structure-activity relationships. AB - Potent ligands for the human complement C3a receptor (C3aR) were developed from the almost inactive tripeptide Leu-Ala-Arg corresponding to the three C-terminal residues of the endogenous peptide agonist C3a. The analogous Leu-Ser-Arg was modified by condensing the serine side chain with the leucine carbonyl with elimination of water to form leucine-oxazole-arginine. Subsequent elaboration with a variety of N-terminal amide capping groups produced agonists as potent as human C3a itself in stimulating Ca(2+) release from human macrophages. Structure activity relationships are discussed. PMID- 26522949 TI - Structure-activity relationship of indoloquinoline analogs anti-MRSA. AB - Indolo[3,2-b]quinoline analogs (3a-3s), 4-(acridin-9-ylamino) phenol hydrochloride (4), benzofuro[3,2-b]quinoline (3t), indeno[1,2-b]quinolines (3u and 3v) have been synthesized. Those compounds were found to exhibit anti bacterial activity towards Methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Structure-activity relationship studies were conducted that indoloquinoline ring, benzofuroquinoline ring and 4-aminophenol group are essential structure for anti-MRSA activity. PMID- 26522950 TI - Discovery of 1H-pyrazolo[3,4-b]pyridines as potent dual orexin receptor antagonists (DORAs). AB - Compound rac-1 was identified by high throughput screening. Here we report SAR studies and MedChem optimization towards the highly potent dual orexin receptor antagonists (S)-2 and (S)-3. Furthermore, strategies to overcome the suboptimal physicochemical properties are highlighted and the pharmacokinetic profiles of representative compounds is presented. PMID- 26522952 TI - Development of a potent and selective cell penetrant Legumain inhibitor. AB - This Letter describes the continued SAR exploration of small molecule Legumain inhibitors with the aim of developing a potent and selective in vitro tool compound. Work continued in this Letter explores the use of alternative P2-P3 linker units and the P3 group SAR which led to the identification of 10t, a potent, selective and cellularly active Legumain inhibitor. We also demonstrate that 10t has activity in both cancer cell viability and colony formation assays. PMID- 26522951 TI - Facile and efficient synthesis and herbicidal activity determination of novel 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one derivatives via microwave irradiation. AB - A series of novel 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one derivatives were synthesized and identified by (1)H NMR, single crystal X-ray diffraction, elemental analysis or HRMS, and their herbicidal activities were determined at different concentrations. It was found that some of the title compounds possess high herbicidal activity. Furthermore, DFT calculation was used to study the SAR. PMID- 26522953 TI - Synthesis and antiproliferativeactivity of new vinca alkaloids containing an alpha,beta-unsaturated aromatic side chain. AB - A new series of vinca-alkaloids derivatives containing various alpha,beta unsaturated aromatic side chains was synthesized. Four new vinca-alkaloids derivatives showed selective cytotoxicities against KB tumor cell lines with IC50 value below 0.1 MUM, thus comparable with vinblastine. PMID- 26522954 TI - Natural Product-Derived Spirooxindole Fragments Serve as Privileged Substructures for Discovery of New Anticancer Agents. AB - The utility of natural products for identifying anticancer agents has been highly pursued in the last decades and over 100 drug molecules in clinic are natural products or natural product-derived compounds. Natural products are believed to be able to cover unexplored chemical space that is normally not occupied by commercially available molecule libraries. However, the low abundance and synthetic intractability of natural products have limited their applications in drug discovery. Recently, the identification of biologically relevant fragments derived from biologically validated natural products has been recognized as a powerful strategy in searching new biological probes and drugs. The spirocyclic oxindoles, as privileged structural scaffolds, have shown their potential in designing new drugs. Several anticancer drug candidates such as SAR405838, RO8994, CFI-400945 and their bioisosteres are undergoing clinical trials or preclinical studies. To highlight the significant progress, we focus on illustrating the discovery of SAR405838, RO8994, CFI-400945 and their bioisosteres for cancer therapy using substructure-based strategies and discussing modes of action, binding models and preclinical data. PMID- 26522955 TI - Simultaneous estimation of cortical bone thickness and acoustic wave velocity using a multivariable optimization approach: Bone phantom and in-vitro study. AB - The paper presents a method that allows the thickness of a compact bone layer and longitudinal wave velocity in the bone to be determined simultaneously with the use of reflected waves, with particular emphasis on the case of layers when the propagation time through the layer is shorter than the time duration of the interrogating pulse. The proposed method estimates simultaneously the thickness of the cortical bone layer and acoustic wave velocity by fitting the temporal spectrum of the simulated reflected wave to the spectrum of the reflected wave measured experimentally. For the purpose of echo-simulations the model of "soft tissue - compact bone layer - cancellous bone" was developed. Next, the cost function was defined as the least square error between the measured and simulated temporal spectra. Minimization of the cost function allowed us to determine the values of the parameters of the cortical bone layer which best fitted the measurements. To solve the optimization problem a simulated annealing algorithm was used. The method was tested using acoustic data obtained at the frequency of 0.6 MHz and 1 MHz respectively for a custom designed bone mimicking phantom and a calf femur. For the cortical shell of the calf femur whose thickness varies from 2.1 mm to 2.4 mm and velocity of 2910 m/s, the relative errors of the thickness estimation ranged from 0.4% to 5.5%. The corresponding error of the acoustic wave velocity estimation in the layer was 3.1%. In the case of artificial bone the thickness of the cortical layer was equal to 1.05 and 1.2 mm and acoustic wave velocity was 2900 m/s. These parameters were determined with the errors ranging from 1.9% to 10.8% and from 3.9% to 4.5% respectively. PMID- 26522956 TI - Induction coil as a non-contacting ultrasound transmitter and detector: Modeling of magnetic fields for improving the performance. AB - A simple copper coil without a voluminous stationary magnet can be utilized as a non-contacting transmitter and as a detector for ultrasonic vibrations in metals. Advantages of such compact EMATs without (electro-)magnet might be: applications in critical environments (hot, narrow, presence of iron filings...), potentially superior fields (then improved ultrasound transmission and more sensitive ultrasound detection). The induction field of an EMAT strongly influences ultrasound transduction in the nearby metal. Herein, a simplified analytical method for field description at high liftoff is presented. Within certain limitations this method reasonably describes magnetic fields (and resulting eddy currents, inductances, Lorentz forces, acoustic pressures) of even complex coil arrangements. The methods can be adapted to conventional EMATS with a separate stationary magnet. Increased distances (liftoff) are challenging and technically relevant, and this practical question is addressed: with limited electrical power and given free space between transducer and target metal, what would be the most efficient geometry of a circular coil? Furthermore, more complex coil geometries ("butterfly coil") with a concentrated field and relatively higher reach are briefly investigated. PMID- 26522957 TI - Influence of ultrasonic scattering in the calculation of thermal dose in ex-vivo bovine muscular tissues. AB - This study explores the effect of ultrasound scattering on the temperature increase in phantoms and in samples of ex-vivo biological tissue through the calculation of the thermal dose (TD). Phantoms with different weight percentages of graphite powder (0-1%w/w, different scattering mean free paths, lS) and ex vivo bovine muscle tissue were isonified by therapeutic ultrasound (1 MHz). The TD values were calculated from the first 4 min of experimental temperature curves obtained at several depths and were compared with those acquired from the numerical solution of the bio-heat transfer equation (simulated with 1 MHz and 0.5-2.0 W cm(-2)). The temperature curves suggested that scattering had an important role because the temperature increments were found to be higher for higher percentages of graphite powder (lower lS). For example, at a 30-mm depth and a 4-min therapeutic ultrasound application (0.5 W cm(-2)), the TDs (in equivalent minutes at 43 degrees C) were 7.2, 17.8, and 58.3 for the phantom with lS of 4.35, 3.85, and 3.03 mm, respectively. In tissue, the inclusion of only absorption or full attenuation in the bio-heat transfer equation (BHTE) heat source term of the simulation leads to under- or overestimation of the TD, respectively, as compared to the TD calculated from experimental data. The experiments with phantoms (with different scatterer concentrations) and ex-vivo samples show that the high values of TD were caused by the increase of energy absorption due to the lengthening of the propagation path caused by the changing in the propagation regime. PMID- 26522959 TI - The future of baby hatches in China. PMID- 26522958 TI - Genetic deletion of Rhes or pharmacological blockade of mTORC1 prevent striato nigral neurons activation in levodopa-induced dyskinesia. AB - Ras homolog enriched in striatum (Rhes) is a small GTP-binding protein that modulates signal transduction at dopamine receptors, and also activates mammalian target of rapamycin complex 1 (mTORC1). Rhes binding to mTORC1 is hypothesized to play a role in motor disorders such as levodopa-induced dyskinesia. Here, we investigate the behavioral and in vivo neurocircuitry changes associated with genetic deletion of Rhes or inhibition of mTORC1 signaling in the mouse model of levodopa-induced dyskinesia. 6-Hydroxydopamine-hemilesioned Rhes knockout mice and wild-type littermates were chronically treated with levodopa. In parallel, 6 hydroxydopamine-hemilesioned naive mice were chronically treated with levodopa or levodopa plus rapamycin, to block mTORC1 pathway activation. Dyskinetic movements were monitored during levodopa treatment along with motor activity on the rotarod. Finally, dyskinetic mice underwent microdialysis probe implantation in the dopamine-depleted striatum and ipsilateral substantia nigra reticulata, and GABA and glutamate levels were monitored upon acute challenge with levodopa. Both Rhes knockouts and rapamycin-treated mice developed less dyskinesia than controls, although only rapamycin-treated mice fully preserved rotarod performance on levodopa. Levodopa elevated nigral GABA and glutamate in controls but not in Rhes knockouts or rapamycin-treated mice. Levodopa also stimulated striatal glutamate in controls and Rhes knockouts but not in rapamycin-treated mice. We conclude that both genetic deletion of Rhes and pharmacological blockade of mTORC1 significantly attenuate dyskinesia development by reducing the sensitization of striato-nigral medium-sized spiny neurons to levodopa. However, mTORC1 blockade seems to provide a more favorable behavioral outcome and a wider effect on neurochemical correlates of dyskinesia. PMID- 26522960 TI - Beyond birth: Women's concerns about post-birth care in an Australian urban community. AB - BACKGROUND: The provision of post-birth care in the community is changing substantially in many parts of Australia including Queensland, where there has been a burgeoning of clinics in private retail outlets such as pharmacies. Little is known about women's experiences of post-birth care in community pharmacies, nor of how their experiences compare with those in publicly-funded Child and Family Health Clinics (CFHC). AIM: To provide qualitative insights into women's experiences of the different forms of post-birth care in the community, and identify where improvements could be made to service provision. METHODS: A purposive sample of mothers of infants aged under 12 months was recruited to maximise variation in the use of private and public postnatal care services. Semi structured interviews were conducted with fifteen mothers whose antenatal, birthing and post-birth experiences varied across public and private sectors and birthing providers. RESULTS: Concerns about lack of information and psychosocial support following discharge from hospital were widely reported, particularly by women who had given birth in a private facility under the care of a private obstetrician. Women used both pharmacy nurses and CFHCs. Pharmacy nurses were generally preferred for their accessibility, psychosocial support for mother, and continuity of care. However, these services are unregulated and without quality assurance mechanisms. Mothers found CFHCs regimented, focused on infant surveillance rather than support for mothers, and difficult to access. CONCLUSION: There is a clear need for community post-birth care that will provide mothers with the information and psychosocial support they need. Currently, private, home-birth midwives and pharmacy nurses are providing women-centred care more effectively than nurses in publicly funded CFHC or GPs. This seems to be linked to continuity of carer, and to service priorities, resulting in inequities and systematic variations in the quality of post-birth care. Further research on this important health care issue is recommended. PMID- 26522961 TI - 'Midwives Overboard!' Inside their hearts are breaking, their makeup may be flaking but their smile still stays on. AB - PROBLEM: Midwifery practice is emotional and, at times, traumatic work. Cumulative exposure to this, in an unsupportive environment can result in the development of psychological and behavioural symptoms of distress. BACKGROUND: As there is a clear link between the wellbeing of staff and the quality of patient care, the issue of midwife wellbeing is gathering significant attention. Despite this, it can be rare to find a midwife who will publically admit to how much they are struggling. They soldier on, often in silence. AIM: This paper aims to present a narrative review of the literature in relation to work-related psychological distress in midwifery populations. Opportunities for change are presented with the intention of generating further conversations within the academic and healthcare communities. METHODS: A narrative literature review was conducted. FINDINGS: Internationally, midwives experience various types of work related psychological distress. These include both organisational and occupational sources of stress. DISCUSSION: Dysfunctional working cultures and inadequate support are not conducive to safe patient care or the sustained progressive development of the midwifery profession. New research, revised international strategies and new evidence based interventions of support are required to support midwives in psychological distress. This will in turn maximise patient, public and staff safety. CONCLUSIONS: Ethically, midwives are entitled to a psychologically safe professional journey. This paper offers the principal conclusion that when maternity services invest in the mental health and wellbeing of midwives, they may reap the rewards of improved patient care, improved staff experience and safer maternity services. PMID- 26522964 TI - Health consequences of climate change interventions. PMID- 26522963 TI - [Urinary infection by Saccharomyces cerevisiae: Emerging yeast?]. AB - Saccharomyces cerevisiae is a commensal yeast of the digestive, respiratory and genito-urinary tract. It is widely used as a probiotic for the treatment of post antibiotic diarrhea. It most often occurs in immunocompromised patients frequently causing fungemia. We report the case of an adult diabetic patient who had a urinary tract infection due to S. cerevisiae. The disease started with urination associated with urinary frequency burns without fever. The diagnosis was established by the presence of yeasts on direct examination and positivity of culture on Sabouraud-chloramphenicol three times. The auxanogramme gallery (Auxacolor BioRad((r))) allowed the identification of S. cerevisiae. The patient was put on fluconazole with good outcome. This observation points out that this is an opportunistic yeast in immunocompromised patients. PMID- 26522962 TI - The relationship between weight change and risk of hip fracture: meta-analysis of prospective studies. AB - The relationship between weight change and risk of hip fracture is still controversial. We searched PubMed and Embase for studies on weight change and risk of hip fracture. Eight prospective studies were included. The weight loss studies included 85592 participants with 1374 hip fractures, and the weight gain studies included 80768 participants with 732 hip fractures. Weight loss is more likely a risk factor of hip fracture, with an adjusted RR (Relative Risk) (95% CI) of 1.84 (1.45, 2.33). In contrast, weight gain can decrease the risk of hip fracture, with an adjusted RR (95% CI) of 0.73 (0.61, 0.89). Dose-response meta analysis shows that the risk of hip fracture is an ascending curve, with an increase of weight loss above the line of RR = 1; this trend is consistent with the results of forest plots that examine weight loss and hip fracture. For weight gain and risk of hip fracture, the descending curve below the line of RR = 1; this trend is consistent with the results of forest plots that examine weight gain and hip fracture. Our meta-analysis suggests that weight loss may be a risk factor for hip fracture and that weight gain may be a protective factor for hip fracture. PMID- 26522965 TI - The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain. AB - Proteins belonging to the 'A Disintegrin And Metalloproteinase' (ADAM) family are membrane-anchored proteases that are able to cleave the extracellular domains of several membrane-bound proteins in a process known as 'ectodomain shedding'. In the central nervous system, ADAM10 has attracted the most attention, since it was described as the amyloid precursor protein alpha-secretase over ten years ago. Despite the excitement over the potential of ADAM10 as a novel drug target in Alzheimer disease, the physiological functions of ADAM10 in the brain are not yet well understood. This is largely because of the embryonic lethality of ADAM10 deficient mice, which results from the loss of cleavage and signaling of the Notch receptor, another ADAM10 substrate. However, the recent generation of conditional ADAM10-deficient mice and the identification of further ADAM10 substrates in the brain has revealed surprisingly numerous and fundamental functions of ADAM10 in the development of the embryonic brain and also in the homeostasis of adult neuronal networks. Mechanistically, ADAM10 controls these functions by utilizing unique postsynaptic substrates in the central nervous system, in particular synaptic cell adhesion molecules, such as neuroligin-1, N cadherin, NCAM, Ephrin A2 and A5. Consequently, a dysregulation of ADAM10 activity is linked to psychiatric and neurological diseases, such as epilepsy, fragile X syndrome and Huntington disease. This review highlights the recent progress in understanding the substrates and function as well as the regulation and cell biology of ADAM10 in the central nervous system and discusses the value of ADAM10 as a drug target in brain diseases. PMID- 26522966 TI - Neither Single nor a Combination of Routine Laboratory Parameters can Discriminate between Gram-positive and Gram-negative Bacteremia. AB - Adequate early empiric antibiotic therapy is pivotal for the outcome of patients with bloodstream infections. In clinical practice the use of surrogate laboratory parameters is frequently proposed to predict underlying bacterial pathogens; however there is no clear evidence for this assumption. In this study, we investigated the discriminatory capacity of predictive models consisting of routinely available laboratory parameters to predict the presence of Gram positive or Gram-negative bacteremia. Major machine learning algorithms were screened for their capacity to maximize the area under the receiver operating characteristic curve (ROC-AUC) for discriminating between Gram-positive and Gram negative cases. Data from 23,765 patients with clinically suspected bacteremia were screened and 1,180 bacteremic patients were included in the study. A relative predominance of Gram-negative bacteremia (54.0%), which was more pronounced in females (59.1%), was observed. The final model achieved 0.675 ROC AUC resulting in 44.57% sensitivity and 79.75% specificity. Various parameters presented a significant difference between both genders. In gender-specific models, the discriminatory potency was slightly improved. The results of this study do not support the use of surrogate laboratory parameters for predicting classes of causative pathogens. In this patient cohort, gender-specific differences in various laboratory parameters were observed, indicating differences in the host response between genders. PMID- 26522967 TI - Human Odorant Reception in the Common Bed Bug, Cimex lectularius. AB - The common bed bug Cimex lectularius is a temporary ectoparasite on humans and currently resurgent in many developed countries. The ability of bed bugs to detect human odorants in the environment is critical for their host-seeking behavior. This study deciphered the chemical basis of host detection by investigating the neuronal response of olfactory sensilla to 104 human odorants using single sensillum recording and characterized the electro-physiological responses of bed bug odorant receptors to human odorants with the Xenopus expression system. The results showed that the D type of olfactory sensilla play a predominant role in detecting the human odorants tested. Different human odorants elicited different neuronal responses with different firing frequencies and temporal dynamics. Particularly, aldehydes and alcohols are the most effective stimuli in triggering strong response while none of the carboxylic acids showed a strong stimulation. Functional characterization of two bed bug odorant receptors and co-receptors in response to human odorants revealed their specific responses to the aldehyde human odorants. Taken together, the findings of this study not only provide exciting new insights into the human odorant detection of bed bugs, but also offer valuable information for developing new reagents (attractants or repellents) for the bed bug control. PMID- 26522968 TI - Initial amplification of the HPV18 genome proceeds via two distinct replication mechanisms. AB - Determining the mechanism of HPV18 replication is paramount for identifying possible drug targets against HPV infection. We used two-dimensional and three dimensional gel electrophoresis techniques to identify replication intermediates arising during the initial amplification of HPV18 episomal genomes. We determined that the first rounds of HPV18 replication proceed via bidirectional theta structures; however, a notable accumulation of almost fully replicated HPV18 genomes indicates difficulties with the completion of theta replication. We also observed intermediates that were created by a second replication mechanism during the initial amplification of HPV18 genomes. The second replication mechanism does not utilize specific initiation or termination sequences and proceeds via a unidirectional replication fork. We suggest a significant role for the second replication mechanism during the initial replication of the HPV18 genome and propose that the second replication mechanism is recombination-dependent replication. PMID- 26522969 TI - Temporal trends in the utilisation of preventive medicines by older people: A 9 year population-based study. AB - BACKGROUND: For older individuals with multimorbidity the appropriateness of prescribing preventive medicines remains a challenge. OBJECTIVE: Investigate the prevalence and temporal trends in utilisation of preventive medicines in older New Zealanders from 2005 to 2013 stratified according to age, sex, ethnicity and district health board domicile. METHODS: A repeated cross-sectional analysis was conducted on pharmaceutical dispensing data for all individuals' >= 65 years. Variable medication possession ratio (VMPR) was used to measure adherence. Prescribing of low-dose aspirin, clopidogrel, dipyridamole, warfarin, dabigatran, statins and bisphosphonates with a VMPR>=0.8 were examined. RESULTS: Aspirin utilisation increased by 19.55% (95% CI: 19.39-19.70), clopidogrel by 2.93% (95% CI: 2.88-2.97) and dipyridamole decreased by 0.65% (95% CI: -0.70 to -0.59). Utilisation of aspirin with clopidogrel increased by 1.78% (95% CI: 1.74-1.81) and aspirin with dipyridamole increased by 0.54% (95% CI: 0.50-0.58%).Warfarin decreased by 0.87% (95% CI: -0.96 to -0.78) and dabigatran increased by 0.65% (95% CI: 0.60-0.70). Statins increased by 7.0% (95% CI: 6.82-7.18) and bisphosphonates decreased by 2.37% (95% CI: -2.44 to -2.30). Aspirin, clopidogrel, dabigatran and statins utilisation showed a greater increase in males. Interestingly, clopidogrel, warfarin and statins use increased in older adults aged 85+ compared to the younger age groups (65-84 years). CONCLUSION: To our knowledge, this is the first study investigating the prevalence and trends of preventive medicines use in older people in New Zealand. This study may facilitate further research to examine the appropriateness of prescribing these medicines in older people with multimorbidity. PMID- 26522970 TI - Editorial Commentary: Striking a balance: Individualizing antithrombotic therapy after myocardial infarction. PMID- 26522971 TI - Investigation of Antibacterial Activity and Biofilm Formation of Silicones Coated With Minocycline-Rifampicin, Silver Nitrate, and Nitrofurantoin for Short-term Utilization in In Vitro Urinary System Models. AB - OBJECTIVE: To analyze antimicrobial activity and biofilm formation on silicones coated with antimicrobial substances in in vivo short-term catheterization simulation using our newly developed in vitro urinary system model and to compare minocycline-rifampin (MR)-, silver nitrate-, and nitrofurantoin (NF)-coated silicone discs. MATERIALS AND METHODS: Silicone discs were exposed to bacterial urine suspension for 168 hours. The antimicrobial activities were assessed in the medium, and the inhibition zone diameters were measured. The weight of the silicones was measured for biofilm growth assessment before and after the experiment, and confocal microscopy images were taken. RESULTS: Although the inhibition zone diameters of silver nitrate silicones were larger than those of pure silicone (PS), MR, and NF silicones, biofilm formation could not be prevented (P < .05). MR and NF silicones were superior to PS in terms of antimicrobial efficacy and prevention of biofilm formation (P < .05). In terms of biofilm prevention, no differences were detected between NF and MR silicones apart from a slightly superior ability of MR silicones to inhibit Escherichia coli (P > .05). Biofilm formation occurred on all silicone discs. CONCLUSION: In short-term urinary catheter utilization, antimicrobial efficacy and biofilm formation prevention were superior in coated silicones, regardless of the type of antibiotic used, compared with the control group (PS). As the study was conducted in an in vitro setting, the findings should be substantiated with in vivo studies on the grounds that different results may be obtained in these settings. PMID- 26522972 TI - Combination Therapy Using Human Adipose-derived Stem Cells on the Cavernous Nerve and Low-energy Shockwaves on the Corpus Cavernosum in a Rat Model of Post prostatectomy Erectile Dysfunction. AB - OBJECTIVE: To investigate combined therapeutic efficacy of human adipose-derived stem cells (h-ADSCs) application on injured cavernous nerve and low-energy shockwave therapy (SWT) on the corpus cavernosum in a rat model of post prostatectomy erectile dysfunction. MATERIALS AND METHODS: Rats were randomly divided into 5 groups: control, bilateral cavernous nerve injury (BCNI), adipose derived stem cell (ADSC) (BCNI group with h-ADSCs on the cavernous nerve), SWT (BCNI group with low-energy SWT on the corpus cavernosum), and ADSC/SWT (BCNI group with a combination of h-ADSCs and low-energy SWT). After 4 weeks, erectile function was assessed using intracavernosal pressure. The cavernous nerves and penile tissue were evaluated through immunostaining, Western blotting, and a cyclic guanosine monophosphate assay. RESULTS: ADSC/SWT significantly improved intracavernosal pressure compared to the other experimental group. ADSC had significantly increased beta-III tubulin expression of the cavernous nerve, and SWT had a markedly enhanced vascular endothelial growth factor expression in corpus cavernosum. The ADSC/SWT group had a significantly increased in alpha smooth muscle actin content (P < .05), neural nitric oxide synthase (nNOS) of the dorsal penile nerve (P < .05), endothelial nitric oxide synthase (eNOS) protein expression (P < .05), and cyclic guanosine monophosphate level (P < .05) compared to the ADSC or SWT alone group. In addition, ADSC/SWT reduces the apoptotic index in the corpus cavernosum. CONCLUSION: In this study, h-ADSCs showed an effect on the recovery of injured cavernous nerve and low-energy SWT improved angiogenesis in the corpus cavernosum. The h-ADSCs combined with low-energy SWT showed beneficial effect on the recovery of erectile function in a rat model of postprostatectomy erectile dysfunction. PMID- 26522973 TI - Spontaneous Recovery of Reflex Voiding Following Spinal Cord Injury Mediated by Anti-inflammatory and Neuroprotective Factors. AB - OBJECTIVE: To investigate the time-dependent changes in expression of cytokines that characterizes the spontaneous recovery of reflex voiding after spinal cord injury (SCI). SCI is known to reorganize the neural circuitry of micturition reflex after injury. METHODS: Under isoflurane anesthesia, spinal cord of 18 adult female Sprague-Dawley rats was completely transected at the Th9-10 level. Awake cystometry was performed at each time point on controls and 6 SCI animals, and bladder was then harvested for analysis of 29 proteins Millipore kit or enzyme-linked immunosorbent assay. Prophylactic dose of ampicillin 100 mg/kg was administered periodically to all SCI animals. RESULTS: Spontaneous recovery of voiding after SCI at 12 weeks was evident from increased intercontractile interval and voiding efficiency during cystometry. Expression of proinflammatory interleukins ([IL] IL-1alpha and IL-1beta, IL-2, IL-5, IL-6, IL-18, tumor necrosis factor alpha [TNF-alpha]) and CXC chemokines (CXCL1, CXCL2, CXCL10), CX3CL1, and CCL2 showed significant elevation at 4 and at 8 weeks with slight decrease at 12 weeks. In contrast, expression of anti-inflammatory IL-10 and neuroprotective factors, CXCL-5, and leptin, was elevated at 8 and at 12 weeks (P < .05). In contrast, expression of CCL3, CCL5, and growth factors (vascular endothelial growth factor, nerve growth factor, epidermal growth factor, granulocyte colony-stimulating factor, and granulocyte macrophage colony stimulating factor) did not show any significant temporal change after SCI. CONCLUSION: Spontaneous recovery of reflex voiding at 12 weeks was marked by increased endogenous expression of anti-inflammatory cytokine IL-10 and neuroprotective factors, CXCL-5, and leptin, which suggests that pharmacological suppression of inflammation, can hasten the emergence of reflex voiding after SCI. PMID- 26522974 TI - Two decades of growth hormone treatment in adulthood. PMID- 26522975 TI - Is vitamin D deficiency being considered in the differential diagnosis of osteoporosis in routine practice? PMID- 26522976 TI - [Barriers to the practice of the medical autopsies in the case of death out of health care institutions: Procedural clarification]. PMID- 26522977 TI - Cerebellar Hemangioblastoma and Pancreatic Cysts in a Case of von Hippel-Lindau Disease. PMID- 26522978 TI - The Pediatric Vestibular Symptom Questionnaire: A Validation Study. AB - OBJECTIVE: To develop and validate the Pediatric Vestibular Symptom Questionnaire (PVSQ) and quantify subjective vestibular symptom (ie, dizziness, unsteadiness) severity in children. STUDY DESIGN: One hundred sixty-eight healthy children (female, n = 91) and 56 children with postconcussion dizziness or a vestibular disorder (female, n = 32), between ages 6 and 17 years, were included. The PVSQ contains questions regarding vestibular symptom frequency during the previous month. The Strengths and Difficulties Questionnaire (SDQ), a brief behavioral screening instrument, was also completed. RESULTS: The PVSQ showed high internal consistency (10 items; Cronbach alpha = 0.88). A significant between-group difference was noted with higher (ie, worse) PVSQ scores for children with vestibular symptoms (P < .001); no significant differences were noted between patient groups. The optimal cut-off score for discriminating between individuals with and without abnormal levels of vestibular symptoms was 0.68 out of 3 (sensitivity 95%, specificity 85%). Emotional and hyperactivity SDQ subscale scores were significantly worse for patients compared with healthy participants (P <= .01). A significant relationship was noted between mean PVSQ and SDQ (parent-rated version) hyperactivity and total scores for patients (P <= .01) and the SDQ (self-rated) emotional, hyperactivity, and total score (P <= .01) in healthy controls. However, mean SDQ subscale and total scores were within normal ranges for both groups. CONCLUSIONS: Self-reported vestibular symptoms, measured by the PVSQ, discriminated between children presenting with vestibular symptoms and healthy controls and should be used to identify and quantify vestibular symptoms that require additional assessment and management. PMID- 26522979 TI - Not Just a Drop in the Bucket-Inversion of Oxymetazoline Nasal Decongestant Container Increases Potential for Severe Pediatric Poisoning. AB - Oxymetazoline is an over-the-counter nasal decongestant with potent alpha agonist properties. In overdoses as small as 1-2 mL, toxicity can be seen including bradycardia and respiratory depression. We demonstrated that inverting the container increased the volume delivered 20- to 30-fold compared with holding it upright in an in vitro model. PMID- 26522982 TI - Double emulsion solvent evaporation techniques used for drug encapsulation. AB - Double emulsions are complex systems, also called "emulsions of emulsions", in which the droplets of the dispersed phase contain one or more types of smaller dispersed droplets themselves. Double emulsions have the potential for encapsulation of both hydrophobic as well as hydrophilic drugs, cosmetics, foods and other high value products. Techniques based on double emulsions are commonly used for the encapsulation of hydrophilic molecules, which suffer from low encapsulation efficiency because of rapid drug partitioning into the external aqueous phase when using single emulsions. The main issue when using double emulsions is their production in a well-controlled manner, with homogeneous droplet size by optimizing different process variables. In this review special attention has been paid to the application of double emulsion techniques for the encapsulation of various hydrophilic and hydrophobic anticancer drugs, anti inflammatory drugs, antibiotic drugs, proteins and amino acids and their applications in theranostics. Moreover, the optimized ratio of the different phases and other process parameters of double emulsions are discussed. Finally, the results published regarding various types of solvents, stabilizers and polymers used for the encapsulation of several active substances via double emulsion processes are reported. PMID- 26522981 TI - Cortical asymmetries in unaffected siblings of patients with obsessive-compulsive disorder. AB - Obsessive-compulsive disorder (OCD) is considered to be associated with atypical brain asymmetry. However, no study has examined the asymmetry in OCD from the perspective of cortical morphometry. This study is aimed to describe the characteristics of cortical asymmetry in OCD patients, and to investigate whether these features exist in their unaffected siblings - a vital step in identifying putative endophenotypes for OCD. A total of 48 subjects (16 OCD patients, 16 unaffected siblings, and 16 matched controls) were recruited who had complete magnetic resonance imaging scans. Left-right hemispheric asymmetries of cortical thickness were measured using a surface-based threshold-free cluster enhancement method. OCD patients and siblings both showed leftward asymmetries of cortical thickness in the anterior cingulate cortex (ACC), which showed a significant positive correlation with compulsive subscale scores. In addition, siblings and healthy controls showed significantly decreased leftward asymmetries in the orbitofrontal cortex (OFC), and the decreased leftward bias in the OFC was accompanied by lower scales on the Yale-Brown Obsessive-Compulsive Scale. To sum up, leftward asymmetries of cortical thickness in the ACC may represent an endophenotype of increased hereditary risk for OCD, while decreased leftward asymmetries of cortical thickness in the OFC may represent a protective factor. PMID- 26522983 TI - Introducing a combined approach of empirical mode decomposition and PCA methods for maternal and fetal ECG signal processing. AB - OBJECTIVES: The purpose of this study was to evaluate the effectiveness of the non-linear adaptive combined approach on the analysis of maternal and fetal signals corrupted by noise. METHODS: Empirical mode decomposition (EMD) is a non linear adaptive technic for data analysis and has been widely used in biomedical data. When we apply EMD on ECG signals, the number of modes that contain cardiac information may vary regarding the subject, type of the signal and recording conditions. This fact can cause some difficulties in signal reconstruction and noise removal using the derived modes. For overcoming this issue, we designed a method to combine principal component analysis (PCA) method with EMD to remove the correlation between the calculated modes and provide a smaller set of uncorrelated orthogonal. RESULTS: We have developed a combined method that proves the power of using PCA on the output of EMD method. The combined method reduces the power of oscillatory artifacts of the baseline. Thus, the PCA-EMD combination provides a noise-free signal. CONCLUSIONS: The combination of EMD and PCA methods worked well in being adaptive (from of EMD) and reconstruction (from PCA). It has been proved that this combined method is helpful in separating the signal components, especially in extracting the pure data from the baseline fluctuations. PMID- 26522984 TI - The PIAS-like Coactivator Zmiz1 Is a Direct and Selective Cofactor of Notch1 in T Cell Development and Leukemia. AB - Pan-NOTCH inhibitors are poorly tolerated in clinical trials because NOTCH signals are crucial for intestinal homeostasis. These inhibitors might also promote cancer because NOTCH can act as a tumor suppressor. We previously reported that the PIAS-like coactivator ZMIZ1 is frequently co-expressed with activated NOTCH1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we show that similar to Notch1, Zmiz1 was important for T cell development and controlled the expression of certain Notch target genes, such as Myc. However, unlike Notch, Zmiz1 had no major role in intestinal homeostasis or myeloid suppression. Deletion of Zmiz1 impaired the initiation and maintenance of Notch-induced T-ALL. Zmiz1 directly interacted with Notch1 via a tetratricopeptide repeat domain at a special class of Notch-regulatory sites. In contrast to the Notch cofactor Maml, which is nonselective, Zmiz1 was selective. Thus, targeting the NOTCH1-ZMIZ1 interaction might combat leukemic growth while avoiding the intolerable toxicities of NOTCH inhibitors. PMID- 26522985 TI - Crossreactive alphabeta T Cell Receptors Are the Predominant Targets of Thymocyte Negative Selection. AB - The precise impact of thymic positive and negative selection on the T cell receptor (TCR) repertoire remains controversial. Here, we used unbiased, high throughput cloning and retroviral expression of individual pre-selection TCRs to provide a direct assessment of these processes at the clonal level in vivo. We found that 15% of random TCRs induced signaling and directed positive (7.5%) or negative (7.5%) selection, depending on strength of signal, whereas the remaining 85% failed to induce signaling or selection. Most negatively selected TCRs exhibited promiscuous crossreactivity toward multiple other major histocompatibility complex (MHC) haplotypes. In contrast, TCRs that were positively selected or non-selected were minimally crossreactive. Negative selection of crossreactive TCRs led to clonal deletion but also recycling into intestinal CD4(-)CD8beta(-) intraepithelial lymphocytes (iIELs). Thus, broadly crossreactive TCRs arise at low frequency in the pre-selection repertoire but constitute the primary drivers of thymic negative selection and iIEL lineage differentiation. PMID- 26522987 TI - Immobilization of proteins onto microbeads using a DNA binding tag for enzymatic assays. AB - A novel DNA-binding protein tag, scCro-tag, which is a single-chain derivative of the bacteriophage lambda Cro repressor, has been developed to immobilize proteins of interest (POI) on a solid support through binding OR consensus DNA (ORC) that is tightly bound by the scCro protein. The scCro-tag successfully bound a transglutaminase 2 (TGase 2) substrate and manganese peroxidase (MnP) to microbeads via scaffolding DNA. The resulting protein-coated microbeads can be utilized for functional analysis of the enzymatic activity using flow cytometry. The quantity of bead-bound proteins can be enhanced by increasing the number of ORCs. In addition, proteins with the scCro-tag that were synthesized using a cell free protein synthesis system were also immobilized onto the beads, thus indicating that this bead-based system would be applicable to high-throughput analysis of various enzymatic activities. PMID- 26522986 TI - The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation. AB - Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions. PMID- 26522988 TI - Correlations between Fruit, Vegetables, Fish, Vitamins, and Fatty Acids Estimated by Web-Based Nonconsecutive Dietary Records and Respective Biomarkers of Nutritional Status. AB - BACKGROUND: It is of major importance to measure the validity of self-reported dietary intake using web-based instruments before applying them in large-scale studies. OBJECTIVE: This study aimed to validate self-reported intake of fish, fruit and vegetables, and selected micronutrient intakes assessed by a web-based self-administered dietary record tool used in the NutriNet-Sante prospective cohort study, against the following concentration biomarkers: plasma beta carotene, vitamin C, and n-3 polyunsaturated fatty acids. PARTICIPANTS/SETTING: One hundred ninety-eight adult volunteers (103 men and 95 women, mean age=50.5 years) were included in the protocol: they completed 3 nonconsecutive-day dietary records and two blood samples were drawn 3 weeks apart. The study was conducted in the area of Paris, France, between October 2012 and May 2013. MAIN OUTCOME MEASURES: Reported fish, fruit and vegetables, and selected micronutrient intakes and plasma beta carotene, vitamin C, and n-3 polyunsaturated fatty acid levels were compared. STATISTICAL ANALYSES: Simple and adjusted Spearman's rank correlation coefficients were estimated after de-attenuation for intra-individual variation. RESULTS: Regarding food groups in men, adjusted correlations ranged from 0.20 for vegetables and plasma vitamin C to 0.49 for fruits and plasma vitamin C, and from 0.40 for fish and plasma c20:5 n-3 (eicosapentaenoic acid [EPA]) to 0.55 for fish and plasma c22:6 n-3 (docosahexaenoic acid). In women, correlations ranged from 0.13 (nonsignificant) for vegetables and plasma vitamin C to 0.41 for fruits and vegetables and plasma beta carotene, and from 0.27 for fatty fish and EPA to 0.54 for fish and EPA+docosahexaenoic acid. Regarding micronutrients, adjusted correlations ranged from 0.36 (EPA) to 0.58 (vitamin C) in men and from 0.32 (vitamin C) to 0.38 (EPA) in women. CONCLUSIONS: The findings suggest that three nonconsecutive web-based dietary records provide reasonable estimates of true intake of fruits, vegetables, fish, beta carotene, vitamin C, and n-3 fatty acids. Along with other validation studies, this study shows acceptable validity of using such diet-assessment methods in large epidemiologic surveys and broadens new perspectives for epidemiology. PMID- 26522990 TI - An activated fluid stream--New techniques for cold water cleaning. AB - Electrochemical, acoustic and imaging techniques are used to characterise surface cleaning with particular emphasis on the understanding of the key phenomena relevant to surface cleaning. A range of novel techniques designed to enhance and monitor the effective cleaning of a solid/liquid interface is presented. Among the techniques presented, mass transfer of material to a sensor embedded in a surface is demonstrated to be useful in the further exploration of ultrasonic cleaning of high aspect ratio micropores. In addition the effect of micropore size on the cleaning efficacy is demonstrated. The design and performance of a new cleaning system reliant on the activation of bubbles within a free flowing stream is presented. This device utilised acoustic activation of bubbles within the stream and at a variety of substrates. Finally, a controlled bubble swarm is generated in the stream using electrolysis, and its effect on both acoustic output and cleaning performance are compared to the case when no bubbles are added. This will demonstrate the active role that the electrochemically generated bubble swarm can have in extending the spatial zone over which cleaning is achieved. PMID- 26522989 TI - Sarcocystis fayeri in skeletal muscle of horses with neuromuscular disease. AB - Recent reports of Sarcocystis fayeri-induced toxicity in people consuming horse meat warrant investigation on the prevalence and molecular characterization of Sarcocystis spp. infection in horses. Sarcocysts in skeletal muscle of horses have been commonly regarded as an incidental finding. In this study, we investigated the prevalence of sarcocysts in skeletal muscle of horses with neuromuscular disease. Our findings indicated that S. fayeri infection was common in young mature horses with neuromuscular disease and could be associated with myopathic and neurogenic processes. The number of infected muscles and number of sarcocysts per muscle were significantly higher in diseased than in control horses. S. fayeri was predominantly found in low oxidative highly glycolytic myofibers. This pathogen had a high glycolytic metabolism. Common clinical signs of disease included muscle atrophy, weakness with or without apparent muscle pain, gait deficits, and dysphagia in horses with involvement of the tongue and esophagus. Horses with myositis were lethargic, apparently painful, stiff, and reluctant to move. Similar to humans, sarcocystosis and cardiomyopathy can occur in horses. This study did not establish causality but supported a possible association (8.9% of cases) with disease. The assumption of Sarcocysts spp. being an incidental finding in every case might be inaccurate. PMID- 26522991 TI - Emotion-attention interactions in fear conditioning: Moderation by executive load, neuroticism, and awareness. AB - Despite increasing evidence suggesting interactive effects of emotion and attention on perceptual processing, it still remains unclear how their interplay influences affective learning, such as fear conditioning. In the present study, a conditioning procedure using threat-related conditioned stimuli (CSs) was implemented while executive load and attentional focus were manipulated. The modulation effects of neuroticism and contingency awareness were also examined. Results showed that fear conditioning depended on the available executive resources even with threat-related CSs. In addition, although individuals with high neuroticism showed an enhanced conditioning effect overall, this facilitation effect still depended on the availability of executive resources. Finally, the impact of attentional focus was most evident among individuals with high neuroticism who were aware of the contingency. Overall, the present study demonstrates interactive effects of emotion and attention in fear conditioning, while illuminating mechanisms of individual differences and clarifying the controversial role of contingency awareness in fear conditioning. PMID- 26522992 TI - Antioxidant Capacity Determination of Complex Samples and Individual Phenolics - Multilateral Approach. AB - Antioxidant (AO) capacity of various medicinal plants extracts and phenolic compounds was assessed by the most widely used spectrophotometric assays such as ferric reducing antioxidant power (FRAP) and scavenging of 2,2-azino-bis-3 ethylbenzothiazoline-6-sulfonic acid (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH). In addition, two direct current (DC) polarographic assays, one based on a decrease of anodic current of [Hg(O2H)(OH)] - HydroxoPerhydroxoMercury(II) Complex (HPMC) formation in alkaline solution of H2O2, at the potential of mercury dissolution and another recently developed Mercury Reduction Antioxidant Power (MRAP), based on a a decrease of cathodic current of Hg(II) reduction were employed. Percentage of both currents decrease was plotted versus the volume of gradually added complex samples or the amount of individual ones and the slopes of these plots were used to express AO capacity. Total phenolic content (TPC) of extracts was determined by Folin- Ciocalteu (FC) assay. Correlations between applied assays were calculated by regression analysis. Relative Antioxidant Capacity Index (RACI), calculated by assigning equal weight to all applied assays and Phenolic Antioxidant Coefficients (PAC), calculated as a ratio between particular AO capacity and TPC, were used to achieve more comprehensive comparison between analyzed samples, as well as applied assays. PMID- 26522993 TI - A Rapid Python-Based Methodology for Target-Focused Combinatorial Library Design. AB - The chemical space is so vast that only a small portion of it has been examined. As a complementary approach to systematically probe the chemical space, virtual combinatorial library design has extended enormous impacts on generating novel and diverse structures for drug discovery. Despite the favorable contributions, high attrition rates in drug development that mainly resulted from lack of efficacy and side effects make it increasingly challenging to discover good chemical starting points. In most cases, focused libraries, which are restricted to particular regions of the chemical space, are deftly exploited to maximize hit rate and improve efficiency at the beginning of the drug discovery and drug development pipeline. This paper presented a valid methodology for fast target focused combinatorial library design in both reaction-based and production-based ways with the library creating rates of approximately 70,000 molecules per second. Simple, quick and convenient operating procedures are the specific features of the method. SHAFTS, a hybrid 3D similarity calculation software, was embedded to help refine the size of the libraries and improve hit rates. Two target-focused (p38-focused and COX2-focused) libraries were constructed efficiently in this study. This rapid library enumeration method is portable and applicable to any other targets for good chemical starting points identification collaborated with either structure-based or ligand-based virtual screening. PMID- 26522994 TI - Time to use mobile health devices to diagnose paroxysmal atrial fibrillation. PMID- 26522995 TI - Fukuoka University apolipoprotein A-I mimetic peptide (FAMP): A novel potential therapeutic for myocardial ischemia reperfusion injury. PMID- 26522996 TI - Hypertensive heart disease in paced-hearts. PMID- 26522997 TI - Inadequate anticoagulation by Vitamin K antagonists and major adverse cardiovascular events other than stroke. PMID- 26522998 TI - Reply to: "Inadequate anticoagulation by vitamin K antagonists and major adverse cardiovascular events other than stroke". PMID- 26522999 TI - Electromechanical delay of the hamstrings during eccentric muscle actions in males and females: Implications for non-contact ACL injuries. AB - Sex differences in neuromuscular functioning has been proposed as one of the factors behind an increased relative risk of non-contact anterior cruciate ligament (ACL) injury in females. The aim of this study was to explore sex differences in electromechanical delay (EMD) of the hamstring muscles during eccentric muscle actions and during a range of movement velocities. This study recruited 110 participants (55 males, 55 females) and electromyography of the semitendinosus, semimembranosus and biceps femoris was determined during eccentric actions at 60, 120 and 240 degrees /s. No significant sex differences were observed irrespective of muscle examined or movement velocity. Irrespective of sex EMD significantly increased with increasing movement velocity (P < 0.01). There was no significant difference in the EMD of the 3 muscles examined. Our findings suggest that during eccentric actions of the hamstrings that there are no sex differences, irrespective of movement velocity. This would suggest that other factors are probably responsible for the increased relative risk of non contact ACL injury in females compared to males. PMID- 26523000 TI - Erratum. PMID- 26523001 TI - Tough and competent. PMID- 26523003 TI - Squire 2.0 (Standards for Quality Improvement Reporting Excellence): revised publication guidelines from a detailed consensus process. AB - Since the publication of Standards for Quality Improvement Reporting Excellence (SQUIRE 1.0) guidelines in 2008, the science of the field has advanced considerably. In this manuscript, we describe the development of SQUIRE 2.0 and its key components. We undertook the revision between 2012 and 2015 using (1) semistructured interviews and focus groups to evaluate SQUIRE 1.0 plus feedback from an international steering group, (2) two face-to-face consensus meetings to develop interim drafts, and (3) pilot testing with authors and a public comment period. SQUIRE 2.0 emphasizes the reporting of 3 key components of systematic efforts to improve the quality, value, and safety of health care: the use of formal and informal theory in planning, implementing, and evaluating improvement work; the context in which the work is done; and the study of the intervention(s). SQUIRE 2.0 is intended for reporting the range of methods used to improve health care, recognizing that they can be complex and multidimensional. It provides common ground to share these discoveries in the scholarly literature (www.squire-statement.org). PMID- 26523004 TI - Lived experience of the intensive care unit for patients who experienced delirium. AB - BACKGROUND: Delirium is a common occurrence for patients in the intensive care unit and can have a profound and lasting impact on them. Few studies describe the experience of intensive care patients who have had delirium. OBJECTIVE: To understand the lived experience of intensive care for critically ill patients who experienced delirium. METHODS: The study participants consisted of 7 men and 3 women, 46 to 70 years old, who had delirium according to the Confusion Assessment Method for the Intensive Care Unit. The van Manen method of hermeneutic phenomenology was used, and data collection entailed audio recorded semistructured interviews. RESULTS: Four themes were detected: "I can't remember," "Wanting to make a connection," "Trying to get it straight," and "Fear and safety concerns." CONCLUSION: Nurses working in intensive care units need to assess patients for delirium, assess the mental status of patients who have delirium, and help patients and patients' families learn about and deal with the psychological effects of the intensive care unit experience. PMID- 26523005 TI - Validation of the confusion assessment method in detecting postoperative delirium in cardiac surgery patients. AB - BACKGROUND: Early detection, prevention, and treatment of delirium after cardiac surgery are important for quick postoperative recovery. The Confusion Assessment Method (CAM) may be an easy-to-use instrument for detecting delirium in clinical practice. OBJECTIVES: To compare the congruent validity of the CAM with the results from repeated assessments by using a combination of the Organic Brain Syndrome Scale and the Mini-Mental State Examination according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) criteria for delirium. METHODS: Patients aged 70 years or older undergoing cardiac surgery were assessed on postoperative days 1 and 4, and the 2 diagnostic methods were compared. The sensitivity and specificity of the CAM were examined. The reference method allowed categorization of delirium into subgroups of psychomotor activities and psychiatric symptom profiles, which were compared with the CAM results. RESULTS: Postoperative delirium was diagnosed in 78 of 141 patients (55.3%). According to the CAM, 59 patients (41.8%) were categorized as delirious, 53 correctly. Thus, the sensitivity was 68% and the specificity was 90%, indicating false-negative rather than false-positive observations. CONCLUSION: Patients with psychomotor hyperactivity and mixed psychotic-emotional symptoms were more likely to have delirium detected via the CAM than were patients with less obvious clinical manifestations of delirium. Repetitive cognitive testing and psychogeriatric experience are probably necessary to improve the results obtained with the CAM. PMID- 26523006 TI - Use of physical restraints in Dutch intensive care units: a prospective multicenter study. AB - BACKGROUND: Increasing evidence indicates that harmful effects are associated with the use of physical restraint. OBJECTIVES: To characterize the use of physical restraint in intensive care units. Prevalence, adherence to protocols, and correlates of the use of physical restraint were determined. For comparisons between ICUs, adjustments were made for differences in patients' characteristics. METHODS: A prospective, cross-sectional, observational multicenter study with a representative sample (n = 25) of all Dutch intensive care units, ranging from local hospitals to academic centers. Each unit was visited twice, and all 379 patients admitted during these visits were included and were examined for use of physical restraint. RESULTS: Physical restraint was used in 23% of all patients (range, 0%-56% for different units). Of all 346 nurses interviewed, 31% reported using a protocol when applying physical restraint. When corrections were made for clustering within units, the risk for use of physical restraint was increased in patients with delirium or coma, in patients who could not communicate verbally, and in patients receiving psychoactive or sedative medications. Sex, severity of illness, and nurse to patient ratio were not independently related to use of physical restraint. In 11 units (44%), use of physical restraint was more frequent than expected on the basis of patients' characteristics, although this finding was not significant. CONCLUSIONS: Physical restraint is frequently used in Dutch intensive care units. The differences in frequency between units suggest that opportunities exist to limit the use of physical restraint. PMID- 26523007 TI - Standardizing communication from acute care providers to primary care providers on critically ill adults. AB - OBJECTIVE: To increase the frequency of communication of patient information between acute and primary care providers. A secondary objective was to determine whether higher rates of communication were associated with lower rates of hospital readmission 30 days after discharge. METHODS: A validated instrument was used for telephone surveys before and after an intervention designed to increase the frequency of communication among acute care and primary care providers. The communication intervention was implemented in 3 adult intensive care units from 2 campuses of an academic medical center. RESULTS: The frequency of communication among acute care and primary care providers, the perceived usefulness of the intervention, and its association with 30-day readmission rates were assessed for 202 adult intensive care episodes before and 100 episodes after a communication intervention. The frequency of documented communication increased significantly (5/202 or 2% before to 72/100 or 72% after the intervention; P < .001) and the communication was considered useful by every participating primary care provider. Rates of rehospitalization at 30 days were lower for the intervention group than the preintervention group, but the difference was not statistically significant (41/202 or 23% vs 16/88 or 18% of discharged patients; P = .45; power 0.112 at P = .05). CONCLUSIONS: The frequency of communication episodes that provide value can be increased through standardized processes. The key aspects of this effective intervention were setting the expectation that communication should occur, documenting when communication has occurred, and reviewing that documentation during multiprofessional rounds. PMID- 26523008 TI - Vasopressors and development of pressure ulcers in adult critical care patients. AB - BACKGROUND: Vasopressors are lifesaving agents used to raise mean arterial pressure in critically ill patients in shock states. The pharmacodynamics of these agents suggest vasopressors may play a role in development of pressure ulcers; however, this aspect has been understudied. OBJECTIVE: To examine associations between type, dose, and duration of vasopressors (norepinephrine, epinephrine, vasopressin, phenylephrine, dopamine) and development of pressure ulcers in medical-surgical and cardiothoracic intensive care unit patients and to examine predictors of the development of pressure ulcers in these patients. METHODS: A retrospective correlational design was used in a sample of 306 medical surgical and cardiothoracic intensive care unit patients who received vasopressor agents during 2012. RESULTS: Norepinephrine and vasopressin were significantly associated with development of pressure ulcers; vasopressin was the only significant predictor in multivariate analysis. In addition, mean arterial pressure less than 60 mm Hg in patients receiving vasopressors, cardiac arrest, and mechanical ventilation longer than 72 hours were predictive of development of pressure ulcers. Patients with a cardiac diagnosis at the time of admission to the intensive care unit were less likely than patients without such a diagnosis to experience pressure ulcers while in the unit. CONCLUSION: The addition of vasopressin administered concomitantly with a first-line agent (often norepinephrine) may represent the point at which the risk for pressure ulcers escalates and may be an early warning to heighten strategies to prevent pressure ulcers. Conversely, because vasopressors cannot be terminated to avert development of pressure ulcers, these findings may add to the body of knowledge on factors that potentially contribute to the development of unavoidable pressure ulcers. PMID- 26523009 TI - Validity and sensitivity of 6 pain scales in critically ill, intubated adults. AB - BACKGROUND: Self-report is the best indicator of pain; however, pain is more difficult to assess in noncommunicative patients who may be receiving mechanical ventilation or sedated and unable to report pain. OBJECTIVES: To evaluate the validity and sensitivity of 6 pain scales (Adult Nonverbal Pain Scale; Behavior Pain Scale [BPS]; Comfort Scale; FACES; Face, Legs, Activity, Cry, and Consolability scale; Pain Assessment Behavioral Scale with Numeric Rating Scale [NRP]) to identify the best measure of pain in noncommunicative patients. METHODS: Fifty communicative and 100 noncommunicative patients receiving mechanical ventilation were observed before and during routine physical examination and endotracheal tube suctioning. RESULTS: All pain scales had moderate to high correlations with the patient's self-report during suctioning. The FACES score reported by the patient had the highest correlation with the patient's NRP score (r = 0.76, P < .001) during suctioning; associations between the BPS and NRP scores during physical examination were the weakest (r = 0.21, P = .20). All scales were sensitive in capturing the patient's pain response in all phases (P < .001); sensitivity was higher during suctioning (P < .001). Both participants and investigators rated pain higher on the FACES scale. CONCLUSIONS: These pain scales commonly used in noncommunicative critically ill adult patients are valid and sensitive for capturing changes in pain response during suctioning in both communicative and noncommunicative patients. However, caution must be used when using the FACES scale because subjectivity may lead to overtreatment or undertreatment of pain. PMID- 26523010 TI - Verifying placement of small-bore feeding tubes: electromagnetic device images versus abdominal radiographs. AB - BACKGROUND: Clinicians are unsure if radiography is needed to confirm correct positioning of feeding tubes inserted with assistance from an electromagnetic system. OBJECTIVES: To compare radiographic reports of feeding tube placement with images generated by an electromagnetic feeding tube placement device. METHODS: The medical records of 200 consecutive patients who had feeding tubes inserted with assistance from an electromagnetic feeding tube placement device were reviewed retrospectively. Radiographic reports of tube site were compared with images generated by the device. RESULTS: Radiographic evidence of tube sites was available in 188 cases: 184 tubes were located in portions of the gastrointestinal tract. Ninety of the 188 tubes were situated in the optimal site (distal duodenum or jejunum) radiographically. Images generated by the electromagnetic device were available in 176 cases; of these, 52 tubes appeared to end in the expected left lower quadrant. Tubes shown on radiographs to be in other sites also occasionally appeared to end in the left lower quadrant. Nurses using the device did not recognize 4 of the 188 tubes (2.1%) that were inadvertently placed in the lung. No consistent pattern of quadrant distribution was found for tubes positioned in the stomach or proximal duodenum. CONCLUSIONS: Images generated by the electromagnetic tube placement device provided inconsistent results regarding tube location. A small percentage of seriously malpositioned tubes were not detected by using the electromagnetic device. These findings do not support eliminating radiographs to confirm correct tube placement following use of an electromagnetic tube placement device. PMID- 26523011 TI - Increasing parental participation during rounds in a pediatric cardiac intensive care unit. AB - BACKGROUND: Inviting parents of sick children to participate during the rounding process may reduce parents' anxiety and improve communication between the parents and the health care team. OBJECTIVES: To increase the percentage of available parents invited to participate in morning rounds in a pediatric cardiothoracic intensive care unit (CTICU). METHODS: Invitations to parents to participate in morning CTICU rounds were randomly audited from June 2012 to April 2014 (mean, 15 audits per month). From June 2012 to February 2013 (before intervention), 73% of parents available during morning rounds received an invitation to participate. From April 2013 to May 2013, the following interventions (family participation bundle) were implemented: (1) staff education, (2)"Invitation to Rounds" handout added to the parent welcome packet with verbal explanation, (3) bedside tool provided for parents to communicate desire to participate in rounds with the team, (4) reminder to invite parents added to nursing rounding sheet. Following interventions, family feedback was obtained by 1-on-1 (physician-parent) open ended conversation. RESULTS: From April 2013 to April 2014, 94% of parents available during morning rounds received an invitation to participate. Reasons for not participating: chose not to participate (63%), sleeping-staff reluctant to wake (25%), not English speaking (7%), breastfeeding (5%). CONCLUSION: Implementation of a family participation bundle was successful in increasing invitations to parents to participate during morning rounds in the CTICU. Engagement of staff and addressing specific staff concerns was instrumental in the project's success. PMID- 26523012 TI - Family presence during invasive procedures. PMID- 26523013 TI - The "cold cord": a review of therapeutic hypothermia for traumatic spinal cord injuries. PMID- 26523014 TI - Bedside ECG alarm management. PMID- 26523015 TI - Being there: inpatients' perceptions of family presence during resuscitation and invasive cardiac procedures. AB - BACKGROUND: Although patients' families want to be invited to the bedside of hospitalized loved ones during crisis events, little is known about patients' perceptions of family presence. OBJECTIVE: To explore adult inpatients' perceptions of family presence during resuscitation, near-resuscitation, and unplanned invasive cardiac procedures shortly after the life-threatening event. METHODS: In this qualitative study, data were collected by interviews at least 13 hours after a crisis event and before hospital discharge. Data were audio recorded, transcribed, and analyzed for themes. RESULTS: From the bedside interviews (N = 48), the overarching theme of "being there" was explained more specifically as "being there is beneficial," "being there is hard," "families in the way," and "desire for control." Most participants preferred family presence, although preferences varied with types of crisis events, patients' predictions of family members' responses, and the nature of family relationships. New perspectives emerged about patients' decision making related to family presence. CONCLUSIONS: This study extends existing knowledge about factors that influence the decision-making processes of hospitalized patients regarding family presence during a crisis event. Health care professionals can provide support as patients ponder difficult decisions about who to have present and can reduce patients' fears that families might interfere with the life-saving efforts. PMID- 26523016 TI - Semiquantitative cough strength score for predicting reintubation after planned extubation. AB - BACKGROUND: Semiquantitative cough strength score (SCSS, graded 0-5) and cough peak flow (CPF) have been used to predict extubation outcome in patients in whom extubation is planned; however, the correlation of the 2 assessments is unclear. METHODS: In the intensive care unit of a university-affiliated hospital, 186 patients who were ready for extubation after a successful spontaneous breathing trial were enrolled in the study. Both SCSS and CPF were assessed before extubation. Reintubation was recorded 72 hours after extubation. RESULTS: Reintubation rate was 15.1% within 72 hours after planned extubation. Patients in whom extubation was successful had higher SCSSs than did reintubated patients (mean [SD], 3.2 [1.6] vs 2.2 [1.6], P = .002) and CPF (74.3 [40.0] vs 51.7 [29.4] L/min, P = .005). The SCSS showed a positive correlation with CPF (r = 0.69, P < .001). Mean CPFs were 38.36 L/min, 39.51 L/min, 44.67 L/min, 57.54 L/min, 78.96 L/min, and 113.69 L/min in patients with SCSSs of 0, 1, 2, 3, 4, and 5, respectively. The discriminatory power for reintubation, evidenced by area under the receiver operating characteristic curve, was similar: 0.677 for SCSS and 0.678 for CPF (P = .97). As SCSS increased (from 0 to 1 to 2 to 3 to 4 to 5), the reintubation rate decreased (from 29.4% to 25.0% to 19.4% to 16.1% to 13.2% to 4.1%). CONCLUSIONS: SCSS was convenient to measure at the bedside. It was positively correlated with CPF and had the same accuracy for predicting reintubation after planned extubation. PMID- 26523017 TI - Peripheral muscle strength and correlates of muscle weakness in patients receiving mechanical ventilation. AB - BACKGROUND: Intensive care unit-acquired weakness is a frequent complication of critical illness because of patients' immobility and prolonged use of mechanical ventilation. OBJECTIVES: To describe daily measurements of peripheral muscle strength in patients receiving mechanical ventilation and explore relationships among factors that influence intensive care unit-acquired weakness. METHODS: Peripheral muscle strength of 120 critically ill patients receiving mechanical ventilation was measured daily by using a standardized handgrip dynamometry protocol. Three grip measurements for each hand were recorded in pounds-force; the mean of these 3 assessments was used in the analysis. Correlates of intensive care unit-acquired weakness (age, sex, illness severity, duration of mechanical ventilation, medications) were analyzed by using mixed models to explore the relationship to grip strength. RESULTS: Median baseline grip strength was variable yet diminished (7.7 pounds-force), with either a pattern of diminishing grip strength or maintenance of the baseline low grip strength over time. With controls for days of measurement, female sex (beta = -10.4; P < .001), age (beta = -0.24; P = .004), and days receiving mechanical ventilation (beta = -0.34; P = .005) explained a significant amount of variance in grip strength over time. CONCLUSIONS: Patients receiving prolonged mechanical ventilation had marked decrements in grip strength, measured by hand dynamometry, a marker for peripheral muscle strength. Hand dynamometry is a reliable method for measuring muscle strength in cooperative critically ill patients and can be used to develop interventions to prevent intensive care unit-acquired weakness. PMID- 26523018 TI - Perceived barriers to anthropometric measurements in critically ill children. AB - BACKGROUND: Anthropometric measurements are vital for safe care in pediatric intensive care units. OBJECTIVE: To identify barriers to anthropometric measurements and determine if perceptions of barriers differ between ordering providers and nurses. METHODS: A 21-item survey to elicit perceptions of barriers to obtaining anthropometric measurements was distributed via e-mail to societies with members who provide care in pediatric intensive care units. RESULTS: Most of the 258 eligible respondents (46% ordering providers) were from North America (90%). Although 84% agreed that anthropometric measurements are important, only 3% knew if these measurements were obtained upon admission to their unit. Estimates of patients' measurements by parents or caregivers were commonly used (72%) when actual measurements were not obtained. Leading barriers were presence of medical devices (57%), use of extracorporeal life support (54%), and unstable hemodynamic status (52%). More ordering providers than nurses considered osteopenia/fragile bones as a barrier to weight measurement (46% vs 29%; P = .007) and traumatic brain injury a barrier to measurement of head circumference (42% vs 24%; P = .002). More nurses than ordering providers perceived dialysis (21% vs 9%; P = .01) and obesity (26% vs 15%; P = .04) as barriers to measurement of stature. Ordering providers more than nurses perceived nurses' workload (51% vs 33%; P < .001) and lack of importance (43% vs 20%; P < .001) as barriers. CONCLUSIONS: Barriers to obtaining anthropometric measurements exist in pediatric intensive care units; ordering providers and nurses have different perceptions of what constitutes a barrier. PMID- 26523019 TI - Rheumatoid Arthritis: Trends in Antirheumatic Drug Use, C-reactive Protein Levels, and Surgical Burden. AB - OBJECTIVE: Over the past decade, the therapeutic approach used to treat patients with rheumatoid arthritis (RA) has considerably changed. It remains unclear whether these changes have been accompanied by decreased disease severity and surgical treatment burden at the population level. Therefore, we investigated time trends in antirheumatic drug consumption, C-reactive protein (CRP) levels, and use of orthopedic surgery among Danish patients with RA. METHODS: Using medical databases, we identified all patients with RA living in Northern Denmark during 1996-2012. For each calendar year, we computed the annual rate of antirheumatic drug use (1996-2010), the median CRP value in mg/l (1996-2011), and the proportions of patients who underwent hip replacement and other orthopedic procedures (1996-2012). RESULTS: Antirheumatic drug consumption per patient increased 5-fold, from 145.0 defined daily doses (DDD) in 1996 to 695.4 DDD in 2010. Median CRP declined from 20.5 mg/l [interquartile range (IQR), 10.0 to 43.5 mg/l] in 1996 to 10.0 mg/l (IQR, 4.2-17.8 mg/l) in 2011. From 1996 to 2012, declining proportions of patients with RA underwent hip replacement (14.9% to 10.1%) and other joint operations (29.1% to 23.4%), while the annual proportion of patients who underwent soft tissue procedures increased from 20.7% to 23.4%. CONCLUSION: Antirheumatic drug consumption has substantially increased among patients with RA since 1996, in association with reduced disease activity (i.e., lower CRP levels), fewer joint procedures (including hip replacements), and more soft tissue procedures. PMID- 26523020 TI - Fatigue in Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis: Analysis from a Longitudinal Observation Cohort. AB - OBJECTIVE: In this study, we aimed to address the prevalence of fatigue, its associated factors, and the effect of tumor necrosis factor inhibitors (TNFi) on this subgroup of patients in a large axial spondyloarthritis (axSpA) cohort. METHODS: The study included 681 patients [ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA)]. The Fatigue Severity Scale (FSS) and the Bath AS Disease Activity Index question 1 (BASDAI Q1) indices were used for fatigue assessment. Severe fatigue was defined as an FSS >= 4 or a BASDAI Q1 >= 5. Disease activity, function, and quality of life (QoL) measures were recorded. Patients who had been treated with TNFi were identified, and baseline and followup data were analyzed. RESULTS: Of the cohort, 67.3% had severe fatigue, and the prevalence was similar between AS (67.2%) and nr-axSpA (68.2%). Severely fatigued patients tended to have higher disease activity scores, increased acute phase proteins, and decreased QoL measures. TNFi therapy was associated with improvement in disease activity, and although this treatment led to significantly decreased fatigue scores, this reduction was not optimal in the majority of patients with 80% continuing to have severe fatigue according to their posttreatment scores. Health Assessment Questionnaire, mean scores of BASDAI Q5 and Q6, and BASDAI enthesitis were independent predictors of fatigue severity. CONCLUSION: Fatigue is a common symptom in axSpA, and the burden of fatigue among patients with nr-axSpA is similar to that seen in AS. While biologics are effective in improving disease activity, their effect on fatigue is more limited. In axSpA, fatigue remains unresponsive to TNFi in nearly 80% of patients. PMID- 26523021 TI - Accelerometer Quantification of Physical Activity and Activity Patterns in Patients with Ankylosing Spondylitis and Population Controls. AB - OBJECTIVE: To compare the total amount of physical activity (TPA) and time spent in various activity intensities of patients with ankylosing spondylitis (AS) and population controls, and to explore factors related to physical activity (PA). METHODS: Subjects were asked to wear a triaxial accelerometer for 7 days and to complete a series of questionnaires. Multivariable regressions were used to assess generic determinants of TPA in patients and controls, and in patients to explore demographic and disease-specific determinants of various PA intensities. RESULTS: One hundred and thirty-five patients [51 +/- 13 yrs, 60% men, body mass index (BMI) 26.0 +/- 4.3 kg/m(2)] and 99 controls (45 +/- 12 yrs, 67% men, BMI 25.1 +/- 4.3 kg/m(2)) were included. Patients did not differ from controls regarding TPA (589 vs 608 vector count/min, p = 0.98), minutes/day spent in sedentary (524 vs 541, p = 0.17), and light PA (290 vs 290 p = 0.95), but spent fewer minutes/day in moderate to vigorous PA (MVPA; 23 vs 30 min/day, p = 0.006). Perceived functional ability (physical component summary of the Medical Outcomes Study Short Form-36) and BMI were associated with TPA independent of having AS (p interaction = 0.21 and 0.94, respectively). Additional analyses in patients showed that time spent in MVPA was negatively influenced by BMI, physical function (Bath AS Functional Index), and disease duration. In patients >= 52 years old, a higher Bath AS Disease Activity Index was associated with less time spent in sedentary and more time spent in light activities. CONCLUSION: Compared with controls, patients with AS had similar TPA, but may avoid engagement in higher intensities of PA. Lower levels of functional ability and higher BMI were associated with lower TPA in both patients and controls. PMID- 26523022 TI - Native Joint Septic Arthritis: Epidemiology, Clinical Features, and Microbiological Causes in a New Zealand Population. AB - OBJECTIVE: To determine the epidemiology, clinical features, and microbiology of adult native joint septic arthritis in Canterbury, New Zealand, over a 5-year period in individuals with and without an underlying rheumatic disorder. METHODS: Patients with native joint septic arthritis were identified retrospectively and classified by Newman's criteria. The clinical characteristics were described and comparisons made between those with and without underlying rheumatic disease. RESULTS: Two hundred forty-eight cases of native joint septic arthritis (mean age 60, range 16-97 yrs) were identified with an overall incidence rate of 12.0/100,000/year (95% CI 10.6-13.6). Yearly incidence increased with age to a maximum of 73.4/100,000 in those > 90 years of age. Septic arthritis was iatrogenic in 16.9% of cases while 27% had an underlying inflammatory arthritis including gout (14.9%), calcium pyrophosphate disease (8.5%), and rheumatoid arthritis (4%). Few patients were taking immunosuppressant therapy, with just 1 taking a biological agent. Staphylococcus aureus was the most commonly identified organism. Those with underlying inflammatory arthritis were significantly older (73.6 yrs vs 55.6 yrs; p < 0.001), more likely to be female (55.2% vs 26.0%; p < 0.001), and to have septic polyarthritis (16.4% vs 4.4%; p = 0.002). The 30-day mortality was 2%, increasing to 6% at 90 days. CONCLUSION: The incidence of septic arthritis in Canterbury, New Zealand, is higher than in previous studies. Crystal arthropathy commonly coexisted with infection although autoimmune arthritis and immunosuppression was less of a factor than anticipated. PMID- 26523023 TI - Association of Body Mass Index Categories with Disease Activity and Radiographic Joint Damage in Rheumatoid Arthritis: A Systematic Review and Metaanalysis. AB - OBJECTIVE: Obesity and overweight are increasing conditions. Adipose tissue with proinflammatory properties could be involved in rheumatoid arthritis (RA) activity and radiographic progression. This study aims to investigate the influence of overweight and obesity on RA activity and severity. METHODS: We conducted a systematic review and metaanalysis to assess the association of body mass index (BMI) categories with the Disease Activity Score in 28 joints (DAS28), functional disability [Health Assessment Questionnaire (HAQ)], and radiographic joint damage in patients with RA. We searched Medline through PubMed, EMBASE, and the Cochrane Database of Systematic Reviews for all studies assessing DAS28, HAQ, or/and radiographic damage according to predefined BMI groups. RESULTS: Among the 737 citations retrieved, 58 articles met the inclusion criteria and 7 were included in the metaanalysis. DAS28 was higher in obese (BMI > 30 kg/m(2)) than non-obese (BMI <= 30 kg/m(2)) patients (mean difference 0.14, 95% CI 0.01-0.27, p = 0.04, I(2) = 0%). HAQ score was also higher among obese patients (mean difference 0.10, 95% CI 0.01-0.19, p = 0.03, I(2) = 0%). Radiographic joint damage was negatively associated with obesity (standardized mean difference 0.15, 95% CI -0.29 to -0.02, p = 0.03, I(2) = 38%). CONCLUSION: Obesity in RA is associated with increased DAS28 and HAQ score and with lower radiographic joint damage. These associations mainly result from an increase of subjective components of the DAS28 (total joint count and global health assessment) in obese patients. Conflicting results were reported concerning inflammation markers (C reactive protein and erythrocyte sedimentation rate). PMID- 26523024 TI - CanVasc Recommendations for the Management of Antineutrophil Cytoplasm Antibody associated Vasculitides. AB - OBJECTIVE: The Canadian Vasculitis research network (CanVasc) is composed of physicians from different medical specialties and researchers with expertise in vasculitis. One of its aims is to develop recommendations for the diagnosis and management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. METHODS: Diagnostic and therapeutic questions were developed based on the results of a national needs assessment survey. A systematic review of existing non-Canadian recommendations and guidelines for the diagnosis and management of AAV and studies of AAV published after the 2009 European League Against Rheumatism/European Vasculitis Society recommendations (publication date: January 2009) until November 2014 was performed in the Medline database, Cochrane library, and main vasculitis conference proceedings. Quality of supporting evidence for each therapeutic recommendation was graded. The full working group as well as additional reviewers, including patients, reviewed the developed therapeutic recommendations and nontherapeutic statements using a modified 2-step Delphi technique and through discussion to reach consensus. RESULTS: Nineteen recommendations and 17 statements addressing general AAV diagnosis and management were developed, as well as appendices for practical use, for rheumatologists, nephrologists, respirologists, general internists, and all other healthcare professionals more occasionally involved in the management of patients with AAV in community and academic practice settings. CONCLUSION: These recommendations were developed based on a synthesis of existing international guidelines, other published supporting evidence, and expert consensus considering the Canadian healthcare context, with the intention of promoting best practices and improving healthcare delivery for patients with AAV. PMID- 26523025 TI - Incidence and Predictors of Biological Antirheumatic Drug Discontinuation Attempts among Patients with Rheumatoid Arthritis in Remission: A CORRONA and NinJa Collaborative Cohort Study. AB - OBJECTIVE: We conducted a longitudinal observational study of biological disease modifying antirheumatic drugs (bDMARD) to describe the proportions of patients with rheumatoid arthritis in remission who discontinued these agents, and to assess the potential predictors of the decision to discontinue. METHODS: We used data from the US COnsortium of Rheumatology Researchers Of North America (CORRONA) and the Japanese National Database of Rheumatic Diseases by iR-net in Japan (NinJa) registries, and ran parallel analyses. Patients treated with bDMARD who experienced remission (defined by the Clinical Disease Activity Index <= 2.8) were included. The outcome of interest was the occurrence of bDMARD discontinuation while in remission. The predictors of discontinuation were assessed in the Cox regression models. Frailty models were also used to examine the effects of individual physicians in the discontinuation decision. RESULTS: The numbers of eligible patients who were initially in remission were 6263 in the CORRONA and 744 in the NinJa. Among these patients, 10.0% of patients in CORRONA and 11.8% of patients in NinJa discontinued bDMARD while in remission over 5 years, whereas many of the remaining patients lost remission before discontinuing bDMARD. Shorter disease duration was associated with higher rates of discontinuation in both cohorts. In CORRONA, methotrexate use and lower disease activity were also associated with discontinuation. In frailty models, physician random effects were significant in both cohorts. CONCLUSION: Among patients who initially experienced remission while receiving bDMARD, around 10% remained in remission and then discontinued bDMARD in both registries. Several factors were associated with more frequent discontinuation while in remission. Physician preference likely is also an important correlate of bDMARD discontinuation, indicating the need for standardization of practice. PMID- 26523026 TI - Clinical and Economic Burden of Antineutrophil Cytoplasmic Antibody-associated Vasculitis in the United States. AB - OBJECTIVE: To describe the prevalence of major relapse and healthcare costs among patients with granulomatosis with polyangiitis (GPA); to find patients with microscopic polyangiitis (MPA) in administrative databases, because no MPA diagnosis code exists; and to describe the clinical and economic burden associated with MPA. METHODS: Adults (>= 18 yrs) with >= 2 diagnoses of GPA [International Classification of Diseases-9-Clinical Modification (ICD-9-CM 446.4)] during 2009-2013 were extracted from the Truven Health MarketScan Commercial and Medicare Supplemental databases. Evidence of major relapse (based on the Birmingham Vasculitis Activity Score) and healthcare costs were collected during 12-month and 24-month followup periods. Adults with >= 2 diagnoses of unspecified arteritis (ICD-9-CM 447.6) were found as potential patients with MPA and additional criteria based on clinical input were applied to refine the sample. Major relapse-associated conditions and healthcare costs in the 6 months pre- and post-diagnosis were measured. Costs were inflated to 2013 US$. RESULTS: A total of 2784 patients with GPA were found and 18.7% experienced a major relapse in the 12-month followup period. The patients with a major relapse incurred higher average all-cause (12-month: $88,065 vs $30,682; p < 0.0001) and GPA-related costs (12-month: $61,636 vs $15,748; p < 0.0001) than patients without a relapse. Trends were consistent over the 24-month followup period. There were 612 incident patients with MPA. Following MPA diagnosis, healthcare costs nearly doubled ($30,166 vs $56,642; p < 0.0001). CONCLUSION: In a real world setting, patients with GPA who experience major relapse have higher economic burden, compared to patients without a relapse. MPA diagnosis was associated with nearly a 2-fold increase in healthcare costs. PMID- 26523027 TI - Evaluating Disease Severity in Chronic Pain Patients with and without Fibromyalgia: A Comparison of the Symptom Impact Questionnaire and the Polysymptomatic Distress Scale. AB - OBJECTIVE: To compare the relative effectiveness of the Polysymptomatic Distress Scale (PSD) with the Symptom Impact Questionnaire (SIQR), the disease-neutral revision of the updated Fibromyalgia Impact Questionnaire (FIQR), in their ability to assess disease activity in patients with rheumatic disorders both with and without fibromyalgia (FM). METHODS: The study included 321 patients from 8 clinical practices with some 16 different chronic pain disorders. Disease severity was assessed by the Medical Outcomes Study Short Form-36 (SF-36). Univariate analyses were used to assess the magnitude of PSD and SIQR correlations with SF-36 subscales. Hierarchical stepwise regression was used to evaluate the unique contribution of the PSD and SIQR to the SF-36. Random forest regression probed the relative importance of the SIQR and PSD components as predictors of SF-36. RESULTS: The correlations with the SF-36 subscales were significantly higher for the SIQR (0.48 to 0.78) than the PSD (0.29 to 0.56; p < 0.001). Stepwise regression revealed that the SIQR was contributing additional unique variance on SF-36 subscales, which was not the case for the PSD. Random forest regression showed SIQR Function, Symptoms, and Global Impact subscales were more important predictors of SF-36 than the PSD. The single SIQR pain item contributed 55% of SF-36 pain variance compared to 23% with the 19-point WPI (the Widespread Pain Index component of PSD). CONCLUSION: The SIQR, the disease neutral revision of the updated FIQ, has several important advantages over the PSD in the evaluation of disease severity in chronic pain disorders. PMID- 26523028 TI - Do We Need Early ACPA Testing in Inflammatory Arthritis? PMID- 26523029 TI - Effects of Aerobic Training in Patients with Ankylosing Spondylitis. AB - OBJECTIVE: To evaluate the effects of aerobic exercise in patients with ankylosing spondylitis (AS). METHODS: Seventy patients classified with AS by the modified New York criteria were included. The patients were randomly assigned into 2 groups. The intervention group (IG) performed 50 min of walking followed by stretching exercises 3 times a week for 12 weeks. The control group (CG) performed only stretching exercises. The outcome measurements were the Bath indexes [Bath AS Functional Index (BASFI), Bath AS Disease Activity Index (BASDAI), and Bath AS Metrology Index (BASMI)], Health Assessment Questionnaire for the Spondyloarthropathies (HAQ-S), AS Disease Activity Score (ASDAS), the 6 min walk test (6MWT), chest expansion, and the Medical Outcomes Study Short Form 36. Aerobic capacity was assessed by ergospirometry on a treadmill. Routine laboratory techniques were used in determining lipid levels. Assessments were performed immediately before randomization and after 6, 12, and 24 weeks. RESULTS: Thirty-five patients were randomized to the IG and 35 to the CG. There was significant improvement in the BASFI, HAQ-S, BASMI, BASDAI, and ASDAS in both groups (p < 0.05), but did not differ between groups. There was a significant increase in the walking distance in the 6MWT in the IG compared with CG (p < 0.001). The IG showed significant improvement in cardiopulmonary capacity compared with CG. Cholesterol and triglyceride levels did not change in either group. CONCLUSION: In patients with AS, aerobic training improved walking distance and aerobic capacity. Aerobic training did not provide additional benefits in functional capacity, mobility, disease activity, quality of life, and lipid levels when compared with stretching exercises alone. PMID- 26523031 TI - Pregnancy Outcomes in Subjects Exposed to Certolizumab Pegol. AB - OBJECTIVE: To provide information on pregnancy outcomes in women receiving certolizumab pegol (CZP). METHODS: The UCB Pharma safety database was searched for pregnancies through to September 1, 2014. Reports for maternal and paternal CZP exposure were included and outcomes examined, and data on CZP exposure, pregnancy, comorbidities, and infant events were extracted by 2 independent reviewers. Concomitant medications and disease activity were reviewed for clinical trial patients. RESULTS: Of 625 reported pregnancies, 372 (59.5%) had known outcomes. Paternal exposure pregnancies (n = 33) reported 27 live births, 4 miscarriages, 1 induced abortion, and 1 stillbirth. Maternal exposure pregnancies (n = 339) reported 254 live births, 52 miscarriages, 32 induced abortions, and 1 stillbirth. Almost all reported pregnancies had exposure to CZP in the first trimester, when organogenesis takes place, and a third of them continued the drug into the second and/or third trimesters. The most frequent indications for maternal CZP use were Crohn disease (192/339) and rheumatic diseases (118/339). Twelve cases of congenital malformation and a single neonatal death were reported. CONCLUSION: Analysis of pregnancy outcomes after exposure to CZP supports previous reports, suggesting a lack of harmful effect of maternal CZP exposure on pregnancy outcomes. However, additional data from a larger number of outcomes after exposure and studies including an unexposed comparison group are required to fully evaluate CZP safety and tolerability in pregnancy. PMID- 26523030 TI - Safety and Efficacy of Belimumab to Treat Systemic Lupus Erythematosus in Academic Clinical Practices. AB - OBJECTIVE: To evaluate the use and efficacy of belimumab in academic practices. Belimumab is a human monoclonal antibody that inhibits soluble B lymphocyte stimulator and has been approved for the treatment of adults with systemic lupus erythematosus (SLE). METHODS: Invitations to participate and complete a 1-page questionnaire for each patient prescribed belimumab were sent to 16 physicians experienced in SLE phase III clinical trials. The outcome was defined as the physician's impression of improvement in the initial manifestation(s) being treated without worsening in other organ systems. RESULTS: Of 195 patients treated with belimumab at 10 academic centers, 96% were taking background medications for SLE at initiation of belimumab, with 74% taking corticosteroids. The main indications for initiation of belimumab were arthritis, rash, and/or worsening serologic activity, with 30% of patients unable to taper corticosteroids. Of the 120 patients taking belimumab for at least 6 months, 51% responded clinically and 67% had >= 25% improvement in laboratory values. While numbers are limited, black patients showed improvement at 6 months. In a subset of 39 patients with childhood-onset SLE, 65% responded favorably at 6 months, and 35% discontinued corticosteroids. CONCLUSION: Our data demonstrate favorable clinical and laboratory outcomes in patients with SLE at 6 months across all racial and ethnic groups, with similar improvement seen among patients with childhood-onset SLE. PMID- 26523032 TI - Validation of the OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) for the Hand and Foot in a Randomized Placebo-controlled Trial. AB - OBJECTIVE: To assess changes following treatment and the reliability and responsiveness to change of the Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) in a randomized controlled trial. METHODS: Forty patients with PsA randomized to either placebo or abatacept (ABA) had MRI of either 1 hand (n = 20) or 1 foot (n = 20) at baseline and after 6 months. Images were scored blindly twice by 3 independent readers according to the PsAMRIS (for synovitis, tenosynovitis, periarticular inflammation, bone edema, bone erosion, and bone proliferation). RESULTS: Inflammatory features improved numerically but statistically nonsignificantly in the ABA group but not the placebo group. Baseline intrareader intraclass correlation coefficients (ICC) were good (>= 0.50) to very good (>= 0.80) for all features in both hand and foot. Baseline interreader ICC were good (ICC 0.72 0.96) for all features, except periarticular inflammation and bone proliferation in the hand and tenosynovitis in the foot (ICC 0.25-0.44). Intrareader and interreader ICC for change scores varied. Guyatt's responsiveness index (GRI) was high for inflammatory features in the hand and metatarsophalangeal joints (GRI 0.67 to -3.13; bone edema not calculable). Minimal change and low prevalence resulted in low ICC and GRI for bone damage. CONCLUSION: PsAMRIS showed overall good intrareader agreement in the hand and foot, and inflammatory feature scores were responsive to change, suggesting that PsAMRIS may be a valid tool for MRI assessment of hands and feet in PsA clinical trials. PMID- 26523033 TI - Patient's Global Assessment as an Outcome Measure for Psoriatic Arthritis in Clinical Practice: A Surrogate for Measuring Low Disease Activity? AB - OBJECTIVE: To assess the low disease activity (LDA) in a group of patients with psoriatic arthritis (PsA) receiving antitumor necrosis factor-alpha (TNF-alpha) by using the patient's global assessment (PtGA) in clinical practice, and to compare PtGA with minimal disease activity (MDA) and other outcome measures. METHODS: Patients with PsA classified by the ClASsification for Psoriatic ARthritis (CASPAR) criteria and consecutively admitted to an outpatient clinic dedicated to biologic therapy were assessed during their routine followup. The primary outcome measure was the proportion of patients achieving a PtGA <= 20 at 4-, 8-, and 12-month followups. Secondary outcome measures included the proportion of patients achieving MDA and other outcome measures. Correlation of PtGA with MDA and other process and outcome measures were also performed. RESULTS: During the period of observation, 124 patients were evaluated. PtGA <= 20 was achieved in 25.7% at 4 months, 48.9% at 8 months, and 65.3% at 12 months of followup. The percentage of PtGA <= 20 statistically improved throughout the 3 timepoint assessments and it was statistically correlated to MDA. A significant correlation with the Disease Activity index for PSoriatic Arthritis (DAPSA), Bath Ankylosing Spondylitis Disease Activity Index, and Health Assessment Questionnaire was also observed. MDA, DAPSA, and Disease Activity Score at 28 joints with C-reactive protein remission were achieved at 12 months in 64%, 36%, and 71% of patients, respectively. CONCLUSION: PtGA can estimate the LDA status and could be considered as a surrogate of outcome measures for the assessment of global disease activity in patients with PsA receiving anti-TNF therapy during routine clinical practice. These data suggest that PtGA might be used in outpatient settings, being a simple, reliable, and not time-consuming instrument. PMID- 26523034 TI - Hippocampal Contributions to the Large-Scale Episodic Memory Network Predict Vivid Visual Memories. AB - A common approach in memory research is to isolate the function(s) of individual brain regions, such as the hippocampus, without addressing how those regions interact with the larger network. To investigate the properties of the hippocampus embedded within large-scale networks, we used functional magnetic resonance imaging and graph theory to characterize complex hippocampal interactions during the active retrieval of vivid versus dim visual memories. The study yielded 4 main findings. First, the right hippocampus displayed greater communication efficiency with the network (shorter path length) and became a more convergent structure for information integration (higher centrality measures) for vivid than dim memories. Second, vivid minus dim differences in our graph theory measures of interest were greater in magnitude for the right hippocampus than for any other region in the 90-region network. Moreover, the right hippocampus significantly reorganized its set of direct connections from dim to vivid memory retrieval. Finally, beyond the hippocampus, communication throughout the whole brain network was more efficient (shorter global path length) for vivid than dim memories. In sum, our findings illustrate how multivariate network analyses can be used to investigate the roles of specific regions within the large-scale network, while also accounting for global network changes. PMID- 26523035 TI - Temporal Dynamics of Acute Stress-Induced Dendritic Remodeling in Medial Prefrontal Cortex and the Protective Effect of Desipramine. AB - Stressful events are associated with increased risk of mood disorders. Volumetric reductions have been reported in brain areas critical for the stress response, such as medial prefrontal cortex (mPFC), and dendritic remodeling has been proposed as an underlying factor. Here, we investigated the time-dependent effects of acute stress on dendritic remodeling within the prelimbic (PL) region of the PFC, and whether treatment with the antidepressant desipramine (DMI) may interfere. Rodents were subjected to foot-shock stress: dendritic length and spine density were analyzed 1 day, 7 days, and 14 days after stress. Acute stress produced increased spine density and decreased cofilin phosphorylation at 1 day, paralleled with dendritic retraction. An overall shift in spine population was observed at 1 day, resulting in a stress-induced increase in small spines. Significant atrophy of apical dendrites was observed at 1 day, which was prevented by chronic DMI, and at 14 days after stress exposure. Chronic DMI resulted in dendritic elaboration at 7 days but did not prevent the effects of FS stress. Collectively, these data demonstrate that 1) acute stressors may induce rapid and sustained changes of PL neurons; and 2) chronic DMI may protect neurons from rapid stress-induced synaptic changes. PMID- 26523036 TI - Routine Hydroxychloroquine Blood Concentration Measurement in Systemic Lupus Erythematosus Reaches Adulthood. PMID- 26523037 TI - Assessing Arthritis in the Temporomandibular Joint. PMID- 26523038 TI - Spinal Intramedullary Tuberculoma: A Rare Cause of Backache. PMID- 26523039 TI - Bone Proliferation in Ankylosing Tarsitis Might Involve Mechanical Stress, and Hormonal and Growth Factors. PMID- 26523040 TI - Dr. Appel replies. PMID- 26523041 TI - Primary Hypertrophic Osteoarthropathy: An Update on Patient Features and Treatment. PMID- 26523042 TI - Diurnal Variation in Distal Femoral Cartilage Thickness. PMID- 26523043 TI - Reflections on Rheumatoid Hands. PMID- 26523044 TI - Foreword: Third Update on Psoriatic Disease. PMID- 26523045 TI - Third Update on Psoriatic Disease Conference: Trainee Session. AB - Trainee sessions have become an established feature of international conferences and were an important part of the proceedings of the Third Update on Psoriatic Disease. Presentations featured a wide range of topics from clinical, etiopathological, and therapeutic aspects of psoriatic disease and spondyloarthropathy. A selection of 7 reports from the sessions is presented here. PMID- 26523046 TI - Verna Wright Lecture: Psoriatic Arthritis: The Need for Early Intervention. AB - About 30% of individuals with skin psoriasis will develop an inflammatory disease of the peripheral or axial skeleton involving synovial and/or entheseal tissue termed psoriatic arthritis (PsA). In most cases psoriasis will precede PsA by several years. Hence skin psoriasis provides an opportune model to investigate genetic and environmental factors that interact and contribute to the development of a common form of inflammatory arthritis. Further, the preexisting presence of psoriasis represents a unique opportunity for the early detection of arthritis and the potential for more effective intervention. However, despite the presence of psoriasis, there may be delay in the diagnosis of PsA that is associated with adverse longterm outcome. Undiagnosed disease is not uncommon, as demonstrated by studies applying screening questionnaires to primary care and dermatology clinic populations. Other potential risk factors, such as obesity and smoking, the presence of certain genetic and biomarker profiles, combined with accurate imaging modalities, offer the potential for more targeted screening. So in future it should be possible to detect PsA at a much earlier stage and prevent significant joint damage and associated disability before it happens. PMID- 26523047 TI - Toward Treating to Target in Psoriatic Arthritis. AB - The concept "treat to target" in rheumatology was first developed for rheumatoid arthritis. A similar attempt to develop such an approach for spondyloarthritis was unsuccessful because the assessment tools and target of therapy had not been developed. In psoriatic arthritis (PsA), composite indices to assess disease activity, disease state, and responsiveness have been developed and can be used as targets. There are a number of definitions for remission, but none are widely accepted. However, a state of minimal disease activity has been defined. There is evidence now that the treat-to-target approach is feasible, using the minimal disease activity state as a target and devising a tight control approach, which is superior to standard of care. Further work will determine the best target and the best approach to reach it. PMID- 26523048 TI - Translational Research in Psoriasis. AB - Translational research is a coordinated process that converts scientific knowledge about diseases from basic research into the development of therapeutic or diagnostic procedures in order to improve public health. Recent insights into the pathogenesis of psoriasis have greatly promoted the rational development of new therapeutic approaches. The integration of genetic predisposition and pathogenetic events defined the cytokine cascade as a target for therapeutic interventions. Applying various phases of translational research has enabled development of novel therapies that combine high efficacy with convincing safety profiles, with important implications for public health. PMID- 26523049 TI - Inflammatory Bowel Diseases and Spondyloarthropathies. AB - Spondyloarthritis (SpA) is a group of diseases with similar clinical, radiologic, and serologic features, including SpA associated with inflammatory bowel disease (IBD-associated SpA). SpA is the most frequent extraintestinal manifestation in patients with IBD. Separate recommendations/guidelines are available for the treatment of axial and peripheral SpA and for both Crohn disease and ulcerative colitis. When IBD and SpA coexist, the therapeutic strategy should be modulated taking into account the variable manifestations and complications of IBD in terms of intestinal and extraintestinal features, and the clinical manifestations of SpA. PMID- 26523050 TI - Psoriatic Disease: Clinical Staging. AB - In 2006, the introduction of the concept "psoriatic disease" (PsD) extended the traditional idea of a condition confined to skin and joints. Now we consider PsD a systemic condition, in which the increased activity of tumor necrosis factor acts as the most potent engine for a series of molecular interactions. These lead not only to the genesis of skin and joint symptoms, but also to other clinical aspects such as inflammatory bowel disease, eye involvement, and metabolic syndrome. The blocking of a precise molecular target has dramatically modified therapeutic strategies, making possible adequate control of all the clinical aspects of the condition. Therefore, an expanded clinical staging of patients could now be considered in order to ensure the best therapeutic approach and prognosis. PMID- 26523051 TI - Uveitis in Spondyloarthritis: An Overview. AB - Autoimmune anterior uveitis (AU) accounts for at least half of the cases of noninfectious uveitis, and similarly to spondyloarthritis (SpA), its occurrence is related to HLA-B27 positivity. AU is significantly more frequently found in HLA-B27-positive subjects with SpA and is characterized by unilateral eye involvement, marked tendency to recur with involvement of both eyes in alternate fashion, and has good prognosis in the majority of cases. The estimated frequency of SpA in patients with AU is around 50%, whereas AU in SpA has been reported in at least 30% of cases. Across the SpA disease spectrum, AU has a frequency peak of 33.4% in patients with ankylosing spondylitis, while the estimated prevalence in psoriatic arthritis (PsA) and inflammatory bowel disease-associated SpA is 2% 25%, and 25%, respectively. In early PsA, the frequency of AU has been found in 9% of patients. The wide range of prevalence reported in PsA may be explained by the variable sets of classification criteria used for patient selection and the different length of followup. AU may precede the clinical features of SpA, may be present at diagnosis, or may complicate the SpA clinical course. However, the occurrence of AU in SpA as well as AU flares has been reduced through treatment of SpA with anti-tumor necrosis factor-alpha agents. PMID- 26523052 TI - Psoriatic Arthritis Registries. AB - The introduction of new biological drugs for the treatment of rheumatoid arthritis and spondyloarthritis has led to the creation of a number of registries in Europe and the United States. Most of them are sponsored by national rheumatology societies, and provide information that is useful in clinical practice concerning the clinical characteristics, efficacy, and safety of all licensed biological drugs. Their findings also help to improve our understanding of the quality of life and working ability of patients receiving biological drugs, and suggest methods for allocating resources. However, there are only a few registries for psoriatic arthritis, and efforts should be made to increase their number to obtain further reliable and useful data. PMID- 26523053 TI - Relationship of Psoriatic Arthritis to Other Spondyloarthritides. AB - In the early 1970s, Moll and co-workers formulated the unified concept of spondyloarthritides, a group of conditions sharing similar clinical features. Subsequently, criteria for their classification have been proposed by Amor and coworkers, the European Spondylarthropathy Study Group, and the Assessment in SpondyloArthritis international Society. Opinion, however, is divided between those who believe that the different entities of the complex represent the variable expression of the same disease ("lumpers") and those who think that these should be considered separately but under the same umbrella ("splitters"). Several sets of criteria have been proposed for psoriatic arthritis (PsA), the most recent being the ClASsification for Psoriatic Arthritis (CASPAR) criteria. According to some authors, there are persuasive arguments to support the view of PsA as a distinct entity. PMID- 26523054 TI - Fragility Fractures in Patients with Psoriatic Arthritis. AB - Psoriatic arthritis (PsA) can have peculiar effects on bone, including mechanisms of bone loss such as erosions, but also of bone formation, such as ankylosis or periostitis. The aim of the present study was to describe the prevalence of fractures in patients with PsA as compared to healthy controls and to investigate determinants of fractures among cases. For both cases and controls, radiographs were read to identify vertebral fractures (VF), and the presence of femoral neck or other nonvertebral fractures was obtained from patients' medical history. The prevalence of fragility fractures on radiographic readings did not differ between cases and controls. The number of subjects showing a VF was 33 (36%) among PsA patients and 36 (36%) among controls, with a prevalence of severe VF of 8% among cases and 4% among controls. Controlling for covariates in a logistic model, the only variables showing a significant correlation with the presence of nonvertebral fractures (NVF) were disease duration (p=0.02), age (p=0.03), and bone mineral density at femoral neck (inverse correlation, p=0.04). Fractures should be carefully considered when evaluating the global picture of the patient with PsA for their contribution to the "fragility" profile. PMID- 26523055 TI - The Definition and Measurement of Axial Psoriatic Arthritis. AB - This review seeks to update the state of the art of axial psoriatic arthritis (axPsA). The definition and assessment of axPsA can be problematic because no agreement and no definitive data on this topic have been published, resulting in uncertainty as to the best approach to deal with these patients. A few recent scientific reports show new data on the possible coincidence of diffuse idiopathic skeletal hyperostosis and axPsA, as well as on the radiological assessment as measured with the validated instruments for axPsA. Moreover, the role of magnetic resonance imaging has also been evaluated for this intriguing subset. All data confirmed that radiological assessment is a useful tool to detect typical findings of axPsA, while other imaging techniques remain to be validated. Finally, there is no evidence to support treatment of axPsA with traditional disease-modifying antirheumatic drugs, while a "leap" to biologic agents is the only treatment after failure with nonsteroidal antiinflammatory drugs. PMID- 26523056 TI - An Integrative Approach to Biomarker Development in Psoriatic Arthritis. AB - The recent discovery that the interleukin 23/Th17 pathway is pivotal in the pathogenesis of psoriatic arthritis (PsA) creates new opportunities for the development of mechanistic biomarkers that will assist in the diagnosis and management of this disorder. While biomarkers are still in the discovery phase, new approaches including multiplex panels, fine sequencing of epigenetic and genetic data in non-coding regions of the human genome, and improved imaging modalities will likely foster the development of actionable biomarkers in PsA. In this report, I review the field of biomarkers, underscore the importance of an integrative approach that incorporates both descriptive and mechanistic biomarkers, and discuss the status of biomarker discovery in PsA. PMID- 26523058 TI - Imaging Techniques in Psoriatic Arthritis: Update 2012-2014 on Current Status and Future Prospects. AB - By providing additional and more sensitive information over clinical examination, imaging techniques are useful in the assessment of patients with psoriatic arthritis (PsA) and have been increasingly used to obtain additional clues to its pathogenesis. This review describes the current status and future development of conventional radiography, computed tomography, magnetic resonance imaging, positron emission tomography, and other novel techniques in the evaluation of PsA, with a focus on their use in diagnosing, monitoring, and predicting disease course and followup treatment response. The role and applications of ultrasonography are outside the scope and are reviewed elsewhere in these proceedings. PMID- 26523057 TI - Ex Vivo Signaling Protein Mapping in T Lymphocytes in the Psoriatic Arthritis Joints. AB - We assessed signaling protein mapping in total T cells, to analyze the proportions of T regulatory (Treg) and TCD4+ effector (Teff) cell phenotypes, and the respective interleukin 6Ralpha (IL-6Ralpha) expression in the inflammatory microenvironment of synovial fluid (SF) of patients with sustained psoriatic arthritis (PsA). Our approach was to measure the IL-6 level in SF using a multiplex bead immunoassay. Reverse-phase protein array was used to assess Janus kinase (JAK) 1 and JAK2, extra-cellular regulated kinase (ERK) 1 and 2, protein kinase Cdelta (PKCdelta), signal transducer and activator and transcription (STAT) 1, STAT3, and STAT5 phosphoproteins in total T cell lysates from SF of patients with PsA. Frequencies of CD4+IL-17A-F+IL-23+ CD4+ Th cells producing IL 17A and IL-17F (Th17) and CD4+CD25high intracellular forkhead box transcription factor+ (FOXP3+) phenotypes, and the percentage of Treg- and Teff- cells were quantified in SF and matched peripheral blood (PB) of patients with PsA and PB of healthy controls (HC) by flow cytometry. Our results were the following: In PsA SF samples, a coordinate increase of JAK1, ERK1/2, STAT1, STAT3, and STAT5 phosphoproteins was found in total T cells in SF of PsA; where IL-6 levels were higher than in PB from HC. Expanded CD4+IL-17A-F+IL-23+ Th17, CD4+ CD25- Teff- and CD4+CD25(high) FoxP3+Treg subsets, showing similar levels of enhanced IL 6Rdelta expression, were confined to PsA joints. In our studies, the transcriptional network profile identified by ex vivo signaling protein mapping in T lymphocytes in PsA joints revealed the complex interplay between IL-1, IL-6, and IL-23 signaling and differentiation of Th17 cells and CD4+Tregs in sustained joint inflammation in PsA. PMID- 26523059 TI - Concept of Remission in Chronic Plaque Psoriasis. AB - Psoriasis is a lifelong chronic inflammatory disease affecting 2-3% of the worldwide population. Current understanding of the pathogenesis of psoriasis assigns central importance to an interaction between acquired and innate immunity. The disease is characterized by a series of linked cellular changes in the skin, including hyperplasia of epidermal keratinocytes, angiogenesis, and infiltration of T lymphocytes, neutrophils, and other types of leukocytes in the affected skin. Plaque psoriasis is the most common clinical form and is characterized by red and scaly plaques generally localized at extensor sites such as elbows and knees. Major determinants of psoriasis severity include the extent of skin involvement; localization in highly affected areas such as scalp, palms, and soles; pruritus; presence of comorbidities including psoriatic arthritis; and impairment on quality of life. About one-third of patients have moderate to severe psoriasis defined as PASI (Psoriasis Area and Severity Index) and/or Dermatology Life Quality Index>10, and/or affected body surface area>10%. The optimal treatment goal is to safely achieve complete or almost complete skin clearance. Treatments available are various and they are chosen according to disease features, comorbidities, and patient characteristics and priorities. Topical treatments including corticosteroids and Vitamin D analogs are reserved for mild disease. Phototherapy, cyclosporine, methotrexate, acitretin, or biologics such as tumor necrosis factor-alpha antagonists and ustekinumab are reserved for the moderate to severe forms. PMID- 26523060 TI - Psoriatic Disease: Update on Traditional Disease-modifying Antirheumatic Drugs. AB - We present an update on the effects of methotrexate (MTX), sulfasalazine (SSZ), leflunomide (LEF), and cyclosporine (CSA) in psoriatic arthritis (PsA) by reviewing data published from January 2010 to June 2014. The most relevant study on MTX, the Methotrexate In Psoriatic Arthritis (MIPA) trial, did not show a significant difference between this drug and placebo in improving peripheral synovitis. The trial, however, had several limitations. A cohort study on a small number of patients found that MTX does not inhibit radiographic progression. In a large observational study, 86% of LEF-treated patients met PsA Response Criteria (PsARC) at Week 24. No studies of sufficient relevance on SSZ were published in the examined time frame. In an open-label trial, CSA alone was compared to adalimumab (ADA) alone and to the combination ADA/CSA. The ADA arms showed a significantly higher response rate, but as many as 65% of CSA-treated patients were PsARC responders at Month 12. No relevant data on the effects of these 4 drugs on psoriatic enthesitis, dactylitis, or spondylitis have recently been published, and no new safety signals have been reported. Observational data from 2 registers suggest that concomitant MTX increases the retention rate of tumor necrosis factor-alpha inhibitors. The studies published in the examined time frame confirm that MTX, SSZ, LEF, and CSA have moderate symptom-modifying effect on psoriatic synovitis, and probably little effect on the other manifestations of PsA. PMID- 26523061 TI - Disease-modifying Antirheumatic Drugs (DMARD) and Combination Therapy of Conventional DMARD in Patients with Spondyloarthritis and Psoriatic Arthritis with Axial Involvement. AB - Treatment with nonsteroidal antiinflammatory drugs (NSAID) is the recommended first-line therapy in patients with axial spondyloarthritis (axSpA); and for those patients who have persistently active disease, the introduction of tumor necrosis factor-alpha (TNF-alpha) inhibitors is indicated. Conventional nonbiological disease-modifying antirheumatic drugs (DMARD), although effective and used in clinical practice for peripheral arthritis, are not recommended. Few studies have been conducted with the aim of evaluating the effect of conventional DMARD, either alone or in combination, in axSpA. As for psoriatic arthritis (PsA), DMARD are widely used, but few trials are available about their effects on axial involvement, which is not often assessed as a primary outcome in clinical trials. In rheumatoid arthritis, combination therapy of 2 or more conventional DMARD appears to confer better response than methotrexate monotherapy, and may even be a viable alternative to TNF-alpha inhibitors. In peripheral PsA, combination therapy can be used after treatment failure with 1 DMARD, but few studies have been conducted. However, available evidence for the combination of conventional DMARD indicates a lack of any significant benefit on axial symptoms; thus this treatment approach does not represent an effective alternative to anti TNF-alpha therapy. PMID- 26523062 TI - New Approaches in Tumor Necrosis Factor Antagonism for the Treatment of Psoriatic Arthritis: Certolizumab Pegol. AB - The pathogenesis of psoriatic arthritis (PsA) is still under discussion but great advances have been made in the last 2 decades that confirm the central role of tumor necrosis factor-alpha (TNF-alpha) in its inflammatory milieu. New therapeutic approaches have been proposed, and new molecules with anti-TNF-alpha activity have been chemically altered to improve their pharmacological properties. Certolizumab pegol (CZP) is a PEGylated Fc-free anti-TNF that has been shown clinically to be effective in the treatment of rheumatoid arthritis (RA), skin psoriasis, and PsA. This article summarizes available data on its clinical efficacy and safety profile in the treatment of patients with PsA. PMID- 26523063 TI - The Role of Tumor Necrosis Factor-alpha Blockers in Psoriatic Disease. Therapeutic Options in Psoriatic Arthritis. AB - Psoriatic arthritis (PsA) is a chronic inflammatory disease affecting peripheral and axial joints, usually associated with psoriasis (PsO) and involving various systems and organs (eye inflammation, such as uveitis; and involvement of nail and enthesis), and it usually requires a multidisciplinary treatment approach. Tumor necrosis factor-alpha (TNF-alpha) is overexpressed in psoriatic synovium and skin plaques and its selective inhibition by anti-TNF-alpha agents has been demonstrated to reduce TNF-alpha levels in the articular environment, reversing the synovial hyperproliferative phenotype. Studies performed on anti-TNF-alpha agents in PsA demonstrated that they are able to reduce neutrophil and macrophage infiltration as well as vascular cell adhesion protein 1 expression with ensuing synovial thickness normalization. The efficacy of anti-TNF-alpha agents for all PsA manifestations (peripheral arthritis, axial involvement, enthesopathy, and skin disease) suggests that anti-TNF-alpha efficacy might be related to the ability to influence angiogenesis and osteoclastogenesis, reduce synovial inflammation, and slow radiological disease progression. This review describes the role of anti-TNF-alpha in each manifestation of PsA. PMID- 26523064 TI - Role of Agents other than Tumor Necrosis Factor Blockers in the Treatment of Psoriatic Arthritis. AB - Psoriatic arthritis (PsA) is a systemic inflammatory disease characterized by possible peripheral and axial joint involvement, enthesitis, dactylitis, and skin and nail disease. It affects up to one-third of psoriatic patients, and may be associated with comorbidities such as cardiovascular and metabolic diseases. The usually prescribed initial treatment of moderate-severe PsA is methotrexate, which may be accompanied or replaced by a tumor necrosis factor (TNF) inhibitor such as etanercept, infliximab, or adalimumab. However, some patients may become unresponsive (or have contraindications) to available anti-TNF agents and require alternative treatment. The aim of this review is to describe the potential role of some new immunomodulatory agents. PMID- 26523065 TI - Obituary: Professor Antonio Spadaro. PMID- 26523066 TI - A new clinical guideline from the Royal College of Paediatrics and Child Health with a national awareness campaign accelerates brain tumor diagnosis in UK children--"HeadSmart: Be Brain Tumour Aware". AB - BACKGROUND: A national survey in 2006 identified that UK referral practice for pediatric CNS tumors ranked poorly in international comparisons, which led to new National Health Service (NHS) Evidence accredited referral guidelines published in 2008 by the Royal College of Paediatrics and Child Health and a campaign to raise awareness of early features of CNS tumors and the need for timely imaging. METHODS: The "HeadSmart: Be Brain Tumour Aware" campaign was launched in June 2011 across the UK as a quality improvement strategy directed at reducing the total diagnostic interval (TDI) from a pre-campaign (2006) median of 14 (mean, 35.4) weeks to a target of 5 weeks in order to equal the best reported internationally. Professional and public awareness was measured by questionnaire surveys. TDI was collected by clinical champions in 18 regional children's cancer centers and the public campaign was coordinated by a national charity, working with a network of community champions. RESULTS: The guidelines and campaign raised awareness among pediatricians and were associated with reduction in TDI to a median of 6.7 (mean, 21.3) weeks by May 2013. This change in referral practice was most pronounced in the time from first medical contact to CNS imaging, for which the median was reduced from 3.3 to 1.4 weeks between January 2011 and May 2013 (P = .009). CONCLUSION: This strategy to accelerate brain tumor diagnosis by the NHS using a public and professional awareness campaign is a "world first" in pediatric cancer and is being emulated internationally and acknowledged by a series of NHS and charity awards for excellence. PMID- 26523067 TI - Education, HIV, and Early Fertility: Experimental Evidence from Kenya. AB - A seven-year randomized evaluation suggests education subsidies reduce adolescent girls' dropout, pregnancy, and marriage but not sexually transmitted infection (STI). The government's HIV curriculum, which stresses abstinence until marriage, does not reduce pregnancy or STI. Both programs combined reduce STI more, but cut dropout and pregnancy less, than education subsidies alone. These results are inconsistent with a model of schooling and sexual behavior in which both pregnancy and STI are determined by one factor (unprotected sex), but consistent with a two-factor model in which choices between committed and casual relationships also affect these outcomes. PMID- 26523068 TI - Does the Value of Dynamic Assessment in Predicting End-of-First-Grade Mathematics Performance Differ as a Function of English Language Proficiency? AB - The purpose of this study was to assess the added value of dynamic assessment (DA) beyond more conventional static measures for predicting individual differences in year-end 1st-grade calculation (CA) and word-problem (WP) performance, as a function of limited English proficiency (LEP) status. At the start of 1st grade, students (129 LEP; 163 non-LEP) were assessed on a brief static mathematics test, an extended static mathematics test, static tests of domain-general abilities associated with CAs and WPs (vocabulary; reasoning), and DA. Near end of 1st grade, they were assessed on CA and WP. Regression analyses indicated that the value of the predictor depends on the predicted outcome and LEP status. In predicting CAs, the extended mathematics test and DA uniquely explained variance for LEP children, with stronger predictive value for the extended mathematics test; for non-LEP children, the extended mathematics test was the only significant predictor. However, in predicting WPs, only DA and vocabulary were uniquely predictive for LEP children, with stronger value for DA; for non-LEP children, the extended mathematics test and DA were comparably uniquely predictive. Neither the brief static mathematics test nor reasoning was significant in predicting either outcome. The potential value of a gated screening process, using an extended mathematics assessment to predict CAs and using DA to predict WPs, is discussed. PMID- 26523069 TI - Impact of the Fano Factor on Position and Energy Estimation in Scintillation Detectors. AB - The Fano factor for an integer-valued random variable is defined as the ratio of its variance to its mean. Light from various scintillation crystals have been reported to have Fano factors from sub-Poisson (Fano factor < 1) to super-Poisson (Fano factor > 1). For a given mean, a smaller Fano factor implies a smaller variance and thus less noise. We investigated if lower noise in the scintillation light will result in better spatial and energy resolutions. The impact of Fano factor on the estimation of position of interaction and energy deposited in simple gamma-camera geometries is estimated by two methods - calculating the Cramer-Rao bound and estimating the variance of a maximum likelihood estimator. The methods are consistent with each other and indicate that when estimating the position of interaction and energy deposited by a gamma-ray photon, the Fano factor of a scintillator does not affect the spatial resolution. A smaller Fano factor results in a better energy resolution. PMID- 26523070 TI - A PROSTHETIC GROUP FOR THE RAPID INTRODUCTION OF FLUORINE INTO PEPTIDES AND FUNCTIONALIZED DRUGS. AB - Fluoride ion as the tetrabutylammonium salt displaces bromide in para-substituted benzyl bromides in acetonitrile or dimethylformamide. The p-bromomethyl benzoyl (BMB) group has been coupled to amino groups, including peptide amino groups, via its N-hydroxysuccinimide ester. In a subsequent step, the facile displacement of bromide by fluoride occurred under conditions compatible for use with (18)F radiotracers. PMID- 26523071 TI - Magmatism at the Eurasian-North American modern plate boundary: Constraints from alkaline volcanism in the Chersky Belt (Yakutia). AB - The Chersky seismic belt (NE-Russia) forms the modern plate boundary of the Eurasian-North American continental plate. The geodynamic evolution of this continent-continent setting is highly complex and remains a matter of debate, as the extent and influence of the Mid-Arctic Ocean spreading center on the North Asian continent since the Eocene remains unclear. The progression from a tensional stress regime to a modern day transpressional one in the Chersky seismic belt, makes the understanding even more complicated. The alkaline volcanism that has erupted along the Chersky range from Eocene through to the Recent can provide constraints on the geodynamic evolution of this continental boundary, however, the source and petrogenetic evolution of these volcanic rocks and their initiating mechanisms are poorly understood. We studied basanites of the central Chersky belt, which are thought to represent the first alkaline volcanic activity in the area, after initial opening of the Arctic Ocean basin. We present mineral and bulk rock geochemical data as well as Sr-Nd-Pb-Hf isotopes of the alkaline suite of rocks combined with new precise K-Ar and 40Ar/39Ar dating, and discuss an integrated tectono-magmatic model for the Chersky belt. Our findings show that the basanites were generated from a homogeneous asthenospheric mantle reservoir with an EM-1 isotopic flavor, under relatively 'dry' conditions at segregation depths around 110 km and temperatures of ~ 1500 degrees C. Trace element and isotope systematics combined with mantle potential temperature estimates offer no confirmation of magmatism related to subduction or plume activity. Mineral geochemical and petrographical observations together with bulk geochemical evidence indicate a rapid ascent of melts and high cooling rates after emplacement in the continental crust. Our preferred model is that volcanism was triggered by extension and thinning of the lithosphere combined with adiabatic upwelling of the underlying mantle at 37 Ma. This suggests that at that time, rift tectonics in the Mid-Arctic Ocean most likely had also affected the North-Asian continent, causing volcanic activity in the Chersky belt, before the regional geodynamic regime changed from a tensional to compressional. Our conclusions contribute not only to the understanding of volcanism in the Chersky seismic belt (NE-Russia) but also to general aspects of plate dynamics between the Eurasian and North American continent. PMID- 26523072 TI - The petrology and geochemistry of a metabasite belt along the southern margin of Alaska. AB - A 600 km long metabasite belt is exposed at the southern border of the Chugach terrane in southern Alaska, south of the Eocene Chugach Metamorphic Complex (CMC). In this contribution, we present petrologic and geochemical results for parts of this metabasite belt. The metabasites studied are amphibolite grade and their PT conditions are evaluated with hornblende-plagioclase thermometry and the average PT method. From west to east the peak metamorphic conditions calculated are: about 730-793 degrees C for pressures between 5 and 15 kbar in the westernmost part, about 740-760 degrees C and 5 kbar in the middle locality and about 640-675 degrees C and 8 kbar in the easternmost locality. These results are comparable with the metamorphic conditions obtained on metapelite of the CMC for the westernmost and easternmost localities. In contrast, in the central part of the CMC, the metabasites experienced probably lower pressures than the metapelites to the north. Rare earth and trace element patterns of the metabasite belt are comparable with typical altered basalt patterns and reveal MORB and arc tholeiitic geochemical characteristics. The presence of Ba and U anomalies are interpreted as a result of alteration prior to subduction, the Pb anomaly as a result of an intra-oceanic island arc signature and the Sr anomaly as a result of the interaction of sediments with the metabasites during subduction. We suggest that the association of MORB and arc tholeiitic rocks in the metabasite belt is likely derived from an intra-oceanic island arc which accreted to the Alaskan margin. PMID- 26523073 TI - Revisiting the Quantitative-Qualitative Debate: Implications for Mixed-Methods Research. AB - Health care research includes many studies that combine quantitative and qualitative methods. In this paper, we revisit the quantitative-qualitative debate and review the arguments for and against using mixed-methods. In addition, we discuss the implications stemming from our view, that the paradigms upon which the methods are based have a different view of reality and therefore a different view of the phenomenon under study. Because the two paradigms do not study the same phenomena, quantitative and qualitative methods cannot be combined for cross validation or triangulation purposes. However, they can be combined for complementary purposes. Future standards for mixed-methods research should clearly reflect this recommendation. PMID- 26523074 TI - Perceptions of a Quality of Work-Life Survey from the Perspective of Employees in a Canadian Cancer Centre. AB - This qualitative (phenomenological) study explored the perceptions of a quality of work-life survey from the perspective of 10 employees from a variety of departments in a Canadian cancer centre. Data were collected through one-on-one interviews at the workplace. The interviews were conducted several months after the survey had been completed and the findings presented to staff. The following themes emerged from the analysis: 1) talking about the survey triggered discussions of quality of work-life issues most of which were not captured in the survey; 2) the impact of the survey was more important than the survey itself; and 3) participants were concerned that departments or groups of employees were labelled based on the survey results. Implications for researchers who wish to use surveys and standardized scales in health care settings are discussed. PMID- 26523075 TI - Direct terrestrial-marine correlation demonstrates surprisingly late onset of the last interglacial in central Europe. AB - An interdisciplinary study of a small sedimentary basin at Neumark Nord 2 (NN2), Germany, has yielded a high-resolution record of the palaeomagnetic Blake Event, which we are able to place at the early part of the last interglacial pollen sequence documented from the same section. We use this data to calculate the duration of this stratigraphically important event at 3400 +/- 350 yr. More importantly, the Neumark Nord 2 data enables precise terrestrial-marine correlation for the Eemian stage in central Europe. This shows a remarkably large time lag of ca. 5000 yr between the MIS 5e 'peak' in the marine record and the start of the last interglacial in this region. PMID- 26523077 TI - Structure and evolution of a rocksalt-mudrock-tectonite: The haselgebirge in the Northern Calcareous Alps. AB - The Northern Calcareous Alps are part of the Eastern Alps in Austria and Germany. The Mesozoic units of this fold-and-thrust belt were detached, thrusted and stacked along the evaporitic Haselgebirge Formation. Exposed in salt mines, rocksalt and mudrock form a two component tectonite: The rock type "haselgebirge" consists of 10-70 wt % halite with silt- to gravel- or block-sized components within a halite matrix, and the "kerngebirge" with >70 wt % halite. All rock types studied are fault rocks. By use of a temperature-independent subgrain size piezometer, the paleo-differential stress of halite was calculated at ca. 2.5 MPa in Altaussee and ca. 4.5 MPa in Berchtesgaden. Including data from a grain-size piezometer, temperatures were estimated at ca. 150 +/- 20 degrees C and 110 +/- 10 degrees C. This implies very high strain rates, which are about 10-10-10-9 s 1. During the tectonic movement, the halite deformed, recrystallized, and crystallized as veins in mudrock fractures. We interpret high overpressure of the pore fluid to have significantly contributed to fracturing of the mudrock. PMID- 26523076 TI - Near-Field High-Energy Spectroscopic Gamma Imaging Using a Rotation Modulation Collimator. AB - Certain trace elements are vital to the body and elemental imbalances can be indicators of certain diseases including cancer and liver diseases. Neutron Stimulated Emission Computed Tomography (NSECT) is being developed as spectroscopic imaging technique to non-invasively and non-destructively measure and image elemental concentrations within the body. A region of interest is illuminated via a high-energy beam of neutrons that scatter inelastically with elemental nuclei within the body. The excited nuclei then relax by emitting characteristic gamma rays. Acquiring the gamma spectrum in a tomographic manner allows not only the identification of elements, but also the formation of images representing spatial distributions of specific elements. We are developing a high energy position-sensitive gamma camera that allows full illumination of the entire region of interest. Because current scintillation crystal based position sensitive gamma cameras operate in too low of an energy range, we are adapting high-energy gamma imaging techniques used in space-based imaging. A High Purity Germanium (HPGe) detector provides high-resolution energy spectra while a rotating modulation collimator (RMC) placed in front of the detector modulates the incoming signal to provide spatial information. The purpose of this manuscript is to describe the near-field RMC geometry, which varies greatly from the infinite-focus space-based applications, and how it modulates the incident gamma flux. A simple geometric model is presented and then used to reconstruct two-dimensional planar images of both simulated point sources and extended sources. PMID- 26523078 TI - Preferential cataclastic grain size reduction of feldspar in deformation bands in poorly consolidated arkosic sands. AB - This study presents microstructural as well as bulk and mineral chemical investigations of deformation bands in uncemented, friable arkosic sands of Miocene age (Vienna Basin, Austria). Our microstructural study indicates grain size reduction by grain flaking in deformation bands with small offsets (0.5-8 cm), and dominant intragranular fracturing and cataclasis of altered feldspar grains at larger displacements (up to 60 cm). Relative to quartz, the sericitized feldspar grains are preferably fractured and abraded, which additionally leads to an enrichment of mainly phyllosilicates by mechanical expulsion from feldspar. Both cataclasis of quartz and feldspar grains and enrichment of phyllosilicates result in grain size reduction within the deformation bands. The measured reduction in porosity of up to 20% is in some cases associated with a permeability reduction, reflected in the retention of iron-oxide rich fluids along deformation bands. These deformation bands formed at very shallow burial depths in unconsolidated sediments indicate that fault sealing may occur in the absence of chemical alteration of the deformation bands and lead to a compartmentalization of a groundwater or hydrocarbon reservoir. PMID- 26523079 TI - The lateral boundary of a metamorphic core complex: The Moutsounas shear zone on Naxos, Cyclades, Greece. AB - We describe the structure, microstructures, texture and paleopiezometry of quartz rich phyllites and marbles along N-trending Moutsounas shear zone at the eastern margin of the Naxos metamorphic core complex (MCC). Fabrics consistently indicate a top-to-the-NNE non-coaxial shear and formed during the main stage of updoming and exhumation between ca. 14 and 11 Ma of the Naxos MCC. The main stage of exhumation postdates the deposition of overlying Miocene sedimentary successions and predates the overlying Upper Miocene/Pliocene conglomerates. Detailed microstructural and textural analysis reveals that the movement along the Moutsounas shear zone is associated with a retrograde greenschist to subgreenschist facies overprint of the early higher-temperature rocks. Paleopiezometry on recrystallized quartz and calcite yields differential stresses of 20-77 MPa and a strain rate of 10-15-10-13 s-1 at 350 degrees C for quartz and ca. 300 degrees C for calcite. Chlorite geothermometry of the shear zone yields two temperature regimes, 300-360 degrees C, and 200-250 degrees C. The lower temperature group is interpreted to result from late-stage hydrothermal overprint. PMID- 26523080 TI - A low-temperature ductile shear zone: The gypsum-dominated western extension of the brittle Fella-Sava Fault, Southern Alps. AB - Based on structural and fabric analyses at variable scales we investigate the evaporitic gypsum-dominated Comeglians-Paularo shear zone in the Southern Alps (Friuli). It represents the lateral western termination of the brittle Fella-Sava Fault. Missing dehydration products of gypsum and the lack of annealing indicate temperatures below 100 degrees C during development of the shear zone. Despite of such low temperatures the shear zone clearly exhibits mylonitic flow, thus evidencing laterally coeval activity of brittle and viscous deformation. The dominant structures within the gypsum rocks of the Lower Bellerophon Formation are a steeply to gently S-dipping foliation, a subhorizontal stretching lineation and pure shear-dominated porphyroclast systems. A subordinate simple shear component with dextral displacement is indicated by scattered sigma-clasts. Both meso- and microscale structures are characteristic of a subsimple shear type of deformation with components of both coaxial and non-coaxial strain. Shortening in a transpressive regime was accommodated by right-lateral displacement and internal pure shear deformation within the Comeglians-Paularo shear zone. The shear zone shows evidence for a combination of two stretching faults, where stretching occurred in the rheologically weaker gypsum member and brittle behavior in enveloping lithologies. PMID- 26523081 TI - Short-selling constraints as cause for price distortions: An experimental study. AB - In this paper we explore the influence of the possibility to short stocks and/or borrow money in laboratory markets. A key innovation of our study is that subjects can simultaneously trade two risky assets on two double-auction markets, allowing us to differentiate between assets with relatively high versus low capitalization. Divergence of opinions is created by providing each trader with noisy information on the intrinsic values of both assets. We find that when borrowing money or shorting stocks is restricted prices are systematically distorted. Specifically, stocks with high (low) capitalization are traded at lower (higher) prices than their fundamental value. Lifting the restrictions leads to more efficient prices and more liquidity, thereby also lowering volatility and bid-ask spreads. PMID- 26523082 TI - Tidal Love and Shida numbers estimated by geodetic VLBI. AB - Frequency-dependent Love and Shida numbers, which characterize the Earth response to the tidal forces, were estimated in a global adjustment of all suitable geodetic Very Long Baseline Interferometry (VLBI) sessions from 1984.0 to 2011.0. Several solutions were carried out to determine the Love and Shida numbers for the tidal constituents at periods in the diurnal band and in the long-period band in addition to values of the Love and Shida numbers common for all tides of degree two. Adding up all twelve diurnal tidal waves that were estimated, the total differences in displacement with respect to the theoretical conventional values of the Love and Shida numbers calculated from an Earth model reach 1.73 +/ 0.29 mm in radial direction and 1.15 +/- 0.15 mm in the transverse plane. The difference in the radial deformation following from the estimates of the zonal Love numbers is largest for the semi-annual tide Ssa with 1.07 +/- 0.19 mm. PMID- 26523083 TI - Quantitative Wavelength Analysis and Image Classification for Intraoperative Cancer Diagnosis with Hyperspectral Imaging. AB - Complete surgical removal of tumor tissue is essential for postoperative prognosis after surgery. Intraoperative tumor imaging and visualization are an important step in aiding surgeons to evaluate and resect tumor tissue in real time, thus enabling more complete resection of diseased tissue and better conservation of healthy tissue. As an emerging modality, hyperspectral imaging (HSI) holds great potential for comprehensive and objective intraoperative cancer assessment. In this paper, we explored the possibility of intraoperative tumor detection and visualization during surgery using HSI in the wavelength range of 450 nm - 900 nm in an animal experiment. We proposed a new algorithm for glare removal and cancer detection on surgical hyperspectral images, and detected the tumor margins in five mice with an average sensitivity and specificity of 94.4% and 98.3%, respectively. The hyperspectral imaging and quantification method have the potential to provide an innovative tool for image-guided surgery. PMID- 26523084 TI - Family Kinship Patterns and Female Sex Work in the Informal Urban Settlement of Kibera, Nairobi, Kenya. AB - A basic ecological and epidemiological question is why some women enter into commercial sex work while other women in the same socio-economic environment never do. To address this question respondent driven sampling principles were adopted to recruit and collect data for 161 female sex workers and 159 same aged women who never engaged in commercial sex in Kibera, a large informal settlement in Nairobi, Kenya. Univariate analysis indicated that basic kinship measures, including number of family members seen during adolescence and at present, not having a male guardian while growing up, and earlier times of ending relationships with both male and female guardians were associated with commercial sex work in Kibera. Multivariate analysis via logistic regression modeling showed that not having a male guardian during childhood, low education attainment and a small number of family members seen at adolescence were all significant predictors of entering sex work. By far the most important predictor of entering sex work was not having any male guardian, e.g., father, uncle, older brother, etc. during childhood. Results are interpreted in light of the historic pattern of sub-Saharan African child fostering and their relevance for young women in Kibera today. PMID- 26523086 TI - Comparison of Hollow-Fiber Ultrafilters with Pleated Capsule Filters for Surface and Tap Water Samples Using U.S. EPA Method 1623. AB - The EPA method 1623 is designed specifically for the detection of Cryptosporidium and Giardia, but the method has some issues with low and variable recoveries. Ultrafiltration has been used effectively for microorganism recovery from water samples but is not approved by the EPA. To determine the efficacy of using ultrafiltration, 10-L tap water and surface water samples were seeded with Cryptosporidium and Giardia and concentrated with either a pleated capsule filter or a hollow-fiber ultrafilter. For Cryptosporidum, oocyst recovery in tap water was significantly higher for ultrafiltration (68%) versus the capsule filter (37%); ultrafiltration recovered 65% of oocysts in surface water versus 61% for the capsule filter. However, Giardia cyst recovery was mixed. In tap water, the capsule filter produced a significantly better recovery (85%) of Giardia compared with ultrafiltration (63%), but the surface water ultrafiltration recovery (81%) was significantly better than the capsule filter recovery (40%). Overall, ultrafiltration recoveries were equal to or better for Cryptosporidium, but recoveries of Giardia were varied depending on the filter used and the type of water analyzed. PMID- 26523087 TI - Improved polynomial remainder sequences for Ore polynomials. AB - Polynomial remainder sequences contain the intermediate results of the Euclidean algorithm when applied to (non-)commutative polynomials. The running time of the algorithm is dependent on the size of the coefficients of the remainders. Different ways have been studied to make these as small as possible. The subresultant sequence of two polynomials is a polynomial remainder sequence in which the size of the coefficients is optimal in the generic case, but when taking the input from applications, the coefficients are often larger than necessary. We generalize two improvements of the subresultant sequence to Ore polynomials and derive a new bound for the minimal coefficient size. Our approach also yields a new proof for the results in the commutative case, providing a new point of view on the origin of the extraneous factors of the coefficients. PMID- 26523088 TI - Regular expression order-sorted unification and matching. AB - We extend order-sorted unification by permitting regular expression sorts for variables and in the domains of function symbols. The obtained signature corresponds to a finite bottom-up unranked tree automaton. We prove that regular expression order-sorted (REOS) unification is of type infinitary and decidable. The unification problem presented by us generalizes some known problems, such as, e.g., order-sorted unification for ranked terms, sequence unification, and word unification with regular constraints. Decidability of REOS unification implies that sequence unification with regular hedge language constraints is decidable, generalizing the decidability result of word unification with regular constraints to terms. A sort weakening algorithm helps to construct a minimal complete set of REOS unifiers from the solutions of sequence unification problems. Moreover, we design a complete algorithm for REOS matching, and show that this problem is NP complete and the corresponding counting problem is #P-complete. PMID- 26523085 TI - A Century of Gibberellin Research. AB - Gibberellin research has its origins in Japan in the 19th century, when a disease of rice was shown to be due to a fungal infection. The symptoms of the disease including overgrowth of the seedling and sterility were later shown to be due to secretions of the fungus Gibberella fujikuroi (now reclassified as Fusarium fujikuroi), from which the name gibberellin was derived for the active component. The profound effect of gibberellins on plant growth and development, particularly growth recovery in dwarf mutants and induction of bolting and flowering in some rosette species, prompted speculation that these fungal metabolites were endogenous plant growth regulators and this was confirmed by chemical characterisation in the late 1950s. Gibberellins are now known to be present in vascular plants, and some fungal and bacterial species. The biosynthesis of gibberellins in plants and the fungus has been largely resolved in terms of the pathways, enzymes, genes and their regulation. The proposal that gibberellins act in plants by removing growth limitation was confirmed by the demonstration that they induce the degradation of the growth-inhibiting DELLA proteins. The mechanism by which this is achieved was clarified by the identification of the gibberellin receptor from rice in 2005. Current research on gibberellin action is focussed particularly on the function of DELLA proteins as regulators of gene expression. This review traces the history of gibberellin research with emphasis on the early discoveries that enabled the more recent advances in this field. PMID- 26523089 TI - Late Miocene sedimentary environments in south-western Amazonia (Solimoes Formation; Brazil). AB - In Miocene times a vast wetland existed in Western Amazonia. Whereas the general development of this amazing ecosystem is well established, many questions remain open on sedimentary environments, stratigraphical correlations as well as its palaeogeographical configuration. Several outcrops located in a barely studied region around Eirunepe (SW Amazonas state, Brazil) were investigated to obtain basic sedimentological data. The observed deposits belong to the upper part of the Solimoes Formation and are biostratigraphically dated to the Late Miocene. Vertically as well as laterally highly variable fine-grained clastic successions were recorded. Based on the lithofacies assemblages, these sediments represent fluvial deposits, possibly of an anastomosing river system. Sand bodies formed within active channels and dominant overbank fines are described (levees, crevasse splays/channels/deltas, abandoned channels, backswamps, floodplain paleosols). Lacustrine environments are restricted to local floodplain ponds/lakes. The mollusc and ostracod content as well as very light delta18O and delta13C values, measured on ostracod valves, refer to exclusively freshwater conditions. Based on palaeontological and geological results the existence of a long-lived lake ("Lake Pebas") or any influx of marine waters can be excluded for that region during the Late Miocene. PMID- 26523090 TI - Ostracods (Crustacea) and their palaeoenvironmental implication for the Solimoes Formation (Late Miocene; Western Amazonia/Brazil). AB - Western Amazonia's landscape and biota were shaped by an enormous wetland during the Miocene epoch. Among the most discussed topics of this ecosystem range the question on the transitory influx of marine waters. Inter alia the occurrence of typically brackish water associated ostracods is repeatedly consulted to infer elevated salinities or even marine ingressions. The taxonomical investigation of ostracod faunas derived from the upper part of the Solimoes Formation (Eirunepe; W-Brazil) documents a moderately diverse assemblage (19 species). A wealth of freshwater ostracods (mainly Cytheridella, Penthesilenula) was found co-occurring with taxa (chiefly Cyprideis) usually related to marginal marine settings today. The observed faunal compositions as well as constantly very light delta18O- and delta13C-values obtained by measuring both, the freshwater and brackish water ostracod group, refer to entirely freshwater conditions. These results corroborate with previous sedimentological and palaeontological observations, which proposed a fluvial depositional system for this part of western Amazonia during the Late Miocene. We demonstrate that some endemic, "brackish" water ostracods (i.e., Cyprideis) have been effectively adapted to freshwater conditions. Thus, their occurrence is no univocal evidence for the influence of brackish or marine waters in western Amazonia during the Miocene. PMID- 26523091 TI - A pilot-scale floating closed culture system for the multicellular cyanobacterium Arthrospira platensis NIES-39. AB - Microalgae are considered to be efficient bio-resources for biofuels and bio based chemicals because they generally have high productivity. The filamentous cyanobacterium Arthrospira (Spirulina) platensis has been widely used for food, feed, and nutrient supplements and is usually cultivated in open ponds. In order to extend the surface area for growing this alga, we designed a pilot-scale floating closed culture system for cultivating A. platensis on open water and compared the growth and quality of the alga harvested at both subtropical and temperate regions. The biomass productivity of A. platensis NIES-39 was ca. 9 g dry biomass m-2 day-1 in summer at Awaji Island (warm temperature region) and ca. 10 and 6 g dry biomass m-2 day-1 in autumn and winter, respectively, at Ishigaki Island, (subtropical region) in Japan. If seawater can be used for culture media, culture cost can be reduced; therefore, we examined the influence of seawater salt concentrations on the growth of A. platensis NIES-39. Growth rates of A. platensis NIES-39 in diluted seawater with enrichment of 2.5 g L-1 NaNO3, 0.01 g L-1 FeSO4.7H2O, and 0.08 g L-1 Na2EDTA were considerably lower than SOT medium, but the biomass productivity (dry weight) was comparable to SOT medium. This is explained by the heavier cell weight of the alga grown in modified seawater media compared to the alga grown in SOT medium. Furthermore, A. platensis grown in modified seawater-based medium exhibited self-flocculation and had more loosely coiled trichomes. PMID- 26523092 TI - Particle size and surface area effects on explosibility using a 20-L chamber. AB - The Mine Safety and Health Administration (MSHA) specification for rock dust used in underground coal mines, as defined by 30 CFR 75.2, requires 70% of the material to pass through a 200 mesh sieve (<75 um). However, in a collection of rock dusts, 47% were found to not meet the criteria. Upon further investigation, it was determined that some of the samples did meet the specification, but were inadequate to render pulverized Pittsburgh coal inert in the National Institute for Occupational Safety and Health (NIOSH) Office of Mine Safety and Health Research (OMSHR) 20-L chamber. This paper will examine the particle size distributions, specific surface areas (SSA), and the explosion suppression effectiveness of these rock dusts. It will also discuss related findings from other studies, including full-scale results from work performed at the Lake Lynn Experimental Mine. Further, a minimum SSA for effective rock dust will be suggested. PMID- 26523093 TI - Micromachined silicon acoustic delay lines for ultrasound applications. AB - In this paper, we present the design, fabrication and testing of novel micromachined silicon-based acoustic delay lines. The acoustic properties of different silicon delay line structures have been characterized. Based on the experiment results, two different acoustic delay line systems (parallel and serial) have been successfully demonstrated to create controlled time delays in multiple channels of ultrasound signals. The time-delayed ultrasound signals are received with a single-element ultrasound transducer in a time-serial manner. This unique capability could be used to merge multiple signal channels, thereby enabling new ultrasound receiver designs with potentially less complexity and lower cost. PMID- 26523095 TI - Inflammation in Cachexia. PMID- 26523094 TI - Nonmuscle Tissues Contribution to Cancer Cachexia. AB - Cachexia is a syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting, and inflammation, being often associated with anorexia. In spite of the fact that muscle tissue represents more than 40% of body weight and seems to be the main tissue involved in the wasting that occurs during cachexia, recent developments suggest that tissues/organs such as adipose (both brown and white), brain, liver, gut, and heart are directly involved in the cachectic process and may be responsible for muscle wasting. This suggests that cachexia is indeed a multiorgan syndrome. Bearing all this in mind, the aim of the present review is to examine the impact of nonmuscle tissues in cancer cachexia. PMID- 26523097 TI - How to establish endoscopic submucosal dissection in Western countries. AB - Endoscopic submucosal dissection (ESD) has been invented in Japan to provide resection for cure of early cancer in the gastrointestinal tract. Professional level of ESD requires excellent staging of early neoplasias with image enhanced endoscopy (IEE) to make correct indications for ESD, and high skills in endoscopic electrosurgical dissection. In Japan, endodiagnostic and endosurgical excellence spread through personal tutoring of skilled endoscopists by the inventors and experts in IEE and ESD. To translocate this expertise to other continents must overcome two fundamental obstacles: (1) inadequate expectations as to the complexity of IEE and ESD; and (2) lack of suitable lesions and master mentors for ESD trainees. Leading endoscopic mucosal resection-proficient endoscopists must pioneer themselves through the long learning curve to proficient ESD experts. Major referral centers for ESD must arise in Western countries on comparable professional level as in Japan. In the second stage, the upcoming Western experts must commit themselves to teach skilled endoscopists from other referral centers, in order to spread ESD in Western countries. Respect for patients with early gastrointestinal cancer asks for best efforts to learn endoscopic categorization of early neoplasias and skills for ESD based on sustained cooperation with the masters in Japan. The strategy is discussed here. PMID- 26523099 TI - Promises and paradoxes of regulatory T cells in inflammatory bowel disease. AB - Since their discovery two decades ago, CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) have become the subject of intense investigation by immunologists. Unlike other T cells, which promote an immune response, Tregs actively inhibit inflammation when activated by their cognate antigen, thus raising hope that these cells could be engineered into a highly targeted, antigen-specific, immunosuppressant therapy. Although Tregs represent less than 10% of circulating CD4(+)T cells, they have been shown to play an essential role in preventing or limiting inflammation in a variety of animal models and human diseases. In particular, spontaneous intestinal inflammation has been shown to occur in the absence of Tregs, suggesting that there may be a Treg defect central to the pathogenesis of human inflammatory bowel disease (IBD). However, over the past decade, multiple groups have reported no qualitative or quantitative deficits in Tregs from the intestines and blood of IBD patients to explain why these cells fail to regulate inflammation in Crohn's disease and ulcerative colitis. In this review, we will discuss the history of Tregs, what is known about them in IBD, and what progress and obstacles have been seen with efforts to employ them for therapeutic benefit. PMID- 26523098 TI - Diagnosis of Helicobacter pylori infection: Current options and developments. AB - Accurate diagnosis of Helicobacter pylori (H. pylori) infection is a crucial part in the effective management of many gastroduodenal diseases. Several invasive and non-invasive diagnostic tests are available for the detection of H. pylori and each test has its usefulness and limitations in different clinical situations. Although none can be considered as a single gold standard in clinical practice, several techniques have been developed to give the more reliable results. Invasive tests are performed via endoscopic biopsy specimens and these tests include histology, culture, rapid urease test as well as molecular methods. Developments of endoscopic equipment also contribute to the real-time diagnosis of H. pylori during endoscopy. Urea breathing test and stool antigen test are most widely used non-invasive tests, whereas serology is useful in screening and epidemiological studies. Molecular methods have been used in variable specimens other than gastric mucosa. More than detection of H. pylori infection, several tests are introduced into the evaluation of virulence factors and antibiotic sensitivity of H. pylori, as well as screening precancerous lesions and gastric cancer. The aim of this article is to review the current options and novel developments of diagnostic tests and their applications in different clinical conditions or for specific purposes. PMID- 26523100 TI - Disease monitoring in inflammatory bowel disease. AB - The optimal method for monitoring quiescent disease in patients with Crohn's disease (CD) and ulcerative colitis is yet to be determined. Endoscopic evaluation with ileocolonoscopy is the gold standard but is invasive, costly, and time-consuming. There are many commercially available biomarkers that may be used in clinical practice to evaluate disease status in patients with inflammatory bowel disease (IBD), but the most widely adopted biomarkers are C-reactive protein (CRP) and fecal calprotectin (FC). This review summarizes the evidence for utilizing CRP and FC for monitoring IBD during clinical remission and after surgical resection. Endoscopic correlation with CRP and FC is evaluated in each disease state. Advantages and drawbacks of each biomarker are discussed with special consideration of isolated ileal CD. Fecal immunochemical testing, traditionally used for colorectal cancer screening, is mentioned as a potential new alternative assay in the evaluation of IBD. Based on a mixture of information gleaned from biomarkers, clinical status, and endoscopic evaluation, the best treatment decisions can be made for the patient with IBD. PMID- 26523102 TI - Arterial structure and function in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is the result of a combination of environmental, genetic and immunologic factors that trigger an uncontrolled immune response within the intestine, which results in inflammation among genetically predisposed individuals. Several studies have reported that the prevalence of classic cardiovascular risk factors is lower among subjects with IBD than in the general population, including obesity, dyslipidaemia, diabetes and hypertension. Therefore, given the risk profile of IBD subjects, the expected cardiovascular morbidity and mortality should be lower in these patients than in the general population. However, this is not the case because the standardized mortality ratio is not reduced and the risk of coronary heart disease is increased in patients with IBD. It is reasonable to hypothesize that other factors not considered in the classical stratification of cardiovascular risk may be involved in these subjects. Therefore, IBD may be a useful model with which to evaluate the effects of chronic low-grade inflammation in the development of cardiovascular diseases. Arterial stiffness is both a marker of subclinical target organ damage and a cardiovascular risk factor. In diseases characterized by chronic systemic inflammation, there is evidence that the inflammation affects arterial properties and induces both endothelial dysfunction and arterial stiffening. It has been reported that decreasing inflammation via anti tumor necrosis factor alpha therapy decreases arterial stiffness and restores endothelial function in patients with chronic inflammatory disorders. Consistent with these results, several recent studies have been conducted to determine whether arterial properties are altered among patients with IBD. In this review, we discuss the evidence pertaining to arterial structure and function and present the available data regarding arterial stiffness and endothelial function in patients with IBD. PMID- 26523101 TI - From the surface to the single cell: Novel endoscopic approaches in inflammatory bowel disease. AB - Inflammatory bowel diseases (IBD) comprise the two major entities Crohn's disease and ulcerative colitis and endoscopic imaging of the gastrointestinal tract has always been an integral and central part in the management of IBD patients. Within the recent years, mucosal healing emerged as a key treatment goal in IBD that substantially decides about the clinical outcome of IBD patients, thereby demanding for a precise, timely and detailed endoscopic assessment of the mucosal inflammation associated with IBD. Further, molecular imaging has tremendously expanded the clinical utility and applications of modern endoscopy, now encompassing not only diagnosis, surveillance, and treatment but also the prediction of individual therapy response. Within this review we describe novel endoscopic approaches and advanced endoscopic imaging methods for the diagnosis, treatment and surveillance of IBD patients. We begin by providing an overview over novel and advanced imaging techniques such as magnification endoscopy and dye-based and dye-less chromoendoscopy, endomicroscopy and endocytoscopy. We then describe how these techniques can be utilized for the precise and ultrastructural assessment of mucosal inflammation and dysplasia development associated with IBD and outline how they have enabled the endoscopist to gain insight onto the cellular level in real-time. Finally, we provide an outlook on how molecular imaging has rapidly evolved in the recent past and can be used to make individual predictions about the therapeutic response towards biological treatment. PMID- 26523103 TI - Irritable bowel syndrome and chronic constipation: Fact and fiction. AB - Irritable bowel syndrome (IBS) and functional constipation (FC) are the most common functional gastrointestinal disorders. According to the Rome III Criteria these two disorders should be theoretically separated mainly by the presence of abdominal pain or discomfort relieved by defecation (typical of IBS) and they should be mutually exclusive. However, many gastroenterologists have serious doubts as regards a clear separation. Both IBS-C and FC, often associated with many other functional digestive and non digestive disorders, are responsible for a low quality of life. The impact of the media on patients' perception of these topics is sometimes disruptive, often suggesting a distorted view of pathophysiology, diagnosis and therapy. These messages frequently overlap with previous subjective opinions and are further processed on the basis of the different culture and the previous experience of the constipated patients, often producing odd, useless or even dangerous behaviors. The aim of this review was to analyze the most common patients' beliefs about IBS-C and CC, helping physicians to understand where they should focus their attention when communicating with patients, detecting false opinions and misconceptions and correcting them on the basis of scientific evidence. PMID- 26523104 TI - Role of environmental pollution in irritable bowel syndrome. AB - Irritable bowel syndrome (IBS), with the prevalence of 10%-20 % of the population has become an emerging problem worldwide. IBS is a functional gastrointestinal (GI) disorder characterized by abdominal pain or discomfort and altered bowel habits. The etiology of IBS contains genetic, psychological, and immunological factors, and has not been fully elucidated; of note, recent studies also point at environmental pollution and its role in the development of functional GI diseases. In this review we focus on several environmental factors, such as bacterial contamination, air pollution, radiation and even stress as potential triggers of IBS. We discuss associated disturbances in homeostasis, such as changes in intestinal microbiome and related pathophysiological mechanisms. Based on the effect of environmental factors on the GI tract, we also propose novel targets in IBS treatment. PMID- 26523105 TI - Cancer immunotherapy for pancreatic cancer utilizing alpha-gal epitope/natural anti-Gal antibody reaction. AB - Pancreatic ductal adenocarcinoma (PDAC) has the poorest prognosis of all malignancies and is largely resistant to standard therapy. Novel treatments against PDAC are desperately needed. Anti-Gal is the most abundant natural antibody in humans, comprising about 1% of immunoglobulins and is also naturally produced in apes and Old World monkeys. The anti-Gal ligand is a carbohydrate antigen called "alpha-gal epitopes" with the structure Galalpha1-3Galbeta1 4GlcNAc-R. These epitopes are expressed as major carbohydrate antigens in non primate mammals, prosimians, and New World monkeys. Anti-Gal is exploited in cancer vaccines to increase the immunogenicity of antigen-presenting cells (APCs). Cancer cells or PDAC tumor lysates are processed to express alpha-gal epitopes. Vaccination with these components results in in vivo opsonization by anti-Gal IgG in PDAC patients. The Fc portion of the vaccine-bound anti-Gal interacts with Fcgamma receptors of APCs, inducing uptake of the vaccine components, transport of the vaccine tumor membranes to draining lymph nodes, and processing and presentation of tumor-associated antigens (TAAs). Cancer vaccines expressing alpha-gal epitopes elicit strong antibody production against multiple TAAs contained in PDAC cells and induce activation of multiple tumor-specific T cells. Here, we review new areas of clinical importance related to the alpha-gal epitope/anti-Gal antibody reaction and the advantages in immunotherapy against PDAC. PMID- 26523106 TI - Tight junction disruption: Helicobacter pylori and dysregulation of the gastric mucosal barrier. AB - Long-term chronic infection with Helicobacter pylori (H. pylori) is a risk factor for gastric cancer development. In the multi-step process that leads to gastric cancer, tight junction dysfunction is thought to occur and serve as a risk factor by permitting the permeation of luminal contents across an otherwise tight mucosa. Mechanisms that regulate tight junction function and structure in the normal stomach, or dysfunction in the infected stomach, however, are largely unknown. Although conventional tight junction components are expressed in gastric epithelial cells, claudins regulate paracellular permeability and are likely the target of inflammation or H. pylori itself. There are 27 different claudin molecules, each with unique properties that render the mucosa an intact barrier that is permselective in a way that is consistent with cell physiology. Understanding the architecture of tight junctions in the normal stomach and then changes that occur during infection is important but challenging, because most of the reports that catalog claudin expression in gastric cancer pathogenesis are contradictory. Furthermore, the role of H. pylori virulence factors, such as cytotoxin-associated gene A and vacoulating cytotoxin, in regulating tight junction dysfunction during infection is inconsistent in different gastric cell lines and in vivo, likely because non-gastric epithelial cell cultures were initially used to unravel the details of their effects on the stomach. Hampering further study, as well, is the relative lack of cultured cell models that have tight junction claudins that are consistent with native tissues. This summary will review the current state of knowledge about gastric tight junctions, normally and in H. pylori infection, and make predictions about the consequences of claudin reorganization during H. pylori infection. PMID- 26523107 TI - Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge. AB - While the incidence of gastric cancer has decreased worldwide in recent decades, the incidence of signet-ring cell carcinoma (SRCC) is rising. SRCC has a specific epidemiology and oncogenesis and has two forms: early gastric cancer, which can be resected endoscopically in some cases and which has a better outcome than non SRCC, and advanced gastric cancer, which is generally thought to have a worse prognosis and lower chemosensitivity than non-SRCC. However, the prognosis of SRCC and its chemosensitivity with specific regimens are still controversial as SRCC is not specifically identified in most studies and its poor prognosis may be due to its more advanced stage. It therefore remains unclear if a specific therapeutic strategy is justified, as the benefit of perioperative chemotherapy and the value of taxane-based chemotherapy are unclear. In this review we analyze recent data on the epidemiology, oncogenesis, prognosis and specific therapeutic strategies in both early and advanced SRCC of the stomach and in hereditary diffuse gastric cancer. PMID- 26523108 TI - Aspects of the non-pharmacological treatment of irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is one of the most commonly diagnosed gastrointestinal conditions. It represents a significant healthcare burden and remains a clinical challenge. Over the years IBS has been described from a variety of different perspectives; from a strict illness of the gastrointestinal tract (medical model) to a more complex multi-symptomatic disorder of the brain gut axis (biopsychosocial/psychosomatic model). In this article we present aspects of the pathophysiology and the non-pharmacological treatment of IBS based on current knowledge. Effects of conditioned stress and/or traumatic influences on the emotional system (top-down) as well as effects on the intestine through stressors, infection, inflammation, food and dysbiosis (bottom-up) can affect brain-gut communication and result in dysregulation of the autonomic nervous system (ANS), playing an important role in the pathophysiology of IBS. Conditioned stress together with dysregulation of the autonomic nervous system and the emotional system may involve reactions in which the distress inside the body is not recognized due to low body awareness. This may explain why patients have difficulty identifying their symptoms despite dysfunction in muscle tension, movement patterns, and posture and biochemical functions in addition to gastrointestinal symptoms. IBS shares many features with other idiopathic conditions, such as fibromyalgia, chronic fatigue syndrome and somatoform disorders. The key to effective treatment is a thorough examination, including a gastroenterological examination to exclude other diseases along with an assessment of body awareness by a body-mind therapist. The literature suggests that early interdisciplinary diagnostic co-operation between gastroenterologists and body-mind therapists is necessary. Re-establishing balance in the ANS is an important component of IBS treatment. This article discusses the current knowledge of body-mind treatment, addressing the topic from a practical point of view. PMID- 26523109 TI - Dysbiotic infection in the stomach. AB - Microbiota in human alimentary tract plays important roles for homeostatic maintenance of the body. Compositional difference of gut microbiota is tightly associated with susceptibility of many diseases, including inflammatory diseases, obesity, diabetes mellitus, cancer, and atherosclerosis. "Dysbiosis" refers to a state of imbalance among the colonies of microorganisms within the body, which brings abnormal increase of specific minor components and decrease in the normally dominant species. Since stomach secrets strong acid for its digestive role, this organ has long been thought a sterile organ. However, the discovery of Helicobacter pylori (H. pylori) has changed the concept. This bacterium has proven to cause gastritis, peptic ulcer, and gastric cancer. However, recent cross-sectional studies revealed that H. pylori carriers had a decreased risk of developing immunological diseases, such as asthma. H. pylori coinfection also suppresses inflammatory bowel diseases. This review describes human gastric microbiota by discussing its mutual interaction and pathogenic enrollment. Gastric "dysbiosis" may affect host inflammatory response and play important role for gastric pathogenesis. We will topically discuss enrollment of dysbiosis for genesis of gastric cancer as well as for disruption of immunological homeostasis affecting oncogenic resistance. PMID- 26523110 TI - Intra-abdominal drainage following pancreatic resection: A systematic review. AB - AIM: To study all the aspects of drain management in pancreatic surgery. METHODS: We conducted a systematic review according to the PRISMA guidelines. We searched the Cochrane Central Registry of Controlled Trials, EMBASE, Web of Science, and PubMed (MEDLINE) for relevant articles on drain management in pancreatic surgery. The reference lists of relevant studies were screened to retrieve any further studies. We included all articles that reported clinical studies on human subjects with elective pancreatic resection and that compared various strategies of intra-abdominal drain management, such as drain vs no drain, selective drain use, early vs late drain extraction, and the use of different types of drains. RESULTS: A total of 19 studies concerned with drain management in pancreatic surgery involving 4194 patients were selected for this systematic review. We included studies analyzing the outcomes of pancreatic resection with and without intra-abdominal drains, studies comparing early vs late drain removal and studies analyzing different types of drains. The majority of the studies reporting equal or superior results for pancreatic resection without drains were retrospective and observational with significant selection bias. One recent randomized trial reported higher postoperative morbidity and mortality with routine omission of intra-abdominal drains. With respect to the timing of drain removal, all of the included studies reported superior results with early drain removal. Regarding the various types of drains, there is insufficient evidence to determine which type of drain is more suitable following pancreatic resection. CONCLUSION: The prophylactic use of drains remains controversial. When drains are used, early removal is recommended. Further trials comparing types of drains are ongoing. PMID- 26523112 TI - Diagnostic accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography in gallbladder cancer: A meta-analysis. AB - AIM: To meta-analyze published data about the diagnostic accuracy of fluorine-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) and PET/computed tomography (PET/CT) in the evaluation of primary tumor in patients with gallbladder cancer (GBCa). METHODS: A comprehensive literature search of studies published through 30(th) June 2014 regarding the role of (18)F-FDG PET and PET/CT in the evaluation of primary gallbladder cancer (GBCa) was performed. All retrieved studies were reviewed. Pooled sensitivity and specificity of (18)F FDG PET or PET/CT in the evaluation of primary GBCa were calculated. The area under the summary receiving operator characteristics curve (AUC) was calculated to measure the accuracy of these methods. Sub-analyses considering the device used (PET vs PET/CT) were carried out. RESULTS: Twenty-one studies comprising 495 patients who underwent (18)F-FDG PET or PET/CT for suspicious GBCa were selected for the systematic review. The meta-analysis of 13 selected studies provided the following results: sensitivity 87% (95%CI: 82%-92%), specificity 78% (95%CI: 68% 86%). The AUC was 0.88. Improvement of sensitivity and specificity was observed when PET/CT was used. CONCLUSION: (18)F-FDG-PET and PET/CT demonstrated to be useful diagnostic imaging methods in the assessment of primary tumor in GBCa patients, nevertheless possible sources of false-negative and false-positive results should be kept in mind. PET/CT seems to have a better diagnostic accuracy than PET alone in this setting. PMID- 26523113 TI - Structural evolution and strain induced mixing in Cu-Co composites studied by transmission electron microscopy and atom probe tomography. AB - A Cu-Co composite material is chosen as a model system to study structural evolution and phase formations during severe plastic deformation. The evolving microstructures as a function of the applied strain were characterized at the micro-, nano-, and atomic scale-levels by combining scanning electron microscopy and transmission electron microscopy including energy-filtered transmission electron microscopy and electron energy-loss spectroscopy. The amount of intermixing between the two phases at different strains was examined at the atomic scale using atom probe tomography as complimentary method. It is shown that Co particles are dissolved in the Cu matrix during severe plastic deformation to a remarkable extent and their size, number, and volume fraction were quantitatively determined during the deformation process. From the results, it can be concluded that supersaturated solid solutions up to 26 at.% Co in a fcc Cu-26 at.% Co alloy are obtained during deformation. However, the distribution of Co was found to be inhomogeneous even at the highest degree of investigated strain. PMID- 26523111 TI - Are faecal markers good indicators of mucosal healing in inflammatory bowel disease? AB - AIM: To review the published literature concerning the accuracy of faecal inflammatory markers for identifying mucosal healing. METHODS: Bibliographical searches were performed in MEDLINE electronic database up to February 2015, using the following terms: "inflammatory bowel disease", "Crohn's disease", "ulcerative colitis", "faecal markers", "calprotectin", "lactoferrin", "S100A12", "endoscop*", "mucosal healing", "remission". In addition, relevant references from these studies were also included. Data were extracted from the published papers including odds ratios with 95%CI, P values and correlation coefficients. Data were grouped together according to each faecal marker, Crohn's disease or ulcerative colitis, and paediatric compared with adult study populations. Studies included in this review assessed mucosal inflammation by endoscopic and/or histological means and compared these findings to faecal marker concentrations in inflammatory bowel diseases (IBD) patient cohorts. Articles had to be published between 1990 and February 2015 and written in English. Papers excluded from the review were those where the faecal biomarker concentration was compared between patients with IBD and controls or other disease groups, those where serum biomarkers were used, those with a heterogeneous study population and those only assessing post-operative disease. RESULTS: The available studies show that faecal markers, such as calprotectin and lactoferrin, are promising non-invasive indicators of mucosal healing. However, due to wide variability in study design, especially with regard to the definition of mucosal healing and evaluation of marker cut offs, the available data do not yet indicate the optimal roles of these markers. Thirty-six studies published between 1990 and 2014 were included. Studies comprised variable numbers of study participants, considered CD (15-164 participants) or UC (12-152 participants) separately or as a combined group (11 252 participants). Eight reports included paediatric patients. Several indices were used to document mucosal inflammation, encompassing eleven endoscopic and eight histologic grading systems. The majority of the available reports focused on faecal calprotectin (33 studies), whilst others assessed faecal lactoferrin (13 studies) and one study assessed S100A12. Across all of the biomarkers, there is a wide range of correlation describing the association between faecal markers and endoscopic disease activity (r values ranging from 0.32 to 0.87, P values ranging from < 0.0001 to 0.7815). Correlation coefficients are described in almost all studies and are used more commonly than outcome measures such as sensitivity, specificity, PPV and/or NPV. Overall, the studies that have evaluated faecal calprotectin and/or faecal lactoferrin and their relationship with endoscopic disease activity show inconsistent results. CONCLUSION: Future studies should report the results of faecal inflammatory markers in the context of mucosal healing with clear validated cut offs. PMID- 26523114 TI - Archaeometallurgical characterization of the earliest European metal helmets. AB - Archaeometric analyses on conical and decorated cap helmets from the Bronze Age are presented. The helmets are dated to the 14-12th century BC according to associated finds in hoards. Alloy composition, material structure and manufacturing processes are determined and shed light on the earliest development of weaponry production in Central and Eastern Europe. Analyses were carried out using light and dark field microscopy, SEM-EDXS, PIXE, TOF-ND and PGAA. The results allowed reconstructing the manufacturing process, the differences between the cap of the helmets and their knobs (i.e. alloy composition) and the joining technique of the two parts. PMID- 26523115 TI - Meeting the complex needs of urban youth and their families through the 4Rs 2Ss Family Strengthening Program: The "real world" meets evidence-informed care. AB - Youth living in poverty face compounding familial and environmental challenges in utilizing effective community mental health services. They have ongoing stressors that increase their dropout rate in mental health service use. Difficulties also exist in staying engaged in services when they are involved with the child welfare system. This study examines the 4Rs 2Ss Family Strengthening Program, developed across four broad conceptual categories related to parenting skills and family processes that form a multiple family group service delivery approach. A total of 321 families were enrolled in this randomized intervention study, assigned to either the 4Rs 2Ss Family Strengthening Program or standard care services. Caregivers and their children randomly assigned to the experimental condition received a 16 week multiple family group intervention through their respective outpatient community mental health clinic. Data was collected at baseline, midtest (8 weeks), posttest (16 weeks), and 6 month follow-up. Major findings include high engagement in the 4Rs 2Ss Family Strengthening Program, compared to standard services. Although child welfare status is not related to attendance, family stress and parental depression are also related to participant engagement in this multiple family group intervention. Involvement in the 4Rs 2Ss Family Strengthening Program resulted in improved effects for child behaviors. Lastly, no evidence of moderation effects on family stress, child welfare involvement, or parental needs were found. The 4Rs 2Ss Family Strengthening Program appeared able to engage families with more complex "real world" needs. PMID- 26523116 TI - Soft Computing Methods for Disulfide Connectivity Prediction. AB - The problem of protein structure prediction (PSP) is one of the main challenges in structural bioinformatics. To tackle this problem, PSP can be divided into several subproblems. One of these subproblems is the prediction of disulfide bonds. The disulfide connectivity prediction problem consists in identifying which nonadjacent cysteines would be cross-linked from all possible candidates. Determining the disulfide bond connectivity between the cysteines of a protein is desirable as a previous step of the 3D PSP, as the protein conformational search space is highly reduced. The most representative soft computing approaches for the disulfide bonds connectivity prediction problem of the last decade are summarized in this paper. Certain aspects, such as the different methodologies based on soft computing approaches (artificial neural network or support vector machine) or features of the algorithms, are used for the classification of these methods. PMID- 26523117 TI - MicroRNA-155 and Its Role in Malignant Hematopoiesis. AB - MicroRNA-155 (miR-155) is a multifunctional molecule involved in both normal and malignant hematopoiesis. It has been found to be involved in the pathogenesis of many different hematological malignancies with either an oncogenic or a tumor repressor effect, depending on the nature of the cell and the type of malignancy. In particular, it has been strongly implicated in the causation of diffuse large B-cell lymphomas. This review focuses on the molecular interactions of miR-155, its oncogenic mechanisms, and its potential as an effective therapeutic target for the associated malignancies. PMID- 26523118 TI - Gene Coexpression Networks in Human Brain Developmental Transcriptomes Implicate the Association of Long Noncoding RNAs with Intellectual Disability. AB - The advent of next-generation sequencing for genetic diagnoses of complex developmental disorders, such as intellectual disability (ID), has facilitated the identification of hundreds of predisposing genetic variants. However, there still exists a vast gap in our knowledge of causal genetic factors for ID as evidenced by low diagnostic yield of genetic screening, in which identifiable genetic causes are not found for the majority of ID cases. Most methods of genetic screening focus on protein-coding genes; however, noncoding RNAs may outnumber protein-coding genes and play important roles in brain development. Long noncoding RNAs (lncRNAs) specifically have been shown to be enriched in the brain and have diverse roles in gene regulation at the transcriptional and posttranscriptional levels. LncRNAs are a vastly uncharacterized group of noncoding genes, which could function in brain development and harbor ID predisposing genetic variants. We analyzed lncRNAs for coexpression with known ID genes and affected biological pathways within a weighted gene coexpression network derived from RNA-sequencing data spanning human brain development. Several ID-associated gene modules were found to be enriched for lncRNAs, known ID genes, and affected biological pathways. Utilizing a list of de novo and pathogenic copy number variants detected in ID probands, we identified lncRNAs overlapping these genetic structural variants. By integrating our results, we have made a prioritized list of potential ID-associated lncRNAs based on the developing brain gene coexpression network and genetic structural variants found in ID probands. PMID- 26523119 TI - Paternal Transmission of Small Supernumerary Marker Chromosome 15 Identified in Prenatal Diagnosis Due to Advanced Maternal Age. AB - The detection of supernumerary marker chromosomes (SMCs) in prenatal diagnosis is always a challenge. In this study, we report a paternally inherited case of a small SMC(15) that was identified in prenatal diagnosis due to advanced maternal age. A 39-year-old woman underwent amniocentesis at 16 weeks of gestation. A fetal abnormal karyotype - 47,XX,+mar - with one sSMC was detected in all metaphases. Since this sSMC was critical in the parental decision to continue or interrupt this pregnancy, we proceeded to study the fetus and their parents. Cytogenetic and molecular analyses revealed a fetal karyotype 47,XX,+mar pat.ish idic(15)(ql2)(D15Zl++,SNRPN-), in which the sSMC(15) was a paternally inherited inverted duplicated chromosome and did not contain the critical region of Prader Willi/Angelman syndromes. Moreover, fetal uniparental disomy was excluded. Based on this information and normal obstetric ultrasounds, the parents decided to proceed with the pregnancy and a phenotypically normal girl was born at 39 weeks of gestation. In conclusion, the clinical effects of sSMCs need to be investigated, especially when sSMCs are encountered at prenatal diagnosis. Here, although the paternal sSMC(15) was not associated with an abnormal phenotype, its characterization allows more accurate genetic counseling for the family progeny. PMID- 26523120 TI - Canagliflozin Treatment in Patients with Type 2 Diabetes Mellitus. AB - Current guidelines for treatment of type 2 diabetes mellitus (T2DM) indicate a patient-centered approach that should go beyond glycemic control. Of the many antihyperglycemic agents available for treatment of T2DM, sodium-glucose cotransporter 2 (SGLT2) inhibitors offer the advantages of reduced glycated hemoglobin (A1C), body weight (BW), and systolic blood pressure (SBP) and are associated with a low risk of hypoglycemia when used either as monotherapy or with other agents not typically associated with increased risk of hypoglycemia. Collaborative, multidisciplinary teams are best suited to provide care to patients with diabetes, and clinical pharmacists can enhance the care provided by these teams. This review aims to provide insight into the mode of action, pharmacology, potential drug-drug interactions, clinical benefits, and safety considerations associated with use of the SGLT2 inhibitor canagliflozin in patients with T2DM and to provide information to enhance clinical pharmacists' understanding of canagliflozin. PMID- 26523121 TI - Neurodevelopmental outcomes in children with Down syndrome and infantile spasms. AB - Down syndrome (DS) is the most common genetic cause of intellectual disability in the United States. The prevalence of seizure in individuals with DS is 1-13%, and infantile spasm (IS) occurs in 6-32% of those with seizures. Since IS is relatively common in children with DS, it is important to understand the impact IS has on the neurodevelopmental outcomes in order to provide appropriate anticipatory guidance to help maximize the potential of these children. Our study is the first to compare the neurodevelopmental outcomes of children with DS and IS (DS + IS) to children with DS and no history of seizures (DS - IS). Using the Bayley Scales of Infant and Toddler Development III, we assessed the neurodevelopment of 29 subjects (eight DS + IS and 21 DS - IS). Neurodevelopmental outcome was poor in the DS + IS cohort, but the delay in treatment does not appear to contribute to any differences in their developmental scores. However, when compared to children with DS - IS, the DS + IS cohort scored approximately 20 points less in all domains including cognitive, motor, and language (P < 0.05). Our results indicate that IS may impact the neurodevelopmental outcomes of children with DS + IS; thus, it is important to provide ongoing developmental and educational assessments and potentially additional therapies for children with DS + IS. PMID- 26523122 TI - The More You Learn the Less You Know?: Interpretive Ambiguity across Three Modes of Qualitative Data. AB - BACKGROUND: Researchers across disciplines face a similar challenge ensuring our methods can give us valid, usable answers to our questions. But what happens when multiple strategies of inquiry give us different answers to the same research question? We explore this question through three different modes of qualitative inquiry--interviews, focus groups, and participant observation - oriented around local attitudes to HIV testing. OBJECTIVE: We introduce the notion of "research awareness" -- the extent to which participants are continuously reminded that they are taking part in a research project, which is a function of the mode of research itself. We hypothesize that as participants' research-awareness decreases across modes, from interviews to focus groups to participant observation, the proportion of statements that conform to officially sanctioned normative discourse about HIV/AIDS will decrease and the proportion expressing non-normative or counter-normative ideas will increase. METHODS: We tabulated positive and negative references to three themes -- knowing one's HIV status, counseling messages, and antiretroviral treatment -- across the three qualitative modes. RESULTS: The distribution is non-uniform, with favorable responses to testing themes predominating in interviews, mixed responses in the focus groups, and negative responses predominating in the observational data. At least 1/3 of references to testing across all three modes, however, do not support officially sanctioned normative discourse. CONCLUSIONS: Researchers who use mixed methods approaches for triangulation should consider the influence of research-awareness on their methods. These situational specifics are crucial for understanding the applicability of research to real life. Substantively, our study revealed a robust level of ambivalence about HIV testing despite normative discourses supporting it at local and global levels. PMID- 26523123 TI - Secondary instabilities modulate cortical complexity in the mammalian brain. AB - Disclosing the origin of convolutions in the mammalian brain remains a scientific challenge. Primary folds form before we are born: they are static, well defined, and highly preserved across individuals. Secondary folds occur and disappear throughout our entire life time: they are dynamic, irregular, and highly variable among individuals. While extensive research has improved our understanding of primary folding in the mammalian brain, secondary folding remains understudied and poorly understood. Here, we show that secondary instabilities can explain the increasing complexity of our brain surface as we age. Using the nonlinear field theories of mechanics supplemented by the theory of finite growth, we explore the critical conditions for secondary instabilities. We show that with continuing growth, our brain surface continues to bifurcate into increasingly complex morphologies. Our results suggest that even small geometric variations can have a significant impact on surface morphogenesis. Secondary bifurcations, and with them morphological changes during childhood and adolescence, are closely associated with the formation and loss of neuronal connections. Understanding the correlation between neuronal connectivity, cortical thickness, surface morphology, and ultimately behavior, could have important implications on the diagnostics, classification, and treatment of neurological disorders. PMID- 26523124 TI - Early experiences in developing and managing the neuroscience gateway. AB - The last few decades have seen the emergence of computational neuroscience as a mature field where researchers are interested in modeling complex and large neuronal systems and require access to high performance computing machines and associated cyber infrastructure to manage computational workflow and data. The neuronal simulation tools, used in this research field, are also implemented for parallel computers and suitable for high performance computing machines. But using these tools on complex high performance computing machines remains a challenge because of issues with acquiring computer time on these machines located at national supercomputer centers, dealing with complex user interface of these machines, dealing with data management and retrieval. The Neuroscience Gateway is being developed to alleviate and/or hide these barriers to entry for computational neuroscientists. It hides or eliminates, from the point of view of the users, all the administrative and technical barriers and makes parallel neuronal simulation tools easily available and accessible on complex high performance computing machines. It handles the running of jobs and data management and retrieval. This paper shares the early experiences in bringing up this gateway and describes the software architecture it is based on, how it is implemented, and how users can use this for computational neuroscience research using high performance computing at the back end. We also look at parallel scaling of some publicly available neuronal models and analyze the recent usage data of the neuroscience gateway. PMID- 26523126 TI - Comprehensive Reports on the Latest Advances in Gastroenterology and Hepatology From:: The 50th Annual Meeting of the European Association for the Study of the LiverApril 22-26, 2015Vienna, AustriaDigestive Disease Week 2015May 16-19, 2015Washington, DC. PMID- 26523125 TI - Computational Calorimetry: High-Precision Calculation of Host-Guest Binding Thermodynamics. AB - We present a strategy for carrying out high-precision calculations of binding free energy and binding enthalpy values from molecular dynamics simulations with explicit solvent. The approach is used to calculate the thermodynamic profiles for binding of nine small molecule guests to either the cucurbit[7]uril (CB7) or beta-cyclodextrin (betaCD) host. For these systems, calculations using commodity hardware can yield binding free energy and binding enthalpy values with a precision of ~0.5 kcal/mol (95% CI) in a matter of days. Crucially, the self consistency of the approach is established by calculating the binding enthalpy directly, via end point potential energy calculations, and indirectly, via the temperature dependence of the binding free energy, i.e., by the van't Hoff equation. Excellent agreement between the direct and van't Hoff methods is demonstrated for both host-guest systems and an ion-pair model system for which particularly well-converged results are attainable. Additionally, we find that hydrogen mass repartitioning allows marked acceleration of the calculations with no discernible cost in precision or accuracy. Finally, we provide guidance for accurately assessing numerical uncertainty of the results in settings where complex correlations in the time series can pose challenges to statistical analysis. The routine nature and high precision of these binding calculations opens the possibility of including measured binding thermodynamics as target data in force field optimization so that simulations may be used to reliably interpret experimental data and guide molecular design. PMID- 26523127 TI - Comprehensive Reports on the Latest Advances in Gastroenterology & Hepatology From:: American College of Gastroenterology 2014 Annual Scientific MeetingOctober 17-22, 2014Philadelphia, Pennsylvania65th Annual Meeting of the American Association for the Study of Liver DiseasesNovember 7-11, 2014Boston, MassachusettsAdvances in Inflammatory Bowel Diseases ConferenceDecember 4-6, 2014Orlando, Florida. PMID- 26523128 TI - Evaluation of Structure and Assembly of Xyloglucan from Tamarind Seed (Tamarindus indica L.) with Atomic Force Microscopy. AB - The role of xyloglucan (XG) in the cell wall of plants and its technological usability depends on several factors, pertaining to molecular structure. Therefore, the goal of this study was to evaluate the nano-structure and self assembly of XG by atomic force microscopy (AFM). As the model, a non-modified xyloglucan from a tamarind seed (Tamarindus indica L.) was used. Samples were minimally processed, i.e., treated with low-power ultrasound and studied on the surface of mica in ambient butanol. AFM topographic images revealed rod-like nanomolecules of xyloglucan with a mean height of 2.3 +/- 0.5 nm and mean length of 640 +/- 360 nm. The AFM study also showed that XG chains possessed a helical structure with a period of 115.8 +/- 29.2 nm. This study showed possible-bending of molecules with a mean angle of 127.8 +/- 25.6 degrees . The xyloglucan molecules were able to aggregate as cross-like and a parallel like assemblies, and possibly as rope-like structures. The self-assembled bundles of xyloglucan chains were often complexed at an angle of 114.2 +/- 36.3 degrees . PMID- 26523129 TI - Is Total Pancreatectomy with Islet Autotransplantation A Reasonable Choice for Pediatric Pancreatitis? AB - Chronic pancreatitis is an emerging and poorly understood disease in childhood. Total pancreatectomy with islet cell autotransplantation is being proposed as a treatment for chronic pancreatitis and recent studies report a more favorable outcome in children compared to adults. Herein, we review the therapeutic alternatives for pediatric chronic pancreatitis, focusing primarily on TP/IAT. PMID- 26523130 TI - Cell-Free miR-27a, a Potential Diagnostic and Prognostic Biomarker for Gastric Cancer. AB - MicroRNAs (miRNAs) have been demonstrated to play an important role in carcinogenesis. Previous studies revealed that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity. In this study, we measured the plasma expression levels of three miRNAs (miR-21, miR 27a, and miR-155) to investigate the usefulness of miRNAs for gastric cancer detection. We initially examined plasma miRNA expression levels in a screening cohort consisting of 15 patients with gastric cancer and 15 healthy controls from Korean population, using TaqMan quantitative real-time polymerase chain reaction. We observed that the expression level of miR-27a was significantly higher in patients with gastric cancer than in healthy controls, whereas the miR-21 and miR 155a expression levels were not significantly higher in the patients with gastric cancer. Therefore, we further validated the miR-27a expression level in 73 paired gastric cancer tissues and in a validation plasma cohort from 35 patients with gastric cancer and 35 healthy controls. In both the gastric cancer tissues and the validation plasma cohort, the miR-27a expression levels were significantly higher in patients with gastric cancer. Receiver-operator characteristic (ROC) analysis of the validation cohort, revealed an area under the ROC curve value of 0.70 with 75% sensitivity and 56% specificity in discriminating gastric cancer. Thus, the miR-27a expression level in plasma could be a useful biomarker for the diagnosis and/or prognosis of gastric cancer. PMID- 26523131 TI - The Construction of Regulatory Network for Insulin-Mediated Genes by Integrating Methods Based on Transcription Factor Binding Motifs and Gene Expression Variations. AB - Type 2 diabetes mellitus is a complex metabolic disorder associated with multiple genetic, developmental and environmental factors. The recent advances in gene expression microarray technologies as well as network-based analysis methodologies provide groundbreaking opportunities to study type 2 diabetes mellitus. In the present study, we used previously published gene expression microarray datasets of human skeletal muscle samples collected from 20 insulin sensitive individuals before and after insulin treatment in order to construct insulin-mediated regulatory network. Based on a motif discovery method implemented by iRegulon, a Cytoscape app, we identified 25 candidate regulons, motifs of which were enriched among the promoters of 478 up-regulated genes and 82 down-regulated genes. We then looked for a hierarchical network of the candidate regulators, in such a way that the conditional combination of their expression changes may explain those of their target genes. Using Genomica, a software tool for regulatory network construction, we obtained a hierarchical network of eight regulons that were used to map insulin downstream signaling network. Taken together, the results illustrate the benefits of combining completely different methods such as motif-based regulatory factor discovery and expression level-based construction of regulatory network of their target genes in understanding insulin induced biological processes and signaling pathways. PMID- 26523132 TI - Efficiency to Discovery Transgenic Loci in GM Rice Using Next Generation Sequencing Whole Genome Re-sequencing. AB - Molecular characterization technology in genetically modified organisms, in addition to how transgenic biotechnologies are developed now require full transparency to assess the risk to living modified and non-modified organisms. Next generation sequencing (NGS) methodology is suggested as an effective means in genome characterization and detection of transgenic insertion locations. In the present study, we applied NGS to insert transgenic loci, specifically the epidermal growth factor (EGF) in genetically modified rice cells. A total of 29.3 Gb (~72* coverage) was sequenced with a 2 * 150 bp paired end method by Illumina HiSeq2500, which was consecutively mapped to the rice genome and T-vector sequence. The compatible pairs of reads were successfully mapped to 10 loci on the rice chromosome and vector sequences were validated to the insertion location by polymerase chain reaction (PCR) amplification. The EGF transgenic site was confirmed only on chromosome 4 by PCR. Results of this study demonstrated the success of NGS data to characterize the rice genome. Bioinformatics analyses must be developed in association with NGS data to identify highly accurate transgenic sites. PMID- 26523133 TI - A Database of Gene Expression Profiles of Korean Cancer Genome. AB - Because there are clear molecular differences entailing different treatment effectiveness between Korean and non-Korean cancer patients, identifying distinct molecular characteristics of Korean cancers is profoundly important. Here, we report a web-based data repository, namely Korean Cancer Genome Database (KCGD), for searching gene signatures associated with Korean cancer patients. Currently, a total of 1,403 cancer genomics data were collected, processed and stored in our repository, an ever-growing database. We incorporated most widely used statistical survival analysis methods including the Cox proportional hazard model, log-rank test and Kaplan-Meier plot to provide instant significance estimation for searched molecules. As an initial repository with the aim of Korean-specific marker detection, KCGD would be a promising web application for users without bioinformatics expertise to identify significant factors associated with cancer in Korean. PMID- 26523135 TI - On optimal Bayesian classification and risk estimation under multiple classes. AB - A recently proposed optimal Bayesian classification paradigm addresses optimal error rate analysis for small-sample discrimination, including optimal classifiers, optimal error estimators, and error estimation analysis tools with respect to the probability of misclassification under binary classes. Here, we address multi-class problems and optimal expected risk with respect to a given risk function, which are common settings in bioinformatics. We present Bayesian risk estimators (BRE) under arbitrary classifiers, the mean-square error (MSE) of arbitrary risk estimators under arbitrary classifiers, and optimal Bayesian risk classifiers (OBRC). We provide analytic expressions for these tools under several discrete and Gaussian models and present a new methodology to approximate the BRE and MSE when analytic expressions are not available. Of particular note, we present analytic forms for the MSE under Gaussian models with homoscedastic covariances, which are new even in binary classification. PMID- 26523134 TI - A Highly Elastic and Rapidly Crosslinkable Elastin-Like Polypeptide-Based Hydrogel for Biomedical Applications. AB - Elastin-like polypeptides (ELPs) are promising for biomedical applications due to their unique thermoresponsive and elastic properties. ELP-based hydrogels have been produced through chemical and enzymatic crosslinking or photocrosslinking of modified ELPs. Herein, a photocrosslinked ELP gel using only canonical amino acids is presented. The inclusion of thiols from a pair of cysteine residues in the ELP sequence allows disulfide bond formation upon exposure to UV light, leading to the formation of a highly elastic hydrogel. The physical properties of the resulting hydrogel such as mechanical properties and swelling behavior can be easily tuned by controlling ELP concentrations. The biocompatibility of the engineered ELP hydrogels is shown in vitro as well as corroborated in vivo with subcutaneous implantation of hydrogels in rats. ELP constructs demonstrate long term structural stability in vivo, and early and progressive host integration with no immune response, suggesting their potential for supporting wound repair. Ultimately, functionalized ELPs demonstrate the ability to function as an in vivo hemostatic material over bleeding wounds. PMID- 26523136 TI - Comparison of Endodontic Retreatment in Teeth Obturated With Resilon or Gutta Percha: A Review of Literature. AB - INTRODUCTION: Retreatment of endodontically treated teeth is a challenge that requires complete removal of the previous filling material. Several techniques are indicated for this procedure. The present review tries to identify the most efficient method for extirpation of Resilon (RS) root fillings and to compare the speed and efficacy of RS and gutta-percha (GP) root filling removal. METHODS AND MATERIALS: Three trained evaluators conducted a search through three major databases (PubMed, Cochrane Library and Lilacs) over the articles published in the period from 2001 to 2014. The search keywords were Epiphany Sealer, Resilon, Retreatment and Removal Procedure. RESULTS: Twelve articles were included in the final sample (three in vitro studies and nine randomized trials). CONCLUSION: The ProTaper (manual or rotatory) system in combination with chemical solvents is the most efficient method for removing Resilon root filling. Retreatment of Resilon is more rapid and associated with less remnants of debris. PMID- 26523137 TI - Scanning Electron Microscopic Evaluation of Residual Smear Layer Following Preparation of Curved Root Canals Using Hand Instrumentation or Two Engine-Driven Systems. AB - INTRODUCTION: In this experimental study, the amount of smear layer (SL) remnants in curved root canals after chemomechanical instrumentation with two engine driven systems or hand instrumentation was evaluated. METHODS AND MATERIALS: Forty-eight mesiobuccal roots of mandibular first molars with curvatures ranging between 25 and 35 degrees (according to Schneider's method) were divided into three groups (n=16) which were prepared by either the ProTaper Universal file series, Reciproc single file system or hand instrumentation. The canals were intermittently irrigated with 5.25% NaOCl and 17% (ethylenediaminetetraacetic acid) EDTA, followed by distilled water as the final rinse. The roots were split longitudinally and the apical third of the specimens were evaluated under 2500* magnification with a scanning electron microscope (SEM). The mean scores of the SL were calculated and analyzed using the non-parametric Kruskal-Wallis and Mann Whitney U tests. RESULTS: The mean scores of the SL were 2.00+/-0.73, 1.94+/-0.68 and 1.44+/-0.63 um for the ProTaper Universal, Reciproc and hand instrumentation, respectively. Mean score of SL was significantly less in the hand instrumentation group than the ProTaper (P=0.027) and Reciproc (P=0.035) groups. The difference between the two engine-driven systems, however, was not significant (P=0.803). CONCLUSION: The amount of smear layer in the apical third of curved root canals prepared with both engine-driven systems was similar and greater than the hand instrumentation technique. Complete cleanliness was not attained. PMID- 26523138 TI - Comparison of Cleaning Efficacy and Instrumentation Time in Primary Molars: Mtwo Rotary Instruments vs. Hand K-Files. AB - INTRODUCTION: Pulpectomy is the preferred treatment for restorable primary teeth with symptomatic irreversible pulpitis or periradicular lesion. Considering the rather new application of rotary files for pulpectomy of primary teeth, the aim of this study was to compare the cleaning efficacy and instrumentation time of hand K-files and Mtwo rotary system for preparation of human primary molars. METHODS AND MATERIALS: This experimental study was conducted on 100 extracted primary maxillary and mandibular intact molars with no resorption. Access cavities were prepared and India ink was injected into the root canal on a vibrator using an insulin syringe. Canals were then divided into 5 groups (n=20): in group I, canals were instrumented using K-files up to #25 for mesial and buccal canals and #30 for palatal and distal canals. In group II, canals were prepared using Mtwo rotary files (15/0.05, 20/0.06 and 25/0.06 for mesial and buccal canals and 15/0.05, 20/0.06, 25/0.06 and finally 30/0.05 for distal and palatal canals). In group III, root canals were only irrigated with saline. Groups IV and V were the positive and negative control groups, respectively. The time required for cleaning and preparation of the canals for each of the specimens in groups I, II and III was recorded. RESULTS: The mean score of cleanliness of Mtwo was not significantly different from K-file group (P>0.05). However the mean instrumentation time in Mtwo group was significantly shorter (P<0.001). CONCLUSION: Although there were no differences regarding the cleaning efficacy of either system, Mtwo rotary files were far more time efficient. PMID- 26523139 TI - The Effect of Orthodontic Forces on Tooth Response to Electric Pulp Test. AB - INTRODUCTION: The current study investigated the pulp response to electric pulp testing (EPT), before, upon initiation and one month after the start of orthodontic tooth movement. METHODS AND MATERIALS: A total of 402 anterior teeth from 39 patients (mean age of 16.8+/-2.7 years) were examined in this non controlled prospective study. The aligning forces were administered using initial NiTi archwires ligated on fixed appliances by using the MBT straight wire technique. The electrical stimulation was provided by the EPT. The EPT readings were recorded at three time points: before bonding (EPT0), immediately upon initiation (EPT1) and 1 month post-treatment (EPT2). The data were statistically analyzed by the ANOVA and Bonferroni tests (P<0.05). RESULTS: Prior to bonding of the orthodontic brackets, the mean EPT value for all the experimental teeth was 3.42 EPT units. Upon initiation, the mean value of EPT1 for each tooth increased to 7.62 units. One month later, the mean EPT2 values dropped to 6.27 units. At this time point, 64 teeth (16%) of the experimental teeth failed to respond. The differences among EPT values at different time points were significant. There was no association between the EPT values and the location or the type of teeth. CONCLUSION: The physiological changes in the pulp affect the nerve fibers in the early stages of the orthodontic force application. As a result, thresholds to electrical stimulation would increase and the EPT may not initiate a response. Therefore results obtained by electrical pulp testing should be interpreted accordingly. PMID- 26523140 TI - The Effect of Different Mixing Methods on Working Time, Setting Time, Dimensional Changes and Film Thickness of Mineral Trioxide Aggregate and Calcium-Enriched Mixture. AB - INTRODUCTION: The aim of the present study was to evaluate the effect of different mixing techniques (conventional, amalgamator and ultrasonic mixing) on the physical properties the working time (WT), setting time (ST), dimensional changes (DC) and film thickness (FT)] of calcium-enriched mixture (CEM) cement and mineral trioxide aggregate (MTA). METHODS AND MATERIALS: The mentioned physical properties were determined using the ISO 6786:2001 specification. Six samples of each material were prepared for three mixing techniques (totally 36 samples). Data were analyzed using descriptive statistics, two-way ANOVA and Post Hoc Tukey's tests. The level of significance was defined at 0.05. RESULTS: Irrespective of mixing technique, there was no significant difference between the WT and FT of the tested materials. Except for the DC of MTA and the FT of the all materials, other properties were significantly affected with mixing techniques (P<0.05). The ultrasonic technique decreased the ST of MTA and CEM cement and increased the WT of CEM cement (P<0.05). CONCLUSION: The mixing technique of the materials had no significant effect on the dimensional changes of MTA and the film thickness of both materials. PMID- 26523141 TI - Effects of Reciproc, Mtwo and ProTaper Instruments on Formation of Root Fracture. AB - INTRODUCTION: The aim of this study was to compare the formation of dentinal crack and craze lines in the root dentin during root canal preparation with three different NiTi endodontic systems, naming Reciproc (RCP), ProTaper Universal (PTU) and Mtwo. METHODS AND MATERIALS: One hundred extracted mandibular premolars with single canals were selected and decoronated. The teeth were randomly divided into four groups of 25 each (n=25). In groups 1, 2 and 3 the teeth were prepared using Mtwo, PTU and RCP, respectively. While in group 4 (control group) the samples were left unprepared. After preparation, all specimens were sectioned perpendicular to the long axis of root at 3, 5 and 9-mm distances from the apex. The sections were then individually observed under 12* magnification using stereomicroscope. The data was analyzed using the chi-square and Fisher's exact tests. The level of significance was set at 0.05. RESULTS: No cracks were observed in the control group. All engine-driven systems caused dentinal cracks. Mtwo and PTU caused cracks significantly more than RCP (P<0.05). There was no significant difference between RCP and control group (P>0.05). CONCLUSION: All three engine-driven systems created dentinal defects. Reciproc caused less cracks than Mtwo and ProTaper Universal. PMID- 26523142 TI - A Survey over the Dentists' and Endodntists' Approaches towards the Management of Endodontic Emergencies in Mashhad, Iran. AB - INTRODUCTION: Pain or swelling caused by various stages of inflammation/infection of the pulp/periradicular area is among endodontic emergencies. Determining the most effective method of emergency treatment is a challenging issue in endodontics. The goal of this study was to determine and compare the level of knowledge in general dentists and endodontists about endodontic emergency treatment plan in Mashhad, Iran in 2012-2013. METHODS AND MATERIALS: In this cross-sectional descriptive study, 152 questionnaires were distributed among 120 general dentists and 32 endodontists of Mashhad. The questionnaire contained two separate parts. The first part included demographic information and in the second part different treatment protocols were suggested for 12 various conditions of pulp/periapical emergencies, and the participants were asked to choose the correct option(s). To determine the relationship between qualitative variables, the chi-square analysis was used. The level of significance was set at 0.05. RESULTS: There were significant differences between treatment plans presented by general dentists and endodontists about endodontic emergencies, especially in cases of necrotic pulp and subsequent swelling. CONCLUSION: Level of knowledge of dentists about the indications of incision and drainage, intra-canal medicament, root filing beyond the apical foramen and antibiotic prescription was not enough. These findings highlight the importance of refreshing courses for general dentists to improve their competency in the management of endodontic emergencies. PMID- 26523143 TI - Effects of Clinical Training and Case Difficulty on the Radiographic Quality of Root Canal Fillings Performed by Dental Students in Saudi Arabia. AB - INTRODUCTION: The aim of this study was to evaluate the effects of training duration and case difficulty on the radiographic quality of root canal fillings performed by dental students in Saudi Arabia. METHODS AND MATERIALS: A longitudinal cohort study was conducted at King Saud University. Root canal treatments performed by 55 dental students from 2012-2014 were included in the study. Each student treated at least five teeth during the first year of clinical endodontic training and another five teeth during the second year. Case difficulty was assessed based on tooth position in the dental arch and preoperative conditions. The radiographic quality of the root canal filling was evaluated by two endodontists blinded to treatment completion date. The evaluation criteria were adequate obturation, presence of mishaps and preparation taper. The data were statistically analysed using univariate and multivariate logistic regression analyses; and the level of significance was set at 0.05. RESULTS: Inadequate obturation and mishaps were significantly less prevalent in teeth treated after 2 years of clinical training. The odds ratios for inadequate obturation and mishaps increased significantly as tooth position moved posteriorly. Inadequate obturation and more mishaps were significantly more prevalent in teeth with preoperative conditions. Preparation taper was not significantly affected by training duration or case difficulty. CONCLUSION: The quality of root canal fillings performed by Saudi students was adversely affected by case difficulty. The radiographic quality of root canal fillings improved significantly after 2 years of clinical training. Preparation taper outcome is likely dependent on the preparation technique and instrument taper. PMID- 26523144 TI - Craniofacial Pain as the Sole Sign of Prodromal Angina and Acute Coronary Syndrome: A Review and Report of a Rare Case. AB - Orofacial pain can arise from different regions and etiologies. Some of the most debilitating pain conditions arise from the structures innervated by the trigeminal system (head, face, masticatory musculature, temporomandibular joint and associated structures). The problem with referred pain is the misdiagnosis and unnecessary therapy directed to the pain location instead of its origin. When craniofacial pain is the sole sign of myocardial ischemia, failure to recognize its cardiac source can endanger the patient. In particular, apart from unnecessary dental treatments, patients with acute myocardial infarction who do not experience chest pain run a very high risk of misdiagnosis and death. As endodontists, each of us may face many patients complaining of pain sensation in the teeth with the main source being other craniofacial/visceral organs. This review plots a diagnostically challenging case paving the way for further literature presentation in this regard. The aim of this compendious review was to gain knowledge about the prevalence, clinical characteristics and possible mechanisms of craniofacial pain of cardiac origin, in order to improve the clinician's ability to make a correct diagnosis. PMID- 26523145 TI - Vital Pulp Therapy of a Mature Molar with Concurrent Hyperplastic Pulpitis, Internal Root Resorption and Periradicular Periodontitis: A Case Report. AB - Vital pulp therapy (VPT) of permanent mature teeth is continuously ascertaining to be a more reliable endodontic treatment. The purpose of this case report was to describe successful VPT of a mature mandibular left first molar with concurrent hyperplastic pulpitis, internal root resorption and periradicular periodontitis in a 35-year-old male patient. After complete caries removal and access cavity preparation, the dental pulp was removed from the coronal third of the roots. To protect the remaining pulp, calcium-enriched mixture (CEM) cement was placed and adapted into the cavities; the tooth was then restored with amalgam. Six months after VPT, radiographic examination showed evidence of periradicular healing. Clinically, the tooth was functional without signs and symptoms of infection/inflammation. The successful outcome of this case suggests that diseased dental pulp (i.e. irreversible pulpitis) has the potential to heal after pulp protection with CEM biocement. PMID- 26523146 TI - Treatment of a Maxillary First Molar with Two Palatal Roots. AB - Thorough knowledge of the morphology and internal anatomy of the root canal system is essential, because it determines the successful outcome of endodontic treatment. The main goal of endodontic treatment is to prevent apical periodontitis and/or to promote the healing of periapical lesion. Presence of two canals or roots on the palatal side of the first maxillary molar has rarely been reported. This case report presents a maxillary first molar with two separate palatal roots. PMID- 26523148 TI - Medicinal Plants Used in the Management of Diabetes Mellitus 2015. PMID- 26523147 TI - STAT3 Signaling in Polycystic Kidney Disease. AB - Mutations in the gene coding for the integral membrane protein polycystin-1 (PC1) are the cause of most cases of autosomal-dominant polycystic kidney disease (ADPKD), a very common disease that leads to kidney failure and currently lacks approved treatment. Recent work has revealed that PC1 can regulate the transcription factor STAT3, and that STAT3 is aberrantly activated in the kidneys of ADPKD patients and PKD mouse models. Recent approaches to directly inhibit STAT3 in PKD mouse models have been promising. Numerous signaling pathways are known to activate STAT3 and many have long been implicated in the pathogenesis of PKD - such as EGF/EGFR, HGF/c-Met, Src. However, a role of STAT3 in the pathogenesis of PKD had never been considered until now. Here, we review the current findings that suggest that STAT3 is a promising target for the treatment of PKD. PMID- 26523149 TI - Effect of Herbal Prescriptions in Accordance with Pattern Identification in Acute Cerebral Infarction Patients: Based on Fire-Heat Pattern. AB - Objectives. This study was conducted to verify the necessity of corresponding prescription to the diagnosed pattern in acute cerebral infarction patients. Methods. We studied cerebral infarction patients hospitalized within 30 days after the ictus. Forty-four clinical indicators, Motricity Index (MI) score, Scandinavian Stroke Scale (SSS) score, and herbal prescriptions were checked twice, two weeks apart. The probability of each pattern was calculated based on the clinical indicators. Changes in MI score, SSS score, and the probability of fire-heat pattern were compared between the pattern-prescription correspondence group and the noncorrespondence group. Results. Increments of MI score and SSS score in the correspondence group were significantly greater than those of the noncorrespondence group (p = 0.003, p = 0.001) while the baseline score of the two groups showed no significant difference. Probability of fire-heat pattern decreased significantly in the correspondence group (p = 0.013) while the noncorrespondence group showed no significant difference after the treatment. Conclusion. Acute cerebral infarction patients who are diagnosed as fire-heat pattern showed better improvement in dysfunctions caused by the disease when they took the pattern corresponding prescriptions. This study provides evidence for the necessity and usefulness of pattern identification in Traditional Korean Medicine. PMID- 26523150 TI - NLR family pyrin domain containing 3 (NLRP3) inflammasome gene polymorphism rs7512998 (C>T) predicts aging-related increase of blood pressure, the TAMRISK study. AB - BACKGROUND: The activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome by cellular stress leads to activation of the inflammasome, and NLRP3 gene polymorphisms have been associated with autoinflammatory diseases. Inflammasomes have also been implicated in the initiation or progression of metabolic disorders such as atherosclerosis, type 2 diabetes and obesity. The association of NLRP3 genetic variant rs7512998 with blood pressure and hypertension was studied in a 50-year-old Finnish cohort with a subpopulation who had available data on blood pressure measurements also at the age of 45 years. RESULTS: NLRP3 gene polymorphism rs7512998 C-allele was associated with higher systolic (p = 0.006) and diastolic (p = 0.011) blood pressure compared to the TT genotype carriers in 50-year-old subjects. In addition, by analysis of variance for repeated measures between ages of 45- and 50 years there was a significant time by genotype interaction; blood pressure increased more in subjects with the C-allele both in systolic (p = 0.035) and diastolic (p = 0.012) values. However, no association with diagnosed hypertension was found. CONCLUSION: We report for the first time that NLRP3 gene polymorphism rs7512998 was associated with systolic and diastolic blood pressure in 50-year-old subjects. In addition, an effect of this variation upon blood pressure was seen in these same subjects in a 5-year follow-up from a 45-year-old cohort to 50 years of age. PMID- 26523151 TI - 3p22.1p21.31 microdeletion identifies CCK as Asperger syndrome candidate gene and shows the way for therapeutic strategies in chromosome imbalances. AB - BACKGROUND: In contrast to other autism spectrum disorders, chromosome abnormalities are rare in Asperger syndrome (AS) or high-functioning autism. Consequently, AS was occasionally subjected to classical positional cloning. Here, we report on a case of AS associated with a deletion of the short arm of chromosome 3. Further in silico analysis has identified a candidate gene for AS and has suggested a therapeutic strategy for manifestations of the chromosome rearrangement. RESULTS: Using array comparative genomic hybridization, an interstitial deletion of 3p22.1p21.31 (~2.5 Mb in size) in a child with Asperger's syndrome, seborrheic dermatitis and chronic pancreatitis was detected. Original bioinformatic approach to the prioritization of candidate genes/processes identified CCK (cholecystokinin) as a candidate gene for AS. In addition to processes associated with deleted genes, bioinformatic analysis of CCK gene interactome indicated that zinc deficiency might be a pathogenic mechanism in this case. This suggestion was supported by plasma zinc concentration measurements. The increase of zinc intake produced a rise in zinc plasma concentration and the improvement in the patient's condition. CONCLUSIONS: Our study supported previous linkage findings and had suggested a new candidate gene in AS. Moreover, bioinformatic analysis identified the pathogenic mechanism, which was used to propose a therapeutic strategy for manifestations of the deletion. The relative success of this strategy allows speculating that therapeutic or dietary normalization of metabolic processes altered by a chromosome imbalance or genomic copy number variations may be a way for treating at least a small proportion of cases of these presumably incurable genetic conditions. PMID- 26523152 TI - Characterization of intragenic tandem duplication in the PAFAH1B1 gene leading to isolated lissencephaly sequence. AB - BACKGROUND: Genetic aberrations in PAFAH1B1 result in isolated lissencephaly sequence (ILS), a neuronal migration disorder associated with severe mental retardation and intractable epilepsy. Approximately 60 % of patients with ILS show a 17p13.3 deletion or an intragenic variation of PAFAH1B1 that can be identified by fluorescence in situ hybridization (FISH) analysis or gene sequencing. Using multiplex ligation-dependent probe amplification (MLPA), 40-80 % of the remaining patients show small genomic deletions or duplications of PAFAH1B1. The intragenic duplications within PAFAH1B1 are predicted to abolish the PAFAH1B1 function, although a detailed characterization of the duplication regions have not been reported. RESULTS: Here we describe a female patient with ILS occurring predominantly in the posterior brain regions. MLPA was used to identify a small duplication within PAFAH1B1. This result was confirmed by array based comparative genomic hybridization analysis, revealing a duplication of the 29-kb region encompassing putative regulatory elements and exon 2 of PAFAH1B1. The region was characterized as an intragenic tandem duplication by sequencing, revealing a 28-bp microhomology sequence at the breakpoint junctions. Parental genetic testing confirmed that the tandem duplication occurred de novo. Reverse transcription-PCR on RNA extracted from peripheral blood leukocytes revealed that the expression level of PAFAH1B1 decreased to that in a patient with Miller Dieker syndrome, a contiguous gene-deletion disorder characterized by classical lissencephaly and a facial dysmorphism. CONCLUSIONS: This study expanded the spectrum of PAFAH1B1 variants and identified a unique genomic architecture including microhomology sequences in PAFAH1B1 underlying an intragenic tandem duplication leading to ILS. PMID- 26523154 TI - Cost-effectiveness of a national population-based screening program for type 2 diabetes: the Brazil experience. AB - BACKGROUND: The cost-effectiveness of screening for type 2 diabetes mellitus (DM2) in developing countries remains unknown. The Brazilian government conducted a nationwide population screening program for type 2 diabetes mellitus (BNDSP) in which 22 million capillary glucose tests were performed in individuals aged 40 years and older. The objective of this study was to evaluate the life-time cost effectiveness of a national population-based screening program for DM2 conducted in Brazil. METHODS: We used a Markov-based cost-effectiveness model to simulate the long-term costs and benefits of screening for DM2, compared to no screening program. The analysis was conducted from a public health care system perspective. Sensitivity analyses were conducted to examine the robustness of results to key model parameters. RESULTS: Brazilian National diabetes screening program will yield a large health benefit and higher costs. Compared with no screening, screen detection of undiagnosed diabetes resulted in US$ 31,147 per QALY gained. Results from sensitivity analyses found that screening targeted at hypertensive individuals would cost US$ 22,695/QALY. When benefits from early glycemic control on cardiovascular outcomes were considered, the cost per QALY gained would reduce significantly. CONCLUSIONS: In the base case analysis, not considering the intangible benefit of transferring diabetes management to primary care nor the benefit of using statin to treat eligible diabetic patients, CE ratios were not cost-effective considering thresholds proposed by the World Health Organization. However, significant uncertainty was demonstrated in sensitivity analysis. Our results indicate that policy-makers should carefully balance the benefit and cost of the program while considering using a population-based approach to screen for diabetes. PMID- 26523153 TI - Raynaud's phenomenon and digital ischemia: a practical approach to risk stratification, diagnosis and management. AB - Digital ischemia is a painful and often disfiguring event. Such an ischemic event often leads to tissue loss and can significantly affect the patient's quality of life. Digital ischemia can be secondary to a vasculopathy, vasculitis, embolic disease, trauma, or extrinsic vascular compression. It is an especially serious complication in patients with scleroderma. Risk stratification of patients with scleroderma at risk for digital ischemia is now possible with clinical assessment and autoantibody profiles. Because there are a variety of conditions that lead to digital ischemia, it is important to understand the pathophysiology underlying each ischemic presentation in order to target therapy appropriately. Significant progress has been made in the last two decades in defining the pathophysiological processes leading to digital ischemia in rheumatic diseases. In this article we review the risk stratification, diagnosis, and management of patients with digital ischemia and provide a practical approach to therapy, particularly in scleroderma. PMID- 26523155 TI - Development of an automated on-chip bead-based ELISA platform. AB - We present a lab-on-a-chip and associated instrument for heterogeneous enzyme linked immunosorbent assay (ELISA)-based detection of proteins from liquid samples. The system performs all necessary ELISA steps (starting from antigen incubation) in a quarter of the time required for corresponding plate-based protocols. We have previously described the instrument, which automates fluidic control via remote valve switching and detects fluorescence from reacted substrate, for use in a molecular diagnostics application. The ELISA chip reported here utilizes a high surface area bead bed to enhance capture efficiency and increase the dynamic range of the assay as compared to a standard plate-based ELISA. Its functionality is demonstrated using human IL-10 as a model antigen, but theoretically any sandwich ELISA could be ported onto this "open source platform." We show that our automated on-chip assays have greater sensitivities than the corresponding standard manual plate-based ELISAs, and that single samples can be assayed in a fraction of the time. PMID- 26523156 TI - Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior. AB - BACKGROUND: Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression. METHODS: Mating of Emx1 (cre) and Met (fx/fx) mice eliminates receptor signaling from all cells arising from the dorsal pallium. Met (fx/fx) and Nestin (cre) crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met. RESULTS: Met (fx/fx) /Emx1 (cre) null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Met (fx/fx; fx/+) /Nestin (cre) null and heterozygous mice exhibited deficits in contextual fear conditioning, and Met (fx/+) /Nestin (cre) heterozygous mice spent less time in the closed arms of the elevated plus maze. CONCLUSIONS: These data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity. PMID- 26523157 TI - Fluorescence Spectroscopy with Metal-Dielectric Waveguides. AB - We describe a hybrid metal-dielectric waveguide structures (MDWs) with numerous potential applications in the biosciences. These structures consist of a thin metal film coated with a dielectric layer. Depending on the thickness of the dielectric layer, the modes can be localized near the metal, within the dielectric, or at the top surface of the dielectric. The optical modes in a metal dielectric waveguide can have either S (TE) or P (TM) polarization. The dielectric spacer avoids the quenching, which usually occurs for fluorophores within about 5 nm from the metal. Additionally, the resonances display a sharp angular dependence and can exhibit several hundred-fold increases in intensity (E2) at the silica-air interface relative to the incident intensity. Fluorophores placed on top of the silica layer couple efficiently with the metal, resulting in a sharp angular distribution of emission through the metal and down from the bottom of the structure. This coupling occurs over large distances to several hundred nm away from the metal and was found to be consistent with simulations of the reflectivity of the metal-dielectric waveguides. Remarkably, for some silica thicknesses, the emission is almost completely coupled through the structure with little free-space emission away from the metal-dielectric waveguide. The efficiency of fluorophore coupling is related to the quality of the resonant modes sustained by the metal-dielectric waveguide, resulting in coupling of most of the emission through the metal into the underlying glass substrates. Metal dielectric waveguides also provide a method to resolve the emission from surface bound fluorophores from the bulk-phase fluorophores. Metal-dielectric waveguides are simple to fabricate for large surface areas, the resonance wavelength can be adjusted by the dielectric thickness, and the silica surface is suitable for coupling to biomolecules. Metal-dielectric waveguides can have numerous applications in diagnostics and high-throughput proteomics or DNA analysis. PMID- 26523158 TI - Selectable Surface and Bulk Fluorescence Imaging with Plasmon-Coupled Waveguides. AB - In this letter, we propose a new method for selective imaging of surface bound probes or simultaneous imaging of surface bound plus fluorescence from dye molecules in bulk water solution. The principle of this method relies on use of two optical modes with different mode distributions, filed decay lengths and polarization states that are sustaining in a plasmon waveguide. The two modes with different decay lengths couple with dye molecules of different regions, at different distances from the PCW-water interface. The emission from two different regions occur as two coupled emission rings with different polarizations and emitting angles in the back focal plane (BFP) images. By using an electric-driven liquid crystal in BFP imaging, we selectively imaged surface or surface plus bulk fluorescence. Accordingly two coupled emissions can be switched ON or OFF independently, that are for either surface or bulk fluorescence imaging. Our work provides a new method for fluorescence imaging or sensing just by using a planar multilayer film, which may be a useful for fluorescence-based techniques in chemistry, materials science, molecular biology, and medicine. PMID- 26523159 TI - Layer-Resolved Evolution of Organic Thin Films Monitored by Photoelectron Emission Microscopy and Optical Reflectance Spectroscopy. AB - Photoelectron emission microscopy (PEEM) and differential (optical) reflectance spectroscopy (DRS) have proven independently to be versatile analytical tools for monitoring the evolution of organic thin films during growth. In this paper, we present the first experiment in which both techniques have been applied simultaneously and synchronously. We illustrate how the combined PEEM and DRS results can be correlated to obtain an extended perspective on the electronic and optical properties of a molecular film dependent on the film thickness and morphology. As an example, we studied the deposition of the organic molecule alpha-sexithiophene on Ag(111) in the thickness range from submonolayers up to several monolayers. PMID- 26523160 TI - Transportation-related barriers to care among African American women living with HIV/AIDS: "What you getting out of the cab for?" AB - Transportation-related problems have been consistently reported as barriers to accessing and remaining in HIV medical care, particularly among African American women living in under-resourced areas. With emphasis on the Southern region of the United States, this commentary presents a brief overview of the HIV/AIDS epidemic among African Americans, barriers to remaining in HIV care, and pilot data from a study conducted among African American women living in Mississippi. A small focus group study was conducted to examine the relative influence of transportation-related barriers on attendance and motivation to attend HIV medical care appointments. Eight African American women (mean age of 43.50, SD = 10.82) who were engaged in medical care participated in one focus group session. Time since diagnosis ranged from 6 to 17 years. Participants reported transportation-related barriers that were generally consistent with previous research, including lack of personal transportation, limited financial resources to pay family and friends for transportation or gasoline, and inconveniences associated with sharing van services with other patients. Participants appeared to have learned how to successfully navigate these barriers in order to remain in care. Interestingly, participants reported significant fear of disclosure related to use of transportation services provided by insurance providers and community organizations. Specifically, many of the women indicated that family, friends, and neighbors questioned them about where they were going and why they used taxis. These types of encounters might influence whether individuals utilize available transportation services. Participants provided several recommendations for improving the transportation system. Additional research is warranted to obtain a more representative sampling of opinions among African American women living in under-resourced areas. PMID- 26523161 TI - Correlates of posttraumatic growth among African Americans living with HIV/AIDS in Mississippi. AB - Individuals diagnosed with HIV face a host of challenges post-diagnosis. At risk for negative psychological outcomes, persons living with HIV/AIDS may also experience posttraumatic growth (i.e., positive cognitive and emotional changes that may occur following HIV diagnosis). African Americans, in particular, experience poorer psychosocial and behavioral outcomes and greater HIV-related health disparities, and also tend to report more posttraumatic growth than European Americans. This exploratory study examined demographic, psychosocial, and behavioral correlates of posttraumatic growth among 45 African American adults living with HIV in Mississippi. Statistical methods included correlational analyses and independent sample t-tests. As measured by the Posttraumatic Growth Inventory, posttraumatic growth was associated with several demographic (i.e., age, education, employment, income), psychosocial (i.e., social support, coping self-efficacy, psychological distress [negative]), and behavioral variables (i.e., church attendance, abstinence from drugs, alcohol, and cigarettes). Findings indicate that African Americans living with HIV in underserved, under resourced areas are capable of perceiving posttraumatic growth post-diagnosis. Moreover, research has shown that perceived positive growth is associated with important sociocultural, psychosocial, and behavioral factors that directly and/or indirectly influence health and treatment outcomes. Implications of findings are discussed. PMID- 26523162 TI - [Pasteurella multocida septic arthritis in total knee prosthesis: report of a case]. PMID- 26523163 TI - Trend in admissions, clinical features and outcome of preeclampsia and eclampsia as seen from the intensive care unit of the Douala General Hospital, Cameroon. AB - INTRODUCTION: Hypertensive disorders in pregnancy (HDP) are a major cause of maternal morbidity and mortality. We aimed at determining the trends in admission, profiles and outcomes of women admitted for preeclampsia and eclampsia to an intensive care unit (ICU) in Cameroon. METHODS: A retrospective study involving 74 women admitted to the ICU of the Douala General Hospital for severe preeclampsia and eclampsia from January 2007 to December 2014. Clinical profiles and outcome data were obtained from patient records. Statistical analysis was performed using SPSS version 20. RESULTS: Of the 74 women admitted to ICU (72.5% for eclampsia), mean age was 30.2years and the majority (90.5%) were aged 20-39 years. While overall trend in admission for HDP increased over the years, mortality remained stable. Mean gestational age (GA) on admission was 34.0 weeks (33.5 for preeclampsia vs 35.4 for eclampsia). Most patients presented with complications of which acute kidney injury was most frequent (66.7%). Visual problems were more common in patients with eclampsia compared to preeclampsia (p = 0.01). HELLP syndrome and acute pulmonary oedema (APO) were predominant in patients with preeclampsia, while cerebrovascular accidents (CVA) occurred more in patients with eclampsia. Overall mortality was 24.3%. Presence of APO was associated with mortality in multivariable analysis (O.R.= 0.03, p = 0,01). CONCLUSION: Trends in admission for HDP were increasing with high but stable mortality rate. Patients presented late most of whom with complications. Interventions improving antenatal care services and multidisciplinary management approach may improve maternal outcome in patients with HDP. PMID- 26523164 TI - Median rhomboid glossitis-developmental or candidal? PMID- 26523165 TI - Patterns of sexually transmitted infections in patients presenting in special treatment clinic in Ibadan south western Nigeria. AB - INTRODUCTION: Sexually transmitted infections (STIs) are infections that are often transferred from one person to another during sexual activity. In developing countries, an increase in the incidence of STIs is attributed to increasing urbanization, modernization, travel, education and exposure to Western media which has led to increased sexual activity, especially among young people. METHODS: This is a retrospective study carried out in the University College Hospital (UCH) Ibadan, Nigeria. The records of a total of 506 patients who attended the clinic between Jan 2010-Dec 2011 were retrieved. The records of the patients' complaints were taken. Detailed demographic data and history of genital symptoms was taken. RESULTS: The records of 506 patients were used 43.7% (221) were males and 56.3% (285) were females. The patient's age ranged from one to eighty, the 1-10 age groups and the 71-80 ages were the least represented age group. Age, sex, level of education, presenting complaints, presence of yeast cells, VDRL positivity were variables that were looked at. Of these only sex and occupation were risk factors for transmission of STI. CONCLUSION: Good clinical care for patients with STIs should extend beyond therapy and include help to avoid future infections. Control activities should focus on the primary prevention of infection through safer sexual practices. Strategies for improving secondary prevention (health care-seeking behavior and case management) should include identification of people at risk and targeting them for intervention. PMID- 26523166 TI - [Angiobehcet: between the hammer and the anvil!]. PMID- 26523167 TI - [Lymph node involvement in multiple myeloma]. PMID- 26523168 TI - [Compressive optic neuropathy following an inflammatory pseudotumor]. PMID- 26523169 TI - [CMV retinitis in a patient with ulcerative colitis taking azathioprine]. PMID- 26523170 TI - Palmar-plantar erythrodysesthesia associated with capecitabine chemotherapy: a case report. AB - We report a case of a 62 year-old patient who developed Palmar-plantar erythrodysesthesia upon receiving four cycles of capacitabine-based chemotherapy. She was on post surgical adjuvant treatment for invasive well differentiated adenocarcinoma of the colon. The clinical and therapeutic aspects of this chemotherapeutic adverse effect are discussed. PMID- 26523171 TI - Multidisciplinary approach to genomics research in Africa: the AfriCRAN model. AB - This article is an outcome of the African Craniofacial Anomalies Research Network (AfriCRAN) Human Hereditary and Health (H3A) grant planning meeting in 2012 in Lagos, Nigeria. It describes the strengths of a multidisciplinary team approach to solving complex genetic traits in the craniofacial region. It also highlights the different components and argues for the composition of similar teams to fast track the discovery of disease genes, diagnostic tools, improved clinical treatment and ultimately prevention of diseases. PMID- 26523172 TI - [Obturator hip dislocation: a rare injury in sport]. PMID- 26523173 TI - Underutilization of cervical cancer prevention services in low and middle income countries: a review of contributing factors. AB - This review aims at identifying barriers to utilization of cervical cancer prevention services in low- and middle-income countries. An electronic search was conducted using the following key words, HPV vaccination, screening, barriers, utilization and low and middle income/developed countries. Using the Garrard (1999) Matrix method approach, a modified matrix was designed and used as a data collection tool and data related to each category listed on the tool were entered into a matrix containing columns reflecting the categories. Constant comparative analysis was used to identify thematic categories. 31 articles published between 2001 and 2014 were yielded from the search. Analysis of the contents of the articles showed that the underutilization of cervical cancer screening services in low and middle-income countries is the result of barriers in accessing and utilizing of the prevention services. Though not mutually exclusive, the barriers were categorized in three categories; individual, community and health system related. Individual barriers include lack of awareness and knowledge about risk factors and prevention of cervical cancer. Age, marital status, diffidence, social economic status, cultural and religious belief of the women also determine the women's' willingness to utilize the services. In some communities there is stigma attached to discussing reproductive health issues and this limits the young women's awareness of cervical cancer and its prevention. Understanding individual, community and health system barriers that hinder women's utilization of cervical cancer prevention services is very crucial in designing effective cervical cancer control programs in low- and middle-income countries. PMID- 26523174 TI - [Rare complication of colonoscopy in a patient on anticoagulant: haemoperitoneum by rupture of a subcapsular hematoma of the spleen, clinical case]. PMID- 26523175 TI - Antenatal diagnosis of isolated omphalocele. AB - The concern of obstetric and surgical teams is when diagnosis of omphalocele, the care of the newborn and the prognosis of the malformation, mainly linked to the existence of associated malformations or chromosomal abnormalities. In our case of isolated omphalocele, the overall prognosis was good. PMID- 26523176 TI - A purple swelling on the tongue. PMID- 26523177 TI - Prostatic fossa calculus. PMID- 26523178 TI - [Papillary carcinoma of the thyroid in Basedow disease]. PMID- 26523179 TI - [Transthoracic myotomy of a case of giant megaesophagus in Mali hospital]. PMID- 26523180 TI - [Anesthesia practice in Lubumbashi: indications, types of surgery and patient types]. PMID- 26523181 TI - [Aneurysm of the thoracic aorta of traumatic origin: a suspected clinical case]. PMID- 26523182 TI - [Breast cancer in Cameroon, histo-epidemiological profile: about 3044 cases]. PMID- 26523183 TI - Sarcoidosis with heart involvement: a rare association of terrible prognosis, a report of two cases. AB - Sarcoidosis is a multisystemic disorder of unknown etiology which is characterized by the formation of non-caseating granulomas in involved tissues. Cardiac involvement is one of the least common manifestations and it can occur at any point of time during the course of sarcoidosis. Here we present the case of 2 patients with known sarcoidosis who develop cardiac abnormalities in the absence of known primary cardiac cause. In our report, we would like to draw attention to the importance of considering heart involvement in any case with systemic sarcoidosis especially in young age. PMID- 26523184 TI - [Abdominal textiloma, about a case]. PMID- 26523185 TI - Determinants of long acting and permanent contraceptive methods utilization among married women of reproductive age groups in western Ethiopia: a cross-sectional study. AB - INTRODUCTION: In Ethiopia information on the level of utilization of the long term and permanent contraceptive methods and associated factorsis lacking. The aim of this study was to understand the determinant factors of long acting and permanent contraceptive methods use among married women of reproductive age in Western Ethiopia. METHODS: A community based cross-sectional study design was employed. Multi stage sampling was used to select 1003 study participants. Data was collected from April 10 to April 25,2014 using a pre- tested structured questionnaire. The data were entered using Epi-info version 3.5.1 and exported to SPSS version 20 for analysis. Multivariate logistic regression analysis was done to identify predictors of long acting and permanent contraceptive methods at 95% CL. RESULTS: Use of long acting and permanent contraceptive methods in this study was found to be 20%. Survey results showed a significant positive association between utilization of long acting and permanent contraceptive methods and women's education (AOR=1.72, 95%CI=1.02-3.05), women's occupation (AOR=2.01, 95% CI=1.11-3.58), number of live children (AOR=2.42, 95% CI: 1.46-4.02), joint fertility related decision (AOR=6.11, 95% CI: 2.29-16.30), having radio/TV (AOR=2.31, 95% CI: 1.40-3.80), and discussion with health care provider about long acting and permanent contraceptive methods (AOR=13.72, 95% CI: 8.37-22.47). CONCLUSION: Efforts need to be aimed at women empowerment, health education, and encouraging open discussion of family planning by couples. PMID- 26523186 TI - [A rare complication of hydatid cyst of the liver: acute pancreatitis]. PMID- 26523187 TI - [A pseudo tumoral form of cholecystitis: xanthogranulomatous cholecystitis]. PMID- 26523188 TI - [Fournier gangrene complicating impalement]. PMID- 26523189 TI - [Historical xanthomata revealing a familial hypercholesterolemia type IIa]. PMID- 26523190 TI - [Lung cancer: treatment pathway in the radiotherapy department at the National Oncology Institute of Rabat]. PMID- 26523192 TI - [Renal disease in a patient with systemic sclerosis]. PMID- 26523191 TI - Current practice of epidemiology in Africa: highlights of the 3rd conference of the African epidemiological association and 1st conference of the Cameroon society of epidemiology, Yaounde, Cameroon, 2014. AB - As the study of disease occurrence and health indicators in human populations, Epidemiology is a dynamic field that evolves with time and geographical context. In order to update African health workers on current epidemiological practices and to draw awareness of early career epidemiologists on concepts and opportunities in the field, the 3(rd) African Epidemiology Association and the 1st Cameroon Society of Epidemiology Conference was organized in June 2-6, 2014 at the Yaounde Mont Febe Hotel, in Cameroon. Under the theme"Practice of Epidemiology in Africa: Stakes, Challenges and Perspectives", the conference attracted close to five hundred guest and participants from all continents. The two main programs were the pre-conference course for capacity building of African Early Career epidemiologists, and the conference itself, providing a forum for scientific exchanges on recent epidemiological concepts, encouraging the use of epidemiological methods in studying large disease burden and neglected tropical diseases; and highlighting existing opportunities. PMID- 26523193 TI - [West syndrome: about an observation]. PMID- 26523194 TI - [Tuberculous osteo-arthritis of the ankle and spondylitis: a rare association]. PMID- 26523195 TI - Ghost cell odontogenic carcinoma of the maxilla: a case report with a literature review. AB - The aim of this report is to present a rare case of a Ghost cell odontogenic carcinoma (GCOC) of a 21-year-old man with review of the literature. The patient was treated surgically, and one of the surgical margins was involved, the patient received adjuvant radiotherapy for local control. Five months later, patient presented with infraorbital lesion which was proven histological to be GCOC. Radiological images, histological sections and clinical photographs are also presented. One year after the second surgery, the patient was tumor free. The only effective treatment modality was surgical removal. PMID- 26523196 TI - [HIV infection in patients with breast cancer in Guinea (West Africa)]. PMID- 26523197 TI - Vertical interventions and system effects; have we learned anything from past experiences? AB - The recent Ebola Virus Outbreak had a devastating effect on West Africa's already feeble national health systems. We suggest that such an impact turned out to be catastrophic because it hit particularly hard human resources for health and the delivery of primary healthcare services, which are cross-sectional to any health system. National and international interventions failed to understand the nature of this interaction, and concentrated on attending urgent specific vertical functions to fight the outbreak--the pillars--such as surveillance, logistics, safe burials etc. Such patchwork and vertical intervention strategy was always going to fail to tackle a system-wide problem, particularly in already fragile systems. We suggest that future interventions will have to learn from the experience of past initiatives for the introduction of HIV-AIDS services, which started as vertical programs and ended up including ever growing health system strengthening components. PMID- 26523198 TI - A rare case of a familial form of nonsyndromic trigonocephaly. PMID- 26523199 TI - A Yeast/Drosophila Screen to Identify New Compounds Overcoming Frataxin Deficiency. AB - Friedreich's ataxia (FA) is a rare neurodegenerative disease which is very debilitating for the patients who progressively lose their autonomy. The lack of efficient therapeutic treatment of the disease strongly argues for urgent need to search for new active compounds that may stop the progression of the disease or prevent the appearance of the symptoms when the genetic defect is diagnosed early enough. In the present study, we used a yeast strain with a deletion of the frataxin homologue gene as a model of FA cells in a primary screen of two chemical libraries, a fraction of the French National Chemical Library (5500 compounds) and the Prestwick collection (880 compounds). We ran a secondary screen on Drosophila melanogaster flies expressing reduced levels of frataxin during larval development. Half of the compounds selected in yeast appeared to be active in flies in this developmental paradigm, and one of the two compounds with highest activities in this assay partially rescued the heart dilatation phenotype resulting from heart specific depletion of frataxin. The unique complementarity of these two frataxin-deficient models, unicellular and multicellular, appears to be very efficient to select new compounds with improved selectivity, bringing significant perspectives towards improvements in FA therapy. PMID- 26523200 TI - Redox Signaling and the Cardiovascular and Skeletal Muscle System. PMID- 26523201 TI - Genome sequence of Oceanobacillus picturae strain S1, an halophilic bacterium first isolated in human gut. AB - Oceanobacillus picturae is a strain of a moderately halophilic bacterium, first isolated from a mural painting. We demonstrate, for the first time, the culture of human Oceanobacillus picturae, strain S1(T), whose genome is described here, from a stool sample collected from a 25-year-old Saoudian healthy individual. We used a slightly modified standard culture medium adding 100 g/L of NaCl. We provide a short description of this strain including its MALDI-TOF spectrum, the main identification tool currently used in clinical microbiology. The 3,675,175 bp long genome exhibits a G + C content of 39.15 % and contains 3666 protein coding and 157 RNA genes. The draft genome sequence of Oceanobacillus picturae has a similar size to the Oceanobacillus kimchii (respectively 3.67 Mb versus 3.83 Mb). The G + C content was higher compared with Oceanobacillus kimchii (respectively 39.15 % and 35.2 %). Oceanobacillus picturae shared almost identical number of genes (3823 genes versus 3879 genes), with a similar ratio of genes per Mb (1041 genes/Mb versus 1012 genes/Mb). The genome sequencing of Oceanobacillus picturae strain S1 isolated for the first time in a human, will be added to the 778 genome projects from the gastrointestinal tract listed by the international consortium Human Microbiome Project. PMID- 26523202 TI - Epigenetic mechanisms in non-alcoholic fatty liver disease: An emerging field. AB - Non-alcoholic fatty liver disease (NAFLD) is an emerging health concern in both developed and non-developed world, encompassing from simple steatosis to non alcoholic steatohepatitis (NASH), cirrhosis and liver cancer. Incidence and prevalence of this disease are increasing due to the socioeconomic transition and change to harmful diet. Currently, gold standard method in NAFLD diagnosis is liver biopsy, despite complications and lack of accuracy due to sampling error. Further, pathogenesis of NAFLD is not fully understood, but is well-known that obesity, diabetes and metabolic derangements played a major role in disease development and progression. Besides, gut microbioma and host genetic and epigenetic background could explain considerable interindividual variability. Knowledge that epigenetics, heritable events not caused by changes in DNA sequence, contribute to development of diseases has been a revolution in the last few years. Recently, evidences are accumulating revealing the important role of epigenetics in NAFLD pathogenesis and in NASH genesis. Histone modifications, changes in DNA methylation and aberrant profiles or microRNAs could boost development of NAFLD and transition into clinical relevant status. PNPLA3 genotype GG has been associated with a more progressive disease and epigenetics could modulate this effect. The impact of epigenetic on NAFLD progression could deserve further applications on therapeutic targets together with future non invasive methods useful for the diagnosis and staging of NAFLD. PMID- 26523203 TI - Recent advances in vaccination of non-responders to standard dose hepatitis B virus vaccine. AB - Hepatitis B virus (HBV) infection is a global health problem. It is estimated there are more than 2 billion individuals exposed to the virus and 250 million are chronically infected. Hepatitis B is the cause of more than 600000 annual deaths due to cirrhosis and hepatocellular carcinoma. An effective vaccine exists and preventative initiatives center around universal vaccination especially in those at highest risk. Effective vaccination algorithms have led to a significant decline in the development of new infections and its devastating consequences. The vaccine is administered intramuscularly in three doses, with 95% showing long lasting serologic immunity. An additional fourth dose or a repeated higher dose three course regimen is given to those that fail to show immunity. Despite these additional regimens, some remain vulnerable to hepatitis B and are deemed non responders. Individuals with chronic disease states such as kidney disease, liver disease, diabetes mellitus, as well as those with a genetic predisposition, and those on immunomodulation therapy, have the highest likelihood of non-response. Various strategies have been developed to elicit an immune response in these individuals. These include increased vaccination dose, intradermal administration, alternative adjuvants, alternative routes of administration, co administration with other vaccines, and other novel therapies. These alternative strategies can show improved response and lasting immunity. In summary, HBV vaccination is a major advance of modern medicine and all individuals at risk should be sought and vaccinated with subsequent adequate titers demonstrated. PMID- 26523204 TI - Liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfection: Diagnostic methods and clinical impact. AB - Several non-invasive surrogate methods have recently challenged the main role of liver biopsy in assessing liver fibrosis in hepatitis C virus (HCV)-monoinfected and human immunodeficiency virus (HIV)/HCV-coinfected patients, applied to avoid the well-known side effects of liver puncture. Serological tests involve the determination of biochemical markers of synthesis or degradation of fibrosis, tests not readily available in clinical practice, or combinations of routine tests used in chronic hepatitis and HIV/HCV coinfection. Several radiologic techniques have also been proposed, some of which commonly used in clinical practice. The studies performed to compare the prognostic value of non-invasive surrogate methods with that of the degree of liver fibrosis assessed on liver tissue have not as yet provided conclusive results. Each surrogate technique has shown some limitations, including the risk of over- or under-estimating the extent of liver fibrosis. The current knowledge on liver fibrosis in HIV/HCV coinfected patients will be summarized in this review article, which is addressed in particular to physicians involved in this setting in their clinical practice. PMID- 26523205 TI - Dietary approach in the treatment of nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) has been identified as one of the most prevalent chronic liver disease in adults and children populations. NAFLD is usually associated with the metabolic syndrome (MS), which is chiefly related to insulin resistance and its consequences. Insulin resistance has a crucial role in the pathogenesis of hepatic steatosis and potentially nonalcoholic steatohepatitis (NASH). Because of the contemporary epidemics of MS and obesity, the burden of NAFLD is also expected to rise. Unhealthy diets, such as the so called western diet, are enriched in fructose, trans-fatty acids and saturated fat and seem to be associated with the development of NAFLD. In human studies, certain dietary sugars, particularly fructose, are used as a substrate for lipogenesis leading to hepatic fatty infiltration, inflammation, and possibly fibrosis. Other investigations have shown that fat consumption especially cholesterol and trans/saturated fatty acids are also steatogenic and seem to increase visceral adiposity. The identification of specific dietary components that favor the development of NASH could be important for the management of this disorder. This review focuses on the effects of different dietary approaches to prevent and treat NAFLD emphasizing the macronutrients and energy composition. PMID- 26523206 TI - Era of direct acting antivirals in chronic hepatitis C: Who will benefit? AB - In the era of highly effective direct acting antiviral (DAA) drugs for the treatment of chronic hepatitis C (CHC) infection, where eradication is almost ensured with minimal side effects, all hepatitis C carriers should benefit theoretically. In the real world setting however, only a small proportion will benefit at this time point due to the multiple barriers to accessing therapy. Given that universal treatment is unlikely, treatment with DAAs will likely be restricted to those with the highest health benefits, and for those who can afford the high expense of a treatment course. Those with the highest unmet needs include those who have failed previous interferon-based therapy or who are interferon-ineligible with evidence of active disease, those with advance liver disease, and those with recurrence of hepatitis C after liver transplantation. In the future, the focus should be on increasing access to treatment for those infected with CHC. PMID- 26523207 TI - Role of pentoxifylline in non-alcoholic fatty liver disease in high-fat diet induced obesity in mice. AB - AIM: To study pentoxifylline effects in liver and adipose tissue inflammation in obese mice induced by high-fat diet (HFD). METHODS: Male swiss mice (6-wk old) were fed a high-fat diet (HFD; 60% kcal from fat) or AIN-93 (control diet; 15% kcal from fat) for 12 wk and received pentoxifylline intraperitoneally (100 mg/kg per day) for the last 14 d. Glucose homeostasis was evaluated by measurements of basal glucose blood levels and insulin tolerance test two days before the end of the protocol. Final body weight was assessed. Epididymal adipose tissue was collected and weighted for adiposity evaluation. Liver and adipose tissue biopsies were homogenized in solubilization buffer and cytokines were measured in supernatant by enzyme immunoassay or multiplex kit, respectively. Hepatic histopathologic analyses were performed in sections of paraformaldehyde-fixed, paraffin-embedded liver specimens stained with hematoxylin-eosin by an independent pathologist. Steatosis (macrovesicular and microvesicular), ballooning degeneration and inflammation were histopathologically determined. Triglycerides measurements were performed after lipid extraction in liver tissue. RESULTS: Pentoxifylline treatment reduced microsteatosis and tumor necrosis factor (TNF)-alpha in liver (156.3 +/- 17.2 and 62.6 +/- 7.6 pg/mL of TNF-alpha for non-treated and treated obese mice, respectively; P < 0.05). Serum aspartate aminotransferase levels were also reduced (23.2 +/- 6.9 and 12.1 +/- 1.6 U/L for non-treated and treated obese mice, respectively; P < 0.05) but had no effect on glucose homeostasis. In obese adipose tissue, pentoxifylline reduced TNF-alpha (106.1 +/- 17.6 and 51.1 +/- 9.6 pg/mL for non-treated and treated obese mice, respectively; P < 0.05) and interleukin-6 (340.8 +/- 51.3 and 166.6 +/- 22.5 pg/mL for non-treated and treated obese mice, respectively; P < 0.05) levels; however, leptin (8.1 +/- 0.7 and 23.1 +/- 2.9 ng/mL for non-treated and treated lean mice, respectively; P < 0.05) and plasminogen activator inhibitor-1 (600.2 +/- 32.3 and 1508.6 +/- 210.4 pg/mL for non-treated and treated lean mice, respectively; P < 0.05) levels increased in lean adipose tissue. TNF-alpha level in the liver of lean mice also increased (29.6 +/- 6.6 and 75.4 +/- 12.6 pg/mL for non-treated and treated lean mice, respectively; P < 0.05) while triglycerides presented a tendency to reduction. CONCLUSION: Pentoxifylline was beneficial in obese mice improving liver and adipose tissue inflammation. Unexpectedly, pentoxifylline increased pro-inflammatory markers in the liver and adipose tissue of lean mice. PMID- 26523209 TI - Way forward: Geriatric frailty assessment as risk predictor in gastric cancer surgery. AB - In gastric cancer patients chronological and biological age might vary greatly between patients. Age as well as American Society of Anaesthesiologists-physical status classifications are very non-specific and do not adequately predict adverse outcome. Improvements have been made such as the introduction of Charlson Comorbidity Index. Geriatric frailty is probably a better measure for patients resistance to stressors and physiological reserves. An increasing amount of evidence shows that geriatric frailty is a better predictor for adverse outcome after surgery, including gastric cancer surgery. Geriatric frailty can be assessed in a number of ways. Questionnaires such as the Groningen Frailty Indicator provide an easy and low cost method for gauging the presence of frailty in gastric cancer patients. This can then be used to provide a better preoperative risk assessment in these patients and improve decision making. PMID- 26523208 TI - Combination Treatment with Apricoxib and IL-27 Enhances Inhibition of Epithelial Mesenchymal Transition in Human Lung Cancer Cells through a STAT1 Dominant Pathway. AB - BACKGROUND: The cyclooxygenase 2 (COX-2) pathway has been implicated in the molecular pathogenesis of many malignancies, including lung cancer. Apricoxib, a selective COX-2 inhibitor, has been described to inhibit epithelial-mesenchymal transition (EMT) in human malignancies. The mechanism by which apricoxib may alter the tumor microenvironment by affecting EMT through other important signaling pathways is poorly defined. IL-27 has been shown to have anti-tumor activity and our recent study showed that IL-27 inhibited EMT through a STAT1 dominant pathway. OBJECTIVE: The purpose of this study is to investigate the role of apricoxib combined with IL-27 in inhibiting lung carcinogenesis by modulation of EMT through STAT signaling. METHODS AND RESULTS: Western blot analysis revealed that IL-27 stimulation of human non-small cell lung cancer (NSCLC) cell lines results in STAT1 and STAT3 activation, decreased Snail protein and mesenchymal markers (N-cadherin and vimentin) and a concomitant increase in expression of epithelial markers (E-cadherin, beta-and gamma-catenins), and inhibition of cell migration. The combination of apricoxib and IL-27 resulted in augmentation of STAT1 activation. However, IL-27 mediated STAT3 activation was decreased by the addition of apricoxib. STAT1 siRNA was used to determine the involvement of STAT1 pathway in the enhanced inhibition of EMT and cell migration by the combined IL-27 and apricoxib treatment. Pretreatment of cells with STAT1 siRNA inhibited the effect of combined IL-27 and apricoxib in the activation of STAT1 and STAT3. In addition, the augmented expression of epithelial markers, decreased expression mesenchymal markers, and inhibited cell migration by the combination treatment were also inhibited by STAT1 siRNA, suggesting that the STAT1 pathway is important in the enhanced effect from the combination treatment. CONCLUSION: Combined apricoxib and IL-27 has an enhanced effect in inhibition of epithelial-mesenchymal transition and cell migration in human lung cancer cells through a STAT1 dominant pathway. PMID- 26523210 TI - Mesh implants: An overview of crucial mesh parameters. AB - Hernia repair is one of the most frequently performed surgical interventions that use mesh implants. This article evaluates crucial mesh parameters to facilitate selection of the most appropriate mesh implant, considering raw materials, mesh composition, structure parameters and mechanical parameters. A literature review was performed using the PubMed database. The most important mesh parameters in the selection of a mesh implant are the raw material, structural parameters and mechanical parameters, which should match the physiological conditions. The structural parameters, especially the porosity, are the most important predictors of the biocompatibility performance of synthetic meshes. Meshes with large pores exhibit less inflammatory infiltrate, connective tissue and scar bridging, which allows increased soft tissue ingrowth. The raw material and combination of raw materials of the used mesh, including potential coatings and textile design, strongly impact the inflammatory reaction to the mesh. Synthetic meshes made from innovative polymers combined with surface coating have been demonstrated to exhibit advantageous behavior in specialized fields. Monofilament, large-pore synthetic meshes exhibit advantages. The value of mesh classification based on mesh weight seems to be overestimated. Mechanical properties of meshes, such as anisotropy/isotropy, elasticity and tensile strength, are crucial parameters for predicting mesh performance after implantation. PMID- 26523211 TI - Risk factors and implications of anastomotic complications after surgery for Crohn's disease. AB - Anastomotic complications occur more frequently in patients with Crohn's disease leading to postoperative intra-abdominal septic complications (IASC). Patients with IASC often require re-operation or drainage to control the sepsis and have an increased frequency of disease recurrence. The aim of this article was to examine the factors affecting postoperative IASC in Crohn's disease after anastomoses, since some risk factors remain controversial. Studies investigating IASC in Crohn's operations were included, and all risk factors associated with IASC were evaluated: nutritional status, presence of abdominal sepsis, medication use, Crohn's disease type, duration of disease, prior operations for Crohn's, anastomotic technique, extent of resection, operative timing, operative length, and perioperative bleeding. In this review, the factors associated with an increased risk of IASC are preoperative weight loss, abdominal abscess present at time of surgery, prior operation, and steroid use. To prevent IASC in Crohn's patients, preoperative optimization with nutritional supplementation or drainage of abscess should be performed, or a diverting stoma should be considered for patients with multiple risk factors. PMID- 26523212 TI - New minimally invasive approaches for cholecystectomy: Review of literature. AB - Laparoscopic cholecystectomy is the most commonly performed abdominal intervention in Western countries. In an attempt to reduce the invasiveness of the procedure, surgeons have developed single-incision laparoscopic cholecystectomy (SILC), minilaparoscopic cholecystectomy (MLC) and natural orifice transluminal endoscopic surgery (NOTES). The aim of this review was to determine the role of these new minimally invasive approaches for elective laparoscopic cholecystectomy in the treatment of gallstone related disease. Current literature remains insufficient for the correct assessment of emerging techniques for laparoscopic cholecystectomy. None of these procedures has demonstrated clear benefits over conventional laparoscopic cholecystectomy. SILC cannot be currently recommended as it can be associated with an increased risk of bile duct injury and incisional hernia incidence. NOTES cholecystectomy is still experimental, although hybrid transvaginal cholecystectomy is gaining popularity in clinical practice. As it is standardized and almost identical to the standard laparoscopic technique, MLC could lead to limited benefits without exposing patients to increased postoperative complications, being therefore adoptable for routine elective cholecystectomy. Technical challenges of SILC and NOTES cholecystectomy could be addressed with the evolution of new surgical tools that need to catch up with the innovative minds of surgeons. Regardless the place of these approaches in the future, robotization may be necessary to impose them as standard treatment. PMID- 26523213 TI - Bursectomy at radical gastrectomy. AB - Radical gastrectomy with extended lymph node dissection and prophylactic resection of the omentum, peritoneum over the posterior lesser sac, pancreas and/or spleen was advocated at the beginning of the 1960s in Japan. In time, prophylactic routine resections of the pancreas and/or spleen were abandoned because of the high incidence of postoperative complications. However, omentectomy and bursectomy continued to be standard parts of traditional radical gastrectomy. The bursa omentalis was thought to be a natural barrier against invasion of cancer cells into the posterior part of the stomach. The theoretical rationale for bursectomy was to reduce the risk of peritoneal recurrences by eliminating the peritoneum over the lesser sac, which might include free cancer cells or micrometastases. Over time, the indication for bursectomy was gradually reduced to only patients with posterior gastric wall tumors penetrating the serosa. Despite its theoretical advantages, its benefit for recurrence or survival has not been proven yet. The possible reasons for this inconsistency are discussed in this review. In conclusion, the value of bursectomy in the treatment of gastric cancer is still under debate and large-scale randomized studies are necessary. Until clear evidence of patient benefit is obtained, its routine use cannot be recommended. PMID- 26523214 TI - What Do We Know about Individuals Who Are Assessed as Being at Moderate Risk for Future Fracture in Canada? AB - OBJECTIVE: We examined what was known about individuals in Canada who were assessed as being at moderate risk for future fracture. METHODS: A scoping review was conducted. Eligible articles were Canadian studies published from 2010 onwards reporting on primary data that included patients at moderate risk for future fracture. We limited the search to Canada as fracture risk categorization is unique to each country. Studies were identified by searching relevant databases. Two reviewers independently reviewed titles and abstracts to determine each study's eligibility. General information about each study, demographic information about the moderate risk groups (including tool used to determine moderate risk (Fracture Risk Assessment Tool (FRAX), Canadian Association of Radiologists and Osteoporosis Canada (CAROC)), and outcomes (number of patients: recommended treatment, prescribed treatment, initiating treatment, persisting with treatment after six months, who re-fractured, who died) were documented. RESULTS: We identified 1193 papers which were further screened for eligibility. Of the 1193 identified, 7 were eligible for the review but only 4 articles contained demographic or outcome data on moderate risk patients. In one study, 1.8% of moderate risk patients died over a mean 5.3 years of observation and in three studies, the risk of fracture was 5.9% over a median of 3 years of follow up, 8.3% over a mean of 5.4 years, and 14.7% over 10 years of follow-up. CONCLUSION: There is a wide knowledge gap in the literature concerning individuals who are assessed as moderate risk for future fracture in Canada. PMID- 26523215 TI - Bone Mineral Density Reporting Underestimates Fracture Risk in Ontario. AB - OBJECTIVE: Analysis of clinical documents such as bone mineral density (BMD) reports is an important component of program evaluation because it can provide insights into the accuracy of assessment of fracture risk communicated to patients and practitioners. Our objective was to compare fracture risk calculations from BMD test reports to those based on the 2010 Canadian guidelines. METHODS: We retrieved BMD reports from fragility fracture patients screened through a community hospital fracture clinic participating in Ontario's Fracture Clinic Screening Program. Fracture risk was determined according to the 2010 Canadian guidelines using age, sex, and T-score at the femoral neck, in addition to three clinical factors. Three researchers classified patients' fracture risk until consensus was achieved. RESULTS: We retrieved reports for 17 patients from nine different BMD clinics in the Greater Toronto Area. Each patient had a different primary care physician and all BMD tests were conducted after the 2010 Canadian guidelines were published. The fracture risk of 10 patients was misclassified with 9 of the 10 reports underestimating fracture risk. Nine reports acknowledged that the prevalence of a fragility fracture raised the risk category by one level but only four of these reports acknowledged that the patient had, or may have sustained, a fragility fracture. When we raised fracture risk by one level according to these reports, eight patients were still misclassified. Fracture risk in the majority of these patients remained underestimated. Inconsistent classification was found in the majority of cases where reports came from the same clinic. Four reports described risk levels for two different types of risk. CONCLUSIONS: More than half of patients received BMD reports which underestimated fracture risk. Bone health management recommendations based on falsely low fracture risk are likely to be sub-optimal. PMID- 26523217 TI - Down-regulation of miR-135b in colon adenocarcinoma induced by a TGF-beta receptor I kinase inhibitor (SD-208). AB - OBJECTIVES: Transforming growth factor-beta (TGF-beta) is involved in colorectal cancer (CRC). The SD-208 acts as an anti-cancer agent in different malignancies via TGF-beta signaling. This work aims to show the effect of manipulation of TGF beta signaling on some miRNAs implicated in CRC. MATERIALS AND METHODS: We investigated the effects of SD-208 on SW-48, a colon adenocarcinoma cell line. The cell line was treated with 0.5, 1 and 2 MUM concentrations of SD-208. Then, the xenograft model of colon cancer was established by subcutaneous inoculation of SW-48 cell line into the nude mice. The animals were treated with SD-208 for three weeks. A quantitative real-time PCR was carried out for expression level analysis of selected oncogenic (miR-21, 31, 20a and 135b) and suppressor-miRNAs (let7-g, miR-133b, 145 and 200c). Data were analyzed using the 2-??CT method through student's t-test via the GraphPad Prism software. RESULTS: Our results revealed that SD-208 could significantly down-regulate the expression of one key onco-miRNA, miR-135b, in either SW-48 colon cells (P=0.006) or tumors orthotopically implanted in nude mice (P=0.018). Our in silico study also predicted that SD-208 could modulate the expression of potential downstream tumor suppressor targets of the miR135b. CONCLUSION: Our data provide novel evidence that anticancer effects of SD-208 (and likely other TGF-beta inhibitors) may be owing to their ability to regulate miRNAs expression. PMID- 26523218 TI - Lack of FLT3-TKD835 gene mutation in toxicity of sulfur mustard in Iranian veterans. AB - OBJECTIVES: Sulfur mustard (SM) was used by the Iraqi army against the Iranian troops in the Iran-Iraq war from 1983-1988. This chemical gas affects different organs including the skin, lungs and the hematopoietic system. Any exposure to SM increases the risk of chromosomal breaking, hyperdiploidy and hypodiploidy. Studies have shown that the risk for acute myeloblastic and lymphoblastic leukemia increases in veterans exposed to SM. FLT3 mutations including ITD and TKD mutations had been observed in some cases of leukemia. Therefore, we aimed to investigate the frequency of FLT3-TKD835 mutations in the veterans exposed to SM agent. MATERIALS AND METHODS: We studied 42 patients who were exposed to SM during the war in Khorasan Razavi province, Mashhad, Iran in 2012. As control group, 30 healthy males were selected from first-degree relatives of the patients. For assessment of TKD835 mutation, DNA was extracted and RFLP-PCR was performed. RESULTS: Analysis of RFLP-PCR data showed no FLT-3 TKD mutation in any of the patients. CONCLUSION: Although contact with SM can increase the risk of malignancy especially hematologic neoplasms, results of the study show that another mechanism of leukemogenesis, other than FLT3-TKD mutation, may be the reason for increased risk of leukemia in SM toxicity. PMID- 26523216 TI - Pigment epithelium-derived factor: clinical significance in estrogen-dependent tissues and its potential in cancer therapy. AB - Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the family of non-inhibitory serpins. The broad spectrum of PEDF biological activity is evident when considering its effects in promoting cell survival and proliferation, as well as its antiangiogenic, antitumor, and anti-metastatic properties. Although the structural domains of the PEDF gene that mediate such diverse effects and their mechanisms of action have not been completely elucidated, there is a large body of evidence describing their diverse range of activities; this evidence combined with the regulation of PEDF expression by sex steroids and their receptors have led to the idea that PEDF is not only a diagnostic and prognostic marker for certain diseases such as cancer, but is also a potential therapeutic target. In this manner, this paper aims to generally review the regulation of PEDF expression and PEDF interactions, as well as the findings that relate PEDF to the role of estrogens and estrogen receptors. In addition, this manuscript will review major advances toward potential therapeutic applications of PEDF. PMID- 26523219 TI - Melatonin treatment reduces astrogliosis and apoptosis in rats with traumatic brain injury. AB - OBJECTIVES: Melatonin is known as an anti-inflammatory agent, and it has been proven to exert neuroprotection through inhibition of cell death (apoptosis) in several models of brain injury. Secondary injury following the primary traumatic brain injury (TBI) results in glial cells activation, especially astrocytes. In fact, astrocyte activation causes the production of pro-inflammatory cytokines that may lead to secondary injury. Since most TBI research studies have focused on injured neurons and paid little attention to glial cells, the aim of current study was to investigate the effects of melatonin against astrocytes activation (astrogliosis), as well as inhibition of apoptosis in brain tissue of male rats after TBI. MATERIALS AND METHODS: The animals were randomly allocated into five groups: sham group, TBI+ vehicle group (1% ethanol in saline) and TBI+ melatonin groups (5 mg/kg, 10 mg/kg and 20 mg/kg). All rats were intubated and then exposed to diffuse TBI, except for the sham group. Immunohistochemical methods were conducted using glial fibrillary acidic protein (GFAP) marker and TUNEL assay to evaluate astrocyte reactivity and cell death, respectively. RESULTS: The results showed that based on the number of GFAP positive astrocytes in brain cortex, astrogliosis was reduced significantly (P<0.05) in melatonin- treated groups (no dose dependent) compared to the vehicle group. Furthermore, based on TUNEL results, melatonin treatment considerably reduced the number of apoptotic cells (P<0.05). CONCLUSION: In total, the present findings suggest that melatonin treatment following TBI diminishes astrocyte reactivity and neuronal cells apoptosis in brain cortex in the rat model. PMID- 26523220 TI - Correlational studies on insulin resistance and leptin gene polymorphisms in peritoneal dialysis patients. AB - OBJECTIVES: The aim of the study was to investigate the relationship between insulin resistance (IR) and leptin (LEP) gene polymorphisms in peritoneal dialysis (PD) patients. MATERIALS AND METHODS: From July 1, 2011 to August 1, 2011, patients who received chronic PD were chosen and divided into three groups (DM, high HOMR-IR, and low HOMR-IR). Two PCR products of LEP were sequenced and aligned and the distribution of polymorphisms was analyzed using chi(2) analysis. In addition, serum leptin level, PD conditions, and biochemical parameters according to different genotype of G-2548A and A19G were statistically analyzed (P-value<0.05). The relationship between LEP gene polymorphisms and prognosis was explored. RESULTS: Totally 157 patients with average age of 55+/-15 years old were chosen. Distribution of genotype frequencies was complied with Hardy Weinberg equilibrium. Leptin level and BMI (body mass index) of the GG genotype of G-2548A were higher than that of GA or AA. The fasting glucose, cholesterol, etc. of AA genotype were lower, and the nPCR was higher than the two other genotypes. Serum leptin level and BMI of AA genotype of A19G was higher than GA and GG genotypes; meanwhile, fasting blood glucose of that genotypes was the highest. In addition, survival rate of AA group of A19G was very low. CONCLUSION: The G-2548A and A19G polymorphisms were correlated with serum leptin level and IR. Leptin A19G polymorphism may be prognostic for PD patients. This study may facilitate early intervention for IR in PD patients. PMID- 26523221 TI - Presentation of a novel model of chitosan- polyethylene oxide-nanohydroxyapatite nanofibers together with bone marrow stromal cells to repair and improve minor bone defects. AB - OBJECTIVES: Various methods for repairing bone defects are presented. Cell therapy is one of these methods. Bone marrow stromal cells (BMSCs) seem to be suitable for this purpose. On the other hand, lots of biomaterials are used to improve and repair the defect in the body, so in this study we tried to produce a similar structure to the bone by the chitosan and hydroxyapatite. MATERIALS AND METHODS: In this study, the solution of chitosan-nanohydroxyapatite-polyethylene oxide (PEO) Nanofibers was produced by electrospinning method, and then the BMSCs were cultured on this solution. A piece of chitosan-nanohydroxyapatite Nanofibers with BMSCs was placed in a hole with the diameter of 1 mm at the distal epiphysis of the rat femur. Then the biomechanical and radiographic studies were performed. RESULTS: Biomechanical testing results showed that bone strength was significantly higher in the Nanofiber/BMSCs group in comparison with control group. Also the bone strength in nanofiber/BMSCs group was significant, but in nanofiber group was nearly significant. Radiographic studies also showed that the average amount of callus formation (radio opacity) in nanofiber and control group was not significantly different. The callus formation in nanofiber/BMSCs group was increased compared to the control group, and it was not significant in the nanofiber group. CONCLUSION: Since chitosan-nanohydroxyapatite nanofibers with BMSCs increases the rate of bone repair, the obtained cell-nanoscaffold shell can be used in tissue engineering and cell therapy, especially for bone defects. PMID- 26523223 TI - Detection and discrimination of two Brucella species by multiplex real-time PCR and high-resolution melt analysis curve from human blood and comparison of results using RFLP. AB - OBJECTIVES: Rapid and accurate detection of Brucella abortus and Brucella melitensis from clinical samples is so important because antibiotic treatment has major side effects. This study reveals a new method in detection of clinical samples of brucellosis using real-time PCR and high-resolution melt (HRM) curve analysis. MATERIALS AND METHODS: 160 brucellosis suspicious samples with more than 1/80 serum antibody titers were collected and the results were compared with the RFLP method. In order to amplify the sequences for HRM analysis, vdcc, int hyp and glk and for RFLP, omp2a and omp2b with PstI and Hinf1 restriction endonuclease were used. At last, the accuracy and specificity of the two methods were compared with each other. RESULTS: Out of these 160 samples, multiplex real time PCR showed 108 positive samples (67.5%), including 56% B. melitensis and 44% B. abortus; whereas in PCR-RFLP 52 out of 160 samples were positive, where recognition of two species were accordant with HRM analysis, separation was based on the size of the amplified fragment. Using the designed primers and performing the assay, we confirmed this method to be much faster and have lower cost with more than 99% accuracy compared to methods such as RFLP. CONCLUSION: The present study showed that this technique, which scans gene segments and creates an analysis pattern for detection of clinical samples, is useful and more dominant compared with PCR-RFLP. Thus, this method can be used for brucellosis detection, and clinical and epidemiological research. PMID- 26523222 TI - Crocin reduced acrylamide-induced neurotoxicity in Wistar rat through inhibition of oxidative stress. AB - OBJECTIVES: Acrylamide (ACR) has many applications in different industries. ACR damages the central and the peripheral nervous system in human and animals. Importance of ACR-induced neurotoxicity encouraged researchers to find both different mechanisms involved in ACR neurotoxicity and potent neuroprotective agents. Therefore, this study was designed to investigate the protective effect of crocin, an active constituent of Crocus sativus L. (saffron) on ACR-induced neurotoxicity in Wistar rats. MATERIALS AND METHODS: Animals were treated with ACR (50 mg/kg, IP) 11 days for induction neurotoxicity. Crocin (12.5, 25 and 50 mg/kg, IP) were used during treatment with ACR. At the end of treatment, gait score examination was performed. Then, rats were sacrificed and the severity of damage in brain tissue was determined using pathological tests. The level of malondialdehyde (MDA) and glutathione (GSH) content were evaluated in cerebral cortex and cerebellum to determine the role of oxidative stress in this model. RESULTS: Exposure to ACR induced severe gait abnormalities and pathological changes, but administration of crocin markedly improved behavioral index and histopathological damages. The elevation of lipid peroxidation parallel with reduction of GSH level was observed in cerebral cortex and cerebellum following exposure to ACR. Treatment with crocin markedly decreased MDA level, while elevated GSH content in nervous system as compared to ACR-treated animals. CONCLUSION: The administration of crocin markedly improved behavioral and histopathological damages in Wistar rats exposed to ACR. Reduction of oxidative stress can be considered as an important mechanism of neuroprotective effects of crocin against ACR-induced toxicity. PMID- 26523224 TI - The activity of ozonated olive oil against Leishmania major promastigotes. AB - OBJECTIVES: Cutaneous Leishmaniasis is a common and endemic disease in Khorasan province in North-East of Iran. The pentavalant antimony (Sb V) is the mainstay of treatment that has many side effects and resistance to the drug has been reported. The microbicidal effect of ozone was proven in different microorganisms. Since there is no study in this respect and to achieve a low cost and effective treatment, we decided to evaluate the efficacy of ozone against promastigotes of Leishmania major, in vitro. MATERIALS AND METHODS: Ozonated olive oil was prepared after production of ozone by bubbling ozone-oxygen gas produced by ozone generator through olive oil until it solidified. Promastigotes of L. major were cultivated in two phasic media. After calculation of the number of promastigotes, they were incubated with ozonated olive oil (0, 0.626, 0.938, 1.25, 2.5, 5, 10 mcg/ml) at 28 degrees c for 24 hr. Parasites survival percentage was evaluated using MTS and microscopic assay, and then compared with Glucantime and non-ozonated olive oil. RESULTS: According to the results, there were significant differences in parasites survival percentage between ozonated olive oil and non-ozonated olive oil, at similar concentrations (P<0.001). Ozonated olive oil was more effective than Glucantime. According to MTS results, Glucantime and ozonated olive oil gel concentrations that are required to inhibit the growth of L. major promastigotes by 50% (IC50), were 165 and 0.002 mg/ml, respectively. CONCLUSION: Ozonated olive oil has in vitro activity against the promastigotes of L. major and this effect is dose dependent. PMID- 26523225 TI - Effects of Ginkgo biloba extract on the structure of Cornu Ammonis in aged rat: A morphometric study. AB - OBJECTIVES: Growing evidence indicates that extract of Ginkgo biloba (EGb) attenuates hippocampal-dependent memory deficit in aged individuals; however, very little is known about the effect of EGb on the structure of hippocampus. Therefore we examined the EGb-induced morphological changes of the Cornu Ammonis (CA) region in aged rats. MATERIALS AND METHODS: Sixteen aged male Wistar rats, 24 months old, were randomly divided into experimental and control groups. Experimental group was orally administered EGb (100 mg/kg/d for 8 weeks), and the control group received a similar volume of water. The volume estimation of CA hippocampal field was done by Cavalieri principle and a quantitative Golgi study was also used for analysis of dendritic arborizations of CA3 and CA1 pyramidal cells. RESULTS: Results revealed that EGb-treated aged rats had greater volumes than control animals in the layers of pyramidal and radiatum lacunosum moleculare in both CA3 and CA1 subfields. The neurons of CA3 and CA1 in experimental rats had more dendritic segments and larger total dendritic length compared to the control. The results also showed that the aged rats treated by EGb had more numerical branching density in the apical dendrites of CA3 and CA1 pyramidal cells. CONCLUSION: The results of the present study show that long-term administration of EGb could produce morphometrical changes in hippocampal pyramidal cells in aged rats. Results also provide a neuroanatomical basis for memory improvement due to chronic treatment with EGb. PMID- 26523226 TI - In vivo anti-Toxoplasma activity of aripiprazole. AB - OBJECTIVES: There are supportive evidences about the possible role of latent Toxoplasma. gondii infections on the behavior and neurologic functions, such as increased dopamine levels in the brain. The aim of this study was to examine anti toxoplasma activity of aripiprazole that is an atypical anti-psychotic drug in mice. MATERIALS AND METHODS: Mice were randomly divided into four groups, including; control, vehicle, aripiprazole 10 mg/kg, and aripiprazole 20 mg/kg. The mice were inoculated intraperitoneally with mice brain suspension containing tissue cysts. At the end of second month, the number of cysts was counted in smears prepared from brain homogenate by optical microscope. RESULTS: There was no significant difference between mean logarithms of brain cyst numbers of aripiprazole groups compared with control. CONCLUSION: Results indicate that in aripiprazole groups, the brain cystogenesis was not decrease. Further study needs to investigate the role of anti-psychotic drugs on T. gondii. PMID- 26523227 TI - Bloch Surface Wave-Coupled Emission from Quantum Dots by Ensemble and Single Molecule Spectroscopy. AB - We report the spectral properties and spatial distribution of quantum dot (QD575 ) emission on a one-dimensional photonic crystal (1DPC). Our 1DPC substrate consists of multiple layers of dielectrics with a photonic band gap (PBG) near the QD575 emission maximum. The 1DPC was designed to display a surface-trapped electromagnetic state known as a Bloch surface wave (BSW) at the 1DPC-air (sample) interface. Ensemble angle-dependent emission intensities revealed a sharp angular emission peak near 41 degrees from the normal which is consistent with the BSW resonance at 575 nm. We further examined the emission from single QDs on the 1DPC. A notable increase in fluorescence intensity from QD575 particles was observed on BSW substrate compared to the glass substrate from the scanning confocal fluorescence images and from the intensity-time trajectories of single QD575 particles. The intensity-decays showed substantially faster decay (4 fold decrease in emission lifetime) from the single QD575 particles on 1DPC substrate (~4.8 nsec) as compared to the glass substrate (~18 nsec). We observed the spectral characteristics of the individual QD575 particles on 1DPC and glass substrates, by recording the single particle emission spectra through the 1DPC. The emission spectra of the single QD575 particles are similar (with emission maxima around 575 nm) on both substrates except a substantial increase in intensity (over 10-fold) on the BSW substrate. Our results demonstrate that quantum dots can interact with Bloch Surface Waves (BSW) on a 1DPC. To the best of our knowledge, this is the first report on the single particle fluorescence studies on 1DPC substrate. The 10-fold increase in intensity in combination with 4-fold reduction in emission lifetime suggest 1DPCs with BSW modes have potential use in sensing and single molecule spectroscopy. PMID- 26523228 TI - The school environment and asthma in childhood. AB - In this article, we discuss the relationship between environmental exposures within the school environment and pediatric asthma morbidity. This article will conclude by reviewing novel school based asthma education and therapeutic programs and environmental interventions designed to help mitigate pediatric asthma morbidity. PMID- 26523229 TI - Elevated anthranilic acid plasma concentrations in type 1 but not type 2 diabetes mellitus. AB - Experimental data suggested involvement of tryptophan (Trp) - kynurenine (Kyn) pathway (TKP) in mechanisms of autoimmune, type 1 (T1D), and metabolic, type 2 (T2D), diabetes. However, clinical evaluations of TKP metabolites were limited to T2D. We assessed Trp, Kyn and TKP metabolites: anthranilic (AA), kynurenic (KYNA) and xanthurenic (XA) acids, in plasma samples of fifteen T1D, thirty T2D patients and twenty eight non-diabetic subjects by HPLC-mass spectrometry. Trp concentrations were higher in T1D than in T2D and controls while Kyn concentrations were not changed suggesting down-regulation of indoleamine-2,3 dioxygenase (IDO), a rate-limiting enzyme of TKP, in T1D. AA concentrations were 2.3-fold higher in T1D than in T2D and in controls. KYNA and XA concentrations were higher in T1D than in controls, and in previously reported T2D. AA elevation might be a specific feature of T1D. TKP shift towards AA formation in T1D may result from riboflavin deficiency, that increases AA in rats and baboons, and is highly associated with T1D but not T2D. AA augments autoimmune-induced apoptosis of pancreatic cells (PC) by increasing formation of antibodies to PC auto antigen. Marked increase of AA was reported in rheumatoid arthritis, another autoimmune disorder. Trp, an essential amino acid for humans, is synthesized from AA by diabetogenic intestinal microbiome. AA down-regulates IDO by inhibition of Trp entry into cells. Resulting elevation of Trp attenuates Trp depletion-induced protection of PC against autoimmunity. Further studies of TKP might offer new tools for prevention and treatment of T1D and other autoimmune disorders. PMID- 26523230 TI - Evaluating community-based medical education programmes in Africa: A workshop report. AB - BACKGROUND: The Medical Education Partnership Initiative (MEPI) supports medical schools in Africa to increase the capacity and quality of medical education, improve retention of graduates, and promote regionally relevant research. Many MEPI programmes include elements of community-based education (CBE) such as: community placements; clinical rotations in underserved locations, community medicine, or primary health; situational analyses; or student-led research. METHODS: CapacityPlus and the MEPI Coordinating Center conducted a workshop to share good practices for CBE evaluation, identify approaches that can be used for CBE evaluation in the African context, and strengthen a network of CBE collaborators. Expected outcomes of the workshop included draft evaluation plans for each school and plans for continued collaboration among participants. The workshop focused on approaches and resources for evaluation, guiding exploration of programme evaluation including data collection, sampling, analysis, and reporting. Participants developed logic models capturing inputs, activities, outputs, and expected outcomes of their programmes, and used these models to inform development of evaluation plans. This report describes key insights from the workshop, and highlights plans for CBE evaluation among the MEPI institutions. RESULTS: Each school left the workshop with a draft evaluation plan. Participants agreed to maintain communication and identified concrete areas for collaboration moving forward. Since the workshop's conclusion, nine schools have agreed on next steps for the evaluation process and will begin implementation of their plans. CONCLUSION: This workshop clearly demonstrated the widespread interest in improving CBE evaluation efforts and a need to develop, implement, and disseminate rigorous approaches and tools relevant to the African context. PMID- 26523232 TI - Erratum to "Size of the Optic Nerve Head and Its Relationship with the Thickness of the Macular Ganglion Cell Complex and Peripapillary Retinal Nerve Fiber Layer in Patients with Primary Open Angle Glaucoma". AB - [This corrects the article DOI: 10.1155/2015/186249.]. PMID- 26523231 TI - Vision Health-Related Quality of Life in Chinese Glaucoma Patients. AB - This cross-sectional study evaluated VRQOL in Chinese glaucoma patients and the potential factors influencing VRQOL. The VRQOL was assessed using the Chinese version low vision quality of life questionnaire. Visual field loss was classified by the Hodapp-Parrish-Anderson method. The correlations of VRQOL to the best corrected visual acuity and the VF loss were investigated. The potential impact factors to VRQOL of glaucoma patients were screened by single factor analysis and were further analyzed by multiple regression analysis. There were significant differences in VRQOL scores between mild VF loss group and moderate VF loss group, moderate VF loss group and severe VF loss group, and mild VF loss group and severe VF loss group according to the better eye. In multiple linear regression, the binocular weighted average BCVA significantly affected the VRQOL scores. Binocular MD was the second influencing factor. In logistic regression, binocular severe VF loss and stroke were significantly associated with abnormal VRQOL. Education was the next influencing factor. This study showed that visual acuity correlated linearly with VRQOL, and VF loss might reach a certain level, correlating with abnormal VRQOL scores. Stroke was significantly associated with abnormal VRQOL. PMID- 26523233 TI - Angle at the Medial Border: The Spinovertebra Angle and Its Significance. AB - Background. The evolution from quadrupedalism to bipedalism has adjusted the balance of the upper limb to extensive movement at the shoulder. The scapular angles provide the point of attachment and control to various muscles and have been associated with the different movements of the shoulder girdle and joint. This has made the morphometric and anthropometric study of scapula a subject of extensive investigation. Aim. In the present study, the angle at the medial border was measured in the South-Southern Nigerian population and an anatomical name was ascribed to the angle. Method. The study was conducted on 173 scapulae (75 right and 98 left) obtained from various Anatomy Department of South-Sothern Nigerian Universities. The angle at medial border was obtained by pinning the edge of the superior and inferior angles, the lined traced out, and the angle measured using a protractor. SPSS version 20 was used to analyse the data. t-test was used to determine mean angular difference in the sides. Result. The mean +/- SD of the medial angle was observed to be 136.88 +/- 7.70 degrees (R = 138.13 +/ 7.06 degrees : L = 135.92 +/- 8.05 degrees ). Statistical analysis using the Z test for mean difference showed the medial angle was found to be higher in the right side of the scapula (mean difference of 2.214 +/- 1.152 degrees ), but the observed difference was not statistically significant (P > 0.05). The above findings have adjusted the scapula from three to four angles (lateral, superior, inferior, and medial) formed from four borders (lateral, superior, inferior, and superomedial and inferomedial). The medial angle because of its anatomical location was named "spinovertebral" angle, owing to its position at the scapulae spine, and located in medial proximity to the vertebra column. Conclusion. The medial angle (now referred to as the spinovertebral angle) of the right side of the scapula is wider than the left. The representation of the spinovertebral angle is very important, as the directional attachment of the levator scapulae may be altered if it increases or decreases greatly hence resulting in stiffness of the neck. At this point, it could be postulated that the scapular is quadrangular rather than triangular. PMID- 26523234 TI - Papillion-Lefevre Syndrome: Periodontists' Perspective. AB - Papillion-Lefevre Syndrome is a very rare disorder of autosomal recessive inheritance distinguished by palmar plantar hyperkeratosis and early onset of periodontitis affecting the dentition. Genetic studies have identified a mutation in the major gene locus of chromosome 11q14 with loss of function. Cathepsin C gene is to be responsible for Papillion-Lefevre Syndrome. The present case report describes a 13-year-old female, who visited the Department of Periodontology with the chief compliant of bleeding gums and loose teeth. She presented with the signs and symptoms of Papillion-Lefevre Syndrome. The patient had premature shedding of her deciduous dentition. On clinical examination, extraorally, the patient presented with persistent thickening, flaking, and scaling of the skin of palms and soles. Her intraoral examination revealed gingival inflammation, abscess formation, and periodontal pockets. Her intraoral radiographs showed bone loss involving the central incisors and molars. The patient underwent periodontal therapy and is under maintenance. PMID- 26523235 TI - Management of Refractory Noninsulinoma Pancreatogenous Hypoglycemia Syndrome with Gastric Bypass Reversal: A Case Report and Review of the Literature. AB - Background. Roux-en-Y gastric bypass (RYGB) is a commonly performed, effective bariatric procedure; however, rarely, complications such as postprandial hypoglycemia due to noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) may ensue. Management of refractory NIPHS is challenging. We report a case that was successfully treated with RYGB reversal. Case Report. A 58-year-old male with history of RYGB nine months earlier for morbid obesity presented for evaluation of postprandial, hypoglycemic seizures. Testing for insulin level, insulin antibodies, oral hypoglycemic agents, pituitary axis hormone levels, and cortisol stimulation was unrevealing. Computed tomography (CT) scan of the abdomen was unremarkable. A 72-hour fast was completed without hypoglycemia. Mixed meal testing demonstrated endogenous hyperinsulinemic hypoglycemia (EHH) and selective arterial calcium stimulation testing (SACST) was positive. Strict dietary modifications, maximal medical therapy, gastrostomy tube feeding, and stomal reduction failed to alleviate symptoms. Ultimately, he underwent laparoscopic reversal of RYGB. Now, 9 months after reversal, he has markedly reduced hypoglycemia burden. Discussion. Hyperfunctioning islets secondary to exaggerated incretin response and altered intestinal nutrient delivery are hypothesized to be causative in NIPHS. For refractory cases, there is increasing skepticism about the safety and efficacy of pancreatic resection. RYGB reversal may be successful. PMID- 26523236 TI - Cardiovascular Risk Factors in Subclinical Hypothyroidism: A Case Control Study in Nepalese Population. AB - Objectives. To assess cardiovascular risk factors in Nepalese population with subclinical hypothyroidism as compared to age and sex matched controls. Materials and Methods. A case control study was conducted among 200 subjects (100 subclinical hypothyroid and 100 euthyroid) at B.P. Koirala Institute of Health Sciences, Dharan, Nepal. Demographic and anthropometric variables including systolic and diastolic blood pressure (BP) were taken. Blood samples were assayed for serum free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), total cholesterol (TC), high density lipoprotein cholesterol (HDL C), low density lipoprotein cholesterol (LDL-C), and high sensitivity C reactive protein (hs-CRP). Results. Subclinical hypothyroid patients had significantly higher diastolic BP, total cholesterol, LDL cholesterol, and hs-CRP than controls. The odds ratio of having hypercholesterolemia (>200 mg/dL), low HDL cholesterol (<40 mg/dL), undesirable LDL-cholesterol (>100 mg/dL), high hs-CRP (>1 mg/L), and high diastolic BP (>80 mmHg) and being overweight (BMI >= 23 Kg/m(2)) in subclinical hypothyroidism was 2.29 (95% CI; 1.2-4.38, p = 0.011), 1.73 (95% CI; 0.82-3.62, p = 0.141), 3.04 (95% CI; 1.66-5.56, p < 0.001), 2.02 (95% CI; 1.12-3.64, p = 0.018), 3.35 (95% CI; 1.72-6.55, p < 0.001), and 0.9 (95% CI; 0.48-1.67, p = 0.753), respectively, as compared to controls. Conclusion. Subclinical hypothyroid patients are associated with higher risk for cardiovascular disease than euthyroid subjects. PMID- 26523237 TI - Understanding the Severity of Wrongdoing in Health Care Delivery and Research: Lessons Learned From a Historiometric Study of 100 Cases. AB - BACKGROUND: Wrongdoing among physicians and researchers causes myriad problems for patients and research participants. While many articles have been published on professional wrongdoing, our literature review found no studies that examined the rich contextual details of large sets of historical cases of wrongdoing. METHODS: We examined 100 cases of wrongdoing in healthcare delivery and research using historiometric methods, which involve the statistical description and analysis of coded historical narratives. We used maximum variation, criterion based sampling to identify cases involving 29 kinds of wrongdoing contained in a taxonomy of wrongdoing developed for the project. We coded the presence of a variety of environmental and wrongdoer variables and rated the severity of wrongdoing found in each case. This approach enabled us to (a) produce rich descriptions of variables characterizing cases; (b) identify factors influencing the severity of wrongdoing; and (c) test the hypothesis that professional wrongdoing is a unified, relatively homogenous phenomenon such as "organizational deviance." RESULTS: Some variables were consistently found across cases (e.g., wrongdoers were male and cases lasted more than 2 years), and some variables were consistently absent across cases (e.g., cases did not involve wrongdoers who were mistreated by institutions or penalized for doing what is right). However, we also found that some variables associated with wrongdoing in research (such as ambiguous legal and ethical norms) differ from those associated with wrongdoing in healthcare delivery (such as wrongdoers with a significant history of professional misbehavior). CONCLUSIONS: Earlier intervention from colleagues might help prevent the pattern we observed of repeated wrongdoing across multiple years. While some variables characterize the vast majority of highly publicized cases of wrongdoing in healthcare delivery and research-regardless of the kind of wrongdoing-it is important to examine and compare sets of relatively homogenous cases in order to identify factors associated with wrongdoing. PMID- 26523238 TI - Facile Protocol for Water-Tolerant "Frustrated Lewis Pair"-Catalyzed Hydrogenation. AB - Despite rapid advances in the field of metal-free, "frustrated Lewis pair" (FLP) catalyzed hydrogenation, the need for strictly anhydrous reaction conditions has hampered wide-scale uptake of this methodology. Herein, we report that, despite the generally perceived moisture sensitivity of FLPs, 1,4-dioxane solutions of B(C6F5)3 actually show appreciable moisture tolerance and can catalyze hydrogenation of a range of weakly basic substrates without the need for rigorously inert conditions. In particular, reactions can be performed directly in commercially available nonanhydrous solvents without subsequent drying or use of internal desiccants. PMID- 26523239 TI - Longitudinal Associations among Impulsivity, Friend Substance Use, and Adolescent Substance Use. AB - Adolescent substance use is an increasing problem in the United States, and some researchers posit a bidirectional relation between adolescent substance use and the personality trait of impulsivity (e.g., Quinn, Stappenbeck, & Fromme, 2011). Friend substance use has been shown to be a powerful predictor of adolescent substance use, with prior research suggesting a bidirectional relation between adolescent substance use and friend substance use (e.g., Simons-Morton & Chen, 2006). Extant literature has not tested the bidirectional relation between adolescent substance use and impulsivity with longitudinal data nor has it examined this relation while considering the bidirectional relation with the social context factor of friend substance use. Using three waves of longitudinal data, we tested if there was a bidirectional relation between adolescent substance use and impulsivity while also examining the influences of friend substance use. Participants were 131 adolescents (male = 55%, mean age = 13 years at Wave 1). We tested nested models and examined whether adding equality constraints degraded the model fit using a Wald test. Results of structural equation modeling indicated that, after controlling for baseline levels of substance use, impulsivity predicted adolescent and friend substance use over time, whereas adolescent and friend substance use did not predict impulsivity. Adolescents with substance using friends were likely to increase their own substance use. The findings imply that aiming at both improving adolescents' ability to regulate impulsivity and deterring associations with friends who are using substances is essential for prevention and intervention efforts against substance use development in adolescents. PMID- 26523240 TI - Hallmarks of HIV-1 pathogenesis are modulated by Nef's Secretion Modification Region. AB - CD4+ T cell depletion and immune activation are hallmarks of HIV infection. Despite extensive studies, the mechanisms underlying immune modulation remain elusive. HIV-1 Nef protein is secreted in exosomes from infected cells and is abundant in the plasma of HIV+ individuals. Exosomal Nef (exNef) was also shown to induce apoptosis in bystander CD4+ T cells. We hypothesized that exNef contributes to HIV pathogenesis. A HIV-1 NL4-3 virus containing alanine substitutions in the secretion modification region (SMR; amino acids 66 to 70; HIVNefsmr5a) was developed. Nef protein containing this modified SMR was shown to be deficient in exNef secretion in nef-transfected cells. Using both HIV-1 NL4-3 wild type (HIVwt) and HIVNefsmr5a, correlates of pathogenesis were evaluated in cell-lines, human peripheral blood mononuclear cells, and humanized NOD-RAG1-/- IL2r-/- double mutant (NRG) mice. Disruption of the SMR did not affect viral replication or exNef secretion from infected cell cultures as compared with nef transfected cells. However, T cell apoptosis was reduced in HIVNefsmr5a infected cell cultures and CD4+ T cell depletion was reduced in the spleen and peripheral blood of similarly infected NRG mice. Inflammatory cytokine release was also decreased in the sera of HIVNefsmr5a infected mice relative to HIVwt infected controls. These findings demonstrate the importance of Nef and the SMR motif in HIV pathogenesis and suggest a potential role for exNef in HIV-driven immune modulation. PMID- 26523241 TI - Recombinant Hemagglutinin and Virus-Like Particle Vaccines for H7N9 Influenza Virus. AB - Cases of H7N9 human infection were caused by a novel, avian-origin H7N9 influenza A virus that emerged in eastern China in 2013. Clusters of human disease were identified in many cities in China, with mortality rates approaching 30%. Pandemic concerns were raised, as historically, influenza pandemics were caused by introduction of novel influenza A viruses into immunologically naive human population. Currently, there are no approved human vaccines for H7N9 viruses. Recombinant protein vaccine approaches have advantages in safety and manufacturing. In this review, we focused on evaluation of the expression of recombinant hemagglutinin (rHA) proteins as candidate vaccines for H7N9 influenza, with the emphasis on the role of oligomeric and particulate structures in immunogenicity and protection. Challenges in preparation of broadly protective influenza vaccines are discussed, and examples of broadly protective vaccines are presented including rHA stem epitope vaccines, as well as recently introduced experimental multi-HA VLP vaccines. PMID- 26523242 TI - Synthesis of Miktoarm Branched Conjugated Copolymers by ROMPing In and Out. AB - Architecture represents an underutilized yet promising control element in polymer design due to the challenging synthesis of compositionally varied branched copolymers. We report the one-pot synthesis of miktoarm branched polymers by ring opening metathesis polymerization. In this work, we graft to and from telechelic poly(3-hexylthiophene), which is end-capped by oxime click chemistry, using various norbornene monomers. The self-assembly of the resulting miktoarm H-shaped conjugated polymers is studied in solution and in the solid state. A dual stimuli responsive miktoarm polymer is prepared which displays pH-switchable lower critical solution temperature and fluorescence. PMID- 26523243 TI - Exercise Training and Insulin Resistance: A Current Review. AB - There is a general perception that increased physical activity will improve glucose homeostasis in all individuals. While this is an attractive concept, this conclusion may be overly simplistic and even misleading. The topic was reviewed extensively over 30 years ago and it was concluded that acute exercise enhances glucose uptake. However, in some cases the chronic influence of interventions utilizing exercise may have little effect on glucose metabolism. Moreover, insulin resistance often returns to near baseline levels within a couple of days following cessation of the exercise bout; leaving the overall effectiveness of the intervention in question. Since improving glucose homeostasis should be the focal endpoint of any intervention designed to mitigate the overwhelming degree of insulin resistance in individuals at risk for metabolic disease, it is essential to evaluate the key components of a successful approach. PMID- 26523244 TI - Initial Evaluation of a Titration Appliance for Temporary Treatment of Obstructive Sleep Apnea. AB - BACKGROUND: Custom oral appliances that adjustably advance the mandible provide superior outcomes when treating patients with moderate or severe sleep apnea. Custom appliances, however, are expensive, must be fitted by a dentist, and the likelihood of successful outcomes are difficult to predict. An inexpensive trial appliance, if proven efficacious, might be used to predict custom appliance outcomes or to provide temporary therapeutic benefit. OBJECTIVE: The aim of this initial study was to assess the treatment efficacy of a novel titration oral appliance with that of an optimized custom appliance. METHODS: Seventeen patients, treated with a custom oral appliance for at least one year, successfully completed a three-night home sleep test. The baseline obstructive sleep apnea severity was established on Night 1 with seven patients exhibiting severe, six moderate and four mild apnea/hypopnea indexes. Patients were randomly assigned to wear their custom appliance or the titration appliance on Nights 2 and 3. RESULTS: Significant reductions in the mean overall and supine apnea indexes (p < 0.05), and the overall (p < 0.01) and supine (p < 0.05) apnea/hypopnea indexes were observed for both the titration and custom appliances. The proportion of patients who exhibited at least a 50% reduction in the overall apnea index and supine apnea/hypopnea were similar for the titration and custom appliance (~60%). The custom appliance reduced the overall apnea/hypopnea index by 50% in a greater proportion of the patients compared to the titration appliance (77% vs. 53%). The titration appliance significantly reduced the degree of hypoxic exposure across sleep disordered breathing events overall (p < 0.05) and supine (p < 0.01). Patients found their custom appliance was more comfortable than the titration appliance, but preferred the titration appliance to no therapy. CONCLUSION: The titration appliance may be useful in assessing oral appliance treatment efficacy. When set to 70% of maximum protrusion, the titration appliance may provide immediate, temporary therapeutic benefit. PMID- 26523245 TI - Homocomposites of Polylactide (PLA) with Induced Interfacial Stereocomplex Crystallites. AB - The demand for "green" degradable composite materials increases with growing environmental awareness. The key challenge is achieving the preferred physical properties and maintaining their eco-attributes in terms of the degradability of the matrix and the filler. Herein, we have designed a series of "green" homocomposites materials based purely on polylactide (PLA) polymers with different structures. Film-extruded homocomposites were prepared by melt-blending PLA matrixes (which had different degrees of crystallinity) with PLLA and PLA stereocomplex (SC) particles. The PLLA and SC particles were spherical and with 300-500 nm size. Interfacial crystalline structures in the form of stereocomplexes were obtained for certain particulate-homocomposite formulations. These SC crystallites were found at the particle/matrix interface when adding PLLA particles to a PLA matrix with d-lactide units, as confirmed by XRD and DSC data analyses. For all homocomposites, the PLLA and SC particles acted as nucleating agents and enhanced the crystallization of the PLA matrixes. The SC particles were more rigid and had a higher Young's modulus compared with the PLLA particles. The mechanical properties of the homocomposites varied with particle size, rigidity, and the interfacial adhesion between the particles and the matrix. An improved tensile strength in the homocomposites was achieved from the interfacial stereocomplex formation. Hereafter, homocomposites with tunable crystalline arrangements and subsequently physical properties, are promising alternatives in strive for eco-composites and by this, creating materials that are completely degradable and sustainable. PMID- 26523246 TI - Oral Mucositis Induced By Anticancer Therapies. AB - Oral mucositis induced by conventional cytotoxic cancer therapies is a common and significant clinical problem in oncology. Mucositis symptoms, which include severe pain, may lead to dose reductions and unplanned interruptions of chemotherapy and/or radiotherapy, and often affect patients' quality of life. In addition, ulcerative mucositis represents a risk factor for local or systemic infectious complications that may be life-threatening in immunosuppressed patients. The development of biologically based targeted cancer therapies, which aim to block the growth, spread, and survival of tumors by interfering with specific molecular targets, may have reduced mucosal injury, but did not eliminate it. This article will review the epidemiology, pathobiology, and management of oral mucositis associated with conventional cytotoxic therapies for malignant diseases and will briefly summarize emerging information on oral mucosal injury associated with targeted therapies. Considerations for future research aimed at the development of more efficient and effective supportive care approaches will be presented, with emphasis on the contribution of dental researchers and clinicians in these efforts. PMID- 26523247 TI - Declining Caries Trends: Are We Satisfied? AB - WHO data suggest that all over the world the prevalence of caries has declined at the end of the previous and in the first decade of the present century. This decline started wherever the use of effective fluoride toothpaste became commonplace. Even though the decline is considerable with a 90 % reduction in DMFT for 12-year-olds in Western Europe and the USA, caries still affects 60-90 % of the children throughout the world. In the high- and middle-income countries, the nature of caries has changed from a rapid progressing disease of childhood to a slowly progressing disease throughout adulthood and even old age. However, throughout the world, the circumstances for caries differ, e.g., low-income countries experience more caries with higher sugar consumption, while between high-income countries this correlation is reversed. In high-income countries, fluoride is widely used and preventive programs in dental offices are in place. These programs, if effective, may not be a realistic option in low-income countries. In order to reduce caries in the world even further, the use of effective and affordable fluoride toothpaste should be encouraged and enabled. PMID- 26523248 TI - Induced Pluripotent Stem Cells and Periodontal Regeneration. AB - Periodontitis is a chronic inflammatory disease which leads to destruction of both the soft and hard tissues of the periodontium. Tissue engineering is a therapeutic approach in regenerative medicine that aims to induce new functional tissue regeneration via the synergistic combination of cells, biomaterials, and/or growth factors. Advances in our understanding of the biology of stem cells, including embryonic stem cells and mesenchymal stem cells, have provided opportunities for periodontal tissue engineering. However, there remain a number of limitations affecting their therapeutic efficiency. Due to the considerable proliferation and differentiation capacities, recently described induced pluripotent stem cells (iPSCs) provide a new way for cell-based therapies for periodontal regeneration. This review outlines the latest status of periodontal tissue engineering and highlights the potential use of iPSCs in periodontal tissue regeneration. PMID- 26523249 TI - Simultaneous Liver-Kidney Transplantation. AB - In 2014, simultaneous liver kidney transplants (SLK) accounted for 8.2 % of all liver transplants performed in the USA. Prior to introduction of the model of end stage liver disease (MELD) system, SLK accounted for 2.5 % in 2001 and only 1.7 % in 1990. Transplant centers have struggled to balance the moral and ethical aspects of SLK in the setting of organ scarcity with an algorithm that best qualifies patients for such treatment options. Few centers have even ventured into DCD territory for SLK. Advancement in immunosuppression protocols and treatment of HCV and HIV have impacted SLK over the years. Simulation modeling has allowed us to analyze the future impact of our decisions that are made today. All of these advancements have given, and will continue to give new perspectives to SLK. The purpose of this review article is to highlight these advances and bring to light the studies that have made this transplant option successful. PMID- 26523250 TI - Clinical and Angiographic Outcomes of Aneurysms Treated with Two Self-expanding Stent-assisted Coiling Systems: A Comparison of Solitaire AB and Enterprise VRD Stents. AB - OBJECTIVE: The purpose of this study was to compare clinical findings and outcomes of Enterprise and Solitaire stent-assisted coiling (SAC). MATERIALS AND METHODS: Between January 2012 and March 2014, 86 patients (mean age, 60.3 years) harboring 89 aneurysms were treated with Enterprise (n = 57) or Solitaire (n = 32) SAC. The patients' demographics, angiographic results, and clinical outcomes were reviewed retrospectively. RESULTS: There were no cases of stent navigation, deployment failure, arterial dissection, or intraoperative aneurysmal rupture. Angiographic follow-up imaging was available for 86 (96.6%) aneurysms (Enterprise group, n = 55; Solitaire group, n = 31). Immediate postoperative and follow-up angiographic results showed no flow or only minimal flow into the neck in 83% (Enterprise group, 77.2%; Solitaire group, 93.8%) and 95.3% (Enterprise group, 92.7%; Solitaire group, 100%) of SAC-treated aneurysms, respectively. Both stent groups showed good immediate postoperative and follow-up clinical outcomes. Excepting 2 cases, all patients achieved modified Rankin Scale scores of 0. Coil loop or tail protrusion into the parent artery was observed in 17 (29.8%) and 7 (21.9%) cases in the Enterprise and Solitaire groups, respectively. No statistically significant difference in terms of angiographic results or clinical outcomes was observed between the groups. CONCLUSION: Excellent and comparable clinical and angiographic outcomes for wide-neck intracranial aneurysms were achieved using both stents. Because of its higher radial strength and better vessel wall apposition, we cautiously propose that the Solitaire stent may be more effective for SAC of aneurysms harboring a large or severe tortuous parent artery. PMID- 26523251 TI - Clinical Variables Correlated with Numbers of Intra-arterial Nimodipine Infusion in Patients with Medically Refractory Cerebral Vasospasm. AB - OBJECTIVE: The objective of this study was to find out the clinical variables correlated with repeated intra-arterial (IA) nimodipine infusions in patients with medically refractory cerebral vasospasm (CV) following subarachnoid hemorrhage (SAH). MATERIALS AND METHODS: During the 36 months between January 2011 and December 2013, 275 patients were treated at our institute for SAH due to a ruptured intracranial aneurysm. Of the 275 patients, 26 patients (9.5%) met the inclusion criteria. For each patient, a retrospective review of their medical records was conducted. RESULTS: Eleven patients underwent a single IA nimodipine infusion and 15 patients underwent more than two IA nimodipine infusions. Multiple IA nimodipine infusion patients had poor improvement (2 of 15 patients, 13.3%) in Glasgow coma scale (GCS) scores after the first IA nimodipine infusion compared to patients of single IA nimodipine infusion (6 of 11 patients, 54.6%) (p = 0.038). The mean middle cerebral artery (MCA) Lindegaard ratio of multiple IA nimodipine infusion patients was 4.3 +/- 1.1 after the first IA nimodipine infusion (p = 0.039). In multiple IA nimodipine infusion patients, CV occurred more often bilaterally (p = 0.035) and distally (p = 0.001). More vessel segments were affected in multiple IA nimodipine infusion patients (3.1 +/- 1.0) (p < 0.001). CONCLUSION: The following factors correlated with multiple IA nimodipine infusions: 1) no improvement in GCS after the IA nimodipine infusion; 2) no decrease of MCA velocity on transcranial doppler over 50 cm/s or Lindegaard ratio over 4.3 after the IA nimodipine infusion; 3) distal, bilateral, or diffuse involvement of CV. PMID- 26523253 TI - Localization and Treatment of Unruptured Paraclinoid Aneurysms: A Proton Density MRI-based Study. AB - OBJECTIVE: The purpose of this study was to evaluate the usefulness of proton density magnetic resonance (PD MR) imaging for localization of paraclinoid internal carotid artery aneurysms. MATERIALS AND METHODS: From April 2014 to April 2015, 76 unruptured paraclinoid aneurysms in 66 patients were evaluated using PD MR and angiography (CT/MR angiography or digital subtraction angiography). The locations (extradural, transdural, intradural) in relation to the distal dural ring (DDR) and projection (superior, inferior/posterior, medial, lateral) of the aneurysms were assessed and compared. RESULTS: The most common location of paraclinoid aneurysms was extradural (n = 48, 63.2%), followed by intradural (n = 18, 23.7%), and transdural (n = 10, 13.2%). In the medial projection group (n = 49, 64.5%), 31 were extradural (63.3%), 5 were transdural (10.2%), and 13 were intradural (26.5%). In the inferior/posterior projection group (n = 19, 25.0%), there were 14 extradural (73.7%), 4 transdural (21.0%), and 1 intradural (5.3%). In the superior (n = 4, 5.3%)/lateral (n = 4, 5.3%) projection groups, there were 0/3 extradural (0/75.0%), 1/0 transdural (25.0/0%), and 3/1 intradural (75.0/25.0%). CONCLUSION: PD MR showed sufficient contrast difference to distinguish paraclinoid aneurysms from surrounding dural structures. PMID- 26523252 TI - Endovascular Treatment for Acute Ischemic Stroke Patients over 80 Years of Age. AB - OBJECTIVE: We evaluated the effect of endovascular treatment (EVT) for acute ischemic stroke in patients over 80 years of age. MATERIALS AND METHODS: The records of 156 acute stroke patients aged over 80 years who were considered as candidates for EVT were analyzed. Fifty-six patients (35.9%, EVT group) underwent EVT and 100 patients (64.1%, non-EVT group) did not. Outcomes, in terms of functional outcomes and rates of symptomatic hemorrhage, in-hospital morbidity and mortality, were compared between groups. Each comparison was adjusted for age, time from onset, initial National Institute of Health Stroke Scale, and pre stroke modified Rankin Scale (mRS). RESULTS: More patients in the EVT group achieved good outcomes (mRS score of 0-2) at 3 months (35.7% vs. 11.0%, adjusted odds ratio [OR] 4.779 [95% confidence interval 1.972-11.579], p = 0.001) and 12 months (35.7% vs. 14.0%, adjusted OR 3.705 [1.574-8.722], p = 0.003) after stroke. During admission, rates of hospital-acquired infection including pneumonia (12.5% vs. 29.0%, adjusted OR 0.262 [0.098-0.703], p = 0.008) and urinary tract infection (16.0% vs. 34.0%, adjusted OR 0.256 [0.099-0.657], p = 0.005) were significantly lower in the EVT group. More symptomatic hemorrhages (10.7% vs. 2.0%, adjusted OR 6.859 [1.139-41.317], p = 0.036) occurred in the EVT group, but no significant difference was observed in in-hospital mortality rate (12.5% vs. 8.0%, adjusted OR 1.380 [0.408-4.664], p = 0.604). CONCLUSION: EVT improved functional outcome and reduced the risk of hospital-acquired infections in acute stroke patients over 80 years of age without increasing the risk of in hospital mortality, although symptomatic hemorrhage occurred more frequently after EVT. PMID- 26523254 TI - Management and Outcome of Spontaneous Cerebellar Hemorrhage. AB - OBJECTIVE: Spontaneous cerebellar hemorrhage (SCH) is less common than supratentorial intracerebral hemorrhage. This study investigated the treatment of SCH and the relation between its clinical and radiological manifestation and outcome. MATERIALS AND METHODS: We presented a SCH management protocol in our institute and analyzed the clinical and radiological findings in 41 SCH patients. The outcomes of each method (surgery and conservative treatment) were compared among patients with initial Glasgow Coma Scale (GCS) score of 9-13 and hematoma volume greater than 10 mL. RESULTS: Two (4.9%), 16 (39%), and 23 (56.1%) patients had an initial GCS score of 3-8, with 3-8, 9-13, and 14-15, respectively. Initial GCS score showed significant correlation with Glasgow Outcome Scale (GOS) score (p = 0.005). The mean largest hematoma diameter was 3.2 +/- 1.5 cm, and the mean volume was 11.0 +/- 11.5 mL. Both of them showed significant inverse correlation with GOS score (p < 0.001). Among patients with an initial GCS score of 9-13 and hematoma volumes greater than 10 mL, 3 (50%) had good outcome and 3 (50%) had poor outcome in the surgical, and all of those in the conservative treatment group had poor outcomes. The outcome distribution differed significantly in the surgical and conservative groups (p = 0.030). CONCLUSION: Initial GCS score and largest hematoma diameter and volume on brain computed tomography are important determinants of outcome in SCH patients. The surgery group showed better outcome than the conservative treatment group among those with an intermediate neurological status and large hematomas. PMID- 26523255 TI - Necessity of Surgical Site Closed Suction Drain for Pterional Craniotomy. AB - OBJECTIVE: The aim of this study was to assess the benefit of using a prophylactic surgical site closed suction drain in pterional craniotomy. MATERIALS AND METHODS: A retrospective review was conducted on 607 consecutive patients who underwent a pterional craniotomy for treatment of intracranial anterior circulation aneurysms over a 5-year period. Between January 2000 and December 2004, 607 patients were divided into two groups, those who had a prophylactic suction drain during closure of the surgical site (drain group, DG) and those who did not (non-drain group, NDG). Head computed tomography (CT) was taken routinely on postoperative day (POD) 1, 7, and 14. Patients' demographics, incidence of surgical site complications, and courses of surgical site healing which were evaluated radiologically by the thickness of the surgical site myocutaneous layer, were analyzed between DG and NDG. RESULTS: Patients' demographics and characteristics did not differ significantly between the two groups. The head CT showed that the degree of changes in the postoperative surgical site thickness was 148% at POD 1, 209% at POD 7, and 198% at POD 14 in DG, and 118% at POD 1, 152% at POD 7, and 158% at POD 14 in NDG compared to the preoperative value. Postoperative surgical site hematoma was 7.9% (22/274) in DG and 2.4% (8/333) in NDG. CONCLUSION: Prophylactic use of an epidural and/or subgaleal closed suction drain does not appear to be necessary for prevention of postoperative surgical site hematoma as well as for promotion of surgical site healing in pterional craniotomy. PMID- 26523256 TI - An Unruptured Cerebral Aneurysm at the Origin of the Duplicated Middle Cerebral Artery. AB - A variety of cerebral vascular anomalies are widely applied, however anomalies of the middle cerebral artery (MCA) are relatively infrequent. The duplicated MCA (DMCA) is a MCA anomaly. Aneurysm arising from the origin of the DMCA is rare. Cerebral angiography in a 61-year-old female demonstrated a small (about 3 mm) saccular aneurysm located at the origin of the DMCA in the anterior direction. Considering the unusual location, the lesion was treated, regardless of the size. Aneurysmal characteristics of a broad neck and small size limited the endovascular approach, necessitating open surgery. Her postoperative course was uneventful and postoperative angiography showed complete obliteration of the aneurysm. The patient was discharged without neurologic deficit. PMID- 26523257 TI - Double Stent Assist Coiling of Ruptured Large Saccular Aneurysm in Proximal Basilar Artery Fenestration. AB - Basilar artery fenestration is infrequent and even rarer in association with a large aneurysm. With proximity to brain stem and vital perforators, endovascular coiling can be considered first. If the large ruptured aneurysm with a wide neck originated from fenestra of the proximal basilar artery and the fenestration loop has branches of posterior circulation, therapeutic consideration should be thorough and fractionized. We report endovascular therapeutic details for a case of a ruptured large saccular aneurysm in proximal basilar artery fenestration. PMID- 26523258 TI - Huge Intramural Hematoma in a Thrombosed Middle Cerebral Artery Aneurysm: A Case Report. AB - We describe a case of a huge intramural hematoma in a thrombosed middle cerebral artery aneurysm. A 47-year-old female patient with liver cirrhosis and thrombocytopenia presented to the neurosurgical unit with a 5-day history of headache and cognitive dysfunction. Magnetic resonance imaging and computed tomography of the brain showed a thrombosed aneurysm located in the right middle cerebral artery with a posteriorly located huge intramural hematoma mimicking an intracerebral hematoma. Imaging studies and cerebrospinal fluid analysis showed no evidence of subarachnoid hemorrhage. Angiography showed a partially thrombosed aneurysm at the origin of the right anterior temporal artery and an incidental aneurysm at the bifurcation of the right middle cerebral artery. Both aneurysms were embolized by coiling. After embolization, the thrombosed aneurysmal sac and intramural hematoma had decreased in size 4 days later and almost completely disappeared 8 months later. This is the first reported case of a nondissecting, nonfusiform aneurysm with a huge intramural hematoma, unlike that of a dissecting aneurysm. PMID- 26523259 TI - Reversible Cerebral Vasoconstriction Syndrome and Posterior Reversible Encephalopathy Syndrome Presenting with Deep Intracerebral Hemorrhage in Young Women. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is a group of syndromes characterized by reversible segmental constriction of cerebral arteries. Posterior reversible encephalopathy syndrome (PRES) is another clinical radiologic syndrome characterized by reversible, posterior-predominant brain edema. Although the exact causes of these reversible syndromes are poorly understood, these entities may share some common pathophysiologic elements leading to hemorrhagic strokes and rarely, deep intracerebral hemorrhage (ICH). Recent studies have suggested that endothelial dysfunction is a common pathophysiologic factor associated with these syndromes. We report on two young female patients who presented with deep ICH and were later diagnosed as RCVS and PRES. Both patients suffered from vasoconstriction and delayed ischemic stroke. Early detection of distinguishing clinical-radiologic features associated with these reversible syndromes and removing triggers would facilitate successful treatment with no complications. PMID- 26523260 TI - Spontaneous Occluded Anterior Communicating Artery Aneurysm during Coil Embolization Treated with One Coil Insertion into Remaining Stump. AB - Spontaneous thrombosis of a ruptured aneurysm during coil embolization is a rare event, and some reports on recanalization of a spontaneous occluded ruptured aneurysm have been published. We report on a case of a 54-year-old male who presented with a subarachnoid hemorrhage due to rupture of a small aneurysm of the anterior communicating artery (ACoA). Cerebral angiography confirmed the presence of the ACoA aneurysm, but, during coil embolization, the aneurysm was near completely occluded with a remaining small neck. A small coil was inserted into the remaining stump of the neck to prevent recanalization, and the angiographic result at 1 year after coil embolization showed complete obliteration of the aneurysm. PMID- 26523261 TI - Stent-assisted Coil Embolization of Petrous ICA in a Teenager with Neurofibromatosis. AB - We herein report on a patient with a cerebral aneurysm located at the petrous portion of the internal carotid artery (ICA). An 18-year-old male, previously diagnosed with neurofibromatosis, was referred to our emergency service complaining of severe headache, pulsatile tinnitus, nausea, and vomiting which occurred suddenly. Neuro-radiological studies including computed tomography and magnetic resonance imaging of the cerebral artery showed a large aneurysm arising from the petrous segment of the left ICA. He was treated with a neuro interventional technique such as intra-arterial stenting and coil embolization for the aneurysm. Several days after the interventional treatment, his symptoms were resolved gradually except for a mild headache. Symptomatic unruptured aneurysm at the petrous portion of the ICA is rare, and our patient was treated successfully using a neuro-intervention technique. Therefore, we describe a case of a petrous aneurysm treated with endovascular coils without compromising the ICA flow, and review the literature. PMID- 26523262 TI - Unusual Presentation of Cerebral Cavernous Malformation. AB - Cerebral cavernous malformations (CMs) are vascular malformations of the central nervous system, which can be detected in the absence of any clinical symptoms. Nodules and cysts with mixed signal intensity and a peripheral hemosiderin rim are considered brain magnetic resonance imaging (MRI) findings typical of CMs. A 48-year-old man was admitted to our hospital because of abnormal MRI findings without significant neurological symptoms. A cyst with an internal fluid-fluid level was found in the left basal ganglia on the initial brain MRI. We decided to observe the natural course of the asymptomatic lesion with serial MRI follow-up. On MRI at the 5-month follow-up, the cystic mass was enlarged and showed findings consistent with those of cystic CM. Surgical resection was performed and the pathological diagnosis was CM. Our experience suggests that the initial presentation of a CM can be a pure cyst and neurosurgeons should consider the likelihood of CMs in cases of cystic cerebral lesions with intracystic hemorrhage. PMID- 26523263 TI - Visual Field Defect after Transfrontal Sinus Approach of Ethmoidal Dural Arteriovenous Fistulas (eDAVFs) : Experience and Complication of Transfrontal Sinus Approach. AB - The approach to ethmoidal dural arteriovenous fistulas (eDAVFs) is usually via a pterional or a frontal craniotomy. However, the transfrontal sinus is a more direct route to the fistula. The aim of this report is to describe our experience and associated complications occurring as a result of flow diversion in the transfrontal sinus approach for eDAVFs. In this report, we discuss visual field defects occurring after a transfrontal sinus operation. This approach is most direct for surgical treatment of an eDAVF, enabling preservation of neural structures with minimal to no negative effects on the brain. Although the surgery was uneventful, the patient presented with a left side visual field defect. An ophthalmologic exam detected an arterial filling delay in the choroidal membrane and ischemic optic neuropathy was highly suspected. The patient is currently recovering under close observation with no special treatment. The transfrontal sinus approach provides the most direct and shortest route for eDAVFs, while minimizing intraoperative bleeding. However, complications, such as visual field defects may result from a sudden flow diversion or eyeball compression due to scalp traction. PMID- 26523264 TI - From DCPD to NTCP: the long journey towards identifying a functional hepatitis B virus receptor. AB - Hepatitis B virus (HBV) is the prototype of hepatotropic DNA viruses (hepadnaviruses) infecting a wide range of human and non-human hosts. Previous studies with duck hepatitis B virus (DHBV) identified duck carboxypeptidase D (dCPD) as a host specific binding partner for full-length large envelope protein, and p120 as a binding partner for several truncated versions of the large envelope protein. p120 is the P protein of duck glycine decarboxylase (dGLDC) with restricted expression in DHBV infectible tissues. Several lines of evidence suggest the importance of dCPD, and especially p120, in productive DHBV infection, although neither dCPD nor p120 cDNA could confer susceptibility to DHBV infection in any cell line. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a binding partner for the N-terminus of HBV large envelope protein. Importantly, knock down and reconstitution experiments unequivocally demonstrated that NTCP is both necessary and sufficient for in vitro infection by HBV and hepatitis delta virus (HDV), an RNA virus using HBV envelope proteins for its transmission. What remains unclear is whether NTCP is the major HBV receptor in vivo. The fact that some HBV patients are homozygous with an NTCP mutation known to abolish its receptor function suggests the existence of NTCP-independent pathways of HBV entry. Also, NTCP very likely mediates just one step of the HBV entry process, with additional co-factors for productive HBV infection still to be discovered. NTCP offers a novel therapeutic target for the control of chronic HBV infection. PMID- 26523265 TI - Personalized management of cirrhosis by non-invasive tests of liver fibrosis. AB - Owing to the high prevalence of various chronic liver diseases, cirrhosis is one of the leading causes of morbidity and mortality worldwide. In recent years, the development of non-invasive tests of fibrosis allows accurate diagnosis of cirrhosis and reduces the need for liver biopsy. In this review, we discuss the application of these non-invasive tests beyond the diagnosis of cirrhosis. In particular, their role in the selection of patients for hepatocellular carcinoma surveillance and varices screening is highlighted. PMID- 26523266 TI - Managing alcoholic liver disease. AB - Alcoholic liver disease continues to be a significant cause of liver-related morbidity and mortality throughout the world. A number of diagnostic and prognostic models have been developed in the management of this condition, although specific roles for liver biopsy still remain particularly in the setting of alcoholic hepatitis. Despite a large number of recent treatment trials, the ideal pharmacotherapy approach remains undefined. Most essential is the supportive care and focus on abstinence and nutrition. Owing in part to a great deal of attention from governmental funding sources, a number of new treatment approaches are undergoing rigorous evaluation, hopefully providing future treatment options in this very severe condition. PMID- 26523267 TI - The mutational landscape of hepatocellular carcinoma. AB - The development of hepatocellular carcinoma (HCC) is a complex process, and HCC arises from the accumulation of multiple genetic alterations leading to changes in the genomic landscape. Current advances in genomic technologies have revolutionized the search for genetic alterations in cancer genomes. Recent studies in which all coding exons in HCC were sequenced have shed new light on the genomic landscape of this malignant disease. Catalogues of these somatic mutations and systematic analysis of catalogued mutations will lead us to uncover candidate HCC driver genes, although further functional validation is needed to determine whether these genes play a causal role in the development of HCC. This review provides an overview of previously known oncogenes and new oncogene candidates in HCC that were uncovered from recent exome or whole-genome sequencing studies. This knowledge provides direction for future personalized treatment approaches for patients with HCC. PMID- 26523268 TI - Static and dynamic prognostic factors for hepatitis-B-related acute-on-chronic liver failure. AB - BACKGROUND/AIMS: Hepatitis-B-related acute-on-chronic liver failure has a poor prognosis. However, the advent of potent oral antiviral agents means that some patients can now recover with medical treatment. We aimed to identify the prognostic factors for hepatitis-B-related acute-on-chronic liver failure including the initial as well as the dynamically changing clinical parameters during admission. METHODS: Sixty-seven patients were retrospectively enrolled from 2003 to 2012 at Samsung Medical Center. The patients were classified into three categories: Recovery group (n=23), Liver transplantation group (n=28), and Death group (n=16). The Liver transplantation and Death groups were combined into an Unfavorable prognosis group. We analyzed the prognostic factors including the Model for End-Stage Liver Disease (MELD) scores determined at 3-day intervals. RESULTS: A multivariable analysis showed that the unfavorable prognostic factors were a high initial MELD score (>=28) (odds ratio [OR] =6.64, p=0.015), moderate to-severe ascites at admission (OR=6.71, P=0.012), and the aggravation of hepatic encephalopathy during hospitalization (>=grade III) (OR=15.41, P=0.013). Compared with the baseline level, significant reductions in the MELD scores were observed on the 7th day after admission in the Recovery group (P=0.016). CONCLUSIONS: Dynamic changes in clinical parameters during admission are useful prognostic factors for hepatitis-B-related acute-on-chronic liver failure. PMID- 26523269 TI - Entecavir plus tenofovir versus entecavir plus adefovir in chronic hepatitis B patients with a suboptimal response to lamivudine and adefovir combination therapy. AB - BACKGROUND/AIMS: We compared the efficacies of entecavir (ETV) plus tenofovir (TDF) and ETV plus adefovir (ADV) in chronic hepatitis B (CHB) patients with genotypic resistance to lamivudine (LAM) who showed a suboptimal response to LAM and ADV combination therapy. METHODS: We reviewed 63 CHB patients with genotypic resistance to LAM who showed a suboptimal response to LAM and ADV combination therapy. Among these patients, 30 were treated with ETV + ADV and 33 were treated with ETV + TDF for 12 months. RESULTS: The only baseline characteristic that differed significantly between the two groups was the ETV resistance profile. The rate of a virologic response [serum hepatitis B virus (HBV) DNA level of <20 IU/mL] was significant higher for ETV+TDF than for ETV+ADV over 12 months (57.6% vs. 23.3%, P=0.006, at 6 months; 84.8% vs. 26.7%, P<0.001, at 12 months). The probability of a virologic response was significantly increased in ETV+TDF (P<0.001, OR=54.78, 95% CI=7.15-419.54) and decreased in patients with higher baseline viral loads (P=0.001, OR=0.18, 95% CI=0.07-0.50) in multivariate analysis. No serious adverse event occurred during the study period. CONCLUSIONS: In patients with CHB who showed a suboptimal response to LAM and ADV combination therapy, ETV+TDF was superior to ETV+ADV in achieving a virologic response regardless of the HBV resistance profile. Further large-scale and long-term follow-up prospective studies are needed to explain these results. PMID- 26523270 TI - Preference elicitation approach for measuring the willingness to pay for liver cancer treatment in Korea. AB - BACKGROUND/AIMS: The Korean government has expanded the coverage of the national insurance scheme for four major diseases: cancers, cardiovascular diseases, cerebrovascular diseases, and rare diseases. This policy may have a detrimental effect on the budget of the national health insurance agency. Like taxes, national insurance premiums are levied on the basis of the income or wealth of the insured. METHODS: Using a preference elicitation method, we attempted to estimate how much people are willing to pay for insurance premiums that would expand their coverage for liver cancer treatment. RESULTS: We calculated the marginal willingness to pay (MWTP) through the marginal rate of substitution between the two attributes of the insurance premium and the total annual treatment cost by adopting conditional logit and mixed logit models. CONCLUSIONS: The effects of various other terms that could interact with socioeconomic status were also estimated, such as gender, income level, educational attainment, age, employment status, and marital status. The estimated MWTP values of the monthly insurance premium for liver cancer treatment range from 4,130 KRW to 9,090 KRW. PMID- 26523272 TI - Imaging findings for intravascular large B-cell lymphoma of the liver. AB - Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma that most commonly involves the central nervous system and skin. To our knowledge, no state-of-the art imaging findings have been reported for hepatic IVLBCL in the English literature. We report the first case of hepatic involvement of IVLBCL along with a literature review. PMID- 26523271 TI - Growth rate of early-stage hepatocellular carcinoma in patients with chronic liver disease. AB - BACKGROUND/AIMS: The goal of this study was to estimate the growth rate of hepatocellular carcinoma (HCC) and identify the host factors that significantly affect this rate. METHODS: Patients with early-stage HCC (n=175) who underwent two or more serial dynamic imaging studies without any anticancer treatment at two tertiary care hospitals in Korea were identified. For each patient, the tumor volume doubling time (TVDT) of HCC was calculated by comparing tumor volumes between serial imaging studies. Clinical and laboratory data were obtained from the medical records of the patients. RESULTS: The median TVDT was 85.7 days, with a range of 11 to 851.2 days. Multiple linear regression revealed that the initial tumor diameter (a tumor factor) and the etiology of chronic liver disease (a host factor) were significantly associated with the TVDT. The TVDT was shorter when the initial tumor diameter was smaller, and was shorter in HCC related to hepatitis B virus (HBV) infection than in HCC related to hepatitis C virus (HCV) infection (median, 76.8 days vs. 137.2 days; P=0.0234). CONCLUSIONS: The etiology of chronic liver disease is a host factor that may significantly affect the growth rate of early-stage HCC, since HBV-associated HCC grows faster than HCV associated HCC. PMID- 26523275 TI - Portal flow steal after liver transplantation. AB - Portal flow steal occasionally persists even after the liver transplantation, which may reduce the portal flow and thus threaten the patients' outcome. Therefore, pre- and peri-operative detection of portal steal phenomenon requiring radiological or surgical interruption is essential for the liver transplantation candidates as well as for the recipients. PMID- 26523273 TI - A case of hepatoblastoma misdiagnosed as combined hepatocellular carcinoma and cholangiocarcinoma in an adult. AB - Hepatoblastoma usually occurs in children under the age of 2 years, with very few cases reported in adults. We experienced a case of adult hepatoblastoma in a 36 year-old female with chronic hepatitis B. She had experienced sudden onset abdominal pain. Her serum alpha-fetoprotein level was markedly elevated, and abdominal CT showed a 9-cm mass with internal hemorrhage in the right hepatic lobe with hemoperitoneum, so an emergency hepatic central bisectionectomy was performed. The initial histologic examination revealed that the mass mimicked combined hepatocellular carcinoma and cholangiocarcinoma with spindle-cell metaplasia of the cholangiocarcinoma element. Follow-up abdominal CT performed 3 months later showed a 5.5-cm metastatic mass in the left subphrenic area. Laparoscopic splenectomy with mass excision was performed, and hepatoblastoma was confirmed histologically. A histologic re-examination of previously obtained surgical specimens also confirmed the presence of hepatoblastoma. Metastatic hepatoblastoma was found at multiple sites of the abdomen during follow-up, and so chemotherapy with cisplatin, 5-fluorouracil (5-FU), and vincristine was applied, followed by carboplatin and doxorubicin. Despite surgery and postoperative chemotherapy, she died 12 months after symptom onset. PMID- 26523274 TI - Sarcomatoid cholangiocarcinoma with osteoclast-like giant cells associated with hepatolithiasis: A case report. PMID- 26523276 TI - Retrospective study of changes in pharyngeal airway space and position of hyoid bone after mandibular setback surgery by cephalometric analysis. AB - BACKGROUND: The posterior movement of mandible was known as the main cause of the changes in the pharyngeal airway space (PAS) and the postoperative obstructive sleep apnea (OSA). The purpose of this study was to know the changes of PAS and position of hyoid bone. METHODS: Lateral cephalographies of 13 patients who had undergone sagittal split ramus osteotomy (SSRO) setback surgery were taken preoperatively (T1), postoperatively within 2 months (T2), and follow-up after 6 months or more (T3). On the basis of F-H plane, diameters of nasopharynx, oropharynx, and hypopharynx were measured. The movements of the soft palate, tongue, and hyoid bone were also measured. RESULTS: The amount of mandible setback was 7.5 +/- 3.8 mm. In the measurements of PAS, there was a statistically significant decrease of 2.8 +/- 2.5 mm in nasopharynx (P < 0.01), and 1.7 +/- 2.4 mm in oropharynx (P < 0.01) were observed after surgery. The hypopharynx decreased 1.0 +/- 2.1 mm after surgery and continuously decreased 1.0 +/- 2.8 mm at follow-up. The changes in hyoid bone position showed the posterior movement only after surgery and posteroinferior movement at follow-up. CONCLUSIONS: The PAS such as nasopharynx, oropharynx, and hypopharynx showed relatively high correlation with the amount of mandibular setback. The change of resistance in upper airway may be important for the prevention of OSA after mandibular setback surgery. PMID- 26523277 TI - Assessing Origins of Quality Gaps in Discharge Summaries: A Survey of Resident Physician Attitudes. AB - Because little is known about attitudes of primary authors of discharge summaries in academic institutions, namely trainees and physician assistants (PAs), we sought to explore values, possible areas for improvement, and interest in formal discharge summary education. A survey composed of Likert scale analyses, dichotomous relationships, and open-ended questions was designed using focus groups and validated via expert committee review. Of 135 total residents (PGY 1 3), 79 residents and 10 PAs in a large academic hospital in New York City completed it. Of surveyed trainees, 77.2% reported that quality discharge summaries are useful in primary care. Interns had less outpatient experience with discharge summaries compared to PGY 2&3s (23.7% vs. 63.4%, p< 0.001) and were less comfortable authoring discharge summaries for patients who were not as familiar to them (47.4% vs. 24.4%, p=0.04). The majority (54.8%) of interns as well as all PAs reported never receiving feedback on discharge summaries. Finally, 63.2% of interns and 90% of PAs responded that formal teaching would be helpful. Interns' greater discomfort may speak to their poor understanding of core components of a useful discharge summary, which teaching sessions may improve. Alternatively, shifting the authorship responsibility from interns to seniors could be explored as a quality improvement initiative. PMID- 26523278 TI - Neuroprotective Effects of Clostridium butyricum against Vascular Dementia in Mice via Metabolic Butyrate. AB - Probiotics actively participate in neuropsychiatric disorders. However, the role of gut microbiota in brain disorders and vascular dementia (VaD) remains unclear. We used a mouse model of VaD induced by a permanent right unilateral common carotid arteries occlusion (rUCCAO) to investigate the neuroprotective effects and possible underlying mechanisms of Clostridium butyricum. Following rUCCAO, C. butyricum was intragastrically administered for 6 successive weeks. Cognitive function was estimated. Morphological examination was performed by electron microscopy and hematoxylin-eosin (H&E) staining. The BDNF-PI3K/Akt pathway related proteins were assessed by western blot and immunohistochemistry. The diversity of gut microbiota and the levels of butyrate in the feces and the brains were determined. The results showed that C. butyricum significantly attenuated the cognitive dysfunction and histopathological changes in VaD mice. C. butyricum not only increased the levels of BDNF and Bcl-2 and decreased level of Bax but also induced Akt phosphorylation (p-Akt) and ultimately reduced neuronal apoptosis. Moreover, C. butyricum could regulate the gut microbiota and restore the butyrate content in the feces and the brains. These results suggest that C. butyricum might be effective in the treatment of VaD by regulating the gut-brain axis and that it can be considered a new therapeutic strategy against VaD. PMID- 26523280 TI - The Expression and Correlation of iNOS and p53 in Oral Squamous Cell Carcinoma. AB - Oral squamous cell carcinoma (OSCC) is the most prevalent form of oral cancer. Inducible nitric oxide synthase (iNOS) and p53 are associated with a variety of human cancers, but their expression and interaction in OSCC have not been fully explored. In this study, we investigated the expression of iNOS and p53 in OSCC and their correlation with tumor development and prognosis. In addition, we explored the interaction of iNOS and p53 in OSCC. The expression of iNOS and p53 in OSCC was investigated using immunohistochemical method and their interaction was studied using RNAi technique. Our results showed that the expression of both iNOS and p53 was significantly correlated with tumor stages and pathological grade of OSCC (P < 0.05). In contrast, there was no correlation between iNOS and p53 expression and lymph node metastasis (P < 0.05). The OSCC survival rate was negatively associated with iNOS expression, but not with p53. A significant increase in the expression of the p53 was observed when iNOS expression was knocked down. The immunoexpression of iNOS is correlated with tumorigenesis and prognosis of OSCC and may serve as a prognostic marker. PMID- 26523279 TI - Breakdown of Epithelial Barrier Integrity and Overdrive Activation of Alveolar Epithelial Cells in the Pathogenesis of Acute Respiratory Distress Syndrome and Lung Fibrosis. AB - Individual alveolar epithelial cells (AECs) collaboratively form a tight barrier between atmosphere and fluid-filled tissue to enable normal gas exchange. The tight junctions of AECs provide intercellular sealing and are integral to the maintenance of the AEC barrier integrity. Disruption and failure of reconstitution of AEC barrier result in catastrophic consequences, leading to alveolar flooding and subsequent devastating fibrotic scarring. Recent evidences reveal that many of the fibrotic lung diseases involve AECs both as a frequent target of injury and as a driver of ongoing pathological processes. Aberrantly activated AECs express most of the growth factors and chemokines responsible for the proliferation, migration, and activation of fibroblasts. Current evidences suggest that AECs may acquire overdrive activation in the initial step of fibrosis by several mechanisms, including abnormal recapitulation of the developmental pathway, defects of the molecules essential for epithelial integrity, and acceleration of aging-related properties. Among these initial triggering events, epithelial Pten, a multiple phosphatase that negatively regulates the PI3K/Akt pathway and is crucial for lung development, is essential for the prevention of alveolar flooding and lung fibrosis through the regulation of AEC barrier integrity after injury. Reestablishment of AEC barrier integrity also involves the deployment of specialized stem/progenitor cells. PMID- 26523281 TI - Material Science in Cervical Total Disc Replacement. AB - Current cervical total disc replacement (TDR) designs incorporate a variety of different biomaterials including polyethylene, stainless steel, titanium (Ti), and cobalt-chrome (CoCr). These materials are most important in their utilization as bearing surfaces which allow for articular motion at the disc space. Long-term biological effects of implanted materials include wear debris, host inflammatory immune reactions, and osteolysis resulting in implant failure. We review here the most common materials used in cervical TDR prosthetic devices, examine their bearing surfaces, describe the construction of the seven current cervical TDR devices that are approved for use in the United States, and discuss known adverse biological effects associated with long-term implantation of these materials. It is important to appreciate and understand the variety of biomaterials available in the design and construction of these prosthetics and the considerations which guide their implementation. PMID- 26523282 TI - Self-recalled Youth Physical Activity and Postmenopausal Cardiovascular Disease. AB - OBJECTIVES: To evaluate the association between childhood physical activity and incident cardiovascular disease (CVD) during postmenopausal years. METHODS: Proportional hazards and logistic regression were used describe the association between self-reported childhood physical activity and CVD incidence and mortality in 36,741 postmenopausal women. RESULTS: Older women, African-Americans, or nondrinkers or past drinkers self-reported the highest levels of youth physical activity and women with a history of diabetes, hypertension, overweight or obesity, or current smoking reported the highest youth physical activity dose. Youth physical activity was not associated with CVD incidence (HR=1.11; 0.93, 1.34) or mortality (HR=1.2; 0.9, 1.73). CONCLUSIONS: Self-reported youth activity was not associated with postmenopausal CVD incidence or mortality. PMID- 26523283 TI - Persistence of Ebola Virus in Sterilized Wastewater. AB - In the wake of the ongoing 2014/2015 Ebola virus outbreak, significant questions regarding the appropriate handling of Ebola virus-contaminated liquid waste remain, including the persistence of Ebola virus in wastewater. To address these uncertainties, we evaluated the persistence of Ebola virus spiked in sterilized domestic sewage. The viral titer decreased approximately 99% within the first test day from an initial viral titer of 106 TCID50 mL-1; however, it could not be determined if this initial rapid decrease was due to aggregation or inactivation of the viral particles. The subsequent viral titer decrease was less rapid, and infectious Ebola virus particles persisted for all 8 days of the test. The inactivation constant (k) was determined to be -1.08 (2.1 days for a 90% viral titer decrease). Due to experimental conditions, we believe these results to be an upper bound for Ebola virus persistence in wastewater. Wastewater composition is inherently heterogeneous; subsequently, we caution that interpretation of these results should be made within a holistic assessment, including the effects of wastewater composition, dilution, and potential exposure routes within wastewater infrastructure. While it remains unknown if Ebola virus may be transmitted via wastewater, these data demonstrate a potential exposure route to infectious Ebola virus via wastewater and emphasize the value of a precautionary approach to wastewater handling in an epidemic response. PMID- 26523284 TI - Full Three-Dimensonal Reconstruction of the Dyadic Green Tensor from Electron Energy Loss Spectroscopy of Plasmonic Nanoparticles. AB - Electron energy loss spectroscopy (EELS) has emerged as a powerful tool for the investigation of plasmonic nanoparticles, but the interpretation of EELS results in terms of optical quantities, such as the photonic local density of states, remains challenging. Recent work has demonstrated that, under restrictive assumptions, including the applicability of the quasistatic approximation and a plasmonic response governed by a single mode, one can rephrase EELS as a tomography scheme for the reconstruction of plasmonic eigenmodes. In this paper we lift these restrictions by formulating EELS as an inverse problem and show that the complete dyadic Green tensor can be reconstructed for plasmonic particles of arbitrary shape. The key steps underlying our approach are a generic singular value decomposition of the dyadic Green tensor and a compressed sensing optimization for the determination of the expansion coefficients. We demonstrate the applicability of our scheme for prototypical nanorod, bowtie, and cube geometries. PMID- 26523285 TI - Optical Plasmons of Individual Gold Nanosponges. AB - The search for novel plasmonic nanostructures, which can act simultaneously as optical detectors and stimulators, is crucial for many applications in the fields of biosensing, electro- and photocatalysis, electrochemistry, and biofuel generation. In most of these areas, a large surface-to-volume ratio, as well as high density of active surface sites, is desirable. We investigate sponge-like, that is, fully porous, nanoparticles, called nanosponges, where both the gold and the air phase are fully percolated in three dimensions. We correlate, on a single nanoparticle basis, their optical scattering spectra (using dark field microscopy) with their individual morphology (using electron microscopy). We find that the scattering spectra of nanosponges depend only weakly on their size and outer shape, but are greatly influenced by their unique percolation, in qualitative agreement with numerical simulations. PMID- 26523286 TI - Metal-Dielectric Waveguides for High Efficiency Coupled Emission. AB - We report a metal-dielectric planar structure which provides high efficiency coupling of fluorescence at distances over 100 nm away from the metal surface. This hybrid metal-dielectric waveguide (MDW) consists of a continuous metal film coated with a dielectric layer. We observed efficient long-range coupling of Rhodamine B on top of a 130 nm layer of silica resulting in a narrow angular distribution of the emission. The high efficiency radiation through the Ag film appears to be due to coupling of the fluorophore to an optical waveguide mode with a long propagation length and a narrow resonance. The results were consistent with simulations. These multi-layer structures can be made using vapor deposition and/or spin coating and the silica surface can be used for conjugation to biomolecules and surface-selective detection. This simple hybrid metal dielectric structures provides new opportunities for fluorescence sensing, genomics, proteomics and diagnostics. PMID- 26523287 TI - Complex in vivo Ligation Using Homologous Recombination and High-efficiency Plasmid Rescue from Saccharomyces cerevisiae. AB - The protocols presented here allow for the facile generation of a wide variety of complex multipart DNA constructs (tagged gene products, gene fusions, chimeric proteins, and other variants) using homologous recombination and in vivo ligation in budding yeast (Saccharomyces cerevisiae). This method is straightforward, efficient and cost-effective, and can be used both for vector creation and for subsequent one-step, high frequency integration into a chromosomal locus in yeast. The procedure utilizes PCR with extended oligonucleotide "tails" of homology between multiple fragments to allow for reassembly in yeast in a single transformation followed by a method for highly efficient plasmid extraction from yeast (for transformation into bacteria). The latter is an improvement on existing methods of yeast plasmid extraction, which, historically, has been a limiting step in recovery of desired constructs. We describe the utility and convenience of our techniques, and provide several examples. PMID- 26523288 TI - Major Global Killer Tamed by Hydrogen. PMID- 26523289 TI - Dynamic spectrin/ankyrin-G microdomains promote lateral membrane assembly by opposing endocytosis. AB - Current physical models for plasma membranes emphasize dynamic 10- to 300-nm compartments at thermodynamic equilibrium but subject to thermal fluctuations. However, epithelial lateral membranes contain micrometer-sized domains defined by an underlying membrane skeleton composed of spectrin and its partner ankyrin-G. We demonstrate that these spectrin/ankyrin-G domains exhibit local microtubule dependent movement on a time scale of minutes and encounter most of the lateral membranes within an hour. Spectrin/ankyrin-G domains exclude clathrin and clathrin-dependent cargo, and inhibit both receptor-mediated and bulk endocytosis. Moreover, inhibition of endocytosis fully restores lateral membrane height in spectrin- or ankyrin-G-depleted cells. These findings support a non equilibrium cellular-scale model for epithelial lateral membranes, where spectrin/ankyrin-G domains actively patrol the plasma membrane, analogous to "window washers," and promote columnar morphology by blocking membrane uptake. PMID- 26523290 TI - Acute Ovarian Insufficiency and Uterine Infarction Following Uterine Artery Embolization for Postpartum Hemorrhage. AB - Uterine artery embolization for intractable postpartum hemorrhage saves lives while preserving fertility. The procedure-related risks of uterine infarction and ovarian insufficiency are rare. A primparous patient underwent bilateral internal hypogastric artery embolization to control severe postpartum hemorrhage following primary cesarean section. The bleeding continued, and a repeat aortogram demonstrated significant filling of the uterus from an anomalous proximal take off of the right uterine artery and from the left ovarian artery. Further embolization was required to control the bleeding. The patient developed acute primary ovarian insufficiency within two weeks of the procedure and subsequently presented with uterine infarction necessitating hysterectomy. This case demonstrates the increased risk of acute ovarian insufficiency and uterine infarction following uterine artery embolization for postpartum hemorrhage in the settings of aberrant pelvic vasculature. PMID- 26523291 TI - Differences in Circulating Endothelial Progenitor Cells among Childhood Cancer Survivors Treated with and without Radiation. AB - Radiation during childhood cancer treatment increases the propensity to atherosclerotic cardiovascular disease among adult survivors of childhood cancer. This is thought to be mediated through the damage to the underlying vascular endothelium. Endothelial progenitor cells (EPCs) involved in vascular endothelial repair after its damage may be affected by radiation therapy but have never been investigated in adult survivors of childhood cancer. In this pilot study, utilizing multi-parametric flowcytometry, endothelial colony forming cells (ECFCs), which are the bonafide EPCs, and circulating endothelial cells (CECs), which are not EPCs, were compared between adult survivors of childhood cancer with or without radiation exposure. In addition, their associations with blood pressure, physical activity and diet were examined. Survivors who received radiotherapy had lower ECFCs and CECs (p<0.05) compared to those without it. Significant positive correlations included physical activity with ECFCs and diet with CECs, while blood-pressure negatively correlated with ECFCs. Further evaluation is needed to examine the effect of radiation and modifiable risk factors on ECFCs and CECs. The preliminary findings from this study suggest evidence of the role of ECFCs as biomarkers of vascular injury following treatment for childhood cancer that may help in early identification of survivors at risk for cardiovascular disease. PMID- 26523293 TI - Editorial: Periodontal Health and Health Promotion. PMID- 26523294 TI - Theranostics for hepatocellular carcinoma with Fe3O4@ZnO nanocomposites. AB - The purpose of the current study is to investigate Fe3O4@ZnO nanocomposites as theranostic agents for hepatocellular carcinoma (HCC). Initially, the transferrin receptor antibody (TfR Ab) functionalized Fe3O4@ZnO nanocomposites, followed by loading with doxorubicin (Dox) and denoted as Fe3O4@ZnO/Dox/TfR Ab, were prepared as an all-in-one system allowing for a targeted drug delivery with simultaneous concurrent chemoradiotherapy and magnetic resonance imaging (MRI) monitoring. The diagnostic and therapeutic functionalities for HCC were evaluated in vitro and in a murine orthotopic models using cell viability assays, cell cycle tests, histopathological examinations, and serum biochemistry tests. The results demonstrated that Fe3O4@ZnO/Dox/TfR Ab could deliver Dox into the targeted HCC SMMC-7721 cells to enhance its chemotherapeutic efficiency. Besides, with the addition of short term and low dose X-ray illumination, the Fe3O4@ZnO nanocomposites showed excellent radiosensitizer properties, further attacking the cancer cells. Tumor cells were also mostly arrested at G2/M, resulting in a distinct inhibition of cell proliferation. In vivo, after the treatment, a noninvasive visualization monitoring through MRI showed that tumor growth was significantly suppressed by the targeted chemoradiotherapy mediated by Fe3O4@ZnO/Dox/TfR Ab. Therefore, Fe3O4@ZnO nanocomposites could mediate the theranostic strategy for hepatocellular carcinoma. PMID- 26523292 TI - New prospects for a preventive HIV-1 vaccine. AB - The immune correlates of risk analysis and recent non-human primate (NHP) challenge studies have generated hypotheses that suggest HIV-1 envelope may be essential and, perhaps, sufficient to induce protective antibody responses against HIV-1 acquisition at the mucosal entry. New prime-boost mosaic and conserved-sequence, together with replicating vector immunisation strategies aiming at inducing immune responses or greater breadth, as well as the development of immunogens inducing broadly neutralising antibodies and mucosal responses, should be actively pursued and tested in humans. Whether the immune correlates of risk identified in RV144 can be extended to other vaccines, other populations, or different modes and intensity of transmission, and against increasing HIV-1 genetic diversity, remains to be demonstrated. Although NHP challenge studies may guide vaccine development, human efficacy trials remain key for answering the critical questions leading to the development of a global HIV-1 vaccine for licensure. PMID- 26523295 TI - The association and aggregation of the metamorphic chemokine lymphotactin with fondaparinux: from nm molecular complexes to MUm molecular assemblies. AB - Transmission electron microscopy, mass spectrometry, and drift tube ion mobility mass spectrometry are used to study the assemblies formed by the metamorphic chemokine lymphotactin in the presence of a model pentameric glycosaminoglycan, fondaparinux. This combination of techniques delineates significant differences in the complexes observed for two forms of the full length protein as well as a truncated form, without the intrinsically disordered C-terminal tail, over a length scale from few nm to MUm assemblies. PMID- 26523296 TI - Carbon monoxide mediated chemical deposition of Pt or Pd quasi-monolayer on Au surfaces with superior electrocatalysis for ethanol oxidation in alkaline media. AB - Electroless deposition of a quasi-monolayer (q-ML) of Pt and/or Pd on different Au substrates is achieved by using CO as both reducing and quenching agents, imparting Au@Pt/C or Au@Pd/C with superior electrocatalytic activity for ethanol oxidation in alkaline media. PMID- 26523297 TI - Cystinosis in adult and adolescent patients: Recommendations for the comprehensive care of cystinosis. AB - INTRODUCTION: Cystinosis is a rare lysosomal systemic disease that mainly affects the kidney and the eye. Patients with cystinosis begin renal replacement therapy during the first decade of life in absence of treatment. Prognosis of cystinosis depends on early diagnosis, and prompt starting and good compliance with cysteamine treatment. Kidney disease progression, extra-renal complications and shorter life expectancy are more pronounced in those patients that do not follow treatment. The objective of this work was to elaborate recommendations for the comprehensive care of cystinosis and the facilitation of patient transition from paediatric to adult treatment, based on clinical experience. The goal is to reduce the impact of the disease, and to improve patient quality of life and prognosis. METHODS: Bibliographic research and consensus meetings among a multidisciplinary professional team of experts in the clinical practice, with cystinotic patients (T-CiS.bcn group) from 5 hospitals located in Barcelona. RESULTS: This document gathers specific recommendations for diagnosis, treatment and multidisciplinary follow-up of cystinotic patients in the following areas: nephrology, dialysis,renal transplant, ophthalmology, endocrinology, neurology, laboratory, genetic counselling,nursing and pharmacy. CONCLUSIONS: A reference document for the comprehensive care of cystinosis represents a support tool for health professionals who take care of these patients. It is based on the following main pillars: (a) a multi-disciplinary approach, (b) appropriate disease monitoring and control of intracellular cystine levels in leukocytes, (c) the importance of adherence to treatment with cysteamine, and (d) the promotion of patient self-care by means of disease education programmes. All these recommendations will lead us, in a second phase, to create a coordinated transition model between paediatric and adult care services which will contemplate the specific needs of cystinosis. PMID- 26523298 TI - Zora Janzekovic (September 30, 1918-March 17, 2015). PMID- 26523299 TI - Response. PMID- 26523300 TI - Response. PMID- 26523301 TI - Response. PMID- 26523302 TI - Response. PMID- 26523303 TI - [A case of unrecognized iatrogenic cardiac tamponade with the pareneteral nutrition fluid]. AB - The authors describe the peculiarities of the commissionary expertise with respect to medical practice and the difficulties facing this procedure using as an example a case of the lethal outcome caused by the injury to the right atrium as a result of unrecognized iatrogenic cardiac tamponade with the pareneteral nutrition fluid administered through the catheterized subclavian vein. It was shown that the great variety and complexity of the problems arising in such expertises should draw enhanced attention not only of forensic medical experts but also medical law specialists and other legal practitioners. It is argued that the majority of the cases of the inadequate medical care provided to the patients as exemplified by the case of death of the 43 year-old patient B resulting from the application of the unsafe technique of catheterization of the main blood vessels are usually due to the subjective ("human") factors. They may occur in any health care facility regardless of its location, staff composition and competence. PMID- 26523305 TI - Prehospital Stabilization of Pulmonary Embolism. Acute PEs can be life threatening emergencies - be prepared to recognize and manage them. PMID- 26523304 TI - [The current problems of injury assessment dealt with in the publications in the journal "Sudebnomeditsinskaya ekspertiza (Forensic medical expertise)" for the period from 2000 till 2014]. AB - The objective of the present study was the analysis of the scientometric characteristics of the publication activity of the authors participating in the journal "Sudebno-meditsinskaya ekspertiza (Forensic medical expertise)" for the long period from 2000 till 2014 with special reference to the assessment of the coverage of the most topical problems, such as diagnostics of various injuries and their variability, expert evaluation of the conditions and mechanisms of their infliction for the purpose of characteristic of the properties of traumatic objects (weapons). The study allowed to identify the leading domestic and foreign periodicals most frequently cited by the authors of "Sudebno-meditsinskaya expertiza". The most active authors of the journal represent the research groups of the departments and laboratories of the forensic medical expertise agencies based at Moscow, Sankt-Peterburg, Novosibirsk, Barnaul, Kazan, Perm, Rostov-on Don, Ryazan, Tver, and Khabarovsk. It is concluded that the continuation of the analysis and assessment of the scientific activity of the specialists in the this field of forensic medical expertise is an indispensable condition for the further development and improvement of forensic medical expertise in the Russian Federation. PMID- 26523306 TI - An FDA Legal Grab Bag: Severe Weather, a U.S. Supreme Court Slip Opinion, Working Interviews, Board of Pharmacy Fines and Patient Abandonment. PMID- 26523307 TI - Overview of Dental Photography. PMID- 26523308 TI - HPV--Changing the Face of Head and Neck Cancer and Dental Societies' Responsibilities. PMID- 26523309 TI - Airway Management of Sedated Patients. PMID- 26523310 TI - Diagnostic Discussion. Periapical Cemento-osseous Dysplasia. PMID- 26523311 TI - Do You Want That Mouthwash Straight Up or on the Rocks? Intoxication Isn't All it Used to Be. PMID- 26523313 TI - Create Your Hurricane Crisis Plan Now! PMID- 26523312 TI - I've Come Across Three Questions Lately.... PMID- 26523314 TI - Mid-level Providers. PMID- 26523315 TI - Decisions, Decisions. PMID- 26523316 TI - Keys to Successful Collections. PMID- 26523317 TI - The Nine Areas of Expertise--No.1: Production. PMID- 26523318 TI - Dr. David Russell: 2015 Dentist of the Year of the Year. PMID- 26523320 TI - Dental Coding Truths and Myths. PMID- 26523319 TI - Diagnostic Discussion: Giant Cell Fibroma. PMID- 26523321 TI - Public Comments on Proposed Regulatory Reforms That Would Impact Biospecimen Research: The Good, the Bad, and the Puzzling. PMID- 26523322 TI - Incidental Findings and the Minimal Risk Standard in Pediatric Neuroimaging Research. PMID- 26523323 TI - Peanut Butter, Nut Butters and Spreads. PMID- 26523324 TI - Smoldering Remediation of Coal-Tar-Contaminated Soil: Pilot Field Tests of STAR. AB - Self-sustaining treatment for active remediation (STAR) is an emerging, smoldering-based technology for nonaqueous-phase liquid (NAPL) remediation. This work presents the first in situ field evaluation of STAR. Pilot field tests were performed at 3.0 m (shallow test) and 7.9 m (deep test) below ground surface within distinct lithological units contaminated with coal tar at a former industrial facility. Self-sustained smoldering (i.e., after the in-well ignition heater was terminated) was demonstrated below the water table for the first time. The outward propagation of a NAPL smoldering front was mapped, and the NAPL destruction rate was quantified in real time. A total of 3700 kg of coal tar over 12 days in the shallow test and 860 kg over 11 days in the deep test was destroyed; less than 2% of total mass removed was volatilized. Self-sustaining propagation was relatively uniform radially outward in the deep test, achieving a radius of influence of 3.7 m; strong permeability contrasts and installed barriers influenced the front propagation geometry in the shallow test. Reductions in soil hydrocarbon concentrations of 99.3% and 97.3% were achieved in the shallow and deep tests, respectively. Overall, this provides the first field evaluation of STAR and demonstrates that it is effective in situ and under a variety of conditions and provides the information necessary for designing the full-scale site treatment. PMID- 26523325 TI - Clinician's Primer to ICD-10-CM Coding for Cleft Lip/Palate Care. AB - On October 1, 2015, the United States required use of the Clinical Modification of the International Classification of Diseases, 10th Revision (ICD-10-CM) for diagnostic coding. This primer was written to assist the cleft care community with understanding and use of ICD-10-CM for diagnostic coding related to cleft lip and/or palate (CL/P). PMID- 26523327 TI - Letter to the Editor. PMID- 26523326 TI - A New Way to Accelerate the Distraction of the Transpalatal Suture in Growing Dogs Using Recombinant Human Bone Morphogenetic Protein-2. AB - OBJECTIVE: The purpose of this study was to evaluate the administration of recombinant human bone morphogenetic protein-2 (rhBMP-2) on trans-sutural distraction osteogenesis (TSDO) of the transverse palatal suture in growing dogs. STUDY DESIGN: A total of 36 growing dogs were used in this study. The experimental animals were treated with different elastic force and rhBMP-2. The bone regeneration was determined with X-ray, histology, and clinical evaluation. The computed values underwent statistical analyses using analysis of variance. RESULTS: The maxillary complex was most noticeably advanced with an applied elastic force of 600 g (22.4 +/- 5.0 mm) and 800 g + rhBMP-2 (24 +/- 5.1 mm). Immunohistochemical staining showed that the expression of bone morphogenetic protein-2 and bone morphogenetic protein-4 varied with different elastic force. These changes were statistically significant when 600 g and 800 g + rhBMP-2 were applied within 2 weeks of distraction when compared with controls (P < .05). CONCLUSIONS: The results of this study suggest that TSDO in the growing dog should be safe and well tolerated when inducing bony lengthening of the maxilla. rhBMP-2 plays an important role in bone regeneration using TSDO. PMID- 26523328 TI - Influences of keratinocyte growth factor - mesenchymal stem cells on chronic liver injury in rats. AB - To study the effects of keratinocyte growth factor (KGF) modified umbilical cord mesenchymal stem cells (MSC) on chronic liver injury in rats, adenovirus carrying human KGF gene (Ad-KGF) was used. Rat liver injury model was established by subcutaneous injection of CCl4 - olive oil solution; 56 male Wistar rats were randomly divided into normal control, model, MSC, KGF, and KGF/MSC groups. Of all three treatments, KGF/MSC had the most obvious therapeutic effects on liver injury, and cell injections did not cause adverse reaction. The experiment provides new data for clinical research of KGF/MSC and possible methods for liver injury treatment. PMID- 26523329 TI - Pregnancy outcomes decline with increasing recipient body mass index: an analysis of 22,317 fresh donor/recipient cycles from the 2008-2010 Society for Assisted Reproductive Technology Clinic Outcome Reporting System registry. AB - OBJECTIVE: To examine the effect of recipient body mass index (BMI) on IVF outcomes in fresh donor oocyte cycles. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 22,317 donor oocyte cycles from the 2008-2010 Society for Assisted Reproductive Technology Clinic Outcome Reporting System registry were stratified into cohorts based on World Health Organization BMI guidelines. Cycles reporting normal recipient BMI (18.5-24.9) were used as the reference group. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation rate, clinical pregnancy rate (PR), pregnancy loss rate, live birth rate. RESULT(S): Success rates and adjusted odds ratios with 95% confidence intervals for all pregnancy outcomes were most favorable in cohorts of recipients with low and normal BMI, but progressively worsened as BMI increased. CONCLUSION(S): Success rates in recipient cycles are highest in those with low and normal BMI. Furthermore, there is a progressive and statistically significant worsening of outcomes in groups with higher BMI with respect to clinical pregnancy and live birth rate. PMID- 26523330 TI - Gonadotropin-releasing hormone agonist trigger in oocyte donors co-treated with a gonadotropin-releasing hormone antagonist: a dose-finding study. AB - OBJECTIVE: To determine the optimal GnRH agonist dose for triggering of oocyte maturation in oocyte donors. DESIGN: Single-center, randomized, parallel, investigator-blinded trial. SETTING: IVFMD, My Duc Hospital, Ho Chi Minh City, Vietnam. PATIENT(S): One hundred sixty-five oocyte donors (aged 18-35 years, body mass index [BMI] <28 kg/m(2), antimullerian hormone level >1.25 ng/mL, and antral follicle count >=6). INTERVENTION(S): Ovulation trigger with 0.2, 0.3, or 0.4 mg triptorelin in a GnRH antagonist cycle. MAIN OUTCOME MEASURE(S): The primary end point was number of metaphase II oocytes. Secondary end points were fertilization and cleavage rates, number of embryos and top-quality embryos, steroid levels, ovarian volume, and ongoing pregnancy rate (PR) in recipients. RESULT(S): There were no significant differences between the triptorelin 0.2, 0.3, and 0.4 mg trigger groups with respect to number of metaphase II oocytes (16.0 +/- 8.5, 15.9 +/- 7.8, and 14.7 +/- 8.4, respectively), embryos (13.2 +/- 7.8, 11.7 +/- 6.9, 11.8 +/- 7.0), and number of top-quality embryos (3.8 +/- 2.9, 3.6 +/- 3.0, 4.1 +/- 3.0). Luteinizing hormone levels at 24 hours and 36 hours after trigger was significantly higher with triptorelin 0.4 mg versus 0.2 mg and 0.3 mg (9.8 +/- 7.1 IU/L vs. 7.3 +/- 4.1 IU/L and 7.2 +/- 3.7 IU/L, respectively; 4.6 +/- 3.2 IU/L vs. 3.2 +/- 2.3 IU/L and 3.3 +/- 2.1 IU/L, respectively. Progesterone level at oocyte pick-up +6 days was significantly higher in the 0.4-mg group (2.2 +/- 3.7 ng/ml) versus 0.2 mg (1.1 +/- 1.0 ng/ml) and 0.3 mg (1.2 +/- 1.6 ng/ml). One patient developed early-onset severe ovarian hyperstimulation syndrome (OHSS). CONCLUSION(S): No significant differences between triptorelin doses of 0.2, 0.3, and 0.4 mg used for ovulation trigger in oocyte donors were seen with regard to the number of mature oocytes and top-quality embryos. CLINICAL TRIAL REGISTRATION NUMBER: NCT02208986. PMID- 26523331 TI - Hydrodynamic Forces on Macromolecules Protruding from Lipid Bilayers Due to External Liquid Flows. AB - It has previously been observed that an externally applied hydrodynamic shear flow above a fluid lipid bilayer can change the local concentration of macromolecules that are associated with the lipid bilayer. The external liquid flow results in a hydrodynamic force on molecules protruding from the lipid bilayer, causing them to move in the direction of the flow. However, there has been no quantitative study about the magnitude of these forces. We here use finite element simulations to investigate how the magnitude of the external hydrodynamic forces varies with the size and shape of the studied macromolecule. The simulations show that the hydrodynamic force is proportional to the effective hydrodynamic area of the studied molecule, Ahydro, multiplied by the mean hydrodynamic shear stress acting on the membrane surface, sigmahydro. The parameter Ahydro depends on the size and shape of the studied macromolecule above the lipid bilayer and scales with the cross-sectional area of the molecule. We also investigate how hydrodynamic shielding from other surrounding macromolecules decreases Ahydro when the surface coverage of the shielding macromolecules increases. Experiments where the protein streptavidin is anchored to a supported lipid bilayer on the floor of a microfluidic channel were finally performed at three different surface concentrations, Phi = 1%, 6%, and 10%, where the protein is being moved relative to the lipid bilayer by a liquid flow through the channel. From photobleaching measurements of fluorescently labeled streptavidin we found the experimental drift data to be within good accuracy of the simulated results, less than 12% difference, indicating the validity of the results obtained from the simulations. In addition to giving a deeper insight into how a liquid flow can affect membrane-associated molecules in a lipid bilayer, we also see an interesting potential of using hydrodynamic flow experiments together with the obtained results to study the size and the intermolecular forces between macromolecules in membranes and lipid bilayers. PMID- 26523332 TI - 3D Behavior of Schottky Barriers of 2D Transition-Metal Dichalcogenides. AB - The transition metal dichalcogenides (TMDs) are two-dimensional layered solids with van der Waals bonding between layers. We calculate their Schottky barrier heights (SBHs) using supercell models and density functional theory. It is found that the SBHs without defects are quite strongly pinned, with a pinning factor S of about S = 0.3, a similar value for both top and edge contact geometries. This arises because there is direct bonding between the contact metal atoms and the TMD chalcogen atoms, for both top and edge contact geometries, despite the weak interlayer bonding in the isolated materials. The Schottky barriers largely follow the metal induced gap state (MIGS) model, like those of three-dimensional semiconductors, despite the bonding in the TMDs being largely constrained within the layers. The pinning energies are found to be lower in the gap for edge contact geometries than for top contact geometries, which might be used to obtain p-type contacts on MoS2. PMID- 26523333 TI - Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug Discovery. AB - The synthesis of a collection of 3-substituted indole derivatives incorporating partially fluorinated n-propyl and n-butyl groups is described along with an in depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aqueous solubility, and metabolic stability. The experimental observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit molecular design in medicinal chemistry and, more broadly, in life as well as materials sciences. PMID- 26523334 TI - Asymmetric Synthesis of (2S,3S)-alpha-(1-Oxoisoindolin-3-yl)glycines under Low Basicity "Kinetic" Control. AB - The previously illusive (2S,3S)-configured alpha-(1-oxoisoindolin-3-yl)glycines can be prepared under mild DBU-catalyzed, low-basicity conditions. The overall process includes a cascade of aldol addition, cyclization, rearrangement, and conjugate addition reactions, leading to the target products with moderate to good chemical yields and diastereoselectivity. PMID- 26523335 TI - High-strength porous biomaterials for bone replacement: A strategy to assess the interplay between cell morphology, mechanical properties, bone ingrowth and manufacturing constraints. AB - High-strength fully porous biomaterials built with additive manufacturing provide an exciting opportunity for load-bearing orthopedic applications. While factors controlling their mechanical and biological response have recently been the subject of intense research, the interplay between mechanical properties, bone ingrowth requirements, and manufacturing constraints, is still unclear. In this paper, we present two high-strength stretch-dominated topologies, the Tetrahedron and the Octet truss, as well as an intuitive visualization method to understand the relationship of cell topology, pore size, porosity with constraints imposed by bone ingrowth requirements and additive manufacturing. 40 samples of selected porosities are fabricated using Selective Laser Melting (SLM), and their morphological deviations resulting from SLM are assessed via micro-CT. Mechanical compression testing is used to obtain stiffness and strength properties, whereas bone ingrowth is assessed in a canine in vivo model at four and eight weeks. The results show that the maximum strength and stiffness ranged from 227.86+/-10.15 to 31.37+/-2.19MPa and 4.58+/-0.18 to 1.23+/-0.40GPa respectively, and the maximum 0.2% offset strength is almost 5 times stronger than that of tantalum foam. For Tetrahedron samples, bone ingrowth after four and eight weeks is 28.6%+/-11.6%, and 41.3%+/-4.3%, while for the Octet truss 35.5%+/-1.9% and 56.9%+/-4.0% respectively. This research is the first to demonstrate the occurrence of bone ingrowth into high-strength porous biomaterials which have higher structural efficiency than current porous biomaterials in the market. STATEMENT OF SIGNIFICANCE: We present two stretch-dominated cell topologies for porous biomaterials that can be used for load-bearing orthopaedic applications, and prove that they encourage bone ingrowth in a canine model. We also introduce an intuitive method to visualize and understand the relationship of cell topology, pore size, porosity with constraints imposed by bone ingrowth requirements and additive manufacturing. We show this strategy helps to gain insight into the interaction of exogenous implant factors and endogenous system factors that can affect the success of load-bearing orthopaedic devices. PMID- 26523336 TI - Marine polysaccharide-based nanomaterials as a novel source of nanobiotechnological applications. AB - Research on marine polysaccharide-based nanomaterials is emerging in nanobiotechnological fields such as drug delivery, gene delivery, tissue engineering, cancer therapy, wound dressing, biosensors, and water treatment. Important properties of the marine polysaccharides include biocompatibility, biodegradability, nontoxicity, low cost, and abundance. Most of the marine polysaccharides are derived from natural sources such as fucoidan, alginates, carrageenan, agarose, porphyran, ulvan, mauran, chitin, chitosan, and chitooligosaccharide. Marine polysaccharides are very important biological macromolecules that widely exist in marine organisms. Marine polysaccharides exhibit a vast variety of structures and are still under-exploited and thus should be considered as a novel source of natural products for drug discovery. An enormous variety of polysaccharides can be extracted from marine organisms such as algae, crustaceans, and microorganisms. Marine polysaccharides have been shown to have a variety of biological and biomedical properties. Recently, research and development of marine polysaccharide-based nanomaterials have received considerable attention as one of the major resources for nanotechnological applications. This review highlights the recent research on marine polysaccharide based nanomaterials for biotechnological and biomedical applications. PMID- 26523337 TI - Extracorporeal ultrafiltration therapy for acute decompensated heart failure. AB - Congestion is the most common reason for hospitalization of patients with acute decompensated heart failure (ADHF) and adversely impacts their outcomes. Extracorporeal ultrafiltration (UF) therapy has re-emerged as an effective strategy for decongestion in this setting. This article is intended to discuss key concepts in UF and its technique, provide a brief historical view of UF application for decongestion in ADHF, review the hemodynamic and neurohormonal effects of UF and their positive effects on the pathophysiology of ADHF, discuss the findings of the landmark trials in this field, and explain key findings of these studies as well as the apparent discrepancies in their findings. In a separate section we discuss the intricacies of renal dysfunction in ADHF as it plays a very important role in understanding the current evidence and designing futures clinical trials of UF in ADHF. In the end, the authors provide their perspective on the future role of UF in management of patients with ADHF and congestion. PMID- 26523338 TI - Goal-oriented training affects decision-making processes in virtual and simulated fire and rescue environments. AB - Decisions made by operational commanders at emergency incidents have been characterized as involving a period of information gathering followed by courses of action that are often generated without explicit plan formulation. We examined the efficacy of goal-oriented training in engendering explicit planning that would enable better communication at emergency incidents. While standard training mirrored current operational guidance, goal-oriented training incorporated "decision controls" that highlighted the importance of evaluating goals, anticipated consequences, and risk/benefit analyses once a potential course of action has been identified. In Experiment 1, 3 scenarios (a house fire, road traffic collision, and skip fire) were presented in a virtual environment, and in Experiment 2 they were recreated on the fireground. In Experiment 3, the house fire was recreated as a "live burn," and incident commanders and their crews responded to this scenario as an emergency incident. In all experiments, groups given standard training showed the reported tendency to move directly from information gathering to action, whereas those given goal-oriented training were more likely to develop explicit plans and show anticipatory situational awareness. These results indicate that training can be readily modified to promote explicit plan formulation that could facilitate plan sharing between incident commanders and their teams. PMID- 26523339 TI - The JOIs of text comprehension: Supplementing retrieval practice to enhance inference performance. AB - Previous research has shown that the Read-Recite-Review (3R) technique, a retrieval-based strategy, enhances free recall but not inference performance relative to a common note-taking strategy. We hypothesize that this may be because retrieval practice enhances memory processes without encouraging learners to build a coherent situation model, a type of processing necessary for successful inference performance. In 2 experiments, we attempted to enhance situation-model processing during restudy by incorporating judgments of inferencing (JOIs) within the 3R technique. In Experiment 1, participants studied a technical passage on brakes (or pumps) under 1 of 3 study conditions: a) standard 3R, b) 3R plus metacomprehension judgments, or c) note-taking plus metacomprehension judgments. The combination of retrieval practice and metacomprehension judgments (i.e., 3R plus metacomprehension) improved inference performance relative to the standard 3R and note-taking plus metacomprehension judgments conditions. In Experiment 2, we manipulated the type of metacomprehension judgments (JOIs vs. judgments of learning) and test-expectancy (TE) instructions. Our results indicated that only the addition of JOIs to the 3R strategy enhanced inference and problem-solving performance relative to the standard 3R condition. These findings suggest that making metacomprehension judgments may not be a neutral event; instead, making JOIs in concert with retrieval practice can influence people's subsequent study behavior, which in turn can have a positive impact on inference performance. PMID- 26523340 TI - Propofol-ketamine combination therapy for effective control of super-refractory status epilepticus. AB - Retrospective analysis was conducted of patients with SRSE who were treated simultaneously with propofol and ketamine. Sixty-seven patients were identified from 2012 to 2015, and outcomes documented were resolution and mortality. The duration of combined ketamine and propofol use ranged from 1 to 28 days (mean - 3.6 days). Infusion rates ranged up to 145 and 175 mcg/kg/min. Vasopressors were used in 53 patients (79%), and were given within the first 5 days of the ICU admission in 48 (91%) patients. The overall SRSE resolution rate was 91%, and the overall mortality including patients with anoxic brain injury was 39%. Of the 13 patients with SRSE as a result of anoxic brain injury, SRSE was controlled in 5 (56%). The primary determinant of mortality was family withdrawing care related to the presence of severe medical/neurological diseases. PMID- 26523341 TI - Genetic risk assessment and prevention: the role of genetic testing panels in breast cancer. AB - Multigene panel tests are being increasingly used for the genetic assessment of women with an apparent predisposition to breast cancer. Here, we review all studies reporting results from individuals who have undergone multigene panel testing for hereditary breast cancer. Across all gene panel studies, the prevalence of pathogenic mutations was highest in BRCA1 (5.3%) and BRCA2 (3.6%) and was lowest in PTEN (0.1%), CDH1 (0.1%) and STK11 (0.01%). After BRCA1/2, the prevalence of pathogenic mutations was highest in CHEK2 (1.3%), PALB2 (0.9%) and ATM (0.8%). The prevalence of variants of unknown significance was highest in ATM (9.6%). Based on the prevalence and penetrance of pathogenic mutations and the prevalence of variants of unknown significance, it is our interpretation that BRCA1, BRCA2, PALB2 and CHEK2 are the best candidates for inclusion in a clinical multigene breast cancer panel. PMID- 26523342 TI - Solid-Phase S-Alkylation Promoted by Molecular Sieves. AB - A solid-phase S-alkylation procedure to introduce chemical modification on the cysteine sulfhydryl group of a peptidyl resin is reported. The reaction is promoted by activated molecular sieves and consists of a solid-solid process, since both the catalyst and the substrate are in a solid state. The procedure was revealed to be efficient and versatile, particularly when used in combination with the solution S-alkylation approach, allowing for the introduction of different molecular diversities on the same peptide molecule. PMID- 26523343 TI - Cardiac autonomic response following high-intensity running work-to-rest interval manipulation. AB - The cardiorespiratory, cardiac autonomic (via heart rate variability (HRV)) and plasma volume responses to varying sequences of high-intensity interval training (HIT) of consistent external work were investigated. Twelve moderately trained males underwent three HIT bouts and one control session. The HIT trials consisted of warm-up, followed by 12 min of 15 s, 30 s or 60 s work:relief HIT sequences at an exercise intensity of 100% of the individual velocity at [Formula: see text]O2max (v[Formula: see text]O2max), interspersed by relief intervals at 60% [Formula: see text]O2max (work/relief ratio = 1). HRV was evaluated via the square root of the mean sum of the squared differences between R-R intervals (rMSSD) before, 1 h, 3 h and 24 h after the exercise. Plasma volume was assessed before, immediately after, and 3 h and 24 h after. There were no substantial between-trial differences in acute cardiorespiratory responses. The rMSSD values remained decreased 1 h after the exercise cessation in all exercise groups. The rMSSD subsequently increased between 1 h and 3 h after exercise, with the most pronounced change in the 15/15 group. There were no relationships between HRV and plasma volume. All HIT protocols resulted in similar cardiorespiratory responses with slightly varying post-exercise HRV responses, with the 30/30 protocol eliciting the least disruption to post-exercise HRV. These post-exercise HRV findings suggest that the 30/30 sequence may be the preferable HIT prescription when the between-training period is limited. PMID- 26523344 TI - Flagellar motility in eukaryotic human parasites. AB - A huge variety of protists rely on one or more motile flagella to either move themselves or move fluids and substances around them. Many of these flagellates have evolved a symbiotic or parasitic lifestyle. Several of the parasites have adapted to human hosts, and include agents of prevalent and serious diseases. These unicellular parasites have become specialised in colonising a wide range of biological niches within humans. They usually have diverse transmission cycles, and frequently manifest a variety of distinct morphological stages. The motility of the single or multiple flagella plays important but understudied roles in parasite transmission, host invasion, dispersal, survival, proliferation and pathology. In this review we provide an overview of the important human pathogens that possess a motile flagellum for at least part of their life cycle. We highlight recently published studies that aim to elucidate motility mechanisms, and their relevance for human disease. We then bring the physics of swimming at the microscale into context, emphasising the importance of interdisciplinary approaches for a full understanding of flagellate motility - especially in light of the parasites' microenvironments and population dynamics. Finally, we summarise some important technological aspects, describing challenges for the field and possibilities for motility analyses in the future. PMID- 26523345 TI - Surface plasmon effect of carbon nanodots. AB - Luminescent ZnO quantum dots (QDs) have been prepared, and the fluorescence intensity of the QDs can be increased greatly with the introduction of carbon nanodots, while the fluorescence lifetime of the QDs decreases significantly. The fluorescence enhancement and lifetime decrement can be attributed to the surface plasmon effect of the carbon nanodots, and the calculated surface plasmon resonance frequency of the nanodots matches well with the fluorescence spectrum of the ZnO QDs. PMID- 26523346 TI - Epidemiological factors associated with ESBL- and non ESBL-producing E. coli causing urinary tract infection in general practice. AB - The purpose of the study was to evaluate how use of antibiotics precedes the presence of ESBL-producing E.coli in general practice. The authors performed a triple-case-control study where three case groups were individually compared to a single control group of uninfected individuals. Urine samples were prospectively collected and retrospective statistical analyses were done. This study included 98 cases with urinary tract infection (UTI) caused by ESBL-producing E. coli, 174 with antibiotic-resistant (non-ESBL) E. coli, 177 with susceptible E. coli and 200 with culture negative urine samples. Case groups had significantly higher use of antibiotics than the control group within 30 days before infection (p < 0.0001). The ESBL group had significantly more hospital admissions than the other case groups (p < 0.05). Hospital admission was an independent risk factor for community onset UTI by ESBL-producing E. coli. Exposure to antibiotics was a risk factor for UTI with E. coli, while prior antibiotic usage was not an indisputable predictor for infection with ESBL-producing E.coli in general practice. PMID- 26523347 TI - Dental prosthesis use and/or need impacting the oral health-related quality of life in Brazilian adults and elders: Results from a National Survey. AB - OBJECTIVES: This study aimed to assess the impact of use of and need for dental prosthesis (DP) on oral health related quality of life (OHRQoL) among Brazilian adults and elders. METHODS: This cross-sectional, population-based study, used data from the Brazilian Oral Health National Survey performed in 2010. The sample was representative of adults (35-44 years of age) and elders (65-74 years) at national level. Oral Impact on Daily Performance (OIDP) questionnaire was used to assess the individuals' OHRQoL. Interest variables included use of and need for DP and location of tooth losses. Covariates included socioeconomic, behavioral and clinical characteristics. Associations were performed using Negative Binomial regression models, estimating the rate ratios (RR) and respective 95% confidence intervals. RESULTS: From the total of 17,398 individuals evaluated, 68.3% needed some type of DP, while the prevalence of DP usage was 49.2%. After adjustments, those needing prosthesis, regardless of already using prosthesis presented an impact more than 50% higher on OHRQoL, and those needing a greater the number of teeth to be replaced and those presenting losses on anterior and posterior regions had higher impact on OHRQoL. CONCLUSIONS: These findings suggest that improvement of strategies focused on oral rehabilitation of adults and elders are crucial to promote population oral health. CLINICAL SIGNIFICANCE: The high prevalence of normative need for prosthetic rehabilitation in adult and elder Brazilian population impacts significantly on oral health-related quality of life highlighting the importance of providing prosthetic oral rehabilitation in this population. PMID- 26523348 TI - Veneered anatomically designed zirconia FDPs resulting from digital intraoral scans: Preliminary results of a prospective clinical study. AB - OBJECTIVES: The aim of this prospective clinical study was to evaluate the clinical performance of veneered anatomically designed zirconia fixed dental prostheses (FDPs) resulting from intraoral digital impressions. METHODS: 24 patients requiring treatment were provided with all-ceramic FDPs. Intraoral scans (iTero) were performed and veneered anatomically designed CAD/CAM-zirconia FDPs (Zerion/VitaVM9) were fabricated. A feldspar veneering ceramic following a slow cooling firing protocol was applied. A self-curing resin based luting material was used for adhesive cementation. Clinical evaluations were performed at baseline and 6, 12, and 18 months recalls according to the modified USPHS criteria. Intraoral digital surface scans (iTero) were performed at each recall examination and were digitally superimposed (Geomagic) to evaluate potential veneer cohesive fractures. Kaplan-Meier survival analysis comprised secondary caries, clinically unacceptable fractures, root canal treatment and debonding. Kaplan-Meier success rate included restorations with minimal crevices, tolerable color deviations and clinically acceptable fractures. Data were statistically analyzed. RESULTS: The Kaplan-Meier survival rate and success rate of the FDPs were 100% and 91.7%, respectively. Clinically acceptable veneer cohesive fractures and crevices at the restoration margin were observed in two patients. These shallow veneer fractures were only detected by overlapping baseline and recall scans. Ceramic surface roughness increased significantly over time (p<0.0001). CONCLUSIONS: Veneered zirconia FDPs fabricated from digital intraoral scans showed a favorable clinical performance over an observation period of 18 months. Anatomical zirconia core design and slow cooling firing protocol of the veneering ceramic reduced the incidence of chip fractures to a level that could not be detected clinically. CLINICAL SIGNIFICANCE: The digital workflow on the basis of intraoral digital impressions resulted in clinically satisfying outcomes for veneered zirconia FDPs. PMID- 26523349 TI - A new procedure for the cloning, expression and purification of the beta-carbonic anhydrase from the pathogenic yeast Malassezia globosa, an anti-dandruff drug target. AB - Malassezia yeasts are almost exclusively the single eukaryotic members of the fungal flora of the skin. Malassezia globosa and Malassezia restricta are found on the skin of practically all humans. Malassezia globosa is highly implicated in the pathogenesis of dandruff and its genome encodes for only one carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the beta-class (MgCA). It has been indeed demonstrated that in many pathogenic microorganisms, CAs are essential for their life cycle and their inhibition can lead to growth impairment and defects. In the previous work, the recombinant MgCA was investigated for its inhibition profile with sulfonamides, which in models of dandruff infection were able to protect animals from the fungal infection, allowing us to propose this enzyme as a new antidandruff target. MgCA was cloned as GST-fusion protein, but the yield was rather low and the protein was often found in inclusion bodies. Here, we propose an alternative procedure consisting in cloning the recombinant MgCA as His-Tag fusion protein. This procedure resulted in a good method to express and purify the active recombinant MgCA, and the protein recovery was better with respect to that used for preparing MG-CA (beta-CA cloned as GST-fusion protein). PMID- 26523350 TI - Lung Function and Bronchial Hyperresponsiveness in Adults Born Prematurely. A Cohort Study. AB - RATIONALE: Bronchopulmonary dysplasia and the long-term consequences of prematurity are underrecognized entities, unfamiliar to adult clinicians. Well described by the pediatric community, these young adults are joining the ranks of a growing population of adults with chronic lung disease. OBJECTIVES: To describe the quality of life, pulmonary lung function, bronchial hyperresponsiveness, body composition, and trends in physical activity of adults born prematurely, with or without respiratory complications. METHODS: Four groups of young adults born in Canada between 1987 and 1993 were enrolled in a cohort study: (1) preterm subjects with no neonatal respiratory complications, (2) preterm subjects with neonatal respiratory distress syndrome, (3) preterm subjects with bronchopulmonary dysplasia, and (4) subjects born at term. The following measurements were compared across the four groups: health-related quality of life, respiratory health, pulmonary function, methacholine challenge test results, and sedentary behavior and physical activity level. MEASUREMENTS AND MAIN RESULTS: Adult subjects who had bronchopulmonary dysplasia in infancy had mild airflow obstruction (FEV1, 80% predicted; FEV1/FCV ratio, 70) and gas trapping compared with others. They also had less total active energy expenditure and more time spent in sedentary behavior compared with subjects born at term. All preterm groups had a high prevalence of bronchial hyperresponsiveness compared with term subjects. CONCLUSIONS: In a population-derived, cross sectional study, we confirmed previous reports that adults 21 or 22 years of age who were born prematurely with neonatal bronchopulmonary dysplasia are more likely to have airflow obstruction, bronchial hyperresponsiveness, and pulmonary gas trapping than subjects born prematurely without bronchopulmonary dysplasia or at term. Clinicians who care for adults need to be better informed of the long term respiratory consequences of premature birth to assist young patients in maintaining lung function and health. PMID- 26523351 TI - Photosensitive atopic dermatitis--a neglected subset: Clinical, laboratory, histological and photobiological workup. AB - BACKGROUND: Photosensitive atopic dermatitis (PhAD) is a scarcely reported entity characterized clinically by a photodistributed rash in patients who fulfil the criteria for atopic dermatitis (AD). OBJECTIVES: The aim of this retrospective study is to define significant clinical, laboratory and immunological parameters as well as photobiological features for diagnosing PhAD. METHODS: We conducted a single-centre retrospective analysis of 17 patients with long-standing AD who in the disease course suddenly developed photosensitivity. All patients with suspected PhAD treated in our department between 2009 and 2014 were included in the study. Diagnostic methods were immunological parameters, prick and patch testing, histology and phototesting procedures. RESULTS: Onset of photosensitivity was observed during spring, summer and during exposure to artificial UVR (Ultraviolet radiation) as part of the patients' treatment regimen. Symptoms appeared 31.5 months on average after AD diagnosis was established. Although the MED (Minimal erythematous dose) was normal compared to a control group, all patients tested with photoprovocation methods exhibited a positive reaction. Two types of reactions were observed: papular and eczematous reactions, both types having similar histology. The wavelength spectrum most commonly involved was UVA. The disease seems to affect women more often than men. Predilection sites included face, neck, exposed trunk areas and arms. Patients with PhAD had coexistent eczematous lesions in non-sun-exposed skin. IgE levels were elevated in 11/17 patients (65%), with a median value of 269 kU/L. CONCLUSION: PhAD is an underreported subset of atopic dermatitis, which is rarely diagnosed. This study suggests that several features including atopic diathesis, eczematous lesions in UVR exposed body regions and positive photoprovocation reaction are suggestive of PhAD as the likely diagnosis. Typically, the atopic eczema starts without a sign of photosensitivity, however, in a subgroup of AD patients after a few months to years, a switch occurs leading to PhAD. PMID- 26523352 TI - FcRgamma-chain deficiency reduces the development of diet-induced obesity. AB - OBJECTIVE: Pathogenic immunoglobulins are produced during the development of obesity and contribute to the development of insulin resistance (IR). However, the mechanisms by which these antibodies affect IR are largely unknown. This study investigated whether Fc-receptors contribute to the development of diet induced obesity and IR by studying FcRgamma(-/-) mice that lack the gamma-subunit necessary for signaling and cell surface expression of FcgammaR and FcepsilonRI. METHODS: FcRgamma(-/-) and wild-type (WT) mice were fed a high-fat diet (HFD) to induce obesity. At 4 and 11 weeks, body weight and insulin sensitivity were measured, and adipose tissue (AT) inflammation was determined. Furthermore, intestinal triglyceride (TG) uptake and plasma TG clearance were determined, and gut microbiota composition was analyzed. RESULTS: FcRgamma(-/-) mice gained less weight after 11 weeks of HFD. They had reduced adiposity, adipose tissue inflammation, and IR. Interestingly, FcRgamma(-/-) mice had higher lean mass compared to WT mice, which was associated with increased energy expenditure. Intestinal TG absorption was increased whereas plasma TG clearance was not affected in FcRgamma(-/-) mice. Gut microbial composition differed significantly and might therefore have added to the observed phenotype. CONCLUSIONS: FcRgamma chain deficiency reduces the development of diet-induced obesity, as well as associated AT inflammation and IR at 11 weeks of HFD. PMID- 26523353 TI - A randomized trial evaluating child dog-bite prevention in rural China through video-based testimonials. AB - OBJECTIVE: Dog-bite injuries pose significant threat to children globally. School age children are especially at risk because of their insufficient safety knowledge and cognitively immature tendency toward low perceived vulnerability to bites, and this risk is elevated further for school-age children living in rural China due to the large number of stray dogs, all potential rabies carriers, present in their communities. METHOD: This randomized controlled trial evaluated whether viewing an educational video of testimonials would change safety knowledge, perceived vulnerability, and simulated behaviors with dogs among a sample of 280 third and fourth graders living in rural China. Participants were randomly assigned to view either an educational video of testimonials on dog-bite prevention (treatment) or an educational video of testimonials on drowning prevention (comparison). Safety knowledge, perceived vulnerability to dog bites, and simulated behavior with dogs using a dollhouse model were assessed both before and after exposure to the video of testimonials. RESULTS: Children who watched the educational video of testimonials on dog-bite prevention had increased safety knowledge, higher perceived vulnerability, and less risky simulated behaviors with dogs compared with the comparison group. Mediation analysis revealed that the intervention successfully changed children's simulated behaviors with dogs through greater safety knowledge and increased perceived vulnerability. CONCLUSIONS: Results suggest the incorporation of testimonials into injury prevention programs has potential for broad global dissemination. The fact that both increased knowledge and heightened perceived vulnerability mediated changes in simulated behavior suggests the dual roles of knowledge and appraisal on children's injury-risk behavior. PMID- 26523354 TI - Higher fasting glucose is associated with poorer cognition among healthy young adults. AB - OBJECTIVE: Obesity is associated with cognitive deficits; however, the mechanisms are unclear, especially among otherwise healthy adults. Our objectives were to examine (a) whether obesity is linked to elevations in fasting glucose and (b) whether these elevations are associated with cognitive impairment among otherwise healthy young adults. METHOD: Participants were 35 normal weight adults and 35 young adults with obesity who completed a task from the Automated Neuropsychological Assessment Metrics-4 (ANAM-4). Measured body mass index (BMI) and fasting blood glucose levels (mg/dL) were examined. RESULTS: Persons with obesity had higher fasting glucose levels than normal weight persons (p = .03). After applying Bonferroni correction for multiple tests, higher fasting glucose predicted less accurate performance on tests of inhibitory control: Go/No-Go Commission Errors (beta = .33, p = .004). No effects were observed for sustained attention or working memory (ps >=. 049). Persons with glucose levels in the prediabetes range had nearly twice as many errors as those with normal glucose, a large effect that was independent of BMI. CONCLUSIONS: Young adults who were obese but otherwise healthy had higher fasting glucose levels compared with normal weight peers. Higher glucose levels were associated with poorer cognitive performance on tests of inhibitory control, especially among individuals with prediabetes levels. Thus, subclinical elevations in blood glucose may contribute to cognitive impairment and, ultimately, greater impulsivity-well in advance of the development of chronic disease states (e.g., insulin resistance or Type 2 diabetes) and independently of excess adiposity--though prospective studies are needed to determine directionality of this relationship. PMID- 26523355 TI - Are we overestimating the prevalence of depression in chronic illness using questionnaires? Meta-analytic evidence in obstructive sleep apnoea. AB - INTRODUCTION: Depression is common in chronic illness, albeit prevalence can be highly variable. This variability may be a function of symptom overlap between depression and chronic illness. Using Obstructive Sleep Apnoea (OSA) as an exemplar, this meta-analysis explored whether the proportion of overlapping symptoms between OSA and depression, within different depression questionnaires, moderates prevalence estimates. METHODS: A systematic search identified 13 studies meeting eligibility criteria. RESULTS: Based on depression questionnaires, the prevalence of depression in OSA ranged from 8% to 68%, reflecting marked heterogeneity. Prevalence estimates based on questionnaires with greater symptom overlap between OSA and depression were higher, whereas questionnaires with a higher proportion of anhedonia symptoms were associated with lower prevalence estimates. DISCUSSION: Overall, these data suggest that when using depression questionnaires to assess the prevalence of depression in OSA, questionnaires that have a lower proportion of symptom overlap between OSA and depression, as well as a higher proportion of anhedonia symptoms, reduce the likelihood of overestimating the prevalence of depression in OSA. This study has implications for other chronic illnesses with symptom overlap with depression, for example diabetes, chronic kidney disease, or heart disease, as well as suggesting that depression questionnaires are not equally appropriate for assessing depression symptomatology in chronic illness populations. PMID- 26523356 TI - Pharmacokinetics and antitumor efficacy of micelles assembled from multiarmed amphiphilic copolymers with drug conjugates in comparison with drug-encapsulated micelles. AB - The premature drug release and structural dissociation before reaching pathological sites have posed major challenges for self-assembled micelles. To address these challenges, star-shaped amphiphilic copolymers derived from 4-armed poly(ethylene glycol) (PEG) were proposed for chemical conjugation of chemotherapeutic drugs and assembly into drug-conjugated micelles (DCM) with reductive sensitivity. The current study aimed to elucidate the in vitro and in vivo performance of DCM and a comparison with conventional drug-encapsulated micelles (DEM) was initially launched. DEM carriers were constructed with a similar structure to DCM from 4-armed PEG, and disulfide linkages were located between the hydrophilic and hydrophobic segments. Both DCM and DEM had an average size of around 130 nm, camptothecin (CPT) loadings of around 7.7% and critical micelle concentrations of around 0.95 MUg/ml. Compared with DEM, DCM showed a lower initial drug release, a lower sensitivity of drug release to glutathione, and a higher structural stability after incubation with human serum albumin (HSA). The CPT derivatives (CPT-SH) released from DCM indicated cytotoxicities similar to CPT and remained a higher lactone stability than CPT in the presence of HSA. DCM showed slightly higher cytotoxicities to 4T1 cells and significantly lower cytotoxicities to normal cells than DEM. Pharmacokinetic analyses after intravenous administration of DCM indicated around 2.65 folds higher AUC0 infinity, 2.66 folds lower clearance, and 1.87 folds higher tumor accumulation than those of DEM. In addition to a less disturbance to hematological and biochemical parameters and a lower acute toxicity to small intestines, DCM showed more significant tumor suppression efficacy and less tumor metastasis to lungs than DEM. It is suggested that DCM could overcome the limitation of conventional micelles by alleviating the premature drug release during blood circulation, relieving the systemic toxicity and promoting the therapeutic efficacy. PMID- 26523357 TI - 3D ordered silver nanoshells silica photonic crystal beads for multiplex encoded SERS bioassay. AB - 3D ordered silver nanoshells silica photonic crystal beads as a novel encoded surface enhanced Raman scattering substrate are proposed for the development of highly efficient multiplex bioassays. PMID- 26523358 TI - Paced QT interval as a risk factor for new-onset left ventricular systolic dysfunction and cardiac death after permanent pacemaker implantation. AB - BACKGROUND: Prolongation of corrected QT (QTc) interval reflects an increased risk of fatal arrhythmia and cardiac death in various populations. However, it is not clear whether the paced-QTc (p-QTc) interval is associated with new-onset left ventricular systolic dysfunction (new-LVSD) or cardiac death. METHODS: In 491 consecutive patients (64 +/- 14 years) with preserved LV ejection fraction (64 +/- 7%), the p-QTc interval was measured within 2 weeks after PPM implantation. We assessed the rates of new-LVSD and cardiac death based on the degree of p-QTc interval. RESULTS: During the follow-up period (78 +/- 51 months), new-LVSD and cardiac death were identified in 53 (10.8%) and 26 (5.3%) patients, respectively. Patients with new-LVSD had more frequent atrioventricular block (P=0.041), a higher percentage of ventricular pacing (P=0.005), a longer p QRS duration (P<0.001), and more prolonged p-QTc interval (P<0.001) compared to those without new-LVSD. There was a graded increase in the rates of new-LVSD (P<0.001) and cardiac death (P=0.001) from the patients in the lowest to those in the highest tertile of the p-QTc interval. Additionally, the incidence of cardiac death was significantly elevated especially in the patients with new-LVSD and wider p-QTc interval. In Cox regression analyses, the p-QTc interval was independently associated with new-LVSD and cardiac death even after adjusted with various relevant confounding factors. CONCLUSIONS: Prolonged p-QTc interval was closely associated with new-LVSD and cardiac death after PPM implantation in patients with preserved LV systolic function. The rate of cardiac death significantly increased especially in patients who showed more p-QTc widening along with new-LVSD. PMID- 26523359 TI - Trends in hospitalizations of young patients with atrial fibrillation: A cause for concern? PMID- 26523360 TI - Suppressive effects of conversion from mycophenolate mofetil to everolimus for the development of cardiac allograft vasculopathy in maintenance of heart transplant recipients. AB - BACKGROUND: Whether converting to everolimus (EVL) from mycophenolate mofetil (MMF) during the maintenance period after heart transplantation (HTx) reduces cardiac allograft vasculopathy (CAV) progression remains unclear. We sought to determine the effect of converting from MMF with standard-dose calcineurin inhibitors (CNIs) to EVL with low-dose CNIs on CAV progression. METHODS: We retrospectively reviewed the medical records of 63 HTx recipients who survived at least at 1 year after HTx. Twenty-four recipients were converted from MMF to EVL (EVL group, 2.2 +/- 2.3 years after HTx), while 39 recipients were maintained on MMF (MMF group, 2.4 +/- 2.2 years after HTx). The EVL group underwent three dimensional intravascular ultrasound (3D-IVUS) analysis before and 1 year after conversion to EVL, and these data were compared with data from 2 consecutive IVUS in the MMF group. RESULTS: IVUS indices in the EVL group at 1 year after conversion did not show increased CAV development, whereas a significant increase in %plaque volume (p=0.006) and decrease in lumen volume (p<0.001) were observed in the MMF group. EVL conversion was significantly associated with smaller increases in %plaque volume (p=0.004) and smaller decreases in lumen volume (p=0.017). IVUS indices in the late EVL conversion group (>= 2 years) also did not exhibit increased CAV development, while those in the MMF group did. CONCLUSIONS: Conversion to EVL from MMF in maintenance periods after HTx may decrease the rate of CAV progression based on IVUS indices. PMID- 26523361 TI - Coronary embolism of left atrial myxoma coexisting with severe aortic stenosis and atherosclerotic coronary disease. PMID- 26523362 TI - Confusion with the diagnosis of acute pulmonary embolism and arrhythmogenic right ventricular cardiomyopathy. PMID- 26523363 TI - Isolated negative T waves in the general population is a powerful predicting factor of cardiac mortality and coronary heart disease. AB - BACKGROUND: Isolated negative T waves (INTW) are considered a common and minor electrocardiographic (ECG) abnormality. However, few recent studies have associated the presence of INTW with an increased risk of all-causes and cardiovascular mortalities. The aim was to evaluate the predictive value of INTW for coronary heart disease (CHD) and all-cause mortality. METHODS: Between 1991 and 1994, 12-lead ECGs were recorded in a sample of 10,600 men (PRIME Study). Among them, 1284 (12.1%) were excluded because of major ECG abnormalities at entry according to Minnesota code, a history of CHD or likely ischemic chest pain on the Rose Questionnaire. INTW were found in 256 subjects (2.74%). The primary outcome was myocardial infarction and angina pectoris after a 10 year follow-up (9.6 +/- 1.4). Secondary outcome was all causes of death. RESULTS: After multivariate adjustment, INTW < 1 mm in anterior or inferior leads was associated with a higher risk of angina pectoris [HR 3.04 95% CI (1.13-8.22) and HR 3.67 95% CI (1.35-9.96) respectively] and INTW >= 1 mm in lateral or anterior leads were associated with a higher incidence of myocardial infarction [HR 2.75, 95% CI (1.29-5.88) and HR 3.20 95% CI (1.68-6.09) respectively]. The association of INTW >= 1 mm in leads V1 to V5 with mortality remained highly significant [HR 3.17 95% CI (1.77-5.65)] after multivariate adjustment. CONCLUSIONS: In middle-age men, INTW is associated with a 2 to 3-fold higher risk of death, myocardial infarction and angina pectoris. PMID- 26523366 TI - Presence and Number of Positive Surgical Margins after Radical Prostatectomy for Prostate Cancer: Effect on Oncological Outcome in a Population-Based Cohort. AB - INTRODUCTION: Additional insight in the occurrence and number of positive surgical margins (PSM) and the potential consequences is needed, since earlier studies show divergent results. This study aims at investigating the effect of the presence and number of PSM on oncological outcomes. METHODS: Retrospective population-based cohort study including 648 consecutive prostate cancer patients who underwent RP in the Southern Netherlands in 2006-2008. The effect of PSM on risk of treatment failure, defined by either biochemical recurrence or necessity of any additional therapy (Cox regression), was evaluated. RESULTS: PSM were observed in 39%; 11% had multiple PSM. Treatment failure was observed in 26% of all patients. Multivariably, the presence (hazard ratio 2.5) and number of PSM (hazard ratios: single 2.3; multiple 3.1) were independently associated with higher treatment failure rates, unlike location of PSM. CONCLUSIONS: Treatment failure rates are high among patients with PSM, especially in those with multiple PSM. This needs to be taken into account when decisions are made on the applicability of the adjuvant and salvage therapy. PMID- 26523364 TI - Extracellular rigidity sensing by talin isoform-specific mechanical linkages. AB - The ability of cells to adhere and sense differences in tissue stiffness is crucial for organ development and function. The central mechanisms by which adherent cells detect extracellular matrix compliance, however, are still unknown. Using two single-molecule-calibrated biosensors that allow the analysis of a previously inaccessible but physiologically highly relevant force regime in cells, we demonstrate that the integrin activator talin establishes mechanical linkages following cell adhesion, which are indispensable for cells to probe tissue stiffness. Talin linkages are exposed to a range of piconewton forces and bear, on average, 7-10 pN during cell adhesion depending on their association with F-actin and vinculin. Disruption of talin's mechanical engagement does not impair integrin activation and initial cell adhesion but prevents focal adhesion reinforcement and thus extracellular rigidity sensing. Intriguingly, talin mechanics are isoform specific so that expression of either talin-1 or talin-2 modulates extracellular rigidity sensing. PMID- 26523365 TI - Functional differentiation of cooperating kinesin-2 motors orchestrates cargo import and transport in C. elegans cilia. AB - Intracellular transport depends on cooperation between distinct motor proteins. Two anterograde intraflagellar transport (IFT) motors, heterotrimeric kinesin-II and homodimeric OSM-3, cooperate to move cargo along Caenorhabditis elegans cilia. Here, using quantitative fluorescence microscopy, with single-molecule sensitivity, of IFT in living strains containing single-copy transgenes encoding fluorescent IFT proteins, we show that kinesin-II transports IFT trains through the ciliary base and transition zone to a 'handover zone' on the proximal axoneme. There, OSM-3 gradually replaces kinesin-II, yielding velocity profiles inconsistent with in vitro motility assays, and then drives transport to the ciliary tip. Dissociated kinesin-II motors undergo rapid turnaround and recycling to the ciliary base, whereas OSM-3 is recycled mainly to the handover zone. This reveals a functional differentiation in which the slower, less processive kinesin II imports IFT trains into the cilium and OSM-3 drives their long-range transport, thereby optimizing cargo delivery. PMID- 26523367 TI - Strengthening laboratory capacity through the surveillance of rotavirus gastroenteritis in Central Africa: the Surveillance Epidemiologique en Afrique Centrale (SURVAC) Project. AB - OBJECTIVES: The goal of the SURVAC pilot project was to strengthen disease surveillance and response in three countries; Cameroon (CAE), Democratic Republic of the Congo (DRC) and Central African Republic (CAR). METHODS: Seven laboratories involved in rotavirus surveillance were provided with equipment, reagents and supplies. CDC and WHO staff provided on-site classroom and bench training in biosafety, quality assurance, quality control (QC), rotavirus diagnosis using Enzyme Immunoassay (EIA) and genotyping of rotavirus strains using the Reverse Transcription Polymerase-chain reaction (RT-PCR). All laboratory data were reported through WHO/AFRO. RESULTS: Twenty-three staff members were trained on RT-PCR for rotavirus genotyping which was introduced for the first time in all three countries. In CAE, the number of samples analysed by EIA and RT-PCR increased tenfold between 2007 and 2013. In DRC, this number increased fivefold, from 2009 to 2013 whereas in CAR, it increased fourfold between 2011 and 2013. All laboratories passed WHO proficiency testing in 2014. CONCLUSION: Laboratory capacity was strengthened through equipping laboratories and strengthening a subregional laboratory workforce for surveillance of rotavirus gastroenteritis. Each of the three countries generated rotavirus surveillance and genotyping data enabling the mapping of circulating genotypes. These results will help monitor the impact of rotavirus vaccination in these countries. PMID- 26523368 TI - Chest shielding for prevention of a haemodynamically significant patent ductus arteriosus in preterm infants receiving phototherapy. AB - BACKGROUND: Patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. Phototherapy is a common treatment for jaundice in preterm infants. However, phototherapy has been associated with failure of closure of the ductus arteriosus in preterm infants. OBJECTIVES: To determine if chest shielding of preterm infants receiving phototherapy reduces the incidence of clinically and/or haemodynamically significant PDA and reduces morbidity secondary to PDA. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library; 2015, Issue 3), MEDLINE, EMBASE, CINAHL, previous reviews, cross-references, abstracts, proceedings of scientific meetings, and trial registries through March 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster-RCTs, or quasi-RCTs of chest shielding during phototherapy compared to sham shielding or no shielding for the prevention of a haemodynamically or clinically significant PDA in preterm infants. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed studies for eligibility and quality and extracted data. We defined a clinically significant PDA as the presence of a PDA with clinical signs of an effect on organ function attributable to the ductus arteriosus. We defined a haemodynamically significant PDA as clinical and/or echocardiographic signs of a significant ductus arteriosus effect on blood flow. MAIN RESULTS: We included two small trials enrolling very preterm infants (Rosenfeld 1986; Travadi 2006). We assessed both as at high risk of bias. No study reported clinically significant PDA, defined as the presence of a PDA with clinical symptoms or signs attributable to the effect of a ductus arteriosus on organ function. Rosenfeld 1986 reported a non-significant reduction in haemodynamically significant PDA with left atrial to aortic root ratio greater than 1.2 (risk ratio (RR) 0.23, 95% confidence interval (CI) 0.05 to 1.01; 74 infants) but a statistically significant risk difference (RD -0.18, 95% CI -0.34 to -0.03; number needed to treat for an additional beneficial outcome (NNTB) 5, 95% CI 3 to 33). Rosenfeld 1986 reported a significant reduction in PDA detected by murmur (RR 0.50, 95% CI 0.29 to 0.88; RD -0.30, 95% CI -0.52 to -0.08; NNTB 3, 95% CI 2 to 12; 74 infants). Rosenfeld 1986 reported a significant reduction in treatment with indomethacin (RR 0.12, 95% CI 0.02 to 0.88; RD -0.21, 95% CI -0.35 to -0.06; NNTB 5, 95% CI 3 to 17; 74 infants), and only one infant had a ductal ligation in the no-shield group. There were no other significant outcomes, including mortality to discharge or 28 days, days in oxygen, days on mechanical ventilation, days in hospital, intraventricular haemorrhage, retinopathy of prematurity, or exchange transfusion. AUTHORS' CONCLUSIONS: The available evidence is very low quality and insufficient to assess the safety or efficacy of chest shield during phototherapy for prevention of PDA in preterm infants. Further trials of chest shielding are warranted, particularly in settings where infants are not receiving prophylactic or early echocardiographic targeted cyclo-oxygenase inhibitors for PDA. PMID- 26523369 TI - Colorectal Cancers with the Uncommon Findings of KRAS Mutation and Microsatellite Instability. AB - Sporadic colorectal cancers with microsatellite instability (MSI) frequently contain a mutation of the BRAF gene. Additionally, it has been shown that BRAF mutations in colorectal cancers are mutually exclusive of KRAS mutation. We evaluated 14 cases of colorectal cancer with MSI that were BRAF wild type but demonstrated a KRAS mutation. The codon 12/13 region in exon 2 of the KRAS oncogene and the codon 600 region in exon 15 of the BRAF gene were analyzed with standard PCR methods. MSI was evaluated by using the Bethesda panel of markers. The methylation status of the mismatch repair system was ascertained using the SALSA((r)) MS-MLPA((r)) methylation-specific DNA detection. The mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 were evaluated by immunohistochemical staining. A total of 530 colorectal cancers were studied for MSI and KRAS gene mutation. Fourteen (2.6%) cancers with both MSI and a KRAS mutation were identified, and all cancers were BRAF wild type. Methylation was present in 7 (50%), 5 demonstrated methylation of MLH1, 1 showed methylation of MGMT, and 1 showed methylation of MSH2. Four patients had simultaneous cancers, some of which showed different genetic changes. Immunohistochemical staining suggested a germ line mutation for 4 of 10 cases with complete staining information. KRAS mutation may occur with MSI in colorectal cancers with wild-type BRAF. If a mutation in KRAS co-exists with MSI, then strong methylation of the MLH1 gene is unlikely. These tumors demonstrate that a small number of colorectal cancers will develop with atypical patterns of molecular genetic changes, suggesting that a specific pattern of genetic changes may not be as crucial as the overall accumulation of changes, consistent with the 'unique tumor principle'. PMID- 26523370 TI - The consequences of tinnitus and tinnitus severity on cognition: A review of the behavioural evidence. AB - People with tinnitus report anecdotal difficulties in mental concentration and psychological treatments for tinnitus advise on concentration difficulties and how to manage them. Yet the literature lacks any coherent discussion about what precise theoretical cognitive constructs might be mediating reported concentration problems. This review addresses this gap by describing and critically appraising the behavioural evidence for the effects of tinnitus on cognitive performance (namely working memory and attention). Empirical evidence is somewhat limited, but there is some support that tinnitus interferes with executive attention, and mixed support that it impairs working memory and selective attention. We highlight a number of methodological considerations to help drive the field forward and we propose a putative model of the complex inter relationships between tinnitus, cognition and confounding factors. This model provides a basis for hypothesis testing. PMID- 26523371 TI - The immediate effects of acoustic trauma on excitation and inhibition in the inferior colliculus: A Wiener-kernel analysis. AB - Noise-induced tinnitus and hyperacusis are thought to correspond to a disrupted balance between excitation and inhibition in the central auditory system. Excitation and inhibition are often studied using pure tones; however, these responses do not reveal inhibition within the excitatory pass band. Therefore, we used a Wiener-kernel analysis, complemented with singular value decomposition (SVD), to investigate the immediate effects of acoustic trauma on excitation and inhibition in the inferior colliculus (IC). Neural responses were recorded from the IC of three anesthetized albino guinea pigs before and immediately after a one-hour bilateral exposure to an 11-kHz tone of 124 dB SPL. Neural activity was recorded during the presentation of a 1-h continuous 70 dB SPL Gaussian-noise stimulus. Spike trains were subjected to Wiener-kernel analysis in which the second-order kernel was decomposed into excitatory and inhibitory components using SVD. Hearing thresholds between 3 and 22 kHz were elevated (13-47 dB) immediately after acoustic trauma. The presence and frequency tuning of excitation and inhibition in units with a low characteristic frequency (CF; < 3 kHz) was not affected, inhibition disappeared whereas excitation was not affected in mid-CF units (3 < CF < 11 kHz), and both excitation and inhibition disappeared in high-CF units (CF > 11 kHz). This specific differentiation could not be identified by tone-evoked receptive-field analysis, in which inhibitory responses disappeared in all units, along with excitatory responses in high-CF units. This study is the first to apply Wiener-kernel analysis, complemented with SVD, to study the effects of acoustic trauma on spike trains derived from the IC. With this analysis, a reduction of inhibition and preservation of good response thresholds was shown in mid-CF units immediately after acoustic trauma. These neurons may mediate noise-induced tinnitus and/or hyperacusis. Moreover, an immediate profound high-frequency hearing loss was reflected by reduced evoked firing rates and loss of both excitation and inhibition in high-CF units. PMID- 26523372 TI - De Novo Donor-Specific HLA Antibody Formation in Two Patients With Crigler-Najjar Syndrome Type I Following Human Hepatocyte Transplantation With Partial Hepatectomy Preconditioning. AB - Clinical hepatocyte transplantation is hampered by low engraftment rates and gradual loss of function resulting in incomplete correction of the underlying disease. Preconditioning with partial hepatectomy improves engraftment in animal studies. Our aim was to study safety and efficacy of partial hepatectomy preconditioning in clinical hepatocyte transplantation. Two patients with Crigler Najjar syndrome type I underwent liver resection followed by hepatocyte transplantation. A transient increase of hepatocyte growth factor was seen, suggesting that this procedure provides a regenerative stimulus. Serum bilirubin was decreased by 50%, and presence of bilirubin glucuronides in bile confirmed graft function in both cases; however, graft function was lost due to discontinuation of immunosuppressive therapy in one patient. In the other patient, serum bilirubin gradually increased to pretransplant concentrations after ~600 days. In both cases, loss of graft function was temporally associated with emergence of human leukocyte antigen donor-specific antibodies (DSAs). In conclusion, partial hepatectomy in combination with hepatocyte transplantation was safe and induced a robust release of hepatocyte growth factor, but its efficacy on hepatocyte engraftment needs to be evaluated with additional studies. To our knowledge, this study provides the first description of de novo DSAs after hepatocyte transplantation associated with graft loss. PMID- 26523373 TI - [Abdominal tuberculosis, a diagnostic dilemma: report of a series of cases]. AB - INTRODUCTION: Abdominal tuberculosis is one of the most common non-pulmonary tuberculosis infection sites, and it relates to immunosuppression. The nonspecific features of this form of tuberculosis make an accurate diagnosis difficult. The aim of this study is to report seven (7) patients diagnosed with abdominal tuberculosis requiring surgery at the Clinical Hospital of Pontificia Universidad Catolica de Chile. METHODS: A descriptive analysis of seven cases of abdominal tuberculosis treated in our center between August 2001 and June 2013 was performed to characterize its clinical presentation and diagnostic elements. RESULTS: Four men and three women (29-68 years old) were diagnosed and operated on for abdominal tuberculosis: three had the peritoneal form of tuberculosis, two had a lymph nodal form and two had the intestinal form. In three cases, abdominal tuberculosis was associated with immunosuppression (HIV and rheumatoid arthritis treatment) and six cases presented with wasting syndrome of at least one month duration. Three patients had an acute presentation with signs of intestinal obstruction. Diagnosis was made by surgical biopsy. Of the seven patients, who underwent surgery, three required bowel resection for intestinal obstruction. CONCLUSION: Abdominal tuberculosis requires a high index of suspicion for an early diagnosis, especially in populations at risk. PMID- 26523374 TI - Background Intestinal 18F-FDG Uptake Is Related to Serum Lipid Profile and Obesity in Breast Cancer Patients. AB - BACKGROUND: This study investigated the relationships between background intestinal uptake on 18F-FDG PET and cardio-metabolic risk (CMR) factors. METHODS: A total of 326 female patients that underwent 18F-FDG PET to determine the initial stage of breast cancer were enrolled. None of the patients had history of diabetes or hypertension. The background intestinal uptake on PET was visually graded (low vs. high uptake group) and quantitatively measured using the maximal standardized uptake value (SUVmax). SUVmax of 7 bowel segments (duodenum, jejunum, ileum, cecum, hepatic flexure, splenic flexure, and descending colon sigmoid junction) were averaged for the total bowel (TB SUVmax). Age, body mass index (BMI), fasting blood glucose level (BST), triglyceride (TG), cholesterol, high density lipoprotein (HDL), and low density lipoprotein (LDL) were the considered CMR factors. The relationships between background intestinal 18F-FDG uptake on PET and diverse CMR factors were analyzed. RESULTS: The visual grades based on background intestinal 18F-FDG uptake classified 100 (30.7%) patients into the low uptake group, while 226 (69.3%) were classified into the high uptake group. Among CMR factors, age (p = 0.004), BMI (p<0.001), and TG (p<0.001) were significantly different according to visual grade of background intestinal 18F FDG uptake. Quantitative TB SUVmax showed significant positive correlation with age (r = 0.203, p<0.001), BMI (r = 0.373, p<0.001), TG (r = 0.338, p<0.001), cholesterol (r = 0.148, p = 0.008), and LDL (r = 0.143, p = 0.024) and significant negative correlation with HDL (r = -0.147, p = 0.022). Multivariate analysis indicated that BMI and TG were independent factors in both visually graded background intestinal 18F-FDG uptake (p = 0.027 and p = 0.023, respectively) and quantitatively measured TB SUVmax (p = 0.006 and p = 0.004, respectively). CONCLUSION: Increased background intestinal 18F-FDG uptake on PET may suggest alteration of lipid metabolism and risk of cardio-metabolic disease in non-diabetic and non-hypertensive breast cancer patients. PMID- 26523375 TI - The microRNA regulatory network: a far-reaching approach to the regulate the Wnt signaling pathway in number of diseases. AB - Wnt signaling pathway plays an important role in cell renewal, tumorigenesis, organogenesis, bone formation and bone resorption. Wnt signaling pathway is divided into two outlets: Wnt-beta-catenin pathway (canonical pathway) and Wnt calcium pathway (non-canonical pathway). miRNAs play a key role in the regulation of Wnt signaling pathway. In this review, we highlight the basic indulgent of miRNAs-mediated regulation of Wnt signaling pathway. We focus on the role of miRNAs at different levels of Wnt signaling: signaling molecules, their associated signaling proteins, regulatory proteins, transcription factors and related cytokines. Finally, we concluded that these multiple levels of targeting may have diagnostic potential as well as therapeutic prospective in future treatment. PMID- 26523376 TI - The Extracellular Domains of IgG1 and T Cell-Derived IL-4/IL-13 Are Critical for the Polyclonal Memory IgE Response In Vivo. AB - IgE-mediated activation of mast cells and basophils contributes to protective immunity against helminths but also causes allergic responses. The development and persistence of IgE responses are poorly understood, which is in part due to the low number of IgE-producing cells. Here, we used next generation sequencing to uncover a striking overlap between the IgE and IgG1 repertoires in helminth infected or OVA/alum-immunized wild-type BALB/c mice. The memory IgE response after secondary infection induced a strong increase of IgE+ plasma cells in spleen and lymph nodes. In contrast, germinal center B cells did not increase during secondary infection. Unexpectedly, the memory IgE response was lost in mice where the extracellular part of IgG1 had been replaced with IgE sequences. Adoptive transfer studies revealed that IgG1+ B cells were required and sufficient to constitute the memory IgE response in recipient mice. T cell derived IL-4/IL-13 was required for the memory IgE response but not for expansion of B cells from memory mice. Together, our results reveal a close relationship between the IgE and IgG1 repertoires in vivo and demonstrate that the memory IgE response is mainly conserved at the level of memory IgG1+ B cells. Therefore, targeting the generation and survival of allergen-specific IgG1+ B cells could lead to development of new therapeutic strategies to treat chronic allergic disorders. PMID- 26523379 TI - Secondary Bone Marrow Fibrosis in Children And Young Adults: An Institutional Experience. AB - Secondary bone marrow fibrosis (BMF) is associated with many disease conditions in children, but its prevalence and characteristics have not been well elucidated. We present our experience with pediatric secondary BMF, in an attempt to characterize it in terms of underlying diagnoses, severity, and outcome. A retrospective chart review of patients diagnosed with secondary BMF by bone marrow aspirate and biopsy between January 1984 and April 2011 showed a total of 214 patients, the majority (67.1%) of whom had an underlying oncologic disease. At diagnosis, 87 patients (39.7%) had mild, 51 (23.3%) had moderate, and 33 (15.1%) had marked BMF; it was not quantified in 48 (21.9%) patients. An underlying oncologic disease was more frequently associated with marked fibrosis compared with hematologic and miscellaneous diagnoses. Follow-up posttreatment bone marrow aspirate assessments were available for 117 patients. The outcome ranges from worsening of fibrosis to complete resolution. A majority of these children (N=70/117, 60%) showed complete resolution of fibrosis. Of note, 27 patients had marked fibrosis at initial diagnosis and 16 (60%) of them showed complete resolution. These findings underscore the importance of appropriate treatment of the underlying disorder in reversing secondary BMF. Ours is the largest series of pediatric secondary BMF reported. PMID- 26523378 TI - The folding of a metallopeptide. AB - We have applied solid-phase synthesis methods for the construction of tris(bipyridyl) peptidic ligands that coordinate Fe(ii) ions with high affinity and fold into stable mononuclear metallopeptides. The main factors influencing the folding pathway and chiral control of the peptidic ligands around the metal ions have been studied both by experimental techniques (CD, UV-vis and NMR) and molecular modeling tools. Amongst the numerous molecular variables that have been studied, this study clearly illustrates how the chirality of a given set of aminoacids (proline in this case) of the peptide dictates the chirality of the metal center of the resulting metallopeptide. Moreover, the relatively hydrophobic peptidic models used in this work show that the most stable structures present reduced solvent contacts and, in counterpart, stabilize the cis configuration of the proline residues. PMID- 26523377 TI - RNA-Seq SSRs of Moth Orchid and Screening for Molecular Markers across Genus Phalaenopsis (Orchidaceae). AB - BACKGROUND: The moth orchid (Phalaenopsis species) is an ornamental crop that is highly commercialized worldwide. Over 30,000 cultivars of moth orchids have been registered at the Royal Horticultural Society (RHS). These cultivars were obtained by artificial pollination of interspecific hybridization. Therefore, the identification of different cultivars is highly important in the worldwide market. METHODS/RESULTS: We used Illumina sequencing technology to analyze an important species for breeding, Phalaenopsis aphrodite subsp. formosana and develop the expressed sequence tag (EST)-simple sequence repeat (SSR) markers. After de novo assembly, the obtained sequence covered 29.1 Mb, approximately 2.2% of the P. aphrodite subsp. formosana genome (1,300 Mb), and a total of 1,439 EST SSR loci were detected. SSR occurs in the exon region, including the 5' untranslated region (UTR), coding region (CDS), and 3'UTR, on average every 20.22 kb. The di- and tri-nucleotide motifs (51.49% and 35.23%, respectively) were the two most frequent motifs in the P. aphrodite subsp. formosana. To validate the developed EST-SSR loci and to evaluate the transferability to the genus Phalaenopsis, thirty tri-nucleotide motifs of the EST-SSR loci were randomly selected to design EST-SSR primers and to evaluate the polymorphism and transferability across 22 native Phalaenopsis species that are usually used as parents for moth orchid breeding. Of the 30 EST-SSR loci, ten polymorphic and transferable SSR loci across the 22 native taxa can be obtained. The validated EST-SSR markers were further proven to discriminate 12 closely related Phalaenopsis cultivars. The results show that it is not difficult to obtain universal SSR markers by transcriptome deep sequencing in Phalaenopsis species. CONCLUSIONS: This study supported that transcriptome analysis based on deep sequencing is a powerful tool to develop SSR loci in non-model species. A large number of EST-SSR loci can be isolated, and about 33.33% EST-SSR loci are universal markers across the Phalaenopsis breeding germplasm after preliminary validation. The potential universal EST-SSR markers are highly valuable for identifying all of Phalaenopsis cultivars. PMID- 26523380 TI - Haploidentical Bone Marrow Transplantation With Clofarabine and Busulfan Conditioning for a Child With Multiple Recurrent Acute Lymphoblastic Leukemia. AB - Outcome of children with acute lymphoblastic leukemia (ALL) has improved over the years, but not for those with multiple recurrences because of high therapy resistance and heavily pretreated history that potentially cause physical damages. We describe the case of an 11-year-old boy with a third relapse of ALL and a history of 2 allogeneic bone marrow transplantations. He was successfully treated with clofarabine combination chemotherapy and achieved a fourth remission at 16 months following haploidentical bone marrow transplantation with conditioning regimen of clofarabine and busulfan. Clofarabine/busulfan conditioning might be a preferable option for children with multiple recurrent ALL, and warrants further investigation. PMID- 26523381 TI - Childhood Ewing Sarcoma of Orbit: Is It So Fatal? PMID- 26523382 TI - JAK2+ Essential Thrombocythemia in a Young Girl With Budd-Chiari Syndrome: Diagnostic and Therapeutic Considerations When Adult Disease Strikes the Young. AB - A 12-year-old female with Budd-Chiari syndrome underwent liver transplant and subsequent splenectomy. Her platelet count began to rise postoperatively after previous normal values. JAK2V617F-positive essential thrombocythemia (ET) was diagnosed. This case demonstrates that the diagnosis of ET should be considered in the face of normal platelet counts and included on the differential diagnosis for pediatric patients. With this population in mind, we review the current literature on long-term use of platelet-lowering agents. We conclude that it is reasonable to use anagrelide as a first-line treatment for ET diagnosed according to the World Health Organization (WHO) system. In cases where WHO criteria do not result in a definitive diagnosis or when a patient experiences thrombotic events despite anagrelide therapy, hydroxyurea may be utilized as a first-line agent or as an adjunct. Further study in this area is warranted. PMID- 26523383 TI - Risk Factors and Clinical Features of Cytomegalovirus Disease in Children Receiving Anticancer Chemotherapy. AB - This study was conducted to identify risk factors for cytomegalovirus (CMV) infection and demonstrate the spectrum of CMV disease in children receiving anticancer chemotherapy without hematopoietic stem cell transplantation (HSCT). A total of 289 children who received chemotherapy and were tested for CMV infection were included in the study. CMV antigenemia and DNAemia were determined by identifying the pp65 antigen in leukocytes and performing real-time PCR. CMV disease was diagnosed by tissue biopsy, culture, or ophthalmic examination. Of the 289 children, CMV infection was demonstrated in 46 patients (15.9%). Young age at cancer diagnosis was the risk factor for CMV infection by multivariate analysis (7 mo vs. 7 y, P<0.001). Among 46 children with CMV infection, 10 (21.7%) were diagnosed with CMV disease; hepatitis (n=4), retinitis (n=3), hepatitis and pneumonia (n=2), and hepatitis and retinitis (n=1). The age of the patients with CMV disease was significantly younger than those without (3 vs. 16 mo, P=0.023). Retinoblastoma and neuroblastoma were the 2 most common underlying malignancies. There were 2 fatal cases associated with CMV disease, including 1 who died of CMV pneumonia. The findings of this study demonstrated significant morbidity of CMV infection and disease in young children during the course of chemotherapy without HSCT. PMID- 26523384 TI - ME20-S as a Potential Biomarker for the Evaluation of Uveal Melanoma. AB - PURPOSE: We previously identified the presence of the melanocyte-specific secreted (ME20-S) glycoprotein in secretomes of uveal melanoma (UM) cultures. The aim of this study was to test for the presence and levels of ME20-S in the serum of patients with choroidal nevi and UM and correlate these levels with individual clinical data. METHODS: Serum ME20-S levels were determined by ELISA in 111 patients distributed into four categories (53 choroidal nevi, 30 untreated UM, 11 10-year disease-free [DF] UM, 17 hepatic metastatic UM) and 32 age- and sex matched controls. ME20-S levels were correlated with individual clinical data. RESULTS: The UM and the metastatic groups showed significantly higher levels of serum ME20-S than the other groups (P < 0.001). ME20-S levels in the DF patients did not differ from those in the control group. In addition, log-transformed serum ME20-S levels showed a positive correlation with the thickness of the lesion mass in UM patients (regression coefficient 0.0689, 95% confidence interval 0.0689-0.1123, R2 = 27.1%). CONCLUSIONS: Elevated ME20-S serum levels are associated with tumor size and advanced stages of UM while low levels are characteristic of DF patients. ME20-S might be a promising serum marker for UM and useful for monitoring metastatic disease. PMID- 26523385 TI - Comparison of the Pattern of Retinal Ganglion Cell Damage Between Patients With Compressive and Glaucomatous Optic Neuropathies. AB - PURPOSE: To compare the patterns of retinal ganglion cell (RGC) damage in the macular and peripapillary areas in compressive optic neuropathy (CON) and glaucomatous optic neuropathy (GON) using spectral-domain optical coherence tomography (SD-OCT), and to determine the usefulness of SD-OCT macular and peripapillary analysis in discriminating between CON and GON. METHODS: Sixty three eyes with CON, 68 eyes with GON, and 73 healthy control eyes were included. Spectral-domain OCT scanning of the circumpapillary and macular area was performed to measure the global and six-sector thicknesses of the circumpapillary retinal nerve fiber layer (cpRNFL), and the macular retinal nerve fiber layer (mRNFL) and macular ganglion cell layer (mGCL) thicknesses in the nine macular subfields as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS). RESULTS: Compared to the healthy eyes, the mRNFL was significantly thinner in six ETDRS subfields (inner and outer subfields of superior, nasal, and inferior areas) in CON, but in only two subfields (outer-inferior and outer-temporal subfields) in GON. The mGCL was thinner in all nine subfields in CON, but in only four subfields (inner and outer subfields of inferior and temporal areas) in GON. The temporal cpRNFL was significantly thinner in CON but was not involved in GON. The macular parameters performed better than cpRNFL parameters in discriminating between the CON and GON. CONCLUSIONS: Distinct differences in the patterns of RGC damage in the macular and peripapillary areas were found between CON and GON. Evaluation of the macular RGC damage may be a useful adjunct for distinguishing CON from GON when optic disc and visual field examinations are inconclusive. PMID- 26523386 TI - Nailfold Capillary Abnormalities in Primary Open-Angle Glaucoma: A Multisite Study. AB - PURPOSE: There is considerable evidence for systemic vascular dysfunction in primary open-angle glaucoma (POAG). We performed nailfold capillary video microscopy to observe directly the nature of nonocular microvasculature abnormalities in POAG. METHODS: We enrolled 199 POAG patients and 124 control subjects from four sites. We used JH-1004 capillaroscopes to perform nailfold capillary video microscopy on the fourth and fifth digits of each subject's nondominant hand. Videos were evaluated for hemorrhages, dilated capillary loops > 50 MUm, and avascular zones > 100 MUm by graders masked to case status. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) for POAG were obtained by means of logistic regression analyses that were applied to data from all cases and controls. Corresponding estimates of moderate or severe POAG versus mild POAG (based on the Hodapp-Anderson-Parrish scale) were obtained among cases only. RESULTS: After controlling for demographic factors, family history of glaucoma, systemic diseases, and use of anticoagulation and antiplatelet therapy, for each 100 nailfold capillaries assessed, all types of microvascular abnormalities were significantly associated with POAG. Specifically, the presence of any dilated capillaries (OR = 2.9; 95% CI, 1.6-5.6), avascular zones (OR = 4.4; 95% CI, 1.7-11.3) and hemorrhages (OR = 12.2; 95% CI, 5.9-25.1) were associated with POAG. Among cases, the frequency of microvascular abnormalities was not associated with glaucoma severity (P >= 0.43). CONCLUSIONS: These data provided support for nonocular capillary bed abnormalities in POAG. Comparable vascular abnormalities in the optic nerve may render it susceptible to glaucomatous damage. PMID- 26523387 TI - Distribution of the Crystalline Lens Power In Vivo as a Function of Age. AB - PURPOSE: To observe the age-related changes in crystalline lens power in vivo in a noncataractous European population. METHODS: Data were obtained though Project Gullstrand, a multicenter population study with data from healthy phakic subjects between 20 and 85 years old. One randomly selected eye per subject was used. Lens power was calculated using the modified Bennett-Rabbetts method, using biometry data from an autorefractometer, Oculus Pentacam, and Haag-Streit Lenstar. RESULTS: The study included 1069 Caucasian subjects (490 men, 579 women) with a mean age of 44.2 +/- 14.2 years and mean lens power of 24.96 +/- 2.18 diopters (D). The average lens power showed a statistically significant decrease as a function of age, with a steeper rate of decrease after the age of 55. The highest crystalline lens power was found in emmetropic eyes and eyes with a short axial length. The correlation of lens power with different refractive components was statistically significant for axial length (r = -0.523, P < 0.01) and anterior chamber depth (r = -0.161, P < 0.01), but not for spherical equivalent and corneal power (P > 0.05). CONCLUSIONS: This in vivo study showed a monotonous decrease in crystalline lens power with age, with a steeper decline after 55 years. While this finding fundamentally concurs with previous in vivo studies, it is at odds with studies performed on donor eyes that reported lens power increases after the age of 55. PMID- 26523388 TI - The Negative Cone Mosaic: A New Manifestation of the Optical Stiles-Crawford Effect in Normal Eyes. AB - PURPOSE: The purpose of this study was to describe a previously unreported manifestation of the optical Stiles-Crawford effect (oSCE) in normal eyes. METHODS: In a cohort of 50 normal subjects, the directional reflectance of cones in the retinal periphery was explored by flood-illuminated adaptive optics (FIAO) and optical coherence tomography (OCT). RESULTS: In 32 eyes (64%), off-axis FIAO images of the retinal periphery (~15-20 degrees from the fovea) showed variably sized patches of hyporeflective dots (called here negative mosaic) coexisting with hyperreflective (positive) cones. In nine cases, shifting the entry pupil toward the optical axis restored the positive cone mosaic, with a point-by-point correspondence between positive and negative mosaics. Rods remained hyperreflective around negative and positive cones. These changes were paralleled by changes of the OCT reflectance of the cone outer segment tips and, to a lesser extent, of the inner/outer segment limit. CONCLUSIONS: By en face FIAO imaging of the retina, the contrast of cones over rods may be strongly dependent on the entry pupil to such an extent that their reflectance is lower than that of rods. We hypothesized that the negative cone mosaic aspect results from the differential Stiles-Crawford effect of cones and rods. Cone reflectance by en face FIAO parallels the reflectance from the cone outer segment tip line and to a lesser extent of the inner/outer segment limit by OCT. Taking this into account, the oSCE is of importance for the interpretation of high-resolution images of photoreceptors. (ClinicalTrials.gov number, NCT01546181.) PMID- 26523389 TI - A robust transcriptional program in newts undergoing multiple events of lens regeneration throughout their lifespan. AB - Newts have the ability to repeatedly regenerate their lens even during ageing. However, it is unclear whether this regeneration reflects an undisturbed genetic activity. To answer this question, we compared the transcriptomes of lenses, irises and tails from aged newts that had undergone lens regeneration 19 times with the equivalent tissues from young newts that had never experienced lens regeneration. Our analysis indicates that repeatedly regenerated lenses showed a robust transcriptional program comparable to young never-regenerated lenses. In contrast, the tail, which was never regenerated, showed gene expression signatures of ageing. Our analysis strongly suggests that, with respect to gene expression, the regenerated lenses have not deviated from a robust transcriptional program even after multiple events of regeneration throughout the life of the newt. In addition, our study provides a new paradigm in biology, and establishes the newt as a key model for the study of regeneration in relation to ageing. PMID- 26523390 TI - Attention stabilizes the shared gain of V4 populations. AB - Responses of sensory neurons represent stimulus information, but are also influenced by internal state. For example, when monkeys direct their attention to a visual stimulus, the response gain of specific subsets of neurons in visual cortex changes. Here, we develop a functional model of population activity to investigate the structure of this effect. We fit the model to the spiking activity of bilateral neural populations in area V4, recorded while the animal performed a stimulus discrimination task under spatial attention. The model reveals four separate time-varying shared modulatory signals, the dominant two of which each target task-relevant neurons in one hemisphere. In attention-directed conditions, the associated shared modulatory signal decreases in variance. This finding provides an interpretable and parsimonious explanation for previous observations that attention reduces variability and noise correlations of sensory neurons. Finally, the recovered modulatory signals reflect previous reward, and are predictive of subsequent choice behavior. PMID- 26523391 TI - ETO family protein Mtgr1 mediates Prdm14 functions in stem cell maintenance and primordial germ cell formation. AB - Prdm14 is a sequence-specific transcriptional regulator of embryonic stem cell (ESC) pluripotency and primordial germ cell (PGC) formation. It exerts its function, at least in part, through repressing genes associated with epigenetic modification and cell differentiation. Here, we show that this repressive function is mediated through an ETO-family co-repressor Mtgr1, which tightly binds to the pre-SET/SET domains of Prdm14 and co-occupies its genomic targets in mouse ESCs. We generated two monobodies, synthetic binding proteins, targeting the Prdm14 SET domain and demonstrate their utility, respectively, in facilitating crystallization and structure determination of the Prdm14-Mtgr1 complex, or as genetically encoded inhibitor of the Prdm14-Mtgr1 interaction. Structure-guided point mutants and the monobody abrogated the Prdm14-Mtgr1 association and disrupted Prdm14's function in mESC gene expression and PGC formation in vitro. Altogether, our work uncovers the molecular mechanism underlying Prdm14-mediated repression and provides renewable reagents for studying and controlling Prdm14 functions. PMID- 26523392 TI - Translocation of interleukin-1beta into a vesicle intermediate in autophagy mediated secretion. AB - Recent evidence suggests that autophagy facilitates the unconventional secretion of the pro-inflammatory cytokine interleukin 1beta (IL-1beta). Here, we reconstituted an autophagy-regulated secretion of mature IL-1beta (m-IL-1beta) in non-macrophage cells. We found that cytoplasmic IL-1beta associates with the autophagosome and m-IL-1beta enters into the lumen of a vesicle intermediate but not into the cytoplasmic interior formed by engulfment of the autophagic membrane. In advance of secretion, m-IL-1beta appears to be translocated across a membrane in an event that may require m-IL-1beta to be unfolded or remain conformationally flexible and is dependent on two KFERQ-like motifs essential for the association of IL-1beta with HSP90. A vesicle, possibly a precursor of the phagophore, contains translocated m-IL-1beta and later turns into an autophagosome in which m-IL-1beta resides within the intermembrane space of the double-membrane structure. Completion of IL-1beta secretion requires Golgi reassembly and stacking proteins (GRASPs) and multi-vesicular body (MVB) formation. PMID- 26523393 TI - Temporal transcriptomics suggest that twin-peaking genes reset the clock. AB - The mammalian suprachiasmatic nucleus (SCN) drives daily rhythmic behavior and physiology, yet a detailed understanding of its coordinated transcriptional programmes is lacking. To reveal the finer details of circadian variation in the mammalian SCN transcriptome we combined laser-capture microdissection (LCM) and RNA-seq over a 24 hr light / dark cycle. We show that 7-times more genes exhibited a classic sinusoidal expression signature than previously observed in the SCN. Another group of 766 genes unexpectedly peaked twice, near both the start and end of the dark phase; this twin-peaking group is significantly enriched for synaptic transmission genes that are crucial for light-induced phase shifting of the circadian clock. 341 intergenic non-coding RNAs, together with novel exons of annotated protein-coding genes, including Cry1, also show specific circadian expression variation. Overall, our data provide an important chronobiological resource (www.wgpembroke.com/shiny/SCNseq/) and allow us to propose that transcriptional timing in the SCN is gating clock resetting mechanisms. PMID- 26523394 TI - Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system. AB - Regulation of ubiquitin-proteasome system (UPS), which controls the turnover of short-lived proteins in eukaryotic cells, is critical in maintaining cellular proteostasis. Here we show that USP14, a major deubiquitinating enzyme that regulates the UPS, is a substrate of Akt, a serine/threonine-specific protein kinase critical in mediating intracellular signaling transducer for growth factors. We report that Akt-mediated phosphorylation of USP14 at Ser432, which normally blocks its catalytic site in the inactive conformation, activates its deubiquitinating activity in vitro and in cells. We also demonstrate that phosphorylation of USP14 is critical for Akt to regulate proteasome activity and consequently global protein degradation. Since Akt can be activated by a wide range of growth factors and is under negative control by phosphoinosotide phosphatase PTEN, we suggest that regulation of UPS by Akt-mediated phosphorylation of USP14 may provide a common mechanism for growth factors to control global proteostasis and for promoting tumorigenesis in PTEN-negative cancer cells. PMID- 26523397 TI - Recent developments in the use of online resources and mobile technologies to support mental health care. AB - This review describes recent developments in online and mobile mental health applications, including a discussion of patient portals to support mental health care. These technologies are rapidly evolving, often before there is systematic investigation of their effectiveness. Though there are some reviews of the effectiveness of mental health mobile apps, perhaps the more significant development is innovation in technology evaluation as well as new models of interprofessional collaboration in developing behavioural health technologies. Online mental health programs have a strong evidence base. Their role in population health strategies needs further exploration, including the most effective use of limited clinical staff resources. Patient portals and personal health records serve to enhance mental health treatment also, though concerns specific to mental health must be addressed to support broader adoption of portals. Provider concerns about sharing psychiatric notes with patients hinder support for portals. Health information exchange for mental health information requires thoughtful consent management strategies so mental health patients can benefit. Finally, the broad array of health information technologies may overwhelm patients. User-friendly, well-designed, patient-centred health information technology homes may integrate these functions to promote a holistic approach to care plans and overall wellness. Such technology homes have special security needs and require providers and patients to be well informed about how best to use these technologies to support behavioural health interventions. PMID- 26523395 TI - A dynamic RNA loop in an IRES affects multiple steps of elongation factor mediated translation initiation. AB - Internal ribosome entry sites (IRESs) are powerful model systems to understand how the translation machinery can be manipulated by structured RNAs and for exploring inherent features of ribosome function. The intergenic region (IGR) IRESs from the Dicistroviridae family of viruses are structured RNAs that bind directly to the ribosome and initiate translation by co-opting the translation elongation cycle. These IRESs require an RNA pseudoknot that mimics a codon anticodon interaction and contains a conformationally dynamic loop. We explored the role of this loop and found that both the length and sequence are essential for translation in different types of IGR IRESs and from diverse viruses. We found that loop 3 affects two discrete elongation factor-dependent steps in the IRES initiation mechanism. Our results show how the IRES directs multiple steps after 80S ribosome placement and highlights the often underappreciated significance of discrete conformationally dynamic elements within the context of structured RNAs. PMID- 26523396 TI - Role of competition between polarity sites in establishing a unique front. AB - Polarity establishment in many cells is thought to occur via positive feedback that reinforces even tiny asymmetries in polarity protein distribution. Cdc42 and related GTPases are activated and accumulate in a patch of the cortex that defines the front of the cell. Positive feedback enables spontaneous polarization triggered by stochastic fluctuations, but as such fluctuations can occur at multiple locations, how do cells ensure that they make only one front? In polarizing cells of the model yeast Saccharomyces cerevisiae, positive feedback can trigger growth of several Cdc42 clusters at the same time, but this multi cluster stage rapidly evolves to a single-cluster state, which then promotes bud emergence. By manipulating polarity protein dynamics, we show that resolution of multi-cluster intermediates occurs through a greedy competition between clusters to recruit and retain polarity proteins from a shared intracellular pool. PMID- 26523398 TI - Enhancing Self-Efficacy and Performance: An Experimental Comparison of Psychological Techniques. AB - PURPOSE: We assessed how 6 psychological performance enhancement techniques (PETs) differentially improved self-efficacy (SE) and skill performance. We also assessed whether vicarious experiences and verbal persuasion as posited sources of SE (Bandura, 1982 ) were supported and, further, if the effects of the 6 PETs remained after controlling for achievement motivation traits and self-esteem. METHOD: A within-subject design assessed each individual across 2 trials for 3 disparate PETs. A between-groups design assessed differences between PETs paired against each other for 3 similar novel tasks. Participants (N = 96) performed 2 trials of 10 attempts at each of the tasks (kick, throw, golf putt) in a counterbalanced sequence using their nondominant limb. Participants completed the Sport Orientation Questionnaire, Rosenberg Self-Esteem Scale, and General Self Efficacy Scale and were randomly allocated to either the modeling or imagery, goal-setting or instructional self-statement, or knowledge-of-results or motivational feedback conditions aligned with each task. RESULTS: An instructional self-statement improved performance better than imagery, modeling, goal setting, and motivational and knowledge-of-results augmented feedback. Motivational auditory feedback most improved SE. Increased SE change scores were related to increased performance difference scores on all tasks after controlling for age, sex, achievement motivation, and self-esteem. CONCLUSIONS: Some sources of SE may be more influential than others on both SE and performance improvements. We provide partial support for the sources of SE proposed by Bandura's social-cognitive theory with verbal persuasion but not vicarious experiences improving SE. PMID- 26523399 TI - The influence of printing parameters on cell survival rate and printability in microextrusion-based 3D cell printing technology. AB - Three-dimensional (3D) cell printing technology has provided a versatile methodology to fabricate cell-laden tissue-like constructs and in vitro tissue/pathological models for tissue engineering, drug testing and screening applications. However, it still remains a challenge to print bioinks with high viscoelasticity to achieve long-term stable structure and maintain high cell survival rate after printing at the same time. In this study, we systematically investigated the influence of 3D cell printing parameters, i.e. composition and concentration of bioink, holding temperature and holding time, on the printability and cell survival rate in microextrusion-based 3D cell printing technology. Rheological measurements were utilized to characterize the viscoelasticity of gelatin-based bioinks. Results demonstrated that the bioink viscoelasticity was increased when increasing the bioink concentration, increasing holding time and decreasing holding temperature below gelation temperature. The decline of cell survival rate after 3D cell printing process was observed when increasing the viscoelasticity of the gelatin-based bioinks. However, different process parameter combinations would result in the similar rheological characteristics and thus showed similar cell survival rate after 3D bioprinting process. On the other hand, bioink viscoelasticity should also reach a certain point to ensure good printability and shape fidelity. At last, we proposed a protocol for 3D bioprinting of temperature-sensitive gelatin-based hydrogel bioinks with both high cell survival rate and good printability. This research would be useful for biofabrication researchers to adjust the 3D bioprinting process parameters quickly and as a referable template for designing new bioinks. PMID- 26523400 TI - Six-year analysis of compliance to weekly concurrent chemoradiotherapy in head and neck carcinomas. AB - OBJECTIVES: To evaluate treatment compliance to weekly concurrent chemoradiotherapy (CRT) in head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Retrospective analysis. SETTING: Tertiary care hospital. MAIN OUTCOME MEASURES: Overall treatment time (OTT), acute radiation morbidity and treatment completion rate without prolongation of overall treatment time of more than 2 days. RESULTS: Three hundred and seventy-eight head and neck carcinoma patients treated with radical CRT with 70 Gy/35 fractions of radiotherapy with weekly cisplatin 40 mg/m(2) were included in the study. Median age was 52 years (range 22-77 years), oropharynx was most commonly (54%) involved site, and 55% were in stage IV disease. Majority (86%) of patients were able to complete cancer directed therapy, median OTT was 52 days (46-140 days). Nineteen per cent of patients completed treatment without prolongation of OTT beyond 2 days and 68% of patients there completed treatment prolongation of OTT beyond 7 days. Nearly, sixty-six of the patients experienced grade II or higher acute radiation morbidities. CONCLUSIONS: Delivery of weekly low-dose concurrent CRT is safe and feasible. Two-thirds of the patients experienced treatment prolongation of more than 2 days and 14% could not complete treatment. Results within in the study suggest to a greater need to lay emphasis on continuity of a course of radical CRT for HNSCC. PMID- 26523402 TI - Deletion of a telomeric region on chromosome 8 correlates with higher productivity and stability of CHO cell lines. AB - Chinese Hamster Ovary (CHO) cells are widely used for large scale production of recombinant biopharmaceuticals. Although these cells have been extensively used, a demand to further increase the performance, for example, to facilitate the process of clone selection to isolate the highest producing cell lines that maintain stability of production over time is still existing. We compared gene expression profiles of high versus low producing CHO clones to identify regulated genes which can be used as biomarkers during clone selection or for cell line engineering. We present evidence that increased production rates and cell line stability are correlated with the loss of the telomeric region of the chromosome 8. A new parental CHO cell line lacking this region was generated and its capability for protein production was assessed. The average volumetric productivity of cells after gene transfer and selection was found to be several fold improved, facilitating the supply of early drug substance material to determine for example, quality. In addition, significantly more cell clones with a higher average productivity and higher protein production stability were obtained with the new host cell line after single cell cloning. This allows reduced efforts in single cell sorting, screening of fewer clones and raises the opportunity to circumvent time and labor-intensive stability studies. PMID- 26523404 TI - Fe- and Co-P4-embedded graphenes as electrocatalysts for the oxygen reduction reaction: theoretical insights. AB - Encouraged by the great promise of metal-nitrogen-carbon (M-N-C) materials in replacing Pt for catalyzing the oxygen reduction reaction (ORR), metal-P species were successfully introduced into carbon matrices in experiments and have exhibited high catalytic activity for the ORR. Here, by means of comprehensive density functional theory (DFT) computations, we investigated the origin and the mechanism of the ORR occurring on Fe- and Co-P-embedded graphenes. Our computations have revealed that the Fe- and Co-P4 moiety-embedded graphenes possess good stability and high chemical reactivity for O2 activation, thus facilitating the subsequent ORR steps, and a more efficient 4e pathway in both acidic and alkaline media is more energetically favorable. Furthermore, by analyzing the computed free energy profiles, the Fe-P4 species-embedded graphene is a more efficient electrocatalyst for the ORR in an alkaline medium than the Co P4 species-embedded graphene. Our DFT computations will be useful for gaining deeper insight into the high activity of metal-P species. PMID- 26523403 TI - The distribution of hepatitis B virus exposure and infection in a population based sample of U.S. Hispanic adults. AB - Little is known regarding the prevalence and distribution of hepatitis B virus (HBV) infection in U.S. Hispanics/Latinos. We sought to determine the prevalence of HBV exposure (serum HBV core antibody; anti-HBc), active HBV infection (serum HBV surface antigen; HBsAg), and vaccine-induced HBV immunity (antibody against HBV surface antigen; anti-HBs) in U.S. Hispanics/Latinos and consider how these data inform clinical screening recommendations. Our analysis included 11,999 women and men of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a population-based, household survey in four urban communities (Bronx, NY; Miami, FL; Chicago, IL; and San Diego, CA) of U.S. civilian, noninstitutionalized self identifying Hispanic/Latino adults ages 18-74. Vaccine-induced immunity was defined as detection of anti-HBs, but not anti-HBc. However, if anti-HBc were present, it was considered evidence of exposure to HBV, with detection of HBsAg used to distinguish those with active HBV infection. Mean age was 45.7 years, and 7,153 were women. Vaccine-induced immunity was greatest among those ages 18-29 years (60.2% in women, 54% in men) and decreased with increasing age, regardless of country of birth. The prevalence of active HBV infection was 0.29% (95% confidence interval: 0.19-0.43), but varied by country of birth. Those born in the Dominican Republic had the highest prevalence of HBV exposure (20.3% in women, 29.7% in men) and active HBV infection (0.95%). CONCLUSIONS: The overall age-standardized prevalence of active HBV infection in Hispanic/Latino adults (0.29%) was no different from the general U.S. population estimate (0.27%) and did not exceed 2%, regardless of country of birth. These data do not support targeting HBV screening to US Hispanic/Latino adults based upon background. PMID- 26523406 TI - Immunoregulation of antigen presenting and secretory functions of monocytic cells by Helicobacter pylori antigens in relation to impairment of lymphocyte expansion. AB - The role of Helicobacter pylori (H. pylori) antigens in driving a specific immune response against the bacteria causing gastroduodenal disorders is poorly understood. Using a guinea pig model mimicking the natural history of H. pylori infection, we evaluated the effectiveness of immature and mature macrophages in promoting the blastogenesis of splenocytes from H. pylori infected and uninfected animals, in response to H. pylori antigens: glycine acid extract (GE), cytotoxin associated gene A protein (CagA), urease A (UreA) and lipopolysaccharide (LPS). Lymphocyte expansion was assessed in 72 h cell cultures, containing: immature or mature macrophages derived from bone marrow monocytes, unstimulated or stimulated with H. pylori antigens for 2 h. The proliferation was expressed as a ratio of [(3)H]-thymidine incorporation into DNA of antigen-stimulated to unstimulated cells and the DNA damage was determined by DAPI cell staining. TGF-beta and IFN gamma were assessed immunoenzymatically in cell culture supernatants. Lymphocytes of control and H. pylori-infected animals proliferated intensively in response to phytohaemagglutinin (PHA) and in co-cultures with immature or mature macrophages treated with CagA or UreA (significantly) and GE (slightly) exluding the cultures containing H. pylori or E. coli LPS. This lymphocyte growth inhibition was related to DNA damage of monocytic cells in response to H. pylori or E. coli LPS and secretion of regulatory TGF-beta, but not proinflammatory IFN-gamma. Impaired homeostasis of monocytic cell function related to DNA damage and TGF-beta release, in response to H. pylori LPS may lead to the suppression of adaptive immune response against the bacteria and development of chronic infection. PMID- 26523405 TI - Atrial Fibrillation Predictors: Importance of the Electrocardiogram. AB - Atrial fibrillation (AF) is the most common arrhythmia in adults and is associated with significant morbidity and mortality. Substantial interest has developed in the primary prevention of AF, and thus the identification of individuals at risk for developing AF. The electrocardiogram (ECG) provides a wealth of information, which is of value in predicting incident AF. The PR interval and P wave indices (including P wave duration, P wave terminal force, P wave axis, and other measures of P wave morphology) are discussed with regard to their ability to predict and characterize AF risk in the general population. The predictive value of the QT interval, ECG criteria for left ventricular hypertrophy, and findings of atrial and ventricular ectopy are also discussed. Efforts are underway to develop models that predict AF incidence in the general population; however, at present, little information from the ECG is included in these models. The ECG provides a great deal of information on AF risk and has the potential to contribute substantially to AF risk estimation, but more research is needed. PMID- 26523407 TI - Changes is genes coding for laccases 1 and 2 may contribute to deformation and reduction of wings in apollo butterfly (Parnassius apollo, Lepidoptera: Papilionidae) from the isolated population in Pieniny National Park (Poland). AB - An isolated population of apollo butterfly (Parnassius apollo, Lepidoptera: Papilionidae) occurs in Pieniny National Park (Poland). Deformations and reductions of wings in a relatively large number of individuals from this population is found, yet the reasons for these defects are unknown. During studies devoted to identify cause(s) of this phenomenon, we found that specific regions of genes coding of enzymes laccases 1 and 2 could not be amplified from DNA samples isolated from large fractions of malformed insects while expected PCR products were detected in almost all (with one exception) normal butterflies. Laccases (p-diphenol:dioxygen oxidoreductases) are oxidases containing several copper atoms. They catalyse single-electron oxidations of phenolic or other compounds with concomitant reduction of oxygen to water. In insects, their enzymatic activities were found previously in epidermis, midgut, Malpighian tubules, salivary glands, and reproductive tissues. Therefore, we suggest that defects in genes coding for laccases might contribute to deformation and reduction of wings in apollo butterflies, though it seems obvious that deficiency in these enzymes could not be the sole cause of these developmental improperties in P. apollo from Pieniny National Park. PMID- 26523408 TI - Hit 'em where it hurts: The growing and structurally diverse family of peptides that target lipid-II. AB - Understanding the mode of action of antibiotics is becoming more and more important in the time that microorganisms start to develop resistance. One very well validated target of several classes of antibiotics is the peptidoglycan precursor lipid II. In this review different classes of lipid II targeting antibiotics will be discussed in detail, including the lantibiotics, human invertebrate defensins and the recently discovered teixobactin. By hitting bacteria where it hurts, at the level of lipid II, we expect to be able to develop efficient antibacterial agents in the future. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. PMID- 26523409 TI - Channel formation by RTX-toxins of pathogenic bacteria: Basis of their biological activity. AB - The pore-forming cytolysins of the RTX-toxin (Repeats in ToXin) family are a relatively small fraction of a steadily increasing family of proteins that contain several functionally important glycine-rich and aspartate containing nonapeptide repeats. These cytolysins produced by a variety of Gram-negative bacteria form ion-permeable channels in erythrocytes and other eukaryotic cells. Hemolytic and cytolytic RTX-toxins represent pathogenicity factors of the toxin producing bacteria and are very often important key factors in pathogenesis of the bacteria. Channel formation by RTX-toxins lead to the dissipation of ionic gradients and membrane potential across the cytoplasmic membrane of target cells, which results in cell death. Here we discuss channel formation and channel properties of some of the best known RTX-toxins, such as alpha-hemolysin (HlyA) of Escherichia coli and the uropathogenic EHEC strains, the adenylate cyclase toxin (ACT, CyaA) of Bordetella pertussis and the RTX-toxins (ApxI, ApxII and ApxIII) produced by different strains of Actinobacillus pleuropneumoniae. The channels formed by these RTX-toxins in lipid bilayers share some common properties such as cation selectivity and voltage-dependence. Furthermore the channels are transient and show frequent switching between different ion conducting states. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale. PMID- 26523410 TI - Retrospective evaluation of recurrent secondary septic peritonitis in dogs (2000 2011): 41 cases. AB - OBJECTIVE: To describe the clinical characteristics of recurrent septic peritonitis in dogs. DESIGN: Multicenter retrospective observational study. ANIMALS: Client-owned dogs with recurrent septic peritonitis. SETTING: Three university emergency and referral hospitals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Medical records from 3 veterinary university teaching hospitals were reviewed and data were collected using a standardized data collection sheet for all cases of septic peritonitis during the study period (2000-2011). Forty one dogs met the inclusion criteria for recurrent peritonitis. All dogs underwent relaparotomy. The original cause of septic peritonitis in these cases included previous surgery for gastrointestinal foreign body removal (n = 26), gastrointestinal neoplasia (n = 3), gastric or duodenal ulceration (n = 3), biliary tract leakage (n = 2), and single instance for each of the following: penetrating foreign body, hernia strangulation, intussusception, mesenteric volvulus, infection of the laparotomy incision, prostatic abscess, and trauma. Eighteen animals survived to discharge. There was no difference detected between survivors and nonsurvivors with recurrent peritonitis in terms of inciting cause, serum albumin concentration, surgical management, or provision of appropriate initial antimicrobials. The survival rate for dogs having recurrent peritonitis was 43.9% (18/41 dogs). CONCLUSIONS: This retrospective study did not identify any significant prognostic indicators for dogs with recurrent peritonitis and that the mortality rate for dogs having more than one surgery for septic peritonitis is similar to that reported for a single surgery for septic peritonitis. PMID- 26523411 TI - Microfluidics for the detection of minimal residual disease in acute myeloid leukemia patients using circulating leukemic cells selected from blood. AB - We report a highly sensitive microfluidic assay to detect minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) that samples peripheral blood to search for circulating leukemic cells (CLCs). Antibodies immobilized within three separate microfluidic devices affinity-selected CLC subpopulations directly from peripheral blood without requiring pre-processing. The microfluidic devices targeted CD33, CD34, and CD117 cell surface antigens commonly expressed by AML leukemic cells so that each subpopulation's CLC numbers could be tracked to determine the onset of relapse. Staining against aberrant markers (e.g. CD7, CD56) identified low levels (11-2684 mL(-1)) of CLCs. The commonly used platforms for the detection of MRD for AML patients are multi parameter flow cytometry (MFC), typically from highly invasive bone marrow biopsies, or PCR from blood samples, which is limited to <50% of AML patients. In contrast, the microfluidic assay is a highly sensitive blood test that permits frequent sampling for >90% of all AML patients using the markers selected for this study (selection markers CD33, CD34, CD117 and aberrant markers such as CD7 and CD56). We present data from AML patients after stem cell transplant (SCT) therapy using our assay. We observed high agreement of the microfluidic assay with therapeutic treatment and overall outcome. We could detect MRD at an earlier stage compared to both MFC and PCR directly from peripheral blood, obviating the need for a painful bone marrow biopsy. Using the microfluidic assay, we detected MRD 28 days following one patient's SCT and the onset of relapse at day 57, while PCR from a bone marrow biopsy did not detect MRD until day 85 for the same patient. Earlier detection of MRD in AML post-SCT enabled by peripheral blood sampling using the microfluidic assay we report herein can influence curative clinical decisions for AML patients. PMID- 26523412 TI - Experimental and Quantum Chemical Evaluations of Pyridine Oxidation Under Drug Development Stress Test Conditions. AB - The oxidation reaction of pyridine by hydrogen peroxides in water media was investigated by combining quantum chemical calculations and laboratory experiments. Pyridine was selected as a model system for aromatic amines that frequently occurs in drug molecules. Several different reaction conditions, commonly used in stress testing of drug molecules during drug development, were investigated to increase mechanistic insight to this class of oxidation reactions. Of special interest is to note that small amounts of acetonitrile, a regularly used cosolvent to keep poorly soluble drug molecules in water solution, could catalyze the oxidation reaction in the presence of hydrogen peroxide. Consequently, attention needs to be taken when comparing data from different stress test studies of amine oxidation by hydrogen peroxides at different pH, and with and without acetonitrile. In particular, they need to be controlled when identifying the proper intrinsic stability of the drug molecule. PMID- 26523413 TI - Marsupial and monotreme serum immunoglobulin binding by proteins A, G and L and anti-kangaroo antibody. AB - Serological studies are often conducted to examine exposure to infectious agents in wildlife populations. However, specific immunological reagents for wildlife species are seldom available and can limit the study of infectious diseases in these animals. This study examined the ability of four commercially available immunoglobulin-binding reagents to bind serum immunoglobulins from 17 species within the Marsupialia and Monotremata. Serum samples were assessed for binding, using immunoblots and ELISAs (Enzyme-linked immunosorbent assays), to three microbially-derived proteins - staphylococcal protein A, streptococcal protein G and peptostreptococcal protein L. Additionally, an anti-kangaroo antibody was included for comparison. The inter- and intra-familial binding patterns of the reagents to serum immunoglobulins varied and evolutionary distance between animal species was not an accurate predictor of the ability of reagents to bind immunoglobulins. Results from this study can be used to inform the selection of appropriate immunological reagents in future serological studies in these clades. PMID- 26523414 TI - The presence of nodules on legume root systems can alter phenotypic plasticity in response to internal nitrogen independent of nitrogen fixation. AB - All higher plants show developmental plasticity in response to the availability of nitrogen (N) in the soil. In legumes, N starvation causes the formation of root nodules, where symbiotic rhizobacteria fix atmospheric N2 for the host in exchange for fixed carbon (C) from the shoot. Here, we tested whether plastic responses to internal [N] of legumes are altered by their symbionts. Glasshouse experiments compared root phenotypes of three legumes, Medicago truncatula, Medicago sativa and Trifolium subterraneum, inoculated with their compatible symbiont partners and grown under four nitrate levels. In addition, six strains of rhizobia, differing in their ability to fix N2 in M. truncatula, were compared to test if plastic responses to internal [N] were dependent on the rhizobia or N2 -fixing capability of the nodules. We found that the presence of rhizobia affected phenotypic plasticity of the legumes to internal [N], particularly in root length and root mass ratio (RMR), in a plant species-dependent way. While root length responses of M. truncatula to internal [N] were dependent on the ability of rhizobial symbionts to fix N2 , RMR response to internal [N] was dependent only on initiation of nodules, irrespective of N2 -fixing ability of the rhizobia strains. PMID- 26523415 TI - Lack of a unique kinetic pathway in the growth and decay of Pluronic micelles. AB - We report kinetic experiments on dilute brine solutions of P84, P94 and P104 Pluronic copolymer micelles. The growth and the decay of micelles after temperature steps are measured by non-standard time resolved multi-angle photon correlation spectroscopy. Several concurrent mechanisms are at work during the very slow equilibration of solutions, namely insertion/expulsion of unimers, aggregation/dissociation of micellar aggregates, and fusion/budding of micellar aggregates. Their relative rates determine both the kinetic pathways and the morphologies of the micellar assemblies, which depend markedly on modest changes in the copolymer molecular weight. For the typical Pluronic copolymers investigated here, none of these elementary processes can be neglected if the resulting morphology is to be explained. This feature imposes multiple kinetic behaviours where growth and decay of Pluronic micelles become strongly dependent on the thermal history. We point out to some possible shortcomings in the studies of micellar growth kinetics by light scattering techniques. Extensive time resolved multiangle measurements are a prerequisite for avoiding these pitfalls. PMID- 26523417 TI - Is Increased Use of Mechanical Circulatory Support Devices Justified? A Cause for Concern. PMID- 26523416 TI - DBSproc: An open source process for DBS electrode localization and tractographic analysis. AB - Deep brain stimulation (DBS) is an effective surgical treatment for movement disorders. Although stimulation sites for movement disorders such as Parkinson's disease are established, the therapeutic mechanisms of DBS remain controversial. Recent research suggests that specific white-matter tract and circuit activation mediates symptom relief. To investigate these questions, we have developed a patient-specific open-source software pipeline called 'DBSproc' for (1) localizing DBS electrodes and contacts from postoperative CT images, (2) processing structural and diffusion MRI data, (3) registering all images to a common space, (4) estimating DBS activation volume from patient-specific voltage and impedance, and (5) understanding the DBS contact-brain connectivity through probabilistic tractography. In this paper, we explain our methodology and provide validation with anatomical and tractographic data. This method can be used to help investigate mechanisms of action of DBS, inform surgical and clinical assessments, and define new therapeutic targets. PMID- 26523418 TI - How the Mediterranean diet and some of its components modulate inflammatory pathways in arthritis. AB - Arthritis encompasses a heterogeneous group of diseases characterised by inflammation that leads not only to joint damage, bone erosion, severe pain and disability, but also affects other organs of the body, resulting in increased morbidity and mortality. Although the mechanisms underlying the pathogenesis of joint diseases are for the most part unknown, a number of nutrient and non nutrient components of food have been shown to affect the inflammatory process and, in particular, to influence clinical disease progression. The Mediterranean diet model has already been linked to a number of beneficial health effects: both fat and non-fat components of the Mediterranean dietary pattern have been shown to exert important anti-inflammatory activities by affecting the arachidonic acid cascade, the expression of some proinflammatory genes, and the activity of immune cells. N-3 polyunsaturated fatty acids, in particular, have been shown to affect lymphocyte and monocyte functions, crucially involved in adaptive and innate immunity. Although some aspects concerning the mechanisms of action through which the Mediterranean diet pattern exerts its beneficial effects remain to be elucidated, arthritis patients may potentially benefit from it in view of their increased cardiovascular risk and the treatment they require which may have side effects. PMID- 26523419 TI - (9betaH)-Pimaranes and Derivatives from the Tuber of Icacina trichantha. AB - New 17-nor-pimaranes (1, 2), (9betaH)-pimaranes (3, 4), and 17-nor-(9betaH) pimarane (5) were isolated from the tuber of Icacina trichantha. The structures were elucidated based on spectroscopic and HRMS data. The absolute configurations of 3 and 5 were determined by single-crystal X-ray diffraction. Compound 5 possesses a unique 19,20-delta-lactone moiety. Compound 3 showed cytotoxicity against MDA-MB-435 (human melanoma cancer) cells with an IC50 value of 7.04 MUM. A plausible biogenetic pathway for compounds 1-5 is proposed. PMID- 26523420 TI - Chemical and Isotopic Thresholds in Charring: Implications for the Interpretation of Charcoal Mass and Isotopic Data. AB - Charcoal plays a significant role in the long-term carbon cycle, and its use as a soil amendment is promoted as a C sequestration strategy (biochar). One challenge in this research area is understanding the heterogeneity of charcoal properties. Although the maximum reaction temperature is often used as a gauge of pyrolysis conditions, pyrolysis duration also changes charcoal physicochemical qualities. Here, we introduce a formal definition of charring intensity (CI) to more accurately characterize pyrolysis, and we document variation in charcoal chemical properties with variation in CI. We find two types of responses to CI: either linear or threshold relationships. Mass yield decreases linearly with CI, while a threshold exists across which % C, % N, and delta(15)N exhibit large changes. This CI threshold co-occurs with an increase in charcoal aromaticity. C isotopes do not change from original biomass values, supporting the use of charcoal delta(13)C signatures to infer paleoecological conditions. Fractionation of N isotopes indicates that fire may be enriching soils in (15)N through pyrolytic N isotope fractionation. This influx of "black N" could have a significant impact on soil N isotopes, which we show theoretically using a simple mass-balance model. PMID- 26523421 TI - Cinchona Alkaloid Squaramide-Catalyzed Asymmetric Michael Addition of alpha-Aryl Isocyanoacetates to beta-Trifluoromethylated Enones and Its Applications in the Synthesis of Chiral beta-Trifluoromethylated Pyrrolines. AB - Cinchona alkaloid squaramide can effectively catalyze the asymmetric Michael addition of alpha-aryl isocyanoacetates to beta-trifluoromethylated enones, affording the corresponding adducts with an adjacent chiral tertiary carbon center bearing a CF3 group and a quaternary carbon center in moderate to good yields along with excellent stereoselectivities. The adduct can be easily transformed into biologically attractive chiral beta-trifluoromethylated pyrroline carboxylate in high yield via an isocyano group hydrolysis/cyclization/dehydration cascade reaction by treating with acid. The one-pot enantioselective Michael addition/isocyano group hydrolysis/cyclization/dehydration sequential protocol has also been investigated. PMID- 26523422 TI - Directing Hybrid Structures by Combining Self-Assembly of Functional Block Copolymers and Atomic Layer Deposition: A Demonstration on Hybrid Photovoltaics. AB - The simplicity and versatility of block copolymer self-assembly offers their use as templates for nano- and meso-structured materials. However, in most cases, the material processing requires multiple steps, and the block copolymer is a sacrificial building block. Here, we combine a self-assembled block copolymer template and atomic layer deposition (ALD) of a metal oxide to generate functional hybrid films in a simple process with no etching or burning steps. This approach is demonstrated by using the crystallization-induced self-assembly of a rod-coil block copolymer, P3HT-b-PEO, and the ALD of ZnO. The block copolymer self-assembles into fibrils, ~ 20 nm in diameter and microns long, with crystalline P3HT cores and amorphous PEO corona. The affinity of the ALD precursors to the PEO corona directs the exclusive deposition of crystalline ZnO within the PEO domains. The obtained hybrid structure possesses the properties desired for photovoltaic films: donor-acceptor continuous nanoscale interpenetrated networks. Therefore, we integrated the films into single-layer hybrid photovoltaics devices, thus demonstrating that combining self-assembly of functional block copolymers and ALD is a simple approach to direct desired complex hybrid morphologies. PMID- 26523423 TI - Moving while Black: Intergroup attitudes influence judgments of speed. AB - Four experiments examined whether intergroup attitudes shape the speed with which Blacks are thought to be moving. When participants rated the speed of Black and White faces that appeared to be moving toward them, greater intergroup anxiety was associated with judging Black targets as moving more slowly relative to White targets (Experiments 1a and 1b). Experiment 2 demonstrated that this effect occurs only for approaching targets. Experiment 3 showed that this slowing bias occurs, at least in part, because of the perceived duration of time each image was moving. Such a slowing bias is consistent with the time expansion and perceptual slowing reported by people who experienced threatening events. PMID- 26523424 TI - Memory, metamemory, and social cues: Between conformity and resistance. AB - When presented with responses of another person, people incorporate these responses into memory reports: a finding termed memory conformity. Research on memory conformity in recognition reveals that people rely on external social cues to guide their memory responses when their own ability to respond is at chance. In this way, conforming to a reliable source boosts recognition performance but conforming to a random source does not impair it. In the present study we assessed whether people would conform indiscriminately to reliable and unreliable (random) sources when they are given the opportunity to exercise metamemory control over their responding by withholding answers in a recognition test. In Experiments 1 and 2, we found the pattern of memory conformity to reliable and unreliable sources in 2 variants of a free-report recognition test, yet at the same time the provision of external cues did not affect the rate of response withholding. In Experiment 3, we provided participants with initial feedback on their recognition decisions, facilitating the discrimination between the reliable and unreliable source. This led to the reduction of memory conformity to the unreliable source, and at the same time modulated metamemory decisions concerning response withholding: participants displayed metamemory conformity to the reliable source, volunteering more responses in their memory report, and metamemory resistance to the random source, withholding more responses from the memory report. Together, the results show how metamemory decisions dissociate various types of memory conformity and that memory and metamemory decisions can be independent of each other. PMID- 26523425 TI - The structure of sequential effects. AB - There is a long history of research into sequential effects, extending more than one hundred years. The pattern of sequential effects varies widely with both experimental conditions as well as for different individuals performing the same experiment. Yet this great diversity of results is poorly understood, particularly with respect to individual variation, which save for some passing mentions has largely gone unreported in the literature. Here we seek to understand the way in which sequential effects vary by identifying the causes underlying the differences observed in sequential effects. In order to achieve this goal we perform principal component analysis on a dataset of 158 individual results from participants performing different experiments with the aim of identifying hidden variables responsible for sequential effects. We find a latent structure consisting of 3 components related to sequential effects-2 main and 1 minor. A relationship between the 2 main components and the separate processing of stimuli and of responses is proposed on the basis of previous empirical evidence. It is further speculated that the minor component of sequential effects arises as the consequence of processing delays. Independently of the explanation for the latent variables encountered, this work provides a unified descriptive model for a wide range of different types of sequential effects previously identified in the literature. In addition to explaining individual differences themselves, it is demonstrated how the latent structure uncovered here is useful in understanding the classical problem of the dependence of sequential effects on the interval between successive stimuli. PMID- 26523426 TI - No evidence for bilingual cognitive advantages: A test of four hypotheses. AB - The question whether being bilingual yields cognitive benefits is highly controversial with prior studies providing inconsistent results. Failures to replicate the bilingual advantage have been attributed to methodological factors such as comparing dichotomous groups and measuring cognitive abilities separately with single tasks. Therefore, the authors evaluated the 4 most prominent hypotheses of bilingual advantages for inhibitory control, conflict monitoring, shifting, and general cognitive performance by assessing bilingualism on 3 continuous dimensions (age of acquisition, proficiency, and usage) in a sample of 118 young adults and relating it to 9 cognitive abilities each measured by multiple tasks. Linear mixed-effects models accounting for multiple sources of variance simultaneously and controlling for parents' education as an index of socioeconomic status revealed no evidence for any of the 4 hypotheses. Hence, the authors' results suggest that bilingual benefits are not as broad and as robust as has been previously claimed. Instead, earlier effects were possibly due to task-specific effects in selective and often small samples. PMID- 26523427 TI - Interface and Composition Analysis on Perovskite Solar Cells. AB - Organometal halide (hybrid) perovskite solar cells have been fabricated following four different deposition procedures and investigated in order to find correlations between the solar cell characteristics/performance and their structure and composition as determined by combining depth-resolved imaging with time-of-flight secondary ion mass spectrometry (ToF-SIMS), X-ray photoelectron spectroscopy (XPS), and analytical scanning transmission electron microscopy (STEM). The interface quality is found to be strongly affected by the perovskite deposition procedure, and in particular from the environment where the conversion of the starting precursors into the final perovskite is performed (air, nitrogen, or vacuum). The conversion efficiency of the precursors into the hybrid perovskite layer is compared between the different solar cells by looking at the ToF-SIMS intensities of the characteristic molecular fragments from the perovskite and the precursor materials. Energy dispersive X-ray spectroscopy in the STEM confirms the macroscopic ToF-SIMS findings and allows elemental mapping with nanometer resolution. Clear evidence for iodine diffusion has been observed and related to the fabrication procedure. PMID- 26523428 TI - Cytotoxic effect of ZnS nanoparticles on primary mouse retinal pigment epithelial cells. AB - The multiple properties of zinc sulphide nanoparticles (ZnS-NPs) are attracting great attention in the field of chemical and biological research. ZnS-NPs also find their application in biosensor and photocatalysis. Zinc is an important metal ion in retina and its deficiency leads to age-related macular degeneration. As of now, not much research is available on bio-interaction of ZnS as nanoform with retinal pigment epithelial (RPE) cells. RPE cells in the retina help in maintaining normal photoreceptor function and vision. To begin with, ZnS-NPs were synthesized and characterized using UV-visible spectra, X-ray diffraction, Fourier transform infrared spectrum, transmission electron microscopy and dynamic light scattering. Followed by the confirmation of nanoparticles, our study extended to investigate the impact of ZnS-NPs in primary mouse RPE (MRPE) cells at different concentrations. ZnS-NPs showed dose-dependent cytotoxicity in MRPE cells and no changes were observed in cells' tight intactness at minimal concentration. In addition, exposure to ZnS-NPs increased cellular permeability in dose- and time-dependent manner in MRPE cells. The findings from DCFH-DA analysis revealed that ZnS-NPs-treated cells had elevated level of reactive oxygen species and partial activation of cell apoptosis was identified after exposure to ZnS-NPs at higher concentration. Furthermore, pre-treatment of the primary MRPE cells with ZnS-NPs led to phosphorylation of Akt (Ser 473), which indicates the crucial role of ZnS-NPs in regulating cell survival at minimal concentration. Altogether, this study enumerates requisite dose of using ZnS-NPs to maintain healthy RPE cells and contributes to future studies in development of therapeutic drug and drug carrier for ocular-related disorders. PMID- 26523429 TI - 2-Oxo-Driven N2 Elimination Induced Decarbonylative Cyclization Reaction in Benzotriazoles to 6-Aminophenanthridines. AB - An efficient functional group induced strategy for the synthesis of 6 aminophenanthridines (6AP) has been developed as a result of an in situ generated novel system "CO-CH(N1N2)". This reaction presents a new mode of N2 extrusion in benzotriazoles that later result in decarbonylative cyclization to 6AP. This method offers an easier protocol for the synthesis of 6AP from readily available inexpensive substrates. PMID- 26523430 TI - U.S. Military Surveillance of Mental Disorders, 1998-2013. AB - OBJECTIVE: Feature articles in the Medical Surveillance Monthly Report (MSMR) reflect the U.S. military's health surveillance priorities. This study examined whether the recent rise in the number of ambulatory encounters for mental disorders in the U.S. military associated with the Iraq and Afghanistan wars was reflected in a proportional increase in MSMR feature articles on this topic. METHODS: Articles published in the MSMR from January 1998 to December 2013 were examined to categorize feature articles according to health outcome. The proportion of articles by topic of outcome was compared with the proportion of all ambulatory encounters by category of disorder. RESULTS: Mental disorders constituted 13% of ambulatory encounters and were the topic of 11% of 329 feature articles during the period, a statistically nonsignificant difference. CONCLUSIONS: The increased number of encounters for mental disorders has been met with a proportional but delayed increase in the number of MSMR feature articles focusing on these disorders. PMID- 26523431 TI - Sapacitabine in the treatment of acute myeloid leukemia. AB - Prognosis of elderly patients with acute myeloid leukemia (AML) remains poor and new treatment approaches are urgently needed. A novel nucleoside analog sapacitabine has recently emerged as a feasible agent because of its oral administration and acceptable toxicity profile. Clinical efficacy of sapacitabine, both as a single agent and in combination, has been evaluated in elderly AML patients or AML patients unfit for standard intensive chemotherapy. Response rates varied from 15 to 45% in phase II studies. Sapacitabine was overall well-tolerated with gastrointestinal and myelosuppression-related complications were the most common side effects. Unfortunately, in a phase III study sapacitabine showed no clinical superiority as compared to low-dose cytarabine (LDAC) in patients with AML. Another large phase III study comparing the combination of sapacitabine with decitabine to decitabine alone is currently ongoing and is expected to be completed by the end of 2015 or by the first half of 2016. PMID- 26523432 TI - Diverging perspectives on children's rehabilitation services: a mixed-methods study. AB - BACKGROUND: Family-centred ideology is increasingly regarded as a conceptual foundation in services to children with disabilities. OBJECTIVE: First, to examine the extent to which parents and therapists perceive the service as family centred; second, to explore factors affecting parents' perceptions of the service; and third, to explore how parents understood service aspects typically characterising family-centred services (FCS), such as the goal-setting process. MATERIAL AND METHODS: Parents of 236 children and 25 therapists completed questionnaires (MPOC-32; MPOC-SP). Five parents shared their experiences in an open interview. RESULTS: On average parents and professionals consider the service to be family-centred from a 'fairly great' extent (Respectful and Supportive Care/Treating People Respectfully) to a 'small' extent (Providing General Information). Parents' experiences were influenced by their child's age, functional performance, and type of disability. Analysis of interview data revealed three categories: Experiencing trust and respect, Collaborating or just following instructions?, and Balancing therapy with daily activities. CONCLUSION: Parents praise interpersonal relations but lack of information limits their possibilities to make informed choices about services. In order to translate better into the daily life of the family the intervention should focus more on their activities, routines and participation within the communities they live in. PMID- 26523433 TI - Randomized Pilot Trial of Two Modified Endotracheal Tubes To Prevent Ventilator associated Pneumonia. AB - RATIONALE: Ventilator-associated pneumonia (VAP) is a prevalent and costly nosocomial infection related to instrumentation of the airway with an endotracheal tube (ETT), enabling microaspiration of contaminated secretions. Modification of the ETT design to reduce microaspiration and/or biofilm formation may play an important role in VAP prevention. However, there is insufficient evidence to provide strong recommendations regarding the use of modified ETT and unaddressed safety concerns. OBJECTIVES: We performed a pilot randomized controlled trial comparing two modified ETTs designed specifically to prevent VAP, with the standard ETT, to test the feasibility of and inform planning for a large, pivotal, randomized trial. METHODS: This study was conducted with institutional review board approval under exception from informed consent. We randomized in a blinded fashion patients undergoing emergency endotracheal intubation both out of and in hospital to receive one of three different ETT types: (1) a polyurethane-cuffed tube (PUC-ETT), (2) a polyurethane-cuffed tube equipped with a port for continuous aspiration of subglottic secretions (PUC-CASS ETT), or a (3) standard polyvinylchloride-cuffed tube (PVC-ETT). In addition to investigating feasibility and safety, the study coprimary end points were tracheal bacterial colonization reaching a cfu count >10(6) cfu per milliliter and the incidence of invasively diagnosed VAP. MEASUREMENTS AND MAIN RESULTS: A total of 102 subjects were randomized and met the eligibility criteria. Randomization procedures performed well and integrity of blinding at randomization was maintained. The majority of intubations occurred in the hospital setting (n = 77), and the remainder occurred out of hospital (n = 25). Compared with the PVC-ETT, there were no significant differences in tracheal colonization for PUC-ETT (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.31-3.09) or for PUC-CASS-ETT (OR, 1.26; 95% CI, 0.42-3.76). There were no differences in the risk of invasively diagnosed VAP (OR, 1.14; 95% CI, 0.21-6.08 for PUC-ETT; OR, 1.47; 95% CI, 0.30-7.10 for PUC-CASS-ETT), or of clinically diagnosed VAP by either clinical signs or chest radiograph criteria. We did not observe unexpected or serious adverse events related to the devices. CONCLUSIONS: A randomized trial of ETTs inserted during emergency intubation for the prevention of VAP is feasible and did not appear to carry heightened safety concerns. These preliminary data did not suggest different patterns of tracheal colonization or occurrence of VAP among the study groups. Clinical trial registered with www.clinicaltrials.gov (NCT01744483). PMID- 26523434 TI - First novel once-weekly DPP-4 inhibitor, trelagliptin, for the treatment of type 2 diabetes mellitus. AB - INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors are weight neutral and well tolerated, and provide better glycaemic control for a longer period compared to conventional therapies. Despite the fact that various drugs are available, glycaemic control remains suboptimal in approximately half of patients with type 2 diabetes mellitus; one of the major reasons for low medication adherence. AREAS COVERED: A novel DPP-4 inhibitor, trelagliptin, was approved in Japan in March 2015, and is the first once-weekly oral antidiabetic agent in the world. In this review, current issues concerning medication adherence for the treatment of diabetes are discussed followed by a summary of the characteristics and future expectations of trelagliptin, by reviewing the recent phase I, II, and III clinical studies of trelagliptin. EXPERT OPINION: Trelagliptin has demonstrated superiority to placebo and non-inferiority to alogliptin, indicating its efficacy and tolerance in Japanese patients. Trelagliptin is expected to improve adherence and prevent complications. Due to the convenient dosing regimen, it is expected to be widely used in the clinical setting. A large-scale long-term study will help further confirm its long-term efficacy and safety, patients' satisfaction, and medication adherence. PMID- 26523435 TI - Evaluating bifactor models: Calculating and interpreting statistical indices. AB - Bifactor measurement models are increasingly being applied to personality and psychopathology measures (Reise, 2012). In this work, authors generally have emphasized model fit, and their typical conclusion is that a bifactor model provides a superior fit relative to alternative subordinate models. Often unexplored, however, are important statistical indices that can substantially improve the psychometric analysis of a measure. We provide a review of the particularly valuable statistical indices one can derive from bifactor models. They include omega reliability coefficients, factor determinacy, construct reliability, explained common variance, and percentage of uncontaminated correlations. We describe how these indices can be calculated and used to inform: (a) the quality of unit-weighted total and subscale score composites, as well as factor score estimates, and (b) the specification and quality of a measurement model in structural equation modeling. (PsycINFO Database Record PMID- 26523436 TI - Overlap between treatment and control distributions as an effect size measure in experiments. AB - The proportion pi of treatment group observations that exceed the control group mean has been proposed as an effect size measure for experiments that randomly assign independent units into 2 groups. We give the exact distribution of a simple estimator of pi based on the standardized mean difference and use it to study the small sample bias of this estimator. We also give the minimum variance unbiased estimator of pi under 2 models, one in which the variance of the mean difference is known and one in which the variance is unknown. We show how to use the relation between the standardized mean difference and the overlap measure to compute confidence intervals for pi and show that these results can be used to obtain unbiased estimators, large sample variances, and confidence intervals for 3 related effect size measures based on the overlap. Finally, we show how the effect size pi can be used in a meta-analysis. PMID- 26523437 TI - Diversity of Sex Chromosome Systems in Ancistrini (Loricariidae, Hypostominae): ZZ/ZW in Ancistrus taunayi Miranda Ribeiro, 1918. AB - The karyotype of the Ancistrini catfish Ancistrus taunayi was analyzed by conventional (Giemsa staining, AgNOR staining and C-banding) and molecular cytogenetic (5S and 18S rDNA-FISH) methods. The diploid chromosome number was 2n = 50 (22 metacentrics + 10 submetacentrics + 10 subtelocentrics + 8 acrocentrics) for both sexes. A single NOR-bearing acrocentric chromosome pair (No. 24) was detected after Ag-staining and 18S rDNA-FISH, while 5S rDNA was found only in the subtelocentric pair No. 21. Conspicuous GC-rich heterochromatin blocks corresponded to the NOR sites and were also observed in the distal regions of the acrocentric chromosome pairs Nos. 22 and 25. Chromosome pair No. 22 differed between males and females; in males, only a small interstitial block of GC-rich heterochromatin was present in both chromosomes, whereas in females, 2 blocks of GC-rich heterochromatin flanked a euchromatic region in one of the homologues, suggesting the occurrence of a ZZ/ZW sex chromosome system. Two mechanisms for the origin and evolution of this simple ZZ/ZW sex chromosome system in A. taunayi are proposed: (1) a paracentric inversion followed by amplification of the proximal heterochromatin and (2) amplification of the interstitial heterochromatin followed by a paracentric inversion. Although ZZ/ZW systems have already been described for other Ancistrus species, our results do not show the same pattern, suggesting an independent origin. PMID- 26523438 TI - [Do antenatal corticosteroids in term elective cesarean sections reduce neonatal respiratory morbidity?]. AB - INTRODUCTION: Neonatal respiratory distress syndrome is closely related to gestational age and mode of birth. Lowest gestational ages and caesarean section are associated with higher risk of developing respiratory distress syndrome. The efficacy of antenatal corticosteroids is well established in the induction of lung maturation in premature births. Its use could be a beneficial intervention in term fetuses that will be born by elective caesarean section. OBJECTIVE: To find the best evidence available to determine whether the use of antenatal corticosteroids reduces the incidence of respiratory distress syndrome in term babies born by elective caesarean section. METHODOLOGY: We searched the available medical literature in different databases: PubMed, LILACS, UpToDate, Trip database, SciELO and Cochrane. We considered controlled, randomized therapeutic studies, performed on humans, in which the intervention included corticosteroids as a treatment in elective term cesareans. RESULTS: We selected two studies. In both, the intervention was two doses of 12 mg of dexamethasone before the caesarean section. The primary objective in both studies was to analyze the incidence of respiratory distress syndrome and the admission of the newborn into intensive care units. In both studies, there was less incidence of neonatal respiratory distress syndrome, with statistically significant results. CONCLUSIONS: We concluded that the use of corticosteroids in elective term caesarean section reduces the incidence of neonatal respiratory distress syndrome and the admission into intensive care units. However, we evidenced certain weaknesses that could modify the internal validity of both studies, so it is necessary to develop new studies that could support these findings in order to modify clinical protocols in term elective caesarean sections. PMID- 26523439 TI - Successful Ifosfamide Rechallenge in Soft-Tissue Sarcoma. AB - OBJECTIVES: Treatment options for metastatic soft-tissue sarcomas are limited. The aim of this study was to investigate the clinical activity of ifosfamide rechallenge in synovial sarcoma (SS), liposarcoma (LPS), leiomyosarcoma (LMS), and high-grade sarcomas not otherwise specified. METHODS: A retrospective search of the Royal Marsden Sarcoma Unit Database was performed to identify patients initially treated with ifosfamide (as single agent or in combination) and who were subsequently rechallenged with single-agent ifosfamide. Baseline demographics and response assessment were retrospectively obtained. RESULTS: Sixty-seven patients were identified and the median age at diagnosis was 41 years (range, 18 to 71 y). There were 29 cases of SS, 17 of LPS, 12 of LMS, and 9 of sarcomas not otherwise specified. First-line ifosfamide-containing therapy was given to 14 patients as adjuvant therapy (adjuvant group) and 53 patients as palliative therapy (palliative group). Clinical activity (partial response or stable disease) with single-agent ifosfamide rechallenge was documented in 50.0% of patients in the adjuvant group (7 in the second line) and 34.0% of patients in the palliative group (15 in the second line, 1 in third line, and 2 in the fourth line). The median progression-free survival in patients with documented clinical activity was 11.5 months (95% CI, 8.8-12.3) and 6.9 months (95% CI, 5.1-9.0), respectively, in the adjuvant and palliative group. Ifosfamide rechallenge was mostly active in SS patients (49.3%, 14 out of 29 patients with partial remission or stable disease). CONCLUSIONS: Ifosfamide rechallenge has clinical activity in soft-tissue sarcoma and can be considered a viable option in treating metastatic disease. PMID- 26523440 TI - Total Lifetime and Cancer-related Costs for Elderly Patients Diagnosed With Anal Cancer in the United States. AB - OBJECTIVE: To determine the lifetime and phase-specific cost of anal cancer management and the economic burden of anal cancer care in elderly (66 y and older) patients in the United States. PATIENTS AND METHODS: For this study, we used Surveillance Epidemiology and End Results-Medicare linked database (1992 to 2009). We matched newly diagnosed anal cancer patients (by age and sex) to noncancer controls. We estimated survival time from the date of diagnosis until death. Lifetime and average annual cost by stage and age at diagnosis were estimated by combining survival data with Medicare claims. The average lifetime cost, proportion of patients who were elderly, and the number of incident cases were used to estimate the economic burden. RESULTS: The average lifetime cost for patients with anal cancer was US$50,150 (N=2227) (2014 US dollars). The average annual cost in men and women was US$8025 and US$5124, respectively. The overall survival after the diagnosis of cancer was 8.42 years. As the age and stage at diagnosis increased, so did the cost of cancer-related care. The anal cancer related lifetime economic burden in Medicare patients in the United States was US$112 million. CONCLUSIONS: Although the prevalence of anal cancer among the elderly in the United States is small, its economic burden is considerable. PMID- 26523442 TI - Hypofractionated Versus Standard Fractionated Proton-beam Therapy for Low-risk Prostate Cancer: Interim Results of a Randomized Trial PCG GU 002. AB - OBJECTIVE: To identify differences in terms of quality of life, the American Urological Association Symptom Index (AUA), or adverse events (AEs) among patients with prostate cancer treated with either standard fractionation or hypofractionation proton-beam therapy. MATERIALS AND METHODS: Patients were prospectively randomized to receive 38 Gy relative biological effectiveness (RBE) in 5 treatments (n=49) or 79.2 Gy RBE in 44 treatments (n=33). All patients had low-risk prostate cancer and were treated with proton therapy using fiducial markers and daily image guidance. RESULTS: Median follow-up for both groups was 18 months; 33 patients had follow-up of 2 years or longer. Baseline median (range) AUA was 4.7 (0 to 13) for the 38 Gy RBE arm and 4.8 (0 to 17) for the 79.2 Gy RBE arm. We observed no difference between the groups regarding the Expanded Prostate Index Composite urinary, bowel, or sexual function scores at 3, 6, 12, 18, or 24 months after treatment. The only significant difference was the AUA score at 12 months (8 for the 38 Gy RBE arm vs. 5 for the 79.2 Gy RBE arm; P=0.04); AUA scores otherwise were similar between groups. No grade 3 or higher AEs occurred in either arm. CONCLUSIONS: Patients treated with proton therapy in this randomized trial tolerated treatment well, with excellent quality-of-life scores, persistent low AUA, and no grade 3 or higher AEs on either arm. We showed no apparent clinical difference in outcomes with hypofractionated proton-beam therapy compared with standard fractionation on the basis of this interim analysis. PMID- 26523441 TI - Clinical Outcomes of Patients With Gastrointestinal Malignancies Participating in Phase I Clinical Trials. AB - OBJECTIVES: Early-phase clinical trials play a pivotal role in drug development. However, limited data are available on outcomes of gastrointestinal (GI) cancer patients enrolled in phase I clinical trials. Here, we evaluated the characteristics associated with survival in GI cancer patients participating in phase I clinical trials and attempted to validate previously established prognostic models. MATERIALS AND METHODS: All consecutive patients with advanced GI tumors who participated in phase I clinical trials at our institution from January 2007 to December 2013 and received at least 1 dose of the study drug were included. Cox regression models were used to estimate multivariable-adjusted hazard ratio (HR) and 95% confidence interval. RESULTS: In 243 study patients (median age, 62 y [range, 26 to 82 y]; 55% male), treatment included chemotherapy only (14%), targeted therapy (41%), chemotherapy+targeted therapy (42%), and others (2%) for the following disease types: pancreatic (42%), colorectal (34%), gastroesophageal (10%), hepatobiliary (13%), and others (2%). Response rate was 4%, with 38% achieving stable disease and 42% having progressive disease. Median survival was 5.8 months (range, 0.2 to 52.4 mo). Our multivariable Cox regression analyses included the following as predictors of survival: Eastern Cooperative Oncology Group performance score >=1 (HR=1.76), prior systemic therapies >=2 (HR=1.63), lactate dehydrogenase >618 IU/L (HR=1.85), sodium >135 mmol/L (HR=0.46), and white blood count >6*10/L (HR=1.5). Our data set was consistent with previous prognostic scores. CONCLUSIONS: This is the largest study to assess clinical outcomes in this patient population. Phase I trials provide clinical benefit to patients with advanced GI malignancies and should be recommended as a treatment option in appropriate patients. PMID- 26523443 TI - Association Between Radiation Dose and Outcomes With Postoperative Radiotherapy for N0-N1 Non-Small Cell Lung Cancer. AB - PURPOSE: To review trends in the use of postoperative radiotherapy (PORT) in the modern era for N0-N1 margin-negative non-small cell lung cancer (NSCLC) following surgical resection and evaluate the association between PORT dose and overall survival. MATERIALS AND METHODS: We performed a retrospective study of nonmetastatic stage II and III N0-N1 margin-negative NSCLC surgically treated patients within the National Cancer Data Base from 2003 to 2011. Cox proportional hazards regression was performed for multivariable analyses of overall survival and PORT dose. Radiation modalities included nonconformal beam radiation, 3 dimensional conformal radiation (3D-CRT), and intensity-modulated radiation therapy. RESULTS: We identified 2167 (6.7%) and 30,269 (93.3%) patients with surgically resected stage II or III N0-N1 margin-negative NSCLC who were treated with and without PORT, respectively. The proportion of patients treated with PORT (dose range, 45 to 74 Gy) decreased from 8.9% in 2003 to 2006 to 4.1% in 2010 to 2011. Among patients receiving PORT, the use of high-dose (60 to 74 Gy) PORT rose throughout the study period, starting at 34.8% in 2003 to 2006 and rising to 49.3% in 2010 to 2011.Overall, patients who received PORT had worse survival (hazards ratio=1.30; 95% confidence interval, 1.20-1.40) compared with those not receiving PORT. This association was unchanged when limited to patients receiving modern treatment with 3-CRT or intensity-modulated radiation therapy (hazards ratio=1.35; 95% confidence interval, 1.10-1.65). CONCLUSIONS: The use of PORT for N0-N1 margin-negative NSCLC decreased from 2003 to 2011. We found no evidence of benefit from PORT for resected N0-N1 margin-negative NSCLC, regardless of dose or technique. PORT should be approached with caution in this group of patients, regardless of radiotherapy technique. PMID- 26523445 TI - Pharmacokinetics of isoforskolin after administration via different routes in guinea pigs. AB - 1. The objective of this study was to characterize the pharmacokinetics of isoforskolin after oral, intraperitoneal and intravenous administration, as well as to compare bioavailability. 2. Isoforskolin was administered to guinea pigs at a dose of 2 mg/kg. Plasma concentrations were determined by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI MS/MS) method. The pharmacokinetic parameters were calculated by a noncompartmental method. A compartment model was also adopted to describe the pharmacokinetic profiles. 3. The pharmacokinetic behavior of intravenously administered isoforskolin was characterized by rapid and extensive distribution (Vz = 16.82 +/- 8.42 L/kg) followed by rapid elimination from the body (Cl = 9.63 +/- 4.21 L/kg/h). After intraperitoneal administration, isoforskolin was absorbed rapidly (Tmax = 0.12 +/- 0.05 h). The pharmacokinetic profiles of isoforskolin were similar after intraperitoneal and intravenous administration, except for the concentrations at the initial sampling times. Isoforskolin was also absorbed rapidly following oral dosing; however, the concentration-time data were best fit to a one-compartment model, which was different from that observed after intravenous and intraperitoneal administration. Following intraperitoneal and oral administration, the absolute bioavailability of isoforskolin was 64.12% and 49.25%, respectively. 4. Isoforskolin is a good candidate for oral administration because of its good oral bioavailability. PMID- 26523444 TI - FOLFOX+Nab-Paclitaxel (FOLFOX-A) for Advanced Pancreatic Cancer: A Brown University Oncology Research Group Phase I Study. AB - BACKGROUND: The Brown University Oncology Research Group performed a phase I study to remove irinotecan from FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) and substitute nab-paclitaxel. METHODS: Patients with newly diagnosed advanced pancreatic adenocarcinoma were eligible. Patients received oxaliplatin 85 mg/m, leucovorin 400 mg/m, and 5-fluorouracil 2400 mg/m with 3 dose levels of nab-paclitaxel (125, 150, and 175 mg/m) every 2 weeks. Dose limiting toxicities were assessed in the first 2 cycles of treatment. The final dose level was expanded to assess cumulative neurotoxicity. RESULTS: Thirty-five patients were entered; 24 with metastatic and 11 with locally advanced pancreatic cancer. The maximum tolerated dose of nab-paclitaxel was 150 mg/m every 2 weeks with FOLFOX. Cumulative neuropathy was the most important toxicity. Grade 3 neuropathy developed in 2 of the first 6 patients at 10 and 11 cycles of FOLFOX A. Following an amendment to reduce oxaliplatin to 65 mg/m if grade 2 neuropathy developed, no additional patients developed grade 3 neurotoxicity. Twenty-one of 35 patients (60%) had a partial response. The median survival for patients with metastatic disease was 15 months. CONCLUSIONS: The maximum tolerated dose of nab paclitaxel is 150 mg/m every 2 weeks with FOLFOX. The regimen of FOLFOX-A represents a promising treatment for pancreatic cancer. PMID- 26523446 TI - Comment on "Predictors of Indoor Radon Concentrations in Pennsylvania, 1989 2013". PMID- 26523447 TI - Improving Empathy in the Prevention of Sexual Abuse Against Children and Youngsters. AB - The aim of this research is to study the improvement of empathy in child-care professionals (i.e., teachers, psychologists, social workers) involved in the prevention of sexual abuse against children and youngsters. An E-Learning training pilot program was conducted with pre- and post-measures (T(1) = at the beginning and T(2) = after 6 months) using the program's standardized questionnaires of Situational Empathy and the Interpersonal Reactivity Index (IRI) as a Dispositional Empathy measure. A sample of 42 experienced professionals involved in activities with children and youngsters was obtained from the International Movement of Popular Education in Latin America called "Fe y Alegria." Significant progress was found in the scales of Situational Empathy and in some Coping subscales. The final outcomes seem to indicate that the prevention program elicits important changes in the cognitive sphere and that these changes are more intense when the implication level for the situation is greater. This research shows that empathy can be improved through professional experience and careful situational involvement. PMID- 26523451 TI - A supersandwich fluorescence in situ hybridization strategy for highly sensitive and selective mRNA imaging in tumor cells. AB - We report a supersandwich fluorescence in situ hybridization (SFISH) strategy for highly sensitive and selective in situ visualization of mRNA expression patterns at the single-cell level. This strategy uses two fluorophore-labeled signal probes to generate a supersandwich product, which in turn generates numerous signal probes located at the target mRNA position, resulting in the in situ fluorescence signal amplification. PMID- 26523449 TI - Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction. AB - Acidotoxicity is common among neurological disorders, such as ischemic stroke. Traditionally, Ca(2+) influx via homomeric acid-sensing ion channel 1a (ASIC1a) was considered to be the leading cause of ischemic acidotoxicity. Here we show that extracellular protons trigger a novel form of neuronal necroptosis via ASIC1a, but independent of its ion-conducting function. We identified serine/threonine kinase receptor interaction protein 1 (RIP1) as a critical component of this form of neuronal necroptosis. Acid stimulation recruits RIP1 to the ASIC1a C-terminus, causing RIP1 phosphorylation and subsequent neuronal death. In a mouse model of focal ischemia, middle cerebral artery occlusion causes ASIC1a-RIP1 association and RIP1 phosphorylation in affected brain areas. Deletion of the Asic1a gene significantly prevents RIP1 phosphorylation and brain damage, suggesting ASIC1a-mediated RIP1 activation has an important role in ischemic neuronal injury. Our findings indicate that extracellular protons function as a novel endogenous ligand that triggers neuronal necroptosis during ischemia via ASIC1a independent of its channel function. PMID- 26523452 TI - Facile preparation and multifunctional applications of boron nitride quantum dots. AB - Boron nitride quantum dots are obtained by a facile sonication-solvothermal technique. They are proven to be promising fluorescent bioimaging probes for bioimaging with remarkably low cytotoxicity and easily integrated into high performance proton exchange membranes. This work will probably trigger research interest in BN and its new applications in a variety of fields. PMID- 26523453 TI - Synthesis, DNA binding, cellular DNA lesion and cytotoxicity of a series of new benzimidazole-based Schiff base copper(II) complexes. AB - A series of new benzimidazole containing compounds 2-((1-R-1-H-benzimidazol-2 yl)phenyl-imino)naphthol HL(1-3) (R = methyl, ethyl or propyl, respectively) have been synthesized by Schiff base condensation of 2-(1-R-1-H-benzo[d]imidazol-2 yl)aniline and 2-hydroxy-1-naphthaldehyde. The reactions of HL(1-3) with Cu(NO3)2.2.5H2O led to the corresponding copper(II) complexes [Cu(L)(NO3)] 1-3. All the compounds were characterized by conventional analytical techniques and, for 1 and 3, also by single-crystal X-ray analysis. The interactions of complexes 1-3 with calf thymus DNA were studied by absorption and fluorescence spectroscopic techniques and the calculated binding constants (K(b)) are in the range of 3.5 * 10(5) M(-1)-3.2 * 10(5) M(-1). Complexes 1-3 effectively bind DNA through an intercalative mode, as proved by molecular docking studies. The binding affinity of the complexes decreases with the size increase of the N-alkyl substituent, in the order of 1 > 2 > 3, which is also in accord with the calculated LUMO(complex) energies. They show substantial in vitro cytotoxic effect against human lung (A-549), breast (MDA-MB-231) and cervical (HeLa) cancer cell lines. Complex 1 exhibits a significant inhibitory effect on the proliferation of the A-549 cancer cells. The antiproliferative efficacy of 1 has also been analysed by a DNA fragmentation assay, fluorescence activated cell sorting (FACS) and nuclear morphology using a fluorescence microscope. The possible mode for the apoptosis pathway of 1 has also been evaluated by a reactive oxygen species (ROS) generation study. PMID- 26523454 TI - Designing the topology of ion nano-channels in the mesophases of amphiphilic wedge-shaped molecules. AB - The wedge-shaped amphiphiles bearing sulfonate groups at the tip of the wedge are prone to form ion nano-channels upon exposure to a humid atmosphere. During swelling, water molecules preferentially accumulate in polar regions of the system resulting in the formation of a lyotropic phase. In this work, the details of the structure formation processes occurring upon swelling in water vapour, including determination of the size and topology of the ion nano-channels, are explored. The electron density profiles across the channel are obtained from the fits of the X-ray scattering data with two- and three-phase structural models the applicability of which is critically analysed. The results show that the ion channel size correlates not only with water uptake but also with the molecular architecture such as the structure of the rigid molecular fragment bearing a polar group. These findings can help optimising the ion transport for development of ion-selective membranes. PMID- 26523455 TI - Effectiveness of second- through sixth-line salvage Helicobacter pylori treatment: Bismuth quadruple therapy is almost always a reasonable choice. PMID- 26523457 TI - Point-of-care ultrasound accurately distinguishes inflammatory from noninflammatory disease in patients presenting with abdominal pain and diarrhea. PMID- 26523458 TI - Adsorption between TC-stabilized AuNPs and the phosphate group: application of the PTP1B activity assay. AB - Based on the adsorption between tetracycline (TC) and phosphate groups, a general colorimetric method is explored in this work by using TC-stabilized gold nanoparticles (TC/AuNPs) and 4-aminophenyl phosphate-functionalized Fe3O4 magnetic nanoparticles (APP/MNPs). Taking protein tyrosine phosphatase 1B (PTP1B) as an example, 4-aminophenyl phosphate (APP) can be hydrolyzed into 4-aminophenol (AP) by PTP1B, resulting in the disappearance of the phosphate group on the outer layer of MNPs and the loss of corresponding adsorptive ability. Upon addition of TC/AuNP solution, TC/AuNPs will remain in the supernatant solution after magnetic separation and a high absorbance value can be observed. So PTP1B activity is related to the concentrations of TC/AuNPs in the supernatant solution. In this work, the enzyme activity can be determined at levels as low as 0.0885 U mL(-1) and over a linear detection range as wide as 0.1 U mL(-1) to 0.9 U mL(-1). Moreover, using the proposed method, the inhibition effect of betulinic acid (BA) and sodium orthovanadate (Na3VO4) on PTP1B activity can be tested with IC50 values of 30 MUM and 4 MUM, respectively. Therefore, a universal platform for the accurate colorimetric analysis of kinase and phosphatase activities can be established through the adsorption between TC and phosphate groups. PMID- 26523459 TI - Vascular rings: a radiological review of anatomical variations. AB - BACKGROUND: The imaging modalities used to diagnose vascular rings have evolved over time, from basic radiographic studies to advanced cross-sectional imaging. The goal of preoperative imaging is to provide the surgeon with an accurate representation of the ring configuration so that the surgical approach may be planned. METHODS: We conducted a review of all patients with vascular rings who underwent surgery at Inkosi Albert Luthuli Central Hospital, Durban, South Africa from 1 July 2008 to 1 July 2013. RESULTS: Eight patients were diagnosed with vascular rings. Seven patients had an abnormal plain chest radiograph (right aortic arch, tracheal narrowing, or abnormal mediastinal silhouette), while in six patients the contrast oesophagogram demonstrated a fixed extrinsic oesophageal indentation. Computed tomography angiography confirmed the pathology in all cases, with six double aortic arches and two right aortic arches with aberrant left subclavian artery and left ligamentum arteriosum. CONCLUSIONS: We advocate a diagnostic imaging algorithm consisting of plain chest radiography, contrast oesophagogram and computed tomography angiography prior to surgery. Magnetic resonance imaging may provide an alternative axial imaging modality depending on institutional preference. PMID- 26523460 TI - Gestational age-adapted oxygen saturation targeting and outcome of extremely low gestational age neonates (ELGANs). AB - QUESTIONS UNDER STUDY: Optimal oxygen saturation (SpO2) targets for extremely low gestational age neonates (ELGANs, gestational age [GA] <28 weeks) are unknown. Conflicting results from five recently published multicentre trials, which randomised ELGANs to high (91 to 95%) or low (85 to 89%) SpO2 targets from birth up to a corrected GA of 36 weeks, prompted us to examine our experience with two different SpO2 policies. METHODS: We retrospectively compared outcomes of two cohorts of ELGANs which were exposed to two different SpO2 target policies adapted to the infants' corrected GA. Between 1 January 2000 and 30 June 2007, SpO2 targets were 85 to 95% at <30 weeks and 88 to 97% at >=30 weeks (high SpO2 target cohort, n = 157). Between 1 July 2007 and 31 December 2011, SpO2 targets were lowered to 80 to 90% at <30 weeks, 85 to 95% between 30 and 34 weeks and finally 88 to 97% at >=34 weeks (low SpO2 target cohort, n = 84). RESULTS: There were no statistically significant differences between the high and low SpO2 target cohorts in mortality rates (15.9 vs 17.9%, risk ratio [RR] 0.89; 95% confidence interval [CI] 0.50-1.60), incidences of severe retinopathy of prematurity (2.3 vs 0%, RR 3.68; 95% CI 0.19-70.3), or moderate/severe bronchopulmonary dysplasia (14.4 vs 21.1%, RR 0.68; 95% CI 0.37-1.26). CONCLUSIONS: Adapting SpO2 targets to the advancing corrected GA seems safe and is associated with low incidences of short-term complications. Mortality rates did not vary with the two different SpO2 target policies utilised and were comparable to those reported from recently published randomised controlled SpO2 target trials. PMID- 26523461 TI - Understanding Variability To Reduce the Energy and GHG Footprints of U.S. Ethylene Production. AB - Recent growth in U.S. ethylene production due to the shale gas boom is affecting the U.S. chemical industry's energy and greenhouse gas (GHG) emissions footprints. To evaluate these effects, a systematic, first-principles model of the cradle-to-gate ethylene production system was developed and applied. The variances associated with estimating the energy consumption and GHG emission intensities of U.S. ethylene production, both from conventional natural gas and from shale gas, are explicitly analyzed. A sensitivity analysis illustrates that the large variances in energy intensity are due to process parameters (e.g., compressor efficiency), and that large variances in GHG emissions intensity are due to fugitive emissions from upstream natural gas production. On the basis of these results, the opportunities with the greatest leverage for reducing the energy and GHG footprints are presented. The model and analysis provide energy analysts and policy makers with a better understanding of the drivers of energy use and GHG emissions associated with U.S. ethylene production. They also constitute a rich data resource that can be used to evaluate options for managing the industry's footprints moving forward. PMID- 26523462 TI - Chemical Mutagenesis of an Emissive RNA Alphabet. AB - An evolved fluorescent ribonucleoside alphabet comprising isomorphic purine ((tz)A, (tz)G) and pyrimidine ((tz)U, (tz)C) analogues, all derived from isothiazolo[4,3-d]pyrimidine as a common heterocyclic core, is described. Structural and biochemical analyses illustrate that the nucleosides, particularly the C-nucleosidic purine analogues, are faithful isomorphic and isofunctional surrogates of their natural counterparts and show improved features when compared to an RNA alphabet derived from thieno[3,4-d]-pyrimidine. The restoration of the nitrogen in a position equivalent to the purines' N7 leads to "isofunctional" behavior, as illustrated by the ability of adenosine deaminase to deaminate (tz)A as effectively as adenosine, the native substrate. PMID- 26523463 TI - gamma- and delta-Lactams from the Leaves of Clausena lansium. AB - Eight new clausenamides, including three gamma-lactams (1-3), four delta-lactams (4-7), and an amide (8), and seven known lactams, including compounds 9-11, which were purified from natural sources for the first time, were characterized from the leaves of Clausena lansium. Their structures were elucidated using spectroscopic methods, and the absolute configurations were determined using electronic circular dichroism and single-crystal X-ray diffraction analyses with Cu Kalpha radiation. Compound 2 (50 MUM) protected 22.24% of cortical neurons against Abeta25-35-induced cell death. PMID- 26523464 TI - Molecular self-assembly on two-dimensional atomic crystals: insights from molecular dynamics simulations. AB - van der Waals (vdW) epitaxy of ultrathin organic films on two-dimensional (2D) atomic crystals has become a sovereign area because of their unique advantages in organic electronic devices. However, the dynamic mechanism of the self-assembly remains elusive. Here, we visualize the nanoscale self-assembly of organic molecules on graphene and boron nitride monolayer from a disordered state to a 2D lattice via molecular dynamics simulation for the first time. It is revealed that the assembly toward 2D ordered structures is essentially the minimization of the molecule-molecule interaction, that is, the vdW interaction in nonpolar systems and the vdW and Coulomb interactions in polar systems that are the decisive factors for the formation of the 2D ordering. The role of the substrate is mainly governing the array orientation of the adsorbates. The mechanisms unveiled here are generally applicable to a broad class of organic thin films via vdW epitaxy. PMID- 26523465 TI - Synthesis of Sterically Protected Xanthene Dyes with Bulky Groups at C-3' and C 7'. AB - Substitution of the xanthene scaffold with bulky groups at C-3' and C-7' is expected to protect the electrophilic central methine carbon against nucleophilic attack and inhibit stacking. However, such structures are not readily prepared via traditional xanthene syntheses. We have devised an alternative and convenient synthesis to enable facile preparation of this subset of xanthene dyes under mild conditions and in good yields. PMID- 26523466 TI - Surface Tension and Adsorption without a Dividing Surface. AB - The ingenious concept of a dividing surface of zero thickness that was introduced by Gibbs is the basis of the theory of surface tension and adsorption. However, some fundamental questions, mainly those related to the location of the dividing surface and the proper definition of relative adsorption, have remained open over the years. To avoid these questions, the present paper proposes to analyze an interfacial phase by defining a thermodynamic system of constant, but nonzero thickness. The interfacial phase is analyzed as it really is, namely a nonuniform three-dimensional entity. The current analysis redevelops the equation for calculating surface tension, though with different assumptions. However, the main point in the proposed model is that the thermodynamic interfacial system, due to its fixed thickness, conforms to the requirement of first-order homogeneity of the internal energy. This property is the key that allows using the Gibbs adsorption isotherm. It is also characteristic of the Gibbs dividing surface model, but has not always been discussed with regard to subsequent models. The resulting equation leads to a simple, "natural" expression for the relative adsorption. This expression may be compared with simulations and sophisticated surface concentration measurements, and from which the dependence of interfacial tension on the solution composition can be derived. Finally, it is important to point out that in order to calculate the interfacial tension as well as the relative adsorption from data on the properties of the interfacial phase, there is no need to know its exact thickness, as long as it is bigger than the actual thickness but sufficiently small. PMID- 26523467 TI - Response to: Anticipatory and reactive responses to chocolate restriction in frequent chocolate consumers. PMID- 26523468 TI - Polymerized Ionic Networks with High Charge Density: Quasi-Solid Electrolytes in Lithium-Metal Batteries. AB - Polymerized ionic networks (PINs) with six ion pairs per repeating unit are synthesized by nucleophilic-substitution-mediated polymerization or radical polymerization of monomers bearing six 1-vinylimidazolium cations. PIN-based solid-like electrolytes show good ionic conductivities (up to 5.32 * 10(-3) S cm( 1) at 22 degrees C), wide electrochemical stability windows (up to 5.6 V), and good interfacial compatibility with the electrodes. PMID- 26523469 TI - Improving expression of recombinant human IGF-1 using IGF-1R knockout CHO cell lines. AB - Chinese Hamster Ovary (CHO) cells are widely used for the large-scale production of recombinant biopharmaceuticals. However, attempts to express IGF-1 (a mutated human Insulin-like growth factor 1 Ea peptide (hIGF-1Ea mut)) in CHO cells resulted in poor cell growth and low productivity (0.1-0.2 g/L). Human IGF-1 variants negatively impacted CHO cell growth via the IGF-1 receptor (IGF-1R). Therefore knockout (KO) of the IGF-1R gene in two different CHO cell lines as well as knockdown (KD) of IGF-1R in one CHO cell line were performed. These cell line engineering approaches decreased significantly the hIGF-1 mediated cell growth inhibition and increased productivity of both KO CHO cell lines as well as of the KD CHO cell line. A productivity increase of 10-fold at pool level and sevenfold at clone level was achieved, resulting in a titer of 1.3 g/L. This data illustrate that cell line engineering approaches are powerful tools to improve the yields of recombinant proteins which are difficult to produce in CHO cells. PMID- 26523470 TI - Insights into genetic alterations of liver metastases from uveal melanoma. AB - The liver is the organ usually affected by metastatic uveal melanoma (MUM). Current treatments are almost always ineffective and mortality remains high. In this study, copy number variations (CNVs) were identified in 12 metastatic and five matched primary UMs (PUMs). Our data revealed a wide spectrum of genetic alterations in MUM. Most common were amplifications of chromosome (chr.) 8q; alterations on chr. 3 included monosomy, isodisomy, and large regions of homozygosity (ROH). Genomic profiles of PUM-MUM pairs varied in their degree of similarity and complexity. However, within the pairs, 135 genes were consistently altered. Protein expression of C-MYC and BAP1 was examined by immunohistochemistry (IHC); a positive association between IHC and CNVs was seen for C-MYC. This comprehensive catalogue of CNVs associated with MUM should facilitate the identification of key alterations that drive tumor growth. This would have the potential to select urgently needed novel, targeted, therapeutic regimens. PMID- 26523471 TI - Immune Cell Phenotyping Using Flow Cytometry. AB - Fluorescent immunophenotyping uses fluorescently-conjugated antibodies to identify, characterize and quantify distinct subpopulations of cells within heterogeneous single-cell populations, either in the context of tissue (using fluorescence and imaging microscopy) or in a single-cell suspension (using multiparameter imaging microscopy, imaging cytometry, and/or flow cytometry). Flow cytometry is an optical, laser-based technology which analyzes the physical and fluorescent properties of cells in suspension in real-time as they flow through the instrument. This approach has a number of advantages over other techniques that can be used for characterizing cell populations in single-cell suspensions, in that it can nonsubjectively interrogate up to millions of cells and acquire data on the presence of different cell subpopulations and phenotypical changes within these populations in seconds. This unit describes basic procedures for the direct and indirect immunofluorescent staining of surface and intracellular proteins that are expressed by lymphoid cells which have been isolated from tissues or blood. Protocols for the resolution of dead cells and for the fixation of cells are also included. This unit also provides essential information relating to the selection and titration of antibodies, fluorochrome choice, spectral overlap and compensation, the use of controls, and the standardization of data acquisition and analysis. It also highlights new technologies and platforms that can be used to interrogate the presence of cell subpopulations and their phenotype to an even greater depth. PMID- 26523472 TI - Caenorhabditis elegans as a Model for Toxic Effects of Nanoparticles: Lethality, Growth, and Reproduction. AB - The nematode Caenorhabditis elegans is extensively utilized in toxicity studies. C. elegans offers a high degree of homology with higher organisms, and its ease of use and relatively inexpensive maintenance have made it an attractive complement to mammalian and ecotoxicological models. C. elegans provides multiple benefits, including the opportunity to perform relatively high-throughput assays on whole organisms, a wide range of genetic tools permitting investigation of mechanisms and genetic sensitivity, and transparent bodies that facilitate toxicokinetic studies. This unit describes protocols for three nanotoxicity assays in C. elegans: lethality, growth, and reproduction. This unit focuses on how to use these well-established assays with nanoparticles, which are being produced in ever-increasing volume and exhibit physicochemical properties that require alteration of standard toxicity assays. These assays permit a broad phenotypic assessment of nanotoxicity in C. elegans, and, when used in combination with genetic tools and other assays, also permit mechanistic insight. PMID- 26523473 TI - Measuring p66Shc Signaling Pathway Activation and Mitochondrial Translocation in Cultured Cells. AB - The adaptor protein p66Shc links membrane receptors to intracellular signaling pathways, with downstream consequences on mitochondrial metabolism and reactive oxygen species production. Moreover, p66Shc has also been implicated in cancer development, progression, and metastasis. Increased phosphorylation of serine 36 residue of p66Shc very often correlates with oxidative stress-associated pathologies. The pro-oxidative role of p66Shc also appears to be involved in chemical toxicity, being an important component of stress responses triggered by xenobiotics. Here, we present a protocol that can be used: (a) for isolation of mitochondrial, cytosolic, and mitochondrial-associated membrane fractions from adherent cells lines; (b) to perform p66Shc detection with specific antibodies in order to monitor its translocation between different cellular compartments in response to the oxidative stress; and (c) to modulate the p66Shc pathway with the use of pharmacological approaches or gene-silencing methods. PMID- 26523474 TI - Seahorse Xfe 24 Extracellular Flux Analyzer-Based Analysis of Cellular Respiration in Caenorhabditis elegans. AB - Mitochondria are critical for their role in ATP production as well as multiple nonenergetic functions, and mitochondrial dysfunction is causal in myriad human diseases. Less well appreciated is the fact that mitochondria integrate environmental and intercellular as well as intracellular signals to modulate function. Because mitochondria function in an organismal milieu, there is need for assays capable of rapidly assessing mitochondrial health in vivo. Here, using the Seahorse XF(e) 24 Extracellular Flux Analyzer and the pharmacological inhibitors dicyclohexylcarbodiimide (DCCD, ATP synthase inhibitor), carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP, mitochondrial uncoupler), and sodium azide (cytochrome c oxidase inhibitor), we describe how to obtain in vivo measurements of the fundamental parameters [basal oxygen consumption rate (OCR), ATP-linked respiration, maximal OCR, spare respiratory capacity, and proton leak] of the mitochondrial respiratory chain in the model organism Caenorhabditis elegans. PMID- 26523475 TI - Use of Ciliogenesis to Detect Aneugens: The Role of Primary Cilia. AB - Primary cilia arise from the centrosomes of quiescent or post-mitotic cells, and serve as sensory organelles that communicate mechanical and chemical stimuli from the environment to the interior of the cell. Cilium formation may, therefore, become a useful end point signaling exposure to genotoxins or aneugens. Here we have used the aneugen, zidovudine (AZT), an antiretroviral drug that induces DNA replication arrest and centrosomal amplification (>2 centrosomes per quiescent cell), to evaluate cilia formation in retinal epithelial (pigmented) cells. Since cilia are derived from centrosomes, and aneugens can induce centrosomal amplification, the production of multiple cilia arising from multiple centrosomes may reveal the aneugenic nature of the agents. Cells were exposed to AZT to induce centrosomal amplification, cultured without serum to allow the centrioles to develop cilia, and immunostained to visualize cilia and centrosomes. Nuclear DNA was stained with DAPI. Preliminary observations suggest that cells with multiple centrosomes are able to generate extra cilia. PMID- 26523476 TI - Epidemiology of hepatitis E virus infection during pregnancy in Benin. AB - OBJECTIVES: Hepatitis E virus (HEV) is the cause of enterically transmitted non A, non-C hepatitis (an infection that is particularly severe during pregnancy) in tropical and subtropical countries. As there are no published data concerning the prevalence of HEV antibodies in Benin, their presence was investigated in pregnant women undergoing routine HIV screening in a rural area in northern Benin and in pregnant women with acute non-A, non-C hepatitis. METHODS: A total of 278 serum samples were collected from asymptomatic pregnant women in 2011 were tested for HEV and hepatitis A virus (HAV) antibodies, and the HEV IgM-positive samples were further tested for HEV-RNA. A further seven samples of pregnant women with acute non-A, non-C hepatitis collected during episodes of acute hepatitis in 2005 were also analysed. RESULTS: Of the 278 samples collected in 2011, 16.19% were positive for HEV IgG and 1.44% for HEV IgM (none positive for HEV-RNA), and 99.64% were positive for total HAV antibodies (none positive for HAV IgM). Six of the seven samples collected in 2005 were positive for HEV IgG and IgM, and two were also positive for HEV-RNA. CONCLUSIONS: The circulation of HEV infection is significant among pregnant women in Benin, in whom the consequences may be fatal. PMID- 26523477 TI - The Interaction Between Lipoxygenase-Catalyzed Oxidation and Autoxidation in Dry Cured Bacon and a Model System. AB - A model system was conducted to characterize the interaction between lipid autoxidation and enzyme-catalyzed oxidation in dry-cured bacon. This involved the use of a hydroxyl radical (HO*) generating system and the extraction and purification of lipoxygenases (LOX) from pork belly. The results showed that LOX activity rapidly (P < 0.05) increased during the curing of dry-cured bacon. This may be because of the hydroxyl-radical-mediated oxidation from LOX-Fe(2+) to LOX Fe(3+), which activates LOX. In addition, experiments of the model system also showed that LOX activity could be inhibited by increasing the substrate concentration, although substrate type and concentration had no effect on autoxidation. Moreover, LOX enzyme-catalyzed oxidation and autoxidation could act synergistically to promote lipid oxidation irrespective of the substrate (linoleic or arachidonic acid). These results provide useful information for regulating lipid oxidation during the production of dry-cured pork products. PMID- 26523479 TI - Outcomes of Recipients With Pancreas Transplant Alone Who Develop End-Stage Renal Disease. AB - Recipients of pancreas transplant alone (PTA) may be at increased risk for developing end-stage renal disease (ESRD). The survival experience of PTA recipients developing ESRD has not been described. Furthermore, the relative survival of these patients as compared to diabetics on chronic dialysis is unknown. We studied all adult PTA recipients from January 1, 1990 to September 1, 2008 using the Scientific Registry of Transplant Recipients. Each PTA recipient developing ESRD was matched to 10 diabetics on chronic dialysis from the United States Renal Data System. Cox proportional hazards models were fitted to determine the relation between ESRD and mortality among PTA recipients, and the relation between PTA and mortality among diabetics on chronic dialysis. There were 1597 PTA recipients in the study, of which 207 developed ESRD. Those with ESRD had a threefold increase in mortality versus those without (adjusted hazard ratio 3.28 [95% confidence interval: 2.27, 4.76]). There was no significant difference in the risk of death among PTA recipients with ESRD versus diabetics on dialysis. PTA recipients developing ESRD are three times more likely to die than PTA recipients without ESRD; however, the risk of death in these patients was similar to diabetics on chronic dialysis without PTA. PMID- 26523478 TI - Respiratory morbidity in a coffee processing workplace with sentinel obliterative bronchiolitis cases. AB - RATIONALE: Obliterative bronchiolitis in former coffee workers prompted a cross sectional study of current workers. Diacetyl and 2,3-pentanedione levels were highest in areas for flavoring and grinding/packaging unflavored coffee. METHODS: We interviewed 75 (88%) workers, measured lung function, and created exposure groups based on work history. We calculated standardized morbidity ratios (SMRs) for symptoms and spirometric abnormalities. We examined health outcomes by exposure groups. RESULTS: SMRs were elevated 1.6-fold for dyspnea and 2.7-fold for obstruction. The exposure group working in both coffee flavoring and grinding/packaging of unflavored coffee areas had significantly lower mean ratio of forced expiratory volume in 1 s to forced vital capacity and percent predicted mid-expiratory flow than workers without such exposure. CONCLUSION: Current workers have occupational lung morbidity associated with high diacetyl and 2,3 pentanedione exposures, which were not limited to flavoring areas. PMID- 26523480 TI - Engineering 3D Nanoplasmonic Assemblies for High Performance Spectroscopic Sensing. AB - We demonstrate the fabrication of plasmonic sensors that comprise gold nanopillar arrays exhibiting high surface areas, and narrow gaps, through self-assembly of amphiphilic diblock copolymer micelles on silicon substrates. Silicon nanopillars with high integrity over arbitrary large areas are obtained using copolymer micelles as lithographic templates. The gaps between metal features are controlled by varying the thickness of the evaporated gold. The resulting gold metal nanopillar arrays exhibit an engineered surface topography, together with uniform and controlled separations down to sub-10 nm suitable for highly sensitive detection of molecular analytes by Surface Enhanced Raman Spectroscopy (SERS). The significance of the approach is demonstrated through the control exercised at each step, including template preparation and pattern-transfer steps. The approach is a promising means to address trade-offs between resolutions, throughput, and performance in the fabrication of nanoplasmonic assemblies for sensing applications. PMID- 26523481 TI - Plants in silico: why, why now and what?--an integrative platform for plant systems biology research. AB - A paradigm shift is needed and timely in moving plant modelling from largely isolated efforts to a connected community endeavour that can take full advantage of advances in computer science and in mechanistic understanding of plant processes. Plants in silico (Psi) envisions a digital representation of layered dynamic modules, linking from gene networks and metabolic pathways through to cellular organization, tissue, organ and whole plant development, together with resource capture and use efficiency in dynamic competitive environments, ultimately allowing a mechanistically rich simulation of the plant or of a community of plants in silico. The concept is to integrate models or modules from different layers of organization spanning from genome to phenome to ecosystem in a modular framework allowing the use of modules of varying mechanistic detail representing the same biological process. Developments in high-performance computing, functional knowledge of plants, the internet and open-source version controlled software make achieving the concept realistic. Open source will enhance collaboration and move towards testing and consensus on quantitative theoretical frameworks. Importantly, Psi provides a quantitative knowledge framework where the implications of a discovery at one level, for example, single gene function or developmental response, can be examined at the whole plant or even crop and natural ecosystem levels. PMID- 26523482 TI - Effects of different forms of chitosan on intercellular junctions of mouse fibroblasts in vitro. AB - Chitosan is a linear polysaccharide that has many biomedical applications. We compared the effects of chitosan, in both solution and membranous form, on intercellular adhesion of Swiss 3T3 mouse fibroblasts. Cells were grown as spheroidal cell cultures. Some control cell spheroids were cultured without chitosan and two experimental groups were cultured with chitosan. Chitosan in solution was used for one experimental group and chitosan in membranous form was used for the other. For each group, intercellular adhesion was investigated on days 5 and 10 of culture. Transmission electron microscopy revealed well-defined cellular projections that were more prominent in cells exposed to either membranous or solution forms of chitosan than to the chitosan-free control. Immunocytochemical staining of ICAM-1 and e-cadherin was used to determine the development of intercellular junctions. Compared to the weakly stained control, strong reactions were observed in both chitosan exposed groups at both 5 and 10 days. Cells were treated with 5-bromo-2-deoxyuridine (BrdU) and incubated with anti-BrdU primary antibody to assess proliferation. Both the solution and membranous forms of chitosan increased proliferation at both 5 and 10 days. Cellular viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT). The MTT assay indicated high cell viability; maximum viability was obtained with the solution form of chitosan at day 5. Chitosan exposure increased the number of intercellular junctions and showed a significant proliferative effect on 3T3 mouse fibroblasts. PMID- 26523483 TI - Golimumab for the treatment of axial spondyloarthritis. AB - Axial spondyloarthritis (axSpA) is a chronic, immune-mediated inflammatory disease of the axial skeleton that includes ankylosing spondylitis (AS) and non radiographic axial spondyloarthritis (nr-axSpA). Patients with AS experience chronic pain due to sacroiliac joint and spinal inflammation, and may develop spinal ankylosing with syndesmophyte formation. Tumor necrosis factor alpha inhibitors (TNFi) have shown promise in the management of AS and axSpA by targeting the underlying inflammatory process, and providing symptomatic relief. Whether they alter the progression of the disease is uncertain. Golimumab is a fully human IgG1 monoclonal antibody that targets and downregulates the pro inflammatory cytokine TNF-alpha. The use of golimumab has been shown to reduce the signs and symptoms of axSpA as well as improve patient function and quality reported outcomes. This review focuses on the biological rationale and the results of clinical trials with golimumab for the treatment of axSpA. PMID- 26523485 TI - Disulfide-Linked Dinitroxides for Monitoring Cellular Thiol Redox Status through Electron Paramagnetic Resonance Spectroscopy. AB - Intracellular thiol-disulfide redox balance is crucial to cell health, and may be a key determinant of a cancer's response to chemotherapy and radiation therapy. The ability to assess intracellular thiol-disulfide balance may thus be useful not only in predicting responsiveness of cancers to therapy, but in assessing predisposition to disease. Assays of thiols in biology have relied on colorimetry or fluorimetry, both of which require UV-visible photons, which do not penetrate the body. Low-frequency electron paramagnetic resonance imaging (EPRI) is an emerging magnetic imaging technique that uses radio waves, which penetrate the body well. Therefore, in combination with tailored imaging agents, EPRI affords the opportunity to image physiology within the body. In this study, we have prepared water-soluble and membrane-permeant disulfide-linked dinitroxides, at natural isotopic abundance, and with D,(15)N-substitution. Thiols such as glutathione cleave the disulfides, with simple bimolecular kinetics, to yield the monomeric nitroxide species, with distinctive changes in the EPR spectrum. Using the D,(15)N-substituted disulfide-dinitroxide and EPR spectroscopy, we have obtained quantitative estimates of accessible intracellular thiol in cultured human lymphocytes. Our estimates are in good agreement with published measurements. This suggests that in vivo EPRI of thiol-disulfide balance is feasible. Finally, we discuss the constraints on the design of probe molecules that would be useful for in vivo EPRI of thiol redox status. PMID- 26523486 TI - Total Synthesis and Determination of the Absolute Configuration of Vinylamycin. AB - The absolute configurations of the three unknown chiral centers in vinylamycin were predicted according to the structural comparison with microtermolide A and rakicidin A, and then total syntheses of vinylamycin were applied to determine the three unknown chiral centers as 14R, 15R, and 16S. PMID- 26523484 TI - Alpha and gamma oscillation amplitudes synergistically predict the perception of forthcoming nociceptive stimuli. AB - Ongoing fluctuations of intrinsic cortical networks determine the dynamic state of the brain, and influence the perception of forthcoming sensory inputs. The functional state of these networks is defined by the amplitude and phase of ongoing oscillations of neuronal populations at different frequencies. The contribution of functionally different cortical networks has yet to be elucidated, and only a clear dependence of sensory perception on prestimulus alpha oscillations has been clearly identified. Here, we combined electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) in a large sample of healthy participants to investigate how ongoing fluctuations in the activity of different cortical networks affect the perception of subsequent nociceptive stimuli. We observed that prestimulus EEG oscillations in the alpha (at bilateral central regions) and gamma (at parietal regions) bands negatively modulated the perception of subsequent stimuli. Combining information about alpha and gamma oscillations predicted subsequent perception significantly more accurately than either measure alone. In a parallel experiment, we found that prestimulus fMRI activity also modulated the perception of subsequent stimuli: perceptual ratings were higher when the BOLD signal was higher in nodes of the sensorimotor network and lower in nodes of the default mode network. Similar to what observed in the EEG data, prediction accuracy was improved when the amplitude of prestimulus BOLD signals in both networks was combined. These findings provide a comprehensive physiological basis to the idea that dynamic changes in brain state determine forthcoming behavioral outcomes. Hum Brain Mapp 37:501-514, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26523487 TI - Validation of a Strategy for Cancer Therapy: Delivering Aminoglycoside Drugs to Mitochondria in HeLa Cells. AB - Mitochondria in human cancer cells have been implicated in cancer cell proliferation, invasion, metastasis, and even drug-resistance mechanisms, making them a potential target organelle for the treatment of human malignancies. Gentamicin (GM), an aminoglycoside drug (AG), is a small molecule that functions as an antibiotic and has ototoxic and nephrotoxic characteristics. Thus, the delivery of GM to mitochondria in cancer cells would be an innovative anticancer therapeutic strategy. In this study, we attempted mitochondrial delivery of GM in HeLa cells derived from a human cervical cancer. For the mitochondrial delivery, we used MITO-Porter, a liposomal nanocarrier for mitochondrial delivery via membrane fusion. We first encapsulated GM in the aqueous phase of the carrier to construct GM-MITO-Porter. Flow cytometry analysis and fluorescent microscopy observations permitted us to confirm that the GM-MITO-Porter was efficiently taken up by HeLa cells and accumulated in mitochondria, whereas naked GM was not taken up by the cells. Moreover, cell viability assays using HeLa cells showed that the GM-MITO-Porter induced strong cytotoxic effects related to mitochondrial disorder. This finding is the first report of the mitochondrial delivery of an AG to cancer cells for cancer therapeutic strategy. PMID- 26523488 TI - An action to an object does not improve its episodic encoding but removes distraction. AB - There is some debate as to whether responding to objects in our environment improves episodic memory or does not impact it. Some authors claim that actively encoding objects improves their representation in episodic memory. Conversely, episodic memory has also been shown to improve in passive conditions, suggesting that the action itself could interfere with the encoding process. This study looks at the impact of attention and action on episodic memory using a novel what where-when (WWW) task that includes information about object identity (what) and spatial (where) and temporal (when) properties. With this approach, we studied the episodic memory of 2 types of objects: a target, where attention or an action is defined, and a distractor, an object to be ignored, following 2 selective states: active versus passive selection. When targets were actively selected, we found no evidence of episodic memory enhancement compared to passive selection; instead, memory from irrelevant sources was suppressed. The pattern was replicated across a 2-D static display and a more realistic 3-D virtual environment. This selective attention effect on episodic memory was not observed on nonepisodic measures, demonstrating a link between attention and the encoding of episodic experiences. (PsycINFO Database Record PMID- 26523489 TI - Value conditioning modulates visual working memory processes. AB - Learning allows the value of motivationally salient events to become associated with stimuli that predict those events. Here, we asked whether value associations could facilitate visual working memory (WM), and whether such effects would be valence dependent. Our experiment was specifically designed to isolate value based effects on WM from value-based effects on selective attention that might be expected to bias encoding. In a simple associative learning task, participants learned to associate the color of tinted faces with gaining or losing money or neither. Tinted faces then served as memoranda in a face identity WM task for which previously learned color associations were irrelevant and no monetary outcomes were forthcoming. Memory was best for faces with gain-associated tints, poorest for faces with loss-associated tints, and average for faces with no outcome-associated tints. Value associated with 1 item in the WM array did not modulate memory for other items in the array. Eye movements when studying faces did not depend on the valence of previously learned color associations, arguing against value-based biases being due to differential encoding. This valence sensitive value-conditioning effect on WM appears to result from modulation of WM maintenance processes. PMID- 26523490 TI - Feature-based attention is functionally distinct from relation-based attention: The double dissociation between color-based capture and color-relation-based capture of attention. AB - The present study used a spatial blink task and a cuing task to examine the boundary between feature-based capture and relation-based capture. Feature-based capture occurs when distractors match the target feature such as target color. The occurrence of relation-based capture is contingent upon the feature relation between target and distractor (e.g., color relation). The results show that color distractors that match the target-nontarget color relation do not consistently capture attention when they appear outside of the attentional window, but distractors appearing outside the attentional window that match the target color consistently capture attention. In contrast, color distractors that best match the target-nontarget color relation but not the target color, are more likely to capture attention when they appear within the attentional window. Consistently, color cues that match the target-nontarget color relation produce a cuing effect when they appear within the attentional window, while target-color matched cues do not. Such a double dissociation between color-based capture and color-relation based capture indicates functionally distinct mechanisms for these 2 types of attentional selection. This also indicates that the spatial blink task and the uninformative cuing task are measuring distinctive aspects of involuntary attention. (PsycINFO Database Record PMID- 26523491 TI - Functional Reconstitution of the Insulin-Secreting Porosome Complex in Live Cells. AB - Supramolecular cup-shaped lipoprotein structures called porosomes embedded in the cell plasma membrane mediate fractional release of intravesicular contents from cells during secretion. The presence of porosomes, have been documented in many cell types including neurons, acinar cells of the exocrine pancreas, GH-secreting cells of the pituitary, and insulin-secreting pancreatic beta-cells. Functional reconstitution of porosomes into artificial lipid membranes, have also been accomplished. Earlier studies on mouse insulin-secreting Min6 cells report 100-nm porosome complexes composed of nearly 30 proteins. In the current study, porosomes have been functionally reconstituted for the first time in live cells. Isolated Min6 porosomes reconstituted into live Min6 cells demonstrate augmented levels of porosome proteins and a consequent increase in the potency and efficacy of glucose-stimulated insulin release. Elevated glucose-stimulated insulin secretion 48 hours after reconstitution, reflects on the remarkable stability and viability of reconstituted porosomes, documenting the functional reconstitution of native porosomes in live cells. These results, establish a new paradigm in porosome-mediated insulin secretion in beta-cells. PMID- 26523492 TI - Is the Presence of a Solitary Kidney an Independent Risk Factor for Acute Kidney Injury after Contrast-enhanced CT? AB - PURPOSE: To determine whether patients with a solitary kidney are at higher risk for contrast material-induced acute kidney injury (AKI) than matched control patients with bilateral kidneys. MATERIALS AND METHODS: This retrospective study was HIPAA compliant and approved by the institutional review board. Adult patients with bilateral kidneys or a solitary kidney from unilateral nephrectomy who underwent contrast material-enhanced computed tomography (CT) at this institution from January 2004 to August 2013 were identified. The effects of contrast material exposure on the rate of AKI--defined as an increase in maximal observed serum creatinine (SCr) level of either (a) >=0.5 mg/dL (44.2 MUmol/L) or (b) >=0.3 mg/dL (26.52 MUmol/L) or 50% over baseline within 24-72 hours of exposure--and 30-day post-CT emergent dialysis and death were determined after propensity score-based 1:3 matching of patients with solitary kidneys and control patients with bilateral kidneys. Differences in clinical characteristics and outcomes between the solitary and bilateral kidney groups were assessed by using the Wilcoxon rank sum test or Pearson chi(2) test prior to matching and by using conditional logistic regression after matching. RESULTS: Propensity score matching yielded a cohort of 247 patients with solitary kidneys and 691 patients with bilateral kidneys. The rate of AKI was similar between the solitary and bilateral kidney groups (SCr >= 0.5 mg/dL AKI definition odds ratio = 1.11 [95% confidence interval {CI}: 0.65, 1.86], P = .70; SCr >= 0.3 mg/dL or 50% over baseline AKI definition odds ratio = 0.96 [95% CI: 0.41, 2.07], P = .99). The rate of emergent dialysis was rare and also similar between cohorts (odds ratio = 1.87 [95% CI: 0.16, 16.4], P = .61). Although the rate of mortality was higher in the solitary kidney group (odds ratio = 1.70 [95% CI: 1.06, 2.71], P = .0202), chart review showed that no death was attributable to AKI. CONCLUSION: Our study did not demonstrate any significant differences in the rate of AKI, dialysis, or death attributable to contrast-enhanced CT in patients with a solitary kidney versus bilateral kidneys. PMID- 26523493 TI - Irreversible Electroporation in Patients with Hepatocellular Carcinoma: Immediate versus Delayed Findings at MR Imaging. AB - PURPOSE: To assess the postprocedure findings of irreversible electroporation (IRE) in patients with hepatocellular carcinoma (HCC) at magnetic resonance (MR) imaging. MATERIALS AND METHODS: This retrospective study was Institutional Review Board approved, and informed consent was waived. Twenty patients with HCC were treated with IRE over a 2.5-year period. The median patient age was 62 years, and 75% of patients had cirrhosis with a Child-Pugh score of A. The median tumor diameter was 2.0 cm (range, 1.0-3.3 cm). Contrast material-enhanced multiphase MR imaging was performed on postprocedure days 1 and 30 and every 90 days thereafter. Ablation zone sizes and signal intensities were compared between each time point for both T1- and T2-weighted images. Trends in signal intensity and tumor dimensions over time were quantified by using generalized linear models. RESULTS: MR imaging appearances of treated tumors include a zone of peripheral enhancement with centripetal filling on delayed contrast-enhanced images. Compared with postprocedure day 1, every 90 days there is a decrease of 28.9% (mean, axis) in the size of the enhancing ablation zone. Over time, there is a trend toward decreasing signal intensity in the peripheral ablation zone on both T2-weighted (P = .01) and contrast-enhanced T1-weighted (P < .08) images. Conversely, the tumor itself typically has increased signal intensity on the same sequences. CONCLUSION: IRE of HCC results in a large region of enhancement on immediate postprocedure MR images that, over time, involutes and is associated with decreasing signal intensity of the peripheral ablation zone. This phenomenon may represent resolution of the reversible penumbra. PMID- 26523494 TI - Drugs acting on homeostasis: challenging cancer cell adaptation. AB - Cancer treatment aims to exploit properties that define malignant cells. In recent years, it has become apparent that malignant cells often survive cancer treatment and ensuing cell stress by switching on auxiliary turnover pathways, changing cellular metabolism and, concomitantly, the gene expression profile. The changed profile impacts the material exchange of cancer cells with affected tissues. Herein, we show that pathways of proteostasis and energy generation regulate common transcription factors. Namely, when one pathway of intracellular turnover is blocked, it triggers alternative turnover mechanisms, which induce transcription factor proteins that control expression of cytokines and regulators of apoptosis, cell division, differentiation, metabolism, and response to hormones. We focus on several alternative turnover mechanisms that can be blocked by drugs already used in clinical practice for the treatment of other non-cancer related diseases. We also discuss paradigms on the challenges posed by cancer cell adaptation mechanisms. PMID- 26523495 TI - The impact of an enhanced recovery pathway on nursing workload: A retrospective cohort study. AB - BACKGROUND & AIMS: The importance of nursing for surgical patients has been frequently underestimated. The success of enhanced recovery programs after surgery (ERAS) depends on preferably complete fulfillment of the protocol and nurses are an important part of it. Due to the additional nursing action required, such protocols are suspected to increase the nursing workload. The aim of the present study was to observe and measure objectively nursing workload before, during and after systematic implementation of a comprehensive enhanced recovery pathway in colorectal surgery. METHODS: The program ERAS was introduced systematically in our tertiary academic centre 2011, since then our experience is based on more than 1500 ERAS patients. Nursing workload was prospectively assessed for all patients on a routine basis by means of a standardized and validated point system (PRN). In a retrospective cohort study, we compared nursing workload based on prospective data before, during and after ERAS implementation and correlated nursing workload to the compliance with the ERAS protocol. RESULTS: The study cohort included 50 patients before ERAS implementation (2010) and 69 (2011) and 148 (2012) consecutive patients after implementation; the baseline characteristics of the 3 groups were similar. Mean PRN values were 61.2 +/- 19.7 per day in 2010 and decreased to 52.3 +/- 13.7 (P = 0.005) and 51.6 +/- 18.6 (P < 0.002) in 2011 and 2012, respectively. Increasing compliance with the ERAS protocol was significantly correlated to decreasing nursing workload (rho = -0.42; P < 0.001). CONCLUSIONS: Nursing workload is- against a common belief--decreased by systematic implementation of enhance recovery protocol. The higher the compliance with the pathway, the lower the burden for the nurses! PMID- 26523496 TI - A cytokine-like factor astakine accelerates the hemocyte production in Pacific oyster Crassostrea gigas. AB - Astakine has been reported to be a hematopoietic growth factor of prokineticin homolog firstly found in arthropods freshwater crayfish Pacifastacus leniusculus. In the present study, an astakine homologous gene was identified from Pacific oyster Crassostrea gigas (designated CgAstakine). The full length cDNA of CgAstakine encoded a polypeptide of 103 amino acids containing a prokineticin (PK) domain homologous to that in astakine from freshwater crayfish P. leniusculus. The deduced amino acid sequence of CgAstakine shared higher similarity with those of other invertebrate astakines than prokineticins from vertebrates. The mRNA of CgAstakine was highly expressed in hepatopancreas and adductor muscle of oyster, while the CgAstakine protein was mainly distributed in hepatopancreas, gill and hemocytes. The mRNA expression of CgAstakine in hemocytes was significantly increased (p < 0.01) and maintained at a high level from 3 h to 9 h after Vibrio anguillarum challenge. After the oyster hemocytes were incubated with 5 MUg/mL recombinant CgAstakine protein (rCgAstakine) for 24 h in vitro, the proliferation of hemocytes was significantly increased to 1.89 fold of that in control group (p < 0.05). Moreover, the total count of oyster hemocytes was significantly upregulated (2.45 fold of that in control group, p < 0.05) at 12 h after the oysters were received an injection of rCgAstakine (0.5 MUg/g). These results collectively indicated that CgAstakine could modulate the hemocytes proliferation both in vitro and in vivo, and probably involved in the hematopoietic process fighting against the invasion of foreign pathogens. PMID- 26523497 TI - Seasonal variation in baseline and maximum whole-body glucocorticoid concentrations in a small-bodied stream fish independent of habitat quality. AB - Alterations to natural habitats are becoming more common due to changes in anthropogenic land use. As such, there is increasing interest in determining how wild animals adapt and respond to environmental stressors. The glucocorticoid (GC) stress response enables animals to react appropriately to environmental challenges but can be affected by many factors, two of which are habitat quality and time of year (i.e., season). This study tested whether baseline and maximum (stress-induced) whole-body cortisol concentrations varied in relation to habitat quality and season using wild central mudminnows (Umbra limi) collected from two connected streams differing in habitat quality in each of four seasons. Overall, baseline and maximum cortisol levels did not differ significantly between the two systems but there was evidence of a seasonal effect. Baseline cortisol levels in the fall and summer were significantly (P<0.01) lower than those in winter and spring and maximum cortisol levels in the summer were significantly lower (P<0.01) than those in the spring. Inconsistent with the prevailing paradigm, our results indicate that habitat quality does not always influence baseline GCs or the stress response. In contrast, baseline and maximum GCs in this species do vary seasonally. As such, seasonality should be considered in the interpretation of stress response data especially when using small-bodied stream fish as biological indicators. PMID- 26523498 TI - Molecular cloning and characterization of Siamese crocodile (Crocodylus siamensis) copper, zinc superoxide dismutase (CSI-Cu,Zn-SOD) gene. AB - Superoxide dismutase (SOD, EC 1.15.1.1) is an antioxidant enzyme found in all living cells. It regulates oxidative stress by breaking down superoxide radicals to oxygen and hydrogen peroxide. A gene coding for Cu,Zn-SOD was cloned and characterized from Siamese crocodile (Crocodylus siamensis; CSI). The full-length expressed sequence tag (EST) of this Cu,Zn-SOD gene (designated as CSI-Cu,Zn-SOD) contained 462bp encoding a protein of 154 amino acids without signal peptides, indicated as intracellular CSI-Cu,Zn-SOD. This agreed with the results from the phylogenetic tree, which indicated that CSI-Cu,Zn-SOD belonged to the intracellular Cu,Zn-SOD. Chromosomal location determined that the CSI-Cu,Zn-SOD was localized to the proximal region of the Siamese crocodile chromosome 1p. Several highly conserved motifs, two conserved signature sequences (GFHVHEFGDNT and GNAGGRLACGVI), and conserved amino acid residues for binding copper and zinc (His(47), His(49), His(64), His(72), His(81), Asp(84), and His(120)) were also identified in CSI-Cu,Zn-SOD. Real-time PCR analysis showed that CSI-Cu,Zn-SOD mRNA was expressed in all the tissues examined (liver, pancreas, lung, kidney, heart, and whole blood), which suggests a constitutively expressed gene in these tissues. Expression of the gene in Escherichia coli cells followed by purification yielded a recombinant CSI-Cu,Zn-SOD, with Km and Vmax values of 6.075mM xanthine and 1.4*10(-3)mmolmin(-1)mg(-1), respectively. This Vmax value was 40 times lower than native Cu,Zn-SOD (56*10(-3)mmolmin(-1)mg(-1)), extracted from crocodile erythrocytes. This suggests that cofactors, protein folding properties, or post-translational modifications were lost during the protein purification process, leading to a reduction in the rate of enzyme activity in bacterial expression of CSI-Cu,Zn-SOD. PMID- 26523499 TI - Closed system respirometry may underestimate tissue gas exchange and bias the respiratory exchange ratio (RER). AB - Closed respirometry is a commonly used method to measure gas exchange in animals due to its apparent simplicity. Typically, the rates of O2 uptake and CO2 excretion (VO2 and VCO2, respectively) are assumed to be in steady state, such that the measured rates of gas exchange equal those at tissue level. In other words, the respiratory gas exchange ratio (RER) is assumed to equal the respiratory quotient (RQ). However, because the gas concentrations change progressively during closure, the animal inspires air with a progressively increasing CO2 concentration and decreasing O2 concentration. These changes will eventually affect gas exchange causing the O2 and CO2 stores within the animal to change. Because of the higher solubility/capacitance of CO2 in the tissues of the body, VCO2 will be more affected than VO2, and we hypothesize therefore that RER will become progressively underestimated as closure time is prolonged. This hypothesis was addressed by a combination of experimental studies involving closed respirometry on ball pythons (Python regius) as well as mathematical models of gas exchange. We show that increased closed duration of the respirometer reduces RER by up to 13%, and these findings may explain previous reports of RER values being below 0.7. Our model reveals that the maximally possible reduction in RER is determined by the storage capacity of the body for CO2 (product of size and specific capacitance) relative to the respirometer storage capacity. Furthermore, modeling also shows that pronounced ventilatory and circulatory response to hypercapnia can alleviate the reduction in RER. PMID- 26523500 TI - Genome-wide identification and characterization of microRNA genes and their targets in large yellow croaker (Larimichthys crocea). AB - MicroRNAs (miRNAs or miRs) are a class of non-coding RNAs of 20-25 nucleotides (nt) in length, which regulates the expression of gene in eukaryotic organism. Studies has been confirmed that miRNA plays an important role in various biological and metabolic processes in both animals and plants. Predicting new miRNAs by computer based homology search analysis is an effective way to discover novel miRNAs. Though a large number of miRNAs have been reported in many fish species, reports of miRNAs in large yellow croaker (L. crocea) are limited especially via the computational-based approaches. In this paper, a method of comparative genomic approach by computational genomic homology based on the conservation of miRNA sequences and the stem-loop hairpin secondary structures of miRNAs was adopted. A total of 199 potential miRNAs were predicted representing 81 families. 12 of them were chose to be validated by real time RT-PCR, apart from miR-7132b-5p which was not detected. Results indicated that the prediction method that we used to identify the miRNAs was effective. Furthermore, 948 potential target genes were predicted. Gene ontology (GO) analysis revealed that 175, 287, and 486 target genes were involved in cellular components, biological processes and molecular functions, respectively. Overall, our findings provide a first computational identification and characterization of L. crocea miRNAs and their potential targets in functional analysis, and will be useful in laying the foundation for further characterization of their role in the regulation of diversity of physiological processes. PMID- 26523501 TI - Hematopoietic lineage skewing and intestinal epithelia degeneration in aged mice with telomerase RNA component deletion. AB - A deletion of a telomerase RNA component (Terc(-/-)) in C57BL/6 (B6) mice resulted in hematopoietic lineage skewing with increased neutrophils and CD11b(+) myeloid cells and decreased red blood cells and CD45R(+) B lymphocytes when animals reach ages older than 12 months. There was no decline in bone marrow (BM) c-Kit(+)Sca-1(+)Lin(-) (KSL) cells in old Terc(-/-) mice, and the lineage skewing phenomenon was not transferred when BM cells from old Terc(-/-) donors were transplanted into young B6 recipients. Necropsy and histological examinations found minimal to no change in the lung, spleen and liver but detected severe epithelia degeneration, ulceration and infection in small and large intestines, leading to enteritis, typhlitis and colitis in old Terc(-/-) mice. In a mouse model of dextran-sulfate-sodium-induced typhlitis and colitis, development of intestinal pathology was associated with increases in neutrophils and CD11b(+) myeloid cells and a decrease in CD45R(+) B cells, similar to those observed in old Terc(-/-) mice. Treatment of 11-13 month old Terc(-/-) mice with antibiotic trimethoprim-sulfa water reduced neutrophils and myeloid cells and increased B lymphocytes in the blood, indicating that mitigation of intestinal infection and inflammation could alleviate hematological abnormalities in old Terc(-/-) animals. PMID- 26523502 TI - Evaluation of root canal morphology of human primary molars by using CBCT and comprehensive review of the literature. AB - OBJECTIVE: Knowledge of primary tooth morphology is essential for clinical dentistry, especially for root canal treatment and dental traumatology. However, this has not been well documented to date with a large sample. This study was carried out to investigate the variation in number and morphology of the root canals of the primary molars, to study the applicability of cone beam computerized tomography (CBCT) in assessing the same and to provide a comprehensive review of the literature. MATERIALS AND METHODS: A total of 343 primary molars, without any root resorption, were divided into four main groups including the maxillary first molars, maxillary second molars, mandibular first molars and mandibular second molars. All of them were analysed in CBCT images in the axial, sagittal and coronal planes. Various parameters such as the number of roots, number of canals, the root canal type, diameter of root and root canal and root canal curvature were studied. RESULTS: Primary molars in all four groups showed variability in the number of roots and root canals. As far as length of the roots was concerned, the palatal root of the maxillary molar was found to be longest, while the distobuccal root was shortest. In mandibular molars, the mesial root was longer than the distal root. The length of distobuccal root canal of the maxillary molars and the distolingual canal of the mandibular molars was found to be shortest. The number of roots and root canals varied from two to four and three to four, respectively. The maxillary molars exhibited more one-canal than two-canal roots. CONCLUSION: The present study provides comprehensive information to the existing literature concerning the variation in root canal morphology of the maxillary and mandibular primary molar teeth. These data may help clinicians in the root canal treatment of these teeth. PMID- 26523503 TI - Laccase-modified gold nanorods for electrocatalytic reduction of oxygen. AB - cathodes. Nanostructuring was provided by gold nanorods (AuNRs), which were characterized and covalently attached to electrodes made of low-density graphite. The nanostructured electrode was the scaffold for covalent and oriented attachment of ThLc. The bioelectrocatalytic currents measured for oxygen reduction were as high as 0.5 mA/cm(2 and 0.7 mA/cm(2), which were recorded under direct and mediated electron transfer regimes, respectively. )The experimental data were fitted to mathematical models showing that when the O2 is bioelectroreduced at high rotation speed of the electrode the heterogeneous electron transfer step is the rate-liming stage. The electrochemical measurement hints a wider population of non-optimally wired laccases than previously reported for 5-8 nm size Au nanoparticle-modified electrode, which could be due to a larger size of the AuNRs when compared to the laccases as well as their different crystal facets. PMID- 26523504 TI - Label-free and direct detection of C-reactive protein using reduced graphene oxide-nanoparticle hybrid impedimetric sensor. AB - For label-free and direct detection of C-reactive protein (CRP), an impedimetric sensor based on an indium tin oxide (ITO) electrode array functionalized with reduced graphene oxide-nanoparticle (rGO-NP) hybrid was fabricated and evaluated. Analytical measurements were performed to examine the properties of rGO-NP modified ITO microelectrodes and to determine the influence upon sensory performance of using nanostructures modified for antibody immobilization and for recognition of CRP binding events. Impedimetric measurements in the presence of the redox couple [Fe(CN)6](3-/4-) showed significant changes in charge transfer resistance upon binding of CRP. The impedance measurements were highly target specific, linear with logarithmic CRP concentrations in PBS and human serum across a 1 ng mL(-1) and 1000 ng mL(-1) range and associated with a detection limits of 0.06 and 0.08 ng mL(-1) respectively. PMID- 26523505 TI - Mediated amperometry reveals different modes of yeast responses to sugars. AB - Menadione-mediated amperometry at carbon paste electrodes modified with various yeasts (Saccharomyces cerevisiae, Candida pulcherrima, Pichia guilliermondii and Debaryomyces hansenii) was employed to monitor redox activity inside the yeast cells induced by glucose, fructose, sucrose, maltose or galactose. Continuous measurements revealed distinct modes (transient or gradually increasing) of the current development during the first 2 to 3 min after subjection to glucose, fructose and sucrose at electrodes containing S. cerevisiae and non-Saccharomyces strains. Different modes (increasing or decreasing) of the current development after yeast subjection to galactose at electrodes with S. cerevisiae or D. hansenii and at electrodes with C. pulcherrima and P. guilliermondii suggested different mechanisms of galactose assimilation. PMID- 26523506 TI - In situ electrochemical evaluation of dsDNA interaction with the anticancer drug danusertib nitrenium radical product using the DNA-electrochemical biosensor. AB - Danusertib is a kinase inhibitor and anti-cancer drug. The evaluation of the interaction between danusertib and dsDNA was investigated in bulk solution and using the dsDNA-electrochemical biosensor. The dsDNA-danusertib interaction occurs in two sequential steps. First, danusertib binds electrostatically todsDNA phosphate backbone through the positively charged piperazine moiety. The second step involved the pyrrolo-pyrazolemoiety and led to small morphological modifications in the dsDNA double helix which were electrochemically characterised through the changes of guanine and adenine residue oxidation peaks and confirmed by electrophoretic and spectrophotometric measurements. The nitrenium cation radical product of danusertib amino group oxidation was electrochemically generated in situ on the dsDNA-electrochemical biosensor surface. The danusertib nitrenium cation radical redox metabolite was covalently attached to the C8 of guanine residues preventing their oxidation. An interaction mechanism of dsDNA-danusertib is proposed and the formation of the danusertib redox nitrenium radical metabolite-guanine adduct explained. PMID- 26523507 TI - Identification of a Hippeastrum hybridum guanylyl cyclase responsive to wounding and pathogen infection. AB - Guanosine 3',5'-cyclic monophosphate (cGMP) is a critical component of many (patho)physiological processes in plants whilst guanylyl cyclases (GCs) which catalyse the formation of cGMP from GTP have remained somewhat elusive. Consequently, the two major aims are the discovery of novel guanylyl cyclases and the identification of GC/cGMP mediated processes. To identify a novel GC from Hippeastrum hybridum plant and facilitate the preparation of guanylyl cyclase in an amount sufficient for further crystallographic studies, we have constructed an overproduction system for this enzyme. This gene encodes a protein of 256 amino acids, with a calculated molecular mass of 28kD. The predicted amino acid sequence contains all the typical features and shows a high identity to other plant GCs. The GST-HpGC1 was catalytically active in Escherichia coli cells and the purified, recombinant HpGC1 was able to convert GTP to cGMP in the presence of divalent cations. The used overexpression system yields a guanylyl cyclase as 6% of the bacterial cytosolic protein. Besides the identification of HpGC1 as a guanylyl cyclase, the study has shown that the level of HpCG1 mRNA changed during stress conditions. Both mechanical damage and a Peyronellaea curtisii (=Phoma narcissi) fungi infection led to an initial decrease in the HpGC1 transcript level, followed by a substantial increase during the remainder of the 48-h test cycle. Moreover, significant changes in cyclic GMP level were observed, taking the form of oscillations. In conclusion, our data unequivocally identified the product of the HpGC1 gene as a guanylyl cyclase and demonstrates that such an overproduction system can be successfully used in enzyme synthesis. Furthermore, they indicate a link between the causing stimulus (wounding, infection) and guanylyl cyclase expression and the increase in cGMP amplitude. Therefore, it is concluded that appearance of cyclic GMP as a mediator in defense and wound healing mechanisms provides a clue to the regulation of these processes. PMID- 26523508 TI - Intraperitoneal injection of microencapsulated Sertoli cells restores muscle morphology and performance in dystrophic mice. AB - Duchenne muscular dystrophy (DMD) is a genetic disease characterized by progressive muscle degeneration leading to impaired locomotion, respiratory failure and premature death. In DMD patients, inflammatory events secondary to dystrophin mutation play a major role in the progression of the pathology. Sertoli cells (SeC) have been largely used to protect xenogeneic engraftments or induce trophic effects thanks to their ability to secrete trophic, antiinflammatory, and immunomodulatory factors. Here we have purified SeC from specific pathogen-free (SPF)-certified neonatal pigs, and embedded them into clinical grade alginate microcapsules. We show that a single intraperitoneal injection of microencapsulated SPF SeC (SeC-MC) in an experimental model of DMD can rescue muscle morphology and performance in the absence of pharmacologic immunosuppressive treatments. Once i.p. injected, SeC-MC act as a drug delivery system that modulates the inflammatory response in muscle tissue, and upregulates the expression of the dystrophin paralogue, utrophin in muscles through systemic release of heregulin-beta1, thus promoting sarcolemma stability. Analyses performed five months after single injection show high biocompatibility and long term efficacy of SeC-MC. Our results might open new avenues for the treatment of patients with DMD and related diseases. PMID- 26523509 TI - C1q/TNF-related protein-9 inhibits cytokine-induced vascular inflammation and leukocyte adhesiveness via AMP-activated protein kinase activation in endothelial cells. AB - Although recent studies have reported cardioprotective effects of C1q/TNF-related protein 9 (CTRP9), the closet adiponectin paralog, its role on cytokine-induced endothelial inflammation is unknown. We investigated whether CTRP9 prevented inflammatory cytokine-induced nuclear factor-kappa B (NF-kappaB) activation and inhibited the expression of adhesion molecules and a chemokine in the vascular endothelial cell. We used human aortic endothelial cells (HAECs) to examine the effects of CTRP9 on NF-kappaB activation and the expression of NF-kappaB-mediated genes, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1). Tumor necrosis factor alpha (TNFalpha) was used as a representative proinflammatory cytokine. In an adhesion assay using THP-1 cells, CTRP9 reduced TNFalpha-induced adhesion of monocytes to HAECs. Treatment with CTRP9 significantly decreased TNFalpha-induced activation of NF-kappaB, as well as the expression of ICAM-1, VCAM-1, and MCP-1. In addition, treatment with CTRP9 significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), the downstream target of AMPK. The inhibitory effect of CTRP9 on the expression of ICAM-1, VCAM-1, and MCP-1 and monocyte adhesion to HAECs was abolished after transfection with an AMPKalpha1 specific siRNA. Our study is the first to demonstrate that CTRP9 attenuates cytokine-induced vascular inflammation in endothelial cells mediated by AMPK activation. PMID- 26523510 TI - Anti-pulmonary fibrotic activity of salvianolic acid B was screened by a novel method based on the cyto-biophysical properties. AB - Various methods have been used to evaluate anti-fibrotic activity of drugs. However, most of them are complicated, labor-intensive and lack of efficiency. This study was intended to develop a rapid method for anti-fibrotic drugs screening based on biophysical properties. A549 cells in vitro were stimulated with transforming growth factor-beta1 (TGF-beta1), and fibrogenesis was confirmed by conventional immunological assays. Meanwhile, the alterations of cyto biophysical properties including morphology, roughness and stiffness were measured utilizing atomic force microscopy (AFM). It was found that fibrogenesis was accompanied with changes of cellular biophysical properties. TGF-beta1 stimulated A549 cells became remarkably longer, rougher and stiffer than the control. Then, the effect of N-acetyl-L-cysteine (NAC) as a positive drug on ameliorating fibrogenesis in TGF-beta1-stimulated A549 cells was verified respectively by immunological and biophysical markers. The result of Principal Component Analysis showed that stiffness was a leading index among all biophysical markers during fibrogenesis. Salvianolic acid B (SalB), a natural anti-oxidant, was detected by AFM to protect TGF-beta1-stimulated A549 cells against stiffening. Then, SalB treatment was provided in preventive mode on a rat model of bleomycin (BLM) -induced pulmonary fibrosis. The results showed that SalB treatment significantly ameliorated BLM-induced histological alterations, blocked collagen accumulations and reduced alpha-SMA expression in lung tissues. All these results revealed the anti-pulmonary fibrotic activity of SalB. Detection of cyto-biophysical properties were therefore recommended as a rapid method for anti-pulmonary fibrotic drugs screening. PMID- 26523511 TI - 1,25(OH)2D3 attenuates TGF-beta1/beta2-induced increased migration and invasion via inhibiting epithelial-mesenchymal transition in colon cancer cells. AB - 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has been reported to inhibit proliferation and migration of multiple types of cancer cells. However, the mechanism underlying its anti-metastasis effect is not fully illustrated. In this study, the effect of 1,25(OH)2D3 on TGF-beta1/beta2-induced epithelial-mesenchymal transition (EMT) is tested in colon cancer cells. The results suggest that 1,25(OH)2D3 inhibited TGF-beta1/beta2-induced increased invasion and migration of in SW-480 and HT-29 cells. 1,25(OH)2D3 also inhibited the cadherin switch in SW 480 and HT-29 cells. TGF-beta1/beta2-induced increased expression of EMT-related transcription factors was also inhibited by 1,25(OH)2D3. 1,25(OH)2D3 also inhibited the secretion of MMP-2 and MMP-9 and increased expression of F-actin induced by TGF-beta1/beta2 in SW-480 cells. Taken together, this study suggests that the suppression of EMT might be one of the mechanisms underlying the anti metastasis effect of 1,25(OH)2D3 in colon cancer cells. PMID- 26523512 TI - Propofol promotes cell apoptosis via inhibiting HOTAIR mediated mTOR pathway in cervical cancer. AB - OBJECTIVES: Cervical cancer is one of the most common gynecologic malignant tumors. Propofol has been proposed to play a role of antitumor in various cancers. However, the functions and mechanisms of Propofol in cervical cancer is still not clear. METHODS: In vitro, the different concentrations of propofol were co-incubated with cervical cancer cell lines, including Hela, Caski and C-33A cells respectively. The pcDNA-HOTAIR plasmid was transfected into cells after the treatment of 10 MUg/ml propofol. The cell viability and apoptosis were detected by MTT assay and TUNEL method. In vivo, propofol was injected into mice of transplantation tumor with Caski cells or with pcDNA-HOTAIR treated Caski cells. RESULTS: Propofol significantly decreased the cell viability and increased the cell apoptosis in Hela, Caski and C-33A cells, while HOTAIR overexpression promoted cell viability and inhibits cell apoptosis. mTOR/p70S6K protein expression levels were also markedly reduced by propofol but the effects were reversed with pcDNA-HOTAIR. In vivo, propofol inhibited the tumor size but had no inhibition effect in HOTAIR overexpression group. CONCLUSION: Propofol inhibited tumor size, cell viability and promoted cell apoptosis via inhibiting mTOR/p70S6K pathway mediated by HOTAIR in cervical cancer. PMID- 26523513 TI - Dehydroepiandrosterone-enhanced dual specificity protein phosphatase (DDSP) prevents diet-induced and genetic obesity. AB - Dehydroepiandrosterone (DHEA) exerts a wide variety of therapeutic effects against medical disorders, such as diabetes and obesity. However, the molecular basis of DHEA action remains to be clarified. Previously, we reported that DHEA enhanced dual specificity protein phosphatase, designated DDSP, is one of the target molecules of DHEA. To examine the role of DDSP in DHEA signaling, we generated mice that carry a DDSP transgene in which expression is driven by the CAG promoter (DDSP-Tg). DDSP-Tg mice weighed significantly less than wild-type (WT) control mice when a high fat diet was supplied (p < 0.01). No difference in food-intake or locomotor activity was found between DDSP-Tg and WT mice. Oxygen consumption of DDSP-Tg mice was higher than that of WT mice (p < 0.01), which suggested an increase in basal metabolism in DDSP-Tg mice. To further investigate the role of DDSP in genetic obese mice, DDSP-Tg mice with a db/db background were generated (DDSP-Tg db/db). We observed cancellation of obesity by the db/db mutation and development of a cachexic phenotype in DDSP-Tg db/db mice. In conclusion, our study shows that expression of DDSP leads to prevention of diet induced and genetic (db/db) obesity. Anti-obese effects of DHEA might be mediated through DDSP, which might be a therapeutic target for intervention of obesity. PMID- 26523514 TI - Vaginal LPS changed gene transcriptional regulation response to ischemic reperfusion and increased vulnerability of fetal brain hemorrhage. AB - During pregnancy, both ischemic reperfusion and bacterial agent LPS are known risk factors for fetal brain damage. However, there is a lack of evidence to explain whether vaginal LPS affects the fetus response to ischemic reperfusion. Here we reported that there was more than 2 folds higher vulnerability of fetal brain hemorrhage response to ischemic reperfusion when mother mouse was treated with vaginal LPS. As our previously reported, ischemic reperfusion induces P53 dependent fetal brain damage was based on a molecular mechanism: the transcriptional pattern was changed from HIF-1alpha-dependent to P53-dependent immediately. In the present work, only with vaginal LPS precondition, phosphorylation of activated transcriptional factor (ATF) 2 at Thr71 appeared in response to ischemic reperfusion. Moreover, this phosphorylation was completely blocked by pre-treatment with a P53 inhibitor, pifithrin-alpha. We concluded that vaginal LPS precondition trigged the p53-dependent phosphorylation of ATF2 in response to ischemic reperfusion, which played an important role of increasing vulnerability to hemorrhage in fetus. PMID- 26523515 TI - How Y-Family DNA polymerase IV is more accurate than Dpo4 at dCTP insertion opposite an N2-dG adduct of benzo[a]pyrene. AB - To bypass DNA damage, cells have Y-Family DNA polymerases (DNAPs). One Y-Family class includes DNAP kappa and DNAP IV, which accurately insert dCTP opposite N(2) dG adducts, including from the carcinogen benzo[a]pyrene (BP). Another class includes DNAP eta and DNAP V, which insert accurately opposite UV-damage, but inaccurately opposite BP-N(2)-dG. To investigate structural differences between Y Family-classes, regions are swapped between DNAP IV (a kappa/IV-class-member) and Dpo4 (a eta/V-class-member); the kinetic consequences are evaluated via primer extension studies with a BP-N(2)-dG-containing template. Four key structural elements are revealed. (1) Y-Family DNAPs have discreet non-covalent contacts between their little finger-domain (LF-Domain) and their catalytic core-domain (CC-Domain), which we call "non-covalent bridges" (NCBs). Arg37 and Arg38 in DNAP IV's CC-Domain near the active site form a non-covalent bridge (AS-NCB) by interacting with Glu251 and Asp252, respectively, in DNAP IV's LF-Domain. Without these interactions dATP/dGTP/dTTP misinsertions increase. DNAP IV's AS-NCB suppresses misinsertions better than Dpo4's equivalent AS-NCB. (2) DNAP IV also suppresses dATP/dGTP/dTTP misinsertions via a second non-covalent bridge, which is ~8A from the active site (Distal-NCB). Dpo4 has no Distal-NCB, rendering it inferior at dATP/dGTP/dTTP suppression. (3) dCTP insertion is facilitated by the larger minor groove opening near the active site in DNAP IV versus Dpo4, which is sensible given that Watson/Crick-like [dCTP:BP-N(2)-dG] pairing requires the BP moiety to be in the minor groove. (4) Compared to Dpo4, DNAP IV has a smaller major groove opening, which suppresses dGTP misinsertion, implying BP-N(2)-dG bulk in the major groove during Hoogsteen syn-adduct-dG:dGTP pairing. In summary, DNAP IV has a large minor groove opening to enhance dCTP insertion, a plugged major groove opening to suppress dGTP misinsertion, and two non-covalent bridges (near and distal to the active site) to suppress dATP/dGTP/dTTP misinsertions; collectively these four structural features enhance DNAP IV's dNTP insertion fidelity opposite a BP-N(2)-dG adduct compared to Dpo4. PMID- 26523516 TI - The development of a mature collagen network in cartilage from human bone marrow stem cells in Transwell culture. AB - Damaged hyaline cartilage shows a limited capacity for innate repair. Potential sources of cells to augment the clinical repair of cartilage defects include autologous chondrocytes and mesenchymal stem cells. We have reported that culture of human bone marrow mesenchymal stem cells with specific growth and differentiation factors as shallow multilayers on Transwell permeable membranes provided ideal conditions for chondrogenesis. Rigid translucent cartilaginous disks formed and expressed cartilage-specific structural proteins aggrecan and type II collagen. We report here the analysis of the collagen network assembled in these cartilage constructs and identify key features of the network as it became mature during 28 days of culture. The type II collagen was co-polymerized with types XI and IX collagens in a fibrillar network stabilized by hydroxylysyl pyridinoline cross-links as in epiphyseal and hyaline cartilages. Tandem ion-trap mass-spectrometry identified 3-hydroxylation of Proline 986 and Proline 944 of the alpha1(II) chains, a post-translational feature of human epiphyseal cartilage type II collagen. The formation of a type II collagen based hydroxy-lysyl pyridinoline cross-linked network typical of cartilage in 28 days shows that the Transwell system not only produces, secretes and assembles cartilage collagens, but also provides all the extracellular mechanisms to modify and generate covalent cross-links that determine a robust collagen network. This organized assembly explains the stiff, flexible nature of the cartilage constructs developed from hMSCs in this culture system. PMID- 26523517 TI - Low shear stress induces M1 macrophage polarization in murine thin-cap atherosclerotic plaques. AB - Macrophages, a significant component of atherosclerotic plaques vulnerable to acute complications, can be pro-inflammatory (designated M1), regulatory (M2), lipid- (Mox) or Heme-induced (Mhem). We showed previously that low (LSS) and oscillatory (OSS) shear stress cause thin-cap fibroatheroma and stable smooth muscle cell-rich plaque formation respectively in ApoE-knockout (ApoE(-/-)) mice. Here we investigated whether different shear stress conditions relate to specific changes in macrophage polarization and plaque morphology by applying a shear stress-altering cast to the carotid arteries of high fat-fed ApoE(-/-) mice. The M1 markers iNOS and IRF5 were highly expressed in macrophage-rich areas of LSS lesions compared to OSS lesions 6weeks after cast placement, while the M2 marker Arginase-1, and Mox/Mhem markers HO-1 and CD163 were elevated in OSS lesions. Our data indicates shear stress could be an important determinant of macrophage polarization in atherosclerosis, with low shear promoting M1 programming. PMID- 26523518 TI - Chromatin remodeling permits cardiac hypertrophy to develop. PMID- 26523519 TI - Assessment of planning ability: Psychometric analyses on the unidimensionality and construct validity of the Tower of London Task (TOL-F). AB - OBJECTIVE: The Tower of London (TOL) is widely used to assess planning ability as a prototypical executive function in healthy and clinical populations. Despite its popularity, there is still no consensus on (a) whether the TOL measures a psychometrically unidimensional trait, and (b) how differences in problem structure relate to the difficulty of individual items. METHOD: Employing the framework of factor analysis and item response theory we investigated these issues of construct validity in a sample of 798 participants (443 female; 16 to 84 years). Participants worked on the TOL-Freiburg version (TOL-F) comprising a set of 24 4- to 6-move problems, which--based on comprehensive cognitive task analyses-systematically differ with regard to several structural problem parameters (minimum number of moves, search depth, goal hierarchy). RESULTS: Results revealed that TOL-F performance is mainly explained by 1 major factor, while further minor factors additionally account for smaller, but possibly still informative, shares of variance. Individual item difficulties can be predicted by the experimentally varied problem parameters to a high degree (r = .89) and can be considered stable across different levels of age, sex, education, and planning ability. CONCLUSION: These findings demonstrate the TOL-F's construct validity as measuring planning ability in terms of an essentially unidimensional cognitive function while adhering to theory-driven concepts of task difficulty. TOL-F task performance hence represents an accurate, robust, and theoretically grounded estimation of a participant's planning ability. The results further highlight the merit of using established concepts from experimental psychology for improving neuropsychological assessment. PMID- 26523520 TI - Cognitive performance in young adulthood and midlife: Relations with age, sex, and education-The Cardiovascular Risk in Young Finns Study. AB - OBJECTIVE: Age, education, and sex associate with cognitive performance. We investigated associations between age, sex, education, and cognitive performance in young or middle-aged adults and evaluated data reduction methods to optimally capture cognitive performance in our population-based data. METHOD: This study is part of the Cardiovascular Risk in Young Finns Study. The 3,596 randomly selected subjects (aged 3-18 years in 1980) have been followed up for 30 years. In 2011, a computer-based cognitive testing battery (the Cambridge Neuropsychological Test Automated Battery [CANTAB]) was used to assess several cognitive domains. Principal component analysis, categorical and standardized classifications were applied to the cognitive data. RESULTS: Among 34- to 49-year-old participants, cognitive performance declined with age, while education associated with better cognitive functions in several cognitive domains. Men had higher performance on all cognitive domains except visual or episodic memory, in which women outperformed men. The results were similar regardless of the data reduction method used. CONCLUSIONS: The associations between sex, age, education, and cognitive performance are already apparent in young adulthood or middle age. Principal component analyses, categorical and standardized classifications are useful tools to analyze CANTAB cognitive data. (PsycINFO Database Record PMID- 26523521 TI - Understanding the role of speech production in reading: Evidence for a print-to speech neural network using graphical analysis. AB - OBJECTIVE: The neural circuitry associated with language processing is complex and dynamic. Graphical models are useful for studying complex neural networks as this method provides information about unique connectivity between regions within the context of the entire network of interest. Here, the authors explored the neural networks during covert reading to determine the role of feedforward and feedback loops in covert speech production. METHOD: Brain activity of skilled adult readers was assessed in real word and pseudoword reading tasks with functional MRI (fMRI). RESULTS: The authors provide evidence for activity coherence in the feedforward system (inferior frontal gyrus-supplementary motor area) during real word reading and in the feedback system (supramarginal gyrus precentral gyrus) during pseudoword reading. Graphical models provided evidence of an extensive, highly connected, neural network when individuals read real words that relied on coordination of the feedforward system. In contrast, when individuals read pseudowords the authors found a limited/restricted network that relied on coordination of the feedback system. CONCLUSION: Together, these results underscore the importance of considering multiple pathways and articulatory loops during language tasks and provide evidence for a print-to speech neural network. (PsycINFO Database Record PMID- 26523522 TI - Mechanical problem-solving strategies in Alzheimer's disease and semantic dementia. AB - OBJECTIVE: The goal of this study was to explore whether the tool-use disorders observed in Alzheimer's disease (AD) and semantic dementia (SD) are of the same nature as those observed in left brain-damaged (LBD) patients. Recent evidence indicates that LBD patients with apraxia of tool use encounter difficulties in solving mechanical problems, characterized by the absence of specific strategies. This pattern may show the presence of impaired mechanical knowledge, critical for both familiar and novel tool use. So, we explored the strategies followed by AD and SD patients in mechanical problem-solving tasks in order to determine whether mechanical knowledge is also impaired in these patients. METHOD: We used a mechanical problem-solving task in both choice (i.e., several tools were proposed) and no-choice (i.e., only 1 tool was proposed) conditions. We analyzed quantitative data and strategy profiles. RESULTS: AD patients but not SD patients met difficulties in solving mechanical problem-solving tasks. However, the key finding is that AD patients, despite their difficulties, showed strategy profiles that are similar to that of SD patients or controls. Moreover, AD patients exhibited a strategy profile distinct from the one previously observed in LBD patients. CONCLUSIONS: Those observations lead us to consider that difficulties met by AD patients to solve mechanical problems or even to use familiar tools may not be caused by mechanical knowledge impairment per se. In broad terms, what we call apraxia of tool use in AD is certainly not the same as apraxia of tool use observed in LBD patients. (PsycINFO Database Record PMID- 26523523 TI - Editorial. PMID- 26523524 TI - [Spontaneous pulmonary hernia: report of a case]. AB - Pulmonary hernia is a protrusion of lung tissue through a defect in the chest wall. Its origin can be congenital or acquired; spontaneous presentation is the least frequent. We report a case of spontaneous intercostal pulmonary hernia with a brief description of the disease. In this case, the patient developed a hematoma in the left hemithorax associated to pain at the base of the left hemithorax after a Valsalva's maneuver. The images obtained by thoracic CT scan revealed the existence of a left intercostal hernia. After radiological diagnosis, surgical treatment of the defect was performed with good results. PMID- 26523525 TI - Omega-3 Fatty Acid Supplementation Lowers Serum FSH in Normal Weight But Not Obese Women. AB - CONTEXT: Dietary omega-3 fatty acids delay ovarian aging and promote oocyte quality in mice. OBJECTIVE: To test whether dietary supplementation with omega-3 polyunsaturated fatty acids (PUFA) modulates reproductive hormones in reproductive-age women. DESIGN: Prospective interventional study. SETTING: Academic center. PARTICIPANTS: Fifteen obese and 12 normal-weight (NW) eumenorrheic women, ages 28-34 years. INTERVENTION: Two frequent blood-sampling studies were performed before and after 1 month of omega-3 PUFA supplementation with 4 g of eicosapentaenoic acid and docosahexaenoic acid daily. MAIN OUTCOME MEASURES: Serum LH and FSH (basal and after GnRH stimulation). RESULTS: The ratio of omega-6 to omega-3 PUFA was significantly reduced in plasma and red blood cell components for both groups after treatment (both P < .01). Omega-3 PUFA supplementation resulted in reduction of FSH and FSH response to GnRH by 17% on average (P = .06 and P = .03, respectively) in NW but not obese women. Serum levels of IL-1beta and TNF-alpha were reduced after omega-3 PUFA supplementation (-72% for IL-1beta; -56% for TNF-alpha; both, P < .05) in obese but not in NW women. This reduction, however, was not associated with a hormonal change in obese women. CONCLUSIONS: Dietary administration with omega-3 PUFA decreased serum FSH levels in NW but not in obese women with normal ovarian reserve. This effect is intriguing and is directionally consistent with murine data whereby higher dietary omega-3 PUFA extends reproductive lifespan. Our results imply that this nutritional intervention should be tested in women with diminished ovarian reserve in an attempt to delay ovarian aging. PMID- 26523526 TI - Single- and Dual-Hormone Artificial Pancreas for Overnight Glucose Control in Type 1 Diabetes. AB - CONTEXT: The added benefit of glucagon in artificial pancreas systems for overnight glucose control in type 1 diabetes has not been fully explored. OBJECTIVE: The objective of the study was to compare the efficacy of dual-hormone (insulin and glucagon) artificial pancreas, single-hormone (insulin alone) artificial pancreas, and conventional insulin pump therapy. DESIGN: This study was a three-center, three-arm, open-label, randomized, crossover controlled trial involving three interventions, each applied over a night after a high carbohydrate/high fat meal and a second after exercise to mimic real-life glycemic excursions. SETTING: The study was conducted in a home setting. PATIENTS: Twenty-eight type 1 diabetes participants (21 adults and seven adolescents) participated in the study. INTERVENTIONS: Dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional pump therapy was activated from 9:00 PM to 7:00 AM. MAIN OUTCOME: The main outcome was a proportion of time in target (4-8 mmol/L) by continuous glucose monitoring from 11:00 PM to 7:00 AM. Analysis was by intention to treat. RESULTS: The median (interquartile range) percentage of time-in-target glucose range was 47% (36% 71%) for conventional therapy, higher on both single-hormone (76% [65%-91%], P < .001) and dual-hormone artificial pancreas (81 [68%-93%], P < .001). The median (interquartile range) time spent below 4 mmol/L was 14% (4%-28%) for conventional therapy, lower on both single-hormone (5% [0%-13%], P = .004) and dual-hormone artificial pancreas (1% [0%-8%], P < .001). There were 14 hypoglycemic events on conventional therapy compared with six incidences on the single-hormone artificial pancreas (P = .059) and three incidences on the dual-hormone artificial pancreas (P = .017). None of these outcomes differed significantly between single- and dual-hormone configurations. CONCLUSIONS: Single- and dual hormone artificial pancreas systems both provided better glucose control than conventional therapy. Although the dual-hormone configuration did not increase overnight time-in-target glucose levels, an effect on lowering hypoglycemia risk cannot be ruled out. PMID- 26523527 TI - Diabetes Genetic Risk Score Modifies Effect of Bisphenol A Exposure on Deterioration in Glucose Metabolism. AB - CONTEXT: Epidemiology studies showed inconsistent results regarding the relationship between bisphenol A (BPA) exposure and risk of type 2 diabetes (T2D). OBJECTIVE: This study sought to prospectively investigate associations of BPA with incident T2D risk and the longitudinal changes in glycemic traits, particularly examining the interaction between gene and BPA exposure on the associations. DESIGN, SETTING, AND PARTICIPANTS: A community-based study was conducted at baseline in 2009, including 2209 nondiabetic middle-age and elderly subjects followed for 4 y. Urinary BPA levels were measured at baseline. A genetic risk score (GRS) based on 34 T2D common variants that identified and validated in East Asians was created. MAIN OUTCOME MEASURES: Incident T2D was defined according to the 1999 World Health Organization criteria. Fasting (FPG) and 2-h post-loading plasma glucose were measured at baseline and followup. RESULTS: Multivariable logistic regression analysis demonstrated no significant association of risk of incident T2D with BPA while with increase in the weighted T2D-GRS (odds ratio, 1.89; 95% confidence interval, 1.31-2.72 for each 10-point increment). Similar results were found in 4-y changes of FPG and 2-h post-loading plasma glucose. The GRS modified the effect of BPA exposure on 4-y changes in FPG (P for interaction = .01). Each 1 unit of Log_BPA was associated with 0.1 mmol/L increase in FPG (P = .007) in the highest quartile of GRS; no associations were found in the lower three quartiles of GRS. CONCLUSIONS: The T2D genetic susceptibility significantly modulated the association of BPA exposure with longitudinal increase in FPG levels. PMID- 26523529 TI - Does maternal diet affect infantile colic? AB - OBJECTIVE: The aim of this study was to investigate the effect of maternal diet on infantile colic without any interventions or food restrictions. METHODS: Thirty colicky and 29 non-colicky infants were included in this prospective study. Mother's diet and baby crying time were recorded for 1 week by mothers; nutritionist classified contents of mother's diet and compared the diet of mother in colicky and non-colicky infants. RESULTS: It was found that mothers of non colicky infants consumed significantly more grapes and lemons than mothers of colicky infants (p = 0.044). The crying time was moderately negatively correlated with the percentage of protein in the maternal diet (R = -0.45, p = 0.01) and the presence of potatoes in the maternal diet (R = -0.38, p = 0.034) and positively correlated with the maternal consumption of walnut (R = 0.38, p = 0.034), banana (R = 0.44, p = 0.01). CONCLUSIONS: Removing bananas from the maternal diet may reduce colic. The consumption of a protein-rich maternal diet, grapes, lemons and potatoes by breastfeeding mothers may protect infants from colic. PMID- 26523528 TI - Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort. AB - CONTEXT: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. OBJECTIVE: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. DESIGN: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. SETTING: The study was conducted in 19 tertiary pediatric endocrinology clinics. PATIENTS: Ninety-five children (48 females, aged 0-18 y, eight familial) with PAI of unknown etiology participated in the study. RESULTS: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP. Several important clinical and molecular insights emerged. CONCLUSION: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future. PMID- 26523531 TI - Reducing the cost of dissociative identity disorder: Measuring the effectiveness of specialized treatment by frequency of contacts with mental health services. AB - It is important to understand and record the impact of therapy on severe mental health conditions through the use of clinical assessment measures. In this article, I propose to extend outcome evaluation by measuring service use and cost prior to and during the commencement of psychological therapy over a period of 4 years for 2 people diagnosed with dissociative identity disorder. The treatment was provided within an outpatient setting in a U.K. National Health Service hospital trust following therapeutic guidelines set out by the International Society for the Study of Trauma and Dissociation. Results show that service use in both inpatient and out-of-hours crisis services reduced as the 2 people received therapy over the 4-year time period. Based on these 2 cases, it appears to be cost effective to provide specialized therapy for dissociative identity disorder in outpatient settings. PMID- 26523530 TI - Lessons from Toxicology: Developing a 21st-Century Paradigm for Medical Research. AB - Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual framework that repurposes the 21st-century transition underway in toxicology. Human disease should be conceived as resulting from integrated extrinsic and intrinsic causes, with research focused on modern human-specific models to understand disease pathways at multiple biological levels that are analogous to adverse outcome pathways in toxicology. Systems biology tools should be used to integrate and interpret data about disease causation and pathophysiology. Such an approach promises progress in overcoming the current roadblocks to understanding human disease and successful drug discovery and translation. A discourse should begin now to identify and consider the many challenges and questions that need to be solved. PMID- 26523532 TI - The normal and fractured physis: an anatomic and physiologic overview. AB - The growth plate (physis) is responsible for enabling and regulating longitudinal growth of upper and lower limbs. This regulation occurs through interaction of the cells in the growth plate with systemic and locally produced factors. This complex interaction leads to precisely controlled changes in chondrocyte size, receptors, and matrix, which ultimately result in endochondral bone formation. With advances in cellular and molecular biology, our knowledge about these complex interactions has increased significantly over the past decade. Deficiency of any of the regulating factors or physeal injury during childhood can alter this well-orchestrated sequence of events and lead to abnormalities in growth. This review highlights the histology of the normal physis, including recent findings at the cellular and molecular levels, mechanics and mechanobiology of the growth plate, pathologies that can affect the physis, and treatment options, including interposition materials. PMID- 26523533 TI - A systematic review of alternative splinting versus complete plaster casts for the management of childhood buckle fractures of the wrist. AB - Paediatric wrist-buckle fractures are common distal radius fractures with inherent stability. Traditional management with complete plaster-cast immobilization necessitates follow-up visits, time off school/work and hospital treatment costs. Treatment with alternative splinting, negating the need for follow-up visits and saving time and money, has been proposed. However, concerns with regard to complications, primarily pain, have been raised; hence, the topic remains controversial. A systematic review was performed with eight randomized controlled trials analysed. Alternative splinting was superior to casting in terms of function, cost and convenience, but with no significantly worse pain or fracture complication level. The evidence endorses the use alternative splinting over casting in paediatric wrist-buckle fractures. PMID- 26523534 TI - Fracture risk and correlating factors of a pediatric population with attention deficit hyperactivity disorder: a nationwide matched study. AB - The aim of this study was to investigate the risk of fracture and the difference between sexes from a nationwide database of fracture risk among children aged 4 17 years with or without attention deficit hyperactivity disorder (ADHD, ICD-9-CD codes 314). The Longitudinal Health Insurance Database (LHID 2000) was used to analyze fracture characteristics of children from the National Health Insurance that covered 96.1% of the Taiwanese population (N=21.4 million). A total of 7200 ADHD children aged between 4 and 17 years whose diagnosis had been confirmed in at least three outpatient clinics between 1 January 2000 and 31 December 2009 were included, and a cohort of 36 000 children without ADHD matched for age, sex, and urbanization was recruited for analysis. The incidence rate of fractures in ADHD children was 21.0 (95% confidence interval=19.4-22.7) per 1000 person-years, significantly (P<0.001) higher than 15.0 (95% confidence interval=14.4-15.6) in non-ADHDs. After adjusting by age, sex, urbanization level, and geographic region, the statistically significant (P<0.001) hazard ratios (HR) of fracture for ADHD children compared with non-ADHD children included 1.62 in girls and 1.38 in boys, 1.53 in the skull, neck, and trunk (ICD-9-CM 800-809), 1.28 in the upper extremity (ICD-9-CM 810-819), and 1.84 in the lower extremity (ICD-9-CM 820-829). The HR also (P<0.001) increased significantly in all age groups, including 1.35 in 4-6, 1.37 in 7-9, and 1.54 in 10-17 years. ADHD should be listed among risk factors of children's fractures in each sex, all age groups, and all body areas that the parents, teachers, caregivers of ADHD children, and pediatric orthopedists should be aware of. Besides, ADHD girls were more affected than ADHD boys, especially after 10 years of age, whereas the adjusted HR was the highest in the lower extremities. Nationwide analysis matched for age and sex showed that ADHD should be considered the risk factor of children's fracture, especially for girls older than 10 years of age. PMID- 26523535 TI - Posterolateral approach for humeral lateral condyle fractures in children. AB - We proposed a simple posterolateral approach to the articular surface of the trochlea for fresh and late fractures of the humeral lateral condyle. Twenty consecutive cases, 16 fresh and four old fractures, were approached between triceps and anconeus before the age of 15 years. All fractures achieved union in 3 months. Nineteen cases were classified as excellent or good by the Hardacre score after 31.3 months of follow-up. One late fracture with elbow subluxation showed radiographic fragmentation of the capitellum and a fair clinical result. This simple optional approach offers good exposure of intra-articular fracture at the trochlea, especially for late fractures. PMID- 26523536 TI - Green microwave switching from oxygen rich yellow anatase to oxygen vacancy rich black anatase TiO2 solar photocatalyst using Mn(II) as 'anatase phase purifier'. AB - Green and rapid microwave syntheses of 'yellow oxygen rich' (YAT-150) and 'black oxygen vacancy rich' (BAT-150) anatase TiO2 nanoparticles are reported for the first time. YAT-150 was synthesized using only titanium(iv) butoxide and water as precursors. The in situ precursor modification by Mn(ii) acetate switched anatase TiO2 from YAT-150 to BAT-150. The entry of Mn(2+) into the crystal lattice of anatase TiO2 paved the way for peak texturing in the existing peak orientations along with the origin of three new anatase TiO2 peaks in the (103), (213) and (105) directions. The as synthesized ultra-small (~5 nm) yellow and black anatase TiO2 nanoparticles were found to be two fold and four fold more photoactive than the commercially available photocatalyst Degussa-P25 under sunlight illumination. PMID- 26523537 TI - Application-oriented computational studies on a series of D-pi-A structured porphyrin sensitizers with different electron-donor groups. AB - A series of D-pi-A zinc porphyrin sensitizers bearing a substituted iminodibenzyl group at the porphyrin meso position, which is expected to have different electron-donating abilities, were designed. Theoretical studies were performed to examine the photovoltaic properties of these molecules in dye-sensitized solar cells (DSSCs). In particular, the important concepts, the Fukui function and the extended condensed Fukui function, are employed to describe the electron-donating abilities accurately at the quantitative level. Tangui Le Bahers model was adopted to analyze charge transfer (CT) during electron transition. A correlation between the electron donating abilities of the derived iminodibenzyl group and CT was built to evaluate the cell performance based on sensitizers . The theoretical studies showed that porphyrins bearing an extremely strong electron-donating group (EDG) would fail in the generation of photocurrent in the closed circuit when applied in DSSCs due to the higher level of the HOMO energy than the redox potential of the redox couple (I(-)/I3(-)). The one with a weaker EDG () is expected to show better photovoltaic performance than porphyrin with an unsubstituted iminodibenzyl group. This study demonstrates a reliable method involving the employment of the Fukui function, the extended condensed Fukui function and the Tangui Le Bahers model for the evaluation of newly designed D-pi A type porphyrin sensitizers for use in DSSCs, and as guidance for future molecular design. PMID- 26523538 TI - H2O-CH4 and H2S-CH4 complexes: a direct comparison through molecular beam experiments and ab initio calculations. AB - New molecular beam scattering experiments have been performed to measure the total (elastic plus inelastic) cross sections as a function of the velocity in collisions between water and hydrogen sulfide projectile molecules and the methane target. Measured data have been exploited to characterize the range and strength of the intermolecular interaction in such systems, which are of relevance as they drive the gas phase molecular dynamics and the clathrate formation. Complementary information has been obtained by rotational spectra, recorded for the hydrogen sulfide-methane complex, with a pulsed nozzle Fourier transform microwave spectrometer. Extensive ab initio calculations have been performed to rationalize all the experimental findings. The combination of experimental and theoretical information has established the ground for the understanding of the nature of the interaction and allows for its basic components to be modelled, including charge transfer, in these weakly bound systems. The intermolecular potential for H2S-CH4 is significantly less anisotropic than for H2O-CH4, although both of them have potential minima that can be characterized as 'hydrogen bonded'. PMID- 26523539 TI - Mammary-type Myofibroblastoma: Clinicopathologic Characterization in a Series of 143 Cases. AB - Mammary-type myofibroblastoma (MTMF) is a benign mesenchymal neoplasm initially described to occur in the breast. MTMF is typically CD34 and desmin positive and genetically has rearrangement or deletion of 13q14, resulting in loss of Rb expression by immunohistochemistry (IHC). Although the wider anatomic distribution of MTMF is increasingly recognized, no large series with clinicopathologic information has been reported to date. Archival cases were retrieved, and the diagnosis of MTMF was confirmed. Hematoxylin and eosin-stained slides and IHC slides were reviewed when available (CD34, Desmin, Rb, SMA, S100, EMA, MDM2, CDK4). The patient age, sex, tumor anatomic location and size, preceding symptoms, and margin status were recorded when possible. Clinical follow-up data were requested for tumor recurrence, metastasis, and patient status at last follow-up. A total of 143 cases of MTMF comprised this study, affecting 94 (66%) male and 49 (34%) female individuals. Mean tumor size was 6.6 cm (range, 1 to 22 cm). Anatomic locations included: inguinal/groin region (65; 45%), breast (15; 10%), chest wall/axilla (7; 5%), trunk (17; 12%), lower (18; 13%) and upper (2; 1%) extremities, or intra-abdominal/retroperitoneal (14; 10%). MTMFs were characterized by spindle cells with relatively short, stubby nuclei and a variable adipocytic component. Hyalinization and myxoid stroma were common. Less common morphologic features included nuclear atypia, epithelioid tumor cell morphology, and neurilemmoma-type nuclear palisading. CD34 and desmin were positive in 89% and 91%, respectively, and were both negative in 3%. Rb expression was lost in 92% (57/62). No cases with follow-up data available had tumor recurrence, although 1 case was reportedly a recurrence itself. In summary, MTMF appears more common at extramammary sites than in the breast and can cause diagnostic difficulty when atypia or epithelioid morphology is present or when located in an unusual anatomic location. MTMF is frequently positive for CD34 and desmin by IHC; however, rare cases are negative for both. There is no evidence of any significant recurrence risk for MTMF, even in the presence of positive resection margins. The degree of morphologic overlap between spindle cell lipoma, cellular angiofibroma, and MTMF, in combination with shared genetics and slightly overlapping anatomic distribution, raises the question of whether or not these tumors are truly distinct entities or instead represent points along a single spectrum of genetically related tumors. PMID- 26523540 TI - Invasive Stratified Mucin-producing Carcinoma and Stratified Mucin-producing Intraepithelial Lesion (SMILE): 15 Cases Presenting a Spectrum of Cervical Neoplasia With Description of a Distinctive Variant of Invasive Adenocarcinoma. AB - Stratified mucin-producing intraepithelial lesion (SMILE) is a cervical intraepithelial lesion, distinct from conventional squamous or glandular counterparts, believed to arise from embryonic cells at the transformation zone by transdifferentiation during high-risk HPV-associated carcinogenesis. It is characterized by stratified, immature epithelial cells displaying varying quantities of intracytoplasmic mucin throughout the majority of the lesional epithelium. We identified a distinct form of invasive cervical carcinoma with morphologic features identical to those in SMILE, which we have termed "invasive stratified mucin-producing carcinoma." Fifteen cases from 15 patients (mean 36 y; range, 22 to 64 y) were retrieved from the pathology archives of multiple institutions with a diagnosis of either SMILE or invasive cervical carcinoma with a description or comment about the invasive tumor's resemblance to SMILE. Seven cases had solely intraepithelial disease with a component of SMILE (mean 29 y; range, 22 to 40 y). The 8 other cases had invasive stratified mucin-producing carcinoma (mean 44; range, 34 to 64 y) in which SMILE was identified in 7. All cases of invasive stratified mucin-producing carcinoma demonstrated stratified, immature nuclei with intracytoplasmic mucin, which morphologically varied between cases from "mucin-rich" to "mucin-poor" in a similar manner to SMILE. All cases had mitotic figures and apoptotic debris, and an intralesional neutrophilic infiltrate was seen in the majority of cases. In cases of invasive carcinoma, the depth of invasion ranged from <1 to 19 mm. Follow-up information was available in 8 cases and ranged from 1 to 36 months (mean 11 mo). Three cases of invasive stratified mucin-producing carcinoma had biopsy or resection-proven metastatic carcinoma on follow-up. These 15 cases of cervical stratified mucin-producing lesions show a combination of intraepithelial and invasive growth patterns. Given that SMILE is well rooted as a distinct intraepithelial lesion, we propose "invasive stratified mucin-producing carcinoma" to describe its corresponding form of invasive carcinoma. PMID- 26523541 TI - Expanding the Spectrum of Renal Tumors in Children: Primary Renal Myoepithelial Carcinomas With a Novel EWSR1-KLF15 Fusion. AB - We report the first 2 examples of primary renal myoepithelial carcinoma (MEC), both occurring in children. Both tumors had the unique morphologic features, immunophenotype, and EWSR1 gene rearrangements supporting the diagnosis. In keeping with the previous observations of an aggressive behavior in pediatric MEC, both cases presented with advanced local stage and distant metastases at the time of diagnosis. The EWSR1 translocation partner was identified as the Kruppel like factor 15 (KLF15) gene in both tumors, and the novel EWSR1-KLF15 gene fusion transcripts were verified using reverse transcription polymerase chain reaction and Sanger dideoxy sequencing. So far, a role for KLF15 in carcinogenesis has not been established, in contrast to other members of the Kruppel-like family of transcription factors, and no rearrangements involving this gene have been documented to our knowledge. These findings expand the spectrum of pediatric renal tumors to include MEC. The characterization of novel EWSR1-KLF15 fusion transcripts carries important diagnostic implications, as well as clues to understand the pathogenesis of these neoplasms. PMID- 26523542 TI - Clinicopathologic Comparison of Lynch Syndrome-associated and "Lynch-like" Endometrial Carcinomas Identified on Universal Screening Using Mismatch Repair Protein Immunohistochemistry. AB - Expanded testing for Lynch syndrome (LS) is increasingly recommended for patients with endometrial carcinomas, and immunohistochemistry (IHC) for tumor loss of mismatch-repair (MMR) protein expression is the most common primary screen. This has led to the recognition of MMR-IHC-deficient cases without identifiable mutations on directed germline sequencing. The clinical implications of such "Lynch-like" (LL) cancers are unclear. We here report the clinicopathologic features of putative familial endometrial carcinoma identified on universal MMR IHC screening with attention to cases with discordant IHC and germline results. The files of the University of Virginia Pathology Department were retrospectively searched for all MMR-deficient endometrial carcinomas identified on screening. Cases were categorized as likely sporadic (MLH1/PMS2 loss, evidence of MLH1 promoter hypermethylation) or putative LS (PLS) (loss of MSH2/MSH6, MSH6, or PMS2). PLS cases were further subdivided into LS and LL groups on the basis of the presence or absence of a confirmatory mutation by germline testing, and the clinicopathologic features of these cases were compared. A deficiency of >=1 MMR protein was observed in 31.4% (66/210) of endometrial carcinomas, including 26 PLS cases, 15 of which had germline testing. Directed germline sequencing confirmed LS in 46.7% (7/15); the remaining cases were classified as LL. High grade and/or biphasic morphology was seen in 42.9% (3/7) of LS and 62.5% (5/8) of LL cases; the remaining cases showed low-grade, conventional endometrioid morphology. High level microsatellite instability was observed in 71.4% (5/7) of LL cases. The majority of cases from both groups (LS: 85.7% [6/7]; LL: 87.5% [7/8]) were low-stage (T1a/T1b). Endometrial carcinoma was the presenting malignancy in 85.7% (6/7) of LS patients and 87.5% (7/8) of LL patients. Family history was suggestive of LS in 28.5% (2/7) of LS patients and 12.5% (1/8) of LL patients. Screening algorithms based on age and cancer history would have failed to identify LS patients in 57.1% (4/7) of cases. Although universal MMR-IHC identifies endometrial carcinoma patients with LS who would have been missed using targeted screening algorithms, it also identifies cancers with discordant IHC and germline results for which the somatic versus germline origin of the MMR defect is unclear. Further study of this LL group is required before drawing definitive conclusions about their familial cancer risk. PMID- 26523543 TI - Perineural Invasion in Prostate Cancer Is More Frequently Detected by Multiparametric MRI Targeted Biopsy Compared With Standard Biopsy. AB - Multiparametric magnetic resonance imaging (MP-MRI) incorporates high-resolution imaging to aid in the detection of lesions suspicious for prostate cancer (PCa). MP-MRI and MRI/ultrasound (US) fusion-guided prostate biopsy has been shown to detect more clinically significant PCa. However, to date there have been no studies in fusion-guided biopsies evaluating the detection of perineural invasion. We assessed whether MRI/US fusion-guided prostate biopsies diagnosed more perineural invasion compared with standard techniques. We reviewed our prospectively maintained prostate biopsy database evaluating men who underwent MP MRI and MRI/US fusion-guided prostate biopsy between January 2014 and June 2015. Patients underwent MP-MRI followed by 12-core standard biopsy and fusion-guided biopsies of MRI-identified lesions. Patients' clinical, radiologic, and pathologic findings were reviewed. A total of 114 patients underwent both 12-core standard biopsy and MRI/US fusion-guided prostate biopsy. The mean age and prebiopsy prostate-specific antigen of our patient cohort was 64.5 years and 10.7 ng/mL, respectively. Sixty-four of 114 (56%) patients were found to have PCa. Perineural invasion was identified in 19/64 (30%) patients. Of the patients with perineural invasion, 9 were diagnosed on the fusion biopsy only, 2 were diagnosed on standard biopsy only, and 8 were diagnosed on both standard and fusion biopsies. Perineural invasion was significantly associated with higher prostate specific antigen and with a higher number of cores involved by cancer (P<0.05). Compared with standard biopsy, MRI/US fusion-guided prostate biopsy improves detection of perineural invasion in PCa. As perineural invasion has only been studied on standard biopsies to date, it is unclear whether this finding has the same clinical significance for MP-MRI targeted lesions. PMID- 26523544 TI - "Apocrine Hidrocystoma and Cystadenoma"-like Tumor of the Digits or Toes: A Potential Diagnostic Pitfall of Digital Papillary Adenocarcinoma. AB - Digital papillary carcinoma (DPC) is a rare, underreported, and often misdiagnosed malignant tumor of the sweat glands. It is often located on the digits and toes and most commonly occurs in male individuals in their fifties to seventies. Because of lack of pain, slow growth, and an inconspicuous appearance, clinical diagnosis is often missed or delayed. In contrast, apocrine hidrocystoma (AH) is a cystic adenoma that arises from the apocrine secretory coil, and it is extremely rare for AHs to develop on the digits. We report 7 cases of DPC, including clinical course, histopathologic and immunohistochemical findings, and therapeutic approach in which the initial histopathologic diagnosis in all cases was AH or cystadenoma. However, complete excision of the neoplasms led to a final diagnosis of DPC. After an adequate treatment, no recurrence or metastasis was found in any of the cases described. All the cases studied showed similar histopathologic and immunohistochemical findings. The initial incisional biopsy showed large unilocular or multilocular cystic spaces situated within the dermis, lined by a double layer of epithelial cells with tiny papillary structures. No cellular atypia, necrosis, or pleomorphism was observed. However, complete excision revealed neoplastic lesions involving the dermis and/or subcutis, with an infiltrative pattern and papillary projections into luminal spaces. Immunoperoxidase studies showed positivity for CK7, S-100 protein, CEA, p63, smooth muscle actin, and calponin. DPC is a rare but life-threatening malignancy, therefore it is important to be able to identify such a lesion both clinically and histopathologically, treat it, and monitor the patient for the tumor's potential recurrence and metastasis. Pathologists and dermatopathologists should be aware that a histopathologic diagnosis of AH or cystadenoma on the fingers and toes should be established with caution, because probably those lesions represent the superficial and cystic component of an underlying DPC, and a wider excision should be performed. PMID- 26523545 TI - B-alpha-[AsW9O33](9-) polyoxometalates incorporating hexanuclear uranium {U6O8} like clusters bearing the U(IV) form or unprecedented mixed valence U(IV)/U(VI) involving direct U(VI)=O-U(IV) bonding. AB - The use of B-alpha-[AsW9O33](9-) anionic moieties in association with the tetravalent 5f uranium UCl4 precursor affords three new hexanuclear uranium {U6O8}-like clusters embedded in a polyoxometalate architecture. Two of them are constituted by an unprecedented uranium mixed valence U(IV)/U(VI) cluster. PMID- 26523546 TI - The CAnadian REgistry for Pulmonary Fibrosis (CARE-PF): Design and rationale of a national pulmonary fibrosis registry. PMID- 26523547 TI - High conductivity organic thin films for spintronics: the interface resistance bottleneck. AB - Highly electrochemically doped poly(2,5-bis(3-dodecyl-2-yl)-thieno[3,2 b]thiophene (pBTTT) thin films exhibiting remarkably high conductivities values reaching 3000-5000 Omega(-1) cm(-1) are investigated. Experimental evidence of delocalized transport properties of this material at the onset of metallicity makes it an ideal candidate for spin valve device integration. Nevertheless, the interface resistance between the polymer and metallic electrodes is orders of magnitudes larger than the expected spin resistance of the active channel. This prevents the collection of a spin current. This finding can explain the lack of success in making lateral organic spin valves reported in the literature, especially the related absence of spin signals in non-local spin valve and Hanle current measurements in organic thin films. PMID- 26523548 TI - Titration of gold nanoparticles in phase extraction. AB - In the organic-aqueous phase transfer process of gold nanoparticles, there are two types of distinctive interfaces involving hydrophilic and hydrophobic ligands, the understanding of which is important for the design of functional nanomaterials for analytical/bioanalytical applications and the control over the nanoparticles' nanoactivity and nanotoxicity in different phases. This report describes new findings of an investigation of the quantitative aspect of ligand ion pairing at the capping monolayer structure that drives the phase extraction of gold nanoparticles. Alkanethiolate-capped gold nanoparticles of 8 nm diameter with high size monodispersity (RSD ~ 5%) were first derivatized by a ligand place exchange reaction with 11-mercaptoundecanoic acid to form a mixed monolayer shell consisting of both hydrophobic (-CH3) and hydrophilic (-COOH) groups. It was followed by quantitative titration of the resulting nanoparticles with a cationic species (-NR4(+)) in a toluene phase, yielding ion pairing of -NR4(+) and -COO(-) on part of the capping monolayer. Analysis of the phase extraction allowed a quantitative determination of the percentage of ion pairing and structural changes in the capping monolayer on the nanoparticles. The results, along with morphological characterization, are discussed in terms of the interfacial structural changes and their implications on the rational design of surface functionalized nanoparticles and fine tuning of the interfacial reactivity. PMID- 26523549 TI - Use of Intra-aortic Balloon Pump in a Japanese Multicenter Percutaneous Coronary Intervention Registry. PMID- 26523551 TI - Association of methionine synthase gene polymorphisms with wool production and quality traits in Chinese Merino population. AB - Methionine synthase (MTR) plays a crucial role in maintaining homeostasis of intracellular methionine, folate, and homocysteine, and its activity correlates with DNA methylation in many mammalian tissues. Our previous genomewide association study identified that 1 SNP located in the gene was associated with several wool production and quality traits in Chinese Merino. To confirm the potential involvement of the gene in sheep wool production and quality traits, we performed sheep tissue expression profiling, SNP detection, and association analysis with sheep wool production and quality traits. The semiquantitative reverse transcription PCR analysis showed that the gene was differentially expressed in skin from Merino and Kazak sheep. The sequencing analysis identified a total of 13 SNP in the gene from Chinese Merino sheep. Comparison of the allele frequencies revealed that these 13 identified SNP were significantly different among the 6 tested Chinese Merino strains ( < 0.001). Linkage disequilibrium analysis showed that SNP 3 to 11 were strongly linked in a single haplotype block in the tested population. Association analysis showed that SNP 2 to 11 were significantly associated with the average wool fiber diameter and the fineness SD and that SNP 4 to 11 were significantly associated with the CV of fiber diameter trait ( < 0.05). Single nucleotide polymorphism 2 and SNP 5 to 12 were weakly associated with wool crimp. Similarly, the haplotypes derived from these 13 identified SNP were also significantly associated with the average wool fiber diameter, fineness SD, and the CV of fiber diameter ( < 0.05). Our results suggest that is a candidate gene for sheep wool production and quality traits, and the identified SNP might be used in sheep breeding. PMID- 26523550 TI - The Effect of Cigarette Smoke Exposure on the Development of Inflammation in Lungs, Gut and Joints of TNFDeltaARE Mice. AB - The inflammatory cytokine TNF-alpha is a central mediator in many immune-mediated diseases, such as Crohn's disease (CD), spondyloarthritis (SpA) and chronic obstructive pulmonary disease (COPD). Epidemiologic studies have shown that cigarette smoking (CS) is a prominent common risk factor in these TNF-dependent diseases. We exposed TNFDeltaARE mice; in which a systemic TNF-alpha overexpression leads to the development of inflammation; to 2 or 4 weeks of air or CS. We investigated the effect of deregulated TNF expression on CS-induced pulmonary inflammation and the effect of CS exposure on the initiation and progression of gut and joint inflammation. Upon 2 weeks of CS exposure, inflammation in lungs of TNFDeltaARE mice was significantly aggravated. However, upon 4 weeks of CS-exposure, this aggravation was no longer observed. TNFDeltaARE mice have no increases in CD4+ and CD8+ T cells and a diminished neutrophil response in the lungs after 4 weeks of CS exposure. In the gut and joints of TNFDeltaARE mice, 2 or 4 weeks of CS exposure did not modulate the development of inflammation. In conclusion, CS exposure does not modulate gut and joint inflammation in TNFDeltaARE mice. The lung responses towards CS in TNFDeltaARE mice however depend on the duration of CS exposure. PMID- 26523552 TI - Tenderness assessments of top loin steaks from retail markets in four U.S. cities. AB - The purpose of this study was to evaluate the tenderness of beef loin steaks from retail markets in 4 U.S. cities. Beef top loin steaks ( = 1,613) were obtained for Warner-Bratzler shear force (WBSF), slice shear force (SSF), and consumer sensory determinations. Personnel at 4 universities (California Polytechnic State University, Colorado State University, University of Missouri, and Texas A&M University) conducted the study over a 12-mo period. Enhanced/blade-tenderized top loin steaks had the lowest ( < 0.05) WBSF and SSF values, whereas nonenhanced top loin, bone-in steaks had the highest ( < 0.05) WBSF and SSF values. Enhanced/blade-tenderized top loin steaks received the highest ( < 0.05) ratings by consumers for palatability scores, whereas nonenhanced top loin, bone-in steaks had the lowest ( < 0.05) consumer panelist ratings. The USDA quality grade did have an effect ( < 0.05) on the tenderness of nonenhanced steaks but did not affect ( > 0.05) steaks that were enhanced/blade tenderized. The WBSF values and consumer sensory values for top loin steaks were comparable to the 2010 National Beef Tenderness Survey, signifying that no drastic changes in tenderness have occurred due to changes in antemortem or postmortem conditions. PMID- 26523553 TI - Searching for causal networks involving latent variables in complex traits: Application to growth, carcass, and meat quality traits in pigs. AB - Structural equation models (SEQM) can be used to model causal relationships between multiple variables in multivariate systems. Among the strengths of SEQM is its ability to consider causal links between latent variables. The use of latent variables allows modeling complex phenomena while reducing at the same time the dimensionality of the data. One relevant aspect in the quantitative genetics context is the possibility of correlated genetic effects influencing sets of variables under study. Under this scenario, if one aims at inferring causality among latent variables, genetic covariances act as confounders if ignored. Here we describe a methodology for assessing causal networks involving latent variables underlying complex phenotypic traits. The first step of the method consists of the construction of latent variables defined on the basis of prior knowledge and biological interest. These latent variables are jointly evaluated using confirmatory factor analysis. The estimated factor scores are then used as phenotypes for fitting a multivariate mixed model to obtain the covariance matrix of latent variables conditional on the genetic effects. Finally, causal relationships between the adjusted latent variables are evaluated using different SEQM with alternative causal specifications. We have applied this method to a data set with pigs for which several phenotypes were recorded over time. Five different latent variables were evaluated to explore causal links between growth, carcass, and meat quality traits. The measurement model, which included 5 latent variables capturing the information conveyed by 19 different phenotypic traits, showed an acceptable fit to data (e.g., chi/df = 1.3, root mean-square error of approximation = 0.028, standardized root-mean-square residual = 0.041). Causal links between latent variables were explored after removing genetic confounders. Interestingly, we found that both growth (-0.160) and carcass traits (-0.500) have a significant negative causal effect on quality traits (-value <= 0.001). This result may have important implications for strategies for pig production improvement. More generally, the proposed method allows further learning regarding phenotypic causal structures underlying complex traits in farm species. PMID- 26523554 TI - Technical note: Genetic principal component models for multitrait single-step genomic evaluation. AB - A reparameterization of the multivariate linear mixed model in genetic evaluation to principal components is described. This yields an equivalent model with a sparser coefficient matrix in the mixed model equations and, thus, reduced computational requirements to solve them. It is especially advantageous for analyses incorporating genomic relationship information with many nonzero elements in the inverse of the relationship matrix. Moreover, the framework lends itself directly to dimension reduction and, thus, further computational savings by omitting genetic principal components with negligible eigenvalues. The potential impact on computational demands is illustrated for an application to single-step genomic evaluation of Australian sheep. PMID- 26523555 TI - Genetic structure of goat breeds from Brazil and the United States: Implications for conservation and breeding programs. AB - The objective of this study was to assess genetic diversity among 5 Brazilian (155 animals) and 5 U.S. goat (120 animals) breeds using 23 microsatellite markers. Samples from the United States represented a broad geographic distribution whereas Brazilian samples were from the northeast region. Samples from Boer were common to each country's breed count. Expected and observed heterozygosity among breeds ranged from 0.55 to 0.72, suggesting ample genetic diversity in the breeds evaluated. United States Angora, U.S. Spanish, and Brazilian Nambi ranked highest for allelic richness, averaging 6.1, 7.1, and 6.5 alleles per locus, respectively. Angora and Spanish also ranked highest in private alleles (7 and 9, respectively). Using STRUCTURE, the U.S. Spanish were also found to share a common cluster assignment with Brazilian Nambi, suggesting that progenitor breeds may have been the same and passed through the Canary Islands or Cape Verde in route to the New World. When non-Boer breeds were pooled by country, the effect of the subpopulation compared with total population () = 0.05, suggesting minor genetic differences exist between countries. The lack of genetic structure among goat breeds when compared with other species (e.g., vs. ) suggests goat breeds may exhibit a plasticity that facilitates productivity across a wide range of countries and environments. Taken a step further, the concept of breed for meat goats may not be as relevant for goat production. PMID- 26523556 TI - Comparison of repeated measurements of methane production in sheep over 5 years and a range of measurement protocols. AB - Emissions of 710 ewes at pasture were measured for 1 h (between 09:00-16:30 h) in batches of 15 sheep in portable accumulation chambers (PAC) after an overnight fast continuing until 2 h before measurement, when the sheep had access to baled hay for 1 h. The test was used to identify a group of 104 low emitters (I-Low) and a group of 103 high emitters (I-Hi) for methane emissions adjusted for liveweight (CHawt). The 207 ewes selected at the initial study were remeasured in 5 repeat tests from 2009 through 2014 at another location. The first repeat used the original measurement protocol. Two modified protocols, each used in 2 yr, drafted unfasted sheep on the morning of the test into a yard or holding paddock until measurement. Emissions of the I-Hi sheep were higher (102-112%) than I-Low sheep in all subsequent PAC tests, with statistical significance ( < 0.05) in 3 tests. Tests without overnight fasting were simpler to conduct and had repeatabilities of 51 to 60% compared with 31 and 43% for the initial and first repeat tests, respectively. After habituation to a diet fed at 20 g/kg liveweight, 160 of the 207 sheep were measured in respiration chambers (RC); 10 high (Hi-10) and 10 low (Low-10) sheep were chosen, representing extremes (top and bottom 6.25%) for methane yield (MY; g CH/kg DMI). The Hi-10 group emitted 14% more methane (adjusted for feed intake) in a follow-up RC test, but Low-10 and Hi-10 sheep differed in only 1 of the 5 PAC tests, when Hi-10 sheep emitted less CHawt than Low-10 sheep ( = 0.002) and tended to eat less in the feeding opportunity ( = 0.085). Compared with their weight on good pasture, Low-10 sheep were proportionately lighter than Hi-10 sheep in the relatively poor pasture conditions of the initial test. Sheep identified as low emitters by PAC tests using the initial protocol did not produce less CH (mg/min) when fed a fixed level of intake in RC. Correlations between estimates of an animal's CHawt measured in PAC and CH adjusted for feed intake in RC were quite low ( = 0-19%) and significant ( < 0.05) in only 1 test of unfasted sheep. With moderate repeatability over the 5 yr, PAC tests of CHawt could be a viable way to select for reduced emissions of grazing sheep. As well as exploiting any variation in MY, selecting for reduced CHawt in PAC could result in lower feed intake than expected for the animals' liveweight and might affect the diurnal feeding pattern. Further work is required on these issues. PMID- 26523557 TI - Should we use the single nucleotide polymorphism linked to in genomic evaluation of French trotter? AB - An A/C mutation responsible for the ability to pace in horses was recently discovered in the gene. It has also been proven that allele C has a negative effect on trotters' performances. However, in French trotters (FT), the frequency of allele A is only 77% due to an unexpected positive effect of allele C in late career FT performances. Here we set out to ascertain whether the genotype at SNP (linked to ) should be used to compute EBV for FT. We used the genotypes of 630 horses, with 41,711 SNP retained. The pedigree comprised 5,699 horses. Qualification status (trotters need to complete a 2,000-m race within a limited time to begin their career) and earnings at different ages were precorrected for fixed effects and evaluated with a multitrait model. Estimated breeding values were computed with and without the genotype at SNP as a fixed effect in the model. The analyses were performed using pedigree only via BLUP and using the genotypes via genomic BLUP (GBLUP). The genotype at SNP was removed from the file of genotypes when already taken into account as a fixed effect. Alternatively, 3 groups of 100 candidates were used for validation. Validations were also performed on 50 random-clustered groups of 126 candidates and compared against the results of the 3 disjoint sets. For performances on which has a minor effect, the coefficients of correlation were not improved when the genotype at SNP was a fixed effect in the model (earnings at 3 and 4 yr). However, for traits proven strongly related to , the accuracy of evaluation was improved, increasing +0.17 for earnings at 2 yr, +0.04 for earnings at 5 yr and older, and +0.09 for qualification status (with the GBLUP method). For all traits, the bias was reduced when the SNP linked to was a fixed effect in the model. This work finds a clear rationale for using the genotype at for this multitrait evaluation. Genomic selection seemed to achieve better results than classic selection. PMID- 26523558 TI - Signatures of selection identify loci associated with fat tail in sheep. AB - Identification of genomic regions that have been targets of selection for phenotypic traits is one of the most challenging applications of dense marker panels in animal genetics. In this study, a genomewide scan using approximately 50,000 SNP was performed in an attempt to identify genomic regions associated with fat deposition in sheep, the importance of this not only being limited to livestock facing future climate changes but also for elucidating the physiology of lipid metabolism. The genotyping results obtained with the Ovine SNP50K BeadChip in 2 fat tail breeds were compared with those obtained in 13 thin tail breeds. Direct sequencing of the annotated genes located in proximity to the markers with opposite allele frequency in thin tail vs. fat tail sheep gave additional SNP of interest. To further confirm the results of the genomewide scan, we genotyped the SNP within these genes in the 2 groups of sheep. A missense mutation in the gene, with different allele frequency in the 2 groups, was detected. The results indicated and as the most probable genes involved in the fat tail phenotype. PMID- 26523559 TI - Technical note: Acceleration of sparse operations for average-information REML analyses with supernodal methods and sparse-storage refinements. AB - The objective of this study was to remove bottlenecks generally found in a computer program for average-information REML. The refinements included improvements to setting-up mixed-model equations on a hash table with a faster hash function as sparse matrix storage, changing sparse structures in calculation of traces, and replacing a sparse matrix package using traditional methods (FSPAK) with a new package using supernodal methods (YAMS); the latter package quickly processed sparse matrices containing large, dense blocks. Comparisons included 23 models with data sets from broiler, swine, beef, and dairy cattle. Models included single-trait, multiple-trait, maternal, and random regression models with phenotypic data; selected models used genomic information in a single step approach. Setting-up mixed model equations was completed without abnormal termination in all analyses. Calculations in traces were accelerated with a hash format, especially for models with a genomic relationship matrix, and the maximum speed was 67 times faster. Computations with YAMS were, on average, more than 10 times faster than with FSPAK and had greater advantages for large data and more complicated models including multiple traits, random regressions, and genomic effects. These refinements can be applied to general average-information REML programs. PMID- 26523560 TI - Comparison of iterated single-step and Bayesian regressions on genomic evaluations for age at 100 kg in swine. AB - The effects of modified single-step genomic best linear unbiased prediction (ssGBLUP) iterations on GEBV and SNP were investigated using 85,388 age at 100 kg phenotypes from the BRF SA breeding program Landrace pure line animals, off tested between 2002 and 2013. Pedigree data comprised animals born between 1999 and 2013. A total of 1,068 animals were assigned to the training population, in which all of them had genotypes, original and corrected age at 100 kg phenotypes, and weighted deregressed proof records. A total of 100 genotyped animals, with high accuracy age at 100 kg estimated breeding values, were assigned to the validation population. After applying the quality control workflow, a set of 41,042 SNP was used for the analysis. Standard and modified ssGBLUP, BayesCpi, and Bayesian Lasso were compared, and their predictive abilities were accessed by approximate true and GEBV correlations. Modified ssGBLUP iteration effects on SNP estimates and GEBV were relevant, in which assigned differential weights and shrinkage caused important losses on ssGBLUP predictive ability for age at 100 kg GEBV. Even though ssGBLUP accuracy can be equal or better than the compared Bayesian methods, additional gains can be obtained by correctly identifying the number of iterations required for best ssGBLUP performance. PMID- 26523561 TI - Accuracy of genome-enabled prediction exploring purebred and crossbred pig populations. AB - Pig breeding companies keep relatively small populations of pure sire and dam lines that are selected to improve the performance of crossbred animals. This design of the pig breeding industry presents challenges to the implementation of genomic selection, which requires large data sets to obtain highly accurate genomic breeding values. The objective of this study was to evaluate the impact of different reference sets (across population and multipopulation) on the accuracy of genomic breeding values in 3 purebred pig populations and to assess the potential of using crossbreed performance in genomic prediction. Data consisted of phenotypes and genotypes on animals from 3 purebred populations (sire line [SL] 1, = 1,146; SL2, = 682; and SL3, = 1,264) and 3 crossbred pig populations (Terminal cross [TER] 1, = 183; TER2, = 106; and TER3, = 177). Animals were genotyped using the Illumina Porcine SNP60 Beadchip. For each purebred population, within-, across-, and multipopulation predictions were considered. In addition, data from the paternal purebred populations were used as a reference set to predict the performance of crossbred animals. Backfat thickness phenotypes were precorrected for fixed effects and subsequently included in the genomic BLUP model. A genomic relationship matrix that accounted for the differences in allele frequencies between lines was implemented. Accuracies of genomic EBV obtained within the 3 different sire lines varied considerably. For within-population prediction, SL1 showed higher values (0.80) than SL2 (0.61) and SL3 (0.67). Multipopulation predictions had accuracies similar to within-population accuracies for the validation in SL1. For SL2 and SL3, the accuracies of multipopulation prediction were similar to the within population prediction when the reference set was composed by 900 animals (600 of the target line plus 300 of another line). For across-population predictions, the accuracy was mostly close to zero. The accuracies of predicting crossbreed performance were similar for the 3 different crossbred populations (ranging from 0.25 to 0.29). In summary, the differences in accuracy of the within-population scenarios may be due to line divergences in heritability and genetic architecture of the trait. Within- and multipopulation predictions yield similar accuracies. Across-population prediction accuracy was negligible. The moderate accuracy of prediction of crossbreed performance appears to be a result of the relationship between the crossbreed and its parental lines. PMID- 26523562 TI - Phenotypic and molecular characterization of intrauterine fetal growth restriction in interspecies sheep pregnancy. AB - Interspecies pregnancies between closely related species are usually performed in livestock to obtain improved and enriched offspring. Indeed, different hybrids have been obtained for research purposes since many years ago, and the maternal fetal interactions have been studied as a possible strategy for species preservation. The aim of this study was to characterize by physiological and molecular approaches the interspecies pregnancy between bighorn sheep () and domestic sheep (). Hybrids were obtained by artificial insemination; the blood pressure and protein urine levels were measured during the last two-thirds of gestation. After parturition, offspring and placentas were weighed and measured and cotyledons were counted and weighed and their surface area determined. Plasma samples were obtained between wk 8 and 21 of gestation to assess progesterone (P4), vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) levels and cell-free RNA was isolated during the same period to assess hypoxia-inducible factor-1 alpha (alpha) gene expression. Hybrid and normal pregnancies were analyzed using physiological and molecular parameters during the last two-thirds of gestation (wk 8-21). The results show that during the measurement period, ewes with a hybrid pregnancy presented normal blood pressure and no alteration in urinary protein content. However, compared with sheep with a normal pregnancy, those with a hybrid pregnancy had a decrease in fetal and placental growth as well as in the cotyledonary surface area. Furthermore, in the hybrid group, there was placental insufficiency, characterized by a decrease in P4 production, as well as indications of endothelial dysfunction, characterized an increase in plasma levels of VEGF and PlGF as well as in plasma gene expression of alpha. Overall, the results indicate that hybrids of and presented intrauterine growth restriction, essentially due to altered endothelial function and chronic placental insufficiency. Further studies are necessary to overcome this primary placental dysfunction and thus obtain improved offspring for future molecular and genomic evaluations. PMID- 26523563 TI - Dietary organic zinc attenuates heat stress-induced changes in pig intestinal integrity and metabolism. AB - Dietary zinc (inorganic and organic or zinc AA complex forms) is essential for normal intestinal barrier function and regeneration of intestinal epithelium. Given that heat stress (HS) exposure can negatively affect intestinal integrity and caloric intake, possible nutritional mitigation strategies are needed to improve health, performance, and well-being. Therefore, our objective was to evaluate 2 dietary zinc sources and reduced caloric intake on intestinal integrity in growing pigs subjected to 12 h of HS. A total of 36 pigs were fed 1 of 2 diets: 1) a control diet (CON; 120 mg/kg of zinc from zinc sulfate) or 2) 60 mg/kg from zinc sulfate and 60 mg/kg from zinc AA complex (ZnAA). After 17 d, the CON pigs were then exposed to thermal neutral (TN) conditions with ad libitum intake (TN-CON), HS (37 degrees C) with ad libitum intake (HS-CON), or pair-fed to HS intake under TN conditions (PFTN); the ZnAA pigs were exposed to only HS (HS-ZnAA). All pigs were sacrificed after 12 h of environmental exposure, and blood and tissue bioenergetics stress markers and ex vivo ileum and colon integrity were assessed. Compared with TN-CON, HS significantly ( < 0.05) increased rectal temperatures and respiration rates. Ileum villus and crypt morphology was reduced by both pair-feeding and HS. Both PFTN and HS-CON pigs also had reduced ileum integrity (dextran flux and transepithelial resistance) compared with the TN-CON pigs. However, ZnAA tended to mitigate the HS-induced changes in ileum integrity. Ileum mucin 2 protein abundance was increased due to HS and pair-feeding. Colonic integrity did not differ due to HS or PFTN treatments. Compared with the HS-CON, HS-ZnAA pigs tended to have reduced blood endotoxin concentrations. In conclusion, HS and reduced feed intake compromised intestinal integrity in pigs, and zinc AA complex source mitigates some of these negative effects. PMID- 26523564 TI - The altitude at which a calf is born and raised influences the rate at which mean pulmonary arterial pressure increases with age. AB - Right heart failure secondary to pulmonary hypertension is a leading cause of mortality among suckling beef calves in the Rocky Mountain region. The objective of this study was to track changes in pulmonary arterial pressures (PAP) in healthy calves born and raised at altitudes ranging from 1,470 to 2,730 m. It was hypothesized that calves located at higher altitudes would show a greater increase in mean PAP (mPAP) with age than would be experienced by calves located at lower altitudes. The rationale is that high altitude hypobaric hypoxia causes a greater rate of vascular remodeling and, consequently, greater resistance to blood flow than calves located at lower altitudes. A prospective study was conducted on 5 cohorts of suckling calves from 4 herds located at altitudes of 1,470, 2,010, 2,170, and 2,730 m. In total, 470 PAP measurements were obtained from 258 calves. As hypothesized, calves located at altitudes >=2,170 m showed a significant increase in mPAP with age ( <= 0.002) whereas calves at 1,470 m did not ( = 0.16). Except for calves at 2,170 m ( < 0.001), systolic PAP did not increase with age ( >= 0.16). Diastolic PAP increased with age at altitudes >= 2,170 m ( <= 0.09) but did not change in calves at 1,470 m ( = 0.20). In summary, mPAP and the rate at which mPAP increases with age are positively associated with the altitude at which calves are born and raised. PMID- 26523565 TI - Effect of betaine and arginine in lysine-deficient diets on growth, carcass traits, and pork quality. AB - Forty entire male pigs from a commercial crossbreed (Duroc * Large White * Landrace) were used to investigate the individual or combined effects of betaine and Arg supplementation in Lys-deficient diets on growth performance, carcass traits, and pork quality. Pigs with 59.9 +/- 1.65 kg BW were randomly assigned to 1 of 5 dietary treatments ( = 8). The 5 dietary treatments were normal Lys and CP diet (0.51% Lys and 16% CP; control), reduced Lys and CP diet (0.35% Lys and 13% CP), reduced Lys and CP diet with betaine supplementation (0.33%), reduced Lys and CP diet with Arg supplementation (1.5%), and reduced Lys and CP diet with betaine and Arg supplementation (0.33% betaine and 1.5% Arg). Pigs were slaughtered at 92.7 +/- 2.54 kg BW. The Lys-deficient diets (-35% Lys) increased intramuscular fat (IMF) content by 25% ( = 0.041) and meat juiciness by 12% ( = 0.041) but had a negative effect on growth performance ( < 0.05) of pigs. In addition, Lys-deficient diets increased L* ( = 0.005) and b* ( = 0.010) muscle color parameters and perirenal fat deposition ( < 0.001) and decreased both HCW ( = 0.015) and loin weight ( = 0.023). Betaine and Arg supplementation of Lys deficient diets had no effect on IMF content but increased ( < 0.05) overall pork acceptability. Arginine supplementation also increased ( = 0.003) meat tenderness. Differences in fatty acid composition of pork were not detected among dietary treatment groups. However, oleic acid was positively correlated ( < 0.05) with IMF content, juiciness, flavor, and overall acceptability of meat. Data confirm that dietary CP reduction enhances pork eating quality but negatively affects pigs' growth performance. Moreover, it is suggested that betaine and Arg supplementation of Lys-deficient diets does not further increase IMF content but improves some pork sensory traits, including overall acceptability. PMID- 26523566 TI - Effects of environmental temperature and dietary energy on energy partitioning coefficients of female broiler breeders. AB - With increasing disparity between broiler breeder target weights and broiler growth potential, maintenance energy requirements have become a larger proportion of total broiler breeder energy intake. Because energy is partitioned to growth and egg production at a lower priority than maintenance, accurate prediction of maintenance energy requirements is important for practical broiler breeder feed allocation decisions. Environmental temperature affects the maintenance energy requirement by changing rate of heat loss to the environment. In the ME system, heat production (energy lost) is part of the maintenance requirement (ME). In the current study, a nonlinear mixed model was derived to predict ME partitioning of broiler breeder hens under varied temperature conditions. At 21 wk of age, 192 Ross 708 hens were individually caged within 6 controlled environmental chambers. From 25 to 41 wk, 4 temperature treatments (15 degrees C, 19 degrees C, 23 degrees C, and 27 degrees C) were randomly assigned to the chambers for 2-week periods. Half of the birds in each chamber were fed a high-energy (HE; 2,912 kcal/kg) diet, and half were fed a low-energy (LE; 2,790 kcal/kg) diet. The nonlinear mixed regression model included a normally distributed random term representing individual hen maintenance, a quadratic response to environmental temperature, and linear ADG and egg mass (EM) coefficients. The model assumed that energy requirements for BW gain and egg production were not influenced by environmental temperature because hens were homeothermic, and the cellular processes for associated biochemical processes occurred within a controlled narrow core body temperature range. Residual feed intake (RFI) and residual ME (RME) were used to estimate efficiency. A quadratic effect of environmental temperature on broiler breeder MEm was predicted ( < 0.0001), with a minimum energy expenditure at 24.3 degrees C. Predicted ME at 21 degrees C was 92.5 kcal/kg; requirements for gain and EM were 2.126 and 1.789 kcal/g, respectively ( < 0.0001). Birds fed the HE diet were more efficient, with a lower RME than birds on the LE diet (-0.63 vs. 0.63 kcal/kg), translating to ME of 135.2 and 136.5 kcal/kg, respectively. In the current experiment, optimal biological efficiency was predicted at 24.3 degrees C in feed-restricted broiler breeders fed the HE diet. PMID- 26523567 TI - Evaluation of methodological aspects of digestibility measurements in ponies fed different grass hays. AB - Methodological aspects of digestibility measurements of feedstuffs for equines were studied in four Welsh pony geldings consuming four grass-hay diets in a 4 * 4 Latin square design. Diets contained either a low (L), medium (M), high (H), or very high (VH) ADF content (264, 314, 375, or 396 g.kg DM, respectively). Diets were supplemented with minerals, vitamins, and TiO (3.9 g Ti.d). Daily feces excreted were collected quantitatively over 10 consecutive days and analyzed for moisture, ash, ADL, AIA, and titanium (Ti). Minimum duration of total fecal collection (TFC) required for an accurate estimation of apparent organic matter digestibility (OMD) of grass hay was assessed. Based on literature and the calculated cumulative OMD assessed over 10 consecutive days of TFC, a minimum duration of at least 5 consecutive days of fecal collection is recommended for accurate estimation of dry matter digestibility (DMD) and OMD in ponies. The 5-d collection should be preceded by a 14-d adaptation period to allow the animals to adapt to the diets and become accustomed to the collection procedures. Mean fecal recovery over 10 d across diets for ADL, AIA, and Ti was 93.1% (SE 1.9), 98.9% (SE 5.5), and 97.1% (SE 1.8), respectively. Evaluation of CV of mean fecal recoveries obtained by ADL, AIA, and Ti showed that variation in fecal Ti (6.8) and ADL excretion (7.0) was relatively low compared to AIA (12.3). In conclusion, the use of internal ADL and externally supplemented Ti are preferred as markers to be used in digestibility trials in equine fed grass-hay diets. PMID- 26523568 TI - The antimicrobial peptide sublancin ameliorates necrotic enteritis induced by Clostridium perfringens in broilers. AB - Sublancin is an antimicrobial peptide produced by 168 containing 37 amino acids. The objective of this study was to investigate its inhibitory efficacy against both in vitro and in vivo. In the in vitro study, we determined that sublancin had a minimum inhibitory concentration of 8 MUM against , which was much higher than the antibiotic lincomycin (0.281 MUM). Scanning electron microscopy showed that sublancin damaged the morphology of . The in vivo study was conducted on broilers for a 28-d period using a completely randomized design. A total of 252 chickens at 1 d of age were randomly assigned to 1 of 6 treatments including an uninfected control; an infected control; 3 infected groups supplemented with sublancin at 2.88, 5.76, or 11.52 mg activity/L of water; and an infected group supplemented with lincomycin at 75 mg activity/L of water (positive control). Necrotic enteritis was induced in the broilers by oral inoculation of on d 15 through 21. Thereafter, the sublancin or lincomycin were administered fresh daily for a period of 7 days. The challenge resulted in a significant decrease in ADG ( < 0.05) and a remarkable deterioration in G:F ( < 0.05) during d 15 to 21 of the experiment. There was a sharp increase of numbers in the cecum ( < 0.05). The addition of sublancin or lincomycin reduced caecal counts ( < 0.05). The counts had a tendency to decrease in the lincomycin treatment ( = 0.051) but were the highest in the sublancin treatment (5.76 mg activity/L of water). A higher villus height to crypt depth ratio in the duodenum and jejunum as well as a higher villus height in the duodenum were observed in broilers treated with sublancin or lincomycin ( < 0.05) compared with infected control broilers. It was observed that sublancin and lincomycin decreased IL-1beta, IL-6, and tumor necrosis factor alpha levels ( < 0.05) in the ileum compared with the infected control. In conclusion, although sublancin's minimum inhibitory concentration is much higher than lincomycin in vitro, less sublancin is needed to control necrotic enteritis induced by in vivo than lincomycin. These novel findings indicate that sublancin could be used as a potential antimicrobial agent to control necrotic enteritis. PMID- 26523569 TI - Estimation of the standardized ileal digestible valine to lysine ratio required for 25- to 120-kilogram pigs fed low crude protein diets supplemented with crystalline amino acids. AB - Four 28-d experiments were conducted to determine the standardized ileal digestible (SID) valine (Val) to lysine (Lys) ratio required for 26- to 46- (Exp. 1), 49- to 70- (Exp. 2), 71- to 92- (Exp. 3), and 94- to 119-kg (Exp. 4) pigs fed low CP diets supplemented with crystalline AA. The first 3 experiments utilized 150 pigs (Duroc * Landrace * Large White), while Exp. 4 utilized 90 finishing pigs. Pigs in all 4 experiments were randomly allocated to 1 of 5 diets with 6 pens per treatment (3 pens of barrows and 3 pens of gilts) and 5 pigs per pen for the first 3 experiments and 3 pigs per pen for Exp. 4. Diets for all experiments were formulated to contain SID Val to Lys ratios of 0.55, 0.60, 0.65, 0.70, or 0.75. In Exp. 1 (26 to 46 kg), ADG increased (linear, = 0.039; quadratic, = 0.042) with an increasing dietary Val:Lys ratio. The SID Val:Lys ratio to maximize ADG was 0.62 using a linear broken-line model and 0.71 using a quadratic model. In Exp. 2 (49 to 70 kg), ADG increased (linear, = 0.021; quadratic, = 0.042) as the SID Val:Lys ratio increased. G:F improved (linear, = 0.039) and serum urea nitrogen (SUN) decreased (linear, = 0.021; quadratic, = 0.024) with an increased SID Val:Lys ratio. The SID Val:Lys ratios to maximize ADG as well as to minimize SUN levels were 0.67 and 0.65, respectively, using a linear broken-line model and 0.72 and 0.71, respectively, using a quadratic model. In Exp. 3 (71 to 92 kg), ADG increased (linear, = 0.007; quadratic, = 0.022) and SUN decreased (linear, = 0.011; quadratic, = 0.034) as the dietary SID Val:Lys ratio increased. The SID Val:Lys ratios to maximize ADG as well as to minimize SUN levels were 0.67 and 0.67, respectively, using a linear broken-line model and 0.72 and 0.74, respectively, using a quadratic model. In Exp. 4 (94 to 119 kg), ADG increased (linear, = 0.041) and G:F was improved (linear, = 0.004; quadratic, = 0.005) as the dietary SID Val:Lys ratio increased. The SID Val:Lys ratio to maximize G:F was 0.68 using a linear broken-line model and 0.72 using a quadratic model. Carcass traits and muscle quality were not influenced by SID Val:Lys ratio. In conclusion, the dietary SID Val:Lys ratios required for 26- to 46-, 49- to 70-, 71- to 92-, and 94- to 119-kg pigs were estimated to be 0.62, 0.66, 0.67, and 0.68, respectively, using a linear broken-line model and 0.71, 0.72, 0.73, and 0.72, respectively, using a quadratic model. PMID- 26523570 TI - Optimal lysine:DE ratio in growing pigs is independent of starch or fat as main energy source at two energy intake levels. AB - In a 2 * 2 factorial arrangement, 28 growing boars (initial BW of 24.7 +/- 1.5 kg) were used to examine the effects of energy source (high starch vs. high fat) and DE level (2.2 vs. 2.7 times the DE requirements for maintenance) on Lys requirements. Pigs were allotted to 1 of 4 dietary treatments. A within-animal Lys titration technique was used to assess the responses to changes in Lys to energy ratio. The amount of apparent ileal digestible Lys in the diet decreased stepwise from 1.74 to 0.5 g/MJ DE in 8 equidistant steps of 3 d each. From 48-h urinary nitrogen excretion, the optimal Lys to energy ratio was estimated for each pig using a linear-plateau model. Feces were collected quantitatively over 27 d to determine apparent total tract digestibility (ATTD) of nutrients. The DE to ADG ratio, but not DE intake and ADG, tended ( < 0.1) to be 4% lower in the high-starch group than in the high-fat group. The ATTD of energy and CP tended ( < 0.1) to be lower (0.8% and 0.9% units, respectively) at the high DE level. The ATTD of energy was 2.2% units greater ( < 0.001) for pigs fed the high-starch diet, but the ATTD of CP was not affected by ES. Estimates for the intercept (21.2% to 22.8%), slope (57.4 to 59.6), transition point (0.84 to 0.86 g Lys/MJ DE), and plateau (70.6% to 72.3%) of the linear-plateau Lys titration curves were not affected by the dietary treatments. In conclusion, ES does not affect Lys requirements in growing pigs regardless the level of DE intake. PMID- 26523571 TI - Quantification of short-chain fatty acids and energy production from hindgut fermentation in cannulated pigs fed graded levels of wheat bran. AB - This study investigated the amount of energy available to growing pigs from fermentation of dietary fiber in the hindgut. Eighteen growing barrows, fitted with a simple T-shaped cannula at the terminal ileum, were allocated to 3 experimental diets in a completely randomized design. The 3 diets were a standard fiber diet (SFD), which contained 75.1 g NDF/kg diet; a medium-fiber diet (MFD) of 105.7 g NDF/kg diet; and a high-fiber diet (HFD), which contained 146.9 g NDF/kg diet. Each diet had 6 replicate pigs. After a 5-d period of adjustment of the pigs to the cage environment, feces were collected on d 6 and 7 and ileal digesta on d 8 and 9 and subsequently freeze-dried. Fecal slurry from a pig was used to inoculate the ileal digesta from the same pig. The amount of energy available was calculated from the amount of short-chain fatty acids (SCFA) produced from a 48-h in vitro fermentation of the ileal digesta. Increasing NDF enhanced ( < 0.01) the ileal DM flow and DM in feces. The energy available in the foregut was reduced ( < 0.05) from 3,360 to 2,974 kcal/kg feed DM and increased ( < 0.01) from 619 to 1,009 kcal/kg feed DM produced in the hindgut with increasing dietary NDF. The amount of SCFA increased ( < 0.01) with higher dietary NDF. Acetic acid was highest ( < 0.01) in the HFD whereas propionic and valeric acids were highest ( < 0.05) in the SFD. The amount of butyric acid was not affected by diet. The amount of energy contributed from SCFA fermentation to total tract digestible energy increased ( < 0.01) from 10.7 to 24.2% as dietary NDF level increased from 75 to 147 g/kg feed. The results of the study showed that increasing level of dietary NDF resulted in reduced energy digestibility in the foregut of growing pigs with a corresponding increase in the amount of energy from microbial fermentation in the hindgut. PMID- 26523572 TI - Protein and amino acid bioavailability estimates for canine foods. AB - Estimates of nutrient bioavailability are required for establishing dietary nutrient requirements and to evaluate the nutritional value of food ingredients or foods that are exposed to processing or extended storage. This study aimed to generate estimates for the bioavailability of dietary CP and AA for adult dogs using existing literature data and to evaluate the accuracy of estimates currently used in 3 authoritative publications. A regression equation was derived relating apparent fecal N outflow to standardized ileal N outflow from a data set containing information on 158 individual diets and their N digestibility when fed to adult dogs. Standardized ileal digestibility (sID) of N (sID) was shown to be nearly perfectly correlated to the sID of the sum of N of AA in 24 diets for which AA digestibility data were available. Regression equations between sID of individual AA and sID were calculated. Bioavailability estimates were subsequently derived from simulated sID values of N and essential and nonessential AA for 10 diets varying in CP content (18 to 42%) and apparent fecal N digestibility (70 and 80%) for an adult dog of 20 kg BW. Calculated bioavailability estimates of the NRC for maintenance dog foods do not lead to realistic nutrient allowance estimates for CP and AA. Estimates used by the Association of American Feed Control Officials and the European Pet Food Industry Federation were closer to calculated values, although the majority were too low, with the exception of CP, Arg, and Lys. Bioavailability estimates for Lys, Met, and Cys as calculated here require further veracity as the chemical form in which these AA are present in commercial pet foods may significantly reduce their bioavailability. PMID- 26523573 TI - Evaluation of pilot-scale microencapsulation of probiotics and product effect on broilers. AB - This study was conducted to evaluate the pilot-scale production of microencapsulated in a 500-L fermenter using emulsion and gelation and to assess the effect of the products on the growth performance, antioxidant activity, immune function, and cecal microbiota in Arbor Acres broilers. A total of seven hundred 1-d-old male Arbor Acres broilers were randomly assigned to 7 dietary treatments with 5 replicate pens per treatment and 20 broilers per pen. The dietary treatments were as follows: 1) basal diet (CON), 2) basal diet containing 0.1% Aureomycin (ANT), 3) basal diet containing unencapsulated at a dose of 1 * 10 cfu/kg of feed (P1), 4) basal diet containing unencapsulated at a dose of 1 * 10 cfu/kg of feed (P2), 5) basal diet containing 0.01% empty microcapsules (CAP), 6) basal diet containing microencapsulated at a dose of 1 * 10 cfu/kg of feed (CAPP1), and 7) basal diet containing microencapsulated at a dose of 1 * 10 cfu/kg of feed (CAPP2). The feeding experiment included 2 phases: the starter phase from d 1 to 21 and the grower phase from d 22 to 42. The results showed that a 500-L fermenter could produce 20.73 +/- 4.05 kg of microcapsules with an approximate diameter of 549 MUm. The feeding experiment showed that ADG of broilers in CAPP1 was significantly ( < 0.05) greater than that in CON and CAP throughout the feeding period, whereas the ratio of feed to gain (G:F) was significantly ( < 0.05) lower. Broilers in P1, P2, CAPP1, and CAPP2 had significantly ( < 0.05) greater levels of total superoxide dismutase, catalase, IgG, and cluster of differentiation 3 than those in CON. Furthermore, broilers in CAPP1 had significantly ( < 0.05) greater richness and diversity of intestinal microorganisms, particularly of , than those in all other dietary treatments. In summary, our results indicate that large-scale microencapsulation of microbial cells can be achieved using emulsion and initial gelation and that the dietary administration of microencapsulated can significantly enhance the growth performance, immune function, cecum microbial community, and overall health of broilers. PMID- 26523575 TI - The effect of frozen grass silage on the feed intake and feeding behavior of pregnant ewes. AB - The aim of the current study was to investigate the effect of frozen grass silage on the feed intake, feed preferences, and feeding behavior of ewes. Two experiments were conducted, each involving 8 pregnant ewes in a Latin square design with 4 treatments: 1) frozen silage; 2) partly frozen silage; 3) frozen, chopped silage; 4) and unfrozen silage (control). In Exp. 2, the ewes in square 1 were fed grass silage with low DM content (LDM) and in square 2 the ewes were fed grass silage with high DM content (HDM). In both experiments, each treatment period lasted for 14 d. A feed preference test was conducted, where the ewes could choose between 2 of the experimental feed treatments for 1 d in a changeover design so that they were exposed to all pairwise combinations of the 4 treatments. On the last day of each experimental period in Exp. 1, the feeding behavior was scored by direct observation for 4 h. In Exp. 1 ( < 0.0001) and in Exp. 2 ( = 0.03), feed intake in the first 4 h after feeding was lowest on the frozen silage treatment and highest on the control treatment. The DMI in the first 4 h after feeding was higher ( = 0.005) in the HDM treatment than in the LDM treatment. The total daily feed intake in Exp. 1 was lowest on the frozen, chopped silage treatment and highest on the unfrozen silage treatment ( = 0.02). In Exp. 2, daily feed intake did not differ ( = 0.32) among treatments. Total daily feed intake was higher ( < 0.0001) in the LDM treatment than in the HDM treatment but there was no difference in the DMI. There was no difference in the preference for the different feed treatments, when considering either the first 4 h ( = 0.12 to = 0.86) or the whole 24-h period ( = 0.25 to = 0.53). Time spent eating normally was longer on the control treatment and shorter on the frozen silage treatments ( < 0.0001) whereas time spent eating by tearing off feed from the frozen block followed the opposite pattern ( < 0.0001). We conclude that intake of frozen silage was lower for the first 4 h but that frozen silage had a very moderate effect on daily feed intake. Partly thawing or chopping improved the feed intake. Treatment had no significant effect on feed preferences. Feeding frozen silage increased time spent tearing off feed from frozen block, but total time eating was moderately increased. PMID- 26523574 TI - Effect of phytate, microbial phytase, fiber, and soybean oil on calculated values for apparent and standardized total tract digestibility of calcium and apparent total tract digestibility of phosphorus in fish meal fed to growing pigs. AB - Two experiments were conducted to determine the effects of phytate, phytase, fiber, and soybean oil on apparent total tract digestibility (ATTD) and standardized total tract digestibility (STTD) of Ca and on ATTD of P in fish meal fed to growing pigs. In Exp. 1, 40 growing pigs (initial average BW: 19.16 +/- 2.04 kg) were randomly allotted to 1 of 5 diets with 8 pigs per treatment and placed in metabolism crates. Four diets were used in a 2 ' 2 factorial design with 2 levels of phytate (0 or 0.7%) and 2 levels of microbial phytase (0 or 500 phytase units/kg). The diet containing no phytate was based on sucrose, cornstarch, fish meal, casein, and soybean oil, and the diet containing 0.7% phytate was based on corn, corn germ, fish meal, casein, and soybean oil. A Ca free diet was used to determine basal endogenous losses of Ca. Feces were collected from d 6 to 13 after a 5-d adaptation period. Results indicated that the ATTD and STTD of Ca in fish meal and the ATTD of P increased ( < 0.001) if phytase was used and were greater ( < 0.05) in the diets based on corn and corn germ. Experiment 2 was conducted to determine the effects of fiber and soybean oil on the ATTD and STTD of Ca and the ATTD of P in fish meal. Fifty growing pigs (initial average BW: 19.36 +/- 0.99 kg) were randomly allotted to 1 of 5 diets with 10 pigs per treatment. Two diets contained sucrose, cornstarch, fish meal, casein, and either 0 or 8% of a synthetic source of fiber. Two additional diets contained fish meal, casein, corn, and either 1 or 7% soybean oil. A Ca-free diet was also used. Pigs were housed individually in metabolism crates and fecal samples were collected. Results indicated that fiber increased ( < 0.001) the ATTD and STTD of Ca and the ATTD of P, but the ATTD and STTD of Ca or the ATTD of P were not affected by soybean oil. In agreement with the results of Exp. 1, the ATTD and STTD of Ca and the ATTD of P in the corn-based diet were greater ( < 0.05) than those in the cornstarch-based diet. In conclusion, phytase and fiber increased the ATTD and STTD of Ca and the ATTD of P in fish meal, but inclusion of soybean oil did not affect digestibility of Ca or P. The observation that values for the ATTD and STTD of Ca and ATTD of P are greater in corn-based diets than in cornstarch-based diets indicates that values for the digestibility of Ca and P obtained in cornstarch-based diets may not always be representative for the digestibility in practical corn-based diets. PMID- 26523576 TI - Partitioning of feed intake into maintenance and gain in growing beef cattle: Evaluation of conventional and Bayesian analyses. AB - The robustness of efficiency estimates depends on theoretical consistency of models from which those estimates are developed; functional forms of the variables must be globally consistent with theoretical properties regarding feed utilization for maintenance and gain in growing and finishing cattle. Model parameter estimates and their dimensions must be unique or estimates of feed utilization and gain will not reflect reality. A linear equation commonly used to estimate daily DMI by the th individual animal (ADFI), based on mean weight and gain during a feeding period, was evaluated to determine if that model was correctly specified and if the vector predicted ADFI differed from the vector observed ADFI. Three independently gathered data sets were evaluated using a multiple linear regression model; variability described by that model failed to capture observed variability in the data (lack of fit, < 0.10), and predicted ADFI differed from observed ( < 0.05); for 1 of the 3 data sets, residuals were not normally distributed ( < 0.001). Functional forms of the variables in the first model evaluated, characterizing ADFI required for maintenance ( * BW) and gain ( * ADG), were consistent with neither published empirical nor theoretical relationships among ADFI, BW, and ADG. Parameter estimates determined for that linear model were not BLUE. Better fits among final BW, initial BW, and ADFI were found for a first-order relationship, in which final BW was a function of initial BW and ADFI, as indicated by > 0.90. The linear model and, to a lesser degree, the first nonlinear model lacked theoretical and global consistency. A second nonlinear model, which described retained energy as a function of ME intake, best fit the data, and functional forms of variables describing ME intake at maintenance and the efficiency of ME utilization for gain were consistent with theoretical estimates found in the literature. Changes in feed intake and live BW in linear and nonlinear models failed to adequately describe efficiencies of metabolic processes, which are better characterized by changes in retained energy as a function of ME intake in nonlinear models. PMID- 26523577 TI - Effects of late gestation distillers grains supplementation on fall-calving beef cow performance and steer calf growth and carcass characteristics. AB - Fall-calving, mature Angus and Simmental * Angus cows ( = 251 total) and their progeny were used to evaluate the effects of late gestation dried distillers grains plus solubles (DDGS) supplementation on cow performance and progeny growth and carcass characteristics. Cows were blocked by breed and allotted to 12 tall fescue pastures (6.8 ha average). Pastures were randomly assigned to 1 of 2 treatments: cows were offered 2.1 kg DM DDGS.cow.d (SUP; CP = 23%, fat = 7%; = 6 pastures) or were not offered a supplement (CON; = 6 pastures) 69 +/- 9 d before expected calving date. Cows remained on treatments until calving. Once weekly, cows that had calved were removed from treatment pastures and were moved to new tall fescue pastures (21.6 ha average) where cows from both treatments were comingled without further supplementation. Cows ( = 74) were removed from study for calving more than 30 d after expected calving date, calf loss and injury, or euthanasia. Cow BW and BCS were recorded at the beginning of the supplementation period, after calving, and at breeding. Calf BW was taken at birth and early weaning (82 +/- 14 d of age). After weaning, 71 steer progeny (representative of dam breed and treatment pastures) were transitioned to a common feedlot diet with individual feed intake monitored using the GrowSafe feeding system. Steers were slaughtered at 47 +/- 4 d after a minimum 12th rib fat thickness (back fat) estimation of 0.6 cm, with cattle being shipped in 3 groups. Forage availability was not different between treatments ( = 0.69). Cows offered SUP gained more BW and BCS ( <= 0.02) during the supplementation period. There were no differences ( >= 0.12) in calving date, calf birth or weaning BW, or preweaning ADG. Cow BW at breeding was not different ( = 0.19); however, BCS at breeding was greater ( < 0.01) for cows offered supplement. No differences ( >= 0.11) in milk production, AI conception, or overall pregnancy rate were detected. For steer progeny, initial feedlot BW, final BW, and days on feed were not different ( >= 0.35); no difference ( = 0.77) in feedlot ADG was detected. Feedlot DMI and G:F were not different ( >= 0.52) across treatments. No differences ( = 0.62) in morbidity were observed in the feedlot. No differences ( >= 0.19) were detected for HCW, LM area, marbling score, or yield grade. Prepartum DDGS supplementation improved cow BW and BCS but did not alter milk production, subsequent reproduction, or subsequent calf performance or carcass characteristics. PMID- 26523578 TI - Evaluation of in vitro models for predicting acidosis risk of barley grain in finishing beef cattle. AB - Our objective was to develop a model to predict the acidosis potential of barley based on the in vitro batch culture incubation of 50 samples varying in bulk density, starch content, processing method, growing location, and agronomic practices. The model was an adaptation of the acidosis index (calculated from a combination of in situ and in vitro analyses and from several components of grain chemical composition) developed in Australia for use in the feed industry to estimate the potential for grains to increase the risk of ruminal acidosis. Of the independent variables considered, DM disappearance at 6 h of incubation (DMD6) using reduced-strength (20%) buffer in the batch culture accounted for 90.5% of the variation in the acidosis index with a root mean square error (RMSE) of 4.46%. To evaluate our model using independent datasets (derived from previous batch culture studies using full-strength [100%] buffer), we performed another batch culture study using full-strength buffer. The full-strength buffer model using in vitro DMD6 (DMD6-FS) accounted for 66.5% of the variation in the acidosis index with an RMSE of 8.30%. When the new full-strength buffer model was applied to 3 independent datasets to predict acidosis, it accounted for 20.1, 28.5, and 30.2% of the variation in the calculated acidosis index. Significant ( < 0.001) mean bias was evident in 2 of the datasets, for which the DMD6 model underpredicted the acidosis index by 46.9 and 5.73%. Ranking of samples from the most diverse independent dataset using the DMD6-FS model and the Black (2008) model (calculated using in situ starch degradation) indicated the relationship between the rankings using Spearman's rank correlation was negative (rho = -0.30; = 0.059). When the reduced-strength buffer model was used, however, there were similarities in the acidosis index ranking of barley samples by the models as shown by the result of a correlation analysis between calculated (using the Australian model) and predicted (using the reduced-strength buffer DMD6 model) acidosis index (rho = 0.67; < 0.001). Results suggest that our model, which is based on a reduced-strength buffer in vitro DMD6, has the potential to predict acidosis risk and can rank barley samples based on their acidotic risk. Nonetheless, the model would benefit from further refinement by expanding the database. PMID- 26523579 TI - Altering ewe nutrition in late gestation: I. The impact on pre- and postpartum ewe performance. AB - The present study was conducted to examine the effects of offering a single diet rationed to 80% (80% ME), 100% (100% ME), or 120% (120% ME) of recommended ME requirements from d 119 of gestation to lambing, with concurrent changes in other dietary nutrients. The effects on pre- and postpartum ewe performance, including estimated milk yield and milk fatty acid concentrations, were monitored. Sixty twin-bearing ewes were allocated to 1 of 3 dietary treatments ( = 20 per treatment) and individually fed for the final 4 wk of gestation. Metabolizable energy requirements were individually calculated for each ewe and amended according to treatment. Ewes were rationed daily on the basis of their treatment ME allocation, which led to concurrent alterations in other nutrient intakes. Diets were grass silage based and supplemented with concentrates to meet treatment ME allocation on an individual ewe basis. Ewes offered the 80% ME treatment had a lower liveweight ( = 0.04) and BCS ( = 0.03) at 24 h postpartum when compared with ewes offered the 120% ME diet. Although there was no difference in liveweight at either d 40 ( = 0.18) or 98 postpartum ( = 0.20), the difference in BCS persisted until d 40 postpartum ( = 0.02). Colostrum yield at 1 h postpartum ( = 0.03) and total yield up to 18 h postpartum ( = 0.04) was greater for ewes offered the 120% ME diet than either of the other treatment groups. Similarly, these ewes had a greater estimated milk yield during wk 3 of lactation ( = 0.04) and elevated concentrations of short-chain SFA ( = 0.02) and long-chain SFA ( <= 0.05) from wk 2 through 6 of lactation. In summary, the negative impact of applying a dietary insult to ewes in late gestation is reflected in colostrum and estimated milk yield and fatty acid composition, thus potentially influencing postpartum growth and development of the offspring. PMID- 26523580 TI - Altering ewe nutrition in late gestation: II. The impact on fetal development and offspring performance. AB - The present study was conducted to evaluate the effects of offering Belclare X ewes a single diet rationed to 80, 100, or 120% of recommended ME requirements from d 119 of gestation to parturition, with concurrent changes in other dietary nutrients. The effects on the development of the fetus and subsequent offspring performance to weaning were monitored. Sixty twin-bearing ewes were allocated to 1 of 3 dietary treatments based on Agricultural and Food Research Council recommendations () as amended by as follows: 80% of predicted ME requirement, 100% of predicted ME requirement, and 120% of predicted ME requirement. Ewes were individually fed for the final 4 wk of gestation. Diets fed were grass silage based; however, when silage intake failed to meet ME requirements, ewes were offered varying quantities of concentrates, on an individual basis, to ensure they met their required daily ME allocation. Concentrates offered were composed of 40% barley, 22% beet pulp nuts, 20% distillers' dried grains, and 14% soybean meal, on a DM basis. At birth, lambs were weighed, behavioral and skeletal measurements were recorded, and plasma blood samples were collected. At 1 h postpartum, a subset of lambs ( = 10) per treatment was euthanized to assess organ weight and intestinal morphology. At birth, there was no effect of treatment on lamb live weight at birth ( = 0.31), although lambs born to ewes offered 120% ME had a larger thoracic circumference ( = 0.05). Lambs born to ewes offered the excess energy treatment (120% ME) were quickest to stand and attempt to suckle after birth, in addition to having a greater live weight at weaning ( = 0.01) and ADG from birth to weaning ( = 0.05). Nutritional treatment had no effect on the organ weights ( >= 0.11) or the ileal morphology ( >= 0.62) of the lamb measured at 1 h postpartum. In summary, the impact of applying a dietary alteration to ewes in late gestation is not directly reflected in organ weight or total live weight at birth but is present at weaning, therefore outlining the poor reliability of using birth weight as an indicator of maternal nutrition during late gestation. PMID- 26523581 TI - Propionate supplementation improves nitrogen use by reducing urea flux in sheep. AB - Feeding and postruminal infusion of propionate is known to increase N retention in ruminants. Our aim was to determine the role of rumen propionate on urea N recycling and gluconeogenesis in growing sheep. In Exp. 1, wether sheep ( = 6; 32.5 +/- 3.57 kg BW) fitted with a rumen cannula were fed to 1.8 * ME requirement a concentrate-type ration (172 g CP/kg DM and 10.4 MJ ME/kg DM) and continuously infused into the rumen with isoenergetic (10% of dietary ME intake) solutions of either sodium acetate (control) or sodium propionate for 9-d periods in a crossover design. In Exp. 2, a different group of wether sheep ( = 5; 33.6 +/- 3.70 kg BW) fitted with a rumen cannula were fed, on an isonitrogenous basis, either a control (151 g CP/kg DM and 8.4 MJ ME/kg DM) or sodium propionate supplemented (139 g CP/kg DM and 8.9 MJ ME/kg DM) diet at 2-h intervals. [N] urea was continuously infused intravenously for the last 5 d of each period, and total urine was collected by vacuum and feces were collected by a harness bag. Over the last 12 h, [C]glucose was continuously infused intravenously and hourly blood samples were collected during the last 5 h. Propionate treatments increased ( < 0.001) the proportion of rumen propionate in both experiments. In Exp. 1, N retention was not affected by propionate infusion as compared with isoenergetic acetate. There was no effect on urea entry (synthesis) rate (UER) in Exp. 1; however, sodium propionate infusion tended ( < 0.1) to increase urinary urea elimination (UUE). In Exp. 2, feeding propionate increased ( < 0.01) N retention by 0.8 g N/d. In addition, UER was reduced by approximately 2 g urea N/d, leading to a reduction ( < 0.05) in UUE (7.0 vs. 6.2 g urea N/d). Between the 2 experiments, the proportion of UER recycled to the gut was greater with the forage-type diet in Exp. 2 (approximately 60%) compared with the concentrate-type diet in Exp. 1 (approximately 40%), although urea N fluxes across the gut remained unchanged in both experiments. In Exp. 1, glucose entry and gluconeogenesis were greater ( < 0.05) and plasma glucose tended ( < 0.1) to be greater with sodium propionate infusion than with sodium acetate infusion, but there was no difference in Cori cycling. In Exp. 2, glucose entry, gluconeogenesis, Cori cycling, and plasma glucose increased ( < 0.05) with dietary propionate. Our studies indicate that propionate inclusion in feed, but not continuous infusion in to the rumen, improves N utilization in growing sheep. The propionate effect is likely mediated by providing additional precursors for gluconeogenesis. PMID- 26523582 TI - Effect of including high-lipid by-product pellets in substitution for barley grain and canola meal in finishing diets for beef cattle on ruminal fermentation and nutrient digestibility. AB - The objective was to determine the effect of replacing barley grain and canola meal with high-lipid by-product pellets (HLBP; 14.6% CP, 29.8% NDF, 9.0% fat, and 5.52 MJ NE/kg in DM) on DMI, ruminal fermentation, nutrient flow at the omasal canal, and nutrient digestibility. Four ruminally cannulated and ovariectomized Hereford * Gelbvieh heifers (initial BW of 631.9 +/- 23.3 kg; mean +/- SD) were used in a 4 * 4 Latin square design. Periods consisted of 28 d, including 10 d for diet transition, 11 d for dietary adaptation, and 7 d for measurements. Heifers were fed a typical finishing diet consisting of 89% of concentrate (barley grain and canola meal; CONT), 6% of barley silage, and 5% of mineral and vitamin supplement (on DM basis). Dietary treatments consisted of a CONT or diets where 30% (HLBP30), 60% (HLBP60), and 90% (HLBP90) of the barley grain and canola meal were replaced with HLBP. Dry matter intake was not affected by treatment ( > 0.10). Total short-chain fatty acid concentration and molar proportions of acetate, propionate, and butyrate ( > 0.10) among treatments and ruminal ammonia did not differ ( > 0.10) among treatments, and ruminal ammonia increased ( = 0.03) linearly with increasing HLBP inclusion rate in the diet. Mean and maximum pH increased, whereas the duration and area that pH was below 5.8, 5.5, and 5.2, thresholds used for mild, severe, and acute ruminal acidosis, respectively, decreased linearly ( <= 0.05) with increasing rates of inclusion of HLBP. Organic matter flow at the omasal canal increased linearly ( = 0.03) with increasing HLBP inclusion rate in the diet. However, OM digestibility coefficients and apparent ruminal NDF and ADF digestibility yielded negative values for some animals, especially those fed HLBP90, indicating that ruminal digestibility was underestimated. Total tract OM digestibility decreased linearly ( < 0.01) with increasing inclusion rates of HLBP. This study showed that HLBP inclusion in substitution for barley grain and canola meal linearly decreases the severity of ruminal acidosis in cattle fed a typical grain-based finishing diet. However, total tract nutrient digestibility was negatively affected. PMID- 26523583 TI - Fattening Holstein heifers by feeding high-moisture corn (whole or ground) ad libitum separately from concentrate and straw. AB - The objectives of this study were to evaluate the effects of high-moisture corn (HMC), either whole or ground, fed separately from concentrate and straw on feeding behavior, rumen fermentation, whole tract digestibility, and nitrogen balance. Twenty-four Holstein heifers (199 +/- 5.5 kg BW and 157 +/- 6.9 d age) housed in individual pens were assigned to 3 treatments: 1) whole (unprocessed) HMC fed along with concentrate and barley straw, all fed separately and ad libitum (WHMC); 2) HMC ground through a 0.4-cm screen before ensiling and fed along with concentrate and barley straw, all fed separately and ad libitum (GHMC); and 3) a concentrate composed of mainly corn meal, ground through a roller mill with screen openings of 6 mm, and barley straw, both fed separately and ad libitum (Control). Concentrate, HMC, and straw were offered separately ad libitum in a free-choice situation and consumption was recorded daily and BW was recorded weekly. Apparent nutrient digestibility and N balance were determined at the beginning, middle, and end of the study. At the same time points, rumen fluid was collected through rumenocentesis to determine rumen pH and VFA concentrations. Feeding behavior was monitored throughout the study. Animals were harvested after 134 d and HCW, rumen and cecum wall lesions, and liver abscesses were recorded. Treatment did not affect total DMI, feed efficiency, ADG, final BW, and carcass weight or classification. Concentrate consumption (6.6 +/- 0.35 kg/d) of Control heifers was greater ( < 0.001) than that of GHMC (4.1 +/- 0.35 kg/d) and WHMC heifers (2.8 +/- 0.35 kg/d), and GHMC heifers consumed less ( < 0.001) HMC than WHMC heifers (2.3 +/- 0.31 and 4.2 +/- 0.31 kg/d, respectively). Dietary treatments did not affect rumination, self-grooming, nonnutritive oral behaviors, and rumen pH. However, rumen acetate to propionate ratio decreased when heifers received HMC (1.77 +/- 0.276) compared with when heifers received the Control (2.82 +/- 0.276). Total tract starch apparent digestibility was greater in Control (97.7 +/- 0.47%) and GHMC heifers (99.4 +/- 0.47%) than in WHMC heifers (95.2 +/- 0.47%), although an interaction between treatment and time was observed ( < 0.01). Treatments did not affect N retention. Feeding HMC, either whole or ground, separately from concentrate and straw resulted in performance and behavioral patterns similar to feeding only concentrate and straw. PMID- 26523584 TI - Intravenous maternal -arginine administration to twin-bearing ewes during late pregnancy enhances placental growth and development. AB - This study aimed to investigate if intravenous maternal Arg administration to well-fed twin-bearing ewes, from 100 to 140 d of gestation or birth, could enhance placental development and placental nutrient transport. Ewes received intravenous infusions of saline (control) or 345 MUmol Arg HCl/kg of BW 3 times daily from d 100 of pregnancy (P100) to d 140 of pregnancy (P140; cohort 1) or from P100 to birth (cohort 2). At P140, ewes in cohort 1 were euthanized and individual placentae per fetus were dissected and placentomes were classed per type (A to D) and size (light to heavy). Placentome number and individual weight were recorded. As an indicator of placental nutrient transport, blood plasma was collected from the uterine ovarian vein (UOV), uterine artery (UA), and umbilical vein and artery at the time of euthanasia and analyzed for metabolites and free AA concentrations. The ewes in cohort 2 were allowed to lamb and lambs were weighed at birth. The expelled placenta was dissected and number of cotyledons and weights of total cotyledons, remaining fetal membranes, and total placenta were recorded. At P140, Arg-infused ewes had a 63% ( = 0.03) greater number of unoccupied caruncles than control ewes. No differences were observed for placental weight at P140. At birth, lambs from Arg-infused ewes tended to have 11% ( = 0.09) greater placental weight and 34% ( = 0.03) greater total cotyledon weight compared with control lambs. Arginine-infused ewes (Arg-infused) had increased concentrations of Arg ( = 0.0001) and ornithine (Orn; = 0.004) but decreased concentrations of Met ( = 0.01) and His ( = 0.02 and = 0.09, respectively) compared with control ewes in plasma UOV and UA. Fetuses from Arg infused ewes had increased concentrations of Orn ( = 0.005) and decreased concentrations of His ( = 0.006), Met ( = 0.003), and Lys ( = 0.01) but no differences in Arg ( > 0.10) concentrations were found compared with control fetuses in umbilical artery and vein plasma. This study showed that maternal Arg administration of well-fed twin-bearing ewes during late pregnancy tended to improve placental growth and development. PMID- 26523585 TI - Prepartum supplement level and age at weaning: I. Effects on pre- and postpartum beef cow performance and calf performance through weaning. AB - Objectives were to determine the interaction of prepartum supplement level and age at weaning on cow BW, BCS, milk production, reproduction, and calf performance up to weaning in a fall-calving system over 2 yr. Mature, multiparous, Angus * Simmental cows (yr 1: 326 cows, 9 pastures, BW = 632 +/- 67 kg, and BCS = 5.7 +/- 0.58; yr 2: 383 cows, 9 pastures, BW = 606 +/- 70 kg, and BCS = 5.8 +/- 0.74) were used in a split-plot design that included 3 supplement levels-no supplement (NS), low supplement (LS; 2.16 kg?cow?d), or high supplement (HS; 8.61 kg?cow?d)-and 2 ages at weaning-78 +/- 11 d of age (early weaned; EW) or 186 +/- 11 d of age (normal weaned; NW). Cows grazed endophyte-infected tall fescue/red clover pastures and were bunk fed supplement (70% dried distillers' grains with solubles and 30% soybean hulls) 103 +/- 11 d prepartum to 2 +/- 11 d postpartum. Cow BW was greater ( < 0.01) for cows fed HS at precalving (49 +/- 11 d prepartum), postcalving (26 +/- 11 d postpartum), and postbreeding (81 d after AI) compared with cows fed NS and LS. Prepartum supplementation did not affect ( >= 0.62) calf birth BW, percent of calves dead at birth, or percent of cows calving unassisted. Prepartum supplementation tended ( = 0.10) to improve AI conception. Early weaning increased ( <= 0.05) AI conception and postbreeding cow BW and BCS compared with cows with NW calves. Neither prepartum supplementation nor age at weaning affected ( >= 0.28) overall pregnancy rate. At time of early weaning, BW was increased ( = 0.05) for steers from cows fed LS compared with steers from cows fed NS. Steer BW at time of normal weaning and ADG between early and normal weaning was greater ( < 0.01) for EW steers compared with NW steers. A year * age at weaning interaction occurred ( < 0.01) for ultrasound marbling score at time of normal weaning. In yr 1, marbling was decreased ( = 0.04) for EW steers compared with NW steers; however, in yr 2, marbling was increased ( < 0.01) for EW steers compared with NW steers. In conclusion, there was no interaction between level of supplement during late gestation and age at weaning on cow BW, BCS, milk production, AI conception, and overall pregnancy rate in mature beef cows nor in their steer progeny's BW or ultrasound marbling. Both prepartum supplementation and early weaning improved cow BW, BCS, and reproduction. Minimal effects of dam prepartum supplement level on calf performance up to weaning were observed. Early weaning improved calf growth but had inconsistent effects on ultrasound marbling across years. PMID- 26523586 TI - Beef cow prepartum supplement level and age at weaning: II. Effects of developmental programming on performance and carcass composition of steer progeny. AB - Objectives were to determine the interaction of prepartum dam supplement level and age at weaning on growth performance, glucose and insulin concentrations, and carcass characteristics of steers (134 steers in yr 1; 147 steers in yr 2). Mature, multiparous Angus * Simmental cows were used in a split-plot design that included 3 supplement levels (no supplement [NS], 2.16 kg.cow.d [LS], and 8.61 kg.cow.d [HS]) and 2 ages at weaning (78 +/- 11 d of age [early weaned; EW] or 186 +/- 11 d of age [normal weaned; NW]). Cows grazed endophyte-infected tall fescue/red clover pastures and were bunk fed supplement (70% dried distiller's grains plus solubles and 30% soybean hulls) 103 +/- 11 d prepartum to 2 +/- 11 d postpartum. Dam prepartum supplement level did not affect ( >= 0.29) finishing phase growth performance or morbidity. The percentage of steers grading Average Choice or greater was increased ( = 0.04) for steers from cows fed HS compared to the percentage of steers from cows fed NS. Early weaning increased ( < 0.01) finishing phase initial BW and final BW and reduced ( < 0.01) G:F compared to normal weaning. A year * wean interaction ( = 0.04) occurred for ADG; EW resulted in reduced ( < 0.01) ADG compared to NW in yr 2. At slaughter, EW steers had greater ( < 0.01) HCW, yield grade, and back fat than NW steers. A year * wean interaction ( <= 0.05) occurred for quality grade distribution; in yr 2, EW steers had a greater ( < 0.01) proportion of carcasses that graded Low Choice or greater and Average Choice or greater than carcasses from NW steers. The EW steers had greater ( <= 0.05) occurrence of single antibiotic treatments in yr 2 and mortality due to respiratory disease than NW steers. A trend for a year * wean interaction ( <= 0.07) occurred for plasma insulin concentration and insulin:glucose; EW steers had numerically greater plasma insulin concentrations and insulin:glucose than NW steers in yr 1. In conclusion, these data suggest that there is no interaction between maternal level of supplement during late gestation and age at weaning on steer finishing phase performance, glucose and insulin concentrations, and carcass yield and quality characteristics. Overfeeding supplement to the dam did not affect finishing phase growth performance but did improve quality grades of steers. Early weaning increased HCW and improved carcass quality. Both dam supplement level and age at weaning are effective strategies in increasing beef quality and are independent of each other. PMID- 26523587 TI - Zilpaterol hydrochloride improves feed efficiency and changes body composition in nonimplanted Nellore heifers. AB - This research aimed to evaluate the effects of zilpaterol hydrochloride (ZH; MSD Animal Health, Sao Paulo, SP, Brazil) on the performance, carcass traits, serum metabolites, body composition, and gain composition of nonimplanted Nellore heifers. Nellore heifers ( = 72; average BW = 267 +/- 16 kg; average 18 mo of age) were maintained in a feedlot system for 118 d. Heifers were separated into 2 groups: Control and ZH. The ZH group received ZH (8.3 mg/kg diet DM) for 30 d with 3 d of withdrawal before slaughter. Heifers were allotted to 18 pens, 9 pens per treatment, and assigned to a randomized block design. The animals were weighed, blood samples were collected, and subgroups of heifers were slaughtered at the beginning of supplementation and after 20 and 33 d to evaluate performance, blood metabolites, empty BW (EBW), and EBW composition. Hot carcass and kidney-pelvic fat weights were recorded at slaughter. At 24 h postmortem, carcasses were fabricated and the 9-10-11th rib (HH) section was removed from the primal rib to analyze moisture, protein, ash, and ether extract (EE) content in empty body (EB) and gain composition. Heifers fed ZH had gains in HCW that were 19.7 kg greater than controls, reflecting the 30% increase ( < 0.01) in ADG. There was no change in DMI, resulting in a 20% greater G:F ratio ( < 0.01) for heifers fed ZH. Heifers supplemented with ZH had carcass dressing percentages that were 3% greater than controls ( < 0.01), and there was also a 19% reduction in kidney-pelvic fat ( = 0.05) in ZH-treated heifers. Zilpaterol increased serum creatinine ( < 0.01), tended to increase ( = 0.06) serum triacylglycerol, decreased serum NEFA ( = 0.04), and tended to decrease ( = 0.06) serum glucose. The EBW composition was changed after 20 d of ZH supplementation ( = 0.02), with ZH increasing the moisture, ash, and protein contents, whereas carcass fat was decreased by ZH by 14%. Consequently, the carcass CP:EE ratio after 20 d was increased ( = 0.03) by 24% with ZH supplementation. There was no change on EBW composition after 30 d of ZH supplementation ( = 0.17). Regarding carcass gain composition, ZH increased EBW gain ( = 0.02) by 842 g/d from d 0 to d 30, EB protein gain by 221 g/d ( = 0.05) from d 0 to d 20, and by 180 g/d ( = 0.01) from d 0 to d 33. In conclusion, ZH supplementation in nonimplanted Nellore heifers altered the composition of body weight gain, promoting greater lean tissue deposition and improving feed efficiency. PMID- 26523588 TI - Effects of feed consumption rate of beef cattle offered a diet supplemented with nitrate ad libitum or restrictively on potential toxicity of nitrate. AB - The objective of the study was to investigate the effects of feed consumption rate on potential toxicity, rumen fermentation, and eating behavior when beef heifers were fed a diet supplemented with nitrate (NI). Twelve ruminally cannulated heifers (827 +/- 65.5 kg BW) were used in a randomized complete block design. The experiment consisted of 10-d adaptation, 8-d urea-feeding, and 3-d nitrate-feeding periods. All heifers were fed a diet supplemented with urea (UR) during the adaptation and urea-feeding periods, whereas the NI diet (1.09% NO in dietary DM) was fed during the nitrate-feeding period. After adaptation, heifers were randomly assigned to ad libitum or restrictive feeding (about 80% of ad libitum intake) for the urea- and nitrate-feeding periods. Ad libitum DMI decreased (14.1 vs. 15.1 kg/d; < 0.01) when heifers were fed the NI diet compared with the UR diet. The amount of feed consumed increased ( < 0.01) at 0 to 3 h and decreased ( <= 0.03) at 3 to 24 h for restrictive vs. ad libitum feeding of both the UR and NI diets. Compared to the UR diet, the NI diet decreased ( < 0.01) feed consumption at 0 to 3 h and increased ( < 0.02) feed consumption at 3 to 24 h (except feed consumption at 9 to 12 h; = 0.90), indicating nitrate feeding changed the consumption pattern (a more even distribution of feed intake over the day). The increased feed consumption from 0 to 3 h after feeding the NI diet restrictively vs. ad libitum numerically decreased ( = 0.11) rumen pH and numerically or significantly increased ( = 0.01 to 0.28) rumen ammonia, NO, and NO; blood methemoglobin; and plasma NO and NO at 3 h. Regression analysis indicated that increased feed consumption (0 to 3 h) exponentially elevated ( < 0.01; = 0.75) blood methemoglobin, and plasma NO + NO among other rumen and blood variables had the greatest correlation (sigmoid response; < 0.01, = 0.47) with feed consumption (0 to 3 h). Particle size distribution of orts was partially altered ( = 0.02 to 0.40) when the NI diet was fed compared with the UR diet. During the nitrate-feeding period, the nitrate content of orts on d 2 and 3 was greater ( = 0.02) than that on d 1. In conclusion, the increased consumption rate of a diet supplemented with nitrate was an important factor influencing risk of nitrate toxicity based on blood methemoglobin and plasma NO. In addition, the pattern of daily feed consumption was altered by nitrate (creating a "nibbling" pattern of eating) in beef heifers. PMID- 26523589 TI - Associative effects between orchardgrass and red clover silages on voluntary intake and digestion in sheep: Evidence of a synergy on digestible dry matter intake. AB - The aim of this study was to assess the associative effects between orchardgrass () and red clover () silages as a model of preserved grass-legume mixture on voluntary intake parameters and digestive efficiency in sheep. Ten sheep were assigned to a repeated 5 * 5 Latin square design, in which 5 proportions of orchardgrass and red clover silages were tested (0:100, 25:75, 50:50, 75:25, and 0:100, on a DM basis). Measurements were performed simultaneously on intake, feeding behavior (eating time and chewing activity), digestive parameters (nutrient digestibility and rumen parameters), nitrogen balance, and enteric methane (CH) emissions using the SF6 tracer technique. Positive associative effects were observed on daily voluntary DMI ( < 0.001), which was greater when sheep were fed with at least 50% red clover (1.56-1.59 kg/d) compared with those fed with 0 or 25% red clover (1.29 and 1.45 kg/d, respectively; < 0.001). This synergy between forages was not observed on nutrient digestibility, as these parameters linearly decreased with increasing proportions of red clover ( < 0.001). As a result, positive associative effects were observed on daily voluntary intake of digestible DM ( < 0.001). Taken together, the results indicate that the synergy on voluntary intake was due to a greater motivation of animals to eat mixtures (seen in increased intake rates) rather than a positive associative effect on digestive efficiency. Methane yield decreased linearly with increasing proportion of red clover ( < 0.001) and ranged from 20.0 g/kg DMI for sheep fed 100% orchardgrass to 16.1 g/kg DMI for sheep fed 100% red clover. Mixtures of orchardgrass and red clover quadratically ( = 0.03) decreased urinary nitrogen losses and tended ( = 0.099) to quadratically increase nitrogen retention. This synergy between orchardgrass and red clover silages could improve animal performances in addition to the known agronomic benefits of grass-legume mixtures. PMID- 26523590 TI - Corn residue stocking rate affects cattle performance but not subsequent grain yield. AB - This study investigated effects of stocking rate on cattle performance, quality and quantity of corn residue, and impact of residue removal on grain yield for 5 yr at the University of Nebraska - Lincoln West Central Water Resources Field Laboratory near Brule, NE. Four removal treatments-1) no removal (control), 2) grazing at 2.5 animal unit month (AUM)/ha, 3) grazing at 5.0 AUM/ha, and 4) baling-were applied to a center pivot-irrigated corn field (53 ha). The field was divided into eight 6.6-ha paddocks to which replicated treatments were assigned. Samples of residue were collected in October and March (before and after residue removal) using ten 0.5-m quadrats per treatment replication. Residue was separated into 5 plant parts-stem, cob, leaf, husk, and grain-and analyzed for nutrient content. Esophageally fistulated cattle were used to measure diet quality. Cattle assigned to the 2.5 AUM/ha stocking rate treatment gained more BW ( < 0.01) and BCS ( < 0.01) than cattle assigned to the 5.0 AUM/ha treatment. Leaf contained the most ( < 0.01) CP and husk had the greatest ( < 0.01) in vitro OM disappearance (IVOMD) but the CP and IVOMD of individual plant parts did not differ ( > 0.69) between sampling dates. Amount of total residue was reduced ( < 0.05) by baling and both grazing treatments between October and March but was not different ( > 0.05) in control paddocks between sampling dates. As a proportion of the total residue, stem increased ( < 0.01) and husk decreased ( < 0.01) between October and March. Diet CP content was similar ( = 0.10) between sampling dates for the 2 grazing treatments but IVOMD was greater after grazing in the 2.5 AUM/ha grazing treatment ( = 0.04). Subsequent grain yields were not different ( = 0.16) across all 4 residue removal treatments. At the proper stocking rate, corn residue grazing results in acceptable animal performance without negatively impacting subsequent corn grain production. PMID- 26523591 TI - Early supplementation of starter pellets with alfalfa improves the performance of pre- and postweaning Hu lambs. AB - This study aims to determine the effects of alfalfa supplementation on the pre- and postweaning performance, rumen development, and feed transition in starter diet-fed lambs. Six of 66 male Hu lambs were slaughtered at the age of 10 d to serve as a control. The other 60 lambs were randomly allocated to 2 dietary treatments: milk replacer and starter pellets without (STA) or with free-choice chopped alfalfa (S-ALF). The animals were offered 300 g/d of the concentrate mixture and had free access to alfalfa after weaning at the end of wk 4 (age 38 d). The alfalfa inclusion in the S-ALF group tended to increase the starter intake before weaning, significantly increased the concentrate intake soon after weaning ( < 0.05), and increased the BW ( < 0.01) and ADG ( < 0.10) in pre- and postweaning lambs. The S-ALF group had heavier carcasses ( < 0.05), rumens ( < 0.05), reticula ( < 0.05), omasums ( < 0.10), abomasums ( < 0.05), and visceral organs ( < 0.10) than the STA lambs after weaning. Alfalfa supplementation increased ( < 0.05) the rumen papillae length and the ratio of the duodenal villus height to the crypt depth; it also decreased ( < 0.05) the concentration and molar proportion of propionate in wk 1 and 5. The STA lambs had higher ( < 0.01) blood concentrations of globulin and blood urea nitrogen and lower beta hydroxybutyrate after weaning. The STA group also had a higher incidence of feed plaque. From the above results, we infer that the free-choice addition of chopped alfalfa to starter diets is beneficial to rumen development, relieves weaning stress, and improves the performance of lambs. PMID- 26523592 TI - Effects of dry-rolled or high-moisture corn with twenty-five or forty-five percent wet distillers' grains with solubles on energy metabolism, nutrient digestibility, and macromineral balance in finishing beef steers. AB - The effects of feeding a dry-rolled corn-based diet (DRCB) or a combination of a high-moisture corn-based diet (HMCB) with dry-rolled corn (DRC; 2:1 ratio of high moisture corn [HMC] and DRC) with 25 and 45% wet distillers' grains with solubles (WDGS) on energy metabolism and nutrient and mineral balance were evaluated in 8 finishing steers using a replicated Latin square design. The model included the fixed effects of dietary treatment, the WDGS * diet type interaction, and period and the random effects of square and steer within square were also included. Treatments consisted of a DRCB with 25% WDGS, a DRCB with 45% WDGS, a combination of HMCB and DRC with 25% WDGS, and a combination of HMCB and DRC with 45% WDGS. Cattle consuming DRCB consumed a greater amount of DM ( < 0.01) and GE intake was also greater when feeding DRCB with 25% WDGS than when feeding DRCB with 45% WDGS ( < 0.01). As a proportion of GE intake, cattle consuming HMCB had a greater fecal energy loss ( = 0.01). Digestible energy loss as a proportion of GE intake was greater when cattle were fed DRCB than when cattle were fed HMCB ( = 0.01) and when WDGS was included at 45% of DM ( = 0.05). As a proportion of GE intake, cattle consuming DRCB and 25% WDGS respired a greater amount of methane (Mcal) than cattle consuming 45% WDGS. As a proportion of GE intake, ME was greater in DRCB than in HMCB ( = 0.01). Within HMCB, 45% WDGS had more megacalories of retained energy than 25% WDGS. Nitrogen excretion (g) was greater in the urine ( < 0.01) and feces ( < 0.05) when 45% WDGS was included. As a proportion of N intake, total N retained was greater when a greater amount of WDGS was included in the diet ( = 0.05). Digestibility was greater in DRCB than in HMCB ( = 0.02). Starch intake, excretion, and digestibility as a proportion of intake were greater in DRCB than in HMCB ( < 0.01) and when WDGS was included at 25% than when WDGS was included at 45% of the diet ( < 0.01). Intake of ether extract was greater in HMCB when 45% WDGS was included ( < 0.01), and fecal excretion was greater in diets including 25% WDGS than in diets including 45% WDGS ( = 0.02). Sulfur intake was greater as the inclusion of WDGS increased from 25 to 45% ( < 0.01). We interpret that if the basal concentrate portion of the diet is based on HMC, adding an increased amount of WDGS can improve retained energy, and within DRCB, more energy is retained as fat and carbohydrate when cattle were fed 25% WDGS. PMID- 26523593 TI - Wider stall space affects behavior, lesion scores, and productivity of gestating sows. AB - Limited space allowance within the standard gestation stall is an important welfare concern because it restricts the ability of the sow to make postural adjustments and hinders her ability to perform natural behaviors. Therefore, we evaluated the impacts of increasing stall space and/or providing sows the freedom to access a small pen area on sow well-being using multiple welfare metrics. A total of 96 primi- and multiparous crossbred sows were randomly assigned in groups of 4 sows/treatment across 8 replicates to 1 of 3 stall treatments (TRT): standard stall (CTL; dimensions: 61 by 216 cm), width-adjustable stall (flex stall [FLX]; dimensions: adjustable width of 56 to 79 cm by 216 cm), or an individual walk-in/lock-in stall with access to a small communal open-pen area at the rear of the stall (free-access stall [FAS]; dimensions: 69 by 226 cm). Lesion scores, behavior, and immune and productivity traits were measured at various gestational days throughout the study. Total lesion scores were greatest for sows in FAS and least for sows in FLX ( < 0.001). Higher-parity sows in FAS had the most severe lesion scores (TRT * parity, < 0.0001) and scores were greatest at all gestational days (TRT * day, < 0.05). Regardless of parity, sows in FLX had the least severe scores ( < 0.0001). As pregnancy progressed, lesion scores increased among sows in CTL ( < 0.05). Sow BW and backfat (BF) were greater for sows in FLX and FAS ( < 0.05), and BCS and BF were greater for parity 1 and 2 sows in FAS than the same parity sows in CTL (TRT * parity, < 0.05). Duration and frequency of some postural behaviors and sham chew behavior were affected by TRT ( < 0.05) and time of day (TRT * day, < 0.05). These data indicate that adequate stall space, especially late in gestation, may improve the well-being of higher parity and heavier-bodied gestating sows as assessed by changes in postural behaviors, lesion severity scores, and other sow traits. Moreover, compromised welfare measures found among sows in various stall environments may be partly attributed to the specific constraints of each stall system such as restricted stall space in CTL, insufficient floor space in the open-pen area of the FAS system, and gate design of the FLX (e.g., direction of bars and feeder space). These results also indicate that parity and gestational day are additional factors that may exacerbate the effects of restricted stall space or insufficient pen space, further compromising sow well-being. PMID- 26523594 TI - Effects of oral meloxicam administration to beef cattle receiving lipopolysaccharide administration or vaccination against respiratory pathogens. AB - This study evaluated the effects of oral meloxicam administration on metabolic, inflammatory, and acute-phase responses of beef cattle receiving a lipopolysaccharide (LPS) challenge (Exp. 1; d -1 to 6) or vaccinated against respiratory pathogens (Exp. 2; d 7 to 21). Twenty-one Angus steers ( = 11) and heifers ( = 10) were housed in individual pens on d -15 and were offered free choice water, mineral-vitamin mix, and hay until d 21. In Exp. 1, cattle were ranked on d -1 by sex and BW and assigned to 1) oral meloxicam administration (1 mg/kg BW daily) from day -1 to 6 (MEL8), 2) oral meloxicam administration (1 mg/kg BW) on d 0 and oral lactose monohydrate administration (1 mg/kg BW) on d -1 and from d 1 to 6 (MEL1), or 3) oral lactose monohydrate administration (1 mg/kg BW daily) from d -1 to 6 (CON). On d 0, cattle received an intravenous LPS bolus (0.5 MUg/kg BW) concurrently with treatment administration. Rectal temperature (RTEMP) was assessed, and blood samples were collected at -2, 0, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, and 144 h relative to LPS administration. No treatment effects were detected ( >= 0.36) for RTEMP, concentrations of serum tumor necrosis factor alpha (TNFalpha), plasma haptoglobin, cortisol, insulin, and leptin, as well as blood mRNA expression of alpha and cyclooxygenase-2, although all variables increased ( < 0.01) across treatments after LPS administration. In Exp. 2, cattle received the same treatments that they were assigned to in Exp. 1 from d 7 to d 13 and were vaccinated against respiratory pathogens concurrently with treatment administration on d 8. Blood samples were collected, and RTEMP was assessed as in Exp. 1 in addition to 168, 240, and 336 h relative to vaccination. No treatment effects were detected ( >= 0.26) for RTEMP, the same plasma and serum variables evaluated in Exp. 1, and serum concentrations of antibodies against or serum titers against bovine respiratory syncytial virus, bovine herpesvirus-1, bovine viral diarrhea virus-1, and parainfluenza-3 virus. All variables increased ( < 0.01) across treatments after vaccination, except for serum TNFalpha and titers against bovine viral diarrhea virus-1 ( >= 0.40). Collectively, this study found no evidence that oral meloxicam administration, at the doses and intervals utilized herein, mitigated the metabolic, inflammatory, and acute-phase reactions elicited by LPS administration or vaccination against respiratory pathogens. PMID- 26523595 TI - Effects of narasin (Skycis) on live performance and carcass traits of finishing pigs sold in a three-phase marketing system. AB - The objective was to evaluate the effect of feeding narasin (Skycis; Elanco Animal Health, Greenfield, IN) on growth performance and carcass characteristics of finishing pigs sold in a 3-phase marketing system. Pigs ( = 1,232) were housed in 56 single-sex pens (22 pigs/pen) divided into 2 even blocks based on initiation of treatment. Each treatment * sex combination was replicated 14 times. Pigs were fed either 0 mg/kg narasin (control) or 15 mg/kg narasin for up to 85 d of finishing (initiated at an average of 52.95 kg BW). In each pen, 18% (4 pigs per pen) of pigs were sold in the first marketing group (Day 64 of dietary treatment), 50% (11 of the original 22) were sold in the second marketing group (Day 78), and 32% (the remaining 7 pigs) were sold in the third marketing group (Day 85). Data were analyzed as a randomized complete block design with pen as the experimental unit. The model included the fixed effects of diet, sex, and their interaction. Block and replicate nested within block were random variables. Carcass data from pigs in marketing group 3 of block 2 was not collected due to inclement weather. Narasin had no effect on growth performance traits ( >= 0.15) in phases 1 (Days 1-28) or 2 (Days 29-56), regardless of sex. Barrows fed narasin had a 2.0% greater overall (Day 0-85) ADG than barrows fed the control diet ( < 0.01), but ADG of gilts was not different due to diet ( = 0.69). Regardless of sex, narasin improved ( = 0.03) feed efficiency (G:F) by 1.3% throughout the 85-d feeding period. There were no effects ( >= 0.21) of narasin on carcass composition in marketing groups 1 and 2. Narasin-fed barrows in marketing group 3 had 0.9 percentage units lower ( < 0.01) estimated carcass lean compared with barrows fed control diets (51.0 vs. 52.0%); no difference existed in gilts ( = 0.21). This is likely due to narasin-fed barrows of marketing group 3 tending ( = 0.06) to have 7.7% greater fat depth than control barrows of marketing group 3. Pooled effects (across all 3 marketing groups) of feeding narasin tended ( = 0.08) to reduce loin depth by 1.1% (60.00 vs. 60.66 mm), but there were no effects on fat depth ( = 0.24) or estimated carcass lean ( = 0.11). Overall, narasin can be used during the last 85 d of feeding to increase feed efficiency of barrows and gilts with minimal impact on carcass composition. PMID- 26523596 TI - Relationship of efficiency indices with performance, heart rate, oxygen consumption, blood parameters, and estimated heat production in Nellore steers. AB - The objective of this study was to examine the relationship of efficiency indices with performance, heart rate, oxygen consumption, blood parameters, and estimated heat production (EHP) in Nellore steers. Eighteen steers were individually lot fed diets of 2.7 Mcal ME/kg DM for 84 d. Estimated heat production was determined using oxygen pulse (OP) methodology, in which heart rate (HR) was monitored for 4 consecutive days. Oxygen pulse was obtained by simultaneously measuring HR and oxygen consumption during a 10- to 15-min period. Efficiency traits studied were feed efficiency (G:F) and residual feed intake (RFI) obtained by regression of DMI in relation to ADG and midtest metabolic BW (RFI). Alternatively, RFI was also obtained based on equations reported by the NRC's to estimate individual requirement and DMI (RFI calculated by the NRC [1996] equation [RFI]). The slope of the regression equation and its significance was used to evaluate the effect of efficiency indices (RFI, RFI, or G:F) on the traits studied. A mixed model was used considering RFI, RFI, or G:F and pen type as fixed effects and initial age as a covariate. For HR and EHP variables, day was included as a random effect. There was no relationship between efficiency indices and back fat depth measured by ultrasound or daily HR and EHP ( > 0.05). Because G:F is obtained in relation to BW, the slope of G:F was positive and significant ( < 0.05). Regardless of the method used, efficient steers had lower DMI ( < 0.05). The initial LM area was indirectly related to RFI and RFI ( < 0.05); however, the final muscle area was related to only RFI. Oxygen consumption per beat was not related to G:F; however, it was lower for RFI- and RFI-efficient steers, and consequently, oxygen volume (mL.min.kg) and OP (MUL O.beat.kg) were also lower ( < 0.05). Blood parameters were not related to RFI and RFI ( > 0.05); however, G:F-efficient steers showed lower hematocrit and hemoglobin concentrations ( < 0.05). Differences in EHP between efficient and inefficient animals were not directly detected. Nevertheless, differences in oxygen consumption and OP were detected, indicating that the OP methodology may be useful to predict growth efficiency. PMID- 26523597 TI - Effect of forage type with or without corn supplementation on animal performance, beef fatty acid composition, and palatability. AB - Thirty-two steers were used to examine forage type (legumes [ and ] vs. grasses [ and ]) with or without individual corn grain supplementation (0 vs. 0.75% of live weight [LW]/d) on beef fatty acid composition and palatability. In each year, steers ( = 16/yr) were randomly assigned to forage type ( = 8/forage type per yr) and to supplementation treatments within forage type ( = 4/supplementation treatment/forage type per yr). Forage types (grasses vs. legumes) were replicated in 2 paddocks of perennial and annual forage type pastures. A mixed model was developed with forage type, corn grain supplementation, and the 2-way interaction as fixed effects and 2 different error terms, one for testing forage and another for testing grain supplement and grain supplement * forage interaction. Corn grain supplementation increased ( = 0.01) ADG by 0.29 kg/d and final LW by 13 kg. Hot carcass weight, dressing percentage (DP), and KPH were greater ( < 0.05) for steers supplemented with corn grain. Carcasses from steers grazing legumes had greater ( = 0.04) DP compared with carcasses from steers grazing grasses. Alpha linolenic acid concentration was higher ( < 0.05) in LM of steers grazing legumes than in LM of steers grazing grasses, both without supplementation. Supplementation decreased ( < 0.05) linolenic acid levels for both forage types; however, the magnitude of this reduction was greater for legumes than for grasses. The ratio of -6 to -3 PUFA was greater ( = 0.03) in the LM of corn grain supplemented steers than in the LM of nonsupplemented steers. Supplementation of corn grain decreased ( < 0.05) the percentage of odd-chain fatty acids and increased ( < 0.05) the percentage of MUFA in the LM. Warner-Bratzler shear force values were not altered ( > 0.05) by forage type, supplementation, or the 2-way interaction. Beef finished on legumes had greater concentrations of -3 PUFA, whereas beef supplemented with corn grain had a greater ratio of -6 to -3 fatty acids. On a gravimetric basis (mg/100 g LM), -3 PUFA and CLA contents were not altered with supplementation, indicating that corn grain can be supplemented at this level in a forage-finishing beef system without negative consequences on perceived beneficial fatty acids. PMID- 26523598 TI - Correlation of fresh muscle firmness with sensory characteristics of pork loins destined for a quality focused market. AB - Production of pork for quality-driven export markets offers economic incentive. Pork processors use subjective firmness as a sorting tool for loins intended for high-quality export. The objectives of this study were to determine 1) durometer efficacy in muscle, 2) if firmness on one portion of the loin is indicative of other locations, 3) if 1 d firmness is related to export quality traits, and 4) if variation in firmness is explained by mechanistic measures. Subjective firmness scores (1 = extremely soft and 5 = extremely firm) were determined by a trained individual 1 d (initial time point) postmortem. Loins (North American Meat Processors number 414 Canadian back; = 154) were wet aged for 28 d at 1.7 degrees C. On d 28, a panel of 4 individuals assigned firmness scores on the ventral side of the loin at the area of the 10th rib, the anterior half, and the posterior half of the loin. Durometer readings were collected at the area of the 10th rib on the dorsal and ventral side of the loin. Spearman correlation coefficients were computed in SAS (version 9.3) to account for nonnormality of categorical data. Subjective firmness measurements at d 28 at the 10th rib and on the anterior portion of the loin were not correlated ( >= 0.21) with whole loin durometer readings on the dorsal or ventral portion of the loin or the average of the whole loin values. Subjective firmness (d 28) at the 10th rib accounted for 38.44 ( = 0.620) and 48.30% ( = 0.695) of the variation in firmness at the anterior portion of the loin and the posterior portion of the loin, respectively ( <= 0.05). One-day subjective firmness measurements were correlated with 28-d Warner-Bratzler shear force measurements ( = 0.174, = 0.03) but were not significantly correlated with sensory characteristics ( >= 0.08). Purge tended to be correlated with 1 d firmness ( = 0.136, = 0.10); however, drip and cooking loss, 24-h and 28-d pH, and soluble and insoluble collagen content were not correlated ( >= 0.34). Firmness measurements collected in the production facility (1 d) were negatively correlated with iodine value (IV; = -0.199, = 0.02), yet no 28-d subjective firmness measurements were correlated with IV ( >= 0.33). When loins not achieving export standards are removed from the population, 1 d firmness was not correlated to export quality or sensory characteristics (d 28). Differences in firmness were not explained by mechanistic measures. Inconsistencies among subjective and objective firmness measurements suggest that the durometer may not be an appropriate way to determine firmness. PMID- 26523599 TI - Modeling of intramuscular lipids in different muscles in bulls, steers, and cows. AB - Intramuscular fat depot is of major interest for consumers, producers, and the industry. To predict intramuscular (i.m.) lipid deposition in cattle of continental breeds, different models were constructed for different muscles in bulls, steers, and cows. Two independent databases (DB1 and DB2) were developed with homogeneous individual data collected in the same slaughterhouse and total lipids, phospholipids, and triglycerides were analyzed in the same lab with the same procedures. Database DB1 was used with the meta-analysis methodology to fit the predictive models of i.m. lipids, phospholipids, and triglycerides with carcass fatness. Database DB2 was used to evaluate the accuracy of the models predicted. Total lipid and triglyceride contents varied linearly with carcass fatness in bulls, steers, and cows, but phospholipids were more independent of carcass fatness, regardless of the type of cattle studied. In bulls, LM had a lower minimal value (intercept in the model) and greater slope than semitendinosus (ST) and triceps brachii (TB) muscles. In cows, LM showed a greater intercept than ST and TB muscles but a similar slope. In steers, lipid content increased similarly in LM, rectus abdominis (RA) muscle, and ST muscle with carcass fatness. Bulls had a lower intercept than steers but showed a similar trend with carcass fatness. According to the external evaluation using DB2, the models obtained to predict total lipids in LM were more accurate than those obtained in the ST muscle in bulls and cows and in the RA muscle in steers. The models proposed for cows should be used only in the range of carcass fatness used to fit the equations, and further data are needed to fully validate them. PMID- 26523600 TI - Growth performance and pork fat quality as measured by three methods of pigs fed 20% DDGS and slaughtered using a standard industry split marketing strategy. AB - A total of 40 pens containing 22 crossbred barrows (initial BW = 43.07 +/- 1.61 kg; PIC 1050 * PIC 337 genetics) were housed in a commercial wean to finish facility. Pens were randomly allotted to dietary treatments in a 2 * 3 factorial arrangement with 2 levels of dried distillers grains with solubles (DDGS; 0% or 20%) and chosen for 1 of 3 marketing cuts removing 4, 8, and 10 animals from each pen. Fat tissue samples were removed from the anterior tip of the jowl and posterior to the sternum on the belly edge 1d postmortem. Fatty acid composition was determined via the Folch method, and iodine values (IV) were calculated from chemical titrations, fatty acid profile (GC IV), and in-plant Bruker near infrared (NIR) spectroscopy. Pearson's correlation coefficients for IV determination methods were estimated. Inclusion of 20% DDGS did not change ( > 0.05) growth performance, whereas marketing cut affected performance, with the second cut producing the most efficient pigs ( < 0.01). Total SFA and MUFA concentrations were higher ( < 0.01) in belly and jowl fat from pigs fed 0% DDGS. Total PUFA and the PUFA:SFA in belly and jowl fat was higher ( < 0.01) when 20% DDGS was fed. Dried distillers grains with solubles inclusion increased IV in belly and jowl as determined by all 3 methods. Regardless of dietary treatment or fat depot, Pearson correlation coefficients between titration and GC IV, titration and NIR, and GC IV and NIR were 0.46 ( < 0.01), 0.68 ( < 0.01), and 0.43 ( < 0.01), respectively. These correlations suggest methods may rank samples equally but do not provide the same absolute IV. Belly fat had a lower IV ( < 0.01) than jowl fat using titration or GC IV methods, suggesting pigs have varied degrees of physiological maturity at specific fat depots when weight end points are used during the finishing phase. In conclusion, feeding 20% DDGS negatively affected fat quality but not growth performance, and marketing time changed growth performance. PMID- 26523601 TI - Erratum. PMID- 26523603 TI - Developing the Bias Blind Spot: Increasing Skepticism towards Others. AB - Two experiments with eighty-eight 7- to 10-year-olds examined the bias blind spot in children. Both younger and older children rated themselves as less likely than a specific other (Experiment 1) or an average child (Experiment 2) to commit various biases. These self-other differences were also more extreme for biased behaviors than for other behaviors. At times, older children demonstrated stronger self-other differences than younger children, which seemed primarily driven by older children's judgments about bias in others. These findings suggest that, although the bias blind spot exists as soon as children recognize other committed biases, what changes over development is how skeptical children are towards others. PMID- 26523602 TI - Mapping of Craniofacial Traits in Outbred Mice Identifies Major Developmental Genes Involved in Shape Determination. AB - The vertebrate cranium is a prime example of the high evolvability of complex traits. While evidence of genes and developmental pathways underlying craniofacial shape determination is accumulating, we are still far from understanding how such variation at the genetic level is translated into craniofacial shape variation. Here we used 3D geometric morphometrics to map genes involved in shape determination in a population of outbred mice (Carworth Farms White, or CFW). We defined shape traits via principal component analysis of 3D skull and mandible measurements. We mapped genetic loci associated with shape traits at ~80,000 candidate single nucleotide polymorphisms in ~700 male mice. We found that craniofacial shape and size are highly heritable, polygenic traits. Despite the polygenic nature of the traits, we identified 17 loci that explain variation in skull shape, and 8 loci associated with variation in mandible shape. Together, the associated variants account for 11.4% of skull and 4.4% of mandible shape variation, however, the total additive genetic variance associated with phenotypic variation was estimated in ~45%. Candidate genes within the associated loci have known roles in craniofacial development; this includes 6 transcription factors and several regulators of bone developmental pathways. One gene, Mn1, has an unusually large effect on shape variation in our study. A knockout of this gene was previously shown to affect negatively the development of membranous bones of the cranial skeleton, and evolutionary analysis shows that the gene has arisen at the base of the bony vertebrates (Eutelostomi), where the ossified head first appeared. Therefore, Mn1 emerges as a key gene for both skull formation and within-population shape variation. Our study shows that it is possible to identify important developmental genes through genome-wide mapping of high dimensional shape features in an outbred population. PMID- 26523604 TI - [Hyperbaric therapy and diving medicine - hyperbaric therapy part 1: evidence based emergency care]. AB - Hyperbaric oxygen therapy (HBOT), i. e. breathing pure oxygen at elevated ambient pressure, remains the gold standard of care in treating air or gas embolism and decompression illness. Guidelines are less clear on the value of HBOT in acute management of carbon monoxide (CO) poisoning or clostridial necrosis. To evaluate the evidence of clinical efficacy of HBOT we performed a systematic literature review. Part 1 assesses acute indications such as air or gas embolism, decompression sickness, CO-poisoning, clostridialmyonecrosis, necrotizing problem wounds, acute traumatic wounds and arterial retinal occlusion. Part 2 discusses further uses of HBOT as adjuvant treatment and highlights problems in assessing the value of HBOT using evidence-based medicine criteria. PMID- 26523605 TI - Cool Roofs in Guangzhou, China: Outdoor Air Temperature Reductions during Heat Waves and Typical Summer Conditions. AB - In this paper, we simulate temperature reductions during heat-wave events and during typical summer conditions from the installation of highly reflective "cool" roofs in the Chinese megacity of Guangzhou. We simulate temperature reductions during six of the strongest historical heat-wave events over the past decade, finding average urban midday temperature reductions of 1.2 degrees C. In comparison, we simulate 25 typical summer weeks between 2004 and 2008, finding average urban midday temperature reductions of 0.8 degrees C, indicating that air temperature sensitivity to urban albedo in Guangzhou varies with meteorological conditions. We find that roughly three-fourths of the variance in air temperature reductions across all episodes can be accounted for by a linear regression, including only three basic properties related to the meteorological conditions: mean daytime temperature, humidity, and ventilation to the greater Guangzhou urban area. While these results highlight the potential for cool roofs to mitigate peak temperatures during heat waves, the temperature reductions reported here are based on the upper bound case, which increases albedos of all roofs (but does not modify road albedo or wall albedo). PMID- 26523606 TI - Supramolecular Assembly of an Evolved Miniprotein Host and Fluorogenic Guest Pair. AB - Small-molecule-induced assembly of defined protein structures could have broad implications for the fabrication of new materials as well as biological signaling pathways. However, the design of new host-guest pairs capable of small-molecule induced assembly in a biologically relevant context remains a significant challenge. Herein, we report a series of miniprotein hosts, evolved from the tenth type III domain of fibronectin (Fn3), that display remarkable binding affinity toward a red-shifted environment-sensitive merocyanine derivative, termed sI-Pht. Importantly, the consensus binder isolated from directed evolution experiments (6.2.18) forms a higher order assembly in response to addition of sI Pht, as assessed by analytical ultracentrifugation. sI-Pht-induced assembly of 6.2.18 results in a 570-fold increase in fluorescence compared to free dye. This property enables the direct visualization of host-guest assemblies by fluorescence microscopy. As a demonstration, we show that supramolecular assembly of the 6.2.18-sI-Pht system can be visualized on the surface of living yeast cells. This new host-guest pair provides a tool for the potential development of new materials as well as pathway engineering. In a broader context, this work details a new design paradigm for the discovery of host-guest systems that function in the context of living cells. PMID- 26523607 TI - Modulating charge recombination and structural dynamics in isolated organometal halide perovskite crystals by external electric fields. AB - Time-resolved photoluminescence (PL) of isolated methylammonium lead tribromide (MAPbBr3) perovskite crystalline platelets is studied under applied electric fields to understand the influence of ion conformational and translational dynamics on charge recombination dynamics. MAPbBr3 PL decays and intensity transients over ~100 ps to 10 s time scales show large modulation upon application of electric fields up to ~ +/-10(7) V/m that we attribute primarily to reorientation of the methylammonium cation (MA(+)) dipole moments. On longer time scales, a large fraction of electric field-dependent PL intensity transients exhibit oscillatory behavior and undergo spontaneous switching on time scales comparable to ion drift (~1-10 s). PL modulation behavior decreases significantly with aging, suggesting diminished reorientational susceptibility (conformational flexibility) of MA(+) groups to applied electric fields. PMID- 26523608 TI - Metal-Organic Frameworks in Adsorption-Driven Heat Pumps: The Potential of Alcohols as Working Fluids. AB - A large fraction of global energy is consumed for heating and cooling. Adsorption driven heat pumps and chillers could be employed to reduce this consumption. MOFs are often considered to be ideal adsorbents for heat pumps and chillers. While most published works to date on this topic have focused on the use of water as a working fluid, the instability of many MOFs to water and the fact that water cannot be used at subzero temperatures pose certain drawbacks. The potential of using alcohol-MOF pairs in adsorption-driven heat pumps and chillers is investigated. To this end, 18 different selected MOF structures in combination with either methanol or ethanol as a working fluid are considered, and their potential is assessed on the basis of adsorption measurements and thermodynamic efficiencies. If alcohols are used instead of water, then (1) adsorption occurs at lower relative pressures for methanol and even lower pressure for ethanol, (2) larger pores can be utilized efficiently, as hysteresis is absent for pores smaller than 3.4 nm (2 nm for water), (3) larger pore sizes need to be employed to ensure the desired stepwise adsorption, (4) the effect of (polar/apolar) functional groups in the MOF is far less pronounced, (5) the energy released or taken up per cycle is lower, but heat and mass transfer may be enhanced, (6) stability of MOFs seems to be less of an issue, and (7) cryogenic applications (e.g., ice making) become feasible. From a thermodynamic perspective, UiO-67, CAU 3, and ZIF-8 seem to be the most promising MOFs for both methanol and ethanol as working fluids. Although UiO-67 might not be completely stable, both CAU-3 and ZIF-8 have the potential to be applied, especially in subzero-temperature adsorption chillers (AC). PMID- 26523610 TI - Synthesis of Functional Nanomaterials in Ionic Liquids. AB - Utilization of ionic liquids (ILs) in material synthesis is a promising field. The unusual properties of ILs provide new opportunities for the design of functional materials, and much excellent work has been reported. Here, the progress in material design and synthesis using ILs, especially nanomaterials, is discussed, including the unitization of ILs as synthetic media, templates, precursors, or components in the synthesis of various categories of nanomaterials. The challenges and opportunities in this interesting and rapid developing area are also discussed. PMID- 26523609 TI - Abdominal adiposity change in white and black midlife women: The study of women's health across the nation. AB - OBJECTIVE: The principal objective of this investigation was to compare the naturalistic intra-abdominal adipose tissue (IAAT) change among black and white women during midlife. METHODS: A cohort of 222 (56%) white and 171 (44%) black midlife women were investigated in the Fat Patterning Study at the Chicago site of the Study of Women's Health Across the Nation. The subjects' total body fat was assessed by dual-energy X-ray absorptiometry and IAAT by a planimetric computed tomography (at the level of L4 -L5 ) annually over up to 4 years. RESULTS: The total body fat at initial evaluation was higher in black women (45.1% +/- 8.2%) when compared with white women (41.3% +/- 8.7%, P < 0.001) and did not significantly change over the longitudinal follow-up. No significant racial differences were found in the mean annualized gain of IAAT (4.4% +/- 0.5%) in models adjusted for total body fat, initial IAAT, age, race, time and race interaction, physical activity, depressive symptoms, menopausal status, and menopausal hormone therapy. CONCLUSIONS: During a naturalistic observation, black and white midlife women had similar abdominal fat gain adjusted for differences in baseline adiposity. These data inform future research aimed to prevent IAAT gain during the critical midlife period of rising cardiovascular risk. PMID- 26523611 TI - More symptoms with sialic receptor-positive adenovirus in epidemic keratoconjunctivitis. PMID- 26523612 TI - Effects of caffeic acid phenethyl ester on matrix molecules and angiogenetic and anti-angiogenetic factors in gastric cancer cells cultured on different substrates. AB - Migration, invasion, metastasis and angiogenesis associated with cancer depend on the surrounding microenvironment. Angiogenesis, the growth of new capillaries, is a regulator of cancer growth and a useful target for cancer therapy. We examined matrix protein interactions in a gastric cancer cell culture that was treated with different doses of caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE). We also investigated the relations among the levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), endostatin (ES) and trombospondin-1 (TSP-1). Cytotoxity of CAPE was measured using the 3 (4,5-dmethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. We examined the behavior of cells on laminin and collagen I coated surfaces in response to the angiogenic effect of these matrix molecules. We examined the protein alterations of these matrix molecules immunohistochemically and measured the levels of VEGF, MMP-9, ES and TSP-1 using the ELISA test. We showed that application of CAPE to the gastric cancer cell line on tissue culture plastic, laminin and collagen I significantly decreased the VEGF and MMP-9 protein levels. We found that TSP-1 levels were increased significantly in the gastric cancer cells after application of CAPE. The protein levels of gastric cancer cells also were increased significantly when tissue was cultured on laminin and collagen I. Application of CAPE to cells on laminin or collagen I coated surfaces significantly increased all of the proteins except ES. ES levels were increased on the collagen I covered surfaces, but the laminin surface decreased the levels of ES significantly. We demonstrated the beneficial effect of CAPE on a gastric cancer cell line including inhibition of proliferation and induction of some proteins that might be related to decreased angiogenesis. PMID- 26523613 TI - Immigrant dairy workers' perceptions of health and safety on the farm in America's Heartland. AB - BACKGROUND: Dairy farming is dangerous. Yearly, farms grow fewer and larger by employing immigrant workers, who have limited industrial agriculture experience and safety and health training. METHODS: We examined results of five focus groups with 37 Hispanic, immigrant dairy workers. Analysis followed a grounded theory approach and employed ATLAS.ti. RESULTS: Reported injury experience affirmed the hazardous nature of dairy. Some workers received appropriate worker compensation benefits, whereas others were instructed to deny work-relatedness. Some employers covered medical injury costs out-of-pocket, whereas others did not. Cows were a major injury source. Pressure to work and weather were noted as injury risk factors. Worker compensation was poorly understood, and immigration status and fear of deportation influenced injury and hazard reporting. CONCLUSION: Injury management practices range from benevolent to threatening. Workers compensation is poorly understood and undocumented status is an occupational hazard. We underscore the need for further research and immigration policy change. PMID- 26523614 TI - An Update on Heart Transplantation in Human Immunodeficiency Virus-Infected Patients. AB - Cardiovascular diseases have become a significant cause of morbidity in patients with human immunodeficiency virus (HIV) infection. Heart transplantation (HT) is a well-established treatment of end-stage heart failure (ESHF) and is performed in selected HIV-infected patients in developed countries. Few data are available on the prognosis of HIV-infected patients undergoing HT in the era of combined antiretroviral therapy (cART) because current evidence is limited to small retrospective cohorts, case series, and case reports. Many HT centers consider HIV infection to be a contraindication for HT; however, in the era of cART, HT recipients with HIV infection seem to achieve satisfactory outcomes without developing HIV-related events. Consequently, selected HIV-infected patients with ESHF who are taking effective cART should be considered candidates for HT. The present review provides epidemiological data on ESHF in HIV-infected patients from all published experience on HT in HIV-infected patients since the beginning of the epidemic. The practical management of these patients is discussed, with emphasis on the challenging issues that must be addressed in the pretransplant (including HIV criteria) and posttransplant periods. Finally, proposals are made for future management and research priorities. PMID- 26523616 TI - The Evaluation of the Patient with Unexplained Palpitations: Maximizing Diagnostic Yield while Minimizing Unnecessary Frustration. PMID- 26523615 TI - A population analysis of self-management and health-related quality of life for chronic musculoskeletal conditions. AB - BACKGROUND: There is growing policy emphasis on self-management as an essential component of musculoskeletal chronic care models. Underpinning this drive is the assumption that with correct 'informational' framing people will better manage their condition's progression and thereby maintain quality of life. OBJECTIVE: To assess associations between self-management behaviours and health-related quality of life for people with chronic musculoskeletal conditions. DESIGN: Using survey data from health census and follow-up structured telephone interviews, linear regression (cumulatively adjusted for potential confounders) and logistic regression examined associations between use of specific self-management behaviours and quality of life. SETTING AND PARTICIPANTS: A total of 885 respondents (2012) who indicated still having a musculoskeletal condition reported in a 2010 health census (Port Lincoln, South Australia). VARIABLES: Specific self-management activities, age, sex, education, marital status, smoking, comorbidities and pain. OUTCOME MEASURE: EQ-5D-5L. RESULTS: Exercise (63%) and diet (19%) were the most commonly reported self-management activities used to manage musculoskeletal conditions. About 24% reported not using any specific self-management activities. Involvement in self-management showed no association with quality of life, with and without adjustment for confounders. Diet had a negative association with quality of life as did use of formal support (self-management course or community group support). DISCUSSION: Taking a real world perspective, these findings raise important questions about how people currently engage with self-management activities and the kinds of outcomes that can be expected from undertaking these activities. The timing of people's uptake of self-management within the musculoskeletal disease continuum is an issue requiring further attention in both research and practice. PMID- 26523617 TI - Craniopharyngioma: long-term consequences of a chronic disease. AB - Childhood-onset craniopharyngiomas (CP) are rare embryonal malformations of low grade histological malignancy. Hypothalamic involvement and/or treatment-related lesions result in impaired physical and social functionality and severe neuroendocrine sequelae. Quality of life in CP with hypothalamic involvement is impaired by severe obesity, physical fatigue, reduced motivation, dyspnea, diarrhea, and non-optimal psychosocial development. 567 CI patients have been recruited between 1998 and 2010 in the German Craniopharyngioma Registry. Only 5 of 567 patients (<1%) presented without confirmed signs of relapse/progression, visual impairment, and endocrine deficiencies during longitudinal follow-up of more than 5 years. Hypothalamic obesity in CP is associated with a severe increase in BMI during the early post-operative period. Patients with CP involving hypothalamic structures show reduced 10-years overall survival, whereas overall and progression-free survival rates are not related to the degree of surgical resection. Accordingly, gross-total resection should be avoided in cases of hypothalamic involvement to prevent further hypothalamic damage. As surgical expertise has been shown to have impact on postoperative morbidity, medical societies should establish criteria of adequate professional expertise for the treatment of CP. Based on these criteria, health authorities should organize the certification of centers of excellence authorized for treatment and care of patients with this chronic disease. PMID- 26523618 TI - Degradation and Characterization of Resorbable Phosphate-Based Glass Thin-Film Coatings Applied by Radio-Frequency Magnetron Sputtering. AB - Quinternary phosphate-based glasses of up to 2.67 MUm, deposited by radio frequency magnetron sputtering, were degraded in distilled water and phosphate buffered saline (PBS) to investigate their degradation characteristics. Magnetron sputtered coatings have been structurally compared to their compositionally equivalent melt-quenched bulk glass counterparts. The coatings were found to have structurally variable surfaces to melt-quenched glass such that the respective bridging oxygen to nonbridging oxygen bonds were 34.2% to 65.8% versus 20.5% to 79.5%, forming metaphosphate (PO3)(-) (Q(2)) versus less soluble (P2O7)(4-) (Q(1)) and (PO4)(3-) (Q(0)), respectively. This factor led to highly soluble coatings, exhibiting a t(1/2) degradation dependence in the first 2 h in distilled water, followed by a more characteristic linear profile because the subsequent layers were less soluble. Degradation was observed to preferentially occur, forming voids characteristic of pitting corrosion, which was confirmed by the use of a focused ion beam. Coating degradation in PBS precipitated a (PO3)(-) metaphosphate, an X-ray amorphous layer, which remained adherent to the substrate and seemingly formed a protective diffusion barrier, which inhibited further coating degradation. The implications are that while compositionally similar, sputter-deposited coatings and melt-quenched glasses are structurally dissimilar, most notably, with regard to the surface layer. This factor has been attributed to surface etching of the as-deposited coating layer during deposition and variation in the thermal history between the processes of magnetron sputtering and melt quenching. PMID- 26523619 TI - Prevalence Analysis and Molecular Characterization of Salmonella at Different Processing Steps in Broiler Slaughter Plants in South Korea. AB - In this study, changes in the prevalence of Salmonella during the processing of broiler chicken carcasses were investigated. A total of 1040 fecal swabs and chicken carcasses samples were collected from 2 processing plants at the 4 stages of broiler processing, which included live birds in slaughter line, postevisceration/prewashing, postwashing/prechilling, and postchilling, respectively. The intraspecific biodiversity of the Salmonella isolates was determined using a DiversiLab automated repetitive sequence-based PCR (rep-PCR) system. In both plants, the prevalence of Salmonella increased considerably after evisceration (from 4.6% to 30.8%, P < 0.05) and decreased after washing (from 30.8% to 25.4%, P < 0.05). However, the chilling step had little effect on Salmonella prevalence (from 25.4% to 22.7%, P > 0.05). The most frequent Salmonella serovar in plant A was Infantis (35.8%), followed by Enteritidis (26.2%) and Montevideo (15.0%), while Montevideo (43.6%) and Enteritidis (35.9%) were most prevalent in plant B. A difference in the rep-PCR banding pattern was found to be related to the processing plant origin and serovar rather than sampling point or sampling day, although there were some exceptional strains. PMID- 26523620 TI - Human umbilical cord-derived mesenchymal stem cells elicit macrophages into an anti-inflammatory phenotype to alleviate insulin resistance in type 2 diabetic rats. AB - Insulin resistance, a major characteristic of type 2 diabetes (T2D), is closely associated with adipose tissue macrophages (ATMs) that induce chronic low-grade inflammation. Recently, mesenchymal stem cells (MSCs) have been identified in alleviation of insulin resistance. However, the underlying mechanism still remains elusive. Thus, we aimed to investigate whether the effect of MSCs on insulin resistance was related to macrophages phenotypes in adipose tissues of T2D rats. In this study, human umbilical cord-derived MSCs (UC-MSCs) infusion produced significantly anti-diabetic effects and promoted insulin sensitivity in T2D rats that were induced by a high-fat diet combined with streptozotocin and directed ATMs into an alternatively activated phenotype (M2, anti-inflammatory). In vitro, MSC-induced M2 macrophages alleviated insulin resistance caused by classically activated macrophages (M1, pro-inflammatory). Further analysis showed that M1 stimulated UC-MSCs to increase expression of interleukin (IL)-6, a molecule which upregulated IL4R expression, promoted phosphorylation of STAT6 in macrophages, and eventually polarized macrophages into M2 phenotype. Moreover, the UC-MSCs effect on macrophages was largely abrogated by small interfering RNA (siRNA) knockdown of IL-6. Together, our results indicate that UC-MSCs can alleviate insulin resistance in part via production of IL-6 that elicits M2 polarization. Additionally, human obesity and insulin resistance were associated with increased pro-inflammatory ATMs infiltration. Thus, MSCs may be a new treatment for obesity-related insulin resistance and T2D concerning macrophage polarized effects. PMID- 26523622 TI - Palladium Catalyzed C-I and Vicinal C-H Dual Activation of Diaryliodonium Salts for Diarylation: Synthesis of 4,5-Benzocoumarins. AB - With a strategy that makes use of palladium activation of both C-I and vicinal C H bonds of diaryliodonium salts, an unprecedented approach in diarylation of coumarins was reported. As such, a wide range of 4,5-benzocoumarins with potential fluorescence properties have been synthesized in good yields. A series of experiments suggested that the formation of two carbon-carbon bonds proceeded in a synergetic manner. PMID- 26523621 TI - Helix-Capping Histidines: Diversity of N-H...N Hydrogen Bond Strength Revealed by (2h)JNN Scalar Couplings. AB - In addition to its well-known roles as an electrophile and general acid, the side chain of histidine often serves as a hydrogen bond (H-bond) acceptor. These H bonds provide a convenient pH-dependent switch for local structure and functional motifs. In hundreds of instances, a histidine caps the N-terminus of alpha- and 310-helices by forming a backbone NH...Ndelta1 H-bond. To characterize the resilience and dynamics of the histidine cap, we measured the trans H-bond scalar coupling constant, (2h)JNN, in several forms of Group 1 truncated hemoglobins and cytochrome b5. The set of 19 measured (2h)JNN values were between 4.0 and 5.4 Hz, generally smaller than in nucleic acids (~6-10 Hz) and indicative of longer, weaker bonds in the studied proteins. A positive linear correlation between (2h)JNN and the difference in imidazole ring (15)N chemical shift (Delta(15)N = |delta(15)Ndelta1 - delta(15)Nepsilon2|) was found to be consistent with variable H-bond length and variable cap population related to the ionization of histidine in the capping and noncapping states. The relative ease of (2h)JNN detection suggests that this parameter can become part of the standard arsenal for describing histidines in helix caps and other key structural and catalytic elements involving NH...N H-bonds. The combined nucleic acid and protein data extend the utility of (2h)JNN as a sensitive marker of local structural, dynamic, and thermodynamic properties in biomolecules. PMID- 26523623 TI - Visual Vignette. PMID- 26523624 TI - GLYCEMIC EFFECTS OF SGLT-2 INHIBITOR CANAGLIFLOZIN IN TYPE 1 DIABETES PATIENTS USING THE DEXCOM G4 PLATINUM CGM. AB - OBJECTIVE: Limited information is available on chronic use of sodium glucose cotransporter 2 inhibitors in type 1 diabetes (T1D). We conducted a retrospective review of T1D patients on Dexcom G4Platinum continuous glucose monitors (DCGMs) >1 year (mean, 4.6 years) who were prescribed canagliflozin (CANA) 100 mg daily and had a baseline DCGM 30-day download prior to and a second download after at least 1 month (mean, 3.7 months) taking CANA 100 mg daily. The glycemic, weight, and systolic blood pressure (SBP) effects are reported. METHODS: We identified 27 patients meeting the selection criteria: 14 men; 25 white; 22 on pump; average T1D duration, 34 years (range, 12 to 48 years); average hemoglobin A1C (A1C), 7.6% (range, 6.1 to 9.8%); 22 with baseline A1C 7.0% or higher. All patients had an estimated glomerular filtration rate (eGFR) at baseline of 60 mL/min/1.73 m(2) or higher and were normotensive or on stable therapy. On average, 29 days of CGM data was reviewed. Total daily insulin dose (TDD) was available in 21 patients. We identified 27 patients who were judged to be candidates for CANA but did not have any change in glycemic therapy other than insulin adjustment as controls. RESULTS: CANA resulted in significant reductions in mean blood glucose, CGM standard deviation, time in hyperglycemia, A1C, weight, SBP, and TDD, with increased time in target, with minimal increase in hypoglycemia and no significant change in eGFR. Three females developed genital mycotic infections but continued therapy, 2 developed ketoacidosis from insulin interruption. CONCLUSION: CANA offers promise as adjunct therapy in T1D, though caution is advised. PMID- 26523625 TI - CHARACTERISTICS AND OUTCOMES OF METASTATIC SDHB AND SPORADIC PHEOCHROMOCYTOMA/PARAGANGLIOMA: AN NATIONAL INSTITUTES OF HEALTH STUDY. AB - OBJECTIVE: Overall about 10 to 20% of pheochromocytomas/paragangliomas (PHEOs/PGLs) are metastatic, with higher metastatic potential observed in succinate dehydrogenase subunit B/fumarate hydratase (SDHB/FH)-related tumors. Due to the improved availability of biochemical and genetic testing and the frequent use of anatomical/functional imaging, there is currently a higher detection rate of metastatic PHEO/PGL. METHODS: A retrospective analysis of 132 patients (27 children, 105 adults) with metastatic PHEO/PGL diagnosed and treated from 2000 to 2014 was conducted. RESULTS: Seventy-seven (58%) males and 55 (42%) females were included; 39 (30%) have died, with no sex preference. Seventy-three (55%) patients had SDHB mutations; 59 (45%) patients had apparently sporadic tumors (AST). SDHB patients had an average age at primary tumor diagnosis of 31 +/- 16 years compared to 40 +/- 15 years in AST patients (P<.001). The average metastatic interval (MI) decreased with increasing age in both SDHB and AST patients (P = .013 for both). Only 16% of all primary tumors were smaller than 4.5 cm. Eleven percent of patients had biochemically silent disease, more with SDHB. Of SDHB patients, 23% had metastatic tumors at first diagnosis, compared to 15% of AST patients. Five- and 10-year survival rates were significantly better for metastatic AST than SDHB patients (P = .01). Overall survival was significantly different between children and adults (P = .037); this was mostly attributed to the SDHB patients, in whom children had statistically significantly longer survival than adults (P = .006). The deceased patients all died due to the PHEO/PGL and mainly had noradrenergic phenotypes. CONCLUSION: In children, metastatic PHEOs/PGLs are mainly due to SDHB mutations; in adults they are equally distributed between in SDHB mutations and AST, with better 5- and 10-year survival rates for ASTs. In SDHB patients, children survive longer than adults. Primary metastatic tumors, most presenting as noradrenergic PGLs, are larger than 4.5 cm in >80% of patients. The frequency of metastatic tumors from primary AST increases with age, including a decreased MI compared to SDHB tumors. These results support several recommendations that are summarized in the Discussion. PMID- 26523626 TI - VITAMIN D DEFICIENCY DOES NOT AFFECT THE LIKELIHOOD OF PRESURGICAL LOCALIZATION IN ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISM. AB - OBJECTIVE: Vitamin D deficiency (VDD) was previously associated with larger adenoma size in primary hyperparathyroidism (PHPT), but this topic was not addressed in patients with the mild/asymptomatic form of the disease (aPHPT). METHODS: We retrospectively retrieved from our series of patients affected by PHPT, 96 consecutive subjects with aPHPT in whom 25-hydroxyvitamin D (25OHD) levels had been assayed and compared those results with localizing imaging studies. RESULTS: Twenty-five of 96 patients had VDD (25OHD <20 ng/mL), but positive ultrasound and scintigraphic studies were not different between patients with and without VDD (52.3% versus 55.7% and 42.9% versus 52.4%, respectively). Upon logistic regression analysis, after adjusting for different variables, including the presence of goiter, VDD was not an independent predictor of localization by imaging studies. CONCLUSION: VDD does not affect the likelihood of positive pre-operative imaging in aPHPT and the consequent surgical decisions. PMID- 26523627 TI - AMH MEASUREMENT VERSUS OVARIAN ULTRASOUND IN THE DIAGNOSIS OF POLYCYSTIC OVARY SYNDROME IN DIFFERENT PHENOTYPES. AB - OBJECTIVE: This study was designed to assess the value of serum anti-Mullerian hormone (AMH) in the diagnosis of polycystic ovary syndrome (PCOS) in various phenotypes and to assess ovarian ultrasound parameters. METHODS: We performed a retrospective matched controlled study of 113 females with various PCOS phenotypes and 47 matched controls. The diagnostic utility of AMH measurement and ovarian ultrasound were compared. Using receiver operating characteristic (ROC) curve analyses, the threshold for AMH (>4.7 ng/mL) and ultrasound parameters (follicle number per ovary [FNPO] >22 and ovarian volume [OV] >8 cc) were established. RESULTS: In the entire cohort, AMH had a low sensitivity of 79%; while FNPO and OV were 93% and 68%, respectively. Specificities ranged from 85 to 96%. In classic anovulatory PCOS, AMH exhibited a sensitivity of 91%, and for FNPO and OV the corresponding sensitivities were 92% and 72%. In the ovulatory phenotype, AMH sensitivity was only 50%, while FNPO and OV were 95% and 50%, respectively. In the nonhyperandrogenic phenotype, the sensitivity of AMH was 53% while those for FNPO and OV were 93% and 67%. CONCLUSION: AMH does not appear to be helpful for all subjects with PCOS but may be of some value in those who are anovulatory. However, FNPO was highly sensitive in all phenotypes, and was the single best criterion assessed for all subjects, suggesting the important role of ultrasound. PMID- 26523628 TI - PRIMARY HYPERPARATHYROIDISM, WITH A FOCUS ON MANAGEMENT OF THE NORMOCALCEMIC FORM: TO TREAT OR NOT TO TREAT? AB - OBJECTIVE: The aim of this study was to determine reasonable care for normocalcemic primary hyperparathyroidism (NCPHPT) patients treated at the endocrine clinic. METHODS: The study is based on 218 outpatient cases of primary hyperparathyroidism (PHPT), 187 (86%) of whom were NCPHPT. Subjective complaints, biochemical tests, imaging, and treatment outcome for NCPHPT patients were monitored and compared with the same parameters in patients with hypercalcemic hyperparathyroidism. The number of patients with newly diagnosed NCPHPT who became hypercalcemic and the time period in which it happened were also recorded. RESULTS: Over 6 years of study, in total, 36 of 187 originally normocalcemic patients became hypercalcemic (19%); 24 of 36 within 2 years and 2 of 36 later than after 4 years. Sestamibi scintigraphy was performed in 103 normocalcemic patients (adenoma was detected in 5 cases) and in 46 hypercalcemic patients with pathologically elevated serum calcium levels at the time of assessment (adenoma was detected in 32 of 46 cases). Surgery was performed in 33 patients, 11 of whom were originally normocalcemic (i.e., 6% of all 187 originally normocalcemic patients), and 22 were hypercalcemic from the outset (i.e., 71% of all 31 originally hypercalcemic patients). CONCLUSION: Some NCPHPT patients converted to hypercalcemic, mostly within 2 years, but some after 4 years or later. Normocalcemic patients should be monitored on a long-term basis, as it is impossible to anticipate when and which normocalcemic patients will become hypercalcemic. Imaging is much less effective in normocalcemic than in hypercalcemic patients. PMID- 26523629 TI - Visual Vignette. PMID- 26523631 TI - Correction to Enzyme-Powered Hollow Mesoporous Janus Nanomotors. PMID- 26523630 TI - The influence of soccer match play on physiological and physical performance measures in soccer referees and assistant referees. AB - The aim of this study was to quantify the acute impact of soccer match officiating on selected physiological and physical performance measures. Twenty four officials from the Spanish National 3rd Division participated in this study. External global positioning system and internal (heart rate) load data were collected for each match official during 8 official matches. Pre- and post matches, the referees were assessed for tympanic temperature, blood lactate, 15- and 30-m sprint speeds and unilateral (dominant and non-dominant legs) and bilateral vertical jump performances. For referees, the acute physiological and physical performance effects of officiating (post-match value minus pre-match value) were large increases in blood lactate (1.7 mmol . l(-1); +/-90% confidence limit, 0.9 mmol . l(-1); effect size, ES = 4.35), small increases in 15-m sprint (0.09; +/-0.04 s; ES = 0.53) and 30-m sprint speeds (0.14; +/-0.08 s; ES = 0.39) and a small increase in non-dominant leg jump performance (2.1; +/-1.4 cm; ES = 0.31). For assistant referees, there was a small decrease in tympanic temperature (-0.3 degrees C; +/-0.2 degrees C; ES = -0.65) and small increases in blood lactate (0.4; +/-0.3 mmol . l(-1); ES = 0.66), 15-m sprint speed (0.06; +/-0.04 s; ES = 0.47), 30-m sprint speed (0.11; +/-0.16 s; ES = 0.49) and bilateral countermovement jump height (3.4; +/-1.5 cm; ES = 0.45). Taken together, these data demonstrate that the physical demands of soccer officiating are sufficient to elicit increases in blood lactate and small decrements in sprint performance and, thereby, provide some evidence for match-related fatigue. PMID- 26523632 TI - Noncovalent PEGylation, An Innovative Subchapter in the Field of Protein Modification. AB - Attachment of a chain of poly(ethylene glycol) (PEG) to a therapeutic protein, a process widely known as PEGylation, can lead to several beneficial effects. It has the potential to significantly delay aggregation of the protein by steric shielding, a frequently encountered issue in the development of protein drugs. Moreover, it can modify the pharmacokinetic profile of the PEGylated protein by delaying renal excretion, leading to a longer half-life (t1/2) of the drug. By steric hindrance, it can also inhibit interactions between the protein drug and proteases as well as the host immune system, thereby inhibiting inactivation of the PEGylated protein and also attenuating its immunogenicity. Unfortunately, the effect of steric hindrance also applies to protein drug-target interaction, leading to a (partial) loss of efficacy. In order to avoid this undesirable effect, several efforts have been made to link PEG to a protein in a noncovalent way, providing the protein with several of the beneficial effects of PEGylation while also taking advantage of its native affinity to its target. PMID- 26523633 TI - Whole genome sequence to decipher the resistome of Shewanella algae, a multidrug resistant bacterium responsible for pneumonia, Marseille, France. AB - We characterize and decipher the resistome and the virulence factors of Shewanella algae MARS 14, a multidrug-resistant clinical strain using the whole genome sequencing (WGS) strategy. The bacteria were isolated from the bronchoalveolar lavage of a hospitalized patient in the Timone Hospital in Marseille, France who developed pneumonia after plunging into the Mediterranean Sea. RESULTS: The genome size of S. algae MARS 14 was 5,005,710 bp with 52.8% guanine cytosine content. The resistome includes members of class C and D beta lactamases and numerous multidrug-efflux pumps. We also found the presence of several hemolysins genes, a complete flagellum system gene cluster and genes responsible for biofilm formation. Moreover, we reported for the first time in a clinical strain of Shewanella spp. the presence of a bacteriocin (marinocin). CONCLUSION: The WGS analysis of this pathogen provides insight into its virulence factors and resistance to antibiotics. PMID- 26523634 TI - Medical Homes for Children With Special Health Care Needs: Primary Care or Subspecialty Service? AB - OBJECTIVE: To examine primary care pediatricians' (PCPs) beliefs about whether the family-centered medical home (FCMH) should be in primary or subspecialty care for children with different degrees of complexity; and to examine practice characteristics associated with these beliefs. METHODS: Data from the American Academy of Pediatrics Periodic Survey (PS 79) conducted in 2012 were analyzed. Outcomes were agreement/strong agreement that 1) primary care should be the FCMH locus for most children with special health care needs (CSHCN) and 2) subspecialty care is the best FCMH locus for children with rare or complex conditions. In multivariate models, we tested associations between outcomes and practice barriers (eg, work culture, time, cost) and facilitators (eg, having a care coordinator) to FCMH implementation. RESULTS: Among 572 PCPs, 65% agreed/strongly agreed primary care is the best FCMH setting for most CSHCN, and 43% agreed/strongly agreed subspecialty care is the best setting for children with complexity. Cost and time as barriers to FCMH implementation were oppositely associated with the belief that primary care was best for most CSHCN (cost: adjusted odds ratio [AOR] 2.31, 1.36-3.90; time: AOR 0.48, 0.29-0.81). Lack of skills to communicate and coordinate care was associated with the belief that specialty care was the best FCMH for children with complexity (AOR 1.99, 1.05 3.79). CONCLUSIONS: A substantial minority endorsed specialty care as the best FCMH locus for children with medical complexity. Several barriers were associated with believing primary care to be the best FCMH for most CSHCN. Addressing medical complexity in FCMH implementation may enhance perceived value by pediatricians. PMID- 26523635 TI - Prediction of Persistent Postconcussion Symptoms in Youth Using a Neuroimaging Decision Rule. AB - OBJECTIVE: To evaluate the ability of risk strata generated by a neuroimaging rule, developed to assess risk of clinically important traumatic brain injury (ciTBI), to predict postconcussive symptoms in youth with an acute mild traumatic brain injury. METHODS: We performed a prospective cohort study of youth aged 5 to 17 years presenting to an emergency department (ED) within 24 hours of mild traumatic brain injury. Risk strata (very low, intermediate, and at risk) of ciTBI were determined in ED by criteria set forth by the neuroimaging rule. Postconcussive symptoms were assessed using the Health and Behavior Inventory (HBI) in the ED and at 1, 2, and 4 weeks after injury. General linear models were used to examine the relationship between the HBI score at 1 week and risk strata. Repeated measures analysis was used to measure change in HBI over time. RESULTS: Of the 120 participants, 46 were categorized by the Pediatric Emergency Care Applied Research Network (PECARN) rule as very low risk, 39 as intermediate risk, and 35 as at risk for ciTBI. Adjusted mean HBI scores (95% confidence intervals) at 1 week were 18.0 (13.9, 22.2) for at risk, 13.8 (9.9, 17.6) for intermediate risk, and 17.1 (13.4, 20.8) for very low risk. Risk strata were not significantly associated with the adjusted HBI score at 1 week (P = .17). While adjusted HBI scores declined significantly over time (P < .0001), the trajectories of the HBI score over time did not differ significantly by risk strata (P = .68). CONCLUSIONS: Risk of ciTBI as determined by factors within a neuroimaging rule alone is insufficient to predict children with persistent postconcussive symptoms. PMID- 26523636 TI - How Accountable Care Organizations Responded to Pediatric Incentives in the Alternative Quality Contract. AB - OBJECTIVE: From 2009 to 2010, 12 accountable care organizations (ACOs) entered into the alternative quality contract (AQC), BlueCross BlueShield of Massachusetts's global payment arrangement. The AQC included 6 outpatient pediatric quality measures among 64 total measures tied to pay-for-performance bonuses and incorporated pediatric populations in their global budgets. We characterized the pediatric infrastructure of these adult-oriented ACOs and obtained leaders' perspectives on their ACOs' response to pediatric incentives. METHODS: We used Massachusetts Health Quality Partners and American Hospital Association Survey data to characterize ACOs' pediatric infrastructure as extremely limited, basic, and substantial on the basis of the extent of pediatric primary care, outpatient specialist, and inpatient services. After ACOs had 16 to 43 months of experience with the AQC, we interviewed 22 leaders to gain insight into how organizations made changes to improve pediatric care quality, tried to reduce pediatric spending, and addressed care for children with special health care needs. RESULTS: ACOs' pediatric infrastructure ranged from extremely limited (eg, no general pediatricians in their primary care workforce) to substantial (eg, 42% of workforce was general pediatricians). Most leaders reported intensifying their pediatric quality improvement efforts and witnessing changes in quality metrics; most also investigated pediatric spending patterns but struggled to change patients' utilization patterns. All reported that the AQC did little to incentivize care for children with special health care needs and that future incentive programs should include this population. CONCLUSIONS: Although ACOs involved in the AQC were adult-oriented, most augmented their pediatric quality improvement and spending reduction efforts when faced with pediatric incentives. PMID- 26523637 TI - Growth and differentiation factor 11 (GDF11): Functions in the regulation of erythropoiesis and cardiac regeneration. AB - Members of the TGF-beta superfamily transduce their signals through type I and II receptor serine/threonine kinases. The regulation of members of the TGF-beta family is known to be complex, because many proteins able to bind the ligands and inhibit their activities have been identified. Growth and differentiation factor 11 (Gdf11) as activins belong to the TGF-beta family. GDF11, like other members of the TGF-beta superfamily, is produced from precursor proteins by proteolytic processing. The binding of activins to activin type IIA (ActRIIA) or type IIB (ActRIIB) receptors induces the recruitment and phosphorylation of an activin type I receptor which then phosphorylates the Smad2 and Smad3 intracellular signaling proteins. GDF11 signal through the ActRIIB pathway. Recent studies have reported that GDF11-ActRIIB-Smad2/3-dependent signaling is a key regulatory mechanism in proliferating erythroid precursors as it controls their late-stage maturation. The administration of GDF11 is effective in experimental cardiac hypertrophy, and the identification of GDF11 as a "rejuvenating factor" opens up perspectives for the treatment of age-related cardiac dysfunction. Recent studies of the heart indicate that exposure to young blood reverses age-related impairments. GDF11 could be one of the circulating molecules that influence the aging of different tissues. Is GDF11 an "elixir of youth"? PMID- 26523638 TI - Use of string test and stool specimens to diagnose pulmonary tuberculosis. AB - BACKGROUND: The Xpert MTB/RIF (MTB/RIF) test has advanced the field of tuberculosis (TB) diagnostics; however, depending on age and HIV status, 10-85% of individuals with presumed pulmonary TB (PTB) are unable to produce sputum. METHODS: The feasibility of using MTB/RIF and culture on stool and string test specimens from 13 adult patients with presumed PTB was studied. RESULTS: The string test was well tolerated with a median Wong Baker Faces score of 2. The string test had 100% sensitivity and specificity by MTB/RIF and 87.5% sensitivity and 100% specificity by culture. In stool, Mycobacterium tuberculosis DNA was detected in all cases of culture-confirmed PTB. CONCLUSION: The string test and stool provide diagnostic specimens that warrant further investigation. PMID- 26523639 TI - Hepatitis B surface antigen quantification at hepatitis B e antigen seroconversion predicts virological relapse after the cessation of entecavir treatment in hepatitis B e antigen-positive patients. AB - OBJECTIVES: To assess off-treatment virological relapse rates and to determine the role of hepatitis B surface antigen (HBsAg) quantification in predicting virological relapse after stopping entecavir (ETV) treatment in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). METHODS: One hundred and twelve CHB patients for whom ETV was stopped in accordance with the Asian Pacific Association for the Study of the Liver guidelines stopping rules were enrolled. Patient HBsAg and HBV DNA levels were monitored every 4-12 weeks during ETV treatment and after ETV cessation. Post-treatment virological relapse was defined as a serum HBV DNA level of >10 000 copies/ml after stopping ETV treatment. RESULTS: The virological relapse rate at 52 weeks after stopping ETV was 48.2%. The post-treatment virological relapse rate was significantly higher in patients aged >50 years than in those aged <50 years (p < 0.001), and the virological relapse rate was significantly lower in patients with an HBsAg level <2.0 log10 IU /ml than in those with a level >= 2.0 log10 IU /ml at ETV cessation (p = 0.005). An HBsAg level of 2.5 log10 IU/ml at HBeAg seroconversion was the optimal cut-off value for predicting post-treatment virological relapse (p < 0.001). In those aged <50 years and with HBsAg <= 2.5 log10 IU/ml at HBeAg seroconversion, the relapse rate was only 5%. In patients with HBsAg <= 2.5 log10 IU/ml at HBeAg seroconversion, 52.4% achieved HBsAg levels <= 2.0 log10 IU/ml at ETV cessation, while in those with HBsAg >2.5 log10 IU/ml at HBeAg seroconversion, only 4.4% achieved this criterion. CONCLUSIONS: HBsAg levels can help guide the timing of cessation of ETV treatment. HBsAg levels of 2.5 log10 IU/ml at HBeAg seroconversion may be a useful marker to predict virological relapse after the cessation of ETV treatment in HBeAg-positive CHB patients. PMID- 26523640 TI - Age and Ebola viral load correlate with mortality and survival time in 288 Ebola virus disease patients. AB - BACKGROUND: A Chinese medical team managed Ebola virus disease (EVD) patients in Sierra Leone from October 2014 to March 2015 and attended to 693 suspected patients, of whom 288 had confirmed disease. METHODS: A retrospective study was conducted of the 288 patients with confirmed disease. Clinical symptoms, manifestations, and serum viral load were analyzed and compared among the different groups for mortality and survival time. RESULTS: Among the 288 confirmed EVD patients (149 male and 139 female, median age 28 years, and median log viral load 6.68), 98 died, 36 recovered, and 154 were lost to follow-up. Common symptoms were fever (77.78%), fatigue (64.93%), abdominal pain (64.58%), headache (62.85%), and diarrhea (61.81%). Compared to patients aged<18 years, those who were older than 40 years had a higher probability of death (odds ratio 2.855, p=0.044). Patients with a viral load of >10(6) copies/ml had a higher case fatality rate than those with <10(6) copies/ml (odds ratio 3.095, p=0.004). Cox regression showed that age, viral load, and the presence of diarrhea correlated with mortality. CONCLUSION: Patients with a high viral load, of older age, and with diarrhea had a higher mortality and shorter survival time. PMID- 26523641 TI - Detection of Bordetella pertussis using a PCR test in infants younger than one year old hospitalized with whooping cough in five Peruvian hospitals. AB - OBJECTIVES: To report the incidence, epidemiology, and clinical features of Bordetella pertussis in Peruvian infants under 1 year old. PATIENTS AND METHODS: A prospective cross-sectional study was conducted in five hospitals in Peru from January 2010 to July 2012. A total of 392 infants under 1 year old were admitted with a clinical diagnosis of whooping cough and tested for B. pertussis by PCR. RESULTS: The pertussis toxin and IS481 genes were detected in 39.54% (155/392) of the cases. Infants aged less than 3 months were the most affected, with a prevalence of 73.55% (114/155). The most common household contact was the mother, identified in 20% (31/155) of cases. Paroxysm of coughing (89.03%, 138/155), cyanosis (68.39%, 106/155), respiratory distress (67.09%, 104/155), and breastfeeding difficulties (39.35%, 61/155) were the most frequent symptoms reported. CONCLUSION: An increase in pertussis cases has been reported in recent years in Peru, despite national immunization efforts. Surveillance with PCR for B. pertussis is essential, especially in infants less than 1 year old, in whom a higher rate of disease-related complications and higher mortality have been reported. PMID- 26523642 TI - Midbrain dopamine neurons bidirectionally regulate CA3-CA1 synaptic drive. AB - Dopamine (DA) is required for hippocampal-dependent memory and long-term potentiation (LTP) at CA1 Schaffer collateral (SC) synapses. It is therefore surprising that exogenously applied DA has little effect on SC synapses, but suppresses CA1 perforant path (PP) inputs. To examine DA actions under more physiological conditions, we used optogenetics to release DA from ventral tegmental area inputs to hippocampus. Unlike exogenous DA application, optogenetic release of DA caused a bidirectional, activity-dependent modulation of SC synapses, with no effect on PP inputs. Low levels of DA release, simulating tonic DA neuron firing, depressed the SC response through a D4 receptor-dependent enhancement of feedforward inhibition mediated by parvalbumin-expressing interneurons. Higher levels of DA release, simulating phasic firing, increased SC responses through a D1 receptor-dependent enhancement of excitatory transmission. Thus, tonic-phasic transitions in DA neuron firing in response to motivational demands may cause a modulatory switch from inhibition to enhancement of hippocampal information flow. PMID- 26523643 TI - Inferring learning rules from distributions of firing rates in cortical neurons. AB - Information about external stimuli is thought to be stored in cortical circuits through experience-dependent modifications of synaptic connectivity. These modifications of network connectivity should lead to changes in neuronal activity as a particular stimulus is repeatedly encountered. Here we ask what plasticity rules are consistent with the differences in the statistics of the visual response to novel and familiar stimuli in inferior temporal cortex, an area underlying visual object recognition. We introduce a method that allows one to infer the dependence of the presumptive learning rule on postsynaptic firing rate, and we show that the inferred learning rule exhibits depression for low postsynaptic rates and potentiation for high rates. The threshold separating depression from potentiation is strongly correlated with both mean and s.d. of the firing rate distribution. Finally, we show that network models implementing a rule extracted from data show stable learning dynamics and lead to sparser representations of stimuli. PMID- 26523644 TI - Neuronal activity is not required for the initial formation and maturation of visual selectivity. AB - Neuronal activity is important for the functional refinement of neuronal circuits in the early visual system. At the level of the cerebral cortex, however, it is still unknown whether the formation of fundamental functions such as orientation selectivity depends on neuronal activity, as it has been difficult to suppress activity throughout development. Using genetic silencing of cortical activity starting before the formation of orientation selectivity, we found that the orientation selectivity of neurons in the mouse visual cortex formed and matured normally despite a strong suppression of both spontaneous and visually evoked activity throughout development. After the orientation selectivity formed, the distribution of the preferred orientations of neurons was reorganized. We found that this process required spontaneous activity, but not visually evoked activity. Thus, the initial formation and maturation of orientation selectivity is largely independent of neuronal activity, and the initial selectivity is subsequently modified depending on neuronal activity. PMID- 26523645 TI - Latent tri-lineage potential of adult hippocampal neural stem cells revealed by Nf1 inactivation. AB - Endogenous neural stem cells (NSCs) in the adult hippocampus are considered to be bi-potent, as they only produce neurons and astrocytes in vivo. In mouse, we found that inactivation of neurofibromin 1 (Nf1), a gene mutated in neurofibromatosis type 1, unlocked a latent oligodendrocyte lineage potential to produce all three lineages from NSCs in vivo. Our results suggest an avenue for promoting stem cell plasticity by targeting barriers of latent lineage potential. PMID- 26523647 TI - Magnetic resonance imaging of mechanical deformations. AB - A method for magnetic resonance imaging of mechanical deformations is presented. The method utilizes an MRI compatible device for inducing elastic deformations of a sample and a modified spin-echo imaging sequence with two position-encoding gradients added to the sequence symmetrically to the RF refocusing pulse. At the end of the first position-encoding gradient pulse, a sample deformation was induced by the deformational device, which applied a force to a plastic rod embedded in a gelatin cylindrical sample. The sample had to withstand repeated elastic deformations. Sample displacements up to 400 MUm were encoded in the image signal phase by the use of position-encoding gradients. Images of different displacement components were acquired first by the use of position-encoding gradients in different directions and then processed by the 2D phase unwrap algorithm. Finally, images of normal and shear strain distribution were calculated from the displacement images. The obtained displacement and strain images enabled clear visualization of deformations and their extent in the sample with the displacement detection threshold in the range 0.3-0.6 MUm, depending on the image echo time. The results of displacements were verified also by a DANTE tagging method and by an optical method. The presented method enables studying of various types of deformations in different soft materials as well as dynamic response of deformations to different stress functions (static, oscillatory, pulsed...). PMID- 26523646 TI - Cell type- and brain region-resolved mouse brain proteome. AB - Brain transcriptome and connectome maps are being generated, but an equivalent effort on the proteome is currently lacking. We performed high-resolution mass spectrometry-based proteomics for in-depth analysis of the mouse brain and its major brain regions and cell types. Comparisons of the 12,934 identified proteins in oligodendrocytes, astrocytes, microglia and cortical neurons with deep sequencing data of the transcriptome indicated deep coverage of the proteome. Cell type-specific proteins defined as tenfold more abundant than average expression represented about a tenth of the proteome, with an overrepresentation of cell surface proteins. To demonstrate the utility of our resource, we focused on this class of proteins and identified Lsamp, an adhesion molecule of the IgLON family, as a negative regulator of myelination. Our findings provide a framework for a system-level understanding of cell-type diversity in the CNS and serves as a rich resource for analyses of brain development and function. PMID- 26523648 TI - Estimation of minimum miscibility pressure (MMP) of CO2 and liquid n-alkane systems using an improved MRI technique. AB - Minimum miscible pressure (MMP) of gas and oil system is a key parameter for the injection system design of CO2 miscible flooding. Some industrial standard approaches such as the experiment using a rising bubble apparatus (RBA), the slim tube tests (STT), the pressure-density diagram (PDD), etc. have been applied for decades to determine the MMP of gas and oil. Some theoretical or experiential calculations of the MMP were also applied to the gas-oil miscible system. In the present work, an improved technique based on our previous research for the estimation of the MMP by using magnetic resonance imaging (MRI) was proposed. This technique was then applied to the CO2 and n-alkane binary and ternary systems to observe the mixing procedure and to study the miscibility. MRI signal intensities, which represent the proton concentration of n-alkane in both the hydrocarbon rich phase and the CO2 rich phase, were plotted as a reference for determining the MMP. The accuracy of the MMP obtained by using this improved technique was enhanced comparing with the data obtained from our previous works. The results also show good agreement with other established techniques (such as the STT) in previous published works. It demonstrates increases of MMPs as the temperature rise from 20 degrees C to 37.8 degrees C. The MMPs of CO2 and n alkane systems are also found to be proportional to the carbon number in the range of C10 to C14. PMID- 26523649 TI - Improved receiver arrays and optimized parallel imaging accelerations applied to time-resolved 3D fluoroscopically tracked peripheral runoff CE-MRA. AB - OBJECTIVES: Three-station stepping-table time-resolved 3D contrast-enhanced magnetic resonance angiography has conflicting demands in the need to limit acquisition time in proximal stations to match the speed of the advancing contrast bolus and in the distal-most station to avoid venous contamination while still providing clinically useful spatial resolution. This work describes improved receiver coil arrays which address this issue by allowing increased acceleration factors, providing increased spatial resolution per unit time. MATERIALS AND METHODS: Receiver coil arrays were constructed for each station (pelvis, thigh, calf) and then integrated into a 48-element array for three station peripheral CE-MRA. Coil element sizes and array configurations for these three stations were designed to improve SENSE-type parallel imaging taking advantage of an increase in coil count for all stations versus the previous 32 channel capability. At each station either acceleration apportionment or optimal CAIPIRINHA selection was used to choose the optimum acceleration parameters for each subject. Results were evaluated in both single- and multi-station studies. RESULTS: Single-station studies showed that SENSE acceleration in the thigh station could be readily increased from R=8 to R=10, allowing reduction of the frame time from 2.5 to 2.1 s to better image the typically rapidly advancing bolus at this station. Similarly, the improved coil array for the calf station permitted acceleration increase from R=8 to R=12, providing a 4.0 vs. 5.2 s frame time. Results in three-station studies suggest an improved ability to track the contrast bolus in peripheral CE-MRA. CONCLUSIONS: Modified receiver coil arrays and individualized parameter optimization have been used to provide improved acceleration at all stations in multi-station peripheral CE-MRA and provide high spatial resolution with frame times as short as 2.1 s. PMID- 26523650 TI - Arterial input functions (AIFs) measured directly from arteries with low and standard doses of contrast agent, and AIFs derived from reference tissues. AB - Measurements of arterial input function (AIF) can have large systematic errors at standard contrast agent doses in dynamic contrast enhanced MRI (DCE-MRI). We compared measured AIFs from low dose (AIFLD) and standard dose (AIFSD) contrast agent injections, as well as the AIF derived from a muscle reference tissue and artery (AIFref). Twenty-two prostate cancer patients underwent DCE-MRI. Data were acquired on a 3T scanner using an mDixon sequence. Gadobenate dimeglumine was injected twice, at doses of 0.015 and 0.085 mmol/kg. Directly measured AIFs were fitted with empirical mathematical models (EMMs) and compared to the AIF derived from a muscle reference tissue (AIFref). EMMs accurately fitted the AIFs. The 1st and 2nd pass peaks were visualized in AIFLD, but not in AIFSD, thus the peak and shape of AIFSD could not be accurately measured directly. The average scaling factor between AIFSD and AIFLD in the washout phase was only 56% of the contrast dose ratio (~6:1). The shape and magnitude of AIFref closely approximated that of AIFLD after empirically determined dose-dependent normalization. This suggests that AIFref may be a good approximation of the local AIF. PMID- 26523651 TI - Gender, BMI and T2 dependencies of glycosaminoglycan chemical exchange saturation transfer in intervertebral discs. AB - PURPOSE: The purpose was to investigate the dependence of glycosaminoglycan chemical exchange saturation transfer (gagCEST) effect of lumbar intervertebral discs (IVD) on gender, body mass index and T2 value. METHODS: T2 imaging and gagCEST imaging was performed in 34 healthy volunteers (17 males, 17 females) without low back pain at a 3T MRI system (Magnetom Trio, A Tim System, Siemens Healthcare, Erlangen, Germany). The body mass index was determined for each volunteer. The mean and standard deviation of MTRasym and T2 values were calculated for nucleus pulposus (NP) and annulus fibrosus (AF) as descriptive statistics for females and males. An unpaired student's t-test was applied in order to validate obtained differences. Pearson correlation was determined in order to reveal, if gagCEST effect and T2 values decrease with increasing body mass index (BMI). Pearson correlation analysis was additionally performed between gagCEST and T2 values. RESULTS: GagCEST effect and T2 values were significantly higher in females compared to males [gagCEST effect (nucleus pulposus, females)=3.58+/-1.49%; gagCEST effect (nucleus pulosus, males)=3.01+/-1.63%, p value (gagCEST effect, nucleus pulposus)=0.02); T2 (nucleus pulposus, females)=134.56+/-30.27 ms, T2 (nucleus pulposus, males)=122.35+/-27.64 ms, p value (T2, nucleus pulposus)=0.01)]. Pearson correlation analysis showed a significant negative relation between BMI and gagCEST effect (nucleus pulposus: rho=-0.16, p=0.03) and between BMI and T2 values (nucleus pulposus: rho=-0.30, p<0.01). The correlation between gagCEST effect and T2-values was highly significant (nucleus pulposus: rho=0.59, p<0.01). CONCLUSIONS: Significantly lower gagCEST effects were found in males compared to females and with increased body mass index. The gagCEST effect was highly correlated with quantitative T2 imaging. PMID- 26523652 TI - Noninvasive biomarkers for acute hepatotoxicity induced by 1,3-dichloro-2 propanol: hyperpolarized 13C dynamic MR spectroscopy. AB - The purpose of this study was to investigate the cellular metabolite change for acute hepatotoxicity induced by 1,3-dichloro-2-propanol (1,3-DCP) in rats and its correlations with the enzyme levels. In order to induce acute hepatotoxicity, a single subcutaneous injection of 1,3-DCP (80 mg/kg) was given to six male Sprague Dawley rats. Hyperpolarized (13)C dynamic magnetic resonance spectroscopy (MRS) was performed on rat liver following injection of hyperpolarized [1-(13)C] pyruvate. The levels of serum aspartate am inotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) in the 1,3-DCP treated rats were significantly increased as compared with those in normal rats. In the dynamic (13)C MR spectra, the ratios of [1-(13)C] lactate to the total carbon and [1-(13)C] alanine to the total carbon in the 1,3-DCP treated rats were significantly increased, and there were positive correlations between cellular metabolic changes and enzyme levels. The levels of [1-(13)C] lactate and [1 (13)C] alanine are potentially considered as important biomarkers for the 1,3-DCP induced acute hepatotoxicity. PMID- 26523653 TI - Intramyocellular lipid content in subjects with impaired fasting glucose after telmisartan treatment, a randomised cross-over trial. AB - Ectopic lipid accumulation in skeletal muscle is associated with insulin resistance. Telmisartan improves metabolic parameters in type 2 diabetic patients. The aim of our study was to evaluate the in vivo effect of telmisartan on intramyocellular lipid content (IMCL) in subjects with impaired fasting glucose (IFG) by magnetic resonance spectroscopy (MRS). We enrolled 10 subjects with IFG in a cross-over, placebo-controlled, randomized, double-blind trial, treated with 3 weeks of telmisartan (160 mg daily) or placebo. After completing each treatment, a hyperinsulinaemic euglycaemic clamp (1 mU/kg per min; 5 mmol/l; 120 min) to assess insulin action (metabolic clearance rate of glucose, MCR) and (1)H MRS of the m. tibialis anterior using a MR Scanner Siemens Vision operating at 1.5 T to evaluate IMCL content, were performed. Plasma adipokine levels were determined simultaneously. Telmisartan treatment resulted in a lower fasting plasma glucose (FPG) (p < 0.05), but insulin action was comparable to after placebo. Telmisartan did not affect IMCL content. After placebo, IMCL correlated negatively with total cholesterol (p < 0.001), MCR (p < 0.05) and adiponectin (p < 0.05) and positively with FPG (p < 0.05). After telmisartan treatment there was only a positive correlation between IMCL and TNFalpha (p < 0.05). IMCL content is related to parameters of glucose metabolism and insulin action in sedentary IFG subjects. A short telmisartan treatment did not affect the IMCL content despite its positive effect on FPG. The improvement in FPG was probably mediated through interference with other metabolic pathways. PMID- 26523654 TI - Prediction of low-risk breast cancer using perfusion parameters and apparent diffusion coefficient. AB - PURPOSE: To assess whether perfusion and diffusion parameters were different between low-risk tumors and non-low-risk tumors. MATERIALS AND METHODS: We prospectively enrolled 87 patients with 91 tumors patients (mean, 49.6 years; range, 29-74 years) who underwent definitive surgery. We defined estrogen receptor (ER)-positive tumors with low histologic grade (HG), low Ki67 (<14%), and negative lymph node metastasis as a low-risk breast cancer. We obtained quantitative and semiquantitative perfusion parameters and apparent diffusion coefficient (ADC) for all tumors. We compared perfusion parameters and ADCs between low-risk tumors (n=33; 36%) and the others (n=58; 64%) using Fisher's exact test, Chi-square test, and student t-test. We developed empirical model to predict low-risk tumor using logistic regression analysis and receiver operating characteristics (ROC) analysis. RESULTS: On univariate analysis, wash-in and the initial area under the curve on qualitative analysis (iAUCqualitative) were significantly different according to HG, ER, HER-2, Ki67 and lymphovascular invasion (P<.05 for all variables). ADCdiff was significantly different according to HG, HER-2, and Ki67 status (P=.010, .007, and .013). On multivariate analysis, Ktrans, iAUCqualitative, and ADCdiff were the significant variables for the prediction of low-risk tumors, and the area under the ROC curve (AUC) of combined parameters was 0.78, which was higher than those of the individual parameter. ADCdiff was positively correlated with wash-in (r=0.263) and iAUCqualitative (r=0.245), respectively. CONCLUSION: The prediction model using Ktrans, wash in, iAUCqualitative, and ADCdiff on DCE-MRI and DWI could be helpful for identifying of low-risk breast cancer and may be used as an imaging biomarker to guide the treatment plan. PMID- 26523655 TI - A human brain atlas derived via n-cut parcellation of resting-state and task based fMRI data. AB - The growth of functional MRI has led to development of human brain atlases derived by parcellating resting-state connectivity patterns into functionally independent regions of interest (ROIs). All functional atlases to date have been derived from resting-state fMRI data. But given that functional connectivity between regions varies with task, we hypothesized that an atlas incorporating both resting-state and task-based fMRI data would produce an atlas with finer characterization of task-relevant regions than an atlas derived from resting state alone. To test this hypothesis, we derived parcellation atlases from twenty nine healthy adult participants enrolled in the Cognitive Connectome project, an initiative to improve functional MRI's translation into clinical decision-making by mapping normative variance in brain-behavior relationships. Participants underwent resting-state and task-based fMRI spanning nine cognitive domains: motor, visuospatial, attention, language, memory, affective processing, decision making, working memory, and executive function. Spatially constrained n-cut parcellation derived brain atlases using (1) all participants' functional data (Task) or (2) a single resting-state scan (Rest). An atlas was also derived from random parcellation for comparison purposes (Random). Two methods were compared: (1) a parcellation applied to the group's mean edge weights (mean), and (2) a two stage approach with parcellation of individual edge weights followed by parcellation of mean binarized edges (two-stage). The resulting Task and Rest atlases had significantly greater similarity with each other (mean Jaccard indices JI=0.72-0.85) than with the Random atlases (JI=0.59-0.63; all p<0.001 after Bonferroni correction). Task and Rest atlas similarity was greatest for the two-stage method (JI=0.85), which has been shown as more robust than the mean method; these atlases also better reproduced voxelwise seed maps of the left dorsolateral prefrontal cortex during rest and performing the n-back working memory task (r=0.75-0.80) than the Random atlases (r=0.64-0.72), further validating their utility. We expected regions governing higher-order cognition (such as frontal and anterior temporal lobes) to show greatest difference between Task and Rest atlases; contrary to expectations, these areas had greatest similarity between atlases. Our findings indicate that atlases derived from parcellation of task-based and resting-state fMRI data are highly comparable, and existing resting-state atlases are suitable for task-based analyses. We introduce an anatomically labeled fMRI-derived whole-brain human atlas for future Cognitive Connectome analyses. PMID- 26523656 TI - Synergistic role of simultaneous PET/MRI-MRS in soft tissue sarcoma metabolism imaging. AB - The primary objective of this study was to develop and validate simultaneous PET/MRI-MRS as a novel biological image-guided approach to neoadjuvant radiotherapy (RT) and/or chemoradiation (chemoRT) in soft tissue sarcomas (STS). A patient with sarcoma of the right thigh underwent PET/MRI scan before and after neoadjuvant (preoperative) radiotherapy. The magnetic resonance imaging (MRI) and 2-deoxy-2-[fluorine-18]-fluoro-D-glucose-Positron Emission Tomography ((18)F-FDG PET) scans were performed simultaneously. In the post-radiation scan, magnetic resonance spectroscopy (MRS) was subsequently acquired with volume of interest positioned in a residual hyper-metabolic region detected by PET. Post-radiation PET/MRI showed a residual T2-hyperintense mass with significantly reduced (18)F FDG-uptake, compatible with near complete response to radiotherapy. However, a small region of residual high (18)F-FDG uptake was detected at the tumor margin. MRS of this region had similar metabolite profile as normal tissue, and was thus considered false positive on PET scan. Pathology results were obtained after surgery for confirmation of imaging findings. PMID- 26523657 TI - Evaluating muscles underlying tongue base retraction in deglutition using muscular functional magnetic resonance imaging (mfMRI). AB - PURPOSE: Tongue base retraction during swallowing is critical to bolus propulsion in normal physiological swallowing. A better understanding of the hyoglossus and styloglossus, muscles thought to be key to tongue base retraction, will improve the quality of physical rehabilitation in dysphagic patients in addition to preventing iatrogenic damage to structures critical to deglutition. This study utilized muscle functional MRI in healthy adult human subjects in order to determine if the hyoglossus and styloglossus are active during swallowing. METHODS AND MATERIALS: Data were collected for 11 subjects with mfMRI before and after swallowing, and after performing the Mendelsohn maneuver. Whole muscle relaxation time profiles (T2 signal in milliseconds) were calculated from weighted averages of multiple dual echo MRI slices, allowing for comparison of physiological response for the muscles in each test condition. Changes in effect size (Cohen's d) of whole muscle T2 profiles were used to establish whether or not the hyoglossus and styloglossus are utilized during swallowing and during the Mendelsohn maneuver. RESULTS: Post-swallowing effect size changes (where a d value of >0.20 indicates significant activity) for the T2 signal profiles of the hyoglossus and styloglossus were found to be d=1.19 and 0.22, respectively. The hyoglossus showed an effect size change of d=0.26 for the Mendelsohn maneuver. CONCLUSIONS: Muscle functional MRI indicates a physiological response of the hyoglossus and styloglossus during swallowing, and the hyoglossus during the Mendelsohn maneuver. PMID- 26523658 TI - Assessment of brain cognitive functions in patients with vitamin B12 deficiency using resting state functional MRI: A longitudinal study. AB - INTRODUCTION: The resting state functional MRI (rsfMRI) approach is useful to explore the brain's functional organization in health and disease conditions. In this study, using rsfMRI the alteration in brain due to vitamin B12 deficiency and reversibility of these alterations following therapy was studied. METHODS: Thirteen patients with clinical and biochemical evidence of vitamin B12 deficiency were recruited in this study. Fifteen age and sex matched healthy controls were also included. Patients and controls were clinically evaluated using neuropsychological test (NPT). The analysis was carried out using regional homogeneity (ReHo) and low frequency oscillations (LFO) of BOLD signals in resting state. Six patients were also evaluated with rsfMRI and NPT after 6 weeks replacement therapy. RESULTS: ReHo values in patients with vitamin B12 deficiency were significantly lower than controls in the entire cerebrum and the brain networks associated with cognition control, i.e., default mode, cingulo-opercular and fronto-parietal network. There was no significant difference using LFO and it did not show significant correlations with NPT scores. ReHo showed significant correlation with NPT scores. All the 6 patients showed increase in ReHo after replacement therapy. CONCLUSION: We conclude that brain networks associated with cognition control are altered in patients with vitamin B12 deficiency, which partially recover following six weeks of replacement therapy. This is the first study to evaluate the rsfMRI in the light of clinical neuropsychological evaluation in patients. rsfMRI may be used as functional biomarker to assess therapeutic response in vitamin B12 deficiency patients. PMID- 26523659 TI - Mapping of global R1 and R2* values versus lipids R1 values as potential markers of hypoxia in human glial tumors: A feasibility study. AB - Availability of an innocuous and repeatable technique for monitoring tumor oxygenation throughout therapeutic course should be a key factor for adaptative therapeutic strategies. We previously qualified lipids R1 as a marker of oxygen level on experimental tumor models. The objectives of the present study were to assess the applicability of measuring lipids R1 in primary central nervous system malignancies in a clinical setting as well as to compare lipids R1 with global (water+lipids) R1 and R2* which are also sensitive to the oxygen environment. 25 patients with brain neuroepithelial tumors were examined on a clinical 3T MR system. Values obtained within regions of interest contouring contrast-enhanced tumor (C+), unenhanced tumor (C-), peritumoral edema, and normal appearing white matter (NAWM) were compared to those obtained for the normal brain parenchyma of 17 healthy volunteers. Global R1 and lipids R1 values were significantly lower in tumors than in NAWM of patients or healthy brain of normal volunteers. In contrast, R2* values were not significantly different in tumors compared to NAWM or healthy brains. None of them showed significant difference between C+ and C- tumors. Global R1 values within NAWM were significantly different from that of both tumor and peritumoral edema, but lacked sensitivity to differentiate between tumor and peritumoral edema. In turn, lipids R1 measurements enabled discrimination between tumor areas and peritumoral edema. In conclusion, global R1 and lipids R1 deserve further attention as potential markers of tumor hypoxia in primary brain tumors. PMID- 26523660 TI - Complete pathological response after chemo-radiation in anaplastic thyroid cancer: A report of two cases. PMID- 26523661 TI - Assessment of Muscle Pain Induced by Elbow-Flexor Eccentric Exercise. AB - CONTEXT: Delayed-onset muscle soreness (DOMS) is a common muscle pain that many people experience and is often used as a model of acute muscle pain. Researchers have reported the effects of various interventions on DOMS, but different DOMS assessment protocols used in these studies make it difficult to compare the effects. OBJECTIVE: To investigate DOMS characteristics after elbow-flexor eccentric exercise to establish a standardized DOMS assessment protocol. DESIGN: Descriptive laboratory study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Ten healthy, untrained men (21-39 years). INTERVENTION(S): Participants performed 10 sets of 6 maximal isokinetic eccentric contractions of the elbow flexors. MAIN OUTCOME MEASURE(S): Indirect muscle-damage markers were maximal voluntary isometric contraction torque, range of motion, and serum creatine kinase activity. Muscle pain was assessed before exercise, immediately postexercise, and 1 to 5 days postexercise using (1) a visual analog scale (VAS), (2) a category ratio-10 scale (CR-10) when applying static pressure and palpation at different sites (3, 9, and 15 cm above the elbow crease), and (3) pressure pain thresholds (PPTs) at 50 sites (pain mapping). RESULTS: Maximal voluntary isometric contraction and range of motion decreased and creatine kinase activity increased postexercise, indicating muscle damage. Palpation induced greater pain than static pressure, and longitudinal and transverse palpations induced greater pain than circular palpation (P < .05). The PPT was lower in the medial region before exercise, but the pain-sensitive regions shifted to the central and distal regions of the biceps brachii at 1 to 3 days postexercise (P < .05). The VAS was correlated with the CR-10 scale (r = 0.91, P < .05) but not with the PPT (r = 0.28, P = .45). CONCLUSIONS: The way in which muscles are assessed affects the pain level score. This finding suggests that pain level and pain threshold cannot be used interchangeably and that the central and distal regions of the biceps brachii should be included in DOMS assessment using the VAS, CR-10 scale, and PPT after elbow-flexor eccentric exercise. PMID- 26523662 TI - Incidence of Patients With Knee Strain and Sprain Occurring at Sports or Recreation Venues and Presenting to United States Emergency Departments. AB - CONTEXT: Knee injuries account for a substantial percentage of all athletic injuries. The relative rates of knee injury for a variety of sports by sex and age need to be understood so we can better allocate resources, such as athletic trainers, to properly assess and treat injuries and reduce injury risk. OBJECTIVE: To describe the epidemiology of patients with sport-related knee strain and sprain presenting to US emergency departments from 2002 to 2011. DESIGN: Cross-sectional study. SETTING: Using the Consumer Products Safety Commission's National Electronic Injury Surveillance System and the US Census Bureau, we extracted raw data to estimate national rates of patients with knee strain and sprain presenting to emergency departments. PATIENTS OR OTHER PARTICIPANTS: Participants were individuals sustaining a knee strain or sprain at sports or recreation venues and presenting to local emergency departments for treatment. We included 12 popular sports for males and 11 for females. Ages were categorized in six 5-year increments for ages 5 to 34 years and one 10-year increment for ages 35 to 44 years. MAIN OUTCOME MEASURE(S): Incidence rates were calculated using weights provided by the National Electronic Injury Surveillance System and reported with their 95% confidence intervals for sport, sex, and age. RESULTS: Strain and sprain injury rates varied greatly by sport, sex, and age group. The highest injury rates occurred in football and basketball for males and in soccer and basketball for females. The most at-risk population was 15 to 19 years for both sexes. CONCLUSIONS: Athletes experience different rates of knee strain and sprain according to sport, sex, and age. Increased employment of athletic trainers to care for the highest-risk populations, aged 10 to 19 years, is recommended to reduce emergency department use and implement injury-prevention practices. PMID- 26523663 TI - Landing Technique and Performance in Youth Athletes After a Single Injury Prevention Program Session. AB - CONTEXT: Injury-prevention programs (IPPs) performed as season-long warm-ups improve injury rates, performance outcomes, and jump-landing technique. However, concerns regarding program adoption exist. Identifying the acute benefits of using an IPP compared with other warm-ups may encourage IPP adoption. OBJECTIVE: To examine the immediate effects of 3 warm-up protocols (IPP, static warm-up [SWU], or dynamic warm-up [DWU]) on jump-landing technique and performance measures in youth athletes. DESIGN: Randomized controlled clinical trial. SETTING: Gymnasiums. PATIENTS OR OTHER PARTICIPANTS: Sixty male and 29 female athletes (age = 13 +/- 2 years, height = 162.8 +/- 12.6 cm, mass = 37.1 +/- 13.5 kg) volunteered to participate in a single session. INTERVENTION(S): Participants were stratified by age, sex, and sport and then were randomized into 1 protocol: IPP, SWU, or DWU. The IPP consisted of dynamic flexibility, strengthening, plyometric, and balance exercises and emphasized proper technique. The SWU consisted of jogging and lower extremity static stretching. The DWU consisted of dynamic lower extremity flexibility exercises. Participants were assessed for landing technique and performance measures immediately before (PRE) and after (POST) completing their warm-ups. MAIN OUTCOME MEASURE(S): One rater graded each jump-landing trial using the Landing Error Scoring System. Participants performed a vertical jump, long jump, shuttle run, and jump-landing task in randomized order. The averages of all jump-landing trials and performance variables were used to calculate 1 composite score for each variable at PRE and POST. Change scores were calculated (POST - PRE) for all measures. Separate 1-way (group) analyses of variance were conducted for each dependent variable (alpha < .05). RESULTS: No differences were observed among groups for any performance measures (P > .05). The Landing Error Scoring System scores improved after the IPP (change = -0.40 +/- 1.24 errors) compared with the DWU (0.27 +/- 1.09 errors) and SWU (0.43 +/- 1.35 errors; P = .04). CONCLUSIONS: An IPP did not impair sport performance and may have reduced injury risk, which supports the use of these programs before sport activity. PMID- 26523664 TI - Reduction of urinary uric acid excretion in patients with proteinuria. AB - Serum uric acid (UA) concentration is positively associated with proteinuria. However, the relationship between proteinuria and urinary metabolites of purine metabolism remains unknown. This study developed a hydrophilic interaction chromatography (HILIC)-based HPLC method with ultraviolet detection (UV) to quantify creatinine (Cr), UA, xanthine, and hypoxanthine in human urine simultaneously. The urinary concentrations of UA and Cr obtained by our method are consistent with those measured by an autoanalyzer. The HPLC-HILIC-UV method was validated as selective and robust with simple sample preparation for measuring UA, xanthine, hypoxanthine and Cr, which is suitable for large clinical studies. The UA/Cr ratios in random urine samples were 5.5 times lower in proteinuria patients (0.077+/-0.008) than in healthy individuals (0.424+/-0.037). Moreover, the UA/hypoxanthine ratio in proteinuria patients was approximately 10 times lower than that in healthy individuals. Our findings revealed a reduced urinary UA excretion, which is one of the factors leading to increased serum UA in proteinuria patients. PMID- 26523665 TI - Indirect chiral separation of tryptophan enantiomers by high performance liquid chromatography with indirect chemiluminiscence detection. AB - In recent years, the study of chiral compounds in vivo has received much attention. In this study, a novel method based on high performance liquid chromatography (HPLC) coupled with chemiluminescence (CL) detection was developed for the separation of tryptophan (Trp) enantiomers. o-Phthalaldehyde and N-acetyl l-cysteine were used as chiral derivatization reagents for Trp before it can be detected by HPLC-CL method. The separation was carried out on an ODS column using a mobile phase composed of methanol-0.01mol/L phosphate buffer (40/60, v/v). Under the optimum conditions, satisfactory results were obtained, including complete separation, good relative standard deviations and low detection limits. The applicability of the proposed method has been validated by determining Trp in biological samples. Linear responses (r>0.9990) were observed over the range of 2.5*10(-7) to 1.2*10(-5)g/mL of Trp enantiomers, with quantitation limit of 2.5*10(-7)g/mL. The assay method shows good specificity to Trp enantiomers, and thus it will have great potential application in clinical diagnosis. The mean extraction efficiency of Trp enantiomers in mice plasma samples were 98.48% and 97.40%, respectively. The mean relative standard deviation (RSD) of Trp enantiomers were <3%. PMID- 26523666 TI - Size-exclusion HPLC as a sensitive and calibrationless method for complex peptide mixtures quantification. AB - This work describes an original methodology to quantify complex peptide mixtures by size-exclusion high-performance liquid chromatography (SE-HPLC). The methodology was first tested on simulated elutions of peptide mixtures. For this set of experiments, a good estimation of the total peptide concentration was observed (error less than 10 %). Then 30 fractions obtained by ultrafiltration of hydrolysates from two different sources were titrated by Kjeldahl or BCA analysis and analysed by SE-HPLC for an experimental validation of the methodology. Very good matchs between methods were obtained. The linear working range depends on the hydrolysate but is generally between 0.2 and 4gL(-1) (i.e. between 10 and 200MUg). Moreover, the presence of organic solvents or salts in samples does not impact the accuracy of the methodology contrary to common quantification methods. Hence, the findings of this study show that total concentration of complex peptide mixture can be efficiently determinate by the proposed methodology using simple SE-HPLC analysis. PMID- 26523667 TI - Synthesis and biological evaluation of methylated scutellarein analogs based on metabolic mechanism of scutellarin in vivo. AB - Scutellarin (1) could be hydrolyzed into scutellarein (2) in vivo and then converted into methylated, sulfated and glucuronidated forms. In order to investigate the biological activities of these methylated metabolites, eight methylated analogs of scutellarein (2) were synthesized via semi-synthetic methods. The antithrombotic activities of these compounds were evaluated through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2 picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2 induced cytotoxicity. Furthermore, the physicochemical properties of these compounds including aqueous solubility and lipophilicity were also investigated. The results showed that 6-O-methylscutellarein (5) demonstrated potent antithrombotic activity, stronger antioxidant activity and balanced solubility and permeability compared with scutellarin (1), which warrants further development of 5 as a promising lead for the treatment of ischemic cerebrovascular disease. PMID- 26523668 TI - Synthesis and evaluation of in vitro and in vivo trypanocidal properties of a new imidazole-containing nitrophthalazine derivative. AB - A series of new phthalazine derivatives (1-4) containing imidazole rings and functionalized with nitro groups in the benzene ring of the phthalazine moiety were prepared and identified on the basis of their MS, elemental analyses and bidimensional (1)H and (13)C NMR data, and their trypanocidal activity was tested. The 8-nitrosubstituted compound (3) was more active in vitro against Trypanosoma cruzi and less toxic against Vero cells than the reference drug benznidazole, and showed a SI value that was 47-fold better than the reference drug in amastigote forms. It also remarkably reduced the infectivity rate in Vero cells and decreased the reactivation of parasitemia in immunodeficient mice. Ultrastructural alterations found in epimastigotes treated with 3 confirmed extensive cytoplasm destruction in the parasites, whereas histopathological analysis of the hearts of mice infected and treated with 3 resulted in a decrease in cardiac damage. Biochemical markers showed that livers, hearts, and kidneys of treated mice were substantially unaffected by the administration of 3, despite the presence of the potentially toxic nitro group. It was also found that this compound selectively inhibited the antioxidant parasite enzyme Fe-superoxide dismutase (Fe-SOD) in comparison with human CuZn-SOD, and molecular modeling suggested interaction with the H-bonding system of the iron-based moiety as a feasible mechanism of action against the enzyme. PMID- 26523669 TI - Exercise improves cardiorespiratory fitness in people with depression: A meta analysis of randomized control trials. AB - OBJECTIVE: Cardiorespiratory fitness (CRF) is an independent predictor of cardiovascular disease and all-cause mortality. CRF improves in response to exercise interventions, yet the effectiveness of such interventions to improve CRF among people with depression is unclear. We conducted a systematic review and meta-analysis to evaluate whether CRF improves in people with depression in exercise randomized control trials (RCTs). METHOD: Three authors identified RCTs from a recent Cochrane review and conducted updated searches of major electronic databases. We included RCTs of exercise interventions in people with depression (including major depressive disorder (MDD) and above-threshold depressive symptoms) that reported CRF (defined as predicted maximal oxygen uptake (VO2max predicted) or peak oxygen uptake (VO2peak)) versus a control condition. A random effects meta-analysis was conducted. RESULTS: Seven unique RCTs including 8 aerobic exercise interventions for depression were eligible, including 293 people allocated to exercise (mean age=40.3 years, range=27.2-64.7 years and 35-100% female) and 205 allocated to control conditions. Across all studies exercise results in a significant increase in CRF (g=0.64, 95%CI=0.32-0.96, p<0.001) equating to a mean increase of 3.05 ml/kg/min. Results remained significant when restricted to MDD only (N=5, g=0.41, 95%CI=0.18-0.64, p<0.001) and in high quality studies (N=5, g=0.60, 95%CI=0.19-1.00, p=0.004). CONCLUSIONS: People with depression can achieve clinically relevant improvements in CRF in response to exercise interventions. Targeting 'fitness' rather than 'fatness' may be another feasible intervention strategy in this population. PMID- 26523670 TI - Nonbiological pharmacotherapies for the treatment of diabetic macular edema. AB - INTRODUCTION: During the past decade, there have been significant advances in the pharmacotherapies for the treatment of diabetic macular edema (DME). Among the presently available treatment options, anti-vascular endothelial growth factors (anti-VEGF) agents are the most favored agents due to their efficacy and safety. The index review focuses on nonbiological therapies that have entered in phase 3 clinical trials for DME. AREAS COVERED: An extensive review of the literature was performed to identify various nonbiological immunotherapies i.e., drugs other than '-mAbs' (monoclonal antibodies including anti-VEGF agents), '-mibs' (proteasome inhibitors), '-NAbs' (nanoparticle albumin-bound), and '-nibs' (small molecule inhibitor/tyrosine kinase inhibitors), among others. Extended-release low-dose corticosteroid devices have been recently approved for the treatment of DME. Other compounds such as non-steroidal anti-inflammatory drugs, antibody mimetic proteins, nonbiological growth factor inhibitors, and inhibitors of protein kinase C have been described. EXPERT OPINION: A number of therapies are under development for the pharmacological management of DME. Due to the rising healthcare costs associated with anti-VEGF agents, a number of alternate treatment options have been explored recently. Some of these agents have reached phase 3 in clinical trials and appear to have a promising role in the management of DME. As further research is conducted, the role of each individual agent will become more defined, alone or in combination therapy. PMID- 26523672 TI - miR-210 and hypoxic microvesicles: Two critical components of hypoxia involved in the regulation of killer cells function. AB - It has become clear that tumor stroma components are engaged in an active and complex molecular cross-talk that has serious implications for immunological recognition of tumor cells in shaping the microenvironment. Hypoxia which is a major component of tumor microenvironment influences the characteristics of neoplasia by favoring heterogeneity, invasiveness, metastatic potency and tumor progression. In this regard, an important mode of communication between carcinoma cells and immune cells may involve tumor-derived microvesicles, which are able to carry lipids, proteins, mRNAs and miRNAs. This review covers new evidence indicating that the efficacy of the cell-mediated cytotoxicity (CTLs and NK) may be dependent on hypoxia induced miRNA and microvesicles in the tumor microenvironment by inhibiting the efficacy of natural host anti-tumor immune response and improving the ability of tumors to avoid immunosurveillance. This emphasizes that hypoxic tumors actively develop additional mechanisms to suppress the sensing of the immunologic danger signals in order to survive and propagate without inciting anti-tumor immunity. PMID- 26523671 TI - MicroRNA-34a induces a senescence-like change via the down-regulation of SIRT1 and up-regulation of p53 protein in human esophageal squamous cancer cells with a wild-type p53 gene background. AB - MiR-34a has been reported as a non-coding RNA universally expressed in normal old cells and a probable suppressor of diverse cancer cells; however, this miRNA's expression and anti-tumor mechanism in esophageal squamous cancer cells (ESCC) remains unclear. We explored these questions in three human ESCC lines, KYSE-450, KYSE-410, and ECa-109, with wild-type p53 and mutant p53 backgrounds. Through a specific stem-loop RT primer for miR-34a, we examined the relevant expression level of miR-34a in these three cell lines using real-time reverse transcription PCR (qRT-PCR). We found that the expression level of miR-34a induced by the DNA damage agent adrmycin (ADR) was both p53- and time-dependent. Following incubation with miR-34a, cellular growth inhibition was exhibited differently in the three cell lines harbored with different p53 backgrounds. Furthermore, the MTT assay demonstrated an miR-34a-related cytotoxic effect in cell growth. Senescence-associated beta-galactosidase (SA-beta-Gal) staining was used to examine senescence-like phenotypes induced by miR-34a. Mechanistic investigation suggested that the down-regulation of Sirtuin1 (SIRT1) and up-regulation of p53/p21 contributed to the anti-tumor mechanism of miR-34a in wild-type p53 ECa 109 cells, while neither of the apoptosis-related proteins PARP and caspase-3 caused significant changes. In summary, our findings indicated that the intrinsic expression of miR-34a was relatively low and was expressed differently among different p53 backgrounds and ADR treatment times. The anti-tumor effect of miR 34a was primarily dependent on the regulation of SIRT1 and p53/p21 protein, not apoptosis-associated proteins. PMID- 26523673 TI - The hetero-transplantation of human bone marrow stromal cells carried by hydrogel unexpectedly demonstrates a significant role in the functional recovery in the injured spinal cord of rats. AB - Spinal cord injury (SCI) often causes a disturbance in the microenvironment in the lesion site resulting in sudden loss of sensory and motor function. Transplantation of stem cells provides a promising strategy in the treatment of SCI. But limited growth and immunological incompatibility of the stem cells with the host limits the application of this strategy. In order to get better survival and integration with the host, we employed a hyaluronic acid (HA) based scaffold covalently modified by poly-l-Lysine (PLL) as a vehicle to deliver the human bone marrow stromal cells (BMSCs) to the injured spinal cord of rats. The BMSCs were chosen as an ideal candidate for its advantage of low expression of major histocompatibility complex II. The data unexpectedly showed that the hetero transplanted cells survived well in the lesion site even at 8 weeks post injury. Both the immunofluorescent and the electrophysiological assay indicated better survival of the transplanted cells and improved axonal growth in SCI rats transplanted with BMSCs in HA-PLL in contrast to the groups without either BMSCs or the HA scaffold transplantation. These promotions may account for the functional recovery assessed by Basso-Beattie-Bresnahan (BBB) locomotor rating scale in the HA-PLL seeded with BMSCs group. These data suggests that hetero transplantation of human BMSCs delivered by HA scaffold demonstrates a significant role in the functional recovery in the injured spinal cord of rats. PMID- 26523674 TI - System-wide survey of proteomic responses of human bone marrow stromal cells (hBMSCs) to in vitro cultivation. AB - Human bone marrow stromal cells (hBMSCs, also loosely called bone marrow-derived mesenchymal stem cells) are the subject of increasing numbers of clinical trials and laboratory research. Our group recently reported on the optimization of a workflow for a sensitive proteomic study of hBMSCs. Here, we couple this workflow with a label-free protein quantitation method to investigate the molecular responses of hBMSCs to long-term in vitro passaging. We explored the proteomic responses of hBMSCs by assessing the expression levels of proteins at early passage (passage 3, P3) and late passage (P7). We used multiple biological as well as technical replicates to ensure that the detected proteomic changes are repeatable between cultures and thus likely to be biologically relevant. Over 1700 proteins were quantified at three passages and a list of differentially expressed proteins was compiled. Bioinformatics-based network analysis and term enrichment revealed that metabolic pathways are largely altered, where many proteins in the glycolytic, pentose phosphate, and TCA pathways were shown to be largely upregulated in late passages. We also observed significant proteomic alterations in functional categories including apoptosis, and ER-based protein processing and sorting following in vitro cell aging. We posit that the comprehensive map outlined in this report of affected phenotypes as well as the underpinning molecular factors tremendously benefit the effort to uncovering targets that are not just used only to monitor cell fitness but can be employed to slowdown the in vitro aging process in hBMSCs and hence ensure manufacturing of cells with known quality, efficacy and stability. PMID- 26523675 TI - GABAA receptor modulating steroid antagonists (GAMSA) are functional in vivo. AB - GABAA receptor modulating steroid antagonists (GAMSA) selectively inhibit neurosteroid-mediated enhancement of GABA-evoked currents at the GABAA receptor. 3alpha-hydroxy-neurosteroids, notably allopregnanolone and tetrahydrodeoxycorticosterone (THDOC), potentiate GABAA receptor-mediated currents. On the contrary, various 3beta-hydroxy-steroids antagonize this positive neurosteroid-mediated modulation. Importantly, GAMSAs are specific antagonists of the positive neurosteroid-modulation of the receptor and do not inhibit GABA-evoked currents. Allopregnanolone and THDOC have both negative and positive actions. Allopregnanolone can impair encoding/consolidation and retrieval of memories. Chronic administration of a physiological allopregnanolone concentration reduces cognition in mice models of Alzheimer's disease. In humans an allopregnanolone challenge impairs episodic memory and in hepatic encephalopathy cognitive deficits are accompanied by increased brain ammonia and allopregnanolone. Hippocampal slices react in vitro to ammonia by allopregnanolone synthesis in CA1 neurons, which blocks long-term potentiation (LTP). Thus, allopregnanolone may impair learning and memory by interfering with hippocampal LTP. Contrary, pharmacological treatment with allopregnanolone can promote neurogenesis and positively influence learning and memory of trace eye blink conditioning in mice. In rat the GAMSA UC1011 inhibits an allopregnanolone induced learning impairment and the GAMSA GR3027 restores learning and motor coordination in rats with hepatic encephalopathy. In addition, the GAMSA isoallopregnanolone antagonizes allopregnanolone-induced anesthesia in rats, and in humans it antagonizes allopregnanolone-induced sedation and reductions in saccadic eye velocity. 17PA is also an effective GAMSA in vivo, as it antagonizes allopregnanolone-induced anesthesia and spinal analgesia in rats. In vitro the allopregnanolone/THDOC-increased GABA-mediated GABAA receptor activity is antagonized by isoallopregnanolone, UC1011, GR3027 and 17PA, while the effect of GABA itself is not affected. PMID- 26523676 TI - The vitamin D-dependent transcriptome of human monocytes. AB - Monocytes are important cells of the innate immune system that can differentiate into macrophages and dendritic cells. The biologically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), serves as a ligand of the nuclear receptor vitamin D receptor (VDR). A key physiological function of 1,25(OH)2D3 is the defense against pathogens, such as those causing tuberculosis, that involves the modulation of the monocyte transcriptome. THP-1 cells are an established model of human monocytes, for which the at present largest set of 1,25(OH)2D3 affected genome-wide data are available. Here we summarize the insight obtained from the recent transcriptome of 1,25(OH)2D3-stimulated THP-1 cells, that was determined by triplicate RNA sequencing (RNA-seq). Primary and secondary vitamin D target genes being up- and down-regulated were related to changes in the epigenome of THP-1 cells, such as 1,25(OH)2D3-dependent chromatin opening and modulation of the genome-wide association of the transcription factors VDR and CCCTC-binding factor (CTCF) with their respective genomic binding sites. The anti microbial response is the top-ranking early physiological function represented by 1,25(OH)2D3-stimulated genomic regions and genes, but also other immunity-related pathways, such as IL10 signaling, are activated. Taken together, the epigenomic and transcriptomic responses of THP-1 cells to 1,25(OH)2D3 represent a master example of the impact of vitamin D on human physiology. PMID- 26523677 TI - Field evidence of reproduction impairment through sperm DNA damage in the fish nase (Chondrostoma nasus) in anthropized hydrosystems. AB - This work aims to explore in the field the relationship between the integrity of sperm DNA and the quality of offspring as a possible cause of the decline of a feral fish population through reproduction impairment. Mature nase (Chondrostoma nasus) were caught during the breeding season in three locations (A-C) of the Rhone River basin and gametes collected by stripping. Sampling locations were chosen according to the following gradient of contamination due to human activities on the watershed: A<=B1.0 (beta=-0.132; rho<0.001), MMSE=20 (beta= 0.105; rho<0.001), and MMSE=15 (beta=-0.124; rho=0.003), more significantly for women and APOE4+ carriers. Mean schooling was 4.18+/-3.7 years, correlated with time to MMSE=20 and MMSE=15 for women and APOE4+ carriers. Body mass index was correlated with time to MMSE=20 only for men (rho=0.006). The 10-year coronary heart disease risk was correlated with time to MMSE=20 only for APOE4+ carriers (rho=0.015). These outcomes suggest interactions among genomic effects of cognitive reserve, cerebral perfusion, and hormonal changes over mechanisms of neurodegeneration. PMID- 26523711 TI - Inverse Association Between Cancer and Dementia: A Population-based Registry Study in Taiwan. AB - Dementia and cancer are 2 common diseases in the elderly. This retrospective cohort study used a population-based insurance claim dataset, merged with a cancer registry, to test whether risk reduction of cancers occurs at various primary sites after diagnosis of dementia. The study included a cohort of 3282 patients who were first diagnosed with dementia between 2001 and 2002. A control cohort consisted of 13,128 subjects matched for age, sex, and year of enrollment. The site of cancer and duration between the diagnosis of dementia and cancer were analyzed. Among the dementia cases, 169 patients (5.2%) were diagnosed with cancer during a median observation period of 40 months. In the control group, 976 subjects (7.4%) were diagnosed with cancer, during a median observation period of 46 months. During a 7-year follow-up period, the adjusted hazard ratio for cancer among dementia patients was 0.77 (95% confidence interval, 0.65-0.91), and significantly lower for colon (0.54, 0.29-0.99) and prostate cancers (0.44, 0.20 0.98). This study showed an inverse association between cancer and dementia. Further studies focusing on colon and prostate cancers may help elucidate the underlying mechanism and expand the therapeutic strategies. PMID- 26523710 TI - Emergency Department Use Among Older Adults With Dementia. AB - Although persons with dementia are frequently hospitalized, relatively little is known about the health profile, patterns of health care use, and mortality rates for patients with dementia who access care in the emergency department (ED). We linked data from our hospital system with Medicare and Medicaid claims, Minimum Data Set, and Outcome and Assessment Information Set data to evaluate 175,652 ED visits made by 10,354 individuals with dementia and 15,020 individuals without dementia over 11 years. Survival rates after ED visits and associated charges were examined. Patients with dementia visited the ED more frequently, were hospitalized more often than patients without dementia, and had an increased odds of returning to the ED within 30 days of an index ED visit compared with persons who never had a dementia diagnosis (odds ratio, 2.29; P<0.001). Survival rates differed significantly between patients by dementia status (P<0.001). Mean Medicare payments for ED services were significantly higher among patients with dementia. These results show that older adults with dementia are frequent ED visitors who have greater comorbidity, incur higher charges, are admitted to hospitals at higher rates, return to EDs at higher rates, and have higher mortality after an ED visit than patients without dementia. PMID- 26523712 TI - Detection and Differentiation of Frontotemporal Dementia and Related Disorders From Alzheimer Disease Using the Montreal Cognitive Assessment. AB - The Montreal Cognitive Assessment (MoCA) is a cognitive screening tool used by practitioners worldwide. The efficacy of the MoCA for screening frontotemporal dementia (FTD) and related disorders is unknown. The objectives were: (1) to determine whether the MoCA detects cognitive impairment (CI) in FTD subjects; (2) to determine whether Alzheimer disease (AD) and FTD subtypes and related disorders can be parsed using the MoCA; and (3) describe longitudinal MoCA performance by subtype. We extracted demographic and testing data from a database of patients referred to a cognitive neurology clinic who met criteria for probable AD or FTD (N=192). Logistic regression was used to determine whether dementia subtypes were associated with overall scores, subscores, or combinations of subscores on the MoCA. Initial MoCA results demonstrated CI in the majority of FTD subjects (87%). FTD subjects (N=94) performed better than AD subjects (N=98) on the MoCA (mean scores: 18.1 vs. 16.3; P=0.02). Subscores parsed many, but not all subtypes. FTD subjects had a larger decline on the MoCA within 13 to 36 months than AD subjects (P=0.02). The results indicate that the MoCA is a useful tool to identify and track progression of CI in FTD. Further, the data informs future research on scoring models for the MoCA to enhance cognitive screening and detection of FTD patients. PMID- 26523713 TI - Global Data Sharing in Alzheimer Disease Research. AB - Many investigators recognize the importance of data sharing; however, they lack the capability to share data. Research efforts could be vastly expanded if Alzheimer disease data from around the world was linked by a global infrastructure that would enable scientists to access and utilize a secure network of data with thousands of study participants at risk for or already suffering from the disease. We discuss the benefits of data sharing, impediments today, and solutions to achieving this on a global scale. We introduce the Global Alzheimer's Association Interactive Network (GAAIN), a novel approach to create a global network of Alzheimer disease data, researchers, analytical tools, and computational resources to better our understanding of this debilitating condition. GAAIN has addressed the key impediments to Alzheimer disease data sharing with its model and approach. It presents practical, promising, yet, data owner-sensitive data-sharing solutions. PMID- 26523714 TI - Patterns of Mortality in Patients Treated with Dental Implants: A Comparison of Patient Age Groups and Corresponding Reference Populations. AB - PURPOSE: Little is known about the relationship between implant patient mortality compared to reference populations. The aim of this study was to report the mortality pattern in patients treated with dental implants up to a 15-year period, and to compare this to mortality in reference populations with regard to age at surgery, sex, and degree of tooth loss. MATERIALS AND METHODS: Patient cumulative survival rate (CSR) was calculated for a total of 4,231 treated implant patients from a single clinic. Information was based on surgical registers in the clinic and the National Population Register in Sweden. Patients were arranged into age groups of 10 years, and CSR was compared to that of the reference population of comparable age and reported in relation to age at surgery, sex, and type of jaw/dentition. RESULTS: A similar, consistent, general relationship between CSR of different age groups of implant patients and reference populations could be observed for all parameters studied. Completely edentulous patients presented higher mortality than partially edentulous patients (P < .05). Furthermore, implant patients in younger age groups showed mortality similar to or higher than reference populations, while older patient age groups showed increasingly lower mortality than comparable reference populations for edentulous and partially edentulous patients (P < .05). CONCLUSION: A consistent pattern of mortality in different age groups of patients compared to reference populations was observed, indicating higher patient mortality in younger age groups and lower in older groups. The reported pattern is not assumed to be related to implant treatment per se, but is assumed to reflect the variation in general health of a selected subgroup of treated implant patients compared to the reference population in different age groups. PMID- 26523715 TI - Treatment Outcomes of Cantilever Fixed Partial Dentures on Vital Abutment Teeth: A Retrospective Analysis. AB - PURPOSE: This retrospective clinical study evaluated the long-term outcomes of cantilever fixed partial dentures (CFPDs) and the factors influencing their survival probability. MATERIALS AND METHODS: The study is based on a convenience sample of 57 patients who received 71 CFPDs on a total of 176 vital abutment teeth. The mean survival time of the CFPDs was calculated using a Kaplan-Meier estimate. The following variables were analyzed as covariates of the survival function (logrank test, P < .05): sex, denture location, number and distribution (Kennedy Class) of the abutment teeth, dentition in the opposing arch (removable dentures, fixed partial dentures, or natural dentition), position of the cantilever unit (mesial or distal), and participation in follow-up visits. RESULTS: The mean observation period was 3.2 +/- 2.8 years (maximum 10.7 years). During the observation period, 22.5% (n = 16) of the CFPDs ceased functioning. The calculated outcome probability was 93.0% after 5 years and 84.5% after 8 years. The number of abutment teeth was the only parameter that significantly (P < .05) impacted this probability. CONCLUSION: The survival rate of CFPDs on vital abutment teeth is comparable to that of conventional fixed partial dentures. Thus, CFPDs on vital abutments are an acceptable alternative to removable dentures. PMID- 26523716 TI - Impact on Dietary Intake of Removable Partial Dentures Replacing a Small Number of Teeth. AB - The aim of this study was to clarify the impact of wearing removable partial dentures (RPDs) replacing a small number of teeth on dietary intake. Participants had at least 20 teeth and were classified as Eichner B1 or B2. The participants underwent dental and oral examinations, and their dietary intake was assessed. Analysis of covariance showed that RPD wearers consumed more vegetables, n-3 fatty acids, calcium, vitamin A, and dietary fiber than nonwearers after adjusting for possible confounding factors. It is concluded that RPDs are effective for improving dietary intake even in participants who have lost a small number of teeth. PMID- 26523717 TI - An Assessment of the Risk of Bias in Randomized Controlled Trial Reports Published in Prosthodontic and Implant Dentistry Journals. AB - PURPOSE: The objective of this study was to assess the risk of bias of randomized controlled trials (RCTs) published in prosthodontic and implant dentistry journals. MATERIALS AND METHODS: The last 30 issues of 9 journals in the field of prosthodontic and implant dentistry (Clinical Implant Dentistry and Related Research, Clinical Oral Implants Research, Implant Dentistry, International Journal of Oral & Maxillofacial Implants, International Journal of Periodontics and Restorative Dentistry, International Journal of Prosthodontics, Journal of Dentistry, Journal of Oral Rehabilitation, and Journal of Prosthetic Dentistry) were hand-searched for RCTs. Risk of bias was assessed using the Cochrane Collaboration's risk of bias tool and analyzed descriptively. RESULTS: From the 3,667 articles screened, a total of 147 RCTs were identified and included. The number of published RCTs increased with time. The overall distribution of a high risk of bias assessment varied across the domains of the Cochrane risk of bias tool: 8% for random sequence generation, 18% for allocation concealment, 41% for masking, 47% for blinding of outcome assessment, 7% for incomplete outcome data, 12% for selective reporting, and 41% for other biases. CONCLUSION: The distribution of high risk of bias for RCTs published in the selected prosthodontic and implant dentistry journals varied among journals and ranged from 8% to 47%, which can be considered as substantial. PMID- 26523718 TI - Epigenetics and Bruxism: Possible Role of Epigenetics in the Etiology of Bruxism. AB - Bruxism is defined as a repetitive jaw muscle activity characterized by clenching or grinding of the teeth and/or bracing or thrusting of the mandible. There are two distinct circadian phenotypes for bruxism: sleep bruxism (SB) and awake bruxism, which are considered separate entities due to the putative difference in their etiology and phenotypic variance. The detailed etiology of bruxism so far remains unknown. Recent theories suggest the central regulation of certain pathophysiological or psychological pathways. Current proposed causes of bruxism appear to be a combination of genetic and environmental (G*E) factors, with epigenetics providing a robust framework for investigating G*E interactions, and their involvement in bruxism makes it a suitable candidate for epigenetic research. Both types of bruxism are associated with certain epigenetically determined disorders, such as Rett syndrome (RTT), Prader-Willi syndrome (PWS), and Angelman syndrome (AS), and these associations suggest a mechanistic link between epigenetic deregulation and bruxism. The present article reviews the possible role of epigenetic mechanisms in the etiology of both types of bruxism based on the epigenetic pathways involved in the pathophysiology of RTT, PWS, and AS, and on other epigenetic disruptions associated with risk factors for bruxism, including sleep disorders, altered stress response, and psychopathology. PMID- 26523719 TI - Prevalence of Temporomandibular Disorders in an Adult Brazilian Community Population Using the Research Diagnostic Criteria (Axes I and II) for Temporomandibular Disorders (The Maringa Study). AB - PURPOSE: The primary objective of this study was to assess the prevalence of temporomandibular disorders (TMDs) and comorbid factors (sleep bruxism and headaches). This study was a cross-sectional population survey in the city of Maringa, state of Parana, Brazil. MATERIALS AND METHODS: Axes I and II of the Research Diagnostic Criteria for TMD (RDC/TMD) were used for assessment of TMD signs and symptoms. The population was users of the Brazilian public health system (SUS), of both sexes, between the ages of 20 and 65 years, and not seeking treatment for TMD. RESULTS: The selected population (N = 1,643) was composed mostly of (a) women (65.9%), (b) married or single individuals (90.6%), (c) Caucasians (70.1%), (d) individuals aged 32.7 +/- 10.3 years, (e) individuals earning a medium income (75.1%), and (f) those who had completed a high school education or higher (79.9%). According to the chronic pain grade classification (CPG) in the RDC/TMD Axis II, 36.2% of the population had some degree of TMD pain (CPG I to IV); however, only 5.1% had severe limitation due to pain (CPG III or IV). In the RDC/TMD Axis I diagnoses, 29.5% presented with muscle disorders (group I), 7.9% with disk displacements (group II), and 39.1% with other joint disorders (group III). Headaches were present in 67.9% and awake and sleep bruxism in 30% and 33.4% of the population, respectively. CONCLUSION: The prevalence of signs and symptoms of TMD was high in this population, but with low disability; however, the proportion of patients in need of treatment was much lower. PMID- 26523720 TI - Clinical Evaluation of a Direct Method for the Intrusion of Supraerupted Maxillary Molars: A Preliminary Study. AB - PURPOSE: This study aimed to evaluate the use of orthodontic mini-implants for the intrusion of supraerupted maxillary molars. MATERIALS AND METHODS: Nine patients were treated using buttons bonded on dental surfaces and mini-implants inserted on the buccal and palatal sides. The intrusion was evaluated by comparing radiographs obtained at the start of treatment and at the end of intrusion. The t test was used to compare the teeth positions. RESULTS: There was statistically significant intrusion using this method (mean: 2.4 mm; minimum: 1.2 mm; and maximum: 4.5 mm; P = .00). CONCLUSION: The direct use of orthodontic mini implants was effective for the intrusion of maxillary molars. PMID- 26523721 TI - A Newly Designed Screw- and Cement-Retained Prosthesis and Its Abutments. AB - The degree of misfit between a prosthesis and its supporting implants is a major concern in screw-retained prostheses because it can lead to screw loosening or mechanical failure of implant components. On the other hand, the difficulty of removing subgingival excess cement and the irretrievability of the superstructure are major drawbacks to cement-retained prostheses. A newly designed screw- and cement-retained prosthesis (SCRP) may solve these problems with its passivity, retrievability, and ease in the complete removal of excess cement, giving it the advantages of both screw-retained and cement-retained prostheses. This prosthetic system is mainly composed of a cement-retained framework with screw holes on the occlusal surface and specially designed cementable abutments for multiunit prostheses. The principle and structure of the SCRP system is described in this article. PMID- 26523722 TI - Transglutaminase 2 May Be Associated with Peri-implant Gingival Overgrowth: Preliminary Assessments. AB - Tissue transglutaminase 2 (TG2) is ubiquitously expressed in normal tissues and plays an important role in the pathophysiology of wound healing. An increase in periodontal tissues has been previously reported in cyclosporine-induced gingival overgrowth. PURPOSE: The aim of this study was to explore associations between TG2 expression and the vascularization and maturation processes of peri-implant soft tissues over time. MATERIALS AND METHODS: Edentulous patients proposed for mandibular implant-retained overdentures were included in the study. Biopsies of the peri-implant mucosa were performed at the first surgical stage and at 4, 8, and 12 months after prosthetic load. A follow-up program was directed to record plaque indexes, bleeding on probing data, and pocket probing depth around implants. An evaluation of the vessels' density was carried out by digital virtual microscopy and using an immunohistochemistry approach (antibodies anti CD31, anti-TG2). A robust multivariable regression model was implemented. RESULTS: According to model results, blood vessel count and probing (as a marker of gingival overgrowth in absence of plaque) significantly decrease over time and are associated with TG2, particularly for values above the median. CONCLUSION: The association of an increased TG2 expression in the extracellular matrix might have a significant impact in the development of gingival overgrowth around a loaded implant. PMID- 26523723 TI - Biomechanical Analysis of Implant-Supported Prostheses with Different Implant Abutment Connections. AB - This study evaluated the influence of implant-abutment connections on stress distribution through 3D finite element analysis. Three-dimensional models of an implant-supported fixed prosthesis in the jaw retained by four implants with different connection systems (external hex and Morse taper) were analyzed. External hex connection promoted higher microstrain values, which were concentrated on the cervical region of the distal implants extending into the trabecular bone, while Morse taper connection provided a more even distribution of the microstrain on all implants. Implant-supported fixed prostheses with external hex connections tend to concentrate strain in the distal implants, while Morse taper connection promoted a better situation. On the other hand, there was greater demand on the prosthetic screws and abutments of Morse taper connections than on external hex connections. PMID- 26523724 TI - Combined Mandibular Guidance Therapy in the Management of a Hemimandibulectomy Patient. AB - This case history report describes two different devices, maxillary ramp prostheses (MRP) and mandibular guide flange prostheses (MGFP), prescribed for managing a hemimandibulectomy patient's deviated mandible. The patient was given muscle reprogramming exercises with coordinated use of both guidance prostheses for 2 months, leading to improvements in both postsurgical mandibular deviation and occlusal equilibration. A successful intercuspal position was eventually accomplished through the use of the combination therapy. MRP and MGFP can be a useful approach to avoid mandibular deviation and compromised function following a partial mandibular resection. PMID- 26523725 TI - Effect of Framework in an Implant-Supported Full-Arch Fixed Prosthesis: 3D Finite Element Analysis. AB - PURPOSE: The aim of this study was to analyze through a three-dimensional finite element analysis (3D-FEA) stress distribution on four implants supporting a full arch implant-supported fixed prosthesis (FFP) using different prosthesis designs. MATERIALS AND METHODS: A 3D edentulous maxillary model was created and four implants were virtually placed into the maxilla and splinted, simulating an FFP without framework, with a cast metal framework, and with a carbon fiber framework. An occlusal load of 150 N was applied, stresses were transmitted into peri-implant bone, and prosthodontic components were recorded. RESULTS: 3D-FEA revealed higher stresses on the implants (up to +55.16%), on peri-implant bone (up to +56.93%), and in the prosthesis (up to +70.71%) when the full-acrylic prosthesis was simulated. The prosthesis with a carbon fiber framework showed an intermediate behavior between that of the other two configurations. CONCLUSION: This study suggests that the presence of a rigid framework in full-arch fixed prostheses provides a better load distribution that decreases the maximum values of stress at the levels of implants, prosthesis, and maxillary bone. PMID- 26523726 TI - Stereophotogrammetry for Recording the Position of Multiple Implants: Technical Description. AB - Dental implants are one of the most widely used treatments for the rehabilitation of partially or completely edentulous areas. Achieving proper passive adjustment of the implant-supported prosthesis improves its long-term prognosis. This article discusses a new technique for digitally printing prostheses supported by multiple implants with optimum passive fit. The technique is based on a stereophotogrammetry system that captures the exact location of prosthetic implant platforms. This photogrammetry device takes 10 pictures per second with an error margin of less than 10 MUm between two scanbodies and identifies the spatial position of each implant without physical contact. Three-dimensional data for each implant are registered in vector format, together with interrelated implant angles and distances. The information is then stored in an STL file. PMID- 26523727 TI - Preliminary Observations Regarding Treatment Outcomes in Patients Treated with Maxillary Implant Overdentures in a University Clinic. AB - PURPOSE: To evaluate the outcome of maxillary implant overdenture treatment in a selected patient sample. MATERIALS AND METHODS: Eighteen out of a total of 26 patients who were prescribed overdentures supported by two to six implants each attended a follow-up clinical assessment. Evaluative criteria included oral health-related quality of life records using the OHIP-14 questionnaire. RESULTS: Good stability and retention were observed, and mechanical failure items were recorded in eight patients. No significant differences in OHIP-14 scores were found between patients treated with two to three implants and patients treated with five to six implants, or between groups treated with a denture with palatal or horseshoe design coverage. CONCLUSION: Maxillary implant overdenture treatment was assessed as a viable treatment option for the selected patient sample, even when only two supporting implants were prescribed. PMID- 26523728 TI - Functional domain walls in multiferroics. AB - During the last decade a wide variety of novel and fascinating correlation phenomena has been discovered at domain walls in multiferroic bulk systems, ranging from unusual electronic conductance to inseparably entangled spin and charge degrees of freedom. The domain walls represent quasi-2D functional objects that can be induced, positioned, and erased on demand, bearing considerable technological potential for future nanoelectronics. Most of the challenges that remain to be solved before turning related device paradigms into reality, however, still fall in the field of fundamental condensed matter physics and materials science. In this topical review seminal experimental findings gained on electric and magnetic domain walls in multiferroic bulk materials are addressed. A special focus is put on the physical properties that emerge at so-called charged domain walls and the added functionality that arises from coexisting magnetic order. The research presented in this review highlights that we are just entering a whole new world of intriguing nanoscale physics that is yet to be explored in all its details. The goal is to draw attention to the persistent challenges and identify future key directions for the research on functional domain walls in multiferroics. PMID- 26523729 TI - Chicken, beams, and Campylobacter: rapid differentiation of foodborne bacteria via vibrational spectroscopy and MALDI-mass spectrometry. AB - Campylobacter species are one of the main causes of food poisoning worldwide. Despite the availability of established culturing and molecular techniques, due to the fastidious nature of these microorganisms, simultaneous detection and species differentiation still remains challenging. This study focused on the differentiation of eleven Campylobacter strains from six species, using Fourier transform infrared (FT-IR) and Raman spectroscopies, together with matrix assisted laser desorption ionisation-time of flight-mass spectrometry (MALDI-TOF MS), as physicochemical approaches for generating biochemical fingerprints. Cluster analysis of data from each of the three analytical approaches provided clear differentiation of each Campylobacter species, which was generally in agreement with a phylogenetic tree based on 16S rRNA gene sequences. Notably, although C. fetus subspecies fetus and venerealis are phylogenetically very closely related, using FT-IR and MALDI-TOF-MS data these subspecies were readily differentiated based on differences in the lipid (2920 and 2851 cm(-1)) and fingerprint regions (1500-500 cm(-1)) of the FT-IR spectra, and the 500-2000 m/z region of the MALDI-TOF-MS data. A finding that was further investigated with targeted lipidomics using liquid chromatography-mass spectrometry (LC-MS). Our results demonstrate that such metabolomics approaches combined with molecular biology techniques may provide critical information and knowledge related to the risk factors, virulence, and understanding of the distribution and transmission routes associated with different strains of foodborne Campylobacter spp. PMID- 26523730 TI - Prophylactic efficacy of lithium, valproic acid, and carbamazepine in the maintenance phase of bipolar disorder: a naturalistic study. AB - Mood stabilizers are used clinically for the management of bipolar disorder. Prophylactic therapy with mood stabilizers is the primary treatment for preventing depressive and manic relapses in bipolar patients once they are stabilized. In this study, we examined the relative efficacy of the three most commonly used mood-stabilizing agents: lithium (Li), valproic acid (VPA), and carbamazepine (CBZ), in preventing relapse episodes. A total of 225 patients with bipolar disorder were included in the present analysis. Patients taking Li, VPA, or CBZ were followed up for up to 124 months, until suffering a manic, mixed, or depressive episode (relapse), or until the end of the study/study termination (no relapse), whichever came first. The median unadjusted survival time was 36 months for patients taking VPA, 42 months for patients taking CBZ, and 81 months for patients taking Li. These results indicate that patients stayed longer on Li, suggesting that it might have been better tolerated than either CBZ or VPA. chi Analysis showed that patients taking Li were significantly less likely to experience relapse during the observational period than patients taking either VPA or CBZ (P<0.05). A Cox regression model showed that the hazard of experiencing relapse was significantly predicted by the total number of depressive (P=0.007) and manic symptoms (P=0.02) assessed before the observation period. In addition, after controlling for symptom covariates, the hazard of experiencing relapse was 1.66 times (95% confidence interval 1.03-2.67) or 66% higher for patients taking VPA compared with patients taking Li (P=0.037). Although the hazard of experiencing relapse was higher for patients taking CBZ compared with those taking Li, the risk was not elevated by a significant amount. Notwithstanding the limitations of the naturalistic design of this study, the differences in relapse prevention and survival time observed in these medications show Li fairing relatively better in prophylactic therapy. PMID- 26523731 TI - Association of Off-label Drug Use and Adverse Drug Events in an Adult Population. AB - IMPORTANCE: Off-label use of prescription drugs has been identified as an important contributor to preventable adverse drug events (ADEs) in children. Despite concerns regarding adverse outcomes, to date, no systematic investigation of the effects of off-label drug use in adult populations has been performed. OBJECTIVE: To monitor and evaluate off-label use of prescription drugs and its effect on ADEs in an adult population. DESIGN, SETTING, AND PARTICIPANTS: A cohort of 46,021 patients who received 151,305 incident prescribed drugs was assembled from primary care clinics in Quebec, Canada, using the Medical Office of the XXIst Century electronic health record, which supports documentation of treatment indications and treatment outcomes. Prescriptions dispensed from January 1, 2005, through December 30, 2009, were followed up from the date of the prescription to the date the drug use was discontinued, the end of treatment, or the end of follow-up (December 30, 2010). Data were analyzed from January 5, 2012, to March 15, 2015. EXPOSURES: Off-label prescription drug use with and without strong scientific evidence. MAIN OUTCOMES AND MEASURES: Adverse drug events in off-label use with and without strong scientific evidence. Analysis used multivariate marginal Cox proportional hazards regression for clustered data with the drug as the unit of analysis. RESULTS: A total of 3484 ADEs were found in the 46,021 study patients, with an incidence rate of 13.2 per 10,000 person months. The rate of ADEs for off-label use (19.7 per 10,000 person-months) was higher than that for on-label use (12.5 per 10,000 person-months) (adjusted hazard ratio [AHR], 1.44; 95% CI, 1.30-1.60). Off-label use lacking strong scientific evidence had a higher ADE rate (21.7 per 10,000 person-months) compared with on-label use (AHR, 1.54; 95% CI, 1.37-1.72). However, off-label use with strong scientific evidence had the same risk for ADEs as on-label use (AHR, 1.10; 95% CI, 0.88-1.38). The risks for ADEs were higher for drugs approved from 1981 to 1995 (14.4 per 10,000 person-months; AHR, 1.62; 95% CI, 1.45-1.80) and for those used by women (14.3 per 10,000 person-months; AHR, 1.17; 95% CI, 1.06 1.28), patients receiving 5 to 7 drugs (12.1 per 10,000 person-months; AHR, 3.23; 95% CI, 2.66-3.92), and patients receiving cardiovascular drugs (15.9 per 10,000 person-months; AHR, 3.30; 95% CI, 2.67-4.08) and anti-infectives (66.2 per 10,000 person-months; AHR, 6.33; 95% CI, 4.58-8.76). Patients with a 1-unit increase in the continuity of care index had a 19% increase in ADEs (AHR, 1.19; 95% CI, 1.12 1.26). CONCLUSIONS AND RELEVANCE: Off-label use of prescription drugs is associated with ADEs. Caution should be exercised in prescribing drugs for off label uses that lack strong scientific evidence. Future electronic health records should be designed to enable postmarket surveillance of treatment indications and treatment outcomes to monitor the safety of on- and off-label uses of drugs. PMID- 26523732 TI - Detailed Anatomical and Electrophysiological Models of Human Atria and Torso for the Simulation of Atrial Activation. AB - Atrial arrhythmias, and specifically atrial fibrillation (AF), induce rapid and irregular activation patterns that appear on the torso surface as abnormal P waves in electrocardiograms and body surface potential maps (BSPM). In recent years both P-waves and the BSPM have been used to identify the mechanisms underlying AF, such as localizing ectopic foci or high-frequency rotors. However, the relationship between the activation of the different areas of the atria and the characteristics of the BSPM and P-wave signals are still far from being completely understood. In this work we developed a multi-scale framework, which combines a highly-detailed 3D atrial model and a torso model to study the relationship between atrial activation and surface signals in sinus rhythm. Using this multi scale model, it was revealed that the best places for recording P waves are the frontal upper right and the frontal and rear left quadrants of the torso. Our results also suggest that only nine regions (of the twenty-one structures in which the atrial surface was divided) make a significant contribution to the BSPM and determine the main P-wave characteristics. PMID- 26523733 TI - Medical Student Knowledge of Neglected Tropical Diseases in Peru: A Cross Sectional Study. AB - In developing countries, education to health-care professionals is a cornerstone in the battle against neglected tropical diseases (NTD). Studies evaluating the level of knowledge of medical students in clinical and socio-demographic aspects of NTD are lacking. Therefore, a cross-sectional study was conducted among students from a 7 year-curriculum medical school in Peru to assess their knowledge of NTD by using a pilot survey comprised by two blocks of 10 short questions. Block I consisted of socio-demographic and epidemiological questions whereas block II included clinical vignettes. Each correct answer had the value of 1 point. Out of 597 responders (response rate: 68.4%), 583 were considered to have valid surveys (male:female ratio: 1:1.01; mean age 21 years, SD +/- 2.42). Total knowledge showed a raising trend through the 7-year curriculum. Clinical knowledge seemed to improve towards the end of medical school whereas socio demographic and epidemiological concepts only showed progress the first 4 years of medical school, remaining static for the rest of the curricular years (p = 0.66). Higher mean scores in socio-demographic and epidemiological knowledge compared to clinical knowledge were seen in the first two years (p<0.001) whereas the last three years showed higher scores in clinical knowledge (p<0.001). In conclusion, students from this private medical school gained substantial knowledge in NTD throughout the career which seems to be related to improvement in clinical knowledge rather than to socio-demographic and epidemiological concepts. This study assures the feasibility of measuring the level of knowledge of NTD in medical students and stresses the importance of evaluating education on NTD as it may need more emphasis in epidemiological concepts, especially at developing countries such as Peru where many people are affected by these preventable and treatable diseases. PMID- 26523734 TI - Conditions for Waveblock Due to Anisotropy in a Model of Human Ventricular Tissue. AB - Waveblock formation is the main cause of reentry. We have performed a comprehensive numerical modeling study of block formation due to anisotropy in Ten Tusscher and Panfilov (2006) ionic model for human ventricular tissue. We have examined the border between different areas of myocardial fiber alignment and have shown that blockage can occur for a wave traveling from a transverse fiber area to a longitudinal one. Such blockage occurs for reasonable values of the anisotropy ratio (AR): from 2.4 to 6.2 with respect to propagation velocities. This critical AR decreases by the suppression of INa and ICa, slightly decreases by the suppression of IKr and IKs, and substantially increases by the suppression of IK1. Hyperkalemia affects the block formation in a complex, biphasic way. We provide examples of reentry formation due to the studied effects and have concluded that the suppression of IK1 should be the most effective way to prevent waveblock at the areas of abrupt change in anisotropy. PMID- 26523735 TI - Silver-Catalyzed Long-Distance Aryl Migration from Carbon Center to Nitrogen Center. AB - Selective cleavage of an inert C-C bond followed by C-O/N bond formation through a long-distance aryl migration from a carbon to a nitrogen center via Ag catalysis is reported. The migration products were easily converted into gamma hydroxy amines and tetrahydroquinoline derivatives in quantitative yields. Preliminary mechanistic studies indicated a radical pathway. PMID- 26523736 TI - Combined Transcriptomics Analysis for Classification of Adverse Effects As a Potential End Point in Effect Based Screening. AB - Environmental risk assessment relies on the use of bioassays to assess the environmental impact of chemicals. Gene expression is gaining acceptance as a valuable mechanistic end point in bioassays and effect-based screening. Data analysis and its results, however, are complex and often not directly applicable in risk assessment. Classifier analysis is a promising method to turn complex gene expression analysis results into answers suitable for risk assessment. We have assembled a large gene expression data set assembled from multiple studies and experiments in the springtail Folsomia candida, with the aim of selecting a set of genes that can be trained to classify general toxic stress. By performing differential expression analysis prior to classifier training, we were able to select a set of 135 genes which was enriched in stress related processes. Classifier models from this set were used to classify two test sets comprised of chemical spiked, polluted, and clean soils and compared to another, more traditional classifier feature selection. The gene set presented here outperformed the more traditionally selected gene set. This gene set has the potential to be used as a biomarker to test for adverse effects caused by chemicals in springtails to provide end points in environmental risk assessment. PMID- 26523738 TI - Threshold energies for single-carbon knockout from polycyclic aromatic hydrocarbons. AB - We have measured absolute cross sections for ultrafast (femtosecond) single carbon knockout from polycyclic aromatic hydrocarbon (PAH) cations as functions of He-PAH center-of-mass collision energy in the 10-200 eV range. Classical molecular dynamics (MD) simulations cover this range and extend up to 105 eV. The shapes of the knockout cross sections are well-described by a simple analytical expression yielding experimental and MD threshold energies of EthExp = 32.5 +/- 0.4 eV and EthMD = 41.0 +/- 0.3 eV, respectively. These are the first measurements of knockout threshold energies for molecules isolated in vacuo. We further deduce semiempirical (SE) and MD displacement energies, i.e., the energy transfers to the PAH molecules at the threshold energies for knockout, of TdispSE = 23.3 +/- 0.3 eV and TdispMD = 27.0 +/- 0.3 eV. The semiempirical results compare favorably with measured displacement energies for graphene (Tdisp = 23.6 eV). PMID- 26523737 TI - Chromatic detection from cone photoreceptors to V1 neurons to behavior in rhesus monkeys. AB - Chromatic sensitivity cannot exceed limits set by noise in the cone photoreceptors. To determine how close neurophysiological and psychophysical chromatic sensitivity come to these limits, we developed a parameter-free model of stimulus encoding in the cone outer segments, and we compared the sensitivity of the model to the psychophysical sensitivity of monkeys performing a detection task and to the sensitivity of individual V1 neurons. Modeled cones had a temporal impulse response and a noise power spectrum that were derived from in vitro recordings of macaque cones, and V1 recordings were made during performance of the detection task. The sensitivity of the simulated cone mosaic, the V1 neurons, and the monkeys were tightly yoked for low-spatiotemporal-frequency isoluminant modulations, indicating high-fidelity signal transmission for this class of stimuli. Under the conditions of our experiments and the assumptions for our model, the signal-to-noise ratio for these stimuli dropped by a factor of ~3 between the cones and perception. Populations of weakly correlated V1 neurons narrowly exceeded the monkeys' chromatic sensitivity but fell well short of the cones' chromatic sensitivity, suggesting that most of the behavior-limiting noise lies between the cone outer segments and the output of V1. The sensitivity gap between the cones and behavior for achromatic stimuli was larger than for chromatic stimuli, indicating greater postreceptoral noise. The cone mosaic model provides a means to compare visual sensitivity across disparate stimuli and to identify sources of noise that limit visual sensitivity. PMID- 26523739 TI - Is 5% weight loss a satisfactory criterion to define clinically significant weight loss? PMID- 26523740 TI - Can Transabdominal Cervical Length Measurement Exclude Short Cervix? AB - OBJECTIVE: This study aims to determine if transabdominal (TA) cervical length may be used to rule out a short cervix on transvaginal (TV) ultrasound. STUDY DESIGN: We conducted a prospective cohort study of women undergoing routine anatomic survey at 17 to 23 weeks gestation. TA and TV cervical length measurements were obtained in each patient. A short cervix was defined as TV cervical length < 30 mm. Predictive characteristics were calculated for different cutoff values of TA cervical length. RESULTS: There were 404 patients enrolled, a TA cervical length could not be obtained in 83 women (20.6%) and 318 women had both TA and TV measurements. Of those, 14 (4.4%) had a TV cervical length < 30 mm. TA cervical length measurement >= 35 mm excluded the possibility of TV cervical length < 30 mm (negative predictive value, 99.5%; 95% confidence interval [CI], 97.4; 100%). In our cohort, 67.6% (95% CI, 62.2; 72.7%) of TV ultrasounds could have been avoided using a TA cervical length cutoff of >= 5 mm. CONCLUSION: ATA cervical length of at least 35 mm excludes a short cervix of < 30 mm. While TA cervical length screening may not be feasible in 1 in 5 women, it may be used to decrease the burden of universal TV cervical length screening. PMID- 26523741 TI - False Alarms, Pseudoepidemics, and Reality: A Case Study with American College of Obstetricians and Gynecologists Practice Bulletins. AB - OBJECTIVES: The objectives of this review are to (1) ascertain the frequency with which odd ratio (OR) and relative risk (RR) are in the zone of potential bias or interest in the American College of Obstetricians and Gynecologists (ACOG) practice bulletins (PB); (2) the likelihood that false alarms have been linked to recommendations; and (3) if there are differences in obstetric versus gynecological PB, vis-a-vis OR and RR in the zone of bias or interest. DATA SOURCES: We reviewed all ACOG PBs published between May 1999 and March 2014. METHODS: Documents were searched for statements with mention of OR and RR. When the reported ORs fell between 0.33 and 3.0, it was categorized as "zone of potential bias"; if ORs fell outside the interval 0.25 to 4.0, it was "zone of potential interest." With RRs, the zones of bias and interest were 0.5 to 2.0 and 0.33 to 3.0, respectively. RESULTS: Of the 79 PBs reviewed, 22% (n = 17) had 44 statements with OR, with 41% (n = 18) of the ORs being in the zone of bias and 54% (n = 24) in the zone of potential interest. Overall, 84% of the ORs did not lead to an actual recommendation by ACOG. In 28% (n = 22) of PBs, there were 67 statements with RRs, with 58% (n = 39) of them being in the zone of bias and 28% (n = 19) were in the zone of interest. In 73% of the PBs the RR citations did not lead to any recommendations. Across the 79 PBs, ACOG made 733 recommendations, and among them only 1 and 2% were linked with ORs and RRs, respectively. CONCLUSIONS: Over 70% of ACOGPBs did not cite OR and RR. To better understand the evidence, ACOG should increase citation of OR and RR; whenever applicable OR and RR should be part of graded recommendations. LEVEL OF EVIDENCE: Level C. PRECIS: Less than a third of ACOG practice bulletins mention odds ratios or relative risks and over 95% of recommendations in them remain unsubstantiated. PMID- 26523742 TI - Treatment-specific utility weightings are needed for cost-utility analysis in metastatic melanoma. PMID- 26523743 TI - The Interplay of Quantum Confinement and Hydrogenation in Amorphous Silicon Quantum Dots. AB - Hydrogenation in amorphous silicon quantum dots (QDs) has a dramatic impact on the corresponding optical properties and band energy structure, leading to a quantum-confined composite material with unique characteristics. The synthesis of a-Si:H QDs is demonstrated with an atmospheric-pressure plasma process, which allows for accurate control of a highly chemically reactive non-equilibrium environment with temperatures well below the crystallization temperature of Si QDs. PMID- 26523744 TI - Self-reported symptoms and patient experience: A British Acoustic Neuroma Association survey. AB - OBJECTIVE: To assess patient-reported outcomes and experience of vestibular schwannoma (VS) management. STUDY DESIGN: Survey of members of the British Acoustic Neuroma Association (BANA). METHODS: Members of the BANA were invited to complete an online survey. Questions were divided into five areas: Demographic details; symptoms at diagnosis; level of information received; treatment after effects; and overall experience of diagnosis and/or treatment. RESULTS: DEMOGRAPHICS: 598 (58%) BANA members completed the survey. 77.1% of respondents were aged between 41 and 70 years. Symptoms at diagnosis: hearing loss (84%), unilateral tinnitus (40%) and imbalance (51%) were commonest. Isolated tinnitus and imbalance occurred in 2% and 6%, respectively. Information received: 39% stated they were given 'just the right amount of information about all management options', and 32% 'not enough information'. Treatment after-effects: Overall quality of life was classified as 'a lot better' (11%), 'a little better' (7%), 'unchanged' (25%), 'a little worse' (38%) and 'a lot worse' (19%). 61% respondents continued in the same job. Return to social life, hobbies and sports was impaired in 65%. Overall experience: Experience of treatment was graded as 'much better than expected' (20%), 'a little better' (15%), 'about the same' (27%), 'a little worse' (22%) and 'much worse' (16%). CONCLUSION: Quality of life measures are important in assessing VS management outcomes, and will increasingly inform clinical decision-making. Further examination of how patients with VS perceive their disease, cope with illness and use social support networks may also help to inform future practice and the creation of decision analytical models. PMID- 26523745 TI - Pupillary response to direct and consensual chromatic light stimuli. AB - PURPOSE: To assess whether the direct and consensual postillumination (ipRGC driven) pupil light responses to chromatic light stimuli are equal in healthy subjects. METHODS: Pupil responses in healthy volunteers were recorded using a prototype binocular chromatic pupillometer (IdeaMedical, Copenhagen), which is capable of both direct and consensual pupillometry measurements. The device uses a pair of dual monochromatic narrow bandwidth LED light sources, red (660 nm) and blue (470 nm). Pupil light responses were recorded with infrared video cameras and analysed using custom-made circuitry and software. Subjects were randomized to receive light stimuli at either the right or left eye after 5 min of dark adaptation. Pupil light responses were recorded in both eyes for 10 seconds before illumination, during illumination and 50 seconds after illumination with red and blue light. Three variables were defined for the recorded pupil responses: the maximal constriction amplitude (CAmax ), the pupil response during illumination and postillumination pupil response (PIPR). RESULTS: No difference was found in the pupil response to blue light. With red light, the pupil response during illumination was slightly larger during consensual illumination compared to direct illumination (0.54 and 0.52, respectively, p = 0.027, paired Wilcoxon's test, n = 12), while no differences were found for CAmax or the PIPR. CONCLUSIONS: No difference was found between direct and consensual pupil response to either red or blue light in the postillumination period. Direct and consensual responses can readily be compared when examining the postillumination pupil response to blue light as estimation of photosensitive retinal ganglion cell activation. PMID- 26523746 TI - Latency attention deficit: Asbestos abatement workers need us to investigate. AB - Little is known of the impact of asbestos on the health of the workers in the United States who have removed or abated asbestos from buildings following recognition of its adverse effects on health. The United States does not have a national occupational health surveillance network to monitor asbestos-related disease and, while the United States Occupational Health and Safety Administration has a strong and detailed asbestos standard, its enforcement resources are limited. A significant proportion of asbestos abatement workers are foreign-born, and may face numerous challenges in achieving safe workplaces, including lack of union representation, economic vulnerability, and inadequate training. Public health surveillance and increased and coordinated enforcement is needed to monitor the health and exposure experiences of asbestos-exposed workers. Alarming disease trends in asbestos removal workers in Great Britain suggest that, in the United States, increased public attention will be necessary to end the epidemic of asbestos-related disease. PMID- 26523747 TI - Broader Geographic Sharing of Pediatric Donor Lungs Improves Pediatric Access to Transplant. AB - US pediatric transplant candidates have limited access to lung transplant due to the small number of donors within current geographic boundaries, leading to assertions that the current lung allocation system does not adequately serve pediatric patients. We hypothesized that broader geographic sharing of pediatric (adolescent, 12-17 years; child, <12 years) donor lungs would increase pediatric candidate access to transplant. We used the thoracic simulated allocation model to simulate broader geographic sharing. Simulation 1 used current allocation rules. Simulation 2 offered adolescent donor lungs across a wider geographic area to adolescents. Simulation 3 offered child donor lungs across a wider geographic area to adolescents. Simulation 4 combined simulations 2 and 3. Simulation 5 prioritized adolescent donor lungs to children across a wider geographic area. Simulation 4 resulted in 461 adolescent transplants per 100 patient-years on the waiting list (range 417-542), compared with 206 (range 180-228) under current rules. Simulation 5 resulted in 388 adolescent transplants per 100 patient-years on the waiting list (range 348-418) and likely increased transplant rates for children. Adult transplant rates, waitlist mortality, and 1-year posttransplant mortality were not adversely affected. Broader geographic sharing of pediatric donor lungs may increase pediatric candidate access to lung transplant. PMID- 26523748 TI - Apology: Readily Removable Directing Group Assisted Chemo- and Regioselective C(sp(3))-H Activation by Palladium Catalysis. PMID- 26523751 TI - R-Peak Time: An Electrocardiographic Parameter with Multiple Clinical Applications. AB - In the 12-lead electrocardiogram (ECG), the time from the onset of the QRS complex (Q or R wave) to the apex or peak of R or to R' (when present), using indirect or semidirect surface unipolar precordial leads, bipolar limb leads or unipolar limb leads, is called ventricular activation time (VAT), R wave peak time (RWPT), R-peak time or intrinsicoid deflection (ID). The R-peak time in a specific ECG lead is the interval from the earliest onset of the QRS complex, preferably determined from multiple simultaneously recorded leads, to the peak (maximum) of the R wave or R' if present. Irrespective of the relative height of the R and R' waves, the R-peak time is measured to the second peak. The parameter corresponds to the time of the electrical activation occurring from the endocardium to the epicardium as reflected by the recording electrode located at a variable distance on the body surface, depending on the lead type: a unipolar precordial lead, a bipolar or unipolar limb lead. In normal conditions, the R peak time for the thinner-walled right ventricle is measured from lead V1 or V2 and its upper limit of normal is 35 ms. The R-peak time for the left ventricle (LV) is measured from leads V5 to V6 and 45 ms is considered the upper limit of normal. In this manuscript, we review the clinical applications of this parameter. PMID- 26523752 TI - Erratum. Correction to: Dopamine and Huntington's disease. PMID- 26523753 TI - Inkjet Printing of Lanthanide-Organic Frameworks for Anti-Counterfeiting Applications. AB - Photoluminescent lanthanide-organic frameworks (Ln-MOFs) were printed onto plastic and paper foils with a conventional inkjet printer. Ln-MOF inks were used to reproduce color images that can only be observed under UV light irradiation. This approach opens a new window for exploring Ln-MOF materials in technological applications, such as optical devices (e.g., lab-on-a-chip), as proof of authenticity for official documents. PMID- 26523754 TI - Molecular operational taxonomic units as approximations of species in the light of evolutionary models and empirical data from Fungi. AB - During the last couple of decades, an increasing number of studies use sequence clusters as units for taxonomic diversity. It is well known that such molecular operational taxonomic units (MOTUs) do not necessarily correspond to species, but they are treated as such when measuring diversity and testing theories. Here, I show that data from studies of molecular evolution and species diversification of fungi indicate that commonly used cut-offs are likely to lump species in many cases. At the same time, empirical studies show that the mean within-species variation is close to these cut-offs. That the within-species variation estimates are plausible is supported by coalescence modelling under a range of parameter settings. In addition, studies using crossing tests to delimit species show that there often is an overlap in within- and between-species distances. The available data therefore indicate that sequence clusters are likely to misrepresent species. However, to keep a biological relevance, MOTUs should be kept in close agreement with species. Studies using them should therefore asses how sensitive the results are to differences between MOTUs and species--something that is rarely done. An even better solution is to directly include the uncertainty in species delimitation in the analyses, but in many cases, we need to increase our knowledge of taxonomy and evolution to do this accurately. Even if the empirical data referred to here pertain to the "barcoding" region of rDNA in fungi, there is nothing indicating that the situation is substantially better for other taxa or genes. PMID- 26523755 TI - Physicochemical and Thermal Properties of Extruded Instant Functional Rice Porridge Powder as Affected by the Addition of Soybean or Mung Bean. AB - Legumes contain protein, micronutrients, and bioactive compounds, which provide various health benefits. In this study, soybean or mung bean was mixed in rice flour to produce by extrusion instant functional legume-rice porridge powder. The effects of the type and percentage (10%, 20%, or 30%, w/w) of legumes on the expansion ratio of the extrudates were first evaluated. Amino acid composition, color, and selected physicochemical (bulk density, water absorption index, and water solubility index), thermal (onset temperature, peak temperature, and transition enthalpy), and pasting (peak viscosity, trough viscosity, and final viscosity) properties of the powder were determined. The crystalline structure and formation of amylose-lipid complexes and the total phenolics content (TPC) and antioxidant activity of the powder were also measured. Soybean-blended porridge powder exhibited higher TPC, 2,2-diphenyl-1-picrylhydrazyl radical scavenging capacity, ferric reducing antioxidant power, amino acid, and fat contents than the mung bean-blended porridge powder. Incorporating either legume affected the product properties by decreasing the lightness and bulk density, while increasing the greenness and yellowness and the peak temperature and transition enthalpy. Expansion capacity of the extrudates increased with percentage of mung bean in the mixture but decreased as the percentage of soybean increased. Amylose-lipid complexes formation was confirmed by X-ray diffraction analysis results. Addition of soybean or mung bean resulted in significant pasting property changes of the porridge powder. PMID- 26523756 TI - Human umbilical tissue-derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration. AB - Retinal pigment epithelium (RPE) cells perform many functions crucial for retinal preservation and vision. RPE cell dysfunction results in various retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration (AMD). Currently, there are no effective treatments for retinal degeneration except for a small percentage of individuals with exudative AMD. Cell therapies targeting RPE cells are being developed in the clinic for the treatment of retinal degeneration. Subretinal injection of human umbilical tissue derived cells (hUTC) in the Royal College of Surgeons (RCS) rat model of retinal degeneration was shown to preserve photoreceptors and visual function. However, the precise mechanism remains unclear. Here, we demonstrate that hUTC rescue phagocytic dysfunction in RCS RPE cells in vitro. hUTC secrete receptor tyrosine kinase (RTK) ligands brain-derived neurotrophic factor (BDNF), hepatocyte growth factor (HGF), and glial cell-derived neurotrophic factor (GDNF), as well as opsonizing bridge molecules milk-fat-globule-epidermal growth factor 8 (MFG-E8), growth arrest-specific 6 (Gas6), thrombospondin (TSP)-1, and TSP-2. The effect of hUTC on phagocytosis rescue in vitro is mimicked by recombinant human proteins of these factors and is abolished by siRNA-targeted gene silencing in hUTC. The bridge molecules secreted from hUTC bind to the photoreceptor outer segments and facilitate their ingestion by the RPE. This study elucidates novel cellular mechanisms for the repair of RPE function in retinal degeneration through RTK ligands and bridge molecules, and demonstrates the potential of using hUTC for the treatment of retinal degenerative diseases. PMID- 26523757 TI - Faculty Performance on the Genomic Nursing Concept Inventory. AB - PURPOSE: To use the newly developed Genomic Nursing Concept Inventory (GNCI) to evaluate faculty understanding of foundational genomic concepts, explore relative areas of strength and weakness, and compare the results with those of a student sample. DESIGN: An anonymous online survey instrument consisting of demographic or background items and the 31 multiple-choice questions that make up the GNCI was completed by 495 nursing faculty from across the United States in the fall of 2014. METHODS: Total GNCI score and scores on four subcategories (genome basics, mutations, inheritance, genomic health) were calculated. Relationships between demographic or background variables and total GNCI score were explored. FINDINGS: The mean score on the GNCI was 14.93 (SD = 5.31), or 48% correct; topical category scores were highest on the inheritance and genomic health items (59% and 58% correct, respectively), moderate on the mutations items (54% correct), and lowest on the genome basics items (33% correct). These results are strikingly similar to those of a recent study of nursing students. Factors associated with a higher total score on the GNCI included higher self-rated proficiency with genetic/genomic content, having a doctoral degree, having taken a genetics course for academic credit or continuing education, and having taught either a stand alone genetic/genomic course or lecture content as part of nursing or related course. Self-rated proficiency with genetic/genomic content was fair or poor (70%), with only 7% rating their proficiency as very good or excellent. CONCLUSIONS: Faculty knowledge of foundational genomic concepts is similar to that of the students they teach and weakest in the areas related to basic science information. CLINICAL RELEVANCE: Genomics is increasingly relevant in all areas of clinical nursing practice, and the faculty charged with educating the next generation of nurses must understand foundational concepts. Faculty need to be proactive in seeking out relevant educational programs that include basic genetic/genomic concepts. PMID- 26523758 TI - Translation of Molecular Order to the Macroscopic Level. PMID- 26523759 TI - A Domino Diels-Alder Approach toward the Tetracyclic Nicandrenone Framework. AB - The tetracarbocyclic framework of the nicandrenone natural products is formed in one step from a linear precursor via a domino intramolecular Diels Alder/intramolecular furan Diels-Alder/aromatization sequence. The approach represents a new 0 -> ABCD strategy for the preparation of aromatic steroids. PMID- 26523760 TI - What is the long term safety of a negative capsule endoscopy in patients with obscure gastrointestinal bleeding? AB - BACKGROUND AND AIMS: There are contradictory findings regarding long-term outcome in patients with obscure gastrointestinal bleeding and negative capsule endoscopy. Factors associated with rebleeding after a negative videocapsule are not entirely known. OBJECTIVE: The aim of this study was to compare the rebleeding rate between negative and positive capsule endoscopy patients and to identify predictive factors for rebleeding in patients with negative findings. MATERIAL AND METHODS: Consecutive patients with obscure gastrointestinal bleeding referred to a single center over a period of 5 years were identified. After exclusion of patients with a follow time < 6 months, 173 patients were included. Clinical information was retrospectively collected from medical records. Rebleeding was defined as evidence of melena/hematochezia, a drop in hemoglobin of >= 2 g/dL, or the need for transfusion 30 days after the index episode. RESULTS: The mean age was 61.7 years and 60% were female. The median follow up time was 27 months. Most patients were referred for occult gastrointestinal bleeding (67.1%) while 32.9% were referred for overt bleeding. More than 50% of the patients had negative capsule endoscopy. The rebleeding rate in negative capsule endoscopy is 16%, with a mean follow-up time of 25.8 months and is significantly lower than positive capsule endoscopy (16% vs. 30.2%, p = 0.02). Rebleeding after negative capsule endoscopy is higher in patients who need more transfusions of packet red blood cells before capsule endoscopy (3.0 vs. 0.9, p = 0.024) and have overt bleeding (46% vs. 13.9%, p = 0.03). In 53% of these patients, rebleeding occurs > 12 months after a negative capsule endoscopy. CONCLUSIONS: Patients with obscure gastrointestinal bleeding and a negative capsule endoscopy had a significantly lower rebleeding rate and can be safely followed. However, a higher transfusion of red blood cells previous to capsule endoscopy and an overt bleeding are associated with a higher rebleeding. So, it is reasonable to consider that these patients may benefit of at least one year of follow-up. PMID- 26523761 TI - Targeting autophagy and mitophagy for mitochondrial diseases treatment. AB - INTRODUCTION: Mitochondrial diseases are a group of rare genetic diseases with complex and heterogeneous origins which manifest a great variety of phenotypes. Disruption of the oxidative phosphorylation system is the main cause of pathogenicity in mitochondrial diseases since it causes accumulation of reactive oxygen species (ROS) and ATP depletion. AREAS COVERED: Current evidences support the main protective role of autophagy and mitophagy in mitochondrial diseases and other diseases associated with mitochondrial dysfunction. EXPERT OPINION: The use of autophagy and/or mitophagy inducers may allow a novel strategy for improving mitochondrial function for both mitochondrial diseases and other diseases with altered mitochondrial metabolism. However, a deeper investigation of the molecular mechanisms behind mitophagy and mitochondrial biogenesis is needed in order to safely modulate these processes. In the coming years, we will also see an increase in awareness of mitochondrial dynamics modulation that will allow the therapeutic use of new drugs for improving mitochondrial function in a great variety of mitochondrial disorders. PMID- 26523762 TI - Surgical Approaches in Symptomatic Tarlov Cysts. PMID- 26523763 TI - Surgery for Acute Subdural Hematoma: Replace or Remove the Bone Flap? AB - OBJECTIVE: In surgery for acute subdural hematoma (ASDH), the bone flap can be fixed onto the skull, left riding to provide partial skull decompression, or removed. This study assessed whether removing the bone flap improved outcome. METHODS: We conducted an observational study on consecutive patients who were operated for ASDH in our hospital from July 2011 to June 2014. We retrospectively collected data on demographics, injury severity, and predicted and observed outcomes at 6 months. The cohort was divided into 2 groups based on whether the bone flap was replaced (fixed and riding flap craniotomy) or removed (decompressive craniectomy). The differences in functional status, postoperative control of intracranial hypertension, and number of cranial reoperations were analyzed. A subgroup analysis compared decompressive craniectomy with riding flap craniotomy alone. RESULTS: Data were obtained for 99 patients; 69 had decompressive craniectomy, 17 had riding flap craniotomy, and 13 had fixed flap craniotomy. The decompressive craniectomy group had statistically worse injuries, more predicted poor outcomes (69% vs. 57%, P = 0.013), more observed poor outcomes (59% vs. 37%, P = 0.037), equivalent control of intracranial hypertension, and a similar number of reoperations compared with the craniotomy groups. Subgroup analysis between decompressive craniectomy and riding flap craniotomy showed no significant difference in baseline characteristics and outcomes. CONCLUSIONS: Our study concluded that removing the bone flap after ASDH evacuation was not associated with a better outcome. We recommend replacing the bone flap if brain conditions allow. Further research is required to evaluate the role of skull decompression in surgery for ASDH. PMID- 26523764 TI - The Era of Neuroendoscopy: Just How Far Can We Go? PMID- 26523765 TI - Elucidation of novel budding yeast separase mutants. AB - The mitotic separase cleaves Scc1 in cohesin to allow sister chromatids to separate from each other upon anaphase onset. Separase is also required for DNA damage repair. Here, we isolated and characterized 10 temperature-sensitive (ts) mutants of separase ESP1 in the budding yeast Saccharomyces cerevisiae. All mutants were defective in sister chromatid separation at the restricted temperature. Some esp1-ts mutants were hypersensitive to the microtubule poison benomyl and/or the DNA-damaging agent bleomycin. Overexpression of securin alleviated the growth defect in some esp1-ts mutants, whereas it rather exacerbated it in others. The Drosophila Pumilio homolog MPT5 was isolated as a high-dosage suppressor of esp1-ts cells. We discuss various features of separase based on these findings. PMID- 26523766 TI - Real-time automated EEG tracking of brain states using neural field theory. AB - A real-time fitting system is developed and used to fit the predictions of an established physiologically-based neural field model to electroencephalographic spectra, yielding a trajectory in a physiological parameter space that parametrizes intracortical, intrathalamic, and corticothalamic feedbacks as the arousal state evolves continuously over time. This avoids traditional sleep/wake staging (e.g., using Rechtschaffen-Kales stages), which is fundamentally limited because it forces classification of continuous dynamics into a few discrete categories that are neither physiologically informative nor individualized. The classification is also subject to substantial interobserver disagreement because traditional staging relies in part on subjective evaluations. The fitting routine objectively and robustly tracks arousal parameters over the course of a full night of sleep, and runs in real-time on a desktop computer. The system developed here supersedes discrete staging systems by representing arousal states in terms of physiology, and provides an objective measure of arousal state which solves the problem of interobserver disagreement. Discrete stages from traditional schemes can be expressed in terms of model parameters for backward compatibility with prior studies. PMID- 26523767 TI - Sensitivity enhancement of task-evoked fMRI using ensemble empirical mode decomposition. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) is widely used to investigate dynamic brain functions in neurological and psychological issues; however, high noise level limits its applicability for intensive and sophisticated investigations in the field of neuroscience. NEW METHOD: To deal with both issue (low sensitivity and dynamic signal), we used ensemble empirical mode decomposition (EEMD), an adaptive data-driven analysis method for nonstationary and nonlinear features, to filter task-irrelevant noise from raw fMRI signals. Using both simulations and representative fMRI data, we optimized the analytic parameters and identified non-meaningful intrinsic mode functions (IMFs) to remove noise. RESULTS: We revealed the following advantages of EEMD in fMRI analysis: (1) EEMD achieved high detectability for task engagement; (2) the functional sensitivity was markedly enhanced by removing task-irrelevant artifacts based on EEMD. COMPARISON WITH EXISTING METHOD(S): Compared with other noise-removal methods (e.g., band-pass filtering and independent component analysis), the EEMD-based artifact-removal method exhibited better spatial specificity and superior Gaussianity of the resulting t-score distribution. CONCLUSIONS: We found that EEMD method was efficient to enhance the functional sensitivity of evoked fMRI. The same strategy would be applicable to resting state fMRI signal in the general purpose. PMID- 26523768 TI - DNA Origami Nanoantennas with over 5000-fold Fluorescence Enhancement and Single Molecule Detection at 25 MUM. AB - Optical nanoantennas are known to focus freely propagating light and reversely to mediate the emission of a light source located at the nanoantenna hotspot. These effects were previously exploited for fluorescence enhancement and single molecule detection at elevated concentrations. We present a new generation of self-assembled DNA origami based optical nanoantennas with improved robustness, reduced interparticle distance, and optimized quantum-yield improvement to achieve more than 5000-fold fluorescence enhancement and single-molecule detection at 25 MUM background fluorophore concentration. Besides outperforming lithographic optical antennas, DNA origami nanoantennas are additionally capable of incorporating single emitters or biomolecular assays at the antenna hotspot. PMID- 26523769 TI - Effect of Calcium Ions on the Disintegration of Enteric-Coated Solid Dosage Forms. AB - To investigate the effect of calcium ions on the disintegration of enteric-coated dosage forms, disintegration testing was performed on enteric-coated aspirin tablets in the presence and absence of calcium in the test media. The results show that the presence of calcium ions retards the disintegration of enteric coated dosage forms. This finding, which has not been reported in scientific literature, sheds light on the importance of conducting well-designed detailed investigations into the potential of calcium from dietary sources, calcium supplements, antacids, and/or phosphate binders affecting the absorption of drugs formulated into enteric-coated dosage forms. Moreover, it shows the necessity to investigate the potential of the occurrence of additional nutrient-excipient interactions. PMID- 26523770 TI - Cognitive Metaphor Theory and the Metaphysics of Immediacy. AB - One of the core tenets of cognitive metaphor theory is the claim that metaphors ground abstract knowledge in concrete, first-hand experience. In this paper, I argue that this grounding hypothesis contains some problematic conceptual ambiguities and, under many reasonable interpretations, empirical difficulties. I present evidence that there are foundational obstacles to defining a coherent and cognitively valid concept of "metaphor" and "concrete meaning," and some general problems with singling out certain domains of experience as more immediate than others. I conclude from these considerations that whatever the facts are about the comprehension of individual metaphors, the available evidence is incompatible with the notion of an underlying conceptual structure organized according to the immediacy of experience. PMID- 26523771 TI - Repurposing historical control clinical trial data to provide safety context. AB - Billions of dollars spent, millions of subject-hours of clinical trial experience and an abundance of archived study-level data, yet why are historical data underutilized? We propose that historical data can be aggregated to provide safety, background incidence rate and context to improve the evaluation of new medicinal products. Here, we describe the development and application of the eControls database, which is derived from the control arms of studies of licensed products, and discuss the challenges and potential solutions to the proper application of historical data to help interpret product safety. PMID- 26523772 TI - Going with the flow: harnessing the power of the vasculature for targeted therapy in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease that leads to excessive joint inflammation and is associated with significant morbidity and mortality. Although much is still to be learned about the aetiology RA, a growing body of evidence suggests that an altered vascular environment is an important aspect of its pathophysiology. In this context, RA shares many similarities with cancer, and it is expected that several angiogenic targets in cancer might be relevant to the treatment of RA. Here, we discuss how these targets can be combined with advances in drug development to generate the next generation of RA therapeutics. PMID- 26523773 TI - Emerging therapeutic targets for the treatment of hepatic fibrosis. AB - Fibrosis represents a response to chronic injury, aimed at maintaining organ integrity. Hepatic fibrosis is mainly related to chronic viral hepatitis B or C (HBV or HCV), alcoholic and nonalcoholic steatohepatitis (NASH), and biliary diseases. A deep understanding of the cellular and molecular mechanisms underlying liver fibrosis has enabled the development of 'pathogenetic tailored' therapeutic interventions. However, effective drugs to prevent or revert hepatic fibrosis are still lacking. In this review, we discuss the cellular populations and the molecular pathways involved in liver fibrogenesis as well as the novel approaches currently being tested in clinical trials. PMID- 26523774 TI - The pineapple genome and the evolution of CAM photosynthesis. AB - Pineapple (Ananas comosus (L.) Merr.) is the most economically valuable crop possessing crassulacean acid metabolism (CAM), a photosynthetic carbon assimilation pathway with high water-use efficiency, and the second most important tropical fruit. We sequenced the genomes of pineapple varieties F153 and MD2 and a wild pineapple relative, Ananas bracteatus accession CB5. The pineapple genome has one fewer ancient whole-genome duplication event than sequenced grass genomes and a conserved karyotype with seven chromosomes from before the rho duplication event. The pineapple lineage has transitioned from C3 photosynthesis to CAM, with CAM-related genes exhibiting a diel expression pattern in photosynthetic tissues. CAM pathway genes were enriched with cis regulatory elements associated with the regulation of circadian clock genes, providing the first cis-regulatory link between CAM and circadian clock regulation. Pineapple CAM photosynthesis evolved by the reconfiguration of pathways in C3 plants, through the regulatory neofunctionalization of preexisting genes and not through the acquisition of neofunctionalized genes via whole-genome or tandem gene duplication. PMID- 26523776 TI - TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. AB - Whole-genome sequencing detected structural rearrangements of TERT in 17 of 75 high-stage neuroblastomas, with five cases resulting from chromothripsis. Rearrangements were associated with increased TERT expression and targeted regions immediately up- and downstream of TERT, positioning a super-enhancer close to the breakpoints in seven cases. TERT rearrangements (23%), ATRX deletions (11%) and MYCN amplifications (37%) identify three almost non overlapping groups of high-stage neuroblastoma, each associated with very poor prognosis. PMID- 26523777 TI - Seed filling in domesticated maize and rice depends on SWEET-mediated hexose transport. AB - Carbohydrate import into seeds directly determines seed size and must have been increased through domestication. However, evidence of the domestication of sugar translocation and the identities of seed-filling transporters have been elusive. Maize ZmSWEET4c, as opposed to its sucrose-transporting homologs, mediates transepithelial hexose transport across the basal endosperm transfer layer (BETL), the entry point of nutrients into the seed, and shows signatures indicative of selection during domestication. Mutants of both maize ZmSWEET4c and its rice ortholog OsSWEET4 are defective in seed filling, indicating that a lack of hexose transport at the BETL impairs further transfer of sugars imported from the maternal phloem. In both maize and rice, SWEET4 was likely recruited during domestication to enhance sugar import into the endosperm. PMID- 26523778 TI - Mirror neuron activation in children with developmental coordination disorder: A functional MRI study. AB - The aim of this study was to reveal cortical areas that may contribute to the movement difficulties seen in children with Developmental Coordination Disorder (DCD). Specifically, we hypothesized that there may be a deficit in the mirror neuron system (MNS), a neural system that responds to both performed and observed actions. Using functional MRI, 14 boys with DCD (x=10.08 years +/- 1.31, range=7.83-11.58 years) and 12 typically developing controls (x=10.10 years +/- 1.15, range=8.33-12.00 years) were scanned observing, executing and imitating a finger sequencing task using their right hand. Cortical activations of mirror neuron regions, including posterior inferior frontal gyrus (IFG), ventral premotor cortex, anterior inferior parietal lobule and superior temporal sulcus were examined. Children with DCD had decreased cortical activation mirror neuron related regions, including the precentral gyrus and IFG, as well as in the posterior cingulate and precuneus complex when observing the sequencing task. Region of interest analysis revealed lower activation in the pars opercularis, a primary MNS region, during imitation in the DCD group compared to controls. These findings provide some preliminary evidence to support a possible MNS dysfunction in children with DCD. PMID- 26523779 TI - Expression of secreted protein acidic and rich in cysteine is an independent prognostic indicator of a poor clinical outcome in oropharyngeal carcinoma patients. AB - CONCLUSION: SPARC-expression is an indicator of the prognosis in terms of OS, independent of HPV-infection. HPV-negative patients with SPARC-Low show survival as favorable as HPV-positive patients, probably because of their higher salvage rate after relapse than SPARC-High patients. OBJECTIVE: The objectives of the study were to clarify the correlation between the expression of secreted protein acidic and rich in cysteine (SPARC) and HPV-status, and to determine the prognostic value of SPARC-expression in oropharyngeal squamous cell carcinoma (OPSCC) patients. METHODS: Fifty-three formalin-fixed and paraffin-embedded tissues were obtained from patients with OPSCC who underwent curative treatment. The SPARC protein was detected by immunohistochemistry. SPARC-expression level was divided into two categories, SPARC-High and SPARC-Low, according to the staining index. RESULTS: Twenty-two out of the 53 OPSCC patients were HPV positive. There was no significant correlation between the HPV-status and SPARC expression level. Multivariate Cox proportional hazards regression analysis revealed that the HPV-status and SPARC-expression are independent prognostic indicators of favorable and unfavorable overall survival (OS) (p = 0.021 and p = 0.012), respectively. For disease-free survival, the HPV-status was the only predictive factor (p = 0.022). After stratification by the HPV-status, high SPARC expression was a significant predictor of poor OS in HPV-negative OPSCC patients using Kaplan-Meier analysis and the log-rank test (p = 0.014). Ten out of 28 SPARC-Low patients relapsed, among which six patients (60%) were salvaged. However, 14 out of 25 SPARC-High patients relapsed, and only three patients (21.4%) were salvaged. PMID- 26523780 TI - Peptide vaccines in breast cancer: The immunological basis for clinical response. AB - This review discusses peptide-based vaccines in breast cancer, immune responses and clinical outcomes, which include studies on animal models and phase I, phase I/II, phase II and phase III clinical trials. Peptide-based vaccines are powerful neoadjuvant immunotherapies that can directly target proteins expressed in tumor cells, mainly tumor-associated antigens (TAAs). The most common breast cancer TAA epitopes are derived from MUC1, HER2/neu and CEA proteins. Peptides derived from TAAs could be successfully used to elicit CD8 and CD4 T cell-specific responses. Thus, choosing peptides that adapt to natural variations of human leukocyte antigen (HLA) genes is critical. The most attractive advantage is that the target response is more specific and less toxic than for other therapies and vaccines. Prominent studies on NeuVax - E75 (epitope for HER2/neu and GM-CSF) in breast cancer and DPX-0907 (HLA-A2-TAAs) expressed in breast cancer, ovarian and prostate cancer have shown the efficacy of peptide-based vaccines as neoadjuvant immunotherapy against cancer. Future peptide vaccine strategies, although a challenge to be applied in a broad range of breast cancers, point to the development of degenerate multi-epitope immunogens against multiple targets. PMID- 26523781 TI - Silk sericin: A versatile material for tissue engineering and drug delivery. AB - Sericin is an inexpensive glycoprotein obtained as a by-product in the silk industry. Its variable amino acid composition and diverse functional groups confer upon it attractive bioactive properties, which are particularly interesting for biomedical applications. Because of its antioxidant character, moisturizing ability, and mitogenic effect on mammalian cells, sericin is useful in cell culture and tissue engineering. Its positive effects on keratinocytes and fibroblasts have led to the development of sericin-based biomaterials for skin tissue repair, mainly as wound dressings. Additionally, sericin can be used for bone tissue engineering owing to its ability to induce nucleation of bone-like hydroxyapatite. Stable silk sericin biomaterials, such as films, sponges, and hydrogels, are prepared by cross-linking, ethanol precipitation, or blending with other polymers. Sericin may also be employed for drug delivery because its chemical reactivity and pH-responsiveness facilitate the fabrication of nano- and microparticles, hydrogels, and conjugated molecules, improving the bioactivity of drugs. Here, we summarized the recent advancements in the study of silk sericin for application in tissue engineering and drug delivery. PMID- 26523782 TI - The art of CHO cell engineering: A comprehensive retrospect and future perspectives. AB - Chinese hamster ovary (CHO) cells represent the most frequently applied host cell system for industrial manufacturing of recombinant protein therapeutics. CHO cells are capable of producing high quality biologics exhibiting human-like post translational modifications in gram quantities. However, production processes for biopharmaceuticals using mammalian cells still suffer from cellular limitations such as limited growth, low productivity and stress resistance as well as higher expenses compared to bacterial or yeast based expression systems. Besides bioprocess, media and vector optimizations, advances in host cell engineering technologies comprising introduction, knock-out or post-transcriptional silencing of engineering genes have paved the way for remarkable achievements in CHO cell line development. Furthermore, thorough analysis of cellular pathways and mechanisms important for bioprocessing steadily unravels novel target molecules which might be addressed by functional genomic tools in order to establish superior production cell factories. This review provides a comprehensive summary of the most fundamental achievements in CHO cell engineering over the past three decades. Finally, the authors discuss the potential of novel and innovative methodologies that might contribute to further enhancement of existing CHO based production platforms for biopharmaceutical manufacturing in the future. PMID- 26523783 TI - Rehospitalization risk factors for psychiatric treatment among elderly Medicaid beneficiaries following hospitalization for a physical health condition. AB - OBJECTIVES: Hospitalizations for physical health problems can cause great mental health challenges. We examined risk factors and expenditures for early readmission for inpatient psychiatric treatment following a hospitalization for a non-psychiatric condition. METHOD: We used eight years of Florida Medicaid enrollment and claims data for (FY 2003-2011) as well as data obtained from the Florida Center for Health Information and Policy Analysis, Inpatient Hospital Database, to identify episodes of hospitalization for all Medicaid-enrolled older adults. There were a total of 781,660 index hospitalizations for non-behavioral health-related hospitalizations, 2690 (0.3%) of which resulted in a behavioral health-related rehospitalization within 30 days after discharge. We estimated the relative risk of early rehospitalization using Cox proportional hazards regression. RESULTS: Participants (n = 276,254) were 76.8 +/- 8.3 years old; 68.4% female and 43.5% White. As expected, we found that having a preexisting behavioral health disorder (including severe mental illness, substance use disorder, or dementia) greatly increased the risk of readmission. We also found that male gender increased the risk of early readmission. Older age, being Black and having one or more comorbid medical conditions as identified by the Charlson Index were associated with substantially reduced risk. CONCLUSION: Identifying hospitalized patients with psychiatric conditions, as well as those who are relatively young within this age group, male, White rather than Black or of other race, alcohol abusers, and those without comorbid conditions, and providing them with care to address their behavioral needs may help in efforts to reduce early rehospitalizations for psychiatric conditions. PMID- 26523775 TI - Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis. AB - Heritability analyses of genome-wide association study (GWAS) cohorts have yielded important insights into complex disease architecture, and increasing sample sizes hold the promise of further discoveries. Here we analyze the genetic architectures of schizophrenia in 49,806 samples from the PGC and nine complex diseases in 54,734 samples from the GERA cohort. For schizophrenia, we infer an overwhelmingly polygenic disease architecture in which >=71% of 1-Mb genomic regions harbor >=1 variant influencing schizophrenia risk. We also observe significant enrichment of heritability in GC-rich regions and in higher-frequency SNPs for both schizophrenia and GERA diseases. In bivariate analyses, we observe significant genetic correlations (ranging from 0.18 to 0.85) for several pairs of GERA diseases; genetic correlations were on average 1.3 tunes stronger than the correlations of overall disease liabilities. To accomplish these analyses, we developed a fast algorithm for multicomponent, multi-trait variance-components analysis that overcomes prior computational barriers that made such analyses intractable at this scale. PMID- 26523784 TI - A microstructurally inspired damage model for early venous thrombus. AB - Accumulative damage may be an important contributor to many cases of thrombotic disease progression. Thus, a complete understanding of the pathological role of thrombus requires an understanding of its mechanics and in particular mechanical consequences of damage. In the current study, we introduce a novel microstructurally inspired constitutive model for thrombus that considers a non uniform distribution of microstructural fibers at various crimp levels and employs one of the distribution parameters to incorporate stretch-driven damage on the microscopic level. To demonstrate its ability to represent the mechanical behavior of thrombus, including a recently reported Mullins type damage phenomenon, we fit our model to uniaxial tensile test data of early venous thrombus. Our model shows an agreement with these data comparable to previous models for damage in elastomers with the added advantages of a microstructural basis and fewer model parameters. We submit that our novel approach marks another important step toward modeling the evolving mechanics of intraluminal thrombus, specifically its damage, and hope it will aid in the study of physiological and pathological thrombotic events. PMID- 26523785 TI - Efficient and optimized identification of generalized Maxwell viscoelastic relaxation spectra. AB - Viscoelastic relaxation spectra are essential for predicting and interpreting the mechanical responses of materials and structures. For biological tissues, these spectra must usually be estimated from viscoelastic relaxation tests. Interpreting viscoelastic relaxation tests is challenging because the inverse problem is expensive computationally. We present here an efficient algorithm that enables rapid identification of viscoelastic relaxation spectra. The algorithm was tested against trial data to characterize its robustness and identify its limitations and strengths. The algorithm was then applied to identify the viscoelastic response of reconstituted collagen, revealing an extensive distribution of viscoelastic time constants. PMID- 26523786 TI - Is socioeconomic incorporation associated with a healthier diet? Dietary patterns among Mexican-origin children in the United States. AB - With each successive generation in the United States, Mexican-origin families lose their initial dietary advantages. Focusing on children's diets, we ask whether greater socioeconomic status (SES) can help buffer Mexican-origin children in immigrant families from negative dietary acculturation or whether it exacerbates these dietary risks. Pooling data from the 1999 to 2009 waves of the continuous National Health and Nutrition Examination Survey, we test whether the association between generational status and Mexican-origin children's nutrition varies by the family's SES. When predicting children's overall dietary quality using the Healthy Eating Index (2010) and predicting unhealthy dietary patterns, we find stronger evidence of segmented assimilation, whereby greater family average SES is associated with better diets across generations of Mexican-origin children. High-status Mexican-origin parents appear able to buffer their children against generational dietary declines documented in the acculturation literature. PMID- 26523787 TI - Therapeutic landscapes of home: Exploring Indigenous peoples' experiences of a Housing First intervention in Winnipeg. AB - In this paper, we explore Indigenous perspectives of culture, place, and health among participants in a landmark Canadian Housing First initiative: At Home/Chez Soi (AHCS) project. Implemented from 2009 to 2013 in Winnipeg and four other Canadian cities, AHCS was a multi-city randomized control trial that sought to test the effectiveness of Housing First as a model for addressing chronic homelessness among people living with mental illnesses. As Winnipeg's homeless population is over 70% Indigenous, significant efforts were made to accommodate the culturally specific health, spiritual, and lifestyle preferences of the project's Indigenous participants. While a daunting challenge from an intervention perspective, Winnipeg's experience also provides a unique opportunity to examine how Indigenous participants' experiences can inform improved housing and mental health policy in Canada. In our study, conducted independently from, but with endorsement of the AHCS project, we utilized a case study approach to explore the experiences of the project's Indigenous participants. Data were collected by means of in-depth qualitative interviews with Indigenous participants (N = 14) and key informant project staff and investigators (N = 6). Our exploratory work demonstrates that despite relative satisfaction with the AHCS intervention, Indigenous peoples' sense of place in the city remains largely disconnected from their housing experiences. We found that structural factors, particularly the shortage of affordable housing and systemic erasure of Indigeneity from the urban sociocultural and political landscape, have adversely impacted Indigenous peoples' sense of place and home. PMID- 26523789 TI - School-level contextual predictors of bullying and harassment experiences among adolescents. AB - BACKGROUND: Bullying and prejudice-based harassment frequently occur in school settings and have significant consequences for the health and wellbeing of young people. Yet far fewer studies have examined the role of the school environment in peer harassment than individual factors. This multilevel study examined associations between a variety of school-level risk and protective factors and student-level reports of bullying and prejudice-based harassment during adolescence. METHODS: Data come from 8th, 9th, and 11th graders who completed the 2013 Minnesota Student Survey (N = 122,180 students nested in 505 schools). School-level variables were created by aggregating student report data in five areas: academic orientation to school, internal assets, teacher-student relationship quality, feelings of safety at school, and receipt of disciplinary action. RESULTS: Results indicated that youth attending schools with a higher proportion of students with strong internal assets had lower odds of nearly every type of bullying and prejudice-based harassment assessed when compared to youth attending schools with a lower proportion of students with strong internal assets. Additionally, the proportion of students feeling unsafe at school was a fairly consistent risk factor for most types of peer harassment. CONCLUSION: Findings support the idea that prevention programs aimed at improving school-wide internal assets and feelings of safety at school may be key prevention points. PMID- 26523788 TI - Relationship dynamics around depression in gay and lesbian couples. AB - Research on intimate relationship dynamics around depression has primarily focused on heterosexual couples. This body of work shows that wives are more likely than husbands to offer support to a depressed spouse. Moreover, when wives are depressed, they are more likely than husbands to try and shield their spouse from the stress of their own depression. Yet, previous research has not examined depression and relationship dynamics in gay and lesbian couples. We analyze in depth interviews with 26 gay and lesbian couples (N = 52 individuals) in which one or both partners reported depression. We find evidence that dominant gender scripts are both upheld and challenged within gay and lesbian couples, providing important insight into how gender operates in relation to depression within same sex contexts. Our results indicate that most gay and lesbian partners offer support to a depressed partner, yet lesbian couples tend to follow a unique pattern in that they provide support both as the non-depressed and depressed partner. Support around depression is sometimes viewed as improving the relationship, but if the support is intensive or rejected, it is often viewed as contributing to relationship strain. Support is also sometimes withdrawn by the non-depressed partner because of caregiver exhaustion or the perception that the support is unhelpful. This study points to the importance of considering depression within gay and lesbian relational contexts, revealing new ways support sustains and strains intimate partnerships. We emphasize the usefulness of deploying couple-level approaches to better understand depression in sexual minority populations. PMID- 26523790 TI - Modulation of T-Bet and GATA-3 expression in experimental autoimmune thyroiditis rats through ginsenoside treatment. AB - Hashimoto's thyroiditis (HT) is one of the most common organ-specific autoimmune diseases. Increasing evidence indicates that HT may be characterized by an imbalance in the helper T cell subsets Th1 and Th2. Traditional Chinese Medicine (TCM) considers HT as a chronic exhaustion disease, leading to deficiency of qi. In TCM, qi indicates the functional power of the organs of the human body; hence TCM recommends focusing the treatment of HT so as to increase qi production. Ginseng is a well-known herbal medicine exhibiting a variety of efficacies, its main function-being to generate qi. Ginseng's principal active component is ginsenoside, and modern pharmacology has shown that ginsenoside demonstrates biphasic immunomodulatory effects that can be utilized for the treatment of immune disorders. Previous work demonstrated that ginsenoside has a therapeutic effect on HT, but its mechanism is unknown. Experimental autoimmune thyroiditis rats were produced in order to investigate whether ginsenoside can modulate Th1/Th2 imbalance, the direct objective being to examine modulation of IFN-gamma and IL-4 by ELISA, and the gene and protein expression of T-bet and GATA-3 by real-time PCR and Western blot. IFN-gamma levels were increased while IL-4 levels decreased in EAT rats; treatment with ginsenoside led to decreased peripheral blood IFN-gamma levels, with low doses statistically significant. Ginsenoside produced a biphasic effect on IL-4, with low and moderate doses promoting and high doses inhibiting secretion. Both protein and mRNA levels of T-bet were markedly reduced, while GATA-3 was significantly increased by ginsenoside. PMID- 26523791 TI - Altered cerebellar-amygdala connectivity in violent offenders: A resting-state fMRI study. AB - It has repeatedly been reported, that there are differences in grey matter volume (GMV) between violent offenders and non-violent controls. However, it remains unclear, if structural brain abnormalities influence resting-state functional connectivity (RS-fc) between brain regions. Therefore, in the present investigation, 31 male high-risk violent prisoners were compared to 30 non criminal controls with respect to RS-fc between brain areas. Seed regions for resting-state analysis were selected based on GMV differences between the two groups. Overall, inmates had more GMV in the cerebellum than controls and revealed higher RS-fc between the cerebellum and the amygdala. In contrast, controls relative to prisoners showed higher RS-fc between the cerebellum and the orbitofrontal cortex (OFC). In addition, controls showed more GMV in the dorsolateral prefrontal cortex (DLPFC). Inmates relative to controls had higher RS-fc within the DLPFC. Results are discussed with respect to cerebellar contributions to a brain network underlying moral behavior and violence. Enhanced cerebellar-amygdala connectivity in violent offenders might reflect alterations in the processing of moral emotions. Heightened functional connectivity between cerebellar hemispheres and the OFC in controls could be a correlate of enhanced emotion regulation capacities. Higher functional intra-DLPFC connectivity in violent offenders might represent an effort to regulate emotions. PMID- 26523792 TI - Estrogen receptor-mediated effect of delta-tocotrienol prevents neurotoxicity and motor deficit in the MPTP mouse model of Parkinson's disease. AB - Neuroprotection following signal transduction has been investigated recently as a strategy for Parkinson's disease (PD) therapy. While oxidative stress is important in the pathogenesis of PD, neuroprotection using antioxidants such as alpha-tocopherol have not been successful. delta-tocotrienol (deltaT3), a member of the vitamin E family, has received attention because of activities other than its antioxidative effects. In the present study, we examined the estrogen receptor-beta (ERbeta)-mediated neuroprotective effects of deltaT3 in a mouse model of PD. ERbeta is expressed in neuronal cells, including dopaminergic neurons in the substantia nigra. Daily forced oral administration of deltaT3 inhibited the loss of dopaminergic neurons in the substantia nigra. In addition, the ER inhibitor tamoxifen canceled the neuroprotective effects of deltaT3. Moreover, deltaT3 administration improved the performance of the PD mice in the wheel running activity, while tamoxifen inhibited this improved performance. These results suggest that the oral administration of deltaT3 may be useful in the treatment of PD patients, and ERbeta may be a candidate target for the neuroprotection activity of deltaT3. PMID- 26523793 TI - Hydrogen sulfide (H2S) attenuates uranium-induced acute nephrotoxicity through oxidative stress and inflammatory response via Nrf2-NF-kappaB pathways. AB - As an endogenous gaseous mediator, H2S exerts anti-oxidative, anti-inflammatory and cytoprotective effects in kidneys. This study was designed to investigate the protective effect of H2S against uranium-induced nephrotoxicity in adult SD male rats after in vivo effect of uranium on endogenous H2S formation was explored in kidneys. The levels of endogenous H2S and H2S-producing enzymes (CBS and CSE) were measured in renal homogenates from rats intoxicated by an intraperitoneally (i.p.) injection of uranyl acetate at a single dose of 2.5, 5 or 10 mg/kg. In rats injected i.p. with uranyl acetate (5 mg/kg) or NaHS (an H2S donor, 28 or 56 MUmol/kg) alone or in combination, we determined biochemical parameters and histopathological alteration to assess kidney function, examined oxidative stress markers, and investigated Nrf2 and NF-kappaB pathways in kidney homogenates. The results suggest that uranium intoxication in rats decreased endogenous H2S generation as well as CBS and CSE protein expression. NaHS administration in uranium-intoxicated rats ameliorated the renal biochemical indices and histopathological effects, lowered MDA accumulation, and restored GSH level and anti-oxidative enzymes activities like SOD, CAT, GPx and GST. NaHS treatment in uranium-intoxicated rats activated uranium-inhibited protein expression and nuclear translocation of transcription factor Nrf2, which increased protein expression of downstream target-Nrf2 genes HO-1, NQO-1, GCLC, and TXNRD-1. NaHS administration in uranium-intoxicated rats inhibited uranium-induced nuclear translocation and phosphorylation of transcription factor kappaB/p65, which decreased protein expression of target-p65 inflammatory genes TNF-alpha, iNOS, and COX-2. Taken together, these data implicate that H2S can afford protection to rat kidneys against uranium-induced adverse effects through induction of antioxidant defense by activating Nrf2 pathway and reduction of inflammatory response by suppressing NF-kappaB pathway. PMID- 26523796 TI - The case for periodic OPV routine vaccination campaigns. AB - The possibility of periodic routine vaccination campaigns (PRVCs) is introduced in the context of a search for optimal oral poliovirus vaccine (OPV) administration strategies. Like the usual continuous routine vaccination campaign (CRVC), PRVCs target only newborns. However, they are not necessarily implemented continuously in time. Using a dynamic and compartmental polio transmission model in a stochastic context, it is shown that some PRVCs can achieve much greater efficiency than CRVC in terms of probability of wild poliovirus (WPV) eradication, even though they never outperform CRVC in terms of total number of paralytic infections. Moreover, these PRVCs results can be obtained at a lower price than CRVC. It is also shown that, even though PRVCs do not perform better than pulse vaccination campaigns (PVCs) when only epidemiological outputs are valued, they can do so when a cost-benefit analysis is preferred. PMID- 26523795 TI - Effect of enzymatic and mechanical methods of dissociation on neural progenitor cells derived from induced pluripotent stem cells. AB - PURPOSE: To determine the most effective method of dissociating neural stem and progenitor cells into a single-cell suspension. MATERIALS/METHODS: Induced pluripotent stem cells were differentiated toward the neural fate for 4 weeks before clusters were subjected to enzymatic (Accutase, trypsin, TrypLE, dispase, or DNase I) or mechanical (trituration with pipettes of varying size) or combined dissociation. Images of cells were analyzed for cluster size using ImageJ. RESULTS: Cells treated with the enzymes Accutase, TrypLE, or trypsin/EDTA, these enzymes followed by trituration, or a combination one of these enzymes followed by incubation with another enzyme, including DNase I, were more likely to be dissociated into a single-cell suspension. CONCLUSIONS: Cells treated with enzymes or combinations of methods were more likely to be dissociated into a single-cell suspension. PMID- 26523794 TI - Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC alpha-synuclein transgenic rat model of Parkinson's disease. AB - Parkinson's disease (PD) is a multisystem disorder, involving several monoaminergic neurotransmitter systems resulting in a broad range of motor and non-motor symptoms. Pathological hallmarks of PD are the loss of dopaminergic neurons and the accumulation of alpha-synuclein, however also being present in the serotonergic raphe nuclei early in the disease course. The dysfunction of the serotonergic system projecting to the hippocampus may contribute to early non motor symptoms such as anxiety and depression. The adult hippocampal dentate gyrus (DG), a unique niche of the forebrain continuously generating new neurons, may particularly present enhanced susceptibility towards accumulating alpha synuclein levels. The underlying molecular mechanisms in the context of neuronal maturation and survival of new-born neurons are yet not well understood. To characterize the effects of overexpression of human full-length alpha-synuclein on hippocampal cellular and synaptic plasticity, we used a recently generated BAC alpha-synuclein transgenic rat model showing important features of PD such as widespread and progressive alpha-synuclein aggregation pathology, dopamine loss and age-dependent motor decline. At the age of four months, thus prior to the occurrence of the motor phenotype, we observed a profoundly impaired dendritogenesis of neuroblasts in the hippocampal DG resulting in severely reduced survival of adult new-born neurons. Diminished neurogenesis concurred with a serotonergic deficit in the hippocampus as defined by reduced levels of serotonin (5-HT) 1B receptor, decreased 5-HT neurotransmitter levels, and a loss of serotonergic nerve terminals innervating the DG/CA3 subfield, while the number of serotonergic neurons in the raphe nuclei remained unchanged. Moreover, alpha synuclein overexpression reduced proteins involved in vesicle release, in particular synapsin-1 and Rab3 interacting molecule (RIM3), in conjunction with an altered ultrastructural architecture of hippocampal synapses. Importantly, BAC alpha-synuclein rats showed an early anxiety-like phenotype consisting of reduced exploratory behavior and feeding. Taken together, these findings imply that accumulating alpha-synuclein severely affects hippocampal neurogenesis paralleled by impaired 5-HT neurotransmission prior to the onset of aggregation pathology and overt motor deficits in this transgenic rat model of PD. PMID- 26523797 TI - Hemodynamic Consequences of Laparoscopy for Patients on Mechanical Circulatory Support. AB - BACKGROUND: Technologic advances and superior survival with mechanical circulatory support (MCS) have led to an expanding population that develops intraabdominal conditions requiring intervention. Whether laparoscopy can be performed without detrimental effects on hemodynamics and device function is not well described. MATERIALS AND METHODS: Effects of laparoscopy performed on MCS were retrospectively assessed. Intraoperative hemodynamics and device function were compared with the same time interval 24 hours prior to surgery using intrapatient paired t tests. Outcomes included survival, transfusion, thromboembolic events, and infection. RESULTS: Twelve patients with ventricular assist devices or total artificial hearts underwent laparoscopy from 2012 to 2014. Median follow-up was 116 days. Operations included cholecystectomy, diagnostic laparoscopy, gastrojejunostomy, and gastrostomy. There were no differences between preoperative and intraoperative mean arterial pressure, heart rate, and inotrope or vasopressor requirements (P > .05). Device fill volume, flow, rate, and power were unchanged (P > .05), whereas pulsatility index decreased by 0.2 (95% confidence interval, 0.03, 0.36) with laparoscopy (P = .03). All intraoperative fluctuations in hemodynamics and device function improved with reduction of pneumoperitoneum, adjusting device speed, or pharmacologic support. There were no operative mortalities. Thirty-day survival and survival to discharge were 75% and 50%, respectively. Despite antiplatelet therapy and preoperative international normalization ratio of 2.2 +/- 0.9, there were no re-operations for bleeding, and 50% did not require transfusion. Two patients with recent cardiac surgery had thromboembolic events: one stroke and one device thrombus. None had postoperative bacteremia or driveline infection. CONCLUSIONS: Laparoscopy can be performed on MCS with low morbidity and mortality and minimal perturbations in hemodynamics and device function. PMID- 26523798 TI - Between Extremes: Health Effects of Heat and Cold. PMID- 26523799 TI - Boron based two-dimensional crystals: theoretical design, realization proposal and applications. AB - The successful realization of free-standing graphene and the various applications of its exotic properties have spurred tremendous research interest for two dimensional (2D) layered materials. Besides graphene, many other 2D materials have been successfully produced by experiment, such as silicene, monolayer MoS2, few-layer black phosphorus and so on. As a neighbor of carbon in the periodic table, element boron is interesting and many researchers have contributed their efforts to realize boron related 2D structures. These structures may be significant both in fundamental science and future technical applications in nanoelectronics and nanodevices. In this review, we summarize the recent developments of 2D boron based materials. The theoretical design, possible experimental realization strategies and their potential technical applications are presented and discussed. Also, the current challenges and prospects of this area are discussed. PMID- 26523801 TI - Putting the Law Into Practice: A Comparison of Isolation and Quarantine As Tools to Control Tuberculosis and Ebola. AB - The recent Ebola epidemic has put the words "isolation and quarantine" in the spotlight. Isolation and quarantine are tools that are often utilized by public health officials around the United States to address various types of infectious disease, including tuberculosis. While voluntary compliance is preferred, it can be difficult to achieve. In cases where an individual chooses not to voluntarily comply with an isolation or quarantine request, public health officials require assistance from the judiciary and law enforcement to effectuate the order. This article compares 2 recent court cases with different outcomes where public health officials sought assistance from the courts to enforce an isolation or quarantine order. PMID- 26523802 TI - Authors' Reply. PMID- 26523803 TI - A three-dimensional interconnected hierarchical FeOOH/TiO2/ZnO nanostructural photoanode for enhancing the performance of photoelectrochemical water oxidation. AB - A novel ZnO/TiO2/FeOOH hierarchical nanostructure has been synthesized by a low temperature chemical bath deposition method. The integrated three-dimensional (3D) nanostructure consists of one-dimensional (1D) ZnO/TiO2 core-shell nanowire arrays and two-dimensional (2D) interconnected FeOOH nanosheets. By applying such a hierarchical nanostructure as a photoanode for photoelectrochemical water reaction, higher photostability and photocurrent density are gained compared with the reported ZnO based nanostructures. It is concluded that the giant enhancement of the properties is because, in the process of photoelectrochemical reaction, electron-hole separation and transfer are enhanced efficiently through the ZnO/TiO2 heterojunction, and in the meanwhile, terminal interconnected FeOOH nanosheets play both the roles of a surface catalyst and a protective layer effectively to accelerate water splitting reaction and enhance photostability. Based on such an environmentally friendly hierarchical nanostructure, photoelectrochemical water splitting and other similar reactions could be performed effectively and economically. PMID- 26523805 TI - [Clinical trials in Latin American countries]. PMID- 26523806 TI - Electrochemistry and speciation of Au(+) in a deep eutectic solvent: growth and morphology of galvanic immersion coatings. AB - In this study we compare the electrochemical and structural properties of three gold salts AuCl, AuCN and KAu(CN)2 in a Deep Eutectic Solvent (DES) electrolyte (Ethaline 200) in order to elucidate factors affecting the galvanic deposition of gold coatings on nickel substrates. A chemically reversible diffusion limited response was observed for AuCl, whereas AuCN and KAu(CN)2 showed much more complicated, kinetically limited responses. Galvanic exchange reactions were performed on nickel substrates from DES solutions of the three gold salts; the AuCN gave a bright gold coating, the KAu(CN)2 solution give a visibly thin coating, whilst the coating from AuCl was dull, friable and poorly adhesive. This behaviour was rationalised by the differing speciation for each of these compounds, as evidenced by EXAFS methods. Analysis of EXAFS data shows that AuCl forms the chlorido-complex [AuCl2](-), AuCN forms a mixed [AuCl(CN)](-) species, whereas KAu(CN)2 maintains its [Au(CN)2](-) structure. The more labile Cl(-) enables easier reduction of Au when compared to the tightly bound cyanide species, hence leading to slower kinetics of deposition and differing electrochemical behaviour. We conclude that metal speciation in DESs is a function of the initial metal salt and that this has a strong influence on the mechanism and rate of growth, as well as on the morphology of the metal deposit obtained. In addition, these coatings are also extremely promising from a technological perspective as Electroless Nickel Immersion Gold (ENIG) finishes in the printed circuit board (PCB) industry, where the elimination of acid in gold plating formulation could potentially lead to more reliable coatings. Consequently, these results are both significant and timely. PMID- 26523804 TI - Clinicopathological Correlations and Concomitant Pathologies in Rapidly Progressive Dementia: A Brain Bank Series. AB - BACKGROUND: Rapidly progressive dementia (RPD) is caused by a heterogeneous group of both neurodegenerative and non-neurodegenerative disorders. The presence of concomitant pathologies, mainly Alzheimer's disease (AD), may act as a confounding variable in the diagnostic process of this group of diseases. OBJECTIVES: We aimed to describe clinicopathological features, including Alzheimer's co-pathology, and diagnostic accuracy in a postmortem series of RPD. METHODS: Retrospective analysis of 160 brain donors with RPD (defined as 2 years of disease duration from the first symptom to death) registered at the Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS, from 2001 to 2011. RESULTS: Prion diseases were the most frequent neuropathological diagnosis (67%), followed by non-prion neurodegenerative pathologies (17%), mostly AD and dementia with Lewy bodies, and non-neurodegenerative diseases (16%). We observed clinicopathological diagnostic agreement in 94% of the patients with prion RPD but only in 21% of those with non-prion RPD. Four patients with potentially treatable disorders were diagnosed, while still alive, as having Creutzfeldt Jakob disease. Concomitant pathologies were detected in 117 (73%). Among all RPD cases, 51 presented moderate or frequent mature beta-amyloid plaques (neuritic plaques), which are considered to be associated with positive amyloid biomarkers in vivo. CONCLUSIONS: Prion diseases were accurately identified in our series. In contrast, non-prion RPD diagnosis was poor while the patients were still alive, supporting the need for better diagnostic tools and confirmatory neuropathological studies. The presence of concomitant AD pathology in RPD should be taken into account in the interpretation of amyloid biomarkers. PMID- 26523807 TI - The role of the [CpM(CO)2](-) chromophore in the optical properties of the [Cp2ThMCp(CO)2](+) complexes, where M = Fe, Ru and Os. A theoretical view. AB - The chemical bond between actinide and the transition metal unsupported by bridging ligands is not well characterized. In this paper we study the electronic properties, bonding nature and optical spectra in a family of [Cp2ThMCp(CO)2](+) complexes where M = Fe, Ru, Os, based on the relativistic two component density functional theory calculations. The Morokuma-Ziegler energy decomposition analysis shows an important ionic contribution in the Th-M interaction with around 25% of covalent character. Clearly, charge transfer occurs on Th-M bond formation, however the orbital term most likely represents a strong charge rearrangement in the fragments due to the interaction. Finally the spin-orbit ZORA calculation shows the possible NIR emission induced by the [FeCp(CO)2](-) chromophore accomplishing the antenna effect that justifies the sensitization of the actinide complexes. PMID- 26523809 TI - Effect of hydration on the organo-noble gas molecule HKrCCH: role of krypton in the stabilization of hydrated HKrCCH complexes. AB - The effect of hydration on the fluorine free organo-noble gas compound HKrCCH and the role of krypton in the stabilization of the hydrated HKrCCH complexes have been investigated using the quantum chemical calculations on the HKrCCH-(H2O)n=1 6 clusters. Structure and energetics calculations show that water stabilizes HKrCCH through the pi hydrogen bond in which the OH group of water interacts with the C[triple bond, length as m-dash]C group of HKrCCH. A maximum of four water molecules can directly interact with the C[triple bond, length as m-dash]C of HKrCCH and after that only inter-hydrogen bonding takes place between the water molecules indicating that the primary hydration shell contains four water molecules. Atom in molecule analysis depicts that pi hydrogen bonded complexes of the hydrated HKrCCH are cyclic structures in which the OKr interaction cooperates in the formation of strong O-HC[triple bond, length as m-dash]C interaction. Structure, energetics and charge analysis clearly established that krypton plays an important role in the stabilization as well as the formation of the primary hydration shell of hydrated HKrCCH complexes. PMID- 26523810 TI - Acute myocardial infarction as a finding of acute promyelocytic leukemia-related coagulation disorder. AB - Acute promyelocytic leukemia (APL) has one of the most favorable prognoses among other leukemia subtypes. However, the major cause of mortality in APL is disseminated intravascular coagulation at the presentation. We present a case of acute myocardial infarction (MI) at the time of APL diagnosis before treatment. The patient suffered from chest pain, sweating and giddiness. He was hypoxic, hypotensive and bradycardic. ECG showed inferior MI. Unfractioned heparin infusion (850 U/h) was started and 5 min after the previous ECG showed total ST resolution. We suggest that in this case, MI was not related to atherosclerotic plaque rupture but related to DIC manifestation. PMID- 26523815 TI - Isolated Pustular Nodule on the Thumb. PMID- 26523811 TI - Proximity hybridization-regulated electrochemical stripping of silver nanoparticles via nanogold induced deposition for immunoassay. AB - A simple and disposable electrochemical immunosensor was developed for sensitive and selective detection of a protein biomarker via target-induced proximity hybridization and electrochemical stripping analysis of silver nanoparticles (AgNPs). The immunosensor was prepared by assembling single-stranded DNA modified gold nanoparticles (ssDNA@AuNPs) on a graphene oxide modified disposable screen printed carbon electrode (SPCE). In the presence of a target protein and two DNA labeled antibodies, the proximate complex formed in homogeneous solution could hybridize with the assembled DNA to take away AuNPs, which decreased AuNP catalyzed deposition of AgNPs on the immunosensor surface, and thus the anodic stripping signal. The proposed method avoided the interference of dissolved oxygen. Using the carcinoembryonic antigen (CEA) as a model analyte, this method showed a linear range of four magnitude orders with a detection limit down to 3.9 pg mL(-1). The electrochemical immunosensor possessed preparation convenience, good stability and high sensitivity, and could be extended to sensitive biosensing of other analytes, showing potential application in point-of-care testing. PMID- 26523816 TI - Breastfeeding and Childhood Leukemia Incidence: Duplicate Data Inadvertently Included in the Meta-analysis and Consideration of Possible Confounders. PMID- 26523817 TI - Breastfeeding and Childhood Leukemia Incidence: Duplicate Data Inadvertently Included in the Meta-analysis and Consideration of Possible Confounders. PMID- 26523819 TI - Duplicate Data Inadvertently Included in the Meta-analysis. PMID- 26523818 TI - Breastfeeding and Childhood Leukemia Incidence--Reply. PMID- 26523820 TI - JAMA Pediatrics Patient Page. Reading to Preschool Children. PMID- 26523821 TI - Implementation of Screening, Brief Intervention, and Referral to Treatment for Adolescents in Pediatric Primary Care: A Cluster Randomized Trial. AB - IMPORTANCE: Early intervention for substance use is critical to improving adolescent outcomes. Studies have found promising results for Screening, Brief Intervention, and Referral to Treatment (SBIRT), but little research has examined implementation. OBJECTIVE: To compare SBIRT implementation in pediatric primary care among trained pediatricians, pediatricians working in coordination with embedded behavioral health care practitioners (BHCPs), and usual care (UC). DESIGN, SETTING, AND PARTICIPANTS: The study is a 2-year (November 1, 2011, through October 31, 2013), nonblinded, cluster randomized, hybrid implementation and effectiveness trial examining SBIRT implementation outcomes across 2 modalities of implementation and UC. Fifty-two pediatricians from a large general pediatrics clinic in an integrated health care system were randomized to 1 of 3 SBIRT implementation arms; patients aged 12 to 18 years were eligible. INTERVENTIONS: Two modes of SBIRT implementation, (1) pediatrician only (pediatricians trained to provide SBIRT) and (2) embedded BHCP (BHCP trained to provide SBIRT), and (3) UC. MAIN OUTCOMES AND MEASURES: Implementation of SBIRT (primary outcome), which included assessments, brief interventions, and referrals to specialty substance use and mental health treatment. RESULTS: The final sample included 1871 eligible patients among 47 pediatricians; health care professional characteristics did not differ across study arms. Patients in the pediatrician only (adjusted odds ratio [AOR], 10.37; 95% CI, 5.45-19.74; P < .001) and the embedded BHCP (AOR, 18.09; 95% CI, 9.69-33.77; P < .001) arms had higher odds of receiving brief interventions compared with patients in the UC arm. Patients in the embedded BHCP arm were more likely to receive brief interventions compared with those in the pediatrician-only arm (AOR, 1.74; 95% CI, 1.31-2.31; P < .001). The embedded BHCP arm had lower odds of receiving a referral compared with the pediatrician-only (AOR, 0.58; 95% CI, 0.43-0.78; P < .001) and UC (AOR, 0.65; 95% CI, 0.48-0.89; P = .006) arms; odds of referrals did not differ between the pediatrician-only and UC arms. CONCLUSIONS AND RELEVANCE: The intervention arms had better screening, assessment, and brief intervention rates than the UC arm. Patients in the pediatrician-only and UC arms had higher odds of being referred to specialty treatment than those in the embedded BHCP arm, suggesting lingering barriers to having pediatricians fully address substance use in primary care. Findings also highlight age and ethnic groups less likely to receive these important services. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02408952. PMID- 26523822 TI - Early Exposure to Dogs and Farm Animals and the Risk of Childhood Asthma. AB - IMPORTANCE: The association between early exposure to animals and childhood asthma is not clear, and previous studies have yielded contradictory results. OBJECTIVE: To determine whether exposure to dogs and farm animals confers a risk of asthma. DESIGN, SETTING AND PARTICIPANTS: In a nationwide cohort study, the association between early exposure to dogs and farm animals and the risk of asthma was evaluated and included all children born in Sweden from January 1, 2001, to December 31, 2010 (N = 1,011,051), using registry data on dog and farm registration, asthma medication, diagnosis, and confounders for parents and their children. The association was assessed as the odds ratio (OR) for a current diagnosis of asthma at age 6 years for school-aged children and as the hazard ratio (HR) for incident asthma at ages 1 to 5 years for preschool-aged children. Data were analyzed from January 1, 2007, to September 30, 2012. EXPOSURES: Living with a dog or farm animal. MAIN OUTCOMES AND MEASURES: Childhood asthma diagnosis and medication used. RESULTS: Of the 1,011,051 children born during the study period, 376,638 preschool-aged (53,460 [14.2%] exposed to dogs and 1729 [0.5%] exposed to farm animals) and 276,298 school-aged children (22,629 [8.2%] exposed to dogs and 958 [0.3%] exposed to farm animals) were included in the analyses. Of these, 18,799 children (5.0%) in the preschool-aged children's cohort experienced an asthmatic event before baseline, and 28,511 cases of asthma and 906,071 years at risk were recorded during follow-up (incidence rate, 3.1 cases per 1000 years at risk). In the school-aged children's cohort, 11,585 children (4.2%) experienced an asthmatic event during the seventh year of life. Dog exposure during the first year of life was associated with a decreased risk of asthma in school-aged children (OR, 0.87; 95% CI, 0.81-0.93) and in preschool-aged children 3 years or older (HR, 0.90; 95% CI, 0.83-0.99) but not in children younger than 3 years (HR, 1.03; 95% CI, 1.00-1.07). Results were comparable when analyzing only first-born children. Farm animal exposure was associated with a reduced risk of asthma in both school-aged children and preschool-aged children (OR, 0.48; 95% CI, 0.31-0.76, and HR, 0.69; 95% CI, 0.56-0.84), respectively. CONCLUSIONS AND RELEVANCE: In this study, the data support the hypothesis that exposure to dogs and farm animals during the first year of life reduces the risk of asthma in children at age 6 years. This information might be helpful in decision making for families and physicians on the appropriateness and timing of early animal exposure. PMID- 26523823 TI - Acute-Onset Sleepiness and Decrease in Consciousness. PMID- 26523824 TI - Dirac Green function for angular projection potentials. AB - The aim of this paper is twofold: first, it is shown that the angular dependence of the Dirac Green function can be described analytically for potentials with non local dependence on the angular variables if they are chosen as projection potentials in angular momentum space. Because the local dependence on the radial variable can be treated to any precision with present computing capabilities, this means that the Green function can be calculated practically exactly. Second, it is shown that a result of this kind not only holds for a single angular projection potential but also more generally, for instance if space is divided into non-overlapping cells and a separate angular projection potential is used in each cell. This opens the way for relativistic density-functional calculations within a different perspective than the conventional one. Instead of trying to obtain the density for a given potential approximately as well as possible, the density is determined exactly for non-local potentials which can approximate arbitrary local potentials as well as desired. PMID- 26523825 TI - New Approach to Exclude the Left Atrial Appendage During Minimally Invasive Cryothermic Surgical Ablation. AB - OBJECTIVE: Atrial fibrillation (AF) is associated with an increased risk for embolic stroke originating from the left atrial appendage (LAA). A recently introduced LAA epicardial clip occluder, the AtriClip PRO, can be applied through midsternotomy or small thoracotomy. We assessed the safety and efficacy of a new surgical approach to apply the AtriClip PRO and exclude the LAA through right minithoracotomy and transverse sinus. METHODS: The AtriClip PRO was applied in 24 patients with the new approach. Intraoperative transesophageal echocardiography was used to exclude LAA thrombi at baseline and evaluate LAA perfusion and residual neck postoperatively. RESULTS: Mean (SD) age was 64.5 (8.6) years; 95% of the patients had nonparoxysmal AF with median AF duration of 39 months (interquartile range, 9.3-85.3 months), and mean (SD) left atrium diameter was 4.5 (0.7) cm (range, 3.1-5.7 cm). In one attempt, the clip was not deployed because of severe adhesions in the transverse sinus area. The procedural success rate was 95%. Nine minimally invasive mitral valve repairs were combined with surgical ablation; the rest were isolated right minithoracotomy Cox maze procedures. There was no remaining LAA neck in 71% of the patients. Perioperative outcomes were acceptable, and median length of stay was 5.5 days. CONCLUSIONS: The development of a reliable approach to LAA management during minimally invasive surgical ablation through right minithoracotomy has been challenging. This new approach is safe and effective and should offer a superior and consistent early and long-term solution compared with the current approach of endocardial stitch closure. PMID- 26523826 TI - Effect of Prolonged Simulated Microgravity on Metabolic Proteins in Rat Hippocampus: Steps toward Safe Space Travel. AB - Mitochondria are not only the main source of energy in cells but also produce reactive oxygen species (ROS), which result in oxidative stress when in space. This oxidative stress is responsible for energy imbalances and cellular damage. In this study, a rat tail suspension model was used in individual experiments for 7 and 21 days to explore the effect of simulated microgravity (SM) on metabolic proteins in the hippocampus, a vital brain region involved in learning, memory, and navigation. A comparative (18)O-labeled quantitative proteomic strategy was used to observe the differential expression of metabolic proteins. Forty-two and sixty-seven mitochondrial metabolic proteins were differentially expressed after 21 and 7 days of SM, respectively. Mitochondrial Complex I, III, and IV, isocitrate dehydrogenase and malate dehydrogenase were down-regulated. Moreover, DJ-1 and peroxiredoxin 6, which defend against oxidative damage, were up regulated in the hippocampus. Western blot analysis of proteins DJ-1 and COX 5A confirmed the mass spectrometry results. Despite these changes in mitochondrial protein expression, no obvious cell apoptosis was observed after 21 days of SM. The results of this study indicate that the oxidative stress induced by SM has profound effects on metabolic proteins. PMID- 26523827 TI - Strategies for Flipping the Script on Opioid Overprescribing. PMID- 26523828 TI - Side Chain Conformational Distributions of a Small Protein Derived from Model Free Analysis of a Large Set of Residual Dipolar Couplings. AB - Accurate quantitative measurement of structural dispersion in proteins remains a prime challenge to both X-ray crystallography and NMR spectroscopy. Here we use a model-free approach based on measurement of many residual dipolar couplings (RDCs) in differentially orienting aqueous liquid crystalline solutions to obtain the side chain chi1 distribution sampled by each residue in solution. Applied to the small well-ordered model protein GB3, our approach reveals that the RDC data are compatible with a single narrow distribution of side chain chi1 angles for only about 40% of the residues. For more than half of the residues, populations greater than 10% for a second rotamer are observed, and four residues require sampling of three rotameric states to fit the RDC data. In virtually all cases, sampled chi1 values are found to center closely around ideal g(-), g(+) and t rotameric angles, even though no rotamer restraint is used when deriving the sampled angles. The root-mean-square difference between experimental (3)JHalphaHbeta couplings and those predicted by the Haasnoot-parametrized, motion-adjusted Karplus equation reduces from 2.05 to 0.75 Hz when using the new rotamer analysis instead of the 1.1-A X-ray structure as input for the dihedral angles. A comparison between observed and predicted (3)JHalphaHbeta values suggests that the root-mean-square amplitude of chi1 angle fluctuations within a given rotamer well is ca. 20 degrees . The quantitatively defined side chain rotamer equilibria obtained from our study set new benchmarks for evaluating improved molecular dynamics force fields, and also will enable further development of quantitative relations between side chain chemical shift and structure. PMID- 26523829 TI - Regioselective Fluorination of Imidazo[1,2-a]pyridines with Selectfluor in Aqueous Condition. AB - A regioselective synthesis of 3-fluorinated imidazo[1,2-a]pyridines using 1 chloromethyl-4-fluoro-1,4-diazoniabi cyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) as the fluorinating reagent in aqueous condition is described. In the presence of DMAP, the reaction mainly gave monofluorinated product via electrophilic fluorinated process in moderate to good yields. PMID- 26523830 TI - Tim Bartness, Ph.D. (1953-2015). PMID- 26523831 TI - Metal-Metal Bonding in Trinuclear, Mixed-Valence [Ti3X12](4-) (X = F, Cl, Br, I) Face-Shared Complexes. AB - Metal-metal bonding in structurally characterized In4Ti3Br12, comprising linear, mixed-valence d(1)d(2)d(1) face-shared [Ti3Br12](4-) units with a Ti-Ti separation of 3.087 A and strong antiferromagnetic coupling (Theta = -1216 K), has been investigated using density functional theory. The antiferromagnetic configuration, in which the single d electron on each terminal Ti(III) (d(1)) metal center is aligned antiparallel to the two electrons occupying the central Ti(II) (d(2)) metal site, is shown to best agree with the reported structural and magnetic data and is consistent with an S = 0 ground state in which two of the four metal-based electrons are involved in a two-electron, three-center sigma bond between the Ti atoms (formal Ti-Ti bond order of ~0.5). However, the unpaired spin densities on the Ti sites indicate that while the metal-metal sigma interaction is strong, the electrons are not fully paired off and consequently dominate the ground state antiferromagnetic coupling. The same overall partially delocalized bonding regime is predicted for the other three halide [Ti3X12](4-) (X = F, Cl, I) systems with the metal-metal bonding becoming weaker as the halide group is descended. The possibility of bond-stretch isomerism was also examined where one isomer has a symmetric structure with identical Ti-Ti bonds while the other is unsymmetric with one short and one long Ti-Ti bond. Although calculations indicate that the latter form is more stable, the barrier to interconversion between equivalent unsymmetric forms, where the short Ti-Ti bond is on one side of the trinuclear unit or the other, is relatively small such that at room temperature only the averaged (symmetric) structure is likely to be observed. PMID- 26523832 TI - Fibroblast Growth Factor Receptor-2 Contributes to the Basic Fibroblast Growth Factor-Induced Neuronal Differentiation in Canine Bone Marrow Stromal Cells via Phosphoinositide 3-Kinase/Akt Signaling Pathway. AB - Bone marrow stromal cells (BMSCs) are considered as candidates for regenerative therapy and a useful model for studying neuronal differentiation. The role of basic fibroblast growth factor (bFGF) in neuronal differentiation has been previously studied; however, the signaling pathway involved in this process remains poorly understood. In this study, we investigated the signaling pathway in the bFGF-induced neuronal differentiation of canine BMSCs. bFGF induced the mRNA expression of the neuron marker, microtubule associated protein-2 (MAP2) and the neuron-like morphological change in canine BMSCs. In the presence of inhibitors of fibroblast growth factor receptors (FGFR), phosphatidylinositol 3 kinase (PI3K) and Akt, i.e., SU5402, LY294002, and MK2206, respectively, bFGF failed to induce the MAP2 mRNA expression and the neuron-like morphological change. bFGF induced Akt phosphorylation, but it was attenuated by the FGFR inhibitor SU5402 and the PI3K inhibitor LY294002. In canine BMSCs, expression of FGFR-1 and FGFR-2 was confirmed, but only FGFR-2 activation was detected by cross linking and immunoprecipitation analysis. Small interfering RNA-mediated knockdown of FGFR-2 in canine BMSCs resulted in the attenuation of bFGF-induced Akt phosphorylation. These results suggest that the FGFR-2/PI3K/Akt signaling pathway is involved in the bFGF-induced neuronal differentiation of canine BMSCs. PMID- 26523833 TI - A Synthetic Aptamer-Drug Adduct for Targeted Liver Cancer Therapy. AB - AS1411 (previously known as AGRO100) is a 26 nucleotide guanine-rich DNA aptamer which forms a guanine quadruplex structure. AS1411 has shown promising utility as a treatment for cancers in Phase I and Phase II clinical trials without causing major side-effects. AS1411 inhibits tumor cell growth by binding to nucleolin which is aberrantly expressed on the cell membrane of many tumors. In this study, we utilized a simple technique to conjugate a widely-used chemotherapeutic agent, doxorubicin (Dox), to AS1411 to form a synthetic Drug-DNA Adduct (DDA), termed as AS1411-Dox. We demonstrate the utility of AS1411-Dox in the treatment of hepatocellular carcinoma (HCC) by evaluating the targeted delivery of Dox to Huh7 cells in vitro and in a murine xenograft model of HCC. PMID- 26523834 TI - Percutaneous Coronary Intervention after Fibrinolysis for ST-Segment Elevation Myocardial Infarction Patients: An Updated Systematic Review and Meta-Analysis. AB - BACKGROUND: Percutaneous coronary intervention (PCI), fibrinolysis and the combination of both methods are current therapeutic options for patients with ST segment elevation myocardial infarction (STEMI). METHODS: We searched PubMed, EMBASE, Google scholar and Cochrane Controlled Trials Register for randomized controlled trials (RCTs) evaluating the efficacy and safety of PCI after fibrinolysis within 24 hours, which was compared with primary PCI alone and ischemia-guided or delayed PCI. Meta-analysis was conducted using Review Manager 5.30 following the methods described by the Cochrane library. RESULTS: A total of 16 studies including 10,034 patients were enrolled. As compared with primary PCI alone group, the short-term mortality (5.8% vs 4.5%, RR 1.29, 95% confidence interval [CI] 1.00-1.65) and re-infarction rate (4.1% vs 2.7%, RR 1.46, 95%CI 1.05-2.03) were higher in the immediate PCI group (median/mean time <= 2 h after fibrinolysis). However, the short-term mortality and re-infarction rate showed no statistically significant differences in the early PCI group (2-24 hours after fibrinolysis). The rate of major bleeding events was higher both in the immediate PCI (6.3% vs 4.4%, RR 1.43, 95%CI 1.11-1.85) and the early PCI group (6.4% vs 4.4%, RR 1.46, 95%CI 1.03-2.06) as compared with primary PCI alone group. As compared with ischemia-guided or delayed PCI, early PCI was associated with significantly reduced re-infarction (2.4% vs 4.0%, RR 0.61, 95%CI 0.41-0.92) and recurrent ischemia (1.5% vs 5.3%, RR 0.29, 95%CI 0.12-0.70) at short-term. And the reduced re-infarction rate was also observed at long-term. CONCLUSIONS: Early PCI after fibrinolysis, with a relatively broader time for PCI preparation, can bring the similar effects with primary PCI alone and is better than ischemia guided or delayed PCI in STEMI patients with symptom onset < 12 h who cannot receive timely PCI. However, immediate PCI after fibrinolysis is detrimental. PMID- 26523835 TI - [Position Paper on Adult Pneumococcal Vaccination: Position Paper of the German Respiratory Society and the German Geriatric Society]. AB - Currently, the German Advisory Committee on Immunization Practices recommends the pneumococcal polysaccharide vaccine (PSV23) instead oft the pneumococcal conjugate vaccine (PCV13) for standard vaccination of adults > 60 years. Whereas the efficacy of PSV23 against bacteraemia has been proven by numerous studies, there is increasing evidence that there is no efficacy against non-bacteraemic pneumococcal pneumonia. This is in contrast to PCV13, for which the CAPITA study has recently revealed an efficacy of 45% against non-bacteraemic pneumonia by the 13 vaccine types.In this position paper we argue that this decision is not justified by the available evidence for the following reasons: i) the main burden of pneumococcal diseases is non-bacteraemic pneumoniaii) the clinical evidence for the efficacy against pneumonia is of higher quality for PCV13 than for PSV23 iii) the duration of clinical efficacy PSV23 starts to decrease after 2 years, whereas this has not yet been observed for PCV13 in the CAPITA study for at least four years, and iv) herd protection effects observed after PCV7 infant vaccination program on invasive pneumococcal disease must not be extrapolated to PCV13 and non-invasive pneumococcal diseases. PMID- 26523838 TI - Temperature Dependence of CN and SCN IR Absorptions Facilitates Their Interpretation and Use as Probes of Proteins. AB - Cyano and thiocyano groups have received attention as IR probes of local protein electrostatics or solvation, due to their strong absorptions and the ability to site specifically incorporate them within proteins. However, interpreting their spectra requires knowing whether they engage in hydrogen bonds (H-bonds). Existing methods for the detection of such H-bonding interactions are based on structural analysis or correlations between IR and NMR signals and are labor intensive and possibly ambiguous. Here, using model systems we show that the absorption frequency of both probes is linearly correlated with temperature and that the slope of the resulting line (frequency-temperature line slope or FTLS) reflects the nature of the probe's microenvironment, including whether or not the probe is engaged in H-bonds. We then show that the same linear dependence is observed with p-cyano phenylalanine, cyanylated cysteine, or cyanylated homocysteine incorporated at different positions within the N-terminal Src homology 3 domain of the murine adapter protein Crk-II. The FTLSs indicate that p cyano phenylalanine incorporated at two positions is engaged in strong H-bonding, while it is involved in weaker H-bonding at a third position. In contrast, the FTLS of the cyanylated cysteine or cyanylated homocysteine absorptions indicates that they do not engage in H-bonding at either a buried or surface exposed position. While the differences likely reflect side chain flexibility and the probe's ability to avoid solvent, the data suggest that the temperature dependence of the absorption provides a simple method to gauge the probe's environment, including the presence of H-bonding. PMID- 26523839 TI - Cell-based screens and phenomics with fission yeast. AB - Next-generation sequencing approaches have considerably advanced our understanding of genome function and regulation. However, the knowledge of gene function and complex cellular processes remains a challenge and bottleneck in biological research. Phenomics is a rapidly emerging area, which seeks to rigorously characterize all phenotypes associated with genes or gene variants. Such high-throughput phenotyping under different conditions can be a potent approach toward gene function. The fission yeast Schizosaccharomyces pombe (S. pombe) is a proven eukaryotic model organism that is increasingly used for genomewide screens and phenomic assays. In this review, we highlight current large-scale, cell-based approaches used with S. pombe, including computational colony-growth measurements, genetic interaction screens, parallel profiling using barcodes, microscopy-based cell profiling, metabolomic methods and transposon mutagenesis. These diverse methods are starting to offer rich insights into the relationship between genotypes and phenotypes. PMID- 26523837 TI - Combinatorial-Designed Epidermal Growth Factor Receptor-Targeted Chitosan Nanoparticles for Encapsulation and Delivery of Lipid-Modified Platinum Derivatives in Wild-Type and Resistant Non-Small-Cell Lung Cancer Cells. AB - Development of efficient and versatile drug delivery platforms to overcome the physical and biological challenges in cancer therapeutics is an area of great interest, and novel materials are actively sought for such applications. Recent strides in polymer science have led to a combinatorial approach for generating a library of materials with different functional identities that can be "mixed and matched" to attain desired characteristics of a delivery vector. We have applied the combinatorial design to chitosan (CS), where the polymer backbone has been modified with polyethylene glycol, epidermal growth factor receptor-binding peptide, and lipid derivatives of varying chain length to encapsulate hydrophobic drugs. Cisplatin, cis-([PtCl2(NH3)2]), is one of the most potent chemotherapy drugs broadly administered for cancer treatment. Cisplatin is a hydrophilic drug, and in order for it to be encapsulated in the developed nanosystems, it was modified with lipids of varying chain length. The library of four CS derivatives and six platinum derivatives was self-assembled in aqueous medium and evaluated for physicochemical characteristics and cytotoxic effects in platinum-sensitive and -resistant lung cancer cells. The results show that the lipid-modified platinate encapsulation into CS nanoparticles significantly improved cellular cytotoxicity of the drug. In this work, we have also reinforced the idea that CS is a multifaceted system that can be as successful in delivering small molecules as it has been as a nucleic acids carrier. PMID- 26523836 TI - Organ iron accumulation in chronically transfused children with sickle cell anaemia: baseline results from the TWiTCH trial. AB - Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH) trial is a randomized, open-label comparison of hydroxycarbamide (also termed hydroxyurea) versus continued chronic transfusion therapy for primary stroke prevention in patients with sickle cell anaemia (SCA) and abnormal TCD. Severity and location of iron overload is an important secondary outcome measure. We report the baseline findings of abdominal organ iron burden in 121 participants. At enrollment, patients were young (9.8 +/- 2.9 years), predominantly female (60:40), and previously treated with transfusions (4.1 +/- 2.4 years) and iron chelation (3.1 +/- 2.1 years). Liver iron concentration (LIC; 9.0 +/- 6.6 mg/g dry weight) and serum ferritin were moderately elevated (2696 +/- 1678 MUg/l), but transferrin was incompletely saturated (47.2 +/- 23.6%). Spleen R2* was 509 +/- 399 Hz (splenic iron ~13.9 mg/g) and correlated with LIC (r(2) = 0.14, P = 0.0008). Pancreas R2* was increased in 38.3% of patients but not to levels associated with endocrine toxicity. Kidney R2* was increased in 80.7% of patients; renal iron correlated with markers of intravascular haemolysis and was elevated in patients with increased urine albumin-creatinine ratios. Extra hepatic iron deposition is common among children with SCA who receive chronic transfusions, and could potentiate oxidative stress caused by reperfusion injury and decellularized haemoglobin. PMID- 26523840 TI - Sensitive Flexible Magnetic Sensors using Organic Transistors with Magnetic Functionalized Suspended Gate Electrodes. AB - Utilizing a magnetic-functionalized suspended gate with combined features of outstanding conductivity, flexibility, and magnetic properties, flexible magnetic sensor based on an organic field-effect transistor (OFET), with a high sensitivity of 115.2% mT(-1) is demonstrated. Gate engineering enables the sensing devices to possess promising applications for flexible touchless switches and spatiallyresolved magnetic-imaging elements. PMID- 26523841 TI - Differences in central and non-central keratoconus, and their effect on the objective screening thresholds for keratoconus. AB - PURPOSE: To evaluate the differences in central and non-central keratoconus (based on cone location), and their effect on the objective screening thresholds for keratoconus. METHODS: This comparative case series was performed at tertiary care cornea and refractive surgery service. Three groups were made: KC apex within central 2 mm (central keratoconus, n = 50), apex outside central 2mm (non central keratoconus, n = 50) and normal controls (n = 100, with 50 cases each with apex within and outside central 2 mm). All cases underwent clinical evaluation and corneal topography (CSO, Sirius, Italy). Apex keratometry (ApexK), simulated keratometry at 3 mm (SimK), central corneal thickness (CCT) and minimum corneal thickness (MCT), anterior corneal higher-order aberrations root mean square (HOARMS), and Zernike's coefficients up to fourth order at different zones were measured. RESULTS: In spite of the keratoconic groups having comparable ApexK (p > 0.05), central keratoconus had higher SimK and thinner CCT and MCT (p < 0.001). HOARMS was significantly more for central keratoconus at 3 mm zones. These findings had moderate to large effect size (Cohen's d). Receiver operating curve analysis was carried out to compare central keratoconus and non-central keratoconus with control group. ApexK and HOARMS had best discriminative parameters. Using single parametric suspicion cut-offs of 'either SimK steep >47.2 D or CCT < 491.6 MU' had a good sensitivity (0.98) for central keratoconus, but not for non-central keratoconus (0.80). Changing this cut-off to 'either SimK steep K >= 45.8 D or CCT <= 503 MU' gave a sensitivity and specificity of 0.95 and 0.87 for non-central keratoconus and 0.99 and 0.87 for central keratoconus. CONCLUSION: Non-central keratoconus has lesser effect on SimK, pachymetry and smaller-aperture HOARMS. Using 'SimK steep >47.2 D or CCT < 491.6 MU' may miss timely referral for topography in many of these cases. Using more stringent criteria of SimK steep K >= 45.8 D or CCT <= 503 MU to get a corneal topography done to rule out keratoconus is recommended, especially in cohorts with higher risk. PMID- 26523842 TI - The long-term burden of work-related carpal tunnel syndrome relative to upper extremity fractures and dermatitis in Washington State. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is among the most burdensome of all musculoskeletal disorders as measured by workers' compensation claims costs and lost earnings. But the burden of CTS extends beyond direct claim costs. METHODS: A survey covering health, social, economic and work-related outcomes was administered to 1,255 injured workers whose Washington State Fund workers' compensation claims had closed 6 years previously. Logistic and linear regression methods were used to model the outcomes of CTS claimants across four separate outcome domains. RESULTS: Workers diagnosed with CTS suffer substantial deficits across all four outcome domains as compared to the two comparison groups of claimants. Former CTS claimants were almost twice as likely not to be working as compared to the fractures cohort. CONCLUSIONS: A comprehensive measurement of the burden of CTS shows losses extend beyond direct claims costs to include continuing pain, loss of function, adverse financial impacts and household disruption which extend long after claim closure. Am. J. Ind. Med. 58:1255-1269, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26523843 TI - Review of Graphene as a Solid State Diffusion Barrier. AB - Conventional thin-film diffusion barriers consist of 3D bulk films with high chemical and thermal stability. The purpose of the barrier material is to prevent intermixing or penetration from the two materials that encase it. Adhesion to both top and bottom materials is critical to the success of the barrier. Here, the effectiveness of a single atomic layer of graphene as a solid-state diffusion barrier for common metal schemes used in microelectronics is reviewed, and specific examples are discussed. Initial studies of electrical contacts to graphene show a distinct separation in behavior between metallic groups that strongly or weakly bond to it. The two basic classes of metal reactions with graphene are either physisorbed metals, which bond weakly with graphene, or chemisorbed metals, which bond strongly to graphene. For graphene diffusion barrier testing on Si substrates, an effective barrier can be achieved through the formation of a carbide layer with metals that are chemisorbed. For physisorbed metals, the barrier failure mechanism is loss of adhesion at the metal-graphene interface. A graphene layer encased between two metal layers, in certain cases, can increase the binding energy of both films with graphene, however, certain combinations of metal films are detrimental to the bonding with graphene. While the prospects for graphene's future as a solid-state diffusion barrier are positive, there are open questions, and areas for future research are discussed. A better understanding of the mechanisms which influence graphene's ability to be an effective diffusion barrier in microelectronic applications is required, and additional experiments are needed on a broader range of metals, as well as common metal stack contact structures used in microelectronic applications. The role of defects in the graphene is also a key area, since they will probably influence the barrier properties. PMID- 26523844 TI - Alkyl hydroperoxide reductase from Bacillus aquimaris MKSC 6.2 protects Esherichia coli from oxidative stress. AB - Alkyl hydroperoxide reductase genes (ahpCF) from the soft coral associated Bacillus aquimaris MKSC6.2 have been isolated. The cloned 546 bp ahpC gene encodes a 181 amino acid residues polypeptide. The AhpC belongs to typical 2-Cys peroxiredoxin (Prx) containing conserved peroxidatic cysteine residue (C46 ) required for hydroperoxide reduction and conserved resolving cysteine (C166 ). The isolated 1530 bp ahpF gene encodes a polypeptide of 509 amino acid residues with two conserved C128 HNC131 and C337 PHC340 catalytic residues required for reduction of oxidized-AhpC during catalytic turnover. A survival study with Escherichia coli showed that overexpression of AhpC and AhpF resulted in a total protection against 0.16 mM t-butyl hydroperoxide. PMID- 26523845 TI - The Value of Lead aVR ST Segment Changes in Localizing Culprit Lesion in Acute Inferior Myocardial Infarction and Its Prognostic Impact. AB - BACKGROUND: Identifying infarct-related artery (IRA) in patients with inferior ST elevation myocardial infarction (STEMI) has prognostic and therapeutic benefits. OBJECTIVES: To differentiate IRA and the location of culprit lesion in inferior STEMI, using ST segment changes in lead aVR. METHODS: ST segment changes in lead aVR were recorded in 150 patients, admitted with first inferior STEMI. The association of IRA and the location of culprit lesion with ST segment changes in aVR were investigated. RESULTS: ST elevation >= 0.5 mm in lead aVR was present in 17 patients (11.3%), ST depression >= 0.5 mm in 74 patients (49.3%) and 59 patients (39.3%) did not have significant ST segment changes. Right coronary artery (RCA) was the IRA in 117 patients (78%) and left circumflex artery (LCX) in 33 patients (22%). Prevalence of RCA involvement as the IRA was different in three study groups (94.1% in ST elevation group, 83.1% in isoelectric group and 70.3% in ST depression group, P = 0.049). Presence of ST elevation had a sensitivity and specificity of 13.68 % and 96.97%, for detecting RCA lesions, respectively. ST depression had 66.67% sensitivity and 55.56% specificity for identifying LCX lesions. Clinical complications were low in our study with no significant difference among patients of three groups. CONCLUSIONS: Presence of ST elevation is highly suggestive of RCA lesions versus LCX lesions, whereas absence of ST elevation cannot rule out RCA lesions. Presence of ST depression has a moderate sensitivity and specificity for LCX lesions. PMID- 26523846 TI - A 6-year trend of the healthcare costs of arthritis in a population-based cohort of older women. AB - OBJECTIVE: To provide an accurate representation of the economic burden of arthritis by estimating the adjusted incremental healthcare cost of arthritis at multiple percentiles and reporting the cost trends across time. METHODS: A healthcare cost study based on health survey and linked administrative data, where costs were estimated from the government's perspective in dollars per person per year. Quantile regression was used to estimate the adjusted incremental cost at the 25th, 50th, 75th, 90th, and 95th percentiles. RESULTS: Data from 4287 older Australian women were included. The median incremental healthcare cost of arthritis was, in 2012 Australian dollars, $480 (95% CI: $498 759) in 2009; however, 5% of individuals had 5-times higher costs than the 'average individual' with arthritis. Healthcare cost of arthritis did not increase significantly from 2003 to 2009. CONCLUSION: Healthcare cost of arthritis represents a substantial burden for the governments. Future research should continue to monitor the economic burden of arthritis. PMID- 26523847 TI - Solvent Effects on the Photothermal Regeneration of CO2 in Monoethanolamine Nanofluids. AB - A potential approach to reduce energy costs associated with carbon capture is to use external and renewable energy sources. The photothermal release of CO2 from monoethanolamine mediated by nanoparticles is a unique solution to this problem. When combined with light-absorbing nanoparticles, vapor bubbles form inside the capture solution and release the CO2 without heating the bulk solvent. The mechanism by which CO2 is released remained unclear, and understanding this process would improve the efficiency of photothermal CO2 release. Here we report the use of different cosolvents to improve or reduce the photothermal regeneration of CO2 captured by monoethanolamine. We found that properties that reduce the residence time of the gas bubbles (viscosity, boiling point, and convection direction) can enhance the regeneration efficiencies. The reduction of bubble residence times minimizes the reabsorption of CO2 back into the capture solvent where bulk temperatures remain lower than the localized area surrounding the nanoparticle. These properties shed light on the mechanism of release and indicated methods for improving the efficiency of the process. We used this knowledge to develop an improved photothermal CO2 regeneration system in a continuously flowing setup. Using techniques to reduce residence time in the continuously flowing setup, such as alternative cosolvents and smaller fluid volumes, resulted in regeneration efficiency enhancements of over 200%. PMID- 26523848 TI - Comparative population genomics of latitudinal variation in Drosophila simulans and Drosophila melanogaster. AB - Examples of clinal variation in phenotypes and genotypes across latitudinal transects have served as important models for understanding how spatially varying selection and demographic forces shape variation within species. Here, we examine the selective and demographic contributions to latitudinal variation through the largest comparative genomic study to date of Drosophila simulans and Drosophila melanogaster, with genomic sequence data from 382 individual fruit flies, collected across a spatial transect of 19 degrees latitude and at multiple time points over 2 years. Consistent with phenotypic studies, we find less clinal variation in D. simulans than D. melanogaster, particularly for the autosomes. Moreover, we find that clinally varying loci in D. simulans are less stable over multiple years than comparable clines in D. melanogaster. D. simulans shows a significantly weaker pattern of isolation by distance than D. melanogaster and we find evidence for a stronger contribution of migration to D. simulans population genetic structure. While population bottlenecks and migration can plausibly explain the differences in stability of clinal variation between the two species, we also observe a significant enrichment of shared clinal genes, suggesting that the selective forces associated with climate are acting on the same genes and phenotypes in D. simulans and D. melanogaster. PMID- 26523849 TI - Immune modulatory mesenchymal stem cells derived from human embryonic stem cells through a trophoblast-like stage. AB - Mesenchymal stem/stromal cells (MSCs) have great clinical potential in modulating inflammation and promoting tissue repair. Human embryonic stem cells (hESCs) have recently emerged as a potentially superior cell source for MSCs. However, the generation methods reported so far vary greatly in quality and efficiency. Here, we describe a novel method to rapidly and efficiently produce MSCs from hESCs via a trophoblast-like intermediate stage in approximately 11-16 days. We term these cells "T-MSCs" and show that T-MSCs express a phenotype and differentiation potential minimally required to define MSCs. T-MSCs exhibit potent immunomodulatory activity in vitro as they can remarkably inhibit proliferation of cocultured T and B lymphocytes. Unlike bone marrow MSCs, T-MSCs do not have increased expression of inflammatory mediators in response to IFNgamma. Moreover, T-MSCs constitutively express a high level of the immune inhibitory ligand PD-L1 and elicit strong and durable efficacy in two distinct animal models of autoimmune disease, dextran sulfate sodium induced colitis, and experimental autoimmune encephalomyelitis, at doses near those approved for clinical trials. Together, we present a simple and fast derivation method to generate MSCs from hESCs, which possess potent immunomodulatory properties in vitro and in vivo and may serve as a novel and ideal candidate for MSC-based therapies. PMID- 26523850 TI - Stability of Silica- and Enzyme-Treated Palm Oil Under Deep Frying Conditions. AB - The oxidative and thermal stability of low diglycerides palm oil produced via silica treatment (sPO) and enzymatic treatment (ePO) compared with standard quality palm oil (SQ) and premium quality palm oil (PQ) was investigated. Both of the oils displayed better oxidative stability compared with SQ as well as significantly higher (P < 0.05) thermal resistance and oxidative strength than SQ and PQ due to lower amounts of partial glycerides. Although the initial induction periods (IPs) of sPO and ePO were significantly lower compared with SQ and PQ, both the oils showed slower drops in their IP values. The darkening effect after frying was significantly (P < 0.05) slower in sPO compared with SQ, PQ, and ePO. Besides, there is no difference p > 0.05 in the rate of FFA formation between sPO and PQ. The anisidine value and peroxide values were lowest in sPO, followed by ePO, PQ, and SQ. PMID- 26523851 TI - Trainees' Self-Reported Challenges in Knowledge Translation, Research and Practice. AB - BACKGROUND: Knowledge translation (KT) refers to the process of moving evidence into healthcare policy and practice. Understanding the experiences and perspectives of individuals who develop careers in KT is important for designing training programs and opportunities to enhance capacity in KT research and practice. To date, however, limited research has explored the challenges that trainees encounter as they develop their careers in KT. AIMS: The purpose of this study is to identify the challenges that KT trainees face in their KT research or practice. METHODS: An online survey was conducted with a sample of trainees associated with the Knowledge Translation Trainee Collaborative or the KT Canada Summer Institutes, with written responses thematically analyzed. FINDINGS: A total of 35 individual responses were analyzed, resulting in the identification of six interrelated themes, listed in descending order of prevalence: limited availability of KT-specific resources (54%), difficulty inherent in investigating KT (34%), KT not recognized as a distinct field (23%), colleagues' limited knowledge and understanding of KT (20%), competing priorities and limited time (20%), and difficulties in relation to collaboration (14%). DISCUSSION: KT trainees experience specific challenges in their work: limited understanding of KT in other stakeholder groups; limited structures or infrastructure to support those who do KT; the inherently interdisciplinary and applied nature of KT; and the resultant complexities of scientific inquiry in this field, such as designing and testing multifaceted, multilevel implementation strategies and accounting for contextual factors. LINKING EVIDENCE TO ACTION: KT training and capacity-building efforts are needed to better position health systems to routinely adopt knowledge into healthcare policy and practice. PMID- 26523852 TI - Palladium-Catalyzed Aerobic Aminooxygenation of Alkenes for Preparation of Isoindolinones. AB - A palladium-catalyzed intramolecular isoindolinone-forming aminooxygenation of alkenes with 1 atm of oxygen as oxidant is reported. A variety of functionalized alkenes and carboxylic acids can be used, and high yields were observed. Preliminary mechanistic studies revealed that the aminooxygenation products were formed through the oxidation of a C-Pd(II) species using a strong oxidant, peroxide, which is generated in situ from a Pd(OAc)2/bpy/O2/HOAc catalytic system. PMID- 26523854 TI - Corrigendum. PMID- 26523853 TI - Alternative Monomers Based on Lignocellulose and Their Use for Polymer Production. PMID- 26523855 TI - Anti-TNF therapy and radiation exposure in Crohn's disease: chicken or egg? PMID- 26523856 TI - Vocal production and playback of altered song do not affect ZENK expression in black-capped chickadees (Poecile atricapillus). AB - The two-note fee bee song of the black-capped chickadee (Poecile atricapillus) is sung at many different absolute frequencies, but the relative frequencies between the start and end of the fee note (the glissando) and between the fee and the bee notes (the inter-note ratio) are preserved regardless of absolute frequency. If these relative frequencies are experimentally manipulated, birds exhibit reduced behavioural responses to playback of altered songs both in field studies and laboratory studies. Interestingly, males appear to be sensitive to alterations in the glissando, while females appear to be sensitive to alterations in both the glissando and the inter-note ratio. In this study, we sought to determine whether the behaviour of male and female chickadees corresponds to differences in zenk protein immunoreactivity (ZENK-ir) in auditory perceptual regions following playback of fee bee songs with typical and altered pitch ratios. Overall, there was a small but significant sex difference in ZENK-ir (females>males), but altering relative frequencies did not reduce ZENK-ir compared to typical song. Birds did vocalize less in response to playback of songs that lacked an inter note interval, but amount of singing fee bee song, chick-a-dee calls, or gargles was not correlated with ZENK-ir in perceptual regions (caudomedial nidopallium, NCM and caudomedial mesopallium, CMM) or in HVC, which is part of the song system. Our results confirm that ZENK-ir in NCM and CMM is not involved in fine grain perceptual discrimination, however it did not support the idea that increased vocalizing increases ZENK-ir in HVC. PMID- 26523857 TI - Cocaine-conditioned place preference is predicted by previous anxiety-like behavior and is related to an increased number of neurons in the basolateral amygdala. AB - The identification of behavioral traits that could predict an individual's susceptibility to engage in cocaine addiction is relevant for understanding and preventing this disorder, but investigations of cocaine addicts rarely allow us to determinate whether their behavioral attributes are a cause or a consequence of drug use. To study the behaviors that predict cocaine vulnerability, male C57BL/6J mice were examined in a battery of tests (the elevated plus maze, hole board, novelty preference in the Y-Maze, episodic-like object recognition and forced swimming) prior to training in a cocaine-conditioned place preference (CPP) paradigm to assess the reinforcing value of the drug. In a second study, the anatomical basis of high and low CPP in the mouse brain was investigated by studying the number of neurons (neuronal nuclei-positive) in two addiction related limbic regions (the medial prefrontal cortex and the basolateral amygdala) and the number of dopaminergic neurons (tyrosine hydroxylase-positive) in the ventral tegmental area by immunohistochemistry and stereology. Correlational analyses revealed that CPP behavior was successfully predicted by anxiety-like measures in the elevated plus maze (i.e., the more anxious mice showed more preference for the cocaine-paired compartment) but not by the other behaviors analyzed. In addition, increased numbers of neurons were found in the basolateral amygdala of the high CPP mice, a key brain center for anxiety and fear responses. The results support the theory that anxiety is a relevant factor for cocaine vulnerability, and the basolateral amygdala is a potential neurobiological substrate where both anxiety and cocaine vulnerability could overlap. PMID- 26523859 TI - Effects of oxygen tension and dextran-shelled/2H,3H-decafluoropentane-cored oxygen-loaded nanodroplets on secretion of gelatinases and their inhibitors in term human placenta. AB - Matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) need to be finely modulated in physiological processes. However, oxygen tension influences MMP/TIMP balances, potentially leading to pathology. Intriguingly, new 2H,3H-decafluoropentane-based oxygen-loaded nanodroplets (OLNDs) have proven effective in abrogating hypoxia-dependent dysregulation of MMP and TIMP secretion by single cell populations. This work explored the effects of different oxygen tensions and dextran-shelled OLNDs on MMP/TIMP production in an organized and multicellular tissue (term human placenta). Chorionic villous explants from normal third-trimester pregnancies were incubated with/without OLNDs in 3 or 20% O2. Explants cultured at higher oxygen tension released constitutive proMMP-2, proMMP-9, TIMP-1, and TIMP-2. Hypoxia significantly altered MMP-2/TIMP-2 and MMP 9/TIMP-1 ratios enhancing TIMP-2 and reducing proMMP-2, proMMP-9, and TIMP-1 levels. Intriguingly, OLNDs effectively counteracted the effects of low oxygen tension. Collectively, these data support OLND potential as innovative, nonconventional, and cost-effective tools to counteract hypoxia-dependent dysregulation of MMP/TIMP balances in human tissues. PMID- 26523860 TI - The Nature of the Interlayer Interaction in Bulk and Few-Layer Phosphorus. AB - Sensitive dependence of the electronic structure on the number of layers in few layer phosphorene raises a question about the true nature of the interlayer interaction in so-called "van der Waals (vdW) solids". We performed quantum Monte Carlo calculations and found that the interlayer interaction in bulk black phosphorus and related few-layer phosphorene is associated with a significant charge redistribution that is incompatible with purely dispersive forces and not captured by density functional theory calculations with different vdW corrected functionals. These findings confirm the necessity of more sophisticated treatment of nonlocal electron correlation in total energy calculations. PMID- 26523861 TI - Assessment of the migration potential of nanosilver from nanoparticle-coated low density polyethylene food packaging into food simulants. AB - An experimental nanosilver-coated low-density polyethylene (LDPE) food packaging was incubated with food simulants using a conventional oven and tested for migration according to European Commission Regulation No. 10/2011. The commercial LDPE films were coated using a layer-by-layer (LbL) technique and three levels of silver (Ag) precursor concentration (0.5%, 2% and 5% silver nitrate (AgNO3), respectively) were used to attach antimicrobial Ag. The experimental migration study conditions (time, temperature and food simulant) under conventional oven heating (10 days at 60 degrees C, 2 h at 70 degrees C, 2 h at 60 degrees C or 10 days at 70 degrees C) were chosen to simulate the worst-case storage period of over 6 months. In addition, migration was quantified under microwave heating. The total Ag migrant levels in the food simulants were quantified by inductively coupled plasma-atomic emission spectroscopy (ICP-AES). Mean migration levels obtained by ICP-AES for oven heating were in the range 0.01-1.75 mg l(-1). Migration observed for microwave heating was found to be significantly higher when compared with oven heating for similar temperatures (100 degrees C) and identical exposure times (2 min). In each of the packaging materials and food simulants tested, the presence of nanoparticles (NPs) was confirmed by scanning electron microscopy (SEM). On inspection of the migration observed under conventional oven heating, an important finding was the significant reduction in migration resulting from the increased Ag precursor concentration used to attach Ag on the LDPE LbL-coated films. This observation merits further investigation into the LbL coating process used, as it suggests potential for process modifications to reduce migration. In turn, any reduction in NP migration below regulatory limits could greatly support the antimicrobial silver nanoparticle (AgNP)-LDPE LbL-coated films being used as a food packaging material. PMID- 26523862 TI - Is It a Name or a Fact? Disambiguation of Reference Via Exclusivity and Pragmatic Reasoning. AB - Adults reason by exclusivity to identify the meanings of novel words. However, it is debated whether, like children, they extend this strategy to disambiguate other referential expressions (e.g., facts about objects). To further inform this debate, this study tested 41 adults on four conditions of a disambiguation task: label/label, fact/fact, label/fact, and fact/label (Scofield & Behrend, ). Participants also provided a verbal explanation for their referent selections to tease apart the underlying processes. Results indicated that adults successfully discerned the target object in the label/label and label/fact condition, yet not the remaining two conditions. Verbal reports indicated that the strategy utilized to disambiguate differed depending upon communicative context. These findings confirm that the tendency to reason by exclusivity becomes restricted to word learning situations with growing linguistic and communicative experience. PMID- 26523863 TI - Psychological Placebo and Nocebo Effects on Pain Rely on Expectation and Previous Experience. AB - Expectation and previous experience are both well established key mediators of placebo and nocebo effects. However, the investigation of their respective contribution to placebo and nocebo responses is rather difficult because most placebo and nocebo manipulations are contaminated by pre-existing treatment expectancies resulting from a learning history of previous medical interventions. To circumvent any resemblance to classical treatments, a purely psychological placebo-nocebo manipulation was established, namely, the "visual stripe pattern induced modulation of pain." To this end, experience and expectation regarding the effects of different visual cues (stripe patterns) on pain were varied across 3 different groups, with either only placebo instruction (expectation), placebo conditioning (experience), or both (expectation + experience) applied. Only the combined manipulation (expectation + experience) revealed significant behavioral and physiological placebo-nocebo effects on pain. Two subsequent experiments, which, in addition to placebo and nocebo cues, included a neutral control condition further showed that especially nocebo responses were more easily induced by this psychological placebo and nocebo manipulation. The results emphasize the great effect of psychological processes on placebo and nocebo effects. Particularly, nocebo effects should be addressed more thoroughly and carefully considered in clinical practice to prevent the accidental induction of side effects. PERSPECTIVE: Even purely psychological interventions that lack any resemblance to classical pain treatments might alter subjective and physiological pain correlates. A manipulation of treatment expectation and actual treatment experience were mandatory to elicit this effect. Nocebo effects were especially induced, which indicated the necessity for prevention of accidental side effects besides exploitation of placebo responses. PMID- 26523864 TI - Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. AB - Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA-mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2(+)CD8(+) T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion. PMID- 26523865 TI - Selective programming of CCR10(+) innate lymphoid cells in skin-draining lymph nodes for cutaneous homeostatic regulation. AB - Innate lymphoid cells (ILCs) 'preferentially' localize into barrier tissues, where they function in tissue protection but can also contribute to inflammatory diseases. The mechanisms that regulate the establishment of ILCs in barrier tissues are poorly understood. Here we found that under steady-state conditions, ILCs in skin-draining lymph nodes (sLNs) were continuously activated to acquire regulatory properties and high expression of the chemokine receptor CCR10 for localization into the skin. CCR10(+) ILCs promoted the homeostasis of skin resident T cells and, reciprocally, their establishment in the skin required T cell-regulated homeostatic environments. CD207(+) dendritic cells expressing the transcription factor Foxn1 were required for the proper generation of CCR10(+) ILCs. These observations reveal mechanisms that underlie the specific programming and priming of skin-homing CCR10(+) ILCs in the sLNs. PMID- 26523866 TI - Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity. AB - The T cell antigen receptor (TCR)-peptide-major histocompatibility complex (MHC) interface is composed of conserved and diverse regions, yet the relative contribution of each in shaping recognition by T cells remains unclear. Here we isolated cross-reactive peptides with limited homology, which allowed us to compare the structural properties of nine peptides for a single TCR-MHC pair. The TCR's cross-reactivity was rooted in highly similar recognition of an apical 'hot spot' position in the peptide with tolerance of sequence variation at ancillary positions. Furthermore, we found a striking structural convergence onto a germline-mediated interaction between the TCR CDR1alpha region and the MHC alpha2 helix in twelve TCR-peptide-MHC complexes. Our studies suggest that TCR-MHC germline-mediated constraints, together with a focus on a small peptide hot spot, might place limits on peptide antigen cross-reactivity. PMID- 26523867 TI - Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS recruited macrophages to limit neuroinflammation. AB - The molecular mechanisms that link the sympathetic stress response and inflammation remain obscure. Here we found that the transcription factor Nr4a1 regulated the production of norepinephrine (NE) in macrophages and thereby limited experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Lack of Nr4a1 in myeloid cells led to enhanced NE production, accelerated infiltration of leukocytes into the central nervous system (CNS) and disease exacerbation in vivo. In contrast, myeloid-specific deletion of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, protected mice against EAE. Furthermore, we found that Nr4a1 repressed autocrine NE production in macrophages by recruiting the corepressor CoREST to the Th promoter. Our data reveal a new role for macrophages in neuroinflammation and identify Nr4a1 as a key regulator of catecholamine production by macrophages. PMID- 26523869 TI - Opioid-Induced Hyperalgesia: A Diagnostic Dilemma. AB - Opioids are utilized frequently for the treatment of moderate to severe acute pain in the perioperative setting, as well as in the treatment of cancer-related pain. When prescribing chronic opioid therapy to patients with chronic pain, it is crucial for the practitioner to be aware not only of the issues of tolerance and withdrawal, but also to have knowledge of the possibility for opioid-induced hyperalgesia (OIH). An understanding of the differences between tolerance and OIH when escalating opioid therapy allows the titration of opioid as well as nonopioid analgesics in order to obtain maximum control of both chronic and acute pain. A case study is described to highlight the importance of judicious utilization of opioids in the treatment of cancer-related pain. In this case, high-dose opioid therapy did not improve chronic pain and contributed to a hyperalgesic state in which a young man experienced severe intractable pain postoperatively after two routine thoracotomies, despite aggressive pharmacologic measures to manage his perioperative pain. Furthermore, it illustrates the potential advantages of opioid rotation to methadone when OIH is suspected. PMID- 26523870 TI - Social capital and mental well-being of older people residing in a residential care facility in Durban, South Africa. AB - INTRODUCTION: Global increases in life expectancy are expected to continue, with accompanying physical and mental well-being challenges specifically for older people living in residential care settings. OBJECTIVE: The aim of the study was to investigate the association between mental well-being and social capital of older residents (60+ years) in an urban residential care facility in South Africa. METHOD: A descriptive survey was conducted with 103 residents living in a residential care facility in an urban environment in South Africa. The social capital framework from the Canadian Policy Research Initiative, the WHO-5 well being index, the Kessler-6 measure of psychosocial distress, the OSLO-3 Social Support Scale and the Australian Bureau of Statistics Indigenous Health Questionnaire were used to develop the questionnaire. RESULTS: The WHO-5 showed moderate ratings of mental well-being for the standard scoring (>13) (62, 82.7%), but lower levels when using 'no negative ratings' (36; 50.6%). Significant differences in the primary network size, average closeness, self-efficacy and social support as well as the ability to confide in primary network was shown between residents with mentally well and unwell ratings. Logistic regression showed that the strongest predictor for mental well-being was participation in activities outside of the residence and having a primary network. CONCLUSION: The study confirms the association between social capital and mental well-being. PMID- 26523868 TI - Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses. AB - Rapid activation of memory CD4(+) T helper 2 (TH2) cells during allergic inflammation requires their recruitment into the affected tissue. Here we demonstrate that group 2 innate lymphoid (ILC2) cells have a crucial role in memory TH2 cell responses, with targeted depletion of ILC2 cells profoundly impairing TH2 cell localization to the lungs and skin of sensitized mice after allergen re-challenge. ILC2-derived interleukin 13 (IL-13) is critical for eliciting production of the TH2 cell-attracting chemokine CCL17 by IRF4(+)CD11b(+)CD103(-) dendritic cells (DCs). Consequently, the sentinel function of DCs is contingent on ILC2 cells for the generation of an efficient memory TH2 cell response. These results elucidate a key innate mechanism in the regulation of the immune memory response to allergens. PMID- 26523871 TI - Is bioengineering a possibility in gastrointestinal disorders? AB - The gastrointestinal (GI) tract is responsible for conducting multiple functions including motility, digestion and absorption. In gastrointestinal disorders, some of those functions are weakened or lost. Excision of the diseased segment of the GI tract is a common treatment; however, patients suffer from complications and low quality of life. Functional replacements are therefore needed to restore, repair or replace damaged parts of the tract. Tissue engineering and regenerative medicine provide an alternative approach to reconstruct different segments of the GI tract. The GI tract is a complex system with multiple cell types and layers. In previous years, bioengineering approaches focused on identifying an optimal cell source and scaffolding material to engineer GI tissues. In this editorial, we address some of our thoughts with regard to the recent discoveries in bioengineering the GI tract. PMID- 26523872 TI - A short review on a complication of lumbar spine surgery: CSF leak. AB - Cerebrospinal fluid (CSF) leak is a common complication of surgery involving the lumbar spine. Over the past decades, there has been significant advancement in understanding the basis, management and techniques of treatment for post operative CSF leak following lumbar spine surgery. In this article, we review previous work in the literature on the various factors and technical errors during or after lumbar spine surgery that may lead to this feared complication, the available options of management with focus on the various techniques employed, the outcomes and also to highlight on the current trends. We also discuss the presentation, factors contributing to its development, basic concepts and practical aspects of the management with emphasis on the different techniques of treatment. Different outcomes following various techniques of managing post operative CSF leak after lumbar spine surgery have been well described in the literature. However, there is currently no most ideal technique among the available options. The choice of which technique to be applied in each case is dependent on each surgeon's cumulative experience as well as a clear understanding of the contributory underlying factors in each patient, the nature and site of the leak, the available facilities and equipment. PMID- 26523873 TI - Iron-associated biology of Trypanosoma brucei. AB - BACKGROUND: Every eukaryote requires iron, which is also true for the parasitic protist Trypanosoma brucei, the causative agent of sleeping sickness in humans and nagana in cattle. T. brucei undergoes a complex life cycle during which its single mitochondrion is subject to major metabolic and morphological changes. SCOPE OF REVIEW: This review covers what is known about processes associated with iron-sulfur clusters and heme metabolism in T. brucei. We discuss strategies by which iron and heme are acquired and utilized by this model parasite, emphasizing the differences between its two life cycle stages residing in the bloodstream of the mammalian host and gut of the insect vector. Finally, the role of iron in the host-parasite interactions is discussed along with their possible exploitation in fighting these deadly parasites. MAJOR CONCLUSIONS: The processes associated with acquisition and utilization of iron, distinct in the two life stages of T. brucei, are fine tuned for the dramatically different host environment occupied by them. Although the composition and compartmentalization of the iron-sulfur cluster assembly seem to be conserved, some unique features of the iron acquisition strategies may be exploited for medical interventions against these parasites. GENERAL SIGNIFICANCE: As early-branching protists, trypanosomes and related flagellates are known to harbor an array of unique features, with the acquisition of iron being another peculiarity. Thanks to intense research within the last decade, understanding of iron-sulfur cluster assembly and iron metabolism in T. brucei is among the most advanced of all eukaryotes. PMID- 26523874 TI - Diagnostic approach to breast cancer patients based on target metabolomics in saliva by liquid chromatography with tandem mass spectrometry. AB - BACKGROUND: Breast cancer is one of the most fearful diseases due to its increasing worldwide prevalence. A number of screening tests has been employed including clinical examinations and mammography. However, another screening method, which is a simple, not embarrassing, and low cost, is highly desired. Based on these findings, we are currently investigating the determination of polyamines including their acetylated structures for the diagnosis of breast cancer patients. We established a diagnostic approach to breast cancer patients based on the ratios of polyamines in saliva by a UPLC-MS/MS analysis. METHODS: Twelve polyamines including their acetylated form were labeled with DBD-F, separated by a reversed-phase chromatography and detected by a Xevo TQ-S tandem mass spectrometer. RESULTS: Eight polyamines (e.g., SPM, CAD, Ac-SPM, N1-Ac-SPD, N8-Ac-SPD) strongly correlated with the cancer patients. A simple 1-order equation was developed for the discrimination of the breast cancer patients and healthy persons (Y=0.5XSPM-3XAc-SPM-0.15XSPD-3.5XN8-Ac-SPD+0.5XN1-Ac SPD+0.04XCAD). The concordance rate of the breast cancer patients and the healthy persons by the equation was 88% and 76% on the training set, respectively, whereas those on the validation set was both 88%. The score Y in the equation tended to correlate with the cancer stage of the patients and increased with the more serious conditions. The determination of polyamines in the saliva after the cancer patient operations was also performed to identify the concentration change before and after the surgical treatment. The discriminant analysis using 6 polyamines (i.e., N8-Ac-SPD, N1-Ac-SPD, CAD, DAc-SPD, PUT, and Ac-PUT), which were the most influenced molecules derived from the ROC analysis, was performed using the relative percentage. Both the sensitivity and specificity indicated nearly 80% from the ROC analysis result using the ratio of N8-Ac-SPD/(N1-Ac SPD+N8-Ac-SPD). CONCLUSION: The discrimination equation appears to be useful for the diagnosis of breast cancer patients. Furthermore, the ratio of N8-Ac-SPD/(N1 Ac-SPD+N8-Ac-SPD) may be adopted as an index of the health status after the surgical treatment. PMID- 26523875 TI - Introducing a checklist for manuscript submission to Pharmacological Research. PMID- 26523876 TI - Deletion of protein tyrosine phosphatase 1b in proopiomelanocortin neurons reduces neurogenic control of blood pressure and protects mice from leptin- and sympatho-mediated hypertension. AB - Protein tyrosine phosphatase 1b (Ptp1b), which represses leptin signaling, is a promising therapeutic target for obesity. Genome wide deletion of Ptp1b, increases leptin sensitivity, protects mice from obesity and diabetes, but alters cardiovascular function by increasing blood pressure (BP). Leptin-control of metabolism is centrally mediated and involves proopiomelanocortin (POMC) neurons. Whether these neurons contribute to leptin-mediated increases in BP remain unclear. We hypothesized that increasing leptin signaling in POMC neurons with Ptp1b deletion will sensitize the cardiovascular system to leptin and enhance neurogenic control of BP. We analyzed the cardiovascular phenotype of Ptp1b+/+ and POMC-Ptp1b-/- mice, at baseline and after 7 days of leptin infusion or sympatho-activation with phenylephrine. POMCPtp1b deletion did not alter baseline cardiovascular hemodynamics (BP, heart rate) but reduced BP response to ganglionic blockade and plasma catecholamine levels that suggests a decreased neurogenic control of BP. In contrast, POMC-Ptp1b deletion increased vascular adrenergic reactivity and aortic alpha-adrenergic receptors expression. Chronic leptin treatment reduced vascular adrenergic reactivity and blunted diastolic and mean BP increases in POMC-Ptp1b-/- mice only. Similarly POMC-Ptp1b-/- mice exhibited a blunted increased in diastolic and mean BP accompanied by a gradual reduction in adrenergic reactivity in response to chronic vascular sympatho activation with phenylephrine. Together these data rule out our hypothesis but suggest that deletion of Ptp1b in POMC neurons protects from leptin- and sympatho mediated increases in BP. Vascular adrenergic desensitization appears as a protective mechanism against hypertension, and POMC-Ptp1b as a key therapeutic target for the treatment of metabolic and cardiovascular dysfunctions associated with obesity. PMID- 26523877 TI - Intracranial hemorrhagic infarct after local anesthesia on nasal mucosa: A case report. AB - INTRODUCTION: Epinephrine containing local anesthetics are used hemostasis in many cases. Otolaryngologists typically selected to decrease bleeding in surgery field for operations such as especially FESS (Functional Endoscopic Sinus Surgery), septoplasty, septorhinoplasty. In addition to known adverse effects of this local anesthetics agents they have rare complications too. PRESENTATION OF CASE: We presented intracranial hemorrhagic infarction in a 41-year-old male patient after using lidocaine with epinephrine for local anesthesia on nasal mucosa. DISCUSSION: There are some publications like this case in the literature. In our case, a hemorrhagic infarction developed after giving the adrenaline/lidocaine infiltration to make up a local anesthesia in the mucosa of the septum. There is not any reported case like this in the literature. CONCLUSION: We want to emphasize that all surgeons especially the ENT surgeons should be careful while using local anesthetic medicines which contains adrenaline for rare complication of intracranial hemorrhagic infarction. Another fact is that the patients must sign an informed consent form including those situations even for all minor surgical procedures to avoid a medicolegal problem. PMID- 26523878 TI - Significant Role of Lifetime Cigarette Smoking in Worsening Bladder Cancer and Upper Tract Urothelial Carcinoma Prognosis: A Meta-Analysis. AB - PURPOSE: Although cigarette smoking is a well established risk factor for urothelial cancer, its role in urothelial cancer prognosis is still undetermined. In this meta-analysis we quantify the role of lifetime smoking history in bladder cancer recurrence, progression and survival by pooling available data on nonmuscle invasive bladder cancer, muscle invasive bladder cancer and upper tract urothelial carcinoma. MATERIALS AND METHODS: A total of 24 studies, comprising data from 13,114 patients with bladder cancer and 2,259 patients with upper tract urothelial carcinoma, were included in this meta-analysis. Publication bias was addressed through Egger's test, and the heterogeneity among studies was assessed by the I(2) test statistic and subgroup analyses. RESULTS: Current smokers at diagnosis are at increased risk for local recurrence in nonmuscle invasive bladder cancer (HR 1.27, 95% CI 1.09-1.46) and smokers with muscle invasive bladder cancer have an increased risk of dying of bladder cancer (HR 1.23, 95% CI 1.02-1.44). In the upper tract urothelial carcinoma population smokers have an increased risk of recurrence in the operative bed (HR 1.57, 95% CI 1.19-1.95) and of death from upper tract urothelial carcinoma (HR 1.53, 95% CI 1.13-1.92). We did not identify significant heterogeneity among included studies. CONCLUSIONS: The body of evidence is limited due to the absence of prospective studies. However, the results from this meta-analysis unambiguously support the hypothesis that lifetime cigarette smokers are at increased risk for a more malignant type of urothelial carcinoma associated with a worse prognosis. PMID- 26523880 TI - Association between Use of Exogenous Testosterone Therapy and Risk of Venous Thrombotic Events among Exogenous Testosterone Treated and Untreated Men with Hypogonadism. AB - PURPOSE: Limited information exists about whether exogenous testosterone therapy is associated with a risk of venous thrombotic events. We investigated via cohort and nested case-control analyses whether exogenous testosterone therapy is associated with the risk of venous thrombotic events in men with hypogonadism. MATERIALS AND METHODS: Databases were reviewed to identify men prescribed exogenous testosterone therapy and/or men with a hypogonadism diagnosis. Propensity score 1:1 matching was used to select patients for cohort analysis. Cases (men with venous thrombotic events) were matched 1:4 with controls (men without venous thrombotic events) for the nested case-control analysis. Primary outcome was defined as incident idiopathic venous thrombotic events. Cox regression and conditional logistic regression were used to assess HRs and ORs, respectively. Sensitivity analyses were also performed. RESULTS: A total of 102,650 exogenous testosterone treated and 102,650 untreated patients were included in cohort analysis after matching, and 2,785 cases and 11,119 controls were included in case-control analysis. Cohort analysis revealed a HR of 1.08 for all testosterone treated patients (95% CI 0.91, 1.27, p = 0.378). Case-control analysis resulted in an OR of 1.02 (95% CI 0.92, 1.13, p = 0.702) for current exogenous testosterone therapy exposure and an OR of 0.92 (95% CI 0.82, 1.03, p = 0.145) for past exogenous testosterone therapy exposure. These results remained nonstatistically significant after stratifying by exogenous testosterone therapy administration route and age category. Most sensitivity analyses yielded consistent results. CONCLUSIONS: No significant association was found between exogenous testosterone therapy and incidents of idiopathic or overall venous thrombotic events in men with hypogonadism. However, some discrepant findings exist for the association between injectable formulations and the risk of overall venous thrombotic events. PMID- 26523879 TI - Microhematuria in Postmenopausal Women: Adherence to Guidelines in a Tertiary Care Setting. AB - PURPOSE: In 2012 the AUA (American Urological Association) released a revision of the asymptomatic microscopic hematuria guidelines. Our study objectives were to assess adherence to these guidelines and describe the prevalence of urinary tract malignancy in postmenopausal women at our institution. MATERIALS AND METHODS: This is a cross-sectional analysis of women older than 55 years evaluated at the Division of Urogynecology or Urology from August 2012 to August 2014 for a diagnosis of asymptomatic microscopic hematuria. Women who underwent evaluation for 3 or more red blood cells per high power field on microscopic urinalysis were considered to have true asymptomatic microscopic hematuria. Those evaluated after a dipstick test with blood who had fewer than 3 red blood cells per high power field on urinalysis or no urinalysis were considered positive dipstick. Demographics, laboratory values, imaging results and cystoscopy findings were extracted from electronic medical records. RESULTS: Our study population included 237 women with a mean +/- SD age of 67.1 +/- 8.3 years. In our overall population 169 of 237 women (71.3%) had true asymptomatic microscopic hematuria, 48 (20.3%) had a positive dipstick test and 20 (8.4%) underwent evaluation in the setting of urinary tract infection. We detected 3 urinary tract malignancies (1.4%). One kidney cancer was identified in a 56-year-old current smoker with a urine dipstick result of 1+ blood. Bladder cancer was detected in a 58-year old smoker with 6 red blood cells per high power field on urinalysis and in a 64-year-old nonsmoker with 42 red blood cells per high power field on urinalysis. CONCLUSIONS: In postmenopausal women evaluated for asymptomatic microscopic hematuria the overall prevalence of urinary tract malignancy was low at 1.4%. Of our population 28.7% underwent evaluation without meeting guideline criteria for asymptomatic microscopic hematuria. This demonstrates an opportunity to improve adherence to existing guidelines to provide high quality care and avoid unnecessary expensive testing. PMID- 26523881 TI - Lithotripsy Performance of Specially Designed Laser Fiber Tips. AB - PURPOSE: We evaluated and compared a standard laser lithotripsy fiber to laser fibers claimed to have lithotripsy performance enhancing features. MATERIALS AND METHODS: A special AccuMaxTM 200 polished tip fiber and an AccuTracTM ball-shaped tip fiber, each with an approximately 240 MUm core, were compared to a standard 272 MUm core fiber (RocamedTM). The polished and ball-shaped tip fibers were used and reused without preparation. The standard fiber was stripped and cleaved according to manufacturer instructions after each experiment. An automated laser fragmentation testing system was used to perform multiple 30-second laser lithotripsy experiments. To mimic most typical lithotripsy conditions soft and hard stone materials were used with high frequency, low pulse energy (20 Hz and 0.5 J) or with low frequency, high pulse energy (5 Hz and 2.0 J) lithotripter settings. Ablation volumes and laser fiber tip photographs before and after lithotripsy were compared. RESULTS: The standard and ball-shaped tip fibers did not differ in ablation volume (p = 0.72) but they ablated 174% and 188% more stone, respectively, than the polished tip fiber (p <0.0001). The ball-shaped tip showed remarkable fiber tip degradation after short-term use at low frequency, high pulse energy settings. When high pulse energy settings were applied first even for short-term use, the ablation volume achieved by the polished and ball shaped tip fibers at high frequency, low pulse energy settings decreased more than 20%. CONCLUSIONS: The standard laser fiber was as good as and sometimes better than the specially designed fibers. Rapid degradation of the specially designed laser fiber tips strongly limits their general usefulness but ball shaped tip fibers may be useful in specific situations. PMID- 26523882 TI - Risk of Prolapse Recurrence after Native Tissue Anterior Vaginal Suspension Procedure with Intermediate to Long-Term Followup. AB - PURPOSE: We report our experience with recurrence of pelvic organ prolapse after native tissue repair for stage 2 anterior prolapse. MATERIALS AND METHODS: We reviewed a prospectively maintained, institutional review board approved database of women with symptomatic stage 2 anterior prolapse who underwent vaginal repair with anterior vaginal wall suspension between 1996 and 2014. Women with concurrent pelvic organ prolapse repair or hysterectomy or without 1 year followup were excluded from analysis. Failure was defined as stage 2 or greater prolapse recurrence on examination or reoperation for symptomatic pelvic organ prolapse. Outcome measures included validated questionnaires (Urogenital Distress Inventory-short form, quality of life), physical examination, standing voiding cystourethrogram at 6 months postoperatively, further surgery for pelvic organ prolapse in other compartments or for secondary stress urinary incontinence or fecal incontinence, and complications. RESULTS: A total of 121 women met the study inclusion criteria with a mean followup of 5.8 +/- 3.7 years. Prolapse recurrence rates were isolated anterior 7.4%, isolated apical 10.7%, isolated posterior 8.3% and multiple compartments 19%. Surgery for recurrent prolapse included anterior compartment 3.3% at 1.4 +/- 1.0 years, apical 9.9% at 2.8 +/- 3.0 years, posterior compartment 5.8% at 2.0 +/- 1.0 years and multiple compartments 17.4% at 3.2 +/- 3.3 years. There was a 1.6% rate of intraoperative complications and a 5.7% rate of 30-day complications (all Clavien I). CONCLUSIONS: Anterior vaginal wall suspension for symptomatic stage 2 anterior prolapse offers a native tissue vaginal repair with minimal morbidity and a low anterior recurrence rate at intermediate to long-term followup. However, 33% of patients required secondary prolapse compartment procedures from 0.6 to 13 years later, highlighting the importance of long-term followup. PMID- 26523883 TI - Age, Gender and R.E.N.A.L. Nephrometry Score do not Improve the Accuracy of a Risk Stratification Algorithm Based on Biopsy and Mass Size for Assigning Surveillance versus Treatment of Renal Tumors. AB - PURPOSE: A previously published risk stratification algorithm based on renal mass biopsy and radiographic mass size was useful to designate surveillance vs the need for immediate treatment of small renal masses. Nonetheless, there were some incorrect assignments, most notably when renal mass biopsy indicated low risk malignancy but final pathology revealed high risk malignancy. We studied other factors that might improve the accuracy of this algorithm. MATERIALS AND METHODS: For 202 clinically localized small renal masses in a total of 200 patients with available R.E.N.A.L. (radius, exophytic/endophytic, nearness of tumor to collecting system or sinus, anterior/posterior, hilar tumor touching main renal artery or vein and location relative to polar lines) nephrometry score, preoperative renal mass biopsy and final pathology we assessed the accuracy of management assignment (surveillance vs treatment) based on the previously published risk stratification algorithm as confirmed by final pathology. Logistic regression was used to determine whether other factors (age, gender, R.E.N.A.L. score, R.E.N.A.L. score components and nomograms based on R.E.N.A.L. score) could improve assignment. RESULTS: Of the 202 small renal masses 53 (26%) were assigned to surveillance and 149 (74%) were assigned to treatment by the risk stratification algorithm. Of the 53 lesions assigned to surveillance 25 (47%) had benign/favorable renal mass biopsy histology while in 28 (53%) intermediate renal mass biopsy histology showed a mass size less than 2 cm. Nine of these 53 masses (17%) were incorrectly assigned to surveillance in that final pathology indicated the need for treatment (ie intermediate histology and a mass greater than 2 cm or unfavorable histology). Final pathology confirmed a correct assignment in all 149 masses assigned to treatment. None of the additional parameters assessed improved assignment with statistical significance. CONCLUSIONS: Age, gender, R.E.N.A.L. nephrometry score, R.E.N.A.L. score components and nomograms or combinations of these factors do not improve the predictive performance of a small renal mass management risk stratification algorithm based on renal mass biopsy and radiographic mass size. PMID- 26523884 TI - Subtilase contributes to the cytotoxicity of a Shiga toxin-producing Escherichia coli strain encoding three different toxins. AB - Food-borne Shiga toxin-producing Escherichia coli (STEC) O113:H21 strain TS18/08, that has previously been isolated from mixed minced meat, harbors the Shiga toxin (Stx) encoding allele stx2a, the plasmid-located subtilase cytotoxin encoding allele subAB1 and the cytolethal distending toxin type V encoding gene cdt-V. In the current study, it could be shown that each of these toxin genes was transcribed with different transcription levels at different time points by RT real time PCR under laboratory batch conditions in LB-broth. The transcription maximum for cdt-V and subAB1 was observed after 3h while stx2a transcription was highest after 6h of incubation. During this time the mean relationship of the amount of stx2a:subAB1:cdt-V transcripts was 1:26:100. Furthermore, isogenic stx2a and cdt-V chromosomal deletion mutants were constructed to measure the contribution of SubAB1 to the overall cytotoxicity of this strain. In this context, a further copy of stx2 was detected in this strain and was also deleted. Comparing the cytotoxicity of supernatants of the resulting mutant strains TS18/08-3 (Deltastx2-1Deltastx2-2Deltacdt-V) and TS18/08-4 (Deltastx2-1Deltastx2 2Deltacdt-VDeltasubAB1) on Vero cells demonstrated a contribution of SubAB1 to the overall cytotoxic effect while the 4-fold isogenic deletion mutant did not show any cytotoxic effect and that was comparable to the non-toxic laboratory E. coli strain C600. The cytotoxic effect could be restored by complementation with the recombinant low copy plasmid pWSK29 harboring subAB1 under the control of its own promoter. In addition, the cytotoxicity of wild type strain TS18/08 to Vero cells was in the same range as the EHEC O157:H7 strain EDL933. Therefore, food borne STEC O113:H21 strain TS18/08 can be considered as a putative human pathogen. PMID- 26523885 TI - A randomized controlled trial of an internet-delivered treatment: Its potential as a low-intensity community intervention for adults with symptoms of depression. AB - BACKGROUND: Internet-delivered treatments for depression have proved successful, with supported programs offering the potential for improved adherence and outcomes. Internet interventions are particularly interesting in the context of increasing access to interventions, and delivering interventions population-wide. METHODS: The study was a randomized controlled trial of an 7-module internet delivered cognitive behavioral therapy (iCBT) program for adults with depressive symptoms (n = 96) compared to a waiting-list control group (n = 92). Participants received weekly support from a trained supporter. The primary outcome was depressive symptoms as measured by the Beck Depression Inventory (BDI-II). The program was made available nationwide from an established and recognized charity for depression. RESULTS: For the treatment group, post-treatment effect sizes reported were large for the primary outcome measure (d = 0.91). The between-group effects were moderate to large and statistically significant for the primary outcomes (d = 0.50) favoring the treatment group. Gains were maintained at 6 month follow-up. CONCLUSION: The study has demonstrated the efficacy of the internet-delivered Space from Depression treatment. Participants demonstrated reliable and statistically significant changes in symptoms from pre-to post intervention. The study supports a model for delivering online depression interventions population-wide using trained supporters. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN03704676. http://dx.doi.org/10.1186/ISRCTN03704676. PMID- 26523886 TI - Effectiveness of an eating disorder preventative intervention in primary care medical settings. AB - OBJECTIVE: To conduct a pilot effectiveness trial of a brief dissonance-based eating disorder preventative program, the Body Project, when implemented at primary care medical clinics. METHOD: Sixty-six female adolescents between the ages of 13 and 17 who reported at least some body image dissatisfaction were recruited at two primary care clinics and randomized to Body Project groups or an educational video control condition; eating disorder risk factors and symptoms were measured at pretest, posttest, and 3-month follow-up. RESULTS: Body Project versus educational video control participants showed significantly greater reductions in thin-ideal internalization, pressure to be thin, dieting, and eating disorder symptoms at posttest, which were medium to large effect sizes. Body Project participants also showed greater decreases in body dissatisfaction and negative affect at posttest, though these moderate sized effects were not significant. Effects persisted through 3-month follow-up. CONCLUSION: Average pre post effect sizes (d = 0.58) compare favorably to those observed in past Body Project efficacy (average d = 0.59) and effectiveness trials (average ds of 0.43 and 0.69), suggesting that primary care clinics may represent a novel venue for offering and extending the reach of this eating disorder prevention program. PMID- 26523888 TI - Interface formation of two- and three-dimensionally bonded materials in the case of GeTe-Sb2Te3 superlattices. AB - GeTe-Sb2Te3 superlattices are nanostructured phase-change materials which are under intense investigation for non-volatile memory applications. They show superior properties compared to their bulk counterparts and significant efforts exist to explain the atomistic nature of their functionality. The present work sheds new light on the interface formation between GeTe and Sb2Te3, contradicting previously proposed models in the literature. For this purpose [GeTe(1 nm) Sb2Te3(3 nm)]15 superlattices were grown on passivated Si(111) at 230 degrees C using molecular beam epitaxy and they have been characterized particularly with cross-sectional HAADF scanning transmission electron microscopy. Contrary to the previously proposed models, it is found that the ground state of the film actually consists of van der Waals bonded layers (i.e. a van der Waals heterostructure) of Sb2Te3 and rhombohedral GeSbTe. Moreover, it is shown by annealing the film at 400 degrees C, which reconfigures the superlattice into bulk rhombohedral GeSbTe, that this van der Waals layer is thermodynamically favored. These results are explained in terms of the bonding dimensionality of GeTe and Sb2Te3 and the strong tendency of these materials to intermix. The findings debate the previously proposed switching mechanisms of superlattice phase-change materials and give new insights in their possible memory application. PMID- 26523887 TI - Early in-session predictors of response to trauma-focused cognitive therapy for posttraumatic stress disorder. AB - Trauma-focused cognitive behaviour therapy is effective in treating posttraumatic stress disorder but non-response rates range between 25% and 50%. Results of previous research on patient characteristics predicting outcome are inconsistent and mainly focused on demographic and diagnostic variables. This study examined whether behavioural predictors of poor treatment response can be observed in early sessions. It was predicted that greater patient perseveration, lower expression of thoughts and feelings and weaker therapeutic alliance would be associated with poorer outcomes. We also explored the relationships of patient behaviours with therapeutic alliance and the efficiency and competence of treatment delivery. Audio or video recordings of the initial treatment sessions of 58 patients who had shown either good (n = 34) or poor response (n = 24) to cognitive therapy for PTSD (CT-PTSD, Ehlers & Clark, 2000) were blindly coded for patient perseveration, expression of thoughts and feelings, therapeutic alliance, efficiency and competency of treatment delivery and therapist competence. Poor responders showed more perseveration and less expression of thoughts and feelings in the initial session. Patient perseveration and low expression of thoughts and feelings were associated with poorer therapeutic alliance and compromised treatment delivery. Patients with these behavioural characteristics may benefit from additional treatment strategies. Limitations of the study and implications for clinical practice are discussed. PMID- 26523889 TI - Outbreak Breakthrough: Using Whole-Genome Sequencing to Control Hospital Infection. PMID- 26523891 TI - Rectification of nanopores in aprotic solvents--transport properties of nanopores with surface dipoles. AB - Nanopores have become a model system to understand transport properties at the nanoscale. We report experiments and modeling of ionic current in aprotic solvents with different dipole moments through conically shaped nanopores in a polycarbonate film and through glass nanopipettes. We focus on solutions of the salt LiClO4, which is of great importance in modeling lithium based batteries. Results presented suggest ion current rectification observed results from two effects: (i) adsorption of Li(+) ions to the pore walls, and (ii) a finite dipole moment rendered by adsorbed solvent molecules. Properties of surfaces in various solvents were probed by means of scanning ion conductance microscopy, which confirmed existence of an effectively positive surface potential in aprotic solvents with high dipole moments. PMID- 26523890 TI - Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats. AB - Oxytocin has been shown to decrease cocaine taking and seeking in male rats, suggesting potential treatment efficacy for drug addiction. In the present study, we extended these findings to the assessment of cocaine seeking and taking in female rats. Further, we made direct comparisons of oxytocin's impact on cocaine induced locomotor activity in both males and females. In females, systemic oxytocin (0.3, 1.0, 3.0 mg/kg) attenuated lever pressing for cocaine during self administration and oxytocin (1.0 mg/kg) attenuated cue-induced cocaine seeking following extinction. Cocaine increased baseline locomotor activity to a greater degree in females relative to males. Oxytocin (0.1, 0.3, 1.0, and 3.0 mg/kg) reduced cocaine-induced locomotor activity in females, but not significantly in males. These data illustrate sex similarities in oxytocin's attenuation of cocaine seeking, but sex differences in cocaine-induced locomotor effects. While reductions in cocaine seeking cannot be attributed to a reduction in locomotor activity in males, attenuation of locomotor function cannot be entirely ruled out as an explanation for a decrease in cocaine seeking in females suggesting that oxytocin's effect on cocaine seeking may be mediated by different mechanisms in male and females. PMID- 26523892 TI - "Health consequences associated with frequent wheezing in adolescents without asthma diagnosis." K. Yeatts, K. Johnston Davis, D. Peden and C. Shy. Eur Respir J 2003; 22: 781-786. PMID- 26523893 TI - B-Type Natriuretic Peptide as a Therapeutic Strategy: Opportunities and Pitfalls. PMID- 26523894 TI - Methods in Neuroepidemiology Characterization of European Longitudinal Cohort Studies in Parkinson's Disease--Report of the JPND Working Group BioLoC-PD. AB - BACKGROUND: Enormous effort is being put into the identification and characterization of symptoms that may be used as predictive and progression markers in Parkinson's disease (PD). An impressive number of PD patients and individuals at risk for or in the prodromal stage of PD are currently followed in longitudinal studies; however, there does not exist an overview on the kind of markers evaluated and the assessments used. METHODS: Information on the design, sample size, evaluated markers and assessments of 21 studies of the Joint Programme - Neurodegenerative Disease Research BioLoC-PD working group were collected by questionnaire. The studies were classified into at risk/prodromal or clinical PD cohorts. The assessments were grouped into quantitative assessments, investigator-rated assessments, investigator interviews, patient-rated questionnaires and caregiver-rated questionnaires. RESULTS: Compilation of these data revealed an interesting consensus on evaluated markers, but there was an enormous variability of assessments. Furthermore, there is a remarkable similarity in the markers assessed and evaluation methods applied in the risk/prodromal and clinical PD cohorts. CONCLUSIONS: The inventory of the longitudinal cohorts that are part of the BioLoC-PD consortium reveals that there is a growing consensus on the markers that should be assessed in longitudinal cohort studies in PD. However, controversy still exists on the specific type of assessment. To allow comparison of data and common analyses it will be essential to harmonize scales and assessment outcomes. PMID- 26523895 TI - Risk factors for multiorgan failure and mortality in severe sepsis patients who need intensive care unit follow-up. AB - INTRODUCTION: Multiorgan failure (MOF) is a primary cause of morbidity and mortality in sepsis patients in intensive care units (ICU). Finding risk factors and solving preventable problems of MOF in patients who have sepsis can be a favourable step for decreasing mortality. We aimed to examine multiorgan failure and mortality related risk factors in intensive care unit patients who have sepsis. MATERIALS AND METHODS: A retrospective data collection and prognostic cohort study was performed. Between January 2009-March 2010, patients accepted to the 22-bed pulmonary intensive care unit with the diagnosis of sepsis were enrolled. Patients' demographic data, ICU severity scores, application of mechanical ventilation, causative agent of sepsis, number of ICU days and presence of mortality were recorded. Logistic regression analysis was carried out for risk factors. RESULT: 347 patients with sepsis were involved in the study. 43 of the patients (12.4%) developed MOF and overall mortality rate was 14.9% (n= 52). Presence of resistant pathogen, presence of shock, application of TPN and high APACHE II score were found to be risk factors for MOF [p= 0.015 Odds ratio (OR) 3.47 confidence interval (CI): 1.27 - 9.47, p= 0.001, OR: 30.8 CI: 11.41 - 83-49, p= 0.028, OR: 3.08, CI: 1.13 - 8.39, p= 0.003, OR: 1.10, CI: 1.04-1.18, respectively]. Risk factors for overall mortality were presence of nosocomial infection, high 3rd day SOFA score, presence of shock, application of TPN and sedation (p= 0.005, OR: 3.39, CI: 1.45 - 7.93; p= 0.001, OR: 1.51, CI: 1.27 - 1.81; p= 0.014, OR: 3.24, CI: 1.27 - 8.25; p= 0.003, OR: 3.64. CI: 1.54 - 8.58; p= 0.001, OR: 3.38, CI: 1.51 - 7.57, respectively). CONCLUSIONS: In sepsis patients who need ICU follow up, presence of resistant pathogen, presence of shock, application of TPN and high APACHE II scores are risk factors for developing MOF. Thus, rational use of antibiotics, reducing the use of TPN, application of infection control programmes and prevention of shock will further reduce multiorgan failure and mortality. PMID- 26523896 TI - YKL-40: may be use as a new inflammatory biomarker in obstructive sleep apnea syndrome? AB - INTRODUCTION: YKL-40 [chitinase-3 like-1 (CHI3L1)] is a glycoprotein, has been implicated in inflammation, endothelial dysfunction, tissue remodelling and it is accepted as a noninvasive prognostic biomarker for inflammation. In this study, we aimed to underline usability of serum YKL-40 as an inflammatory biomarker in patients with obstructive sleep apnea syndrome (OSAS). PATIENTS AND METHODS: Two groups OSAS patients [Group I: Mild-moderate OSAS, n:43; median apnea-hypopnea index: AHI, /hour:18], Group II: Severe OSAS, n: 25; AHI:41.6] and healthy control group [n:25, AHI: 3.6] were included in the study. Serum YKL-40 level was tested in serum samples taken after polysomnography in OSAS patients and control group. In addition, the association of serum YKL-40 level with age, body mass index and polysomnografic parameters were analyzed in the OSAS patient groups. RESULTS: Median serum YKL-40 level was 20.30 ng/mL (range 8.01-73 ng/mL) in mild moderate OSAS patients, and 22.58 ng/mL (9.17-99 ng/mL in severe OSAS patients, 18 ng/mL (range 7.36-88 ng/mL) in control group (p< 0.05). Serum YKL-40 level was found to be correlated with AHI in patient with mild-moderate OSAS patients (p< 0.05) and serum YKL-40 level was found to be correlated with age, total hypopnea time (minutes) in severe OSAS patients (p< 0.05). There was no relationship serum YKL-40 level with other studied variables (p> 0.05). CONCLUSION: At the end of this study, we found that serum YKL-40 level increase with severity of OSAS. The findings suggest that YKL-40 may be a useful biomarker for inflammation in patients with OSAS. PMID- 26523897 TI - [Comparison of the combination and quinolone therapy in community acquired pneumonia]. AB - INTRODUCTION: Objective of this study is to compare the difference between the length of hospitalisation, cost of treatment and treatment outcome of patients diagnosed with community acquired pneumonia and treated with beta-lactam macrolide combination or fluoroquinolone monotherapy, according to 2009 Turkish Thoracic Society (TTS) Guide of Diagnosis and Treatment of Community Acquired Pneumonia in Adults (TTSCAPG). PATIENTS AND METHODS: Patients diagnosed with community-acquired pneumonia (CAP) between November 2010 and November 2011 in our hospital were included. The data was entered into TTS pneumonia database. Cases were examined for their accordance with TTSCAPG. Clinical outcomes of the patients treated with beta-lactam-macrolide combination or fluoroquinolone, were compared. RESULTS: One hundred and fifty six patients diagnosed with community acquired pneumonia were included. 67.3% of the patients were treated according to the guideline. Of the patients treated in accordance with the guideline, 86.7% were treated with beta-lactam-macrolide combination and 13.3% with fluoroquinolone. Of the patients treated with combination therapy, the treatment was effective in 77.7%, ineffective in 11.8% and 10.6% resulted in death; where as the patients treated with fluoroquinolone, the treatment was effective in 84.7%, ineffective in 15.4%, none of them resulted in death. CONCLUSION: Cases diagnosed with community-acquired pneumonia and treated according to the TTSCAPG guideline were evaluated for effectiveness of combination therapy versus fluoroquinolone; no statistically difference in terms of age, diseases, length of stay, treatment outcomes, cost of treatment could be established. There was only a numerical difference between mortality outcomes of the two antibiotherapy groups compared, however the statistical difference was not significant. PMID- 26523898 TI - Prevalence of chronic obstructive pulmonary disease in Zonguldak province of Turkey. AB - INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is increasingly recognized as a leading cause of global morbidity and mortality. This study is the first spirometry-based, cross-sectional survey of COPD from Western Black Sea Region of Turkey. In this study we aimed to investigate COPD prevalence in Zonguldak province of Turkey. MATERIALS AND METHODS: Adult population of 71.630 persons living in central Zonguldak were enrolled to the study. They were selected by random sampling methods based on regional inhabitant listings. 611 adult persons were finally enrolled to the study. They were interviewed face to face, and were given a questionnaire. Spirometry and early reversibility testing were also performed. Results were evaluated according to Global Obstrucive Lung Disease (GOLD) criteria. RESULTS: 42.6% of the study population were males. Mean age was 49.2 +/- 15.4. The number of inividuals 40 years and older was 447 (73.1%). COPD prevalence was found as 11.1% in the study population and 14.1% in the population 40 years and older. COPD prevalence in males and females 40 years and older were 19.6% and 9.8% respectively. Mean age of the COPD patients (60.06 +/- 13.2 years) was higher than the subjects without COPD (47.8 +/- 15.1) (p< 0.001). COPD prevalence was increasing with age categories. COPD severity based on GOLD criteria were as follows: Stage 1 (23.5%), Stage 2 (58.8%), Stage 3 (16.2%) and Stage 4 (1.5%). Prevalence of smoking history was 95.3% in male COPD patients, and 56% in female COPD patients. Smoking was the most common risk factor present in 80.9% of COPD cases, followed by biomass exposure (63.2%), occupational exposure (41.2%) and passive smoking (7.3%). Smoking history and occupational exposure were higher statistically in males than females in both study populatian and COPD cases. CONCLUSION: COPD is prevalent and an important public health problem in central Zonguldak province. PMID- 26523899 TI - [Pulmonary rehabilitation efficiency in COPD patients with pulmonary hypertension]. AB - INTRODUCTION: COPD is among the most common causes for secondary pulmonary hypertension (PH). Pulmonary rehabilitation (PR) is recommended in the standard treatment of COPD. In this study, efficiency of multidisciplinary PR in COPD patients with PH was examined. PATIENTS AND METHODS: 88 patients stable COPD patients who applied to our center between 2008-2013 were enrolled. Un-likely PH patients were grouped as Group 1 while possible and likely PH cases were accepted as Group 2. There were no other cause for PH. All the patients received patient specific, multidisciplinary 8-week PR. Dyspnea perception was assessed via MRC dyspnea scale, health-related quality of life with S. George life quality questionnaire, exercise capacity via incremental shuttle walking test and endurance shuttle walking test and body composition via bioelectrical impedance test before and after PR program. RESULTS: In all the patients there were significant improvements in body composition (BMI p= 0.013), quality of life (SGRQ semp., activity, total p< 0.001), dyspnea perception (MRC p< 0.001) and exercise capacity (ISWTT, ESWT, VO2 peak p< 0.001) after PR program. Improvements in Group 2 were observed to be significantly greater. CONCLUSION: PR is an effective and safe option in COPD patients with PH. These patients should be directed to PH programs for supervised exercise training and chronic disease management and patient-specific PR programs should be established. PMID- 26523900 TI - [Where the tuberculosis patients are diagnosed and started to treatment?]. AB - INTRODUCTION: Tuberculosis dispensaries have played important roles in management of patients with tuberculosis. Tuberculosis patients diagnosed and treatments are started at dispensaries as well as other health care institutions. Other institutions must be aware of the mission of dispensaries especially at the treatment and follow-up of patients. We aimed to investigate in which health care institutions tuberculosis patients diagnosed and treatment started and whether the awareness about dispanseries is sufficient. PATIENTS AND METHODS: Records of tuberculosis patients in Elazig dispansery examined retrospectively. The data obtained were analyzed by Microsoft Excel. RESULTS: Records of 854 patients with tuberculosis has been reached those followed in Elazig dispensary between the years 2005-2011. Percentages of the patients diagnosed in university hospital, dispensary and state hospitals were 36.3%, 18.5% and 17.3%; respectively. Treatments of patients were started in dispensary (81.9%), university hospital (7.7%), and chest disease hospital (4.3%). CONCLUSION: Treatment starting rate of dispensary was high because patients diagnosed by other health institutions directed to dispensary for taking the first drugs and beginning of the treatment. In tuberculosis control program; dispensaries carry out important operational functions in management of tuberculosis patients and other health institutions are aware of this situation. PMID- 26523901 TI - [Stigma of tuberculosis scale: validity and reliability]. AB - INTRODUCTION: In many health conditions, stigma is receiving increasing attention. Public stigmatization toward social illness can affect particularly the patients and family memberships to help seeking behavior and treatment. This study, the aim of this study was to investigate the validity and reliability of the Turkish "Stigma of Tuberculosis Scale " which was developed to evaluate of perception of stigma with tuberkulosis patient. PATIENTS AND METHODS: This methodological study was conducted with 150 with tuberculosis disease people who above 18 age and without known psychological and mental disability. In the study, "Stigma of Tuberculosis Scale" was used as data collection tool. During the study, language equivalence, content validity, reliability and construct validity of the scale was performed. The data was assessed by using mean, median, standard deviation, Spearman Correlation, Cronbach Alpha coefficient and confirmatory factor analysis. RESULTS: The mean age of study participants was 45.6 +/- 16.1 (20 - 85). years. Spearman correlation coefficient of the scale for test-retest reliability was 0.853 and the Cronbach Alpha coefficient was 0.95. According to fit indexes of confirmatory factor analysis [x2/SD= 481.38/230= 2.09; RMSEA= 0.087; GFI= 0.776; CFI= 0.776; NNFI= 0.875] it was found that one factors were appropriate for the scale. CONCLUSION: The adoption of the translated "Stigma of Tuberculosis Scale"in Turkey is found reliable and valid to evaluate of perception of stigma with tuberkulosis patient. PMID- 26523903 TI - Treatment of tuberculosis in Turkey in terms of medical ethics. AB - Having a history as old as the history of humanity, Tuberculosis (TB) is a serious disease and it is regarded as an important a public health problem not only for its medical aspect but also for its social and ethical aspects. As a result of the discovery of the cure for TB and the improvement of humans' living conditions, the TB problem was believed to be solved and a relaxation in the battle against TB was observed around the world by 1980s. World Health Organization (WHO) declared a state of emergency for the battle against TB in 1993. According to the "Global Tuberculosis Control 2014" which was published by WHO, TB remains one of the world's deadliest communicable diseases. This article argues that tuberculosis is one of the most important neglected topics in medical ethics as regards individual obligations to avoid infecting others, coercive social distancing measures, third-party notification, health workers' duty to treat contagious patients, and justice.The purpose of this article is provide a picture of the current situation of TB treatment in Turkey in terms of medical ethics. PMID- 26523904 TI - PET/CT positive in a case with eosinophilic granuloma. PMID- 26523905 TI - Pseudotumor by lateral process of the vertebra. PMID- 26523906 TI - Italian psychiatrists' perception on cognitive symptoms in major depressive disorder. AB - OBJECTIVE: Differently than Schizophrenia, the investigation of cognitive impairment in bipolar disorder and major depressive disorder (MDD) attracted the interest of research only recently. Therefore, it is worth understanding clinicians' perception about cognitive dysfunction in MDD and raising awareness about this issue. METHODS: Between December 2014 and January 2015, 128 Italian psychiatrists participated in an on-line survey aiming at understanding psychiatrists' perception about cognitive symptoms in MDD. The questionnaire comprised three sections: the first investigating psychiatrists' socio demographic profile, the second assessing cognitive symptoms relevance without mentioning that they represented the study focus and the third explicitly investigating cognitive symptoms. RESULTS: Cognitive symptoms were considered as a relevant dimension of MDD and appeared among the most frequently cited residual symptoms influencing patients' work and relapse risk. About 70% of psychiatrists declared that cognitive symptoms significantly influence antidepressant choice. However, in the second questionnaire section cognitive symptoms appeared less frequently considered for antidepressant choice. CONCLUSIONS: Results revealed a clear understanding of cognitive symptoms relevance in MDD. Nevertheless, the discrepancy between psychiatrists' perception and their therapeutical choices underlines the presence of an unmet-need that should be addressed increasing the awareness about the positive effects on cognitive symptoms of existing drugs, which could allow a more symptom-oriented therapeutical intervention. Key points Major depressive disorder (MDD) is a common mental disorder often associated with deficits in cognitive function. Psychiatrists considered cognitive symptoms among the most relevant residual symptoms in MDD patients that compromise patients working and influence the relapse risk. The importance given to residual cognitive symptoms seemed not to be reflected by psychiatrists' therapeutical choice. There is a gap between what psychiatrists know and what psychiatrists apply to their clinical practice reflecting the feeling of a therapeutical unmet need. PMID- 26523907 TI - A sulfur-free iridium(III) complex for highly selective and multi-signaling mercury(II)-chemosensors. AB - A sulfur-free iridium(III) complex (pbi)2Ir(mtpy) (1) was successfully prepared and adopted as a Hg(II)-chemosensor with high selectivity and sensitivity. Multi signaling responses towards Hg(II) ions were observed by UV-vis absorption, phosphorescence and electrochemistry measurements. With addition of Hg(II) ions, complex 1 presented quenched emission in its phosphorescence spectrum and the detection limit was as low as 2.5 * 10(-7) M. Additionally, its redox peak currents showed a broad linear relationship with the concentration of Hg(II) ions ranging from 0 to 500 MUM, which was beneficial for the quantitative detection. Based on the (1)H NMR and ESI-MS analyses, the probing mechanism was tentatively supposed to be the Hg(2+)-induced changes in the local environment of complex 1. Such a response process was useful for achieving simple and effective detection of Hg(II) ions as well as developing more chemosensors. PMID- 26523909 TI - Understanding a Normal Distribution of Data. AB - Assuming data follow a normal distribution is essential for many common statistical tests. However, what are normal data and when can we assume that a data set follows this distribution? What can be done to analyze non-normal data? PMID- 26523911 TI - Macrocyclic Versus Linear Gadolinium Chelates. PMID- 26523910 TI - High-Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1 Weighted Images: Evaluation of the Macrocyclic Gadolinium-Based Contrast Agent Gadobutrol. AB - OBJECTIVE: The aim of this study was to compare changes in the signal intensity (SI) ratio of the dentate nucleus (DN) to the pons, DN to cerebrospinal fluid (CSF), and globus pallidus (GP) to thalamus on unenhanced T1-weighted magnetic resonance imaging (MRI) scans after serial injections of the macrocyclic gadolinium-based contrast agent gadobutrol. MATERIALS AND METHODS: Thirty patients who had received at least 5 MRI examinations (plus an additional last MRI for reference) with the exclusive use of gadobutrol, resulting in a total cumulative dose of 54.1 +/- 30.4 mL gadobutrol, were analyzed retrospectively. Signal intensity ratio differences were calculated for DN-to-pons, DN-to-CSF, and GP-to-thalamus ratios by subtracting the SI ratio at the first MRI from the SI ratio at the last MRI scan. One-sample t tests were employed to examine if they differed from 0. Regression and correlational analyses were performed to examine whether the SI ratio differences were predicted by a number of control variables. RESULTS: Signal intensity ratio differences did not differ significantly from 0, neither for the DN-to-pons ratio (-0.0035 +/- 0.0476, P = 0.69), the DN-to-CSF ratio (-0.0539 +/- 0.3217, P = 0.37), nor the GP-to-thalamus ratio (-0.0020 +/- 0.0211, P = 0.60). None of the control variables predicted changes in SI ratios. CONCLUSIONS: In contrast to a recently published study, we did not find signal increases in the DN or in the GP after serial injections of gadobutrol, even though the total dose applied here was considerably larger than in the respective study. This finding adds further support to the hypothesis that the molecular structure of a gadolinium-based contrast agent as either macrocyclic or linear is a crucial factor for its potential to cause gadolinium deposition in the brain. Future studies should further assess this hypothesis by additional animal investigations as well as histopathological and clinical correlation studies. PMID- 26523912 TI - Usefulness of the second-derivative curve of activated partial thromboplastin time on the ACL-TOP coagulation analyzer for detecting factor deficiencies. PMID- 26523913 TI - Evaluation of coagulation tests before newborn circumcision: is it necessary? AB - Evaluation of coagulation parameters prior to newborn circumcision is routinely performed in many countries. However, the value of this screening in predicting the bleeding risk is unknown. The aim of this study was to evaluate the correlation between the preoperative prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT) and excessive bleeding after the circumcision in term, healthy newborns without family history of coagulopathy. The medical records of healthy, full term newborns born at VKV American Hospital, in Istanbul, Turkey, between 2009 and 2012 who were circumcised within the first week of life, were reviewed retrospectively. The data for family history of coagulopathy, clinical sign(s) of bleeding during and/or after delivery, preoperative PT, aPTT levels and the amount of bleeding after circumcision were gathered. The most recent medical records of the patients' were also reviewed for any possible, lately diagnosed bleeding disorder. A total of 450 newborns met the above criteria. None had a family history of bleeding disorder or clinical bleeding. A total of 158 (35%) newborns had an aPTT result greater than 54.5 s, 269 (59%) had PT result greater than 15.9 s and 72 (16%) had international normalized ratio result greater than 1.62. Neither of the patients with prolonged PT and/or aPTT had prolonged or excessive bleeding. The evaluation of PT and aPTT before elective newborn circumcision is not necessary in the absence of clinical bleeding or a family history of bleeding disorder. It is rather a habit in general practice and possibly a result of defensive medicine. PMID- 26523914 TI - Relationship between high on aspirin platelet reactivity and oxidative stress in coronary artery by-pass grafted patients. AB - The aim of the study was to assess the responsiveness of blood platelets to acetylsalicylic acid (ASA) in patients following coronary artery bypass grafting (CABG) surgery with relation to oxidative and antioxidative plasma status. The study included 37 patients treated with the CABG procedure. During the first 24 h after CABG patients were given 300 mg of ASA with the following dose of 150 mg daily. The blood was collected before the procedure and 10 days after. Whole blood platelet aggregation induced with arachidonic acid, collagen and adenosine diphosphate (ADP) was performed together with whole blood generation of thromboxane B2 (TxB2). Oxidative stress was measured before and 10 days after CABG with total oxidative plasma status (TOS) and total antioxidative status of the plasma (TAS). TOS/TAS index was calculated. We observed a significant increase in the TOS and TOS/TAS index and ADP-induced aggregation 10 days after CABG in comparison with its level before operation. There was a significant decrease in the arachidonic acid-induced aggregation and serum TxB2 level. Patients with ADP-induced and collagen-induced aggregation in the upper quartile had significantly higher TOS and TOS/TAS index before (ADP) and after the operation (ADP and collagen). There were 19 patients (51%) with high on aspirin platelet reactivity after CABG who had also higher TOS and TOS/TAS index and lower TAS value in comparison with aspirin responders. Despite ASA use, increased oxidative stress after CABG can overcome its antiplatelet effect and increase platelet activation through other pathways. PMID- 26523915 TI - Laparoscopic Totally Extraperitoneal Groin Hernia Repair Using a Self-Gripping Mesh: Clinical Results of 235 Primary and Recurrent Groin Hernias. AB - INTRODUCTION: Compared with open surgery, laparoscopic groin hernia repair has been shown to significantly reduce postoperative pain. However, chronic pain remains a problem with the laparoscopic approach, affecting approximately 10% of patients. The purpose of this study was to evaluate clinical outcomes following the use of Parietex ProGripTM (Covidien, Dublin, Ireland) self-gripping mesh during laparoscopic totally extraperitoneal groin hernia repair. MATERIALS AND METHODS: Data were collected prospectively from 145 male and 15 female patients with 235 inguinal hernias. All patients underwent repair by the laparoscopic totally extraperitoneal approach using Parietex ProGrip mesh. During follow-up ranging from 5 to 24 months, complications, pain score, patient satisfaction, and recurrence were analyzed. RESULTS: All patients were discharged on the day of surgery or the next morning. There were no immediate complications or returns to the operating room. Delayed postoperative complications included minor bruising to the genital region (3 cases), hematoma/seroma (1 case), and wound infection (1 case). The mean follow-up was 15 months, at which time there were no reports of hernia recurrence and 99% of patients were satisfied with their hernia repair. One patient (0.63%) reported severe pain (numeric rating scale score of >7), and 4 patients (2.5%) reported intermittent mild pain on exertion. CONCLUSIONS: The results of this study suggest that the use of a self-gripping mesh during the laparoscopic totally extraperitoneal approach is a promising and effective technique for repairing both primary and recurrent inguinal hernias. PMID- 26523916 TI - Electronic interference transport and its electron-phonon interaction in the Sb doped Bi2Se3 nanoplates synthesized by a solvothermal method. AB - Here we synthesized the antimony doped [Formula: see text] nanoplates by the solvothermal method. The angle-dependent magnetoconductance study was carried out and all the [Formula: see text] were found to be normalized to the perpendicular field, indicating a clear 2D electronic state. The features of weak antilocalization and universal conductance fluctuations were clearly identified in the magnetoresistance transport of the 4-probe nanodevices. The dephasing lengths are extracted respectively according to the Hikami-Larkin-Nagaoka theory. It is attributed to the involvement of the dynamic spin centers. The dephasing lengths are found to increase with the decreasing temperature following a [Formula: see text] law with [Formula: see text]. This reveals the additional dephasing source of electron-phonon interaction, which is often absent for pure 2D electronic systems. PMID- 26523917 TI - Physicochemical perspectives (aggregation, structure and dynamics) of interaction between pluronic (L31) and surfactant (SDS). AB - The influence of the water soluble non-ionic tri-block copolymer PEO-PPO-PEO [poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide)] i.e., E2P16E2 (L31) on the microstructure and self-aggregation dynamics of the anionic surfactant sodium dodecylsulfate (SDS) in aqueous solution was investigated using cloud point (CP), isothermal titration calorimetry (ITC), high resolution nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and small-angle neutron scattering (SANS) measurements. CP provided the thermodynamic information on the Gibbs free energy, enthalpy, entropy and heat capacity changes pertaining to the phase separation of the system at elevated temperature. The ITC and NMR self-diffusion measurements helped to understand the nature of the binding isotherms of SDS in the presence of L31 in terms of the formation of mixed aggregates and free SDS micelles in solution. EPR analysis provided the micro viscosity of the spin probe 5-DSA in terms of rotational correlation time. The SANS study indicated the presence of prolate ellipsoidal mixed aggregates, whose size increased with the increasing addition of L31. At a large [L31], SANS also revealed the progressive decreasing size of the ellipsoidal mixed aggregates of SDS-L31 into nearly globular forms with the increasing SDS addition. Wrapping of the spherical SDS micelles by L31 was also corroborated from (13)C NMR and SANS measurements. PMID- 26523918 TI - Direct determination of ionic transference numbers in ionic liquids by electrophoretic NMR. AB - Charge transport in ionic liquids is a phenomenon of utmost interest for electrochemical (e.g. battery) applications, but also of high complexity, involving transport of ion pairs, charged clusters and single ions. Molecular understanding is limited due to unknown contributions of cations, anions and clusters to the conductivity. Here, we perform electrophoretic NMR to determine electrophoretic mobilities of cations and anions in seven different ionic liquids. For the first time, mobilities in the range down to 10(-10) m(2) V(-1) s(-1) are determined. The ionic transference number, i.e. the fractional contribution of an ionic species to overall conductivity, strongly depends on cation and anion structure and its values show that structurally very similar ionic liquids can have cation- or anion-dominated conductivity. Transference numbers of cations, for example, vary from 40% to 58%. The results further prove the relevance of asymmetric clusters like [CationXAnionY](X-Y), X ? Y, for charge transport in ionic liquids. PMID- 26523919 TI - Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned. AB - IMPORTANCE: Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials. OBJECTIVE: To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS: Two 12-week, phase 3, randomized, placebo controlled, double-blind trials performed from July 15, 2010, to April 16, 2013. The setting included neurology clinics, clinical research centers, and hospitals in the Americas, the European Union, Eastern Europe, India, and South Africa. Participants included patients with moderate to severe PD taking levodopa who were experiencing motor fluctuations. INTERVENTIONS: In trial 1, a total of 778 eligible patients were randomized to the addition of preladenant (2 mg, 5 mg, or 10 mg twice daily), placebo, or rasagiline mesylate (1 mg/d) in a 1:1:1:1:1 ratio. In trial 2, a total of 476 eligible patients were randomized to the addition of preladenant (2 mg or 5 mg twice daily) or placebo in a 1:1:1 ratio. MAIN OUTCOMES AND MEASURES: The primary outcome measure was change in off time from baseline to week 12. RESULTS: In trial 1, neither preladenant nor rasagiline was superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.10 hour (95% CI, -0.69 to 0.46 hour) for preladenant 2 mg twice daily, -0.20 hour (95% CI, -0.75 to 0.41 hour) for preladenant 5 mg twice daily, -0.00 hour (95% CI, -0.62 to 0.53 hour) for preladenant 10 mg twice daily, and -0.30 hour (95% CI, -0.90 to 0.26 hour) for rasagiline mesylate 1 mg/d. In trial 2, preladenant was not superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were 0.20 hour (95% CI, -0.72 to 0.35 hour) for preladenant 2 mg twice daily and -0.30 hour (95% CI, -0.86 to 0.21 hour) for preladenant 5 mg twice daily. Preladenant was well tolerated, with the most common adverse event that showed an increase over placebo in both trials being constipation (6%-8% for preladenant vs 1%-3% for placebo). CONCLUSIONS AND RELEVANCE: In these phase 3 trials, preladenant did not significantly reduce off time compared with placebo. That the active control rasagiline also failed to demonstrate a significant reduction in off time suggests that issues of study design or conduct may have affected these trials. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01155466 and NCT01227265. PMID- 26523921 TI - A Liquid Junction Photoelectrochemical Solar Cell Based on p-Type MeNH3PbI3 Perovskite with 1.05 V Open-Circuit Photovoltage. AB - A liquid junction photoelectrochemical (PEC) solar cell based on p-type methylammonium lead iodide (p-MeNH3PbI3) perovskite with a large open-circuit voltage is developed. MeNH3PbI3 perovskite is readily soluble or decomposed in many common solvents. However, the solvent dichloromethane (CH2Cl2) can be employed to form stable liquid junctions. These were characterized with photoelectrochemical cells with several redox couples, including I3(-)/I(-), Fc/Fc(+), DMFc/DMFc(+), and BQ/BQ(*-) (where Fc is ferrocene, DMFc is decamethylferrocene, BQ is benzoquinone) in CH2Cl2. The solution-processed MeNH3PbI3 shows cathodic photocurrents and hence p-type behavior. The difference between the photocurrent onset potential and the standard potential for BQ/BQ(*-) is 1.25 V, which is especially large for a semiconductor with a band gap of 1.55 eV. A PEC photovoltaic cell, with a configuration of p-MeNH3PbI3/CH2Cl2, BQ (2 mM), BQ(*-) (2 mM)/carbon, shows an open-circuit photovoltage of 1.05 V and a short-circuit current density of 7.8 mA/cm(2) under 100 mW/cm(2) irradiation. The overall optical-to-electrical energy conversion efficiency is 6.1%. The PEC solar cell shows good stability for 5 h under irradiation. PMID- 26523920 TI - Parent-Adolescent Communication About Contraception and Condom Use. PMID- 26523922 TI - Ultrafine Pt nanoparticle-decorated robust 3D N-doped porous graphene as an enhanced electrocatalyst for methanol oxidation. AB - Ultrafine Pt nanoparticles supported on a robust 3D N-doped porous graphene (PtNP/R-3DNG) composite are fabricated. The composite exhibits a considerable enhancement of activity and stability toward the methanol electrooxidation reaction. The robust 3D porous structure and abundant nitrogen atoms are believed to be responsible for the enhanced performance. PMID- 26523924 TI - Retraction statement: In Bangladesh, overweight individuals have fewer symptoms of depression than nonoverweight individuals. AB - The above article, published online on 1 October 2009 in Wiley Online Library (wileyonlinelibrary.com), and in volume 18, pp. 1143-1145, has been retracted by agreement between the authors, the journal Editors-in-Chief, Eric Ravussin and Donna Ryan, the Obesity Society and Wiley Periodicals, Inc. Although there is no implication that the data collection was carried out unethically, the retraction has been agreed to because the subsequent data analysis was conducted without the required approval of the university ethics board while the published paper incorrectly stated that Norwegian ethical approval had been obtained. REFERENCE: Asghar, S., Magnusson, A., Khan, A., Ali, K. and Hussain, A. In Bangladesh, overweight individuals have fewer symptoms of depression than nonoverweight individuals. Obesity 2010;18:1143-1145. doi: 10.1038/oby.2009.332. PMID- 26523923 TI - Copper-Catalyzed Phosphonation-Annulation Approaches to the Synthesis of beta Phosphonotetrahydrofurans Involving C-P and C-O Bonds Formation. AB - Substituted tetrahydrofuran derivatives play important roles as biological activities. A versatile method for the synthesis of beta phosphonotetrahydrofurans has been developed based on Cu-catalyzed difunctionalization of alkenes. This transformation would provide a new pathway for the formation of Csp(3)-P and Csp(3)-O bonds in one step. Furthermore, this copper catalyst system can be used in the synthesis of beta phosphonotetrahydropyrans and phosphono-gamma-butyrolactones. These reactions were also performed well by using 3 equiv of Mn(OAc)3.2H2O as the oxidant without copper catalyst. PMID- 26523925 TI - AmpliconDuo: A Split-Sample Filtering Protocol for High-Throughput Amplicon Sequencing of Microbial Communities. AB - High throughput sequencing (HTSeq) of small ribosomal subunit amplicons has the potential for a comprehensive characterization of microbial community compositions, down to rare species. However, the error-prone nature of the multi step experimental process requires that the resulting raw sequences are subjected to quality control procedures. These procedures often involve an abundance cutoff for rare sequences or clustering of sequences, both of which limit genetic resolution. Here we propose a simple experimental protocol that retains the high genetic resolution granted by HTSeq methods while effectively removing many low abundance sequences that are likely due to PCR and sequencing errors. According to this protocol, we split samples and submit both halves to independent PCR and sequencing runs. The resulting sequence data is graphically and quantitatively characterized by the discordance between the two experimental branches, allowing for a quick identification of problematic samples. Further, we discard sequences that are not found in both branches ("AmpliconDuo filter"). We show that the majority of sequences removed in this way, mostly low abundance but also some higher abundance sequences, show features expected from random modifications of true sequences as introduced by PCR and sequencing errors. On the other hand, the filter retains many low abundance sequences observed in both branches and thus provides a more reliable census of the rare biosphere. We find that the AmpliconDuo filter increases biological resolution as it increases apparent community similarity between biologically similar communities, while it does not affect apparent community similarities between biologically dissimilar communities. The filter does not distort overall apparent community compositions. Finally, we quantitatively explain the effect of the AmpliconDuo filter by a simple mathematical model. PMID- 26523926 TI - Metastable Ni7B3: A New Paramagnetic Boride from Solution Chemistry, Its Crystal Structure and Magnetic Properties. AB - We trapped an unknown metastable boride by applying low-temperature solution synthesis. Single-phase nickel boride, Ni7B3, was obtained as bulk samples of microcrystalline powders when annealing the amorphous, nanoscale precipitate that is formed in aqueous solution of nickel chloride upon reaction with sodium tetrahydridoborate. Its crystal structure was solved based on a disordered Th7Fe3 type model (hexagonal crystal system, space group P63mc, no. 186, a = 696.836(4) pm, c = 439.402(4) pm), using synchrotron X-ray powder data. Magnetic measurements reveal paramagnetism, which is in accordance with quantum chemical calculations. According to high-temperature X-ray diffraction and differential scanning calorimetry this nickel boride phase has a narrow stability window between 300 and 424 degrees C. It crystallizes at ca. 350 degrees C, then starts decomposing to form Ni3B and Ni2B above 375 degrees C, and shows an exothermic effect at 424 degrees C. PMID- 26523927 TI - Resilience in the General Population: Standardization of the Resilience Scale (RS 11). AB - BACKGROUND: The objectives of the study were to generate normative data for the RS-11 for different age groups for men and women and to further investigate the construct validity and factor structure in the general population. METHODS: Nationally representative face-to face household surveys were conducted in Germany in 2006 (n = 5,036). RESULTS: Normative data for the RS-11 were generated for men and women (53.7% female) and different age levels (mean age (SD) of 48.4 (18.0) years). Men had significantly higher mean scores compared with women (60.0 [SD = 10.2] vs. 59.3 [SD = 11.0]). Results of CFA supported a one-factor model of resilience. Self-esteem (standardized beta = .50) and life satisfaction (standardized beta =.20) were associated with resilience. CONCLUSIONS: The normative data provide a framework for the interpretation and comparisons of resilience with other populations. Results demonstrate a special importance of self-esteem in the understanding of resilience. PMID- 26523928 TI - Pluronic-Functionalized Silica-Lipid Hybrid Microparticles: Improving the Oral Delivery of Poorly Water-Soluble Weak Bases. AB - A Pluronic-functionalized silica-lipid hybrid (Plu-SLH) microparticle system for the oral delivery of poorly water-soluble, weak base drugs is reported for the first time. A highly effective Plu-SLH microparticle system was composed of Labrasol as the lipid phase, Pluronic F127 as the polymeric precipitation inhibitor (PPI), and silica nanoparticles as the solid carrier. For the model drug cinnarizine (CIN), the Plu-SLH delivery system was shown to offer significant biopharmaceutical advantages in comparison with unformulated drug and drug in the silica-lipid hybrid (SLH) system. In vitro two-phase dissolution studies illustrated significantly reduced pH provoked CIN precipitation and an 8- to 14-fold improvement in the extent of dissolution in intestinal conditions. In addition, under simulated intestinal digesting conditions, the Plu-SLH provided approximately three times more drug solubilization than the SLH. Oral administration in rats resulted in superior bioavailability for Plu-SLH microparticles, i.e., 1.6- and 2.1-fold greater than the SLH and the unformulated CIN, respectively. A physical mixture of Pluronic and SLH (Plu&SLH), having the same composition as Plu-SLH, was also evaluated, but showed no significant increase in CIN absorption when compared to unmodified CIN or SLH. This work represents the first study where different methods of incorporating PPI to formulate solid-state lipid-based formulations were compared for the impact on the biopharmaceutical performance. The data suggest that the novel physicochemical properties and structure of the fabricated Plu-SLH microparticle delivery system play an important role in facilitating the synergistic advantage of Labrasol and Pluronic F127 in preventing drug precipitation, and the Plu-SLH provides efficient oral delivery of poorly water-soluble weak bases. PMID- 26523929 TI - Rituximab intolerance in patients with Waldenstrom macroglobulinaemia. PMID- 26523930 TI - Energetics, Thermodynamics, and Molecular Recognition of Piperine with DNA. AB - Piperine, the bioactive phytochemical from black pepper (Piper nigrum L.), is a nontoxic natural compound exhibiting many physiological and pharmacological properties. They include antioxidant, anti-inflammatory, antimutagenic, antitumor, antiapoptotic, antigenotoxic, antiarthritic, antifungal, antimicrobial, antidepressant, anti-HBV, and gastro-protective activities. It also enhances the bioavailability of phytochemicals and drugs. The molecular mechanism of action of piperine with DNA has not yet been addressed, while its pharmacological activities have been reported. In this work we report for the first time the interaction of piperine molecule with DNA duplex. We have carried out UV-vis absorption and fluorescence spectroscopy to confirm the binding of piperine with calf thymus DNA (ctDNA). The energetics of interaction of piperine with ctDNA was monitored by isothermal titration calorimetry (ITC). Differential scanning calorimetry (DSC) and melting temperature (Tm) analysis were also performed, confirming a minor groove mode of binding of piperine with ctDNA. The binding free energy DeltaG values obtained from molecular dynamics simulation studies agree well with ITC values and reveal a sequence dependent minor groove binding exhibiting a specificity toward AT rich sequences. PMID- 26523931 TI - Label-Free and Enzyme-Free Homogeneous Electrochemical Biosensing Strategy Based on Hybridization Chain Reaction: A Facile, Sensitive, and Highly Specific MicroRNA Assay. AB - Homogenous electrochemical biosensing strategies have attracted substantial attention, because of their advantages of being immobilization-free and having rapid response and improved recognition efficiency, compared to heterogeneous biosensors; however, the high cost of labeling and the strict reaction conditions of tool enzymes associated with current homogeneous electrochemical methods limit their potential applications. To address these issues, herein we reported, for the first time, a simple label-free and enzyme-free homogeneous electrochemical strategy based on hybridization chain reaction (HCR) for sensitive and highly specific detection of microRNA (miRNA). The target miRNA triggers the HCR of two species of metastable DNA hairpin probes, resulting in the formation of multiple G-quadruplex-incorporated long duplex DNA chains. Thus, with the electrochemical indicator Methylene Blue (MB) selectively intercalated into the duplex DNA chain and the multiple G-quadruplexes, a significant electrochemical signal drop is observed, which is dependent on the concentration of the target miRNA. Thus, using this "signal-off" mode, a simple, label-free and enzyme-free homogeneous electrochemical strategy for sensitive miRNA assay is readily realized. This strategy also exhibits excellent selectivity to distinguish even single-base mismatched miRNA. Furthermore, this method also exhibits additional advantages of simplicity and low cost, since both expensive labeling and sophisticated probe immobilization processes are avoided. Therefore, the as-proposed label-free and enzyme-free homogeneous electrochemical strategy may become an alternative method for simple, sensitive, and selective miRNA detection, and it has great potential to be applied in miRNA-related clinical diagnostics and biochemical research. PMID- 26523933 TI - A Resonance-Shifting Hybrid n-Type Layer for Boosting Near-Infrared Response in Highly Efficient Colloidal Quantum Dots Solar Cells. AB - A new configuration of a plasmonic quantum dots solar structure is proposed. Gold silver core-shell metal nanoparticles (Au@Ag NCs) are incorporated into the TiO2 layer (Au@Ag NCs-HL) of PbS-based solar cells. The TiO2 layer enables the Au@Ag NCs to have broad plasmonic responses and the external quantum efficiency and absorption of the plasmonic devices are significantly enhanced. The electrical performance of the solar cells is also improved. PMID- 26523932 TI - Portal Hyperperfusion after Extended Hepatectomy Does Not Induce a Hepatic Arterial Buffer Response (HABR) but Impairs Mitochondrial Redox State and Hepatocellular Oxygenation. AB - BACKGROUND & AIMS: Portal hyperperfusion after extended hepatectomy or small-for size liver transplantation may induce organ dysfunction and failure. The underlying mechanisms, however, are still not completely understood. Herein, we analysed whether hepatectomy-associated portal hyperperfusion induces a hepatic arterial buffer response, i.e., an adaptive hepatic arterial constriction, which may cause hepatocellular hypoxia and organ dysfunction. METHODS: Sprague-Dawley rats underwent 30%, 70% and 90% hepatectomy. Baseline measurements before hepatectomy served as controls. Hepatic arterial and portal venous flows were analysed by ultrasonic flow measurement. Microvascular blood flow and mitochondrial redox state were determined by intravital fluorescence microscopy. Hepatic tissue pO2 was analysed by polarographic techniques. Hepatic function and integrity were studied by bromosulfophthalein bile excretion and liver histology. RESULTS: Portal blood flow was 2- to 4-fold increased after 70% and 90% hepatectomy. This, however, did not provoke a hepatic arterial buffer response. Nonetheless, portal hyperperfusion and constant hepatic arterial blood flow were associated with a reduced mitochondrial redox state and a decreased hepatic tissue pO2 after 70% and 90% hepatectomy. Microvascular blood flow increased significantly after hepatectomy and functional sinusoidal density was found only slightly reduced. Major hepatectomy further induced a 2- to 3-fold increase of bile flow. This was associated with a 2-fold increase of bromosulfophthalein excretion. CONCLUSIONS: Portal hyperperfusion after extended hepatectomy does not induce a hepatic arterial buffer response but reduces mitochondrial redox state and hepatocellular oxygenation. This is not due to a deterioration of microvascular perfusion, but rather due to a relative hypermetabolism of the remnant liver after major resection. PMID- 26523934 TI - [High-Flow Nasal Cannulae (HFNC) in Neonates: A Survey of Current Practice in Level 1 Perinatal Centres in the German State of North Rhine-Westphalia]. AB - INTRODUCTION: High-flow nasal cannulae (HFNC) is a kind of non-invasive respiratory support. In recent years, its application has gained increasing popularity for treating neonates with respiratory failure. Within this study, neonatologists employed at high level perinatal centres within the region of North Rhine-Westphalia, Germany were interviewed. We evaluated their personal experience as well as the underlying indication for using HFNC. METHOD: We undertook an online survey. RESULTS: 93% of the interviewed participants use HFNC systems in their NICU. The most prominent indications were CPAP-weaning, nasal trauma, and apnoea of prematurity. Both initial flow and maximum and minimum flow rates varied widely. The primary benefit of HFNC vs. conventional CPAP was the improved neonate tolerance, less nasal traumata and ease of application and care. A common disadvantage was the inability to conduct PEEP measurements. DISCUSSION: The application of the HFNC system is increasing for specific neonatal indications, thereby increasing the data for the evaluation of effectivity and safety. Nevertheless, detailed investigations of the appropriate flow rate settings are still lacking. PMID- 26523935 TI - Structural and Dielectric Properties of Subnanometric Laminates of Binary Oxides. AB - Capacitors with a dielectric material consisting of amorphous laminates of Al2O3 and TiO2 with subnanometer individual layer thicknesses can show strongly enhanced capacitance densities compared to the bulk or laminates with nanometer layer thickness. In this study, the structural and dielectric properties of such subnanometer laminates grown on silicon by state-of-the-art atomic layer deposition are investigated with varying electrode materials. The laminates show a dielectric constant reaching 95 combined with a dielectric loss (tan delta) of about 0.2. The differences of the observed dielectric properties in capacitors with varying electrodes indicate that chemical effects at the interface with the TiN electrode play a major role, while the influence of the local roughness of the individual layers is rather limited. PMID- 26523936 TI - Anticipatory and reactive responses to chocolate restriction in frequent chocolate consumers. PMID- 26523937 TI - A study update of mortality in workers at a phosphate fertilizer production facility. AB - OBJECTIVE: To evaluate the mortality experience among 3,199 workers employed 1951 1976 at a phosphate fertilizer production plant in central Florida with follow-up through 2011. METHODS: Cause-specific standardized mortality ratios (SMRs) for the full cohort were calculated with the U.S. population as referent. Lung cancer and leukemia risks were further analyzed using conditional logistic regression. RESULTS: The mortality due to all-causes (SMR = 1.07, 95% confidence interval [CI] 1.02-1.13, observed deaths [n] = 1,473), all-cancers (SMR = 1.16, 95%CI 1.06 1.28, n = 431), and a priori outcomes of interests including lung cancer (SMR = 1.32, 95%CI = 1.13-1.53, n = 168) and leukemia (SMR = 1.74, 95%CI = 1.11-2.62, n = 23) were statistically significantly elevated. Regression modeling on employment duration or estimated radiation scores did not show exposure-response relation with lung cancer or leukemia mortality. CONCLUSION: SMR results showed increased lung cancer and leukemia mortality in a full cohort of the phosphate fertilizer production facility. There was, however, no exposure-response relation observed among cases and matched controls. PMID- 26523938 TI - Integrating Cell Phone Imaging with Magnetic Levitation (i-LEV) for Label-Free Blood Analysis at the Point-of-Living. AB - There is an emerging need for portable, robust, inexpensive, and easy-to-use disease diagnosis and prognosis monitoring platforms to share health information at the point-of-living, including clinical and home settings. Recent advances in digital health technologies have improved early diagnosis, drug treatment, and personalized medicine. Smartphones with high-resolution cameras and high data processing power enable intriguing biomedical applications when integrated with diagnostic devices. Further, these devices have immense potential to contribute to public health in resource-limited settings where there is a particular need for portable, rapid, label-free, easy-to-use, and affordable biomedical devices to diagnose and continuously monitor patients for precision medicine, especially those suffering from rare diseases, such as sickle cell anemia, thalassemia, and chronic fatigue syndrome. Here, a magnetic levitation-based diagnosis system is presented in which different cell types (i.e., white and red blood cells) are levitated in a magnetic gradient and separated due to their unique densities. Moreover, an easy-to-use, smartphone incorporated levitation system for cell analysis is introduced. Using our portable imaging magnetic levitation (i-LEV) system, it is shown that white and red blood cells can be identified and cell numbers can be quantified without using any labels. In addition, cells levitated in i-LEV can be distinguished at single-cell resolution, potentially enabling diagnosis and monitoring, as well as clinical and research applications. PMID- 26523939 TI - Screening bactericidal effect of Pectobacterium carotovorum subsp. carotovorum strains against causal agent of potato soft rot. AB - This study focuses on the potential of Pectobacterium carotovorum subsp. carotovorum (Pcc) strains producing bacteriocin as a tool to control potato soft rot disease. Thirty out of 48 purified bacterial strains were characterized as Pcc using specific PCR and phenotypic tests. The pathogenicity and pectate degrading assays were recorded positive for 13 strains. Bacteriocin typing clustered producers into three groups according to their antimicrobial spectra. Majority of the producers except strains of group II showed antibacterial activity toward relative genus and the role of UV or mitomycin C was inductive. In addition, none of the distant genus was sensitive to Pcc bacteriocins except Rhizobium vitis. Molecular detection of four bacteriocins including carotovoricin, carosin S1, S2 and carosin D was performed. Overall, 54.5% of group I, 47.3 and 70% of groups II and III strains carried carotovoricin and four strains harbored gene corresponding to carosin S1. According to our data divers antimicrobial patterns obtained by Pcc strains and existence of new bateriocines could be possible. Moreover, our findings recommended that direct application of P29 or expression of corresponding genes of Pog22 or P21 in a nonpathogenic strain as a biocontrol agent may improve soft rot disease control. PMID- 26523940 TI - Point mutations which should not be overlooked in Hb H disease. AB - BACKGROUND: Hb H disease is an alpha-thalassemia (alpha-thal) syndrome characterized by chronic hemolytic anemia that occurs when three of total four alpha-globin genes lost their function due to completely deletions or different kind of mutations. OBJECTIVE: We here described 66 patients who have been diagnosed for Hb H disease during the last five years in our center. The genotypes involving point mutations present more severe phenotype than deletional forms that make them of primary important to health management. STUDY DESIGN: Hb H subjects carry different alpha-globin genotypes including deletional and non deletional mutations showing heterogenous clinical manifestations. RESULTS: The Hb H patients presenting a wide range of phenotype carried different deletional, non-deletional mutations or compound heterozygosity of them. CONCLUSION: We emphasize the importance of some point mutations responsible for more severe form of Hb H disease in Iranian population and the necessity for consideration of prenatal diagnosis (PND) in high-risk couples. PMID- 26523941 TI - Total Mortality, Major Adverse Cardiac Events, and Echocardiographic-Derived Cardiac Parameters with Fragmented QRS Complex. AB - BACKGROUND: Fragmented QRS complex (fQRS), an easily evaluated noninvasive electrocardiographic parameter, is associated with worse outcomes in patients with several cardiovascular conditions. The presence of fQRS on ECG may be an indicator of myocardial damage in patients with coronary artery disease (CAD). In this article, we performed a meta-analysis in order to characterize the presence of fQRS on ECG in patients with CAD. METHODS: We searched English-language randomized controlled trials involving fQRS on ECG in patients with CAD (n = 3279 patients, 12 trials). Two reviewers independently extracted data. Data on LVEF, LVESD, LVEDD, LVESV, LVEDV, total mortality, stroke, and MACE were collected. fQRS was performed a comparison with non-fQRS, calculating pooled relatives risk (RRs) and weighted mean difference (WMD), and associated 95% confidence intervals (CIs). RESULTS: fQRS was associated with significant increased WMD of LVEDD (WMD, 2.26; 95%CI, 0.92 to 0.36, P = 0.0009), LVESD (WMD, 2.71; 95%CI, 1.23 to 4.19, P = 0.0003), LVEDV (WMD, 31.37; 95%CI, 24.82 to 37.92, P < 0.00001), and LVESV (WMD, 28.45; 95%CI, 22.92 to 33.98, P < 0.00001). As compared to non-fQRS, fQRS increased risk of total mortality (RR, 3.09; 95%CI, 1.76 to 5.44, P < 0.0001) and MACE (RR, 2.85; 95%CI, 1.98 to 4.09, P < 0.00001) in patients with CAD. However, a decreased trend was observed for LVEF (WMD, -3.59; 95%CI, -7.05 to -0.12, P = 0.04). For the incidence of stoke, there was no difference between fQRS and non fQRS group. CONCLUSIONS: Our findings indicate that fQRS is a valuable factor to predict total mortality and MACE in patients with CAD. PMID- 26523942 TI - UV-Induced [2+2] Grafting-To Reactions for Polymer Modification of Cellulose. AB - Benzaldehyde-functional cellulose paper sheets have been synthesized via tosylation of cellulose (Whatman No 5) followed by addition of p-hydroxy benzaldehyde. Via UV-induced Paterno-Buchi [2+2] cycloaddition reactions, these aldehyde functional surfaces are grafted with triallylcyanurate, trimethylolpropane allyl ether, and vinyl chloroacetate. In the following, allyl functional polymers (poly(butyl acrylate), pBA, Mn = 6990 g mol(-1) , D = 1.12 and poly(N-isopropyl acrylamide), pNIPAAm, Mn = 9500 g mol(-1) , D = 1.16) synthesized via reversible addition fragmentation chain transfer polymerization are conjugated to the celloluse surface in a UV-induced grafting-to approach. With pBA, hydrophobic cellulose sheets are obtained (water contact angle 116 degrees ), while grafting of pNIPAAm allows for generation of "smart" surfaces, which are hydrophilic at room temperature, but that become hydrophobic when heated above the characteristic lower critical solution temperature (93 degrees contact angle). The Paterno-Buchi reaction has been shown to be a versatile synthetic tool that also performs well in grafting-to approaches whereby its overall performance seems to be close to that of radical thiol-ene reactions. PMID- 26523943 TI - High Performance Carbon Nanotube Yarn Supercapacitors with a Surface-Oxidized Copper Current Collector. AB - Threadlike linear supercapacitors have demonstrated high potential for constructing fabrics to power electronic textiles (eTextiles). To improve the cyclic electrochemical performance and to produce power fabrics large enough for practical applications, a current collector has been introduced into the linear supercapcitors to transport charges produced by active materials along the length of the supercapacitor with high efficiency. Here, we first screened six candidate metal filaments (Pt, Au, Ag, AuAg, PtCu, and Cu) as current collectors for carbon nanotube (CNT) yarn-based linear supercapacitors. Although all of the metal filaments significantly improved the electrochemical performance of the linear supercapacitor, two supercapacitors constructed from Cu and PtCu filaments, respectively, demonstrate far better electrochemical performance than the other four supercapacitors. Further investigation shows that the surfaces of the two Cu containing filaments are oxidized by the surrounding polymer electrolyte in the electrode. While the unoxidized core of the Cu-containing filaments remains highly conductive and functions as a current collector, the resulting CuO on the surface is an electrochemically active material. The linear supercapacitor architecture incorporating dual active materials CNT + Cu extends the potential window from 1.0 to 1.4 V, leading to significant improvement to the energy density and power density. PMID- 26523944 TI - Chocolate Milk with Chia Oil: Ideal Sweetness, Sweeteners Equivalence, and Dynamic Sensory Evaluation Using a Time-Intensity Methodology. AB - The ideal sucrose concentration and equivalent concentrations of the stevia, sucralose, aspartame, and neotame in chocolate milk with chia oil as well as the dynamic behavior of certain sensory attributes were investigated using a time intensity methodology. The use of just-about-right (JAR) identified an ideal sucrose concentration of 9% (w/w). In addition, the magnitude estimation method showed that stevia had the lowest sweetness power whereas neotame presented the highest. Furthermore, the time-intensity analysis indicated that there was no significant change between the maximum intensities of the sweetness for any evaluated sweeteners. In general, the desired sensory profile and some economic considerations are decisive on the choice of which sweetener is better to be used in chocolate milk formulation added with chia oil. PMID- 26523946 TI - Combined Overexpression of JARID2, PRDM14, ESRRB, and SALL4A Dramatically Improves Efficiency and Kinetics of Reprogramming to Induced Pluripotent Stem Cells. AB - Identification of a gene set capable of driving rapid and proper reprogramming to induced pluripotent stem cells (iPSCs) is an important issue. Here we show that the efficiency and kinetics of iPSC reprogramming are dramatically improved by the combined expression of Jarid2 and genes encoding its associated proteins. We demonstrate that forced expression of JARID2 promotes iPSC reprogramming by suppressing the expression of Arf, a known reprogramming barrier, and that the N terminal half of JARID2 is sufficient for such promotion. Moreover, JARID2 accelerated silencing of the retroviral Klf4 transgene and demethylation of the Nanog promoter, underpinning the potentiating activity of JARID2 in iPSC reprogramming. We further show that JARID2 physically interacts with ESRRB, SALL4A, and PRDM14, and that these JARID2-associated proteins synergistically and robustly facilitate iPSC reprogramming in a JARID2-dependent manner. Our findings provide an insight into the important roles of JARID2 during reprogramming and suggest that the JARID2-associated protein network contributes to overcoming reprogramming barriers. PMID- 26523945 TI - Participant, rater, and computer measures of coherence in posttraumatic stress disorder. AB - We examined the coherence of trauma memories in a trauma-exposed community sample of 30 adults with and 30 without posttraumatic stress disorder. The groups had similar categories of traumas and were matched on multiple factors that could affect the coherence of memories. We compared the transcribed oral trauma memories of participants with their most important and most positive memories. A comprehensive set of 28 measures of coherence including 3 ratings by the participants, 7 ratings by outside raters, and 18 computer-scored measures, provided a variety of approaches to defining and measuring coherence. A multivariate analysis of variance indicated differences in coherence among the trauma, important, and positive memories, but not between the diagnostic groups or their interaction with these memory types. Most differences were small in magnitude; in some cases, the trauma memories were more, rather than less, coherent than the control memories. Where differences existed, the results agreed with the existing literature, suggesting that factors other than the incoherence of trauma memories are most likely to be central to the maintenance of posttraumatic stress disorder and thus its treatment. PMID- 26523947 TI - The origin and evolution of the acidocalcisome and its interactions with other organelles. AB - Acidocalcisomes are acidic calcium stores that have been found from bacteria to human cells. They are rich in phosphorus compounds in the form of orthophosphate (Pi), pyrophosphate (PPi), and polyphosphate (polyP) and their acidity is maintained by proton pumps such as the vacuolar proton pyrophosphatase (V-H+ PPase, or VP1), the vacuolar proton ATPase (V-H+-ATPase), or both. Recent studies in trypanosomatids and in other species have revealed their role in phosphate metabolism, and cation and water homeostasis, as suggested by the presence of novel pumps, transporters, and channels. An important role in autophagy has also been described. The study of the biogenesis of acidocalcisomes as well as of the interactions of these lysosome-related organelles with other organelles have uncovered important roles in calcium signaling and osmoregulation. Significantly, despite conservation of acidocalcisomes across all of cellular life, there is evidence for intimate integration of these organelles with eukaryotic cellular functions, and which are directly relevant to parasites. PMID- 26523948 TI - Expanding the tool box for genetic manipulation of Trypanosoma cruzi. AB - Trypanosoma cruzi is a protozoan parasite that causes Chagas disease, an illness that affects 6-7 million people and for which there is no effective drug therapy or vaccine. The publication of its complete genome sequence allowed a rapid advance in molecular studies including in silico screening of genes involved with pathogenicity as well as molecular targets for the development of new diagnostic methods, drug therapies and prophylactic vaccines. Alongside with in silico genomic analyses, methods to study gene function in this parasite such as gene deletion, overexpression, mutant complementation and reporter gene expression have been largely explored. More recently, the use of genome-wide strategies is producing a shift towards a global perspective on gene function studies, with the examination of the expression and biological roles of gene networks in different stages of the parasite life cycle and under different contexts of host parasite interactions. Here we describe the molecular tools and protocols currently available to perform genetic manipulation of the T. cruzi genome, with emphasis on recently described strategies of gene editing that will facilitate large-scale functional genomic analyses. These new methodologies are long overdue, since more efficient protocols for genetic manipulation in T. cruzi are urgently needed for a better understanding of the biology of this parasite and molecular processes involved with the complex and often harmful, interaction with its human host. PMID- 26523949 TI - To round or not to round: that is the question! AB - Bedside rounding and clinical examination has been an integral part of medical education and patient care for centuries. With the advent of computers and regulatory requirements for documentation by insurance carriers and third party providers, bedside rounding time has consistently decreased over the past several decades. Several studies have attempted to address the most effective way of bedside rounding, but no definite conclusion has been reached. We suggest multi center broad base studies of key stakeholders to address this challenging issue. PMID- 26523950 TI - Effects of Lavender Tea on Fatigue, Depression, and Maternal-Infant Attachment in Sleep-Disturbed Postnatal Women. AB - BACKGROUND: Lavender inhalation aromatherapy is widely believed to impart a hypnotic effect, act as a mood stabilizer, and enhance the positive feelings of mothers toward their infants. However, research into these and other potential therapeutic effects of lavender tea has been limited. AIMS: This study was conducted in Taiwan to evaluate the effectiveness of lavender tea in relieving sleep quality, fatigue, and depression; and in improving maternal-infant attachment during the early postpartum period. METHODS: A total of 80 Taiwanese postnatal women with poor sleep quality (Postpartum Sleep Quality Scale; PSQS score >=16) and with no history of allergy to herbal teas, foods, or medicines were assigned systematically to either the experimental group (n = 40) or the control group (n = 40). The participants in the experimental group were instructed to drink one cup of lavender tea after spending time to appreciate and smell the aroma each day for a period of 2 weeks, whereas their control group peers received regular postpartum care only. The PSQS, Edinburgh Postnatal Depression Scale, Postpartum Fatigue Scale, and Postpartum Bonding Questionnaire were used to assess outcomes. RESULTS: ANCOVA analyses using education level and pretest scores as covariates showed that experimental group participants perceived less fatigue (F = 6.281, p = .014) and depression (F = 4.731, p = .033) and showed greater bonding with their infant (F = 4.022, p = .049) compared with the control group. However, the scores for all four instruments were similar for both groups at the 4-week posttest, suggesting that the positive effects of lavender tea were limited to the immediate term. LINKING EVIDENCE TO ACTION: Healthcare researchers assume accountability for integrating research results into clinical practice. The findings in this study can gain greater attention among healthcare practitioners and encourage the correct and positive use of herbal therapy in postpartum health care. PMID- 26523951 TI - The contribution of Nicolae Botnariuc to evolutionary biology using systems theory. PMID- 26523952 TI - Imaging the Three-Dimensional Conductive Channel in Filamentary-Based Oxide Resistive Switching Memory. AB - Filamentary-based oxide resistive memory is considered as a disruptive technology for nonvolatile data storage and reconfigurable logic. Currently accepted models explain the resistive switching in these devices through the presence/absence of a conductive filament (CF) that is described as a reversible nanosized valence change in an oxide material. During device operation, the CF cycles billion of times at subnanosecond speed, using few tens of microamperes as operating current and thus determines the whole device's performance. Despite its importance, the CF observation is hampered by the small filament size and its minimal compositional difference with the surrounding material. Here we show an experimental solution to this problem and provide the three-dimensional (3D) characterization of the CF in a scaled device. For this purpose we have recently developed a tomography technique which combines the high spatial resolution of scanning probe microscopy with subnanometer precision in material removal, leading to a true 3D-probing metrology concept. We locate and characterize in three-dimensions the nanometric volume of the conductive filament in state-of-the art bipolar oxide-based devices. Our measurements demonstrate that the switching occurs through the formation of a single conductive filament. The filaments exhibit sizes below 10 nm and present a constriction near the oxygen-inert electrode. Finally, different atomic-size contacts are observed as a function of the programming current, providing evidence for the filament's nature as a defects modulated quantum contact. PMID- 26523953 TI - What Are the Potential Sites of Protein Arylation by N-Acetyl-p-benzoquinone Imine (NAPQI)? AB - Acetaminophen (paracetamol, APAP) is a safe and widely used analgesic medication when taken at therapeutic doses. However, APAP can cause potentially fatal hepatotoxicity when taken in overdose or in patients with metabolic irregularities. The production of the electrophilic and putatively toxic compound N-acetyl-p-benzoquinone imine (NAPQI), which cannot be efficiently detoxicated at high doses, is implicated in APAP toxicity. Numerous studies have identified that excess NAPQI can form covalent linkages to the thiol side chains of cysteine residues in proteins; however, the reactivity of NAPQI toward other amino acid side chains is largely unexplored. Here, we report a survey of the reactivity of NAPQI toward 11 N-acetyl amino acid methyl esters and four peptides. (1)H NMR analysis reveals that NAPQI forms covalent bonds to the side-chain functional groups of cysteine, methionine, tyrosine, and tryptophan residues. Analogous reaction products were observed when NAPQI was reacted with synthetic model peptides GAIL-X-GAILR for X = Cys, Met, Tyr, and Trp. Tandem mass spectrometry peptide sequencing showed that the NAPQI modification sites are located on the "X" residue in each case. However, when APAP and the GAIL-X-GAILR peptide were incubated with rat liver microsomes that contain many metabolic enzymes, NAPQI formed by oxidative metabolism reacted with GAIL-C-GAILR exclusively. For the peptides where X = Met, Tyr, and Trp, competing reactions between NAPQI and alternative nucleophiles precluded arylation of the target peptide by NAPQI. Although Cys residues are favorably targeted under these conditions, these data suggest that NAPQI can, in principle, also damage proteins at Met, Tyr, and Trp residues. PMID- 26523954 TI - Antiarrhythmic and alpha-Adrenoceptor Antagonistic Properties of Novel Arylpiperazine Derivatives of Pyrrolidin-2-one. AB - In an effort to develop alpha-adrenoceptor antagonists with antiarrhythmic activity, we designed a series of pyrrolidin-2-one derivatives. The alpha1- and alpha2-adrenorecepor affinities of the new pyrrolidin-2-one derivatives were determined using a radioligand binding assay. The most active compound was then tested in vitro for intrinsic activity toward alpha(1A)- and alpha(1B) adrenoceptors and in vitro for antiarrhythmic activity in epinephrine-induced arrhythmia in rats. The highest affinity for the alpha1-adrenoceptor (pK(i) = 7.01) was displayed by 1-{4-[4-(2-methoxy-5-chlorophenyl)-piperazin-1-yl]-methyl} pyrrolidin-2-one (9). 1-[4-(2-Fluorophenyl)-piperazin-1-yl]-methyl-pyrrolidin-2 one (7) showed the highest affinity toward the alpha2-adrenoceptor (pK(i) = 6.52). Intrinsic activity studies of compound 9 showed that this compound is an antagonist of both alpha(1A)- (EC50 = 0.5 nM) and alpha(1B)- (EC50 = 51.0 nM) adrenoceptors. Compound 9 displayed antiarrhythmic activity in rats (ED50 = 5.0 mg/kg (3.13-7.99)). New derivatives of pyrrolidin-2-one with alpha1 -adrenoceptor affinity were identified. We propose that the antiarrhythmic activity of compound 9 is related to its antagonism of alpha(1A)- and alpha(1B)-adrenoceptors. PMID- 26523955 TI - Cucumis sativus secretes 4'-ketoriboflavin under iron-deficient conditions. AB - A new compound in cucumber, Cucumis sativus, nutrient solution that appears under iron-deficient conditions, but not under ordinary culture conditions, has been revealed by HPLC analysis. The chemical structure of this compound was identified using LC-MS and NMR techniques as that of 4'-ketoriboflavin. This is the first report to show that 4'-ketoriboflavin can be found in metabolites from organisms. PMID- 26523956 TI - A Comprehensive Computational Study of the Interaction between Human Serum Albumin and Fullerenes. AB - Human serum albumin (HSA) is the most abundant blood plasma protein, which transports fatty acids, hormones, and drugs. We consider nanoparticle-HSA interactions by investigating the binding of HSA with three fullerene analogs. Long MD simulations, quantum mechanical (fragment molecular orbital, energy decomposition analysis, atoms-in-molecules), and free energy methods elucidated the binding mechanism in these complexes. Such a systematic study is valuable due to the lack of comprehensive theoretical approaches to date. The main elements of the mechanism include the following: binding to IIA site results in allosteric modulation of the IIIA and heme binding sites with an increase in alpha-helical structure of IIIA. Fullerenes displayed high binding affinities for HSA; therefore, HSA can be used as a fullerene carrier, facilitating any toxic function the fullerene may exert. Complex formation is driven by hydrogen bonding, van der Waals, nonpolar, charge transfer, and dispersion energy contributions. Proper functionalization of C60 has enhanced its binding to HSA by more than an order of magnitude. This feature may be important for biological applications (e.g., photodynamic therapy of cancer). Satisfactory agreement with relevant experimental and theoretical data has been obtained. PMID- 26523957 TI - Molecular phenology in plants: in natura systems biology for the comprehensive understanding of seasonal responses under natural environments. AB - Phenology refers to the study of seasonal schedules of organisms. Molecular phenology is defined here as the study of the seasonal patterns of organisms captured by molecular biology techniques. The history of molecular phenology is reviewed briefly in relation to advances in the quantification technology of gene expression. High-resolution molecular phenology (HMP) data have enabled us to study phenology with an approach of in natura systems biology. I review recent analyses of FLOWERING LOCUS C (FLC), a temperature-responsive repressor of flowering, along the six steps in the typical flow of in natura systems biology. The extensive studies of the regulation of FLC have made this example a successful case in which a comprehensive understanding of gene functions has been progressing. The FLC-mediated long-term memory of past temperatures creates time lags with other seasonal signals, such as photoperiod and short-term temperature. Major signals that control flowering time have a phase lag between them under natural conditions, and hypothetical phase lag calendars are proposed as mechanisms of season detection in plants. Transcriptomic HMP brings a novel strategy to the study of molecular phenology, because it provides a comprehensive representation of plant functions. I discuss future perspectives of molecular phenology from the standpoints of molecular biology, evolutionary biology and ecology. PMID- 26523959 TI - Elevated levels of tumor necrosis factor-alpha and TNFR1 in recurrent herniated lumbar discs correlate with chronicity of postoperative sciatic pain. AB - BACKGROUND CONTEXT: Sciatica is a condition characterized by radicular pain that can be secondary to a lumbar disc herniation (LDH). More than 10% of patients report persistent pain after surgery. The underlying mechanisms of postoperative sciatica remain unclear. There is evidence demonstrating that inflammation plays a role in the pathophysiology of sciatica. PURPOSE: The study aimed to assess if the expression of tumor necrosis factor (TNF)-alpha and its receptors (TNFR) was correlated with the severity of pre- and postoperative leg pain in LDH patients who underwent single or multiple decompressive discectomies. SETTING: This is an experimental prospective human study of intraoperative intervertebral disc (IVD) samples, as well as a clinical scores evaluation. METHODS: We analyzed the mRNA and protein levels of TNF-alpha, TNFR1, and TNFR2 in IVD biopsies, and correlated them with visual analogue scale (VAS) scores 1 day before surgery to 6 weeks and 6 months postoperatively. RESULTS: We evaluated the correlation between the inflammation in IVD with pre- and postoperative pain scores after discectomy in LDH patients operated for the first time (fLDH, N=12) and for recurrent cases (rLDH, N=8). This analysis showed that TNF-alpha and TNFR1 mRNA levels were significantly greater in rLDH patients; there was a twofold increase for TNF alpha and a 50% increase for TNFR1. Similarly, protein levels in IVD samples positively correlated with postoperative VAS scores, whereas TNFR2 protein levels negatively correlated with postoperative VAS scores. CONCLUSIONS: These findings indicate that rLDH patients present higher postoperative VAS scores compared with fLDH patients, and also that these scores are correlated with increased inflammation and may contribute to pain chronicity. PMID- 26523958 TI - Poor visualization limits diagnosis of proximal junctional kyphosis in adolescent idiopathic scoliosis. AB - BACKGROUND CONTEXT: Multiple methods are used to measure proximal junctional angle (PJA) and diagnose proximal junctional kyphosis (PJK) after fusion for adolescent idiopathic scoliosis (AIS); however, there is no gold standard. Previous studies using the three most common measurement methods, upper instrumented vertebra (UIV)+1, UIV+2, and UIV to T2, have minimized the difficulty in obtaining these measurements, and often exclude patients for which measurements cannot be recorded. PURPOSE: The purpose of this study is to assess the technical feasibility of measuring PJA and PJK in a series of AIS patients who have undergone posterior instrumented fusion and to assess the variability in results depending on the measurement technique used. STUDY DESIGN/SETTING: A retrospective cohort study was carried out. PATIENT SAMPLE: There were 460 radiographs from 98 patients with AIS who underwent posterior spinal fusion at a single institution from 2006 through 2012. OUTCOME MEASURES: The outcomes for this study were the ability to obtain a PJA measurement for each method, the ability to diagnose PJK, and the inter- and intra-rater reliability of these measurements. METHODS: Proximal junctional angle was determined by measuring the sagittal Cobb angle on preoperative and postoperative lateral upright films using the three most common methods (UIV+1, UIV+2, and UIV to T2). The ability to obtain a PJA measurement, the ability to assess PJK, and the total number of patients with a PJK diagnosis were tabulated for each method based on established definitions. Intra- and inter-rater reliability of each measurement method was assessed using intra-class correlation coefficients (ICCs). RESULTS: A total of 460 radiographs from 98 patients were evaluated. The average number of radiographs per patient was 5.3+/-1.7 (mean+/-standard deviation), with an average follow-up of 2.1 years (780+/-562 days). A PJA measurement was only readable on 13%-18% of preoperative filmsand 31%-49% of postoperative films (range based on measurement technique). Only 12%-31% of films were able to be assessed for PJK based on established definitions. The rate of PJK diagnosis ranged from 1% to 29%. Of these diagnoses, 21%-100% disappeared on at least one subsequent film for the given patient. ICC ranges for intra-rater and inter-rater reliability were 0.730-0.799 and 0.794-0.836, respectively. CONCLUSIONS: This study suggests significant limitations of the three most common methods of measuring and diagnosing PJK. The results of studies using these methods can be significantly affected based on the exclusion of patients for whom measurements cannot be made and choice of measurement technique. PMID- 26523960 TI - Left ventricle thrombus after tranexamic acid for spine surgery in an HIV positive patient. AB - BACKGROUND CONTEXT: Our case highlights the underappreciated thrombotic risks of tranexamic acid (TXA) use in non-cardiac surgery and emphasizes the need to elucidate these risks with appropriate clinical trials. PURPOSE: The use of TXA in non-cardiac surgery has significantly expanded in the past 5 years, especially after the 2010 publication of the CRASH-2 Trial. We submit a case with the intent to highlight the thrombotic risk of TXA use during non-cardiac surgery and discuss the need for careful risk stratification before the use of TXA in this context. STUDY DESIGN: A 66-year-old man with long-standing HIV infection, hypertension, and no history of coronary artery disease (CAD) presented for revision spinal fusion surgery with the use of TXA is presented. METHODS: To limit perioperative blood loss, the case patient received TXA intraoperatively. His operative course was uneventful. RESULTS: During the first 12 hours postoperatively the patient was noted to have persistent tachycardia and ST elevation on electrocardiogram. Echocardiography showed a new apical wall motion abnormality and a left ventricle thrombus; cardiac catheterization confirmed two vessel CAD, treated with a bare-metal stent and anticoagulation. CONCLUSIONS: The thrombotic risks of TXA use in non-cardiac surgery have yet to be adequately studied in clinical trials. Hence, TXA use in this context is still an area of uncertainty, and its thrombogenic risks have yet to be studied as a primary outcome in any large prospective trial to date. Patients with any hypercoagulable risk factors, including HIV infection or any prior thrombotic history in which TXA use is being considered, should prompt a discussion among the perioperative physicians involved. PMID- 26523962 TI - Management of spinal giant cell tumors. AB - BACKGROUND CONTEXT: Spinal giant cell tumors (SGCT) remain challenging tumors to treat. Although advancements in surgical techniques and adjuvant therapies have provided new options for treatment, evidence-based algorithms are lacking. PURPOSE: This study aims to review the peer-reviewed literature that addresses current treatment options and management of SGCT, to produce an evidence-based treatment algorithm. STUDY DESIGN/SETTING: A systematic review was performed. METHODS: Articles published between January 1, 1970 and March 31, 2015 were selected from PubMed and EMBASE searches using keywords "giant cell tumor" AND "spine" AND "treatment." Relevant articles were selected by the authors and reviewed. RESULTS: A total of 515 studies were identified, of which 81 studies were included. Complete surgical resections of SCGT resulted in the lowest recurrence rates. However, morbidity of en bloc resections is high and in some cases, surgery is not possible. Intralesional resection can be coupled with adjuvant therapies, but evidence-based algorithms for use of adjuvants remain elusive. Several recent advancements in adjuvant therapy may hold promise for decreasing SGCT recurrence, specifically stereotactic radiotherapy, selective arterial embolization, and medical therapy using denosumab and interferon. CONCLUSIONS: Complete surgical resection of SGCT should be the goal when possible, particularly if neurologic impairment is present. Denosumab holds promise as an adjuvant and perhaps stand-alone therapy for SGCT. Spinal giant cell tumors should be approached as a case-by-case problem, as each presents unique challenges. Collaboration of spine surgeons, radiation oncologists, and medical oncologists is the best practice for treating these difficult tumors. PMID- 26523961 TI - Neuroprotective effect of hydrogen sulfide on acute cauda equina injury in rats. AB - BACKGROUND: Hydrogen sulfide (H2S), as a novel gaseous messenger molecule, plays an important role in signal transduction and biological modulation. PURPOSE: In the present study the effect of H2S after compression injury of cauda equina was studied. STUDY DESIGN: The setting of this study is the laboratory investigation. METHODS: A total of 162 rats were randomly allocated into three groups: sham group, compression group, and H2S group. Cauda equina compression (CEC) injury in rats was induced by implanting silicone gels (10*1*1 mm) into the epidural spaces L5 and L6; laminectomy was performed at the L4 level of the vertebra in the sham operated group. The experimental group was treated with sodium hydrosulfide intraperitoneally (20 umol/kg body weight), whereas the compression and sham groups received equal volumes of physiological saline. Levels of malonaldehyde (MDA) and glutathione (GSH) were determined immediately before CEC surgery, 12 h, 24 h, 48 h, and 72 h after CEC surgery. Furthermore, hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) assay were performed 48 h after CEC. RESULTS: Hematoxylin and eosin staining showed that myelin sheath and the cauda equina fibers in the compression group were less compact and highly degenerated compared with the sham group, and that H2S treatment could improve the status. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling staining exhibited that decreased number of TUNEL positive cells was found in the H2S group than in the compression group. The level of MDA was increased in the sham and H2S groups compared with the compression group (p<.05, p<.01), whereas the level of GSH was decreased (p<.05, p<.01). CONCLUSIONS: With the above data, we conclude that H2S could reduce the oxidative stress and has neuroprotective effect in acute cauda equina syndrome. PMID- 26523963 TI - Clinical utility of ultrasound to prospectively monitor distraction of magnetically controlled growing rods. AB - BACKGROUND CONTEXT: Growing rods are commonly used for surgical treatment of skeletally immature patients with scoliosis, but require repeated surgeries for distractions and are fraught with complications. As an alternative, the use of magnetically controlled growing rods (MCGR) allows for more frequent non-invasive distractions to mimic normal growth. However, more plain radiographs are needed to monitor increased distraction frequency, thereby increasing ionizing radiation exposure to the developing child. The use of ultrasound, which emits no radiation, has been found in a cross-sectional study to be reliable in measuring MCGR distractions. PURPOSE: The study aims to address the prospective clinical utility of ultrasound compared with plain radiographs for assessing MCGR distractions. STUDY DESIGN: This is a prospective study. PATIENT SAMPLE: The study includes patients with early-onset scoliosis undergoing distractions after MCGR implant. OUTCOME MEASURES: The distraction length on plain radiographs and ultrasound was measured. METHODS: This is a prospective study of patients treated with MCGR. Patients with both single- and dual-rod systems were included. Outpatient distractions were performed at monthly intervals, targeting 2 mm of distraction on each occasion. Assessment of distraction length was monitored by ultrasound at each visit; plain radiographs were taken every 6 months and were compared with ultrasound measurements. RESULTS: Nine patients (5 female, 4 male), with a mean of 29 distractions (standard deviation [SD] +/-14.3), were recruited. The mean distracted length per 6 months was 5.7 mm (SD +/-3.6 mm) on plain radiographs and 5.2 mm (SD +/-3.9 mm) on ultrasound for the concave rod, and 6.1 mm (SD +/-3.6 mm) on plain radiographs and 5.9 mm (SD +/-3.8 mm) on ultrasound for the convex rod. Excellent inter- and intra-rater reliabilities were observed for radiographic and ultrasound measurements. An excellent correlation was noted between the two imaging modalities (r=0.93; p<.0001). CONCLUSIONS: This is the first prospective study to validate that ultrasound assessment of MCGR distraction lengths was highly comparable with that of plain radiographs. The present study has verified that ultrasound can be used to document length changes by distraction over time and that it had high clinical utility. Ultrasound can be a reliable alternative to plain radiographs, thereby avoiding radiation exposure and its potential detrimental sequelae in the developing child. PMID- 26523964 TI - Spinal epidural cavernous hemangioma: a rare site of involvement. PMID- 26523965 TI - Symptoms of depression as a prognostic factor for low back pain: a systematic review. AB - BACKGROUND CONTEXT: It has been proposed that depression plays an important role in the course of low back pain; however, there is considerable uncertainty on its predictive value. PURPOSE: This systematic review aims to investigate the effect of depression on the course of acute and subacute low back pain. STUDY DESIGN: This is a systematic review. METHODS: We searched the following databases using optimized search strategies: AMED, CINAHL, EMBASE, Health & Society Database, LILACS, MEDLINE, PsycINFO, Scopus, and Web of Science. We only included prospective studies that investigated a cohort of participants with acute or subacute non-specific low back pain (pain of less than 12 weeks' duration). The prognostic factor of interest was depression or symptoms of depression assessed at baseline. The outcomes of interest included pain intensity, chronicity (non recovery from low back pain), disability, return to work, health-related quality of life, and overall patient satisfaction. Two independent reviewers selected the studies, extracted the data, and assessed the methodological quality of the studies that were included. FUNDING: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare no conflicts of interest-associated biases. RESULTS: Seventeen articles reporting 13 cohort studies were included in this review. There was considerable variability between studies in terms of the method of assessment of depression and low back pain, statistical methods, and follow-up length, which precluded the quantitative synthesis of the results. Definition of outcomes varied across studies, but overall they could be divided into work-related outcome measures, followed by disability, pain, self-perceived recovery, and mixed outcomes. Eleven out of 17 articles (or 8 out of 13 cohorts) reported that symptoms of depression at baseline are related to worse low back pain outcomes (measured in various ways) at follow-up, and the effect sizes (odds ratio [OR]) ranged from 1.04 to 2.47. Only two studies that did not find a statistically significant association reported quantitative results: OR=1.03, 95% confidence interval (CI) 0.98-1.08; and OR=1.02, 95% CI 0.99-1.06. All included studies, regardless of statistical significance, showed an effect in the direction of harm. CONCLUSIONS: Although a definitive answer on the effect of depression on the course of low back pain is not available, the findings of this systematic review suggest that depression might have an adverse effect on the prognosis of low back pain. Future large studies that enroll an inception cohort and that employ a standardized method for assessing depression and low back pain are needed. PMID- 26523967 TI - Relationship between T1 slope and loss of lordosis after laminoplasty in patients with cervical ossification of the posterior longitudinal ligament. AB - BACKGROUND CONTEXT: Laminoplasty is a major surgical method used to treat patients with cervical ossification of the posterior longitudinal ligament (OPLL). Sometimes, patients with cervical OPLL demonstrate postoperative kyphosis despite sufficient preoperative lordosis. Recently, the impact of T1 slope has emerged as a predictor of kyphotic alignment change after laminoplasty. However, the relationship between T1 slope and postoperative cervical alignment change is not yet fully established. PURPOSE: The goals of the present study were to investigate the relationship between T1 slope and loss of cervical lordosis (LCL), and to identify the role of T1 slope as a predictor of postoperative kyphosis after laminoplasty in patients with OPLL. STUDY DESIGN: This is a retrospective case study. PATIENT SAMPLE: Between January 2011 and January 2012, 64 consecutive patients who underwent cervical laminoplasty for OPLL were enrolled (male:female ratio=47:17; mean age=55.9 years). Cervical spine lateral radiographs in neutral, flexion, and extension were taken before surgery and at 2 year follow-up. OUTCOME MEASURES: The C2-C7 Cobb angle, cervical range of motion (ROM), T1 slope, neck tilt, and C2-C7 sagittal vertical axis (SVA) were measured from lateral radiographs of the cervical spine preoperatively and postoperatively at 2-year follow-up. METHODS: Patients were divided into two groups according to preoperative T1 slope, and the postoperative cervical alignment change was compared between the groups. Postoperative kyphosis and LCL incidence were also evaluated at 2-year follow-up. The relationships between postoperative cervical alignment change and preoperative variables, including age, T1 slope, cervical ROM, C2-C7 SVA, and T1 slope minus C2-C7 Cobb angle (T1S-CL), were investigated. RESULTS: Patients were divided into two groups above and below median preoperative T1 slope (23.2 degrees ). There were no differences in age, sex, type of OPLL, or operation level between the two groups. Patients with higher preoperative T1 slope demonstrated significantly more lordotic preoperative cervical alignment (p=.001). Patients with higher preoperative T1 slope were more likely to exhibit postoperative LCL (p=.03), and when it occurred the degree of LCL was greater (p=.06). In multiple linear regression analysis, higher T1 slope (B=0.414, p=.04) and lower T1S-CL (B=-0.412, p=.03) were significantly associated with more postoperative LCL. In spite of these results, postoperative kyphosis did not occur more frequently in patients with higher T1 slope (p=.64). CONCLUSIONS: Patients with higher T1 slope had more lordotic curvature before surgery and demonstrated more LCL at 2-year follow-up. Cervical alignment was compromised after laminoplasty, and the degree of LCL was correlated with preoperative T1 slope. After laminoplasty for cervical OPLL, patients with higher T1 slope tended to exhibit a greater LCL yet did not drift into frank postoperative kyphosis. PMID- 26523966 TI - The benefit of nonoperative treatment for adult spinal deformity: identifying predictors for reaching a minimal clinically important difference. AB - BACKGROUND CONTEXT: Adult spinal deformity (ASD) patients may gain minimal clinically important difference (MCID) in one or more of the health-related quality-of-life instruments without surgical intervention. The present study identifies the baseline characteristics of this subset of nonoperative patients and proposes predictors of those most likely to benefit. PURPOSE: The study aims to determine the factors that affect likelihood of nonoperative patients to reach MCID. STUDY DESIGN/SETTING: This is a retrospective review of a prospective, multicenter database. PATIENT SAMPLE: The study includes nonoperative ASD patients. OUTCOME MEASURES: Health-related quality-of-life measures, including the Scoliosis Research Society (SRS)-22 questionnaire, were used. METHODS: The study used a multicenter database of 215 nonoperative patients with ASD and with minimum 2-year follow-up. Using a multivariate analysis, two groups were compared to identify possible predictors: those who reached MCID in the SRS pain or activity (N=86) at 2 years and those who did not reach MCID (N=129). A subgroup multivariate analysis of patients with a deficit (potential improvement) in both SRS pain and activity (N=84) was performed. Data collection was supported by a grant from DePuy for the International Spine Study Group Foundation. RESULTS: At baseline, the nonoperative patients who reached MCID had a significantly lower SRS pain score (3.0 vs. 3.6), smaller thoracolumbar Cobb (TL Cobb) angle (29.6 degrees vs. 36.5 degrees ; 87 patients with SRS-Schwab classification of lumbar or double), lower sacral slope (33.1 degrees vs. 36.4 degrees ), and less lumbar lordosis (46.5 degrees vs. 52.8 degrees ) (all p<.05). The SRS pain and TL Cobb were significant predictors for reaching MCID. The pelvic incidence minus lumbar lordosis (PI-LL) was significant on univariate analysis but not on multivariate analysis (7.5 degrees vs. 2.6 degrees ; p=.14). In the subset of severely disabled patients, worse vertebral obliquity was a predictor for not achieving MCID (p<.05). CONCLUSIONS: Nonoperative ASD patients who achieved MCID in SRS activity or pain had a lower baseline SRS pain score and less coronal deformity in the TL region. Greater baseline pain offers significant room for potential improvement, which may be important in identifying ASD patients who have the potential to reach MCID nonoperatively. Coronal deformities in the TL region and associated vertebral obliquity may negatively impact potential for improvement in nonoperative care. PMID- 26523968 TI - Dietary intake of non-nutritive sweeteners in type 1 diabetes mellitus children. AB - The aims of the current cross-sectional study were (1) to assess the intake of aspartame, cyclamate, acesulfame-k, neohesperidine dihydrochalcone, sucralose, saccharin, steviol glycosides and neotame among children with type 1 diabetes mellitus (T1D); (2) to compare the obtained intakes with the respective acceptable daily intake (ADI) values; and (3) to conduct a scenario analysis to obtain practical guidelines for a safe consumption of non-nutritive sweeteners (NNS) among children with T1D. T1D patients of the Paediatrics Department of the University Hospitals Leuven were invited to complete a food frequency questionnaire designed to assess NNS intake using a tier 2 and tier 3 exposure assessment approach. A scenario analysis was conducted by reducing the P95 consumption of the most contributing food categories in order to reach a total sweetener intake lower than or equal to the ADI. Estimated total intakes higher than ADIs were only found for the P95 consumers only of acesulfame-k, cyclamate and steviol glycosides (tier 2 and tier 3 approach). Scenario analysis created dietary guidelines for each age category for diet soda, bread spreads and dairy drinks. There is little chance for T1D children to exceed the ADI of the different NNS, however diabetes educators and dieticians need to pay attention regarding the use of NNS. PMID- 26523969 TI - Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancers. AB - Human tumors show a high level of genetic heterogeneity, but the processes that influence the timing and route of metastatic dissemination of the subclones are unknown. Here we have used whole-exome sequencing of 103 matched benign, malignant and metastatic skin tumors from genetically heterogeneous mice to demonstrate that most metastases disseminate synchronously from the primary tumor, supporting parallel rather than linear evolution as the predominant model of metastasis. Shared mutations between primary carcinomas and their matched metastases have the distinct A-to-T signature of the initiating carcinogen dimethylbenzanthracene, but non-shared mutations are primarily G-to-T, a signature associated with oxidative stress. The existence of carcinomas that either did or did not metastasize in the same host animal suggests that there are tumor-intrinsic factors that influence metastatic seeding. We also demonstrate the importance of germline polymorphisms in determining allele-specific mutations, and we identify somatic genetic alterations that are specifically related to initiation of carcinogenesis by Hras or Kras mutations. Mouse tumors that mimic the genetic heterogeneity of human cancers can aid our understanding of the clonal evolution of metastasis and provide a realistic model for the testing of novel therapies. PMID- 26523970 TI - The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity. AB - The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-beta to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development. PMID- 26523972 TI - MARCH8 inhibits HIV-1 infection by reducing virion incorporation of envelope glycoproteins. AB - Membrane-associated RING-CH 8 (MARCH8) is one of 11 members of the recently discovered MARCH family of RING (really interesting new gene)-finger E3 ubiquitin ligases. MARCH8 downregulates several host transmembrane proteins, including major histocompatibility complex (MHC)-II, CD86, interleukin (IL)-1 receptor accessory protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 and the transferrin receptor. However, its physiological roles remain largely unknown. Here we identify MARCH8 as a novel antiviral factor. The ectopic expression of MARCH8 in virus-producing cells does not affect levels of lentivirus production, but it does markedly reduce viral infectivity. MARCH8 blocks the incorporation of HIV-1 envelope glycoprotein into virus particles by downregulating it from the cell surface, probably through their interaction, resulting in a substantial reduction in the efficiency of viral entry. The inhibitory effect of MARCH8 on vesicular stomatitis virus G-glycoprotein is even more remarkable, suggesting a broad-spectrum inhibition of enveloped viruses by MARCH8. Notably, the endogenous expression of MARCH8 is high in monocyte-derived macrophages and dendritic cells, and MARCH8 knockdown or knockout in macrophages significantly increases the infectivity of virions produced by these cells. Our findings thus indicate that MARCH8 is highly expressed in terminally differentiated myeloid cells, and that it is a potent antiviral protein that targets viral envelope glycoproteins and reduces their incorporation into virions. PMID- 26523971 TI - An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development. AB - Focal malformations of cortical development (FMCDs) account for the majority of drug-resistant pediatric epilepsy. Postzygotic somatic mutations activating the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)-protein kinase B (AKT) mammalian target of rapamycin (mTOR) pathway are found in a wide range of brain diseases, including FMCDs. It remains unclear how a mutation in a small fraction of cells disrupts the architecture of the entire hemisphere. Within human FMCD affected brain, we found that cells showing activation of the PI3K-AKT-mTOR pathway were enriched for the AKT3(E17K) mutation. Introducing the FMCD-causing mutation into mouse brain resulted in electrographic seizures and impaired hemispheric architecture. Mutation-expressing neural progenitors showed misexpression of reelin, which led to a non-cell autonomous migration defect in neighboring cells, due at least in part to derepression of reelin transcription in a manner dependent on the forkhead box (FOX) transcription factor FOXG1. Treatments aimed at either blocking downstream AKT signaling or inactivating reelin restored migration. These findings suggest a central AKT-FOXG1-reelin signaling pathway in FMCD and support pathway inhibitors as potential treatments or therapies for some forms of focal epilepsy. PMID- 26523973 TI - Macrophage activation induced by Brucella DNA suppresses bacterial intracellular replication via enhancing NO production. AB - Brucella DNA can be sensed by TLR9 on endosomal membrane and by cytosolic AIM2 inflammasome to induce proinflammatory cytokine production that contributes to partially activate innate immunity. Additionally, Brucella DNA has been identified to be able to act as a major bacterial component to induce type I IFN. However, the role of Brucella DNA in Brucella intracellular growth remains unknown. Here, we showed that stimulation with Brucella DNA promote macrophage activation in TLR9-dependent manner. Activated macrophages can suppresses wild type Brucella intracellular replication at early stage of infection via enhancing NO production. We also reported that activated macrophage promotes bactericidal function of macrophages infected with VirB-deficient Brucella at the early or late stage of infection. This study uncovers a novel function of Brucella DNA, which can help us further elucidate the mechanism of Brucella intracellular survival. PMID- 26523974 TI - Opioids for the Management of Dyspnea in Cancer Patients: Evidence of the Last 15 Years--A Systematic Review. AB - The objective of this study was to review the evidence on the use of opioids for treatment of the dyspnea in adult cancer patients. A systematic literature review was conducted in the databases MEDLINE, CINAHL (EBSCO), ScienceDirect, and Cochrane Library of trials testing the effect of opioids in relieving dyspnea in cancer patients. Fourteen trials met the criteria for inclusion in the review. Eight randomized trials and six nonrandomized trials. All randomized clinical trials analyzed present risks of bias. Morphine has been the most studied strong opioid showing efficacy in alleviating dyspnea when administered, either orally or subcutaneously, in cancer patients. The potential benefit of the strong opioids in the alleviation of dyspnea in cancer patients is modest and limited to some opioids. More studies are needed to sufficiently support the role of opioids in dyspnea at rest, at exertion, and for breakthrough dyspnea and to clarify the safety issues. PMID- 26523976 TI - Three indel variants in chicken LPIN1 exon 6/flanking region are associated with performance and carcass traits. AB - LPIN1 is a Mg(2+)-dependent phosphatidic acid phosphatase. Variation in chicken LPIN1 exon 6 and its flanking regions were identified and three indel variants in 6 breeds and their associations with performance traits were studied. Seven variants were detected from 6 breeds, which contained a synonymous tri-allelic variant (c.924A/T/C) and three indels. The exon 6 variants detected from chicken breeds were conserved among bird species. The indel variation frequency presented clear differences among breeds. Two coding indels (c.1014-1018del3 and c.1125 1138del12) were multiples of three nucleotides and maintained the open reading frames of LPIN1 proteins. However, they were predicted to result in the clear change of the RNA secondary structure of chicken LPIN1 exon 6 and LPIN1 protein conformation. The association analysis showed that c.871-15-22del6 variation had a significant effect on body weight at hatch (BW0) and 2 weeks (BW2); c. 1014 1018del3 variation had a significant effect on BW4, BW6, caecum length and gizzard weight (GW) traits; c.1125-1138del12 variation had a significant effect on BW12, shank length at 4 weeks (SL4), carcass weight, lactate dehydrogenase traits (LDH), glucose (GLU) and albumin (ALB) traits. The genotype combination for c.1014-1018del3 and c.1125-1138del12 also presented significant effects on SL4, SL8, GW, leg muscle weight, ALB, GLU and LDH. The study demonstrated that chicken LPIN1 has an important effect on body, carcass and organ weight, serum LDH, GLU and ALB level. PMID- 26523977 TI - Platform of integrated tools to support environmental studies and management of dredging activities. AB - Dredging activities can cause environmental impacts due to, among other, the increase of the Suspended Solid Concentration (SSC) and their subsequent dispersion and deposition (DEP) far from the dredging point. The dynamics of the resulting dredging plume can strongly differ in spatial and temporal evolution. This evolution, for both conventional mechanical and hydraulic dredges, depends on the different mechanisms of sediment release in water column and the site specific environmental conditions. Several numerical models are currently in use to simulate the dredging plume dynamics. Model results can be analysed to study dispersion and advection processes at different depths and distances from the dredging source. Usually, scenarios with frequent and extreme meteomarine conditions are chosen and extreme values of parameters (i.e. maximum intensity or total duration) are evaluated for environmental assessment. This paper presents a flexible, consistent and integrated methodological approach. Statistical parameters and indexes are derived from the analysis of SSC and DEP simulated time-series to numerically estimate their spatial (vertical and horizontal) and seasonal variability, thereby allowing a comparison of the effects of hydraulic and mechanical dredges. Events that exceed defined thresholds are described in term of magnitude, duration and frequency. A new integrated index combining these parameters, SSCnum, is proposed for environmental assessment. Maps representing the proposed parameters allow direct comparison of effects due to different (mechanical and hydraulic) dredges at progressive distances from the dredging zone. Results can contribute towards identification and assessment of the potential environmental effects of a proposed dredging project. A suitable evaluation of alternative technical choices, appropriate mitigation, management and monitoring measure is allowed in this framework. Environmental Risk Assessment and Decision Support Systems (DSS) may take advantage of the proposed tool. The approach is applied to a hypothetical dredging project in the Augusta Harbour (Eastern coast of Sicily Island-Italy). PMID- 26523975 TI - The management of autoimmunity in patients with cholestatic liver diseases. AB - Cholestatic liver diseases are rare diseases that often lead to cirrhosis and its consequent complications. In addition to liver-related morbidity, patients with cholestatic liver diseases often suffer from autoimmune diseases that affect several organs and tissues. The robust and efficient data collection and collaboration between hepatologists and rheumatologists have led to significant advancements in understanding the relationship between the cholestatic liver diseases and associated autoimmune diseases. In this paper, we discuss the cholestatic liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis and immunoglobulin G4 associated cholangitis) and associated autoimmune diseases. PMID- 26523978 TI - Involvement of endoplasmic reticulum stress in the necroptosis of microglia/macrophages after spinal cord injury. AB - Microglia/macrophages play a crucial role in inflammation after spinal cord injury (SCI). Although extensive studies have been performed on the mechanisms of microglia/macrophage activation and recruitment, how microglia/macrophages are eliminated remains unclear. In the present study, we observed a high-level expression of mixed lineage kinase domain-like protein (MLKL), a key molecule in the execution of necroptosis, in microglia/macrophages after SCI in mice. In vivo PI-labeling and Necrostatin-1 treatment confirmed the necroptosis of microglia/macrophages. Interestingly, our electronic microscopic (EM) study revealed that MLKL localized not only at the membrane but also on the endoplasmic reticulum (ER) of necroptotic microglia/macrophages. Furthermore, receptor interacting protein 3 (RIP3), another necrosome component, was also found on the ER of necroptotic microglia/macrophages. And Glucose-regulated protein 78 (GRP78), an ER stress sensor, was up-regulated in MLKL-positive microglia/macrophages after SCI, suggesting a possible link between necroptosis and ER stress. In vitro, oxygen-glucose deprivation (OGD) stress induced ER stress and necroptosis in microglia. Inhibiting ER stress by 4-phenylbutyrate (4 PBA) significantly blocked the OGD-induced necroptosis of microglia. In the end, our data showed that, GRP78 and phosphorylated MLKL were co-expressed by the microglia/macrophages in the injured human spinal cord. Taken together, these results suggested that microglia/macrophages undergo an ER-stress involved necroptosis after SCI, implying that ER stress and necroptosis could be manipulated for modulating inflammation post-SCI. PMID- 26523979 TI - Regional differences in mu and kappa opioid receptor G-protein activation in brain in male and female prairie voles. AB - Prairie voles are unusual mammals in that, like humans, they are capable of forming socially monogamous pair bonds, display biparental care, and engage in alloparental behaviors. Both mu and kappa opioid receptors are involved in behaviors that either establish and maintain, or result from pair bond formation in these animals. Mu and kappa opioid receptors both utilize inhibitory G proteins in signal transduction mechanisms, however the efficacy by which these receptor subtypes stimulate G-protein signaling across the prairie vole neuraxis is not known. Utilizing [(35)S]GTPgammaS autoradiography, we characterized the efficacy of G-protein stimulation in coronal sections throughout male and female prairie vole brains by [D-Ala2,NMe-Phe4,Gly-ol5]-enkephalin (DAMGO) and U50,488H, selective mu and kappa opioid agonists, respectively. DAMGO stimulation was highest in the forebrain, similar to that found with other rodent species. U 50,488H produced greater stimulation in prairie voles than is typically seen in mice and rats, particularly in select forebrain areas. DAMGO produced higher stimulation in the core versus the shell of the nucleus accumbens (NAc) in females, while the distribution of U-50,488H stimulation was the opposite. There were no gender differences for U50,488H stimulation of G-protein activity across the regions examined, while DAMGO stimulation was greater in sections from females compared to those from males for NAc core, entopeduncular nucleus, and hippocampus. These data suggest that the kappa opioid system may be more sensitive to manipulation in prairie voles compared to mice and rats, and that female prairie voles may be more sensitive to mu agonists in select brain regions than males. PMID- 26523980 TI - Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia. AB - Microglia are the prime cellular sources of reactive oxygen species (ROS) in the central nervous system (CNS). Chronic activation of microglia has been linked to aging-associated neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) since they produce excessive amounts of ROS for a prolonged duration leading to oxidative stress. The present study was aimed at investigating the expression and role of Sirtuin 3 (Sirt3), a protein deacetylase which is implicated in regulating cellular ROS levels. It has been shown that Sirt3 reduces cellular ROS levels by deacetylating forkhead box O 3a (Foxo3a), a transcription factor which transactivates antioxidant genes, catalase (Cat) and manganese superoxide dismutase (mnSod). In the present study, Sirt3 immunoreactivity was localized in the ameboid microglial cells distributed in the corpus callosum (CC) of the early postnatal rat brain and diminished in the ramified microglial cells in the CC of the adult rat brain. A marked induction of Sirt3 expression was seen in lipopolysaccharide (LPS)-activated microglia in vivo and in vitro as well as in adult rat brains subjected to traumatic brain injury (TBI). Knockdown of Sirt3 in microglia led to an increase in the cellular and mitochondrial ROS and decrease in the expression of antioxidant, mnSod which is indicative of the function of Sirt3 in ROS regulation in microglia. Conversely, Sirt3 overexpression led to increase in the expression of antioxidants Cat and mnSod. Further, increase in the expression and nuclear translocation of Foxo3a was observed following Sirt3 overexpression, suggesting that Sirt3 regulates ROS by inducing the expression of antioxidants via activation of Foxo3a. The above results point to an antioxidant defense mechanism presented by Sirt3 through the activation of Foxo3a, in microglia. PMID- 26523981 TI - CUSUM-Logistic Regression analysis for the rapid detection of errors in clinical laboratory test results. AB - OBJECTIVE: The main drawback of the periodic analysis of quality control (QC) material is that test performance is not monitored in time periods between QC analyses, potentially leading to the reporting of faulty test results. The objective of this study was to develop a patient based QC procedure for the more timely detection of test errors. METHOD: Results from a Chem-14 panel measured on the Beckman LX20 analyzer were used to develop the model. Each test result was predicted from the other 13 members of the panel by multiple regression, which resulted in correlation coefficients between the predicted and measured result of >0.7 for 8 of the 14 tests. A logistic regression model, which utilized the measured test result, the predicted test result, the day of the week and time of day, was then developed for predicting test errors. The output of the logistic regression was tallied by a daily CUSUM approach and used to predict test errors, with a fixed specificity of 90%. RESULTS: The mean average run length (ARL) before error detection by CUSUM-Logistic Regression (CSLR) was 20 with a mean sensitivity of 97%, which was considerably shorter than the mean ARL of 53 (sensitivity 87.5%) for a simple prediction model that only used the measured result for error detection. CONCLUSION: A CUSUM-Logistic Regression analysis of patient laboratory data can be an effective approach for the rapid and sensitive detection of clinical laboratory errors. PMID- 26523982 TI - HPV-associated head and neck cancers in the Asia Pacific: A critical literature review & meta-analysis. AB - BACKGROUND: Malignancies of the upper aero-digestive tract are a major public health problem, especially in the Asia Pacific. Certain Human papillomaviruses (HPVs) are well-established risk factors for carcinoma of the uterine cervix and for a subset of head and neck carcinomata: however their true importance in different populations and anatomical subsites remains unclear. The major risk factors in Asia Pacific remain smoked/smokeless tobacco, areca nut, alcohol abuse and poor diet, with limited evidence for HPVs. We review published studies of association of HPV with anatomical site-specific Head & Neck Squamous Cell Carcinoma (HNSCC) in these populations and attempt a meta-analysis. MATERIALS AND METHODS: From MEDLINE/PubMed/WEB-of SCIENCE/EMBASE/Scopus databases we found 67 relevant studies with a total of 7280 cases: 15 case-control studies met our inclusion criteria for meta-analysis, totaling 1106 cases & 638 controls. HPV detection rates, sample site and size, and methods of tissue preservation and HPV detection were tabulated for each study. RESULTS: Studies were heterogeneous in terms of sample selection and method of detection of HPVs. Most were of limited quality. Averaging data from 67 studies of HNSCC, the prevalence of HPV of any subtype is approximately 36%. PCR (polymerase chain reaction) was the most used detection method and HPV16 the most common genotype reported. Meta-analyses of case-control studies from this region reveal significant heterogeneity but suggest higher HPV prevalence in oropharyngeal cancer (OR: 14.66; 95%CI: 6.09 35.26) compared to oral cavity cancer and laryngeal cancer; (OR: 4.06; 95%CI: 3.05-5.39 & OR: 3.23; 95%CI: 1.37-7.61) respectively. CONCLUSION: In view of the significant association of HPV with HNSCC, studies with accurate subsite classification and more sensitive detection methods are necessary. Accurate data from this geographical region are essential to inform public health policies and treatment decisions, especially as studies from Europe and North America reveal HPV-driven cancers to be less aggressive, permitting treatment de intensification. PMID- 26523983 TI - Trends in major cancer mortality in Korea, 1983-2012, with a joinpoint analysis. AB - BACKGROUND: Cancer is the leading cause of death in Korea. This study aims to examine changes in temporal trends in major cancer mortality. MATERIALS AND METHODS: Mortality data for 1993-2012 were obtained from the Korean Statistics Information Service(KOSIS) database and age-standardized to the 2000 Korean population. Joinpoint analysis was used to identify significant changes in trends over time. The annual percentage rate change (APC) was computed for each segment of the trends. RESULTS: The age-standardized mortality rates (ASR) for all cancer sites combined decreased by 9.1% and 1.1% in men and women, respectively, from 1983 to 2012. ASRs from cancers of esophagus, stomach, and liver decreased substantially, whereas ASRs from cancer for all other sites increased markedly. ASRs for all cancer sites combined increased until 1994 and thereafter decreased significantly in both genders except for the period of 1998-2002 (APC: -5.5% for men [p<0.05] and 0.07% for women). ASRs for esophagus and liver cancers increased until the early 1990s and thereafter declined, leading to significant decreases [p<0.05] for esophagus cancer (APC: -1.85% for men and -3.82% for women) and liver cancer (APC: -1.55% for men and -0.56% for women) in 1983-2012. ASRs for stomach cancer declined (APC: -4.06% for men and -4.07% for women) except for 1990-1994. ASRs for uterine cancer peaked in 2003 and then declined (APC: 2.85%). ASRs increased significantly until 2002 for colorectal cancer in men (APC: 7.52%) and lung cancer in both genders. The most consistently upward trend was observed for non-Hodgkin's lymphoma (APC: 3.55% for men and 5.29% for women; number of joinpoints=0). The greatest ASR increase was seen for prostate cancer for which mortality increased until 2002 at an APC of 12.56%. CONCLUSION: While mortality decreased significantly for esophagus, stomach and liver cancers in recent decades in Korea, challenges still remain for many other cancers, especially pancreatic, breast, and prostate cancers and non-Hodgkin's lymphoma. Surveillance of cancer mortality trends can lend valuable insights as to the prevention and control of cancer. Public health promotion efforts to control cancer such as lowering smoking rate and obesity could reduce the burden of cancer in many sites. PMID- 26523984 TI - Molecular and functional characterization of goldfish (Carassius auratus L.) Serum Amyloid A. AB - Quantitative expression analysis of goldfish SAA revealed the highest mRNA levels in the kidney, spleen and intestine with lower mRNA levels in muscle and liver. Goldfish SAA was differentially expressed in goldfish immune cells with highest mRNA levels observed in neutrophils. To functionally assess goldfish SAA, recombinant protein (rgSAA) was generated by prokaryotic expression and functionally characterized. Monocytes and macrophages treated with rgSAA exhibited differential gene expression of pro-inflammatory and anti-inflammatory cytokines. rgSAA induced gene expression of both pro-inflammatory (TNFalpha1, TNFalpha2) and anti-inflammatory cytokines (IL-10, TGFbeta) in monocytes. rgSAA induced IL-1beta1 and SAA gene expression in macrophages. rgSAA was chemotactic to macrophages and neutrophils, but not monocytes. rgSAA did not affect respiratory burst induced by heat-killed Aeromonas salmonicida. rgSAA treatment of macrophages down-regulated their production of nitric oxide. rgSAA exhibited antibacterial properties against Escherichia coli in a concentration dependent manner. PMID- 26523985 TI - Chronic iron overload in rats increases vascular reactivity by increasing oxidative stress and reducing nitric oxide bioavailability. AB - AIMS: Iron overload in animal models and humans increases oxidative stress and induces cardiomyopathy. It has been suggested that the vasculature is also damaged, but the impacts on vascular reactivity and the underlying mechanisms remain poorly understood. In this study, we aimed to identify possible changes in the vascular reactivity of aortas from iron overloaded rats and investigate the underlying mechanisms. MAIN METHODS: Rats were treated with 100mg/kg/day iron dextran, ip, five days a week for four weeks and compared to a saline-injected group. KEY FINDINGS: Chronic iron administration increased serum iron and transferrin saturation with significant deposition in the liver. Additionally, iron overload significantly increased the vasoconstrictor response in aortic rings as assessed in vitro, with reduced influence of endothelial denudation or l NAME incubation on the vascular reactivity. In vitro assay with DAF-2 indicated reduced NO production in the iron overload group. Iron overload-induced vascular hyperactivity was reversed by incubation with tiron, catalase, apocynin, allopurinol and losartan. Moreover, malondialdehyde was elevated in the plasma, and O2(*-) generation and NADPH oxidase subunit (p22phox) expression were increased in the aortas of iron-loaded rats. SIGNIFICANCE: Our results demonstrated that chronic iron overload is associated with altered vascular reactivity and the loss of endothelial modulation of the vascular tone. This iron loading-induced endothelial dysfunction and reduced nitric oxide bioavailability may be a result of increased production of reactive oxygen species and local renin-angiotensin system activation. PMID- 26523986 TI - Time and Temperature: Changes in Heat-Related Mortality over 27 Years. PMID- 26523987 TI - Should trypanocidal therapy be used to treat patients in the chronic phase of Chagas disease? AB - Antiparasitic treatment of patients with Chagas? disease in chronic stage could prevent the complications related to the disease. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified five systematic reviews including eight randomized trials and 11 observational studies. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded it is not clear whether antiparasitic treatment improves survival or reduces complications related to chronic Chagas? disease because the certainty of the evidence is very low. PMID- 26523988 TI - Sedentary behaviour patterns and arterial stiffness in a Spanish adult population - The EVIDENT trial. AB - OBJECTIVE: Arterial stiffness is a contributor to the development of atherosclerosis and cardiovascular disease. The aim of the study was to analyse the relationship between sedentary behaviour and arterial stiffness in a Spanish adult population. METHODS: This cross-sectional study included 1365 subjects belonging to the EVIDENT project. Physical activity and sedentary behaviour were measured objectively over 7 days using ActiGraph accelerometers. Thresholds of 10 consecutive minutes were used to estimate the daily sedentary time in bouts >=10 min. Each interruption in sedentary time (counts/min >=100) was considered a break. Arterial stiffness was evaluated using the B-pro device through the following indicators: radial Augmentation Index (rAIx), Ambulatory Arterial Stiffness Index (AASI), and central and peripheral pulse pressure (PP). RESULTS: We found a positive relationship between central and peripheral pulse pressure (office, 24 h, awake and sleep PP) and total sedentary time. These arterial stiffness parameters were also associated with sedentary time in bouts >=10 min. Significance disappeared in both cases, however, after adjusting for MVPA and breaks per sedentary hour. Adults who reported fewer breaks per sedentary hour (25th percentile < 2 n/day) had higher levels of AASI, awake and sleep PP. CONCLUSIONS: In a medium-sized sample of adult attenders of community clinics our data showed that it seems to be important to avoid prolonged uninterrupted periods of sedentary time. PMID- 26523989 TI - microRNA-185 modulates low density lipoprotein receptor expression as a key posttranscriptional regulator. AB - OBJECTIVE: Low-density lipoprotein receptor (LDLR) mediates endocytosis of LDL particles and is important in maintaining plasma cholesterol levels, thus its expression is under extensive regulation at multiple levels, including transcriptional and posttranscriptional regulation by transcription factors (TFs) and RNA-binding proteins (RBPs). Here, we identified microRNA-185 (miR-185) as a novel direct posttranscriptional regulator of LDLR and an indirect LDLR modulator through KSRP in hepatic cells. METHODS AND RESULTS: Using quantitative real-time PCR (qPCR), we detected the effect of predicted LDLR-targeting miRNAs and found that overexpression of miR-185 repressed LDLR expression and LDL uptake in HepG2 cells by 62.4 +/- 6.0% (p = 7.0 * 10(-5)) and 32.5 +/- 6.0% (p = 7.7 * 10(-4)) respectively, through directly targeting LDLR 3'UTR. Unexpectedly, the antisense inhibitor of miR-185 had similar repression effect on LDLR although it reduced the association of endogenous miR-185 with LDLR mRNA. Further experiments revealed that KH-type splicing regulatory protein (KSRP), one of the LDLR destabilizing RBPs, is also a target of miR-185. KSRP silencing reversed the repression effects of miR-185-inhibitor on LDLR. Thus miR-185 regulates LDLR expression not only through directly targeting but also by a RBP-involved indirect pathway. Finally, the in vivo results showed that miR-185-inhibitor upregulated hepatic LDLR expression and correlated with a decrease in plasma cholesterol level and arterial plaque area in ApoE KO mice. CONCLUSIONS: These findings reveal that miR-185 controls cholesterol homeostasis as a key posttranscriptional LDLR modulator in hepatic cells, providing novel insight into the regulatory mechanism for LDLR expression and the anti-atherosclerosis effect of miR-185-inhibitor. PMID- 26523990 TI - Complement proteins and arterial calcification in middle aged women: Cross sectional effect of cardiovascular fat. The SWAN Cardiovascular Fat Ancillary Study. AB - BACKGROUND: CVD risk increases in women after menopause. Recent data suggest higher levels of complement protein C3 and cardiovascular fat (CF) in postmenopausal women. Whether complement proteins are associated with early markers of atherosclerosis in healthy midlife women has never been evaluated. Additionally, the potential impact of the local CF on these associations has never been assessed. METHODS: Participants (n = 100, age (mean(SD)):50.48(2.63), 50% premenopausal) were from the Study of Women's Health Across the Nation (SWAN). Arterial calcification (aortic-AC and coronary-CAC) and CF volumes around the heart and aorta (total heart-TAT and aortic perivascular adipose tissue-PVAT) were quantified using EBCT scans. AC and CAC were each evaluated as presence (Agatston scores >0) and extent of calcification (log (Agatston scores+1)). Logistic and linear regression models were used for statistical analysis. RESULTS: Adjusting for age, race, menopausal status and lipids, C3 was significantly associated with both presence and extent of AC and CAC, all P values <0.05. Associations between C3 and presence and extent of AC and CAC were explained by additional adjustment for log TAT and log PVAT, respectively. Association between C3 and log(AC+1) was more pronounced at higher volumes of log TAT (interaction-P = 0.013) adjusting for study variables. No associations were found with C4. CONCLUSIONS: Higher C3 was significantly associated with presence and greater extent of arterial calcification in midlife women. These associations were explained by higher volumes of CF, suggesting CF as a potential source of C3. C3 could be a potential non-invasive biomarker of early diagnosis of atherosclerosis. These findings need to be replicated in larger studies. PMID- 26523992 TI - Soluble endothelial cell selective adhesion molecule and cardiovascular outcomes in patients with stable coronary disease: A report from the Heart and Soul Study. AB - BACKGROUND AND AIMS: Endothelial cell-selective adhesion molecule (ESAM) is selectively expressed on vascular endothelium and is postulated to play a role in atherogenesis. We investigated the association of serum soluble ESAM (sESAM) levels with subsequent cardiovascular outcomes in patients with stable ischemic heart disease. METHODS: We measured sESAM levels in 981 patients with stable coronary disease enrolled between September 2000 and December 2002 in a prospective cohort study. Poisson regression models were used to define the relationship between baseline sESAM levels and cardiovascular outcomes, including myocardial infarction, heart failure hospitalization, and mortality. RESULTS: There were 293 occurrences of the composite endpoint over a median follow-up of 8.9 years. After adjusting for demographic and clinical risk factors, participants in the highest sESAM quartile (compared to the lower three sESAM quartiles) had a higher rate of the composite endpoint (incident rate ratio (IRR) 1.52 (95% CI 1.16-1.99) as well as of its individual components: myocardial infarction (IRR 1.64 (1.06-2.55)), heart failure hospitalizations (IRR 1.96 (1.32 2.81)), and death (IRR 1.5 (1.2-1.89)). These associations were no longer significant after adjustment for estimated glomerular filtration rate. CONCLUSIONS: sESAM levels associate with myocardial infarction, heart failure, and death after adjustment for demographic and clinical risk factors, but not after adjustment for kidney function. sESAM may be involved in the pathogenesis of concurrent kidney and cardiovascular disease. PMID- 26523991 TI - In vivo evidence for chylomicrons as mediators of postprandial inflammation. AB - BACKGROUND AND AIMS: The postprandial situation is a pro-inflammatory condition most likely linked to the development of atherosclerosis. We evaluated the relationship between apolipoprotein (apo) B48 and fasting and postprandial leukocyte activation markers. METHODS: Leukocyte activation markers and apo B48 were determined in 80 subjects with and without coronary artery disease (CAD). Twelve healthy subjects underwent an oral fat loading test (up to 8 h). RESULTS: Fasting apo B48 was significantly higher in patients with CAD (n = 47, 8.1 +/- 5.2 mg/L) than in subjects without CAD (n = 33, 5.9 +/- 3.9 mg/L, p = 0.022). Fasting apo B48 and triglycerides correlated positively with fasting monocyte CD11b and neutrophil CD66b expression. Plasma apo B48 and leukocyte activation markers increased after an oral fat load. No correlations were found between fasting or postprandial triglycerides and postprandial leukocyte activation markers. We observed no correlations between postprandial apo B48 and postprandial neutrophil CD11b or CD66b expression. CONCLUSION: This study suggests that chylomicron remnants may be responsible for postprandial leukocyte activation in the circulation. The postprandial chylomicron response may be a stronger mediator of postprandial inflammation than postprandial triglyceridemia. PMID- 26523993 TI - Effects of aliskiren in diabetic and non-diabetic patients with coronary artery disease: Insights from AQUARIUS. AB - BACKGROUND: Aliskiren previously was found to have potentially harmful effects in diabetic individuals prescribed concomitant angiotensin converting enzyme inhibitors (ACEI) or angiotenisn receptor antagonists (ARB). We explored potential effects of aliskiren on coronary atheroma progression and major adverse cardiovascular events (MACE: death/non-fatal MI/non-fatal stroke/hospitalization for heart failure/hospitalization for ACS/arterial revascularization) in patients with and without diabetes mellitus (DM). METHODS: AQUARIUS employed serial intravascular ultrasound measures of coronary atheroma volume in coronary artery disease patients randomized to receive daily aliskiren 300 mg or placebo for 104 weeks. This post hoc analysis compared changes in plaque volume [percent atheroma volume (PAV) and total atheroma volume (TAV)] and MACE in patients with (n = 115) and without (n = 343) DM stratified by treatment allocation. RESULTS: In multivariable propensity-weighted analyses, which included controlling for baseline and concomitant ACEI/ARB therapy and duration of aliskiren therapy, aliskiren-treated non-DM patients demonstrated the greatest PAV and TAV regression, whereas aliskiren-treated DM patients demonstrated the greatest TAV progression and greater PAV. Aliskiren-treated non-DM patients appeared at significantly lower risk of MACE compared with their aliskiren-treated DM counterparts [HR 95% CI 0.28 (0.10, 0.80)]. Statistical interactions were noted between DM status and treatment allocation for both changes in PAV (p < 0.001), TAV (p = 0.010) and MACE (p = 0.057). CONCLUSIONS: Aliskiren appears to be relatively anti-atherosclerotic in non-diabetic patients. Due to the limited number MACE and low numbers of diabetic patients in AQUARIUS, the pro atherosclerotic effects of aliskiren in this population are inconclusive, and these results should be thus considered hypothesis generating. Further outcome studies are required in non-diabetic patients to confirm the possible favorable effects of aliskiren. PMID- 26523995 TI - An Aggregate of Four Anthrax Cases during the Dry Summer of 2011 in Epirus, Greece. AB - BACKGROUND: Human anthrax is currently a sporadic disease in Europe, without significant regional clustering. OBJECTIVE: To report an unexpected aggregate of anthrax cases and correlate local climatic factors with yearly anthrax admissions. METHODS: Clinical description of a geographical-temporal anthrax aggregate, correlation of disease admissions with local weather data in the period 2001-2014 and literature reports of anthrax clusters from Europe in the last 20 years. RESULTS: We identified 5 cases, all cutaneous: an unexpected aggregate of 4 cases in mid-summer 2011 (including a probable human-to-human transmission) and a sporadic case in August 2005, all in relatively dry periods (p < 0.05). Remarkably, 3/6 reports of human anthrax aggregates from Europe were observed in Balkan Peninsula countries in the year 2011. CONCLUSION: In the light of the predicted climatic change, unexpected anthrax aggregates during dry periods in southern Europe underscore the risk of future anthrax re-emergence on this continent. PMID- 26523994 TI - Plasma concentrations of molecular lipid species in relation to coronary plaque characteristics and cardiovascular outcome: Results of the ATHEROREMO-IVUS study. AB - BACKGROUND AND AIMS: Previous lipidomics analyses have demonstrated that several lipid molecules in plasma are associated with fatal outcome in patients with coronary artery disease (CAD). This study aims to investigate the associations of previously identified high risk lipid molecules in plasma with coronary plaque characteristics derived from intravascular ultrasound virtual histology (IVUS-VH) imaging, with coronary lipid core burden index (LCBI) on near-infrared spectroscopy (NIRS), and with one year cardiovascular outcome in patients with CAD. METHODS: Between 2008 and 2011, IVUS-VH imaging of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography for acute coronary syndrome (ACS) or stable CAD. NIRS imaging was additionally performed in 191 patients. Plasma concentrations of molecular lipids were measured with mass spectrometry. RESULTS: Several cholesteryl ester, ceramide and lactosylceramide species and ceramide ratios were associated with vulnerable plaque characteristics on IVUS-VH and NIRS imaging and with 1-year major adverse cardiac events (MACE, defined as all-cause mortality, ACS and unplanned coronary revascularization). In particular, ceramide d18:1/16:0 was consistently associated with higher necrotic core fraction on IVUS-VH (p = 0.001), higher LCBI (p = 0.024) on NIRS and higher MACE rate (adjusted HR 1.79 per standard deviation increase in log-transformed lipid concentration, 95%CI 1.24-2.59, p = 0.002). CONCLUSION: Several molecular lipid species, and particularly ceramide(d18:1/16:0), are associated with the fraction of necrotic core tissue and lipid core burden in coronary atherosclerosis, and are predictive for 1-year clinical outcome after coronary angiography. These molecular lipids may improve risk stratification in CAD and may also be interesting therapeutic targets for the treatment of atherosclerotic disease. PMID- 26523996 TI - Freeze-drying synthesis of an amorphous Zn(2+) complex and its transformation to a 2-D coordination framework in the solid state. AB - An amorphous and metastable precursor for a Zn two-dimensional coordination framework was synthesised via freeze drying. The precursor comprises randomly packed discrete clusters of a Zn complex. The amorphous-to-crystalline framework transformation, which was triggered by the gentle application of heat or pressure, was accompanied by a change in the coordination geometry of the Zn(2+) ions from tetrahedral to octahedral symmetry. PMID- 26523997 TI - Do you get where I'm coming from?: Perceived understanding buffers against the negative impact of conflict on relationship satisfaction. AB - Conflict can have damaging effects on relationship health. But is all conflict detrimental? Across 7 studies, we tested the overarching hypothesis that conflict in close relationships is only detrimental when people do not feel their thoughts, feelings, and point of view are understood by their relationship partners. Supporting this, conflict was negatively associated with relationship satisfaction among participants who perceived their romantic partner as less understanding, but not among those who felt more understood by their partners. This was true cross-sectionally (Study 1), experimentally (Studies 2, 3, 6a, and 6b), in daily life (Study 4), and for both members of couples pre- to postconflict conversation in the laboratory (Study 5). The buffering effects of feeling understood could not be explained by people who felt more understood being more understanding themselves, having more general positive perceptions of their partners, fighting about less important or different types of issues, engaging in more pleasant conflict conversations, or being more satisfied with their relationships before the conflict. Perceived understanding was positively associated with conflict resolution, but this did not explain the benefits of feeling understood. Evidence from Studies 6a and 6b suggests that feeling understood during conflict may buffer against reduced relationship satisfaction in part because it strengthens the relationship and signals that one's partner is invested. Overall, these studies suggest that perceived understanding may be a critical buffer against the potentially detrimental effects of relationship conflict. PMID- 26523998 TI - People both high and low on religious fundamentalism are prejudiced toward dissimilar groups. AB - [Correction Notice: An Erratum for this article was reported in Vol 112(1) of Journal of Personality and Social Psychology (see record 2016-61714-004). In the article, the sample size of N = 5,806 in the abstract is incorrect. The correct sample size is N = 6,047.] Research linking religion to prejudice suggests that highly religious individuals, and religious fundamentalists specifically, may be especially susceptible to expressing prejudice toward dissimilar others, whereas people who are less religious and fundamentalist do not show the same effect. The selective prejudice hypothesis predicts that this pattern of results occurs because the cognitive and motivational styles or particular values associated with fundamentalism exacerbate prejudice. In 3 studies, using 4 data sets (N = 6,047), we test this selective prejudice hypothesis against the religious values conflict hypothesis, which predicts that both people with high and low levels of fundamentalism will be prejudiced toward those with dissimilar beliefs to protect the validity and vitality of people's belief systems. Consistent with the religious values conflict hypothesis, we found that people both high and low in fundamentalism were prejudiced toward dissimilar others (Study 1) and these differences were primarily due to differences in the content of religious belief rather than the style of belief (Study 2). In Study 3, we expanded these findings to additional measures of prejudice, found that multiple measures of threat were potential mediators, and explored the possibility of an integrative perspective. In total, these results suggest that people with both relatively high and low levels of fundamentalism are susceptible to prejudice and in some cases the size of this religious intergroup bias may be higher among people with high levels of fundamentalism. (PsycINFO Database Record PMID- 26523999 TI - I don't want the money, I just want your time: How moral identity overcomes the aversion to giving time to prosocial causes. AB - Four studies show that moral identity reduces people's aversion to giving time particularly as the psychological costs of doing so increase. In Study 1, we demonstrate that even when the cost of time and money are held equivalent, a moral cue enhances the expected self-expressivity of giving time-especially when it is given to a moral cause. We found that a moral cue reduces time aversion even when giving time was perceived to be unpleasant (Study 2), or when the time to be given was otherwise seen to be scarce (Study 3). Study 4 builds on these studies by examining actual giving while accounting for the real costs of time. In this study, we found that the chronic salience of moral identity serves as a buffer to time aversion, specifically as giving time becomes increasingly costly. These findings are discussed in terms of the time-versus-money literature and the identity literature. We also discuss policy implications for prosocial cause initiatives. (PsycINFO Database Record PMID- 26524000 TI - Right-wing authoritarianism predicts prejudice equally toward "gay men and lesbians" and "homosexuals". AB - Two recent experiments found evidence for what we term the social category label (SCL) effect-that the relationship between right-wing authoritarianism (RWA) and prejudice against gay men and lesbians can be reduced or even eliminated when the target group is labeled "gay men and lesbians" rather than "homosexuals" (Rios, 2013). Although this appears a promising approach to reduce self-reported sexual prejudice, with both theoretical implications for the meaning of RWA itself and practical implications for question wording for assessing these attitudes, there are several reasons to further examine these findings, including (a) inconsistencies with extant evidence, (b) small sample sizes in the original 2 experiments, and (c) concerns with the RWA measures used in the 2 experiments. We tested the SCL hypothesis with a nationally representative sample (Study 1) and close and conceptual replications of Rios' (2013) 2 studies (Studies 2-5) using multiple measures of RWA and prejudice. Across 23 tests of the SCL hypothesis, we obtained 1 statistically significant and 1 marginally significant effect consistent with the hypothesis, 2 significant effects opposite the hypothesis, and 19 nonsignificant effects. A meta-analysis of evidence reported here and in Rios (2013) indicates that RWA strongly predicts antigay prejudice, with no significant variation by label. This confirms the typically robust association between RWA and antigay prejudice and confirms that the SCL effect is not robust. We discuss potential limitations of these studies, theoretical, methodological, and practical implications for our failures to replicate the original SCL studies, and future directions for examining social category label effects. (PsycINFO Database Record PMID- 26524001 TI - Closing achievement gaps with a utility-value intervention: Disentangling race and social class. AB - Many college students abandon their goal of completing a degree in science, technology, engineering, or math (STEM) when confronted with challenging introductory-level science courses. In the U.S., this trend is more pronounced for underrepresented minority (URM) and first-generation (FG) students, and contributes to persisting racial and social-class achievement gaps in higher education. Previous intervention studies have focused exclusively on race or social class, but have not examined how the 2 may be confounded and interact. This research therefore investigates the independent and interactive effects of race and social class as moderators of an intervention designed to promote performance, measured by grade in the course. In a double-blind randomized experiment conducted over 4 semesters of an introductory biology course (N = 1,040), we tested the effectiveness of a utility-value intervention in which students wrote about the personal relevance of course material. The utility-value intervention was successful in reducing the achievement gap for FG-URM students by 61%: the performance gap for FG-URM students, relative to continuing generation (CG)-Majority students, was large in the control condition, .84 grade points (d = .98), and the treatment effect for FG-URM students was .51 grade points (d = 0.55). The UV intervention helped students from all groups find utility value in the course content, and mediation analyses showed that the process of writing about utility value was particularly powerful for FG-URM students. Results highlight the importance of intersectionality in examining the independent and interactive effects of race and social class when evaluating interventions to close achievement gaps and the mechanisms through which they may operate. (PsycINFO Database Record PMID- 26524002 TI - Failures to change stimulus evaluations by means of subliminal approach and avoidance training. AB - Previous research suggests that the repeated performance of approach and avoidance (AA) actions in response to a stimulus causes changes in stimulus evaluations. Kawakami, Phills, Steele, and Dovidio (2007) and Jones, Vilensky, Vasey, and Fazio (2013) provided evidence that these AA training effects occur even when stimuli are presented only subliminally. We also examined whether reliable AA training effects can be observed with subliminal stimulus presentations but added more sensitive checks of perceptual stimulus discriminability. Three experiments, including a direct replication of the study by Kawakami et al. (2007), failed to provide any evidence for effects of subliminal AA training on implicit or explicit evaluations. Bayesian analyses indicated that our data provide robust evidence that subliminal AA training does not cause changes in evaluations. In contrast, we observed changes in evaluations when participants were provided with (either correct or incorrect) information about the stimulus-action contingencies in the subliminal AA training task and when participants performed a supraliminal AA training task that allowed participants to detect these contingencies. These findings support the idea that contingency awareness is necessary for the occurrence of AA training effects. PMID- 26524003 TI - Desired emotions across cultures: A value-based account. AB - Values reflect how people want to experience the world; emotions reflect how people actually experience the world. Therefore, we propose that across cultures people desire emotions that are consistent with their values. Whereas prior research focused on the desirability of specific affective states or 1 or 2 target emotions, we offer a broader account of desired emotions. After reporting initial evidence for the potential causal effects of values on desired emotions in a preliminary study (N = 200), we tested the predictions of our proposed model in 8 samples (N = 2,328) from distinct world cultural regions. Across cultural samples, we found that people who endorsed values of self-transcendence (e.g., benevolence) wanted to feel more empathy and compassion, people who endorsed values of self-enhancement (e.g., power) wanted to feel more anger and pride, people who endorsed values of openness to change (e.g., self-direction) wanted to feel more interest and excitement, and people who endorsed values of conservation (e.g., tradition) wanted to feel more calmness and less fear. These patterns were independent of differences in emotional experience. We discuss the implications of our value-based account of desired emotions for understanding emotion regulation, culture, and other individual differences. (PsycINFO Database Record PMID- 26524004 TI - Spatial control of chromosomal location in a live cell with functionalized magnetic particles. AB - Long-range chromosomal travel is a phenomenon unique to cell division. Methods for non-invasive, artificial manipulation of chromosomes, such as optical or magnetic tweezers, have difficulty in producing the motion of whole chromosomes in live cells. Here, we report the spatial control of chromosomes over 10 MUm in a live mouse oocyte using magnetic particles driven by an external magnetic field. Selective capture of the chromosomes was achieved using antibodies specific for histone H1 in the chromosome that were conjugated to magnetic particles (H1-BMPs). When an external magnetic field was applied, the chromosomes captured by the H1-BMPs traveled through the cytosol and accumulated near the cell membrane though the movement of the chromosomes captured by H1-BMPs was strongly disturbed by the distribution of the cytoskeleton (e.g. actin filaments). Being non-invasive in nature, our approach will enable new opportunities in the remote manipulation of subcellular elements. PMID- 26524005 TI - Biointerfacing polymeric microcapsules for in vivo near-infrared light-triggered drug release. AB - Seeking safe and effective water-soluble drug carriers is of great significance in nanomedicine. To achieve this goal, we present a novel drug delivery system based on biointerfacing hollow polymeric microcapsules for effectively encapsulating water-soluble antitumor drug and gold nanorod (GNR) functionalization for triggered release of therapeutic drugs on-demand using low power near-infrared (NIR) radiation. The surface of polymeric microcapsules is covered with fluidic lipid bilayers to decrease the permeability of the wall of polymeric capsules. The temperature increase upon NIR illumination deconstructs the structure of the lipid membrane and polyelectrolyte multilayers, which in turn results in the rapid release of encapsulated water-soluble drug. In vivo antitumor tests demonstrate that this microcapsule has the effective ability of inhibiting tumor growth and preventing metastases. Real time in vivo fluorescence imaging results confirm that capsules can be excreted gradually from the animal body which in turn demonstrates the biocompatibility and biodegradation of these biointerfacing GNR-microcapsules. This intelligent system provides a novel anticancer platform with the advantages of controlled release, biological friendliness and credible biosafety. PMID- 26524006 TI - Diagnostic value of MRI and computed tomography in anorectal malignant melanoma. AB - Here, we report 12 cases of anorectal malignant melanoma (ARMM), which has a very rare incidence. Patients were examined by either computed tomography or MRI or computed tomography combined with MRI before they underwent a remission operation. Because of the paramagnetic contribution from melanin, the short T(1) and short T(2) signals in MRI were specific to melanoma. MRI is reliable in the early diagnosis of ARMM, which is confirmed by pathological reports. Therefore, we advocate the application of a radiological screen using MRI for those patients with a mole in the anorectal region and abnormal colonoscopy findings. PMID- 26524007 TI - Mood and anxiety disorders in patients with chronic low back and neck pain caused by disc herniation. AB - OBJECTIVE: We investigated the prevalence of mood and anxiety disorders in patients with chronic low back and neck pain caused by disc herniation and the relationships between pain and mood, and anxiety disorders. METHODS: In total, 149 patients with disc herniation and 60 healthy subjects were included. Disc herniation was diagnosed based on a physical examination and magnetic resonance imaging. Mood and anxiety disorders were diagnosed using the Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition/Clinical Version. RESULTS: The mean age of the study subjects (n = 209) was 45.96 +/- 11.45 years. Seventy (46.6%) patients with disc herniation met the criteria for at least one mood or anxiety disorder. The prevalence rates of mood and anxiety disorders were 16.6% and 35.8%, respectively. The most common specific diagnoses were major depression (n = 25, 16.9%) and generalised anxiety disorder (n = 19, 12.8%). CONCLUSIONS: Mood and anxiety disorders were more commonly seen in patients with lumbar or cervical disc herniation than in those without herniation. No relationship was detected between pain severity and mood or anxiety disorders. However, mood and anxiety disorders were associated with neurological deficits. PMID- 26524008 TI - Editorial: Would You Like A Hypothesis With Those Data? Omics and the Age of Discovery Science. PMID- 26524012 TI - Spontaneous transition of a water droplet from the Wenzel state to the Cassie state: a molecular dynamics simulation study. AB - It is widely accepted that the superhydrophobic state is attributed to the formation of the Cassie state. The Cassie state is mostly metastable, which can be turned into the Wenzel state. Therefore, the superhydrophobic state is generally considered to be unstable. In this study, the wetting behaviors of a water droplet on different pillar surfaces are simulated. The spontaneous transition from the Wenzel state to the Cassie state is achieved, which is significant for the stable existence of superhydrophobicity. The transition process is analyzed in detail and can be chronologically divided into two stages: the contact area decreases and the water droplet rises. Moreover, the transition mechanism is studied, which is due to the combined effect of the surrounding pillars and the central pillar. The surrounding pillars form a no-wetting gap under the droplet, and the central pillar forces the droplet to move upward. Furthermore, three parameters that may influence the transition are studied: the pillar height, the droplet size and the hollow size. PMID- 26524011 TI - Health Behaviours As a Mechanism in the Prospective Relation between Workplace Reciprocity and Absenteeism: A Bridge too Far ? AB - BACKGROUND: The persistent lack of evidence on causal mechanisms between social capital and health threatens the credibility of the social capital-health association. The present study aims to address this ongoing problem by investigating whether health behaviours (i.e. smoking, alcohol consumption, and physical activity) mediate the prospective relation between workplace reciprocity and future sickness absence. METHODS: A cohort of 24,402 Belgian employees was followed up during 12 months for sickness absence. Workplace reciprocity was measured with four indicators-colleague help, colleague interest, supervisor help, and supervisor concern. Three types of multilevel mediation models were applied. RESULTS: Overall, workplace reciprocity negatively related to high sickness absence (>= 10 days) mainly independently from health behaviours. Uniquely, colleague interest positively related to smoking (OR = 1.058, 95% CI = 1.019, 1.098) and smoking in turn, positively related to sickness absence (OR = 1.074, 95% CI = 1.047, 1.101). No behavioural pathways could be identified between company-level reciprocity and sickness absence, and company-level health related behaviours did not mediate the relation between company-level reciprocity and individual sickness absence. CONCLUSIONS: These results suggest that both social capital and health behaviours are relevant for employee health, but health behaviours seem not to be the underlying explanatory mechanism between workplace reciprocity and health. PMID- 26524013 TI - [Analysis of Immunophenotypes in 329 Patients with B-ALL at Different Ages]. AB - OBJECTIVE: To investigate the immunophenotypes of B cell acute lymphoblastic leukemia (B-ALL) in patients at different age and to explore its clinical application in prognosis prediction and individualized treatment. METHOD: The immunophenotyping in 329 patients with B-ALL at different ages was performed by CD45/SSC gate four-color fluorescence flow cytometry. RESULTS: In all patients detected the highest incidence of lymphoid-associated antigens was CD19, HLA-DR, CyCD79a and cTdT, followed by CD10, CD22, CD34, CD38, CD20 and CyIg. B-ALL showed a higher concomitant expression rate of myeloid antigens CD13 and CD33; the CD11b, CD15, CD117 and T antigens (CD4, CD7 and CD56) were rarely expressed. CD10 pro-B acute lymphoblastic leukemia (Pro - B-ALL) was predo-minant in infantile group (60%) with CD117 higher expression (40%). Subtype Pro-B-ALL was rarely expressed in childhood and adolescent group, but the incidence of disease increased as the age increase, the incidence of youth group (22.7%) and middle aged' group (14.8%) were significantly higher than childhood group (4.4%). The influence of age on immunophenotypic characteristics of the adult B-ALL was not significant, the heterogeneity of antigen expression was less in the adult patients at different ages. The expression of CD10 and CD38 was lower, while expression of CD34, CD13 and CD33 were higher in adult patients than those in children patients. There was no significant difference in incidence of precursor B-ALL (Pre-B-ALL) among different age groups (P > 0.05), but its incidence increased along with age increasing, and the expression of CD20 was higher in Pre - B-ALL than that in Pro - B-ALL and common B-ALL. CONCLUSION: The immunophenotype characteristics of B-ALL in the patients at different ages is of great value in prediction for disease prognosis and guidence of individualized treatment. PMID- 26524014 TI - [Immunophenotypic Analysis of Patients with CD56+ Acute Myeloid Leukemia]. AB - OBJECTIVE: To explore the immunophenotype characteristics of newly diagnosed patients with CD56+ acute myeloid leukemia (AML). METHODS: Combining with cytomorphology, four-color flow cytometry was used to analyze the immunophenotype of 342 AML patients with CD56+ or CD56-. RESULTS: In 342 AML patients, the CD56+ expression was found in 83 AML patients who accounted for 24.27% and included 10 cases of M1, 45 cases of M2, 5 cases of M3, 6 cases of M6 and 17 cases of M5. The statistical analysis showed that there was statistical difference between CD56+ and CD11b+ patients (P < 0.05), but there was no statistical difference between CD56+ and HLA-DR, CD34, CD38, CD13, CD33, CD15, CD117, CD14, CD64, CD2, CD7, CD5, CD3, CD4, CD10, CD19, CD20, CD22 (P > 0.05). CONCLUSION: AML with only CD56 positive always has poor prognosis, thus the prognosis of patients with CD56+ AML accompanied by other antigens still needs more research. PMID- 26524015 TI - [Expression and Promoter CpG Island Methylation Status of miR-34b in Leukemia Cell Lines and Their Clinical Significance]. AB - OBJECTIVE: To explore the expression and promoter CpG island methylation status of miR-34b in leukemia cell lines and their clinical significance. METHODS: A total of 10 cases of non-hematologic diseases were selected as control group, and the bone marrow cells of control group and HL-60, K562 cells were selected; the relative expression of miR-34b was detected in bone marrow cells, HL-60 and K562 cell lines by fluorescence quantitative PCR, and the MiR-34b methylation status was detected by methylation-specific PCR, the HL-60 and K562 cell lines were treated with decitabine, and the expression levels and methylation status of miR 34b in the 2 cell lines were detected by the same method. Has-miR-34b was transfected into K562 cells, which were divided into non-transfection group, negative control group and Has-miR-34b transfection group; if the transfection was successful, the cell proliferation should be recorded at different time points of culture, and the proliferation inhibition rate should be calculated. RESULTS: The relative expression level of miR-34b in the control group was (5.23 +/- 0.75), in HL-60 was (0.05 +/- 0.01) and in K562 was (0.04 +/- 0.01). The difference between 3 groups was statistically significant (F = 44.812, P < 0.01). The promoter regions of CpG island in HL-60 and K562 cell lines were methylated, while the bone marrow cells were not methylated in 10 cases of non hematologic diseases children.Through miR-34b expression levels of HL-60 and K562 cell lines significantly increased by decitabine treatment (P < 0.05), and the methylation of leukemia cell line promoter region CpG island was found before and after decitabine treatment, but after administration of decitabine the methylation significantly decreased, suggesting that decitabine has an inhibitory effect on methylation of promoter region CpG island. After being cultured for 48, 72, 96 and 120 hrs, the cell proliferation in Has-miR-34b transfection group reached to 24.8%, 46.7%, 33.6% and 4.7%, repectively, and significantly lower than that in non transfection group (P < 0.05). CONCLUSION: CpG island methylation of miR-34b promoter region in leukemia cell lines can decrease the expression levels of miR 34b, which is also the reason why miR-34b can reduce the inhibition of cell proliferation, thus miR-34b might be a tumor suppressor gene involved in the regulation of leukemia. PMID- 26524016 TI - [Expression level of p53 in Tumor Tissue of Patients with Acute Leukemia and Its Clinical Significance]. AB - OBJECTIVE: To study the expression level of p53 in tumor tissue of patients with acute leukemia (AL) and its clinical significance. METHODS: From April 2013 to April 2015, 80 patients with AL in our hospital were chosen as leukemia group, at the same time, 50 patients with non-hematologic diseases were chosen as control group. All the patients were detected by bone marrow smear mean and p53 staining. The positive rate of p53 and staining score were compared between 2 groups. The clinical data of leukemia group were collected, and the correlation of clinical features with p53 expression was analyzed. RESULTS: In the control group, the positive rate of p53 was 6.00%, the staining score was (0.2 +/- 0.1); in the leukemia group, the positive rate of p53 was 73.75%, the staining score was (1.9 +/- 0.4), the difference was statistically significant (P < 0.05). The expression of p53 significantly correlated with the blood routine indicators, clinical manifestation, multiple infiltration and curative effects (P < 0.05), and the p53 expression not correlated statistically with the sex, age, anamnesis, family history (P > 0.05). CONCLUSION: Compared with the patients with non-hematologic diseases, the expression level of p53 in the AL patients increases significantly, the p53 expression correlates significantly with the blood routine indicators, clinical manifestation and curative effect of the patients. PMID- 26524017 TI - [Expression of HMGB1 and NF-kappaB in Patients with Acute Leukemia and Its Significance]. AB - OBJECTIVE: To explore the expression of high mobility group box protein 1 (HMGB1) and nuclear factor-kappa B (NF-kappaB) in patients with acute leukemia and its significance. METHOD: 20 samples of bone marrow and peripheral blood from each acute leukemia groups (newly diagnozed, relapsed and complete remission groups) and 20 samples as control from patients with no-hematologic malignancies were collected. The expression level of HMGB1 in peripheral blood plasma was determined by ELISA; HMGB1 and NF-kappaB level in mononuclear cells were examined by RT-PCR. Western blot was used to determine HMGB1 and NF-kappaB protein levels. HMGB1 and NF-kappaB in bone marrow smears were determined by immnohistochemistry method (IHC). RESULTS: The expression level of HMGB1 obviously increased in patients of newly diagnosed and relapsed groups, as compared with control group there was statistical significance (P < 0.05), but there was no obvious difference in expression level of HMGB1 between complete remission group and control group (P > 0.05). The expression level of HMGB1 and NF-kB in monnuclear cells of bone marrow in newly-diagnosed group and relapsed group was significantly higher than that in control group (P < 0.05), but the expression levels of HMGB1 and NF-kB in complete remisson group did not change (P > 0.05). The results of immnohistochemistry method indicated that the possitive expression of HMGB1 and NF-kB maily was found in bone marrow smears of newly diagnosed and relapsed groups. CONCLUSION: HMGB1 is overexpressed in acute leukemia, which may be involved in the occurrence and development of acute leukemia by activating the NF-kappaB signaling pathway, HMGB1 may be a important index for observing therapeutic effectiveness and predicting recurrence of acute leukemia. PMID- 26524018 TI - [IDH1 Gene Mutation and Its Clinical Significance in patients with Acute Myeloid Leukemia]. AB - OBJECTIVE: To evaluate the incidence rate of IDH1 in acute myeloid leukemia and analyze its effect on clinical characteristics and prognosis. METHODS: Mononuclear cells in bone marrow samples were collected from 192 adult patients with newly diagnosed AML. Polymerase chain reaction (PCR) and direct sequencing were used to amplify exon 4 of IDH1 gene, the gene sequencing was used to analyze the gene mutations, at same time, the detection of NPM1, FLT3-TKD, FLT3-ITD, C KIT, CEPBA, TET2 and JAK2V617F and MLL mutations were carried out, the follow-up was used to determine its therapeutic efficacy and outcomes of patients. The clinical and laboratory data of these cases were collected, and their clinical characteristics and prognosis were then analyzed. RESULTS: Among the 192 AML patients, 13 cases were detected with IDH1 gene mutation, the mutation rate was 6.77% [95% CI (5.70%-13.38%)]. The sequencing chart of IDH1 gene showed double peaks, the mutations were heterozygous, out of them c.G395A (p.R132H) was found in 8 cases, c.C394T was found in 4 cases (p.R132C), c.C394A (p.R132S) was found in 1 cases, R132H and R132C are common, 13 cases showed missense mutation. The median age in mutation group was 52 years old, the median age in unnutration group was 40 years, there was significant difference between them (P = 0.010). Mutation rate of IDH1 gene in M1 and M2 was significantly higher than that in other FAB subtypes. There were no significant difference in sex, newly diagnosed peripheral white blood cell count, hemoglobin, platelet count, peripheral blood and bone marrow original cell proportion of primitive cells between them. Mutation of IDH1 gene had certain correlation with NPM1 gene mutation, but no correlation with FLT3-TKD, FLT3-ITD, C-KIT, TET2 and JAK2V617F and MLL natations was found. In addition, the IDH1 mutation easily occurred in patients with normal karyotype or in patients with middle prognostic risk karyotype, IDH1 mutation occurred in 11 cases with normal karyotype, the mutation rate was 10.28%, IDH1 mutation were observed in 2 cases with abnormal karyotype, the mutation rate was 3.50%, there was significant difference. In AML patients with middle prognostic risk karyotype. The complete remission (CR) and the 3 year survival (OS) rate of IDH1 mut patients were less than that in IDH1 wt, there was significant difference (P < 0.05). CONCLUSIONS: The IDH1 mutation more easily occurr in older AML patients and mutations effect of IDH1 on clinical characteristics may represent a molecular marker for poor prognosis in AML. PMID- 26524019 TI - [Relation of MBL ExonI 54 and NFkappaB1-94ins/del ATTG Polymorphism with Fever during Neutropenia in Patients with Acute Leukaemia after Chemotherapy]. AB - OBJECTIVE: To explore the correlation between MBL ExonI 54 and NFkappaB1 94ins/del ATTG polymorphism and fever during neutropenia in patients with acute leukaemia (AL) (except M3) after first chemotherapy in Chinese Han population. METHODS: Blood samples obtained from 76 fever patients with AL during neutropenia episodes were detected to analyse single nucleotide polymorphism (SNP) in the MBL ExonI 54 and NFkappaB1-94ins/del ATTG gene, and analyse the correlation between above-mentioned 2 polymorphisms and fever during neutropenia of AL patients after chemotherapy. RESULTS: In 76 patients, no correlation were found between MBL ExonI 54 and NFkappaB1-94ins/del ATTG polymorphism and fever during neutropenia in patients with acute leukaemia after chemotherapy (P > 0.05). No significant relation were found in sex, age, underlying disease, disease status or degrees of neutropenia in febrile neutropenia between MBL ExonI 54 and NFkappaB1-94ins/del ATTG polymorphism (P > 0.05). However, patients with MBL ExonI 54 mutation presented longer febrile duration with a median of 5 days compared to 3 days of patients with wildtype MBL ExonI 54 genotype (P < 0.05). CONCLUSIONS: There is no clear correlation between MBL ExonI 54 and NFkappaB1-94ins/del ATTG polymorphism and fever during neutropenia in patients with acute leukaemia after chemotherapy. However, the patients with MBL ExonI 54 mutation have been observed to present a longer febrile duration. PMID- 26524020 TI - [Effect of Emodin Combined with AZT on the Proliferation and the Expression of BCL-2, NF-kappaB, TGF-beta in the Leukemia Stem Cells-KG-1a cells]. AB - OBJECTIVE: To investigate the effect of Emodin combined with 3'-azido-3' deoxythymidine (AZT) on the proliferation and apoptosis of concentrated leukemia stem cells (CLSC)-human acute myeloid leukemia KG-la cells and expression of BCL 2, NF-kappaB and TGF-beta. METHODS: The tumor stem cell-like subpopulation in human leukemia cell line KG-1a was enriched with 5-fluorouracil (5-FU). The CD34+ CD38- subpopulation in the KG-1a cells was detected with flow cytometry, the cell proliferation was detected by MTT method to study the of Emodin and AZT in the CLSC. The cell apoptosis was analyzed by flow cytometry. The expression of NF kappaB, BCL-2 and TGF-beta mRNA and proteins were measured with RT-PCR and Western blot respectively. RESULTS: As compared with cells treated with mentioned above drugs alone, the inhibition of proliferation potential and apoptosis rate of cells in combination group markedly increase with time and concentration dependent member (P < 0.01), the expression of NF-kappaB, BCL-2 and TGF-beta mRNA and proteins decreased. CONCLUSION: Emodin combined AZT can synergistically inhibit the proliferation, induce cell apoptosis, and down regulate the expression of NF-kappaB, BCL-2 and TGF-beta mRNA and proteins in the CLSC, the possible mechanism of synergistic effect may be associated with inhibiton of BCL 2 activation and down-regulation of the expression of NF-kappaB, and TGF-beta. PMID- 26524021 TI - [Cloning of VH and VL Gene of Human anti-IL1RAP McAb and Construction of Recombinant Chimeric Receptor]. AB - OBJECTIVE: To clone the variable region genes of human anti-IL1RAP (IL-1 receptor accessory protein) monoclonal antibodies (McAb) and to construct IL1RAP chimeric antigen receptors (CARs). METHODS: The VH and VL DNA of IL1RAP single chain antibodies were amplified by RACE and overlap extension PCR from total RNA extracted from 3H6E10 and 10D8A7 hybridoma and ligated into specific IL1RAP single-chain variable fragments (scFv). CD8alpha transmembrane domain, CD137 intracellular domain, TCR zeta chain, human CD8alpha signal peptide and scFv-anti IL1RAP were cloned into plasmid LV-lac. Recombinant lentiviruses were generated by co-transfection of recombinant plasmid LV-lac, pMD2. G, and psPAX2 helper vectors into 293FT packing cells. RESULTS: The VH and VL genes of 2 human anti IL1RAP McAb were acquired. The 3H6E10 VH and VL genes consisted of 402 bp and 393 bp encoding 134 and 131 aminoacid residues, respectively; 10D8A7 VH and VL genes consisted of 423 bp and 381 bp encoding 141 and 127 amine acid residues, respectively. Recombinant expression vertors LV-3H6E10 scFv-ICD and LV-10D8A7 scFv-ICD (ICD: CD8alpha transmembrane domain-CD137 intracellular domain-TCR zeta chain) were constructed. The target fragments were demonstrated by sequencing analysis. Recombinant plasmids were transfected into 293FT cells and lentiviral particles were acquired. CONCLUSION: Human anti-IL1RAP recombinant receptors are constructed successfully and lay a good foundation for the construction of IL1RAP CAR killer T cell vaccine. PMID- 26524022 TI - [Expression of CSN Complex in ATRA-induced APL Cell Differentiation and Its Clinical Significance]. AB - OBJECTIVE: To investigate the expression of CSN complex (COP9 signal some subunits) in the patients with acute promyelocytic leukemia (APL) and its significance in the ATRA-induced APL differentiation. METHODS: Using the NB4 cells as a model, morphologic observation and myeloid differentiation marker CD11b detection were used to monitor ATRA-induced APL differentiation, the expression of CSN complex in cell differentiation was detected by Western blot and reverse transcription real time fluorescent quantitative PCR (RT-qPCR) method. RT-qPCR was also used to detect the relative expression level of COP9 signalosome subunits in the APL patients and remission after treatment. RESULTS: ATRA could obviously enhance CD11b expression; the cell morphology showed obvious differentiation characteristics. During the differentiation, the expression of COP9 signalosome subunits was down-regulated by ATRA. Meanwhile, the CSN expression level in newly diagnosed APL patients was much higher than that in controls (non-leukemia) (P < 0.05). The level of CSN expression was obviously down-regulated when APL patients achieved complete remission. CONCLUSION: The high CSN expression level in APL patients can be down-regulated by ATRA. CSN complex may have a significant effect on the pathogenesis and therapy of APL. PMID- 26524023 TI - [Diagnostic value of R-banding Technique, Dual-color Fluore- scence In Situ Hybridization and Quantitative Real-time PCR in Acute Promyelocytic Leukemia]. AB - OBJECTIVE: To explore the diagnostic value of R-banding technique (RT), dual color fluorescence in situ hybridization (D-FISH) and quantitative real-time PCR (RT-PCR) for acute promyelocytic leukemia. METHODS: The cytogenetic characteristics and PML/RARalpha fusion gene in 340 patients with suspectable APL were analyzed by using 3 detection methods. MICM (morphology, immunology, cytogenetic and molecular biology) was used as diagnostic standard of APL, and the diagnostic value of RT, D-FISH and RT-PCR was evaluated by comparing the detection results of RT, D-FISH and RT-PCR as well as their combination. RESULTS: For the diagnosis of APL, the sensitivity of RT, D-FISH and RT-PCR was 81.3% (78/96), 95.0% (91/96) and 96.9% (93/96) respectively. RT failed to detect 18 cases, the results of D-FISH showed 5 cases with false positive and 2 cases with false negative, the RT-PCR showed 4 cases with false positive, 3 cases with false negative. The sensitivity and specificity of combined detection of 3 methods were 99.97% and 100% respectively. CONCLUSION: The 3 detection methods alone all have certain defects for diagnosis of APL, but their combined detection is helpful to improve the definitive diagnostic rate and can decrease misdiagnosis rate and missed diagnostic rate. PMID- 26524024 TI - [RNAi-mediated Silencing of CXCR4 Inhibits the Adhesion, Invasion and Tumorigenicity of Acute Monocytic Leukemic Cell Line SHI-1]. AB - OBJECTIVE: To investigate the effect of CXCR4 gene on the proliferation, adhesion, invasion and tumorigenicity of a human monocytic leukemic cell line SHI 1. METHODS: The lentivirus vector silencing the expression of CXCR4 was constructed for infection of SHI-1 cells silencing expression of CXCR4 in SHI-1 cells. The expression of CXCR4, MMP-2 and MMP-9 was detected by real time PCR. The expression of CXCR4 on membrane of SHI-1 cells was detected by flow cytometry. The SHI-1 cell proliferation ability was detected by MTT. The co culture system of the leukemia cells and bone marrow stromal cells was used to detect the adhesion and migration ability of leukemia cells. SHI-1 cells were inoculated subcutaneously in nude mice to investigate the growth ability in vivo. RESULTS: After SHI-1 cells were infected by lentivirus silencing expression of CXCR4, the expression of CXCR4 mRNA in SHI-1 CXCR-4i cells decreased by 76% as compared with expression of SHI-1/NC of negative control virus, the expression of CXCR4 on membrane of SHI-1/CXCR4i obviously downregulated; the expression of MMP 2 and MMP-9 in SHI-1/CXCRi cells also declined by 63% and 62% respectively; the proliferation ability of SHI-1/CXCR4i in vitro did not obviously changed, but the adhesion and trans-matrigel invasion ability significantly decreased, the SHI 1/CXCR4i cells could not form neoplasm subcutaneously in mice, but the SHI-1 and SHI-1/NC cells could form neoplasm subcutaneously in mice, and there was no significant difference in volumn of neoplasm mass. CONCLUSION: The silencing expression of CXCR4 can decline the adhesion and migration ability of SHI-1 cells, and can completely suppress the formation of neoplasm subcutaneously, so the CXCR4 may serve as a target for treating leukemia. PMID- 26524025 TI - [Efficacy Analysis of Arsenic Trioxide Combined with All Trans Retinoic Acid for Acute Promyelocytic Leukemia]. AB - OBJECTIVE: To investigate the efficacy of arsenic trioxide combined with all trans retinoic acid (ATRA) for patients with acute promyelocytic leukemia (APL). METHODS: A total of 159 cases of APL were selected from January 2011 to December 2014 in our hospital, among them 75 cases were treated by As2O3combined with ATRA, 43 cases were treated with As2O3alone, 41 cases were treated with ATRA alone. The cardiac enzymes level, lever function index change, death rate, complate remission (CR) rate, time of reaching CR and complicatiens were compared in 3 groups. RESULTS: After treatment of 8 courses, ALT and AST levels in As2O3+ ATRA group were significantly higher than those in As2O3and ATRA alone groups; the CK-MB and TnI-UI index increased in As2O3group (P < 0.05); as compared with As2O3group, the mortality and CR rate in As2O3+ ATRA group were no significant different, but the time of reaching CR was significantly shortened. For relapsed patients, the CR rate in As2O3+ ATRA group was no significantly different from that in As2O3group, while was significantly higher than that in ATRA group. The ratio of liver function damage in As2O3+ ATRA group was increased, moreover the incidence of leukocytosis and headache in ATRA group was significantly higher than that in As2O3+ ATRA and As2O3group (P < 0.05). CONCLUSIONS: The efficacy of As2O3conbined with ATRA for inducing remission is better than that of single drug treatment, moreover the adverse reactions occur less. PMID- 26524027 TI - [Analysis of Clinicopathological Characteristics and Prognosis of 112 Patients with Primary Waldeyer's Ring Lymphoma]. AB - OBJECTIVE: To investigate the clinical and pathological characteristics of patients with primary Waldeyer's ring lymphomas (PWRL), and to analyze its therapeutic efficacy and prognostic factors. METHODS: A total of 112 patients with PWRL confirmed by pathological and immunohistochemical methods between January 2009 and January 2014 were studied. Clinical data were collected and analyzed retrospectively. RESULTS: PWRL accounted for 3.9% of lymphoma over the same period. Median age of patients with PWRL was 51.5 years old. The affected areas were tonsil, nasopharynx, tongue base and oropharynx, which accounted for 63.4% (71/112), 22.3% (25/112), 5.3% (6/112) and 4.5% (5/112) respectively. The most common pathological types of these four areas were diffused large B-cell lymphoma (DLBCL) and extranodal NK/T cell lymphoma (NKTCL) which accounted for 58% and 15.2%. The overall response rate (CR/CRu = 51.4%; PR = 30.8%) in all patients was 82.2%, the estimated 5-year overall survival (OS) rate were 71.6%. The 5-year OS rate were 94.7% in the group used Rituximab. Meanwhile, chemotherapy combined with radiotherapy could improve the outcome of T-cell PWRL patients and the 5-year OS rate were 88.9%. Age, disease stages, pathological types, IPI scores, LDH level, beta2-MG level and the efficacy of initial therapy were prognostic factors with statistical significance. Cox multivariate analysis showed that age of more than 60 years, LDH level, pathological types and the efficacy of the initial therapy were independently associated with OS. CONCLUSION: PWRL has a relatively good prognosis. The pathological types affect the prognosis directly and guide treatment. Combined modality therapy should be chosen for patients with PWRL. Patients with T-cell PWRL should accept chemotherapy combined with radiotherapy, while rituximab may be better for B-cell PWRL. The efficacy of initial therapy is crucial for the outcome of patients. Age and LDH level are also important prognostic factors. PMID- 26524028 TI - [Analysis of Clinical Curative Efficacy for 91 Cases of Splenic Marginal Lymphoma]. AB - OBJECTIVE: To investigate the clinical characteristics, treatment and prognosis of splenic marginal zone lymploma (SMZL). METHODS: A total of 91 cases of SMZL admitted in our hospital from January 2002 to March 2013 were enrolled in this study. The clinical characteristics and immunophenotypes were summarized, and the clinical therapeute response and prognostic factors were analyzed statistically. RESULTS: The median age of 91 patients was 56 (28-79); all the patients displayed splenomegaly with 73.6% of large spleen, hepatomegaly (14.6%) and lymphadenophathy (28.2%); the bone marrow involvement was observed in 98.9% patients, the B symptom was found in 47.1% patients. The positive expression of CD20 was observed in 100% patients, the positive expression of CD5 was in 8.3% patients, the positive expression of CD23 was found in 47.6% patients, no specific antigen was observed by now for SMZL. The clinical treatment showed that total ORR was 87.7%, CRR was 53.8% in chemotherapy group, chemotherapy combined with rituximab showed a better response than that of chemotherapy alone, which ORR was 100%, CRR was 72.4%, the difference between them was statistically significant. The Hb < 120 g/L, elevated LDH level and treatment without rituximab were the poor prognostic factors for PFS, while the elevated LDH level was related with OS of patients. CONCLUSION: The patients with SMZL often display splenomegaly, involvement in bone marrow and absence of specific immunophenotypes. Chemotherapy combined with rituximab can definitely improve the outcome of SMZL. The Hb level, LDH level and treatment combined with or without rituximab seem to be related to the prognosis of the disease. PMID- 26524026 TI - [Analysis of Clinical Characteristics and Prognostic Factors of 223 Newly Diagnosed Hodgkin's Lymphoma Patients]. AB - OBJECTIVE: To analyze the clinical characteristics and prognostic factors of the newly diagnosed Hodgkin's lymphoma (HL) patients. METHOD: The clinical data of 223 patients with pathologically confirmed and newly diagnosed HL (since January 2001 to December 2012) were collected from Tianjin Medical University Cancer Hospital. The patients' route features, laboratory examination results, clinical manifestations and short-term efficacy were analyzed. Furthermore, the Log-rank test and Cox proportional hazard model were applied to analyze the prognosis. All data were analyzed with SPSS software version 1.0 and graphPad Prism 5. RESULTS: Among the 223 newly diagnosed HL patients, the ratio of male to female was approximately 1.25:1 and the median age was 40 years old (range 3-84 years). The median survival period is 62 months (range 8-189 months). The 5-year overall survival (OS) rate was 92.8% for all 223 HL patients. Multivariate analysis showed that HL originated from mediastinal lymph node region, the extranodal sites were involved, lactate dehydrogenase (LDH) level increased and CR2 was unable to fulfil the CR/CRu which are independent prognostic factors of HL patients (P < 0.05). Therefore, according to the above-mentioned adverse prognostic factors, 223 cases of HL patients were regrouped as low, intermediate and high risk. The HL 5-year OS rate of three groups were 100%, 96.9% and 42.9%, OS in each group was significantly different (P < 0.05). CONCLUSION: HL displays a high incidence in young male patients but the curative efficacy is optimal and the survival period is long. The HL originated at mediastinal lymph node region, involved extranodal sites, lactate dehydrogenase (LDH) level increased and CR2 is unable to fulfil the CR/CRu which are independent prognostic factors of HL patients. According to the above-mentioned factors for the initial treatment of patients with HL, risk discrimination can predict the prognosis of patients with HL to a certain extent. PMID- 26524029 TI - [Role of CyclinD1/IgH Detection by FISH in Differential Diagnostic Significance between Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia]. AB - OBJECTIVE: To investigate the feasibility of CyclinD1/IgH detection by FISH in diferential diagnosis between mantle cell lymphoma (MCL) and chronic lymphocytic leukeamia (CLL). METHODS: The FISH detection was performed for CyclinD1/IgH fusion gene. A comprehensive analysis was carried out for clinical features, such as age, sex , WBC count and lymphocyte count, the bone marrow morphology and immunohistochemical staining were carried for CyclinD1/IgH. RESULTS: It is often difficult to distinguish MCL from CLL by bone marrow morphology, when the cell morphology was not typical; there was no difference in age, sex, WBC count and lymphocyte count between MCL and CLL groups; 9 out of 52 patients were diagnosed as MCL, and the direction of CyclinD1/IgH by FISH was positive in 7 of 9 MCL, while 3 of the 7 patients were negative by immunohistochemical staining for CyclinD1. CONCLUSION: Detection of CyclinD1/IgH by FISH can be used as a specific and feasible method for differential diagnosis of mantle cell lymphoma from chronic lymphocytic leukeamia. PMID- 26524031 TI - [Relationship between Chemotactic Factor CCL5 and Diabet-associated Diffuse Large B Cell Lymphoma]. AB - OBJECTIVE: To explore whether the chemotactic factor CCL5 is the major factor of diffuse large B cell lymphoma (DLBCL) induced by diabetes or not. METHODS: The normal human B cells and DLBCL cells were cultured in vitro; the RT-PCR was used to detect their CCL5 mRNA expression, the human DLBCL cell line and mouse-derived DLBCL cell line A20 were cultured in vitro by using glucose at 5 and 30 mmol/L, respectively, then their CCL5 mRNA expression was detected by PT-PCR; the diabetic mouse model was constructed through peritoneal injection of streptozotocin at low dose in the BALB/c mice; the cell lines with stably high and low expression of CCL5 were established via lentiviral transfection and the cell lines with low and high expression of CCL5 were subcutaneously injected into diabetic mice and mice with normal blood sugar level. According to blood sugar level, the experimental mice were divided into 2 groups: diabetic group (A group) and normal blood sugar group as control (B group); then according to CCL5 expression level, the A group and B group were divided as well into high expression group (A1 group and B1 group) and low expression group (A2 group and B2 group), respectively, the tumor-formation rate, tumor-formation time, tumor size and texture were analyzed, respectively; the CCL5 expression was detected by using HE staining of tumor tissue and immunohistochemical method. RESULTS: The expression of CCL5 mRNA in human DLBCL cell line cultured in vitro was higher than that in normal B cells (P < 0.05); the expressions of CCL5 mRNA in human DLBCL cells cultured in high sugar concentration in vitro and mouse DLBCL cells were higher than those in cells cultured in low sugar concentration (P < 0.05). The tumor-formation rates in diabetic mice injected with high and low expression of CCL5 cell line A20 were 93.3% in A1 group and 60% in A2 group; the their tumor formation time was 7.0 +/- 0.85 days in A1 group and 9.5 +/- 2.8 days in A2 group, while the tumor formation rates in mice with normal blood sugar level were 20% in B1 group and 20% in B2 group, and their tumor-formation time was 12 +/- 1.3 days and 14 +/- 2.5 days respectively; the CCL5 expression level in tumor tissue of diabetic mice was higher than that in tumor tissue of mice with normal blood sugar level. CONCLUSION: The high blood glucose level can casase increase of DLBCL risk and promote the tumor growth; the chemotactic factor CCL5 may play an important role in the growth and migration of DLBCL caused by diabetes mellitus. PMID- 26524030 TI - [Influence of Fe3O4Magnetic Nanoparticles Combined with As2O3 and Adriamycin on Raji Cell Apoptosis and Autophagy]. AB - OBJECTIVE: To explore the effect of magnetic iron nanoparticles ( Fe3O4- MNP) in combination with arsenic trioxide and adriamycin on apoptosis and autophagy of Raji cells, a non-Hodgkin's lymphoma (NHL) cell line. METHODS: The growth inhibition rate of Raji cells was analyzed by MTT assay, the cells apoptosis and intracellular concentration of ADM were determined by flow cytometry (FCM), the expression levels of apoptosis-related proteins such as BCL-2, NFkappaB, Survivin, BAX, P53, and Caspase-3, and related to autophagy-proteins, such as LC3, Beclin-1, and P62/SQSTM1 were detected by Western blot. RESULTS: The growth inhibition of Raji cells in the group of ADM + As2O3were higher than that in the group of ADM or As2O3alone, however, lower than that in the group of Fe3O4- MNP combined with ADM and As2O3(ADM+As2O3+ MNP) (P < 0.05). The apoptotic rate and accumulation of intracellular ADM in the group of Fe3O4- MNP combined with ADM and As2O3were significantly higher than those in control, ADM, As2O3, and ADM plus As2O3groups (P < 0.05). The upregulation of BAX, P53 and Caspase-3 expression and the down regulation of BCL-2, NFkappaB, and Survivin expression at protein level were more remarkable in the group of ADM+As2O3 + MNP, compared with the other groups (P < 0.05). Moreover, the expressions of LC3 and Beclin-1 proteins in the group of ADM+As2O3+ MNP were higher, while the expression of P62/SQSTM1 was lower than that in other groups (P < 0.05). CONCLUSION: The Fe3O4 MNP combined with ADM and As2O3can increase the antitumor efficacy on Raji cells by promoting apoptosis and inducing autophagy. It would be a promising strategy for malignant lymphoma therapy. PMID- 26524032 TI - [Prognostic Value of Maximum Standard Uptake on Pretreatment 18F-FDG PET/CT Scan in Newly Diagnosed Follicular Lymphoma]. AB - OBJECTIVE: To determine the prognostic value of maximum standard uptake (SUV(max)) of pretreatment 18F-FDG PET/CT scan in newly diagnosed follicular lymphoma (FL). METHODS: The clinical data and detection results of 18F-FDG PET/CT scan of 30 patients with FL before treatment from November 2005 to October 2013 were analyzed retrospectively. The relation of SUV(max) with prognostic factors, therapeutic efficacy and survival time was evaluated in term of pathologic grade, FLIPI2 absence and presence of bulky disease and bone marrow involvement, clinical indicators and outcome of treatment. RESULTS: There was significant differences of SUV(max) among pathological grade 1, grade 2 and grade 3 (P = 0.040), but no significant difference was found among FLIPI 2 low risk group, intermediate risk group and high risk groups (P = 0.431). No difference of SUV(max) was observed in patients with and without bulky disease, or with and without bone marrow involvement (both P > 0.05). SUV(max) was not related with such patient characteristics as stage, beta2-microglobulin level, hemoglobin content, lactate dehydrogenase and Ki-67 (both P > 0.05). And the difference of SUV(max) was no significant for patients with complete remission (CR) and non-CR, or with efficacy and no efficacy (both P > 0.05). With the cutoff values of 10 and 15, the CR rate, overall response rate, 3-year progression-free survival (PFS) rate and 2-year overall survival (OS) rate were not different between the patients with SUV(max) below and above cut-off value (both P > 0.05). CONCLUSION: In our study the prognostic value of SUV(max) on PET/CT is indeterminate, and it can not be used to predict the FL patients prognosis. PMID- 26524033 TI - [Effect of Alantolactone on Proliferation of RPMI-8226 Cells and Its Possible Mechnism]. AB - OBJECTIVE: To investigate the effect of alantolactone on perliferation and apoptosis of multiple myeloma (MM) RPMI-8226 cells, and to explore its possible mechism in vitro and in vivo. METHODS: The RPMI-8226 cells were treated with alantolactone (1, 2.5, 5, 7.5 and 10 umol/L) for 48 h, cell viability was detected by CCK-8 assay and the value of IC50 was calculated; The RPMI-8226 cells were treated with alantolactone (2.5, 5 and 7.5 umol/L) for 48 h, the apoptotic rate was detected by flow cytmetry with Annexin V/PI staining; the expression level of cleaved caspase-3 and phosphorylation of ERK were measured by Western blot; the nude mice was used to further confirm the proapoptotic effect of alantolactone on MM cells in vivo. RESULTS: The alantolactone inhibited RPMI-8226 cell viability remarkably with a dose-dependent manner; the IC50 value of RPMI 8226 cells at 48 h was 4.32 +/- 0.15 umol/L; the apoptotic rate increased observably with a dose-dependent manner; the levels of cleaved-caspase-3 increased and the phosphorylation of ERK decreased significantly; as compared to control, the volum of tumor was much smaller, the expression levels of Ki67 and p ERK decreased. CONCLUSION: The alantolactone can efficiently inhibit the proliferation and induce the apoptosis of multiple myeloma RPMI-8226 cells in vitro and in vivo through inhibiting the activation of ERK signal pathway. PMID- 26524034 TI - [Effects of Thalidomide on Peripheral Blood Th17 Cells of Patients with Multiple Myeloma]. AB - OBJECTIVE: To explore the change of T help cell 17 (Th17) in the peripheral blood of patients with multiple myeloma (MM) before and after treatment with thalidomide. METHODS: A total of 35 MM patients treated with thalidomide and 35 healthy controls were enrolled in this study. The percentage of Th17 cells were detected by flow cytometry. The mRNA levels of retinoid-related orphan receptor gamma-t (RORgammat) were detected by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) and the plasm IL-17 levels were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: The percentage of Th17 cells, the mRNA expression of RORgammat and the plasm IL-17 levels in patients with MM were statistically higher than those in normal controls (P < 0.05). The percentage of Th17 cells was not correlate with the sex, age, disease type, globulin, immune globulin, light chain, M-protein and the proportion of plasmocytes (P > 0.05), but correlated with ISS stage, the level of beta2 microglobulin and the plasm IL-17 levels (P < 0.05). The percentage of Th17 cells, the mRNA expression of RORgammat and the plasm IL-17 levels in patients with response to thalidomide were statistically lower than those in patients before treatment (P < 0.05). CONCLUSION: The Th17 cells increase in the peripheral blood of patients with MM, the Th17 cells may participate in the occurrence of MM. Thalidomide may exert anti-MM through down-regulating Th17 cells. PMID- 26524035 TI - [Influence of CD117 Expression on Response of Multiple Myeloma Patients to Chemotherapy]. AB - OBJECTIVE: To investigate the influence of CD117 expression on response of multiple myeloma patients to chemo-therapy. METHODS: A total of 65 cases of newly diagnosed multiple myeloma in our hospital from 2011 to 2013 were enrolled in this study. Cytogenetic abnormalities and immunophenotype were detected by using fluorescence in situ hybridization and flow cytometry before chemotherapy. The therapeutic efficacy of patients was evaluated after 4 cycles of PAD or TAD regimen. RESULTS: The positive rates of 1q21 amplification, RB1: 13q14 deletion, D13S319: 13q14.3 deletion, IgH: 14q32 rearrangement and p53: 17p13 deletion were 32.2%, 40%, 40%, 20% and 3.1% respectively; the positive rates of CD38, CD138, CD56, CD117, CD20 were respectively 100%, 100%, 60%, 20%, 10.8%; the positive rates of CD19 and CD10 were 4.6% and 4.6% respectively; the positive CD22, CD7, CD5, CD103 did not found in any patients. The therapeutic efficacy of CD117- patients was better than that of CD117+ patients (P < 0.05), there was no correlation of the remaining indicators with efficacy; the proportion of CD117+ patients with beta2-microglobulin >= 5.5 mg/L was significantly higher than that of CD117- patients (P < 0.05); the rest of baseline data had no significant difference (P > 0.05). CONCLUSION: CD117 can be used as an indicator for evaluating efficacy of patients with newly diagnosed multiple myeloma. PMID- 26524036 TI - [Detection of Molecular Cytogenetic Aberrations by Fluorescence in Situ Hybridization in Different Bone Marrow Samples of Multiple Myeloma]. AB - OBJECTIVE: To detect the molecular cytogenetic abnormalities in different bone marrow samples of multiple myeloma by using fluorescence in situ hybridization (FISH) technology. The bone marrow cells from 48 cases of MM were taken for sorting the plasma cells using CD138 magnetic beads, and the biopsy tissue from 10 cases of MM was taken and embedded in parafin, then the 2 kinds of samples were detected by using FISH. D13s319/RB1, 1q21/P53, IgH, IgH/FGFR3, IgH/MAF probes were detected in 58 patients with new diagnosed multiple myeloma (MM) by FISH technology. RESULTS: Fluorescent signals were both seen in 2 different types of bone marrow samples and cytogenetic aberrations were detected in 30/58 (51.7%) patients, 29.3% (17 out of 58) cases had both D13S319 and RB1 deletion. The positive rates of P53 deletion, 1q21 amplification and IgH rearrangement were 12%, 27.6% and 20.7%, respectively. Only 7 cases (23.3%) had one cytogenetic abnormality, other 23 (76.7%) cases all had 2 to 5 kinds of different abnormalities. CONCLUSION: More than half of MM patients have cytogenetic change, and most of them are complex chromosomal abnormality. The different kinds of samples can expand the useful extension of FISH technology and acquire more cytogenetic information for clinician. PMID- 26524037 TI - [Test of Serum Free Light Chain and Its Clinical Significance in Light Chain Multiple Myeloma]. AB - OBJECTIVE: To investigate the clinical significance of serum free light chain (sFLC) detection in light chain multiple myeloma (LCMM). METHODS: A total of 37 newly diagnosed LCMM patients were enrolled in this study, including 17 patients with k light chain type and 20 patients with lambda light chain type, the sFLC and 24 hours urine light chain (ULC) were measured before and after chemotherapy. The correlation of sFLC level with ULC and renal impairment was analyzed. RESULTS: All the patients displayed an abnormally increased level of sFLC at diagnosis wtih median value of 105.44 mg/L and 146.39 mg/L for k and lambda light chain types, respectively. The sFLC did not correlate with ULC before and after chemotherapy. Among the 12 patients with very good partial remission and normal ULC level, the sFLC still was abnormally increased in 8 patients. Renal impairment was associated with the urine lambda-type light chain, and the area under the ROC curve of urine lambda light chain at diagnosis is 0.792 (P = 0.031). CONCLUSION: All patients with LCMM show an abnormally increased level of sFLC at diagnosis. sFLC can be used to monitor the response to chemotherapy because it is more sensitive for analysis of therapeutic effect than urine lambda light chain. PMID- 26524038 TI - [Values of Detecting the Levels of beta2-MG, TNF-alpha, CRP, IL-6 in the Patients with Multiple Myeloma]. AB - OBJECTIVE: To explore the values of detecting the serum levels of beta2-MG, TNF alpha, CRP, IL-6 in the patients with multiple myeloma. METHODS: A total of 40 patents with multiple myeloma were included in the experiment group, and 40 healthy volunteers were selected as the control group. The levels of beta2-MG, TNF-alpha, CRP and IL-6 were detected and compared in 2 groups, the different durie-salmon (DS) stages of beta2-MG, TNF-alpha, CRP and IL-6 in the experiment group were analyzed. RESULTS: The levels of beta2-MG, CRP, IL-6 in the experiment group were higher than those in control group (P < 0.05); the level of TNF-alpha in the experiment group was lower than that in control group (P < 0.05); the levels of beta2-MG, CRP, IL-6 at stage I, II, III in the experiment group was higher than those in control group (P < 0.05); the level of TNF-alpha at stage I, II, III in the experiment group was lower than that in the control group (P < 0.05); the levels of beta2-MG, CRP, IL-6 at stage I, II, III in the experiment group displayed an increasing tendency, the levels of TNF-alpha at stage I, II, III in the experiment group displayed a declining trend (P < 0.05); the levels of beta2-MG, CRP, IL-6 in the experiment group after treatment for 8, 16 weeks were higher than those in control group (P < 0.05); the level of TNF-alpha in the experiment group after treatment for 8, 16 weeks was lower than that in control group (P < 0.05); the levels of beta2-MG, CRP and IL-6 in the experiment group after treatment for 16 weeks were lower than those for 8 weeks (P < 0.05); the levels of TNF-alpha in the experiment group after treatment for 16 weeks were higher than those for 8 weeks (P < 0.05). The levels of APE1 after treatment in the experiment group were lower than that before treatment. CONCLUSION: The serum levels of beta2-MG, TNF-alpha, CRP and IL-6 can be as index for diagnosis of multiple myeloma, can effectively evaluate the disease severity; their combination with APE1 expression level can evaluate the therapeutic efficacy; thus the detection of above-mentioned indexes is possessed of higher value for clinical applications. PMID- 26524039 TI - [MUC1-2VNTR DNA Vaccine Induces Immune Responses in Mouse Model with Multiple Myeloma]. AB - OBJECTIVE: To investigate the humoral and cellular immune responses induced by MUC1-2VNTR DNA vaccine in multiple myeloma (MM) tumor-bearing mice. METHODS: In vitro, multiple myeloma cells were transfected by plasmid pcDNA3.1-2VNTR/myc-hisB with Lipofectamine2000. The above-mentioned mouse myeloma cells were inoculated subcutaneously into female BALB/c mice for establishing tumor-bearing animal models. These female BALB/c mice were immunized with pcDNA-2VNTR/myc-hisB or pcDNA/myc-hisB. The cytotoxic T lymphocyte (CTL) activity was detected by the LDH method and the spleen lymphocyte proliferation activity was detected by CCK-8 method. RESULTS: After immunization of BALB/c tumor-bearing mice with recombinant plasmid for 25 days, the tumor mass (0.5605 +/- 0.2065 g) was significantly lighter than that in the empty plasmid control group (1.521 +/- 0.6985 g) (P < 0.01) and the control group (1.5315 +/- 0.5425 g) (P < 0.01). The difference of tumor mass was not statislically significant between empty plasmid control group (1.521 +/- 0.6985 g) and the control group (1.5315 +/- 0.5425 g) (P > 0.05). The CTL and NK cell activity was significantly higher in the group of intramuscular injection with recombinant plasmid than that in control group. The spleen lymphocyte proliferation was statistically significantly increased after being immunized with recombinant plasmid pcDNA3.1-2VNTR/myc-hisB, compared with empty vector (P < 0.01). The results showed that MUC1-2VNTR gene immunization could induce anti-tumor effect in MM tumor-bearing mice. CONCLUSION: MUC1-2VNTR DNA immunization can elicit both humoral and cellular tumor specific immune response to multiple myeloma in MM tumor-bearing mice. It suggested that the MUC1-2VNTR DNA vaccine may be a potential treatment measure for patients with MM. PMID- 26524040 TI - [Serum Ferritin Level - Risk Factors of Myelodysplastic Syndrome Prognosis]. AB - OBJECTIVE: To investigate whether serum ferritin (SF) level may be used as a indicator for predicting mortality of patients with myelodysplastic syndrome (MDS). METHODS: A total of 151 patients with MDS were followed up in our study, their blood routine indicators, bone marrow blasts and SF level were detected. All of the patients were divided into the dead group and survival group. RESULTS: The average survival time of all patients was 30.0 +/- 10.86 months. There were statistical differences in age, IPSS score, chromosome grouping and SF level between 2 groups (P < 0.05). COX model analysis showed that age, MDS type, IPSS score, chromosome grouping and SF level all were related with mortality of patients with MDS, which were risk factors of death for patients with MDS (P < 0.05). The receiver-operating characteristic curve (ROC) area for SF was 0.826 with a Cut off value of 622.95, the sensitivity and specificity was 77.5% and 75% respectively. Log-rank test showed that the mortalities of patients with different levels of SF were statistically and very significantly different (P < 0.01). CONCLUSION: The age, IPSS score, chromosome grouping and SF level closely correct with mortality of the patients with MDS, the SF level may be considered as a predictor of death for MDS patients. PMID- 26524041 TI - [Relationship between Single Nucleotide Polymorphism of Interferon-gamma Gene +874 T/A and Efficacy of Immunosuppressive Therapy in Patients with Aplastic Anemia]. AB - OBJECTIVE: To investigate whether the single nucleotide polymorphism (SNP) of interferon-gamma (interferon-gamma + 874 A/T correlates with aplastic anemia (AA) and its efficacy of immunosuppressive therapy. METHODS: The blood samples were collected from 133 AA patients in West China Hospital, out of them 62 AA patients received immunosuppressive therapy and were observed for more than 4 months. A total of 100 healthy adults were selected as control. The polymerase chain reation (PCR), agarose gel electrophoresis and DNA sequencing were performed for detecting the polymorphism gene fragment of IFN-gamma + 874 A/T in AA patients and controls. RESULTS: (1) The frequences of IFN-gamma + 874 TT genotype and T allele in AA group were 24.8% and 48.9% respectively and were significantly higher than those in control group 7.0% and 23.0% (P < 0.001, P < 0.001); (2) In 62 AA patients, 34 AA patients achived response to immunosuppressive therapy, among them the response rates of patients with IFN-gamma + 874A/T and patients with T allele were 75% and 71.4%, and were significantly higher than those of patients with AA genotype and A allele (27.3% and 41.2%) (P = 0.008, P = 0.001). CONCLUSION: The IFN-gamma + 874A/T gene polymorphism not only correlates with the susceptibility to aplastic anemia, but also with the efficacy of immuno suppressive therapy. PMID- 26524042 TI - [Influence of Anticoagulants on Detection of ITP Platelet-Specific Autoantibodies and Relationship of Autoantibody Types with Glucocorticoid Efficacy]. AB - OBJECTIVE: To investigate the influence of divalent cation chelator EDTA and heparin sodium on the detection of ITP platelet-specific autoantibodies by the modified monoclonal antibody immobilization of platelet antigen assay (MAIPA) and to explore the relationship between types of platelet specific autoantibodies and glucocorticoid efficacy. METHODS: The samples were obtained from EDTA- and heparin- anticoagulant ITP patients, respectively, so as to detect the platelet specific autoantibodies (GPIIb/IIIa and GPIbalpha) in 140 ITP samples by modified MAIPA, then the differences between these two methods were compared. RESULTS: Out of 140 cases in EDTA group, 55 cases were positive for GPIIb/IIIa, while 76 cases in heparin group were positive for GPIIb/IIIa, 42 cases in both group were repeatable; among them 13 cases were positive in EDTA group and negative in heparin group, while 34 cases were positive in heparin group and negative in EDTA group, there was significant difference between them (x (2) = 9.38, P < 0.05), 62 cases in 140 cases of EDTA group were positive for GPIba, while 51 cases in heparin group were positive for GPIba, 42 cases in both group were repeatabe; among them 20 cases were positive in EDTA group and negative in heparin group, while 9 cases were positive in heparin group and negative in EDTA group, there was no significant difference between them (x (2) = 3.44, P > 0.05). A total of 320 cases received a standard glucocorticoid treatment, out of them 143 cases were positive for GPIbalpha with effective rate 39.9%, 177 cases were negative for GPIbalpha with effective rate 79.7%, there was statisticalty significant difference between them (x (2) = 53.115, P < 0.05). CONCLUSION: EDTA anticoagulant (a divalent cation chelator) has a significant influence on detection of ITP platelet-specific autoantibodies (GPIIb/IIIa) by a modified MAIPA method and the GPIbalpha antibody positive may be one of the important factors that results in un-sensitivity of ITP patients to glucocorticoid treatment. PMID- 26524043 TI - [Analysis of Human Platelet Antigen-1 System Alloantibodies Using Recombinant GPIIIa Fragments Coupled to Luminex Beads]. AB - OBJECTIVE: To detect platelet anti-HPA-1a and -1b antibodies using recombinant GPIIIa fragments coupled to Luminex beads. METHODS: The sensitivity of 2 techniques, monoclonal antibody specific immobilization of platelet antigen (MAIPA) and Luminex bead assay, was compared using 12 twofold-serial dilutions (from neat to 1 in 2048) of an anti-HPA-1a WHO international standard. The specificity of Luminex assay to identify anti-HPA-1a and -1b antibodies was assessed using 8 negative or positive controls and 36 blinded samples provided by WHO Platelet Workshop. RESULTS: The sensitivity of MAIPA and Luminex bead assay to detect anti-HPA-1a was dilution 1/64 (i.e. 1.56 IU/ml) and far more than dilution 1/2048 (i.e. 0.049 IU/mL), respectively. The Luminex bead assay could specifically identify negative and positive controls of anti-HPA-1a and -1b. All results of 36 blinded samples by Luminex assay were accordant to reference results except one sample which contained high concentration antithetical antibody and resulted in false positive of anti-HPA-1b. Cross-reactivity was also not observed with the samples containing HLA, ABO or other platelet antibodies. CONCLUSION: The Luminex beads coupled with recombinant GPIIIa fragments can be used to detect HPA-1 system antibodies with sufficient sensitivity and specificity, that is suitable for the detection of platelet alloantibodies in clinical alloimmune thrombocytopenia. PMID- 26524045 TI - [Analysis of Megakaryocytes and Platelet Parameters of ITP Patients]. AB - OBJECTIVE: To investigate the value of bone marrow megakaryocyte (BMK) and peripheral platelet parameter changes in differential diagnosis of idiopathic thrombocytopenic purpura (ITP). METHODS: The 91 patients were divided into 2 groups: ITP group (46 cases) and non-ITP group (45 cases), while 48 healthy volunteers were used as healthy controls. The parameters of BMK and peripheral platelets of ITP and non-ITP patients, and parameters of peripheral platelets of healthy controls were detected and compared. RESULTS: As compared with non-ITP group, the BMK count in ITP group obviously increased, including the gramlar MK and proo-MK, while the MK producing platelets obviously dicreased with statistical difference (P < 0.01); the platelet parameters in 2 groups did not show significant difference (P > 0.05). As compared with healthy control group, the platelet level and PCT of peripheral blood in ITP group significantly decreased (P < 0.01). CONCLUSION: The BMK level and platelet parameters, especially the platelet count and PCT have clinical value for differential diagnosis of ITP to a certain degree. PMID- 26524044 TI - [Role of Imbalance between Th17 Cells and Treg Cells in the Pathogenesis of Children with Henoch-Schonlein Purpura]. AB - OBJECTIVE: To explore the role of Th17 cells, CD4+ CD25+ regulatory Treg cells (Treg) and its transcription factor RORgammat and FoxP3 in the pathogenesis of children with Henoch-Schonlein purpura (HSP) so as to provide a new strategy for treatment of children with Henoch-Schonlein purpura by regulating the balance of Th17 and Treg cells. METHODS: Forty children with Henoch-Schonlein purpura in acute phase admitted in our hospital from February 2012 to March 2013 were enrolled in this study, forty healthy children were simultaneously used as controls. The expression of RORgammat mRNA and FoxP3 mRNA in peripheral blood mononuclear cells was detected by real-time PCR using SYBR Green I. The levels of IL-17A, TGF-beta1, IL-2 and IL-6 in serum were measured by ABC-ELISA. The ratio of Th17 cells to Treg cells in peripheral blood T lymphocytes was detected by flow cytometry. RESULTS: The levels of Th17 cells (2.75 +/- 0.60%) and RORgammat mRNA (1.11 +/- 0.51) in HSP group were significantly higher than levels of Th17 cells (1.41 +/- 0.29%) and RORgammat mRNA (0.65 +/- 0.24) (P < 0.01) in control group, but the levels of Treg cells (4.56 +/- 1.26%) and FoxP3 mRNA (1.15 +/- 0.45) in HSP group were lower than those of Treg cells (7.85 +/- 1.97%) and FoxP3 mRNA (2.32 +/- 1.1) (P < 0.01) in the control group. The relative levels of serum IL-17A, IL-6, TGF-beta1 (40.40 +/- 11.81 pg/ml, 75.38 +/- 27.19 pg/ml, 309.41 +/- 81.03 pg/ml) in the HSP group were significantly higher than those in the control group [IL-17A (20.32 +/- 10.70 pg/ml), IL-6 (25.16 +/- 8.31 pg/ml), TGF-beta1 (236.34 +/- 66.01 pg/ml)] (P < 0.01), but the level of serum IL-2 (25.60 +/- 13.19 pg/ml) in the HSP group was lower than that (34.42 +/- 11.69 pg/ml) in the control group (P < 0.01). The further detection demonstrated that in the children with acute HSP, the expression of Th17 cells positively correlated with RORgammat mRNA, IL-17A and IL-6 with the correlation coefficients of 0.887, 0.938 and 0.934 (P < 0.01), respectively. The positive correlation was also shown between the Treg cells and FoxP3 mRNA, IL-2 with the correlation coefficients of 0.834 and 0.932 (P < 0.01), respectively. CONCLUSION: There are higher expression levels of Th17 cells, RORgammat mRNA and IL-17A, and lower expression levels of Treg cells, FoxP3 mRNA of children with HSP in acute phase, which shows that Th17/Treg imbalance exists in children with HSP in acute phase. The levels of serum IL-6, TGF-beta1 increase and the serum IL-2 decrease in children with HSP in acute phase, moreover, there are the positive correlations between the levels of Th17 cells and expression of IL-6, as well as the level of Treg cells and expression of IL-2 in children with HSP in acute phase. PMID- 26524046 TI - [Therapeutic Efficacy of Multigly-Cosidorum Tripterygium Combined with rhIL-11 for Immune Thrombocytopenia]. AB - OBJECTIVE: To study the therapeutic efficacy of multigly-cosidorum Tripterygium combined with rhIL-11 for treating patients with immune thrombocytopenia (ITP). METHODS: A total of 75 patients with ITP were divided into 2 group: experimental group and control group. The experimental group included 40 patients who had been treated with multigly-cosidorum Tripterygium combined with rhIL-11. Multigly cosidorum Tripterygium was given at a dose of 1mg/kg.d for 2 months and rhIL-11 was injected at a dose of 16,000,000 units per day. Control group included 35 patients who had been treated with prednisone at a dose of 1 mg/kg.d. Platelet counts were performed every day before platelet counts >30 * 109/L. Peripheral blood T cells were collected before and after treated for 2 months. The ratios of CD4+, CD8+ T cells in peripheral blood T cells were analyzed by flow cytometry. RESULTS: Totally effective rate in experimental group was 77.5%. Totally effective rate in control group was 82.9%. Totally effective rate showed no statistical difference between these two groups (P > 0.05). The average time of platelet count 30 * 109/L in experimental and control groups were 13.06 +/- 6.10 days and 9.76 +/- 5.71 days respectively; in experimental group, the ratio of CD4+ T cells in peripheral blood was 21.03% before treatment, then rised to 34.49% after treatment for 2 months (P < 0.01); The ratio of CD8+ T cells in peripheral blood was 26.35% before treatment, then decreased to 20.18% (P < 0.01). In control group, the ratio of CD4+ T cells was 22.30% before treatment, then rised to 25.11% after treatment for 2 months (P < 0.05); The ratio of CD8+ T cells in peripheral blood was 27.24% before treatment, then decreased to 21.35% (P < 0.01). CONCLUSION: Multigly-cosidorum tripterygium can correct disorder of T lymphocytes, the combination of multigly-cosidorum triptergium and rhIL-11 can accelerate therapeutic efficacy for treating ITP and with less adverse reaction, so this combination may be effective and safe for treating patients with ITP. PMID- 26524047 TI - [Application of Next Generation Sequencing to Screen the Neonatal Thalassemia Genes]. AB - OBJECTIVE: To explore the feasibility of using next-generation sequencing technology (NGS) to screen the neonatal thalassemia genes. METHODS: Plantar blood of 206 cases of neonatal born in our hospital were randomly collected to be made into dried blood, which can be screened for thalassemia genes by next-generation sequencing, and then a further analysis would be performed on the basis on the detection results. RESULTS: In 206 cases of neonates tested, the thalassemia gene mutations in 22 cases were screened, including 11 cases of alpha-thalassemia, 11 cases of beta-thalassemia, 5 cases of new mutations. Out of 11 cases of alpha thalassemia 7 cases were proved to be the gene deletion, accounting for 64% (7/11), and the specific genotype distribution was as follows: 4 cases of alphaalpha/-alpha(3.7), 2 cases of alphaalpha/-SEA, 1 case of alphaalpha/ alpha(4.2), the remaining 4 cases with point mutations (4/11, 36%): Hb Part-Dieu hybrid, Hb Quong Sze hybrid, Hb Westmead hybrid, HBA1: c. 95 + 9 c > T (rewly discovered gene mutation). The whole 11 cases of beta-thalassemia are proved to be with beta chain point mutations, 7 kinds of mutation genotype were detected , CD17 (A->T) is the most common point locus mutation, accounted for 27% (3/11), and 50 G>A hybrid in 2 cases, 1 cases of Hb Hamilton hybrid, IVS-II-654 (C->T) in 1 case. The remaining 4 cases are of the new gene point mutation, they are as follows respectively: HBB: c. 316-116 c>A, HBB: c.316-248G>T, HBB: c.315 + 63 T>c, HBB: c. -23 A>G. CONCLUSION: The next-generation sequencing technology can be used to screen neonatal plantar dried blood for the thalassemia genetic mutation, which not only can effectively detect thalassemia gene types, but also can look for new gene mutations. The advantages of this method include easy collecting samples, precise result and wide use for clinical diagnosis, thus possibly give an early diagnosis for thalassemia. PMID- 26524048 TI - [Clinical Significance of the Serum EPO Level in Patients with Iron Deficiency Anemia]. AB - OBJECTIVE: To investigate the expression level of erythropoietin (EPO) and ferritin before and after treatment of patients with iron deficiency anemia (IDA) so as to explore their clinical significance in diagnosis and discrimination. METHODS: The EPO and ferritin levels in serum of 37 patients with IDA were determined by using chemiluminescence analysis (CLIA method) and electrical chemiluminescence analysis (ECLIA method), 30 healthy people were randomly selected as normal controls. RESULTS: (1) the sEPO level in IDA patients of group before treatment, group treated for 1 month and group treated for 2 months was higher than that in normal control group (P < 0.05). The level of sEPO of IDA patients in different groups after treatment was lower than that in IDA patients of groups before treatment, along with improvement of anemia status, the level of EPO was gradually reduced, and the level of sEPO in patients of group treated for 3 months was not statistical significant in comparison with that in normal control (P > 0.05). The level of ferritin in IDA patients before and after treatment was lower than that in normal control group (P < 0.05). The level of ferritin in IDA patient of groups after treatment was all higher than that in patients of groups before treatment, but comparision of serum ferritin level in patients of groups after treatment did not show statistical significance. (2) The level of logEPO in IDA patient before and after treatment was negatively related with level of Hb, but the level of ferritin in IDA patients was positively related with the level of Hb before treatment (r = 0.449, P = 0.005), the level of ferritin in patients of different group after treatment and in normal group did not related with level of HB. (3) The level of serum EPO in patients of severe anemia group was obviously higher than that in patients of moderate and mild anemia groups, and along with aggravation of anemia, the EPO level was gradually arised. CONCLUSION: The serum EPO is involved in the process of erythrocyte hematopoiesis, and can indicate the level of anemia, its sensitivity for anemia is higher than that of ferritin, and has important clinical value for evaluating status of diseases, observing therapeutic efficacy and judging prognosisi of IDA. PMID- 26524049 TI - [Establishment of Integration-Free Human Induced Pluripotent Stem Cells from A Patient with Primary Myelofibrosis]. AB - OBJECTIVE: To establish the primary myelofibrosis (PMF)-induced pluripotent stem cell line (iPSC) by means of iPSC techinique so as to provide a experimental model for studying the blood disease mechanisms. METHODS: Induced pluripotent stem cells were generated from mononuclear cells isolated from a PMF patient with JAK2(V617F) mutation by using episomal vectors. RESULTS: PMF-derived iPSC was established from the patient with JAK2(V617F) gene mutation. The PMF-iPSC could be stably passaged, highly expressed pluripotent genes as human embryonic stem (ES) cells, and were able to form teratoma in NOD/SCID mice in vivo. H & E staining of the teratoma showed the presence of tissue type derived from all three embryonic germ layers. Sanger sequencing confirmed that PMF-derived iPSC carried different allele burdens of JAK2(V617F) gene mutation. CONCLUSION: The interation-free iPSC from primary myelofibrosis patient in vitro has been established. This PMF-derived iPSC line provides a valuable tool for studying the pathogenesis, screening of chimical drugs and realizing the standard therapy of PMF. PMID- 26524050 TI - [Silymarin Protects Umbilical Cord-Derived Mesenchymal Stem Cells against Apoptosis Induced by Serum-Deprivation]. AB - OBJECTIVE: To investigate the protection of silymarin against the human mesenchymal stem cell (MSC) apoptosis induced by serum deprivation and its underlying mechanism. METHODS: Human umbilical cord MSCs were cultured in the absence of serum, and the silymain of different concentration (1-10 ug/ml) was added into the medium. MTT test was performed to observe the cell proliferation status. After being cultured for 72 hours, the cells were collected, and flow cytometry with Annexin-V-PI double-staining was used to detect the apoptotic cells from the control and silymarin-treated groups. Furthermore, the intracellular contents of BAX and BCL-2 were detected by Western blot for exploring the potential mechanism. RESULTS: The silymarin promoted the proliferation of human UC-MSCs in a dose-dependent manner, reaching its maximal at a dose of 5 ug/ml. Moreover, silymarin could inhibit the serum deprivation induced apoptosis of MSCs and, the inhibitory rate reached up to 30% when it was added at a concentration of 5 ug/ml. The content of intracellular BAX was obviously elevated after serum-deprivation treatment, and this increase could be blunted by the addition of silymarin. Meanwhile, the content of BCL-2 was not obviously changed. CONCLUSION: The silymarin can stimulate MSC growth and inhibit the apoptosis of MSCs probably by the mitochondria pathway. PMID- 26524051 TI - [Mobilization Effect of HS6101 on Hematopoietic Cells of Mice]. AB - OBJECTIVE: This study was aimed to investigate the mobilization effect of HS6101 on hematopoietic cells of mice. METHODS: The normal ICR mice were injected subcutaneously once or twice with HS6101 at 9 ug/d/mouse, or a single dose of HS6101 3, 9, 27 and 81 ug/mouse was administrated, and the mobilization effect of HS6101 in different administration times and different dosage was observed, and compared with the synergistic effects of administration of single dose of HS6101 combined with rhG-CSF (2 ug/d/mouse was injected subcutaneously for 5 consecutive days). The peripheral blood cell counts of mice were detected at different time after administration. The hematopoietic stem/progenitor cells of bone marrow and peripheral blood were detected at day 5 and 10 after administration. RESULTS: There was no significant difference in peripheral blood cell counts after once or twice injections of HS6101 9 ug/mouse. The peripheral platelet counts dose dependently increased in ICR mice, which accounted for 121.1% to 118.0%, 138.7% to 123.1%, 146.4% to 139.2%, and 156.2% to 168.7% (P < 0.001) after HS6101 (3, 9, 27 and 81 ug/mouse) treatments at 5 and 7 d, respectively. HS6101 (3, 9, 27 and 81 ug/mouse) showed dose-response relationship to platelets, with R value of 0.777 and 0.954 at day 5 and 7 after administration, respectively. HS6101 significantly increased numbers of hematopoietic stem/progenitor cells in both bone marrow and peripheral blood, and elevated peripheral blood leukocytes at 27 ug/mouse dose at day 5 after administration. CONCLUSION: HS6101 has significant mobilization effect on hematopoietic stem/progenitor cells, platelets and leukocytes in mouse. PMID- 26524052 TI - [Expression of Hydrodynamic Injection-mediated PD-L1 in Myeloablative Conditioning Mouse Model]. AB - OBJECTIVE: To establish the mouse model for the expression of PD-L1 by hydrodynamic injection and to study the effects of myeloablative conditioning on hydrodynamic injection-mediated PD-L1 expression. METHODS: Plasmid amplification, hydrodynamic injection, collagenase perfusion, real time PCR, ELISA and flow cytometry were applied to test the expression and function of PD-L1. Also, animal models were set up to test the effects of chemical or radiactive myeloablative conditioning on hydrodynamic injection-mediated PD-L1 expression. RESULTS: The expression of PD-L1 mRNA and protein could be detected as early as 8 h after hyrodynamic injection and reached peak expression by 24 h, and returned to baseline level by 7 d after injection. Serum PD-L1 level reached to 100 ug/ml as early as 24 h after injection and plateaued at 7 d after injection. Serum PD-L1 persisted for 3 weeks and declined to baseline after 1 month of hydrodynamic injection. The PD-L1 function induced by hydrodynamic injection was consistent with literature reports. At each time point, the PD-L1 expression was not different significantly between the myeloablative conditioning group and control group; the mice transfected with PD-L1 showed a higher survival rate than that in control group. CONCLUSION: Myeloablative conditioning does not affect hydrodynamic injection-mediated PD-L1 expression, indicating that the PD-L1 can be used in HSCT mouse model. PMID- 26524053 TI - [Clinical Analysis of Cytomegalovirus Infection after Different Patterns of Hematopoietic Stem Cell Transplantation]. AB - OBJECTIVE: To investigate the clinical difference of cytomegalovirus (CMV) infection between HLA-matched allogeneic hematopoietic stem cell transplantation (allo-HSCT) and haploidentical hematopoietic stem cell transplantation (hi-HSCT). METHODS: The clinical data of 83 patients who had undergone allo-HSCT were retrospectively analyzed. Out of them 50 patients underwent hi-HSCT and 33 patients received grafts from HLA-matched donors. The sera of all recipients and donors were CMV-negative before transplantation. All patients accepted myeloablative regimen without total body irradiation. PCR was performed to detect CMV in the peripheral blood twice a week after neutrophil recovery. CMV-DNA>500 copies/ml was defined as CMV viremia. RESULTS: 68 patients (81.9%) were diagnosed as CMV viremia before 100 days after transplantation. The incidence of CMV infection in hi-HSCT group was 90% and significantly higher than that in HLA matched HSCT group (69.7%) (P < 0.05). All the patients responded well to anti CMV therapy; however, 63 cases experienced CMV reactivation. The occurrence rate of CMV reactivation in hi-HSCT group (95.6%) was comparable to that in HLA matched HSCT group (87.0%) (P > 0.05). Univariate analysis showed that the transplantation pattern, the recovery time of peripheral neutrophils and the occurrence of acute graft-versus-host disease (aGVHD) significantly related to the episode of CMV viremia, while the sex and age of the recipients, and the recovery time of platelets did not associate with the incidence. Further analysis found that the recovery time of neutropils and platelets in HLA-matched HSCT group were greatly shorter than those in hi-HSCT group (P < 0.05). The incidence of aGVHD was comparable between two groups however, incidence of severe aGVHD was significantly higher in hi-HSCT (P < 0.05). CONCLUSION: The hi-HSCT is more susceptible to CMV infection, which may be related to the higher incidence of severe aGVHD and the relative delay of hematopoietic reconstruction as compared with HLA-matched HSCT. PMID- 26524054 TI - [Unrelated Donor Peripheral Blood Stem Cell Transplantation Combined with Umbilical Cord Mesenchymal Stem Cells in Patients with Hematologic Malignancies]. AB - OBJECTIVE: To explore the safety and efficiency of unrelated donor peripheral blood stem cells (URD-PBSC) transplantation combined with umbilical cord mesenchymal stem cells (UC-MSC). METHODS: The clinical data of 49 patients received unrelated donor peripheral blood stem cells transplantation (URD-PBSCT) for treating hematologic malignancies were retrospectively evaluated, including 12 ANLL, 17 ALL, 18 CML and 2 MDS. Out of them, 22 patients received the URD PBSCT combined with UC-MSC and 27 patients received only URD-PBSCT. The average number of infusing UC-MSC was 1.0 * 106/kg in the UC-MSC+URD-PBSCT group. RESULTS: As compared with URD-PBSCT group, in UC-MSC+URD-PBSCT group the median recovery time of neutrophilc granulocytes was shorter (12 d vs 15 d) (P = 0.041), the incidence and severity of chronic graft versus host disease (cGVHD) were lower (20.0% vs 51.9%) (P = 0.026) (5.0% vs 33.3%) (P = 0.040), the incidence of CMV infection after transplantation was higher (81.8% vs 51.9%) (P = 0.028). In addition to these, the differences were not statistically significant in term of implantation level, PLT reconstitution, aGVHD, lung infection, hemorrhagic cystitis, 1-year relapse and survival between the 2 groups (P > 0.05). CONCLUSION: The transplantation of URD-PBSC combined with UC-MSC is effective and safe. The speed of neutrophils reconstitution is faster. The incidence and severity of cGVHD are lower, but the attention should be paid to prevent the CMV infection. PMID- 26524055 TI - [Establishment and Applications of Double-Fluorescent Protein Allo Transplantation Mice Model]. AB - OBJECTIVE: To establish allo-transplantation model by using mRFP+ to eGFP+ transgenic mice and to observe the distribution of donor cells and donor recipient cellular interaction in the bone marrow after semi-solid decalcification (SSD). METHODS: After myeloablative irradiation, C57BL/6 female eGFP+ transgenic mice were infused with (5 * 106) bone marrow cells from FVB male donor mice through tail vein. The control group was infused with PBS. Then the general conditions, engraftment level, hematopoietic recovery, incidence of GVHD and survival of recipients were evaluated after transplantation. In the recovery process, SSD was used to treat the femora before observing the cells distribution, morphology and interaction by confocal microscopy directly or after making frozen section. RESULTS: WBC of recipient eGFP+ mice was recovered on (20 +/- 3.07) d, (93.94 +/- 1.59)% in peripheral cells were RFP+ cells (n = 10), GVHD happened in 4 of 10 mice within 1 month. During SSD, the hard components were replaced gradually and RFP+ cells could be seen mainly in the bone trabecula and surrounded by eGFP+ cells under confocal microscope, their interactions could be further observed clearly in bone marrow microenvironment in three-dimensional reconstruction. CONCLUSION: The double fluorescent allo-transplantation mouse model successfully established, by means of our novel protocol named SSD, the donor and recipient cell location and their interaction can be visually observed, which provides the basis for clinical studies on the distribution and homing of donor cells, and some related explorations after transplantation. PMID- 26524056 TI - [Identification of A Novel HLA Allele DRB1 * 16:36 by Sequencing-Based Typing]. AB - OBJECTIVE: To identify a novel HLA allele DRB1 * 16:36 from a Uygur woman. METHODS: PCR-SBT technology was applied to the extracted DNA for genotyping, and a possible new gene was sequenced by using sequence specific primers and single stranded SBT. This novel allele was compared with known most homologous gene sequences and their difference was analyzed. RESULTS: This novel allele was different from HLA alle DRB1 * 16:23, and had highest similarity in 2 nucleotides at position 227 A->T and 236 T->C in exon 2, resulting in 3 amino acid changes from Tyr to Phe at codon 47 and Val to Ala at codon 50. The sequence of this novel allele had been submitted to GenBank. CONCLUSION: This HLA allele DRB1 * 16:23 has been confirmed to be a novel allele, and has been officially named DRB1 * 16:36 by the World Health Organization (WHO) Nomenclature Committee in May 2015. PMID- 26524057 TI - [Arginase Level in Suspended Red Blood Cells Storaged for Different Time]. AB - OBJECTIVE: To explore the effect of storage time on arginase level, and the possible source of arginase in suspended red blood cells (RBC). METHODS: The arginase and myeloperoxidase (MPO) levels in suspended RBC and control plasma were detected by ELISA. The free hemoglobin level in suspended RBC and control plasma were detected by colorimetric method. The relationship between arginase level, MPO level and free hemoglobin level in suspended RBC was analyzed by the related methods. RESULTS: The arginase and free hemoglobin levels in suspended RBC were higher than those in control plasma. Otherwise, MPO level was not significantly different between suspended RBC and control plasma. All of them did not increase along with prolonging of storage time. There was not a significant correlation between arginase level and free hemoglobin level in suspended RBC of different storage time (r = 0.03), but arginase level positively correlated with MPO level in the suspended RBC of different storage time (r = 0.76). CONCLUSION: The arginase level in suspended RBC storaged for different time increases significantly, but not along with prolonging of storage time. The main possible source of arginase in the suspended RBC is the residual white blood cell, especially neutrophils. PMID- 26524058 TI - [A PKLR Gene Novel Complex Mutation in Erythrocyte Pyruvate Kinase Deficiency Detected by Targeted Sequence Capture and Next Generation Sequencing]. AB - OBJECTIVE: To explore the molecular mechanism of erythrocyte pyruvate kinase deficiency (PKD). METHODS: Targeted sequence capture and next-generation sequencing (NGS) were used to detect the regions of exon and exon-intron boundarie of PKLR gene in a clinical suspected PKD patient. The protein function of mutant gene was forecasted by the SIFT and PolyPhen-2 databank, after the mutation of PKLR gene in the patient was detected by the NGS technology, its genotype was confirmed by Sanger sequencing. RESULTS: The patient was found to have peculiar double heterozygous mutations: 661 G>A (Asp221Asn) of exon 5 and 1528 C>T (Arg510Ter) of exon 10, resulting in amino acid substitution Asp221Asn and Arg510Ter, these mutations were also further confirmed by Sanger sequencing. The complex mutations were infrequent and each of them was able to cause diseases. CONCLUSION: The complex mutations of both 661 G>A and 1528 C>T of PKLR gene are the molecular mechanism of PKD. Simultaneous existance of above mentioned complex mutations in PDK patient was never been previously reported at home and abroad. PMID- 26524059 TI - [Frequency of HLA-Cw and Its Corresponding Killer Cell Immunoglobulin-like Receptors (KIR) among Blood Donors in Chinese Nanjing Han Ethnic Group]. AB - OBJECTIVE: To investigate the frequency of HLA-Cw and its KIR2D genotypes in Han blood donor population in Chinese Nanjing area and to analyze the match and distinguish modes of them so as to provide the basis for further studying their roles in incidence and development of disease. METHODS: The PCR-SSP was used to genotyping of HLA-Cw and KIR2D for 241 Han blood donors in Jiangsu Provincial blood center; according to distingush modes of HLA-Cw and KIR2D genes, the distingushed results of HLA-Cw and corresponding activating or inhibitory KIR2D receptors of individuals were analyzed. RESULTS: The frequency of HLA-C1 expression in donor population of Nanjing area was 76.35% which was much higher than that of HLA-C2 expression (23.65%); the expression C1/C2 alleles was accorded with Handy-weinberg balance. The expression frequencies of 5 KIR2Ds (L1, L2, L3, S1 and S2) matched to HLA-Cw were 97.93%, 29.05%, 98.34%, 29.05% and 21.16%, respectively. The match of HLA-C1/C2 to 2DL1+/2DL2-/2DL3+/2DS1-/2DS2- was predominated (75/241). Couclusion: The polymorphism data of HLA-Cw and 5 KIR2Ds from blood donors in Chinese Nanjing area has been provided in this study. The match analysis found that the expression of inhibitory HLA-Cw-KIR is higher than that of activated HLA-Cw-KIR, suggesting that the HLA-Cw/KIR2D combination is characterized by preponderance of inhibitory signal pathway. PMID- 26524061 TI - [Effect of 25 Gy (60)Co Irradiation on the Physico-chemical Property and Functions of the Platelets During Storage]. AB - OBJECTIVE: To evaluate the effects of the 25 Gy 60Co irradiation on the physiological and biochemical properties and the functions of the platelets during storage. METHODS: A total of 15 bags of platelets were apheresis-collected from 15 healthy donors, and each bag of platelets were divided into 2 parts, then the platelets were divided into the control group (without 25 Gy 60Co irradiation) and the irradiated group (with 25 Gy 60Co irradiation) groups. The two groups of platelets were kept under the condition of (22 +/- 2) degrees C and shaken. The Platelet count and pH value were detected on the d 1, d 2, d 3, d 4 and d 5. The variables such as R, K values, alpha angle and maximal amplitude (MA) were measured by thrombelastography on the same days. Hypotonic shock response (HSR), morphological score were devised. RESULTS: There were no statistically significant difference in Plt counts, mean platelet volume (MPV), platelet distribute width (PDW) and pH between the two groups (P > 0.05), and Plt count decreased on the end of storage. There were no marked changes in HSR level and morphological score between the two groups during storage, and there were no significant difference between the two groups (P > 0.05). In the TEG analysis there were no significant difference of the R, K, alpha angle and MA values between the two groups (P > 0.05). R value showed upward trend increased along with prolongation of preserved time (P < 0.01), no significant changes in alpha angle (P > 0.05), K value was slightly higher and MA value was lower in the last day of storage than the days 1-4 (P < 0.01), respectively. CONCLUSION: 25 Gy 60Co gamma-ray irradiation can not damage the physiological, biochemical properties and the functions of the platelets during storage. In order to ensure the best curative effect, it is suggested that no matter the platelets were irradiated or not, the platelets should be used as soon as possible. PMID- 26524060 TI - [A Survey for Colton and Other 3 Rare Blood Group Systems in Chinese Nanjing Han Population]. AB - OBJECTIVE: To investigate the distribution of Colton, Diego, Kell and Yt rare blood groups in Chinese Nanjing Han population, so as to improve the transfusion capability of patients with rare blood group and to further enrich the rare-blood donor bank. METHODS: A total of 2 015 blood samples from the blood donors were selected randomly to screen the presence of K+ and Kp(c+) (Kell), Yt(b+) (Yt), Co(b+) (Colton), Di(a+b+) and Di(a+b-) (Digeo) antigen allele by using PCR and multiplex PCR. RESULTS: Out of 2005 samples, 1 case with K+ gene, 8 cases with Yt(b+) gene and 100 cases with Di(a+b+) gene, 2 cases with Di(a+b-) were identified, while no Kp(c+) and Co(b+) were detected. CONCLUSION: The frequencies of K+, Yt(b+) and Di(a+), Di(b+) are 0.0003, 0.0013 and 0.0258, 0.9742, respectively. They are very rare blood groups in Chinese Nanjing Han population. PMID- 26524062 TI - [Epidemiologic Survey of Blood Donors with HBsAg-/HBV DNA+ in Chinese Xiamen Area]. AB - OBJECTIVE: To understand the characteristics of infections from blood donors with HBsAg-/HBV DNA+ in Xiamen area. METHODS: Donors in Xiamen area were assayed by routine ELISA and those with negative results were tested by nucleic acid amplification testing (NAT). HBsAg-/HBV DNA+ samples were tested by quantitative detection of HBV DNA. Epidemiological analysis and following up examination were conducted in HBsAg-/HBV DNA+ donors. RESULTS: Out of 130659 samples 113 were tested as HBsAg-/HBV DNA+ and with a rate of 0.09%. Among those, 62 samples were tested by quantitative detection of HBV DNA. All of the quantitative results were less than 1 * 103 IU/ml and 93.5% (58/62) of which were less than 100 IU/ml. The possitive rate of HBsAg-/HBV DNA+ donors rose with ages. The possitive rate in male donors was higher than that in female and was lower in highly educated ones. Students and public servants had a lower positive rate. CONCLUSION: The possitive rate of HBsAg-/HBV DNA+ donors is higher in Xiamen and the distribution of possitive donors has certain epidemiological characteristics. It is necessary to mobilize and recruit more people with a lower rate of HBsAg-/HBV DNA+ infection. PMID- 26524063 TI - [Significance of Th1/Th17 Imbalance in Mice with Acute Graft-versus-Host Disease]. AB - OBJECTIVE: To investigate the effects of Th1/Th17 cell imbalance on the pathogenesis of acute graft-versus-host disease (GVHD) in mice. METHODS: In a murine GVHD model of C57BL/6 (H-2(b)), a low dose of halofuginone (HF) was applied for treating the recipients in order to result in Th1/Th17 imbalance. Rechipient mice were divided into GVHD group (without HF intervention) and GVHD plus HF group (treated by HF). The recipients were monitored for survival rate, clinical scores of acute GVHD, contents of circulatory Th1 and Th17 cells, Th1/Th17 ratio and serum level of IFN-gamma and IL-17A. Expression levels of IFN gamma and IL-17A in target organs were analyzed by using real-time PCR, and the target organs were delivered for histological examinations. RESULTS: Recipients treated with HF showed that all the mortality, circulatory Th1/Th17 ratio and clinical score were higher than those in the mice without HF intervention (P < 0.05). Circulatory Th1/Th17 ratio positively correlates with clinical score (P < 0.001). HF administration reduces the expression level of intestinal IL-17A and increases intrahepatic and intestinal IFN-gamma level (P < 0.05), HF treatment aggravates GVHD in liver and small intestine with augmented hepatic and intestinal inflammation. CONCLUSION: Th1/Th17 imbalance contributes to the pathogenesis of acute GVHD. PMID- 26524064 TI - [Effects of Different Dose of Cyclophosphamide on Peripheral Blood Cells of Normal ICR Mice]. AB - OBJECTIVE: To investigate effective doses of cyclophosphamide (CTX) for establishment of leukopenia model in ICR mouse. METHODS: Normal ICR mice (n = 96) were divided into CTX(80), CTX(100), CTX(120), CTX(150) and CTX(300) groups, of which mice received CTX intraperitoneally at a dose of 80, 100, 120, or 150 mg/kg once a day for 3 consecutive days, or 300 mg/kg with single injection. The peripheral blood cell counts were detected at various times before and after CTX administration. RESULTS: The peripheral white blood cell nadirs in the mice injected with CTX appeared on day 4 after the first dose of CTX. The peripheral white blood cell nadir in group CTX(100) was 26.7% of the value measured in mice before CTX administrated, and that of group CTX(80) was 35.0%. Higher doses of CTX, however, caused too severity in hematopoietic injury. CONCLUSION: The dose of CTX 100 mg/(kg.d) * 3d is appropriate for leucopenia model of ICR mouse. PMID- 26524065 TI - [Research Progress on Gene Expression Abnormality of Hematopoietic Stem/Progenitor Cells in Myelodysplastic Syndromes]. AB - Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal disease involving one or more series of hematopoietic cells. Its pathogenesis is still unclear. No effective targeted drug is available to prevent this disease progression. MDS originates in hematopoietic stem cells. Recent researches found that the complex abnormal gene expression occurred in bone marrow CD34+ cells plays a key role in development of MDS. Some of these genes are closely related with the patient's prognosis and survival, such as DLK1, ribosomal transcripts gene, Toll-like receptors gene, EPA-1 and interferon-stimulated genes. Due to heterogeneity of this disease, abnormal gene expression profiles in bone marrow CD34+ cells are closely associated with particular FAB or cytogenetic subtypes. To elucidate the pathogenesis of MDS and investigate its therapeutic target, this article reviews progress of researches on abnormal gene expression profiles of hematopoietic stem/progenitor cells in low-risk, high-risk patients and MDS patients who carry common cytogenetic abnormalities. PMID- 26524066 TI - [Abnormal Proliferation and Differentiation of Hematopoietic Cells in Myelodysplastic Syndrome Patients]. AB - Myelodysplastic Syndrome (MDS) is a group of clonal disorders of hematopoietic stem cells characterized by peripheral cytopenia, ineffective hematopoiesis, morphologically apparent multilineage dysplasia, and enhanced risk of evolution towards acute myeloid leukemia (AML). Most of the research findings have verified the abnormal proliferation and differentiation of hematopoietic cells in MDS. The defects of cellular and molecular factors such as transcription factors (GATA 1~GATA-3, FOG1, Pu.1), growth factors (Epo, G-CSF, GM-CSF) and anti-apoptosis genes ultimately affect the cell cycle regulation and mismatch repair of DNA, changes of hematopoietic microenvironment and immune response. These defects result in ineffective hematopoiesis and dysplasia. PMID- 26524067 TI - [Chromosomal Aberrations in Myelodysplastic Syndromes]. AB - Myelodysplastic syndromes (MDS) are a group of clonal hematopioetic disorders characterized by myelodysplasia, decreased peripheral blood cells and high-risk of transformation into acute leukemia. MDS are often accompanied by a variety of chromosomal aberrations which play a role in disease pathogenesis, and are crucial in diagnosis and prognostic evaluation of this disease. About half of the patients with MDS have chromosomal abnormalities, mainly unbalanced chromosomal aberration. Different chromosomal aberration types are associated with different clinical outcome of this disease. Though balanced chromosomal translocations are not common in MDS, it seems that the patients with them have a higher leukemia transformation rate than those with other type of chromosomal aberrations. In this review, the chromosomal aberrations in MDS and their clinical significance for diagnosis and prognosis are briefly summarized. PMID- 26524068 TI - [Molecular Mechanism and Malignant Clonal Evolution of Multiple Myeloma]. AB - Almost all patients with multiple myeloma (MM) have chromosomal translocation which can result in genetic variation. There are mainly five types of chromosomal translocations, involving the IGH gene translocation to 11q13 (CCND1), 4p16 (FGFR/MMSET), 16q23 (MAF), 6p21 (CCND3) and 20q11 (MAFB). It is possible that all IGH translocations converge on a common cell cycle signal pathway. Some MM develops through a multistep transformation from monoclonal gammopathy of undetermined significance (MGUS) to smoldering MM (SMM) and eventually to MM and plasma cell leukemia (PCL). Similarly to what Darwin proposed in the mid-19th century-random genetic variation and natural selection in the context of limited resources, MM clonal evolution follow branching and nonlinear mode. The failure of MM treatment is usually related with the minimal subclone which is hardly found at newlydiagnosed. PMID- 26524069 TI - [Research Progress on Expression and Function of P2 Purinergic Receptor in Blood Cells]. AB - Nucleotides have unambiguously emerged as a family of mediators of intercellular communication, which bind a class of plasma membrane receptors, P2 purinergic receptors, to trigger intercellular signaling. P2 receptors can be further divided into two structurally and functionally different sub-famlies, the P2X and P2Y receptors. Different blood cells express diverse spectrum of P2 receptors at different levels. Extracellular adenosine triphosphate (ATP) exerts different effects on blood cells, regulating cell proliferation, differentiation, migration, chemotaxis, release of cytokines or lysosomal constituents, and generation of reactive oxygen or nitrogen species. The relationship between abnormal P2 receptors and human diseases attracts more and more attention. This review briefly discusses the expression and function of P2 receptors in hematopoietic system. PMID- 26524070 TI - [Research Progress on Muscle-derived Stem Cells Capable of Hematopoiesis]. AB - Muscle-derived stem cells (MDSC) are defined as myogenic stem cells endowed with their ability to self-renew and differentiate into multiple cell types of their derivative tissue, and are proved to be over 10 times more efficient in hematopoiesis than hematopoietic stem cells (HSC). Although the mechanism which MDSC differentiate into blood cells is still unclear, MDSC were considered to replace HSC to treat the patients suffering from bone marrow diseases such as aplastic anemia and tumor. MDSC are different from HSC in a variety aspects like biological characteristics, protein expression and cell proliferation. On the other hand, MDSC contain multiple distinct stem cell populations. Among these, there is only a small part with the ability to repopulate hematopoietic cells, and it is still uncertain whether their origin is same as HSC. This review summarizes the difference between MDSC and HSC, the ability of MDSC to repopulate hematopoietic cells, and the prospect of MDSCs' transplantation. PMID- 26524071 TI - [Abnormal Karyotypes Involving 1q21 and 12p13 and Their Clinical Significance]. AB - Many hematological malignances involve recurrent chromosomal abnormalities, and the reciprocal translocation is one of them. However, there are a lot of chromosomal abnormalities with lower incidence and unclear clinical significance. Among them, the one abnormal karyotype translocation, t (1;12) (q21; p13) is a rare karyotype change. Only 6 patients had been reported to have this karyotype and all of them suffered from hematologic diseases, including one case of acute myeloid leukemia, one case of high-risk myelodysplastic syndrome, two children with acute lymphoblastic leukemia, one case of chronic myeloid leukemia at accelerated phase and one case of multiple myeloma. Among them, the fusion gene were detectable in two cases. In this article, the common chromoscme karyotype abnormality involving 1q21 and 12p13, and genes involving in these regious are summarized, moreover the reported cases of t(1;12) (q21;p13) are reviewed. PMID- 26524072 TI - [Relationship between Calreticulin Gene Mutation and JAK2/MPL Negative Myeloproliferative Neoplasms]. AB - In 2008, WHO made the JAK2V617F gene mutation as one of the specific molecular diagnostic markers of BCR/ABL-negative myeloproliferative neoplasms (MPN). In 2013 two research teams demonstrated that whole genome sequencing technology (WGS) was used to detect calreticulin gene mutation in essential thrombocythaemia (ET) and primary myelofibrosis (PMF) patients with JAK2V617F- and MPL- mutations. In this review, the relationship of CALR gene mutation with MPN is briefly summarized. PMID- 26524073 TI - Simple Detection Methods for Antinutritive Factor beta-ODAP Present in Lathyrus sativus L. by High Pressure Liquid Chromatography and Thin Layer Chromatography. AB - Lathyrus sativus L. (Grass pea) is the source for cheap and nutritious food choice in drought and famine susceptible zones in greater part of North India and Africa. The non-protein amino acid beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (beta-ODAP) has been known for decades for its potent neurotoxic effect, causing irreversible neurodegenerative disease "neurolathyrism", present in both seed and leaf of Lathyrus sativus L. and other species in varying proportions. It is crucial to establish a rapid as well as reliable detection methodology for beta-ODAP content in various Lathyrus plants. Currently available HPLC based methods involve multi-step derivatization of the sample. To overcome this, we have developed beta-ODAP analysis method by HPLC without any prior derivatization. This method is statistically significant in the range of 2 to 100MUg/ml and exhibited linear response with r2 > 0.99. Limit of detection and quantitation of the later method was determined to be 5.56 MUg/ml and 16.86 MUg/ml, respectively. In addition to this, a TLC based method has also been developed. The limit of detection of beta-ODAP is 0.6MUg and for its substrate, L 1,2-diaminopropionic acid is 5MUg. Both HPLC and TLC methods were validated by conducting in-vitro bioconversion test to detect the presence of biocatalyst in plant extract. This method is economical, rapid and simple. PMID- 26524074 TI - Endovascular Stroke Treatment Outcomes After Patient Selection Based on Magnetic Resonance Imaging and Clinical Criteria. AB - IMPORTANCE: Which imaging modality is optimal to select patients for endovascular stroke treatment remains unclear. OBJECTIVE: To evaluate the effectiveness of specific magnetic resonance imaging (MRI) and clinical criteria in the selection of patients with acute ischemic stroke for thrombectomy. DESIGN, SETTING, AND PARTICIPANTS: In this observational, single-center, prospective cohort study, we studied 72 patients with middle cerebral artery or terminal internal carotid artery occlusion using computed tomographic angiography, followed by core infarct volume determination by diffusion weighted MRI, who underwent thrombectomy after meeting institutional criteria from January 1, 2012, through December 31, 2014. In this period, 31 patients with similar ischemic strokes underwent endovascular treatment without MRI and are categorized as computed tomography only and considered in a secondary analysis. INTERVENTIONS: Patients were prospectively classified as likely to benefit (LTB) or uncertain to benefit (UTB) using diffusion-weighted imaging lesion volume and clinical criteria (age, National Institutes of Health Stroke Scale score, time from onset, baseline modified Rankin Scale [mRS] score, life expectancy). MAIN OUTCOMES AND MEASURES: The 90 day mRS score, with favorable defined as a 90-day mRS score of 2 or less. RESULTS: Forty patients were prospectively classified as LTB and 32 as UTB. Reperfusion (71 of 103 patients) and prospective categorization as LTB (40 of 103 patients) were associated with favorable outcomes (P < .001 and P < .005, respectively). Successful reperfusion positively affected the distribution of mRS scores of the LTB cohort (P < .001). Reperfusion was achieved in 27 LTB patients (67.5%) and 24 UTB patients (75.0%) (P = .86). Favorable outcomes were obtained in 21 (52.5%) and 8 (25.0%) of LTB and UTB patients who were treated, respectively (P = .02). Favorable outcomes were observed in 20 of the 27 LTB patients (74.1%) who had successful reperfusion compared with 8 of the 24 UTB patients (33.3%) who had successful reperfusion (P = .004). The ratio of treated to screened patients was 1:3. CONCLUSIONS AND RELEVANCE: Prospective classification as LTB by MRI and clinical criteria is associated with likelihood of favorable outcome after thrombectomy, particularly if reperfusion is successful. Selection of patients using MRI compares favorably with selection using computed tomographic techniques with the distinction that a higher proportion of screened patients were treated. PMID- 26524076 TI - Multi-center covalency: revisiting the nature of anion-pi interactions. AB - Exploring the nature of anion-pi bonding by means of the Quantum Theory of Atoms in Molecules (QTAIM) and an energy decomposition scheme on the basis of Interacting Quantum Atoms (IQA) theory led us to conclude that these non classical interactions benefit from "multi-center covalency" far more than from the electrostatics. Comparing anion-pi systems to closely related covalent anion sigma complexes reveals that the anion-pi systems benefit from an extensive degree of electron sharing between the anions and all atoms of the pi-rings. Besides, decomposition of the binding energy into classical (electrostatics) and non-classical (exchange-correlation) components demonstrates that in contrast to previous reports, the anion-pi complexes are local minima, if and only if the non classical contribution to binding energy surpasses that of the electrostatics. This suggests that the stable anion-pi complexes with the anions atop the pi rings might be prepared with pi-systems that benefit more from the exchange correlation term, such as extended pi-systems, but not with strong electrostatic pi-receptors. This conclusion is in line with the tendency of strong pi-acids to form the sigma-complexes with more covalent character instead of the pi complexes. PMID- 26524075 TI - Ventilator-Associated Events in Neonates and Children--A New Paradigm. AB - OBJECTIVES: To identify a pediatric ventilator-associated condition definition for use in neonates and children by exploring whether potential ventilator associated condition definitions identify patients with worse outcomes. DESIGN: Retrospective cohort study and a matched cohort analysis. SETTING: Pediatric, cardiac, and neonatal ICUs in five U.S. hospitals. PATIENTS: Children 18 years old or younger ventilated for at least 1 day. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated the evidence of worsening oxygenation via a range of thresholds for increases in daily minimum fraction of inspired oxygen (by 0.20, 0.25, and 0.30) and daily minimum mean airway pressure (by 4, 5, 6, and 7 cm H2O). We required worsening oxygenation be sustained for at least 2 days after at least 2 days of stability. We matched patients with a ventilator-associated condition to those without and used Cox proportional hazard models with frailties to examine associations with hospital mortality, hospital and ICU length of stay, and duration of ventilation. The cohort included 8,862 children with 10,209 hospitalizations and 77,751 ventilator days. For the fraction of inspired oxygen 0.25/mean airway pressure 4 definition (i.e., increase in minimum daily fraction of inspired oxygen by 0.25 or mean airway pressure by 4), rates ranged from 2.9 to 3.2 per 1,000 ventilator days depending on ICU type; the fraction of inspired oxygen 0.30/mean airway pressure 7 definition yielded ventilator-associated condition rates of 1.1-1.3 per 1,000 ventilator days. All definitions were significantly associated with greater risk of hospital death, with hazard ratios ranging from 1.6 (95% CI, 0.7-3.4) to 6.8 (2.9-16.0), depending on thresholds and ICU type. Each definition was associated with prolonged hospitalization, time in ICU, and duration of ventilation, among survivors. The advisory board of the study proposed using the fraction of inspired oxygen 0.25/mean airway pressure 4 thresholds to identify pediatric ventilator-associated conditions in ICUs. CONCLUSIONS: Pediatric patients with ventilator-associated conditions are at substantially higher risk for mortality and morbidity across ICUs, regardless of thresholds used. Next steps include identification of risk factors, etiologies, and preventative measures for pediatric ventilator-associated conditions. PMID- 26524078 TI - Correlating Microstructural Lithium Metal Growth with Electrolyte Salt Depletion in Lithium Batteries Using 7Li MRI. AB - Lithium dendrite growth in lithium ion and lithium rechargeable batteries is associated with severe safety concerns. To overcome these problems, a fundamental understanding of the growth mechanism of dendrites under working conditions is needed. In this work, in situ (7)Li magnetic resonance (MRI) is performed on both the electrolyte and lithium metal electrodes in symmetric lithium cells, allowing the behavior of the electrolyte concentration gradient to be studied and correlated with the type and rate of microstructure growth on the Li metal electrode. For this purpose, chemical shift (CS) imaging of the metal electrodes is a particularly sensitive diagnostic method, enabling a clear distinction to be made between different types of microstructural growth occurring at the electrode surface and the eventual dendrite growth between the electrodes. The CS imaging shows that mossy types of microstructure grow close to the surface of the anode from the beginning of charge in every cell studied, while dendritic growth is triggered much later. Simple metrics have been developed to interpret the MRI data sets and to compare results from a series of cells charged at different current densities. The results show that at high charge rates, there is a strong correlation between the onset time of dendrite growth and the local depletion of the electrolyte at the surface of the electrode observed both experimentally and predicted theoretical (via the Sand's time model). A separate mechanism of dendrite growth is observed at low currents, which is not governed by salt depletion in the bulk liquid electrolyte. The MRI approach presented here allows the rate and nature of a process that occurs in the solid electrode to be correlated with the concentrations of components in the electrolyte. PMID- 26524077 TI - Quality of Life, Emotional Wellbeing and Family Repercussions in Dermatological Patients Experiencing Chronic Itching: A Pilot Study. AB - A better understanding of the psychosocial impact of chronic itching could lead to improved intervention strategies. The aim of this study is to examine the prevalence and characteristics of chronic itching in dermatological patients. The Itch Severity Scale (ISS) was completed by a sample of 201 patients from a Dermatology Outpatient Clinic in Spain and 61.69% (n = 124) of participants recorded a positive score (X = 8.89, DT = 4.06). The results indicate that chronic itching has significant psychosocial repercussions. The Dermatology Life Quality Index (DLQI) showed that the negative impact on quality of life was significantly greater for the group that experienced chronic itching (p < 0.001). Scores on the Anxiety and Depression Scale (HADS) revealed that the group with chronic itching had more symptoms associated with anxiety (p = 0.001). The Family APGAR found no statistically significant differences between the groups with regards to repercussions on the family dynamic. PMID- 26524079 TI - Association of Newborn Apgar Score With Maternal Admission to the Intensive Care Unit. PMID- 26524080 TI - High-yield halide-free synthesis of biocompatible Au nanoplates. AB - We communicate an unconventional synthesis of Au nanoplates with high yield and excellent reproducibility through polyvinylpyrrolidone (PVP)-assisted H2O2 reduction. Unlike the ones prepared using halide-based surfactants, the PVP capped Au nanoplates are found to afford fairly easy bio-functionalization, suggesting a vastly expanded spectrum of applications in bio-related fields. PMID- 26524081 TI - Pt-B System Revisited: Pt2B, a New Structure Type of Binary Borides. Ternary WAl12-Type Derivative Borides. AB - On the basis of a detailed study applying X-ray single-crystal and powder diffraction, differential scanning calorimetry, and scanning electron microscopy analysis, it was possible to resolve existing uncertainties in the Pt-rich section (>=65 atom % Pt) of the binary Pt-B phase diagram above 600 degrees C. The formation of a unique structure has been observed for Pt2B [X-ray single crystal data: space group C2/m, a = 1.62717(11) nm, b = 0.32788(2) nm, c = 0.44200(3) nm, beta = 104.401(4) degrees , RF2 = 0.030]. Within the homogeneity range of "Pt3B", X-ray powder diffraction phase analysis prompted two structural modifications as a function of temperature. The crystal structure of "hT-Pt3B" complies with the hitherto reported structure of anti-MoS2 [space group P63/mmc, a = 0.279377(2) nm, c = 1.04895(1) nm, RF = 0.075, RI = 0.090]. The structure of the new "[Formula: see text]T-Pt3B" is still unknown. The formation of previously reported Pt~4B has not been confirmed from binary samples. Exploration of the Pt rich section of the Pt-Cu-B system at 600 degrees C revealed a new ternary compound, Pt12CuB6-y [X-ray single-crystal data: space group Im3, a = 0.75790(2) nm, y = 3, RF2 = 0.0129], which exhibits the filled WAl12-type structure accommodating boron in the interstitial trigonal-prismatic site 12e. The isotypic platinum-aluminum-boride was synthesized and studied. The solubility of copper in binary platinum borides has been found to attain ~7 atom % Cu for Pt2B but to be insignificant for "[Formula: see text]T-Pt3B". The architecture of the new Pt2B structure combines puckered layers of boron-filled and empty [Pt6] octahedra (anti-CaCl2-type fragment) alternating along the x axis with a double layer of boron-semifilled [Pt6] trigonal prisms interbedded with a layer of empty tetrahedra and tetragonal pyramids (B-deficient alpha-T[Formula: see text]I fragment). Assuming boron vacancies ordering (space group R3), the Pt12CuB6-y structure exhibits serpentine-like columns of edge-connected boron-filled [Pt6] trigonal prisms running infinitely along the z axis and embedding the icosahedrally coordinated Cu atom. Pt2B, (Pt1-yCuy)2B (y = 0.045), and Pt12CuB6-y (y = 3) behave metallically, as revealed by temperature-dependent electrical resistivity measurements. PMID- 26524082 TI - Measuring Fast and Slow Enzyme Kinetics in Stationary Droplets. AB - We present a new microfluidic platform for the study of enzymtatic reactions using static droplets on demand. This allows us to monitor both fast and slow reactions with the same device and minute amounts of reagents. The droplets are produced and displaced using confinement gradients, which allows the experiments to be performed without having any mean flow of the external phase. Our device is used to produce six different pairs of drops, which are placed side by side in the same microfluidic chamber. A laser pulse is then used to trigger the fusion of each pair, thus initiating a chemcial reaction. Imaging is used to monitor the time evolution of enzymatic reactions. In the case of slow reactions, the reagents are completely mixed before any reaction is detected. This allows us to use standard Michaelis-Menten theory to analyze the time evolution. In the case of fast reactions, the time evolution takes place through a reaction-diffusion process, for which we develop a model that incorporates enzymatic reactions in the reaction terms. The theoretical predictions from this model are then compared to experiments in order to provide measurements of the chemical kinetics. The approach of producing droplets through confinement gradients and analyzing reactions within stationary drops provides an ultralow consumption platform. The physical principles are simple and robust, which suggests that the platform can be automated to reach large throughput analyses of enzymes. PMID- 26524083 TI - Sulfate Radical Anion (SO4(*-)) Mediated C(sp(3))-H Nitrogenation/Oxygenation in N-Aryl Benzylic Amines Expanded the Scope for the Synthesis of Benzamidine/Oxazine Heterocycles. AB - A transition-metal-free, K2S2O8-mediated intramolecular oxidative nitrogenation/oxygenation of C(sp(3))-H in N-aryl benzylic amines followed by oxidation at the benzylic center has been developed for the synthesis of benzamidine/benzoxazine heterocycles, providing an expedient access to quinazolin 4(3H)-ones, N-aryl-2-arylbenzimidazoles, and 4H-3,1-benzoxazin-4-ones. A considerable amount of work dealing with the mechanistic study to understand the crucial intramolecular cyclization step largely favors an iminium ion as the key intermediate. PMID- 26524085 TI - Differential Cross Sections and Product Rovibrational Distributions for (16)O + (32)O2 and (18)O + (36)O2 Collisions. AB - We report rotationally resolved opacity functions, product rotational distributions, and differential cross sections for the (16)O + (16)O(16)O (v = 0,j = 1) -> (16)O(16)O (v' = 0,j') + (16)O and (18)O + (18)O(18)O (v = 0,j = 1) > (18)O(18)O (v' = 0,j') + (18)O collisions calculated by a time-independent quantum mechanical method employing one of the latest potential energy surface of ozone [ Dawes ; et al. J. Chem. Phys. 2013 , 139 , 201103 ]. The results obtained for both collisional systems in the energy range 0.001-0.2 eV are examined, and interesting mass scaling effects have been discovered. The shapes of product angular distributions suggest a transition from an indirect to a direct scattering, via an osculating intermediate complex. PMID- 26524084 TI - Chenopodium ambrosioides L. Reduces Synovial Inflammation and Pain in Experimental Osteoarthritis. AB - The chronicity of osteoarthritis (OA), characterized by pain and inflammation in the joints, is linked to a glutamate receptor, N-methyl-D-aspartate (NMDA). The use of plant species such as Chenopodium ambrosioides L. (Amaranthaceae) as NMDA antagonists offers a promising perspective. This work aims to analyze the antinociceptive and anti-inflammatory responses of the crude hydroalcoholic extract (HCE) of C. ambrosioides leaves in an experimental OA model. Wistar rats were separated into six groups (n = 24): clean (C), negative control (CTL-), positive control (CTL+), HCE0.5, HCE5 and HCE50. The first group received no intervention. The other groups received an intra-articular injection of sodium monoiodoacetate (MIA) (8 mg/kg) on day 0. After six hours, they were orally treated with saline, Maxicam plus (meloxicam + chondroitin sulfate) and HCE at doses of 0.5 mg/kg, 5 mg/kg and 50 mg/kg, respectively. After three, seven and ten days, clinical evaluations were performed (knee diameter, mechanical allodynia, mechanical hyperalgesia and motor activity). On the tenth day, after euthanasia, synovial fluid and draining lymph node were collected for cellular quantification, and cartilage was collected for histopathological analysis. Finally, molecular docking was performed to evaluate the compatibility of ascaridole, a monoterpene found in HCE, with the NMDA receptor. After the third day, HCE reduced knee edema. HCE5 showed less cellular infiltrate in the cartilage and synovium and lower intensities of allodynia from the third day and of hyperalgesia from the seventh day up to the last treatment day. The HCE5 and HCE50 groups improved in forced walking. In relation to molecular docking, ascaridole showed NMDA receptor binding affinity. C. ambrosioides HCE was effective in the treatment of OA because it reduced synovial inflammation and behavioral changes due to pain. This effect may be related to the antagonistic effect of ascaridole on the NMDA receptor. PMID- 26524086 TI - Rapid, High-Resolution 3D Interference Printing of Multilevel Ultralong Nanochannel Arrays for High-Throughput Nanofluidic Transport. AB - 3D interference printing enables the single-step production of multilayered ultralong nanochannel arrays with nanoscale regularity. The superior depth-of focus of this technique realizes a state-of-the-art nanostructure which has intensively stacked 32 layers of inch-long, horizonontal nanochannels with sub 100 nm holes in a monolithic matrix (~15 MUm). This exceptional structure can be integrated into microfluidic devices, facilitating high-flux rheological platforms using nanocapillarity. PMID- 26524088 TI - Octreotide-Mediated Tumor-Targeted Drug Delivery via a Cleavable Doxorubicin Peptide Conjugate. AB - Although recent methods for targeted drug delivery have addressed many of the existing problems of cancer therapy associated with undesirable side effects, significant challenges remain that have to be met before they find significant clinical relevance. One such area is the delicate chemical bond that is applied to connect a cytotoxic drug with targeting moieties like antibodies or peptides. Here we describe a novel platform that can be utilized for the preparation of drug-carrier conjugates in a site-specific manner, which provides excellent versatility and enables triggered release inside cancer cells. Its key feature is a cleavable doxorubicin-octreotide bioconjugate that targets overexpressed somatostatin receptors on tumor cells, where the coupling between the two components was achieved through the first cleavable disulfide-intercalating linker. The tumor targeting ability and suppression of adrenocorticotropic hormone secretion in AtT-20 cells by both octreotide and the doxorubicin hybrid were determined via a specific radioimmunoassay. Both substances reduced the hormone secretion to a similar extent, which demonstrated that the tumor homing peptide is able to interact with the relevant cell surface receptors after the attachment of the drug. Effective drug release was quickly accomplished in the presence of the physiological reducing agent glutathione. We also demonstrate the relevance of this scaffold in biological context in cytotoxicity assays with pituitary, pancreatic, and breast cancer cell lines. PMID- 26524087 TI - Utilizing time-driven activity-based costing to understand the short- and long term costs of treating localized, low-risk prostate cancer. AB - BACKGROUND: Given the costs of delivering care for men with prostate cancer remain poorly described, this article reports the results of time-driven activity based costing (TDABC) for competing treatments of low-risk prostate cancer. METHODS: Process maps were developed for each phase of care from the initial urologic visit through 12 years of follow-up for robotic-assisted laparoscopic prostatectomy (RALP), cryotherapy, high-dose rate (HDR) and low-dose rate (LDR) brachytherapy, intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and active surveillance (AS). The last modality incorporated both traditional transrectal ultrasound (TRUS) biopsy and multiparametric-MRI/TRUS fusion biopsy. The costs of materials, equipment, personnel, and space were calculated per unit of time and based on the relative proportion of capacity used. TDABC for each treatment was defined as the sum of its resources. RESULTS: Substantial cost variation was observed at 5 years, with costs ranging from $7,298 for AS to $23,565 for IMRT, and they remained consistent through 12 years of follow-up. LDR brachytherapy ($8,978) was notably cheaper than HDR brachytherapy ($11,448), and SBRT ($11,665) was notably cheaper than IMRT, with the cost savings attributable to shorter procedure times and fewer visits required for treatment. Both equipment costs and an inpatient stay ($2,306) contributed to the high cost of RALP ($16,946). Cryotherapy ($11,215) was more costly than LDR brachytherapy, largely because of increased single-use equipment costs ($6,292 vs $1,921). AS reached cost equivalence with LDR brachytherapy after 7 years of follow-up. CONCLUSIONS: The use of TDABC is feasible for analyzing cancer services and provides insights into cost-reduction tactics in an era focused on emphasizing value. By detailing all steps from diagnosis and treatment through 12 years of follow-up for low-risk prostate cancer, this study has demonstrated significant cost variation between competing treatments. PMID- 26524089 TI - Industrial systems biology and its impact on synthetic biology of yeast cell factories. AB - Engineering industrial cell factories to effectively yield a desired product while dealing with industrially relevant stresses is usually the most challenging step in the development of industrial production of chemicals using microbial fermentation processes. Using synthetic biology tools, microbial cell factories such as Saccharomyces cerevisiae can be engineered to express synthetic pathways for the production of fuels, biopharmaceuticals, fragrances, and food flavors. However, directing fluxes through these synthetic pathways towards the desired product can be demanding due to complex regulation or poor gene expression. Systems biology, which applies computational tools and mathematical modeling to understand complex biological networks, can be used to guide synthetic biology design. Here, we present our perspective on how systems biology can impact synthetic biology towards the goal of developing improved yeast cell factories. Biotechnol. Bioeng. 2016;113: 1164-1170. (c) 2015 Wiley Periodicals, Inc. PMID- 26524090 TI - Revision Anterior Cruciate Ligament Reconstruction in Military Personnel. AB - This study aims to report the clinical and functional outcomes of revision anterior cruciate ligament (ACL) reconstruction in a young, active duty military population. Patients undergoing revision ACL reconstruction were enrolled in an institutional clinical database and followed prospectively. The primary outcomes were patients' scores on a timed run, as compared with recorded scores before reinjury. Secondary outcomes included scores on the Knee Injury and Osteoarthritis Outcome Score (KOOS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC), the International Knee Documentation Committee subjective (IKDC subjective), the Short Form - 36 health survey (SF-36) version 2, the Single Assessment Numeric Evaluation (SANE), and the Tegner activity scale. A total of 13 patients were identified who met the inclusion criteria and had complete follow-up. The mean age at revision ACL reconstruction was 20.5 years (range, 19-22 years), and mean follow-up was 40.2 months (range, 13-66 months). All patients underwent a single stage revision ACL reconstruction with ipsilateral bone-patellar tendon-bone autograft, ipsilateral hamstring autograft, or bone-tendon-bone allograft. Mean physical readiness test (PRT) score at final follow-up was not statistically different than documented preinjury PRT score (77.9 vs. 85.5, p > 0.05), nor was the mean run time (7:12 vs. 6:43/mile, p > 0.05). Significant improvements exceeding published minimal clinically important differences were seen in SANE score, SF-36 physical component summary score, KOOS sports and recreation, KOOS quality of life, WOMAC pain score, and WOMAC function score. Patients undergoing revision ACL reconstruction at our facility show good recovery of baseline physical performance as measured by the semiannual PRT and timed run test, and significant improvements in patient-reported outcome scores. Level of Evidence Level IV, case series. PMID- 26524091 TI - Characteristics of workplace violence prevention training and violent events among home health and hospice care providers. AB - BACKGROUND: In the rapidly growing home health and hospice industry, little is known about workplace violence prevention (WVP) training and violent events. METHODS: We examined the characteristics of WVP training and estimated violent event rates among 191 home health and hospice care providers from six agencies in California. Training characteristics were identified from the Occupational Safety and Health Administration guidelines. Rates were estimated as the number of violent events divided by the total number of home visit hours. RESULTS: Between 2008 and 2009, 66.5% (n = 127) of providers reported receiving WVP training when newly hired or as recurrent training. On average, providers rated the quality of their training as 5.7 (1 = poor to 10 = excellent). Among all providers, there was an overall rate of 17.1 violent events per 1,000 visit-hours. CONCLUSION: Efforts to increase the number of home health care workers who receive WVP training and to improve training quality are needed. PMID- 26524092 TI - Formation of Semimetallic Cobalt Telluride Nanotube Film via Anion Exchange Tellurization Strategy in Aqueous Solution for Electrocatalytic Applications. AB - Metal telluride nanostructures have demonstrated several potential applications particularly in harvesting and storing green energy. Metal tellurides are synthesized by tellurization process performed basically at high temperature in reducing gas atmosphere, which makes the process expensive and complicated. The development of a facile and economical process for desirable metal telluride nanostructures without complicated manipulation is still a challenge. In an effort to develop an alternative strategy of tellurization, herein we report a thin film formation of self-standing cobalt telluride nanotubes on various conducting and nonconducting substrates using a simple binder-free synthetic strategy based on anion exchange transformation from a thin film of cobalt hydroxycarbonate nanostructures in aqueous solution at room temperature. The nanostructured films before and after ion exchange transformation reaction are characterized using field emission scanning electron microscope, energy dispersive X-ray analyzer, X-ray photoelectron spectroscopy, thin film X-ray diffraction technique, high resolution transmission electron microscope, and selected area electron diffraction analysis technique. After the ion exchange transformation of nanostructures, the film shows conversion from insulator to highly electrical conductive semimetallic characteristic. When used as a counter electrode in I3(-)/I(-) redox electrolyte based dye-sensitized solar cells, the telluride film exhibits an electrocatalytic reduction activity for I3(-) with a demonstration of solar-light to electrical power conversion efficiency of 8.10%, which is highly competitive to the efficiency of 8.20% exhibited by a benchmarked Pt-film counter electrode. On the other hand, the telluride film electrode also demonstrates electrocatalytic activity for oxygen evolution reaction from oxidation of water. PMID- 26524093 TI - Executive Function Is Associated With Antisocial Behavior and Aggression in Athletes. AB - Poor executive function has been linked to increased antisocial and aggressive behavior in clinical and nonclinical populations. The present study investigated the relationship between executive and nonexecutive cognitive function and antisocial behavior in sport as well as reactive and proactive aggression. Cognitive function was assessed in young adult male and female athletes using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Antisocial behavior in sport and aggression were assessed via self-report instruments and were found to be positively correlated. Executive function (but not nonexecutive function) scores were negatively correlated with both self-reported antisocial behavior and aggression in males but not females. Our findings suggest that prefrontal deficits among male athletes could contribute to poor impulse control and difficulty in anticipating the consequences of their antisocial and aggressive behavior. PMID- 26524094 TI - Self-Control Strength Depletion Reduces Self-Efficacy and Impairs Exercise Performance. AB - The purpose of this study was to investigate the role of task self-efficacy as a psychological factor involved in the relationship between self-control depletion and physical endurance. Participants (N = 37) completed two isometric handgrip endurance trials, separated by a Stroop task, which was either congruent (control) or incongruent (causing depletion). Task self-efficacy for the second endurance trial was measured following the Stroop task. Participants in the depletion condition reported lower task self-efficacy and showed a greater reduction in performance on the second endurance trial when compared with controls. Task self-efficacy also mediated the relationship between self-control depletion and endurance performance. The results of this study provide evidence that task self-efficacy is negatively affected following self-control depletion. We recommend that task self-efficacy be further investigated as a psychological factor accounting for the negative change in self-control performance of physical endurance and sport tasks following self-control strength depletion. PMID- 26524095 TI - Appraisal in a Team Context: Perceptions of Cohesion Predict Competition Importance and Prospects for Coping. AB - Athletes' precompetitive appraisal is important because it determines emotions, which may impact performance. When part of a team, athletes make their appraisal within a social context, and in this study we examined whether perceived team cohesion, as a characteristic of this context, related to appraisal. We asked 386 male and female intercollegiate team-sport athletes to respond to measures of cohesion and precompetitive appraisal before an in-season game. For males and females, across all teams, (a) an appraisal of increased competition importance was predicted by perceptions of higher task cohesion (individual level), better previous team performance, and a weaker opponent (team level) and (b) an appraisal of more positive prospects for coping with competitive demands was predicted by higher individual attractions to the group (individual level). Consequently, athletes who perceive their team as more cohesive likely appraise the pending competition as a challenge, which would benefit both emotions and performance. PMID- 26524096 TI - Competitive Cycling and Doping: Proposing a Functional Analysis Based on the Color Yellow. AB - The authors demonstrate in three experiments (N = 241) that yellow impacts on social perceptions when associated with competitive cycling. In Experiment 1, the image of a syringe evocated competitive cycling and doping more strongly when presented on yellow as compared with gray. In Experiment 2, a performance improvement scenario yielded more discredit of a depicted racer and higher suspicions of doping when ending on a yellow frame, as opposed to a gray one. In Experiment 3, the image of a racer wearing a yellow jersey (instead of a gray or a white one) yielded the lowest scores on measures of suitability as a role model and attractiveness of sport participation. Moreover, no significant differences emerged for gender, thereby suggesting equivalent effects for female and male participants. Finally, the authors discuss conceptual and practical implications as well as limitations before proposing a number of avenues for future research. PMID- 26524097 TI - Applying the Theory of Planned Behavior to Physical Activity: The Moderating Role of Mental Toughness. AB - This study explored whether mental toughness, the capacity to maintain performance under pressure, moderated the relation between physical activity intentions and subsequent behavior. Participants (N = 117) completed the Mental Toughness Index and a theory of planned behavior questionnaire. Seven days later, physical activity was assessed using the International Physical Activity Questionnaire. Attitudes, subjective norms, and perceived behavioral control explained substantial variance (63.1%) in physical activity intentions. Intentions also significantly predicted physical activity behavior. The simple slopes analyses for the moderation effect revealed a nonsignificant intention behavior relation at low levels of mental toughness. However, intentions were significantly and positively related to physical activity when mental toughness was moderate or high, suggesting that the development of a mentally tough mindset may reduce the gap between behavior and physical activity intention. Future research is needed to confirm these findings and apply them in the design of mental toughness interventions to facilitate physical activity engagement. PMID- 26524098 TI - Using Masculine Capital to Understand the Role of a Sport Program in the Lives of Men From a Western Canadian Inner City. AB - The purpose of this study was to examine the role of a sport program in the lives of homeless men with severe mental illnesses and addictions. Interviews were conducted with eight men who attended a floor hockey program, and data examined using categorical-content narrative methodology. Five themes captured the role of the floor hockey program in the men's lives: (a) relationships with program leader, (b) therapy, (c) community, (d) action, and (e) achievement. These themes were interpreted using theories of masculinity (Connell, 1995; Gough, 2014). Relationships with the program leader and other men, and ways in which they were allowed to play with physicality, provided opportunities to accumulate masculine capital (i.e., ways in which competence in traditionally masculine behaviors provides masculine credit). Practically, the findings suggest that sport program delivery for men such as those in this study can be enhanced by providing opportunities for accruing masculine capital. PMID- 26524099 TI - Examination of the Consistency in Affective Response to Acute Exercise in Overweight and Obese Women. AB - This study examined whether inactive, overweight/obese women experience consistent affective responses to moderate-intensity exercise. Twenty-eight women participated in 3 identical (same treadmill grade and speed within a subject) 30 min exercise sessions. The Feeling Scale (FS), Positive and Negative Affect Schedule and Subjective Exercise Experience Scale were administered pre- and postexercise and FS was also administered every 5 min during exercise. All measures exhibited less than optimal agreement in pre-to-postexercise change within an individual across the 3 sessions (ICCs = 0.02-0.60), even after controlling for within-subject variations in heart rate. Only FS exhibited "good" consistency when controlling for preexercise values (ICC = 0.72). However, the mean FS score during exercise was highly consistent within an individual (ICC = 0.83). Thus, an individual's affective response to an exercise session does not provide reliable information about how they will respond to subsequent exercise sessions. Taking the average of FS measurements during exercise may yield more consistent findings. PMID- 26524100 TI - Moving to Self-Present: An Investigation Into Proposed Antecedents of 2 x 2 Self Presentation Motives. AB - Two studies involving high school physical education students were conducted to investigate associations between 2 x 2 self-presentation motives and theorized antecedents. In Study 1 (n = 445), using path analysis, we found that positive predictive pathways emerged from fear of negative evaluation, trait agency and communion, self-presentational efficacy, and social self-efficacy to 2 x 2 motives. In Study 2 (n = 301), using cluster analysis, we found that approximately half the cohort was classified into a high motive endorsement cluster and half into a low motive endorsement cluster. The high cluster had significantly higher 2 x 2 motive, fear of negative evaluation, trait agency and communion, and self-efficacy scores. This work represents the first concerted effort to empirically examine proposed antecedents of 2 x 2 motives and serves to inform theorists and practitioners about dispositional and context-specific factors that may align with these motives. PMID- 26524101 TI - Intense Physical Exercise Reduces Overt Attentional Capture. AB - The abrupt onset of a visual stimulus typically results in overt attentional capture, which can be quantified by saccadic eye movements. Here, we tested whether attentional capture following onset of task-irrelevant visual stimuli (new object) is reduced after a bout of intense physical exercise. A group of participants performed a visual search task in two different activity conditions: rest, without any prior effort, and effort, immediately after an acute bout of intense exercise. The results showed that participants exhibited (1) slower reaction time of the first saccade toward the target when a new object was simultaneously presented in the visual field, but only in the rest activity condition, and (2) more saccades to the new object in the rest activity condition than in the effort activity condition. We suggest that immediately after an acute bout of effort, participants improved their ability to inhibit irrelevant (distracting) stimuli. PMID- 26524103 TI - Retraction statement: LA sprouts randomized controlled nutrition, cooking and gardening program reduces obesity and metabolic risk in Latino youth. AB - The above article, published online on 9 May 2015 in Wiley Online Library (wileyonlinelibrary.com), and in Volume 23, pp. 1244-1251, has been retracted by agreement between the authors, the journal Editors-in-Chief, Eric Ravussin and Donna Ryan, the Obesity Society, and Wiley Periodicals, Inc. The retraction has been agreed to because the statistical analysis was not correct given the cluster randomized design, and the wrong degrees of freedom were used. The conclusion that the original paper drew about having demonstrated treatment efficacy was not supported in the corrected analysis. REFERENCE: Gatto, N. M., Martinez, L. C., Spruijt-Metz, D. and Davis, J. N. LA Sprouts randomized controlled nutrition and gardening program reduces obesity and metabolic risk in Latino youth. Obesity 2015;23:1244-1251. doi: 10.1002/oby.21077. PMID- 26524104 TI - Measuring breath acetone for monitoring fat loss: Review. AB - OBJECTIVE: Endogenous acetone production is a by-product of the fat metabolism process. Because of its small size, acetone appears in exhaled breath. Historically, endogenous acetone has been measured in exhaled breath to monitor ketosis in healthy and diabetic subjects. Recently, breath acetone concentration (BrAce) has been shown to correlate with the rate of fat loss in healthy individuals. In this review, the measurement of breath acetone in healthy subjects is evaluated for its utility in predicting fat loss and its sensitivity to changes in physiologic parameters. RESULTS: BrAce can range from 1 ppm in healthy non-dieting subjects to 1,250 ppm in diabetic ketoacidosis. A strong correlation exists between increased BrAce and the rate of fat loss. Multiple metabolic and respiratory factors affect the measurement of BrAce. BrAce is most affected by changes in the following factors (in descending order): dietary macronutrient composition, caloric restriction, exercise, pulmonary factors, and other assorted factors that increase fat metabolism or inhibit acetone metabolism. Pulmonary factors affecting acetone exchange in the lung should be controlled to optimize the breath sample for measurement. CONCLUSIONS: When biologic factors are controlled, BrAce measurement provides a non-invasive tool for monitoring the rate of fat loss in healthy subjects. PMID- 26524105 TI - Direct Synthesis of Few-Layer Graphene on NaCl Crystals. AB - Chemical vapor deposition is used to synthesize few-layer graphene on micro crystalline sodium chloride (NaCl) powder. The water-soluble nature of NaCl makes it convenient to produce free standing graphene layers via a facile and low-cost approach. Unlike traditional metal-catalyzed or oxygen-aided growth, the micron size NaCl crystal planes play an important role in the nucleation and growth of few-layer graphene. Moreover, the possibility of synthesizing cuboidal graphene is also demonstrated in the present approach for the first time. Raman spectroscopy, optical microscopy, scanning electron microscopy, transmission electron microscopy, and atomic force microscopy are used to evaluate the quality and structure of the few-layer graphene along with cuboidal graphene obtained in this process. The few-layer graphene synthesized using the present method has an adsorption ability for anionic and cationic dye molecules in water. The present synthesis method may pave a facile way for manufacturing few-layer graphene on a large scale. PMID- 26524106 TI - The role of autologous haemopoietic stem cell transplantation in the treatment of autoimmune disorders. AB - Autologous haemopoietic stem cell transplantation (HSCT) has been used for over 30 years for malignant haematological diseases, such as myeloma and lymphoma, with considerable success. More recently this procedure has been adopted as a form of high dose immunosuppression in selected patients with autoimmune diseases that are resistant to conventional therapies. Animal models have previously outlined the rationale and validity of HSCT in patients with these non-malignant, but in many cases, life-threatening conditions. Recent data have that deletion of putative autoreactive immune clones with reconstitution of a thymic driven, tolerant immune system occurs in HSCT for auto-immune patients. Two randomised control trials have confirmed that HSCT is superior to monthly cyclophosphamide in systemic sclerosis with a highly significant disease free and overall survival benefit demonstrated in the Autologous Stem cell Transplantation International Scleroderma trial. Over 2000 patients worldwide with autoimmune conditions have been treated with HSCT - the commonest indications being multiple sclerosis (MS) and systemic sclerosis. Encouraging relapse free survival of 70-80% at 4 years, in heavily pre-treated MS patients, has been demonstrated in Phase II trials. A Phase III trial in MS patients who have failed interferon is currently accruing patients. Future challenges include improvements in safety of HSCT, particularly in cardiac assessment of systemic sclerosis patients, cost-benefit analyses of HSCT compared to standard therapy and establishment of centres of excellence to continue to enhance the safety and benefit of this exciting new therapy. PMID- 26524107 TI - Streptococcus pneumoniae proteomics: determinants of pathogenesis and vaccine development. AB - Streptococcus pneumoniae is a major pathogen that is responsible for a variety of invasive diseases. The bacteria gain entry initially by establishing a carriage state in the nasopharynx from where they migrate to other sites in the body. The worldwide distribution of the bacteria and the severity of the diseases have led to a significant level of interest in the development of vaccines against the bacteria. Current vaccines, based on the bacterial polysaccharide, have a number of limitations including poor immunogenicity and limited effectiveness against all pneumococcal serotypes. There are many challenges in developing vaccines that will be effective against the diverse range of isolates and serotypes for this highly variable bacterial pathogen. This review considers how proteomic technologies have extended our understanding of the pathogenic mechanisms of nasopharyngeal colonization and disease development as well as the critical areas in developing protein-based vaccines. PMID- 26524108 TI - Extent of recovery in the first 12 months of complex regional pain syndrome type 1: A prospective study. AB - BACKGROUND: The literature concerning the outcomes of complex regional pain syndrome (CRPS) is contradictory, with some studies suggesting high rates of symptom resolution, whilst others demonstrate that CRPS symptoms can persist and lead to significant disability. The aim of the present study was to carefully document the extent of recovery from each of the signs and symptoms of CRPS. METHODS: A sample of 59 patients with recently onset (<12 weeks) CRPS-1 were followed prospectively for 1 year, during which time they received treatment-as usual. At baseline, 6 and 12 months, the following were measured: CRPS severity scores (symptoms and signs of CRPS), pain, disability, work status and psychological functioning. RESULTS: Analyses showed that rates of almost all signs and symptoms of CRPS reduced significantly over 1 year. Reductions in symptom severity were clinically relevant and were greatest in the first 6 months and plateaued thereafter. However, at 1 year, nearly 2/3 of patients continued to meet the IASP-Orlando criteria for CRPS and 1/4 met the Budapest research criteria for CRPS. Only 5.4% of patients were symptom-free at 12 months. CONCLUSIONS: Overall the results were less optimistic than several previously conducted prospective studies and suggest that few cases of CRPS resolve completely within 12 months of onset. Improvements were generally greater in the first 6 months, and suggest that it may be worth exploring early interventions to prevent long-term disability in CRPS. PMID- 26524109 TI - Controlled-Release System of Small Molecules Triggered by the Photothermal Effect of Polypyrrole. AB - In this paper, a novel synthesis of polyethylene glycol (PEG)-modified polypyrrole (PPy) nanomaterials is demonstrated by combining reversible addition fragmentation chain transfer polymerization and oxidative polymerization. Dye molecules with a heat-labile linker are used as a model drug and covalently anchored onto the PEGlated PPy nanomaterials via "click chemistry." The strong absorption of such PPy nanomaterials in the near-infrared region endows the system excellent photothermal effect, which can be used not only as efficient photothermal agents for photothermal therapy but also good controllers of a drug release system by retro D-A reaction. PMID- 26524110 TI - Gum Sensor: A Stretchable, Wearable, and Foldable Sensor Based on Carbon Nanotube/Chewing Gum Membrane. AB - Presented in this work is a novel and facile approach to fabricate an elastic, attachable, and cost-efficient carbon nanotube (CNT)-based strain gauge which can be efficiently used as bodily motion sensors. An innovative and unique method is introduced to align CNTs without external excitations or any complicated procedure. In this design, CNTs are aligned and distributed uniformly on the entire chewing gum by multiple stretching and folding technique. The current sensor is demonstrated to be a linear strain sensor for at least strains up to 200% and can detect strains as high as 530% with a high sensitivity ranging from 12 to 25 and high durability. The gum sensor has been used as bodily motion sensors, and outstanding results are achieved; the sensitivity is quite high, capable of tracing slow breathing. Since the gum sensor can be patterned into various forms, it has wide applications in miniaturized sensors and biochips. Interestingly, we revealed that our gum sensor has the ability to monitor humidity changes with high sensitivity and fast resistance response capable of monitoring human breathing. PMID- 26524111 TI - When does power disparity help or hurt group performance? AB - Power differences are ubiquitous in social settings. However, the question of whether groups with higher or lower power disparity achieve better performance has thus far received conflicting answers. To address this issue, we identify 3 underlying assumptions in the literature that may have led to these divergent findings, including a myopic focus on static hierarchies, an assumption that those at the top of hierarchies are competent at group tasks, and an assumption that equality is not possible. We employ a multimethod set of studies to examine these assumptions and to understand when power disparity will help or harm group performance. First, our agent-based simulation analyses show that by unpacking these common implicit assumptions in power research, we can explain earlier disparate findings--power disparity benefits group performance when it is dynamically aligned with the power holder's task competence, and harms group performance when held constant and/or is not aligned with task competence. Second, our empirical findings in both a field study of fraud investigation groups and a multiround laboratory study corroborate the simulation results. We thereby contribute to research on power by highlighting a dynamic understanding of power in groups and explaining how current implicit assumptions may lead to opposing findings. PMID- 26524112 TI - Why and when workplace ostracism inhibits organizational citizenship behaviors: An organizational identification perspective. AB - Why and when do employees respond to workplace ostracism by withholding their engagement in citizenship behavior? Beyond perspectives proposed in past studies, we offer a new account based on a social identity perspective and propose that workplace ostracism decreases citizenship behavior by undermining employees' identification with the organization. We also theorize that perceived job mobility influences the extent to which employees identify with the organization when being ostracized. These hypotheses were examined in two time-lagged studies conducted in China. The proposed hypotheses were supported by results in Study 1, and findings were generally replicated in Study 2, where effects of other known mediators (i.e., organization-based self-esteem, job engagement, and felt obligation toward the organization) and moderators (i.e., collectivism, power distance, and future orientation) suggested by previous perspectives were controlled. Results of Study 2 provided further support of the hypothesized directional effect of workplace ostracism on citizenship behavior via organizational identification. Our studies support the identification perspective in understanding workplace ostracism and also strengthen the application of this perspective in understanding workplace aggression broadly. PMID- 26524113 TI - Concentration of Umami Compounds in Pork Meat and Cooking Juice with Different Cooking Times and Temperatures. AB - This study examined the concentrations of umami compounds in pork loins cooked at 3 different temperatures and 3 different lengths of cooking times. The pork loins were cooked with the sous vide technique. The free amino acids (FAAs), glutamic acid and aspartic acid; the 5'-nucleotides, inosine-5'-monophosphate (IMP) and adenosine-5'-monophosphate (AMP); and corresponding nucleoside inosine of the cooked meat and its released juice were determined by high-performance liquid chromatography. Under the experimental conditions used, the cooking temperature played a more important role than the cooking time in the concentration of the analyzed compounds. The amino acid concentrations in the meat did not remain constant under these experimental conditions. The most notable effect observed was that of the cooking temperature and the higher amino acid concentrations in the released juice of meat cooked at 80 degrees C compared with 60 and 70 degrees C. This is most likely due to the heat induced hydrolysis of proteins and peptides releasing water soluble FAAs from the meat into the cooking juice. In this experiment, the cooking time and temperature had no influence on the IMP concentrations observed. However, the AMP concentrations increased with the increasing temperature and time. This suggests that the choice of time and temperature in sous vide cooking affects the nucleotide concentration of pork meat. The Sous vide technique proved to be a good technique to preserve the cooking juice and the results presented here show that cooking juice is rich in umami compounds, which can be used to provide a savory or brothy taste. PMID- 26524114 TI - Clinical Significance of Upsloping ST Depression on Resting Electrocardiogram. AB - INTRODUCTION: Upsloping ST depression is generally not associated with myocardial ischemia, yet there have been published reports that suggest otherwise. CASE HISTORY: A 34-year-old pregnant female presented with chest pain and palpitations. She was found to have supraventricular tachycardia, which resolved with intravenous adenosine. Few minutes later her ECG showed upsloping ST depression in leads V4-V6 that persisted for 1 hour after the resolution of the tachycardia. The patient was discharged in stable condition with outpatient follow-up. CONCLUSION: Upsloping ST depression in resting electrocardiogram may indicate cardiac ischemia in the presence of active cardiac symptoms. In the absence of ongoing symptoms however, it may be secondary to conditions other than ischemia. PMID- 26524116 TI - Hyperglycemia grand rounds: descriptive findings of outcomes from a continuing education intervention to improve glycemic control and prevent hypoglycemia in the hospital setting. AB - Hyperglycemia is common in the hospital in-patient setting and is associated with adverse outcomes. Healthcare professionals (HCPs) often fail to use best practices established to manage this condition or to coordinate care among team members. OBJECTIVES: The objective of the Hyperglycemia Grand Rounds (HGR) continuing education initiative was to improve knowledge levels in a team setting, leading to improved clinical competence, evidence-based behaviors, and improved patient care. METHODS: To achieve that goal, a four-module seminar series was presented to HCPs on-site in a "Grand Rounds" format at healthcare institutions across the United States. Outcomes data included satisfaction, learning, impact, and intent-to-implement measures at event time and at follow up. At the site level, detailed questionnaires assessed skill gaps and expected outcomes from administrators at the time the modules were scheduled and the impact after modules were completed. Demographic information allowed identification of HCPs receiving maximum benefits; data on barriers to implementation are reported. RESULTS: Seventy-eight percent of participants self reported a positive impact on competence, performance, or patient outcomes. Forty percent of learners said they intended to make specific changes in practices. Eighty-two percent of administrators confirmed expected changes in their health system. The follow-up study concurred with the initial findings. CONCLUSION: The HGR was an effective program in improving self-reported competence amongst attendees that could potentially lead to improved care. This descriptive report summarizes outcomes from 1 year of educational efforts to more than 2000 healthcare professionals. PMID- 26524117 TI - Racial and Ethnic Disparities in the Pediatric Hodgkin Lymphoma Population. AB - BACKGROUND: Little is known about the association between race/ethnicity and survival in pediatric Hodgkin lymphoma (HL) patients. In a state-wide pediatric cohort diagnosed with HL, we assessed demographic, disease, and treatment characteristics associated with overall survival (OS). We then attempted to validate these findings and assess disease-specific survival (DSS) in a national Surveillance, Epidemiology, and End Results (SEER) cohort. PROCEDURE: HL patients of 0.1-21 years diagnosed from 1981 to 2010 were evaluated using the Florida Cancer Data System (FCDS). Kaplan-Meier curves estimated OS from 5 to 25 years based on race/ethnicity, treatment, decade of diagnosis, and sex. Multivariate Cox proportional hazard regressions tested independent factors associated with differences in OS. These methods were replicated in the SEER with additional assessment of DSS. RESULTS: A total of 1,778 patients were identified in the FCDS and 6,027 in the SEER. Median diagnosis age was 17 years in both cohorts. In the FCDS, Blacks had worse OS than Whites and Hispanics at 25 years (33% vs. 49.2% vs. 44.7%, respectively; P = 0.0005), and Black race was associated with inferior OS on multivariate regression (hazard ratio [HR]: 1.81, P = 0.0003). In the SEER, Blacks had inferior OS (Blacks 74.2% vs. Whites 82% vs. Hispanics 82%; P = 0.0005) and DSS (85.7% vs. 90.8% vs. 88.1%, respectively; P = 0.0002) at 25 years. Hispanic males had inferior DSS compared to White males (84.8% vs. 90.6%; P = 0.0478), and Hispanic race was a predictor for inferior DSS on multivariate analysis (HR: 1.238; P < 0.0001). CONCLUSIONS: Racial/ethnic disparities persist in the pediatric HL population despite modern treatment; underlying causes of these disparities are complex and need further examination. PMID- 26524118 TI - New Family of Quantum Spin Hall Insulators in Two-dimensional Transition-Metal Halide with Large Nontrivial Band Gaps. AB - Topological insulators (TIs) are promising for achieving dissipationless transport devices due to the robust gapless states inside the insulating bulk gap. However, currently realized two-dimensional (2D) TIs, quantum spin Hall (QSH) insulators, suffer from ultrahigh vacuum and extremely low temperature. Thus, seeking for desirable QSH insulators with high feasibility of experimental preparation and large nontrivial gap is of great importance for wide applications in spintronics. On the basis of the first-principles calculations, we predict a novel family of 2D QSH insulators in transition-metal halide MX (M = Zr, Hf; X = Cl, Br, and I) monolayers, especially, which is the first case based on transition-metal halide-based QSH insulators. MX family has the large nontrivial gaps of 0.12-0.4 eV, comparable with bismuth (111) bilayer (0.2 eV), stanene (0.3 eV), and larger than ZrTe5 (0.1 eV) monolayers and graphene-based sandwiched heterstructures (30-70 meV). Their corresponding 3D bulk materials are weak topological insulators from stacking QSH layers, and some of bulk compounds have already been synthesized in experiment. The mechanism for 2D QSH effect in this system originates from a novel d-d band inversion, significantly different from conventional band inversion between s-p, p-p, or d-p orbitals. The realization of pure layered MX monolayers may be prepared by exfoliation from their 3D bulk phases, thus holding great promise for nanoscale device applications and stimulating further efforts on transition metal-based QSH materials. PMID- 26524115 TI - Cardiomyocytes from human pluripotent stem cells: From laboratory curiosity to industrial biomedical platform. AB - Cardiomyocytes from human pluripotent stem cells (hPSCs-CMs) could revolutionise biomedicine. Global burden of heart failure will soon reach USD $90bn, while unexpected cardiotoxicity underlies 28% of drug withdrawals. Advances in hPSC isolation, Cas9/CRISPR genome engineering and hPSC-CM differentiation have improved patient care, progressed drugs to clinic and opened a new era in safety pharmacology. Nevertheless, predictive cardiotoxicity using hPSC-CMs contrasts from failure to almost total success. Since this likely relates to cell immaturity, efforts are underway to use biochemical and biophysical cues to improve many of the ~30 structural and functional properties of hPSC-CMs towards those seen in adult CMs. Other developments needed for widespread hPSC-CM utility include subtype specification, cost reduction of large scale differentiation and elimination of the phenotyping bottleneck. This review will consider these factors in the evolution of hPSC-CM technologies, as well as their integration into high content industrial platforms that assess structure, mitochondrial function, electrophysiology, calcium transients and contractility. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26524120 TI - A spontaneous segmental deletion from chromosome arm 3DL enhances Fusarium head blight resistance in wheat. AB - Much effort has been directed at identifying sources of resistance to Fusarium head blight (FHB) in wheat. We sought to identify molecular markers for what we hypothesized was a new major FHB resistance locus originating from the wheat cultivar 'Freedom' and introgressed into the susceptible wheat cultivar 'USU Apogee'. An F2:3 mapping population from a cross between Apogee and A30, its BC4 near-isoline exhibiting improved FHB resistance, was evaluated for resistance. The distribution of FHB resistance in the population approximated a 1:3 moderately resistant : moderately susceptible + susceptible ratio. Separate disease evaluations established that A30 accumulated less deoxynivalenol and yielded a greater proportion of sound grain than Apogee. Molecular mapping revealed that the FHB resistance of A30 is associated with molecular markers on chromosome arm 3DL that exhibit a null phenotype in A30 but are present in both Apogee and Freedom, indicating a spontaneous deletion occurred during the development of A30. Aneuploid analysis revealed that the size of the deleted segment is approximately 19% of the arm's length. Our results suggest that the deleted interval of chromosome arm 3DL in Apogee may harbor FHB susceptibility genes that promote disease spread in infected spikes, and that their elimination increases FHB resistance in a novel manner. PMID- 26524121 TI - Atomic Structure of Graphene Subnanometer Pores. AB - The atomic structure of subnanometer pores in graphene, of interest due to graphene's potential as a desalination and gas filtration membrane, is demonstrated by atomic resolution aberration corrected transmission electron microscopy. High temperatures of 500 degrees C and over are used to prevent self healing of the pores, permitting the successful imaging of open pore geometries consisting of between -4 to -13 atoms, all exhibiting subnanometer diameters. Picometer resolution bond length measurements are used to confirm reconstruction of five-membered ring projections that often decorate the pore perimeter, knowledge which is used to explore the viability of completely self-passivated subnanometer pore structures; bonding configurations where the pore would not require external passivation by, for example, hydrogen to be chemically inert. PMID- 26524122 TI - Development and Validation of Decision Forest Model for Estrogen Receptor Binding Prediction of Chemicals Using Large Data Sets. AB - Some chemicals in the environment possess the potential to interact with the endocrine system in the human body. Multiple receptors are involved in the endocrine system; estrogen receptor alpha (ERalpha) plays very important roles in endocrine activity and is the most studied receptor. Understanding and predicting estrogenic activity of chemicals facilitates the evaluation of their endocrine activity. Hence, we have developed a decision forest classification model to predict chemical binding to ERalpha using a large training data set of 3308 chemicals obtained from the U.S. Food and Drug Administration's Estrogenic Activity Database. We tested the model using cross validations and external data sets of 1641 chemicals obtained from the U.S. Environmental Protection Agency's ToxCast project. The model showed good performance in both internal (92% accuracy) and external validations (~ 70-89% relative balanced accuracies), where the latter involved the validations of the model across different ER pathway related assays in ToxCast. The important features that contribute to the prediction ability of the model were identified through informative descriptor analysis and were related to current knowledge of ER binding. Prediction confidence analysis revealed that the model had both high prediction confidence and accuracy for most predicted chemicals. The results demonstrated that the model constructed based on the large training data set is more accurate and robust for predicting ER binding of chemicals than the published models that have been developed using much smaller data sets. The model could be useful for the evaluation of ERalpha-mediated endocrine activity potential of environmental chemicals. PMID- 26524123 TI - Bridging Experiments and Native-Centric Simulations of a Downhill Folding Protein. AB - Experiments and atomistic simulations have independently contributed to the mechanistic understanding of protein folding. However, a coherent detailed picture explicitly combining both is currently lacking, a problem that seriously limits the amount of information that can be extracted. An alternative to atomistic models with physics-based potentials is the native-centric (i.e., Go type) coarse-grained models, which for many years have been successfully employed to qualitatively understand features of protein folding energy landscapes. Again, quantitative validation of Go models against experimental equilibrium unfolding curves is often not attempted. Here we use an atomistic topology-based model to study the folding mechanism of PDD, a protein that folds over a marginal thermodynamic barrier of ~0.5 kBT at midpoint conditions. We find that the simulations are in exquisite agreement with several equilibrium experimental measurements including differential scanning calorimetry (DSC), an observable that is possibly the most challenging to reproduce from explicit-chain models. The dynamics, inferred using a detailed Markov state model, display a classical Chevron-like trend with a continuum of relaxation times under both folding and unfolding conditions, a signature feature of downhill folding. The number of populated microstates and the connectivity between them are shown to be temperature dependent with a maximum near the thermal denaturation midpoint, thus linking the macroscopic observation of a peak in the DSC profile of downhill folding proteins and the underlying microstate dynamics. The mechanistic picture derived from our analysis thus sheds light on the intricate and tunable nature of the downhill protein folding ensembles. In parallel, our work highlights the power of coarse-grained models to reproduce experiments at a quantitative level while also pointing at specific directions for their improvement. PMID- 26524124 TI - In silico studies on the interaction between bioactive ligands and ALK5, a biological target related to the cancer treatment. AB - Studies have showed that there are many biological targets related to the cancer treatment, for example, TGF type I receptor (TGF-betaRI or ALK5). The ALK5 inhibition is a strategy to treat some types of cancer, such as breast, lung, and pancreas. Here, we performed CoMFA and CoMSIA studies for 70 ligands with ALK5 inhibition. The internal validation for both models (q(2)LOO = 0.887 and 0.822, respectively) showed their robustness, while the external validations showed their predictive power (CoMFA: r(2)test = 0.998; CoMSIA: r(2)test = 0.975). After all validations, CoMFA and CoMSIA maps indicated physicochemical evidences on the main factors involved in the interaction between bioactive ligands and ALK5. Therefore, these results suggest molecular modifications to design new ALK5 inhibitors. PMID- 26524125 TI - Digital venography in ruminants--a review. AB - Digital venography is a contrast angiography technique used to study digital vascularity. The technique is simple to be carried out and can be performed under field conditions using a standard radiographic unit. The venogram examination is used to complement conventional radiographic examinations in animals affected by foot diseases. Discrepancy in the contrast vascular pattern may be observed before the clinical signs of the foot disease. Digital venography studies in ruminants are in smaller number than those in horses. The herein presented review discusses digital venography techniques used in ruminants as well as the differences and similarities between ruminants (cattle, sheep and goat) and horses. PMID- 26524126 TI - Effect of working memory load on electrophysiological markers of visuospatial orienting in a spatial cueing task simulating a traffic situation. AB - Visuospatial attentional orienting has typically been studied in abstract tasks with low ecological validity. However, real-life tasks such as driving require allocation of working memory (WM) resources to several subtasks over and above orienting in a complex sensory environment. The aims of this study were twofold: firstly, to establish whether electrophysiological signatures of attentional orienting commonly observed under simplified task conditions generalize to a more naturalistic task situation with realistic-looking stimuli, and, secondly, to assess how these signatures are affected by increased WM load under such conditions. Sixteen healthy participants performed a dual task consisting of a spatial cueing paradigm and a concurrent verbal memory task that simulated aspects of an actual traffic situation. Behaviorally, we observed a load-induced detriment of sensitivity to targets. In the EEG, we replicated orienting-related alpha lateralization, the lateralized ERPs ADAN, EDAN, and LDAP, and the P1-N1 attention effect. When WM load was high (i.e., WM resources were reduced), lateralization of oscillatory activity in the lower alpha band was delayed. In the ERPs, we found that ADAN was also delayed, while EDAN was absent. Later ERP correlates were unaffected by load. Our results show that the findings in highly controlled artificial tasks can be generalized to spatial orienting in ecologically more valid tasks, and further suggest that the initiation of spatial orienting is delayed when WM demands of an unrelated secondary task are high. PMID- 26524127 TI - Discovering treatment pattern in Traditional Chinese Medicine clinical cases by exploiting supervised topic model and domain knowledge. AB - In Traditional Chinese Medicine (TCM), the prescription is the crystallization of clinical experience of doctors, which is the main way to cure diseases in China for thousands of years. Clinical cases, on the other hand, describe how doctors diagnose and prescribe. In this paper, we propose a framework which mines treatment patterns in TCM clinical cases by exploiting supervised topic model and TCM domain knowledge. The framework can reflect principle rules in TCM and improve function prediction of a new prescription. We evaluate our method on 3090 real world TCM clinical cases. The experiment validates the effectiveness of our method. PMID- 26524128 TI - eQTL networks unveil enriched mRNA master integrators downstream of complex disease-associated SNPs. AB - The causal and interplay mechanisms of Single Nucleotide Polymorphisms (SNPs) associated with complex diseases (complex disease SNPs) investigated in genome wide association studies (GWAS) at the transcriptional level (mRNA) are poorly understood despite recent advancements such as discoveries reported in the Encyclopedia of DNA Elements (ENCODE) and Genotype-Tissue Expression (GTex). Protein interaction network analyses have successfully improved our understanding of both single gene diseases (Mendelian diseases) and complex diseases. Whether the mRNAs downstream of complex disease genes are central or peripheral in the genetic information flow relating DNA to mRNA remains unclear and may be disease specific. Using expression Quantitative Trait Loci (eQTL) that provide DNA to mRNA associations and network centrality metrics, we hypothesize that we can unveil the systems properties of information flow between SNPs and the transcriptomes of complex diseases. We compare different conditions such as naive SNP assignments and stringent linkage disequilibrium (LD) free assignments for transcripts to remove confounders from LD. Additionally, we compare the results from eQTL networks between lymphoblastoid cell lines and liver tissue. Empirical permutation resampling (p<0.001) and theoretic Mann-Whitney U test (p<10(-30)) statistics indicate that mRNAs corresponding to complex disease SNPs via eQTL associations are likely to be regulated by a larger number of SNPs than expected. We name this novel property mRNA hubness in eQTL networks, and further term mRNAs with high hubness as master integrators. mRNA master integrators receive and coordinate the perturbation signals from large numbers of polymorphisms and respond to the personal genetic architecture integratively. This genetic signal integration contrasts with the mechanism underlying some Mendelian diseases, where a genetic polymorphism affecting a single protein hub produces a divergent signal that affects a large number of downstream proteins. Indeed, we verify that this property is independent of the hubness in protein networks for which these mRNAs are transcribed. Our findings provide novel insights into the pleiotropy of mRNAs targeted by complex disease polymorphisms and the architecture of the information flow between the genetic polymorphisms and transcriptomes of complex diseases. PMID- 26524129 TI - Observation of superconductivity induced by a point contact on 3D Dirac semimetal Cd3As2 crystals. AB - Three-dimensional (3D) Dirac semimetals, which possess 3D linear dispersion in the electronic structure as a bulk analogue of graphene, have lately generated widespread interest in both materials science and condensed matter physics. Recently, crystalline Cd3As2 has been proposed and proved to be a 3D Dirac semimetal that can survive in the atmosphere. Here, by using point contact spectroscopy measurements, we observe exotic superconductivity around the point contact region on the surface of Cd3As2 crystals. The zero-bias conductance peak (ZBCP) and double conductance peaks (DCPs) symmetric around zero bias suggest p wave-like unconventional superconductivity. Considering the topological properties of 3D Dirac semimetals, our findings may indicate that Cd3As2 crystals under certain conditions could be topological superconductors, which are predicted to support Majorana zero modes or gapless Majorana edge/surface modes in the boundary depending on the dimensionality of the material. PMID- 26524130 TI - Evolution of the Fermi surface of Weyl semimetals in the transition metal pnictide family. AB - Topological Weyl semimetals (TWSs) represent a novel state of topological quantum matter which not only possesses Weyl fermions (massless chiral particles that can be viewed as magnetic monopoles in momentum space) in the bulk and unique Fermi arcs generated by topological surface states, but also exhibits appealing physical properties such as extremely large magnetoresistance and ultra-high carrier mobility. Here, by performing angle-resolved photoemission spectroscopy (ARPES) on NbP and TaP, we directly observed their band structures with characteristic Fermi arcs of TWSs. Furthermore, by systematically investigating NbP, TaP and TaAs from the same transition metal monopnictide family, we discovered their Fermiology evolution with spin-orbit coupling (SOC) strength. Our experimental findings not only reveal the mechanism to realize and fine-tune the electronic structures of TWSs, but also provide a rich material base for exploring many exotic physical phenomena (for example, chiral magnetic effects, negative magnetoresistance, and the quantum anomalous Hall effect) and novel future applications. PMID- 26524131 TI - Unconventional superconductivity at mesoscopic point contacts on the 3D Dirac semimetal Cd3As2. AB - Three-dimensional (3D) Dirac semimetals exist close to topological phase boundaries which, in principle, should make it possible to drive them into exotic new phases, such as topological superconductivity, by breaking certain symmetries. A practical realization of this idea has, however, hitherto been lacking. Here we show that the mesoscopic point contacts between pure silver (Ag) and the 3D Dirac semimetal Cd3As2 (ref. ) exhibit unconventional superconductivity with a critical temperature (onset) greater than 6 K whereas neither Cd3As2 nor Ag are superconductors. A gap amplitude of 6.5 meV is measured spectroscopically in this phase that varies weakly with temperature and survives up to a remarkably high temperature of 13 K, indicating the presence of a robust normal-state pseudogap. The observations indicate the emergence of a new unconventional superconducting phase that exists in a quantum mechanically confined region under a point contact between a Dirac semimetal and a normal metal. PMID- 26524132 TI - Patients' Knowledge About Analgesic-Antipyretic Medications Purchased in Community Pharmacies: A Descriptive Study. AB - The objective of this study was to describe the level of knowledge about paracetamol (acetaminophen), ibuprofen, and aspirin of subjects who purchased nonprescription medications containing one of these drugs. We conducted this cross-sectional descriptive study in 42 community pharmacies located in southwestern France between July and November 2013. A six-item self-administered questionnaire was used. Participants were asked to identify the active ingredient contained in 14 brand-name analgesic-antipyretics, to state the maximum daily dose of paracetamol, ibuprofen, and aspirin, the recommended first-line analgesic, and precautions of use or contraindications for paracetamol, ibuprofen, and aspirin. Among 576 participants, the identification of paracetamol ranged from 58% (for Dafalgan or Efferalgan) to 90% (for Doliprane), the identification of ibuprofen from 34% (for Nureflex) to 63% (for Nurofen), and the identification of aspirin was 70% (for Aspegic). The maximum recommended daily dose of paracetamol, ibuprofen, and aspirin was known by 58.3%, 17.7%, and 19.3% of participants, respectively, whereas 6.8%, 17.2%, and 13.2% stated supratherapeutic daily doses. Paracetamol was correctly stated as the first-line analgesic-antipyretic by 76.2% of participants. Knowledge on major precautions of use or contraindications was poor (45.8% and 53.6% for ibuprofen and aspirin use during pregnancy, and 14.1% for concurrent use of anticoagulants and ibuprofen). Purchasers of nonprescription analgesic-antipyretics had poor knowledge on the medication they purchased. PMID- 26524133 TI - The role of chronic inflammation in the development of gastrointestinal cancers: reviewing cancer prevention with natural anti-inflammatory intervention. AB - Inflammatory mediators alter the local environment of tumors, known as the tumor microenvironment. Mechanistically, chronic inflammation induces DNA damage, but understanding this hazard may help in the search for new chemopreventive agents for gastrointestinal (GI) cancer which attenuate inflammation. In the clinic, GI cancer still remains a major cause of cancer-associated mortality, chemoprevention with anti-inflammatory agents is thought to be a realistic approach to reduce GI cancer. Proton pump inhibitors, monoclonal antibodies targeting tumor necrosis factor-alpha, anti-sense targeted smad7 and non steroidal anti-inflammatory agents have been investigated for their potential to prevent inflammation-based GI cancer. Besides these, a wide variety of natural products have also shown potential for the prevention of GI cancer. In this review, the authors will provide insights to explain the mechanistic connection between inflammation and GI cancer, as well as describe a feasible cancer prevention strategy based on anti-inflammatory treatments. PMID- 26524134 TI - Kinked Graft and Anastomotic Stenosis-Induced Hemolytic Anemia Requiring Reoperation. AB - We report a case of hemolytic anemia caused initially by narrowing of a proximal anastomotic site and subsequently by a kinked prosthetic graft after total aortic arch replacement. A 55-year-old man was diagnosed with acute type A aortic dissection by computed tomography (CT). After total aortic arch replacement, hemolytic anemia and renal dysfunction developed. CT detected narrowing of proximal anastomotic site of the graft. Removing the graft and ascending aortic replacement resolved the signs of hemolytic anemia. However, 50 days after the surgery, severe hemolytic anemia developed again. CT revealed a sharply kinked graft. Total arch replacement was again performed to resect the kinked graft. He was discharged on the 24th postoperative day without hemodialysis. PMID- 26524135 TI - Endovascular Coil Embolization in the Treatment of a Rare Case of Post-Traumatic Abdominal Aortic Pseudoaneurysms: Brief Report and Review of Literature. AB - Traumatic aortic injury, a consequence of penetrating injuries or blunt trauma, is a life threatening condition which requires prompt diagnosis and management. Most abdominal aortic injuries have been repaired via an open surgical approach with endovascular stent graft as an alternative. Traumatic pseudoaneurysms (PSA) of the abdominal aorta are uncommon, and they are managed similar to other abdominal aortic injuries. However, the presence of a perianeurysmal hematoma and the potential risk of an associated concomitant bowel communication could make surgery and endovascular stent graft placement risky. In such patients, coil embolization could be a valued option. In this article, we present a case in which traumatic PSAs are repaired using coil embolization with technical and clinical success. Endovascular coil embolization could be an alternative approach for PSAs that cannot be treated by stent grafting or open surgical repair, in the appropriate anatomy and by using the right coil material and technique. PMID- 26524136 TI - Characterization of the VP39 envelope protein from Singapore grouper iridovirus. AB - Singapore grouper iridovirus (SGIV) is a major pathogen that causes heavy economic losses to the grouper aquaculture industry in China and Southeast Asian countries. In the present study, a viral envelope protein, VP39, encoded by SGIV ORF39L, was identified and characterized. SGIV ORF39L was found in all sequenced iridoviruses and is now considered to be a core gene of the family Iridoviridae. ORF39L was classified as a late gene during in vitro infection using reverse transcription-polymerase chain reaction, western blotting, and a drug inhibition analysis. An indirect immunofluorescence assay revealed that the VP39 protein was confined to the cytoplasm, especially at viral assembly sites. Western blot and matrix-assisted laser desorption/ionization-time of flight tandem mass spectrometry analyses suggested that VP39 is an envelope protein. Immunogold electron microscopy further confirmed that VP39 is a viral envelope protein. Furthermore, a mouse anti-VP39 polyclonal antibody exhibited SGIV-neutralizing activity in vitro, suggesting that VP39 is involved in SGIV infection. Taken together, the current data suggest that VP39 represents a conserved envelope protein of iridoviruses that contributes to viral infection. PMID- 26524137 TI - Electro-acupuncture at LI11 and ST36 acupoints exerts neuroprotective effects via reactive astrocyte proliferation after ischemia and reperfusion injury in rats. AB - Reactive astrogliosis is a common phenomenon in central nervous system (CNS) injuries such as ischemic stroke. The present study aimed to deeply investigate the relationships between the neuroprotective effect of electro-acupuncture (EA) and reactive astrocytes following cerebral ischemia. EA treatment at the Quchi (LI11) and Zusanli (ST36) acupoints at Day 3 attenuated neurological deficits and cerebral infarct volume in ischemia and reperfusion (I/R) injured rats. Animal behavior assessments found that the speed of Catwalk gait, equilibrium and coordination of Rotarod test were improved. Furthermore, EA treatment exerted neuroprotective effects via activation of glial fibrillary acidic protein (GFAP), vimentin and nestin positive cells. Simultaneously, an obvious increase in GFAP/vimentin, GFAP/nestin and GFAP/BrdU co-labeling appeared in the peri-infract cortex and striatum, suggesting EA can promote the proliferation of GFAP/vimentin/nestin-positive reactive astrocytes. The expression of cell cycle associated proteins Cyclin Dl, CDK4 and phospho-Rb were increased in the peri infract cortex and striatum, indicating proliferated reactive astrocytes-mediated CyclinDl/CDK4 regulation of the transition of the G1-to-S cell cycle phases. In addition, EA enhanced the localized expression of brain-derived neurotrophic factor (BDNF) in the peri-infract cortex and striatum. These results demonstrated that EA treatment at the LI11 and ST36 acupoints on Day 3 exerted neuroprotection via proliferation of GFAP/vimentin/nestin-positive reactive astrocytes and, potentially, secretion of reactive astrocytes-derived BDNF in I/R injured rats. PMID- 26524138 TI - Sparse SPM: Group Sparse-dictionary learning in SPM framework for resting-state functional connectivity MRI analysis. AB - Recent studies of functional connectivity MR imaging have revealed that the default-mode network activity is disrupted in diseases such as Alzheimer's disease (AD). However, there is not yet a consensus on the preferred method for resting-state analysis. Because the brain is reported to have complex interconnected networks according to graph theoretical analysis, the independency assumption, as in the popular independent component analysis (ICA) approach, often does not hold. Here, rather than using the independency assumption, we present a new statistical parameter mapping (SPM)-type analysis method based on a sparse graph model where temporal dynamics at each voxel position are described as a sparse combination of global brain dynamics. In particular, a new concept of a spatially adaptive design matrix has been proposed to represent local connectivity that shares the same temporal dynamics. If we further assume that local network structures within a group are similar, the estimation problem of global and local dynamics can be solved using sparse dictionary learning for the concatenated temporal data across subjects. Moreover, under the homoscedasticity variance assumption across subjects and groups that is often used in SPM analysis, the aforementioned individual and group analyses using sparse dictionary learning can be accurately modeled by a mixed-effect model, which also facilitates a standard SPM-type group-level inference using summary statistics. Using an extensive resting fMRI data set obtained from normal, mild cognitive impairment (MCI), and Alzheimer's disease patient groups, we demonstrated that the changes in the default mode network extracted by the proposed method are more closely correlated with the progression of Alzheimer's disease. PMID- 26524139 TI - With God on our side: Religious primes reduce the envisioned physical formidability of a menacing adversary. AB - The imagined support of benevolent supernatural agents attenuates anxiety and risk perception. Here, we extend these findings to judgments of the threat posed by a potentially violent adversary. Conceptual representations of bodily size and strength summarize factors that determine the relative threat posed by foes. The proximity of allies moderates the envisioned physical formidability of adversaries, suggesting that cues of access to supernatural allies will reduce the envisioned physical formidability of a threatening target. Across two studies, subtle cues of both supernatural and earthly social support reduced the envisioned physical formidability of a violent criminal. These manipulations had no effect on the perceived likelihood of encountering non-conflictual physical danger, raising the possibility that imagined supernatural support leads participants to view themselves not as shielded from encountering perilous situations, but as protected should perils arise. PMID- 26524140 TI - Random and non-random mating populations: Evolutionary dynamics in meiotic drive. AB - Game theoretic tools are utilized to analyze a one-locus continuous selection model of sex-specific meiotic drive by considering nonequivalence of the viabilities of reciprocal heterozygotes that might be noticed at an imprinted locus. The model draws attention to the role of viability selections of different types to examine the stable nature of polymorphic equilibrium. A bridge between population genetics and evolutionary game theory has been built up by applying the concept of the Fundamental Theorem of Natural Selection. In addition to pointing out the influences of male and female segregation ratios on selection, configuration structure reveals some noted results, e.g., Hardy-Weinberg frequencies hold in replicator dynamics, occurrence of faster evolution at the maximized variance fitness, existence of mixed Evolutionarily Stable Strategy (ESS) in asymmetric games, the tending evolution to follow not only a 1:1 sex ratio but also a 1:1 different alleles ratio at particular gene locus. Through construction of replicator dynamics in the group selection framework, our selection model introduces a redefining bases of game theory to incorporate non random mating where a mating parameter associated with population structure is dependent on the social structure. Also, the model exposes the fact that the number of polymorphic equilibria will depend on the algebraic expression of population structure. PMID- 26524141 TI - A two-clones tumor model: Spontaneous growth and response to treatment. AB - The paper aims at providing a general theoretical frame bridging the macroscopic growth law with the complex heterogeneous structure of real tumors. We apply the "Phenomenological Universality" approach to model the growth of cancer cells accounting for "populations", which are defined not as biologically pre-defined cellular ensemble but as groups of cells behaving homogeneously with respect to their position (e.g. primary or metastatic tumor), growth characteristics, response to treatment, etc. Populations may mutually interact, limit each other their growth or even mutate into another population. To keep the description as simple and manageable as possible only two populations are considered, but the extension to a multiplicity of cell populations is straightforward. Our findings indicate that the eradication of the metastatic population is much more critical in the presence of mutations, either spontaneous or therapy-induced. Furthermore, a treatment that eradicates only the primary tumor, having a low kill rate on the metastases, is ultimately not successful but promotes a "growth spurt" in the latter. PMID- 26524142 TI - Partial equilibrium approximations in apoptosis. II. The death-inducing signaling complex subsystem. AB - This paper is a continuation of our previous work (Huang and Yong, 2013) for simplifying the Fas signaling-induced apoptotic pathway identified by Hua et al. (2005) for human tumor T cells. The previous paper studied the downstream intracelluar-signaling subsystem, while the present one is concerned with the upstream death-inducing signaling complex (DISC) subsystem. Under the assumption that the bind of Fas-associated death domains and FLICE-inhibitory proteins to the DISC is much faster than that of the initiator procaspases, we greatly simplify the upstream subsystem from 35 reactions with 26 species to 6 reactions with 9 species by adopting the classical and recently justified partial equilibrium approximation method. Numerical simulations show that the simplified model is in an excellent agreement with the original model. Most importantly, the simplified model clearly reveals the key reactants and dominated pathways in the Fas signaling process, and thus provides new insights into the apoptosis. PMID- 26524143 TI - Bias in Environmental Cohort Studies: The Example of Bone Lead and Mortality. PMID- 26524144 TI - Activation of AhR-mediated toxicity pathway by emerging pollutants polychlorinated diphenyl sulfides. AB - Polychlorinated diphenyl sulfides (PCDPSs) are a group of environmental pollutants for which limited toxicological information is available. This study tested the hypothesis that PCDPSs could activate the mammalian aryl hydrocarbon receptor (AhR) mediated toxicity pathways. Eighteen PCDPSs were tested in the H4IIE-luc transactivation assay, with 13/18 causing concentration-dependent AhR activation. Potencies of several congeners were similar to those of mono-ortho substituted polychlorinated biphenyls. A RNA sequencing (RNA-seq)-based transcriptomic analysis was performed on H4IIE cells treated with two PCDPS congeners, 2,2',3,3',4,5,6-hepta-CDPS, and 2,4,4',5-tetra-CDPS. Results of RNA seq revealed a remarkable modulation on a relatively short gene list by exposure to the tested concentrations of PCDPSs, among which, Cyp1 responded with the greatest fold up-regulation. Both the identities of the modulated transcripts and the associated pathways were consistent with targets and pathways known to be modulated by other types of AhR agonists and there was little evidence for significant off-target effects within the cellular context of the H4IIE bioassay. The results suggest AhR activation as a toxicologically relevant mode of action for PCDPSs suggests the utility of AhR-related toxicity pathways for predicting potential hazards associated with PCDPS exposure in mammals and potentially other vertebrates. PMID- 26524145 TI - Fluorescent approach for visually observing quantum dot uptake in living organisms. AB - This study examines the in vivo uptake and internalization of fluorescent quantum dots (QDs) in Escherichia coli and Caenorhabditis elegans models. E. coli cells were directly exposed to QDs of different concentrations (up to 20 nM), and the uptake or sorption of QDs was monitored by flow cytometry. We observed a concentration-dependent increase in QD fluorescence with no changes in the forward or side scatter for any QD concentration, likely because the QDs are very small. Furthermore, QD uptake/adsorption did not significantly affect E. coli viability assessed by colony formation and size. QD-exposed E. coli were then fed to C. elegans to monitor the localization and effects of QDs. In our study, QDs had no observable effect on the viability or reproduction of C. elegans. We visualized QD incorporation and biodistribution by using confocal laser scanning microscopy (CLSM) with z-stacks, lambda scanning, and linear unmixing techniques, which allowed us to observe QDs in vivo and deconvolute QD fluorescence from autofluorescence. CLSM z-stacks with 10-MUm depth revealed that the QDs exclusively localized to the gut and intestine with no transfer to other tissues. The combination of these techniques for in vivo imaging of QDs and other fluorescent nanoparticles will be a powerful tool for future studies examining the uptake and biodistribution of nanoparticles. PMID- 26524146 TI - Pubertal exposure to di-(2-ethylhexyl) phthalate influences social behavior and dopamine receptor D2 of adult female mice. AB - DEHP, one of the most commonly phthalates used in plastics and many other products, is an environmental endocrine disruptor (EED). Puberty is another critical period for the brain development besides the neonatal period and is sensitive to EEDs. Social behavior is organized during puberty, so the present study is to investigate whether pubertal exposure to DEHP influenced social behavior of adult female mice. The results showed that pubertal exposure to DEHP for 2 weeks did not change the serum level of 17beta-estradiol and the weight of uterus of adult females, but decreased the number of grid crossings and the frequency of rearing, and increased grooming in open field. DEHP reduced the open arm entries and the time spent in open arms in the elevated plus maze. DEHP reduced mutual sniffing and grooming between unfamiliar conspecifics in social play task and reduced the right chamber (containing unfamiliar female mouse) entries and the frequency of sniffing unfamiliar female mouse. DEHP at 1 mg kg( 1) d(-1) reduced the time spent in right chamber. Furthermore, Western blot analyses showed that DEHP decreased the levels of estrogen receptor beta (ERbeta), dopamine receptor D2, and the phosphorylation of ERKs in striatum. These results suggest that pubertal exposure to DEHP impaired social investigation and sociability and influenced anxiety-like state of adult female mice. The decreased activity of ERK1/2, and the down-regulated D2 and ERbeta in striatum may be associated with the DEHP-induced changes of emotional and social behavior in mice. PMID- 26524147 TI - Transformation of polyfluorinated compounds in natural waters by advanced oxidation processes. AB - The presence of perfluorocarboxylic acids (PFCAs) in source and finished drinking waters is a concern with studies showing bioaccumulation and adverse toxicological effects in wildlife and potentially humans. Per/Polyfluoroalkyl substances (PFAS) such as fluorotelomer alcohols have been identified as precursors for PFCAs in biological pathways. In this study, we investigated the fate of 6:2 and 8:2 homologues of the fluorotelomer unsaturated carboxylic acids (FTUCAs) during advanced oxidation process (AOPs). Results showed 6:2 FTUCA and 8:2 FTUCA transformed into 6-C PFCA (PFHxA) and 8-C PFCA (PFOA) respectively with very little other PFCA formation for all AOPs. The degradation of 6:2 FTUCA and 8:2 FTUCA was greater in the GW compared to SW for the ozone processes but similar for UV/H2O2. The formation of n-C PFCA followed O3>O3/H2O2 at same dose and UV/H2O2 had much lower formation at the doses tested. Non-targeted analysis with the LC-MS-qTOF indicated the production of other PFCAs which contribute to the total mass balance, although no intermediate product was discovered indicating a rapid and direct transformation from the FTUCAs to the PFCAs and/or significant volatilization of intermediates. With the use of AOPs essential to water reuse treatment schemes, this work raises concerns over the risk of potential formation of PFCAs in the treatment and their adverse health effects in finished drinking water. PMID- 26524148 TI - Temporal and spatial variation of trace elements in atmospheric deposition around the industrial area of Puchuncavi-Ventanas (Chile) and its influence on exceedances of lead and cadmium critical loads in soils. AB - Fractionation of elemental contents in atmospheric samples is useful to evaluate pollution levels for risk assessment and pollution sources assignment. We present here the main results of long-term characterization of atmospheric deposition by using a recently developed atmospheric elemental fractionation sampler (AEFS) for major and trace elements monitoring around an important industrial complex located in Puchuncavi region (Chile). Atmospheric deposition samples were collected during two sampling campaigns (2010 and 2011) at four sampling locations: La Greda (LG), Los Maitenes (LM), Puchuncavi (PU) and Valle Alegre (VA). Sample digestion and ICP-MS gave elements deposition values (Al, As, Ba, Cd, Co, Cu, Fe, K, Mn, Pb, Sb, Ti, V and Zn) in the insoluble fraction of the total atmospheric deposition. Results showed that LG location, the closest location to the industrial complex, was the more polluted sampling site having the highest values for the analyzed elements. PU and LM were the next more polluted and, finally, the lowest elements concentrations were registered at VA. The application of Principal Component Analysis and Cluster Analysis identified industrial, traffic and mineral-crustal factors. We found critical loads exceedances for Pb at all sampling locations in the area affected by the industrial emissions, more significant in LG close to the industrial complex, with a trend to decrease in 2011, whereas no exceedances due to atmospheric deposition were detected for Cd. PMID- 26524149 TI - Enhanced phosphorus recovery and biofilm microbial community changes in an alternating anaerobic/aerobic biofilter. AB - The operation of an alternating anaerobic/aerobic biofilter (AABF), treating synthetic wastewater, was modified to enhance recovery of phosphorus (P). The AABF was periodically fed with an additional carbon source during the anaerobic phase to force the release of biofilm-sequestered P which was then harvested and recovered. A maximum of 48% of the total influent P was found to be released in the solution for recovery. Upon implementation of periodic P bio-sequestering and P harvesting, the predominant bacterial communities changed from beta Proteobacteria to gamma-Proteobacteria groups. The genus Pseudomonas of gamma Proteobacteria was found to enrich greatly with 98% dominance. Dense intracellular poly-P granules were found within the cells of the biofilm, confirming the presence of P accumulating organisms (PAOs). Periodic addition of a carbon source to the AABF coupled with intracellular P reduction during the anaerobic phase most probably exerted environmental stress in the selection of Pseudomonas PAOs over PAOs of other phylogenic types. Results of the study provided operational information on the selection of certain microbial communities for P removal and recovery. This information can be used to further advance P recovery in biofilm systems such as the AABFs. PMID- 26524150 TI - Antibiotics for acute otitis media in children. AB - Acute otitis media is one of the most common infectious diseases diagnosed in children. Antibiotic treatment use remains controversial. This summary aims to evaluate the effectiveness and safety of antibiotics in children with acute otitis media. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 18 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded antibiotics reduce pain at 48-72 hours and reduce the risk of tympanic perforations in children with acute otitis media, but they do not reduce late recurrences and increase the risk of side effects (rash, vomiting and diarrhea). PMID- 26524151 TI - NSAID-induced Gastrointestinal Injury: A Focused Update for Clinicians. AB - Gastroenterologists care for users of nonsteroidal anti-inflammatory drugs (NSAIDs) when the vast population exposed to the medication class experiences a relatively uncommon serious gastrointestinal (GI) side effect. As serious adverse cardiovascular (CV) effects of these drugs have also been recognized, there remains continued confusion about the best treatment for patients who benefit from NSAID therapy and are at risk for GI and CV adverse events. Recognition of those patients at risk and strategies to reduce the adverse side effects of NSAIDs continues to provide an opportunity to improve patient outcomes. This review discusses the injury induced by these agents throughout the GI tract as well as strategies to prevent acute injury and reduce the development of serious adverse events. NSAID medication selection as well as GI cotherapy should balance individual patients' GI and CV risks. PMID- 26524152 TI - Celiac Disease and Double-Balloon Enteroscopy: What Can We Achieve?: The Experience of 2 European Tertiary Referral Centers. AB - BACKGROUND: Indications to double-balloon enteroscopy (DBE) are not standardized in celiac disease (CD). GOALS: To evaluate the clinical usefulness of DBE in complicated CD. STUDY: DBE findings in celiac patients with suspected small bowel (SB) complications were retrospectively evaluated in 2 tertiary referral centers (Milan and Sheffield). Demographic data of the studied cohort were compared with a database of 1000 noncomplicated CD patients. RESULTS: Twenty-four CD cases (12 males, P=0.01 vs. controls) were reviewed. Mean age at CD diagnosis (y+/-SD) was 37+/-20 versus 27+/-18 and at SB evaluation 47+/-15 versus 38+/-13 (P<0.01 compared with controls). Indications for DBE were refractory CD (#9), gastrointestinal symptoms (#6), severe iron-deficiency anemia (#6), and long standing poor dietary adherence (#3). Two jejunal adenocarcinomas and an ileal neuroendocrine tumor were detected in presence of iron-deficiency anemia. Three type I and 3 type II refractory CD patients showed jejunal ulcerations; 2 of type II presented small white raised patches. Patchy atrophy was observed in nonadherent patients and in 2 on a gluten-free diet for a short time. Therapy was planned in 33% of patients after DBE. No adverse events were detected at follow up [21 mo (range, 0 to 60 mo)]. CONCLUSIONS: This is the largest international study on the outcomes of DBE in CD demonstrating its usefulness to exclude/confirm malignant or premalignant conditions, associated with even minor lesions. Studies are needed to understand the clinical relevance of the SB endoscopic features and to optimize DBE indications. PMID- 26524153 TI - Hexaethylsubporphyrins: beta-alkyl analogues in the subporphyrin family. AB - Two new subporphyrins were synthesized for the first time from a beta-substituted pyrrole i.e. 3,4-diethylpyrrole via pyridine-tri-N-(3,4-diethylpyrrolyl)borane as building blocks. These beta-hexaethylsubporphyrins are true contracted congeners of beta-octaethylporphyrin (OEP). While the meso-triphenyl derivative of hexaethylsubporphyrin could be synthesized by following the reported method, the meso-free analogue could only be synthesized by condensation with trioxane, in the presence of catalytic methanesulfonic acid. These contracted macrocycles display interesting absorption, and emission behaviour including substituent dependent S2 fluorescence owing to the presence of flexible electron donating ethyl groups at their beta-positions. The optical response and ultrafast S2 state dynamics of these systems suggest that it may be possible to tune the properties of the subporphyrin to develop efficient systems for solar energy capture and conversion processes. PMID- 26524154 TI - A critical examination of the evidence for sensitivity loss in modern vigilance tasks. AB - It is well known that when human observers must monitor for rare but critical events, probability of detection tends to wane over time, a phenomenon known as the "vigilance decrement." Over 60 years of empirical study on this topic has culminated in the general consensus that performance suffers due to a loss in observers' ability to distinguish signal from noise (a loss in sensitivity) provided that the task loads memory and stimuli are presented at a relatively high rate. We challenge this assertion on 2 fronts: First, we contend on a theoretical level that the metrics employed to measure observer sensitivity in modern vigilance tasks (derived from signal detection theory) are inappropriate and largely uninterpretable. This contention is supported by an evaluation of recent empirical work in the vigilance domain. Second, we present the results of an experiment that demonstrates that shifts in response bias (the observer's "willingness to respond") over time can masquerade as a loss in sensitivity. Consequently, the basic underlying cause of the vigilance decrement is actually unclear, and may simply reflect a shift in response criterion rather than sensitivity. The theoretical, as well as practical implications of these conclusions are discussed with respect to sustained attention in general, and vigilance in particular. PMID- 26524155 TI - Suicide as a derangement of the self-sacrificial aspect of eusociality. AB - Building upon the idea that humans may be a eusocial species (i.e., rely on multigenerational and cooperative care of young, utilize division of labor for successful survival), we conjecture that suicide among humans represents a derangement of the self-sacrificial aspect of eusociality. In this article, we outline the characteristics of eusociality, particularly the self-sacrificial behavior seen among other eusocial species (e.g., insects, shrimp, mole rats). We then discuss parallels between eusocial self-sacrificial behavior in nonhumans and suicide in humans, particularly with regard to overarousal states, withdrawal phenomena, and perceptions of burdensomeness. In so doing, we make the argument that death by suicide among humans is an exemplar of psychopathology and is due to a derangement of the self-sacrificial behavioral suite found among eusocial species. Implications and future directions for research are also presented. PMID- 26524156 TI - In vitro Diagnosis of Immediate Drug Hypersensitivity: Should We Go with the Flow. AB - BACKGROUND: Diagnosis of immediate drug hypersensitivity reactions (IDHRs) is based upon history taking, skin prick or intradermal tests and quantification of specific immunoglobulin E (IgE) antibodies. Unfortunately, this is often insufficient to correctly identify patients with IgE-mediated IDHRs and is impossible in the case of non-IgE-mediated IDHRs. Drug provocation tests (DPT) are considered the 'gold standard' diagnostic but are not always possible, for ethical and practical reasons. Therefore, the validation of new cellular tests such as basophil activation testing (BAT) was necessary. This review focuses on the applications of BAT in IDHRs. METHODS: A literature search was conducted, using the words basophil, flow cytometry, immediate drug allergy and drugs; this was complemented by the authors' own expertise. RESULTS: BAT/HistaFlow(r) is a useful diagnostic tool in IDHRs, mainly used to diagnose allergy to neuromuscular blocking agents (NMBAs), antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs) and iodinated radiocontrast media. Its sensitivity varies between 50 and 60%, and specificity attains 80%, except for with quinolones and NSAIDs. CONCLUSIONS: The diagnostic utility of BAT (and to lesser extent HistaFlow) has been demonstrated and is mostly applied in IDHRs. However, larger-scale collaborative studies are necessary to optimize test protocols and validate the entry of BAT as a diagnostic instrument in drug allergy. PMID- 26524157 TI - Electrically-charged recyclable graphene flakes entangled with electrospun nanofibers for the adsorption of organics for water purification. AB - Graphene flakes were entrapped between nylon 6 nanofiber layers and the resulting assembly was used as a recyclable water purification membrane. Water purification was achieved via adsorption of the model organic pollutant (methylene blue; MB) on the surface of the graphene component. Desorption of these MB molecules was achieved by applying high voltage, which increased the removal efficiency of the recycled membrane. The adsorption and desorption mechanisms were evaluated in detail. The material characteristics of the membrane were analyzed by scanning electron microscopy, Raman, UV-visible, and Fourier transform infrared analyses. PMID- 26524158 TI - Controllable assembly of well-defined monodisperse Au nanoparticles on hierarchical ZnO microspheres for enhanced visible-light-driven photocatalytic and antibacterial activity. AB - A high-efficiency visible-light-driven photocatalyst composed of homogeneously distributed Au nanoparticles (AuNPs) well-defined on hierarchical ZnO microspheres (ZMS) via a controllable layer-by-layer self-assembly technique is demonstrated. The gradual growth of the characteristic absorption bands of Au loaded on ZnO in the visible light region with an increasing number of assemblies indicates the enhancement of the light harvesting ability of the ZMS/Au composites as well as the reproducibility and controllability of the entire assembly process. Results on the photoelectrochemical performance characterized by EIS and transient photocurrent response spectra indicate that the ZMS/Au composites possess increased photoinduced charge separation and transfer efficiency compared to the pure ZMS film. As a result, the hybrid composites exhibited enhanced decomposition activity for methylene blue and salicylic acid as well as antibacterial activity in killing S. aureus and E. coli under visible light irradiation. It can be noted that well-distributed Au components even at a rather low Au/ZnO weight ratio of ~1.2% also exhibited extraordinary photocatalysis. Such a facile and controllable self-assembly approach may be viable for preparing high-performance visible-light-driven ZMS/Au photocatalysts in a simple and controllable way, and consequently, the technology may extend to other plasmon-enhanced heterostructures made of nanostructured semiconductors and noble metals for great potential application in environmental protection. PMID- 26524159 TI - Severe Pediatric Thyroid Eye Disease: Surgical Case Series. AB - Thyroid eye disease (TED) usually has mild manifestations in pediatric patients, and orbital decompression is rarely necessarily. The authors present the clinical course of 3 pediatric patients age 16 or younger at the time of decompression surgery with severe orbitopathy. Case 1 is a 9-year-old prepubertal Asian American female with Graves' disease and TED who underwent balanced decompression for compressive optic neuropathy. Case 2 is a 14-year-old white female with Graves' disease and TED who underwent balanced decompression for compressive optic neuropathy, stretch optic neuropathy, and globe subluxation. Case 3 is a 14 year-old African-American male with unilateral euthyroid TED who underwent staged right-sided lateral, medial, and floor decompressions for asymmetric proptosis. All cases also had disfiguring proptosis and exposure keratopathy, and in all cases, surgery successfully ameliorated the indications. Children, both pre- and post-pubertal, can rarely manifest visually threatening severe orbitopathy due to TED. This represents the first reports of thyroid-related optic neuropathy and globe subluxation in pediatric patients. Further studies examining the mechanism responsible for the disparities in pediatric and adult TED are warranted. PMID- 26524160 TI - Orbital Complication Following Calcium Hydroxylapatite Filler Injection. AB - Cosmetic facial fillers have gained immense popularity in recent years. Although some patients opt to undergo an injection over surgery in light of the risks of an operation, there have been numerous reports of complications from these injections, including blindness. It is thought that filler particles can migrate within an artery and become emboli within small vessels. This case of focal orbital inflammation and dysmotility as a consequence of calcium hydroxylapatite filler injection in the face has not yet been documented in the literature. PMID- 26524161 TI - Editorial. PMID- 26524162 TI - Epigenetic Mechanisms: An Emerging Player in Plant-Microbe Interactions. AB - Plants have developed diverse molecular and cellular mechanisms to cope with a lifetime of exposure to a variety of pathogens. Host transcriptional reprogramming is a central part of plant defense upon pathogen recognition. Recent studies link DNA methylation and demethylation as well as chromatin remodeling by posttranslational histone modifications, including acetylation, methylation, and ubiquitination, to changes in the expression levels of defense genes upon pathogen challenge. Remarkably these inducible defense mechanisms can be primed prior to pathogen attack by epigenetic modifications and this heightened resistance state can be transmitted to subsequent generations by inheritance of these modification patterns. Beside the plant host, epigenetic mechanisms have also been implicated in virulence development of pathogens. This review highlights recent findings and insights into epigenetic mechanisms associated with interactions between plants and pathogens, in particular bacterial and fungal pathogens, and demonstrates the positive role they can have in promoting plant defense. PMID- 26524163 TI - Fluorescence emissions of imide compounds and end-capped polyimides enhanced by intramolecular double hydrogen bonds. AB - The structure and optical properties of a newly synthesized imide compound (DHNHPI) that forms intramolecular double hydrogen bonds (intra-HBs) were investigated. This compound exhibits intense absorption at 372 nm (epsilon = 5091 cm(-1) M(-1)) and strong emission at 427 nm (Phi = 0.507) in CHCl3. Under basic conditions, the absorption and fluorescence peaks showed large bathochromic shifts by 70 nm and 95 nm, respectively, compared with the neutral condition due to conversion to anion form. Based on the single-crystal X-ray diffraction analysis, DHNHPI can exert intermolecular pi-pi interactions between adjacent molecules along the stacking direction, with resultant emission peaks exhibiting longer wavelengths (~525 nm) in the solid state. Moreover, an end-capped polyimide having DHNHPI moieties at the termini exhibited a strong fluorescence peak at 427 nm by photo-excitation at 332 nm. The large Stokes shift of 6701 cm( 1) clearly indicates the occurrence of an effective Forster-resonance energy transfer from the main chains to the fluorescent end-groups. These facts demonstrate that the incorporation of two -OH groups, which form intra-HBs, endows imide compounds and polyimides with enhanced fluorescence properties as well as high sensitivity towards pH. PMID- 26524164 TI - An investigation of the electron density of a Jahn-Teller-distorted Cr(II) cation: the crystal structure and charge density of hexakis(acetonitrile kappaN)chromium(II) bis(tetraphenylborate) acetonitrile disolvate. AB - In the crystal structure of the title homoleptic Cr(II) complex, [Cr(CH3CN)6](C24H20B)2.CH3CN, the [Cr(CH3CN)6](2+) cation is a high-spin d(4) complex with strong static, rather than dynamic, Jahn-Teller distortion. The electron density of the cation was determined by single-crystal X-ray refinements using aspherical structure factors from wavefunction calculations. The detailed picture of the electronic density allowed us to assess the extent and directionality of the Jahn-Teller distortion of the Cr(II) cation away from idealized octahedral symmetry. The topological analysis of the aspherical d electron density about the Cr(II) cation showed that there are significant valence charge concentrations along the axial Cr-N axes. Likewise, there were significant valence charge depletions about the Cr(II) cation along the equatorial Cr-N bonds. These charge concentrations are in accordance with a Jahn Teller-distorted six-coordinate complex. PMID- 26524165 TI - Hirshfeld surface analysis of sulfameter (polymorph III), sulfameter dioxane monosolvate and sulfameter tetrahydrofuran monosolvate, all at 296 K. AB - The ability of the antibacterial agent sulfameter (SMT) to form solvates is investigated. The X-ray crystal structures of sulfameter solvates have been determined to be conformational polymorphs. Both 1,4-dioxane and tetrahydrofuran form solvates with sulfameter in a 1:1 molar ratio. 4-Amino-N-(5-methoxypyrimidin 2-yl)benzenesulfonamide (polymorph III), C11H12N4O3S, (1), has two molecules of sulfameter in the asymmetric unit cell. 4-Amino-N-(5-methoxypyrimidin-2 yl)benzenesulfonamide 1,4-dioxane monosolvate, C11H12N4O3S.C4H8O2, (2), and 4 amino-N-(5-methoxypyrimidin-2-yl)benzenesulfonamide tetrahydrofuran monosolvate, C11H12N4O3S.C4H8O, (3), crystallize in the imide form. Hirshfeld surface analyses and fingerprint analyses were performed to study the nature of the interactions and their quantitative contributions towards the crystal packing. Finally, Hirshfeld surfaces, fingerprint plots and structural overlays were employed for a comparison of the two independent molecules in the asymmetric unit of (1), and also for a comparison of (2) and (3) in the monoclinic crystal system. A three dimensional hydrogen-bonding network exists in all three structures, involving one of the sulfone O atoms and the aniline N atom. All three structures are stabilized by strong intermolecular N-H...N interactions. The tetrahydrofuran solvent molecule also takes part in forming significant intermolecular C-H...O interactions in the crystal structure of (3), contributing to the stability of the crystal packing. PMID- 26524166 TI - Dehydration of raffinose pentahydrate: structures of raffinose 5-, 4.433-, 4.289- and 4.127-hydrate at 93 K. AB - Raffinose [or O-alpha-D-galactopyranosyl-(1->6)-alpha-D-glucopyranosyl-(1->2) beta-D-fructofuranoside] pentahydrate, C18H32O16.5H2O, (I), and three lower hydrates, namely the 4.433-, (II), 4.289-, (III), and 4.127-hydrated, (IV), forms, obtained in the course of the dehydration of (I), have been studied. The unit cells in the space group P212121 are of similar dimensions for all the crystals. The conformation of the raffinose molecules remains almost the same across the four crystal structures. The raffinose molecules are linked into a three-dimensional hydrogen-bonded network involving all the -OH groups, the ring and glycosidic O atoms, and the water molecules. Six water sites were identified in the structures of (II), (III) and (IV), of which W1, W4 and W6 (W = water) are partially occupied with their populations coupled. W1, W4 and one of the -OH groups of the galactose ring form an infinite hydrogen-bonding chain around a 21 axis parallel to the a axis (denoted chain A), and W6 and the same -OH group form a similar chain (chain A') disordered with chain A. The occupancy ratio of chain A to chain A' for N-hydrates (N is a hydration number between 4 and 5) is (N - 4):(5 - N). The transformation of chain A to chain A' as part of the dehydration process has little effect on the rest of the structure. Thus, the dehydration proceeds without significant impact on the crystal structure. PMID- 26524167 TI - The interplay of solvation, molecular conformation and supramolecular assembly in 1,1'-({[(ethane-1,2-diyl)dioxy](1,2 phenylene)}bis(methanylylidene))bis(thiosemicarbazide) and its N,N dimethylformamide disolvate. AB - The wide diversity of applications of thiosemicarbazones and bis(thiosemicarbazones) has seen them used as anticancer and antitubercular agents, and as ligands in metal complexes designed to act as site-specific radiopharmaceuticals. Molecules of 1,1'-({[(ethane-1,2-diyl)dioxy](1,2 phenylene)}bis(methanylylidene))bis(thiosemicarbazide) {alternative name: 2,2' [ethane-1,2-diylbis(oxy)]dibenzaldehyde bis(thiosemicarbazide)}, C18H20N6O2S2, (I), lie across twofold rotation axes in the space group C2/c, with an O-C-C-O torsion angle of -59.62 (13) degrees and a trans-planar arrangement of the thiosemicarbazide fragments relative to the adjacent aryl rings. The molecules of (I) are linked by N-H...S hydrogen bonds to form sheets containing R(2)4(38) rings and two types of R(2)2(8) ring. In the N,N-dimethylformamide disolvate, C18H20N6O2S2.2C3H7NO, (II), the independent molecular components all lie in general positions, but one of the solvent molecules is disordered over two sets of atomic sites having occupancies of 0.839 (3) and 0.161 (3). The O-C-C-O torsion angle in the ArOCH2CH2OAr component is -75.91 (14) degrees and the independent thiosemicarbazide fragments both adopt a cis-planar arrangement relative to the adjacent aryl rings. The ArOCH2CH2OAr components in (II) are linked by N-H...S hydrogen bonds to form deeply puckered sheets containing R(2)2(8), R(2)4(8) and two types of R(2)2(38) rings, and which contain cavities which accommodate all of the solvent molecules in the interior of the sheets. Comparisons are made with some related compounds. PMID- 26524168 TI - Synthesis and structures of ruthenium di- and tricarbonyl complexes derived from 4,5-diazafluoren-9-one. AB - Carbon monoxide (CO) has recently been shown to impart beneficial effects in mammalian physiology and considerable research attention is now being directed toward metal-carbonyl complexes as a means of delivering CO to biological targets. Two ruthenium carbonyl complexes, namely trans-dicarbonyldichlorido(4,5 diazafluoren-9-one-kappa(2)N,N')ruthenium(II), [RuCl2(C11H6N2O)(CO)2], (1), and fac-tricarbonyldichlorido(4,5-diazafluoren-9-one-kappaN)ruthenium(II), [RuCl2(C11H6N2O)(CO)3], (2), have been isolated and structurally characterized. In the case of complex (1), the trans-directing effect of the CO ligands allows bidentate coordination of the 4,5-diazafluoren-9-one (dafo) ligand despite a larger bite distance between the N-donor atoms. In complex (2), the cis disposition of two chloride ligands restricts the ability of the dafo molecule to bind ruthenium in a bidentate fashion. Both complexes exhibit well defined (1)H NMR spectra confirming the diamagnetic ground state of Ru(II) and display a strong absorption band around 300 nm in the UV. PMID- 26524169 TI - Structure and magnetic properties of a copper(II) coordination polymer based on azide, pyridine and homophthalic acid. AB - The azide anion is a short bridging ligand that has been used extensively to construct magnetic coordination polymers, and fundamental magneto-structural correlations have been substantiated by theoretical calculations. The copper(II) coordination polymer poly[bis(MU-azido-kappa(2)N(1):N(1))(MU4-homophthalato kappa(4)O:O':O'':O''')bis(pyridine-kappaN)dicopper(II)], [Cu2(C9H6O4)(N3)2(C5H5N)2]n, was synthesized from homophthalic acid (2 carboxyphenylacetic acid), pyridine and azide (N3(-)) by a hydrothermal reaction. Single-crystal structure analysis indicated that it features a one-dimensional chain structure which is comprised of (MU1,1-N3(-))(MU-syn-syn-COO(-))2- and (MU1,1-N3(-))2-bridged tetranuclear Cu(II) units. Magnetic measurements revealed that the compound exhibits dominant antiferromagnetic behaviour. PMID- 26524170 TI - Two new isatin derivatives: 1-benzyl-4,5,6-trimethoxyindoline-2,3-dione and 1 benzyl-5-fluoroindoline-2,3-dione. AB - Isatin (1H-indole-2,3-dione) derivatives represent synthetically useful substrates which can be used to prepare a broad range of heterocyclic compounds. In the title compounds, C18H17NO5, (I), and C15H10FNO2, (II), the isatin ring systems are planar and form a dihedral angle of 73.04 (7) degrees in (I) and 76.82 (11) degrees in (II) with the benzyl groups. The bicyclic scaffolds in both compounds are almost superimposable, with an r.m.s. deviation of 0.061 A. The crystal structures of both derivatives are stabilized by C-H...O interactions. These contacts generate an R(1)2(7) ring motif in (I) and a C(7) chain motif in (II). PMID- 26524171 TI - Two different one-dimensional Cd(II) halide coordination polymers constructed through bridging carboxylate ligands. AB - Two cadmium halide complexes, catena-poly[[chloridocadmium(II)]-di-MU-chlorido [chloridocadmium(II)]-bis[MU2-4-(dimethylamino)pyridin-1-ium-1-acetate] kappa(3)O:O,O';kappa(3)O,O':O], [CdCl2(C9H12N2O2)]n, (I), and catena-poly[1 cyanomethyl-1,4-diazoniabicyclo[2.2.2]octane [[dichloridocadmium(II)]-MU-oxalato kappa(4)O(1),O(2):O(1'),O(2')] monohydrate], {(C8H15N3)[CdCl2(C2O4)].H2O}n, (II), were synthesized in aqueous solution. In (I), the Cd(II) cation is octahedrally coordinated by three O atoms from two carboxylate groups and by one terminal and two bridging chloride ligands. Neighbouring Cd(II) cations are linked together by chloride anions and bridging O atoms to form a one-dimensional zigzag chain. Hydrogen-bond interactions are involved in the formation of the two-dimensional network. In (II), each Cd(II) cation is octahedrally coordinated by four O atoms from two oxalic acid ligands and two terminal Cl(-) ligands. Neighbouring Cd(II) cations are linked together by oxalate groups to form a one-dimensional anionic chain, and the water molecules and organic cations are connected to this one dimensional zigzag chain through hydrogen-bond interactions. PMID- 26524172 TI - Supramolecular hydrogen-bonding patterns in two cocrystals of the N(7)-H tautomeric form of N(6)-benzoyladenine: N(6)-benzoyladenine-3-hydroxypyridinium-2 carboxylate (1/1) and N(6)-benzoyladenine-DL-tartaric acid (1/1). AB - Two novel cocrystals of the N(7)-H tautomeric form of N(6)-benzoyladenine (BA), namely N(6)-benzoyladenine-3-hydroxypyridinium-2-carboxylate (3HPA) (1/1), C12H9N5O.C6H5NO3, (I), and N(6)-benzoyladenine-DL-tartaric acid (TA) (1/1), C12H9N5O.C4H6O6, (II), are reported. In both cocrystals, the N(6)-benzoyladenine molecule exists as the N(7)-H tautomer, and this tautomeric form is stabilized by intramolecular N-H...O hydrogen bonding between the benzoyl C=O group and the N(7)-H hydrogen on the Hoogsteen site of the purine ring, forming an S(7) motif. The dihedral angle between the adenine and phenyl planes is 0.94 (8) degrees in (I) and 9.77 (8) degrees in (II). In (I), the Watson-Crick face of BA (N6-H and N1; purine numbering) interacts with the carboxylate and phenol groups of 3HPA through N-H...O and O-H...N hydrogen bonds, generating a ring-motif heterosynthon [graph set R2(2)(6)]. However, in (II), the Hoogsteen face of BA (benzoyl O atom and N7; purine numbering) interacts with TA (hydroxy and carbonyl O atoms) through N-H...O and O-H...O hydrogen bonds, generating a different heterosynthon [graph set R2(2)(4)]. Both crystal structures are further stabilized by pi-pi stacking interactions. PMID- 26524173 TI - Halogen bonds on demand: I...S contacts in cocrystals of trans-bis(thiocyanato kappaN)tetrakis(4-vinylpyridine-kappaN)nickel(II) and 2,3,5,6-tetrafluoro-1,4 diiodobenzene. AB - Hydrogen bonds are considered a powerful organizing force in designing supramolecular architectures because they are directional, selective and reversible at room temperature. trans-Dithiocyanatotetrakis(4 vinylpyridine)nickel(II) is a popular host for the inclusion of small molecules and 2,3,5,6-tetrafluoro-1,4-diiodobenzene (TFDIB) represents a strong halogen bond donor. These constituents cocrystallize in a 1:1 stoichiometry, [Ni(NCS)2(C7H7N)4].C6F4I2, in the tetragonal space group I41/a. Both residues occupy special positions, i.e. the pseudo-octahedral Ni(II) complex is located on a twofold axis and the TFDIB molecule sits about a crystallographic centre of inversion. The components interact via a short S...I contact of 3.2891 (12) A between the thiocyanate S atom of the host and the iodine substituent at the perhalogenated aromatic ring of the smaller guest molecule. This interaction meets the commonly accepted criteria for a halogen bond. Such halogen bonds to sulfur are significantly less common than to smaller electronegative atoms. PMID- 26524174 TI - The new structure type Gd3Ni7Al14. AB - The crystal structure of Gd3Ni7Al14 (trigadolinium heptanickel tetradecaaluminide) belongs to a family of two-layer structures and can be described as an assembly of interpenetrating centred straight prisms. For the Ni atoms, trigonal prisms (Al4Gd2 and Al6) are observed, the Al atoms are inside tetragonal (Ni2Al2Gd4, Ni2Al4Gd2, Al4Gd4, Ni4Al4 and Al8) and pentagonal (Ni4Al6 and Al10) prisms, while the Gd atoms are at the centres of pentagonal (Ni4Al6) and hexagonal (Ni4Al8) prisms. In each case, the true coordination polyhedron is a capped prism, also including atoms from the same layer. The structural features of Gd3Ni7Al14 are similar to those of the intermetallides PrNi2Al3 and ZrNiAl. In all these structures, Ni-centred trigonal prisms form infinite columns via common triangular faces. The columns share prism edges and form a three-dimensional framework with six-membered rings in the (001) plane in the case of the PrNi2Al3 and ZrNiAl types. In the case of Gd3Ni7Al14, six-membered rings are also observed, but only two-thirds of the rings are interconnected via prism edges. PMID- 26524175 TI - Structural consequences of weak interactions in dispirooxindole derivatives. AB - Spiro scaffolds are being increasingly utilized in drug discovery due to their inherent three-dimensionality and structural variations, resulting in new synthetic routes to introduce spiro building blocks into more pharmaceutically active molecules. Multicomponent cascade reactions, involving the in situ generation of carbonyl ylides from alpha-diazocarbonyl compounds and aldehydes, and 1,3-dipolar cycloadditon with 3-arylideneoxindoles gave a novel class of dispirooxindole derivatives, namely 1,1''-dibenzyl-5'-(4-chlorophenyl)-4'-phenyl 4',5'-dihydrodispiro[indoline-3,2'-furan-3',3''-indoline]-2,2''-dione, C44H33ClN2O3, (I), 1''-acetyl-1-benzyl-5'-(4-chlorophenyl)-4'-phenyl-4',5' dihydrodispiro[indoline-3,2'-furan-3',3''-indoline]-2,2''-dione, C39H29ClN2O4, (II), 1''-acetyl-1-benzyl-4',5'-diphenyl-4',5'-dihydrodispiro[indoline-3,2'-furan 3',3''-indoline]-2,2''-dione, C39H30N2O4, (III), and 1''-acetyl-1-benzyl-4',5' diphenyl-4',5'-dihydrodispiro[indoline-3,2'-furan-3',3''-indoline]-2,2''-dione acetonitrile hemisolvate, C39H30N2O4.0.5C2H3N, (IV). All four compounds exist as racemic mixtures of the SSSR and RRRS stereoisomers. In these structures, the two H atoms of the dihydrofuran ring and the two substituted oxindole rings are in a trans orientation, facilitating intramolecular C-H...O and pi-pi interactions. These weak interactions play a prominent role in the structural stability and aid the highly regio- and diastereoselective synthesis. In each of the four structures, the molecular assembly in the crystal is also governed by weak noncovalent interactions. Compound (IV) is the solvated analogue of (III) and the two compounds show similar structural features. PMID- 26524176 TI - Crystal structures of the pyrazinamide-p-aminobenzoic acid (1/1) cocrystal and the transamidation reaction product 4-(pyrazine-2-carboxamido)benzoic acid in the molten state. AB - The synthesis of pharmaceutical cocrystals is a strategy to enhance the performance of active pharmaceutical ingredients (APIs) without affecting their therapeutic efficiency. The 1:1 pharmaceutical cocrystal of the antituberculosis drug pyrazinamide (PZA) and the cocrystal former p-aminobenzoic acid (p-ABA), C7H7NO2.C5H5N3O, (1), was synthesized successfully and characterized by relevant solid-state characterization methods. The cocrystal crystallizes in the monoclinic space group P21/n containing one molecule of each component. Both molecules associate via intermolecular O-H...O and N-H...O hydrogen bonds [O...O = 2.6102 (15) A and O-H...O = 168.3 (19) degrees ; N...O = 2.9259 (18) A and N H...O = 167.7 (16) degrees ] to generate a dimeric acid-amide synthon. Neighbouring dimers are linked centrosymmetrically through N-H...O interactions [N...O = 3.1201 (18) A and N-H...O = 136.9 (14) degrees ] to form a tetrameric assembly supplemented by C-H...N interactions [C...N = 3.5277 (19) A and C-H...N = 147 degrees ]. Linking of these tetrameric assemblies through N-H...O [N...O = 3.3026 (19) A and N-H...O = 143.1 (17) degrees ], N-H...N [N...N = 3.221 (2) A and N-H...N = 177.9 (17) degrees ] and C-H...O [C...O = 3.5354 (18) A and C-H...O = 152 degrees ] interactions creates the two-dimensional packing. Recrystallization of the cocrystals from the molten state revealed the formation of 4-(pyrazine-2-carboxamido)benzoic acid, C12H9N3O3, (2), through a transamidation reaction between PZA and p-ABA. Carboxamide (2) crystallizes in the triclinic space group P1 with one molecule in the asymmetric unit. Molecules of (2) form a centrosymmetric dimeric homosynthon through an acid-acid O-H...O hydrogen bond [O...O = 2.666 (3) A and O-H...O = 178 (4) degrees ]. Neighbouring assemblies are connected centrosymmetrically via a C-H...N interaction [C...N = 3.365 (3) A and C-H...N = 142 degrees ] engaging the pyrazine groups to generate a linear chain. Adjacent chains are connected loosely via C-H...O interactions [C...O = 3.212 (3) A and C-H...O = 149 degrees ] to generate a two-dimensional sheet structure. Closely associated two-dimensional sheets in both compounds are stacked via aromatic pi-stacking interactions engaging the pyrazine and benzene rings to create a three-dimensional multi-stack structure. PMID- 26524178 TI - Crystallographic identification of an unexpected by-product in an Ullman's reaction toward biphenyls: 1-(4-hexyloxy-3-hydroxyphenyl)ethanone. AB - The synthesis of 3,3'-diacetoxy-4,4'-bis(hexyloxy)biphenyl following the nickel modified Ullmann reaction yielded a by-product which was identified successfully by crystallographic analysis as 1-(4-hexyloxy-3-hydroxyphenyl)ethanone, C14H20O3. This unexpected nonbiphenyl by-product exhibited IR, (1)H NMR, (13)C NMR and COSY (correlation spectroscopy) spectra fully consistent with the proposed structure. The compound crystallized in the orthorombic Pbca space group, with two independent formula units in the asymmetric unit (one of which was slightly disordered), and showed a supramolecular architecture in which molecules linked by hydroxy-ethanone O-H...O interactions are organized in columns separated by the aliphatic tails. PMID- 26524177 TI - A new one-dimensional Zn(II) coordination polymer based on 2-[(1H-imidazol-1 yl)methyl]-1H-benzimidazole and benzene-1,2-dicarboxylate. AB - Multidentate N-heterocyclic compounds form a variety of metal complexes with many intriguing structures and interesting properties. The title coordination polymer, catena-poly[zinc(II)-bis{MU-2-[(1H-imidazol-1-yl)methyl]-1H-benzimidazole} kappa(2)N(3):N(3');N(3'):N(3)-zinc(II)-bis(MU-benzene-1,2-dicarboxylato) kappa(2)O(1):O(2);kappa(3)O(1),O(1'):O(2)], [Zn2(C8H4O4)2(C11H10N4)2]n, has been synthesized by the reaction of Zn(NO3)2 with 2-[(1H-imidazol-1-yl)methyl]-1H benzimidazole (imb) and benzene-1,2-dicarboxylic acid (H2bdic) under hydrothermal conditions. There are two crystallographically distinct imb ligands [imb(A) and imb(B)] in the structure which adopt very similar coordination geometries. The imb(A) ligand bridges two symmetry-related Zn1 ions, yielding a binuclear [(Zn1)2{imb(A)}2] unit, and the imb(B) ligand bridges two symmetry-related Zn2 ions resulting in a binuclear [(Zn2)2{imb(B)}2] unit. The above-mentioned binuclear units are further connected alternately by pairs of bridging bdic(2-) ligands, forming an infinite one-dimensional chain. These one-dimensional chains are further connected through N-H...O hydrogen bonds, leading to a two dimensional layered structure. In addition, the title polymer exhibits good fluorescence properties in the solid state at room temperature. PMID- 26524179 TI - (5RS)-6H-Spiro[pyrazolo[1,5-c]quinazoline-5,4'-thiochroman]: efficient synthesis under mild conditions, molecular structure and supramolecular assembly. AB - Pyrazolo[1,5-c]quinazolines are fused-quinazoline derivatives which have been reported as potential agents against neurological disorders. The normal synthesis routes to these compounds require harsh reaction conditions, long reaction times or multistep sequences. The title compound, C18H15N3S, has been prepared under very mild conditions by condensation of thiochroman-4-one with 5-(2-aminophenyl) 1H-pyrazole, which had itself been prepared by the reaction of hydrazine hydrate with 4-hydroxyquinoline mediated by a brief period of microwave heating. Within the molecule in the crystal structure, the reduced pyrimidine ring adopts an envelope conformation, whereas the thiane ring adopts a half-chair conformation. Molecules are linked into sheets by a combination of one N-H...S hydrogen bond and two independent C-H...pi(arene) hydrogen bonds, which utilize the same aryl ring as the acceptor, with one C-H bond donating to each face of the ring. Comparisons are made with some related compounds. PMID- 26524182 TI - Efficient detection of Escherichia coli O157:H7 using a reusable microfluidic chip embedded with antimicrobial peptide-labeled beads. AB - The ability of antimicrobial peptides (AMPs) for effective binding to multiple target microbes has drawn lots of attention as an alternative to antibodies for detecting whole bacteria. We investigated pathogenic Escherichia coli (E. coli) detection by applying a microfluidic based biosensing device embedded with AMP labeled beads. According to a new channel design, our device is reusable by the repeated operation of detection and regeneration modes, and the binding rate is more enhanced due to even distribution of the bacterial suspension inside the chamber by implementing influx side channels. We observed higher binding affinity of pathogenic E. coli O157:H7 for AMP-labeled beads than nonpathogenic E. coli DH5alpha, and the fluorescence intensity of pathogenic E. coli was about 3.4 times higher than the nonpathogenic one. The flow rate of bacterial suspension should be applied above a certain level for stronger binding and rapid detection by attaining a saturation level of detection within a short time of less than 20 min. A possible improvement in the limit of detection in the level of 10 cells per mL for E. coli O157:H7 implies that the AMP-labeled beads have high potential for the sensitive detection of pathogenic E. coli at an appropriate flow rate. PMID- 26524181 TI - Electroacupuncture Ameliorates Acute Renal Injury in Lipopolysaccharide Stimulated Rabbits via Induction of HO-1 through the PI3K/Akt/Nrf2 Pathways. AB - Electroacupuncture at select acupoints have been verified to protect against organ dysfunctions during endotoxic shock. And, heme oxygenase (HO)-1 as a phase II enzyme and antioxidant contributed to the protection of kidney in septic shock rats. The phosphatidylinositol 3-kinase (PI3K)-Akt pathway mediated the activation of NF-E2 related factor-2 (Nrf2), which was involved in HO-1 induction. To understand the efficacy of electroacupuncture stimulation in ameliorating acute kidney injury (AKI) through the PI3K/Akt/Nrf2 pathway and subsequent HO-1 upregulation, a dose of LPS 5mg/kg was administered intravenously to replicate the rabbit model of AKI induced by endotoxic shock. Electroacupuncture pretreatment was handled bilaterally at Zusanli and Neiguan acupoints for five consecutive days while sham electroacupuncture at non acupoints as control. Results displayed that electroacupuncture stimulation significantly alleviated the morphologic renal damage, attenuated renal tubular apoptosis, suppressed the elevated biochemical indicators of AKI caused by LPS, enhanced the expressions of phospho-Akt, HO-1protein, Nrf2 total and nucleoprotein, and highlighted the proportions of Nrf2 nucleoprotein as a parallel. Furthermore, partial protective effects of elecroacupuncture were counteracted by preconditioning with wortmannin (the selective PI3K inhibitor), indicating a direct involvement of PI3K/Akt pathway. Inconsistently, wortmannin pretreatment made little difference to the expressions of HO-1, Nrf2 nucleoprotein and total protein, which indicated that PI3K/Akt may be not the only pathway responsible for electroacupuncture-afforded protection against LPS induced AKI. These findings provide new insights into the potential future clinical applications of electroacupuncture for AKI induced by endotoxic shock instead of traditional remedies. PMID- 26524183 TI - Surface modified multifunctional ZnFe2O4 nanoparticles for hydrophobic and hydrophilic anti-cancer drug molecule loading. AB - Multifunctional ZnFe2O4 nanoparticles were successfully synthesized via thermolysis of Fe-oleate and Zn-oleate precursors. Monodisperse, single phase ZnFe2O4 nanoparticles with an average particle size of ~22 nm, exhibiting green emission (lambdamax~ 480 nm) and ferromagnetism at room temperature (saturation magnetization of 48.46 emu gm(-1)) have been formed by this novel approach. By appropriate surface functionalization, these materials have been converted into smart carriers of hydrophobic (water insoluble) drug molecule-curcumin and hydrophilic (water soluble) drug molecule-daunorubicin. The in vitro cytotoxicity of both the hydrophobic and hydrophilic drug loaded ZnFe2O4 nanoparticles was studied using the conventional MTT assay which revealed that the drug loaded nanoparticles induce significant death of the carcinoma cells (HeLa). Interestingly, this appears to be a significant development towards the capability of surface functionalized multifunctional ZnFe2O4 nanoparticles as carriers for both water soluble and insoluble drugs for anti-cancer therapy. PMID- 26524184 TI - Use of Electronic Nurse Reminders to Improve Documentation: A Process Improvement for a Comprehensive Stroke Center. AB - Nurses on a neurological step-down unit were challenged to switch from documenting assessments by hand to documenting by using a highly technological, electronic format. Upon the switch to electronic documentation, it was discovered through a chart audit that neurological assessments were not being documented properly. The purpose of this project was to implement Care Organizer, an electronic nurse reminder tool, on a neurological step-down unit and to evaluate the tool's ability to assist RNs in documentation of neurological assessments. Fifty patients' charts were audited for documentation of neurological assessments. Thirty-two RNs completed an anonymous demographic survey and were provided with eight training sessions related to utilization of Care Organizer. The RNs were asked to complete an evaluation of the tool 2 weeks after training and again at 1 month after training. A second chart audit was conducted at 1 month to assess for improvement of documentation 1 month after training. Preimplementation/postimplementation chart audits revealed improvements in documentation of neurological assessments in seven of eight criteria examined. Nurses admitted discomfort with Care Organizer and verbalized concerns that it was not convenient and/or user-friendly. Most admitted that with collaboration between information technology department and nursing, the tool could be further developed to become more applicable to nurses. PMID- 26524185 TI - Nursing Informatics Competencies Among Nursing Students and Their Relationship to Patient Safety Competencies: Knowledge, Attitude, and Skills. AB - With implementation of information technology in healthcare settings to promote safety and evidence-based nursing care, a growing emphasis on the importance of nursing informatics competencies has emerged. This study assessed the relationship between nursing informatics and patient safety competencies among nursing students and nursing interns. A descriptive, cross-sectional correlational design with a convenience sample of 154 participants (99 nursing students and 55 interns) completed the Self-assessment of Nursing Informatics Competencies and Patient Safety Competencies. The nursing students and interns were similar in age and years of computer experience, and more than half of the participants in both groups had taken a nursing informatics course. There were no significant differences between competencies in nursing informatics and patient safety except for clinical informatics role and applied computer skills in the two groups of participants. Nursing informatics competencies and patient safety competencies were significantly correlated except for clinical informatics role both with patient safety knowledge and attitude. These results provided feedback to adjust and incorporate informatics competencies in the baccalaureate program and to recommend embracing the nursing informatics course as one of the core courses, not as an elective course, in the curriculum. PMID- 26524186 TI - Expression of CD164 on Malignant T cells in Sezary Syndrome. AB - Sezary syndrome is a primary cutaneous T-cell lymphoma characterized by pruritic erythroderma, peripheral lymphadenopathy and the presence of malignant T cells in the blood. Unequivocal detection of malignant cells in patients with Sezary syndrome is of important diagnostic, prognostic and therapeutic value. However, no single Sezary syndrome specific cell surface marker has been identified. In a cohort of patients with Sezary syndrome, CD164 expression on total CD4+ lymphocytes was significantly upregulated compared with healthy controls. CD164 expression was in most cases limited to CD4+CD26- malignant T lymphocytes, unequivocally identified using flow-cytometry by the expression of a specific Vbeta clone for each patient. Increased expression of CD164 may be a promising diagnostic parameter and a potential target for a CD164-linked therapeutic approach in Sezary syndrome. PMID- 26524187 TI - Identical Location Transmission Electron Microscopy Imaging of Site-Selective Pt Nanocatalysts: Electrochemical Activation and Surface Disordering. AB - We have employed identical location transmission electron microscopy (IL-TEM) to study changes in the shape and morphology of faceted Pt nanoparticles as a result of electrochemical cycling; a procedure typically employed for activating platinum surfaces. We find that the shape and morphology of the as-prepared hexagonal nanoparticles are rapidly degraded as a result of potential cycling up to +1.3 V. As few as 25 potential cycles are sufficient to cause significant degradation, and after about 500-1000 cycles the particles are dramatically degraded. We also see clear evidence of particle migration during potential cycling. These finding suggest that great care must be exercised in the use and study of shaped Pt nanoparticles (and related systems) as electrocatlysts, especially for the oxygen reduction reaction where high positive potentials are typically employed. PMID- 26524188 TI - Acute Effects of Whole Body Vibration on Inhibition in Healthy Children. AB - OBJECTIVES: Whole Body Vibration (WBV) is a passive exercise method known to have beneficial effects on various physical measures. Studies on adults furthermore demonstrated beneficial effects of WBV treatment on cognition (e.g. inhibition). The present study replicated these findings in healthy children and examined acute effects of WBV treatment on inhibition. METHODS: Fifty-five healthy children (aged 8-13) participated in this within-subject design study. WBV treatment was applied by having the children sit on a chair mounted to a vibrating platform. After each condition (vibration vs. non-vibration), inhibition was measured by using the Stroop Color-Word Interference Test. Repeated measures analyses were applied in order to explore the effects of WBV treatment on inhibition, and correlations were computed between the treatment effect and participant characteristics in order to explore individual differences in treatment sensitivity. RESULTS: Three-minute WBV treatments had significant beneficial effects on inhibition in this sample of healthy children. Especially the repeated application (three times) of WBV treatment appeared beneficial for cognition. Stronger WBV treatment effects were correlated with higher intelligence and younger age, but not with symptoms of Attention Deficit Hyperactivity Disorder (ADHD). CONCLUSIONS: This study demonstrates that especially repeated WBV treatment improves inhibition in healthy children. As this cognitive function is often impaired in children with developmental disorders (e.g. ADHD), future studies should further explore the effects, working mechanism and potential applicability of WBV treatment for this target group. PMID- 26524190 TI - Single nanoporous gold nanowire as a tunable one-dimensional platform for plasmon enhanced fluorescence. AB - We introduce individual nanoporous Au nanowire (AuNW) as a tunable one dimensional platform for plasmon-enhanced fluorescence, with an enhancement factor of ~62, which is ~8-fold higher than that of smooth AuNWs. Besides, nanoporous AuNWs have much lower background emission than smooth AuNWs. These results indicate that nanoporous AuNWs are an excellent optical sensing platform. PMID- 26524189 TI - Parent-Adolescent Sexual Communication and Adolescent Safer Sex Behavior: A Meta Analysis. AB - IMPORTANCE: Parent-adolescent sexual communication has received considerable attention as a factor that can positively affect safer sex behavior among youth; however, the evidence linking such communication to youth contraceptive and condom use has not been empirically synthesized. OBJECTIVES: To examine the effect of parent-adolescent sexual communication on safer sex behavior among youth and explore potential moderators of this association. DATA SOURCES: A systematic search of studies published from database inception through June 30, 2014, using the MEDLINE, PsycINFO, and Communication & Mass Media Complete databases and relevant review articles yielded 5098 studies, of which 52 studies with 25,314 adolescents met the study eligibility criteria. Analysis was conducted from July 1, 2014, to July 27, 2015. STUDY SELECTION: Studies were included if they sampled adolescents (mean sample age <=18 years), included an adolescent report of sexual communication with one or both parents, measured safer sex behavior, and were published in English. DATA EXTRACTION AND SYNTHESIS: Correlation coefficients (r) and 95% CIs were computed from studies and meta analyzed using random-effects models. MAIN OUTCOMES AND MEASURES: Safer sex behavior, including use of contraceptives or condoms. RESULTS: Fifty-two articles, including 71 independent effects representing more than 3 decades of research on 25,314 adolescents (weighted mean age, 15.2 years) were synthesized. Across studies, there was a significant weighted mean effect (r = 0.10; 95% CI, 0.08-0.13) linking parent-adolescent sexual communication with safer sex behavior, which was statistically heterogeneous (Q = 203.50, P < .001, I2 = 65.60). Moderation analyses revealed larger effects for communication with girls (r = 0.12) than boys (r = 0.04) and among youth who discussed sex with their mothers (r = 0.14) compared with their fathers (r = 0.03). Effects did not differ for contraceptive vs condom use or among longitudinal vs cross-sectional studies, indicating that parent sexual communication had a similar effect across study designs and outcomes. Several methodological issues were identified in the literature; future studies can improve on these issues by measuring parent adolescent communication with robust, multi-item measures, clearly specifying the target parent, and applying multimethod longitudinal designs. CONCLUSIONS AND RELEVANCE: Sexual communication with parents, particularly mothers, plays a small protective role in safer sex behavior among adolescents; this protective effect is more pronounced for girls than boys. We discuss the implications for practice and make suggestions for future research on parent-adolescent sexual communication. PMID- 26524191 TI - Reaction of Triplet Phenylnitrene with Molecular Oxygen. AB - Triplet carbenes react with molecular oxygen with rates that approach diffusion control to carbonyl O-oxides, whereas triplet nitrenes react much slower. For investigating the reaction of phenylnitrene with O2, the nitrene was generated by flash vacuum thermolysis (FVT) of phenylazide and subsequently isolated in O2 doped matrices. FVT of the azide produces the nitrene in high yield and with only minor contaminations of the rearranged products that are frequently observed if the nitrene is produced by photolysis. The phenylnitrene was isolated in solid Ar, Xe, mixtures of these rare gases with O2, and even in pure solid O2. At temperatures between 30 and 35 K an extremely slow thermal reaction between the nitrene and O2 was observed, whereas at higher temperatures, solid Ar and O2 rapidly evaporate. Only O2-doped Xe matrices allowed us to anneal at temperatures above 40 K, and at these temperatures, the nitrene reacts with O2 to produce nitroso O-oxide mainly in its syn conformation. Upon visible light irradiation (450 nm), the nitroso oxide rapidly rearranges to nitrobenzene. PMID- 26524192 TI - Aptamer/Graphene Quantum Dots Nanocomposite Capped Fluorescent Mesoporous Silica Nanoparticles for Intracellular Drug Delivery and Real-Time Monitoring of Drug Release. AB - Great challenges in investigating the release of drug in complex cellular microenvironments necessitate the development of stimuli-responsive drug delivery systems with real-time monitoring capability. In this work, a smart drug nanocarrier based on fluorescence resonance energy transfer (FRET) is fabricated by capping graphene quantum dots (GQDs, the acceptor) onto fluorescent mesoporous silica nanoparticles (FMSNs, the donor) via ATP aptamer for real-time monitoring of ATP-triggered drug release. Under extracellular conditions, the fluorescence of FMSNs remains in the "off" state in the low ATP level which is unable to trigger the release of drug. Once specifically recognized and internalized into the target tumor cells by AS1411 aptamer, in the ATP-rich cytoplasm, the conformation switch of the ATP aptamer causes the shedding of the GQDs from the nanocarriers, leading to the release of the loaded drugs and consequently severe cytotoxicity. Simultaneously, the fluorescence of FMSNs turns "on" along with the dissociation of GQDs, which allows real-time monitoring of the release of drug from the pores. Such a drug delivery system features high specificity of dual target recognition with AS1411 and ATP aptamer as well as high sensitivity of the FRET-based monitoring strategy. Thus, the proposed multifunctional ATP triggered FRET-nanocarriers will find potential applications for versatile drug-release monitoring, efficient drug transport, and targeted cancer therapeutics. PMID- 26524193 TI - Millimeter Wave Spectrum of the Weakly Bound Complex CH2?CHCN.H2O: Structure, Dynamics, and Implications for Astronomical Search. AB - The weakly bound 1:1 complex between acrylonitrile (CH2?CHCN) and water has been characterized spectroscopically in the millimeter wave range (59.6-74.4 GHz) using a Free Jet Absorption Millimeter Wave spectrometer. Precise values of the rotational and quartic centrifugal distortion constants have been obtained from the measured frequencies of the normal and isotopically substituted water moiety (DOH, DOD, H(18)OH). Structural parameters have been estimated from the rotational constants and their differences among isotopologues: the complex has a planar structure with the two subunits held together by a O-H...N (2.331(3) A) and a C-H...O (2.508(4) A) interaction. The ab initio intermolecular binding energy, obtained at the counterpoise corrected MP2/aug-cc-pVTZ level of calculation, is De = 24.4 kJ mol(-1). PMID- 26524194 TI - Muscle mass and insulin sensitivity in postmenopausal women after 6-month exercise training. AB - OBJECTIVE: The common belief that high muscle mass improves insulin sensitivity is controversial and even recent studies have established that larger muscle mass is associated with insulin resistance in sedentary postmenopausal women. Physical activity induces a beneficial effect in muscle size and its metabolic properties. Hence, larger muscle mass induced by exercise training should ameliorate insulin sensitivity and the negative relationship between larger muscle mass and insulin sensitivity should disappear. This study examined the induced changes in muscle mass and insulin sensitivity in postmenopausal women after 6-month exercise training along with their possible correlations. METHODS: Forty-eight sedentary, overweight-to-obese postmenopausal women followed a 6-month mixed exercise training (three sessions/week; endurance and resistance). Lean body mass (LBM) and fat mass (FM) were measured by DXA, then the muscle mass index (MMI) was calculated (MMI = LBM (kg)/height (m(2))). Fasting glucose and insulin measurements were obtained and insulin resistance (IR) was estimated by the HOMA IR formula. RESULTS: Baseline MMI was correlated with IR (r = 0.219, p = 0.015). After intervention, significant differences were observed in body weight, FM%, MMI, and glycemia, and changes in MMI were significantly correlated with changes in IR (r = 0.345, p = 0.016). Also linear regression showed that the increase in MMI explained 28% of the deterioration in insulin sensitivity (p = 0.001). CONCLUSIONS: After 6 months of mixed training, changes in muscle mass remained correlated with changes in insulin resistance, overweight-to-obese women with large muscle gains being more insulin-resistant. This supports that muscle quality and functionality, and the loss of fat mass, should be targeted rather than muscle mass gains in postmenopausal women, especially in a context of no energy restriction. PMID- 26524180 TI - Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression. AB - IMPORTANCE: The extent to which large-caliber axonal degeneration contributes to Alzheimer disease (AD) progression is unknown. Cerebrospinal fluid (CSF) neurofilament light (NFL) concentration is a general marker of damage to large caliber myelinated axons. OBJECTIVE: To test whether CSF NFL concentration is associated with cognitive decline and imaging evidence of neurodegeneration and white matter change in AD. DESIGN, SETTING, AND PARTICIPANTS: A commercially available immunoassay was used to analyze CSF NFL concentration in a cohort of patients with AD (n = 95) or mild cognitive impairment (MCI) (n = 192) and in cognitively normal individuals (n = 110) from the Alzheimer's Disease Neuroimaging Initiative. The study dates were January 2005 to December 2007. The NFL analysis was performed in November 2014. MAIN OUTCOMES AND MEASURES: Correlation was investigated among baseline CSF NFL concentration and longitudinal cognitive impairment, white matter change, and regional brain atrophy within each diagnostic group. RESULTS: Cerebrospinal fluid NFL concentration (median [interquartile range]) was higher in the AD dementia group (1479 [1134-1842] pg/mL), stable MCI group (no progression to AD during follow up; 1182 [923-1687] pg/mL), and progressive MCI group (MCI with progression to AD dementia during follow-up; 1336 [1061-1693] pg/mL) compared with control participants (1047 [809-1265] pg/mL) (P < .001 for all) and in the AD dementia group compared with the stable MCI group (P = .01). In the MCI group, a higher CSF NFL concentration was associated with faster brain atrophy over time as measured by changes in whole-brain volume (beta = -4177, P = .003), ventricular volume (beta = 1835, P < .001), and hippocampus volume (beta = -54.22, P < .001); faster disease progression as reflected by decreased Mini-Mental State Examination scores (beta = -1.077, P < .001) and increased Alzheimer Disease Assessment Scale cognitive subscale scores (beta = 2.30, P < .001); and faster white matter intensity change (beta = 598.7, P < .001). CONCLUSIONS AND RELEVANCE: Cerebrospinal fluid NFL concentration is increased by the early clinical stage of AD and is associated with cognitive deterioration and structural brain changes over time. This finding corroborates the contention that degeneration of large-caliber axons is an important feature of AD neurodegeneration. PMID- 26524195 TI - Dynamic Bonds in Covalently Crosslinked Polymer Networks for Photoactivated Strengthening and Healing. AB - A photoactivated-strengthening polymer network is reported. This approach incorporates dynamic bonds into the network architecture, which enables a secondary polymerization triggered by UV light. Three attributes of this material are demonstrated, including: i) there is simultaneous photoinduced strengthening and healing after the material is severed, ii) bulk property changes are spatially confined via photopatterning, and iii) there is permanent shape change post-irradiation. PMID- 26524197 TI - Linking hydrolysis performance to Trichoderma reesei cellulolytic enzyme profile. AB - Trichoderma reesei expresses a large number of enzymes involved in lignocellulose hydrolysis and the mechanism of how these enzymes work together is too complex to study by traditional methods, for example, by spiking with single enzymes and monitoring hydrolysis performance. In this study, a multivariate approach, partial least squares regression, was used to see whether it could help explain the correlation between enzyme profile and hydrolysis performance. Diverse enzyme mixtures were produced by T. reesei Rut-C30 by exploiting various fermentation conditions and used for hydrolysis of washed pretreated corn stover as a measure of enzyme performance. In addition, the enzyme mixtures were analyzed by liquid chromatography-tandem mass spectrometry to identify and quantify the different proteins. A multivariate model was applied for the prediction of enzyme performance based on the combination of different proteins present in an enzyme mixture. The multivariate model was used for identification of candidate proteins that are correlated to enzyme performance on pretreated corn stover. A very large variation in hydrolysis performance was observed and this was clearly caused by the difference in fermentation conditions. Besides beta-glucosidase, the multivariate model identified several xylanases, Cip1 and Cip2, as relevant proteins to study further. PMID- 26524199 TI - 2D Electronic Transport with Strong Spin-Orbit Coupling in Bi(2-) Square Net of Y2O2Bi Thin Film Grown by Multilayer Solid-Phase Epitaxy. AB - Highly crystalline Y2O2Bi epitaxial thin film with monatomic Bi(2-) square net layer was grown by newly developed multilayer solid phase epitaxy. High reactivity of the nanometer-scale multilayered precursor enabled efficient formation of single crystalline Y2O2Bi phase with one-step heating. The reductive state of Bi(2-) square net was observed by X-ray photoemission spectroscopy. The electrical resistivity was one order lower than that of polycrystalline powder in previous study. The magnetotransport showed weak antilocalization effect well fitted by the Hikami-Larkin-Nagaoka model, exhibiting two-dimensional electronic nature with strong spin-orbit coupling in the Bi(2-) square net. PMID- 26524196 TI - Nanotechnology Approaches for the Delivery of Exogenous siRNA for HIV Therapy. AB - RNA interference (RNAi) is triggered by oligonucleotides that are about 21-23 nucleotides long and are capable of inducing the destruction of complementary mRNA. The RNAi technique has been successfully utilized to target HIV replication; however, the main limitation to the successful utilization of this technique in vivo is the inability of naked siRNA to cross the cell membrane by diffusion due to its strong anionic charge and large molecular weight. This review describes current nonviral nanotechnological approaches to deliver anti HIV siRNAs for the treatment of HIV infection. PMID- 26524198 TI - Identification, Characterization, and Diel Pattern of Expression of Canonical Clock Genes in Nephrops norvegicus (Crustacea: Decapoda) Eyestalk. AB - The Norway lobster, Nephrops norvegicus, is a burrowing decapod with a rhythmic burrow emergence (24 h) governed by the circadian system. It is an important resource for European fisheries and its behavior deeply affects its availability. The current knowledge of Nephrops circadian biology is phenomenological as it is currently the case for almost all crustaceans. In attempt to elucidate the putative molecular mechanisms underlying circadian gene regulation in Nephrops, we used a transcriptomics approach on cDNA extracted from the eyestalk, a structure playing a crucial role in controlling behavior of decapods. We studied 14 male lobsters under 12-12 light-darkness blue light cycle. We used the Hiseq 2000 Illumina platform to sequence two eyestalk libraries (under light and darkness conditions) obtaining about 90 millions 100-bp paired-end reads. Trinity was used for the de novo reconstruction of transcriptomes; the size at which half of all assembled bases reside in contigs (N50) was equal to 1796 (light) and 2055 (darkness). We found a list of candidate clock genes and focused our attention on canonical ones: timeless, period, clock and bmal1. The cloning of assembled fragments validated Trinity outputs. The putative Nephrops clock genes showed high levels of identity (blastx on NCBI) with known crustacean clock gene homologs such as Eurydice pulchra (period: 47%, timeless: 59%, bmal1: 79%) and Macrobrachium rosenbergii (clock: 100%). We also found a vertebrate-like cryptochrome 2. RT-qPCR showed that only timeless had a robust diel pattern of expression. Our data are in accordance with the current knowledge of the crustacean circadian clock, reinforcing the idea that the molecular clockwork of this group shows some differences with the established model in Drosophila melanogaster. PMID- 26524200 TI - Branched-chain in situ hybridization for kappa and lambda light chains: A powerful ancillary technique for determining B-cell clonality in cytology samples. AB - BACKGROUND: Current immunohistochemical and in situ hybridization (ISH) assays are generally inconclusive for clonality unless plasmacytic differentiation is present. This study examined a series of cytology specimens and explored the ability of a branched-chain RNA (bRNA) ISH assay for immunoglobulin kappa constant (IGKC) and immunoglobulin lambda constant (IGLC) to detect a clonal population of B lymphocytes. METHODS: Pathology databases were used to identify fine-needle aspiration biopsies (n = 28) and exfoliative cytology samples (n = 20). Demographic, flow cytometry, and excision biopsy results were recorded. bRNA ISH was performed on the Leica Bond platform with the following probes: IGKC, IGLC, immunoglobulin lambda-like polypeptide 5 (IGLL5), and a housekeeping gene (HKG). RESULTS: The bRNA ISH assay was validated with 30 surgical biopsies. On bRNA ISH, a clonal B-cell population (light-chain ratio > 10:1) was detected in 22 of 28 cases with a final diagnosis of lymphoma. In 2 cases, a kappa predominance was present, although the ratio was <10:1. Eleven of the 17 kappa clonal lymphomas also expressed IGLL5, the latter recognized by the presence of an intranuclear signal. Two B-cell lymphomas lacked IGKC and IGLC, whereas 2 cases were negative for the HKG. In 12 of the 20 cases with reactive lymphoid tissue, bRNA ISH identified a polyclonal lymphoid population. No light-chain messenger RNA was detected in 6 cases (typically those associated with very few B cells). CONCLUSIONS: The automated bRNA ISH platform is a robust technique for detecting a clonal B-cell population in cytology material. PMID- 26524202 TI - Stabilization of Coronary Stents Using the Floating-Wire Technique. AB - AIMS: Excessive movement of coronary stents within the artery can make accurate stent placement difficult. This study assessed the use of the floating-wire technique to reduce stent motion to improve placement accuracy. METHODS AND RESULTS: During percutaneous coronary intervention, if excessive stent movement prevented accurate stent placement, the floating-wire technique was performed to reduce stent motion within the coronary artery during both stent positioning and deployment. Postprocedural angiograms were analyzed by two independent operators to measure the motion length of the stent delivery system relative to the coronary artery before and after using the floating-wire technique. The floating wire technique was considered necessary in 19 patients. No procedural complications occurred. The extent of motion was markedly reduced by using the floating-wire technique (4.04 +/- 1.25 mm to 1.11 +/- 0.81 mm; P<.001). CONCLUSIONS: The floating-wire technique is an effective and safe method to reduce stent movement and facilitate accurate stent deployment. This simple technique can be easily applied in any interventional cardiac catheterization laboratory without the need for additional training or equipment. PMID- 26524201 TI - Disconnect between adipose tissue inflammation and cardiometabolic dysfunction in Ossabaw pigs. AB - OBJECTIVE: The Ossabaw pig is emerging as an attractive model of human cardiometabolic disease because of its size and susceptibility to atherosclerosis, among other characteristics. The relationship between adipose tissue inflammation and metabolic dysfunction in this model was investigated here. METHODS: Young female Ossabaw pigs were fed a Western-style high-fat diet (HFD) (n = 4) or control low-fat diet (LFD) (n = 4) for a period of 9 months and compared for cardiometabolic outcomes and adipose tissue inflammation. RESULTS: The HFD-fed "OBESE" pigs were 2.5 times heavier (P < 0.001) than LFD-fed "LEAN" pigs and developed severe obesity. HFD feeding caused pronounced dyslipidemia, hypertension, and insulin resistance (systemic and adipose), as well as induction of inflammatory genes, impairments in vasomotor reactivity to insulin, and atherosclerosis in the coronary arteries. Remarkably, visceral, subcutaneous, and perivascular adipose tissue inflammation (via FACS analysis and RT-PCR) was not increased in OBESE pigs, nor were circulating inflammatory cytokines. CONCLUSIONS: These findings reveal a disconnect between adipose tissue inflammation and cardiometabolic dysfunction induced by Western diet feeding in the Ossabaw pig model. PMID- 26524203 TI - True First-Line Local-Anesthesia Only Protocol for Transfemoral TAVI. AB - AIMS: To evaluate the safety and feasibility of transcatheter aortic valve implantation (TAVI) via femoral access under local anesthesia only (without concomitant sedation) as the initial strategy. METHODS AND RESULTS: Patients undergoing planned transfemoral TAVI without routine general anesthesia between May 2005 and December 2013 were identified. Baseline characteristics, procedural outcomes, and a 30-day clinical follow-up were obtained. A total of 215 patients underwent TAVI with local anesthesia only as the initial strategy (LA group). Of these patients, 40 (18.6%) received additional sedation (LAS group) during the procedure due to inadequate pain control or agitation and 7 patients (3.3%) underwent conversion to general anesthesia (GA group). TAVI was successfully performed in 211 cases (98.2%). When 30-day outcomes for patients requiring only local anesthesia were compared with patients requiring additional sedation, there was a significantly longer duration of Intensive Care Unit (ICU) stay in the group with additional sedation (LAS, 5.0 days [range, 3.0-6.0 days] vs LA 3 days [range, 2.0-5.0 days]; P=.02) and general anesthesia (GA 7.0 days [range, 2.5 18.0 days] vs LA 3 days [range, 2.0-5.0]; P=.04). CONCLUSION: Our study suggests that TAVI with LA only as the initial strategy is a feasible alternative to GA, with potential benefit of this strategy over using routine concomitant sedation. LA only may be considered a primary option in many patients. PMID- 26524204 TI - "Like a Patient Etherized Upon a Table"? - Not Exactly. PMID- 26524205 TI - New Pediatric Version of Balloon-Assisted Technique for Atrial Septal Defect Closure Using Self-Centering Devices: Relation to Interatrial Septal Thickness. AB - AIM: Some difficult atrial septal defect (ASD) cases with deficient rims or large defects may require specific maneuvers to facilitate transcatheter occlusion of these defects with self-centering devices. In our center, we developed a modification of balloon-assisted technique (BAT) for difficult ASDs to assist proper positioning of the device. Our aim was to demonstrate the efficiency of ASD closure with self-centering devices in children and to present the results of the new pediatric version of BAT (PBAT) in young children and its relation to the interatrial septal thickness. METHODS AND RESULTS: Over 2 years, a total of 65 patients with ASD secundum were referred for closure, from which 50 cases were deemed suitable for transcatheter closure by transthoracic echocardiography during precatheter evaluation. Ten difficult defects required assisted techniques; 6 of these were successfully closed using the PBAT with a small-sized valvuloplasty balloon. The cut-off levels for needing an assistance technique in pediatric patients were age >5 years, ASD >16 mm, and weight >22 kg. The interatrial septal thickness was thinner in young ASD patients. CONCLUSION: The PBAT was needed to optimize device closure in difficult cases, especially in large defects without rim deficiency. This technique is easy to learn and results in quick and simple device closure. PMID- 26524206 TI - Subanalysis of the CONFIRM Registries: Acute Procedural Outcomes in Claudicant and Critical Limb Ischemia Patients With Varying Levels of Calcification Treated for Peripheral Arterial Disease With Orbital Atherectomy. AB - PURPOSE: Patients with peripheral arterial disease (PAD) can be classified into groups based upon the severity of the disease using the Rutherford classification system. This analysis compares the procedural outcomes of PAD patients treated with orbital atherectomy stratified by Rutherford class (1-3 = intermittent claudication; 4-6 = critical limb ischemia [CLI]), and acute angiographic outcomes of these patients stratified by degree of lesion calcification. METHODS: The CONFIRM registry series was analyzed and included 1697 patients with intermittent claudication (Rutherford class 1-3) and 1320 patients with CLI (Rutherford class 4-6) treated with orbital atherectomy. The composite rate of dissection, perforation, slow-flow, vessel closure, spasm, embolism, and thrombus formation was compared between claudicants and CLI patients with varying degrees of lesion calcification. RESULTS: Patients with CLI were older and had a higher prevalence of diabetes, coronary artery disease, and renal disease (P<.001). Claudicants with moderately/severely calcified lesions had a lower rate of dissection (both non-flow limiting and flow-limiting) than claudicants with mildly/minimally calcified lesions. CLI patients with mildly/minimally calcified lesions had higher rates of embolism and thrombus than CLI patients with moderately/severely calcified lesions. CONCLUSIONS: Plaque modification with orbital atherectomy resulted in similar low procedural complication rates in the CLI group compared with the claudicant group. These results suggest that orbital atherectomy is safe and effective for treating calcified lesions in high-risk patients with varying severity of PAD symptoms. PMID- 26524207 TI - The Impact of Short or Long Transcatheter Occluder Waist Lengths on Postprocedure Complete Atrioventricular Block: A Retrospective Study. AB - BACKGROUND: Complete atrioventricular block (cAVB) is considered the most serious adverse event after transcatheter closure of ventricular septal defect (VSD). OBJECTIVES: To evaluate the incidence of postprocedure cAVB and its relationship with different waist lengths of transcatheter occluders. METHODS: This is a retrospective study of patients with VSD who had been treated with transcatheter closure at the Shanghai Changhai Hospital from December 2001 to December 2010. Patients were treated with short-waist (n = 234) or long-waist occluders (n = 571). All patients were monitored by electrocardiogram (ECG) within 7 days post procedure. RESULTS: Nine patients (3.8%) treated with short-waist occluders suffered from cAVB and 3 patients (1.3%) required permanent pacemaker implantation, compared with 4 patients (0.7%) and 1 patient (0.2%), respectively, in the long-waist occluder group (P<.001). There was a significantly higher incidence of postprocedure incomplete right bundle branch block (IRBBB) in patients treated with short-waist occluders compared with patients treated with long-waist occluders. There were no significant differences in other procedure related complications between the two groups. CONCLUSIONS: Long-waist VSD occluders are beneficial in the prevention of cAVB and the need for pacemaker implantation after transcatheter closure of VSD. PMID- 26524208 TI - Superficial Femoral Artery Intervention by Single Transpedal Arterial Access. AB - BACKGROUND: Atherosclerotic disease of the superficial femoral artery (SFA) is frequently seen and can be treated with percutaneous interventions, traditionally via femoral artery access. There are limited reports of transpedal artery access for peripheral artery interventions, but none to date describing routine primary transpedal artery approach for SFA stenting. METHODS: In this preliminary study, we report 4 patients who underwent successful endovascular SFA stenting using a single transpedal artery access via a new ultra-low profile 6 Fr sheath (Glidesheath Slender; Terumo Corporation). RESULTS: All patients underwent successful SFA stenting without complication. Procedure time varied from 51 to 72 minutes. The mean contrast amount used was 56 mL; mean fluoroscopy time was 21 minutes; mean radiation dose was 91 mGy. At 1-month follow-up, duplex ultrasonography showed that all pedal arteries had remained patent. CONCLUSIONS: Transpedal artery approach as a primary approach to SFA stenting appears feasible and safe. Comparative trials with standard percutaneous femoral approach are warranted. PMID- 26524209 TI - Transradial Approach of Alcohol Septal Ablation Using a Sheathless Guiding Catheter: A Feasibility Study. AB - OBJECTIVES: We aimed to investigate the feasibility and safety of alcohol septal ablation (ASA) via transradial approach using a sheathless guiding catheter. BACKGROUND: Although ASA is conventionally performed via the femoral artery, there is a potential risk of bleeding and other vascular complications. The transradial approach may be associated with a lower rate of such complications. A sheathless guiding catheter, with an advanced hydrophilic coating along its full length, could reduce radial artery occlusion and spasm. METHODS: We enrolled 14 consecutive patients with hypertrophic obstructive cardiomyopathy treated with ASA via the radial access at Sendai Kousei Hospital from December 2012 to May 2014. Left radial access was used for the sheathless guiding catheter, while right radial access was used for monitoring left ventricular pressure with a 4 Fr diagnostic catheter. A temporary pacemaker was inserted via the right jugular vein. RESULTS: Procedural success rate was 93% (13/14 patients). The left ventricular outflow tract pressure gradient at rest was reduced from a median of 128 mm Hg (interquartile range, 49-147 mm Hg) at baseline to a median of 16 mm Hg (interquartile range, 13-26 mm Hg) at 30-day follow-up (P=.01). The New York Heart Association functional class improved from a median of II (II-III) at baseline to a median of I (I-I) at 30-day follow-up (P=.01). There were no cases of access-site complication, including radial artery occlusion and spasm. CONCLUSIONS: The transradial approach using a sheathless guiding catheter was feasible and safe for ASA. PMID- 26524210 TI - The Chameleon's Technique: A Novel 3-in-6 Mother-and-Child Technique for Simultaneous Contralateral Angiography During Transradial Angioplasty of CTO via One Guide and One Puncture Site. AB - In order to obviate double arterial access for bi-coronary visualization during transradial intervention of chronic total coronary occlusions, a novel technique was used. A 3-in-6 mother-and-child technique was applied in which a 3 Fr intracoronary catheter was advanced via a 6 Fr guide into the artery supplying collaterals to the distal occluded segment of the right coronary artery (RCA). The same guide was used, with the 3 Fr catheter in situ, to visualize the occluded target vessel. With double contrast injections, the guidewire could be guided through the RCA occlusion while the intraluminal position could be visualized and confirmed. This was followed by successful drug-eluting stent implantation. This method to visualize both coronary arteries simultaneously is named the "Chameleon's technique." PMID- 26524211 TI - Safety and Feasibility of the Coronary Orbital Atherectomy System via the Transradial Approach. AB - Technological innovations have enabled higher success rates with percutaneous coronary intervention (PCI) of complex coronary lesions via the transradial approach. The orbital atherectomy system (OAS; Cardiovascular Systems, Inc) is the most recent innovation that abrades plaque using a rotation device for the facilitation of stent placement in heavily calcified lesions. Fifty patients with classic anginal symptoms and an abnormal stress test demonstrating ischemia underwent PCI using the coronary OAS. In all, 46 out of 50 patients received stents in the target lesion after orbital atherectomy. At follow-up, there were no major adverse cardiovascular events, including cardiac death, myocardial infarction, and need for target-vessel revascularization. Radial artery occlusion rate was 6% at 30 days. The use of the OAS via the radial approach may be a safe and feasible option to assist in the treatment of heavily calcified coronary lesions. PMID- 26524212 TI - Ventriculography to Identify Ventricular Free-Wall Rupture in Acute Coronary Syndrome. AB - A 76-year-old previously well female with late-presentation acute coronary syndrome underwent left ventriculography, which demonstrated contrast leak into the pericardium consistent with left ventricular free-wall rupture. Confirmatory imaging, including echocardiography, was performed. Our case highlights the persistent utility of ventriculography as an imaging modality to identify free wall rupture in acute coronary syndromes. PMID- 26524214 TI - AIMRadial2015 Abstracts: Coronary & Vascular 4th Advanced International Masterclass, Liverpool, United Kingdom, September 17-18, 2015. PMID- 26524213 TI - Should We Routinely Stent the Femoropopliteal Artery? An Interventionalist's Perspective. AB - Stenting of femoropopliteal (FP) arterial disease is currently the most common strategy adopted by endovascular specialists. Several randomized trials have shown that stenting with nitinol self-expanding stents leads to less restenosis on intermediate-term and long-term follow-up when compared with plain old balloon angioplasty (POBA) and provisional stenting. In this overview, we present the pros and cons of primary stenting of FP arteries vs alternative approaches including provisional stenting following POBA, atherectomy and/or drug-coated balloons, and how these initial non-stent strategies play a significant role in treating FP arterial disease. PMID- 26524215 TI - Surface-Supported Robust 2D Lanthanide-Carboxylate Coordination Networks. AB - Lanthanide-based metal-organic compounds and architectures are promising systems for sensing, heterogeneous catalysis, photoluminescence, and magnetism. Herein, the fabrication of interfacial 2D lanthanide-carboxylate networks is introduced. This study combines low- and variable-temperature scanning tunneling microscopy (STM) and X-ray photoemission spectroscopy (XPS) experiments, and density functional theory (DFT) calculations addressing their design and electronic properties. The bonding of ditopic linear linkers to Gd centers on a Cu(111) surface gives rise to extended nanoporous grids, comprising mononuclear nodes featuring eightfold lateral coordination. XPS and DFT elucidate the nature of the bond, indicating ionic characteristics, which is also manifest in appreciable thermal stability. This study introduces a new generation of robust low dimensional metallosupramolecular systems incorporating the functionalities of the f-block elements. PMID- 26524216 TI - Conservation implications of omitting historical data sources: response to Baisre. PMID- 26524217 TI - Anaemia in elective orthopaedic surgery - Royal Adelaide Hospital, Australia. AB - BACKGROUND: An anaemia clinic was established to improve the preoperative management of elective orthopaedic patients scheduled for arthroplasty. This paper is a report on the first 100 patients assessed. AIM: To assess the incidence and causes of anaemia in patients on a waiting list for elective arthroplasty in a public hospital and to assess the impact of anaemia detection in this patient population. METHODS: Patients attending an Anaemia Clinic for elective orthopaedic surgical patients, during March 2010 to June 2013 were studied. Outcome measures included change in haemoglobin preoperative results and perioperative transfusion rates by preoperative haemoglobin. RESULTS: Seventeen per cent of patients scheduled for elective surgery were found to be anaemic. Of the 100 patients who attended, approximately half were found to be iron deficient and the remainder had anaemia of chronic disease. Serum ferritin <30 ug/L alone did not identify iron deficiency in 80% of patients with iron deficiency. Patients with iron deficient anaemia were able to be treated, in all cases, to achieve a significant increase in preoperative haemoglobin. The general unavailability of erythropoietin limited effective intervention for the non-iron deficient anaemic patients. Seven patients had their surgery cancelled because of the screening programme. CONCLUSIONS: Half of the anaemic patients in a joint replacement screening clinic were iron deficient, and treatment was effective in improving the pre-operative haemoglobin and reducing perioperative transfusion rates. This screening process should improve patient outcome. Another important finding in this group of patients is that ferritin levels cannot be reliably used as the sole indicator in the diagnosis of iron deficiency anaemia in this group of patients undergoing elective arthroplasty. PMID- 26524218 TI - Viability of Yersinia pestis subcultures in agar stabs. AB - Since its identification as the causative agent of plague in 1894, thousands of Yersinia pestis strains have been isolated and stored. Here, we report the ability of Y. pestis to survive up to 47 years in agar stabs, in rubber-stoppered tubes, under refrigeration (+4 to +10 degrees C), although overall subculture recovery rates were poor and inversely related to the length of time stored. Genetic characterization of virulence gene presence among these subcultures was suggestive of significant variation in the genomic stability of Y. pestis subcultures stored under these conditions. Specifically, we found variation in the presence of plasmid and chromosomal virulence markers (genes pla, lcrV, caf1 and irp2) among multiple subcultures of Y. pestis strains in the 'Collection of Yersinia pestis' (Fiocruz-CYP) maintained by the SRP of FIOCRUZ-PE in Brazil. This variation, together with all of the inherent temporal, geographic and other genetic variation represented by all of the recoverable strains in this historical collection was preserved in new frozen culture stocks stored at -70 degrees C as a result of this study. These frozen culture stocks represent a valuable resource for future comparative studies of Y. pestis. SIGNIFICANCE AND IMPACT OF THE STUDY: We report the ability of Yersinia pestis to survive up to 47 years in agar stabs, in rubber-stoppered tubes, under refrigeration (+4 to +10 degrees C), although overall subculture recovery rates were poor and inversely related to the length of time stored. Genetic characterization of virulence gene presence among these subcultures was suggestive of significant variation in the genomic stability of Y. pestis subcultures stored under these conditions. This variation, together with all of the inherent temporal, geographic and other genetic variation represented by all of the recoverable strains in the historical 'Collection of Yersinia pestis' (Fiocruz-CYP) maintained by the SRP of FIOCRUZ-PE in Brazil was preserved in new frozen culture stocks stored at -70 degrees C as a result of this study. These frozen culture stocks represent a valuable resource for future comparative studies of Y. pestis. PMID- 26524219 TI - Water-Soluble Blue Fluorescence-Emitting Hyperbranched Polysiloxanes Simultaneously Containing Hydroxyl and Primary Amine Groups. AB - In this Communication, novel water-soluble hyperbranched polysiloxanes (WHPSs) simultaneously containing hydroxyl and primary amine groups are developed. The polymers are constructed via melt polycondensation, that is, transesterification reaction between ethoxyl groups of (3-aminopropyl)triethoxysilane and hydroxyl groups of dihydric alcohols, using a one-step process under catalyst-free conditions. Surprisingly, the resultant WHPSs can emit bright blue fluorescence in the 100% solid state under the irradiation of UV light, and their photoluminescence intensities in aqueous solutions continuously go up along with increasing concentrations. Interestingly, their hydrolyzates display more intense luminescence compared to the unhydrolyzed. The efficient and easily controllable preparation strategy provides a remarkable and versatile platform for the fabrication of neoteric fluorescent materials for various potential applications. PMID- 26524220 TI - PDZ-Reactive Peptide Activates Ephrin-B Reverse Signaling and Inhibits Neuronal Chemotaxis. AB - Intracellular reactions on nonenzymatic proteins that activate cellular signals are rarely found. We report one example here that a designed peptide derivative undergoes a nucleophilic reaction specifically with a cytosolic PDZ protein inside cells. This reaction led to the activation of ephrin-B reverse signaling, which subsequently inhibited SDF-1 induced neuronal chemotaxis of human neuroblastoma cells and mouse cerebellar granule neurons. Our work provides direct evidence that PDZ-RGS3 bridges ephrin-B reverse signaling and SDF-1 induced G protein signaling for the first time. PMID- 26524221 TI - Biofilm formation of the L. monocytogenes strain 15G01 is influenced by changes in environmental conditions. AB - Listeria monocytogenes 15G01, a strain belonging to the persistent pulsotype 5132, was isolated from a seafood processing plant in New Zealand. Simple monoculture assays using crystal violet staining showed good biofilm formation for this strain and it was therefore chosen to be further investigated in regard to its biofilm forming ability. To evaluate its behaviour in different conditions commonly encountered in food processing environments, biofilm assays and growth studies were performed using common laboratory media under a range of temperatures (20 degrees C, 30 degrees C and 37 degrees C). Furthermore, the effects of incubation time and different environmental conditions including static, dynamic and anaerobic incubation on biofilm formation were investigated. Changes in the environmental conditions resulted in different biofilm phenotypes of L. monocytogenes 15G01. We demonstrated that increasing temperature and incubation time led to a higher biofilm mass and that dynamic incubation has little effect on biofilm formation at 37 degrees C but encourages biofilm formation at 30 degrees C. Biofilm production at 20 degrees C was minimal regardless of the medium used. We furthermore observed that anaerobic environment led to reduced biofilm mass at 30 degrees C for all tested media but not at 37 degrees C. Biofilm formation could not be narrowed down to one factor but was rather dependent on multiple factors with temperature and medium having the biggest effects. PMID- 26524222 TI - Assessment of Microvolt T Wave Alternans in Children with Repaired Tetralogy of Fallot during 24-Hour Holter Electrocardiography. AB - BACKGROUND: We aimed to examine microvolt T wave alternans (MTWA) in 24-hour Holter electrocardiography (ECG) of children with repaired tetralogy of Fallot (TOF) to assess associations of MTWA with ventricular arrhythmias, ECG parameters, and echocardiographic findings. METHODS: Holter ECG records and archive files of 56 repaired TOF patients (62.5% male) who were analyzed retrospectively. Subjects' ECG parameters and MTWA values were compared with age sex-matched control group. T wave changes were analyzed by time-domain-modified moving average method from the three channels of 24-hour Holter ECG. RESULTS: Mean age was 123.4 +/- 48.3 months. Median MTWA value was 55.5 MUV in the control group, whereas 95.5 MUV in patients group (P < 0.001). A significant weak positive correlation was found between the presence of ventricular extrasystoles and tricuspid regurgitation. There was no correlation between ECG parameters, echocardiographic findings, and MTWA. CONCLUSIONS: MTWA was increased in children with repaired TOF as reported before. To our knowledge, this is the first study analyzing MTWA with 24-hour Holter ECG in repaired TOF patients. PMID- 26524223 TI - Thermal build-up, decay and retention responses to local therapeutic application of 448 kHz capacitive resistive monopolar radiofrequency: A prospective randomised crossover study in healthy adults. AB - PURPOSE: Radiofrequency-based electrophysical agents are widely used in therapy related clinical practice for their thermal effects, mainly relieving pain and inflammation and improving tissue extensibility. The most commonly used and researched are shortwave therapies that operate at 27.12 MHz. Although relatively new, electrophysical agents employing much lower frequencies have also emerged. Capacitive resistive monopolar radiofrequency employing 448 kHz is one such therapy. This laboratory-based study was aimed to investigate the skin thermal responses to 448 kHz radiofrequency-based therapy in healthy adults. METHODS: In a two-group randomised crossover study, 15 volunteers attended two modes (capacitive and resistive) of 448 kHz radiofrequency-based therapy (using 'Indiba Activ 902') administered locally to the lower thigh region. Starting at minimum, the intensity was increased incrementally until thermal discomfort was felt. Participants reported three time points: thermal onset, definite thermal sensation, and onset of thermal discomfort. Local skin temperature was measured before, immediately post-treatment and up to 45 min post-treatment. RESULTS: Both capacitive and resistive modes of therapy significantly increased the skin temperature and sustained it over the 45-min follow-up. There was statistically significant difference between the thermal response patterns produced by the two modes. Peak post-treatment temperatures attained were not significantly different between the two; however, the retention rate at follow-up was significantly higher for the resistive mode. CONCLUSIONS: This study confirms that radiofrequency-based therapy at 448 kHz can significantly increase and sustain skin temperature. The study also provides useful baseline data for further research in the low frequency ranges of radiofrequency-based therapy that remain largely unexplored. PMID- 26524224 TI - Texture-based segmentation and a new cell shape index for quantitative analysis of cell spreading in AFM images. AB - A new cell shape index is defined for use with atomic force microscopy height images of cell cultures. The new cell shape index reveals quantitative cell spreading information not included in a conventional cell shape index. A supervised learning-based cell segmentation algorithm was implemented by texture feature extraction and a multi-layer neural network classifier. The texture feature sets for four different culture surfaces were determined from the gray level co-occurrence matrix and local statistics texture models using two feature selection algorithms and by considering computational cost. The quantitative morphometry of quiescent-like and reactive-like cerebral cortical astrocytes cultured on four different culture environments was investigated using the new and conventional cell shape index. Inclusion of cell spreading with stellation information through use of the new cell shape index was shown to change biomedical conclusions derived from conventional cell shape analysis based on stellation alone. The new CSI results showed that the quantitative astrocyte spreading and stellation behavior was induced by both the underlying substrate and the immunoreactivity of the astrocytes. PMID- 26524225 TI - Epitaxial Growth of Twinned Au-Pt Core-Shell Star-Shaped Decahedra as Highly Durable Electrocatalysts. AB - Pt epitaxial layer on a nanoparticle with twinned structure and well-defined shape is highly desirable in order to achieve high performance in both catalytic activity and durability toward oxygen reduction reaction (ORR). However, it remains tremendously challenging to produce conformal, heterogeneous, twinned nanostructures due to the high internal strain and surface energy of Pt. In addition, these twinned nanostructures may be subject to degradation in highly corrosive ORR environments due to the high energy of twin boundary. Here we report the synthesis of Au-Pt core-shell star-shaped decahedra bounded mainly by {111} facets, in which Pt shells with controlled thickness epitaxially grew on Au cores with a 5-fold twinned structure. The incorporation of the amine group decreases the surface energy of Pt by strong adsorption and thus facilitates the epitaxial growth of Pt on Au core instead of the dendritic growth. In addition, Br(-) ion could largely stabilize the {111} facets of Pt, which prevent the formation of spherical nanoparticles. The Au-Pt core-shell decahedra with thicker Pt shell exhibited enhanced ORR properties in terms of activity and durability. Specifically, AuPt1.03 star-shaped decahedra achieved the highest mass activity (0.94 mA/MUg(Pt)) and area activity (1.09 mA/cm(2)(Pt)), which is ~6.7 and 5 times, respectively, as high as those of the commercial Pt/C (ETEK). Significantly, such star-shaped decahedra were highly stable with ~10% loss in area activity and ~20% loss in mass activity after 30,000 CV cycles in O2 saturated acid solution. PMID- 26524226 TI - A Proposed In Vitro Method to Assess Effects of Inhaled Particles on Lung Surfactant Function. AB - The lung surfactant (LS) lining is a thin liquid film covering the air-liquid interface of the respiratory tract. LS reduces surface tension, enabling lung surface expansion and contraction with minimal work during respiration. Disruption of surface tension is believed to play a key role in severe lung conditions. Inhalation of aerosols that interfere with the LS may induce a toxic response and, as a part of the safety assessment of chemicals and inhaled medicines, it may be relevant to study their impact on LS function. Here, we present a novel in vitro method, based on the constrained drop surfactometer, to study LS functionality after aerosol exposure. The applicability of the method was investigated using three inhaled asthma medicines, micronized lactose, a pharmaceutical excipient used in inhaled medication, and micronized albumin, a known inhibitor of surfactant function. The surfactometer was modified to allow particles mixed in air to flow through the chamber holding the surfactant drop. The deposited dose was measured with a custom-built quartz crystal microbalance. The alterations allowed the study of continuously increasing quantified doses of particles, allowing determination of the dose of particles that affects the LS function. The tested pharmaceuticals did not inhibit the function of a model LS even at extreme doses--neither did lactose. Micronized albumin, however, impaired surfactant function. The method can discriminate between safe inhaled aerosols- as exemplified by the approved inhaled medicines and the pharmaceutical excipient lactose--and albumin known to impair lung functionality by inhibiting LS function. PMID- 26524227 TI - Predicting normal densities of amines using quantitative structure-property relationship (QSPR). AB - This paper reports on a quantitative structure-property relationship (QSPR) approach applied to predict the normal density of amines. A heuristic method was applied to a dataset of experimental densities measured for more than 140 amines extracted from the literature. Statistical processing was performed to find the best correlations. The resulting model was validated successfully based on an external test set. The QSPR analysis showed the importance of intrinsic density, obtained by dividing molecular weight by calculated molecular volume. Further improvement of the model's predictive ability was achieved by introducing descriptors quantifying the influence of intermolecular volume. It has been shown that a simple correlation equation is sufficient to predict the density of amines with satisfactory accuracy. The equation requires only three descriptors: intrinsic density, overall or summation solute hydrogen bond acidity and a sum of intrinsic state values, each of which can be easily calculated using the Simplified Molecular Input Line Entry System Specification (SMILES). The equation provided may be applied to determine the density of amines or their derivatives which are unavailable or unknown. PMID- 26524228 TI - Visualizing Optoelectronic Processes at the Nanoscale. AB - In this issue of ACS Nano, Nienhaus et al. report the optoelectronic properties of carbon nanotube chiral junctions with nanometer resolution in the presence of strong electric fields (~1 V/nm). Here, we provide an overview of recent studies that combine scanning tunneling microscope (STM) and laser or microwave illumination. These techniques reveal nanoscale laser- or microwave-induced phenomena utilizing the intrinsic atomic resolution of the tunneling current, and do not require substantial modification of the STM itself. The merits of atomic scale spatial resolution and chemical sensitivity of the laser or microwave spectroscopes make these techniques useful for nanoscale characterization. PMID- 26524229 TI - Chemical and Enzymatic Transformations of Nimesulide to GSH Conjugates through Reductive and Oxidative Mechanisms. AB - Nimesulide (NIM) is a nonsteroidal anti-inflammatory drug, and clinical treatment with NIM has been associated with severe hepatotoxicity. The bioactivation of nitro-reduced NIM (NIM-NH2), a major NIM metabolite, has been thought to be responsible for the hepatotoxicity of NIM. However, we found that NIM-NH2 did not induce toxic effects in primary rat hepatocytes. This study aimed to investigate other bioactivation pathways of NIM and evaluate their association with hepatotoxicity. After incubating NIM with NADPH- and GSH-supplemented human or rat liver microsomes, we identified two types of GSH conjugates: one was derived from the attachment of GSH to NIM-NH2 (NIM-NH2-GSH) and the other one was derived from a quinone-imine intermediate (NIM-OH-GSH). NIM-NH2-GSH was generated not only by the oxidative activation of NIM-NH2 but also from the reductive activation of NIM. Both NADPH and GSH could act as reducing agents. Moreover, aldehyde oxidase also participated in the reductive activation of NIM. NIM-OH-GSH was generated mainly from NIM via epoxidation with CYP1A2 as the main catalyzing enzyme. NIM was toxic to both primary human and rat hepatocytes, with IC50 values of 213 and 40 MUM, respectively. Inhibition of the oxidative and reductive activation of NIM by the nonspecific CYP inhibitor 1-aminobenzotriazole and selective aldehyde oxidase inhibitor estradiol did not protect the cells from NIM mediated toxicity. Moreover, pretreating cells with l-buthionine-sulfoximine (a GSH depletor) did not affect the cytotoxicity of NIM. These results suggested that oxidative and reductive activation of NIM did not cause the hepatotoxicity and that the parent drug concentration was associated with the cytotoxicity. PMID- 26524230 TI - Simulations of Ice Nucleation by Kaolinite (001) with Rigid and Flexible Surfaces. AB - Nucleation of ice by airborne particles is a process vital to weather and climate, yet our understanding of the mechanisms underlying this process is limited. Kaolinite is a clay that is a significant component of airborne particles and is an effective ice nucleus. Despite receiving considerable attention, the microscopic mechanism(s) by which kaolinite nucleates ice is not known. We report molecular dynamics simulations of heterogeneous ice nucleation by kaolinite (001) surfaces. Both the Al-surface and the Si-surface nucleate ice. For the Al-surface, reorientation of the surface hydroxyl groups is essential for ice nucleation. This flexibility allows the Al-surface to adopt a structure which is compatible with hexagonal ice, Ih, at the atomic level. On the rigid Si surface, ice nucleates via an unusual structure that consists of an ordered arrangement of hexagonal and cubic ice layers, joined at their basal planes where the interfacial energy cost is low. This ice structure provides a good match to the atomistic structure of the Si-surface. This example is important and may have far-reaching implications because it demonstrates that potential ice nuclei need not be good atomic-level matches to particular planes of ice Ih or cubic ice, Ic. It suggests that surfaces can act as effective ice nuclei by matching one of the much larger set of planes that can be constructed by regular arrangements of hexagonal and cubic ice. PMID- 26524231 TI - Identification of potential inhibitors for AIRS from de novo purine biosynthesis pathway through molecular modeling studies - a computational approach. AB - In cancer, de novo pathway plays an important role in cell proliferation by supplying huge demand of purine nucleotides. Aminoimidazole ribonucleotide synthetase (AIRS) catalyzes the fifth step of de novo purine biosynthesis facilitating in the conversion of formylglycinamidine ribonucleotide to aminoimidazole ribonucleotide. Hence, inhibiting AIRS is crucial due to its involvement in the regulation of uncontrollable cancer cell proliferation. In this study, the three-dimensional structure of AIRS from P. horikoshii OT3 was constructed based on the crystal structure from E. coli and the modeled protein is verified for stability using molecular dynamics for a time frame of 100 ns. Virtual screening and induced fit docking were performed to identify the best antagonists based on their binding mode and affinity. Through mutational studies, the residues necessary for catalytic activity of AIRS were identified and among which the following residues Lys35, Asp103, Glu137, and Thr138 are important in determination of AIRS function. The mutational studies help to understand the structural and energetic characteristics of the specified residues. In addition to Molecular Dynamics, ADME properties, binding free-energy, and density functional theory calculations of the compounds were carried out to find the best lead molecule. Based on these analyses, the compound from the NCI database, NCI_121957 was adjudged as the best molecule and could be suggested as the suitable inhibitor of AIRS. In future studies, experimental validation of these ligands as AIRS inhibitors will be carried out. PMID- 26524232 TI - Data Harmonization in Aging Research: Not so Fast. AB - BACKGROUND/STUDY CONTEXT: Harmonizing measures in order to conduct pooled data analyses has become a scientific priority in aging research. Retrospective harmonization where different studies lack common measures of comparable constructs presents a major challenge. This study compared different approaches to harmonization with a crosswalk sample who completed multiple versions of the measures to be harmonized. METHODS: Through online recruitment, 1061 participants aged 30 to 98 answered two different depression scales, and 1065 participants answered multiple measures of subjective health. Rational and configural methods of harmonization were applied, using the crosswalk sample to determine their success; and empirical item response theory (IRT) methods were applied in order empirically to compare items from different measures as answered by the same person. RESULTS: For depression, IRT worked well to provide a conversion table between different measures. The rational method of extracting semantically matched items from each of the two scales proved an acceptable alternative to IRT. For subjective health, only configural harmonization was supported. The subjective health items used in most studies form a single robust factor. CONCLUSION: Caution is required in aging research when pooling data across studies using different measures of the same construct. Of special concern are response scales that vary widely in the number of response options, especially if the anchors are asymmetrical. A crosswalk sample that has completed items from each of the measures being harmonized allows the investigator to use empirical approaches to identify flawed assumptions in rational or configural approaches to harmonizing. PMID- 26524233 TI - Age Effects in Implicit Memory: The Role of Response Competition Induced by Relative Word Frequency. AB - BACKGROUND/STUDY CONTEXT: This study examined the effect of age and response competition on implicit memory performance. METHODS: Younger and older adults studied high- and low-frequency words and took a word stem completion test that could be completed with multiple solutions. To manipulate response competition, the test list consisted of word stems that could be completed with target low frequency words, as well as multiple other solutions with higher frequencies than the target (the high response competition condition) and word stems that could be completed with target high-frequency words, as well as multiple other solutions with lower frequencies than the target (the low response competition condition). RESULTS: Relative to younger adults, older adults showed reduced levels of priming only under conditions of high response competition (low-frequency targets with high-frequency competitors). CONCLUSION: In support of a response competition mechanism, older adults were more likely to complete stems with nonstudied high-frequency solutions than were younger adults. Results demonstrate that older adults have reduced priming compared with younger adults under some conditions of high response competition. PMID- 26524234 TI - The Interaction Between Memory Trace and Memory Judgment in Age-Related Decline. AB - BACKGROUND/STUDY CONTEXT: Associative memory deficit and executive functioning deficit are two alternative--but nonexclusive--accounts of the episodic memory deficit observed in aging. The first explain the episodic memory decline generally observed in aging by an associative memory deficit (memory decline per se), whereas the second explains it by an executive functioning deficit. This distinction could be critical in early discrimination between healthy aging and very mild Alzheimer's-type dementia. METHODS: Memory performance was measured in older adults (n = 20) and paired younger participants (n = 20), whereas the facial expression and auditory context (spoken voice) associated with the face were manipulated between study and test. Recollection and familiarity were estimated using a remember/know judgment, and source memory performance was obtained depending on the information to retrieve. RESULTS: Although no between group difference was observed for correctly recognized old faces, older participants made more false alarms than younger ones, thus revealing lower discriminability (d'). Facial expression change decreased recognition for all participants, whereas auditory context change decreased recognition only for younger participants. Remember/know judgments revealed age-related deficits in both recollection and familiarity, the relative decrease in familiarity reported by older adults was particularly large in the expression change conditions, and a disadvantage in source memory performance was particularly pronounced when the task was to retrieve auditory context associated with the face at study. CONCLUSIONS: The present findings show that age-related associative memory differences occur with familiarity as well as recollection and are observed in situations that do not necessarily require conscious retrieval. This age-related decline is more prominent for multimodal (face-auditory context) than for intraitem (face-expression) associations. The value of exploring both memory trace and memory judgment was discussed, and potential applications for the development of neuropsychological tools for memory assessment in aging were highlighted. PMID- 26524235 TI - Physical Activity and Depressive Symptoms Interact to Predict Executive Functioning Among Community-Dwelling Older Adults. AB - BACKGROUND/STUDY CONTEXT: Physical activity is beneficial for the executive functioning (EF) of older adults, but may be particularly protective of EF when they are cognitively vulnerable, such as during depressive episodes. Intervention studies support more potent effects of physical activity on EF among clinically depressed older adults, although these results may have limited generalizability to the daily mood and physical activity of healthy, community-dwelling older adults. METHODS: The current study aimed to test whether physical activity among older adults was more protective of EF during periods of cognitive vulnerability due to mildly elevated depressive symptoms. Longitudinal data from 150 generally healthy, community-dwelling older adults were collected semiannually and analyzed with multilevel modeling. RESULTS: Physical activity was more protective of EF within individuals during periods of relatively elevated depressive symptoms. CONCLUSIONS: The power of physical activity to protect EF during periods of cognitive vulnerability may extend to community-dwelling older adults with nonclinical levels of depressive symptoms. PMID- 26524236 TI - The Association in Elderly Hospitalized Patients, Between Psychotropic Drugs and Hip Fractures Resulting from Falls. AB - BACKGROUND/STUDY CONTEXT: Psychotropic drug treatment has been associated with increased risk for falls and hip fractures in elderly patients. The authors examined the association between drug treatment and hip fractures resulting from falls in elderly hospitalized patients, focusing on the medications' anticholinergic properties. METHODS: This retrospective case-control study was conducted in an acute geriatric ward in a general medical center. Medical records, including demographic, clinical, biochemical, and pharmacological variables, of elderly patients with hip fractures from falls (N = 185), admitted during a 2-year period, were reviewed and compared with a control group (N = 187) of patients matched for age and gender and without hip fractures. RESULTS: The usage rates of antipsychotics, antidepressants, mood stabilizers, and various nonpsychiatric medications were similar in the two groups, except for hypnotics anxiolytics (higher rates in hip-fracture patients). The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) and diastolic blood pressure constituted very modest predictors of falls (R(2) = .038, p = .004). There were no significant differences in the anticholinergic burden values, clinical dementia ratings, and comorbidity burden between the two groups. CONCLUSION: The rate of psychotropic drug use in general and their anticholinergic burden are similar in acutely admitted elderly patients with or without hip fractures. However, higher usage rate of anxiolytics found in the patients with hip fractures may indicate that this is a risk factor for hip fractures related to falls in elderly patients living in the community. PMID- 26524237 TI - Age Differences in the Complexity of Emotion Perception. AB - BACKGROUND/STUDY CONTEXT: The current study examined age differences in the number of emotion components used in the judgment of emotion from facial expressions. METHODS: Fifty-eight younger and 58 older adults were compared on the complexity of perception of emotion from standardized facial expressions that were either clear or ambiguous exemplars of emotion. RESULTS: Using an intra individual factor analytic approach, results showed that older adults used more emotion components in perceiving emotion in faces than younger adults. Both age groups reported greater emotional complexity for the clear and prototypical emotional stimuli. Age differences in emotional complexity were more pronounced for the ambiguous expressions compared with the clear expressions. CONCLUSION: These findings demonstrate that older adults showed increased elaboration of emotion, particularly when emotion cues were subtle and provide support for greater emotion differentiation in older adulthood. PMID- 26524238 TI - Influence of Meibomian Gland Expression Methods on Human Lipid Analysis Results. AB - PURPOSE: To compare the lipid composition of human meibum across three different meibum expression techniques. METHODS: Meibum was collected from five healthy non contact lens wearers (aged 20-35 years) after cleaning the eyelid margin using three meibum expression methods: cotton buds (CB), meibomian gland evaluator (MGE) and meibomian gland forceps (MGF). Meibum was also collected using cotton buds without cleaning the eyelid margin (CBn). Lipids were analyzed by chip based, nano-electrospray mass spectrometry (ESI-MS). Comparisons were made using linear mixed models. RESULTS: Tandem MS enabled identification and quantification of over 200 lipid species across ten lipid classes. There were significant differences between collection techniques in the relative quantities of polar lipids obtained (P<.05). The MGE method returned smaller polar lipid quantities than the CB approaches. No significant differences were found between techniques for nonpolar lipids. No significant differences were found between cleaned and non-cleaned eyelids for polar or nonpolar lipids. CONCLUSION: Meibum expression technique influences the relative amount of phospholipids in the resulting sample. The highest amounts of phospholipids were detected with the CB approaches and the lowest with the MGE technique. Cleaning the eyelid margin prior to expression was not found to affect the lipid composition of the sample. This may be a consequence of the more forceful expression resulting in cell membrane contamination or higher risk of tear lipid contamination as a result of reflex tearing. PMID- 26524239 TI - Fixed single-cell transcriptomic characterization of human radial glial diversity. AB - The diverse progenitors that give rise to the human neocortex have been difficult to characterize because progenitors, particularly radial glia (RG), are rare and are defined by a combination of intracellular markers, position and morphology. To circumvent these problems, we developed Fixed and Recovered Intact Single-cell RNA (FRISCR), a method for profiling the transcriptomes of individual fixed, stained and sorted cells. Using FRISCR, we profiled primary human RG that constitute only 1% of the midgestation cortex and classified them as ventricular zone-enriched RG (vRG) that express ANXA1 and CRYAB, and outer subventricular zone-localized RG (oRG) that express HOPX. Our study identified vRG and oRG markers and molecular profiles, an essential step for understanding human neocortical progenitor development. FRISCR allows targeted single-cell profiling of any tissues that lack live-cell markers. PMID- 26524240 TI - Protein-RNA networks revealed through covalent RNA marks. AB - Protein-RNA networks are ubiquitous and central in biological control. We present an approach termed RNA Tagging that enables the user to identify protein-RNA interactions in vivo by analyzing purified cellular RNA, without protein purification or cross-linking. An RNA-binding protein of interest is fused to an enzyme that adds uridines to the end of RNA. RNA targets bound by the chimeric protein in vivo are covalently marked with uridines and subsequently identified from extracted RNA via high-throughput sequencing. We used this approach to identify hundreds of RNAs bound by a Saccharomyces cerevisiae PUF protein, Puf3p. The results showed that although RNA-binding proteins productively bind specific RNAs to control their function, they also 'sample' RNAs without exerting a regulatory effect. We used the method to uncover hundreds of new and likely regulated targets for a protein without canonical RNA-binding domains, Bfr1p. RNA Tagging is well suited to detect and analyze protein-RNA networks in vivo. PMID- 26524241 TI - Thermal proteome profiling monitors ligand interactions with cellular membrane proteins. AB - We extended thermal proteome profiling to detect transmembrane protein-small molecule interactions in cultured human cells. When we assessed the effects of detergents on ATP-binding profiles, we observed shifts in denaturation temperature for ATP-binding transmembrane proteins. We also observed cellular thermal shifts in pervanadate-induced T cell-receptor signaling, delineating the membrane target CD45 and components of the downstream pathway, and with drugs affecting the transmembrane transporters ATP1A1 and MDR1. PMID- 26524242 TI - Tissue cartography: compressing bio-image data by dimensional reduction. AB - The high volumes of data produced by state-of-the-art optical microscopes encumber research. We developed a method that reduces data size and processing time by orders of magnitude while disentangling signal by taking advantage of the laminar structure of many biological specimens. Our Image Surface Analysis Environment automatically constructs an atlas of 2D images for arbitrarily shaped, dynamic and possibly multilayered surfaces of interest. Built-in correction for cartographic distortion ensures that no information on the surface is lost, making the method suitable for quantitative analysis. We applied our approach to 4D imaging of a range of samples, including a Drosophila melanogaster embryo and a Danio rerio beating heart. PMID- 26524243 TI - Family caregiver burden in mental illnesses: The case of affective disorders and schizophrenia - a qualitative exploratory study. AB - BACKGROUND: Caregivers of people with mental illnesses often experience a wide range of burdens. Although many studies have confirmed burdens among family caregivers of mentally ill relatives in general, specific knowledge regarding the concrete everyday hassle and existential sorrows from the caregivers subjective reasoning perspective is lacking. Furthermore, there is little evidence on the possible different effects of affective disorders and schizophrenia on the quality of burden; this is also true with regard to the role of cultural traditions and lay beliefs. AIMS: The aim of this study was to explore the specific burdens experienced by caregivers of patients with schizophrenia and affective disorders. METHODS: A qualitative study was conducted by semi structured interviews with 45 caregivers of patients with schizophrenia and affective disorders. Data were analysed by qualitative content analysis. RESULTS: Eleven encumbering themes resulted from the interviews including incertitude, unawareness, emotional burden, stigma and blame, financial burden, physical burden, restriction in routine, disruption in routine, dissatisfaction with family, relatives, and acquaintances, troubles with patients' adherence to medication, and problems with health services and governmental support. CONCLUSIONS: Caring for a person with mental illness affects caregivers emotionally, financially, physically, and it elicits some restrictions in their routine (daily hassles). Finally, it causes conflicts in family relationships. Despite some differences regarding perceived burden among caregivers of schizophrenia and affective disorders, a common pattern of burden could be identified. Thus, authorities should provide adequate financial, educational, and psychosocial supports for caregivers of mental illnesses. PMID- 26524244 TI - Determinants of quality of care and treatment initiation in Medicare disabled patients with chronic hepatitis C. AB - BACKGROUND: Aligning with a national priority to bridge health disparities in disadvantaged populations, we explored contextual determinants of pretreatment quality of care and treatment receipt of Medicare disabled patients with hepatitis C virus (HCV) infection. METHODS: We used Medicare claims (2006-2009) linked to the Area Health Resource Files. Ordinal partial proportional odds and weighted modified Poisson regressions were used to model the determinants of quality care receipt and interferon-based treatment, respectively. RESULTS: We identified 1936 Medicare disabled HCV patients, of whom 10.4% were treated with peg-interferon. Despite the high comorbidity burden among HCV disabled patients, greater engagement in care correlated with greater likelihood of quality care and treatment receipt. CONCLUSION: Our study highlights the need for process and linkage to care in Medicare disabled HCV patients, but future research relevant to novel interferon-free agents is needed to assess patterns of quality of care and treatment receipt in this vulnerable population. PMID- 26524246 TI - Evaluation of early fetal exposure to vaginally-administered metronidazole in pregnant cynomolgus monkeys. AB - Given concern about potential embryo-fetal harm following seminal exposure to drugs with teratogenic potential, pharmaceutical companies use theoretical calculations to estimate seminal concentrations, maternal exposure, and distribution across the placenta to the embryo-fetal compartment for risk assessment. However, it is plausible that there are additional mechanisms whereby the conceptus is exposed. In order to determine if theoretical calculations are sufficiently conservative to predict embryo-fetal exposure from drugs in semen, pregnant cynomolgus monkeys were given a vaginal dose of metronidazole during the early fetal period and cesarean-sectioned. Maternal, fetal, and amniotic fluid samples were analyzed for metronidazole and 2-hydroxymetronidazole. Exposure to metronidazole and its metabolite were comparable in all matrices. These data demonstrated no preferential transfer mechanism to conceptus following intravaginal administration of a small molecule drug; and therefore, suggest that traditional modeling for embryo-fetal exposure to drugs in semen in support of risk assessment for pharmaceutical agents is sufficiently conservative. PMID- 26524245 TI - Gonadotoxic effects of busulfan in two strains of mice. AB - Busulfan is a chemotherapy drug that has side effects on spermatogonial stem cells (SSC). The effects of bulsufan treatment on male germ cells and fertility vary significantly between individuals. In this study, we have used molecular, cellular and histopathology approaches to investigate the effects of a single intraperitoneal dose of busulfan (40mgkg(-1)) in two mice strains, Balb/C and Swiss, at two different periods after treatment, 30 and 90 days. Testicular degeneration was observed in both Balb/C and Swiss mice after busulfan injection. Interestingly, testicular functions and fertility recovered spontaneously post busulfan treatment in Swiss mice, but not in Balb/C mice. Abnormal fertility induced by busulfan in Balb/C mice was associated with altered seminiferous tubules, sperm morphology and transcript levels of Nanos2, Nanos3, Gdnf and Plzf genes. These findings revealed that SSC of Balb/C mice are more sensitive to the toxic effects of busulfan then those of Swiss mice. PMID- 26524247 TI - Characterization of the peristaltic reflex in murine distal colon. AB - Ascending and descending neuromuscular reflexes play an important role in gastrointestinal motility. However, the underlying mechanisms in colon are incompletely understood. Nerve stimulation (NS)- and balloon distention (BD) mediated reflexes in distal colonic circular smooth muscle (CSM) and longitudinal smooth muscle (LSM) of mice were investigated using conventional intracellular recordings. In the CSM, NS evoked ascending purinergic inhibitory junction potentials (IJPs), whereas BD induced atropine-sensitive ascending depolarization with superimposed action potentials (APs). The ascending depolarization reached a peak ~4-7 s after the onset of distention and gradually returned to baseline after termination of the distention. In the LSM, NS produced an ascending biphasic IJP followed by a train of atropine-sensitive APs. Both stimuli produced similar descending IJPs in CSM and LSM, which were blocked by MRS-2500 and MRS 2179, putative purinergic receptor blockers. These data indicate that in the murine distal colon, descending purinergic inhibition in both CSM and LSM occurs. Ascending responses are more complex, with NS producing both inhibition and excitation to CSM and LSM, and BD evoking only cholinergic excitation. PMID- 26524248 TI - Plant synthetic promoters and transcription factors. AB - Synthetic promoters and transcription factors (TFs) have become incredibly powerful and efficient components for precise regulation of targeted plant transgene expression. Synthetic promoters can be rationally designed and constructed using specific type, copy number and spacing of motifs placed upstream of synthetic or native core promoters. Similarly, synthetic TFs can be constructed using a variety of DNA binding domains (DBDs) and effector domains. Synthetic promoters and TFs can provide tremendous advantages over their natural counterparts with regards to transgene expression strength and specificity. They will probably be needed for coordinated transgene expression for metabolic engineering and synthetic circuit applications in plants for bioenergy and advanced crop engineering. In this article we review the recent advances in synthetic promoters and TFs in plants and speculate on their future. PMID- 26524249 TI - Potent antitrypanosomal triterpenoid saponins from Mussaenda luteola. AB - Five new triterpenoid saponins, heinsiagenin A 3-O-[alpha-l-rhamnopyranosyl-(1 >2)-beta-d-glucopyranosyl-(1->2)]-beta-d-glucopyranoside (1), heinsiagenin A 3-O [alpha-l-rhamnopyranosyl-(1->2)-beta-d-glucopyranosyl-(1->2)]-[beta-d glucopyranosyl-(1->4)]-beta-d-glucopyranoside (2), 2alpha-hydroxyheinsiagenin A 3 O-[alpha-l-rhamnopyranosyl-(1->2)-beta-d-glucopyranosyl-(1->2)]-beta-d glucopyranoside (3), 2alpha-hydroxyheinsiagenin A 3-O-[beta-d-glucopyranosyl-(1 >2)]-[beta-d-glucopyranosyl-(1->4)]-beta-d-glucopyranoside (4) and N-(2S, 3R, 4R 3-methyl-4-pentanolid-2-yl)-18-hydroxylanosta-8 (9), 22E, 24E-trien-27-amide-3-O [alpha-l-rhamnopyranosyl-(1->2)-beta-d-glucopyranosyl-(1->2)]-[beta-d glucopyranosyl-(1->4)]-beta-d-glucopyranoside (5) were isolated from the aerial parts of Mussaenda luteola Delile (Rubiaceae). Structural elucidation was based on the analysis of spectroscopic data (1D and 2D NMR) and HR-ESI-MS. Compound 1 showed potent antitrypanosomal activity with an IC50 value of 8.80MUM. Compounds 2-4 showed highly potent antitrypanosomal activity with IC50 values ranging between (2.57-2.84MUM) and IC90 values ranging between (3.36-4.35MUM), which are 5 fold greater than the positive control DFMO (IC50 and IC90 values of 13.06 and 28.99MUM, respectively). Compounds 1 and 2 showed moderate affinity to MU-opioid receptors with Ki values of 9.936MUM and 0.872MUM, respectively compared to a Ki value of 1.958nM for the positive control, naloxone HCl. PMID- 26524250 TI - The densification of bio-char: Effect of pyrolysis temperature on the qualities of pellets. AB - The densification of bio-chars pyrolyzed at different temperatures were investigated to elucidate the effect of temperature on the properties of bio-char pellets and determine the bonding mechanism of pellets. Optimized process conditions were obtained with 128MPa compressive pressure and 35% water addition content. Results showed that both the volume density and compressive strength of bio-char pellets initially decreased and subsequently increased, while the energy consumption increased first and then decreased, with the increase of pyrolysis temperature. The moisture adsorption of bio-char pellets was noticeably lower than raw woody shavings but had elevated than the corresponding char particles. Hydrophilic functional groups, particle size and binder were the main factors that contributed to the cementation of bio-char particles at different temperatures. The result indicated that pyrolysis of woody shavings at 550-650 degrees C and followed by densification was suitable to form bio-char pellets for application as renewable biofuels. PMID- 26524251 TI - Spirulina cultivation with a CO2 absorbent: Influence on growth parameters and macromolecule production. AB - The objective of this study was to select a concentration of CO2 absorbents to supplement Spirulina sp. LEB 18 cultivation and to evaluate the effect of these compounds on the growth and production of macromolecules. Three initial biomass concentrations (X0), eight concentrations of monoethanolamine (MEA), and three NaOH concentrations were tested. The selected MEA concentrations did not inhibit the growth of Spirulina and doubled the dissolved inorganic carbon concentration in the assay medium in relation to the concentration of NaOH. The protein concentration in the biomass grown with MEA was, on average, 17% higher than that obtained with NaOH. Thus, it was found that MEA did not reduce the productivity of Spirulina sp. LEB 18, and its use can be further explored as a means for converting the carbon dissolved in the medium to biomolecules. PMID- 26524252 TI - Calcium ion on membrane fouling reduction and bioflocculation promotion in membrane bioreactor at high salt shock. AB - Fouling propensity of activated sludge in membrane bioreactor (MBR) is closely related to the disturbance of a salt shock. In this work, the characteristics of membrane fouling and bioflocculation were compared in two laboratory-scale MBRs (one with calcium addition, MBR-Ca, the other without, MBR-C) with a transient salt shock. Particle size distributions, zeta potential, relative hydrophobicity, modified fouling index, the content of polysaccharides, proteins and calcium ions in different layers of sludge were monitored prior to, during and after the salt shock. Comparison with MBR-C showed that the recovery time and fouling rate of MBR-Ca were reduced by 50% and 34%, respectively. Remarkable variations of sludge properties in terms of bioflocculation, such as larger particle sizes, higher relative hydrophobicity and zeta potential, lower polysaccharides in supernatant, higher proteins/polysaccharides ratio in slime and loose bound extracellular polymeric substances, were observed in MBR-Ca after the salt shock. PMID- 26524253 TI - Soluble inhibitors generated during hydrothermal pretreatment of oil palm mesocarp fiber suppressed the catalytic activity of Acremonium cellulase. AB - Oil palm mesocarp fiber was subjected to hydrothermal pretreatment under isothermal and non-isothermal conditions. The pretreated slurries were separated by filtration, pretreated liquids and solids were characterized. An enzymatic digestibility study was performed for both pretreated slurries and solids to understand the effect of soluble inhibitors generated during the pretreatment process. The highest glucose yield obtained from pretreated slurries was 70.1%, and gradually decreased with higher pretreatment severities. The highest glucose yield obtained in pretreated solids was 100%, after pretreatment at 210 degrees C for 20min. In order to study the inhibitory effects of compounds generated during pretreatment with cellulase, technical grade solutions that mimic the pretreated liquid were prepared and their effect on Acremonium cellulase activity was monitored using Avicel. Xylo-oligomers and tannic acid were identified as powerful inhibitors of Acremonium cellulase, and the lowest hydrolysis rate of Avicel of 0.18g/g-glucose released/L/h was obtained from tannic acid. PMID- 26524254 TI - Altered cerebellum development and impaired motor coordination in mice lacking the Btg1 gene: Involvement of cyclin D1. AB - Cerebellar granule neurons develop postnatally from cerebellar granule precursors (GCPs), which are located in the external granule layer (EGL) where they massively proliferate. Thereafter, GCPs become postmitotic, migrate inward to form the internal granule layer (IGL), further differentiate and form synapses with Purkinje cell dendrites. We previously showed that the Btg family gene, Tis21/Btg2, is required for normal GCP migration. Here we investigated the role in cerebellar development of the related gene, Btg1, which regulates stem cell quiescence in adult neurogenic niches, and is expressed in the cerebellum. Knockout of Btg1 in mice caused a major increase of the proliferation of the GCPs in the EGL, whose thickness increased, remaining hyperplastic even after postnatal day 14, when the EGL is normally reduced to a few GCP layers. This was accompanied by a slight decrease of differentiation and migration of the GCPs and increase of apoptosis. The GCPs of double Btg1/Tis21-null mice presented combined major defects of proliferation and migration outside the EGL, indicating that each gene plays unique and crucial roles in cerebellar development. Remarkably, these developmental defects lead to a permanent increase of the adult cerebellar volume in Btg1-null and double mutant mice, and to impairment in all mutants, including Tis21-null, of the cerebellum-dependent motor coordination. Gain- and loss-of-function strategies in a GCP cell line revealed that Btg1 regulates the proliferation of GCPs selectively through cyclin D1. Thus, Btg1 plays a critical role for cerebellar maturation and function. PMID- 26524255 TI - Impact of biogenic amine molecular weight and structure on surfactant adsorption at the air-water interface. AB - The oligoamines, such as ethylenediamine to pentaethylenetetramine, and the aliphatic biogenic amines, such as putrescine, spermidine and spermine, strongly interact with anionic surfactants, such as sodium dodecylsulfate, SDS. It has been shown that this results in pronounced surfactant adsorption at the air-water interface and the transition from monolayer to multilayer adsorption which depends upon solution pH and oligoamine structure. In the neutron reflectivity, NR, and surface tension, ST, results presented here the role of the oligoamine structure on the adsorption of SDS is investigated more fully using a range of different biogenic amines. The effect of the extent of the intra-molecular spacing between amine groups on the adsorption has been extended by comparing results for cadavarine with putrescine and ethylenediamine. The impact of more complex biogenic amine structures on the adsorption has been investigated with the aromatic phenethylamine, and the heterocyclic amines histamine and melamine. The results provide an important insight into how surfactant adsorption at interfaces can be manipulated by the addition of biogenic amines, and into the role of solution pH and oligoamine structure in modifying the interaction between the surfactant and oligoamine. The results impact greatly upon potential applications and in understanding some of the important biological functions of biogenic amines. PMID- 26524256 TI - Core-satellite ZnS-Ag nanoassemblies: Synthesis, structure, and optical properties. AB - We synthesized hollow core-satellite nanoassemblies comprised of hollow zinc sulfide (ZnS) shells decorated with silver nanoparticles (Ag NPs). This was achieved by solution-phase attachment of Ag NPs to hollow ZnS nanospheres (NSs) prepared by spray pyrolysis. This produces an aqueous dispersion of ZnS-Ag hybrid structures, 50-500nm in overall diameter. We characterized the nanostructures by scanning electron microscopy (SEM), transmission electron microscopy (TEM), powder X-ray diffraction (XRD), and energy dispersive X-ray spectroscopy (EDX) to elucidate the ZnS (core)-Ag (satellite) morphology and optimize conditions for producing such structures. Optical spectroscopy showed that photoluminescence of ZnS was quenched by Ag while absorbance was enhanced. This work provides a simple and general means of producing hollow core-satellite structures that could be of broad applicability. PMID- 26524257 TI - Low-cost mussel inspired poly(catechol/polyamine) coating with superior anti corrosion capability on copper. AB - A low-cost mussel inspired approach was developed to produce anti-corrosion coating on copper substrate. Catechol (CA) and polyamine (PA) were spontaneously polymerized to form adhesive coating of poly(cetechol/polyamine) (P(CA/PA)) onto copper surface and then P(CA/PA) was grafted by 1-dodecanethiol. The SEM, contact angle, XPS, FTIR and TG results demonstrated the formation of uniform, compact and thermal stable coatings through multiple interactions and chemically grafting. Electrochemical tests indicated of Cu-P(CA/PA)-SH possessed a highest corrosion potential of -81mV, a lowest corrosion current density of 0.15MUA/cm(2), and a highest coating resistance of 57.19kOmegacm(2), and also exhibit great long-term stability whether in solution immersion or salt spray tests. The remarkable anti-corrosion capability of Cu-P(CA/PA)-SH could be ascribed to the synergistic effect of the hydrophobicity, good stability, and strong wet adhesion of the mussel-inspired coating. This study provides an effective and cheap way for material protection and may give inspiration in the fields of material, biology and medicine relating to surface and interface engineering. PMID- 26524258 TI - Photovoltaic performances of Cu2-xTe sensitizer based on undoped and indium(3+) doped TiO2 photoelectrodes and assembled counter electrodes. AB - Novel binary Cu2-xTe nanoparticles based on undoped and indium-doped TiO2 photoelectrodes were synthesized using a successive ionic layer adsorption and reaction (SILAR) technique as a sensitizer for liquid-junction solar cells. A larger diameter of TiO2 promoted a narrower energy band gap after indium doping, attributing to yield a broader absorption range of nanoparticle sensitizer due to the increasing amount of Cu2-xTe NPs on TiO2 surface. The atomic percentages showed the stoichiometric formation of Cu2Te incorporated in a Cu2-xTe structure. The best photovoltaic performance with the lower SILAR cycle, i.e., n=13 was performed after indium doping in both of carbon and Cu2S CEs and revealed that the efficiency of 0.73% under the radiant 100mW/cm(2) (AM 1.5G). The electrochemical impedance spectroscopy (EIS) was used to investigate the electrical properties via effect of material doping and counter electrodes with a lower charge-transfer resistance (Rct) and it was also found that the electron lifetime was improved after the sample doped with indium and assembled with carbon CE. PMID- 26524259 TI - Phylogeny, biogeography and systematic revision of plain long-nosed squirrels (genus Dremomys, Nannosciurinae). AB - The plain long-nosed squirrels, genus Dremomys, are high elevation species in East and Southeast Asia. Here we present a complete molecular phylogeny for the genus based on nuclear and mitochondrial DNA sequences. Concatenated mitochondrial and nuclear gene trees were constructed to determine the tree topology, and date the tree. All speciation events within the plain-long nosed squirrels (genus Dremomys) were ancient (dated to the Pliocene or Miocene), and averaged older than many speciation events in the related Sunda squirrels, genus Sundasciurus. Within the plain long-nosed squirrels, the most recent interspecific split occurred 2.9 million years ago, older than some splits within Sunda squirrels, which dated to the Pleistocene. Our results demonstrate that the plain long-nosed squirrels are not monophyletic. The single species with a distinct distribution, the Bornean mountain ground squirrel (Dremomys everetti), which is endemic to the high mountains of Borneo, is nested within the Sunda squirrels with high support. This species diverged from its sister taxa in the Sunda squirrels 6.62 million years ago, and other plain long-nosed squirrels over 11 million years ago. Our analyses of morphological traits in these related genera support the re-classification of the Bornean mountain ground squirrel, Dremomys everetti, to the genus Sundasciurus, which changes its name to Sundasciurus everetti. Past inclusion in the plain long-nosed squirrels (Dremomys) reflects convergent evolution between these high elevation species. PMID- 26524260 TI - Electrokinetically modulated peristaltic transport of power-law fluids. AB - The electrokinetically modulated peristaltic transport of power-law fluids through a narrow confinement in the form of a deformable tube is investigated. The fluid is considered to be divided into two regions - a non-Newtonian core region (described by the power-law behavior) which is surrounded by a thin wall adhering layer of Newtonian fluid. This division mimics the occurrence of a wall adjacent cell-free skimming layer in blood samples typically handled in microfluidic transport. The pumping characteristics and the trapping of the fluid bolus are studied by considering the effect of fluid viscosities, power-law index and electroosmosis. It is found that the zero-flow pressure rise is strongly dependent on the relative viscosity ratio of the near-wall depleted fluid and the core fluid as well as on the power-law index. The effect of electroosmosis on the pressure rise is strongly manifested at lower occlusion values, thereby indicating its importance in transport modulation for weakly peristaltic flow. It is also established that the phenomenon of trapping may be controlled on-the-fly by tuning the magnitude of the electric field: the trapping vanishes as the magnitude of the electric field is increased. Similarly, the phenomenon of reflux is shown to disappear due to the action of the applied electric field. These findings may be applied for the modulation of pumping in bio-physical environments by means of external electric fields. PMID- 26524261 TI - Factors associated with post-traumatic stress symptoms experienced in the acute phase following haemopoietic stem cell transplant. PMID- 26524262 TI - Risk factors and impact of non-Aspergillus mold infections following allogeneic HCT: a CIBMTR infection and immune reconstitution analysis. AB - Risk factors for non-Aspergillus mold infection (NAMI) and the impact on transplant outcome are poorly assessed in the current era of antifungal agents. Outcomes of 124 patients receiving allogeneic hematopoietic cell transplantation (HCT) diagnosed with either mucormycosis (n=72) or fusariosis (n=52) between days 0 and 365 after HCT are described and compared with a control cohort (n=11 856). Patients with NAMI had more advanced disease (mucormycois: 25%, fusariosis: 23% and controls: 18%; P=0.004) and were more likely to have a Karnofsky performance status (KPS) <90% at HCT (mucormycosis: 42%, fusariosis: 38% and controls: 28%; P=0.048). The 1-year survival after HCT was 22% (15-29%) for cases and was significantly inferior compared with controls (65% (64-65%); P<0.001). Survival from infection was similarly dismal regardless of mucormycosis: 15% (8-25%) and fusariosis: 21% (11-33%). In multivariable analysis, NAMI was associated with a sixfold higher risk of death (P<0.0001) regardless of the site or timing of infection. Risk factors for mucormycosis include preceding acute GvHD, prior Aspergillus infection and older age. For fusariosis, increased risks including receipt of cord blood, prior CMV infection and transplant before May 2002. In conclusion, NAMI occurs infrequently, is associated with high mortality and appears with similar frequency in the current antifungal era. PMID- 26524263 TI - Early application of related SCT might improve clinical outcome in adult T-cell leukemia/lymphoma. AB - Allogeneic hematopoietic SCT (allo-HSCT) is a curative treatment for aggressive adult T-cell leukemia/lymphoma (ATLL). Considering the dismal prognosis associated with conventional chemotherapies, early application of allo-HSCT might be beneficial for patients with ATLL. However, no previous study has addressed the optimal timing of allo-HSCT from related donors. Hence, to evaluate the impact of timing of allo-HSCT for patients with ATLL, we retrospectively analyzed data from patients with ATLL who received an allo-HSCT from a related donor. The median age was 52 years. Patients were grouped according to the interval from diagnosis to allo-HSCT: early transplant group, <100 days, n=72; late transplant group, ?100 days, n=428. The corresponding constituents of disease status were not statistically different between the two groups (P=0.11). The probability of OS in the early transplant group was significantly higher than that in the late transplant group (4-year OS, 49.3% vs 31.2%). Multivariate analysis revealed that late allo-HSCT was an unfavorable prognostic factor for OS (hazard ratio, 1.46; 95% confidence interval (CI), 1.01-2.11; P=0.04). Despite the limitations of a retrospective study, it might be acceptable to consider early application of allo HSCT for ATLL. PMID- 26524264 TI - Tandem high-dose chemotherapy with thiotepa and busulfan-melphalan and autologous stem cell transplantation in very high-risk neuroblastoma patients. AB - High-risk neuroblastoma is characterised by poor long-term survival, especially for very high-risk (VHR) patients (poor response of metastases after induction therapy). We report the results of an intensified high-dose chemotherapy (HDC) strategy to improve the prognosis of VHR patients. This strategy was based on tandem HDC with thiotepa and busulfan-melphalan (Bu-Mel) followed by autologous stem cell transplantation (ASCT). All data were prospectively recorded in the Gustave Roussy Paediatric ASCT database. From April 2004 to August 2011, 26 patients were eligible for tandem HDC. The median age at diagnosis was 4.4 years (1-15.9). All patients had metastatic disease. MYCN was amplified in 5/26 tumours. Despite the cumulative toxicity of alkylating agents, the toxicity of the intensified HDC strategy was manageable. Thiotepa-related toxicity was mainly digestive, whereas sinusoidal obstruction syndrome was the main toxicity observed after Bu-Mel. The 3-year event-free survival of this cohort was 37.3% (21.3 56.7). This strategy will be compared with combined (131)I-mIBG/Bu-Mel in the upcoming SIOPEN VHR Neuroblastoma Protocol. PMID- 26524265 TI - Early and late graft-failure after transplants. PMID- 26524266 TI - Bendamustine-based conditioning for non-Hodgkin lymphoma autologous transplantation: an increasing risk of renal toxicity. PMID- 26524267 TI - Administration of an anti-CC chemokine receptor 4 monoclonal antibody, mogamulizumab, before allogeneic bone marrow transplantation for adult T-cell leukemia/lymphoma. PMID- 26524271 TI - 'Shrink' losses in commercially sized corn silage piles: Quantifying total losses and where they occur. AB - Silage 'shrink' (i.e., loss of fresh chopped crop between ensiling and feedout) represents a nutrient loss which can degrade air quality as volatile carbon compounds, degrade surface waterways due to seepage, or degrade aquifers due to seepage. Virtually no research has documented shrink in large silage piles. The term 'shrink' is often ill defined, but can be expressed as losses of wet weight (WW), oven dry matter (oDM), and oDM corrected for volatiles lost in the drying oven (vcoDM). Corn silage piles (4 wedge, 2 rollover/wedge, 1 bunker) from 950 to 12,204 tonnes as built, on concrete (4), soil (2) and a combination (1) in California's San Joaquin Valley, using a bacterial inoculant, covered within 24 h with an oxygen barrier inner film and black/white outer plastic, fed out using large front end loaders through an electronic feed tracking system, and from the 2013 crop year, were used. Shrink as WW, oDM and vcoDM were 90+/-17, 68+/-18 and 28+/-21 g/kg, suggesting that much WW shrink is water and much oDM shrink is volatiles lost during analytical oven drying. Most shrink occurred in the silage mass with losses from exposed silage faces, as well as between exposed face silage removal and the total mixed ration mixer, being low. Silage bulk density, exposed silage face management and face use rate did not have obvious impacts on any shrink measure, but age of the silage pile during silage feedout impacted shrink losses ('older' silage piles being higher), but most strongly for WW shrink. Real shrink losses (i.e., vcoDM) of large well managed corn silage piles are low, the exposed silage face is a small portion of losses, and many proposed shrink mitigations appeared ineffective, possibly because shrink was low overall and they are largely directed at the exposed silage face. PMID- 26524270 TI - Organochlorine contaminant concentrations in multiple tissues of free-ranging Steller sea lions (Eumetopias jubatus) in Alaska. AB - The relationships of selected organochlorine (OC) contaminants between blubber, blood, feces, and milk of young, free-ranging Steller sea lions (Eumetopias jubatus) were examined. Both between and within each tissue there was considerable individual variation. In spite of the variation, similar patterns were observed across the tissues for most of the selected PCB congeners. In all four tissues, the major PCB congeners were PCB101, PCB118, PCB138, and PCB153. The most prominent congener, both as a weight (ng/g lipid) and as a percentage of summed PCBs (?PCBs), was PCB 153. Comparisons between paired tissues showed that ?DDTs in blubber samples were related to concentrations in blood, feces, and milk. The ?PCBs in blubber were related to concentrations in milk and fecal samples, though the relationship with feces was weak. Our findings show milk samples, in particular, are useful for assessing OCs in young sea lions. Blubber concentrations of PCB101, PCB118, and PCB138 were an order of magnitude higher than those in milk, supporting the biomagnification of these PCB congeners in SSL tissues. The findings indicate alternative tissues may be used as indicators of relative contaminant exposure in lieu of surgical blubber biopsy. PMID- 26524272 TI - Soil quality index for evaluation of reclaimed coal mine spoil. AB - Success in the remediation of mine spoil depends largely on the selection of appropriate tree species. The impacts of remediation on mine soil quality cannot be sufficiently assessed by individual soil properties. However, combination of soil properties into an integrated soil quality index provides a more holistic status of reclamation potentials of tree species. Remediation potentials of four tree species (Acacia auriculiformis, Cassia siamea, Dalbergia sissoo, and Leucaena leucocephala) were studied on reclaimed coal mine overburden dumps of Jharia coalfield, Dhanbad, India. Soil samples were collected under the canopies of the tree species. Comparative studies on the properties of soils in the reclaimed and the reference sites showed improvements in soil quality parameters of the reclaimed site: coarse fraction (-20.4%), bulk density (-12.8%), water holding capacity (+0.92%), pH (+25.4%), EC (+2.9%), cation exchange capacity (+46.6%), organic carbon (+91.5%), N (+60.6%), P (+113%), K (+19.9%), Ca (+49.6%), Mg (+12.2%), Na (+19.6%), S (+46.7%), total polycyclic aromatic hydrocarbons (-71.4%), dehydrogenase activity (+197%), and microbial biomass carbon (+115%). Principal component analysis (PCA) was used to identify key mine soil quality indicators to develop a soil quality index (SQI). Selected indicators include: coarse fraction, pH, EC, soil organic carbon, P, Ca, S, and dehydrogenase activity. The indicator values were converted into a unitless score (0-1.00) and integrated into SQI. The calculated SQI was significantly (P<0.001) correlated with tree biomass and canopy cover. Reclaimed site has 52-93% higher SQI compared to the reference site. Higher SQI values were obtained for sites reclaimed with D.sissoo (+93.1%) and C.siamea (+86.4%). PMID- 26524273 TI - Fluorine. PMID- 26524274 TI - Being My Own Virgil: My Journey Through Inferno From Military Sexual Trauma. AB - This article provides a first-hand experience of military sexual abuse and trauma. The course of the abusive events unfolded over a span of 12 months. The abuse started almost immediately and continued over time, despite direct comments to stop, report to others, and other attempts by the victim at obtaining help to stop the abuse. The fact that the victim did not manifest the expected behaviors of a victim of abuse led many either to not see the effects or not view the effects as having significant impact on the victim. At different choice points, both colleagues and senior personnel either blamed the victim or refused to concern themselves with the events or get involved. Although the military system eventually understood and resolved the situation, it was a long, arduous, and painful process for the victim. PMID- 26524275 TI - Preliminary data suggest rates of male military sexual trauma may be higher than previously reported. AB - Stigma associated with disclosing military sexual trauma (MST) makes estimating an accurate base rate difficult. Anonymous assessment may help alleviate stigma. Although anonymous research has found higher rates of male MST, no study has evaluated whether providing anonymity sufficiently mitigates the impact of stigma on accurate reporting. This study used the unmatched count technique (UCT), a form of randomized response techniques, to gain information about the accuracy of base rate estimates of male MST derived via anonymous assessment of Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) combat veterans. A cross sectional convenience sample of 180 OEF/OIF male combat veterans, recruited via online websites for military populations, provided data about history of MST via traditional anonymous self-report and the UCT. The UCT revealed a rate of male MST more than 15 times higher than the rate derived via traditional anonymous assessment (1.1% vs. 17.2%). These data suggest that anonymity does not adequately mitigate the impact of stigma on disclosure of male MST. Results, though preliminary, suggest that published rates of male MST may substantially underestimate the true rate of this problem. The UCT has significant potential to improve base rate estimation of sensitive behaviors in the military. PMID- 26524276 TI - Sexual intimate partner violence as a form of MST: An initial investigation. AB - Military sexual trauma (MST) is known to impact women's health, but little is known about the occurrence of MST perpetrated by a past or current intimate partner. This study identified the occurrence of intimate partner violence (IPV) related MST in a sample of female veterans. We also examined the associations between MST history (no MST history, IPV-related MST, and MST by a nonintimate partner) and mental and physical health symptoms. Participants were 369 female veteran patients of Department of Veteran Affairs (VA) facilities in the New England region of the United States who completed a larger 2012 mail survey that included validated assessments of MST, posttraumatic stress disorder (PTSD Checklist) and depressive symptoms (CES-D), and general physical and mental health functioning (Short Form-36). Approximately half (49%) of the women in this sample reported a history of MST, of which 27 (15%) were categorized as IPV related MST. Few differences in health measures were observed among women with IPV-related MST compared with women who experienced MST by a nonintimate partner or women with no MST history. However, women who experienced IPV-related MST had similarly severe health symptoms as women who reported MST by a nonintimate partner and more severe PTSD symptoms than women without a history of MST. Some women veterans have experienced MST at the hands of an intimate partner and face health impacts. This topic warrants additional attention in clinical and research efforts. PMID- 26524277 TI - Don't tell: Military culture and male rape. AB - The issue of sexual assault that occurs during military service has been a focus of attention over the past several years. Although approximately 50% of survivors of military sexual assault are men, virtually all of the literature focuses on the assault of female service members. Research has demonstrated that cultural variables are robust correlates of the sexual assault of women. This paper proposes that cultural variables are equally important when examining the rape of men, especially when this assault occurs in military contexts. We discuss male rape myths and related constructs as they are expressed within military culture. The results of data analysis from a treatment sample of veterans with military sexual trauma (MST)-related posttraumatic stress disorder (PTSD) and clinical case examples are presented to further explore the concepts. We conclude that male rape myths and related beliefs that arise from cultural norms and are further amplified and modified by military culture impact male MST survivors and delay or obstruct their recovery. Suggestions for clinical application and future research are offered to encourage further efforts in this important area of practice. PMID- 26524278 TI - Associations of military sexual trauma, combat exposure, and number of deployments with physical and mental health indicators in Iraq and Afghanistan veterans. AB - Trauma exposure (TE) and numerous deployments have been associated with negative health outcomes in veterans, many of whom have military sexual trauma (MST) and combat exposure (CE). The aims of this study were to examine the relationships between physical and mental health symptoms with MST and CE and number of deployments. Iraq and Afghanistan veterans at the Veterans Affairs San Diego Healthcare System completed self-report measures for MST, CE, number of deployments, posttraumatic stress disorder (PTSD) symptoms, depression symptoms, alcohol use, somatic symptoms, health functioning, and body mass index (BMI). Regression analyses examined main and interaction effects of CE and MST and the linear and quadratic trends of number of deployments. The sample (N = 1,294) had a mean age of 31 and was 85% male. The MST by CE interaction on BMI was significant (p = .005), such that MST was associated with lower BMI in veterans with CE and with higher BMI in veterans without CE. MST and CE were associated with higher somatic, PTSD, and depression symptoms and with lower mental health functioning (ps < .001 to .002). CE was associated with lower physical health functioning and higher alcohol use (ps < .001 to .025). Number of deployments was linearly related to higher BMI (p = .004) and had a quadratic association with alcohol use (p = .008). Findings highlight the relationship between TE and poor health outcomes and the need to further study the mechanisms of TE on physical and mental health. PMID- 26524279 TI - Military sexual trauma, combat exposure, and negative urgency as independent predictors of PTSD and subsequent alcohol problems among OEF/OIF veterans. AB - This study tested a path model of relationships between military sexual trauma (MST), combat exposure, negative urgency, posttraumatic stress disorder (PTSD) symptoms, and alcohol use and related problems. The sample consisted of 86 Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans who reported drinking at least one alcoholic beverage per week. PTSD mediated the relationships between MST and alcohol-related problems, negative urgency and alcohol-related problems, and combat exposure and alcohol-related problems. In addition, negative urgency had a direct effect on alcohol problems. These results indicate that MST, combat exposure, and negative urgency independently predict PTSD symptoms and PTSD symptoms mediate their relationship with alcohol-related problems. Findings support previous literature on the effect of combat exposure and negative urgency on PTSD and subsequent alcohol-related problems. The current study also contributes to the limited research regarding the relationship between MST, PSTD, and alcohol use and related problems. Clinical interventions aimed at reducing emotional dysregulation and posttraumatic stress symptomology may subsequently improve alcohol-related outcomes. PMID- 26524280 TI - Functional correlates of military sexual assault in male veterans. AB - Despite research findings that similar numbers of male and female veterans are affected by military sexual trauma (MST), there has been considerably less research on the effects of MST specific to male veterans. The aim of the present study was to provide preliminary data describing functional correlates of military sexual assault (MSA) among male Iraq/Afghanistan-era veterans to identify potential health care needs for this population. We evaluated the following functional correlates: posttraumatic stress disorder (PTSD) symptoms, depression symptoms, alcohol use, drug use, suicidality, social support, violent behavior in the past 30 days, incarceration, disability eligibility status, and use of outpatient mental health treatment. We compared 3 groups: (a) male veterans who endorsed a history of MSA (n = 39), (b) a general non-MSA sample (n = 2,003), and (c) a matched non-MSA sample (n = 39) identified by matching algorithms on the basis of factors (e.g., age, education, adult premilitary sexual trauma history, childhood sexual and physical trauma history, and race) that could increase veterans' vulnerability to the functional correlates examined. MSA in men was associated with greater PTSD symptom severity, greater depression symptom severity, higher suicidality, and higher outpatient mental health treatment, above and beyond the effects of vulnerability factors. These findings suggest that, for male veterans, MSA may result in a severe and enduring overall symptom profile requiring ongoing clinical management. PMID- 26524281 TI - Sexual trauma in the military: Exploring PTSD and mental health care utilization in female veterans. AB - Sexual trauma remains a pervasive problem in the military. The deleterious mental health outcomes related to incidents of sexual assault have been well-documented in the literature, with particular attention given to the development of posttraumatic stress disorder (PTSD) and utilization of mental health services. Much effort has focused on addressing issues of sexual trauma in the military. The purpose of this study was to examine the incidences of sexual assault in female veterans, the relationship to PTSD and mental health care utilization. The research explored differences in pre- and post-9/11 veterans. Data were collected using a 6-prong recruitment strategy to reach veterans living in Southern California. A total of 2,583 veterans completed online and in-person surveys, of which 325 female veterans were identified for inclusion in the analysis. Forty percent of the sample reported experiencing sexual assault during their military service. A history of military sexual trauma was found to be a substantial contributor to symptoms of PTSD. A majority of female veterans who indicated being sexually assaulted during their military service met the cutoff for a diagnosis of PTSD. Although only a minority of participants who indicated being a victim of sexual assault reported receiving immediate care after the incident, most had received mental health counseling within the past 12 months. Findings point to the need for additional prevention programs within the military and opportunities for care for victims of military sexual assault. PMID- 26524282 TI - The influence of military sexual trauma on returning OEF/OIF male veterans. AB - Military sexual trauma (MST) encompasses experiences of sexual harassment and/or assault that occur during active duty military service. MST is associated with postdeployment mental health, interpersonal, and physical difficulties and appears to be more influential in the development of posttraumatic stress disorder (PTSD) than other active duty experiences, including combat, among women veterans. Although some literature suggests that men who experience MST also evidence significant postdeployment difficulties, research in this area is lacking. The current study evaluated a large sample of returning male veterans (N = 961) who served in Iraq and/or Afghanistan. Veterans were referred for treatment in a trauma and anxiety specialty clinic at a large VA hospital. Of this sample, 18% (n = 173) reported MST perpetrated by a member of their unit. Results indicated veterans who reported MST were younger (p = .001), less likely to be currently married (p < .001), more likely to be diagnosed with a mood disorder (p = .040), and more likely to have experienced non-MST sexual abuse either as children or adults (p < .001). Analyses revealed that MST was negatively associated with postdeployment social support (p < .001 and positively associated with postdeployment perceived emotional mistreatment (p = .004), but was not associated with postdeployment loss of romantic relationship (p = .264), job loss (p = .351), or unemployment (p = .741) after statistically controlling for other trauma exposures and current social support. Results reflect the detrimental associations of MST on male veterans and the need for more research in this area. These findings also highlight the need for treatment interventions that address social and interpersonal functioning in addition to symptoms of depressive disorders. PMID- 26524283 TI - Predicting utilization of healthcare services in the veterans health administration by returning women veterans: The role of trauma exposure and symptoms of posttraumatic stress. AB - Combat exposure and military sexual trauma (MST) are prevalent among returning women veterans and are associated with increased alcohol use and psychological distress. However, it remains unclear the extent to which combat exposure and MST are associated with utilization of health care in the Veterans Health Administration (VHA). The current study explored the relationships among alcohol use and distress in women who deployed in support of Operations Enduring Freedom, Iraqi Freedom, and New Dawn. It was hypothesized that increased posttraumatic stress disorder (PTSD) and depression symptomatology and trauma exposure would be related to greater VHA utilization, whereas alcohol misuse would predict lower VHA use. Participants (N = 133) completed an Internet-based survey of deployment experiences, substance use, mental health, and utilization of VHA services. In this sample, 33% endorsed MST exposure, 64% endorsed combat exposure, and 78% indicated exposure to the aftermath of battle. Multiple regression models found combat exposure-but not MST or aftermath-to be significantly associated with alcohol use and symptoms of PTSD and depression. Only 37% of participants reported use of VHA services, and logistic regression models indicated that PTSD symptomatology was the only unique predictor of VHA use. Findings suggest potential barriers for women who endured sexually based trauma in a military setting in seeking treatment at the VHA. PMID- 26524284 TI - Self-efficacy, male rape myth acceptance, and devaluation of emotions in sexual trauma sequelae: Findings from a sample of male veterans. AB - Sexual trauma is an understudied but regrettably significant problem among male Veterans. As in women, sexual trauma often results in serious mental health consequences for men. Therefore, to guide potential future interventions in this important group, we investigated associations among self-efficacy, male rape myth acceptance, devaluation of emotions, and psychiatric symptom severity after male sexual victimization. We collected data from 1,872 Gulf War era Veterans who applied for posttraumatic stress disorder (PTSD) disability benefits using standard mailed survey methods. The survey asked about history of childhood sexual abuse, sexual assault during the time of Gulf War I, and past-year sexual assault as well as Veterans' perceived self-efficacy, male rape myth acceptance, devaluation of emotions, PTSD, and depression symptoms. Structural equation modeling revealed that self-efficacy partially mediated the association between participants' sexual trauma history and psychiatric symptoms. Greater male rape myth acceptance and greater devaluation of emotions were directly associated with lower self-efficacy, but these beliefs did not moderate associations between sexual trauma and self-efficacy. In this population, sexual trauma, male rape myth acceptance, and devaluation of emotions were associated with lowered self efficacy, which in turn was associated with more severe psychiatric symptoms. Implications for specific, trauma-focused treatment are discussed. PMID- 26524285 TI - The role of cognitive processing therapy in improving psychosocial functioning, health, and quality of life in veterans with military sexual trauma-related posttraumatic stress disorder. AB - Although research has identified evidence-based treatments (EBTs) for military sexual trauma (MST)-related posttraumatic stress disorder (PTSD), few studies have examined the effect of such treatments on psychosocial functioning, health or quality of life in individuals with MST-related PTSD. Male and female veterans (N = 45) with MST-related PTSD took part in a randomized clinical trial that included either 12 weeks of an evidence-based psychotherapeutic treatment (cognitive processing therapy; [CPT]) or a standard control condition (present centered therapy) and 6 months of follow-up. To assess quality of life and psychosocial functioning, each participant was administered the Quality of Life Inventory and the Short Form (36) Health Survey. Using a hierarchical linear modeling approach, results demonstrated that participants treated with CPT reported significantly higher physical functioning over time than did participants treated with PCT. Implications are discussed with regard to the role of psychotherapy in improving a patient's psychosocial and health functioning. PMID- 26524286 TI - Establishing a new military sexual trauma treatment program: Issues and recommendations for design and implementation. AB - This article presents a review of issues and considerations when developing a comprehensive military sexual trauma (MST) treatment program. A review of the current literature was conducted, which we argue is the first step in informing programmatic design. Next, information on how to obtain local public data and then a description of how we used this information to design the new MST program at our facility are discussed. Our clinic design reflects best practice while simultaneously incorporating real-world information and will be more likely to positively influence overall care to patients. As such, we recommend that clinicians involved in clinic development will use this process as a model for successful clinic planning and program development. PMID- 26524287 TI - Quantum spin hall insulators in strain-modified arsenene. AB - By means of density functional theory (DFT) computations, we predict that the suitable strain modulation of honeycomb arsenene results in a unique two dimensional (2D) topological insulator (TI) with a sizable bulk gap (up to 696 meV), which could be characterized and utilized at room temperature. Without considering any spin-orbit coupling, the band inversion occurs around the Gamma (G) point at tensile strains larger than 11.7%, which indicates the quantum spin Hall effect in arsenene at appropriate strains. The nontrivial topological phase was further confirmed by the topological invariant nu = 1 and edge states with a single Dirac-type crossing at the G point. Our results provide a promising strategy for designing 2D TIs with large bulk gaps from commonly used materials. PMID- 26524288 TI - Predictors and Outcomes of Post-Hospitalization Dialysis Dependent Acute Kidney Injury. AB - BACKGROUND: Acute kidney injury (AKI) is a frequent complication of hospitalized patients and is associated with poor outcomes. Hospitalized patients with AKI may need prolonged dialysis, necessitating post-hospitalization dialysis (PHD-AKI). Scarce information is available to stratify the risks and predict outcomes. This study aims to assess outcomes and identify predictors of outcomes of PHD-AKI within 90 days. METHODS: All adult AKI patients initiating hemodialysis (HD) at the University of Virginia (UVA) between June 1, 2012, and September 30, 2013 were retrospectively studied. PHD-AKI patients continued treatment at a specifically designated unit. They were followed until an outcome (end-stage renal disease [ESRD], death or dialysis-independence) was achieved. RESULTS: During the study period, 108 patients required outpatient dialysis out of 365 AKI patients initiating in-patient HD at UVA. An additional 11 patients who developed dialysis-requiring AKI at referring hospitals but underwent HD at our unit were included for a total of 119 patients studied. ESRD was declared in 48.7%, while 9.2% expired and 42.0% achieved dialysis independence. Congestive heart failure, baseline renal function and a prior episode of AKI within the preceding 6 months were statistically significant predictors of renal outcomes. CONCLUSION: Dialysis independence of PHD-AKI patients is not uncommon. Certain clinical parameters may help predict renal outcome. Identifying predictors of renal recovery will guide further interventions, especially with the Centers for Medicare and Medicaid Services soon to allow AKI patients to be dialyzed at outpatient ESRD facilities. Ongoing biomarkers research may add further knowledge for optimum diagnosis and prognosis of AKI. PMID- 26524289 TI - Multicatalytic colloids with highly scalable, adjustable, and stable functionalities in organic and aqueous media. AB - Despite a large number of developments of noble metal (or metal oxide) NP-based catalysts, it has been a great challenge to prepare high-performance recyclable catalysts with integrated functionalities that can be used in various solvent media. Here, we report on layer-by-layer (LbL) assembled multicatalysts with high catalytic performance, showing high dispersion and recycling stability in organic and aqueous media. The remarkable advantages of our approach are as follows. (i) Various metal or metal oxide NPs with desired catalytic performance can be easily incorporated into multilayered shells, forming densely packed arrays that allow one colloid to be used as a multicatalyst with highly integrated and controllable catalytic properties. (ii) Additionally, the dispersion stability of catalytic colloids in a desired solvent can be determined by the type of ultrathin outermost layer coating each colloid. (iii) Lastly, the covalent bonding between inorganic NPs and dendrimers within multilayer shells enhances the recycling stability of multicatalytic colloids. The resulting core-shell colloids including OA-Fe3O4 NPs, TOABr-Pd NPs, and OA-TiO2 NPs exhibited excellent performance in the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) and photocatalysis in aqueous media and in the Sonogashira coupling reaction (99% yield) in organic media. Given that the catalytic properties of recyclable colloids reported to date have entirely depended on the functionality of a single catalytic NP layer deposited onto colloids in selective solvent media, our approach provides a basis for the design and exploitation of high-performance recyclable colloids with integrated multicatalytic properties and high dispersion stability in a variety of solvents. PMID- 26524290 TI - A candidate-gene association study of topiramate-induced weight loss in obese patients with and without type 2 diabetes mellitus. AB - OBJECTIVE: Clinical response to topiramate can vary greatly in obese patients. Identifying genetic variants associated with treatment response could help gain insight into the mechanism of action of topiramate. Little is known about the relationship between genetic variability and topiramate treatment response. We performed a large-scale candidate-gene study to identify genetic risk factors predictive of topiramate-induced weight loss. METHODS: We collected DNA samples from patients who had previously participated in clinical trials to assess the efficacy of topiramate for the treatment of obesity. A custom chip containing single nucleotide polymorphisms from ~ 480 candidate genes was utilized to genotype a discovery cohort of 445 obese patients from a clinical study. Variants predictive of topiramate-induced weight loss were identified and further tested in an independent replication cohort of drug-naive, obese patients with type 2 diabetes (N=139). RESULTS: We identified a haplotype in INSR that may contribute to differential topiramate-induced weight loss. Carriers and noncarriers of an INSR haplotype lost 9.1 and 7.0% of body weight, respectively (P = 6.5 * 10(-6), P adj = 0.001). This finding was replicated, with carriers and noncarriers losing 9.5 and 7.3% of body weight, respectively (P Bonf=0.02), in the independent replication cohort. We also identified an SNP in HNF1A that may be associated with topiramate response and an SNP in GRIA3 that may be associated with nonpharmacologic treatment response. CONCLUSION: According to our preliminary findings, genetic variation in the INSR and HNF1A genes may differentially affect weight loss in obese individuals treated with topiramate and genes related to insulin action are implicated in modulating topiramate response. However, these findings need to be further replicated in additional larger samples. PMID- 26524292 TI - Measurement and modelling of reactive transport in geological barriers for nuclear waste containment. AB - Compacted clays are considered as excellent candidates for barriers to radionuclide transport in future repositories for nuclear waste due to their very low hydraulic permeability. Diffusion is the dominant transport mechanism, controlled by a nano-scale pore system. Assessment of the clays' long-term containment function requires adequate modelling of such pore systems and their evolution. Existing characterisation techniques do not provide complete pore space information for effective modelling, such as pore and throat size distributions and connectivity. Special network models for reactive transport are proposed here using the complimentary character of the pore space and the solid phase. This balances the insufficient characterisation information and provides the means for future mechanical-physical-chemical coupling. The anisotropy and heterogeneity of clays is represented using different length parameters and percentage of pores in different directions. Resulting networks are described as mathematical graphs with efficient discrete calculus formulation of transport. Opalinus Clay (OPA) is chosen as an example. Experimental data for the tritiated water (HTO) and U(vi) diffusion through OPA are presented. Calculated diffusion coefficients of HTO and uranium species are within the ranges of the experimentally determined data in different clay directions. This verifies the proposed pore network model and validates that uranium complexes are diffusing as neutral species in OPA. In the case of U(vi) diffusion the method is extended to account for sorption and convection. Rather than changing pore radii by coarse grained mathematical formula, physical sorption is simulated in each pore, which is more accurate and realistic. PMID- 26524293 TI - Recombinant Fusion Allergens, Cry j 1 and Cry j 2 from Japanese Cedar Pollen, Conjugated with Polyethylene Glycol Potentiate the Attenuation of Cry j 1 Specific IgE Production in Cry j 1-Sensitized Mice and Japanese Cedar Pollen Allergen-Sensitized Monkeys. AB - BACKGROUND: Japanese cedar (Cryptomeria japonica) pollinosis is the most prevalent seasonal rhinitis in Japan. A standardized Japanese cedar pollen extract (CPE) containing 1.5-4.2 MUg of Cry j 1 is currently the highest concentration extract available for allergen-specific immunotherapy (SIT) against this pollinosis. Therefore, we developed a PEGylated fusion protein as a more effective SIT vaccine against Japanese cedar pollinosis. METHODS: The fusion protein of major allergens for Japanese cedar pollen, Cry j 1 and Cry j 2, was expressed in Escherichia coli and conjugated with polyethylene glycol (PEG). The purified PEGylated Cry j 1/2 fusion protein (PEG-fusion) was subcutaneously injected four times into Cry j 1- sensitized mice and CPE-sensitized monkeys. The mice were then subcutaneously challenged with Cry j 1 and serum levels of Cry j 1 specific immunoglobulin, and the proliferation and cytokine production of splenocytes were analyzed. The monkeys were intranasally challenged with CPE and analyzed for Cry j 1-specific immunoglobulin levels in plasma. RESULTS: Cry j 1 specific IgE was significantly attenuated in the PEG-fusion-treated group after Cry j 1-challenge and Cry j 1-specific IgG was significantly increased following PEG-fusion treatment in mice and monkeys. Proliferation and Th2-type cytokine production in splenocytes stimulated with Cry j 1 were also reduced in PEG-fusion treated mice. IL10 and IL2 production were reduced, but not significantly, while IFN-x03B3; was significantly increased in the PEG-fusion-treated group. CONCLUSIONS: A high-dose injection of PEG-fusion appears to be a valid candidate for a safer and more effective vaccine than the conventional SIT extract for Japanese cedar pollinosis. PMID- 26524294 TI - Blood-Brain Barrier Permeability and Gadolinium: Benefits and Potential Pitfalls in Research. PMID- 26524295 TI - Crystallography in the 21st century. PMID- 26524297 TI - Sorting algorithms for single-particle imaging experiments at X-ray free-electron lasers. AB - Modern X-ray free-electron lasers (XFELs) operating at high repetition rates produce a tremendous amount of data. It is a great challenge to classify this information and reduce the initial data set to a manageable size for further analysis. Here an approach for classification of diffraction patterns measured in prototypical diffract-and-destroy single-particle imaging experiments at XFELs is presented. It is proposed that the data are classified on the basis of a set of parameters that take into account the underlying diffraction physics and specific relations between the real-space structure of a particle and its reciprocal-space intensity distribution. The approach is demonstrated by applying principal component analysis and support vector machine algorithms to the simulated and measured X-ray data sets. PMID- 26524296 TI - A strenuous experimental journey searching for spectroscopic evidence of a bridging nickel-iron-hydride in [NiFe] hydrogenase. AB - Direct spectroscopic evidence for a hydride bridge in the Ni-R form of [NiFe] hydrogenase has been obtained using iron-specific nuclear resonance vibrational spectroscopy (NRVS). The Ni-H-Fe wag mode at 675 cm(-1) is the first spectroscopic evidence for a bridging hydride in Ni-R as well as the first iron hydride-related NRVS feature observed for a biological system. Although density function theory (DFT) calculation assisted the determination of the Ni-R structure, it did not predict the Ni-H-Fe wag mode at ~ 675 cm(-1) before NRVS. Instead, the observed Ni-H-Fe mode provided a critical reference for the DFT calculations. While the overall science about Ni-R is presented and discussed elsewhere, this article focuses on the long and strenuous experimental journey to search for and experimentally identify the Ni-H-Fe wag mode in a Ni-R sample. As a methodology, the results presented here will go beyond Ni-R and hydrogenase research and will also be of interest to other scientists who use synchrotron radiation for measuring dilute samples or weak spectroscopic features. PMID- 26524298 TI - Applications of VUV extra-focus mechanism: high-performance dual-mode monochromator from VUV to soft X-ray. AB - A new monochromator scheme is presented in which an extra-focus constant-included angle varied-line-spacing cylindrical-grating monochromator (extra-focus CIA VCGM) is conveniently combined with a variable-included-angle varied-line-spacing plane-grating monochromator (VIA-VPGM). This dual-mode solution delivers high performance in the energy range from vacuum ultraviolet (VUV) to soft X-ray. The resolving power and the efficiency of this dual-mode grating monochromator are analyzed in detail based on realistic parameters. Comparisons with the commonly used variable-included-angle plane-grating monochromator and normal-incidence monochromator (VIA-PGM/NIM) hybrid monochromator are made. PMID- 26524299 TI - In situ removal of carbon contamination from a chromium-coated mirror: ideal optics to suppress higher-order harmonics in the carbon K-edge region. AB - Carbon-free chromium-coated optics are ideal in the carbon K-edge region (280-330 eV) because the reflectivity of first-order light is larger than that of gold coated optics while the second-order harmonics (560-660 eV) are significantly suppressed by chromium L-edge and oxygen K-edge absorption. Here, chromium-, gold and nickel-coated mirrors have been adopted in the vacuum ultraviolet and soft X ray branch beamline BL-13B at the Photon Factory in Tsukuba, Japan. Carbon contamination on the chromium-coated mirror was almost completely removed by exposure to oxygen at a pressure of 8 * 10(-2) Pa for 1 h under irradiation of non-monochromated synchrotron radiation. The pressure in the chamber recovered to the order of 10(-7) Pa within a few hours. The reflectivity of the chromium coated mirror of the second-order harmonics in the carbon K-edge region (560-660 eV) was found to be a factor of 0.1-0.48 smaller than that of the gold-coated mirror. PMID- 26524300 TI - Custom AFM for X-ray beamlines: in situ biological investigations under physiological conditions. AB - A fast atomic force microscope (AFM) has been developed that can be installed as a sample holder for grazing-incidence X-ray experiments at solid/gas or solid/liquid interfaces. It allows a wide range of possible investigations, including soft and biological samples under physiological conditions (hydrated specimens). The structural information obtained using the X-rays is combined with the data gathered with the AFM (morphology and mechanical properties), providing a unique characterization of the specimen and its dynamics in situ during an experiment. In this work, lipid monolayers and bilayers in air or liquid environment have been investigated by means of AFM, both with imaging and force spectroscopy, and X-ray reflectivity. In addition, this combination allows the radiation damage induced by the beam on the sample to be studied, as has been observed on DOPC and DPPC supported lipid bilayers under physiological conditions. PMID- 26524301 TI - A modular and compact portable mini-endstation for high-precision, high-speed fixed target serial crystallography at FEL and synchrotron sources. AB - The design and implementation of a compact and portable sample alignment system suitable for use at both synchrotron and free-electron laser (FEL) sources and its performance are described. The system provides the ability to quickly and reliably deliver large numbers of samples using the minimum amount of sample possible, through positioning of fixed target arrays into the X-ray beam. The combination of high-precision stages, high-quality sample viewing, a fast controller and a software layer overcome many of the challenges associated with sample alignment. A straightforward interface that minimizes setup and sample changeover time as well as simplifying communication with the stages during the experiment is also described, together with an intuitive naming convention for defining, tracking and locating sample positions. The setup allows the precise delivery of samples in predefined locations to a specific position in space and time, reliably and simply. PMID- 26524302 TI - Structural characterization and low-temperature properties of Ru/C multilayer monochromators with different periodic thicknesses. AB - Ru/C multilayer monochromators with different periodic thicknesses were investigated using X-ray grazing-incidence reflectivity, diffuse scattering, Bragg imaging, morphology testing, etc. before and after cryogenic cooling. Quantitative analyses enabled the determination of the key multilayer structural parameters for samples with different periodic thicknesses, especially the influence from the ruthenium crystallization. The results also reveal that the basic structures and reflection performance keep stable after cryogenic cooling. The low-temperature treatment smoothed the surfaces and interfaces and changed the growth characteristic to a low-frequency surface figure. This study helps with the understanding of the structure evolution of multilayer monochromators during cryogenic cooling and presents sufficient experimental proof for using cryogenically cooled multilayer monochromators in a high-thermal-load undulator beamline. PMID- 26524303 TI - In situ X-ray data collection and structure phasing of protein crystals at Structural Biology Center 19-ID. AB - A prototype of a 96-well plate scanner for in situ data collection has been developed at the Structural Biology Center (SBC) beamline 19-ID, located at the Advanced Photon Source, USA. The applicability of this instrument for protein crystal diffraction screening and data collection at ambient temperature has been demonstrated. Several different protein crystals, including selenium-labeled, were used for data collection and successful SAD phasing. Without the common procedure of crystal handling and subsequent cryo-cooling for data collection at T = 100 K, crystals in a crystallization buffer show remarkably low mosaicity (<0.1 degrees ) until deterioration by radiation damage occurs. Data presented here show that cryo-cooling can cause some unexpected structural changes. Based on the results of this study, the integration of the plate scanner into the 19-ID end-station with automated controls is being prepared. With improvement of hardware and software, in situ data collection will become available for the SBC user program including remote access. PMID- 26524304 TI - Pixelated transmission-mode diamond X-ray detector. AB - Fabrication and testing of a prototype transmission-mode pixelated diamond X-ray detector (pitch size 60-100 um), designed to simultaneously measure the flux, position and morphology of an X-ray beam in real time, are described. The pixel density is achieved by lithographically patterning vertical stripes on the front and horizontal stripes on the back of an electronic-grade chemical vapor deposition single-crystal diamond. The bias is rotated through the back horizontal stripes and the current is read out on the front vertical stripes at a rate of ~ 1 kHz, which leads to an image sampling rate of ~ 30 Hz. This novel signal readout scheme was tested at beamline X28C at the National Synchrotron Light Source (white beam, 5-15 keV) and at beamline G3 at the Cornell High Energy Synchrotron Source (monochromatic beam, 11.3 keV) with incident beam flux ranges from 1.8 * 10(-2) to 90 W mm(-2). Test results show that the novel detector provides precise beam position (positional noise within 1%) and morphology information (error within 2%), with an additional software-controlled single channel mode providing accurate flux measurement (fluctuation within 1%). PMID- 26524305 TI - Investigation of a CPG-array CdZnTe gamma-ray imaging detector with single collecting electrodes readout. AB - The single-electrode readout method has been applied to a coplanar grid (CPG) array CdZnTe detector in order to halve the number of preamplifiers previously needed and to facilitate imaging applications of CPG detectors. A method of predetermining the width of the optimum collecting electrodes has also been proposed, using the calculated optimum relative gain factor G. Meanwhile, a detailed process for calculating the charge induction efficiency (CIE) is presented. To simplify the calculation process, the computational formula of the CIE was deduced through the integration of the weighting potential. For performance evaluation, a 2 * 2 CPG-array CdZnTe detector was elaborately designed and tested with (137)Cs at 662 keV. Experimental results showed the capability of using the CPG-array CdZnTe detector with single collecting electrode readout for gamma-ray imaging applications, with the same complexity of associated readout electronics as that of the pixelated CdZnTe detectors. PMID- 26524306 TI - X-ray third-order nonlinear plane-wave Bragg-case dynamical diffraction effects in a perfect crystal. AB - Two-wave symmetric Bragg-case dynamical diffraction of a plane X-ray wave in a crystal with third-order nonlinear response to the electric field is considered theoretically. For certain diffraction conditions for a non-absorbing perfect semi-infinite crystal in the total reflection region an analytical solution is found. For the width and for the center of the total reflection region expressions on the intensity of the incidence wave are established. It is shown that in the nonlinear case the total reflection region exists below a maximal intensity of the incidence wave. With increasing intensity of the incidence wave the total reflection region's center moves to low angles and the width decreases. Using numerical calculations for an absorbing semi-infinite crystal, the behavior of the reflected wave as a function of the intensity of the incidence wave and of the deviation parameter from the Bragg condition is analyzed. The results of numerical calculations are compared with the obtained analytical solution. PMID- 26524307 TI - X-ray fluorescence induced by standing waves in the grazing-incidence and grazing exit modes: study of the Mg-Co-Zr system. AB - The characterization of Mg-Co-Zr tri-layer stacks using X-ray fluorescence induced by X-ray standing waves, in both the grazing-incidence (GI) and the grazing-exit (GE) modes, is presented. The introduction of a slit in the direction of the detector improves the angular resolution by a factor of two and significantly improves the sensitivity of the technique for the chemical characterization of the buried interfaces. By observing the intensity variations of the Mg Kalpha and Co Lalpha characteristic emissions as a function of the incident (GI mode) or detection (GE mode) angle, it is shown that the interfaces of the Si/[Mg/Co/Zr] * 30 multilayer are abrupt, whereas in the Si/[Mg/Zr/Co] * 30 multilayer a strong intermixing occurs at the Co-on-Zr interfaces. An explanation of this opposite behavior of the Co-on-Zr and Zr-on-Co interfaces is given by the calculation of the mixing enthalpies of the Co-Mg, Co-Zr and Mg-Zr systems, which shows that the Co-Zr system presents a negative value and the other two systems present positive values. Together with the difference of the surface free energies of Zr and Co, this leads to the Mg/Zr/Co system being considered as a Mg/CoxZry bi-layer stack, with x/y estimated around 3.5. PMID- 26524308 TI - X-ray spectroscopy for chemistry in the 2-4 keV energy regime at the XMaS beamline: ionic liquids, Rh and Pd catalysts in gas and liquid environments, and Cl contamination in gamma-Al2O3. AB - The 2-4 keV energy range provides a rich window into many facets of materials science and chemistry. Within this window, P, S, Cl, K and Ca K-edges may be found along with the L-edges of industrially important elements from Y through to Sn. Yet, compared with those that cater for energies above ca. 4-5 keV, there are relatively few resources available for X-ray spectroscopy below these energies. In addition, in situ or operando studies become to varying degrees more challenging than at higher X-ray energies due to restrictions imposed by the lower energies of the X-rays upon the design and construction of appropriate sample environments. The XMaS beamline at the ESRF has recently made efforts to extend its operational energy range to include this softer end of the X-ray spectrum. In this report the resulting performance of this resource for X-ray spectroscopy is detailed with specific attention drawn to: understanding electrostatic and charge transfer effects at the S K-edge in ionic liquids; quantification of dilution limits at the Cl K- and Rh L3-edges and structural equilibria in solution; in vacuum deposition and reduction of [Rh(I)(CO)2Cl]2 to gamma-Al2O3; contamination of gamma-Al2O3 by Cl and its potential role in determining the chemical character of supported Rh catalysts; and the development of chlorinated Pd catalysts in 'green' solvent systems. Sample environments thus far developed are also presented, characterized and their overall performance evaluated. PMID- 26524309 TI - The competitive growth of cubic domains in Ti(1-x)AlxN films studied by diffraction anomalous near-edge structure spectroscopy. AB - Titanium and aluminium nitride films deposited by magnetron sputtering generally grow as columnar domains made of oriented nanocrystallites with cubic or hexagonal symmetry depending on Al content, which are embedded in more disordered grain boundaries. The substitution of Al atoms for Ti in the cubic lattice of the films improves their resistance to wear and oxidation, allowing their use as protective coatings. Ti K-edge X-ray absorption spectroscopy, which probes both crystallized and more disordered grain boundaries, and X-ray diffraction anomalous fine structure, which is sensitive to short- and long-range order within a given crystallized domain, are carried out on a set of Ti(1-x)AlxN films deposited by magnetron sputtering on Si substrates. Attention is paid to the shape of the pre-edge region, which is sensitive to the symmetry of the site occupied by Ti atoms, either octahedral in face-centred-cubic Ti-rich (TiN, Ti0.54Al0.46N) samples or tetrahedral in hexagonal-close-packed Al-rich (Ti0.32Al0.68N) films. In order to obain information on the titanium environment in the well crystallized areas, subtraction of the smooth part of the energy dependent structure factor for the Bragg reflections is applied to the pre-edge region of the diffraction anomalous data in order to restore their spectroscopic appearance. A flat pre-edge is related to the typical octahedral environment of Ti atoms for cubic reflections. The difference observed between pre-edge spectra associated with face-centred-cubic 200 and 111 Bragg reflections of Ti0.54Al0.46N is assigned to Ti enrichment of 111 large well ordered domains compared with the more disordered 200 ones. The sharp peak observed in the spectrum recorded from the hexagonal 002 peak of Ti0.32Al0.68N can be regarded as a standard for the pure tetrahedral Ti environment in hexagonal-close-packed nitride. PMID- 26524310 TI - Influence of crystal structure, ligand environment and morphology on Co L-edge XAS spectral characteristics in cobalt compounds. AB - The electronic structure of a material plays an important role in its functionality for different applications which can be probed using synchrotron based spectroscopy techniques. Here, various cobalt-based compounds, differing in crystal structure, ligands surrounding the central metal ion and morphology, have been studied by soft X-ray absorption spectroscopy (XAS) at the Co L-edge in order to measure the effect of these parameters on the electronic structure. A careful qualitative analysis of the spectral branching ratio and relative intensities of the L3 and L2 peaks provide useful insight into the electronic properties of compounds such as CoO/Co(OH)2, CoCl2.6H2O/CoF2.4H2O, CoCl2/CoF2, Co3O4 (bulk/nano/micro). For further detailed analysis of the XAS spectra, quantitative analysis has been performed by fitting the spectral profile with simulated spectra for a number of cobalt compounds using crystal field atomic multiplet calculations. PMID- 26524311 TI - Synchrotron study of metal localization in Typha latifolia L. root sections. AB - Understanding mechanisms that control plant root metal assimilation in soil is critical to the sustainable management of metal-contaminated land. With the assistance of the synchrotron X-ray fluorescence technique, this study investigated possible mechanisms that control the localization of Fe, Cu, Mn, Pb and Zn in the root tissues of Typha latifolia L. collected from a contaminated wetland. Metal localizations especially in the case of Fe and Pb in the dermal tissue and the vascular bundles were different. Cluster analysis was performed to divide the dermal tissue into iron-plaque-enriched dermal tissue and regular dermal tissue based on the spatial distribution of Pb and Fe. Factor analysis showed that Cu and Zn were closely correlated to each other in the dermal tissues. The association of Cu, Zn and Mn with Fe was strong in both regular dermal tissue and iron-plaque-enriched dermal tissue, while significant (p < 0.05) correlation of Fe with Pb was only observed in tissues enriched with iron plaque. In the vascular bundles, Zn, Mn and Cu showed strong association, suggesting that the localization of these three elements was controlled by a similar mechanism. Iron plaque in the peripheral dermal tissues acted as a barrier for Pb and a buffer for Zn, Cu and Mn. The Casparian strip regulated the transportation of metals from dermal tissues to the vascular bundles. The results suggested that the mechanisms controlling metal localization in root tissues varied with both tissue types and metals. PMID- 26524312 TI - An EXAFS spectroscopic study of Am(III) complexation with lactate. AB - The pH dependence (1-7) of Am(III) complexation with lactate in aqueous solution is studied using extended X-ray absorption fine-structure (EXAFS) spectroscopy. Structural data (coordination numbers, Am--O and Am--C distances) of the formed Am(III)-lactate species are determined from the raw k(3)-weighted Am LIII-edge EXAFS spectra. Between pH 1 and pH 6, Am(III) speciation shifts continuously towards complexed species with increasing pH. At higher pH, the amount of complexed species decreases due to formation of hydroxo species. The coordination numbers and distances (3.41-3.43 A) of the coordinating carbon atoms clearly point out that lactate is bound 'side-on' to Am(III) through both the carboxylic and the alpha-hydroxy function of lactate. The experimentally determined coordination numbers are compared with speciation calculations on the basis of tabulated thermodynamic stability constants. Both EXAFS data and thermodynamic modelling are in very good agreement. The EXAFS spectra are also analyzed by iterative transformation factor analysis to further verify the determined Am(III) speciation and the used structural model. PMID- 26524313 TI - Structural investigation of mM Ni(II) complex isomers using transmission XAFS: the significance of model development. AB - High-accuracy transmission XAFS determined using the hybrid technique has been used to refine the geometries of bis(N-n-propyl-salicylaldiminato) nickel(II) (n pr Ni) and bis(N-i-propyl-salicylaldiminato) nickel(II) (i-pr Ni) complexes which have approximately square planar and tetrahedral metal coordination. Multiple scattering formalisms embedded in FEFF were used for XAFS modelling of the complexes. Here it is shown that an IFEFFIT-like package using weighting from experimental uncertainty converges to a well defined XAFS model. Structural refinement of (i-pr Ni) was found to yield a distorted tetrahedral geometry providing an excellent fit, chir(2) = 2.94. The structure of (n-pr Ni) is best modelled with a distorted square planar geometry, chir(2) = 3.27. This study demonstrates the insight that can be obtained from the propagation of uncertainty in XAFS analysis and the consequent confidence which can be obtained in hypothesis testing and in analysis of alternate structures ab initio. It also demonstrates the limitations of this (or any other) data set by defining the point at which signal becomes embedded in noise or amplified uncertainty, and hence can justify the use of a particular k-range for one data set or a different range for another. It is demonstrated that, with careful attention to data collection, including the correction of systematic errors with statistical analysis of uncertainty (the hybrid method), it is possible to obtain reliable structural information from dilute solutions using transmission XAFS data. PMID- 26524314 TI - In situ microradioscopy and microtomography of fatigue-loaded dental two-piece implants. AB - Synchrotron real-time radioscopy and in situ microtomography are the only techniques providing direct visible information on a micrometre scale of local deformation in the implant-abutment connection (IAC) during and after cyclic loading. The microgap formation at the IAC has been subject to a number of studies as it has been proposed to be associated with long-term implant success. The next step in this scientific development is to focus on the in situ fatigue procedure of two-component dental implants. Therefore, an apparatus has been developed which is optimized for the in situ fatigue analysis of dental implants. This report demonstrates both the capability of in situ radioscopy and microtomography at the ID19 beamline for the study of cyclic deformation in dental implants. The first results show that it is possible to visualize fatigue loading of dental implants in real-time radioscopy in addition to the in situ fatigue tomography. For the latter, in situ microtomography is applied during the cyclic loading cycles in order to visualize the opening of the IAC microgap. These results concur with previous ex situ studies on similar systems. The setup allows for easily increasing the bending force, to simulate different chewing situations, and is, therefore, a versatile tool for examining the fatigue processes of dental implants and possibly other specimens. PMID- 26524315 TI - Coherent diffractive imaging: towards achieving atomic resolution. AB - The next generation of X-ray sources will feature highly brilliant X-ray beams that will enable the imaging of local nanoscale structures with unprecedented resolution. A general formalism to predict the achievable spatial resolution in coherent diffractive imaging, based solely on diffracted intensities, is provided. The coherent dose necessary to reach atomic resolution depends significantly on the atomic scale structure, where disordered or amorphous materials require roughly three orders of magnitude lower dose compared with the expected scaling of uniform density materials. Additionally, dose reduction for crystalline materials are predicted at certain resolutions based only on their unit-cell dimensions and structure factors. PMID- 26524316 TI - A feasibility study of X-ray phase-contrast mammographic tomography at the Imaging and Medical beamline of the Australian Synchrotron. AB - Results are presented of a recent experiment at the Imaging and Medical beamline of the Australian Synchrotron intended to contribute to the implementation of low dose high-sensitivity three-dimensional mammographic phase-contrast imaging, initially at synchrotrons and subsequently in hospitals and medical imaging clinics. The effect of such imaging parameters as X-ray energy, source size, detector resolution, sample-to-detector distance, scanning and data processing strategies in the case of propagation-based phase-contrast computed tomography (CT) have been tested, quantified, evaluated and optimized using a plastic phantom simulating relevant breast-tissue characteristics. Analysis of the data collected using a Hamamatsu CMOS Flat Panel Sensor, with a pixel size of 100 um, revealed the presence of propagation-based phase contrast and demonstrated significant improvement of the quality of phase-contrast CT imaging compared with conventional (absorption-based) CT, at medically acceptable radiation doses. PMID- 26524317 TI - X-ray-induced Cu deposition and patterning on insulators at room temperature. AB - X-ray irradiation is shown to trigger the deposition of Cu from solution, at room temperature, on a wide variety of insulating substrates: glass, passivated Si, TiN/Ti/SiO2/Si and photoresists like PMMA and SU-8. The process is suitable for patterning and the products can be used as seeds for electroplating of thicker overlayers. PMID- 26524318 TI - Effect of X-ray spot size on liquid jet photoelectron spectroscopy. AB - A 30 um pinhole is introduced in the intermediate focus of the SIM beamline at the Swiss Light Source to improve the spot size at the second downstream focus, which is used here for liquid jet X-ray photoelectron spectroscopy experiments. The 30 um pinhole reduces the beam dimensions from 250 (v) * 100 (h) um to 75 * 45 um for a vertical exit slit of 100 um. The smaller X-ray spot results in a substantial decrease in the gas-phase contribution of the spectra from 40% down to 20% and will help to simplify the interpretation and peak assignments of future experiments. PMID- 26524319 TI - Design, development and first experiments on the X-ray imaging beamline at Indus 2 synchrotron source RRCAT, India. AB - A full-field hard X-ray imaging beamline (BL-4) was designed, developed, installed and commissioned recently at the Indus-2 synchrotron radiation source at RRCAT, Indore, India. The bending-magnet beamline is operated in monochromatic and white beam mode. A variety of imaging techniques are implemented such as high resolution radiography, propagation- and analyzer-based phase contrast imaging, real-time imaging, absorption and phase contrast tomography etc. First experiments on propagation-based phase contrast imaging and micro-tomography are reported. PMID- 26524321 TI - The time-resolved and extreme conditions XAS (TEXAS) facility at the European Synchrotron Radiation Facility: the general-purpose EXAFS bending-magnet beamline BM23. AB - BM23 is the general-purpose EXAFS bending-magnet beamline at the ESRF, replacing the former BM29 beamline in the framework of the ESRF upgrade. Its mission is to serve the whole XAS user community by providing access to a basic service in addition to the many specialized instruments available at the ESRF. BM23 offers high signal-to-noise ratio EXAFS in a large energy range (5-75 keV), continuous energy scanning for quick-EXAFS on the second timescale and a micro-XAS station delivering a spot size of 4 um * 4 um FWHM. It is a user-friendly facility featuring a high degree of automation, online EXAFS data reduction and a flexible sample environment. PMID- 26524320 TI - MASSIF-1: a beamline dedicated to the fully automatic characterization and data collection from crystals of biological macromolecules. AB - MASSIF-1 (ID30A-1) is an ESRF undulator beamline operating at a fixed wavelength of 0.969 A (12.8 keV) that is dedicated to the completely automatic characterization of and data collection from crystals of biological macromolecules. The first of the ESRF Upgrade MASSIF beamlines to be commissioned, it has been open since September 2014, providing a unique automated data collection service to academic and industrial users. Here, the beamline characteristics and details of the new service are outlined. PMID- 26524322 TI - A miniature closed-circle flow cell for high photon flux X-ray scattering experiments. AB - A closed-circle miniature flow cell for high X-ray photon flux experiments on radiation-sensitive liquid samples is presented. The compact cell is made from highly inert material and the flow is induced by a rotating magnetic stir bar, which acts as a centrifugal pump inside the cell. The cell is ideal for radiation sensitive yet precious or hazardous liquid samples, such as concentrated acids or bases. As a demonstration of the cell's capabilities, X-ray Raman scattering spectroscopy data on the oxygen K-edge of liquid water under ambient conditions are presented. PMID- 26524324 TI - Computational investigation of NH3 adsorption and dehydrogenation on a W-modified Fe(111) surface. AB - Hydrogen gas will play an important role in the future since it could be a replacement for gasoline, heating oil, natural gas, and other fuels. In previous reports ammonia (NH3), which has a high hydrogen content, provides a promising mode for the transferring and storing of hydrogen for its on-site generation. Therefore, the dehydrogenation of NH3 on a metal surface has been studied widely in the last few decades. In our study, we employed monolayer tungsten metal to modify the Fe(111) surface, denoted as W@Fe(111), and calculated the adsorption and dehydrogenation behaviors of NH3 on W@Fe(111) surface via first-principles calculations based on density functional theory (DFT). The three adsorption sites of the surface, top (T), 3-fold-shallow (S), and 3-fold-deep (D) were considered. The most stable structure of the NHx (x = 0-3) species on the surface of W@Fe(111) have been predicted. The calculated activation energies for NHx (x = 1 3) dehydrogenations are 19.29 kcal mol(-1) (for H2N-H bond activation), 29.17 kcal mol(-1) (for HN-H bond activation) and 27.94 kcal mol(-1) (for N-H bond activation), and the entire process is exothermic by 33.05 kcal mol(-1). To gain detailed knowledge of the catalytic processes of the NH3 molecule on the W@Fe(111) surface, the physical insights between the adsorbate/substrate interaction and interface morphology were subjected to a detailed electronic analysis. PMID- 26524325 TI - Interleukin-36gamma (IL-1F9) Identifies Psoriasis Among Patients With Erythroderma. PMID- 26524327 TI - Managing Pseudomonas aeruginosa respiratory infections in cystic fibrosis. AB - PURPOSE OF REVIEW: The current guidelines and recent clinical research in the management of Pseudomonas aeruginosa respiratory infections in cystic fibrosis (CF) are reviewed. Areas where further research is required will also be highlighted. RECENT FINDINGS: P. aeruginosa is a key respiratory pathogen in CF. Inhaled tobramycin or colistin is recommended for early eradication to prevent establishment of chronic infection. Other antibiotic options are currently being investigated. The long-term success of eradication strategies is also now being assessed. The use of inhaled antibiotics in the management of chronic P. aeruginosa infection is an area of active investigation. Acute pulmonary exacerbations are still a major cause of morbidity and mortality. Guidelines continue to recommend combination intravenous therapy but further research is required to clarify the advantage of this approach. Multidrug resistance is common and potentially more effective antipseudomonal antibiotics may soon become available. SUMMARY: The management of P. aeruginosa respiratory infection in CF remains a challenging area, especially in the setting of multidrug resistance. The role of inhaled antibiotics continues to be expanded. Further research is required in the key areas of eradication and management of chronic infection and acute pulmonary exacerbations to identify those treatments that optimize long term, clinical benefits. PMID- 26524326 TI - Clinical perspectives on echinocandin resistance among Candida species. AB - PURPOSE OF REVIEW: We review and offer our clinical perspectives on the emergence of echinocandin-resistant Candida. RECENT FINDINGS: Candida FKS gene mutations attenuate echinocandin activity, but overall mutation rates among clinical isolates remain low (Candida glabrata, ~4%; other species, <1%). Rates are higher with prior echinocandin exposure, exceeding 50% among C. glabrata or Candida albicans isolates causing breakthrough invasive candidiasis. The median duration of prior echinocandin exposure among FKS mutant isolates is ~100 days. The clinical usefulness of echinocandin susceptibility testing is limited by the low overall prevalence of resistance, and uncertainties surrounding testing methods and interpretation of minimum inhibitory concentrations (MICs). In single-center studies, caspofungin resistance (defined using institution-specific MIC breakpoints) was 32-53% sensitive and 75-95% specific for predicting treatment outcomes of C. glabrata invasive candidiasis; corresponding values for the presence of an FKS mutation were 35-41% and 90-98%. Results were similar using anidulafungin and micafungin MICs. Clinical data are scarce for non-C. glabrata species. SUMMARY: Echinocandins remain preferred agents against invasive Candida infections. Susceptibility testing and FKS genotypic testing do not have roles in routine clinical practice, but may be useful in newly-diagnosed patients who are echinocandin-experienced or those who have not responded to echinocandin treatment. PMID- 26524328 TI - The hepatitis C revolution part 1: antiviral treatment options. AB - PURPOSE OF REVIEW: The rapid evolution in the therapeutic landscape of hepatitis C presents a minefield to clinicians seeking to optimize therapy for their patients. Efficacy, evidence-base, side-effects, and drug combinations must be tailored to individual patients, taking into account comorbidities, degree of fibrosis, evidence of hepatic decompensation, and life expectancy. The review article aims to discuss novel hepatitis C virus (HCV) treatments with an overview of recent breakthrough research validating their potential. It is hoped that this systematic evaluation will clarify best available evidence for clinicians treating patients with HCV on a regular basis. RECENT FINDINGS: With greater understanding of the HCV life cycle and viral genome, the last decade has seen the emergence of novel direct-acting antiviral (DAA) agents, which specifically target proteins responsible for viral replication. Landmark clinical trials have offered robust evidence supporting the use of DAA agents as pioneer treatments, alone, or in combination with standard pegylated interferon (peg-IFN) and ribavirin (RBV)-based regimens. DAAs have proved highly efficacious, with pan genotypic activity, shortened treatment duration, and an improved side-effect profile when compared with historical peg-IFN/RBV treatment. Recent phase 3 studies have provided proof-of-concept that all-oral, IFN-free DAA regimens can yield high rates of sustained virological response across most HCV genotypes. SUMMARY: The ability of DAAs to dramatically improve virological clearance heralds a new era in clinical therapeutics, as the unprecedented prospect of cure for a chronic viral infection becomes tangible. However, myriad clinical challenges remain before global eradication of HCV can become reality. PMID- 26524329 TI - The hepatitis C revolution part 2: difficult-to-treat groups and experimental approaches. AB - PURPOSE OF REVIEW: Novel direct-acting antiviral (DAA) agents are highly effective in the treatment of hepatitis C, achieving unprecedented rates of sustained virological response, a functional cure. However, a significant minority of patients belong to 'difficult-to-treat' groups, in which efficacy of DAAs appears less robust. The review article aims to discuss additional treatment strategies which may be employed in these patient cohorts, as well as evidence for the potential role of experimental DAAs. RECENT FINDINGS: Patients with genotype 3 infection have consistently lower rates of virological clearance following DAA therapy when compared with other genotypes. However, in combination with sofosbuvir, the novel nonstructural protein 5A inhibitor daclatasvir has demonstrated high efficacy in the treatment of noncirrhotic genotype 3 infection. Recent data from phase 2 and 3 clinical studies support the use of currently approved DAA regimens in the treatment of patients with hepatitis C virus and human immunodeficiency virus (HIV) coinfection. Sustained virological response rates in coinfected patients are analogous to those observed in monoinfection, such that HIV infection itself does not pose a barrier to DAA efficacy. In posttransplant populations, DAAs have again shown great potential, with trial data validating use of sofosbuvir/ledipasvir. SUMMARY: Unmet need persists in certain subsets of the hepatitis C patient population. The arrival on scene of novel DAAs is likely to further expand the repertoire of available therapy for these 'difficult-to-treat' groups. PMID- 26524331 TI - Herpes simplex virus and varicella zoster virus: recent advances in therapy. AB - PURPOSE OF REVIEW: The mainstay of antiviral therapy for the alpha-herpesviruses [herpes simplex virus (HSV)-1, HSV-2, and varicella zoster virus (VZV)] over the past 40 years has been the nucleoside analogues such as aciclovir. Although conventional antiviral therapy has reduced mortality in severe disease, novel agents are needed to address the emergence of resistance and toxicity associated with current second-line therapy. Treatment and prophylaxis of VZV and HSV reactivations remains a challenge. RECENT FINDINGS: A number of compounds have recently been evaluated in human clinical trials, amongst them brincidofovir, an intracellularly acting derivative of cidofovir currently undergoing phase III trials. The helicase-primase inhibitors are a new class of antiviral agent and may circumvent resistance to existing agents. Amenamevir and pritelivir are two examples of these agents that have been evaluated clinically along with novel nucleoside analogues such as valomaciclovir and FV-100. Tenofovir, an agent used in HIV and hepatitis B therapy, may also have a role in the prevention of HSV-2 acquisition and reduce viral shedding. SUMMARY: Although several novel antiviral agents have undergone clinical trials in recent years, all are yet to gain licensure. Brincidofovir appears to be the candidate with most promise for adoption into routine practice in the near future. PMID- 26524330 TI - Hepatitis C virus treatment as prevention in people who inject drugs: testing the evidence. AB - PURPOSE OF REVIEW: The majority of hepatitis C virus (HCV) infections in the United Kingdom and many developing countries were acquired through injecting. New clinical guidance suggests that HCV treatment should be offered to people with a transmission risk - such as people who inject drugs (PWID) - irrespective of severity of liver disease. We consider the strength of the evidence base and potential problems in evaluating HCV treatment as prevention among PWID. RECENT FINDINGS: There is good theoretical evidence from dynamic models that HCV treatment for PWID could reduce HCV chronic prevalence and incidence among PWID. Economic evaluations from high-income settings have suggested HCV treatment for PWID is cost-effective, and that in many settings HCV treatment of PWID could be more cost-effective than treating those at an equivalent stage with no ongoing transmission risk. Epidemiological studies of older interferon treatments have suggested that PWID can achieve similar treatment outcomes to other patient groups treated for chronic HCV. Impact and cost-effectiveness of HCV treatment is driven by the potential 'prevention benefit' of treating PWID. Model projections suggest that more future infections, end stage liver disease, and HCV-related deaths will be averted than lost through reinfection of PWID treated successfully for HCV. However, there is to date no empirical evidence from trials or observational studies that test the model projections and 'prevention benefit' hypothesis. In part this is because of uncertainty in the evidence base but also there is unlikely to have been a change in HCV prevalence due to HCV treatment because PWID HCV treatment rates historically in most sites have been low, and any scale-up and switch to the new direct acting antiviral has not yet occurred. There are a number of key uncertainties in the data available on PWID that need to be improved and addressed to evaluate treatment as prevention. These include estimates of the prevalence of PWID, measurements of HCV chronic prevalence and incidence among PWID, and how to interpret reinfection rates as potential outcome measures. SUMMARY: Eliminating HCV through scaling up treatment is a theoretical possibility. But empirical data are required to demonstrate that HCV treatment can reduce HCV transmission, which will require an improved evidence base and analytic framework for measuring PWID and HCV prevalence. PMID- 26524332 TI - The future of antivirals: broad-spectrum inhibitors. AB - PURPOSE OF REVIEW: Potent antivirals are successfully used for the treatment of infections with herpesviruses, hepatitis B and C viruses, HIV, and with some success for influenza viruses. However, no selective inhibitors are available for a multitude of medically important viruses, most of which are (re-)emerging RNA viruses. As it is impossible to develop drugs against each of these viruses, broad-spectrum antiviral agents (BSAA) are a prime strategy to cope with this challenge. RECENT FINDINGS: We propose four categories of antiviral molecules that hold promise as BSAA. Several nucleoside analogues with broad antiviral activity have been described and given the relatively conserved nature of viral polymerases, it may be possible to develop more broad-spectrum nucleoside analogues. A number of viral proteins are relatively conserved between families and may also be interesting targets. Host-targeting antiviral drugs such as modulators of lipid metabolism and cyclophilin inhibitors can be explored as well. Finally, the potent and broad antiviral function of the immune system can be exploited by the development of immune-modulating BSAA. SUMMARY: Despite the recent advances, the BSAA field is still in its infancy. Nevertheless, the discovery and development of such molecules will be a key aim of antiviral research in the coming decades. PMID- 26524333 TI - Delivery of long-acting injectable antivirals: best approaches and recent advances. AB - PURPOSE OF REVIEW: Treatment of chronic disease in a manner that promotes compliance and patient adherence has necessitated the consideration for drug delivery approaches that reduce the burden of regimens requiring daily treatment. Long-acting injectable (LAI) products have been developed in many disease areas and are now being exploited for the treatment of infectious disease, most notably HIV. RECENT FINDINGS: Research published over the past 3 years has shown that LAI nanosuspensions of nonnucleoside reverse transcriptase inhibitors and integrase inhibitors provide extended exposure to the active drug over a period of days to weeks. Some of these candidates are currently in clinical study and are highly anticipated medications for the prevention of HIV. SUMMARY: LAIs represent a growing need in the treatment of chronic infections. To date, the approach has been most successfully applied in the treatment of HIV, but could certainly be expanded into other diseases like tuberculosis. Most importantly, LAIs can provide a means to help prevent the emergence of resistance which may be attributed to lack of compliance to regimens requiring daily, oral administration. PMID- 26524334 TI - Kaposi's sarcoma-associated herpesvirus: the role of lytic replication in targeted therapy. AB - PURPOSE OF REVIEW: To discuss the role of Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication in viral-associated diseases and assess the progress on targeting KSHV lytic replication as a strategy to prevent KSHV-related malignancies. RECENT FINDINGS: New inhibitors of viral lytic replication are being developed as well as novel modalities are being investigated to target cellular processes that the virus hijacks during its life cycle. Research has also focused on reactivating viral lytic replication in latently infected tumour cells (lytic induction therapy) to promote death of tumour cells. SUMMARY: KSHV is linked to three malignancies: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Despite significant progress in understanding KSHV pathobiology, no therapeutic guidelines for the management of KSHV-related diseases exist, and current treatments are suboptimal and associated with toxicity. Antiherpesvirus drugs have shown inconsistent results in KSHV associated malignancies that harbour the virus in a latent state. However, lytic replication plays a crucial role in the process of tumorigenesis. Therefore, not only antiviral agents directed against the virus replicative cycle but also agents that target cellular processes that are activated by the virus are being investigated. Antivirals may also be used in combination with inducers of the viral lytic stage. PMID- 26524336 TI - Carnivory during Ontogeny of the Plagioscion squamosissimus: A Successful Non Native Fish in a Lentic Environment of the Upper Parana River Basin. AB - This study evaluated feeding patterns and ontogenetic variations in a non-native fish species (Plagioscion squamosissimus) in an isolated lake in the Upper Parana River floodplain. Quarterly samplings were performed from April 2005 to February 2006 using plankton nets to capture larvae, seining nets for juveniles, and gill nets and trammel for adults. Stomach contents (n = 378) were examined according to the volumetric method in which the volume of each food item was estimated using graduated test tubes or a glass counting plate. During early development (larval stage), P. squamosissimus consumed mainly Cladocera and Copepoda. Juveniles showed a more diverse diet, including shrimp (Macrobrachium amazonicum), fish, aquatic insects (Trichoptera, Ephemeroptera, Chironomidae and pupae of Diptera) and plants. It was notable the high proportion of cannibalism (23.3%) in this stage. Adults consumed predominantly shrimp and fish. The use of food resources varied significantly between development stages (ANOSIM; r = 0.458; p<0.005), showing changes in food preferences during ontogeny. The Similarity Percentage Analysis (SIMPER) indicated that Cladocera and Copepoda were responsible for the differences observed between the larval stages of pre flexion, flexion and post-flexion. M. amazonicum and Chironomidae were responsible for the differences between juvenile and larval stages, while M. amazonicum and other fishes caused the differences between adults and other ontogenetic stages. These results are confirmed by the relationship between standard length and developmental periods (ANCOVA; r2 = 0.94; p<0.0001). In general, there were low values of trophic niche breadth. The essentially carnivorous habit from the early stages of P. squamosissimus and the predominant use of M. amazonicum by adults have important roles in feeding patterns of the species, suggesting a major contribution to its success and establishment, especially in lentic environments. PMID- 26524337 TI - pH-Responsive Gas-Water-Solid Interface for Multiphase Catalysis. AB - Despite their wide utility in laboratory synthesis and industrial fabrication, gas-water-solid multiphase catalysis reactions often suffer from low reaction efficiency because of the low solubility of gases in water. Using a surface modification protocol, interface-active silica nanoparticles were synthesized. Such nanoparticles can assemble at the gas-water interface, stabilizing micrometer-sized gas bubbles in water, and disassemble by tuning of the aqueous phase pH. The ability to stabilize gas microbubbles can be finely tuned through variation of the surface-modification protocol. As proof of this concept, Pd and Au were deposited on these silica nanoparticles, leading to interface-active catalysts for aqueous hydrogenation and oxidation, respectively. With such catalysts, conventional gas-water-solid multiphase reactions can be transformed to H2 or O2 microbubble reaction systems. The resultant microbubble reaction systems exhibit significant catalysis efficiency enhancement effects compared with conventional multiphase reactions. The significant improvement is attributed to the pronounced increase in reaction interface area that allows for the direct contact of gas, water, and solid phases. At the end of reaction, the microbubbles can be removed from the reaction systems through changing the pH, allowing product separation and catalyst recycling. Interestingly, the alcohol oxidation activation energy for the microbubble systems is much lower than that for the conventional multiphase reaction, also indicating that the developed microbubble system may be a valuable platform to design innovative multiphase catalysis reactions. PMID- 26524338 TI - Harnessing Social Media for Child Health Research: Pediatric Research 2.0. PMID- 26524339 TI - Methyl tunnelling of adsorbed methoxy on alumina catalysts. AB - The aim of this paper is to investigate whether the methyl group of the adsorbed methoxy intermediate on industrial grade alumina catalysts undergoes rotational tunnelling on the wavenumber energy scale. The data show that this is clearly the case for a fraction of the methyl groups and potentially allows the subtle intermolecular interactions between adsorbed species and catalyst to be probed through the exponential dependence of the tunnel frequency on the rotational potential. PMID- 26524340 TI - Red and Near-Infrared Photoluminescence of D-pi-A-Type Compounds Based on a 1,4 Diaryl-1-thio-1,3-butadiene Conjugated System in a Dibenzobarrelene Skeleton. AB - 1,4-Diaryl-1-thio-1,3-butadiene derivatives having a pi-donor dimethylamino group and several pi-acceptor substituents at both terminals of the conjugated system were synthesized by intramolecular [4 + 2] cycloaddition of 1-thio-enynes and subsequent chemical transformations. They displayed largely red-shifted absorption and emission spectra in solution, the powder state, and in polymer films. The derivatives with a 2,2-dicyanoethenyl group as the pi-acceptor exhibited inverted solvatochromism in both optical absorption and fluorescence spectroscopies. PMID- 26524342 TI - Laser-Induced Fluorescence Spectroscopy of Jet-Cooled t-Butoxy. AB - The vibrational structures of the A(2)A1 and X(2)E states of t-butoxy were obtained in jet-cooled laser-induced fluorescence (LIF) and dispersed fluorescence (DF) spectroscopic measurements. The observed transitions are assigned based on vibrational frequencies calculated using the complete active space self-consistent field (CASSCF) method and the predicted Franck-Condon factors. The spin-orbit splitting was measured to be 36(5) cm(-1) for the lowest vibrational level of the ground (X(2)E) state, which is significantly smaller than that of methoxy, and increases with increasing vibrational quantum number of the CO stretch mode. Vibronic analysis of the DF spectra suggests that Jahn Teller active modes of the ground-state t-butoxy radical are similar to those of methoxy and would be the same if methyl groups were replaced by hydrogen atoms. The rotational and fine structure of the LIF transition to the first CO stretch overtone level of the A(2)A1 state has been simulated using a spectroscopic model first proposed for methoxy, yielding an accurate determination of the rotational constants of both A and X states. PMID- 26524341 TI - Sulforaphane Bioavailability from Glucoraphanin-Rich Broccoli: Control by Active Endogenous Myrosinase. AB - Glucoraphanin from broccoli and its sprouts and seeds is a water soluble and relatively inert precursor of sulforaphane, the reactive isothiocyanate that potently inhibits neoplastic cellular processes and prevents a number of disease states. Sulforaphane is difficult to deliver in an enriched and stable form for purposes of direct human consumption. We have focused upon evaluating the bioavailability of sulforaphane, either by direct administration of glucoraphanin (a glucosinolate, or beta-thioglucoside-N-hydroxysulfate), or by co-administering glucoraphanin and the enzyme myrosinase to catalyze its conversion to sulforaphane at economic, reproducible and sustainable yields. We show that following administration of glucoraphanin in a commercially prepared dietary supplement to a small number of human volunteers, the volunteers had equivalent output of sulforaphane metabolites in their urine to that which they produced when given an equimolar dose of glucoraphanin in a simple boiled and lyophilized extract of broccoli sprouts. Furthermore, when either broccoli sprouts or seeds are administered directly to subjects without prior extraction and consequent inactivation of endogenous myrosinase, regardless of the delivery matrix or dose, the sulforaphane in those preparations is 3- to 4-fold more bioavailable than sulforaphane from glucoraphanin delivered without active plant myrosinase. These data expand upon earlier reports of inter- and intra-individual variability, when glucoraphanin was delivered in either teas, juices, or gelatin capsules, and they confirm that a variety of delivery matrices may be equally suitable for glucoraphanin supplementation (e.g. fruit juices, water, or various types of capsules and tablets). PMID- 26524343 TI - Ameliorative effect of quercetin against arsenic-induced sperm DNA damage and daily sperm production in adult male rats. AB - In this study, the protective effect of quercetin was evaluated against arsenic induced reproductive ailments in male rats. For this purpose, male rats (n = 5/group) weighing 180-250 g were used. First group served as control, second group received arsenic (50 ppm) in drinking water. Third group was treated with quercetin (50 mg/kg) alone, while fourth group received arsenic + quercetin. All treatments were carried out for 49 days. After treatment, animals were killed by decapitation; testis and epididymis were dissected out. Right epididymis was minced immediately for comet assay, while left epididymis was processed for histology. Similarly, right testis was homogenized for estimation of daily sperm production (DSP) and detection of metal concentration. The results of our research revealed that arsenic treatment did not cause any significant change in body weight and testicular volume. Quercetin treatment significantly prevented tissue deposition of arsenic within the testis. Arsenic treatment caused a significant reduction in DSP, however, in the arsenic + quercetin-treated group and quercetin alone-treated group, DSP was significantly high as compared to the arsenic-treated group. Histological study of epididymis showed empty lumen in arsenic-treated group while in arsenic + quercetin-treated group and quercetin alone-treated group, lumen were filled with sperm and were comparable to control. Sperm DNA damage, induced by arsenic, was significantly reversed toward control levels by supplementation of quercetin. These results suggest that quercetin not only prevents deposition of arsenic in tissues, but can also protect the sperm DNA damage. PMID- 26524345 TI - "Advection, Dispersion and Confusion,". PMID- 26524344 TI - Improving the Performance of Organic Thin-Film Transistors by Ion Doping of Ethylene-Glycol-Based Self-Assembled Monolayer Hybrid Dielectrics. AB - Tuning the electrostatics of ethylene-glycol-based self-assembled monolayers (SAMs) by doping with ions is shown. Molecular dynamics simulations unravel binding mechanisms and predict dipole strengths of the doped layers. Additionally, by applying such layers as dielectrics in organic thin-film transistors, the incorporated ions are proven to enhance device performance by lowering the threshold voltage and increasing conductivity. PMID- 26524346 TI - Molecular variation of the nonribosomal peptide-polyketide siderophore yersiniabactin through biosynthetic and metabolic engineering. AB - The production of the mixed nonribosomal peptide-polyketide natural product yersiniabactin (Ybt) has been established using E. coli as a heterologous host. In this study, precursor-directed biosynthesis was used to generate five new analogs of Ybt, demonstrating the flexibility of the heterologous system and the biosynthetic process in allowing compound diversity. A combination of biosynthetic and cellular engineering was then used to influence the production metrics of the resulting analogs. First, the cellular levels and activity of FadL, a hydrocarbon transport protein, were tested for subsequent influence upon exogenous precursor uptake and Ybt analog production with a positive correlation observed between FadL over-production and analog formation. Next, a Ybt biosynthetic editing enzyme was removed from the heterologous system which decreased native compound production but increased analog formation. A final series of experiments enhanced endogenous anthranilate towards complete pathway formation of the associated analog which showed a selective ability to bind gold. PMID- 26524348 TI - Sleep positioning systems for children with cerebral palsy. AB - BACKGROUND: Sleep positioning systems can be prescribed for children with cerebral palsy to help reduce or prevent hip migration, provide comfort to ease pain and/or improve sleep. As sleep disturbance is common in children with developmental disabilities, with impact on their carers' sleep, and as sleep positioning systems can be expensive, guidance is needed to support decisions as to their use. OBJECTIVES: To determine whether commercially-available sleep positioning systems, compared with usual care, reduce or prevent hip migration in children with cerebral palsy. Any negative effect of sleep positioning systems on hip migration will be considered within this objective.Secondary objectives were to determine the effect of sleep positioning systems on: (1) number or frequency of hip problems; (2) sleep patterns and quality; (3) quality of life of the child and family; (4) pain; and (5) physical functioning. We also sought to identify any adverse effects from using sleep positioning systems. SEARCH METHODS: In December 2014, we searched CENTRAL, Ovid MEDLINE, Embase, and 13 other databases. We also searched two trials registers. We applied no restrictions on date of publication, language, publication status or study design. We checked references and contacted manufacturers and authors for potentially relevant literature, and searched the internet using Google. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) evaluating whole body sleep positioning systems for children and adolescents (up to 18 years of age) with cerebral palsy. DATA COLLECTION AND ANALYSIS: Two review authors independently screened reports retrieved from the search against pre-determined inclusion criteria and assessed the quality of eligible studies.Members of the public (parent carers of children with neurodisability) contributed to this review by suggesting the topic, refining the research objectives, interpreting the findings, and reviewing the plain language summary. MAIN RESULTS: We did not identify any randomised controlled trials that evaluated the effectiveness of sleep positioning systems on hip migration.We did find two randomised cross-over trials that met the inclusion criteria in respect of secondary objectives relating to sleep quality and pain. Neither study reported any important difference between sleeping in sleep positioning systems and not for sleep patterns or sleep quality (two studies, 21 children, very low quality evidence) and pain (one study, 11 children, very low quality evidence). These were small studies with established users of sleep positioning systems and were judged to have high risk of bias.We found no eligible trials that explored the other secondary objectives (number or frequency of hip problems, quality of life of the child and family, physical functioning, and adverse effects). AUTHORS' CONCLUSIONS: We found no randomised trials that evaluated the effectiveness of sleep positioning systems to reduce or prevent hip migration in children with cerebral palsy. Nor did we find any randomised trials that evaluated the effect of sleep positioning systems on the number or frequency of hip problems, quality of life of the child and family or on physical functioning.Limited data from two randomised trials, which evaluated the effectiveness of sleep positioning systems on sleep quality and pain for children with cerebral palsy, showed no significant differences in these aspects of health when children were using and not using a sleep positioning system.In order to inform clinical decision-making and the prescription of sleep positioning systems, more rigorous research is needed to determine effectiveness, cost-effectiveness, and the likelihood of adverse effects. PMID- 26524347 TI - Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2 tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311). AB - Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies. PMID- 26524350 TI - Adequacy in voided urine cytology specimens: The role of volume and a repeat void upon predictive values for high-grade urothelial carcinoma. AB - BACKGROUND: Adequacy assessment is one of the most controversial and overlooked components in the daily practice of cytopathology, because it is generally determined from limited samples. Because voided urine varies widely in terms of its volume and cellularity, there is little consensus about the proper role for these variables in assessing specimen adequacy. In this study, the authors explored the role of volume in voided urine specimens to determine whether it plays a role in determining adequacy for the detection of high-grade urothelial carcinoma. METHODS: Voided urine specimens received at the authors' laboratory over the 9.5 years since the introduction of the Johns Hopkins Template for Reporting Urinary Cytopathology were analyzed for correlations between volume, specimen adequacy, and the diagnosis of high-grade malignancy. The same data set also was queried to determine whether a patient who provided a voided low-volume specimen could yield a higher volume specimen and thereby increase adequacy. RESULTS: In total, 15,731 voided urine specimens with a cumulative volume of 891 liters originating from 8594 individual patients were analyzed. Specimen adequacy increased linearly for each increment of volume submitted to the laboratory up to 30 mL, after which the correlation was nonlinear. Low-volume specimens below this cutoff also had lower fractions of specimens that were diagnosed as malignant or suspicious. CONCLUSIONS: Volume is an important component in the evaluation of adequacy for voided urine cytology specimens. PMID- 26524349 TI - Nitrogen-Doped Graphene Quantum Dots@SiO2 Nanoparticles as Electrochemiluminescence and Fluorescence Signal Indicators for Magnetically Controlled Aptasensor with Dual Detection Channels. AB - We proposed a facile method to prepare the nitrogen-doped graphene quantum dots (NGQDs) doped silica (NGQDs@SiO2) nanoparticles (NPs). The NGQDs@SiO2 NPs were further explored as a versatile signal indicator for ochratoxin A (OTA) aptasensing by combination with electrochemiluminescence (ECL) and fluorescence (FL) detection. In this strategy, the core-shell Fe3O4@Au magnetic beads (MBs) acted as a nanocarrier to immobilize the thiolated aptamer specific for OTA, and the amino modified capture DNA (cDNA) was efficiently tagged with NGQDs@SiO2 NPs. The multifunctional aptasensor was thus fabricated by assembly of the NGQDs@SiO2 NPs onto the surface of Fe3O4@Au MBs through the high specific DNA hybridization between aptamer and cDNA. Upon OTA incubation, the aptamer linked with Fe3O4@Au MBs preferred to form an aptamer-OTA complex, which resulted in the partial release of the preloaded NGQDs@SiO2 NPs. The more OTA molecules in the detection system, the more NGQDs@SiO2 NPs were released into the bulk solution and the less preloaded NGQDs@SiO2 NPs were accumulated on the magnetic electrode surface. This provided a dual channel for OTA detection by combination with the enriched solid state ECL and homogeneous FL detection. The FL assay exhibits a wide dynamic range and is more reproducible due to the homogeneous detection while the ECL assay possesses a lower detection limit and is preferable by using a cheaper instrument. One can obtain a preliminary screen from FL assay and a more accurate result from ECL assay. Integrating the virtues of dual analytical modality, this aptasensing strategy well-balanced the rapidity, sensitivity, and dynamic range, making it promising to other targets with aptamer sequences. PMID- 26524352 TI - Emotional Sentence Annotation Helps Predict Fiction Genre. AB - Fiction, a prime form of entertainment, has evolved into multiple genres which one can broadly attribute to different forms of stories. In this paper, we examine the hypothesis that works of fiction can be characterised by the emotions they portray. To investigate this hypothesis, we use the work of fictions in the Project Gutenberg and we attribute basic emotional content to each individual sentence using Ekman's model. A time-smoothed version of the emotional content for each basic emotion is used to train extremely randomized trees. We show through 10-fold Cross-Validation that the emotional content of each work of fiction can help identify each genre with significantly higher probability than random. We also show that the most important differentiator between genre novels is fear. PMID- 26524351 TI - Hyperinsulinemia in individuals with obesity: Role of insulin clearance. AB - OBJECTIVE: Several studies have shown decreased insulin clearance rate (ICR) in individuals with obesity, but it remains unclear whether this is predominately due to obesity-associated insulin resistance (IR) or obesity itself. This study aimed to clarify the complex interrelationship that exists between obesity, IR, and ICR. METHODS: Healthy volunteers (n = 277) had measurement of IR and ICR using the insulin suppression test (IST). IR was quantified by determining the steady-state plasma glucose (SSPG) during the IST. ICR was estimated by dividing the insulin infusion rate by the steady-state plasma insulin concentration. We performed our analysis by stratifying the experimental population into four dichotomous categories, varying in obesity and IR. Obesity was defined as a body mass index (BMI) >= 30 kg/m(2) , and IR was defined as SSPG >= 150 mg/dL. RESULTS: Individuals with obesity had higher fasting insulin compared with individuals without obesity, regardless of IR. ICR was similar between individuals with and without obesity but was higher in insulin resistant individuals compared with insulin-sensitive individuals. In multivariate analysis, both fasting insulin and SSPG were significantly associated with ICR. No significant relationships were observed between BMI and ICR. CONCLUSIONS: Reduced ICR in obesity is secondary to IR, not excess adiposity. PMID- 26524353 TI - Patterned Polypeptoid Brushes. AB - Patterned polypeptoid brushes on gold and oxide substrates are synthesized by surface-initiated polymerization of N-substituted glycine N-carboxyanhydrides. Their biofouling resistance is shown by protein and cell adhesion experiments. The accessibility of the system to common patterning protocols is demonstrated by UV-lithography and a MUCP approach. Moreover, the terminal secondary amine group of the polypeptoid brushes is functionalized with different fluorescent dyes to demonstrate their chemical accessibility. PMID- 26524354 TI - [Role of pegylated-interferon in the treatment of hepatitis C in Chinese patients]. PMID- 26524355 TI - [Now is the time to cure hepatitis C]. PMID- 26524356 TI - [Antiviral treatment and long-term clinical outcome of decompensated cirrhotic patients with hepatitis C virus infection]. AB - OBJECTIVE: To investigate the efficacy and safety of antiviral treatment in patients with hepatitis C virus (HCV) infection and decompensated cirrhosis and determine the effects of virological response on long-term prognosis. METHODS: Sixty-six consecutive,interferon (IFN)-na(i)ve patients with HCV infection and decompensated cirrhosis were enrolled in this prospective study. All patients were given a 48-to 72-week course of IFN plus ribavirin (RBV) combined therapy,with a low accelerating dosage regimen using either:pegylated (PEG)-IFNa 2b at 1.0-1.5 mug/kg/week,PEG-IFNa-2a at 90-180 mug,or standard IFN-a-2b at 3MU,every other day.RBV was given at 800 to 1000 mg/day. All patients were routinely monitored for adverse drug reactions and virological response.Effects of treatments on patient survival were assessed by Kaplan-Meier analysis. RESULTS: At the end of treatment,74.2% of patients were HCV RNA-negative,with 45.5% having achieved sustained virological response and 28.8% having relapsed;the remaining 25.7% of patients showed non-virological response (NVR). Among the patients with HCV genotype 1, 65.9% achieved end-of-treatment virological response (ETVR) and 34.1% achieved SVR;among the patients with HCV genotype 2,90.9% achieved ETVR and 68.2% achieved SVR. The positive and negative predictive values of early virological response (EVR) for ETVR were 95.7% and 75.0% respectively, and for SVR were 65.2% and 100% respectively. Compared with baseline,patients who achieved ETVR had better liver function,as evidenced by changes in levels of total bilirubin,alanine aminotransferase and albumin,as well as prothrombin activity and Child-Pugh score (t =4.564,11.486,2.303,2.699,3.694 respectively, all P less than 0.05).Compared with the NVR patients, the ETVR patients had lower risk of hepatic decompensation and hepatocellular carcinoma, and had improved survival (x2=18.756,6.992,7.580, respectively, all P less than 0.05).Twelve (18.2%) patients experienced serious adverse events,with 10 requiring premature treatment withdrawal and 2 dying. CONCLUSION: Antiviral treatment for patients with HCV infection and decompensated cirrhosis using interferon in a low accelerating dosage regimen in combination with ribavirin is feasible.Patients who achieved ETVR had significantly improved long-term prognosis. PMID- 26524357 TI - [Naturally occurring NS5B variants resistant to non-nucleoside or nucleoside polymerase inhibitors among treatment-naive hepatitis C patients in south China]. AB - OBJECTIVE: To determine the prevalence of mutations in the non-structural protein 5B (NS5B) of the hepatitis C virus (HCV),which are associated with natural resistance to non-nucleoside and nucleoside polymerase inhibitors (PIs),in treatment-naive hepatitis C patients in south China. METHODS: A nested PCR protocol that amplified three different regions of NS5B was used to detect the naturally occurring drag-resistant substitutions.Direct PCR sequencing was performed to analyze the sequences. RESULTS: NS5B mutations known to confer resistance to nucleoside PIs,such as A15G,S96T and S282T,were mainly detected in HCV genotype 6a (20/88,22.73%).Of the NS5B mutations known to confer resistance to non-nucleoside PIs,C316N and S365A were detected in HCV genotype lb (60/60,100% and 2/60,3.33%, respectively) and I482L and V499A were mainly detected in HCV genotype 2a (9/9,100% and 4/4,100%, respectively) and HCV genotype 6a (9/9,100% and 4/4,100%, respectively).Other NS5B mutations found in the study population included A1 5S,S365F,S365P,S368A and S368L;although none of these has been previously shown to confer resistance to PIs. CONCLUSION: Naturally occurring dominant PI resistance mutations in NS5B exist in treatment na(i)ve hepatitis C patients in south China and may be related to the virus genotype. PMID- 26524358 TI - [Heparin-treated dendritic cells promote Th0 to Th1 differentiation via the Toll like receptor 3 in peripheral blood monocytes of patients with chronic hepatitis B]. AB - OBJECTIVE: To investigate the mechanisms underlying the ability ofheparin-treated dendritic cells (DCs) to promote Th0 to Th1 differentiation in chronic hepatitis B (CHB). METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from CHB patients and cultured in RPMI-1640 with recombinant GM-CSF and IL-4 with or without heparin to obtain DCs for study. The levels of Toll-like receptors (TLRs) on the DCs were measured using FACS and qPCR techniques.DC subsets with high expression of TLRs were selected for analysis of functional changes by treatment with the corresponding TLR-siRNA. The CD4+ T cell subpopulation was purified from peripheral blood by Dynal immunomagnetic beads, and then the production of IL-12 by DCs in the presence of poly(I:C) or R848 and ofIFN and IL-4 by Th cells co cultured with DCs was evaluated by ELISA. The t-test was used for statistical analysis. RESULTS: TLR3 expression, and not expression of TLR 7 or TLR8,was significantly increased in heparin-treated DCs as compared to levels detected in the DCs without heparin treatment (t =2.849,P less than 0.05;t =3.027,P less than 0.05). The level of IL-12 produced by heparin-treated DCs stimulated with poly(I:C) was obviously higher than that produced by DCs without heparin treatment and stimulated with poly(I: C) (t =8.68,P less than 0.01) or with R848 (t =19.01,P less than 0.01). However, the IL-12 production by TLR3-siRNA transfected-DCs was significantly reduced (t =31.49, P less than 0.01).When Th cells from allogenic patients with CHB were co-cultured with the TLR3-siRNA transfectedDCs, the frequency ofCD4+ IFN+ cells was significantly reduced (1.64+/ 0.57% vs.6.31+/-0.88%,P less than 0.01),as was the capability of Thl to generate IFNg (t =20.83,Pless than 0.01). CONCLUSION: Heparin may have up-regulated the TLR3 expression level of DCs, and sequentially promoted Th0 to Th1 differentiation. PMID- 26524359 TI - [Trends and forecast of hepatocellular carcinoma in Nantong, China: mortality rates from 1999 to 2011]. AB - OBJECTIVE: To investigate the mortality rates of hepatocellular carcinoma (HCC) in Nantong,China from 1999 to 2011, in order to uncover dynamic trends and provide reasoned advice on intervention strategies to decrease HCC incidence and mortality in Nantong in the future. METHODS: Versions 10 and 9 of the WHO International Classification of Diseases (ICD-10 and ICD-9) were used to determine the number of HCC deaths in Nantong,China for the study's range of years. Thex2 test was applied to compare the HCC mortality rates according to sex and age. The Grey system GM(1,1) model was used to predict the next-5-year HCC mortality for Nantong. RESULTS: Analysis of the standardized mortality in Nantong showed a slight decreasing trend from 1999 to 2011 (x2=57 545.98, P less than 0.001),with males showing a steeper decrease than females. The total mortality of HCC during these years was 53.41 per 100,000 people,with mortality among males being significantly higher than that among females (80.81 per 100,000 people vs. 26.94 per 100,000 people; x2=13 625.42, P less than 0.001). In general, HCC mortality increased with increase in age (general trend:x2=57 545.98, P less than 0.001; male trend: x2=39 878.8, P less than 0.001; female trend: x2=20 105.3, P less than 0.001). However,HCC mortality increased significantly in women after the age of 40 and in men after the age of 35. The GM(1,1) equation was: Yt= 1265.28e(-0.0375t)+1315.5, which predicted that the HCC mortality will decrease to 25.56 per 100,000 people in 2016. CONCLUSION: Although HCC mortality generally decreased from 1999 to 2011, the rate remained high. Public health intervention strategies may be more effective if they focus on males over the age of 35 and females over the age of 40. PMID- 26524360 TI - [Matrine enhances the anticancer effect of cisplatin against hepatocellular carcinoma xenografts in nude mice by influencing expression of survivin/caspase 3]. AB - OBJECTIVE: To investigate the effect and molecular mechanism of cisplatin (DDP) combined with Matrine (Ma;plant alkaloid) against hepatocellular carcinoma using a nude mouse model with xenografted human tumors. METHODS: Twenty-four 6-week old male BALB/c nude mice were subcutaneously injected with HepG2 cells into the axilla, and randomly divided into four groups:control (NS) group,Ma treatment group,DDP treatment group and DDP+Ma combination treatment group. All treatments were delivered via intraperitoneal injection.Changes in whole body weights and tumor volume were assessed by before and after treatment measurements and plotting of growth curves. After 14 days of drug intervention, the mice were sacrificed for collection of tumor tissue and assessment of the tumor inhibition rates for each treatment. Affects on expression of survivin and caspase-3 were assessed by immunohistochemistry. ANOVA test and t-test were performed for the statistical analyses. RESULTS: The tumor inhibition rates for the various treatments were:37.5%,Ma alone;75.0% DDP alone;83.3%,DDP+Ma group DDP combined. The DDP+Ma-induced inhibition was significantly greater than that achieved wit Ma or DDP alone (both P less than 0.05). The average weight of the DDP+Ma group (21.5 g) was lower than that of the NS group (28.5 g) and the Ma group (26.67 g),but higher than that of the DDP group (17.33 g).In addition, the DDP+Ma group also showed more robust general health,as indicated by activity,participation in life routines and appetite,than the DDP group. The rate of positive staining for survivin expression in tumor tissues was significantly lower in the DDP+Ma group (19.58%+/-4.52%) than in the NS group (83.26%+/-15.56%), the Ma group (62.50%+/ 8.09%), and the DDP group (38.67%+/-8.26%) (all P less than 0.05).In contrast, the rate of positive staining for Bax expression was significantly higher in the DDP+Ma group (78.26%+/-6.09%) than in the NS group (21.15%+/-3.68%), the Ma group (35.13%+/-10.57%), and the DDP group (65.88%+/-4.81%) (all P less than 0.05). CONCLUSION: Treatment with Ma alone or DDP alone is sufficient to inhibit the growth ofxenografted human hepatocellular carcinoma cells in nude mice. The DDP+Ma combination treatment,however,shows greater inhibitory effect,suggesting that Ma may enhance DDP's anticancer properties. The improved health status of mice treated with DDP+Ma suggests that Ma may reduce DDP toxicity. The mechanism underlying these beneficial treatment effects may involve modulation of survivin/caspase-3 expression and subsequent apoptosis. PMID- 26524361 TI - [Relationship between non-alcoholic fatty liver disease and incidence of type 2 diabetes mellitus in Chinese adults: a prospective cohort study]. AB - OBJECTIVE: To explore the relationship between nonalcoholic fatty liver disease (NAFLD) and the incidence of type 2 diabetes mellitus (T2DM) in Chinese adults. METHODS: A total of 4847 Chinese adults were enrolled in this prospective study. All participants underwent physical examination at one of three hospitals in Nanjing during 2008. According to results from B ultrasound, the participants were grouped according to NAFLD diagnosis, with 1468 in the NAFLD group and 3379 in the control group.Participants were followed up until diagnosis of T2DM or for 4 years. The cumulative incidence rates of T2DM were calculated for and compared between the NAFLD group and the control group. The relationship between NAFLD and risk of T2DM was examined by Cox proportional hazards modeling. RESULTS: During the 4-year follow-up,387 (8.0%) of the patients were diagnosed with T2DM. The cumulative incidence rates of T2DM in the NAFLD group and the control group were 17.2% and 4.0%, respectively. After adjusting for age,sex,body mass index,blood pressure,triglyceride level and alanine aminotransferase level, NAFLD was found to be closely related to the incidence of T2DM (relative risk:3.465,95% confidence interval:2.755-4.358). CONCLUSION: NAFLD is associated with elevated risk of T2DM in adult patients in Nanjing,China. The general population of this region may benefit from focused public health intervention and treatment strategies targeting to prevent development of T2DM in conjunction with NAFLD. PMID- 26524362 TI - [Clinical characteristics of 4132 patients with alcoholic liver disease]. AB - OBJECTIVE: To study the clinical characteristics of patients with alcoholic liver disease (ALD). METHODS: The records of the 302 Hospital of People's Liberation Army (Beijing, China) were searched to identify patients diagnosed with liver disease for retrospective analysis of ALD. Measurement data was summarized as mean +/- standard deviation and intergroup comparisons were made using ANOVA; count data was assessed using the chi-square test. RESULTS: Among the total 4132 ALD cases, 97.68% were male and 2.32% were female; ages ranged from 18 to 95 years-old,with the average age being 48.11+/-10.58 years and the range of 40 to 60 years-old being the most frequently represented.Considering all patients with liver disease from 2003 to 2012,ALD cases increased over time (from 2.00% in 2003 to 5.05% in 2012). The overall ALD cases were represented by alcoholic cirrhosis (70.35%), alcoholic hepatitis (19.26%), alcoholic fatty liver (6.29%), and alcoholic liver failure (4.09%). Among the ALD patients between 40 and 60 years of age, 73.81% had cirrhosis,compared to 50.42% of ALD patients less than 40 years-old (P less than 0.001). Comparison of ALD cases in 5-year increments showed increasing trends in rates of alcoholic cirrhosis and alcoholic hepatic failure;moreover, there was an increasing annual trend in the percentage of alcoholic liver failure cases among the total cases of liver failure in our hospital. CONCLUSION: From 2003 to 2012,our hospital admissions increased for patients with alcoholic liver disease, and the patients were primarily in the age range of 40-60 years-old. In general, incidences of alcoholic liver failure and cirrhosis increased in recent years, and cirrhosis has been common among the elderly patients with ALD. PMID- 26524363 TI - [Comparison of different criteria to evaluate acute kidney injury and determine short-term prognosis of patients with acute-on-chronic liver failure]. AB - OBJECTIVE: To compare the acute kidney injury classification systems of RIFLE,AKIN,KDIGO and conventional criteria for determining prognosis of acute-on chronic liver failure (ACLF) patients. METHODS: Patients with ACLF admitted to our hospital between July 2008 and March 2014 were enrolled in the study. The incidence, stages, and outcomes of acute kidney injury were determined according to the RIFLE, AKIN,KDIGO and conventional criteria.ROC curves were generated to compare the predictive ability for 30-day mortality of the four systems.Chi square test and Fisher's exact test were used for statistical analyses, as well. RESULTS: All four classification systems detected acute kidney injury among the patients in the study population (n =358), but the detection rates were not consistent (expressed as % of total): KDIGO criteria: 45.0%, AKIN: 38.8%, rIFLE: 35.5%, conventional criterion: 20.4%. The KDIGO and AKIN criteria showed higher sensitivity (72%), especially to early kidney injury, but the conventional criterion showed higher specificity (92%). The AUC for 30-day mortality was highest for the conventional criteria (0.75), followed by AKIN (0.72), rIFLE (0.70) and KDIGO (0.69) (all, P less than 0.05). In-hospital mortality increased with severity of AKI in a stepwise manner. CONCLUSION: Among the four common evaluation systems for acute kidney injury, the conventional criteria has the highest specificity for predicting short-term prognosis of patients with ACLF, while the AKIN and KDIGO criteria have the highest sensitivity for the presence of acute kidney injury, especially at the early stage. PMID- 26524364 TI - [Effects of fenofibrate on hepatocyte apoptosis in nonalcoholic fatty liver]. AB - OBJECTIVE: To use a rat model of nonalcoholic liver disease (NAFLD) to observe effects of the peroxisome proliferator-activated receptor-a (PPAR-a) agonist fenofibrate on hepatic steatosis in nonalcoholic fatty liver and to investigate the underlying mechanism. METHODS: Sixty-six Sprague-Dawley rats were given adaptive feeding for 1 week and then randomly allocated into the following three groups: unmodeled control (group C,n =18), untreated NAFLD model (group M, n =24), and fenofibrate-treated NAFLD model (group F, n =24).Group C rats were given a normal diet, while group M and group F rats were given a high-fat diet. After model establishment, the group F rats were treated with fenofibrate (10 mg/kg/d, intraperitoneal) and the group C and group M rats were given sham treatment with cosolvent (5 mL/kg/d, intraperitoneal). At the end of treatment weeks 4, 6 and 8, one-third of rats in each group were euthanized.Liver tissues were assessed by hematoxylin-eosin (HE) staining to determine level of steatosis and inflammaion activity, and by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling to measure changes in hepatocyte apoptosis index. Changes in expression levels of the PPAR-a receptor and apoptosis factors (bcl-2, bax and caspase-3) were assessed by reverse transcription-PCR and immunohistochemistry. RESULTS: The NAFLD modeled rats showed appropriate induction of hepatic steatosis, hepatic inflammation, and hepatocyte apoptosis. Compared to the group M rats, the group F rats showed lower expression of PPAR-and bcl-2 and higher expression of bax and caspase-3 at both the mRNA and protein level. CONCLUSION: Fenofibrate can ameliorate hepatic steatosis in an experimental rat model of NAFLD, and the mechanism may be associated with inhibition of hepatocyte apoptosis. PMID- 26524365 TI - [Association of liver enzyme and long-term weight growth in adults]. PMID- 26524366 TI - [Clinical feature analysis of 334 chronic hepatitis B patients coinfected with hepatitis E virus]. PMID- 26524367 TI - [Preliminary research of velocity vector imaging in the evaluation of portal vein inner membrane condition in chronic liver diseases]. PMID- 26524368 TI - [The causes of death and clinical characteristic of patients with HBV-ACLF]. PMID- 26524369 TI - [Efficacy of nucleos(t)ide analogues and analysis of the short-term prognosis in patients with HBV-related acute-on-chronic liver failure]. PMID- 26524370 TI - [Pathogenic role of the adiponectin-SIRT 1-AMPK signaling pathway in alcoholic fatty liver disease]. PMID- 26524371 TI - [Ursodeoxycholic acid-induced hepatic disease: a case report]. PMID- 26524372 TI - [Report of the Eighth National Severe Liver Disease Conference]. PMID- 26524373 TI - [Advancement in chronic drug-induced liver injury]. PMID- 26524374 TI - The uncritical use of anecdotes in marine historical ecology: response to McClenachan et al. PMID- 26524375 TI - Reply. PMID- 26524376 TI - Quantitative benefit-risk assessment by MCDA of the quadrivalent HPV vaccine for preventing anal cancer in males. AB - OBJECTIVES: To quantify the benefit-risk (BR) balance of the quadrivalent human papillomavirus (qHPV) vaccine for use in males, including anal cancer prevention, by using the multicriteria decision analysis (MCDA). METHODS: Value tree and an effect table were compiled using relevant qHPV vaccine efficacy/safety data. An expert panel validated the final model inputs. RESULTS: On a scale of 0-100, the MCDA qHPV vaccine score (66) was superior to the no vaccination score (46), indicating a more favorable BR balance for the qHPV vaccine. Significant changes in weight of individual outcomes were needed to change BR balance in sensitivity analyses. The qHPV vaccine maintained a better BR profile in all alternative models. CONCLUSIONS: MCDA can be used to transparently evaluate BR balance of vaccines. The qHPV vaccine had a favorable BR balance in males. Including anal cancer as a new indication further improves the BR profile of the qHPV vaccine. PMID- 26524377 TI - Viral O-GalNAc peptide epitopes: a novel potential target in viral envelope glycoproteins. AB - Viral envelope glycoproteins are major targets for antibodies that bind to and inactivate viral particles. The capacity of a viral vaccine to induce virus neutralizing antibodies is often used as a marker for vaccine efficacy. Yet the number of known neutralization target epitopes is restricted owing to various viral escape mechanisms. We expand the range of possible viral glycoprotein targets, by presenting a previously unknown type of viral glycoprotein epitope based on a short peptide stretch modified with small O-linked glycans. Besides being immunologically active, these epitopes have a high potential for antigenic variation. Thus, sera from patients infected with EBV develop individual IgG responses addressing the different possible glycopeptide glycoforms of one short peptide backbone that reflect individual variations in the course of virus infection. In contrast, in HSV type 2 meningitis patients, CSF antibodies are focussed to only one single glycoform peptide of a major viral glycoprotein. Thus, dependent on the viral disease, the serological response may be variable or constant with respect to the number of targeted peptide glycoforms. Mapping of these epitopes relies on a novel three-step procedure that identifies any reactive viral O-glycosyl peptide epitope with respect to (i) relevant peptide sequence, (ii) the reactive glycoform out of several possible glycopeptide isomers of that peptide sequence, and (iii) possibly tolerated carbohydrate or peptide structural variations at glycosylation sites. In conclusion, the viral O glycosyl peptide epitopes may be of relevance for development of subunit vaccines and for improved serodiagnosis of viral diseases. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26524378 TI - Melanocytes are more responsive to IFN-gamma and produce higher amounts of kynurenine than melanoma cells. AB - A key link between amino acid catabolism and immune regulation in cancer is the augmented tryptophan (Trp) catabolism through the kynurenine pathway (KP), a metabolic route induced by interferon-gamma (IFN-gamma) and related to poor prognosis in melanomas. Besides its role in cancer, IFN-gamma plays a key role in the control of pigmentation homeostasis. Here we measured KP metabolites in human melanoma lines and skin melanocytes and fibroblasts in response to IFN-gamma. In general, IFN-gamma affected KP in skin cells more than in melanoma cells, supporting IFN-gamma roles in skin physiology and that of stromal cells in modulating the tumor microenvironment. PMID- 26524380 TI - Trajectories of mental health over 16 years amongst young adult women: The Australian Longitudinal Study on Women's Health. AB - This article used data from 5,171 young women participating in the Australian Longitudinal Study on Women's Health, a nationally representative longitudinal cohort study, to identify longitudinal trajectory patterns of mental health across 6 surveys over 16 years of early adulthood, from age 18-23 to age 34-39. In addition, we identified both predictors and outcomes of these trajectories. Using group-based trajectory modeling, we identified 4 distinct trajectory groups of mental health. The mental health of most participants (55%) was consistently high, with 12% improving, 24% varying, and 9% frequently low. The authors considered characteristics at the beginning and end of the trajectory period, taking a life-course perspective to understand vulnerabilities to, and outcomes of, low or variable poor mental health trajectories. Financial difficulties, poor general health, and weight or shape dissatisfaction were characteristics at Survey 1 that distinguished all other trajectory groups from those with consistently high mental health. Other differences were specific to 1 or 2 groups. By the end of the trajectory period, the improving mental health group showed few differences from those with consistently high mental health. However, those with varying and low mental health showed evidence of social disadvantage, poor physical and emotional health, and unhealthy behaviors, and were less likely to be mothers. The ability to identify distinct trajectories of mental health in early adulthood, and their correlates, provides evidence to underpin population health interventions targeting the prevention of mental health problems among this population group. (PsycINFO Database Record PMID- 26524379 TI - First-in-Class Inhibitors of Sulfur Metabolism with Bactericidal Activity against Non-Replicating M. tuberculosis. AB - Development of effective therapies to eradicate persistent, slowly replicating M. tuberculosis (Mtb) represents a significant challenge to controlling the global TB epidemic. To develop such therapies, it is imperative to translate information from metabolome and proteome adaptations of persistent Mtb into the drug discovery screening platforms. To this end, reductive sulfur metabolism is genetically and pharmacologically implicated in survival, pathogenesis, and redox homeostasis of persistent Mtb. Therefore, inhibitors of this pathway are expected to serve as powerful tools in its preclinical and clinical validation as a therapeutic target for eradicating persisters. Here, we establish a first functional HTS platform for identification of APS reductase (APSR) inhibitors, a critical enzyme in the assimilation of sulfate for the biosynthesis of cysteine and other essential sulfur-containing molecules. Our HTS campaign involving 38 350 compounds led to the discovery of three distinct structural classes of APSR inhibitors. A class of bioactive compounds with known pharmacology displayed potent bactericidal activity in wild-type Mtb as well as MDR and XDR clinical isolates. Top compounds showed markedly diminished potency in a conditional DeltaAPSR mutant, which could be restored by complementation with Mtb APSR. Furthermore, ITC studies on representative compounds provided evidence for direct engagement of the APSR target. Finally, potent APSR inhibitors significantly decreased the cellular levels of key reduced sulfur-containing metabolites and also induced an oxidative shift in mycothiol redox potential of live Mtb, thus providing functional validation of our screening data. In summary, we have identified first-in-class inhibitors of APSR that can serve as molecular probes in unraveling the links between Mtb persistence, antibiotic tolerance, and sulfate assimilation, in addition to their potential therapeutic value. PMID- 26524381 TI - Development of audience design in children with and without ASD. AB - We examined 2 hypotheses concerning the development of audience design by contrasting children with and without autistic spectrum disorder (ASD) in referential communication. The 2-stage hypothesis predicts that the ability to use contrastive size adjectives for ambiguity avoidance develops separately from and faster than the ability to avoid perspective-inappropriate descriptions for their addressee. The single-stage hypothesis assumes that both abilities reflect speakers' perspective-taking, and they should develop in tandem with each other. Experiment 1 found that 6- to 10-year-olds with and without ASD produced disambiguating size adjectives ("small door") equally often when the size contrasting competitor (large door) was in the visual context shared with their addressee. When the competitor was hidden from their addressee, that is, it was part of children's privileged context, children with ASD produced more perspective-inappropriate size adjectives than those without ASD, providing support for the 2-stage model. Experiment 2 showed a similar pattern of results with 11- to 16-year-old adolescents. Compared with adults, 6- to 10-year-olds without ASD produced more perspective-inappropriate size adjectives in the privileged context, while producing fewer disambiguating size adjectives in the shared context, demonstrating more "egocentric" behaviors than adults. Importantly, whereas 11- to 16-year-olds without ASD produced disambiguating adjectives nearly as often as adults in the shared context, they produced perspective-inappropriate adjectives more than adults in the privileged context. This indicated that even in non-ASD, the ability to avoid perspective inappropriate descriptions develops more slowly than the ability to avoid ambiguous descriptions, delaying the onset of adult-like audience design, consistent with the 2-stage hypothesis. (PsycINFO Database Record PMID- 26524383 TI - Peer social skills and theory of mind in children with autism, deafness, or typical development. AB - Consequences of theory of mind (ToM) development for daily social lives of children are uncertain. Five to 13-year-olds (N = 195) with typical development, autism, or deafness (both native and late signers) took ToM tests and their teachers reported on their social skills for peer interaction (e.g., leadership, group entry). Groups differed in both ToM understanding (with late-signing deaf children especially delayed even relative to autistic children) and peer social skills (with autistic children especially delayed even relative to deaf late signers). Crucially, for the typically developing hearing children and deaf children alike, ToM understanding independently predicted peer social skills over and above age, gender, language ability, and, for deaf children, status as native or late-signer. These novel findings offer some of the best evidence to date of the relevance of ToM cognitions to real-world social behavior for both these groups. However, for those with autism spectrum disorders (ASD) the pattern was different. The apparent link of ToM to peer competence was not a direct one but instead was significantly mediated by language ability. Several possible explanations for this intriguing autism-specific result were also discussed. (PsycINFO Database Record PMID- 26524382 TI - Children's expressions of positive emotion are sustained by smiling, touching, and playing with parents and siblings: A naturalistic observational study of family life. AB - Research on family socialization of positive emotion has primarily focused on the infant and toddler stages of development, and relied on observations of parent child interactions in highly structured laboratory environments. Little is known about how children's spontaneous expressions of positive emotion are maintained in the uncontrolled settings of daily life, particularly within the family and during the school-age years. This naturalistic observational study examines 3 family behaviors-mutual display of positive emotion, touch, and joint leisure that surround 8- to 12-year-old children's spontaneous expressions of positive emotion, and tests whether these behaviors help to sustain children's expressions. Recordings taken of 31 families in their homes and communities over 2 days were screened for moments when children spontaneously expressed positive emotion in the presence of at least 1 parent. Children were more likely to sustain their expressions of positive emotion when mothers, fathers, or siblings showed positive emotion, touched, or participated in a leisure activity. There were few differences in the ways that mothers and fathers socialized their sons' and daughters' positive emotion expressions. This study takes a unique, ecologically valid approach to assess how family members connect to children's expressions of positive emotion in middle childhood. Future observational studies should continue to explore mechanisms of family socialization of positive emotion, in laboratory and naturalistic settings. (PsycINFO Database Record PMID- 26524384 TI - A high-throughput, in-vitro assay for Bacillus thuringiensis insecticidal proteins. AB - A high-throughput, in-vitro assay for Bacillus thuringiensis (Bt) insecticidal proteins designated as Cry was developed and evaluated for screening a large number of Cry protein variants produced by DNA shuffling. This automation amenable assay exploits an insect cell line expressing a single receptor of Bt Cry proteins. The Cry toxin used to develop this assay is a variant of the Cry1Ab protein called IP1-88, which was produced previously by DNA shuffling. Cell mortality caused by the activated Bt Cry toxin was determined by chemical cell viability assay in 96/384-well microtiter plates utilizing CellTiter 96((r)) obtained from Promega. A widely-accepted mode-of-action theory of certain Bt Cry proteins suggests that the activated toxin binds to one or more receptors and forms a pore through the insect gut epithelial cell apical membrane. A number of insect proteins such as cadherin-like protein (Cad), aminopeptidase-N (APN), alkaline phosphatase (ALP) and ABC transporter (ABCC) have been identified as the receptors of Bt Cry toxins. In this study, Bt Cry toxin receptors Ostrinia nubilalis (European corn borer) cadherin-like protein (On-Cad) and aminopeptidase N 1 and 3 (On-APN1, On-APN3) and Spodoptera frugiperda (fall armyworm) cadherin like protein (Sf-Cad) were cloned in an insect cell line, Sf21, and a mammalian cell line, Expi293F. It was observed by ligand blotting and immunofluorescence microscopy that trypsin-activated IP1-88 bound to On-Cad and On-APN1, but not Sf Cad or On-APN3. In contrast, IP1-88 bound only to APN1 in BBMV (Brush Border Membrane Vesicles) prepared from the third and fourth-instar O. nubilalis larval midgut. The sensitivity of the recombinant cells to the toxin was then tested. IP1-88 showed no toxicity to non-recombinant Sf21 and Expi293F. Toxicity was observed only when the On-Cad gene was cloned and expressed. Sf-Cad and On-APN1 were not able to make those cells sensitive to the toxin. Since the expression of On-Cad alone was sufficient to make both insect and mammalian cells sensitive to the IP1-88 toxin, it is not likely that a secondary receptor, which may exist specifically in the Sf21 insect cell but not in the Expi293F cell, is involved in the cytotoxicity of IP1-88. PMID- 26524385 TI - Pulmonary Cement Embolism After Kyphoplasty. AB - Pulmonary polymethylmethacrylate (PMMA) cement embolism after kyphoplasty (KP) surgery is a quite frequent event as well as the pulmonary embolization of central venous catheter fragment. This report shows the case of a subject who, after KP, developed pulmonary embolism and who underwent thoracic surgery. After hospital discharge, the subject advanced a claim for damages toward the hospital where he was operated, complaining sensation of tenderness at the chest surgical scar and esthetic damage. To understand the nature of the embolism (either central venous catheter fragment or cement), chemical investigations were then ordered. Spectrometry identified the PMMA cement used for KP. When doubts rise about the origin of the embolized material, chemical investigations may reveal important data not only for clinical but also for forensic purposes. PMID- 26524386 TI - Electrocardiographic Manifestations of Calcium Abnormalities. PMID- 26524387 TI - Characteristics of laparoscopic microwave ablation with renal tissue: Experimental in vivo study using a porcine model. AB - PURPOSE: A model of in vivo porcine kidneys is used to clarify the characteristics of laparoscopic microwave ablation (MWA) of renal tissue. MATERIALS AND METHODS: Six pigs were utilised for the experiment using 18G water circulating-cooling microwave needles. The operating frequency was 2450 MHz, and the independent variables were power (50-60 W) and time (300-600 s). The kidneys were dissociated laparoscopically and ablated with a single or double needle at different power/time combinations and depths of puncture. Changes in the kidneys were carefully observed. Specimens of the ablated lesions were stained with haematoxylin-eosin (H&E) to evaluate the pathological features. RESULTS: Thirty four thermoablations were applied. The effective ablation shape was similar to a chestnut. The ablated lesions could be divided into three zones: carbonization zone, coagulation zone, and inflammatory reaction zone. The ablation zone enlarged with increasing power and time. When combined with two needles, the maximum diameter of the ablated lesions significantly increased. Pathological results indicated that renal tissues of the carbonisation zone were thoroughly necrotic. Coagulative necrosis was observed in the coagulation zone. No 'skipped' areas were noted in any ablation zone. The structure of the inflammatory reaction zone was integrated, and interstitial small blood vessels were highly expanded and congested with infiltrated inflammatory cells. CONCLUSIONS: MWA achieved excellent effects in this porcine model. It can be safely and effectively used in renal tissue. For patients with poor physical condition or small renal masses (<4 cm), we can refer to these data and select the appropriate combinations to obtain satisfactory therapeutic efficacy. PMID- 26524388 TI - High-Current Gain Two-Dimensional MoS2-Base Hot-Electron Transistors. AB - The vertical transport of nonequilibrium charge carriers through semiconductor heterostructures has led to milestones in electronics with the development of the hot-electron transistor. Recently, significant advances have been made with atomically sharp heterostructures implementing various two-dimensional materials. Although graphene-base hot-electron transistors show great promise for electronic switching at high frequencies, they are limited by their low current gain. Here we show that, by choosing MoS2 and HfO2 for the filter barrier interface and using a noncrystalline semiconductor such as ITO for the collector, we can achieve an unprecedentedly high-current gain (alpha ~ 0.95) in our hot-electron transistors operating at room temperature. Furthermore, the current gain can be tuned over 2 orders of magnitude with the collector-base voltage albeit this feature currently presents a drawback in the transistor performance metrics such as poor output resistance and poor intrinsic voltage gain. We anticipate our transistors will pave the way toward the realization of novel flexible 2D material-based high-density, low-energy, and high-frequency hot-carrier electronic applications. PMID- 26524389 TI - Effects of remineralization procedures on shear bond strengths of brackets bonded to demineralized enamel surfaces with self-etch systems. AB - OBJECTIVE: To compare the effects of different remineralization procedures on the surface roughness of teeth, shear bond strengths (SBSs), and Adhesive Remnant Index scores of self-etching primer (SEP) used to bond orthodontic brackets to previously treated demineralized enamel surfaces. MATERIALS AND METHODS: A total of 140 extracted human premolar teeth were randomly divided into seven equal groups. Group I was the control group. A demineralization procedure was performed in the other six groups. A remineralization procedure was performed before bonding by using casein phosphopeptide-amorphous calcium phosphate, fluoride, a microabrasion mixture (18% hydrochloric acid-fine pumice), a microabrasion agent, and resin infiltration in groups III to VII. Brackets were bonded using a self etching primer/adhesive system. The specimens were tested for SBS. The roughness and morphology of the enamel surfaces were analyzed using profilometer and scanning electron microscopy. Data were analyzed with analysis of variance, Tukey, and G-tests at the alpha = .05 level. RESULTS: Significant differences were found in the SBS values among the seven groups (F = 32.69, P = .003). The lowest SBS value was found in group II (2.62 +/- 1.46 MPa). No significant differences were found between groups I, III, and VII, between groups III and IV, or between groups V and VI. The differences in the roughness values were statistically significant among the groups (P = .002). CONCLUSIONS: Remineralization procedures restore the decreased SBS of orthodontic brackets and decrease surface roughness caused by enamel demineralization. SEPs provide clinically acceptable SBS values for bonding orthodontic brackets to previously treated demineralized enamel surfaces. PMID- 26524390 TI - First report on exploring classification and regression based QSAR modelling of Plasmodium falciparum glycogen synthase kinase (PfGSK-3) inhibitors. AB - Recent advances in the knowledge of parasite biology have unveiled many new antimalarial targets for drug development. The glycogen synthase kinase-3 from Plasmodium falciparum (PfGSK-3) plays an active role in the completion of the asexual erythrocytic stage of P. falciparum life cycle. Due to the limited availability of experimental information (only one dataset is publicly available to our knowledge) and the absence of the target protein structure, the discovery of new inhibitors against PfGSK-3 is quite challenging. Against this background, we have made an effort to develop classification-based (using linear discriminant analysis or LDA) and regression-based quantitative structure-activity relationship (using group based-QSAR or G-QSAR) models for the categorization and quantitative prediction, respectively, of the activity of PfGSK-3 inhibitors. The classification model highlighted the contribution of electronic (Dipole-mag) and topological (S_tsC) descriptors in discriminating the PfGSK-3 inhibitors into more active and less active classes. The regression-based G-QSAR model showed the contribution of fragment-based descriptors (R1-chiV3 and R2-Most-vePotential) in determining the PfGSK-3 inhibitory activity, and also suggested modification sites for the improvement of PfGSK-3 inhibitory activity. The information obtained from this work could be utilized for the identification of novel PfGSK-3 inhibitors with a hope of overcoming the antimalarial resistance problem. PMID- 26524391 TI - Country-based reference values and international comparisons of clitoral size in healthy Nigerian newborn infants. AB - AIM: Clitoral size references are useful for diagnosing genital abnormalities. Despite the fact that examining the genitalia is an important aspect of newborn evaluation, few studies have been carried out to determine normal clitoral size in newborn infants. The aim of this study was to establish reference values for clitoral size in Nigerian newborn girls and to compare them with references from other ethnic populations. METHODS: A total of 244 healthy newborn girls delivered at 28-43 weeks gestation were enrolled in the study, and clitoral lengths and widths were measured at <72 hours. RESULTS: The mean clitoral length was 7.7 mm with a standard deviation of +/-1.37 mm, while the mean clitoral width was 4.40 +/- 0.89 mm. The clitoral length was significantly longer than those reported for Caucasian (4.00 +/- 1.24 mm), Korean (3.82 +/- 1.47), Turkish (4.93 +/- 1.61) and Japanese (4.30 +/- 1.10) babies. CONCLUSION: The present results make it possible to evaluate clitoral size in Nigerian newborn baby girls in an objective way, to identify genital abnormalities and endocrine disorders. Based on this study, a clitoral length of more than 10 mm would be considered clitoromegaly in a newborn girl in Nigeria. PMID- 26524392 TI - Uncovering the Geometry of Barrierless Reactions Using Lagrangian Descriptors. AB - Transition-state theories describing barrierless chemical reactions, or more general activated problems, are often hampered by the lack of a saddle around which the dividing surface can be constructed. For example, the time-dependent transition-state trajectory uncovering the nonrecrossing dividing surface in thermal reactions in the framework of the Langevin equation has relied on perturbative approaches in the vicinity of the saddle. We recently obtained an alternative approach using Lagrangian descriptors to construct time-dependent and recrossing-free dividing surfaces. This is a nonperturbative approach making no reference to a putative saddle. Here we show how the Lagrangian descriptor can be used to obtain the transition-state geometry of a dissipated and thermalized reaction across barrierless potentials. We illustrate the method in the case of a 1D Brownian motion for both barrierless and step potentials; however, the method is not restricted and can be directly applied to different kinds of potentials and higher dimensional systems. PMID- 26524393 TI - 2-Deoxyglucose conjugated platinum (II) complexes for targeted therapy: design, synthesis, and antitumor activity. AB - Malignant neoplasms exhibit an elevated rate of glycolysis over normal cells. To target the Warburg effect, we designed a new series of 2-deoxyglucose (2-DG) conjugated platinum (II) complexes for glucose transporter 1 (GLUT1)-mediated anticancer drug delivery. The potential GLUT1 transportability of the complexes was investigated through a comparative molecular docking analysis utilizing the latest GLUT1 protein crystal structure. The key binding site for 2-DG as GLUT1's substrate was identified with molecular dynamics simulation, and the docking study demonstrated that the 2-DG conjugated platinum (II) complexes can be recognized by the same binding site as potential GLUT1 substrate. The conjugates were synthesized and evaluated for in vitro cytotoxicity study with seven human cancer cell lines. The results of this study revealed that 2-DG conjugated platinum (II) complexes are GLUT1 transportable substrates and exhibit improved cytotoxicities in cancer cell lines that over express GLUT1 when compared to the clinical drug, Oxaliplatin. The correlation between GLUT1 expression and antitumor effects are also confirmed. The study provides fundamental information supporting the potential of the 2-DG conjugated platinum (II) complexes as lead compounds for further pharmaceutical R&D. PMID- 26524394 TI - The Surgical "Robot" in Benign Gynecology: Surgical Advance or a Set of Costly Training Wheels? PMID- 26524395 TI - Plasmonic optical tweezers: A long arm and a tight grip. PMID- 26524396 TI - A multiphase transitioning peptide hydrogel for suturing ultrasmall vessels. AB - Many surgeries are complicated by the need to anastomose, or reconnect, micrometre-scale vessels. Although suturing remains the gold standard for anastomosing vessels, it is difficult to place sutures correctly through collapsed lumen, making the procedure prone to failure. Here, we report a multiphase transitioning peptide hydrogel that can be injected into the lumen of vessels to facilitate suturing. The peptide, which contains a photocaged glutamic acid, forms a solid-like gel in a syringe and can be shear-thin delivered to the lumen of collapsed vessels (where it distends the vessel) and the space between two vessels (where it is used to approximate the vessel ends). Suturing is performed directly through the gel. Light is used to initiate the final gel-sol phase transition that disrupts the hydrogel network, allowing the gel to be removed and blood flow to resume. This gel adds a new tool to the armamentarium for micro- and supermicrosurgical procedures. PMID- 26524397 TI - A stochastic DNA walker that traverses a microparticle surface. AB - Molecular machines have previously been designed that are propelled by DNAzymes, protein enzymes and strand displacement. These engineered machines typically move along precisely defined one- and two-dimensional tracks. Here, we report a DNA walker that uses hybridization to drive walking on DNA-coated microparticle surfaces. Through purely DNA:DNA hybridization reactions, the nanoscale movements of the walker can lead to the generation of a single-stranded product and the subsequent immobilization of fluorescent labels on the microparticle surface. This suggests that the system could be of use in analytical and diagnostic applications, similar to how strand exchange reactions in solution have been used for transducing and quantifying signals from isothermal molecular amplification assays. The walking behaviour is robust and the walker can take more than 30 continuous steps. The traversal of an unprogrammed, inhomogeneous surface is also due entirely to autonomous decisions made by the walker, behaviour analogous to amorphous chemical reaction network computations, which have been shown to lead to pattern formation. PMID- 26524398 TI - Long-range and rapid transport of individual nano-objects by a hybrid electrothermoplasmonic nanotweezer. AB - Plasmon-enhanced optical trapping is being actively studied to provide efficient manipulation of nanometre-sized objects. However, a long-standing issue with previously proposed solutions is how to controllably load the trap on-demand without relying on Brownian diffusion. Here, we show that the photo-induced heating of a nanoantenna in conjunction with an applied a.c. electric field can initiate rapid microscale fluid motion and particle transport with a velocity exceeding 10 MUm s(-1), which is over two orders of magnitude faster than previously predicted. Our electrothermoplasmonic device enables on-demand long range and rapid delivery of single nano-objects to specific plasmonic nanoantennas, where they can be trapped and even locked in place. We also present a physical model that elucidates the role of both heat-induced fluidic motion and plasmonic field enhancement in the plasmon-assisted optical trapping process. Finally, by applying a d.c. field or low-frequency a.c. field (below 10 Hz) while the particle is held in the trap by the gradient force, the trapped nano-objects can be immobilized into plasmonic hotspots, thereby providing the potential for effective low-power nanomanufacturing on-chip. PMID- 26524399 TI - The association of oxidant-antioxidant status in patients with chronic renal failure. AB - Oxidative stress has been linked to disease progression, including chronic renal failure (CRF). The aim of the present study was to determine malondialdehyde (MDA) as a sign of lipid peroxidation, and to investigate the association between antioxidant activities and three trace elements, in 49 patients with CRF. The erythrocyte and plasma trace elements [selenium (Se), zinc (Zn), and copper (Cu)] and antioxidant defense levels were determined: glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), vitamins E and C. The obtained values were compared with 42 age- and sex-matched healthy controls. There were significantly lower mean values of plasma Se, GPx, vitamins E and C, erythrocyte Se, SOD and CAT levels in the patient group compared to the control group (p < 0.001). Plasma MDA showed a significant increase in all CRF patients in comparison with controls. No significant difference was found in plasma Cu, Zn, and erythrocyte GPx, Cu and Zn levels between patient and control groups. These findings indicate oxidative stress is present in patients of CRF, and may serve to establish a simple protocol for evaluation of renal function. PMID- 26524400 TI - Stimulation of vasculogenesis and leukopoiesis of embryonic stem cells by extracellular transfer RNA and ribosomal RNA. AB - OBJECTIVE: Cell injury releases nucleic acids supporting inflammation and stem cell activation. Here, the impact of extracellular ribonucleic acid, especially transfer RNA (ex-tRNA), on vasculogenesis and leukopoiesis of mouse embryonic stem (ES) cells was investigated. APPROACH AND RESULTS: ex-tRNA, whole cell RNA and ribosomal RNA (ex-rRNA) but not DNA increased CD31-positive vascular structures in embryoid bodies. Ex-tRNA and ex-rRNA increased numbers of VEGFR2(+), CD31(+) and VE-cadherin(+) vascular cells as well as CD18(+), CD45(+) and CD68(+) cells, indicating leukocyte/macrophage differentiation. This was paralleled by mRNA and protein expression of hypoxia-inducible factor-1alpha (HIF 1alpha), vascular endothelial growth factor-165 (VEGF165) and neuropilin 1 (NRP1), phosphorylation of phosphatidyl inositol 3-kinase (PI3K) and VEGF receptor 2 (VEGFR2) as well as mRNA expression of alpha-smooth muscle actin (alpha-SMA). ex-tRNA was taken up by endosomes, increased expression of the pro angiogenic semaphorin B4 receptor plexin B1 as well as the ephrin-type B receptor 4 (EphB4) and ephrinB2 ligand and enhanced cell migration, which was inhibited by the VEGFR2 antagonist SU5614 and the PI3K inhibitor LY294002. This likewise abolished the effects of ex-tRNA on vasculogenesis and leukopoiesis of ES cells. Ex-tRNA increased NOX1, NOX2, NOX4 and DUOX2 mRNA and boosted the generation of superoxide and hydrogen peroxide which was inhibited by radical scavengers, the NADPH oxidase inhibitors apocynin, VAS2870, ML171, and plumbagin as well as shRNA silencing of NOX1 and NOX4. CONCLUSIONS: Our findings indicate that ex-tRNA treatment induces vasculogenesis and leukopoiesis of ES cells via superoxide/hydrogen peroxide generated by NADPH oxidase and activation of VEGFR2 and PI3K. PMID- 26524401 TI - TRIM4; a novel mitochondrial interacting RING E3 ligase, sensitizes the cells to hydrogen peroxide (H2O2) induced cell death. AB - The emerging evidences suggest that posttranslational modification of target protein by ubiquitin (Ub) not only regulate its turnover through ubiquitin proteasome system (UPS) but is a critical regulator of various signaling pathways. During ubiquitination, E3 ligase recognizes the target protein and determines the topology of ubiquitin chains. In current study, we studied the role of TRIM4, a member of the TRIM/RBCC protein family of RING E3 ligase, in regulation of hydrogen peroxide (H2O2) induced cell death. TRIM4 is expressed differentially in human tissues and expressed in most of the analyzed human cancer cell lines. The subcellular localization studies showed that TRIM4 forms distinct cytoplasmic speckle like structures which transiently interacts with mitochondria. The expression of TRIM4 induces mitochondrial aggregation and increased level of mitochondrial ROS in the presence of H2O2. It sensitizes the cells to H2O2 induced death whereas knockdown reversed the effect. TRIM4 potentiates the loss of mitochondrial transmembrane potential and cytochrome c release in the presence of H2O2. The analysis of TRIM4 interacting proteins showed its interaction with peroxiredoxin 1 (PRX1), including other proteins involved in regulation of mitochondrial and redox homeostasis. TRIM4 interaction with PRX1 is critical for the regulation of H2O2 induced cell death. Collectively, the evidences in the current study suggest the role of TRIM4 in regulation of oxidative stress induced cell death. PMID- 26524402 TI - Kinetics of reaction of peroxynitrite with selenium- and sulfur-containing compounds: Absolute rate constants and assessment of biological significance. AB - Peroxynitrite (the physiological mixture of ONOOH and its anion, ONOO(-)) is a powerful biologically-relevant oxidant capable of oxidizing and damaging a range of important targets including sulfides, thiols, lipids, proteins, carbohydrates and nucleic acids. Excessive production of peroxynitrite is associated with several human pathologies including cardiovascular disease, ischemic-reperfusion injury, circulatory shock, inflammation and neurodegeneration. This study demonstrates that low-molecular-mass selenols (RSeH), selenides (RSeR') and to a lesser extent diselenides (RSeSeR') react with peroxynitrite with high rate constants. Low molecular mass selenols react particularly rapidly with peroxynitrite, with second order rate constants k2 in the range 5.1 * 10(5)-1.9 * 10(6)M(-1)s(-1), and 250-830 fold faster than the corresponding thiols (RSH) and many other endogenous biological targets. Reactions of peroxynitrite with selenides, including selenosugars are approximately 15-fold faster than their sulfur homologs with k2 approximately 2.5 * 10(3)M(-1)s(-1). The rate constants for diselenides and sulfides were slower with k2 0.72-1.3 * 10(3)M(-1)s(-1) and approximately 2.1 * 10(2)M(-1)s(-1) respectively. These studies demonstrate that both endogenous and exogenous selenium-containing compounds may modulate peroxynitrite-mediated damage at sites of acute and chronic inflammation, with this being of particular relevance at extracellular sites where the thiol pool is limited. PMID- 26524403 TI - Absolute risk reduction may depend on the duration of the follow-up. AB - Response to: Diamond DA and Ravnskov U. How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease. Expert Rev Clin Pharm 2015;8(2):201-210. PMID- 26524404 TI - Inhibition of islet amyloid polypeptide aggregation and associated cytotoxicity by nonsteroidal anti-inflammatory drugs. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) constitute an important pharmacotherapeutic class that, over the past decade, have expanded in application to a panoply of medical conditions. They have been tested for neurodegenerative diseases such as Alzheimer's to reduce inflammation and also in the attempt to abrogate amyloid deposition. However, the use of NSAIDs as aggregation inhibitors has not been extensively studied in pancreatic amyloid deposition. Pancreatic amyloidosis involves the misfolding of islet amyloid polypeptide (IAPP) and contributes to the progression of type-2 diabetes in humans and felines. To ascertain their antiamyloidogenic activity, several NSAIDs were tested using fluorometric thioflavin-T assays, circular dichroism, photo induced cross-linking assays, and cell culture. Celecoxib, diclofenac, indomethacin, meloxicam, niflumic acid, nimesulide, phenylbutazone, piroxicam, sulindac, and tenoxicam reduced fibrillization at a molar ratio of 1:10. The circular dichroism spectra of diclofenac, piroxicam, and sulindac showed characteristic spectral signatures found in predominantly alpha-helical structures. The oligomerization of human IAPP was abrogated with diclofenac and sulindac at a molar ratio of 1:5. The cytotoxic effects of pre-incubated human IAPP on cultured INS-1 cells were noticeably reduced in the presence of diclofenac, meloxicam, phenylbutazone, sulindac, and tenoxicam at a molar ratio of 1:10. Our results demonstrate that NSAIDs can provide chemical scaffolds to generate new and promising antiamyloidogenic agents that can be used alone or as a coadjuvant therapy. PMID- 26524405 TI - Preliminary evaluation of the potential of 99mTc carbonyl-DTPA-Rituximab as a tracer for sentinel lymph node detection. AB - Preliminary work with (99m)Tc carbonyl-DTPA-Rituximab was attempted to test its feasibility as a sentinel lymph node (SLN) tracer for patients with breast cancer. (99m)Tc labeling of DTPA-Rituximab conjugate was carried out via (99m)Tc carbonyl synthon which exhibited >95% radiochemical purity and good in vitro stability. In vitro studies of (99m)Tc carbonyl-DTPA-Rituximab in normal and malignant B cells showed higher binding in malignant cells. In vivo distribution of (99m)Tc carbonyl-DTPA-Rituximab in Wistar rat footpad model indicated good retention by B-cells present in the sentinel lymph node. PMID- 26524407 TI - Modeling the transmission of beta rays through thin foils in planar geometry. AB - This paper is concerned with the modeling of the transmission of beta rays through thin foils in planar geometry based on the plane source concept, using Monte Carlo simulation of electron transport and least squares fitting. Applications of modeling results for calculating the efficiency of large-area beta sources, transmission coefficient of beta rays through thin foils and the beta detection efficiency of large-area detectors used in surface contamination measurements are also presented. PMID- 26524406 TI - Production and separation of carrier-free 7Be. AB - A high-purity carrier-free (7)Be was efficiently isolated following proton bombardment of a lithium hydroxide-aluminum target. The separation of beryllium from lithium and aluminum was achieved through a hydrochloric acid elution system utilizing cation exchange chromatography. The beryllium recovery, +99%, was assessed through gamma spectroscopy while the chemical purity was established by mass spectrometry. The decontamination factors of beryllium from lithium and aluminum were determined to be 6900 and 300, respectively. PMID- 26524408 TI - Strain- and context-dependent behavioural responses of acute alarm substance exposure in zebrafish. AB - We investigate the behavioural responses of wild type (WT) and leopard (leo) zebrafish elicited by alarm substances of conspecifics at three contexts: during the exposure period (Experiment 1); after exposure, in habituation to novelty (Experiment 2); or after exposure, in the light-dark preference test (Experiment 3), and analyse their influence on pigment response. During the exposure, leo showed decreased vertical drifts, increased number and duration of erratic movements, while WT had increased erratic movements and latency to enter the top. In the novel tank, we observed that angular velocity decreased in WT exposed to alarm substance, which also presented increased fear responses. Contrastingly, leo increased the number of entries and time in top, indicating differences in habituation profile. Alarm substance increased the number of erratic movements in the light-dark test, but elicited different responses between strains in scototaxis, latency to enter the dark compartment and risk assessment episodes. Moreover, the body colour of zebrafish did not change after alarm substance exposure. Principal component analyses suggest that burst swimming, anxiety-like behaviours, and locomotion/exploration were the components that most accounted for total variances of Experiments 1, 2, and 3, respectively. We conclude that chemical cue from conspecifics triggers strain- and context-dependent responses. PMID- 26524409 TI - Subchronic and mild social defeat stress alter mouse nest building behavior. AB - Behavioral and physiological evaluations of animal models of depression are essential to thoroughly understand the mechanisms of depression in humans. Various models have been developed and characterized, and the socially defeated mouse has been widely used for studying depression. Here, we developed and characterized a mouse model of social aversion using a subchronic and mild social defeat stress (sCSDS) paradigm. Compared to control mice, sCSDS mice showed significantly increased body weight gain, water intake, and social aversion to dominant mice on the social interaction test. We observed nest building behavior in sCSDS mice using the pressed cotton as a nest material. Although sCSDS mice eventually successfully built nests, the onset of nest building was severely delayed compared to control mice. The underlying mechanism of this significant delay in nest building by sCSDS mice is unclear. However, our results demonstrate that nest building evaluation is a simple and useful assay for understanding behavior in socially defeated mice and screening drugs such as antidepressants. PMID- 26524410 TI - Des-aspartate-angiotensin I causes specific release of PGE2 and PGI2 in HUVEC via the angiotensin AT1 receptor and biased agonism. AB - DAA-I (des-aspartate-angiotensin I), an endogenous angiotensin, had been shown earlier to ameliorate animal models of cardiovascular diseases via the angiotensin AT1 receptor and prostaglandins. The present study investigated further the action of DAA-I on the release of PGE2, PGI2, PGF2alpha and TXA2 in HUVEC. 10(-11)-10(-8)M DAA-I and 15min incubation specifically released PGE2 and PGI2. The release was inhibited by losartan and indomethacin but not by PD123319 and NS398 indicating that the angiotensin AT1 receptor and COX-1 mediate the release. At concentrations higher than 10(-7)M, DAA-I mimics the action of angiotensin II by releasing TXA2 but had no effect on the production of PGF2alpha. At similar concentrations and 4h incubation, DAA-I increased the release of the 4 prostaglandins via the angiotensin AT1 receptor and COX-2, again mimicking the action of angiotensin II. HUVEC that were preincubated with DAA-I or angiotensin II, released similar profiles of prostaglandins when incubated with arachidonic acid after the angiotensin had been washed off. We postulate that the internalized DAA-I/receptor complex remains active and mediates the conversion of arachidonic acid to the respective prostaglandins. The release of PGE2 and PGI2 via the angiotensin AT1 receptor and COX-1 is a novel specific action of DAA-I and is likely responsible for its beneficial effects seen in earlier studies. This specific action is definable as a biased agonism of the angiotensin AT1 receptor, which identifies DAA-I as a novel biased agonist and potential therapeutic that is able to produce specific prostaglandins at nanomolar concentrations. PMID- 26524411 TI - Activation of the hypothalamic-pituitary-adrenal axis in lithium-induced conditioned taste aversion learning. AB - Intraperitoneal injections (ip) of lithium chloride at large doses induce c-Fos expression in the brain regions implicated in conditioned taste aversion (CTA) learning, and also activate the hypothalamic-pituitary-adrenal (HPA) axis and increase the plasma corticosterone levels in rats. A pharmacologic treatment blunting the lithium-induced c-Fos expression in the brain regions, but not the HPA axis activation, induced CTA formation. Synthetic glucocorticoids at conditioning, but not glucocorticoid antagonist, attenuated the lithium-induced CTA acquisition. The CTA acquisition by ip lithium was not affected by adrenalectomy regardless of basal corticosterone supplement, but the extinction was delayed in the absence of basal corticosterone. Glucocorticoids overloading delayed the extinction memory formation of lithium-induced CTA. ip lithium consistently induced the brain c-Fos expression, the HPA activation and CTA formation regardless of the circadian activation of the HPA axis. Intracerebroventricular (icv) injections of lithium at day time also increased the brain c-Fos expression, activated the HPA axis and induced CTA acquisition. However, icv lithium at night, when the HPA axis shows its circadian activation, did not induce CTA acquisition nor activate the HPA axis, although it increased the brain c-Fos expression. These results suggest that the circadian activation of the HPA axis may affect central, but not peripheral, effect of lithium in CTA learning in rats, and the HPA axis activation may be necessary for the central effect of lithium in CTA formation. Also, glucocorticoids may be required for a better extinction; however, increased glucocorticoids hinder both the acquisition and the extinction of lithium-induced CTA. PMID- 26524412 TI - Acid ceramidase treatment enhances the outcome of autologous chondrocyte implantation in a rat osteochondral defect model. AB - OBJECTIVE: The overall aim of this study was to evaluate how supplementation of chondrocyte media with recombinant acid ceramidase (rhAC) influenced cartilage repair in a rat osteochondral defect model. METHODS: Primary chondrocytes were grown as monolayers in polystyrene culture dishes with and without rhAC (added once at the time of cell plating) for 7 days, and then seeded onto Bio-Gide(r) collagen scaffolds and grown for an additional 3 days. The scaffolds were then introduced into osteochondral defects created in Sprague-Dawley rat trochlea by a microdrilling procedure. Analysis was performed 6 weeks post-surgery macroscopically, by micro-CT, histologically, and by immunohistochemistry. RESULTS: Treatment with rhAC led to increased cell numbers and glycosaminoglycan (GAG) production (~2 and 3-fold, respectively) following 7 days of expansion in vitro. Gene expression of collagen 2, aggrecan and Sox-9 also was significantly elevated. After seeding onto Bio-Gide(r), more rhAC treated cells were evident within 4 h. At 6 weeks post-surgery, defects containing rhAC-treated cells exhibited more soft tissue formation at the articular surface, as evidenced by microCT, as well as histological evidence of enhanced cartilage repair. Notably, collagen 2 immunostaining revealed greater surface expression in animals receiving rhAC treated cells as well. Collagen 10 staining was not enhanced. CONCLUSION: The results further demonstrate the positive effects of rhAC treatment on chondrocyte growth and phenotype in vitro, and reveal for the first time the in vivo effects of the treated cells on cartilage repair. PMID- 26524413 TI - Modulation of triglyceride accumulation in adipocytes by psychopharmacological agents in vitro. AB - Weight gain is a major problem during psychopharmacological treatment. Research has concentrated on the appetite inducing properties and mechanisms of these drugs in the central nervous system. The potential contribution of direct effects of drugs on metabolically relevant peripheral cells such as adipocytes is less well understood. We examined the influence of the antidepressant imipramine, the antipsychotic clozapine, and the mood stabilizer lithium on preadipocytes and adipocytes in vitro, using Simpson-Golabi-Behmel syndrome (SGBS) cells, an established human preadipocyte model. Parameters of cell differentiation and signaling, and cell metabolism were measured. We found significantly increased triglyceride accumulation in adipocytes after supplementation with imipramine and lithium at therapeutic concentrations, compared to non-supplemented control samples. However, gene expression levels of an early marker of adipogenesis, the peroxisome proliferator-activated receptor gamma (PPAR-gamma) and a late marker of adipogenesis, the fatty acid binding protein 4 (FABP4), as well as expression of adiponectin (ADIPOQ) did not change significantly in the presence of these psychopharmacological agents. The results suggest a direct influence of imipramine and lithium but not clozapine on fat storage of adipocytes. The underlying mechanisms of fatty acid storage and adipocyte differentiation however remain to be elucidated. PMID- 26524414 TI - Economic evaluation of stuttering treatment in preschool children: The RESTART study. AB - PURPOSE: The purpose of this study was to evaluate the incremental cost effectiveness and cost-utility of the Lidcombe Program (LP) compared with treatment based on the Demands and Capacities Model (RESTART-DCM) for preschool children who stutter. METHOD: A cost-effectiveness and cost-utility analysis were carried out alongside a Randomized Clinical Trial (the RESTART-study). In total, 199 children in 20 speech clinics participated. Outcome measures included the number needed to treat, based on the percentage of children who did not stutter at 18 months, and Health-related Quality of Life (EQ-VAS and HUI3) at 3, 6, 12 and 18 months. Health-related Quality of Life scores were used to calculate quality adjusted life years (V-QALYs for the EQ-VAS and U-QALYs for the HUI3). Direct and indirect costs were measured by cost questionnaires. Missing data were multiply imputed. Percentages of children who did not stutter in both groups were compared by a chi-square test. Between-group differences in mean QALYs and costs, as well as cost effectiveness and cost-utility ratios, were evaluated by applying bootstrapping techniques. RESULTS: After 18 months, health outcomes were slightly better in the LP group, although only the difference in V-QALYs was statistical significant (0.018; 95% CI: 0.008 to 0.027) with a small effect size (Cohen's d=0.17). Mean costs for the LP group were significantly higher compared to the RESTART-DCM group (?3199 versus ?3032), again with a small effect size (Cohen's d=0.14). The incremental cost-effectiveness ratio was ?3360 for one additional child who did not stutter with the LP, and the estimated cost-utility ratios were ?10,413 (extra cost per extra V-QALY) and ?18,617 (extra cost per extra U-QALY). The results indicated a high probability that the LP is cost-effective compared to RESTART-DCM treatment given a threshold for willingness-to-pay of ?20,000 per QALY. CONCLUSIONS: Differences in effects and costs between the LP and RESTART DCM treatment were small. Cost-effectiveness and cost-utility ratios were in favor of the LP. The LP is considered a good alternative to RESTART-DCM treatment in Dutch primary care. PMID- 26524415 TI - Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model. AB - Recent studies have highlighted the involvement of the kynurenine pathway in the pathology of neurodegenerative diseases, but the role of this system in neuropathic pain requires further extensive research. Therefore, the aim of our study was to examine the role of kynurenine 3-monooxygenase (Kmo), an enzyme that is important in this pathway, in a rat model of neuropathy after chronic constriction injury (CCI) to the sciatic nerve. For the first time, we demonstrated that the injury-induced increase in the Kmo mRNA levels in the spinal cord and the dorsal root ganglia (DRG) was reduced by chronic administration of the microglial inhibitor minocycline and that this effect paralleled a decrease in the intensity of neuropathy. Further, minocycline administration alleviated the lipopolysaccharide (LPS)-induced upregulation of Kmo mRNA expression in microglial cell cultures. Moreover, we demonstrated that not only indirect inhibition of Kmo using minocycline but also direct inhibition using Kmo inhibitors (Ro61-6048 and JM6) decreased neuropathic pain intensity on the third and the seventh days after CCI. Chronic Ro61-6048 administration diminished the protein levels of IBA-1, IL-6, IL-1beta and NOS2 in the spinal cord and/or the DRG. Both Kmo inhibitors potentiated the analgesic properties of morphine. In summary, our data suggest that in neuropathic pain model, inhibiting Kmo function significantly reduces pain symptoms and enhances the effectiveness of morphine. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology and indicate that Kmo represents a novel pharmacological target for the treatment of neuropathy. PMID- 26524417 TI - The Effects of Handed Bias of Physicians and the Laterality of Recumbent Position of Patients on the Success Rate of Lumbar Puncture. PMID- 26524418 TI - Congenital Dysfibrinogenemia, An Unusual Cause for Subdural Hematoma in an Infant. PMID- 26524416 TI - G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice. AB - Granulocyte colony-stimulating factor (G-CSF) was investigated for its capacity to induce autophagy and related neuroprotective mechanisms in an acute spinal cord injury model. To accomplish this goal, we established a mouse spinal cord hemisection model to test the effects of recombinant human G-CSF. The results showed that autophagy was activated after spinal cord injury and G-CSF appears to induce a more rapid activation of autophagy within injured spinal cords as compared with that of non-treated animals. Apoptosis as induced in mechanically injured neurons with G-CSF treatment was enhanced after inhibiting autophagy by 3 methyladenine (3-MA), which partially blocked the neuroprotective effect of autophagy as induced by G-CSF. In addition, G-CSF inhibited the activity of the NF-kappaB signal pathway in neurons after mechanical injury. We conclude that G CSF promotes autophagy by inhibiting the NF-kappaB signal pathway and protects neuronal structure after spinal cord injury. We therefore suggest that G-CSF, which rapidly induces autophagy after spinal cord injury to inhibit neuronal apoptosis, may thus provide an effective auxiliary therapeutic intervention for spinal cord injury. PMID- 26524419 TI - Transcranial Color Duplex Ultrasound: A Reliable Tool for Cerebral Hemodynamic Assessment in Brain Injuries. AB - BACKGROUND: Transcranial color duplex ultrasound (TCCD) is becoming an important tool for cerebral monitoring of brain-injured patients. To date, TCCD reproducibility has been studied in healthy volunteers or patients with subarachnoid hemorrhage and its efficiency in many brain injuries has not been proved. Our aim was to evaluate TCCD interobserver agreement in different brain injuries. PATIENTS AND METHODS: We performed a prospective monocentric trial conducted from January 2014 to September 2014 in intensive care unit (ICU) of Saint-Etienne university teaching hospital, France.Brain-damaged patients admitted in ICU were included, excluding those with decompressive craniectomy. Two randomized operators among the ICU medical staff consecutively performed measurements of cerebral blood flow velocities with TCCD. RESULTS: One hundred measurements were obtained from 42 patients. Hemodynamic and end-tidal CO2 pressure were similar between both measurement set. The results obtained with the Bland-Altman method showed bias at 0.52 (95% confidence interval [CI], -4.19 to 3.16), 0.53 (95% CI, -1.86 to 2.92), and 0.002 (95% CI, -0.06 to 0.06) for mean velocity, diastolic velocity, and pulsatility index, respectively. The limits of agreement were (-32.4; 31.4), (-20.4; 21.4), (-0.5; 0.5) for mean velocity, diastolic velocity, and pulsatility index, respectively. The Passing and Bablok regression have shown a quasilinear relationship between measurements. CONCLUSIONS: We reported the reliability of TCCD interobserver agreement in brain damaged patients. PMID- 26524420 TI - Supplementary Motor Area (SMA) Syndrome: An Enigma to Anesthesiologists! PMID- 26524422 TI - The decrease in the IgG-binding capacity of intensively dry heated whey proteins is associated with intense Maillard reaction, structural changes of the proteins and formation of RAGE-ligands. AB - Heat treatment is the most common way of milk processing, inducing structural changes as well as chemical modifications in milk proteins. These modifications influence the immune-reactivity and allergenicity of milk proteins. This study shows the influence of dry heating on the solubility, particle size, loss of accessible thiol and amino groups, degree of Maillard reaction, IgG-binding capacity and binding to the receptor for advanced glycation end products (RAGE) of thermally treated and glycated whey proteins. A mixture of whey proteins and lactose was dry heated at 130 degrees C up to 20 min to mimic the baking process in two different water activities, 0.23 to mimic the heating in the dry state and 0.59 for the semi-dry state. The dry heating was accompanied by a loss of soluble proteins and an increase in the size of dissolved aggregates. Most of the Maillard reaction sites were found to be located in the reported conformational epitope area on whey proteins. Therefore the structural changes, including exposure of the SH group, SH-SS exchange, covalent cross-links and the loss of available lysine, subsequently resulted in a decreased IgG-binding capacity (up to 33%). The binding of glycation products to RAGE increased with the heating time, which was correlated with the stage of the Maillard reaction and the decrease in the IgG-binding capacity. The RAGE-binding capacity was higher in samples with a lower water activity (0.23). These results indicate that the intensive dry heating of whey proteins as it occurs during baking may be of importance to the immunological properties of allergens in cow's milk, both due to chemical modifications of the allergens and formation of AGEs. PMID- 26524423 TI - Authoritative school climate, aggression toward teachers, and teacher distress in middle school. AB - Aggression toward teachers is linked to burnout and disengagement from teaching, but a positive school climate may reduce aggression and associated teacher distress. Using authoritative school climate theory, the study examined whether schools with high disciplinary structure and student support were associated with less aggression and less distress. The sample of 9,134 teachers in 389 middle schools came from the Virginia Secondary School Climate Survey, a statewide survey administered to all public schools with 7th and 8th grade enrollment. The majority of teachers (75%) were female. More than half (53%) reported that they had more than 10 years of teaching experience; 23% reported 6 to 10 years; 24% reported 1 to 5 years. Students reported on the degree to which their schools were structured and supportive. Teachers reported on their experiences of aggression by students, their level of distress, and their feelings of safety. Staff-related infractions computed from Department of Education records were also used. Multilevel modeling revealed that teachers in authoritative schools experienced less aggression and felt safer and less distressed. Lower aggression by students mediated the association between more authoritative schools and lower distress such that more structured and supportive schools had greater teacher safety and, in turn, less distress. The findings support the idea that more structured and supportive schools relate to greater safety for teachers and, in turn, less distress. Research limitations and implications for practice are discussed. PMID- 26524424 TI - Reliability of Direct Behavior Ratings - Social Competence (DBR-SC) data: How many ratings are necessary? AB - The purpose of this investigation was to evaluate the reliability of Direct Behavior Ratings-Social Competence (DBR-SC) ratings. Participants included 60 students identified as possessing deficits in social competence, as well as their 23 classroom teachers. Teachers used DBR-SC to complete ratings of 5 student behaviors within the general education setting on a daily basis across approximately 5 months. During this time, each student was assigned to 1 of 2 intervention conditions, including the Social Competence Intervention-Adolescent (SCI-A) and a business-as-usual (BAU) intervention. Ratings were collected across 3 intervention phases, including pre-, mid-, and postintervention. Results suggested DBR-SC ratings were highly consistent across time within each student, with reliability coefficients predominantly falling in the .80 and .90 ranges. Findings further indicated such levels of reliability could be achieved with only a small number of ratings, with estimates varying between 2 and 10 data points. Group comparison analyses further suggested the reliability of DBR-SC ratings increased over time, such that student behavior became more consistent throughout the intervention period. Furthermore, analyses revealed that for 2 of the 5 DBR SC behavior targets, the increase in reliability over time was moderated by intervention grouping, with students receiving SCI-A demonstrating greater increases in reliability relative to those in the BAU group. Limitations of the investigation as well as directions for future research are discussed herein. (PsycINFO Database Record PMID- 26524426 TI - Cascade synthesis of a gold nanoparticle-network polymer composite. AB - The multi-step, cascade synthesis of a self-supporting, hierarchically-structured gold nanoparticle hydrogel composite is described. The composite is spontaneously prepared from a non-covalent, lamellar lyotropic mesophase composed of amphiphiles that support the reactive constituents, a mixture of hydroxyl- and acrylate-end-derivatized PEO117-PPO47-PEO117 and [AuCl4](-). The reaction sequence begins with the auto-reduction of aqueous [AuCl4](-) by PEO117-PPO47 PEO117 which leads to both the production of Au NPs and the free radical initiated polymerization and crosslinking of the acrylate end-derivatized PEO117 PPO47-PEO117 to yield a network polymer. Optical spectroscopy and TEM monitored the reduction of [AuCl4](-), formation of large aggregated Au NPs and oxidative etching into a final state of dispersed, spherical Au NPs. ATR/FT-IR spectroscopy and thermal analysis confirms acrylate crosslinking to yield the polymer network. X-ray scattering (SAXS and WAXS) monitored the evolution of the multi-lamellar structured mesophase and revealed the presence of semi-crystalline PEO confined within the water layers. The hydrogel could be reversibly swollen without loss of the well-entrained Au NPs with full recovery of composite structure. Optical spectroscopy shows a notable red shift (Deltalambda ~ 45 nm) in the surface plasmon resonance between swollen and contracted states, demonstrating solvent mediated modulation of the internal NP packing arrangement. PMID- 26524425 TI - Self-assembly of cationic multidomain peptide hydrogels: supramolecular nanostructure and rheological properties dictate antimicrobial activity. AB - Hydrogels are an important class of biomaterials that have been widely utilized for a variety of biomedical/medical applications. The biological performance of hydrogels, particularly those used as wound dressing could be greatly advanced if imbued with inherent antimicrobial activity capable of staving off colonization of the wound site by opportunistic bacterial pathogens. Possessing such antimicrobial properties would also protect the hydrogel itself from being adversely affected by microbial attachment to its surface. We have previously demonstrated the broad-spectrum antimicrobial activity of supramolecular assemblies of cationic multi-domain peptides (MDPs) in solution. Here, we extend the 1-D soluble supramolecular assembly to 3-D hydrogels to investigate the effect of the supramolecular nanostructure and its rheological properties on the antimicrobial activity of self-assembled hydrogels. Among designed MDPs, the bactericidal activity of peptide hydrogels was found to follow an opposite trend to that in solution. Improved antimicrobial activity of self-assembled peptide hydrogels is dictated by the combined effect of supramolecular surface chemistry and storage modulus of the bulk materials, rather than the ability of individual peptides/peptide assemblies to penetrate bacterial cell membrane as observed in solution. The structure-property-activity relationship developed through this study will provide important guidelines for designing biocompatible peptide hydrogels with built-in antimicrobial activity for various biomedical applications. PMID- 26524427 TI - Official Position of the American Academy of Clinical Neuropsychology Social Security Administration Policy on Validity Testing: Guidance and Recommendations for Change. AB - The milestone publication by Slick, Sherman, and Iverson (1999) of criteria for determining malingered neurocognitive dysfunction led to extensive research on validity testing. Position statements by the National Academy of Neuropsychology and the American Academy of Clinical Neuropsychology (AACN) recommended routine validity testing in neuropsychological evaluations. Despite this widespread scientific and professional support, the Social Security Administration (SSA) continued to discourage validity testing, a stance that led to a congressional initiative for SSA to reevaluate their position. In response, SSA commissioned the Institute of Medicine (IOM) to evaluate the science concerning the validation of psychological testing. The IOM concluded that validity assessment was necessary in psychological and neuropsychological examinations (IOM, 2015 ). OBJECTIVE: The AACN sought to provide independent expert guidance and recommendations concerning the use of validity testing in disability determinations. METHOD: A panel of contributors to the science of validity testing and its application to the disability process was charged with describing why the disability process for SSA needs improvement, and indicating the necessity for validity testing in disability exams. RESULTS: This work showed how the determination of malingering is a probability proposition, described how different types of validity tests are appropriate, provided evidence concerning non-credible findings in children and low-functioning individuals, and discussed the appropriate evaluation of pain disorders typically seen outside of mental consultations. CONCLUSIONS: A scientific plan for validity assessment that additionally protects test security is needed in disability determinations and in research on classification accuracy of disability decisions. PMID- 26524428 TI - How to write an educational research grant: AMEE Guide No. 101. AB - Writing an educational research grant in health profession education is challenging, not only for those doing it for the first time but also for more experienced scholars. The intensity of the competition, the peculiarities of the grant format, the risk of rejection, and the time required are among the many obstacles that can prevent educational researchers with interesting and important ideas from writing a grant, that could provide the funding needed to turn their scholarly ideas into reality. The aim of this AMEE Guide is to clarify the grant writing process by (a) explaining the mechanics and structure of a typical educational research grant proposal, and (b) sharing tips and strategies for making the process more manageable. PMID- 26524429 TI - Radiation-induced transformations of matrix-isolated formic acid: evidence for the HCOOH -> HOCO + H channel. AB - The effect of X-ray irradiation on the isolated formic acid molecules (HCOOH) in solid noble gas matrices (Xe, Kr, Ar, and Ne) at very low temperatures (6 K) was first studied by FTIR spectroscopy. Carbon oxides (CO and CO2) and hydrocarboxyl radicals (HOCO) have been detected as the principal degradation products. The formation of HOCO radicals represents a primary dissociation channel for formic acid, which was not reported previously under UV photolysis in solids. This reaction can be explained by the involvement of the recombination-induced excited states, which are not populated in photolysis. The effects of the matrix and the absorbed dose on the product formation were studied in detail and possible mechanisms are discussed with particular attention to the difference between radiolysis and UV-photolysis of the matrix-isolated formic acid. The results obtained provide a new insight into the effects of high-energy impact on the simplest carboxylic acid with possible implications to the astrochemical problems, in particular, the prebiotic evolution in the interstellar medium. PMID- 26524430 TI - The Role of Genome Instability in Frailty: Mitochondria versus Nucleus. AB - Late-life aging in humans is often associated with severe frailty. This suggests catastrophic events reaching an undeniable biological threshold in cellular stability and a rapidly diminished homeostasis. The driving force of the syndrome is likely 'genetic instability' or 'genomic instability', a high frequency of mutations and deletions within the genome (both nuclear and mitochondrial DNA) of bodily somatic cells caused by DNA damage and inefficient repair. Reactive oxygen species, calcium deregulation, and iron dyshomeostasis are potential chemical triggers of nucleic acid sequence alterations and chromosomal rearrangements. These include mutations, deletions, translocations, chromosomal inversions, and single- and double-strand DNA breaks. Nuclear damage, such as telomere shortening, also appears to cause an abnormal expression of several proteins, including p53, which leads to impaired mitochondrial biogenesis, mitochondrial permeability transition pore opening, apoptosis, and other biological events. Moreover, mitochondrial DNA damage could produce inaccurate translation and synthesis of proteins important for energy production in the inner mitochondrial membrane. Another cause of genomic instability may be a reduced expression and function of DNA repair genes, especially when stressful events trigger slow responses. With late-life frailty, overall endogenous damage occurs much more frequently and repair is much less efficient, which further accelerates genomic instability. PMID- 26524431 TI - A Young Woman With Heart Failure and Altered Mental Status--The Answer in the Electrocardiogram. PMID- 26524432 TI - Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors. AB - Small chemicals like drugs tend to bind to proteins via noncovalent bonds, e.g. hydrogen bonds, salt bridges or electrostatic interactions. Some chemicals interact with other molecules than the actual target ligand, representing so called 'off-target' activities of drugs. Such interactions are a main cause of adverse side effects to drugs and are normally classified as predictable type A reactions. Detailed analysis of drug-induced immune reactions revealed that off target activities also affect immune receptors, such as highly polymorphic human leukocyte antigens (HLA) or T cell receptors (TCR). Such drug interactions with immune receptors may lead to T cell stimulation, resulting in clinical symptoms of delayed-type hypersensitivity. They are assigned the 'pharmacological interaction with immune receptors' (p-i) concept. Analysis of p-i has revealed that drugs bind preferentially or exclusively to distinct HLA molecules (p-i HLA) or to distinct TCR (p-i TCR). P-i reactions differ from 'conventional' off-target drug reactions as the outcome is not due to the effect on the drug-modified cells themselves, but is the consequence of reactive T cells. Hence, the complex and diverse clinical manifestations of delayed-type hypersensitivity are caused by the functional heterogeneity of T cells. In the abacavir model of p-i HLA, the drug binding to HLA may result in alteration of the presenting peptides. More importantly, the drug binding to HLA generates a drug-modified HLA, which stimulates T cells directly, like an allo-HLA. In the sulfamethoxazole model of p i TCR, responsive T cells likely require costimulation for full T cell activation. These findings may explain the similarity of delayed-type hypersensitivity reactions to graft-versus-host disease, and how systemic viral infections increase the risk of delayed-type hypersensitivity reactions. PMID- 26524433 TI - Hydrogen bond mediated stabilization of the salt bridge structure for the glycine dimer anion. AB - The formation of a salt bridge in deprotonated glycine dimer anions in a solvent free environment is investigated using both infrared multiple photon dissociation spectroscopy between 600 and 1800 cm(-1) and theory. The zwitterionic and nonzwitterionic forms of glycine in this complex are computed to be nearly iso energetic, yet predominantly the zwitterionic form is observed experimentally. The zwitterion stability is attributed to both the Coulombic attraction and the high stabilization from intramolecular hydrogen bonding that drives the energetic cost of proton transfer in a solvent free environment. These results show that there is a fine balance between the stabilities of these two forms of the anion. Elucidating the role of intrinsic factors, such as hydrogen bonding, can lead to a better understanding of the stabilities of salt bridges in the interiors of large proteins or at protein interfaces. PMID- 26524434 TI - The ring-stage of Plasmodium falciparum observed in RBCs of hospitalized malaria patients. AB - Raman spectra of the blood samples obtained directly from hospitalized malaria patients with Plasmodium falciparum (P. falciparum) in the ring-stage were analyzed. Changes observed in the Raman band intensities of the infected patients compared to healthy volunteers are the result of parasite activity inside red blood cells. The obtained spectra were discussed by analyzing differences in particular spectral regions by evaluating changes in the band intensity ratios as well as using PCA analysis. The alterations of erythrocyte membranes caused by parasite penetration are visible by a reduced I1130/I1075 intensity ratio expressing the lowering of the amount of domains arranged in trans conformation. The I2930/I2850 ratio, which is a measure of modifications in structures of membrane proteins and lipids, in infected red blood cells increases, which is caused by malaria protein export to the erythrocyte membrane and expresses the membrane disarrangement. In the pyrrole ring vibration region, the nu4 band marker of the oxygenated-Hb shows at 1371 cm(-1) whereas the nu4 band at 1353 cm( 1) related to the deoxygenated-Hb is observed for malaria patients and is characterized by a higher intensity in infected erythrocytes. The amide I analysis shows the modifications in the secondary structure composition in the infected RBCs. We found that the P. falciparum infection leads to a decrease in the alpha-helical content and a concurrent increase in undefined (random-coil) structures. It was observed that the Raman spectra changes are also the result of the hemozoin formation process. In the pyrrole ring stretching vibration region, the increase of 1220 cm(-1) (deoxyHb) as against 1248 cm(-1) (oxyHb) may be considered as a signal of hemozoin formation in the RBCs. Relatively intense band patterns at 1560 cm(-1) and also at 1570 cm(-1) and 1552 cm(-1) may be due to the hemozoin that is formed according to parasite activity. The results of medical diagnostic tests had not presented changes in patient RBC parameters. A significant reduction in WBC count was noticed along with a decrease in neutrophil and platelet count when compared with the control group. Although no change is observed in the overall picture of the erythrocytes, pathological changes are evident in the Raman spectrum. PMID- 26524435 TI - Lipid Content and Barrier Function Analysis in Uraemic Pruritus. PMID- 26524436 TI - Transport of sucrose-modified nanoscale zero-valent iron in saturated porous media: role of media size, injection rate and input concentration. AB - The growing use of nanoscale zero-valent iron (NZVI) in the remediation of contaminated groundwater raises concerns regarding its transport in aquifers. Laboratory-scale sand-packed column experiments were conducted with bare and sucrose-modified NZVI (SM-NZVI) to improve our understanding of the transport of the nanoparticles in saturated porous media, as well as the role of media size, suspension injection rate and concentration on the nanoparticle behavior. As the main indicative parameters, the normalized effluent concentration was measured and the deposition rate coefficient (k) was calculated for different simulated conditions. Overall, compared to the high retention of bare NZVI in the saturated silica column, SM-NZVI suspension could travel through the coarse sand column easily. However, the transport of SM-NZVI particles was not very satisfactory in a smaller size granular matrix especially in fine silica sand. Furthermore, the value of k regularly decreased with the increasing injection rate of suspension but increased with suspension concentration, which could reflect the role of these factors in the SM-NZVI travel process. The calculation of k-value at the tests condition adequately described the experimental results from the point of deposition dynamics, which meant the assumption of first-order deposition kinetics for the transport of NZVI particles was reasonable and feasible. PMID- 26524437 TI - Integrated conceptual modelling of faecal contamination in an urban estuary catchment. AB - Urban stormwater is regarded as a key input of faecal contamination in receiving water bodies and therefore, a major concern for health risks associated with aquatic recreation. Wastewater leakages, cross connections and overflows, together with faeces washed from surfaces during rainfall events, are possible origins of faecal contamination which enter these water bodies through stormwater drains. This paper applies conceptual models to a case study of the Yarra River estuary to understand the relative importance of fluxes derived from an urban creek and the 219 urban stormwater pipes which drain directly to the estuary as compared with other inputs, such as the Yarra River itself. Existing hydrologic microorganism models were used for the estimation of the inputs from riverine and urban stormwater fluxes. These predictions were applied as boundary conditions for a new, highly simplified, model which accounts for the transport and survival of faecal microorganisms in the estuary. All models were calibrated using a rich dataset, containing over 2,000 measured Escherichia coli concentrations. Mass balances from the riverine and stormwater models indicate the limited influence of urban stormwater drains on the estuary during dry weather; less than 0.05% to 10% (5th and 95th percentile; median 0.5%) of the total daily E. coli load entering the estuary was derived from urban stormwater drains. While wet weather contributions from stormwater drains could be more significant (2% to 50%; 5th and 95th percentile), the average contribution remained marginal (median 10%). Sensitivity testing of the estuarine microorganism model by switching off stormwater boundary conditions resulted in minimal model efficiency reduction; this may reflect the low average daily contribution from urban stormwater drains. While these results confirm previous studies which show that E. coli loads derived from stormwater drains are dwarfed by other inputs, it is essential to note that these results also demonstrate that some conditions reveal the opposite; high proportions from stormwater are possible when combined with low riverine inputs and high urban rainfall. Furthermore, this study focuses on the overall impacts of direct urban stormwater inputs on the faecal contamination levels within the estuary, and localized impacts would certainly require further investigation. PMID- 26524438 TI - Occurrence and enrichment of 'bacterial sherpas': climb to sustainability in wastewater treatment. AB - The paper presents research on hemoglobin (Hb)-expressing bacteria in biological wastewater treatment systems. The outcome(s) will greatly reduce the aeration needs of wastewater treatment plants (WWTPs) and provide insight into emerging biological nitrogen removal processes using low dissolved oxygen (DO) conditions. In anthropogenic terms, the bacteria that express Hb could be considered as 'bacterial sherpas' that can function under low DO conditions. Hitherto, this functionality of bacteria has not been realized due to the initial response of the aerobic treatment stage: namely, morphology change by bacteria to filamentous forms to overcome oxygen mass transfer limitations causing bulking/foaming and nitrification inhibition. There is evidence, however, of the potential expression of Hb proteins by activated sludge (AS) bacteria. First, bacteria known to possess genes coding Hb proteins have been isolated from AS systems. Secondly, there is evidence that WWTPs are able to operate their biological processes at low DO without sludge bulking or incomplete nitrification. Our research has focused on nitrifying systems and has shown that this is due to prolonged operation at low DO conditions (0.1 mg O2/L), which allows sufficient time for bacterial acclimation. Additionally, it has been shown that enhanced Hb expression is linked to acclimation to low DO conditions. PMID- 26524439 TI - EPS production and bioremoval of heavy metals by mixed and pure bacterial cultures isolated from Ankara Stream. AB - This study is focused on isolation of Ni(II), Cu(II) and Cr(VI) resistant bacteria to assess their exopolysaccharide (EPS) production and related bioremoval capacities. Mixed cultures had higher heavy metal removal capacity in media with molasses (MAS) than the control cultures lacking this carbon (AS) containing 50 mg/l of heavy metal. The yields were 32%, 75.7%, and 51.1% in MAS, while the corresponding values were 29%, 55.1%, and 34.5% in AS, respectively. Purification of the strains 1, 5 and 6 present in the mixed cultures decreased the bioremoval capacities of the mixed culture samples, although these strains produced higher EPS amounts in MAS agar. Strain 5 had the highest Cu(II) (69.1%) and Cr(VI) (43.1%) removal rates at 25 mg/l initial concentration of each pollutant with EPS amounts of 0.74 g/l and 1.05 g/l, respectively. This strain was identified as Stenotrophomonas maltophilia. The presented data show that especially mixed and also pure cultures of bacterial strains isolated from Ankara Stream could be assessed as potential bioremoval agents in the treatment of Cu(II) or Cr(VI) containing wastewaters. PMID- 26524440 TI - Do wastewater treatment plants act as a potential point source of microplastics? Preliminary study in the coastal Gulf of Finland, Baltic Sea. AB - This study on the removal of microplastics during different wastewater treatment unit processes was carried out at Viikinmaki wastewater treatment plant (WWTP). The amount of microplastics in the influent was high, but it decreased significantly during the treatment process. The major part of the fibres were removed already in primary sedimentation whereas synthetic particles settled mostly in secondary sedimentation. Biological filtration further improved the removal. A proportion of the microplastic load also passed the treatment and was found in the effluent, entering the receiving water body. After the treatment process, an average of 4.9 (+/-1.4) fibres and 8.6 (+/-2.5) particles were found per litre of wastewater. The total textile fibre concentration in the samples collected from the surface waters in the Helsinki archipelago varied between 0.01 and 0.65 fibres per litre, while the synthetic particle concentration varied between 0.5 and 9.4 particles per litre. The average fibre concentration was 25 times higher and the particle concentration was three times higher in the effluent compared to the receiving body of water. This indicates that WWTPs may operate as a route for microplastics entering the sea. PMID- 26524441 TI - Study of the kinetics and the adsorption isotherm of cadmium(II) from aqueous solution using green algae (Ulva lactuca) biomass. AB - Batch experiments were conducted to study the adsorption of hazardous cadmium onto low-cost algae biomass in aqueous solution with respect to concentration of adsorbate, adsorbent dosage, contact time, solution pH and temperature. Langmuir and Freundlich adsorption models were applied to describe the equilibrium isotherms and the isotherm constants were determined. The activation energy of adsorption was also evaluated for the adsorption of cadmium onto Ulva lactuca biomass. Experimental data were tested in terms of biosorption kinetics using pseudo-first-order and pseudo-second-order kinetic models. The results showed that the biosorption processes of Cd(II) followed well pseudo-second-order kinetics. Langmuir and Freundlich models were applied to describe the biosorption isotherm of the metal ions by Ulva lactuca biomass. Langmuir model fitted the equilibrium data better than the Freundlich isotherm. The biosorption capacity of Ulva lactuca biomass for cadmium was found to be 3.02 mg/g at pH 5.60 min equilibrium time and 20 degrees C. The mean free energy which was calculated was 6.24 kJ/mol for Cd(II) biosorption, which shows that the adsorption is physical. The calculated thermodynamic parameters (DeltaG0, DeltaH0 and DeltaS0) showed that the biosorption of Cd(II) onto Ulva lactuca biomass was feasible, spontaneous and exothermic under examined conditions. The results indicate that algae Ulva lactuca could be employed as a low-cost material for the removal of metal ions from aqueous solution. PMID- 26524442 TI - Boosting innovation in the water sector--the role and lessons learned from collaborative projects. AB - A key worldwide challenge in most sectors is to boost the effective adoption of innovation, as underpinned by the new European Union research programme Horizon 2020, which focuses on increasing innovation in Europe from 2014 to 2020. This is particularly relevant in the water sector, often perceived as conservative and averse to change. This paper discusses the role that collaborative knowledge transfer projects can play in effectively rolling out R&D in the water industry. LNEC (Laboratorio Nacional de Engenharia Civil) has designed a structured model based on a phased programme and a network of utilities and researchers. The paper presents the core principles, the rationale, the model and methods used, and the theoretical background, as well as the project's impact, outcomes and products. The discussion highlights the lessons learnt and provides a formal analysis of the advantages of focusing on middle management as an effective entry point, even if innovation is needed across the organization. Making training materials, guidelines, use cases, data and software publicly available after the project's end has proven to have a decisive multiplying effect. The paper also argues in favour of the collaborative model as a basis for R&D sustainability, and details on-going and planned developments. PMID- 26524443 TI - An event-based hydrologic simulation model for bioretention systems. AB - Bioretention systems are designed to treat stormwater and provide attenuated drainage between storms. Bioretention has shown great potential at reducing the volume and improving the quality of stormwater. This study introduces the bioretention hydrologic model (BHM), a one-dimensional model that simulates the hydrologic response of a bioretention system over the duration of a storm event. BHM is based on the RECARGA model, but has been adapted for improved accuracy and integration of pollutant transport models. BHM contains four completely-mixed layers and accounts for evapotranspiration, overflow, exfiltration to native soils and underdrain discharge. Model results were evaluated against field data collected over 10 storm events. Simulated flows were particularly sensitive to antecedent water content and drainage parameters of bioretention soils, which were calibrated through an optimisation algorithm. Temporal disparity was observed between simulated and measured flows, which was attributed to preferential flow paths formed within the soil matrix of the field system. Modelling results suggest that soil water storage is the most important short term hydrologic process in bioretention, with exfiltration having the potential to be significant in native soils with sufficient permeability. PMID- 26524444 TI - Sludge reduction by direct addition of chlorine dioxide into a sequencing batch reactor under operational mode of repeatedly alternating aeration/non-aeration. AB - The effect of direct addition of chlorine dioxide (ClO2) into a repeatedly alternating aeration/non-aeration sequencing batch reactor (SBR) on its sludge reduction and process performance was investigated. The experimental results showed that the sludge reduction efficiency was 32.9% and the observed growth yield (Yobs) of SBR was 0.11 kg VSS (volatile suspended solids) /kg COD (chemical oxygen demand) for 80 days' operation at the optimum ClO2 dosage of 2.0 mg/g TSS (total suspended solids). It was speculated that cell lysis and cryptic growth, uncoupled metabolism and endogenous metabolism were jointly responsible for the sludge reduction in this study. COD, NH3-N, total nitrogen (TN) and total phosphorus (TP) in the effluent increased on average 29.47, 4.44, 1.97 and 0.05 mg/L, respectively. However, the effluent quality still satisfied the first-class B discharge standards for municipal wastewater treatment plants in China. In that case, the sludge maintained fine viability with the specific oxygen uptake rate (SOUR) being 14.47 mg O2/(g VSS.h) and demonstrated good settleability with the sludge volume index (SVI) being 116 mL/g. The extra cost of sludge reduction at the optimum ClO2 dosage was estimated to be 2.24 CNY (or 0.36 dollar)/kg dry sludge. PMID- 26524445 TI - Feasibility of anaerobic membrane bioreactors (AnMBR) for onsite sanitation and resource recovery (nutrients, energy and water) in urban slums. AB - Slums are challenging locations for sanitation technologies. High population densities, a lack of water and electricity infrastructure, and space constraints combine to ensure that many traditional waste treatment technologies fail when implemented in this context. This paper proposes the use of anaerobic membrane bioreactors (AnMBRs) for slum sanitation. AnMBRs allow for localized water reuse, high quality treatment, and energy production at the point of treatment. A water, energy, nutrient, and mass balance was conducted on a theoretical AnMBR directly coupled to a public toilet. The combined system would be capable of recycling its water for use in toilet flushing and would be capable of providing enough energy to power both the toilet and AnMBR operation. The addition of food waste to the feed would help to ensure process stability and energy production by the AnMBR. Ammonia accumulation within the system would have to be managed through struvite precipitation, ion exchange, oxidation, plant uptake or other means. Generated biogas can be converted into heat and/or electricity using small scale gas generators. AnMBR technology has high potential for success in slum settings, if considerations for maintenance and supplies are made as part of the design and system delivery. PMID- 26524446 TI - Remediation of phenanthrene contaminated soils by nonionic-anionic surfactant washing coupled with activated carbon adsorption. AB - Batch experiments were conducted to investigate the performance of nonionic anionic mixed surfactants and their recovery through activated carbon. The solubilization capabilities of mixed surfactants toward phenanthrene (PHE) were reduced by addition of anionic surfactant to the mixed systems. Results showed that sorption of Triton X-100 (TX100) onto soil decreased with increasing mass fraction of sodium dodecyl sulfate (SDS) in the mixed surfactant solutions. Soil contaminated with PHE at 200 mg/kg was washed with different surfactant concentrations at various mass ratios of nonionic-anionic mixed surfactant. Experiments with low-concentrations of mixed surfactants revealed that removal efficiencies for PHE-contaminated soil close to the individual higher nonionic surfactant concentration can be achieved. Overall performance considering both soil washing and surfactant recovery steps is apposite when an TX100:SDS mass ratio of 8:2 at 3 g/L is used. PMID- 26524447 TI - Role of ferric and ferrous ions in the enhancement of the heterogeneous solar photocatalytic degradation of combined mixture of chlorophenols. AB - The solar photocatalytic degradation of 4-chlorophenol (4-CP) and 2,4 dichlorophenol (2,4-DCP) was investigated individually and combined in the presence of Fe2+ and Fe3+ ions. The results revealed that both Fe2+ and Fe3+ ions enhanced the heterogeneous photocatalytic degradation. Fe3+ ions rapidly converted to Fe2+ ions as soon as the irradiation started. The intermediates formed during the degradation of 4-CP/2,4-DCP were also monitored and identified. Three main intermediates were observed, hydroquinone, phenol, and 4 chlorocatechol with traces of benzoquinone. The results support a new trend of research by utilising other cheap iron ion sources in the photocatalytic degradation. PMID- 26524448 TI - Extremely fast increase in the organic loading rate during the co-digestion of rapeseed oil and sewage sludge in a CSTR--characterization of granules formed due to CaO addition to maintain process stability. AB - In a co-digestion system running with rapeseed oil and sewage sludge, an extremely fast increase in the organic loading rate was studied to develop a procedure to allow for flexible and demand-driven energy production. The over acidification of the digestate was successfully prevented by calcium oxide dosage, which resulted in granule formation. Mineralogical analyses revealed that the granules were composed of insoluble salts of long chain fatty acids and calcium and had a porous structure. Long chain fatty acids and calcium formed the outer cover of granules and offered interfaces on the inside thereby enhancing the growth of biofilms. With granule size and age, the pore size increased and indicated degradation of granular interfaces. A stable biogas production up to the organic loading rate of 10.4 kg volatile solids m(-3) d(-1) was achieved although the hydrogen concentration was not favorable for propionic acid degradation. However, at higher organic loading rates, unbalanced granule formation and degradation were observed. Obviously, the adaption time for biofilm growth was too short to maintain the balance, thereby resulting in a low methane yield. PMID- 26524449 TI - Application of XCMS Online and toxicity bioassays to the study of transformation products of levofloxacin. AB - We studied the nature and antimicrobial activity of ozonolysis transformation products (OTPs) of levofloxacin (LEV), a frequently detected fluoroquinolone antimicrobial in environmental waters. Two bioassays, the Kirby-Bauer test and the broth microdilution assay, were used to measure changes in the antimicrobial activity of solutions at low LEV to O3 molar ratios (2:1, 2:3 and 1:3) compared to solutions without added O3 (LEV:O3 1:0). The Kirby-Bauer test was not sensitive enough to detect significant differences in the growth inhibition zones in samples LEV:O3 2:1 and LEV:O3 1:0; however, the broth microdilution assay showed that bacterial growth inhibition was significantly lower (P<0.001) in the solutions exposed to O3. Loss of antimicrobial activity in LEV:O3 2:1 solutions of (48+/-16)% was in agreement with the concentration decrease of LEV of (36+/ 3)% in those same samples. A method of identification of OTPs using XCMS Online was applied to LEV:O3 2:1 and 1:0 samples and indicated the presence of an OTP of LEV of formula C18H20O5N3F, which was identified as LEV-N-oxide. The molecular structure of this compound was partially confirmed by tandem mass spectrometry experiments. This study showed that even at sub-optimal ozone doses, OTPs of higher antimicrobial activity than LEV were not formed. PMID- 26524450 TI - Research on the treatment of oily wastewater by coalescence technology. AB - Recently, oily wastewater treatment has become a hot research topic across the world. Among the common methods for oily wastewater treatment, coalescence is one of the most promising technologies because of its high efficiency, easy operation, smaller land coverage, and lower investment and operational costs. In this research, a new type of ceramic filter material was chosen to investigate the effects of some key factors including particle size of coarse-grained materials, temperature, inflow direction and inflow velocity of the reactor. The aim was to explore the optimum operating conditions for coarse-graining. Results of a series of tests showed that the optimum operating conditions were a combination of grain size 1-3 mm, water temperature 35 degrees C and up-flow velocity 8 m/h, which promised a maximum oil removal efficiency of 93%. PMID- 26524451 TI - Synthesis of porous sulfonated carbon as a potential adsorbent for phenol wastewater. AB - The work reports a facile synthesis procedure for preparation of porous sulfonated carbons and its suitability for adsorption of phenol. The sulfonated carbon was synthesized utilizing a simplified, single-step, shorter duration process by sulfonation, dehydration and carbonization of sucrose in sulfuric acid and tetraethylorthosilicate. The surface and internal structures of the adsorbents were characterized utilizing various characterization techniques to understand the porous nature and surface functional groups of the porous matrix. Adsorption capacity was found to be highest for the sample heat treated at 600 degrees C, with the maximum adsorption capacity of 440 mg/g at 30 degrees C. The adsorption isotherms were tested with the Freundlich and Langmuir adsorption isotherms models to identify the appropriate adsorption mechanism. PMID- 26524452 TI - Development of a simplified model for the fixed biofilm reactor. AB - A simplified fixed biofilm model was developed to formulate the relationship between the substrate concentrations at both the entry and exit, at the biofilm liquid interface and at the biofilm attached surface along with average substrate flux in the biofilm, substrate flux at the biofilm-liquid interface and effective biofilm thickness. The model considered the substrate mass transport external to the biofilm and into the biofilm as per Fick's law and the steady state substrate as well as biomass balance for attached growth microorganisms. Monod's growth kinetics has been adopted in substrate utilization, incorporating relevant boundary conditions. The numerical solution of model equations was accomplished for calculating average flux and exit substrate concentration and thereafter the Runge-Kutta method was employed for determining effective biofilm thickness. Consequently, two computer programs were developed for the purpose of rapid solution. The model was satisfactorily applied to data available from the literature for checking its accuracy and was validated with the experimental results. The model was found to be an easy, accurate and fast method that can be used for process design of a fixed biofilm reactor. PMID- 26524453 TI - Performance of chlorination process during nanofiltration of sulfonamide antibiotic. AB - The effectiveness of combined nanofiltration and disinfection processes was studied by comparing the pre-disinfection and post-disinfection when in combination with nanofiltration. Four types of sulfonamide (sulfanilamide, sulfadiazine, sulfamethoxazole, and sulfadimethoxine) were chosen as substrates, with sodium hypochlorite as a disinfectant. A laboratory-scale nanofiltration system was used to conduct the following sets of experiment: (1) a pre chlorination system, where the free active chlorine (FAC) was added to the membrane influent; and (2), a post-chlorination system, where the FAC was added to the membrane effluent. Overall, the pre-disinfection nanofiltration system showed higher sulfonamide removal efficiency compared to the post-chlorination nanofiltration system (>99.5% versus >89.5%). In the case of limited FAC ([FAC]0: [sulfonamide]0<=1), the removal efficiency for the post-chlorination nanofiltration system was higher, due to the prior nanofiltration process that could remove 12.5% to 80% of sulfonamide. The flux of the treated feed system was considerably higher than in the untreated feed system; however, the membrane was observed to be slightly damaged due to residual chlorine attack. PMID- 26524454 TI - Contrasting suspended covers reveal the impact of an artificial monolayer on heat transfer processes at the interfacial boundary layer. AB - The highly variable performance of artificial monolayers in reducing evaporation from water storages has been attributed to wind speed and wave turbulence. Other factors operating at the interfacial boundary layer have seldom been considered. In this paper, two physical shade covers differing in porosity and reflectivity were suspended over 10 m diameter water tanks to attenuate wind and wave turbulence. The monolayer octadecanol was applied to one of the covered tanks, and micrometeorological conditions above and below the covers were monitored to characterise diurnal variation in the energy balance. A high downward (air-to water) convective heat flux developed under the black cover during the day, whereas diurnal variation in the heat flux under the more reflective, wind permeable white cover was much less. Hourly air and water temperature profiles under the covers over 3 days when forced convection was minimal (low wind speed) were selected for analysis. Monolayer application reduced temperature gain in surface water under a downward convective heat flux, and conversely reduced temperature loss under an upward convective heat flux. This 'dual property' may explain why repeat application of an artificial monolayer to retard evaporative loss (reducing latent heat loss) does not inevitably increase water temperature. PMID- 26524455 TI - Investigation into cyclic utilization of carbon source in an advanced sludge reduction, inorganic solids separation, phosphorus recovery, and enhanced nutrient removal (SIPER) wastewater treatment process. AB - An advanced wastewater treatment process (SIPER) was developed to simultaneously reduce sludge production, prevent the accumulation of inorganic solids, recover phosphorus, and enhance nutrient removal. The ability to recover organic substance from excess sludge to enhance nutrient removal (especially nitrogen) and its performance as a C-source were evaluated in this study. The chemical oxygen demand/total nitrogen (COD/TN) and volatile fatty acids/total phosphorus (VFA/TP) ratios for the supernatant of the alkaline-treated sludge were 3.1 times and 2.7 times those of the influent, respectively. The biodegradability of the supernatant was much better than that of the influent. The system COD was increased by 91 mg/L, and nitrogen removal was improved by 19.6% (the removal rate for TN reached 80.4%) after the return of the alkaline-treated sludge as an internal C-source. The C-source recovered from the excess sludge was successfully used to enhance nitrogen removal. The internal C-source contributed 24.1% of the total C-source, and the cyclic utilization of the system C-source was achieved by recirculation of alkaline-treated sludge in the sludge reduction, inorganic solids separation, phosphorus recovery (SIPER) process. PMID- 26524456 TI - Municipal wastewater reclamation for non-potable reuse--environmental assessments based on pilot-plant studies and system modelling. AB - Wastewater reclamation is an upcoming approach that will significantly affect wastewater treatment systems. Despite the fact that technology for treating wastewater to an effluent water quality that meets various quality standards for reuse is already available and applied, the reuse of water is not just a simple and straightforward road. Significant additional energy and civil infrastructure is required to treat the water to a standard that allows it to be safely reused. The total impact of treating and reusing water may be higher than the environmental benefits. Thus, it is crucial the life-cycle impacts from upstream and downstream processes of various reuse technologies, i.e. production of chemicals, energy use, eutrophication, sludge handling, etc. The present paper provides a comprehensive evaluation considering different reuse purposes, treatment technologies and plant size. The results of this study suggest that all these factors are highly significant for the environmental impact of wastewater treatment systems for non-potable applications. PMID- 26524457 TI - Sulfidogenesis interference on methane production from carbohydrate-rich wastewater. AB - Two anaerobic fixed-structured bed reactors were fed with synthetic wastewater simulating the soluble fraction of sugarcane vinasse to evaluate the interference of sulfidogenesis on methanogenesis. The reactors running in parallel were subjected to the same operating conditions. The influent organic matter concentration (in term of chemical oxygen demand (COD)) remained close to 4,000 mgCOD L(-1) and the hydraulic retention time was 24 hours. One reactor, the methanogenic (control reactor), received sulfate only to provide the sulfur required as a nutrient to the methanogenic biomass. The other one, the sulfidogenic/methanogenic reactor (SMR), received sulfate concentration corresponding to COD/sulfate ratios of 4, 5 and 3. In the last phase, the COD removal efficiencies were higher than 96% in both reactors and the SMR achieved 97% of sulfate removal efficiency (COD/sulfate ratio of 3 and influent sulfate concentration close to 1,300 mgSO4(2-) L(-1)). Both reactors also had similar methane yields in this phase, close to 350 mLCH4 gCODremoved(-1) at standard temperature and pressure. These results indicated no significant inhibition of methanogenic activity under the sulfidogenic conditions assessed. PMID- 26524458 TI - Effect of continuously dosing Cu(II) on pollutant removal and soluble microbial products in a sequencing batch reactor. AB - The effects of synthetic wastewater that contained 20 mg/L Cu(II) on the removal of organic pollutants in a sequencing batch reactor were investigated. Results of continuous 20 mg/L Cu(II) exposure for 120 days demonstrated that the chemical oxygen demand (COD) removal efficiency decreased to 42% initially, followed by a subsequent gradual recovery, which peaked at 78% by day 97. Effluent volatile fatty acid (VFA) concentration contributed 67 to 89% of the influent COD in the experimental reactor, which indicated that the degradation of the organic substances ceased at the VFA production step. Meanwhile, the varieties of soluble microbial products (SMP) content and main components (protein, polysaccharide, and DNA) were discussed to reveal the response of activated sludge to the toxicity of 20 mg/L Cu(II). The determination of Cu(II) concentrations in extracellular polymeric substances (EPS) and SMP throughout the experiment indicated an inverse relationship between extracellular Cu(II) concentration and COD removal efficiency. PMID- 26524459 TI - Bioremediation of heavy metal contaminated aqueous solution by using red algae Porphyra leucosticta. AB - Bioremediation is an effective process for the removal and recovery of heavy metal ions from aqueous solutions. In this study, red algae Porphyra leucosticta was examined to remove Cd(II) and Pb(II) ions from wastewater through biological enrichment and biological precipitation. The experimental parameters that affect the bioremediation process such as pH, contact time and biomass dosage were studied. The maximum bioremediation capacity of metal ions was 31.45 mg/g for Cd(II) and 36.63 mg/g for Pb(II) at biomass dosage 15 g/L, pH 8.0 and contact time 120 minutes containing initial 10.0 mg/L of Cd(II) and 10.0 mg/L of Pb(II) solution. Red algae Porphyra leucosticta biomass was efficient at removing metal ions of 10.0 mg/L of Cd(II) and 10.0 mg/L of Pb(II) solution with bioremediation efficiency of 70% for Cd(II) and 90% for Pb(II) in optimal conditions. At the same time, the removal capacity for real industrial effluent was gained at 75% for 7.6 mg/L Cd(II) and 95% for 8.9 mg/L Pb(II). In conclusion, it is demonstrated that red algae Porphyra leucosticta is a promising, efficient, cheap and biodegradable sorbent biomaterial for reducing heavy metal pollution in the environment and wastewater. PMID- 26524460 TI - Heterogeneity of the environmental regulation of industrial wastewater: European wineries. AB - The European legislation of the pollution of industrial wastewater shows a high degree of heterogeneity. This fact implies that there is a market failure with relevant consequences. Within the European Union, each Member State performs a specific transposition of the Water Framework Directive 2000/60. The member states introduce different sanitation fees to correct water pollution. In this paper, the case of the European wine industry is analyzed. It studies the sanitation fees of the five major wine producing countries: France, Italy, Spain, Germany and Portugal. Results show significant differences among the wastewater fees and the study reveals how such heterogeneity leads to relevant market distortions. The research concludes that more homogeneous environmental regulation would promote more sustainable wine production processes with more efficient water management and purification systems, as well as the introduction of cutting edge technologies. PMID- 26524461 TI - Getting Serious About Reducing Suicide: More "How" and Less "Why". PMID- 26524463 TI - General Photoinduced Sequential Electrocyclization/[1,9]-Sigmatropic Rearrangement/Ring-Opening Reaction of Diarylethenes. AB - A novel and efficient photochemical transformation of diarylethenes comprising a five-membered heterocyclic ring and phenyl moiety is described. This reaction provides a simple method for the preparation of functionalized naphthalene derivatives via photorearrangement reaction of diarylethenes, and the process is characterized by high efficiency that was determined by NMR monitoring. Some mechanistic aspects of this process have been also explored. It was found that the reaction includes tandem transformation of three basic processes: the photocyclization of the hexatriene system, [1,9]-sigmatropic rearrangement, and heterocyclic ring opening. Diarylethenes with different heterocycle moieties (thiophene, benzo[b]thiophene, furan, indole, imidazole, thiazole, oxazole, pyrazole) have been involved into this process, and the target naphthalenes with good yields have been obtained. The opportunity for use in the transformation of diarylethenes with different heterocyclic residues permits synthesis of naphthalenes with desired functional groups. The general character and high efficiency of the reaction promise that the transformation can be an effective synthetic route for the annulation of benzene rings to various aromatic systems, including heterocycles. PMID- 26524462 TI - CXCL4 Plasma Levels Are Not Associated with the Extent of Coronary Artery Disease or with Coronary Plaque Morphology. AB - BACKGROUND: CXCL4 is a platelet chemokine released at micromolar concentrations upon platelet activation. CXCL4 has been shown to promote atherogenesis by various mechanisms. However, data on CXCL4 plasma levels in patients with coronary artery disease are largely inconclusive. Computed coronary artery angiography (CCTA) represents an excellent tool to quantify and characterize coronary atherosclerotic plaques. We hypothesized that increased CXCL4 plasma levels may be associated with features of plaque instability resulting in adverse cardiovascular events. Specifically, we sought to determine whether CXCL4 levels are correlated with specific features of coronary artery disease including (1) plaque volume, (2) calcium score, (3) degree of stenosis, or (4) vascular remodeling. METHODS AND RESULTS: CXCL4 plasma levels were measured by ELISA in 217 patients undergoing CCTA for suspected CAD (mean age 64.2 +/- 9.4 years, 107 (49.3%) male). Mean CXCL4 plasma levels were 12.5 +/- 4.6 ng/mL. There was no significant correlation between CXCL4 levels and any clinical or demographic parameters including cardiovascular risk factors. CXCL4 plasma levels did not differ between patient with or without coronary artery disease (CAD: 12.5 +/- 4.5 ng/ml, no CAD: 12.5 +/- 4.8 ng/ml). Neither univariate nor multivariate analysis showed an association between CXCL4 levels and plaque volume, total calcium score, degree of stenosis, or vascular remodeling. Subgroup analysis of patients with CAD as confirmed by CCTA did not show any association of CXCL4 levels with the extent of CAD. CONCLUSIONS: While CXCL4 may be present and active within the arterial wall, local increase of CXCL4 may not translate into systemically elevated CXCL4 levels. Further studies will have to test whether CXCL4 may still represent a suitable therapeutic target in human atherosclerosis. PMID- 26524464 TI - Preparation of fluoro-functionalized graphene oxide via the Hunsdiecker reaction. AB - We report our effort in the development of a new synthetic method for fluoro functionalized graphene oxide, which was prepared via the Hunsdiecker reaction, and the treatment of carboxylated graphene oxide with selectfluor at 90 degrees C for 10 h under an atmosphere of nitrogen, using silver nitrate as a catalyst. PMID- 26524465 TI - Marching along to an Offbeat Drum: Entrainment of Synthetic Gene Oscillators by a Noisy Stimulus. AB - Modulation of biological oscillations by stimuli lies at the root of many phenomena, including maintenance of circadian rhythms, propagation of neural signals, and somitogenesis. While it is well established that regular periodic modulation can entrain an oscillator, an aperiodic (noisy) modulation can also robustly entrain oscillations. This latter scenario may describe, for instance, the effect of irregular weather patterns on circadian rhythms, or why irregular neural stimuli can still reliably transmit information. A synthetic gene oscillator approach has already proven to be useful in understanding the entrainment of biological oscillators by periodic signaling, mimicking the entrainment of a number of noisy oscillating systems. We similarly seek to use synthetic biology as a platform to understand how aperiodic signals can strongly correlate the behavior of cells. This study should lead to a deeper understanding of how fluctuations in our environment and even within our body may promote substantial synchrony among our cells. Specifically, we investigate experimentally and theoretically the entrainment of a synthetic gene oscillator in E. coli by a noisy stimulus. This phenomenon was experimentally studied and verified by a combination of microfluidics and microscopy using the real synthetic circuit. Stochastic simulation of an associated model further supports that the synthetic gene oscillator can be strongly entrained by aperiodic signals, especially telegraph noise. Finally, widespread applicability of aperiodic entrainment beyond the synthetic gene oscillator is supported by results derived from both a model for a natural oscillator in D. discoideum and a model for predator-prey oscillations. PMID- 26524466 TI - Theoretical Investigation of the Adsorption Properties of CO, NO, and OH on Monometallic and Bimetallic 13-Atom Clusters: The Example of Cu13, Pt7Cu6, and Pt13. AB - We report a density functional theory investigation of the adsorption properties of CO, NO, and OH on the Cu13, Pt7Cu6, and Pt13 clusters in the cationic, neutral, and anionic states with the aim to improve our atomistic understanding of the adsorption properties on bimetallic clusters compared with monometallic clusters. The adsorption energy of CO and NO are substantially stronger on Pt13 than on Cu13, and hence, CO and NO bind preferentially on Pt sites on Pt7Cu6. Thus, it can contribute to drive the migration of the Pt atoms from the core to the surface region in large PtCu nanoalloys. The CO and NO adsorption energies on the bimetallic cluster are enhanced by a few percent compared with the energies of the monometallic clusters, which shows that the Pt-Cu interaction can contribute to an increase in the adsorption energy. In contrast with CO and NO trends, the OH adsorption energies on Cu13, Pt7Cu6, and Pt13 deviates only up to 0.31 eV, and hence, there is no clear preference for Cu or Pt sites on Pt7Cu6 or an enhancement of the adsorption energy on the bimetallic systems. We found a reduction of the CO and NO vibrational frequencies upon adsorption, which indicates a weakening of the CO and NO binding energies, and it is supported by a slight increase in the bond lengths. However, the OH vibrational frequency increases upon adsorption, which indicates an enhancement of the OH binding energy, which is supported by a slight decrease in the bond length by about 0.01 A. It can be explained by the large charge transfer from the clusters to the O atom, which enhances the electrostatic interaction in the O-H bonding. PMID- 26524468 TI - New and improved AAVenues: current status of hemophilia B gene therapy. AB - INTRODUCTION: Hemophilia B is a sex linked, monogenic, coagulation disorder caused by a deficiency in functional factor IX protein. Gene therapy for this disorder via systemic administration of an adeno-associated virus (AAV) encoding an optimized factor IX construct has shown considerable success, ameliorating the bleeding phenotype in a number of patients. However challenges to sustained curative gene transfer in this patient population remain, and as such there are efforts in the field to improve long term factor IX expression, via optimisations to the AAV vector, transgene cassette and correction strategy. AREAS COVERED: In this article we review the current state of AAV mediated gene therapy for hemophilia B in the clinic, detail progress since the first successful trial, and discuss alternative approaches from the AAV gene therapy field. EXPERT OPINION: AAV mediated gene therapy for hemophilia B is safe and efficacious; however, to achieve gene therapy success on a global scale, improvements to large scale production and alternative AAV serotype approaches need to be designed. With the current means of AAV gene therapy treatment entering the market concomitantly with the advent of long half-life clotting factor products, the quality of life for hemophilia patients worldwide is likely to improve significantly. PMID- 26524467 TI - Study on Post-Treatment Relapse in HBeAg Positive CHB Patients. AB - BACKGROUND: Many factors are associated with post-treatment relapse in CHB patients, and there are no effective factors to predict relapse. In this study, we investigate the influence factors associated with post-treatment relapse and their predictive value in HBeAg positive CHB (eP-CHB). METHODS: The factors associated with post-treatment relapse were analyzed firstly by a retrospective study in eP-CHB. Variables included age, sex, regimen, baseline HBeAg and HBV DNA level, total course of treatment as well as duration of consolidation therapy after HBeAg seroconversion. The predictive effects of the influence factors were evaluated in an eP-CHB prospective cohort. RESULTS: 89 patients were enrolled in the retrospective study, 42(47.2%) relapsed after discontinuation of treatment. Factors related to post-treatment relapse were total course of treatment, duration of consolidation therapy and baseline HBV DNA level. Relapse rates in patients with total course >36 months, consolidation duration >12 months and baseline HBV DNA level < 1.0E+5IU/ml were lower than those of total course <24 months (P = 0.002), consolidation duration<=12 months (P = 0.011) and baseline HBV DNA level > 1.0E+7IU/ml (P = 0.01) respectively. Patients with HBV DNA>=1.0E+7IU/ml plus HBeAg<200COI at baseline had the highest relapse rate and cumulative relapse rate than the other three arms (P = 0.048 and 0.008 respectively). Logistic regression analysis demonstrated that baseline HBV DNA level, duration of consolidation therapy and combination of baseline HBV DNA and HBeAg (IgDNA/IgHBeAg) were independent factors to predict post-treatment relapse. The model based on baseline IgDNA/IgHBeAg and consolidation duration worked well in predicting post-treatment relapse in the prospective study and the accuracy, specificity, sensitivity, PPV and NPV for prediction were 80.3%, 81.1%, 79.2%, 73.1% and 85.7% respectively. CONCLUSIONS: Virological factors including baseline HBV DNA, HBeAg and treatment course were major influence factors associated with post-treatment relapse in eP-CHB. Patients with higher HBV DNA and lower HBeAg levels at baseline, shorter total course as well as consolidation therapy were more likely to develop relapse after discontinuation of therapy. The antiviral therapy in eP-CHB patients should be individually managed at different levels. It is better to treat those with higher viral load and lower HBeAg levels at baseline for a longer course, especially longer consolidation duration so as to decrease the relapse rate. PMID- 26524469 TI - Ultrafast Dynamic Piezoresistive Response of Graphene-Based Cellular Elastomers. AB - Ultralight graphene-based cellular elastomers are found to exhibit nearly frequency-independent piezoresistive behaviors. Surpassing the mechanoreceptors in the human skin, these graphene elastomers can provide an instantaneous and high-fidelity electrical response to dynamic pressures ranging from quasi-static up to 2000 Hz, and are capable of detecting ultralow pressures as small as 0.082 Pa. PMID- 26524470 TI - Mechanistic modeling of enzymatic hydrolysis of cellulose integrating substrate morphology and cocktail composition. AB - A mechanistic model of enzymatic hydrolysis taking into account the morphology of the cellulosic particles and its evolution with time was developed. The individual behavior of the main enzymes involved in the reaction (cellobiohydrolases, endoglucanases, and beta-glucosidases), as well as synergy effects, were also included. A large panel of experimental tests was done to fit and validate the model. This database included different enzymes mixtures and operating conditions and allowed to determine and compare with accuracy the adsorption and kinetic parameters of the different enzymes. Model predictions on short hydrolysis times were very satisfactory. On longer times, a deactivation constant was added to represent the hydrolysis slowdown. The model also allowed to predict the impact of enzymes ratios and initial substrate parameters (chain length distribution, polymerization degree) on hydrolysis, and to follow the evolution of these parameters with time. This model revealed general trends on the impact of cellulose morphology on hydrolysis. It is a useful tool to better understand the mechanisms involved in enzymatic hydrolysis of cellulose and to determine optimal cellulolytic cocktails for process design. PMID- 26524471 TI - Edging along a Warming Coast: A Range Extension for a Common Sandy Beach Crab. AB - Determining the position of range edges is the first step in developing an understanding of the ecological and evolutionary dynamics in play as species' ranges shift in response to climate change. Here, we study the leading (poleward) range edge of Ocypode cordimanus, a ghost crab that is common along the central to northern east coast of Australia. Our study establishes the poleward range edge of adults of this species to be at Merimbula (36.90 degrees S, 149.93 degrees E), 270 km (along the coast) south of the previous southernmost museum record. We also establish that dispersal of pelagic larvae results in recruitment to beaches 248 km (along the coast; 0.9 degrees of latitude) beyond the adult range edge we have documented here. Although we cannot conclusively demonstrate that the leading range edge for this species has moved polewards in response to climate change, this range edge does fall within a "hotspot" of ocean warming, where surface isotherms are moving southwards along the coast at 20-50 km.decade 1; coastal air temperatures in the region are also warming. If these patterns persist, future range extensions could be anticipated. On the basis of their ecology, allied with their occupancy of ocean beaches, which are home to taxa that are particularly amenable to climate-change studies, we propose that ghost crabs like O. cordimanus represent ideal model organisms with which to study ecological and evolutionary processes associated with climate change. The fact that "hotspots" of ocean warming on four other continents correspond with poleward range edges of ghost crab species suggests that results of hypothesis tests could be generalized, yielding excellent opportunities to rapidly progress knowledge in this field. PMID- 26524473 TI - Self-Size-Limiting Nanoscale Perforation of Graphene for Dense Heteroatom Doping. AB - A scalable and controllable nanoscale perforation method for graphene is developed on the basis of the two-step thermal activation of a graphene aerogel. Different resistance to the thermal oxidation between graphitic and defective domains in the weakly reduced graphene oxide is exploited for the self-limiting nanoscale perforation in the graphene basal plane via selective thermal degradation of the defective domains. The resultant nanoporous graphene with a narrow pore-size distribution addresses the long-standing challenge for the high level doping of graphene with lattice-mismatched large-size heteroatoms (S and P). Noticeably, this novel heteroatom doping strategy is demonstrated to be highly effective for oxygen reduction reaction (ORR) catalysis. Not only the higher level of heteroatom doping but also favorable spin and charge redistribution around the pore edges leads to a strong ORR activity as supported by density functional theory calculations. PMID- 26524472 TI - Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy MU-Opioid Receptor (MOR) Agonists/delta-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities. AB - In a previously described peptidomimetic series, we reported the development of bifunctional MU-opioid receptor (MOR) agonist and delta-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the kappa-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h. PMID- 26524474 TI - Haloperidol for the treatment of nausea and vomiting in palliative care patients. AB - BACKGROUND: Nausea and vomiting are common symptoms in patients with terminal, incurable illnesses. Both nausea and vomiting can be distressing. Haloperidol is commonly prescribed to relieve these symptoms. This is an updated version of the original Cochrane review published in Issue 2, 2009, of Haloperidol for the treatment of nausea and vomiting in palliative care patients. OBJECTIVES: To evaluate the efficacy and adverse events associated with the use of haloperidol for the treatment of nausea and vomiting in palliative care patients. SEARCH METHODS: For this updated review, we performed updated searches of CENTRAL, EMBASE and MEDLINE in November 2013 and in November 2014. We searched controlled trials registers in March 2015 to identify any ongoing or unpublished trials. We imposed no language restrictions. For the original review, we performed database searching in August 2007, including CENTRAL, MEDLINE, EMBASE, CINAHL and AMED, using relevant search terms and synonyms. Handsearching complemented the electronic searches (using reference lists of included studies, relevant chapters and review articles) for the original review. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) of haloperidol for the treatment of nausea or vomiting, or both, in any setting, for inclusion. The studies had to be conducted with adults receiving palliative care or suffering from an incurable progressive medical condition. We excluded studies where nausea or vomiting, or both, were thought to be secondary to pregnancy or surgery. DATA COLLECTION AND ANALYSIS: We imported records from each of the electronic databases into a bibliographic package and merged them into a core database where we inspected titles, keywords and abstracts for relevance. If it was not possible to accept or reject an abstract with certainty, we obtained the full text of the article for further evaluation. The two review authors independently assessed studies in accordance with the inclusion criteria. There were no differences in opinion between the authors with regard to the assessment of studies. MAIN RESULTS: We considered 27 studies from the 2007 search. In this update we considered a further 38 studies from the 2013 search, and two in the 2014 search. We identified one RCT of moderate quality with low risk of bias overall which met the inclusion criteria for this update, comparing ABH (Ativan(r), Benadryl(r), Haldol(r)) gel, applied to the wrist, with placebo for the relief of nausea in 22 participants. ABH gel includes haloperidol as well as diphenhydramine and lorazepam. The gel was not significantly better than placebo in this small study; however haloperidol is reported not to be absorbed significantly when applied topically, therefore the trial does not address the issue of whether haloperidol is effective or well tolerated when administered by other routes (e.g. by mouth, subcutaneously or intravenously). We identified one ongoing trial of haloperidol for the management of nausea and vomiting in patients with cancer, with initial results published in a conference abstract suggesting that haloperidol is effective for 65% of patients. The trial had not been fully published at the time of our review. A further trial has opened, comparing oral haloperidol with oral methotrimeprazine (levomepromazine) for patients with cancer and nausea unrelated to their treatment, which we aim to include in the next review update. AUTHORS' CONCLUSIONS: Since the last version of this review, we found one new study for inclusion but the conclusion remains unchanged. There is incomplete evidence from published RCTs to determine the effectiveness of haloperidol for nausea and vomiting in palliative care. Other than the trial of ABH gel vs placebo, we did not identify any fully published RCTs exploring the effectiveness of haloperidol for nausea and vomiting in palliative care patients for this update, but two trials are underway. PMID- 26524475 TI - Enough is enough: Adequacy of voided urine cytology. PMID- 26524477 TI - Retraction: Altered affective, executive and sensorimotor resting state networks in patients with pediatric mania. PMID- 26524476 TI - A new look at the genetic and environmental coherence of metabolic syndrome components. AB - OBJECTIVE: Metabolic syndrome, a clustering of risk factors including insulin resistance, dyslipidemia, central obesity, and hypertension, increases risk for cardiovascular disease and cognitive decline. The etiology of the risk factors' cohesion remains unclear. How genetic and environmental influences explained co occurrence of metabolic syndrome components was examined. METHODS: Continuous measures of body mass index (BMI), waist circumference, blood pressure (BP), fasting insulin and glucose, high-density lipoprotein cholesterol (HDL), and triglycerides from 1,193 middle-aged twin men participating in the Vietnam Era Twin Study of Aging at average age 62 (range 56-67) were analyzed using multivariate biometrical modeling. RESULTS: Four heritable factors were found: adiposity (BMI, waist circumference), insulin resistance (glucose, insulin), lipids (HDL, triglycerides), and BP (systolic, diastolic). Heritabilities were 0.42-0.68. In the best-fitting model, insulin resistance, lipids, and adiposity comprised a higher-order latent genetic factor. Adiposity and BP shared genetic influences independent of the latent genetic factor. All factors aggregated on a latent unique environmental factor. CONCLUSIONS: Metabolic syndrome components form the equivalent of two genetic factors. BP was genetically unrelated to insulin resistance and lipids. Adiposity was the only characteristic genetically and environmentally related to all other factors. These results inform strategies for gene discovery and prediction of health outcomes. PMID- 26524478 TI - Self-disseminating vaccines for emerging infectious diseases. AB - Modern human activity fueled by economic development is profoundly altering our relationship with microorganisms. This altered interaction with microbes is believed to be the major driving force behind the increased rate of emerging infectious diseases from animals. The spate of recent infectious disease outbreaks, including Ebola virus disease and Middle East respiratory syndrome, emphasize the need for development of new innovative tools to manage these emerging diseases. Disseminating vaccines are one such novel approach to potentially interrupt animal to human (zoonotic) transmission of these pathogens. PMID- 26524479 TI - Efficacy of outpatient continuous terlipressin infusions for hepatorenal syndrome. PMID- 26524480 TI - Long-Term Survival of Dental Implants with Different Prosthetic Loading Times in Healthy Patients: A 5-Year Retrospective Clinical Study. AB - PURPOSE: To compare survival rates among dental implants restored with immediate, early, and conventional loading protocols, also comparing between maxillary and mandibular implants, and to evaluate the influence of implant length and diameter and the type of prosthesis on treatment outcomes. MATERIALS AND METHODS: This retrospective cohort study initially included all 52 patients receiving dental implants between July 2006 and February 2008 at a private oral surgery clinic in Granada (Southern Spain). Clinical and radiographic examinations were performed, including periapical or panoramic radiographs, and incidences during completion of the restoration were recorded at 1 week, 3 months, 6 months, and at 1, 2, 3, 4, and 5 years. After a 5-year follow-up, 1 patient had died, 3 were lost to follow-up, and 6 required grafting before implant placement; therefore, the final study sample comprised 42 patients with 164 implants. RESULTS: Variables associated with the survival/failure of the restoration were: number of implants (higher failure rate with fewer implants), bone type (higher failure rate in type III or IV bone), and type of prosthesis (higher failure rate with single crowns). No significant association was found in univariate or multivariate analyses between survival rate and the loading protocol, implant length or diameter, or maxillary/mandibular location. CONCLUSIONS: Immediate occlusal loading, immediate provisionalization without occlusal loading, and early loading are viable treatment options with similar survival rates to those obtained with conventional loading. Bone quality and number of implants per patient were the most influential factors. PMID- 26524481 TI - Taming the Reactivity of Glycosyl Iodides To Achieve Stereoselective Glycosidation. AB - Although glycosyl iodides have been known for more than 100 years, it was not until the 21st century that their full potential began to be harnessed for complex glycoconjugate synthesis. Mechanistic studies in the late 1990s probed glycosyl iodide formation by NMR spectroscopy and revealed important reactivity features embedded in protecting-group stereoelectronics. Differentially protected sugars having an anomeric acetate were reacted with trimethylsilyl iodide (TMSI) to generate the glycosyl iodides. In the absence of C-2 participation, generation of the glycosyl iodide proceeded by inversion of the starting anomeric acetate stereochemistry. Once formed, the glycosyl iodide readily underwent in situ anomerization, and in the presence of excess iodide, equilibrium concentrations of alpha- and beta-iodides were established. Reactivity profiles depended upon the identity of the sugar and the protecting groups adorning it. Consistent with the modern idea of disarmed versus armed sugars, ester protecting groups diminished the reactivity of glycosyl iodides and ether protecting groups enhanced the reactivity. Thus, acetylated sugars were slower to form the iodide and anomerize than their benzylated analogues, and these disarmed glycosyl iodides could be isolated and purified, whereas armed ether-protected iodides could only be generated and reacted in situ. All other things being equal, the beta-iodide was orders of magnitude more reactive than the thermodynamically more stable alpha-iodide, consistent with the idea of in situ anomerization introduced by Lemieux in the mid-20th century. Glycosyl iodides are far more reactive than the corresponding bromides, and with the increased reactivity comes increased stereocontrol, particularly when forming alpha-linked linear and branched oligosaccharides. Reactions with per-O-silylated glycosyl iodides are especially useful for the synthesis of alpha-linked glycoconjugates. Silyl ether protecting groups make the glycosyl iodide so reactive that even highly functionalized aglycon acceptors add. Following the coupling event, the TMS ethers are readily removed by methanolysis, and since all of the byproducts are volatile, multiple reactions can be performed in a single reaction vessel without isolation of intermediates. In this fashion, per-O-TMS monosaccharides can be converted to biologically relevant alpha-linked glycolipids in one pot. The stereochemical outcome of these reactions can also be switched to beta-glycoside formation by addition of silver to chelate the iodide, thus favoring SN2 displacement of the alpha-iodide. While iodides derived from benzyl and silyl ether-protected oligosaccharides are susceptible to interglycosidic bond cleavage when treated with TMSI, the introduction of a single acetate protecting group prevents this unwanted side reaction. Partial acetylation of armed glycosyl iodides also attenuates HI elimination side reactions. Conversely, fully acetylated glycosyl iodides are deactivated and require metal catalysis in order for glycosidation to occur. Recent findings indicate that I2 activation of per-O-acetylated mono-, di , and trisaccharides promotes glycosidation of cyclic ethers to give beta-linked iodoalkyl glycoconjugates in one step. Products of these reactions have been converted into multivalent carbohydrate displays. With these synthetic pathways elucidated, chemical reactivity can be exquisitely controlled by the judicious selection of protecting groups to achieve high stereocontrol in step-economical processes. PMID- 26524483 TI - Regulation of experienced and anticipated regret in daily decision making. AB - Decisions were sampled from 108 participants during 8 days using a web-based diary method. Each day participants rated experienced regret for a decision made, as well as forecasted regret for a decision to be made. Participants also indicated to what extent they used different strategies to prevent or regulate regret. Participants regretted 30% of decisions and forecasted regret in 70% of future decisions, indicating both that regret is relatively prevalent in daily decisions but also that experienced regret was less frequent than forecasted regret. In addition, a number of decision-specific regulation and prevention strategies were successfully used by the participants to minimize regret and negative emotions in daily decision making. Overall, these results suggest that regulation and prevention of regret are important strategies in many of our daily decisions. PMID- 26524482 TI - Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma. AB - Repeat tumor biopsies to study genomic changes during therapy are difficult, invasive and data are confounded by tumoral heterogeneity. The analysis of circulating tumor DNA (ctDNA) can provide a non-invasive approach to assess prognosis and the genetic evolution of tumors in response to therapy. Mutation specific droplet digital PCR was used to measure plasma concentrations of oncogenic BRAF and NRAS variants in 48 patients with advanced metastatic melanoma prior to treatment with targeted therapies (vemurafenib, dabrafenib or dabrafenib/trametinib combination) or immunotherapies (ipilimumab, nivolumab or pembrolizumab). Baseline ctDNA levels were evaluated relative to treatment response and progression-free survival (PFS). Tumor-associated ctDNA was detected in the plasma of 35/48 (73%) patients prior to treatment and lower ctDNA levels at this time point were significantly associated with response to treatment and prolonged PFS, irrespective of therapy type. Levels of ctDNA decreased significantly in patients treated with MAPK inhibitors (p < 0.001) in accordance with response to therapy, but this was not apparent in patients receiving immunotherapies. We show that circulating NRAS mutations, known to confer resistance to BRAF inhibitors, were detected in 3 of 7 (43%) patients progressing on kinase inhibitor therapy. Significantly, ctDNA rebound and circulating mutant NRAS preceded radiological detection of progressive disease. Our data demonstrate that ctDNA is a useful biomarker of response to kinase inhibitor therapy and can be used to monitor tumor evolution and detect the early appearance of resistance effectors. PMID- 26524484 TI - Do losses loom larger for children than adults? AB - The large impact of loss of reward on behavior has been well documented in adult populations. However, whether responsiveness to loss relative to gain is similarly elevated in child versus adult populations remains unclear. It is also unclear whether relations between incentive behaviors and self-reported reward/punishment sensitivity are similar within different developmental stages. To investigate these questions, 7- to 10-year-old children (N = 70) and young adults (N = 70) completed the Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scale, along with 2 probabilistic incentive tasks assessing gain approach and loss avoidance behavior. BIS/BAS subscales were calculated per Pagliaccio et al. (2015), which established an age invariant model of the BIS/BAS. Bias toward responses more frequently followed by gain feedback and away from responses more frequently followed by loss feedback, approach, and avoidance behavior, respectively, were quantified via signal detection statistics. Gain approach behavior did not differ across age groups; however, children exhibited significantly elevated loss avoidance relative to adults. Children also showed greater reductions in accuracy and slower RTs specifically following loss feedback relative to adults. Interestingly, despite age group differences in loss avoidance behavior, relations between self-report measures and approach/avoidance behaviors were similar across age groups. Participants reporting elevated motivation (BAS Drive) showed both elevated gain approach and elevated loss avoidance, with both types of behavior predicting unique variance in BAS Drive. Results highlight the often-neglected developmental and motivational roles of responsiveness to loss of reward. PMID- 26524485 TI - Determination of Fracture Patterns in Glass and Glassy Polymers. AB - The study of fractures of glass, glassy-type materials, and plastic has long been of interest to the forensic community. The focus of this interest has been the use of glass and polymer fractures to associate items of evidence under the assumption that each fracture is different. Generally, it is well-accepted that deviations exist; however, the emphasis has been on classifying and predicting fracture rather than determining that each fracture is different. This study documented the controlled fracture patterns of 60 glass panes, 60 glass bottles, and 60 plastic tail light lens covers using both dynamic impact and static pressure methods under closely controlled conditions. Each pattern was intercompared, and based on the limited specimens tested in this study, the results illustrate that the fracture patterns are different. Further repetitive studies, under controlled conditions, will be needed to provide more statistical significance to the theory that each fracture forms a nonreproducible fracture pattern. PMID- 26524486 TI - Methods for Improving the Diagnosis of a Brugada ECG Pattern. AB - Brugada syndrome (BrS) is an inherited channelopathy that predisposes individuals to malignant arrhythmias and can lead to sudden cardiac death. The condition is characterized by two electrocardiography (ECG) patterns: the type-1 or "coved" ECG and the type-2 or "saddleback" ECG. Although the type-1 Brugada ECG pattern is diagnostic for the condition, the type-2 Brugada ECG pattern requires differential diagnosis from conditions that produce a similar morphology. In this article, we present a case that is suspicious but not diagnostic for BrS and discuss the application of ECG methodologies for increasing or decreasing suspicion for a diagnosis of BrS. PMID- 26524487 TI - p-TsOH Promoted Au(I)-Catalyzed Consecutive Endo Cyclization of Yne-Tethered Ynamide: Access to Benzofused Dihydroisoquinolones. AB - A novel synthetic route to benzo[f]dihydroisoquinolone through a p-TsOH promoted cascade cyclization of easily accessible diyne-tethered ynamides in the presence of a Au(I)-catalyst is described. This reaction unveils a broad substrate scope, constructing a wide range of benzo[f]dihydroisoquinolones in good yields. The diyne-tethered ynamides are synthesized from inexpensive o-iodoaniline through Sonogashira couplings and the Cu-mediated C-N bond formation. The role of p-TsOH is examined, and the reaction pathway is also deduced. The benzo[f]isoquinoline scaffold is constructed from benzo[f]dihydroisoquinolones. PMID- 26524489 TI - QSAR analysis of thiolactone derivatives using HQSAR, CoMFA and CoMSIA. AB - The development of resistant malaria and lethality of the disease demands the search for new therapeutic candidates. In this line-up, thiolactone was identified as the potential lead structure and subjected to hologram quantitative structure-activity relationship (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Overall, the QSAR results shows that the LOO cross-validated q(2) values of HQSAR, CoMFA and CoMSIA models are 0.791, 0.737 and 0.753, respectively. According to HQSAR, the hydrogen bond donor and acceptor were found to play an important role in governing antimalarial activity of thiolactone derivatives. The fragment contribution map of HQSAR, and contour maps of CoMFA and CoMSIA showed the presence of an electronegative group at the fifth position, and a bulky group at the third and fourth positions of the thiolactone ring, positively contributing to antimalarial activity. Furthermore, molecular docking was performed to analyze the binding mode of newly designed thiolactones with the active site residues of pf KAS I/II. The prediction of newly designed thiolactone molecules based on QSAR and docking score are in good accordance with each other. Therefore the ligand based QSAR models and target structure-based docking model developed in this study may be successfully utilized for the design of new antimalarial agents. PMID- 26524488 TI - Undiagnosed Obstructive Lung Disease in the United States. Associated Factors and Long-term Mortality. AB - RATIONALE: Understanding factors associated with undiagnosed obstructive lung disease and its impact on mortality could inform the ongoing discussions about benefits and risks of screening and case finding. OBJECTIVES: To define factors associated with undiagnosed obstructive lung disease and its long-term mortality. METHODS: Cross-sectional analysis of participants, aged 20 to 79 years, in two National Health and Nutritional Examination Surveys (NHANES), NHANES III (1988 1994) and NHANES 2007-2012, with longitudinal follow-up of NHANES III participants. MEASUREMENTS AND MAIN RESULTS: We classified participants with spirometry-confirmed obstructive disease, based on the fixed ratio definition (FEV1/FVC < 0.7), as "diagnosed" (physician diagnosis of either asthma or chronic obstructive pulmonary disease), and "undiagnosed" (no recorded physician diagnosis). For the longitudinal analysis of NHANES III participants, mortality was the outcome of interest. We tested the contribution of self-reported health status and comorbidity burden (exposure) to the odds of being undiagnosed using logistic models adjusted for demographics, smoking status, and lung function. We estimated hazard ratios (HRs) for all-cause mortality for diagnosed and undiagnosed subjects participating in NHANES III who had spirometry using Cox- proportional regression analysis. Among those with spirometry-defined obstruction, 71.2% (SE, 1.8) in NHANES III and 72.0% (SE, 1.9) in NHANES 2007 2012 were undiagnosed. In multivariate models, undiagnosed obstructive disease was consistently associated in both surveys with self-reported good/excellent health status, lower comorbidity burden, higher lung function, and being of racial/ethnic minority. Among NHANES III participants (median follow up, 14.5 yr), both undiagnosed (HR, 1.23; 95% confidence interval, 1.08-1.40) and correctly diagnosed participants (HR, 1.74; 95% confidence interval, 1.45-2.09) had higher risk for all-cause mortality than participants without obstruction. CONCLUSIONS: Undiagnosed obstructive lung disease is common among American adults and remained unchanged over 2 decades. Although undiagnosed subjects appear healthier than those with a diagnosis, their risk of death was increased compared with subjects without obstruction. These findings need to be considered when judging the implications of case-finding programs for obstructive lung disease. PMID- 26524490 TI - Trinucleotide's quadruplet symmetries and natural symmetry law of DNA creation ensuing Chargaff's second parity rule. AB - For almost 50 years the conclusive explanation of Chargaff's second parity rule (CSPR), the equality of frequencies of nucleotides A=T and C=G or the equality of direct and reverse complement trinucleotides in the same DNA strand, has not been determined yet. Here, we relate CSPR to the interstrand mirror symmetry in 20 symbolic quadruplets of trinucleotides (direct, reverse complement, complement, and reverse) mapped to double-stranded genome. The symmetries of Q-box corresponding to quadruplets can be obtained as a consequence of Watson-Crick base pairing and CSPR together. Alternatively, assuming Natural symmetry law for DNA creation that each trinucleotide in one strand of DNA must simultaneously appear also in the opposite strand automatically leads to Q-box direct-reverse mirror symmetry which in conjunction with Watson-Crick base pairing generates CSPR. We demonstrate quadruplet's symmetries in chromosomes of wide range of organisms, from Escherichia coli to Neanderthal and human genomes, introducing novel quadruplet-frequency histograms and 3D-diagrams with combined interstrand frequencies. These "landscapes" are mutually similar in all mammals, including extinct Neanderthals, and somewhat different in most of older species. In human chromosomes 1-12, and X, Y the "landscapes" are almost identical and slightly different in the remaining smaller and telocentric chromosomes. Quadruplet frequencies could provide a new robust tool for characterization and classification of genomes and their evolutionary trajectories. PMID- 26524491 TI - A mutation in MT-TW causes a tRNA processing defect and reduced mitochondrial function in a family with Leigh syndrome. AB - Leigh syndrome (LS) is a progressive mitochondrial neurodegenerative disorder, whose symptoms most commonly include psychomotor delay with regression, lactic acidosis and a failure to thrive. Here we describe three siblings with LS, but with additional manifestations including hypertrophic cardiomyopathy, hepatosplenomegaly, cholestatic hepatitis, and seizures. All three affected siblings were found to be homoplasmic for an m. 5559A>G mutation in the T stem of the mitochondrial DNA-encoded MT-TW by next generation sequencing. The m.5559A>G mutation causes a reduction in the steady state levels of tRNA(Trp) and this decrease likely affects the stability of other mitochondrial RNAs in the patient fibroblasts. We observe accumulation of an unprocessed transcript containing tRNA(Trp), decreased de novo protein synthesis and consequently lowered steady state levels of mitochondrial DNA-encoded proteins that compromise mitochondrial respiration. Our results show that the m.5559A>G mutation at homoplasmic levels causes LS in association with severe multi-organ disease (LS-plus) as a consequence of dysfunctional mitochondrial RNA metabolism. PMID- 26524492 TI - The architecture of a eukaryotic replisome. AB - At the eukaryotic DNA replication fork, it is widely believed that the Cdc45-Mcm2 7-GINS (CMG) helicase is positioned in front to unwind DNA and that DNA polymerases trail behind the helicase. Here we used single-particle EM to directly image a Saccharomyces cerevisiae replisome. Contrary to expectations, the leading strand Pol E is positioned ahead of CMG helicase, whereas Ctf4 and the lagging-strand polymerase (Pol) alpha-primase are behind the helicase. This unexpected architecture indicates that the leading-strand DNA travels a long distance before reaching Pol E, first threading through the Mcm2-7 ring and then making a U-turn at the bottom and reaching Pol E at the top of CMG. Our work reveals an unexpected configuration of the eukaryotic replisome, suggests possible reasons for this architecture and provides a basis for further structural and biochemical replisome studies. PMID- 26524493 TI - A new vertebrate SUMO enzyme family reveals insights into SUMO-chain assembly. AB - SUMO chains act as stress-induced degradation tags or repair factor-recruiting signals at DNA lesions. Although E1 activating, E2 conjugating and E3 ligating enzymes efficiently assemble SUMO chains, specific chain-elongation mechanisms are unknown. E4 elongases are specialized E3 ligases that extend a chain but are inefficient in the initial conjugation of the modifier. We identified ZNF451, a representative member of a new class of SUMO2 and SUMO3 (SUMO2/3)-specific enzymes that execute catalysis via a tandem SUMO-interaction motif (SIM) region. One SIM positions the donor SUMO while a second SIM binds SUMO on the back side of the E2 enzyme. This tandem-SIM region is sufficient to extend a back side anchored SUMO chain (E4 elongase activity), whereas efficient chain initiation also requires a zinc-finger region to recruit the initial acceptor SUMO (E3 ligase activity). Finally, we describe four human proteins sharing E4 elongase activities and their function in stress-induced SUMO2/3 conjugation. PMID- 26524495 TI - An interrupted time series analysis showed suboptimal improvement in reporting quality of trial abstract. AB - OBJECTIVE: To assess and compare the immediate and long-term change in reporting quality of randomized controlled trial (RCT) abstracts published in Pediatrics, The Journal of Pediatrics, and JAMA Pediatrics before and after the publication of Consolidated Standards of Reporting Trial (CONSORT)-abstract statement. STUDY DESIGN AND SETTINGS: Study had "Interrupted time-series" design. Eligible RCT abstracts were retrieved by PubMed search in two study periods from January 2003 to December 2007 (pre-CONSORT) and January 2010 to December 2014 (post-CONSORT). These abstracts were matched with the CONSORT checklist for abstracts. The primary outcome measure was CONSORT-abstract score defined as number of CONSORT items correctly reported divided by 18 and expressed as percentage. The mean percentage scores were used to compare reporting quality between pre- and post CONSORT using segmented linear regression. RESULTS: A total of 424 RCT abstracts in pre-CONSORT and 467 in post-CONSORT were analyzed. A significant change in slope of regression line between two time periods (0.151 [confidence interval CI, 0.004-0.298], P = 0.044) was observed. Intercepts did not show a significant difference (-2.39 [CI, 4.93-0.157], P = 0.065). CONCLUSION: The overall reporting quality of RCT abstracts in the high-impact pediatrics journals was suboptimal (<50%); however, it improved when assessed over a 5-year period, implying slow but gradual adoption of guideline. PMID- 26524494 TI - Structural basis for catalytic activation by the human ZNF451 SUMO E3 ligase. AB - E3 protein ligases enhance transfer of ubiquitin-like (Ubl) proteins from E2 conjugating enzymes to substrates by stabilizing the thioester-charged E2~Ubl in a closed configuration optimally aligned for nucleophilic attack. Here, we report biochemical and structural data that define the N-terminal domain of the Homo sapiens ZNF451 as the catalytic module for SUMO E3 ligase activity. The ZNF451 catalytic module contains tandem SUMO-interaction motifs (SIMs) bridged by a Pro Leu-Arg-Pro (PLRP) motif. The first SIM and PLRP motif engage thioester-charged E2~SUMO while the next SIM binds a second molecule of SUMO bound to the back side of E2. We show that ZNF451 is SUMO2 specific and that SUMO modification of ZNF451 may contribute to activity by providing a second molecule of SUMO that interacts with E2. Our results are consistent with ZNF451 functioning as a bona fide SUMO E3 ligase. PMID- 26524496 TI - Questionable assumptions hampered interpretation of a network meta-analysis of primary care depression treatments. AB - OBJECTIVES: We aimed to evaluate the underlying assumptions of a network meta analysis investigating which depression treatment works best in primary care and to highlight challenges and pitfalls of interpretation under consideration of these assumptions. STUDY DESIGN AND SETTING: We reviewed 100 randomized trials investigating pharmacologic and psychological treatments for primary care patients with depression. Network meta-analysis was carried out within a frequentist framework using response to treatment as outcome measure. Transitivity was assessed by epidemiologic judgment based on theoretical and empirical investigation of the distribution of trial characteristics across comparisons. Homogeneity and consistency were investigated by decomposing the Q statistic. RESULTS: There were important clinical and statistically significant differences between "pure" drug trials comparing pharmacologic substances with each other or placebo (63 trials) and trials including a psychological treatment arm (37 trials). Overall network meta-analysis produced results well comparable with separate meta-analyses of drug trials and psychological trials. Although the homogeneity and consistency assumptions were mostly met, we considered the transitivity assumption unjustifiable. CONCLUSION: An exchange of experience between reviewers and, if possible, some guidance on how reviewers addressing important clinical questions can proceed in situations where important assumptions for valid network meta-analysis are not met would be desirable. PMID- 26524497 TI - Interleukin-10-1082 G/a polymorphism and acute renal graft rejection: a meta analysis. AB - OBJECTIVE: The aim of this study was to investigate the association between interleukin (IL)-10-1082 (G/A) promoter polymorphism and acute rejection (AR) in renal transplant recipients. METHODS: We searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register from the inception to March 2015 for relevant studies. Data concerning publication information, population characteristics, and transplant information were extracted. Odds ratios (ORs) was calculated for the association between IL-10-1082 GG genotype (or IL-10-1082 G allele) and AR risk. RESULTS: This meta-analysis included 22 case-control studies including 2779 cases of renal transplant recipients. The pooled estimate showed that the IL-10-1082 GG genotype was not significantly associated with AR risk (ORrandom=1.07, 95% CI 0.80-1.43, p = 0.64). Similarly, the pooled estimate showed that the IL-10-1082 G allele was not significantly associated with AR risk (ORfixed=1.02, 95% CI 0.90-1.16, p = 0.74). None of subgroup analyses yielded significant results in the association between IL-10-1082 GG genotype (or IL-10 1082 G allele) and AR risk. Meta-regression confirmed that there was no significant correlation between the pre-selected trial characteristics and our study results. CONCLUSIONS: This meta-analysis suggests that IL-10-1082 G/A polymorphism is not significantly associated with AR risk in renal transplant recipients. PMID- 26524498 TI - Who will deliver comprehensive healthy lifestyle interventions to combat non communicable disease? Introducing the healthy lifestyle practitioner discipline. AB - Unhealthy lifestyle characteristics (i.e., physical inactivity, excess body mass, poor diet, and smoking) as well as associated poor health metrics (i.e., dyslipidemia, hyperglycemia, and hypertension) are the primary reasons for the current non-communicable disease crisis. Compared to those with the poorest of lifestyles and associated health metrics, any movement toward improving lifestyle and associated health metrics improves health outcomes. To address the non communicable disease crisis we must: 1) acknowledge that healthy lifestyle (HL) interventions are a potent medicine; and 2) move toward a healthcare system that embraces primordial as much as, if not more than, secondary prevention with a heavy focus on HL medicine. This article introduces the Healthy Lifestyle Practitioner, focused on training health professionals to deliver HL medicine. PMID- 26524499 TI - Enhanced expression of Gialpha proteins contributes to the hyperproliferation of vascular smooth muscle cells from spontaneously hypertensive rats via MAP kinase- and PI3 kinase-independent pathways. AB - Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit hyperproliferation, enhanced MAP kinase (MAPK) activity, and overexpression of Gialpha proteins. This study was undertaken to examine whether the overexpression of Gialpha proteins contributes to the hyperproliferation of VSMC of SHR through MAPK signaling. The hyperproliferation of VSMC from SHR in the absence and presence of angiotensin II was restored towards those in Wistar Kyoto (WKY) rats levels by pertussis toxin (PT) treatment. In addition, siRNA knockdown of Gialpha proteins also resulted in the attenuation of hyperproliferation towards control levels. The overexpression of Gialpha proteins was also inhibited by MAPK and PI3 kinase (PI3K) inhibitors. In addition, the hyperproliferation and enhanced phosphorylation of ERK1/2 and Akt in VSMC from SHR were attenuated towards WKY levels by the inhibitors of MAPK, PI3K, c-Src, and antioxidants, whereas PT was unable to attenuate the enhanced phosphorylation of ERK1/2 and Akt. Furthermore, 8Br-cAMP and forskolin also attenuated the hyperproliferation of VSMC from SHR. These results suggest that the hyperproliferation of VSMC from SHR may be attributed to the enhanced expression of Gialpha proteins and increased activation of MAPK and PI3 kinase. However, Gialpha-mediated hyperproliferation may not be mediated through MAPK- and PI3 kinase-dependent pathways and may involve decreased levels of intracellular cAMP. PMID- 26524500 TI - The effect of vagus nerve stimulation on cardiorespiratory parameters during rest and exercise. AB - PURPOSE: Vagus nerve stimulation (VNS) has been successfully applied to reduce seizure frequency in numerous patients with epilepsy. However, various side effects, including dyspnea and bradycardia have been reported, that appear exercise related in some patients. This pilot study aims to obtain insight in the cardiorespiratory effects of VNS during both rest and exercise. METHODS: Patients with a VNS device who experience side effects during exercise are compared with patients without side effects. Respiratory and cardiac parameters measured during rest and exercise include heart rate, breathing frequency and tidal volume. RESULTS: Sixty-two episodes of VNS in five patients with and five patients without side effects were recorded. In addition, five control subjects have been measured. During rest, all subjects showed stable values for the cardiorespiratory parameters. During the first minutes of exercise, heart rate, breathing frequency and tidal volume increased. Thereafter, a steady state was reached again for all subjects. During VNS episodes, eight out of 10 patients showed a small but consistent decrease in heart rate, along with an increase in breathing frequency in eight out of nine patients. Tidal volumes decreased during VNS episodes. These effects, induced by VNS, occurred during both rest and exercise. Magnitude of these effects varied between patients, but was not necessarily related to the intensity of the experienced side effects. CONCLUSION: This pilot study shows that VNS causes an increase in breathing frequency and a decrease in tidal volume and heart rate in the majority of patients, during both rest and exercise. PMID- 26524501 TI - Ectopic expression of a Ve homolog VvVe gene from Vitis vinifera enhances defense response to Verticillium dahliae infection in tobacco. AB - Verticillium wilt is a soil borne disease that can cause devastating losses to the production of many economically important crops. A Ve1 homologous gene responding to Verticillium dahliae infection was identified in Vitis vinifera cv. "HeiFeng" by semi-quantitative reverse transcription polymerase chain reaction and was designated as VvVe. The overexpression of VvVe in transgenic Nicotiana benthamiana plants significantly enhanced the resistance to isolate V991 of V. dahliae when compared with the wild type plants. The expressions of defense related genes including the salicylic acid regulated gene pathogen-related 1 (PR1) but not PR2, the ethylene- and jasmonic acid-regulated genes ethylene response factor 1 (ERF1) and lipoxygenase (LOX) were significantly increased due to over expression of VvVe. And greater accumulation of active oxygen, callose and phenylalanine-ammonia lyase were observed in the leaves of transgenic VvVe tobacco plants than the wild type when under infection by V. dahliae. Moreover, the hypersensitive response mimicking cell death was exclusively occurred in the transgenic VvVe tobacco plants but not in the wild type. Taken together, the VvVe gene is a Ve1 like gene which involves in the signal cascade of salicylic acid, jasmonate, and ethylene defense pathways and enhances defense response to V. dahliae infection in the transgenic tobacco. PMID- 26524502 TI - Bioinformatic survey of ABC transporters in dermatophytes. AB - ATP binding cassette (ABC) transporters constitute a very large and ubiquitous superfamily of membrane proteins. They are responsible for ATP hydrolysis driven translocation of countless substrates. Being a very old and diverse group of proteins present in all organisms they share a common feature, which is the presence of an evolutionary conservative nucleotide binding domain (NBD)--the engine that drives the transport. Another common domain is a transmembrane domain (TMD) which consists of several membrane-spanning helices. This part of protein is substrate-specific, thus it is much more variable. ABC transporters are known for driving drug efflux in many pathogens and cancer cells, therefore they are the subject of extensive studies. There are many examples of conferring a drug resistance phenotype in fungal pathogens by ABC transporters, however, little is known about these proteins in dermatophytes--a group of fungi causing superficial mycoses. So far only a single ABC transporter has been extensively studied in this group of pathogens. We analyzed available genomic sequences of seven dermatophyte species in order to provide an insight into dermatophyte ABC protein inventory. Phylogenetic studies of ABC transporter genes and their products were conducted and included ABC transporters of other fungi. Our results show that each dermatophyte genome studied possesses a great variety of ABC transporter genes. Detailed analysis of selected genes and their products indicates that relatively recent duplication of ABC transporter genes could lead to novel substrate specificity. PMID- 26524503 TI - Transgenic expression of green fluorescent protein in caprine embryos produced through electroporation-aided sperm-mediated gene transfer. AB - Current methods of transgenic animal production are afflicted by low efficiency and high cost. Recently, the electroporation aided sperm-mediated gene transfer (SMGT) emerges as a promising alternative with variable success rate. Among the domestic animal species, the electroporation-aided SMGT is less investigated in goats, except a few reports in which attempts have been made using the auto uptake method of SMGT. In this study, we report an optimized electroporation condition for SMGT of caprine sperm cells. Results of this study demonstrated that electroporation of caprine sperm cells at 300 V for 200 mS in TALP medium allowed the maximum uptake of foreign DNA with minimum adverse effects on the vital semen parameters viz., progressive motility, viability, and membrane and acrosome integrity. Further, DNA binding assay revealed DNA uptake by 81.3% sperm cells when 1.0 MUg of DNA was used under optimum electroporation conditions as compared to 16.5% on simple incubation. The qPCR analysis showed four-fold more (P<0.05) DNA uptake by sperm cells under electroporation than incubation. A similar cleavage rate was observed after IVF using either electroporated (23.20 +/- 1.20) or non-electroporated (25.20 +/- 2.41) sperm cells suggesting the absence of adverse effect of electroporation on the fertilizing ability. Out of the 116 embryos produced by electroporated sperm, five (4.31%) embryos showed the expression of the foreign gene. In conclusion, our results confirm that using optimized electroporation conditions, the caprine sperm cells can uptake foreign DNA effectively with minimum negative effect on the semen parameters and could produce transgenic embryos. PMID- 26524504 TI - Increased tone-offset response in the lateral nucleus of the amygdala underlies trace fear conditioning. AB - Accumulating evidence suggests that the lateral nucleus of the amygdala (LA) stores associative memory in the form of enhanced neural response to the sensory input following classical fear conditioning in which the conditioned stimulus (CS) and the unconditioned stimulus (US) are presented in a temporally continuous manner. However, little is known about the role of the LA in trace fear conditioning where the CS and the US are separated by a temporal gap. Single-unit recordings of LA neurons before and after trace fear conditioning revealed that the short-latency activity to the CS offset, but not that to the onset, increased significantly and accompanied the conditioned fear response. The increased short latency activity was evident in two aspects: the number of offset-responsive neurons was increased and the latency of the neuronal response to the CS offset was shortened. On the contrary, changes in the firing rate to either the onset or the offset were negligible following unpaired presentations of the CS and US. In sum, our results suggest that increased synaptic efficacy in the CS offset pathway in the LA might underlie the association between temporally distant stimuli in trace fear conditioning. PMID- 26524506 TI - Heart lipid droplets and lipid droplet-binding proteins: Biochemistry, physiology, and pathology. PMID- 26524505 TI - Mechanosensing via cell-matrix adhesions in 3D microenvironments. AB - The extracellular matrix (ECM) microenvironment plays a central role in cell migration by providing physiochemical information that influences overall cell behavior. Much of this external information is accessed by direct interaction of the cell with ECM ligands and structures via integrin-based adhesions that are hypothesized to act as mechanosensors for testing the surrounding microenvironment. Our current understanding of these mechanical complexes is derived primarily from studies of cellular adhesions formed on two-dimensional (2D) substrates in vitro. Yet the rules of cell/ECM engagement and mechanosensing in three-dimensional (3D) microenvironments are invariably more complex under both in vitro and in vivo conditions. Here we review the current understanding of how cellular mechanosensing occurs through adhesion complexes within 3D microenvironments and discuss how these mechanisms can vary and differ from interactions on 2D substrates. PMID- 26524507 TI - Overexpression of transcription factor FOXC2 in cultured human podocytes upregulates injury markers and increases motility. AB - Obesity and diabetes-related kidney diseases associate with renal failure and cardiovascular morbidity, and represent a major health issue worldwide. However, the molecular mechanisms leading to their development remain poorly understood. We observed increased expression of transcription factor FoxC2 in the podocytes of obese Zucker rats that are insulin resistant and albuminuric. We also found that depletion of adiponectin, an adipocyte-derived hormone whose secretion is decreased in obesity, upregulated FOXC2 in differentiated human podocytes in vitro. Overexpression of FOXC2 in cultured human podocytes led to increased nuclear expression of FOXC2 associated with a change of cellular morphology. This was accompanied by upregulation of vimentin, a key mesenchymal marker, and active beta-catenin, associated with podocyte injury. We also observed re-organization of the actin cytoskeleton, disrupted localization of the tight junction protein ZO-1, and increased motility of podocytes overexpressing FOXC2. These data indicate that the expression of FOXC2 in podocytes needs to be tightly regulated, and that its overexpression induces a chain of cellular events leading to podocyte dysfunction. These changes may lead to podocyte detachment and depletion ultimately contributing to albuminuria. We also suggest a novel molecular mechanism linking obesity-induced decrease in adiponectin to podocyte dysfunction via upregulation of FOXC2. PMID- 26524508 TI - beta2-Agonist clenbuterol hinders human monocyte differentiation into dendritic cells. AB - Clenbuterol (CLB) is a beta2-adrenergic agonist commonly used in asthma therapy, but is also a non-steroidal anabolic drug often abused in sport doping practices. Here we evaluated the in vitro impact of CLB on the physiology and function of human monocytes and dendritic cells (DCs), instrumental in the development of immune responses. We demonstrate that CLB inhibits the differentiation of monocytes into DCs and this effect is specific and dependent on beta2-adrenergic receptor (AR) activation. We found that CLB treatment reduced the percentage of CD1a(+) immature DCs, while increasing the frequency of monocytes retaining CD14 surface expression. Moreover, CLB inhibited tumor necrosis factor-alpha (TNF alpha) enhanced IL-(interleukin)-10 and IL-6 production. In contrast, CLB did not modulate the phenotypic and functional properties of monocytes and DCs, such as the surface expression of HLA-DR, CD83, CD80 and CD86 molecules, cytokine production, immunostimulatory activity and phagocytic activity. Moreover, we found that CLB did not modulate the activation of NF-kB in DCs. Moreover, we found that the differentiation of monocytes into DCs was associated with a significant decrease of beta2-ARs mRNA expression. These results provide new insights on the effect of CLB on monocyte differentiation into DCs. Considering the frequent illegal use of CLB in doping, our work suggests that this drug is potentially harmful to immune responses decreasing the supply of DCs, thus subverting immune surveillance. PMID- 26524509 TI - Nanoscale and mechanical properties of the physiological cell-ECM microenvironment. AB - Studying biological processes in vitro requires faithful and successful reconstitution of the in vivo extracellular matrix (ECM) microenvironment. However, the physiological basis behind in vitro studies is often forgotten or ignored. A number of diverse cell-ECM interactions have been characterized throughout the body and in disease, reflecting the heterogeneous nature of cell niches. Recently, a greater emphasis has been placed on characterizing both the chemical and physical characteristics of the ECM and subsequently mimicking these properties in the lab. Herein, we describe physiological measurement techniques and reported values for the three main physical aspects of the ECM: tissue stiffness, topography, and ligand presentation. PMID- 26524510 TI - Role of YAP/TAZ in cell-matrix adhesion-mediated signalling and mechanotransduction. AB - Signalling from the extracellular matrix (ECM) is a fundamental cellular input that sustains proliferation, opposes cell death and regulates differentiation. Through integrins, cells perceive both the chemical composition and physical properties of the ECM. In particular, cell behaviour is profoundly influenced by the mechanical elasticity or stiffness of the ECM, which regulates the ability of cells to develop forces through their contractile actomyosin cytoskeleton and to mature focal adhesions. This mechanosensing ability affects fundamental cellular functions, such that alterations of ECM stiffness is nowadays considered not a simple consequence of pathology, but a causative input driving aberrant cell behaviours. We here discuss recent advances on how mechanical signals intersect nuclear transcription and in particular the activity of YAP/TAZ transcriptional coactivators, known downstream transducers of the Hippo pathway and important effectors of ECM mechanical cues. PMID- 26524511 TI - Temporal and qualitative dynamics of conditioned taste aversions in C57BL/6J and DBA/2J mice self-administering LiCl. AB - Self-administration of LiCl solution has been shown to result in the formation of a conditioned taste aversion (CTA) that generalizes to NaCl in rats. This paradigm may have considerable ecological validity as it models CTA learning in natural settings, and also allows for the investigation of drinking microstructure as an assay of potential shifts in stimulus palatability. We used this paradigm to examine possible mouse strain differences in CTA acquisition, generalization, and extinction. In the first experiment, C57BL/6J (B6) and DBA/2J (D2) mice self-administered LiCl (or control NaCl) over a 20-minute free access acquisition period and were tested on the following day with a panel of taste solutions available in brief (5-s) trials delivered in random order. In the second experiment, mice again self-administered LiCl or NaCl (at low, 0.12 M, or high, 0.24 M concentrations) in a 20-minute session, and on the following day received a 20-minute free access period to equimolar NaCl. Strain differences were found for aspects of ingestive behavior, with B6 mice showing greater consumption of all stimuli, including water, while D2 mice lick faster, in less frequent but longer bursts. We did not, however, find evidence of a robust strain difference in taste aversion learning. Both strains demonstrated profound alterations in licking microstructure in the generalization session relative to controls. We suggest that a decrease in "lick efficiency" (the percentage of inter-lick intervals within a burst of short duration vs. longer duration) reflects avoidance behavior, and signals a shift in palatability of a stimulus following CTA. PMID- 26524512 TI - Beta-adrenoreceptor blockade abolishes atomoxetine-induced risk taking. AB - RATIONALE: Clinical studies have shown that patients with exaggerated risk-taking tendencies have high baseline levels of norepinephrine. In this work, we systemically manipulated norepinephrine levels in rats and studied their behavioral changes in a probabilistic discounting task, which is a paradigm for gauging risk taking. METHODS: This study aims to explore the effects of the selective norepinephrine reuptake inhibitor (atomoxetine at doses of 0.6, 1.0 and 1.8 mg/kg), and receptor selective antagonists (propranolol at a single dose of 1.0/kg, and prazosin at a single dose of 0.1 mg/kg), on risk taking using a probabilistic discounting task. In this task, there were two levers available to rats: pressing the 'small/certain' lever guaranteed a single food pellet, and pressing the 'large/risky' lever yielded either four pellets or none. The probability of receiving four food pellets decreased across the four experimental blocks from 100% to 12.5%. RESULTS: Atomoxetine increased the tendency to choose the large/risky lever. It significantly reduced the lose-shift effect (i.e. pressing a different lever after losing a trial), but did not affect the win-stay effect (i.e. pressing the same lever after winning a trial). Furthermore, co administration of beta-adrenoreceptor antagonist, propranolol, eliminated the effects of atomoxetine on risk taking and the lose-shift effect; but co administration of alpha1-adrenoreceptor antagonist, prazosin, did not. CONCLUSIONS: Atomoxetine boosted NE levels and increased risk taking. This was because atomoxetine decreased rats' sensitivity to losses. These effects were likely mediated by beta-adrenoreceptor. PMID- 26524513 TI - Amino acid substitutions in the heptad repeat A and C regions of the F protein responsible for neurovirulence of measles virus Osaka-1 strain from a patient with subacute sclerosing panencephalitis. AB - Measles virus (MV) is the causative agent of subacute sclerosing panencephalitis (SSPE). We previously reported that the F gene of the SSPE Osaka-2 strain is the major determinant of MV neurovirulence. Because the sites and extents of mutations differ among SSPE strains, it is necessary to determine the mutations responsible for the SSPE-specific phenotypes of individual viral strain. In this study, recombinant viruses containing the envelope-associated genes from the SSPE Osaka-1 strain were generated in the IC323 wild-type MV background. Hamsters inoculated with MV containing the H gene of the Osaka-1 strain displayed hyperactivity and seizures, but usually recovered and survived. Hamsters inoculated with MV containing the F gene of the Osaka-1 strain displayed severe neurologic signs and died. Amino acid substitutions in the heptad repeat A and C regions of the F protein, including a methionine-to-valine substitution at amino acid 94, play major roles in neurovirulence. PMID- 26524516 TI - The Physical Results of Nonsuicidal Self-Injury: The Meaning Behind the Scars. AB - The psychological meaning of scars from nonsuicidal self-injury (NSSI) has been examined in case studies, but descriptive studies are needed to better understand the meaning of NSSI scars. College students with NSSI scars (n = 49) completed questionnaires concerning the interpretive meaning of their scars, emotions associated with their scars, and clinical symptoms. Levels of scar-related growth were positively correlated with interpersonal functions of NSSI (e.g., autonomy, self-care) and negatively correlated with likelihood of future self-injury, self disgust, self-injury regret, and self-injury scar regret. Conversely, higher levels of scar-related shame were associated with higher likelihood of future self-injury, depressive and borderline personality disorder symptoms, self disgust, NSSI scar-related regret, and intrapersonal functions of NSSI (e.g., marking distress, self-punishment). Individuals finding shame or guilt may be a more clinically severe group than those finding growth from their scars. PMID- 26524515 TI - The Family Value of Information, Community Support, and Experience Study: Rationale, Design, and Methods of a "Family-Centered" Research Study. AB - The Patient Protection and Affordable Care Act focuses on improving consumer engagement and patient-centered care. This article describes the design and rationale of a study targeting family engagement in pediatric mental health services. The study is a 90-day randomized trial of a telephone-delivered Family Navigator services versus usual care for parents of Medicaid-insured youth younger than 13 years with serious mental illness. Youth are identified through a pediatric antipsychotic medication preauthorization program. Family Navigators offer peer support to empower and engage parents in their child's recovery. Outcomes include parent report of empowerment, social support, satisfaction with child mental health services, and child functioning as well as claims-based measures of psychotherapy service utilization and antipsychotic medication dosage. The focus on "family-centered" care in this study is strongly supported by the active role of consumers in study design and implementation. PMID- 26524514 TI - Modeling of the rotavirus group C capsid predicts a surface topology distinct from other rotavirus species. AB - Rotavirus C (RVC) causes sporadic gastroenteritis in adults and is an established enteric pathogen of swine. Because RVC strains grow poorly in cell culture, which hinders generation of virion-derived RVC triple-layered-particle (TLP) structures, we used the known Rotavirus A (RVA) capsid structure to model the human RVC (Bristol) capsid. Comparative analysis of RVA and RVC capsid proteins showed major differences at the VP7 layer, an important target region for vaccine development due to its antigenic properties. Our model predicted the presence of a surface extended loop in RVC, which could form a major antigenic site on the capsid. We analyzed variations in the glycosylation patterns among RV capsids and identified group specific conserved sites. In addition, our results showed a smaller RVC VP4 foot, which protrudes toward the intermediate VP6 layer, in comparison to that of RVA. Finally, our results showed major structural differences at the VP8* glycan recognition sites. PMID- 26524518 TI - The Role of Alexithymia in the Incidence of Poststroke Depression. AB - Poststroke depression (PSD) is the most frequent neuropsychiatric consequence of stroke, and alexithymia is a construct characterized by the inability to identify and describe emotions. Our study aimed to determine whether alexithymia is a risk factor for the development of PSD. Patients with ischemic stroke admitted to a general teaching hospital were enrolled in this 6-month study. The patients were evaluated with the Toronto Alexithymia Scale-20 (TAS-20), Beck Anxiety Inventory (BAI), National Institute of Health Stroke Scale (NIHHS), and Mini-Mental Status Examination at baseline and then followed up each month for detection of PSD using the Center for Epidemiologic Studies of Depression scale. In all, 285 patients with ischemic stroke were enrolled, and 93.3% completed the 6-month study. The overall incidence of PSD within 6 months was 16.5%. In multivariate regression analyses, the incidence of PSD was significantly associated with higher BAI, higher NIHSS, and higher TAS-20 scores. In conclusion, our study highlights the importance of alexithymic symptoms as a risk factor for PSD. PMID- 26524517 TI - Medically Serious Suicide Attempters With or Without Plan in Rural China. AB - Although previous studies have discussed the risk factors of unplanned suicide behavior in several countries, the unplanned suicide attempt in China was not explored in a large sample. We aim to look into the characteristics of unplanned suicide attempters in China and compare them with those suicide attempters with plans. Subjects were 791 medically serious suicide attempters aged 15-54 years in rural China. The sixth item of Beck's Suicide Intent Scale was used to estimate the planned and unplanned suicide attempt. Logistic regression analysis was performed to examine the factors related to planned or unplanned suicide attempt. The results showed that the planned suicide attempts were associated with higher education, hopelessness, and previous suicide act. The unplanned suicide attempt tends to be suicide by pesticide and store pesticide at home. A ban of lethal pesticides may be a method for suicide prevention in rural China. PMID- 26524519 TI - Large anomalous Hall effect in a non-collinear antiferromagnet at room temperature. AB - In ferromagnetic conductors, an electric current may induce a transverse voltage drop in zero applied magnetic field: this anomalous Hall effect is observed to be proportional to magnetization, and thus is not usually seen in antiferromagnets in zero field. Recent developments in theory and experiment have provided a framework for understanding the anomalous Hall effect using Berry-phase concepts, and this perspective has led to predictions that, under certain conditions, a large anomalous Hall effect may appear in spin liquids and antiferromagnets without net spin magnetization. Although such a spontaneous Hall effect has now been observed in a spin liquid state, a zero-field anomalous Hall effect has hitherto not been reported for antiferromagnets. Here we report empirical evidence for a large anomalous Hall effect in an antiferromagnet that has vanishingly small magnetization. In particular, we find that Mn3Sn, an antiferromagnet that has a non-collinear 120-degree spin order, exhibits a large anomalous Hall conductivity of around 20 per ohm per centimetre at room temperature and more than 100 per ohm per centimetre at low temperatures, reaching the same order of magnitude as in ferromagnetic metals. Notably, the chiral antiferromagnetic state has a very weak and soft ferromagnetic moment of about 0.002 Bohr magnetons per Mn atom (refs 10, 12), allowing us to switch the sign of the Hall effect with a small magnetic field of around a few hundred oersted. This soft response of the large anomalous Hall effect could be useful for various applications including spintronics--for example, to develop a memory device that produces almost no perturbing stray fields. PMID- 26524520 TI - Conformational control of DNA target cleavage by CRISPR-Cas9. AB - Cas9 is an RNA-guided DNA endonuclease that targets foreign DNA for destruction as part of a bacterial adaptive immune system mediated by clustered regularly interspaced short palindromic repeats (CRISPR). Together with single-guide RNAs, Cas9 also functions as a powerful genome engineering tool in plants and animals, and efforts are underway to increase the efficiency and specificity of DNA targeting for potential therapeutic applications. Studies of off-target effects have shown that DNA binding is far more promiscuous than DNA cleavage, yet the molecular cues that govern strand scission have not been elucidated. Here we show that the conformational state of the HNH nuclease domain directly controls DNA cleavage activity. Using intramolecular Forster resonance energy transfer experiments to detect relative orientations of the Cas9 catalytic domains when associated with on- and off-target DNA, we find that DNA cleavage efficiencies scale with the extent to which the HNH domain samples an activated conformation. We furthermore uncover a surprising mode of allosteric communication that ensures concerted firing of both Cas9 nuclease domains. Our results highlight a proofreading mechanism beyond initial protospacer adjacent motif (PAM) recognition and RNA-DNA base-pairing that serves as a final specificity checkpoint before DNA double-strand break formation. PMID- 26524522 TI - Evolution: On the crest of becoming vertebrate. PMID- 26524521 TI - Endoperoxide formation by an alpha-ketoglutarate-dependent mononuclear non-haem iron enzyme. AB - Many peroxy-containing secondary metabolites have been isolated and shown to provide beneficial effects to human health. Yet, the mechanisms of most endoperoxide biosyntheses are not well understood. Although endoperoxides have been suggested as key reaction intermediates in several cases, the only well characterized endoperoxide biosynthetic enzyme is prostaglandin H synthase, a haem-containing enzyme. Fumitremorgin B endoperoxidase (FtmOx1) from Aspergillus fumigatus is the first reported alpha-ketoglutarate-dependent mononuclear non haem iron enzyme that can catalyse an endoperoxide formation reaction. To elucidate the mechanistic details for this unique chemical transformation, we report the X-ray crystal structures of FtmOx1 and the binary complexes it forms with either the co-substrate (alpha-ketoglutarate) or the substrate (fumitremorgin B). Uniquely, after alpha-ketoglutarate has bound to the mononuclear iron centre in a bidentate fashion, the remaining open site for oxygen binding and activation is shielded from the substrate or the solvent by a tyrosine residue (Y224). Upon replacing Y224 with alanine or phenylalanine, the FtmOx1 catalysis diverts from endoperoxide formation to the more commonly observed hydroxylation. Subsequent characterizations by a combination of stopped flow optical absorption spectroscopy and freeze-quench electron paramagnetic resonance spectroscopy support the presence of transient radical species in FtmOx1 catalysis. Our results help to unravel the novel mechanism for this endoperoxide formation reaction. PMID- 26524523 TI - Corrigendum: Influence maximization in complex networks through optimal percolation. PMID- 26524524 TI - Molecular biology: DNA repair without flipping out. PMID- 26524525 TI - Structural insight into substrate preference for TET-mediated oxidation. AB - DNA methylation is an important epigenetic modification. Ten-eleven translocation (TET) proteins are involved in DNA demethylation through iteratively oxidizing 5 methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Here we show that human TET1 and TET2 are more active on 5mC-DNA than 5hmC/5fC-DNA substrates. We determine the crystal structures of TET2-5hmC-DNA and TET2-5fC-DNA complexes at 1.80 A and 1.97 A resolution, respectively. The cytosine portion of 5hmC/5fC is specifically recognized by TET2 in a manner similar to that of 5mC in the TET2-5mC-DNA structure, and the pyrimidine base of 5mC/5hmC/5fC adopts an almost identical conformation within the catalytic cavity. However, the hydroxyl group of 5hmC and carbonyl group of 5fC face towards the opposite direction because the hydroxymethyl group of 5hmC and formyl group of 5fC adopt restrained conformations through forming hydrogen bonds with the 1-carboxylate of NOG and N4 exocyclic nitrogen of cytosine, respectively. Biochemical analyses indicate that the substrate preference of TET2 results from the different efficiencies of hydrogen abstraction in TET2-mediated oxidation. The restrained conformation of 5hmC and 5fC within the catalytic cavity may prevent their abstractable hydrogen(s) adopting a favourable orientation for hydrogen abstraction and thus result in low catalytic efficiency. Our studies demonstrate that the substrate preference of TET2 results from the intrinsic value of its substrates at their 5mC derivative groups and suggest that 5hmC is relatively stable and less prone to further oxidation by TET proteins. Therefore, TET proteins are evolutionarily tuned to be less reactive towards 5hmC and facilitate the generation of 5hmC as a potentially stable mark for regulatory functions. PMID- 26524526 TI - Retraction: Non-blinking semiconductor nanocrystals. PMID- 26524527 TI - Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. AB - Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment. PMID- 26524528 TI - Autophagy mediates degradation of nuclear lamina. AB - Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases. Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery, is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis. PMID- 26524529 TI - Cancer: Organ-seeking vesicles. PMID- 26524531 TI - The DNA glycosylase AlkD uses a non-base-flipping mechanism to excise bulky lesions. AB - Threats to genomic integrity arising from DNA damage are mitigated by DNA glycosylases, which initiate the base excision repair pathway by locating and excising aberrant nucleobases. How these enzymes find small modifications within the genome is a current area of intensive research. A hallmark of these and other DNA repair enzymes is their use of base flipping to sequester modified nucleotides from the DNA helix and into an active site pocket. Consequently, base flipping is generally regarded as an essential aspect of lesion recognition and a necessary precursor to base excision. Here we present the first, to our knowledge, DNA glycosylase mechanism that does not require base flipping for either binding or catalysis. Using the DNA glycosylase AlkD from Bacillus cereus, we crystallographically monitored excision of an alkylpurine substrate as a function of time, and reconstructed the steps along the reaction coordinate through structures representing substrate, intermediate and product complexes. Instead of directly interacting with the damaged nucleobase, AlkD recognizes aberrant base pairs through interactions with the phosphoribose backbone, while the lesion remains stacked in the DNA duplex. Quantum mechanical calculations revealed that these contacts include catalytic charge-dipole and CH-pi interactions that preferentially stabilize the transition state. We show in vitro and in vivo how this unique means of recognition and catalysis enables AlkD to repair large adducts formed by yatakemycin, a member of the duocarmycin family of antimicrobial natural products exploited in bacterial warfare and chemotherapeutic trials. Bulky adducts of this or any type are not excised by DNA glycosylases that use a traditional base-flipping mechanism. Hence, these findings represent a new model for DNA repair and provide insights into catalysis of base excision. PMID- 26524530 TI - Tumour exosome integrins determine organotropic metastasis. AB - Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins alpha6beta4 and alpha6beta1 were associated with lung metastasis, while exosomal integrin alphavbeta5 was linked to liver metastasis. Targeting the integrins alpha6beta4 and alphavbeta5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ specific metastasis. PMID- 26524532 TI - Migratory neuronal progenitors arise from the neural plate borders in tunicates. AB - The neural crest is an evolutionary novelty that fostered the emergence of vertebrate anatomical innovations such as the cranium and jaws. During embryonic development, multipotent neural crest cells are specified at the lateral borders of the neural plate before delaminating, migrating and differentiating into various cell types. In invertebrate chordates (cephalochordates and tunicates), neural plate border cells express conserved factors such as Msx, Snail and Pax3/7 and generate melanin-containing pigment cells, a derivative of the neural crest in vertebrates. However, invertebrate neural plate border cells have not been shown to generate homologues of other neural crest derivatives. Thus, proposed models of neural crest evolution postulate vertebrate-specific elaborations on an ancestral neural plate border program, through acquisition of migratory capabilities and the potential to generate several cell types. Here we show that a particular neuronal cell type in the tadpole larva of the tunicate Ciona intestinalis, the bipolar tail neuron, shares a set of features with neural-crest derived spinal ganglia neurons in vertebrates. Bipolar tail neuron precursors derive from caudal neural plate border cells, delaminate and migrate along the paraxial mesoderm on either side of the neural tube, eventually differentiating into afferent neurons that form synaptic contacts with both epidermal sensory cells and motor neurons. We propose that the neural plate borders of the chordate ancestor already produced migratory peripheral neurons and pigment cells, and that the neural crest evolved through the acquisition of a multipotent progenitor regulatory state upstream of multiple, pre-existing neural plate border cell differentiation programs. PMID- 26524533 TI - Entangling two transportable neutral atoms via local spin exchange. AB - To advance quantum information science, physical systems are sought that meet the stringent requirements for creating and preserving quantum entanglement. In atomic physics, robust two-qubit entanglement is typically achieved by strong, long-range interactions in the form of either Coulomb interactions between ions or dipolar interactions between Rydberg atoms. Although such interactions allow fast quantum gates, the interacting atoms must overcome the associated coupling to the environment and cross-talk among qubits. Local interactions, such as those requiring substantial wavefunction overlap, can alleviate these detrimental effects; however, such interactions present a new challenge: to distribute entanglement, qubits must be transported, merged for interaction, and then isolated for storage and subsequent operations. Here we show how, using a mobile optical tweezer, it is possible to prepare and locally entangle two ultracold neutral atoms, and then separate them while preserving their entanglement. Ground state neutral atom experiments have measured dynamics consistent with spin entanglement, and have detected entanglement with macroscopic observables; we are now able to demonstrate position-resolved two-particle coherence via application of a local gradient and parity measurements. This new entanglement-verification protocol could be applied to arbitrary spin-entangled states of spatially separated atoms. The local entangling operation is achieved via spin-exchange interactions, and quantum tunnelling is used to combine and separate atoms. These techniques provide a framework for dynamically entangling remote qubits via local operations within a large-scale quantum register. PMID- 26524534 TI - Corrigendum: A basal ichthyosauriform with a short snout from the Lower Triassic of China. PMID- 26524535 TI - Co-delivery of small molecule hedgehog inhibitor and miRNA for treating liver fibrosis. AB - In liver fibrosis, secretion of growth factors and hedgehog (Hh) ligands by hepatic parenchyma upon repeated insults results in transdifferentiation of quiescent hepatic stellate cells (HSCs) into active myofibroblasts which secrete excessive amounts of extracellular matrix (ECM) proteins. An Hh inhibitor GDC 0449 and miR-29b1 can play an important role in treating liver fibrosis by inhibiting several pro-fibrotic genes. Our in-silico analysis indicate that miR 29b1 targets several profibrotic genes like collagen type I & IV, c-MYC, PDGF beta and PI3K/AKT which are upregulated in liver fibrosis. Common bile duct ligation (CBDL) resulted in an increase in Ptch-1, Shh and Gli-1 expression. miR 29b1 and GDC-0449 were co-formulated into micelles using methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol-graft tetraethylenepentamine) (mPEG-b-PCC-g-DC-g-TEPA) copolymer, and injected systemically into CBDL mice. High concentrations of GDC-0449 and miR-29b1 were delivered to liver cells as determined by in situ liver perfusion at 30 min post systemic administration of their micelle formulation. There was a significant decrease in collagen deposition in the liver and serum injury markers, leading to improvement in liver morphology. Combination therapy was more effective in providing hepatoprotection, lowering liver injury related serum enzyme levels, reducing fibrotic protein markers such as collagen, alpha-SMA, FN-1 and p-AKT compared to monotherapy. In conclusion, inhibition of Hh pathway and restoration of miR-29b1 have the potential to act synergistically in treating CBDL-induced liver fibrosis in mice. PMID- 26524536 TI - Human in vitro 3D co-culture model to engineer vascularized bone-mimicking tissues combining computational tools and statistical experimental approach. AB - The generation of functional, vascularized tissues is a key challenge for both tissue engineering applications and the development of advanced in vitro models analyzing interactions among circulating cells, endothelium and organ-specific microenvironments. Since vascularization is a complex process guided by multiple synergic factors, it is critical to analyze the specific role that different experimental parameters play in the generation of physiological tissues. Our goals were to design a novel meso-scale model bridging the gap between microfluidic and macro-scale studies, and high-throughput screen the effects of multiple variables on the vascularization of bone-mimicking tissues. We investigated the influence of endothelial cell (EC) density (3-5 Mcells/ml), cell ratio among ECs, mesenchymal stem cells (MSCs) and osteo-differentiated MSCs (1:1:0, 10:1:0, 10:1:1), culture medium (endothelial, endothelial + angiopoietin 1, 1:1 endothelial/osteo), hydrogel type (100%fibrin, 60%fibrin+40%collagen), tissue geometry (2 * 2 * 2, 2 * 2 * 5 mm(3)). We optimized the geometry and oxygen gradient inside hydrogels through computational simulations and we analyzed microvascular network features including total network length/area and vascular branch number/length. Particularly, we employed the "Design of Experiment" statistical approach to identify key differences among experimental conditions. We combined the generation of 3D functional tissue units with the fine control over the local microenvironment (e.g. oxygen gradients), and developed an effective strategy to enable the high-throughput screening of multiple experimental parameters. Our approach allowed to identify synergic correlations among critical parameters driving microvascular network development within a bone-mimicking environment and could be translated to any vascularized tissue. PMID- 26524537 TI - A multimodal Pepstatin A peptide-based nanoagent for the molecular imaging of P glycoprotein in the brains of epilepsy rats. AB - Regional overexpression of the multidrug transporter P-glycoprotein (P-gp) in epileptic brain tissues may lower antiepileptic drugs concentrations at the target site and contribute to pharmacoresistance in refractory epilepsy. However, few techniques are available to quantitate the level of P-gp expression noninvasively in vivo. In this study, we developed a nanoagent by conjugating superparamagnetic iron oxide nanoparticles with a near infrared probe and the targeting element Pepstatin A, a peptide with specific affinity for P-gp. In a rat model of epilepsy, the nanoagent was readily and selectively accumulated within epileptogenic cerebral regions, which were detectable by both magnetic resonance imaging and optical imaging modalities. This P-gp-targeted nanoagent could be used not only in the molecular imaging of P-gp expression changes in seizure-induced regional, understanding the mechanisms of P-gp disorders, and the prediction of refractory epilepsy, but also in targeted therapies with P-gp modulators. PMID- 26524538 TI - Early in-situ cellularization of a supramolecular vascular graft is modified by synthetic stromal cell-derived factor-1alpha derived peptides. AB - In an in-situ approach towards tissue engineered cardiovascular replacement grafts, cell-free scaffolds are implanted that engage in endogenous tissue formation. Bioactive molecules can be incorporated into such grafts to facilitate cellular recruitment. Stromal cell derived factor 1alpha (SDF1alpha) is a powerful chemoattractant of lymphocytes, monocytes and progenitor cells and plays an important role in cellular signaling and tissue repair. Short SDF1alpha peptides derived from its receptor-activating domain are capable of activating the SDF1alpha-specific receptor CXCR4. Here, we show that SDF1alpha-derived peptides can be chemically modified with a supramolecular four-fold hydrogen bonding ureido-pyrimidinone (UPy) moiety, that allows for the convenient incorporation of the UPy-SDF1alpha-derived peptides into a UPy-modified polymer scaffold. We hypothesized that a UPy-modified material bioactivated with these UPy-SDF1alpha-derived peptides can retain and stimulate circulating cells in an anti-inflammatory, pro-tissue formation signaling environment. First, the early recruitment of human peripheral blood mononuclear cells to the scaffolds was analyzed in vitro in a custom-made mesofluidic device applying physiological pulsatile fluid flow. Preferential adhesion of lymphocytes with reduced expression of inflammatory factors TNFalpha, MCP1 and lymphocyte activation marker CD25 was found in the bioactivated scaffolds, indicating a reduction in inflammatory signaling. As a proof of concept, in-vivo implantation of the bioactivated scaffolds as rat abdominal aorta interposition grafts showed increased cellularity by CD68+ cells after 7 days. These results indicate that a completely synthetic, cell-free biomaterial can attract and stimulate specific leukocyte populations through supramolecular incorporation of short bioactive SDF1alpha derived peptides. PMID- 26524539 TI - siRNA delivered by EGFR-specific scFv sensitizes EGFR-TKI-resistant human lung cancer cells. AB - The overexpression of epidermal growth factor receptor (EGFR) is closely associated with a poor outcome in non-small cell lung cancer (NSCLC), and EGFR is an ideal biomarker for the targeted therapy of NSCLC. Although patients with EGFR activating mutations respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs), they eventually acquire resistance, which typically results from a secondary EGFR mutation or the activation of other signaling pathways. Novel approaches to overcome or prevent EGFR-TKI resistance are clinically important. In this study, we developed an EGFR-scFv-arginine nonamer peptide fusion protein, s-9R, as an siRNA carrier. Here, we show that s-9R effectively and specifically delivers EGFR siRNAs, KRAS-siRNA and MET-siRNA into NSCLC cells and silences the expression of target genes. The sensitivity of NSCLC cells to gefitinib was restored after treatment with the s-9R/siRNA complex, and the apoptosis rates of the treated cells were significantly higher than those of the control groups. Furthermore, the co-administration of s-9R/siRNA and gefitinib successfully suppressed the progression of H1975 xenograft tumors and extended the life span of tumor-bearing nude mice. Collectively, the results of this study provide not only a new scFv derivative for delivering siRNA into EGFR-overexpressing, TKI-resistant NSCLC cells but also a novel method for overcoming TKI resistance. PMID- 26524540 TI - Cancer cell aggregate hypoxia visualized in vitro via biocompatible fiber sensors. AB - To fully understand biological behavior in vitro often dictates that oxygen be reported at either a local or a cellular level. Oxygen sensors based on the luminescent quenching of a specific form of electrospun fiber were developed for measurement of both gaseous and dissolved oxygen concentrations. Electrospinning was used to fabricate "core-shell" fiber configurations in which oxygen-sensitive transition-metal porphyrin complexes are embedded in an optically clear, gas permeable polycarbonate polymer 'core' while polycaprolactone provided a protective yet biocompatible 'shell'. By taking advantage of the resulting high sensitivity and fast response of electrospun core-shell fiber sensors, we were able to locate and image hypoxic regions in contact with aggregates of glioblastoma cells. Nanoscale, biomimetic sensors containing oxygen-sensitive porphyrins are particularly well suited to biological applications. These 'smart' nanofiber based sensors do not consume oxygen, their mechanical and chemical characteristics can be finely tuned allowing tailoring of biocompatibility and microstructure. Core-shell nanofiber oxygen sensing fibers could provide real time assessments of tumor cell response to pharmacological innovations designed to target hypoxic regions driving new knowledge and technological advancement. PMID- 26524541 TI - Effects of a comprehensive training program on clinician beliefs about and intention to use prolonged exposure therapy for PTSD. AB - OBJECTIVE: Evidence for treatment efficacy does not guarantee adoption in clinical practice. Attitudinal "buy-in" from clinicians is also important. This study examines evaluation data from a national training program in an evidence based treatment for PTSD, Prolonged Exposure (PE) therapy, to assess changes in clinician beliefs related to the importance of specific treatment goals, PE outcome expectations, self-efficacy to deliver PE, perceived time and emotional burdens associated with delivering PE, and intentions to use PE. METHOD: Training included both an interactive workshop and posttraining telephone consultation. Participants were 943 licensed mental health clinicians who treated veterans with PTSD. They completed questionnaires before and after the workshop, and after consultation. RESULTS: Results indicated that workshop participation was associated with significant increases in perceptions of the importance of helping patients improve by employing PE, expectations that patients would benefit from PE, and self-efficacy to deliver PE, and with reduced expectations of negative patient outcomes and concerns about distressing patients. The workshop alone had little impact on expected clinician emotional burden and no impact on anticipated time burden. Participation in ongoing case consultation was associated with additional increases in expected positive patient outcomes and clinician self efficacy and further reductions in concerns about distressing patients and negative patient outcomes. Unlike the workshop, consultation was associated with decreased expectancies that PE would take too much time and would be emotionally burdensome to provide. CONCLUSION: Overall, the results suggest that the combination of workshop and ongoing consultation can significantly improve beliefs likely to affect treatment adoption. (PsycINFO Database Record PMID- 26524542 TI - Trauma Coping Self-Efficacy: A Context-Specific Self-Efficacy Measure for Traumatic Stress. AB - OBJECTIVE: The psychometric properties of a Trauma Coping Self-Efficacy (CSE-T) scale that assesses general trauma-related coping self-efficacy perceptions were assessed. METHOD: Measurement equivalence was assessed using several different samples: hospitalized trauma patients (n1 = 74, n2 = 69, n3 = 60), 3 samples of disaster survivors (n1 = 273, n2 = 227, n3 = 138), and trauma-exposed college students (N = 242). This is the first multisample evaluation of the psychometric properties for a general trauma-related CSE measure. RESULTS: Results showed that a brief and parsimonious 9-item version of the CSE performed well across the samples with a robust factor structure; factor structure and factor loadings were similar across study samples. DISCUSSION: The 9-item scale CSE-T demonstrated measurement equivalence across samples indicating that the underlying concept of general posttraumatic CSE is organized in a similar manner in the different trauma-exposed groups. These results offer strong support for cross-event construct validity of the CSE-T scale. Associations of the CSE-T with important expected covariates showed significant evidence for convergent validity. Finally, discriminant validity was also supported. Replication of the factor structure, internal reliability, and other evidence for construct validity is a critical next step for future research. (PsycINFO Database Record PMID- 26524543 TI - Shape-controlled gold nanoparticles supported on MoS2 nanosheets: synergistic effect of thionine and MoS2 and their application for electrochemical label-free immunosensing. AB - Herein, a facile approach for shape-controlled gold nanoparticle (AuNP) decorated thionine-MoS2 nanocomposites (AuNP-Thi-MoS2) had been reported by using the synergistic effect of MoS2 and Thi. Thi was not only used as an electrochemical indicator, but also as a reducing agent to tune the resulting morphologies of AuNPs. With the ratio of MoS2/Thi decreasing, the shapes of AuNPs changed from spherical, triangle, clover-like to flower-like nanostructures. TEM, XRD and XPS were employed to characterize the formation and chemical composition of AuNP-Thi MoS2 nanocomposites. On the basis of synthesis, a MoS2-based label-free electrochemical immunosensor had been designed to detect carcino-embryonic antigen (CEA). The proposed immunosensor could detect as low as 0.52 pg mL(-1) CEA with excellent selectivity. Moreover, the expected immunosensor showed high stability and excellent reproducibility, which could detect CEA in human serum with satisfactory results. Therefore, the AuNP-Thi-MoS2 nanocomposites may be considered as a candidate sensing platform for fabrication of simple, label-free and ultrasensitive electrochemical sensors. PMID- 26524544 TI - Ni-catalyzed reductive addition of alkyl halides to isocyanides. AB - This paper highlights Ni-catalyzed reductive trapping of secondary and tertiary alkyl radicals with both electron-rich and electron-deficient aryl isocyanides using zinc as the terminal reductant, affording 6-alkylated phenanthridine in good yields. The employment of carbene ligands necessitates the alkyl radical process, and represents the first utility in the Ni-catalyzed reductive conditions for the generation of unactivated alkyl radicals from the halide precursors. PMID- 26524545 TI - Development of a DNA Microarray-Based Assay for the Detection of Sugar Beet Root Rot Pathogens. AB - Sugar beet root rot diseases that occur during the cropping season or in storage are accompanied by high yield losses and a severe reduction of processing quality. The vast diversity of microorganism species involved in rot development requires molecular tools allowing simultaneous identification of many different targets. Therefore, a new microarray technology (ArrayTube) was applied in this study to improve diagnosis of sugar beet root rot diseases. Based on three marker genes (internal transcribed spacer, translation elongation factor 1 alpha, and 16S ribosomal DNA), 42 well-performing probes enabled the identification of prevalent field pathogens (e.g., Aphanomyces cochlioides), storage pathogens (e.g., Botrytis cinerea), and ubiquitous spoilage fungi (e.g., Penicillium expansum). All probes were proven for specificity with pure cultures from 73 microorganism species as well as for in planta detection of their target species using inoculated sugar beet tissue. Microarray-based identification of root rot pathogens in diseased field beets was successfully confirmed by classical detection methods. The high discriminatory potential was proven by Fusarium species differentiation based on a single nucleotide polymorphism. The results demonstrate that the ArrayTube constitute an innovative tool allowing a rapid and reliable detection of plant pathogens particularly when multiple microorganism species are present. PMID- 26524546 TI - Isolation and Characterization of Plant-Pathogenic Streptomyces Species Associated with Common Scab-Infected Potato Tubers in Newfoundland. AB - Potato common scab (CS) is an economically important crop disease that is caused by several members of the genus Streptomyces. In this study, we characterized the plant-pathogenic Streptomyces spp. associated with CS-infected potato tubers harvested in Newfoundland, Canada. A total of 17 pathogenic Streptomyces isolates were recovered from potato scab lesions, of which eight were determined to be most similar to the known CS pathogen S. europaeiscabiei. All eight S. europaeiscabiei isolates were found to produce the thaxtomin A phytotoxin and to harbor the nec1 virulence gene, and most also carry the putative virulence gene tomA. The remaining isolates appear to be novel pathogenic species that do not produce thaxtomin A, and only two of these isolates were determined to harbor the nec1 or tomA genes. Of the non-thaxtomin-producing isolates, strain 11-1-2 was shown to exhibit a severe pathogenic phenotype against different plant hosts and to produce a novel, secreted phytotoxic substance. This is the first report documenting the plant-pathogenic Streptomyces spp. associated with CS disease in Newfoundland. Furthermore, our findings provide further evidence that phytotoxins other than thaxtomin A may also contribute to the development of CS by Streptomyces spp. PMID- 26524547 TI - Genome-Wide Analysis of Small Secreted Cysteine-Rich Proteins Identifies Candidate Effector Proteins Potentially Involved in Fusarium graminearum-Wheat Interactions. AB - Pathogen-derived, small secreted cysteine-rich proteins (SSCPs) are known to be a common source of fungal effectors that trigger resistance or susceptibility in specific host plants. This group of proteins has not been well studied in Fusarium graminearum, the primary cause of Fusarium head blight (FHB), a devastating disease of wheat. We report here a comprehensive analysis of SSCPs encoded in the genome of this fungus and selection of candidate effector proteins through proteomics and sequence/transcriptional analyses. A total of 190 SSCPs were identified in the genome of F. graminearum (isolate PH-1) based on the presence of N-terminal signal peptide sequences, size (<=200 amino acids), and cysteine content (>=2%) of the mature proteins. Twenty-five (approximately 13%) SSCPs were confirmed to be true extracellular proteins by nanoscale liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) analysis of a minimal medium-based in vitro secretome. Sequence analysis suggested that 17 SSCPs harbor conserved functional domains, including two homologous to Ecp2, a known effector produced by the tomato pathogen Cladosporium fulvum. Transcriptional analysis revealed that at least 34 SSCPs (including 23 detected in the in vitro secretome) are expressed in infected wheat heads; about half are up-regulated with expression patterns correlating with the development of FHB. This work provides a solid candidate list for SSCP-derived effectors that may play roles in mediating F. graminearum-wheat interactions. The in vitro secretome-based method presented here also may be applicable for identifying candidate effectors in other ascomycete pathogens of crop plants. PMID- 26524548 TI - Hip Preservation: Current Concepts and Future Frontiers. PMID- 26524549 TI - Biomechanics of the Hip Capsule and Capsule Management Strategies in Hip Arthroscopy. AB - Recent advances in our understanding of the function of the hip capsule have clarified its importance to normal hip function and kinematics. The iliofemoral ligament is the primary stabilizing structure for controlling anterior translation and external rotation of the hip, and is violated by the arthroscopic interportal capsulotomy. Microinstability of the hip occurring after surgical trauma remains a poorly defined clinical entity. In certain at-risk populations, capsular repair should be considered as part of an arthroscopic hip procedure to achieve optimal outcomes and avoid iatrogenic instability (dislocation or microinstability). Despite a lack of conclusive evidence-based indications, we recommend capsular repair in the settings of borderline hip dysplasia (or dysplastic variants such as increased femoral anteversion), hip hypermobility, connective tissue disorders, and traumatic or atraumatic instability. With careful attention to arthroscopic capsular management, adequate exposure can be achieved and reproducibly allow for an effective capsular repair when indicated. PMID- 26524550 TI - Biomechanical Implications of Corrective Surgery for FAI: An Evidence-based Review. AB - Femoroacetabular impingement (FAI) has been identified as a potential cause of hip osteoarthritis. The goal of FAI surgery is to relieve pain, and hopefully delay or prevent osteoarthritis of the hip. Several studies have now demonstrated favorable clinical outcomes after arthroscopic and open surgical correction of symptomatic FAI. The concept is restoration of normal hip anatomy may result in improved biomechanical function and kinematics of the hip, which may prevent or delay the progression of osteoarthritis. Although many clinical studies demonstrate restoration of "normal" anatomy, there are few studies evaluating improvement of biomechanics and function. To date, only 5 studies have been published in the English literature that study biomechanics and/or kinematics of the hip both preoperatively and postoperatively. At this point in the understanding of FAI, critical analysis of the literature suggests that FAI surgery can improve several parameters of biomechanical hip function. However, the impact of these improved biomechanics on the natural history and progression of degenerative changes in patients that are treated for symptomatic FAI has not been demonstrated. PMID- 26524551 TI - Does Femoroacetabular Impingement Contribute to the Development of Hip Osteoarthritis? A Systematic Review. AB - Femoroacetabular impingement (FAI) has been linked to specific patterns of cartilage damage. The goal of this systematic review is to answer the following questions: (1) Does FAI contribute to the development and progression of hip osteoarthritis (OA)? (2) If FAI does contribute to the development and progression of hip OA, does CAM-type or pincer-type impingement play a greater role? A search of the electronic databases, MEDLINE and EMBASE, was performed to identify relevant studies performed between January 1, 2000 and January 1, 2015 that link the pathophysiology of OA to FAI. Methodological quality of included studies was assessed by 2 reviewers using the Methodological Index for Non Randomized Studies criteria. An intraclass correlation coefficient with 95% confidence intervals was used to determine agreement between reviewers on quality scores. Overall 35 studies were identified that met inclusion criteria. Certain morphologic features of CAM-type FAI, particularly elevated alpha angle, do seem to predispose select patients to radiographic progression of hip OA. In comparison with pincer-type impingement, the association between CAM-type impingement and hip OA is better understood. Long-term surgical outcome studies will further delineate the role of FAI in the development and progression of hip OA. PMID- 26524552 TI - The Dysplastic and Unstable Hip: A Responsible Balance of Arthroscopic and Open Approaches. AB - The treatment of young adult hip disorders, including hip dysplasia, has evolved significantly in the last decade. The association of hip dysplasia with hip osteoarthritis is well accepted, but remains based on basic radiographic parameters. Our understanding of the complexity and variability of hip dysplasia continues to evolve. As the clinical presentation of mild and borderline acetabular dysplasia is very similar to that of other young adult hip disorders, such as femoroacetabular impingement, a thorough history, physical examination, and radiographic evaluation are important to properly diagnose these patients. Acetabular reorientation via the periacetabular osteotomy has become the most common treatment for acetabular dysplasia with good outcomes reported at over 20 years postoperatively. The treatment of intra-articular labrochondral pathology and femoral head-neck offset abnormalities at the time of periacetabular osteotomy has become more common place with the theoretical goal of improving long-term outcomes. The borderline dysplastic hip remains a controversial topic, with significant overlap with other causes of hip microinstability such as connective tissue laxity. In the current article, we present a relevant review of the literature and a balanced approach to the treatment of acetabular dysplasia. PMID- 26524553 TI - Complications in Hip Arthroscopy: A Systematic Review and Strategies for Prevention. AB - The primary objective of this study was to determine the minor and major complication rate of hip arthroscopy. The secondary objective was to provide strategies for avoiding complications. A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines and checklist. Therapeutic hip arthroscopy investigations that reported on adverse events or complications were included. Narrative and other systematic reviews, meta-analyses, conference abstracts or proceedings, and level V evidence studies were excluded. No follow-up minimum was imposed. The results yielded 53 studies (8189 hip arthroscopies in 8071 subjects). Most studies were level IV evidence (74%) with a mean of 2.2+/-2.1 years follow-up. Femoroacetabular impingement (FAI) and labral pathology were the 2 most common indications for surgery, and osteochondroplasty for FAI and labral treatment were the 2 most common procedures performed. The minor and major complication rates were 7.9% and 0.45%, respectively. Iatrogenic chondrolabral damage and temporary nerve injury were the 2 most common minor complications. Extra-articular fluid extravasation was the most common major complication encountered. Minor complications associated with hip arthroscopy are generally technical in nature and may be related to the learning curve associated with hip arthroscopy. As surgeon experience increases and patient selection improves, a corresponding decline should be observed in minor complications. Strategies to prevent complications include careful preoperative planning, appropriate surgical indications, attention to detail in the operating room, and proper postoperative rehabilitation. PMID- 26524555 TI - Management of Labral and Chondral Disease in Hip Preservation Surgery. AB - The techniques utilized for the management of articular cartilage and labrum injuries during hip preservation surgery have changed dramatically recently. Conservative treatment may involve image-guided injection of cortisone or viscosupplementation in conjunction with oral NSAIDs and physical therapy. Damage to the labrum runs a broad spectrum, and the treatments are individualized, but span from debridement to repair and reconstruction. The overarching goal of labral treatment is to restore the native functions of the labrum to allow for more normal biomechanical function. Similarly, cartilage injuries can be managed a number of different ways, including with debridement, microfracture or drilling, cartilage transplants, and higher level restorative techniques. These cartilage restoration techniques have evolved rapidly as well, and may include the use of scaffolds, allograft cartilage cells, and other stem-cell-related procedures. PMID- 26524554 TI - Understanding and Treating the Snapping Hip. AB - Snapping hip, or coxa saltans is a palpable or auditory snapping with movement of the hip joint. Extra-articular snapping is divided into external and internal types, and is caused laterally by the iliotibial band and anteriorly by the iliopsoas tendon. Snapping of the iliopsoas usually requires contraction of the hip flexors and may be difficult to distinguish from intra-articular coxa saltans. Ultrasound can be a useful modality to dynamically detect tendon translation during hip movement to support the diagnosis of extra-articular snapping. Coxa saltans is typically treated with conservative measures including anti-inflammatories, stretching, and avoidance of inciting activities. Recalcitrant cases are treated with surgery to lengthen the iliopsoas or the iliotibial band. PMID- 26524556 TI - Evidence and Approach for Management of Labral Deficiency: The Role for Labral Reconstruction. AB - The acetabular labrum is a complex fibrocartilaginous structure with unique anatomy. Its unique anatomy imparts biomechanical functions important in hip stability, synovial fluid dynamics, contact pressure dissipation, proprioception, and nociception. Although the importance of labral preservation through surgical repair techniques has been increasingly recognized, situations do occur where the labrum is either absent, deficient, or simply irreparable. In these situations, both open and arthroscopic reconstructive techniques have been described to help restore the function of the native labral tissue. Efforts should be made to maintain or reestablish the native structure and function of the labrum in young patients with at least 2 mm of joint space based on the available biomechanical and clinical evidence. Return to sport, significant improvements in pain and function, high levels of satisfaction, and avoidance of hip arthroplasty have been shown in patients undergoing labral reconstruction. Although short-term results of labral reconstruction are promising, long-term follow-up and comparative studies will be necessary to further define its indications and contraindications. PMID- 26524557 TI - Core Muscle Injury/Sports Hernia/Athletic Pubalgia, and Femoroacetabular Impingement. AB - Core muscle injury/sports hernia/athletic pubalgia is an increasingly recognized source of pain, disability, and time lost from athletics. Groin pain among athletes, however, may be secondary to various etiologies. A thorough history and comprehensive physical examination, coupled with appropriate diagnostic imaging, may improve the diagnostic accuracy for patients who present with core muscular injuries. Outcomes of nonoperative management have not been well delineated, and multiple operative procedures have been discussed with varying return-to-athletic activity rates. In this review, we outline the clinical entity and treatment of core muscle injury and athletic pubalgia. In addition, we describe the relationship between athletic pubalgia and femoroacetabular impingement along with recent studies that have investigated the treatment of these related disorders. PMID- 26524558 TI - Disorders of the Peritrochanteric and Deep Gluteal Space: New Frontiers for Arthroscopy. AB - Arthroscopic techniques for the hip joint have evolved into endoscopic methods for extra-articular disorders. These endoscopic strategies provide a less invasive alternative to open procedures for traditionally recognized forms of pathology. Endoscopy has defined new disorders amenable to surgical correction and has redefined some of these existing disorders. The peritrochanteric and deep gluteal regions represent 2 of the most currently active areas of exploration. Peritrochanteric problems include trochanteric bursitis, full-thickness and partial-thickness tears of the abductors including the gluteus medius and minimus, and external coxa saltans (snapping iliotibial band). Deep gluteal disorders include piriformis syndrome, and other variations of deep gluteal syndrome, and ischiofemoral impingement. Each of these evolving areas is highlighted in this chapter. PMID- 26524559 TI - Three-dimensional Imaging and Computer Navigation in Planning for Hip Preservation Surgery. AB - Hip preservation surgery is performed to address femoroacetabular impingement, alleviate any associated pain, and reduce the risk of early onset of osteoarthritis. In the last decade, arthroscopy has become more popular in addressing femoroacetabular impingement, due to its minimally invasive approach. However, poor visualization and limited spatial awareness of the joint make arthroscopy of the hip difficult, resulting in a steep learning curve. This paper reviews the utility and benefits of 3-dimensional imaging and computer navigation and what these tools may add to the preoperative planning stages of hip preservation surgery. PMID- 26524562 TI - The hidden process of positive doctor role modelling. AB - BACKGROUND: Role modelling is highlighted as an important phenomenon. The aim of this research study was to explore the process of positive doctor role modelling. METHODS: This study used focus group interviews with 52 medical students, semi structured interviews with 25 consultants and interviews after clinics with five consultants and five medical students. A qualitative methodology using the grounded theory inquiry approach of Strauss and Corbin was then used to generate an explanation of the process of modelling. RESULTS: Role modelling is a process that involves conscious and subconscious elements and consists of an exposure phase followed by an evolution phase: The exposure phase involves demonstration of the attributes by the doctor role models. The evolution phase begins with observation of the role model, following which the modellee makes a judgement whether to trial the observed behaviours; when the decision to trial is reached, this then leads to a model-trialling cycle. CONCLUSION: This research study generated a detailed explanation of the process of doctor role modelling. It is aspired that this can now be incorporated into medical curricula worldwide to enhance the development of the doctor role model and the professional development of the modellee. PMID- 26524564 TI - Error in Abstract. PMID- 26524563 TI - Dual-fluorescence pH probe for bio-labelling. AB - Although seminaphtorhodafluor (SNARF) dyes are already widely used to measure pH in cells and at biofilms, their synthesis has low yield and results in an unspecific position of a carboxy-group. The separation of 5'- and 6'-carboxy SNARF reveals a pKa difference of 0.15, calling into question pH measurements with the (commercially available) mixture. Here we replace the bulky external dicarboxyphenyl ring with a propionate group and evaluate the spectral properties of the new derivative. Proceeding to the ethyl-iodoacetamide, covalent linkage to cysteine protein sites is achieved efficiently as shown with a cyanobacterial phytochrome, extending the scarce application of SNARF in bio-labelling in the current literature. Application in fluorescence lifetime imaging is demonstrated both with the lifetime-based and ratiometric-yield method. PMID- 26524565 TI - Correction: Towards the rationalization of catalytic activity values by means of local hyper-softness on the catalytic site: a criticism about the use of net electric charges. AB - Correction for 'Towards the rationalization of catalytic activity values by means of local hyper-softness on the catalytic site: a criticism about the use of net electric charges' by Jorge Ignacio Martinez-Araya et al., Phys. Chem. Chem. Phys., 2015, DOI: 10.1039/c5cp03822g. PMID- 26524566 TI - Insertion Depth in Cochlear Implantation and Outcome in Residual Hearing and Vestibular Function. AB - OBJECTIVES: It has long been known that cochlear implantation may cause loss of residual hearing and vestibular function. Different insertion depths may cause varying degrees of intracochlear trauma in the apical region of the cochlea. The present study investigated the correlation between the insertion depth and postoperative loss of residual hearing and vestibular function. DESIGN: Thirty nine adults underwent unilateral cochlear implantation. One group received a Med El +Flex electrode array (24 mm; n = 4), 1 group received a Med-El +Flex electrode array (28 mm; n = 18), and 1 group received a Med-El +Flex electrode array (31.5 mm; n = 17). Residual hearing, cervical vestibular-evoked myogenic potentials, videonystagmography, and subjective visual vertical/horizontal were explored before and after surgery. The electrode insertion depth and scalar position were examined with high-resolution rotational tomography after implantation in 29 subjects. RESULTS: There was no observed relationship between the angular insertion depth (405 degrees to 708 degrees ) and loss of low frequency pure-tone average. Frequency-specific analysis revealed a weak relationship between the angular insertion depth and loss of hearing at 250 Hz (R= 0.20; p = 0.02). There was no statistically significant difference in the residual hearing and vestibular function between the +Flex and the +Flex electrode array. Eight percent of the cases had vertigo after surgery. The electrode arrays were positioned inside the scala tympani and not scala vestibuli in all subjects. In 18% of the cases, the +Flex electrode array was not fully inserted. CONCLUSIONS: The final outcome in residual hearing correlates very weakly with the angular insertion depth for depths above 405 degrees . Postoperative loss of vestibular function did not correlate with the angular insertion depth or age at implantation. The surgical protocol used in this study seems to minimize the risk of postoperative vertigo symptoms. PMID- 26524567 TI - Diagnosis of Amelanotic Lentigo Maligna by Using In vivo Reflectance Confocal Microscopy. PMID- 26524568 TI - Physical Exercise as Therapy for Frailty. AB - Longitudinal studies demonstrate that regular physical exercise extends longevity and reduces the risk of physical disability. Decline in physical activity with aging is associated with a decrease in exercise capacity that predisposes to frailty. The frailty syndrome includes a lowered activity level, poor exercise tolerance, and loss of lean body and muscle mass. Poor exercise tolerance is related to aerobic endurance. Aerobic endurance training can significantly improve peak oxygen consumption by ~10-15%. Resistance training is the best way to increase muscle strength and mass. Although the increase in muscle mass in response to resistance training may be attenuated in frail older adults, resistance training can significantly improve muscle strength, particularly in institutionalized patients, by ~110%. Because both aerobic and resistance training target specific components of frailty, studies combining aerobic and resistance training provide the most promising evidence with respect to successfully treating frailty. At the molecular level, exercise reduces frailty by decreasing muscle inflammation, increasing anabolism, and increasing muscle protein synthesis. More studies are needed to determine which exercises are best suited, most effective, and safe for this population. Based on the available studies, an individualized multicomponent exercise program that includes aerobic activity, strength exercises, and flexibility is recommended to treat frailty. PMID- 26524569 TI - A Nonconventional Model of Protocell-like Vesicles: Anionic Clay Surface-Mediated Formation from a Single-Tailed Amphiphile. AB - We report a novel model system of precursor cellular membranes, self-assembled from micellar solution of a common anionic single-tailed amphiphile (STA), including sodium dodecyl sulfate (SDS) and sodium dodecylbenzenesulfonate (SDBS). The self-assembly process was mediated with solid surfaces of Mg2Al-CO3 hydrotalcite-like compound (HTlc), an anionic clay, in the absence of cosurfactants or any additives. The resultant STA vesicles were characterized using negative-staining and cryogenic transmission electron microscopies, as well as dynamic light scattering and steady state fluorescence techniques. Interestingly, the obtained STA vesicles displayed good stability even after the removal of the anionic clay surface (ACS), and a self-reproduction phenomenon was observed for the "preformed" STA vesicles when mixing with corresponding STA micellar solutions. More importantly, the micelle-to-vesicle transition for SDS could be still arisen in high-salinity artificial seawater under the ACS mediation. Instead of conventional fatty acid scenario, our finding provides another novel possible model for protocell-like vesicles, which are easily formed under the plausible prebiotic conditions. PMID- 26524570 TI - Could Profilin Be a 'Canary in a Coal Mine' of the Increasing Allergy Epidemic? PMID- 26524573 TI - Celebrating the ACP Centennial: From the Annals Archive--Emergency Response and Life Support. PMID- 26524571 TI - Alexander Technique Lessons or Acupuncture Sessions for Persons With Chronic Neck Pain: A Randomized Trial. AB - BACKGROUND: Management of chronic neck pain may benefit from additional active self-care-oriented approaches. OBJECTIVE: To evaluate clinical effectiveness of Alexander Technique lessons or acupuncture versus usual care for persons with chronic, nonspecific neck pain. DESIGN: Three-group randomized, controlled trial. (Current Controlled Trials: ISRCTN15186354). SETTING: U.K. primary care. PARTICIPANTS: Persons with neck pain lasting at least 3 months, a score of at least 28% on the Northwick Park Questionnaire (NPQ) for neck pain and associated disability, and no serious underlying pathology. INTERVENTION: 12 acupuncture sessions or 20 one-to-one Alexander lessons (both 600 minutes total) plus usual care versus usual care alone. MEASUREMENTS: NPQ score (primary outcome) at 0, 3, 6, and 12 months (primary end point) and Chronic Pain Self-Efficacy Scale score, quality of life, and adverse events (secondary outcomes). RESULTS: 517 patients were recruited, and the median duration of neck pain was 6 years. Mean attendance was 10 acupuncture sessions and 14 Alexander lessons. Between-group reductions in NPQ score at 12 months versus usual care were 3.92 percentage points for acupuncture (95% CI, 0.97 to 6.87 percentage points) (P = 0.009) and 3.79 percentage points for Alexander lessons (CI, 0.91 to 6.66 percentage points) (P = 0.010). The 12-month reductions in NPQ score from baseline were 32% for acupuncture and 31% for Alexander lessons. Participant self-efficacy improved for both interventions versus usual care at 6 months (P < 0.001) and was significantly associated (P < 0.001) with 12-month NPQ score reductions (acupuncture, 3.34 percentage points [CI, 2.31 to 4.38 percentage points]; Alexander lessons, 3.33 percentage points [CI, 2.22 to 4.44 percentage points]). No reported serious adverse events were considered probably or definitely related to either intervention. LIMITATION: Practitioners belonged to the 2 main U.K. based professional associations, which may limit generalizability of the findings. CONCLUSION: Acupuncture sessions and Alexander Technique lessons both led to significant reductions in neck pain and associated disability compared with usual care at 12 months. Enhanced self-efficacy may partially explain why longer-term benefits were sustained. PRIMARY FUNDING SOURCE: Arthritis Research UK. PMID- 26524575 TI - Through My Eyes. PMID- 26524576 TI - Informed Consent for Research on Medical Practices. PMID- 26524577 TI - Informed Consent for Research on Medical Practices. PMID- 26524578 TI - Screening for Type 2 Diabetes Mellitus. PMID- 26524579 TI - Screening for Type 2 Diabetes Mellitus. PMID- 26524580 TI - Opportunities and Challenges for Reducing Hospital Revisits. PMID- 26524581 TI - Opportunities and Challenges for Reducing Hospital Revisits. PMID- 26524582 TI - Summaries for Patients. Alexander Technique Lessons or Acupuncture Sessions for Persons With Chronic Neck Pain. PMID- 26524583 TI - Web Exclusives. Annals Graphic Medicine: The Daily Grind: A Day in the Life of Someone Living With Diabetes. PMID- 26524584 TI - In the Clinic. Restless Legs Syndrome. AB - This issue provides a clinical overview of restless legs syndrome, focusing on diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers. PMID- 26524585 TI - Mechanistic Aspects of the Phosphine-Catalyzed Isomerization of Allenic Sulfones to 2-Arylsulfonyl 1,3-Dienes. AB - When an allenic sulfone is treated with a phosphine nucleophile and a proton shuttle, an isomerization to a 2-arylsulfonyl 1,3-diene occurs. Mechanistic aspects of the process were investigated leading to the formulation of a mechanism for the reaction. Some further optimization studies of this process are reported. PMID- 26524586 TI - The one-step synthesis and surface functionalization of dumbbell-like gold-iron oxide nanoparticles: a chitosan-based nanotheranostic system. AB - The first one-step synthesis of dumbbell-like gold-iron oxide nanoparticles has been reported here. Surface functionalization with a biocompatible chitosan matrix allowed us to obtain a novel targetable diagnostic and therapeutic tool. PMID- 26524587 TI - Dishonesty in scientific research. AB - Fraudulent business practices, such as those leading to the Enron scandal and the conviction of Bernard Madoff, evoke a strong sense of public outrage. But fraudulent or dishonest actions are not exclusive to the realm of big corporations or to evil individuals without consciences. Dishonest actions are all too prevalent in everyone's daily lives, because people are constantly encountering situations in which they can gain advantages by cutting corners. Whether it's adding a few dollars in value to the stolen items reported on an insurance claim form or dropping outlier data points from a figure to make a paper sound more interesting, dishonesty is part of the human condition. Here, we explore how people rationalize dishonesty, the implications for scientific research, and what can be done to foster a culture of research integrity. PMID- 26524588 TI - A conversation with Oliver Smithies. PMID- 26524589 TI - HA-ving lymphatics improves lung transplantation. AB - Lung allografts are prone to rejection, even though recipients undergo aggressive immunosuppressive therapy. Lymphatic vessels serve as conduits for immune cell trafficking and have been implicated in the mediation of allograft rejection. In this issue of the JCI, Cui et al. provide compelling evidence that lymphatic vessel formation improves lung allograft survival in a murine transplant model. Moreover, their data suggest a potential mechanism for the beneficial effects of lymphatics that does not involve immune cell or antigen transport. Together, the results of this study provide new insight into the role of lymphatic vessels in transplant tolerance. PMID- 26524590 TI - Mucosal-associated invariant T cell-rich congenic mouse strain allows functional evaluation. AB - Mucosal-associated invariant T cells (MAITs) have potent antimicrobial activity and are abundant in humans (5%-10% in blood). Despite strong evolutionary conservation of the invariant TCR-alpha chain and restricting molecule MR1, this population is rare in laboratory mouse strains (~0.1% in lymphoid organs), and lack of an appropriate mouse model has hampered the study of MAIT biology. Herein, we show that MAITs are 20 times more frequent in clean wild-derived inbred CAST/EiJ mice than in C57BL/6J mice. Increased MAIT frequency was linked to one CAST genetic trait that mapped to the TCR-alpha locus and led to higher usage of the distal Valpha segments, including Valpha19. We generated a MAIThi congenic strain that was then crossed to a transgenic Rorcgt-GFP reporter strain. Using this tool, we characterized polyclonal mouse MAITs as memory (CD44+) CD4 CD8lo/neg T cells with tissue-homing properties (CCR6+CCR7-). Similar to human MAITs, mouse MAITs expressed the cytokine receptors IL-7R, IL-18Ralpha, and IL 12Rbeta and the transcription factors promyelocytic leukemia zinc finger (PLZF) and RAR-related orphan receptor gamma (RORgammat). Mouse MAITs produced Th1/2/17 cytokines upon TCR stimulation and recognized a bacterial compound in an MR1 dependent manner. During experimental urinary tract infection, MAITs migrated to the bladder and decreased bacterial load. Our study demonstrates that the MAIThi congenic strain allows phenotypic and functional characterization of naturally occurring mouse MAITs in health and disease. PMID- 26524591 TI - Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. AB - Autosomal recessive mutations in proteasome subunit beta 8 (PSMB8), which encodes the inducible proteasome subunit beta5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes alpha7), PSMB4 (encodes beta7), PSMB9 (encodes beta1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production. PMID- 26524592 TI - Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. AB - FOXP3+ Tregs are central for the maintenance of self-tolerance and can be defective in autoimmunity. In multiple sclerosis and type-1 diabetes, dysfunctional self-tolerance is partially mediated by a population of IFNgamma secreting Tregs. It was previously reported that increased NaCl concentrations promote the induction of proinflammatory Th17 cells and that high-salt diets exacerbate experimental models of autoimmunity. Here, we have shown that increasing NaCl, either in vitro or in murine models via diet, markedly impairs Treg function. NaCl increased IFNgamma secretion in Tregs, and reducing IFNgamma either by neutralization with anti-IFNgamma antibodies or shRNA-mediated knockdown - restored suppressive activity in Tregs. The heightened IFNgamma secretion and loss of Treg function were mediated by the serum/glucocorticoid regulated kinase (SGK1). A high-salt diet also impaired human Treg function and was associated with the induction of IFNgamma-secreting Tregs in a xenogeneic graft-versus-host disease model and in adoptive transfer models of experimental colitis. Our results demonstrate a putative role for an environmental factor that promotes autoimmunity by inducing proinflammatory responses in CD4 effector cells and Treg pathways. PMID- 26524594 TI - Calcium release channel RyR2 regulates insulin release and glucose homeostasis. PMID- 26524595 TI - A conversation with Helen Hobbs. PMID- 26524596 TI - Strong Quantum Coupling in the Vibrational Signatures of a Symmetric Ionic Hydrogen Bond: The Case of (CH3OH)2H(.). AB - Vibrational coupling between proton and flanking group motions in the ionic hydrogen bond (IHB) of (CH3OH)2H(+) were studied by solving reduced-dimension vibrational Schrodinger equations. Potential energy and dipole surfaces along a few key normal modes were constructed with high-level ab initio methods. It was found that the IHB stretch parallel to O-O axis strongly couples with the out-of phase C-O stretch and out-of-phase in-plane CH3 rock with COH deformation. Such strong quantum coupling leads to a complex triplet at 850-1100 cm(-1) region. Furthermore, we have investigated the possible active role of torsional motion in intensity redistribution. PMID- 26524593 TI - Histone deacetylase 6 inhibition enhances oncolytic viral replication in glioma. AB - Oncolytic viral (OV) therapy, which uses genetically engineered tumor-targeting viruses, is being increasingly used in cancer clinical trials due to the direct cytolytic effects of this treatment that appear to provoke a robust immune response against the tumor. As OVs enter tumor cells, intrinsic host defenses have the potential to hinder viral replication and spread within the tumor mass. In this report, we show that histone deacetylase 6 (HDAC6) in tumor cells appears to alter the trafficking of post-entry OVs from the nucleus toward lysosomes. In glioma cell lines and glioma-stem-like cells, HDAC6 inhibition (HDAC6i) by either pharmacologic or genetic means substantially increased replication of oncolytic herpes simplex virus type 1 (oHSV). Moreover, HDAC6i increased shuttling of post entry oHSV to the nucleus. In addition, electron microscopic analysis revealed that post-entry oHSVs are preferentially taken up into glioma cells through the endosomal pathway rather than via fusion at the cell surface. Together, these findings illustrate a mechanism of glioma cell defense against an incoming infection by oHSV and identify possible approaches to enhance oHSV replication and subsequent lysis of tumor cells. PMID- 26524598 TI - Safety and tolerability of ingenol mebutate in the treatment of actinic keratosis. AB - INTRODUCTION: Ingenol mebutate is a topical therapeutic agent for the treatment of actinic keratosis (AK). It has a novel mode of action and has shown comparable efficacy to other topical field therapies. This article summarizes and provides perspective on the safety profile of ingenol mebutate from clinical studies of this agent. AREAS COVERED: The unique mechanism of action of ingenol mebutate, the basis for a rapid clinical effect, is outlined. Safety and tolerability data, including mean composite local skin response (LSR) scores, type of LSR, and adverse events from a range of clinical studies both in healthy volunteers and patients with AK, are reviewed. The safety profile of ingenol mebutate is then compared with other agents used to treat AK lesions. EXPERT OPINION: Ingenol mebutate has a dosing period of 2 - 3 days, which is short compared with other field therapies, and there is no evidence of systemic absorption. The fact that most of the LSRs observed are mild to moderate in intensity and transient, with a majority resolved within 2 weeks, makes for a favorable safety profile. Ingenol mebutate enhances the armamentarium available to the dermatologist for the treatment of AK. PMID- 26524597 TI - Structural and Enzymatic Characterization of a Nucleoside Diphosphate Sugar Hydrolase from Bdellovibrio bacteriovorus. AB - Given the broad range of substrates hydrolyzed by Nudix (nucleoside diphosphate linked to X) enzymes, identification of sequence and structural elements that correctly predict a Nudix substrate or characterize a family is key to correctly annotate the myriad of Nudix enzymes. Here, we present the structure determination and characterization of Bd3179 -- a Nudix hydrolase from Bdellovibrio bacteriovorus-that we show localized in the periplasmic space of this obligate Gram-negative predator. We demonstrate that the enzyme is a nucleoside diphosphate sugar hydrolase (NDPSase) and has a high degree of sequence and structural similarity to a canonical ADP-ribose hydrolase and to a nucleoside diphosphate sugar hydrolase (1.4 and 1.3 A Calpha RMSD respectively). Examination of the structural elements conserved in both types of enzymes confirms that an aspartate-X-lysine motif on the C-terminal helix of the alpha beta-alpha NDPSase fold differentiates NDPSases from ADPRases. PMID- 26524600 TI - Synthesis of Large-Sized Single-Crystal Hexagonal Boron Nitride Domains on Nickel Foils by Ion Beam Sputtering Deposition. AB - Large-sized single-crystal h-BN domains with a lateral size up to 100 MUm are synthesized on Ni foils by ion-beam sputtering deposition. The nucleation density of h-BN is dramatically decreased by reducing the concentrations of both active sites and species on the Ni surface through a brief in situ pretreatment of the substrate and optimization of the growth parameters, enabling the growth of large sized domains. PMID- 26524599 TI - Multimorbidity Patterns in Elderly Primary Health Care Patients in a South Mediterranean European Region: A Cluster Analysis. AB - OBJECTIVE: The purpose of this study was to identify clusters of diagnoses in elderly patients with multimorbidity, attended in primary care. DESIGN: Cross sectional study. SETTING: 251 primary care centres in Catalonia, Spain. PARTICIPANTS: Individuals older than 64 years registered with participating practices. MAIN OUTCOME MEASURES: Multimorbidity, defined as the coexistence of 2 or more ICD-10 disease categories in the electronic health record. Using hierarchical cluster analysis, multimorbidity clusters were identified by sex and age group (65-79 and >=80 years). RESULTS: 322,328 patients with multimorbidity were included in the analysis (mean age, 75.4 years [Standard deviation, SD: 7.4], 57.4% women; mean of 7.9 diagnoses [SD: 3.9]). For both men and women, the first cluster in both age groups included the same two diagnoses: Hypertensive diseases and Metabolic disorders. The second cluster contained three diagnoses of the musculoskeletal system in the 65- to 79-year-old group, and five diseases coincided in the >=80 age group: varicose veins of the lower limbs, senile cataract, dorsalgia, functional intestinal disorders and shoulder lesions. The greatest overlap (54.5%) between the three most common diagnoses was observed in women aged 65-79 years. CONCLUSION: This cluster analysis of elderly primary care patients with multimorbidity, revealed a single cluster of circulatory-metabolic diseases that were the most prevalent in both age groups and sex, and a cluster of second-most prevalent diagnoses that included musculoskeletal diseases. Clusters unknown to date have been identified. The clusters identified should be considered when developing clinical guidance for this population. PMID- 26524601 TI - Hydrolysis of synthetic polyesters by Clostridium botulinum esterases. AB - Two novel esterases from the anaerobe Clostridium botulinum ATCC 3502 (Cbotu_EstA and Cbotu_EstB) were expressed in Escherichia coli BL21-Gold(DE3) and were found to hydrolyze the polyester poly(butylene adipate-co-butylene terephthalate) (PBAT). The active site residues (triad Ser, Asp, His) are present in both enzymes at the same location only with some amino acid variations near the active site at the surrounding of aspartate. Yet, Cbotu_EstA showed higher kcat values on para-nitrophenyl butyrate and para-nitrophenyl acetate and was considerably more active (sixfold) on PBAT. The entrance to the active site of the modeled Cbotu_EstB appears more narrowed compared to the crystal structure of Cbotu_EstA and the N-terminus is shorter which could explain its lower activity on PBAT. The Cbotu_EstA crystal structure consists of two regions that may act as movable cap domains and a zinc metal binding site. PMID- 26524602 TI - What is the best therapeutic strategy for colonoscopy of colorectal neoplasia? Future perspectives from the East. AB - Development and improvement of endoscopic techniques and devices have changed the treatment of colorectal tumors over the last decade. For the treatment of diminutive polyps, the cold snare technique of the West is becoming a promising treatment in the East because of its short procedure time and low rate of delayed bleeding by eliminating the delayed effect of electrocautery. Rather than using piecemeal endoscopic mucosal resection or surgical resection for the treatment of large superficial tumors, the technique of the East of endoscopic submucosal dissection (ESD) achieves a high success rate of en bloc R0 resection, enabling detailed pathological evaluation with less invasive treatment. This procedure should also be useful in the West where large colorectal tumors are more frequent than in the East. Regarding outcomes, however, in the literature, the definition of 'curative resection' remains somewhat inconsistent and long-term outcomes of patients with deep submucosal and/or lymphovascular invasion in the en bloc specimen have not yet been determined. Large prospective, as well as retrospective, studies of these patients are warranted. When colorectal ESD is difficult because of size or location, the pocket-creation method and/or double balloon-assisted technique may be useful. In the East, high-quality magnified chromoendoscopy is widely available, and endoscopists try to identify focal submucosal invasion. In the West, a systematic evaluation of surveillance for the prevention of colorectal cancer has been done and is highly refined. The East and West have much to learn from each other. PMID- 26524604 TI - A Novel Mesoporous Single-Crystal-Like Bi2WO6 with Enhanced Photocatalytic Activity for Pollutants Degradation and Oxygen Production. AB - The porous single-crystal-like micro/nanomaterials exhibited splendid intrinsic performance in photocatalysts, dye-sensitized solar cells, gas sensors, lithium cells, and many other application fields. Here, a novel mesoporous single-crystal like Bi2WO6 tetragonal architecture was first achieved in the mixed molten salt system. Its crystal construction mechanism originated from the oriented attachment of nanosheet units accompanied by Ostwald ripening process. Additionally, the synergistic effect of mixed alkali metal nitrates and electrostatic attraction caused by internal electric field in crystal played a pivotal role in oriented attachment process of nanosheet units. The obtained sample displayed superior photocatalytic activity of both organic dye degradation and O2 evolution from water under visible light. We gained an insight into this unique architecture's impact on the physical properties, light absorption, photoelectricity, and luminescent decay, etc., that significantly influenced photocatalytic activity. PMID- 26524603 TI - "I Spent a Full Month Bleeding, I Thought I Was Going to Die..." A Qualitative Study of Experiences of Women Using Modern Contraception in Wakiso District, Uganda. AB - INTRODUCTION: There is high unmet need for family planning (FP) in Uganda as well as high contraceptive discontinuation rates. These contribute to the high fertility rates that in part are due to unplanned pregnancies. There are gaps in knowledge about experiences that couples go through while using contraceptives in their lives. This study explored women's experiences during the course of their contraceptive use. METHODS: We conducted a qualitative study involving 30 women who had used modern contraception for at least one year in Wakiso district, central Uganda. We used in-depth interviews to obtain their personal accounts. Index women were approached through health officers at four health centres in the district. All ethical approvals and informed consent were obtained. We used conventional content analysis; identifying codes through open coding, on which basis categories were developed and grouped into overarching themes. RESULTS: Women's accounts were summarised in the following themes: negative experiences with modern contraceptive use, motivation to continue using FP in spite of these negative experiences, the role of influential people, and discontinuation of use. Negative accounts dominated the experiences of most women but they expressed strong desire to continue using modern contraception even amidst all challenges. Health workers emerged as the most influential people that played a vital role in women's decisions. CONCLUSION: Varied negative experiences with modern contraception and misperceptions exist amidst a determination to continue use. Partner engagement, health service strengthening to improve side effects management and health worker skills, and engaging older women that have successfully used contraception as community champions, are potential strategies to support women's contraceptive decisions. PMID- 26524605 TI - Zinc transporter 7 deficiency affects lipid synthesis in adipocytes by inhibiting insulin-dependent Akt activation and glucose uptake. AB - Mice deficient for zinc transporter 7 protein (ZnT7) are mildly zinc deficient with low body weight gain and body fat accumulation. To investigate the underlying mechanism of ZnT7 deficiency in body adiposity, we examined fatty acid composition and insulin sensitivity in visceral (epididymal) and subcutaneous fat pads from Znt7 knockout and control mice. We showed that ZnT7 deficiency had adverse effects on fatty acid metabolism and insulin action in subcutaneous fat but not in epididymal fat in mice, consistent with the ZnT7 protein expression pattern in adipose tissues. Importantly, we found that the expression of ZnT7 protein was induced by lipogenic differentiation and reached a peak when the adipocyte was fully differentiated in mouse 3T3-L1 adipocytes. We demonstrated, using Znt7 knockdown (Znt7KD) 3T3-L1 adipocytes, that reduction in Znt7 expression blunted activations of the signal transduction pathways that regulated both basal and insulin-stimulated glucose uptake in adipocytes, resulting in low glucose uptake and lipid accumulation. The expression of the signaling mediators critical for the initiation of pre-adipocyte differentiation, including Ppargamma and C/Ebpalpha, appeared not to be affected by Znt7KD in 3T3-L1 adipocytes. These findings strongly suggest a role for ZnT7 in adipocyte lipogenesis. PMID- 26524606 TI - Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2. AB - Both orthosteric and allosteric antagonists of the group II metabotropic glutamate receptors (mGlus) have been used to establish a link between mGlu2/3 inhibition and a variety of CNS diseases and disorders. Though these tools typically have good selectivity for mGlu2/3 versus the remaining six members of the mGlu family, compounds that are selective for only one of the individual group II mGlus have proved elusive. Herein we report on the discovery of a potent and highly selective mGlu2 negative allosteric modulator 58 (VU6001192) from a series of 4-oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides. The concept for the design of this series centered on morphing a quinoline series recently disclosed in the patent literature into a chemotype previously used for the preparation of muscarinic acetylcholine receptor subtype 1 positive allosteric modulators. Compound 58 exhibits a favorable profile and will be a useful tool for understanding the biological implications of selective inhibition of mGlu2 in the CNS. PMID- 26524607 TI - Effect of Lipopolysaccharide on the Progression of Non-Alcoholic Fatty Liver Disease in High Caloric Diet-Fed Mice. AB - The incidence of non-alcoholic steatohepatitis (NASH) is increasing. Because gut microbiota have been highlighted as one of the key factors in the pathogenesis of metabolic syndrome, we investigated the involvement of the bacterial component in the progression of non-alcoholic fatty liver (NAFL) to NASH. C57BL/6 mice were fed with maintenance food (MF, groups A and B) or a high caloric diet (HCD, groups C and D) for 1 month. Mice were then divided into four groups: Groups A and C were inoculated with PBS, while groups B and D were inoculated with lipopolysaccharide (LPS) plus complete Freund's adjuvant (CFA). The inoculations were performed a total of 3 times over 3 months. At 6 months, while hepatic steatosis was observed in groups C and D, cellular infiltration and fibrosis were less evident in group C than in group D. Inflammatory cytokines were upregulated in groups B and D. 16S rRNA pyrosequencing of whole colon homogenates containing faeces showed that certain bacterial groups, such as Bacteroidaceae, Peptostreptococcaceae and Erysipelotrichaceae, were increased in groups C and D. Although loading of bacterial components (LPS) resulted in hepatic inflammation in both MF- and HCD-fed mice, HCD feeding was more crucial in the progression of NAFL during the triggering phase. PMID- 26524608 TI - Response to letter by Popov, Todor regarding our paper: Exhaled breath temperature measurement and asthma control in children prescribed inhaled corticosteroids: A cross sectional study. PMID- 26524609 TI - Bariatric surgery and bone health. PMID- 26524610 TI - Summary and Way Forward: Doing more of ICF in physical therapy. PMID- 26524611 TI - Day care versus in-patient surgery for age-related cataract. AB - BACKGROUND: Age-related cataract accounts for more than 40% of cases of blindness in the world with the majority of people who are blind from cataract living in lower income countries. With the increased number of people with cataract, it is important to review the evidence on the effectiveness of day care cataract surgery. OBJECTIVES: To provide authoritative, reliable evidence regarding the safety, feasibility, effectiveness and cost-effectiveness of day case cataract extraction by comparing clinical outcomes, cost-effectiveness, patient satisfaction or a combination of these in cataract operations performed in day care versus in-patient units. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2015), EMBASE (January 1980 to August 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 17 August 2015. SELECTION CRITERIA: We included randomised controlled trials comparing day care and in-patient surgery for age related cataract. The primary outcome was the achievement of a satisfactory visual acuity six weeks after the operation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected adverse effects information from the trials. MAIN RESULTS: We included two trials. One study was conducted in the USA in 1981 (250 people randomised and completed trial) and one study conducted in Spain in 2001 (1034 randomised, 935 completed trial). Both trials used extracapsular cataract extraction techniques that are not commonly used in higher income countries now. Most of the data in this review came from the larger trial, which we judged to be at low risk of bias.The mean change in visual acuity (in Snellen lines) of the operated eye four months postoperatively was similar in people given day care surgery (mean 4.1 lines standard deviation (SD) 2.3, 464 participants) compared to people treated as in-patients (mean 4.1 lines, SD 2.2, 471 participants) (P value = 0.74). No data were available from either study on intra-operative complications.Wound leakage, intraocular pressure (IOP) and corneal oedema were reported in the first day postoperatively and at four months after surgery. There was an increased risk of high IOP in the day care group in the first day after surgery (risk ratio (RR) 3.33, 95% confidence intervals (CI) 1.21 to 9.16, 935 participants) but not at four months (RR 0.61, 95% CI 0.14 to 2.55, 935 participants). The findings for the other outcomes were inconclusive with wide CIs. There were two cases of endophthalmitis observed at four months in the day care group and none in the in-patient group. The smaller study stated that there were no infections or severe hyphaemas.In a subset of participants evaluated for quality of life (VF14 questionnaire) similar change in quality of life before and four months after surgery was observed (mean change in VF14 score: day care group 25.2, SD 21.2, 150 participants; in-patient group: 23.5, SD 25.7, 155 participants; P value = 0.30). Subjective assessment of patient satisfaction in the smaller study suggested that participants preferred to recuperate at home, were more comfortable in their familiar surroundings and enjoyed the family support that they received at home. Costs were 20% more for the in-patient group and this was attributed to higher costs for overnight stay. AUTHORS' CONCLUSIONS: This review provides evidence that there is cost saving with day care cataract surgery compared to in-patient cataract surgery. Although effects on visual acuity and quality of life appeared similar, the evidence with respect to postoperative complications was inconclusive because the effect estimates were imprecise. Given the wide-spread adoption of day care cataract surgery, future research in cataract clinical pathways should focus on evidence provided by high quality clinical databases (registers), which would enable clinicians and healthcare planners to agree clinical and social indications for in-patient care and so make better use of resources. PMID- 26524612 TI - The hepatic, biliary, and pancreatic network of stem/progenitor cell niches in humans: A new reference frame for disease and regeneration. AB - Stem/progenitors for liver, biliary tree, and pancreas exist at early stages of development in the definitive ventral endoderm forming the foregut. In humans, they persist postnatally as part of a network, with evidence supporting their contributions to hepatic and pancreatic organogenesis throughout life. Multiple stem cell niches persist in specific anatomical locations within the human biliary tree and pancreatic ducts. In liver and pancreas, replication of mature parenchymal cells ensures the physiological turnover and the restoration of parenchyma after minor injuries. Although actively debated, multiple observations indicate that stem/progenitor cells contribute to repair pervasive, chronic injuries. The most primitive of the stem/progenitor cells, biliary tree stem cells, are found in peribiliary glands within extrahepatic and large intrahepatic bile ducts. Biliary tree stem cells are comprised of multiple subpopulations with traits suggestive of maturational lineage stages and yet capable of self replication and multipotent differentiation, being able to differentiate to mature liver cells (hepatocytes, cholangiocytes) and mature pancreatic cells (including functional islet endocrine cells). Hepatic stem cells are located within canals of Hering and bile ductules and are capable of differentiating to hepatocyte and cholangiocyte lineages. The existence, phenotype, and anatomical location of stem/progenitors in the adult pancreas are actively debated. Ongoing studies suggest that pancreatic stem cells reside within the biliary tree, primarily the hepatopancreatic common duct, and are rare in the pancreas proper. Pancreatic ducts and pancreatic duct glands harbor committed pancreatic progenitors. CONCLUSION: The hepatic, biliary, and pancreatic network of stem/progenitor cell niches should be considered as a framework for understanding liver and pancreatic regeneration after extensive or chronic injuries and for the study of human chronic diseases affecting these organs. (Hepatology 2016;64:277 286). PMID- 26524613 TI - Bibliometric analysis of the top 50 cited respiratory articles. AB - BACKGROUND: Citation classics have been published in almost all medical fields. The main objective of this study was to provide the readers with a complete updated guide using two different citation tracking sources in assessing respiratory literature published in respiratory specific or general medical journals. METHODS: Scopus Library database ( www.scopus.com ) was used to determine the 50 most cited articles regarding respiratory medicine using the subject category "respiratory system." The results from the database were sorted using the option "Times cited." RESULTS: The top 50 articles were published during the time period 1987-2008, with most articles (n = 22) published from 1996 to 2000.The topic that had the highest number of articles (n = 15) was chronic obstructive pulmonary disorders (COPD) followed by asthma (n = 10). CONCLUSION: A periodic evaluation of the top cited articles can help researchers identify the quality of work in respiratory system and pinpoint subtopics which have not been given due consideration. PMID- 26524614 TI - In Vitro Comparison of the Bond Strength between Ceramic Repair Systems and Ceramic Materials and Evaluation of the Wettability. AB - PURPOSE: When fracture of an all-ceramic restoration occurs, it can be necessary to repair without removing the restoration. Although there are many studies about the repair of metal-ceramic restorations, there are few about all-ceramic restorations. The aim of this study was to evaluate the shear bond strength between ceramic repair systems and esthetic core materials and to evaluate the wettability of all-ceramic core materials. MATERIALS AND METHODS: Disk-like specimens (N = 90) made of three dental ceramic infrastructure materials (zirconia ceramic, alumina ceramic, glass ceramic) were polished with silicon carbide paper, prepared for bonding (abrasion with 30 MUm diamond rotary cutting instrument). Thirty specimens of each infrastructure were obtained. Each infrastructure group was divided into three subgroups; they were bonded using 3 repair systems: Bisco Intraoral Repair Kit, Cimara & Cimara Zircon Repair System, and Clearfil Repair System. After 1200 thermocycles, shear bond strength was measured in a universal testing machine at a 0.5 mm/min crosshead speed. In addition, the contact angle values of the infrastructures after surface treatments were examined for wettability. Data were analyzed by using ANOVA and Tukey post hoc tests. RESULTS: Although there were no significant differences among the repair systems (p > 0.05) in the glass ceramic and zirconia groups, a significant difference was found among the repair systems in alumina infrastructure (p < 0.001). There were no statistically significant differences among the infrastructures (p > 0.05); however, a statistically significant difference was found among the repair systems (p < 0.05). No difference was found among the infrastructures and repair systems in terms of contact angle values. CONCLUSIONS: Cimara & Cimara Zircon Repair System had higher bond strength values than the other repair systems. Although no difference was found among the infrastructures and repair systems, contact wettability angle was decreased by surface treatments compared with polished surfaces. PMID- 26524615 TI - Considerations for a Human Rights Impact Assessment of a Population Wide Treatment for HIV Prevention Intervention. AB - Increasing attention is being paid to the potential of anti-retroviral treatment (ART) for HIV prevention. The possibility of eliminating HIV from a population through a universal test and treat intervention, where all people within a population are tested for HIV and all positive people immediately initiated on ART, as part of a wider prevention intervention, was first proposed in 2009. Several clinical trials testing this idea are now in inception phase. An intervention which relies on universally testing the entire population for HIV will pose challenges to human rights, including obtaining genuine consent to testing and treatment. It also requires a context in which people can live free from fear of stigma, discrimination and violence, and can access services they require. These challenges are distinct from the field of medical ethics which has traditionally governed clinical trials and focuses primarily on patient researcher relationship. This paper sets out the potential impact of a population wide treatment as prevention intervention on human rights. It identifies five human right principles of particular relevance: participation, accountability, the right to health, non-discrimination and equality, and consent and confidentiality. The paper proposes that explicit attention to human rights can strengthen a treatment as prevention intervention, contribute to mediating likely health systems challenges and offer insights on how to reach all sections of the population. PMID- 26524616 TI - Collagenase clostridium histolyticum for the treatment of Dupuytren's contracture: systematic review and economic evaluation. AB - BACKGROUND: Dupuytren's disease is a slowly progressive condition of the hand, characterised by the formation of nodules in the palm that gradually develop into fibrotic cords. Contracture of the cords produces deformities of the fingers. Surgery is recommended for moderate and severe contractures, but complications and/or recurrences are frequent. Collagenase clostridium histolyticum (CCH) has been developed as a minimally invasive alternative to surgery for some patients. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of collagenase as an alternative to surgery for adults with Dupuytren's contracture with a palpable cord. DATA SOURCES: We searched all major electronic databases from 1990 to February 2014. REVIEW METHODS: Randomised controlled trials (RCTs), non-randomised comparative studies and observational studies involving collagenase and/or surgical interventions were considered. Two reviewers independently extracted data and assessed risk of bias of included studies. A de novo Markov model was developed to assess cost-effectiveness of collagenase, percutaneous needle fasciotomy (PNF) and limited fasciectomy (LF). Results were reported as incremental cost per quality-adjusted life-year (QALY) gained. Deterministic and probabilistic sensitivity analyses were undertaken to investigate model and parameter uncertainty. RESULTS: Five RCTs comparing collagenase with placebo (493 participants), three RCTs comparing surgical techniques (334 participants), two non-randomised studies comparing collagenase and surgery (105 participants), five non-randomised comparative studies assessing various surgical procedures (3571 participants) and 15 collagenase case series (3154 participants) were included. Meta-analyses of RCTs assessing CCH versus placebo were performed. Joints randomised to collagenase were more likely to achieve clinical success. Collagenase-treated participants experienced significant reduction in contracture and an increased range of motion compared with placebo-treated participants. Participants treated with collagenase also experienced significantly more adverse events, most of which were mild or moderate. Four serious adverse events were observed in the collagenase group: two tendon ruptures, one pulley rupture and one complex regional pain syndrome. Two tendon ruptures were also reported in two collagenase case series. Non-randomised studies comparing collagenase with surgery produced variable results and were at high risk of bias. Serious adverse events across surgery studies were low. Recurrence rates ranged from 0% (at 90 days) to 100% (at 8 years) for collagenase and from 0% (at 2.7 years for fasciectomy) to 85% (at 5 years for PNF) for surgery. The results of the de novo economic analysis show that PNF was the cheapest treatment option, whereas LF generated the greatest QALY gains. Collagenase was more costly and generated fewer QALYs compared with LF. LF was L1199 more costly and generated an additional 0.11 QALYs in comparison with PNF. The incremental cost-effectiveness ratio was L10,871 per QALY gained. Two subgroup analyses were conducted for a population of patients with moderate and severe disease and up to two joints affected. In both subgroup analyses, collagenase remained dominated. LIMITATIONS: The main limitation of the review was the lack of head-to-head RCTs comparing collagenase with surgery and the limited evidence base for estimating the effects of specific surgical procedures (fasciectomy and PNF). Substantial differences across studies further limited the comparability of available evidence. The economic model was derived from a naive indirect comparison and was hindered by a lack of suitable data. In addition, there was considerable uncertainty about the appropriateness of many assumptions and parameters used in the model. CONCLUSIONS: Collagenase was significantly better than placebo. There was no evidence that collagenase was clinically better or worse than surgical treatments. LF was the most cost-effective choice to treat moderate to severe contractures, whereas collagenase was not. However, the results of the cost-utility analysis are based on a naive indirect comparison of clinical effectiveness, and a RCT is required to confirm or refute these findings. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013006248. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26524617 TI - A Highly Efficient Diversification of 2-Amino/Amido-1,3,4-oxadiazole and 1,3,4 Thiadiazole Derivatives via Reagent-Based Cyclization of Thiosemicarbazide Intermediate on Solid-Phase. AB - A 2-amino/amido-1,3,4-oxadiazole and 1,3,4-thiadiazole library has been constructed on solid-phase organic synthesis. The key step on this solid-phase synthesis involves the preparation of polymer-bound 2-amino-1,3,4-oxadiazole and 1,3,4-thiadiazole core skeleton resin by cyclization of thiosemicarbazide with EDC.HCl and p-TsCl, respectively. The resulting core skeleton undergoes functionalization reaction with various electrophiles such as alkyl halides, and acid chlorides to generate N-alkylamino and N-acylamino-1,3,4-oxadiazole, and 1,3,4-thiadiazole resin, respectively. Finally, the 2-amino and 2-amido-1,3,4 oxadiazole and 1,3,4-thiadiazole library was then generated in good yields and high purities by cleavage of the respective resin under trifluoroacetic acid(TFA) in dichloromethane(DCM). The constructed library shows reasonable, oral bioavailability drug properties as determine by using the Lipinski's Rule and similar parameters. PMID- 26524618 TI - The heart of change: Acceptance and intimacy mediate treatment response in a brief couples intervention. AB - In this study, we examined mediators of a brief couples intervention. Intimate safety, acceptance, and activation were examined in 2 roles: their contribution to marital satisfaction gains in the first 2 weeks after treatment (contemporaneous effects), and how early changes in the mediators influenced longer term changes in marital satisfaction over 2 years of follow-up (lagged effects). Married couples (N = 215) were randomized to either an intervention group or a wait-list control group and followed for 2 years. Latent change-score models were used to examine contemporaneous and time-lagged mediation. A booster intervention in the 2nd year was used for a replication study. Changes in intimate safety and acceptance were uniquely associated with contemporaneous treatment effects on relationship satisfaction in Year 1, but only acceptance was uniquely associated with contemporaneous effects in Year 2. With respect to lagged effects, early changes in acceptance partially mediated later changes in marital satisfaction in Year 1, whereas the same effect for intimate safety was marginally significant. These lagged paths were moderate in size and indirect effects were small. No lagged effects were significant in Year 2. Change in activation was not significant as either a contemporaneous or a lagged predictor of change in relationship satisfaction. We found moderate support for acceptance and more limited support for intimate safety as mediators of short- and long-term treatment response, suggesting that these processes play an important role in sustaining marital health. PMID- 26524619 TI - Prolonged Cardiac Monitoring to Detect Atrial Fibrillation after Cryptogenic Stroke or Transient Ischemic Attack: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: The cause of ischemic stroke or transient ischemic attack (TIA) remains unclear after initial cardiac monitoring in approximately one-third of patients. Randomized controlled trials (RCTs) showed that the prolonged cardiac monitoring of patients with cryptogenic stroke or TIA increased detection of atrial fibrillation (AF). We aimed to perform a meta-analysis of all RCTs that evaluated the prolonged monitoring >=7 days in patients with cryptogenic stroke or TIA. METHODS: We searched PubMed, EMBASE, Cochrane CENTRAL, and relevant references for RCTs without language restriction (inception through December 2014) and performed meta-analysis using random effects model. Detection of AF, use of anticoagulation at follow-up, recurrent stroke or TIA, and mortality were major outcomes. RESULTS: Four RCTs with 1149 total patients were included in the meta-analysis. Prolonged cardiac monitoring >=7 days compared to shorter cardiac monitoring of <=48 hours duration increased the detection of AF (>=30 seconds duration) in patients after cryptogenic stroke or TIA (13.8% vs. 2.5%; odds ratio [OR], 6.4; 95% confidence interval [CI], 3.50-11.73; P < 0.00001; I(2) , 0%]. It also increased the odds of AF detection of any duration (22.6% vs. 5.2%; 5.68[3.3 9.77]; P < 0.00001; I(2) , 0%). The patients who underwent prolonged monitoring were more likely to be on anticoagulation at follow-up (2.21[1.52-3.21]; P < 0.0001; I(2) , 0%). No differences in recurrent stroke or TIA (0.78[0.40-1.55]; P = 0.48; I(2) , 0%) and mortality (1.33[0.29-6.00]; P = 0.71; I(2) , 0%] were observed between two strategies. CONCLUSION: Prolonged cardiac monitoring improves detection of atrial fibrillation and anti-coagulation use after cryptogenic stroke or TIA and therefore should be considered instead of shorter duration of cardiac monitoring. PMID- 26524620 TI - Who are the Unclaimed Dead? AB - Unclaimed dead are deceased persons with no known next of kin (NoK) or NoK was located but did not claim the deceased. Unclaimed dead in Marion County, Indiana, 2004-2011, are examined. Comparisons are provided of the unclaimed to the claimed dead population and county death patterns. Race, gender, marital status, age, location, manner and cause of death, NoK, and days to disposition are analyzed. The unclaimed dead were disproportionately male, slightly more likely to be Black, younger at death, died from natural causes, had unknown marital status, were equally likely as not to have NoK, did not die in a hospital, and were subject to autopsy. Nearly half the unclaimed had NoK who did not claim the body; the other half had no identifiable NoK. Unclaimed were more likely to have an autopsy and to die from external causes. Most unclaimed were identified by means outside fingerprints or DNA. PMID- 26524621 TI - Hemolymph coagulation and phenoloxidase activity in Uca tangeri induced by Escherichia coli endotoxin. AB - Uca tangeri is a marine fiddler crab found commonly in the West African coast and is often exposed to Gram-negative pathogens upon injury. The aim of this study was to document the patterns of endotoxin-induced protein coagulation and phenoloxidase (PO) activity in hemolymph fractions of Uca tangeri. Hemolymph from live crabs was obtained by carapace puncture, pooled. and then separated into plasma, hemocyte Lysate (HL), hemocyte lysate supernatant (HLS) and hemocyte lysate debris (HLD). The effect of Escherichia coli (O1111:B4) endotoxin and calcium ion (Ca(2+)) on protein coagulation in the presence/absence of endotoxin and the endotoxin dose-dependence of coagulation and PO activity were each studied in the plasma, HL, HLS and HLD. The results showed Ca(2+) was required to induce coagulation, and was endotoxin concentration-dependent in the plasma. PO activity was highest in the HLS but PO specific activity was highest in HLD. PO activity remained relatively constant with increased LPS concentration in the range studied 0-10 EU/ml. From the data we conclude that endotoxin-induced protein coagulation occurs in the plasma alone and might be mediated by trans glutaminases, while PO activity is localized inside hemocytes and cell membranes in Uca tangeri. PMID- 26524622 TI - Etiology and Outcome of Diffuse Acute Infectious Bronchiolitis in Adults. AB - RATIONALE: The etiology and outcome of diffuse acute infectious bronchiolitis (DAIB) in adults is not well known. OBJECTIVES: To retrospectively review adult patients with DAIB without pneumonia, document the etiologies and outcomes, and assess the relation between DAIB and postinfectious bronchiolitis obliterans. METHODS: We retrospectively analyzed medical records of 1,664 patients with lower respiratory tract infections admitted to our institution in Saitama, Japan. DAIB was diagnosed when patients developed acute feverish lower respiratory tract infection and chest computed tomography demonstrated mainly multiple centrilobular nodules in four or more lobes. Pneumonia was diagnosed when patients developed acute feverish lower respiratory tract infection and chest computed tomography demonstrated consolidation and/or ground-glass opacities with or without centrilobular nodules. MEASUREMENTS AND MAIN RESULTS: Of the 1,664 patients, 20 (1.2%) and 1,644 (98.8%) patients were diagnosed as having DAIB and pneumonia, respectively. Of the 20 patients with DAIB, the etiology was determined in 16 (80%): 13 (65.0%) had a single pathogen and 3 (15.0%) had two pathogens. Detected organisms included Mycoplasma pneumoniae in eight (40.0%) patients, influenza virus in two (10.0%), influenza virus and Streptococcus pneumoniae in two (10.0%), Haemophilus influenzae in three (15.0%), and respiratory syncytial virus and rhinovirus in one (5.0%) patient. All patients improved and none developed postinfectious bronchiolitis obliterans. CONCLUSIONS: The three most common etiologies of DAIB in the studied adults were M. pneumoniae, influenza virus, and H. influenzae. None of the patients with DAIB developed postinfectious bronchiolitis obliterans. PMID- 26524623 TI - A Quinine-Squaramide Catalyzed Enantioselective Aza-Friedel-Crafts Reaction of Cyclic Trifluoromethyl Ketimines with Naphthols and Electron-Rich Phenols. AB - A highly enantioselective aza-Friedel-Crafts (aza-F-C) reaction of cyclic trifluoromethyl ketimines and naphthols/phenols was developed with fluorenyl substituted quinine-squaramide as the catalyst. This protocol enables direct access to biologically important chiral trifluoromethyl dihydroquinazolinones with up to 99% yields and up to 99% ee's. PMID- 26524624 TI - Control of liver glucokinase activity: A potential new target for incretin hormones? AB - We tested the exendin-4 and des-fluoro-sitagliptin effects on fructose-induced increase in liver glucokinase activity in rats with impaired glucose tolerance and the exendin-4 effect on glucokinase activity in HepG2 cells incubated with fructose in the presence/absence of exendin-9-39. After 3 weeks of in vivo fructose administration we measured: (1) serum glucose, insulin and triglyceride levels; (2) liver and HepG2 cells glucokinase activity and (3) liver glucokinase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase mRNA and protein levels. Fructose fed rats had: hypertriglyceridemia, hyperinsulinemia and high liver glucokinase activity (mainly located in the cytosolic fraction) together with higher glucokinase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase mRNA and protein concentrations compared to control rats. Co-administration of either exendin-4 or des-fluoro-sitagliptin prevented serum and liver changes except glucokinase protein expression. Exendin-4 also prevented fructose-induced increase in glucokinase activity in cultured HepG2 cells, effect blunted by co incubation with exendin-9-36. In conclusion exendin-4/des-fluro-sitagliptin prevented fructose-induced effect on glucokinase activity, mainly affecting enzyme activity modulators. Exendin 9-39 blunted in vitro protective exendin-4 effect on glucokinase activity, thus suggesting a direct effect of the later on hepatocytes through GLP-1 receptor. Alterations of glucokinase activity modulators could play a role in the pathogenesis of liver dysfunction, becoming a potential new treatment target for GLP-1 receptor agonists. PMID- 26524626 TI - Structure-based design and optimization of antihypertensive peptides to obtain high inhibitory potency against both renin and angiotensin I-converting enzyme. AB - The human renin-angiotensin system (RAS) plays an essential role in regulating blood pressure and systemic vascular resistance. Renin and angiotensin I converting enzyme (ACE) are two key enzymes in RAS and have long been recognized as attractive antihypertensive targets. Here, a synthetic strategy was proposed integrating quantitative structure-activity relationship (QSAR), molecular dynamics (MD) simulation and binding free energy analysis to discover novel dual renin and ACE peptidic inhibitors. With the strategy a number of candidates were generated virtually, from which eight promising peptides were selected and synthesized for biological assay. Consequently, three peptides (RYLP, YTAWVP and YRAWVL) were successfully identified to have satisfactory inhibitory profile against both renin and ACE with IC50 values of <1 mM and <10 MUM, respectively. Structural analysis and energetic dissection revealed different binding modes of peptide to renin and ACE; a peptide only inserts its C-terminus into the active site of ACE, whereas the whole peptide packs tightly against renin. In addition, when limited to structural diversity it is hard to reconcile the renin and ACE inhibitory activities of short peptides such as dipeptides. These findings can be used to guide peptide optimization with improved biological activity. PMID- 26524625 TI - Novel chiral-diazepines function as specific, selective receptor agonists with variable coupling and species variability in human, mouse and rat BRS-3 receptor cells. AB - Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein coupled receptor which is classified in the bombesin receptor (BnR) family with which it shares high homology. It is present widely in the central nervous system and peripheral tissues and primarily receptor-knockout studies suggest it is involved in metabolic-glucose-insulin homeostasis, feeding and other CNS behaviors, gastrointestinal motility and cancer growth. However, the role of BRS-3 physiologically or in pathologic disorders has been not well defined because the natural ligand is unknown. Until recently, no selective agonists/antagonists were available; however, recently synthetic high-affinity agonists, chiral-diazepines nonpeptide-analogs (3F, 9D, 9F, 9G) with low CNS penetrance, were described, but are not well-categorized pharmacologically or in different labarotory species. The present study characterizes the affinities, potencies, selectivities of the chiral-diazepine BRS-3 agonists in human and rodents (mice,rat). In human BRS-3 receptors, the relative affinities of the chiral-diazepines was 9G>9D>9F>3F; each was selective for BRS-3. For stimulating PLC activity, in h-BRS-3 each of the four chiral diazepine analogs was fully efficacious and their relative potencies were: 9G (EC50: 9 nM)>9D (EC50: 9.4 nM)>9F (EC50: 39 nM)>3F (EC50: 48 nM). None of the four chiral diazepine analogs activated r,m,h-GRPR/NMBR. The nonpeptide agonists showed marked differences from each other and a peptide agonist in receptor-coupling-stiochiometry and in affinities/potencies in different species. These results demonstrate that chiral diazepine analogs (9G, 9D, 9F, 3F) have high/affinity/potency for the BRS-3 receptor in human and rodent cells, but different coupling-relationships and species differences from a peptide agonist. PMID- 26524627 TI - Knowledge of Exercise Prescription Guidelines Across One 4-Year Kinesiology Curriculum. AB - PURPOSE: Knowledge of evidence-based exercise prescription guidelines is considered a cornerstone of responsible professional practice. While many academics insist that a university degree in kinesiology or a related field should be required for all exercise professionals, the learning of exercise prescription guidelines that takes place during the course of a university degree program has not been investigated. METHOD: An 11-question knowledge quiz about the frequency, duration, and intensity of cardiovascular exercise recommended by the American College of Sports Medicine (Garber et al., 2011) was administered to 683 undergraduate students majoring in kinesiology and 89 certified exercise professionals. RESULTS: Knowledge scores improved significantly, F(4, 764) = 16.69, p < .001, eta2 = .08, from the freshmen, who scored 24.30%, to the seniors, who scored 36.25%. Seniors did not differ significantly from the professionals, who scored 40.65%, despite the fact that 58.14% of professionals had graduate degrees and 44.95% had multiple certifications. However, 82.77% of seniors perceived that their knowledge of the guidelines (rated 5.48 out of 10) was lower than that required "to be able to function as an exercise professional safely and effectively" (rated 8.17). CONCLUSION: These data suggest that although significant learning of the guidelines occurs in a typical kinesiology curriculum, there is considerable room for improvement. PMID- 26524628 TI - Giardia duodenalis in Damascus, Syria: Identification of Giardia genotypes in a sample of human fecal isolates using polymerase chain reaction and restriction fragment length polymorphism analyzing method. AB - Giardia duodenalis is a common gastrointestinal parasite that infects humans and many other mammals. It is most prevalent in many developing and industrialized countries. G. duodenalis is considered to be a complex species. While no morphological distinction among different assemblages exist, it can be genetically differentiated into eight major assemblages: A to H. The aim of this study was to determine the genetic heterogeneity of G. duodenalis in human isolates (a study conducted for the first time in Syria). 40 fecal samples were collected from three different hospitals during the hot summer season of 2014. Extraction of genomic DNA from all Giardia positive samples (based on a microscopic examination) was performed using QIAamp DNA Stool Mini Kit. beta giardin gene was used to differentiate between different Giardia assemblages. The 514 bp fragment was amplified using the Polymerase Chain Reaction method, followed by digestion in HaeIII restriction enzyme. Our result showed that genotype A was more frequent than genotype B, 27/40 (67.5%); 4/40 (10%) respectively. A mixed genotype of A+B was only detected in 9 isolates (22.5%). This is the first molecular study performed on G. duodenalis isolates in Syria in order to discriminate among the different genotypes. Further expanded studies using more genes are needed to detect and identify the Giardia parasite at the level of assemblage and sub-assemblage. PMID- 26524629 TI - Deciphering structure-activity relationships in a series of Tat/TAR inhibitors. AB - A series of pentameric "Polyamide Amino Acids" (PAAs) compounds derived from the same trimeric precursor have been synthesized and investigated as HIV TAR RNA ligands, in the absence and in the presence of a Tat fragment. All PAAs bind TAR with similar sub-micromolar affinities but their ability to compete efficiently with the Tat fragment strongly differs, IC50 ranging from 35 nM to >2 MUM. While NMR and CD studies reveal that all PAA interact with TAR at the same site and induce globally the same RNA conformational change upon binding, a comparative thermodynamic study of PAA/TAR equilibria highlights distinct TAR binding modes for Tat competitor and non-competitor PAAs. This led us to suggest two distinct interaction modes that have been further validated by molecular modeling studies. While the binding of Tat competitor PAAs induces a contraction at the TAR bulge region, the binding of non-competitor ones widens it. This could account for the distinct PAA ability to compete with Tat fragment. Our work illustrates how comparative thermodynamic studies of a series of RNA ligands of same chemical family are of value for understanding their binding modes and for rationalizing structure-activity relationships. PMID- 26524632 TI - Preserved recovery of cardiac function following ischemia-reperfusion in mice lacking SIRT3. AB - Lack of the mitochondrial deacetylase sirtuin 3 (SIRT3) impairs mitochondrial function and increases the susceptibility to induction of the mitochondrial permeability transition pore. Because these alterations contribute to myocardial ischemia-reperfusion (IR) injury, we hypothesized that SIRT3 deficiency may increase cardiac injury following myocardial IR. Hearts of 10-week-old mice were perfused in the isolated working mode and subjected to 17.5 min of global no-flow ischemia, followed by 30 min of reperfusion. Measurements before ischemia revealed a decrease in cardiac power (-20%) and rate pressure product (-15%) in SIRT3(-/-) mice. Mitochondrial state 3 respiration (-15%), ATP synthesis (-39%), and ATP/O ratios (-29%) were decreased in hearts of SIRT3(-/-) mice. However, percent recovery of cardiac power (WT 94% +/- 9%; SIRT3(-/-) 89% +/- 9%) and rate pressure product (WT 89% +/- 16%; SIRT3(-/-) 96% +/- 3%) following IR was similar in both groups. Myocardial infarct size was not increased in SIRT3(-/-) mice following permanent ligation of the left anterior descending coronary artery (LAD). Left ventricular pressure and dP/dtmax, and mitochondrial respiration and ATP synthesis were not different between groups following LAD ligation. Thus, despite pre-existing defects in cardiac function and mitochondrial respiratory capacity in SIRT3(-/-) mice, SIRT3 deficiency does not additionally impair cardiac function following IR or following myocardial infarction. PMID- 26524631 TI - Evolutionary implications of C3 -C4 intermediates in the grass Alloteropsis semialata. AB - C4 photosynthesis is a complex trait resulting from a series of anatomical and biochemical modifications to the ancestral C3 pathway. It is thought to evolve in a stepwise manner, creating intermediates with different combinations of C4 -like components. Determining the adaptive value of these components is key to understanding how C4 photosynthesis can gradually assemble through natural selection. Here, we decompose the photosynthetic phenotypes of numerous individuals of the grass Alloteropsis semialata, the only species known to include both C3 and C4 genotypes. Analyses of delta(13) C, physiology and leaf anatomy demonstrate for the first time the existence of physiological C3 -C4 intermediate individuals in the species. Based on previous phylogenetic analyses, the C3 -C4 individuals are not hybrids between the C3 and C4 genotypes analysed, but instead belong to a distinct genetic lineage, and might have given rise to C4 descendants. C3 A. semialata, present in colder climates, likely represents a reversal from a C3 -C4 intermediate state, indicating that, unlike C4 photosynthesis, evolution of the C3 -C4 phenotype is not irreversible. PMID- 26524633 TI - The current state of left ventricular assist devices: challenges facing further development. AB - Heart failure is a clinical syndrome with significant morbidity and mortality. The use of left ventricular assist devices has improved outcomes for patients with advanced heart failure in the face of limited donor organs available for heart transplantation. This article describes current issues and limitations facing the left ventricular assist device field and explores how the field can be expanded in this setting. PMID- 26524630 TI - Genomic dynamics associated with malignant transformation in IDH1 mutated gliomas. AB - The genomic mechanism responsible for malignant transformation remains an open question for glioma researchers, where differing conclusions have been drawn based on diverse study conditions. Therefore, it is essential to secure direct evidence using longitudinal samples from the same patient. Moreover, malignant transformation of IDH1-mutated gliomas is of potential interest, as its genomic mechanism under influence of oncometabolite remains unclear, and even higher rate of malignant transformation was reported in IDH1-mutated low grade gliomas than in wild-type IDH1 tumors. We have analyzed genomic data using next-generation sequencing technology for longitudinal samples from 3 patients with IDH1-mutated gliomas whose disease had progressed from a low grade to a high grade phenotype. Comprehensive analysis included chromosomal aberrations as well as whole exome and transcriptome sequencing, and the candidate driver genes for malignant transformation were validated with public database. Integrated analysis of genomic dynamics in clonal evolution during the malignant transformation revealed alterations in the machinery regulating gene expression, including the spliceosome complex (U2AF2), transcription factors (TCF12), and chromatin remodelers (ARID1A). Moreover, consequential expression changes implied the activation of genes associated with the restoration of the stemness of cancer cells. The alterations in genetic regulatory mechanisms may be the key factor for the major phenotypic changes in IDH1 mutated gliomas. Despite being limited to a small number of cases, this analysis provides a direct example of the genomic changes responsible for malignant transformation in gliomas. PMID- 26524634 TI - Lasting glycolytic stress governs susceptibility to urethane-induced lung carcinogenesis in vivo and in vitro. AB - Urethane is a recognized genotoxic carcinogen in fermented foods and beverages. This study is to compare susceptibility of ICR mice, BALB/c mice and C57BL/6 mice to urethane-induced lung carcinogenesis. The mice were injected intraperitoneally with 600 mg/kg of urethane for three times or ten times at 7-day intervals. At week 26, lung carcinogenic incidence was found in 40% ICR mice, 20% BALB/c mice and 10% C57BL/6 mice of the 3* injection group, respectively, whereas 100% lung tumor incidence took place in three mouse strains of the 10* injection group. In the 10* injection group, urethane induced lasting glycolytic stress of lung with an increase in lactate, monocarboxylate transporter 1 (MCT-1), reactive oxygen species(ROS) and 7,8-dihydro-8-oxo-29-deoxyguanosine (8-OHdG) and a decrease in pyruvate dehydrogenase (PDH) and cytochrome C oxidase (COX). In the 3* injection group, urethane also promoted lung glycolytic stress at the end of urethane injection but it lasted no more than 7 days besides in lung tumor-bearing mice. Metformin as a glycolytic enhancer promoted urethane carcinogenic efficacy in the 3* injection group, whereas 2-deoxy-glucose (2-DG) as a glycolytic inhibitor decreased urethane carcinogenic efficacy in the 10* injection group. Further, urethane promoted tumor survival in A549 cells by inducing cancer stem-like cellular state. These data suggest that lasting glycolytic stress is sufficient for urethane-induced lung tumorigenesis, and that urethane 10* injection-induced lung cancer can serve as a valuable model for lung tumor biology and tumor prevention. PMID- 26524635 TI - Role of PUMA in methamphetamine-induced neuronal apoptosis. AB - Exposure to methamphetamine (METH), a widely used illicit drug, has been shown to cause neuron apoptosis. p53 upregulated modulator of apoptosis (PUMA) is a key mediator in neuronal apoptosis. This study aimed to examine the effects of PUMA in METH-induced neuronal apoptosis. We determined PUMA protein expression in PC12 cells and SH-SY5Y cells after METH exposure using western blot. We also observed the effect of METH on neuronal apoptosis after silencing PUMA expression with siRNA using TUNEL staining and flow cytometry. Additionally, to investigate possible mechanisms of METH-induced PUMA-mediated neuronal apoptosis, we measured the protein expression of apoptotic markers, including cleaved caspase-3, cleaved PARP, Bax, B-cell leukemia/lymphoma-2 (Bcl-2) and cytochrome c (cyto c), after METH treatment with or without PUMA knockdown. Results showed that METH exposure induced cell apoptosis, increased PUMA protein levels, activated caspase-3 and PARP, elevated Bax and reduced Bcl-2 expression, as well as increased the release of cyto c from mitochondria to the cytoplasm in both PC12 and SH-SY5Y cells. All these effects were attenuated or reversed after silencing PUMA. A schematic depicting the role of PUMA in METH-induced mitochondrial apoptotic pathway was proposed. Our results suggest that PUMA plays an important role in METH-triggered apoptosis and it may be a potential target for ameliorating neuronal injury and apoptosis caused by METH. PMID- 26524636 TI - Signal transduction and epigenetic mechanisms in the control of microglia activation during neuroinflammation. AB - Activation of microglia is a common denominator and a pathophysiological hallmark of the central nervous system (CNS) disorders. Damage or CNS disorders can trigger inflammatory responses in resident microglia and initiate a systemic immune system response. Although a repertoire of inflammatory responses differs in those diseases, there is a spectrum of transcriptionally activated genes that encode various mediators such as growth factors, inflammatory cytokines, chemokines, matrix metalloproteinases, enzymes producing lipid mediators, toxic molocules, all of which contribute to neuroinflammation. The initiation, progression and termination of inflammation requires global activation of gene expression, postranscriptional regulation, epigenetic modifications, changes in chromatin structure and these processes are tightly regulated by specific signaling pathways. This review focuses on the function of "master regulators" and epigenetic mechanisms in microglia activation during neuroinflammation. We review studies showing impact of epigenetic enzyme inhibitors on microglia activation in vitro and in vivo, and critically discuss potential of such molecules to prevent/moderate pathological events mediated by microglia under brain pathologies. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID- 26524637 TI - Neuroinflammatory biomarkers: From stroke diagnosis and prognosis to therapy. AB - Stroke is the third leading cause of death in industrialized countries and one of the largest causes of permanent disability worldwide. Therapeutic options to fight stroke are still limited and the only approved drug is tissue-plasminogen activator (tPA) and/or mechanical thrombectomy. Post-stroke inflammation is well known to contribute to the expansion of the ischemic lesion, whereas its resolution stimulates tissue repair and neuroregeneration processes. As inflammation highly influences susceptibility of stroke patients to overcome the disease, there is an increasing need to develop new diagnostic, prognostic and therapeutic strategies for post-stroke inflammation. This review provides a brief overview of the contribution of the inflammatory mechanisms to the pathophysiology of stroke. It specially focuses on the role of inflammatory biomarkers to help predicting stroke patients' outcome since some of those biomarkers might turn out to be targets to be therapeutically altered overcoming the urgent need for the identification of potent drugs to modulate stroke associated inflammation. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID- 26524638 TI - Omentin-1 plasma levels and cholesterol metabolism in obese patients with diabetes mellitus type 1: impact of weight reduction. AB - BACKGROUND: Omentin-1 is an anti-inflammatory adipokine produced preferentially by visceral adipose tissue. Plasma levels of omentin-1 are decreased in obesity and other insulin-resistant states. Insulin resistance contributes to the changes of cholesterol synthesis and absorption as well. The aim of this study was to characterise omentin-1 plasma levels in obese patients with diabetes mellitus type 1 during weight reduction, and to elucidate the relationship between cholesterol metabolism and omentin-1. METHODS: Plasma levels of omentin-1 were measured in obese type 1 diabetics (n=14, body mass index >30 kg m(-2), age 29-62 years) by enzyme-linked immunosorbent assay (BioVendor). Gas chromatography with flame ionisation detector (Fisons Plc.,) was used to measure squalene and non cholesterol sterols-markers of cholesterol synthesis and absorption (phase I). Measurements were repeated after 1 month (phase II; 1 week of fasting in the hospital setting and 3 weeks on a diet containing 150 g saccharides per day) and after 1 year (phase III) on a diet with 225 g saccharides per day. RESULTS: Omentin-1 plasma levels were stable during phases I and II, but significantly increased (P<0.001) during phase III. Omentin-1 plasma dynamics were significantly associated with plasma levels of high-density lipoprotein (P=0.005) and triacylglycerols (P=0.01), as well as with lathosterol (P=0.03). CONCLUSION: Omentin-1 plasma levels significantly increased during the weight reduction programme. Omentin-1 plasma dynamics suggest a close relationship with cholesterol metabolism. PMID- 26524639 TI - GPR39 activates proliferation and differentiation of porcine intramuscular preadipocytes through targeting the PI3K/AKT cell signaling pathway. AB - BACKGROUND: The orphan G protein-coupled receptor (GPR) 39 was originally identified as the receptor of obestatin. In this study, the effects and mechanisms of GPR39 on cell proliferation and differentiation were investigated in cultured porcine intramuscular preadipocytes. METHODS: Morphology of preadipocytes and accumulated lipid droplets within cells were identified by an inverted microscope. After transfected with constructed pCMV-GPR39 plasmid, cell proliferation was measured by using methyl thiazolyl tetrazolium method, mRNA expression of GPR39, CCAAT/enhancer binding protein-alpha (C/EBPalpha), peroxisome proliferator-activated receptor-gamma (PPARgamma), Caspase-9 and adipocyte determination and differentiation factor-1 (ADD1) was determined by RNA preparation and reverse transcription polymerase chain reaction, protein expression of phosphoinositide-3 kinase (PI3K), 3-phosphoinositide-dependent protein kinase 1, phosphorylated glycogen synthase kinase 3 (pGSK3), total Akt and phosphorylated Akt (pAkt) was analyzed by Western blot. RESULTS: It found that GPR39 mRNA and protein were expressed in porcine intramuscular preadipocytes and its expression was significantly up-regulated after treatment with Zn(2+) whose function is found to be mediated by GPR39. Furthermore, over-expression of GPR39 further promoted the optical density value of cells, enhanced mRNA expression of PPARgamma, C/EBPalpha and ADD1, and inhibited mRNA expression of Caspase-9. Protein expression of pGSK3 and pAkt was also increased by GPR39 stimulation. In addition, GPR39-induced proliferation and differentiation of porcine intramuscular preadipocytes was partially blocked by the Akt inhibitor (PDTC) and the PI3K inhibitor (LY294002). CONCLUSION: It indicated that GPR39 was a transducer of Zn(2+), and enhanced proliferation and differentiation of porcine intramuscular preadipocytes through activation of the PI3K/Akt signaling pathway. PMID- 26524640 TI - Serum antinuclear and extractable nuclear antigen antibody prevalence and associated morbidity and mortality in the general population over 15 years. AB - The prevalence of ANA and anti-ENA in the general population is not well established, especially their clinical significance in healthy subjects. We herein determined the prevalence and predictive value of serum ANA and anti-ENA for connective tissue diseases (CTD), cancer, and mortality. We took advantage of a randomly selected sample of the 1998 general population (Isola I) consisting of 2828 subjects (53% women, age 43+/-13 years) from a well-defined Northern Italian area. Serum ANA and anti-ENA were tested on the 2690 samples available in 2012 (Isola II, 50% women, age 58+/-13 years). Administrative databases were searched for CTD, cancer diagnosis, and death cases occurring between enrollment and December 31, 2013. The hazard ratio (HR) was calculated for incident cases. Serum ANA is positive in 18.1% for any titer and 6.1% for titers >=1:160, 23% in subjects over 50 years and 13.1% and 6.1% for any titer and titers >=1:160, respectively, in women. The HR for CTD development was significantly high for all ANA titers, with the highest for ANA >=1:160 (HR 14.19, 95% CI 3.07-65.68). ANA positivity was not associated with cancer (HR 1.03; 95% CI 0.75-1.43), or with mortality (HR adjusted for age and sex 1.40; 95% CI 0.94-2.09). Serum anti-ENA is positive in a minority of subjects with highest figures for anti-nucleosome (1.9%), -histone (1.6%) and -PM/Scl (1.5%). In conclusion, serum ANA prevalence in the general population is highest in senior subjects and in women, while the female predominance is significantly lower compared to overt CTD. Serum ANA is associated with an increased probability of CTD development over time, but does not influence survival or cancer risk. PMID- 26524641 TI - Combined Mirizzi syndrome with Bouveret syndrome. PMID- 26524642 TI - Second-generation peroral cholangioscopy and holmium:YAG laser lithotripsy for rescue of impacted biliary stone extraction basket. PMID- 26524643 TI - Risk of pancreatic cancer in patients with pancreatic cyst. AB - BACKGROUND AND AIMS: Certain pancreatic cysts (mucinous cystic neoplasm and side branch intraductal papillary mucinous neoplasm [IPMN]) have malignant potential and require surveillance. However, whether patients with pancreatic cysts have a higher long-term risk of pancreatic cancer (PaCa) has still not been established. METHODS: This was a retrospective study of Veterans Administration patients. Patients noted to have pancreatic cysts on CT/magnetic resonance imaging (n = 1050) were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes. Patients aged <15 years (n = 425), patients with <1 year of follow-up (n = 13,259), and patients diagnosed to have PaCa within 1 year of identification of a pancreatic cyst (n = 102) or within 1 year of follow-up in the remaining patients in the database (n = 200) were excluded. Patients with pancreatic cystic lesions (group A, n = 755) and the remaining patients in the database without cysts (group B, n = 520,215) were followed from 1998 to 2007. RESULTS: During the study period, in group A and B PaCa was diagnosed in 17 and 1206 patients, respectively, and the incidence rate of PaCa was 5.08 and .32 per 1000 patient-years, respectively. The hazard ratio of PaCa in all patients with cysts was 19.64 (95% CI, 12.12-31.82; P < .0001) when compared with the rest of the patients without cysts. In the subset of patients with cysts, without a history of acute or chronic pancreatitis (n = 241), the hazard ratio of PaCa (n = 5) was 18.80 (95% CI, 7.80-45.31; P < .0001). CONCLUSION: Patients with pancreatic cysts have a significantly higher overall risk of PaCa. The etiologic distribution of cysts in our study patients is not available. Patients with mucinous cystic neoplasm and side branch IPMN are likely to have a higher risk of PaCa than our estimation of risk based on all etiologies. PMID- 26524644 TI - Clipping and transection of a crossing blood vessel during transgastric endoscopic necrosectomy. PMID- 26524645 TI - Unirradiated cells rescue cells exposed to ionizing radiation: Activation of NF kappaB pathway in irradiated cells. AB - We studied the involvement of NF-kappaB pathway activation in the rescue effect in HeLa and NIH/3T3 cells irradiated by alpha particles. Firstly, upon irradiation by 5 cGy of alpha particles, for both cell lines, the numbers of 53BP1 foci/cell at 12 h post-irradiation were significantly smaller when only 2.5% of the cell population was irradiated as compared to 100% irradiation, which demonstrated the rescue effect. Secondly, we studied the effect of NF-kappaB on the rescue effect through the use of the NF-kappaB activation inhibitor BAY-11 7082. Novel experimental setup and procedures were designed to prepare the medium (CM) which had conditioned the bystander cells previously partnered with irradiated cells, to ensure physical separation between rescue and bystander signals. BAY-11-7082 itself did not inflict DNA damages in the cells or have effects on activation of the NF-kappaB response pathway in the irradiated cells through direct irradiation. The rescue effect was induced in both cell lines by the CM, which was abrogated if BAY-11-7082 was added to the CM. Thirdly, we studied the effect of NF-kappaB on the rescue effect through staining for phosphorylated NF-kappaB (p-NF-kappaB) expression using the anti-NF-kappaB p65 (phospho S536) antibody. When the fraction of irradiated cells dropped from 100% to 2.5%, the p-NF-kappaB expression in the cell nuclei of irradiated NIH/3T3 cells increased significantly, while that in the cell nuclei of irradiated HeLa cells also increased although not significantly. Moreover, the p-NF-kappaB expression in the cell nuclei of irradiated HeLa cells and NIH/3T3 cells treated with CM also increased significantly. PMID- 26524646 TI - Professional Development and Mentorship Needs of Nurse Practitioners. AB - The Patient Protection and Affordable Care Act of 2010 and the aging U.S. population have created a substantial shortage of primary care providers. Nurse practitioners (NPs) provide a cost-effective solution to meet this growing demand; however, the professional development and mentoring needs of NPs have not been clearly defined. This quantitative descriptive study assessed the professional development and mentorship needs of NPs as a first step toward development of effective programs to meet those needs. PMID- 26524648 TI - Gamma convolution models for self-diffusion coefficient distributions in PGSE NMR. AB - We introduce a closed-form signal attenuation model for pulsed-field gradient spin echo (PGSE) NMR based on self-diffusion coefficient distributions that are convolutions of n gamma distributions, n?1. Gamma convolutions provide a general class of uni-modal distributions that includes the gamma distribution as a special case for n=1 and the lognormal distribution among others as limit cases when n approaches infinity. We demonstrate the usefulness of the gamma convolution model by simulations and experimental data from samples of poly(vinyl alcohol) and polystyrene, showing that this model provides goodness of fit superior to both the gamma and lognormal distributions and comparable to the common inverse Laplace transform. PMID- 26524647 TI - 1020MHz single-channel proton fast magic angle spinning solid-state NMR spectroscopy. AB - This study reports a first successful demonstration of a single channel proton 3D and 2D high-throughput ultrafast magic angle spinning (MAS) solid-state NMR techniques in an ultra-high magnetic field (1020MHz) NMR spectrometer comprised of HTS/LTS magnet. High spectral resolution is well demonstrated. PMID- 26524649 TI - Design and characterization of a W-band system for modulated DNP experiments. AB - Magnetic-field and microwave-frequency modulated DNP experiments have been shown to yield improved enhancements over conventional DNP techniques, and even to shorten polarization build-up times. The resulting increase in signal-to-noise ratios can lead to significantly shorter acquisition times in signal-limited multi-dimensional NMR experiments and pave the way to the study of even smaller sample volumes. In this paper we describe the design and performance of a broadband system for microwave frequency- and amplitude-modulated DNP that has been engineered to minimize both microwave and thermal losses during operation at liquid helium temperatures. The system incorporates a flexible source that can generate arbitrary waveforms at 94GHz with a bandwidth greater than 1GHz, as well as a probe that efficiently transmits the millimeter waves from room temperature outside the magnet to a cryogenic environment inside the magnet. Using a thin walled brass tube as an overmoded waveguide to transmit a hybrid HE11 mode, it is possible to limit the losses to 1dB across a 2GHz bandwidth. The loss is dominated by the presence of a quartz window used to isolate the waveguide pipe. This performance is comparable to systems with corrugated waveguide or quasi optical components. The overall excitation bandwidth of the probe is seen to be primarily determined by the final antenna or resonator used to excite the sample and its coupling to the NMR RF coil. Understanding the instrumental limitations imposed on any modulation scheme is key to understanding the observed DNP results and potentially identifying the underlying mechanisms. We demonstrate the utility of our design with a set of triangular frequency-modulated DNP experiments. PMID- 26524650 TI - Deterministic multidimensional nonuniform gap sampling. AB - Born from empirical observations in nonuniformly sampled multidimensional NMR data relating to gaps between sampled points, the Poisson-gap sampling method has enjoyed widespread use in biomolecular NMR. While the majority of nonuniform sampling schemes are fully randomly drawn from probability densities that vary over a Nyquist grid, the Poisson-gap scheme employs constrained random deviates to minimize the gaps between sampled grid points. We describe a deterministic gap sampling method, based on the average behavior of Poisson-gap sampling, which performs comparably to its random counterpart with the additional benefit of completely deterministic behavior. We also introduce a general algorithm for multidimensional nonuniform sampling based on a gap equation, and apply it to yield a deterministic sampling scheme that combines burst-mode sampling features with those of Poisson-gap schemes. Finally, we derive a relationship between stochastic gap equations and the expectation value of their sampling probability densities. PMID- 26524651 TI - Quantitative mapping of chemical compositions with MRI using compressed sensing. AB - In this work, a magnetic resonance (MR) imaging method for accelerating the acquisition time of two dimensional concentration maps of different chemical species in mixtures by the use of compressed sensing (CS) is presented. Whilst 2D concentration maps with a high spatial resolution are prohibitively time consuming to acquire using full k-space sampling techniques, CS enables the reconstruction of quantitative concentration maps from sub-sampled k-space data. First, the method was tested by reconstructing simulated data. Then, the CS algorithm was used to reconstruct concentration maps of binary mixtures of 1,4 dioxane and cyclooctane in different samples with a field-of-view of 22mm and a spatial resolution of 344MUm*344MUm. Spiral based trajectories were used as sampling schemes. For the data acquisition, eight scans with slightly different trajectories were applied resulting in a total acquisition time of about 8min. In contrast, a conventional chemical shift imaging experiment at the same resolution would require about 17h. To get quantitative results, a careful weighting of the regularisation parameter (via the L-curve approach) or contrast-enhancing Bregman iterations are applied for the reconstruction of the concentration maps. Both approaches yield relative errors of the concentration map of less than 2mol-% without any calibration prior to the measurement. The accuracy of the reconstructed concentration maps deteriorates when the reconstruction model is biased by systematic errors such as large inhomogeneities in the static magnetic field. The presented method is a powerful tool for the fast acquisition of concentration maps that can provide valuable information for the investigation of many phenomena in chemical engineering applications. PMID- 26524652 TI - Response of microbial communities from an apple orchard and grassland soils to the first-time application of the fungicide tetraconazole. AB - The aim of the study was to assess the impact of the triazole fungicide tetraconazole applied at the field rate (FR) and at ten-fold the FR (10FR) on microorganisms in orchard soil with a long-term history of fungicides application and in grassland soil that had not previously been treated with pesticides. To ascertain this impact, the microbial activity determined by fluorescein diacetate (FDA) hydrolysis, the culturable number of bacteria, fungi and tetraconazole resistant fungi, and the phospholipid microbial biomass and the structural and functional biodiversity assessed by the PLFA and Biolog approaches, respectively, were examined under laboratory conditions during 28-day experiment. The response of soil microorganisms to the fungicide tetraconazole, which had never been used before in these soils, depended on the management of the soils. In apple orchard soil that had been treated with FR or 10FR tetraconazole, a decrease in microbial activity was still observed on the 28th day after the application of the fungicide. In contrast, a significant impact of tetraconazole on the number of bacteria was still observed at the end of experiment in grassland soil. Results of principal component analysis (PCA) indicated that the application of tetraconazole significantly changed the structure of the microbial communities in the orchard soil. In addition, analysis of the Biolog profiles revealed a decrease in the catabolic activity of the microbial communities in grassland soil that had been treated with tetraconazole at both rates over time. The evaluation of the structural and functional diversity of microbial communities using PCA appears to be the most valuable monitoring tool for assessing the impact of tetraconazole application on soil microorganisms. PMID- 26524653 TI - Prediction of octanol-air partition coefficients for polychlorinated biphenyls (PCBs) using 3D-QSAR models. AB - Based on the experimental data of octanol-air partition coefficients (KOA) for 19 polychlorinated biphenyl (PCB) congeners, two types of QSAR methods, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), are used to establish 3D-QSAR models using the structural parameters as independent variables and using logKOA values as the dependent variable with the Sybyl software to predict the KOA values of the remaining 190 PCB congeners. The whole data set (19 compounds) was divided into a training set (15 compounds) for model generation and a test set (4 compounds) for model validation. As a result, the cross-validation correlation coefficient (q(2)) obtained by the CoMFA and CoMSIA models (shuffled 12 times) was in the range of 0.825-0.969 (>0.5), the correlation coefficient (r(2)) obtained was in the range of 0.957-1.000 (>0.9), and the SEP (standard error of prediction) of test set was within the range of 0.070-0.617, indicating that the models were robust and predictive. Randomly selected from a set of models, CoMFA analysis revealed that the corresponding percentages of the variance explained by steric and electrostatic fields were 23.9% and 76.1%, respectively, while CoMSIA analysis by steric, electrostatic and hydrophobic fields were 0.6%, 92.6%, and 6.8%, respectively. The electrostatic field was determined as a primary factor governing the logKOA. The correlation analysis of the relationship between the number of Cl atoms and the average logKOA values of PCBs indicated that logKOA values gradually increased as the number of Cl atoms increased. Simultaneously, related studies on PCB detection in the Arctic and Antarctic areas revealed that higher logKOA values indicate a stronger PCB migration ability. From CoMFA and CoMSIA contour maps, logKOA decreased when substituents possessed electropositive groups at the 2-, 3-, 3'-, 5- and 6- positions, which could reduce the PCB migration ability. These results are expected to be beneficial in predicting logKOA values of PCB homologues and derivatives and in providing a theoretical foundation for further elucidation of the global migration behaviour of PCBs. PMID- 26524654 TI - H2S induces vasoconstriction of rat cerebral arteries via cAMP/adenylyl cyclase pathway. AB - Hydrogen sulfide (H2S), traditionally known for its toxic effects, is now involved in regulating vascular tone. Here we investigated the vasoconstrictive effect of H2S on cerebral artery and the underlying mechanism. Sodium hydrosulfide (NaHS), a donor of H2S, concentration-dependently induced vasoconstriction on basilar artery, which was enhanced in the presence of isoprenaline, a beta-adrenoceptor agonist or forskolin, an adenylyl cyclase activator. Administration of NaHS attenuated the vasorelaxant effects of isoprenaline or forskolin. Meanwhile, the NaHS-induced vasoconstriction was diminished in the presence of 8B-cAMP, an analog of cAMP, but was not affected by Bay K-8644, a selective L-type Ca(2+) channel agonist. These results could be explained by the revised effects of NaHS on isoprenaline-induced cAMP elevation and forskolin-stimulated adenylyl cyclase activity. Additionally, NaHS-induced vasoconstriction was enhanced by removing the endothelium or in the presence of L NAME, an inhibitor of nitric oxide synthase. L-NAME only partially attenuated the effect of NaHS which was given together with forskolin on the pre-contracted artery. In conclusion, H2S induces vasoconstriction of cerebral artery via, at least in part, cAMP/adenylyl cyclase pathway. PMID- 26524658 TI - Structural change and dynamics of colloidal gels under oscillatory shear flow. AB - The dynamics and rheological behavior of colloidal gels under oscillatory shear flow have been studied by using the Brownian dynamics simulations. The dynamics is studied under the oscillatory shear of small, medium, and large amplitudes. In the small amplitude oscillatory shear (SAOS) regime, the colloidal gel retains a rigid-chain network structure. The colloidal gel oscillates with small structural fluctuations and the elastic stress shows a linear viscoelastic response. In the medium amplitude oscillatory shear (MAOS) regime, the rigid network structure is ruptured, and a negative correlation between the absolute value of strain and the average bond number is observed. The elastic stress shows a transient behavior in between the SAOS and LAOS responses. In the large amplitude oscillatory shear (LAOS) regime, the colloidal gel shows a soft chain structure. Contrary to the negative correlation in the MAOS regime, the colloidal gel shows an oscillating dynamics with a positive correlation between the absolute value of strain and the average bond number. The soft chain structure exhibits no elasticity at small strain, while it shows strong elasticity at large strain. The oscillating dynamics and the rheological behavior are discussed in terms of the microstructural change from the rigid to soft chain structure. PMID- 26524657 TI - Simultaneous in-situ sludge reduction and nutrient removal in an A(2)MO-M system: Performances, mechanisms, and modeling with an extended ASM2d model. AB - Among the existing in-situ sludge reduction processes, the oxic-settling anaerobic (OSA) process is of particular interest because it has shown significant sludge reduction with several advantages. However, an ideal process for practical application must simultaneously incorporate effluent quality with sludge reduction. In this study, an improved OSA system, the stage-aerated anaerobic, anoxic, micro-aerobic, and oxic system combining a micro-aerobic starvation tank (abbreviated as A(2)MO-M system) was developed. Compared with OSA3# (hydraulic retention time (HRT) of 12 h), the A(2)MO-M2# system with optimized HRT of 9 h yielded almost 16.3% less sludge. The average total nitrogen (87.3%) and total phosphorus (91.9%) removal efficiencies in A(2)MO-M2# were 20.6 and 42.2% higher than those in OSA3#. Investigation of the mechanisms of sludge reduction revealed that, except for the main factors of energy uncoupling metabolism (16.7%) and sludge decay (21.2%), enrichment of slow-growing bacteria and lysis-cryptic growth metabolism analyzed by high-throughput 454 pyrosequencing were shown to contribute to sludge reduction in the A(2)MO-M system. On the basis of effluent organic matters (EfOM) measurements, soluble microbial products (SMP) were the major components in EfOM; and different reduction-oxidation (redox) potentials controlled in the OSA and A(2)MO-M systems led to different SMP formation mechanisms. To explore the mechanism and kinetics of SMP formation under different redox potentials, three new components (SUAP, SBAP, and XEPS) were integrated in an extended ASM2d model. Experimental and modeling results revealed that biomass-associated products (BAP) supported a substantial population of SMP that were quite sensitive to different redox potentials. The extended ASM2d model further illustrated that more BAP produced in the alternating anaerobic and aerobic conditions in the OSA system adversely affected its effluent quality. PMID- 26524656 TI - Evaluating the influence of wastewater composition on the growth of Microthrix parvicella by GCxGC/qMS and real-time PCR. AB - This study underlines the significance of long chain fatty acid (LCFA) content in wastewater influents as an influencing factor promoting the growth of Candidatus 'Microthrix parvicella' (M. parvicella), the most common filamentous bacteria causing foam in activated sludge systems worldwide. Quantification of M. parvicella by real-time polymerase chain reaction (real-time PCR) and analysis of LCFAs by means of two-dimensional gas chromatography coupled with mass spectrometry (GCxGC/qMS), involving solid phase micro-extraction (SPME) to enhance sensitivity, were combined for the first time as a monitoring tool. The results indicate a highly significant correlation between the abundance of M. parvicella and the total LCFA loading (r = 0.96) and linolenic acid C18:3 (r = 0.98) in particular. Additionally, comparison of slope values for the direct correlations of all significant LCFAs found in the analyses showed that the influence of LCFAs on M. parvicella growth increases with an increasing degree of unsaturation of carbon chains. These findings suggest that by removing lipid compounds from the incoming waters, substrate availability would be limited for M. parvicella. PMID- 26524655 TI - Prenatal nicotinic exposure upregulates pulmonary C-fiber NK1R expression to prolong pulmonary C-fiber-mediated apneic response. AB - Prenatal nicotinic exposure (PNE) prolongs bronchopulmonary C-fiber (PCF) mediated apneic response to intra-atrial bolus injection of capsaicin in rat pups. The relevant mechanisms remain unclear. Pulmonary substance P and adenosine and their receptors (neurokinin-A receptor, NK1R and ADA1 receptor, ADA1R) and transient receptor potential cation channel subfamily V member 1 (TRPV1) expressed on PCFs are critical for PCF sensitization and/or activation. Here, we compared substance P and adenosine in BALF and NK1R, ADA1R, and TRPV1 expression in the nodose/jugular (N/J) ganglia (vagal pulmonary C-neurons retrogradely labeled) between Ctrl and PNE pups. We found that PNE failed to change BALF substance P and adenosine content, but significantly upregulated both mRNA and protein TRPV1 and NK1R in the N/J ganglia and only NK1R mRNA in pulmonary C neurons. To define the role of NK1R in the PNE-induced PCF sensitization, the apneic response to capsaicin (i.v.) without or with pretreatment of SR140333 (a peripheral and selective NK1R antagonist) was compared and the prolonged apnea by PNE significantly shortened by SR140333. To clarify if the PNE-evoked responses depended on action of nicotinic acetylcholine receptors (nAChRs), particularly alpha7nAChR, mecamylamine or methyllycaconitine (a general nAChR or a selective alpha7nAChR antagonist) was administrated via another mini-pump over the PNE period. Mecamylamine or methyllycaconitine eliminated the PNE-evoked mRNA and protein responses. Our data suggest that PNE is able to elevate PCF NK1R expression via activation of nAChRs, especially alpha7nAChR, which likely contributes to sensitize PCFs and prolong the PCF-mediated apneic response to capsaicin. PMID- 26524659 TI - Axillary Nerve Reconstruction: Anterior-Posterior Exposure With Sural Nerve Cable Graft Pull-Through Technique. AB - Deltoid paralysis after axillary nerve injury results in limitations in shoulder function and stability. In the setting of an isolated axillary nerve injury with no clinical or electromyographic evidence of recovery that is within 6 to 9 months postinjury, the authors' preferred technique to reinnervate the deltoid is to reconstruct the axillary nerve with sural nerve grafting. Intraoperative neuromuscular electrophysiology is critical to determine the continuity of the axillary nerve before proceeding with reconstruction. The majority of the time, both an anterior and posterior incision and dissection of the axillary nerve is required to adequately delineate the zone of injury. This also ensures that both proximally and distally, uninjured axillary nerve is present before graft inset and also facilitates the ability to perform a meticulous microsurgical inset of the nerve graft posteriorly. The nerve graft must be pulled through from posterior to anterior to span the zone of injury and reconstruct the axillary nerve. Careful infraclavicular brachial plexus dissection is necessary to prevent further injury to components of the brachial plexus in the setting of a scarred bed. Patients will require postoperative therapy to prevent limitations in shoulder range of motion secondary to postoperative stiffness. This paper presents a detailed surgical technique for axillary nerve reconstruction by an anterior-posterior approach with a pull-through technique of a sural nerve cable graft. PMID- 26524660 TI - Defective ZnFe2O4 nanorods with oxygen vacancy for photoelectrochemical water splitting. AB - A one-dimensional zinc ferrite (ZnFe2O4) nanorod photoanode was prepared by a simple solution method on the F-doped tin oxide glass substrate. Thermal treatment under a hydrogen or vacuum atmosphere improved the photoelectrochemical water oxidation activity up to 20 times. The various physical characterization techniques used revealed that oxygen vacancies were created by the treatments in the near surface region, which increased the donor density and passivated the surface states. Hydrogen treatment was more effective and it was important to find optimum treatment conditions to take advantage of the positive role of oxygen vacancy as a source of electron donors and avoid its negative effect as electron trap sites. PMID- 26524661 TI - GFP-specific CD8 T cells enable targeted cell depletion and visualization of T cell interactions. AB - There are numerous cell types with scarcely understood functions, whose interactions with the immune system are not well characterized. To facilitate their study, we generated a mouse bearing enhanced green fluorescent protein (EGFP)-specific CD8+ T cells. Transfer of the T cells into EGFP reporter animals can be used to kill EGFP-expressing cells, allowing selective depletion of desired cell types, or to interrogate T-cell interactions with specific populations. Using this system, we eliminate a rare EGFP-expressing cell type in the heart and demonstrate its role in cardiac function. We also show that naive T cells are recruited into the mouse brain by antigen-expressing microglia, providing evidence of an immune surveillance pathway in the central nervous system. The just EGFP death-inducing (Jedi) T cells enable visualization of a T cell antigen. They also make it possible to utilize hundreds of existing EGFP expressing mice, tumors, pathogens and other tools, to study T-cell interactions with many different cell types, to model disease states and to determine the functions of poorly characterized cell populations. PMID- 26524662 TI - Broadening the targeting range of Staphylococcus aureus CRISPR-Cas9 by modifying PAM recognition. AB - CRISPR-Cas9 nucleases target specific DNA sequences using a guide RNA but also require recognition of a protospacer adjacent motif (PAM) by the Cas9 protein. Although longer PAMs can potentially improve the specificity of genome editing, they limit the range of sequences that Cas9 orthologs can target. One potential strategy to relieve this restriction is to relax the PAM recognition specificity of Cas9. Here we used molecular evolution to modify the NNGRRT PAM of Staphylococcus aureus Cas9 (SaCas9). One variant we identified, referred to as KKH SaCas9, showed robust genome editing activities at endogenous human target sites with NNNRRT PAMs, thereby increasing SaCas9 targeting range by two- to fourfold. Using GUIDE-seq, we show that wild-type and KKH SaCas9 induce comparable numbers of off-target effects in human cells. Our strategy for evolving PAM specificity does not require structural information and therefore should be applicable to a wide range of Cas9 orthologs. PMID- 26524663 TI - Proteomic analyses of early response of unicellular eukaryotic microorganism Tetrahymena thermophila exposed to TiO2 particles. AB - Key biological functions involved in cell survival have been studied to understand the difference between the impact of exposure to TiO2 nanoparticles (TiO2-NPs) and their bulk counterparts (bulk-TiO2). By selecting a unicellular eukaryotic model organism and applying proteomic analysis an overview of the possible impact of exposure could be obtained. In this study, we investigated the early response of unicellular eukaryotic protozoan Tetrahymena thermophila exposed to TiO2-NPs or bulk-TiO2 particles at subtoxic concentrations for this organism. The proteomic analysis based on 2DE + nLC-ESI-MS/MS revealed 930 distinct protein spots, among which 77 were differentially expressed and 18 were unambiguously identified. We identified alterations in metabolic pathways, including lipid and fatty acid metabolism, purine metabolism and energetic metabolism, as well as salt stress and protein degradation. This proteomic study is consistent with our previous findings, where the early response of T. thermophila to subtoxic concentrations of TiO2 particles included alterations in lipid and fatty acid metabolism and ion regulation. The response to the lowest TiO2-NPs concentration differed significantly from the response to higher TiO2 NPs concentration and both bulk-TiO2 concentrations. Alterations on the physiological landscape were significant after exposure to both nano- and bulk TiO2; however, no toxic effects were evidenced even at very high exposure concentrations. This study confirms the relevance of the alteration of the lipid profile and lipid metabolism in understanding the early impact of TiO2-NPs in eukaryotic cells, for example, phagocytosing cells like macrophages and ciliated cells in the respiratory epithelium. PMID- 26524664 TI - Coexistence of Mayer-Rokitansky-Kuster-Hauser Syndrome and Turner Syndrome: A Case Report. AB - BACKGROUND: Turner syndrome is a common chromosomal disorder, with an incidence of 1 in 2000 live-born female infants. Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) affects 1 in 4500 female births and, rarely, it might be associated with gonadal dysgenesis. CASE: A 17-year-old girl was referred to our clinic with short stature and primary amenorrhea. The patient was diagnosed with Turner syndrome and underwent estrogen therapy. At the age of 24 years, just after the patient's sexual initiation, the first complete gynecological examination was performed. A blind-ending vagina was revealed and the patient was diagnosed with MRKH. SUMMARY AND CONCLUSION: Early diagnosis of coexistence of MRKH and Turner syndrome, although very difficult, might prevent patients from developing serious complications. PMID- 26524665 TI - Pediatric Benign Cystic Peritoneal Mesothelioma. AB - BACKGROUND: Benign cystic peritoneal mesothelioma is a rare tumor comprising multiple cysts typically found within the abdominal cavity. Although the literature has numerous accounts of this entity in adults, only a handful of cases have been published regarding its presence in the pediatric population. CASE: We present the case of a prepubertal 10-year-old girl with the finding of benign cystic peritoneal mesothelioma at laparoscopy for suspected appendicitis, the management, and outcome. SUMMARY AND CONCLUSION: Although benign cystic peritoneal mesothelioma can be treated with primary excision, the high recurrence rate in adult cases of this disease necessitates the need for long-term follow-up of these patients and provides a challenge to surgeons in providing continuing care. PMID- 26524666 TI - Virtual Week: Translation and adaptation for the Italian population. AB - The present study adapted a computerised version of Virtual Week, a laboratory measure of prospective memory designed to simulate the kinds of prospective memory tasks encountered in daily life. In particular, this study aimed to translate and adapt Virtual Week for an Italian population. We collected data from 198 subjects that were divided into five groups based on age: young-young adults (20-29 years, n = 47), young adults (30-45 years, n = 32), middle-age adults (46-59 years, n = 32), young-old adults (60-69 years, n = 41), and old-old adults (70 years plus, n = 39). Results showed that PM performance was best in younger adults, relatively stable over middle adulthood and then decreased with age, with older adults performing the least accurately, in particular for the time-based condition. Results also demonstrated good reliability estimates across a range of ages and task types. Thus, the adaptation of Virtual Week into Italian appears to be a reliable measure of prospective memory for the Italian population. PMID- 26524668 TI - Off-label Drug Use and Adverse Drug Events: Turning up the Heat on Off-label Prescribing. PMID- 26524670 TI - Polymers and the p-block elements. AB - A survey of the state-of-the-art in the development of synthetic methods to incorporate p-block elements into polymers is given. The incorporation of main group elements (groups 13-16) into long chains provides access to materials with fascinating chemical and physical properties imparted by the presence of inorganic groups. Perhaps the greatest impedance to the widespread academic and commercial use of p-block element-containing macromolecules is the synthetic challenge associated with linking inorganic elements into long chains. In recent years, creative methodologies have been developed to incorporate heteroatoms into polymeric structures, with perhaps the greatest advances occurring with hybrid organic-inorganic polymers composed of boron, silicon, phosphorus and sulfur. With these developments, materials are currently being realized that possess exciting chemical, photophysical and thermal properties that are not possible for conventional organic polymers. This review focuses on highlighting the most significant recent advances whilst giving an appropriate background for the general reader. Of particular focus will be advances made over the last two decades, with emphasis on the novel synthetic methodologies employed. PMID- 26524669 TI - Demystifying fluorine chemical shifts: electronic structure calculations address origins of seemingly anomalous (19)F-NMR spectra of fluorohistidine isomers and analogues. AB - Fluorine NMR spectroscopy is a powerful tool for studying biomolecular structure, dynamics, and ligand binding, yet the origins of (19)F chemical shifts are not well understood. Herein, we use electronic structure calculations to describe the changes in (19)F chemical shifts of 2F- and 4F-histidine/(5-methyl)-imidazole upon acid titration. While the protonation of the 2F species results in a deshielded chemical shift, protonation of the 4F isomer results in an opposite, shielded chemical shift. The deshielding of 2F-histidine/(5-methyl)-imidazole upon protonation can be rationalized by concomitant decreases in charge density on fluorine and a reduced dipole moment. These correlations do not hold for 4F histidine/(5-methyl)-imidazole, however. Molecular orbital calculations reveal that for the 4F species, there are no lone pair electrons on the fluorine until protonation. Analysis of a series of 4F-imidazole analogues, all with delocalized fluorine electron density, indicates that the deshielding of (19)F chemical shifts through substituent effects correlates with increased C-F bond polarity. In summary, the delocalization of fluorine electrons in the neutral 4F species, with gain of a lone pair upon protonation may help explain the difficulty in developing a predictive framework for fluorine chemical shifts. Ideas debated by chemists over 40 years ago, regarding fluorine's complex electronic effects, are shown to have relevance for understanding and predicting fluorine NMR spectra. PMID- 26524671 TI - Use and role of monoclonal antibodies and other biologics in preventive cardiology. AB - Biotechnological advances now enable the design of fully human antibodies to target specific antigens in a growing number of diseases. Monoclonal antibodies (mAbs) differ from traditional small chemical molecules in several ways: (1) biological production - they are grown in and extracted from cell cultures; (2) specificity - they demonstrate high target specificity, with a low risk of drug drug interactions; (3) administration - they are delivered parenterally (intravenously or subcutaneously); (4) dosage interval - their extended half lives generally allow for spaced dosing (from weekly to monthly). In cardiology, fully human mAbs directed against proprotein convertase subtilisin / kexin type 9 (PCSK9) have shown to be effective in reducing low-density lipoprotein cholesterol (LDL-C) in phase II clinical trials among patients with familial hypercholesterolaemia (FH). PCSK9 inhibitors have just received approval for the treatment of FH and clinical atherosclerotic disease, and patients not at target under maximally tolerated statin therapy or intolerant to statins. Large-scale phase III trials are currently assessing the role of PCSK9 inhibitors in the secondary prevention setting for patients with acute coronary syndromes (ACS) and poorly controlled LDL-C under evidence-based therapies. Another area currently under investigation for fully human mAbs in secondary prevention is their potential ability to inhibit inflammatory pathways. In this context, canakinumab, a specific mAb inhibiting interleukin-1beta (IL-1beta), has already received approval for the treatment of systemic juvenile idiopathic arthritis. The canakinumab anti-inflammatory thrombosis outcomes trial (CANTOS) is an ongoing trial assessing whether inhibition of IL-1beta could reduce the occurrence of cardiovascular adverse events in 17,200 patients with ACS and with defined persisting inflammation. PMID- 26524672 TI - An MRM-based workflow for absolute quantitation of lysine-acetylated metabolic enzymes in mouse liver. AB - As a key post-translational modification mechanism, protein acetylation plays critical roles in regulating and/or coordinating cell metabolism. Acetylation is a prevalent modification process in enzymes. Protein acetylation modification occurs in sub-stoichiometric amounts; therefore extracting biologically meaningful information from these acetylation sites requires an adaptable, sensitive, specific, and robust method for their quantification. In this work, we combine immunoassays and multiple reaction monitoring-mass spectrometry (MRM-MS) technology to develop an absolute quantification for acetylation modification. With this hybrid method, we quantified the acetylation level of metabolic enzymes, which could demonstrate the regulatory mechanisms of the studied enzymes. The development of this quantitative workflow is a pivotal step for advancing our knowledge and understanding of the regulatory effects of protein acetylation in physiology and pathophysiology. PMID- 26524673 TI - Predicted VO2max and effectiveness of external chest compression by Chinese nurses. AB - OBJECTIVES: The aims of this study were to assess the influence of sex and body position on external chest compression (ECC) to a manikin by Chinese nurses and to determine the relationship between rescuer's predicted VO2max and ECC depth. PARTICIPANTS AND METHODS: A total of 40 nurses performed ECC on a manikin for 5 min in the standing (S) and bed-mount kneeling (K) position, then completed a Chester step-test, in 3 separate days. The rate and depth of compressions and oxygen consumption during ECC were measured. RESULTS: Mean compression rate recorded was above 100/min in both positions throughout ECC. Mean compression depth for male participants was more than 38 mm for 5 min in the K-position but only 3 min in the S-position. Female participants achieved this compression depth for less than 90 s in the K-position but not at all in the S-position. CONCLUSION: Irrespective of sex, the K-position appears to facilitate effective ECC. The relationship between aerobic fitness of female nurses and their ability to perform effective cardiopulmonary resuscitation warrants further investigation. PMID- 26524674 TI - Emergency physician sex and emergency department resource use. AB - OBJECTIVE: We investigated whether there are differences in emergency department (ED) patient management associated with emergency physician (EP) sex, specifically in terms of ordering investigations and hospital admissions. METHODS: We included all EPs working as consultants for at least 24 consecutive months at a Spanish ED during an 8-year period. Every annual period was considered independently. The classificatory variable was EP sex. For every annual period we compiled age and years of experience of each EP, the number of patients who attended, and patient distribution in triage categories. To analyze ED resource use by each EP and period, we recorded percentages of blood tests, radiography, ultrasonography, computerized tomography (CT) scan, and hospital admission orders. RESULTS: Fifty EPs (27 women and 23 men) were included, 291 annual periods were analyzed (132 for women and 159 for men) and 256 524 patient attendances were recorded (114 086 by women and 142 438 by men). Blood tests were ordered in 57.2% of cases, radiography in 58.0%, ultrasounds in 5.0%, CT scans in 7.0%, and hospitalizations in 28.4%. Compared with men, women ordered 6.8% (95% confidence interval 6.1-7.5%) more blood tests, 4.6% (4.3-5.3%) more radiographies, 15.2% (11.6-18.9%) more ultrasonographies, 11.1% (8.1-14.1%) more CT scans, and 12.1% (10.8-13.4%) more hospitalizations. These differences maintained statistical significance in the stratified analysis by EP experience, and were observed for most of the years analyzed. CONCLUSION: Female EPs order more investigations and admit more patients, although from our results the reason for this is unclear, and the impact on healthcare effectiveness and patient outcome is unknown. PMID- 26524675 TI - The SPEED (sepsis patient evaluation in the emergency department) score: a risk stratification and outcome prediction tool. AB - OBJECTIVES: The aim of the study was to identify covariates associated with 28 day mortality in septic patients admitted to the emergency department and derive and validate a score that stratifies mortality risk utilizing parameters that are readily available. METHODS: Patients with an admission diagnosis of suspected or confirmed infection and fulfilling at least two criteria for severe inflammatory response syndrome were included in this study. Patients' characteristics, vital signs, and laboratory values were used to identify prognostic factors for mortality. A scoring system was derived and validated. The primary outcome was the 28-day mortality rate. RESULTS: A total of 440 patients were included in the study. The 28-day hospital mortality rate was 32.4 and 25.2% for the derivation (293 patients) and validation (147 patients) sets, respectively. Factors associated with a higher mortality were immune-suppressed state (odds ratio 4.7; 95% confidence interval 2.0-11.4), systolic blood pressure on arrival less than 90 mmHg (3.8; 1.7-8.3), body temperature less than 36.0 degrees C (4.1; 1.3 12.9), oxygen saturation less than 90% (2.3; 1.1-4.8), hematocrit less than 0.38 (3.1; 1.6-5.9), blood pH less than 7.35 (2.0; 1.04-3.9), lactate level more than 2.4 mmol/l (2.27; 1.2-4.2), and pneumonia as the source of infection (2.7; 1.5 5.0). The area under the receiver operating characteristic curve was 0.81 (0.75 0.86) in the derivation and 0.81 (0.73-0.90) in the validation set. The SPEED (sepsis patient evaluation in the emergency department) score performed better (P=0.02) than the Mortality in Emergency Department Sepsis score when applied to the complete study population with an area under the curve of 0.81 (0.76-0.85) as compared with 0.74 (0.70-0.79). CONCLUSION: The SPEED score predicts 28-day mortality in septic patients. It is simple and its predictive value is comparable to that of other scoring systems. PMID- 26524676 TI - Pediatric Intraparenchymal Meningioma: Case Report and Comparative Review. AB - Intra-axial (intraparenchymal) meningiomas are an extremely rare pathology with only dozens of cases reported. In children, the unusual characteristics of intraparenchymal meningiomas can easily create an atypical preoperative differential. The authors present the case of an otherwise healthy 14-year-old girl presenting with new-onset seizures and an intracranial lesion upon investigation. CT and MRI revealed a lesion both cystic and calcified in nature, residing completely within the brain parenchyma. Upon operative examination, the mass was found to be completely surrounded by cortex and to be of two disparate consistencies. Pathological analysis revealed the mass to be a meningioma. Despite the rarity in children, meningiomas must be kept on the differential for cystic, calcified lesions. The differential diagnosis based on imaging as well as the operative strategy taken are further discussed. In addition, the authors review the current understanding of pediatric meningiomas as compared with adult meningiomas. PMID- 26524677 TI - Optimal estimation reconstruction of the optical properties of a two-layered tissue phantom from time-resolved single-distance measurements. AB - In this work, we have tested the optimal estimation (OE) algorithm for the reconstruction of the optical properties of a two-layered liquid tissue phantom from time-resolved single-distance measurements. The OE allows a priori information, in particular on the range of variation of fit parameters, to be included. The purpose of the present investigations was to compare the performance of OE with the Levenberg-Marquardt method for a geometry and real experimental conditions typically used to reconstruct the optical properties of biological tissues such as muscle and brain. The absorption coefficient of the layers was varied in a range of values typical for biological tissues. The reconstructions performed demonstrate the substantial improvements achievable with the OE provided a priori information is available. We note the extreme reliability, robustness, and accuracy of the retrieved absorption coefficient of the second layer obtained with the OE that was found for up to six fit parameters, with an error in the retrieved values of less than 10%. A priori information on fit parameters and fixed forward model parameters clearly improves robustness and accuracy of the inversion procedure. PMID- 26524678 TI - Intravital autofluorescence 2-photon microscopy of murine intestinal mucosa with ultra-broadband femtosecond laser pulse excitation: image quality, photodamage, and inflammation. AB - Ultra-broadband excitation with ultrashort pulses may enable simultaneous excitation of multiple endogenous fluorophores in vital tissue. Imaging living gut mucosa by autofluorescence 2-photon microscopy with more than 150 nm broad excitation at an 800-nm central wavelength from a sub-10 fs titanium-sapphire (Ti:sapphire) laser with a dielectric mirror based prechirp was compared to the excitation with 220 fs pulses of a tunable Ti:sapphire laser at 730 and 800 nm wavelengths. Excitation efficiency, image quality, and photochemical damage were evaluated. At similar excitation fluxes, the same image brightness was achieved with both lasers. As expected, with ultra-broadband pulses, fluorescence from NAD(P)H, flavines, and lipoproteins was observed simultaneously. However, nonlinear photodamage apparent as hyperfluorescence with functional and structural alterations of the tissue occurred earlier when the laser power was adjusted to the same image brightness. After only a few minutes, the immigration of polymorphonuclear leucocytes into the epithelium and degranulation of these cells, a sign of inflammation, was observed. Photodamage is promoted by the higher peak irradiances and/or by nonoptimal excitation of autofluorescence at the longer wavelength. We conclude that excitation with a tunable narrow bandwidth laser is preferable to ultra-broadband excitation for autofluorescence based 2-photon microscopy, unless the spectral phase can be controlled to optimize excitation conditions. PMID- 26524679 TI - Bessel-beam Grueneisen relaxation photoacoustic microscopy with extended depth of field. AB - The short focal depth of a Gaussian beam limits the volumetric imaging speed of optical resolution photoacoustic microscopy (OR-PAM). A Bessel beam, which is diffraction free, provides a long focal depth, but its side lobes deteriorate image quality when the Bessel beam is directly employed to excite photoacoustic (PA) signals in OR-PAM. We present a nonlinear approach based on the Grueneisen relaxation effect to suppress the side-lobe artifacts in PA imaging. This method extends the focal depth of OR-PAM and speeds up volumetric imaging. We experimentally demonstrated a 1-mm focal depth with a 7-MUm lateral resolution and volumetrically imaged a carbon fiber and red blood cell samples. PMID- 26524680 TI - Noninvasive enhanced mid-IR imaging of breast cancer development in vivo. AB - Lumpectomy coupled with radiation therapy and/or chemotherapy is commonly used to treat breast cancer patients. We are developing an enhanced thermal IR imaging technique that has the potential to provide real-time imaging to guide tissue excision during a lumpectomy by delineating tumor margins. This enhanced thermal imaging method is a combination of IR imaging (8 to 10 MUm ) and selective heating of blood (~0.5 degrees C ) relative to surrounding water-rich tissue using LED sources at low powers. Postacquisition processing of these images highlights temporal changes in temperature and the presence of vascular structures. In this study, fluorescent, standard thermal, and enhanced thermal imaging modalities, as well as physical caliper measurements, were used to monitor breast cancer tumor volumes over a 30-day study period in 19 mice implanted with 4T1-RFP tumor cells. Tumor volumes calculated from fluorescent imaging follow an exponential growth curve for the first 22 days of the study. Cell necrosis affected the tumor volume estimates based on the fluorescent images after day 22. The tumor volumes estimated from enhanced thermal imaging, standard thermal imaging, and caliper measurements all show exponential growth over the entire study period. A strong correlation was found between tumor volumes estimated using fluorescent imaging, standard IR imaging, and caliper measurements with enhanced thermal imaging, indicating that enhanced thermal imaging monitors tumor growth. Further, the enhanced IR images reveal a corona of bright emission along the edges of the tumor masses associated with the tumor margin. In the future, this IR technique might be used to estimate tumor margins in real time during surgical procedures. PMID- 26524681 TI - Statistical analysis of motion contrast in optical coherence tomography angiography. AB - Optical coherence tomography angiography (Angio-OCT), mainly based on the temporal dynamics of OCT scattering signals, has found a range of potential applications in clinical and scientific research. Based on the model of random phasor sums, temporal statistics of the complex-valued OCT signals are mathematically described. Statistical distributions of the amplitude differential and complex differential Angio-OCT signals are derived. The theories are validated through the flow phantom and live animal experiments. Using the model developed, the origin of the motion contrast in Angio-OCT is mathematically explained, and the implications in the improvement of motion contrast are further discussed, including threshold determination and its residual classification error, averaging method, and scanning protocol. The proposed mathematical model of Angio-OCT signals can aid in the optimal design of the system and associated algorithms. PMID- 26524682 TI - Multifrequency synthesis and extraction using square wave projection patterns for quantitative tissue imaging. AB - We present a method for spatial frequency domain data acquisition utilizing a multifrequency synthesis and extraction (MSE) method and binary square wave projection patterns. By illuminating a sample with square wave patterns, multiple spatial frequency components are simultaneously attenuated and can be extracted to determine optical property and depth information. Additionally, binary patterns are projected faster than sinusoids typically used in spatial frequency domain imaging (SFDI), allowing for short (millisecond or less) camera exposure times, and data acquisition speeds an order of magnitude or more greater than conventional SFDI. In cases where sensitivity to superficial layers or scattering is important, the fundamental component from higher frequency square wave patterns can be used. When probing deeper layers, the fundamental and harmonic components from lower frequency square wave patterns can be used. We compared optical property and depth penetration results extracted using square waves to those obtained using sinusoidal patterns on an in vivo human forearm and absorbing tube phantom, respectively. Absorption and reduced scattering coefficient values agree with conventional SFDI to within 1% using both high frequency (fundamental) and low frequency (fundamental and harmonic) spatial frequencies. Depth penetration reflectance values also agree to within 1% of conventional SFDI. PMID- 26524683 TI - Whole blood glucose analysis based on smartphone camera module. AB - Complementary metal oxide semiconductor (CMOS) image sensors have received great attention for their high efficiency in biological applications. The present work describes a CMOS image sensor-based whole blood glucose monitoring system through a point-of-care (POC) approach. A simple poly-ethylene terephthalate (PET) chip was developed to carry out the enzyme kinetic reaction at various concentrations (110-586 mg/dL) of mouse blood glucose. In this technique, assay reagent is immobilized onto amine functionalized silica (AFSiO2) nanoparticles as an electrostatic attraction in order to achieve glucose oxidation on the chip. The assay reagent immobilized AFSiO2 nanoparticles develop a semi-transparent reaction platform, which is technically a suitable chip to analyze by a camera module. The oxidized glucose then produces a green color according to the glucose concentration and is analyzed by the camera module as a photon detection technique; the photon number decreases when the glucose concentration increases. The combination of these components, the CMOS image sensor and enzyme immobilized PET film chip, constitute a compact, accurate, inexpensive, precise, digital, highly sensitive, specific, and optical glucose-sensing approach for POC diagnosis. PMID- 26524684 TI - Supramolecular rulers enabling selective detection of pure short ssDNA via chiral self-assembly. AB - Multivalent self-assembly of trifunctional aromatic propellers and ssDNA results in the formation of chiral supramolecular assemblies that can be used for the detection of small fragments of ssDNA with different lengths and compositions. PMID- 26524685 TI - Copy Number Analysis of the DLX4 and ERBB2 Genes in South African Breast Cancer Patients. AB - Breast cancer is one of the main causes of cancer death among South African women. Although several risk factors can be attributed to the observed high mortality rate, the biology of the tumors is not extensively investigated. Copy number gain of the DLX4 homeobox gene has been observed in breast cancer in association with poor prognosis and specific racial groups. Therefore, we aimed to assess the copy number and prognostic role of DLX4 in breast cancer from South African patients. Due to the co-location of ERBB2 and DLX4 in the 17q21 region, its copy number was also evaluated. Our results in the analysis of 66 cases demonstrated copy number gains of DLX4 and ERBB2 in 24.1 and 29.7% of the cases, respectively. Linear regression analysis showed no dependency between the copy number alterations in these genes. Although not significant, patients with DLX4 and ERBB2 gains presented a higher frequency of advanced-grade tumors. In addition, copy number alterations of these genes were not significantly differently observed in the 3 main racial groups of the Western Cape population: Colored, White, and Black. These findings indicate that gains of DLX4 and ERBB2 occur in South African breast cancer patients irrespectively of their race and factors known to influence prognosis. PMID- 26524686 TI - Ambient Temperature and Prevalence of Obesity: A Nationwide Population-Based Study in Korea. AB - BACKGROUND: Recent studies have suggested a possible association between outdoor or indoor temperature and obesity. We aimed to examine whether ambient temperature is associated with the prevalence of obesity or abdominal obesity in the Korean population. METHODS: Data on anthropometric, socio-demographic, laboratory and lifestyle factors were retrieved from National Health Insurance System data obtained in 2009-2010. Thirty years (1981 to 2010) of meteorological parameters for 71 observation areas were acquired from the Korea Meteorological Administration. Included in this analysis were 124,354 individuals. A body mass index (BMI) >= 25 kg/m2 and a waist circumference (WC) >= 90 cm (men) or 85 cm (women) were considered to represent obesity and abdominal obesity, respectively. RESULTS: The mean annual temperature (MAT) ranged from 6.6 degrees C to 16.6 degrees C, and BMI was positively correlated with MAT (r = 0.0078, P = 0.0065). WC was positively correlated with MAT (r = 0.0165, P < 0.0001) and negatively correlated with the number of days with mean temperature < 0 degrees C (DMT0; r = -0.0129, P = 0.0002). After adjusting for age, sex, smoking status, alcohol consumption, exercise, income, residential area and altitude, the odds ratios (95% CI) for obesity and abdominal obesity in the highest quintile MAT group were 1.045 (1.010, 1.081) and 1.082 (1.042, 1.124), respectively, compared with the lower four quintiles of the MAT group. Similarly, subjects in the area of the lowest quintile of DMT0 had significantly higher odds of abdominal obesity compared with the higher four quintile groups of DMT0. CONCLUSION: This study finds an association between ambient temperature and prevalence of obesity in the Korean population when controlling for several confounding factors. Adaptive thermogenesis might be a possible explanation for this phenomenon. PMID- 26524687 TI - Pyrosequencing of Plaque Microflora In Twin Children with Discordant Caries Phenotypes. AB - Despite recent successes in the control of dental caries, the mechanism of caries development remains unclear. To investigate the causes of dental decay, especially in early childhood caries, the supragingival microflora composition of 20 twins with discordant caries phenotypes were analyzed using high-throughput pyrosequencing. In addition, the parents completed a lifestyle questionnaire. A total of 228,789 sequencing reads revealed 10 phyla, 84 genera, and 155 species of microflora, the relative abundances of these strains varied dramatically among the children, Comparative analysis between groups revealed that Veillonella, Corynebacterium and Actinomyces were presumed to be caries-related genera, Fusobacterium, Kingella and Leptotrichia were presumed to be healthy-related genus, yet this six genera were not statistically significant (P>0.05). Moreover, a cluster analysis revealed that the microbial composition of samples in the same group was often dissimilar but that the microbial composition observed in twins was usually similar. Although the genetic and environmental factors that strongly influence the microbial composition of dental caries remains unknown, we speculate that genetic factors primarily influence the individual's susceptibility to dental caries and that environmental factors primarily regulate the microbial composition of the dental plaque and the progression to caries. By using improved twins models and increased sample sizes, our study can be extended to analyze the specific genetic and environmental factors that affect the development of caries. PMID- 26524688 TI - Lactic acid production from cellobiose and xylose by engineered Saccharomyces cerevisiae. AB - Efficient and rapid production of value-added chemicals from lignocellulosic biomass is an important step toward a sustainable society. Lactic acid, used for synthesizing the bioplastic polylactide, has been produced by microbial fermentation using primarily glucose. Lignocellulosic hydrolysates contain high concentrations of cellobiose and xylose. Here, we constructed a recombinant Saccharomyces cerevisiae strain capable of fermenting cellobiose and xylose into lactic acid. Specifically, genes (cdt-1, gh1-1, XYL1, XYL2, XYL3, and ldhA) coding for cellobiose transporter, beta-glucosidase, xylose reductase, xylitol dehydrogenase, xylulokinase, and lactate dehydrogenase were integrated into the S. cerevisiae chromosomes. The resulting strain produced lactic acid from cellobiose or xylose with high yields. When fermenting a cellulosic sugar mixture containing 10 g/L glucose, 40 g/L xylose, and 80 g/L cellobiose, the engineered strain produced 83 g/L of lactic acid with a yield of 0.66 g lactic acid/g sugar (66% theoretical maximum). This study demonstrates initial steps toward the feasibility of sustainable production of lactic acid from lignocellulosic sugars by engineered yeast. PMID- 26524690 TI - Profile of vemurafenib-induced severe skin toxicities. AB - BACKGROUND: Vemurafenib, a BRAF inhibitor, is commonly associated with skin toxicity. The impact of severe forms is unknown. OBJECTIVE: To determine the rate of permanent vemurafenib discontinuation due to grade 3-4 skin toxicity, features of these toxicities, their recurrence rate after a switch to dabrafenib and their impact on overall survival. METHODS: Retrospective cohort study of 131 patients treated with vemurafenib for melanoma between November 2010 and December 2014. Data on skin toxicities, the need for vemurafenib adjustment and the impact of switching to dabrafenib were collected. Regarding survival analysis, a conditional landmark analysis was performed to correct lead-time bias. RESULTS: Among the 131 vemurafenib-treated patients, 26% developed grade 3-4 skin toxicity. Forty-four percent of them permanently discontinued their treatment, mainly due to rash and classic skin adverse reactions (Steven-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms). Conversely, photosensitivity and carcinomas rarely required treatment adjustment. Grade 3-4 rashes were associated with clinical or biological abnormalities in 94% of patients. Among the 10 patients who subsequently switched to dabrafenib, skin toxicity recurred only in one patient. Overall survival was significantly prolonged in case of severe skin toxicity emerging within the first 4 (P = 0.014) and 8 weeks (P = 0.038) on vemurafenib, with only a trend at 12 weeks (P = 0.052). Median overall survival was also prolonged in case of severe rash. CONCLUSION: In this study, vemurafenib was continued in 56% of patients with grade 3-4 skin toxicity, which was associated with prolonged overall survival when emerging within the first 4 and 8 weeks of treatment. While developing severe skin adverse reactions permanently contraindicates vemurafenib use, other rashes should lead to retreatment attempts with dose reduction. In case of recurrence, dabrafenib seems to be an interesting option. For other skin toxicities, including photosensitivity and cutaneous carcinoma, treatment adjustment is usually not needed. PMID- 26524691 TI - Gut colonization with methanobrevibacter smithii is associated with childhood weight development. AB - OBJECTIVE: To prospectively investigate the presence and counts of archaea in feces of 472 children in association with weight development from 6 to 10 years of age. METHODS: Within the KOALA Birth Cohort Study, a single fecal sample from each child was analyzed by quantitative polymerase chain reaction to quantify archaea (Methanobrevibacter smithii, Methanosphera stadtmanae). Anthropometric outcomes (overweight [body mass index {BMI} >= 85th percentile], age- and sex standardized BMI, weight, and height z-scores) were repeatedly measured at ages (mean +/- SD) of 6.2 +/- 0.5, 6.8 +/- 0.5, 7.8 +/- 0.5, and 8.8 +/- 0.5 years. Generalized estimating equation was used for statistical analysis while controlling for confounders. RESULTS: Methanobrevibacter smithii colonization was associated with an increased risk of overweight (adjusted odds ratio [OR] = 2.69; 95% confidence interval [CI] 0.96-7.54) from 6 to 10 years of age. Children with high levels (>7 log10 copies/g feces) of this archaeon were at highest risk for overweight (OR = 3.27; 95% CI 1.09-9.83). Moreover, M. smithii colonization was associated with higher weight z-scores (adj. beta 0.18; 95% CI 0.00-0.36), but not with height. For BMI z-scores, the interaction (P = 0.008) between M. smithii and age was statistically significant, implying children colonized with M. smithii had increasing BMI z-scores with age. CONCLUSIONS: Presence and higher counts of M. smithii in the gut of children are associated with higher weight z scores, higher BMI z-scores, and overweight. PMID- 26524692 TI - Correction: Increased Blood-Reelin-Levels in First Episode Schizophrenia. PMID- 26524693 TI - Levomepromazine for nausea and vomiting in palliative care. AB - BACKGROUND: This is an updated version of the original Cochrane Review published in Issue 4, 2013, on Levomepromazine for nausea and vomiting in palliative care.Nausea and vomiting are common, distressing symptoms for patients receiving palliative care. There are several drugs which can be used to treat these symptoms, known as antiemetics. Levomepromazine is an antipsychotic drug is commonly used as an antiemetic to alleviate nausea and vomiting in palliative care settings. OBJECTIVES: To evaluate the efficacy of, and adverse events associated with, levomepromazine for the treatment of nausea and vomiting in palliative care patients. SEARCH METHODS: For this update we searched electronic databases, including those of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, up to February 2015. We searched clinical trial registers on 7 October 2015 for ongoing trials. SELECTION CRITERIA: Randomised controlled trials of levomepromazine for the treatment of nausea or vomiting, or both, in adults receiving palliative care. We excluded studies in which symptoms were thought to be due to pregnancy or surgery. DATA COLLECTION AND ANALYSIS: We assessed the potential relevance of studies based on titles and abstracts. We obtained copies of any study reports that appeared to meet the inclusion criteria for further assessment. At least two review authors read each paper to determine suitability for inclusion and discussed discrepancies in order to achieve a consensus. MAIN RESULTS: In the original review, we identified 421 abstracts using the search strategy. We considered eight studies for inclusion but ultimately excluded them all from the review. We updated the search in February 2015 and identified 35 abstracts, but again none met the inclusion criteria. We identified two trials from clinical trial registers, one of which is ongoing and one of which was closed due to poor recruitment. AUTHORS' CONCLUSIONS: As in the initial review, we identified no published randomised controlled trials examining the use of levomepromazine for the management of nausea and vomiting in adults receiving palliative care, and our conclusion (that further studies of levomepromazine and other antiemetic agents are needed to provide better evidence for their use in this setting) remains unchanged. We did, however, identify one ongoing study that we hope will contribute to the evidence base for this intervention in future updates of this review. PMID- 26524694 TI - Different Effects of Tacrolimus on Innate and Adaptive Immune Cells in the Allograft Transplantation. AB - While tacrolimus (FK506) is currently used as immunosuppression therapy in transplant recipient, the immunological mechanism remains unknown. Herein, the immunoregulatory effects of FK506 were investigated in the physiological status and allogeneic skin transplantation. FK506 cannot significantly alter the functions of innate immune cells (macrophages and neutrophils) and adaptive immune cells (T cells) in the physiological status. However, it can effectively delay allogeneic skin-graft rejection through ameliorating the T cell responses, but not myeloid-derived innate immune cell responses. Importantly, it did not affect the allograft recipient macrophage innate immune defence capacity to bacteria. In clinics, FK506 treatment can significantly control the cytokine production in T cells, but not non-T cells. This study shows targeting calcineurin signalling, FK506, to be essential in inducing allograft tolerance, but not to damage the innate defence capacity, validating the immune cell phenotypes as a potential marker in transplantation following FK506 treatment. PMID- 26524696 TI - Low-dose rotenone exposure induces early senescence leading to late apoptotic signaling cascade in human trabecular meshwork (HTM) cell line: An in vitro glaucoma model. AB - This study aimed to determine whether the prolonged exposure of the human trabecular meshwork (HTM) cell line to a low dose (1 nM) of rotenone could simulate a glaucomatous-like condition and serve as a cellular model for its etiological analysis. Under 1-nM rotenone exposure for 24-72 h, HTM cells showed a decrease in cell viability as assessed by an MTT assay and showed mitochondrial dysfunction as assessed by measuring H2 DCFDA fluorescence; a decrease in ATP level was also observed. Flow cytometric analysis showed an increase in cellular size and granularity. Elevated AF showed initial senescence. LF staining with SBB and its spectrofluorometric quantification confirmed growth arrest. An accumulation of cytoplasmic myocilin, IL-6, and MMP-9 at 72 h of exposure supported glaucomatous induction. TEM revealed morphological changes in mitochondria and nuclei of treated cells. Signaling cascades were assessed by immunoblotting and immunocytochemical analysis. This study showed a shift in status of the cells from initial senescence to induction of apoptosis in the HTM cell line due to continuous low-dose exposure to rotenone; however, at 72 h, both senescence and apoptotic features are apparent in these cells. This is the first report that reveals the potential of a prolonged low-dose exposure of rotenone to simulate senescence in the HTM cell line to cause a glaucomatous condition. PMID- 26524695 TI - Cost-effectiveness of new antiviral regimens for treatment-naive U.S. veterans with hepatitis C. AB - Recently approved, interferon-free medication regimens for treating hepatitis C are highly effective, but extremely costly. We aimed to identify cost-effective strategies for managing treatment-naive U.S. veterans with new hepatitis C medication regimens. We developed a Markov model with 1-year cycle length for a cohort of 60-year-old veterans with untreated genotype 1 hepatitis C seeking treatment in a typical year. We compared using sofosbuvir/ledipasvir or ombitasvir/ritonavir/paritaprevir/dasabuvir to treat: (1) any patient seeking treatment; (2) only patients with advanced fibrosis or cirrhosis; or (3) patients with advanced disease first and healthier patients 1 year later. The previous standard of care, sofosbuvir/simeprevir or sofosbuvir/pegylated interferon/ribavirin, was included for comparison. Patients could develop progressive fibrosis, cirrhosis, or hepatocellular carcinoma, undergo transplantation, or die. Complications were less likely after sustained virological response. We calculated the incremental cost per quality-adjusted life year (QALY) and varied model inputs in one-way and probabilistic sensitivity analyses. We used the Veterans Health Administration perspective with a lifetime time horizon and 3% annual discounting. Treating any patient with ombitasvir based therapy was the preferred strategy ($35,560; 14.0 QALYs). All other strategies were dominated (greater costs/QALY gained than more effective strategies). Varying treatment efficacy, price, and/or duration changed the preferred strategy. In probabilistic sensitivity analysis, treating any patient with ombitasvir-based therapy was cost-effective in 70% of iterations at a $50,000/QALY threshold and 65% of iterations at a $100,000/QALY threshold. CONCLUSION: Managing any treatment-naive genotype 1 hepatitis C patient with ombitasvir-based therapy is the most economically efficient strategy, although price and efficacy can impact cost-effectiveness. It is economically unfavorable to restrict treatment to patients with advanced disease or use a staged treatment strategy. (Hepatology 2016;63:428-436). PMID- 26524697 TI - Liver diseases in sub-Saharan Africa: the importance of dedicated public clinics. PMID- 26524698 TI - [Statins Use in Elderly Patients]. AB - The risk of cardiovascular disease in elderly is significantly higher than in young subjects; paradoxically some treatments that have proven their efficacy in reducing cardiovascular risk are often under prescribed in this age group. The benefits of statins in secondary cardiovascular prevention are well established in patients <80 years. In primary prevention, these drugs reduce the risk of myocardial infarction and stroke, but their effects on cardiovascular mortality remain uncertain. In very elderly patients, there are no randomized trials relative to the impact of statins on morbi-mortality in primary prevention as well in secondary prevention. Adverse effects in the elderly seem to be statistically similar to those occurring in young people , but the prescription in very old people should be individualized, taking into account the life expectancy, the life quality, the comorbidities, and especially the risk of drug interactions. PMID- 26524699 TI - Positive Effects of the Reversion of Depression on the Sympathovagal Balance after Telerehabilitation in Heart Failure Patients. AB - BACKGROUND: Autonomic nervous system (ANS) dysfunction appears in the course of both chronic heart failure (CHF) and depression. Comprehensive cardiac rehabilitation (CCR), apart from improving physical capacity, can reduce depressive symptoms and leads to the restoration of ANS function among CHF patients. The purpose was to evaluate the influence of the reversion of depression (measured by Beck Depression Inventory [BDI] score, cut point <10) and the physical capacity improvement (measured by peak oxygen consumption [peak VO2 ; ml/kg per minute]) on the sympathovagal balance (measured by low/high frequency ratio [LF/HF]) after CCR in CHF patients. METHODS: The study group comprised 111 CHF patients (New York Heart Association II-III; left ventricular ejection fraction <= 40%). Patients were randomized (2:1) to 8-week CCR based on Nordic walking training (five times weekly) at 40-70% of maximal heart rate, training group (TG) n = 77, or to control group (CG) n = 34. The effectiveness of CCR was assessed by changes-delta (Delta) in LF/HF, BDI score, and peak VO2 , as a result of comparing these parameters from the beginning and the end of the program. RESULTS: Eventually, 46 patients in TG and 23 patients in CG were eligible for simultaneous ANS and psychological status analysis. Only in TG the LF/HF decreased 2.06 +/- 1.14 versus 1.19 +/- 0.80 (P < 0.0001) and peak VO2 increased 16.83 +/- 3.72 versus 19.14 +/- 4.20 ml/kg per minute (P < 0.0001). Favorable results in CG were not observed. The differences between TG and CG were significant: Deltapeak VO2 (P < 0.0001); DeltaLF/HF (P = 0.0001). Depressive symptoms were substantially reduced in both groups (TG, P = 0.0006; CG, P = 0.0490). Nevertheless, the greatest improvement of sympathovagal balance was observed in patients whose depression was reversed, thanks to the CCR in comparison to other patients from TG and the entire CG. CONCLUSION: Positive effect of the sympatho-parasympathetic balance obtained during the home CCR based on Nordic walking training results from the additive effects of the reversion of depression and physical capacity improvement in CHF patients. PMID- 26524700 TI - High-Throughput Melanin-Binding Affinity and In Silico Methods to Aid in the Prediction of Drug Exposure in Ocular Tissue. AB - Drugs possessing the ability to bind to melanin-rich tissue, such as the eye, are linked with higher ocular exposure, and therefore have the potential to affect the efficacy and safety profiles of therapeutics. A high-throughput melanin chromatographic affinity assay has been developed and validated, which has allowed the rapid melanin affinity assessment for a large number of compounds. Melanin affinity of compounds can be quickly assigned as low, medium, or high melanin binders. A high-throughput chromatographic method has been developed and fully validated to assess melanin affinity of pharmaceuticals and has been useful in predicting ocular tissue distribution in vivo studies. The high-throughput experimental approach has also allowed for a specific training set of 263 molecules for a quantitative structure-affinity relationships (QSAR) method to be developed, which has also been shown to be a predictor of ocular tissue exposure. Previous studies have reported the development of in silico QSAR models based on training sets of relatively small and mostly similar compounds; this model covers a broader range of melanin-binding affinities than what has been previously published and identified several physiochemical descriptors to be considered in the design of compounds where melanin-binding modulation is desired. PMID- 26524701 TI - The effect of HMGB1 on sub-toxic chlorpyrifos exposure-induced neuroinflammation in amygdala of neonatal rats. AB - Chlorpyrifos (CPF), one of organophosphorus pesticides (OPs), is associated with developmental neurotoxicity. Inflammatory response is closely related with CPF induced neurotoxicity. The present study aimed at exploring whether sub-toxic CPF exposure on neonatal rats results in neuroinflammation that mediated by HMGB1/TLR4/NF-kappaB signaling pathway in the amygdala. The neonatal rats were subcutaneously injected with 5mg/kg CPF for 4 consecutive days (postnatal day 11 14) with or without HMGB1 inhibitor, glycyrrhizin. We assessed the levels of pro inflammatory cytokines at 12, 24, and 72 h after CPF exposure. The role of HMGB1 on neuroinflammation in sub-toxic exposure during brain development was studied. CPF-treated neonatal rats exhibited a significant increase in the expression of pro-inflammatory cytokines, such as IL-6, TNF-alpha and HMGB1, and a significant increase in the activation of NF-kappaB in the amygdala after CPF exposure. Inhibited HMGB1 reduced the release of IL-6 and TNF-alpha, and inhibited activation of NF-kappaB. Our findings indicate that CPF exposure on developmental brain might induce the activation of neuroinflammation mediated by HMGB1/TLR4/NF kappaB pathway in the amygdala. PMID- 26524703 TI - Moderate Alcohol Consumption Is Not Associated with Reduced All-cause Mortality. AB - BACKGROUND: A large body of research suggests that light or moderate alcohol consumption is associated with reduced all-cause mortality. However, concerns remain that the observed relationship is due to selection bias, misclassification of ex-drinkers, or residual confounding. METHODS: The association between alcohol consumption and all-cause mortality was analyzed using Cox regression. The analysis was performed using data from the Health and Retirement Study, a longitudinal cohort of 24,029 individuals from a nationally representative sample of US adults aged more than 50 years. Drinking level was based on alcohol consumption measured at 3 points over the 4 years before the start of follow-up. Occasional drinkers-those who reported drinking on at least 1 occasion, but always less than once per week-served as the reference category. There was extensive adjustment for sociodemographic variables, health status, and functional status. RESULTS: During 206,966 person-years of follow up, 7902 individuals died. No level of regular alcohol consumption was associated with reduced all-cause mortality. The hazard ratio and 95% confidence interval in fully adjusted analyses was 1.02 (0.94-1.11) for <7 drinks/week, 1.14 (1.02-1.28) for 7 to <14 drinks/week, 1.13 (0.96-1.35) for 14 to <21 drinks/week, and 1.45 (1.16-1.81) for >= 21 drinks/week. CONCLUSIONS: Moderate alcohol consumption is not associated with reduced all-cause mortality in older adults. The previously observed association may have been due to residual confounding. PMID- 26524702 TI - Association Between Anemia, Bleeding, and Transfusion with Long-term Mortality Following Noncardiac Surgery. AB - BACKGROUND: Preoperative anemia is a well-established risk factor for short-term mortality in patients undergoing noncardiac surgery, but appropriate thresholds for transfusion remain uncertain. The objective of this study was to determine long-term outcomes associated with anemia, hemorrhage, and red blood cell transfusion in patients undergoing noncardiac surgery. METHODS: We performed a long-term follow-up study of consecutive subjects undergoing hip, knee, and spine surgery between November 1, 2008 and December 31, 2009. Clinical data were obtained from administrative and laboratory databases, and retrospective record review. Preoperative anemia was defined as baseline hemoglobin < 13 g/dL for men and < 12 g/dL for women. Hemorrhage was defined by International Classification of Diseases, Ninth Revision coding. Data on long-term survival were collected from the Social Security Death Index database. Logistic regression models were used to identify factors associated with long-term mortality. RESULTS: There were 3050 subjects who underwent orthopedic surgery. Preoperative anemia was present in 17.6% (537) of subjects, hemorrhage occurred in 33 (1%), and 766 (25%) received at least one red blood cell transfusion. Over 9015 patient-years of follow-up, 111 deaths occurred. Anemia (hazard ratio [HR] 3.91; confidence interval [CI], 2.49-6.15) and hemorrhage (HR 5.28; 95% CI, 2.20-12.67) were independently associated with long-term mortality after multivariable adjustment. Red blood cell transfusion during the surgical hospitalization was associated with long-term mortality (HR 3.96; 95% CI, 2.47-6.34), which was attenuated by severity of anemia (no anemia [HR 4.39], mild anemia [HR 2.27], and moderate/severe anemia [HR 0.81]; P for trend .0015). CONCLUSIONS: Preoperative anemia, perioperative bleeding, and red blood cell transfusion are associated with increased mortality at long-term follow-up after noncardiac surgery. Strategies to minimize anemia and bleeding should be considered for all patients, and restrictive transfusion strategies may be advisable. Further investigation into mechanisms of these adverse events is warranted. PMID- 26524705 TI - A Home Diagnosis. PMID- 26524704 TI - Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration. AB - BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of visual loss among the elderly. A key cell type involved in AMD, the retinal pigment epithelium, expresses a G protein-coupled receptor that, in response to its ligand, L-DOPA, up-regulates pigment epithelia-derived factor, while down regulating vascular endothelial growth factor. In this study we investigated the potential relationship between L-DOPA and AMD. METHODS: We used retrospective analysis to compare the incidence of AMD between patients taking vs not taking L DOPA. We analyzed 2 separate cohorts of patients with extensive medical records from the Marshfield Clinic (approximately 17,000 and approximately 20,000) and the Truven MarketScan outpatient and databases (approximately 87 million) patients. We used International Classification of Diseases, 9th Revision codes to identify AMD diagnoses and L-DOPA prescriptions to determine the relative risk of developing AMD and age of onset with or without an L-DOPA prescription. RESULTS: In the retrospective analysis of patients without an L-DOPA prescription, AMD age of onset was 71.2, 71.3, and 71.3 in 3 independent retrospective cohorts. Age related macular degeneration occurred significantly later in patients with an L DOPA prescription, 79.4 in all cohorts. The odds ratio of developing AMD was also significantly negatively correlated by L-DOPA (odds ratio 0.78; confidence interval, 0.76-0.80; P <.001). Similar results were observed for neovascular AMD (P <.001). CONCLUSIONS: Exogenous L-DOPA was protective against AMD. L-DOPA is normally produced in pigmented tissues, such as the retinal pigment epithelium, as a byproduct of melanin synthesis by tyrosinase. GPR143 is the only known L DOPA receptor; it is therefore plausible that GPR143 may be a fruitful target to combat this devastating disease. PMID- 26524706 TI - Cardiovascular Outcomes of Patients in SAVOR-TIMI 53 by Baseline Hemoglobin A1c. AB - BACKGROUND: The effect of saxagliptin on cardiovascular outcomes according to different hemoglobin A1c (HbA1c) levels has not been described. Thus, we analyzed the SAVOR-TIMI 53 trial to compare the cardiovascular effects of saxagliptin vs placebo according to baseline HbA1c. METHODS: A total of 16,492 patients with type 2 diabetes (HbA1c 6.5%-12.0% in the 6 months before randomization) and either a history of established cardiovascular disease or multiple risk factors for atherosclerosis were randomized to saxagliptin or placebo in addition to usual care. Patients were followed for a median of 2.1 years. The primary endpoint was cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS: Patients were stratified by HbA1c at randomization into the following prespecified groups: <7%, 7%-<8%, 8%-<9%, and >=9%. Baseline HbA1c >=7% was associated with increased risk of cardiovascular death, myocardial infarction, or ischemic stroke (adjusted hazard ratio [HR(adj)] 1.35; 95% confidence interval [CI], 1.17-1.58) but not hospitalization for heart failure (HR(adj) 1.09; 95% CI, 0.88-1.36). Saxagliptin neither increased nor decreased the risk of cardiovascular death, myocardial infarction, or ischemic stroke in patients with HbA1c <7% (HR 1.01; 95% CI, 0.78-1.31), 7%-<8% (HR 0.98; 95% CI, 0.80-1.20), 8% <9% (HR 1.09; 95% CI, 0.85-1.39), >=9% (HR 0.95; 95% CI, 0.77-1.18) (P interaction = .89). CONCLUSIONS: Baseline HbA1c is associated with increased risk of macrovascular events but not hospitalization for heart failure. There was no heterogeneity in the effect of saxagliptin on cardiovascular events by baseline HbA1c, with cardiovascular death, myocardial infarction, or ischemic stroke neither increased nor decreased across the spectrum of baseline HbA1c values. PMID- 26524707 TI - Cluster Syncope. PMID- 26524708 TI - Vertebral Fractures: Clinical Importance and Management. AB - Vertebral fractures are common and can result in acute and chronic pain, decreases in quality of life, and diminished lifespan. The identification of vertebral fractures is important because they are robust predictors of future fractures. The majority of vertebral fractures do not come to clinical attention. Numerous modalities exist for visualizing suspected vertebral fracture. Although differing definitions of vertebral fracture may present challenges in comparing data between different investigations, at least 1 in 5 men and women aged >50 years have one or more vertebral fractures. There is clinical guidance to target spine imaging to individuals with a high probability of vertebral fracture. Radiology reports of vertebral fracture need to clearly state that the patient has a "fracture," with further pertinent details such as the number, recency, and severity of vertebral fracture, each of which is associated with risk of future fractures. Patients with vertebral fracture should be considered for antifracture therapy. Physical and pharmacologic modalities of pain control and exercises or physiotherapy to maintain spinal movement and strength are important components in the care of vertebral fracture patients. PMID- 26524709 TI - Prognostic Value of Undetectable hs Troponin T in Suspected Acute Coronary Syndrome. AB - BACKGROUND: The search for improved strategies for safe and early discharge of patients with suspected acute coronary syndrome in emergency departments is ongoing. This Biomarkers in Cardiology (BIC)-8 biomarker substudy evaluated the usefulness of high-sensitivity troponin T (hsTnT) below or above the limit of detection (LoD) in low-to-intermediate-risk patients with suspected acute coronary syndrome in the emergency department. METHODS: Patients were categorized into hsTnT >= the 99th percentile, between the 99th percentile and LoD, or undetectable hsTnT (=LoD). Among the 305 patients (34.6%) with undetectable hsTnT, no myocardial infarctions or deaths occurred within 90 days. In patients with detectable hsTnT at admission (>=LoD but <=99th percentile), the combined endpoint occurred in 1.5% (6/410) of the copeptin-negative patients and in 6.3% (6/96) of copeptin-positive patients within 90 days (hazard ratio 4.39; 95% confidence interval, 1.42-13.61; P = .01). In patients with an initially elevated hsTnT (>=14 ng/L), 9.7% (3/31) of the copeptin-negative patients and 15.4% (4/26) of the copeptin-positive patients experienced the combined endpoint (hazard ratio 1.61; 95% confidence interval, 0.36-7.17; P = .536). CONCLUSIONS: In low-to-intermediate-risk patients with suspected acute coronary syndrome, undetectable hsTnT values at admission allow a safe discharge without occurrence of death or myocardial infarction within 90 days. PMID- 26524710 TI - Purulent Pericarditis and Abscessed Myocardium with Acute Myocardial Infarction. PMID- 26524711 TI - The nitrogen-potassium intersection: membranes, metabolism, and mechanism. AB - Nitrogen (N) and potassium (K) are the two most abundantly acquired mineral elements by plants, and their acquisition pathways interact in complex ways. Here, we review pivotal interactions with respect to root acquisition, storage, translocation and metabolism, between the K+ ion and the two major N sources, ammonium (NH4+ ) and nitrate (NO3- ). The intersections between N and K physiology are explored at a number of organizational levels, from molecular genetic processes, to compartmentation, to whole plant physiology, and discussed in the context of both N-K cooperation and antagonism. Nutritional regulation and optimization of plant growth, yield, metabolism and water-use efficiency are also discussed. PMID- 26524712 TI - Preparation and evaluation of amoxicillin loaded dual molecularly imprinted nanoparticles for anti-Helicobacter pylori therapy. AB - This paper reports studies on preparation and evaluation of amoxicillin loaded dual molecularly imprinted nanoparticles (Amo/Dual-MIPs) designed for anti-H. pylori therapy. Both MNQA and AmoNa were chosen as templates to prepare Dual-MIPs using inverse microemulsion polymerization method. NQA was modified with myristic acid (MNQA) to become amphiphilic and assist in leaving NQA cavities on the surface of Dual-MIPs for H. pylori adhesion. AmoNa was applied to produce imprinting sites in Dual-MIPs for rebinding AmoNa to exert its anti-H. pylori effect. Batch rebinding test demonstrated a preferential rebinding effect of NQA toward the Dual-MIPs. In vivofluorescence imaging showed the prolonged residence time of Dual-MIPs in H. pylori infected mice stomachs after intragastric administration of nanoparticles.In vivo H. pylori clearance tests indicated Amo/Dual-MIPs had a better aniti-H. pylori effect than amoxicillin powder did. In conclusion, Amo/Dual-MIPs may provide an alternative drug delivery strategy for anti-H. pylori therapy. PMID- 26524713 TI - Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults. AB - Clopidogrel (Plavix(r)), is a widely used antiplatelet agent, which shows high inter-individual variability in treatment response in patients following the standard dosing regimen. In this study, a physiology-directed population pharmacokinetic/pharmacodynamic (PK/PD) model was developed based on clopidogrel and clopidogrel active metabolite (clop-AM) data from the PAPI and the PGXB2B studies using a step-wise approach in NONMEM (version 7.2). The developed model characterized the in vivo disposition of clopidogrel, its bioactivation into clop AM in the liver and subsequent platelet aggregation inhibition in the systemic circulation reasonably well. It further allowed the identification of covariates that significantly impact clopidogrel's dose-concentration-response relationship. In particular, CYP2C19 intermediate and poor metabolizers converted 26.2% and 39.5% less clopidogrel to clop-AM, respectively, compared to extensive metabolizers. In addition, CES1 G143E mutation carriers have a reduced CES1 activity (82.9%) compared to wild-type subjects, which results in a significant increase in clop-AM formation. An increase in BMI was found to significantly decrease clopidogrel's bioactivation, whereas increased age was associated with increased platelet reactivity. Our PK/PD model analysis suggests that, in order to optimize clopidogrel dosing on a patient-by-patient basis, all of these factors have to be considered simultaneously, e.g. by using quantitative clinical pharmacology tools. PMID- 26524714 TI - Pregnancy risk factors in autism: a pilot study with artificial neural networks. AB - BACKGROUND: Autism is a multifactorial condition in which a single risk factor can unlikely provide comprehensive explanation for the disease origin. Moreover, due to the complexity of risk factors interplay, traditional statistics is often unable to explain the core of the problem due to the strong inherent nonlinearity of relationships. The aim of this study was to assess the frequency of 27 potential risk factors related to pregnancy and peri-postnatal period. METHODS: The mothers of 45 autistic children and of 68 typical developing children completed a careful interview. Twenty-four siblings of 19 autistic children formed an internal control group. RESULTS: A higher prevalence of potential risk factors was observed in 22 and 15 factors in external control and internal control groups, respectively. For six of them, the difference in prevalence was statistically significant. Specialized artificial neural networks (ANNs) discriminated between autism and control subjects with 80.19% global accuracy when the dataset was preprocessed with TWIST (training with input selection and testing) system selecting 16 out of 27 variables. Logistic regression applied to 27 variables gave unsatisfactory results with global accuracy of 46%. CONCLUSION: Pregnancy factors play an important role in autism development. ANNs are able to build up a predictive model, which could represent the basis for a diagnostic screening tool. PMID- 26524715 TI - By the Way.... PMID- 26524716 TI - Expanding research, relevance, and reach. PMID- 26524717 TI - Low immunoglobulin M memory B-cell percentage in patients with heterotaxy syndrome correlates with the risk of severe bacterial infection. AB - BACKGROUND: Patients with heterotaxy syndrome, commonly associated with complex congenital heart disease (CHD), exhibit a higher risk of severe bacterial infection (SBI). We sought to define the change of a novel immunologic marker, the immunoglobulin M (IgM) memory B-cell percentage, and its association with SBI. METHODS: We enrolled 46 (M/F 29/17) heterotaxy syndrome patients (42 right atrial isomerism (RAI) and 4 left atrial isomerism (LAI)) aged > 1 y during the period 2010-2012 in a tertiary care center. We analyzed IgM(+)CD27(+) memory B cell percentages. Patients with simple and complex CHD served as controls. RESULTS: The mean IgM memory B-cell percentages were the lowest in the heterotaxy syndrome group, compared with those in complex and simple CHD groups (1.8 +/- 2.1 vs. 3.9 +/- 3.2 vs. 5.1 +/- 4.7, P < 0.001). In the heterotaxy syndrome group, 41.3% had low IgM memory B-cell percentages (<1% of B cells). Seven had a history of community-acquired SBI and 85.7% of these had low IgM memory B-cell percentages, which was the only significant factors related to community-acquired SBI (P = 0.028). CONCLUSION: The memory B cell and IgM memory B-cell percentages are low in patients with heterotaxy syndrome, and the presence of IgM memory B cell percentage < 1% correlates with community-acquired SBI. PMID- 26524718 TI - The metabolic cost of breathing in red-eared sliders: An attempt to resolve an old controversy. AB - Accurately measuring the metabolic cost of breathing in turtles has been a challenge with cost estimates varying greatly between different studies and/or methods used. To determine the source of discrepancy, we calculated costs using two methods in a single group of red-eared sliders (Trachemys scripta elegans). The unidirectional ventilation method yielded an estimate of 3.3ml O2/L air ventilated while the regression method (using hypoxia as a respiratory stimulus) produced an estimate of 0.8ml O2/L air ventilated when corrected for hypoxia induced metabolic suppression. Cost differences may be in part due to the non linear nature of the relationship between metabolic cost and ventilation. They are also likely due to the challenge of accurately estimating costs from irregular, episodic breathing pattern of turtles and the buffering capacity of their large lungs that lead to inconsistency in the amount of O2 extracted from each breath/breathing episode. Given the difficulty in obtaining consistent measures, the values reported here must be taken cautiously. PMID- 26524719 TI - Does corticosterone regulate the onset of breeding in free-living birds?: The CORT-Flexibility Hypothesis and six potential mechanisms for priming corticosteroid function. AB - For many avian species, the decision to initiate breeding is based on information from a variety of environmental cues, including photoperiod, temperature, food availability, and social interactions. There is evidence that the hormone corticosterone may be involved in delaying the onset of breeding in cases where supplemental cues, such as low food availability and inclement weather, indicate that the environment is not suitable. However, not all studies have found the expected relationships between breeding delays and corticosterone titers. In this review, we present the hypothesis that corticosterone physiology mediates flexibility in breeding initiation (the "CORT-Flexibility Hypothesis"), and propose six possible corticosterone-driven mechanisms in pre-breeding birds that may delay breeding initiation: altering hormone titers, negative feedback regulation, plasma binding globulin concentrations, intracellular receptor concentrations, enzyme activity and interacting hormone systems. Based on the length of the breeding season and species-specific natural history, we also predict variation in corticosterone-regulated pre-breeding flexibility. Although few studies thus far have examined mechanisms beyond plasma hormone titers, the CORT-Flexibility Hypothesis is grounded on a solid foundation of research showing seasonal variation in the physiological stress response and knowledge of physiological mechanisms modulating corticosteroid effects. We propose six possible mechanisms as testable and falsifiable predictions to help clarify the extent of HPA axis regulation of the initiation of breeding. PMID- 26524720 TI - A genetically encoded biosensor for in vitro and in vivo detection of NADP(.). AB - NADP(+), the oxidized form of nicotinamide adenine dinucleotide phosphate, plays an essential role as a coenzyme in cellular electron transfer reactions. The concentration of NADP(+) in cytoplasm or organelles is dynamic due to its conversion to many important derivatives. To track the NADP(+) concentration in single living cells, we developed a genetically encoded NADP(+) biosensor by inserting a reporter element, ketopantoate reductase (KPR), between the Forster resonance energy transfer (FRET) pair, cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP). This recombinant sensor showed a NADP(+) concentration dependent decrease in the fluorescence ratio in vitro assay. In order to optimize this biosensor, we performed peptide-length optimization and site-directed mutagenesis in the binding pocket of KPR guided by predictions from computational protein redesign. This modified biosensor showed a 70% Deltaratio increase compared to the wild type and was found to be highly specific to NADP(+), with a detection limit of 1 MUM. The sensor also reported NADP(+) real-time cellular dynamics in Escherichia coli (E. coli) after the addition of its precursor, nicotinic acid (NA). Altogether, these results demonstrate the feasibility of the biosensor for visualizing NADP(+) both in vitro and in vivo. PMID- 26524721 TI - Predictors of the Health-Promoting Behaviors of Nepalese Migrant Workers. AB - BACKGROUND: Health-promoting behaviors assist individuals to prevent disease, promote health, increase longevity, and enjoy a better quality of life. A number of interpersonal, social, and environmental factors have been shown to influence health-promoting behaviors. Little empirical evidence exists about the predictors of health-promoting behaviors among migrant workers. PURPOSE: This study uses Pender's health promotion model to describe and identify the predictors of health promoting behaviors in Nepalese migrant workers in Korea. METHODS: A cross sectional research design was used. Nepalese migrants who had been working in South Korea (n = 169) for over 6 months were surveyed between July and December 2012. Self-efficacy was measured using the Perceived Health Competence Scale, the Health-Promoting Lifestyle Profile II was used to measure health-promoting lifestyle behaviors, and perceived health status was measured using a single-item question. Descriptive statistics, correlation analysis, and multiple regression analysis were used to analyze data. RESULTS: Spiritual activity was the highest reported health-promoting behavior, whereas physical activity was the least practiced behavior. Self-efficacy was the only significant predictor of health promoting behavior. CONCLUSIONS: The results of this study suggest that future health-promoting interventions should enhance the self-efficacy of target populations for individual health behaviors. Factors such as working conditions, culture, and economic background that may affect the health-promoting behaviors of migrant workers must be considered when planning nursing interventions. Multicultural nursing structures and policies are needed to reach out proactively to all adult migrant groups. PMID- 26524722 TI - Body mass index and mortality in endometrial cancer: A systematic review and meta analysis. AB - OBJECTIVE: To evaluate the association between body mass index (BMI) and mortality in women with endometrial cancer. METHODS: A systematic review was performed utilizing a Medline search with Mesh keywords 'endometrial neoplasms' and ('body mass index' or 'obesity') and ('survival analysis' or 'mortality' or 'survivor' or 'survival') for studies published prior to June 2013. Inclusion criteria included studies that assessed associations between BMI and survival in endometrial cancer patients. Two investigators independently reviewed the title and abstract and full-text of articles for inclusion or exclusion decision; discordant decisions were adjudicated by a third reviewer. A random-effects model was constructed that was comparable to the standard random-effects models used in the meta-analysis of odds ratios. The model was fitted using SAS PROC NLMIXED. RESULTS: 1451 studies were identified and reviewed in duplicate, 18 met inclusion criteria. A random-effects meta-analysis demonstrated significantly higher odds of mortality with increasing BMI in endometrial cancer patients. Specifically the odds ratios were 1.01, 1.17, 1.26, and 1.66 for BMI categories of 25-29.9, 30 34.9, 35-39.9, and 40+, respectively. The odds ratio for all-cause mortality in endometrial cancer patients with a BMI>=40 compared to those with a BMI<25 was 1.66 (CI: 1.10-2.51, p=0.02). A single dose-response model indicated that a 10% increase in BMI resulted in a 9.2% increase in the odds of all-cause mortality (p=0.007). CONCLUSION: Increased BMI is significantly associated with increased all-cause mortality in women with endometrial cancer, with the highest risk for those with a BMI>=40. PMID- 26524724 TI - Purification and biochemical characterization of dipeptidyl peptidase-II (DPP7) homologue from germinated Vigna radiata seeds. AB - Dipeptidyl peptidases (DPPs) are potent exopeptidases, which possess central role in proteolysis. As compared to other members of DPP family, proline containing dipeptide hydrolysing activity of DPP-II (Dipeptidyl peptidase II) is unique as it hydrolyses imino group and plays a key role in protein metabolism. In present study, DPP-II was purified from germinated moong bean seeds using acid and ammonium sulphate precipitation followed by successive chromatographies on gel filtration (pH 7.4) and cation exchanger (pH 5.9). Native PAGE and in-situ gel assay confirmed the apparent homogeneity. Purified plant DPP-II is an oligomeric enzyme with molecular weight of 97.3kDa. Highest DPP-II activity was observed at pH 7.5 and 37 degrees C, with stability in the range of neutral to alkaline pH. Substrate specificity showed consequent activity for proline containing dipeptide followed by Lys-Ala and other hydrophobic dipeptides, but none of the studied endopeptidase and monopeptidase substrate was hydrolysed. Catalytic characterization with modifier studies revealed the involvement of Ser and His residues in its catalytic mechanism. Its dipeptidyl peptidase activity for proline containing dipeptide supported its role in the bioactive peptide generation and food industry. Functional studies of DPP-II revealed the significant involvement of this glycoproteinous enzyme in protein mobilization during germination. Further studies on industrial applications exploring physiological role are in progress. PMID- 26524723 TI - Downregulation of FOXO1 mRNA levels predicts treatment failure in patients with endometrial pathology conservatively managed with progestin-containing intrauterine devices. AB - OBJECTIVE: To examine hormone receptor expression levels and downstream gene activation in pre-treatment and post-treatment biopsies in a cohort of patients with endometrial pathology who were being conservatively managed with a progestin containing intrauterine device (IUD). A molecular signature of treatment failure is proposed. METHODS: A retrospective analysis of pre- and post-treatment biopsy specimens from 10 women treated with progestin-containing IUD for complex atypical hyperplasia (CAH) or grade 1 endometrioid adenocarcinoma was performed. Expression of estrogen receptor (ER), progesterone receptor (PR) and PR target genes was examined by immunohistochemistry (IHC) and quantitative RT-PCR. RESULTS: The mean treatment duration was 14.3 months. Four CAH patients had stable disease or regressed after treatment, and four progressed to endometrioid adenocarcinoma. Both patients with an initial diagnosis of endometrioid adenocarcinoma regressed to CAH or no disease. In general, hormone receptor levels diminished post-treatment compared to pre-treatment biopsies; however, we noted unexpected higher expression of the B isoform of PR (PRB) as well as ER in those patients who progressed to frank cancer. There was a trend towards a non nuclear cytoplasmic location of PRB in these patients. Importantly, the differentiating impact of PR signaling, as determined by the expression of the progestin-controlled tumor suppressor FOXO1, was lost in individuals who progressed on therapy. CONCLUSIONS: FOXO1 mRNA levels may serve as a biomarker for response to therapy and an indicator of PR function in patients being conservatively managed with a progestin-containing IUD. PMID- 26524725 TI - Intervention effects on emotion regulation in preterm infants with very low birth weight: A randomize controlled trial. AB - Preterm infants are at risk for emotional difficulties and behavioral problems. This study was aimed to investigate the effects of a clinic-based intervention program (CBIP) and a home-based intervention program (HBIP) compared with a usual care program (UCP) on emotion regulation to stress in preterm infants with very low birth weight (VLBW, birth weight <1500 g). A total of 178 VLBW preterm infants had been previously randomly assigned to receive one of three interventions (57 in CBIP, 63 in HBIP and 58 in UCP). The CBIP and HBIP contained identical child-, parent- and dyad-focused interventions that were provided to infants during hospitalization and were respectively delivered at clinics and at home at PMA 36-38 and 40 weeks, and 1, 2, 4, 6, 9, 12 months of corrected age. All infants were prospectively observed for behavioral reactivity and regulation in response to experimentally evoke stress evoked by a toy-behind-barrier procedure at 12, 18, and 24 months of corrected age. Their cognitive and language abilities, and mothers' responsiveness were also assessed at 12 months as potential covariates. Compared to the UCP-group infants, the HBIP-group infants exhibited shorter durations of visual orientation to a toy (adjusted difference [95% CI]=-1.60 [-3.07 to -0.13], p=0.03), and the CBIP-group infants exhibited shorter durations of avoidance (adjusted difference [95% CI]=-0.84 [-1.57 to 0.10], p=0.03) from 12 to 24 months of corrected age. The CBIP and HBIP showed no difference in the stress reactivity from the UCP, however. These results suggest that comprehensive interventions incorporating child-, parent- and dyad-focused services enhanced VLBW preterm infants' emotion regulation in response to stress at toddler age. PMID- 26524726 TI - The relative contributions of speechreading and vocabulary to deaf and hearing children's reading ability. AB - BACKGROUND: Vocabulary knowledge and speechreading are important for deaf children's reading development but it is unknown whether they are independent predictors of reading ability. AIMS: This study investigated the relationships between reading, speechreading and vocabulary in a large cohort of deaf and hearing children aged 5 to 14 years. METHODS AND PROCEDURES: 86 severely and profoundly deaf children and 91 hearing children participated in this study. All children completed assessments of reading comprehension, word reading accuracy, speechreading and vocabulary. OUTCOMES AND RESULTS: Regression analyses showed that vocabulary and speechreading accounted for unique variance in both reading accuracy and comprehension for deaf children. For hearing children, vocabulary was an independent predictor of both reading accuracy and comprehension skills but speechreading only accounted for unique variance in reading accuracy. CONCLUSIONS AND IMPLICATIONS: Speechreading and vocabulary are important for reading development in deaf children. The results are interpreted within the Simple View of Reading framework and the theoretical implications for deaf children's reading are discussed. PMID- 26524727 TI - An examination of within-session responding following access to reinforcing stimuli. AB - Previous research has shown tangibly maintained challenging behavior can be temporarily decreased by providing presession access to the relevant tangible. However, the duration of this beneficial effect is unknown. We measured the subsequent duration of behavior reduction effects following presession access during extended classroom observation sessions by analyzing within-session patterns of responding in three children with autism. An alternating treatments design was used to analyze within- and across-session responding following presession access and presession restriction conditions. The cumulative frequency of challenging behavior was higher following the presession restriction condition for all participants and lower following presession access. Within-session analysis revealed the same basic pattern of responding across participants. Specifically, the first half of the sessions contained very little, if any, challenging behavior; however, after 60 min, the rate of challenging behavior began to increase rapidly for two of the three participants. Results are discussed in terms of implications for practitioners, satiation, habituation, and behavioral contrast. PMID- 26524728 TI - Does obstructive sleep apnea confer risk to induce or enhance tumor malignancy? PMID- 26524729 TI - Systematic Tracking of Disrupted Modules Identifies Altered Pathways Associated with Congenital Heart Defects in Down Syndrome. AB - BACKGROUND: This work aimed to identify altered pathways in congenital heart defects (CHD) in Down syndrome (DS) by systematically tracking the dysregulated modules of reweighted protein-protein interaction (PPI) networks. MATERIAL AND METHODS: We performed systematic identification and comparison of modules across normal and disease conditions by integrating PPI and gene-expression data. Based on Pearson correlation coefficient (PCC), normal and disease PPI networks were inferred and reweighted. Then, modules in the PPI network were explored by clique merging algorithm; altered modules were identified via maximum weight bipartite matching and ranked in non-increasing order. Finally, pathways enrichment analysis of genes in altered modules was carried out based on Database for Annotation, Visualization, and Integrated Discovery (DAVID) to study the biological pathways in CHD in DS. RESULTS: Our analyses revealed that 348 altered modules were identified by comparing modules in normal and disease PPI networks. Pathway functional enrichment analysis of disrupted module genes showed that the 4 most significantly altered pathways were: ECM-receptor interaction, purine metabolism, focal adhesion, and dilated cardiomyopathy. CONCLUSIONS: We successfully identified 4 altered pathways and we predicted that these pathways would be good indicators for CHD in DS. PMID- 26524730 TI - Optimal Threshold and Time of Absolute Lymphocyte Count Assessment for Outcome Prediction after Bone Marrow Transplantation. AB - The recovery pace of absolute lymphocyte count (ALC) is prognostic after hematopoietic stem cell transplantation. Previous studies have evaluated a wide range of ALC cutoffs and time points for predicting outcomes. We aimed to determine the optimal ALC value for outcome prediction after bone marrow transplantation (BMT). A total of 518 patients who underwent BMT for acute leukemia or myelodysplastic syndrome between 1999 and 2010 were divided into a training set and a test set to assess the prognostic value of ALC on days 30, 60, 90, 120, 180, as well as the first post-transplantation day of an ALC of 100, 200, 300, 400, 500, and 1000/MUL. In the training set, the best predictor of overall survival (OS), relapse-free survival (RFS), and nonrelapse mortality (NRM) was ALC on day 60. In the entire patient cohort, multivariable analyses demonstrated significantly better OS, RFS, and NRM and lower incidence of graft versus-host disease (GVHD) in patients with an ALC >300/MUL on day 60 post-BMT, both including and excluding patients who developed GVHD before day 60. Among the patient-, disease-, and transplant-related factors assessed, only busulfan-based conditioning was significantly associated with higher ALC values on day 60 in both cohorts. The optimal ALC cutoff for predicting outcomes after BMT is 300/MUL on day 60 post-transplantation. PMID- 26524731 TI - Correlation of Pain and Fluoride Concentration in Allogeneic Hematopoietic Stem Cell Transplant Recipients on Voriconazole. AB - Supportive care guidelines recommend antimold prophylaxis in hematopoietic stem cell transplant (HSCT) recipients deemed to have high risk for invasive fungal infection, leading to long-term use of voriconazole after allogeneic HSCT in patients who remain immunocompromised. Voriconazole has been associated with periostitis, exostoses, and fluoride excess in patients after solid organ transplantation, HSCT, and leukemia therapy. The aims of this study were to describe the frequency and clinical presentation of patients presenting with pain and fluoride excess among allogeneic HSCT patients taking voriconazole, to identify when a plasma fluoride concentration was measured with respect to voriconazole initiation and onset of pain, and to describe the outcomes of patients with fluoride excess in the setting of HSCT. A retrospective review was conducted of all adult allogeneic HSCT patients receiving voriconazole at Mayo Clinic in Rochester, Minnesota, between January 1, 2009 and July 31, 2012. Of 242 patients included, 32 had plasma fluoride measured to explore the etiology of musculoskeletal pain. In 31 patients with fluoride measurement while on voriconazole, 29 (93.5%) had elevated levels. The median plasma fluoride was 11.1 MUmol/L (range, 2.4 to 24.7). The median duration of voriconazole was 163 days (range, 2 to 1327). The median time to fluoride measurement was 128 days after voriconazole initiation (range, 28 to 692). At 1 year after the start of voriconazole after HSCT, 15.3% of patients had developed pain associated with voriconazole use and 35.7% developed pain while on voriconazole after 2 years. Of the patients with an elevated fluoride level, 22 discontinued voriconazole; pain resolved or improved in 15, stabilized in 3, and worsened in 4 patients. Ten patients continued voriconazole; pain resolved or improved in 7, was attributable to alternative causes in 2, and undefined in 1. Serum creatinine, estimated glomerular filtration rate, alkaline phosphatase, and voriconazole concentration did not predict for fluoride excess and associated pain. Periostitis due to fluoride excess is a common adverse effect of voriconazole that should be considered in patients presenting with pain and is often reversible after drug discontinuation. Alternative antifungal agents with a lower risk for fluoride excess should be considered in patients receiving voriconazole who develop fluoride excess and pain. PMID- 26524732 TI - Comparison of Subcutaneous versus Intravenous Alemtuzumab for Graft-versus-Host Disease Prophylaxis with Fludarabine/Melphalan-Based Conditioning in Matched Unrelated Donor Allogeneic Stem Cell Transplantation. AB - The objective of this study was to compare infusion-related reactions and outcomes of using subcutaneous (subQ) alemtuzumab versus intravenous (i.v.) alemtuzumab as graft-versus-host disease (GVHD) prophylaxis for matched unrelated donor stem cell transplantations. Outcomes include incidence of cytomegalovirus (CMV)/Epstein-Barr (EBV) viremia, development of CMV disease or post transplantation lymphoproliferative disorder, fatal infections, acute and chronic GVHD, time to engraftment, relapse rate, and survival. We conducted a retrospective study of all adult matched unrelated donor stem cell transplantations patients who received fludarabine/melphalan with subQ or i.v. alemtuzumab in combination with tacrolimus as part of their conditioning for unrelated donor transplantation at New York-Presbyterian/Weill Cornell Medical Center from January 1, 2012 to March 21, 2014. Alemtuzumab was administered at a total cumulative dose of 100 mg (divided over days -7 to -3). Forty-six patients received an unrelated donor stem cell transplantation with fludarabine/melphalan and either subQ (n = 26) or i.v. (n = 20) alemtuzumab in combination with tacrolimus. Within the evaluable population, 130 subQ and 100 i.v. alemtuzumab doses were administered. For the primary outcome, >=grade 2 infusion-related reactions occurred in 11 (8%) versus 25 (25%) infusions in the subQ and i.v. cohorts, respectively (P = .001). Overall, 12 injections (9%) in the subQ arm versus 26 infusions (26%) in the i.v. arm experienced an infusion-related reaction of any grade (P = .001). There were no significant differences between the subQ and i.v. arms in rates of reactivation of CMV/EBV, development of CMV disease or post-transplantation lymphoproliferative disorder, fatal infections, acute and chronic GVHD, relapse, or survival. Subcutaneous administration of alemtuzumab for GVHD prophylaxis was associated with fewer infusion-related reactions compared with i.v. administration in the SCT setting. Incidences of acute and chronic GVHD were similar between both arms. There was also no difference in reactivation of CMV/EBV viremia, development of CMV disease or post transplantation lymphoproliferative disorder, fatal infections, relapse, or survival. PMID- 26524733 TI - Post-artesunate delayed haemolysis - report of four cases and review of the literature. AB - As a result of a huge effort of the international community, the burden of malaria dropped impressively during the last decade. One of the reasons is probably the availability of effective and safe treatments such as artemisinin derivatives. However, along with the greater use of intravenous artesunate recently in severe malaria, as recommended by the World Health Organization, a new adverse event has been described: post-artesunate delayed haemolysis (PADH). It appears after the end of the treatment in a phase of clinical improvement. Even though several causes may act as co-factors, the mechanism of pitting of the infected erythrocytes is most probably the main explanation. After the description of four PADH cases, we hereby present a short review of the current knowledge on this problem. PMID- 26524736 TI - Measurement Methodology: What Does Blood Pressure Mean in the PARTAGE Study? PMID- 26524737 TI - Measurement Methodology: What Does Blood Pressure Mean in the PARTAGE Study? Reply. PMID- 26524738 TI - Careful Considerations Concerning Psychogenic Itch. PMID- 26524739 TI - Careful Considerations Concerning Psychogenic Itch-Reply. PMID- 26524740 TI - Shared Decision-Making for Cancer Screening: Visual Tools and a 4-Step Method. PMID- 26524741 TI - Physical Activity and Successful Aging: Even a Little Is Good. PMID- 26524742 TI - Physical Activity and Successful Aging-Reply: Even a Little Is Good. PMID- 26524743 TI - Physical Activity Is Key for Successful Aging-Reply: Even a Little Is Good. PMID- 26524744 TI - Dosing Strategies of Bone-Targeting Agents. PMID- 26524745 TI - Dosing Strategies of Bone-Targeting Agents. PMID- 26524746 TI - Dosing Strategies of Bone-Targeting Agents-Reply. PMID- 26524747 TI - Appropriate Care of a Swollen Joint. PMID- 26524748 TI - Appropriate Care of a Swollen Joint-Reply. PMID- 26524749 TI - The True Environmental Cost of Chlorofluorocarbon-Based Inhalers. PMID- 26524750 TI - The Lariat for Left Atrial Appendage Closure: Rehash of Known Literature or a True Analysis? PMID- 26524751 TI - The Lariat for Left Atrial Appendage Closure: Rehash of Known Literature or a True Analysis? PMID- 26524752 TI - The Lariat for Left Atrial Appendage Closure: Rehash of Known Literature or a True Analysis?-Reply. PMID- 26524753 TI - US Department of Veterans Affairs Primary Care Provider Turnover and Patient Satisfaction. PMID- 26524754 TI - US Department of Veterans Affairs Primary Care Provider Turnover and Patient Satisfaction-Reply. PMID- 26524755 TI - Whole-Arm Ultrasound for Suspected Upper-Extremity Deep Venous Thrombosis in Outpatients. PMID- 26524756 TI - Whole-Arm Ultrasound for Suspected Upper-Extremity Deep Venous Thrombosis in Outpatients-Reply. PMID- 26524757 TI - Subclinical Hypothyroidism Overdiagnosis in Pregnant Women. PMID- 26524758 TI - Imaging Tests for Suspected Deep Vein Thrombosis. PMID- 26524759 TI - Subclinical Hypothyroidism Overdiagnosis in Pregnant Women-Reply. PMID- 26524760 TI - Misinterpretation of the Comparative Safety of Testosterone Dosage Forms. PMID- 26524761 TI - Imaging Tests for Suspected Deep Vein Thrombosis-Reply. PMID- 26524762 TI - Misinterpretation of the Comparative Safety of Testosterone Dosage Forms-Reply. PMID- 26524763 TI - Circulating Human Eosinophils Share a Similar Transcriptional Profile in Asthma and Other Hypereosinophilic Disorders. AB - Eosinophils are leukocytes that are released into the peripheral blood in a phenotypically mature state and are capable of being recruited into tissues in response to appropriate stimuli. Eosinophils, traditionally considered cytotoxic effector cells, are leukocytes recruited into the airways of asthma patients where they are believed to contribute to the development of many features of the disease. This perception, however, has been challenged by recent findings suggesting that eosinophils have also immunomodulatory functions and may be involved in tissue homeostasis and wound healing. Here we describe a transcriptome-based approach-in a limited number of patients and controls-to investigate the activation state of circulating human eosinophils isolated by flow cytometry. We provide an overview of the global expression pattern in eosinophils in various relevant conditions, e.g., eosinophilic asthma, hypereosinophilic dermatological diseases, parasitosis and pulmonary aspergillosis. Compared to healthy subjects, circulating eosinophils isolated from asthma patients differed in their gene expression profile which is marked by downregulation of transcripts involved in antigen presentation, pathogen recognition and mucosal innate immunity, whereas up-regulated genes were involved in response to non-specific stimulation, wounding and maintenance of homeostasis. Eosinophils from other hypereosinophilic disorders displayed a very similar transcriptional profile. Taken together, these observations seem to indicate that eosinophils exhibit non-specific immunomodulatory functions important for tissue repair and homeostasis and suggest new roles for these cells in asthma immunobiology. PMID- 26524765 TI - Correction: Deep Sequencing for Evaluation of Genetic Stability of Influenza A/California/07/2009 (H1N1) Vaccine Viruses. PMID- 26524764 TI - Cellular Defense and Sensory Cell Survival Require Distinct Functions of ebi in Drosophila. AB - The innate immune response and stress-induced apoptosis are well-established signaling pathways related to cellular defense. NF-kappaB and AP-1 are redox sensitive transcription factors that play important roles in those pathways. Here we show that Ebi, a Drosophila homolog of the mammalian co-repressor molecule transducin beta-like 1 (TBL1), variously regulates the expression of specific genes that are targets of redox-sensitive transcription factors. In response to different stimuli, Ebi activated gene expression to support the acute immune response in fat bodies, whereas Ebi repressed genes that are involved in apoptosis in photoreceptor cells. Thus, Ebi seems to act as a regulatory switch for genes that are activated or repressed in response to different external stimuli. Our results offer clear in vivo evidence that the Ebi-containing co repressor complex acts in a distinct manner to regulate transcription that is required for modulating the output of various processes during Drosophila development. PMID- 26524766 TI - Changes taking place under the new kidney transplant allocation system. PMID- 26524767 TI - Government-transplant community partnership eases financial burden for donors. PMID- 26524768 TI - Federal Employees Health Benefits Program: Enrollment Options Following the Termination of a Plan or Plan Option. Final rule. AB - The U.S. Office of Personnel Management (OPM) is issuing a final rule to amend the Federal Employees Health Benefits (FEHB) Program regulations regarding enrollment options following the termination of a plan or plan option. PMID- 26524769 TI - Expanded Access to Non-VA Care Through the Veterans Choice Program. Final rule. AB - This document amends the Department of Veterans Affairs (VA) medical regulations implementing section 101 of the Veterans Access, Choice, and Accountability Act of 2014, which directed VA to establish a program to furnish hospital care and medical services through eligible non-VA health care providers to eligible veterans who either cannot be seen within the wait-time goals of the Veterans Health Administration or who qualify based on their place of residence (hereafter referred to as the "Veterans Choice Program'', or the "Program''). VA published an interim final rule implementing the Veterans Choice Program on November 5, 2014, and published a subsequent interim final rule making further amendments on April 24, 2015. This final rule responds to public comments received from both interim final rules and amends the regulations to modify payment rates under the Program. PMID- 26524770 TI - Medicare Program; Final Waivers in Connection With the Shared Savings Program. Final rule. AB - This final rule finalizes waivers of the application of the physician self referral law, the Federal anti-kickback statute, and the civil monetary penalties (CMP) law provision relating to beneficiary inducements to specified arrangements involving accountable care organizations (ACOs) under section 1899 of the Social Security Act (the Act) (the "Shared Savings Program''), as set forth in the Interim Final Rule with comment period (IFC) dated November 2, 2011. As explained in greater detail below, in light of legislative changes that occurred after publication of the IFC, this final rule does not finalize waivers of the application of the CMP law provision relating to "gainsharing'' arrangements. Section 1899(f) of the Act, as added by the Affordable Care Act, authorizes the Secretary to waive certain fraud and abuse laws as necessary to carry out the provisions of section 1899 of the Act. PMID- 26524771 TI - Medical Devices; Immunology and Microbiology Devices; Classification of Gastrointestinal Microorganism Multiplex Nucleic Acid-Based Assay. Final order. AB - The Food and Drug Administration (FDA) is classifying a gastrointestinal microorganism multiplex nucleic acid-based assay into class II (special controls). The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26524772 TI - Medicaid Program; Methods for Assuring Access to Covered Medicaid Services. Final rule with comment period. AB - This final rule with comment period provides for a transparent data-driven process for states to document whether Medicaid payments are sufficient to enlist providers to assure beneficiary access to covered care and services consistent with section 1902(a)(30)(A) of the Social Security Act (the Act) and to address issues raised by that process. The final rule with comment period also recognizes electronic publication as an optional means of providing public notice of proposed changes in rates or ratesetting methodologies that the state intends to include in a Medicaid state plan amendment (SPA). We are providing an opportunity for comment on whether future adjustments would be warranted to the provisions setting forth requirements for ongoing state reviews of beneficiary access. PMID- 26524773 TI - Frailty in Aging. Biological, Clinical and Social Implications. Introduction. PMID- 26524774 TI - [A sound mind in a sound body]. PMID- 26524775 TI - [Design and Implementation of a Novel Networked Sleep Monitoring System]. AB - To meet the need of cost-effective multi-biosignal monitoring devices nowadays, we designed a system based on super low power MCU. It can collect, record and transfer several signals including ECG, Oxygen saturation, thoracic and abdominal wall expansion, oronasal airflow signal. The data files can be stored on a flash chip and transferred to a computer by a USB module. In addition, the sensing data can be sent wirelessly in real time. Considering that long term work of wireless module consumes much energy, we present a low-power optimization method based on delay constraint. Lower energy consumption comes at the cost of little delay. Experimental results show that it can effectively decrease the energy consumption without changing wireless module and transfer protocol. Besides, our system is powered by two dry batteries and can work at least 8 hours throughout a whole night. PMID- 26524776 TI - [Design and Application of Portable Micro Sleep Monitoring System]. AB - Through the study of the pathology of sleep apnea-hypopnea syndrome, evaluation indexes, diagnosis requirements and so on, a portable sleep monitoring system was designed, which had the characteristics of convenience, wireless transmission and no disturbance. The system can be assessed by respiration monitoring and pulse oximetry, which is based on the pressure variation in miniature air-bag and spectral absorption method. It provides the value of the apnea-hypopnea index (AHI), which is used to evaluate OSAHS severity. The experiment of the system's stability and accuracy is done, which exhibits good performance, it can diagnose OSAHS effectively and provide convenience for home monitoring. PMID- 26524777 TI - [A Meridian Visualization System Based on Impedance and Binocular Vision]. AB - To ensure the meridian can be measured and displayed correctly on the human body surface, a visualization method based on impedance and binocular vision is proposed. First of all, using alternating constant current source to inject current signal into the human skin surface, then according to the low impedance characteristics of meridian, the multi-channel detecting instrument detects voltage of each pair of electrodes, thereby obtaining the channel of the meridian location, through the serial port communication, data is transmitted to the host computer. Secondly, intrinsic and extrinsic parameters of cameras are obtained by Zhang's camera calibration method, and 3D information of meridian location is got by corner selection and matching of the optical target, and then transform coordinate of 3D information according to the binocular vision principle. Finally, using curve fitting and image fusion technology realizes the meridian visualization. The test results show that the system can realize real-time detection and accurate display of meridian. PMID- 26524778 TI - [Mechanical Shimming Method and Implementation for Permanent Magnet of MRI System]. AB - A mechanical shimming method and device for permanent magnet of MRI system has been developed to meet its stringent homogeneity requirement without time consuming passive shimming on site, installation and adjustment efficiency has been increased. PMID- 26524779 TI - [Investigation on Mobile Phone Based Thermal Imaging System and Its Preliminary Application]. AB - The technical structure of a low-cost thermal imaging system (TIM) lunched on a mobile phone was investigated, which consists of a thermal infrared module and mobile phone and application software. The designing strategies and technical factors toward realizing various TIM array performances are interpreted, including sensor cost and Noise Equivalent Temperature Difference (NETD). In the software algorithm, a mechanism for scene-change detection was implemented to optimize the efficiency of non-uniformity correction (NUC). The performance experiments and analysis indicate that the NETD of the system can be smaller than 150 mK when the integration time is larger than 16 frames. Furthermore, a practical application for human temperature monitoring during physical exercise is proposed and interpreted. The measurement results support the feasibility and facility of the system in the medical application. PMID- 26524780 TI - [Analysis of Optical Coherence Tomography Based on Monte Carlo Simulation Model]. AB - A Monte Carlo model for optical coherence tomography of human skin is proposed. The new model includes importance sampling technique which is designed to suit for the multi-layer human skin, new rules for back scattered photon classification are correspondingly proposed. Based on the new simulation model, we analyzed the focusing of Gaussian beam through skin and the maximum detecting depth of optical coherence tomography. The experimental results show that there exists focus distortion when beam propagates in skin, including focus shift and diffusion. Object lens with greater NA will lower the maximum detecting depth of optical coherence tomography. PMID- 26524781 TI - [Temperature Measurement with Bluetooth under Android Platform]. AB - To realize the real-time transmission of temperature data and display using the platform of intelligent mobile phone and bluetooth. Application of Arduino Uno R3 in temperature data acquisition of digital temperature sensor DS18B20 acquisition, through the HC-05 bluetooth transmits the data to the intelligent smart phone Android system, realizes transmission of temperature data. Using Java language to write applications program under Android development environment, can achieve real-time temperature data display, storage and drawing temperature fluctuations drawn graphics. Temperature sensor is experimentally tested to meet the body temperature measurement precision and accuracy. This paper can provide a reference for other smart phone mobile medical product development. PMID- 26524782 TI - [Design of Oxygen Saturation, Heart Rate, Respiration Rate Detection System Based on Smartphone of Android Operating System]. AB - In this paper, we designed an oxygen saturation, heart rate, respiration rate monitoring system based on smartphone of android operating system, physiological signal acquired by MSP430 microcontroller and transmitted by Bluetooth module. PMID- 26524783 TI - [Design of Rehabilitation Training System with Electromyography Feedback for Stroke Patients]. AB - This paper proposed a rehabilitation training system with electromyography (sEMG) feedback for stroke patients based on ARM embedded system and LabVIEW. The system can achieve real-time acquisition, processing and dualview of multi-channel sEMGs and compute related sEMG parameters including iEMG, RMS, MPF and co-contraction ratio. The system was detected by clinical experiments and related inspection department. The result showed that the system is functional, interactive and in accordance with the relevant standards for medical devices so that it can fully satisfy the clinical demands. In addition, the system can help doctors to master the training state of the patient more effectively in a real-time and quantitative way that is direct to improve the training programs of stroke patients. PMID- 26524784 TI - [The Application of Compound Tabletop in Medical Imaging Equipment]. AB - This paper mainly introduces the material composition and structure of two kinds of compound tabletop which currently used in large medical imaging equipment, also introduces the proper material choosing and production processing, together with the advantage and shortage of this two kinds of tabletop and different application occasion. PMID- 26524785 TI - [Wearable Medical Devices' MCU Selection Analysis Based on the ARM Cortex-MO+ Architecture]. AB - According to the characteristics of low cost, high performance, high integration and long battery life of wearable medical devices, the mainstream low-power microcontroller(MCU) series were compared, and came to the conclusion that the MCU series based on ARM Cortex-M0+ architecture were suitable for the development of wearable medical devices. In aspects of power consumption, operational performance, integrated peripherals and cost, the MCU series based on Cortex-M0+ architecture of primary semiconductor companies were compared, aimed at providing the guides of MCU selection for wearable medical devices. PMID- 26524786 TI - [Generation and Regulation Technology of Stimulating Signals for Implantable Neural Stimulators]. AB - The accuracy and robustness of stimulating signals are critical important for implantable neural stimulators since they stimulate neurons directly. The characteristics and applications of stimulating signals were depicted in the paper. The principles and features of five common generation and regulation technology of stimulating signals for implantable neural stimulators were introduced. The technical characteristics of them were analyzed. Finally, the development of the implantable neural simulators was prospected. PMID- 26524787 TI - [Batteries Used in Active Implantable Medical Devices]. AB - In recent years active implantable medical devices(AIMD) are being developed rapidly. Many battery systems have been developed for different AIMD applications. These batteries have the same requirements which include high safety, reliability, energy density and long service life, discharge indication. History, present and future of batteries used in AIMD are introduced in the article. PMID- 26524788 TI - [Study on Tracheal Intubation's Circular Arc Radius Measuring Method Based on Machine Vision]. AB - It is difficult to measure the circular arc radius for central angle less than 30 degrees. The existing measuring methods are of low efficiency and big error. Through designing the machine vision system and studying the image detecting method for measurement, It is obtained good results by using the new measurement for tracheal intubation's circular arc radius, Realized a rapid and accurate measurement of the circular arc radius, and expanded the application in the field of machine vision. PMID- 26524789 TI - [Ideas about Registration for Prenatal Diagnosis of Chromosome Aneuploidy by Next Generation Sequencing Technology]. AB - To review the registration and technical data for prenatal diagnosis of chromosome aneuploidy by next generation sequencing technology. On the basis of introducing declarations of the reagents, analysis registration dossier common problems. And analysis the requirement of performance evaluation, reference intervals and clinical evaluation study. PMID- 26524790 TI - [In Vitro Cytotoxicity Study of Nickel Ion]. AB - The purpose of this study was to investigate the cytotoxicity of the nickel ion and provide with basic data for the biological evaluation of those medical devices containing nickel. Seven cell lines were chosen. They were L929, h9c2(2 1), 293[HEK-293], hFOB1.19, THLE-3, H9 and IM-9 respectively. According to the principle of biological evaluation of medical devices, MTT method was chosen to test the cytotoxicity in different concentrations of nickel ion. For each cell line, the relative growth rate (RGR) was obtained and the cytotoxic grade was classified. Besides, IC50 values were calculated. As a result, it was found that the sensitivity was different among all cell lines. H9 was the most sensitive one, while the L929 was the most tolerant one. The concentration which is not above 1.25 mg/L was safe for all seven cell lines, because the cytotoxicity for all cells exposed in this concentration were not higher than grade 1. According to the criteria for medical devices, the concentrations not above 5 mg/L were safe for L929 cells. This result helps us to roughly assess the cytotoxicity and systematic toxicity caused by nickel contained in medical devices. PMID- 26524791 TI - [Troubleshooting of Electro-Static Discharge Test for Medical Injection Pump]. AB - This article presents several common problems.of medical injection pump through one case of ESD troubleshooting. Expounds the causes of the problem and provides solutions. PMID- 26524792 TI - [The Application of Noninvasive Central Blood Pressure Detection in Blood Pressure Management and Vessel Function Assessment of Hypertension]. AB - OBJECTIVES: To explore the significance of noninvasive central blood pressure detection in blood pressure management and vessel function assessment of hypertension. METHODS: A total of 348 subjects were recruited in the study and A pulse CASP software were derived to measure the parameters of CASP and vessel function. The recruited subjects were divided into different groups for analysis according to age and disease. RESULTS: (1) CASP in hypertension group were both higher than those in normal group, while RAI and PRT lower. (2) Hypertensive patients of which brachial blood pressure were controlled have lower CASP and RAI than those above the level. (3) Hypertensive patients whose brachial blood pressure were controlled have significantly higher CASP than normal subjects. CONCLUSIONS: Central blood pressure is more reflective of actural blood pressure and vessel function. Enhanced control of CASP in hypertensive patients contributes to improving vessel compliance. PMID- 26524793 TI - [The Dose Effect of Isocenter Selection during IMRT Dose Verification with the 2D Chamber Array]. AB - To investigate the dose effect of isocenter difference during IMRT dose verification with the 2D chamber array. The samples collected from 10 patients were respectively designed for IMRT plans, the isocenter of which was independently defined as P(o), P(x) and P(y). P(o) was fixed on the target center and the other points shifted 8cm from the target center in the orientation of x/y. The PTW729 was used for 2D dose verification in the 3 groups which beams of plans were set to 0 degrees. The gamma-analysis passing rates for the whole plan and each beam were gotten using the different standards in the 3 groups, The results showed the mean passing rate of gamma-analysis was highest in the P(o) group, and the mean passing rate of the whole plan was better than that of each beam. In addition, it became worse with the increase of dose leakage between the leaves in P(y) group. Therefore, the determination of isocenter has a visible effect for IMRT dose verification of the 2D chamber array, The isocenter of the planning design should be close to the geometric center of target. PMID- 26524794 TI - [Development of a Software for Automatically Generated Contours in Eclipse TPS]. AB - OBJECTIVE: The automatic generation of planning targets and auxiliary contours have achieved in Eclipse TPS 11.0. METHODS: The scripting language autohotkey was used to develop a software for automatically generated contours in Eclipse TPS. This software is named Contour Auto Margin (CAM), which is composed of operational functions of contours, script generated visualization and script file operations. RESULTS Ten cases in different cancers have separately selected, in Eclipse TPS 11.0 scripts generated by the software could not only automatically generate contours but also do contour post-processing. For different cancers, there was no difference between automatically generated contours and manually created contours. CONCLUSION: The CAM is a user-friendly and powerful software, and can automatically generated contours fast in Eclipse TPS 11.0. With the help of CAM, it greatly save plan preparation time and improve working efficiency of radiation therapy physicists. PMID- 26524795 TI - [A New Exploration of Security Event Monitoring, Assessment and Control Methods of Using Medical Equipment]. AB - Based on the research of risk assessment of medical equipment safety and operation to formulate evaluation criteria and methods of how to use the practical management work. Objective to evaluate the practical method is to use and the risk of adverse events of medical equipment in operation risk in order to find the risk, control risk, ensure safety in time, so that Improve the level of risk management of medical equipment. PMID- 26524796 TI - [Discussion about Management of In Vitro Diagnostic Reagent]. AB - OBJECTIVE: In order to adapt the rapid development of modern medicine, this paper is aimed to analyze the application of in vitro diagnostic reagents (IVD Reagents) in hospital management and improve the overall level of hospital management. METHODS: By groping the management experience of IVD reagents, we discuss the internal hospital management mode of IVD reagents in reality. RESULTS: With the continuous improvements on the information platform of IVD reagents,we can realize benefit analysis of IVD reagents within the process of management. CONCLUSION: Reasonable management on IVD reagentscan improve the working efficiency in hospitals and provide swifter and better medical service for patients. PMID- 26524797 TI - Serum levels of the progesterone induced blocking factor do not precipitously rise in women with gynecologic cancer in contrast to women exposed to progesterone. AB - PURPOSE: To determine if an immunomodulatory protein (progesterone induced blocking factor [PIBF]) that is progesterone induced and found in higher concentration during pregnancy is similarly found with increased levels in women with gynecologic cancers. MATERIALS AND METHODS: A newly developed enzyme linked immunoabsorbent assay (ELISA) assay was used to measure PIBF in the sera of six women with various gynecologic cancers and compare them to five controls (three with benign tumors and two having gynecologic procedures for non-tumors. RESULTS: The PIBF levels in women with gynecologic cancer did not rise precipitously as historical controls of women or men exposed to progesterone. The two highest PIBF levels of the 11 subjects were in women with gynecologic cancer. CONCLUSIONS: The data suggest that if PIBF helps cancer cells to evade immune surveillance, it probably operates through an intracytoplasmic presence. If an increase in sera PIBF could have been detected in women with gynecologic cancer, then this ELISA test could have been used to detect tumor recurrence. Future studies may concentrate on evaluating intracytoplasmic PIBF to possibly help determine which tumors may respond to progesterone antagonist receptors. PMID- 26524798 TI - Effect of taking a one time injection of one mg leuprolide acetate three days after embryo transfer on pregnancy outcome and level of first beta human chorionic gonadotropin (beta-hCG) level. AB - PURPOSE: To determine if the injection of a gonadotropin releasing hormone agonist (GnRHa) three days after embryo transfer will improve pregnancy and implantation rates. MATERIALS AND METHODS: One mg s.c. of leuprolide acetate was randomly given based on patient decision three days after embryo transfer to some patients undergoing in vitro fertilization-embryo transfer (IVF-ET). RESULTS: For women aged <= 43 the clinical pregnancy rate for those not taking the GnRHa was 39.5% (68/122) vs. 54.5% (42/77) for those taking leuprolide acetate (Chi-square, p = 0.0275). The respective implantation rates were 22.6% vs. 30.2% (p = 0.0495). There was no difference in first serum beta human chorionic gonadotropin (beta hCG) levels according to whether leuprolide was used or not. CONCLUSIONS: Leuprolide acetate similar to other GnRH agonists can improve implantation rates following IVF-ET when injected once in mid-luteal phase. The beneficial effect may be on GnRH receptors in the endometrium rather than the embryo (which had been hypothesized to direct increased placental production of hCG). PMID- 26524799 TI - The effect of conventional vs. mild ovarian hyperstimulation on the total number of live babies born from a given oocyte retrieval. AB - PURPOSE: To compare pregnancy outcome in women with normal oocyte reserve according to whether they received conventional or mild follicle stimulating hormone (FSH) controlled ovarian hyperstimulation (COH) further stratified by age. MATERIALS AND METHODS: A ten-year retrospective study including all cycles (even multiple in given patients) was performed. Mild stimulation including all cycles initiated and continued with 150 IU FSH or less from early follicular phase. Everything else was considered conventional stimulation. Mild stimulation included natural cycles or those with just a boost of 75 IU FSH from the mid to late follicular phase. Only women with normal oocyte reserve were selected--serum FSH < 12 mIU/mL and serum E2 < 50 pg/mL. Live delivered pregnancy rates within three age groups (<= 35, 36-39, and 40-42 years) were compared per embryo transfer and per embryo retrieval, i.e., the percentage of women having a live baby without proceeding to another IVF-ET cycle. Also compared were the average number of babies born from one retrieval. RESULTS: For aged <= 35 there were no differences in pregnancy rates per transfer but a trend for higher pregnancy rates per retrieval with conventional stimulation. For all other age groups both pregnancy rates per transfer and retrieval were significantly higher with conventional stimulation. This was reflected with a higher average number of babies born per retrieval with conventional. CONCLUSIONS: For women with normal oocyte reserve in general, there is no advantage of mild vs. conventional COH other than cost saving. Of course there are exceptions, e.g., ovarian hyperstimulation with conventional COH. PMID- 26524800 TI - The effect of oocyte reserve on pregnancy rates per oocyte harvest in women aged 36-39. AB - PURPOSE: To determine the relative effect of diminished oocyte reserve on clinical viable and live delivered pregnancy rates per transfer and live delivery pregnancy rate per oocyte harvest in women aged 36-39. MATERIALS AND METHODS: A retrospective comparison of pregnancy outcome was performed over a ten-year time period in women with normal oocyte reserve (day 3 serum FSH <= 11 mIU/mL) vs. diminished reserve (day 3 serum FSH >= 12 mIU/mL). Pregnancy rate per oocyte harvest equals the odds of conceiving with fresh or frozen embryos from a given retrieval before proceeding to another oocyte retrieval. RESULTS: The clinical and viable (at end of first trimester) pregnancy rate per transfer was only 20% lower for the group with diminished oocyte reserve, but was 50% lower for the pregnancy rate per oocyte harvest. CONCLUSIONS: Mild stimulation for women with diminished oocyte reserve allows a higher percentage of chromosomally normal embryos in women with diminished oocyte reserve, leading to only a 20% lower clinical and viable pregnancy rate per transfer. However, overall, there are less normal total number of normal embryos leading to a pregnancy rate per oocyte harvest only half as good in the group with lower reserve vs. normal. PMID- 26524801 TI - Assessment of follicular and serum VEGF and IGF-1 in ICSI patients: hMG vs rFSH. AB - PURPOSE: To investigate the effect of recombinant follicular stimulating hormone (r-FSH) and human menopausal gonadotropin (hMG) on follicular microenvironment via assessment of follicular and serum vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) levels in intracytoplasmic sperm injection (ICSI) cycles. MATERIALS AND METHODS: Designed as a prospective cohort study. Twenty-five patients underwent controlled ovarian hyperstimulation (COH) with r-FSH and 20 patients underwent with hMG. RESULTS: Both groups were comparable regarding the women's mean age and body mass index (BMI). The amount of VEGF (pg/ml) in serum and follicular fluid in the group I and II were comparable (275 +/- 135.3 vs 330.7 +/- 190.0; p > 0.05 and 2,081.1 +/- 1095.1 vs 1,971.1 +/- 975.6; p > 0.05, respectively). The amount of IGF-1 (ng/ml) in serum and follicular fluid in the group I and II were also comparable (225.3 +/- 69.3 vs 204.1 +/- 56.3, p > 0.05 and 176.1 +/- 67.2 vs 185.8 +/- 48.7, p > 0.05, respectively). Pregnancy rates were also comparable between groups. CONCLUSIONS: The hMG and r-FSH in COH produced comparable follicular microenvironment regarding follicular VEGF and IGF-l. PMID- 26524802 TI - Methamphetamine, smoking, and gestational hypertension affect norepinephrine levels in umbilical cord tissues. AB - BACKGROUND: These studies were undertaken to determine methamphetamine (METH) and smoking effects on umbilical vascular dynamics and pregnancy outcomes. MATERIALS AND METHODS: Umbilical cords (54) were collected prospectively at birth, washed of blood, and stored at -80 degrees C. Cords were thawed and lysates prepared, then catecholamine levels quantified with enzyme-linked immunosorbent assay (ELISA). RESULTS: Catecholamine levels in umbilical cords were not associated with maternal or gestational age, gravidity, parity, neonatal or placental weight. Neither smoking nor METH affected dopamine or epinephrine. However, smoking (two-fold) and METH (four-fold) decreased norepinephrine and together a 60-fold reduction occurred (p = 0.025). Cesarean section and hypertension were both associated with lower norepinephrine levels (p < 0.001) regardless of drug status. In normotensive pregnancies, smoking and METH significantly decreased norepinephrine levels (two-fold and 3.5-fold each, respectively) with a 40-fold decrease for METH/smoking together. DISCUSSION: Depletion of norephinephrine by METH and smoking likely contributes to pregnancy complications, including the higher incidence of respiratory distress and postpartum hemorrhage in cesarean section. PMID- 26524803 TI - Prenatal karyotype results of fetuses with nuchal edema, cystic hygroma, and non immune hydrops. AB - PURPOSE: Subcutaneous edema detected sonographically in the forms of nuchal edema, cystic hygroma (CH), or non-immune hydrops (NIH) may be a sign of chromosomal abnormalities. The aim of this study was to investigate the chromosome abnormality incidence in fetuses with nuchal edema, CH, or NIH. MATERIALS AND METHODS: The authors performed cytogenetic analysis of 218 singleton fetuses with ultrasound diagnosis of subcutaneous edema in the forms of nuchal edema in the first and second trimesters. RESULTS: Chromosomal abnormality rates were 30.4, 10.4, 36.8, 34.1, and 60% in the nuchal translucency (NT), nuchal fold thickness (NF), CH, NIH, and CH with NIH groups, respectively. In 71 cases with detected chromosomal abnormalities, 37%, 44%, 15%, and 4% of the pathologic karyotypes were identified as monosomy X, trisomy 21, trisomy 18, and trisomy 13, respectively. CONCLUSIONS: This study confirms that subcutaneous edema detected sonographically, in the forms of nuchal edema, CH, or NIH, is a significant indicator of abnormal karyotype and deserves further investigation. PMID- 26524804 TI - Asymptomatic bacteriuria screened by catheterized samples at pregnancy term in women undergoing cesarean delivery. AB - OBJECTIVE: The objective of this study was to assess the frequency of urinary tract infection (UTI) with urine samples obtained via catheterization among women undergoing cesarean delivery at term pregnancy. MATERIALS AND METHODS: A cross sectional study involving 159 women in whom cesarean delivery was conducted at term pregnancy after a regular follow-up from first to third trimester. For screening and diagnosis of UTI during antenatal period, the authors used dipstick test and microscopic urinalysis, and urine culture was used in the presence of symptomatic UTI unresponsive to initial antibiotic therapy. A urine sample was obtained immediately after insertion of Foley catheter for urine dipstick test, microscopic urinalysis, and culture during cesarean delivery. Obstetric and UTI data were recorded. RESULTS: Of 159 pregnant women, 95 (59.8%) did not develop UTI during antenatal care. There was no patient with symptomatic UTI at the admission for cesarean delivery. The authors found UTI with urine dipstick and microscopic urinalysis in 12 patients and of them, four patients had no history of UTI, and all the remaining eight patients had asymptomatic UTI during antenatal follow-up. UTI according to urine culture was encountered in three patients, two of them had one episode of UTI, and one had two episodes of UTI during antenatal follow-up. CONCLUSIONS: After regular antenatal follow-up screening with urine dipstick, microscopic urinalysis, and counseling of pregnant women regarding UTIs, the frequency of bacteriuria decreases considerably during cesarean delivery. PMID- 26524805 TI - Construction and measuring combination of KDR-targeted ultrasound contrast agent in vitro for evaluating endometrial receptivity. AB - OBJECTIVE: To investigate the preparation of a new kind of targeted lipid ultrasound contrast agent with anti-KDR antibody based on biotin-avidin bridge (MB-BAB-KDR) which could combine specifically with KDR that increases during the time of embryo implantation. Then its binding capability in vitro was evaluated. MATERIALS AND METHODS: The agitation of high-speed method was employed to prepare biotin-microbubbles (MB-B), and biotin-avidin mediated technique was used to produce MB-BAB-KDR. MB-BAB-KDR, MB-B, and biotin-microbubbles-KDR (MB-B-KDR) were incubated with fluorescein-conjugated affiniPure goat anti-rat IgG (H+L) to assess the linked condition. Second, MB-BAB-KDR and control groups (MB-B and MB-B KDR) were incubated with human umbilical vein endothelial cell (HUVEC). Rosette formation rate was observed and calculated. Then, the parallel plate flow chamber technology was used to access attachment efficiency to KDR Fc. RESULTS: The surface of bubbles could carry KDR antibody through "biotin-avidin" bridge. After incubated with second antibody, bright green fluorescence (II grade) could be observed in MB-BAB-KDR group, as compared with weak fluorescence in control groups of MB-B (0 grade) and MB-B-KDR (I grade). The surrounding rosette formation rate on HUVEC was 89.86% in MB-BAB-KDR group and that of control groups were 7.13% (MB-B-KDR) and 3.02% (MB-B) (p < 0.05). The number of MB-BAB-KDR bound to KDR Fc increased as the KDR Fc density increased (p < 0.05). Under the same concentration, the MB-BAB-KDR bound to KDR Fc increased as time extended. CONCLUSION: The successful preparation of MB-BAB-KDR with anti-KDR antibody which shows specially targeting binding capability with HUVEC and stability in shear stress may be served as a noninvasive detection of endometrial vascular KDR expression and provide an experimental foundation for evaluating endometrial receptivity in vivo. PMID- 26524806 TI - Assessment of quantitative and qualitative changes of proteoglycans and glycosaminoglycans in normal breast tissue during the follicular and luteal phases of the menstrual cycle. AB - The effect of sex hormones on extracellular matrix compounds, such as proteoglycans (PGs) and glycosaminoglycans (GAGs), in mammary tissue remains poorly understood. The elucidation of extracellular matrix component functions could clarify pathophysiological conditions, such as cyclical mastalgia (breast pain). The authors examined the quantitative and qualitative changes of PGs and GAGs in normal breast tissue during the follicular and luteal phases of the menstrual cycle. Twenty-eight eumenorrheic patients with benign breast nodules were divided into groups: Group A included 15 follicular patients and Group B included 13 luteal phase patients. Breast tissue adjacent to the nodules was biochemically analyzed to evaluate the types and concentrations of PGS and GAGs. The distribution of proteoglycans during the menstrual cycle was analyzed with immunofluorescence. PG concentrations were elevated (p < 0.01) during the luteal phase compared with the follicular phase, whereas the concentrations of GAGs did not differ significantly. Immunofluorescence revealed that decorin was mainly found in the intralobular stroma. PG concentrations were elevated during the luteal phase, likely due to the influence of sex hormones on macromolecular synthesis. The PG decorin was observed in normal breast tissue in the intralobular stroma. Although the concentration of GAGs, including dermatan and heparan sulfate, varied cyclically, the differences were not significant. PMID- 26524807 TI - Can we predict postpartum depression in pregnant women? AB - OBJECTIVE: The authors aimed to determine risk factors for postpartum depression (PPD) in this prospective study. MATERIALS AND METHODS: The study included 285 pregnant women. The first assessment was conducted during pregnancy and a second time at 24 weeks after delivery. The participants were asked to fill out a series of questionnaires, which included psychosocial variables and socio- demographic characteristics, the Beck Depression Inventory (BDI), and Edinburgh Postnatal Depression Scale (EPDS). After delivery, 276 mothers participated again in the study and filled out a similar series of questionnaires. RESULTS: A significant difference was not found between the socio-demographic and obstetric factors of mothers. A significant relation was found between the BDI score, which is used in antepartum depression evaluation, and EPDS score, which is used on postpartum depression evaluation (rho: 0.433 to 0.645, p < 0.0001). In cases in which BDI score was more than 6 were selected, phenomena in which could develop PPD had 90.3% sensitivity and 45.3% specificity. CONCLUSIONS: The authors found that there was a correlation between EPDS score and BDI. The rate of PPD was found to be significantly higher in women, who had a depression history. Patients who have a potential risk of PPD should be evaluated during the postpartum period in terms of depression. PMID- 26524808 TI - Maternal hemodynamic influence on uteroplacental oxygen distribution during cesarean section. AB - This study investigated maternal hemodynamic influence on uteroplacental oxygen distribution and neonatal outcome during cesarean section (CS). CS was performed on 80 parturients using two anaesthetic techniques: spinal anaesthesia (SA) and general balanced anaesthesia (GBA). Indications for CS were exclusively obstetric related. Monitored maternal parameters were: ECG, heart rate (HR), non-invasive blood pressure (NIBP), saturation (SaO2). Gas parameters in umbilical artery, vein, and neonatal capillary blood were sampled. Vitality was assessed by the Apgar scoring, first breath-taking time and the first breastfeeding attempt. Hypotension was the most common finding after SA induction. GBA group presented changes such as QT inversion (12.5%), tachycardia (55%), and bradycardia (2.5%). SA group experienced higher rates of sinus tachycardia (45%) and ventricular dysrhythmias (2.5%). Neonatal oxygenation was significantly higher in SA group. Higher quality of early neonatal adaptation in the SA group confirms it as the technique with the least neonatal risk during CS. PMID- 26524809 TI - Comparison of second trimester uterine artery pulsatility index between IVF and spontaneous twin pregnancies. AB - PURPOSE OF INVESTIGATION: The authors aimed to determine and compare the uterine artery pulsatility index (PI) between spontaneous and IVF twins in the second trimester. MATERIALS AND METHODS: All medical records of twin pregnancies, whose fetal screening was done between May 1999 and December 2013, were evaluated retrospectively. All twin pregnancies without detected/suspicious anatomical or genetic fetal anomalies, systemic diseases, biochemical abnormalities, and familial genetic diseases were included in the data analyses. Fetuses with no information on spontaneous or IVF conception and fetuses with undetermined uterine artery impedance of second trimester were excluded from the data analyses. RESULTS: A total of 151 twin pregnancies were evaluated in the analyses. The percentages of spontaneous and IVF twins were 24.5% and 75.5%, respectively. Mean gestational age was 19.95 +/- 2.25 weeks in IVF twin group and 20.10 +/- 2.19 weeks in spontaneous twin group. The difference of the gestational age between groups was not statistically significant. Mean uterine artery impedance was found as 0.78 +/- 0.22 in IVF twins and 0.96 +/- 0.31 in spontaneous twins respectively). Mean values were significantly lower in the IVF twins (p = 0.09). CONCLUSION: The uterine artery PI in the second trimester is significantly lower in IVF twins compared to the spontaneous twins. PMID- 26524810 TI - Pregnancy-associated plasma protein a levels are decreased in obstetric cholestasis. AB - OBJECTIVE: Obstetric cholestasis is a cholestatic disease usually commencing in the third trimester of pregnancy and characterized by pruritus, elevation of liver enzymes, and increase in bile acids. The objective of this study was to compare the first trimester serum indicators of obstetric cholestasis with normal pregnancies. MATERIALS AND METHODS: Thirty-five patients diagnosed with obstetric cholestasis in a three-year period with first trimester biochemical assessment available were included in the study. Seventy patients with concordant pregnancy weeks, matched-age normal pregnancies were included as the control group. Pregnancy-associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG) levels were analyzed. RESULTS: No difference was observed between the two groups in terms of age and week of pregnancy. While the mean PAPP A level was 0.76 +/- 0.31 multiples of the medians (MoM) in the obstetric cholestasis group, it was determined to be 1.5 +/- 0.84 in the control group (p = 0.0001). Among the two groups, the hCG levels were found to be higher in the obstetric cholestasis group (1.2 +/- 0.79 MoM vs. 0.98 +/- 0.53, p = 0.041). CONCLUSION: In this study, the first trimester PAPP-A levels in the obstetric cholestasis cases were found to be significantly lower than the control group. Low PAPP-A levels should be a warning for obstetric cholestasis. PMID- 26524811 TI - Incidence and factors associated with nosocomial infections in a neonatal intensive care unit (NICU) of an urban children's hospital in China. AB - OBJECTIVE: The study's aim was to assess incidence and epidemiologic profile of nosocomial infection (NI) in a NICU of China, and to identify main risk factors of NIs. MATERIALS AND METHODS: Chi square test for discrete variables and independent t-test for continuous variables to examine the association with NI. Univariate regression model was applied to the variables to predict the NI status. Finally the multivariate model was utilized with stepwise methods included all variables in the univariate model to extrapolate the independent variables to NI. RESULTS: Infection rate in NICU during the study period was 6.2 episodes per 100 patients. Infection density was 4.2 episodes per 1,000 patient days. Infection rate of ventilation-related pneumonia was 3.4 episodes per 1,000 mechanical ventilation (MV) days. Central line-associated bloodstream infection rate was 5.4 episodes per 1,000 central line days. Gestational age < 32 weeks, with congenital malformation, twins or triplets, gastric tube feeding, operation, duration of prophylaxis antibiotic use, duration of probiotic use, duration of parenteral nutrition were the risk factors associated with NI in NICU. We discussed the association between intrinsic factors of infants and health care procedures with NI. CONCLUSION: This study provided information for prevention strategies of NI, that will ultimately improve the healthcare service level. PMID- 26524812 TI - Ultrastructural analysis of granulosa cells of IVF patients. AB - OBJECTIVE: To compare the percentage and ultrastructure of normal and abnormal granulosa cells and their effect on fertilization and pregnancy rate between gonadotropin releasing hormone (GnRH) agonist and antagonist treatment. MATERIALS AND METHODS: In this study, granulosa cells obtained from 22 women undergoing in vitro fertilization (IVF) treatment due to unexplained infertility with either with GnRH agonist (n = 11) or GnRH antagonist (n = 11) were evaluated by light and electron microscopy. RESULTS: GnRH agonist and antagonist therapy was found to have no effect in terms of abnormal granulosa cell percentage (0.0679 +/- 0.08977 vs 0.0481 +/- 0.05164; p > 0.05), fertilization [85 (45-90) vs 75 (64 93)] and pregnancy rate (37% vs 46%). Light microscopic observations showed similar features of normal cells of agonist and antagonist-treated cells. Ultrastructural evaluation also revealed that there was no difference between cells of two treatment groups. CONCLUSION: Both GnRH agonist and antagonist treatment for ovarian stimulation may have similar effects on granulosa cells at the morphological and ultrastructural level, as well as on fertilization and pregnancy rates. PMID- 26524813 TI - AT1R A1166C polymorphism and risk of pregnancy-induced hypertension: a meta analysis of case control studies. AB - PURPOSE: The purpose of this study was to perform a quantitative review of previous case control studies examining the association between AT1R A1166C polymorphism and pregnancy-induced hypertension (PIH). MATERIALS AND METHODS: Odds ratio (OR) and 95% confidence intervals (CI) were used as measures of effect sizes. Overall effect sizes were derived using a random-effects model or fixed effects model when appreciated, and stratified by ethnicity. Funnel plots and Egger's regression asymmetry tests were utilized for publication bias detection. RESULTS: A total of ten articles (including 920 PIH cases and 1408 controls) were included in this meta-analysis. The overall effect sizes (OR = 2.14, 95% CI: 1.54 2.98, p < 0.00001) of additive model indicated PIH patients had a significant higher frequency of allele C. Meanwhile, the OR of the dominant model was 2.22 (95% CI: 1.51-3.26,p < 0.00001) which signified that PIH patients also had a significant higher frequency of AC+CC genotypes. The subgroup analyses were in line with the overall outcomes except the Caucasians PIH patients had a non significant CA+CC genotypes (OR = 1.37, 95% CI: 0.95-1.98, p > 0.05). The Egger's test of additive model (p = 0.451) and dominant model (p = 0.623) revealed no statistical significance for publication bias. CONCLUSION: The meta-analysis suggested that the AT1R Al166C polymorphism was significantly associated with the PIH, especially in Asian subjects. PMID- 26524814 TI - Uterine artery pulsatility index and diastolic notch laterality according to the placental location. AB - PURPOSE OF INVESTIGATION: The authors aimed to determine the effect of placental site on uterine artery pulsatility index (PI) values and tendency for laterality of uterine artery diastolic notch in singleton pregnancies. MATERIALS AND METHODS: All medical records of singleton pregnancies whose first trimester screening was done between years of 2004-2014, were evaluated retrospectively. Singleton pregnancies with detected/suspicious anatomical or genetic fetal anomalies, any systemic disease, familial genetic diseases, artificial reproduction techniques or missing data were excluded. Mean left and right uterine artery PI values and diastolic notch laterality ratios according to placental sites were determined and compared. RESULTS: A total of 2,067 singleton pregnancies were included in data analyses. Mean gestational age was 12.57 +/- 0.61 weeks. Left and right uterine artery PI was 1.42 +/- 0.47 and 1.48 +/- 0.56, respectively. Uterine artery notch was present in 18.86%. PI measurements did not show any statistical difference according to placental locations. Uterine artery notch laterality ratios according to common placental sites are as following; in anterior location (n = 190) 67% bilateral, 21% left sided, 12% right sided; in posterior (n = 136) 66% bilateral, 18% left sided, 16% right sided. CONCLUSION: The placental site has no effect on uterine artery PI values and the laterality of uterine artery notch in singletons. PMID- 26524815 TI - Comprehensive effect assessment of medical nutrition guidance during pregnancy towards the health of mothers and children. AB - OBJECTIVE: This study evaluates the effects of medical nutrition guidance provided to pregnant women to reduce pregnancy complications and occurrence of low birth-weight children and macrosomia. This guideline aims to provide the basis for improving birth delivery outcomes. MATERIALS AND METHODS: A randomized controlled method was used. A total of 261 parturient women who enrolled in regular pregnancy testing were sampled and selected. The subjects were randomly divided into experimental group (EG, n = 124) and control group (CG, n = 132). The differences in maternal health, pregnancy outcomes, and newborn health between the two groups were compared. RESULTS: Hypertensive disorders in pregnancy and gestational diabetes risks in EG were significantly lower than those in CG (p < 0.05). The cesarean section rate decreased (EG 36.29%, CG 51.50%), and the vaginal delivery rate increased (EG 63.71%, CG 51.50%). The incidence of macrosomia in EG was significantly lower than that in CG (p < 0.05). CONCLUSION: Medical nutrition guidance during pregnancy improves the perinatal outcomes of mothers and children. PMID- 26524816 TI - The effectiveness of misoprostol or dinoprostone in neonatal outcome after labour induction in post-term nulliparas. AB - OBJECTIVE: The object of this study was to investigate the efficacy of vaginal administration of misoprostol versus dinoprostone in neonatal outcome. MATERIALS AND METHODS: The first Group A included 77 pregnant women, who requested pregnancy termination one week after labour term and received vaginally misoprostol 50 ug, while the other 69 pregnant women in Group B were vaginally administrated three mg dinoprostone. According to the authors' protocol this procedure was repeated after six hours for a maximum of two times. RESULTS: The labour duration was longer in Group B (p = 0.000), while the APGAR score was better in Group A (p = 0.015). In Group A the labour modus was as follows: 86.9% normal vaginal labour, 3.8% vacuum extraction, and 9.3% cesarean section, while in Group B it was 82.83% normal vaginal labour, 3.07% vacuum extraction, and 14.1% cesarean section. CONCLUSION: Misoprostol has advantages according to neonatal outcome compared to administration of dinoprostone. PMID- 26524817 TI - The oocyte-to-baby rate of day 2, day 3 versus day 5 embryo transfer: a retrospective study. AB - OBJECTIVES: To investigate whether the time of embryo transfer (ET) affect the oocyte-to-baby rate. MATERIALS AND METHODS: The database was retrospectively analyzed including total number of oocytes collected and corresponding oocyte-to live baby born (LBB) rate. Then the relationship between different time of embryo transfer and oocyte-to-baby rate was compared. In a year period all patients undergoing infertility treatment were included in the study. The outcome parameters were total number of oocytes collected and corresponding oocyte-to LBB. RESULTS: For patients under the age of 35 years, there was no increase in oocyte-to-LBB regardless of the time of ET. For patients older than 35 years, the oocyte use rate increased significantly when embryo was transferred on day 2. Oocyte-to-baby rates were also analyzed after grouping patients on the number of oocytes retrieved per cycle. For patients < 35 years, the oocyte- to -LBB rate increased significantly on day 3 if < ten oocytes were obtained. whereas for patients > 35 years, the oocyte-to-baby rate was best on day 2 when about 15 oocytes were retrieved. CONCLUSIONS: This retrospective analysis demonstrated the relationship between the time of ET and ooctye-to-baby rate that is indicative of a more biologically efficient reproductive system. PMID- 26524818 TI - Ultrasound-guided intrauterine insemination versus blind intrauterine insemination: a randomized controlled trial. AB - PURPOSE: This study was performed to determine the effects of ultrasound (US) guidance during intrauterine insemination (IUI) on pregnancy rate. MATERIALS AND METHODS: This study is a prospective randomized controlled trial which was performed in Women's Health Research and Education Hospital, Infertility Unit. The study enrolled 130 couples who were scheduled to undergo IUI. The couples were randomized according to a computer-generated list into two groups; 1) the ultrasound-guided IUI group included 64 couples (n = 64) treated for 99 cycles 2) blind IUI group included 66 couples (n = 66) treated for 104 cycles. All women underwent controlled ovarian stimulation before IUI. The study's main measurements were pregnancy rate per cycle; pregnancy rate per woman. RESULTS: The pregnancy rates were similar in both the ultrasound-guided (USG) (16.2%, 16/99) and non-ultrasound-guided (NUSG)(12.5%, 13/104) groups (p = 0.386). CONCLUSIONS: The present results suggest a routine ultrasound guidance during IUI is not essential as it does not increase pregnancy rates but it can be used in such cases to overwhelm some sort of difficulties. PMID- 26524819 TI - The association between anti-Mullerian hormone and IVF-ICSI outcome in poor responder patients performing long protocol. AB - PURPOSE OF INVESTIGATION: Ovarian reserve reflects the capacity of the ovaries for a successful pregnancy. Anti-Mullerian hormone (AMH) could be a useful marker to predict ovarian reserve and to adjust controlled ovarian stimulation. The aim of this study was to assess the relationship between AMH and intracytoplasmic sperm injection-in vitro fertilization (IVF-ICSI) outcome in poor responder women. MATERIALS AND METHODS: This study was conducted prospectively for a period of 12 months. Inclusion criteria were FSH value > 15 iu/l or antral follicle number < 4, on the 2nd day of cycle. All patients underwent GnRH agonist stimulation with long protocol. Serum AMH levels were measured in the treatment cycle just before the stimulation. After the treatment, patients who were pregnant formed the study group and patients who were not pregnant formed the control group. Serum AMH level was the main outcome measure. RESULTS: The study and control group consisted of 34 and 70 patients, respectively. No significant difference was found in duration of infertility, antral follicular count, basal E2 and FSH levels. The mean serum AMH level was significantly higher in study group (p = 0.005). The retrieved oocyte number, metaphase 2 oocyte number, and fertilization rate were also significantly higher in the study group. DISCUSSION: Evaluation of serum AMH seems to be a useful marker to predict IVF-ICSI outcome in poor responder patients. PMID- 26524820 TI - Does level of antenatal care affect birthweight? Study of a Central Anatolian Region. AB - PURPOSE OF INVESTIGATION: The objective of this research was to measure the impact of the level and quality of antenatal care (ANC) on the birthweight (BW) of hospital-born infants. MATERIALS AND METHODS: This study was cross-sectional research. This study was conducted at the maternity hospital and a private hospital in the center of the province of Yozgat, Turkey. Women (N=788) were included in the research who had a singleton live delivery at hospitals. RESULTS: It was found that adequate receipt of ANC was significant, although had little affect on BW; the number of ANC visits or whether ANC was adequate was not found to be significant. BW increased depending on primarily the mother's gestational age (GA) and then her age, height, and weight gained during pregnancy (p < 0.05). CONCLUSIONS: It is GA that impacts BW primarily. It is recommended that necessary interventions be made to minimize the factors leading to preterm births. PMID- 26524821 TI - Resolution of pelvic pain related to adenomyosis following treatment with dextroamphetamine sulfate. AB - PURPOSE: To determine if treatment with dextroamphetamine sulfate can reduce pelvic pain that was attributed to adenomyosis. MATERIALS AND METHODS: Dextroamphetamine sulfate was given to a 32-year-old woman who suffered on a daily basis from severe chronic pelvic pain that was not relieved by laparoscopic removal of endometriosis by oral contraceptive and ibuprofen. The adenomyosis was diagnosed by magnetic resonance imaging. RESULTS: Within three months the pain was completely gone and has remained absent for six months. CONCLUSIONS: Dextroamphetamine sulfate relieved pain from adenomyosis similar to its effect on endometriosis. PMID- 26524822 TI - Hashimoto thyroiditis onset after laparoscopic removal of struma ovarii: an overview to unravel a rare and intriguing finding. AB - Struma ovarii is an uncommon type of ovarian tumor derived by germinal cells, characterized by the predominance of thyroid tissue (> 50%); 90-95% of these formations are benign and mainly affect the left ovary, while in 6% of the cases struma ovarii is bilateral. The malignant transformation is a rare condition that often occurs after 50 years. In most instances, diagnosis of malignant struma ovarii is made postoperatively during histological analysis. This tumor appears to derive by one germinal cell through loss of heterozygosity of the androgen receptor gene and of the X chromosome. Clinical symptoms comprise abdominopelvic mass, lower abdominal pain, abnormal vaginal bleeding, and ascites (the occurrence of this condition has been observed in one-third of the cases). The patients with struma ovarii generally do not manifest symptoms related to thyroid hyperfunction, reported only in 8% of the cases, and due to hyperstimulation of the thyroid by auto-antibodies. Thyroid tissue of the struma ovarii, often embedded in a teratoma, may be papillary, follicular or with mixed pattern and it can include elements of mucinous cystoadenomas, Brenner's tumor or carcinoid or melanomas cells. Here the authors report their experience with an unusual case of Hashimoto thyroiditis onset after laparoscopic removal of struma ovarii. PMID- 26524823 TI - Complete resolution of frozen shoulder syndrome in a woman treated with dextroamphetamine sulfate for chronic urinary urgency. AB - PURPOSE: To evaluate the efficacy of dextroamphetamine sulfate for idiopathic frozen shoulder in a woman being treated for blad- der urgency and inability to lose weight despite dieting. MATERIALS AND METHODS: Dextroamphetamine sulfate was initiated at 15 mg extended release capsules increasing to 25 mg extended release capsules to a 47-year-old woman. RESULTS: She lost 19 pounds in four months, her bladder urgency disappeared, and she had complete resolution of the idiopathic frozen shoulder problem. CONCLUSIONS: Idiopathic frozen shoulder syndrome can be added to the long list of conditions that are related to hypofunction of the sympathetic nervous system and all respond to dextroamphetamine sulfate therapy. They gynecologist is more familial with this syndrome be- cause of it being the main cause of pelvic pain. Thus the gynecologist may become the physician who subsequently treats orthopedic or rheumatological problems or other health issues. PMID- 26524824 TI - Isolated fallopian tube torsion during pregnancy: a case report. AB - Isolated fallopian tube torsion is a rare pregnancy-related complication. It is frequently misdiagnosed as acute appendicitis or ovarian torsion owing to the lack of specific symptoms or signs. Here, the authors report a case of a 35-year old primigravida at 30 weeks and six days of gestation who had presented with right isolated fallopian tube torsion and a history of right oophorectomy. The authors propose that isolated fallopian tube torsion should be included in the list of differential diagnosis when encountered with patients complaining of lower abdominal pain. PMID- 26524825 TI - Pregnancy after ovarian wedge resection in a polycystic ovarian patient after laparoscopic ovarian cauterization. AB - The authors present a case of a pregnancy after ovarian wedge resection by laparotomy after unsuccessful ovarian drilling. A 28-year- old patient was admitted to the present outpatient clinic because of infertility, secondary amenorrhea, and hirsutism. Three years prior she had undergone laparoscopic ovarian drilling with no effect on menstrual pattern and fertility. After clinical and ultrasonographic ex- aminations, polycystic ovarian syndrome (PCOS) was diagnosed and consequently laparotomy with ovarian wedge resection was de- cided upon. Six weeks later patient was diagnosed with an early pregnancy. PMID- 26524826 TI - Severe ascites as the primary symptom of fulminant postpartum HELLP syndrome: a case report. AB - Previous studies show that HELLP syndrome occurring in postpartum period was more dangerous to both fetus and the mother than if presented before delivery. So far, there is a lack of screening or predictive tests for postpartum HELLP syndrome in clinical practice. CASE: Here the authors report a rare case of postpartum HELLP syndrome with severe ascites as the primary symptom. The patient was diagnosed with severe preeclampsia and fetal growth retardation at 34+2 weeks gestation and received anti-hypertensive therapy. Severe ascites were found intraoperatively during emergency caesarean section. On the second postoperative day, complete HELLP syndrome was diagnosed. This case gradually complicated by hypoproteinemia, acute renal failure, severe anaemia, and infection and required renal haemodialysis, blood transfusion, and other supportive treatments for about one month. CONCLUSION: Although this case has a fulminant and long course, it has a well clinical prognosis and also shows that severe ascites may be a clue for postpartum HELLP syndrome in patient with severe preeclampsia. PMID- 26524827 TI - Successful term delivery following second-trimester excision of a massive hydrosalpinx presenting as an adnexal mass in pregnancy: management and considerations. AB - To the best of the authors' knowledge, a massive hydrosalpinx presenting as an adnexal mass complicating pregnancy has never been reported. They report the case of a 26-year-old female diagnosed with a persistent right adnexal cyst in a pregnancy resulting from spontaneous conception, confirmed to be a 30-cm. hydrosalpinx at the time of surgery. Though laparoscopy was envisioned, due to the size of the mass, a right salpingectomy was performed during the second trimester by laparotomy, and the patient had an uncomplicated course of her pregnancy following the intervention, delivering a healthy infant at term. Herein, the authors explore the potential etiologies and different considerations when faced with an adnexal mass in pregnancy. They emphasize that, though rare and uncommon, a hydrosalpinx should be included in the differential diagnosis of persistent adnexal cysts in pregnancy. PMID- 26524828 TI - Giant cervical myoma associated with urinary incontinence and hydroureteronephrosis. AB - Cervical leiomyomas compromise fewer than 5% of all uterine leiomyomas. Cervical myomas exacerbates surgical difficulties, such as poor operative field, difficult suture repairs, and blood loss. When performing myomectomy for cervical myomas, care must be taken to avoid injuries to neighboring structures in the pelvic cavity.These structures include the bladder in front of the cervix, the rectum behind the cervix, and the uterine arteries and ureters on both sides. Myomectomy for cervical myoma is empirically difficult and frequently problematic. The authors report a case of giant cervical myoma presenting with urinary incontinence. PMID- 26524829 TI - Treatment of pregnant patient with disseminated intravascular coagulation (DIC) due to placental abruption--a case report. AB - A primigravid woman at 29th gestational week with placental abruption causing fetal death, that underwent instant cesarean section, developed a disseminated intravascular coagulation (DIC), revealed by hemoperitoneum and hematoma of the abdominal wall. After re-laparotomy and transfusion of blood, fresh plasma, and platelets, the patient was discharged from hospital on the 14th postoperative day completely recovered. To conclude, conservative surgical approach for DIC treatment is possible and safe. Novel antifibrinolitic drugs are recommended for obstetrical patients with DIC to enable a healthy subsequent pregnancy. PMID- 26524830 TI - Selective termination in discordant twin pregnancy with early onset preeclampsia: case report. AB - OBJECTIVE: To study the effectiveness of selective termination for discordant twins in treating early onset preeclampsia. MATERIALS AND METHODS: After literature review, ethical review, and discussion with the couple, one patient with early onset preeclampsia complicated with a lethal condition in one twin, was performed selective termination by intracardiac injection of potassium chloride at 27 weeks' and four days' gestation in an effort to reverse preeclampsia and prolong the pregnancy. RESULTS: The clinical manifestation of preeclampsia was alleviated in this patient. At 29 weeks, the stillborn fetus was delivered because of spontaneous preterm labor. A live birth was achieved five days later. All procedures allowed continuation of the pregnancy for an additional two weeks and one day of the remaining fetus. CONCLUSION: Selective termination may be an option for treating early onset preeclampsia in discordant twins, instead of termination of whole pregnancy. PMID- 26524831 TI - Right angular pregnancy at seven weeks' gestation: a case report treated by laparoscopic approach. AB - Angular pregnancy (AP) or implantation of the embryo in the lateral angle of the uterine cavity close to the internal ostium of the fallopian tube is a very rare event. In fact, angular pregnancy refers to implantation of the embryo just medial to the uterotubal junction, in the lateral angle of the uterine cavity. AP must be distinguished, anatomically, from interstitial pregnancy by its position in relation to the round ligament, which crosses the Mullerian duct at the side of the uterotubal junction. AP is associated with a high rate of complications such as bleeding and ruptured uterus due to delayed diagnosis. The authors present a clinical report of AP at seven weeks' gestation without uterine rupture. They performed directly operative laparoscopy because of acute intra abdominal hemorrhage. Laparoscopy was useful in the treatment of early angular pregnancy and could avoid the need for invasive surgery or hysterectomy. PMID- 26524832 TI - Delayed diagnosis of ureteral injuries following gynecological laparoscopic surgery: three case reports and review. AB - PURPOSE OF INVESTIGATION: The clinical manifestations, causes, and methods for the treatment and prevention of ureteral injuries presenting late after gynecological laparoscopic surgeries were investigated. MATERIALS AND METHODS: The medical records of patients who experienced delayed recognition of ureteral injuries after gynecological laparoscopic surgeries in the present hospital between 2008 and 2012 were reviewed retrospectively. RESULTS: There are three cases of ureteral injuries which are diagnose-delayed, The incidence of the malignant tumor groups was 0.99%, and for malignant patients undergoing laparoscopic lymphadenectomy it was 1.3%. CONCLUSION: The main way to prevent delayed ureteral injuries is to avoid adhesion between the ureter and surrounding tissues as well as eliminate electrothermal trauma during laparoscopic operations. Surgical repair is effective for such patients. PMID- 26524833 TI - Isthmocele in a retroflexed uterus: a report of an unrecognized case. AB - The term "isthmocele" refers to a niche on the anterior wall of the uterine isthmus or of the cervical canal at the site of a previous cesarean delivery scar. Such anatomic defect can cause many gynecologic sequelae that only recently have being identified and described. Hysteroscopy is commonly considered the gold standard for the diagnosis and also for the treatment, at least in the case of defects of small size. The authors described the case of a 37-year-old woman who underwent a cesarean section (CS) seven years before, with a long lasting history of menstrual irregularities, and pelvic pain increasing during menstruation at the hypogastric level. Magnetic resonance imaging (MRI) showed an exceptionally large isthmocele on the anterior wall of a retroflexed uterus which was otherwise misinterpreted as the uterine cavity filled with menstrual blood during a previous hysteroscopy (HSC). Although exceptional, this case highlights the possibility that a large sized isthmocele in a retroflexed uterus could be misinterpreted as the uterine cavity filled by menstrual blood at HSC. In this case MRI definitely clarified the diagnosis. PMID- 26524834 TI - Recurrent multiple endometrial polyposis in patient treated by antipsychotic drugs. AB - Irregular uterine bleeding and profuse menstrual bleeding often occur in patients treated by antipsychotics, antiepileptics, and some antihypertensive drugs. Such bleedings represent an important problem in clinical practice, especially when related to antipsychotic treatment. Nonetheless, this problem has not been often analyzed in references. This paper describes a recurrent multiple endometrial polyposis accompanied by profuse menstrual bleeding in a patient undergoing a multi-year treatment of bipolar affective disorder by antipsychotics and discusses the possibilities of prevention of irregular and profuse menstrual bleeding in patients that must use antipsychotic therapy in order to treat a psychiatric illness. PMID- 26524835 TI - Prenatal diagnosis of lipomyelomeningocele by ultrasound and magnetic resonance imaging (MRI). AB - OBJECTIVE: The authors report a case of a lipomyelomengocele with tethered cord, revealed on prenatal ultrasonography and confirmed by fetal magnetic resonance imaging (MRI). MATERIALS AND METHODS: A 32-year-old woman, gravida 1 para 1 underwent the routine second trimester prenatal ultrasound scan at 22(+5) weeks of gestation at the present hospital. RESULTS: The scan indicated an echoic semisolid subcutaneous mass covered by skin, posterior to the lumbosacral spinal canal of the fetus. Based on the findings indicating occult dysraphism, a fetal MRI examination was conducted, revealing that the mass was extending to the spinal cord, tethering the cauda equina. The diagnosis of lipomyelomeningocele was established. CONCLUSION: Lipomyelomeningocele is a form of closed neural tube defect with unclear predisposing factors. Its prevalence ranges between 0.3 and 0.6 per 10,000 live births. It leads to progressive conus tethering with associated neurological, urinary, and gastrointestinal deficits, demonstrating the importance of prenatal diagnosis. PMID- 26524836 TI - Mature mesenteric teratoma in a child: a case report. AB - A 15-month-old girl with a palpable and mobile mass was misdiagnosed as an ovarian teratoma by computed tomography (CT). A midline laparotomy was performed and the pathology report identified that it was a mature mesenteric teratoma. PMID- 26524837 TI - [Cotard's Syndrome in Three Patients with Schizophrenia--Pathology of Involutional and Senile-onset Endogenous Psychosis]. AB - A large number of case studies on Cotard's syndrome have reported that this syndrome develops after repeated episodes of depression in the presenile stage of life. Therefore, it has been defined as a severe type of affective spectrum disorder. This report describes three patients who exhibited symptoms characteristic of Cotard's syndrome, such as negative thoughts and delusions of immortality, in the presenile and senile stages of their lives. They also had a history of long-term treatment for schizophrenia based on a diagnosis in early adulthood. Our review of reports on Cotard's syndrome revealed that the syndrome is more prevalent among presenile and senile female patients, who initially visit psychiatrists in their involutional and presenile stages of life with symptoms of an affective spectrum disorder, and later exhibit the symptoms of Cotard's syndrome. The results of the three case studies suggest that biological factors related to aging and sex differences may be associated with the development of Cotard's syndrome, regardless of the primary disorder. The pathology of "involutional and senile-onset endogenous psychosis," including Cotard's syndrome, is also discussed. PMID- 26524838 TI - [Threshold of Application of Antidepressant Drugs for Treatment of Depressive Disorder]. AB - In recent years, along with the expansion of medical care for depressive disorder, there has been much controversy regarding the application of antidepressant drugs for its treatment. The aim of this paper is to consider critical issues concerning the threshold of application of antidepressant drugs for the treatment of depression. It was formerly important to diagnose the 'quality' of depression (melancholia or non-melancholia) in order to choose antidepressant treatment, whereas an assessment of the 'quantity' of depression (severity of symptoms) is crucial today to decide on the threshold. Recent guidelines for the treatment of major depressive disorder do not positively recommend the use of medication for the treatment of mild depression. The guidelines published by the Japanese Society of Mood Disorders also state that doctors have to give priority to treatments avoiding medication, although the effectiveness of antidepressant drugs for mild depression is controversial. Actually, in a clinical setting, doctors have to understand the conditions of individual cases and cope with many issues, such as a risk of suicide, comorbidity of other psychiatric disorders, target symptoms of pharmacotherapy, and choices of classes and doses of antidepressant drugs. The threshold of application of antidepressant drugs for the treatment of depression may vary according to the doctor-patient relationship and surrounding conditions. Doctors are required to provide treatment options other than pharmacotherapy. PMID- 26524839 TI - [Clinical Problems before Initiating Pharmacotherapy for Insomnia]. AB - Insomnia is one of the most common complaints of psychiatric patients. Educational approaches for mental health always recommend early detection and intervention for insomnia. However, too much emphasis on insomnia may lead to overdiagnosis and overtreatment. Psychiatrists are often accused of overprescribing hypnotics to patients with sleep disturbance. This drug is difficult to discontinue due to factors associated with both patients and prescribers. In order to prevent the unneccessary administration of hypnotics, clinicians should evaluate both the sleep quality and daytime activities of patients. A sleep diary may help this process. Clinicians should prescribe hypnotics only when a patient's sleep disturbance is neither a part of the symptoms of major psychiatric disorders nor sleep-wake schedule disorders, and is not a consequence of inadequate lifestyle behavior. The reasonable goal of hypnotic treatment should be set in advance, and then pharmacological and psychosocial interventions for insomnia should be initiated. PMID- 26524840 TI - [Social Anxiety Disorder]. AB - Social Anxiety Disorder (SAD) is not a rare psychiatric disorder, and the recent World Mental Health Japan Survey, Second (WMHJ2) reported the possibility that the twelve-month prevalence of SAD has increased from 0.7 to 2.3% over the last ten years. However, ten years have already passed since selective serotonin reuptake inhibitors (SSRI) were approved for the treatment of SAD in Japan, and not only laypersons but also mental health professionals still misunderstand SAD as public speech phobia. As a result, the boundary between normal shyness and SAD and threshold to start pharmacotherapy have been debated. Participants in most double-blind studies of SSRI were limited to those with a generalized subtype of SAD. While benzodiazepine led to a significantly more favorable response and symptom improvement and the effect size of benzodiazepine was larger than those of SSRI, it did not lead to a "cure" and is sometimes deleterious for atypical SAD patients. To sum up, a psychotherapeutic approach including cognitive behavioral therapy is suggested as first-line treatment for non-generalized SAD according to the NICE guidelines. On the other hand, patients with generalized SAD and secondary depression are still misunderstood (and under-recognized) as those with "treatment-resistant depression", and they suffer from severe impairment of the psycho-social function, including absences or withdrawal from working or schooling. They need more effective combination treatment of SSRI and cognitive behavioral therapy as generalized SAD patients. PMID- 26524841 TI - [Premenstrual Dysphoric Disorder (PMDD)]. AB - Premenstrual dysphoric disorder (PMDD) is categorized as a subclass in depressive disorders of DSM-5. Speaking without fear of misunderstanding, my opinion is that patients with PMDD should be treated with medication, if there is no misdiagnosis as premenstrual syndrome (PMS). For the appropriate treatment of PMDD, it must be diagnosed accurately according to the DSM-5 criteria. The differential diagnosis and treatment of PMDD should be carried out by experienced psychiatrists. PMID- 26524842 TI - [Acute Drug Poisoning: Focus on Psychotropic Drugs]. AB - In acute psychotropic drug poisoning, it is important to diagnose and treat complications, including aspiration pneumonitis, abnormal body temperature, and atraumatic crush syndrome/compartment syndrome (3As). For the gastrointestinal decontamination (GID) of psychotropic drugs, excluding lithium, the administration of activated charcoal through a nasogastric tube should be considered first. For the GID of sustained-release or enteric-coated psychotropic drugs, total bowel irrigation is an option. To eliminate phenobarbital and carbamazepine, multiple doses of activated charcoal or direct hemoperfusion should be considered. To eliminate lithium, hemodialysis is an option. As an antidote to tricyclic antidepressants, the intravenous administration of sodium bicarbonate may be effective. PMID- 26524843 TI - [Individually Safe and Realistic Correction of Antipsychotic Polypharmacy and High-dose Regimens in Japanese Patients with Chronic Schizophrenia: The SCAP method]. AB - Compared with other countries, Japan exhibits prominent levels of antipsychotic polypharmacy and high-dose regimens. In view of these circumstances, the Safe Correction of Antipsychotic Polypharmacy and high-dose regimens (SCAP) method was developed based on previous findings as a realistic way to reduce medication consumption in patients already experiencing polypharmacy and high-dose regimens. In the SCAP method, "clinicians can reduce medications one by one, gradually, with occasional breaks permitted." A clinical study conducted to evaluate this method found no change in clinical symptoms, side effects, or quality of life (QOL), and the number of withdrawals due to aggravation was also small. A leaflet describing these results, and which is designed to support efforts to reduce medications, has been released. Future research will involve the examination and analysis of data from this study, taking into account its limitations, with a view toward developing guidelines applicable to clinical settings. The pragmatic, gradual correction of polypharmacy and high-dose regimens that goes beyond the "multiple drugs or single agent" dichotomy can decrease the burden experienced by patients. This is a practical approach that can be applied when developing comprehensive plans for the future psychiatric care of aging patient populations. PMID- 26524844 TI - [Negative Symptoms Revisited--Toward the Recovery of Persons with Schizophrenia]. AB - The negative symptoms of schizophrenia are usually treatment-refractory, and considered to be a major cause of a poor outcome. Recently, it has become an important issue to elucidate the etiology of and develop treatment for negative symptoms in order to improve the outcome of schizophrenia patients. Firstly, the history of negative symptoms was reviewed. Several lines of factor-analysis studies have suggested that negative symptoms are independent from other symptoms of schizophrenia, and consist of two factors, the poverty of expression and avolition, while the results depend upon the assessment scale employed in each analysis. Anhedonia, a part of avolition, may be considered as the impairment of pleasure-seeking behavior, the impairment of remembering non-current feelings, and a person's belief that he/she cannot experience pleasure, rather than the loss of pleasure itself. As neurological bases for avolition, decreases in reward expectancy, value representation, and the behavior to seek uncertain reward were observed, which resulted in poor social functioning due to the difficulties of initiating adaptive behaviors for the future. These impairments are the bases of decreased intrinsic motivation. The negative symptoms were considered to result in poor social functioning mediated by neuro-and social cognitive dysfunction and dysfunctional cognition, such as low self-efficacy and self-stigma. Pharmacotherapy for negative symptoms remains to be established due to a lack of evidence. Several psycho-social interventions in self-efficacy, self-stigma, intrinsic motivation, and environmental contexts are now being developed, while their effects are rather limited. The principles of psychiatric rehabilitation, i.e., respecting one's own value system and preference, self-determination, and motivation, are worth revisiting from the viewpoint of neuro-cognitive science. Furthermore, a hope-oriented approach, the presence of peers, and reconstructing social values as barrier-free may be considered to be of marked help not only for treating negative symptoms through re-establishing self-esteem, but also to aid the general population. PMID- 26524845 TI - [Perspectives on the Outpatient Clinic and Rehabilitation Program Exclusively Provided for Adults with Autism Spectrum Disorder]. AB - Developmental disorders came to be recognized by the Japanese general public only during the last decade. With the spread of recognition, consultations to medical institution and administrative agencies are growing rapidly. Since the opening of Developmental Disorders Clinic and Day Care at Karasuyama Hospital in 2008, the number of patients has exceeded 3,000. In this paper, the present state and perspectives are presented and discussed on the activity in Karasuyama Hospital, Showa University. PMID- 26524846 TI - [Challenges Related to Employees with Developmental Disabilities, from the Perspective of an Occupational Physician]. AB - Changing in the work environment in recent years, an occupational physician needs to make a countermeasure to mental health disorders. When the occupational physician works with employees who have, or are suspected of having, high functioning developmental disorders, it is necessary to consider the following: Whether, in the course of addressing problems faced by employees, occupational health staff members are able to consider the possibility of developmental disorders. An additional issue is whether the occupational physician, when working with the treating psychiatrist, is able to appropriately provide precise information. Furthermore, when an employee is diagnosed with a developmental disorder, there are questions of whether a smooth internal company approach is possible in the context of appropriate workplace support, and whether it is possible to obtain the understanding of colleagues prior to implementing appropriate workplace assignments and accommodations. Additionally, it is necessary to consider the career paths of employees with high-functioning developmental disorders that are discovered subsequent to being hired. In this paper, introducing some cases, It was summarized the challenges of developmental disabilities in the workplace and discussed correspondence in the workplace. PMID- 26524847 TI - [The Outpatient Clinic and Rehabilitation Program Specialized in Adult Developmental Disorders]. AB - The rehabilitation program has been conducted at our psychiatric clinic for depressive patients who are absent from work, with the aim of assisting them to return to work. We have noticed that a substantial number of the patients have traits of developmental disorders, which contribute to chronicity and/or recurrence of depression. Therefore, we have recently created a new rehabilitation program in addition to the specialty outpatient clinic and peer support group. All these programs specialize in treating adult patients with mild developmental disorders [mostly autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD)]. Since then, we have investigated a lot of depressive patients whose ASD symptoms have been identified for the first time in their life. Symptoms were first noted after they started work where they experienced impaired social functioning because the social demands were higher than those at schools. To assist patients with their goals of improving symptoms and stabilizing social functions, it is valid to evaluate whether the autistic traits cause mental stress and impairment during occupational functioning, even if the diagnosis of ASD is not definitive or the symptoms are below the diagnostic threshold for ASD. The profile of ASD symptoms is different for each patient, and therefore personalized support is essential. PMID- 26524848 TI - [Support for Adult ASD in Medical Rework Program: Mutual Communication Program and Psychodrama]. AB - While carrying out the Medical Rework Program, we realized the necessity for a supplementary medical treatment program aimed at adult ASD. Consequently, we started the Mutual Communication Program, which consists of standard SST and the new element of psychodrama. As a result, 32 participants have returned to their workplace in the three-year period, and the rate of successfully continuing to work was 93.8% at the time of the investigation. Various psychological tests also indicated significant improvement. In this article, we present a case study, explain psychodrama techniques employed in the program, and discuss their usefulness. The results suggest that psychodrama is a very effective assistive technique when the characteristics of ASD are taken into consideration. PMID- 26524849 TI - [Vocational Training and Job Placement for People with Autism Spectrum Disorders in the Business Sector]. AB - Kaien was founded in 2009 in order to help people with autism spectrum disorders work by leveraging their unique capabilities. Our four offices are all located in the Tokyo Metropolitan Area. Our services include job training and placement for adults, career awareness programs for college students, and career experience programs for teens with autism spectrum disorders. Currently, we help over 100 people on a daily basis. We believe that two factors play important roles when we provide job training programs for people. Firstly, they usually find it difficult to identify their occupational "fit" by themselves due to their weakness regarding imagination. It is not a good idea to convince them only through counseling. Rather, when we take their weaknesses into consideration, multiple trial sessions in the work environment are key because even people without imagination can understand their occupational "fit" once they try. The other aspect is to articulate communication as much as possible. In this case, it is also true that words are not enough to help people fully develop the communication skills necessary in an office. Thus, our trainers intervene very frequently in the job programs in order for trainees to get feedback at the right time on the spot. In other words, our five-year experience at Kaien has revealed that our "Here and Now" approach in the quasi-work environment is the most effective way. Most of our trainers do not have medical or social welfare backgrounds. This fact has revealed huge possibilities when it comes to helping people with autism spectrum disorders to get a job. That is, in many cases, autism experts may not be mandatory, and supervisors or colleagues, who work with people with autism every day, can become "job supporters" with a little knowledge and some training. Some estimates indicate that the prevalence rate of autism spectrum disorders is above one in one hundred, and might be as high as five or six percent. This number is daunting because only autism experts with marked experience cannot handle all issues. Therefore, we believe that empowering amateur supporters in the business arena is important, and we are thrilled to think that our findings and programs may be helpful to increase the proficiency of such amateur supporters. PMID- 26524850 TI - [As a Child of a Parent with Schizophrenia, as a Patient, and as a Psychiatrist: A Message to All JSPN Members]. AB - I previously published an article, entitled About "Regarding a person Who recovers". It documents the actual situation and recovery of a family member with schizophrenia, and it does not describe my recovery as a patient as a psychiatrist. At the time of publication, the main purpose was to disclose the real name of the family member. Since the disclosure, I have met many patients and families, and learned their true thoughts and strengths that I would have never known simply through consultation, and this totally changed my perceptions of them. Meanwhile, I also received many comments from medical professionals who were also family members of patients at the same time. I learned that they were struggling with conflicting emotions of being a family member as well as a professional, and I realized the isolations of families, and persistent stigma attached to psychiatric disorders. The disclosure broadened my perspectives as a psychiatrist. Now, more than 30 years after becoming a doctor, I still question myself: 'what have I done?', 'Have I listened to the voices of patients and their families?' I still have persisted, as a psychiatrist, until today. Psychiatry is a field that can be neglected if you do not question its contradictions. I think this is also why 'patient-centered recovery' has been neglected, and, as a result, psychiatry has been left behind. I often hear people asking: 'how can we increase numbers of psychiatrists?' I did not become a psychiatrist because of my own experience. I believe that, by providing medical care that the patients and their families can appreciate, from those families, some younger members will desire to become psychiatrists ; that is the way psychiatry should be developed. For that purpose, I believe it is necessary more than anything to approach each case with great care, valuing the 'real voices' of patients and their families, and respecting their strengths. PMID- 26524851 TI - A Hospital-Based Analysis in the Department of Clinical Chemistry for the Patients with HBV Reactivation after Anti-Cancer or Immunosuppressive Therapy. AB - OBJECTIVES: Anti-cancer and immunosuppressive drugs often induce hepatitis B virus (HBV) reactivation, resulting in lethal hepatitis in the worst cases. It is to elucidate the clinical characteristics of the patients in our hospital, who underwent HBV-related examinations to help prevent HBV-associated hepatitis by reactivation during the two-year period after the announcement of new guidelines by the Ministry of Health, Labour and Welfare of Japan in January 2009. STUDY DESIGN: We enrolled 811 patients who were examined for HBs antigen, anti-HBc antibody, anti-HBs antibody and HBV DNA regarding HBV reactivation. RESULTS: The underlying diseases were hematological malignancies, followed by various other cancers, rheumatoid arthritis, Crohn's disease, and so on. The patients in their 60s showed the peak in the age distribution. The positive ratio of anti-HBc antibody was higher over the age of 40. The rate of reactivation was 7.7% in HBV carriers and 2.0% in the HBV-resolved patients. HBV reactivation occurred in two HBV carriers and four HBV-resolved patients. The three patients, showing hepatitis were two HBV carriers and one HBV-resolved patient without monitoring of HBV DNA, because their therapies started before announcement of the guidelines. In other three patients with reactivation from HBV-resolved infections, HBV DNA returned under detection by immediate administration of entecavir without following hepatitis. CONCLUSION: The patients at high risk of HBV reactivation were prevented from HBV-related hepatitis only by following the guideline. The screening for such patients and monitoring HBV DNA in the guideline are requisite to prevent HBV-related hepatitis. PMID- 26524852 TI - High Frequency of Hepatitis B Core and Surface Antibodies in Hepatitis C Virus Infected Patients on the Screening Examination. AB - BACKGROUND: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are important human pathogens that cause chronic liver disease and hepatocellular carcinoma. Co infection of HBV and HCV is not uncommon, particularly in countries where these two viruses are endemic. Therefore, the characteristics of HBV co-infection in HCV antibody (HCVAb) -positive Japanese patients found on the screening examination were analyzed. PATIENTS AND METHODS: Between January and December 2011, HCVAb status was evaluated as the screening examination in 12,582 patients in Gunma University Hospital, and it was positive in 402 patients (3.2%). In 331 HCVAb-positive/HBs antigen (HBsAg) -negative patients with available residual serum, HBs antibody (HBsAb) and HBc antibody (HBcAb) were examined. In addition, HCV-RNA was examined in 291 patients with available residual serum. HBV-DNA and HBV core-related antigen (HBcrAg) were examined in 106 patients with available residual serum. RESULTS: The HCVAb titer was distributed between 1 and 18 sample/cutoff index (S/CO). 275 patients (83.1%) had a high HCVAb titer (S/CO >=10). HCV-RNA was positive in 230 (79.0%) patients, and it was more frequently detected in HCVAb high-titer patients (88%) than in low-titer patients (32%; p < 0.0001); 61 (18.4%) and 101(30.5%) patients were positive for HBsAb and HBcAb, respectively. Of 230 HCV-RNA-positive patients, 38 (16.5%) and 59 (25.6%) were positive for HBsAb and HBcAb, respectively. Three (2.8%) and 2 (1.9%) of 106 patients had HBV-DNA and HBVCrAg. The ALT level was higher than 30 IU/L in 146/327 (44.6%) HCVAb-positive patients who had ALT levels measured. Abnormal ALT elevation was more frequent in HCVAb high-titer patients than in low-titer patients (48.3% vs. 26.8%; p = 0.0031), and in HCV-RNA-positive patients than in HCV-RNA-negative patients (54.2% vs. 13.3%; p < 0.001). CONCLUSION: HBV reactivation should be noted in these HCVAb-positive/HBsAg-negative patients on the screening examination if these patients must receive chemotherapy or immunosuppressive therapy. In addition, surveying of HBsAb in addition to HBcAb is also necessary. PMID- 26524853 TI - [Differences in Measured Values among Homogenous Assay Reagents of LDL-C in LP-X Positive Serum Samples]. AB - The LDL-C level measures with homogeneous (direct) assays in almost of clinical laboratories. Several reports however showed differences in measured values among the assay reagents. We investigated the differences in LDL-C values among direct assays and Friedewald formula (F-f) in 58 LP-X positive serum samples from jaundice patients by comparing LDL-C values measured by anion-exchange chromatography (AEX-HPLC), largely comparable to ultracentrifugation method. Changes in LDL-C values during the treatment of 8 patients were also investigated. Direct assay reagents from Sekisui Medical (S-r), Denka-Seiken (D r), Wako Chemical (W-r), and Kyowa Medics (K-r) were used for comparison. F-f, S r, and D-r correlated with AEX-HPLC with r values < 0.6 while W-r and K-r correlated with AEX-HPLC with r-vales > 0.6. Two samples in which F-f values provided 500 mg/dL plus bias to AEX-HPLC (LDL-C value of 220 mg/dL) demonstrated increased levels of IDL-C before treatment. LDL-C values (S-r and D-r) of the 2 samples were relatively high and near to F-f data while LDL-C values (W-r and K r) were relatively low and close to AEX-HPLC data. The jaundice treatment decreased LDL-C values (S-r and D-r) and converged to 220 mg/dL, indicating that S-r and D-r might react markedly to IDL. These changes were consistent with decreases in serum free cholesterol and phospholipid in support of LP-X. By contrast, W-r and K-r data showed upward tendency and also converged to 220 mg/dL. These results suggest that LDL-C direct assay reagents would be classified into 2 groups with respect to the reagent reactivity to LP-X. PMID- 26524854 TI - [Hormonal Receptor and HER2 Analyses for Breast Cancer Using Cell Blocks in Routine Work: Experience at Our Institution]. AB - Hormonal receptor and HER2 analyses were performed in 20 cell blocks from breast cancer, mainly metastatic sites. The sites were as follows: 15 pleural effusions, 2 ascites, 1 cardiac effusion, 1 lymph node, and 1 cystic fluid from the primary site. Cancer cells were detected at 15 (75%) sites. The reasons of examination were as follows: unknown receptor status at the primary site (9 cases), multiple primary sites (3 cases), recurrence during hormone therapy (1 case), and new metastatic sites in originally metastatic disease patients (2 cases). The number of cells on each slide was fewer in routine work compared to that of our studies. We need new criteria for cytological analysis of receptor status measurement. PMID- 26524855 TI - [Biomarker Discovery of Colorectal Cancer Using Membrane Proteins Extracted from Cancer Tissues]. AB - Colorectal cancer is the leading cause of cancer-related death in women and third leading cause of death in men. The prognosis worsens when cancer metastasizes to other organs. Thus, there is an urgent need to develop biomarkers for the early diagnosis of metastasis as well as cancer development. Mass spectrometry-based technologies have been applied to the discovery of protein biomarkers, especially in the field of cancer. These results have identified numerous candidate protein biomarkers. Unfortunately, only a few are currently being applied in clinical diagnostics. Recent advances in proteomic technology such as selected/multiple reaction monitoring (SRM/MRM) facilitated the detection and quantitation of specific proteins in complex samples without the need for antibodies. We performed a quantitative proteomic analysis of membrane proteins extracted from colorectal cancer tissues using the iTRAQ shotgun method to discover biomarker candidates, and then extensively validated the biomarker candidate proteins by SRM/MRM. A total of 5,566 proteins were identified in tissue samples obtained from adenoma and cancer with and without metastasis. Differences were observed in the expression of about 400 proteins. Among them, 105 biomarker candidates which were predicted to be membrane proteins and extracellular proteins by gene ontology analysis were quantitated using SRM/MRM. As a result, we could confirm differences in the expressions of 69 of these proteins using the same set of patient samples as discovery experiments, and this was subsequently verified in an independent set of samples. Significant differences were observed in the expression of 44 of these proteins. Moreover, some of the biomarker candidates were detected and quantitated in the serum of colorectal cancer patients. These biomarker candidates are promising diagnostic tools on investigating the development and progression of colorectal cancer. PMID- 26524856 TI - [Metabolome Analysis of Human Serum: Implications for Early Detection of Colorectal Cancer]. AB - With the recent development of novel technologies capable of comprehensively detecting and accurately identifying small molecules within biological samples- the field of metabolomics--new information about disease biology is emerging. A comprehensive metabolomics strategy was used to discover novel small molecules which were significantly decreased in the serum of colorectal cancer (CRC) patients relative to normal individuals. The metabolite markers, hydroxylated polyunsaturated ultra long-chain fatty acids (hPULCFAs), were characterized using HPLC-coupled tandem mass spectrometry, and a high-throughput screening (HTS) method compatible with conventional triple-quadrupole mass spectrometers in clinical labs. around the world was developed. The HTS method was used to determine serum levels of the 28 carbon-containing hPULCFA C28H46O4 (named GTA 446) in independent clinical validation studies to investigate the effect of tumor removal after surgery, chemo- or radiation therapy and the correlation with age. We have also obtained results from a two-year prospective trial. Serum samples from a representative cohort of physician-referred colonoscopy subjects (n = 4,923) were collected between July 2008 and August 2010. Ninety-eight new CRC cases were detected in the colonoscopy cohort. Overall sensitivity in this cohort was 85.7%, with 86.5% in the early stage (0-II) and 84.8% in the late stage (III-IV). This trial represents the first prospective study of this magnitude investigating a metabolic biomarker for CRC. The results indicate that pre-colonoscopy screening using serum GTA-446 levels is a viable approach to detecting early-stage CRC. PMID- 26524857 TI - [Circulating MicroRNAs as Biomarkers of Colorectal Cancer]. AB - Colorectal cancer is a common tumor in Japan, causing almost 50,000 deaths per year. The development of new biomarkers is strongly desired, in order to detect the early stage of colorectal cancer with high sensitivity and specificity, using less invasive and high through-put methods. miRNA is a small non-coding RNA which regulates gene expression by digesting mRNA or suppressing translation. miRNAs are stable and present in blood, urine, stool, and other body fluids. The profiles of miRNAs in body fluid are specific to pathological states. There is accumulating data showing the usefulness of miRNAs as new biomarkers for colorectal cancer. We summarize the current knowledge in the previous literature (10 plasma analyses: sensitivity: 83.3 to 89%, specificity: 41 to 84.7%, AUC: 0.606 to 0.896; 13 serum analyses: sensitivity: 66.7 to 96.4%, specificity: 63.9 to 88.1%, AUC: 0.679 to 0.918; and 8 fecal analyses: sensitivity: 70.9 to 81.8%, specificity: 68.4 to 96.3%, AUC: 0.64 to 0.829). We focus on the standardization of miRNA analysis, namely: 1) preanalytical processes: difference of miRNA levels between plasma and serum, sampling methods, preparation of plasma or serum, and preservation of samples; 2) analytical processes: mRNA extraction methods, amplification, normalizer, and cut-off values. In conclusion, miRNAs are expected to become new biomarkers for colorectal cancer screening. PMID- 26524858 TI - [Alternative Splicing Detection as Biomarker Candidates for Cancer Diagnosis and Treatment with Establishment of Clinical Biobank in Chiba University]. AB - Alternative splicing is a fundamental process of gene regulation that contributes to protein diversity, a common phenomenon in the mammalian genome. Alternative splicing events not only happen in the normal gene regulation process, but are also closely related to certain diseases, including cancer. In this review, we briefly demonstrate the proof of concept (POC) of the relationship between alternative splicing and DNA damage, and describe the associations among alternative splicing and cancer pathogenesis, DNA damage, and gastrointestinal cancers. We discuss whether alternative splicing leads to genetic instability, which is considered to be a driving force for tumorigenesis. FUSE-binding protein (FBP) -interacting repressor (FIR) is a c-myc transcriptional suppressor. A splice variant of FIR that lacks exon 2 in the transcriptional repressor domain (FIRDeltaexon2), upregulates c-myc transcription by inactivating wild-type FIR. FIR+/- mice exhibited marked c-myc mRNA upregulation, particularly in the peripheral blood (PB), without any significant pathogenic phenotype. Because the single knockout of TP53 generates thymic lymphoma, FIR+/-TP53-/- mice developed T cell type acute lymphocytic/lymphoblastic leukemia (T-ALL) with increased organ or bone marrow invasion and showed a poor prognosis. After describing the POC of alternative splicing of FIR in DNA damage and carcinogenesis, clinical application for cancer diagnosis and treatment by FIR/FIRDeltaexon2 was briefly summarized. Chiba University has prepared a biobank to support studies to develop biomarker detection, molecular diagnosis, and "Omics" research. In conclusion, alternative splicing of FIR, generating FIRDeltaexon2, potentially contributes to not only colorectal carcinogenesis, but also leukemogenesis, and a better understanding of the role and mechanism of alternative splicing in tumorigenesis may reveal new directions for cancer biomarker detection. PMID- 26524859 TI - [Fecal Biomarker for Colorectal Cancer Diagnosis]. AB - The fecal occult blood test (FOBT) is widely used for colorectal cancer (CRC) screening to reduce the mortality rate associated with this cancer. However, several problems exist, as FOBT results can contain some false-negative CRC patients and some-false positive healthy subjects. Thus, to resolve these problems, several fecal biomarkers based on fecal protein, fecal DNA, and fecal RNA have been reported. Fecal calprotectin, which indicates intestinal bleeding or inflammation of the colon mucosa, and fecal tumor M2-PK, which is produced by cancer cells, have been extensively investigated as fecal protein biomarkers. To detect small amounts of CRC-specific proteins, the chemiluminescent enzyme immunoassay (CLEIA), which is a highly sensitive protein detection method using immunomagnetic beads, will be used. DNA mutation of APC, KRAS, and TP53 genes and DNA methylation of VIM, TFPI2, BMP3, NDRG4, and SFRP2 genes were reported as fecal DNA biomarkers. Consequently, a fecal DNA test named Cologuard from Exact Sciences was approved by the FDA in August 2014. Fecal COX2, MMP7, miR-106a, miR 92a, and miR-223 were also reported as fecal RNA biomarkers. This review article summarizes fecal biomarkers using fecal samples for CRC diagnosis. PMID- 26524860 TI - [Necessity of Genetic Examination in Treatment for Hematological Malignancies]. AB - Generally, hematological malignancies are morphologically diagnosed and classified. However, since their clinical characteristics are markedly heterogeneous, routinely used classification systems are not necessarily useful for the benefit of patients. Recent progress in the detection system for genetic alterations has revealed several mutations, which are associated with the development and/or progression of hematological malignancies, and the accumulation of data on the prognostic significance of recurrent genetic alterations has made more detailed risk stratification possible in patients with hematological malignancies. In acute myeloid leukemia (AML), prognostic risk classification based on cytogenetics has been established, while there is a clinical heterogeneity in the intermediate risk group, particularly in those with cytogenetically normal AML. The European LeukemiaNet (ELN) recommended a novel risk classification system based on the cytogenetic and genetic status. The long term prognosis according to the ELN classification system was retrospectively evaluated in two well-established cohorts, and both analyses demonstrated that the ELN system is useful for further risk stratification of younger adult patients with CN-AML. A genetic diagnosis and classification system will provide important information for both patients and physicians, while the overall picture of molecular pathogenesis in hematological malignancies remains to be elucidated. PMID- 26524861 TI - [Genomic Tests: From Basic Research to Clinical Practice]. AB - Advanced genomic analytical technologies are developing and challenging the current framework of clinical laboratory testing. However, most genomic tests have been devised as laboratory-developed tests (LDTs) without sufficient validation of their analytical validity. Quality assurance (QA) of tests is mandatory for routine clinical practice. External quality management systems such as ISO add QA. Other than QAs of pre-analysis, analytical procedures, reports, and laboratory personnel should be regularly assessed using appropriate best practices and guidelines for analytical validity. Moreover, ethical, legal, and social issues concerning genomic information should be resolved in genomic tests. Taken together, clinicians and health care policymakers must consider the accuracy with which a test identifies a patient's clinical status and the risks and benefits resulting from test use. Genomic tests in current use vary in terms of their accuracy and potential to improve health outcomes. Recently, high throughput analysis using next-generation sequencing and microarrays is being developed and introduced into clinical practice. As analysis of these data sets is a huge challenge, it requires novel analytical processes that include data quality assessment, comprehensive analysis, interpretation of the results, and presenting the results to users. Especially, human resources are required to develop genome informatics to interpret large amounts of data. Another issue is to regulate Direct To Consumers (DTC) genetic tests by medical institutions as a salutary health service. Although advanced genomic analytical technologies present some issues, they are useful and powerful tools in clinical practice. Thus, they will be properly introduced into clinical practices in a step by step manner. PMID- 26524862 TI - [Current Advances and Future Development of Thyroid Ultrasound Examination--Steps toward State-of-the-Art Laboratory Medicine in Fukushima]. AB - Since the accidents at the Fukushima Daiichi Nuclear Power Plant after the Great East Japan Earthquake on March 11, 2011, large quantities of radionuclides have leaked into the surrounding environment. Fukushima Prefecture started the Fukushima Health Management Survey Project including Thyroid Ultrasound Examination to screen for thyroid cancer in all residents aged 0 to 18 years at the time of the nuclear accident. This accident also led to increased interest in thyroid ultrasound examination in Japan. This article reviews the studies to establish ultrasound diagnostic criteria for thyroid nodules and the clinical guidelines of thyroid nodule management, both of which are fundamental to Thyroid Ultrasound Examination in Fukushima. This article also reviews a study designed to clarify the actual frequency of sonographically detected thyroid nodular lesions among Japanese children, which will become appropriate reference data to interpret the results from Thyroid Ultrasound Examination. Further advances in the screening and management of thyroid diseases are important responsibilities of clinicians and researchers in Fukushima. PMID- 26524863 TI - [Integration of Internal and Clinical Laboratory Medicine]. AB - The mission of our department is to contribute to diagnostic improvement in medicine in order to promote better outcomes. We have clinical expertise in internal medicine including primary care medicine, hematology, allergy, rheumatology, and nephrology. We also have expertise in clinical laboratory medicine and hospital infection control. Specific areas of academic interest include immune-mediated hematological diseases, allergic diseases, autoimmune diseases, and chronic kidney disease. Immune recovery following hematopoietic stem cell transplantation and the immunopathophysiology of bone marrow failure syndrome have been our main topics of interest, and we have been applying our knowledge of T-cell receptor diversity to these areas in order to explore the mechanisms of immunodeficiency and autoimmunity in hematological disorders. We have found that the peripheral expansion of mature T cells in grafts plays an important role in immune reconstitution after stem cell transplantation in humans, and have also found altered T-cell repertoires in immune-mediated chronic acquired pure red cell aplasia. Thus, quantitative and qualitative analyses of immune receptors could be a promising method for assessing immunocompetence and exploring the pathophysiology of autoimmune diseases. Research and development of novel approaches in this field should be intensively conducted. PMID- 26524864 TI - [Issues Associated with the Management of Clinical Laboratories and Their Future: What is the Problem in Our Laboratory?--Chairmen's Introductory Remarks]. AB - The management of clinical laboratories in hospitals has to be changed in accordance with the trends in the healthcare-providing system. In this symposium, six presenters talked about various issues associated with their laboratories. The issues raised included conflict between specialty and generality, phlebotomy as a duty of laboratory technologists, management of the phlebotomy section, imbalance of numbers between retirees and newcomers, and cooperation with the division of clinical research. Presenters, chairmen, and the audience were able to understand that we are now facing these issues, and we could identify some of their solutions. PMID- 26524865 TI - [Strategies to Cope with the Shortage of Technologists: Facing the Mass Retirement of the 'Baby-Boomer' Generation]. AB - In Japan, the primary 'baby-boomer' generation, born between 1947 and 1949, is now in its retirement. This has caused a marked shortage of human resources nationwide. Clinical laboratory technologists are no exception, and many clinical laboratories in Japanese healthcare facilities are struggling with management because the number of new graduates, i.e., newly licensed technologists, is mostly fixed and, therefore, their recruitment is becoming more and more competitive. Our laboratory is now facing a wave of mass-retirement associated with our history. In addition, in the early 2000s, there was almost no position for new graduates replacing those retiring because of the change in the social healthcare system as well as our hospital's policy. This resulted in uneven numbers of technologists in generations, and it seemed to be getting worse. Fortunately, five years ago, the direction of social health care was changed and lots of positions became available as a result. We have been trying to recruit new graduates and experienced technologists as well, and were able to hire 18 people. Among them, 8 were non-freshmen. The generation gap has been mostly resolved. We will continue to make our laboratory more attractive not just to new graduates but also to experienced technologists, especially those who wish to return to work after a several-year absence to raise their children. We believe that this will energize our laboratory. PMID- 26524866 TI - [Clinical Handling of Patients with Dissociative Disorders]. AB - This paper discusses the way informed psychiatrists are expected to handle dissociative patients in clinical situations, with a specific focus on dissociative identity disorders and dissociative fugue. On the initial interview with dissociative patients, information on their history of trauma and any nascent dissociative symptoms in their childhood should be carefully obtained. Their level of stress in their current life should also be assessed in order to understand their symptomatology, as well as to predict their future clinical course. A psychoeducational approach is crucial; it might be helpful to give information on dissociative disorder to these patients as well as their family members in order to promote their adherence to treatment. Regarding the symptomatology of dissociative disorders, detailed symptoms and the general clinical course are presented. It was stressed that dissociative identity disorder and dissociative fugue, the most high-profile dissociative disorders, are essentially different in their etiology and clinical presentation. Dissociative disorders are often confused with and misdiagnosed as psychotic disorders, such as schizophrenia. Other conditions considered in terms of the differential diagnosis include borderline personality disorder as well as temporal lobe epilepsy. Lastly, the therapeutic approach to dissociative identity disorder is discussed. Each dissociative identity should be understood as potentially representing some traumatically stressful event in the past. The therapist should be careful not to excessively promote the creation or elaboration of any dissociative identities. Three stages are proposed in the individual psychotherapeutic process. In the initial stage, a secure environment and stabilization of symptoms should be sought. The second stage consists of aiding the "host" personality to make use of other more adaptive coping skills in their life. The third stage involves coaching as well as continuous awareness of their comorbid psychiatric conditions. Lastly, factors preventing the patients' smooth recovery process are mentioned. They include their contact with past and current aggressors, chronic and ongoing stress within the family, including abuse and violence, and comorbid conditions such as depression and chronic medical conditions. PMID- 26524867 TI - [Diagnosis and Treatment of Social Anxiety Disorder]. AB - Many studies of social anxiety disorder (SAD) have been conducted because diagnostic criteria are defined as social phobia in DSM-III in the West. In Japan, several studies have examined pathological conditions similar to SAD, known as taijin-kyofu (TK). This highly remarkable disorder involves a convincing fear of giving another person discomfort from one's physical faults (e.g. feeling that neighboring people detect an unpleasant smell from one's body, "jikoshu kyofu", or feeling that neighboring people feel unpleasant because of one's appearance,"shukei-kyofu") termed "convinced subtype of TK" (c-TK; also known as offensive subtype of TK). In DSM-5, the definitions of feeling rejection and offense of others are added to a fear of humiliating or embarrassing oneself. Moreover, TK is a sufficient criterion for SAD. However, it is confusing that body dysmorphic disorder is not in category of somatoform disorders but in that of obsessive-compulsive disorder and related disorders and that the Japanese terms of "jikoshu-kyofu" and "shubo-kyofu" are categorized as other specified obsessive-compulsive disorder and related disorders. The efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) for the treatment of SAD has been reported in many controlled studies. Recently, SSRIs are regarded as first line pharmacotherapy for SAD. Cognitive behavioral therapy is also effective for SAD treatment. High rates of co-occurring SAD and other psychiatric disorders can be found in clinical samples and in the general population. Additional research must be conducted for these patients and for the management of treatment-refractory SAD patients. PMID- 26524868 TI - [It is Not an Antidepressant but Psychotherapy with Encouragement that Reassures Depressed People with Demoralization]. PMID- 26524869 TI - [Psychoanalysis and Side Effect]. AB - A study of psychoanalysis from the perspective of side effects reveals that its history was a succession of measures to deal with its own side effects. This, however, does not merely suggest that, as a treatment method, psychoanalysis is incomplete and weak: rather, its history is a record of the growth and development of psychoanalysis that discovered therapeutic significance from phenomena that were initially regarded as side effects, made use of these discoveries, and elaborated them as a treatment method. The approach of research seen during the course of these developments is linked to the basic therapeutic approach of psychoanalysis. A therapist therefore does not draw conclusions about a patient's words and behaviors from a single aspect, but continues to make efforts to actively discover a variety of meanings and values from them, and to make the patient's life richer and more productive. This therapeutic approach is undoubtedly one of the unique aspects of psychoanalysis. I discuss the issue of psychoanalysis and side effects with the aim of clarifying this unique characteristic of psychoanalysis. The phenomenon called resistance inevitably emerges during the process of psychoanalytic treatment. Resistance can not only obstruct the progress of therapy; it also carries the risk of causing a variety of disadvantages to the patient. It can therefore be seen as an adverse effect. However, if we re-examine this phenomenon from the perspective of transference, we find that resistance is in fact a crucial tool in psychoanalysis, and included in its main effect, rather than a side effect. From the perspective of minimizing the character of resistance as a side effect and maximizing its character as a main effect, I have reviewed logical organization, dynamic evaluation, the structuring of treatment, the therapist's attitudes, and the training of therapists. I conclude by stating that psychoanalysis has aspects that do not match the perspective known as a side effect. PMID- 26524870 TI - [Adverse Events and Precautions Regarding Cognitive Behavioral Therapy]. AB - Adverse events of cognitive behavioral therapy (CBT) can be used to identify two types depending on whether or not CBT is practiced appropriately. The results of a randomized control trial (RCT) when CBT is performed effectively show that the rate of adverse events is as low as, or lower than, that on using a pill placebo. Many adverse events are associated with a low quality of CBT caused by inappropriate practice due to therapists' lack of knowledge, skills, and experience. In order to achieve effective CBT for RCT, it is considered important to frequently assess the status of patients before and during CBT sessions, utilize the Cognitive Therapy Rating Scale after the session, and conduct supervision based on audio recordings of the session. PMID- 26524871 TI - [Side Effects of Rogerian Psychotherapy and Counseling]. AB - Rogerian psychotherapy relies on a patient's potential for self-healing and assumes that the patient will show desirable personality changes if the psychotherapist is satisfied with necessary and sufficient demands. Rogerian psychotherapy is usually not considered intrusive because of its supportive features. However, there is no treatment without side effects. Insufficient informed consent for psychotherapy, the risk of dependence, regression, traumatic stress caused by probing too deeply, and missing the chance to perform suitable medical treatment are discussed. PMID- 26524872 TI - [Prolonged Exposure Therapy for Post-traumatic Stress Disorder]. AB - Prolonged exposure therapy (PE), a well-known trauma-focused cognitive behavioral treatment (TFCBT), is the most scientifically established treatment for post traumatic stress disorder (PTSD) among a variety of pharmacotherapies and psychotherapies. It is comprised of two types of exposure technique: imaginal exposure and in vivo exposure. This paper overviews a recent review of psychotherapies for adult chronic PTSD, the emotional processing theory and structure of PE, and the effectiveness and dissemination of PE in Japan. PMID- 26524873 TI - [Uses of Language in Psychotherapy--at the Place Where the Evaluation Becomes Divided]. AB - The psychiatrist sometimes has to read a patients' tragic script. There has been a point of view since long ago that one has a repetitive script of life, reversing roles, and Freudian psychoanalysis tries to make such a script conscious, reading it word by word. There is a script of life which was implanted together with one's special others during infancy, which is called object relations. If such a repetitive object relation is to be repeated always in a tragic manner, it is better to read it. The purpose of reading the script is to rethink and rewrite it. However, any historical events that actually took place cannot be changed. In addition, psychoanalysis has a history of being initiated from "dramatic" hysterics and we can say that it has a dramatic point of view of thinking about the patients' life in terms of dramatic metaphors from the beginning. Moreover, there is a point of view of reading the psychological movement as a drama of actors/actresses and therapy might also become a drama. The word 'transference' frequently used in the psychoanalysis also indicates the repetition in a clinical relationship such as script of mind or object relations. Then, the analytic therapist understands the events, while participating in the clinical setting, attends the drama as an object in the script and sometimes plays such given role. In the therapeutic relations in play therapy for children, the script of drama is repeated, which can be called a dramatization of transference. The English word 'play' can also signify 'drama' and therefore it becomes a goal of therapists of children to read and understand the story, while participating in the drama. Thus, the interpretation of transference in psychoanalysis is the words made to trace and to re-weave the script of one's life story. PMID- 26524874 TI - [The Present Status of, and Issues Related to, Mental Health Activities in the Ishinomaki Region, with a Focus on Outreach Activities]. AB - The Great East Japan Earthquake was a colossal event, registering a magnitude of 9.0 and causing huge tsunami that in some places were more than 40 meters in height. As of March 31, 2014, the number of dead nationwide stood at 15,882, while 2,668 persons were listed as missing; 3,089 other deaths have also been classified as being disaster-related. There were 5,500 victims in the Ishinomaki area alone. The disaster, comprising the earthquake itself, the subsequent tsunami, fires, and the nuclear power plant accident, was a combined natural and man-made catastrophe of epic proportions, affecting a broad, underpopulated region. Those hit by the disaster were affected not only by the loss of life, but also the loss of homes and livelihoods. These people experience psychological stress, fear, and anxiety as a result of lifestyle and environmental changes associated with moving from evacuation areas to prefab temporary housing, or the homes of parents, siblings, relatives, friends, or acquaintances, followed by attempts to rebuild their own homes. Other changes, such as the loss of employment, the transition to new workplaces, or having to change schools, also take a psychological and emotional toll. Delays in the construction of new housing and the resulting prolongation of life as evacuees only serve to increase anxiety and the sense of stagnation. With the above as a backdrop, the author will report on activities being conducted by his organization, particularly outreach efforts. PMID- 26524875 TI - [Usefulness of Immunochromatography Method for Malaria and Dengue Fever Diagnosis]. AB - There are three major differential diagnosis of febrile patients with history of travels to the tropical countries i.e., malaria, typhoid fever and dengue fever. Diagnosis of malaria patients undergoes sometimes arduous process due to the variable skills of laboratory technician, and more convenient method is warranted. Immunochromatography (IC) method is simple method and recently used for diagnosis of several infectious diseases. Here, we reported usefulness of IC method for malaria and dengue fever diagnosis. Forty-seven samples from 46 patients were retrospectively analyzed by both malaria IC method and microscopic examination. Furthermore, three patients were undergone dengue IC method followed by PCR and antibody examination (ELISA) if the results were positive. Several factors such as rheumatoid factor (RF) are known to affect the results of IC method. We also checked malaria and dengue IC method using serum known to be high RF results without malaria infection. Totally six patients were diagnosed as malaria i.e., 1 vivax malaria and 5 falciparum malaria. Sensitivity and specificity of the malaria IC method were excellent, 100% and 97.6%, respectively. Among three patients, one patient revealed false-negative results of dengue IC method, however, results of the other two patients revealed good correlation between IC method and PCR/ELISA results. Among four RF positive serums, 2 malaria IC method and 4 dengue IC method revealed false-positive results. In summary, IC method for malaria and dengue fever might be quick and convenient method and considered to be used as an adjunctive diagnostic tool. PMID- 26524876 TI - [Evaluation of the Fundamental Performance of 4 Latex Agglutination Reagents to Measure Anti-TP Antibody Concentration and Detailed Investigation of Decision Mismatched Samples]. AB - Serological diagnosis of syphilis can be made by using the serological test for syphilis (STS) method for detecting a lipid antibody and Treponema pallidum (TP) method for detecting the anti-TP-specific antibody. In STS and TP methods, the basis using latex agglutination reaction has been used in many facilities. However, in latex agglutination, false-positive results due to non-specific reaction have sometimes been obtained in reactions of a routine laboratory test reagent detecting the anti-TP antibody used in our medical laboratory. We evaluated the fundamental performance of 4 reagents to measure anti-TP antibody concentration using latex agglutination: Reagents A, B, C and D produced by SEKISUI MEDICAL, FUJI REBIO, DENKA SEIKEN and SHINO TEST, respectively. We examined the correlations between Reagent A (routine laboratory test reagent) and Reagents B, C, and D in sera from 68 patients, and we performed additional investigation by using a neutralization test, immunochromatography, Western blotting, FTA-ABS (IgG), and STS method by an automatic analyzer for 13 decision mismatched samples. The fundamental performance of each reagent was as good as that previously reported. Eight of the 13 decision-mismatched samples were false positives due to non-specific reaction of Reagent A. In latex agglutination non specific reaction is inevitable. However, this study strongly suggests that using a neutralization test and immunochromatography that can be performed quickly is sufficient to verify whether positive reactions are true or false. PMID- 26524877 TI - The NAFLD Index: A Simple and Accurate Screening Tool for the Prediction of Non Alcoholic Fatty Liver Disease. AB - OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a common debilitating condition in many industrialized countries that increases the risk of cardiovascular disease. The aim of this study was to derive a simple and accurate screening tool for the prediction of NAFLD in the Japanese population. METHODS: A total of 945 participants, 279 men and 666 women living in Hokkaido, Japan, were enrolled among residents who attended a health check-up program from 2010 to 2014. Participants with an alcohol consumption > 20 g/day and/or a chronic liver disease, such as chronic hepatitis B, chronic hepatitis C or autoimmune hepatitis, were excluded from this study. Clinical and laboratory data were examined to identify predictive markers of NAFLD. RESULTS: A new predictive index for NAFLD, the NAFLD index, was constructed for men and for women. The NAFLD index for men = -15.5693+0.3264 [BMI] +0.0134 [triglycerides (mg/dl)], and for women = -31.4686+0.3683 [BMI] +2.5699 [albumin (g/dl)] +4.6740[ALT/AST] -0.0379 [HDL cholesterol (mg/dl)]. The AUROC of the NAFLD index for men and for women was 0.87(95% CI 0.88-1.60) and 0.90 (95% CI 0.66-1.02), respectively. The cut-off point of -5.28 for men predicted NAFLD with an accuracy of 82.8%. For women, the cut-off point of -7.65 predicted NAFLD with an accuracy of 87.7%. CONCLUSION: A new index for the non-invasive prediction of NAFLD, the NAFLD index, was constructed using available clinical and laboratory data. This index is a simple screening tool to predict the presence of NAFLD. PMID- 26524878 TI - [Development of Highly Sensitive Quantitative HBsAg Reagent and Its Availability]. AB - HBsAg is an envelope surface protein of the hepatitis B virus, and a marker of hepatitis B infection. In Japan, an HBsAg reagent was adopted as a blood screening test by the Japan Red Cross in 1972. Furthermore, a highly sensitive HBsAg reagent has been in use since 2008. Blood screening with HBsAg reagent use has contributed to a decrease in hepatitis B infections following blood donation. From the year 2000, the HBsAg reagent requirements have changed according to the progress in hepatitis B treatment. Serum levels of HBsAg and their temporal changes over long periods are used to understand a patient's clinical state and the effect of nucleoside analogue treatment. In 2013, we developed a highly sensitive quantitative chemiluminescent enzyme immunoassay (HBsAg-HQ) for HBsAg. Characteristics of the HBsAg-HQ reagent include the use of a pretreatment mixture and anti-HBs antibodies for the inner portion of HBsAg. The detection limit of HBsAg-HQ reagent (zero +3SD) is 0.0006 IU/mL, and the quantitative limit below 10% of the CV is 0.002 IU/mL. Therefore, we configured the measurement range from 0.005 to 150 IU/mL. Diagnostic sensitivity was tested for 10 seroconversion panels with HBsAg-HQ, and HBsAg-HQ yielded the same or higher sensitivity than other immunoassay products. In the report of Wai-Kay Seto et al., 25.8% of HBV patients whose sera were classified as HBs seroclearance by CLIA HBsAg reagent were judged as positive using our HBsAg-HQ reagent. Furthermore measurement of HBsAg levels is recommended to confirm the effect of nucleoside analogue treatment for chronic hepatitis patients or assessing the clinical condition before immunosuppression therapy for rheumatoid patients based on the guidelines of "The Japan Society of Hepatology" and "Japan College of Rheumatology". HBsAg qualitative reagents with high sensitivity are thus desirable for use in monitoring HBsAg. PMID- 26524879 TI - [Clinical Impact of High Sensitive Troponin I Assay]. AB - Cardiac Troponin is drawing increasing attention from cardiologists, clinicians, researchers, and authorities in Japan, as illustrated by the revision of the PCI reimbursement plan in April 2014 and that of the JCS STEMI Guidelines in December 2013. In the revised PCI reimbursement plan, it is stated that 10,000 points will be added for the performance of PCI when Troponin is positive together with myocardial ischemic observations. In the revised STEMI Guidelines, a description was added stating that high sensitive Troponiri assays are superior to all other cardiac markers, including myoglobin, CK-MB, H-FABP, and conventional Troponin assays. With high sensitive Troponin assays, including hsTnI recently developed by Abbott that can measure 96% of the normal population, increasing numbers of researchers are actively involved in research to elucidate whether high sensitive Troponin assays are useful not only for the diagnosis of ACS (acute coronary syndromes), but also for the prognosis of chronic heart diseases such as heart failure, high blood pressure, diabetes, or metabolic syndrome. In this review, we describe high sensitive Troponin assays from various viewpoints. PMID- 26524880 TI - [Usefulness of Presepsin Measurement: A New Biomarker for Sepsis]. AB - Sepsis is a systemic inflammatory response syndrome (SIRS) caused by infection, and it is one of the major causes of mortality of critical care patients. Since it has been reported that early, optimal treatment of patients is important to reduce mortality from sepsis, a sepsis marker with a high sensitivity and specificity is required. Presepsin (P-SEP) was discovered as a new marker whose levels elevated specifically in the blood of patients with sepsis in Japan in 2002. Presepsin is a 13-kDa glycoprotein that is a truncated N-terminal fragment of CD14. Since one of the production mechanisms of presepsin is related to the phagocytosis of bacteria, the biological characteristics of presepsin are different from those of other inflammatory markers. Presepsin has three features in comparison with procalcitonin(PCT), C-reactive protein(CRP), and interleukin-6 (IL-6): 1) Presepsin can be detected earlier after the onset of infection; 2) Presepsin is not affected by severe trauma, severe burn, or invasive surgical procedures, which lead to SIRS, more than PCT, CRP, or IL-6; 3) Presepsin levels reflect the clinical condition of septic patients. Although clinical evidence is not sufficient at present, presepsin may be a strong tool for the development of novel treatment strategies for sepsis. PMID- 26524881 TI - [Measurement of Liver Fibrosis Marker Targeting Sugar Chain Marker]. AB - The degree of liver fibrosis progression is an important factor in hepatocarcinogenesis, and monitoring liver fibrosis is important for predicting and preventing hepatocellular carcinoma. It is proportional to the appearance of a new hepatitis C therapy, or the expectation of liver fibrosis therapy, and liver fibrosis research is attracting attention. Although the Gold Standard for the diagnosis of liver fibrosis is liver biopsy, various problems, such as in the difficulty of invasive and frequent measurement, exist. The present non-invasive examination methods for the assessment of liver fibrosis also have a problem in the fields of organ specificity and diagnostic performance. Using a fully automated immunoassay system "HISCL", an assay system based on the lectin bound sugar reaction which is not an antigen-bound antibody reaction was developed. Measurements using the fully automated immunoassay system "HISCL" series and HISCL M2BPGi assay kit facilitated rapid assay (17 minutes) with a small sample volume (10 MUL). Serum M2BPGi values can be used in various ways, such as for assessment of the risk and treatment associated with hepatocellular carcinoma, reflecting the liver fibrosis stage. Furthermore, many studies are currently in progress. The development of a new assay system for the detection of a cancer production sugar chain marker is expected in the future owing to the advent of a lectin-bound sugar chain reaction system. PMID- 26524882 TI - [Possibility of Using ELF Score as Index for Hepatic Fibrosis Evaluation]. AB - Liver fibrosis, most commonly caused by hepatitis virus (such as HBV and HCV) infections, excessive alcohol consumption, and obesity-induced steatosis, is characterized by the excessive accumulation of extracellular matrix proteins (including collagen) and an increase in connective-tissue (liver fibrogenesis) in the human liver. Today, while the reference standard for detecting and assessing liver fibrosis is needle biopsy of the liver, this invasive procedure can cause physical and emotional distress for patients. On the other hand, medical imaging systems and various blood markers have been developed and become available for routine laboratory practices. These non-invasive procedures, as well as pathological biopsy, have significantly contributed to assessing liver fibrosis. The Enhanced Liver Fibrosis (ELF) test is a simple blood test to create an ELF score by combining three markers: hyaluronic acid (HA), amino-terminal propeptide of type III procollagen (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP-1). The ELF test is one of the promising techniques for diagnosing patients with liver fibrosis. PMID- 26524883 TI - [[-2] proPSA: A Novel Marker of Prostate Cancer]. AB - Over the decades, prostate-specific antigen (PSA) has contributed to the early detection of and screening for prostate cancer (PCa). However, PSA is now in the spotlight due to issues of overdetection and subsequent overtreatment of PCa, causing a serious drawback in PSA-based screening. The challenge of a PSA assay for PCa detection is that the sensitivity is high, whereas the specificity is relatively low. With advancements in molecular biology and genomics, numbers of novel PCa markers has been discovered. One of the promising serum biomarkers is proPSA. proPSA is a pre-mature form of PSA. The molecules are fractions of free PSA, and [-2]proPSA contains 2 amino acids as N-terminus pro-peptides of PSA. Studies have shown the possibilities of using [-2] proPSA-related indices like the Prostate Health Index and %2PSA as tumor markers for diagnosis. [-2]proPSA related indices have improved specificity compared to commonly used PSA and free PSA to detect PCa, while maintaining high-level sensitivity. Reports on clinical utilities of [-2]proPSA are rapidly increasing, and recent studies suggested the utility of [-2] proPSA-related indices for the enhancement of optimized treatment strategies and patient management. At present, several investigations which may reveal clinical utilities of [-2]proPSA are on-going in Japan. Attention: At the time of the submission of this article, [-2] proPSA had yet to be approved as an in vitro diagnostic test in Japan. PMID- 26524884 TI - [Quality of Human Liquid Specimens Appropriate for Laboratory Tests and Analyses- Chairmen's Introductory Remarks]. AB - One of the major concerns for laboratory medicine communities is the quality of human specimens. Thanks to previous efforts in laboratory medicine field, routine quality control is almost guaranteed. Evidence is continually accumulating, and this evidence keeps the analytical levels in the clinical laboratory high. There is still, however, insufficient scientific evidence when handling and storing routine specimens, especially liquid specimens. Data based on poor quality specimens affects designs of patients' diagnostic and therapeutic strategies. Furthermore, such poor data also affect the outcomes of clinical trials. The only solution to avoid this situation is to acquire specimens of favorable quality. In this symposium, six experts involved in basic science to the clinical frontline gave unique presentations to share their expertise with us, and their concerns about specimen quality. PMID- 26524885 TI - [Anomalous Properties of Water and Aqueous Solutions at Low Temperatures]. AB - Water has many anomalous properties below the room temperature. The temperature range overlaps with that of the Earth's atmosphere and also with that natural life forms favor. We review the origin of the anomalous properties of water and aqueous solutions in association with the hypothetical second critical point and liquid-liquid phase separation of water hidden in the supercooled state of liquid water. PMID- 26524886 TI - [Physicochemical Environmental Change during Bio-Preservation in Cellular and Biomolecular Suspension Samples and Its Effects on the Sample Quality]. AB - The quality of biospecimens is an important issue for clinical assays. These specimens contain various biomarkers, e.g., cells, proteins, nucleic acids, and phospholipids, most of which start to degrade just after sampling from patients. Because this degradation proceeds in a water-rich condition, under which water, as a solvent, dominates the degradation rate, the samples are often preserved at a low temperature in a frozen, lyophilized, or desiccated state to inhibit the motion of water molecules. However, frozen and/or desiccated water solutions surrounding the biomarkers markedly change the physicochemical environment, and can sometimes accelerate the degradation process. This physicochemical variation in water solutions includes dehydration by freezing or desiccation, osmotic stress by frozen-induced condensation, intra-/extracellular ice formation, and vitrification. This article provides an outline of such physicochemical variation in water solutions and its effects, especially on a fluid specimen, like a blood sample. The outline is composed of three parts after the introduction chapter: 1) general physicochemical changes in the water solution during freezing, frozen storage, and thawing, 2) damage of cells and proteins during freezing, frozen storage, and thawing, and 3) physicochemical changes of the water solution during desiccation and lyophilization and their effects on cells and proteins. As the mechanism of cellular damage is different from that of protein damage, they are discussed separately. PMID- 26524887 TI - [Sample Quality Control through the Depository and Distribution of Cancer-Related Human Materials: Experience of Kanagawa Cancer Research & Information Association (KCRIA)]. AB - Kanagawa Prefecture and its department of hospital business established the Kanagawa Cancer Research and Information Association (KCRIA) in 2006, and the Kanagawa Cancer Center (KCC) and related institutes have started to collect and distribute patient-derived cancer-related biomaterials to researchers. The tumor tissue center of KCC is collecting frozen tumor tissues, formalin-fixed and paraffin-embedded (FFPE) tumor tissues, serum of patients before treatment, and genomic DNA of peripheral white blood cells. Corresponding normal tissues are also collected if possible. Clinical information on patients is annotated in each sample as accurately as possible under linkable anonymization to follow the prognosis. We are evaluating the quality of tumor samples with two indices: the RNA Integrity Number (RIN) of extracted total RNAs from randomly chosen frozen tissues examined with the 2100 Bioanalyzer (Agilent Technologies, Inc., Santa Clara, CA, USA), and the histopathological examination of parts of all frozen tissues prepared in the Optimal Cutting Temperature (OTC) compound and evaluation of the contents of tumor cells. Management of the sample quality is an important issue for any biomaterial repository. The quality of samples is influenced by the procedures of sample collection and storage, and also by the storage duration. The quality could be periodically examined by monitoring analyte stability and integrity, such as RIN of frozen cancer tissues. However, the best way to collect and store RNA might not always be the same for different analytes. Therefore, sample quality control at biomaterial repositories that are preparing samples for future studies on undefined analytes is a very difficult problem. At least the standard sample operation procedure (SOP) should be available for users. PMID- 26524888 TI - [Quality Management and Quality Specifications of Laboratory Tests in Clinical Studies--Challenges in Pre-Analytical Processes in Clinical Laboratories]. AB - The cost, speed, and quality are the three important factors recently indicated by the Ministry of Health, Labour and Welfare (MHLW) for the purpose of accelerating clinical studies. Based on this background, the importance of laboratory tests is increasing, especially in the evaluation of clinical study participants' entry and safety, and drug efficacy. To assure the quality of laboratory tests, providing high-quality laboratory tests is mandatory. For providing adequate quality assurance in laboratory tests, quality control in the three fields of pre-analytical, analytical, and post-analytical processes is extremely important. There are, however, no detailed written requirements concerning specimen collection, handling, preparation, storage, and shipping. Most laboratory tests for clinical studies are performed onsite in a local laboratory; however, a part of laboratory tests is done in offsite central laboratories after specimen shipping. As factors affecting laboratory tests, individual and inter-individual variations are well-known. Besides these factors, standardizing the factors of specimen collection, handling, preparation, storage, and shipping, may improve and maintain the high quality of clinical studies in general. Furthermore, the analytical method, units, and reference interval are also important factors. It is concluded that, to overcome the problems derived from pre-analytical processes, it is necessary to standardize specimen handling in a broad sense. PMID- 26524889 TI - [Utilization of Multi-Institutional Laboratory Data as an Evidence Database: The Current Status and Future Tasks--Chairmen's Introductory Remarks]. AB - The construction of a database that integrates raw laboratory data and diagnostic information with patient backgrounds is an effective tool in the practice of Evidence-Based Laboratory Medicine (EBLM). By exploring this type of database, it is possible to understand the diagnostic characteristics of the tests for a specific patient subgroup or condition. Although several studies have been carried out recently, these databases contain single-hospital data, and are thus limited regarding their external validity. In order to improve the reliability of the evidence, joint multi-institutional research is required. Therefore, the EBLM Committee of the Japanese Society of Clinical Laboratory Medicine arranged the symposium, entitled: "Utilization of multi-institutional laboratory data as an evidence database", which discusses current problems and solutions for the integration of multi-institutional laboratory data. In the symposium, five speakers presented on the following subjects: 1) Standardization of laboratory test coding (JLAC10); 2) The construction of a data warehouse in the hospital; 3) Multi-institutional study on long-term data changes; 4) Multi-institutional study on diagnostic accuracy; and 5) The construction of databases for the practice of EBLM and the need for the standardization/harmonization of laboratory data. PMID- 26524890 TI - [The JLAC Coding System for Clinical Laboratory Tests]. AB - Clinical laboratory data are essential for the diagnosis of and therapy for patients in hospital. In addition to such direct clinical use in hospitals, the collected personal clinical laboratory data have been recognized as very important for the life-long health care of individual patients. Furthermore, the data derived from a large number of patients are utilized for epidemiological studies and safety evaluation of new drugs. For the above-mentioned secondary use, laboratory data which are obtained at different times and in different facilities must be comparable. Recently, a huge amount of medical information has been accumulated and utilized as "big data" for the development of national healthcare and life science industries. Under these circumstances, the JLAC, a coding system of laboratory tests developed and maintained by JSLM, is attracting increasing attention for the spatial and temporal comparison of laboratory test data. PMID- 26524891 TI - [Role of Medical Technologists' Training in the Future]. AB - Tokyo University of Technology established a Faculty of Health Sciences, consisting of Departments of Nursing, Clinical Engineering, Physical Therapy, and Occupational Therapy in 2000, and established the Department of Medical Technology in 2014. Now, more than half a century after medical technologists' education started in 1959, medical technologists' training schools exist in 80 facilities, with universities making up 52 schools. On this occasion, we consider the role of medical technologists' training in the future. The role of the clinical laboratory is to provide quick, timely, and useful medical information for the diagnosis, treatment, and prevention of diseases. Advances in medical technology in recent years have been marked. Today, the appropriateness of clinical laboratory services and systems is evaluated, focusing on the fulfillment of social and technical requirements, and this necessitates medical institutions to disclose their purposes and goal achievement levels. For the advancement of clinical laboratories, the process of assessing their achievements is important, which will maintain and improve reliability and promote development of the organization. Self-assessment is ongoing, and the improvement is required in clinical laboratories. Medical technologists in the future must be able to adapt flexibly to these situations. The nature of medical technologists' training is also similar, as they must acquire practical skills on-site, realize their self-growth potential, and understand that human power is important. PMID- 26524892 TI - [Increase in Alkaline Phosphatase Activity after High-Fat Meal Ingestion is Correlated to the Amount of ABH Substances in Saliva]. AB - Intestinal alkaline phosphatase (IAP) appears in the circulation more frequently in blood group B or O secretors than in blood group A or AB secretors and non secretors, and serum IAP activity rises following the ingestion of a high-fat meal. In a previous study, the occurrence of two IAP isoforms, with high (HIAP) and normal molecular mass (NIAP), in healthy sera was demonstrated by 6.0% polyacrylamide gel electrophoresis in the presence of 1% Triton X-100. NIAP was present in the fasting serum of only healthy blood group B or O secretors, but was present in all subjects following ingestion of a high-fat meal. We classified 56 healthy subjects into 3 blood groups: B (n = 19), O (n = 17), and A (n = 20), and measured their serum ALP activity in a fasting state and 6 h after a high-fat meal. The amount of ABH substances in the saliva of each subject was determined by the hemagglutination inhibition test. Correlation coefficients between the change in ALP activity after high-fat meal ingestion and the hemagglutination inhibition values in saliva were 0.925 in blood group B, 0.879 in blood group O, and 0.906 in blood group A. These results suggest that increases in ALP activity in the circulation following the ingestion of a high-fat meal are closely related to the amount of ABH substances in saliva. PMID- 26524893 TI - Age and Bone Marrow Cellularity are Associated with Response to Eltrombopag in Japanese Adult Immune Thrombocytopenia Patients: A Retrospective Single-Center Study. AB - In the present retrospective single-center study, we examined the efficacy and safety of eltrombopag, a thrombopoietin (TPO) -receptor agonist (TPO-RA), and found clinical factors associated with its efficacy in Japanese patients with chronic immune thrombocytopenia (ITP). According to the definition of a response, which is to attain a platelet count of more than 50,000/MUL at least once during eltrombopag treatment, 42 enrolled patients were divided into two groups: responders (29 patients, 69%) and non-responders (13 patients, 31%). In analyses of the clinical and laboratory data of these two groups, we extracted two factors that are significantly associated with a better response to eltrombopag, which have not been recognized previously, namely, (1) an older age of patients at eltrombopag initiation (>= 70 years old) and (2) normal or decreased cellularity of iliac bone marrow (BM) biopsy at diagnosis. The significance of patient age contradicts previous findings from studies in which the Caucasian population was the major focus. However, factors such as changes of pharmacokinetics might modulate the effects of eltrombopag in older patients in Japan because East Asians show higher bioavailability of eltrombopag by as-yet-unknown mechanisms. BM cellularity in ITP may represent an impairment and/or lower responsiveness of pluripotent hematopoietic stem cells, not limited to the megakaryocyte (MgK) platelet axis, to endogenous TPO, because recent evidence shows that TPO-RA can successfully restore hematopoiesis in aplastic anemia. These results should be useful for the therapeutic use of TPO-RA for ITP and also related thrombocytopenia in Japan. PMID- 26524894 TI - [Testicular Tumor in a Patient with Delta Thalassemia Complicated with Hereditary Persistence of Fetal Hemoglobin]. AB - A 30s male was diagnosed as having the left testicular tumor in 2010. He received the anti-neoplastic chemotherapy, and could achieve the complete remission. But, he relapsed with solitary retroperitoneal lymph node swelling in 2012, and he was referred to our hospital. Laboratory examination on his admission showed the significant increase of fetal hemoglobin (HbF) up to 16.4%. But, neither anemia nor hemolysis was found at that time. Coexistence of therapy-related myeloid neoplasm or HbF production by metastatic lesion was not definite. Isoelectrofocusing of his hemolysate showed the faint HbA2 in addition to dense HbF band. Molecular analysis of his Hb gene revealed the homozygous (G)gamma-158 (C-T) together with homozygous delta-77(T-C). From these findings, he was diagnosed as having hereditary persistence of HbF (HPFH) and homozygous delta thalassemia. The precise incidence of such combined genetic variation has been unknown because the majority of such cases seem to show no significant clinical symptoms as our case. Whereas, it seems necessary to remind the possibility of such genetic variation when adult patients with various acquired diseases such as testicular tumor or hematologic malignancies show the elevated HbF level. PMID- 26524895 TI - [Progress of Autoantibody Examinations for Connective Tissue Diseases]. AB - Connective tissue diseases are chronic inflammatory diseases that can affect multiple organs and, thus, have a broad spectrum of clinical presentations. Various autoantibodies are detected in patients with connective tissue diseases, represented by anti-nuclear antibody for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), Sjogren's syndrome, and mixed connective tissue disease. Assessment of the autoantibody profile is fundamental for the clinical management of patients with connective tissue diseases, providing important data for the diagnosis, clinical characterization, and disease activity evaluation. Anti-ribosomal P antibody and anti-NMDA receptor antibody are associated with neuropsychiatric SLE. Anti synthetase syndrome comprises the association of myositis (PM/DM), interstitial lung disease, fever, Raynaud's phenomenon, mechanic's hands, and anti-aminoacyl tRNA synthetase antibodies. Anti-MDA5 antibody is detected in patients with clinically amyopathic DM, often complicated by rapidly progressive interstitial lung disease. Between 50 and 75% of malignancy-associated DM patients are positive for anti-TIF1-gamma antibody. Anti-RNA polymerase III antibody is associated with diffuse cutaneous SSc and renal crisis. This review focuses on the importance and usefulness of these autoantibodies for the diagnosis and management of patients with connective tissue diseases in clinical practice. PMID- 26524896 TI - [The Diagnosis and Treatment of Osteoporosis]. AB - Osteoporosis is a common and under-diagnosed disease characterized by the systemic impairment and structural deterioration of bone tissue, leading to bone fragility and an increased risk of fractures of the hip, spine, and wrist. Recent progress in osteoporosis revealed new information on its pathogenesis, the relative risks of fragility fractures, and new treatment measures. In the wake of progress in osteoporosis research, the Japanese Society for Bone and Mineral Research (JSBMR) and Japan Osteoporosis Society Joint Review Committee revised the diagnostic criteria for primary osteoporosis, aimed at obtaining international consensus on the new findings, in 2012. The JSBMR also published guidelines for the use of bone metabolic markers in the diagnosis and treatment of osteoporosis in that year. Then, the JSBMR revised the guidelines on the management and treatment of glucocorticoid-induced osteoporosis in 2014. This article focuses on the diagnosis and pharmacological treatment of osteoporosis, with an overview of the Japanese guidelines. PMID- 26524897 TI - [Roles of Musculoskeletal Ultrasonography in the Management of Rheumatic Diseases]. AB - Inflammation of soft tissues and the subsequent structural damage are the characteristic features of many rheumatic conditions. However, the conventional measures to evaluate these features are not accurate, potentially causing under- and over-diagnosis or treatment. Musculoskeletal ultrasonography, on the other hand, directly visualizes features which are characteristic to rheumatic conditions, such as synovitis, tenosynovitis, bursitis, enthesitis, crystal depositions, bone erosions, and osteophytes/enthesophytes. By visualizing these key features, ultrasound facilitates a more accurate evaluation of rheumatic diseases such as rheumatoid arthritis (RA), spondyloarthropathy, crystal-induced arthritis, and osteoarthritis. For RA, we investigated the impact of ultrasound on the 2010 ACR/EULAR RA classification criteria when joint involvement was determined. We assessed 109 patients with early arthritis using ultrasound. When the presence of joint swelling and number of involved joints were determined by ultrasound, the classification of RA was different from that without ultrasound in approximately 20% of the patients. Moreover, the accuracy of the classification to identify patients who required methotrexate treatment within a year improved by ultrasound. In addition, we and other investigators demonstrated the advantage of ultrasound over conventional measures in the assessment of disease activity of RA. Ultrasound also supports the education of both physicians and patients and communication between them. The utilization of musculoskeletal ultrasonography in more hospitals and clinics is expected to improve the quality of daily practice for rheumatic diseases. PMID- 26524898 TI - [Clinical Practice and Examination for IgG4-Related Disease]. AB - IgG4-related disease (IgG4-RD) is a systemic chronic disease characterized by tumefactive lesions, elevated levels of serum IgG4, and prominent infiltration of IgG4-positive plasma cells with fibrosis. Both lacrimal and salivary glands and the pancreas are the most affected organs during the clinical course of IgG4-RD. The existence of common characteristics associated with IgG4 and frequent overlapping of both diseases has contributed to the establishment of IgG4-RD as a systemic entity. Patients with IgG4-RD are often asymptomatic in the early stage and constitutional symptoms are rarely observed. A typical facial appearance, thirst, and submandibular swelling are initial symptoms that aid in the diagnosis. On suspecting IgG4-RD based on the swelling of various organs, the measurement of serum levels of IgG4 and histopathological examinations including immunostaining with anti-IgG4 antibody are performed, and diagnosis should be made according to comprehensive diagnostic criteria. In addition, careful examination is necessary to exclude other disorders, such as malignancy. Although organ damage in IgG4-RD is thought to be reversible with a favorable responsiveness to glucocorticoids (GC), a delay in treatment intervention causing irreversible dysfunction has been reported. Accordingly, the significance of early diagnosis and therapy has been recognized. Although the first-line treatment for IgG4-RD is empirically the administration of GC, careful observation without treatment may be possible on considering the age and complications. However, severe organ damage such as obstructive jaundice and hydronephrosis is a clear indication for prompt intervention. Multiple organ involvement and subjective symptoms also necessitate treatment. PMID- 26524899 TI - [Diagnosis and Clinical Examination of Autoinflammatory Syndrome]. AB - Autoinflammatory syndrome is characterized by: 1) episodes of seemingly unprovoked inflammation, 2) the absence of a high titer of autoantibodies or auto reactive T cells, and 3) an inborn error of innate immunity. In this decade, many autoinflammatory syndromes have been reported in Japan, and so many Japanese physicians have become aware of this syndrome. Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. The main monogenic autoinflammatory syndromes are familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), cryopyrin-associated periodic syndrome (CAPS), Blau syndrome, and pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. We diagnosed these syndromes as clinical manifestations and performed genetic screening. Many serum cytokines are elevated in patients with autoinflammatory syndrome, but this is not disease-specific. The pathogeneses of many autoinflammatory syndromes are known to be related to inflammasomes, which are multiprotein complexes that serve as a platform for caspase 1 activation and interleukin-1beta (IL-1beta) and IL-18 muturation. Especially, NLRP3 inflammasomes may play a crucial role in the intiation and progression of FMF and CAPS. In the future, we hope to discover new clinical examinations which can provide evidence of inflammasome activation independent of genetic screening. In this issue, I introduce autoinflammatory syndromes and discuss the diagnosis and clinical examination of these syndromes. PMID- 26524900 TI - [Atherosclerosis, Chronic Inflammation, and Thrombosis: In Search of the Missing Link in Laboratory Medicine]. AB - Atherosclerosis is one of the leading causes of death in Japan. With accumulating data from animal experiments, it has become recognized that atherosclerosis involves a chronic inflammatory process of the arterial wall with a dyslipidemic background. However, clinical applications utilizing this knowledge remain scarce. In spite of optimal interventional and pharmacologic therapies, the risk of recurrent ischemia remains high and novel therapies to prevent atherogenesis or detect atherosclerosis in the early stage are needed. One of the potential molecular inflammatory targets that may be clinically relevant is natural killer T cells (NKT cells). Sphingosine-1-phosphate(S1P), one of the biologically active sphingolipids, increases TNF-alpha production in NKT cells and induces the migration of NKT cells, suggesting that S1P can regulate inflammatory processes in atherogenesis. Patients with high plasma S1P levels exhibit high levels of plasma TNF-alpha, plasma antigen levels of plasminogen activator inhibitor (PAI) 1, the major physiologic inhibitors of fibrinolysis, and a reduced endothelial function as assessed by the flow-mediated dilation of brachial arteries (FMD). Also, recent advances in research on circulating microRNA derived from endothelial cells are discussed as potential biomarkers of atherosclerosis. Specific efforts that promote translational science are encouraged to improve the outcome and prognosis of patients with atherosclerosis. PMID- 26524901 TI - [Laboratory Medicine Learned Through Research on the Pathogenesis of Hypertension]. AB - Laboratory tests used in clinical practice to assess hypertension include a differential diagnosis, the assessment of complications, and detection of adverse events with medication, which cover a variety of fields of laboratory medicine. I learned laboratory medicine through basic and clinical studies on the pathogenesis of hypertension, and summarized those findings and my interpretations. Basic research using animal models points to a causal role of the central nervous system in essential hypertension; however, since clinical research is technically difficult to perform, this connection has not been confirmed in humans. Recently, renal nerve ablation in humans proved to continuously decrease the blood pressure in the presence of resistant hypertension. Furthermore, when electrical stimulation was continuously applied to the carotid baroreceptor nerve of human adults, their blood pressure lowered. These findings promoted the concept that the central nervous system may actually be involved in the pathogenesis of essential hypertension, which is closely associated with excess sodium intake. We demonstrated that endogenous digitalis plays a key role in hypertension associated with excess sodium intake via sympathetic activation in rats. An increased sodium concentration inside the brain activates epithelial sodium channels and the renin-angiotensin-aldosterone system in the brain. Aldosterone releases ouabain from neurons in the paraventricular nucleus in the hypothalamus. Angiotensin II and aldosterone of peripheral origin reach the brain to augment sympathetic outflow. Collectively essential hypertension associated with excess sodium intake and obesity, renovascular hypertension, and primary aldosteronism and pseudoaldosteronism are all suggested to have a common cause originating from the central nervous system. PMID- 26524902 TI - [Alteration of Lifestyle-Related Diseases in Japanese: Current Status and Challenges--the Hisayama Study]. AB - Japan has the world's fastest aging society and is characterized by a rapid increase in the prevalence of metabolic disorders, such as obesity and diabetes mellitus, due to the westernization of the lifestyle. These situations might affect the risk of cardiovascular disease in Japanese. To overview the secular trends in the incidence of cardiovascular disease along with the prevalence of risk factors during the past half century in the general Japanese population, we established 5 cohorts consisting of residents aged >= 40 years in a community, Hisayama, in 1961(n = 1,618), 1974 (n = 2,038), 1983 (n = 2,459), 1993 (n = 1,983), and 2002 (n = 3,108), and followed up each cohort for 7 years. In both sexes, the age-adjusted incidence of ischemic stroke decreased markedly from the 1960s to 1970s, but this decreasing trend slowed down from the 1970s to 2000s, while the incidence of acute myocardial infarction did not change during this period. From the 1960s to 2000s, blood pressure control among hypertensive individuals improved significantly, and the smoking rate decreased, but the prevalence of glucose intolerance (prediabetes and diabetes), hypercholesterolemia, and obesity increased steeply. These changes in the incidence of cardiovascular disease probably occurred because the benefits of hypertension control and smoking cessation have been negated by increases in population aging and metabolic risk factors. In addition, the recent findings of the Hisayama study indicated that diabetes is a risk factor for the development of cancer and dementia, and the prevalence of the latter increased rapidly in the Japanese elderly. PMID- 26524903 TI - [Pathogenesis of Acute Promyelocytic Leukemia]. AB - Acute promyelocytic leukemia (APL) is one of the well-characterized subtypes of acute myeloid leukemia (AML). The essential drugs used in the treatment strategy for APL include all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which are both pioneer molecular-targeting agents. They were initially administered to patients based on the therapeutic experience of traditional Chinese medicine, and their marked effectiveness has been demonstrated. Subsequently, the molecular mechanisms of these drugs, as well as the molecular pathogenesis of APL, have been elucidated, whereby the chimeric gene product PML-RARalpha induces epigenetic changes and transcription repression. This review summarizes the findings of previous studies related to the in vitro and in vivo function of PML RARalpha and the effects of ATRA and ATO on PML-RARalpha and APL cells. These findings are very important, because the concept of epigenetic modulation in oncogenesis and their application as molecular targets in APL therapy have now been accepted in other types of leukemia, as well as for other malignancies. PMID- 26524904 TI - [Sequencing and Phylogenetic Analyses of Structural and Accessory Proteins of Middle East Respiratory Syndrome Coronavirus from the First Imported Case in China, 2015]. AB - To investigate the genetic character and origin of the first imported infection case of middle East respiratory syndrome coronavirus (named as MERS-CoV_China GD01), RNA was extracted from swabs of this patient followed by RT-PCR amplification. All coding gene of structural (S, E, M, E) and accessory (ORF3, ORF4a, ORF4b, ORF5, ORF8b) proteins were sequenced and analyzed. Phylogenetic analyses of structural protein coding genes of MERS-CoV_ China GD01 indicates that several substitutes exists in S coding gene and its origin belong group 5 of MERS-CoV, which were recent circulated in Saudi Arabia area, while other three structural genes (N, E, M) were very conserved. Phylogenetic analyses of accessory protein coding genes of MERS-CoV China GD01 indicates that several substitutes exists among ORF3, ORF4a, ORF4b and ORF5, while ORF8b was conserved. In conclusion, genome of MERS-CoV_ China GD01 was general conserved although several genetic variations were found among structural and accessory protein coding genes. This is the first report on sequencing and phylogenetic analyses of the first imported MERS case in China, which may pay the way for prevention and control of imported MERS-CoV infection. PMID- 26524905 TI - [Construction of Recombinant Marek's Disease Virus Expressing the NDV-F gene and its Replication in Chickens and in Vitro]. AB - We used a meq-deleted attenuated MDV-I strain GX0101Deltameq as a vector to construct a recombinant virus expressing the exogenous gene NDV-F. The ORF of exogenous gene NDV-F was inserted into the eukaryotic expression vector pcDNA3.1( ). Then, the expression cassette of NDV-F which contains the CMV promoter was amplified. Simultaneously, we amplified the selected gene Kan+ expression cassette and inserted them into the PMD18-T vector. Tandem expression cassettes were amplified using primers containing the 50-bp homologous arm of MDV-US2. The PCR product was electroporated into EL250 host bacteria containing GX0101Deltameq. Then, the Kan+ expression cassette was deleted from the recombinant virus genome using 1% arabinose. The plasmid of the positive clone which the Kan+ expression cassette was deleted was extracted and transfected into CEFs to rescue the recombinant virus. The recombinant virus was injected into chickens to observe its growth and replication. The recombinant virus rMDV-F containing the exogenous gene NDV-F was rescued successfully. The recombinant virus could duplicate and express well in CEFs, and grow and replicate well in chickens. Using GX0101Deltameq as a vector, combined with a recombinant system of Red E/T and FLP/FRT, we constructed a recombinant virus that expressed the exogenous gene NDV-F. This study could lay the foundation for further study of recombinant viruses. PMID- 26524906 TI - [Establishment and Application of a Model of Well-differentiated Porcine Airway Epithelial Cells in Vitro]. AB - Pigs are increasingly recognized as "natural" hosts of infection by human respiratory viruses because of their similarities to humans in terms of lung physiology, airway morphology, cell types, and distribution of cell receptors in the respiratory tract. We wished to explore the mechanisms of infection by respiratory viruses and screening of drug that could be used to treat respiratory system diseases. Hence, we developed a model of well-differentiated porcine airway epithelial cells (PAECs) derived from pig-lung tissue and cultured them with serum-free medium under an air-liquid interface condition in vitro. We identified the PAEC model using scanning electron microscopy, electrophysiology, and immunohistology. To evaluate application of gene therapy of adeno-associated virus (AAV)6 on the PAEC model, we generated recombinant adeno-associated virus 6 green fluorescent protein (rAAV6-GFP) using the three-plasmid transfection method and infected PAECs from the apical surface with rAAV6-GFP. Results demonstrated that the PAEC model comprised a multilayer epithelial structure containing ciliated mucous secretory cells, with basal cells located directly beneath the multilayer. rAAV6-GFP could infect PAECs from the apical surface and efficiently transduce PAECs to mediate the long-term expression of the exogenous gene. Establishment of a model of well-differentiated PAECs in vitro could lay a solid foundation for the study of infection by respiratory pathogens, as well as the screening and gene therapy of agents used to treat diseases of the respiratory system. PMID- 26524907 TI - [Immune Protection against H9N2 Provided by H1N1 Pre-infection in Pigs]. AB - To explore the impact of the history of infection by the influenza A virus subtype H1N1 on secondary infection by the influenza A virus subtype H9N2, pigs non-infected and pre-infected with H1N1 were inoculated with H9N2 in parallel to compare nasal shedding and seroconversion patterns. Unlike pigs without a background of H1N1 infection, nasal shedding was not detected in pigs pre infected with H1N1. Both groups generated antibodies against H9N2. However, levels of H1N1 antibodies in pigs pre-infected with H1N1 increased quickly and dramatically after challenge with H9N2. Cross-reaction was not observed between H1N1 antibodies and H9N2 viruses. These findings suggest that circulation of the H1N1 virus might be a barrier to the introduction and transmission of the avian H9N2 virus, thereby delaying its adaptation in pigs. PMID- 26524908 TI - [Hsp70 Fused with the Envelope Glycoprotein E0 of Classical Swine Fever Virus Enhances Immune Responses in Balb/c Mice]. AB - Heat-shock protein (Hsp) 70 potentiates specific immune responses to some antigenic peptides fused to it. Here, the prokaryotic plasmids harboring the envelope glycoprotein E0 gene of classical swine fever virus (CSFV) and/or the Hsp70 gene of Haemophilus parasuis were constructed and expressed in Escherichia coli Rosseta 2(R2). The fusion proteins were then purified. Groups of Balb/c mice were immunized with these fusion proteins, respectively, and sera collected 7 days after the third immunization. Immune effects were determined via an enzyme linked immunosorbent assay and flow cytometric analyses. E0-Hsp70 fusion protein and E0+Hsp70 mixture significantly improved the titer of E-specific antibody, levels of CD4+ and CD8+ T cells, and release of interferon-gamma. These findings suggested that Hsp70 can significantly enhance the immune effects of the envelope glycoprotein E0 of CSFV, thereby laying the foundation of further application in pigs. PMID- 26524909 TI - [Sequence and Structural Analyses of the Complete Genome of Bovine Papillomavirus 2 Genotype Aks-01 Strain from Skin Samples of Cows in Southern Xinjiang, China]. AB - To study the complete genomic sequence, genomic characteristics, and genetic variation of the bovine papillomavirus 2 genotype (BPV-2) Aks-01 strain at the molecular level, genotyping of this strain from the skin samples of cows in southern Xinjiang (China) was first detected by the polymerase chain reaction with FAP59/FAP64 primers. Based on the complete genome of the BPV-2 reference strain, specific primers and sequencing primers were designed, and the complete genome of the Aks-01 strain amplified and sequenced. Sequence analyses showed that genotyping of the Aks-01 strain belonged to BPV-2. The Aks-01 strain had the structural characteristics of BPV-2. The 7944-bp full-length genomic sequence of the Aks-01 strain was compiled using DNAStarTM. The sequence of the Aks-01 strain had 98% similarity to the reference strain from GenBank. The Aks-01 strain was most closely related to BPV-1 and BPV-13. BPV-2, BPV-1 and BPV-13 were grouped within the genus Deltapapillomavirus. The Aks-01 strain is the first BPV-2 strain reported in southern Xinjiang. PMID- 26524910 TI - [Infection of the Severe Fever with Thrombocytopenia Syndrome Virus in Balb/C Mice and Hamsters]. AB - The severe fever with thrombocytopenia syndrome virus (SFTSV) is the causative pathogen of an emerging infectious disease severe fever with thrombocytopenia syndrome and a new member in the genus Phlebovirus of family Bunyaviridae. Immune responses and pathological lesions in SFTSV-infected Balb/C mice and hamsters were evaluated by inoculation of SFTSV at 105 TCID50 or 103 TCID50 per animal through four different routes of infection, including intravenous, intramuscular, intraperitoneal, and intracerebral injections. The vehicle control groups were also included. At different time points after the inoculation blood and plasma samples were collected. Blood cell counts, blood viral RNA copies, and plasma antibodies were detected by automatic blood cell counters, real-time PCR, and luminex assays, respectively. At two weeks post inoculation, the animals were sacrificed. Tissues including heart, liver, spleen, lung, kidney, intestine, muscle, and brain, were collected for pathological analyses. Results showed that the SFTSV could infect Balb/C mice and hamsters with SFTSV-specific immunoglobulin (Ig) M and IgG antibodies detected in plasma samples on day 7 post inoculation. The SFTSV-specific IgM levels peaked on day 7 post inoculation and then decreased, whereas the SFTSV-specific IgG levels started to increase on day 7 and then peaked on day 14 post inoculation. Pathological analyses indicated significant pathological lesions in liver and kidney tissues. In conclusion, SFTSV could can infect different strains of rodent animals and cause similar immunological and pathological responses. PMID- 26524911 TI - [Mechanism Underlying Increased Expression of a Member of the Serine/Threonine Kinase Family (Citron kinase) Induced by HIV-1 Infection]. AB - Human immunodeficiency virus (HIV)-1 infection changes transcriptional profiles and regulates. the factors and machinery of the host that facilitate viral replication. Our previous study suggested that the serine/threonine kinase citron kinase (citK) promotes HIV-1 egress. To ascertain if HIV-1 infection affects citK expression in primary cells, peripheral blood mononuclear cells were infected with vesicular stomatitis virus G protein (VSV-G)-pseudotyped HIV-1 vector NL4-3 luc viruses, which resulted in remarkably increased expression of citK. citK overexpression led to a more than two-fold increase in HIV-1 production, whereas a significant decrease was observed when citK was depleted in CD4+ T cells. Infection with HIV-1 pseudoviruses induced increases in the mRNA and protein levels of citK by 2. 5- and 2. 7-fold in HEK293T cells, respectively. By cloning the 5-kb promoter of citK into a luciferase reporter system and transfecting the construct into HEK293T cells, enhanced luciferase activity was observed during HIV-1 infection. Taken together, these data demonstrate that HIV-1 infection upregulates citK expression at the transcriptional level, and thereby renders the host more susceptible to invasion by HIV-1. PMID- 26524912 TI - [Prediction of Promoter Motifs in Virophages]. AB - Virophages have crucial roles in ecosystems and are the transport vectors of genetic materials. To shed light on regulation and control mechanisms in virophage--host systems as well as evolution between virophages and their hosts, the promoter motifs of virophages were predicted on the upstream regions of start codons using an analytical tool for prediction of promoter motifs: Multiple EM for Motif Elicitation. Seventeen potential promoter motifs were identified based on the E-value, location, number and length of promoters in genomes. Sputnik and zamilon motif 2 with AT-rich regions were distributed widely on genomes, suggesting that these motifs may be associated with regulation of the expression of various genes. Motifs containing the TCTA box were predicted to be late promoter motif in mavirus; motifs containing the ATCT box were the potential late promoter motif in the Ace Lake mavirus . AT-rich regions were identified on motif 2 in the Organic Lake virophage, motif 3 in Yellowstone Lake virophage (YSLV)1 and 2, motif 1 in YSLV3, and motif 1 and 2 in YSLV4, respectively. AT-rich regions were distributed widely on the genomes of virophages. All of these motifs may be promoter motifs of virophages. Our results provide insights into further exploration of temporal expression of genes in virophages as well as associations between virophages and giant viruses. PMID- 26524913 TI - [Effect of Deletion of the Carboxyl Terminal of the NS1 Protein on Pathogenicity of the Influenza B Virus]. AB - To analyze the molecular basis of the variation of the pathogenicity of the influenza B virus, we rescued a recombinant virus with a deletion in the carboxyl terminal of the NS1 protein using reverse genetics based on the parental virus B S9 of B/Yamagata/16/88. A mutant strain with a deletion of 171 amino acids in the carboxyl terminal of the NS1 protein was named "B-L5". BALB/c mice were inoculated with 3 X 105 EID50 of B-L5 and the parental virus B-S9, respectively. Then, weight changes, survival, and viral titers were documented. During 3 days post-inoculation (dpi) to 7 dpi, the weight of mice infected with B-S9 decreased. However, the weight of mice infected with B-L5 showed weight decreases only at 2 dpi, and quickly recovered at 3 dpi. B-S9 and B-L5 could replicate in the lungs of BALB/c mice. However, viral titers in the lungs of mice infected with B-L5 were 7900-times lower than those of mice infected with B-S9 at 3 dpi. Viral titers in the lungs of mice infected with B-L5 were not detected at 6 dpi. These results showed that, compared with the parent virus B-S9, the mutant virus B-L5 showed lower pathogenicity in BALB/c mice. Our study suggests that deletion of the carboxyl terminal of the NS1 protein decreases the pathogenicity of the influenza B virus. Establishment of a reverse-genetics system for the B influenza virus will provide a platform for studying its pathogenesis, and mechanism of transmission, and for developing live-attenuated influenza B virus vaccines. PMID- 26524914 TI - [Genetic Characterization of Hemagglutinin on Measles Virus Epidemic Strain Genotype H1a in Liaoning Province (China) from 1997 to 2014]. AB - To wished to characterize the hemagglutinin (H) gene of the measles virus epidemic strain H1a in Liaoning Province (China) from 1997-2014 to provide a basis for the control and elimination of measles. All 63 measles virus strains were the H1a genotype. Fragments of the H gene (1854 nucleotides) and nucleoprotein (N) gene (450 nucleotides) were amplified by reverse transcription polymerase chain reaction (RT-PCR) and the PCR products sequenced and analyzed. Phylogenetic-trees were constructed with reference strains of the genotype-H measles virus downloaded from GenBank, including Chinese measles virus strains isolated in 1993-1994 and the vaccine reference strains S-191 and C-47. Sixty three strains of the measles virus in 1997-2014 belonged to genotype H1a. The mean evolutionary rate for gene N-450 was higher than that for the H gene. All 63 strains of the measles virus were mutated from: serine (Ser S) to asparagine (Asn N) in the 240th amino acid; arginine (Arg R) to glycine (Gly G) in the 243th; and tyrosine (Tyr Y) to Asn N in the 481th amino acid. All measles virus strains in cluster 2 were mutated from proline (Pro P) to leucine (Leu L) in the 397th amino acid. The other neutralization sites showed no apparent difference when comparing the nucleotides/amino acids of the H gene of S191 vaccine strains. PMID- 26524915 TI - [Structure, Immunogenicity and Clinical Value of Chlamydiaphage Capsid Protein 3]. AB - We wished to assess the role of chlamydia micro virus capsid protein Vp3 in recombinant molecules, chart its molecular evolution, screen the wild-type strain, and reveal its value in clinical research. Using a protein BLAST multiple alignment program, we compared various strains of Chlamydia micro virus capsid protein Vp3 sequences. Using a "distance tree" of those results, we created a phylogenetic tree. We applied the Karplus-Schulz method of flexible-region analyses for highly conserved alignments of amino-acid sequences. Gamier-Robson and Chou-Fasman methods were employed to analyze two-level structures of sequences. The Emini method was used for analyses of the accessibility of surface epitopes. Studies of hydrophilic proteins were undertaken using Kyte-Doolittle and Hopp-Woods methods. Analyses of antigen epitopes helped to reveal the antigen index using the Jameson-Wolf method. All sequences in the six strains of chlamydia micro virus capsid protein Vp3 were highly conserved, with the main differences being between Vp3 protein in Chp1 and the other five strains of the micro virus. The viral strain of Vp3 protein was based mainly on micro-alpha helix structures, and multiple epitopes were noted in highly conserved regions. Vp3 protein was highly conserved structurally, and was an important protein of the chlamydiaphage capsid. Vp3 protein has a complicated molecular structure, highly conserved regions with strong immunogenicity, and has considerable research value. PMID- 26524916 TI - [Phylogenetic Analyses and Characterization of the VP7 Genes of Serotype G9 Rotaviruses Circulating in Nanjing (China), 2012-2013]. AB - Group-A rotaviruses are recognized as the most common cause of acute diarrhea. Phylogenetic analyses of the VP7 genes of rotaviruses circulating in Nanjing (China) could aid in the development of rotavirus vaccines. A total of 908 stool specimens were collected from patients suffering from acute diarrhea in Nanjing between October 2012 and December 2013, and were tested further for rotaviruses. Fifty rotavirus isolates selected randomly were typed by reverse transcription polymerase chain reaction using serotype-specific primers for G genotyping. VP7 genes of 19 G9 strains were sequenced for further genetic characterization. Among the 908 stool specimens examined during the surveillance period, 103 (11.34%) were rotavirus-positive. G9 was the most predominant genotype (78.0%), followed by G2, G1 and G3. Sequence and phylogenetic analyses of the VP7 genes of serotype G9 rotaviruses revealed these strains to comprise two lineages (G9-VI, G9-III) and to be dominated by the G9-VI lineage (which belonged to a unique subcluster of Japanese and Chinese G9 strains). Amino-acid sequences of the four antigenic regions (A, B, C or F) were variant among a portion of strains, which may have contributed to the prevalence of G9 rotaviruses in this area. PMID- 26524917 TI - [Variability of Reverse Transcriptase Gene and S Gene in Lamivudine-treated Chronic Hepatitis B Patients]. AB - We wished to undertake molecular characterization of the reverse transcriptase (RT) gene and overlapping surface (S) gene in lamivudine-treated patients with chronic infection with the hepatitis B virus (HBV). Sequencing analyses of the HBV RT/S gene of isolates from 25 chronic hepatitis B (CHB) patients with the YMDD mutation and 30 treatment-naive CHB patients were undertaken. In patients with the YMDD mutation, rtM2041 was the major type of mutation (20/25, 80%). rtL80I was present in most of the patients with rtM204I (14/20, 70%). rtL180M coexisted with rtM204V (5/5, 100%). Patients with the YMDD mutation had a significantly higher prevalence of mutation of the RT gene than treatment-naive CHB patients (P < 0.05). Classical primary resistance and secondary/compensatory mutations were detected at only five sites (rtL80, rtV173, rtL180, rtM204, rtM250) in CHB patients with the YMDD mutation. The frequency of nucleos(t)ide analog resistance (NAr) mutation within the RT gene in patients with the YMDD mutation was significantly higher than that in treatment-naive patients (P < 0.05). Amino-acid mutations within the RT gene were also associated with other types of NAr in patients with the YMDD mutation. The rate of amino-acid variants within the S gene region was significantly higher in patients with the YMDD mutation than that in treatment-naive patients (P < 0.05). sM133L and sG145R variants were also present in patients with the YMDD mutation. These observations suggest that CHB patients with the YMDD mutation also have NAr mutations related to other NA drugs, which might lead to cross-resistance in CHB patients. Variants present in the S gene region could cause changes in the antigenicity of HBsAg, which could result in a false-negative diagnosis of HBsAg and immune in escape of the HBV. PMID- 26524918 TI - [Research Progress of Study on Function of T Cell Immunity against Influenza Virus]. AB - The influenza A virus (IAV) belongs to the family Influenza Virus and subfamily Orthomyxoviridae. The IAV can cause acute infections of the lower respiratory in human and animals. Recently, many studies have been performed to reveal the lung CD4+ T cells, CD8+ T cells and Tregs via multiple effector and regulatory mechanisms to against IAV. In this paper, we review the state of progress with regards to various strategies of IAV escape from T cell responses, T cells and innate T cells immunity against influenza virus, which will provide a useful reference tool for future related reseach. PMID- 26524919 TI - [Development of Targets for Anti-influenza Virus Based on Nucleoprotein]. AB - The influenza A is an acute respiratory infection persistently threatening human health and social stability, and has caused high morbidity and mortality. The development of novel anti-influenza drugs based on new targets is very significant because of high mutation and drug resistance of influenza virus. The nucleoprotein of influenza A virus identified high conservation, provides cross immune protection as a potential target of anti-influenza drugs and reports on relevant studies have been published at home and a- board. Herbal drug as a traditional Chinese medicine shows the distinct advantages in the aspect of prevention and treatment of influenza A. This paper analyzes the structure and function of influenza a virus, and reviews the advances in the research on anti influenza targets based on the nucleoprotein of the influenza A virus. PMID- 26524920 TI - [Advance in Deep Sequencing of Small RNAs for Virus Identification and Discovery]. AB - Small RNAs (sRNA) are produced abundantly in either plants or animals and function in regulating gene expression or in defense against virus infection. Deep sequencing of small RNAs is an emerging technology in virus identification and de novo assembly of virus genomes and is demonstrated to be an effective method to discover new viruses and monitor virus variation. A significant number of viruses from plants, invertebrates and human cells has been successfully identified using this technology. In this paper, we summarized the principle, operation process and latest advances of sRNA deep sequencing We also showed the feasibility of sRNA deep sequencing by bioinformatic analysis using sRNA deep sequencing dataset public available for the detection of viruses. PMID- 26524921 TI - [Advances in Correlation between Rotaivrus and Histo-blood Group Antigens]. AB - Group A rotaviruses (RVs) are major pathogens associated with acute gastroenteritis in young children and animals worldwide. VP4 is responsible for interaction with the host and viral attachment. Recent study showed that the distal portion of rotavirus (RV) VP4 spike protein (VP8*) is implicated in binding to human histo-blood group antigens (HBGAs), which is new cellular receptors on rotavirus, Published in Nature and Journal of Virology in 2012. The paper describes advances in correlation between rotaivrus and HBGAs, summarizes the main achievements has gotten, Clarify the significance of study on Rotaivrus and HBGAs. PMID- 26524922 TI - [Progress in Research on Structure, Function and Antiviral of Enterovirus A71 3C Protein]. AB - Enterovirus A71 (EV-A71) causes hand, foot, and mouth disease (HFMD) and various neurological complications, including aseptic meningitis and neurogenic pulmonary edema in young children. HFMD caused by EV-A71 have broken out several times in the Asia-Pacific region since 2007. And it has been a serious threat to public health. There is no effective vaccine or antiviral drug. The pathogenesis of EV A71 infection is unknown, and EV-A71 3C protein plays an irreplaceable role in replication and anti - innate immunity. Further research on EV-A71 3C protein is conducive to understand the pathogenesis of EV-A71 infection and antiviral drug. PMID- 26524923 TI - [Advances of Researches on Anti-phage Mechanisms of Host]. AB - Phages also known as bacteria viruses, are recognized as the most abundant and diverse microbes. This diversity is adapting to the selective pressures such as the prevalence of the phage resistance mechanisms of bacteria. Phages invade and lyse bacterial through six steps (adsorption, injection, replication, transcription translation, assemble, release). Bacteria evolve to many anti-phage mechanisms to avoid phage infection and lysis. This paper focus on a variety of anti-phage mechanisms of bacteria. PMID- 26524924 TI - Current and Future Therapies for Advanced Gastric Cancer. AB - The treatment of patients with advanced gastric cancer remains a challenging area of oncology. Extensive trials of differing chemotherapy regimens have yielded no international consensus on the optimal combination, and overall survival with chemotherapy alone remains poor. Recently an improved understanding of the molecular drivers of the disease has opened up promising new avenues of treatment through the use of biological targeted agents. The anti-HER2 monoclonal antibody trastuzumab was the first targeted agent to significantly prolong survival in the first-line treatment of a molecularly-selected subgroup of patients. More recently the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab has demonstrated a modest survival benefit in previously treated patients as both a monotherapy and in combination with chemotherapy. Immunotherapy and the use of checkpoint inhibitors are a further exciting area of development with promising preliminary results for the activity of the anti Programmed Death 1 Receptor antibody pembrolizumab and ongoing trials of a number of immune-modulating agents. Continuing research to identify novel targets and therapies aims to make further incremental gains in survival. In this review we outline the evidence base supporting current chemotherapy regimens and describe the latest advances in the development and use of molecularly targeted and immune modulating agents. PMID- 26524925 TI - Population-Based Cost-Minimization Analysis of CAPOX Versus Modified FOLFOX6 in the Adjuvant Treatment of Stage III Colon Cancer. AB - BACKGROUND: Evidence suggests that CAPOX (capecitabine and oxaliplatin) has efficacy similar to 5-fluorouracil and oxaliplatin (mFOLFOX6) in the adjuvant treatment of colon cancer. CAPOX is partly administered orally and associated with a 3-week rather than a 2-week treatment cycle. A population-based cost minimization analysis was conducted from the health care payer and societal perspectives to evaluate the potential cost savings of replacing mFOLFOX6 with CAPOX. METHODS: We applied treatment and toxicity data from phase III trials of CAPOX and FOLFOX-based regimens to the adjuvant colon cancer population in British Columbia, Canada. In this cost-minimization analysis we compared the total costs associated with chemotherapy medications, drug administration and delivery, hospital and clinic visits, treatment-related toxicities, and central venous access devices. Costs to patients in terms of lost time and travel were also considered. It was assumed that patients would receive either 8 cycles of CAPOX or 12 cycles of mFOLFOX6. RESULTS: From the payer perspective, the use of CAPOX resulted in cost savings of $5339 CAD per patient compared with the use of mFOLFOX6. From a societal perspective, CAPOX was also associated with savings of $6080 CAD per patient. The greatest cost savings with CAPOX were attributed to fewer visits for chemotherapy treatment and decreased central venous access device usage. CAPOX was also associated with reduced loss of time and decreased travel for patients because of the requirement of fewer clinic visits. CONCLUSIONS: Replacement of mFOLFOX6 with CAPOX in the adjuvant treatment of colon cancer might be associated with potential cost savings from the payer and societal perspectives. PMID- 26524928 TI - Mutant p53 and sIL-1Ra. PMID- 26524929 TI - Exposure-response modeling of non-cancer effects in humans exposed to Libby Amphibole Asbestos; update. AB - The United States Environmental Protection Agency (EPA) developed a quantitative exposure-response model for the non-cancer effects of Libby Amphibole Asbestos (LAA) (EPA, 2014). The model is based on the prevalence of localized pleural thickening (LPT) in workers exposed to LAA at a workplace in Marysville, Ohio (Lockey et al., 1984; Rohs et al., 2008). Recently, Lockey et al. (2015a) published a follow-up study of surviving Marysville workers. The data from this study increases the number of cases of LPT and extends the observation period for a number of workers, thereby providing a strengthened data set to define and constrain the optimal exposure-response model for non-cancer effects from inhalation exposure to LAA. The new data were combined with the previous data to update the exposure-response modeling for LPT. The results indicate that a bivariate model using cumulative exposure and time since first exposure is appropriate, and the benchmark concentration is similar to the findings previously reported by EPA (2014). In addition, the data were also used to develop initial exposure-response models for diffuse pleural thickening (DPT) and small interstitial opacities (SIO). PMID- 26524930 TI - High-Efficiency Genome Editing in Arabidopsis Using YAO Promoter-Driven CRISPR/Cas9 System. PMID- 26524931 TI - Multidisciplinary Team Management of Cerebral Metastases: Recent Trends and Future Implications. PMID- 26524932 TI - Effect of oxytocin during labor on neonatal acidemia. AB - OBJECTIVE: To assess the factors affecting neonatal acidemia, including occurrence of tachysystole/hypertonus in fetuses exposed to oxytocin during labour and with continuously-monitored fetal heart rate (FHR) tracings. METHODS: Prospective observational study of all women with term pregnancies who received oxytocin for induction/augmentation of labour. FHR tracings were prospectively classified using ACOG classification. Independent predictors of neonatal acidemia were identified using multivariate linear regression with p < 0.05 considered significant. RESULTS: We included 430 women, 236 of whom (54.9%) had spontaneous onset of labour. The duration of active phase of the second stage of labour and the presence of abnormal FHR tracing during labour were significantly associated with UA pH (p < 0.001) and BE (p < 0.001), while maximum dose of oxytocin (p < 0.17; p < 0.7) and tachysystole (p < 0.9; p < 0.8) were not. At logistic regression, the duration of active phase of the second stage of labour was independently predictive of neonatal acidemia (p < 0.009) while abnormal FHR tracing approached significance (p < 0.088). CONCLUSIONS: In women receiving oxytocin during labour, the duration of active phase of the second stage of labour correlates with neonatal acidemia, whereas maximum dose of oxytocin, duration of oxytocin administration and occurrence of tachysystole during labour do not. PMID- 26524933 TI - Epinephrine Diluted Saline-Irrigation Fluid in Arthroscopic Shoulder Surgery: A Significant Improvement of Clarity of Visual Field and Shortening of Total Operation Time. A Randomized Controlled Trial. AB - PURPOSE: To determine the influence of epinephrine saline irrigation in therapeutic shoulder arthroscopy procedures on the clarity of arthroscopic view. Three subgroups were analyzed; (1) Bankart/SLAP repairs; (2) rotator cuff repairs; and (3) subacromial procedures without rotator cuff repair. Secondary objectives were to evaluate the influence on total operating time and potential cardiovascular adverse reactions. METHODS: The design of the study was a prospective, randomized, double-blind controlled trial. A total of 101 patients were included. Pressure pump-controlled regular saline irrigation fluid was used in the control group. In the epinephrine group, epinephrine (0.33 mg/L) was added to the saline-irrigation fluid. Visual clarity was rated by a Numeric Rating Scale. Total operation time, total use of irrigation fluid, increases in pump pressure, heart rate, blood pressure, and electrocautery use were registered. RESULTS: Visual clarity (P = .002) was significantly better and total operating time (P = .008) significantly shorter in the epinephrine group. Total irrigation fluid used was significantly lower in the epinephrine group (P = .001). The greatest effect on visual clarity and shortening of operation time up to 15 minutes was seen in Bankart and SLAP repairs. No significant effect of the addition of epinephrine on heart rate and blood pressure was observed. CONCLUSIONS: The addition of epinephrine (0.33 mg/L) to irrigation fluid significantly improves visual clarity in most common types of therapeutic shoulder arthroscopy. A significant reduction in total operating time and use of irrigation fluid was observed. The greatest effect on visual clarity and shortening of operation time was seen in Bankart and SLAP group. Therefore, one of our initial hypotheses that the greatest effect would be observed in subacromial and rotator cuff repair procedures was not supported by the data presented. No cardiovascular adverse reactions were seen. LEVEL OF EVIDENCE: Level 1, Randomized controlled trial. PMID- 26524934 TI - Return to Sport After Articular Cartilage Repair in Athletes' Knees: A Systematic Review. AB - PURPOSE: To perform a systematic review of cartilage repair in athletes' knees to (1) determine which (if any) of the most commonly implemented surgical techniques help athletes return to competition, (2) identify which patient- or defect specific characteristics significantly affect return to sport, and (3) evaluate the methodologic quality of available literature. METHODS: A systematic review of multiple databases was performed. Return to preinjury level of sport was defined as the ability to play in the same or greater level (i.e., league or division) of competition after surgery. Study methodologic quality for all studies analyzed in this review was evaluated with the Coleman Methodology Score. RESULTS: Systematic review of 1,278 abstracts identified 20 level I-IV studies for inclusion but only 1 randomized controlled trial. Twenty studies (1,117 subjects) were included. Subjects (n = 970) underwent 1 of 4 surgeries (microfracture [n = 529], autologous chondrocyte implantation [ACI, n = 259], osteochondral autograft [n = 139], or osteochondral allograft [n = 43]), and 147 were control patients. The rate of return to sports was greatest after osteochondral autograft transplantation (89%) followed by osteochondral allograft, ACI, and microfracture (88%, 84%, and 75%, respectively). Osteochondral autograft transplantation and ACI had statistically significantly greater rates of return to sports compared with microfracture (P < .001, P < .01; Fisher exact test). CONCLUSIONS: Athletes may return to sports participation after microfracture, ACI, osteochondral autograft, or osteochondral allograft, but microfracture patients were least likely to return to sports. The athletes who had a better prognosis after surgery were younger, had a shorter preoperative duration of symptoms, underwent no previous surgical interventions, participated in a more rigorous rehabilitation protocol, and had smaller cartilage defects. LEVEL OF EVIDENCE: Level IV, systematic review of Level I-IV studies. PMID- 26524935 TI - Correlation of Synovial Fluid Biomarkers With Cartilage Pathology and Associated Outcomes in Knee Arthroscopy. AB - PURPOSE: To correlate the intraoperative concentrations of 20 synovial fluid biomarkers with preoperative symptoms, intraoperative findings, and postoperative outcomes in patients undergoing knee arthroscopy, with comparisons made to samples obtained from asymptomatic knees. METHODS: Synovial fluid samples were obtained from 81 patients undergoing knee arthroscopy meeting the inclusion criteria, which included 70 samples from operative knees and 32 samples from contralateral knees. Preoperatively, baseline data obtained from clinical questionnaires including a visual analog scale (VAS) score, the Lysholm score, and the Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form were recorded. Synovial fluid was collected from both the operative knee and asymptomatic contralateral knee. Synovial fluid was stored with a protease inhibitor at -80 degrees C until analysis. Intraoperative findings, procedures performed, and International Cartilage Repair Society (ICRS) cartilage status scores in all operative knees were documented. The concentrations of the following 20 biomarkers were measured using a multiplex magnetic bead immunoassay: matrix metalloproteinase (MMP) 3; MMP-13; tissue inhibitor of metalloproteinase (TIMP) 1; TIMP-2; TIMP-3; TIMP-4; fibroblast growth factor 2; eotaxin; interferon gamma; interleukin (IL) 10; platelet-derived growth factor BB; IL-1 receptor antagonist; IL-1beta; IL-6; monocyte chemotactic protein 1 (MCP 1); macrophage inflammatory protein 1alpha; macrophage inflammatory protein 1beta; RANTES (regulated upon activation, normal T cell expressed and secreted); tumor necrosis factor alpha; and vascular endothelial growth factor. Clinical outcome scores were obtained in 83% of patients at a mean of 17 months' follow-up postoperatively. Analysis of variance and Pearson correlation analysis were performed to determine statistical significance between preoperative data, intraoperative findings, postoperative outcomes, and synovial fluid biomarker concentrations compared with asymptomatic contralateral knees. RESULTS: Analysis was performed on 70 operative and 32 contralateral samples. There were strong positive correlations between ICRS score and age, symptom duration, VAS score, and Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form. A strong positive correlation was found between MCP-1 and IL-6 concentrations, intraoperative ICRS score, and continued pain at the time of final follow-up. MCP 1 and IL-6 were the strongest predictors of severe cartilage lesions, whereas IL 1 receptor antagonist was inversely related. MMP-3 levels were consistently elevated in all operative samples and directly correlated to increased preoperative VAS scores. RANTES, vascular endothelial growth factor, and platelet derived growth factor BB were the strongest predictors of postoperative improvement at final follow-up regardless of injury and cartilage status. CONCLUSIONS: Synovial fluid biomarkers have the capacity to reflect the intra articular environment before surgery and potentially predict postoperative clinical outcomes. Recognition of key molecular players may yield future therapeutic targets, and large clinical trials exploring these discoveries are anticipated. LEVEL OF EVIDENCE: Level III, therapeutic case-control study. PMID- 26524936 TI - Suture Anchor Biomechanics After Rotator Cuff Footprint Decortication. AB - PURPOSE: To identify the biomechanical consequences of violating the cortical shelf when preparing the greater tuberosity for suture anchor repair. METHODS: Demographic information and bone mineral density were obtained for 20 fresh frozen human humeri (10 matched pairs). Suture anchors were placed at a predetermined location in decorticated and non-decorticated settings after randomization. Anchors were tested under cyclic loads followed by load-to-failure testing. The number of cycles, failure mode, stiffness, and final pullout strength were recorded. RESULTS: Nineteen specimens met the inclusion criteria for final testing. A significant difference in mean ultimate load to failure was seen between the non-decorticated specimens (244.04 +/- 89.06 N/mm) and the decorticated humeri (62.84 +/- 38.04 N/mm, P < .0001). Regression analysis showed positive correlations with female gender and decreased bone mineral density (P = .008 and P = .0005, respectively). CONCLUSIONS: Decortication of the rotator cuff footprint significantly decreases the pullout strength of the suture anchor. Gender and bone mineral density also play a significant role in bone-anchor biomechanics and should be considered during repair. CLINICAL RELEVANCE: Caution should be exercised when preparing the rotator cuff footprint before suture anchor placement because of the significant risk of early repair failure at the bone-anchor interface. PMID- 26524937 TI - Biomechanical Effect of Thickness and Tension of Fascia Lata Graft on Glenohumeral Stability for Superior Capsule Reconstruction in Irreparable Supraspinatus Tears. AB - PURPOSE: To investigate the effects of graft length and thickness on shoulder biomechanics after superior capsule reconstruction. METHODS: Subacromial peak contact pressure and glenohumeral superior translation were measured at 0 degrees , 30 degrees , and 60 degrees of glenohumeral abduction in 8 fresh-frozen cadaveric shoulders under 5 conditions: (1) intact shoulder; (2) irreparable supraspinatus tendon tear, (3) superior capsule reconstruction with a fascia lata allograft 4-mm thick and 15 mm longer than the distance from the superior glenoid to the lateral edge of the greater tuberosity, as determined during placement at 30 degrees of glenohumeral abduction; (4) superior capsule reconstruction with a fascia lata allograft 8-mm thick and with the same 15 mm relative length determined at 10 degrees of glenohumeral abduction, and (5) superior capsule reconstruction with a fascia lata allograft 8-mm thick and with the 15-mm relative length determined at 30 degrees of glenohumeral abduction. To investigate the effect of graft thickness, we compared the data from conditions 1, 2, 3, and 5. To assess the effect of graft length, we compared conditions 1, 2, 4, and 5. RESULTS: With superior capsule reconstruction using a 4-mm graft, subacromial peak contact pressure (but not superior translation) was significantly lower than with irreparable supraspinatus tears (at 0 degrees abduction: 259% decrease; P = .0002; at 30 degrees abduction: 113% decrease; P = .01). The superior capsule reconstruction using an 8-mm graft significantly decreased both subacromial peak contact pressure (at 0 degrees abduction: 246% decrease, P = .0002; at 30 degrees abduction: 158% decrease; P = .0008; at 60 degrees abduction: 57% decrease; P = .04) and superior translation (at 0 degrees abduction: 135% decrease; P = .02; at 30 degrees abduction; 130% decrease; P = .004). Graft length with placement at 10 degrees glenohumeral abduction was 5 mm greater than that at 30 degrees abduction. The 8-mm superior capsule reconstruction performed at 10 degrees or 30 degrees of glenohumeral abduction significantly decreased subacromial peak contact pressure (placement at 10 degrees and 30 degrees : 0 degrees abduction, P = .0002 and .0002, respectively; 30 degrees abduction, P = .0004 and .0005, respectively; 60 degrees abduction, P = .04 and .04, respectively) and superior translation (placement at 10 degrees and 30 degrees ; 0 degrees abduction, P =.04 and .02, respectively; 30 degrees abduction, P = .02 and .004, respectively) compared with irreparable supraspinatus tears. CONCLUSIONS: Superior capsule reconstruction normalized the superior stability of the shoulder joint when the graft was attached at 10 degrees or 30 degrees of glenohumeral abduction. An 8 mm-thick graft of fascia lata had greater stability than did a 4-mm-thick graft. CLINICAL RELEVANCE: Grafts 8-mm thick and attached at 15 degrees to 45 degrees of shoulder abduction (equal to 10 degrees to 30 degrees of glenohumeral abduction) biomechanically restore shoulder stability during superior capsule reconstruction using fascia lata. PMID- 26524938 TI - Radiographic Comparison of Anterior Acetabular Rim Morphology Between Pincer Femoroacetabular Impingement and Control. AB - PURPOSE: To define and compare 3 new parameters (anterior rim angle [ARA], anterior wall angle [AWA], and anterior margin ratio [AMR]), in addition to the lateral center-edge angle of Wiberg and the Tonnis angle, for measuring pincer type femoroacetabular impingement (FAI) in an asymptomatic versus symptomatic FAI population. METHODS: We reviewed anteroposterior pelvis radiographs of patients verified to have no hip complaints between December 2009 and December 2011. We also reviewed anteroposterior pelvis radiographs of patients who underwent a rim trimming procedure for pincer FAI between December 2010 and December 2011. Patients aged older than 65 years or younger than 18 years were excluded. Radiographs with a Tonnis grade of 2 or greater were also excluded. For the group of patients with symptomatic hip impingement, radiographs that did not have a crossover sign were excluded. The 2 cohorts were matched for age, sex, and body mass index. Measurements included the Tonnis angle, lateral center-edge angle of Wiberg, ARA, AWA, and AMR. These measurements were compared between the groups. RESULTS: Seventy-two asymptomatic hips were measured. There were 44 female patients (61%) and 28 male patients (39%), aged 25 to 51 years, in the asymptomatic group. The mean ARA was 88.91 degrees +/- 8.06 degrees , the mean AWA was 34.89 degrees +/- 8.09 degrees , and the mean AMR was 0.49 +/- 0.15. Seventy-two symptomatic hips were measured. There were 40 female patients (56%) and 32 male patients (44%), aged 27 to 58 years, in the symptomatic group. The mean ARA was 82.98 degrees +/- 10.82 degrees , the mean AWA was 39.11 degrees +/- 9.00 degrees , and the mean AMR was 0.56 +/- 0.14. The mean difference in the ARA between asymptomatic patients and symptomatic patients was 5.92 degrees (P = .0001). The mean difference in the AWA was 4.22 degrees (P = .0019). The mean difference in the AMR was 0.07 (P = .0039). CONCLUSIONS: Our study provides information on several measurements within an asymptomatic cohort and a symptomatic cohort. Although we found statistically significant differences between the 2 populations, the clinical significance remains unknown. We recommend using this asymptomatic population as a guideline for limits on resection of the anterior acetabular rim. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 26524939 TI - Clinical Outcomes of Combined Lateral Extra-articular Tenodesis and Intra articular Anterior Cruciate Ligament Reconstruction in Addressing High-Grade Pivot-Shift Phenomenon. AB - PURPOSE: To evaluate the clinical outcomes of combined lateral extra-articular tenodesis (LET) and intra-articular anterior cruciate ligament (ACL) reconstruction (ACLR) in addressing the high-grade pivot-shift phenomenon. METHODS: The PubMed/Medline database was searched for articles reporting clinical outcomes of combined LET and intra-articular ACLR in treating ACL injuries with high-grade pivot shift. High-grade pivot shift was defined as the presence of moderate to severe rotational instability shown by a grade II or III manual pivot shift preoperatively (grade 0, normal; grade I, glide; grade II, clunk; and grade III, locking, according to International Knee Documentation Committee [IKDC] form). The postoperative manual pivot-shift grading during the clinical follow-up visit was the primary outcome variable. Moreover, the prevalence of residual pivot shift (grade I, II, or III), distribution of objective IKDC scores, and anterior knee stability were also compared between patients with and without an additional LET procedure. RESULTS: Seven studies were included. Overall, 326 patients (326 knees) with high-grade pivot shift underwent combined LET and intra articular ACLR with a mean follow-up period of 46.2 months (range, 24 to 76 months). There were 274 patients (84.1%) with grade 0, 42 (12.9%) with grade I, and 10 (3.0%) with grade II pivot shift at the final follow-up. Among the 5 comparative studies, the prevalence of residual pivot shift was significantly lower (P < .05) in patients with LET plus ACLR (13.3%, 30 of 226) than those with isolated ACLR (27.2%, 67 of 246). However, the distribution of objective IKDC scores and anterior knee stability showed no significant differences between groups. CONCLUSIONS: The combination of LET and intra-articular ACLR was effective in eliminating the high-grade pivot-shift phenomenon. For ACL injuries with high-grade pivot shift, LET plus ACLR provided a significant reduction in the prevalence of residual pivot shift but no differences in objective IKDC scores and anterior knee stability compared with isolated ACLR at short-term follow-up. LEVEL OF EVIDENCE: Level IV, systematic review of Level I, III, and IV studies. PMID- 26524940 TI - Pain intensity attenuates movement control of the lumbar spine in low back pain. AB - INTRODUCTION: Pain intensity attenuates muscular activity, proprioception, and tactile acuity, with consequent changes of joint kinematics. People suffering from low back pain (LBP) frequently show movement control impairments of the lumbar spine in sagittal plane. This cross-sectional, observational study investigated if the intensity of LBP attenuates lumbar movement control. The hypothesis was that lumbar movement control becomes more limited with increased pain intensity. METHODS: The effect of LBP intensity, measured with a numeric rating scale (NRS), on lumbar movement control was tested using three movement control tests. The lumbar range of motion (ROM), the ratio of lumbar and hip ROM as indicators of direction specific movement control, and the recurrence and determinism of repetitive lumbar movement patterns were assessed in ninety-four persons suffering from LBP of different intensity and measured with an inertial measurement unit system. Generalized linear models were fitted for each outcome. RESULTS: Lumbar ROM (+ 0.03 degrees , p = 0.24) and ratio of lumbar and hip ROM (0.01, p = 0.84) were unaffected by LBP intensity. Each one point increase on the NRS resulted in a decrease of recurrence and determinism of lumbar movement patterns (-3.11 to -0.06, p ? 0.05). DISCUSSION: Our results indicate changes in movement control in people suffering from LBP. Whether decreased recurrence and determinism of lumbar movement patterns are intensifiers of LBP intensity or a consequence thereof should be addressed in a future prospective study. PMID- 26524941 TI - Nanoprobe-Initiated Enzymatic Polymerization for Highly Sensitive Electrochemical DNA Detection. AB - Electrochemical DNA (E-DNA) sensors have been greatly developed and play an important role in early diagnosis of different diseases. To determine the extremely low abundance of DNA biomarkers in clinical samples, scientists are making unremitting efforts toward achieving highly sensitive and selective E-DNA sensors. Here, a novel E-DNA sensor was developed taking advantage of the signal amplification efficiency of nanoprobe-initiated enzymatic polymerization (NIEP). In the NIEP based E-DNA sensor, the capture probe DNA was thiolated at its 3' terminal to be immobilized onto gold electrode, and the nanoprobe was fabricated by 5'-thiol-terminated signal probe DNA conjugated gold nanoparticles (AuNPs). Both of the probes could simultaneously hybridize with the target DNA to form a "sandwich" structure followed by the terminal deoxynucleotidyl transferase (TdT) catalyzed elongation of the free 3'-terminal of DNA on the nanoprobe. During the DNA elongation, biotin labels were incorporated into the NIEP-generated long single-stranded DNA (ssDNA) tentacles, leading to specific binding of avidin modified horseradish peroxidase (Av-HRP). Since there are hundreds of DNA probes on the nanoprobe, one hybridization event would generate hundreds of long ssDNA tentacles, resulting in tens of thousands of HRP catalyzed reduction of hydrogen peroxide and sharply increasing electrochemical signals. By employing nanoprobe and TdT, it is demonstrated that the NIEP amplified E-DNA sensor has a detection limit of 10 fM and excellent differentiation ability for even single-base mismatch. PMID- 26524942 TI - Synthesis and antitumor activity evaluation of novel ursolic acid derivatives. AB - Eleven novel ursolic acid (UA) derivatives were designed and synthesized with modification at positions of C-2, C-3, and C-28 of UA. Their structures were confirmed by MS, (1)H NMR, and elemental analysis. Their in vitro cytotoxicities against various cancer cell lines (HeLa, HepG2, and BGC-823) were evaluated by MTT assay. The results indicated that all compounds could inhibit cell proliferation of HeLa, HepG2, and BGC-823 cells. Among them, compounds I3 and I4 showed more potent cytotoxicity on these three tumor cells than gefitinib (positive control), worthy to be studied further. PMID- 26524943 TI - Vascular Access: Inukshuk. PMID- 26524944 TI - Transforming Hemodialysis Vascular Access Care: One Aspect at a Time. PMID- 26524945 TI - Pre-Access Creation Evaluation--Is Vein Mapping Enough? AB - The changing demographic of the hemodialysis population in the United States is posing significant challenge for selection and creation of an optimal vascular access. An arteriovenous fistula (AVF) is by far the most reliable access provided it matures and functions successfully. System-wide changes implemented by Fistula First Breakthrough Initiative and Kidney Disease Outcomes Quality Initiative guidelines have increased the awareness and incidence of AVF in the prevalent dialysis population; however, achieving the current goal of 68% AVF rate continues to remain elusive. The present article reviews the evidence in literature in support of and against using vessel mapping alone as a strategy to improve AVF rate. The current strategy of evaluating the vessels before an access is created seems to be inadequate. A patient-centered approach for an optimal vascular access needs to be considered to improve the AVF rate. PMID- 26524946 TI - Arteriovenous Fistula Creation by Nephrologist Access Surgeons Worldwide. AB - Several years ago, we published an article in this journal entitled "Autologous Arteriovenous Fistula Creation by Nephrologists." The goal of that effort was to review outcomes published by nephrologist access surgeons from around the world. An attempt was also made to define the elements that were necessary for successful autologous fistula creation in hopes that they might be used by others in an effort to increase the number of and durability of autologous fistulas in the dialysis population. Our goal, here, is to update the previous information based on recently published literature to better understand the role that nephrologist access surgeons play in the care of our dialysis patients worldwide. PMID- 26524947 TI - New Developments in Our Understanding of Neointimal Hyperplasia. AB - The vascular access remains the lifeline for the hemodialysis patient. The most common etiology of vascular access dysfunction is venous stenosis at the vein artery anastomosis in arteriovenous fistula and at the vein-graft anastomosis in arteriovenous grafts (AVG). This stenotic lesion is typically characterized on histology as aggressive venous neointimal hyperplasia in both arteriovenous fistula and AVG. In recent years, we have advanced our knowledge and understanding of neointimal hyperplasia in vascular access and begun testing several novel therapies. This article will (1) review recent developments in our understanding of the pathophysiology of neointimal hyperplasia development in AVG and fistula failure, (2) discuss atypical factors leading to neointimal hyperplasia development, (3) highlight key novel therapies that have been evaluated in clinical trials, and (4) discuss future opportunities and challenges to improve our understanding of vascular access dysfunction and translate this knowledge into novel and innovative therapies. PMID- 26524948 TI - Accessory Vein Obliteration for Early Fistula Failure: A Myth or Reality? AB - Early fistula failure (EFF) is a significant clinical problem causing lower rates of arteriovenous fistulae (AVFs) use in patients with ESRD on hemodialysis. The 2 main factors amenable to treatment and widely accepted to cause EFF are stenosis anywhere in the AVF circuit and/or presence of accessory vein (av). The role of stenotic lesions in causing EFF and their treatment options are relatively better defined with clear guidelines. On the other hand, assessing the significance of an av in causing EFF and the indications for its treatment seem to lack scientific recommendations based on robust clinical data. In this article, we review the pathophysiology of EFF as pertains to the presence of av's. Current recommendations for obliteration of av, the available techniques and the evidence to support current clinical practice are discussed. The possible cons of av obliteration are highlighted, while newer concepts and the need for future clinical trials are addressed. PMID- 26524949 TI - Vascular Access Monitoring and Surveillance: An Update. AB - Vascular access in dialysis patients remains both a critical link to survival and a significant source of morbidity. Currently, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) vascular access guidelines recommend routine vascular access monitoring and encourage dedicated surveillance techniques to be used for early detection of access stenosis and prevention of thrombosis. There is a paucity of clear evidence supporting 1 surveillance technique over another. The purpose of this review is to describe the benefits and limitations of various surveillance techniques commonly used in the care of dialysis patients. Further studies in this area will be useful to determine the most appropriate combination of aggressive clinical monitoring and additional surveillance data to strike a balance between graft thrombosis and unnecessary vascular interventions. PMID- 26524950 TI - The Role of Endovascular Stents in Dialysis Access Maintenance. AB - Vascular stenosis is most often the culprit behind hemodialysis vascular access dysfunction, and although percutaneous transluminal angioplasty remains the gold standard treatment for vascular stenosis, over the past decade the use of stents as a treatment option has been on the rise. Aside from the 2 Food and Drug Administration-approved stent grafts for the treatment of venous graft anastomosis stenosis, use of all other stents in vascular access dysfunction is off-label. Kidney Disease Outcomes Quality Initiative recommends limiting stent use to specific conditions, such as elastic lesions and recurrent stenosis; otherwise, additional adapted indications are in procedure-related complications, such as grade 2 and 3 hematomas. Published reports have shown the potential use of stents in a variety of conditions leading to vascular access dysfunction, such as venous graft anastomosis stenosis, cephalic arch stenosis, central venous stenosis, dialysis access aneurysmal elimination, cardiac implantable electronic device-induced stenosis, and thrombosed arteriovenous grafts. Although further research is needed for many of these conditions, evidence for recommendations has been clear in some; for instance, we know now that stents should be avoided along cannulation sites and should not be used in eliminating dialysis access aneurysms. In this review article, we evaluate the available evidence for the use of stents in each of the aforementioned conditions leading to hemodialysis vascular access dysfunctions. PMID- 26524951 TI - Systemic Effects of Hemodialysis Access. AB - Patients with advanced chronic kidney disease are at a high risk of cardiovascular events. Patients with end-stage renal disease have a particularly high morbidity and mortality, in part attributed to the complications and dysfunction related to vascular access in this population. Creation of an arteriovenous access for HD is considered standard of care for most patients and has distinct advantages including less likelihood of infections, less need for intervention, and positive impact on survival as compared with usage of a catheter. However, creation of an arteriovenous shunt incites a series of events that significantly impacts cardiovascular and neurohormonal health in both positive and negative ways. This article will review the short- and long-term effects of dialysis access on cardiovascular, neurohormonal, and pulmonary systems as well as a brief review of their effect on survival on HD. Presence of other comorbidities in a patient with dialysis access can amplify these effects, and these considerations are of paramount importance in individualizing the approach to not only the choice of vascular access but also the modality of kidney replacement therapy. PMID- 26524952 TI - Vascular Access Creation and Care--Perspective From India. AB - India has one of the fastest growing economies in the world and is home to nearly one sixth of world's population. Chronic diseases such as diabetes mellitus and hypertension are common. Kidney disease is a known complication of these chronic diseases and is on the rise. Improving affordability with advanced care delivery has led to the increasing use of maintenance hemodialysis. Along with this hemodialysis comes the inevitable need for vascular access. Interventional nephrology in India is a fast-evolving discipline and promises to be a critical component of hemodialysis care in the future. This review provides a background on the current state of the CKD burden in India and the various vascular access options in use currently. In addition, we describe the experience of 2 centers in western and southern India in managing vascular access needs in hopes that they will serve as a model of the proliferation of vascular access care throughout India and in other developing countries. PMID- 26524953 TI - Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer. AB - The presence of IL-17-positive cells is observed in a variety of inflammatory associated cancers and IL-17 has been found to be involved in angiogenesis. However, it remains unclear how IL-17 might contribute to tumor angiogenesis. In our study, IL-17 enhanced the formation of vessel-like tubes in HUVECs both directly (when HUVECs were incubated with IL-17) and indirectly (when HUVECs were incubated in conditioned cell media (CCM) from IL-17-treated cancer cells). Our results from experiments using siRNA-mediated knockdowns of STAT3 and GIV suggest that the effects of IL-17 were mediated by activating STAT3/GIV signaling in NSCLC cells and subsequently up-regulating its downstream target VEGF. Consistent with these findings, immunostaining experiments on human NSCLC tissues indicated that IL-17 and GIV expression were significantly and positively associated with increased tumor vascularity. The clinical significance of IL-17 was authenticated by our finding that the combination of intratumoral IL-17 + cells and GIV expression served as a better prognosticator for survival than either marker alone. Therefore, our finding highlights a novel aspect of STAT3/GIV pathway in the IL-17 promotes tumor angiogenesis of NSCLC. PMID- 26524954 TI - Association analysis of APOA5 rs662799 and rs3135506 polymorphisms with obesity in Moroccan patients. AB - The aim of the present study is to explore the association between the APOA5 polymorphisms and haplotypes with obesity in Moroccan patients. The study was performed in 459 subjects, Obese (n=164) and non-obese (n=295). All subjects were genotyped for the APOA5 -1131T>C (rs662799) and c.56C>G (rs3135506) polymorphisms. The contribution of APOA5 polymorphisms and haplotypes in the increased risk of obesity were explored using logistic regression analyses. The 1131T>C and c.56C>G polymorphisms were significantly associated with obesity. Both polymorphisms were strongly associated with increased BMI. Analysis of constructed haplotypes showed a significant association between CG haplotype and susceptibility to obesity (OR [95%CI]=3.09 [1.93-4.97]; P<0.001). These results support a potential role for APOA5 common variants and related haplotypes as risk factors for obesity. PMID- 26524955 TI - [Diagnostic performance of graphical anomalies in the detection of large platelets and platelet clumps]. AB - Thrombocytopenia is a current situation for making a blood smear in routine practice in a medical analysis laboratory. Recent automated hematology analyzers enumerate platelets and generate histograms and specific flags. Operators must be aware of the characteristics of their analyzer in order to avoid spurious results in the case where microscopy review is not possible. OBJECTIVE: We evaluated the diagnostic performance of various graphical anomalies in the detection of large platelets and platelet clumps. PATIENTS AND METHODS: Three hundred cases of thrombocytopenia were included in the study on the basis of a platelet count less than 150 * 10(9)/L. This evaluation is expressed by the results of the sensitivity, specificity, positive predictive value and negative predictive value compared to the microscopic review of blood smear. RESULTS: Graphical performances are variable according to microscopic review of blood smears. Indeed, a not fitted curve is the most sensitive change on platelet histogram to the presence of large platelet. A high specificity to the presence of platelet clumps is announced when the platelet curve fails to return to the baseline. Moreover, characteristic findings on the DIFF scattergram are very specific to the presence of platelet clumps. CONCLUSION: A normal platelet histogram can validate with great confidence thrombocytopenia in cases where a blood smear cannot be read immediately. PMID- 26524956 TI - Characteristics of nutrient intakes, basal physical fitness and serum markers in elderly women with osteopenia. AB - PURPOSE: This study investigated the correlations among BMD, nutrient intake, basal physical fitness and serum markers in elderly women with osteopenia. METHODS: Bone Mineral Density (BMD) was measured in 54 elderly women (60-77yrs) by using dual energy X-ray absorptiometry (DEXA). The subjects were divided into an osteopenia group (OG; n = 29) and a normal group (NG; n = 25). A physical fitness test was conducted to determine muscle strength, muscle endurance, flexibility, agility, and balance. The dietary nutrient intake for one day was analyzed. The serum Ca, Pi and Mg concentration was also analyzed. RESULTS: There was significant correlation between All subject's weight and their total-BMD as well as the T-score (p < .01). There was also significant correlation between the fat free mass and Total-BMD (p < .01). There was significant positive correlation between energy intake and dietary carbohydrate with Total-BMD and T-score in the OG (p < .05). The Serum Pi of the OG was significantly lower than that of the NG (p < .05), and there was significant correlation with the BMD in most regions as well as with the Total-BMD and T-score (p < .05, p < .01). CONCLUSION: These results suggested that the fat free mass in elderly women plays an important role in maintaining their BMD and that sufficient caloric intake would be likely to improve BMD in elderly women with osteopenia. In addition, the results suggested the possibility of a decrease in bone mass by hypophosphatemia in elderly women. PMID- 26524957 TI - Robust levitation control for maglev systems with guaranteed bounded airgap. AB - The robust control design problem for the levitation control of a nonlinear uncertain maglev system is considered. The uncertainty is (possibly) fast time varying. The system has magnitude limitation on the airgap between the suspended chassis and the guideway in order to prevent undesirable contact. Furthermore, the (global) matching condition is not satisfied. After a three-step state transformation, a robust control scheme for the maglev vehicle is proposed, which is able to guarantee the uniform boundedness and uniform ultimate boundedness of the system, regardless of the uncertainty. The magnitude limitation of the airgap is guaranteed, regardless of the uncertainty. PMID- 26524958 TI - Adaptive fuzzy predictive sliding control of uncertain nonlinear systems with bound-known input delay. AB - In this paper, a new Adaptive Fuzzy Predictive Sliding Mode Control (AFP-SMC) is presented for nonlinear systems with uncertain dynamics and unknown input delay. The control unit consists of a fuzzy inference system to approximate the ideal linearization control, together with a switching strategy to compensate for the estimation errors. Also, an adaptive fuzzy predictor is used to estimate the future values of the system states to compensate for the time delay. The adaptation laws are used to tune the controller and predictor parameters, which guarantee the stability based on a Lyapunov-Krasovskii functional. To evaluate the method effectiveness, the simulation and experiment on an overhead crane system are presented. According to the obtained results, AFP-SMC can effectively control the uncertain nonlinear systems, subject to input delays of known bound. PMID- 26524959 TI - Baseline cerebral oximetry values depend on non-modifiable patient characteristics. AB - OBJECTIVE: The aim of the present study was to evaluate baseline regional cerebral oxygen saturation (rSO2) values and identify factors influencing preoperative rSO2 in elective minor surgery. STUDY DESIGN: Observational analysis post-hoc. PATIENTS AND METHODS: Observational post-hoc analysis of data for the patient sample (n=50) of a previously conducted clinical trial in patients undergoing tumourectomy for breast cancer or inguinal hernia repair. Exclusion criteria included pre-existing cerebrovascular diseases, anaemia, baseline pulse oximetry <97% and low quality rSO2 sensor signals. Demographic data, comorbidities, and ASA physical status as well as height and weight were collected prospectively from all patients. Baseline rSO2 values were recorded while the patient breathed room air, using the INVOS 5100C monitorTM (Covidien, Dublin, Ireland). RESULTS: Thirty-seven women (72%) and 13 men (28%) 48 +/- 13 years of age were enrolled in this study. Baseline rSO2 was 62.01 +/- 10.38%. Baseline rSO2 was significantly different between men (67.6 +/- 11.2%) and women (60 +/- 9.4%), (P=0.023). There were also differences between baseline rSO2 and ASA physical status (ASA I: 67.6 +/- 10.7%, ASA II: 61.6 +/- 8.4%, ASA III: 55.8 +/- 13.9%, P=0.045). Baseline rSO2 had a positive correlation with body weight (r=0.347, P=0.014) and height (r=0.345, P=0.014). We also found significant differences in baseline rSO2 among patients with and without chronic renal failure (P=0.005). No differences were found in any other studied variables. CONCLUSIONS: Non-modifiable patient characteristics (ASA physical status, sex, chronic renal failure, body weight and height) influence baseline rSO2. PMID- 26524960 TI - Histopathological Examination may be Useful for Assessment of Fibrosis and Lipomatosis of Pancreas Allograft Prior to Solid Organ Transplantation. AB - BACKGROUND: The results of pancreas transplantation depend in a large degree on appropriate pancreas allograft donor selection. Several risk factors of early surgical complications or pancreas allograft loss following transplantation have been identified, but the final decision on pancreas harvesting for transplantation belongs to the surgeon. In the present study we aimed to assess whether histopathological examination may be utilized for detection of fibrosis and lipomatosis in tissue from a potential pancreas allograft. Additionally, we aimed to test whether presence of pancreatic fibrosis and lipomatosis may be explained solely by donor age and/or body mass index (BMI). MATERIAL AND METHODS: Pancreata retrieved from 50 deceased organ donors referred to our institution and not transplanted between 2010 and 2013 were used for the present study. Tissue samples were excised from pancreata, fixed in formalin, and embedded in paraffin. Presence and intensity of pancreatic fibrosis and lipomatosis were assessed semi quantitatively. RESULTS: Fibrosis was found in the majority of study samples (72%), but it was usually mild or moderate. Lipomatosis was present in 34% of the study cases. Presence of fibrosis was more frequent in older donors, but was still not rare in donors under 40 years old. Presence of lipomatosis did not seem to be significantly related to donor age. Neither pancreatic fibrosis nor lipomatosis was related to donor BMI. CONCLUSIONS: There is no clear relationship between histological parenchymal changes in potential pancreas allograft and donor age and BMI. Histopathological assessment of pancreatic fibrosis and/or lipomatosis can potentially facilitate decision making on pancreas allograft acceptance for solid organ transplantation. PMID- 26524961 TI - Characterization of the HBB: c.*233G > C Variant: No Evidence of a beta Thalassemic Phenotype. AB - beta-Thalassemia (beta-thal) results from homozygous or compound heterozygous inheritance of beta-globin alleles that yield decreased or absent synthesis of the beta chain. Disease is frequently severe, requiring lifelong transfusion therapy. Heterozygosity for a beta-thal allele results in an asymptomatic carrier state with mild but characteristic hematological findings. More than 200 beta globin alleles have been demonstrated to produce beta-thal. For populations with a high prevalence of beta-thal, screening for carrier status, genetic counseling and prenatal diagnosis are important components of efforts to both reduce disease incidence and provide early diagnosis and treatment. It is therefore important to define and characterize potential beta-thal alleles. We sought to further characterize the previously reported beta-thal allele, HBB: c.*233G > C. This variant is provisionally included in the HbVar database based on a study of Palestinians in the Gaza Strip with beta-thal disease or carrier status (known or suspected) where 4.2% of subjects were found to have HBB: c.*233G > C. In our patient population, we detected the HBB: c.*233G > C variant in 17.3% of individuals (17 heterozygotes, one homozygote) undergoing beta hemoglobin (Hb) gene sequencing at our laboratory over a 25-month period. Hematological parameters were analyzed to determine if these individuals demonstrated findings consistent with inheritance of a beta-thal allele. Individuals with the HBB: c.*233G > C variant did not demonstrate any abnormalities in hematological parameters characteristic of beta-thal carrier state (17 heterozygotes) or clinical evidence of disease (homozygote). Our data demonstrate no evidence for pathogenicity of the HBB: c.*233G > C variant but rather demonstrate that this variant is a common benign polymorphism. PMID- 26524962 TI - Molecular and functional characterization of a novel sodium channel TipE-like auxiliary subunit from the American cockroach Periplaneta americana. AB - In Drosophila melanogaster, the functions of voltage-gated sodium (Nav) channels are modulated by TipE and its orthologs. Here, we describe a novel TipE homolog of the American cockroach, Periplaneta americana, called PaTipE. Like DmTipE, PaTipE mRNAs are ubiquitously expressed. Surprisingly, PaTipE mRNA was undetectable in neurosecretory cells identified as dorsal unpaired median neurons. Phylogenetic analysis placed this new sequence in TipE clade, indicating an independent evolution from a common ancestor. Contrary to previous reports, our data indicate that the auxiliary subunits of insect Nav channels are very distant from the mammalian BKCa auxiliary subunits. To decipher the functional roles of PaTipE, we characterized the gating properties of DmNav1-1 channels co expressed with DmTipE or PaTipE, in Xenopus oocytes. Compared to DmTipE, PaTipE increased Na(+) currents by a 4.2-fold. The voltage-dependence of steady-state fast inactivation of DmNav1-1/PaTipE channels was shifted by 5.8 mV to more negative potentials than that of DmNav1-1/DmTipE channels. DmNav1-1/PaTipE channels recovered 3.2-fold slower from the fast-inactivated state than DmNav1 1/DmTipE channels. In conclusion, this study supports that the insect Nav auxiliary subunits share functional features with their mammalian counterparts, although structurally and phylogenetically distant. PMID- 26524963 TI - Gustatory receptors required for sensing umbelliferone in Drosophila melanogaster. AB - Studies of taste modality using the animal model Drosophila melanogaster have elucidated a number of uncharacterized mechanisms of sensory responses. Gustatory receptors expressed in taste organs are not only responsible for the acceptance and rejection of different foods, but are also involved in the process of selecting an oviposition site. This contact-chemosensation is essential for animals to discriminate between nutritious and contaminated foods. In this study, we characterized the function of gustatory receptors that play a dual role in feeding and oviposition using the plant metabolite umbelliferone. The combined electrophysiological and behavioral evidence demonstrated that two broadly tuned gustatory receptors, GR33a and GR66a, and one narrowly tuned gustatory receptor, GR93a, are all required to generate a functional umbelliferone receptor. PMID- 26524964 TI - Adaptation to Resistance Training Is Associated with Higher Phagocytic (but Not Oxidative) Activity in Neutrophils of Older Women. AB - Failure in antimicrobial activity contributes to high morbidity and mortality in the geriatric population. Little is known about the potential effect of resistance training (RT) on the functional properties of the innate immunity. This study aimed to investigate the influence of long-term RT on the endocytic and oxidative activities of neutrophils and monocytes in healthy older women. Our results indicate that the phagocytosis index (PhI) of neutrophils (but not of monocytes) in the RT-adapted group was significantly higher (P < 0.001; effect size, (d) = 0.90, 95% CI: [0.75-1.04]) compared to that in sedentary subjects. In contrast, the oxidative activity of either neutrophils or monocytes was not significantly influenced by RT. Also, total energy and carbohydrate intake as well as serum IL6 levels had a significant influence on the phagocytic activity of neutrophils (P = 0.04), being considered in the model. Multivariate regression identified the physical condition of the subject (beta = 0.425; P = 0.01) as a significant predictor of PhI. In conclusion, circulating neutrophils of older women adapted to a long-term RT program expressed higher phagocytic activity. PMID- 26524965 TI - Capillary blood sampling: national recommendations on behalf of the Croatian Society of Medical Biochemistry and Laboratory Medicine. AB - Capillary blood sampling is a medical procedure aimed at assisting in patient diagnosis, management and treatment, and is increasingly used worldwide, in part because of the increasing availability of point-of-care testing. It is also frequently used to obtain small blood volumes for laboratory testing because it minimizes pain. The capillary blood sampling procedure can influence the quality of the sample as well as the accuracy of test results, highlighting the need for immediate, widespread standardization. A recent nationwide survey of policies and practices related to capillary blood sampling in medical laboratories in Croatia has shown that capillary sampling procedures are not standardized and that only a small proportion of Croatian laboratories comply with guidelines from the Clinical Laboratory Standards Institute (CLSI) or the World Health Organization (WHO). The aim of this document is to provide recommendations for capillary blood sampling. This document has been produced by the Working Group for Capillary Blood Sampling within the Croatian Society of Medical Biochemistry and Laboratory Medicine. Our recommendations are based on existing available standards and recommendations (WHO Best Practices in Phlebotomy, CLSI GP42-A6 and CLSI C46-A2), which have been modified based on local logistical, cultural, legal and regulatory requirements. We hope that these recommendations will be a useful contribution to the standardization of capillary blood sampling in Croatia. PMID- 26524968 TI - Isosakuranetin, a 4'-O-methylated flavonoid, stimulates melanogenesis in B16BL6 murine melanoma cells. AB - AIMS: The beneficial effects of 4'-O-methylated flavonoids on induction of melanogenesis are well established. Here, we report the effect of isosakuranetin (Iso) on melanogenesis in B16BL6 melanoma cells and an analysis of the signaling pathways involved in this activity. METHODS: B16BL6 melanoma cells were treated with several concentrations of Iso and melanin content was measured. Activation and expression of factors involved in melanogenesis were assessed via western blotting. KEY FINDINGS: Iso (15 and 30MUmol/L) strongly stimulated melanogenesis in a dose-dependent manner. Iso increased tyrosinase activity and up-regulated tyrosinase (Tyr), tyrosinase related protein 1 (TRP1), and tyrosinase related protein 2 (TRP2) in a time-dependent manner. Iso decreased B16 cell proliferation at a concentration above 45MUmol/L, and had no effect on cell viability as revealed by MTT and trypan blue assays. Iso up-regulated expression of microphthalmia transcription factor (MITF), with a maximum effect after 12h. H89, a specific inhibitor of PKA, showed that MITF up-regulation is mediated through PKA/CREB activation. Furthermore, Iso decreased phosphorylation of MITF at Ser73 after 24h and 48h of exposure, activating MITF and leading to up-regulation of Tyr, TRP1, and TRP2. Iso inhibited phosphorylation and activation of ERK1/2 after 12h, while no significant effects on p38 and JNK phosphorylation were observed. Iso inhibited AKT phosphorylation and led to activation of GSK3beta. SIGNIFICANCE: Iso stimulates melanogenesis in B16 melanoma cells via up regulation of MITF. Furthermore, Iso-induced inhibition of ERK1/2 and PI3K/AKT signaling pathways activate MITF and subsequent expression of Tyr, TRP1, and TRP2. PMID- 26524966 TI - The role of host genetic factors in respiratory tract infectious diseases: systematic review, meta-analyses and field synopsis. AB - Host genetic factors have frequently been implicated in respiratory infectious diseases, often with inconsistent results in replication studies. We identified 386 studies from the total of 24,823 studies identified in a systematic search of four bibliographic databases. We performed meta-analyses of studies on tuberculosis, influenza, respiratory syncytial virus, SARS-Coronavirus and pneumonia. One single-nucleotide polymorphism from IL4 gene was significant for pooled respiratory infections (rs2070874; 1.66 [1.29-2.14]). We also detected an association of TLR2 gene with tuberculosis (rs5743708; 3.19 [2.03-5.02]). Subset analyses identified CCL2 as an additional risk factor for tuberculosis (rs1024611; OR = 0.79 [0.72-0.88]). The IL4-TLR2-CCL2 axis could be a highly interesting target for translation towards clinical use. However, this conclusion is based on low credibility of evidence - almost 95% of all identified studies had strong risk of bias or confounding. Future studies must build upon larger scale collaborations, but also strictly adhere to the highest evidence-based principles in study design, in order to reduce research waste and provide clinically translatable evidence. PMID- 26524967 TI - Genetic variants of SLC17A1 are associated with cholesterol homeostasis and hyperhomocysteinaemia in Japanese men. AB - Hyperuricaemia is an undisputed and highly predictive biomarker for cardiovascular risk. SLC17A1, expressed in the liver and kidneys, harbours potent candidate single nucleotide polymorphisms that decrease uric acid levels. Therefore, we examined SLC17A1 polymorphisms (rs1165196, rs1179086, and rs3757131), which might suppress cardiovascular risk factors and that are involved in liver functioning, via a large-scale pooled analysis of the Japanese general population in a cross-sectional study. Using data from the Japan Multi Institutional Collaborative Cohort Study, we identified 1842 participants of both sexes, 35-69-years-old, having the requisite data, and analysed their SLC17A1 genotypes. In men, logistic regression analyses revealed that minor alleles in SLC17A1 polymorphisms (rs1165196 and rs3757131) were associated with a low-/high density lipoprotein cholesterol ratio >2.0 (rs1165196: odds ratio [OR], 0.703; 95% confidence interval [CI], 0.536-0.922; rs3757131: OR, 0.658; 95% CI, 0.500 0.866), and with homocysteine levels of >10.0 nmol/mL (rs1165196: OR, 0.544; 95% CI, 0.374-0.792; rs3757131: OR, 0.509; 95% CI, 0.347-0.746). Therefore, these polymorphisms had dominant negative effects on cholesterol homeostasis and hyperhomocysteinaemia, in men, independent of alcohol consumption, physical activity, or daily energy and nutrition intake. Thus, genetic variants of SLC17A1 are potential biomarkers for altered cholesterol homeostasis and hyperhomocysteinaemia in Japanese men. PMID- 26524969 TI - Molecular aspects of metal oxide nanoparticle (MO-NPs) mediated pharmacological effects. AB - Metal oxide nanoparticles (MO-NPs) are the multidisciplinary nano-scaled molecules which are being used in the diagnosis and treatment of the challenging diseases including cancer. Evidence suggest that antimicrobial formulations in the form of MO-NPs can be possibly used as effective antimicrobial agents. In addition, MO-NPs are known to target various cellular signaling pathways associated with apoptosis, angiogenesis, metastasis and inflammation of cancer. In combination with other chemotherapeutic/anticancer agents, MO-NPs not only increase their bioavailability and efficacy but also lower down the requirement of active dosages. To date, to our knowledge there is no single comprehensive report on cellular and molecular interactions of MO-NPs which have been well elaborated in this review. Also we highlight various action mechanisms through which MO-NPs act as antimicrobial, anticancer, antioxidant and anti-inflammatory agents. PMID- 26524970 TI - Complete Versus Culprit-Only Revascularization for Patients With Multi-Vessel Disease Undergoing Primary Percutaneous Coronary Intervention: An Updated Meta Analysis of Randomized Trials. AB - OBJECTIVES: To perform an updated meta-analysis to determine whether complete revascularization of significant coronary lesions at the time of primary percutaneous coronary intervention (PCI) would be associated with better outcomes compared with culprit-only revascularization. BACKGROUND: Individual trials have demonstrated conflicting evidence regarding the optimum revascularization strategy at the time of primary PCI. METHODS: Clinical trials that randomized ST elevation myocardial infarction (STEMI) patients with multi-vessel disease to a complete versus culprit-only revascularization strategy were included. Random effects summary risk ratios (RR) were constructed using a DerSimonian-Laird model. The primary outcome of interest was mortality or myocardial infarction (MI). RESULTS: A total of seven trials with 1,939 patients were included in the analysis. Compared with culprit-only revascularization, complete revascularization was associated with a non-significant reduction in the risk of mortality or MI (RR 0.69, 95% confidence interval (CI) 0.42-1.12, P = 0.14). Complete revascularization was associated with a reduced risk of major adverse cardiac events (MACE) (RR 0.61, 95% CI 0.45-0.81, P < 0.001), due to a significant reduction in urgent revascularization (RR 0.46, 95% CI 0.29-0.70, P < 0.001). The risk of major bleeding and contrast-induced nephropathy was similar with both approaches (RR 0.83, 95% CI 0.41-1.71, P = 0.62, and RR 0.94, 95% CI 0.42-2.12, P = 0.82). CONCLUSIONS: Complete revascularization of all significant coronary lesions at the time of primary PCI was associated with a reduction in the risk of MACE due to reduction in the risk of urgent revascularization. This approach appears to be safe, with no excess major bleeding, or contrast-induced nephropathy. (c) 2015 Wiley Periodicals, Inc. PMID- 26524971 TI - Short-term effects of scaling and root planing with or without adjunctive use of an essential-oil-based mouthwash in the treatment of periodontal inflammation in smokers. AB - OBJECTIVE: The aim of the present short-term follow-up study was to assess the effects of scaling and root planing (SRP) with or without adjunctive use of an essential-oil-based mouthwash in the treatment of periodontal inflammation in smokers. METHODS: In total, 120 individuals were divided into 2 groups. In Group 1, 60 smokers with periodontal inflammation received SRP alone; and in Group-2, 60 smokers with periodontal inflammation received adjunct essential-oil mouthwash therapy. Periodontal parameters (plaque index [PI], bleeding-on-probing [BOP], and probing pocket depth [PD] >= 4 mm) were assessed at baseline and after 90 days of treatment. RESULTS: There was no significant difference in periodontal parameters (PI, BOP, and PD >= 4 mm) among participants in Group-1 and -2. Participants in both groups showed significant reductions in PI (P < 0.01), BOP (P < 0.01), and PD >= 4 mm (P < 0.01) at follow-up compared to baseline. At 90 days of follow-up, PI (P < 0.05), BOP (P < 0.05), and PD >= 4 mm (P < 0.05) were significantly higher in Group-1 compared to Group-2. CONCLUSIONS: SRP with adjunct essential-oil mouthwash therapy is more effective in the treatment of periodontal inflammation in smokers as compared to when SRP is performed alone. PMID- 26524972 TI - Preschool children's attachment security is associated with their sharing with others. AB - The current study examined relations between preschool children's attachment pattern and their sharing behavior. To this end, 26 German children aged five years (15 girls) were first administered an Attachment Story Completion Task to assess their attachment pattern and the degree of their attachment security. Immediately thereafter, they participated in an established paradigm, a mini dictator game, that assessed their inclination to share costly as well as noncostly with a friend, a disliked other, and a stranger. Analyses showed that degree of attachment security was positively correlated with children's generosity towards a disliked other and their inclination to engage in costly sharing. Moreover, the absence of an organized attachment pattern was related to a general decrease in generosity towards all recipients. The results point to the functional role of children's attachment for the early development of sharing behavior. PMID- 26524974 TI - Extremophile microbiomes in acidic and hypersaline river sediments of Western Australia. AB - We investigated the microbial community compositions in two sediment samples from the acidic (pH ~3) and hypersaline (>4.5% NaCl) surface waters, which are widespread in Western Australia. In West Dalyup River, large amounts of NaCl, Fe(II) and sulfate are brought by the groundwater into the surface run-off. The presence of K-jarosite and schwertmannite minerals in the river sediments suggested the occurrence of microbial Fe(II) oxidation because chemical oxidation is greatly reduced at low pH. 16S rRNA gene diversity analyses revealed that sequences affiliated with an uncultured archaeal lineage named Aplasma, which has the genomic potential for Fe(II) oxidation, were dominant in both sediment samples. The acidophilic heterotrophs Acidiphilium and Acidocella were identified as the dominant bacterial groups. Acidiphilium strain AusYE3-1 obtained from the river sediment tolerated up to 6% NaCl at pH 3 under oxic conditions and cells of strain AusYE3-1 reduced the effects of high salt content by forming filamentous structure clumping as aggregates. Neither growth nor Fe(III) reduction by strain AusYE3-1 was observed in anoxic salt-containing medium. The detection of Aplasma group as potential Fe(II) oxidizers and the inhibited Fe(III)-reducing capacity of Acidiphilium contributes to our understanding of the microbial ecology of acidic hypersaline environments. PMID- 26524973 TI - Basal forebrain control of wakefulness and cortical rhythms. AB - Wakefulness, along with fast cortical rhythms and associated cognition, depend on the basal forebrain (BF). BF cholinergic cell loss in dementia and the sedative effect of anti-cholinergic drugs have long implicated these neurons as important for cognition and wakefulness. The BF also contains intermingled inhibitory GABAergic and excitatory glutamatergic cell groups whose exact neurobiological roles are unclear. Here we show that genetically targeted chemogenetic activation of BF cholinergic or glutamatergic neurons in behaving mice produced significant effects on state consolidation and/or the electroencephalogram but had no effect on total wake. Similar activation of BF GABAergic neurons produced sustained wakefulness and high-frequency cortical rhythms, whereas chemogenetic inhibition increased sleep. Our findings reveal a major contribution of BF GABAergic neurons to wakefulness and the fast cortical rhythms associated with cognition. These findings may be clinically applicable to manipulations aimed at increasing forebrain activation in dementia and the minimally conscious state. PMID- 26524975 TI - (13)C-tryptophan breath test detects increased catabolic turnover of tryptophan along the kynurenine pathway in patients with major depressive disorder. AB - Altered tryptophan-kynurenine (KYN) metabolism has been implicated in major depressive disorder (MDD). The L-[1-(13)C]tryptophan breath test ((13)C-TBT) is a noninvasive, stable-isotope tracer method in which exhaled (13)CO2 is attributable to tryptophan catabolism via the KYN pathway. We included 18 patients with MDD (DSM-IV) and 24 age- and sex-matched controls. (13)C-tryptophan (150 mg) was orally administered and the (13)CO2/(12)CO2 ratio in the breath was monitored for 180 min. The cumulative recovery rate during the 180-min test (CRR0 180; %), area under the Delta(13)CO2-time curve (AUC; %*min), and the maximal Delta(13)CO2 (Cmax; %) were significantly higher in patients with MDD than in the controls (p = 0.004, p = 0.008, and p = 0.002, respectively). Plasma tryptophan concentrations correlated negatively with Cmax in both the patients and controls (p = 0.020 and p = 0.034, respectively). Our results suggest that the (13)C-TBT could be a novel biomarker for detecting a subgroup of MDD with increased tryptophan-KYN metabolism. PMID- 26524977 TI - Multi-layered, membrane-integrated microfluidics based on replica molding of a thiol-ene epoxy thermoset for organ-on-a-chip applications. AB - In this study we have investigated a photosensitive thermoset (OSTEMER 322-40) as a complementary material to readily fabricate complex multi-layered microdevices for applications in life science. Simple, versatile and robust fabrication of multifunctional microfluidics is becoming increasingly important for the development of customized tissue-, organ- and body-on-a-chip systems capable of mimicking tissue interfaces and biological barriers. In the present work key material properties including optical properties, vapor permeability, hydrophilicity and biocompatibility are evaluated for cell-based assays using fibroblasts, endothelial cells and mesenchymal stem cells. The excellent bonding strength of the OSTEMER thermoset to flexible fluoropolymer (FEP) sheets and poly(dimethylsiloxane) (PDMS) membranes further allows for the fabrication of integrated microfluidic components such as membrane-based microdegassers, microvalves and micropumps. We demonstrate the application of multi-layered, membrane-integrated microdevices that consist of up to seven layers and three membranes that specially confine and separate vascular cells from the epithelial barrier and 3D tissue structures. PMID- 26524976 TI - CD74/DQA1 dimers predispose to the development of arthritis in humanized mice. AB - Rheumatoid arthritis (RA) is associated with the presence of certain HLA class II genes. However, why some individuals carrying RA non-associated alleles develop arthritis is still unexplained. The trans-heterodimer between two RA non associated HLA genes can render susceptibility to develop arthritis in humanized mice, DQA1*0103/DQB1*0604, suggesting a role for DQ alpha chains in pathogenesis. In this study we determined the role of DQA1 in arthritis by using mice expressing DQA1*0103 and lacking endogenous class II molecules. Proximity ligation assay showed that DQA1*0103 is expressed on the cell surface as a dimer with CD74. Upon immunization with type II collagen, DQA1*0103 mice generated an antigen-specific cellular and humoral response and developed severe arthritis. Structural modelling suggests that DQA1*0103/CD74 form a pocket with similarity to the antigen binding pocket. DQA1*0103 mice present type II collagen-derived peptides that are not presented by an arthritis-resistant DQA1*0103/DQB1*0601 allele, suggesting that the DQA1*0103/CD74 dimer may result in presentation of unique antigens and susceptibility to develop arthritis. The present data provide a possible explanation by which the DQA1 molecule contributes to susceptibility to develop arthritis. PMID- 26524978 TI - Relaxation and Mindfulness in Pain: A Review. AB - This article reviews the existing, peer-reviewed evidence for the use of relaxation and mindfulness in both acute and chronic pain.There is some evidence that relaxation can reduce pain outcomes in both acute and chronic pain, however there is evidence that these improvements are not maintained over time.More limited research suggests that mindfulness can lead to improvements in psychological measures and physical functioning and these improvements appear to be maintained at follow-up.Further research is needed. Both researchers and practitioners need to be clearer on the outcomes that their techniques best facilitate and the processes which are active within them. PMID- 26524979 TI - Transient diabetes insipidus in pregnancy. AB - Gestational diabetes insipidus (DI) is a rare complication of pregnancy, usually developing in the third trimester and remitting spontaneously 4-6 weeks post partum. It is mainly caused by excessive vasopressinase activity, an enzyme expressed by placental trophoblasts which metabolises arginine vasopressin (AVP). Its diagnosis is challenging, and the treatment requires desmopressin. A 38-year old Chinese woman was referred in the 37th week of her first single-gestation due to polyuria, nocturia and polydipsia. She was known to have gestational diabetes mellitus diagnosed in the second trimester, well-controlled with diet. Her medical history was unremarkable. Physical examination demonstrated decreased skin turgor; her blood pressure was 102/63 mmHg, heart rate 78 beats/min and weight 53 kg (BMI 22.6 kg/m(2)). Laboratory data revealed low urine osmolality 89 mOsmol/kg (350-1000), serum osmolality 293 mOsmol/kg (278-295), serum sodium 144 mmol/l (135-145), potassium 4.1 mmol/l (3.5-5.0), urea 2.2 mmol/l (2.5-6.7), glucose 3.5 mmol/l and HbA1c 5.3%. Bilirubin, alanine transaminase, alkaline phosphatase and full blood count were normal. The patient was started on desmopressin with improvement in her symptoms, and normalisation of serum and urine osmolality (280 and 310 mOsmol/kg respectively). A fetus was delivered at the 39th week without major problems. After delivery, desmopressin was stopped and she had no further evidence of polyuria, polydipsia or nocturia. Her sodium, serum/urine osmolality at 12-weeks post-partum were normal. A pituitary magnetic resonance imaging (MRI) revealed the neurohypophyseal T1-bright spot situated ectopically, with a normal adenohypophysis and infundibulum. She remains clinically well, currently breastfeeding, and off all medication. This case illustrates some challenges in the diagnosis and management of transient gestational DI. LEARNING POINTS: Gestational DI is a rare complication of pregnancy occurring in two to four out of 100 000 pregnancies. It usually develops at the end of the second or third trimester of pregnancy and remits spontaneously 4-6 weeks after delivery.Gestational DI occurrence is related to excessive vasopressinase activity, an enzyme expressed by placental trophoblasts during pregnancy, which metabolises AVP. Its activity is proportional to the placental weight, explaining the higher vasopressinase activity in third trimester or in multiple pregnancies.Vasopressinase is metabolised by the liver, which most likely explains its higher concentrations in pregnant women with hepatic dysfunction, such acute fatty liver of pregnancy, HELLP syndrome, hepatitis and cirrhosis. Therefore, it is important to assess liver function in patients with gestational DI, and to be aware of the risk of DI in pregnant women with liver disease.Serum and urine osmolality are essential for the diagnosis, but other tests such as serum sodium, glucose, urea, creatinine, liver function may be informative. The water deprivation test is normally not recommended during pregnancy because it may lead to significant dehydration, but a pituitary MRI should be performed at some point to exclude lesions in the hypothalamo-pituitary region.These patients should be monitored for vital signs, fluid balance, body weight, fetal status, renal and liver function, and treated with desmopressin. The recommended doses are similar or slightly higher than those recommended for central DI in non-pregnant women, and should be titrated individually. PMID- 26524980 TI - [Dipeptidyl peptidase 4 inhibitors and the risk of cardiovascular disease: The case of sitagliptin]. PMID- 26524981 TI - High-grade focal areas in low-grade central osteosarcoma: high-grade or still low grade osteosarcoma? AB - BACKGROUND: High-grade foci (grade 3 according to Broder's grading system) are sometimes detected in low-grade (grade 1 and 2) central osteosarcoma. The aim of this study was to retrospectively evaluate the clinical outcome in patients upgraded to high grade (grade 3) after a first diagnosis of low-grade osteosarcoma, following the detection of high-grade areas (grade 3) in the resected specimen. METHODS: Of the 132 patients with a diagnosis of low-grade central osteosarcoma at surgical biopsy at our Institute, 33 patients were considered eligible for the study. RESULTS: Median age was 37 (range 13-58 years). Location was in an extremity in 29 patients (88 %). Post-operative chemotherapy was given in 22 (67 %) patients. Follow-up data were available for all patients, with a median observation time of 115 months (range 4-322 months). After histological revision, areas of high-grade (grade 3) osteosarcoma accounting for less than 50 % of the tumor were found in 20 (61 %) patients, whereas the majority of the tumor was composed of a high-grade (grade 3) component in 13 (39 %) patients. In the 20 cases of low-grade osteosarcoma with high-grade foci (grade 3) in less than 50 % of the tumor, 9 patients did not receive adjuvant chemotherapy; only one of them died, of unrelated causes. In the adjuvant chemotherapy group (11 out of 20 patients), one patient developed multiple lung metastases and died of disease 39 months after the first diagnosis. In the other 13 cases of low-grade osteosarcoma with high-grade foci (grade 3) in more than 50 % of the tumor, 12 patients received adjuvant chemotherapy: 2 had recurrence, 4 developed multiple lung metastases and 3 died of disease. The only patient who did not receive chemotherapy is alive without disease 232 months after complete surgical remission. CONCLUSION: Our data indicate that patients with a diagnosis of low-grade osteosarcoma where the high-grade (grade 3) component is lower than 50 % of the resected specimen, may not require chemotherapy, achieving high survival rates by means of complete surgical resection only. PMID- 26524982 TI - [Diabetes in urban setting in Ouagadougou, Burkina Faso: epidemiological profile and level of perception in the adult population]. PMID- 26524983 TI - The temporal-relevance temporal-uncertainty model of prospective duration judgment. AB - A model aimed at explaining prospective duration judgments in real life settings (as well as in the laboratory) is presented. The model is based on the assumption that situational meaning is continuously being extracted by humans' perceptual and cognitive information processing systems. Time is one of the important dimensions of situational meaning. Based on the situational meaning, a value for Temporal Relevance is set. Temporal Relevance reflects the importance of temporal aspects for enabling adaptive behavior in a specific moment in time. When Temporal Relevance is above a certain threshold a prospective duration judgment process is evoked automatically. In addition, a search for relevant temporal information is taking place and its outcomes determine the level of Temporal Uncertainty which reflects the degree of knowledge one has regarding temporal aspects of the task to be performed. The levels of Temporal Relevance and Temporal Uncertainty determine the amount of attentional resources allocated for timing by the executive system. The merit of the model is in connecting timing processes with the ongoing general information processing stream. The model rests on findings in various domains which indicate that cognitive-relevance and self relevance are powerful determinants of resource allocation policy. The feasibility of the model is demonstrated by analyzing various temporal phenomena. Suggestions for further empirical validation of the model are presented. PMID- 26524984 TI - Narrowband Ultraviolet B Exposures Maintain Vitamin D Levels During Winter: A Randomized Controlled Trial. AB - Exposure to solar ultraviolet B radiation during the summer months is the main source of vitamin D (VD) for people living in northern latitudes. The aim of this study was to determine whether artificial narrowband ultraviolet B (NB-UVB) whole body exposures could maintain VD levels in winter. The intervention group received 2 standard erythema doses (SEDs) of NB-UVB exposures every second week from October 2013 to April 2014. In October 2013 serum 25-hydroxyvitamin D concentrations were 78.3 nmol/l in the intervention group (n = 16) and 76.8 nmol/l in the control group (n = 18). By April 2014 the concentrations had increased by 11.7 nmol/l (p = 0.029) in the intervention group and decreased by 11.1 nmol/l (p = 0.022) in the control group. The baseline VD concentration showed a negative correlation (p = 0.012) with body mass index (BMI). In conclusion, a suberythemal NB-UVB dose of 2 SED every second week maintains and even increases serum VD concentrations during the winter. A high BMI seems to predispose subjects to low levels of VD. PMID- 26524985 TI - Pain Assessment with Cognitively Impaired Older People in the Acute Hospital Setting. AB - Research reveals that older people continue to experience much suffering from acute and chronic pain conditions.People with cognitive impairment receive less analgesia than their cognitively intact peers.Postoperative pain assessment with older people in the acute hospital setting remains a challenge.Context and culture have a significant impact of pain assessment practices.Due to a paucity of research exploring how pain assessment and management practices with cognitively impaired older people may be realised in the acute hospital setting, there is a need for further research to be conducted. PMID- 26524986 TI - A case of anti-NMDAR encephalitis presented hypotensive shock during plasma exchange. AB - We are reporting on a case of pediatric anti-NMDAR encephalitis with autonomic instability. The patient showed little response to first-line treatment of steroid and IVIG. We initiated plasma exchange, also a first-line treatment. This worsened his autonomic instability, resulting in hypotensive shock. He responded well to rituximab and cyclophosphamide, second-line therapies. Anti-NMDAR encephalitis is often accompanied by autonomic instability. Our and other reported cases, raise the question of plasma exchange as a first-line therapy for pediatric NMDAR encephalitis, which is frequently accompanied by autonomic instability. Plasma exchange should be performed cautiously in such patients. PMID- 26524987 TI - Basic Opioid Pharmacology. AB - Opioids can be classified according to their mode of synthesis into alkaloids, semi-synthetic and synthetic compounds.There are three classical receptors (DOP, KOP and MOP). The novel NOP receptor is considered to be a non-opioid branch of the opioid receptor family.Opioids can either act as agonists, antagonists or partial agonists at these receptors.Opioid agonists bind to G-protein coupled receptors to cause cellular hyperpolarisation.MOP receptor agonists act in the central and peripheral nervous system to elicit analgesia. PMID- 26524988 TI - The Impacts of China's Urban Employee Basic Medical Insurance on Healthcare Expenditures and Health Outcomes. AB - At the end of 1998, China launched a government-run mandatory insurance program, the urban employee basic medical insurance (UEBMI), to replace the previous medical insurance system. Using the UEBMI reform in China as a natural experiment, this study identifies variations in patient cost sharing that were imposed by the UEBMI reform and examines their effects on the demand for healthcare services. Using data from the 1991-2006 waves of the China Health and Nutrition Survey, we find that increased cost sharing is associated with decreased outpatient medical care utilization and expenditures but not with decreased inpatient care utilization and expenditures. Patients from low-income and middle-income households or with less severe medical conditions are more sensitive to prices. We observe little impact on patient's health, as measured by self-reported health status. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26524989 TI - Cardiovascular imaging in pediatric patients using dual source CT. AB - Cardiovascular CT acquisition protocol optimization in pediatric patients, including newborns is often challenging. This might be due to non-cooperative patients, the complexity and variety of diseases and the need for stringent dose minimization. Motion artifacts caused by voluntary and involuntary motion are most frequently seen in cardiac imaging with high heart and respiratory rates. Dual source scanners of the second and third generation are particularly well suited to respond to these challenges. This can be accomplished with advanced scan options, such as high pitch scanning, short rotation times, automated tube voltage selection, tube current modulation and iterative reconstruction. PMID- 26524991 TI - The interplay between tectonics, sediment dynamics and gateways evolution in the Danube system from the Pannonian Basin to the western Black Sea. AB - Understanding the natural evolution of a river-delta-sea system is important to develop a strong scientific basis for efficient integrated management plans. The distribution of sediment fluxes is linked with the natural connection between sediment source areas situated in uplifting mountain chains and deposition in plains, deltas and, ultimately, in the capturing oceans and seas. The Danube River-western Black Sea is one of the most active European systems in terms of sediment re-distribution that poses significant societal challenges. We aim to derive the tectonic and sedimentological background of human-induced changes in this system and discuss their interplay. This is obtained by analysing the tectonic and associated vertical movements, the evolution of relevant basins and the key events affecting sediment routing and deposition. The analysis of the main source and sink areas is focused in particular on the Miocene evolution of the Carpatho-Balkanides, Dinarides and their sedimentary basins including the western Black Sea. The vertical movements of mountains chains created the main moments of basin connectivity observed in the Danube system. Their timing and effects are observed in sediments deposited in the vicinity of gateways, such as the transition between the Pannonian/Transylvanian and Dacian basins and between the Dacian Basin and western Black Sea. The results demonstrate the importance of understanding threshold conditions driving rapid basins connectivity changes superposed over the longer time scale of tectonic-induced vertical movements associated with background erosion and sedimentation. The spatial and temporal scale of such processes is contrastingly different and challenging. The long-term patterns interact with recent or anthropogenic induced modifications in the natural system and may result in rapid changes at threshold conditions that can be quantified and predicted. Their understanding is critical because of frequent occurrence during orogenic evolution, as commonly observed in the Mediterranean area and discussed elsewhere. PMID- 26524992 TI - Electrospun cellulose acetate composites containing supported metal nanoparticles for antifungal membranes. AB - Electrospun cellulose acetate composites containing silver and copper nanoparticles supported in sepiolite and mesoporous silica were prepared and tested as fungistatic membranes against the fungus Aspergillus niger. The nanoparticles were in the 3-50nm range for sepiolite supported materials and limited by the size of mesopores (5-8nm) in the case of mesoporous silica. Sepiolite and silica were well dispersed within the fibers, with larger aggregates in the micrometer range, and allowed a controlled release of metals to create a fungistatic environment. The effect was assessed using digital image analysis to evaluate fungal growth rate and fluorescence readings using a viability stain. The results showed that silver and copper nanomaterials significantly impaired the growth of fungi when the spores were incubated either in direct contact with particles or included in cellulose acetate composite membranes. The fungistatic effect took place on germinating spores before hyphae growth conidiophore formation. After 24h the cultures were separated from fungistatic materials and showed growth impairment only due to the prior exposure. Growth reduction was important for all the particles and membranes with respect to non-exposed controls. The effect of copper and silver loaded materials was not significantly different from each other with average reductions around 70% for bare particles and 50% for membranes. Copper on sepiolite was particularly efficient with a decrease of metabolic activity of up to 80% with respect to controls. Copper materials induced rapid maturation and conidiation with fungi splitting in sets of subcolonies. Metal-loaded nanomaterials acted as reservoirs for the controlled release of metals. The amount of silver or copper released daily by composite membranes represented roughly 1% of their total load of metals. Supported nanomaterials encapsulated in nanofibers allow formulating active membranes with high antifungal performance at the same time minimizing the risk of nanoparticle release into the environment. PMID- 26524993 TI - Photodegradation of organic pollutants in water and green hydrogen production via methanol photoreforming of doped titanium oxide nanoparticles. AB - Novel nanomaterials based on doped TiO2 nanoparticles with different morphological, textural and band-gap properties have been synthesized using scalable methods. The influence of synthetic parameters such as titanium source (titanium(IV) isopropoxide and titanium(IV) butoxide), doping quantity (0%, 2% or 5% Zn), acidic solution for the hydrolysis reaction (ascorbic acid, nitric acid) and calcination temperatures (500 degrees C and 600 degrees C) was simultaneously investigated. The obtained nanomaterials were characterized by different methods and photocatalytic tests of methylene blue (MB) degradation under UV-light were conducted to determine their activity. The results revealed that the synthesized nanomaterials are porous aggregates with very high crystallinity and are mainly composed of the anatase phase; although their physical properties vary depending on the different synthetic parameters employed. These changes are able to modify the apparent rate constant of the degradation of MB up to one order of magnitude, indicating, substantial changes in their photoactivity. Hybrid materials TiO2-Pd nanoparticles have also been prepared, characterized and tested for hydrogen production using photocatalytic methanol reforming where supported palladium nanoparticles acted as co-catalyst. Furthermore, the hybrid materials TiO2-Pd nanoparticles were studied in photocatalytic tests of methylene blue degradation under visible LED-light. The results obtained in the production of hydrogen from the photocatalytic reforming of methanol by hybrid materials suggest that the reported hybrid systems could be suitable photocatalysts for future sustainable hydrogen production upon tuning of the morphological, textural and band gap energy properties to allow processes to be carried out under visible light. PMID- 26524994 TI - Comparative bioremediation of heavy metals and petroleum hydrocarbons co contaminated soil by natural attenuation, phytoremediation, bioaugmentation and bioaugmentation-assisted phytoremediation. AB - Biological remediation technologies are an environmentally friendly approach for the treatment of polluted soils. This study evaluated through a pot experiment four bioremediation strategies: a) natural attenuation, b) phytoremediation with alfalfa (Medicago sativa L.), c) bioaugmentation with Pseudomonas aeruginosa and d) bioaugmentation-assisted phytoremediation, for the treatment of a co contaminated soil presenting moderate levels of heavy metals (Cu, Pb and Zn at 87, 100 and 110mgkg(-1) DW, respectively) and petroleum hydrocarbons (3800mgkg( 1) DW). As demonstrated by plant biomass and selected physiological parameters alfalfa plants were able to tolerate and grow in the co-contaminated soil, especially when soil was inoculated with P. aeruginosa, which promoted plant growth (56% and 105% increase for shoots and roots, respectively) and appeared to alleviate plant stress. The content of heavy metals in alfalfa plants was limited and followed the order: Zn>Cu>Pb. Heavy metals were mainly concentrated in plant roots and were poorly translocated, favouring their stabilization in the root zone. Bioaugmentation of planted soil with P. aeruginosa generally led to a decrease of plant metal concentration and translocation. The highest degree of total petroleum hydrocarbon removal was obtained for bioaugmentation-assisted phytoremediation treatment (68%), followed by bioaugmentation (59%), phytoremediation (47%) and natural attenuation (37%). The results of this study demonstrated that the combined use of plant and bacteria was the most advantageous option for the treatment of the present co-contaminated soil, as compared to natural attenuation, bioaugmentation or phytoremediation applied alone. PMID- 26524995 TI - A groundwater management plan for Stuttgart. AB - In general, groundwater in urban areas is exposed to anthropogenic influence and suffers from concentrations of contaminants. Stuttgart, as a highly industrialized city, has more than 5000 contaminated sites which might influence the Stuttgart's mineral water quality. Despite tremendous efforts and intensive single site orientated remediation since 1984 in downtown, the mineral springs were still affected with chlorinated hydrocarbons at low concentrations. Therefore, the applied practices of environmental management and measures for mitigation of pollution sources were not sufficient and had to be adjusted. The main goal of this study is to define an integral remediation plan (a groundwater management plan), focusing on the key sources of chlorinated solvents which are relevant for the mineral springs. For the large-scale investigated area of 26.6km(2) and eight aquifers, an extensive investigation and characterization methods were used in order to delineate the contamination plumes. By means of a 3D numerical model, the prioritization of the contaminated sites could be performed. Five contaminated sites with high remediation priority and need for optimized or additional remediation efforts were determined. For those five contaminated sites feasibility studies were performed which resulted in recommendation of remediation measures with total costs of more than 12.5 million euros. The proposed strategy and approach are suitable for multiple sources of contamination. Only in this way, the contributions of single contaminated sites to the total groundwater contamination can be identified and local remediation measures with their spatial impact simulated. Due to very complex geological conditions, technically there is no alternative to this strategy in order to achieve the contamination reduction in groundwater. PMID- 26524996 TI - Stock-outs, uncertainty and improvisation in access to healthcare in war-torn Northern Uganda. AB - Stock-outs, also known as shortages or complete absence of a particular inventory, in public health facilities have become a hallmark in Uganda's health system making the notions of persistent doubt in access to healthcare - uncertainty, and doing more with less - 'improvisation', very pronounced. The situation becomes more critical in post-conflict areas with an over whelming burden of preexisting and conflict-related ailments amidst weak health systems. Particularly in the war-torn Northern Uganda, the intersection between the effects of violent conflict and shortage of medications is striking. There are problems getting the right type of medications to the right people at the right time, causing persistent shortages and uncertainty in access to healthcare. With reference to patients on Antiretroviral Therapy (ART), we present temporal trends in access to healthcare in the context of medication shortages in conflict affected areas. We examine uncertainties in access to care, and how patients, medical practitioners, and the state - the key actors in the domain of supplying and utilizing medicines, respond. Our observation is that, while improvisation is a feature of biomedicine and facilitates problem solving in daily life, it is largely contextual. Given the rapidly evolving contexts and social and professional sensitivities that characterize war affected areas, there is a need for deliberate healthcare programs tailored to the unique needs of people and to the shaping of appropriate policies in post-conflict settings, which call for more North-South collaboration on equal terms. PMID- 26524997 TI - Can videostroboscopy predict early glottic cancer? A systematic review and meta analysis. AB - OBJECTIVE: Correct assessment of patients with a glottic lesion is crucial for ensuring proper treatment in cases of cancer or premalignancy and for avoiding unnecessary surgery. For years, videostroboscopy (VS) has been the gold standard for assessing such lesions, but diagnostic difficulties have been described. We aim to estimate the diagnostic accuracy of VS in differentiating early glottic cancer from noninvasive lesions by conducting a systematic review and meta analysis of published studies. DATA SOURCES: PubMed and Embase databases were searched without restrictions on publication date. REVIEW METHODS: A systematic review and subsequent meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. We systematically searched the literature for publications on stroboscopic diagnosis of cancer or premalignant lesions on the vocal cords. All retrieved studies were reviewed and qualitatively assessed. The pooled sensitivity and specificity of VS were calculated, and bubble and summary receiver operating characteristics plots were created. RESULTS: A meta-analysis was conducted on five studies with a total of 307 patients. The sensitivities of VS within the single studies ranged from 86% to 100% and specificities ranged from 7% to 93%. The meta-analysis showed that the sensitivity of the combined results was 0.96 (95% confidence interval [CI]: 0.89-0.98), and the specificity was 0.65 (95% CI: 0.21-0.93). CONCLUSION: VS is able to identify almost all patients with cancer, but only approximately two-thirds of patients with noninvasive lesions are correctly identified as not having cancer. Further research concerning assessment of patients with vocal cord lesions is needed. LEVEL OF EVIDENCE: NA Laryngoscope, 126:2079-2084, 2016. PMID- 26524998 TI - Left dominant circulation increases mortality in acute coronary syndrome: A systematic review and meta-analysis of observational studies involving 255,718 patients. AB - BACKGROUND: The effect of coronary dominance on mortality in patients with acute coronary syndrome (ACS) remains unclear. We performed a meta-analysis to evaluate the effect of coronary dominance in patients with ACS. METHODS: Several data sources were searched for studies which compared studies that compared outcomes between right and left dominant coronary circulation in patients with ACS. The measured outcomes were in-hospital, 30-day or long-term mortality as reported in individual studies. The Generic inverse variance method was used in a random effects model to pool mortality as an outcome. Odds ratio (OR) was calculated for mortality in the left dominant circulation relative to a right dominant one. Sub group analysis was performed after stratification of mortality by duration. RESULTS: A total of 5 studies with 8 comparisons and 255,718 participants revealed an increased risk mortality (OR = 1.27 (95% CI: 1.13 - 1.42; P < 0.0001; I(2) = 34%). Sub-group analysis revealed that the increased risk was evident at all time periods after the ACS; in-hospital (OR = 1.37; 95% CI: 1.07 - 1.76; P = 0.01; I(2) = 50%), at 30 days (OR = 1.69; 95% CI: 1.14 - 2.52; P = 0.009; I(2) = 18%) and long-term (OR = 1.15; 95% CI: 1.03 - 1.28; P = 0.01; I(2) = 0%). CONCLUSIONS: In this meta-analysis we found that there is an increased risk of mortality with LD coronary circulation in patients with ACS. The knowledge of coronary dominance may not only be helpful as an incremental prognostic factor beyond pre-procedural risk scores in all patients with ACS, but may also aid in clinical decision making in a subset of these patients. (c) 2015 Wiley Periodicals, Inc. PMID- 26524999 TI - Ab Initio Molecular Dynamics with Explicit Solvent Reveals a Two-Step Pathway in the Frustrated Lewis Pair Reaction. AB - The role solvent plays in reactions involving frustrated Lewis pairs (FLPs)-for example, the stoichiometric mixture of a bulky Lewis acid and a bulky Lewis base still remains largely unexplored at the molecular level. For a reaction of the phosphorus/boron FLP and dissolved CO2 gas, first principles (Born-Oppenheimer) molecular dynamics with explicit solvent reveals a hitherto unknown two-step reaction pathway-one that complements the concerted (one-step) mechanism known from the minimum-energy-path calculations. The rationalization of the discovered reaction pathway-that is, the stepwise formation of P?C and O?B bonds-is that the environment (typical organic solvents) stabilizes an intermediate which results from nucleophilic attack of the phosphorus Lewis base on CO2 . This finding is significant because presently the concerted reaction-path paradigm predominates in the rationalization of FLP reactivity. Herein we point out how to attain experimental proof of our results. PMID- 26525000 TI - Placebo Analgesia - Understanding the Mechanisms and Implications for Clinical Practice. AB - There are neurobiological, cognitive and conditioning processes involved in placebo mechanismsMechanisms research has demonstrated that there is not one placebo effect, but manyPlacebo effects are an inherent element in routine clinical practiceModulation of placebo mechanisms in routine practice could provide an opportunity for improving clinical care. PMID- 26525002 TI - Editorial: Science Met Practice at the IAAD Meeting in Orlando: A Resounding Success. PMID- 26525003 TI - Meta-Analysis of the Influence of Bonding Parameters on the Clinical Outcome of Tooth-colored Cervical Restorations. AB - PURPOSE: To meta-analyze the literature on the clinical performance of Class V restorations to assess the factors that influence retention, marginal integrity, and marginal discoloration of cervical lesions restored with composite resins, glass-ionomer-cement-based materials [glass-ionomer cement (GIC) and resin modified glass ionomers (RMGICs)], and polyacid-modified resin composites (PMRC). MATERIALS AND METHODS: The English literature was searched (MEDLINE and SCOPUS) for prospective clinical trials on cervical restorations with an observation period of at least 18 months. The studies had to report about retention, marginal discoloration, marginal integrity, and marginal caries and include a description of the operative technique (beveling of enamel, roughening of dentin, type of isolation). Eighty-one studies involving 185 experiments for 47 adhesives matched the inclusion criteria. The statistical analysis was carried out by using the following linear mixed model: log (-log (Y /100)) = beta + alpha log(T ) + error with beta = log(lambda), where beta is a summary measure of the non-linear deterioration occurring in each experiment, including a random study effect. RESULTS: On average, 12.3% of the cervical restorations were lost, 27.9% exhibited marginal discoloration, and 34.6% exhibited deterioration of marginal integrity after 5 years. The calculation of the clinical index was 17.4% of failures after 5 years and 32.3% after 8 years. A higher variability was found for retention loss and marginal discoloration. Hardly any secondary caries lesions were detected, even in the experiments with a follow-up time longer than 8 years. Restorations placed using rubber-dam in teeth whose dentin was roughened showed a statistically significantly higher retention rate than those placed in teeth with unprepared dentin or without rubber-dam (p < 0.05). However, enamel beveling had no influence on any of the examined variables. Significant differences were found between pairs of adhesive systems and also between pairs of classes of adhesive systems. One-step self-etching had a significantly worse clinically index than two-step self-etching and three-step etch-and-rinse (p = 0.026 and p = 0.002, respectively). CONCLUSION: The clinical performance is significantly influenced by the type of adhesive system and/or the adhesive class to which the system belongs. Whether the dentin/enamel is roughened or not and whether rubberdam isolation is used or not also significantly influenced the clinical performance. Composite resin restorations placed with two-step self etching and three-step etch-and-rinse adhesive systems should be preferred over onestep self-etching adhesive systems, GIC-based materials, and PMRCs. PMID- 26525004 TI - One-year Clinical Evaluation of Resin Composite Restorations of Noncarious Cervical Lesions in Smokers. AB - PURPOSE: To evaluate the one-year clinical performance of composite restorations in noncarious cervical lesions placed in smoking and non-smokers using a multimode adhesive system with two adhesive strategies. MATERIALS AND METHODS: Among the selected cervical lesions, four experimental groups were formed based on the patients' smoking habit and bonding strategies with a multimode adhesive system (n = 38): G1: etchand- rinse in non-smokers; G2: selective enamel etching in non-smokers; G3: etch-and-rinse in smokers; G4: selective enamel etching in smokers. The restorations were paired, ie, each patient received at least two restorations. A nanofilled resin composite was applied and light cured incrementally in all groups by one operator. Two calibrated examiners evaluated the restorations at baseline, 6 and 12 months after placement. The modified USPHS criteria were used for evaluation. Data were analyzed using the chi-square (for associations between groups) and McNemar tests. RESULTS: No statistically significant difference was found between groups for the criteria of retention, marginal discoloration, color match, marginal integrity, or sensitivity after 6 and 12 months. The assessments over time showed a statistically significant difference only for marginal discoloration at 12 months for groups 1, 3, and 4 when compared to baseline (p = 0.031). There were no statistical differences for any criteria evaluated among smokers and non-smokers, except for color match, where a difference was found after the baseline evaluation. Regarding the adhesive strategy, etch-and-rinse resulted in a clinical performance similar to that of selective enamel etching over 12 months. CONCLUSION: Neither cigarette smoking habit nor adhesive strategy influenced the clinical performance of resin composite cervical restorations over the first year. PMID- 26525001 TI - 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. AB - The World Allergy Organization (WAO) Guidelines for the assessment and management of anaphylaxis provide a unique global perspective on this increasingly common, potentially life-threatening disease. Recommendations made in the original WAO Anaphylaxis Guidelines remain clinically valid and relevant, and are a widely accessed and frequently cited resource. In this 2015 update of the evidence supporting recommendations in the Guidelines, new information based on anaphylaxis publications from January 2014 through mid- 2015 is summarized. Advances in epidemiology, diagnosis, and management in healthcare and community settings are highlighted. Additionally, new information about patient factors that increase the risk of severe and/or fatal anaphylaxis and patient co-factors that amplify anaphylactic episodes is presented and new information about anaphylaxis triggers and confirmation of triggers to facilitate specific trigger avoidance and immunomodulation is reviewed. The update includes tables summarizing important advances in anaphylaxis research. PMID- 26525005 TI - Aging Effect of Atmospheric Air on Zirconia Surfaces Treated by Nonthermal Plasma. AB - PURPOSE: The purpose of this study was twofold: 1) to characterize the zirconia (Y-TZP) surfaces through scanning electronic microscopy associated with energy dispersive spectroscopy and atomic force microscopy after the deposition of a thin organosilicon film by nonthermal plasma (NTP) treatment, and 2) to determine the zirconia surface hydrophilicity, before and after aging, through surface energy analysis. MATERIALS AND METHODS: Surfaces of 16 zirconia disks (10 x 3 mm) were treated for 30 min each with hexamethyldisiloxane and argon plasmas, followed by oxygen plasma. Disks were analyzed before NTP treatment, immediately after NTP treatment, and after aging for 7, 15, and 30 days. The surface energy of the Y-TZP disks was measured with a goniometer. Quantitative data were submitted to statistical analysis using ANOVA and Tukey's test (p < 0.05). RESULTS: Immediately after NTP treatment, the surface energy of the zirconia disks was significantly higher than at any other tested period (p < 0.001), and the water contact angle on the zirconia disks was reduced to 0 degrees. Similar surface energy results were obtained before NTP treatment and after 15 or 30 days of aging (p > 0.05; Tukey's test). Energy-dispersive spectroscopy results revealed the presence of carbon, oxygen, and silicon on the surface after NTP treatment. CONCLUSION: NTP treatment was useful for treating the zirconia surface for cementation procedures, as it produced a high level of hydrophilicity on the zirconia surface. However, this high level of hydrophilicity did not persist after aging. PMID- 26525006 TI - Effects of Different Surface Treatments on Composite Repairs. AB - PURPOSE: To evaluate the influence of different surface treatments on roughness and bond strength of composite repairs. MATERIALS AND METHODS: 120 truncated conical specimens were prepared with composite Grandio SO (VOCO) and submitted to 5000 thermal cycles. Specimens were divided into 12 groups (n = 10) regarding the surface treatments: negative control (NC), without treatment; medium-grit diamond bur (MGD); coarse-grit diamond bur (CGD); conventional carbide bur (ConC); crosscut carbide bur (CutC); chemical vapor deposition diamond bur (CVD); sandblasting with aluminum oxide (AlO); Er:YAG laser 200 mJ/10 Hz (Er200); Er:YAG laser 60 mJ/10 Hz (Er50); Nd:YAG laser 120 mJ/15 Hz (Nd120); Nd:YAG laser 60 mJ/ 15Hz (Nd60); air abrasion with 110-MUm silica modified aluminum oxide (Rocatec Plus-3M) (SIL). After the surface treatments, the surface roughness (Ra) was measured using a profilometer, and then the adhesive system Admira Bond (VOCO) was applied. Another truncated conical restoration was built up with the same composite over the bonded area of each specimen. In order to evaluate the cohesive strength, double-cone specimens were made and considered as a control group (CoheC). The specimens were submitted to tensile bond strength testing and the obtained data (MPa) were evaluated by one-way ANOVA, Tukey's and correlation tests. RESULTS: ANOVA showed significant differences among experimental groups for roughness and adhesive strength (p < 0.00). The roughness values (Ra) were: NC (0.21 +/- 0.19)(c); ConC (0.30 +/- 0.08)(c); CutC (0.50 +/- 0.22)(cd); CVD (0.74 +/- 0.14)(bd); MGD (0.89 +/- 0.39)(ab); Er50 (0.89 +/- 0.14)(ab); AlO (0.90 +/- 0.07)(ab); Nd60 (0.94 +/- 0.33ab; SIL (0.98 +/- 0.07)(ab); Nd120 (1.10 +/- 0.19)(a); CGD (1.10 +/- 0.32)(a); Er200 (1.12 +/- 0.21)(a). The results of the tensile bond strength test in MPa were: CGD (11.58 +/- 3.03)(a); MGD (12.66 +/- 3.82)(ab); NC (13.51 +/- 3.95(ab); Nd120 (14.11 +/- 5.95)(ab); ConC (14.73 +/- 6.12)(ab); Er200 (15.51 +/- 1.45)(abc); CVD (15.61 +/- 5.00(abc); Er50 (16.44 +/- 2.75) (abc); CutC (16.79 +/- 2.98)(abc); Nd60 (17.72 +/- 2.45)(abcd); AlO (18.33 +/- 3.19)(bcd); SIL (21.13 +/- 4.48(cd); CoheC (23.50 +/- 5.81)(d). The groups followed by the same letters were not statistically significantly different (Tukey's test). No correlation was found between bond strength and roughness (r = 0.007). CONCLUSION: Air abrasion with silica coating (Rocatec) was the only method which resulted in significantly higher bond strength in relation to the negative control group. The increase in laser energy produced a rougher surface, but reduced the bond strength. PMID- 26525007 TI - Bond Strength of a Flowable Bulk-fill Resin Composite in Class II MOD Cavities. AB - PURPOSE: To evaluate the microtensile bond strength (MUTBS) of a bulk-fill low stress resin-based composite to dentin from gingival walls of Class II MOD cavities. MATERIALS AND METHODS: Class II MOD cavities were prepared in 44 human molars with the distal and mesial proximal boxes 4 and 6 mm deep, respectively. Eight experimental groups (n = 11) were obtained by a factorial design including 1. "composite" in two levels: a bulk-fill low-stress composite (SureFil SDR Flow, Dentsply Caulk) and a conventional composite (Filtek Z350 XT, 3M ESPE); 2. "filling technique" in two levels: bulk-fill (Bf) and incremental (In); and 3. "depth" in two levels: 4 mm and 6 mm in order to create different polymerization conditions. Twenty-four hours after placement of restorations, teeth were sectioned into beams with a cross-sectional bonded area of approximately 1 mm2. Bonded beams obtained from the gingival walls of the proximal boxes were tested in tension at a crosshead speed of 1 mm/min. Data were submitted to a 3-way ANOVA followed by a post-hoc Tukey's test (p < 0.05). RESULTS: ANOVA failed to identify significant differences for the triple and double interaction between factors. However, significant differences were observed for the factors "composite" and "filling technique" (p < 0.05). SDR presented significantly higher MUTBS values for bulk and incremental filling techniques (p < 0.05), and the incremental filling technique presented significantly higher MUTBS values for both composites (p < 0.05). CONCLUSION: It can be concluded that the bulk-fill flowable composite SDR may improve the bond strength to the gingival walls of Class II MOD cavities. PMID- 26525008 TI - Ten-year Clinical Performance of Posterior Resin Composite Restorations. AB - PURPOSE: To investigate the clinical behavior of two different resin-based restorative systems in Class II cavities in a controlled prospective split-mouth study over 10 years. MATERIALS AND METHODS: Thirty patients received 68 resin composite restorations (Solobond M + Grandio: n = 36; Syntac + Tetric Ceram: n = 32) by one dentist in a private practice. 35% of cavities revealed no enamel at the bottom of the proximal box, 48% of cavities provided < 0.5 mm of remaining proximal enamel. Restorations were examined according to modified USPHS criteria at baseline, after 6 months, and 1, 2, 4, 6, 8, and 10 years. RESULTS: Twenty nine out of 30 patients attended the 10-year recall. The overall success rate of all restorations was 96.9%. One Grandio restoration suffered marginal fracture with exposed dentin and one Tetric Ceram restoration failed due to cusp fracture. After 10 years, Grandio showed higher surface roughness (p = 0.03) and less color match (p = 0.024; Mann-Whitney U-test). Molar restorations performed worse than premolar fillings regarding marginal integrity (4 and 10 years), filling integrity (4, 8, and 10 years), and tooth integrity (4, 8, and 10 years). The main reasons for degradation of resin composites were chipping and cracks in molar restorations after 8 years. Beyond the 4-year recall, marginal staining increased (43% bravo for stained margins at four years, 52% at 8 years, and 71% at 10 years). Tooth integrity deteriorated significantly due to more enamel cracks and chipping over time (9% at baseline and 89% after 10 years (p<0.05). CONCLUSIONS: Direct resin composite restorations performed satisfactorily over 10 years of clinical service. PMID- 26525011 TI - Protocol for Removal of Clinically Relevant Contaminants from Glass Ceramic-based Restorations. PMID- 26525012 TI - Improving the arterial input function in dynamic contrast enhanced MRI by fitting the signal in the complex plane. AB - PURPOSE: Dynamic contrast enhanced (DCE) imaging is a widely used technique in oncologic imaging. An essential prerequisite for obtaining quantitative values from DCE-MRI is the determination of the arterial input function (AIF). However, it is very challenging to accurately estimate the AIF using MR. A comprehensive model, which uses complex data instead of either magnitude or phase, was developed to improve AIF estimation. THEORY AND METHODS: The model was first applied to simulated data. Subsequently, the accuracy of the estimated contrast agent concentration was validated in a phantom. Finally the method was applied to existing DCE scans of 13 prostate cancer patients. RESULTS: The complex signal method combines the complementary strengths of the magnitude and phase method, increasing the precision and accuracy of concentration estimation in simulated and phantom data. The in vivo AIFs show a good agreement between arterial voxels (standard deviation in the peak and tail equal 0.4 mM and 0.12 mM, respectively). Furthermore, the dynamic behavior closely followed the AIF obtained with DCE-CT in the same patients (mean correlation coefficient: 0.92). CONCLUSION: By using the complex signal, the AIF estimation becomes more accurate and precise. This might enable patient specific AIFs, thereby improving the quantitative values obtained from DCE-MRI. Magn Reson Med 76:1236-1245, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26525014 TI - Secretome analysis of Pleurotus eryngii reveals enzymatic composition for ramie stalk degradation. AB - Pleurotus eryngii (P. eryngii) can secrete large amount of hydrolytic and oxidative enzymes to degrade lignocellulosic biomass. In spite of several researches on the individual lignolytic enzymes, a direct deconstruction of lignocellulose by enzyme mixture is not yet possible. Identifying more high performance enzymes or enzyme complexes will lead to efficient in vitro lignocelluloses degradation. In this report, secretomic analysis was used to search for the new or interesting enzymes for lignocellulose degradation. Besides, the utilization ability of P. eryngii to ramie stalk substrate was evaluated from the degradation of cellulose, hemicellulose, and lignin in medium and six extracellular enzymes activities during different growth stages were discussed. The results showed that a high biological efficiency of 71% was obtained; cellulose, hemicelluloses, and lignin decomposition rates of P. eryngii were 29.2, 26.0, and 51.2%, respectively. Enzyme activity showed that carboxymethyl cellulase, xylanase, laccase, and peroxidase activity peaks appeared at the primordial initiation stage. In addition, we profiled a global view of the secretome of P. eryngii cultivated in ramie stalk media to understand the mechanism behind lignocellulosic biomass hydrolysis. Eighty-seven nonredundant proteins were identified and a diverse group of enzymes, including cellulases, hemicellulases, pectinase, ligninase, protease, peptidases, and phosphatase implicated in lignocellulose degradation were found. In conclusion, the information in this report will be helpful to better understand the lignocelluloses degradation mechanisms of P. eryngii. PMID- 26525015 TI - Colorectal Cancer: Advances in Prevention and Early Detection. PMID- 26525016 TI - Impacts on the third line of defense specialized against microbial infection as a result of exposure to gamma-radiation. AB - To understand the toxicity and the potential role of gamma-radiation (GR) as a therapeutic tool, the effects of different GR doses on haematological and dimensional properties of rats' blood were investigated in vivo. 60 healthy male Wistar-Kyoto rats were used in this study, and were randomly divided into 5 groups, 4 GR rat groups (1st group was radiated with 5 R, 2nd group 25 Gy; 3rd group with 50 Gy, 4th group with 100 Gy and 5th group was the control). Different haematological and dimensional parameters were measured using the standard haematological technique for complete blood count (CBC). A significant decrease in white blood cells (WBCs) count and lymphocytes (LYM) was observed compared with the control. While a significant increase in monocytes (MON), neutrophils (NEU), basophils (BAS), and eosinophils (EOS) were observed. A non-significant decrease in platelets (PLTs) count was observed with GR compared with the control. PMID- 26525017 TI - Curative effect of paclitaxel and cisplatin combined chemotherapy on cervical cancer and its relation with tissue micro vascular and lymphatic vessels density. AB - This study was to discuss the curative effect of paclitaxel and cisplatin combined chemotherapy on cervical cancer and its relation with tissue micro vascular and lymphatic vessels density. The combined chemotherapy of paclitaxel 135 mg/m2 and cisplatin 25mg/m2 were taken to observe the clinical curative effect. The postoperative paraffin tissue had been collected, had performed the LYVE-1 (lymphatic endothelium specific hyaluronan receptor-1) and CD31 immunohistochemical staining. The complete remission rate of high micro lymphatic vessels density group (was or more 6.0) and high micro vascular density group were obviously higher than in low micro lymphatic vessels density group and low micro vascular density group, the difference was statistically significance (P<0.05). This study further analyzed the relation of MVD and LVD with clinical pathological parameters. The difference was statistically significant (P<0.01). The curative effect of paclitaxel and cisplatin combined therapy was promising, positive and was closely related with cervical cancer tissue LVD and MVD. The LVD and MVD could be one of the predictors of early cervical CIN and early cervical cancer development. PMID- 26525013 TI - Current stage in inflammatory bowel disease: What is next? AB - In recent years, the incidence of inflammatory bowel disease (IBD) has been on the rise, extending to countries where it was infrequent in the past. As a result, the gap between high and low incidence countries is decreasing. The disease, therefore, has an important economic impact on the healthcare system. Advances in recent years in pharmacogenetics and clinical pharmacology have allowed for the development of treatment strategies adjusted to the patient profile. Concurrently, new drugs aimed at inflammatory targets have been developed that may expand future treatment options. This review examines advances in the optimization of existing drug treatments and the development of novel treatment options for IBD. PMID- 26525018 TI - Effect and treatment of lactobacillus on inflammation around the implant. AB - Ultrasonic scaling and antibiotic therapy are traditional therapeutic methods for inflammation around the implant but therapeutic effect is not ideal. In view of maintaining flora balance around the implant and implant long-term solid holdup, this experiment observes impact and clinical effect of lactobacillus metabolite on inflammation around the impact to explore a new kind of ecological drug. This drug has little or no side effect, good curative effect and low recurrence rate, which can be applied for broad groups of people. 16 cases with inflammation around the impact were divided into experimental group and control group, 8 cases for each group. Lactobacillus metabolites gargle was offered to experimental group; purified water was offered to control group. Gargle way is 3 times/day, 20 ml/time, 3 min/time and for 7 days. Two groups of cases were clinical and microbiological tested before gargle, 3 days, 7 days and 30 days after gargle. Based on clinical and microbiological test of 8 cases of health implant, we observe sub gingival flora variation trend and clinical effects of infectors with inflammation around implant. Lactobacillus metabolite can improve clinical index of inflammation around the impact including MPLI, GI, MBI and PD. Lactobacillus metabolite has a strong treatment effect on inflammation around the implant and has no side effect. PMID- 26525019 TI - Bioremediation of petroleum hydrocarbon contaminated soil by Rhodobacter sphaeroides biofertilizer and plants. AB - Bio-augmentation is a promising technique for remediation of polluted soils. This study aimed to evaluate the bio-augmentation effect of Rhodobacter sphaeroides biofertilizer (RBF) on the bioremediation of total petroleum hydrocarbons (TPH) contaminated soil. A greenhouse pot experiment was conducted over a period of 120 days, three methods for enhancing bio-augmentation were tested on TPH contaminated soils, including single addition RBF, planting, and combining of RBF and three crop species, such as wheat (W), cabbage (C) and spinach (S), respectively. The results demonstrated that the best removal of TPH from contaminated soil in the RBF bio-augmentation rhizosphere soils was found to be 46.2%, 65.4%, 67.5% for W+RBF, C+RBF, S+RBF rhizosphere soils respectively. RBF supply impacted on the microbial community diversity (phospholipid fatty acids, PLFA) and the activity of soil enzymes, such as dehydrogenase (DH), alkaline phosphatase (AP) and urease (UR). There were significant difference among the soil only containing crude oil (CK), W, C and S rhizosphere soils and RBF bio augmentation soils. Moreover, the changes were significantly distinct depended on crops species. It was concluded that the RBF is a valuable material for improving effect of remediation of TPH polluted soils. PMID- 26525020 TI - Essential oils from Zanthoxylum fagara Wild Lime, Ruta chalepensis L. and Thymus vulgaris L.: Composition and activity against Aedes aegypti larvae. AB - The dengue virus is transmitted by Aedes aegypti. Several plants are used to control this mosquito. In the present study the chemical composition of the essential oils of Ruta chalepensis, Zanthoxylum fagara and Thymus vulgaris were analyzed, and their activities against larvae of two A. aegypti populations were evaluated. The major compounds found in T. vulgaris were thymol and ?-cymene at 39.8% and 30.5%, respectively, with the major components being oxygenated monoterpenes and monoterpene hydrocarbons at 55.5% and 40.4%, respectively. For Z. fagara, the major compounds were sylvestrene and E-caryophyllene at 25.3% and 23.6%, respectively, with the major components being sesquiterpene and monoterpene hydrocarbons at 51.1% and 37.5%, respectively. Ketones were the predominant group of compounds found in R. chalepensis, with the major components being 2-undecanone and 2-nonanona at 43.7% and 35.4%, respectively. Essential oils from T. vulgaris, Z. fagara and R. chalepensis showed activity against larvae of the A. aegypti New Orleans strain, producing median lethal concentrations (LC50) of 2.14, 27.57 and 2.69 g/mL, respectively, at 24 h. LC50 values produced against larvae of a local A. aegypti population in Nuevo Leon, Mexico, were 25.37, 60.42 and 20.13 g/mL, respectively, at 24 h. PMID- 26525021 TI - The effects of gamma-radiation on red blood cell corpuscles and dimensional properties in rats. AB - In an attempt to understand the toxicity and the potential role of gamma radiation as a therapeutic tool, the effects of different Gamma-radiation doses on haematological and dimensional properties of rats' blood were investigated in vivo. 60 healthy male Wistar-Kyoto rats were used, which were randomly divided into five groups, 4 Gamma-radiated rat groups (1st group was radiated with five Gamma-radiation dose, 2nd group 25 Gy; 3rd group with 50 Gy, 4th group with 100 Gy, and 5th group was control). Different haematological and dimensional parameters were measured using the standard haematological technique. A significant decrease in red blood cells (RBCs) count, haemoglobin (HGB), and haematocrit (HCT) was observed compared with the control. While a significant increase in mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC), red distribution width (RDW) were observed compared with the control. This study suggested that low RBCs, HGB, and HCT might produce anemia and cessation of erythrocytes production in the bone marrow. Moreover, the RBCs size increase might be attributed to changes in the morphology and deformability of RBCs, which was confirmed by a slightly increase in RDW. PMID- 26525022 TI - Clinical study of Butylphthalide combined with Xue Shuan Tong on serum inflammatory factors and prognosis effect of patients with cerebral infarction. AB - To investigate the effect of Butylphthalide and Xue Shuan Tong on serum inflammatory factors and prognosis of patients with cerebral infarction. One hundred and twenty patients with acute cerebral infarction were randomly divided into control group, Butylphthalide group and Xue Shuan Tong group, with 40 patients in each group. Conventional therapy was performed in the control group; On the basis of conventional therapy, 100ml Butylphthalide intravenously twice a day was administrated among patients in Butylphthalide group; On the basis of conventional therapy, 250ml 0.9% NaCl intravenously once a day was conducted among patients in Xue Shuan Tong group. A treatment course of continuous 7 days was taken in the three groups. The serum levels of IL-2 and CGRP were detected for patients in the three groups before and after treatment. Carotid plaque thickness and size as well as intima-media thickness were detected by ultrasonic testing for patients in three groups before treatment and 90 days after follow up. The NIHSS, Barthel and MRS scoring were performed for all the patients after 90-day follow-up to evaluate the prognosis. After treatment, differences in the levels of IL-2 and CGRP for patients in the three groups showed statistical significance (P<0.05), while the levels of IL-2 and CGRP in Xue Shuan Tong group were significantly higher than those in the other two groups (P<0.05). After 7 day treatment, plaque size and thickness in Xue Shuan Tong group and Butylphthalide group were significantly reduced, compared with those before treatment (P<0.05), but no significant differences was shown in the plaque size and thickness between Xue Shuan Tong group and Butylphthalide group (P>0.05) .The CA-IMT in Xue Shuan Tong group and Butylphthalide group was significantly reduced after treatment, and that in Butylphthalide group was significantly larger than that in Xue Shuan Tong group (P<0.05). After 90-day follow-up, NIHSS scores in Butylphthalide group were significantly less than those in the other two groups (P<0.05). After 90-day follow-up, Barthel scores in Butylphthalide group and Xue Shuan Tong group were significantly larger than those in control group (P<0.05), while differences between Butylphthalide group and Xue Shuan Tong group indicated no statistical significance (P>0.05). There were significant differences in MRS scores among patients in the three groups after 90-day follow-up (P<0.05). Butylphthalide and Xue Shuan Tong are clinically effective in treating acute cerebral infarction. Butylphthalide has significant efficacy in inhibiting inflammation and improving prognosis of neurological function, while Xue Shuan Tong has obvious effect in improving carotid intima-media thickness. PMID- 26525023 TI - Effects of smokeless dipping tobacco (Naswar) consumption on antioxidant enzymes and lipid profile in its users. AB - Dipping tobacco, traditionally referred to as moist snuff, is a type of finely ground, moistened smokeless tobacco product. Naswar is stuffed in the floor of the mouth under the lower lip, or inside the cheek, for extended periods of time. Tobacco use causes dyslipidemia and also induces oxidative stress, leading to alteration in levels of antioxidant enzymes. Dyslipidemia and oxidative stress in turn play a vital role in the development of cardiovascular disease (CVD). Studies conducted on smokeless tobacco products reveal contradictory findings regarding its effects on lipid profile and antioxidant enzymes. As use of Naswar is quite common in Pakistan, the current study aimed to evaluate levels of the antioxidant enzymes viz glutathione per oxidase (GPx) and super oxide dismutase (SOD), alongside lipid profile parameters such as total cholesterol, triglycerides, High density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) to assess the risk of adverse cardiovascular events in Naswar users.90 Healthy males aged 16-43 years, who consumed Naswar daily, were selected for the study, alongside 68 age-matched non-tobacco users as controls. Both GPx and SOD levels as well as serum HDL-C were significantly reduced (P<0.01) in Naswar users, whereas serum total cholesterol, LDL-C, triglycerides and LDL-C/HDL-C ratio were significantly increased (P<0.01) in Naswar consumers compared to controls. Our findings indicate deleterious effects of Naswar usage on health by causing altered lipid profile and antioxidant enzymes thereby placing its consumers at an increased risk of cardiovascular disease. PMID- 26525024 TI - Study of the radiotherapy sensitizea-tion of retroperitoneal lymph node metastasis in patients by sodium glycididazole. AB - To observe the radiotherapy sensitization effect of retroperitoneal lymph node metastasis in patients by sodium glycididazole in recent clinical efficacy and toxicity. A total of 42 patients admitted with metastasis and recurrence of retroperitoneal lymph node from September 2006 to December 2009 were classified with the method of case-control. After three dimensional conformal radiation therapy with or without sodium glycididazole (800 mg/m2) for sensitization, the results of recent clinical efficacy, relief of pain, and Karnofsky score were obtained. Tumor remission rate of patients in sensitization group (with sodium glycididazole) at post-radiotherapy 3 months was significant higher than that in control group (without sodium glycididazole) (52% vs. 24%; P<0.05). Oral dose of morphine daily, and Karnofsky score in anterior-posterior radiotherapy of patients in the sensitization group were significant different with those in the control group (93 +/- 12 and 42 +/- 6 mg vs. 94 +/- 12 and 20 +/- 5 mg and (65 +/ 4) and (90 +/- 9) vs. (64 +/- 5) and (80 +/- 10), respectively; P<0.01). Sodium glycididazole has positive radiotherapy sensitization to the metastasis or recurrence of retroperitoneal lymph node for digestive tract cancer, which could obviously improve the life quality or release the pain for patients. PMID- 26525025 TI - Detection and adequacy assessment of erythrocyte glutathione transferase on the cycle toxin level of hemodialysis patient. AB - To explore detection and adequacy evaluation of erythrocyte glutathione S transferase (GST) in hemodialysis patients on circular toxin levels, this paper divided 84 cases of long-term hemodialysis end-stage patients into 33 cases of adequate hemodialysis group (spKt/V >= 1.3) and 51 cases of inadequate hemodialysis group (spKt/V<1.3) according to urea index value of unit chamber model (spKt/V). Take the other 50 cases of healthy physical examination people for control group, compare and analyze related clinical and biochemical indexes differences of three groups. The level of hemodialysis group GST, creatinine, high sensitivity C-reactive protein (hs-CRP), transferrin saturation (TSAT), parathyroid hormone (PTH), interleukin-2,6,8 (IL-2,6,8) and tumor necrosis factor alpha (TNF-alpha) was significantly higher than the control group (P<0.05), and GST, IL-2, 6, 8, TNF-alpha level of inadequate hemodialysis group was significantly higher than adequate hemodialysis group (P<0.05). Pearson's relevant analysis showed that GST and spKt/V, IL-2, IL-6, IL-8, TNF-alpha have positive correlation (P<0.05) and had no correlation with creatinine, hs-CRP, TSAT, PHT (P>0.05). There was 23 patients spKt/V>1.3 after adjusting the dialysis solution for 51 cases of inadequate hemodialysis patients, GST level after the adjustment was significantly lower than before the adjustment, but still higher than adequate dialysis group. It concludes that the maintenance of hemodialysis patients' level has certain relevance on spKt/V and associated inflammatory factors. Through the determination, GST can effectively response the adequate hemodialysis, which has a guiding significance on adjusting blood dialysis solution in clinic. PMID- 26525026 TI - SERS measurement of the bladder cancer cells with the nanoparticles. AB - The surfaced enhanced Raman spectroscopy (SERS) of bladder cancer cells and tissues were measured in this paper. Both depth SERS and map SERS of SCABER bladder cancer cells were measured with confocal Raman microscope using gold nanoparticles as the enhance substrate. We also measured SERS of normal bladder tissue and bladder cancer tissue, and analyzed the difference of two different tissues. The SERS spectra of more samples need to be measured and analyzed for bladder cancer tissue and the normal bladder tissue in the future and the spectra will be helpful for bladder cancer diagnosis. PMID- 26525027 TI - Analysis on diagnostic value of esophageal electrophysiological examination for positive atropine test. AB - To discuss the cause of positive atropine test and the possible reason for false positive atropine test, providing a certain aids for clinical diagnosis and treatment. Eighty patients, conducted atropine test due to sinus bradycardia, with positive results from January 2010 to June 2013, were selected. Sinus heart rate were calculated and the changes in heart rhythm were observed by tracing electrocardiogram. Esophageal electrophysiological examination and atropine test were administrated. SPSS 10.0 statistical software was adopted and x2 test was applied for comparison. The positive results of atropine test and results of esophageal electrophysiological examination in different ages showed that as age grows, false positive rate of atropine test was significantly reduced, presenting statistically significant difference (x2 =6.2821, P<0.05); The positive results of atropine test and results of esophageal electrophysiological examination in different heart rates showed that false positive rate of atropine test on those with bradycardia was smaller than those with significant bradycardia, presenting statistically significant difference (x2 =5.1792, P<0.05). Simple sinus bradycardia is mostly caused by the increase of vagus nerve tension, almost negative in atropine test. Sick sinus syndrome (SSS) leads to abnormity in pacemaking and conduction induced by organic lesions in sinus nodes. Moreover, as the disease progresses, it is able to cause severe and persistent sinus bradycardia, almost positive in atropine test. Therefore, to identify the increase in vagus nerve tension or sinus bradycardia induced by SSS has a crucial clinical significance. Furthermore, the false positive and false negative profiles in atropine test can easily lead to misdiagnosis and mistreatment in clinic. PMID- 26525028 TI - Studies on nursing risks and measures of clinical medication. AB - To investigate the cause analysis of clinical medication nursing risks and propose relevant nursing measures, so as to control and reduce the clinical nursing risks and reach the physical and mental safety of patients and nurses. Clinical nursing risk events with 30 cases in TCM Hospital of Zhengzhou City from June 2010 to April 2012 were underwent statistical analyses. The risk of medication error ranked the first in the direct reasons of nursing risks, accounting for a higher ratio. Moreover, the reasons of nursing risks were also involved in nonstandard operation, disease observation and other relative factors. Nurses must fully understand the relative factors of medication nursing risks, regarding the patients as their own family and always permeating the consciousness of nursing risks into the working process. PMID- 26525029 TI - Effect of incubating egg exposure to magnetic field on the biophysical blood properties of newly-hatched chicks. AB - Due to widespread of human exposure to electromagnetic fields, there has been increasing public concern about the potential health risks from low-frequency electromagnetic fields; ELF-EMF. The magnetic fields (MFs) affects functions of the living organisms, such as DNA synthesis and ion transportation through the cell membranes. In the present work, the effects of short-term exposure to magnetic fields (MFs) prior to incubation were investigated on the biophysical blood properties of chicks hatched from layer-type breeder eggs. The eggs were exposed to a MF of 0.75 mT at 50 Hz for 20, 40 and 60 min before incubation. This study was performed by measuring the dielectric relaxation of hemoglobin (Hb) molecules and the membrane solubility of red blood cells (RBCs) using the non ionic detergent octylglucoside. Exposure of the eggs to a MF increased the conductivity of the Hb molecules. The pronounced increase in the conductivity of the exposed eggs might be attributed to an increase in the surface charge of the Hb macromolecules, resulted from the formation of highly active molecular species. This speculation can be supported by the increase in the relaxation time of the exposed groups. The solubilization process of the RBC membrane indicates a loss in the mobility of RBCs in the blood of hatching chicks. PMID- 26525030 TI - Application prospect and clinical effect analysis of Fu Chan Xue Jing during bleeding after abortion. AB - To investigate the application future of Fu Chan Xue Jing during bleeding after abortion and to observe the clinical effect analysis of Fu Chan Xue Jing on the treatment of bleeding after medical abortion. 86 patients who were willing to perform medical abortion in Women and infants Hospital of Zhengzhou from December 2013 to November 2014 were randomly divided into two groups, with 43 cases in either observation group or control group. Basic medical abortion was conducted on the patients in control group, apart from which Fu Chan Xue Jing was added on the patients in observation group. Meanwhile, the vaginal bleeding volume and vaginal bleeding time for patients in both groups were observed and compared. The treatment results showed that the vaginal bleeding volume for patients in treatment group was lower than that in control group, showing statistically significant difference (P<0.05); the average time (7.5 +/- 1.3 d) of vaginal bleeding for patients in treatment group was shorter than that (13.5 +/- 4.1d) in control group, showing statistically significant difference for the data of the two groups (P<0.05). Fu Chan Xue Jing is conducive to reduce the bleeding after abortion and help to recovery the normal menstruation faster, which has good effects to prevent the bleeding volume after medical abortion and control the bleeding time, worth popularizing on clinic. PMID- 26525031 TI - Antitumor activity of a novel survivin siRNA. AB - Breast cancer resistance to therapy can result from expression of antiapoptotic genes. Survivin is an antiapoptotic gene that is over expressed in most human tumors. RNA interference using short interfering RNA (siRNA) can be used to specifically inhibit survivin expression. A novel siRNA targeting survivin was used to process MCF-7 cells. Cellular survivin mRNA and protein levels were determined by real-time qRT-PCR and Western blot, respectively. Cellular morphology and cell cycle were determined by fluorescence microscopy and flow cytometry. Cell proliferation was measured by MTT assay. Our data showed that the novel survivin-targeted siRNA could efficiently knockdown the expression of survivin, inhibit cell proliferation and cell cycle, especially at the G2/M checkpoint. These data suggest that the siRNA has potential for therapeutic applications. PMID- 26525032 TI - Model development for prediction of soil water dynamics in plant production. AB - Optimizing water use in agriculture and medicinal plants is crucially important worldwide. Soil sensor-controlled irrigation systems are increasingly becoming available. However it is questionable whether irrigation scheduling based on soil measurements in the top soil could make best use of water for deep-rooted crops. In this study a mechanistic model was employed to investigate water extraction by a deep-rooted cabbage crop from the soil profile throughout crop growth. The model accounts all key processes governing water dynamics in the soil-plant atmosphere system. Results show that the subsoil provides a significant proportion of the seasonal transpiration, about a third of water transpired over the whole growing season. This suggests that soil water in the entire root zone should be taken into consideration in irrigation scheduling, and for sensor controlled irrigation systems sensors in the subsoil are essential for detecting soil water status for deep-rooted crops. PMID- 26525033 TI - Isolation of flavonoids from Delonix elata and determination of its rutin content using capillary electrophoresis. AB - Delonix elata (L.) Gamble (Fabaceae) is an important, traditionally used plant in Saudi Arabia. It is used to relieve rheumatic pain, flatulence and the seeds are employed as purgatives. The aim of the present study was to isolate chemical constituents of the n-butanol fraction (BF) of D. elata and to find out, by capillary electrophoresis (CE), percentage of rutin present in this BF. Three quercetin glycosides and one kaempferol rutinoside were isolated from the BF of aerial parts of D. elata; namely, Quercetin 3-O-rutinoside-7-O-glucoside (1), Quercetin 3,7-diglucoside (2), Quercetin 3-O-rutinoside (RUT) (3) and Kaempferol 3-O-rutinoside (4). Rutin, an active constituent has been reported to possess good pharmacological as well as therapeutic potentials. A sensitive and rapid procedure for quantitative determination of RUT by capillary electrophoresis was developed and its content was found to be 7.349 mg/gm, relative to n-butanol fraction and 18.373 mg%, relative to the dry powder of D. elata. The method could be recommended for approval and use in the pharmaceutical and food industries. PMID- 26525034 TI - The antioxidant, general toxicity and insecticidal activities of Nepeta scrophularioides Rech. f. extracts in different developmental stages. AB - The essence of the present study is to focus on the antioxidant, general toxicity and insecticidal properties of the extracts of Nepeta scrophularioides Rech.f. during different developmental (vegetative, flowering, post-flowering) stages. The samples were subjected to screening for their possible antioxidant activities by using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assay. The extracts of the flowering and the post-flowering stages showed higher antioxidant activity than those from the vegetative stage. The MeOH extracts of N. scrophularioides in different development stages were tested for cytotoxicity by brine shrimp toxicity assay. The result obtained for the bio assay was found to be significantly lethality. Among the samples, the extracts of flowering stage were found to be the most active with a LC50 value of 0.078 mg/mL. All three extracts showed significant insecticidal activity at the concentration of 20 mg/mL dose of test sample after 24 h. The extracts of vegetative and post-flowering were the most potent samples. PMID- 26525035 TI - Optic neuritis as an initial manifestation of human herpesvirus 6 reactivation after unrelated bone marrow transplantation. PMID- 26525036 TI - The specific functionalization of cyclotriphosphazene for the synthesis of smart dendrimers. AB - Hexachlorocyclotriphosphazene is an old compound which affords very new properties in the field of dendrimers. Indeed, it can be used as a branching point for the rapid synthesis of highly dense dendrimers, but also for the synthesis of dendrimers having precisely one function different from all the others. These types of dendrimers are useful in the field of materials, affording highly reusable catalysts, chemical sensors, or supports for cell cultures. However, the most developed uses concern fluorescence. These dendrimers have been used for in vivo imaging, and for trying to elucidate biological mechanisms, in particular for anti-inflammatory dendrimers. This review will display important examples in the field. PMID- 26525037 TI - Severe maternal morbidity-actions are more important than definitions. PMID- 26525038 TI - Casein kinase 1gamma acts as a molecular switch for cell polarization through phosphorylation of the polarity factor Tea1 in fission yeast. AB - Fission yeast undergoes growth polarity transition from monopolar to bipolar during G2 phase, designated NETO (New End Take Off). It is known that NETO onset involves two prerequisites, the completion of DNA replication and attainment of a certain cell size. However, the molecular mechanism remains unexplored. Here, we show that casein kinase 1gamma, Cki3 is a critical determinant of NETO onset. Not only did cki3? cells undergo NETO during G1- or S-phase, but they also displayed premature NETO under unperturbed conditions with a smaller cell size, leading to cell integrity defects. Cki3 interacted with the polarity factor Tea1, of which phosphorylation was dependent on Cki3 kinase activity. GFP nanotrap of Tea1 by Cki3 led to Tea1 hyperphosphorylation with monopolar growth, whereas the same entrapment by kinase-dead Cki3 resulted in converse bipolar growth. Intriguingly, the Tea1 interactor Tea4 was dissociated from Tea1 by Cki3 entrapment. Mass spectrometry identified four phosphoserine residues within Tea1 that were hypophosphorylated in cki3? cells. Phosphomimetic Tea1 mutants showed compromised binding to Tea4 and NETO defects, indicating that these serine residues are critical for protein-protein interaction and NETO onset. Our findings provide significant insight into the mechanism by which cell polarization is regulated in a spatiotemporal manner. PMID- 26525039 TI - Laparoscopic vs mini-incision open appendectomy. AB - AIM: To compare laparoscopic vs mini-incision open appendectomy in light of recent data at our centre. METHODS: The data of patients who underwent appendectomy between January 2011 and June 2013 were collected. The data included patients' demographic data, procedure time, length of hospital stay, the need for pain medicine, postoperative visual analog scale of pain, and morbidities. Pregnant women and patients with previous lower abdominal surgery were excluded. Patients with surgery converted from laparoscopic appendectomy (LA) to mini incision open appendectomy (MOA) were excluded. Patients were divided into two groups: LA and MOA done by the same surgeon. The patients were randomized into MOA and LA groups a computer-generated number. The diagnosis of acute appendicitis was made by the surgeon with physical examination, laboratory values, and radiological tests (abdominal ultrasound or computed tomography). All operations were performed with general anaesthesia. The postoperative vision analog scale score was recorded at postoperative hours 1, 6, 12, and 24. Patients were discharged when they tolerated normal food and passed gas and were followed up every week for three weeks as outpatients. RESULTS: Of the 243 patients, 121 (49.9%) underwent MOA, while 122 (50.1%) had laparoscopic appendectomy. There were no significant differences in operation time between the two groups (P = 0.844), whereas the visual analog scale of pain was significantly higher in the open appendectomy group at the 1(st) hour (P = 0.001), 6(th) hour (P = 0.001), and 12(th) hour (P = 0.027). The need for analgesic medication was significantly higher in the MOA group (P = 0.001). There were no differences between the two groups in terms of morbidity rate (P = 0.599). The rate of total complications was similar between the two groups (6.5% in LA vs 7.4% in OA, P = 0.599). All wound infections were treated non-surgically. Six out of seven patients with pelvic abscess were successfully treated with percutaneous drainage; one patient required surgical drainage after a failed percutaneous drainage. There were no differences in the period of hospital stay, operation time, and postoperative complication rate between the two groups. Laparoscopic appendectomy decreases the need for analgesic medications and the visual analog scale of pain. CONCLUSION: The laparoscopic appendectomy should be considered as a standard treatment for acute appendicitis. Mini-incision appendectomy is an alternative for a select group of patients. PMID- 26525040 TI - Pharmacokinetic study of dendrobine in rat plasma by ultra-performance liquid chromatography tandem mass spectrometry. AB - Dendrobine, considered as the major active alkaloid compound, has been used for the quality control and discrimination of Dendrobium which is documented in the Chinese Pharmacopoeia. In this work, a sensitive and simple ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for determination of dendrobine in rat plasma is developed. After addition of caulophyline as an internal standard (IS), protein precipitation by acetonitrile methanol (9:1, v/v) was used to prepare samples. Chromatographic separation was achieved on a UPLC BEH C18 (2.1 *100 mm, 1.7 um) column with acetonitrile and 0.1% formic acid as the mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reaction monitoring mode was used for quantification using target fragment ions m/z 264.2 -> 70.0 for dendrobine and m/z 205.1 -> 58.0 for IS. Calibration plots were linear throughout the range 2-1000 ng/mL for dendrobine in rat plasma. The RSDs of intra-day and inter-day precision were both <13%. The accuracy of the method was between 95.4 and 103.9%. The method was successfully applied to pharmacokinetic study of dendrobine after intravenous administration. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26525041 TI - Target-triggered cascade recycling amplification for label-free detection of microRNA and molecular logic operations. AB - A cascade recycling amplification (CRA) that implements cascade logic circuits with feedback amplification function is developed for label-free chemiluminescence detection of microRNA-122 with an ultrahigh sensitivity of 0.82 fM and excellent specificity, which is applied to construct a series of molecular scale two-input logic gates by using microRNAs as inputs and CRA products as outputs. PMID- 26525042 TI - Therapeutic Potential of Adipose-Derived Therapeutic Factor Concentrate for Treating Critical Limb Ischemia. AB - Transplantation of adipose-derived stem cells (ADSCs) is an emerging therapeutic option for addressing intractable diseases such as critical limb ischemia (CLI). Evidence suggests that therapeutic effects of ADSCs are primarily mediated through paracrine mechanisms rather than transdifferentiation. These secreted factors can be captured in conditioned medium (CM) and concentrated to prepare a therapeutic factor concentrate (TFC) composed of a cocktail of beneficial growth factors and cytokines that individually and in combination demonstrate disease modifying effects. The ability of a TFC to promote reperfusion in a rabbit model of CLI was evaluated. A total of 27 adult female rabbits underwent surgery to induce ischemia in the left hindlimb. An additional five rabbits served as sham controls. One week after surgery, the ischemic limbs received intramuscular injections of either (1) placebo (control medium), (2) a low dose of TFC, or (3) a high dose of TFC. Limb perfusion was serially assessed with a Doppler probe. Blood samples were analyzed for growth factors and cytokines. Tissue was harvested postmortem on day 35 and assessed for capillary density by immunohistochemistry. At 1 month after treatment, tissue perfusion in ischemic limbs treated with a high dose of TFC was almost double (p < 0.05) that of the placebo group [58.8 +/- 23 relative perfusion units (RPU) vs. 30.7 +/- 13.6 RPU; mean +/- SD]. This effect was correlated with greater capillary density in the affected tissues and with transiently higher serum levels of the angiogenic and prosurvival factors vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). The conclusions from this study are that a single bolus administration of TFC demonstrated robust effects for promoting tissue reperfusion in a rabbit model of CLI and that a possible mechanism of revascularization was promotion of angiogenesis by TFC. Results of this study demonstrate that TFC represents a potent therapeutic cocktail for patients with CLI, many of whom are at risk for amputation of the affected limb. PMID- 26525043 TI - A Population Pharmacokinetic-Pharmacodynamic Meta-Analysis of Vortioxetine in Patients with Major Depressive Disorder. AB - Vortioxetine is approved for the treatment of major depressive disorder (MDD). This analysis aimed to develop pharmacokinetic (PK) and PK/Efficacy models to evaluate the exposure-response relationship for vortioxetine in patients with MDD. PK data from 10 MDD and two generalized anxiety disorder studies of vortioxetine (3160 patients), and efficacy data [Montgomery-Asberg Depression Rating Scale (MADRS)] from seven MDD studies (2537 patients), were used for the development of PK and PK/Efficacy models. One- and two-compartment models were evaluated as structural PK models, and linear and nonlinear (Emax) models were used to describe the relationship between average vortioxetine concentration at steady-state (Cav) and change in MADRS score from baseline (DeltaMADRS). The impact of selected covariates on the PK and efficacy parameters of vortioxetine was also investigated. PK of vortioxetine was best characterized by a two compartment model with first-order absorption and elimination. Mean estimates for oral clearance (CL/F) and volume of distribution for the central compartment of vortioxetine were 42 L/hr and 2920 L. Creatinine clearance, height and geographic region had statistically significant effects on vortioxetine CL/F, but the effect of each of these covariates was not considered clinically relevant, as they lead to +/-26% change in area under the curve or Cmax of vortioxetine. An Emax model best described the relationship between DeltaMADRS and Cav. Half-maximal effective concentration (EC50) and Emax estimates were 24.9 ng/mL and 7.0. No identified covariates, except region, had clinically meaningful effects on vortioxetine efficacy. These PK/Efficacy models adequately characterized the vortioxetine exposure-response relationship. PMID- 26525044 TI - Integrating multiple data sources (MUDS) for meta-analysis to improve patient centered outcomes research: a protocol. AB - BACKGROUND: Systematic reviews should provide trustworthy guidance to decision makers, but their credibility is challenged by the selective reporting of trial results and outcomes. Some trials are not published, and even among clinical trials that are published partially (e.g., as conference abstracts), many are never published in full. Although there are many potential sources of published and unpublished data for systematic reviews, there are no established methods for choosing among multiple reports or data sources about the same trial. METHODS: We will conduct systematic reviews of the effectiveness and safety of two interventions following the Institute of Medicine (IOM) guidelines: (1) gabapentin for neuropathic pain and (2) quetiapine for bipolar depression. For the review of gabapentin, we will include adult participants with neuropathic pain who do not require ventilator support. For the review of quetiapine, we will include adult participants with acute bipolar depression (excluding mixed or rapid cycling episodes). We will compare these drugs (used alone or in combination with other interventions) with placebo or with the same intervention alone; direct comparisons with other medications will be excluded. For each review, we will conduct highly sensitive electronic searches, and the results of the searches will be assessed by two independent reviewers. Outcomes, study characteristics, and risk of bias ratings will be extracted from multiple reports by two individuals working independently, stored in a publicly available database (Systematic Review Data Repository) and analyzed using commonly available statistical software. In each review, we will conduct a series of meta-analyses using data from different sources to determine how the results are affected by the inclusion of data from multiple published sources (e.g., journal articles and conference abstracts) as well as unpublished aggregate data (e.g., "clinical study reports") and individual participant data (IPD). We will identify patient centered outcomes in each report and identify differences in the reporting of these outcomes across sources. SYSTEMATIC REVIEW REGISTRATION: CRD42015014037 , CRD42015014038. PMID- 26525045 TI - Once-weekly teriparatide in hemodialysis patients with hypoparathyroidism and low bone mass: a prospective study. AB - Once-weekly 56.5-MUg teriparatide treatment was significantly associated with the increase in lumbar spine bone mineral density at 48 weeks among hemodialysis patients with hypoparathyroidism and low bone mass; however, discontinuation of treatment because of adverse events was frequently observed. Careful monitoring for adverse events should be required. INTRODUCTION: Once-weekly 56.5-MUg teriparatide is reportedly effective for treating osteoporotic patients without renal insufficiency. However, little is known about the efficacy and safety of once-weekly teriparatide in hemodialysis patients. METHODS: We conducted a 48 week prospective, observational cohort study including 22 hemodialysis patients aged 20 years or older with hypoparathyroidism and low bone mass who received once-weekly teriparatide at 56.5 MUg at a tertiary care hospital between January 2013 and January 2015. Primary outcomes were within-subject percent changes of bone mineral density (BMD) at the lumbar spine, femoral neck, and distal one third radius at 24 and 48 weeks. Secondary outcomes included percent changes of serum bone turnover markers (osteocalcin, bone-specific alkaline phosphatase (BAP), N-terminal propeptide of procollagen type 1 (P1NP), and tartrate-resistant acid phosphatase 5b (TRAP-5b)). Adverse events were evaluated. RESULTS: The BMD increased at the lumbar spine by 3.3 +/- 1.9 % (mean +/- SEM) and 3.0 +/- 1.8 % at 24 and 48 weeks but not in the femoral neck and distal one-third radius. Serum osteocalcin, BAP, and P1NP increased significantly at 4 weeks, maintaining higher concentrations up to 48 weeks, although TRAP-5b decreased gradually during treatment. The baseline BAP was significantly associated with the 48-week percent change in lumbar spine BMD. Transient hypotension was the most common adverse event. Ten patients discontinued treatment because of adverse events. CONCLUSIONS: Once-weekly teriparatide was associated with increased lumbar spine BMD in hemodialysis patients with hypoparathyroidism and low bone mass. Careful monitoring should be required for treatment of such patients. PMID- 26525046 TI - Social encounter profiles of greater Melbourne residents, by location--a telephone survey. AB - BACKGROUND: Models of infectious disease increasingly seek to incorporate heterogeneity of social interactions to more accurately characterise disease spread. We measured attributes of social encounters in two areas of Greater Melbourne, using a telephone survey. METHODS: A market research company conducted computer assisted telephone interviews (CATIs) of residents of the Boroondara and Hume local government areas (LGAs), which differ markedly in ethnic composition, age distribution and household socioeconomic status. Survey items included household demographic and socio-economic characteristics, locations visited during the preceding day, and social encounters involving two-way conversation or physical contact. Descriptive summary measures were reported and compared using weight adjusted Wald tests of group means. RESULTS: The overall response rate was 37.6%, higher in Boroondara [n = 650, (46%)] than Hume [n = 657 (32%)]. Survey conduct through the CATI format was challenging, with implications for representativeness and data quality. Marked heterogeneity of encounter profiles was observed across age groups and locations. Household settings afforded greatest opportunity for prolonged close contact, particularly between women and children. Young and middle-aged men reported more age-assortative mixing, often with non-household members. Preliminary comparisons between LGAs suggested that mixing occurred in different settings. In addition, gender differences in mixing with household and non-household members, including strangers, were observed by area. CONCLUSIONS: Survey administration by CATI was challenging, but rich data were obtained, revealing marked heterogeneity of social behaviour. Marked dissimilarities in patterns of prolonged close mixing were demonstrated by gender. In addition, preliminary observations of between-area differences in socialisation warrant further evaluation. PMID- 26525047 TI - Panax Notoginseng Saponins Ameliorates Coxsackievirus B3-Induced Myocarditis by Activating the Cystathionine-gamma-Lyase/Hydrogen Sulfide Pathway. AB - This study is to determine the therapeutic effects of Panax notoginseng saponins (PNSs) on coxsackievirus B3 (CVB3)-induced myocarditis, and whether cystathionine gamma-lyase (CSE)/hydrogen sulfide (H2S) pathway is involved. Mouse model of myocarditis was induced by CVB3 infection, and the mice were subjected to vehicle (saline) or drug treatments (sodium bisulfide (NaHS), propargylglycine (PAG), or PNSs). The results showed that there were inflammatory cell infiltrations, interstitial edemas, and elevated inflammatory cytokines, in CVB3-induced myocarditis. PAG administration increased, whereas NaHS treatment decreased the severity of the myocarditis. PNS treatment dramatically alleviated these myocardial injuries and decreased the viral messenger RNA (mRNA) expression by the enhanced expression of CSE/H2S pathway. Moreover, the therapeutic effects of PNSs on myocarditis were stronger than those of NaHS. Finally, the effect of PNSs on CSE/H2S pathway and cardiac cell protection were verified in cultured cardiac cells. PNSs may be a promising medication for viral myocarditis therapy. PMID- 26525048 TI - Patients' perceptions of palliative care: adaptation of the Quality from the Patient's Perspective instrument for use in palliative care, and description of patients' perceptions of care received. AB - BACKGROUND: Instruments specific to palliative care tend to measure care quality from relative perspectives or have insufficient theoretical foundation. The instrument Quality from the Patient's Perspective (QPP) is based on a model for care quality derived from patients' perceptions of care, although it has not been psychometrically evaluated for use in palliative care. The aim of this study was to adapt the QPP for use in palliative care contexts, and to describe patients' perceptions of the care quality in terms of the subjective importance of the care aspects and the perceptions of the care received. METHOD: A cross-sectional study was conducted between November 2013 and December 2014 which included 191 patients (73% response rate) in late palliative phase at hospice inpatient units, hospice day-care units, wards in nursing homes that specialized in palliative care and homecare districts, all in Norway. An explorative factor analysis using principal component analysis, including data from 184 patients, was performed for psychometric evaluation. Internal consistency was assessed by Cronbach's alpha and paired t-tests were used to describe patients' perceptions of their care. RESULTS: The QPP instrument was adapted for palliative care in four steps: (1) selecting items from the QPP, (2) modifying items and (3) constructing new items to the palliative care setting, and (4) a pilot evaluation. QPP instrument specific to palliative care (QPP-PC) consists of 51 items and 12 factors with an eigenvalue >=1.0, and showed a stable factor solution that explained 68.25% of the total variance. The reliability coefficients were acceptable for most factors (0.79-0.96). Patients scored most aspects of care related to both subjective importance and actual care received as high. Areas for improvement were symptom relief, participation, continuity, and planning and cooperation. CONCLUSION: The QPP-PC is based on a theoretical model of quality of care, and has its roots in patients' perspectives. The instrument was developed and psychometrically evaluated in a sample of Norwegian patients with various diagnoses receiving palliative care in different care contexts. The evaluation of the QPP-PC shows promising results, although it needs to be further validated and tested in other contexts and countries. PMID- 26525049 TI - Randomized controlled pilot of an intervention to reduce and break-up overweight/obese adults' overall sitting-time. AB - BACKGROUND: Too much prolonged sitting is a prevalent health risk among adults. Interventions have focused mainly on the workplace, with limited attention to non work settings. The effectiveness of a short-term intervention to reduce and break up sitting-time in overweight/obese adults was examined. This pilot study sought to determine the feasibility of interrupting sitting to stand/ambulate objectively with ActivPAL devices which provide a valid measurement of sit/stand transitions. METHODS: This is a cross-over randomized controlled pilot that included 10 participants (aged 37-65 years) and although a small and short-term intervention (1-week intervention; no washout) further informs on the feasibility of interventions on a larger scale. At the workplace, screen-delivered hourly alerts prompted participants to break-up sitting-time through adopting walking behaviors (approximately 30-60 minutes day(-1)). During transportation/home/leisure-time individual goals for steps day(-1) were set and sitting-reduction strategies (including behavioral self-monitoring) were delivered through daily text messages. Change in inclinometer-derived sitting time is the main outcome. Standing, stepping, number of sit/stand transitions and participant satisfaction were also examined. RESULTS: For the intervention compared to the control-week (mean difference (95 % confidence interval); p value), participants had less sitting-time (1.85 hours (0.96-2.75); p = 0.001), more standing (0.77 hours (0.06-1.48); p = 0.036), and more stepping (1.09 hours (0.79- 1.38); p < 0.001). Importantly, there was no change in the total number of sit/stand transitions (3.28 (-2.33-8.89); p = 0.218) despite successfully reducing sitting-time and increasing time spent standing and walking. CONCLUSIONS: Sitting-time in overweight/obese adults can be reduced following a brief multi-component intervention based on prompts, telephone support, goal setting and behavioral self-monitoring. However, the results from this pilot study provide new insight that when overweight/obese adults attempted to reduce sedentary-time by walking and standing for approximately 2 hour day(-1) more than usual, they did not actually get up from sitting more often (i.e. increasing the number of sit/stand transitions), but instead remained on their feet for longer during each non-sitting bout. This behavioral resistance to make more sit/stand transitions (i.e. get-up from sitting more often) may have important implications for future modification programs and supports the concept that when overweight/obese people are sitting, people seem to prefer not to interrupt the sedentary behavior to get-up from sitting. TRIAL REGISTRATION: 26 November 2013, ClinicalTrials.govID: NCT02007681 (first participant was randomized on 2 September 2013). PMID- 26525050 TI - Genomic correlation: harnessing the benefit of combining two unrelated populations for genomic selection. AB - BACKGROUND: The success of genomic selection in animal breeding hinges on the availability of a large reference population on which genomic-based predictions of additive genetic or breeding values are built. Here, we explore the benefit of combining two unrelated populations into a single reference population. METHODS: The datasets consisted of 1829 Brahman and 1973 Tropical Composite cattle with measurements on five phenotypes relevant to tropical adaptation and genotypes for 71,726 genome-wide single nucleotide polymorphisms (SNPs). The underlying genomic correlation for the same phenotype across the two breeds was explored on the basis of consistent linkage disequilibrium (LD) phase and marker effects in both breeds. RESULTS: The proportion of genetic variance explained by the entire set of SNPs ranged from 37.5 to 57.6 %. Estimated genomic correlations were drastically affected by the process used to select SNPs and went from near 0 to more than 0.80 for most traits when using the set of SNPs with significant effects and the same LD phase in the two breeds. We found that, by carefully selecting the subset of SNPs, the missing heritability can be largely recovered and accuracies in genomic predictions can be improved six-fold. However, the increases in accuracy might come at the expense of large biases. CONCLUSIONS: Our results offer hope for the effective implementation of genomic selection schemes in situations where the number of breeds is large, the sample size within any single breed is small and the breeding objective includes many phenotypes. PMID- 26525052 TI - Addition of dexmedetomidine to benzodiazepines for patients with alcohol withdrawal syndrome in the intensive care unit: a randomized controlled study. AB - BACKGROUND: Dexmedetomidine (DEX) is a centrally acting alpha-2-adrenoceptor agonist that has potential in the management of alcohol withdrawal syndrome (AWS) owing to its ability to produce arousable sedation and to inhibit the adrenergic system without respiratory depression. The objective of this randomized controlled study was to evaluate whether addition of DEX to benzodiazepine (BZD) therapy is effective and safe for AWS patients in the intensive care unit (ICU). METHODS: Eligible participants were randomly assigned to intervention (Group D; n = 36) or control (Group C; n = 36). In Group D, DEX infusion was started at a dose of 0.2-1.4 MUg/kg/h and titrated to achieve the target sedation level (-2 to 0 on the Richmond Agitation Sedation Scale (RASS)) with symptom-triggered BZD (10 mg diazepam bolus) was used as needed. Patients in Group C received only symptom triggered 10 mg boluses of diazepam. The primary efficacy outcomes were 24-h diazepam consumption and cumulative diazepam dose required over the course of the ICU stay; secondary outcomes included length of ICU stay, sedation and communication quality and haloperidol requirements. RESULTS: Median 24-h diazepam consumption during the study was significantly lower in Group D (20 vs. 40 mg, p < 0.001), as well as median cumulative diazepam dose during the ICU stay (60 vs. 90 mg, p < 0.001). The median percentage of time in the target sedation range was higher in Group D (median 90 % (90-95) vs. 64.5 % (60-72.5; p < 0.001). DEX infusion was also associated with better nurse-assessed patient communication (<0.001) and fewer patients requiring haloperidol treatment (2 vs. 10 p = 0.02). One patient in Group D and four in Group C were excluded owing to insufficient control of AWS symptoms and use of additional sedatives (p = 0.36). There were no severe adverse events in either group. Spontaneous breathing remained normal in all patients. Bradycardia was a common adverse event in Group D (10 vs. 2; p = 0.03). CONCLUSIONS: DEX significantly reduced diazepam requirements in ICU patients with AWS and decreased the number of patients who required haloperidol for severe agitation and hallucinations. DEX use was also associated with improvement in diverse aspects of sedation quality and the quality of patient communication. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02496650. PMID- 26525051 TI - Long-term meditation training induced changes in the operational synchrony of default mode network modules during a resting state. AB - Using theoretical analysis of self-consciousness concept and experimental evidence on the brain default mode network (DMN) that constitutes the neural signature of self-referential processes, we hypothesized that the anterior and posterior subnets comprising the DMN should show differences in their integrity as a function of meditation training. Functional connectivity within DMN and its subnets (measured by operational synchrony) has been measured in ten novice meditators using an electroencephalogram (EEG) recording in a pre-/post meditation intervention design. We have found that while the whole DMN was clearly suppressed, different subnets of DMN responded differently after 4 months of meditation training: The strength of EEG operational synchrony in the right and left posterior modules of the DMN decreased in resting post-meditation condition compared to a pre-meditation condition, whereas the frontal DMN module on the contrary exhibited an increase in the strength of EEG operational synchrony. These findings combined with published data on functional-anatomic heterogeneity within the DMN and on trait subjective experiences commonly found following meditation allow us to propose that the first-person perspective and the sense of agency (the witnessing observer) are presented by the frontal DMN module, while the posterior modules of the DMN are generally responsible for the experience of the continuity of 'I' as embodied and localized within bodily space. Significance of these findings is discussed. PMID- 26525053 TI - Associations between bolus infusion of hydrocortisone, glycemic variability and insulin infusion rate variability in critically Ill patients under moderate glycemic control. AB - BACKGROUND: We retrospectively studied associations between bolus infusion of hydrocortisone and variability of the blood glucose level and changes in insulin rates in intensive care unit (ICU) patients. METHODS: 'Glycemic variability' and 'insulin infusion rate variability' were calculated from and expressed as the standard deviation (SD) of all blood glucose levels and insulin infusion rates during stay in the ICU, respectively. Glycemic and insulin infusion rate variability in patients who received bolus infusion of hydrocortisone were compared to those in patients who never received bolus infusion of hydrocortisone. Multivariate analysis was performed to correct for potential covariates including disease severity. RESULTS: We included 6409 patients over 6 years; of them 962 received bolus infusion of hydrocortisone. Compared to patients who never received bolus infusion of hydrocortisone, patients who received hydrocortisone had their blood glucose level measured more frequently, had higher glycemic variability; were more frequently treated with intravenous insulin and had higher insulin infusion rate variability. The association between hydrocortisone treatment and glycemic variability was independent of disease severity, but the effect of hydrocortisone treatment on blood glucose variability was less strong in the more severely ill patients. The association between hydrocortisone and insulin infusion rate variability was also independent of disease severity, and independent of glycemic variability. CONCLUSIONS: Bolus infusion of hydrocortisone is independently associated with higher glycemic variability and higher insulin infusion rate variability in ICU patients. Studies are needed to see if continuous infusion of hydrocortisone prevents higher glycemic variability and higher insulin infusion rate variability. PMID- 26525054 TI - Does prophylactic antibiotic reduce surgical site infections after rhomboid excision and Limberg flap for pilonidal disease: a prospective randomized double blind study. PMID- 26525055 TI - Successful treatment of chronic Pouchitis utilizing fecal microbiota transplantation (FMT): a case report. PMID- 26525056 TI - Color Correction Parameter Estimation on the Smartphone and Its Application to Automatic Tongue Diagnosis. AB - BACKGROUND: An automatic tongue diagnosis framework is proposed to analyze tongue images taken by smartphones. Different from conventional tongue diagnosis systems, our input tongue images are usually in low resolution and taken under unknown lighting conditions. Consequently, existing tongue diagnosis methods cannot be directly applied to give accurate results. MATERIALS AND METHODS: We use the SVM (support vector machine) to predict the lighting condition and the corresponding color correction matrix according to the color difference of images taken with and without flash. We also modify the state-of-the-art work of fur and fissure detection for tongue images by taking hue information into consideration and adding a denoising step. RESULTS: Our method is able to correct the color of tongue images under different lighting conditions (e.g. fluorescent, incandescent, and halogen illuminant) and provide a better accuracy in tongue features detection with less processing complexity than the prior work. CONCLUSIONS: In this work, we proposed an automatic tongue diagnosis framework which can be applied to smartphones. Unlike the prior work which can only work in a controlled environment, our system can adapt to different lighting conditions by employing a novel color correction parameter estimation scheme. PMID- 26525057 TI - Simulation and Visualization of Liver Cancer Ablation Focus in Optical Surgical Navigation. AB - Radiofrequency ablation therapy of liver cancer is a local mini-invasive treatment technology with several advantages, such as low trauma, safety, effectiveness, and quick postoperative recovery. The application of the optical surgical navigation system in radiofrequency ablation therapy can realize the real-time positioning of surgical instruments and focus. The positioning results can be displayed on the computer, thereby guiding doctors to accurately insert the radiofrequency electrode into the focus and improving surgical efficiency. Meanwhile, the accurate evaluation of the form and size of the ablation focus by the navigation system is the key to realizing the complete ablation of liver cancer. Therefore, based on the heat conduction equation, this paper simplifies the simulation process of the ablation focus, calculates the volume of the ablation focus by distinguishing boundary points and internal points, achieves the effective simulation of the ablation results in the surgery, and reconstructs the ablation focus by using ray casting algorithm and mobile cube algorithm for 3D visualization processing, thereby providing doctors the convenience of being able to simulate the radiofrequency ablation surgery before the actual surgery. PMID- 26525060 TI - Mdm4: don't judge an isoform by its mRNA levels! PMID- 26525059 TI - Age-Related Differences in Pressures Generated During Isometric Presses and Swallows by Healthy Adults. AB - The aim of this prospective observational study was to determine the associations among age, maximum lingual isometric pressures, and maximum swallow pressures in specific regions of the tongue. Individuals 21 years and older who reported normal swallowing were enrolled. Seventy-one healthy adults were stratified by age into young (21-40 years), middle (41-60), and old (61-82) groups. Maximum pressures were measured for each individual during isometric tongue press tasks as well as saliva, 5, and 10 mL thin liquid bolus swallows at 5 sensors located on the hard palate: front, middle, left, right, and back. Lower maximum lingual pressures for all tasks were associated with increased age (p < 0.04). Saliva pressures exhibited a different pressure pattern than bolus swallows with pressures higher than bolus swallows on middle (p < 0.03) and back (p < 0.05) tongue sensors but not in the front. Diminished swallow pressure reserve (maximum isometric pressure-maximum swallow pressure) also was found with increased age (p < 0.03). Isometric pressures were greater than swallow pressures in young and middle age groups at both the front (p < 0.04) and back (p < 0.03) sensors, but only significantly greater at the front sensor for the oldest group (p < 0.04). Older healthy adults have lower lingual isometric pressures and lower swallow pressures than younger healthy adults. Elders have a decreased swallow pressure reserve to draw upon during occasions of physiological stress. While the exact mechanisms for age-related decline in lingual pressures remain unclear, they are likely due, at least in part, to sarcopenia. Saliva, 5, and 10 mL thin boluses also exhibit different age-related declines in pressure at specific sensors, indicating they may elicit different muscle activation patterns. PMID- 26525058 TI - Proteomic analysis of protein carbonylation: a useful tool to unravel nanoparticle toxicity mechanisms. AB - BACKGROUND: Oxidative stress, a commonly used paradigm to explain nanoparticle (NP)-induced toxicity, results from an imbalance between reactive oxygen species (ROS) generation and detoxification. As one consequence, protein carbonyl levels may become enhanced. Thus, the qualitative and quantitative description of protein carbonylation may be used to characterize how biological systems respond to oxidative stress induced by NPs. METHODS: We investigated a representative panel of 24 NPs including functionalized amorphous silica (6), zirconium dioxide (4), silver (4), titanium dioxide (3), zinc oxide (2), multiwalled carbon nanotubes (3), barium sulfate and boehmite. Surface reactivities of all NPs were studied in a cell-free system by electron spin resonance (ESR). NRK-52E cells were treated with all NPs, analyzed for viability (WST-1 assay) and intracellular ROS production (DCFDA assay). Carbonylated proteins were assessed by 1D and/or 2D immunoblotting and identified by matrix assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF/TOF). In parallel, tissue homogenates from rat lungs intratracheally instilled with silver NPs were studied. RESULTS: Eleven NPs induced elevated levels of carbonylated proteins. This was in good agreement with the surface reactivity of the NPs as obtained by ESR and the reduction in cell viability as assessed by WST-1 assay. By contrast, results obtained by DCFDA assay were deviating. Each NP induced an individual pattern of protein carbonyls on 2D immunoblots. Affected proteins comprised cytoskeletal components, proteins being involved in stress response, or cytoplasmic enzymes of central metabolic pathways such as glycolysis and gluconeogenesis. Furthermore, induction of carbonyls upon silver NP treatment was also verified in rat lung tissue homogenates. CONCLUSIONS: Analysis of protein carbonylation is a versatile and sensitive method to describe NP-induced oxidative stress and, therefore, can be used to identify NPs of concern. Furthermore, detailed information about compromised proteins may aid in classifying NPs according to their mode of action. PMID- 26525061 TI - Cytokinin: a key driver of seed yield. AB - The cytokinins have been implicated in many facets of plant growth and development including cell division and differentiation, shoot and root growth, apical dominance, senescence, fruit and seed development, and the response to biotic and abiotic stressors. Cytokinin levels are regulated by a balance between biosynthesis [isopentenyl transferase (IPT)], activation [Lonely Guy (LOG)], inactivation (O-glucosyl transferase), re-activation (beta-glucosidase), and degradation [cytokinin oxidase/dehydrogenase (CKX)]. During senescence, the levels of active cytokinins decrease, with premature senescence leading to a decrease in yield. During the early stages of fruit and seed development, cytokinin levels are transiently elevated, and coincide with nuclear and cell divisions which are a determinant of final seed size. Exogenous application of cytokinin, ectopic expression of IPT, or down-regulation of CKX have, on occasions, led to increased seed yield, leading to the suggestion that cytokinin may be limiting yield. However, manipulation of cytokinins is complex, not only because of their pleiotropic nature but also because the genes coding for biosynthesis and metabolism belong to multigene families, the members of which are themselves spatially and temporally differentiated. Previous research on yield of rice showed that plant breeders could directly target the cytokinins. Modern genome editing tools could be employed to target and manipulate cytokinin levels to increase seed yield with the concurrent aim of maintaining quality. However, how the cytokinin level is modified and whether IPT or CKX is targeted may depend on whether the plant is considered to be in a source-limiting environment or to be sink limited. PMID- 26525062 TI - Death after cardiac surgery is chiefly due to patient risk factors, study finds. PMID- 26525063 TI - Patterns of Electronic Cigarette Use Among Adults in the United States. AB - INTRODUCTION: Amid increasing rates of electronic cigarette (e-cigarette) use in the United States, there is an urgent need to monitor patterns of use at the population level in order to inform practice, policy and regulation. This article examines how patterns of e-cigarette use among adults differ between users and nonusers of cigarettes using the most current national data. METHODS: We analyzed data from the 2014 National Health Interview Survey. We estimated prevalence of ever, current, and daily e-cigarette use and examined how use patterns differed by demographic subgroups and measures of cigarette smoking status that accounted for the recent availability of e-cigarettes in the US marketplace. RESULTS: Current e-cigarette use is extremely low among never cigarette smokers (0.4%) and former smokers who quit cigarettes 4 or more years ago (0.8%). Although e cigarette experimentation is most common among current cigarette smokers and young adults, daily use is highest among former smokers who quit in the past year (13.0%) and older adults. Compared to daily cigarette smokers, recently quit smokers were more than four times as likely to be daily users of e-cigarettes (AOR: 4.33 [95% CI: 3.08-6.09]). CONCLUSIONS: Extremely low e-cigarette use among never-smokers and longer term former smokers suggest that e-cigarettes neither promote widespread initiation nor relapse among adults. Recognition of the heterogeneity of smokers, including the time since quitting, is critical to draw accurate conclusions about patterns of e-cigarette use at the population level and its potential for public health benefit or harm. IMPLICATIONS: Data from 2014 National Health Interview Survey indicate that e-cigarettes have not been attracting adult non-smokers or promoting relapse in longer term former smokers. Moreover, the data are suggestive that some recent quitters may have done so with the assistance of e-cigarettes. Creating measures of smoking status that treat former smokers as a homogenous group is insufficient to assess the epidemiology of e-cigarette use and the potential impact on public health. PMID- 26525064 TI - Contrast volume to creatinine clearance ratio for the prediction of contrast induced nephropathy in patients undergoing coronary angiography or percutaneous intervention. AB - BACKGROUND: Contrast-induced nephropathy is a common complication of procedures that are likely to use contrast media. The identification of high-risk patients and preventive optimal hydration are key measures to reduce the incidence of contrast-induced nephropathy. The aim of this study was to evaluate the role of the contrast volume to creatinine clearance ratio (V/CrCl) in the prediction of contrast-induced nephropathy after coronary angiography or percutaneous coronary intervention. METHODS: Our population consisted of 2308 consecutive patients undergoing coronary angiography and/or percutaneous coronary intervention. The risk of contrast-induced nephropathy was evaluated across quartiles of the V/CrCl. Receiver operating characteristic curves were used to identify the best predictive value. Contrast-induced nephropathy was defined as an absolute increase of 0.5 mg/dL or a relative increase of >25% in creatinine levels 24-48 hours after the procedure. RESULTS: The total incidence of contrast-induced nephropathy was 12.2% and was significantly higher in the fourth quartile (first quartile 8.8%, second quartile 8.9%, third quartile 11.6% and fourth quartile 19.4%; P < 0.001). Using receiver operating characteristic curves we identified V/CrCl >= 6.15 as the best discriminant value for the prediction of contrast induced nephropathy, which occurred in 25.1% of patients with V/CrCl >= 6.15 versus 9.7% in patients with V/CrCl < 6.15. These results were also confirmed at multivariate analysis after correction for all baseline confounders (adjusted odds ratio (AOR) (95% confidence interval (CI)) 1.81 (1.19-2.76); P = 0.005). The association between V/CrCl > 6.15 and an increased risk of contrast-induced nephropathy was confirmed among diabetic (11% vs. 27.7%; p P < 0.001) and non diabetic patients (8.9% vs. 23%; Pp < 0.001), also after correction for all baseline confounders. CONCLUSIONS: This is one of the largest studies evaluating the association between the V/CrCl ratio and the risk of contrast-induced nephropathy in patients undergoing coronary angiography or percutaneous coronary intervention. We found that a V/CrCl ratio >6.15 was independently associated with an increased risk of contrast-induced nephropathy. PMID- 26525065 TI - Improving cardiovascular prevention in general practice: Results of a comprehensive personalized strategy in subjects at high risk. AB - BACKGROUND: Although high cardiovascular risk patients should be the main target of preventive strategies, modifiable risk factors are often inadequately controlled. AIM: To assess feasibility and results of a comprehensive personalized method for cardiovascular prevention in high risk patients followed by their general practitioner. METHODS: Between 2004 and 2007, 12,513 patients (mean age 64.0 +/- 9.5 years; 61.5% males) with multiple cardiovascular risk factors or history of atherosclerotic disease were identified and followed for five years. If control of major modifiable cardiovascular risk factors (hypertension, hypercholesterolaemia, diabetes, obesity, smoking, unhealthy diet, physical inactivity) was sub-optimal, at baseline and yearly thereafter general practitioners planned with patients, with the help of a brief checklist, preventive interventions to improve the global risk profile. Main outcome was the control of the seven major modifiable cardiovascular risk factors during follow up. Secondary outcome was the incidence of cardiovascular deaths and hospitalization for cardiovascular reasons according to the improvement in global cardiovascular risk profile during the first year. RESULTS: Control of all major modifiable risk factors except physical inactivity improved gradually and significantly (p < 0.0001) during follow-up.The improvement in the global cardiovascular risk profile during the first year was independently and significantly associated with a lower rate of major cardiovascular events in the following years (hazard ratio 0.939; 95% confidence interval 0.887-0.994, p = 0.03). CONCLUSIONS: Our comprehensive, personalized method for cardiovascular risk prevention in people at high risk appears feasible in general practice. The improvement in the global cardiovascular risk profile was associated with a better prognosis. PMID- 26525066 TI - Effects of long-term resistance exercise training on autophagy in rat skeletal muscle of chloroquine-induced sporadic inclusion body myositis. AB - PURPOSE: We examined whether resistance exercise training restores impaired autophagy functions caused by Chloroquine (CQ)-induced Sporadic Inclusion Body Myositis (sIBM) in rat skeletal muscle. METHODS: Male wistar rats were randomly assigned into three groups: Sham (n = 6), CQ (n = 6), and CQ + Exercise (CE, n = 6). To create a rat model of sIBM, rats in the CQ and CE group were intraperitoneally injected with CQ 5 days a week for 16 weeks. Rats in the CE group performed resistance exercise training 3 times a week for 8 weeks in conjunction with CQ starting from week 9 to week 16. During the training period, maximal carrying load, body weight, muscle weight, and relative muscle weight were measured. Autophagy responses were examined by measuring specific markers. RESULTS: While maximal carrying capacity for resistance exercise training was dramatically increased in the CE group, no significant changes occurred in the skeletal muscle weight as well as in the relative muscle weight of CE compared to the other groups. CQ treatment caused significant increases in the levels of Beclin-1 and p62, and decreases in the levels of LAMP-2 proteins. Interestingly, no significant differences in the LC3-II/I ratio or the LC3-II protein levels were observed. Although CQ-treatment groups suppressed the levels of the potent autophagy inducer, BNIP3, p62 levels were decreased in only the CE group. CONCLUSION: Our findings demonstrate that sIBM induced by CQ treatment results in muscle degeneration via impaired autophagy and that resistance exercise training improves movable loading activity. Finally, regular exercise training may provide protection against sIBM by enhancing the autophagy flux through p62 protein. PMID- 26525067 TI - Alkyne Carbonyl Metathesis As a Means To Make 4-Acyl Chromenes: Syntheses of (+/ )-Deguelin and (+/-)-Munduserone. AB - A highly convergent synthetic approach to rotenoid natural products is described. Successful pairing of two building blocks for Sonogashira cross-coupling and intramolecular alkyne carbonyl metathesis allows ready access to 4-acylchromene, a key substructure of these natural products, leading to syntheses of (+/-) deguelin and (+/-)-munduserone in high overall yields. PMID- 26525068 TI - Non-Small Cell Lung Cancer in a Very Young Woman: A Case Report and Critical Review of the Literature. AB - BACKGROUND: Lung cancer in young patients is quite uncommon; clinical presentation and outcome in this population compared to the older group are not yet well defined and data about this setting are mostly single-institutional retrospective analyses. CASE REPORT: We report here a case of a very young woman with diagnosis of early-stage lung adenocarcinoma harboring EML4-ALK rearrangement; she underwent radical surgery and adjuvant chemotherapy according to the pathologic stage. Potential risk factors for lung cancer in our patient are discussed and clinico-pathologic features and outcomes of lung cancer in the young population compared to the elderly are reviewed through discussing studies with sample sizes larger than 100 patients. CONCLUSIONS: A wide clinical overview should be performed when lung cancer is diagnosed in a young patient. Large population studies are required to define the molecular signature and clinical behavior of lung cancer in young patients. PMID- 26525069 TI - Hemolysis from a nurses' standpoint--survey from four Croatian hospitals. AB - INTRODUCTION: Hemolysis can occur during sample collection, handling and transport. It is more frequent when the non-laboratory staff performs sampling. The aim of this study was to assess nurses' knowledge on the causes of hemolysis and consequential impact on the laboratory tests results. Additionally, the differences in knowledge, related to work experience, professional degree and previous education about hemolysis were explored. MATERIALS AND METHODS: An anonymus survey, containing 11 questions on demographics, causes of hemolysis, its impact on biochemical parameters and nurses' attitude towards additional education in preanalytics, was conducted in four Croatian hospitals. The answers were compared by Chi-squared and Fischer exact test. RESULTS: In total, 562 survey results were collected. Majority of nurses declared familiarity with the term "hemolysis" (99.6%). There were 77% of correct answers regarding questions about the causes of hemolysis, but only 50% when it comes to questions about interference in biochemical tests. The percentage of correct answers about causes was significantly lower (P=0.029) among more experienced nurses, and higher (P=0.027) in those with higher professional degree, while influence of previous education was not significant. Also, higher percentage of correct answers about interferences was encountered in nurses with longer work experience (P=0.039). More than 70% of nurses declared that additional education about preanalytical factors would be beneficial. CONCLUSION: Croatian nurses are familiar with the definition of hemolysis, but a lack of knowledge about causes and influence on laboratory test results is evident. Nurses are eager to improve their knowledge in this field of preanalytical phase. PMID- 26525070 TI - Enhancing Ecoefficiency in Shrimp Farming through Interconnected Ponds. AB - The future development of shrimp farming needs to improve its ecoefficiency. The purpose of this study was to evaluate water quality, flows, and nitrogen balance and production parameters on a farm with interconnected pond design to improve the efficiency of the semi-intensive culture of Litopenaeus vannamei ponds. The study was conducted in 21 commercial culture ponds during 180 days at densities of 30-35 ind m(-2) and daily water exchange <2%. Our study provides evidence that by interconnecting ponds nutrient recycling is favored by promoting the growth of primary producers of the pond as chlorophyll a. Based on the mass balance and flow of nutrients this culture system reduces the flow of solid, particulate organic matter, and nitrogen compounds to the environment and significantly increases the efficiency of water (5 to 6.5 m(3) kg(-1) cycle(-1)), when compared with traditional culture systems. With this culture system it is possible to recover up to 34% of the total nitrogen entering the system, with production in excess of 4,000 kg ha(-1) shrimp. We believe that the production system with interconnected ponds is a technically feasible model to improve ecoefficiency production of shrimp farming. PMID- 26525071 TI - Effects of soybean milk, chitosan, and anti-Streptococcus mutans IgY in malnourished rats' dental biofilm and the IgY persistency in saliva. AB - OBJECTIVE: This study aims to evaluate the eff ect of soybean milk containing a combination of anti-Streptococcus mutans IgY and chitosan to the colonization of S. mutans in the saliva and to the IgY persistency in the saliva. MATERIALS AND METHODS: Experimental malnourished Sprague-Dawley rats were fed with soybean milk that is enriched with anti-S. mutans IgY and chitosan. After 15 days of feeding, we evaluated the S. mutans in dental biofilm, in addition to the persistency level of anti-S. mutans IgY. RESULTS: The rats that received soybean milk supplemented with anti-S. mutans IgY had the lowest number of S. mutans colonies (p < 0.05). Anti-S. mutans IgY was detected in saliva after 15 days of feeding. CONCLUSIONS: Soybean milk supplemented with anti-S. mutans IgY and chitosan could signifi cantly reduce S. mutans biofilm, and the supplemented anti-S. mutans IgY persisted in these rats' saliva following the feeding period. PMID- 26525072 TI - The Foundations of Literacy Development in Children at Familial Risk of Dyslexia. AB - The development of reading skills is underpinned by oral language abilities: Phonological skills appear to have a causal influence on the development of early word-level literacy skills, and reading-comprehension ability depends, in addition to word-level literacy skills, on broader (semantic and syntactic) language skills. Here, we report a longitudinal study of children at familial risk of dyslexia, children with preschool language difficulties, and typically developing control children. Preschool measures of oral language predicted phoneme awareness and grapheme-phoneme knowledge just before school entry, which in turn predicted word-level literacy skills shortly after school entry. Reading comprehension at 81/2 years was predicted by word-level literacy skills at 51/2 years and by language skills at 31/2 years. These patterns of predictive relationships were similar in both typically developing children and those at risk of literacy difficulties. Our findings underline the importance of oral language skills for the development of both word-level literacy and reading comprehension. PMID- 26525073 TI - Rats Fed a Diet Rich in Fats and Sugars Are Impaired in the Use of Spatial Geometry. AB - A diet rich in fats and sugars is associated with cognitive deficits in people, and rodent models have shown that such a diet produces deficits on tasks assessing spatial learning and memory. Spatial navigation is guided by two distinct types of information: geometrical, such as distance and direction, and featural, such as luminance and pattern. To clarify the nature of diet-induced spatial impairments, we provided rats with standard chow supplemented with sugar water and a range of energy-rich foods eaten by people, and then we assessed their place- and object-recognition memory. Rats exposed to this diet performed comparably with control rats fed only chow on object recognition but worse on place recognition. This impairment on the place-recognition task was present after only a few days on the diet and persisted across tests. Critically, this spatial impairment was specific to the processing of distance and direction. PMID- 26525074 TI - A Thousand Words Are Worth a Picture: Snapshots of Printed-Word Processing in an Event-Related Potential Megastudy. AB - In the experiment reported here, approximately 1,000 words were presented to 75 participants in a go/no-go lexical decision task while event-related potentials (ERPs) were recorded. Partial correlations were computed for variables selected to reflect orthographic, lexical, and semantic processing, as well as for a novel measure of the visual complexity of written words. Correlations were based on the item-level ERPs at each electrode site and time slice while a false-discovery rate correction was applied. Early effects of visual complexity were seen around 50 ms after word onset, followed by the earliest sustained orthographic effects around 100 to 150 ms, with the bulk of orthographic and lexical influences arising after 200 ms. Effects of a semantic variable (concreteness) emerged later, at around 300 ms. The overall time course of these ERP effects is in line with hierarchical, cascaded, interactive accounts of word recognition, in which fast feed-forward influences are consolidated by top-down feedback via recurrent processing loops. PMID- 26525075 TI - When Delays Improve Memory: Stabilizing Memory in Children May Require Time. AB - Memory is critical for learning, cognition, and cognitive development. Recent work has suggested that preschool-age children are vulnerable to catastrophic levels of memory interference, in which new learning dramatically attenuates memory for previously acquired knowledge. In the work reported here, we investigated the effects of consolidation on children's memory by introducing a 48-hr delay between learning and testing. In Experiment 1, the delay improved children's memory and eliminated interference. Results of Experiment 2 suggest that the benefit of this delay is limited to situations in which children are given enough information to form complex memory structures. These findings have important implications for understanding consolidation processes and memory development. PMID- 26525076 TI - Women's Preference for Attractive Makeup Tracks Changes in Their Salivary Testosterone. AB - Previous research suggests that women's motivation to appear attractive is increased around the time of ovulation. However, the specific hormonal correlates of within-woman changes in motivation to appear attractive have not been investigated. To address this issue, we used a longitudinal design and a data driven visual preference task. We found that women's preference for attractive makeup increases when their salivary testosterone levels are high. The relationship between testosterone level and preference for attractive makeup was independent of estradiol level, progesterone level, and estradiol-to-progesterone ratio. These results suggest that testosterone may contribute to changes in women's motivation to wear attractive makeup and, potentially, their motivation to appear attractive in general. Our results are also consistent with recent models of the role of testosterone in social behavior, according to which testosterone increases the probability of behaviors that could function to support the acquisition of mates and competition for resources. PMID- 26525077 TI - The patient experience of remote telemonitoring for heart failure in the rural setting: a literature review. AB - BACKGROUND: Remote telemonitoring is utilised to provide specialised care to people with heart failure living in rural locations. There is limited research into the patients' experience of telemonitoring. OBJECTIVE: This literature review was completed to examine the available evidence and inform the development of a telemonitoring service. METHODS: Cochrane Database of Systematic Reviews; Medline; CINAHL database, Joanna Briggs Institute, AMED, EMBASE were searched using the key words. A thematic analysis was applied. RESULTS: Forty-six studies reviewed, 11 met inclusion criteria. Individual health status, use of technology, and effect on lifestyle influenced the patient experience. CONCLUSION: Limited literature was available addressing the patient experience of telemonitoring and no studies were found that specifically investigated the experiences of patients with heart failure in rural locations. Further research is required to examine the patient/user perspective of this type of service, and explore the feasibility of including telemonitoring in usual care. PMID- 26525078 TI - The effect of visual feedback and training in auditory-perceptual judgment of voice quality. AB - The aim of the present investigation was to evaluate the effect of visual feedback on rating voice quality severity level and the reliability of voice quality judgment by inexperienced listeners. For this purpose two training programs were created, each lasting 2 hours. In total 37 undergraduate speech language therapy students participated in the study and were divided into a visual plus auditory-perceptual feedback group (V + AF), an auditory-perceptual feedback group (AF), and a control group with no feedback (NF). All listeners completed two rating sessions judging overall severity labeled as grade (G), roughness (R), and breathiness (B). The judged voice samples contained the concatenation of continuous speech and sustained phonation. No significant rater reliability changes were found in the pre- and posttest between the three groups in every GRB-parameter (all p > 0.05). There was a training effect seen in the significant improvement of rater reliability for roughness within the NF and AF groups (all p < 0.05), and for breathiness within the V + AF group (p < 0.01). The rating of the severity level of roughness changed significantly after the training in the AF and V + AF groups (p < 0.01), and the breathiness severity level changed significantly after the training in the V + AF group (p < 0.01). The training of V + AF and AF may only minimally influence the reliability in the judgment of voice quality but showed significant influence on rating the severity level of GRB parameters. Therefore, the use of both visual and auditory anchors while rating as well as longer training sessions may be required to draw a firm conclusion. PMID- 26525079 TI - The aortic mechanical properties in patients with the essential hypertension environmentally exposed to cigaret smoke. AB - CONTEXT: The impairment of the aortic mechanical features constitutes the independent predictor of all-cause and cardiovascular mortality and morbidity. OBJECTIVE: The purpose of the present research has been the determination of the influence of the environmental exposure to cigaret smoke on the aortic mechanical properties, namely, the stiffness and elasticity of aorta, in patients with essential hypertension. MATERIALS AND METHODS: The research has covered 128 people with essential hypertension: 64 nonsmokers, declaring the environmental exposure to cigaret smoke (group A) and 64 nonsmokers declaring the lack of environmental exposure to cigaret smoke selected on the case to case basis (group B). Aortic mechanical properties have been evaluated on the basis of the parameters: aortic stiffness index (AoSI), aortic strain (AoS) and aortic distensibility (AoD). RESULTS: In group A, the average values of AoSI were significantly higher, and the average values of AoS and AoD significantly lower than in group B. It has been documented that the older age and environmental exposure to cigaret smoke form independent risk factors of increasing the aortic stiffness expressed by higher values of AoSI, whereas the older age, higher pulse pressure (PP) values and environmental exposure to cigaret smoke - independent risk factors of aortic elasticity reduction expressed for the age and "passive smoking" by lower values of AoS and AoD and for PP - lower values of AoD. CONCLUSION: In patients with essential hypertension, the environmental exposure to cigaret smoke seems to result in impairment of the aortic mechanical properties. PMID- 26525080 TI - Anticancer effect of ethanol Lycium barbarum (Goji berry) extract on human breast cancer T47D cell line. AB - The anticancer activity of ethanol extract isolated from Goji berry (EEGB) on T47D human breast cancer cell line has been reported. Cell viability and cell proliferation were examined with the use of BrdU, MTT and NR methods. Induction of apoptosis was assessed by propidium iodide and Hoechst 33342 staining. Expression of genes involved in cell proliferation, apoptosis, cell cycle control and regulation of transcription was estimated using Western blotting analysis. EEGB inhibited the proliferation of breast cancer cells in a time-, and dose dependent manner. The study confirmed the lack of EEGB cytotoxic activity to normal human skin fibroblasts. Western blot analysis demonstrated an increase in pro-apoptotic and a decrease in anti-apoptotic proteins' expression in cells treated with the extract. Anticancer activity and lack of toxicity against normal cells indicate a chemopreventive potential of Goji berries in breast cancer treatment. PMID- 26525081 TI - An Open-source Toolbox for Analysing and Processing PhysioNet Databases in MATLAB and Octave. AB - The WaveForm DataBase (WFDB) Toolbox for MATLAB/Octave enables integrated access to PhysioNet's software and databases. Using the WFDB Toolbox for MATLAB/Octave, users have access to over 50 physiological databases in PhysioNet. The toolbox provides access over 4 TB of biomedical signals including ECG, EEG, EMG, and PLETH. Additionally, most signals are accompanied by metadata such as medical annotations of clinical events: arrhythmias, sleep stages, seizures, hypotensive episodes, etc. Users of this toolbox should easily be able to reproduce, validate, and compare results published based on PhysioNet's software and databases. PMID- 26525082 TI - Factors associated with major structural birth defects among newborns delivered at Muhimbili National Hospital and Municipal Hospitals in Dar Es Salaam, Tanzania 2011 - 2012. AB - INTRODUCTION: Ninety-four percent of all birth defects and 95% of deaths due to the birth defects occur in low and middle income countries, Tanzania among them. In Tanzania there are currently limited birth defects prevention strategies in place due to limited information on factors associated with the occurrence of birth defects. METHODS: We conducted a case control study that included newborns born from October, 2011 through February, 2012 at 4 participating hospitals. A case was defined as any newborn of a Dar es salaam resident with a neural tube defect, orofacial clefts, limb reduction defects or musculo-skeletal defects (SBD) born during the study period. A control was defined as the next three newborns (delivered after the case) without birth defects. Univariate, bivariate and multivariate analysis were done using Epi Info version 3.5.1. RESULTS: A total of 400 newborns participated in the study, 100 cases and 300 controls. Factors associated with higher odds of a SBD included maternal fever (adjusted odds ratio (AOR) = 1.99; 95% confidence interval (CI): 1.14-3.52), maternal hypertension (AOR = 3.99; 95% CI: 1.67-9.54), and low birth weight (AOR = 3.48; 95% CI: 1.77-6.85). Antimalarial use during pregnancy was protective (AOR = 0.48; 95% CI: 0.28-0.84). Folic acid supplementation was protective only in bivariate analysis (OR = 0.56; 95% CI: 0.32-0.96). CONCLUSION: Maternal fever, hypertension, and low birth weight are associated with higher odds of SBD. Antimalarial use during pregnancy was associated with lower odds of SBD. Early screening of pregnant mothers for hypertension and other causes of low birth weight may reduce SBD in Dar Es Salaam. PMID- 26525083 TI - Parenting an Adolescent with Chronic Pain: Impact on Parents and Association with Adolescent Functioning. AB - Chronic pain and associated disability is a serious problem for a significant number of adolescents.Individuals who parent an adolescent with chronic pain report high levels of impaired psychological and social functioning.Parents of adolescents with chronic pain face unique parenting challenges.Typically, treatment of adolescent chronic pain does not specifically focus on managing parental functioning and behaviour.The relationship between parental functioning/behaviour and adolescent outcomes is complex and not yet fully understood. PMID- 26525084 TI - Cultural Influences on Pain. AB - The relationship between pain and ethnicity is shaped by experience, learning and culture.Mistaken beliefs about the nature of pain and disability, resistance to treatment seeking, reluctance to comply with treatment and failure to accept responsibility of the treatment outcome are not culturally or sub-culturally specific obstacles to pain management.A cultural group's expectations and acceptance of pain as a normal part of life will determine whether pain is seen as a clinical problem that requires a clinical solution.The reviewed literature shows disparities in pain treatment based on ethnic background.Multidisciplinary research needs to investigate the models of pain and treatment in different cultural groups to allow us to understand how pain is presented and how beliefs and expectations about treatment can be married with practical solutions and effective evidence-based pain management. PMID- 26525085 TI - GIMS-Software for asset market experiments. AB - In this article we lay out requirements for an experimental market software for financial and economic research. We then discuss existing solutions. Finally, we introduce GIMS, an open source market software which is characterized by extensibility and ease of use, while offering nearly all of the required functionality. PMID- 26525086 TI - Iatrogenic myxoedema madness following radioactive iodine ablation for Graves' disease, with a concurrent diagnosis of primary hyperaldosteronism. AB - Myxoedema madness was first described as a consequence of severe hypothyroidism in 1949. Most cases were secondary to long-standing untreated primary hypothyroidism. We present the first reported case of iatrogenic myxoedema madness following radioactive iodine ablation for Graves' disease, with a second concurrent diagnosis of primary hyperaldosteronism. A 29-year-old woman presented with severe hypothyroidism, a 1-week history of psychotic behaviour and paranoid delusions 3 months after treatment with radioactive iodine ablation for Graves' disease. Her psychiatric symptoms abated with levothyroxine replacement. She was concurrently found to be hypertensive and hypokalemic. Primary hyperaldosteronism from bilateral adrenal hyperplasia was diagnosed. This case report serves as a reminder that myxoedema madness can be a complication of acute hypothyroidism following radioactive iodine ablation of Graves' disease and that primary hyperaldosteronism may be associated with autoimmune hyperthyroidism. LEARNING POINTS: Psychosis (myxoedema madness) can present as a neuropsychiatric manifestation of acute hypothyroidism following radioactive iodine ablation of Graves' disease.Primary hyperaldosteronism may be caused by idiopathic bilateral adrenal hyperplasia even in the presence of an adrenal adenoma seen on imaging.Adrenal vein sampling is a useful tool for differentiating between a unilateral aldosterone-producing adenoma, which is managed surgically, and an idiopathic bilateral adrenal hyperplasia, which is managed medically.The management of autoimmune hyperthyroidism, iatrogenic hypothyroidism and primary hyperaldosteronism from bilateral idiopathic adrenal hyperplasia in patients planning pregnancy includes delaying pregnancy 6 months following radioactive iodine treatment and until patient is euthyroid for 3 months, using amiloride as opposed to spironolactone, controlling blood pressure with agents safe in pregnancy such as nifedipine and avoiding beta blockers.Autoimmune hyperthyroidism and primary hyperaldosteronism rarely coexist; any underlying mechanism associating the two is still unclear. PMID- 26525087 TI - Motor Function Is Associated With Incident Disability in Older African Americans. AB - BACKGROUND: Disability in older African American adults is common, but its basis is unclear. We tested the hypothesis that the level of motor function is associated with incident disability in older African Americans after adjusting for cognition. METHODS: A prospective observational cohort study of 605 older community-dwelling African American adults without dementia was carried out. Baseline global motor score summarized 11 motor performances, cognition was based on 19 cognitive tests, and self-reported disability was obtained annually. We examined the association of motor function with incident disability (instrumental activities of daily living [IADL], activities of daily living [ADL], and mobility disability) with a series of Cox proportional hazards models which controlled for age, sex, and education. RESULTS: Average follow-up was about 5 years. In proportional hazards models, a 1-SD increase in baseline level of global motor score was associated with about a 50% decrease in the risk of subsequent IADL, ADL, and mobility disability (all p values < .001). These associations were unchanged in analyses controlling for cognition and other covariates. Further, the association of global motor score and incident ADL disability varied with the level of cognition (estimate -5.541, SE 1.634, p < .001), such that higher motor function was more protective at higher levels of cognition. Mobility and dexterity components of global motor score were more strongly associated with incident disability than strength (all p values < .001). CONCLUSIONS: Better motor function in older African Americans is associated with a decreased risk of developing disability. Moreover, the association of motor function and disability is stronger in individuals with better cognitive function. PMID- 26525088 TI - Dietary Protein Intake Is Protective Against Loss of Grip Strength Among Older Adults in the Framingham Offspring Cohort. AB - BACKGROUND: Age-related decline in muscle strength is an important public health issue for older adults. Dietary protein has been associated with maintenance of muscle mass, yet its relation to muscle strength remains unclear. METHODS: We determined the association of dietary protein (total, animal, and plant) intake, measured by food frequency questionnaire, with change in grip strength over 6 years in 1,746 men and women from the Framingham Offspring cohort. RESULTS: Mean age at baseline was 58.7 years (range: 29-85), and mean total, animal, and plant protein intakes were 79, 57, and 22 g/d, respectively. Adjusted baseline mean grip strength did not differ across quartiles of energy-adjusted total, animal or protein intake. Greater protein intake, regardless of source, was associated with less decrease in grip strength (all p for trend <=.05): participants in the lowest quartiles lost 0.17% to 0.27% per year while those in the highest quartiles gained 0.52% to 0.60% per year. In analyses stratified by age, participants aged 60 years or older (n = 646) had similar linear trends on loss of grip strength for total and animal (all p for trend <.03) but not plant protein, while the trends in participants younger than 60 years (n = 896) were not statistically significant. CONCLUSIONS: Higher dietary intakes of total and animal protein were protective against loss of grip strength in community dwelling adults aged 60 years and older. Increasing intake of protein from these sources may help maintain muscle strength and support prevention of mobility impairment in older adults. PMID- 26525089 TI - Diminished Cognitive Function Among Chronic Obstructive Pulmonary Disease Patients During Periods of Acute Illness Exacerbation. PMID- 26525090 TI - The Association Between Midlife Physical Activity and Depressive Symptoms in Late Life: Age Gene/Environment Susceptibility-Reykjavik Study. AB - BACKGROUND: There is little evidence on the long-term association between physical activity (PA) and depressive symptoms in old age. We examined the association of midlife PA and depressive symptoms in late life. METHODS: A large community-based population residing in Reykjavik, Iceland, participated in a longitudinal study with an average of 25 years of follow up. Midlife PA was categorized as active and inactive groups (n = 4,140, Active = 1,292, Inactive = 2,848, mean age 52+/-7 years). The main outcome had six or higher depressive symptoms assessed by the 15-item Geriatric Depression scale. Participants who had a history of depression (n = 226), and were diagnosed with dementia (n = 393), and had incomplete cognitive data (n = 595) and incomplete analytical data (n = 422) were excluded. Level of weekly PA was ascertained by a questionnaire at midlife. Depressive symptoms were assessed on average 25 (+/-4) years later. RESULTS: After controlling for demographic and health-related risk factors, those who were active at midlife were less likely to have high level of depressive symptomatology (6 or higher Geriatric Depression scale scores, odds ratio = 0.58, 95% confidence interval: 0.41-0.83, p < .005) compared with those who were inactive in midlife. After full adjustment of three domains of late-life cognitive function the results remained significant (odds ratio = 0.61, 95% confidence interval: 0.43-0.86, p = .005). CONCLUSION: Our study shows that midlife PA is associated with lower depressive symptoms 25 years later. Participating in regular PA in midlife may improve mental health in late life. PMID- 26525091 TI - Aging-Related Considerations When Evaluating the Forced Expiratory Volume in 1 Second (FEV1) Over Time. AB - BACKGROUND: Forced expiratory volume in 1 second (FEV1) over time is commonly expressed in liters and percent predicted (%Pred), or alternatively in L/m(3) and Z-scores-which approach is more clinically meaningful has not been evaluated. Because it uniquely accounts for the effect of aging on FEV1 and spirometric performance, we hypothesized that the Z-score approach is more clinically meaningful, based on associations between cardiopulmonary predictors and FEV1 over time. METHODS: Using linear mixed-effects models and data from the Baltimore Longitudinal Study on Aging, including 501 white participants aged 40-95 who had completed at least three longitudinal spirometric assessments, we evaluated the associations between cardiopulmonary predictors (obesity, smoking status, hypertension, chronic bronchitis, diabetes mellitus, and myocardial infarction) and FEV1 over time, in liters, %Pred, L/m(3), and Z-scores. RESULTS: Mean baseline values for FEV1 were 3.240L, 96.4%Pred, 0.621L/m(3), and -0.239 as a Z score (40.6th percentile). The annual decline in FEV1 was 0.040L, 0.234 %Pred, 0.007L/m(3), and 0.008 Z-score units. Baseline age was associated with FEV1 over time in liters and L/m(3) (p < .001), and included a time interaction for %Pred (p < .001), but was not associated with Z-scores (p = .933). The associations of cardiopulmonary predictors with FEV1 over time were all significant when using Z scores (p < .05), but varied for other methods of expressing FEV1. CONCLUSION: A Z-score approach is more clinically meaningful when evaluating FEV1 over time, as it accounted for the effect of aging and was more frequently associated with multiple cardiopulmonary predictors. PMID- 26525092 TI - Association Between Circulating Osteogenic Progenitor Cells and Disability and Frailty in Older Persons: The Nepean Osteoporosis and Frailty Study. AB - Circulating osteogenic progenitor (COP) cells are considered as surrogates of the mesenchymal repository in the body. In this study, we hypothesized that COP cells decrease with age and that lower levels of COP cells are associated with greater frailty and disability in older persons. Using well-established clinical criteria, we quantified physical performance and disability and stratified frailty in a random sample of community-dwelling individuals enrolled in the Nepean Osteoporosis and Frailty (NOF) Study (mean age 82.8; N = 77; 70% female; 27 nonfrail, 23 prefrail, and 27 frail). Percentage of COP cells was quantified by flow cytometry. Logistic regression models estimated the relationship between the percentage of COP cells and prevalent disability, poor physical performance, and frailty. We found that aging is associated with a significant decrease in COP cells (p < .001). Lower percentages of COP cells were associated with disability and poor physical performance (p < .001). Older adults with COP cells in the lower quartile were more likely to be frail (odds ratio 2.65, 95% confidence interval 2.72-3.15, p < .001). In conclusion, COP cells in the circulation decrease with age. Lower percentages of COP cells in late life are associated with prevalent frailty and disability. Further longitudinal studies are needed to understand COP cells as a risk stratifier, biomarker, or therapeutic target and to predict disability in frail older persons. PMID- 26525093 TI - Intralesional Rituximab Treatment for Primary Cutaneous B-cell Lymphoma: Nine Finnish Cases. PMID- 26525094 TI - [Patients' satisfaction and waiting time in oncology day care centers in Champagne-Ardenne]. AB - AIM: Quality of life of patients suffering from cancer may be influenced by the way healthcare is organized and by patient experiences. Nowadays, chemotherapy is often provided in day care centers. This study aimed to assess patient waiting time and satisfaction in oncology day care centers in Champagne-Ardenne, France. METHODS: This cross-sectional survey involved all patients receiving ambulatory chemotherapy during a one-week period in day care centers of Champagne-Ardenne public and private healthcare institutions participating in the study. Sociodemographic, medical and outpatient data were collected. Patient satisfaction was measured using the Out-Patsat35 questionnaire. RESULTS: Eleven (out of 16) oncology day care centers and 441 patients participated in the study. Most of the patients were women (n=252, 57.1%) and the mean age was 61+/-12 years. The mean satisfaction score was 82+/-14 (out of 100) and the mean waiting time between the assigned appointment time and administration of chemotherapy was 97+/-60 min. CONCLUSION: This study has shown that waiting times are important. However, patients are satisfied with the healthcare organization, especially regarding nursing support. Early preparation of chemotherapy could improve these parameters. PMID- 26525095 TI - [Cigarette smoking initiation among Tunisian adolescents: Risk and protective factors]. AB - BACKGROUND: Since smoking is a major public health problem among Tunisian teenagers, it is important to identify the underlying risk and protective factors associated with initiation of this behavior. METHODS: A cross-sectional, school based survey of students was conducted by the Tunisian Ministry of Health among a nationally representative sample of 4172 adolescents aged between 12 and 20 years attending public, private, and professional secondary schools across Tunisia who participated in the Survey of the Health of Tunisian adolescents in 2000. For data analysis, we first calculated crude odds ratios (OR) followed by calculating adjusted OR after using multivariate logistic regression models. RESULTS: Almost one-third of respondents had already started smoking at an average age of 13 years, 6.4% among them smoked daily. Demographic vulnerabilities to smoking behavior were gender (boys more than girls), age and residence in urban areas and particularly in Greater Tunis and the North East. Familial and school factors were parental divorce, poor relationship with parents, poor integration into the peer group, and poor school investment. Psychological and behavioral factors were low self-esteem level and the occurrence of stressful life events, risk taking and alcohol consumption when there was no association with the depression, anxiety and body image. Protective factors against the experimental cigarettes were mainly sports and reading. CONCLUSION: There are many factors associated with smoking behavior among adolescents. All of these predictors need to be considered in smoking prevention among Tunisian teenagers. PMID- 26525096 TI - Impulsivity toward food reward is related to BMI: Evidence from intertemporal choice in obese and normal-weight individuals. AB - Obesity is a medical condition frequently associated with psychopathological symptoms and neurocognitive and/or personality traits related to impulsivity. Impulsivity during intertemporal choices seems to be typical of obese individuals. However, so far, the specific relationship between different types of reward and neuropsychological and psychopathological profile are yet to be unravelled. Here, we investigated impulsive choice for primary and secondary reward in obese individuals and normal-weight controls with comparable neuropsychological and psychopathological status. Participants performed three intertemporal choice tasks involving food, money, and discount voucher, respectively. Moreover, they completed a battery of neuropsychological tests and psychometric questionnaires assessing psychopathological state, impulsivity, and personality traits. Obese individuals showed increased preference for immediate food reward compared with controls, whereas no group difference emerged concerning money and discount voucher. Moreover, the higher the body mass index (BMI), the steeper the food discounting. These findings emerged in light of comparable neuropsychological and psychopathological profile between groups. Steeper food discounting in obese individuals appears to be related to BMI but not to psychopathological and neuropsychological profile. We suggest using intertemporal choice in the clinical practice as measure of the effectiveness of different types of intervention (e.g., educational, psychological, pharmacological or surgical) aimed at reducing impulsivity toward food and increasing cognitive control during food intake in obese individuals. PMID- 26525097 TI - An unusual penetrating hand injury from a hurling helmet. AB - We report on an unusual case of a penetrating injury from a bar from a metal grille from a hurling face protector. The bar impaled the patient's thumb after a collision with a patient. The bar was surgically removed in theatre with minimal injury. The authors highlight the need to ensure that helmets and face protectors are regularly checked, particularly ensuring that the bars have not become detached. PMID- 26525098 TI - Age-related alterations in phase synchronization of oxyhemoglobin concentration changes in prefrontal tissues as measured by near-infrared spectroscopy signals. AB - The prefrontal cortex plays an important role in planning complex cognitive behavior, personality expression, and decision making. This study aims to assess the phase synchronization of signals of the oxyhemoglobin concentration changes (Delta[HbO2]) in the left and right prefrontal tissues through near-infrared spectroscopy (NIRS) with wavelet phase coherence (WPCO) method. The NIRS signals were continuously recorded from the left and right prefrontal lobes in 43 healthy elderly subjects (age: 69.6 +/- 8.4 years) and 40 young healthy subjects (age: 24.5 +/- 1.7 years) during the resting state. Phase synchronization between the left and right prefrontal oscillations in six frequency intervals (I, 0.6-2 Hz; II, 0.145-0.6 Hz; III, 0.052-0.145 Hz; IV, 0.021-0.052 Hz; V, 0.0095-0.021 Hz; and VI, 0.005-0.0095 Hz) was analyzed using the WPCO method. The WPCO values of elderly subjects were significantly lower in frequency intervals I (F=7.376, p=0.010) and III (F=6.418, p=0.016) than those of the young subjects. Low phase coherence in intervals I and III indicates reduced synchronization of cardiac activity in the prefrontal area and weakened prefrontal functional connectivity, respectively. PMID- 26525099 TI - Electronic structure of quasi-one-dimensional superconductor K2Cr3As3 from first principles calculations. AB - The electronic structure of quasi-one-dimensional superconductor K2Cr3As3 is studied through systematic first-principles calculations. The ground state of K2Cr3As3 is paramagnetic. Close to the Fermi level, the Cr-3dz(2), dxy, and d(x(2)-y(2)) orbitals dominate the electronic states, and three bands cross EF to form one 3D Fermi surface sheet and two quasi-1D sheets. The electronic DOS at EF is less than 1/3 of the experimental value, indicating a large electron renormalization factor around EF. Despite of the relatively small atomic numbers, the antisymmetric spin-orbit coupling splitting is sizable (~60 meV) on the 3D Fermi surface sheet as well as on one of the quasi-1D sheets. Finally, the imaginary part of bare electron susceptibility shows large peaks at Gamma, suggesting the presence of large ferromagnetic spin fluctuation in the compound. PMID- 26525101 TI - High-grade urothelial carcinoma with squamous differentiation metastasizing to the tongue. AB - Tumors metastasizing to the head and neck region are uncommon. Metastasis of urothelial carcinoma to the maxillofacial region is exceedingly rare and mostly involves the jaw. We present a case of urothelial carcinoma metastasizing to the tongue. Immunohistochemistry in conjunction with fluorescent in situ hybridization was used to confirm the relation between the primary and metastatic lesions, making it the first such reported case employing the UroVysion (Catalogue number 02 J27-025, Abbott Molecular Inc., Des Plaines, IL, USA) fluorescent in situ hybridization probe in a metastatic lesion in the head and neck region. PMID- 26525100 TI - Soluble Abeta oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance. AB - Epileptic activity may be more prevalent in early stage Alzheimer's disease (AD) than previously believed. Several studies report spontaneous seizures and interictal discharges in mouse models of AD undergoing age-related Abeta accumulation. The mechanism by which Abeta-induced neuronal excitability can trigger epileptiform activity remains unknown. Here, we systematically examined field excitatory postsynaptic potentials (fEPSP) in stratum radiatum and population spikes (PSs) in the adjacent stratum pyramidale of CA1 in wild-type mouse hippocampal slices. Soluble Abeta oligomers (oAbeta) blocked hippocampal LTP and EPSP-spike (E-S) potentiation, and these effects were occluded by prior treatment with the glutamate uptake inhibitor TBOA. In accord, oAbeta elevated glutamate levels in the hippocampal slice medium. Recording the PS revealed that oAbeta increased PS frequency and reduced LTP, and this LTP deficit was occluded by pretreatment with the GABAA antagonist picrotoxin. Whole-cell recordings showed that oAbeta significantly increased spontaneous EPSC frequency. Decreasing neuronal activity by increasing GABA tone or partially blocking NMDAR activity prevented oAbeta impairment of hippocampal LTP. Finally, treating slices with two antiepileptic drugs rescued the LTP inhibition induced by oAbeta. We conclude that soluble Abeta oligomers at the low nanomolar levels present in AD brain increase neuronal excitability by disrupting glutamatergic/GABAergic balance, thereby impairing synaptic plasticity. PMID- 26525102 TI - Modulation of C-reactive protein and plasma omega-6 fatty acid levels by phospholipase A2 gene polymorphisms following a 6-week supplementation with fish oil. AB - This clinical trial investigated the impact of a six-week supplementation with fish oil and single nucleotide polymorphisms (SNPs) in PLA2G4A and PLA2G6 genes on total omega-6 fatty acid (n-6 FA) levels in plasma phospholipids (PL) and plasma C-reactive protein (CRP) levels in 191 subjects. Interaction effects between SNPs and supplementation modulated total n-6 FAs and CRP levels in both men and women. Associations between SNPs and total n-6 FA levels and between SNPs and CRP levels were identified in men, independently of supplementation. Supplementation decreased total n-6 FAs without affecting plasma CRP levels. Changes in CRP levels correlated positively with changes in total n-6 FAs in men (r=0.25 p=0.01), but not in women. In conclusion, total n-6 FA levels in plasma PL and plasma CRP levels are modulated by SNPs within PLA2G4A and PLA2G6 genes alone or in combination with fish oil supplementation. PMID- 26525103 TI - T Cells Engineered against a Native Antigen Can Surmount Immunologic and Physical Barriers to Treat Pancreatic Ductal Adenocarcinoma. AB - Pancreatic ductal adenocarcinomas (PDAs) erect physical barriers to chemotherapy and induce multiple mechanisms of immune suppression, creating a sanctuary for unimpeded growth. We tested the ability of T cells engineered to express an affinity-enhanced T cell receptor (TCR) against a native antigen to overcome these barriers in a genetically engineered model of autochthonous PDA. Engineered T cells preferentially accumulate in PDA and induce tumor cell death and stromal remodeling. However, tumor-infiltrating T cells become progressively dysfunctional, a limitation successfully overcome by serial T cell infusions that resulted in a near-doubling of survival without overt toxicities. Similarly engineered human T cells lyse PDA cells in vitro, further supporting clinical advancement of this TCR-based strategy for the treatment of PDA. PMID- 26525105 TI - The increase of oncogenic miRNA expression in tongue carcinogenesis of a mouse model. AB - OBJECTIVES: This study investigated the oncogenic miRNA level in the tissue and biofluids in the Nitroquinoline 1-Oxide (4NQO)-induced mouse tongue carcinogenesis model for potential diagnostic or therapeutic application. MATERIALS AND METHODS: The histological examination, immunohistochemistry, in situ hybridization, quantitative PCR analysis and bioinformatic algorithms were performed to unravel the signaling activation and miRNA expression in female murine samples. RESULTS: The increase of miR-21 and miR-31 staining, and EGFR activation paralleled the severity of 4NQO-induced epithelial pathogenesis in tongue epithelium. A progressive increase of miR-21, miR-31 and miR-146a in both saliva and plasma samples was also noted. miR-31 was the earliest emerging miRNA in the saliva. The increase of plasma miR-146a, miR-184 and miR-372 was detectable early in the induction, and it was particularly eminent at the most advanced lesion state. The combined analysis of the multiple oncogenic miRNAs in the plasma signified a potent discriminative capacity between normal and pathological states. As the blockage of EGFR or AKT activation drastically reverted the miR-21, miR-31 and miR-146a expression induced by 4NQO in human oral carcinoma cell lines, the results implicated a mechanistic linkage of the oncogenic miRNAs' induction through EGFR/AKT activation. CONCLUSIONS: In this study, we show the dysregulation of oncogenic miRNAs in murine tongue tumorigenesis, which simulates human counterparts. Increased multiple miRNAs in the biofluids may be valuable non-invasive markers in detecting oral carcinogenesis at an early stage. This animal model may also be useful for developing liquid biopsies and prevention strategies against oral carcinoma by abrogating EGFR or oncogenic miRNAs. PMID- 26525104 TI - RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics. AB - Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood based "liquid biopsies". PMID- 26525106 TI - Update on Mastocytosis (Part 2): Categories, Prognosis, and Treatment. AB - Mastocytosis is a term used to describe a heterogeneous group of disorders characterized by clonal proliferation of mast cells in different organs. The organ most often affected is the skin. The World Health Organization classifies cutaneous mastocytosis into mastocytoma, maculopapular cutaneous mastocytosis, and diffuse mastocytosis. The systemic variants in this classification are as follows: indolent systemic mastocytosis (SM), aggressive SM, SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma, and extracutaneous mastocytoma. The two latest systemic variants are rare. Although the course of disease is unpredictable in children, lesions generally resolve by early adulthood. In adults, however, the disease tends to persist. The goal of treatment should be to control clinical manifestations caused by the release of mast cell mediators and, in more aggressive forms of the disease, to reduce mast cell burden. PMID- 26525108 TI - Frequency of Antiretroviral Resistance Mutations among Infants Exposed to Single Dose Nevirapine and Short Course Maternal Antiretroviral Regimens: ACTG A5207. AB - BACKGROUND: Intrapartum single-dose nevirapine (sdNVP) reduces HIV-1 perinatal transmission but selects NVP resistance among mothers and infants. We evaluated the frequency of antiretroviral resistance among infants with intrauterine HIV-1 infection exposed to sdNVP and maternal antenatal or breastfeeding antiretroviral therapy. METHODS: This analysis included 429 infants from sub-Saharan Africa, India and Haiti whose 422 mothers received sdNVP plus maternal study treatment. At entry mothers had CD4>250/MUL and were ART-naive except for antenatal ZDV per local standard of care. Maternal study treatment started intrapartum and included ZDV/3TC, TDF/FTC or LPV/r for 7 or 21 days in a randomized factorial design. Infants received sdNVP study treatment and ZDV if local standard of care. Infant HIV RNA or DNA PCR and samples for genotype were obtained at birth and weeks 2, 4 and 12; infants who ever breast-fed were also tested at weeks 16, 24, 48 and 96. Samples from HIV-1-infected infants were tested for drug resistance by population genotype (ViroSeq). NVP or NRTI resistance mutations were assessed using the IAS USA mutation list. RESULTS: Perinatal HIV-1 transmission occurred in 17 (4.0%) infants including 12 intrauterine infections. Resistance mutations were detected among 5 (42%) intrauterine-infected infants; of these, 3 had mutations conferring resistance to NVP alone, 1 had resistance to NRTI alone, and 1 had dual-class resistance mutations. Among the 2 infants with NRTI mutations, one (K70R) was likely maternally transmitted and one (K65R) occurred in the context of breastfeeding exposure to maternal antiretroviral therapy. CONCLUSIONS: Infants with intrauterine HIV infection are at risk of acquiring resistance mutations from exposure to maternal antiretroviral medications intrapartum and/or during breastfeeding. New approaches are needed to lower the risk of antiretroviral resistance in these infants. PMID- 26525109 TI - Acute Pain Management in Opioid Dependent Patients. AB - Acute pain management remains a challenge in opioid dependent patients, and it has been recognised that these patients are commonly under-treated.Chronic opioid exposure leads to widespread adaptations both at cellular and synaptic level.Physical dependence is a neuropharmacological phenomenon as a result of neuroadaptation and neuroplasticity, in contrast to addiction that is both neuropharmacological and behavioural.While providing the patient's pre-existing opioid requirement, the acute pain episode should be managed using additional multimodal analgesia: non-opioid medications in combination with local anaesthetic techniques and as required, short-acting opioid titrated to effect.Patients on long term buprenorphine and methadone with acute pain episode should be continued with their maintenance therapy and an additional short-acting opioid analgesic titrated to achieve therapeutic effect. PMID- 26525107 TI - The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-kappaB signalling. AB - Antigen receptor signalling activates the canonical NF-kappaB pathway via the CARD11/BCL10/MALT1 (CBM) signalosome involving key, yet ill-defined roles for linear ubiquitination. The paracaspase MALT1 cleaves and removes negative checkpoint proteins, amplifying lymphocyte responses in NF-kappaB activation and in B-cell lymphoma subtypes. To identify new human MALT1 substrates, we compare B cells from the only known living MALT1(mut/mut) patient with healthy MALT1(+/mut) family members using 10-plex Tandem Mass Tag TAILS N-terminal peptide proteomics. We identify HOIL1 of the linear ubiquitin chain assembly complex as a novel MALT1 substrate. We show linear ubiquitination at B-cell receptor microclusters and signalosomes. Late in the NF-kappaB activation cycle HOIL1 cleavage transiently reduces linear ubiquitination, including of NEMO and RIP1, dampening NF-kappaB activation and preventing reactivation. By regulating linear ubiquitination, MALT1 is both a positive and negative pleiotropic regulator of the human canonical NF-kappaB pathway-first promoting activation via the CBM--then triggering HOIL1-dependent negative-feedback termination, preventing reactivation. PMID- 26525110 TI - Bone marrow fat: What is it good for? PMID- 26525111 TI - Changes in tissue oxidative stress, brain biogenic amines and acetylcholinesterase following co-exposure to lead, arsenic and mercury in rats. AB - The present study investigated the toxic effects of individual, combined (binary and ternary) exposure to lead, arsenic and mercury on, (i) oxidative stress (ii) alterations in brain biogenic amines and (iii) tissue metals concentration. Rats were exposed to lead, arsenic and mercury either individually (30 ppm in drinking water), various binary (15 ppm each) or ternary combination (10 ppm each) for a period of 6 months. Lead + arsenic and lead + arsenic + mercury co-exposure led to a significant increase in the blood oxidative stress. Mercury + arsenic and lead + arsenic + mercury co-exposure produced a more pronounced hepatotoxicity while, lead + arsenic and lead + arsenic + mercury produced a significant increase in hepatic oxidative stress. Kidney oxidative stress and changes in brain biogenic amines were more prominent in animals exposed to three metals. Accumulation of three metals did not exhibit the pattern as in the case of oxidative stress. Exposure to two toxic metals also showed less accumulation of toxic metals suggesting possible antagonism. The present study thus provides some interesting observations on the interaction between lead, arsenic and mercury. Co exposure to lead + arsenic + mercury led to a more pronounced increase in oxidative stress in liver and kidneys compared to other exposed groups. PMID- 26525112 TI - Transmembrane transport of steviol glucuronide and its potential interaction with selected drugs and natural compounds. AB - Steviol glucuronide (SVG) is the major metabolite derived from steviol, the aglycone of stevioside and rebaudioside A. After the ingestion of stevioside and rebaudioside A, SVG is formed and excreted into the urine in humans. In the present study, transporter mediated efflux and uptake of SVG was investigated in order to understand molecular mechanisms underlying its renal clearance. Results showed that SVG was not a substrate of efflux transporters BCRP, MRP2, MATE1 or P gp. In contrast, OAT3 played a predominant role in the uptake of SVG in comparison to OATP1B1, OATP1B3, or OATP2B1. Quercetin, telmisartan, diclofenac, and mulberrin displayed a relatively strong inhibition against OAT3 mediated uptake of SVG with IC50 values of 1.8, 2.9, 8.0, and 10.0 MUM, respectively. Because OAT3 is a major uptake transporter in the kidney, inhibition of OAT3 activity may alter SVG's renal clearance by drugs and natural compounds that are used concomitantly with stevia leaf extracts. PMID- 26525113 TI - Structure-activity relationship of dendrimers engineered with twenty common amino acids in gene delivery. AB - Systematic explorations on the structure-activity relationship of surface engineered dendrimers are essential to design high efficient and safe gene vectors. The chemical diversity of residues in naturally occurring amino acids allows us to generate a library of dendrimers with various surface properties. Here, we synthesized a total number of 40 dendrimers engineered with the twenty common amino acids and investigated their performances in gene delivery. The results show that gene transfection efficacy of the synthesized materials depends on both the type of amino acid and the conjugation ratio. Dendrimers engineered with cationic and hydrophobic amino acids possess relatively higher transfection efficacies. Engineering dendrimers with cationic amino acids such as arginine and lysine facilitates polyplex formation and cellular uptake, with histidine improves endosomal escape of the polyplexes, and with hydrophobic amino acids such as tyrosine and phenylalanine modulates the balance between hydrophobicity and hydrophilicity on dendrimer surface, which is beneficial for efficient cellular internalization. Dendrimers engineered with anionic or hydrophilic amino acids show limited transfection efficacy due to poor DNA binding capacity and/or limited cellular uptake. In the aspect of cytotoxicity, dendrimers engineered with arginine, lysine, tyrosine, phenylalanine and tryptophan show much higher cytotoxicity than other engineered dendrimers. These results are helpful for us to tailor the surface chemistry of dendrimers for efficient gene delivery. STATEMENT OF SIGNIFICANCE: Cationic polymers such as dendrimers were widely used as gene vectors but are limited by relatively low delivery efficacy and high toxicity. To achieve efficient and low toxic gene delivery, the polymers were modified with various ligands. However, these ligand-modified polymers in gene delivery are reported by independent researchers using different polymer scaffolds and cell lines. It is hard to provide structure-function information of these materials based on current knowledge and experience, which are essential for the design of ideal polymeric vectors for gene delivery. Here, we prepared a small library of amino acid-modified dendrimers, which is used as a screening pool to discover efficient gene vectors. The results obtained from this study, especially the structure-activity relationship of the screened materials are helpful for us to further design efficient and biocompatible polymers for gene delivery. This manuscript will appeal to a wide readership such as nanomaterial chemist, dendrimer chemist, biological chemist, pharmaceutical scientist, and biomedical researchers. PMID- 26525114 TI - Micromechanical model of biphasic biomaterials with internal adhesion: Application to nanocellulose hydrogel composites. AB - The mechanical properties of hydrated biomaterials are non-recoverable upon unconfined compression if adhesion occurs between the structural components in the material upon fluid loss and apparent plastic behaviour. We explore these micromechanical phenomena by introducing an aggregation force and a critical yield pressure into the constitutive biphasic formulation for transversely isotropic tissues. The underlying hypothesis is that continual fluid pressure build-up during compression temporarily supresses aggregation. Once compression stops and the pressure falls below some critical value, internal aggregation occurs over a time scale comparable to the poroelastic time. We demonstrate this model by predicting the mechanical response of bacterial nanocellulose hydrogel composites, which are promising biomaterials and a structural mimetic for the plant cell wall. Cross-linking of cellulose by xyloglucan creates an extensional resistance and substantially increases the compressive modulus under large compression and densification. In comparison, incorporating non-crosslinking arabinoxylan into the hydrogel has little effect on its mechanics at the strain rates investigated. These results assist in elucidating the mechanical role of these polysaccharides in the complex plant cell wall structure. They also suggest xyloglucan is a suitable candidate to tailor the stiffness of nanocellulose hydrogels in biomaterial design, which includes modulating cell-adhesion in tissue engineering applications. The model and overall approach may be utilised to characterise and design a myriad of biomaterials and mammalian tissues, particularly those with a fibrillar structure. STATEMENT OF SIGNIFICANCE: The mechanical properties of hydrated biomaterials can be non-recoverable upon compression due to increased adhesion occurring between the structural components in the material. Cellulose-hemicellulose composite hydrogels constitute a classical example of this phenomenon, since fibres can freely re-orient and adhere upon fluid loss to produce significant variations in the mechanical response to compression. Here, we model their micromechanics by introducing an aggregation force and a critical yield pressure into the constitutive formulation for transversely isotropic biphasic materials. The resulting model is easy to implement for routine characterization of this type of hydrated biomaterials through unconfined compression testing and produces physically meaningful and reproducible mechanical parameters. PMID- 26525115 TI - Shape of chondrocytes within articular cartilage affects the solid but not the fluid microenvironment under unconfined compression. AB - Metabolic activity of the chondrocytes in articular cartilage is strongly related to their zone-specific shape and the composition and mechanical properties of their surrounding extracellular matrix (ECM). However the mechanisms by which cell shape influences the response of the ECM microenvironment to mechanical loading is yet to be elucidated. This relationship was studied using a biphasic multiscale finite element model of different shaped chondrocytes in the superficial and deep zones of the ECM during unconfined stress relaxation. For chondrocytes in the superficial zone, increasing the cell's initial aspect ratio (length/height) increased the deformation and solid stresses of the chondrocyte and pericellular matrix (PCM) during the loading phase; for chondrocytes in the deep zone the effect of the cell shape on the solid microenvironment was time and variable dependent. However, for superficial and deep zone chondrocytes the cell shape did not affect the fluid pressure and fluid shear stress. These results suggest that mechanotransduction of chondrocytes in articular cartilage may be regulated through the solid phase rather than the fluid phase, and that high stresses and deformations in the solid microenvironment in the superficial zone may be essential for the zone-specific biosynthetic activity of the chondrocyte. The biphasic multiscale computational analysis suggests that maintaining the cell shape is critical for regulating the microenvironment and metabolic activity of the chondrocyte in tissue engineering constructs. STATEMENT OF SIGNIFICANCE: We investigated the effect of chondrocyte shape on the cellular microenvironment using a biphasic multiscale finite element analysis. Our study showed that cell shapes affects the solid but not the fluid microenvironment of the chondrocyte, and that maintaining the cell shape is critical for regulating the microenvironment and metabolic activity of the chondrocyte in native cartilage and tissue engineering constructs. As far as we know, this is the first study on the mechanotransduction mechanisms by which cell shape influences the response of the microenvironment to mechanical loading. This study is important for understanding cell mechanobiology, not only for regulation of cell phenotype in tissue engineered constructs but, as important, for understanding changes in normal chondrocyte function after post-traumatic injury and in the initiation and progression of osteoarthritis. PMID- 26525116 TI - Fabrication of hydrogels with elasticity changed by alkaline phosphatase for stem cell culture. AB - The objective of this study is to design hydrogels whose elasticity can be changed by alkaline phosphatase (ALP) in cell culture and evaluate the effect of hydrogel elasticity on an osteogenic gene expression of cells. Hydrogels were prepared by the radical polymerization of acrylamide (AAm), N,N' methylenebisacrylamide (BIS), and PhosmerTMM containing phosphate groups (PE-PAAm hydrogels). The storage modulus of PE-PAAm hydrogels prepared was changed by the preparation conditions. When human mesenchymal stem cells (hMSC) were cultured on the ALP-responsive PE-PAAm hydrogels in the presence or absence of ALP, the morphology of hMSC was observed and one of the osteogenic differentiation markers, Runx2, was evaluated. By ALP addition into the culture medium, the morphology of hMSC was changed into an elongated shape without cell damage. ALP addition modified the level of Runx2 gene expression, which was influenced by the modulus of PE-PAAm hydrogels. It is concluded that the elasticity change of hydrogel substrates in cell culture had an influence on the Runx2 gene expression of hMSC. STATEMENT OF SIGNIFICANCE: Stem cells sense the surface elasticity of culture substrates, and their differentiation fate is biologically modified by substrate properties. Most of experiments have been performed in static conditions during cell culture, while the in vivo microenvironment is dynamically changed. In this study, we established to design an enzyme-responsive hydrogel whose elasticity can be changed by alkaline phosphatase (ALP) in cell culture to mimic in vivo conditions. As a result, the cells were deformed and the gene expression level of an osteogenic maker, Runx2, was modified by ALP treatment. This is the novel report describing to demonstrate that the dynamic alteration of hydrogel substrate elasticity could modulate the osteoblastic gene expression of human MSC in vitro. PMID- 26525117 TI - Biogeographical patterns of biomass allocation in leaves, stems, and roots in China's forests. AB - To test whether there are general patterns in biomass partitioning in relation to environmental variation when stand biomass is considered, we investigated biomass allocation in leaves, stems, and roots in China's forests using both the national forest inventory data (2004-2008) and our field measurements (2011-2012). Distribution patterns of leaf, stem, and root biomass showed significantly different trends according to latitude, longitude, and altitude, and were positively and significantly correlated with stand age and mean annual precipitation. Trade-offs among leaves, stems, and roots varied with forest type and origin and were mainly explained by stand biomass. Based on the constraints of stand biomass, biomass allocation was also influenced by forest type, origin, stand age, stand density, mean annual temperature, precipitation, and maximum temperature in the growing season. Therefore, after stand biomass was accounted for, the residual variation in biomass allocation could be partially explained by stand characteristics and environmental factors, which may aid in quantifying carbon cycling in forest ecosystems and assessing the impacts of climate change on forest carbon dynamics in China. PMID- 26525118 TI - Management of High Hepatopulmonary Shunting in Patients Undergoing Hepatic Radioembolization. AB - PURPOSE: To review the safety of hepatic radioembolization (RE) in patients with high (>= 10%) hepatopulmonary shunt fraction (HPSF) using various prophylactic techniques. MATERIALS AND METHODS: A review was conducted of 409 patients who underwent technetium 99m-labeled macroaggregated albumin scintigraphy before planned RE. Estimated pulmonary absorbed radiation doses based on scintigraphy and hepatic administered activity were calculated. Outcomes from dose reductions and adjunctive catheter-based prophylactic techniques used to reduce lung exposure were assessed. RESULTS: There were 80 patients with HPSF >= 10% who received RE treatment (41 resin microspheres for metastases, 39 glass microspheres for hepatocellular carcinoma). Resin microspheres were used in 17 patients according to consensus guideline-recommended dose reduction; 38 patients received no dose reduction because the expected lung dose was < 30 Gy. Prophylactic techniques were used in 25 patients (with expected lung dose <= 74 Gy), including hepatic vein balloon occlusion, variceal embolization, or bland arterial embolization before, during, or after RE delivery. Repeated scintigraphy after prophylactic techniques to reduce HPSF in seven patients demonstrated a median change of -40% (range, +32 to -69%). Delayed pneumonitis developed in two patients, possibly related to radiation recall after chemoembolization. Response was lower in patients treated with resin spheres with dose reduction, with an objective response rate of 13% and disease control rate of 47% compared with 56% and 94%, respectively, without dose reduction (P = .023, P = .006). CONCLUSIONS: Dose reduction recommendations for HPSF may compromise efficacy. Excessive shunting can be reduced by prophylactic catheter-based techniques, which may improve the safety of performing RE in patients with high HPSF. PMID- 26525119 TI - Evaluation of an Oral Health Promotion and Preventive Programme: A Case-Control Study. AB - PURPOSE: To evaluate the oral health of children who were beneficiaries of a promotion and preventive programme for more than 6 years and to estimate the factors relating to their oral condition. MATERIALS AND METHODS: In this case control study, the total population comprised all 7- to 13-year-old children who attended the Paediatric Dentistry Centre of Reference Simon Bolivar (CROSB), a programme for students of the community of Vina del Mar, Chile. The case group was treated from the age of 7 to 13 years and controls were only seen at the age of 13 (had not been previously enrolled in the programme). The compilation of data was carried out through examination of clinical records. Statistical analysis included Fisher's Exact Test, the chi-square and Mantel-Haenszel tests to determine odds ratios, log-linear models to study some types of relationships between the different qualitative variables and Mood's Median Test for quantitative variables. Finally, a logit-type generalised linear model (GLM) was adjusted to estimate the probability of a caries-free child according to the different variables under study. RESULTS: The main finding is that this programme does not successfully control the local risk factors of caries. The factors that jointly explain the presence of caries-free children were: non-participation in the programme, attending public school and the presence of sealed teeth. CONCLUSION: Even though the evaluated programme creates equity in the indicators of oral health among its beneficiaries, it does not reach the levels of oral health of the non-vulnerable population. It is recommended that this programme seek more effective tools. PMID- 26525120 TI - Caries Assessment Spectrum and Treatment (CAST) Index in the Primary Molars of 6- to 7-year-old Polish Children. AB - PURPOSE: To evaluate the caries prevalence and experience in primary molars in Polish 6- to 7-year-old children using the Caries Assessment Spectrum and Treatment index. MATERIALS AND METHODS: This cross-sectional study was carried out on a sample of 332 out of 468 invited children (140 6- and 192 7-year-olds). Cluster sampling was used to select the participating schools. Dental status was evaluated according to the criteria dedicated to CAST. The means of the individual CAST scores were assessed. Data were statistically analysed using the Mann-Whitney U-test (p < 0.05). The percentage of children according to the highest CAST score was calculated. The mean values of the dmft index, based on three different caries thresholds--CAST codes 3 to 7 (d3-7t), 4 to 7 (d4-7t) and 5 to 7 (d5-7t)--were calculated. RESULTS: The response rate was 70.9%. One-fifth of the participants showed a healthy, functional dentition (CAST codes 0-2). The highest percentage of children had at least one carious tooth with pulpal involvement (26.2%), followed by children having an obvious dentin caries lesion (20.8%). The means for CAST codes 3, 4 and 5 were 0.61 +/- 1.0, 0.19 +/- 0.53 and 1.23 +/- 1.61, respectively. The means of molars with pulpal involvement was 0.83 +/- 1.32 and with dental sepsis 0.07 +/- 0.33. Apart from filled teeth, no age dependent differences were observed. The d3-7mft, d4-7mft and d5-7mft were as follows: 5.18, 4.61 and 4.41, respectively. CONCLUSION: The surveyed Polish children showed high caries prevalence and severe caries experience in the primary molars. The CAST index was a useful tool for the epidemiological analysis of primary molars. PMID- 26525121 TI - Relationship Between Social and Behavioural Factors and Caries Experience in Schoolchildren in Italy. AB - PURPOSE: The aims of this study were to: 1) determine the oral health status of Campanian (Italy) 5- and 12-year-old schoolchildren; 2) establish an oral health baseline prior to introducing promotion and prevention strategies and appropriate healthcare for specific groups; 3) provide the starting point for monitoring changes over time according to the World Health Organization 2020 global goals for oral health. MATERIALS AND METHODS: A cross-sectional observational study was performed on schoolchildren from public schools. 828 children were clinically evaluated, recording DMFT, dmft and SiC (Significant Caries Index). A questionnaire investigating demographic and oral health behaviour was completed by parents. RESULTS: 56.6% of the 5-year-old children were caries free (deciduous dentition) and the mean dmft value was 1.44 +/- 2.13. In 12-year-old children, caries prevalence was 35.8%. The mean DMFT value was 1.17 +/- 1.96, while the SiC was 3.42 +/- 1.97. There were significant relationships between dmft/DMFT (caries experience) and family income level (p < 0.001), mother's educational level (p < 0.001) and history of recent dental visits (p < 0.01). CONCLUSION: Information drawn from this study can be helpful to describe future and specific dental prevention programmes in order to reduce caries incidence and promote better oral health in the Campania region of Italy. PMID- 26525122 TI - Early Childhood Caries: Epidemiology, Severity and Sociobehavioural Determinants. AB - PURPOSE: To investigate the association between sociobehavioural variables and the pattern and severity of early childhood caries in Brazilian infants and toddlers ages 0-3 years. MATERIALS AND METHODS: This was a cross-sectional study with 768 children who attended 58 public nursery schools. Five previously calibrated teams (Kappa = 0.842) performed oral examinations, using the decayed, missing, filled teeth (dmft) index according to the WHO methodology. A pretested, self-administered questionnaire was given to the subjects' parents or guardians to obtain sociobehavioural information. RESULTS: Caries was observed in 134 of the 768 (17%) children. Caries and rampant caries were significantly more prevalent in low-income families (p = 0.0121) and the incidence of caries was associated with access to dental services (p < 0.05). The percentages of children who were caries free in the age groups of 0-11 months, 12-23 months, 24-35 months and 36-47 months were 100%, 96%, 88% and 76%, respectively. CONCLUSION: Programmes for prevention and oral health education should be instituted, preferably during the first year of life, especially for those in the most socioeconomically deprived groups. PMID- 26525123 TI - Oral Health-Related Quality of Life in the Elderly in Israel--Results from the National Health and Nutrition Survey of the Elderly 2005-2006. AB - PURPOSE: To assess the oral health-related quality of life of the Israeli elderly. MATERIALS AND METHODS: Data were collected from a subsample of those interviewed for the cross-sectional Mabat Zahav National Health and Nutrition Survey of the Elderly, carried out in 2005 and 2006 by the Ministry of Health in Israel. In-person interviews were conducted in the interviewees' homes using a structured questionnaire which included 7 questions on subjective dental health status and the 14 questions of the Oral Health Impact Profile 14 (OHIP-14). Statistical significance of continuous variables was assessed with the Student t test; categorical variables with normal distribution were analysed using the chi square test and those with non-normal distribution with the Wilcoxon Mann-Whitney two-sample test. RESULTS: 828 Jews and 159 Arabs from the total survey population of 1852 elderly (1536 Jews and 316 Arabs) completed the OHIP-14 questionnaire. An impact of oral health on the quality of life was reported by 16.6% of the respondents, 19.2% of females and 13.9% of males (p<0.05). There were statistically significant differences in impact prevalence by gender, place of birth and economic status. No such differences were found by age group, population group or education. Significant statistical correlation was found between subjective assessment of general and dental health and OHIP impact prevalence, with poorer assessment correlated with increased prevalence of impact. CONCLUSIONS: The quality of life of 17% of Israeli elderly is affected by oral health. The OHIP-14 findings emphasise the importance of including basic dental treatment (treatment of dental pain and infections) in the range of services covered by the National Health Insurance Law. PMID- 26525124 TI - Practice of Sealants and Preventive Resin Restorations Among Malaysian Dentists. AB - PURPOSE: To assess the knowledge, attitude and utilisation regarding fissure sealants (FS) and preventive resin restorations (PRR) among Malaysian dentists. MATERIALS AND METHODS: A questionnaire consisting of 35 questions was distributed by mail or an online survey to 425 registered dentists selected according to place of work by stratified random sampling. RESULTS: One hundred fifty-three dentists responded to the survey. A positive attitude towards FS and PRR was noted among most Malaysian dentists. About half of the respondents used FS/PRR occasionally (48.4%), while few (13.7%) applied them routinely. The majority of the dentists agreed that minimally invasive dentistry is important and FS are effective in caries prevention, using them on high caries-risk individuals. Most of the dentists used pumice or paste to clean teeth before placing FS/PRR. A significant number of dentists used a bonding agent prior to placing FS. Although only 57.5% dentists were aware of guidelines for FS use, most dentists agreed that guidelines are important. CONCLUSION: Although there was a positive attitude towards FS/PRR, few dentists applied them routinely. Some of the steps undertaken for placement of FS and PRR were outdated. Updating local guidelines for dentists to ensure uniform practice of FS and PRR is justified. PMID- 26525125 TI - Practice of Self-Medication for Dental Problems in Uttar Pradesh, India. AB - PURPOSE: To assess the practice of self-medication for oral health problems in Uttar Pradesh, India. MATERIALS AND METHODS: This multiregional cross-sectional questionnaire-based study was conducted in four towns; Moradabad, Meerut, Ghaziabad and Bareilly over a 2-month period on 352 subjects. The questionnaire consisted of a demographic profile, questions related to problems of oral health for self-medication, substances used, source of the substance, duration, reason and source of advice for self-medication. The data were analysed using the chi square test with significance set at p < 0.05. RESULTS: The prevalence of self medication was 72%. The source of substances in most of the cases was a pharmacy shop (62.5%). The most frequent self-medicated oral health problem was toothache (55.6%), followed by other problems, and the most frequently used substance was analgesics (59%). 49.8% self-medicated due to lack of money for consulting a doctor and 45% of the population received advice from the pharmacist for self medication. CONCLUSION: The majority of those surveyed practiced self-medication using an array of drugs, e.g. analgesics, native herbs, antibiotics, etc, either alone or in combination. The main reason identified for self-medication was motivation from relatives and friends. PMID- 26525126 TI - Perception of Non-surgical Periodontal Treatment in Individuals Receiving or Not Receiving Local Anaesthesia. AB - PURPOSE: Patients might refuse the offer of local anaesthesia (LA) administration prior to dental treatment. This study investigates subjective discomfort perception during non-surgical mechanical periodontal therapy delivered with or without LA. MATERIALS AND METHODS: Sixty patients with mild to moderate chronic periodontitis and prior periodontal debridement experience were randomly enrolled in nonsurgical therapy of a quadrant with or without LA administration. Patients were free to comply or not with the allocated LA arrangement. Visual analogue scales (VAS) of discomfort perception at various stages of the treatment as well as overall satisfaction were recorded. Demographic, psychosocial and periodontal parameters were recorded. RESULTS: Thirty-one patients undergoing nonsurgical periodontal therapy not receiving (LA-) and 29 participants receiving LA (LA+) were studied. Compared to LA- patients, LA+ individuals perceived less discomfort during treatment and reported less dental anxiety (p<0.05). Lower overall treatment satisfaction was associated with prior unpleasant periodontal experience (p=0.047). Overall, debridement discomfort was associated with not receiving LA, noncompliance with the pain control regimen allocated, longer treatment duration, greater gingival inflammation and a higher percentage sites with probing pocket depths>=5 mm (p<0.05). CONCLUSION: Clinicians should be aware that patients who refuse LA can experience higher dental anxiety and therefore may require various pain control strategies for comfort during nonsurgical periodontal therapy, which, if not employed, can lead to less periodontal treatment satisfaction. PMID- 26525127 TI - Association Between Obstructive Sleep Apnea and Periodontitis Among Male Adults Attending a Primary Healthcare Facility in Jordan. AB - PURPOSE: To determine the association between periodontitis and a high risk for obstructive sleep apnea (HR-OSA). MATERIALS AND METHODS: A sample of 296 males with a mean (+/-SD) age 40 (8.5) years was selected. Subjects who scored positive in two or more categories of the Berlin questionnaire were considered as having HR-OSA. RESULTS: Based on the self-reported symptoms of obstructive sleep apnea, 15% of patients were considered as HROSA. Patients with HR-OSA showed higher probing pocket depth (PPD) and clinical attachment level (CAL) compared with those with low risk for obstructive sleep apnea (LR-OSA)-2.35+/-0.69 vs 1.97+/ 0.34 (p=0.000) and 2.95+/-0.82 vs 2.12+/-0.55 (p=0.000), respectively. Patients with HR-OSA were more likely to have periodontitis (OR=2.3; 95% CI: 1.03/5.10) compared to patients with LR-OSA. The prevalence of periodontitis varied significantly only among patients according to their response to category 1 (37% responded positively and 20% responded negatively, p=0.003). When the OSA variable was replaced by the individual categories (1, 2 and 3), patients with a positive category 1 (OR=2.27; 95% CI: 11.14/4.45) were more likely to have periodontitis than were patients with a negative response. CONCLUSION: The risk of finding periodontitis in HR-OSA patients was approximately double that of LR OSA patients. Habitual snoring was also associated with increased risk for periodontitis. PMID- 26525128 TI - Untreated Gross Dental Malocclusion in Adolescents: Psychological Impact and Effect on Academic Performance in School. AB - PURPOSE: To evaluate the psychological impact and effect on academic performance of untreated gross dental malocclusion in adolescents. MATERIALS AND METHODS: A total of 366 (181 girls and 185 boys) adolescents with gross dental malocclusion were selected for the study group. A modified oral aesthetic subjective impact scale questionnaire was applied in face-to-face interviews. Similar data were collected from parents, schoolteachers and one friend of each adolescent selected for the study. Academic performance was evaluated from school records and compared with a control group of 400 adolescents (200 girls and 200 boys) having normal occlusion and an aesthetically pleasing facial appearance. The Kruskal Wallis H and chi-square tests were used to analyse the data. The correlation between the academic performance of adolescents and the psychological impact of malocclusion was assessed using the Spearman rank correlation. RESULTS: Significant numbers of adolescents (81.1%) were concerned about the appearance of their teeth, with significant gender variation (0.02). 88.5% of the adolescents received comments from others about their appearance. The results differed significantly by gender for 'avoiding smiling' (p = 0.02) and 'participation in social activities' (p = 0.02). The evaluation of academic performance showed that 42.1% of the adolescents with gross dental malocclusion performed below average; this also differed statistically significantly by gender (p = 0.04). CONCLUSION: Untreated gross dental malocclusion significantly affects the psychosocial well being of adolescents, who may avoid participating in social activities and tend to underperform in school. PMID- 26525129 TI - Exploring Oral Health Beliefs and Behaviour Among Tibetan Immigrants of Bylakkupe. AB - PURPOSE: To explore the oral health beliefs and behaviour among Tibetan immigrants of Bylakkupe village. MATERIALS AND METHODS: A stratified random sampling technique involving 366 Tibetan monks in Bylakkupe monasteries was used in this study. The oral health beliefs were measured using a pre-tested questionnaire. RESULTS: The results showed that seriousness was higher compared to other domains in the health belief model. Further, as the duration of the stay increased, the perceived importance was also higher among the population studied. CONCLUSION: The results show that in general, although the seriousness of oral health was high among the participants, the perceived benefit of dental treatment was relatively low. PMID- 26525130 TI - Economic Models of Preventive Dentistry for Australian Children and Adolescents: A Systematic Review. AB - PURPOSE: To identify economic evaluation models and parameters that could be replicated or adapted to construct a generic model to assess cost-effectiveness of and prioritise a wide range of community-based oral disease prevention programmes in an Australian context. METHODS: The literature search was conducted using MEDLINE, ERIC, PsycINFO, CINHAL (EBSCOhost), EMBASE (Ovid), CRD, DARE, NHSEED, HTA, all databases in the Cochrane library, Scopus and ScienceDirect databases from their inception to November 2012. RESULTS: Thirty-three articles met the criteria for inclusion in this review (7 were Australian studies, 26 articles were international). Existing models focused primarily on dental caries. Periodontal disease, another common oral health problem, was lacking. Among caries prevention studies, there was an absence of clear evidence showing continuous benefits from primary through to permanent dentition and the long-term effects of oral health promotion. CONCLUSION: No generic model was identified from previous studies that could be immediately adopted or adapted for our purposes of simulating and prioritising a diverse range of oral health interventions for Australian children and adolescents. Nevertheless, data sources specified in the existing Australian-based models will be useful for developing a generic model for such purposes. PMID- 26525131 TI - Increased Expression of TNF-alpha Occurs Before the Development of Periodontitis Among Obese Chinese Children: A Potential Marker for Prediction and Prevention of Periodontitis. AB - PURPOSE: Because the relationship between childhood obesity and periodontal diseases has rarely been studied, this study investigated the potential association between obesity and periodontitis among Chinese school-age children and its underlying mechanisms. MATERIALS AND METHODS: The periodontal status of normal and obese Chinese children was examined and the expression of several inflammatory factors was compared between the normal and obese group. The periodontal status, including the sulcus bleeding index (SBI), plaque index (PI), bleeding on probing percentage (BOP%) and probing depth (PD) of normal and obese children was recorded. A correlation analysis between obesity degree and periodontitis was performed. The plasma levels of tumor necrosis factor-alpha (TNF-alpha) and soluble intercellular adhesion molecule-1 (sICAM-1) in gingival crevicular fluid (GCF) samples were examined using ELISA. RESULTS: No obvious correlation was observed between obesity and the four clinical periodontal indices SBI, PI, SBI and BOP% was observed, which is in contrast to the contribution of obesity to periodontitis in adults. However, the concentration of serum TNF-alpha was significantly elevated in the obese group (219.91 +/- 24.57 pg/ml, n = 30) when compared with the normal group (169.31 +/- 23.62 pg/ml, n = 23) (t = 2.844, p < 0.05), indicating that obesity still reinforces the inflammation responses in the periodontium. CONCLUSION: Among the Chinese school age children, obesity leads to the accumulation of TNF-alpha in the gingival crevicular fluid, which occurs much earlier than and may contribute to the development of periodontitis associated with obesity. PMID- 26525132 TI - Can the Application of Fluoride Iontophoresis Improve Remineralisation of Early Caries Lesions? AB - PURPOSE: To determine the optimal electric current intensity of fluoride iontophoresis (FI) for remineralisation of early caries lesions in vitro. MATERIALS AND METHODS: Sixty specimens were made from bovine incisors and immersed in a demineralising gel for 96 h. Specimens were divided into control (conventional fluoride application) and experimental (FI) groups. All of the specimens were covered with fluoride for 4 min every day. Different electric current intensities (100, 200, 300 and 400 MUA) were applied in the FI groups using the FI device. The concentration of KOH-soluble fluoride was determined to evaluate the amount of CaF2 formed on the tooth surface. The reduction in lesion depth was measured by polarised light microscopy. RESULTS: The concentration of KOH-soluble fluoride was the highest in the specimens of the 300 MUA FI group. However, there was no significant difference in the reduction of lesion depth between the experimental groups and the control group. CONCLUSION: Variations in the electric current intensity influenced the amount of CaF2 formed on the enamel surface, with the greatest amount found for 300 MUA. PMID- 26525133 TI - [Alcohol's impact on children and families. A population survey]. AB - INTRODUCTION: Alcohol is widely used among young families, and leisure time is frequently family time. Heavy alcohol consumption can adversely affect children. The objective of this work is to measure the harm to others in Chile. SUBJECTS AND METHOD: This descriptive and probabilistic study forms part of a collaborative research funded by Thai Health and WHO. The survey was adapted by co-researchers and applied to a nationally representative sample of 1500 Chileans over 18years of age. RESULTS: A total of 408 respondents (27.2%) lived with children at home. Of this total, 10.5% felt that the use of alcohol by any member of the family had adversely affected a child. The most common adverse effects were verbal violence (29.7%), domestic violence (23.1%), unsupervised homes (18.7%), lack of money to provide basic needs of the child (14.3%), and physical violence (7.7%). Furthermore, in 6.6% of the cases child or family services agencies became involved. In almost half of the cases (46.3%), the drinker was the father, mother or step-parents. This was followed by other relatives (24.4%) and brothers (4.9%), or guardian of the child (2.4%). CONCLUSION: These data support the clinical observation that alcohol is common in Chilean homes. Its consumption not only damages the physical and mental health of the drinker but also those around him. Verbal violence and witnessing serious physical violence are frequent issues, as well as economic problems that end up with the inability to provide the child with its basic needs. PMID- 26525135 TI - [The syndrome of increased upper airways resistance: What are the clinical features and diagnostic procedures?]. AB - The upper airway resistance syndrome "UARS" is a poorly defined entity, often described as a moderate variant of the obstructive sleep apnea syndrome. It is associated with respiratory effort-related arousal, absence of obstructive sleep apnea, and absence of significant desaturation. It is a relatively common condition that predominantly affects non-obese young adults, with no predominance in either sex. The degree of upper airway collapsibility during sleep of patients with UARS is intermediate between that of normal subjects and that of patients with mild-to-moderate sleep apnea syndrome. Craniofacial and palatal abnormalities are often noted. Patients frequently complain of a functional somatic syndrome, especially daytime sleepiness and chronic fatigue. Polysomnography with esophageal pressure measurements remains the gold standard diagnostic test. The absence of any neurological abnormality gives UARS a good prognosis and it is potentially reversible if treated early. However, some studies suggest that untreated UARS has an increased risk of arterial hypertension. It can also evolve into obstructive sleep apnea. PMID- 26525134 TI - Age-Related Differences in Percentages of Regulatory and Effector T Lymphocytes and Their Subsets in Healthy Individuals and Characteristic STAT1/STAT5 Signalling Response in Helper T Lymphocytes. AB - The dynamic process of the development of the immune system can in itself result in age-related immune malfunctions. In this study, we analysed lymphocyte subsets in the peripheral blood of 60 healthy donors, divided into groups of children, adolescents, and adults, focusing on effector (Teff) and regulatory (Treg) T lymphocytes and STAT1/STAT5 signalling response in helper T lymphocytes (Th) in adults, using flow cytometry. Our results demonstrate a decrease in the percentage of total Tregs and an increase in the percentage of total Teffs with age and a consequential immense increase in the Teff/Treg ratio. The increase of Teffs was most apparent in Th1, Th1Th17, and Th17CD161- subsets. Significant Th lymphocyte STAT1 expression differences were observed between children and adolescents, which were associated with the decrease in activated Tregs. Higher expression of STAT1 was found in FoxP3hi than in FoxP3low Th lymphocytes, while significant IL-2 induced STAT5 phosphorylation differences were found among the subsets of Th lymphocytes in adults. Our study demonstrates age-related changes in circulating Teff and Treg, as well as significant differences in STAT5/STAT1 signalling among FoxP3+ Th lymphocytes, providing new advances in the understanding of immunosenescence. PMID- 26525136 TI - Antiperovskite Chalco-Halides Ba3(FeS4)Cl, Ba3(FeS4)Br, and Ba3(FeSe4)Br with Spin Super-Super Exchange. AB - Perovskite-related materials have received increasing attention for their broad applications in photovoltaic solar cells and information technology due to their unique electrical and magnetic properties. Here we report three new antiperovskite chalco-halides: Ba3(FeS4)Cl, Ba3(FeS4)Br, and Ba3(FeSe4)Br. All of them were found to be good solar light absorbers. Remarkably, although the shortest Fe-Fe distance exceeds 6 A, an unexpected anti-ferromagnetic phase transition near 100 K was observed in their magnetic susceptibility measurement. The corresponding complex magnetic structures were resolved by neutron diffraction experiments as well as investigated by first-principles electronic structure calculations. The spin-spin coupling between two neighboring Fe atoms along the b axis, which is realized by the Fe-S...S-Fe super-super exchange mechanism, was found to be responsible for this magnetic phase transition. PMID- 26525137 TI - Carbon mineralization pathways and bioturbation in coastal Brazilian sediments. AB - Carbon mineralization processes and their dependence on environmental conditions (e.g. through macrobenthic bioturbation) have been widely studied in temperate coastal sediments, but almost nothing is known about these processes in subtropical coastal sediments. This study investigated pathways of organic carbon mineralization and associated effects of macrobenthic bioturbation in winter and summer (September 2012 and February 2014) at the SE Brazilian coast. Iron reduction (FeR) was responsible for 73-81% of total microbial carbon mineralization in September 2012 and 32-61% in February 2014. Similar high rates of FeR have only been documented a few times in coastal sediments and can be sustained by the presence of large bioturbators. Denitrification accounted for 5 27% of total microbial carbon mineralization while no SO4(2-) reduction was detected in any season. Redox profiles suggested that conditions were less reduced in February 2014 than in September 2012, probably associated with low reactivity of the organic matter, higher rates of aerobic respiration and bioirrigation by the higher density of small-macrofauna. Bioturbation by small macrofauna may maintain the sediment oxidized in summer, while large-sized species stimulate the reoxidation of reduced compounds throughout the year. Therefore, bioturbation seems to have an important role modulating the pathways of carbon mineralization in the area. PMID- 26525139 TI - Anal cushion lifting method is a novel radical management strategy for hemorrhoids that does not involve excision or cause postoperative anal complications. AB - AIM: To describe the anal cushion lifting (ACL) method with preliminary clinical results. METHODS: Between January to September 2007, 127 patients who received ACL method for hemorrhoid was investigated with informed consent. In this study, three surgeons who specialized in anorectal surgery performed the procedures. Patients with grade two or more severe hemorrhoids according to Goligher's classification were considered to be indicated for surgery. The patients were given the choice to undergo either the ACL method or the ligation and excision method. ACL method is an original technique for managing hemorrhoids without excision. After dissecting the anal cushion from the internal sphincter muscle, the anal cushion was lifted to oral side and ligated at the proper position. Clinical characteristics and outcomes of patients were recorded including complications after surgery. RESULTS: A total of 127 patients were enrolled. Their median age was 42 (19-84) years, and 74.8% were female. In addition, more than 99% of the patients had grade 3 or worse hemorrhoids. The median follow-up period was 26 (0-88) mo, and the median operative time was 15 (4-30) min. After surgery, analgesics were used for a median period of three days (0-21). Pain control was achieved using extra-oral analgesic drugs, although some patients required intravenous injections of analgesic drugs. The median duration of the patients' postoperative hospital stay was 7 (2-13) d. A total of 10 complications (7.9%) occurred. Bleeding was observed in one patient and was successfully controlled with manual compression. Urinary retention occurred in 6 patients, but it disappeared spontaneously in all cases. Recurrent hemorrhoids developed in 3 patients after 36, 47, and 61 mo, respectively. No anal stenosis or persistent anal pain occurred. CONCLUSION: We consider that the ACL method might be better than all other current methods for managing hemorrhoids. PMID- 26525138 TI - Minimally invasive surgery for paediatric inflammatory bowel disease: Personal experience and literature review. AB - The incidence of paediatric inflammatory bowel disease (PIBD) has dramatically increased in the last 20 years. Although first reported in mid 1970s', diagnostic laparoscopy has started to be routinely adopted in paediatric surgical practice since late 1990s'. Minimally invasive surgery was first limited to diagnostic purposes. After 2002 it was also applied to the radical treatment of PIBD, either Crohn's disease (CD) or Ulcerative colitis. During the last decade minimally invasive approaches to PIBD have gained popularity and have recently became the "gold standard" for the treatment of such invalidating and troublesome chronic diseases. The authors describe and track the historical evolution of minimally invasive surgery for PIBD and address all available opportunities, including most recent advancements such as robotic surgery, single port approaches and minimally invasive treatment of perianal fistulising CD. A systematic review of all series of PIBD treated with minimally invasive approaches published so far is provided in order to determine the incidence and type of patients' complications reported up to present days. The authors also describe their experience with minimally invasive surgery for PIBD and will report the results of 104 laparoscopic procedures performed in a series of 61 patients between January 2006 and December 2014. PMID- 26525140 TI - The image charge effect and vibron-assisted processes in Coulomb blockade transport: a first principles approach. AB - We present a combination of density functional theory and of both non-equilibrium Green's function formalism and a Master equation approach to accurately describe quantum transport in molecular junctions in the Coulomb blockade regime. We apply this effective first-principles approach to reproduce the experimental results of Perrin et al., [Nat. Nanotechnol., 2013, 8, 282] for the transport properties of a Au-(Zn)porphyrin-Au molecular junction. We demonstrate that energy level renormalization due to the image charge effect is crucial to the prediction of the current onset in the current-voltage, I-V, curves as a function of electrode separation. Furthermore, we show that for voltages beyond that setting the current onset, the slope of the I-V characteristics is determined by the interaction of the charge carriers with molecular vibrations. This corresponds to current-induced local heating, which may also lead to an effective reduced electronic coupling. Overall our scheme provides a fully ab initio description of quantum transport in the Coulomb blockade regime in the presence of electron vibron coupling. PMID- 26525141 TI - The effectiveness of interventions to improve uptake and retention of HIV infected pregnant and breastfeeding women and their infants in prevention of mother-to-child transmission care programs in low- and middle-income countries: protocol for a systematic review and meta-analysis. AB - BACKGROUND: Despite recent improvements, uptake and retention of mothers and infants in prevention of mother-to-child transmission (PMTCT) services remain well below target levels in many low- and middle-income countries (LMICs). Identification of effective interventions to support uptake and retention is the first step towards improvement. We aim to complete a systematic review and meta analysis to evaluate the effectiveness of interventions at the patient, provider or health system level in improving uptake and retention of HIV-infected mothers and their infants in PMTCT services in LMICs. METHODS/DESIGN: We will include studies comparing usual care or no intervention to any type of intervention to improve uptake and retention of HIV-infected pregnant or breastfeeding women and their children from birth to 2 years of age attending PMTCT services in LMICs. We will include randomized controlled trials (RCTs), cluster RCTs, non-randomized controlled trials, and interrupted time series. The primary outcomes of interest are percentage of HIV-infected women receiving/initiated on anti-retroviral prophylaxis or treatment, percentage of infants receiving/initiated on anti retroviral prophylaxis, and percentage of women and infants completing the anti retroviral regimen/retained in PMTCT care. The following databases will be searched from inception: Ovid MEDLINE and EMBASE, The WHO Global Health Library, CAB abstracts, EBM Reviews, CINAHL, HealthSTAR and Web of Science databases, Scopus, PsychINFO, POPLINE, Sociological Abstracts, ERIC, AIDS Education Global Information System, NLM Gateway, LILACS, Google Scholar, British Library Catalogue, DARE, ProQuest Dissertation & Theses, the New York Academy of Grey Literature, Open Grey, The Cochrane Library, WHO International Clinical Trials Registry, Controlled Clinical Trials, and clinicaltrials.gov. Reference lists of included articles will be hand searched and study authors and content experts contacted to inquire about eligible unpublished or in progress studies. Screening, data abstraction, and risk of bias appraisal using the Cochrane Effective Practice and Organization of Care criteria will be conducted independently by two team members. Results will be synthesized narratively and a meta-analysis conducted using the DerSimonian Laird random effects method if appropriate based on assessment of clinical and statistical heterogeneity. DISCUSSION: Our findings will be useful to PMTCT implementers, policy makers, and implementation researchers working in LMICs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015020829. PMID- 26525143 TI - Quantitative analysis of a Maori and Pacific admission process on first-year health study. AB - BACKGROUND: Universities should provide flexible and inclusive selection and admission policies to increase equity in access and outcomes for indigenous and ethnic minority students. This study investigates an equity-targeted admissions process, involving a Multiple Mini Interview and objective testing, advising Maori and Pacific students on their best starting point for academic success towards a career in medicine, nursing, health sciences and pharmacy. METHODS: All Maori and Pacific Admission Scheme (MAPAS) interviewees enrolled in bridging/foundation or degree-level programmes at the University of Auckland were identified (2009 to 2012). Generalised linear regression models estimated the predicted effects of admission variables (e.g. MAPAS Maths Test; National Certificate in Educational Achievement (NCEA) Rank Score; Any 2 Sciences; Followed MAPAS Advice) on first year academic outcomes (i.e. Grade Point Average (GPA) and Passes All Courses) adjusting for MAPAS interview year, gender, ancestry and school decile. RESULTS: 368 First Year Tertiary (bridging/foundation or degree-level) and 242 First Year Bachelor (degree-level only) students were investigated. NCEA Rank Score (estimate 0.26, CI: 0.18-0.34, p< 0.0001); MAPAS Advice Followed (1.26, CI: 0.18-1.34, p = 0.0002); Exposure to Any 2 Sciences (0.651, CI: 0.15-1.15, p = 0.012); and MAPAS Mathematics Test (0.14, CI: 0.02 0.26, p = 0.0186) variables were strongly associated with an increase in First Year Tertiary GPA. The odds of passing all courses in First Year Tertiary study was 5.4 times higher for students who Followed MAPAS Advice (CI: 2.35-12.39; p< 0.0001) and 2.3 times higher with Exposure to Any Two Sciences (CI: 1.15-4.60; p = 0.0186). First Year Bachelor students who Followed MAPAS Advice had an average GPA that was 1.1 points higher for all eight (CI: 0.45-1.73; p = 0.0009) and Core 4 courses (CI: 0.60-2.04; p = 0.0004). CONCLUSIONS: The MAPAS admissions process was strongly associated with positive academic outcomes in the first year of tertiary study. Universities should invest in a comprehensive admissions process that includes alternative entry pathways for indigenous and ethnic minority applicants. PMID- 26525142 TI - Vision-based markerless registration using stereo vision and an augmented reality surgical navigation system: a pilot study. AB - BACKGROUND: This study evaluated the use of an augmented reality navigation system that provides a markerless registration system using stereo vision in oral and maxillofacial surgery. METHOD: A feasibility study was performed on a subject, wherein a stereo camera was used for tracking and markerless registration. The computed tomography data obtained from the volunteer was used to create an integral videography image and a 3-dimensional rapid prototype model of the jaw. The overlay of the subject's anatomic site and its 3D-IV image were displayed in real space using a 3D-AR display. Extraction of characteristic points and teeth matching were done using parallax images from two stereo cameras for patient-image registration. RESULTS: Accurate registration of the volunteer's anatomy with IV stereoscopic images via image matching was done using the fully automated markerless system, which recognized the incisal edges of the teeth and captured information pertaining to their position with an average target registration error of < 1 mm. These 3D-CT images were then displayed in real space with high accuracy using AR. Even when the viewing position was changed, the 3D images could be observed as if they were floating in real space without using special glasses. CONCLUSION: Teeth were successfully used for registration via 3D image (contour) matching. This system, without using references or fiducial markers, displayed 3D-CT images in real space with high accuracy. The system provided real-time markerless registration and 3D image matching via stereo vision, which, combined with AR, could have significant clinical applications. PMID- 26525145 TI - A new class of deep-blue emitting Cu(I) compounds--effects of counter ions on the emission behavior. AB - Three deep blue emitting Cu(I) compounds, [Cu(PPh3)tpym]PF6, [Cu(PPh3)tpym]BF4, and [Cu(PPh3)tpym]BPh4 (tpym = tris(2-pyridyl)methane, PPh3 = triphenylphosphine) featuring the tripodally coordinating tpym and the monodentate PPh3 ligands were studied with regard to their structural and photophysical properties. The compounds only differ in their respective counter ions which have a strong impact on the emission properties of the powder samples. For example, the emission quantum yield can be significantly increased for the neat material from less than 10% to more than 40% by exchanging BPh4(-) with PF6(-). These effects can be linked to different molecular packings which depend on the counter ion. In agreement with these results, it was found that the emission properties also strongly depend on the surrounding matrix environment which was elucidated by investigating photophysical properties of the compounds as powders, doped into a polymer matrix, and dissolved in a fluid solution, respectively. The observed differences in the emission behavior can be explained by different and pronounced distortions that occur in the excited state. These distortions are also displayed by density functional theory (DFT) calculations. PMID- 26525144 TI - Evaluation of multisystemic therapy pilot services in Services for Teens Engaging in Problem Sexual Behaviour (STEPS-B): study protocol for a randomized controlled trial. AB - BACKGROUND: Clinically effective and cost-effective methods for managing problematic sexual behaviour in adolescents are urgently needed. Adolescents who show problematic sexual behaviour have a range of negative psychosocial outcomes, and they and their parents can experience stigma, hostility and rejection from their community. Multisystemic therapy (MST) shows some evidence for helping to reduce adolescent sexual reoffending and is one of the few promising interventions available to young people who show problematic sexual behaviour. This paper describes the protocol for Services for Teens Engaging in Problem Sexual Behaviour (STEPS-B), a feasibility trial of MST for problem sexual behaviour (MST-PSB) in antisocial adolescents at high risk of out-of-home placement due to problematic sexual behaviour. METHODS/DESIGN: Eighty participants and their families recruited from five London boroughs will be randomized to MST-PSB or management as usual with follow-up to 20 months post randomization. The primary outcome is out-of-home placement at 20 months. Secondary outcomes include sexual and non-sexual offending rates and antisocial behaviours, participant well-being, educational outcomes and total service and criminal justice sector costs. Feasibility outcomes include mapping the clinical service pathways needed to recruit adolescents displaying problematic sexual behaviour, acceptability of a randomized controlled trial to the key systems involved in managing these adolescents, and acceptability of the research protocol to young people and their families. Data will be gathered from police computer records, the National Pupil Database and interviews and self-report measures administered to adolescents and parents and will be analysed on an intention-to-treat basis. DISCUSSION: The STEPS-B feasibility trial aims to inform policymakers, commissioners of services and professionals about the potential for implementing MST-PSB as an intervention for adolescents showing problem sexual behaviour. Should MST-PSB show potential, STEPS-B will determine what would be necessary to implement the programme more fully and at a scale that would warrant a full trial. TRIAL REGISTRATION: ISRCTN28441235 (registered 25 January 2012). PMID- 26525146 TI - Use and mis-use of supplementary material in science publications. AB - Supplementary material is a ubiquitous feature of scientific articles, particularly in journals that limit the length of the articles. While the judicious use of supplementary material can improve the readability of scientific articles, its excessive use threatens the scientific review process and by extension the integrity of the scientific literature. In many cases supplementary material today is so extensive that it is reviewed superficially or not at all. Furthermore, citations buried within supplementary files rob other scientists of recognition of their contribution to the scientific record. These issues are exacerbated by the lack of guidance on the use of supplementary information from the journals to authors and reviewers. We propose that the removal of artificial length restrictions plus the use of interactive features made possible by modern electronic media can help to alleviate these problems. Many journals, in fact, have already removed article length limitations (as is the case for BMC Bioinformatics and other BioMed Central journals). We hope that the issues raised in our article will encourage publishers and scientists to work together towards a better use of supplementary information in scientific publishing. PMID- 26525147 TI - Four cases of cell cannibalism in highly malignant feline and canine tumors. AB - Four cases of tumors in which cell internalization was frequently visualized are reported: one feline mammary carcinoma, one feline cutaneous squamous cell carcinoma, one canine pulmonary squamous cell carcinoma and one canine pleural mesothelioma. Cell internalization was observed by cytology in two of these cases (the feline mammary tumour and the pleural effusion in the canine mesothelioma) and by histopathology in all but the canine mesothelioma. Immunohistochemical staining for pancytokeratin was positive for both internalized and host cells, while E-cadherin expression was frequently absent, although internalized cells occasionally stained positive. This cell-to-cell interaction seems to be associated with tumors displaying a strong epithelial-mesenchymal transitional phenotype, in which cancer cells become engulfed by other cancer cells. Such event could be regarded as an important hallmark of very high malignancy. PMID- 26525149 TI - Activity Dependency and Aging in the Regulation of Adult Neurogenesis. AB - Age and activity might be considered the two antagonistic key regulators of adult neurogenesis. Adult neurogenesis decreases with age but remains present, albeit at a very low level, even in the oldest individuals. Activity, be it physical or cognitive, increases adult neurogenesis and thereby seems to counteract age effects. It is, thus, proposed that activity-dependent regulation of adult neurogenesis might contribute to some sort of "neural reserve," the brain's ability to compensate functional loss associated with aging or neurodegeneration. Activity can have nonspecific and specific effects on adult neurogenesis. Mechanistically, nonspecific stimuli that largely affect precursor cell stages might be related by the local microenvironment, whereas more specific, survival promoting effects take place at later stages of neuronal development and require the synaptic integration of the new cell and its particular synaptic plasticity. PMID- 26525150 TI - Neurogenesis following Stroke Affecting the Adult Brain. AB - A bulk of experimental evidence supports the idea that the stroke-damaged adult brain makes an attempt to repair itself by producing new neurons also in areas where neurogenesis does not normally occur (e.g., the striatum and cerebral cortex). Knowledge about mechanisms regulating the different steps of neurogenesis after stroke is rapidly increasing but still incomplete. The functional consequences of stroke-induced neurogenesis and the level of integration of the new neurons into existing neural circuitries are poorly understood. To have a substantial impact on the recovery after stroke, this potential mechanism for self-repair needs to be enhanced, primarily by increasing the survival and differentiation of the generated neuroblasts. Moreover, for efficient repair, optimization of neurogenesis most likely needs to be combined with promotion of other endogenous neuroregenerative responses (e.g., protection and sprouting of remaining mature neurons, transplantation of neural stem/progenitor cells [NSPC]-derived neurons and glia cells, and modulation of inflammation). PMID- 26525148 TI - An Overview of the Molecular Mechanisms of Recombinational DNA Repair. AB - Recombinational DNA repair is a universal aspect of DNA metabolism and is essential for genomic integrity. It is a template-directed process that uses a second chromosomal copy (sister, daughter, or homolog) to ensure proper repair of broken chromosomes. The key steps of recombination are conserved from phage through human, and an overview of those steps is provided in this review. The first step is resection by helicases and nucleases to produce single-stranded DNA (ssDNA) that defines the homologous locus. The ssDNA is a scaffold for assembly of the RecA/RAD51 filament, which promotes the homology search. On finding homology, the nucleoprotein filament catalyzes exchange of DNA strands to form a joint molecule. Recombination is controlled by regulating the fate of both RecA/RAD51 filaments and DNA pairing intermediates. Finally, intermediates that mature into Holliday structures are disjoined by either nucleolytic resolution or topological dissolution. PMID- 26525153 TI - Pharmacokinetics of the Experimental Non-Nucleosidic DNA Methyl Transferase Inhibitor N-Phthalyl-L-Tryptophan (RG 108) in Rats. AB - DNA methyl transferase (DNMT) inhibitors can re-establish the expression of tumour suppressor genes in malignant diseases, but might also be useful in other diseases. Inhibitors in clinical use are nucleosidic cytotoxic agents that need to be integrated into the DNA of dividing cells. Here, we assessed the in vivo kinetics of a non-nucleosidic inhibitor that is potentially free of cytotoxic effects and does not require cell division. The non-specific DNMT inhibitor N phthalyl-L-tryptophan (RG 108) was injected subcutaneously in rats. Blood was drawn 0, 0.5, 1, 2, 4, 6, 8 and 24 hr after injection and RG 108 in plasma was measured by high-performance liquid chromatography coupled to mass spectrometry. Trough levels and area under the curve (AUC) were significantly higher with multiple-dose administration and cytochrome inhibition. In this group, time to maximal plasma concentration (tmax , mean +/- S.D.) was 37.5 +/- 15 min., terminal plasma half-life was approximately 3.7 h (60% CI: 2.1-15.6 h), maximal plasma concentration (Cmax) was 61.3 +/- 7.6 MUM, and AUC was 200 +/- 54 MUmol.h/l. RG 108 peak levels were not influenced by cytochrome inhibition or multiple-dose administration regimens. Maximal tissue levels (Cmax in MUmol/kg) were 6.9 +/- 6.7, 1.6 +/- 0.4 and 3.4 +/- 1.1 in liver, skeletal and heart muscle, respectively. We conclude that despite its high lipophilicity, RG 108 can be used for in vivo experiments, appears safe and yields plasma and tissue levels in the range of the described 50% inhibitory concentration of around 1 to 5 MUM. RG 108 can therefore be a useful tool for in vivo DNMT inhibition. PMID- 26525151 TI - Germline and Pluripotent Stem Cells. AB - Epigenetic mechanisms play an essential role in the germline and imprinting cycle. Germ cells show extensive epigenetic programming in preparation for the generation of the totipotent state, which in turn leads to the establishment of pluripotent cells in blastocysts. The latter are the cells from which pluripotent embryonic stem cells are derived and maintained in culture. Following blastocyst implantation, postimplantation epiblast cells develop, which give rise to all somatic cells as well as primordial germ cells, the precursors of sperm and eggs. Pluripotent stem cells in culture can be induced to undergo differentiation into somatic cells and germ cells in culture. Understanding the natural cycles of epigenetic reprogramming that occur in the germline will allow the generation of better and more versatile stem cells for both therapeutic and research purposes. PMID- 26525154 TI - Simultaneous and rapid determination of gefitinib, erlotinib and afatinib plasma levels using liquid chromatography/tandem mass spectrometry in patients with non small-cell lung cancer. AB - A simultaneous, selective, sensitive and rapid liquid chromatography/tandem mass spectrometry method was developed and validated for the quantification of gefitinib, erlotinib and afatinib in 250 MUL samples of human blood plasma. Diluted plasma samples were extracted using a liquid-phase extraction procedure with tert-butyl methyl ether. The three drugs were separated by high-performance liquid chromatography using a C18 column and an isocratic mobile phase running at a flow rate of 0.2 mL/min for 5 min. The drugs were detected using a tandem mass spectrometer with electrospray ionization using imatinib as an internal standard. Calibration curves were generated over the linear concentration range of 0.05-100 nm in plasma with a lower limit of quantification of 0.01 or 0.05 nm for all compounds. Finally, the validated method was applied to a clinical pharmacokinetic study in patients with nonsmall-cell lung cancer (NSCLC) following the oral administration of afatinib. These results indicate that this method is suitable for assessing the risks and benefits of chemotherapy in patients with NSCLC and is useful for therapeutic drug monitoring for NSCLC treatment. As far as we know, this is the first report on LC-MS/MS method for the simultaneous quantification of NSCLC tyrosine kinase inhibitor plasma concentrations including afatinib. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26525152 TI - The Corticohippocampal Circuit, Synaptic Plasticity, and Memory. AB - Synaptic plasticity serves as a cellular substrate for information storage in the central nervous system. The entorhinal cortex (EC) and hippocampus are interconnected brain areas supporting basic cognitive functions important for the formation and retrieval of declarative memories. Here, we discuss how information flow in the EC-hippocampal loop is organized through circuit design. We highlight recently identified corticohippocampal and intrahippocampal connections and how these long-range and local microcircuits contribute to learning. This review also describes various forms of activity-dependent mechanisms that change the strength of corticohippocampal synaptic transmission. A key point to emerge from these studies is that patterned activity and interaction of coincident inputs gives rise to associational plasticity and long-term regulation of information flow. Finally, we offer insights about how learning-related synaptic plasticity within the corticohippocampal circuit during sensory experiences may enable adaptive behaviors for encoding spatial, episodic, social, and contextual memories. PMID- 26525156 TI - Targeted next-generation sequencing of familial platelet disorder with predisposition to acute myeloid leukaemia. PMID- 26525155 TI - Highly Fluorescent Green Fluorescent Protein Chromophore Analogues Made by Decorating the Imidazolone Ring. AB - The synthesis and photophysical behavior of an unexplored family of green fluorescent protein (GFP)-like chromophore analogues is reported. The compound (Z)-4-(4-hydroxybenzylidene)-1-propyl-2-(propylamino)-1H-imidazol-5(4 H)-one (p HBDNI, 2 a) exhibits significantly enhanced fluorescence properties relative to the parent compound (Z)-5-(4-hydroxybenzylidene)-2,3-dimethyl-3,5-dihydro-4H imidazol-4-one (p-HBDI, 1). p-HBDNI was considered as a model system and the photophysical properties of other novel 2-amino-3,5-dihydro-4H-imidazol-4-one derivatives were evaluated. Time-dependent DFT calculations were carried out to rationalize the results. The analogue AIDNI (2 c), in which the 4-hydroxybenzyl group of p-HBDNI was replaced by an azaindole group, showed improved photophysical properties and potential for cell staining. The uptake and intracellular distribution of 2 c in living cells was investigated by confocal microscopy imaging. PMID- 26525157 TI - Off-label use of the amplatzer ductal occluder II additional size for percutaneous closure of congenital and acquired coronary fistulae. AB - We report two cases in which congenital and acquired fistulae (CAFs) have been successfully closed by using the Amplatzer Ductal Occluder (ADO) II AS in children. Because of the flexibility, small profile and short length of ADO II AS, this device proved to be an excellent option in case of tortuous and short CAFs with coronary branches next to the fistulous orifice. (c) 2015 Wiley Periodicals, Inc. PMID- 26525158 TI - Temporal succession in carbon incorporation from macromolecules by particle attached bacteria in marine microcosms. AB - We investigated bacterial carbon assimilation from stable isotope-labelled macromolecular substrates (proteins; lipids; and two types of polysaccharides, starch and cellobiose) while attached to killed diatom detrital particles during laboratory microcosms incubated for 17 days. Using Chip-SIP (secondary ion mass spectrometry analysis of RNA microarrays), we identified generalist operational taxonomic units (OTUs) from the Gammaproteobacteria, belonging to the genera Colwellia, Glaciecola, Pseudoalteromonas and Rheinheimera, and from the Bacteroidetes, genera Owenweeksia and Maribacter, that incorporated the four tested substrates throughout the incubation period. Many of these OTUs exhibited the highest isotope incorporation relative to the others, indicating that they were likely the most active. Additional OTUs from the Gammaproteobacteria, Bacteroidetes and Alphaproteobacteria exhibited generally (but not always) lower activity and did not incorporate all tested substrates at all times, showing species succession in organic carbon incorporation. We also found evidence to suggest that both generalist and specialist OTUs changed their relative substrate incorporation over time, presumably in response to changing substrate availability as the particles aged. This pattern was demonstrated by temporal succession from relatively higher starch incorporation early in the incubations, eventually switching to higher cellobiose incorporation after 2 weeks. PMID- 26525159 TI - Prognostic marker and target in prostate cancer. PMID- 26525160 TI - Assessment of exposure to MRI motion-induced fields based on the International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines. AB - PURPOSE: The goal of this study was to conduct an exposure assessment for workers moving through the stray stationary field of common MRI scanners, performed according to the recent International Commission on Non-Ionizing Radiation Protection (ICNIRP) Guidelines, which aim at avoiding annoying sensory effects. THEORY AND METHODS: The analysis was performed through numerical simulations, using a high-resolution anatomical model that moved along realistic trajectories in proximity to a tubular and open MRI scanner. Both dosimetric indexes indicated by ICNIRP (maximum variation of the magnetic flux density vector and exposure index for the motion-induced electric field) were computed for three statures of the human model. RESULTS: A total of 51 exposure situations were analyzed. None of them exceeded the limit for the maximum variation of the magnetic flux density, whereas some critical cases were found when computing the induced electric field. In the latter case, the exposure indexes computed via Fourier transform and through an equivalent filter result to be consistent. CONCLUSION: The results suggest the adoption of some simple precautionary rules, useful when sensory effects experienced by an operator could reflect upon the patient's safety. Moreover, some open issues regarding the quantification of motion-induced fields are highlighted, putting in evidence the need for clarification at standardization level. Magn Reson Med 76:1291-1300, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26525161 TI - Treatment of delocalized electron transfer in periodic and embedded cluster DFT calculations: The case of Cu on ZnO (10(1)0). AB - We assess the consequences of the interface model-embedded-cluster or periodic slab model-on the ability of DFT calculations to describe charge transfer (CT) in a particularly challenging case where periodic-slab calculations indicate a delocalized charge-transfer state. Our example is Cu atom adsorption on ZnO(10(1)0), and in fact the periodic slab calculations indicate three types of CT depending on the adsorption site: full CT, partial CT, and no CT. Interestingly, when full CT occurs in the periodic calculations, the calculated Cu atom adsorption energy depends on the underlying ZnO substrate supercell size, since when the electron enters the ZnO it delocalizes over as many atoms as possible. In the embedded-cluster calculations, the electron transferred to the ZnO delocalizes over the entire cluster region, and as a result the calculated Cu atom adsorption energy does not agree with the value obtained using a large periodic supercell, but instead to the adsorption energy obtained for a periodic supercell of roughly the same size as the embedded cluster. Different density functionals (of GGA and hybrid types) and basis sets (local atom-centered and plane-waves) were assessed, and we show that embedded clusters can be used to model Cu adsorption on ZnO(10(1)0), as long as care is taken to account for the effects of CT. PMID- 26525162 TI - Comparison of simplified and comprehensive methods for assessing the index of microvascular resistance in heart transplant recipients. AB - OBJECTIVES: The objectives of the present study were to compare a simplified and a comprehensive method of estimating the index of microvascular resistance (IMR) and assess the changes from 7-11 weeks to 1 year after heart transplant (HTx). BACKGROUND: he IMR is specific to the microvasculature and reflects the status of the microcirculation in cardiac patients and can be estimated via a simplified method (IMR(s)) or a comprehensive method (IMR(c)). The calculation for the latter includes coronary wedge pressure and central venous pressure. METHODS: Consecutively transplanted patients (n = 48) underwent left and right heart catheterization including physiological evaluation at two time points post-HTx. The agreement between the values of IMR obtained using the IMR(s) and IMR(c) methods were assessed using Bland-Altman analysis. The agreements and differences were assessed using mixed model analysis. RESULTS: The mean bias between IMRs and IMRc was 1.3 mm Hg.s (95% limits of agreement: -1.2, 3.8 mm Hg). Between 7-11 weeks and 1 year post-HTx there was a significant decline in IMR(s) values (P = 0.03) but a smaller and statistically nonsignificant decline in IMR(c) values (P = 0.13). The significant difference (P = 0.04) between IMR(c) and IMR(s) 7-11 weeks post-HTx was no longer present at 1 year (P = 0.24). CONCLUSIONS: The IMR(s) method resulted in slightly higher IMR estimates and exhibited a somewhat larger change over the 10-month follow-up period than the IMR(c) method. However, the differences between the methods were small and unlikely to be of clinical importance. PMID- 26525163 TI - Identification and virulence properties of Aeromonas veronii bv. sobria isolates causing an ulcerative syndrome of loach Misgurnus anguillicaudatus. PMID- 26525164 TI - Plasma hyperosmolality attenuates skin sympathetic nerve activity during passive heat stress in humans. AB - KEY POINTS: Plasma hyperosmolality delays the onset for sweat production and cutaneous vasodilatation during heat stress in humans; however, the mechanism by which hyperosmolality exerts this effect remains unknown. This study examined if plasma hyperosmolality exerts a central and/or peripheral modulation of thermoregulatory function in humans. The main findings are that plasma hyperosmolality delays the increase in skin sympathetic nerve activity during whole-body passive heat stress in humans. In contrast, local intradermal infusion of hyperosmotic saline did not affect sweating or cutaneous vasodilatation. These results suggest that plasma hyperosmolality delays the onset threshold for sweating and cutaneous vasodilatation by inhibiting efferent thermoregulatory activity in humans. ABSTRACT: In humans, plasma hyperosmolality delays the onset of sweating and cutaneous vasodilatation during heat stress. However, it remains unknown if hyperosmolality exerts this effect through a central (i.e. CNS) and/or peripheral (i.e. effector organ) modulation of thermoregulatory activity. We examined if intravenous infusion of hyperosmotic saline affects skin sympathetic nerve activity (SSNA) during whole-body passive heating in healthy humans. Furthermore, we examined if local intradermal infusion of hyperosmotic saline affects sweating and cutaneous vasodilatation during passive heating. Following intravenous infusion of either 0.9% (ISO) or 3.0% (HYPER) NaCl saline, 12 subjects were passively heated until core temperature increased by ~0.6 degrees C. During each condition, sweating and cutaneous vascular conductance were measured over two intradermal microdialysis probes, one perfused with ISO saline and the other with HYPER saline. Intravenous infusion of HYPER saline increased plasma osmolality (294 +/- 3 to 316 +/- 5 mOsm kg(-1) H2O, P <= 0.01), which remained greater than ISO throughout heating. Plasma hyperosmolality delayed the mean body temperature onset of sweating (+1.24 +/- 0.18 vs. +1.60 +/- 0.18 degrees C, P <= 0.01) and cutaneous vasodilatation (+1.15 +/- 0.18 vs. +1.53 +/- 0.22 degrees C, P <= 0.01), and attenuated the increase in SSNA during heating (+147 +/- 178 vs. +427 +/- 281%, P <= 0.01). Intradermal infusion of HYPER saline increased baseline cutaneous vascular conductance (P <= 0.01), which did not increase further during the subsequent heating period (P = 0.11). In contrast, intradermal infusion of HYPER saline did not affect sweating (P = 0.99). These results provide direct evidence that plasma hyperosmolality exerts a central modulatory effect governing efferent thermoregulatory activity in humans. PMID- 26525165 TI - Economic evaluation of a psychological intervention for high distress cancer patients and carers: costs and quality-adjusted life years. AB - OBJECTIVE: This study compared the cost-effectiveness of a psychologist-led, individualised cognitive behavioural intervention (PI) to a nurse-led, minimal contact self-management condition for highly distressed cancer patients and carers. METHODS: This was an economic evaluation conducted alongside a randomised trial of highly distressed adult cancer patients and carers calling cancer helplines. Services used by participants were measured using a resource use questionnaire, and quality-adjusted life years were measured using the assessment of quality of life - eight-dimension - instrument collected through a computer assisted telephone interview. The base case analysis stratified participants based on the baseline score on the Brief Symptom Inventory. Incremental cost effectiveness ratio confidence intervals were calculated with a nonparametric bootstrap to reflect sampling uncertainty. The results were subjected to sensitivity analysis by varying unit costs for resource use and the method for handling missing data. RESULTS: No significant differences were found in overall total costs or quality-adjusted life years (QALYs) between intervention groups. Bootstrapped data suggest the PI had a higher probability of lower cost and greater QALYs for both carers and patients with high distress at baseline. For patients with low levels of distress at baseline, the PI had a higher probability of greater QALYs but at additional cost. Sensitivity analysis showed the results were robust. CONCLUSIONS: The PI may be cost-effective compared with the nurse led, minimal contact self-management condition for highly distressed cancer patients and carers. More intensive psychological intervention for patients with greater levels of distress appears warranted. Copyright (c) 2015 John Wiley & Sons, Ltd. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26525166 TI - Relative contribution of four nucleases, CtIP, Dna2, Exo1 and Mre11, to the initial step of DNA double-strand break repair by homologous recombination in both the chicken DT40 and human TK6 cell lines. AB - Homologous recombination (HR) is initiated by double-strand break (DSB) resection, during which DSBs are processed by nucleases to generate 3' single strand DNA. DSB resection is initiated by CtIP and Mre11 followed by long-range resection by Dna2 and Exo1 in Saccharomyces cerevisiae. To analyze the relative contribution of four nucleases, CtIP, Mre11, Dna2 and Exo1, to DSB resection, we disrupted genes encoding these nucleases in chicken DT40 cells. CtIP and Dna2 are required for DSB resection, whereas Exo1 is dispensable even in the absence of Dna2, which observation agrees with no developmental defect in Exo1-deficient mice. Despite the critical role of Mre11 in DSB resection in S. cerevisiae, loss of Mre11 only modestly impairs DSB resection in DT40 cells. To further test the role of CtIP and Mre11 in other species, we conditionally disrupted CtIP and MRE11 genes in the human TK6 B cell line. As with DT40 cells, CtIP contributes to DSB resection considerably more significantly than Mre11 in TK6 cells. Considering the critical role of Mre11 in HR, this study suggests that Mre11 is involved in a mechanism other than DSB resection. In summary, CtIP and Dna2 are sufficient for DSB resection to ensure efficient DSB repair by HR. PMID- 26525167 TI - The effect of swimming exercise and powdered-Salicornia herbacea L. ingestion on glucose metabolism in STZ-induced diabetic rats. AB - PURPOSE: The purpose of this study is to observe the effects of Salicornia herbacea L. powder ingestion on carbohydrate metabolism in STZ-induced diabetic rats. METHODS: To achieve this objective, 35 Sprague-Dawley male rats were raised with feed mixed with Salicornia herbacia L. powder and given specific periods to swim for 5 weeks. There was no significant difference in the insulin increase rate while ingesting Salicornia herbacea L. powder and simultaneously exercising. RESULTS: Compared to the diabetes mellitus group, HOMA-IR was significantly decreased in the diabetes mellitus + exercise group, diabetes mellitus + Salicornia herbacea group, and the diabetes mellitus + Salicornia herbacea + exercise group. However, changes in blood glucose were significant in each group. Thus, for the result of GLUT-4 and GLUT-2, which are the glycose transporters of the liver and muscle, diabetes mellitus + exercise group, diabetes mellitus + Salicornia herbacea group, and diabetes mellitus + Salicornia herbacea + exercise group showed significantly higher expressions. The glycogen concentration of the liver and muscle was significantly increased in the diabetes mellitus + exercise group, diabetes mellitus + Salicornia herbacea group, and diabetes mellitus + Salicornia herbacea + exercise group. CONCLUSION: With the results above, it seems that taking Salicornia herbacea L. powder and exercise will help prevent various diabetic complications. Therefore, the findings of this study could justify Salicornia herbacea L. powder with its basal data of physiological activities and pharmacological components as a type of health functional food. PMID- 26525168 TI - Associations of maternal prepregnancy body mass index and gestational weight gain with cardio-metabolic risk factors in adolescent offspring: a prospective cohort study. AB - OBJECTIVE: To assess the associations of maternal prepregnancy body mass index (BMI) and rates of early-pregnancy, mid-pregnancy and total gestational weight gain with adolescent body fat distribution and cardio-metabolic outcomes. DESIGN: Population-based prospective cohort study. SETTING: Western Australia. POPULATION: Thousand three hundred and ninety-two mothers and their children. METHODS: Maternal prepregnancy weight was assessed by questionnaire. Maternal weights at a mean of 16.5 +/- 2.2 SD and 34.1 +/- 1.5 SD weeks of gestation were obtained from medical records. Offspring adiposity and cardio-metabolic outcomes were assessed at a median age 17.0 years [95% confidence interval (CI) range: 16.7, 17.7]. MAIN OUTCOME MEASURES: Adolescent BMI, waist circumference (WC), waist-to-hip ratio (WHR), blood pressure, total and HDL-cholesterol, triglycerides, insulin, glucose and HOMA-IR. RESULTS: Higher prepregnancy BMI was associated with higher adolescent BMI, WC, WHR, systolic blood pressure, insulin, glucose and HOMA-IR levels (P-values <0.05). Adjustment for adolescent current BMI attenuated the associations of prepregnancy BMI with adolescent cardio metabolic outcomes. Higher weight gain in early-pregnancy, but not mid-pregnancy, was associated with higher adolescent BMI, WC and WHR (P-values <0.05), but not with other cardio-metabolic risk factors. Total gestational weight gain was associated with adolescent BMI and WC (P-values <0.05). Higher prepregnancy BMI and early-pregnancy weight gain were associated with increased risks of the high metabolic risk cluster in adolescents (OR 1.57, 95% CI 1.33, 1.85 and OR 1.23, 95% CI 1.03, 1.47 per SD increase in prepregnancy BMI and early-pregnancy weight gain, respectively). CONCLUSIONS: Higher maternal prepregnancy BMI and early pregnancy weight gain rate are associated with an adverse adolescent cardio metabolic profile. These associations are largely mediated by adolescent BMI. PMID- 26525169 TI - TNNT2 Gene Polymorphisms are Associated with Susceptibility to Idiopathic Dilated Cardiomyopathy in Kazak and Han Chinese. AB - BACKGROUND: Dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement, systolic dysfunction, and heart failure. Both genetic and non genetic factors have been linked to DCM pathogenesis. Familial DCM (FDCM) accounts for 20%-50% of all DCM cases, highlighting the importance of genetics in pathogenesis. Indeed, more than 40 DCM-associated genes have been identified, including the gene encoding cardiac troponin T type-2 (TNNT2). We examined polymorphisms of the TNNT2 gene in idiopathic DCM (IDCM) patients of Kazak and Han ethnicity compared with healthy Kazak and Han controls. MATERIAL AND METHODS: Peripheral blood samples were collected from 180 patients with IDCM (90 Kazak and 90 Han), and 180 healthy controls (90 Kazak and 90 Han). PCR was used to amplify 15 exons and nearby introns of the TNNT2 gene. The amplified products were sequenced and compared to the standard sequence in PubMed by BLAST and CHROMAS software, to identify mutation sites. RESULTS: Results from Kazak and Han IDCM patients were complied for Hardy-Weinberg equilibrium analysis. There was a significant difference in the genotype distribution (chi2=6.67, P=0.015) and allele frequency (chi2=5.71, P=0.017) between Kazaks with IDCM and Kazak controls of SNP rs3729547. There was also a difference in the genotype distribution (chi2=6.62, P=0.036) and allele frequency (chi2=4.91, P=0.018) between Han with IDCM and Han controls. The TNNT2 gene polymorphism loci rs3729547 may be associated with the IDCM onset in Kazak and Han patients (OR=2.5, 95% CI: 1.233~5.068). CONCLUSIONS: The TNNT2 polymorphisms might play an important role in susceptibility to DCM in Xinjiang Kazak and Han patients. PMID- 26525170 TI - Endolymphatic hydrops in superior canal dehiscence and large vestibular aqueduct syndromes. AB - OBJECTIVES/HYPOTHESIS: Pathologic third window lesions, such as superior semicircular canal dehiscence syndrome (SCDS) or large vestibular aqueduct syndrome (LVAS), cause several auditory and vestibular symptoms, which might affect perilymphatic pressure and induce endolymphatic hydrops (EH). In this study, the existence of EH in subjects with SCDS or LVAS was investigated using contrast-enhanced magnetic resonance imaging (MRI). STUDY DESIGN: Case series at university hospital. METHODS: Seventeen ears from nine subjects who were diagnosed as having SCDS (five ears from three cases) or LVAS (12 ears from six cases) were studied. Ears were evaluated by 3-T MRI performed 4 hours after intravenous injection of gadodiamide hydrate. Imaging data concerning the degree of EH in the cochlea and the vestibule were compared with clinical symptoms and hearing levels for all ears. RESULTS: All ears showed air-bone gaps at low frequencies on pure tone audiometry. None of the subjects with SCDS had episodes of acute sensorineural hearing loss (SNHL) or vestibular symptoms, except for one patient who complained of head vibration induced by loud noise. Conversely, five of six subjects with LVAS had episodes of acute SNHL or vestibular symptoms. Four of five ears with SCDS showed severe EH in the cochlea, and two ears showed mild EH in the vestibule. All ears with LVAS showed mild to severe EH in both the cochlea and vestibule. CONCLUSIONS: The present study demonstrated the existence of EH in ears with pathologic third window lesions, which might affect patients' auditory or vestibular symptoms. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1446 1450, 2016. PMID- 26525171 TI - Sound Richness of Music Might Be Mediated by Color Perception: A PET Study. AB - OBJECTS: We investigated the role of the fusiform cortex in music processing with the use of PET, focusing on the perception of sound richness. METHOD: Musically naive subjects listened to familiar melodies with three kinds of accompaniments: (i) an accompaniment composed of only three basic chords (chord condition), (ii) a simple accompaniment typically used in traditional music text books in elementary school (simple condition), and (iii) an accompaniment with rich and flowery sounds composed by a professional composer (complex condition). Using a PET subtraction technique, we studied changes in regional cerebral blood flow (rCBF) in simple minus chord, complex minus simple, and complex minus chord conditions. RESULTS: The simple minus chord, complex minus simple, and complex minus chord conditions regularly showed increases in rCBF at the posterior portion of the inferior temporal gyrus, including the LOC and fusiform gyrus. CONCLUSIONS: We may conclude that certain association cortices such as the LOC and the fusiform cortex may represent centers of multisensory integration, with foreground and background segregation occurring at the LOC level and the recognition of richness and floweriness of stimuli occurring in the fusiform cortex, both in terms of vision and audition. PMID- 26525172 TI - Revised spectroscopic parameters of SH(+) from ALMA and IRAM 30m observations. AB - Hydrides represent the first steps of interstellar chemistry. Sulfanylium (SH(+)), in particular, is a key tracer of energetic processes. We used ALMA and the IRAM 30 m telescope to search for the lowest frequency rotational lines of SH(+) toward the Orion Bar, the prototypical photo-dissociation region illuminated by a strong UV radiation field. On the basis of previous Herschel/HIFI observations of SH(+), we expected to detect emission of the two SH(+) hyperfine structure (HFS) components of the NJ = 10-01 fine structure (FS) component near 346 GHz. While we did not observe any lines at the frequencies predicted from laboratory data, we detected two emission lines, each ~15 MHz above the SH(+) predictions and with relative intensities and HFS splitting expected for SH(+). The rest frequencies of the two newly detected lines are more compatible with the remainder of the SH(+) laboratory data than the single line measured in the laboratory near 346 GHz and previously attributed to SH(+). Therefore, we assign these new features to the two SH(+) HFS components of the NJ = 10-01 FS component and re-determine its spectroscopic parameters, which will be useful for future observations of SH(+), in particular if its lowest frequency FS components are studied. Our observations demonstrate the suitability of these lines for SH(+) searches at frequencies easily accessible from the ground. PMID- 26525173 TI - The effects of aqueous extract of alfalfa on blood glucose and lipids in alloxan induced diabetic rats. AB - Diabetes is a common metabolic disorder that is specified by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The use of nonpharmacological treatments (herbal agents) is a new approach in the management of diabetes. The aim of this study was to investigate the effect of aqueous extract of alfalfa on blood glucose and serum lipids in alloxan-induced diabetic rats. In this study, 32 female rats (210-250 g) were used which were divided randomly into 4 groups including intact control group, diabetic control group, and 2 diabetic groups which received 250 and 500 mg/kg doses of aqueous extract of alfalfa, respectively. In the diabetic groups, alloxan-monohydrate was injected peritoneally to create diabetic condition. The two last groups orally received aqueous extract of alfalfa for 21 days. At the end of experiment, sugar, cholesterol, triglycerides, high-density and low-density lipoprotein, and aspartate aminotransferase (ALT) and alanine aminotransferase (AST) levels were measured in the samples. Consumption of aqueous alfalfa extract significantly reduced glucose, cholesterol, triglycerides, and low-density lipoprotein (LDL) levels in the diabetic rats but enhanced high-density lipoprotein (HDL) levels. ALT and AST liver enzyme levels were also reduced in blood. Histological examination showed that the aqueous alfalfa extract caused reconstruction of damaged liver and enhanced Langerhans islets' diameter in pancreas. Therefore, all signs of diabetes were improved by oral administration of alfalfa in defined dose. PMID- 26525174 TI - Comparison of athletic movement between elite junior and senior Australian football players. AB - This study compared the athletic movement skill between elite Under-18 (U18) Australian football (AF) and senior Australian Football League (AFL) players. The U18 sample (n = 13; 17.7 +/- 0.6 years) were representatives of an elite talent development programme. The AFL players were classified accordingly; Group 1 (1-4 AFL seasons; n = 20; 21.2 +/- 1.9 years) and Group 2 (>5 AFL seasons; n = 14; 26.3 +/- 2.6 years). Participants performed an athletic movement skill assessment, inclusive of five foundational movements. Each movement was scored across three assessment points using a three-point scale. Total score for each movement (maximum of nine) and overall score (maximum of 63) were used as criteria. Multivariate analysis of variance (MANOVA) was used to test the effect of developmental group (three levels) on the criteria. Receiver operating curves were built to examine the discriminant capability of the overall score. A significant effect of developmental group was noted, with the U18 sample having a lower mean total score for four of the five movements. Overall scores of 49/63 and 50/63 discriminated the elite U18 sample from Group 1 and Group 2, respectively. U18 players may have less developed athletic movement skills when compared to their senior AFL counterparts. PMID- 26525175 TI - Body distribution of SiO2-Fe3O4 core-shell nanoparticles after intravenous injection and intratracheal instillation. AB - Nano-silicon dioxide (SiO2) is used nowadays in several biomedical applications such as drug delivery and cancer therapy, and is produced on an industrial scale as additive to paints and coatings, cosmetics and food. Data regarding the long term biokinetics of SiO2 engineered nanoparticles (ENPs) is lacking. In this study, the whole-body biodistribution of SiO2 core-shell ENPs containing a paramagnetic core of Fe3O4 was investigated after a single exposure via intravenous injection or intratracheal instillation in mice. The distribution and accumulation in different organs was evaluated for a period of 84 days using several techniques, including magnetic resonance imaging, inductively coupled plasma mass spectrometry, X-ray fluorescence and X-ray absorption near edge structure spectroscopy. We demonstrated that intravenously administered SiO2 ENPs mainly accumulate in the liver, and are retained in this tissue for over 84 days. After intratracheal instillation, an almost complete particle clearance from the lung was seen after 84 days with distribution to spleen and kidney. Furthermore, we have strong evidence that the ENPs retain their original core-shell structure during the whole observation period. This work gives an insight into the whole body biodistribution of SiO2 ENPs and will provide guidance for further toxicity studies. PMID- 26525176 TI - Alterations in DNA methylation and airway hyperreactivity in response to in utero exposure to environmental tobacco smoke. AB - Growing evidence indicates that prenatal exposure to maternal smoking is a risk factor for the development of asthma in children. However, the effects of prenatal environmental tobacco smoke (ETS) exposure on the genome and lung immune cells are unclear. This study aims to determine whether in utero ETS exposure alters DNA methylation patterns and increases airway hyperreactivity (AHR) and inflammation. Pregnant C57BL/6 mice were exposed daily to a concentration of 1.0 mg/m(3) ETS. AHR was determined in the 6-week-old offspring by measurement of airway resistance. Global and gene promoter methylation levels in lung DNA from offspring were analyzed by luminometric methylation and pyrosequencing assays, respectively. Offspring exposed to ETS showed a marked increase in the number of alveolar macrophages in the bronchoalveolar lavage fluid and level of IL-13 in the airways compared with offspring of filtered-air exposed dams (controls). ETS exposure significantly augmented AHR compared with controls. In the methylation analysis, ETS-exposed offspring had a significantly lower level of global DNA methylation than the controls. We observed a significant increase in IFN-gamma, and significant decrease in IL-13 methylation levels in the ETS group compared with controls. Collectively, these data suggest that in utero ETS exposure increases the risk of pulmonary inflammation and AHR through altered DNA methylation, but additional studies are needed to fully determine the causal link between changes in methylation and cytokines levels, as well as AHR. PMID- 26525177 TI - A new isoflavone glycoside from Pueraria alopecuroides. AB - A new isoflavone glycoside, (-)-tuberosin-3-O-beta-D-glucopyranoside (1), along with 10 known compounds 1a-10, was isolated from Pueraria alopecuroides. Their structures were determined on the basis of spectral data including 1D and 2D NMR and HREIMS. These compounds were isolated from this plant for the first time. PMID- 26525178 TI - A Computational Study of the Effects of Syk Activity on B Cell Receptor Signaling Dynamics. AB - The kinase Syk is intricately involved in early signaling events in B cells and is required for proper response when antigens bind to B cell receptors (BCRs). Experiments using an analog-sensitive version of Syk (Syk-AQL) have better elucidated its role, but have not completely characterized its behavior. We present a computational model for BCR signaling, using dynamical systems, which incorporates both wild-type Syk and Syk-AQL. Following the use of sensitivity analysis to identify significant reaction parameters, we screen for parameter vectors that produced graded responses to BCR stimulation as is observed experimentally. We demonstrate qualitative agreement between the model and dose response data for both mutant and wild-type kinases. Analysis of our model suggests that the level of NF-kappaB activation, which is reduced in Syk-AQL cells relative to wild-type, is more sensitive to small reductions in kinase activity than Erkp activation, which is essentially unchanged. Since this profile of high Erkp and reduced NF-kappaB is consistent with anergy, this implies that anergy is particularly sensitive to small changes in catalytic activity. Also, under a range of forward and reverse ligand binding rates, our model of Erkp and NF-kappaB activation displays a dependence on a power law affinity: the ratio of the forward rate to a non-unit power of the reverse rate. This dependence implies that B cells may respond to certain details of binding and unbinding rates for ligands rather than simple affinity alone. PMID- 26525179 TI - Multiple Choice Questions. PMID- 26525180 TI - Osmium Atoms and Os2 Molecules Move Faster on Selenium-Doped Compared to Sulfur Doped Boronic Graphenic Surfaces. AB - We deposited Os atoms on S- and Se-doped boronic graphenic surfaces by electron bombardment of micelles containing 16e complexes [Os(p-cymene)(1,2-dicarba-closo dodecarborane-1,2-diselenate/dithiolate)] encapsulated in a triblock copolymer. The surfaces were characterized by energy-dispersive X-ray (EDX) analysis and electron energy loss spectroscopy of energy filtered TEM (EFTEM). Os atoms moved ca. 26* faster on the B/Se surface compared to the B/S surface (233 +/- 34 pm.s( 1) versus 8.9 +/- 1.9 pm.s(-1)). Os atoms formed dimers with an average Os-Os distance of 0.284 +/- 0.077 nm on the B/Se surface and 0.243 +/- 0.059 nm on B/S, close to that in metallic Os. The Os2 molecules moved 0.83* and 0.65* more slowly than single Os atoms on B/S and B/Se surfaces, respectively, and again markedly faster (ca. 20*) on the B/Se surface (151 +/- 45 pm.s(-1) versus 7.4 +/- 2.8 pm.s(-1)). Os atom motion did not follow Brownian motion and appears to involve anchoring sites, probably S and Se atoms. The ability to control the atomic motion of metal atoms and molecules on surfaces has potential for exploitation in nanodevices of the future. PMID- 26525181 TI - Seismic signature of the Alpine indentation, evidence from the Eastern Alps. AB - The type of collision between the European and the Adriatic plates in the easternmost Alps is one of the most interesting questions regarding the Alpine evolution. Tectonic processes such as compression, escape and uplift are interconnected and shape this area. We can understand these ongoing processes better, if we look for signs of the deformation within the Earth's deep crust of the region. By collecting records from permanent and temporary seismic networks, we assemble a receiver function dataset, and analyze it with the aim of giving new insights on the structure of the lower crust and of the shallow portion of the upper mantle, which are inaccessible to direct observation. Imaging is accomplished by performing common conversion depth stacks along three profiles that crosscut the Eastern Alpine orogen, and allow isolating features consistently persistent in the area. The study shows a moderately flat Moho underlying a seismically anisotropic middle-lower crust from the Southern Alps to the Austroalpine nappes. The spatial progression of anisotropic axes reflects the orientation of the relative motion and of the stress field detected at the surface. These observations suggest that distributed deformation is due to the effect of the Alpine indentation. In the shallow upper mantle right below the Moho interface, a further anisotropic layer is recognized, extended from the Bohemian Massif to the Northern Calcareous Alps. PMID- 26525182 TI - Insomnia Co-Occurring with Chronic Pain: Clinical Features, Interaction, Assessments and Possible Interventions. AB - Insomnia is a major source of distress to people with chronic pain; many of whom presenting for treatment want tangible help with sleep.Compared to chronic pain patients who do not have trouble sleeping, those who do, report more severe pain, longer pain duration, greater levels of anxiety, depression and health anxiety, and worse impairment in physical and psychosocial functioning.Sleep disturbance experienced by patients with chronic pain can be characterised by longer sleep onset, more frequent and longer awakenings after sleep onset, shorter total sleep time, lower sleep efficiency and poorer sleep quality. Such pattern of disturbance is analogous to that of primary insomnia.The relationship between pain and sleep is likely to be bi-directional, although exactly how the two problems interact is little understood.The offer of sleep advice and the use of pharmacotherapy for pain-related insomnia have their respective limitations. Psychological and behavioural treatments demonstrated to be effective for both primary and comorbid insomnia may be a viable treatment alternative. PMID- 26525183 TI - Cushing's storm secondary to a rare case of ectopic ACTH secreting metastatic breast cancer. AB - Ectopic ACTH secretion from breast cancer is extremely rare. We report a case of a 30-year-old woman with a history of breast cancer, who presented with psychosis and paranoid behaviour. CT of the head showed white matter disease consistent with posterior reversible encephalopathy syndrome (PRES). Despite using mifepristone with multiple antihypertensives including lisinopril, spironolactone and metoprolol, she was hypertensive. Transaminitis did not allow mifepristone dose escalation and ketoconazole utilization. Etomidate infusion at a non sedating dose in the intensive care unit controlled her hypertension and cortisol levels. She was transitioned to metyrapone and spironolactone. She was discharged from the hospital on metyrapone with spironolactone and underwent chemotherapy. She died 9 months later after she rapidly redeveloped Cushing's syndrome and had progressive metastatic breast cancer involving multiple bones, liver and lungs causing respiratory failure. LEARNING POINTS: Cushing's syndrome from ectopic ACTH secreting breast cancer is extremely rare.Cushing's syndrome causing psychosis could be multifactorial including hypercortisolism and PRES.Etomidate at non-sedating doses in intensive care setting can be effective to reduce cortisol production followed by transition to oral metyrapone. PMID- 26525184 TI - Solitary Plaque-type Morphea with Dystrophic Calcinosis Cutis. PMID- 26525185 TI - Bacillus cereus infection: 57 case patients and a literature review. AB - OBJECTIVES: We aimed to study the characteristics of patients presenting with a Bacillus cereus infection in a university hospital. METHODS: We performed a retrospective analysis of the clinical, biological, and treatment-related data of patients hospitalized in our university hospital between January 1st, 2008 and December 31st, 2012 and diagnosed with a B. cereus infection. We identified a subgroup of patients presenting with bacteremia and looked for risk factors for death within that group of patients. RESULTS: We included 57 patients in our study; 31 (54.4%) were hospitalized in a medical ward. We identified 24 bacteremia case patients, including 17 patients presenting with bacteremia alone (29.8%). Other frequently observed infection sites were skin infections (16; 28.1%) and bone and joint infections (10; 17.5%). We recorded 9 deaths (11.8%); 2 patients, despite being on an appropriate antibiotic therapy, died from a medical device-related infection that had not been removed. The empirical administration of a beta-lactam antibiotic was significantly associated with death (P=0.022). Three patients presenting with recurrent bacteremia were identified. The patients only recovered once the infected device had been removed. CONCLUSION: B. cereus infections may have various clinical presentations. Prospective data is needed to put forward a consensual treatment approach and guide physicians in choosing the appropriate antibiotic therapy and in removing the infected device. PMID- 26525186 TI - Neuroleptospirosis and MRI evidence of basal ganglia involvement. PMID- 26525187 TI - Babesiosis and Lyme disease co-infection in a female patient returning from the United States. PMID- 26525188 TI - Auricular acupressure relieves anxiety and fatigue, and reduces cortisol levels in post-caesarean section women: A single-blind, randomised controlled study. AB - BACKGROUND: Anxiety and fatigue adversely affect women's postpartum recovery, but few effective non-pharmacological interventions are known to relieve these two common and unpleasant symptoms. OBJECTIVES: To examine the efficacy of an auricular acupressure intervention provided during early postpartum in reducing anxiety, fatigue levels, cortisol levels, blood pressure, and heart rate. DESIGN: A single-blind, randomised controlled trial. SETTING: A 40-bed postpartum unit. PARTICIPANTS: Women who underwent caesarean section were randomly allocated to two groups: intervention (auricular pressure, n=40), and control (usual care, n=40). METHODS: The intervention group received auricular acupressure on the shenmen acupoint twice a day (9 AM and 5 PM), and the control group received usual postpartum care. Serum cortisol levels were assessed by immunochemiluminescence, with blood pressure and heart rate assessed by electric sphygmomanometer. Anxiety and fatigue symptoms were assessed using the State Anxiety subscale of the State-Trait Anxiety Inventory and the Fatigue Continuum Form, respectively. RESULTS: Of the 76 women who completed the study, those who received auricular acupressure had significantly lower mean cortisol levels (mean difference=4MUg/dl, p<0.05), heart rate (mean difference=9.2 beats/min, p<0.001), anxiety symptoms (mean difference=3.8, p<0.01), and fatigue symptoms (mean difference=7.1, p<0.01) than women in the control group at 5 days postpartum. CONCLUSIONS: Auricular acupressure is an effective non-pharmacological method for reducing cortisol levels, heart rate, anxiety, and fatigue in early postpartum after caesarean section. PMID- 26525189 TI - Social isolation rearing increases dopamine uptake and psychostimulant potency in the striatum. AB - Social isolation rearing (SI) is a model of early life stress that results in neurobiological alterations leading to increased anxiety-like behaviors. These animals also exhibit an increased propensity to administer psychostimulants, such as cocaine; however, the mechanisms governing this increased addiction vulnerability remain to be elucidated. Long-term stressors have been shown to produce important alterations in nucleus accumbens core (NAc) function. The NAc regulates motivated and goal-directed behaviors, and individual differences in NAc function have been shown to be predictive of addiction vulnerability. Rats were reared in group (GH; 4/cage) or SI (1/cage) conditions from weaning (PD 28) into early adulthood (PD 77) and dopamine release was assessed using voltammetry in brain slices containing the NAc and dorsomedial striatum. SI rats exhibited enhanced dopamine release and uptake in both regions compared to GH rats. In regard to psychostimulant effects directly at the dopamine transporter (DAT), methylphenidate and amphetamine, but not cocaine, inhibited uptake more in SI than GH rats. The increased potencies were positively correlated with uptake rates, suggesting that increased potencies of amphetamine-like compounds are due to changes in DAT function. Cocaine's effects on uptake were similar between rearing conditions, however, cocaine enhanced evoked dopamine release greater in SI than GH rats, suggesting that the enhanced cocaine reinforcement in SI animals involves a DAT independent mechanism. Together, the results provide the first evidence that greater psychostimulant effects in SI compared to GH rats are due to effects on dopamine terminals related to uptake dependent and independent mechanisms. PMID- 26525190 TI - Neuroprotective effects of ginsenoside Rg1 through the Wnt/beta-catenin signaling pathway in both in vivo and in vitro models of Parkinson's disease. AB - Ginsenoside Rg1 (Rg1) is a major bioactive ingredient in Panax ginseng that has low toxicity and has been shown to have neuroprotective effects. The objectives of the present study were to explore the potential of the application of Rg1 for the treatment of Parkinson's disease (PD) and to determine whether its neuroprotective effects are exerted through the Wnt/beta-catenin signaling pathway by using in vivo and in vitro models of PD. In the in vivo study, Rg1 treatment ameliorated the behavioral deficits of "Pole test", and reduced dopaminergic cell loss that were induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine(MPTP) in a dose-dependent manner in an in vivo model of PD. In the in vitro study, cell viability was increased and cell apoptosis induced by 1 methyl-4-phenylpyridinium(MPP+) was decreased by Rg1 pretreatment. Rg1 induced protective effects on the protein and mRNA expression levels of markers of the Wnt/beta-catenin signaling pathway in both the in vivo and the in vitro studies, and these neuroprotective effects were blocked by DKK1 in the in vitro study. Our results provide evidence that Rg1 has neuroprotective effects in both in vivo and in vitro PD models, and these effects act through the Wnt/beta-catenin signaling pathway. Taken together, these results indicate that Rg1 may exert therapeutic effects on PD via the Wnt/beta-catenin signaling pathway and may therefore provide a novel approach for the treatment of PD. PMID- 26525191 TI - Anticonvulsant and procognitive properties of the non-imidazole histamine H3 receptor antagonist DL77 in male adult rats. AB - It has become clear that histamine H3 receptors (H3Rs) are implicated in modulating epilepsy and memory in laboratory animals. The new non-imidazole H3R antagonist DL77 has excellent selectivity profile and shows high in-vivo potency as well as in-vitro antagonist affinity with ED50 values of 2.1 +/- 0.2 mg/kg and 8.4 +/- 1.3 [nM], respectively. In the present study, the anticonvulsant effects of DL77 on maximal electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced seizure models were investigated. Moreover, the procognitive properties of DL77 were tested on acquisition, consolidation and retrieval processes in a one-trial inhibitory avoidance task in male Wistar rats. The results indicate that DL77 (5, 10, and 15 mg/kg, i.p.) significantly and dose dependently reduced MES-induced seizure duration, whereas no protection was observed in PTZ- or STR-induced seizures. Importantly, the protective action observed for DL77 in MES-induced seizure was comparable to that of the reference antiepileptic drug (AED) phenytoin (PHT), and was also reversed when rats were pretreated with the CNS penetrant pyrilamine (PYR) (10 mg/kg, i.p.), or with the selective H3R agonist R-(alpha)-methyl-histamine (RAMH) (10 mg/kg, i.p.). Furthermore, the procognitive studies indicate that acute pre-training systemic administration of DL77 (2.5 mg/kg, i.p.) facilitated acquisition, whereas pre testing acute administration of DL77 (5 and 10 mg/kg, i.p.) improved retrieval. Interestingly, the procognitive effect of DL77 on retrieval was completely abrogated when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL) but not the centrally acting H1R antagonist PYR, indicating that histaminergic pathways through activation of H2Rs appear to be participating in neuronal circuits involved in retrieval processes. Taken together, our results show that DL77 demonstrates anticonvulsant properties in the MES-induced seizure model and improves cognitive performance through actions on different memory stages. Therefore, H3Rs may have implications for the treatment of degenerative disorders associated with impaired memory function and may represent a novel therapeutic pharmacological target to tackle cognitive problems associated with the chronic use of antiepileptic drugs. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID- 26525192 TI - Biochemical and structural characterization of a novel ubiquitin-conjugating enzyme E2 from Agrocybe aegeria reveals Ube2w family-specific properties. AB - Ubiquitination is a post-translational modification that is involved in myriad cellar regulation and disease pathways. The ubiquitin-conjugating enzyme (E2) is an important player in the ubiquitin transfer pathway. Although many E2 structures are available, not all E2 families have known structures, and three dimensional structures from fungal organisms other than yeast are lacking. We report here the crystal structure of UbcA1, which is a novel ubiquitin conjugating enzyme identified from the edible and medicinal mushroom Agrocybe aegerita and displays potential antitumor properties. The protein belongs to the Ube2w family and shows similar biochemical characteristics to human Ube2w, including monomer-dimer equilibrium in solution, alpha-NH2 ubiquitin-transfer activity and a mechanism to recognize backbone atoms of intrinsically disordered N-termini in substrates. Its structure displays a unique C-terminal conformation with an orientation of helix alpha3 that is completely different from the reported E2 structures but similar to a recently reported NMR ensemble of Ube2w. A mutagenesis study on this novel enzyme revealed that an intact C-terminus is significant for protein dimerization and enzymatic activity. As the first crystallized full-length protein of this family, UbcA1 may supersede the truncated X-ray structure of Ube2w (PDB entry 2A7L) as the representative structure of the Ube2w family. PMID- 26525193 TI - Controlling transcription in human pluripotent stem cells using CRISPR-effectors. AB - The ability to manipulate transcription in human pluripotent stem cells (hPSCs) is fundamental for the discovery of key genes and mechanisms governing cellular state and differentiation. Recently developed CRISPR-effector systems provide a systematic approach to rapidly test gene function in mammalian cells, including hPSCs. In this review, we discuss recent advances in CRISPR-effector technologies that have been employed to control transcription through gene activation, gene repression, and epigenome engineering. We describe an application of CRISPR effector mediated transcriptional regulation in hPSCs by targeting a synthetic promoter driving a GFP transgene, demonstrating the ease and effectiveness of CRISPR-effector mediated transcriptional regulation in hPSCs. PMID- 26525194 TI - Efficient genomic correction methods in human iPS cells using CRISPR-Cas9 system. AB - Precise gene correction using the CRISPR-Cas9 system in human iPS cells holds great promise for various applications, such as the study of gene functions, disease modeling, and gene therapy. In this review article, we summarize methods for effective editing of genomic sequences of iPS cells based on our experiences correcting dystrophin gene mutations with the CRISPR-Cas9 system. Designing specific sgRNAs as well as having efficient transfection methods and proper detection assays to assess genomic cleavage activities are critical for successful genome editing in iPS cells. In addition, because iPS cells are fragile by nature when dissociated into single cells, a step-by-step confirmation during the cell recovery process is recommended to obtain an adequate number of genome-edited iPS cell clones. We hope that the techniques described here will be useful for researchers from diverse backgrounds who would like to perform genome editing in iPS cells. PMID- 26525195 TI - Pathognomonic MRI and MR spectroscopy findings in cerebral hydatid cyst. PMID- 26525196 TI - Urinary markers in the early stage of nephropathy in patients with childhood onset type 1 diabetes. AB - BACKGROUND: The aim of this study was to evaluate the association of a urinary tubular marker, liver-type fatty acid binding protein (L-FABP) and an inflammatory marker, serum/urinary YKL-40, with albuminuria in patients with childhood-onset type 1 diabetes (T1D). METHODS: Twenty-nine patients with childhood-onset T1D and 32 controls were enrolled. Serum and urinary concentrations of YKL-40 and urinary concentrations of L-FABP were measured. RESULTS: The serum levels of YKL-40 were not significantly different between the control group and the patient groups. However, the levels of urinary YKL 40/creatinine (Cr) were higher in the patients, even those with normoalbuminuria than in the controls (p < 0.001). The levels of urinary L-FABP/Cr were not different between the control group and the patient groups. However, the level of urinary L-FABP/Cr in the microalbuminuria group was higher than that in the normoalbuminuria group (p = 0.03). There were no associations between the levels of urinary albumin-to-creatinine ratio and urinary L-FABP/Cr or YKL-40/Cr. However, the urinary L-FABP/Cr level was significantly correlated with the hemoglobin A1C level (p = 0.005) and the urinary YKL-40/Cr level (p = 0.043). CONCLUSIONS: Urinary L-FABP/Cr and YKL-40/Cr may reflect renal injury in early stages of nephropathy in patients with childhood-onset T1D, even in the normoalbuminuric state. PMID- 26525197 TI - Defining and predicting 'intrauterine fetal renal failure' in congenital lower urinary tract obstruction. AB - BACKGROUND: The aim of this study was to identify predictors of 'intrauterine fetal renal failure' in fetuses with severe congenital lower urinary tract obstruction (LUTO). METHODS: We undertook a retrospective study of 31 consecutive fetuses with a diagnosis of LUTO in a tertiary Fetal Center between April 2013 and April 2015. Predictors of 'intrauterine fetal renal failure' were evaluated in those infants with severe LUTO who had either a primary composite outcome measure of neonatal death in the first 24 h of life due to severe pulmonary hypoplasia or a need for renal replacement therapy within 7 days of life. The following variables were analyzed: fetal bladder re-expansion 48 h after vesicocentesis, fetal renal ultrasound characteristics, fetal urinary indices, and amniotic fluid volume. RESULTS: Of the 31 fetuses included in the study, eight met the criteria for 'intrauterine fetal renal failure'. All of the latter had composite poor postnatal outcomes based on death within 24 h of life (n = 6) or need for dialysis within 1 week of life (n = 2). The percentage of fetal bladder refilling after vesicocentesis at time of initial evaluation was the only predictor of 'intrauterine fetal renal failure' (cut-off <27 %, area under the time-concentration curve 0.86, 95 % confidence interval 0.68-0.99; p = 0.009). CONCLUSION: We propose the concept of 'intrauterine fetal renal failure' in fetuses with the most severe forms of LUTO. Fetal bladder refilling can be used to reliably predict 'intrauterine fetal renal failure', which is associated with severe pulmonary hypoplasia or the need for dialysis within a few days of life. PMID- 26525199 TI - Cyclophosphamide and rituximab in frequently relapsing/steroid-dependent nephrotic syndrome. AB - BACKGROUND: Steroid-sensitive nephrotic syndrome is the most common form of nephrotic syndrome in childhood, defined by the response to treatment with glucocorticoids with consequent remission. While most children eventually experience spontaneous resolution of the disease, some have a difficult course with frequent relapses or steroid dependence nephrotic syndrome (FRSDNS). The consequent steroid toxicity often prompts administration of other immunosuppressive drugs, traditionally cyclophosphamide. Recently, rituximab has been reported as effective in this disorder, but long-term experience is lacking. METHODS: Retrospective note review of all children with FRSDNS treated with a first course of cyclophosphamide and/or rituximab in our center between December 2006 and April 2015. We reviewed time to first relapse after treatment, co medications, and side effects. RESULTS: A total of 102 children were treated with cyclophosphamide (79) and/or rituximab (42). Of these, 34 received cyclophosphamide prior to rituximab. Median time to first relapse was 7 months after cyclophosphamide and 14 months after rituximab. Documented side effects of cyclophosphamide included neutropenia, hair loss, and hemorrhagic cystitis (1). Rituximab was associated with an allergic reaction at infusion in two patients. CONCLUSIONS: Rituximab was used in children with the most difficult to treat FRSDNS, yet was associated with longer remission time and less side effects than cyclophosphamide. A randomized controlled trial is needed to directly compare these drugs. PMID- 26525198 TI - Differences between the pediatric and adult presentation of fibromuscular dysplasia: results from the US Registry. AB - BACKGROUND: Fibromuscular dysplasia (FMD) is a non-inflammatory arteriopathy that causes significant morbidity in children. METHODS: The clinical features, presenting symptoms, and vascular beds involved are reviewed in the first 33 patients aged <18 years who are enrolled in the United States Registry for FMD from five registry sites and compared with 999 adult patients from 12 registry sites. RESULTS: Mean age at diagnosis was 8.4 +/- 4.8 years (16 days to 17 years). Compared with adults, pediatric FMD occurs in more males (42.4 vs 6 %, p < 0.001). Children with FMD have a stronger previous history of hypertension (93.9 vs 69.9 %, p = 0.002). Hypertension (100 %), headache (55 %), and abdominal bruits (10.7 %) were the most common presenting signs and symptoms. FMD affects renal vasculature in almost all children (97 vs 69.7 %, p = 0.003). The extra cranial carotid vessels are less commonly involved in children (23.1 vs 73.3 %, p < 0.001). The mesenteric arteries (38.9 vs 16.2 %, p = 0.02) and aorta (26.3 vs 2.4 %, p < 0.001) are more commonly involved in children. CONCLUSIONS: In the United States Registry for FMD, pediatric FMD affects children from infancy throughout childhood. All children presented with hypertension and many presented with headache and abdominal bruits. In children, FMD most commonly affects the renal vasculature, but also frequently involves the mesenteric arteries and abdominal aorta; the carotid vessels are less frequently involved. PMID- 26525200 TI - Effects of acute kidney injury and chronic hypoxemia on fibroblast growth factor 23 levels in pediatric cardiac surgery patients. AB - BACKGROUND: Fibroblast growth factor-23 (FGF23) levels are elevated in cardiopulmonary bypass (CPB)-associated acute kidney injury (AKI); however, it is unknown how much of the circulating FGF23 is intact and bioactive. Hypoxia may induce FGF23 production, yet its impact in humans is unknown. Pediatric cardiac surgery patients have both a high incidence of CPB-associated AKI and a high prevalence of chronic hypoxemia. METHODS: We assessed the effects of hypoxemia and CPB-associated AKI on C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 32 pediatric cardiac surgery patients with normal estimated glomerular filtration rate (eGFR). Plasma cFGF23 and iFGF23 were measured preoperatively and serially postoperatively. RESULTS: Despite normal renal and ventricular function, preoperative cFGF23 levels were high and elevated out of proportion to iFGF23 levels. Preoperative oxygen saturation measurements correlated inversely with FGF23 levels. Preoperative cFGF23 and oxygen saturation both predicted postoperative AKI. Postoperatively, cFGF23 and iFGF23 increased by 2 h postreperfusion; iFGF23 then returned to baseline, but cFGF23 remained elevated through 24 h postreperfusion. Group status (AKI vs. non-AKI) modified the effect of time on changes in iFGF23 levels but not cFGF23 levels. CONCLUSIONS: Preoperative cFGF23 may predict CPB-associated kidney dysfunction. Changes over time in cFGF23 and iFGF23 levels post-CPB differ. Chronic hypoxemia may affect FGF23 production in humans. PMID- 26525202 TI - HPV testing in the context of post-treatment follow up (test of cure). AB - BACKGROUND: Women treated for cervical lesions are at higher risk of subsequent disease compared to the general population. Consequently, post treatment surveillance strategies are required to ensure the success of treatment, so called "test of cure". The high sensitivity and negative predictive value of HPV assays can enhance post-treatment strategies. OBJECTIVES: To provide an overview of the current data on test of cure strategies with a particular focus on HPV testing and to identify knowledge gaps and areas for further research. RESULTS: HPV testing is sensitive for the detection of residual or recurrent disease post treatment for CIN2+ and is more sensitive than cytology alone. Co-testing increases sensitivity, marginally and there is a lack of consensus regarding the efficiency and safety to release negative women. Most test of cure studies have applied HPV DNA tests and post treatment positivity rates vary widely depending on assay and potentially, treatment type. CONCLUSIONS: Globally, an increasing number of test of cure algorithms now incorporate HPV testing although there is heterogeneity of practice with respect to assay, number of post treatment tests, testing intervals, follow up time. While type specific persistence identified through genotyping may identify those at greater risk of disease there is no consensus as to how this may be applied, clinically. Data on HPV testing in women treated for glandular lesions would be welcome as would the performance of different HPV assays and associated biomarkers in this context. PMID- 26525201 TI - Positive trends in paediatric renal biopsy service provision in the UK: a national survey and re-audit of paediatric renal biopsy practice. AB - BACKGROUND: Paediatric renal biopsy standards introduced in the UK in 2010 were intended to reduce variation and improve practice. A concurrent national drive was aimed at building robust paediatric nephrology networks to ensure services cater for the needs of the family and minimise time away from home. We aimed to identify current national practice since these changes on behalf of the British Association for Paediatric Nephrology. METHODS: All UK paediatric nephrology centres were invited to complete a survey of their biopsy practice, including advance preparation. From 1 January to 30 June 2012, a national prospective audit of renal biopsies was undertaken at participating centres comparing practice with the British Association for Paediatric Nephrology (BAPN) standards and audit results from 2005. RESULTS: Survey results from 11 centres demonstrated increased use of pre-procedure information leaflets (63.6 % vs 45.5 %, P = 0.39) and play preparation (90.9 % vs 9.1 %, P = 0.0001). Audit of 331 biopsies showed a move towards day-case procedures (49.5 % vs 32.9 %, P = 0.17) and reduced major complications (4.5 % vs 10.4 %, P = 0.002). Biopsies with 18-gauge needles had significantly higher mean pass rates (3.2 vs 2.3, P = 0.0008) and major complications (15.3 % vs 3.3 %, P = 0.0015) compared with 16-gauge needles. CONCLUSIONS: Percutaneous renal biopsy remains a safe procedure in children, thus improving family-centered service provision in the UK. PMID- 26525203 TI - Modulation of nuclear PI-PLCbeta1 during cell differentiation. AB - PI-PLCbeta1 plays an important role in cell differentiation, and particularly in myogenesis, osteogenesis and hematopoiesis. Indeed, the increase of PI-PLCbeta1, along with Cyclin D3, has been detected in C2C12 mouse myoblasts induced to differentiate, as well as in human cells obtained from myotonic dystrophy. Also in the case of osteogenic differentiation there is a specific induction of PI PLCbeta1, but in this case the role of PI-PLCbeta1 seems to be independent from Cyclin D3, so that a different mechanism could be involved. As for the hematopoietic system, PI-PLCbeta1 has a peculiar behavior: it increases during myeloid differentiation and decreases during erythroid differentiation, thus confirming the role of PI-PLCbeta1 as a modulator of hematopoiesis. PMID- 26525204 TI - Novel roles of androgen receptor, epidermal growth factor receptor, TP53, regulatory RNAs, NF-kappa-B, chromosomal translocations, neutrophil associated gelatinase, and matrix metalloproteinase-9 in prostate cancer and prostate cancer stem cells. AB - Approximately one in six men will be diagnosed with some form of prostate cancer in their lifetime. Over 250,000 men worldwide die annually due to complications from prostate cancer. While advancements in prostate cancer screening and therapies have helped in lowering this statistic, better tests and more effective therapies are still needed. This review will summarize the novel roles of the androgen receptor (AR), epidermal growth factor receptor (EGFR), the EGFRvIII variant, TP53, long-non-coding RNAs (lncRNAs), microRNAs (miRs), NF-kappa-B, chromosomal translocations, neutrophil associated gelatinase, (NGAL), matrix metalloproteinase-9 (MMP-9), the tumor microenvironment and cancer stem cells (CSC) have on the diagnosis, development and treatment of prostate cancer. PMID- 26525205 TI - Modified Appleby Procedure with Arterial Reconstruction for Locally Advanced Pancreatic Adenocarcinoma: A Literature Review and Report of Three Unusual Cases. AB - BACKGROUND: Pancreatic body and tail ductal adenocarcinomas are often diagnosed with local vascular invasion of the celiac axis (CA) and its various branches. With such involvement, these tumors have traditionally been considered unresectable. The modified Appleby procedure allows for margin negative resection of some such locally advanced tumors. This procedure involves distal pancreatectomy with en bloc splenectomy and CA resection and relies on the presence of collateral arterial circulation via an intact pancreaticoduodenal arcade and the gastroduodenal artery to maintain prograde hepatic arterial perfusion. When the resultant collateral circulation is inadequate to provide sufficient hepatic and gastric arterial inflow, arterial reconstruction (AR) is necessary to "supercharge" the inflow. Herein, we review all reported cases of AR with modified Appleby procedures that we have identified in the literature, and we report our experience of three recent cases with arterial reconstruction including two cases with arterial bypasses not requiring interposition grafting. METHODS: Perioperative and oncologic outcomes from our Institutional Review Board approved database of pancreatic resections at the Thomas Jefferson University were reviewed. Additionally, PubMed search for cases of distal or total pancreatectomy with celiac axis resection and concurrent AR was performed. RESULTS: From the literature, 12 reports involving 28 patients were identified of distal and total pancreatectomy with AR after CA resection. The most common AR in the literature, performed in 12 patients, was a bypass from the aorta to the common hepatic artery (CHA) using a variety of interposition conduits. In our institutional experience, patient #1 had a primary side-to-end aorto-CHA bypass, patient #2 had a primary end-to-end bypass of the transected distal CHA to the left gastric artery in the setting a replaced left hepatic artery, and patient #3 required an aortic to proper hepatic artery bypass with saphenous vein graft and portal venous reconstruction. All patients recovered from their operations without ischemic complications, and they are currently 16, 15, and 13 months post op, respectively. CONCLUSIONS: The criteria for resectability in patients with locally advanced pancreatic body and tail neoplasms are expanding due to increasing experience with AR in the setting of the modified Appleby procedure. When performing AR, primary arterial re-anastomosis may be considered preferable to interposition grafting as it decreases the potential for the infectious and thrombotic complications associated with conduits and it reduces the number of vascular anastomoses from two to one. Consideration must also be given to normal variant anatomy of the hepatic circulation during operative planning as the origin of the left gastric artery is resected with the CA. The modified Appleby procedure with AR, when used in appropriately selected patients, offers the potential for safe, margin negative resection of locally advanced pancreatic body and tail tumors. PMID- 26525206 TI - Single-Layer Continuous Versus Double-Layer Continuous Suture in Colonic Anastomoses-a Randomized Multicentre Trial (ANATECH Trial). AB - PURPOSE: Apart from stapling methods, single- or double-layer continuous hand sutures are established techniques for colonic anastomoses. It is unclear which hand suture technique has superior anastomotic safety. This randomized trial evaluated the incidence of postoperative complications depending on anastomosis technique. METHODS: This multicentre randomized trial enrolled adult elective patients between February 2004 and June 2012 in four German university hospitals. Primary endpoint was incidence of clinical anastomotic leakage until 3 months postoperatively. Estimated sample size was 768 randomized patients. Main secondary endpoints were duration of anastomotic suture, postoperative morbidity and stool patterns at 3-month follow-up. Patients and postoperative outcome assessors were blinded to the group assignment. This trial is registered (NCT00996554). RESULTS: Due to slow recruitment, the trial was stopped prematurely. Two hundred fifty-two patients (129 to single-layer suture anastomosis (SLA), 123 to double-layer suture anastomosis (DLA)) were randomized and analysed. Nine patients (3.6 %) were lost during follow-up. Exploratory primary endpoint analysis by intention-to-treat principle showed no significant difference for clinical anastomotic leakage between suturing techniques (SLA, 4 of 129 (3.1 %) vs. DLA, 6 of 123 (4.9 %), p = 0.532). Secondary endpoint analysis showed on average a 6-min shorter suture duration for SLA than DLA (18 min (4-49) vs. 24 min (8-50), p < 0.001). At 3-month follow-up, subjective well-being and stool patterns were not significantly different between groups. CONCLUSIONS: The present study did not reach sufficient power and cannot confirm whether both techniques might be equally or if one technique might be superior. Exploratory analysis suggests that in elective colonic resections, the single-layer continuous hand suture technique may be equally effective as the double-layer technique regarding incidence of anastomotic leakage, length of hospital stay, overall postoperative complications, subjective short-term well-being and stool patterns. Lessons learned from this trial course are summarized. TRIAL REGISTRATION: This trial is registered (Trial registration: NCT00996554). Link: https://clinicaltrials.gov/ct2/show/NCT00996554 . PMID- 26525207 TI - Parenchyma-Sparing, Limited Pancreatic Head Resection for Benign Tumors and Low Risk Periampullary Cancer--a Systematic Review. AB - BACKGROUND: Parenchyma-sparing local extirpation of benign tumors of the pancreatic head provides the potential benefits of preservation of functional tissue and low postoperative morbidity. METHODS: Medline/PubMed, Embase, and Cochrane library databases were surveyed for studies performing limited resection of the pancreatic head and resection of a segment of the duodenum and common bile duct or preservation of the duodenum and common bile duct (CBD). The systematic analysis included 27 cohort studies that reported on limited pancreatic head resections for benign tumors. In a subgroup analysis, 12 of the cohort studies were additionally evaluated to compare the postoperative morbidity after total head resection including duodenal segment resection (DPPHR-S) and total head resection conserving duodenum and CBD (DPPHR-T). RESULTS: Three hundred thirty nine of a total of 503 patients (67.4%) underwent total head resections. One hundred forty-seven patients (29.2%) of them underwent segmental resection of the duodenum and CBD (DPPHR-S) and 192 patients (38.2%) underwent preservation of duodenum and CBD. One hundred sixty-four patients experienced partial head resection (32.6%). The final histological diagnosis revealed in 338 of 503 patients (67.2%) cystic neoplasms, 53 patients (10.3%) neuroendocrine tumors, and 20 patients (4.0%) low-risk periampullary carcinomas. Severe postoperative complications occurred in 62 of 490 patients (12.7%), pancreatic fistula B + C in 40 of 295 patients (13.6%), resurgery was experienced in 2.7%, and delayed gastric emptying in 12.3%. The 90-day mortality was 0.4%. The subgroup analysis comparing 143 DPPHR-S patients with 95 DPPHR-T patients showed that the respective rates of procedure-related biliary complications were 0.7% (1 of 143 patients) versus 8.4% (8 of 95 patients) (p <= 0.0032), and rates of duodenal complications were 0 versus 6.3% (6 of 95 patients) (p <= 0.0037). DPPHR-S was associated with a higher rate of delay of gastric emptying compared to DPPHR-T (18.9 vs. 2.1%, p <= 0.0001). CONCLUSION: Parenchyma-sparing, limited head resection for benign tumors preserves functional pancreatic and duodenal tissue and carries in terms of fistula B + C rate, resurgery, rehospitalization, and 90 day mortality a low risk of postoperative complications. A subgroup analysis exhibited after total pancreatic head resection that preserves the duodenum and CBD an association with a significant increase in procedure-related biliary and duodenal complications compared to total head resection combined with resection of the periampullary segment of the duodenum and resection of the intrapancreatic CBD. PMID- 26525208 TI - The association between admission systolic blood pressure of heart failure patients with preserved systolic function and mortality outcomes. AB - INTRODUCTION: Heart failure is a major cause of death and disability and poses a significant public health concern. Approximately half of the patients admitted with heart failure, have preserved left ventricular ejection fraction. The association between systolic blood pressure (SBP) and long-term outcome in this group has not been well established. AIM: The aim of our study is to evaluate the association between admission SBP and short term and long-term mortality outcomes in patients with heart failure and preserved systolic function. METHODS: 1230 consecutive patients presenting with preserved left ventricular (LV) systolic function (defined as an LV ejection fraction >=40%) were included in this survey. Patients were divided into quartiles according to admission SBP: low admission SBP (<127mmHg), intermediate admission SBP (128-145mmHg), high admission SBP (146 170mmHg) and very-high admission SBP (>170mmHg). Primary outcome included in hospital, one and four year mortality rates. RESULTS: Elevated admission SBP was found to be associated with improved short and long-term mortality (HR=0.25 95% CI - 0.09-0.7, p=0.007 and HR=0.7 95% CI - 0.56-0.88, p=0.002 for the highest versus low SBP group, respectively). This finding was most notable in patients with acute heart failure and patients with ejection fraction>=50%. CONCLUSION: Elevated admission SBP is associated with a favorable short and long-term outcome in patients with heart failure and preserved systolic function. KEY MESSAGE: Low admission SBP is an independent predictor for short and long-term mortality in patients with HF and PSF. PMID- 26525209 TI - Medicare Policy Initiatives and the Relative Utilization of "Double-Scan" CT. AB - PURPOSE: Commonly called "double scans" by the media, combined pre- and postcontrast thoracic and abdominal CT examinations have been the focus of recent CMS policy initiatives. The aim of this study was to examine trends in the relative utilization of double-scan CT before and after 2006 legislation mandating relevant Medicare reporting initiatives. METHODS: Medicare Physician Supplier Procedure Summary Master Files from 2001 through 2012 were used to identify claims for thoracic and abdominal CT examinations. Double-scan rates by billing physician specialty and place of service were analyzed over time. Rates of double-scan CT between radiologists and nonradiologists were compared using t tests. RESULTS: From 2001 to 2006, double-scan rates for thoracic and abdominal CT examinations declined by 1.7% and 7.5% for radiologists, respectively (from 6.0% to 5.9% and from 22.6% to 20.9%) but increased by 15.8% and 23.6% for nonradiologists (from 5.7% to 6.6% and from 28.8% to 35.6%). From 2006 through 2012, double-scan rates declined by 42.3% and 35.2% (from 5.9% to 3.4% and from 20.9% to 13.5%) for radiologists but only by 31.8% and 8.1% (from 6.6% to 4.5% and from 35.6% to 32.7%) for nonradiologists. Double-scan rates were significantly lower for radiologists than nonradiologists for all years for abdominal CT (P < .001) and for all years after 2006 legislation for thoracic CT (P < .05). CONCLUSIONS: Reductions in thoracic and abdominal CT double-scan rates followed legislation mandating CMS initiatives designed to reduce costs and radiation. For nonradiologists, double-scan rates were consistently higher and declined more slowly than those for radiologists. Medicare policy initiatives directed toward imaging utilization seem to influence behavior differently for radiologists compared with nonradiologists. PMID- 26525210 TI - March of the Living, a Holocaust Educational Tour: An Assessment of Anxiety and Depression. AB - March of the Living (MOTL) is a 2-week international educational tour for high school seniors to learn about the Holocaust by visiting concentration/deaths camps and other Jewish historical sites in Poland, culminating in a week-long excursion in Israel. Although the trip is primarily educational, there is recent research evidence to suggest that attendees may suffer from a variety of mental health sequelae. To determine symptoms of anxiety and depression, 196 Los Angeles delegation participants voluntarily completed the State-Trait Anxiety Inventory, composed of a trait anxiety scale (i.e., STAI-T) and a state anxiety scale (i.e., STAI-S), and the Center for Epidemiologic Studies Depression Scale (CES-D). Pre MOTL, students completed an initial background questionnaire along with the STAI T, STAI-S, and the CES-D. At end-Poland and end-Israel, the STAI-S and CES-D were administered again. Results demonstrated that depression scores increased during end-Poland and returned to baseline; however, anxiety scores mildly increased end Poland and rose slightly more and persisted through end-Israel. PMID- 26525211 TI - Bioethics, Religion, and Public Policy: Intersections, Interactions, and Solutions. AB - Bioethics in America positions itself as a totalizing discipline, capable of providing guidance to any individual within the boundaries of a health or medical setting. Yet the religiously observant or those driven by spiritual values have not universally accepted decisions made by "secular" bioethics, and as a result, religious bioethical thinkers and adherents have developed frameworks and rich counter-narratives used to fend off encroachment by policies perceived as threatening. This article uses brain death in Jewish law, the case of Jahi McMath, and vaccination refusal to observe how the religious system of ethics is presently excluded from bioethics and its implications. PMID- 26525212 TI - Diagnosing Paroxysmal Atrial Fibrillation in Patients With Ischemic Strokes and Transient Ischemic Attacks Using Echocardiographic Measurements of Left Atrium Function. AB - Twenty-five to 35 percentage of stroke cases are cryptogenic, and it has been demonstrated that paroxysmal atrial fibrillation (AF) is the causal agent in up to 25% of these incidents. The purpose of this study was to investigate if left atrial (LA) parameters have value for diagnosing paroxysmal AF in patients with ischemic stroke (IS) and transient ischemic attack (TIA). We retrospectively analyzed 219 patients who after acute IS or TIA underwent a transthoracic echocardiographic examination. Patients were designated as patients with paroxysmal AF if they had one or more reported incidents of AF before or after their echocardiographic examination. Patients in the paroxysmal AF group were significantly older and had higher CHA2DS2-VASc score than patients without paroxysmal AF (p <0.05 for both). None of the conventional echocardiographic parameters were significantly associated with paroxysmal AF. However, the atrial measurements evaluating LA function (min LA volume and LA emptying fraction) were significantly different (LA emptying fraction: 45% +/- 10% vs 50% +/- 10%, p = 0.004; minimal LA volume: 30.2 ml +/- 17.3 ml vs 24 ml +/- 10 ml, p = 0.035 in patients with paroxysmal AF, even after adjustment for age, gender, CHA2DS2-VASc score, and stroke severity [p <0.05 for both]). By combining the cut-off values of age, LA emptying fraction, and minimal LA volume the diagnostic accuracy of paroxysmal AF was improved, resulting in a sensitivity of 95% and negative predictive value of 97%. In conclusion, in patients with IS and TIA, LA function measurements (minimal LA volume and LA emptying fraction) are independently associated with paroxysmal AF and may improve risk stratification for paroxysmal AF presence after IS or TIA. PMID- 26525213 TI - High-Output Heart Failure from a Hepatic Hemangioma With Exertion-Induced Hypoxia. AB - Patients with hepatic hemangiomas have been known to have high-output heart failure as a result of left-to-right arteriovenous shunting. We report a patient with a hepatic hemangioma that presented with high-output heart failure with hypoxia on exertion. After embolization of the hemangioma, the patient's hypoxia resolved and ejection fraction improved. In the absence of cardiopulmonary pathophysiology, we presume that our patient's hemangioma was causing a right-to left shunt as opposed to an expected left-to-right shunt. PMID- 26525214 TI - Is supplemental external beam radiation therapy essential to maximize brachytherapy outcomes in patients with unfavorable intermediate-risk disease? AB - PURPOSE: To evaluate whether supplemental external beam radiotherapy (EBRT) is essential to maximize Pd-103 brachytherapy outcomes in patients with unfavorable intermediate-risk (IR) disease. METHODS AND MATERIALS: A total of 630 patients were assessed from two prospective randomized brachytherapy trials evaluating the role of supplemental EBRT in patients with higher risk features. Patients were stratified into unfavorable IR (primary Gleason pattern 4, >=50% positive biopsies, or >=2 IR features), favorable IR, and high-risk (HR) cohorts. Median follow-up was 7.5 years. The brachytherapy prescription dose was prescribed to the prostate gland with generous periprostatic margins. Biochemical failure (BF) was defined as a prostate-specific antigen >0.40 ng/mL after nadir. Patients with metastatic prostate cancer or nonmetastatic castrate-resistant disease who died of any cause were classified as dead of prostate cancer. Multiple parameters were evaluated for effect on outcomes. RESULTS: The 10-year BF for favorable IR, unfavorable IR, and HR was 1.7%, 6.6%, and 15.5% (p < 0.001). At 10 years, prostate cancer-specific mortality (PCSM) and overall mortality (OM) were 0% and 20.4%, 2.1% and 23.2%, and 4.3% and 42.4% for favorable IR, unfavorable IR, and HR. Although unfavorable IR patients had a greater incidence of BF, PCSM, and OM when compared with favorable IR, neither the addition nor dose of supplemental EBRT influenced outcome. CONCLUSIONS: Outcomes for favorable IR were superior to those with unfavorable IR. Within the confines of this study, neither the addition nor dose of supplemental EBRT influenced BF, PCSM, or OM in patients with IR disease. PMID- 26525215 TI - Long-term visual acuity outcomes in patients with uveal melanoma treated with 125I episcleral OSU-Nag plaque brachytherapy. AB - PURPOSE: To report our experience in long-term follow-up of ocular melanoma patients treated with custom OSU-Nag eye plaques using (125)I sources. METHODS: A retrospective chart review was conducted for 113 consecutive ocular melanoma patients with follow-up visual acuity data who were treated with OSU-Nag plaque episcleral brachytherapy at The Ohio State University Medical Center from 1994 to 2009. Visual acuity, complication data, and recurrence rates were recorded up to 120 months after brachytherapy. RESULTS: Median age at presentation was 63.0 years (range, 22-93). Median follow-up was 65.5 months (range, 2-180). Median radiation dose at the prescription point was 85.8 Gy (range, 51.8-103.7). Preservation of useful visual acuity, defined as better than 20/200, was noted in 43 of 74 (58%) of patients in the present study at 36 months compared with 50.1% of Collaborative Ocular Melanoma Study participants. By 120 months, 17 of 30 (57%; 95% confidence interval, 45-69%) progressed to visual acuity worse than 20/200, whereas 9 of 30 (30%) retained visual acuity of 20/40 or better, and 4 of 30 (13%) were 20/50-20/200. The rate of retinopathy after radiation was approximately 40% of all those observed by 60 months. Baseline visual acuity, apical tumor height, American Joint Committee on Cancer tumor category, and distance between the tumor and the fovea were all significantly associated with loss of visual acuity. The local tumor control rate by 60 months of follow-up was 93% (95% confidence interval, 85-97%). CONCLUSIONS: The OSU-Nag custom (125)I plaque is an effective treatment for uveal melanoma, with preservation of useful visual acuity in 58% of eyes 3 years after treatment and 43% of eyes 10 years after treatment. PMID- 26525216 TI - Perfluorocarbon nanoparticles enhance reactive oxygen levels and tumour growth inhibition in photodynamic therapy. AB - Photodynamic therapy (PDT) kills cancer cells by converting tumour oxygen into reactive singlet oxygen ((1)O2) using a photosensitizer. However, pre-existing hypoxia in tumours and oxygen consumption during PDT can result in an inadequate oxygen supply, which in turn hampers photodynamic efficacy. Here to overcome this problem, we create oxygen self-enriching photodynamic therapy (Oxy-PDT) by loading a photosensitizer into perfluorocarbon nanodroplets. Because of the higher oxygen capacity and longer (1)O2 lifetime of perfluorocarbon, the photodynamic effect of the loaded photosensitizer is significantly enhanced, as demonstrated by the accelerated generation of (1)O2 and elevated cytotoxicity. Following direct injection into tumours, in vivo studies reveal tumour growth inhibition in the Oxy-PDT-treated mice. In addition, a single-dose intravenous injection of Oxy-PDT into tumour-bearing mice significantly inhibits tumour growth, whereas traditional PDT has no effect. Oxy-PDT may enable the enhancement of existing clinical PDT and future PDT design. PMID- 26525219 TI - [Room for possibilities is reflected in patterns of meaning: From limited time of life to eternal time]. PMID- 26525217 TI - Cerebellar Bottom-of-Fissure Dysplasia-a Novel Cerebellar Gray Matter Neuroimaging Pattern. AB - We report on seven patients with a novel neuroimaging finding that involves exclusively the cerebellar gray matter at the bottom of several fissures of both hemispheres but spares the vermis. The abnormal fissures were predominantly located in the lower and lateral parts of the cerebellar hemispheres. The affected cerebellar cortex was hypointense on T1-weighted and hyperintense on T2 weighted and fluid attenuation inversion recovery sequences. In some patients, the involved cerebellar gray matter was mildly thickened and the affected fissures slightly widened. In three of seven patients, the neuroimaging findings were unchanged on follow-up studies up to 6 years. The seven patients had various indications for the brain magnetic resonance imaging studies, and none of them had cerebellar dysfunction. Based on the similarity of the neuroimaging pattern with the cerebral "bottom-of-sulcus dysplasia," we coined the term "cerebellar bottom-of-fissure dysplasia" to refer to this novel neuroimaging finding. The neuroimaging characteristic as well as the unchanged findings on follow-up favors a stable "developmental" (malformative) nature. The lack of cerebellar dysfunction in the affected patients suggests that cerebellar bottom-of-fissure dysplasia represents most likely an incidental finding that does not require specific diagnostic investigation but allows a reassuring attitude. PMID- 26525220 TI - Insights from genome of Clostridium butyricum INCQS635 reveal mechanisms to convert complex sugars for biofuel production. AB - Clostridium butyricum is widely used to produce organic solvents such as ethanol, butanol and acetone. We sequenced the entire genome of C. butyricum INCQS635 by using Ion Torrent technology. We found a high contribution of sequences assigned for carbohydrate subsystems (15-20 % of known sequences). Annotation based on protein-conserved domains revealed a higher diversity of glycoside hydrolases than previously found in C. acetobutylicum ATCC824 strain. More than 30 glycoside hydrolases (GH) families were found; families of GH involved in degradation of galactan, cellulose, starch and chitin were identified as most abundant (close to 50 % of all sequences assigned as GH) in C. butyricum INCQS635. KEGG metabolic pathways reconstruction allowed us to verify possible routes in the C. butyricum INCQS635 and C. acetobutylicum ATCC824 genomes. Metabolic pathways for ethanol synthesis are similar for both species, but alcohol dehydrogenase of C. butyricum INCQS635 and C. acetobutylicum ATCC824 was different. The genomic repertoire of C. butyricum is an important resource to underpin future studies towards improved solvents production. PMID- 26525221 TI - Improvements in Depression and Changes in Fatigue: Results from the SLAM DUNC Depression Treatment Trial. AB - Fatigue and depression are common co-morbid conditions among people with HIV infection. We analyzed a population of HIV-infected adults with depression, who were enrolled in a depression treatment trial, to examine the extent to which improvements in depression over time were associated with improvements in HIV related fatigue. Data for this analysis come from a randomized controlled trial to evaluate the effectiveness of improved depression treatment on antiretroviral adherence. Fatigue was measured using the HIV-Related Fatigue Scale, and depressive symptoms were measured with the Hamilton Depression Rating Scale. Participants (n = 234) were on average nearly 44 years of age and predominantly male, black or African American, and unemployed. Individuals who experienced stronger depression response (i.e., greater improvement in depression score) had larger decreases in fatigue. However, even among those who demonstrated a full depression response, nearly three-quarters continued to have either moderate or severe fatigue at 6 and 12 months. PMID- 26525223 TI - "Angle to Be Corrected" in Preoperative Evaluation for Hallux Valgus Surgery: Analysis of a New Angular Measurement. AB - BACKGROUND: The most common methods for assessing severity of hallux valgus deformity and the effects of an operative procedure are the angular measurements in weightbearing radiographs, specifically the hallux valgus angle and intermetatarsal angle (IMA). Our objective was to analyze the interobserver variability in hallux valgus patients of a new angle called the "angle to be corrected" (ATC), and to compare its capacity to differentiate between different deformities against IMA. METHODS: We included 28 symptomatic hallux valgus patients with 48 weightbearing foot x-rays. Three trained observers measured the 1 to 2 IMA and the ATC. We then identified retrospectively 45 hallux valgus patients, which were divided into 3 operative technique groups having used the ATC as reference, and analyzed the capacity of the IMA to differentiate between them. RESULTS: The IMA average value was 13.6 degrees, and there was a significant difference between observer 3 and observer 1 (P = .001). The average value for the ATC was 8.9 degrees, and there was no difference between observers. Both angles showed a high intraclass correlation. Regarding the capacity to differentiate between operative technique groups, the ATC was different between the 3 operative technique groups analyzed, but the IMA showed differences only between 2. CONCLUSIONS: The ATC was at least as reliable as the intermetatarsal angle for hallux valgus angular measurements, showing a high intraclass correlation with no interobserver difference. It can be suggested that the ATC was better than the IMA to stratify hallux valgus patients when deciding between different operative treatments. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 26525224 TI - Perceived Family Support and Antiretroviral Adherence in HIV-Positive Individuals: Results from a Community-Based Positive Living With HIV Study. AB - The purpose of this study was to examine the association between perceived family support, either positive or negative, and adherence to antiretroviral medication regimens among HIV-positive individuals in the Kathmandu Valley, Nepal. We measured past 3-month antiretroviral adherence among 233 HIV-positive individuals, in relation to perceived family support, both positive (in terms of emotional and instrumental support) and negative (in the form of negative interactions), using the 10-item Nepali Family Support and Difficulty Scale. Medium and high levels of perceived emotional support from family were associated with reduced risk of antiretroviral nonadherence, compared with low levels of perceived emotional support (adjusted odds ratio [AOR] = 0.37, 95% confidence interval [CI] [0.16, 0.88], and AOR = 0.23, 95% CI [0.08, 0.64], respectively). Conversely, higher levels of felt emotional distance (AOR = 1.46, 95% CI [1.00, 2.14]) and experienced physical harm (AOR = 2.04, 95% CI [1.07, 3.91]) were associated with increased risk of nonadherence. The results support the recommendation that service providers need to be aware of the significant role of family support in shaping antiretroviral adherence and to consider ways to strengthen positive family support while minimizing negative family interactions to increase adherence rates. PMID- 26525222 TI - Retention in Early Care at an HIV Outpatient Clinic in Rio de Janeiro, Brazil, 2000-2013. AB - Retention in early HIV care has been associated with virologic suppression and improved survival, but remains understudied in Brazil. We estimated retention in early HIV care for the period 2000-2013, and identified socio-demographic and clinical factors associated with good retention in an urban cohort from Rio de Janeiro, Brazil. Antiretroviral therapy-naive, HIV-infected persons >=18 years old linked to care between 2000 and 2011 were included. Retention in the first 2 years post-linkage (i.e. early care) was defined by the proportion of 6-month intervals with >=1 HIV laboratory result. "Good" retention was defined as >=1 HIV laboratory result recorded in at least three intervals. Overall, 80 % of participants met criteria for good retention and retention significantly improved over the study period. Older age, higher education level and early antiretroviral therapy initiation were associated with good retention. Efforts to improve retention in early care in this population should target younger and less educated HIV-infected persons. PMID- 26525225 TI - Superlatives are commonly used in news coverage of cancer drugs, study finds. PMID- 26525226 TI - Driving, Space, and Access to Activity. PMID- 26525227 TI - In-depth characterization of CD24(high)CD38(high) transitional human B cells reveals different regulatory profiles. AB - BACKGROUND: CD24(high)CD38(high) transitional B cells represent cells at a key stage in their developmental pathway. In addition, these B cells have been widely ascribed regulatory functions and involvement in the control of chronic inflammatory diseases. However, the phenotypic and functional overlap between these cells and regulatory B cells remains controversial. OBJECTIVE: In this study we wanted to explore the regulatory properties of CD24(high)CD38(high) human B cells. METHODS: We used multicolor flow cytometry in combination with bioinformatics and functional studies to show that CD24(high)CD38(high) B cells can be distinguished into multiple subsets with different regulatory functions. RESULTS: For the first time, the study reveals that human transitional B cells encompass not only transitional type 1 and type 2 B cells, as previously suggested, but also distinct anergic type 3 B cells, as well as IL-10-producing CD27(+) transitional B cells. Interestingly, the latter 2 subsets differentially regulate CD4(+) T-cell proliferation and polarization toward TH1 effector cells. Additional analyses reveal that the percentage of type 3 B cells is reduced and the frequency of CD27(+) transitional B cells is increased in patients with autoimmune diseases compared with those in matched healthy subjects. CONCLUSION: This study provides evidence for the existence of different transitional B-cell subsets, each displaying unique phenotypic and regulatory functional profiles. Furthermore, the study indicates that altered distribution of transitional B-cell subsets highlights different regulatory defects in patients with different autoimmune diseases. PMID- 26525228 TI - Common variable immunodeficiency and natural killer cell lymphopenia caused by Ets-binding site mutation in the IL-2 receptor gamma (IL2RG) gene promoter. PMID- 26525230 TI - Post Surgical Pain- The Transition from Acute to Chronic Pain. AB - Chronic pain after surgery is common.Surgery is widely performed therefore the at risk population is large.The mechanisms of chronic pain after surgery are complex.There are many risk factors associated with onset of chronic post surgical pain: demographic, genetic and medical.Unnecessary and inappropriate surgery should be avoided. PMID- 26525231 TI - A Scalable Protocol for the Regioselective Alkylation of 2-Methylcyclohexane-1,3 dione with Unactivated sp3 Electrophiles. AB - A method for the C-selective alkylation of 2-methylcyclohexane-1,3-dione with unactivated sp3 electrophiles is accomplished via alkylation and subsequent deprotection of the derived ketodimethyl hydrazones. The present method provides a high-yielding entry to dialkyl cycloalkanones that cannot be accessed via direct alkylation of 2-methylcyclohexane-1,3-dione. The title reaction may be useful in the scalable preparation of terpene and steroidal building blocks in the arena of natural product synthesis. PMID- 26525229 TI - Airway factor XIII associates with type 2 inflammation and airway obstruction in asthmatic patients. AB - BACKGROUND: Coagulation Factor XIII (FXIII) plays an important role in wound healing by stabilizing fibrin clots and cross-linking extracellular matrix proteins. FXIII is expressed in cells of the monocyte/macrophage and dendritic cell lineages in response to type 2 cytokines. OBJECTIVE: We sought to determine the association between FXIII and asthma pathobiology. METHODS: We analyzed the expression of FXIII mRNA and protein levels in bronchoalveolar lavage samples obtained before and after segmental allergen challenge from patients with mild asthma and in induced sputum samples collected from patients with mild-to moderate and severe asthma. RESULTS: FXIII mRNA and protein levels were highly upregulated in bronchoalveolar cells and fluid after allergen challenge and mRNA levels correlated with protein levels. In sputum of asthmatic patients, FXIII expression was positively correlated with type 2 immune response and dendritic cell markers (CD209 and CD207). FXIII expression was also associated with increased airflow limitation (FEV1/forced vital capacity and residual volume/total lung capacity ratios) and greater reversibility to beta-agonists. CONCLUSIONS: FXIII expression was upregulated in the airways of asthmatic patients after allergen exposure. Expression in the sputum of asthmatic patients correlated with the type 2 immune response and airflow limitation. Excessive activity of FXIII could contribute to the pathophysiology of airway obstruction in asthmatic patients. PMID- 26525232 TI - New Trends in Pesticide Residue Analysis in Food, Dietary Supplements, and Highly Processed Consumer Products. PMID- 26525233 TI - Recent Trends in Sample Preparation and Liquid Chromatography/Mass Spectrometry for Pesticide Residue Analysis in Food and Related Matrixes. AB - A rising interest by consumers and various governmental organizations towards the quality of food has been continuously observed. Pesticide residue analysis has a significant role in assessing food safety and quality. This article reviews the new analytical approaches for efficient extraction and reliable identification and quantification of pesticides in foodstuffs and related matrixes. Emphasis is given to the new materials used for effective extract purification. We discuss the potential and pitfalls of the different LC/MS approaches, including application of high resolution mass spectrometry in the area of pesticide residue analysis. Untargeted and retrospective screening is outlined, highlighting prospects and achievements as well as its major drawbacks. PMID- 26525234 TI - New Trends in Pesticide Residue Analysis in Cereals, Nutraceuticals, Baby Foods, and Related Processed Consumer Products. AB - Pesticide residue methods have been developed for a wide variety of food products including cereal-based foods, nutraceuticals and related plant products, and baby foods. These cereal, fruit, vegetable, and plant-based products provide the basis for many processed consumer products. For cereal and nutraceuticals, which are dry sample products, a modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) method has been used with additional steps to allow wetting of the dry sample matrix and subsequent cleanup using dispersive or cartridge format SPE to reduce matrix effects. More processed foods may have lower pesticide concentrations but higher co-extracts that can lead to signal suppression or enhancement with MS detection. For complex matrixes, GC/MS/MS or LC/electrospray ionization (positive or negative ion)-MS/MS is more frequently used. The extraction and cleanup methods vary with different sample types particularly for cereal-based products, and these different approaches are discussed in this review. General instrument considerations are also discussed. PMID- 26525235 TI - Applications of Experimental Design to the Optimization of Microextraction Sample Preparation Parameters for the Analysis of Pesticide Residues in Fruits and Vegetables. AB - Sample preparation has been identified as the most important step in analytical chemistry and has been tagged as the bottleneck of analytical methodology. The current trend is aimed at developing cost-effective, miniaturized, simplified, and environmentally friendly sample preparation techniques. The fundamentals and applications of multivariate statistical techniques for the optimization of microextraction sample preparation and chromatographic analysis of pesticide residues are described in this review. The use of Placket-Burman, Doehlert matrix, and Box-Behnken designs are discussed. As observed in this review, a number of analytical chemists have combined chemometrics and microextraction techniques, which has helped to streamline sample preparation and improve sample throughput. PMID- 26525237 TI - Human Health Risk of Dietary Intake of Some Organochlorine Pesticide Residues in Camels Slaughtered in the Districts of Al-Qassim Region, Saudi Arabia. AB - Organochlorine residues were detected in 54/200 of muscles and 55/200 of livers of camels slaughtered in different districts of Al-Qassim region, Saudi Arabia, by using GC/MS analysis. The SigmaDDT residues (Sigma-DDT=p,p'-DDT+p,p'-DDE+p,p' DDD+p,p'-DDA) in muscles and livers were the most frequent. The levels and distribution of residues varied with location. Al-Qassim region population's average estimated daily intake (EDI) was between 0.0 and 12.74 MUg/kg body weight/day, and the hazard index [EDI/acceptable daily intake (ADI)] was higher than unity for SigmaDDT and lindane in some samples. The intakes were much higher than the ADIs in some districts of Al-Qassim region, and the exposure level of all tested residues was high enough to produce health risk, suggesting the need for regular monitoring programs for pesticide residues in camel meat at the national level to protect consumers' health. PMID- 26525236 TI - Development and Validation of a Multiresidue Method for the Determination of Pesticides in Dry Samples (Rice and Wheat Flour) Using Liquid Chromatography/Triple Quadrupole Tandem Mass Spectrometry. AB - A rapid and sensitive multiresidue method was developed and validated for the determination of around 100 pesticides in dry samples (rice and wheat flour) by ultra-performance LC coupled to a triple quadrupole mass analyzer working in tandem mode (UPLC/QqQ-MS/MS). The sample preparation step was optimized for both matrixes. Pesticides were extracted from rice samples using aqueous ethyl acetate, while aqueous acetonitrile extraction [modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) method] was used for wheat flour matrixes. In both cases the extracts were then cleaned up by dispersive solid phase extraction with MgSO4 and primary secondary amine+C18 sorbents. A further cleanup step with Florisil was necessary to remove fat in wheat flour. The method was validated at two concentration levels (3.6 and 40 MUg/kg for most compounds), obtaining recoveries ranging from 70 to 120%, intraday and interday precision values<=20% expressed as RSDs, and expanded uncertainty values<=50%. The LOQ values ranged between 3.6 and 20 MUg/kg, although it was set at 3.6 MUg/kg for the majority of the pesticides. The method was applied to the analysis of 20 real samples, and no pesticides were detected. PMID- 26525238 TI - Visual and Real-Time Event-Specific Loop-Mediated Isothermal Amplification Based Detection Assays for Bt Cotton Events MON531 and MON15985. AB - Bt cotton events MON531 and MON15985 are authorized for commercial cultivation in more than 18 countries. In India, four Bt cotton events have been commercialized; more than 95% of total area under genetically modified (GM) cotton cultivation comprises events MON531 and MON15985. The present study reports on the development of efficient event-specific visual and real-time loop-mediated isothermal amplification (LAMP) assays for detection and identification of cotton events MON531 and MON15985. Efficiency of LAMP assays was compared with conventional and real-time PCR assays. Real-time LAMP assay was found time efficient and most sensitive, detecting up to two target copies within 35 min. The developed real-time LAMP assays, when combined with efficient DNA extraction kit/protocol, may facilitate onsite GM detection to check authenticity of Bt cotton seeds. PMID- 26525239 TI - Simultaneous Determination of Octinoxate, Oxybenzone, and Octocrylene in a Sunscreen Formulation Using Validated Spectrophotometric and Chemometric Methods. AB - Accurate, reliable, and sensitive spectrophotometric and chemometric methods were developed for simultaneous determination of octinoxate (OMC), oxybenzone (OXY), and octocrylene (OCR) in a sunscreen formulation without prior separation steps, including derivative ratio spectra zero crossing (DRSZ), double divisor ratio spectra derivative (DDRD), mean centering ratio spectra (MCR), and partial least squares (PLS-2). With the DRSZ technique, the UV filters could be determined in the ranges of 0.5-13.0, 0.3-9.0, and 0.5-9.0 MUg/mL at 265.2, 246.6, and 261.8 nm, respectively. By utilizing the DDRD technique, UV filters could be determined in the above ranges at 237.8, 241.0, and 254.2 nm, respectively. With the MCR technique, the UV filters could be determined in the above ranges at 381.7, 383.2, and 355.6 nm, respectively. The PLS-2 technique successfully quantified the examined UV filters in the ranges of 0.5-9.3, 0.3-7.1, and 0.5-6.9 MUg/mL, respectively. All the methods were validated according to the International Conference on Harmonization guidelines and successfully applied to determine the UV filters in pure form, laboratory-prepared mixtures, and a sunscreen formulation. The obtained results were statistically compared with reference and reported methods of analysis for OXY, OMC, and OCR, and there were no significant differences with respect to accuracy and precision of the adopted techniques. PMID- 26525240 TI - Simultaneous Detection of Three Phosphodiesterase Type 5 Inhibitors and Eight of Their Analogs in Lifestyle Products and Screening for Adulterants by High Performance Thin-Layer Chromatography. AB - An HPTLC method is proposed to permit effective screening for the presence of three phosphodiesterase type 5 inhibitors (PDE5-Is; sildenafil, vardenafil, and tadalafil) and eight of their analogs (hydroxyacetildenafil, homosildenafil, thiohomosildenafil, acetildenafil, acetaminotadalafil, propoxyphenyl hydroxyhomosildenafil, hydroxyhomosildenafil, and hydroxythiohomosildenafil) in finished products, including tablets, capsules, chocolate, instant coffee, syrup, and chewing gum. For all the finished products, the same simple sample preparation may be applied: ultrasound-assisted extraction in 10 mL methanol for 30 min followed by centrifugation. The Rf values of individual HPTLC bands afford preliminary identification of potential PDE5-Is. Scanning densitometry capabilities enable comparison of the unknown UV spectra with those of known standard compounds and allow further structural insight. Mass spectrometric analysis of the material derived from individual zones supplies an additional degree of confidence. Significantly, the proposed screening technique allows focus on the already known PDE5 Is and provides a platform for isolation and chemical categorization of the newly-synthesized analogs. Furthermore, the scope could be expanded to other therapeutic categories (e.g., analgesics, antidiabetics, and anorexiants) that are occasionally coadulterated along with the PDE5-Is. The method was successfully applied to screening of 45 commercial lifestyle products. Of those, 31 products tested positive for at least one illegal component (sildenafil, tadalafil, propoxyphenyl hydroxyhomosildenafil, or dimethylsildenafil). PMID- 26525241 TI - Development and Validation of an HPLC Method for Simultaneous Determination of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol Hydrochloride in Pharmaceutical Formulations. AB - Tuberculosis treatment consists of a fixed dose combination of rifampicin (RIF), isoniazid (INH), pyrazinamide (PYZ), and ethambutol hydrochloride (EMB). The combined treatment using various drugs is necessary for patient curing, without recrudescence, and for prevention of drug-resistant mutants, which may occur during treatment. An HPLC-diode array detector (DAD) method for the simultaneous determination of RIF, INH, PYZ, and EMB in fixed dose combination tablets was developed and validated. Chromatographic experiments were performed on an Agilent 1200 HPLC system, and the separation was carried out on a Purospher STAR RP18e (250*4.6 mm id, 5 MUm, Merck) analytical column. Gradient elution was carried out with a mobile phase of 20 mM monobasic sodium phosphate buffer with 0.2% triethylamine (pH 7.0) and acetonitrile at a flow rate of 1.5 mL/min. The total run time was 12 min, and the re-equilibration time was 5 min. EMB detection was performed at 210 nm, and RIF, INH, and PYZ were detected at 238 nm, using a DAD. The method proved to be specific, linear (r2>0.99), precise (RSD<2%), accurate, and robust and may be applied to the QC analysis of pharmaceutical formulations. PMID- 26525242 TI - HPLC and HPLC/MS/MS Studies on Stress, Accelerated and Intermediate Degradation Tests of Antivirally Active Tricyclic Analog of Acyclovir. AB - The degradation behavior of a tricyclic analog of acyclovir [6-(4-MeOPh)-TACV] was determined in accordance with International Conference on Harmonization guidelines for good clinical practice under different stress conditions (neutral hydrolysis, strong acid/base degradation, oxidative decomposition, photodegradation, and thermal degradation). Accelerated [40+/-2 degrees C/75%+/ 5% relative humidity (RH)] and intermediate (30+/-2 degrees C/65%+/-5% RH) stability tests were also performed. For observation of the degradation of the tested compound the RP-HPLC was used, whereas for the analysis of its degradation products HPLC/MS/MS was used. Degradation of the tested substance allowed its classification as unstable in neutral environment, acidic/alkaline medium, and in the presence of oxidizing agent. The tested compound was also light sensitive and was classified as photolabile both in solution and in the solid phase. However, the observed photodegradation in the solid phase was at a much lower level than in the case of photodegradation in solution. The study showed that both air temperature and RH had no significant effect on the stability of the tested substance during storage for 1 month at 100 degrees C (dry heat) as well as during accelerated and intermediate tests. Based on the HPLC/MS/MS analysis, it can be concluded that acyclovir was formed as a degradation product of 6-(4 MeOPh)-TACV. PMID- 26525243 TI - Forced Degradation and Photodegradation Studies of Pyrrolo[3,4-c]pyridine-1,3 dione Derivatives as Analgesic Active Compounds Using HPLC, UV and IR Spectrometry, and HPLC/MS Methods. AB - The stress and accelerated tests as well as photostability analysis in solutions and the solid phase of three selected derivatives of pyrrolo[3,4-c]pyridine-1,3 dione were carried out according the International Conference on Harmonization guidelines. For observation of the degradation of tested compounds, the RP-HPLC method was used. The study included the effect of temperature, relative humidity, water, H+ and OH- ions, hydrogen peroxide, and light (6.0*10(6), 1.2*10(6) lux.h) on the stability of pyrrolo[3,4-c]pyridine-1,3-dione derivatives. Studies have shown that these derivatives are photolabile, extremely unstable in an alkaline medium, labile in an acidic medium, and stable in a neutral medium. Their sensitivity to oxidizing agents depends on the chemical structure. The shortening of the aliphatic chain leads to an increase in the sensitivity to hydrolytic and oxidizing factors. The presence of the 1,3,4-tetraisoquinoline group promotes an increase in the susceptibility to photodegradation. The introduction of a carbonyl group to the aliphatic chain and the tetrafluoromethyl group to the phenyl ring stabilizes the molecule in the case of hydrolysis and oxidation and also increases sensitivity to light. The analysis of observed photodegradation products using the HPLC-diode array detector, HPLC/MS, and UV and IR spectrometry techniques showed degradation targeted at the breaking of the pyrrolo[3,4 c]pyridine-1,3-dione, piperazine, and/or tetrahydroisoquinoline rings. PMID- 26525244 TI - Electrochemical Determination of Uric Acid at CdTe Quantum Dot Modified Glassy Carbon Electrodes. AB - Cyclic voltammetry and differential pulse voltammetry were used to investigate the electrochemical behavior of uric acid (UA) at a CdTe quantum dot (QD) modified the glassy carbon electrode (GCE). CdTe QDs, as new semiconductor nanocrystals, can greatly improve the peak current of UA. The anodic peak current of UA was linear with its concentration between 1.0*10(-6) and 4.0*10(-4) M in 0.1 M pH 5.0 phosphate buffer solution. The LOD for UA at the CdTe electrode (1.0*10(-7) M) was superior to that of the GCE. In addition, we also determined the effects of scan rate, pH, and interferences of UA for the voltammetric behavior and detection. The results indicated that modified electrode possessed excellent reproducibility and stability. Finally, a new and efficient electrochemical sensor for detecting UA was developed. PMID- 26525245 TI - Development, Optimization, and Validation of a Microplate Bioassay for Relative Potency Determination of Linezolid Using a Design Space Concept, and its Measurement Uncertainty. AB - The aim of this study was to develop, optimize, and validate a microplate bioassay for relative potency determination of linezolid in pharmaceutical samples using quality-by-design and design space approaches. In addition, a procedure is described for estimating relative potency uncertainty based on microbiological response variability. The influence of culture media composition was studied using a factorial design and a central composite design was adopted to study the influence of inoculum proportion and triphenyltetrazolium chloride in microbial growth. The microplate bioassay was optimized regarding the responses of low, medium, and high doses of linezolid, negative and positive controls, and the slope, intercept, and correlation coefficient of dose-response curves. According to optimization results, design space ranges were established using: (a) low (1.0 MUg/mL), medium (2.0 MUg/mL), and high (4.0 MUg/mL) doses of pharmaceutical samples and linezolid chemical reference substance; (b) Staphylococcus aureus ATCC 653 in an inoculum proportion of 10%; (c) antibiotic No. 3 culture medium pH 7.0+/-0.1; (d) 6 h incubation at 37.0+/-0.1oC; and (e) addition of 50 MUL of 0.5% (w/v) triphenyltetrazolium chloride solution. The microplate bioassay was linear (r2=0.992), specific, precise (repeatability RSD=2.3% and intermediate precision RSD=4.3%), accurate (mean recovery=101.4%), and robust. The overall measurement uncertainty was reasonable considering the increased variability inherent in microbiological response. Final uncertainty was comparable with those obtained with other microbiological assays, as well as chemical methods. PMID- 26525246 TI - Development, Optimization, and Validation of a Green and Stability-Indicating HPLC Method for Determination of Daptomycin in Lyophilized Powder. AB - Daptomycin is an antimicrobial that plays an important role in clinical practice today because it is considered a promising drug to combat resistant strains, such as methicilin and vancomycin-resistant Gram-positive bacteria. Considering the analysis of daptomycin in a pharmaceutical dosage form, the only method found in literature uses potentially toxic organic solvents. Therefore, the objective of this work was to develop a green and stability-indicating HPLC method for determination of daptomycin in lyophilized powder. The mobile phase was ethanol water (55+45, v/v) at pH 4.5 pumped at a flow rate of 0.6 mL/min. A C18 column was used, and UV detection was performed at 221 nm. Stress degradation studies were conducted in order to demonstrate the specificity and stability-indicating capability of the method. The method was validated according to International Conference on Harmonization guidelines, proving to be linear (r=0.9996), precise, accurate, robust (demonstrated by the Plackett-Burman model), and specific within the range 20-70 MUg/mL. The retention time of daptomycin was 5.8 min. It can be concluded that the validated method can be a fast, safe, and environmentally friendly alternative for the analysis of daptomycin. PMID- 26525247 TI - Validation of a Minor Modification to the Soleris(r) Direct Yeast and Mold Vial and Selective Supplement. AB - Here we describe results of a study to validate minor reagent formulation changes to the Soleris Direct Yeast and Mold (DYM) automated growth-based method for semi quantitative detection of yeast and mold in food products. In order to reduce the maximum concentration of the selective agent chloramphenicol in the Soleris reagents, chloramphenicol was removed from the selective supplement and added to the vial growth medium itself. Therefore, both the vial medium and supplement have been reformulated in an alternative version of the method. A probability of detection (POD) statistical model was used to compare Soleris results at multiple test thresholds (dilutions) with plate counts determined using the U.S. Food and Drug Administration Bacteriological Analytical Manual dilution plating procedure. Three matrixes were tested; yogurt, tomato juice, and cocoa powder. POD analysis showed that the percentage of positive Soleris tests at various test thresholds were within the limits predicted by the reference method plate counts for all matrixes evaluated. Real-time stability data on three manufactured lots showed that the modified Soleris vial and supplement are stable for at a minimum of 10 months when stored at 2-8 degrees C. In sum, results presented here demonstrate that the modifications to the Soleris DYM vial and supplement do not impact method performance. The modified Soleris DYM method can be used as an accurate alternative to conventional dilution plating procedures for semi-quantitative determination of yeast and mold at threshold levels, while saving as much as 3 days in analysis time. PMID- 26525248 TI - Validation of the ANSR(r) Listeria Method for Detection of Listeria spp. in Selected Foods. AB - ANSR(r) Listeria was previously certified as Performance Tested Method(SM) 101202 for detection of Listeria spp. on selected environmental surfaces. This study proposes a matrix extension to the method for detection of Listeria spp. in selected food matrixes. The method is an isothermal nucleic acid amplification assay based on the nicking enzyme amplification reaction technology. Following single-step sample enrichment for 16-24 h, the assay is completed in less than 50 min, requiring only simple instrumentation. Inclusivity testing was performed using a panel of 51 strains of Listeria spp., representing the species L. grayi, L. innocua, L. ivanovii, L. monocytogenes, L. seeligeri, and L. welshimeri. All strains tested were detected by the ANSR assay. Exclusivity testing of 30 strains representing non-Listeria Gram-positive bacteria yielded no evidence of cross reactivity. Performance of the ANSR method for detection of Listeria spp. was compared to that of reference culture procedures for pasteurized liquid egg, pasteurized 2% milk, Mexican-style cheese, ice cream, smoked salmon, lettuce, cantaloupe, and guacamole. Data obtained in these unpaired studies and analyzed using a probability of detection model demonstrated that there were no statistically significant differences in results between the ANSR and reference culture methods, except for milk at 16 h and cantaloupe. In milk and smoked salmon, ANSR sensitivity was low at 16 h and therefore the recommended incubation time is 24 h. In cantaloupe, ANSR was found to be more sensitive than the reference culture method at both 16 and 24 h in independent laboratory testing. The ANSR Listeria method can be used as an accurate, rapid, and simple alternative to standard culture methods for detection of Listeria spp. in selected food types. PMID- 26525249 TI - Validation of the Thermo Scientific SureTect Escherichia coli O157:H7 Real-Time PCR Assay for Raw Beef and Produce Matrixes. AB - The Thermo ScientificTM SureTectTM Escherichia coli O157:H7 Assay is a new real time PCR assay which has been validated through the AOAC Research Institute (RI) Performance Tested Methods(SM) program for raw beef and produce matrixes. This validation study specifically validated the assay with 375 g 1:4 and 1:5 ratios of raw ground beef and raw beef trim in comparison to the U.S. Department of Agriculture, Food Safety Inspection Service, Microbiology Laboratory Guidebook (USDS-FSIS/MLG) reference method and 25 g bagged spinach and fresh apple juice at a ratio of 1:10, in comparison to the reference method detailed in the International Organization for Standardization 16654:2001 reference method. For raw beef matrixes, the validation of both 1:4 and 1:5 allows user flexibility with the enrichment protocol, although which of these two ratios chosen by the laboratory should be based on specific test requirements. All matrixes were analyzed by Thermo Fisher Scientific, Microbiology Division, Vantaa, Finland, and Q Laboratories Inc, Cincinnati, Ohio, in the method developer study. Two of the matrixes (raw ground beef at both 1:4 and 1:5 ratios) and bagged spinach were additionally analyzed in the AOAC-RI controlled independent laboratory study, which was conducted by Marshfield Food Safety, Marshfield, Wisconsin. Using probability of detection statistical analysis, no significant difference was demonstrated by the SureTect kit in comparison to the USDA FSIS reference method for raw beef matrixes, or with the ISO reference method for matrixes of bagged spinach and apple juice. Inclusivity and exclusivity testing was conducted with 58 E. coli O157:H7 and 54 non-E. coli O157:H7 isolates, respectively, which demonstrated that the SureTect assay was able to detect all isolates of E. coli O157:H7 analyzed. In addition, all but one of the nontarget isolates were correctly interpreted as negative by the SureTect Software. The single isolate giving a positive result was an E. coli O157:NM isolate. Nonmotile isolates of E. coli O157 have been demonstrated to still contain the H7 gene; therefore, this result is not unexpected. Robustness testing was conducted to evaluate the performance of the SureTect assay with specific deviations to the assay protocol, which were outside the recommended parameters and which are open to variation. This study demonstrated that the SureTect assay gave reliable performance. A final study to verify the shelf life of the product, under accelerated conditions was also conducted. PMID- 26525250 TI - Method Modification of the Thermo Scientific SureTect Listeria monocytogenes Assay for Raw Meat, Dairy, Produce, and Seafood. AB - The Thermo ScientificTM SureTectTM Listeria monocytogenes assay is a real-time PCR assay for the detection of Listeria monocytogenes in food and environmental samples, which was certified during 2013 by the AOAC Research Institute (RI) as Performance Tested Method(SM) (PTM) 061302 for a representative range of key food matrixes and production surfaces. This report details the method modification study, which was conducted during 2014, using the AOAC-RI PTM program to extend the validated matrix claims of the assay in comparison to the reference method detailed in International Organization for Standardization 11290-1:1996, including Amendment 1:2004, to gain certification for raw ground turkey, raw ground pork, pasteurized 2% milk, raw pork sausages, raw cod, pasteurized brie cheese, cooked sliced ham, and bagged lettuce. All matrixes were tested by Thermo Fisher Scientific, Microbiology Division, Basingstoke, UK. In addition, brie cheese, bagged lettuce, and raw cod were analyzed independently by the University of Guelph, Canada, during the AOAC-RI controlled independent laboratory study. Using probability of detection (POD) statistical analysis, a significant difference was demonstrated between the candidate and reference methods for the high spiking level with raw ground pork and brie cheese. For all other matrixes and the low spiked levels for raw ground pork and brie cheese, no significant difference by POD was seen between the two methods during the study. PMID- 26525251 TI - Comparative Evaluation of Veriflow(r) Listeria monocytogenes to USDA and AOAC Culture Based Methods for the Detection of Listeria monocytogenes in Food. AB - Veriflow(r) Listeria monocytogenes (LM) is a molecular based assay for the presumptive detection of Listeria monocytogenes from environmental surfaces, dairy, and ready-to-eat (RTE) food matrixes (hot dogs and deli meat). The assay utilizes a PCR detection method coupled with a rapid, visual, flow-based assay that develops in 3 min post PCR amplification and requires only 24 h of enrichment for maximum sensitivity. The Veriflow LM system eliminates the need for sample purification, gel electrophoresis, or fluorophore-based detection of target amplification, and does not require complex data analysis. This Performance Tested Method(SM) validation study demonstrated the ability of the Veriflow LM method to detect low levels of artificially inoculated L. monocytogenes in seven distinct environmental and food matrixes. In each unpaired reference comparison study, probability of detection analysis indicated no significant difference between the Veriflow LM method and the U.S. Department of Agriculture, Food Safety and Inspection Service Microbiology Laboratory Guidebook 8.08 or AOAC 993.12 reference method. Fifty strains of L. monocytogenes were detected in the inclusivity study, while 39 nonspecific organisms were undetected in the exclusivity study. The study results show that Veriflow LM is a sensitive, selective, and robust assay for the presumptive detection of L. monocytogenes sampled from environmental, dairy, or RTE (hot dogs and deli meat) food matrixes. PMID- 26525252 TI - Development and Validation of an HPLC-UV Method for Determination of Eight Phenolic Compounds in Date Palms. AB - A simple, precise, accurate, and selective method was developed and validated for determination of eight phenolic compounds (gallic acid, p-hydroxybenzoic acid, vanilic acid, caffeic acid, syringic acid, p-coumaric acid, ferulic acid, and sinapic acid) in date palms. Separation was achieved on an RP C18 column using the mobile phase methanol-water with 2% acetic acid (18+82, v/v). This method was validated according to the requirements for new methods, which include accuracy, precision, selectivity, robustness, LOD, LOQ, linearity, and range. The method demonstrated good linearity over the range 1-1000 ppm of gallic acid, p hydroxybenzoic acid, vanilic acid, caffeic acid, and syringic acid with r2 greater than 0.99, and in the range of 3-1000 ppm for p-coumaric acid, ferulic acid, and sinapic acid with r2 greater than 0.99. The recovery of the eight phenolic compounds ranged from 97.1 to 102.2%. The method is selective because adjacent peaks of phenolic compounds were well separated with good resolution. The degree of reproducibility of the results obtained as a result of small deliberate variations in the method parameters and by changing analytical operators proved that the method is robust and rugged. PMID- 26525253 TI - Antioxidant Activity and Validation of Quantification Method for Lycopene Extracted from Tomato. AB - Lycopene is a carotenoid found in tomatoes with potent antioxidant activity. The aim of the study was to obtain an extract containing lycopene from four types of tomatoes, validate a quantification method for the extracts by HPLC, and assess its antioxidant activity. Results revealed that the tomatoes analyzed contained lycopene and antioxidant activity. Salad tomato presented the highest concentration of this carotenoid and antioxidant activity. The quantification method exhibited linearity with a correlation coefficient of 0.9992. Tests for the assessment of precision, accuracy, and robustness achieved coefficients with variation of less than 5%. The LOD and LOQ were 0.0012 and 0.0039 MUg/mL, respectively. Salad tomato can be used as a source of lycopene for the development of topical formulations, and based on performed tests, the chosen method for the identification and quantification of lycopene was considered to be linear, precise, exact, selective, and robust. PMID- 26525254 TI - Partially Hydrolyzed Gluten in Fermented Cereal-Based Products by R5 Competitive ELISA: Collaborative Study, First Action 2015.05. AB - In 2008, the AACC International Protein Technical Committee (now Protein and Enzymes Technical Committee) initiated a collaborative study of a method for determining gluten in fermented products, using an R5 competitive ELISA system. The method has been approved as AACCI Approved Method AACCI 38-55.02. The new method has been validated for testing fermented foods and beverages to determine that they conform to the Codex threshold of 20 mg of gluten/kg in total for gluten-free products. It is recommended that the method be accepted by AOAC as Official First Action. PMID- 26525255 TI - Development of a Method for Crustacean Allergens Using Liquid Chromatography/Tandem Mass Spectrometry. AB - An LC/MS/MS analysis method was developed for crustacean allergens, tropomyosin, and arginine kinase. A protein extract from shrimp was reduced, alkylated, and digested by trypsin. Peptide spectra were obtained using full scan analysis by LC/MS/MS, and we determined a sequence through a protein search. 22ADTLEQQNK30, 92IQLLEEDLER101, 113LAEASQAADESER125, 134SLSDEER140, 153FLAEEADR160, and 190IVELEEELR198 of tropomyosin and 152VSSTLSSLEGELK164 and 217TFLVWVNEEDHLR229 of arginine kinase were selected as the specific peptides, and optimal multiple reaction monitoring conditions were used. The results obtained through the LC/MS/MS analysis correlated well with those using the ELISA method for various crustacean samples (r2>0.9). Moreover, unregulated species, such as krill or insects, which produce positive results in some crustacean ELISA assays, can be differentiated by LC/MS/MS. These findings suggest that LC/MS/MS analysis may be effective for crustacean food allergen analysis. PMID- 26525256 TI - Simultaneous Detection of Genetically Modified Organisms in a Mixture by Multiplex PCR-Chip Capillary Electrophoresis. AB - An efficient PCR-based method to trace genetically modified food and feed products is in demand due to regulatory requirements and contaminant issues in India. However, post-PCR detection with conventional methods has limited sensitivity in amplicon separation that is crucial in multiplexing. The study aimed to develop a sensitive post-PCR detection method by using PCR-chip capillary electrophoresis (PCR-CCE) to detect and identify specific genetically modified organisms in their genomic DNA mixture by targeting event-specific nucleotide sequences. Using the PCR-CCE approach, novel multiplex methods were developed to detect MON531 cotton, EH 92-527-1 potato, Bt176 maize, GT73 canola, or GA21 maize simultaneously when their genomic DNAs in mixtures were amplified using their primer mixture. The repeatability RSD (RSDr) of the peak migration time was 0.06 and 3.88% for the MON531 and Bt176, respectively. The RSD (RSDR) of the Cry1Ac peak ranged from 0.12 to 0.40% in multiplex methods. The method was sensitive in resolving amplicon of size difference up to 4 bp. The PCR-CCE method is suitable to detect multiple genetically modified events in a composite DNA sample by tagging their event specific sequences. PMID- 26525257 TI - A Quercetin Biosensor Based on Chitosan-Entrapped Carbon Nanotube Paste Electrode Coated with DNA. AB - This paper presents an easy, fast, low cost, and sensitive approach for the electrochemical determination of quercetin based on its intercalation into DNA double helix. Electrochemical studies of the interaction between quercetin and DNA showed a decrease in peak currents with a reduction in redox reversibility of quercetin in the presence of the DNA. The electrochemical behavior of quercetin at a chitosan-entrapped carbon nanotube paste electrode coated with DNA was studied. A considerable increase was observed in the oxidation signal of quercetin at the DNA-coated electrode compared with a DNA-free electrode, indicating the preconcentration of quercetin due to its interaction with the surface-confined DNA layer. After optimizing the main experimental parameters influencing the biosensor response, its performance was evaluated from an analytical point of view. Two linear dependences of the anodic peak current of quercetin on its concentration were observed in the ranges of 0.40-7.50 and 7.50 30.0 MUmol/L, with LOD and LOQ of 0.039 and 0.13 MUmol/L, respectively. The proposed biosensor was successfully applied to the analysis of black and green tea extracts for their quercetin content. PMID- 26525258 TI - Determination of Vitamin K1 in Infant, Pediatric, and Adult Nutritionals by HPLC with Fluorescence Detection: Single-Laboratory Validation, First Action 2015.09. AB - This normal-phase HPLC method with postcolumn reduction and fluorescence detection allows for the quantitative determination of trans vitamin K1 in infant, pediatric, and adult nutritionals. Vitamin K1 is extracted from products with iso-octane after precipitation of proteins and release of lipids with methanol. Prepared samples are injected onto a silica HPLC column where cis and trans vitamin K1 are separated with an iso-octane-isopropanol mobile phase. The column eluent is mixed with a dilute ethanolic solution of zinc chloride, sodium acetate, and acetic acid, and vitamin K1 is reduced to a fluorescent derivative in a zinc reactor column. The resulting hydroquinone is then detected by fluorescence at an excitation wavelength of 245 nm and an emission wavelength of 440 nm. During a single-laboratory validation of this method, repeatability and intermediate precision ranged from 0.6 to 3.5% RSD and 1.1 to 6.0% RSD, respectively. Mean overspike recoveries ranged from 91.9 to 106%. The method demonstrated good linearity over a standard range of approximately 2-90 MUg/L trans vitamin K1 with r2 averaging 0.99995 and average calibration errors of <1%. LOQ and LOD in ready-to-feed nutritionals were estimated to be 0.03 and 0.09 MUg/100 g, respectively. The method met AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals Standard Method Performance Requirements(r) and was approved as a first action method at the 2015 AOAC Mid-Year Meeting. PMID- 26525259 TI - Determination of Chloride in Infant Formula and Adult/Pediatric Nutritional Formula by Automated Potentiometry: Single-Laboratory Validation, First Action 2015.08. AB - A direct potentiometric method involving titration against a standard volumetric silver nitrate solution using a silver electrode to detect the end point was evaluated for the determination of chloride in infant formula and adult/pediatric nutritional formula. It was assessed for compliance against AOAC Standard Method Performance Requirements (SMPR(r)) established by the AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN). A single-laboratory validation (SLV) study was conducted as a first step in the process to validate the method. In this SLV, 17 SPIFAN matrixes representing a range of infant formula and adult nutritional products were evaluated for their chloride content. The analytical range was found to be between 1.4 and 1060 mg/100 g reconstituted product or ready-to-feed (RTF) liquid. The LOQ was estimated as 1.4 mg/100 g. Method repeatability was between 0.03 and 1.60% in the range of 20 to 167 mg/100 g RTF, and intermediate precision was between 0.09 and 2.77% in the same range. Recovery values based on spiking experiments at two different levels of chloride ranged from 99.0 to 103% for 15 different SPIFAN products. Evaluation of trueness was performed on National Institute of Standards and Technology Standard Reference Material 1849a (Infant/Adult Nutritional Formula) and showed 97.2% of the theoretical value, with no bias at the 95% confidence level. Based on the results of the SLV, the method met the SMPR and was approved as a First Action method by the AOAC Expert Review Panel on Infant Formula and Adult Nutritionals on March 17, 2015. PMID- 26525260 TI - Determination of Total Iodine in Infant Formula and Adult/ Pediatric Nutritional Formula by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS): Collaborative Study, Final Action 2012.15. AB - A collaborative study was conducted to determine total iodine in infant formula and adult/pediatric nutritional formula by inductively coupled plasma-MS (ICP-MS) using AOAC First Action Official Method(SM) 2012.15. The purpose of this study was to evaluate the method's intralaboratory and interlaboratory performance and submit the results to AOAC INTERNATIONAL for adoption as a Final Action Official Method for the determination of total iodine in infant formula and adult/pediatric nutritional formula. Upon providing acceptable results for practice samples National Institute of Standard and Technology (NIST) Standard Reference Material (SRM) 1849a and a low-fat adult nutritional powder, 13 laboratories analyzed seven various infant and adult nutritional products including a blind duplicate of each. Products were chosen with varying levels of iodine and included low-fat, soy-based, and milk-based formulas and NIST SRM 1849a. Random identification numbers were assigned to each of the seven fortified test materials. Digestion of the test samples occurred using a potassium hydroxide solution in an oven or open-vessel microwave system. Iodine was stabilized with ammonium hydroxide and sodium thiosulfate after digestion. The solutions were brought to volume followed by filtration. The filtrates were then analyzed by ICP-MS after dilution. Results for all seven test samples met all the AOAC Standard Method Performance Requirements (SMPR((r)) 2012.008) guidelines. The RSDr ranged from 0.77 to 4.78% and the RSDR from 5.42 to 11.5%. The Horwitz ratio (HorRat) for each result was excellent, ranging from 0.35 to 1.31%. The results demonstrate that the method is fit-for-purpose to determine iodine in infant formula and adult/pediatric nutritional formula. PMID- 26525261 TI - Imidazole-Modified Nanoporous Silica for Lead Ion Solid Phase Extraction Prior to Determination from Industrial Wastewaters by Flame Atomic Absorption Spectrometry. AB - A new method was applied to produce modified nanoporous silica as a novel sorbent for Pb(II) ion SPE from industrial wastewater samples. In this modified method, the produced nanoporous silica has a higher functional group loading, which leads to a higher preconcentration factor as well as a lower LOD. This modified nanoporous silica was used for preconcentration prior to subsequent determination of Pb(II) ions by flame atomic absorption spectrometry. Various parameters such as the eluent, pH of the sample solution, and flow rate were optimized during this work. Also, the effect of a variety of ions on preconcentration and recovery of Pb(II) ions was investigated. The LOD, defined as five times the SD of the blank, was determined to be lower than 0.1 mg/L with an RSD of <2%. The accuracy of the method was established by analyzing standard reference materials with certified Pb concentrations. Finally, the established method was successfully applied for determination of the Pb(II) ion concentration in industrial wastewater samples. PMID- 26525262 TI - Quantifying Residues from Postharvest Propylene Oxide Fumigation of Almonds and Walnuts. AB - A novel analytical approach involving solvent extraction with methyl tert-butyl ether (MTBE) followed by GC was developed to quantify residues that result from the postharvest fumigation of almonds and walnuts with propylene oxide (PPO). Verification and quantification of PPO, propylene chlorohydrin (PCH) [1 chloropropan-2-ol (PCH-1) and 2-chloropropan-1-ol (PCH-2)], and propylene bromohydrin (PBH) [1-bromopropan-2-ol (PBH-1) and 2-bromopropan-1-ol (PBH-2)] was accomplished with a combination of electron impact ionization MS (EIMS), negative ion chemical ionization MS (NCIMS), and electron capture detection (ECD). Respective GC/EIMS LOQs for PPO, PCH-1, PCH-2, PBH-1, and PBH-2 in MTBE extracts were [ppm (MUg/g nut)] 0.9, 2.1, 2.5, 30.3, and 50.0 for almonds and 0.8, 2.2, 2.02, 41.6, and 45.7 for walnuts. Relative to GC/EIMS, GC-ECD analyses resulted in no detection of PPO, similar detector responses for PCH isomers, and >100-fold more sensitive detection of PBH isomers. NCIMS did not enhance detection of PBH isomers relative to EIMS and was, respectively, approximately 20-, 5-, and 10 fold less sensitive to PPO, PCH-1, and PCH-2. MTBE extraction efficiencies were >90% for all analytes. The 10-fold concentration of MTBE extracts yielded recoveries of 85-105% for the PBH isomers and a concomitant decrease in LODs and LOQs across detector types. The recoveries of PCH isomers and PPO in the MTBE concentrate were relatively low (approximately 50 to 75%), which confound improvements in LODs and LOQs regardless of detector type. PMID- 26525263 TI - High Throughput Analytical Techniques for the Determination and Confirmation of Residues of 653 Multiclass Pesticides and Chemical Pollutants in Tea by GC/MS, GC/MS/MS, and LC/MS/MS: Collaborative Study, First Action 2014.09. AB - Thirty laboratories from fom North and South America, Europe, and Asia participated in this AOAC collaborative study (15 from China; five from Germany; two each from Italy and the United States; and one each from the Republic of Korea, Canada, Spain, Japan, Belgium, and India). Participants represented government regulatory, commercial testing, university, research institute, and private laboratories. The single-laboratory validated (SLV) tea method was evaluated in the collaborative study to determine the recovery and reproducibility of the method under multilaboratory conditions. Since there were no restrictions regarding the type of analytical instrumentation to use for the analyses, laboratories used a combination of equipment that included GC/MS, GC/MS/MS, and LC/MS/MS instruments from 22 different manufacturers, 21 brands of GC and LC columns, 13 different GC temperature programming profiles, 11 LC gradient elution programs, and six different vendor manufactured SPE cartridges. Even though all the analytical performance parameters for all the 653 compounds had been determined in the SLV study, guidance was obtained from an expert review panel of the AOAC Method-Centric Committee on Pesticide Residues to conduct the multilaboratory collaborative study based on 20 selected compounds that can be analyzed by GC/MS and 20 compounds that can be analyzed by LC/MS/MS. Altogether, 560 samples covering the 40 selected pesticides were analyzed in the study. These samples included green tea and oolong tea samples fortified typically at the European Union maximum residue limit for regulatory guidance and compliance, aged tea samples incurred with 20 pesticides, and green tea and oolong tea samples incurred with five pesticides. The analysis of the 560 samples generated a total of 82 459 test results by the 30 participating laboratories. One laboratory failed to meet the proficiency requirements in the precollaborative study. Therefore, its data submitted for the collaborative study were excluded from further analysis and interpretation. The results presented are therefore the 6638 analytical results obtained from the 29 remaining laboratories, which included 1977 results generated by GC/MS, 1704 results by GC/MS/MS, and 2957 results by LC/MS/MS. It was determined after application of the Grubbs and Dixon tests for outliers to the data sets that there were 65 outlier results from the 1977 GC/MS results (3.3%), 65 outlier results from the 1704 GC/MS/MS results (3.8%), and 57 outlier results out of 2957 LC/MS/MS results (1.9%), representing 0.98, 0.98, and 0.86%, respectively, of the 6638 results generated in the study. Analysis with the AOAC statistical software package also confirmed that the method is rugged, and average recovery, average concentration, RSDr, RSDR, and HorRat values all meet recovery and reproducibility criteria for use in multiple laboratories. The Study Director is recommending this method for adoption as an AOAC First Action Official MethodSM. PMID- 26525264 TI - Uniform Sampling Table Method and its Applications II--Evaluating the Uniform Sampling by Experiment. AB - A new method of uniform sampling is evaluated in this paper. The items and indexes were adopted to evaluate the rationality of the uniform sampling. The evaluation items included convenience of operation, uniformity of sampling site distribution, and accuracy and precision of measured results. The evaluation indexes included operational complexity, occupation rate of sampling site in a row and column, relative accuracy of pill weight, and relative deviation of pill weight. They were obtained from three kinds of drugs with different shape and size by four kinds of sampling methods. Gray correlation analysis was adopted to make the comprehensive evaluation by comparing it with the standard method. The experimental results showed that the convenience of uniform sampling method was 1 (100%), odds ratio of occupation rate in a row and column was infinity, relative accuracy was 99.50-99.89%, reproducibility RSD was 0.45-0.89%, and weighted incidence degree exceeded the standard method. Hence, the uniform sampling method was easy to operate, and the selected samples were distributed uniformly. The experimental results demonstrated that the uniform sampling method has good accuracy and reproducibility, which can be put into use in drugs analysis. PMID- 26525265 TI - A Complementary Study of Mechanisms and Behaviors in Chromatography via Modeling. AB - Evolution in preparation of chromatographic columns has created the need for studying and evaluating them with the use of smart software. This research is an attempt to compare the retention mechanism between two stationary phases (butyl and phenyl) with the use of multivariate analysis for a large number of probes. Partial least squares has the ability to spot either major or minor differences in the chromatographic behavior of probes, with regard to changes in the stationary or mobile phases. The models developed refer to a total of 108 miscellaneous chemical compounds, described by 63 X variables (physicochemical properties and structural features) and one Y variable (retention time). The results showed that in both columns and mobile phases (40% methanol or 40% acetonitrile) the retention of an analyte is mainly affected by its lipophilicity, molar volume, and refractivity, which tend to cause delayed elution. On the contrary, solubility in water, polar surface area, and hydrogen bond donor or acceptor properties promote faster elution. The most important difference proved to be the effect of the presence of the carboxylic group and the solubility that affected the retention in a similar way in both columns but not with both mobile phases. PMID- 26525266 TI - A Short Interspersed Nuclear Element (SINE)-Based Real-Time PCR Approach to Detect and Quantify Porcine Component in Meat Products. AB - Real-time PCR amplification of mitochondria gene could not be used for DNA quantification, and that of single copy DNA did not allow an ideal sensitivity. Moreover, cross-reactions among similar species were commonly observed in the published methods amplifying repetitive sequence, which hindered their further application. The purpose of this study was to establish a short interspersed nuclear element (SINE)-based real-time PCR approach having high specificity for species detection that could be used in DNA quantification. After massive screening of candidate Sus scrofa SINEs, one optimal combination of primers and probe was selected, which had no cross-reaction with other common meat species. LOD of the method was 44 fg DNA/reaction. Further, quantification tests showed this approach was practical in DNA estimation without tissue variance. Thus, this study provided a new tool for qualitative detection of porcine component, which could be promising in the QC of meat products. PMID- 26525267 TI - Sensitivity and Specificity of Body Mass Index as a Marker of Obesity in Elderly Patients on Hemodialysis. AB - OBJECTIVES: Diagnosing obesity by body mass index (BMI) may not be reliable in elderly individuals due to the changes in body composition. We aimed to analyze the accuracy of BMI thresholds by World Health Organization (WHO) and Nutrition Screening Initiative (NSI) to diagnose obesity in elderly patients on hemodialysis (HD). DESIGN: Multicenter cross-sectional study. SETTING: Six dialysis facilities. SUBJECTS: 169 elderly on chronic HD (70.4 +/- 7.1 years; 63.9% men). MAIN OUTCOME VARIABLE: Total body fat percentage (BF%) was assessed by the sum of skinfold thicknesses and abdominal fat by waist circumference (WC). Both were used as reference to test the specificity and sensitivity of BMI thresholds (WHO: >=30 kg/m(2); NSI: >27 kg/m(2)). RESULTS: The prevalence of obesity according to NSI-BMI, WHO-BMI, BF%, and WC thresholds were 31%, 13%, 27%, and 29.6% in men, respectively, and 36%, 15%, 13%, and 75% in women. Compared to BF%, the sensitivity of NSI-BMI was moderate (65.5%) for men and high (100%) for women, whereas that of WHO-BMI was low (31%) for men and high (87.5%) for women. Compared with WC, NSI-BMI had good (75%) sensitivity for men and moderate (47.8%) for women, whereas WHO-BMI had moderate (43.8%) sensitivity for men and low (19.6%) for women. The best agreement with BF% was observed for NSI-BMI in men (kappa = 0.46) and for WHO-BMI in women (kappa = 0.80). For WC, the best agreement was for WHO-BMI for men (kappa = 0.63) and NSI-BMI for women (kappa = 0.31). CONCLUSIONS: BMI thresholds do not accurately diagnose adiposity in elderly on HD. Therefore, using BMI may lead to misclassifications in this segment population. PMID- 26525268 TI - Long term subjective cure rate, urinary tract symptoms and dyspareunia following mesh augmented anterior vaginal wall prolapse repair. AB - INTRODUCTION: The aim of this study was to assess patient-centered long term outcomes following anterior vaginal repair with mesh. METHODS: In January 2015, we identified 124 women who underwent anterior pelvic floor repair with mesh between January 2006 and February 2009. Patient records were reviewed and demographic, clinical, intra-operative and post-operative follow-up data retrieved. Telephone interviews were conducted to access information on clinical outcomes. Associations between baseline characteristics and long term symptoms were assessed by multivariable logistic regression models. RESULTS: Seventy-nine women were reached and consented to participate. Patients were interviewed 79-104 months after surgery. Their mean age at the time of surgery was 62.48 +/- 9.53 years; all had stage III cystocele with a mean POP Q point Ba of 5.32 +/- 1.47. Twenty-four (30%) had a previous hysterectomy and 26 (33%) had a previous pelvic organ prolapse or stress urinary incontinence operation. At telephone interviews, recurrence of prolapse symptoms was reported by 11 (13.9%) patients, mostly in the posterior compartment. Only 6 needed a corrective procedure. One patient had her mesh removed due to dyspareunia. Eleven (13.9%) reported lower urinary tract symptoms other than prolapse, as follows: stress urinary incontinence (1), overactive bladder (8) and dyspareunia (2). CONCLUSION: Long term rates of recurrent prolapse, dyspareunia and lower urinary tract symptoms were low for patients who underwent anterior vaginal wall mesh augmentation surgery for symptomatic cystoceles. PMID- 26525269 TI - The Association of Surgeons in Training Conference: #ASiT2015 Glasgow. AB - The Association of Surgeons in Training (ASiT) is a professional body and registered charity working to promote excellence in surgical training for the benefit of junior doctors and patients alike. ASiT is in-dependent of the National Health Service (NHS), Surgical Royal Colleges, and specialty associations and represents trainees in all ten surgical specialties. ASiT was delighted to welcome a number of distinguished guests and speakers to Glasgow for #ASiT2015. The theme of 'The Future of Surgery' delved into challenges surgical training faces, exciting developments into using technology to help patients, a glance at the past with the development of the Glasgow Coma Score and whether mortality truly is the future of measured outcomes. More than L3500 of prizes was awarded by the incoming President, Miss. Rhiannon Harries to the highest scoring papers presented selected from over 1000 abstracts submitted. PMID- 26525270 TI - Extracellular DNA amplicon sequencing reveals high levels of benthic eukaryotic diversity in the central Red Sea. AB - The present study aims to characterize the benthic eukaryotic biodiversity patterns at a coarse taxonomic level in three areas of the central Red Sea (a lagoon, an offshore area in Thuwal and a shallow coastal area near Jeddah) based on extracellular DNA. High-throughput amplicon sequencing targeting the V9 region of the 18S rRNA gene was undertaken for 32 sediment samples. High levels of alpha diversity were detected with 16,089 operational taxonomic units (OTUs) being identified. The majority of the OTUs were assigned to Metazoa (29.2%), Alveolata (22.4%) and Stramenopiles (17.8%). Stramenopiles (Diatomea) and Alveolata (Ciliophora) were frequent in a lagoon and in shallower coastal stations, whereas metazoans (Arthropoda: Maxillopoda) were dominant in deeper offshore stations. Only 24.6% of total OTUs were shared among all areas. Beta-diversity was generally lower between the lagoon and Jeddah (nearshore) than between either of those and the offshore area, suggesting a nearshore-offshore biodiversity gradient. The current approach allowed for a broad-range of benthic eukaryotic biodiversity to be analysed with significantly less labour than would be required by other traditional taxonomic approaches. Our findings suggest that next generation sequencing techniques have the potential to provide a fast and standardised screening of benthic biodiversity at large spatial and temporal scales. PMID- 26525272 TI - Advanced Google life support: Leveraging search results to improve bystander out of-hospital cardiac arrest response. PMID- 26525271 TI - Predictive value of interleukin-6 in post-cardiac arrest patients treated with targeted temperature management at 33 degrees C or 36 degrees C. AB - AIM: Post-cardiac arrest syndrome (PCAS) is characterized by systemic inflammation, however data on the prognostic value of inflammatory markers is sparse. We sought to investigate the importance of systemic inflammation, assessed by interleukin-6 (IL-6) in comatose survivors of out-of-hospital cardiac arrest. METHODS: A total of 682 patients enrolled in the Target Temperature Management (TTM) trial, surviving >24h with available IL-6 data were included. IL 6 was measured on days 1, 2 and 3 after return of spontaneous circulation. Severity of PCAS was assessed daily by the Sequential Organ Failure Assessment score. Survival status was recorded at 30 days. RESULTS: High levels of IL-6 at day 1-3 (all p<0.0001) were independently associated with severity of PCAS with no interaction of target temperature (all p=NS). IL-6 levels did not differ between temperature groups (p(interaction)=0.99). IL-6 levels at day 2 (p<0.0001) and day 3 (p<0.0001) were associated with crude mortality. Adjusted Cox proportional-hazards analysis showed that a two-fold increase of IL-6 levels at day 2 (HR=1.15 (95% CI: 1.07-1.23), p=0.0002) and day 3 (HR=1.18 (95% CI: 1.09 1.27), p<0.0001) were associated with mortality. IL-6 levels at day 3 had the highest discriminative value in predicting mortality (AUC=0.66). IL-6 did not significantly improve 30-day mortality prediction compared to traditional prognostic factors (p=0.08). CONCLUSIONS: In patients surviving >24h following cardiac arrest, IL-6 levels were significantly elevated and associated with severity of PCAS with no significant influence of target temperature. High IL-6 levels were associated with increased mortality. Measuring levels of IL-6 did not provide incremental prognostic value. PMID- 26525273 TI - Are regional variations in activity of dispatcher-assisted cardiopulmonary resuscitation associated with out-of-hospital cardiac arrests outcomes? A nation wide population-based cohort study. AB - AIM: Dispatcher-assisted cardiopulmonary resuscitation (DA-CPR) impacts the rates of bystander CPR (BCPR) and survival after out-of-hospital cardiac arrests (OHCAs). This study aimed to elucidate whether regional variations in indexes for BCPR and emergency medical service (EMS) may be associated with OHCA outcomes. METHODS: We conducted a population-based observational study involving 157,093 bystander-witnessed, resuscitation-attempted OHCAs without physician involvement between 2007 and 2011. For each index of BCPR and EMS, we classified the 47 prefectures into the following three groups: advanced, intermediate, and developing regions. Nominal logit analysis followed by multivariable logistic regression including OHCA backgrounds was employed to examine the association between neurologically favourable 1-month survival, and regional classifications based on BCPR- and EMS-related indexes. RESULTS: Logit analysis including all regional classifications revealed that the number of BLS training course participants per population or bystander's own performance of BCPR without DA-CPR was not associated with the survival. Multivariable logistic regression including the OHCA backgrounds known to be associated with survival (BCPR provision, arrest aetiology, initial rhythm, patient age, time intervals of witness-to-call and call-to-arrival at patient), the following regional classifications based on DA CPR but not on EMS were associated with survival: sensitivity of DA-CPR [adjusted odds ratio (95% confidence intervals) for advanced region; those for intermediate region, with developing region as reference, 1.277 (1.131-1.441); 1.162 (1.058 1.277)]; the proportion of bystanders to follow DA-CPR [1.749 (1.554-1.967); 1.280 (1.188-1.380)]. CONCLUSIONS: Good outcomes of bystander-witnessed OHCAs correlate with regions having higher sensitivity of DA-CPR and larger proportion of bystanders to follow DA-CPR. PMID- 26525274 TI - When an old pacemaker misleads a new automated external defibrillator. A case from the Pavia CARe (Cardiac Arrest Registry). PMID- 26525275 TI - Simulation-based training and its effect on management of severe anaphylaxis--Are 4 Hs enough? PMID- 26525276 TI - Susceptibility of bacteria isolated from acute gastrointestinal infections to rifaximin and other antimicrobial agents in Mexico. AB - BACKGROUND: Bacterial resistance may hamper the antimicrobial management of acute gastroenteritis. Bacterial susceptibility to rifaximin, an antibiotic that achieves high fecal concentrations (up to 8,000MUg/g), has not been evaluated in Mexico. OBJECTIVE: To determine the susceptibility to rifaximin and other antimicrobial agents of enteropathogenic bacteria isolated from patients with acute gastroenteritis in Mexico. MATERIAL AND METHODS: Bacterial strains were analyzed in stool samples from 1,000 patients with diagnosis of acute gastroenteritis. The susceptibility to rifaximin (RIF) was tested by microdilution (<100, <200, <400 and <800MUg/ml) and susceptibility to chloramphenicol (CHL), trimethoprim-sulfamethoxazole (T-S), neomycin (NEO), furazolidone (FUR), fosfomycin (FOS), ampicillin (AMP) and ciprofloxacin (CIP) was tested by agar diffusion at the concentrations recommended by the Clinical & Laboratory Standards Institute and the American Society for Microbiology. RESULTS: Isolated bacteria were: enteropathogenic Escherichia coli (E. coli) (EPEC) 531, Shigella 120, non-Typhi Salmonella 117, Aeromonas spp. 80, enterotoxigenic E. coli (ETEC) 54, Yersinia enterocolitica 20, Campylobacter jejuni 20, Vibrio spp. 20, Plesiomonas shigelloides 20, and enterohemorrhagic E. coli (EHEC 0:157) 18. The overall cumulative susceptibility to RIF at <100, <200, <400, and <800MUg/ml was 70.6, 90.8, 99.3, and 100%, respectively. The overall susceptibility to each antibiotic was: AMP 32.2%, T-S 53.6%, NEO 54.1%, FUR 64.7%, CIP 67.3%, CLO 73%, and FOS 81.3%. The susceptibility to RIF <400 and RIF <800MUg/ml was significantly greater than with the other antibiotics (p<0.001). CONCLUSIONS: Resistance of enteropathogenic bacteria to various antibiotics used in gastrointestinal infections is high. Rifaximin was active against 99-100% of these enteropathogens at reachable concentrations in the intestine with the recommended dose. PMID- 26525277 TI - Proton pump inhibitor-responsive esophageal eosinophilia: A new entity in search of recognition? PMID- 26525278 TI - What Has Caused Desertification in China? AB - Desertification is the result of complex interactions among various factors, including climate change and human activities. However, previous research generally focused on either meteorological factors associated with climate change or human factors associated with human activities, and lacked quantitative assessments of their interaction combined with long-term monitoring. Thus, the roles of climate change and human factors in desertification remain uncertain. To understand the factors that determine whether mitigation programs can contribute to desertification control and vegetation cover improvements in desertified areas of China, and the complex interactions that affect their success, we used a pooled regression model based on panel data to calculate the relative roles of climate change and human activities on the desertified area and on vegetation cover (using the normalized-difference vegetation index, NDVI, which decreases with increasing desertification) from 1983 to 2012. We found similar effect magnitudes for socioeconomic and environmental factors for NDVI but different results for desertification: socioeconomic factors were the dominant factor that affected desertification, accounting for 79.3% of the effects. Climate change accounted for 46.6 and 20.6% of the effects on NDVI and desertification, respectively. Therefore, desertification control programs must account for the integrated effects of both socioeconomic and natural factors. PMID- 26525280 TI - Expression of epigenetic modifiers is not significantly altered by exposure to secondhand smoke. AB - OBJECTIVES: Secondhand smoke (SHS) is a major risk factor for lung cancer in nonsmokers. DNA damage-derived mutagenicity is a well-established mechanism of SHS-carcinogenicity; however very little is known about the impact of SHS exposure on the epigenome. MATERIALS AND METHODS: We have investigated whether exposure to SHS can modulate the expression of key epigenetic regulators responsible for the establishment and/or maintenance of DNA methylation and histone modification patterns in vivo. We have sub-chronically exposed mice to a mutagenic but non-tumorigenic dose of SHS, and subsequently determined the expression levels of major epigenetic modifiers in the lungs of SHS-exposed mice, immediately after termination of exposure and following 7-month recovery in clean air. RESULTS AND CONCLUSION: Quantification of the expression of genes encoding DNA methyltransferases (Dnmt1, Dnmt3a, Dnmt3b and Dnmt3l), methyl binding domain proteins (Mecp2, Mbd2 and Mbd3) and histone deacetylases (Hdac1 and Hdac2) by quantitative reverse-transcription polymerase chain reaction analysis showed modest but not statistically significant differences in the relative transcription of these key epigenetic regulators between SHS-exposed mice and age matched controls. The non-significant changes in the expression of main epigenetic modifiers in SHS-exposed mice imply that SHS may predominantly induce genotoxic effects, particularly at non-tumorigenic doses, whereas epigenetic effects may only be secondary and manifest en route to tumor formation. PMID- 26525279 TI - Helicobacter pylori and T Helper Cells: Mechanisms of Immune Escape and Tolerance. AB - Helicobacter pylori colonizes the gastric mucosa of at least half of the human population, causing a worldwide infection that appears in early childhood and if not treated, it can persist for life. The presence of symptoms and their severity depend on bacterial components, host susceptibility, and environmental factors, which allow H. pylori to switch between commensalism and pathogenicity. H. pylori driven interactions with the host immune system underlie the persistence of the infection in humans, since the bacterium is able to interfere with the activity of innate and adaptive immune cells, reducing the inflammatory response in its favour. Gastritis due to H. pylori results from a complex interaction between several T cell subsets. In particular, H. pylori is known to induce a T helper (Th)1/Th17 cell response-driven gastritis, whose impaired modulation caused by the bacterium is thought to sustain the ongoing inflammatory condition and the unsuccessful clearing of the infection. In this review we discuss the current findings underlying the mechanisms implemented by H. pylori to alter the T helper lymphocyte proliferation, thus facilitating the development of chronic infections and allowing the survival of the bacterium in the human host. PMID- 26525281 TI - Developmental Screening in the Primary Care Setting: A Qualitative Integrative Review for Nurses. AB - Standardized developmental screening leads to the identification of children with developmental delays who may benefit from early intervention. Many children with developmental delays are not identified early in life. An integrative review was performed to synthesize and critically analyze qualitative studies on the developmental screening experiences of parents and providers to develop a deeper understanding of the developmental screening gaps in clinical practice and increase awareness among healthcare professionals who care for children. ELIGIBILITY CRITERIA: Qualitative studies written in English that focused on developmental screening in children from birth to school age and that included registered nurses, advanced practice nurses, pediatric or family physicians, or parents were considered. SAMPLE: Ten studies met the inclusion criteria. RESULTS: The analysis resulted in four main themes: developmental screening behaviors, developmental screening barriers, developmental screening facilitators, and parent interactions. CONCLUSIONS: Positive parent interactions and practice-wide engagement facilitated successful implementation of standardized developmental screening in primary care settings. Barriers associated with developmental screening included time, lack of reimbursement, poor communication with parents, and unfamiliarity with developmental screening instruments. A limited number of studies have examined developmental screening methods used by advanced practice nurses. Only two studies in the review included advanced practice nurses. IMPLICATIONS: The developmental screening experiences of providers and parents increases awareness about the challenges associated with conducting developmental screening in primary care. Recommendations for future research are offered with a focus on advanced practice nurses in primary care. PMID- 26525283 TI - Impaired day-to-day activities worsened but diabetes control improved self-rated health: The UK diabetes survey, 2006. PMID- 26525282 TI - Effect of traditional Chinese exercise on the quality of life and depression for chronic diseases: a meta-analysis of randomised trials. AB - Traditional Chinese exercise (TCE) has many uses in the prevention and treatment of chronic diseases. However, there is no consensus regarding the benefit of TCE for chronic diseases. Our objective is to examine the effect of TCE on the quality of life and depression for chronic diseases by performing a meta-analysis of randomized controlled trials (RCTs). We only cover published RCTs. The outcome measures included quality of life and depression. Sixty articles with a total of 4311 patients were included. The pooling revealed that TCE could improve the SF 36 physical function subscale in the short term [SMD (95% CI) = 0.35 (0.13, 0.56), P = 0.002] and mid-term [SMD (95% CI) = 0.49 (0.12, 0.85), P = 0.009], GHQ [SMD (95% CI) = -0.68 (-1.26, -0.09), P = 0.02], the Center for Epidemiologic Studies depression scale in the short term [SMD (95% CI) = -0.86 (-1.42, -0.31), P = 0.002] and mid-term [SMD (95% CI) = -0.41 (-0.64, -0.18), P < 0.001]. The meta-analysis of RCT demonstrates that TCE can significantly improve the quality of life and depression of patients with chronic diseases. These findings provide useful information for patients with chronic diseases as well as for medical staff. PMID- 26525284 TI - Origins of Highly Stable Al-evaporated Solution-processed ZnO Thin Film Transistors: Insights from Low Frequency and Random Telegraph Signal Noise. AB - One long-standing goal in the emerging field of flexible and transparent electronic devices is to meet the demand of key markets, such as enhanced output performance for metal oxide semiconductor thin film transistors (TFTs) prepared by a solution process. While solution-based fabrication techniques are cost effective and ensure large-area coverage at low temperature, their utilization has the disadvantage of introducing large trap states into TFTs. Such states, the formation of which is induced by intrinsic defects initially produced during preparation, have a significant impact on electrical performance. Therefore, the ability to enhance the electrical characteristics of solution-processed TFTs, along with attaining a firm understanding of their physical nature, remains a key step towards extending their use. In this study, measurements of low-frequency noise and random telegraph signal noise are employed as generic alternative tools to examine the origins of enhanced output performance for solution-processed ZnO TFTs through the control of defect sites by Al evaporation. PMID- 26525285 TI - Seaweed floating in the pericardium: a rare case of primary dedifferentiated liposarcoma. AB - Primary cardiac tumors are uncommon and primary liposarcoma of the pericardium is extremely rare. We describe the case of a 55-year-old Caucasian woman without significant medical history, who presented with 3weeks complain of dyspnea, peripheral edema, and gain weight. Echocardiography revealed a huge pericardial mass confirmed by computed tomography and by magnetic resonance. The lesion was primitive of the pericardium but the surgery was not able to cut it off because of the absence of cleavage planes. Histopathologic analysis detected a dedifferentiated liposarcoma. Mediastinum compression syndrome brought the patient to the exitus in a few days. PMID- 26525286 TI - Monosodium Urate Crystals Induce Upregulation of NK1.1-Dependent Killing by Macrophages and Support Tumor-Resident NK1.1+ Monocyte/Macrophage Populations in Antitumor Therapy. AB - Macrophages display phenotypic and functional heterogeneity dependent on the changing inflammatory microenvironment. Under some conditions, macrophages can acquire effector functions commonly associated with NK cells. In the current study, we investigated how the endogenous danger signal monosodium urate (MSU) crystals can alter macrophage functions. We report that naive, primary peritoneal macrophages rapidly upregulate the expression of the NK cell-surface marker NK1.1 in response to MSU crystals but not in response to LPS or other urate crystals. NK1.1 upregulation by macrophages was associated with mechanisms including phagocytosis of crystals, NLRP3 inflammasome activation, and autocrine proinflammatory cytokine signaling. Further analysis demonstrated that MSU crystal-activated macrophages exhibited NK cell-like cytotoxic activity against target cells in a perforin/granzyme B-dependent manner. Furthermore, analysis of tumor hemopoietic cell populations showed that effective, MSU-mediated antitumor activity required coadministration with Mycobacterium smegmatis to induce IL 1beta production and significant accumulation of monocytes and macrophages (but not granulocytes or dendritic cells) expressing elevated levels of NK1.1. Our findings provide evidence that MSU crystal-activated macrophages have the potential to develop tumoricidal NK cell-like functions that may be exploited to boost antitumor activity in vivo. PMID- 26525287 TI - M2b Monocytes Provoke Bacterial Pneumonia and Gut Bacteria-Associated Sepsis in Alcoholics. AB - Chronic alcohol consumption markedly impairs host antibacterial defense against opportunistic infections. gamma-irradiated NOD-SCID IL-2Rgamma(null) mice inoculated with nonalcoholic PBMCs (control PBMC chimeras) resisted Klebsiella pneumonia and gut bacteria-associated sepsis, whereas the chimeras created with alcoholic PBMCs (alcoholic PBMC chimeras) were very susceptible to these infections. M1 monocytes (IL-12(+)IL-10(-)CD163(-)CD14(+) cells), major effector cells in antibacterial innate immunity, were not induced by a bacterial Ag in alcoholic PBMC cultures, and M2b monocytes (CCL1(+)CD163(+)CD14(+) cells), which predominated in alcoholic PBMCs, were shown to be inhibitor cells on the Ag stimulated monocyte conversion from quiescent monocytes to M1 monocytes. CCL1, which functions to maintain M2b macrophage properties, was produced by M2b monocytes isolated from alcoholic PBMCs. These M2b monocytes reverted to quiescent monocytes (IL-12(-)IL-10(-)CCL1(-)CD163(-)CD14(+) cells) in cultures supplemented with CCL1 antisense oligodeoxynucleotide, and the subsequent quiescent monocytes easily converted to M1 monocytes under bacterial Ag stimulation. Alcoholic PBMC chimeras treated with CCL1 antisense oligodeoxynucleotide were resistant against pulmonary infection by K. pneumoniae and sepsis stemming from enterococcal translocation. These results indicate that a majority of monocytes polarize to an M2b phenotype in association with alcohol abuse, and this polarization contributes to the increased susceptibility of alcoholics to gut and lung infections. Bacterial pneumonia and gut bacteria associated sepsis, frequently seen in alcoholics, can be controlled through the polarization of macrophage phenotypes. PMID- 26525288 TI - Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization. AB - It is well established how effector T cells exit the vasculature to enter the peripheral tissues in which an infection is ongoing. However, less is known regarding how CTLs migrate toward infected cells after entry into peripheral organs. Recently, it was shown that the chemokine receptor CXCR3 on T cells has an important role in their ability to localize infected cells and to control vaccinia virus infection. However, the search strategy of T cells for virus infected targets has not been investigated in detail and could involve chemotaxis toward infected cells, chemokinesis (i.e., increased motility) combined with CTL arrest when targets are detected, or both. In this study, we describe and analyze the migration of CTLs within HSV-1-infected epidermis in vivo. We demonstrate that activated T cells display a subtle distance-dependent chemotaxis toward clusters of infected cells and confirm that this is mediated by CXCR3 and its ligands. Although the chemotactic migration is weak, computer simulations based on short-term experimental data, combined with subsequent long-term imaging indicate that this behavior is crucial for efficient target localization and T cell accumulation at effector sites. Thus, chemotactic migration of effector T cells within peripheral tissue forms an important factor in the speed with which T cells are able to arrive at sites of infection. PMID- 26525289 TI - Social Media and HIV: A Systematic Review of Uses of Social Media in HIV Communication. AB - BACKGROUND: Social media, including mobile technologies and social networking sites, are being used increasingly as part of human immunodeficiency virus (HIV) prevention and treatment efforts. As an important avenue for communication about HIV, social media use may continue to increase and become more widespread. OBJECTIVE: The objective of this paper is to present a comprehensive systematic review of the current published literature on the design, users, benefits, and limitations of using social media to communicate about HIV prevention and treatment. METHODS: This review paper used a systematic approach to survey all literature published before February 2014 using 7 electronic databases and a manual search. The inclusion criteria were (1) primary focus on communication/interaction about HIV/acquired immunodeficiency syndrome (AIDS), (2) discusses the use of social media to facilitate communication, (3) communication on the social media platform is between individuals or a group of individuals rather than the use of preset, automated responses from a platform, (4) published before February 19, 2014, and (5) all study designs. RESULTS: The search identified 35 original research studies. Thirty studies had low or unclear risk of at least one of the bias items in the methodological quality assessment. Among the 8 social media platform types described, short message service text messaging was most commonly used. Platforms served multiple purposes including disseminating health information, conducting health promotion, sharing experiences, providing social support, and promoting medication adherence. Social media users were diverse in geographic location and race/ethnicity; studies commonly reported users aged 18-40 years and users with lower income. Although most studies did not specify whether use was anonymous, studies reported the importance of anonymity in social media use to communicate about HIV largely due to the stigma associated with HIV. The ability to share and receive information about HIV was the most commonly reported benefit of social media use and the most common challenges were related to technology. Measures of frequency of use, satisfaction, and effects of use varied across studies. CONCLUSIONS: Using social media to bridge communication among a diverse range of users, in various geographic and social contexts, may be leveraged through pre-existing platforms and with attention to the roles of anonymity and confidentiality in communication about HIV prevention and treatment. More robust research is needed to determine the effects of social media use on various health and social outcomes related to HIV. PMID- 26525290 TI - Pathological and therapeutic interactions between bacteriophages, microbes and the host in inflammatory bowel disease. AB - The intestinal microbiome is a dynamic system of interactions between the host and its microbes. Under physiological conditions, a fine balance and mutually beneficial relationship is present. Disruption of this balance is a hallmark of inflammatory bowel disease (IBD). Whether an altered microbiome is the consequence or the cause of IBD is currently not fully understood. The pathogenesis of IBD is believed to be a complex interaction between genetic predisposition, the immune system and environmental factors. In the recent years, metagenomic studies of the human microbiome have provided useful data that are helping to assemble the IBD puzzle. In this review, we summarize and discuss current knowledge on the composition of the intestinal microbiota in IBD, host microbe interactions and therapeutic possibilities using bacteria in IBD. Moreover, an outlook on the possible contribution of bacteriophages in the pathogenesis and therapy of IBD is provided. PMID- 26525291 TI - Temporal-spatially transformed synthesis and formation mechanism of gold bellflowers. AB - Anisotropic gold nanostructures with unique plasmonic properties, specifically the strong absorption of light in the near-infrared region (650-900 nm) due to the excitation of plasmon oscillations, have been widely employed as photothermal conversion agents (PTCAs) for cancer photothermal therapy (PTT). However, the reported PTCAs show suboptimal photothermal conversion efficiency (eta), even gold nanocages (eta = 63%), which limits their biomedical applications. Herein, we fabricated gold bellflowers (GBFs) with an ultrahigh photothermal conversion efficiency (eta = 74%) via a novel liquid/liquid/gas triphasic interface system, using chloroauric acid as a gold source, and o-phenetidine as a reducing agent. The well-defined GBFs with multiple-branched petals show adjustable localized surface plasmon resonance (LSPR) from 760 to 1100 nm by tuning the petal length and circular bottom diameter. Originating from the monophasic and biphasic systems used in the creation of gold nanourchins (GNUs) and gold microspheres (GMPs) respectively, the triphasic interface system successfully produced GBFs. The possible formation mechanisms of GNUs, GMPs, and GBFs in the different systems were also investigated and discussed. We found that the formation mechanism of GNUs and GBFs followed classical crystallization, while the formation of GMPs followed non-classical crystallization. PMID- 26525292 TI - Positive Instruction in Music Studios: Introducing a New Model for Teaching Studio Music in Schools Based upon Positive Psychology. AB - This practice paper explores the intersection of school studio-music pedagogy and positive psychology in order to enhance students' learning and engagement. The paper has a practitioner focus and puts forward a new model of studio teaching, the Positive Instruction in Music Studios (PIMS) model that guides teachers through four key positive psychology processes that can be used in a music lesson: positive priming, strengths spotting, positive pause, and process praise. The model provides a new, positively oriented approach to studio-music pedagogy that can be integrated into specific methods-based programs to enhance student learning and engagement. PMID- 26525293 TI - Algorithm based patient care protocol to optimize patient care and inpatient stay in head and neck free flap patients. AB - OBJECTIVE: To determine if rigid adherence (where medically appropriate) to an algorithm/checklist-based patient care pathway can reduce the duration of hospitalization and complication rates in patients undergoing head and neck reconstruction with free tissue transfer. METHODS: Study design was a retrospective case-control study of patients undergoing major head and neck cancer resections and reconstruction at a tertiary referral centre. The intervention was rigid adherence to a pre-existing care pathway including flow algorithms and multidisciplinary checklists incorporated into patient charting and care orders. 157 patients were enrolled prospectively and were compared to 99 patients in a historical cohort. Patient charts were reviewed and information related to the patient, procedure, and post-operative course was extracted. The two groups were compared for number of major and minor complications (using the Clavien-Dindo system) and length of stay in hospital. RESULTS: Comparing pre- and post-intervention groups, no significant difference was identified in duration of hospital stay (21.5 days vs. 20.5 days, p = 0.750), the rate of major complications was significantly higher in the pre-intervention cohort (25.3% vs. 14.0%, p = 0.031), the rate of minor complications was not significantly higher (34.3% vs 30.8%, p = 0.610). CONCLUSION: Rigid adherence to our patient care pathway, and improved charting techniques including flow algorithms and multidisciplinary checklists has improved patient care by showing a significant reduction in the rate of major complications. PMID- 26525295 TI - Diolefins with an ether/thioether functionality as ligands in the coordination sphere of Ni and Rh. AB - A diolefin ether, trop2O (2), and a diolefin thioether, trop2S (3), have been investigated as ligand analogues of the well-established diolefin amine, trop2NH (1). Compounds 2 and 3 form different conformers in solution and in the solid state. Whereas 2 could be coordinated to Ni(0), 3 was found to be more suited for coordination to Rh(I). The coordination chemistry, electrochemical properties, and ligand exchange phenomena of the resulting complexes, [Ni(trop2O)(PPh3)] (5) and [Rh(trop2S)(L)n][OTf] (6: L = NCMe, n = 2; 7: L = 2,2'-bipy, n = 1) were investigated by analytical techniques including NMR spectroscopy, single crystal X-ray analysis, and cyclic voltammetry. The results were compared with those obtained for the amine analogues of 5, 6, and 7. PMID- 26525294 TI - Increased circulating follicular helper T cells with decreased programmed death-1 in chronic renal allograft rejection. AB - BACKGROUND: Chronic antibody-mediated rejection is a major issue that affects long-term renal allograft survival. Since follicular helper T (Tfh) cells promote the development of antigen-specific B cells in alloimmune responses, we investigated the potential roles of Tfh cells, B cells and their alloimmune regulating molecules in the pathogenesis of chronic renal allograft rejection in this study. METHODS: The frequency of Tfh, B cells and the levels of their alloimmune-regulating molecules including chemokine receptor type 5 (CXCR5), inducible T cell co-stimulator (ICOS), programmed death-1 (PD-1), ICOSL, PDL-1 and interleukin-21 (IL-21), of peripheral blood were comparatively measured in 42 primary renal allograft recipients within 1-3 years after transplantation. Among them, 24 patients had definite chronic rejection, while other 18 patients had normal renal function. RESULTS: Tfh-cell ratio was significantly increased with PD-1 down-regulation in the patients with chronic renal allograft rejection, while B cells and the alloimmune-regulating molecules studied did not show any appreciable change in parallel. CONCLUSIONS: The patients with chronic renal allograft rejection have a characteristic increase in circulating Tfh cells with a decrease in PD-1 expression. These pathological changes may be a therapeutic target for the treatment of chronic renal allograft rejection and can be useful as a clinical index for monitoring conditions of renal transplant. PMID- 26525296 TI - A home-based rehabilitation intervention for people living with HIV and disability in a resource-poor community, KwaZulu-Natal: study protocol for a randomised controlled trial. AB - BACKGROUND: In the era of highly active antiretroviral therapy HIV is now viewed as a chronic disease. Although people living with HIV are living longer lives, they are prone to a number of disabilities. Home-based rehabilitation has been shown to be an effective means of improving quality of life and function for people with a wide range of chronic diseases. There is a dearth of evidence, however, related to home-based rehabilitation interventions for people living with HIV, particularly in sub-Saharan Africa - the region with the highest global prevalence of HIV. METHODS: A randomised controlled trial design will be employed. Adults living with HIV who have been on antiretroviral therapy for at least six months and with defined limited mobility will be randomly allocated to either an intervention group or the control group. Pre and post-intervention testing will be conducted at a public hospital in KwaZulu-Natal, South Africa in order to assess the participants' quality of life, perceived level of disability, functional ability and endurance. Individuals randomly allocated to the intervention group will participate in a four-month home-based rehabilitation programme, conducted once a week in their homes. This programme will be implemented by community workers who will be trained and supervised by a qualified physiotherapist. The participants in the control group will continue with the standard clinic management offered to them. On completion of the intervention, all participants will be re-assessed using the same outcome measures. Analysis of results will be carried out on intention-to-treat basis in order to identify any changes between intervention and control groups. DISCUSSION: The researchers aim to employ a novel task shifting approach to implement a needs-based home-based rehabilitation programme for people living with HIV in order to improve their quality of life and functional ability. It is hoped that this study will provide rehabilitation professionals and researchers with evidence that can be utilised to improve existing rehabilitation interventions for people living with HIV. TRIAL REGISTRATION: South African National Clinical Trials Register: NHREC#4094 (Date of registration: 21 July 2015). PMID- 26525297 TI - Cell-Penetrating Peptides as Carriers for Oral Delivery of Biopharmaceuticals. AB - Oral delivery of biopharmaceuticals, for example peptides and proteins, constitutes a great challenge in drug delivery due to their low chemical stability and poor permeation across the intestinal mucosa, to a large extent limiting the mode of administration to injections, which is not favouring patient compliance. Nevertheless, cell-penetrating peptides (CPPs) have shown promising potential as carriers to overcome the epithelium, and this minireview highlights recent knowledge gained within the field of CPP-mediated transepithelial delivery of therapeutic peptides and proteins from the intestine. Two approaches may be pursued: co-administration of the carrier and therapeutic peptide in the form of complexes obtained by simple bulk mixing, or administration of covalent conjugates demanding more advanced production methodologies. These formulation approaches have their pros and cons, and which is to be preferred depends on the physicochemical properties of both the specific CPP and the specific cargo. In addition to the physical epithelial barrier, a metabolic barrier must be overcome in order to obtain CPP-mediated delivery of a cargo drug from the intestine, and a number of strategies have been employed to delay enzymatic degradation of the CPP. The mechanisms by which CPPs translocate across membranes are not fully understood, but possibly involve endocytosis as well as direct translocation, and the CPP-mediated transepithelial delivery of cargo drugs thus likely involves similar mechanisms for the initial membrane interaction and translocation. However, the mechanisms responsible for transcytosis of the cargo drug, if taken up by an endocytic mechanism, or direct translocation across the epithelium are so far not known. PMID- 26525298 TI - Cnidaria: fast, reference-free clustering of raw and assembled genome and transcriptome NGS data. AB - BACKGROUND: Identification of biological specimens is a requirement for a range of applications. Reference-free methods analyse unprocessed sequencing data without relying on prior knowledge, but generally do not scale to arbitrarily large genomes and arbitrarily large phylogenetic distances. RESULTS: We present Cnidaria, a practical tool for clustering genomic and transcriptomic data with no limitation on genome size or phylogenetic distances. We successfully simultaneously clustered 169 genomic and transcriptomic datasets from 4 kingdoms, achieving 100% identification accuracy at supra-species level and 78% accuracy at the species level. CONCLUSION: CNIDARIA allows for fast, resource-efficient comparison and identification of both raw and assembled genome and transcriptome data. This can help answer both fundamental (e.g. in phylogeny, ecological diversity analysis) and practical questions (e.g. sequencing quality control, primer design). PMID- 26525299 TI - Impact of a multifaceted education program on implementing a pediatric palliative care guideline: a pilot study. AB - BACKGROUND: A national clinical practice guideline for pediatric palliative care was published in 2013. So far there are only few reports available on whether an educational program fosters compliance with such a guideline implementation. We aimed to test the effect of the education program on actual compliance as well as documentation of compliance to the guideline. METHODS: We performed a prospective study with pre- and post-intervention evaluation on compliance to the guideline of the nurse specialists of a pediatric palliative care team for case management at a children's university hospital. Eleven quality indicators were selected from 192 recommendations from the pediatric palliative care guideline, based on frequency, measurability and relevance. The multifaceted education program included e-learning and an interactive educational meeting. Four e-learning modules addressed 19 patient cases on symptoms, diagnostics and treatment, and a chart-documentation exercise. During the interactive educational meeting patient cases were discussed on how to use the guideline. Documentation of compliance to the guideline in the web-based patient-charts as well as actual compliance to the guideline through weekly web-based parent reports was measured before and after completion of the e-learning. RESULTS: Eleven quality indicators were selected. The educational program did not result in significant improvement in compliance for any of these indicators. The indicators "treatment of nausea", "pain medications two steps ahead" and "pain medication for 48 h present", measured through parent reports, scored a compliance beyond 80 % before and after e learning. The remaining indicators measuring compliance, as well as six indicators measuring documentation by chart review, showed a compliance below 80 % before and after e-learning. CONCLUSIONS: The multifaceted education program did not lead to improvement in documentation of compliance to the guideline. Parent reported outcome revealed better performance and might be the more adequate assessment tool for future studies. PMID- 26525301 TI - Cu2 S/ZnS Heterostructured Nanorods: Cation Exchange vs. Solution-Liquid-Solid like Growth. AB - Cu2 S/ZnS heterostructured nanorods (HNRs) with uncommon morphologies are achieved through single-pot and multi-batch synthetic strategies. In both cases, Cu2 S NRs form first, which then undergo partial cation exchange and solution liquid-solid (SLS)-like growth catalyzed by the remaining Cu2 S parts of the NRs. The location and the volume of ZnS achieved through partial cation exchange control the size of the Cu2 S catalysts, which in turn determine whether tapered rod-rod, body/tail, or barbell-like structure results from subsequent SLS-like growth. Concurrent cation exchange can sometimes cause Cu2 S catalysts to be lost during SLS-like growth, leading to further diversity in achievable morphologies of Cu2 S/ZnS HNRs. Additional insights are gained on how parameters such as Zn precursor, ligand choice, and concentration alter cation exchange and SLS-like growth steps. PMID- 26525300 TI - Prenatal Triptan Exposure and Internalising and Externalising Behaviour Problems in 3-Year-Old Children: Results from the Norwegian Mother and Child Cohort Study. AB - BACKGROUND: Triptans are commonly prescribed for migraine, a pain condition that is highly prevalent in women of childbearing age. No prior studies have investigated associations between exposure to triptans during fetal life and risk of externalising and internalising behaviours in children. METHODS: This study was set in the Norwegian Mother and Child Cohort study, a prospective birth cohort. A total of 41,173 live, singleton births without major malformations present at 36-month post-partum follow-up were included in this study; 396 used a triptan during pregnancy, 798 used a triptan prior to pregnancy only, 3291 reported migraine without triptan use, and 36,688 reported no history of migraine or triptan use. Marginal structural models were used to analyse the association between timing of triptan exposure and neurodevelopmental outcome. RESULTS: Children exposed to triptans during pregnancy had a 1.39-fold increased risk of externalising behaviours compared with those whose mothers used triptans prior to pregnancy only (95% CI 0.97, 1.97), a 1.36-fold increased risk compared with the unmedicated migraine group (95% CI 1.02, 1.81), and a 1.41-fold increased risk compared with the population comparison group (95% CI 1.08, 1.85). The greatest risk was associated with first trimester exposure (RR 1.77, 95% CI 0.98, 3.14). Risk differences were small, ranging from 3-6%. CONCLUSIONS: This study found an increased risk of clinically relevant externalising behaviours in children with prenatal exposure to triptans, and this risk was highest for first trimester exposure. Absolute risks were small, and the results may be due to confounding by underlying migraine severity. PMID- 26525302 TI - Physicians discuss the risks of smoking with their patients, but seldom offer practical cessation support. AB - BACKGROUND: Our aim was to study the smoking cessation-related 1) attitudes & experiences and 2) consultation practices of Finnish physicians and to determine if there is a relationship between the two. METHODS: An online survey on smoking cessation was sent to 39 % of all Finnish physicians, with emphasis on physicians working in fields relevant to smoking cessation. A total of 1141 physicians (response rate 15 %) responded to the online survey, 53 % of whom were employed in primary health care. A total of 1066 respondents were eligible for the analysis. The questionnaire included questions on the physician's own smoking status, their attitudes and experiences on smoking cessation, and the implementation of smoking cessation in clinical practice. Two sub-scales concerning smoking-related consultation activities were constructed: one for conversation, and another for practical actions. RESULTS: The most common consultation activities (respondents who reported doing the following actions "nearly always") were asking how much the patient smokes (65 %), marking smoking status in patient records (58 %) and recommending quitting to the patient (55 %). The least common activity was prescribing withdrawal medication (4 %). Primary care physicians were more active than those working in secondary health care in nearly all activities mapped. A positive attitude and experiences on smoking cessation were associated with actively offering withdrawal support. Those who were familiar with the local treatment guidelines for tobacco addiction were 30 % more active in offering practical cessation help to their patient. The respondents were more active in discussing smoking with their patients than in offering practical cessation help. CONCLUSION: Physicians offer their patients practical cessation support relatively infrequently. Practical cessation calls for continuous education of physicians about the nature of tobacco and nicotine addiction, the role of smoking as a risk factor for various diseases, and the practical measures needed for smoking cessation. Secondary care physicians should acknowledge the authority they pose toward smoking patients. PMID- 26525303 TI - Diversity Oriented Synthesis of Indoloazepinobenzimidazole and Benzimidazotriazolobenzodiazepine from N(1)-Alkyne-1,2-diamines. AB - A one-pot protocol for the diversity oriented synthesis of two N-polyheterocycles indoloazepinobenzimidazole and benzimidazotriazolobenzodiazepine from a common N(1)-alkyne-1,2-diamine building block is described. The approach involves sequential formation of benzimidazole through cyclocondensation and oxidation, which is followed by the formation of either an azepine ring (through alkyne activation and 6-endo-dig cyclization, 1,2-migration with ring expansion, and re aromatization), or diazepine and triazole rings through 1,3-dipolar cycloaddition. PMID- 26525304 TI - Multi-set factor analysis by means of Parafac2. AB - We consider multi-set data consisting of Nk observations, k = 1,..., K (e.g., subject scores), on J variables in K different samples. We introduce a factor model for the J * J covariance matrices Sigmak, k = 1,..., K, where the common part is modelled by Parafac2 and the unique variances Uk, k = 1,..., K, are diagonal. The Parafac2 model implies a common loadings matrix that is rescaled for each k, and a common factor correlation matrix. We estimate the unique variances Uk by minimum rank factor analysis on Sigmak for each k. The factors can be chosen orthogonal or oblique. We present a novel algorithm to estimate the Parafac2 part and demonstrate its performance in a simulation study. Also, we fit our model to a data set in the literature. Our model is easy to estimate and interpret. The unique variances, the factor correlation matrix and the communalities are guaranteed to be proper, and a percentage of explained common variance can be computed for each k. Also, the Parafac2 part is rotationally unique under mild conditions. PMID- 26525305 TI - Fate of fenestration in children treated with fontan operation. AB - OBJECTIVE: To review the operative history and clinical and catheterization data on patients treated with total cavopulmonary connection (TCPC) with baffle fenestration and to study whether it is possible to predict the fate of fenestration. BACKGROUND: A baffle fenestration may improve postoperative outcomes after Fontan operation but is later associated with cyanosis and thromboembolic risk. Fenestration may close spontaneously or it can be closed percutaneously in patients with favorable hemodynamics. METHODS: Patients were divided into three groups: those with spontaneous closure of fenestration (group S, n = 34) and those with patent fenestration and favorable (group F, n = 36) or unfavorable (group U, n = 20) response to fenestration test occlusion. Clinical records were reviewed for demographic and anatomical characteristics, previous surgeries, and catheterizations. RESULTS: Predominant ventricular morphology was right ventricle (RV)/left ventricle (LV)/undeterminate in 19/14/1 patients in group S, 14/22/0 in group F, and 14/6/0 in group U. No differences were detected between groups in pre-TCPC catheterization data. Type of baffle fenestration was window/tube in 20/14 in group S, 28/8 in group F, and 20/0 in group U. All tube fenestrations either closed spontaneously or could be closed percutaneously. Twenty-nine percent of patients with window-type fenestrations failed the test occlusion. CONCLUSIONS: Spontaneous closure and favorable result in test occlusion are more common in tube than in window fenestrations. Since most preoperative anatomic and hemodynamic factors were similar in all patient groups, we find it difficult to predict the fate of a window-type fenestration and the result of test occlusion. (c) 2015 Wiley Periodicals, Inc. PMID- 26525306 TI - Enantiopure Indolizinoindolones with in vitro Activity against Blood- and Liver Stage Malaria Parasites. AB - Malaria continues to be a major cause of morbidity and mortality to this day, and resistance to drugs like chloroquine has led to an urgent need to discover novel chemical entities aimed at new targets. Here, we report the discovery of a novel class of potential antimalarial compounds containing an indolizinoindolone scaffold. These novel enantiopure indolizinoindolones were synthesized, in good to-excellent yields and excellent diastereoselectivities, by cyclocondensation reaction of (S)- or (R)-tryptophanol and 2-acyl benzoic acids, followed by intramolecular alpha-amidoalkylation. Interestingly, we were able to synthesize for the first time 7,13b-cis indolizinoindolones in a two-step route. The novel compounds showed promising activity against erythrocytic stages of the human malaria parasite, Plasmodium falciparum, and liver stages of the rodent parasite Plasmodium berghei. In particular, an (S)-tryptophanol-derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite's life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro. PMID- 26525307 TI - Antagonizing Bcl-2's BH4 domain in cancer. PMID- 26525308 TI - Archeological Echocardiography: Digitization and Speckle Tracking Analysis of Archival Echocardiograms in the HyperGEN Study. AB - BACKGROUND: Several large epidemiologic studies and clinical trials have included echocardiography, but images were stored in analog format and these studies predated tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE). We hypothesized that digitization of analog echocardiograms, with subsequent quantification of cardiac mechanics using STE, is feasible, reproducible, accurate, and produces clinically valid results. METHODS: In the NHLBI HyperGEN study (N = 2234), archived analog echocardiograms were digitized and subsequently analyzed using STE to obtain tissue velocities/strain. Echocardiograms were assigned quality scores and inter-/intra-observer agreement was calculated. Accuracy was evaluated in: (1) a separate second study (N = 50) comparing prospective digital strain versus post hoc analog-to-digital strain, and (2) in a third study (N = 95) comparing prospectively obtained TDI e' velocities with post hoc STE e' velocities. Finally, we replicated previously known associations between tissue velocities/strain, conventional echocardiographic measurements, and clinical data. RESULTS: Of the 2234 HyperGEN echocardiograms, 2150 (96.2%) underwent successful digitization and STE analysis. Inter/intra-observer agreement was high for all STE parameters, especially longitudinal strain (LS). In accuracy studies, LS performed best when comparing post hoc STE to prospective digital STE for strain analysis. STE-derived e' velocities correlated with, but systematically underestimated, TDI e' velocity. Several known associations between clinical variables and cardiac mechanics were replicated in HyperGEN. We also found a novel independent inverse association between fasting glucose and LS (adjusted beta = -2.4 [95% CI -3.6, -1.2]% per 1 SD increase in fasting glucose; P < 0.001). CONCLUSIONS: Archeological echocardiography, the digitization and speckle tracking analysis of archival echocardiograms, is feasible and generates indices of cardiac mechanics similar to contemporary studies. PMID- 26525309 TI - Factors associated with psychological distress in women with breast cancer related lymphoedema. AB - BACKGROUND: Previous research has shown that lymphoedema impacts negatively on an individual, including psychological distress and body image disturbance, particularly for younger women. This study identified psychological factors associated with distress in women with breast cancer-related lymphoedema and determined whether age moderated the specific relationship between body image disturbance and distress. METHODS: Australian women (n = 166) diagnosed with breast cancer-related lymphoedema were recruited through a community-based breast cancer organisation and lymphoedema treatment clinics. Participants completed an online survey assessing lymphoedema-related cognitions (personal control, perceived treatment effectiveness, and consequences of lymphoedema), perceived ability to self-regulate lymphoedema-related negative affect, body image disturbance, psychological distress (depression, anxiety and stress), and demographic/medical information. RESULTS: Beliefs about the consequences, perceived effectiveness of treatment and controllability of lymphoedema, perceived ability to self-regulate negative affect, body image disturbance, and number of lymphoedema symptoms were correlated with depression, anxiety, and stress scores. Multivariate regression analyses indicated that body image disturbance was significantly associated with depression, anxiety, and stress, and perceived treatment effectiveness was associated with stress. Age was a significant moderator of the relationship between body image disturbance and depression and anxiety, with older women with greater body image disturbance more distressed. CONCLUSIONS: Health professionals need to be aware that women diagnosed with lymphoedema are at risk of experiencing psychological distress, particularly arising from body image disturbance and beliefs that treatment cannot control lymphoedema. Furthermore, older women may be at an increased risk of anxiety and depression arising from body image disturbance. Copyright (c) 2015 John Wiley & Sons, Ltd. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26525310 TI - Pharmacokinetics of florfenicol and behaviour of its metabolite florfenicol amine in orange-spotted grouper (Epinephelus coioides) after oral administration. AB - Pharmacokinetics and elimination of florfenicol and florfenicol amine in grouper held in sea water at 23.3 +/- 0.8 degrees C were studied using HPLC method after they were given a single peroral dose of florfenicol at 24 mg kg(-1) body weight. Florfenicol was rapidly absorbed from intestine and distributed extensively to all the tissues examined. The maximum concentrations (Cmax , MUg g(-1) or MUg mL( 1) ) in plasma and tissues were observed at 2-6 h (the time to reach maximum concentration, Tmax ) except for bile (Tmax = 24 h) and were in the order of intestine (52.02 +/- 25.07) > bile (49.41 +/- 28.16) > gill (45.12 +/- 11.10) > plasma (28.28 +/- 5.43) > liver (21.97 +/- 12.08) > muscle (21.63 +/- 6.12) > kidney (20.88 +/- 11.28) > skin (19.10 +/- 5.88). The drug distribution level was higher in plasma than in extravascular tissues except for bile, based on the ratios of the area under concentration-time curve between tissue and plasma (AUCtissue/plasma ). The elimination of florfenicol was rapid in fish, and the corresponding half-lives (T1/2beta ) in the order of magnitude were bile (13.92 h) > muscle or liver (12.31 h) > skin (11.77 h) > plasma (11.57) > gill (11.04 h) > intestine (10.55 h) > kidney (10.05 h). The delayed Tmax , lower Cmax and longer T1/2beta for florfenicol amine compared with florfenicol were measured in grouper. PMID- 26525311 TI - Comparison of the accuracy of periodic reaction field methods in molecular dynamics simulations of a model liquid crystal system. AB - A periodic reaction field (PRF) method is a technique to estimate long-range interactions. The method has the potential to effectively reduce the computational cost while maintaining adequate accuracy. We performed molecular dynamics (MD) simulations of a model liquid-crystal system to assess the accuracy of some variations of the PRF method in low-charge-density systems. All the methods had adequate accuracy compared with the results of the particle mesh Ewald (PME) method, except for a few simulation conditions. Furthermore, in all of the simulation conditions, one of the PRF methods had the same accuracy as the PME method. PMID- 26525312 TI - Psychological predictors of pain severity, pain interference, depression, and anxiety in rheumatoid arthritis patients with chronic pain. AB - OBJECTIVES: Rheumatoid arthritis is a chronic and progressive autoimmune disorder with symptoms sometimes including chronic pain and depression. The current study aimed to explore some of the psychological variables which predict both pain related outcomes (pain severity and pain interference) and psychological outcomes (depression and anxiety) amongst patients with rheumatoid arthritis experiencing chronic pain. In particular, this study aimed to establish whether either self concealment, or the satisfaction of basic psychological needs (autonomy, relatedness, and competence), could explain a significant portion of the variance in pain outcomes and psychological outcomes amongst this patient group. DESIGN/METHODS: Online questionnaires were completed by 317 rheumatoid arthritis patients with chronic pain, providing data across a number of predictor and outcome variables. RESULTS: Hierarchical multiple linear regressions indicated that the predictive models for each of the four outcome variables were significant, and had good levels of fit with the data. In terms of individual predictor variables, higher relatedness significantly predicted lower depression, and higher autonomy significantly predicted lower anxiety. CONCLUSIONS: The model generated by this study may identify factors to be targeted by future interventions with the goal of reducing depression and anxiety amongst patients with rheumatoid arthritis experiencing chronic pain. The findings of this study have shown that the autonomy and the relatedness of patients with rheumatoid arthritis play important roles in promoting psychological well-being. Targeted interventions could help to enhance the lives of patients despite the presence of chronic pain. STATEMENT OF CONTRIBUTION: What is already known about the subject? Amongst a sample of chronic pain patients who primarily had a diagnosis of fibromyalgia, it was found that higher levels of self-concealment were associated with higher self-reported pain levels and reduced well-being (as measured by anxiety/depression), and these associations were mediated by patients' needs for autonomy not being met (Uysal & Lu, Health Psychology, 2011, 30, 606). What does this study add? For the first time amongst a rheumatoid arthritis population experiencing chronic pain, we found that higher levels of relatedness significantly predicted lower depression. For the first time amongst the same population, we found that higher levels of autonomy significantly predicted lower anxiety. PMID- 26525314 TI - Self-Assembled Resonance Energy Transfer Keys for Secure Communication over Classical Channels. AB - Modern authentication and communication protocols increasingly use physical keys in lieu of conventional software-based keys for security. This shift is primarily driven by the ability to derive a unique, unforgeable signature from a physical key. The sole demonstration of an unforgeable key, thus far, has been through quantum key distribution, which suffers from limited communication distances and expensive infrastructure requirements. Here, we show a method for creating unclonable keys by molecular self-assembly of resonance energy transfer (RET) devices. It is infeasible to clone the RET-key due to the inability to characterize the key using current technology, the large number of input-output combinations per key, and the variation of the key's response with time. However, the manufacturer can produce multiple identical devices, which enables inexpensive, secure authentication and communication over classical channels, and thus any distance. Through a detailed experimental survey of the nanoscale keys, we demonstrate that legitimate users are successfully authenticated 99.48% of the time and the false-positives are only 0.39%, over two attempts. We estimate that a legitimate user would have a computational advantage of more than 10(340) years over an attacker. Our method enables the discovery of physical key based multiparty authentication and communication schemes that are both practical and possess unprecedented security. PMID- 26525313 TI - Use of local anesthetic (0.25% bupivacaine) for pain control after pediatric cardiac catheterization: A randomized controlled trial. AB - OBJECTIVES: To investigate the effects of local infiltration of 0.25% bupivacaine on post-operative pain and analgesic use in children undergoing cardiac catheterization procedures. BACKGROUND: In pediatric catheterization procedures performed under general anesthesia, a local anesthetic is often used prior to femoral sheath removal. There are no published reports of the impact of local anesthetic infiltration on pain after pediatric procedures, and mixed reports on its effectiveness in adults. METHODS: A randomized controlled trial was undertaken of 140 children, aged 7-18 years undergoing cardiac catheterization under general anesthesia via the femoral vein or artery. Participants received a subcutaneous infiltration of 0.25% bupivacaine at the access site prior to sheath removal, or usual care without bupivacaine. Outcomes included patient reported pain scores and analgesic use up to 6 hr after the procedure. RESULTS: Pain scores were similar between groups through the 6-hr post-procedure period. The proportion of children reporting a maximal pain score of <=2/10 was higher in the bupivacaine group (64% vs. 44%, P = 0.03). A significantly higher proportion of children in the control group required IV morphine (18.8% vs. 4.5%, P = 0.02). CONCLUSIONS: Morphine use can be reduced with the use of 0.25% bupivacaine given prior to femoral sheath removal and should be considered for post-procedural pain control for pediatric patients undergoing cardiac catheterization. This study is the first to contribute evidence to the effectiveness of 0.25% bupivacaine after pediatric cardiac catheterization. PMID- 26525315 TI - Connecting learners: The role of biotechnology programme in preparing students for the industry. AB - The recent growth of biotechnology requires a wide range of expertise within the industry. Education is the primary platform for students to gain information and knowledge on biotechnology. In Malaysia where biotechnology is relatively new, education programs and courses must be tailored to meet the demands of the industry. A combination of theoretical knowledge as well as practical and industrial training is essential to ensure graduates are prepared for their career in the fields of biotechnology. Results from this study show that university students lack literacy on biotechnology information and access to facilities provided by the universities. This may be a significant contributing factor to the lack of knowledge and information amongst graduates. Furthermore comparative analysis on the biotechnology program in Malaysian universities with that of other countries show the need to restructure the program by offering more specialized courses as well as soft skills and business subjects. This is to meet the demands of the related professionals as well as the various branches that exist in the biotechnology industry. PMID- 26525316 TI - [The replacement of defects in the frontal walls of the paranasal sinuses by the allotransplants]. AB - The aim of the present work were the development and clinical testing of the method for the closure of defects in the anterior wallsof the frontal and maxillary sinuses with the use of the allotransplants. We have carried out the experimental studies with the transposition of the cartilaginous allograft into the bone defect by means of the press-fit technique. Within six months after the operation, the transplantation resulted in the formation of a regenerate composed of the lamellar bone tissue. We have also undertaken the clinical testing of the method forthe closure of defects in the anterior wallsof the frontal and maxillary sinuses using the cartilaginous allograft. In all the cases, the favourable clinical outcome has been achieved as evidenced by the integrity of the restored anterior wall of the sinus. PMID- 26525317 TI - [The comparative immunohistochemical characteristic of the pharyngeal tonsil under conditions of different environmental impacts]. AB - The objective of the present work was the comparative comprehensive immunohistochemical study of thepharyngeal tonsillar tissues taken from the children living in the regions of the Republic of Tatarstan (RT) differing in the degree of pollution of the atmospheric air. A total of 100 samples of hyperplastic adenoid vegetation tissuesdivided into three groups were available for the examination. Group 1 included pharyngeal tonsillar tissues obtained from the children (n=20) living in the regions of RT with the low level of atmospheric pollution. Groups 2 and 3 were composed of tissue samples from 48 and 32 children respectively living in the regions of TR with the moderate and high levels of environmental pollution. The analysis of the results obtained in this study demonstrated that the morphological changes in the hyperplastic pharyngeal tonsillar tissues depend on the strength of the environmental impacts. The lymphoid tissue was shown to respond to the effect of the ecopathological factors in the form of both non-specific stromal-vascular reactions and specific immunomorphological reactions. The former are apparent as microcirculatory disorders followed by sclerosis and the latter as the reduced intensity of the local immune response associated with inactivation of its T- and B-cellular components mediated through the changes in the monocytic-macrophagal system. PMID- 26525318 TI - [The prevention and treatment of nasal liquorrhea in transnasal surgery of the base of the skull]. AB - The objective of the present study was to estimate the effectiveness of different methods for the reconstruction of defects in the base of the skull. It was shown that the use of the modern technique for this purpose decreases the risk of the development of postoperative complications. The vascularized flaps can be applied to hermetically close defects in the base of the skull during surgery with the use of the extended transnasal approach. It is concluded that the proposed procedure accelerates the healing process and allows the flaps to be used repeatedly if necessary. PMID- 26525319 TI - [The state of vegetative homeostasis in the patients presenting with ronchopathy]. AB - The objective of the present work was the clinical and instrumental study of the vegetative nervous system in 25 patients of different age presenting with ronchopathy. The results of the study indicate the prevalence of the vagotonic type of primary vegetative tone and the specific features of vegetative reactivity differing from those in the control subjects (n=12). Moreover, all the patients were shown to have concomitant diseases of the upper respiratory tract. The data obtained give evidence of vegetative disbalance in the patientspresenting with ronchopathy which makes it necessary to design and develop new methods producing the vegetostabilizing effect for the treatment of snoring during sleep to be used together with other conservative and surgical methods. PMID- 26525320 TI - [The role of mycological culture studies in diagnostics of otomycoses]. AB - The present work was designed to analyze the results of themycological culture study involving 350 patients at the age varying from 14 to 75 years with the diagnosis otomycosis. The pathogenic fungi known to induce the clinical picture of otomycosiswere identified in 227 (64.8%) patients. The majority of the pathogeneticall most significant species belonged to the genus Candida (45.4%). The mold fungi occurred in 30.8% of the patients. In 11.5% of the cases, they occurred together with bacterial microflora and in 6.7% of the cases in association with the yeast fungi. The species of the genus Aspergillus prevailed among the mold fungi. It is concluded that the complicated forms of otomycosisdevelop as a result of infection caused not only by mold fungi but also by yeast fungi and/or associations of the two groups. These findings suggestthe necessity of usingthe differential approach to the prescription of the adequate medications. PMID- 26525321 TI - [Petrositis complicated by cavernous sinus thrombosis and meningitis]. PMID- 26525322 TI - [The speech audiometry test with the verbal tasks and motor responses]. AB - The objective of the present study was to estimate the possibility of using the Russian version of the speech audiometry test with the verbal tasks and motor responses (VTMR test) for the examination of the patients of the advanced and senile age suffering from hearing impairment and cognitive disorders. A total of 20 subjects at the age between 60 and 83 years were enrolled in the study. All of them presented with grade II-III bilateral symmetric chronic sensorineural hearing loss associated with mild cognitive disorders. The patients used the hearing aids. Twelve subjects aged 64-88 years presenting with the normal hearing threshold in both ears and mild cognitive impairment (25-27 points in the MMSE test) were included in the study to serve as controls. All the listeners underwent tonal threshold audiometry in combination with speech tests in a free acoustic field (perception of polysyllabic words and VTMR) and filled in the relevant questionnaires (MMSE and HHIE). The results of the study indicate that the VTMR test can be recommended for the evaluation of the effectiveness of hearing aids prescribed to the elderlysubjects and for the study of the auditory function in the patients presenting with cognitive disorders. PMID- 26525323 TI - [The clinical picture and specific microbiological features of acute otitis media]. AB - The objective of the present work was to study the spectrum of bacterial pathogenic agents responsible for the development of acute otitis media under present conditions and to elucidate the relationship between the pathogen species and the clinical course of the inflammatory process in the middle ear. A total of 60 patients of either sex at the age varying from 18 to 64 patients were available for the examination. All of them complained of ear pain, purulent discharge from the ears, hearing impairment, and general weakness. The following methods were employed: the analysis of the patients' complaints and their medical histories, visualexamination of the ENT organs, tonal threshold audiometry, tympanometry, and the analysis of secretion from the tympanic cavity using the real-time PCR technique. The study has demonstrated some regular patterns of the clinical manifestations of the disease depending on its causative agent. Specifically, it turned out that acute otitis media associated with the infection by Streptococcus pneumoniae is characterized by the more reactive clinical symptoms and the greater amount of complications compared with acute otitis media caused by Haemophilus influenzae that is largely a subclinical pathology. However, the latter condition more frequently leads to chronization of the pathological process. PMID- 26525324 TI - [The analysis of the influence of the adenoiditis treatment by different methods on the nasopharyngeal microbiocenosis in the children]. AB - The objective of the present study was to analyze the quality of nasopharyngeal sanation during the treatment of the children presenting with exacerbations of chronic adenoiditis with the use of different methods. Another objective was to estimate the influence of individual methods on the indigenous microflora. The study has revealed the prevailing groups of microflora in the nasopharynx, nasal cavity, and palatine tonsils of 2.228 patients. The clinical examination and comparative analysis of the results of the bacteriological study of nasopharyngeal discharge involved 170 children at the mean age of 5.06+/-2.6 years presenting with exacerbations of chronic adenoiditis. The patients of group 1 (n=60, control group) underwent nasopharyngeal sanation by means of the low frequency ultrasound treatment, those of group 2 (n=53) were given an oral antibiotics (amoxicillin/clavulanic acid) at an age-based dose during 7-10 days. The patients of group 3 (n=57) were treated with bacterial lysate OM-85 BV (Broncho-Vaxom) (a 3.5 mg capsule once daily in the morning hours under the fasting condition for 3 months (during 10 days of every month). The amount of anaerobic bacteria in the control cultures from the patients of group 1decreased six-fold and that of pneumococci by 3 times. In the children comprising group 2 all pathogenic species persisted despite the treatment whereas in group 3 the number of those species largely decreased whose lysates were contained in the medication. In the patients treated with Broncho-Vaxom the beneficial results of therapy 1 and 3 months after its onset were more apparent than in the children of two other groups. Moreover, this preparation did not affect the indigenous microflora. PMID- 26525325 TI - [The algorithm for laboratory diagnostics of chlamydial infection in the patients presenting with chronic sinusitis]. AB - The objective of the present study was to develop a system of laboratory diagnostics ofchlamydial infection in the mucous membrane of the nose and paranasal sinuses in the patients presenting with chronic sinusitis. A total of 168 subjects at the age varying from 18 to 65 years were available for the examination based at the Department of Otorhinolaryngologyduring the period of exacerbation of chronic sinusitis. Chlamydia were identified by simultaneously using two direct (polymerase chain reaction and direct immunofluorescence) and one indirect (immunoenzymatic assay) methods. The study has demonstrated the high degree of probability of the detection of chlamydial infection based on the above complex of the laboratory methods. It is concluded that the use of the proposed algorithm in practical medicine makes it possible to improve the quality of laboratory verification of chlamydial infection and thereby to choose the adequate diagnostic strategy for the patients suspected of having chlamydial infection and to evaluate the effectiveness of the therapeutic measures being taken. PMID- 26525326 TI - [The structure of childhood diseases in the patients presenting with hospital acquired ENT pathology estimated based on the results of monitoring children's hospitals in Moscow]. AB - The objective of the present work was to study the structure of childhood diseases in the patients presenting with hospital-acquired ENT pathology based at the results of analysis of the annual reports presented by the heads of departments of otorhinolaryngology of Moscow children's hospitals for the period from 2011 till 2013. It was shown that pharyngeal pathologies predominate among the children amounting to 43.9% of the total ENT morbidity. These conditions are followed by nose and paranasal sinus pathologies (29.2%), ear diseases (22.5%), laryngeal, bronchial and tracheal pathologies (4.4%). The analysis of the internal structure of different classes of diseases was made separately for the ear, throat, and nose (ICD-10). The results of the study give evidence of the tendency toward the higher incidence of selected forms of acute inflammatory diseases and chronic ENT pathologies in the childhood. PMID- 26525327 TI - [The use of the method of photodynamic therapy for the treatment of the patients presenting with primary and recurrent laryngeal cancer]. AB - The objective of the present study was to evaluate the effectiveness of the method of photodynamic therapy (PDT) for the treatment of the patients presenting with primary and recurrent laryngeal cancer. A total of 20 patients at the age from 46 to 82 (mean 61.3+/-7.5) years suffering from laryngeal cancer (17 men and 3 women) were available for the observation. PDT was based on the use of "Atkus" lasers (Russia) operated at a wavelength of 662 nm and a power up to 3 W as well as "Lagus" lasers(wavelength: 662 nm, power: up to 3 W). It was shown that the effective treatment of laryngeal cancer by PDT is possible under condition of the thorough selection of the patients with a definite growth type and localization of the tumour. Complete resorption (CR) was achieved in 100% of the patients with the early (I-II) stages of laryngeal cancer and in 90% of those having exophyticneoplasms less than 1 cm in size. Moreover, the beneficial effect of PDT was documented in the treatment of limited relapses of laryngeal cancer in tracheostoma following combined therapy. It is concluded that the proposed method can be recommended for the palliative care in order to reach homeostasis in the patients with extended bleeding tumours and also for the reduction of their volume andrecanalization of the trachea to improve the patients' quality of life. The authors maintain that PDT can be in many cases performed under the outpatient conditions. PMID- 26525328 TI - [The application of digital video-otoscopy for diagnostics of various forms of otitis in the children]. AB - Digital video-otoscopy (DVO) is one of the modern high-tech methods for otiatric diagnostics that allows to enlarge the image of the area being examined, i.e. the otoscopic picture. DVO has been shown to facilitate the objective dynamic observation of the clinical course of the disease by means of photo- and videodocumentation of he changes in the tympanic membrane and other otoscopicstructures. The DVO technique makes it possible to substantially improve the quality of diagnostics, detect the middle ear conditions at the early stagesof their alteration, and choose the optimal strategy for the continued conservative and/or surgical treatment. PMID- 26525329 TI - [The effectiveness of topical antihistamine monotherapy in the patients presenting with the manifestations of seasonal allergic rhinitis]. AB - The objective of the present study was to evaluate the effectiveness and safety of monotherapy with the use of allergoferon gel composed of topical recombinant human interferon-alpha-2beta and loratadine. A total of 105 patients at the age varying from 18 to 55 years presenting with the manifest form of seasonal allergic rhinitis were available for the examination. They were given the topical treatment in the recommended standard doses. The patients included in group 1 (n=65) were treated with allergoferon while those comprising group 3 (n=40) received mometasonefuorate (nasonex). Changes in the clinical symptoms were recorded on days 3, 7, 14, 21, and 28. The best results of the treatment were documented in the patients of group 1 on day 3 afterthe onset of therapy; this effect was attributed to the rapid beginning of the drug action that was apparent within15 minutes after the topical application of the medication. There were no significant difference between the manifestations of the symptoms on days 7 and 14 in the patients of both groups. None of the patients in group 1 refused to continue therapy up to day 28. Two patients in group 2 (5%) wished to discontinue the treatment due to side effects. It is concluded that the treatment with the allergoferon gel for the topical and external applications extends the possibilities for efficacious and safe therapy of the clinical manifestations of seasonal allergic rhinitis. PMID- 26525330 TI - [The place of mucoactuve therapy of rhinosinisitis in the international and Russian guidelines]. AB - The results of clinical studies giving evidence of the therapeutic effectiveness of the mucoactive preparations for the treatment of rhinosinusitis made it possible to introduce the herbal medicinal product Myrtol into the European position paper on rhinosinusitis and nasal polyps (EPOS 2012). It was shown that the intake of Myrtol standardized preparation accelerates the regress of clinical symptoms of the disease, decreases the requirement for antibiotic therapy, and reduces the period of disability as compared with the similar effects of placebo. PMID- 26525331 TI - [Early diagnostics of acoustic shwannoma]. PMID- 26525332 TI - [Chronic tonsillitis complicated by juvenile rheumatoid arthritis]. PMID- 26525333 TI - Effects of skim milk powder intake and treadmill training exercise on renal, bone and metabolic parameters in aged obese rats. AB - PURPOSE: we aim to examine whether adding exercise has impact on obesity prevention and bone metabolism in senior rats, to which dietary obesity was induced through skim milk intake. METHODS: We used 47, 14-week old Sprague Dawley (SD) female rats (CLEA Japan, Inc.). The Rats were separated into four random groups: 1) a Non-Ex group with a normal diet (n = 12), 2) an Ex group with a normal diet (n = 12), 3) a Non-Ex group with a skim milk diet (n = 11), and 4) an Ex group with a skim milk diet (n = 12). As the exercise for each Ex group, rats ran on a treadmill starting at 27-week old (TREADMILL CONTROL LE8710 and TREADMILL CONTROL LE8700, Harvard Bioscience). Training protocol stipulated a frequency of five times a week for 12 weeks. RESULTS: The leptin concentration differed with dietary content: compared to the Ex group with a skim milk diet, Non-Ex and Ex groups with a normal diet showed significantly higher values (p < 0.05). The Ex group had significantly lower values in both the normal diet and skim milk diet groups with or without exercise (p < 0.05). Compared to the Non-Ex group with a normal diet, BS/BV (mm(2)/mm(3)), BV/TV (%), Tb.Th (MUm), TBPf (/mm) and Tb.N (/mm) had significantly lower in the Ex group, the Ex and Non-Ex groups with a whey protein diet, and the Ex group with a skim milk protein diet (p < 0.05). CONCLUSION: These findings suggest that senior female rats fed SMP would have higher bone structural and strength parameters than rats fed a normal diet. PMID- 26525334 TI - Internal carotid artery injury in endoscopic endonasal surgery: A systematic review. AB - OBJECTIVES/HYPOTHESIS: Internal carotid artery (ICA) injury during endoscopic endonasal surgery (EES) is a known and feared complication of paranasal sinus and skull base procedures. These ICA injuries can result in stroke, cranial nerve palsies, and death. This review examines the setting of injury along with the treatment approaches, and patient outcomes. STUDY DESIGN: Systematic review using PubMed/MEDLINE and EMBASE. METHODS: The databases were searched for articles reporting cases of ICA injury during EES. Variables analyzed included patient demographics, operative approach, preoperative diagnosis, setting of injury, repair method, imaging studies, patient outcomes, and follow-up. RESULTS: Twenty five articles with 50 cases were included in this review. The EES approach was used for skull base procedures in 34 cases and for inflammatory disease in 16 cases. The most commonly injured ICA segment was the cavernous (34 cases), followed by the ophthalmic (three cases). Injuries occurred more commonly on the left (1.3:1). Injury occurred in the setting of various steps during EES with instruments. Stereotactic image guidance was reported in two cases. Initial hemostasis was achieved with packing in 35 cases, endoscopic clip sacrifice in four cases, bipolar coagulation with the intent to seal defect in three cases, and bipolar coagulation with the intent to sacrifice the ICA in one case. Intraoperative or immediate postoperative angiography was reported in 27 cases. CONCLUSIONS: The incidence of reported cases of ICA injury during EES remains low. Left-sided injuries to the cavernous segment of the ICA occurred more frequently than injuries on the right. LEVEL OF EVIDENCE: NA Laryngoscope, 126:582-590, 2016. PMID- 26525335 TI - Corrigendum. PMID- 26525337 TI - Physiologists Can Answer Big Questions. PMID- 26525338 TI - Use of Computer Simulations to Understand Female Physiology: Where's the Data? PMID- 26525339 TI - Physiology in Perspective: Why Do We Continue to Ignore Sex Differences? PMID- 26525341 TI - Skeletal Muscle Microvasculature: A Highly Dynamic Lifeline. AB - Skeletal muscle is highly irrigated by blood vessels. Beyond oxygen and nutrient supply, new vessel functions have been identified. This review presents vessel microanatomy and functions at tissue, cellular, and molecular levels. Mechanisms of vessel plasticity are described during skeletal muscle development and acute regeneration, and in physiological and pathological contexts. PMID- 26525340 TI - Sex and Gender Impact Immune Responses to Vaccines Among the Elderly. AB - In response to the recommended vaccines in older-aged individuals, sex differences occur in response to those that protect against influenza, tetanus, pertussis, shingles, and pneumococcal infections. The efficacy of vaccines recommended for older-aged adults is consistently greater for females than for males. Gender differences as well as biological sex differences can influence vaccine uptake, responses, and outcome in older-aged individuals, which should influence guidelines, formulations, and dosage recommendations for vaccines in the elderly. PMID- 26525342 TI - Integration of ChREBP-Mediated Glucose Sensing into Whole Body Metabolism. AB - Since glucose is the principal energy source for most cells, many organisms have evolved numerous and sophisticated mechanisms to sense glucose and respond to it appropriately. In this context, cloning of the carbohydrate responsive element binding protein has unraveled a critical molecular link between glucose metabolism and transcriptional reprogramming induced by glucose. In this review, we detail major findings that have advanced our knowledge of glucose sensing. PMID- 26525343 TI - Plasma Membrane Repair: A Central Process for Maintaining Cellular Homeostasis. AB - Plasma membrane repair is a conserved cellular response mediating active resealing of membrane disruptions to maintain homeostasis and prevent cell death and progression of multiple diseases. Cell membrane repair repurposes mechanisms from various cellular functions, including vesicle trafficking, exocytosis, and endocytosis, to mend the broken membrane. Recent studies increased our understanding of membrane repair by establishing the molecular machinery contributing to membrane resealing. Here, we review some of the key proteins linked to cell membrane repair. PMID- 26525345 TI - Kinetic Profiles of Inflammatory Mediators in the Conjunctival Sac Fluid of Patients upon Photorefractive Keratectomy. AB - Photorefractive keratectomy (PRK) represents a therapeutic option to remodel corneal stroma and to compensate refractive errors, which involves inflammatory and/or regenerative processes. In this context, the modulation of cytokines/chemokines in the conjunctival sac fluid and their role in the maintenance of the corneal microenvironment during the healing process upon refractive procedures has not been deeply investigated. In this study, serial samples of conjunctival sac fluid of patients (n = 25) undergoing PRK were harvested before and at different time points after surgery. The levels of 29 cytokines/chemokines/growth factors involved in inflammatory/immune processes were measured with a multiplex array system. The results have firstly highlighted the different pattern of cytokine expression between the microenvironment at the anterior surface of the eye and the systemic circulation. More importantly, the kinetic of modulation of cytokines/chemokines at the conjunctival level following PRK revealed that while the majority of cytokines/chemokines showed a significant decrease, MCP-1 emerged in light of its pronounced and significant increase soon after PRK and during the follow-up. This methodological approach has highlighted the role of MCP-1 in the healing process following PRK and has shown a potential for the identification of expression/modulation of soluble factors for biomarker profiling in ocular surface diseases. PMID- 26525344 TI - ASICs Mediate Pain and Inflammation in Musculoskeletal Diseases. AB - Chronic musculoskeletal pain is debilitating and affects ~ 20% of adults. Tissue acidosis is present in painful musculoskeletal diseases like rheumatoid arthritis. ASICs are located on skeletal muscle and joint nociceptors as well as on nonneuronal cells in the muscles and joints, where they mediate nociception. This review discusses the properties of different types of ASICs, factors affecting their pH sensitivity, and their role in musculoskeletal hyperalgesia and inflammation. PMID- 26525346 TI - Privacy-Preserving Data Sharing for Genome-Wide Association Studies. PMID- 26525347 TI - Neuropathic Pain Multiple Choice Questions. PMID- 26525348 TI - Targeted Therapy for MAPK Alterations in Pediatric Gliomas. AB - Although the mitogen-activated protein kinase (MAPK) pathway helps promote normal cell development, the pathway is known to contribute to the initiation and growth of many types of cancers. Tumorigenesis can result from mutations in a number of the pathway's key proteins, including but not limited to RAS, any one of the three RAF kinases, or MEK1/2. Moreover, by discovering and understanding the biology of oncogenic mutations, scientists can develop novel targeted therapies. This review describes the general history of such targeted therapies in the context of pediatric gliomas. We first describe the biology of gliomas and oncogenic mutations in the MAPK pathway and then summarize notable pre-clinical data and clinical trials for these targeted therapies. PMID- 26525351 TI - Endobronchial recurrence of non-Hodgkin's lymphoma mimicking foreign body aspiration. AB - A 2-year-old patient with a history of non-Hodgkin's lymphoma (NHL) was presented to our hospital with the complaint of shortness of breath and wheezing. Posteroanterior chest radiograph revealed hyperlucency and hyperexpansion of the right hemithorax. We performed computed tomography (CT) because of a suspicion of foreign body aspiration. CT revealed right main bronchus occlusion by a hypodense lesion. Bronchoscopy revealed a mass lesion in the right main bronchus which was histopathologically diagnosed as NHL. Only a few cases of endobronchial recurrence of lymphoma have been reported in the current literature, but there is no reported case in a pediatric patient. PMID- 26525350 TI - Computer-aided design of carbon nanotubes with the desired bioactivity and safety profiles. AB - Growing experimental evidences suggest the existence of direct relationships between the surface chemistry of nanomaterials and their biological effects. Herein, we have employed computational approaches to design a set of biologically active carbon nanotubes (CNTs) with controlled protein binding and cytotoxicity. Quantitative structure-activity relationship (QSAR) models were built and validated using a dataset of 83 surface-modified CNTs. A subset of a combinatorial virtual library of 240 000 ligands potentially attachable to CNTs was selected to include molecules that were within the chemical similarity threshold with respect to the modeling set compounds. QSAR models were then employed to virtually screen this subset and prioritize CNTs for chemical synthesis and biological evaluation. Ten putatively active and 10 putatively inactive CNTs decorated with the ligands prioritized by virtual screening for either protein-binding or cytotoxicity assay were synthesized and tested. We found that all 10 putatively inactive and 7 of 10 putatively active CNTs were confirmed in the protein-binding assay, whereas all 10 putatively inactive and 6 of 10 putatively active CNTs were confirmed in the cytotoxicity assay. This proof of-concept study shows that computational models can be employed to guide the design of surface-modified nanomaterials with the desired biological and safety profiles. PMID- 26525352 TI - Transurethral resection of intravesical synthetic mesh extrusion with an electrode loop following anterior vaginal mesh surgery: a case report. PMID- 26525353 TI - Decreased expression of miR-20a and miR-92a in the serum from sulfur mustard exposed patients during the chronic phase of resulting illness. AB - CONTEXT: Sulfur mustard (SM), with extensive nucleophilic and alkylating properties, was employed during the Iran-Iraq war by Iraqi forces. The most critical complications attributed to SM are related to dangerous pulmonary disorders collectively known as "mustard lung". The symptoms gradually emerge over a long period, becoming chronic, and are dependent on time and the amount of exposed SM. Because of the unknown and complex nature of the disease, no differential diagnostic method or absolute treatment strategy has been formally developed. OBJECTIVE: The aim of our study was to determine the expression pattern of the microRNAs (miRNAs) miR-92a and miR-20a in the serum of patients with mustard lung along with that of normal individuals. miRNAs have been shown to possess stable persistence in biofluids like plasma and serum and are considered non-aggressive biomarkers helpful for diagnosis and treatment of many diseases. MATERIALS AND METHODS: A highly sensitive approach called stem-loop real-time quantitative polymerase chain reaction was employed to study the expression of miRNAs. RESULTS: The expression of miR-92a and miR-20a was significantly down-regulated in the serum of patients with mustard lung compared to the control group. DISCUSSION: Down-regulation of miR-92a and miR-20a may be due to chronic epigenetic alterations after SM exposure, which finally leads to changes in vital cellular processes such as differentiation, proliferation and so forth. CONCLUSION: Our findings may provide a differential diagnostic method that is effective for diagnosing lung diseases caused by SM exposure. Additionally, these miRNAs may be regarded as probable targets for treatment of lung injuries. PMID- 26525354 TI - A Greek girl with 11beta-hydroxylase deficiency due to compound heterozygosity for two novel mutations in CYP11B1 gene. AB - 11beta-hydroxylase deficiency (11beta-OHD), an autosomal recessive inherited disorder, accounts for 5-8% of congenital adrenal hyperplasia. In Greece, no cases of 11beta-OHD have been described so far. The patient presented at the age of 13 months with mild virilization of external genitalia and pubic hair development since the age of 3 months. Hormonal profile showed elevated 11 deoxycortisol, adrenal androgens and ACTH levels. ACTH stimulation test was compatible with 11beta-OHD. DNA of the proband and her parents was isolated and genotyped for CYP11B1 gene coding cytochrome P450c11. The girl was found to be compound heterozygous for two CYP11B1 novel mutations, p.Ala386Glu (exon 7), inherited from the father and p.Leu471Argin (exon 9) from the mother. Hydrocortisone supplementation therapy was initiated. Four years after presentation she remains normotensive, her growth pattern is normal and the bone age remains advanced despite adequate suppression of adrenal androgens. LEARNING POINTS: 11beta-hydroxylase (CYP11B1) deficiency (11OHD; OMIM +202010) is the second most common cause of CAH accounting for approximately 5-8% of cases with an incidence of 1:100 000-1:200 000 live births in non-consanguineous populations.Two CYP11B1 inactivating novel mutations, p.Ala386Glu and p.Leu471Arg are reportedRegarding newborn females, in utero androgen excess results in ambiguous genitalia, whereas in the male newborn diagnosis may go undetected. In infancy and childhood adrenal androgen overproduction results in peripheral precocious puberty in boys and various degrees of virilization in girls.Accumulation of 11-deoxycorticosterone and its metabolites causes hypertension in about two thirds of patients.Diagnosis lies upon elevated 11 deoxycortisol and DOC plus upstream precursors, such as 17alpha hydroxyprogesterone and Delta4-androstenedione.The established treatment of steroid 11beta-OHD is similar to that of steroid 21-hydroxylase deficiency and consists of glucocorticoid administration in order to reduce ACTH-driven DOC overproduction resulting in hypertension remission and improvement of the virilization symptoms. PMID- 26525355 TI - Distance-responsive predation is not necessary for the Janzen-Connell hypothesis. AB - The Janzen-Connell hypothesis states that tree diversity in tropical forests is maintained by specialist predators that are distance- or density-responsive (i.e. predators that reduce seed or seedling survival near adults of their hosts). Many empirical studies have investigated whether predators are distance-responsive; however, few studies have examined whether distance-responsiveness matters for how predators maintain tree diversity. Using a site-occupancy model, we show analytically that distance-responsive predators are actually less able to maintain diversity than specialist predators that are not distance-responsive. Generally, specialist predators maintain diversity because they become rare when their host's densities are low, reducing predation risk. However, if predators are distance-responsive, and most seeds cannot disperse away from these predators, then seed predation rates will remain high, even if predator density is low across the landscape. Consequently, a reduction in a host's population density may not lead to a significant reduction in seed and seedling predation. We show that habitat partitioning can cause recruitment to be highest near conspecific adults, even in the presence of distance-responsive predators, without any change in the effect that the predators have on coexistence (a result contrary to predictions of the Janzen-Connell hypothesis). Rather, specialist predators and habitat partitioning have additive effects on species coexistence in our model, i.e., neither mechanism alters the effect of the other one. PMID- 26525356 TI - Let's not forget about injury. PMID- 26525357 TI - Editorial. PMID- 26525358 TI - The behaviour of monazite from greenschist facies phyllites to anatectic gneisses: An example from the Chugach Metamorphic Complex, southern Alaska. AB - Monazite is a common accessory mineral in various metamorphic and magmatic rocks, and is widely used for U-Pb geochronology. However, linking monazite U-Pb ages with the PT evolution of the rock is not always straightforward. We investigated the behaviour of monazite in a metasedimentary sequence ranging from greenschist facies phyllites into upper amphibolites facies anatectic gneisses, which is exposed in the Eocene Chugach Metamorphic Complex of southern Alaska. We investigated textures, chemical compositions and U-Pb dates of monazite grains in samples of differing bulk rock composition and metamorphic grade, with particular focus on the relationship between monazite and other REE-bearing minerals such as allanite and xenotime. In the greenschist facies phyllites, detrital and metamorphic allanite is present, whereas monazite is absent. In lower amphibolites facies schists (~ 550-650 degrees C and >= 3.4 kbar), small, medium Y monazite is wide-spread (Mnz1), indicating monazite growth prior and/or simultaneous with growth of garnet and andalusite. In anatectic gneisses, new low Y, high-Th monazite (Mnz2) crystallised from partial melts, and a third, high-Y, low-Th monazite generation (Mnz3) formed during initial cooling and garnet resorption. U-Pb SHRIMP analysis of the second and third monazite generations yields ages of ~ 55-50 Ma. Monazite became unstable and was overgrown by allanite and/or allanite/epidote/apatite coronas within retrograde muscovite- and/or chlorite-bearing shear zones. This study documents polyphase, complex monazite growth and dissolution during a single, relatively short-lived metamorphic cycle. PMID- 26525359 TI - Isorhamnetin protects mice from lipopolysaccharide-induced acute lung injury via the inhibition of inflammatory responses. AB - OBJECTIVE AND DESIGN: Isorhamnetin (Isor), a 3-O-methylated metabolite of quercetin, has shown antioxidant and anti-proliferative effects in previous studies. In this study, we investigated the anti-inflammatory effect of Isor on LPS-induced acute lung injury (ALI). Accordingly, we evaluated the effect of Isor on cytokine production elevated by LPS (1 MUg/ml) in vitro. An in vivo ALI murine model was also established via lipopolysaccharide inhalation (LPS, 20 mg/kg), and the cytokine levels and inflammatory cell count in bronchoalveolar lavage fluid (BALF) were evaluated. The observed lung injury was assessed using histopathologic sections via H&E straining. Furthermore, to investigate whether the anti-inflammatory effect of Isor is associated with NF-kappaB and MAPKs pathway activation, the phosphorylated levels of ERK, JNK, IkappaBa and NF kappaB(p65) were determined. RESULTS: Isor significantly inhibited LPS-induced TNF-alpha, IL-1beta and IL-6 secretion both in vitro and in vivo. Neutrophil infiltration and edema in an ALI model were substantially alleviated. The histopathological changes induced by LPS were lessened by Isor. Additionally, Isor notably suppressed the phosphorylation of ERK, JNK, IkappaBa and NF kappaB(p65) activated by LPS in vivo. CONCLUSIONS: Isor showed efficient protective effects on an LPS-induced ALI model. MAPKs and NF-kappaB pathways are critical for Isor to perform its protective effects. PMID- 26525360 TI - Diazoxide protects L6 skeletal myoblasts from H2O2-induced apoptosis via the phosphatidylinositol-3 kinase/Akt pathway. AB - OBJECTIVES AND DESIGN: Transplanted cell survival might greatly improve the therapeutic efficacy of cell therapy. Diazoxide (DZ), a highly selective mitochondrial ATP-sensitive potassium channel opener, is known to suppress cell apoptosis and protect cells in oxidative stressed ischemic environment. We explored the mechanisms involved in DZ pre-treatment-induced anti-apoptotic effect on L6 skeletal myoblast (SKM). MATERIALS AND METHODS: L6 SKMs were divided into control group, H2O2 group, DZ + H2O2 group and DZ + LY + H2O2 group. Treatments of 400 MUmol/L H2O2 for 24 h alone, or after 200 MUmol/L DZ pre treatment for 30 min, or after DZ and 50 MUmol/L LY294002 co-administration for 30 min were performed. The cell apoptosis rates were assessed by flow cytometric analysis. The changes of mitochondrial membrane potential were determined by JC-1 mitochondrial staining. The activation of phosphatidylinositol-3 kinase (PI3K)/Akt, caspase-9 and caspase-3 was detected by western blot. RESULTS: Compared with the H2O2 group, DZ pre-treatment protected cells from H2O2-induced damage, increased Akt phosphorylation, prevented mitochondrial membrane depolarization as well as the activation of caspase-9 and caspase-3 and decreased the cell apoptosis rate. However, the DZ-induced cytoprotective and anti apoptosis effects were partly inhibited by co-administration of a PI3K inhibitor, LY294002. CONCLUSIONS: These data suggest that DZ pre-treatment contributes to protection of L6 SKMs against apoptosis at least partly by activating the PI3K/Akt pathway and subsequently inhibiting the mitochondrial-mediated caspase dependent apoptotic signalling pathway. PMID- 26525361 TI - Crude oil as a microbial seed bank with unexpected functional potentials. AB - It was widely believed that oil is a harsh habitat for microbes because of its high toxicity and hydrophobicity. However, accumulating evidence has revealed the presence of live microbes in crude oil. Therefore, it's of value to conduct an in depth investigation on microbial communities in crude oil. To this end, microorganisms in oil and water phases were collected from four oil-well production mixtures in Qinghai Oilfield, China, and analyzed for their taxonomic and functional compositions via pyrosequencing and GeoChip, respectively. Hierarchical clustering of 16S rRNA gene sequences and functional genes clearly separated crude oil and water phases, suggestive of distinct taxonomic and functional gene compositions between crude oil and water phases. Unexpectedly, Pseudomonas dominated oil phase where diverse functional gene groups were identified, which significantly differed from those in the corresponding water phases. Meanwhile, most functional genes were significantly more abundant in oil phase, which was consistent with their important roles in facilitating survival of their host organisms in crude oil. These findings provide strong evidence that crude oil could be a "seed bank" of functional microorganisms with rich functional potentials. This offers novel insights for industrial applications of microbial-enhanced oil recovery and bioremediation of petroleum-polluted environments. PMID- 26525362 TI - Dual stoichiometry and subunit organization in the ClpP1/P2 protease from the cyanobacterium Synechococcus elongatus. AB - The Clp protease is conserved among eubacteria and most eukaryotes, and uses ATP to drive protein substrate unfolding and translocation into a chamber of sequestered proteolytic active sites. To investigate the proteolytic core of the ClpXP1/P2 protease from the cyanobacterium Synechococcus elongatus we have used a non-denaturing mass spectrometry approach. We show that the proteolytic core is a double ring tetradecamer consisting of an equal number of ClpP1 and ClpP2 subunits with masses of 21.70 and 23.44 kDa, respectively. Two stoichiometries are revealed for the heptameric rings: 4ClpP1+3ClpP2 and 3ClpP1+4ClpP2. When combined in the double ring the stoichiometries are (4ClpP1+3ClpP2)+(3ClpP1+4ClpP2) and 2*(3ClpP1+4ClpP2) with a low population of a 2*(4ClpP1+3ClpP2) tetradecamer. The assignment of the stoichiometries is confirmed by collision-induced dissociation of selected charge states of the intact heptamer and tetradecamer. Presence of the heterodimers, heterotetramers and heterohexamers, and absence of the mono-oligomers, in the mass spectra of the partially denatured protease indicates that the ring complex consists of a chain of ClpP1/ClpP2 heterodimers with the ring completed by an additional ClpP1 or ClpP2 subunit. PMID- 26525363 TI - Evidence of brainstem dysfunction in patients with familial dysautonomia and carriers of the IKBKAP mutation. PMID- 26525364 TI - Neurophysiological correlates of motor deficits in patients in Benign Epilepsy with Centro-Temporal Spikes. PMID- 26525365 TI - A self-assessment efficacy tool for spermicide contraceptive users. AB - BACKGROUND: Easily accessible contraceptive methods, such as chemical and barrier methods, are used currently by approximately 1 in 6 women who use contraception in the United States. Even in the face of suboptimal effectiveness, coitally dependent methods likely will always have a role in fertility management. Because most contraceptive efficacy stratifications use population-based data, for women to make informed decisions about the individual fit of a contraceptive method, better evidence-based, user-friendly tools are needed. OBJECTIVES: Spermicides are a readily available, over-the counter, woman-controlled contraceptive method, but their effectiveness is user-dependent. Patient-decision aids for spermicides and other barrier methods are not well-developed, and overall failure rates could be improved by aids that account for individual characteristics. We sought to derive a prediction rule for successful use of spermicides for pregnancy prevention and to convert those data to a point-of-care instrument that women can use when they are considering spermicide use during contraceptive decision making. STUDY DESIGN: We pooled local data from 3 randomized clinical trials that were published in 2004, 2007, and 2010 that tested spermicide efficacy. We constructed a prediction rule for unintended pregnancy using bootstrap validation and developed a scoring system. RESULTS: Data from 621 women showed a mean age of 29 years; 49% of the women were African American, and 43% were white. The overall pregnancy rate was 10.3% (95% confidence interval, 7.9-12.7) over 6 months. In adjusted logistic regression, age >35 years was protective against pregnancy (odds ratio, 0.19; 95% confidence interval, 0.06-0.58; P = .003), and multigravidity was associated with high failure rates (odds ratio, 7.24; 95% confidence interval, 3.04-17.3; P < .001). These risk factors (together with frequency of unprotected sex) were used in a model that maximized sensitivity for pregnancy prediction to compute the predicted probability of unintended pregnancy for each woman. This model was 97% accurate in predicting women who had a <5% pregnancy risk while using spermicides. CONCLUSION: Using prospectively collected data, we built a simple risk calculator for contraceptive failure that women can consult when considering spermicide use. This instrument could support patient centered contraceptive decision-making. PMID- 26525366 TI - What's in a learning environment? Recognizing teachers' roles in shaping a learning environment to support competency. PMID- 26525367 TI - Technique or technology? Evaluating leaks after gastric bypass. AB - OBJECTIVE: To assess the relationship between technique and surgical devices on anastomotic and staple-line leaks after laparoscopic Roux-en-Y gastric bypass. BACKGROUND: Leaks after bariatric surgery remain a major source of morbidity and mortality. The association of surgical technique and devices with leaks after gastric bypass is poorly understood. SETTING: Multi-centered study that included teaching and non-teaching hospitals that participate in a statewide consortium for quality improvement using a payer-funded outcome registry. METHODS: We analyzed data from the Michigan Bariatric Surgery Collaborative and performed a case-control study comparing patients who sustained a leak with those who did not after primary laparoscopic Roux-en-Y gastric bypass. A total of 71 (.44%) patients with leaks were identified between January 2007 and December 2011. The leak group was matched 1:2 to a control group (nonleak) based on procedure type, age, body mass index, sex, and the year in which the procedure was performed. Technique-specific case characteristics and device-specific factors were assessed by reviewing operative notes from all primary bariatric procedures in our study population. RESULTS: The rate of leak decreased during the study period, and there was a significant downward trend (slope estimate: -.19961%, P = .0372). After performing multivariate analysis, the type of anastomosis (circular stapler, hand-sewn, or linear stapler) and stapler manufacturer were not associated with leaks. The use of buttressing material was associated with a higher rate of leaks (odds ratio: 8.79 [95% confidence interval: 2.49-31.01], P = .0007), whereas the use of fibrin sealant was associated with a lower rate of leaks (odds ratio .11 [95% confidence interval: .03-.41], P = .0013). These findings could not be explained by differences in measures of surgeon performance. CONCLUSION: Leak rates after laparoscopic gastric bypass have fallen in Michigan despite variations in technique and device utilization. Although the type of anastomosis and stapler manufacturer do not appear to be significantly associated with leaks, it appears that the use of buttressing material was more common in cases in which leaks occurred, whereas the use of fibrin sealant was not. Given the complex interplay of multiple variables that affect surgical outcomes, future studies justifying the benefits of operative devices should be evaluated prospectively in the context of surgeon technique and skill. PMID- 26525368 TI - Psychological predictors of body image concerns 3 months after bariatric surgery. AB - BACKGROUND: Although studies have associated postoperative weight loss with improvement in body image dissatisfaction, some individuals continue to report body image concerns after bariatric surgery. These concerns are linked to increased depressive symptoms and decreased self-esteem in bariatric populations. OBJECTIVE: This study sought to explore preoperative factors that may predict early body image concerns 3 months after bariatric surgery. SETTING: Academic medical center. METHOD: Data were analyzed from 229 patients evaluated for bariatric surgery who completed a 3-month postoperative psychology appointment and the Minnesota Multiphasic Personality Inventory, Second Edition, Restructured Form (MMPI-2-RF). Scales measuring depression, persecution, self-doubt, and inadequacy were examined. Medical records were reviewed for demographic characteristics, psychotropic medication usage, history of psychological treatment, and current or lifetime depression diagnosis. RESULTS: Patients who preoperatively scored higher on demoralization (F [1, 227] = 35.40, P< .001), low positive emotions (F [1, 227] = 4.18, P< .05), ideas of persecution (F [1, 227] = 15.24, P< .001), self-doubt (F [1, 227] = 27.47, P< .001), and inefficacy (F [1, 227] = 21.34, P< .001) were significantly more likely to report body image concerns 3 months after bariatric surgery. Similarly, body image concerns were more common in patients with a preoperative depression diagnosis (chi(2) = 8.76, P<.01), current psychotropic medication usage (chi(2) = 7.13, P<.01), and history of outpatient therapy (chi(2) = 8.34, P<.01) and psychotropic medication (chi(2) = 9.66, P< .001). CONCLUSION: Bariatric surgery candidates with psychopathology and other psychological risk factors are more likely to report body image concerns early after bariatric surgery. Future research is warranted to determine whether this association remains further out from surgery. PMID- 26525369 TI - Randomized trial of OFIRMEV versus placebo for pain management after laparoscopic sleeve gastrectomy. AB - BACKGROUND: OFIRMEV is an intravenous form of acetaminophen approved by the Food and Drug Administration for use as an antipyretic and treatment of mild to moderate pain alone or in conjunction with opioid medications. Intravenous APAP use in postsurgical pain management has been reported to decrease opioid usage, time to rescue dose, and subjective pain. OBJECTIVES: We used a placebo controlled, randomized double-blind study to test the efficacy of OFIRMEV in decreasing opioid use and subjective pain after laparoscopic sleeve gastrectomy. SETTING: U.S. military training hospital. METHODS: Thirty-four patients who met criteria were enrolled and randomly assigned to 2 separate limbs of the study. The OFIRMEV and placebo groups had similar mean age ranges (48+/-11 and 50+/-11 yr) and a female/male ratio of 5:1 and 6:1, respectively. The patients received an intraoperative dose and then postoperative administration of intravenous OFIRMEV 1 g or placebo every 6 hours for 24 hours in addition to fentanyl via patient-controlled analgesia. Subjective pain scores, the total amount of fentanyl used, time to rescue of first narcotic dose, and total postanesthesia care unit (PACU) narcotic use were measured during the first 24 hours after surgery. RESULTS: Subjective pain score was significantly decreased compared with baseline at 12, 16, and 20 hours after surgery in OFIRMEV-treated patients but not in the placebo group. However, total narcotic use, time to rescue of first narcotic dose, and total PACU narcotic dose were not statistically different between the 2 groups. CONCLUSION: Intravenous OFIRMEV use caused a modest but statistically significant decrease in subjective pain without affecting narcotic use after laparoscopic sleeve gastrectomy. (Surg Obes Relat Dis 2015;0:000-00.) (c) 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved. PMID- 26525370 TI - Repeat sleeve gastrectomy for the treatment of incomplete sleeve gastrectomy. PMID- 26525371 TI - Bariatric surgery acutely changes the expression of inflammatory and lipogenic genes in obese adipose tissue. AB - BACKGROUND: Adipose tissue of obese subjects is known to exhibit increased inflammatory activity linked to altered expression of factors involved in glucose and lipid metabolism. The surgical procedure constitutes an injury per se, evoking a systemic inflammatory response. OBJECTIVE: To evaluate changes in the expression of key-genes in adipose tissue after common surgical procedures performed in obese patients. SETTING: A tertiary hospital. METHODS: Paired subcutaneous (SAT) and visceral (VAT) adipose tissue samples were collected at the beginning and the end of surgery in 33 obese patients that underwent laparoscopic Roux-en-Y gastric bypass (RYGB, n = 17) or laparoscopic vertical sleeve gastrectomy (SG, n = 16). The expression of genes involved in inflammation, glucose and lipid metabolism was assessed. RESULTS: The surgical procedure led to increased expression of interleukin 6, interleukin 8 (P<.0001 in both depots), tumor necrosis factor alpha (P = .001 in SAT), and lipopolysaccharide binding protein (P = .0004 in VAT). Surgery also induced concomitant decreased expression of GLUT4, IRS1 (P = .046 in VAT), and adiponectin, whereas the messenger RNA of lipogenic genes [fatty acid synthase (P = .024); sterol regulatory element binding transcription factor 1 (P = .011) and aquaporin 9 (P<.0001) in SAT; and PPARgamma (P = .018) and solute carrier family 27 (fatty acid transporter), member 2 (P = .028) in VAT] increased in parallel to inflammation. Changes in gene expression during surgery were enhanced in patients following RYGB, when compared with SG. CONCLUSIONS: Bariatric surgery acutely changes the expression of inflammatory and lipogenic genes in adipose tissue. This information should be considered cautiously when designing studies to assess adipose tissue gene expression in morbidly obese patients. The same timing of sampling is mandatory. PMID- 26525372 TI - Body composition changes in adolescents after laparoscopic sleeve gastrectomy. AB - BACKGROUND: Sleeve gastrectomy (SG) is a commonly used bariatric procedure in severely obese adolescents. Weight loss after SG is associated with marked changes in body composition, but factors associated with such changes have not yet been described in adolescents. OBJECTIVE: To identify factors associated with changes in body weight and composition in adolescents 1 year after SG. SETTING: University Hospital, Tel Hashomer, Israel. METHODS: Age, sex, weight, height, preoperative body mass index (BMI), and body fat percent measured by bioimpedance were collected in 25 adolescents (16 males, 9 females, age 16.6+/-1.5 yr) before and 1 year after SG. Obesity-related complications, preoperative weight loss, and physical activity after surgery were also recorded. Repeated-measures analyses of variance and linear mixed model analyses were performed. RESULTS: One year after SG, weight decreased by 32%, fat mass by 55%, and fat-free mass by 9% from baseline. Male participants lost significantly more weight than female participants, with larger decreases in fat mass (-65% versus -41%, P<.001) and body fat percent (-48% versus -21%, P<.001). The amount of physical activity at 1 year follow-up was also associated with larger reductions in body fat percent in both genders. Age or baseline BMI, fat mass, and fat-free mass were not associated with changes in BMI or body composition. CONCLUSION: Among obese adolescents 1 year after SG, the only modifiable factor associated with larger decreases in body fat percent was physical activity. Larger studies are needed to formally identify other possible predictors of body composition changes after SG. PMID- 26525373 TI - Histidine-rich glycoprotein and idiopathic pulmonary fibrosis. AB - Histidine-rich glycoprotein (HRG) is an enigmatic glycoprotein able to interact with a variety of ligands such as IgG, complement components, heparan sulfate, thrombospondin, fibrinogen and plasminogen. HRG is present at high concentrations in plasma and there is evidence indicating that it is able to modulate the course of biological processes such as angiogenesis, fibroblast proliferation, complement activation, coagulation and fibrinolysis. Because these processes are involved in the pathogeneses of lung fibrosis we here analyzed a possible link between HRG and idiopathic pulmonary fibrosis (IPF). We found that plasma concentrations of HRG are significantly diminished in IPF patients compared to healthy subjects. Moreover, we found a positive correlation between HRG plasma levels and forced vital capacity (FVC) values, suggesting that plasma concentration of HRG would be a useful indicator of disease activity in IPF. HRG has been described as a negative acute phase reactant able to accumulate at sites of tissue injury. Hence, we also measured the concentrations of HRG in BAL samples from IPF patients. We found that the concentrations of HRG in samples from IPF patients were significantly higher compared to controls, suggesting that the reduced concentration of HRG in plasma from IPF patients could be due, at least in part, to an enhanced uptake of this protein in the lung. PMID- 26525374 TI - Understanding asthma-chronic obstructive pulmonary disease overlap syndrome. AB - Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is a loosely defined clinical entity referring to patients who exhibit characteristics of both asthma and chronic obstructive pulmonary disease (COPD). Clinical definitions and classifications for ACOS vary widely, which impacts our understanding of prevalence, diagnosis and treatment of the condition. This literature review was therefore conducted to characterize the prevalence of ACOS and the effect of different disease definitions on these estimates, as this has not previously been explored. From an analysis of English language literature published from 2000 to 2014, the estimated prevalence of ACOS ranges from 12.1% to 55.2% among patients with COPD and 13.3%-61.0% among patients with asthma alone. This variability is linked to differences in COPD and asthma diagnostic criteria, disease ascertainment methods (spirometry-based versus clinical or symptom-based diagnoses and claims data), and population characteristics including age, gender and smoking. Understanding the reasons for differences in prevalence estimates of ACOS across the literature may help guide decision making on the most appropriate criteria for defining ACOS and aid investigators in designing future ACOS clinical studies aimed at effective treatment. PMID- 26525375 TI - Pulmonary manifestations of renal cell carcinoma. AB - Renal cell carcinoma (RCC) accounts for majority of all primary renal neoplasms. Classic manifestations of RCC include the triad of flank pain, hematuria and a palpable renal mass. Patients with RCC can develop various extra renal manifestations including involvements of the lungs, inferior vena cava, liver and the bones. The pulmonary manifestations of renal cell carcinoma include metastatic disease including endobronchial, pleural, parenchymal or lymph node metastasis, pleural effusion or hemothorax. Pulmonary embolism and tumor embolism is another common manifestation of renal cell carcinoma. RCC is a highly vascular tumor and can cause pulmonary arterio-venous fistulas leading to high output failure. Rarely, RCC can also present with paraneoplastic presentations including cough or bilateral diaphragm paralysis. Drugs used to treat RCC have been associated with drug related pneumonitis and form an important differential diagnosis in patients with RCC on therapy presenting with shortness of breath. In this review we discuss the various pulmonary manifestations of RCC. A high index of suspicion with these presentations can lead to an early diagnosis and assist in instituting an appropriate intervention. PMID- 26525376 TI - [MUW researcher of the month]. PMID- 26525377 TI - Clinical Practice Guideline for the prevention and early detection of breast and ovarian cancer in women from HBOC (hereditary breast and ovarian cancer) families. AB - An estimated 10% of breast cancer cases exhibit a higher familial incidence, and functional mutations in BRCA (breast cancer-gene) 1 or 2 are responsible for the development of malignant tumors in approximately half of these cases. Women with a germline mutation in either of the two genes have a lifetime risk of up to 85% to develop breast cancer, and of up to 60% risk to develop ovarian cancer. This clinical practice guideline defines the individual and familial tumor constellations that represent an indication for BRCA germline testing. It also describes the therapeutic options (early detection programme vs prophylactic surgery) that arise from the result of a BRCA mutational analysis. This guideline further includes recommendations regarding the use of multigene panels and therapeutic aspects that arise from the selective use of poly ADP ribose polymerase (PARP) inhibitors in patients with known BRCA1 or 2 mutations. It replaces the previous version of the "Clinical Practice Guideline for the Prevention and Early Detection of Breast- and Ovarian Cancer in women from HBOC (hereditary breast and ovarian cancer) families" which was published in 2012. PMID- 26525378 TI - [Treatment of haemophilia in Austria]. AB - This guideline which is endorsed by the Austrian Society of Haemophilia, the Austrian Society of Paediatrics, and the Austrian Society of Haematology & Medical Oncology is intended to give a clear and practical guidance for diagnosing and treating haemophilia in Austria. In the treatment of haemophilia there are few controlled interventional trials, and recommendations usually have a rather low level of evidence.The main basis for this paper are the new international guidelines by the World Federation of Hemophilia, published in 2013. These were adapted according to the local situation and experience.Covered topics are diagnostics, control visits, pharmacological treatment options, prophylaxis and treatment in children and adults, possible problems arising in haemophilia carriers and special aspects like home therapy, options for venous catheters, management of various traumas, bleedings and interventions, including dental procedures, and last not least inhibitors and their treatment. PMID- 26525379 TI - Deleterious effects of lard-enriched diet on tissues fatty acids composition and hypothalamic insulin actions. AB - Altered tissue fatty acid (FA) composition may affect mechanisms involved in the control of energy homeostasis, including central insulin actions. In rats fed either standard chow or a lard-enriched chow (high in saturated/low in polyunsaturated FA, HS-LP) for eight weeks, we examined the FA composition of blood, hypothalamus, liver, and retroperitoneal, epididymal and mesenteric adipose tissues. Insulin-induced hypophagia and hypothalamic signaling were evaluated after intracerebroventricular insulin injection. HS-LP feeding increased saturated FA content in adipose tissues and serum while it decreased polyunsaturated FA content of adipose tissues, serum, and liver. Hypothalamic C20:5n-3 and C20:3n-6 contents increased while monounsaturated FA content decreased. HS-LP rats showed hyperglycemia, impaired insulin-induced hypophagia and hypothalamic insulin signaling. The results showed that, upon HS-LP feeding, peripheral tissues underwent potentially deleterious alterations in their FA composition, whist the hypothalamus was relatively preserved. However, hypothalamic insulin signaling and hypophagia were drastically impaired. These findings suggest that impairment of hypothalamic insulin actions by HS-LP feeding was not related to tissue FA composition. PMID- 26525380 TI - Reply. PMID- 26525381 TI - How Secure Are We? Radiology Resident Use and Storage of Protected Health Information. PMID- 26525382 TI - An Aspect of Radiology Worth Considering. PMID- 26525383 TI - Equanimity, Ambiguity, and the Physician's Task. PMID- 26525384 TI - Pyoderma Gangrenosum After Enzymatic Debridement. PMID- 26525385 TI - Capsule Commentary on Jenssen et al., Using Digital Technology to Engage and Communicate with Patients: A Survey of Patient Attitudes. PMID- 26525386 TI - Onset of two-dimensional superconductivity in space charge doped few-layer molybdenum disulfide. AB - Atomically thin films of layered materials such as molybdenum disulfide (MoS2) are of growing interest for the study of phase transitions in two-dimensions through electrostatic doping. Electrostatic doping techniques giving access to high carrier densities are needed to achieve such phase transitions. Here we develop a method of electrostatic doping which allows us to reach a maximum n doping density of 4 * 10(14) cm(-2) in few-layer MoS2 on glass substrates. With increasing carrier density we first induce an insulator to metal transition and subsequently an incomplete metal to superconductor transition in MoS2 with critical temperature ~10 K. Contrary to earlier reports, after the onset of superconductivity, the superconducting transition temperature does not depend on the carrier density. Our doping method and the results we obtain in MoS2 for samples as thin as bilayers indicates the potential of this approach. PMID- 26525387 TI - Peer Influence, Peer Status, and Prosocial Behavior: An Experimental Investigation of Peer Socialization of Adolescents' Intentions to Volunteer. AB - Peer influence processes have been documented extensively for a wide range of maladaptive adolescent behaviors. However, peer socialization is not inherently deleterious, and little is known about whether adolescents influence each other's prosocial behaviors, or whether some peers are more influential than others towards positive youth outcomes. This study addressed these questions using an experimental "chat room" paradigm to examine in vivo peer influence of prosocial behavior endorsement. A school-based sample of 304 early adolescents (55% female, 45% male; M(age) = 12.68) believed they were interacting electronically with same gender grademates (i.e., "e-confederates"), whose peer status was experimentally manipulated. The participants' intent to engage in prosocial behaviors was measured pre-experiment and in subsequent "public" and "private" experimental sessions. Overall, the adolescents conformed to the e-confederates' prosocial responses in public; yet, these peer influence effects were moderated by the peer status of the e-confederates, such that youth more strongly conformed to the high status e-confederates than to the low-status ones. There also was some evidence that these peer influence effects were maintained in the private session, indicating potential internalization of prosocial peer norms. These findings help bridge the positive youth development and peer influence literatures, with potential implications for campaigns to increase prosocial behaviors. PMID- 26525388 TI - Sex Differences in Sources of Resilience and Vulnerability to Risk for Delinquency. AB - Research on adolescent risk factors for delinquency has suggested that, due to genetic differences, youth may respond differently to risk factors, with some youth displaying resilience and others a heightened vulnerability. Using a behavioral genetic design and data from the National Longitudinal Study of Adolescent to Adult Health, this study examines whether there are sex differences in the genetic and environmental factors that influence the ways in which adolescents respond to cumulative risk for violent, nonviolent, and overall delinquency in a sample of twins (152 MZ male, 155 MZ female, 140 DZ male, 130 DZ female, and 204 DZ opposite-sex twin pairs). The results revealed that males tended to show greater vulnerability to risk for all types of delinquency, and females exhibited greater resilience. Among males, additive genetic factors accounted for 41, 29, and 43 % of the variance in responses to risk for violent, nonviolent, and overall delinquency, respectively. The remaining proportion of variance in each model was attributed to unique environmental influences, with the exception of 11 % of the variance in nonviolent responses to risk being attributed to common environmental factors. Among females, no significant genetic influences were observed; however, common environmental contributions to differences in the ways females respond to risk for violent, nonviolent, and overall delinquency were 44, 42, and 45 %, respectively. The remaining variance was attributed to unique environmental influences. Overall, genetic factors moderately influenced males' responses to risk while environmental factors fully explain variation in females' responses to risk. The implications of these findings are discussed in the context of improving the understanding of relationships between risks and outcomes, as well as informing policy and practice with adolescent offenders. PMID- 26525389 TI - The Temporal Association Between Traditional and Cyber Dating Abuse Among Adolescents. AB - While research has explored adolescents' use of technology to perpetrate dating violence, little is known about how traditional in-person and cyber abuse are linked, and no studies have examined their relationship over time. Using our sample of 780 diverse adolescents (58 % female), we found that traditional and cyber abuse were positively associated, and cyber abuse perpetration and victimization were correlated at each time point. Cyber abuse perpetration in the previous year (spring 2013) predicted cyber abuse perpetration 1 year later (spring 2014), while controlling for traditional abuse and demographic variables. In addition, physical violence victimization and cyber abuse perpetration and victimization predicted cyber abuse victimization the following year. These findings highlight the reciprocal nature of cyber abuse and suggest that victims may experience abuse in multiple contexts. PMID- 26525390 TI - Effect of Ivabradine on Endothelial Function in Patients with Stable Angina Pectoris: Assessment with the Endo-PAT 2000 Device. AB - INTRODUCTION: Ivabradine has opened up new possibilities for treating stable angina and chronic heart failure by lowering heart rate. Ivabradine lowers heart rate by selectively inhibiting the I f current in the sinoatrial node. This study aimed to determine whether the decrease in heart rate achieved with ivabradine was accompanied by hemodynamic changes that might lead to an enhancement of endothelial function. METHODS: Thirty patients with stable angina pectoris were included in the study. Ivabradine (5 mg bid) was added to the recommended standard treatment. Endothelial function was assessed at baseline and after 3 months of ivabradine therapy, with an Endo-PAT 2000 device (Itamar Medical, Israel). This device was recently developed for the noninvasive assessment for endothelial dysfunction. We evaluated reactive hyperemia index (RHI), which reflects endothelial function, and augmentation index (AI), which provides an indication of arterial stiffness. RESULTS: The study population consisted of 25 (83.3%) men and five (16.7%) women. The mean age of the patients was 65.4 +/- 6.7 years. Twenty-eight (93.3%) patients had a history of myocardial infarction (ST segment elevation myocardial infarction or non-ST-segment elevation myocardial infarction), 23 (76.6%) had undergone revascularization (percutaneous coronary intervention or coronary artery bypass graft), 16 (53.3%) had type 2 diabetes mellitus, and 29 (96.6%) had arterial hypertension. The mean resting heart rate decreased significantly, from 77 +/- 7 bpm at the start of the study to 65 +/- 6 bpm after treatment (P < 0.0001). Endothelial function was found to have improved significantly after 3 months of ivabradine therapy. Mean RHI before treatment was 1.54 +/- 0.30, suggesting probable endothelial dysfunction, whereas mean RHI at the end of the study was 1.83 +/- 0.36 (P < 0.0001). AI also improved significantly on treatment, from 21 +/- 20% to 10 +/- 21% (P < 0.0001). CONCLUSION: The addition of ivabradine to the treatment regimen of patients with stable angina pectoris both lowered heart rate and improved endothelial function. However, broader, randomized, double-blind, placebo-controlled clinical trials are required to confirm these findings. PMID- 26525391 TI - Polypharmacy and major adverse events in atrial fibrillation: observations from the AFFIRM trial. AB - BACKGROUND: Polypharmacy, as the use of five or more drugs, has commonly been associated with the elderly and multiple co-morbidities and related to impairment of clinical state and adverse outcomes, in general population. Limited data are available on the relationship between polypharmacy and adverse outcomes in atrial fibrillation (AF). We describe the prevalence of polypharmacy and AF, and its association with major adverse events, such as stroke and cardiovascular (CV) death. METHODS AND RESULTS: For this study, we analysed all AFFIRM Trial patients with complete pharmacological data. Polypharmacy was recorded in 40 % of 4056 AF patients. The crude incidence of CV death was 3.45 % patient-years among patients with polypharmacy, vs 1.65 % patient-years without polypharmacy. Kaplan-Meier analysis showed that patients with polypharmacy had a higher cumulative incidence of CV death (p < 0.001). Cox regression analysis demonstrated that female gender (p = 0.038), diabetes mellitus (p = 0.029), previous myocardial infarction (MI) (p = 0.004), prior stroke (p = 0.011) and polypharmacy (p = 0.029) were independently associated with CV death. Polypharmacy was associated with an adjusted relative risk of 1.30 (95 % CI 1.03-1.64) for CV death. A linear increase in the number of drugs was significantly associated with CV death. No significant association was found with stroke occurrence. CONCLUSIONS: Polypharmacy is highly prevalent in AF patients and associated with a worse clinical outcome, conferring 30 % excess relative risk for CV death. Thus, polypharmacy may be a health status marker. Strategies to reduce inappropriate prescription and polypharmacy should be tested in prospective longitudinal studies of AF patients. PMID- 26525392 TI - Use of high-throughput RT-qPCR to assess modulations of gene expression profiles related to genomic stability and interactions by cadmium. AB - Predictive test systems to assess the mode of action of chemical carcinogens are urgently required. Within the present study, we applied the Fluidigm dynamic array on the BioMarkTM HD System for quantitative high-throughput RT-qPCR analysis of 95 genes and 96 samples in parallel, selecting genes crucial for maintaining genomic stability, including stress response as well as DNA repair, cell cycle control, apoptosis and mitotic signaling. The specificity of each individually designed sequence-specific primer pair and their respective target amplicons were evaluated via melting curve analysis as part of qPCR and size verification via agarose gel electrophoresis. For each gene, calibration curves displayed high efficiencies and correlation coefficients in the identified linear dynamic range as well as low intra-assay variations. Data were processed via Fluidigm real-time PCR analysis and GenEx software, and results were depicted as relative gene expression according to the DeltaDeltaC q method. Subsequently, gene expression analyses were conducted in cadmium-treated adenocarcinoma A549 and epithelial bronchial BEAS-2B cells. They revealed distinct dose- and time dependent and also cell-type-specific gene expression patterns, including the induction of genes coding for metallothioneins, the oxidative stress response, cell cycle control, mitotic signaling and apoptosis. Interestingly, while genes coding for the DNA damage response were induced, distinct DNA repair genes were down-regulated at the transcriptional level. Thus, this approach provided a comprehensive overview on the interaction by cadmium with distinct signaling pathways, also reflecting molecular modes of action in cadmium-induced carcinogenicity. Therefore, the test system appears to be a promising tool for toxicological risk assessment. PMID- 26525393 TI - Inter-laboratory study of human in vitro toxicogenomics-based tests as alternative methods for evaluating chemical carcinogenicity: a bioinformatics perspective. AB - The assessment of the carcinogenic potential of chemicals with alternative, human based in vitro systems has become a major goal of toxicogenomics. The central read-out of these assays is the transcriptome, and while many studies exist that explored the gene expression responses of such systems, reports on robustness and reproducibility, when testing them independently in different laboratories, are still uncommon. Furthermore, there is limited knowledge about variability induced by the data analysis protocols. We have conducted an inter-laboratory study for testing chemical carcinogenicity evaluating two human in vitro assays: hepatoma derived cells and hTERT-immortalized renal proximal tubule epithelial cells, representing liver and kidney as major target organs. Cellular systems were initially challenged with thirty compounds, genome-wide gene expression was measured with microarrays, and hazard classifiers were built from this training set. Subsequently, each system was independently established in three different laboratories, and gene expression measurements were conducted using anonymized compounds. Data analysis was performed independently by two separate groups applying different protocols for the assessment of inter-laboratory reproducibility and for the prediction of carcinogenic hazard. As a result, both workflows came to very similar conclusions with respect to (1) identification of experimental outliers, (2) overall assessment of robustness and inter-laboratory reproducibility and (3) re-classification of the unknown compounds to the respective toxicity classes. In summary, the developed bioinformatics workflows deliver accurate measures for inter-laboratory comparison studies, and the study can be used as guidance for validation of future carcinogenicity assays in order to implement testing of human in vitro alternatives to animal testing. PMID- 26525394 TI - Investigations of putative reproductive toxicity of low-dose exposures to flutamide in Wistar rats. AB - The current investigation examines whether the model anti-androgenic substance flutamide is capable of disrupting endocrine homeostasis at very low doses. The data generated clarify whether a non-monotonic dose-response relationship exists to enhance the current debate about the regulation of endocrine disruptors. Moreover, it is part of a series of investigations assessing the dose-response relationship of single and combined administration of anti-androgenic substances. A pre-postnatal in vivo study design was chosen, which was compliant with regulatory testing protocols. The test design was improved by additional endpoints addressing hormone levels, morphology, and histopathological examinations. Doses were chosen to represent a clear effect level (2.5 mg/kg bw/d), a low endocrine effect level (LOAEL, 0.25 mg/kg bw/d), a NOAEL for endocrine effects (0.025 mg/kg bw/d), a further dose at 0.0025 mg/kg bw/d flutamide, as well as an "ADI" (0.00025 mg/kg bw/d or 100-fold below the NOAEL) for the detection of a possible non-monotonic dose-response curve. Anti androgenic changes were observable at LOAEL and the clear effect dose level but not at lower exposures. Nipple retention appeared to be the most sensitive measure of anti-androgenic effects, followed by age at sexual maturation, anogenital distance/anogenital index and male sex organ weights, as well as gross and histopathological findings. The results of all five doses indicate the absence of evidence for effects at very low dose levels. A non-monotonic dose response relationship was not evident for the anti-androgenic drug flutamide. PMID- 26525395 TI - The role of mid-chain hydroxyeicosatetraenoic acids in the pathogenesis of hypertension and cardiac hypertrophy. AB - The incidence, prevalence, and hospitalization rates associated with cardiovascular diseases (CVDs) are projected to increase substantially in the world. Understanding of the biological and pathophysiological mechanisms of survival can help the researchers to develop new management modalities. Numerous experimental studies have demonstrated that mid-chain HETEs are strongly involved in the pathogenesis of the CVDs. Mid-chain HETEs are biologically active eicosanoids that result from the metabolism of arachidonic acid (AA) by both lipoxygenase and CYP1B1 (lipoxygenase-like reaction). Therefore, identifying the localizations and expressions of the lipoxygenase and CYP1B1 and their associated AA metabolites in the cardiovascular system is of major importance in understanding their pathological roles. Generally, the expression of these enzymes is shown to be induced during several CVDs, including hypertension and cardiac hypertrophy. The induction of these enzymes is associated with the generation of mid-chain HETEs and subsequently causation of cardiovascular events. Of interest, inhibiting the formation of mid-chain HETEs has been reported to confer a protection against different cardiac hypertrophy and hypertension models such as angiotensin II, Goldblatt, spontaneously hypertensive rat and deoxycorticosterone acetate (DOCA)-salt-induced models. Although the exact mechanisms of mid-chain HETEs-mediated cardiovascular dysfunction are not fully understood, the present review proposes several mechanisms which include activating G-protein-coupled receptor, protein kinase C, mitogen-activated protein kinases, and nuclear factor kappa B. This review provides a clear understanding of the role of mid-chain HETEs in the pathogenesis of cardiovascular diseases and their importance as novel targets in the treatment for hypertension and cardiac hypertrophy. PMID- 26525396 TI - Highlight report: cytoprotective signaling in toxicology. PMID- 26525397 TI - The impact of bacteriospermia on boar sperm storage and reproductive performance. AB - Bacteriospermia is a documented risk to reproductive performance when using extended boar semen for artificial insemination. A substantial list of bacteria have been recovered from boar semen attributed to fecal, preputial, skin, and hair microorganisms, with these and other environmental bacteria from processing areas identified in doses prepared for artificial insemination. Gram-negative bacteria are most commonly recovered from extended doses, including both Enterobacteriaceae and environmental contaminants, such as those that inhabit water purification systems. The method of processing, distributing, and storing fresh liquid boar semen before insemination plays a role in bacterial growth dynamics and the degree to which the bacteria may damage the sperm or affect the sow. Not all bacterial isolates or contamination levels have the same impact on sperm, with multiple factors governing if and when storage longevity will be reduced through sperm-to-sperm agglutination, impaired motility, acrosome disruption, or loss of membrane viability. Suboptimal reproductive performance can occur because of reduced fertilizing capacity of the sperm or induction of a uterine environment hostile to sperm and/or embryonic survival. Effective bacterial control strategies are necessary to minimize the risk of bacteria contaminating extended semen doses, including monitoring programs designed for quick detection and intervention, should the need arise. PMID- 26525398 TI - Expression of estrus modifies the gene expression profile in reproductive tissues on Day 19 of gestation in beef cows. AB - The aim of this study was to test the effect of expression of estrus at artificial insemination (AI) on endometrium, conceptus, and CL gene expression of beef cows. Thirty-six multiparous nonlactating Nelore cows were enrolled on an estradiol- and progesterone (P4)-based timed AI protocol (AI = Day 0) and then slaughtered for the endometrium, CL, and conceptus collection on Day 19. The animals were retrospectively grouped on the basis of cows that (1) showed signs of estrus near AI (n = 19; estrus) and (2) did not show any signs of estrus (n = 17; nonestrus). Body condition score, blood sampling, and ultrasound examination were performed on Days 0, 7, and 18 of the experiment followed by messenger RNA extraction and quantitative reverse transcription polymerase chain reaction analysis of 58 target genes. Data were checked for normality and analyzed by ANOVA for repeated measures using proc GLM, MIXED, and UNIVARIATE of SAS. Only pregnant cows were included in the analyses (n = 12; nonestrus, n = 11). Estrous expression had no correlation with parameters such as body condition score, preovulatory follicle and CL diameter, P4 concentration in plasma on Days 7 and 18 after AI, and interferon-tau concentration in the uterine flushing (P > 0.15); however, a significant increase was observed in conceptus size from cows that expressed estrus (P = 0.02; 38.3 +/- 2.8 vs. 28.2 +/- 2.9 mm). The majority of transcripts affected by estrous expression in the endometrium belong to the immune system and adhesion molecule family (MX1, MX2, MYL12A, MMP19, CXCL10, IGLL1, and SLPI; P <= 0.05), as well as those related with prostaglandin synthesis (OTR and COX-2; P <= 0.05). Genes related to apoptosis, P4 synthesis, and prostaglandin receptor were downregulated (CYP11A, BAX, and FPr; P < 0.05) in the CL tissue of cows that expressed estrus. In addition, four genes were identified as differentially expressed in the 19-day-old conceptus from cows that expressed estrus (ISG15, PLAU, BMP15, and EEF1A1; P < 0.05). There was also a significant effect of Day 7 concentration of P4 mainly affecting the immune system, adhesion molecules, and wnt signaling pathway of the endometrium (IGLL1, MX2, SLPI, TRD, APC, WNT2, GLYCAM1, and MYL12A; P < 0.05). A significant interaction between estrous expression and P4 concentration on Day 7 was more pronounced in immune system genes (MX1, MX2, TRD, SLPI, and IGLL1; P < 0.05). This study reported that estrous expression at the time of AI favorably altered the gene expression profile in reproductive tissues during the preimplantation phase toward a more receptive state to the elongating conceptus. These effects seem to be more evident in the endometrium during the time of dynamic remodeling for embryo implantation. PMID- 26525399 TI - Aglepristone: A review on its clinical use in animals. AB - Aglepristone (RU 46534) is a competitive progesterone antagonist that is indicated for the treatment of various progesterone-dependent physiological or pathologic conditions. Aglepristone has proven to be an effective means of terminating pregnancy in most species. When used to induce parturition, aglepristone was effective in all cases in the bitch, cow, and goat, with no apparent adverse effects on neonatal health or milk production. When used to schedule an elective cesarean section, aglepristone treatment was deemed safe for dams and puppies, providing that the ovulation date had been accurately assessed at the time of breeding. Irrespective of the stage of pregnancy at injection, treatment with aglepristone has no apparent negative effects on subsequent fertility. Aglepristone is also a safe and relatively effective means of treating pyometra. However, given the high level of septic risk and the likelihood of rapid deterioration, such therapy is not recommended in emergency situations. Treatment of feline fibroadenomatosis using aglepristone has given promising results, but repeat treatment may be necessary in cats previously treated with long-acting progestagens. The use of aglepristone in other progesterone-dependent diseases has yet to be fully evaluated but may prove valuable, especially in the treatment of insulin-resistant diabetes mellitus, acromegaly, and the treatment of some vaginal tumors in the bitch. PMID- 26525400 TI - Illness and the Internet: From Private to Public Experience. AB - Illness is a ubiquitous experience in all societies. Until the past two decades, illness remained largely a private experience. With the development of the Internet, especially what has been termed Web 2.0, with interactive websites, illness has become increasingly a public experience. Vehicles like bulletin boards, chat rooms, listservs, electronic support groups, and more recently social media facilitate thousands of online communities where individuals with illness share information, interaction, experience, and advocacy. With the advent of social media, communication has increased and brought new challenges for online interaction. It is likely that the transformation of illness from a largely private to an increasingly public experience is a revolutionary change that is here to stay, with numerous social consequences. PMID- 26525401 TI - Robotic Thyroidectomy Versus Nonrobotic Approaches: A Meta-Analysis Examining Surgical Outcomes. AB - Background Robotic surgery has been recently used as a novel tool for remote access thyroid surgery. We performed a meta-analysis of the current literature to examine the safety and oncological efficacy of robotic surgery compared to endoscopic and conventional approaches for different thyroid procedures. Methods A systematic search of the online data bases was done using the following (MeSH) terms "robotic surgery," "robotic thyroidectomy," "robot-assisted thyroidectomy," and "robot-assisted thyroid surgery." Outcomes measured included total operative time, length of hospital stay, postoperative thyroglobulin levels, and postoperative complications. Statistical differences were analyzed between groups through the standard means and/or relative risk by using STATA analytical software. Results In this study, 144 articles were identified; of which 18 of them met our inclusion criteria, totaling 4878 patients. Robotic approach was associated with longer total operative time (mean difference of 43.5 minutes) when compared to the conventional cervical approach (95% CI = 20.9-66.2; P < .001). Robotic approach was also found to have a similar risk of total postoperative complications when compared to the conventional and endoscopic approaches. Conclusion Robotic thyroid surgery is as safe, feasible and provides similar periperative complications and oncological outcomes when compared to both, conventional cervical and endoscopic approaches. However, robotic thyroid surgery is associated with longer operative time when compared to the conventional open approach. PMID- 26525402 TI - Candida albicans beta-1,2-mannosyltransferase Bmt3 prompts the elongation of the cell-wall phosphopeptidomannan. AB - beta-1,2-Linked mannosides are expressed on numerous cell-wall glycoconjugates of the opportunistic pathogen yeast Candida albicans. Several studies evidenced their implication in the host-pathogen interaction and virulence mechanisms. In the present study, we characterized the in vitro activity of CaBmt3, a beta-1,2 mannosyltransferase involved in the elongation of beta-1,2-oligomannosides oligomers onto the cell-wall polymannosylated N-glycans. A recombinant soluble enzyme Bmt3p was produced in Pichia pastoris and its enzyme activity was investigated using natural and synthetic oligomannosides as potential acceptor substrates. Bmt3p was shown to exhibit an exquisite enzymatic specificity by adding a single terminal beta-mannosyl residue to alpha-1,2-linked oligomannosides capped by a Manbeta1-2Man motif. Furthermore, we demonstrated that the previously identified CaBmt1 and CaBmt3 efficiently act together to generate Manbeta1-2Manbeta1-2[Manalpha1-2]n sequence from alpha-1,2-linked oligomannosides onto exogenous and endogenous substrates. PMID- 26525403 TI - A rare case of everolimus-induced pulmonary alveolar proteinosis. PMID- 26525404 TI - Successful lung transplantation from a donation after cardiocirculatory death donor taking more than 120 minutes to cardiac arrest after withdrawal of life support therapies. PMID- 26525405 TI - Editorial. PMID- 26525406 TI - SIMcheck: a Toolbox for Successful Super-resolution Structured Illumination Microscopy. AB - Three-dimensional structured illumination microscopy (3D-SIM) is a versatile and accessible method for super-resolution fluorescence imaging, but generating high quality data is challenging, particularly for non-specialist users. We present SIMcheck, a suite of ImageJ plugins enabling users to identify and avoid common problems with 3D-SIM data, and assess resolution and data quality through objective control parameters. Additionally, SIMcheck provides advanced calibration tools and utilities for common image processing tasks. This open source software is applicable to all commercial and custom platforms, and will promote routine application of super-resolution SIM imaging in cell biology. PMID- 26525407 TI - Short-term Treatment With Interferon Alfa Diminishes Expression of HIV-1 and Reduces CD4+ T-Cell Activation in Patients Coinfected With HIV and Hepatitis C Virus and Receiving Antiretroviral Therapy. AB - Long-term treatment with interferon (IFN) alfa plus ribavirin decreases the proviral human immunodeficiency virus type 1 (HIV) DNA level. However, the short term impact of IFN alfa on persistent HIV and its effects on immune activation after antiretroviral therapy remain unknown. Our study showed that the cell associated HIV RNA level and CD4(+) T-cell activation decreased in the IFN group (n = 10). No changes were detected in levels of residual plasma viremia, replication-competent reservoirs, proviral DNA, or 2-long-terminal repeat circles, although APOBEC3G, TRIM5alpha, BST2, and TRIM22 were upregulated in the IFN group. These data suggest that short-term treatment with IFN alfa combined with RBV decreases HIV expression, in part through inhibition of HIV transcription by TRIM22 and decrease in T-cell activation. PMID- 26525408 TI - Phylogeographic data revealed shallow genetic structure in the kelp Saccharina japonica (Laminariales, Phaeophyta). AB - BACKGROUND: Population structure and genetic diversity of marine organisms in the Northwestern Pacific Ocean exhibited complex patterns. Saccharina japonica is a commercially and ecologically important kelp species widely distributed along the coast of Japan Sea. However, it is still poorly known about population genetics and phylogeographic patterns of wild S. japonica populations on a large geographic scale, which is an important contribution to breeding and conservation of this marine crop. RESULTS: We collected 612 mitochondrial COI and trnW-trnL sequences. Diversity indices suggested that S. japonica populations along the coast of Hokkaido exhibited the highest genetic diversity. Bayesian Analysis of Population Structure (BAPS) revealed four clusters in the kelp species (cluster 1: Hokkaido and South Korea; cluster 2: northwestern Hokkaido; cluster 3: Far Eastern Russia; cluster 4: China). The network inferred from concatenated data exhibited two shallow genealogies corresponding to two BAPS groups (cluster 2 and cluster 3). We did not detect gene flow between the two shallow genealogies, but populations within genealogy have asymmetric gene exchange. Bayesian skyline plots and neutrality tests suggested that S. japonica experienced postglacial expansion around 10.45 ka. CONCLUSIONS: The coast of Hokkaido might be the origin and diversification center of S. japonica. Gene exchange among S. japonica populations could be caused by anthropogenic interference and oceanographic regimes. Postglacial expansions and gene exchange apparently led to more shared haplotypes and less differentiation that in turn led to the present shallow phylogeographical patterns in S. japonica. PMID- 26525409 TI - Leadership in the clinical workplace: what residents report to observe and supervisors report to display: an exploratory questionnaire study. AB - BACKGROUND: Within the current health care system, leadership is considered important for physicians. leadership is mostly self-taught, through observing and practicing. Does the practice environment offer residents enough opportunities to observe the supervisor leadership behaviours they have to learn? In the current study we investigate which leadership behaviours residents observe throughout their training, which behaviours supervisors report to display and whether residents and supervisors have a need for more formal training. METHODS: We performed two questionnaire studies. Study 1: Residents (n = 117) answered questions about the extent to which they observed four basic and observable Situational Leadership behaviours in their supervisors. Study 2: Supervisors (n = 201) answered questions about the extent to which they perceived to display these Situational Leadership behaviours in medical practice. We asked both groups of participants whether they experienced a need for formal leadership training. RESULTS: One-third of the residents did not observe the four basic Situational Leadership behaviours. The same pattern was found among starting, intermediate and experienced residents. Moreover, not all supervisors showed these 4 leadership behaviours. Both supervisors and residents expressed a need for formal leadership training. CONCLUSION: Both findings together suggest that current practice does not offer residents enough opportunities to acquire these leadership behaviours by solely observing their supervisors. Moreover, residents and supervisors both express a need for more formal leadership training. More explicit attention should be paid to leadership development, for example by providing formal leadership training for supervisors and residents. PMID- 26525410 TI - Evaluating the QUIT-PRIMO clinical practice ePortal to increase smoker engagement with online cessation interventions: a national hybrid type 2 implementation study. AB - BACKGROUND: Effective web-assisted tobacco interventions (WATIs) have been underutilized by smokers; moreover, despite practice guideline recommendations, clinical teams do not routinely refer smokers to WATIs. Our goal was to test a clinical practice innovation, an ePortal designed to change practice and patient behavior. Our hypotheses were that the integrated system would result in increased smoker referrals, with an automated follow-up system resulting in more smoker registrations and finally augmentations of the WATI would result in more smokers quitting at 6 months. METHODS: Practice ePortal Implementation Trial: Practices (n = 174) were randomized to an online practice ePortal with an "e referral tool" to the WATI (e-referred smokers received automated email reminders from the practice) and with practice feedback reports with patient tracking and practice-to-patient secure messaging versus comparison (a paper "referral prescription"). Implementation success was measured by the number of smokers referred and smokers registering. Clinical Effectiveness Trial: To estimate the effectiveness of the WATI components on 6-month smoking cessation, registered smokers were randomized into three groups: a state-of-the-art tailored WATI control [control], the WATI enhanced with proactive, pushed tailored email motivational messaging (messaging), and the WATI with messaging further enhanced with personal secure messaging with a tobacco treatment specialist and an online support group (personalized). RESULTS: Practice ePortal Trial results: A total of 4789 smokers were referred. The mean smokers referred per practice was not statistically different by group (ePortal 24.89 (SD 22.29) versus comparison 30.15 (SD 25.45), p = 0.15). The e-referral portal implementation program resulted in nearly triple the rate of smoker registration (31 % of all smokers referred registered online) versus comparison (11 %, p < 0.001). Clinical Effectiveness Trial results: Active smokers randomized to the personalized group had a 6-month cessation rate of 25.2 %, compared with the messaging group (26.7 %) and the control (17 %). Next, when using an inverse probability weighted selection model to account for attrition, those randomized to the two groups that received motivational messaging (messaging or personalized) were more likely to quit than those in the control (p = 0.04). CONCLUSIONS: Among all smokers referred, the e-referral resulted in nearly threefold greater registrants (31 %) than paper (11 %). The practice ePortal smokers received multiple reminders (increasing registration opportunities), and the practices could track patient progress. The result was more smokers registering and, thus, more cessation opportunities. Combining the proactive referral and the WATI resulted in higher rates of smoking cessation. TRIAL REGISTRATION: Web-delivered Provider Intervention for Tobacco Control (QUIT-PRIMO) - a randomized controlled trial: NCT00797628 . PMID- 26525411 TI - Comparison of antiplatelet regimens in secondary stroke prevention: a nationwide cohort study. AB - BACKGROUND: In patients with ischemic stroke of non-cardioembolic origin, acetylsalicylic acid, clopidogrel, or a combination of acetylsalicylic acid and dipyridamole are recommended for the prevention of a recurrent stroke. The purpose of this study was to examine the risk of bleeding or recurrent stroke associated with these three treatments. METHODS: Patients who were discharged with first-time ischemic stroke from 2007-2010, with no history of atrial fibrillation were identified from Danish nationwide registries. Hazard ratios (HRs) and 1-year risks of recurrent ischemic stroke and bleeding were calculated for each antiplatelet regimen. RESULTS: Among patients discharged after first time ischemic stroke, 3043 patients were treated with acetylsalicylic acid, 12,295 with a combination of acetylsalicylic acid and dipyridamole, and 3885 with clopidogrel. Adjusted HRs for clopidogrel versus the combination of acetylsalicylic acid and dipyridamole were 1.02 (95% confidence interval [CI]: 0.89-1.17) for ischemic stroke and 1.06 (95% CI: 0.83-1.35) for bleeding. Adjusted HRs for acetylsalicylic acid versus the combination of acetylsalicylic acid and dipyridamole were 1.48 (95% CI: 1.31-1.67) for stroke and 1.47 (95% CI: 1.18-1.82) for bleeding. Clopidogrel versus acetylsalicylic acid yielded HRs of 0.69 (95% CI: 0.59-0.81) and 0.72 (95% CI: 0.55-0.96) for stroke and bleeding, respectively. The 1-year predicted risks associated with acetylsalicylic acid, the combination of acetylsalicylic acid and dipyridamole, and clopidogrel were 11.1 (95% CI: 10.2-12.2), 7.7 (95% CI: 7.3-8.3), and 8.0 (95% CI: 6.9-8.7) for ischemic stroke, respectively; while, the risks for bleeding were 3.4 (95% CI: 2.8-3.9), 2.4 (95% CI: 2.1-2.7), and 2.4 (95% CI: 1.9-2.9), respectively. CONCLUSION: Clopidogrel and the combination of acetylsalicylic acid and dipyridamole were associated with similar risks for recurrent ischemic stroke and bleeding; whereas acetylsalicylic acid was associated with higher risks for both ischemic stroke and bleeding. The latter finding may partially be explained by selection bias. PMID- 26525412 TI - Proteomic profiling of host-biofilm interactions in an oral infection model resembling the periodontal pocket. AB - Periodontal infections cause inflammatory destruction of the tooth supporting tissues. We recently developed a dynamic, in vitro periodontal organotypic tissue model in a perfusion bioreactor system, in co-culture with an 11-species subgingival biofilm, which may recapitulate early events during the establishment of periodontal infections. This study aimed to characterize the global proteome regulations in this host-biofilm interaction model. Semi-quantitative shotgun proteomics were applied for protein identification and quantification in the co culture supernatants (human and bacterial) and the biofilm lysates (bacterial). A total of 896 and 3363 proteins were identified as secreted in the supernatant and expressed in the biofilm lysate, respectively. Enriched gene ontology analysis revealed that the regulated secreted human tissue proteins were related to processes of cytoskeletal rearrangement, stress responses, apoptosis, and antigen presentation, all of which are commensurate with deregulated host responses. Most secreted bacterial biofilm proteins derived from their cytoplasmic domain. In the presence of the tissue, the levels of Fusobacterium nucleatum, Actinomyces oris and Campylobacter rectus proteins were significantly regulated. The functions of the up-regulated intracellular (biofilm lysate) proteins were associated with cytokinesis. In conclusion, the proteomic overview of regulated pathways in this host-biofilm interaction model provides insights to the early events of periodontal pathogenesis. PMID- 26525413 TI - Different responses to treatment across classified diseases and severities in Japanese patients with microscopic polyangiitis and granulomatosis with polyangiitis: a nationwide prospective inception cohort study. AB - INTRODUCTION: This study aims to elucidate the prognosis and the effectiveness of current treatments for Japanese patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: Patients with newly diagnosed MPA and GPA were enrolled in a nationwide, prospective, inception cohort study from 22 tertiary Japanese institutions, and treatment patterns and responses were evaluated for 24 months. Primary outcome measures were rates of remission (Birmingham Vasculitis Activity Score, 0) and remission with low-dose glucocorticoids (GC) (prednisolone <= 10 mg) (GC remission). RESULTS: Of 156 enrolled patients, 78 MPA patients and 33 GPA patients were included. Concomitant cyclophosphamide (CY) was used in 24 MPA (31 %) and 20 GPA (60 %) patients during the initial 3 weeks of treatment. After 6 months, remission was achieved in 66 MPA (85 %) and 29 GPA (87 %) patients, while GC remission was obtained in only 31 MPA (40 %) and 13 GPA (39 %) patients. During the 24-month period, 14 MPA patients and 2 GPA patients died; end stage renal disease (ESRD) was noted in 13 MPA patients but no GPA patients. Patients with severe disease, according to the European Vasculitis Study Group (EUVAS) classification, showed poorer ESRD-free and overall survival rates than those with generalized disease (p < 0.0001). There were no differences in relapse-free survival rates between GPA and MPA, among EUVAS-defined disease severity categories, and between anti-neutrophil cytoplasmic antibody subspecialties. CONCLUSIONS: The majority of Japanese patients with MPA and GPA received treatment with high-dose GC and limited CY use, and showed high remission and relapse-free survival rates but low GC remission rates in clinical practice. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000001648 . Registered 28 February 2009. PMID- 26525415 TI - Circulating microRNAs as novel biomarkers for bone diseases - Complex signatures for multifactorial diseases? AB - Biomarkers are essential tools in clinical research and practice. Useful biomarkers must combine good measurability, validated association with biological processes or outcomes, and should support clinical decision making if used in clinical practice. Several types of validated biomarkers have been reported in the context of bone diseases. However, because these biomarkers face certain limitations there is an interest in the identification of novel biomarkers for bone diseases, specifically in those that are tightly linked to the disease pathology leading to increased fracture-risk. MicroRNAs (miRNAs) are the most abundant RNA species to be found in cell-free blood. Encapsulated within microvesicles or bound to proteins, circulating miRNAs are remarkably stable analytes that can be measured using gold-standard technologies such as quantitative polymerase-chain-reaction (qPCR). Nevertheless, the analysis of circulating miRNAs faces several pre-analytical as well as analytical challenges. From a biological view, there is accumulating evidence that miRNAs play essential roles in the regulation of various biological processes including bone homeostasis. Moreover, specific changes in miRNA transcription levels or miRNA secretory levels have been linked to the development and progression of certain bone diseases. Only recently, results from circulating miRNAs analysis in patients with osteopenia, osteoporosis and fragility fractures have been reported. By comparing these findings to studies on circulating miRNAs in cellular senescence and aging or muscle physiology and sarcopenia, several overlaps were observed. This suggests that signatures observed during osteoporosis might not be specific to the pathophysiology in bone, but rather integrate information from several tissue types. Despite these promising first data, more work remains to be done until circulating miRNAs can serve as established and robust diagnostic tools for bone diseases in clinical research, clinical routine and in personalized medicine. PMID- 26525416 TI - Early adolescent substance use in Mexican origin families: Peer selection, peer influence, and parental monitoring. AB - BACKGROUND: Because adolescents vary in their susceptibility to peer influence, the current study addresses potential reciprocal effects between associating with deviant peers and use of alcohol, tobacco and other drugs (ATOD), as well as the potential buffering role of parental monitoring on these reciprocal effects. METHOD: 674 children of Mexican origin reported at fifth and seventh grade (10.4 years old at fifth grade) on the degree to which they associated with deviant peers, intended to use alcohol, tobacco or other drugs (ATOD) in the future, and had used controlled substances during the past year. Trained observers rated parental monitoring from video-recorded family interactions at the first assessment. RESULTS: Youth who intended to use ATODs during fifth grade experienced a relative increase in number of deviant peers by seventh grade, and youth with more deviant peers in fifth grade were more likely to use ATODs by seventh grade. Parental monitoring buffered (i.e., moderated) the reciprocal association between involvement with deviant peers and both intent to use ATODs and actual use of ATODs. CONCLUSIONS: Parental monitoring can disrupt the reciprocal associations between deviant peers and ATOD use during the transition from childhood to adolescence. PMID- 26525414 TI - Nuclear import of the thyroid hormone receptor alpha1 is mediated by importin 7, importin beta1, and adaptor importin alpha1. AB - The thyroid hormone receptor alpha1 (TRalpha1) is a nuclear receptor for thyroid hormone that shuttles rapidly between the nucleus and cytoplasm. Our prior studies showed that nuclear import of TRalpha1 is directed by two nuclear localization signals, one in the N-terminal A/B domain and the other in the hinge domain. Here, we showed using in vitro nuclear import assays that TRalpha1 nuclear localization is temperature and energy-dependent and can be reconstituted by the addition of cytosol. In HeLa cells expressing green fluorescent protein (GFP)-tagged TRalpha1, knockdown of importin 7, importin beta1 and importin alpha1 by RNA interference, or treatment with an importin beta1-specific inhibitor, significantly reduced nuclear localization of TRalpha1, while knockdown of other importins had no effect. Coimmunoprecipitation assays confirmed that TRalpha1 interacts with importin 7, as well as importin beta1 and the adapter importin alpha1, suggesting that TRalpha1 trafficking into the nucleus is mediated by two distinct pathways. PMID- 26525417 TI - Synthetic cannabimimetics in Bulgaria 2010-2013. AB - BACKGROUND: The manufacturing, distribution and use of synthetic cannabimimetics (SCs) have seen dynamic changes over the last few years, and have had an unprecedented growth. Forensic toxicologists in Bulgaria faced SCs for the first time in 2010, as compounds detected in seized blends. METHODS: This is a retrospective survey on the SCs seized in Bulgaria 2010-2013. RESULTS: The number of SCs increased progressively: 17 cases in 2010, 38 in 2011, 75 in 2012, and 80 in 2013. In Bulgaria, from 2010 to 2013, there were two cases of toxicologically proved intoxications (with JWH-018). JWH-018 was the most often detected SC in Bulgaria for the whole studied period. The most popular combination detected in 2013 was: UR-144+MAM-2201 with or without STS-135. Highly potent halogenated SCs appeared in 2013. 5F-AKB-48 (nearly 3 kg) was seized in 12 cases. Published data suggest that SCs may have more severe side effects than marijuana. Parallel adaptation of Bulgarian law with adoption of analog laws tried to meet the increased forensic challenges. CONCLUSIONS: Over the last decade, the rapid growth in the number and types of SCs distributed in Europe has challenged the capacity, and sometimes the credibility, of identification, risk assessment and control systems. Forensic toxicology needs to adapt in a timely manner, providing scientific basis of legislative changes. PMID- 26525418 TI - A new approach in the synthesis of La(1-x)Gd(x)FeO3 perovskite nanoparticles- structural and magnetic characterization. AB - A series of highly crystalline orthoferrite nanoparticles (type La(1-x)Gd(x)FeO3, where x = 0 to 1) were prepared using the self-combustion method. Extensive studies including X-ray diffraction, Rietveld refinement and Fourier transform infrared spectroscopy as well as Raman spectroscopy confirmed the orthorhombic space group Pnma of the obtained materials. The calculated average grain size for powders is in the range of 30 to 80 nm. Magnetic characterization of the La(1 x)Gd(x)FeO3 series, performed at 1.72 K, indicated an antiferromagnetic state characterized by some canting of iron magnetic moments, in good agreement with the data reported for similar fine-particle systems. PMID- 26525419 TI - Cost-effectiveness of integrated COPD care: the RECODE cluster randomised trial. AB - OBJECTIVES: To investigate the cost-effectiveness of a chronic obstructive pulmonary disease (COPD) disease management (COPD-DM) programme in primary care, called RECODE, compared to usual care. DESIGN: A 2-year cluster-randomised controlled trial. SETTING: 40 general practices in the western part of the Netherlands. PARTICIPANTS: 1086 patients with COPD according to GOLD (Global Initiative for COPD) criteria. Exclusion criteria were terminal illness, cognitive impairment, alcohol or drug misuse and inability to fill in Dutch questionnaires. Practices were included if they were willing to create a multidisciplinary COPD team. INTERVENTIONS: A multidisciplinary team of caregivers was trained in motivational interviewing, setting up individual care plans, exacerbation management, implementing clinical guidelines and redesigning the care process. In addition, clinical decision-making was supported by feedback reports provided by an ICT programme. MAIN OUTCOME MEASURES: We investigated the impact on health outcomes (quality-adjusted life years (QALYs), Clinical COPD Questionnaire, St. George's Respiratory Questionnaire and exacerbations) and costs (healthcare and societal perspective). RESULTS: The intervention costs were ?324 per patient. Excluding these costs, the intervention group had ?584 (95% CI ?86 to ?1046) higher healthcare costs than did the usual care group and ?645 (95% CI ?28 to ?1190) higher costs from the societal perspective. Health outcomes were similar in both groups, except for 0.04 (95% CI -0.07 to -0.01) less QALYs in the intervention group. CONCLUSIONS: This integrated care programme for patients with COPD that mainly included professionally directed interventions was not cost effective in primary care. TRIAL REGISTRATION NUMBER: Netherlands Trial Register NTR2268. PMID- 26525420 TI - Prevalence, associated factors and heritabilities of metabolic syndrome and its individual components in African Americans: the Jackson Heart Study. AB - OBJECTIVE: Both environmental and genetic factors play important roles in the development of metabolic syndrome (MetS). Studies about its associated factors and genetic contribution in African Americans (AA) are sparse. Our aim was to report the prevalence, associated factors and heritability estimates of MetS and its components in AA men and women. PARTICIPANTS AND SETTING: Data of this cross sectional study come from a large community-based Jackson Heart Study (JHS). We analysed a total of 5227 participants, of whom 1636 from 281 families were part of a family study subset of JHS. METHODS: Participants were classified as having MetS according to the Adult Treatment Panel III criteria. Multiple logistic regression analysis was performed to isolate independently associated factors of MetS (n=5227). Heritability was estimated from the family study subset using variance component methods (n=1636). RESULTS: About 27% of men and 40% of women had MetS. For men, associated factors with having MetS were older age, lower physical activity, higher body mass index, and higher homocysteine and adiponectin levels (p<0.05 for all). For women, in addition to all these, lower education, current smoking and higher stress were also significant (p<0.05 for all). After adjusting for covariates, the heritability of MetS was 32% (p<0.001). Heritability ranged from 14 to 45% among its individual components. Relatively higher heritability was estimated for waist circumference (45%), high density lipoprotein-cholesterol (43%) and triglycerides (42%). Heritability of systolic blood pressure (BP), diastolic BP and fasting blood glucose was 16%, 15% and 14%, respectively. CONCLUSIONS: Stress and low education were associated with having MetS in AA women, but not in men. Higher heritability estimates for lipids and waist circumference support the hypothesis of lipid metabolism playing a central role in the development of MetS and encourage additional efforts to identify the underlying susceptibility genes for this syndrome in AA. PMID- 26525421 TI - Independent and joint effects of sedentary time and cardiorespiratory fitness on all-cause mortality: the Cooper Center Longitudinal Study. AB - OBJECTIVES: To examine the independent and joint effects of sedentary time and cardiorespiratory fitness (fitness) on all-cause mortality. DESIGN, SETTING, PARTICIPANTS: A prospective study of 3141 Cooper Center Longitudinal Study participants. Participants provided information on television (TV) viewing and car time in 1982 and completed a maximal exercise test during a 1-year time frame; they were then followed until mortality or through 2010. TV viewing, car time, total sedentary time and fitness were the primary exposures and all-cause mortality was the outcome. The relationship between the exposures and outcome was examined utilising Cox proportional hazard models. RESULTS: A total of 581 deaths occurred over a median follow-up period of 28.7 years (SD=4.4). At baseline, participants' mean age was 45.0 years (SD=9.6), 86.5% were men and their mean body mass index was 24.6 (SD=3.0). Multivariable analyses revealed a significant linear relationship between increased fitness and lower mortality risk, even while adjusting for total sedentary time and covariates (p=0.02). The effects of total sedentary time on increased mortality risk did not quite reach statistical significance once fitness and covariates were adjusted for (p=0.05). When examining this relationship categorically, in comparison to the reference category (<=10 h/week), being sedentary for >=23 h weekly increased mortality risk by 29% without controlling for fitness (HR=1.29, 95% CI 1.03 to 1.63); however, once fitness and covariates were taken into account this relationship did not reach statistical significance (HR=1.20, 95% CI 0.95 to 1.51). Moreover, spending >10 h in the car weekly significantly increased mortality risk by 27% in the fully adjusted model. The association between TV viewing and mortality was not significant. CONCLUSIONS: The relationship between total sedentary time and higher mortality risk is less pronounced when fitness is taken into account. Increased car time, but not TV viewing, is significantly related to higher mortality risk, even when taking fitness into account, in this cohort. PMID- 26525424 TI - Revision of the GROMOS 56A6(CARBO) force field: Improving the description of ring conformational equilibria in hexopyranose-based carbohydrates chains. AB - This article describes a revised version 56A6(CARBO_R) of the GROMOS 56A6(CARBO) force field for hexopyranose-based carbohydrates. The simulated properties of unfunctionalized hexopyranoses are unaltered with respect to 56A6CARBO . In the context of both O1 -alkylated hexopyranoses and oligosaccharides, the revision stabilizes the regular (4) C1 chair for alpha-anomers, with the opposite effect for beta-anomers. As a result, spurious ring inversions observed in alpha(1->4) linked chains when using the original 56A6(CARBO) force field are alleviated. The (4) C1 chair is now the most stable conformation for all d-hexopyranose residues, irrespective of the linkage type and anomery, and of the position of the residue along the chain. The methylation of a d-hexopyranose leads to a systematic shift in the ring-inversion free energy ((4) C1 to (1) C4 ) by 7-8 kJ mol(-1), positive for the alpha-anomers and negative for the beta-anomers, which is qualitatively compatible with the expected enhancement of the anomeric effect upon methylation at O1. The ring-inversion free energies for residues within chains are typically smaller in magnitude compared to those of the monomers, and correlate rather poorly with the latter. This suggests that the crowding of ring substituents upon chain formation alters the ring flexibility in a nonsystematic fashion. In general, the description of carbohydrate chains afforded by 56A6(CARBO_R) suggests a significant extent of ring flexibility, i.e., small but often non negligible equilibrium populations of inverted chairs, and challenges the "textbook" picture of conformationally locked carbohydrate rings. PMID- 26525422 TI - Bath additives for the treatment of childhood eczema (BATHE): protocol for multicentre parallel group randomised trial. AB - INTRODUCTION: Bath emollients are widely prescribed for childhood eczema, yet evidence of their benefits over direct application of emollients is lacking. Objectives To determine the clinical and cost-effectiveness of adding bath emollient to the standard management of eczema in children METHODS AND ANALYSIS: DESIGN: Pragmatic open 2-armed parallel group randomised controlled trial. SETTING: General practitioner (GP) practices in England and Wales. PARTICIPANTS: Children aged over 12 months and less than 12 years with eczema, excluding inactive or very mild eczema (5 or less on Nottingham Eczema Severity Scale). INTERVENTIONS: Children will be randomised to either bath emollients plus standard eczema care or standard eczema care only. OUTCOME MEASURES: Primary outcome is long-term eczema severity, measured by the Patient-Oriented Eczema Measure (POEM) repeated weekly for 16 weeks. Secondary outcomes include: number of eczema exacerbations resulting in healthcare consultations over 1 year; eczema severity over 1 year; disease-specific and generic quality of life; medication use and healthcare resource use; cost-effectiveness. Aiming to detect a mean difference between groups of 2.0 (SD 7.0) in weekly POEM scores over 16 weeks (significance 0.05, power 0.9), allowing for 20% loss to follow-up, gives a total sample size of 423 children. We will use repeated measures analysis of covariance, or a mixed model, to analyse weekly POEM scores. We will control for possible confounders, including baseline eczema severity and child's age. Cost effectiveness analysis will be carried out from a National Health Service (NHS) perspective. ETHICS AND DISSEMINATION: This protocol was approved by Newcastle and North Tyneside 1 NRES committee 14/NE/0098. Follow-up will be completed in 2017. Findings will be disseminated to participants and carers, the public, dermatology and primary care journals, guideline developers and decision-makers. TRIAL REGISTRATION NUMBER: ISRCTN84102309. PMID- 26525423 TI - Piloting the Impact of Three Interventions on Guaiac Faecal Occult Blood Test Uptake within the NHS Bowel Cancer Screening Programme. AB - This study evaluated the impact of three interventions on uptake of the guaiac faecal occult blood test (gFOBT) in Greater London. The interventions were designed to improve awareness and understanding of the NHS Bowel Cancer Screening Programme (BCSP) and assist stool sampling. Logistic regression analysis of BCSP London data (N = 205,541 invitees aged 60-74) compared uptake at 12 weeks between intervention groups and a control group, sent kits as usual between January-April 2013 and January-April 2014. An endorsement flyer, included with gFOBT kits, had no impact on uptake (P = 0.68). In 60-69-year-olds, there was a small but significant increase in modelled uptake amongst invitees sent both the flyer and a kit enhancement pack compared with controls (45.1% versus 43.4%, OR = 1.07, P = 0.047). In North East London, the flyer together with outdoor advertising was associated with a small but significant increase (45.6% versus 43.4%, OR = 1.09, P = 0.027). The largest increases were seen when all three interventions (flyer, pack, and advertising) were combined (49.5% versus 43.4%, OR = 1.28, P < 0.001). The increased uptake in the intervention groups was largest in "first-timers" and smaller amongst previous nonresponders and previously screened invitees. PMID- 26525425 TI - Normal cortisol response to cold pressor test, but lower free thyroxine, after recovery from undernutrition. AB - Undernutrition is a stressor with long-term consequences, and the effect of nutritional recovery on cortisol and thyroid hormone status is unknown. To investigate basal thyroid hormones and the cortisol response to a cold pressor test in children recovered from undernutrition, a cross-sectional study was undertaken on children (6-16 years) separated into four groups: control (n 41), stunted (n 31), underweight (n 27) and recovered (n 31). Salivary cortisol was collected over the course of 10 h: upon awakening, before and after an unpleasant and a pleasant stimulus. Cortisol upon awakening was highest in the stunted and lowest in the underweight groups: control=5.05 (95% CI 3.71, 6.89) nmol/l, stunted=6.62 (95% CI 3.97, 11.02) nmol/l, underweight=2.51 (95% CI 1.75, 3.63) nmol/l and recovered=3.46 (95% CI 2.46, 4.90) nmol/l (P=0.005). Girls had higher cortisol concentrations upon awakening compared with boys (P=0.021). The undernourished groups showed an elevated cortisol response both to the unpleasant stimulus and at the last measurement (16.00 hours) compared with that of the recovered group: AUC, control=2.07 (95% CI 1.69, 2.45) nmol/l*30 min, stunted=2.48 (95% CI 1.91, 3.06) nmol/l*30 min, underweight=2.52 (95% CI 2.07, 2.97) nmol/l*30 min, recovered=1.68 (95% CI 1.26, 2.11) nmol/l*30 min (P=0.042); and control=2.03 (95% CI 1.75, 2.39) nmol/l*30 min, stunted=2.51 (95% CI 1.97, 3.19) nmol/l*30 min, underweight=2.61 (95% CI 2.16, 3.16) nmol/l*30 min, recovered=1.70 (95% CI 1.42, 2.03) nmol/l*30 min (P=0.009). Lower free thyroxine (T4) was found in the recovered and stunted groups: control=1.28 (95% CI 1.18, 1.39) pmol/l, stunted=0.98 (95% CI 0.87, 1.10) pmol/l, underweight=1.10 (95% CI 1.01, 1.21) pmol/l and recovered=0.90 (95% CI 0.83, 0.99) pmol/l (P<0.001). Multivariate analysis showed a lower cortisol concentration along 10 h (06.00 16.00 hours) in the recovered compared with the other groups (P=0.017), and similar concentrations between the recovered and control group. In conclusion, the children with recovery in weight and height had a cortisol stress response similar to control but a lower basal free T4. Longitudinal studies are warranted to determine the extent of these endocrine changes after recovery of undernutrition and in adulthood. PMID- 26525426 TI - A Transtubular Microsurgical Approach to Treat Lateral Cervical Disc Herniation. AB - OBJECTIVE: Different surgical options are available to treat radicular pain syndromes of the cervical spine. Use of the posterior approach for foraminotomy and sequestrectomy (Frykholm) fusion can be avoided, but neck pain affects the postoperative course. This retrospective study compares the classical Frykholm approach and the transtubular microsurgical approach for foraminotomy. METHODS: From 2004 to 2012, 40 patients fulfilled the inclusion criteria and were enrolled into this retrospective study. The classical Frykholm approach was performed on 25 affected levels. The transtubular microsurgical approach was used on 19 affected levels. Endpoints were neck pain, radicular pain, surgery time, duration of hospital stay, and long-term outcomes. RESULTS: For the transtubular microsurgical approach and the classical Frykholm approach, the mean surgery time was 77.65 +/- 23 minutes and 104 +/- 27.59 minutes (P = 0.003), respectively. Radicular pain improved in all patients regardless of the technical approach. Significant differences were observed in neck pain on the first postoperative day (P = 0.003) and at discharge (P = 0.006), resulting in a shorter hospital stay of 4.82 days +/- 2.1 for the transtubular microsurgical approach in comparison with 7.43 days +/- 3.2 for the Frykholm approach (P = 0.005). According to the criteria of Odom, the rate of an excellent or good outcome was 97.5% (67.5% excellent and 30% good), without any differences between the compared approaches. CONCLUSION: The transtubular microsurgical approach shows advantages regarding postoperative neck pain, surgery time, and hospital stay with a trend towards an earlier return to work. PMID- 26525427 TI - Surgery's Day in Court--the Time Has Come! PMID- 26525428 TI - Intraneural Ganglia of the Common Peroneal Nerve in Children: Case Report and Review of the Literature. AB - OBJECTIVES: Intraneural ganglia are nonneoplastic cystic formations contained within the epineurium of peripheral nerves. The common peroneal nerve at the fibular neck is the most frequently affected site. Intraneural ganglia are not a frequent occurrence in the adult patients and are even rarer in children, with only 10 pediatric cases reported in the English language literature. We report on a new pediatric case of intraneural ganglion of common peroneal nerve and present a review of the English language literature on this topic in children. METHODS: A 10-year-old girl was admitted to our institution because of pain referred to posterior and anterior aspects of the right leg and right foot drop. The radiologic investigations showed a wide (20 cm long) intraneural ganglion cyst of the right common peroneal nerve. The patient underwent surgical treatment according to the Spinner technique. RESULTS: Postoperative course was uneventful. A gradual improvement of motor and sensory functions was observed, starting from the third postoperative day, with a complete motor function restoration registered 26 months after surgery. CONCLUSIONS: Intraneural ganglia of the common peroneal nerve should always be considered in the differential diagnosis of foot drop in pediatric age since because early diagnosis and adequate surgical treatment play a crucial role in the patient's motor and sensory outcomes. PMID- 26525429 TI - A Computational Model for Predicting Experimental RNA Nearest-Neighbor Free Energy Rankings: Inosine*Uridine Pairs. AB - A computational model for predicting RNA nearest neighbor free energy rankings has been expanded to include the nonstandard nucleotide inosine. The model uses average fiber diffraction data and molecular dynamic simulations to generate input geometries for Quantum mechanic calculations. This resulted in calculated intrastrand stacking, interstrand stacking, and hydrogen bonding energies that were combined to give total binding energies. Total binding energies for RNA dimer duplexes containing inosine were ranked and compared to experimentally determined free energy ranks for RNA duplexes containing inosine. Statistical analysis showed significant agreement between the computationally determined ranks and the experimentally determined ranks. PMID- 26525430 TI - Where and When do Species Interactions Set Range Limits? AB - A long-standing theory, originating with Darwin, suggests that abiotic forces set species range limits at high latitude, high elevation, and other abiotically 'stressful' areas, while species interactions set range limits in apparently more benign regions. This theory is of considerable importance for both basic and applied ecology, and while it is often assumed to be a ubiquitous pattern, it has not been clearly defined or broadly tested. We review tests of this idea and dissect how the strength of species interactions must vary across stress gradients to generate the predicted pattern. We conclude by suggesting approaches to better test this theory, which will deepen our understanding of the forces that determine species ranges and govern responses to climate change. PMID- 26525432 TI - Nanoporous Copper Doped Aluminium Pillared Montmorillonite for Dye-containing Wastewater Treatment. AB - Copper doped aluminium pillared montmorillonite (Cu-Alpill-MMT) was prepared by adding Cu2+ into the suspension of aluminium pillared montmorillonite (Alpill MMT) using high power ultrasonic treatment and calcining to CuO at 500 degrees C. The XRD and XRF data revealed that the doped CuO partially occupied both internal and external surfaces of the Alpill-MMT. The N2 adsorption/desorption analysis showed that the Cu-Alpill-MMT consisted of slit-like mesopores with two ranges of pore diameter, i.e. ~3.8 nm and ~6-30 nm. The Cu-Alpill-MMT exhibited the superior adsorption capacity for Basic Yellow 1 (BY1), however, it hardly adsorbed Reactive Orange 16 (RO16). The decolorization of RO16 was achieved when the H2O2 or H2O2/UV was introduced into the treatment system together with the Cu Alpill-MMT, acting as heterogeneous catalyst for Fenton or photo-Fenton oxidation processes, respectively. The Cu-Alpill-MMT could exhibit the antibacterial activity after intimate contact with Escherichia coli ATCC(r)25922 under JIS L 1902: 1998 (Qualitative) test method. PMID- 26525431 TI - Towards an Understanding of Racial Differences in Post-stroke Disability. AB - Due to the aging of the baby boomer generation, the number of stroke survivors is expected to increase from 7 million to over 10 million in 2030. Stroke survivorship will be particularly important for African Americans who have a higher incidence of strokes compared to non-Hispanics whites and greater post stroke disability. Current evidence suggests that the most prominent racial differences in post-stroke disability emerge in the post-stroke period. Further work, with a focus on modifiable factors, is needed to understand which factors in the post-stroke period lead to racial differences in post-stroke disability. PMID- 26525433 TI - Russel-Silver syndrome: A historical note and comment on an older adult. AB - Five cases of recognizable "Intra-uterine" dwarfism with cranio-facial dysostosis, disproportionately short arms, and other anomalies were written up by endocrinologist, Dr. Alex Russell in 1954. The syndrome he described went on to be named Russell-Silver syndrome. This report gives further information about the life and medical history of the most pictorially documented boy that Dr. Russell originally described in his seminal paper. The gentleman is now 69 years old and we believe him to be the oldest person known to date to have Russell-Silver syndrome. The article includes information relating to his development of type 2 diabetes mellitus, osteopenia, testosterone deficiency, and hypercholesterolemia. Methylation studies have now confirmed the diagnosis of Russell-Silver syndrome by demonstrating partial hypomethylation at the H19 Locus at IGF2P0 on chromosome 11. PMID- 26525435 TI - Bio-grout based on microbially induced sand solidification by means of asparaginase activity. AB - Bio-grout, a new ground improvement method, has been recently developed to improve the mechanical properties, decrease the permeability of porous materials, reinforce or repair cementitious materials and modify the properties of soil or sand. Bio-grout production depends on microbially induced calcite precipitation (MICP), which is driven mainly by an enzyme, urease. However, urease-based MICP process produces excessive ammonia, in addition to secondary pollution generated by urea that is used as substrate in it. In the present study, we reported asparaginase-based MICP process for sand bio-grout development using Bacillus megaterium, and results were also compared with urease-based bio-grouts. The asparaginase activity led to significantly less ammonia production compared to urease without compromising with desired properties of a novel grout. The UCS of bio-grout was obtained at 980 kPa, while the permeability was decreased substantially. The mineralogical composition of precipitated substance was identified as calcite using XRD and the crystal morphology was observed under SEM. The mass percentage of calcite in bio-grout was calculated by thermogravimetric analysis and XCT verified calcite precipitation in it. The results confirmed that biocalcification by means of bacterial asparaginase is a potential solution for geotechnical problems. The asparaginase-based MICP process could be of wider acceptance in future. PMID- 26525436 TI - LGBTI Ageing and Aged Care. PMID- 26525434 TI - How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease? AB - In the last 15 years the management of inflammatory bowel disease has evolved greatly, largely through the increased use of immunomodulators and, especially, anti-tumor necrosis factor (anti-TNF) biologic agents. Within this time period, confidence in the use of anti-TNFs has increased, whilst, especially in recent years, the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines, combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease, especially those who are recently diagnosed. Concurrently, therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and anti-TNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent, or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also, however there are few data to support this. Similarly, the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention, including post hoc analyses of the pivotal registration trials, has focused on the optimization of anti-TNF agents, when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy, including an evaluation of recent data addressing unanswered questions regarding the optimal timing, dosage and duration of immunomodulator therapy in combination therapy patients. PMID- 26525437 TI - Little black bastard. PMID- 26525438 TI - Silver Rainbows: Advances in Australian ageing and aged care. PMID- 26525439 TI - Old lesbians: Gendered histories and persistent challenges. AB - AIM: This article provides an overview of how gender and historical contexts influence the well-being of old lesbians. It aims to inform the practice of aged care providers in addressing the needs of these women. METHODS: The lived experience of old lesbians is examined using feminist methodology with a focus on hegemonic femininity, social structures and cultural life. RESULTS: Old lesbians being selectively 'open', their use of health services and desire for lesbian specific aged care are all influenced by lesbophobia, a complex of discriminations. The age women began living as lesbian and fluidity of orientation, are central to understanding their particular needs. Many old lesbians have created social groups and intentional communities where there is support and freedom. CONCLUSION: The current 'inclusivity' approach is insufficient for culturally appropriate aged care for old lesbians. Developing practices that meet their needs requires better understanding of lesbians' different life courses and why they created lesbian cultures. PMID- 26525440 TI - Challenging cisgenderism in the ageing and aged care sector: Meeting the needs of older people of trans and/or non-binary experience. AB - Recent Australian legislative and policy changes can benefit people of trans and/or non-binary experience (e.g. men assigned female with stereotypically 'female' bodies, women assigned male with stereotypically 'male' bodies, and people who identify as genderqueer, agender [having no gender], bi-gender [having two genders] or another gender option). These populations often experience cisgenderism, which previous research defined as 'the ideology that invalidates people's own understanding of their genders and bodies'. Some documented forms of cisgenderism include pathologising (treating people's genders and bodies as disordered) and misgendering (disregarding people's own understanding and classifications of their genders and bodies). This system of classifying people's lived experiences of gender and body invalidation is called the cisgenderism framework. Applying the cisgenderism framework in the ageing and aged care sector can enhance service providers' ability to meet the needs of older people of trans and/or non-binary experience. PMID- 26525441 TI - Appropriate bodies and other damn lies: Intersex ageing and aged care. PMID- 26525442 TI - It is more than sex and clothes: Culturally safe services for older lesbian, gay, bisexual, transgender and intersex people. AB - This paper outlines the development of culturally safe services for older lesbian, gay, bisexual, transgender and intersex people. It draws on a framework for cultural safety, developed in New Zealand which incorporates an understanding of how history, culture and power imbalances influence the relationship between service providers and Maori people. This has been adapted to the needs of older lesbian, gay, bisexual, transgender and intersex Australians. PMID- 26525443 TI - Welcoming and celebrating diversity: The Uniting journey of learning on inclusive practice. PMID- 26525444 TI - Coming out narratives of older gay men living in New Zealand. AB - AIM: Explore the coming out narratives in a group of older gay men. METHODS: A narrative gerontological approach was employed to explore the coming out narratives of older gay men. Semi-structured digitally recorded individual interviews were undertaken with 12 gay men aged between 65 and 81 years who lived in the community. Data were analysed using a narrative data analytic process. RESULTS: Three collective narratives related to the coming out of older gay men were identified: 'early gay experiences', 'trying not to be gay' and 'acceptance'. CONCLUSION: Older gay men come from diverse socio-cultural backgrounds. However, they all grew up in an era where same-sex attraction was a criminal offence. The path to accepting being a gay man was individualised and stressful for these participants. Consequently health and social service providers need to support the ongoing development of resilience and provide a person-centred approach to care that promotes wellbeing. PMID- 26525445 TI - Understanding the experiences and needs of lesbian, gay, bisexual and trans Australians living with dementia, and their partners. AB - AIM: To outline the experiences and needs of lesbian, gay, bisexual and trans (LGBT) Australians living with dementia - and their partners. METHODS: In-depth interviews were conducted with LGBT people, their partners and service providers. RESULTS: LGBT people living with dementia experience unique challenges including the failure of some families of origin and service providers to understand and value their sexual orientation or gender identity. The fear of discrimination by service providers results in greater reliance on intimate partners for care and compounds social isolation. CONCLUSIONS: The unique experiences of LGBT people with dementia are not well understood. There is a need to recognise historical experiences, including familial relationships, and provide advocacy to ensure sexual and gender rights are not violated. There is also a need to ensure that the experiences and perspectives of LGBT people living with dementia inform the development of services. PMID- 26525446 TI - Lesbian, gay, bisexual and transgender people's attitudes to end-of-life decision making and advance care planning. AB - AIM: To examine lesbian, gay, bisexual and transgender (LGBT) people's attitudes to advance care planning (ACP) options and alternative decision-making at the end of life. METHOD: Three hundred and five LGBT people completed an online or paper based questionnaire, comprising fixed-choice questions and open-ended questions. RESULTS: Most respondents, particularly those identifying as female or transgender, preferred a partner to be their alternative decision-maker at the end of life should the need arise. Fifty-two per cent of respondents had spoken to this person about their wishes. Regarding legal options enabling end-of-life decision-making, 29% had an enduring power of attorney, 18% an enduring guardian and 12% an advance care directive. CONCLUSION: Despite the significance of ACP for promoting the rights of LGBT people at the end of life, the take-up of these options was nearly as low as for the general population. The potential for targeted strategies to increase the take-up of ACP is identified. PMID- 26525448 TI - How the 'warped' relationships between nurses' emotions, attitudes, social support and perceived organizational conditions impact customer orientation. AB - AIMS: Much research focuses on organizational culture and its impact on customer orientation or emotional states and their impact on job satisfaction and well being. This study aims to combine the complex roles of nurses' emotion states and job satisfaction in a model that identifies the effects of standards for service delivery (organizational culture), supervisor and co-worker support and the development of customer orientation. BACKGROUND: A previous study examined the relationships between nurses' personal resources, job satisfaction and customer orientation. This study examines how these variables relate to organizational standards and social support. DESIGN: A cross-sectional survey using a self completion questionnaire with validated, existing scales to measure standards for service delivery, supervisor and co-worker support, job satisfaction, empathic concern, emotional exhaustion and customer orientation. METHOD: Nurses (159) completed the questionnaire in 2010. The data were analysed using WarpPLS, a structural equation modelling software package. RESULTS: The results indicate that the final model fits the data well and explains 84% of the variance in customer orientation. The findings show the importance of standard for service delivery (organizational culture), supervisor and co-worker support on customer orientation. Nurses' personal resources interact with these, particularly supervisor and co-worker support, to develop staff job satisfaction and empathy. CONCLUSION: The need for support mechanisms in stressful times is discussed. We propose that training in compassion and empathy would help leaders to model desirable attributes that contribute towards customer orientation. PMID- 26525449 TI - Deciphering a 20-Year-Old Conundrum: The Mechanisms of Reduction by the Water/Amine/SmI2 Mixture. AB - The reaction of SmI2 with the substrates 3-methyl-2-butanone, benzyl chloride, p cyanobenzyl chloride, and anthracene were studied in the presence of water and an amine. In all cases, the water content versus rate profile shows a maximum at around 0.2 M H2 O. The rate versus amine content profile shows in all cases, except for benzyl chloride, saturation behavior, which is typical of a change in the identity of the rate-determining step. The mechanism that is in agreement with the observed data is that electron transfer occurs in the first step. With substrates that are not very electrophilic, the intermediate radical anions lose the added electron back to samarium(III) relatively quickly and the reaction cannot progress efficiently. However, in a mixture of water/amine, the amine deprotonates a molecule of water coordinated to samarium(III). The negatively charged hydroxide, which is coordinated to samarium(III), reduces its electrophilicity, and therefore, lowers the rate of back electron transfer, which allows the reaction to progress. In the case of benzyl chloride, in which electron transfer is rate determining, deprotonation by the amine is coupled to the electron-transfer step. PMID- 26525450 TI - Effect of Hepatic or Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of Ponesimod, a Selective S1P1 Receptor Modulator. AB - Ponesimod, a selective S1P1 receptor modulator, is a potential therapeutic agent for autoimmune disorders. The impact of hepatic or renal impairment on the pharmacokinetics, safety and tolerability of ponesimod and its inactive metabolites, ACT-204426 and ACT-338375, was evaluated. Two separate single centre, open-label studies with 32 (hepatic study) and 24 (renal study) male and female individuals were conducted. Hepatic impairment was based on the Child-Pugh classification, and renal impairment was determined by creatinine clearance using the Cockcroft-Gault equation. Individuals with severe hepatic or renal impairment were to be matched (sex and body mass index) with healthy individuals. All individuals received a single dose of 10 mg ponesimod. For ponesimod, the ratio of geometric means of AUC0-infinity for individuals with severe hepatic impairment versus healthy individuals was 3.07 (90% CI: 2.19, 4.32). For severely renally impaired individuals versus healthy individuals, this ratio was 1.14 (0.82, 1.58). Cmax and tmax values of ponesimod were comparable across all groups in both studies. Exposure to metabolites was increased in individuals with moderate or severe hepatic impairment as compared to healthy individuals. During the course of these studies, there were no clinically relevant abnormalities related to vital signs, 12-lead electrocardiograms and clinical laboratory values. Sixteen adverse events (AEs) were reported, 12 of them of mild intensity. No AEs were considered to be treatment related. Overall, ponesimod was well tolerated. In individuals with renal function impairment, dose adjustment is not warranted, whereas the dose should be reduced in individuals with moderate and severe hepatic impairment. PMID- 26525451 TI - Mesoporous bioactive glass nanolayer-functionalized 3D-printed scaffolds for accelerating osteogenesis and angiogenesis. AB - The hierarchical microstructure, surface and interface of biomaterials are important factors influencing their bioactivity. Porous bioceramic scaffolds have been widely used for bone tissue engineering by optimizing their chemical composition and large-pore structure. However, the surface and interface of struts in bioceramic scaffolds are often ignored. The aim of this study is to incorporate hierarchical pores and bioactive components into the bioceramic scaffolds by constructing nanopores and bioactive elements on the struts of scaffolds and further improve their bone-forming activity. Mesoporous bioactive glass (MBG) modified beta-tricalcium phosphate (MBG-beta-TCP) scaffolds with a hierarchical pore structure and a functional strut surface (~100 nm of MBG nanolayer) were successfully prepared via 3D printing and spin coating. The compressive strength and apatite-mineralization ability of MBG-beta-TCP scaffolds were significantly enhanced as compared to beta-TCP scaffolds without the MBG nanolayer. The attachment, viability, alkaline phosphatase (ALP) activity, osteogenic gene expression (Runx2, BMP2, OPN and Col I) and protein expression (OPN, Col I, VEGF, HIF-1alpha) of rabbit bone marrow stromal cells (rBMSCs) as well as the attachment, viability and angiogenic gene expression (VEGF and HIF 1alpha) of human umbilical vein endothelial cells (HUVECs) in MBG-beta-TCP scaffolds were significantly upregulated compared with conventional bioactive glass (BG)-modified beta-TCP (BG-beta-TCP) and pure beta-TCP scaffolds. Furthermore, MBG-beta-TCP scaffolds significantly enhanced the formation of new bone in vivo as compared to BG-beta-TCP and beta-TCP scaffolds. The results suggest that application of the MBG nanolayer to modify 3D-printed bioceramic scaffolds offers a new strategy to construct hierarchically porous scaffolds with significantly improved physicochemical and biological properties, such as mechanical properties, osteogenesis, angiogenesis and protein expression for bone tissue engineering applications, in which the incorporation of nanostructures and bioactive components into the scaffold struts synergistically play a key role in the improved bone formation. PMID- 26525452 TI - Hepatitis D Virus Replication. AB - This work reviews specific related aspects of hepatitis delta virus (HDV) reproduction, including virion structure, the RNA genome, the mode of genome replication, the delta antigens, and the assembly of HDV using the envelope proteins of its helper virus, hepatitis B virus (HBV). These topics are considered with perspectives ranging from a history of discovery through to still unsolved problems. HDV evolution, virus entry, and associated pathogenic potential and treatment of infections are considered in other articles in this collection. PMID- 26525453 TI - Single-Gene Determinants of Epilepsy Comorbidity. AB - Common somatic conditions are bound to occur by chance in individuals with neurological disorders as prevalent as epilepsy, but when biological links underlying the comorbidity can be uncovered, the relationship may provide clues into the origin and mechanisms of both. The expanding list of monogenic epilepsies and their associated clinical features offer a remarkable opportunity to mine the epilepsy genome for coordinate neurodevelopmental phenotypes and examine their pathogenic mechanisms. Defined single-gene-linked epilepsy syndromes identified to date include all of the most frequently cited comorbidities, such as cognitive disorders, autism, migraine, mood disorders, late-onset dementia, and even premature lethality. Gene-linked comorbidities may be aggravated by, or independent of, seizure history. Mutations in these genes establish clear biological links between abnormal neuronal synchronization and a variety of neurobehavioral disorders, and critically substantiate the definition of epilepsy as a complex spectrum disorder. Mapping the neural circuitry of epilepsy comorbidities and understanding their single-gene risk should substantially clarify this challenging aspect of clinical epilepsy management. PMID- 26525454 TI - Microcircuits in Epilepsy: Heterogeneity and Hub Cells in Network Synchronization. AB - Epilepsy is a complex disorder involving neurological alterations that lead to the pathological development of spontaneous, recurrent seizures. For decades, seizures were thought to be largely repetitive, and had been examined at the macrocircuit level using electrophysiological recordings. However, research mapping the dynamics of large neuronal populations has revealed that seizures are not simply recurrent bursts of hypersynchrony. Instead, it is becoming clear that seizures involve a complex interplay of different neurons and circuits. Herein, we will review studies examining microcircuit changes that may underlie network hyperexcitability, discussing observations from network theory, computational modeling, and optogenetics. We will delve into the idea of hub cells as pathological centers for seizure activity, and will explore optogenetics as a novel avenue to target and treat pathological circuits. Finally, we will conclude with a discussion on future directions in the field. PMID- 26525456 TI - Past, Present, and Future of Healthy Life Expectancy. AB - The success of the current biomedical paradigm based on a "disease model" may be limited in the future because of large number of comorbidities inflicting older people. In recent years, there has been growing empirical evidence, based on animal models, suggesting that the aging process could be delayed and that this process may lead to increases in life expectancy accompanied by improvements in health at older ages. In this review, we explore past, present, and future prospects of healthy life expectancy and examine whether increases in average length of life associated with delayed aging link with additional years lived disability-free at older ages. Trends in healthy life expectancy suggest improvements among older people in the United States, although younger cohorts appear to be reaching old age with increasing levels of frailty and disability. Trends in health risk factors, such as obesity and smoking, show worrisome signs of negative impacts on adult health and mortality in the near future. However, results based on a simulation model of delayed aging in humans indicate that it has the potential to increase not only the length of life but also the fraction and number of years spent disability-free at older ages. Delayed aging would likely come with additional aggregate costs. These costs could be offset if delayed aging is widely applied and people are willing to convert their greater healthiness into more years of work. PMID- 26525457 TI - Unilateral ectopic insertion of the pectoralis minor: Clinical and functional significance. AB - During routine dissection of a 70-year-old female, we observed a unilateral ectopic insertion of the left pectoralis minor muscle. The tendon was cord-like and passed through a tendon sheath superior to the coracoid process to insert on the greater tubercle of the humerus. Additionally, an aponeurosis extended from the distal aspect of the muscle's tendon and passed medially to insert near the base of the coracoid process. This is the first report of an additional aponeurosis extending from the tendon of the pectoralis minor and attaching to the coracoid process. We also observed that the pectoralis minor tendon caused an unusually smooth deep indentation on the superior aspect of the coracoid process; considering its insertion on the humerus, we hypothesize that the muscle acted as an abductor of the shoulder along with the supraspinatus. The medial extension of an aponeurotic tendon from the pectoralis minor tendon near its insertion, to the base of the coracoid process further suggests that the muscle provided stability to the glenohumeral joint while acting as an abductor. Pectoralis minor variations have been described since 1897; however, few studies have demonstrated functional or clinical significance. The redundancy of the actions of this muscle along with its long tendon suggests a potential source for autograft. PMID- 26525458 TI - A qualitative exploration of the unmet psychosocial rehabilitation needs of cancer survivors in China. AB - OBJECTIVE: This study explores the unmet psychosocial rehabilitation needs of cancer survivors. METHODS: Sixty-eight cancer survivors from the Shanghai Cancer Rehabilitation Club in China participated in one of the eight focus groups. These were transcribed verbatim, coded using thematic analysis and analysed using NVivo 10. RESULTS: Five main themes were identified: the need for (1) better information: Chinese cancer survivors find it difficult to sort and evaluate the overwhelming mass of information with which they are confronted; (2) psychological support: survivors fear cancer relapse and neighbours' discrimination against them; support from other cancer survivors can relieve the stress; (3) support for survivors' families: like the survivors, family members are under great but usually unacknowledged pressure; (4) improved health and medical services: community health service centres provide little medical, informational or psychological support for cancer survivors, who seek and expect more communication with doctors; and (5) assistance with the financial burden: costs of treatment and lack of adequate medical insurance cause substantial financial pressure for survivors. CONCLUSIONS: This study shows that, in addition to their illness, Chinese cancer survivors experience a range of stresses related to their financial circumstances, lack of reliable and summarised information, poor access to support and services (including for their families) and discrimination. Support from families seems to improve survivors' ability to cope. Cancer survivors (and their families) need an integrated package of support from their families, doctors and other service providers, hospitals and communities. These findings can inform approaches to continuing care for cancer survivors. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26525459 TI - Service Responses to People with Intellectual Disabilities and Epilepsy: A Systematic Review. AB - BACKGROUND: Epilepsy is highly prevalent in people with intellectual disabilities and is associated with increased mortality and high healthcare usage. This systematic review summarizes research on service responses to people with intellectual disabilities and epilepsy. METHOD: Studies published from 1990 were identified via electronic searches using Medline, Cinahl, PsycINFO and Web of Science, email requests to researcher networks, and cross-citations. Information extracted from studies was reviewed narratively in relation to identified themes. RESULTS: Thirty-five studies met the inclusion criteria. Overall study quality was low, with no RCTs or similarly robust intervention study designs. Access to specialists was inconsistent. The importance of proxies and the need for education regarding epilepsy for staff, carers and people with intellectual disabilities were highlighted. CONCLUSION: There are no methodologically robust studies on service-related interventions for people with intellectual disabilities and epilepsy. Further research on improving service delivery is required to substantiate findings reported here. PMID- 26525460 TI - Association of periprocedural myocardial infarction with long-term survival in patients treated with coronary revascularization therapy of chronic total occlusion. AB - OBJECTIVE: To evaluate the impact of periprocedural myocardial infarction (PMI) on long-term survival after coronary revascularization in patients with chronic total occlusion (CTO). BACKGROUND: Little is known about the clinical impact of PMI on long-term cardiac mortality after CTO revascularization in patients with stable angina. METHODS: We analyzed data from 927 patients with CTO and stable angina who were treated with coronary artery bypass grafting (CABG, n = 367) or percutaneous coronary intervention (PCI, n = 560). PMI was defined as a peak CK MB >= 3 times the upper limit of normal (ULN) after PCI or a CK-MB >= 5 times the ULN after CABG. The primary outcome was cardiac death in patients with PMI (PMI group, n = 118 [12.7%]) or without PMI (no-PMI group, n = 809 [87.3%]) after revascularization. RESULTS: During a median follow-up of 42 months, PMI occurred in 118 patients (12.7% of the overall study population). Fifty-nine patients treated with PCI (10.5% of PCI subgroup) and 59 patients treated with CABG (16.1% of CABG subgroup) suffered from PMI. In multivariate analysis, the PMI group and the no-PMI group had a similar incidence of cardiac death (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.20 to 1.62; P = 0.29). CONCLUSIONS: PMI may not be associated with increased cardiac mortality after coronary revascularization in patients with stable CTO. (c) 2015 Wiley Periodicals, Inc. PMID- 26525455 TI - Biochemical Genetic Pathways that Modulate Aging in Multiple Species. AB - The mechanisms underlying biological aging have been extensively studied in the past 20 years with the avail of mainly four model organisms: the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, the fruitfly Drosophila melanogaster, and the domestic mouse Mus musculus. Extensive research in these four model organisms has identified a few conserved genetic pathways that affect longevity as well as metabolism and development. Here, we review how the mechanistic target of rapamycin (mTOR), sirtuins, adenosine monophosphate activated protein kinase (AMPK), growth hormone/insulin-like growth factor 1 (IGF 1), and mitochondrial stress-signaling pathways influence aging and life span in the aforementioned models and their possible implications for delaying aging in humans. We also draw some connections between these biochemical pathways and comment on what new developments aging research will likely bring in the near future. PMID- 26525461 TI - Isolating active ingredients in a parent-mediated social communication intervention for toddlers with autism spectrum disorder. AB - BACKGROUND: Behavioral interventions are commonplace in the treatment of autism spectrum disorders, yet relatively little is known about how and why these interventions work. This study tests the relationship between isolated core components of a packaged social communication intervention and the primary outcome, joint engagement, to better understand how the intervention is affecting change in individuals. METHODS: A total of 86 toddlers and their parents were enrolled in the study and randomized to one of two treatments, the joint attention, symbolic play, engagement, and regulation (JASPER) parent-mediated intervention or a psychoeducational intervention. Measures regarding the parent's use of intervention strategies were collected before and after the 10-week intervention. Additional measures of child and parent joint engagement were also collected. RESULTS: A significant effect of treatment was found for all four of the core strategies of the intervention, favoring a larger increase in the JASPER condition. A hierarchical linear regression revealed several individual predictors of joint engagement, including parent-rated buy-in, interventionist rated parent involvement, and parental use of strategies. To complement the hierarchical analysis, we also tested the potential mediating effect the strategies may have on the relationship between treatment and joint engagement. Results showed that the strategy of mirrored pacing mediated the relationship between treatment and joint engagement in the positive direction. CONCLUSIONS: These results strongly suggest that the mirrored pacing strategy is an active ingredient of the JASPER treatment. PMID- 26525462 TI - Utility of Real Time 3D Echocardiography for the Assessment of Left Ventricular Mass in Patients with Hypertrophic Cardiomyopathy: Comparison with Cardiac Magnetic Resonance. AB - INTRODUCTION AND OBJECTIVES: Patients with hypertrophic cardiomyopathy (HCM) have irregular ventricular shapes with small and sometimes obliterated cavities at end systole that affect the quantification of left ventricular mass (LVM) by conventional methods, such as M-mode or two-dimensional echocardiography. The goal of this study was to validate the use of real time three-dimensional echocardiography (RT3DE) to quantify LVM using cardiac magnetic resonance imaging (CMR) as a reference, in a large population of patients with different types of HCM. METHODS: Forty-eight consecutive patients with HCM had a complete transthoracic examination and CMR performed within 7 days. LVM was calculated by M-mode and RT3DE and compared to CMR that served as gold standard. RESULTS: Left ventricular mass calculated by RT3DE was 195 +/- 41 g and 187 +/- 49 g by CMR. The correlation between the two methods was moderate, with a Lin index of 0.63 and good linear correlation (r = 0.63, P < 0.0001). The correlation was high when RT3DE was of high or adequate image quality. The correlation between LVM by M mode and CMR was poor. CONCLUSION: Three-dimensional echocardiography is an accurate method for the quantification of LVM in patients with different subtypes of HCM that is in better agreement with CMR reference values than M-mode measurements. PMID- 26525463 TI - [The application of the modern radiodiagnostic methods in otorhinolaryngology]. AB - This paper highlights the problems and difficulties associated with the introduction of the modern radiodiagnostic methods including computed and magnetic resonance tomography into the otorhinolaryngological practice in this country. The approaches to addressing these problems and overcoming difficulties are proposed. The review of the diagnostic potential of various modalities is presented. The modern algorithms for the examination of the patients presenting with various diseases of the ears, nose, and throat are described with special reference to their diagnostic value. PMID- 26525464 TI - [Differential diagnostics of chronic tonsillitis based on the severity of manifestations of tonsillogenic intoxication of the organism]. AB - The objective of the present study was to elucidate the objective diagnostic criteria for the differentiation between various forms of chronic tonsillitis (CT) based on the results of clinical, bacteriological, and serological investigations. A total of 13 patients presenting with various forms of CT were available for the examination. The mathematical analysis of the data thus obtained made it possible to identify the most clinically significant diagnostic criteria allowing to verify the form of CT. It is concluded that their application in the combination with the classification of chronic tonsillitis proposed earlier by B.S. Preobrazhensky and V.T. Pal'chun can be recommended for the choice of the most adequate strategy for the treatment of the patients chronic tonsillitis on an individual basis. PMID- 26525465 TI - [The current problems of diagnostics and expertise of occupational diseases of the upper respiratory tract]. AB - The objective of the present study was to systematize the main etiological factors as well as specific clinical, morphological, immunological, and microbiological features characteristic of the development of pathogenic changes in nasal cavity mucosa associated with occupational diseases of the upper respiratory tract (URT) of the subjects professionally exposed to the inhaled industrial aerosols (IA) with the special emphasis laid on the role of URT disorders in the development of occupational pathology of the respiratory system. The main clinical forms of occupational diseases of the upper respiratory tract are considered in accordance with the List of occupational diseases. Much attention is given to the criteria for the occupational origin of dystrophic and allergic diseases of the upper respiratory tract developing under the action of industrial aerosols. PMID- 26525466 TI - [The efficacious algorithm for the diagnostics and treatment of benign paroxysmal positional vertigo]. AB - The objective of the present study was to elucidate the prevalence of various forms of benign paroxysmal positional vertigo (BPPV) among the patients with the complaints of dizziness who had applied for the medical aid. The secondary objective was to evaluate the effectiveness of the newly developed algorithm for the diagnostics and treatment of various forms of the disease. A total of 195 patients with the verified BPPD diagnosis were available for the examination. The fraction of the patients visiting the otoneurologist's office with complaints of this conditions is estimated at 17.8%. It was shown that the women suffer from benign paroxysmal positional vertigo 1.8 times more frequently than the men. The mean age of the patients of either sex experiencing this problem is above 50 years. Most of them have idiopathic pathology. The relationship between benign paroxysmal positional vertigo and vascular neurological disorders or inner and middle ear diseases remains to be elucidated. The present study also included the assessment of the effectiveness of the combination of various repositioning maneuvers, self-assisted vestibular gymnastics in the domestic environment, and training in long lying on the unaffected side. PMID- 26525467 TI - [The specific clinical features of otogenic intracranial complications: the current views]. AB - The objective of the present study was to elucidate the specific clinical features of otogenic intracranial complications (ICC) encountered in the current otorhinolaryngological practice. The work is based on the results of the retrospective analysis of 106 adult patients presenting with otogenic intracranial complications admitted for the treatment to multidisciplinary clinics of Sankt-Peterburg and Krasnoyarsk. Forty six (42.5%) patients presented with acute otitis media. 90% of them had suppurative destructive mastoiditis. In sixty (56.6%) patients, chronic suppurative otitis media (epitympanophonia) was associated with the extensive destructive process spreading toward dura mater of the medial and posterior cranial fossae and onto the sigmoid sinus. The prevalence of intracranial complications among the adult patients suffering from suppurative otitis media and treated in the otorhinolaryngological clinics amounted to 3.17%. The overall structure of otogenic intracranial complications was as follows: meningitis 42.5%, brain and cerebellum abscess 24.5%, suppurative meningoencephalitis 19.8%, sinus thrombosis 5.7%, epidural and subdural empyemas 4.7%, the combined suppurative brain lesions 2.8%. Systemic inflammatory response syndrome (sepsis) was diagnosed in 33 (31%) patients with otogenic ICC. The high intrahospital mortality rate among the patients with this condition (20.8%) is emphasized. The main causes of the fatal outcome in the patients with otogenic intracranial complications are supposed to be brain oedema with the concomitant development of dyslocation syndrome and sepsis. PMID- 26525468 TI - [The specific features of the anatomical structure of the artery of labyrinth (an anatomical and topographical study)]. AB - The objective of the present work was to study syntopy of the artery of labyrinth using block-preparations of the posterior cranial fossa, variants of its branching-off from the vertebro-basiliar basin (VBB), and peculiar features of its anatomical structure. A total of 12 block-preparations of the posterior cranial fossa were available for the investigation. They were preliminarily stained with red latex and fixed in a three-point system. These procedures were followed by retrosigmoid craniotomy, opening of dura mater in the supero-lateral part of the cerebellomedulllary cistern, traction of the cerebellum, and blunt separation of the basiliar artery (BA). Variants of branching of the antero inferior cerebellar artery (AICA) and branching of the artery of labyrinth from AICA were studied. It was shown that the artery of labyrinth branches off from the antero-inferior cerebellar artery in 100% of the cases. The latter artery formed a loop in 14% of the cases (3 ears). The average diameter of the labyrinth artery was 0.32 mm and its mean area 0.06 sq.cm. The artery of labyrinth branched off from the posterior para-stem segment of the antero-inferior cerebellar artery in 42.6% of the cases (9 ears), and from the anterior para-stem segment of AICA in 14.2% of the cases (3 ears). Within the conventional "rhombus", the artery of labyrinth was straight in 76.2% of the cases (16 ears) and arc-shaped in 23.8% (4 ears). PMID- 26525469 TI - [Microflora of laryngeal mucosa in the healthy subjects and the patients presenting with non-specific post-intubation laryngeal granuloma]. AB - This comparative study was designed to determine the qualitative and quantitative composition of microflora of laryngeal mucosa in the healthy subjects and the patients presenting with non-specific post-intubation laryngeal granuloma. The secondary objective was to measure the sensitivity of the isolated microorganisms to antibiotic therapy. The quantitative characteristic and the species composition of the microbial associations in laryngeal mucosa were investigated in 40 healthy subjects and 72 patients presenting with non-specific post intubation laryngeal granuloma. The mean age of the participants of the study varied from 31 to 69 years. The total microbial population density in the healthy subjects was 2.672+/-614 CFU/ml compared with 21.514+/-2.382 CFU/ml in the patients. The healthy subjects were found to carry streptococci in 87.5% of the cases, staphylococci and neisseria in 60.0% and 42.5% of the cases respectively. As many as 77.8%, 83.3%, and 90.3% of the patients with non-specific post intubation laryngeal granuloma were carriers of these microorganism respectively. The dominant microorganisms in the mucous membrane of the larynx in these patients were N. flavescence (17.6%), S. aureus (9.01%), S. pneumonia (7.3%), and S. pyogenes (6.0%).The staphylococci isolated from the mucous membrane of the larynx of the patients presenting with non-specific post-intubation laryngeal granuloma exhibited the highest sensitivity to cephalosporin antibiotics (cefuroxime, cefprome or ceftriaxone) and fluoroquinolone (levofloxacin) antibiotics (100, 100, 91.7 and 96.7% respectively). PMID- 26525470 TI - [The physiological changes in the larynx of the opera singers]. AB - A total of 30 opera soloists (15 men and 15 women) at the age from 27 to 35 years were examined to elucidate the influence of vocal loading on the vocal fold colour. Two types of the vocal load were used (20 and 60 minutes in duration). In the former case, the participants were examined prior to singing and 15 min after it. In the latter case, the examination was repeated in triplicate, viz. in the morning before singing, thereafter 15 min and 12 hours after singing. Mirror laryngosopy, laryngostroboscopy, and the acoustic test were employed for the examination. It was shown that 20 minute singing did not cause an appreciable vocal fold hyperemia. It developed after singing during 60 minutes and persisted for at least the next 12 minutes in 12 men and 13 women. However, simultaneous stroboscopy and the acoustic test failed to reveal any abnormalities in these singers. It is concluded that the majority of the singers develop physiological hyperemia of the vocal folds after singing during 60 minutes that exerts neither subjectively nor objectively noticeable influence on the voice quality even though it lasts at least 12 hours. PMID- 26525471 TI - [Pathogenesis of nasal bleeding in the patients presenting with arterial hypertension]. AB - The objective of the present work was to study the pathogenetic mechanisms underlying nasal bleeding (NB) in the patients presenting with arterial hypertension (AH). A total of 47 patients with AH suffering from NB were available for the examination of whom 28 experienced a single bleeding episode and 19 had recurrent bleeding. 11 of them were treated by endonasal surgical intervention for the achievement of hemostasis. Simultaneously, mucoperichondreal biopsies were taken from the anterior septal portions and used for histological and ultrastructural investigations. The laboratory examination of all the patients has demonstrated hyperfibrinogenemia and the enhanced level of soluble monomeric fibrin complexes in the blood (especially in the patients with recurrent nasal bleeding) despite the normal platelet levels, prothrombin and thrombin times. These findings gave reason to characterize the hemostasiological status of the patients as chronic compensated disseminated intravascular coagulation (DIC) syndrome. The histological study revealed hyaline, erythrocyte rich and fibrin thrombi in the vessels of the microcirculatory system whereas ultrastructural studies showed desquamation of endothelial cells, massive desendothelization, and disintegration of the basal membrane with the exposure of subendothelium. It is supposed that these changes provoked the development of thrombosis and focal necrosis in nasal mucosa. The authors conclude that the cause of nasal bleeding associated with arterial hypertension is directly related to the lesions of vascular endothelial, microcirculatory disorders, and modification of the blood coagulation processes rather than to the mechanical rupture of blood vessels. These changes are believed to be responsible for the development of local intravascular coagulation. PMID- 26525472 TI - [Persistent infections in the children presenting with chronic ENT diseases: the potential of etiotropic therapy]. AB - The objective of the present study that involved 176 children at the age varying from 2 to 12 years presenting with chronic ENT diseases was etiological diagnostics and etiotropic therapy of these pathologies taking into consideration the duration of the disease of less than one year (n=72), from 1 to 2 years (n=54), and over 2 years (n=50). The bacteriological method was employed to identify microflora from the upper respiratory tract and the molecular-biological methods for the detection of Epstein-Barr virus DNA, cytomegalovirus, and 6 types of human herpes virus in the blood and saliva. All the children were treated with the recombinant interferon preparations given for 1-1.5 months. For 41% of the children this treatment was combined with antibacterial therapy followed by immunocorrective therapy with interferon inducers (in 79.4% of the patients) or bacterial lysates (20.6%). The study revealed the predominant role of types 4, 5, and 6 type herpes viruses in the development of chronic ENT pathologies in the children with the gradual lowering of activity of these infections over 2 years. Staphylococcus aureus and Streptococcus pyogenes as well as fungi of the genus Candida were the commonest bacterial and fungal pathogenic agents isolated from the naso- and oropharynx of the children suffering from chronic ENT pathology.The effectiveness of etiotropic therapy was shown to decrease with time, from 78% during 1 year after the onset of the disease to 30% within the next 2 years. PMID- 26525473 TI - [Local anesthesia in the children undergoing the fibroendoscopic study of the nasal cavity, nasopharynx, and larynx: are topical anesthetics needed?]. AB - This prospective randomized study with double blind control was designed to evaluate the effectiveness of various anesthetic techniques employed prior to fibroendoscopy of the nose, nasopharynx, and larynx of the children. The study included 160 children at the age varying from 3 to 14 (mean 7.4+/-2.96) years randomly allocated to four statistically comparable groups matched for age and sex. The following preparations were used to treat the children prior to fibroendoscopy: physiological solution (group 1), a 0.05% xylometazoline solution (group 2), a 10% lidocaine solution (group 3), and a mixture of 0.05% xylometazoline and 10% lidocaine solutions (group 4). The evaluation of the tolerance to the pretreatment of the nasal cavity with lidocaine and lidocaine plus xylometazoline (groups 3 and 4) showed that it was significantly (p<0.05) worse than in groups 1 and 2. The subjective tolerance to fibroendoscopy as reported by the patients was on the average similar in the children of all four groups (p>0.05). The doctors found the tolerance of fibroendoscopy to be the worst following pretreatment with the physiological solution (group 1) and the best after pretreatment with a mixture of lidocaine and xylometazoline (group 4) (p=0.03). The children comprising groups 2 and 3 were not significantly different in terms of the tolerance to fibroendoscopy (p>0.05). It is concluded that the pretreatment of the nasal cavity of the children with a 10% lidocaine solution before fibroendoscopy has no advantage over the pretreatment with a 0.05% xylometazoline solution; at the same time, insuflation of lidocaine as an anesthetic induces more pronounced negative emotions compared with the application of 0.05% xylometazoline. PMID- 26525474 TI - [The size of the vocal folds in the children during the first years of life]. AB - The objective of the present study was to determine the size of the vocal folds in the children during the first several years of life. The study included 137 children at the age from the birth up to 3 years who were referred to our clinic for the pre-planned surgical intervention with the use of endotracheal intubation. The length and the width of the vocal folds from the muscle tubercle to the anterior commissure in abduction were measured using a probe specially designed and adapted for this purpose. In all the cases, the endoscope was positioned at the same distance from the vocal folds. The fold length (ab) and width (cd) were expressed in millimeters. These parameters were measured in the following age groups of the patients: from the birth to 1 month 29 days (group 1), from 12 mo to 23 mo 29 d (group 2), from 24 mo to 35 mo 29 d (group 3), and above 36 months (group 4). The length and the width of the vocal folds varied from 2.6 mm to 7.8 mm and from 1.3 mm to 3.2 mm respectively. The length of the vocal folds increased at a rate of 1.025 mm per year showing marked variations within each age group, from the maximum value of 1.79 mm during the second year of life to the minimum of 0.48 mm during the fourth year. The authors conclude that these data may be of use for the improvement of the quality of the surgical treatment and subsequent rehabilitation of the respiratory and voice-generating functions of the larynx. PMID- 26525475 TI - [The otoneurological examination of a patient suffering from dizziness]. AB - The up-to-date bedside otoneurological examination of the dizzy patients consists of a number of tests and procedures of paramount importance for the localization and diagnostics of the causes underlying dizziness. Recent progress in neurootology made it possible to improve the quality of physical examination and diagnostics; thereby, it promoted the choice of the most adequate treatment. The authors maintain that the modern otoneurological examination must include the following mandatory stages: the measurement of the head tilt and the eye position; the assessment of the presence and the character of nystagmus, oculomotor reactions (saccades, smooth pursuit movements, optokinetic reflex), and vestibular-ocular reflex; the performance of provocative tests and positioning maneuvers; posture and balance control estimation; evaluation of the hearing function. PMID- 26525476 TI - [Tympanophonia as a topical problem of practical medicine]. AB - This paper contains the data suggesting the necessity and importance of the comprehensive treatment of tympanophonia on an individual basis including the rational choice of the combination of pharmacotherapeutic and non-medicamental modalities, such as classical acupuncture and the like. The special emphasis is laid on the importance of compliance with the prescribed hygienic procedures for the organs of hearing and prophylaxis of cochlear disorders. PMID- 26525477 TI - [Acute tonsillopharyngitis: the effectiveness of topical therapy]. AB - The objective of the present study was to evaluate the clinical effectiveness of a furasol sore throat gargle solution for the treatment of acute tonsillopharyngitis. Forty patients presenting with acute tonsillopharyngitis were allocated to two groups, 20 subjects in each, by means of independent sequential randomization. Prior to the onset of the treatment, all the patients were examined for determining the species composition of pharyngeal microflora with the use of an "AutoScan4 System" analyzer ("Siemens", USA) and estimating the resistance to antibacterial preparations (by the disk diffusion method). All the participants of the study were prescribed antibacterial therapy. In the patients of group 1 (study group), the antibacterial treatment of acute tonsillopharyngitis was supplemented by a furasol sore throat gargle solution whereas those of group 2 (controls) were treated without topical therapy. The quantitative evaluation of the severity of manifestations of the disease before and after the treatment was based on a 5-point visual-analog scale. It was shown that systemic antibacterial therapy resulted in the consistent decrease of the frequency of occurrence of pathogenic and potentially pathogenic microflora in the patients comprising both groups. Treatment with a furasol sore throat gargle solution did not lead to the appearance of bacterial species alien to the oropharynx, nor was it accompanied by the impairment of resistance of its mucous membrane to the colonization by microorganisms. The results of the study give evidence of the well apparent regression of the subjective signs of tonsillopharyngitis and the inflammatory changes in the mucous membrane of the pharynx in the patients given the topical treatment in the form of a furasol sore throat gargle solution in addition to antibacterial therapy. It is concluded that a furasol sore throat gargle solution can be recommended for the introduction into the combined treatment of the patients presenting with acute tonsillopharyngitis. PMID- 26525478 TI - [The comparative analysis of the effectiveness of various forms of the surgical treatment of the patients presenting with chronic odontogenic maxillary sinusitis]. AB - The objective of the present study was to evaluate the clinical effectiveness of various forms of the surgical treatment of the patients presenting with chronic odontogenic maxillary sinusitis (COMS) with special reference to its long-term RESULTS: The secondary objective was to assess the quality of life of such patients during the postoperative period. The study included 107 patients divided into two groups. The patients of group 1 (n=32) underwent radical operation on the maxillary sinuses (MS) as described by Caldwell and Luc. The patients of group 2 (n=75) were treated with the use of endoscopic surgery on maxillary sinuses. The results of the study suggest that endoscopic surgery on maxillary sinuses can be employed for the minimally invasive revision of the maxillary sinuses; it thereby ensures a smoother course of the postoperative period and improves the quality of life of the treated patients. PMID- 26525479 TI - [Immunoprophylaxis of infections of the upper respiratory tract in the frequently ill children]. AB - The review of the clinical studies designed to evaluate the prophylactic effectiveness of ribosomal immunization is presented. It is shown that the application of the ribosomal vaccine ribomunyl causes a significant reduction in the occurrence of acute respiratory infections in the frequently ill children, lowers the frequency of exacerbation of chronic diseases of the upper respiratory tract, and allows to decrease the use of antibiotics. The authors emphasize the high therapeutic effectiveness and safety of preventive measures against respiratory infections in the frequently ill children with the use of the anti influenza vaccine in combination with ribosomal immunization. PMID- 26525480 TI - [The new possibility for the treatment of acute cough]. AB - Acute cough associated with influenza and acute respiratory viral infection (ARVI) is one of the most common complaints prompting the patient to visit a general practitioner or an otorhinolaryngologist based at the outpatient clinic. Acute cough during ARVI in the practically healthy subjects is as a rule non productive, frequently dry, and becomes resolved within 2-3 weeks. In certain cases, however, the cough during ARVI can be productive with the well apparent abnormal expectoration of sputum especially in the aged and elderly subjects, young children, and patients suffering from the chest injuries, dry pleuritis, and other disorders. The early prescription of mucoactive preparations can prevent the development of subacute cough. In such cases, it is recommended to use the mucokinetic ambroxol that improves the mucociliary clearance (MCC) and does not require strong exertion for sputum expectoration. An important aspect in the mechanism of action of ambroxol is the stimulation of surfactant production, antioxidation effect, the improvement of rheological properties of bronchial mucus, ant-inflammatory and antiviral effects. The application of the new pharmaceutical dose form of ambroxol, neo-bronchol (orally disintegrating tablets), produces a very rapid effect (within 1 day after the intake) due to the fast absorption of this medication in the oral cavity, its rapid penetration into the circulatory system and achievement of the high concentration in blood plasma. The volatile metabolites of ambroxol that form as a result of tablet disintegration, such as ambroxol itself, menthol, and cineol, exert the mucolytic, antiseptic, and antibacterial actions, after they reach the trachea and bronchi. Irrigation of the receptors present in the inflamed mucous membrane of the larynx, pharynx, and nasal cavity, with these volatile substances produces an immediate cough-suppressive effect. It is concluded that the preparations of neo-bronchol (orally disintegrating tablets) can be recommended for the inclusion in the combined treatment of the patients presenting with acute and chronic diseases accompanied by the excretion of viscous and difficult-of-discharge bronchial mucus (such as acute and chronic bronchitis, pneumonia, chronic obstructive pulmonary disease, bronchial asthma with difficulty in sputum discharge, and bronchoectatic disease). PMID- 26525481 TI - [A case of the successful function-preserving treatment of hyoid bone chondrosarcoma]. AB - The authors report a case of the successful function-preserving treatment of a rare neck tumour, chondrosarcoma originating from the hyoid bone. The proposed combined treatment allowed to preserve the respiratory, voice-generating and protective functions of the larynx. The dynamic follow up failed to reveal the development of relapse or metastases during 1 year after surgery. PMID- 26525482 TI - Cell death inhibition by KSHV. PMID- 26525483 TI - Rapid acquisition of high-affinity DNA aptamer motifs recognizing microbial cell surfaces using polymer-enhanced capillary transient isotachophoresis. AB - We present a polymer-enhanced capillary transient isotachophoresis (PectI) selection methodology for acquisition of high-affinity (kinetically inert) DNA aptamers capable of recognizing distinct microbial cell surfaces, which requires only a single electrophoretic separation between particles (free cells and cells bound with aptamers) and molecules (unbound or dissociated DNA) in free solution. PMID- 26525484 TI - The Association of Hair Cortisol with Self-Reported Chronic Psychosocial Stress and Symptoms of Anxiety and Depression in Women Shortly after Delivery. AB - BACKGROUND: Psychosocial stress during pregnancy including anxiety and depression is known to have adverse health effects on newborns. However, measuring these psychological constructs is complex with psychological, endocrinological, and physiological systems being affected. Hair cortisol concentrations (HCC), assumed to reflect long-term endocrine consequences of stress exposure, represent a promising instrument for epidemiological research. However, the association between HCC and questionnaire-based instruments is unclear. METHODS: In the Ulm SPATZ Health Study, mothers were recruited shortly after delivery in the University Medical Centre Ulm, Germany between April 2012 and May 2013. HCC of 768 participants were determined in scalp-near 3 cm maternal hair segments, assumed to reflect cortisol exposure over the last trimester of pregnancy. Chronic stress, anxiety, and depressive symptomatology were self-reported in questionnaire-based instruments. Spearman correlation coefficients between HCC and these instruments as well as means of HCC in highly and low stressed subgroups were calculated. RESULTS: HCC were not correlated with self-reported chronic stress, anxiety, or depressive symptomatology. Furthermore, the investigation of sub-populations did not reveal substantial differences of HCC across highly and low stressed women. CONCLUSIONS: HCC were not found to correlate with self-reports of chronic stress, anxiety, or depressive symptomatology. Among other things, these findings could reflect problems with questionnaire-based assessments obtained shortly after delivery such as recall bias and/or suggest that associations between cortisol secretion and psychosocial stress are difficult to detect due to, e.g. a strong physiological increase of cortisol in the last trimester. PMID- 26525485 TI - Value of a novel PGA-collagen tube on recurrent laryngeal nerve regeneration in a rat model. AB - OBJECTIVES/HYPOTHESIS: Nerbridge (Toyobo Co., Ltd., Osaka, Japan) is a novel polyglycolic acid (PGA) tube that is filled with collagen fibers and that facilitates nerve fiber expansion and blood vessel growth. It is biocompatible and commercially available, with governmental approval for practical use in Japan. We hypothesized that the PGA-collagen tube would promote regeneration of the recurrent laryngeal nerve (RLN). This hypothesis was examined in a rat axotomy model of the RLN. STUDY DESIGN: Prospective animal study. METHODS: The axotomy model was established by transection of the left RLN in adult Sprague Dawley rats. The cut ends of the nerve were bridged using Nerbridge (Toyobo Co., Ltd.) with a 1-mm gap (tube-treatment group) or direct sutures (sutured-control group). Left vocal fold mobility, nerve conduction velocity, morphology, and histology were assessed after 15 weeks. RESULTS: Fifteen weeks after treatment, nerve fiber connections were observed macroscopically in both groups, and more clear myelinated fibers and better prevention of laryngeal muscle atrophy were observed in the tube-treatment group compared with the sutured-control group. However, vocal fold movement recovery was not observed in either group, and the conduction velocity of the RLN did not differ between the two groups. CONCLUSIONS: Better nerve regeneration was observed in the tube-treatment group. The combination therapy with molecular or gene therapy might be an effective strategy to improve vocal fold movement. The PGA-collagen tube has the potential to promote regeneration of the RLN and to be a scaffold for drug administration in these combination therapies. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:E233 E239, 2016. PMID- 26525486 TI - The Importance of Risk Adjustment in Reporting Total Joint Arthroplasty Outcomes. AB - BACKGROUND: This study describes and tests a risk adjustment model developed for the California Joint Replacement Registry to report predictors of complication rates. METHODS: Complication rates were analyzed for 9960 patients enrolled in the California Joint Replacement Registry at 22 medical centers. Multivariable logistic risk models were created to analyze risks of postoperative complications. RESULTS: Age and American Society of Anesthesiologists class were the strongest predictors of complication rates (P < .0001). Congestive heart failure and peripheral vascular disease were also statistically significant predictors of complications. Three hospitals were found to have statistically significantly worse than expected complication rates, and one was found to have a better than expected complication rate after case mix risk adjustment. CONCLUSION: Adequate risk adjustment is a key element in objective comparison of surgeons, hospitals, and devices using total joint arthroplasty registry data. PMID- 26525487 TI - Effectiveness of Intermittent Pneumatic Compression Devices for Venous Thromboembolism Prophylaxis in High-Risk Surgical Patients: A Systematic Review. AB - BACKGROUND: Thromboprophylaxis regimens include pharmacologic and mechanical options such as intermittent pneumatic compression devices (IPCDs). There are a wide variety of IPCDs available, but it is uncertain if they vary in effectiveness or ease of use. This is a systematic review of the comparative effectiveness of IPCDs for selected outcomes (mortality, venous thromboembolism [VTE], symptomatic or asymptomatic deep vein thrombosis, major bleeding, ease of use, and adherence) in postoperative surgical patients. METHODS: We searched MEDLINE (via PubMed), Embase, CINAHL, and Cochrane CENTRAL from January 1, 1995, to October 30, 2014, for randomized controlled trials, as well as relevant observational studies on ease of use and adherence. RESULTS: We identified 14 eligible randomized controlled trials (2633 subjects) and 3 eligible observational studies (1724 subjects); most were conducted in joint arthroplasty patients. Intermittent pneumatic compression devices were comparable to anticoagulation for major clinical outcomes (VTE: risk ratio, 1.39; 95% confidence interval, 0.73-2.64). Limited data suggest that concurrent use of anticoagulation with IPCD may lower VTE risk compared with anticoagulation alone, and that IPCD compared with anticoagulation may lower major bleeding risk. Subgroup analyses did not show significant differences by device location, mode of inflation, or risk of bias elements. There were no consistent associations between IPCDs and ease of use or adherence. CONCLUSIONS: Intermittent pneumatic compression devices are appropriate for VTE thromboprophylaxis when used in accordance with current clinical guidelines. The current evidence base to guide selection of a specific device or type of device is limited. PMID- 26525488 TI - Blue genes: An integrative laboratory to differentiate genetic transformation from gene mutation for underclassmen. AB - The ability of students to understand the relationship between genotype and phenotype, and the mechanisms by which genotypes and phenotypes can change is essential for students studying genetics. To this end, we have developed a four week laboratory called Blue Genes, which is designed to help novice students discriminate between two mechanisms by which the genetic material can be altered: genetic transformation and gene mutation. In the first week of the laboratory, students incubate a plasmid DNA with calcium chloride-treated Escherichia coli JM109 cells and observe a phenotype change from ampicillin sensitive to ampicillin resistant and from white color to blue color on plates containing 5 bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal) and isopropyl beta-D thiogalactopyranoside (IPTG). Over the course of the next three weeks, students use a battery of approaches including plasmid DNA isolation experiments, restriction maps, and PCR to differentiate between mutation and transformation. The students ultimately come to the conclusion that the changes in phenotypes are due to genetic transformation and not mutation based on the evidence generated over the four-week period. Pre-laboratory tests and post-laboratory tests indicate that this set of exercises is successful in helping students differentiate between transformation and mutation. The laboratory is designed for underclassmen and is a good prerequisite for an apprentice-based research opportunity, although it is not designed as a class based research experience. Potential modifications and future directions of the laboratory based upon student experiences and assessment are presented. PMID- 26525489 TI - Recent Developments in Neuropathic Pain Mechanisms: Implications for Treatment. AB - Neuropathic pain is defined as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system".Characteristic symptoms include an increased evoked pain response to noxious (hyperalgesia) and innocuous (allodynia) stimuli, spontaneous pain, shooting electric shock like pain. Sensory deficits can also exist.Available treatments are not adequate in many patients due to many factors including the complexity of the pain state, disease progression, intolerable side effects and low analgesic efficacy.A number of peripheral, spinal and supraspinal mechanisms of hyperexcitability underlie neuropathic pain, these include changes in the activity and expression of voltage gated sodium, calcium and potassium channels, as well as TRPV1 channels and alterations in the activity of neuroimmue pathways.NeP patients often experience depression, anxiety, sleep disturbances etc. alongside their pain. These co morbidites significantly reduce quality of life and as such are key treatment considerations..Improved understanding of NeP mechanisms is encouraging targeting of treatment to the mechanisms that produce painful symptoms as opposed to the etiology of disease. PMID- 26525490 TI - Genetic and Environmental Parent-Child Transmission of Value Orientations: An Extended Twin Family Study. AB - Despite cross-cultural universality of core human values, individuals differ substantially in value priorities, whereas family members show similar priorities to some degree. The latter has often been attributed to intrafamilial socialization. The analysis of self-ratings on eight core values from 399 twin pairs (ages 7-11) and their biological parents (388 mothers, 249 fathers; ages 26 65) allowed the disentanglement of environmental from genetic transmission accounting for family resemblance in value orientations. Results indicated that parent-child similarity is primarily due to shared genetic makeup. The primary source of variance in value priorities represented environmental influences that are not shared by family members. These findings do not provide evidence for parental influences beyond genetic influences contributing to intrafamilial similarity in value priorities. PMID- 26525491 TI - Cutaneous myxidiosis in European eel, Anguilla anguilla (Linnaeus, 1758): histopathology, histochemistry and laminin immunohistochemistry. AB - Histopathology, histochemistry and immunohistochemistry of the integument of European eel, Anguilla anguilla (Linnaeus, 1758), infected by Myxidium sp. are reported. Skin samples from affected and unaffected eels were dissected, formalin fixed, paraffin embedded, sectioned and stained with H&E, Periodic acid-Schiff's staining method, Alcian Blue 8 GX pH 2.5/Periodic acid-Schiff's and McCallum Goodpasture's Gram stain. Moreover, immunohistochemistry was performed using a primary polyclonal laminin antibody. Histologically, cysts (diameter 2-3 mm) were observed mainly under the scale pockets, encircled by a thin collagen layer, lined by elongated, flattened fibroblasts and containing bipolar, PAS- and Gram positive spores with opposite polar capsules. The epidermis stretched by the underlying cyst appeared dysplastic, thinned with a significant reduction in mucous cells number. Only inconsistent and aspecific inflammatory reaction was noted around the cysts at the dermis/epidermis interface. Intense laminin-like protein immunolabel was documented in the plasmodial ectoplasm and related to host anergia. This was the first report of laminin immunolabel in a member of the Myxozoa. Epidermal dysplasia represents likely an aspecific response against the underlying tensile force exerted by the developing parasite cyst, while fibroblast and collagen encapsulation denote a parasite-driven host response protecting, rather than harming, the encircled parasite. PMID- 26525492 TI - The effect of surgery with radiation on pelvic Ewing sarcoma survival. AB - BACKGROUND: Pelvic Ewing sarcoma (ES) has poorer outcomes than extremity-based lesions and the method of local control is controversial. METHODS: A retrospective review was performed of 40 primary pelvic or sacral ES treated by a single surgeon. All received modern chemotherapy and those that received radiation were treated with modern dosages. RESULTS: Fifty-five percent were disease-free at latest follow-up (median, 83.1 mos). Sixty-one percent had >= 99% necrosis, which was associated with 65% disease-free survival. Larger size (P = 0.016) and the absence of metastatic disease (P = 0.005) was predictive of survival. Eighty-three percent of relapsed patients were DOD. Half of patients who received surgery alone or RT alone have NED while 57% of those who received S/RT have NED. Complication rates were 69% (S/RT), 75% (surgery alone), 10% (RT alone). Functional outcomes were similar. CONCLUSION: Primary pelvic ES is localized at presentation in 50% and the absence of metastases is the strongest predictor for survival. Chemotherapy is key, but excellent histologic response is neither a guarantee nor a necessity for survival. More than one-third die despite an excellent histologic response and at least one-third with lung metastases survive. With chemotherapy, radiation, and surgery, reasonable control of disease can be achieved. LEVEL OF EVIDENCE III: Case-control or retrospective cohort study. PMID- 26525493 TI - Ethyl acetate Salix alba leaves extract-loaded chitosan-based hydrogel film for wound dressing applications. AB - High toxicity and multidrug resistance associated with various standard antimicrobial drugs have necessitated search for safer alternatives in plant derived materials. In this study, we performed biological examination of chitosan based hydrogel film loaded with ethyl acetate Salix alba leaves extract against 11 standard laboratory strains. FTIR showed regeneration of saccharide peak in CP1A at 1047 cm(-1) and increased in height of other peaks. DSC exothermic decomposition peaks at 112 degrees C, 175 degrees C and 251 degrees C reveal the effect of extract on hydrogel film. From FESEM images, three-dimensional cross-linking and extract easily seen in the globular form from the surface. MTT assay on HEK 293 cells showed that CP1A was non-toxic. Minimum inhibitory concentration ranges from 4000 MUg/ml to 125 MUg/ml. Enterococcus faecium, Candida glabrata and Candida tropicalis were the most resistant, while Salmonella typhi and Candida guilliermondii were the most susceptible micro-organisms. PMID- 26525494 TI - Metal-Dielectric Waveguides for High Efficiency Fluorescence Imaging. AB - We demonstrate that Metal-Dielectric Waveguide structures (MDWs) with high efficiency of fluorescence coupling can be suitable as substrates for fluorescence imaging. This hybrid MDWs consists of a continuous metal film and a dielectric top layer. The optical modes sustaining inside this structure can be excited with a high numerical aperture (N.A) objective, and then focused into a virtual optical probe with high intensity, leading to efficient excitation of fluorophores deposited on top of the MDWs. The emitted fluorophores couple with the optical modes thus enabling the directional emission, which is verified by the back focal plane (BFP) imaging. These unique properties of MDWs have been adopted in a scanning laser confocal optical microscopy, and show the merit of high efficiency fluorescence imaging. MDWs can be easily fabricated by vapor deposition and/or spin coating, the silica surface of the MDWs is suitable for biomolecule tethering, and will offer new opportunities for cell biology and biophysics research. PMID- 26525496 TI - Measurement of Ultrafast Excitonic Dynamics of Few-Layer MoS2 Using State Selective Coherent Multidimensional Spectroscopy. AB - We report the first coherent multidimensional spectroscopy study of a MoS2 film. A four-layer sample of MoS2 was synthesized on a silica substrate by a simplified sulfidation reaction and characterized by absorption and Raman spectroscopy, atomic force microscopy, and transmission electron microscopy. State-selective coherent multidimensional spectroscopy (CMDS) on the as-prepared MoS2 film resolved the dynamics of a series of diagonal and cross-peak features involving the spin-orbit split A and B excitonic states and continuum states. The spectra are characterized by striped features that are similar to those observed in CMDS studies of quantum wells where the continuum states contribute strongly to the initial excitation of both the diagonal and cross-peak features, while the A and B excitonic states contributed strongly to the final output signal. The strong contribution from the continuum states to the initial excitation shows that the continuum states are coupled to the A and B excitonic states and that fast intraband relaxation is occurring on a sub-70 fs time scale. A comparison of the CMDS excitation signal and the absorption spectrum shows that the relative importance of the continuum states is determined primarily by their absorption strength. Diagonal and cross-peak features decay with a 680 fs time constant characteristic of exciton recombination and/or trapping. The short time dynamics are complicated by coherent and partially coherent pathways that become important when the excitation pulses are temporally overlapped. In this region, the coherent dynamics create diagonal features involving both the excitonic states and continuum states, while the partially coherent pathways contribute to cross peak features. PMID- 26525495 TI - Effect of a 12-week walking exercise program on body composition and immune cell count in patients with breast cancer who are undergoing chemotherapy. AB - PURPOSE: The purpose of this study was to examine the effect of a 12-week walking exercise program on body composition and immune cell count in patients with breast cancer who are undergoing chemotherapy. METHODS: Twenty patients (age, 47.8 +/- 3.12) participated in the study. Body composition (weight, body mass index, muscle weight, body fat mass, and percent body fat) and the cell counts for immune cells (white blood corpuscles, lymphocytes, helper T cells, cytotoxic T cells, natural killer cells, and natural killer T cells) were measured before and after the 12-week walking exercise program. SPSS 17.0 statistical software was used. The two-way repeated ANOVA with post hoc was used to determine the difference between time and interaction. RESULTS: There were significant reductions in the weight (p < .05), BMI (p < .01), and percent body fat (p < .05) after the 12-week walking exercise program. However, the immune cell counts did not change significantly. CONCLUSION: These results indicated that the 12-week walking exercise program had an effect on the balances among weight, BMI and percent body fat in patients with breast cancer. PMID- 26525497 TI - Editor's Introduction to This Issue. PMID- 26525498 TI - Heavy Metal Detoxification by Different Bacillus Species Isolated from Solar Salterns. AB - The biosorption mechanism is an alternative for chemical precipitation and ultrafiltration which have been employed to treat heavy metal contamination with a limited success. In the present study, three species of Bacillus which were isolated from solar salterns were screened for their detoxification potential of the heavy metals, lead, chromium, and copper, by biosorption. Biosorption potential of each isolate was determined by Atomic Absorption Spectroscopy (AAS), Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES), and Energy Dispersive Spectroscopy (EDS) as the amount of metal present in the medium after the treatment with the isolates. Bacterial isolates, Bacillus licheniformis NSPA5, Bacillus cereus NSPA8, and Bacillus subtilis NSPA13, showed significant level of lead biosorption with maximum of 87-90% by Bacillus cereus NSPA8. The biosorption of copper and chromium was relatively low in comparison with lead. With the obtained results, we have concluded that the bacterial isolates are potential agents to treat metal contamination in more efficient and ecofriendly manner. PMID- 26525499 TI - Re: Reproducibility of first- and second-trimester uterine artery pulsatility index measured by transvaginal and transabdominal ultrasound. A.E.G.M.T. Ferreira, F. Mauad Filho, P.S.G. Abreu, F.M. Mauad, E. Araujo Jr and W.P. Martins. Ultrasound Obstet Gynecol 2015; 46: 546-552. PMID- 26525500 TI - Re: Cardiac axis shift within the cardiac cycle of normal fetuses and fetuses with congenital heart defect. Y. Zhao, S. Abuhamad, E. Sinkovskaya, M. Mlynarczyk, L. Romary and A. Abuhamad. Ultrasound Obstet Gynecol 2015; 46: 558 563. PMID- 26525501 TI - Prenatal diagnosis of congenital heart disease: improving survival. PMID- 26525502 TI - Reply: To PMID 25904437. PMID- 26525503 TI - Diagnostic rate and accuracy of the ESHRE-ESGE classification for septate uterus and other common uterine malformations: why do we not see that the Emperor is naked? PMID- 26525504 TI - Reply. PMID- 26525506 TI - Methodological approach to brain derived neurotrophic factor in children with autism spectrum disorder. PMID- 26525505 TI - Repeated dose (28-day) administration of silver nanoparticles of varied size and coating does not significantly alter the indigenous murine gut microbiome. AB - Silver nanoparticles (AgNPs) have been used as antimicrobials in a number of applications, including topical wound dressings and coatings for consumer products and biomedical devices. Ingestion is a relevant route of exposure for AgNPs, whether occurring unintentionally via Ag dissolution from consumer products, or intentionally from dietary supplements. AgNP have also been proposed as substitutes for antibiotics in animal feeds. While oral antibiotics are known to have significant effects on gut bacteria, the antimicrobial effects of ingested AgNPs on the indigenous microbiome or on gut pathogens are unknown. In addition, AgNP size and coating have been postulated as significantly influential towards their biochemical properties and the influence of these properties on antimicrobial efficacy is unknown. We evaluated murine gut microbial communities using culture-independent sequencing of 16S rRNA gene fragments following 28 days of repeated oral dosing of well-characterized AgNPs of two different sizes (20 and 110 nm) and coatings (PVP and Citrate). Irrespective of size or coating, oral administration of AgNPs at 10 mg/kg body weight/day did not alter the membership, structure or diversity of the murine gut microbiome. Thus, in contrast to effects of broad-spectrum antibiotics, repeat dosing of AgNP, at doses equivalent to 2000 times the oral reference dose and 100-400 times the effective in vitro anti microbial concentration, does not affect the indigenous murine gut microbiome. PMID- 26525507 TI - Bilateral malignant mixed serous adenocarcinoma and malignant transitional cell carcinoma of the ovaries: An extremely rare neoplasm. AB - Mixed epithelial ovarian carcinomas are extremely rare and comprise less than 4% of all malignant ovarian tumors. We report a 61-year-old postmenopausal woman with bilateral adnexal masses. In the postoperative histopathological evaluation, mixed epithelial carcinoma with areas of disseminated serous adenocarcinoma and less prevalent areas of malignant transitional cell carcinoma was observed. Up-to date, there have been only two cases with mixed serous adenocarcinoma and malignant transitional cell carcinoma reported in the English literature, and our case is the first case with bilateral tumors. PMID- 26525508 TI - Transdifferentiation via transcription factors or microRNAs: Current status and perspective. AB - Transdifferentiation as a new approach for obtaining the ideal cells for transplantation has gradually become a hot research topic. Compared with the induced pluripotent stem cells technique, transdifferentiation may have better efficiency and safety. Although the mechanism of transdifferentiation is still unknown, many studies have achieved transformation of one cell type to another through transcription factors or microRNA. The current major strategy for transdifferentiation is via transcription factors; however, there are some safety issues with the use of transcription factors. In contrast, microRNA as a novel tool for inducing transdifferentiation through post-transcriptional regulation may be more safe and efficient. In addition, the present transdifferentiation strategies involve obtaining the terminal cell directly, so the amount of cells produced may not be sufficient and they may have low capacity for cell immigration and integration. Therefore, an indirect transdifferentiation strategy for producing unipotent cells is ideal as it can preserve the proliferation capacity and differentiation pathway. PMID- 26525509 TI - Osthole promotes neuronal differentiation and inhibits apoptosis via Wnt/beta catenin signaling in an Alzheimer's disease model. AB - Neurogenesis is the process by which neural stem cells (NSCs) proliferate and differentiate into neurons. This is diminished in several neurodegenerative disorders such as Alzheimer's disease (AD), which is characterized by the deposition of amyloid (A)beta peptides and neuronal loss. Stimulating NSCs to replace lost neurons is therefore a promising approach for AD treatment. Our previous study demonstrated that osthole modulates NSC proliferation and differentiation, and may reduce Abeta protein expression in nerve cells. Here we investigated the mechanism underlying the effects of osthole on NSCs. We found that osthole enhances NSC proliferation and neuronal differentiation while suppressing apoptosis, effects that were exerted via activation of Wnt/beta catenin signaling. These results provide evidence that osthole can potentially be used as a therapeutic agent in the treatment of AD and other neurodegenerative disorders. PMID- 26525510 TI - Myricetin ameliorates the symptoms of collagen-induced arthritis in mice by inhibiting cathepsin K activity. AB - Myricetin, a common dietary flavonoid, is widely distributed in fruits and vegetables. It is known to be a food supplement contributing to human health because of its immune modulatory function, and its antioxidation, antitumor, and anti-inflammatory properties. In the present study, myricetin was shown to directly inhibit cathepsin K activity, a highly potent collagenase, which is the predominant papain-like cysteine protease expressed in osteoclasts and synovial fibroblasts. It was shown that the IC50 of myricetin for the recombinant human cathepsin was 585.3 umol/L. Also, myricetin proved to have positive effects in murine collagen-induced arthritis (CIA). Mice suffering from CIA received a daily dose of myricetin (25 mg/kg, per os). During the study, the clinical severity of the CIA and the histopathology were evaluated. Biomarkers related to the histological evaluation of cartilage degradation, namely deoxypyridinoline, cartilage oligomeric matrix protein and C-terminal telopeptide degradation product of type I collagen (CTX-I), were analyzed. Myricetin treatment reduced the levels of biomarkers indicative of cartilage degradation (p < 0.05) and ameliorated the symptoms of CIA in mice at the clinical level (p < 0.01). As the inhibitory effect of myricetin on cathepsin K activity induced beneficial effects on CIA in mice, further investigation of therapeutic interventions with myricetin in other mammals or in human rheumatoid arthritis is recommended. PMID- 26525511 TI - Origin and age of the Eisenkappel gabbro to granite suite (Carinthia, SE Austrian Alps). AB - The northern part of the Karawanken plutonic belt is a gabbro-granite complex located just north of the Periadriatic lineament near the Slovenian-Austrian border. Petrographic and geochemical studies of the Eisenkappel intrusive complex indicate that this multiphase plutonic suite developed by a combination of crystal accumulation, fractional crystallization and assimilation processes, magma mixing and mingling. The mafic rocks are alkaline and have within-plate geochemical characteristics, indicating anorogenic magmatism in an extensional setting and derivation from an enriched mantle source. The mafic melts triggered partial melting of the crust and the formation of granite. The granitic rocks are alkalic, metaluminous and have the high Fe/Fe + Mg characteristics of within plate plutons. Temperature and pressure conditions, derived from amphibole plagioclase and different amphibole thermobarometers, suggest that the analysed Eisenkappel gabbros crystallized at around 1000 +/- 20 degrees C and 380-470 MPa, whereas the granitic rock crystallized at T <= 800 +/- 20 degrees C and <= 350 MPa. Mineral-whole rock Sm-Nd analyses of two cumulate gabbros yielded 249 +/ 8.4 Ma and 250 +/- 26 Ma (epsilonNd: + 3.6), garnet-whole rock Sm-Nd analyses of two silicic samples yielded well-constrained ages of 238.4 +/- 1.9 Ma and 242.1 +/- 2.1 Ma (epsilonNd: - 2.6). PMID- 26525512 TI - Case 1: Arm immobility in an infant. PMID- 26525513 TI - Different dosages of intravenous immunoglobulin (IVIg) in treating immune thrombocytopenia with long-term follow-up of three years: Results of a prospective study including 167 cases. AB - This study compared the effects of different dosages of intravenous immunoglobulin (IVIg) against immune thrombocytopenia (ITP). A total of 167 patients, 91 adults and 76 children, with ITP, followed-up for three years in the case-control study, were divided into three subgroups according to the dosages of IVIg administered: group A (0.2 g/kg/day), group B (0.3 g/kg/day) and group C (0.4 g/kg/day). The therapeutic response in 91 adult patients did not differ significantly among the three groups of IVIg dosages (p = 0.459). The response rate of IVIg treatment in the three adult groups was 97.1% for group A, 97.2% for group B and 100% for group C. The mean time for raising platelets to 30 * 10(9)/L in group A was 2.5 days, group B 3.2 days and group C 2.9 days (p = 0.324). The median IVIg consumption in group A was 0.83 g/kg, group B 1.22 g/kg and group C 1.64 g/kg (p < 0.01). Similar results were shown in the children groups. The follow-up results showed no significant difference of clinical outcome between groups A, B and C. In conclusion, low-dose IVIg treatment is shown to be as effective as high-dose regimen without increasing the risk of developing the patients into chronic ITP conditions, suggesting that ITP patients could be treated more cost-effectively by lower conventional dosage of IVIg regimen. PMID- 26525514 TI - Sex differences in running mechanics and patellofemoral joint kinetics following an exhaustive run. AB - Patellofemoral joint pain (PFP) is a common running-related injury that is more prevalent in females and thought to be associated with altered running mechanics. Changes in running mechanics have been observed following an exhaustive run but have not been analyzed relative to the sex bias for PFP. The purpose of this study was to test if females demonstrate unique changes in running mechanics associated with PFP following an exhaustive run. For this study, 18 females and 17 males ran to volitional exhaustion. Peak PFJ contact force and stress, PFJ contact force and stress loading rates, hip adduction excursion, and hip and knee joint frontal plane angular impulse were analyzed between females and males using separate 2 factor ANOVAs (2 (male/female)*2 (before/after exhaustion)). We observed similar changes in running mechanics among males and females over the course of the exhaustive run. Specifically, greater peak PFJ contact force loading rate (5%, P=.01), PFJ stress loading rate (5%, P<.01), hip adduction excursion (1.3 degrees , P<.01), hip abduction angular impulse (4%, P<.01), knee abduction angular impulse (5%, P=.03), average vertical ground reaction force loading rate (10%, P<.01) and step length (2.1cm, P=.001) were observed during exhausted running. These small changes in suspected PFP pathomechanical factors may increase a runner's propensity for PFP. However, unique changes in female running mechanics due to exhaustion do not appear to contribute to the sex bias for PFP. PMID- 26525515 TI - Paediatric Pain Management: Using Complementary and Alternative Medicine. AB - Children undergo acute painful procedures and many also experience chronic pain.Due to their developing systems, infants and children may be at greater risk than adults for protracted pain sensitivity.There is a need to manage acute and chronic paediatric pain to reduce children's suffering and to prevent future pain problems.Consistent with a biopsychosocial perspective, complementary and alternative medicine (CAM) should be considered in management of acute and chronic paediatric pain.Although research is limited for paediatric pain, CAM interventions receiving the most empirical attention include hypnotherapy, acupuncture and music therapy. Evidence also exists for the therapeutic benefits of yoga, massage, humor therapy and the use of certain biological based therapies. PMID- 26525517 TI - Cathelicidin modulates the function of monocytes/macrophages via the P2X7 receptor in a teleost, Plecoglossus altivelis. AB - Cathelicidins (CATHs) are a family of endogenous antimicrobial peptides that are capable of both direct bacteria-killing and immunomodulatory effects. P2X7 receptor (P2X7R) is a mediator of CATH in mammalian immune cells. Here, we studied the function and regulation of CATH in head kidney-derived monocytes/macrophages (MO/MF) from ayu, Plecoglossus altivelis. We investigated the chemotaxis of MO/MF in response to ayu CATH (PaCATH), and found that PaCATH had a dose-dependent effect on MO/MF chemotaxis with the optimal concentration of 10.0 MUg/ml. The qPCR and Western blot analysis revealed that PaCATH inhibited the expression of ayu P2X7R (PaP2X7R) at both mRNA and protein levels. Knockdown of the PaP2X7R expression in ayu MO/MF by RNA interference not only significantly inhibited the chemotactic effect of PaCATH on MO/MF, but also obviously reduced the effect of PaCATH on the phagocytosis, bacteria-killing, respiratory burst, and cytokine expression of ayu MO/MF. Our study revealed that the immunomodulatory effect of fish CATH is mediated by P2X7R. PMID- 26525516 TI - Coherent and Tunable Terahertz Radiation from Graphene Surface Plasmon Polarirons Excited by Cyclotron Electron Beam. AB - Terahertz (THz) radiation can revolutionize modern science and technology. To this date, it remains big challenges to develop intense, coherent and tunable THz radiation sources that can cover the whole THz frequency region either by means of only electronics (both vacuum electronics and semiconductor electronics) or of only photonics (lasers, for example, quantum cascade laser). Here we present a mechanism which can overcome these difficulties in THz radiation generation. Due to the natural periodicity of 2pi of both the circular cylindrical graphene structure and cyclotron electron beam (CEB), the surface plasmon polaritions (SPPs) dispersion can cross the light line of dielectric, making transformation of SPPs into radiation immediately possible. The dual natural periodicity also brings significant excellences to the excitation and the transformation. The fundamental and hybrid SPPs modes can be excited and transformed into radiation. The excited SPPs propagate along the cyclotron trajectory together with the beam and gain energy from the beam continuously. The radiation density is enhanced over 300 times, up to 10(5) W/cm(2). The radiation frequency can be widely tuned by adjusting the beam energy or chemical potential. This mechanism opens a way for developing desired THz radiation sources to cover the whole THz frequency regime. PMID- 26525518 TI - Dr Richard Bump, AJOG editor extraordinaire. PMID- 26525519 TI - Saving lives with contraceptive coverage. PMID- 26525520 TI - [Surgical results and monitoring of postoperative atrial myxomas]. AB - OBJECTIVE: To analyze the casuistics of left atrial myxoma with emphasis on results and follow-up. METHOD: We reviewed the clinical records of patients operated in the Hospital Cardiac Myxomas South Central High Specialty (HCSAE) of PEMEX in the last 7 years, with an emphasis on results and follow-up. RESULTS: The analysis showed 10 patients, of whom 60% were female and 40% male, with ages from 12 to 76 years, with a mean age of 50 years. In the clinical characteristics of patients predominated dyspnea in 90%, followed by fatigue (80%) and chest pain (60%). The incidence was 90% for the left atrium and 10% for the right atrium, had tumors less than 3cm to up to over 10cm (average of 6 to 7cm). The pathology report was myxoma in the 100% of cases, the morbidity and early mortality was 0%, with a mean hospital stay of 6 days, and a patient of 12 years of age recurred and underwent surgery five months later. The 5-year survival was 100%. CONCLUSIONS: The incidence of myxomas is well known for rare presentation, the experience in this national medical center is one patient for every 350 operations, one case per year with no mortality and excellent survival. PMID- 26525522 TI - [Device therapy for chronic heart failure]. PMID- 26525521 TI - Ticagrelor vs. clopidogrel in non-ST-elevation acute coronary syndromes. AB - AIM: The aim of this study was to evaluate the bradyarrhythmic events associated with ticagrelor combination therapy in the management of patients presenting with non-ST-segment elevation myocardial infarction (NSTEMI). PATIENTS AND METHODS: The study comprised 300 patients with NSTEMI who were treated via percutaneous coronary intervention (PCI). Patients were randomly assigned to two groups: the clopidogrel group (initial dose of 300 mg and then maintenance dose of 75 mg once daily, n = 151) and the ticagrelor group (initial dose of 180 mg and then maintenance dose of 90 mg twice daily, n = 149). All patients were followed up in the outpatient clinic. Follow-up included 12-lead electrocardiography and 24-h Holter monitoring performed 1, 6, and 12 months after the revascularization procedure. RESULTS: Of the 300 patients, 112 patients (36.7 %) had a decrease in heart rate at the 12-month follow-up. Of these, 80 patients were in the ticagrelor group (53.3 %) vs. 32 patients in the clopidogrel group (24.7 %; p < 0.05). However, the difference was not statistically significant at the 1-month and 6-month follow-up visits. After adjusting for potential confounders, the reduction in heart rate with ticagrelor combination therapy remained independently associated with a reduced risk of major adverse cardiovascular events (hazard ratio, 2.1; 95 % CI, 1.90-2.23), while ticagrelor therapy reduced the risk to a level equivalent to that of patients in the clopidogrel group. CONCLUSION: Ticagrelor can lower the resting heart rate of patients and cause bradyarrhythmias in the 12th month after PCI. PMID- 26525523 TI - [Baroreflex activation therapy. A novel interventional approach to treat heart failure with reduced ejection fraction]. AB - Sympathovagal imbalance plays an important role in the progression of heart failure with reduced ejection fraction. Baroreflex activation therapy (BAT), i. e. electrical stimulation of baroreceptors located at the carotid sinus, can reduce sympathetic and enhance parasympathetic tone. Large animal studies on BAT demonstrated improvements in cardiac function, arrhythmogenic risk and a survival benefit compared to untreated controls. The recently published Neo Randomized Heart Failure Study, the first multicenter, randomized and controlled trial of optimal medical and device therapy alone or plus BAT in patients with a left ventricular ejection fraction <= 35 %, demonstrated a reasonable safety profile of BAT in this severely ill patient population and no relevant interactions with other devices. The study found significant improvements in the New York Heart Association (NYHA) class of heart failure, quality of life as well as 6 min walking distance and data pointed to a reduction in hospitalization rates. Moreover, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were significantly reduced. This review gives an overview on BAT for the treatment of heart failure with reduced ejection fraction, from the rationale and animal experiments to the most recent clinical data and future perspectives. PMID- 26525524 TI - Submaximal Exercise-Based Equations to Predict Maximal Oxygen Uptake in Older Adults: A Systematic Review. AB - OBJECTIVE: To evaluate and discuss the accuracy of submaximal exercise-based equations to predict maximum oxygen uptake (Vo2max), validated using direct gas analysis, in older apparently healthy adults. DATA SOURCES: Studies were identified by searching 5 electronic databases and manually scanning reference lists of included articles from the respective inception of each database through April 2015. STUDY SELECTION: Studies were included if they used at least 1 submaximal exercise-based variable in the prediction, the actual Vo2max was directly measured using a gas analysis device, and if participants were apparently healthy older adults (mean age >=65y). Eligible studies were required to report at least 1 validity statistic (eg, Pearson product-moment correlation [r]) and either a predicted and measured Vo2max value or a directional significant difference between the measured and predicted Vo2max values. No limits were placed on year of publication, but only full-text, published articles in the English language were included. DATA EXTRACTION: Nine articles and 13 equations were retained from the systematic search strategy. If the same prediction equation was used across multiple trials, data from the most accurate trial were reported. DATA SYNTHESIS: Submaximal equations predicted directly measured Vo2max with a moderate to strong correlation strength (r range, 0.4 0.9). Predicted Vo2max significantly differed from directly measured in 2 of the 13 equations. The preferred mode of ergometry was walking or running (7 equations); a stepping protocol was the most accurate (R(2)=0.9, not significant between predicted and measured Vo2max). CONCLUSIONS: Factors to consider when choosing a submaximal exercise-based equation are the accuracy of the equation, the population tested, the mode of ergometry, the equipment availability, and the time needed to conduct familiarization sessions. PMID- 26525526 TI - Perception of Muscular Effort During Dynamic Elbow Extension in Multiple Sclerosis. AB - OBJECTIVE: To investigate the perception of muscular effort in individuals with multiple sclerosis (MS) and healthy controls during dynamic contractions. DESIGN: Case-control study. SETTING: MS day care center. PARTICIPANTS: Individuals with MS (n=28) and controls (n=28) (N=56). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Perceived muscular effort during dynamic elbow extensions was rated at 9 different weight intensities (10%-90% of 1-repetition maximum) in a single blind, randomized order using the OMNI-Resistance Exercise Scale. Muscle activity of the triceps brachii muscle (lateral head) was measured via surface electromyography and normalized to maximal voluntary excitation. RESULTS: According to OMNI-level ratings, significant main effects were found for the diagnostic condition (F=27.33, P<.001, eta(2)=.11), indicating 0.7 (95% confidence interval [CI], 0.3-1.1) lower mean OMNI-level ratings for MS, and for the intensity level (F=46.81, P<.001, eta(2)=.46), showing increased OMNI-level ratings for increased intensity levels for both groups. Furthermore, significant main effects were found for the diagnostic condition (F=16.52, P<.001, eta(2)=.07), indicating 7.1% (95% CI, -8.6 to 22.8) higher maximal voluntary excitation values for MS, and for the intensity level (F=33.09, P<.001, eta(2)=.36), showing higher relative muscle activities for increasing intensity levels in both groups. CONCLUSIONS: Similar to controls, individuals with MS were able to differentiate between different intensities of weight during dynamic elbow extensions when provided in a single-blind, randomized order. Therefore, perceived muscular effort might be considered to control resistance training intensities in individuals with MS. However, training intensity for individuals with MS should be chosen at approximately 1 OMNI level lower than recommended, at least for dynamic elbow extension exercises. PMID- 26525525 TI - Depression Trajectories During the First Year After Spinal Cord Injury. AB - OBJECTIVE: To determine the number and type of longitudinal depression trajectories during the first year after spinal cord injury (SCI) and to identify baseline predictors of these trajectories. DESIGN: Cohort study. SETTING: Rehabilitation and postacute community settings. PARTICIPANTS: Of 168 consecutive admissions to inpatient rehabilitation for acute SCI, 141 (115 men, 26 women) patients were enrolled in a randomized controlled trial telephone follow-up intervention, which showed no outcome differences, and completed assessments on at least 2 of the 4 follow-up occasions (3, 6, 9, and 12 months after SCI). Participants were on average 41 years old, most were non-Hispanic (96%) and white (86%), and 61.7% had tetraplegia. INTERVENTIONS: Data were drawn from the ineffective randomized controlled trial. MAIN OUTCOME MEASURE: Patient Health Questionnaire-9 (PHQ-9). RESULTS: Unconditional linear latent class growth analysis models of PHQ-9 total scores revealed an optimal 3-class solution: stable low depression (63.8%), mild to moderate depression (29.1%), and persistent moderate to severe depression (7.1%). Preinjury mental health history and baseline pain, quality of life, and grief predicted class membership. CONCLUSIONS: The modal response to SCI was stable low depression, whereas persistent moderate to severe depression primarily represented a continuation or relapse of preinjury depression. This line of research has the potential to improve identification of subgroups destined for poor outcomes and to inform early intervention studies. PMID- 26525527 TI - Influence of the Number of Predicted Words on Text Input Speed in Participants With Cervical Spinal Cord Injury. AB - OBJECTIVES: To determine whether the number of words displayed in the word prediction software (WPS) list affects text input speed (TIS) in people with cervical spinal cord injury (SCI), and whether any influence is dependent on the level of the lesion. DESIGN: A cross-sectional trial. SETTING: A rehabilitation center. PARTICIPANTS: Persons with cervical SCI (N=45). Lesion level was high (C4 and C5, American Spinal Injury Association [ASIA] grade A or B) for 15 participants (high-lesion group) and low (between C6 and C8, ASIA grade A or B) for 30 participants (low-lesion group). INTERVENTION: TIS was evaluated during four 10-minute copying tasks: (1) without WPS (Without); (2) with a display of 3 predicted words (3Words); (3) with a display of 6 predicted words (6Words); and (4) with a display of 8 predicted words (8Words). MAIN OUTCOME MEASURES: During the 4 copying tasks, TIS was measured objectively (characters per minute, number of errors) and subjectively through subject report (fatigue, perception of speed, cognitive load, satisfaction). RESULTS: For participants with low-cervical SCI, TIS without WPS was faster than with WPS, regardless of the number of words displayed (P<.001). For participants with high-cervical SCI, the use of WPS did not influence TIS (P=.99). There was no influence of the number of words displayed in a word prediction list on TIS; however, perception of TIS differed according to lesion level. CONCLUSIONS: For persons with low-cervical SCI, a small number of words should be displayed, or WPS should not be used at all. For persons with high-cervical SCI, a larger number of words displayed increases the comfort of use of WPS. PMID- 26525528 TI - Locomotor Adaptability Task Promotes Intense and Task-Appropriate Output From the Paretic Leg During Walking. AB - OBJECTIVE: To test the hypothesis that participants with stroke will exhibit appropriate increase in muscle activation of the paretic leg when taking a long step with the nonparetic leg compared to during steady-state walking, with a consequent increase in biomechanical output and symmetry during the stance phase of the modified gait cycle. DESIGN: Single-session observational study. SETTING: Clinical research center in an outpatient hospital setting. PARTICIPANTS: Adults with chronic poststroke hemiparesis (N=15). INTERVENTIONS: Participants walked on an instrumented treadmill while kinetic, kinematic, and electromyogram data were recorded. Participants performed steady-state walking and a separate trial of the long-step adaptability task in which they were instructed to intermittently take a longer step with the nonparetic leg. MAIN OUTCOME MEASURES: Forward progression, propulsive force, and neuromuscular activation during walking. RESULTS: Participants performed the adaptability task successfully and demonstrated greater neuromuscular activation in appropriate paretic leg muscles, particularly increased activity in paretic plantarflexor muscles. Propulsion and forward progression by the paretic leg were also increased. CONCLUSIONS: These findings support the assertion that the nonparetic long-step task may be effective for use in poststroke locomotor rehabilitation to engage the paretic leg and promote recovery of walking. PMID- 26525529 TI - People of the Earth: Inviting a New Animism. PMID- 26525530 TI - Assessment of tomato and wine processing solid wastes as soil amendments for biosolarization. AB - Pomaces from tomato paste and wine production are the most abundant fruit processing residues in California. These residues were examined as soil amendments for solarization to promote conditions conducive to soil disinfestation (biosolarization). Simulated biosolarization studies were performed in both aerobic and anaerobic soil environments and soil temperature elevation, pH, and evolution of CO2, H2 and CH4 gases were measured as metrics of soil microbial activity. Tomato pomace amendment induced conditions associated with soil pest inactivation, including elevation of soil temperature by up to 2 degrees C for a duration of 4days under aerobic conditions and a reduction of soil pH from 6.5 to 4.68 under anaerobic conditions. White wine grape pomace amendment showed similar trends but to a lesser extent. Red wine grape pomace was generally less suitable for biosolarization due to significantly lower soil temperature elevations, reduced acidification relative to the other pomaces and induction of methanogenesis in the soil. PMID- 26525531 TI - Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with clinical outcome. AB - BACKGROUND: Cirrhotic cardiomyopathy has been characterized by impaired contractile response to stress and/or altered diastolic relaxation, with electrophysiological abnormalities in the absence of known cardiac disease. However, the clinical significance of diastolic dysfunction (DDF) in cirrhotic patients has not been clarified. METHODS: We studied 84 cirrhotic patients with normal systolic function to evaluate the prevalence of DDF using tissue Doppler imaging, and to investigate the possible correlation of DDF with outcomes (hospitalization, death) and with the specific causes of death. RESULTS: The mean follow-up was 10+/-8months. DDF was diagnosed in 22 patients (26.2%). Patients with DDF more frequently had ascites (90.9% vs. 64.5 %; p=0.026), lower levels of albumin (OR: 5.39; p=0.004), higher NT-proBNP levels, and longer QTc interval (464+/-23ms vs. 452+/-30ms; p=0.039). At follow-up, patients with DDF did not have a higher incidence of adverse events in terms of hospitalization and death. CONCLUSIONS: The presence of diastolic dysfunction has not been found to be clearly associated with outcome, and prognosis has been determined primarily by the severity of liver disease. PMID- 26525532 TI - Inferior vena cava filter placement at bedside using computed tomography scan information: a new technique for accurate deployment. AB - BACKGROUND: An inferior vena cava filter (IVCF) is indicated for the prophylaxis of pulmonary embolism where anticoagulation is contraindicated. The majority of these filters are placed using fluoroscopy and venogram. We hypothesized that a computed tomography (CT) scan of the abdomen and pelvis provides sufficient information for successful deployment of an IVCF at bedside without the need for any further imaging during the procedure. METHODS: A retrospective review of prospectively collected data of a bedside IVCF placement technique using measurements from abdominal/pelvic CT scans without additional intraoperative imaging in 38 patients at a level 1 trauma center was conducted. RESULTS: The most common indication for IVCF placement was high-risk patients without deep venous thrombosis. All these procedures were performed at bedside. Nonretrievable (TrapEase) and retrievable (OptEase) type filters were used. All these IVCFs were placed below the renal veins without any complications. CONCLUSIONS: IVCFs can be placed based on measurements from abdominal CT scans without the need for further imaging such as fluoroscopy or an inferior vena cava venogram. This technique is as simple as bedside femoral venous line placement. PMID- 26525533 TI - Contemporary management of anastomotic leak after colon surgery: assessing the need for reoperation. AB - BACKGROUND: We sought to investigate contemporary management of anastomosis leakage (AL) after colonic anastomosis. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database 2012 to 2013 was used to identify patients with AL. Multivariate regression analysis was performed to find predictors of the need for surgical intervention in management of AL. RESULTS: A total of 32,280 patients underwent colon resection surgery with 1,240 (3.8%) developing AL. Overall, 43.9% of patients with AL did not require reoperation. Colorectal anastomosis had significantly higher risk of AL compared with ileocolonic anastomosis (adjusted odds ratio [AOR], 1.20; P = .04). However, the rate of need for reoperation was higher for AL in colocolonic anastomosis compared with ileocolonic anastomosis (AOR, 1.48; P = .04). White blood cell count (AOR, 1.07; P < .01), the presence of intra-abdominal infection with leakage (AOR, 1.47; P = .01), and protective stoma (AOR, .43, P = .02) were associated with reoperation after AL. CONCLUSIONS: Nonoperative treatment is possible in almost half of the patients with colonic AL. The anatomic location of the anastomosis impacts the risk of AL. Severity of leakage, the presence of a stoma, and general condition of patients determine the need for reoperation. PMID- 26525534 TI - Phosphoproteomics Identifies CK2 as a Negative Regulator of Beige Adipocyte Thermogenesis and Energy Expenditure. AB - Catecholamines promote lipolysis both in brown and white adipocytes, whereas the same stimuli preferentially activate thermogenesis in brown adipocytes. Molecular mechanisms for the adipose-selective activation of thermogenesis remain poorly understood. Here, we employed quantitative phosphoproteomics to map global and temporal phosphorylation profiles in brown, beige, and white adipocytes under beta3-adrenenoceptor activation and identified kinases responsible for the adipose-selective phosphorylation profiles. We found that casein kinase2 (CK2) activity is preferentially higher in white adipocytes than brown/beige adipocytes. Genetic or pharmacological blockade of CK2 in white adipocytes activates the thermogenic program in response to cAMP stimuli. Such activation is largely through reduced CK2-mediated phosphorylation of class I HDACs. Notably, inhibition of CK2 promotes beige adipocyte biogenesis and leads to an increase in whole-body energy expenditure and ameliorates diet-induced obesity and insulin resistance. These results indicate that CK2 is a plausible target to rewire the beta3-adrenenoceptor signaling cascade that promotes thermogenesis in adipocytes. PMID- 26525536 TI - Consensus Management of Gastrointestinal Events Associated with Delayed-Release Dimethyl Fumarate: A Delphi Study. AB - INTRODUCTION: Delayed-release dimethyl fumarate (DMF, also known as gastro resistant DMF) is indicated for the treatment of patients with relapsing multiple sclerosis. Gastrointestinal (GI) adverse events (AEs) occur with DMF therapy. METHODS: We used a Delphi process to reach consensus among North American clinicians on effective real-world management strategies for GI AEs associated with DMF. Clinicians were asked to complete two rounds of questionnaires developed by a steering committee; consensus in round 2 was attained if >=70% of respondents agreed on a particular strategy. RESULTS: Consensus was reached on several strategies to manage GI AEs, including administering DMF with food, slow titration, dose reduction, and use of symptomatic therapies. CONCLUSION: These consensus strategies provide clinicians with information on real-world approaches used to address the tolerability of DMF in patients with multiple sclerosis. FUNDING: Biogen. PMID- 26525537 TI - The European LEMS Registry: Baseline Demographics and Treatment Approaches. AB - INTRODUCTION: Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder affecting the neuromuscular junction, clinically characterized by proximal muscle weakness and autonomic changes. LEMS is often associated with an underlying tumor (paraneoplastic form) but also occurs in the absence of cancer (idiopathic form). Treatment consists of immunomodulation (immunosuppression), anticancer treatment when carcinoma is present, and symptomatic treatment [acetylcholinesterase inhibitors and potassium channel blockers, e.g., amifampridine (3,4-diaminopyridine, i.e., 3,4-DAP), to improve neurotransmission]. Although there has long been information from case reports, several randomized controlled trials, and treatment guidelines, population data are still scarce. METHODS: The LEMS patient registry was launched in the European community in mid-2010 as a voluntary, multinational, observational, non interventional program to collect structured empirical data on clinical course, treatment utilization, and safety and efficacy from the use of LEMS-specific treatments. RESULTS: Sixty-nine patients have been enrolled [36 males, 32 females, 1 gender not reported; mean age 61.5 (27-84) years]. Eighteen patients (26%) were diagnosed with an associated carcinoma. At the time of enrollment, the majority of patients (65%) were receiving amifampridine [either compounded 3,4 DAP (22%) or 3,4-DAP phosphate, Firdapse((r)) (43%)]. At enrollment, most patients demonstrate a profile of mild-to-moderate deficits in daily functioning but generally have good muscle strength, albeit with reduced deep tendon reflexes, frequent ataxia during walking, and signs of autonomic dysfunction including dry mouth, bladder dysfunction, and constipation. CONCLUSION: The LEMS European Union registry will continue to enroll patients and periodically report the accrued longitudinal data obtained on clinical assessments and laboratory findings, treatment practices, the safety and efficacy of treatment approaches, and long-term clinical outcomes. FUNDING: BioMarin Pharmaceutical Inc., Novato, CA, USA. PMID- 26525535 TI - Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice. AB - The gut microbiota plays a key role in host metabolism. Toll-like receptor 5 (TLR5), a flagellin receptor, is required for gut microbiota homeostasis. Accordingly, TLR5-deficient (T5KO) mice are prone to develop microbiota-dependent metabolic syndrome. Here we observed that T5KO mice display elevated neutral lipids with a compositional increase of oleate [C18:1 (n9)] relative to wild-type littermates. Increased oleate contribution to hepatic lipids and liver SCD1 expression were both microbiota dependent. Analysis of short-chain fatty acids (SCFAs) and (13)C-acetate label incorporation revealed elevated SCFA in ceca and hepatic portal blood and increased liver de novo lipogenesis in T5KO mice. Dietary SCFAs further aggravated metabolic syndrome in T5KO mice. Deletion of hepatic SCD1 not only prevented hepatic neutral lipid oleate enrichment but also ameliorated metabolic syndrome in T5KO mice. Collectively, these results underscore the key role of the gut microbiota-liver axis in the pathogenesis of metabolic diseases. PMID- 26525538 TI - Assessment of an electronic learning system for colon capsule endoscopy: a pilot study. AB - BACKGROUND: Training for colon capsule endoscopy (CCE) procedures is currently performed as a lecture and hands-on seminar. The aims of this pilot study were to assess the utility of an electronic learning system for CCE (ELCCE) designed for the Japanese Association for Capsule Endoscopy using an objective scoring engine, and to evaluate the efficacy of ELCCE on the acquisition of CCE reading competence. METHODS: ELCCE is an Internet-based learning system with the following steps: step 1, introduction; step 2, CCE reading competence assessment test (CCAT), which evaluates the competence of CCE reading prior to training; step 3, learning reading theory; step 4, training with guidance; step 5, training without guidance; step 6, final assessment; and step 7, the same as step 2. The CCAT, step 5 and step 6 were scored automatically according to: lesion detection, diagnosis (location, size, shape of lesion), management recommendations, and quality of view. Ten trainee endoscopists were initially recruited (cohort 1), followed by a validating cohort of 11 trainee endoscopists (cohort 2). RESULTS: All but one participant finished ELCCE training within 7 weeks. In step 6, accuracy ranged from 53 to 98 % and was not impacted by step 2 pretest scores. The average CCAT scores significantly increased between step 2 pretest and step 7 in both cohorts, from 42 +/- 18 % to 79 +/- 15 % in cohort 1 (p = 0.0004), and from 52 +/- 15 % to 79 +/- 14 % in cohort 2 (p = 0.0003). CONCLUSIONS: ELCCE is useful and effective for improving CCE reading competence. PMID- 26525539 TI - Aspirin-induced gastrointestinal damage is associated with an inhibition of epithelial cell autophagy. AB - BACKGROUND: Aspirin (ASA) causes gastrotoxicity by hampering the epithelial defense against luminal contents through cyclooxygenase inhibition. Since cell survival in tough conditions may depend on rescue mechanisms like autophagy, we analyzed whether epithelial cells rely on this process to defend themselves from aspirin's damaging action. METHODS: Rats received a single dose of ASA (150 mg/kg, p.o.) with or without pretreatment with the autophagy inhibitor 3 methyladenine, and gastric injury and epithelial autophagy were evaluated 3 h later. The effects of ASA on cell viability and autophagy were also evaluated in gastric epithelial AGS cells. RESULTS: Basal autophagy in the gastric mucosa was inhibited by ASA as demonstrated by increased levels of p62 and ubiquitinated proteins and total LC3 and a reduced LC3-II/LC3-I ratio. Similarly, ASA increased p62 and decreased LC3-II accumulation and the number of EmGFP/LC3B puncta in AGS cells. ASA activated the PI3K/Akt-GSK3-mTOR pathway, which phosphorylates ULK1 to prevent autophagy initiation, changes that were inhibited by the PI3K-inhibitor wortmannin. Autophagy inhibition seems to enhance the vulnerability of gastric epithelial cells as a combination of ASA with 3-methyladenine exacerbated rat gastric damage and AGS cell apoptosis. CONCLUSIONS: Our data highlight the importance of autophagy in the gastric mucosa as a protective mechanism when the epithelium is injured. In the stomach, aspirin induces mucosal damage and reduces autophagy, thus, eliminating a protective mechanism that epithelial cells could use to escape death. We hypothesize that the combination of aspirin with drugs that activate autophagy could protect against gastric damage. PMID- 26525540 TI - Reply to the letter by Kawada entitled ''Combined effect of proton-pump inhibitors and other drugs with regard to lower gastrointestinal tract bleeding with special reference to low-dose aspirin''. PMID- 26525541 TI - Heart failure: Central sleep apnoea in HF--what can we learn from SERVE-HF? PMID- 26525542 TI - Predictors, treatment, and outcomes of STEMI occurring in hospitalized patients. AB - ST-segment elevation myocardial infarction (STEMI) is most commonly caused by an acute thrombotic occlusion of a coronary artery. For patients in whom the onset of STEMI occurs outside of hospital (outpatient STEMI), early reperfusion therapy with either fibrinolysis or primary percutaneous coronary intervention reduces complications and improves survival, compared with delayed reperfusion. STEMI systems of care are defined as integrated groups of separate entities focused on reperfusion therapy for STEMI, generally including emergency medical services, emergency medicine, cardiology, nursing, and hospital administration. These systems of care have been successful at reducing total ischaemia time and outpatient STEMI mortality. By contrast, much less is known about STEMI that occurs in hospitalized patients (inpatient STEMI), which has unique clinical features and much worse outcomes than outpatient STEMI. Inpatient STEMI is associated with older age, a higher female:male ratio, and more comorbidities than outpatient STEMI. Delays in diagnosis and infrequent use of reperfusion therapy probably also contribute to unfavourable outcomes for inpatient STEMI. PMID- 26525544 TI - Common glory: the traditional and the contemporary-complementary nature of Chinese and modern medicine--a speech at Nobel laureate summit and academician forum of medicine (2014). PMID- 26525545 TI - Recent highlights of experimental research for inhibiting tumor growth by using Chinese medicine. AB - To give an overview of contemporary experimental research using Chinese medicine (CM) for the treatment of cancer. As an integral part of mainstream medicine in the People's Republic of China, CM emphasizes improvements in holistic physical condition instead of merely killing tumor cells, which is consistent with the current medical model that advocates patient-oriented treatment. Great progress has been made in experimental research, and the principle aspects include anti tumor angiogenesis, inducing apoptosis and differentiation, reversing multidrug resistance, and improving immune function. As a current hot topic in cancer research, tumor microenvironment (TME) highlights the mutual and interdependent interaction between tumor cells and their surrounding tissues, and the CM treatment concept bears a striking resemblance to it. To date, primary points of TME include extracellular matrix remodeling, inflammation, hypoxia, and angiogenesis, but trials using CM with a focus on TME are rare. Despite considerable recent development, experimental research on CM for solving cancer issues appears insufficient. Greater efforts in this field are urgently needed. PMID- 26525546 TI - Effect of meteorological factors on incidence of tuberculosis: A 15-year retrospective study based on Chinese medicine theory of five circuits and six qi. AB - OBJECTIVE: To analyze the correlations between the incidence of tuberculosis and meteorological factors over the same period and previous periods including 1, 2 and 3 years ago, defined according to the Chinese medicine theory of five circuits (Wu Yun) and six qi, to establish medical-meteorological forecast models for the Beijing area of China. METHODS: Data regarding the incidence of tuberculosis between 1990 and 2004 were obtained from the Beijing Center for Disease Control and Prevention, and the data regarding the meteorological factors (including daily average temperatures, wind speeds, precipitations, relative humidities, vapor pressures and low cloud covers) between 1987 and 2004 were collected from the Beijing Meteorological Observatory and analyzed. Descriptive statistics and a back-propagation artificial neural network were adopted to analyze the data. RESULTS: There were significant correlations between the incidence of tuberculosis and the meteorological factors in the corresponding year and previous years. Among these correlations, wind speed was the factor with the strongest influence on tuberculosis (the standardized significance was 100%). Additionally, all prediction models would successfully established, suggesting the use of a collection of meteorological factors spanning from three years ago to the present is superior to the use of single data. CONCLUSIONS: The incidence of tuberculosis in Beijing area is correlated to meteorological factors in the current year and previous years, which verifies the practicality of the theory of five circuits and six qi. PMID- 26525543 TI - Regulatory T cells in cardiovascular diseases. AB - Inflammation is essential in the initial development and progression of many cardiovascular diseases involving innate and adaptive immune responses. The role of CD4(+)CD25(+)FOXP3(+) regulatory T (TREG) cells in the modulation of inflammation and immunity has received increasing attention. Given the important role of TREG cells in the induction and maintenance of immune homeostasis and tolerance, dysregulation in the generation or function of TREG cells can trigger abnormal immune responses and lead to pathology. A wealth of evidence from experimental and clinical studies has indicated that TREG cells might have an important role in protecting against cardiovascular disease, in particular atherosclerosis and abdominal aortic aneurysm. In this Review, we provide an overview of the roles of TREG cells in the pathogenesis of a number of cardiovascular diseases, including atherosclerosis, hypertension, ischaemic stroke, abdominal aortic aneurysm, Kawasaki disease, pulmonary arterial hypertension, myocardial infarction and remodelling, postischaemic neovascularization, myocarditis and dilated cardiomyopathy, and heart failure. Although the exact molecular mechanisms underlying the cardioprotective effects of TREG cells are still to be elucidated, targeted therapies with TREG cells might provide a promising and novel future approach to the prevention and treatment of cardiovascular diseases. PMID- 26525547 TI - Bone protection effects of a novel Chinese herbal formula, taikong yangxin prescription, in hindlimb unloaded rats against bone deterioration. AB - OBJECTIVE: To investigate the protective effects of a Chinese herbal formula, taikong yangxin prescription (TKYXP) against bone deterioration in a hindlimb unloaded (tail-suspension) rat model. METHODS: Thirty-two male Sprague-Dawley rats were divided into 4 groups: tail-suspension group fed with 2.5 g*kg(-1)*day( 1) of TKYXP extract (high dose), tail-suspension group fed with 1.25 g*kg( 1)*day(-1) (low dose), tail-suspended group treated with water placebo (placebo control group) and non tail-suspended group. The effects of TKYXP on bone were assessed using peripheral quantitative computed tomography (pQCT), microcomputerized tomography (micro-CT) and three-point bending biomechanical test on the femur in vivo. RESULTS: TKYXP had a significant protective effect against bone loss induced by tail-suspension on day 28, as shown in the reduction in bone mineral density (BMD) loss, preservation of bone micro-architecture and biomechanical strength. The administration ofhigh dose TKYXP could significantly reduce the total BMD loss by 4.8% and 8.0% at the femur and tibia regions, respectively, compared with the placebo control group (P<0.01) on day 28. Its bone protective effect on the femur was further substantiated by the increases of the trabecular BMD (by 6.6%), bone volume fraction (by 20.9%), trabecular number (by 9.5%) and thickness (by 11.9%) as compared with the placebo control group. CONCLUSION: TKYXP may protect the bone under weightless influence from gradual structural deterioration in the tail-suspension model. PMID- 26525548 TI - Qualitative analysis of xinyue capsules by high-performance liquid chromatography: Preliminary evaluation of drug quality in a Sino-Austrian joint study. AB - OBJECTIVE: To develop a reliable method to assess the stability of xinyue capsules containing Panax quinquefolius saponins according to European quality standards. METHODS: An efficient high-performance liquid chromatography ultraviolet (HPLC-UV) method was established to analyse six main ginsenosides (Rb1, Rb2, Rc, Rd, Re and Rg1) in six different batches (120 capsules/batch) from the same lot of xinyue capsules and in one batch measured six times within one day. The six ginsenosides were separated on a Hypersil BDS-C18 column (3 MUm, 100 mm*3 mm) at a flow rate of 0.5 mL/min. Gradient elution was performed using a mobile phase gradient of acetonitrile-water modified with 0.01% formic acid. The HPLC chromatograms were analyzed with "LC data comparison" using Lab Solutions software. RESULTS: The HPLC peaks were identified by comparing their retention times (Rg1: 23.44 min, Re: 23.77 min, Rb1: 35.24 min, Rc: 36.18 min, Rb2: 38.55 min and Rd: 40.88 min) with those of the standards under the same chromatographic conditions, which showed similar results among the samples of six different batches and among the samples from one batch detected six times within one day. CONCLUSIONS: Xinyue capsules have good drug intra-day consistency at room temperature and exhibit a consistent quality between different batches. This study established a reliable method to assess the stability of xinyue capsules, which is suitable for further qualitative analysis and may assist in promoting the safe and effective use of Chinese herbal medicine. PMID- 26525549 TI - Effect of Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood on reproductive endocrine activity and immune functions in patients with primary Sjogren's syndrome. AB - OBJECTIVE: To investigate the effect of Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood on the reproductive endocrine-immune network and its mechanisms in patients with primary Sjogren's syndrome (pSS). METHODS: Seventy pSS patients were randomly assigned to two groups using a randomized digital table: the integrative therapy group (36 cases) and the control group (34 cases). Thirty healthy subjects were taken as a normal group. The control group was treated with hydroxychloroquine sulfate tablets alone, and the integrative therapy group was treated by Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood combined with hydroxychloroquine sulfate tablets. The treatment course was 6 months for both groups. Before and after treatment, serum estradiol (E2), testosterone (T), luteinizing hormone (LH), prolactin (PRL) by radioimmunoassay and immunoglobulin (IgG) by immunodiffusion, erythrocyte sedimentation rate (ESR) by Westergren, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) by enzyme linked immunosorbent assay were determined. RESULTS: E2 and T levels in all patients were lower than those of normal subjects before treatment (P<0.05) and were increased significantly after 6-month treatment (P<0.05). ESR, FSH, LH, IgG, IFN gamma, IL - 4 and ratios of E2/T, and IFN -gamma/IL in the patients were higher than those of normal subjects before the treatments (P<0.05), and were reduced significantly after the treatments (P<0.05). The T and IFN - gamma levels and E2/T ratio in the patients treated with integrative therapy were reduced significantly compared with the control group (P<0.05). However, the PRL levels before and after treatment were not significantly changed in the two groups (P>0.05). The ratios of E2/T and IFN -gamma/IL-4, and levels of IgG and ESR were positively correlated before and after treatment (P<0.05). CONCLUSIONS: The ratios of E2/T and IFN -gamma/IL-4 might be used as indicators of pSS activity. Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood combined with Western medicine could improve the therapeutic effect by regulating the reproductive endocrine-immune network in pSS patients. PMID- 26525550 TI - Clinical application of fast-track surgery with Chinese medicine treatment in the devascularization operation for cirrhotic portal hypertension. AB - OBJECTIVE: To investigate the clinical effect of fast-track surgery combined with Chinese medicine treatment in devascularization operation for cirrhotic esophageal varices. METHODS: Seventy-two patients with cirrhotic esophageal varices were selected from January 2009 to June 2013, and randomly assigned to a conventional group and a fast-track group (fast-track surgery combined with Chinese medicine treatment) using a randomized digital table, 36 cases in each group. Operation and anesthesia recovery time, postoperative hospitalization and quality of life were recorded and compared between groups during the perioperative period. RESULTS: Compared with the conventional group, the fast track group had longer operation time (253.6+/-46.4 min vs. 220.6+/-51.0 min) and anesthesia recovery time (50.5+/-15.9 min vs. 23.5+/-9.6 min; P<0.01); less bleeding (311.3+/-46.8 mL vs. 356.2+/-57.5 mL; P<0.01) and less transfusion (1932.3+/-106.9 mL vs. 2045.6+/-115.4 mL; P<0.01); as well as faster recovery of gastrointestinal function, shorter postoperative hospitalization and higher quality of life. There were no serious postoperative complications and no further bleeding occurred. CONCLUSION: Fast-track surgery combined with Chinese medicine treatment is a safe and feasible approach to accelerate the recovery of patients with cirrhotic portal hypertension in perioperative period of devascularization operation. PMID- 26525551 TI - Paradox of using intensive lowering of blood glucose in diabetics and strategies to overcome it and decrease cardiovascular risks. AB - Hyperglycemia significantly increases the risk of cardiovascular disease (CVD) in diabetics. However, it has been shown by a series of large scale international studies that intensive lowering of blood glucose levels not only has very limited benefits against cardiovascular problems in patients, but may even be harmful to patients at a high risk for CVD and/or poor long-term control of blood glucose levels. Therefore, Western medicine is faced with a paradox. One way to solve this may be administration of Chinese herbal medicines that not only regulate blood glucose, blood fat levels and blood pressure, but also act on multiple targets. These medicines can eliminate cytotoxicity of high glucose through anti inflammatory and anti-oxidant methods, regulation of cytokines and multiple signaling molecules, and maintenance of cell vitality and the cell cycle, etc. This allows hyperglycemic conditions to exist in a healthy manner, which is called "harmless hyperglycemia" Furthermore, these cardiovascular benefits go beyond lowering blood glucose levels. The mechanisms of action not only avoid cardiovascular injury caused by intensive lowering of blood glucose levels, but also decrease the cardiovascular dangers posed by hyperglycemia. PMID- 26525552 TI - Treatment of Mature Permanent Teeth with Necrotic Pulps and Apical Periodontitis Using Regenerative Endodontic Procedures: A Case Series. AB - INTRODUCTION: Regenerative endodontic procedures (REPs) are usually used to treat human immature permanent teeth with necrotic pulps and/or apical periodontitis. Successful REPs result in the elimination of clinical signs/symptoms, the resolution of apical periodontitis, and, in some cases, thickening of the canal walls and/or continued root development with or without apical closure. REPs can restore the vitality of tissue in the canals of immature permanent teeth previously destroyed by infection or trauma. Vital tissue is inherited with immune defense mechanisms to protect itself from foreign invaders. Recently, REPs have also been used to successfully treat human mature permanent teeth with necrotic pulps and apical periodontitis. The purpose of this case series was to present the potential of using REPs for mature permanent teeth with necrotic pulps and apical periodontitis. METHODS: This case series consisted of 6 patients, 4 females and 2 males. The patients' ages ranged from 8-21 years old. Seven permanent teeth, 4 anterior and 3 molar teeth, with necrotic pulps and apical periodontitis were treated using REP. Radiographically, the root development of all teeth was almost completed except the apices of 2 molars, which showed slightly open. Complete chemomechanical debridement of the canals of the teeth was performed, and the canals were dressed with Metapaste (Meta Biomed Co, Ltd, Chungbuk, Korea) during treatment visits. Periapical bleeding into the canals was induced at the last treatment visit by placing a hand #20 or #25 K file with the tip slightly bent through the apical foramina into the periapical tissues. A 3-mm thickness of mineral trioxide aggregate was placed into the coronal canals over semicoagulated blood. The access cavities were restored with either composite resin or amalgam. RESULTS: Follow-ups of the 7 teeth ranged from 8 to 26 months. The periapical lesions of 2 teeth were considered healed, and 5 teeth revealed healing. Clinical signs/symptoms were absent in all teeth at follow-up visits at different time points. None of the treated teeth responded to cold and electric pulp tests. CONCLUSIONS: This case series shows the potential of using REPs for mature teeth with necrotic pulp and apical periodontitis. PMID- 26525553 TI - Pulpal Responses to Direct Capping with Betamethasone/Gentamicin Cream and Mineral Trioxide Aggregate: Histologic and Micro-Computed Tomography Assessments. AB - INTRODUCTION: This clinical trial was conducted to evaluate the response of human dental pulp to direct capping with betamethasone/gentamicin (BG) cream and mineral trioxide aggregate (MTA). We hypothesized that the results of direct pulp capping with a topical BG combination would be similar to or better than those with MTA. METHODS: Thirty-six human first premolar teeth scheduled for orthodontic extraction were randomly divided into 4 groups: BG1 group (n = 9), BG cream with 2-week follow-up; BG2 group (n = 10), BG cream with 8-week follow-up; MTA1 group (n = 8), MTA with 2-week follow-up; and MTA2 group (n = 9), MTA with 8 week follow-up. Teeth were extracted and evaluated at respective time intervals. Micro-computed tomography scanning and histologic analyses were performed for all specimens. Pulp pathology (inflammation, pulp abscesses, and pulp necrosis) and reparative reaction (formation of dentin bridges) were recorded. RESULTS: Both BG cream and MTA resulted in significantly better pulpal responses at 8 weeks than at 2 weeks. Dentin bridge formation was significantly thicker in the MTA group at 8 weeks than in any other group (P < .05). Inflammation was of the acute type in all groups; no statistically significant differences in the distribution of inflammatory cells were found among the groups. Pulpal abscesses and/or necrosis were observed more often in teeth capped with BG than with MTA. CONCLUSIONS: Direct pulp capping with both BG cream and MTA was associated with dentin bridge formation. MTA resulted in a significantly better pulpal response, with less inflammation and a thicker dentin bridge at 8 weeks. PMID- 26525554 TI - Perinatal Preparation for Effective Parenting Behaviors: A Nationally Representative Survey of Patient Attitudes and Preferences. AB - OBJECTIVE: To characterize patient preferences about parenting preparation during pregnancy and the role of healthcare providers. METHODS: A nationally representative, cross-sectional survey was administered to parents of children 0 3 years old. Respondents (N = 459 non-institutionalized US adults from the GfK Knowledge Panel(r)) completed an online survey about parenting preparation (response rate = 61.2 %). Primary outcomes were perceived importance of parenting, regret about opportunities to prepare for parenting, acceptability of parenting support from healthcare workers, and preferred healthcare setting for perinatal parenting support. Statistical analyses included descriptive statistics, Chi square analyses and logistic regression. RESULTS: A majority of respondents (87.6 %, 95 % CI 83.3-90.8) believed that parenting had an equal or greater effect on early childhood behavior than the child's personality. Overall, 68.7 % (63.5-73.5 %) wished there were more opportunities during pregnancy to prepare for parenting, and a large majority (89.2, 84.9-92.4 %) believed that it would be helpful to receive parenting information from healthcare providers during pregnancy, with no differences across demographic groups. The preferred clinical encounters for receiving parenting education were at "a visit with my ObGyn/midwife" during pregnancy (58.2, 52.5-63.7 %) and at "a visit with my child's doctor/nurse practitioner" during 0-2 months postpartum (60.7, 55.0-66.2 %). CONCLUSION: A majority of US parents of young children express interest in receiving parenting support at perinatal healthcare visits. Preferences for parenting support at prenatal visits during pregnancy and at pediatric visits in the immediate postpartum period should guide clinicians, community-based outreach organizations, and governmental stakeholders seeking to design and evaluate parenting preparation interventions. PMID- 26525555 TI - Healthy Immigrant Effect: Preterm Births Among Immigrants and Refugees in Syracuse, NY. AB - OBJECTIVES: The healthy immigrant effect is the phenomenon by which immigrants experience more positive health outcomes than the native-born population in developed countries. The strength of this effect appears to be related to country of origin, health outcome, healthcare and integration policies of receiving countries, as well as immigration class. This secondary analysis of birth records examines whether immigrants and mothers from refugee countries have lower adjusted risk of preterm births than US-born mothers in Syracuse, NY, a preferred refugee resettlement area. METHODS: This secondary analysis included 6354 electronic birth records for residents in the city of Syracuse, NY who gave birth to singleton infants between 2009 and 2011. Multivariate log-binomial regression was used to calculate the adjusted relative risk for preterm birth among foreign born mothers and mothers from refugee countries, compared to US-born mothers. RESULTS: Infants born to both foreign-born women and to women from refugee countries had decreased risks of being born preterm compared to infants born to US mothers, controlling for race, late/no prenatal care, maternal age less than 18 years and smoking. CONCLUSION: Our findings support a healthy immigrant effect for preterm births both among all foreign-born immigrants and among the subsample of women from refugee countries. Mother's nativity is likely a proxy for unmeasured factors (e.g., prenatal stress, maternal diet, etc.) that may explain the relationship between mother's nativity and preterm births. Additional research is needed to better understand the underlying factors. PMID- 26525556 TI - A Typology of Substance Use Among Pregnant Teens in the United States. AB - OBJECTIVES: Previous research suggests that, in general, youth who become pregnant during their teenage years tend to report elevated levels of substance use prior to conception and substantial reductions in use during pregnancy. While such studies provide insight into aggregate patterns of adolescent substance use in relation to pregnancy, they may have the unintended effect of masking the behavioral heterogeneity of pregnant teens. METHODS: The present study employs data from a large, population-based study of adolescents in the United States. We employ latent class analysis to identify subgroups of pregnant adolescents (ages 12-17; n = 810) on the basis of variables measuring the past 12-month and past 30 day use of an extensive array of substances. RESULTS: Results revealed a four class solution. Classes were identified as Class 1: Abstainers (n = 344, 42.47 %), Class 2: Drinkers (n = 303, 37.41 %), Class 3: Alcohol and Cannabis Users (n = 77, 9.51 %), and Class 4: Polydrug Users (n = 86, 10.62 %). The Abstainers class had the highest proportion of Hispanic youth (34.3 %) as well as the highest proportion of youth residing in households earning less than $20,000 per year (44.2 %). The Polydrug Users class had the highest proportion of youth who were in late adolescence (75.58 %), non-Hispanic white (54.65 %), high-income (13.95 %), and in their first trimester of pregnancy (58.33 %). CONCLUSIONS FOR PRACTICE: Findings point to an important degree of heterogeneity among pregnant teens and may have implications for the development of interventions designed for youth exhibiting disconcerting patterns of substance use prior to pregnancy. PMID- 26525557 TI - Maternal Highly Active Antiretroviral Therapy and Child HIV-Free Survival in Malawi, 2004-2009. AB - OBJECTIVES: Highly active antiretroviral therapy (HAART) provision to eligible HIV-infected pregnant and post-partum women is critical for optimizing maternal health. We assessed the impact of maternal HAART on HIV-free survival of breastfed infants in Malawi. METHODS: The post-exposure prophylaxis of infants Malawi trial (2004-2009) enrolled mothers/infants during labor or immediately post-partum to evaluate 14-week extended infant antiretroviral prophylaxis for preventing HIV transmission through breastfeeding. Mothers meeting national HAART guidelines were referred for therapy. Child HIV-free survival-survival without HIV infection-was compared by maternal HAART status. RESULTS: Overall, 3022 mother-infant pairs contributed 4214 infant/person-years (PY) at-risk for HIV infection or death, with 532 events (incidence 12.6/100 PY, 95 % confidence interval [CI] 11.6-13.7). During follow-up, 349 mothers were HAART initiated; 581 remained HAART naive with CD4 cell counts <250 cells/mm(3), and 2092 were never HAART-eligible. By 3 months, 11 % of infants with HAART naive mothers (CD4 < 250) were infected with HIV or died versus 7 % of infants of HAART-initiated mothers and 4 % of infants of HAART-ineligible mothers. Maternal HAART was associated with a 46 % reduction in infant HIV infection or death as compared to infants with HAART naive mothers (CD4 < 250) (adjusted hazards ratio 0.54, 95 % CI 0.36 0.81). Among HIV-exposed, uninfected infants, breastfeeding, but not HAART, was significantly associated with decreased child mortality. CONCLUSIONS: HIV infection and mortality are high during the first 3 months post-partum in infants of mothers with advanced HIV, and rapid maternal HAART initiation can significantly improve HIV-related infant outcomes. Clinical Trials Registration This study is registered at http://clinicaltrials.gov/ under trial number NCT00115648. PMID- 26525558 TI - The Associations of Maternal Weight Change with Breastfeeding, Diet and Physical Activity During the Postpartum Period. AB - OBJECTIVE: To determine the association between breastfeeding practices, diet and physical activity and maternal postpartum weight. METHODS: This was a secondary data analysis of a randomized community trial on beneficiaries of the Programa de Desarrollo Humano Oportunidades, recently renamed Prospera (n = 314 pregnant women), without any diseases that could affect body weight. Generalized estimating equations were used to determine the association between postpartum weight change and changes in diet, physical activity and type of breastfeeding. RESULTS: The mean postpartum weight change from the first to the third month was 0.6 +/- 2.2 kg. Women who breastfed exclusively for 3 months had a 4.1 (SE = 1.9) kg weight reduction in comparison with women who did not provide exclusive breastfeeding or who discontinued breastfeeding before 3 months (p = 0.04). There was no association between postpartum weight change and physical activity (p = 0.24) or energy intake (p = 0.06). CONCLUSIONS: Exclusive breastfeeding was associated with maternal postpartum weight reduction. These results reinforce the World Health Organization recommendation of exclusive breastfeeding during the first 6 months of life in order to reduce the risk of weight retention or weight gain in postpartum women. It has been well established that exclusive breastfeeding is beneficial for both infants and mothers, but promoting breastfeeding as a strategy to promote postpartum weight loss is of paramount importance, especially in countries like Mexico where excessive weight in women of reproductive age is a public health problem. PMID- 26525559 TI - The Association Between Health Insurance Coverage and Skilled Birth Attendance in Ghana: A National Study. AB - OBJECTIVES: Skilled birth attendance (SBA) is a key health intervention used by roughly two-thirds of women in Ghana. The National Health Insurance Scheme provided by the Government of Ghana is widely expected to improve maternal health outcomes by removing financial barriers to health services. In this paper, we examine if indeed health insurance is able to improve SBA, a key maternal outcome. METHODS: We use data from the 2011 Ghana Multiple Indicator Cluster Survey implemented by the Ghana Statistical Services with support from the United Nations Children's Fund (UNICEF). We use a multivariate logistic model controlling for a number of enabling and predisposing factors and past experience with the health system to examine the effect of health insurance on skilled birth attendance. The sample is 2528 women. RESULTS: Our results show that women with health insurance are 47 % more likely to use SBA than women without health insurance. Results also underscore that women with repetitive contact with the health system (such as antenatal care) are more likely to have a skilled delivery (OR 3.00, p value 0.000). We also find that higher parity, rural and poor women are much less likely to use SBA. CONCLUSIONS: Health insurance may indeed be a useful mechanism to improve coverage of SBA, though many barriers to delivery care still exist for women. Further work to understand the effect of health insurance on other maternal outcomes is also warranted. PMID- 26525560 TI - Professional Quality of Life and Associated Factors Among Ugandan Midwives Working in Mubende and Mityana Rural Districts. AB - OBJECTIVE: To explore the professional quality of life and associated factors among Ugandan midwives working in Mubende and Mityana rural district to recommend interventions to improve professional well-being and outcomes of midwifery care. BACKGROUND: Professional quality of life of midwives working in rural areas may be influenced by several personal and work setting factors of care professionals often impacting the quality and outcomes of patient care. METHODS: A cross sectional study design was used to collect data from 224 midwives working in two rural districts of Uganda. FINDINGS: The majority of participants were female (80 %), with an associate degree in midwifery (92 %). The mean age and years of experience were 34 +/- 6.3 and 4 +/- 2.1 years, respectively. The mean scores on the professional quality of life scale showed average compassionate satisfaction (19 +/- 4.88), burnout (36.9 +/- 6.22) and secondary traumatic stress (22.9 +/- 6.69). The midwives' compassion satisfaction was related to psychological well being (p < 0.01) and job satisfaction (p < 0.01). Conversely, their burnout levels and secondary traumatic stress were associated with education level (p < 0.01), marital status (p < 0.01), involvement in non-midwifery health care activities (p < 0.01), and physical well-being (p < 0.01). CONCLUSION AND IMPLICATION TO PRACTICE: Midwives working in rural areas of resource-poor countries have moderate professional quality of life and tend to experience moderate to high levels of burnout, secondary traumatic stress and compassion satisfaction in their professional work. Therefore, employers need to provide deliberate work based services such as counselling, debriefing, training and social support to enhance midwives professional quality of life and quality of midwifery care and practice. PMID- 26525561 TI - Prevalence and Characteristics of Bed-Sharing Among Black and White Infants in Georgia. AB - OBJECTIVES: To examine: (1) the prevalence and characteristics of bed-sharing among non-Hispanic Black and White infants in Georgia, and (2) differences in bed sharing and sleep position behaviors prior to and after the American Academy of Pediatrics' 2005 recommendations against bed-sharing. METHODS: Georgia Pregnancy Risk Assessment Monitoring System (PRAMS) data were obtained from the Georgia Department of Public Health. Analysis was guided by the socioecological model levels of: Infant, Maternal, Family, and Community/Society within the context of race. Data from 2004 to 2011 were analyzed to address the first objective and from 2000 to 2004 and 2006 to 2011 to address the second objective. Rao-Scott Chi square tests and backward selection unconditional logistic regression models for weighted data were built separately by race; odds ratios (OR) and 95 % Confidence Intervals (CIs) were calculated. RESULTS: A total of 6595 (3528 Black and 3067 White) cases were analyzed between 2004 and 2011. Significantly more Black mothers (81.9 %) reported "ever" bed-sharing compared to White mothers (56 %), p < 0.001. Logistic regression results indicated that the most parsimonious model included variables from all socioecological levels. For Blacks, the final model included infant age, pregnancy intention, number of dependents, and use of Women, Infant and Children (WIC) Services. For Whites, the final model included infant age, maternal age, financial stress, partner-related stress, and WIC. When comparing the period 2000-2004 to 2006-2011, a total of 10,015 (5373 Black and 4642 White cases) were analyzed. A significant decrease in bedsharing was found for both Blacks and Whites; rates of non-supine sleep position decreased significantly for Blacks but not Whites. CONCLUSIONS FOR PRACTICE: Continued high rates of bed-sharing and non-supine sleep position for both Blacks and Whites demonstrate an ongoing need for safe infant sleep messaging. Risk profiles for Black and White mothers differed, suggesting the importance of tailored messaging. Specific research and practice implications are identified and described. PMID- 26525562 TI - Association between body weight and composition and plasma 25-hydroxyvitamin D level in the Diabetes Prevention Program. AB - OBJECTIVE: We examined associations between body weight and plasma 25 hydroxyvitamin D concentration (25OHD) in prediabetes and sought to estimate the impact of adiposity on these associations. METHODS: The study was conducted in the placebo (n = 1082) and intensive lifestyle (n = 1079) groups of the Diabetes Prevention Program (DPP), a multicenter trial to prevent type 2 diabetes in adults with prediabetes. Weight and 25OHD were measured at baseline, month 6, years 1 and 2. In a subset (n = 584), visceral (VAT) and subcutaneous (SAT) adiposity were assessed by computed tomography at baseline and year 1. RESULTS: In cross-sectional analyses, baseline body weight, total fat, VAT, and SAT were inversely associated with plasma 25OHD concentration after multivariable adjustment. VAT accounted for 40 % [95 % CI 11, 69] of the association of body weight with plasma 25OHD concentration. There was no significant contribution by total fat or SAT. Two-year changes in plasma 25OHD concentration varied inversely with changes in body weight (p < 0.0001). One-year changes in total fat, VAT, or SAT were not significant mediators of the association between change in plasma 25OHD concentration and body weight. CONCLUSION: Our study found an inverse association between body weight and plasma 25OHD concentration at baseline and over a 2-year period in adults with prediabetes. These findings in the DPP, a weight loss intervention study, raise the possibility that weight loss increases plasma 25OHD concentration. Whether adiposity mediates this association remains inconclusive. PMID- 26525563 TI - Endogenous endophthalmitis: diagnosis, management, and prognosis. AB - Endogenous endophthalmitis is an ophthalmic emergency that can have severe sight threatening complications. It is often a diagnostic challenge because it can manifest at any age and is associated with a number of underlying predisposing factors. Microorganisms associated with this condition vary along a broad spectrum. Depending upon the severity of the disease, both medical and surgical interventions may be employed. Due to rarity of the disease, there are no guidelines in literature for optimal management of these patients. In this review, treatment guidelines based on clinical data and microorganism profile have been proposed. PMID- 26525564 TI - Integrating Mental Health and HIV Services in Zimbabwean Communities: A Nurse and Community-led Approach to Reach the Most Vulnerable. AB - Alcohol use and depression negatively impact adherence, retention in care, and HIV progression, and people living with HIV (PLWH) have disproportionately higher depression rates. In developing countries, more than 76% of people with mental health issues receive no treatment. We hypothesized that stepped-care mental health/HIV integration provided by multiple service professionals in Zimbabwe would be acceptable and feasible. A three-phase mixed-method design was used with a longitudinal cohort of 325 nurses, community health workers, and traditional medicine practitioners in nine communities. During Phase 3, 312 PLWH were screened by nurses for mental health symptoms; 28% were positive. Of 59 PLWH screened for harmful alcohol and substance use, 36% were positive. Community health workers and traditional medicine practitioners screened 123 PLWH; 54% were positive for mental health symptoms and 29% were positive for alcohol and substance abuse. Findings indicated that stepped-care was acceptable and feasible for all provider types. PMID- 26525565 TI - Cyclic GMP-mediated memory enhancement in the object recognition test by inhibitors of phosphodiesterase-2 in mice. AB - RATIONALE AND OBJECTIVES: Cyclic nucleotide phosphodiesterase-2 (PDE2) is a potential therapeutic target for the treatment of cognitive dysfunction. Using the object recognition test (ORT), this study assessed the effects of two PDE2 inhibitors, Bay 60-7550 and ND7001, on learning and memory, and examined underlying mechanisms. METHODS: To assess the role of PDE2 inhibition on phases of memory, Bay 60-7550 (3 mg/kg) was administered: 30 min prior to training; 0, 1, or 3 h after training; or 30 min prior to recall testing. To assess cyclic nucleotide involvement in PDE2 inhibitor-enhanced memory consolidation, either the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg; intraperitoneal (IP)), soluble guanylyl cyclase inhibitor 1H-[ 1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; 20 mg/kg; IP), protein kinase G inhibitor KT5823 (2.5 MUg; intracerebroventricular (ICV)), or protein kinase A inhibitor H89 (1 MUg; ICV) was administered 30 min prior to the PDE2 inhibitor Bay 60-7550 (3 mg/kg) or ND7001 (3 mg/kg). Changes in the phosphorylation of 3'5' cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) at Ser-133 and vasodilator-stimulated phosphoprotein (VASP) at Ser-239 were determined to confirm activation of cAMP and 3'5'-cyclic guanosine monophosphate (cGMP) signaling. RESULTS: Bay 60-7550 (3 mg/kg) enhanced memory of mice in the ORT when given 30 min prior to training, immediately after training, or 30 min prior to recall. Inhibitors of the cGMP pathway blocked the memory-enhancing effects of both Bay 60-7550 (3 mg/kg) and ND7001 (3 mg/kg) on early consolidation processes. Bay 60-7550 (3 mg/kg) enhanced phosphorylation of CREB and VASP, both targets of cGMP-dependent protein kinase (PKG). CONCLUSIONS: These results confirm a potential of PDE2, or components of its signaling pathway, as a therapeutic target for drug discovery focused on restoring memory function. PMID- 26525566 TI - Immediate and lasting effects of chronic daily methamphetamine exposure on activation of cells in hypothalamic-pituitary-adrenal axis-associated brain regions. AB - RATIONALE: Chronic methamphetamine (MA) abuse leads to dependence and symptoms of withdrawal after use has ceased. Negative mood states associated with withdrawal, as well as drug reinstatement, have been linked to drug-induced disruption of the hypothalamic-pituitary-adrenal (HPA) axis. However, effects of chronic MA exposure or acute MA exposure following withdrawal on neural activation patterns within brain regions that regulate the HPA axis are unknown. OBJECTIVES: In this study, neural activation patterns were assessed by quantification of c-Fos protein in mice exposed to different regimens of MA administration. METHODS: (Experiment 1) Adult male mice were treated with MA (5 mg/kg) or saline once or once daily for 10 days. (Experiment 2) Mice were treated with MA or saline once daily for 10 days and following a 10-day withdrawal period were re-administered a final dose of MA or saline. c-Fos was quantified in brains after the final injection. RESULTS: (Experiment 1) Compared to exposure to a single dose of MA (5 mg/kg), chronic MA exposure decreased the number of c-Fos expressing cells in the paraventricular hypothalamus, dorsomedial hypothalamus, central amygdala, basolateral amygdala, bed nucleus of the stria terminalis (BNST), and CA3 hippocampal region. (Experiment 2) Compared to mice receiving their first dose of MA, mice chronically treated with MA, withdrawn, and re-administered MA, showed decreased c-Fos expressing cells within the central and basolateral amygdala, BNST, and CA3. CONCLUSIONS: HPA axis-associated amygdala, extended amygdala, and hippocampal regions endure lasting effects following chronic MA exposure and therefore may be linked to stress-related withdrawal symptoms. PMID- 26525568 TI - Stroke prevention in atrial fibrillation: Still room for practice improvement. PMID- 26525567 TI - Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism. AB - RATIONALE: Abnormalities in excitatory/inhibitory neurotransmission are hypothesized to contribute to autism spectrum disorder (ASD) etiology. BTBR T (+) Itpr3 (tf) /J (BTBR), an inbred mouse strain, displays social deficits and repetitive self-grooming, offering face validity to ASD diagnostic symptoms. Reduced GABAergic neurotransmission in BTBR suggests that GABAA receptor positive allosteric modulators (PAMs) could improve ASD-relevant BTBR phenotypes. The neuroactive steroid ganaxolone acts as a PAM, displaying anticonvulsant properties in rodent epilepsy models and an anxiolytic-like profile in the elevated plus-maze. OBJECTIVES: We evaluated ganaxolone in BTBR and C57BL/6J mice in standardized assays for sociability and repetitive behaviors. Open field and anxiety-related behaviors were tested as internal controls and for comparison with the existing neuroactive steroid literature. RESULTS: Ganaxolone improved aspects of social approach and reciprocal social interactions in BTBR, with no effect on repetitive self-grooming, and no detrimental effects in C57BL/6J. Ganaxolone increased overall exploratory activity in BTBR and C57BL/6J in the open field, social approach, and elevated plus-maze, introducing a confound for the interpretation of social improvements. Allopregnanolone and diazepam similarly increased total entries in the elevated plus-maze, indicating that behavioral activation may be a general property of GABAA receptor PAMs in these strains. CONCLUSIONS: Ganaxolone shows promise for improving sociability. In addition, ganaxolone, as well as other GABAA receptor PAMs, enhanced overall BTBR activity. The translational implications of specific sociability improvements and nonspecific behavioral activation by ganaxolone in the BTBR model remain to be determined. Future studies to explore whether PAMs provide a novel profile with unique benefits for ASD treatment will be worthwhile. PMID- 26525569 TI - New insights into symptomatic or silent atrial fibrillation complicating acute myocardial infarction. AB - Atrial fibrillation (AF) is the most frequent heart rhythm disorder in the general population and contributes not only to a major deterioration in quality of life but also to an increase in cardiovascular morbimortality. The onset of AF in the acute phase of myocardial infarction (MI) is a major event that can jeopardize the prognosis of patients in the short-, medium- and long-term, and is a powerful predictor of a poor prognosis after MI. The suspected mechanism underlying the excess mortality is the drop in coronary flow linked to the acceleration and arrhythmic nature of the left ventricular contractions, which reduce the left ventricular ejection fraction. The principal causes of AF associated death after MI are linked to heart failure. Moreover, the excess risk of death in these heart failure patients has also been associated with the onset of sudden death. Whatever its form, AF has a major negative effect on patient prognosis. In recent studies, symptomatic AF was associated with inhospital mortality of 17.8%, to which can be added mortality at 1year of 18.8%. Surprisingly, silent AF also has a negative effect on the prognosis, as it is associated with an inhospital mortality rate of 10.4%, which remains high at 5.7% at 1year. Moreover, both forms of AF are independent predictors of mortality beyond traditional risk factors. The frequency and seriousness of silent AF in the short- and long-term, which were until recently rarely studied, raises the question of systematically screening for it in the acute phase of MI. Consequently, the use of continuous ECG monitoring could be a simple, effective and inexpensive solution to improve screening for AF, even though studies are still necessary to validate this strategy. Finally, complementary studies also effect of oxidative stress and endothelial dysfunction, which seem to play a major role in triggering this rhythm disorder. PMID- 26525570 TI - Internalized Homophobia Influences Perceptions of Men's Sexual Orientation from Photos of Their Faces. AB - Although researchers have explored the perceiver characteristics that make people accurate at identifying others' sexual orientations, characteristics of the targets remain largely unexplored. In the current study, we examined how individual differences in internalized homophobia among gay men can affect perceptions of their sexual orientation by asking 49 individuals to judge the sexual orientations of 78 gay men from photos of their faces. We found that gay men reporting higher levels of internalized homophobia were less likely to have come out of the closet and were, in turn, less likely to be perceived as gay. Thus, internalized homophobia and the concealment of one's sexual minority status can impact perceptions of sexual orientation. PMID- 26525571 TI - Event-Level Analysis of Anal Sex Roles and Sex Drug Use Among Gay and Bisexual Men in Vancouver, British Columbia, Canada. AB - This study analyzed event-level partnership data from a computer-assisted survey of 719 gay and bisexual men (GBM) enrolled in the Momentum Health Study to delineate potential linkages between anal sex roles and the so-called "sex drugs," i.e., erectile dysfunction drugs (EDD), poppers, and crystal methamphetamine. Univariable and multivariable analyses using generalized linear mixed models with logit link function with sexual encounters (n = 2514) as the unit of analysis tested four hypotheses: (1) EDD are significantly associated with insertive anal sex roles, (2) poppers are significantly associated with receptive anal sex, (3) both poppers and EDD are significantly associated with anal sexual versatility, and (4) crystal methamphetamine is significantly associated with all anal sex roles. Data for survey respondents and their sexual partners allowed testing these hypotheses for both anal sex partners in the same encounter. Multivariable results supported the first three hypotheses. Crystal methamphetamine was significantly associated with all anal sex roles in the univariable models, but not significant in any multivariable ones. Other multivariable significant variables included attending group sex events, venue where first met, and self-described sexual orientation. Results indicate that GBM sex-drug use behavior features rational decision-making strategies linked to anal sex roles. They also suggest that more research on anal sex roles, particularly versatility, is needed, and that sexual behavior research can benefit from partnership analysis. PMID- 26525572 TI - Burning Mouth Syndrome. AB - The aetiology of BMS remains an enigma, however novel evidence suggests a neuropathic basis, which may explain concomitant vulvodynia in some patients.The constant high level spontaneous chronic pain in BMS has significant functional and psychological repercussions for these patients.Cognitive behavioural therapy remains the sole evidence based management of this condition, whilst some patients respond to treatment with Tricyclic antidepressants, SSRIs or SNRIs, compliance with medication remains an issue due to pharma side effects.Increasing evidence suggests that there may be 3 subgroups that should be managed differently. PMID- 26525573 TI - Pollen-mediated gene flow from transgenic cotton under greenhouse conditions is dependent on different pollinators. AB - With the large-scale release of genetically modified (GM) crops, there are ecological concerns on transgene movement from GM crops to non-GM counterparts and wild relatives. In this research, we conducted greenhouse experiments to measure pollen-mediated gene flow (PGF) in the absence and presence of pollinators (Bombus ignitus, Apis mellifera and Pieris rapae) in one GM cotton (resistant to the insect Helicoverpa armigera and the herbicide glyphosate) and two non-GM lines (Shiyuan321 and Hai7124) during 2012 and 2013. Our results revealed that: (1) PGF varied depending on the pollinator species, and was highest with B. ignitus (10.83%) and lowest with P. rapae (2.71%); (2) PGF with B. ignitus depended on the distance between GM and non-GM cottons; (3) total PGF to Shiyuan321 (8.61%) was higher than to Hai7124 (4.10%). To confirm gene flow, we tested hybrids carrying transgenes for their resistance to glyphosate and H. armigera, and most hybrids showed strong resistance to the herbicide and insect. Our research confirmed that PGF depended on pollinator species, distance between plants and the receptor plant. PMID- 26525574 TI - Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis. AB - OBJECTIVE: Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role. DESIGN: Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin. RESULTS: Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2*10-10 for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3*10-11; OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis). CONCLUSIONS: HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis. PMID- 26525575 TI - Growth trajectories in the cave bear and its extant relatives: an examination of ontogenetic patterns in phylogeny. AB - BACKGROUND: The study of postnatal ontogeny can provide insights into evolution by offering an understanding of how growth trajectories have evolved resulting in adult morphological disparity. The Ursus lineage is a good subject for studying cranial and mandibular shape and size variation in relation to postnatal ontogeny and phylogeny because it is at the same time not diverse but the species exhibit different feeding ecologies. Cranial and mandibular shapes of Ursus arctos (brown bear), U. maritimus (polar bear), U. americanus (American black bear), and the extinct U. spelaeus (cave bear) were examined, using a three-dimensional geometric morphometric approach. Additionally, ontogenetic series of crania and mandibles of U. arctos and U. spelaeus ranging from newborns to senile age were sampled. RESULTS: The distribution of specimens in morphospace allowed to distinguish species and age classes and the ontogenetic trajectories U. arctos and U. spelaeus were found to be more similar than expected by chance. Cranial shape changes during ontogeny are largely size related whereas the evolution of cranial shape disparity in this clade appears to be more influenced by dietary adaptation than by size and phylogeny. The different feeding ecologies are reflected in different cranial and mandibular shapes among species. CONCLUSIONS: The cranial and mandibular shape disparity in the Ursus lineage appears to be more influenced by adaptation to diet than by size or phylogeny. In contrast, the cranial and mandibular shape changes during postnatal ontogeny in U. arctos and U. spelaeus are probably largely size related. The patterns of morphospace occupation of the cranium and the mandible in adults and through ontogeny are different. PMID- 26525576 TI - Multi-Omic Dynamics Associate Oxygenic Photosynthesis with Nitrogenase-Mediated H2 Production in Cyanothece sp. ATCC 51142. AB - To date, the proposed mechanisms of nitrogenase-driven photosynthetic H2 production by the diazotrophic unicellular cyanobacterium Cyanothece sp. ATCC 51142 have assumed that reductant and ATP requirements are derived solely from glycogen oxidation and cyclic-electron flow around photosystem I. Through genome scale transcript and protein profiling, this study presents and tests a new hypothesis on the metabolic relationship between oxygenic photosynthesis and nitrogenase-mediated H2 production in Cyanothece 51142. Our results show that net positive rates of oxygenic photosynthesis and increased expression of photosystem II reaction centers correspond and are synchronized with nitrogenase expression and H2 production. These findings provide a new and more complete view on the metabolic processes contributing to the energy budget of photosynthetic H2 production and highlight the role of concurrent photocatalytic H2O oxidation as a participating process. PMID- 26525577 TI - Assessing the performance of maternity care in Europe: a critical exploration of tools and indicators. AB - BACKGROUND: This paper critically reviews published tools and indicators currently used to measure maternity care performance within Europe, focusing particularly on whether and how current approaches enable systematic appraisal of processes of minimal (or non-) intervention in support of physiological or "normal birth". The work formed part of COST Actions IS0907: "Childbirth Cultures, Concerns, and Consequences: Creating a dynamic EU framework for optimal maternity care" (2011-2014) and IS1405: Building Intrapartum Research Through Health - an interdisciplinary whole system approach to understanding and contextualising physiological labour and birth (BIRTH) (2014-). The Actions included the sharing of country experiences with the aim of promoting salutogenic approaches to maternity care. METHODS: A structured literature search was conducted of material published between 2005 and 2013, incorporating research databases, published documents in english in peer-reviewed international journals and indicator databases which measured aspects of health care at a national and pan-national level. Given its emergence from two COST Actions the work, inevitably, focused on Europe, but findings may be relevant to other countries and regions. RESULTS: A total of 388 indicators were identified, as well as seven tools specifically designed for capturing aspects of maternity care. Intrapartum care was the most frequently measured feature, through the application of process and outcome indicators. Postnatal and neonatal care of mother and baby were the least appraised areas. An over-riding focus on the quantification of technical intervention and adverse or undesirable outcomes was identified. Vaginal birth (no instruments) was occasionally cited as an indicator; besides this measurement few of the 388 indicators were found to be assessing non-intervention or "good" or positive outcomes more generally. CONCLUSIONS: The tools and indicators identified largely enable measurement of technical interventions and undesirable health (or pathological medical) outcomes. A physiological birth generally necessitates few, or no, interventions, yet most of the indicators presently applied fail to capture (a) this phenomenon, and (b) the relationship between different forms and processes of care, mode of birth and good or positive outcomes. A need was identified for indicators which capture non-intervention, reflecting the reality that most births are low-risk, requiring few, if any, technical medical procedures. PMID- 26525578 TI - Mitral degenerative disease mimicking a valvular tumor: a case report. AB - BACKGROUND: In rare cases, echo findings of degenerative valve disease is similar to valvular mass. CASE PRESENTATION: A 56-year-old woman was evaluated for palpitation. Echocardiography revealed an 8- mm mass on the anterior mitral leaflet with minimal mitral insufficiency. Resection of the valve tumor was attempted to prevent a possible embolism. However, the lesion was not a tumor, but an aneurysm-like bulge on the anterior leaflet without chorda elongation. Triangular resection and ring annuloplasty were performed. The patient's postoperative course was uneventful. Pathological examination revealeddegenerative disease. CONCLUSIONS: This case illustrates that a valvular mass that looks like a tumor by echocardiography may actually be degenerative regardless of the presence of mitral insufficiency. PMID- 26525579 TI - STAT3-regulated exosomal miR-21 promotes angiogenesis and is involved in neoplastic processes of transformed human bronchial epithelial cells. AB - Although microRNA (miRNA) enclosed in exosomes can mediate intercellular communication, the roles of exosomal miRNA and angiogenesis in lung cancer remain unclear. We investigated functions of STAT3-regulated exosomal miR-21 derived from cigarette smoke extract (CSE)-transformed human bronchial epithelial (HBE) cells in the angiogenesis of CSE-induced carcinogenesis. miR-21 levels in serum were higher in smokers than those in non-smokers. The medium from transformed HBE cells promoted miR-21 levels in normal HBE cells and angiogenesis of human umbilical vein endothelial cells (HUVEC). Transformed cells transferred miR-21 into normal HBE cells via exosomes. Knockdown of STAT3 reduced miR-21 levels in exosomes derived from transformed HBE cells, which blocked the angiogenesis. Exosomes derived from transformed HBE cells elevated levels of vascular endothelial growth factor (VEGF) in HBE cells and thereby promoted angiogenesis in HUVEC cells. Inhibition of exosomal miR-21, however, decreased VEGF levels in recipient cells, which blocked exosome-induced angiogenesis. Thus, miR-21 in exosomes leads to STAT3 activation, which increases VEGF levels in recipient cells, a process involved in angiogenesis and malignant transformation of HBE cells. These results, demonstrating the function of exosomal miR-21 from transformed HBE cells, provide a new perspective for intervention strategies to prevent carcinogenesis of lung cancer. PMID- 26525580 TI - Immune modulation by ER stress and inflammation in the tumor microenvironment. AB - It is now increasingly evident that the immune system represents a barrier to tumor emergence, growth, and recurrence. Although this idea was originally proposed almost 50 years ago as the "immune surveillance hypothesis", it is commonly recognized that, with few rare exceptions, tumor cells always prevail. Thus, one of the central unsolved paradoxes of tumor immunology is how a tumor escapes immune control, which is reflected in the lack of effective autochthonous or vaccine-induced anti-tumor T cell responses. In this review, we discuss the role of the endoplasmic reticulum (ER) stress response/unfolded protein response (UPR) in the immunomodulation of myeloid cells and T cells. Specifically, we will discuss how the tumor cell UPR polarizes myeloid cells in a cell-extrinsic manner, and how in turn, thus polarized myeloid cells negatively affect T cell activation and clonal expansion. PMID- 26525581 TI - Higher proliferation of peritumoral endothelial cells to IL-6/sIL-6R than tumoral endothelial cells in hepatocellular carcinoma. AB - BACKGROUND: This study aimed to explore the responses to the interleukin-6 (IL 6)/soluble interleukin-6 receptor (sIL-6R) complex in peritumoral endothelial cells (PECs) and tumor endothelial cells (TECs), as well as determine the signaling pathways in the angiogenesis of hepatocellular carcinoma (HCC). METHODS: The expression of IL-6, IL-6R, gp130, CD68, HIF-1alpha, and microvessel density (MVD) were assessed with an orthotopic xenograft model in nude mice. ECs were incubated under hypoxic conditions to detect IL-6 and gp130. The proliferation of PECs and TECs in the presence of IL-6 and sIL-6R, as well as the expression of gp130, JAK2/STAT3, PI3K/AKT in endothelial cells were measured. RESULTS: Peritumoral IL-6, IL-6R, gp130, CD68, and HIF-1alpha expression, as well as MVD, gradually increased during tumor growth. Hypoxia could directly induce IL 6 expression, but not gp130 in PECs. The co-culture of IL-6/sIL-6R induced much higher PEC proliferation and gp130 expression, as well as the elevated phosphorylation of JAK2 and STAT3, however not the phosphorylation of PI3K and AKT. CONCLUSIONS: PECs exhibited higher proliferation in response to IL-6/sIL-6R co-treatment compared with TECs in HCC via the up-regulation of gp130 /JAK2/STAT3. PEC and its associated peritumoral angiogenesis microenvironment may be a potential novel target for anti-angiogenic treatment. PMID- 26525583 TI - Considering the chemical energy requirements of the tri-n-propylamine co-reactant pathways for the judicious design of new electrogenerated chemiluminescence detection systems. AB - The introduction of a 'co-reactant' was a critical step in the evolution of electrogenerated chemiluminescence (ECL) from a laboratory curiosity to a widely utilised detection system. In conjunction with a suitable electrochemiluminophore, the co-reactant enables generation of both the oxidised and reduced precursors to the emitting species at a single electrode potential, under the aqueous conditions required for most analytical applications. The most commonly used co-reactant is tri-n-propylamine (TPrA), which was developed for the classic tris(2,2'-bipyridine)ruthenium(II) ECL reagent. New electrochemiluminophores such as cyclometalated iridium(III) complexes are also evaluated with this co-reactant. However, attaining the excited states in these systems can require much greater energy than that of tris(2,2' bipyridine)ruthenium(II), which has implications for the co-reactant reaction pathways. In this tutorial review, we describe a simple graphical approach to characterise the energetically feasible ECL pathways with TPrA, as a useful tool for the development of new ECL detection systems. PMID- 26525582 TI - Update on mesenchymal stem cell-based therapy in lupus and scleroderma. AB - Current systemic therapies are rarely curative for patients with severe life threatening forms of autoimmune diseases (ADs). During the past 15 years, autologous hematopoietic stem cell transplantation has been demonstrated to cure some patients with severe AD refractory to all other available therapies. As a consequence, ADs such as lupus and scleroderma have become an emerging indication for cell therapy. Multipotent mesenchymal stem cells (MSCs), isolated from bone marrow and other sites, display specific immunomodulation and anti-inflammatory properties and appear as ideal tools to treat such diseases. The present update aims at summarizing recent knowledge acquired in the field of MSC-based therapies for lupus and scleroderma. PMID- 26525584 TI - Amish-Initiated Burn Care Project: Case Report and Lessons Learned in Participatory Research. AB - PURPOSE: This case report describes the phases of an Amish Burn Care Project and the lessons learned throughout the process. METHOD: Data sources to construct the case report included participant observation, interviews, archival documents, and a focus group. RESULTS: The narrative is organized into five phases of a participatory research approach: engagement, formalization, mobilization, maintenance, and expansion. LESSONS LEARNED: Community-initiated research led to legitimate change, working together for change took time, team members grew in mutual trust and respect for each other, cultural humility brought personal and professional growth, and capacity building took place through mutually supported efforts. PMID- 26525585 TI - A Culturally Appropriate Self-Management Program for Hispanic Adults With Type 2 Diabetes and Low Health Literacy Skills. AB - PURPOSE: This study assessed the feasibility of adapting a patient-centered educational intervention for type 2 diabetes (T2D) self-management for a Hispanic population with low health literacy skills. DESIGN: A descriptive qualitative study design and phenomenological analyses were used. Nine Hispanic adults with T2D recruited from a rural community health center participated in an educational program that instructed on low glycemic food choices, meaningful glucose self monitoring, and physical activity to decrease blood glucose spikes. Participants' feedback was recorded during four 2-hour focus group sessions. Findings/Results: Participants' feedback clustered around four themes: information and knowledge, motivation and barriers to change, experiences with new behaviors, and personal responsibility. DISCUSSION/CONCLUSIONS: Data support the feasibility of adapting an established health-enhancing approach for promoting self-management of T2D to a low health literacy Spanish-speaking population. IMPLICATIONS FOR PRACTICE: The findings may help in further development of tools and strategies for improved T2D self-management in the study population. PMID- 26525586 TI - Cultural Adaptation and Validation of the Cultural Self-Efficacy Scale for Colombian Nursing Professionals. AB - PURPOSE: The level of cultural self-efficacy indicates the degree of confidence nursing professionals possess for their ability to provide culturally competent care. Cultural adaptation and validation of the Cultural Self-Efficacy Scale was performed for nursing professionals in Colombia. DESIGN: A scale validation study was conducted. METHOD: Cultural adaptation and validation of the Cultural Self Efficacy Scale was performed using a sample of 190 nurses in Colombia, between September 2013 and April 2014. This sample was chosen via systematic random sampling from a finite population. RESULTS: The scale was culturally adapted. Cronbach's alpha for the revised scale was .978. Factor analysis revealed the existence of six factors grouped in three dimensions that explained 68% of the variance. CONCLUSION: The results demonstrated that the version of the Cultural Self-Efficacy Scale adapted to the Colombian context is a valid and reliable instrument for determining the level of cultural self-efficacy of nursing professionals. PMID- 26525587 TI - Increased expression of TLR9 associated with pro-inflammatory S100A8 and IL-8 in diabetic wounds could lead to unresolved inflammation in type 2 diabetes mellitus (T2DM) cases with impaired wound healing. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia which causes a chain of abrupt biochemical and physiological changes. Immune dys-regulation is the hallmark of T2DM that could contribute to prolonged inflammation causing transformation of wounds into non-healing chronic ulcers. Toll like receptor -9 (TLR9) is a major receptor involved in innate immune regulation. TLR9 activation induces release of pro-inflammatory molecules like S100A8 and interleukin-8 (IL-8) by myeloid cells causing migration of myeloid cells to the site of inflammation. We hypothesized that pro-inflammatory S100A8 and IL-8 proteins could cause persistent inflammation in chronic wounds like diabetic foot ulcer (DFU) and may contribute to impaired wound healing in T2DM patients. MATERIALS AND METHODS: Expression of TLR9 and its downstream effector molecules S100A8, and IL-8 were analyzed in chronic diabetic wound and non-diabetic control wound tissue samples by semiquantitative reverse transcriptase - polymerase chain reaction (RT-PCR), quantitative RT-PCR, western blot and immunofluorescence. CD11b(+)CD33(+) myeloid cells were analyzed by flow cytometry. RESULTS: TLR9 message and protein were higher in diabetic wounds compared to control wounds (p=0.03, t=2.21 for TLR9 mRNA; p=<0.001, t=4.21 for TLR9 protein). TLR9 down-stream effector molecules S100A8 and IL-8 were also increased in diabetic wounds (p=0.003, t=3.1 for S100A8 mRNA; p=0.04, t=2.04 for IL-8). CD11b(+) CD33(+) myeloid cells were decreased in T2DM as compared to non diabetic controls (p=0.001, t=3.6). DFU subjects had higher levels of CD11b(+) CD33(+) myeloid cells as compared to non-DFU T2DM control (p=0.003, t=2.8). Infection in the wound microenvironment could be the cause of increase in CD11b(+)CD33(+) myeloid cells in DFU (p=0.03, t=2.5). CONCLUSION: The up regulation of myeloid cell-derived pro-inflammatory molecules S100A8 and IL-8 in combination with lower levels of CD11b(+) CD33(+) myeloid cells may cause the impairment of wound healing in T2DM subjects leading to chronic ulcers. PMID- 26525588 TI - Gender-specific differences in diabetic neuropathy in BTBR ob/ob mice. AB - AIMS: To identify a female mouse model of diabetic peripheral neuropathy (DPN), we characterized DPN in female BTBR ob/ob mice and compared their phenotype to non-diabetic and gender-matched controls. We also identified dysregulated genes and pathways in sciatic nerve (SCN) and dorsal root ganglia (DRG) of female BTBR ob/ob mice to determine potential DPN mechanisms. METHODS: Terminal neuropathy phenotyping consisted of examining latency to heat stimuli, sciatic motor and sural sensory nerve conduction velocities (NCV), and intraepidermal nerve fiber (IENF) density. For gene expression profiling, DRG and SCN were dissected, RNA was isolated and processed using microarray technology and differentially expressed genes were identified. RESULTS: Similar motor and sensory NCV deficits were observed in male and female BTBR ob/ob mice at study termination; however, IENF density was greater in female ob/ob mice than their male counterparts. Male and female ob/ob mice exhibited similar weight gain, hyperglycemia, and hyperinsulinemia compared to non-diabetic controls, although triglycerides were elevated more so in males than in females. Transcriptional profiling of nerve tissue from female mice identified dysregulation of pathways related to inflammation. CONCLUSIONS: Similar to males, female BTBR ob/ob mice display robust DPN, and pathways related to inflammation are dysregulated in peripheral nerve. PMID- 26525589 TI - Testicular Leydig Cell Tumor with Metachronous Lesions: Outcomes after Metastasis Resection and Cryoablation. AB - Leydig cell tumors represent 3% of testicular masses and usually occur in prepubertal boys and men between 30 and 60 years of age. Leydig cell tumors are benign in children but can be malignant in 10% of adults. This case report describes a 41-year-old patient who was diagnosed with a Leydig cell tumor that originated in his right testicle that subsequently metastasized to his liver, lungs, and retroperitoneum. We discuss the patient's presentation and review the radiographic findings, surgical treatment, surgical pathology, chemotherapeutic treatment, and published literature on this rare pathology. PMID- 26525590 TI - It Takes Two? An Exploration of Processes and Outcomes in a Two-Session Couple Intervention. AB - Although relationship distress is common, couples often forego professional help due to concerns such as time constraints, financial costs, and stigma. The two session relationship checkup is an alternative format of couple intervention developed to address these concerns. In this qualitative study, we interviewed 20 coupled participants and six clinicians to examine the checkup's processes and outcomes. The phenomenological themes that emerged revealed sequential processes by which this format works. Couple themes included client motivation, the therapeutic relationship, and therapeutic change in terms of perceptions and behaviors-particularly with regard to communication. Clinician data largely mirrored these themes. The results suggest the intervention addressed barriers to help-seeking and may be a viable selective option for at-risk couples. PMID- 26525591 TI - Prevalence and characteristics of misreporting of energy intake in US children and adolescents: National Health and Nutrition Examination Survey (NHANES) 2003 2012. AB - Using data from the National Health and Nutrition Examination Survey (NHANES) 2003-2012, we investigated the prevalence and characteristics of under- and over reporting of energy intake (EI) among 14 044 US children and adolescents aged 2 19 years. For the assessment of EI, two 24-h dietary recalls were conducted with the use of the US Department of Agriculture Automated Multiple-Pass Method. Under , plausible and over-reporters of EI were identified using two methods: based on the 95 % confidence limits (1) for agreement between the ratio of EI:BMR and a physical activity level for sedentary lifestyle (1.55) and (2) of the expected ratio of EI:estimated energy requirement (EER) of 1.0. BMR was calculated using Schofield's equations. EER was calculated using equations from the US Dietary Reference Intakes, assuming 'low active' level of physical activity. The risk of being an under- or over-reporter compared with a plausible reporter was analysed using multiple logistic regression. Percentages of under-, plausible and over reporters were 13.1, 81.5 and 5.4 %, respectively, based on EI:BMR and 18.8, 72.3 and 8.8 %, respectively, based on EI:EER. Under-reporting was associated with older age, non-Hispanic blacks (compared with non-Hispanic whites) and overweight and obesity (compared with normal weight). Over-reporting was associated with younger age, lower family poverty income ratio, normal weight and the first survey cycle. Similar findings were obtained when analysing only the first 24-h recall data from NHANES 1999-2012 (n 22 949). In conclusion, we found that EI misreporting remains prevalent and differential in US children and adolescents. PMID- 26525592 TI - Monitoring immune responses in a mouse model of fracture fixation with and without Staphylococcus aureus osteomyelitis. AB - Post-traumatic bone fractures are commonly fixed with implanted devices to restore the anatomical position of bone fragments and aid in the healing process. Bacterial infection in this situation is a challenge for clinicians due to the need for aggressive antibiotic therapy, debridement of infected tissues, and the need to maintain fracture stability. The aim of this study was to monitor immune responses that occur during healing and during Staphylococcus aureus infection, in a clinically relevant murine model of fracture fixation. Skeletally mature C57bl/6 mice received a transverse osteotomy of the femur, which was treated with commercially available titanium fracture fixation plates and screws. In the absence of infection, healing of the fracture was complete within 35days and was characterized by elevated Interleukin (IL)-4 and Interferon-gamma secretion from bone-derived cells and expression of these same genes. In contrast, mice inoculated with S. aureus could not heal the fracture within the observation period and were found to develop typical signs of implant-associated bone infection, including biofilm formation on the implant and osteolysis of surrounding bone. The immune response to infection was characterized by a TH17 led bone response, and a pro-inflammatory cytokine-led Tumor necrosis factor (TNF)-alpha, Interleukin (IL)-1beta) soft tissue response, both of which were ineffectual in clearing implant related bone and soft tissue infections respectively. In this murine model, we characterize the kinetics of pro inflammatory responses to infection, secondary to bone trauma and surgery. A divergent local immune polarization is evident in the infected versus non infected animals, with the immune response ultimately unable to clear the S. aureus infection. PMID- 26525593 TI - Age-related changes in bone strength from HR-pQCT derived microarchitectural parameters with an emphasis on the role of cortical porosity. AB - The high resolution peripheral computed tomography (HR-pQCT) technique has seen recent developments with regard to the assessment of cortical porosity. In this study, we investigated the role of cortical porosity on bone strength in a large cohort of women. The distal radius and distal tibia were scanned by HR-pQCT. We assessed bone strength by estimating the failure load by microfinite element analysis (MUFEA), with isotropic and homogeneous material properties. We built a multivariate model to predict it, using a few microarchitecture variables including cortical porosity. Among 857 Caucasian women analyzed with MUFEA, we found that cortical and trabecular properties, along with the failure load, impaired slightly with advancing age in premenopausal women, the correlations with age being modest, with |rage| ranging from 0.14 to 0.38. After the onset of the menopause, those relationships with age were stronger for most parameters at both sites, with |rage| ranging from 0.10 to 0.64, notably for cortical porosity and failure load, which were markedly deteriorated with increasing age. Our multivariate model using microarchitecture parameters revealed that cortical porosity played a significant role in bone strength prediction, with semipartial r(2)=0.22 only at the tibia in postmenopausal women. In conclusion, in our large cohort of women, we observed a small decline of bone strength at the tibia before the onset of menopause. We also found an age-related increase of cortical porosity at both scanned sites in premenopausal women. In postmenopausal women, the relatively high increase of cortical porosity accounted for the decline in bone strength only at the tibia. PMID- 26525594 TI - [Retinal arteriolar tortuosity in a patient with HANAC syndrome (dominant hereditary angiopathy with nephropathy, aneurysms and muscle cramps)]. PMID- 26525595 TI - Assessment of patient safety culture in clinical laboratories in the Spanish National Health System. AB - INTRODUCTION: There is increasing awareness of the importance of transforming organisational culture in order to raise safety standards. This paper describes the results obtained from an evaluation of patient safety culture in a sample of clinical laboratories in public hospitals in the Spanish National Health System. MATERIAL AND METHODS: A descriptive cross-sectional study was conducted among health workers employed in the clinical laboratories of 27 public hospitals in 2012. The participants were recruited by the heads of service at each of the participating centers. Stratified analyses were performed to assess the mean score, standardized to a base of 100, of the six survey factors, together with the overall patient safety score. RESULTS: 740 completed questionnaires were received (88% of the 840 issued). The highest standardized scores were obtained in Area 1 (individual, social and cultural) with a mean value of 77 (95%CI: 76 78), and the lowest ones, in Area 3 (equipment and resources), with a mean value of 58 (95%CI: 57-59). In all areas, a greater perception of patient safety was reported by the heads of service than by other staff. CONCLUSIONS: We present the first multicentre study to evaluate the culture of clinical safety in public hospital laboratories in Spain. The results obtained evidence a culture in which high regard is paid to safety, probably due to the pattern of continuous quality improvement. Nevertheless, much remains to be done, as reflected by the weaknesses detected, which identify areas and strategies for improvement. PMID- 26525596 TI - Mixed Phenotype Acute Leukemia with Low Hypodiploidy in a Pediatric Patient. AB - We describe the case of a 16 year-old female with mixed phenotype acute leukemia B/myeloid, NOS (formerly biphenotypic leukemia) with masked hypodiploidy and somatic TP53 and CDKN2A/B deletions. She achieved morphologic remission with lymphoid-directed multi-agent chemotherapy, but experienced an early medullary relapse 11 months from initial diagnosis. Her case details the unusual finding of hypodiploidy in a patient with ambiguous lineage leukemia and highlights the complexity of therapy selection for these high-risk patients. PMID- 26525597 TI - Ebola virus disease in the Democratic Republic of the Congo, 1976-2014. AB - The Democratic Republic of the Congo has experienced the most outbreaks of Ebola virus disease since the virus' discovery in 1976. This article provides for the first time a description and a line list for all outbreaks in this country, comprising 996 cases. Compared to patients over 15 years old, the odds of dying were significantly lower in patients aged 5 to 15 and higher in children under five (with 100% mortality in those under 2 years old). The odds of dying increased by 11% per day that a patient was not hospitalised. Outbreaks with an initially high reproduction number, R (>3), were rapidly brought under control, whilst outbreaks with a lower initial R caused longer and generally larger outbreaks. These findings can inform the choice of target age groups for interventions and highlight the importance of both reducing the delay between symptom onset and hospitalisation and rapid national and international response. PMID- 26525598 TI - Contesting the presence of wheat in the British Isles 8,000 years ago by assessing ancient DNA authenticity from low-coverage data. AB - Contamination with exogenous DNA is a constant hazard to ancient DNA studies, since their validity greatly depend on the ancient origin of the retrieved sequences. Since contamination occurs sporadically, it is fundamental to show positive evidence for the authenticity of ancient DNA sequences even when preventive measures to avoid contamination are implemented. Recently the presence of wheat in the United Kingdom 8000 years before the present has been reported based on an analysis of sedimentary ancient DNA (Smith et al. 2015). Smith et al. did not present any positive evidence for the authenticity of their results due to the small number of sequencing reads that were confidently assigned to wheat. We developed a computational method that compares postmortem damage patterns of a test dataset with bona fide ancient and modern DNA. We applied this test to the putative wheat DNA and find that these reads are most likely not of ancient origin. PMID- 26525599 TI - Use of internal control T-cell populations in the flow cytometric evaluation for T-cell neoplasms. AB - OBJECTIVES: Flow cytometry is an important tool for identification of neoplastic T-cells, but immunophenotypic abnormalities are often subtle and must be distinguished from nonneoplastic subsets. Use of internal control (IC) T-cells in the evaluation for T-cell neoplasms was explored, both as a quality measure and as a reference for evaluating abnormal antigen expression. METHODS: All peripheral blood specimens (3-month period), or those containing abnormal T-cells (29-month period), stained with CD45 V500, CD2 V450, CD3 PE-Cy7, CD7 PE, CD4 Per CP-Cy5.5, CD8 APC-H7, CD56 APC, CD16&57 FITC, were evaluated. IC T-cells were identified (DIVA, BD Biosciences) and median fluorescence intensity (MFI) recorded. Selected files were merged and reference templates generated (Infinicyt, Cytognos). RESULTS: IC T-cells were present in all specimens, including those with abnormal T-cells, but subsets were less well-represented. IC T-cell CD3 MFI differed between instruments (p = 0.0007) and subsets (p < 0.001), but not specimen categories, and served as a longitudinal process control. Merged files highlighted small unusual IC-T subsets: CD2+(dim) (0.25% total), CD2- (0.03% total). An IC reference template highlighted neoplastic T-cells, but was limited by staining variability (IC CD3 MFI reference samples different from test (p = 0.003)). CONCLUSIONS: IC T-cells present in the majority of specimens can serve as positive and longitudinal process controls. Use of IC T-cells as an internal reference is limited by variable representation of subsets. Analysis of merged IC T-cells from previously analyzed patient samples can alert the interpreter to less-well-recognized non-neoplastic subsets. However, application of a merged file IC reference template was limited by staining variability. (c) 2016 Clinical Cytometry Society. PMID- 26525600 TI - Transgenerational Developmental Programming of Ovarian Reserve. AB - Exposure to an adverse early-life environment leads to long-term health problems, many of which are recapitulated in subsequent generations. The female reproductive tract is particularly sensitive to early-life influences, and plays a pivotal role in programming the conceptus. We examine the influence of suboptimal grandmaternal diet on reproductive potential of granddaughters in the absence of any further dietary manipulations in the daughters in a rat low protein diet model. Exposure to low-protein grand-maternal diet leads to decreased ovarian reserve and increased intra-abdominal fat mass in granddaughters, accompanied by accelerated accumulation of oxidative stress and mtDNA copy number instability in the ovaries. Ovarian telomere length declines more rapidly in the exposed granddaughters, indicating accelerated ageing in the reproductive tract. Thus, we demonstrate that suboptimal grandmaternal diet during pregnancy accelerates reproductive ageing across subsequent generations. These findings have important implications for understanding both individual rates of decline in fertility with age, and the clinical impact of current global trends towards delayed childbearing. PMID- 26525601 TI - Developing a CTG simulator app: theory and practice. AB - BACKGROUND: Cardiotocograph (CTG) interpretation is a core skill for health care professionals working on the labour ward; however, training appears to be deficient in respect of the development of decision-making skills relating to CTG findings. Simulation offers a potential solution to address such 'human factors'. Current access to simulators is limited by cost and operational complexity. We therefore decided to develop an accessible CTG simulator application ('app') that could be operated on a smartphone, a technology already possessed by the majority of health care professionals in the UK and elsewhere. CTG interpretation is a core skill for health care professionals working on the labour ward CONTEXT: A multidisciplinary team with backgrounds in obstetrics, anaesthesia and information technology was assembled to undertake the software development process. An evaluation of the pilot software was undertaken by trainee obstetric doctors. INNOVATION: A software development project was undertaken in order to produce a mobile app that simulates CTG accurately and dynamically. This process was based on Davis' Technology Acceptance Model, in which usefulness and ease of use are the central principles. IMPLICATIONS: Mobile technology can be used to run simulation software that is both useful and easy to use; however, our evaluation indicated that in order to use the app effectively the operator requires some expertise in the behaviour of the CTG in response to interventions, in common with all current patient simulators. We envisage using this app in hybrid simulation scenarios, in which a live actor and a simulated monitor are used together. PMID- 26525602 TI - Evaluation of a New Zealand program to improve transition of care for older high risk adults. AB - Transition interventions aim to improve care and reduce hospital readmissions but evaluations of these interventions have reported inconsistent results. We report on the evaluation of an intervention implemented in Auckland, New Zealand. Participants were people over the age of 65 who had an acute medical admission and were at high risk of readmission. The intervention included an improved discharge process and nurse telephone follow-up soon after discharge. Outcomes were 28 day readmission rates and emergency attendances. The study is observational, using both interrupted times series and regression discontinuity designs. 5239 patients were treated over a one year period. There was no change in readmission rates or ED attendances or secondary outcomes. Not all patients received all components of the intervention. This transition intervention was not successful. Possible reasons for this and implications are discussed. Although non-experimental methods were used, we believe the results are robust. PMID- 26525604 TI - Ni12P5 nanoparticles decorated on carbon nanotubes with enhanced electrocatalytic and lithium storage properties. AB - Transition-metal phosphides (TMPs) have been proved to be of great importance in electrochemical energy conversion and Li-ion storage. In this work, we have designed a useful one-pot hot-solution colloidal synthetic route for synthesizing a new kind of unique hybrid nanostructures (the Ni12P5/CNT nanohybrids) by direct in situ growth of Ni12P5 nanocrystals onto oxidized multiwall carbon nanotubes (CNTs). The CNTs can improve the conductivity of the hybrids and effectively prevent the aggregation of Ni12P5 nanoparticles in the cycle process. When they are evaluated as a novel non-noble-metal hydrogen evolution reaction (HER) catalyst operating in acidic electrolytes, the Ni12P5/CNT nanohybrids exhibit an onset overpotential as low as 52 mV and a Tafel slope of 56 mV dec(-1) and only require overpotentials of 65 and 129 mV to attain current densities of 2 and 10 mA cm(-2), respectively. Moreover, they also exhibit enhanced electrochemical performance for lithium-ion batteries serving as an anode material; the Ni12P5/CNT nanohybrids show a high capacity, excellent cycling stability and good rate performance. Their unusual properties arise from a synergetic effect between Ni12P5 and CNTs. PMID- 26525603 TI - Nanomedicine and drug delivery strategies for treatment of inflammatory bowel disease. AB - Crohn's disease and ulcerative colitis are two important categories of human inflammatory bowel disease (IBD). Because the precise mechanisms of the inflammation and immune responses in IBD have not been fully elucidated, the treatment of IBD primarily aims to inhibit the pathogenic factors of the inflammatory cascade. Inconsistencies exist regarding the response and side effects of the drugs that are currently used to treat IBD. Recent studies have suggested that the use of nanomedicine might be advantageous for the treatment of intestinal inflammation because nano-sized molecules can effectively penetrate epithelial and inflammatory cells. We reviewed nanomedicine treatments, such as the use of small interfering RNAs, antisense oligonucleotides, and anti inflammatory molecules with delivery systems in experimental colitis models and clinical trials for IBD based on a systematic search. The efficacy and usefulness of the treatments reviewed in this manuscript have been demonstrated in experimental colitis models and clinical trials using various types of nanomedicine. Nanomedicine is expected to become a new therapeutic approach to the treatment of IBD. PMID- 26525606 TI - Functional Hallmarks of a Catalytic DNA that Makes Lariat RNA. AB - Catalytic DNAs, also known as deoxyribozymes, are of practical value for the synthesis of structurally or topologically complex RNAs, but little is known about the molecular details of DNA catalysis. We have investigated a deoxyribozyme that catalyzes the formation of a specific intramolecular 2',5' phosphodiester bond to produce lariat RNA, which is an important biological intermediate in eukaryotic mRNA splicing. The results of combinatorial mutation interference analysis (CoMA) allowed us to shrink the catalytic core to 70 % of its original length and revealed that the essential part of the deoxyribozyme sequence contained more than 50 % guanosines. Nucleotide analogue interference mapping (dNAIM) and dimethyl sulfate interference (DMSi) experiments provided atomic details of individual guanosine functional groups. Additional spectroscopic experiments and structural probing data identified conformational changes upon metal-ion binding and catalysis. Overall, this comprehensive analysis of the DNA-catalyzed reaction has provided specific insights into the synthesis of 2',5'-branched RNA, and suggested the general features of deoxyribozymes that catalyze nucleic acid ligation reactions. PMID- 26525605 TI - The curious ability of polyethylene glycol fusion technologies to restore lost behaviors after nerve severance. AB - Traumatic injuries to PNS and CNS axons are not uncommon. Restoration of lost behaviors following severance of mammalian peripheral nerve axons (PNAs) relies on regeneration by slow outgrowths and is typically poor or nonexistent when after ablation or injuries close to the soma. Behavioral recovery after severing spinal tract axons (STAs) is poor because STAs do not naturally regenerate. Current techniques to enhance PNA and/or STA regeneration have had limited success and do not prevent the onset of Wallerian degeneration of severed distal segments. This Review describes the use of a recently developed polyethylene glycol (PEG) fusion technology combining concepts from biochemical engineering, cell biology, and clinical microsurgery. Within minutes after microsuturing carefully trimmed cut ends and applying a well-specified sequence of solutions, PEG-fused axons exhibit morphological continuity (assessed by intra-axonal dye diffusion) and electrophysiological continuity (assessed by conduction of action potentials) across the lesion site. Wallerian degeneration of PEG-fused PNAs is greatly reduced as measured by counts of sensory and/or motor axons and maintenance of axonal diameters and neuromuscular synapses. After PEG-fusion repair, cut-severed, crush-severed, or ablated PNAs or crush-severed STAs rapidly (within days to weeks), more completely, and permanently restore PNA- or STA mediated behaviors compared with nontreated or conventionally treated animals. PEG-fusion success is enhanced or decreased by applying antioxidants or oxidants, trimming cut ends or stretching axons, and exposure to Ca(2+) -free or Ca(2+) containing solutions, respectively. PEG-fusion technology employs surgical techniques and chemicals already used by clinicians and has the potential to produce a paradigm shift in the treatment of traumatic injuries to PNAs and STAs. PMID- 26525607 TI - Global DNA hypomethylation is associated with the development and poor prognosis of tongue squamous cell carcinoma. AB - BACKGROUNDS: Oral cancer is the 4th leading cause of cancer death for males and the top cancer in young adult males in Taiwan. Tongue squamous cell carcinoma (TSCC) is a common oral cancer and generally associated with poor prognosis. Global DNA hypomethylation at the 5 position of cytosine (5mC) is a well-known epigenetic feature of cancer. Therefore, the purpose of this study was to investigate the relationship of the global 5mC content with the tumorigenesis and prognosis of patients with TSCC. METHODS: The levels of global 5mC were evaluated by immunohistochemistry using tissue microarray slides of 248 surgically resected TSCC and 202 corresponding tumor adjacent normal (TAN) tissues. RESULTS: We found that the level of 5mC in TSCC (P < 0.001) was significantly decreased as compared to TAN. Among TSCC tissues, decreased levels of 5mC were associated with female gender (P = 0.036). In addition, the global hypomethylation was associated with the poor disease-specific survival in TSCC patients (adjusted hazard ratio: 1.55, P = 0.043), especially for patients in older age group (> 50 years, P = 0.013), with moderate or poor cell differentiation (P = 0.044), early stage of disease (I II, P = 0.046), small tumor size (T1-T2, P = 0.005), without lymph node involvement (P = 0.041), and ever received postoperative radiotherapy (P = 0.009). CONCLUSIONS: Global hypomethylation was an independent biomarker for the development and poor prognosis of TSCC. PMID- 26525608 TI - Retrospective study of two fixation methods for 4-corner fusion: Shape-memory staple vs. dorsal circular plate. AB - The purpose of this study was to compare the results of two groups of patients with four-corner fusion, one group fixed with shape-memory staples and the other with locked circular plates. This retrospective study compared 52 wrists operated for scaphoid excision and four-corner fusion between 2005 and 2011. The arthrodesis was ensured by a shape-memory quadripodal staple (4Fusion((r)), MemometalTM) in 37 cases and a locking dorsal circular plate (Xpode((r)), Biotech OrthoTM) in 15 cases. In the staple group, the mean age was 58.5 years and the average follow-up was 4.3 years. In the circular plate group, the mean age was 58.6 years and the average follow-up was 3.1 years. Pain, range of motion, grip strength, functional scores (QuickDASH and PWRE), fusion of the midcarpal joint, complications (implant fracture and reoperation) and patients' satisfaction were used as outcome measures. There was no pain in 43% of patients in the staple group and 40% of patients in the circular plate group at the follow-up; range of motion and functional scores were similar in both groups. Seventy-five percent of patients in the staple group were satisfied or very satisfied versus 60% in the circular plate group. The implant broke in 24.3% of cases in the staple group and 60% in the circular plate group. Reoperation was needed in 18% of the staple cases and 14% of the plate cases. There was no difference between the implants in terms of pain, range of motion, functional scores and patient satisfactory. The implant fracture rate in the plate group was high. This study brings into question implant reliability for the four-corner fusion procedure. PMID- 26525609 TI - Treatment of Madelung's deformity. AB - Treatment of Madelung's deformity is still controversial. We reviewed retrospectively 19 patients with Madelung's deformity (two bilateral, 21 cases) who underwent surgery to the radius and ulna to improve range of motion, decrease pain and improve appearance of the wrist. Nineteen patients underwent 21 distal radial osteotomy procedures using three different techniques: subtraction, addition or dome osteotomy. Ulnar shortening and redirection of the distal ulna was performed in 12 cases; a long oblique osteotomy was used in 10 of these cases. The Sauve-Kapandji technique was performed in five cases, an ulnar distal epiphysiodesis in two cases and a combination of osteotomy and epiphysiodesis in one case. The aim was to reduce the distal radial slope and to restore the orientation and congruity of the distal radio-ulnar joint and to improve its function. Pain was reduced as a result of the procedure: more than 75% of the cases had no or intermittent pain at the review. Pronation improved from 63 degrees to 68 degrees (P=0.467, not significant) and supination improved from 48 degrees to 72 degrees on average (P=0.034, significant). Grip strength increased from 11 to 18 kgf (P=0.013, significant). Madelung's deformity is not always a benign condition and it responds well to corrective osteotomies. PMID- 26525610 TI - On My Own: A Qualitative Phenomenological Study of Mothers of Young Children with Autism Spectrum Disorder in Taiwan. AB - BACKGROUND: There has been a dramatic increase in autism around the world. However, little is known about the impact of the Taiwanese primogeniture system on mothers of children with ASD. Greater knowledge is needed to understand the life experiences of Taiwanese mothers with ASD children when a healthy male descendent is expected. MATERIALS AND METHODS: Research follows the hermeneutic phenomenological approach with in-depth interviews and participant observation (Agar, Speaking of Ethnography. Sage, California, 1986). The researchers collected and analysed stories from seven mothers who are the major caregivers of their school-aged autistic children. RESULTS: The data revealed the following themes that represented the mothers' experiences: taking the blame, my world was turned upside down, a child-centred life and two lives as one. CONCLUSIONS: The findings provide a deeper understanding of common expectations of, and behaviours directed towards, Taiwanese mothers of children with autism. This offers healthcare professionals ways of reconceptualizing therapeutic practice, thus benefitting these mothers. PMID- 26525611 TI - Morphologic characterization of the patent ductus arteriosus in the premature infant and the choice of transcatheter occlusion device. AB - OBJECTIVES: The aim of this study was to describe and differentiate the morphology of patent ductus arteriosus (PDA) seen in children born prematurely from other PDA types. BACKGROUND: PDAs are currently classified as types A-E using the Krichenko's classification. Children born prematurely with a PDA morphology that did not fit this classification were described as Type F PDA. METHODS: A review of 100 consecutive children who underwent transcatheter device closure of PDA was performed. The diameter and length (L) of the PDA and the device diameter (D) were indexed to the descending aorta (DA) diameter. RESULTS: Comparison of 26 Type F PDAs was performed against, 29 Type A, 7 Type C and 32 Type E PDAs. Children with Type F PDAs (median 27.5 weeks gestation) were younger during the device occlusion compared with types A, C, and E (median age: 6 vs. 32, 11, and 42 months; P = 0.002). Type F PDAs were longer and larger, requiring a relatively large device for occlusion than types A, C, and E (Mean L/DA: 1.88 vs. 0.9, 1.21, and 0.89, P <= 0.01 and Mean D/DA: 1.04 vs. 0.46, 0.87, and 0.34, P <=0.01). The Amplatzer vascular plug-II (AVP-II) was preferred for occlusion of Type F PDAs (85%; P <0.001). CONCLUSIONS: Children born prematurely have relatively larger and longer PDAs. These "fetal type PDAs" are best classified separately. We propose to classify them as Type F PDAs to add to types A-E currently in use. The AVP-II was effective in occluding Type F PDAs. PMID- 26525612 TI - Neural stem cell transplantation decreases neuroinflammation in a transgenic mouse model of Alzheimer's disease. AB - Inflammatory processes are considered to play an important role in the progression of neurodegenerative changes in Alzheimer's disease (AD). A number of studies have reported that inflammatory processes are highly correlated with cognitive deficits in AD-like mice. Transplantation of neural stem cells (NSCs) has been considered as a potential new therapy for the treatment of AD because of its effects in improving cognitive ability. However, NSCs have not been evaluated for their protective effects against inflammatory changes in AD. Here, we injected NSCs into amyloid precursor protein (APP)/PS1 transgenic mice to analyse cognitive function and to measure glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule-1 (Iba-1) and toll-like receptors 4(TLR4) activation. We also quantified TLR-4 pathway-related agents, Abeta concentration and the levels of proinflammatory mediators. Our results showed that in NSC injected APP/PS1 mice, activation of GFAP, Iba-1, TLR4 and TLR4 pathway-related agents (MyD88, TRIF, P38 MAPK and NF-kappaB P65) were significantly decreased with decreased expression of proinflammatory mediators (IL-1, IL-6, TNF-alpha and PGE2). These changes were associated with the amelioration of cognitive deficits, but no difference was found in Abeta concentration. Our results provide novel evidence that NSC transplantation in APP/PS1 mice significantly improved cognitive deficits and was accompanied by the attenuation of inflammatory injury via suppression of glial and TLR4-mediated inflammatory pathway activation. Our data indicate that these pathways may potentially be important therapeutic targets to prevent or delay AD. This study investigated the neuroprotective effect of neural stem cell (NSC) transplantation against Alzheimer's disease (AD) inflammation. We found that NSC treatment in APP/PS1 mice significantly improved cognitive deficits and was accompanied by the attenuation of inflammatory injury via suppression of glial and toll-like receptor 4 (TLR4) activation and its downstream signalling pathways. Our findings indicate that these pathways may be potentially important therapeutic targets to prevent or delay AD. PMID- 26525613 TI - [Perception of emotions in patients with ischemic stroke]. AB - OBJECTIVE: To study neuropsychological characteristics of perception processes, recognition and differentiation of emotional distress in post stroke patients with regard to localization of ischemic lesion. MATERIAL AND METHODS: Authors examined 47 post stroke patients with right-hemisphere and left hemisphere localization of ischemic stroke in the early stage of hospitalization. The Subjective Feelings Scale and a battery of neuropsychological tests were used. RESULTS AND CONCLUSION: In patients with right-hemisphere localization of the lesion, positive emotional reactions were more frequent, neuropsychological implementation level was realized through details and differentiation of the image. In patients with left-hemispheric localization of ischemic stroke, negative emotional reactions were dominated and neuropsychological implementation level was realized through a vague and undifferentiated way. PMID- 26525614 TI - [Clinical and genetic characteristics of the X chromosome distal long arm microduplications encompassing the MECP2 gene]. AB - OBJECTIVE: Microduplications of the long arm of the X chromosome including the MECP2 gene are relatively common causes of neurodevelopmental disorders in males. Authors analyzed clinical presentations of this disease in children. MATERIAL AND METHODS: Authors performed a clinical and genetic analysis of four cases using contemporary cytogenetic, molecular cytogenetic studies (FISH, array CGH) and X chromosome inactivation analysis. RESULTS AND CONCLUSION: We described somatic, neurologic and mental symptoms of the patients. The genetic imbalance impact on the patients' phenotype, necessity of comprehensive family studies for correct genetic diagnosis and effective genetic counseling in cases of microduplications of the long arm of the X chromosome including the MECP2 gene are discussed. PMID- 26525615 TI - [Efficacy of cytoflavin in the treatment of hypoxic-ischemic lesions of the nervous system in 1-month old children with transient neonatal hypothyroidism]. AB - OBJECTIVE: To evaluate the efficacy of cytoflavin in the treatment of hypoxic ischemic lesions of the nervous system in young infants with transient neonatal hypothyroidism. MATERIAL AND METHODS: Authors analyzed the efficacy of cytoflavin in the treatment of cerebral ischemia in the combination with transient neonatal hypothyroidism in 89 newborns. The main group comprised 43 children treated with intravenous cytoflavin in dose 2 ml per 1 kg of body weight per day for five days; 46 newborns of the comparison group received basic therapy. RESULTS AND CONCLUSION: It was found that the moderate depression of motor activity and autonomic-visceral dysfunctions were the leading clinical neurological manifestations in these groups. In the main group, there was a significantly more rapid decline of hyperthyreotropinemia, indirect hyperbilirubinemia, reduced severity of cerebral ischemia by the results of neurosonography on the 5th or 6th day and regression of the main clinical symptoms compared to the control group. The positive neuroprotective and thyroid protective effect of cytoflavin, good tolerability and its compatibility with other drugs used in the standard treatment of hypoxic-ischemic lesions of the central nervous system were identified. PMID- 26525616 TI - [Myofascial pain syndrome]. AB - OBJECTIVE: To analyze clinical characteristics of pain syndrome in patients with dorsalgia. MATERIAL AND METHODS: Authors studied 43 patients (mean age 41.9+/-1.2 years), 34 women and 9 men, with acute and subacute chronic back pain. The study included neurological examination, MRI and/or CT of the spine, measurement of anxiety and depression with the Hospital Anxiety and Depression Scale (HADS), The Brief Pain Inventory (BPI) and the McGill Pain Inventory. RESULTS AND CONCLUSION: Chronic myofascial pain syndrome (MFPS) was frequently associated with anxiety depressive disorders found in patients with cervical and cervical/pectoral pain, fibromyalgia with minimal neurological symptoms and no signs of neural structure compression according to MRI and CT. The results of the study of chronic MFPS should be taken into account in the choice of tactics of treatment of MFPS patients. The use of amelotex in the combination with compligam B in patients with dorsopathy and MFPS is effective together with correction of emotional disorders and treatment with chondroprotectors. PMID- 26525617 TI - [The efficacy of low calorie diet therapy in patients with arterial hypertension and chronic cerebral ischemia]. AB - OBJECTIVE: To evaluate an impact of low calorie diet therapy (LCDT) on cerebral hemodynamics, cognitive functions and quality-of-life of patients with arterial hypertension and chronic cerebral ischemia. MATERIAL AND METHODS: The main group consisted of 22 patients, 16 women and 6 men (mean age 54.4+/-2.4 years), assigned to the diet. The comparison group included 20 patients, 12 women and 8 men (mean age 55.6+/-1,0 years), who received standard antihypertensive treatment. The results of Doppler ultrasound of cerebral arteries, cognitive functions and quality-of-life were assessed after 6 months of treatment. RESULTS AND CONCLUSION: A positive effect of LCDT on the cerebral hemodynamics, cognitive functions and quality-of-life indices maintained for 6 months. The efficacy of LCDT was comparable to that of standard treatment in the comparison group. PMID- 26525618 TI - [Current possibilities of treatment of generalized convulsive seizures]. AB - Current possibilities of treatment of generalized convulsive seizures are presented. Progress in the field of pharmacotherapy of epilepsy allowed to introduce new antiepileptic drugs (AED). Some of them are modified AED with higher efficacy or better tolerability and others represent a generation of new drugs with different mechanisms of action. Perampanel, an agonist of AMPA receptors, is a new drug approved in more than 40 countries, including Russia. At present, the use of some AED is limited by the high risk of sudden death (sudden unexpected death in epilepsy (SUDEP)). SUDEP is a common cause of death directly associated with epilepsy, with the highest frequency in patients with active epilepsy. Subtherapeutic concentrations of SED in the serum of SUDEP patients may be the consequence of inadequate treatment and low compliance to treatment that causes the development of pseudoresistant seizures and, hence, the higher risk of SUDEP. At the same time, AED per se play an important role in the modification of functions of the autonomic nervous system and may induce disturbances of heart rate and conductivity. PMID- 26525619 TI - [Migraine and temporomandibular joint dysfunction: mechanisms of comorbidity]. AB - OBJECTIVE: to analyze the frequency of different forms of temporomandibular joint dysfunction (TMJD) in episodic and chronic migraine and to study mechanisms of their comorbidity. MATERIAL AND METHODS: Sixty-three patients with chronic migraine (CM) and 40 patients with episodic migraine (EM) were examined. Anxiety and depression were assessed with the HADS, quality-of-life related to headache was measured with the HIT-6. To evaluate the antinociceptive system function, we studied blink reflex (BR) and nociceptive flexion reflex (NFR). RESULTS: The higher frequency of TMJD was identified in patients with CM compared to those with EM (47.5 and 28.5%, respectively), CM patients more frequently had disturbances related to the myofascial pain syndrome of masticatory muscles. R3 BR and NFR thresholds were significantly decreased in CM patients as well. CONCLUSION: TMJD is a component of the pathogenesis in many patients with CM. Masticatory muscles may generate nociceptive impulses in CNS, ie be a source of peripheral sensitization, that promote pain chronification, including migraine. Dysfunction of masticatory muscles may reflect the central sensitization and disturbance of efferent pain control. PMID- 26525620 TI - [A double-blind randomized placebo-controlled study of the efficacy of the combined treatment with naltrexone and guanfacine for relapse prevention in opiate dependence]. AB - OBJECTIVE: Authors studied the effect of alpha-2-adrenoreceptor agonist guanfacine on replace prevention in opiate addicts. MATERIAL AND METHODS: Three hundred and one recently detoxified opiate addicts were randomized under the double-blind double-dummy conditions into one of four treatment groups: naltrexone 50 mg/day+guanfacine 1 mg/day (N+G), naltrexone+guanfacine placebo (N+GP), naltrexone placebo+guanfacine (NP+G), and double placebo (NP+GP). The primary outcome was retention in treatment. The secondary outcomes were perceived stress (Perceived Stress Scale) and craving. RESULTS: At the end of six months, 20 (26.7%) patients in the N+G group and 15 (19.7%) (p=0.26 to N+G) in N+GP group were retained in treatment compared to 5 (6.7%) in the NP+G group (p=0.002 to N+G group and p=0.017 to N+GP group) and 8 (10.7%) in the double placebo group (p=0.013 to N+G group). There is no significant difference in retention between the N+G group and N+GP group at the end of treatment. CONCLUSION: Guanfacine had significant craving and stress reducing effect. Naltrexone was more effective than placebo for relapse prevention in opioid dependent patients. The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone alone. Guanfacine moderately reduced both stress and craving. PMID- 26525621 TI - [Therapy of psychotic schizophrenia spectrum disorders in adolescents]. AB - OBJECTIVE: To assess the clinical efficacy, tolerability and safety of prolonged treatment with paliperidone in adolescents with the exacerbation of psychotic schizophrenia spectrum disorders. MATERIAL AND METHODS: Thirty-six adolescents at the age from 14 to 18 years with ICD-10 diagnosis F20-21, F25 were examined by clinical/psychopathological method (PANSS and CGI scale). The duration of the disease was from 1 to 3 years. The duration of the study was 12 months. RESULTS AND CONCLUSION: The efficacy and safety of prolonged use of paliperidone in a dose of 3 to 12 mg/day in adolescents with schizophrenia spectrum disorders were identified. PMID- 26525622 TI - [Diagnosis and correction of cognitive impairment in preschool age children with epilepsy]. AB - OBJECTIVE: To study cognitive impairment and the efficacy of hopantenic acid (pantogam) in children, aged from 4 to 7 years, with epilepsy and cognitive impairment. MATERIAL AND METHODS: The study included 40 children with epilepsy treated with pantogam (the main group) and 23 children with epilepsy who did not receive pantogam (the comparison group). All children were diagnosed with cryptogenic epilepsy and symptomatic epilepsy. We presented the main results of the clinical examination including routine EEG, video-EEG monitoring and brain MRI. An analysis of cognitive impairment in children of the comparison group and in the main group before and after treatment with pantogam was performed using a set of neurocognitive tests (the Luscher Color Test, "Piano playing test", "Three word test" and "Four is redundant test"). RESULTS AND CONCLUSION: There were a significant decrease in cognitive impairment in children of the main group compared to the comparison group as well as age normalization and improvement of EEG after 2 months of treatment in 15% of the patients. The good tolerability of the drug and no increase in the frequency of seizures were observed. PMID- 26525623 TI - [A comparison of the efficacy and safety of memantal and original memantine in the treatment of mild and moderate dementia in Alzheimer's disease]. AB - OBJECTIVE: To estimate the efficacy and safety of original memantine and generic medication (memantal) in patients with mild/ moderate dementia due to Alzheimer's disease (AD). MATERIAL AND METHODS: A six-month randomized controlled comparative study included 50 patients with mild/moderate dementia due to AD. Patients were naive to memantine and IAChe. Original memantine and generic medication dosage (5 mg daily) was titrated according to the manufacturer's recommendations. Patient's condition was assessed with MMSE, the Neuropsychiatric Inventory (NPI) and IADL. Side-effects were recorded. RESULTS: There were no statistically significant differences in cognitive functions, neuropsychiatric symptoms, instrumental activity and safety between original memantine and generic medication. Both medications slightly improved patient's cognitive functioning, mostly in patients with mild dementia due to senile type of AD. CONCLUSION: The generic medication (memantal) and original memantine have equal efficacy and safety in patients with mild/moderate dementia due to AD. PMID- 26525624 TI - [The efficacy of sulpiride in patients with anxiety disorders depending on the serum serotonin concentrations]. AB - OBJECTIVE: The efficacy of sulpiride in patients with anxiety disorders depending on the serum serotonin concentrations was evaluated. MATERIAL AND METHODS: We examined 132 patients with anxiety disorders. The higher levels of serotonin were found in 81 (61.3%) of patients, normal levels in 24 (25.8%) and lower levels in 27 (20.5%). Sulpiride was used in doses from 50 to 400 mg. Average treatment duration was >90 days. RESULTS: The positive effect of sulpiride monotherapy was identified in patients with higher and normal levels of serotonin. No clinical effect of sulpiride was noted in patients with lower serotonin concentrations. CONCLUSION: The efficacy of sulpiride depends on serum concentrations of serotonin. It can be assumed that serotonin concentration is a marker of sulpiride treatment efficacy in patients with anxiety disorders. PMID- 26525625 TI - [The efficacy of cytoflavin in the treatment of burnout syndrome]. AB - OBJECTIVE: To evaluate the efficacy of cytoflavin in the treatment of patients with burnout syndrome. MATERIAL AND METHODS: Authors performed clinical, psychological and neurophysiological examinations of 60 patients, aged 34-43 years. Results of pharmacological therapy with cytoflavin (30 patients) or ethylmethylhydroxypyridine succinate (30 patients) were compared. Control examination was conducted immediately after treatment and then after 30 days to assess the stability of the resulting effect. RESULTS AND CONCLUSION: The higher efficacy of cytoflavin (improvement in 80% of cases) as compared to ethylmethylhydroxypyridine succinate (improvement in 70% of cases) was identified. After cytoflavin treatment, the improvement was more persistent. These clinical results are confirmed by the results of psychological and neurophysiological research. PMID- 26525626 TI - [Formation of paroxysmal brain activity in the liquidators of the consequences of the Chernobyl nuclear disaster]. AB - OBJECTIVE: To investigate the effect of ionizing radiation on the formation of paroxysmal brain activity (PBA) in the liquidators of the consequences of the Chernobyl nuclear disaster in view of their age on the date of exposure to radiation. MATERIAL AND METHODS: EEG examinations were performed in 105 liquidators of the consequences of the nuclear disaster (LCND) and 90 people without radiation anamnesis (control group). RESULTS AND CONCLUSION: It has been determined that the formation of paroxysmal brain activity in LCND occurs 3.5 times more frequent (p<0.001) and 15-17 years earlier (p<0.001) than in the control group and mainly during the first 10 years after the exposure to radiation. The history of the exposure to ionizing radiation is associated with the increased risk of the development of convulsive PBA as focal seizures by 5.5 times (p<0.001), interictal epileptiform discharges (IED) in EEG by 3.3 times (p<0.001). Radiation effect on LCND under 30 years old increases (as compared to the control group) the risk of the formation of elevated paroxysmal brain activity by 19 times (p<0.001), convulsive epileptic seizures by 33.3 times (p<0.001), interictal epileptiform discharges in EEG by 12 times (p<0.001), asymptomatic focal epileptoid nidus in EEG by 9.3 times (p<0.001). Stimulating effect of ionizing radiation on the development of PBA related to the age on the date of exposure to radiation was found. PMID- 26525627 TI - [The relationship between the parameters of cognitive potential P300 and emotional/affective state of patients with chronic pain]. AB - OBJECTIVE: To study emotional state and parameters of cognitive evoked potentials (P300) to target emotional stimuli in patients with chronic back pain. MATERIAL AND METHODS: A study included 62 patients. Trait and state anxiety was measured using the Spilberger-Khanin questionnaire. Cognitive evoked potentials were investigated. RESULTS AND CONCLUSION: The changes in parameters and topographic distribution of cognitive evoked potentials to target emotional stimuli in patients with chronic back pain with different emotional/affective states were identified. Recording of P300 elicited by emotional stimuli allows to evaluate the characteristics of chronification of pain syndromes. PMID- 26525628 TI - [Clinical characteristics of syringomyelia in the Bashkir disease cluster]. AB - OBJECTIVE: To analyze clinical characteristics of syringomyelia based on the data of the Bashkir Disease Cluster. MATERIAL AND METHODS: Authors present the results of examination of 712 patients from the population of Bashkortostan. Disease duration varied in the wide range. In most of the patients, first symptoms usually occurred between 10 and 30 years old. RESULTS AND CONCLUSION: Clinical symptoms included sensory and motor disorders, trophic changes of the skin, joint and bone deformations. A mixed form with lesion localization in the cervical thoracic region of the spine and slowly progressive course was most frequent. PMID- 26525629 TI - [Epilepsy in alcohol and drug abusers]. PMID- 26525630 TI - [Diagnosis of tuberous sclerosis complex]. AB - Tuberous sclerosis complex is a autosomal dominant instantly progressing disease, causing the development of benign tumors in all organs and tissues of human body. According to International Consensus Conference (2012), definite or possible TSC diagnosis can be made. For the definite diagnosis of TSC, two major criteria or one major criterion and >=2 minor criteria have to be present. For a possible diagnosis, 1 major criterion or >=2 minor criteria should be found. A pathogenic mutation in the TSC1 or TSC2 gene is by itself sufficient for a definite diagnosis. There are following major diagnostic criteria: angiofibromas (>=3) or forehead plaque; hypomelanotic macules (>=3); ungual fibromas (>=2); chagrin patch; multiple retinal hamartomas; cortical dysplasias (>=3, include tubers and cerebral white matter radial migration lines; subependymal nodules; subependymal giant cell astrocytoma; cardiac rhabdomyoma; lymphagioleiomatosis and renal angiomyolipomas (>=2). The minor criteria are the following ones: dental enamel pits (>=3); intraoral fibromas (>=2); non-renal hamartomas; retinal achromatic patch; confetti skin lesions; multiple renal cysts. Diagnosis of TSC is not difficult if a physician is familiar with clinical presentation of the disease. PMID- 26525631 TI - [The use of piribedil in early and late stages of Parkinson's disease]. AB - In this article, we present clinical cases at an early stage of Parkinson's disease with mild affective and cognitive disorders, and at a later stage with motor fluctuations and levodopa-induced dyskinesia. The efficacy of dopamine receptor agonists in treatment of Parkinson's disease in the early and late stages is illustrated by the example of piribedil. PMID- 26525632 TI - [Combined prosopalgia with acute onset]. AB - Complexity of facial anatomy and its rich innervation complicate the diagnosis of prosopalgias. An acute syndrome, including trigeminal, myofascial and cervical pains, is described. Authors discuss algesic interrelations, combined therapeuric effect and peculiarities of diagnosis. PMID- 26525633 TI - Kinase overexpressing cancers responsive to drug withdrawal. PMID- 26525634 TI - The Relationship between Total Fibroid Burden and First Trimester Bleeding and Pain. AB - BACKGROUND: Few studies comment on the association between fibroids and symptoms among pregnant women. These studies generally are retrospective and do not to assess the influence of number of tumours or their volume on risk of symptoms. METHODS: Right from the Start is a prospective cohort that enrolled pregnant women from the southeastern USA between 2000 and 2012. In the first trimester, all participants had standardised ultrasounds to determine the presence or absence of fibroids. Symptoms were queried in a telephone survey. We used polytomous logistic regression to model odds of bleeding, pain, or both symptoms in relation to increasing total fibroid number and volume among white and black women. RESULTS: Among 4509 participants, the prevalence of fibroids was 11%. Among those reporting symptoms (70%), 11% reported only bleeding, 59% reported only pain, and 30% reported both symptoms. After adjusting for age, race, parity, hypertension, smoking, alcohol use, and study site, increasing number of fibroids was associated with pain [odds ratio (OR) 1.16, 95% confidence interval (CI) 1.00, 1.33] and both symptoms [OR 1.25, 95% CI 1.08, 1.45] but not with bleeding among all women. Fibroid volume was not associated with symptoms among black women, but white women with the smallest fibroid volumes were more likely to report both symptoms than those without fibroids [OR 1.79, 95% CI 1.17, 2.72]. CONCLUSIONS: Very large tumours are not requisite for experiencing symptoms, as small fibroids and increasing number of tumours are associated with pain and both symptoms. PMID- 26525636 TI - Current Concepts in Adult CRPS. PMID- 26525635 TI - Dexamethasone modulation of MUC5AC and MUC2 gene expression in a generalized model of middle ear inflammation. AB - OBJECTIVES/HYPOTHESIS: To examine the effect of dexamethasone on basal and proinflammatory cytokine-induced gel-forming mucin expression in human middle ear epithelial cell line (HMEEC-1). METHODS: HMEEC-1 was exposed to proinflammatory cytokines, tumor necrosis factor-alpha (TNF-), and interleukin-1 beta (IL-1beta) to identify optimal mucin induction. The HMEEC-1 was incubated with dexamethasone in the steady state and in the presence of proinflammatory cytokine stimulation. Expression of MUC2 and MUC5AC was determined by quantitative polymerase chain reaction. RESULTS: Proinflammatory cytokines, TNF-alpha and IL-1beta, induced MUC2 and MUC5AC expression in HMEEC-1. Dexamethasone reduced steady state mRNA level of MUC5AC in a time-dependent (P < 0.05) and dose-dependent (P < 0.0001) manner. MUC2 was effectively suppressed at all time points tested (P < 0.05). Temporal difference between dexamethasone suppression of MUC2 and MUC5AC was demonstrated. Dexamethasone inhibits the proinflammatory cytokine-induced expression of both MUC2 and MUC5AC. CONCLUSION: This work provides a conclusive picture of the ability of using glucocorticoids to downregulate mucin gene expression in human MEE using a generalizable model of inflammation that is applicable to multiple potential causes of MEE mucosal hypertrophy. This data adds to the promising potential of future interventions for patients with chronic otitis media. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:E248-E254, 2016. PMID- 26525637 TI - Children Seek Historical Traces of Owned Objects. AB - An object's mental representation includes not just visible attributes but also its nonvisible history. The present studies tested whether preschoolers seek subtle indicators of an object's history, such as a mark acquired during its handling. Five studies with 169 children 3-5 years of age and 97 college students found that children (like adults) searched for concealed traces of object history, invisible traces of object history, and the absence of traces of object history, to successfully identify an owned object. Controls demonstrated that children (like adults) appropriately limit their search for hidden indicators when an owned object is visibly distinct. Altogether, these results demonstrate that concealed and invisible indicators of history are an important component of preschool children's object concepts. PMID- 26525638 TI - The effect of race and socioeconomic status on outcomes following adrenal operations. AB - BACKGROUND: Disparities following different operations exist. We seek to measure the effects of race/ethnicity and socioeconomic status on outcomes following adrenal surgery. METHODS: Cross-sectional analysis of adrenal operations identified in the Nationwide Inpatient Sample (NIS) from 2003 to 2009. RESULTS: A total of 7,537 procedures were included. Operations by high-volume surgeons had shorter length of stay (LOS) (3.4 days vs. 5.2 days, P < 0.001) and fewer complications (11.6% vs. 16.7%, P < 0.001). Hispanics were more likely to be operated on by low-volume surgeons [OR: 2.17, 95%CI: (1.33, 3.55)]. There were significant differences in LOS and cost among races/ethnicities, income categories, and insurance types (P < 0.05). Hispanics had longer LOS compared to Whites (P = 0.002) and their management was associated with a higher cost ($20,754.00 +/- 1,478.40). Patients with either Medicaid [OR: 1.70, 95%CI: (1.30, 2.22)] or Medicare [OR: 1.86, 95%CI: (1.36, 2.54)] were more likely to have a LOS >5 days. CONCLUSIONS: Racial and socioeconomic disparities exist; however, they are not solely related to access. A complex interplay between various racial, cultural, and socioeconomic factors likely influence outcomes in adrenal surgery. PMID- 26525639 TI - Design, development and evaluation of a compact telerobotic catheter navigation system. AB - BACKGROUND: Remote catheter navigation systems protect interventionalists from scattered ionizing radiation. However, these systems typically require specialized catheters and extensive operator training. METHODS: A new compact and sterilizable telerobotic system is described, which allows remote navigation of conventional tip-steerable catheters, with three degrees of freedom, using an interface that takes advantage of the interventionalist's existing dexterity skills. The performance of the system is evaluated ex vivo and in vivo for remote catheter navigation and ablation delivery. RESULTS: The system has absolute errors of 0.1 +/- 0.1 mm and 7 +/- 6 degrees over 100 mm of axial motion and 360 degrees of catheter rotation, respectively. In vivo experiments proved the safety of the proposed telerobotic system and demonstrated the feasibility of remote navigation and delivery of ablation. CONCLUSION: The proposed telerobotic system allows the interventionalist to use conventional steerable catheters; while maintaining a safe distance from the radiation source, he/she can remotely navigate the catheter and deliver ablation lesions. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26525640 TI - LightWAVE: Waveform and Annotation Viewing and Editing in a Web Browser. AB - This paper describes LightWAVE, recently-developed open-source software for viewing ECGs and other physiologic waveforms and associated annotations (event markers). It supports efficient interactive creation and modification of annotations, capabilities that are essential for building new collections of physiologic signals and time series for research. LightWAVE is constructed of components that interact in simple ways, making it straightforward to enhance or replace any of them. The back end (server) is a common gateway interface (CGI) application written in C for speed and efficiency. It retrieves data from its data repository (PhysioNet's open-access PhysioBank archives by default, or any set of files or web pages structured as in PhysioBank) and delivers them in response to requests generated by the front end. The front end (client) is a web application written in JavaScript. It runs within any modern web browser and does not require installation on the user's computer, tablet, or phone. Finally, LightWAVE's scribe is a tiny CGI application written in Perl, which records the user's edits in annotation files. LightWAVE's data repository, back end, and front end can be located on the same computer or on separate computers. The data repository may be split across multiple computers. For compatibility with the standard browser security model, the front end and the scribe must be loaded from the same domain. PMID- 26525641 TI - gamma-PARCEL: Control of Molecular Release Using gamma-Rays. AB - We previously have developed the photoresponsive tetra-gel and nanoparticles for controlling the function of the encapsulated substance by UV irradiation. However, the penetration ability of the UV is not high enough. Here, we developed a radiation-responsive tetra-gel and nanoparticle based on gamma-ray-responsive X shaped polyethylene glycol (PEG) linker with a disulfide bond. The nanoparticle could retain small molecules and biomacromolecules. gamma-Rays were used as a trigger signal because of their higher penetrating ability. This allowed a spatiotemporal release and control of the encapsulated substances from the nanoparticle in the deeper region, which is impossible by using light exposure (ultraviolet, visible, and near-infrared). PMID- 26525642 TI - Spiroscytalin, a new tetramic acid and other metabolites of mixed biogenesis from Scytalidium cuboideum. AB - Spiroscytalin (1), a new tetramic acid that possesses an uncommon spiro-ring fusion between a polyketide-derived octalin ring system and a 2,4 pyrrolidinedione, along with two known compounds, leporin B (2) and purpactin A (3), were isolated from a solid phase culture of the fungus Scytalidium cuboideum (MSX 68345). The molecular connectivity of 1-3 was determined using NMR spectroscopy and mass spectrometry. The relative configurations of 1 and 2 were determined by NOESY experiments. The absolute configuration of 1 was determined by electronic circular dichroism (ECD) via a combination of experimental measurements and computational calculations. While leporin B was known, it displayed activities that had not been reported previously, including cytotoxicity against three human tumor cell lines and antibacterial activity against Candida albicans and Staphylococcus aureus. PMID- 26525643 TI - Comparative usefulness of inflammatory markers to indicate bacterial infection analyzed according to blood culture results and related clinical factors. AB - To assess relationships of inflammatory markers and 2 related clinical factors with blood culture results, we retrospectively investigated inpatients' blood culture and blood chemistry findings that were recorded from January to December 2014 using electronic medical records and analyzed the data of 852 subjects (426 culture-positive and 426 culture-negative). Results suggested that the risk of positive blood culture statistically increased as inflammatory marker levels and the number of related factors increased. Concerning the effectiveness of inflammatory markers, when the outcome definition was also changed for C-reactive protein (CRP), the odds ratio had a similar value, whereas when the outcome definition of blood culture positivity was used for procalcitonin (PCT), the greatest effectiveness of that was detected. Therefore, the current results suggest that PCT is more useful than CRP as an auxiliary indication of bacterial infection. PMID- 26525644 TI - Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest. AB - Cytokines are well known mediators of numerous physiological and pathological processes. They contribute to the regulation of normal hematopoiesis but increasing data suggest that they also have a clinical impact in some hematopoietic malignancies. In particular, there is evidence that cytokines are implicated in the functional symptoms of Philadelphia negative myeloproliferative neoplasms (Ph- MPNs), suggesting that evaluation of circulating levels of cytokines could be of clinical interest for the characterization of patients at the time of diagnosis and for disease prognosis. In this review, we present the current knowledge on alteration of circulating cytokine profiles in MPNs and their role in myelofibrosis pathogenesis. Phenotypic correlation, prognostic value of cytokines, and impact of JAK inhibitors are also discussed. PMID- 26525645 TI - VBioindex: A Visual Tool to Estimate Biodiversity. AB - Biological diversity, also known as biodiversity, is an important criterion for measuring the value of an ecosystem. As biodiversity is closely related to human welfare and quality of life, many efforts to restore and maintain the biodiversity of species have been made by government agencies and non governmental organizations, thereby drawing a substantial amount of international attention. In the fields of biological research, biodiversity is widely measured using traditional statistical indices such as the Shannon-Wiener index, species richness, evenness, and relative dominance of species. However, some biologists and ecologists have difficulty using these indices because they require advanced mathematical knowledge and computational techniques. Therefore, we developed VBioindex, a user-friendly program that is capable of measuring the Shannon Wiener index, species richness, evenness, and relative dominance. VBioindex serves as an easy to use interface and visually represents the results in the form of a simple chart and in addition, VBioindex offers functions for long-term investigations of datasets using time-series analyses. PMID- 26525647 TI - Coincidence of monosodium urate monohydrate, calcium pyrophosphate dihydrate, and basic calcium phosphate crystals in the synovial fluid from a single joint. PMID- 26525646 TI - Impact of Ultrasonic Activation on the Effectiveness of Sodium Hypochlorite: A Review. AB - Using ultrasonic devices in endodontics can enhance the antibacterial and tissue dissolving ability of different root canal irrigants such as sodium hypochlorite (NaOCl) which is the most common irrigant with excellent antibacterial and tissue dissolving abilities. However, due to its high surface tension, its penetration into the irregularities of the root canal system is a challenge. The purpose of this paper was to review the different ultrasonic devices, different types of ultrasonic irrigation, the effect(s) of ultrasonic activation on the antibacterial and biofilm-removal abilities of NaOCl as well as the effect of ultrasonic activation on the smear layer removal ability of NaOCl. PMID- 26525649 TI - Neural Networks of the Mouse Neocortex Cell. 2014 Feb 27;156(5):1096-111. PMID- 26525648 TI - Detection of autoantibodies using chemiluminescence technologies. AB - CONTEXT: Although autoantibody detection methods such as indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assays (ELISAs) have been available for many years and are still in use the innovation of fast, fully automated instruments using chemiluminescence technology in recent years has led to rapid adoption in autoimmune disease diagnostics. In 2009, BIO-FLASH, a fully automated, random access chemiluminescent analyzer, was introduced, proceeded by the development of the QUANTA Flash chemiluminescent immunoassays (CIA) for autoimmune diagnostics. OBJECTIVE: To summarize the evolution of CIAs for the detection of autoantibodies and to review their performance characteristics. METHODS: Pubmed was screened for publications evaluating novel QUANTA Flash assays and how they compare to traditional methods for the detection of autoantibodies. In addition, comparative studies presented at scientific meetings were summarized. RESULTS: Several studies were identified that compared the novel CIAs with conventional methods for autoantibody detection. The agreements ranged from moderate to excellent depending on the assay. The studies show how the CIA technology has enhanced the analytical and clinical performance characteristics of many autoantibody assays supporting both diagnosis and follow-up testing. CONCLUSION: CIA has started to improve the diagnostic testing of autoantibodies as an aid in the diagnosis of a broad range of autoimmune diseases. PMID- 26525650 TI - Intelligent navigation to improve obstetrical sonography. AB - 'Manual navigation' by the operator is the standard method used to obtain information from two-dimensional and volumetric sonography. Two-dimensional sonography is highly operator dependent and requires extensive training and expertise to assess fetal anatomy properly. Most of the sonographic examination time is devoted to acquisition of images, while 'retrieval' and display of diagnostic planes occurs rapidly (essentially instantaneously). In contrast, volumetric sonography has a rapid acquisition phase, but the retrieval and display of relevant diagnostic planes is often time-consuming, tedious and challenging. We propose the term 'intelligent navigation' to refer to a new method of interrogation of a volume dataset whereby identification and selection of key anatomical landmarks allow the system to: 1) generate a geometrical reconstruction of the organ of interest; and 2) automatically navigate, find, extract and display specific diagnostic planes. This is accomplished using operator-independent algorithms that are both predictable and adaptive. Virtual Intelligent Sonographer Assistance (VIS-Assistance(r)) is a tool that allows operator-independent sonographic navigation and exploration of the surrounding structures in previously identified diagnostic planes. The advantage of intelligent (over manual) navigation in volumetric sonography is the short time required for both acquisition and retrieval and display of diagnostic planes. Intelligent navigation technology automatically realigns the volume, and reorients and standardizes the anatomical position, so that the fetus and the diagnostic planes are consistently displayed in the same manner each time, regardless of the fetal position or the initial orientation. Automatic labeling of anatomical structures, subject orientation and each of the diagnostic planes is also possible. Intelligent navigation technology can operate on conventional computers, and is not dependent on specific ultrasound platforms or on the use of software to perform manual navigation of volume datasets. Diagnostic planes and VIS-Assistance videoclips can be transmitted by telemedicine so that expert consultants can evaluate the images to provide an opinion. The end result is a user-friendly, simple, fast and consistent method of obtaining sonographic images with decreased operator dependency. Intelligent navigation is one approach to improve obstetrical sonography. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26525651 TI - Standard B-Mode Ultrasound Measures Local Carotid Artery Characteristics as Reliably as Radiofrequency Phase Tracking in Symptomatic Carotid Artery Patients. AB - Local arterial stiffness can be assessed with high accuracy and precision by measuring arterial distension on the basis of phase tracking of radiofrequency ultrasound signals acquired at a high frame rate. However, in clinical practice, B-mode ultrasound registrations are made at a low frame rate (20-50 Hz). We compared the accuracy and intra-subject precision of edge tracking and phase tracking distension in symptomatic carotid artery patients. B-mode ultrasound recordings (40 mm, 37 fps) and radiofrequency recordings (31 lines covering 29 mm, 300 fps) were acquired from the left common carotid artery of 30 patients (aged 45-88 y) with recent cerebrovascular events. To extract the distension, semi-automatic echo edge and phase tracking algorithms were applied to B-mode and radiofrequency recordings, respectively. Both methods exhibited a similar intra subject precision for distension (standard deviation = 44 MUm and 47 MUm, p = 0.66) and mean distension (difference: -6 +/- 69 MUm, p = 0.67). Intra-subject distension inhomogeneity tends to be larger for edge tracking (difference: 15 +/- 35 MUm, p = 0.04). Standard B-mode scanners are suitable for measuring local artery characteristics in symptomatic carotid artery patients with good precision and accuracy. PMID- 26525652 TI - Image-Guided Focused Ultrasound-Mediated Regional Brain Stimulation in Sheep. AB - Non-invasive brain stimulation using focused ultrasound has largely been carried out in small animals. In the present study, we applied stimulatory focused ultrasound transcranially to the primary sensorimotor (SM1) and visual (V1) brain areas in sheep (Dorset, all female, n = 8), under the guidance of magnetic resonance imaging, and examined the electrophysiologic responses. By use of a 250 kHz focused ultrasound transducer, the area was sonicated in pulsed mode (tone burst duration of 1 ms, duty cycle of 50%) for 300 ms. The acoustic intensity at the focal target was varied up to a spatial peak pulse-average intensity (Isppa) of 14.3 W/cm(2). Sonication of SM1 elicited electromyographic responses from the contralateral hind leg, whereas stimulation of V1 generated electroencephalographic potentials. These responses were detected only above a certain acoustic intensity, and the threshold intensity, as well as the degree of responses, varied among sheep. Post-sonication animal behavior was normal, but minor microhemorrhages were observed from the V1 areas exposed to highly repetitive sonication (every second for >=500 times for electroencephalographic measurements, Isppa = 6.6-10.5 W/cm(2), mechanical index = 0.9-1.2). Our results suggest the potential translational utility of focused ultrasound as a new brain stimulation modality, yet also call for caution in the use of an excessive number of sonications. PMID- 26525653 TI - Plastic straw: future of high-speed signaling. AB - The ever-increasing demand for bandwidth triggered by mobile and video Internet traffic requires advanced interconnect solutions satisfying functional and economic constraints. A new interconnect called E-TUBE is proposed as a cost-and power-effective all-electrical-domain wideband waveguide solution for high-speed high-volume short-reach communication links. The E-TUBE achieves an unprecedented level of performance in terms of bandwidth-per-carrier frequency, power, and density without requiring a precision manufacturing process unlike conventional optical/waveguide solutions. The E-TUBE exhibits a frequency-independent loss profile of 4 dB/m and has nearly 20-GHz bandwidth over the V band. A single sideband signal transmission enabled by the inherent frequency response of the E TUBE renders two-times data throughput without any physical overhead compared to conventional radio frequency communication technologies. This new interconnect scheme would be attractive to parties interested in high throughput links, including but not limited to, 100/400 Gbps chip-to-chip communications. PMID- 26525655 TI - Deep brain stimulation of the ventromedial prefrontal cortex causes reorganization of neuronal processes and vasculature. AB - BACKGROUND: Chronic high-frequency electrical deep brain stimulation (DBS) of the subcallosal cingulate region is currently being investigated clinically as a therapy for treatment of refractory depression. Experimental DBS of the homologous region, the ventromedial prefrontal cortex (VMPFC), in rodent models has previously demonstrated anti-depressant-like effects. Our goal was to determine if structural remodeling accompanies the alterations of brain function previously observed as a result of chronic DBS. METHODS: Here we applied 6h of high-frequency bilateral VMPFC DBS daily to 8 9-week old C57Bl/6 mice for 5days. We investigated the "micro-lesion" effect by using a sham stimulation group (8 mice) and a control group (8 mice with a hole drilled into the skull only). Whole brain anatomy was investigated post-mortem using high-resolution magnetic resonance imaging and areas demonstrating volumetric expansion were further investigated using histology and immunohistochemistry. RESULTS: The DBS group demonstrated bilateral increases in whole hippocampus and the left thalamus volume compared to both sham and control groups. Local hippocampal and thalamic volume increases were also observed at the voxel-level; however these increases were observed in both DBS and sham groups. Follow-up immunohistochemistry in the hippocampus revealed DBS increased blood vessel size and synaptic density relative to the control group whereas the sham group demonstrated increased astrocyte size. CONCLUSIONS: Our work demonstrates that DBS not only works by altering function with neural circuits, but also by structurally altering circuits at the cellular level. Neuroplastic alterations may play a role in mediating the clinical efficacy of DBS therapy. PMID- 26525656 TI - Capturing heterogeneous group differences using mixture-of-experts: Application to a study of aging. AB - In MRI studies, linear multi-variate methods are often employed to identify regions or connections that are affected due to disease or normal aging. Such linear models inherently assume that there is a single, homogeneous abnormality pattern that is present in all affected individuals. While kernel-based methods can implicitly model a non-linear effect, and therefore the heterogeneity in the affected group, extracting and interpreting information about affected regions is difficult. In this paper, we present a method that explicitly models and captures heterogeneous patterns of change in the affected group relative to a reference group of controls. For this purpose, we use the Mixture-of-Experts (MOE) framework, which combines unsupervised modeling of mixtures of distributions with supervised learning of classifiers. MOE approximates the non-linear boundary between the two groups with a piece-wise linear boundary, thus allowing discovery of multiple patterns of group differences. In the case of patient/control comparisons, each such pattern aims to capture a different dimension of a disease, and hence to identify patient subgroups. We validated our model using multiple simulation scenarios and performance measures. We applied this method to resting state functional MRI data from the Baltimore Longitudinal Study of Aging, to investigate heterogeneous effects of aging on brain function in cognitively normal older adults (>85years) relative to a reference group of normal young to middle-aged adults (<60years). We found strong evidence for the presence of two subgroups of older adults, with similar age distributions in each subgroup, but different connectivity patterns associated with aging. While both older subgroups showed reduced functional connectivity in the Default Mode Network (DMN), increases in functional connectivity within the pre-frontal cortex as well as the bilateral insula were observed only for one of the two subgroups. Interestingly, the subgroup showing this increased connectivity (unlike the other subgroup) was, cognitively similar at baseline to the young and middle-aged subjects in two of seven cognitive domains, and had a faster rate of cognitive decline in one of seven domains. These results suggest that older individuals whose baseline cognitive performance is comparable to that of younger individuals recruit their "cognitive reserve" later in life, to compensate for reduced connectivity in other brain regions. PMID- 26525657 TI - Clinical features of serum sickness after Australian snake antivenom. AB - Serum sickness is a delayed immune reaction in which the immune system responds to a protein in antiserum as a potentially harmful substance and mounts an IgG mediated antibody response. A 32 year-old female patient had systemic envenoming following a bite by a red-bellied black snake (Pseudechis porphyriacus). She was treated with Tiger snake antivenom and recovered over 24 h and did not develop myotoxicity. She then presented with local pain, itching and swelling, which was partially treated with antihistamines. Eleven days after the bite she presented again with symptoms of worsening serum sickness including rash on the upper legs, joint and muscle pain in arms, ankles and knees, and nausea. The patient was prescribed five days of prednisone 50 mg/day, antihistamine 10 mg/day and analgesia 1000 mg/day and improved over 2 days. She had no further problems on follow up at 4 months. This case highlights that serum sickness can cause significant effects after the treatment of snake envenoming. It develops 5-14 days after antivenom administration and has characteristic clinical and laboratory features. Severe cases of serum sickness can result in morbidity but it appears to respond well to corticosteroid treatment. PMID- 26525658 TI - Vagal efferent stimulation protects against Mesobuthus tamulus venom-induced acute respiratory distress syndrome in rats. AB - Mesobuthus tamulus (MBT) venom and oleic acid (OA) have been shown to produce acute respiratory distress syndrome (ARDS) involving different mechanisms. The role of vagally mediated anti-inflammatory pathway in ARDS is poorly understood. Therefore, the effects of vagal efferent stimulation on these two models of ARDS were examined. Experiments were performed on anesthetized adult rats. Parameters like ventilatory changes (respiratory frequency and minute ventilation), hypoxemic status (PaO2/FiO2 ratio; P/F ratio), survival time, pulmonary water content and histopathological evidences of lung injury were determined to assess the severity of ARDS. In addition, heart rate (HR) and mean arterial pressure (MAP) were monitored. Injection of OA/MBT venom produced respiratory alterations, hypoxemia, pulmonary edema and histopathological changes demonstrating the development of ARDS. In both the groups, animals died around 60 min. Tachypnea and hyperventilation were seen after OA while bradypnea and hypoventilation were seen after MBT venom. Pulmonary edema was absent in vagotomised animals in MBT venom group but not in OA group. Further, electrical stimulation of the cut peripheral ends of vagii prolonged the survival time and attenuated all the parameters of MBT venom-induced ARDS significantly. In case of OA, there was improvement in histopathological changes but the survival time of animals was not prolonged. Stimulation of alpha7-nicotinic receptors (by pretreatment with GTS 21) exacerbated OA as well as MBT venom-induced ARDS. The present results indicate that vagal efferent stimulation protects against MBT venom-induced ARDS. PMID- 26525654 TI - Diffusion kurtosis imaging probes cortical alterations and white matter pathology following cuprizone induced demyelination and spontaneous remyelination. AB - Although MRI is the gold standard for the diagnosis and monitoring of multiple sclerosis (MS), current conventional MRI techniques often fail to detect cortical alterations and provide little information about gliosis, axonal damage and myelin status of lesioned areas. Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) provide sensitive and complementary measures of the neural tissue microstructure. Additionally, specific white matter tract integrity (WMTI) metrics modelling the diffusion in white matter were recently derived. In the current study we used the well-characterized cuprizone mouse model of central nervous system demyelination to assess the temporal evolution of diffusion tensor (DT), diffusion kurtosis tensor (DK) and WMTI-derived metrics following acute inflammatory demyelination and spontaneous remyelination. While DT-derived metrics were unable to detect cuprizone induced cortical alterations, the mean kurtosis (MK) and radial kurtosis (RK) were found decreased under cuprizone administration, as compared to age-matched controls, in both the motor and somatosensory cortices. The MK remained decreased in the motor cortices at the end of the recovery period, reflecting long lasting impairment of myelination. In white matter, DT, DK and WMTI-derived metrics enabled the detection of cuprizone induced changes differentially according to the stage and the severity of the lesion. More specifically, the MK, the RK and the axonal water fraction (AWF) were the most sensitive for the detection of cuprizone induced changes in the genu of the corpus callosum, a region less affected by cuprizone administration. Additionally, microgliosis was associated with an increase of MK and RK during the acute inflammatory demyelination phase. In regions undergoing severe demyelination, namely the body and splenium of the corpus callosum, DT-derived metrics, notably the mean diffusion (MD) and radial diffusion (RD), were among the best discriminators between cuprizone and control groups, hence highlighting their ability to detect both acute and long lasting changes. Interestingly, WMTI derived metrics showed the aptitude to distinguish between the different stages of the disease. Both the intra-axonal diffusivity (Da) and the AWF were found to be decreased in the cuprizone treated group, Da specifically decreased during the acute inflammatory demyelinating phase whereas the AWF decrease was associated to the spontaneous remyelination and the recovery period. Altogether our results demonstrate that DKI is sensitive to alterations of cortical areas and provides, along with WMTI metrics, information that is complementary to DT-derived metrics for the characterization of demyelination in both white and grey matter and subsequent inflammatory processes associated with a demyelinating event. PMID- 26525659 TI - Rapid detection of fumonisin B1 using a colloidal gold immunoassay strip test in corn samples. AB - Fumonisin B1 (FB1) is the most common and highest toxic of fumonisins species, exists frequently in corn and corn-based foods, leading to several animal and human diseases. Furthermore, FB1 was reported that it was associated with the human esophageal cancer. In view of the harmful of FB1, it is urgent to develop a feasible and accuracy method for rapid detection of FB1. In this study, a competitive immunoassay for FB1 detection was developed based on colloidal gold antibody conjugate. The FB1-keyhole limpet hemoeyanin (FB1-KLH) conjugate was embedded in the test line, and goat anti-mouse IgG antibody embedded in the control line. The color density of the test line correlated with the concentration of FB1 in the range from 2.5 to 10 ng/mL, and the visual limit detection of test for FB1 was 2.5 ng/mL. The results indicated that the test strip is specific for FB1, and no cross-reactivity to other toxins. The quantitative detection for FB1 was simple, only needing one step without complicated assay performance and expensive equipment, and the total time of visual evaluation was less than 5 min. Hence, the developed colloidal gold antibody assay can be used as a feasible method for FB1 rapid and quantitative detection in corn samples. PMID- 26525660 TI - Clinical radiation oncology trials in Germany: Time for clarification and professionalization. PMID- 26525661 TI - Growth hormone for risk stratification and effects of therapy in acute myocardial infarction. AB - CONTEXT: Excess growth hormone (GH) is associated with early mortality. OBJECTIVES: We assessed the association of GH with prognosis after acute myocardial infarction (AMI), and the effects of secondary prevention therapies. METHODS: GH was measured using a high-sensitivity assay in 953 AMI patients (687 males, mean age 66.1 +/- 12.8 years). RESULTS: During 2 years follow-up, there were 281 major adverse cardiac events (MACE). Patients with MACE had higher GH levels (median [range], 0.91 [0.04-26.28] MUg/L) compared to event-free survivors (0.59 [0.02-21.6], p < 0.0005). In multivariate Cox survival analysis, GH was a significant predictor of MACE (hazard ratios 1.43, p = 0.026 and 1.49, p = 0.01, respectively) with significant interactions with beta blocker therapy (p = 0.047) and angiotensin converting enzyme inhibitor or angiotensin receptor blocker (ACE/ARB) therapy (p = 0.016). CONCLUSIONS: GH levels post-AMI are prognostic for MACE and may indicate those patients who benefit from beta blocker and ACE/ARB therapy. PMID- 26525662 TI - In situ and real time investigation of the evolution of a Pseudomonas fluorescens nascent biofilm in the presence of an antimicrobial peptide. AB - Against the increase of bacterial resistance to traditional antibiotics, antimicrobial peptides (AMP) are considered as promising alternatives. Bacterial biofilms are more resistant to antibiotics that their planktonic counterpart. The purpose of this study was to investigate the action of an AMP against a nascent bacterial biofilm. The activity of dermaseptin S4 derivative S4(1-16)M4Ka against 6 h-old Pseudomonas fluorescens biofilms was assessed by using a combination of Attenuated Total Reflectance-Fourier Transform InfraRed (ATR-FTIR) spectroscopy in situ and in real time, fluorescence microscopy using the BaclightTM kit, and Atomic Force Microscopy (AFM, imaging and force spectroscopy). After exposure to the peptide at three concentrations, different dramatic and fast changes over time were observed in the ATR-FTIR fingerprints reflecting a concentration dependent action of the AMP. The ATR-FTIR spectra revealed major biochemical and physiological changes, adsorption/accumulation of the AMP on the bacteria, loss of membrane lipids, bacterial detachment, bacterial regrowth, or inhibition of biofilm growth. AFM allowed estimating at the nanoscale the effect of the AMP on the nanomechanical properties of the sessile bacteria. The bacterial membrane elasticity data measured by force spectroscopy were consistent with ATR-FTIR spectra, and they allowed suggesting a mechanism of action of this AMP on sessile P. fluorescens. The combination of these three techniques is a powerful tool for in situ and in real time monitoring the activity of AMPs against bacteria in a biofilm. PMID- 26525663 TI - Antimicrobial peptides and their interaction with biofilms of medically relevant bacteria. AB - Biofilm-associated infections represent one of the major threats of modern medicine. Biofilm-forming bacteria are encased in a complex mixture of extracellular polymeric substances (EPS) and acquire properties that render them highly tolerant to conventional antibiotics and host immune response. Therefore, there is a pressing demand of new drugs active against microbial biofilms. In this regard, antimicrobial peptides (AMPs) represent an option taken increasingly in consideration. After dissecting the peculiar biofilm features that may greatly affect the development of new antibiofilm drugs, the present article provides a general overview of the rationale behind the use of AMPs against biofilms of medically relevant bacteria and on the possible mechanisms of AMP-antibiofilm activity. An analysis of the interactions of AMPs with biofilm components, especially those constituting the EPS, and the obstacles and/or opportunities that may arise from such interactions in the development of new AMP-based antibiofilm strategies is also presented and discussed. This article is part of a Special Issue entitled: Antimicrobial Peptides edited by Karl Lohner and Kai Hilpert. PMID- 26525665 TI - Determination of bisphenols in beverages by mixed-mode solid-phase extraction and liquid chromatography coupled to tandem mass spectrometry. AB - Facing growing restrictions on the use of bisphenol A in food contact materials, several bisphenol analogs are arising as major alternatives to replace this chemical in most of its applications. This work reports a simple and robust method based on mixed-mode solid-phase extraction and stable-isotope dilution liquid chromatography-tandem mass spectrometry for the analysis of bisphenol A and its main analogs - bisphenol S, 4,4'-sulfonylbis(2-methylphenol), bisphenol F, bisphenol E, bisphenol B, bisphenol Z, bisphenol AF, bisphenol AP, tetrabromobisphenol A and bisphenol P - in alcoholic and non-alcoholic beverages. Mixed-mode solid-phase extraction, combining cationic exchange and reversed-phase mechanisms, was optimized to provide a selective extraction and purification of the target analytes. Derivatization of bisphenols with pyridine-3-sulfonyl chloride allowed increasing their ionization efficiency by electrospray ionization. Validation of the proposed method was performed in terms of selectivity, matrix effects, linearity, precision, measurement uncertainty, trueness and limits of detection. Satisfactory repeatability and intermediate precision were obtained; the related relative standard deviations were <=9% and <=12%, respectively. The relative expanded uncertainty (k=2) was below 20% for all bisphenol analogs and the trueness of the method was demonstrated by recovery experiments. Limits of detection (LOD) ranged from 1.6ngL(-1) to 27.9ngL(-1) for all compounds. Finally, several canned and non-canned beverages were analyzed to demonstrate the applicability of the method. Only bisphenol A and three bisphenol F isomers were detected in any of the samples. Bisphenol A concentration ranged from 90 years?). If evidence-based medicine does not exist within this framework, there are many registries that can guide us in their care. First, age should not in itself be an indication against reperfusion conventional techniques. In fact recommendations put no upper age limit. The primary angioplasty technical success, which is identical to the younger populations, is the treatment of choice and should be performed preferably by radial arterial access. The thrombolytic alternative, validated for octogenarians, has not been studied for older. Bleeding, neurological, ischemic complications and hospital mortality are more common than in younger populations, especially as the initial hemodynamic alteration is important, but the survivors have the same life-threatening or even better than that of a same reference population ages. Which in itself even justifies maximum adhesion to the therapeutic recommendations taking into account the co-morbidities and possible visceral shortcomings. PMID- 26525682 TI - Familial pseudotail, scoliosis and synpolydactyly syndrome. AB - PURPOSE: This case series describes a novel condition characterized by familial pseudotail associated with scoliosis, and synpolydactyly that has not been previously reported in literature. METHODS: The authors present three siblings and one cousin from the same family living in the northern region of the Arabian Peninsula. All cases presented with pseudotail, scoliosis, and complex synpolydactyly. The authors demonstrated complete clinical and radiological descriptions in addition the detailed performed surgeries. RESULTS: The histopathological result of the resected pseudotail specimens revealed bony lesion covered with thick fibrous tissue and evidence of mature adipocytes within trabecular spaces. CONCLUSIONS: The described cases represent a novel condition that has not been previously reported in the literature. Familial pseudotail scoliosis synpolydactyly syndrome is a newly recognized form of familial pseudotail. PMID- 26525684 TI - Skin cancer: Nicotinamide reduces new skin cancer risk. PMID- 26525683 TI - Novel immunotherapies in lymphoid malignancies. AB - The success of the anti-CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted 'breakthrough' designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T-cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T-cell engager (BiTE((r))) antibody, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD-1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens. PMID- 26525685 TI - [Prevalence of Y-chromosome sequences and gonadoblastoma in Turner syndrome]. AB - OBJECTIVE: To assess the prevalence of Y-chromosome sequences and gonadoblastoma in patients with Turner syndrome using molecular techniques. DATA SOURCE: A literature search was performed in Pubmed, limiting the period of time to the years 2005 to 2014 and using the descriptors: Turner syndrome and Y sequences (n=26), and Turner syndrome and Y-chromosome material (n=27). The inclusion criteria were: articles directly related to the subject and published in English or Portuguese. Articles which did not meet these criteria and review articles were excluded. After applying these criteria, 14 papers were left. DATA SYNTHESIS: the main results regarding the prevalence of Y-chromosome sequences in Turner syndrome were: 1-about 60% of the studies were conducted by Brazilian researchers; 2-the prevalence varied from 4.6 to 60%; 3-the most frequently investigated genes were SRY, DYZ3 and TSPY; 4-seven studies used only PCR, while in the remaining seven it was associated with FISH. Nine of the 14 studies reported gonadectomy and gonadoblastoma. The highest prevalence of gonadoblastoma (33%) was found in two studies. In five out of the nine papers evaluated the prevalence of gonadoblastoma was 10 to 25%; in two of them it was zero. CONCLUSIONS: according to these data, molecular analysis to detect Y-chromosome sequences in TS patients is indicated, regardless of their karyotype. In patients who test positive for these sequences, gonadoblastoma needs to be investigated. PMID- 26525686 TI - [Neonatal atrial flutter after the insertion of an intracardiac umbilical venous catheter]. AB - OBJECTIVE: To describe a case of neonatal atrial flutter after the insertion of an intracardiac umbilical venous catheter, reporting the clinical presentation and reviewing the literature on this subject. CASE DESCRIPTION: A late-preterm newborn, born at 35 weeks of gestational age to a diabetic mother and large for gestational age, with respiratory distress and rule-out sepsis, required an umbilical venous access. After the insertion of the umbilical venous catheter, the patient presented with tachycardia. Chest radiography showed that the catheter was placed in the position that corresponds to the left atrium, and traction was applied. The patient persisted with tachycardia, and an electrocardiogram showed atrial flutter. As the patient was hemodynamically unstable, electric cardioversion was successfully applied. COMMENTS: The association between atrial arrhythmias and misplaced umbilical catheters has been described in the literature, but in this case, it is noteworthy that the patient was an infant born to a diabetic mother, which consists in another risk factor for heart arrhythmias. Isolated atrial flutter is a rare tachyarrhythmia in the neonatal period and its identification is essential to establish early treatment and prevent systemic complications and even death. PMID- 26525687 TI - [Frequency of overweight and obesity in children and adolescents with autism and attention deficit/hyperactivity disorder]. AB - OBJECTIVE: To assess the frequency of overweight and obesity in children and adolescents with autism spectrum disorder (ASD) and with attention deficit/hyperactivity disorder (ADHD) and their parents, in comparison with children and adolescents without developmental disorders. METHODS: Anthropometric measures were obtained in 69 outpatients with ASD (8.4+/-4.2 years old), 23 with ADHD (8.5+/-2.4) and 19 controls without developmental disorders (8.6+/-2.9) between August and November 2014. Parents of patients with ASD and ADHD also had their anthropometric parameters taken. Overweight was defined as a percentile >=85; obesity as a percentile >=95; and underweight as a percentile <=5. For adults, overweight was defined as a BMI between 25 and 30kg/m(2) and obesity as a BMI higher than 30kg/m(2). RESULTS: Children and adolescents with ASD and ADHD had higher BMI percentile (p<0.01) and z-score (p<0.01) than controls, and increased frequency of overweight and obesity (p=0.04). Patients with ASD and ADHD did not differ between them in these variables, nor regarding abdominal circumference. Parents of children with ASD and ADHD did not differ between themselves. CONCLUSIONS: Children and adolescents with ASD and ADHD are at a higher risk of overweight and obesity than children without developmental problems in the community. PMID- 26525688 TI - Neuropad for the detection of cardiovascular autonomic neuropathy in patients with type 2 diabetes. AB - BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is a prevalent and neglected chronic complication of diabetes, with a large impact on morbidity and mortality. Part of the reason why it is not detected and treated opportunely is because of the complexity of the tests required for its diagnosis. We evaluated the Neuropad(r), a test based on sudomotor function, as a screening tool for CAN in adult patients with type 2 diabetes in Bogota, Colombia. METHODS: This was a cross-sectional evaluation of Neuropad(r) for the detection of CAN. Patients were 20-75years of age and did not suffer from any other type of neuropathy. CAN was diagnosed using the Ewing battery of tests for R-R variability during deep breathing, Valsalva and lying-to-standing maneuvers. Additionally, distal symmetric polyneuropathy (DSP) was diagnosed using a sign-based scale (Michigan Neuropathy Disability Score - NDS) and a symptom-based score (Total Symptom Score - TSS). The primary outcome was the sensitivity and specificity of the Neuropad(r) for the diagnosis of CAN, and secondary outcomes were the sensitivity and specificity of Neuropad(r) for DSP. RESULTS: We studied 154 patients (74 men and 80 women). Prevalence of CAN was extremely high (68.0% of study participants), but also DSP was prevalent, particularly according to the signs based definition (45%). The sensitivity of the Neuropad(r) for any degree of CAN was 70.1%, being slightly higher for the deep breathing and Valsalva tests than for lying-to-standing. The specificity of the Neuropad(r) for any type of CAN was only 37.0%, as expected for a screening exam. The negative predictive value was higher for the deep breathing and Valsalva tests (69.4 and 81.6%, respectively). Neuropad showed also a good sensitivity and negative predictive value for DSP. The sensitivity and specificity of Neuropad were better among men, and among patients with diabetes duration above the group median. CONCLUSIONS: The Neuropad is a simple and inexpensive device that demonstrated an adequate performance as a screening tool for cardiovascular autonomic neuropathy in Latin American patients with DM2. PMID- 26525689 TI - Heat stroke in Karachi: An unprecedented medical emergency. PMID- 26525690 TI - Mental and Physical Health and Spiritual Healing: An Evaluation of Complementary Religious Therapies Provided by Spiritist Centers in the City of Sao Paulo, Brazil. AB - The present study aims to describe the characteristics of the complementary religious treatment conducted by Spiritist centers in the city of Sao Paulo (Brazil), to understand how physical and mental health problems are addressed and how the directors of these centers differentiate between persons with spiritual experiences from those with psychiatric disorders. From 365 Spiritist centers, which received the questionnaire, 55 (15.1 %) were included in the final analysis. There were on average 261 people per week attending spiritual sessions in each center, totalizing approximately 15,000 attendees per week in all 55 centers. The most common treatment performed in these centers was disobsession (Spirit release therapy) (92.7 %); the least common was the 'spiritual surgery', present in only 5.5 %. The most frequent health problems reported by attendees were depression (45.1 %), cancer (43.1 %) and diseases in general (33.3 %). Concerning the directors' awareness to differentiate between spiritual experiences and psychiatric disorders, we found some remarkable divergent opinions. In conclusion, the Spiritist centers are an important health related support system for the city of Sao Paulo, responsible for a significant share of the city's total health consultations. The most common conditions the patients suffer from were depression and cancer. PMID- 26525691 TI - Prenatal sonographic ultrasound predictors for the outcome in fetal gastroschisis: a retrospective analysis. AB - PURPOSE: To identify predictive ultrasound signs for unfavorable outcome in fetal gastroschisis (GS). METHODS: This is a retrospective cohort study among pregnant women with the prenatal diagnosis of GS between 1998 and 2011 at the University of Wuerzburg, Germany. Analysis included prenatal ultrasound scans, neonatal intensive care unit (NICU) records, and pediatric records. The collected variables included maternal and fetal demographics, as well as an analysis of predictors for unfavorable fetal outcome. Unfavorable outcome was defined by more than 2 postnatal surgical interventions, intestinal resections, and long time to oral feeding (>=4 weeks). RESULTS: 35 cases of fetal GS were diagnosed, whereby 23 cases met the inclusion criteria and were evaluated by prenatal ultrasound and postnatal outcome. Based on the postnatal situation, 15 patients were classified in a good prognosis group and 8 patients in a poor prognosis group. Fetuses with poor prognosis were presented later during pregnancy (21.1 +/- 6 vs. 26.9 +/- 5.3 weeks; p < 0.01) and delivered at earlier gestational age (35.6 +/- 0.8 vs. 33.4 +/- 1.4 weeks; p < 0.01) with lower birth weight (2074 +/- 306.3 vs. 2559 +/- 255.4 g; p < 0.01). There were no differences in prenatal findings like growth restriction, amniotic fluid index, or Doppler results between good and poor prognosis group. However, early detected and long-lasting bowel dilatation was associated with poor prognosis. CONCLUSION: Late presentation and early gestational age at delivery are associated with poor prognosis in neonates with GS. Furthermore, early onset as well as long duration of bowel dilatation is associated with poor fetal outcome, while other ultrasound characteristics are not able to predict poor prognosis of GS. PMID- 26525692 TI - Uterine artery embolization combined with intra-arterial MTX infusion: its application in treatment of cervical pregnancy. AB - OBJECTIVE: To investigate the efficacy and safety of uterine artery chemoembolization (UAE) combined with intra-arterial MTX infusion for the treatment of cervical pregnancy. METHODS: Retrospective chart review for 26 cervical pregnancy patients treated at Renji hospital between January 2000 and December 2012. 14 patients received UAE combined with intra-arterial MTX infusion (UAE group) and 12 patients received single intramuscular MTX injection combined with subsequent uterine curettage (non-UAE group). RESULTS: All 14 patients in the UAE group were treated successfully and 1 patient in the non-UAE group had 1200 ml vaginal bleeding during uterine curettage and was then treated with emergency UAE. The mean estimated blood loss during uterine curettage in the UAE group was much less than in non-UAE Group. A quicker regression of serum beta-hCG level and normal menses resumed and a shorter hospital stay were observed in the UAE group than in the non-UAE group. CONCLUSIONS: Uterine artery chemoembolization combined with intra-arterial MTX infusion is an efficient conservative treatment for cervical pregnancy. PMID- 26525693 TI - Effect of colchicine on polycystic ovary syndrome: an experimental study. AB - PURPOSE: To investigate whether there is any therapeutic effect of colchicine on a rat model of polycystic ovary syndrome (PCOS). METHODS: Twenty-two Wistar Albino rats were randomly assigned into four with 8 rats in each group: control group; PCOS only group; PCOS-metformin group and PCOS-colchicine group. PCOS was induced by gavage with letrozole once daily at the concentration of 1 mg/kg orally with 21 consecutive days. After PCOS model assessment, PCOS-metformin group was received metformin orally with 500 mg/kg and PCOS-colchicine group was received colchicine orally with 1 mg/kg for the 35 day. Histopathology of ovaries, circulating estrone (E1), estradiol (E2), total testosterone, androstenedione and c-reactive protein (CRP) levels were evaluated. RESULTS: cystic and atretic follicle number was significantly decreased, but CRP and hormone parameters were not significantly changed with colchicine treatment. CONCLUSION: Colchicine has provided histopathological improvement compared with metformin in PCOS rat model. PMID- 26525694 TI - Implementation of enhanced recovery after surgery (ERAS) in gynaecological oncology. AB - OBJECTIVES: To evaluate the outcomes of enhanced recovery after surgery (ERAS) implementation in a gynaecological oncology centre. METHOD: Non-randomised control trial, evaluating morbidity outcomes, before and after implementation of ERAS programme. All consecutive major gynaecological oncology operations performed during two specified periods were included. Data were collected prospectively for a study group in the initial 7.5 months of ERAS implementation and compared with a consecutive historic control group from the exact same period, the year before. Patients' characteristics and perioperative outcomes were compared. Further analysis stratified abdominal and laparoscopic surgery. RESULTS: In total, 265 cases identified; 99 patients followed ERAS and 99 historic controls, managed with a traditional peri-operative approach, the exact same period the year before (vulval surgery excluded, 67 cases). Groups were comparable in demographics and co-morbidities (age, BMI, ASA, WHO), level of surgery and 30 days post-operative complication (grading Clavien-Dindo classification) and readmission rates (p > 0.05). Overall, the post-operative length of hospital stay (LOS) was significantly reduced for patients who followed ERAS (4.29 +/- 2.78 days versus 7.23 +/- 5.68 days, p < 0.001). Stratification to subgroups was based on the type of surgery, abdominal versus laparoscopic. Those who underwent abdominal surgery and followed ERAS benefited the maximum (LOS: 5.09 +/- 2.74 days versus 8.70 +/- 5.75, p < 0.001) CONCLUSIONS: ERAS programme is feasible and safe in Gynae-oncology. In this study, there was a reduction of 3.61 (SE: 0.78, CI 95 %) days in the total LOS, in major abdominal Gynae-oncology surgery (level 3 and 4) without affecting complication or readmission rates. PMID- 26525695 TI - The correlation of cumulus mucification patterns with oocyte maturation rate in vitro in FSH + LH-primed IVM cycles: a prospective study. AB - PURPOSE: This prospective study was conducted to compare the oocyte maturation rate in vitro among four types of cumulus cell (CC) morphology, in dual gonadotropin-primed in vitro maturation (IVM) oocyte cycles. METHODS: Two-hundred and thirty cumulus-oocyte complexes (COCs) were retrieved from FSH + hCG-primed in vitro maturation cycles of 20 patients diagnosed with polycystic ovarian syndrome. The COCs that contained immature oocytes were classified into four groups according to their cumulus mucification patterns (dispersed, clumped, compacted or sparse) and their oocyte maturation rates were compared. Chi square test and Fisher's exact test were used as appropriate. RESULTS: Oocytes enclosed by dispersed and clumped CCs exhibited higher maturation rates than those with compacted and sparse patterns (P < 0.001). CONCLUSION: In dual gonadotropin primed IVM cycles, oocyte maturation rates are highest in those showing dispersed and clumped CC patterns. PMID- 26525696 TI - AMH trend after laparoscopic cystectomy and ovarian suturing in patients with endometriomas. AB - PURPOSE: To evaluate the ovarian reserve after laparoscopic cystectomy with suturing in patients with endometriomas. METHODS: A total of 80 women with unilateral or bilateral endometriomas underwent laparoscopic cystectomy using sutures for hemostasis after the excision of ovarian cysts. Serum levels of antimullerian hormone (AMH) and FSH were measured at the day 3 of menstrual cycles preoperatively, 6 and 12 months postoperatively. RESULTS: In the bilateral endometrioma group, serum AMH level decreased significantly from the baseline (4.68 +/- 2.87 ng/ml) to 6 months (3.05 +/- 1.99 ng/ml) and 12 months (2.26 +/- 1.88 ng/ml) postoperatively, whereas the FSH level increased significantly from baseline to 12 months postoperatively (P < 0.05). Those patients with unilateral endometriomas also had lower levels of AMH in 6 and 12 months after operation. When compared between unilateral and bilateral endometrioma group, the rate of AMH decline 6 and 12 months and the rate of FSH increase 12 months postoperatively reached statistical significance (P < 0.05). CONCLUSIONS: The changes of the AMH and FSH values suggest that the ovarian reserve is obviously reduced in spite of suturing technology used as a method of hemostasis after stripping ovarian endometriomas, especially in those with bilateral cysts. The protective effect of the ovarian suturing for ovarian reserve may be marginal. PMID- 26525697 TI - European trainee exchange: experiences due the ENTOG exchange programme 2015 in Utrecht, the Netherlands. AB - BACKGROUND: The European Network of Trainees in Obstetrics and Gynaecology (ENTOG) is a Europe wide association of trainees in gynaecology and obstetric. It is closely associated with the European Board and College of Obstetrics and Gynaecology. Both organisations aim to improve the training in gynaecology and obstetrics as the fundamental step to overcome large differences in women's health across Europe. Annually, ENTOG meeting takes place which brings together trainees from the member countries to share their professional experience. The training session of the meeting which is preceded by an exchange programme. The exchange programme aims to learn something about the everyday work of the host country. METHOD: This article reports about the ENTOG exchange program that took place in the Netherlands this year and outlines difference to the German health system. RESULT AND PERSPECTIVE: The inter-collegiate exchange within Europe represents both a challenge as well as an opportunity to learn from each other. The 2016 ENTOG exchange will take place in Turkey. PMID- 26525698 TI - Prenatal predictors in postpartum recovery for acute fatty liver of pregnancy: experiences at a tertiary referral center. AB - PURPOSE: The purpose of this study was to describe some prenatal characteristics and laboratory findings of acute fatty liver of pregnancy (AFLP) and provide the clinicians with reasonable predictors and expectation in postpartum recovery. METHODS: At a tertiary referral center 43 patients with AFLP were entered into this retrospective study in 5 years based on the Swansea criteria. Emergent cesarean sections were performed within 24 h, and the criteria of recovery after operation was based on a uniform standard. All of them were hospitalized and treated at the same department of obstetrics and maternal intensive care unit. RESULTS: Prenatally, all women with AFLP had elevated serum hepatic aminotransferase and serum bilirubin levels. Albumin level was decreased in 88 % women and hypoglycemia was documented in 56 % women. Plasma fibrinogen level of 93 % patients was less than 1.75 g/L and prothrombin time (PT) of 91 % was prolonged abnormally. The duration of recovery after delivery ranged from 5 to 20 days. Pearson correlation coefficient between duration of recovery and hyperbilirubinemia was 0.639 (P = 0.001). The levels of PT, plasma fibrinogen and platelet counts were also correlated with the recovery time (R = 0.459, P = 0.002; R = 0.427, P = 0.004; R = 0.435, P = 0.004). Elevated leukocytes, hypoglycaemia, hepatic aminotransferase and uric acid levels showed no value for predicting the prognosis of AFLP (P > 0.01). CONCLUSIONS: AFLP is a rare but serious complication in the third trimester. Prenatal serum bilirubin, PT, plasma fibrinogen levels and platelet counts are the predictors of postpartum recovery, but some Swansea diagnosis criteria do not have the same prognostic significance as others. PMID- 26525699 TI - Is there an association between assisted reproductive technologies and time and complications of the third stage of labor? AB - PURPOSE: To determine if vaginal deliveries exposed to assisted reproductive technologies (ART) are associated with an increased time between delivery of the neonate and placenta and select complications. METHODS: A retrospective cohort of patients enrolled in an infertility practice who had term, singleton, vaginal deliveries at two academic hospitals from 2008 to 2013 was analyzed. Controls were patients with spontaneous conceptions after infertility consultations. The exposure groups were patients with controlled ovarian hyper-stimulation (COH) with in vivo fertilization, COH with in vitro fertilization and fresh embryo transfer (COH/IVF), and frozen embryo transfer or oocyte donation recipients without COH (non-COH ET). Multiple gestations and stillbirths were excluded. Median time of third stage was compared using the Mann-Whitney U test. Secondary outcomes of retained placenta, manual placental extraction, and post-partum hemorrhage (PPH) were compared using Chi-square or Fisher's exact analyses. RESULTS: A total of 769 patients met criteria and were analyzed. While there were no differences in time of third stage of labor, retained placenta, or PPH, manual extraction was significantly more common among non-COH ET [age-adjusted OR 5.6 (95 % CI 2.2-13.8); p < 0.001]. CONCLUSIONS: Patients who conceived after non-COH ET were at increased risk for manual placental extraction. This association was not influenced by age differences between groups. Further research must be done to determine which elements of the ART process are responsible for these differences. PMID- 26525700 TI - The challenge of preoperative identification of uterine myomas: Is ultrasound trustworthy? A prospective cohort study. AB - PURPOSE: To correlate preoperative ultrasound examination with intraoperative and anatomo-pathological findings, including estimation of number, localization and size of uterine myomas, uterine diameters and volume. METHODS: A prospective study on 126 women undergoing surgery for uterine myomatosis at Campus Bio-medico between May 2013 and April 2014. The patients were divided into two groups: one submitted to hysterectomy and the other submitted to open myomectomy. Ultrasound scans were performed 1 day before surgery by the same expert sonographer. The number of myomas at ultrasound was compared to intraoperative visualization and anatomo-pathological findings. Wilcoxon Test was applied to compare data registered with each technique. RESULTS: There was no significant difference between the number of myomas recorded at visualization and at ultrasound, while there was a significant difference between visualization and anatomo-pathology (p = 0.0006). The analysis showed a non-significant difference between myoma number at ultrasound and at anatomo-pathology in the two groups, if the number of myomas was less than or equal to six. Contrarily, we observed a significant difference if the number of myomas was more than six (p = 0.003). CONCLUSIONS: Our data show that ultrasound has limits in identifying the exact number of uterine myomas. This mapping is particularly needed in a minority of patients with usually desiring fertility who need a debulking procedure due to the large size and/or number of myomas or myoma location causing symptomatology. In patients with more than six myomas, voluminous uterus, a second-level examination such as Magnetic Resonance may be helpful. PMID- 26525701 TI - Prevalence of uterine myomas in women in Germany: data of an epidemiological study. AB - PURPOSE: Currently, no reliable data are available concerning the prevalence of uterine myomas in Germany. In this prospective study, we examined the prevalence of myomas in women older than 30 years by means of vaginal ultrasound. METHODS: 2296 women, who consented to the procedure, were examined by means of vaginal ultrasound for the presence of myomas in seven gynaecological outpatient departments in Germany. RESULTS: PREVALENCE: myomas were detected in 41.6 % of all women. Age dependence: With increasing age, the prevalence of uterine myomas rose from 21.3 % (30-35 years) to 62.8 % (46-50 years). Later, the number of myomas decreased again from 56.1 % (51-55 years) to 29.4 % in women older than 55 years. Menarche/BMI: no correlation could be found between the age at first menstrual period or the body mass index and the occurrence of myomas. Parity: since the group of nulliparous women and the group of women with more than four deliveries stand out by increased occurrence of myomas, a non-linear correlation seems to exist, necessitating more in-depth discussion with regard to age dependency. CONCLUSIONS: The results of this study suggest that more than 40 % of women over 30 years of age suffered from myomas and more than 50 % of all women in Germany may develop uterine myomas at some time in their life. PMID- 26525702 TI - Synthesis and Functions of Ag2S Nanostructures. AB - The paper presents a review about synthesis and applications of Ag2S nanostructures. As the modern photoelectric and biological materials, Ag2S nanomaterials are potentially useful for both structure and function purposes. Ag2S is a direction narrow band gap semiconductor with special properties. Ag2S nanostructures have been widely researched in chemistry and biochemistry fields because of their unusual optical, electrical, and mechanical properties. It can also be used in many fields, such as photovoltaic cells and infrared detector. In the past few years, Ag2S nanostructures have been synthesized by various methods. The article mainly discusses the four types of preparation methods. Moreover, this article shows a detailed review on the new properties, fabrication, and applications of Ag2S nanocrystals. PMID- 26525703 TI - Phase-Change Memory Properties of Electrodeposited Ge-Sb-Te Thin Film. AB - We report the properties of a series of electrodeposited Ge-Sb-Te alloys with various compositions. It is shown that the Sb/Ge ratio can be varied in a controlled way by changing the electrodeposition potential. This method opens up the prospect of depositing Ge-Sb-Te super-lattice structures by electrodeposition. Material and electrical characteristics of various compositions have been investigated in detail, showing up to three orders of magnitude resistance ratio between the amorphous and crystalline states and endurance up to 1000 cycles. PMID- 26525704 TI - Orofacial Pain: Part Two. PMID- 26525705 TI - Measuring empathy for human and robot hand pain using electroencephalography. AB - This study provides the first physiological evidence of humans' ability to empathize with robot pain and highlights the difference in empathy for humans and robots. We performed electroencephalography in 15 healthy adults who observed either human- or robot-hand pictures in painful or non-painful situations such as a finger cut by a knife. We found that the descending phase of the P3 component was larger for the painful stimuli than the non-painful stimuli, regardless of whether the hand belonged to a human or robot. In contrast, the ascending phase of the P3 component at the frontal-central electrodes was increased by painful human stimuli but not painful robot stimuli, though the interaction of ANOVA was not significant, but marginal. These results suggest that we empathize with humanoid robots in late top-down processing similarly to human others. However, the beginning of the top-down process of empathy is weaker for robots than for humans. PMID- 26525706 TI - [Diagnostic imaging in dementia: use of imaging modalities in Dutch memory clinics]. AB - PURPOSE: To evaluate the use of MRI and CT in the diagnostic work-up of dementia in Dutch memory clinics, and to analyse the rationale for choosing each modality. MATERIALS AND METHODS: A digital survey was sent by e-mail to all medical specialists (n=235) working at a memory clinic in the Netherlands. RESULTS: The survey was completed by 64% (151). 85% of the respondents were geriatricians, 13% neurologists and 2% other, working at a total of 69 clinics. 40% variably orders CT or MRI, 37% orders MRI, 19% CT, and 4% CT plus MRI. Primary factors influencing this choice are: MRI contraindications, physical limitations, age, vascular or oncological medical history, and waiting time. With CT, 87% indicates information is lacking: vascular disease/white matter lesions, (hippocampal) atrophy, and specific pathologies (metastases, amyloid angiopathy). Furthermore, respondents prefer MRI because they can assess the images more easily themselves. Only 50% of respondents indicate that CT protocol dictates coronal reconstructions. Additionally, these reconstructions are not provided consistently. Rating-scales are used to describe images in 5%. In 75% assessment is not uniform. CONCLUSION: MRI is preferred over CT in diagnostic imaging of dementia, in accordance with existing guidelines. However, these guidelines are mostly out-dated and modern multislice CT potential is relatively unknown among geriatricians. In memory clinics, multislice CT could offer a well suitable imaging alternative, but only if multiplanar reconstructions are performed consistently. Furthermore, radiology reports need to be improved by using more standardized assessment. PMID- 26525708 TI - Effect of local versus remote tonic heat pain during training on acquisition and retention of a finger-tapping sequence task. AB - Although pain is present in a large proportion of patients receiving rehabilitation, its impact on motor learning is still unclear, especially in the case of neuropathic pain that is not tightly linked to specific movements. The aim of this study was to determine the effect of local and remote tonic cutaneous heat pain applied during training on motor learning of a finger-tapping sequence task. Forty-five healthy participants, randomized to the control, local pain or remote pain groups, were trained to perform an explicit finger motor sequence of five items as fast as possible. During the 10 training blocks (30 s each), local pain and remote pain groups received a heat pain stimulus on the wrist or leg, respectively. Performance was tested in the absence of pain in all groups before (baseline), immediately after (post-immediate), 60 min after (post-60 min) and 24 h after training (post-24 h) to assess both acquisition and next-day retention. Speed increased over time from baseline to post-24 h (p < 0.001), without any significant effect of group (p = 0.804) or time * group interaction (p = 0.385), indicating that the acquisition and retention were not affected by the presence of pain during training. No changes were observed on error rates, which were very low even at baseline. These results with experimental heat pain suggest that the ability to relearn finger sequence should not be affected by concomitant neuropathic pain in neurorehabilitation. However, these results need to be validated in the context of chronic pain, by including pain as a co-variable in motor rehabilitation trials. PMID- 26525707 TI - Perceptuo-motor compatibility governs multisensory integration in bimanual coordination dynamics. AB - The brain has the remarkable ability to bind together inputs from different sensory origin into a coherent percept. Behavioral benefits can result from such ability, e.g., a person typically responds faster and more accurately to cross modal stimuli than to unimodal stimuli. To date, it is, however, largely unknown whether such multisensory benefits, shown for discrete reactive behaviors, generalize to the continuous coordination of movements. The present study addressed multisensory integration from the perspective of bimanual coordination dynamics, where the perceptual activity no longer triggers a single response but continuously guides the motor action. The task consisted in coordinating anti symmetrically the continuous flexion-extension of the index fingers, while synchronizing with an external pacer. Three different configurations of metronome were tested, for which we examined whether a cross-modal pacing (audio-tactile beats) improved the stability of the coordination in comparison with unimodal pacing condition (auditory or tactile beats). We found a more stable bimanual coordination for cross-modal pacing, but only when the metronome configuration directly matched the anti-symmetric coordination pattern. We conclude that multisensory integration can benefit the continuous coordination of movements; however, this is constrained by whether the perceptual and motor activities match in space and time. PMID- 26525709 TI - Learning dynamic control of body roll orientation. AB - Our objective was to examine how the control of orientation is learned in a task involving dynamically balancing about an unstable equilibrium point, the gravitational vertical, in the absence of leg reflexes and muscle stiffness. Subjects (n = 10) used a joystick to set themselves to the gravitational vertical while seated in a multi-axis rotation system (MARS) device programmed with inverted pendulum dynamics. The MARS is driven by powerful servomotors and can faithfully follow joystick commands up to 2.5 Hz with a 30-ms latency. To make the task extremely difficult, the pendulum constant was set to 600 degrees /s(2). Each subject participated in five blocks of four trials, with a trial ending after a cumulative 100 s of balancing, excluding reset times when a subject lost control. To characterize performance and learning, we used metrics derived from joystick movements, phase portraits (joystick deflections vs MARS position and MARS velocity vs angular position), and stabilogram diffusion functions. We found that as subjects improved their balancing performance, they did so by making fewer destabilizing joystick movements and reducing the number and duration of joystick commands. The control strategy they acquired involved making more persistent short-term joystick movements, waiting longer before making changes to ongoing motion, and only intervening intermittently. PMID- 26525710 TI - Antinociceptive effects induced by intra-lateral habenula complex injection of the galanin receptor 1 agonist M617 in rats. AB - The present study was performed to explore the antinociceptive effects of the galanin receptor 1 agonist M617 in lateral habenula complex in rats. Intra lateral habenula injection of 0.1, 0.5, 1 or 2 nmol of galanin induced dose dependent increases in hindpaw withdrawal latencies (HWLs) to noxious thermal and mechanical stimulations in rats. Furthermore, intra-lateral habenula injection of 0.1, 0.5, 1 or 2 nmol of the galanin receptor 1 agonist M617 also induced dose dependent increases in HWLs to noxious thermal and mechanical stimulations in rats. Interestingly, there were no significant differences between the antinociceptive effects induced by intra-lateral habenula injection of 2 nmol of M617 and 2 nmol of galanin. The results indicate that galanin receptor 1 may be involved in the galanin-induced antinociceptive effects in the lateral habenula. PMID- 26525711 TI - Individual differences in action co-representation: not personal distress or subclinical psychotic experiences but sex composition modulates joint action performance. AB - Successful social interaction requires the ability to integrate as well as distinguish own and others' actions. Normally, the integration and distinction of self and other are a well-balanced process, occurring without much effort or conscious attention. However, not everyone is blessed with the ability to balance self-other distinction and integration, resulting in personal distress in reaction to other people's emotions or even a loss of self [e.g., in (subclinical) psychosis]. Previous research has demonstrated that the integration and distinction of others' actions cause interference with one's own action performance (commonly assessed with a social Simon task). The present study had two goals. First, as previous studies on the social Simon effect employed relatively small samples (N < 50 per test), we aimed for a sample size that allowed us to test the robustness of the action interference effect. Second, we tested to what extent action interference reflects individual differences in traits related to self-other distinction (i.e., personal distress in reaction to other people's emotions and subclinical psychotic symptoms). Based on a questionnaire study among a large sample (N = 745), we selected a subsample (N = 130) of participants scoring low, average, or high on subclinical psychotic symptoms, or on personal distress. The selected participants performed a social Simon task. Results showed a robust social Simon effect, regardless of individual differences in personal distress or subclinical psychotic symptoms. However, exploratory analyses revealed that the sex composition of interaction pairs modulated social Simon effects. Possible explanations for these findings are discussed. PMID- 26525712 TI - Optic flow improves adaptability of spatiotemporal characteristics during split belt locomotor adaptation with tactile stimulation. AB - Human locomotor adaptation requires feedback and feed-forward control processes to maintain an appropriate walking pattern. Adaptation may require the use of visual and proprioceptive input to decode altered movement dynamics and generate an appropriate response. After a person transfers from an extreme sensory environment and back, as astronauts do when they return from spaceflight, the prolonged period required for re-adaptation can pose a significant burden. In our previous paper, we showed that plantar tactile vibration during a split-belt adaptation task did not interfere with the treadmill adaptation however, larger overground transfer effects with a slower decay resulted. Such effects, in the absence of visual feedback (of motion) and perturbation of tactile feedback, are believed to be due to a higher proprioceptive gain because, in the absence of relevant external dynamic cues such as optic flow, reliance on body-based cues is enhanced during gait tasks through multisensory integration. In this study, we therefore investigated the effect of optic flow on tactile-stimulated split-belt adaptation as a paradigm to facilitate the sensorimotor adaptation process. Twenty healthy young adults, separated into two matched groups, participated in the study. All participants performed an overground walking trial followed by a split-belt treadmill adaptation protocol. The tactile group (TC) received vibratory plantar tactile stimulation only, whereas the virtual reality and tactile group (VRT) received an additional concurrent visual stimulation: a moving virtual corridor, inducing perceived self-motion. A post-treadmill overground trial was performed to determine adaptation transfer. Interlimb coordination of spatiotemporal and kinetic variables was quantified using symmetry indices and analyzed using repeated-measures ANOVA. Marked changes of step length characteristics were observed in both groups during split-belt adaptation. Stance and swing time symmetries were similar in the two groups, suggesting that temporal parameters are not modified by optic flow. However, whereas the TC group displayed significant stance time asymmetries during the post-treadmill session, such aftereffects were absent in the VRT group. The results indicated that the enhanced transfer resulting from exposure to plantar cutaneous vibration during adaptation was alleviated by optic flow information. The presence of visual self-motion information may have reduced proprioceptive gain during learning. Thus, during overground walking, the learned proprioceptive split-belt pattern is more rapidly overridden by visual input due to its increased relative gain. The results suggest that when visual stimulation is provided during adaptive training, the system acquires the novel movement dynamics while maintaining the ability to flexibly adapt to different environments. PMID- 26525713 TI - High noise correlation between the functionally connected neurons in emergent V1 microcircuits. AB - Neural correlations (noise correlations and cross-correlograms) are widely studied to infer functional connectivity between neurons. High noise correlations between neurons have been reported to increase the encoding accuracy of a neuronal population; however, low noise correlations have also been documented to play a critical role in cortical microcircuits. Therefore, the role of noise correlations in neural encoding is highly debated. To this aim, through multi electrodes, we recorded neuronal ensembles in the primary visual cortex of anaesthetized cats. By computing cross-correlograms, we divulged the functional network (microcircuit) between neurons within an ensemble in relation to a specific orientation. We show that functionally connected neurons systematically exhibit higher noise correlations than functionally unconnected neurons in a microcircuit that is activated in response to a particular orientation. Furthermore, the mean strength of noise correlations for the connected neurons increases steeply than the unconnected neurons as a function of the resolution window used to calculate noise correlations. We suggest that neurons that display high noise correlations in emergent microcircuits feature functional connections which are inevitable for information encoding in the primary visual cortex. PMID- 26525714 TI - Effect of alpha7n-Acetylcholine Receptor Activation and Antibodies to TNF-alpha on Mortality of Mice and Concentration of Proinflammatory Cytokines During Early Stage of Sepsis. AB - Experiments on random-bred albino mice showed that activation alpha7n acetylcholine receptors with anabasine (0.5 LD50) and the use of antibodies to TNF-alpha (1 mg/kg) 2 h before sepsis modeling significantly reduces mortality of mice from experimental sepsis (intraperitoneal injection of E. coli) due to a decrease in the blood concentration of proinflammatory cytokines TNF-alpha, IL 1beta, and IL-6. After combined administration of anti-TNF-alpha antibodies and anabasine, an additive effect was observed. PMID- 26525715 TI - Point-of-service, quantitative analysis of ascorbic acid in aqueous humor for evaluating anterior globe integrity. AB - Limited training, high cost, and low equipment mobility leads to inaccuracies in decision making and is concerning with serious ocular injuries such as suspected ruptured globe or post-operative infections. Here, we present a novel point-of service (POS) quantitative ascorbic acid (AA) assay with use of the OcuCheck Biosensor. The present work describes the development and clinical testing of the paper-based biosensor that measures the changes in electrical resistance of the enzyme-plated interdigitated electrodes to quantify the level of AA present in ocular fluid. We have demonstrated the proof-of-concept of the biosensor testing 16 clinical samples collected from aqueous humor of patients undergoing therapeutic anterior chamber paracentesis. Comparing with gold standard colorimetric assay for AA concentration, OcuCheck showed accuracy of >80%, sensitivity of >88% and specificity of >71%. At present, there are no FDA approved POS tests that can directly measures AA concentration levels in ocular fluid. We envisage that the device can be realized as a handheld, battery powered instrument that will have high impact on glaucoma care and point-of-care diagnostics of penetrating ocular globe injuries. PMID- 26525716 TI - Prevalence and temporal pattern of hospital readmissions for patients with type I and type II diabetes. AB - OBJECTIVE: Repeated hospitalisation for patients is common and costly, yet partly preventable. However, we know little about readmissions for patients with diabetes in China. The current study aims to assess the frequency and temporal pattern of and risk factors for all-cause readmission among hospitalised patients with diabetes in Tianjin, China. METHOD: This retrospective, cohort analysis used the Tianjin Basic Medical Insurance Register System data of 2011. The patterns of and the reasons for all-cause readmissions for patients with diabetes were described. The differences of readmission-free survival (RFS) between newly and previously diagnosed patients were compared. Time-dependent Cox models were established to identify the risk factors for readmission at different time intervals after discharge. RESULTS: Readmission rates were approximately 30%, with the most common diagnoses of cerebral infarction (for type I) or diabetes (for type II) for patients with diabetes. The majority of patients were readmitted to the hospital after more than 90 days, followed by 8-30 days (all p=0.002). Approximately 37.2% and 42.8% of readmitted patients with type I and type II diabetes were diagnosed previously, and the RFS rates for previously diagnosed patients were significantly lower than for newly diagnosed patients at any time interval after discharge. Prior history of diabetes (all p<0.05), length of stay (all p<0.01) and reimbursement ratio (90% vs >92%, all p<0.0002) were consistently associated with the RFS for patients readmitted to the hospital at <7, 8-30, 31-60 and 61-90 days. CONCLUSIONS: Hospital readmissions among patients with diabetes were affected by the diagnosis status. Patient characteristics and the quality of healthcare might regulate short-interval and long-interval hospital readmission, respectively, after discharge. PMID- 26525717 TI - 'The phone reminder is important, but will others get to know about my illness?' Patient perceptions of an mHealth antiretroviral treatment support intervention in the HIVIND trial in South India. AB - OBJECTIVES: The recent explosion of mHealth applications in the area of HIV care has led to the development of mHealth interventions to support antiretroviral treatment adherence. Several of these interventions have been tested for effectiveness, but few studies have explored patient perspectives of such interventions. Exploring patient perspectives enhances the understanding of how an intervention works or why it does not. We therefore studied perceptions regarding an mHealth adherence intervention within the HIVIND trial in South India. METHODS: The study was conducted at three clinics in South India. The intervention comprised an automated interactive voice response (IVR) call and a pictorial short messaging service (SMS), each delivered weekly. Sixteen purposively selected participants from the intervention arm in the HIVIND trial were interviewed. All participants had completed at least 84 weeks since enrollment in the trial. Perceptions on the usefulness and perceived benefits and risks of receiving the intervention were sought. The interviews were transcribed and analysed using the framework approach to qualitative data analysis. RESULTS: Despite varying perceptions of the intervention, most participants found it useful. The intervention was perceived as a sign of 'care' from the clinic. The IVR call was preferred to the SMS reminder. Two-way communication was preferred to automated calls. Participants also perceived a risk of unintentional disclosure of their HIV status and stigma thereof via the intervention and took initiatives to mitigate this risk. Targeting reminders at those with poor adherence and those in need of social support was suggested. CONCLUSIONS: mHealth adherence interventions go beyond their intended role to provide a sense of care and support to the recipient. Although automated interventions are impersonal, they could be a solution for scale up. Interventions that engage both the recipient and the healthcare provider have greater potential for success. Personalising mHealth interventions could mitigate the risk of stigma and promote their uptake. TRIAL REGISTRATION NUMBER: ISRCTN79261738. PMID- 26525718 TI - Contributions of maternal and paternal adiposity and smoking to adult offspring adiposity and cardiovascular risk: the Midspan Family Study. AB - OBJECTIVE: Obesity has some genetic basis but requires interaction with environmental factors for phenotypic expression. We examined contributions of gender-specific parental adiposity and smoking to adiposity and related cardiovascular risk in adult offspring. DESIGN: Cross-sectional general population survey. SETTING: Scotland. PARTICIPANTS: 1456 of the 1477 first generation families in the Midspan Family Study: 2912 parents (aged 45-64 years surveyed between 1972 and 1976) who had 1025 sons and 1283 daughters, aged 30-59 years surveyed in 1996. MAIN MEASURES: Offspring body mass index (BMI), waist circumference (WC), cardiometabolic risk (lipids, blood pressure and glucose) and cardiovascular disease as outcome measures, and parental BMI and smoking as determinants. All analyses adjusted for age, socioeconomic status and family clustering and offspring birth weight. RESULTS: Regression coefficients for BMI associations between father-son (0.30) and mother-daughter (0.33) were greater than father-daughter (0.23) or mother-son (0.22). Regression coefficient for the non-genetic, shared-environment or assortative-mating relationship between BMIs of fathers and mothers was 0.19. Heritability estimates for BMI were greatest among women with mothers who had BMI either <25 or >=30 kg/m(2). Compared with offspring without obese parents, offspring with two obese parents had adjusted OR of 10.25 (95% CI 6.56 to 13.93) for having WC >=102 cm for men, >=88 cm women, 2.46 (95% CI 1.33 to 4.57) for metabolic syndrome and 3.03 (95% CI 1.55 to 5.91) for angina and/or myocardial infarct (p<0.001). Neither parental adiposity nor smoking history determined adjusted offspring individual cardiometabolic risk factors, diabetes or stroke. Maternal, but not paternal, smoking had significant effects on WC in sons (OR=1.50; 95% CI 1.13 to 2.01) and daughters (OR=1.42; 95% CI 1.10 to 1.84) and metabolic syndrome OR=1.68; 95% CI 1.17 to 2.40) in sons. CONCLUSIONS: There are modest genetic/epigenetic influences on the environmental factors behind adverse adiposity. Maternal smoking appears a specific hazard on obesity and metabolic syndrome. A possible epigenetic mechanism linking maternal smoking to obesity and metabolic syndrome in offspring is proposed. Individuals with family histories of obesity should be targeted from an early age to prevent obesity and complications. PMID- 26525719 TI - Bicycling injury hospitalisation rates in Canadian jurisdictions: analyses examining associations with helmet legislation and mode share. AB - OBJECTIVES: The purpose of this study was to calculate exposure-based bicycling hospitalisation rates in Canadian jurisdictions with different helmet legislation and bicycling mode shares, and to examine whether the rates were related to these differences. METHODS: Administrative data on hospital stays for bicycling injuries to 10 body region groups and national survey data on bicycling trips were used to calculate hospitalisation rates. Rates were calculated for 44 sex, age and jurisdiction strata for all injury causes and 22 age and jurisdiction strata for traffic-related injury causes. Inferential analyses examined associations between hospitalisation rates and sex, age group, helmet legislation and bicycling mode share. RESULTS: In Canada, over the study period 2006-2011, there was an average of 3690 hospitalisations per year and an estimated 593 million annual trips by bicycle among people 12 years of age and older, for a cycling hospitalisation rate of 622 per 100 million trips (95% CI 611 to 633). Hospitalisation rates varied substantially across the jurisdiction, age and sex strata, but only two characteristics explained this variability. For all injury causes, sex was associated with hospitalisation rates; females had rates consistently lower than males. For traffic-related injury causes, higher cycling mode share was consistently associated with lower hospitalisation rates. Helmet legislation was not associated with hospitalisation rates for brain, head, scalp, skull, face or neck injuries. CONCLUSIONS: These results suggest that transportation and health policymakers who aim to reduce bicycling injury rates in the population should focus on factors related to increased cycling mode share and female cycling choices. Bicycling routes designed to be physically separated from traffic or along quiet streets fit both these criteria and are associated with lower relative risks of injury. PMID- 26525720 TI - How different terminology for ductal carcinoma in situ impacts women's concern and treatment preferences: a randomised comparison within a national community survey. AB - OBJECTIVE: There have been calls to remove 'carcinoma' from terminology for in situ cancers such as ductal carcinoma in situ (DCIS), to reduce overdiagnosis and overtreatment. We investigated the effect of describing DCIS as 'abnormal cells' versus 'pre-invasive breast cancer cells' on women's concern and treatment preferences. SETTING AND PARTICIPANTS: Community sample of Australian women (n=269) who spoke English as their main language at home. DESIGN: Randomised comparison within a community survey. Women considered a hypothetical scenario involving a diagnosis of DCIS described as either 'abnormal cells' (arm A) or 'pre-invasive breast cancer cells' (arm B). Within each arm, the initial description was followed by the alternative term and outcomes reassessed. RESULTS: Women in both arms indicated high concern, but still indicated strong initial preferences for watchful waiting (64%). There were no differences in initial concern or preferences by trial arm. However, more women in arm A ('abnormal cells' first term) indicated they would feel more concerned if given the alternative term ('pre-invasive breast cancer cells') compared to women in arm B who received the terms in the opposite order (67% arm A vs 52% arm B would feel more concerned, p=0.001). More women in arm A also changed their preference towards treatment when the terminology was switched from 'abnormal cells' to 'pre invasive breast cancer cells' compared to arm B. In arm A, 18% of women changed their preference to treatment while only 6% changed to watchful waiting (p=0.008). In contrast, there were no significant changes in treatment preference in arm B when the terminology was switched (9% vs 8% changed their stated preference). CONCLUSIONS: In a hypothetical scenario, interest in watchful waiting for DCIS was high, and changing terminology impacted women's concern and treatment preferences. Removal of the cancer term from DCIS may assist in efforts towards reducing overtreatment. PMID- 26525721 TI - Understanding the motivation and performance of community health volunteers involved in the delivery of health programmes in Kampala, Uganda: a realist evaluation. AB - OBJECTIVES: This paper presents the results of a realist evaluation that aimed to understand how, why and under what circumstances a Red Cross (RC) capacity building intervention influences the motivation and the performance of RC community health volunteers involved in the delivery of an immunisation programme in Kampala, Uganda. METHOD: Given the complexity of the intervention, we adopted realist evaluation as our methodological approach and the case study as our study design. Data collection included document review, participant observation and interviews. The constant comparative method was used for the analysis. Two contrasted cases were selected within the five Kampala districts. Each case covers the management of the immunisation programme implemented at a RC branch. In each case, a programme manager and 15 RC volunteers were interviewed. The selection of the volunteers was purposive. RESULTS: We found that a capacity building programme including supervision supportive of autonomy, skills and knowledge enhancement, and adapted to the different subgroups of volunteers, leads to satisfaction of the three key drivers of volunteer motivation: feelings of autonomy, competence and connectedness. This contributes to higher retention, and better task performance and well-being among the volunteers. Enabling contextual conditions include the responsiveness of the Uganda Red Cross Society (URCS) to community needs, and recognition of the work of the volunteers, from the URCS and the community. CONCLUSIONS: A management approach that caters for the different motivational states and changing needs of the volunteers will lead to better performance. The findings will inform not only the management of community health volunteers, but also the management of all kinds of health workers. PMID- 26525722 TI - Is it possible to predict improved diabetes outcomes following diabetes self management education: a mixed-methods longitudinal design. AB - OBJECTIVE: To predict the diabetes-related outcomes of people undertaking a type 2 Diabetes Self-Management Education (DSME) programme from their baseline data. DESIGN: A mixed-methods longitudinal experimental study. 6 practice nurses and 2 clinical academics undertook blind assessments of all baseline and process data to predict clinical, behavioural and psychological outcomes at 6 months post-DSME programme. SETTING: Primary care. PARTICIPANTS: -31 people with type 2 diabetes who had not previously undertaken DSME. INTERVENTION: All participants undertook the Diabetes Manual 1:1 self-directed learning 12-week DSME programme supported by practice nurses trained as Diabetes Manual facilitators. OUTCOME VARIABLES: Glycated haemoglobin (HbA1c), diabetes knowledge, physical activity, waist circumference, self-efficacy, diabetes distress, anxiety, depression, demographics, change talk and treatment satisfaction. These variables were chosen because they are known to influence self-management behaviour or to have been influenced by a DSME programme in empirical evidence. RESULTS: Baseline and 6 month follow-up data were available for 27 participants of which 13 (48%) were male, 22 (82%) white British, mean age 59 years and mean duration of type 2 diabetes 9.1 years. Significant reductions were found in HbA1c t(26)=2.35, p=0.03, and diabetes distress t(26)=2.30, p=0.03, and a significant increase in knowledge t(26)=-2.06, p=0.05 between baseline and 6 months. No significant changes were found in waist circumference, physical activity, anxiety, depression or self-efficacy. Accuracy of predictions varied little between clinical academics and practice nurses but greatly between outcome (0-100%). The median and mode accuracy of predicted outcome was 66.67%. Accuracy of prediction for the key outcome of HbA1c was 44.44%. Diabetes distress had the highest prediction accuracy (81.48%). CONCLUSIONS: Clinicians in this small study were unable to identify individuals likely to achieve improvement in outcomes from DSME. DSME should be promoted to all patients with diabetes according to guidelines. PMID- 26525723 TI - Can clinical features be used to differentiate type 1 from type 2 diabetes? A systematic review of the literature. AB - OBJECTIVE: Clinicians predominantly use clinical features to differentiate type 1 from type 2 diabetes yet there are no evidence-based clinical criteria to aid classification of patients. Misclassification of diabetes is widespread (7-15% of cases), resulting in patients receiving inappropriate treatment. We sought to identify which clinical criteria could be used to discriminate type 1 and type 2 diabetes. DESIGN: Systematic review of all diagnostic accuracy studies published since 1979 using clinical criteria to predict insulin deficiency (measured by C peptide). DATA SOURCES: 14 databases including: MEDLINE, MEDLINE in Process and EMBASE. The search strategy took the form of: (terms for diabetes) AND (terms for C-Peptide). ELIGIBILITY CRITERIA: Diagnostic accuracy studies of any routinely available clinical predictors against a reference standard of insulin deficiency defined by cut-offs of C-peptide concentrations. No restrictions on race, age, language or country of origin. RESULTS: 10,917 abstracts were screened, and 231 full texts reviewed. 11 studies met inclusion criteria, but varied by age, race, year and proportion of participants who were C-peptide negative. Age at diagnosis was the most discriminatory feature in 7/9 studies where it was assessed, with optimal cut-offs (>70% mean sensitivity and specificity) across studies being <30 years or <40 years. Use of/time to insulin treatment and body mass index (BMI) were also discriminatory. When combining features, BMI added little over age at diagnosis and/or time to insulin (<1% improvement in classification). CONCLUSIONS: Despite finding only 11 studies, and considerable heterogeneity between studies, age at diagnosis and time to insulin were consistently the most discriminatory criteria. BMI, despite being widely used in clinical practice, adds little to these two criteria. The criteria identified are similar to the Royal College of General Practitioners National Health Service (RCGP/NHS) Diabetes classification guidelines, which use age at diagnosis <35 years and time to insulin <6 m. Until further studies are carried out, these guidelines represent a suitable classification scheme. SYSTEMATIC REVIEW REGISTRATION: PROSPERO reference CRD42012001736. PMID- 26525724 TI - Disability pension and symptoms of anxiety and depression: a prospective comparison of farmers and other occupational groups. The HUNT Study, Norway. AB - OBJECTIVES: Agriculture has undergone major changes, and farmers have been found to have a high prevalence of depression symptoms. We investigated the risk of work disability in Norwegian farmers compared with other occupational groups, as well as the associations between symptoms of anxiety and depression and future disability pension. METHODS: We linked working participants of the HUNT2 Survey (1995-97) aged 20-61.9 years, of whom 3495 were farmers and 25,521 had other occupations, to national registry data on disability pension, with follow-up until 31 December 2010. We used Cox proportional hazards regression to estimate hazard ratios (HRs) of disability pension, and to investigate the associations between symptoms of anxiety and depression caseness at baseline (score on the anxiety or depression subscales of the Hospital Anxiety and Depression Scale (HADS) >=8) and disability pension. RESULTS: Farmers had a twofold increased risk of disability pension (age-adjusted and sex-adjusted HR 2.07, 95% CI 1.80 to 2.38) compared with higher grade professionals. Farmers with symptoms of depression caseness had a 53% increased risk of disability pension (HR 1.53, 95% CI 1.25 to 1.87) compared with farmers below the cut-off point of depression caseness symptoms, whereas farmers with symptoms of anxiety caseness had a 51% increased risk (HR 1.51, 95% CI 1.23 to 1.86). CONCLUSIONS: Farmers have an increased risk of disability pension compared with higher grade professionals, but the risk is lower than in most other manual occupational groups. Farmers who report high levels of depression or anxiety symptoms are at substantially increased risk of future work disability, and the risk increase appears to be fairly similar across most occupational groups. PMID- 26525725 TI - Oncology practices are being faced with a multitude of challenges. Introduction. PMID- 26525726 TI - Doctor of Nursing Practice: The Role of the Advanced Practice Nurse. AB - OBJECTIVES: To explore the evolution and emerging roles of the Doctor of Nursing Practice (DNP) Advanced Practice Nurse (APN). DATA SOURCES: Published peer reviewed literature, cancer-related professional resources, and Web-based resources. CONCLUSION: The DNP education has prepared the APN for process improvement initiatives, providing quality care, and evidence-based practice translation, which are critical with the emerging trends in this complex health care environment. IMPLICATIONS FOR NURSING PRACTICE: DNP-prepared APNs have the opportunity to impact oncology care across the cancer trajectory, in various settings, and in various innovative roles as entrepreneurs. PMID- 26525727 TI - Doctor of Nursing Practice Education: Impact on Advanced Nursing Practice. AB - OBJECTIVE: To discuss how doctoral education, specifically the doctorate of nursing practice (DNP) can promote changes in advanced practice nursing. DATA SOURCES: Medline, CINAHL, PubMed. CONCLUSION: Variations continue to exist in educational curricula, program plans, and scholarly projects, leading to a lack of consistency in experiential learning. At this point in time it is too early in the DNP implementation process to determine ultimate impact. IMPLICATIONS FOR NURSING PRACTICE: Continuous program self-assessment and evaluation of DNP education programs will be of paramount importance to assure program quality and optimization of health trajectories. PMID- 26525728 TI - Establishing an Advanced Practice Nursing Clinic in the Cancer Setting. AB - OBJECTIVES: To explore the roles of the Advanced Practice Nurse (APN), specifically the Nurse Practitioner (NP) in oncology and the issues, resources, and planning involved in establishing an NP clinic in the cancer setting. DATA SOURCES: Published peer reviewed literature, web-based resources, and cancer related professional resources. CONCLUSION: The number of cancer patients is increasing and demands for oncology services are rising. With a shortage of oncologists projected over the next decade, the oncology NP can play a key role in providing oncology services across the cancer continuum. IMPLICATIONS FOR NURSING PRACTICE: Oncology APNs in the role of Nurse Practitioner (NP) can facilitate and enhance the delivery of oncology care. Traditional and innovative opportunities exist for the NP including the establishment of a NP clinic in the cancer setting; ultimately providing needed oncology services and quality care for patients with cancer. PMID- 26525729 TI - The Role of the Advanced Practice Nurse in the Academic Setting. AB - OBJECTIVES: To explore how advanced practice nurses implement practice change in academic medical centers to support optimal patient and staff outcomes. DATA SOURCES: Published peer reviewed literature, web-based resources, and professional society materials. CONCLUSION: Cancer care is rapidly evolving and advanced practice nurses can shape the future of how care is delivered as well as the setting it is delivered in. IMPLICATIONS FOR NURSING PRACTICE: Advanced practice oncology nurses (Nurse Practitioners and Clinical Nurse Specialists) have an opportunity to significantly shape the patient experience by implementing programmatic changes across the continuum of care by engaging stakeholders in project design. Knowledge of change management and implementation science is critical to success. PMID- 26525730 TI - Bridging the Research-to-Practice Gap: The Role of the Nurse Scientist. AB - OBJECTIVES: To describe the emerging role of the nurse scientist in health care organizations. Historical perspectives of the role are explored along with the roles of the nurse scientist, facilitators, barriers, and future implications. DATA SOURCES: Relevant literature on evidence-based practice and research in health care organizations; nurse scientist role; interview with University of Colorado nurse scientist. CONCLUSION: The nurse scientist role is integral for expanding evidence-based decisions and nursing research. A research mentor is considered the most important facilitator for a successful nursing research program. IMPLICATIONS FOR NURSING PRACTICE: Organizations should consider including the nurse scientist role to facilitate evidence-based practice and expand opportunities for nursing research. PMID- 26525731 TI - Risk Assessment, Prevention, and Early Detection: Challenges for the Advanced Practice Nurse. AB - OBJECTIVES: To review research and evidence-based resources on risk assessment, prevention, and early detection and its application in clinical nursing practice. DATA SOURCES: Journal articles, texts, and personal cancer prevention and early detection clinical program experience. CONCLUSION: There are multiple roles and clinical settings for advance practice nurses to implement cancer risk assessment and promote the prevention and early detection of cancer for patients and their families. IMPLICATIONS FOR NURSING PRACTICE: Every patient deserves cancer risk assessment and clear recommendations for the primary, secondary, and tertiary prevention of cancer as appropriate. PMID- 26525732 TI - Palliative Care: Delivering Comprehensive Oncology Nursing Care. AB - OBJECTIVES: To describe palliative care as part of comprehensive oncology nursing care. DATA SOURCES: A review of the palliative care, oncology, and nursing literature over the past 10 years. CONCLUSION: Palliative care is mandated as part of comprehensive cancer care. A cancer diagnosis often results in distress in the physical, psychosocial, spiritual, and emotional domains of care. Oncology nurses are essential in providing palliative care from diagnosis to death to patients with cancer. They address the myriad aspects of cancer. With palliative care skills and knowledge, oncology nurses can provide quality cancer care. There are many opportunities in which oncology nurses can promote palliative care. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses must obtain knowledge and skills in primary palliative care to provide comprehensive cancer care. PMID- 26525733 TI - The Role of Advanced Practice Nurses in Cancer Survivorship Care. AB - OBJECTIVES: To review advanced practice nursing roles in planning, implementing, and evaluating survivorship care. DATA SOURCES: Review of the literature, published articles, government and organizational reports. CONCLUSION: The increased focus on improving post-treatment cancer care presents opportunities for advanced practice nurses to meet the physical and psychosocial needs of cancer survivors. IMPLICATIONS FOR NURSING PRACTICE: As experts in the comprehensive delivery of care, oncology advanced practice nurses are positioned to initiate, deliver, and evaluate survivorship care through innovative models. PMID- 26525734 TI - Body size, swimming speed, or thermal sensitivity? Predator-imposed selection on amphibian larvae. AB - BACKGROUND: Many animals rely on their escape performance during predator encounters. Because of its dependence on body size and temperature, escape velocity is fully characterized by three measures, absolute value, size-corrected value, and its response to temperature (thermal sensitivity). The primary target of the selection imposed by predators is poorly understood. We examined predator (dragonfly larva)-imposed selection on prey (newt larvae) body size and characteristics of escape velocity using replicated and controlled predation experiments under seminatural conditions. Specifically, because these species experience a wide range of temperatures throughout their larval phases, we predict that larvae achieving high swimming velocities across temperatures will have a selective advantage over more thermally sensitive individuals. RESULTS: Nonzero selection differentials indicated that predators selected for prey body size and both absolute and size-corrected maximum swimming velocity. Comparison of selection differentials with control confirmed selection only on body size, i.e., dragonfly larvae preferably preyed on small newt larvae. Maximum swimming velocity and its thermal sensitivity showed low group repeatability, which contributed to non-detectable selection on both characteristics of escape performance. CONCLUSIONS: In the newt-dragonfly larvae interaction, body size plays a more important role than maximum values and thermal sensitivity of swimming velocity during predator escape. This corroborates the general importance of body size in predator-prey interactions. The absence of an appropriate control in predation experiments may lead to potentially misleading conclusions about the primary target of predator-imposed selection. Insights from predation experiments contribute to our understanding of the link between performance and fitness, and further improve mechanistic models of predator-prey interactions and food web dynamics. PMID- 26525735 TI - Ab initio electron propagator calculations of transverse conduction through DNA nucleotide bases in 1-nm nanopore corroborate third generation sequencing. AB - BACKGROUND: The conduction properties of DNA molecule, particularly its transverse conductance (electron transfer through nucleotide bridges), represent a point of interest for DNA chemistry community, especially for DNA sequencing. However, there is no fully developed first-principles theory for molecular conductance and current that allows one to analyze the transverse flow of electrical charge through a nucleotide base. METHODS: We theoretically investigate the transverse electron transport through all four DNA nucleotide bases by implementing an unbiased ab initio theoretical approach, namely, the electron propagator theory. RESULTS: The electrical conductance and current through DNA nucleobases (guanine [G], cytosine [C], adenine [A] and thymine [T]) inserted into a model 1-nm Ag-Ag nanogap are calculated. The magnitudes of the calculated conductance and current are ordered in the following hierarchies: gA>gG>gC>gT and IG>IA>IT>IC correspondingly. The new distinguishing parameter for the nucleobase identification is proposed, namely, the onset bias magnitude. Nucleobases exhibit the following hierarchy with respect to this parameter: Vonset(A) .05. CONCLUSIONS: Different analysis standards of Delt 4 were analyzed in different field sizes to improve the detection sensitivity of the multileaf collimator position on the basis of 90% throughout rate. In stereotactic body radiation therapy of spinal tumor, the 2.0 mm/2.0% standard can reveal the dosimetric differences caused by the minor multileaf collimator position compared with the 3.0 mm/3.0% statistical standard. However, some position derivations of the misalignments that caused high dose amount to the spinal cord cannot be detected. However, some misalignments were not detected when a large number of multileaf collimator were administered into the spinal cord. PMID- 26525749 TI - The use of oral antibiotics before isotretinoin therapy in patients with acne. AB - BACKGROUND: Systemic antibiotics are used widely to treat moderate to severe acne, but increasing antibiotic resistance makes appropriate use a priority. OBJECTIVE: We sought to determine the duration of systemic antibiotic use in patients with inflammatory/nodulocystic acne who eventually required isotretinoin. METHODS: We performed a retrospective, single-site chart review of patients with acne diagnostic codes evaluated January 1, 2005 to December 31, 2014, at a dermatology practice in an academic medical center. Included patients were prescribed isotretinoin during the study period and received 30 days or more of antibiotics. RESULTS: The average duration of antibiotic use was 331.3 days. In all, 21 patients (15.3%) were prescribed antibiotics for 3 months or less, 88 patients (64.2%) for 6 months or more, and 46 patients (33.6%) for 1 year or longer. Patients treated only at the study site had a mean duration of antibiotic treatment of 283.1 days whereas patients who also received antibiotics from another institution had a mean duration of 380.2 days. This difference approached statistical significance (P = .054). LIMITATIONS: This study was limited to a single center. CONCLUSION: Expert guidelines recommend responsible use of antibiotics in acne in light of emerging resistance. We found that patients who eventually received isotretinoin had extended exposure to antibiotics, exceeding recommendations. Early recognition of antibiotic failure and the need for isotretinoin can curtail antibiotic use. PMID- 26525752 TI - COSA President's Welcome. PMID- 26525750 TI - Detection of acute kidney injury in premature asphyxiated neonates by serum neutrophil gelatinase-associated lipocalin (sNGAL)--sensitivity and specificity of a potential new biomarker. AB - INTRODUCTION: Acute kidney injury (AKI) is common in neonatal intensive care units (NICU). In recent years, every effort is made for early detection of AKI. Our hypothesis was that serum neutrophil gelatinase-associated lipocalin (sNGAL) may be a reliable screening test for early diagnosis of AKI in premature neonates after perinatal asphyxia. Therefore, our aim was to assess the diagnostic accuracy of sNGAL for AKI in premature asphyxiated neonates. MATERIALS AND METHODS: AKI was defined in the third day of life (DOL 3) as a serum creatinine (sCr) increase >=26.5 MUmol/L from baseline (the lowest previous sCr). According to the increase of sCr, AKI patients were divided in AKIN1 (sCr increase up to 1.9 baseline) and AKIN2 (sCr increase from 2.0 to 2.9 baseline). sNGAL levels were measured on DOL 1, 3 and 7. RESULTS: AKI was diagnosed in 73 (0.676) of 108 enrolled premature asphyxiated neonates. Sixty one patients (0.836) were classified in AKIN1 and 12 patients (0.164) in AKIN2. sNGAL reached the maximal concentrations on DOL 1 within 4 hours after admission to NICU, being higher in AKI compared with no-AKI group (160.8+/-113.1 vs. 87.1+/-81.6; P<0.001) as well as in AKIN2 compared with AKIN1 group (222.8+/-112.9 vs. 147.8+/-109.9; P<0.001). The best areas under the receiver operating characteristic curves (AUC) for prediction of AKI were 0.72 [95% (0.62-0.80) P<0.001] on DOL1 at 2h and 0.72 [95% (0.63-0.80) P<0.001] at 4th hour after admission respectively. The corresponding sNGAL cutoff concentrations were 84.87 ng/mL (sensitivity 69.0% and specificity 71.9%) and 89.43 ng/mL (sensitivity 65.7% and specificity 74.3%). CONCLUSIONS: In premature asphyxiated neonates sNGAL measured within the first 4 hours of DOL 1 is predictive of the occurrence and severity of AKI. Therefore, plasma levels of NGAL may be used for early diagnosis of AKI in these patients. PMID- 26525751 TI - Anhedonia and the brain reward circuitry in depression. AB - Anhedonia, or the loss of pleasure in previously rewarding stimuli, is a core symptom of major depressive disorder that may reflect an underlying dysregulation in reward processing. The mesolimbic dopamine circuit, also known as the brain's reward circuit, is integral to processing the rewarding salience of stimuli to guide actions. Manifestation of anhedonia and associated depression symptoms like feelings of sadness, changes in appetite, and psychomotor effects, may reflect changes in the brain reward circuitry as a common underlying disease process. This review will synthesize the recent literature from human and rodent studies providing a circuit-level framework for understanding anhedonia in depression, with emphasis on the nucleus accumbens. PMID- 26525754 TI - COSA Committees. PMID- 26525753 TI - COSA Convenors' Welcome 2015. PMID- 26525755 TI - Highlighted Lectures and Awards. PMID- 26525756 TI - 2015 Announcement. PMID- 26525761 TI - Tuesday 17 November 2015. PMID- 26525758 TI - National Speakers. PMID- 26525762 TI - Wednesday 18 November 2015. PMID- 26525763 TI - Thursday 19 November 2015. PMID- 26525764 TI - Poster Listing - Tuesday 17 November 2015. PMID- 26525765 TI - Poster Listing - Wednesday 18 November 2015. PMID- 26525766 TI - COSA's 42nd Annual Scientific Meeting. Rare Cancers: Common Goals, 17-19 November 2015, The Federation Conference and Exhibition Centre Hotel Grand Chancellor Hobart. PMID- 26525768 TI - Exhibitor Listing. PMID- 26525767 TI - Floor Plan. PMID- 26525769 TI - COSA Exhibitor Profiles. PMID- 26525770 TI - Expression of CD2 and CD25 on mast cell populations can be seen outside the setting of systemic mastocytosis. AB - BACKGROUND: Systemic mastocytosis (SM) is a diagnosis made using clinical, laboratory, and histologic parameters. Aberrant CD2 and/or CD25 expression on mast cells provides one minor criterion for a diagnosis of SM. To validate a tube (CD45/CD117/CD2/CD25) for mast cell evaluation, flow cytometry (FC) on residual material from marrow aspirates samples submitted to the hematopathology laboratory was performed. METHODS: Samples evaluated (n = 98) had no clinical or morphologic suspicion for SM. Samples were excluded if there was history of a myeloid stem cell neoplasm. Ten documented cases of SM were evaluated for comparison. RESULTS: Among cases without history of SM, 17.3% (n = 17) showed expression of CD2 and/or CD25 on >=10% of the mast cell population (CD25 alone in 14 cases, CD2 alone in 2 cases, both in one case), while 82.6% (n = 81) showed no expression of these antigens. The percentage of mast cells showing aberrant CD2 and/or CD25 expression respectively ranged from 12.1% to 98.8% and 22.2% to 95.7% Interestingly, all of the cases with evidence of aberrant antigen expression on mast cells were collected post-therapy while 22.1% of the negative samples were collected pre-therapy. A cut-off of 60% CD25 expression on mast cells identified all cases of SM while minimizing false positives. CONCLUSIONS: These findings demonstrate that aberrant expression of CD2 and/or CD25 may be seen on mast cells outside of the setting of SM. The data suggests that this phenomenon may be seen more commonly following chemotherapy and that FC of mast cells should be interpreted with caution in the post-chemotherapy setting. (c) 2015 International Clinical Cytometry Society. PMID- 26525772 TI - Re: Division of the spinal accessory nerve in the anterior triangle: a prospective clinical study. PMID- 26525771 TI - Ailanthone Inhibits Huh7 Cancer Cell Growth via Cell Cycle Arrest and Apoptosis In Vitro and In Vivo. AB - While searching for natural anti-hepatocellular carcinoma (HCC) components in Ailanthus altissima, we discovered that ailanthone had potent antineoplastic activity against HCC. However, the molecular mechanisms underlying the antitumor effect of ailanthone on HCC have not been examined. In this study, the antitumor activity and the underlying mechanisms of ailanthone were evaluated in vitro and in vivo. Mechanistic studies showed that ailanthone induced G0/G1-phase cell cycle arrest, as indicated by decreased expression of cyclins and CDKs and increased expression of p21 and p27. Our results demonstrated that ailanthone triggered DNA damage characterized by activation of the ATM/ATR pathway. Moreover, ailanthone-induced cell death was associated with apoptosis, as evidenced by an increased ratio of cells in the subG1 phase and by PARP cleavage and caspase activation. Ailanthone-induced apoptosis was mitochondrion-mediated and involved the PI3K/AKT signaling pathway in Huh7 cells. In vivo studies demonstrated that ailanthone inhibited the growth and angiogenesis of tumor xenografts without significant secondary adverse effects, indicating its safety for treating HCC. In conclusion, our study is the first to report the efficacy of ailanthone against Huh7 cells and to elucidate its underlying molecular mechanisms. These findings suggest that ailanthone is a potential agent for the treatment of liver cancer. PMID- 26525773 TI - Endoscopic modalities for upper gastrointestinal leaks, fistulae and perforations. AB - BACKGROUND: Endotherapy techniques are a recent addition to the suite of non surgical and minimally invasive strategies to manage patients with perforations, leaks and fistulae. The emergency nature of these conditions and the heterogeneity of pathologies encountered create difficulties when trying to select appropriate tools in these complex situations. The purpose of this article is to review experience at a tertiary academic centre, describe the various endoscopic tools available and the situations where they can be considered for use. METHODS: Single-centre series and review of the published literature. RESULTS: Of 64 patients, 57 were successfully treated using endoscopic therapy, with surgery used only to provide drainage and suture fully covered metal stents in place to prevent migration. DISCUSSION: Selection of an appropriate endotherapy or stent for a patient with an oesophago-gastric perforation or fistula requires an understanding of the anatomy and physiology underlying the patient's presentation and an understanding of the strengths and weaknesses of the available methods. Standard surgical principles of drainage, avoidance of distal obstruction and nutrition remain central to successful outcomes. A combination of surgical and endoscopic treatments may reduce the number of required treatments and can provide the ability to anchor fully covered stents to prevent them from migrating. PMID- 26525774 TI - Minocycline mitigates the gliogenic effects of proinflammatory cytokines on neural stem cells. AB - Mobilizing endogenous neural stem cells (NSCs) in the adult brain is designed to enhance the brain's regenerative capacity after cerebral lesions, e.g., as a result of stroke. Cerebral ischemia elicits neuroinflammatory processes affecting NSCs in multiple ways, the precise mechanisms of which currently remain elusive. An inhibitory effect of minocycline on microglia activation, a hallmark of postischemic neuroinflammation, has already been demonstrated in clinical trials, showing minocycline to be safe and potentially effective in ischemic stroke. Here we investigate the direct effects of minocycline and of proinflammatory cytokines on the differentiation potential of NSCs in vitro and in vivo. Primary fetal rat NSCs were treated with minocycline plus a combination of the proinflammatory cytokines tumor necrosis factor-alpha, interleukin 1beta, and interleukin 6. The differentiation fate of NSCs was assessed immunocytochemically. To investigate the effects of minocycline and inflammation in vivo, minocycline or lipopolysaccharides were injected intraperitoneally into adult rats, with subsequent immunohistochemistry. Minocycline alone did not affect the differentiation potential of NSCs in vivo or in vitro. In contrast, proinflammatory cytokines accelerated the differentiation of NSCs, promoting an astrocytic fate while inhibiting neurogenesis in vitro and in vivo. It is interesting to note that minocycline counteracted this cytokine-induced rapid astrocytic differentiation and restored the neurogenic and oligodendrogliogenic potential of NSCs. Data suggest that minocycline antagonizes the rapid glial differentiation induced by proinflammatory cytokines following cerebral ischemia but without having a direct effect on the differentiation potential of NSCs. Thus, minocycline constitutes a promising drug for stroke research, counteracting the detrimental effects of postischemic neuroinflammation in multiple ways. PMID- 26525776 TI - A New Structural Family of Gas-Sorbing Coordination Polymers Derived from Phenolic Carboxylic Acids. AB - The structure of Li(inox)?2/3 DMF (inox(-) =the N-oxide of the isonicotinate anion) consists of a 3D framework with solvent-filled, square cross-section channels of approximate dimensions 5.5*5.5 A. Unfortunately, the Li(inox) framework is unstable upon removal of DMF from the channels. When the structurally related 4-hydroxybenzoic acid (H2 hba) was used in place of Hinox, and Zn(2+) in place of the Li(+) , a structurally similar but more robust network, Zn(hba), was obtained; the isostructural compound, Co(hba), may also be prepared. Longer ligands with phenolate and carboxylate functional groups at opposite ends, such as the dianions of 4-coumaric acid (H2 cma) and 4'-hydroxy-4 biphenylcarboxylic acid (H2 hbpc), in combination with Zn(2+) yield Zn(cma) and Zn(hbpc) frameworks, respectively, with the same PtS topology but with larger channels. The coordination polymers remain intact after desolvation and exhibit microporosity, showing the ability to sorb significant quantities of CO2 , CH4 , and H2 . PMID- 26525775 TI - Genetic epidemiology of irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder characterized by presence of abdominal pain or discomfort associated with altered bowel habits. It has three main subtypes - constipation predominant IBS (C-IBS), diarrhea predominant IBS (D-IBS) and IBS with mixed features of both diarrhea as well as constipation (M-IBS). Its pathophysiology and underlying mechanisms remain elusive. It is traditionally believed that IBS is a result of multiple factors including hypersensitivity of the bowel, altered bowel motility, inflammation and stress. Initial studies have shown familial aggregation of IBS suggesting shared genetic or environmental factors. Twin studies of IBS from different parts of world have shown higher concordance rates among monozygotic twins than dizygotic twins, and thus suggesting a genetic component to this disorder. Multiple studies have tried to link single-nucleotide polymorphisms (SNPs) to IBS but there is little evidence that these SNPs are functional. Various molecules have been studied and investigated by the researchers. Serotonin, a known neurotransmitter and a local hormone in the enteric nervous system, has been most extensively explored. At this time, the underlying gene pathways, genes and functional variants linked with IBS remain unknown and the promise of genetically-determined risk prediction and personalize medicine remain unfulfilled. However, molecular biological technologies continue to evolve rapidly and genetic investigations offer much promise in the intervention, treatment and prevention of IBS. PMID- 26525777 TI - Wafer-scale metamaterials for polarization-insensitive and dual-band perfect absorption. AB - Mid-infrared (IR) perfect absorbers have great potential in practical applications such as biomedical sensing and thermal energy and have been successfully demonstrated in a number of plasmonic metallic nanostructures. However, all the experimental realizations of perfect absorbers are strongly dependent on nanofabrication techniques, which usually require high costs and a long time to fabricate a wafer scale device. Here we propose and experimentally demonstrate a wafer scale, polarization independent, wide angle, and dual-band IR perfect absorber. By fabricating double "E"-shaped metallic structures on a ZnSe coated gold film, a dual-band metamaterial absorber has been uniformly realized on a 2'' silicon wafer. Two absorption peaks have been realized at 18 and 27 THz, which are well consistent with the designs. We believe that our research will boost the applications of metamaterial perfect absorbers. PMID- 26525778 TI - E-cadherin regulators are differentially expressed in the epithelium and stroma of keratocystic odontogenic tumors. AB - BACKGROUND: The epithelial-mesenchymal transition (EMT) is the process where cells lose their epithelial features and acquire properties of typical mesenchymal cells. The dissociation of tumor cells due to changes in cell-cell adhesion is one of the key principles of tumor invasion and EMT. Thus, the knowledge of the molecular features of EMT in keratocyst odontogenic tumor (KOT) can provide useful markers to aid in the diagnosis and prognosis and perhaps contribute to an alternative therapeutic approach as it shows an aggressive clinical behavior and high recurrence rates. This study aimed to evaluate the EMT in KOT by the immunoexpression of E-cadherin, N-cadherin, Snail, and Slug and comparing to radicular cysts and dental follicles. METHODS: Thirty-two KOTs, 15 radicular cysts, and 08 dental follicles were used for immunohistochemistry, evaluating the extent, intensity, labeling pattern, cellular compartment in the epithelium and stroma, and the presence of inflammation. RESULTS: E-cadherin was preserved in most cases of keratocystic odontogenic tumor. N-cadherin was increased in the tumor epithelium, a result that was positively correlated with the heterogeneous and nuclear immunoexpression of Slug in the epithelium; Slug also correlated with high Snail immunoexpression. N-cadherin was positively correlated with Slug in the stroma of keratocystic odontogenic tumors. CONCLUSIONS: The high immunoexpression of Snail and nuclear Slug in keratocystic odontogenic tumors suggests these proteins as transcription factors without necessarily participating in 'cadherin switching'. However, the knowledge of their induction of the epithelial-mesenchymal transition in odontogenic tumors is still limited. PMID- 26525779 TI - Characterisation of dynamic couplings at lower limb residuum/socket interface using 3D motion capture. AB - Design and fitting of artificial limbs to lower limb amputees are largely based on the subjective judgement of the prosthetist. Understanding the science of three-dimensional (3D) dynamic coupling at the residuum/socket interface could potentially aid the design and fitting of the socket. A new method has been developed to characterise the 3D dynamic coupling at the residuum/socket interface using 3D motion capture based on a single case study of a trans-femoral amputee. The new model incorporated a Virtual Residuum Segment (VRS) and a Socket Segment (SS) which combined to form the residuum/socket interface. Angular and axial couplings between the two segments were subsequently determined. Results indicated a non-rigid angular coupling in excess of 10 degrees in the quasi sagittal plane and an axial coupling of between 21 and 35 mm. The corresponding angular couplings of less than 4 degrees and 2 degrees were estimated in the quasi-coronal and quasi-transverse plane, respectively. We propose that the combined experimental and analytical approach adopted in this case study could aid the iterative socket fitting process and could potentially lead to a new socket design. PMID- 26525780 TI - Identification of patients prone to hypotension during hemodialysis based on the analysis of cardiovascular signals. AB - Intradialytic hypotension (IDH) is a major complication during hemodialysis treatment, and therefore it is highly desirable to identify, at an early stage during treatment, whether the patient is prone to IDH. Heart rate variability (HRV), blood pressure variability (BPV) and baroreflex sensitivity (BRS) were analyzed during the first 30 min of treatment to assess information on the autonomic nervous system. Using the sequential floating forward selection method and linear classification, the set of features with the best discriminative power was selected, resulting in an accuracy of 92.1%. Using a classifier based on the HRV features only, thereby avoiding that continuous blood pressure has to be recorded, accuracy decreased to 90.2%. The results suggest that an HRV-based classifier is useful for determining whether a patient is prone to IDH at the beginning of the treatment. PMID- 26525781 TI - Performance of the Real Fungus-ID kit based on multiplex RT-PCR assay for the rapid detection and identification of Trichophyton spp. and Microsporum spp. in clinical specimens with suspected dermatophyte infection. AB - AIMS: The aim of this study was to evaluate the performance of a commercially available multiplex RT-PCR assay for the rapid detection and identification of dermatophytes directly from clinical samples and cultures. METHODS AND RESULTS: The multiplex RT-PCR assay was used to evaluate 118 clinical isolates from various specimen types and a total of 140 known specimens were compared with both conventional methods, commercially available PCR-REBA, and ITS sequence analysis. In this study, multiplex RT-PCR assay yield significantly more positive results than culture (91.9 vs 39.5%) and conventional methods including KOH microscopy (91.9 vs 71.3%). Although the results among the multiplex RT-PCR, PCR-REBA and ITS sequence analysis were concordant (100%) in 118 clinical isolates, concordant results between multiplex RT-PCR assay and culture were at 66% (78/118). The overall positive rates for the PCR-REBA, multiplex RT-PCR assay and ITS sequence analysis were 98.8, 91.9, and 52.9% respectively. In addition, the concordance rate of multiplex RT-PCR assay and the PCR-REBA assay was 93% (95% confidence interval (CI), 89.9-96.1, P < 0.0001), 93.7% (95% CI, 90.5-96.4, P < 0.0001) sensitivity, 100% (95% CI, 80.0-100, P < 0.0001) specificity, and 99.6% positive and 81% negative predictive values, respectively. Among the 258 samples, the most frequently identified dermatophyte species were Trichophyton rubrum (n = 199, 77.1%) and Trichophyton mentagrophytes (n = 28, 10.9%). CONCLUSIONS: The entire multiplex RT-PCR procedure takes about 3 h, while results from culture can take up to 2-3 weeks. The use of the multiplex RT-PCR molecular diagnostic assay was rapid and reliable for detecting pathogen infections. SIGNIFICANCE AND IMPACT OF THE STUDY: Even though the use of molecular diagnostic technology is more expensive than conventional methods, the clinical and economic benefit of saving time relative to expense remains to be elucidated. Therefore, the multiplex RT PCR assay may provide the essential information to accelerate therapeutic decisions for earlier and adequate antibiotic treatment in the acute phase of fungal pathogen infections. PMID- 26525782 TI - Network Meta-analysis and Pharmacoeconomic Evaluation of Fluconazole, Itraconazole, Posaconazole, and Voriconazole in Invasive Fungal Infection Prophylaxis. AB - Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting. PMID- 26525783 TI - Expression of Plasmodium vivax crt-o Is Related to Parasite Stage but Not Ex Vivo Chloroquine Susceptibility. AB - Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o (pvcrt-o) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax beta-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5; P < 0.001). Twenty-nine isolates fulfilled the criteria for ex vivo drug susceptibility testing and showed high variability in CQ responses (median, 107.9 [range, 6.5 to 345.7] nM). After controlling for the parasite stage, we found that pvcrt-o expression levels did not correlate with the ex vivo response to CQ or with that to any of the other antimalarials tested. Our results highlight the importance of development-stage composition for measuring pvcrt-o expression and suggest that pvcrt-o transcription is not a primary determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in depth investigation of the role of gene expression levels and P. vivax drug resistance. PMID- 26525785 TI - In Vitro Activity of beta-Lactams in Combination with beta-Lactamase Inhibitors against Multidrug-Resistant Mycobacterium tuberculosis Isolates. AB - The combination of beta-lactams and beta-lactamase inhibitors has been shown to have potent in vitro activity against multidrug-resistant tuberculosis (MDR-TB) isolates. In order to identify the most potent beta-lactam-beta-lactamase inhibitor combination against MDR-TB, we selected nine beta-lactams and three beta-lactamase inhibitors, which belong to different subgroups. A total of 121 MDR-TB strains were included in this study. Out of the beta-lactams used herein, biapenem was the most effective against MDR-TB and had an MIC50 value of 8 MUg/ml. However, after the addition of clavulanate or sulbactam, meropenem exhibited the most potent anti-MDR-TB activity with an MIC50 value of 4 MUg/ml. For meropenem, 76 (62.8%), 41 (33.9%), and 22 (18.2%) of the 121 MDR-TB strains were subjected to a synergistic effect when the drug was combined with sulbactam, tazobactam, or clavulanate, respectively. Further statistical analysis revealed that significantly more strains experienced a synergistic effect when exposed to the combination of meropenem with sulbactam than when exposed to meropenem in combination with tazobactam or clavulanate, respectively (P < 0.01). In addition, a total of 10.7% (13/121) of isolates harbored mutations in the blaC gene, with two different nucleotide substitutions: AGT333AGG and ATC786ATT. For the strains with a Ser111Arg substitution in BlaC, a better synergistic effect was observed in the meropenem-clavulanate and in the amoxicillin-clavulanate combinations than that in a synonymous single nucleotide polymorphism (SNP) group. In conclusion, our findings demonstrate that the combination of meropenem and sulbactam shows the most potent activity against MDR-TB isolates. In addition, the Ser111Arg substitution of BlaC may be associated with an increased susceptibility of MDR-TB isolates to meropenem and amoxicillin in the presence of clavulanate. PMID- 26525784 TI - Analysis of the Structure and Function of FOX-4 Cephamycinase. AB - Class C beta-lactamases poorly hydrolyze cephamycins (e.g., cefoxitin, cefotetan, and moxalactam). In the past 2 decades, a new family of plasmid-based AmpC beta lactamases conferring resistance to cefoxitin, the FOX family, has grown to include nine unique members descended from the Aeromonas caviae chromosomal AmpC. To understand the basis for the unique cephamycinase activity in the FOX family, we determined the first X-ray crystal structures of FOX-4, apo enzyme and the acyl-enzyme with its namesake compound, cefoxitin, using the Y150F deacylation deficient variant. Notably, recombinant expression of N-terminally tagged FOX-4 also yielded an inactive adenylylated enzyme form not previously observed in beta lactamases. The posttranslational modification (PTM), which occurs on the active site Ser64, would not seem to provide a selective advantage, yet might present an opportunity for the design of novel antibacterial drugs. Substantial ligand induced changes in the enzyme are seen in the acyl-enzyme complex, particularly the R2 loop and helix H10 (P289 to N297), with movement of F293 by 10.3 A. Taken together, this study provides the first picture of this highly proficient class C cephamycinase, uncovers a novel PTM, and suggests a possible cephamycin resistance mechanism involving repositioning of the substrate due to the presence of S153P, N289P, and N346I substitutions in the ligand binding pocket. PMID- 26525786 TI - Reactive Oxygen Species Contribute to the Bactericidal Effects of the Fluoroquinolone Moxifloxacin in Streptococcus pneumoniae. AB - We studied the transcriptomic response of Streptococcus pneumoniae to the fluoroquinolone moxifloxacin at a concentration that inhibits DNA gyrase. Treatment of the wild-type strain R6, at a concentration of 10* the MIC, triggered a response involving 132 genes after 30 min of treatment. Genes from several metabolic pathways involved in the production of pyruvate were upregulated. These included 3 glycolytic enzymes, which ultimately convert fructose 6-phosphate to pyruvate, and 2 enzymes that funnel phosphate sugars into the glycolytic pathway. In addition, acetyl coenzyme A (acetyl-CoA) carboxylase was downregulated, likely leading to an increase in acetyl-CoA. When coupled with an upregulation in formate acetyltransferase, an increase in acetyl-CoA would raise the production of pyruvate. Since pyruvate is converted by pyruvate oxidase (SpxB) into hydrogen peroxide (H2O2), an increase in pyruvate would augment intracellular H2O2. Here, we confirm a 21-fold increase in the production of H2O2 and a 55-fold increase in the amount of hydroxyl radical in cultures treated during 4 h with moxifloxacin. This increase in hydroxyl radical through the Fenton reaction would damage DNA, lipids, and proteins. These reactive oxygen species contributed to the lethality of the drug, a conclusion supported by the observed protective effects of an SpxB deletion. These results support the model whereby fluoroquinolones cause redox alterations. The transcriptional response of S. pneumoniae to moxifloxacin is compared with the response to levofloxacin, an inhibitor of topoisomerase IV. Levofloxacin triggers the transcriptional activation of iron transport genes and also enhances the Fenton reaction. PMID- 26525787 TI - Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR34/L98H- and TR46/Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014. AB - We employed an endpoint genotyping method to update the prevalence rate of positivity for the TR34/L98H mutation (a 34-bp tandem repeat mutation in the promoter region of the cyp51A gene in combination with a substitution at codon L98) and the TR46/Y121F/T289A mutation (a 46-bp tandem repeat mutation in the promoter region of the cyp51A gene in combination with substitutions at codons Y121 and T289) among clinical Aspergillus fumigatus isolates obtained from different regions of Iran over a recent 5-year period (2010 to 2014). The antifungal activities of itraconazole, voriconazole, and posaconazole against 172 clinical A. fumigatus isolates were investigated using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution method. For the isolates with an azole resistance phenotype, the cyp51A gene and its promoter were amplified and sequenced. In addition, using a LightCycler 480 real-time PCR system, a novel endpoint genotyping analysis method targeting single-nucleotide polymorphisms was evaluated to detect the L98H and Y121F mutations in the cyp51A gene of all isolates. Of the 172 A. fumigatus isolates tested, the MIC values of itraconazole (>=16 mg/liter) and voriconazole (>4 mg/liter) were high for 6 (3.5%). Quantitative analysis of single-nucleotide polymorphisms showed the TR34/L98H mutation in the cyp51A genes of six isolates. No isolates harboring the TR46/Y121F/T289A mutation were detected. DNA sequencing of the cyp51A gene confirmed the results of the novel endpoint genotyping method. By microsatellite typing, all of the azole-resistant isolates had genotypes different from those previously recovered from Iran and from the Dutch TR34/L98H controls. In conclusion, there was not a significant increase in the prevalence of azole resistant A. fumigatus isolates harboring the TR34/L98H resistance mechanism among isolates recovered over a recent 5-year period (2010 to 2014) in Iran. A quantitative assay detecting a single-nucleotide polymorphism in the cyp51A gene of A. fumigatus is a reliable tool for the rapid screening and monitoring of TR34/L98H- and TR46/Y121F/T289A-positive isolates and can easily be incorporated into clinical mycology algorithms. PMID- 26525788 TI - Complete Sequences of IncU Plasmids Harboring Quinolone Resistance Genes qnrS2 and aac(6')-Ib-cr in Aeromonas spp. from Ornamental Fish. AB - The nucleotide sequences of three IncU plasmids from Aeromonas spp. isolated from ornamental fish are described. They had a typical IncU backbone for plasmid replication and maintenance functions, but conjugative transfer modules were disrupted. The gene qnrS2 was inserted into mpR as a mobile insertion cassette. Novel Tn3 family transposons carrying putative toxin-antitoxin and plasmid stability genes were identified. The study demonstrates high plasticity of IncU plasmids from aquatic environments. PMID- 26525789 TI - Role of Non-Active-Site Residue Trp-93 in the Function and Stability of New Delhi Metallo-beta-Lactamase 1. AB - New Delhi metallo-beta-lactamase-1 (NDM-1) is expressed by various members of Enterobacteriaceae as a defense mechanism to hydrolyze beta-lactam antibiotics. Despite various studies showing the significance of active-site residues in the catalytic mechanism, there is a paucity of reports addressing the role of non active-site residues in the structure and function of NDM-1. In this study, we investigated the significance of non-active-site residue Trp-93 in the structure and function of NDM-1. We cloned blaNDM-1 from an Enterobacter cloacae clinical strain (EC-15) and introduced the mutation of Trp-93 to Ala (yielding the Trp93Ala mutant) by PCR-based site-directed mutagenesis. Proteins were expressed and purified to homogeneity by affinity chromatography. The MICs of the Trp93Ala mutant were reduced 4- to 8-fold for ampicillin, cefotaxime, ceftazidime, cefoxitin, imipenem, and meropenem. The poor hydrolytic activity of the Trp93Ala mutant was also reflected by its reduced catalytic efficiency. The overall catalytic efficiency of the Trp93Ala mutant was reduced by 40 to 55% (the Km was reduced, while the kcat was similar to that of wild-type NDM-1 [wtNDM-1]). Heat induced denaturation showed that the DeltaGD (o) and Tm of Trp93Ala mutant were reduced by 1.8 kcal/mol and 4.8 degrees C, respectively. Far-UV circular dichroism (CD) analysis showed that the alpha-helical content of the Trp93Ala mutant was reduced by 2.9%. The decrease in stability and catalytic efficiency of the Trp93Ala mutant was due to the loss of two hydrogen bonds with Ser-63 and Val 73 and hydrophobic interactions with Leu-65, Val-73, Gln-123, and Asp-124. The study provided insight into the role of non-active-site amino acid residues in the hydrolytic mechanism of NDM-1. PMID- 26525790 TI - Pharmacodynamics of Ceftazidime and Avibactam in Neutropenic Mice with Thigh or Lung Infection. AB - Avibactam is a new non-beta-lactam beta-lactamase inhibitor that shows promising restoration of ceftazidime activity against microorganisms producing Ambler class A extended-spectrum beta-lactamases (ESBLs) and carbapenemases such as KPCs, class C beta-lactamases (AmpC), and some class D enzymes. To determine optimal dosing combinations of ceftazidime-avibactam for treating infections with ceftazidime-resistant Pseudomonas aeruginosa, pharmacodynamic responses were explored in murine neutropenic thigh and lung infection models. Exposure-response relationships for ceftazidime monotherapy were determined first. Subsequently, the efficacy of adding avibactam every 2 h (q2h) or q8h to a fixed q2h dose of ceftazidime was determined in lung infection for two strains. Dosing avibactam q2h was significantly more efficacious, reducing the avibactam daily dose for static effect by factors of 2.7 and 10.1, whereas the mean percentage of the dosing interval that free drug concentrations remain above the threshold concentration of 1 mg/liter (%fT>C(T) 1 mg/liter) yielding bacteriostasis was similar for both regimens, with mean values of 21.6 (q2h) and 18.5 (q8h). Dose fractionation studies of avibactam in both the thigh and lung models indicated that the effect of avibactam correlated well with %fT>C(T) 1 mg/liter. This parameter of avibactam was further explored for four P. aeruginosa strains in the lung model and six in the thigh model. Parameter estimates of %fT>C(T) 1 mg/liter for avibactam ranged from 0 to 21.4% in the lung model and from 14.1 to 62.5% in the thigh model to achieve stasis. In conclusion, addition of avibactam enhanced the effect of ceftazidime, which was more pronounced at frequent dosing and well related with %fT>C(T) 1 mg/liter. The thigh model appeared more stringent, with higher values, ranging up to 62.5% fT>C(T) 1 mg/liter, required for a static effect. PMID- 26525791 TI - Effect of High-Dose Antimicrobials on Biofilm Growth of Achromobacter Species Isolated from Cystic Fibrosis Patients. AB - MICs and biofilm inhibitory concentrations (BICs) were measured for 68 cystic fibrosis (CF) Achromobacter isolates for amikacin, aztreonam, colistin, levofloxacin, and tobramycin. With the exception of colistin and levofloxacin, the remaining antibiotics had MIC90s, BICs at which 50% of the isolates were susceptible (BIC50s), and BICs at which 90% of the isolates were susceptible (BIC90s) equal to or above the highest concentrations tested. In a biofilm model, tobramycin was able to significantly increase killing of bacterial cells compared to controls, for intermediate-resistant strains only, at concentrations of 1,000 and 2,000 MUg/ml. PMID- 26525792 TI - Incompatible Natures of the HIV-1 Envelope in Resistance to the CCR5 Antagonist Cenicriviroc and to Neutralizing Antibodies. AB - Cenicriviroc is a CCR5 antagonist which prevents human immunodeficiency virus type 1 (HIV-1) from cellular entry. The CCR5-binding regions of the HIV-1 envelope glycoprotein are important targets for neutralizing antibodies (NAbs), and mutations conferring cenicriviroc resistance may therefore affect sensitivity to NAbs. Here, we used the in vitro induction of HIV-1 variants resistant to cenicriviroc or NAbs to examine the relationship between resistance to cenicriviroc and resistance to NAbs. The cenicriviroc-resistant variant KK652-67 (strain KK passaged 67 times in the presence of increasing concentrations of cenicriviroc) was sensitive to neutralization by NAbs against the V3 loop, the CD4-induced (CD4i) region, and the CD4-binding site (CD4bs), whereas the wild type (WT) parental HIV-1 strain KKWT from which cenicriviroc-resistant strain KK652-67 was obtained was resistant to these NAbs. The V3 region of KK652-67 was important for cenicriviroc resistance and critical to the high sensitivity of the V3, CD4i, and CD4bs epitopes to NAbs. Moreover, induction of variants resistant to anti-V3 NAb 0.5gamma and anti-CD4i NAb 4E9C from cenicriviroc-resistant strain KK652-67 resulted in reversion to the cenicriviroc-sensitive phenotype comparable to that of the parental strain, KKWT. Resistance to 0.5gamma and 4E9C was caused by the novel substitutions R315K, G324R, and E381K in the V3 and C3 regions near the substitutions conferring cenicriviroc resistance. Importantly, these amino acid changes in the CCR5-binding region were also responsible for reversion to the cenicriviroc-sensitive phenotype. These results suggest the presence of key amino acid residues where resistance to cenicriviroc is incompatible with resistance to NAbs. This implies that cenicriviroc and neutralizing antibodies may restrict the emergence of variants resistant to each other. PMID- 26525793 TI - Fluoroquinolone and Macrolide Exposure Predict Clostridium difficile Infection with the Highly Fluoroquinolone- and Macrolide-Resistant Epidemic C. difficile Strain BI/NAP1/027. AB - Antibiotics have been shown to influence the risk of infection with specific Clostridium difficile strains as well as the risk of C. difficile infection (CDI). We performed a retrospective case-control study of patients infected with the epidemic BI/NAP1/027 strain in a U.S. hospital following recognition of increased CDI severity and culture of stools positive by C. difficile toxin immunoassay. Between 2005 and 2007, 72% (103/143) of patients with first-episode CDIs were infected with the BI strain by restriction endonuclease analysis (REA) typing. Most patients received multiple antibiotics within 6 weeks of CDI onset (median of 3 antibiotic classes). By multivariate analysis, fluoroquinolone and macrolide exposure was more frequent among BI cases than among non-BI-infected controls (odds ratio [OR] for fluoroquinolones, 3.2; 95% confidence interval [CI], 1.3 to 7.5; (P < 0.001; OR for macrolides, 5.2; 95% CI, 1.1 to 24.0; P = 0.04)). In contrast, clindamycin use was less frequent among the BI cases than among the controls (OR, 0.1; 95% CI, 0.03 to 0.4; P = 0.001). High-level resistance to moxifloxacin and azithromycin was more frequent among BI strains (moxifloxacin, 49/102 [48%] BI versus 0/40 non-BI, P = 0.0001; azithromycin, 100/102 [98%] BI versus 22/40 [55%] non-BI, P = 0.0001). High-level resistance to clindamycin was more frequent among non-BI strains (22/40 [55%] non-BI versus 7/102 [7%] BI, P = 0.0001). Fluoroquinolone use, macrolide use, and C. difficile resistance to these antibiotic classes were associated with infection by the epidemic BI strain of C. difficile in a U.S. hospital during a time when CDI rates were increasing nationally due to the highly fluoroquinolone-resistant BI/NAP1/027 strain. PMID- 26525794 TI - Double Copies of bla(KPC-3)::Tn4401a on an IncX3 Plasmid in Klebsiella pneumoniae Successful Clone ST512 from Italy. AB - A carbapenem-resistant sequence type 512 (ST512) Klebsiella pneumoniae carbapenemase 3 (KPC-3)-producing K. pneumoniae strain showing a novel variant plasmid content was isolated in Palermo, Italy, in 2014. ST512 is a worldwide successful clone associated with the spread of bla(KPC) genes located on the IncFIIk pKpQIL plasmid. In our ST512 strain, the bla(KPC-3) gene was unusually located on an IncX3 plasmid, whose complete sequence was determined. Two copies of bla(KPC-3)::Tn4401a caused by intramolecular transposition events were detected in the plasmid. PMID- 26525796 TI - Characterization of a cfr-Carrying Plasmid from Porcine Escherichia coli That Closely Resembles Plasmid pEA3 from the Plant Pathogen Erwinia amylovora. AB - The multiresistance gene cfr was found in two porcine Escherichia coli isolates, one harboring it on the conjugative 33,885-bp plasmid pFSEC-01, the other harboring it in the chromosomal DNA. Sequence analysis of pFSEC-01 revealed that a 6,769-bp fragment containing the cfr gene bracketed by two IS26 elements was inserted into a plasmid closely related to pEA3 from the plant pathogen Erwinia amylovora, suggesting that pFSEC-01 may be transferred between different bacterial genera of both animal and plant origin. PMID- 26525795 TI - Type III Secretion-Dependent Sensitivity of Escherichia coli O157 to Specific Ketolides. AB - A subset of Gram-negative bacterial pathogens uses a type III secretion system (T3SS) to open up a conduit into eukaryotic cells in order to inject effector proteins. These modulate pathways to enhance bacterial colonization. In this study, we screened established bioactive compounds for any that could repress T3SS expression in enterohemorrhagic Escherichia coli (EHEC) O157. The ketolides telithromycin and, subsequently, solithromycin both demonstrated repressive effects on expression of the bacterial T3SS at sub-MICs, leading to significant reductions in bacterial binding and actin-rich pedestal formation on epithelial cells. Preincubation of epithelial cells with solithromycin resulted in significantly less attachment of E. coli O157. Moreover, bacteria expressing the T3SS were more susceptible to solithromycin, and there was significant preferential killing of E. coli O157 bacteria when they were added to epithelial cells that had been preexposed to the ketolide. This killing was dependent on expression of the T3SS. Taken together, this research indicates that the ketolide that has accumulated in epithelial cells may traffic back into the bacteria via the T3SS. Considering that neither ketolide induces the SOS response, nontoxic members of this class of antibiotics, such as solithromycin, should be considered for future testing and trials evaluating their use for treatment of EHEC infections. These antibiotics may also have broader significance for treating infections caused by other pathogenic bacteria, including intracellular bacteria, that express a T3SS. PMID- 26525797 TI - Penicillin Binding Protein 1 Is Important in the Compensatory Response of Staphylococcus aureus to Daptomycin-Induced Membrane Damage and Is a Potential Target for beta-Lactam-Daptomycin Synergy. AB - The activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA) is enhanced in the presence of beta-lactam antibiotics. This effect is more pronounced with beta-lactam antibiotics that exhibit avid binding to penicillin binding protein 1 (PBP1). Here, we present evidence that PBP1 has a significant role in responding to DAP-induced stress on the cell. Expression of the pbpA transcript, encoding PBP1, was specifically induced by DAP exposure whereas expression of pbpB, pbpC, and pbpD, encoding PBP2, PBP3, and PBP4, respectively, remained unchanged. Using a MRSA COL strain with pbpA under an inducible promoter, increased pbpA transcription was accompanied by reduced susceptibility to, and killing by, DAP in vitro. Exposure to beta-lactams that preferentially inactivate PBP1 was not associated with increased DAP binding, suggesting that synergy in the setting of anti-PBP1 pharmacotherapy results from increased DAP potency on a per-molecule basis. Combination exposure in an in vitro pharmacokinetic/pharmacodynamic model system with beta-lactams that preferentially inactivate PBP1 (DAP-meropenem [MEM] or DAP-imipenem [IPM]) resulted in more-rapid killing than did combination exposure with DAP-nafcillin (NAF) (nonselective), DAP-ceftriaxone (CRO) or DAP-cefotaxime (CTX) (PBP2 selective), DAP-cefaclor (CEC) (PBP3 selective), or DAP-cefoxitin (FOX) (PBP4 selective). Compared to beta-lactams with poor PBP1 binding specificity, exposure of S. aureus to DAP plus PBP1-selective beta-lactams resulted in an increased frequency of septation and cell wall abnormalities. These data suggest that PBP1 activity may contribute to survival during DAP-induced metabolic stress. Therefore, targeted inactivation of PBP1 may enhance the antimicrobial efficiency of DAP, supporting the use of DAP-beta-lactam combination therapy for serious MRSA infections, particularly when the beta-lactam undermines the PBP1-mediated compensatory response. PMID- 26525798 TI - No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV Infected Subjects. AB - Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC0-12) and concentration prior to dosing (Cpredose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC0-12 or Cpredose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir ritonavir 400/100-mg twice-daily dose during pregnancy. PMID- 26525799 TI - Acquired Flucytosine Resistance during Combination Therapy with Caspofungin and Flucytosine for Candida glabrata Cystitis. AB - Treatment of Candida glabrata cystitis remains a therapeutic challenge, and an antifungal combination using flucytosine is one option. We describe two patients with refractory C. glabrata cystitis who failed flucytosine combined with caspofungin with early-acquired high-level resistance to flucytosine due to nonsense mutations in the FUR1 gene. Rapidly acquired flucytosine resistance with microbiological failure should discourage combination of caspofungin and flucytosine during urinary candidiasis. PMID- 26525800 TI - Cefotaxime and Amoxicillin-Clavulanate Synergism against Extended-Spectrum-beta Lactamase-Producing Escherichia coli in a Murine Model of Urinary Tract Infection. AB - We investigated the efficacies of cefotaxime (CTX) and amoxicillin (AMX) clavulanate (CLA) (AMC) against extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli in vitro and in a murine model of urinary tract infection (UTI). MICs, the checkerboard dilution method, and time-kill curves were used to explore the in vitro synergism between cefotaxime and amoxicillin-clavulanate against two isogenic E. coli strains-CFT073-RR and its transconjugant, CFT073-RR Tc bla(CTX-M 15)-harboring a bla(CTX-M-15) plasmid and a bla(OXA-1) plasmid. For in vivo experiments, mice were separately infected with each strain and treated with cefotaxime, amoxicillin, and clavulanate, alone or in combination, or imipenem, using therapeutic regimens reproducing time of free-drug concentrations above the MIC (fT>=MIC) values close to that obtained in humans. MICs of amoxicillin, cefotaxime, and imipenem were 4/>1,024, 0.125/1,024, and 0.5/0.5 mg/liter, for CFT073-RR and CFT073-RR Tc bla(CTX-M-15), respectively. The addition of 2 mg/liter of clavulanate (CLA) restored the susceptibility of CFT073-RR Tc bla(CTX M-15) to CTX (MICs of the CTX-CLA combination, 0.125 mg/liter). The checkerboard dilution method and time-kill curves confirmed an in vitro synergy between amoxicillin-clavulanate and cefotaxime against CFT073-RR Tc bla(CTX-M-15). In vivo, this antibiotic combination was similarly active against both strains and as effective as imipenem. In conclusion, the cefotaxime and amoxicillin clavulanate combination appear to be an effective, easy, and already available alternative to carbapenems for the treatment of UTI due to CTX-M-producing E. coli strains. PMID- 26525801 TI - Treatment Outcomes with Fluoroquinolone-Containing Regimens for Isoniazid Resistant Pulmonary Tuberculosis. AB - Resistance to isoniazid (INH) is the most common form of drug resistance in pulmonary tuberculosis (TB). Although fluoroquinolones (FQs) are recommended to strengthen treatment regimens for INH-resistant pulmonary TB, few studies have evaluated the clinical efficacy of FQ-containing regimens in patients with INH resistant pulmonary TB. A retrospective cohort study of 140 patients with INH resistant pulmonary TB was performed between 2005 and 2012. We evaluated whether FQ-containing regimens yielded improved treatment outcomes for patients with INH resistant pulmonary TB. Overall, favorable outcomes were achieved in 128 (91.4%) patients. Unfavorable outcomes occurred in 12 patients (8.6%), including 7 with treatment failure (5.0%) and 5 with relapse after initial treatment completion (3.6%). FQs, such as levofloxacin and moxifloxacin, were given to 75 (53.6%) patients. Favorable treatment outcomes were more frequent for patients who received FQs (97.3% [73/75 patients]) than for those who did not receive FQs (84.6% [55/65 patients]) (P = 0.007). Patients who did not receive FQs were more likely to develop treatment failure (9.2% [6/65 patients] versus 1.3% [1/75 patients]) (P = 0.049) than patients who received FQs. The adjusted proportion of unfavorable outcomes was significantly higher among patients who did not receive FQs (8.8%; 95% confidence interval [CI], 3.3 to 21.5%) than among those who did receive FQs (1.5%; 95% CI, 0.3 to 7.7%) (P = 0.037). These results suggest that the addition of FQs can improve treatment outcomes for patients with INH resistant pulmonary TB. PMID- 26525802 TI - Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli. AB - The increasing prevalence of multidrug-resistant (MDR) nosocomial infections accounts for increased morbidity and mortality of such infections. Infections with MDR Gram-negative isolates are frequently treated with colistin. Based on recent pharmacokinetic studies, current colistin dosing regimens may result in a prolonged time to therapeutic concentrations, leading to suboptimal and delayed effective treatment. In addition, studies have demonstrated an association between an increased colistin dose and improved clinical outcomes. However, the specific dose at which these outcomes are observed is unknown and warrants further investigation. This retrospective study utilized classification and regression tree (CART) analysis to determine the dose of colistin most predictive of global cure at day 7 of therapy. Patients were assigned to high- and low-dose cohorts based on the CART-established breakpoint. The secondary outcomes included microbiologic outcomes, clinical cure, global cure, lengths of intensive care unit (ICU) and hospital stays, and 7- and 28-day mortalities. Additionally, safety outcomes focused on the incidence of nephrotoxicity associated with high dose colistin therapy. The CART-established breakpoint for high-dose colistin was determined to be >4.4 mg/kg of body weight/day, based on ideal body weight. This study evaluated 127 patients; 45 (35%) received high-dose colistin, and 82 (65%) received low-dose colistin. High-dose colistin was associated with day 7 global cure (40% versus 19.5%; P = 0.013) in bivariate and multivariate analyses (odds ratio [OR] = 3.40; 95% confidence interval [CI], 1.37 to 8.45; P = 0.008). High dose colistin therapy was also associated with day 7 clinical cure, microbiologic success, and mortality but not with the development of acute kidney injury. We concluded that high-dose colistin (>4.4 mg/kg/day) is independently associated with day 7 global cure. PMID- 26525804 TI - Rotational atherectomy before paclitaxel-eluting stent implantation in complex calcified coronary lesions: Two-year clinical outcome of the randomized ROTAXUS trial. AB - BACKGROUND: In the randomized ROTAXUS trial, routine lesion preparation of complex calcified coronary lesions using rotational atherectomy (RA) prior to paclitaxel-eluting stent implantation did not reduce the primary endpoint of angiographic late lumen loss at 9 months compared to stenting without RA. So far, no long-term data of prospective head-to-head comparisons between both treatment strategies have been reported. METHODS AND RESULTS: ROTAXUS randomly assigned patients with complex calcified coronary lesions to RA followed by stenting (n = 120) or stenting without RA (n = 120). The primary endpoint of the current analysis was the occurrence of major adverse cardiac events (MACE) at 2-year follow-up defined as the composite of death, myocardial infarction, and target vessel revascularization (TVR). At 2 years, MACE occurred in 32 patients in the RA group and 37 patients in the standard therapy group (29.4% vs. 34.3%, P = 0.47). The rates of death (8.3% vs. 7.4%, P = 1.00), myocardial infarction (8.3% vs. 6.5%, P = 0.80), target lesion revascularization (TLR, 13.8% vs. 16.7%, P = 0.58), and TVR (19.3% vs. 22.2%, P = 0.62) were similar in both groups. CONCLUSION: Despite high rates of initial angiographic success, nearly one third of patients enrolled in ROTAXUS experienced MACE within 2-year follow-up, with no differences between patients treated with or without RA. PMID- 26525805 TI - Sox13 functionally complements the related Sox5 and Sox6 as important developmental modulators in mouse spinal cord oligodendrocytes. AB - The role of transcription factor Sox13, which together with Sox5 and Sox6 belongs to the SoxD family, is only poorly characterized in central nervous system development. Therefore, we analysed whether Sox13 expression and function overlaps with or differs from that of its close relatives Sox5 and Sox6. In the developing mouse spinal cord, we found Sox13 predominantly expressed in neuroepithelial precursors, oligodendroglial and astroglial cells. The substantially overlapping expression with Sox5 and Sox6 in oligodendroglial cells prompted us to study potential roles during specification, lineage progression and differentiation of oligodendrocytes. In contrast to Sox5 and Sox6, Sox13 expression continues after differentiation and even increases in myelinating oligodendrocytes. Sox13 deletion did not interfere with oligodendroglial development, which was normal in Sox13-deficient mice. However, the premature differentiation of oligodendrocyte precursors triggered by loss of Sox6 was slightly more prominent in Sox6/Sox13 double-deficient mice. Sox13 can bind to the same sites in myelin gene promoters as Sox5 and Sox6 in vitro. Reporter gene assays furthermore reveal a similar antagonizing effect on Sox10-dependent transactivation of myelin gene promoters as previously shown for Sox5 and Sox6. This argues that Sox13 is functionally redundant with the other SoxD proteins and complements Sox5 and Sox6 in their role as important modulators of oligodendrocyte development. The transcription factor Sox13 is co-expressed with the related Sox5 and Sox6 in cells of the oligodendroglial lineage. By itself, it has little impact on oligodendrocyte development but supports Sox5 and Sox6 during the process as a functionally redundant transcription factor. PMID- 26525803 TI - Fosfomycin plus beta-Lactams as Synergistic Bactericidal Combinations for Experimental Endocarditis Due to Methicillin-Resistant and Glycopeptide Intermediate Staphylococcus aureus. AB - The urgent need of effective therapies for methicillin-resistant Staphylococcus aureus (MRSA) infective endocarditis (IE) is a cause of concern. We aimed to ascertain the in vitro and in vivo activity of the older antibiotic fosfomycin combined with different beta-lactams against MRSA and glycopeptide-intermediate resistant S. aureus (GISA) strains. Time-kill tests with 10 isolates showed that fosfomycin plus imipenem (FOF+IPM) was the most active evaluated combination. In an aortic valve IE model with two strains (MRSA-277H and GISA-ATCC 700788), the following intravenous regimens were compared: fosfomycin (2 g every 8 h [q8h]) plus imipenem (1 g q6h) or ceftriaxone (2 g q12h) (FOF+CRO) and vancomycin at a standard dose (VAN-SD) (1 g q12h) and a high dose (VAN-HD) (1 g q6h). Whereas a significant reduction of MRSA-227H load in the vegetations (veg) was observed with FOF+IPM compared with VAN-SD (0 [interquartile range [IQR], 0 to 1] versus 2 [IQR, 0 to 5.1] log CFU/g veg; P = 0.01), no statistical differences were found with VAN-HD. In addition, FOF+IPM sterilized more vegetations than VAN-SD (11/15 [73%] versus 5/16 [31%]; P = 0.02). The GISA-ATCC 700788 load in the vegetations was significantly lower after FOF+IPM or FOF+CRO treatment than with VAN-SD (2 [IQR, 0 to 2] and 0 [IQR, 0 to 2] versus 6.5 [IQR, 2 to 6.9] log CFU/g veg; P < 0.01). The number of sterilized vegetations after treatment with FOF+CRO was higher than after treatment with VAN-SD or VAN-HD (8/15 [53%] versus 4/20 [20%] or 4/20 [20%]; P = 0.03). To assess the effect of FOF+IPM on penicillin binding protein (PBP) synthesis, molecular studies were performed, with results showing that FOF+IPM treatment significantly decreased PBP1, PBP2 (but not PBP2a), and PBP3 synthesis. These results allow clinicians to consider the use of FOF+IPM or FOF+CRO to treat MRSA or GISA IE. PMID- 26525806 TI - Role of incretin-based therapies and sodium-glucose co-transporter-2 inhibitors as adjuncts to insulin therapy in Type 2 diabetes, with special reference to IDegLira. AB - The progressive nature of Type 2 diabetes necessitates treatment intensification over time in order to maintain glycaemic control, with many patients ultimately requiring insulin therapy. While insulin has unlimited potential efficacy, its initiation is often delayed and improvements in glycaemic control are typically accompanied by weight gain and an increased risk of hypoglycaemia, particularly as HbA1c approaches and falls below target levels. This may account for the sub optimal control often achieved after insulin initiation. Combining insulin with antihyperglycaemic therapies that have a low risk of hypoglycaemia and are weight neutral or result in weight loss is a therapeutic strategy with the potential to improve Type 2 diabetes management. Although the effects differ with each individual class of therapy, clinical trials have shown that adding a glucagon like peptide-1 receptor agonist, dipeptidyl peptidase-4 inhibitor or sodium glucose co-transporter-2 inhibitor to insulin regimens can offer a significant reduction in HbA1c without substantially increasing hypoglycaemia risk, or weight. The evidence and merit of each approach are reviewed in this paper. Once daily co-formulations of a basal insulin and a glucagon-like peptide-1 receptor agonist have been developed (insulin degludec/liraglutide) or are under development (lixisenatide/insulin glargine). Insulin degludec/liraglutide phase III trials and a lixisenatide/insulin glargine phase II trial have shown robust HbA1c reductions, with weight loss and a low risk of hypoglycaemia. With insulin degludec/liraglutide now approved in Europe, an important consideration will be the types of patients who may benefit most from a fixed-ratio combination; this is discussed in the present review, and we also take a look toward future developments in the field. PMID- 26525807 TI - [A role of long-term stress and functional properties of the endothelium in the development of autonomic dystonia syndrome]. AB - OBJECTIVE: To study a role of long-term stress and endothelial function in the development of autonomic dystonia syndrome (ADS) in young patients. MATERIAL AND METHODS: Authors examined 75 male patients, aged from 17 to 28 years, with ADS including 41 patients without clinically evident symptoms of psycho-emotional stress (group I) and 34 patients with high level of psycho-emotional stress (group II). A comparison group consisted of 21 healthy volunteers. The level of anxiety was assessed using the Spilberger-Khanin Inventory and the functional state of endothelium with the use of endothelium-dependent vasodilatation (EDV). Standard bicycle physical exercise (PE) test was performed. RESULTS: Correlations between state and trait anxiety in all groups were shown. In group II, these values were maximal thus demonstrating marked anxiety. In EDV and PE tests, patients of group I had general reactivity of the vascular wall, while patients of group II showed opposite reactions, either increase or decrease in the brachial artery diameter. This instability may result from the increased liability of the sympathetic part of the autonomic nervous system in stress conditions. CONCLUSIONS: Long-term stress causes vascular endothelial dysfunction in young patients with ADS that increases the severity of clinical manifestations of the disease and leads to the increased risk of cardiovascular pathology. PMID- 26525808 TI - [Clinical and psychopathological aspects of deficit disorders in the structure of initial stages of youth-onset endogenous psychosis]. AB - OBJECTIVE: To study the structure of deficit disorders identified in the initial phase (first 5 years) of youth-onset endogenous psychosis. MATERIAL AND METHODS: Author examined 232 patients with the first episode of juvenile endogenous psychosis during the period from 2005 to 2015 using integrated phenomenological and clinical/psychopathological approaches. The follow-up was administered to 151 patients. RESULTS AND CONCLUSION: The working hypothesis on the formation of deficit symptom variants based on the mutual competition of its components was formulated. Identified typological species allowed to hypothesize the existence of continual series of variations of deficit disorders manifested as phenomena with multilateral dependencies, characterized by dynamism and a wide range of modifications and verifiable in remission at the initial stages of attack-like endogenous psychosis. PMID- 26525809 TI - [A clinical-electroneuromyographic study of the efficacy of ipidacrine in patients with mononeuropathies]. AB - OBJECTIVE: To evaluate the efficacy and tolerability of axamon (ipidacrine) therapy in patients with focal neuropathies--mononeuropathies. MATERIAL AND METHODS: We examined 35 patients, aged 18 years and older, with focal neuropathies (tunnel syndromes, radiculopathies). In the main group (n=20) axamon (ipidacrine) was prescribed in addition to the basic (standard) therapy (group B vitamins, lipoic acid) during 6 week, in the control group (n=15) patients remained only on the basic (standard) treatment. RESULTS: In the main group positive clinical changes were accompanied by the more significant positive electroneuromyographic (ENMG) dynamics as compared to the control group (the increased amplitude of M-response in the muscles of the hand and feet; increased nerve conduction velocity in the peripheral nerves as a manifestation of remyelination activity, and others). CONCLUSION: The obtained clinical and ENMG data indicate that axamon (ipidacrine) is a unique cholinesterase inhibitor with conduction action primarily targeting on efferent (motor) fibers of the peripheral nerves. PMID- 26525810 TI - [Alcohol use disorders: current approaches to diagnosis and treatment]. AB - Alcohol abuse and alcoholism are the leading causes of disability, health worsening and increased mortality. Diagnosis of alcohol use disorders is based on the formal criteria of ICD-10 and DSM-V. Sobriety-oriented therapy has extremely low efficiency. The difficulties of therapy are compounded by the fact that less than 10% patients with alcohol use disorder participate in treatment programs. Serious expectations in addressing unsatisfactory efficiency of alcoholism treatment are associated with WHO reducing alcohol consumption strategy. Nalmefene is the first and still only drug registered as a medicine for reducing alcohol use. Recent studies show that the decrease of alcohol consumption using nalmefene creates opportunities for significant lessening of alcohol-related morbidity, injuries and deaths. PMID- 26525811 TI - [The use of agomelatine (valdoxan) in gambling therapy: a pilot study]. AB - OBJECTIVE: To study the antidepressant agomelatine (M1/M2 agonist and 5-HT2C antagonist) in pathological gambling (PG) (ICD-10 item F63.0). MATERIAL AND METHODS: An open label 8-week trial was carried out in 22 outpatients (17 male and 5 female, mean age 38+/-7). PG severity was assessed by the Yale-Brown Obsessive-Compulsive Scale adapted for Pathological Gambling (PG-YBOCS). Anxiety and depression level was measured by the Hospital Anxiety Depression Scale (HADS). RESULTS: Agomelatine significantly decreased PG-YBOCS scores from the second week of the trial (12.6+/-3.0 compared to 24.2+/-2.1 at baseline, p<0.05). In the end of the trial, PG-YBOCS score decreased to 5.3. The total HADS score decreased significantly in the end of the study (from 23.6+/-2.9 to 11.4+/-1.9, p<0.05). There was an improvement in behavior as well. CONCLUSION: Thus, agomelatine has demonstrated efficacy in PG patients. PMID- 26525812 TI - [What do the doctors of different specialties know about sleep disorders and their treatment]. AB - OBJECTIVE: To assessdoctor's knowledge on the relevance of the problem of sleep disorders, methods of their diagnosis and treatment. MATERIAL AND METHODS: The survey was conducted among90physicians of different the rapeuticspecialties of Kazan medical institutions. RESULTS: The doctors believe that main causes of sleep disorders are stressors (20%), depression (13%), neurosis (13%), chronic diseases (13%), asthenia (10%), pain (10%). An analysis of treatment prescribed to patients with sleep disorders revealed large differences. CONCLUSION: Physicians are not well informed about the problems of sleep disorders, have a small idea of the methods of sleepresearch and drugs for their treatment as well as of a sequence of operations that should be used to resolve this problem. PMID- 26525813 TI - [Catecholamine excretion in patients with eating disorders]. AB - OBJECTIVE: To compare clinical features of eating disorders and parameters of monoamine metabolism. MATERIAL AND METHODS: Authors examined 21 patients with eating disorders during 2008-2011 using clinical/psychopathological method. To evaluate the status of monoamine neuromediator system, urine levels of dopamine, noradrenalin and adrenaline excretion were measured using high-yield liquid chromatography with electrochemical detection. The reference group included 26 sex- and age-matched volunteers. RESULTS AND CONCLUSION: The common patterns of the pathogenesis of compulsive urges of different origin were identified. The results indicate not only nonspecific changes in catecholamine systems of patients with eating disorders associated with different stress disorders but also demonstrate the pathogenetic correlations between dopaminergic activity and clinical symptoms of addiction. PMID- 26525814 TI - [Pain fluctuations in Parkinson's disease]. AB - OBJECTIVE: To specify the character of pain syndromes and determine their relationship with main symptoms of ON and OFF periods in patients with complications of long-term treatment with levodopa medications. MATERIAL AND METHODS: Authors examined 40 patients with Parkinson's disease (27 women and 13 men), mean age 69.2+/-8 years (from 62 to 85 years), illness duration 9.2+/-1.2 years (from 7 to 11 years), duration of treatment with levodopa 6.9+/-1.2 years (from 5 to 9 years). The severity of disease course, character and intensity of pain syndrome were assessed. RESULTS AND CONCLUSION: We described pain syndromes that had differences in the pathogenesis and localization. Adjustment of the antiparkinsonian treatment resulted in the decrease in their severity. Motor fluctuations and drug-induced dyskinesia that was accompanied by pain sensations were the most frequent signs of Parkinson's disease during its progression. The pain syndrome was related to main symptoms of the ON and OFF period in patients with complications of long-term treatment with levodopa. The pain fluctuations had both nociceptive and central neuropathic pain phenotypes. PMID- 26525815 TI - [To the question of pathophysiological fundamentals of endocrine system functioning in patients with a first psychotic episode]. AB - OBJECTIVE: To study the characteristics of prolactin secretion in patients with a first psychotic episode (FPE) with regard to disease severity, gender and patient's neuromediator system state. MATERIAL AND METHODS: Author studied 76 patients with schizophrenic spectrum disorders and 34 normals (control group). RESULTS AND CONCLUSION: There was a significant negative sex-related correlation between the severity of psychopathologic symptoms and plasma prolactin levels. Based on the results author attempted to explain the hormonal disbalance in the patients with FPE taking into account the state of monoaminergic mediator systems in patients. PMID- 26525816 TI - [Hakim-Adams syndrome]. AB - Hakim-Adams syndrome is little known, although quite common disease. The etiology is not fully clear. Pathogenetic mechanisms included the blockage of cerebrospinal fluid outflow along the upper lateral surface of the brain, development of hydrocephalus with the expansion of the brain ventricles while maintaining normotensive cerebrospinal fluid (CSF). Main manifestations are ataxia, apraxia, symptoms of dementia and urinary disturbances, up to incontinence. Diagnosis is based on clinical symptoms, exploratory lumbar and neuroimaging. Main treatment is ventriculoperitoneal (stomach) shunt placement for fluid drainage. Timely surgical intervention gives good results and improves quality of life of patients. PMID- 26525817 TI - [Cases of non-standard approach to treatment of super-refractory status epilepticus]. AB - Authors assume that super-refractoriness is probably characterized by the specific pathophysiological mechanisms of status epilepticus development and can't be treated using standard treatment schemes. By the example of two clinical cases, we have analyzed the efficacy of complex treatment of super-refractory nonconvulsive and myoclonic status using intravenous valproate, central anesthetics (thiopental sodium, propofol), levetiracetam and cortexin. Preliminary results suggest that cortexin and levetiracetam as add-on to standard treatment may be vitally important drugs for the patients. PMID- 26525818 TI - [The use of neurobion in neurological practice]. AB - Vitamins are actively involved in many metabolic processes of the nervous system. Their deficit may cause severe and, sometimes, irreversible consequences. Mechanisms of the therapeutic effects of the vitamin B complex neurobion are considered. Results of the studies on the efficacy and safety of neurobion in patients with polyneuropathies, including those caused by diabetes mellitus, pain syndromes of origin (skeletal/muscle pain, trauma etc) are presented. The necessity of using neurobion in treatment of a wide spectrum of nervous system diseases is emphasized. PMID- 26525819 TI - [Cerebrovascular diseases: perspectives of pathogenetic metabolic haemangiocorrective treatment]. AB - Metabolic syndrome is a serious risk factor for acute and chronic cerebrovascular disease, which are a leading cause of disabling conditions. The association of proatherogenic effects of the main components of metabolic syndrome- hyperinsulinemia, arterial hypertension, dyslipidemia and obesity--leads to prominent haemorheological and hemostasis changes, which in turn play a pivotal role in the initiation, course and outcome of cerebrovascular pathology. Metabolic syndrome also influences the efficacy of the main pathogenetic therapy of cerebrovascular diseases--antithrombotic therapy. Thus, primary and secondary prevention of cerebrovascular disease in patients with metabolic syndrome should include haemangiocorrective, antithrombotic, antioxidant and endothelium protective treatment, as well as therapy of the main components of metabolic syndrome. PMID- 26525820 TI - [A current view on dopamine receptor agonists in the treatment of Parkinson's disease]. AB - Dopamine receptor agonists (DRA) is a widely used group of antiparkinsonian drugs. The article presents short results: related to the mechanism of the stimulation of different types of dopamine receptors. The advantages of this group of drugs compared to levodopa medications as well as the studies of DRA in vitro and in vivo are described. Multiple studies demonstrate an important role of DRA in the treatment of Parkinson's disease (PD): a good control of motor symptoms, the possibility of monotherapy in the early stages of disease, the reduced risk of motor complications compared to start therapy with levodopa and decrease in the duration of "OFF-period" and UPDRS scores as well as the possibility to reduce the dose of levodopa in case of combined treatment with levodopa containing preparations. Pramipexole has demonstrated the efficacy in the treatment of persistent tremor and depression in double-blind placebo controlled trials. A significant improvement of quality of life index has been shown in PD patients treated with these drugs. Side-effects often limited the use of DRA in clinical practice. The data on the dose equivalence of different DRA are recommended to use if it is necessary to switch from one DRA to another. PMID- 26525821 TI - A new method of fabricating a blend scaffold using an indirect three-dimensional printing technique. AB - Due to its simplicity and effectiveness, the physical blending of polymers is considered to be a practical strategy for developing a versatile scaffold having desirable mechanical and biochemical properties. In the present work, an indirect three-dimensional (i3D) printing technique was proposed to fabricate a 3D free form scaffold using a blend of immiscible materials, such as polycaprolactone (PCL) and gelatin. The i3D printing technique includes 3D printing of a mold and a sacrificial molding process. PCL/chloroform and gelatin/water were physically mixed to prepare the blend solution, which was subsequently injected into the cavity of a 3D printed mold. After solvent removal and gelatin cross-linking, the mold was dissolved to obtain a PCL-gelatin (PG) scaffold, with a specific 3D structure. Scanning electron microscopy and Fourier transform infrared spectroscopy analysis indicated that PCL masses and gelatin fibers in the PG scaffold homogenously coexisted without chemical bonding. Compression tests confirmed that gelatin incorporation into the PCL enhanced its mechanical flexibility and softness, to the point of being suitable for soft-tissue engineering, as opposed to pure PCL. Human adipose-derived stem cells, cultured on a PG scaffold, exhibited enhanced in vitro chondrogenic differentiation and tissue formation, compared with those on a PCL scaffold. The i3D printing technique can be used to blend a variety of materials, facilitating 3D scaffold fabrication for specific tissue regeneration. Furthermore, this convenient and versatile technique may lead to wider application of 3D printing in tissue engineering. PMID- 26525822 TI - Comprehensive application of robotic retroauricular thyroidectomy: The evolution of robotic thyroidectomy. AB - OBJECTIVES/HYPOTHESIS: As an evolvement of the robotic application to the thyroidectomy, we sought to seek the potential role of robotic thyroidectomy with the retroauricular (RA) approach prior to future comparative study between RA and transaxillary thyroidectomy. This study aims to verify the surgical feasibility of robotic RA thyroidectomy. STUDY DESIGN: Case series with planned data collection. METHODS: A total of 87 patients who underwent robotic RA thyroidectomy for clinically suspicious papillary thyroid carcinoma or benign lesions from January 2013 to May 2014 were retrospectively reviewed and analyzed. RESULTS: All robotic surgeries via RA approach were successfully performed, without any significant intraoperative complications or conversion to open surgery. Based on patient-reported outcome questionnaires, all patients were satisfied with their postoperative surgical scars. CONCLUSION: Robotic RA thyroidectomy is technically feasible and safe, with satisfactory cosmetic results for patients where indicated. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1952-1957, 2016. PMID- 26525823 TI - Erratum. PMID- 26525824 TI - Local Therapies for Localised Neuropathic Pain. PMID- 26525825 TI - Maternal Sensitivity and Child Secure Base Use in Early Childhood: Studies in Different Cultural Contexts. AB - This study tested whether maternal sensitivity and child security are related during early childhood and whether such an association is found in different cultural and social contexts. Mother-child dyads (N = 237) from four different countries (Colombia, Mexico, Peru, and the United States) were observed in naturalistic settings when children were between 36 and 72 months of age. Maternal and child behavior during interactions at home and in the playground were described using Q methodology. Findings reveal that across cultures, concurrent maternal sensitivity and more specific behavioral domains of maternal care (e.g., contributions to harmonious interactions and secure base support) are important for children's attachment security during early childhood. Implications for the study of attachment relationships beyond infancy and in diverse contexts are highlighted. PMID- 26525826 TI - Functional outcome after Ivor Lewis esophagectomy for cancer. AB - BACKGROUND: Little is known on functional outcome after Ivor Lewis esophagectomy (ILE) with intrathoracic anastomosis. METHODS: Patients who underwent ILE were identified from a prospective database. Clinicopathological data were retrieved and compared with functional outcome data based on patient self-assessment by a standard questionnaire. Predictive factors for selected functional complaints were identified with logistic regression analyses. RESULTS: Three hundred and twenty-two patients (80.4% male, mean age 62 years) were studied. Indications for surgery were adenocarcinoma (62.4%), squamous cell carcinoma (28%), and HG Barrett dysplasia (7%). Preoperative chemoradiation (CRT) was administered to 42.5% of patients. Anastomotic leakage occurred in 5.6% and was associated with higher age and diabetes mellitus. Functional symptoms identified were reflux (39%), delayed gastric emptying (37%), dumping (21.4%), and anastomotic stenosis (16%). In the multivariate models, anastomotic stenosis was associated with smaller stapler diameter and presence of esophagitis. Postoperative reflux was associated with higher BMI, whereas dumping was predicted by female gender and age. The quality of life questionnaires revealed a good general health status in 82% of the patients. CONCLUSIONS: Functional complaints after ILE consist of reflux, delayed gastric emptying, dumping, and dysphagia, and are affected by age, gender, BMI, diabetes mellitus, and stapler diameter. PMID- 26525827 TI - Da Vinci single site(c) surgical platform in clinical practice: a systematic review. AB - BACKGROUND: The Da Vinci single-site(c) surgical platform (DVSSP) is a set of single-site instruments and accessories specifically dedicated to robot-assisted single-site surgery. METHODS: The PubMed database from inception to June 2015 was searched for English literature on the clinical use of DVSSP in general surgery, urology and gynecology. RESULTS: Twenty-nine articles involving the clinical application of DVSSP were identified; 15 articles on general surgery (561 procedures), four articles on urology (48 procedures) and 10 articles on gynecology (212 procedures). All studies have proven the safety and feasibility of the use of DVSSP. The principal reported advantage is the restoration of intra abdominal triangulation, while the main reported limitation is the lack of the endowrist. CONCLUSIONS: Da Vinci systems have proven to be valuable assets in single-site surgery, owing to the combination of robot use with the dedicated single-incision platform. However, case-control or prospective trials are warranted to draw more definitive conc lusions. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26525829 TI - Mass Spectrometry: Reflections across Twenty-Six Years with Analytical Chemistry. PMID- 26525828 TI - The strange case of the tetragenous Anodonta anatina. AB - Unionoid freshwater mussels have a unique life cycle with a form of parental care where the larvae are developed and kept inside the gills until release, followed by an obligate parasitic stage on fish. The size and location of the marsupium have been used as important phylogenetic characters in unionoids and in Anodontini its location was described exclusively on the outer demibranchs. Two recent surveys in a lake in the North of Portugal revealed large anodontine mussels morphological identical to Anodonta anatina but with glochidia in both demibranchs and with an unusual large size. In order to establish the identity of these mussels, a barcoding approach was used and an anatomical description of the gills and glochidia was performed. These mussels were identified as A. anatina and presented an inner demibranch pair with tripartite tubes. The glochidial sizes were much higher than previously reported for the species reaching maximum (length * height) values of 566 * 552 MUm. This species reveals a high ecological plasticity being able to change its size and anatomy to increase its fertility as well as infestation performance. J. Exp. Zool. 325A:52-56, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26525830 TI - Multi-modal data fusion using source separation: Two effective models based on ICA and IVA and their properties. AB - Fusion of information from multiple sets of data in order to extract a set of features that are most useful and relevant for the given task is inherent to many problems we deal with today. Since, usually, very little is known about the actual interaction among the datasets, it is highly desirable to minimize the underlying assumptions. This has been the main reason for the growing importance of data-driven methods, and in particular of independent component analysis (ICA) as it provides useful decompositions with a simple generative model and using only the assumption of statistical independence. A recent extension of ICA, independent vector analysis (IVA) generalizes ICA to multiple datasets by exploiting the statistical dependence across the datasets, and hence, as we discuss in this paper, provides an attractive solution to fusion of data from multiple datasets along with ICA. In this paper, we focus on two multivariate solutions for multi-modal data fusion that let multiple modalities fully interact for the estimation of underlying features that jointly report on all modalities. One solution is the Joint ICA model that has found wide application in medical imaging, and the second one is the the Transposed IVA model introduced here as a generalization of an approach based on multi-set canonical correlation analysis. In the discussion, we emphasize the role of diversity in the decompositions achieved by these two models, present their properties and implementation details to enable the user make informed decisions on the selection of a model along with its associated parameters. Discussions are supported by simulation results to help highlight the main issues in the implementation of these methods. PMID- 26525831 TI - Visfatin: New marker of oxidative stress in preterm newborns. AB - BACKGROUND: Oxidative stress is involved in several neonatal conditions characterized by an upregulation in the production of oxidative or nitrative free radicals and a concomitant decrease in the availability of antioxidant species. Oxygen, which is obviously vital to survival, can be highly damaging to neonatal tissue which is known to be poorly equipped to neutralize toxic derivatives. Thus, exposure of the newborn infant to high oxygen concentrations during resuscitation at birth increases oxidative damage. Visfatin is an adipocytokine involved in oxidative stress and an important mediator of inflammation that induces dose-dependent production of both pro-inflammatory and anti-inflammatory cytokines. To our knowledge, the diagnostic value of visfatin as a marker of oxidative stress in preterm newborns has not been investigated. OBJECTIVE: The aim of this study was to evaluate visfatin levels in preterm neonates resuscitated with different concentrations of oxygen in the delivery room. PATIENTS: Fifty-two preterm newborns with gestational age less than 32 weeks, resuscitated randomly with different oxygen concentrations (40%, 60%, or 100%) were enrolled at the University Hospital of Messina, over a 12-month period to evaluate serum visfatin levels at T0 (within 1 h after birth), T24 h, T72 h, and T168 h of life. RESULTS: At T72 h and T168 h, higher serum visfatin values in the high-oxygen group compared to the low- and mild-oxygen subjects (P=0.002 and P<0.001, respectively) were noted. CONCLUSION: The results of this study suggest that visfatin could be a new marker of oxidative stress in preterm newborns. PMID- 26525832 TI - The Merli-Missiroli-Pozzi Two-Slit Electron-Interference Experiment. AB - In 2002 readers of Physics World voted Young's double-slit experiment with single electrons as "the most beautiful experiment in physics" of all time. Pier Giorgio Merli, Gian Franco Missiroli, and Giulio Pozzi carried out this experiment in a collaboration between the Italian Research Council and the University of Bologna almost three decades earlier. I examine their experiment, place it in historical context, and discuss its philosophical implications. PMID- 26525833 TI - Pretreatment or Posttreatment with Aripiprazole Attenuates Methamphetamine induced Stereotyped Behavior in Mice. AB - Aripiprazole is a third-generation atypical antipsychotic and a dopamine D2 receptor partial agonist. In the present study, we investigated whether a single administration of aripiprazole to mice, either as a pretreatment or as a posttreatment, would affect stereotypy induced by methamphetamine (METH). Pretreatment of male ICR mice with aripiprazole (1 or 10 mg/kg, i.p.) attenuated the incidence of METH-induced stereotypical behavior in a dose-dependent manner. Pretreatment of mice with 1 mg/kg aripiprazole produced an increase in the locomotor activity in mice treated with METH compared with mice treated with vehicle plus METH and with 10 mg/kg aripiprazole plus METH. This increase in locomotion is indicative of a rightward shift in the dose-response curve for METH, consistent with a shift in the type of stereotypical behavior observed from biting to sniffing. Aripiprazole posttreatment, after METH-induced stereotypical behavior, was fully expressed and also significantly attenuated overall stereotypy in an aripiprazole dose-dependent manner. These data suggest that the antagonism of METH effects by aripiprazole should be investigated as a potential treatment for acute METH overdose. PMID- 26525834 TI - Cytotoxicity of a New Nano Zinc-Oxide Eugenol Sealer on Murine Fibroblasts. AB - INTRODUCTION: The aim of this study was to evaluate the cytotoxicity of a new nano zinc-oxide eugenol (NZOE) sealer in comparison with AH-26 and Pulpdent root canal sealers. METHODS AND MATERIALS: The L929 mouse fibroblast cells were cultivated and incubated for 24, 48 or 72 h with different dilutions (1/1, 1/2, 1/4, 1/8, 1/16 and 1/32) of culture media previously exposed to either of the test sealers naming NZOE, AH-26 or Pulpdent. At the end of incubation period, the effect of sealers on cell viability was evaluated using Mosmann's Tetrazolium Toxicity (MTT) colorimetric assay. The data was compared using the one-way analysis of variance (ANOVA) followed by the Tukey's post hoc test for multiple comparisons. RESULTS: After 24, 48 or 72 h, both NZOE and Pulpdent sealers inhibited cell viability at 1/1, 1/2 and 1/8 dilutions. Within the 24 and 48 h, the AH-26 sealer reduced the cell viability at all dilutions except the 1/32 solution; however after 72 h even the 1/32 dilution was cytotoxic. CONCLUSION: The biocompatibility of the nano zinc-oxide eugenol sealer was comparable to Pulpdent sealer and lower than AH-26. PMID- 26525835 TI - Cardiovascular training vs. resistance training for improving quality of life and physical function in patients with systemic lupus erythematosus: a randomized controlled trial. AB - OBJECTIVES: To compare the efficacy of cardiovascular training (CT) with resistance training (RT) in improving the health-related quality of life (HRQoL) and physical function of patients with systemic lupus erythematosus (SLE). METHOD: A randomized controlled trial was conducted with participants randomly allocated to either a CT (n = 21), RT (n = 21), or control group (n = 21). The outcomes assessed were: HRQoL using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), severity of depression using the Beck Depression Inventory (BDI), disease activity using the SLE Disease Activity Index (SLEDAI), and aerobic capacity using a 12-minute walk test (T12). RESULTS: Sixty-three patients (61 women and two men), aged 42.9 +/- 14.4 years, with a mean body mass index (BMI) of 28.7 +/- 10.6 kg/m(2), disease duration of 3.8 +/- 3.3 years, and not physically active participated in the study. HRQoL improved for both exercise groups but was superior in the RT group. There was no significant difference in physical function between the intervention groups, except for aerobic capacity. Neither training programme was associated with a change in disease activity. CONCLUSIONS: Exercise intervention proved to be better than not exercising. CT was better than RT in improving HRQoL. PMID- 26525836 TI - The evaluation of enteric-coated mycophenolate sodium in cardiac deceased donor liver transplant patients in China. AB - OBJECTIVE: The management of liver receivers requires intense immunosuppression to prevent graft rejection. Mycophenolate mofetil (MMF) is a common immunosuppressant but frequently suffer dose reduction for gastrointestinal adverse reactions (GI). Hence, the enteric-coated mycophenolate sodium (EC-MPS) is introduced as a substitute for MMF to reduce GI. The study was designed to investigate the efficacy, safety and exposure equation of EC-MPS in liver transplant patients in China. METHODS: Ninety-two liver receivers who administered EC-MPS or MMF as a primary immunosuppressant were enrolled in this single-center study and divided into MMF group and EC-MPC group, respectively. Efficacy and safety of EC-MPS were compared with MMF. The MPA exposure was measured at time 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 h after mean 4.5 days of EC MPS treatment. An equation of limited time points for estimating serum MPA exposure of EC-MPS was established using multiple stepwise regression model. RESULTS: Data show an interpatient variation in MPA AUC, Cmax and Tmax. After a first dose of EC-MPS, the mean value of serum AUC0-12 h was 20.68 mg/L (SD 8.94, range 8.1-46.3). Cmax was 9.7 mg/L (SD 6.48, range 2.7-16.3); Tmax was 1.90 h (SD 0.97, range 0.5-4). The best equation for estimating the AUC was 6.0 1 4 + 0.946C2 + 0.606C3 + 1.154C4 + 2.479C6 + 5.07C12. Comparing with MMF, EC-MPS not only effectively maintained immunosuppression, but also had similar incidences of infection, renal dysfunction and hematological disorders. However, EC-MPS markedly improved GI, the incidence of GI was half of the MMF group. CONCLUSION: This analysis presented that EC-MPS is an effective and safe immunosuppressant as similar as MMF. The conversion of MMF to EC-MPS could be administered. PMID- 26525837 TI - The Effects of Focal Therapy for Prostate Cancer on Sexual Function: A Combined Analysis of Three Prospective Trials. AB - BACKGROUND: Tissue preservation by means of focal therapy offers some men with clinically significant prostate cancer an alternative to standard care that appears to confer favourable genito-urinary outcomes. The precise estimates of these outcomes have so far been based on small series. OBJECTIVE: This analysis pools the sexual domain related patient reported outcomes from three prospective, registered studies that represent a range of inclusion criteria. DESIGN, SETTING, AND PARTICIPANTS: One-hundred and eighteen men with localised prostate cancer (prostate specific antigen <= 15ng/ml, Gleason <= 4+3, stage <= T3aN0M0) treated in a tissue-preserving manner using high intensity focused ultrasound from three registered studies were included. Data on International Index of Erectile Function (IIEF-5) scores and use of phosphodiesterase-5-inhibitors were collected at baseline, and 1 mo, 3 mo, 6 mo, 9 mo, and 12 mo postoperatively. The IIEF-15 total and individual domain scores were used to assess overall sexual function. Urinary function was assessed with the International Prostate Symptom Score (IPSS), IPSS quality-of-life, and UCLA-Expanded Prostate Cancer Index Composite continence questionnaires. General health status was derived by means of the Charlson score. Multiple linear regression was used to assess whether age, grade, stage, qualitative scores (IIEF, IPSS, Expanded Prostate Cancer Index Composite, Charlson), or focal therapy type duration were associated with IIEF-5 and IIEF-15 scores at 12 mo. RESULTS AND LIMITATIONS: Median age was 63 yr (interquartile range [IQR] 52-70 yr). Median IIEF-erectile score at baseline was 23 (IQR 11-28). This declined significantly to 9 (IQR 3-22, p<0.01) at 1 mo, but improved to 20 (IQR 9-29, p=0.30) at 1 yr posttreatment. Changes in total IIEF and other IIEF domains were only significantly different from preoperative values at 1 mo and 3 mo postoperatively. In the same period, the proportion of men using phosphodiesterase-5-inhibitors was 10% preoperatively, reaching 43% and 42% at 6 mo and 9 months before declining to 37% at 1 yr. The only baseline determinants of postoperative erectile function were total IIEF and IIEF-erectile function scores (p=0.002). The primary limitation of our study is the relatively short follow-up of 1 yr. CONCLUSION: Men who received a range of tissue preserving therapies from the three pertinent studies experienced small decreases in total IIEF, erectile, and individual sexual domain scores that are not significantly different to those recorded at baseline. The only determinant of erectile dysfunction after tissue preserving therapy was preoperative erectile dysfunction status. Tissue preservation confers a high probability of maintaining erectile function that appears independent of all perioperative factors with the exception of baseline status. PATIENT SUMMARY: In this report, the largest prospectively collected and published set of patients with erectile dysfunction outcomes post focal therapy for prostate cancer, we have found a return to baseline International Index of Erectile Function-erectile and total International Index of Erectile Function scores by 6 mo post-focal therapy which was maintained at 1 yr, with the majority of patients not on any form of medical treatment for their erectile dysfunction at that point. Focal therapy may represent a suitable alternative for men of any age or comorbidity wishing to maintain erectile function. PMID- 26525838 TI - Acute Kidney Injury after Partial Nephrectomy: Role of Parenchymal Mass Reduction and Ischemia and Impact on Subsequent Functional Recovery. AB - BACKGROUND: Acute increase of serum creatinine (SCr) after partial nephrectomy (PN) is primarily due to parenchymal mass reduction or ischemia; however, only ischemia can impact subsequent functional recovery. OBJECTIVE: We evaluate etiologies of acute kidney injury (AKI) after PN and their prognostic significance. DESIGN, SETTING, AND PARTICIPANTS: From 2007-2014, 83 solitary kidneys managed with PN had necessary studies for detailed analysis of function and parenchymal mass before/after surgery. AKI was classified by Risk/Injury/Failure/Loss/Endstage classification and defined by either standard criteria (comparison to preoperative SCr) or proposed criteria (comparison to projected postoperative SCr based on parenchymal mass reduction). Subsequent recovery was defined as percent function preserved/percent mass saved. INTERVENTION: PN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Predictive factors for AKI were evaluated by logistic regression. Relationship between AKI grade and subsequent functional recovery was assessed by linear regression. RESULTS AND LIMITATIONS: Median duration warm ischemia (n=39) was 20 min and hypothermia (n=44) was 29 min. Median parenchymal mass reduction was 11%. AKI occurred in 45 patients based on standard criteria and 38 based on proposed criteria, and reflected injury/failure (grade = 2/3) in 23 and 16 patients, respectively. On multivariable analysis, only ischemia time associated with AKI occurrence (p=0.016). Based on the proposed criteria, median recovery from ischemia was 99% in patients without AKI and 95%/90%/88% for patients with grades 1/2/3 AKI, respectively. The coefficient for association between AKI grade based on proposed criteria and subsequent functional recovery was -4.168 (p=0.018). Main limitation is limited patient cohort. CONCLUSIONS: Parenchymal mass reduction and ischemia both contribute to acute changes in SCr after PN. Classification of AKI by proposed criteria significantly associates with subsequent functional recovery. However, more robust numbers will be needed to further assess the merits of the proposed criteria. While AKI is associated with suboptimal recovery, even patients with grade 2/3 AKI reached 88-90% of recovery expected. PATIENT SUMMARY: Acute decline in function after partial nephrectomy associates with more prolonged ischemia time, and appears to impact subsequent functional recovery. However, most kidneys eventually recover strongly, even if their function is sluggish in the first few days after surgery. PMID- 26525839 TI - Size-adjusted Quantitative Gleason Score as a Predictor of Biochemical Recurrence after Radical Prostatectomy. AB - BACKGROUND: The risk of biochemical recurrence (BCR) following radical prostatectomy for pathologic Gleason 7 prostate cancer varies according to the proportion of Gleason 4 component. OBJECTIVE: We sought to explore the value of several novel quantitative metrics of Gleason 4 disease for the prediction of BCR in men with Gleason 7 disease. DESIGN, SETTING, AND PARTICIPANTS: We analyzed a cohort of 2630 radical prostatectomy cases from 1990-2007. All pathologic Gleason 7 cases were identified and assessed for quantity of Gleason pattern 4. Three methods were used to quantify the extent of Gleason 4: a quantitative Gleason score (qGS) based on the proportion of tumor composed of Gleason pattern 4, a size-weighted score (swGS) incorporating the overall quantity of Gleason 4, and a size index (siGS) incorporating the quantity of Gleason 4 based on the index lesion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between the above metrics and BCR were evaluated using Cox proportional hazards regression analysis. RESULTS AND LIMITATIONS: qGS, swGS, and siGS were significantly associated with BCR on multivariate analysis when adjusted for traditional Gleason score, age, prostate specific antigen, surgical margin, and stage. Using Harrell's c-index to compare the scoring systems, qGS (0.83), swGS (0.84), and siGS (0.84) all performed better than the traditional Gleason score (0.82). CONCLUSIONS: Quantitative measures of Gleason pattern 4 predict BCR better than the traditional Gleason score. PATIENT SUMMARY: In men with Gleason 7 prostate cancer, quantitative analysis of the proportion of Gleason pattern 4 (quantitative Gleason score), as well as size-weighted measurement of Gleason 4 (size-weighted Gleason score), and a size-weighted measurement of Gleason 4 based on the largest tumor nodule significantly improve the predicted risk of biochemical recurrence compared with the traditional Gleason score. PMID- 26525840 TI - Pax6 influences expression patterns of genes involved in neuro- degeneration. AB - BACKGROUND: Pax6, a highly conserved multifunctional transcription factor, has been critical for neurogenesis and neuronal plasticity. It is presumed that if level of Pax6 approaches either low or null, critical genes responsible for maintaining functional status of neurons or glia would be modulated. PURPOSE: Therefore, it has been intended to explore possibility of either direct or indirect influence of Pax6 in neurodegeneration. METHODS: The cell lines having origin of murine embryonic fibroblast (Pax6-non expressing, NIH3T3-cell line), murine neuroblastoma (Pax6-expressing brain-derived, Neuro-2a-cell line), and human glioblastoma-astrocytoma (U87MG) were cultured and maintained in a CO2 incubator at 37 degrees C and 5% CO2 in DMEM containing 10% fetal bovine serum. The knockdown of endogenous Pax6 in Neuro-2a cells was achieved through siRNA based gene knock-down approach. The efficiency and validation of knock-down was done by real time PCR. The knock-down of Pax6 was successfully achieved. RESULTS: The levels of expression of transcripts of some of the proposed putative markers of neurodegeneration like Pax6, S100beta, GFAP, BDNF, NGN2, p73alpha, p73delta, LDH, SOD, and Catalase were analyzed in Pax6 knockdown condition for analysis of role of Pax6 in neurodegeneration. Since the Pax6 has been proposed to bind to promoter sequences of catalase, and catalase suppresses TGFbeta, relative lower levels of catalase in Neuro-2a and U-87MG as compared to NIH-3T3 indicates a possible progressive dominant negative impact of Pax6. However, presence of SOD and LDH indicates alternative protective mechanism. CONCLUSION: Presence of BDNF and TGFbeta indicates association between them in glioblastoma-astrocytoma. Therefore, Pax6 seems to be involved directly with p53 and TGFbeta mediated pathways and indirectly with redox-sensitive pathway regulation. The neurodegenerative markers S100beta, GFAP, BDNF, NGN2, p73alpha, p73delta, observed downregulated in Pax6 knockdown condition suggest Pax6-mediated regulation of these markers. Observations enlighten Pax6-mediated influences on cascades of genes involved in growth, differentiation and maturation of neurons and glia. PMID- 26525841 TI - Dynamic nano-imaging of label-free living cells using electron beam excitation assisted optical microscope. AB - Optical microscopes are effective tools for cellular function analysis because biological cells can be observed non-destructively and non-invasively in the living state in either water or atmosphere condition. Label-free optical imaging technique such as phase-contrast microscopy has been analysed many cellular functions, and it is essential technology for bioscience field. However, the diffraction limit of light makes it is difficult to image nano-structures in a label-free living cell, for example the endoplasmic reticulum, the Golgi body and the localization of proteins. Here we demonstrate the dynamic imaging of a label free cell with high spatial resolution by using an electron beam excitation assisted optical (EXA) microscope. We observed the dynamic movement of the nucleus and nano-scale granules in living cells with better than 100 nm spatial resolution and a signal-to-noise ratio (SNR) around 10. Our results contribute to the development of cellular function analysis and open up new bioscience applications. PMID- 26525842 TI - Editorial: IFN-beta immunomodulation: a tail of two STATS. PMID- 26525843 TI - Editorial: Tweaking T cell receptor signaling thresholds through DAG: the role of diacylglycerol kinase zeta in T cell responses to TGF-beta. PMID- 26525844 TI - Non-linear retinal processing supports invariance during fixational eye movements. AB - Fixational eye movements can rapidly shift the retinal image, but typically remain unnoticed. We identify and simulate a model mechanism for the suppression of erroneous motion signals under fixational eye movements. This mechanism exploits the non-linearities common to many classes of large retinal ganglion cells in the mammalian retina, and negates the need for extra-retinal signals or explicit gaze information. When tested using natural images undergoing simulated fixational eye movements, our model successfully distinguishes "real world" motion from retinal motion induced by eye movements. In addition, this model suggests a possible explanation for several fixational eye movement related visual illusions such as the Ouchi-Spillmann and "Out-of-focus" illusions. PMID- 26525845 TI - Gestalt-like constraints produce veridical (Euclidean) percepts of 3D indoor scenes. AB - This study, which was influenced a lot by Gestalt ideas, extends our prior work on the role of a priori constraints in the veridical perception of 3D shapes to the perception of 3D scenes. Our experiments tested how human subjects perceive the layout of a naturally-illuminated indoor scene that contains common symmetrical 3D objects standing on a horizontal floor. In one task, the subject was asked to draw a top view of a scene that was viewed either monocularly or binocularly. The top views the subjects reconstructed were configured accurately except for their overall size. These size errors varied from trial to trial, and were shown most-likely to result from the presence of a response bias. There was little, if any, evidence of systematic distortions of the subjects' perceived visual space, the kind of distortions that have been reported in numerous experiments run under very unnatural conditions. This shown, we proceeded to use Foley's (Vision Research 12 (1972) 323-332) isosceles right triangle experiment to test the intrinsic geometry of visual space directly. This was done with natural viewing, with the impoverished viewing conditions Foley had used, as well as with a number of intermediate viewing conditions. Our subjects produced very accurate triangles when the viewing conditions were natural, but their performance deteriorated systematically as the viewing conditions were progressively impoverished. Their perception of visual space became more compressed as their natural visual environment was degraded. Once this was shown, we developed a computational model that emulated the most salient features of our psychophysical results. We concluded that human observers see 3D scenes veridically when they view natural 3D objects within natural 3D environments. PMID- 26525847 TI - Pulmonary Metastases from NSCLC and MPLC (Multiple Primary Lung Cancers): Management and Outcome in a Single Centre Experience. AB - BACKGROUND: This is an institutional review of surgical management of second pulmonary tumours in patients with history of Non-small Cell Lung Cancer (NSCLC) resection according to The American College of Chest Physicians' (ACCP) revision to the Martini and Melamed's criteria for the classification of multiple primary lung cancers (MPLC). METHODS: All patients who underwent iterative pulmonary resections for pulmonary metastasis (Group A) or MPLC (Group B) between 2006 and 2012 were reviewed and their survivals compared accordingly. The main criteria of insertion in Group B were different histology and the same histology with disease free interval <= 4 years; we excluded loco-regional recurrence in nodes and/or on bronchial stump. RESULTS: Group A: Twenty patients; Disease free time (DFT) after first operation was 15.2 months (range 2-44). One, two and three years overall survival after second resection was 74%, 29%, 14% respectively. Group B: Thirty six patients. One, two and three years overall survival was 94%, 81%, and 69% respectively. No statistical differences on outcome were found between the two groups in spite of the apparent worse survival rate for Group A (p=.197). CONCLUSIONS: A further resection for additional nodules, whether designated as intrapulmonary metastases or second primary NSCLC, can be an appropriate curative strategy in selected patients with unimpaired respiratory function and no evidence of distant metastatic disease. The site, the extent of the second resection, the histology and even the stage are unlikely to be related to survival. PMID- 26525846 TI - Cost-effectiveness of nonsteroidal anti-inflammatory drugs and opioids in the treatment of knee osteoarthritis in older patients with multiple comorbidities. AB - OBJECTIVE: To evaluate long-term clinical and economic outcomes of naproxen, ibuprofen, celecoxib or tramadol for OA patients with cardiovascular disease (CVD) and diabetes. DESIGN: We used the Osteoarthritis Policy Model to examine treatment with these analgesics after standard of care (SOC) - acetaminophen and corticosteroid injections - failed to control pain. NSAID regimens were evaluated with and without proton pump inhibitors (PPIs). We evaluated over-the-counter (OTC) regimens where available. Estimates of treatment efficacy (pain reduction, occurring in ~57% of patients on all regimens) and toxicity (major cardiac or gastrointestinal toxicity or fractures, risk ranging from 1.09% with celecoxib to 5.62% with tramadol) were derived from published literature. Annual costs came from Red Book Online((r)). Outcomes were discounted at 3%/year and included costs, quality-adjusted life expectancy, and incremental cost-effectiveness ratios (ICERs). Key input parameters were varied in sensitivity analyses. RESULTS: Adding ibuprofen to SOC was cost saving, increasing QALYs by 0.07 while decreasing cost by $800. Incorporating OTC naproxen rather than ibuprofen added 0.01 QALYs and increased costs by $300, resulting in an ICER of $54,800/QALY. Using prescription naproxen with OTC PPIs led to an ICER of $76,700/QALY, while use of prescription naproxen with prescription PPIs resulted in an ICER of $252,300/QALY. Regimens including tramadol or celecoxib cost more but added fewer QALYs and thus were dominated by several of the naproxen-containing regimens. CONCLUSIONS: In patients with multiple comorbidities, naproxen- and ibuprofen containing regimens are more effective and cost-effective in managing OA pain than opioids, celecoxib or SOC. PMID- 26525848 TI - The Relationship between Galectin-3 and Different Patterns of Ventricular Geometry Remodelling in Aortic Valve Stenosis. AB - BACKGROUND: This study was conducted to assess expression of Galectin-3 (Gal-3) in patients with different types of left ventricle (LV) hypertrophy geometry, and the relationship between Gal-3 expression and LV remodelling in patients with aortic valve stenosis (AS). METHODS: Galectin-3 expression was measured in the plasma and myocardia of AS patients who underwent an aortic valve replacement procedure. RESULTS: The study enrolled 77 consecutive patients with severe AS. Fifty-five (71.43%) of the enrolled patients had concentric hypertrophy (CH group), and had the highest degree of fibrosis (27.10+/-5.25%; p<0.001) and expression of Gal-3 in both plasma (19.11+/-2.06 ng/mL) and myocardial tissue (3.01+/-0.79). There was a strong positive correlation between the levels of fibrosis and Gal-3 expression in both plasma (r=0.584, p<0.001) and myocardium (r=0.522, p<0.001). Relative wall thickness (RWT) was strongly correlated with Gal-3 expression in both myocardium (r=0.594, p<0.001) and plasma (r=0.323, p=0.005). Additionally, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were positively correlated with both fibrosis (r=0.313, p=0.036) and LV mass index (r=0.559, p<0.001). CONCLUSIONS: Concentric hypertrophy geometry was the most common type of myocardium remodelling, and AS patients with CH geometry showed the highest levels of Gal-3 expression. Galectin-3 levels were positively correlated with fibrosis and RWT, both of which are crucial indicators of geometric remodelling. Galectin-3 and NT-proBNP levels may be valuable prognostic predictors in AS patients with myocardial remodelling. PMID- 26525849 TI - Switching from usual brand cigarettes to a tobacco-heating cigarette or snus: Part 1. Study design and methodology. AB - A randomized, multi-center study was conducted to assess potential improvement in health status measures, as well as changes in biomarkers of tobacco exposure and biomarkers of biological effect, in current adult cigarette smokers switched to tobacco-heating cigarettes, snus or ultra-low machine yield tobacco-burning cigarettes (50/group) evaluated over 24 weeks. Study design, conduct and methodology are presented here along with subjects' disposition, characteristics, compliance and safety results. This design and methodology, evaluating generally healthy adult smokers over a relatively short duration, proved feasible. Findings from this randomized study provide generalized knowledge of the risk continuum among various tobacco products (ClinicalTrials.gov Identifier: NCT02061917). PMID- 26525851 TI - WITHDRAWN: Identification of an antimycin gene cluster and characterization of the tryptophan 2,3-dioxygenase from the deep sea-derived Streptomyces somaliensis HND1201. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26525850 TI - Deregulation of energy metabolism promotes antifibrotic effects in human hepatic stellate cells and prevents liver fibrosis in a mouse model. AB - Liver fibrosis and cirrhosis result from uncontrolled secretion and accumulation of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) that are activated by liver injury and inflammation. Despite the progress in understanding the biology liver fibrogenesis and the identification of potential targets for treating fibrosis, development of an effective therapy remains elusive. Since an uninterrupted supply of intracellular energy is critical for the activated-HSCs to maintain constant synthesis and secretion of ECM, we hypothesized that interfering with energy metabolism could affect ECM secretion. Here we report that a sublethal dose of the energy blocker, 3-bromopyruvate (3-BrPA) facilitates phenotypic alteration of activated LX-2 (a human hepatic stellate cell line), into a less-active form. This treatment-dependent reversal of activated-LX2 cells was evidenced by a reduction in alpha-smooth muscle actin (alpha-SMA) and collagen secretion, and an increase in activity of matrix metalloproteases. Mechanistically, 3-BrPA-dependent antifibrotic effects involved down-regulation of the mitochondrial metabolic enzyme, ATP5E, and up-regulation of glycolysis, as evident by elevated levels of lactate dehydrogenase, lactate production and its transporter, MCT4. Finally, the antifibrotic effects of 3-BrPA were validated in vivo in a mouse model of carbon tetrachloride-induced liver fibrosis. Results from histopathology & histochemical staining for collagen and alpha-SMA substantiated that 3-BrPA promotes antifibrotic effects in vivo. Taken together, our data indicate that sublethal, metronomic treatment with 3-BrPA blocks the progression of liver fibrosis suggesting its potential as a novel therapeutic for treating liver fibrosis. PMID- 26525852 TI - Affinity of the heparin binding motif of Noggin1 to heparan sulfate and its visualization in the embryonic tissues. AB - Heparin binding motifs were found in many secreted proteins and it was suggested that they are responsible for retardation of the protein diffusion within the intercellular space due to the binding to heparan sulfate proteoglycanes (HSPG). Here we used synthetic FITC labeled heparin binding motif (HBM peptide) of the Xenopus laevis secreted BMP inhibitor Noggin1 to study its diffusion along the surface of the heparin beads by FRAP method. As a result, we have found out that diffusivity of HBM-labeled FITC was indeed much lesser than those predicted by theoretical calculations even for whole protein of the Noggin size. We also compared by isothermal titration calorimetry the binding affinity of HBM and the control oligolysine peptide to several natural polyanions including heparan sulfate (HS), heparin, the bacterial dextran sulfate and salmon sperm DNA, and demonstrated that HBM significantly exceeds oligolysine peptide in the affinity to HS, heparin and DNA. By contrast, oligolysine peptide bound with higher affinity to dextran sulfate. We speculate that such a difference may ensure specificity of the morphogen binding to HSPG and could be explained by steric constrains imposed by different distribution of the negative charges along a given polymeric molecule. Finally, by using EGFP-HBM recombinant protein we have visualized the natural pattern of the Noggin1 binding sites within the X. laevis gastrula and demonstrated that these sites forms a dorsal-ventral concentration gradient, with a maximum in the dorsal blastopore lip. In sum, our data provide a quantitative basis for modeling the process of Noggin1 diffusion in embryonic tissues, considering its interaction with HSPG. PMID- 26525853 TI - Enzymatic fragments of hyaluronan inhibit adipocyte differentiation in 3T3-L1 pre adipocytes. AB - Hyaluronan has diverse biological activities depending on its molecular size. High molecular weight hyaluronan (2000 kDa) is a major component of extracellular matrix, and has been used in wounding healing, extracellular matrix regeneration, and in the treatment of osteoarthritis. Hyaluronan fragments can stimulate inflammation or induce loss of extracellular matrix. Hyaluronan is expressed during adipocyte differentiation, and down regulation of hyaluronan synthesis can reduce adipogenic differentiation. However, the direct effects of hyaluronan fragments on adipocyte differentiation have not been elucidated. Therefore, we prepared hyaluronan fragments by enzymatic digestion, and examined the inhibitory effects of these hyaluronan fragments on the accumulation of lipid droplets and on adipogenic gene mRNA expression in differentiating 3T3-L1 pre-adipocytes. Medium sized hyaluronan fragments (50 kDa) decreased lipid droplet accumulation in a dose-dependent manner. However, high molecular weight hyaluronan did not inhibit lipid droplet accumulation when used at a concentration of 600 MUg/ml. Two or 4 day treatments with medium molecular weight of hyaluronan resulted in similar inhibitory levels of lipid accumulation as did treatment for 8 days. Medium sized hyaluronan inhibited the differentiation of 3T3-L1 pre-adipocytes during the early stages of adipogenesis. When 3T3-L1 cells were treated with 180 MUg/ml of medium sized hyaluronan, the mRNAs for the master adipogenic transcription factors PPAR-gamma and C/EBP-alpha were inhibited. Additionally, medium molecular weight hyaluronan suppressed mRNA expression of PPAR-gamma target genes, including aP2 and FAS. This study is the first to report that medium molecular weight hyaluronan fragments can inhibit adipocyte differentiation. PMID- 26525854 TI - [Prevalence of experience of physical and psychological violence in the general population in the past 12 months. Results of the German Health Interview and Examination Survey for Adults (DEGS1)]. AB - Experiences of violence may have considerable psychosocial and health implications. A violence screening tool was implemented in the German Health Interview and Examination Survey for Adults (DEGS1) to depict the perpetrators' and victims' point of view. The study participants were between 18 and 64 years old (n = 5939). The aim of this article is to assess the percentage of people who experienced physical and psychological violence in the last 12 months or who suffered negative effects on their quality of life as a consequence or who were perpetrators of multiple acts of violence. The characteristics of victims, offenders, and their conflict partners are described. Furthermore, specific constellations of violence experience with regard to health-related quality of life are described. Finally, the association between being a victim of violence and different factors is estimated. In total, 2.7% of women and 4.3% of men reported multiple experiences of physical violence in the last 12 months or having their lives negatively impacted as a consequence of violence. Experience of psychological violence was reported by 18.9% of women and 15.4% of men. Women are more likely than men to be both perpetrator and victim within the family. Men are more likely than women to be both the perpetrator and victim outside of the family environment. Regardless of whether they are the victim or perpetrator of violence, the psychological well-being is significantly worse than those of people who did not experience violence. Experience of violence in childhood and adolescence increases the risk of becoming victim or perpetrator of violence later on in life. The findings presented here describe the psychological and physical experience of violence as one part of violence committed in the whole population. Some prevention advice is also presented. PMID- 26525855 TI - Evaluations of intergroup resource allocations: The role of theory of mind. AB - The purpose of this study was to investigate the relations between children's social cognitive skills and their evaluations of resource allocations in intergroup contexts (N=73, 3-6years of age). Participants evaluated three snack time resource allocation scenarios (self-disadvantaged, self-advantaged, and other-disadvantaged) in either a school ingroup or outgroup context. They evaluated the acceptability of the resource allocation and provided reasoning about their evaluation. Participants who had false belief theory of mind (FB ToM) competence were more likely than participants who did not have FB ToM to evaluate inequality as unacceptable. In addition, participants without FB ToM evaluated unequal allocations to another child as more okay in an outgroup condition than participants with FB ToM. Participants reasoned about their allocations differently depending on the context. Results reveal the importance of FB ToM for recognizing unfair resource allocations, especially in intergroup contexts. PMID- 26525856 TI - Legally flawed, scientifically problematic, potentially harmful: The UK Psychoactive Substance Bill. PMID- 26525858 TI - Antibiotics for acute pyelonephritis in children. PMID- 26525857 TI - Confirming the theoretical structure of expert-developed text messages to improve adherence to anti-hypertensive medications. AB - BACKGROUND: Text messages can improve medication adherence and outcomes in several conditions. For this study, experts developed text messages addressing determinants of medication adherence: disease beliefs, medication necessity, medication concerns, and forgetfulness, as well as positive reinforcement messages for patients who were adherent. OBJECTIVES: To validate expert-developed text messages to address medication non-adherence with a group of non researchers. METHODS: A two-wave, card-sorting activity was conducted with students and staff at the University of Michigan. In the first wave, 40 participants grouped 32 messages addressing barriers for medication adherence (disease beliefs, medication necessity, medication concerns, and forgetfulness) according to their perceived relationship. Messages with poor grouping agreement were deleted or modified. In the second wave, positive reinforcement messages were developed and tested along with the previous categories (36 messages) by 37 participants. Similarity and cluster analyses were used to assess agreement between experts and participants. RESULTS: In the first card-sorting wave, participants grouped messages into between 2 and 13 separate categories. Similarity analysis showed four groupings of messages, however, some had an agreement below 50% and clusters appeared dispersed. In the second wave, and after messages being edited, participants grouped the messages into between 4 and 9 categories. Five groups (now including positive reinforcement messages) were identified with higher agreement in the similarity and cluster analyses. CONCLUSIONS: The structure of expert-developed text messages to address medication adherence key barriers was confirmed. Messages will be used in future research to determine their impact on affecting medication adherence to anti hypertensive medications using a reinforcement learning controlled text messaging service. PMID- 26525859 TI - Trends in PET Scan Usage for Imaging of Patients Diagnosed With Nonmetastatic Urologic Cancer. AB - The precise utility of positron emission tomography (PET) scanning for urologic cancers is not well defined. We examined the trends of usage in a population based data set. PET scans were performed in 3.60% of patients with bladder cancer, 1.09% of those with prostate cancer, and 5.32% of those with renal cell carcinoma. This selective usage might be driven by reimbursement constraints or identification of appropriate medical indications. INTRODUCTION: Positron emission tomography (PET) scanning is increasingly being used for imaging a variety of cancers, including urologic cancers. The precise utility of PET scanning for bladder cancer, prostate cancer, and renal cell carcinoma (RCC) is not yet well known. We examined the trends in PET scan usage for 3 cancers using a large population-based data set. MATERIALS AND METHODS: We analyzed all individuals identified with a diagnosis of nonmetastatic bladder cancer, prostate cancer, and RCC from the Surveillance, Epidemiology, and End Results-Medicare data set for 2004 to 2009 with follow-up data available to 2010. Logistic regression analysis and chi(2) and trend tests were performed to determine the predictors of performing PET scanning. Separate models were run for each of the cancer diagnoses. All analyses were performed using SAS, version 9.3, and P < .05 was considered significant. RESULTS: We identified 20,865, 70,414, and 7007 patients with a diagnosis of bladder cancer, prostate cancer, and RCC, respectively, from 2004 to 2009. PET scans had been performed for 3.60% of patients with bladder cancer, 1.09% of those with prostate cancer, and 5.32% of those with RCC. On regression analysis, a more recent year of diagnosis, younger age, and high stage or grade were predictors of PET scan usage for patients with bladder cancer and RCC. A higher Gleason score and higher D'Amico risk group predicted imaging with prostate cancer. CONCLUSION: The usage of PET scanning for bladder cancer, prostate cancer, and RCC is increasing but still very selective. The selective use might be driven by a combination of reimbursement constraints and careful identification of the appropriate medical indication. PMID- 26525860 TI - A bio-economic analysis of harvest control rules for the Northeast Arctic cod fishery. AB - Harvest control rules (HCRs) have been implemented for many fisheries worldwide. However, in most instances, those HCRs are not based on the explicit feedbacks between stock properties and economic considerations. This paper develops a bio economic model that evaluates the HCR adopted in 2004 by the Joint Norwegian Russian Fishery Commission to manage the world's largest cod stock, Northeast Arctic cod (NEA). The model considered here is biologically and economically detailed, and is the first to compare the performance of the stock's current HCR with that of alternative HCRs derived with optimality criteria. In particular, HCRs are optimized for economic objectives including fleet profits, economic welfare, and total yield and the emerging properties are analyzed. The performance of these optimal HCRs was compared with the currently used HCR. This paper show that the current HCR does in fact comes very close to maximizing profits. Furthermore, the results reveal that the HCR that maximizes profits is the most precautionary one among the considered HCRs. Finally, the HCR that maximizes yield leads to un-precautionary low levels of biomass. In these ways, the implementation of the HCR for NEA cod can be viewed as a success story that may provide valuable lessons for other fisheries. PMID- 26525861 TI - Lipophilic vancomycin aglycon dimer with high activity against vancomycin resistant bacteria. AB - Antibiotic-resistant superbugs such as vancomycin-resistant Enterococci (VRE) and Staphylococci have become a major global health hazard. To address this issue, we synthesized vancomycin aglycon dimers to systematically probe the impact of a linker on biological activity. A dimer having a pendant lipophilic moiety in the linker showed ~300-fold more activity than vancomycin against VRE. The high activity of the compound is attributed to its enhanced binding affinity to target peptides which resulted in improved peptidoglycan (cell wall) biosynthesis inhibition. Therefore, our studies suggest that these compounds, prepared by using facile synthetic methodology, can be used to combat vancomycin-resistant bacterial infections. PMID- 26525862 TI - An abietane diterpene from Salvia cuspidata and some new derivatives are active against Trypanosoma cruzi. AB - The Plant Kingdom is an excellent source for obtaining natural compounds with antiprotozoal activity. In the present work, we studied the effect of the diterpene 12-hydroxy-11,14-diketo-6,8,12-abietatrien-19,20-olide (HABTO) obtained from the aerial parts of Salvia cuspidata on Trypanosoma cruzi epimastigotes. This compound was found to inhibit parasite growth even at low concentrations (IC50 5 MUg/mL) and with low toxicity on mammalian cells. In addition, this diterpene induced an intense vacuolization within the parasites. In order to obtain analogs with greater lipophilicity, chemical modifications on the enol moiety were carried out to obtain the acetyl (AABTO), the sylil (SABTO) and the allyl (ALLABTO) derivatives. We observed that the SABTO was the most effective one on the parasites, and the effect could be attributed to a greater lipophilicity of this compound. Taking into account these data we conclude that the increase of lipophilicity by chemical modifications is an adequate strategy for improving the trypanocidal activity of this kind abietane diterpenes. PMID- 26525863 TI - Anion and sulfonamide inhibition studies of an alpha-carbonic anhydrase from the Antarctic hemoglobinless fish Chionodraco hamatus. AB - An alpha-carbonic anhydrase (CA, EC 4.2.1.1) has been purified from the Antarctic hemoglobinless fish Chionodraco hamatus (icefish). The new enzyme, denominated ChaCA, has a good catalytic activity for the physiologic CO2 hydration to bicarbonate reaction, similar to that of the low activity human isoform hCA I, with a kcat of 5.3*10(5) s(-1), and a kcat/Km of 3.7*10(7) M(-1) s(-1). The enzyme was inhibited in the submillimolar range by most inorganic anions (cyanate, thiocyanate, cyanide, bicarbonate, halides), whereas sulfamide, sulfamate, phenylboronic/phenylarsonic acids were micromolar inhibitors, with KIs in the range of 9-77 MUM. Many clinically used drugs, such as acetazolamide, methazolamide, dorzolamide, brinzolamide, topiramate and benzolamide were low nanomolar inhibitors, with KIs in the range of 39.1-77.6 nM. As the physiology of CO2/bicarbonate transport or the Root effect in this Antarctic fish are poorly understood at this moment, such inhibition data may give a more detailed insight in the role that CAs play in these phenomena, by the use of inhibitors described here as physiologic tools. PMID- 26525864 TI - Solid-supported reagents composed of a copolymer possessing 2-O-sulfonyl mannosides and phase-transfer catalysts for the synthesis of 2-fluoroglucose. AB - We described the synthesis of a solid-supported co-polymer possessing mannosides and phase-transfer catalysts and synthesis of 2-fluoroglucoside from it. We first prepared a soluble copolymer from two allene monomers possessing a precursor for the synthesis of 2-fluoroglycose and a crown ether. The copolymerization of the monomers via the pi-ally nickel-catalyst smoothly proceeded at room temperature to provide a desired copolymer without decomposition of the sulfonate esters. The copolymer exhibited high reactivity towards fluorination in comparison with a conventional precursor. We next synthesized the solid-supported copolymer by using the solid-supported initiator attached with TentaGel(r) resins. TentaGel(r) enabled polymerization under stirring with stirring bar without decomposition. The solid-supported copolymer exhibited comparable reactivity towards fluorination in comparison with the soluble copolymer. In addition, it can be easily separated from the reaction vessel by filtration. PMID- 26525865 TI - A selective delta opioid receptor antagonist based on a stilbene core. AB - Studies of directed ortho metalation reactions on an aromatic substrate with multiple potential directing groups have identified conditions that favor either of two regioisomers. One of these regioisomers has been converted to an analogue of the stilbene pawhuskin A, and been shown to have high selectivity as an antagonist of the delta opioid receptor. Docking studies have suggested that this compound can adopt a conformation similar to naltrindole, a known delta antagonist. PMID- 26525866 TI - A novel class of negative allosteric modulators of NMDA receptor function. AB - NMDA receptors mediate a slow Ca(2+)-permeable component of excitatory synaptic transmission, and are involved in numerous normal brain functions including learning and memory. NMDA receptor over-activation can lead to cell death and abnormal excitation in ischemia associated with stroke, traumatic brain injury, and epilepsy. We have explored a series of novel noncompetitive allosteric modulators of NMDA receptor function characterized by an iminothiazolidinone ring. Saturating concentrations of these compounds inhibit NMDA receptors to varying maximal extents, raising the possibility that they may attenuate over activation in pathological situations while preserving some minimal receptor function, which may limit side-effects. The best in class compounds have sub micromolar IC50 values and show modest preference for GluN2C- and GluN2D containing receptors. PMID- 26525867 TI - Outcomes of Mild to Moderate Functional Tricuspid Regurgitation in Patients Undergoing Mitral Valve Operations: A Meta-Analysis of 2,488 Patients. AB - This meta-analysis examined the prognosis of patients who were found to have mild to moderate functional tricuspid regurgitation during mitral valve operations. Overall, this meta-analysis included 2,488 patients in 10 studies. Compared with the group without tricuspid valve annuloplasty, the probability of not progressing to moderate to severe functional tricuspid regurgitation was significantly higher in the tricuspid valve annuloplasty group. A more aggressive surgical approach involving concomitant tricuspid repair with mitral valve operations may be considered to avoid the development of moderate to severe functional tricuspid regurgitation in the follow-up. PMID- 26525868 TI - Introduction to the STS National Database Series: Outcomes Analysis, Quality Improvement, and Patient Safety. AB - The Society of Thoracic Surgeons (STS) National Database is the foundation for most of the Society's quality, research, and patient safety activities. Beginning in January 2016 and repeating each year, The Annals of Thoracic Surgery will publish a monthly Database series of scholarly articles on outcomes analysis, quality improvement, and patient safety. Six articles will be directly derived from the STS National Database and will be published every other month: three articles on outcomes and quality (one each from the STS Adult Cardiac Surgery Database, the STS Congenital Heart Surgery Database, and the STS General Thoracic Surgery Database), and three articles on research (one from each of these three specialty databases). These six articles will alternate with five additional articles on topics related to patient safety. The final article, to be published in December, will provide a summary of the prior 11 manuscripts. This series will allow STS and its Workforces on National Databases, Research Development, and Patient Safety to convey timely information aimed at improving the quality and safety of cardiothoracic surgery. PMID- 26525869 TI - Timetable for oral prevention in childhood--developing dentition and oral habits: a current opinion. AB - As most of the etiologic factors of malocclusion are of genetic origin and thus cannot be prevented, environmental causative factors have become the focus for correction. Early interception of oral habits may be an important step in order to prevent occlusal disturbances in children. The identification of an abnormal habit and the assessment of its potential immediate and long-term effects on the dentition and potentially on the craniofacial complex should be made at an early stage. This paper focuses on the most common oral habits influencing dentofacial growth in childhood and management of these habits in the developing dentition. PMID- 26525871 TI - The size-structure of corals with contrasting life-histories: A multi-scale analysis across environmental conditions. AB - We report variation in the size-structure of three coral taxa in the Society Islands (French Polynesia) using a hierarchical sampling design that integrates the regional (among three islands: Moorea, Raiatea, Tahiti), island (among three locations around each island), and local levels (among three depths: 6, 12, 18 m, at each location). All coral taxa exhibited strong heterogeneity in their size structure, with marked variation among depths, locations, and islands. Porites spp. and Acropora globiceps populations at 6 m depth were dominated by smaller size classes compared to other depths. Regional-scale variation was particularly evident for Pocillopora meandrina and A. globiceps, with a higher proportion of smaller colonies found at Raiatea, probably as a result of recent cyclones followed by higher recruitment rates. Porites spp. populations were characterized by a preponderance of larger colonies, and greater size ranges compared to the other two taxa. PMID- 26525872 TI - Influence of fish aggregating devices (FADs) on anti-predator behaviour within experimental mesocosms. AB - Commercial fishers have used fish aggregating devices throughout the Mediterranean Sea for over 40 years. These devices attract numerous predatory and forage species in both coastal and offshore environments. This study examined the influence of fish aggregating devices on schooling and aggregating behaviour by small forage fish in quasi-natural mesocosms. Anti-predator behaviour was evaluated for juvenile Caranx crysos under a variety of treatment conditions. Results suggest that, in the absence of physical structure, C. crysos first respond to a predatory threat by forming a school. When a physical structure is present, however, C. crysos show an occasional tendency to aggregate near the structure. These results suggest that a threatened prey species can change their defensive strategy against predatory behaviour. Further examination is required to explain if fish aggregating devices can increase survival rates of post-larval and juvenile prey species in the southern Mediterranean Sea. Management agencies should consider the relationship between the use of fish aggregating devices by commercial fisheries and the potential influence such devices possess on population dynamics of aggregating fish species. PMID- 26525870 TI - Analysis of the relationships between type 2 diabetes status, glycemic control, and neuroimaging measures in the Diabetes Heart Study Mind. AB - AIMS: To examine the relationships between type 2 diabetes (T2D) status, glycemic control, and T2D duration with magnetic resonance imaging (MRI)-derived neuroimaging measures in European Americans from the Diabetes Heart Study (DHS) Mind cohort. METHODS: Relationships were examined using marginal models with generalized estimating equations in 784 participants from 514 DHS Mind families. Fasting plasma glucose, glycated hemoglobin, and diabetes duration were analyzed in 682 participants with T2D. Models were adjusted for potential confounders, including age, sex, history of cardiovascular disease, smoking, educational attainment, and use of statins or blood pressure medications. Association was tested with gray and white matter volume, white matter lesion volume, gray matter cerebral blood flow, and white and gray matter fractional anisotropy and mean diffusivity. RESULTS: Adjusting for multiple comparisons, T2D status was associated with reduced white matter volume (p = 2.48 * 10(-6)) and reduced gray and white matter fractional anisotropy (p <= 0.001) in fully adjusted models, with a trend toward increased white matter lesion volume (p = 0.008) and increased gray and white matter mean diffusivity (p <= 0.031). Among T2D-affected participants, neither fasting glucose, glycated hemoglobin, nor diabetes duration were associated with the neuroimaging measures assessed (p > 0.05). CONCLUSIONS: While T2D was significantly associated with MRI-derived neuroimaging measures, differences in glycemic control in T2D-affected individuals in the DHS Mind study do not appear to significantly contribute to variation in these measures. This supports the idea that the presence or absence of T2D, not fine gradations of glycemic control, may be more significantly associated with age-related changes in the brain. PMID- 26525874 TI - External Reviewers 2007-2008. PMID- 26525873 TI - Temporal variability in epifaunal assemblages associated with temperate gorgonian gardens. AB - The present study is one of the few that investigate the temporal variability of epifaunal assemblages associated with coral species, particularly the octocorals Eunicella gazella and Leptogorgia lusitanica in south Portugal. The results suggest time rather than colony size as a primary driver of the ecological patterns of these assemblages, which were dominated by amphipods, molluscs and polychaetes. Temporal variability was linked to changes in environmental parameters, namely temperature, chlorophyll a and particulate organic carbon. Hence, temporal variability must be taken into account for the design of future biodiversity assessment studies, as different patterns may be observed depending on the sampling time. Associated epifaunal assemblages were consistently dominated by resident species (i.e. species present in all sampling periods) and a peak of rare species was observed in the transition from spring to summer following the increase in seawater temperature. Turnover was particularly high in the transition between the spring and summer periods. In both hosts, turnover was higher in the small sized colonies, which harboured less diverse and less abundant assemblages that also differed from those inhabiting larger size colonies. The high levels of diversity associated with gorgonian colonies highlight the need for the conservation of this priority habitat. PMID- 26525878 TI - Paediatric endocrinology: Defining treatment thresholds for neonatal hypoglycaemia-how low is too low? PMID- 26525879 TI - Tuning the Lewis acid phenol ortho-prenylation as a molecular diversity tool. AB - A diversity-oriented approach for the synthesis of various structurally different prenylated alcohols from readily accessible and common precursors was developed. With varying approaches, this article describes some successful examples of a Friedel-Crafts alkylation using methoxyphenols and different prenyl alcohols (geraniol and (E,E)-farnesol). We demonstrated that just by varying the stoichiometry of the Lewis acid used, the course of the reaction can be shifted to produce the alkylated or the cyclized product. Eighteen unique products were obtained with good isolated yields by direct alkylation with or without a consecutive pi-cationic cyclization. PMID- 26525880 TI - Lifestyle and Metformin Ameliorate Insulin Sensitivity Independently of the Genetic Burden of Established Insulin Resistance Variants in Diabetes Prevention Program Participants. AB - Large genome-wide association studies of glycemic traits have identified genetics variants that are associated with insulin resistance (IR) in the general population. It is unknown whether people with genetic enrichment for these IR variants respond differently to interventions that aim to improve insulin sensitivity. We built a genetic risk score (GRS) based on 17 established IR variants and effect sizes (weighted IR-GRS) in 2,713 participants of the Diabetes Prevention Program (DPP) with genetic consent. We tested associations between the weighted IR-GRS and insulin sensitivity index (ISI) at baseline in all participants, and with change in ISI over 1 year of follow-up in the DPP intervention (metformin and lifestyle) and control (placebo) arms. All models were adjusted for age, sex, ethnicity, and waist circumference at baseline (plus baseline ISI for 1-year ISI change models). A higher IR-GRS was associated with lower baseline ISI (beta = -0.754 [SE = 0.229] log-ISI per unit, P = 0.001 in fully adjusted models). There was no differential effect of treatment for the association between the IR-GRS on the change in ISI; higher IR-GRS was associated with an attenuation in ISI improvement over 1 year (beta = -0.520 [SE = 0.233], P = 0.03 in fully adjusted models; all treatment arms). Lifestyle intervention and metformin treatment improved the ISI, regardless of the genetic burden of IR variants. PMID- 26525881 TI - TCF7L2 Genotype and alpha-Cell Function in Humans Without Diabetes. AB - The diabetes-associated allele in TCF7L2 increases the rate of conversion to diabetes; however, the mechanism by which this occurs remains elusive. We hypothesized that the diabetes-associated allele in this locus (rs7903146) impairs insulin secretion and that this defect would be exacerbated by acute free fatty acid (FFA)-induced insulin resistance. We studied 120 individuals of whom one-half were homozygous for the diabetes-associated allele TT at rs7903146 and one-half were homozygous for the protective allele CC. After a screening examination during which glucose tolerance status was determined, subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, FFA was elevated by infusion of Intralipid plus heparin. On the other study day, subjects received the same amount of glycerol as present in the Intralipid infusion. beta-Cell responsivity indices were estimated with the oral C-peptide minimal model. We report that beta-cell responsivity was slightly impaired in the TT genotype group. Moreover, the hyperbolic relationship between insulin secretion and beta-cell responsivity differed significantly between genotypes. Subjects also exhibited impaired suppression of glucagon after an oral challenge. These data imply that a genetic variant harbored within the TCF7L2 locus impairs glucose tolerance through effects on glucagon as well as on insulin secretion. PMID- 26525882 TI - A novel nasopharyngeal stent for the treatment of obstructive sleep apnea: a case series of nasopharyngeal stenting versus continuous positive airway pressure. AB - The objective of the study was to investigate the first-night treatment success of a nasopharyngeal stent compared to standard nCPAP-titration. This is a case series and a single-center study. Eight participants (n = 8) were selected with untreated obstructive sleep apnea with a prestudy AHI >= 10. A newly developed nasopharyngeal stent was tested individually versus standard nCPAP-titration. Cardiorespiratory polysomnography was performed on two consecutive nights (random order: stent, nCPAP). The AHI, the number of obstructive apneas and hypopneas, the mean oxygen saturation, and the minimum oxygen saturation were compared before and after using the nasopharyngeal stent or standard nCPAP. The AHI value before treatment (AHIpre) was 31.1 +/- 12.0 (mean +/- standard deviation). After inserting the AlaxoStent, the mean AHIstent was 19 +/- 12.0 compared to mean AHInCPAP 8.2 +/- 11.9 with standard nCPAP-titration. Both nasopharyngeal stenting and nCPAP-titration could reduce the mean number of obstructive apneas by >94 %. Compared to responder rates of classic surgical interventions like uvulopalatopharyngoplasty or multi-level surgery, the nasopharyngeal stent seems to give a comparable responder rate of 50 %. There were no complications associated with the use of the stent and it was well tolerated by all subjects. Nasopharyngeal stenting widens the range of non-invasive mechanical treatment and seems to be an effective mechanical therapeutic alternative to surgery in nCPAP non-compliant patients with OSA. Careful selection of the patient population is a prerequisite of treatment and therefore it should be reserved for individual cases only. PMID- 26525883 TI - Is neutrophil-lymphocyte ratio associated with the severity of allergic rhinitis in children? AB - Neutrophil lymphocyte ratio (NLR) could be an important measure of systemic inflammation. There is a lack of knowledge about the neutrophil-lymphocyte ratio in rhinitis. We aimed to determine the relationship between the clinical parameters of allergic rhinitis and NLR in children. 438 children who were diagnosed with allergic rhinitis and followed up in our hospital were included in the study. The control group included 180 control children with no evidence of allergic disease. The immunoglobulin E levels, skin prick tests and complete blood count were measured. Mean NLR was 1.77 +/- 1.67 in the study group and 1.70 +/- 1.65 in the control group. Mean NLR was significantly higher in children with allergic rhinitis compared to controls (p < 0.05). The patients with allergic rhinitis were grouped according to the severity of AR as Group I (mild group) and Group II (moderate/severe group). No statistically significant difference was present between groups in terms of gender, age, familial atopy, exposure to smoke, the presence of asthma and/or eczema, the percentage of eosinophil, serum IgE levels, number of positive sensitivity, and sensitivity to allergens (p > 0.05). However, NLR was significantly higher in the moderate/severe AR compared to mild AR (p < 0.05). Mean NLR was statistically higher in children with allergic rhinitis compared to the control group. In addition, elevated ratio is associated with the severity of allergic rhinitis in children. Neutrophil lymphocyte can be used as an indicator of inflammation in allergic rhinitis. But further studies are needed in this issue. PMID- 26525884 TI - Osteitis and chronic rhinosinusitis: a review of the current literature. AB - Chronic rhinosinusitis is a common debilitating condition characterized by inflammation of the nose and paranasal sinuses. Osteitis is an associated finding but it is not clear whether it is cause or effect. This review will report on studies that have examined the role of osteitis in CRS, with the ultimate aim of clarifying the definition, pathogenesis and clinical implications of this relatively new clinical entity. Literature searches of Medline, EMBASE and CENTRAL using the search terms osteitis, rhinosinusitis, sinusitis, rhinitis, chronic disease, and recurrence were performed. 21 articles were identified and reviewed. The papers highlighted key pathological features including periosteal thickening, new woven bone formation, bone resorption, fibrosis and inflammatory cell infiltration. Radiological grading systems and basic science research into the role of matrix metalloproteinases and P-glycoprotein were also identified and reviewed. PMID- 26525885 TI - Emergent treatments based on the pathophysiology of bipolar disorder: A selective review. AB - Bipolar disorder is a chronic psychiatric disorder that is a cause of significant symptomatology even in the setting of optimal treatment. Most current treatments are developed from serendipity, and not based on known pathophysiology. In this review we examine a number of somatic and pharmacologic therapies that are poised to become part of the armamentarium of interventions to treat bipolar illness. As a group, these interventions are derived from a growing understanding of the biological underpinnings of bipolar disorders. We will look at emergent treatments based on our understanding of the molecular biology, neuroanatomy, and the genetics of bipolar disorder. PMID- 26525886 TI - Primary Headache Disorders: Focus on Migraine. AB - Migraine is the most common disabling headache disorder.Most patients with disabling tension-type headache are likely to have migraine and accordingly respond to treatments efficacious in migraine.Individuals are genetically predisposed to experiencing recurrent migraine.Evidence supports migraine to be a primarily neural and not vascular mediated disorder.1-2% of the population have chronic daily headache associated with acute-relief medication overuse; the majority are migraineurs.The presence of acute-relief medication overuse renders preventative medication less adequately efficacious. PMID- 26525887 TI - Abnormal asymmetry in frontostriatal white matter in children with attention deficit hyperactivity disorder. AB - A growing body of work utilizing structural and functional brain imaging and neurocognitive measures of executive and attentional function indicates anomalous asymmetry in ADHD. This study examined the white-matter volume and diffusion properties of frontostriatal tracts, as a function of hemisphere, in ADHD and healthy controls. Forty-three young males (21 ADHD-Combined Type and 22 controls) aged 10-18 years underwent structural and diffusion weighted MRI. Tractography applying constrained spherical deconvolution (CSD) was used to construct frontostriatal tracts between each of caudate and putamen and each of dorsolateral prefrontal, ventrolateral prefrontal and orbitofrontal cortices (DLPFC, VLPFC and OFC) in each hemisphere, to examine both volumetric and diffusion microstructure properties. Young people with ADHD did not show the right hemisphere lateralization of volume in the Caudate-VLPFC and Caudate-DLPFC tracts that was evident in controls, however the ADHD group displayed a pronounced lateralization to the left for fractional anisotropy in the Putamen VLPFC tracts. The degree of volume asymmetry did not correlate with symptom severity; however fractional anisotropy (FA) values that were more strongly lateralized to the left in the Putamen-VLPFC white matter were associated with greater symptom severity. ADHD was associated with anomalous hemispheric asymmetries in both tract volume and underlying white-matter microstructure in major fibre tracts of the frontostriatal system. Our observations of both weaker lateralization to the right in terms of tract volume and stronger lateralization to the left in terms of FA values for the ADHD group, suggests that previous inconsistencies in the literature may reflect the influence of such asymmetries. PMID- 26525888 TI - Tuning the Reactivity of Radical through a Triplet Diradical Cu(II) Intermediate in Radical Oxidative Cross-Coupling. AB - Highly selective radical/radical cross-coupling is paid more attention in bond formations. However, due to their intrinsic active properties, radical species are apt to achieve homo-coupling instead of cross-coupling, which makes the selective cross-coupling as a great challenge and almost untouched. Herein a notable strategy to accomplish direct radical/radical oxidative cross-coupling has been demonstrated, that is metal tuning a transient radical to a persistent radical intermediate followed by coupling with another transient radical. Here, a transient nitrogen-centered radical is tuned to a persistent radical complex by copper catalyst, followed by coupling with a transient allylic carbon-centered radical. Firstly, nitrogen-centered radical generated from N-methoxybenzamide stabilized by copper catalyst was successfully observed by EPR. Then DFT calculations revealed that a triplet diradical Cu(II) complex formed from the chelation N-methoxybenzamide nitrogen-centered radical to Cu(II) is a persistent radical species. Moreover, conceivable nitrogen-centered radical Cu(II) complex was observed by high-resolution electrospray ionization mass spectrometry (ESI MS). Ultimately, various allylic amides derivatives were obtained in good yields by adopting this strategy, which might inspire a novel and promising landscape in radical chemistry. PMID- 26525889 TI - Predicting the Binding Affinity of ERbeta Ligands Based on a Novel Variable Selection Method. AB - A number of descriptors were employed to characterize the molecular structures of the 128 estrogen receptor beta ligands. A quantitative structure-activity relationship (QSAR) model of these compounds was developed by the variable selection method based on variable interaction. The QSAR model with five descriptors was internally and externally validated. The determination coefficient (R 2) and the leave-one-out cross-validated correlation coefficient (Q 2) are 0.8272 and 0.8041, respectively. The estimated correlation coefficient of the external validation is 0.8255. The mechanistic interpretation of the final model was carried out according to the definition of descriptors. As the model meets the five principles proposed by Organization for Economic Co-operation and Development, it can be used to predict the binding affinity of other derivatives. PMID- 26525890 TI - Influence of bariatric surgery on the use of medication. AB - PURPOSE: Bariatric surgery can influence the prevalence and incidence of comorbidities, as well as the pharmacokinetics of drugs. This might lead to changes in the use of drugs. This study aimed to assess the influence of bariatric surgery on the use of medication in patients before and after surgery, focusing on type, number of medications, and daily dosage. METHODS: In a retrospective and prospective observational study, drug dispensing data from pharmacies of patients undergoing their first bariatric surgery between January 2008 and September 2011 was collected. Dispensing data from 1 month before until 12 months after surgery was analyzed. Drugs were classified according to the WHO ATC classification system. Dosages of drugs were compared using defined daily dose (DDD). RESULTS: Among 450 patients, 12 months after surgery, the mean number of drugs per patient for antidiabetics, drugs acting on the cardiovascular system, anti-inflammatory and antirheumatic drugs, and drugs for obstructed airway diseases decreased by, respectively, 71.3 % (95 % CI 57.2 to 85.4), 34.5 % (95 % CI 28.2 to 43.0), 45.5 % (95 % CI 13.3 to 72.6), and 33.1 % (95 % CI 15.3 to 53.2). Patients used lower median DDD of oral antidiabetics, beta-blocking agents, and lipid-modifying drugs. CONCLUSIONS: For some major drug classes 12 months after bariatric surgery, the use of drugs decreases in terms of mean number per patient. A reduction in dose intensity was observed for oral antidiabetics, beta-blocking agents, and lipid-modifying drugs. Dispensing data from pharmacies may provide detailed information on the use of medications by patients after bariatric surgery. PMID- 26525892 TI - Cortical and corticospinal output modulations during reaching movements with varying directions and magnitudes of interaction torques. AB - The neural command required to coordinate a multi-joint movement is inherently complex. During multi-joint movement of the limb, the force created from movement at one joint may create a torque at a second joint known as an interaction torque. Interaction torques may be assistive or resistive thereby aiding or opposing the motion of the second joint, respectively. For movement to be effectively controlled, the central nervous system should modulate neural output to the muscles to appropriately account for interaction torques. The present study examined the neural output from the primary motor cortex before and during reaching movements that required different combinations of assistive and resistive interaction torques occurring at the shoulder and elbow joints. Using transcranial magnetic stimulation to probe neural output from the primary motor cortex, results indicate that corticospinal output controlling the upper arm is related to resistive interaction torques occurring at the shoulder joint. Further, cortical output to bi-articular muscles is associated with interaction torque and this may be driven by the fact that these muscles are in an advantageous position to control torques produced between inter-connection segments. Humans have a tendency to avoid reaching movements that involve resistive interaction torques and this may be driven by the requirement of increased neural output associated with these movements. PMID- 26525891 TI - Inhibition of HMGB1 release via salvianolic acid B-mediated SIRT1 up-regulation protects rats against non-alcoholic fatty liver disease. AB - The inflammatory mediator high-mobility group box 1 (HMGB1) plays a critical role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the regulation of HMGB1 in NAFLD, particularly through sirtuin 1 (SIRT1), remains unclear. In this study, we investigated the role of SIRT1-mediated inhibition of HMGB1 release in NAFLD and the effect of salvianolic acid B (SalB), which is a water-soluble phenolic acid extracted from Radix Salvia miltiorrhiza, on NAFLD through SIRT1/HMGB1 signaling. In vivo, SalB treatment significantly attenuated high-fat diet (HFD)-induced liver damage, hepatic steatosis, and inflammation. Importantly, SalB significantly inhibited HMGB1 nuclear translocation and release, accompanied by SIRT1 elevation. In HepG2 cells, palmitic acid (PA) induced pro-inflammatory cytokines release were blocked by HMGB1 small interfering RNA (siRNA) transfection. Moreover, pharmacological SIRT1 inhibition by Ex527 induced HMGB1 translocation and release, whereas SIRT1 activation by resveratrol or SalB reversed this trend. SIRT1 siRNA abrogated the SalB-mediated inhibition of HMGB1 acetylation and release, suggesting that SalB-mediated protection occurs by SIRT1 targeting HMGB1 for deacetylation. We are the first to demonstrate that the SIRT1/HMGB1 pathway is a key therapeutic target for controlling NAFLD inflammation and that SalB confers protection against HFD- and PA-induced hepatic steatosis and inflammation through SIRT1-mediated HMGB1 deacetylation. PMID- 26525893 TI - Biological reduction of uranium coupled with oxidation of ammonium by Acidimicrobiaceae bacterium A6 under iron reducing conditions. AB - This study investigated the possibility of links between the biological immobilization of uranium (U) and ammonium oxidation under iron (Fe) reducing conditions. The recently-identified Acidimicrobiaceae bacterium A6 (ATCC, PTA 122488) derives energy from ammonium oxidation coupled with Fe reduction. This bacterium has been found in various soil and wetland environments, including U contaminated wetland sediments. Incubations of Acidimicrobiaceae bacteria A6 with nontronite, an Fe(III)-rich clay, and approximately 10 uM U indicate that these bacteria can use U(VI) in addition to Fe(III) as an electron acceptor in the presence of ammonium. Measurements of Fe(II) production and ammonium oxidation support this interpretation. Concentrations of approximately 100 uM U were found to entirely inhibit Acidimicrobiaceae bacteria A6 activity. These results suggest that natural sites of active ammonium oxidation under Fe reducing conditions by Acidimicrobiaceae bacteria A6 could be hotspots of U immobilization by bioreduction. This is the first report of biological U reduction that is not coupled to carbon oxidation. PMID- 26525895 TI - Ethnic differences in birth gender ratio responses in the United States after the September 11 Attacks and the President Kennedy assassination. AB - INTRODUCTION: Male exceed female live births. The ratio is expressed as M/F (male/total live births). Many factors influence this ratio including stress, which depresses it. The 9/11 attacks lowered M/F in the United States a few months after the event. This study was carried out to identify any racial differences in the observed M/F reduction. This paper also analysed racial M/F responses to the assassination of President John Kennedy. METHODS: For the JKF assassination, births were available as White and Non-White births. For 9/11, births were available for four racial groups: American Indian/Alaska Native, Asian/Pacific, Black/African and White. RESULTS: For the JFK assassination (November 1963), total M/F was lowest in 1964 (1958-1970, p<=0.01). M/F dipped in March 1964 in Non-White births only (p<0.0001). For 9/11, M/F dips showed a nonsignificant gradient, being greater in Asian/Pacific births, followed by White and Black/African. Baseline M/F was Asian/Pacific>White>Black/African and American Indian/Alaska Native. DISCUSSION: President Kennedy actively attempted to usher in civil rights, and his assassination may have stressed Non-Whites far more than Whites. For 9/11, the low Black/African M/F dips may be due to chronic stress associated with being overall disadvantaged and of lower socio-economic status. These factors decrease M/F and potentially dampen M/F dips in response to additional stressors. The observed M/F dips often exceed the perinatal mortality statistic. Public Health should be more cognizant of the effect of stress on population M/F as a sentinel health indicator. KEY GUIDELINES: 1. The male to female ratio at birth is decreased by stressful events. 2. This is due to an excess of male foetal losses in established pregnancies. 3. Such losses in response to acute events are transient. 4. This ratio may be a useful indicator of population stress. 5. Socioeconomically deprived subpopulations, such as Black/African and American Indian/Alaska Native races may have a low ratio due to chronic stress and may thus be less responsive to stress in their ratio responses.6. The habitually high ratio in Asian/Pacific subpopulations may be due to the former practicing gender-selective abortion, favouring male over female offspring. RESEARCH DIRECTIONS: 1. Gender ratios in populations could be routinely monitored in order to assess the impact of stressful events that may reduce the male to female birth ratio. PMID- 26525896 TI - Terrorist attacks and the male-to-female ratio at birth: The Troubles in Northern Ireland, the Rodney King riots, and the Breivik and Sandy Hook shootings. AB - INTRODUCTION: Males are usually born in excess of females. The ratio is often expressed as M/F (male divided by total births). A wide variety of factors have been shown to influence M/F. Terrorist attacks reduce M/F. This study was carried out in order to ascertain whether individual terrorist attacks influenced M/F in relevant populations. METHODS: The following events were studied: the Troubles in Northern Ireland, the Los Angeles Riots (the Rodney King affair), the Breivik shooting (Norway), and the Sandy Hook shooting (Connecticut). RESULTS: Northern Ireland M/F was significantly lower during the Troubles (1969-1998) than during the period before (p=0.0006). There was a very sharp dip in 1978 (p<=0.004) during this particular year of renewed violence and heavy civilian attacks. Rodney King riots-late April 1992 M/F dipped significantly in August 1992, 4months after the riots (p=0.044). Breivik Shooting-22/07/2011 M/F dipped significantly in December 2011, 5months after the event (p=0.004). Sandy Hook Shooting-14/12/2012 M/F dipped significantly in April 2013, 4months after the event (p=0.009). DISCUSSION: M/F dips follow catastrophic or tragic events if these are felt to be momentous enough by a given population. All of the above events caused significant population stress. The M/F dips noted may have been caused by population stress which is known to lead to the culling of frail/small male foetuses. The dips noted are comparable to a substantial proportion of quoted values for perinatal mortality, potentially elevating this a public health issue. KEY GUIDELINES: 1. The male-to-female ratio at birth is decreased by stressful events. 2. This is due to an excess of male foetal losses in established pregnancies. 3. Such losses in response to acute events are transient. 4. This ratio may be a useful indicator of population stress. RESEARCH DIRECTIONS: 1. Gender ratios in populations could be routinely monitored in order to assess the impact of stressful events that may reduce the male-to-female birth ratio. PMID- 26525894 TI - Comparison of Xenorhabdus bovienii bacterial strain genomes reveals diversity in symbiotic functions. AB - BACKGROUND: Xenorhabdus bacteria engage in a beneficial symbiosis with Steinernema nematodes, in part by providing activities that help kill and degrade insect hosts for nutrition. Xenorhabdus strains (members of a single species) can display wide variation in host-interaction phenotypes and genetic potential indicating that strains may differ in their encoded symbiosis factors, including secreted metabolites. METHODS: To discern strain-level variation among symbiosis factors, and facilitate the identification of novel compounds, we performed a comparative analysis of the genomes of 10 Xenorhabdus bovienii bacterial strains. RESULTS: The analyzed X. bovienii draft genomes are broadly similar in structure (e.g. size, GC content, number of coding sequences). Genome content analysis revealed that general classes of putative host-microbe interaction functions, such as secretion systems and toxin classes, were identified in all bacterial strains. In contrast, we observed diversity of individual genes within families (e.g. non-ribosomal peptide synthetase clusters and insecticidal toxin components), indicating the specific molecules secreted by each strain can vary. Additionally, phenotypic analysis indicates that regulation of activities (e.g. enzymes and motility) differs among strains. CONCLUSIONS: The analyses presented here demonstrate that while general mechanisms by which X. bovienii bacterial strains interact with their invertebrate hosts are similar, the specific molecules mediating these interactions differ. Our data support that adaptation of individual bacterial strains to distinct hosts or niches has occurred. For example, diverse metabolic profiles among bacterial symbionts may have been selected by dissimilarities in nutritional requirements of their different nematode hosts. Similarly, factors involved in parasitism (e.g. immune suppression and microbial competition factors), likely differ based on evolution in response to naturally encountered organisms, such as insect hosts, competitors, predators or pathogens. This study provides insight into effectors of a symbiotic lifestyle, and also highlights that when mining Xenorhabdus species for novel natural products, including antibiotics and insecticidal toxins, analysis of multiple bacterial strains likely will increase the potential for the discovery of novel molecules. PMID- 26525897 TI - Temporal and regional trends in the secondary sex ratio: The Nordic experience. AB - The sex ratio (SR) at birth, also known as the secondary sex ratio, is defined as the number of males per 100 females and approximates 106. According to the literature, the SR shows notable heterogeneity and attempts have been made to identify factors influencing it, but comparisons demand large data sets. Attempts to identify associations between SRs and stillbirth rates (SBRs) have yielded inconsistent results. A common pattern observed in different countries is that during the first half of the twentieth century, the SR showed increasing trends, but during the second half, the trend decreased. Secular increases are thought to be caused by improved socio-economic conditions. The recent downward trends have been attributed to new reproductive hazards. Similar findings have been made in the Nordic countries. Factors affecting the SR within families remain poorly understood. Although these factors have an effect on family data, they have not been identified in large. PMID- 26525898 TI - Erratum to: Fibroblast viability and phenotypic changes within glycated stiffened three-dimensional collagen matrices. PMID- 26525899 TI - Nitrenium ions and trivalent boron ligands as analogues of N-heterocyclic carbenes in olefin metathesis: a computational study. AB - We used the density functional theory to evaluate the suitability of nitrenium ions and trivalent boron ligands as analogues of N-heterocyclic carbenes in ruthenium-based metathesis catalysts. We demonstrate that these analogues induce only minor structural changes in Hoveyda-Grubbs-like precatalysts, but have major impact on precatalyst initiation. Nitrenium ion-modified precatalysts are characterized by a weak Ru-N bond resulting in a relatively strong Ru-O bond and large free energy barriers for initiation, making them good candidates for efficient latent Ru-based catalysts. On the other hand the trivalent boron ligand, bearing a formal -1 charge, binds strongly to the ruthenium ion, weakening the Ru-O bond and facilitating its dissociation, to promote fast reaction initiation. We show that the calculated bond dissociation energy of the Ru-C/N/B bond may serve as an accurate indicator of the Ru-O bond strength and the rate of metathesis initiation. PMID- 26525900 TI - Early introduction of tolvaptan after cardiac surgery: a renal sparing strategy in the light of the renal resistive index measured by ultrasound. AB - BACKGROUND: Renal failure is a serious complication after cardiac surgery, which can be caused by long-term intravenous (IV) loop diuretic use. Tolvaptan is an oral selective vasopressin-2 receptor antagonist used in patients irresponsive to loop diuretics. We investigated their renal perfusion changes using the resistive index (RI) postoperatively. METHODS: Serial renal RI, echocardiography, and laboratory examinations from 14 patients requiring continuous postoperative IV loop diuretics were reviewed. Eight patients received tolvaptan (Group T) and six received oral loop diuretics before the discontinuation of IV loop diuretics (Group L). The 1(st) data were obtained between postoperative day 0 and 2, the 2(nd) when patients were still under IV loop diuretic treatment, the 3(rd) after the initiation of tolvaptan or oral loop diuretic, and the 4(th) after the discontinuation of IV diuretics. RESULTS: The 2(nd) RI value was higher in Group T than Group L (0.77 +/- 0.09 vs. 0.69 +/- 0.01, p = 0.049) but significantly decreased after tolvaptan administration [0.77 +/- 0.09 to 0.65 +/- 0.05 (2(nd) to 3(rd)), to 0.62 +/- 0.04 (to 4(th)), both p = 0.006], while no such changes were seen in Group L. The serum sodium and albumin levels, and echo-derived tricuspid annular plane systolic excursion increased only in Group T (134.1 +/- 1.5 to 138.8 +/- 3.2 mEq/L, 3.3 +/- 0.3 to 3.7 +/- 0.5 g/dL, 16.4 +/- 3.6 to 19.7 +/- 4.2 mm, all p <0.05). The duration of IV loop diuretics tended to be shorter in Group T than Group L (5.6 +/- 1.6 vs. 8.7 +/- 3.6 days, p = 0.051). CONCLUSIONS: Administration of tolvaptan in patients undergoing cardiac surgery may improve their renal perfusion, as reflected by the renal RI measured using renal Doppler ultrasound. PMID- 26525901 TI - Analysis of affinities between specific biological ligands using atomic force microscopy. AB - In the cell, protein-ligand recognition involves association and dissociation processes controlled by the affinity of the two binding partners and chemical harvesting of adenosine triphosphate energy. Fundamental knowledge of selected recognition events is currently translated in a synthetic environment for biosensors, immunoassays and diagnosis applications, or for pharmaceutical development. However, in order to advance such fields, one needs to determine the lifetime and binding efficiency of the two partners, as well as the complex energy landscape parameters. We employed contact mode atomic force microscopy to evaluate the association and dissociation events between streptavidin protein and its anti-streptavidin antibody ligand currently used for nucleotide array, ELISA, and flow cytometry applications, just to name a few. Using biotin as the control, our analysis helped characterize and differentiate multi- or single bonds of different strengths as well as associated energy landscapes to determine the protein-ligand structural arrangement at nanointerfaces and how these depend on the specificity of the ligand-recognition reaction. Our results suggest that understanding the importance of the rupture forces between a protein and its ligand could serve as the first step to protect on-off switches for biomedical research applications where specificity and selectivity are foremost sought. PMID- 26525902 TI - Reprogramming energy metabolism and inducing angiogenesis: co-expression of monocarboxylate transporters with VEGF family members in cervical adenocarcinomas. AB - BACKGROUND: Deregulation of cellular energetic metabolism was recently pointed out as a hallmark of cancer cells. This deregulation involves a metabolic reprogramming that leads to a high production of lactate. Lactate efflux, besides contributing for the glycolytic flux, also acts in the extracellular matrix, contributing for cancer malignancy, by, among other effects, induction of angiogenesis. However, studies on the interplay between cancer metabolism and angiogenesis are scarce. Therefore, the aim of the present study was to evaluate the metabolic and vascular molecular profiles of cervical adenocarcinomas, their co-expression, and their relation to the clinical and pathological behavior. METHODS: The immunohistochemical expression of metabolism-related proteins (MCT1, MCT4, CD147, GLUT1 and CAIX) as well as VEGF family members (VEGF-A, VEGF-C, VEGF D, VEGFR-1, VEGFR-2 and VEGFR-3) was assessed in a series of 232 cervical adenocarcinomas. The co-expression among proteins was assessed and the expression profiles were associated with patients' clinicopathological parameters. RESULTS: Among the metabolism-related proteins, MCT4 and CAIX were the most frequently expressed in cervical adenocarcinomas while CD147 was the less frequently expressed protein. Overall, VEGF family members showed a strong and extended expression with VEGF-C and VEGFR-2 as the most frequently expressed and VEGFR-1 as the less expressed member. Co-expression of MCT isoforms with VEGF family members was demonstrated. Finally, MCT4 was associated with parametrial invasion and HPV18 infection, CD147 and GLUT1 with distant metastasis, CAIX with tumor size and HPV18 infection, and VEGFR-1 with local and lymphnode metastasis. CONCLUSIONS: The results herein presented provide additional evidence for a crosstalk between deregulating cellular energetics and inducing angiogenesis. Also, the metabolic remodeling and angiogenic switch are relevant to cancer progression and aggressiveness in adenocarcinomas. PMID- 26525903 TI - Microsatellite markers for the Jaera albifrons species complex (marine isopods). AB - BACKGROUND: The Jaera albifrons complex contains five species of marine isopods (J. albifrons, J. praehirsuta, J. ischiosetosa, J. forsmani, and J. posthirsuta). These species, occurring on the shores of the North-Atlantic Ocean, are partially reproductively isolated by barriers due to sexual isolation (mate choice), genetic incompatibilities, and ecological specialization. Microsatellite loci would be useful for parentage-based analyses of sexual selection and studies of genetic structure in the context of speciation. FINDINGS: Twenty-four microsatellite markers were developed for J. albifrons using pyrosequencing of enriched libraries. Patterns of polymorphisms were analyzed in 49 J. albifrons adult males sampled in two populations from Brittany (Western France). The average number of alleles per locus was 4.73 +/- 2.45 and the average gene diversity was 0.55 +/- 0.23. Most markers also successfully amplified in the three sibling species J. praehirsuta, J. ischiosetosa, and J. forsmani. CONCLUSIONS: These polymorphic and cross-amplifiable markers will be useful for population genetics and parentage studies in the J albifrons complex. PMID- 26525904 TI - Towards unsupervised polyaromatic hydrocarbons structural assignment from SA-TIMS FTMS data. AB - With the advent of high resolution ion mobility analyzers and their coupling to ultrahigh resolution mass spectrometers, there is a need to further develop a theoretical workflow capable of correlating experimental accurate mass and mobility measurements with tridimensional candidate structures. In the present work, a general workflow is described for unsupervised tridimensional structural assignment based on accurate mass measurements, mobility measurements, in silico 2D-3D structure generation, and theoretical mobility calculations. In particular, the potential of this workflow will be shown for the analysis of polyaromatic hydrocarbons from Coal Tar SRM 1597a using selected accumulation - trapped ion mobility spectrometry (SA-TIMS) coupled to Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS). The proposed workflow can be adapted to different IMS scenarios, can utilize different collisional cross-section calculators and has the potential to include MSn and IMSn measurements for faster and more accurate tridimensional structural assignment. PMID- 26525905 TI - A Comparative Study of Retinal Function in Rabbits after Panretinal Selective Retina Therapy versus Conventional Panretinal Photocoagulation. AB - Purpose. This study evaluates functional changes in electroretinographic findings after selective retina therapy (SRT) compared to panretinal photocoagulation (PRP) in rabbits. Methods. The right eyes of 12 Chinchilla rabbits received 200 laser treatment spots. The right eyes of six rabbits received SRT (SRT group), whereas the other six animals were treated using PRP on the right eye (PRP group). The eyes were investigated using full-field ERG 1 hour and 3 weeks after treatment. Histologic exam to assess the tissue response of lasers was performed on 3 weeks. Results. No significant changes in the mean ROD or CR b-wave amplitudes of the SRT lesions were evident, compared to baseline, 1 h after laser treatment (p = 0.372 and 0.278, resp.). In addition, the OPs and 30 Hz flickers of the SRT lesions were not significantly altered (p = 0.17 and 0.243, resp.). At 3 weeks, similar results were found. Comparing the two groups, the ROD b-wave amplitude was reduced in the PRP and SRT groups to 60.04 +/- 4.2% and 92.32 +/- 6.43% of baseline (p < 0.001). Histologically, there was no visible photoreceptor alterations on week 3. Conclusions. SRT in rabbit eyes induced less functional loss than PRP in both rod-mediated retinal function and cone-mediated retinal function. In addition, SRT irradiated eyes had no functional loss compared to its control. PMID- 26525906 TI - High throughput optical lithography by scanning a massive array of bowtie aperture antennas at near-field. AB - Optical lithography, the enabling process for defining features, has been widely used in semiconductor industry and many other nanotechnology applications. Advances of nanotechnology require developments of high-throughput optical lithography capabilities to overcome the optical diffraction limit and meet the ever-decreasing device dimensions. We report our recent experimental advancements to scale up diffraction unlimited optical lithography in a massive scale using the near field nanolithography capabilities of bowtie apertures. A record number of near-field optical elements, an array of 1,024 bowtie antenna apertures, are simultaneously employed to generate a large number of patterns by carefully controlling their working distances over the entire array using an optical gap metrology system. Our experimental results reiterated the ability of using massively-parallel near-field devices to achieve high-throughput optical nanolithography, which can be promising for many important nanotechnology applications such as computation, data storage, communication, and energy. PMID- 26525907 TI - Systematic Review and Meta-analysis of Flaxseed. PMID- 26525908 TI - Erratum for Khalesi et al. Flaxseed consumption may reduce blood pressure: a systematic review and meta-analysis of controlled trials. J Nutr 2015;145:758-65. PMID- 26525910 TI - Respiratory symptoms and ventilatory function among health-care workers exposed to cleaning and disinfectant chemicals, a 2-year follow-up study. AB - Previous cross-sectional studies have shown that exposure to cleaning chemicals among health-care workers (HCWs) is associated with respiratory disorders and ventilatory function changes. This study aimed to further explore this association using a longitudinal approach. A prospective 2-year follow-up study was carried out at a tertiary care hospital in Saudi Arabia from June 2012 to June 2014 among 56 nurses who were responsible for disinfection and sterilization of medical instruments and equipment. The workplaces of the participants were assessed for engineering, environmental, and safety control measures. Self administered questionnaires were distributed to all participants to assess their exposure to cleaning chemicals and their medical history. Spirometric parameters were measured for all nurses in 2012 (baseline) and again in 2014 (follow-up). The prevalence of work-related respiratory symptoms did not increase significantly over this time. Among all the spirometric parameters, only forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio decreased significantly, and only 10.7% of participants who were exposed to cleaning chemicals for more than 10 years had FEV1 and FVC less than their longitudinal normal limits at the end of the study. Smoking and gender were associated with statistically significant decreases in some of the spirometric parameters. Our 2 year follow-up study did not demonstrate significant association between exposure to cleaning chemicals among HCWs and changes in the prevalence of work-related respiratory symptoms, but indicated early effects on ventilatory function among them. The study highlights the importance of periodic spirometry, proper work practices, and effective control measures to protect HCWs against potentially harmful workplace chemicals for disinfection and sterilization. PMID- 26525911 TI - Biochemia Medica's editorial policy on authorship. AB - Recent findings of authorship criteria violations in the manuscripts submitted to Biochemia Medica show that almost 40% of authors do not meet necessary criteria for authorship and thus indicate the need for better dissemination of editorial policy on authorship in our journal. We believe that such cases are mostly due to the authors' unawareness or the lack of understanding of the authorship criteria. With this article we therefore wish to declare our editorial policy on authorship and authorship criteria. Biochemia Medica endorses the authorship policy provided by the International Committee of Medical Journal Editors (ICMJE). Information on authorship is assessed by self-reported authorship claims during on-line manuscript submission. Those who meet ICMJE criteria shall be listed as authors, and all listed authors shall fulfill ICMJE criteria. All authors should be responsible for content of the article and have to know other authors' contributions to the study. Biochemia Medica will follow recommendations provided by Committee on Publication Ethics (COPE) flowcharts for possible disputes. By adhering to this procedure we hope to raise awareness about the importance of compliance with ICMJE authorship recommendations. PMID- 26525912 TI - Calculated spinal cord electric fields and current densities for possible neurite regrowth from quasi-DC electrical stimulation. AB - The prime goal of this work was to model essentially steady (DC) fields from electrodes, implanted in several ways, which have been suggested as possible means to encourage nerve fiber regrowth in spinal cord injuries. A simplified model of the human spinal cord in the lumbar region and the SEMCAD-X computer program were used to calculate electric field and current density patterns from electrodes outside vertebrae and those inserted extradurally within the spinal canal. DC electric fields guide nerve growth in developing organisms and in vitro. They also have been shown to encourage healing of injured peripheral nerves, and application of a longitudinal field has been used in attempts to bridge spinal cord injuries. When calculated results are scaled to the experimental level used in the literature, all modeled electrodes produced fields in the spinal cord below fields needed in the literature for stimulation of spinal as well as peripheral nerve growth in vitro, in dogs, and in a published clinical human trial. The highly-conducting cerebrospinal fluid appeared to provide effective shielding; there was also a very high degree of polarization at electrodes. PMID- 26525913 TI - In vitro trichomonacidal activity and preliminary in silico chemometric studies of 5-nitroindazolin-3-one and 3-alkoxy-5-nitroindazole derivatives. AB - A selection of 1,2-disubstituted 5-nitroindazolin-3-ones (1-19) and 3-alkoxy-5 nitroindazoles substituted at positions 1 (20-24) or 2 (25-39) from our in-house compound library were screened in vitro against the most common curable sexually transmitted pathogen, Trichomonas vaginalis. A total of 41% of the studied molecules (16/39) achieved a significant activity of more than 85% growth inhibition at the highest concentration assayed (100 ug mL(-1)). Among these compounds, 3-alkoxy-5-nitroindazole derivatives 23, 24, 25 and 27 inhibited parasite growth by more than 50% at 10 ug mL(-1). In addition, the first two compounds (23, 24) still showed remarkable activity at the lowest dose tested (1 ug mL(-1)), inhibiting parasite growth by nearly 40%. Their specific activity towards the parasite was corroborated by the determination of their non-specific cytotoxicity against mammalian cells. The four mentioned compounds exhibited non cytotoxic profiles at all of the concentrations assayed, showing a fair antiparasitic selectivity index (SI > 7.5). In silico studies were performed to predict pharmacokinetic properties, toxicity and drug-score using Molinspiration and OSIRIS computational tools. The current in vitro results supported by the virtual screening suggest 2-substituted and, especially, 1-substituted 3-alkoxy-5 nitroindazoles as promising starting scaffolds for further development of novel chemical compounds with the main aim of promoting highly selective trichomonacidal lead-like drugs with adequate pharmacokinetic and toxicological profiles. PMID- 26525914 TI - Lithium-doped beta-tricalcium phosphate: Effects on physical, mechanical and in vitro osteoblast cell-material interactions. AB - In this work, we have investigated the effects of lithium (Li) dopant at different concentrations and sintering temperatures on the physical and mechanical properties of beta-tricalcium phosphate (beta-TCP). Our results showed that Li addition at concentrations of 0.65 and 1.0 wt % inhibits the beta-TCP to alpha-TCP phase transformation. 0.15 wt % Li addition resulted in grain growth and extensive liquid phase was formed at higher concentrations. At 1150 degrees C, compressive strength of beta-TCP increased from 138.7 +/- 19.9 MPa to 170.9 +/ 29.8 MPa with the addition of 0.15 wt % Li. Addition of higher amounts of Li decreased the compressive strength and the lowest compressive strength of 99.8 +/ 13.7 MPa was found in samples containing 1.0 wt % Li. After 3 days of culture, osteoblast cells grew to confluence on samples containing 0.65 and 1.0 wt % Li. Cells grew to confluence on all doped samples after 11 days of culture and optical cell density was 4-5 folds higher on 0.15 and 1.0 wt % Li-doped TCP samples. Our results show that both Li content and sintering temperature have significant influence toward physicochemical and mechanical properties of beta TCP which affects the osteoblast cell-materials interaction in Li-doped TCP scaffolds. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 391-399, 2017. PMID- 26525915 TI - Green tea supplementation benefits body composition and improves bone properties in obese female rats fed with high-fat diet and caloric restricted diet. AB - This study investigated the effects of green tea polyphenols (GTP) supplementation on body composition, bone properties, and serum markers in obese rats fed a high-fat diet (HFD) or a caloric restricted diet (CRD). Forty-eight female rats were fed an HFD ad libitum for 4 months, and then either continued on the HFD or the CRD with or without 0.5% GTP in water. Body composition, bone efficacy, and serum markers were measured. We hypothesized that GTP supplementation would improve body composition, mitigate bone loss, and restore bone microstructure in obese animals fed either HFD or CRD. CRD lowered percent fat mass; bone mass and trabecular number of tibia, femur and lumbar vertebrae; femoral strength; trabecular and cortical thickness of tibia; insulin-like growth factor-I and leptin. CRD also increased percent fat-free mass; trabecular separation of tibia and femur; eroded surface of tibia; bone formation rate and erosion rate at tibia shaft; and adiponectin. GTP supplementation increased femoral mass and strength (P = .026), trabecular thickness (P = .012) and number (P = .019), and cortical thickness of tibia (P < .001), and decreased trabecular separation (P = .021), formation rate (P < .001), and eroded surface (P < .001) at proximal tibia, and insulin-like growth factor-I and leptin. There were significant interactions (diet type * GTP) on osteoblast surface/bone surface, mineral apposition rate at periosteal and endocortical bones, periosteal bone formation rate, and trabecular thickness at femur and lumbar vertebrate (P < .05). This study demonstrates that GTP supplementation for 4 months benefited body composition and improved bone microstructure and strength in obese rats fed with HFD or HFD followed by CRD diet. PMID- 26525916 TI - Amyloid-beta peptides act as allosteric modulators of cholinergic signalling through formation of soluble BAbetaACs. AB - Amyloid-beta peptides, through highly sophisticated enzymatic machinery, are universally produced and released in an action potential synchronized manner into the interstitial fluids in the brain. Yet no native functions are attributed to amyloid-beta. The amyloid-beta hypothesis ascribes just neurotoxicity properties through build-up of soluble homomeric amyloid-beta oligomers or fibrillar deposits. Apolipoprotein-epsilon4 (APOE4) allele is the only confirmed genetic risk factor of sporadic Alzheimer's disease; once more it is unclear how it increases the risk of Alzheimer's disease. Similarly, central cholinergic signalling is affected selectively and early in the Alzheimer's disease brain, again why cholinergic neurons show this sensitivity is still unclear. However, the three main known Alzheimer's disease risk factors, advancing age, female gender and APOE4, have been linked to a high apolipoprotein-E and accumulation of the acetylcholine degrading enzyme, butyrylcholinesterase in cerebrospinal fluids of patients. Furthermore, numerous reports indicate that amyloid-beta interacts with butyrylcholinesterase and apolipoprotein-E. We have proposed that this interaction leads to formation of soluble ultrareactive acetylcholine-hydrolyzing complexes termed BAbetaACs, to adjust at demand both synaptic and extracellular acetylcholine signalling. This hypothesis predicted presence of acetylcholine synthesizing enzyme, choline acetyltransferase in extracellular fluids to allow maintenance of equilibrium between breakdown and synthesis of acetylcholine through continuous in situ syntheses. A recent proof-of-concept study led to the discovery of this enzyme in the human extracellular fluids. We report here that apolipoprotein-E, in particular epsilon4 isoprotein acts as one of the strongest endogenous anti-amyloid-beta fibrillization agents reported in the literature. At biological concentrations, apolipoprotein-E prevented amyloid-beta fibrillization for at least 65 h. We show that amyloid-beta interacts readily in an apolipoprotein-facilitated manner with butyrylcholinesterase, forming highly stable and soluble complexes, BAbetaACs, which can be separated in their native states by sucrose density gradient technique. Enzymological analyses further evinced that amyloid-beta concentration dependently increased the acetylcholine hydrolyzing capacity of cholinesterases. In silico biomolecular analysis further deciphered the allosteric amino acid fingerprint of the amyloid-beta cholinesterase molecular interaction in formation of BAbetaACs. In the case of butyrylcholinesterase, the results indicated that amyloid-beta interacts with a putative activation site at the mouth of its catalytic tunnel, most likely leading to increased acetylcholine influx into the catalytic site, and thereby increasing the intrinsic catalytic rate of butyrylcholinesterase. In conclusion, at least one of the native physiological functions of amyloid-beta is allosteric modulation of the intrinsic catalytic efficiency of cholinesterases, and thereby regulation of synaptic and extrasynaptic cholinergic signalling. High apolipoprotein-E may pathologically alter the biodynamics of this amyloid-beta function. PMID- 26525917 TI - MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis. AB - Tar DNA-binding protein 43 (TDP-43) is an RNA-binding protein normally localized to the nucleus of cells, where it elicits functions related to RNA metabolism such as transcriptional regulation and alternative splicing. In amyotrophic lateral sclerosis, TDP-43 is mislocalized from the nucleus to the cytoplasm of diseased motor neurons, forming ubiquitinated inclusions. Although mutations in the gene encoding TDP-43, TARDBP, are found in amyotrophic lateral sclerosis, these are rare. However, TDP-43 pathology is common to over 95% of amyotrophic lateral sclerosis cases, suggesting that abnormalities of TDP-43 play an active role in disease pathogenesis. It is our hypothesis that a loss of TDP-43 from the nucleus of affected motor neurons in amyotrophic lateral sclerosis will lead to changes in RNA processing and expression. Identifying these changes could uncover molecular pathways that underpin motor neuron degeneration. Here we have used translating ribosome affinity purification coupled with microarray analysis to identify the mRNAs being actively translated in motor neurons of mutant TDP 43(A315T) mice compared to age-matched non-transgenic littermates. No significant changes were found at 5 months (presymptomatic) of age, but at 10 months (symptomatic) the translational profile revealed significant changes in genes involved in RNA metabolic process, immune response and cell cycle regulation. Of 28 differentially expressed genes, seven had a >= 2-fold change; four were validated by immunofluorescence labelling of motor neurons in TDP-43(A315T) mice, and two of these were confirmed by immunohistochemistry in amyotrophic lateral sclerosis cases. Both of these identified genes, DDX58 and MTHFSD, are RNA binding proteins, and we show that TDP-43 binds to their respective mRNAs and we identify MTHFSD as a novel component of stress granules. This discovery-based approach has for the first time revealed translational changes in motor neurons of a TDP-43 mouse model, identifying DDX58 and MTHFSD as two TDP-43 targets that are misregulated in amyotrophic lateral sclerosis. PMID- 26525919 TI - Colorectal multidisciplinary meeting audit to determine patient benefit. AB - BACKGROUND: New Zealand tumour standards require discussion of all cases of colorectal cancer in a multidisciplinary meeting (MDM), but supporting evidence is lacking. The aim was to determine which patients benefit from MDM discussion. METHODS: A retrospective and prospective audit was undertaken of all patients discussed in the Christchurch Hospital colorectal MDM over 12 months to November 2014, who were compared with contemporaneous patients not discussed and identified through Hospital discharge codes. RESULTS: In total, 641 patients were identified, with 459 (70%) discussed in the MDM, on average 7 years younger than not discussed. The proportion discussed by location was 39.2% colon, 63% rectosigmoid, 98% rectal, 96.6% anal. Discussed patients were more likely to have magnetic resonance imaging (68% cf 9.3%), fluorodeoxyglucose positron emission tomography scan (18% versus 2%) and chest computerized tomography scan (50% versus 26%). For colon cancer, American Joint Committee on Cancer (AJCC) stage I and II, 91% of 68 non-discussed patients went straight to surgery compared with 48% of 27 discussed in the MDM; for AJCC stage III uptake of adjuvant chemotherapy was the same whether discussed or not. An R0 resection was achieved for 91% of discussed patients, and 96% of not discussed. A clear referrer's plan, prospectively recorded in 94 patients, was changed after the MDM in 23%. Clinical staging was changed in 20 patients (4%), none with colon cancers. CONCLUSIONS: Discussion in the MDM influenced management, but was unlikely to change management for AJCC stage I/II colon cancer, who could be spared mandatory review in the MDM and be discussed selectively as treating clinicians decide. PMID- 26525920 TI - Contribution of amygdala pathology to comorbid emotional disturbances in temporal lobe epilepsy. AB - The amygdala contributes to the generation and propagation of epileptiform activity in temporal lobe epilepsy (TLE). Ictal symptoms such as fear, dreamy states (deja vu, memory flashbacks, experiential hallucinations), epigastric auras, or sympathetic outflow with cardiovascular changes are often linked to a seizure focus in the amygdala. However, the amygdala may also play a role in comorbid anxiety, depression, and other psychiatric symptoms experienced in the interictal phase, especially in pharmacoresistant TLE. The few studies available on TLE-related alterations in surgical amygdala specimens indicate loss of both excitatory spiny projection neurons as well as interneurons in nuclei with a cortex-like architecture, which may influence mechanisms of feedforward and feedback inhibition. Studies of the human amygdala indicate global alterations in the density of AMPA/kainate, metabotropic glutamate, gamma-aminobutyric acid type A (GABAA ), muscarinic M2 and M3, serotonergic 5-HT1A, and adrenergic alpha1 receptors. Also, amygdala GABAergic and neuropeptide Y (NPY) systems affected in human TLE are both involved in antiepileptic and anxiolytic effects. Experimental and human positron emission tomography studies indicate changes in amygdala serotonergic, NPY Y1 receptor, neurokinin, and opioid systems in emotional disturbances in TLE. Of particular interest is the reduction in amygdala volume in conjunction with ictal fear, seizure focus in the amygdala, and amygdala and hippocampal sclerosis in TLE patients. In contrast, patients with interictal depression often have an intact or even enlarged amygdala and a negative MRI associated with amygdala hypometabolism, which can be associated with limbic autoimmune encephalitis. These findings suggest a differential role of TLE related amygdala changes in ictal and interictal emotional disturbances. PMID- 26525918 TI - Neural correlates underlying micrographia in Parkinson's disease. AB - Micrographia is a common symptom in Parkinson's disease, which manifests as either a consistent or progressive reduction in the size of handwriting or both. Neural correlates underlying micrographia remain unclear. We used functional magnetic resonance imaging to investigate micrographia-related neural activity and connectivity modulations. In addition, the effect of attention and dopaminergic administration on micrographia was examined. We found that consistent micrographia was associated with decreased activity and connectivity in the basal ganglia motor circuit; while progressive micrographia was related to the dysfunction of basal ganglia motor circuit together with disconnections between the rostral supplementary motor area, rostral cingulate motor area and cerebellum. Attention significantly improved both consistent and progressive micrographia, accompanied by recruitment of anterior putamen and dorsolateral prefrontal cortex. Levodopa improved consistent micrographia accompanied by increased activity and connectivity in the basal ganglia motor circuit, but had no effect on progressive micrographia. Our findings suggest that consistent micrographia is related to dysfunction of the basal ganglia motor circuit; while dysfunction of the basal ganglia motor circuit and disconnection between the rostral supplementary motor area, rostral cingulate motor area and cerebellum likely contributes to progressive micrographia. Attention improves both types of micrographia by recruiting additional brain networks. Levodopa improves consistent micrographia by restoring the function of the basal ganglia motor circuit, but does not improve progressive micrographia, probably because of failure to repair the disconnected networks. PMID- 26525921 TI - Polyaromatic Profluorescent Nitroxide Probes with Enhanced Photostability. AB - Novel profluorescent mono- and bis-isoindoline nitroxides linked to napthalimide and perylene diimide structural cores are described. These nitroxide-fluorophore probes display strongly suppressed fluorescence in comparison to their corresponding non-radical diamagnetic methoxyamine derivatives. The perylene based probe possessing two isoindoline systems tethered through ethynyl linkages was shown to be the most photostable in solution, demonstrating significantly enhanced longevity over the 9,10-bis(phenylethynyl)anthracene fluorophore used in previous profluorescent nitroxide probes. PMID- 26525922 TI - A new approach for crystallization of copper(II) oxide hollow nanostructures with superior catalytic and magnetic response. AB - We report the synthesis of copper(II) oxide hollow nanostructures at ambient pressure and close to room temperature by applying the soft templating effect provided by the confinement of droplets in miniemulsion systems. Particle growth can be explained by considering a mechanism that involves both diffusion and reaction control. The catalytic reduction of p-nitrophenol in aqueous media is used as a model reaction to prove the catalytic activity of the materials: the synthesized hollow structures show nearly 100 times higher rate constants than solid CuO microspheres. The kinetic behavior and the order of the reduction reaction change due to the increase of the surface area of the hollow structures. The synthesis also leads to modification of physical properties such as magnetism. PMID- 26525923 TI - MMP-9 in translation: from molecule to brain physiology, pathology, and therapy. AB - Matrix metalloproteinase-9 (MMP-9) is a member of the metzincin family of mostly extracellularly operating proteases. Despite the fact that all of these enzymes might be target promiscuous, with largely overlapping catalogs of potential substrates, MMP-9 has recently emerged as a major and apparently unique player in brain physiology and pathology. The specificity of MMP-9 may arise from its very local and time-restricted actions, even when released in the brain from cells of various types, including neurons, glia, and leukocytes. In fact, the quantity of MMP-9 is very low in the naive brain, but it is markedly activated at the levels of enzymatic activity, protein abundance, and gene expression following various physiological stimuli and pathological insults. Neuronal MMP-9 participates in synaptic plasticity by controlling the shape of dendritic spines and function of excitatory synapses, thus playing a pivotal role in learning, memory, and cortical plasticity. When improperly unleashed, MMP-9 contributes to a large variety of brain disorders, including epilepsy, schizophrenia, autism spectrum disorder, brain injury, stroke, neurodegeneration, pain, brain tumors, etc. The foremost mechanism of action of MMP-9 in brain disorders appears to be its involvement in immune/inflammation responses that are related to the enzyme's ability to process and activate various cytokines and chemokines, as well as its contribution to blood-brain barrier disruption, facilitating the extravasation of leukocytes into brain parenchyma. However, another emerging possibility (i.e., the control of MMP-9 over synaptic plasticity) should not be neglected. The translational potential of MMP-9 has already been recognized in both the diagnosis and treatment domains. The most striking translational aspect may be the discovery of MMP-9 up-regulation in a mouse model of Fragile X syndrome, quickly followed by human studies and promising clinical trials that have sought to inhibit MMP-9. With regard to diagnosis, suggestions have been made to use MMP 9 alone or combined with tissue inhibitor of matrix metalloproteinase-1 or brain derived neurotrophic factor as disease biomarkers. MMP-9, through cleavage of specific target proteins, plays a major role in synaptic plasticity and neuroinflammation, and by those virtues contributes to brain physiology and a host of neurological and psychiatric disorders. This article is part of the 60th Anniversary special issue. PMID- 26525924 TI - Parental Perceptions of Aggressive Behavior in Preschoolers: Inhibitory Control Moderates the Association With Negative Emotionality. AB - Inhibitory control (IC) and negative emotionality (NE) are both linked to aggressive behavior, but their interplay has not yet been clarified. This study examines different NE * IC interaction models in relation to aggressive behavior in 855 preschoolers (aged 2-5 years) using parental questionnaires. Hierarchical regression analyses revealed that NE and IC predict aggression both directly and interactively. The highest aggression levels were reported in children with high NE and low IC. Interestingly, the protective effect of IC for aggressive behavior increases with rising levels of NE. Analyses focusing on physical aggression revealed a significant NE * IC interaction in boys aged 4-5 years only. These findings shed new light on potential compensatory mechanisms for aggressive behavior in developing children. PMID- 26525925 TI - Food, fibre, bile acids and the pelvic floor: An integrated low risk low cost approach to managing irritable bowel syndrome. AB - Patients presenting with abdominal pain and diarrhea are often labelled as suffering from irritable bowel syndrome, and medications may be used often without success. Advances in the understanding of the causes of the symptoms (including pelvic floor weakness and incontinence, bile salt malabsorption and food intolerance) mean that effective, safe and well tolerated treatments are now available. PMID- 26525926 TI - Using attenuation coefficients from optical coherence tomography as markers of vocal fold maturation. AB - OBJECTIVES/HYPOTHESIS: Optical coherence tomography (OCT) is a promising technology to noninvasively assess vocal fold microanatomy. The goal of this study was to develop a methodology using OCT to identify quantifiable markers of vocal fold development. STUDY DESIGN: In vivo study. METHODS: A two-step process was developed to reproducibly image the midmembranous vocal fold edge of 10 patients younger than 2 years and 10 patients between 11 and 16 years of age using OCT. An image analysis algorithm was implemented to extract OCT-derived A lines for each patient. These A-lines were divided into three zones according to apparent changes in slope. Relative attenuation coefficients, or tissue- and system-dependent parameters that describe the rate at which optical signal decays, were calculated for each zone. RESULTS: Young patients had distinct relative attenuation coefficients in zone 1 (P < .0001), whereas zones 2 and 3 were indistinct (P = .1129). Older patients had distinct relative attenuation coefficients in zones 1, 2, and 3 (P < .0370). Between age groups, relative attenuation coefficients were different in zones 2 and 3 (P < .0001, P = .0315, respectively) and indistinct in zone 1 (P = .1438). CONCLUSIONS: Relative attenuation coefficients can be used as markers of vocal fold development. Differences in relative attenuation coefficients likely represent changes in extracellular matrix structure within the lamina propria and may become useful for guiding treatment of voice disorders in the pediatric population. LEVEL OF EVIDENCE: NA Laryngoscope, 126:E218-E223, 2016. PMID- 26525927 TI - The reduction of graphene oxide with hydrazine: elucidating its reductive capability based on a reaction-model approach. AB - We have performed an experimental investigation on the effects of hydrazine treatment on graphene oxide via a reaction-model approach. Hydrazine was reacted with small conjugated aromatic compounds containing various oxygen functional groups to mimic the structure of graphene oxide. The hydroxyl and carboxylic groups were not readily removed while carbonyl groups reacted with hydrazine to form the corresponding hydrazone complexes. In the presence of adjacent hydroxyl groups, carboxyl groups underwent thermal decarboxylation. PMID- 26525928 TI - Aggregation of egg white proteins with pulsed electric fields and thermal processes. AB - BACKGROUND: Pulsed electric field (PEF) processing is progressing towards application for liquid egg to ensure microbial safety. However, it usually causes protein aggregation, and the mechanism is still unclear. In this study, egg white protein was applied to investigate the changes in protein structure and mechanism of aggregates formation and a comparison was made with thermal treatment. RESULTS: Soluble protein content decreased with the increase of turbidity after both treatments. Fluorescence intensity and free sulfhydryl content were increased after being treated at 70 degrees C for 4 min. Less-remarkable changes of hydrophobicity were observed after PEF treatments (30 kV cm(-1) , 800 us). Soluble and insoluble aggregates were observed by thermal treatment, and disulfide bonds were the main binding forces. The main components of insoluble aggregates formed by thermal treatment were ovotransferrin (30.58%), lysozyme (18.47%) and ovalbumin (14.20%). While only insoluble aggregates were detected during PEF processes, which consists of ovotransferrin (11.86%), lysozyme (21.11%) and ovalbumin (31.07%). Electrostatic interaction played a very important role in the aggregates formation. CONCLUSION: PEF had a minor impact on the structure of egg white protein. PEF had insignificant influence on heat sensitive protein, indicating that PEF has potential in processing food with high biological activity and heat sensitive properties. (c) 2015 Society of Chemical Industry. PMID- 26525929 TI - [Stroke epidemiology in Irkutsk according to the territorial population register]. AB - AIM: To study the dynamics of main epidemiological indices of stroke in Irkutsk in 2009-2013 and to compare the results with those in Russia. MATERIAL AND METHODS: The study was based on the data of the clinical/epidemiological analysis of stroke in open population of men and women in Irkutsk, the data analysis was performed using SAS 8.0. RESULTS: The territorial population register showed changes in disease and death rates for all stroke cases in the group of 25-74 years old both in men and women. The morbidity in men did not significantly exceed that in Russia. In the period of 5 years, the morbidity in women decreased by 28%. The stable trend towards the decrease in deaths from stroke in men and women was observed. During the observational period it decreased two-fold. PMID- 26525930 TI - [Quality of life of the patients who had an atherotrombotic stroke in the carotid artery territory]. AB - AIM: To assess quality of life of patients with first-ever atherothrombotic stroke in the carotid artery territory 2 years after the disease onset. MATERIAL AND METHODS: Authors examined 119 patients. Quality of life was measured with the "SF-36 Health Status Survey" using two parameters: level of mental (MH) and physical (PH) health. A control group consisted of 20 sex- and age-matched healthy persons without neurological diseases. RESULTS: After two years, 67% of the patients assessed their health condition as satisfactory. In the patients, a decrease in PH was greater compared to MH than in controls. CONCLUSION: In post stroke period, patients for a long time had lower quality of life indices with marked physical impairment. Elimination of or reduction in the focal neurological deficit that led to the decrease in the level of physical wellbeing may be considered as a significant rehabilitation reserve. PMID- 26525931 TI - [The influence of the immunity activation and suppression on the outcome of brain ischemia]. AB - AIM: To explore the influence of the immunity activation and suppression on the outcome of brain ischemia in experimental animals. MATERIAL AND METHODS: Brain ischemia has been modulated by irreversible staged bilateral common carotid arteries occlusion. Suppression of the immune system has been conducted by administration of cyclosporin A (5 mg/kg, per os). Activation of the immune system has been conducted by administration of lipopolysaccharide (10 mkg/kg, i.p.). RESULTS: Authors have established that in animals with immunosuppression there is an increase in the concentration of the neuron specific proteins in blood serum (NSE and MBP), mortality (by 20%) and severity of neurological deficit (by 33%). Rats with immunosuppression have reduced general locomotor activity (by 44%), exploratory behavior in the Open Field Test (by 43%) and decrease in the motor activity in the Rotarod Test (by 19%) compared to the group of rats with brain ischemia and intact immune systems. During the immunity activation after brain ischemia injury, the decrease in NSE and MBP levels, mortality (by 15%) and severity of neurological deficit (by 13%) as well as higher concentrations of neurotrophins BDNF and NGF and higher general locomotor activity of animals (by 34%) and physical endurance (by 55%) in the Open Field and Rotarod Tests, respectively, were observed. CONCLUSION: Immunosupression negatively affected the outcome of brain ischemia. PMID- 26525932 TI - [The effect of cholesterol on the electrokinetic properties of erythrocyte membranes in chronic cerebral ischemia]. AB - AIM: To determine the effects of total plasma cholesterol on the electrokinetic properties of erythrocyte membranes of healthy volunteers and patients with chronic cerebral ischemia (CCI). MATERIAL AND METHODS: Authors studied the erythrocytes from venous blood of 95 patients with CCI and 54 healthy people (controls). To perform an electrophoretic cell analysis of erythrocytes, we used the shorthand method of computer microelectrophoresis. RESULTS AND CONCLUSION: Plasma cholesterol level increased with the age. In the control group, there were the increase in percentage of fixed red blood cells, decrease in the amplitude of oscillations and electrophoretic mobility of red blood cells. In CCI patients, a significant increase in the share of fixed red blood cells, decrease in the amplitude of oscillations and electrophoretic mobility were observed compared to the controls. An increase in percentage of fixed red blood cells as well as in the qualitative heterogeneity of red blood cells in the amplitude of the oscillations was identified both in patients and controls, regardless of sex and age, with higher levels of total cholesterol. PMID- 26525933 TI - [The relationship between polymorphism 640A>G of the CYBA gene with the risk of ischemic stroke in the population of the Central Russia]. AB - AIM: Reactive oxygen species an important role in the pathogenesis of cerebrovascular disorders. NAD(P)H oxidases are one of the main sources of superoxide anions in cerebral arteries. NAD(P)H oxidase represents molecular complex and its p22phox subunit is coded by the CYBA gene located in the long arm of chromosome 16. We studied the association between the 640A>G polymorphism (rs1049255) of the CYBA gene with the risk of stroke in the Russian population. MATERIAL AND METHODS: Authors examined 887 people: 445 stroke patients, including 393 patients with ischemic stroke and 52 patients with hemorrhagic stroke, and 442 healthy people (controls). Genotyping was performed using real-time PCR and TaqMan allele discrimination assays. RESULTS: It was found that carriers of the heterozygous genotype 640AG of the CYBA gene were at a lower risk of stroke compared to the controls (OR=0.77, 95% CI=0.59-1.01, p=0.05). The stratified analysis showed that the genotype 640AG was associated with decreased risk of ischemic stroke (OR=0.75, 95% CI=0.57-0.99, p=0.04). CONCLUSION: The present study is the first to show that polymorphism 640A>G of the CYBA gene is associated with the risk of ischemic stroke. PMID- 26525934 TI - [The investigation of kinematic features of gait in healthy subjects and patients with post-stroke atactic disorders]. AB - AIM: To study spatial/temporal parameters of gait in post-stroke vestibular atactic syndrome. MATERIAL AND METHODS: Authors investigated the speed, rhythmic and angle parameters of the gait in healthy subjects (n=15) and in patients with atactic disorders in the recovery period of vertebrobasillar ischemic stroke (n=15). Physical examination with elements of anthropometry, clinical assessment of gait function with the Dynamic Gait Index, objective assessment of gait parameters using the system for 3D movement video analysis VICON Motion Capture Systems were used. RESULTS: There were a statistically significant decrease in the speed and pace of the gait, increase in the step duration and duration of the double support phase. The speed and rhythmic parameters of the left and right lower limb differed significantly. A delay of the moments of foot lifting from the surface was observed. Authors also revealed a decrease in the amplitude of flexion and extension in all segments of the lower limbs in the double step phase. CONCLUSION: These characteristics represent the activation of the "sitting" strategy and facilitate the objective assessment of the hyperfunction of the reactive postural synergies in patients with post-stroke atactic disorders. PMID- 26525935 TI - [The recovery of the function of hyporesponsive platelets during the antiplatelet therapy in patients with chronic cerebral ischemia]. AB - AIM: To establish the ability of recovery of platelet proagregation status in patients with chronic cerebral ischemia receiving standard medical therapy. MATERIAL AND METHODS: Thirty patients were studied. Platelets were isolated from peripheral blood by centrifugation. For in vitro platelet stimulation we used ADP, epinephrine and PAF. Platelet aggregation was recorded on aggregometer. RESULTS AND CONCLUSION: 24 hours after the beginning of standard therapy, the patients had 13 platelet phenotypes related to the functional state of three main receptors (purine receptors P2Y1 and P2Y12, alpha2-adrenergic receptors, and PAF- receptors. After 9-21 days of treatment (before discharge from the hospital), 15 patients (50%) had platelet phenotypes that did not change, i.e. standard medical therapy did not affect the performance of at least one of the receptor clusters, so the risk for initiation of thrombogenesis still remained. Remaining 15 patients had a phenotype with low platelet reactivity to all three agonists studied - cluster [ADP (?) epinephrine (?) PAF (?)] indicating the achievement of antiplatelet effect. The given phenotype is characterized by summation or potentiation of the effects of agonists - ADP and epinephrine in 6 cases (40%), epinephrine and PAF in 6 (40%), ADP and PAF in 3 (20%), which means that conditions for recovery of functional activity of hyporeactive platelets could be further created. PMID- 26525936 TI - [Low-molecular-weight DNA in blood plasma and cerebrospinal fluid of patients with acute stroke]. AB - AIM: To characterize the value of low-molecular-weight DNA in blood plasma and cerebrospinal fluid for the diagnosis of acute stroke of ischemic and hemorrhagic types early after the onset of the disease. MATERIAL AND METHODS: DNA from plasma and cerebrospinal fluid was isolated by phenol deproteinization, analyzed by gradient polyacrylamide electrophoresis. Content of low-molecular-weight DNA was determined on the electrophoregram by comparison with standards. RESULTS: Authors discovered the differences in the changes in the content of low-molecular-weight DNA in the blood plasma of patients with acute ischemic and hemorrhagic types of cerebrovascular accident within 3 days after onset. Patients with hemorrhagic stroke were characterized by an increase in low-molecular-weight DNA after 3 hours, while patients with ischemic stroke after 24 hours from onset. Low molecular-weight DNA was also detected in the cerebrospinal fluid of patients with ischemia during the first day of the disease. CONCLUSION: The results indicate a role of apoptosis in the formation of ischemic lesion. PMID- 26525937 TI - [A trace element analysis of hair in stroke with comorbid depression and cognitive impairment]. AB - AIM: To identify changes in the concentration of trace elements in hair of post stroke patients with comorbid depression and cognitive impairment. MATERIAL AND METHODS: Authors examined macro - and trace element hair composition of 63 stroke patients with comorbid depressive and cognitive disorders. The quantity determination was performed by atomic emission spectroscopy. RESULTS: An increase in hair concentrations of conditionally toxic elements Cd and Pb, essential trace elements Cu, Fe, Mn and decrease in concentrations of Zn were found in the patients with comorbid depression compared to reference values. CONCLUSION: Post stroke patients with comorbid depression and cognitive impairment had disturbances of the metabolism of trace elements involved in the intrinsic systems of homeostasis. PMID- 26525938 TI - [Possibilities of the treatment of speech impairment in the acute stage of ischemic stroke using neuroprotective therapy]. AB - AIM: To estimate an effect of cellex on the dynamics and time of speech functions recovery in the acute stage of ischemic stroke. MATERIAL AND METHODS: A multicenter, randomized, double-blind, placebo controlled clinical study included 8 Russian clinical sites. Four hundred eighty patients were involved. During the standard base therapy, cellex (or placebo) was introduced subcutaneously in dose 0,1 mg once a day in the first 10 days from the beginning of hospitalization. RESULTS AND CONCLUSION: The rapid and complete regress of aphasia, especially in cases of severe and middle to severe clinical course, was observed. PMID- 26525939 TI - [Rehabilitation of patients in the recovery period after stroke in Kazakhstan]. AB - AIM: To evaluate the effectiveness of complex rehabilitation of post stroke patients in a Stroke Rehabilitation Centre. MATERIAL AND METHODS: The results of rehabilitative treatment of 86 patients, aged from 50 to 68 years, in early and late recovery periods of ischemic stroke in the middle cerebral artery were analyzed. Neurological deficit was assessed with the Scandinavian Stroke Scale, the dynamics of recovery of neurological disorder with Barthel daily activity index, the degree of misbalance with the modified Rankin scale. RESULTS AND CONCLUSION: After the rehabilitation, a decrease in neurological deficit, improvement of gait and self-service skills, decrease in disability level were observed. The average scores before and after rehabilitation were 35.9+/-3.9 and 42.7+/-4.1 on the Scandinavian Stroke Scale, 41.8+/-4.9 and 52.4+/-4.4 on Barthel index, 3.3+/-0.6 and 2.5+/-0.5 on the modified Rankin scale, respectively. The importance of complex multidisciplinary approach to rehabilitative measures is emphasized. PMID- 26525940 TI - [The realization of the program of medical care to patients with vascular pathology in the Central Russia: a three year experience of the Saratov Regional Vascular Center]. AB - Creation of vascular centers in Russian regions is one of the ways of prevention of spreading of vascular diseases. AIM: To analyze three year (2012-2014) activity of the Saratov Regional Vascular Center (RVS). MATERIAL AND METHODS: Several stages of creation and development of RVS as well as the progress achieved in the treatment of acute coronary and cerebrovascular pathology have been analyzed. RESULTS AND CONCLUSION: The realization of protocols, standards, procedures of medical care to patients with cerebrovascular diseases by RVS personnel, wide use of high-technology methods of diagnosis and treatment during 3 years allowed not only to achieve positive results but to find unrealized possibilities of the activity in this direction. PMID- 26525941 TI - [An analysis of the work of vascular service in Smolensk from 2009 to 2014]. AB - MATERIAL AND METHODS: Report of the regional vascular service center of Smolensk work and work of vascular service of Smolensk region were analyzed. The aim of the study is to analyze work of the vascular service in Smolensk and Smolensk region in 2009-2014. RESULTS AND CONCLUSION: Mortality and morbidity in patients with cardio-vascular diseases in Smolensk Region are higher than in other regions of Russia. Recently a number of patients hospitalized to vascular service centers are increased. Infectious complications (pneumonia, bedsores, pyoderma) take lead place in mortality. Nowadays it's very important to solve the problem with prophylaxis of infectious complications in patients with acute ischemic stroke, also to solve problem with rehabilitation in patients with mild and severe motor disorders and disorders of praxis, gnosis. Continuous training of doctors and nurses in regional vascular service centers is needed. It will increase quality of medical service and improve rehabilitation prognosis in patients with ischemic stroke. PMID- 26525942 TI - (CH3NH3)2Pb(SCN)2I2: a more stable structural motif for hybrid halide photovoltaics? AB - Hybrid halide perovskites have recently emerged as a highly efficient class of light absorbers; however, there are increasing concerns over their long-term stability. Recently, incorporation of SCN(-) has been suggested as a novel route to improving stability without negatively impacting performance. Intriguingly, despite crystallizing in a 2D layered structure, (CH3NH3)2Pb(SCN)2I2 (MAPSI) possesses an ideal band gap of 1.53 eV, close to that of the 3D connected champion hybrid perovskite absorber, CH3NH3PbI3 (MAPI). Here, we identify, using hybrid density functional theory, the origin of the smaller than expected band gap of MAPSI through a detailed comparison with the electronic structure of MAPI. Furthermore, assessment of the MAPSI structure reveals that it is thermodynamically stable with respect to phase separation, a likely source of the increased stability reported in experiment. PMID- 26525943 TI - Suicidal ideation reported by adults with Type 1 or Type 2 diabetes: results from Diabetes MILES-Australia. AB - AIMS: To examine the prevalence and correlates of suicidal ideation (SI) in a community-based sample of adults with Type 1 or Type 2 diabetes. METHODS: Participants were 3338 adults aged 18-70 years with Type 1 diabetes (n = 1376) or Type 2 diabetes (non-insulin: n = 1238; insulin: n = 724) from a national survey administered to a random sample registered with the National Diabetes Services Scheme. Depression and SI were assessed using the Patient Health Questionnaire, and diabetes-specific distress with the Problem Areas In Diabetes scale. Separate logistic regression analyses by diabetes type/treatment were used to determine relative contribution to SI. RESULTS: Overall, we observed a SI rate of 14% in our sample. Participants with Type 2 diabetes using insulin reported more frequent depressive symptoms, and were more likely to report recent SI (19%) compared with those with either Type 1 diabetes or Type 2 diabetes not using insulin (14 and 12%, respectively). After controlling for depression, there was little difference in the prevalence of SI between diabetes types/treatments, but higher diabetes-specific distress significantly increased the odds of SI. CONCLUSIONS: As SI is a significant risk factor for a suicide attempt, the findings have implications for healthcare professionals, pointing to the importance of adequate screening and action plans for appropriate follow-up of those reporting depression. Our findings are also indicative of the psychological toll of diabetes more generally, and the need to integrate physical and mental healthcare for people with diabetes. PMID- 26525944 TI - Neuropathic Pain. PMID- 26525945 TI - Parents' Use of Praise and Criticism in a Sample of Young Children Seeking Mental Health Services. AB - Parents' use of praise and criticism are common indicators of parent-child interaction quality and are intervention targets for mental health treatment. Clinicians and researchers often rely on parents' self-reports of parenting behavior, although studies about the correlation of parents' self-reports and actual behavior are rare. We examined the concordance between parents' self reports of praise and criticism of their children and observed use of these behaviors during a brief parent-child play session. Parent self-report and observational data were collected from 128 parent-child dyads referred for child mental health treatment. Most parents reported praising their children often and criticizing their children rarely. However, parents were observed to criticize their children nearly three times more often than they praised them. Self reported and observed praise were positively correlated (rs = 0.32, p < .01), whereas self-reported and observed criticisms were negatively correlated (rs = 0.21, p < .05). Parents' tendencies to overestimate their use of praise and underestimate their use of criticism are discussed. PMID- 26525946 TI - Translating Research to Practice for Children With Autism Spectrum Disorder: Part 2: Behavior Management in Home and Health Care Settings. AB - INTRODUCTION: Managing home and health care for children with autism spectrum disorder can be challenging because of the range of symptoms and behaviors exhibited. METHOD: This article presents an overview of the emerging science related to the methods to foster family self-management of common concerns regarding activities of daily living and behaviors, as well as for the health care provider in primary and acute health care settings. RESULTS: Recommendations are provided to enhance the overall delivery of services, including understanding and managing a child's challenging behaviors, and supporting family management of common activities of daily living and behaviors. DISCUSSION: Health care providers' knowledge of evidence-based recommendations for providing care, supporting family self-management of common concerns, and referral heighten the likelihood of better outcomes for children with autism spectrum disorder. PMID- 26525947 TI - Cooling Methods in Heat Stroke. AB - BACKGROUND: Heat stroke is an illness with a high risk of mortality or morbidity, which can occur in the young and fit (exertional heat stroke) as well as the elderly and infirm (nonexertional heat stroke). In the United States, from 2006 to 2010, there were at least 3332 deaths attributed to heat stroke. OBJECTIVE: To summarize the available evidence on the principal cooling methods used in the treatment of heat stroke. DISCUSSION: Although it is generally agreed that rapid, effective cooling increases survival in heat stroke, there continues to be debate on the optimal cooling method. Large, controlled clinical trials on heat stroke are lacking. Cooling techniques applied to healthy volunteers in experimental models of heat stroke have not worked as rapidly in actual patients with heat stroke. The best available evidence has come from large case series using ice water immersion or evaporation plus convection to cool heat-stroke patients. CONCLUSIONS: Ice-water immersion has been shown to be highly effective in exertional heat stroke, with a zero fatality rate in large case series of younger, fit patients. In older patients with nonexertional heat stroke, studies have more often promoted evaporative plus convective cooling. Evaporative plus convective cooling may be augmented by crushed ice or ice packs applied diffusely to the body. Chilled intravenous fluids may also supplement primary cooling. Based on current evidence, ice packs applied strategically to the neck, axilla, and groin; cooling blankets; and intravascular or external cooling devices are not recommended as primary cooling methods in heat stroke. PMID- 26525948 TI - Improvements for international medicine donations: a review of the World Health Organization Guidelines for Medicine Donations, 3rd edition. AB - Some humanitarian and development organizations respond to major natural disasters and emergencies by donating medicines. Many provide medicines on a routine basis to support health systems, particularly those run by Faith-Based Organizations. Although such donations can provide essential medicines to populations in great need, inappropriate donations also take place, with burdensome consequences. The World Health Organization (WHO) has developed the interagency Guidelines for Medicine Donations for use by donors and recipients in the context of emergency aid and international development assistance. Although comprehensive in nature and transferable to various emergency situations, adjustments to both content and formatting would improve this resource. Recommendations for the next version of these guidelines include: specific wording and consistent formatting; definition of who is a recipient, clear distinction between acute and long-term emergencies, and proper donation procedures pertaining to each; inclusion of visual aides such as flowcharts, checklists, and photos; and improving the citations system. PMID- 26525950 TI - Encapsulated paclitaxel nanoparticles exhibit enhanced anti-tumor efficacy in A549 non-small lung cancer cells. AB - In the present study, paclitaxel (PTX) were encapsulated with polyethylene glycol (PEG)-polylactide (PLA)/D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) (PEG-PLA/TPGS) and the enhanced anti-tumor activity of this PTX mixed micelles (PTX-MM) was evaluated in lung cancer cells. The PTX-MM prepared by a solvent evaporation method was demonstrated to have high drug-loading efficiency (23.2%), high encapsulation efficiency (76.4%), and small size (59 nm). In vitro release assay showed the slow release behavior of PTX-MM, suggesting the good stability of the PTX-MM essential for long circulation time. In vitro kinetics assay demonstrated that PTX-MM could promote absorption and increase relative bioavailability. The anti-cancer efficiency of PTX-MM was also examined by both in vitro and in vivo studies. PTX-MM exhibits obvious cytotoxicity against lung cancer cells with much lower IC50 value when compared with commercial formulated PTX or PTX + TPGS. The xenograft tumor model studies on nude mice indicated that PTX-MM inhibits tumor growth more effectively than other formulations. It was also found that most of mixed micelles were integral in tumor site to exhibit anti-cancer activity. Our results suggested that the use of PTX-MM as an anti cancer drug may be an effective approach to treat lung cancer. PMID- 26525949 TI - The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention. AB - The pleiotropic second messenger adenosine 3',5'-cyclic monophosphate (cAMP) regulates a myriad of biological processes under both physiological and pathophysiological conditions. Exchange protein directly activated by cAMP 1 (EPAC1) mediates the intracellular functions of cAMP by acting as a guanine nucleotide exchange factor for the Ras-like Rap small GTPases. Recent studies suggest that EPAC1 plays important roles in immunomodulation, cancer cell migration/metastasis, and metabolism. These results, coupled with the successful development of EPAC-specific small molecule inhibitors, identify EPAC1 as a promising therapeutic target for cancer treatments. PMID- 26525951 TI - Development and Characterization of the Recombinant Human VEGF-EGF Dual-Targeting Fusion Protein as a Drug Delivery System. AB - The design, preparation, as well as structural and functional characterizations of the recombinant fusion protein hVEGF-EGF as a dual-functional agent that may target both EGFR (R: receptor) and angiogenesis are reported. hVEGF-EGF was found to bind to EGFR more strongly than did EGF, and to bind to VEGFR similarly to VEGF. Mass spectrometry measurements showed that the sites of DTPA (diethylenetriaminepentaacetic acid) conjugated hVEGF-EGF (for radiolabeling) were the same as those of its parent hEGF and hVEGF proteins. All DTPA-conjugated proteins retained similar binding capacities to their respective receptors as compared to their respective parent proteins. In vitro cell binding studies using BAEC (a bovine aortic endothelial cell) and MDA-MB-231 (a human breast cancer) cells expressing both EGFR and VEGFR confirmed similar results. Treating BAEC cells with hVEGF-EGF induced remarkable phosphorylation of EGFR, VEGFR, and their downstream targets ERK1/2. Nevertheless, the radiolabeled (111)In-DTPA-hVEGF-EGF showed cytotoxicity against MDA-MB-231 cells. Pharmacokinetic studies using (111)In-DTPA-hVEGF-EGF in BALB/c nude mice showed that appreciable tracer activities were accumulated in liver and spleen. In all, this study demonstrated that the fusion protein hVEGF-EGF maintained the biological specificity toward both EGFR and VEGFR and may be a potential candidate as a dual-targeting moiety in developing anticancer drugs. PMID- 26525952 TI - Identifying Connectome Module Patterns via New Balanced Multi-Graph Normalized Cut. AB - Computational tools for the analysis of complex biological networks are lacking in human connectome research. Especially, how to discover the brain network patterns shared by a group of subjects is a challenging computational neuroscience problem. Although some single graph clustering methods can be extended to solve the multi-graph cases, the discovered network patterns are often imbalanced, e.g. isolated points. To address these problems, we propose a novel indicator constrained and balanced multi-graph normalized cut method to identify the connectome module patterns from the connectivity brain networks of the targeted subject group. We evaluated our method by analyzing the weighted fiber connectivity networks. PMID- 26525954 TI - Systemic Teriparatide Administration Promotes Osseous Regeneration of an Intrabony Defect: A Case Report. AB - INTRODUCTION: Teriparatide comprises the first 34 amino acids of parathyroid hormone and is a systemic anabolic agent that is Food and Drug Administration approved for the treatment of osteoporosis but not for periodontitis. To our knowledge, this is the first clinical case report to document the treatment of a patient with severe periodontitis using an open-flap debridement procedure in conjunction with teriparatide. CASE PRESENTATION: A 45-year-old female patient was diagnosed with severe chronic periodontitis, including the presence of an intrabony defect on tooth #6. She received open-flap debridement surgery in conjunction with daily systemic administration of 20 ug teriparatide, oral vitamin D, and calcium supplements for 6 weeks. Radiographic, clinical, gingival crevicular fluid (pyridinoline cross-linked carboxy-terminal propeptide of type I procollagen, procollagen type 1 N-propeptide, and osteocalcin), and serum parameters (parathyroid hormone, bone alkaline phosphatase, calcium, and 25 hydroxyvitamin D) were assessed. Treatment outcomes were evaluated over 4 years, with successful radiographic and clinical results throughout the follow-up period. CONCLUSION: Teriparatide administration in conjunction with traditional open-flap debridement surgery offers potential for the treatment of severe intrabony defects resulting from chronic periodontitis. PMID- 26525953 TI - Surveillance of Food- and Smear-Transmitted Pathogens in European Soldiers with Diarrhea on Deployment in the Tropics: Experience from the European Union Training Mission (EUTM) Mali. AB - Introduction. Since 2013, European soldiers have been deployed on the European Union Training Mission (EUTM) in Mali. From the beginning, diarrhea has been among the most "urgent" concerns. Diarrhea surveillance based on deployable real time PCR equipment was conducted between December 2013 and August 2014. Material and Methods. In total, 53 stool samples were obtained from 51 soldiers with acute diarrhea. Multiplex PCR panels comprised enteroinvasive bacteria, diarrhea associated Escherichia coli (EPEC, ETEC, EAEC, and EIEC), enteropathogenic viruses, and protozoa. Noroviruses were characterized by sequencing. Cultural screening for Enterobacteriaceae with extended-spectrum beta-lactamases (ESBL) with subsequent repetitive sequence-based PCR (rep-PCR) typing was performed. Clinical information was assessed. Results. Positive PCR results for diarrhea associated pathogens were detected in 43/53 samples, comprising EPEC (n = 21), ETEC (n = 19), EAEC (n = 15), Norovirus (n = 10), Shigella spp./EIEC (n = 6), Cryptosporidium parvum (n = 3), Giardia duodenalis (n = 2), Salmonella spp. (n = 1), Astrovirus (n = 1), Rotavirus (n = 1), and Sapovirus (n = 1). ESBL-positive Enterobacteriaceae were grown from 13 out of 48 samples. Simultaneous infections with several enteropathogenic agents were observed in 23 instances. Symptoms were mild to moderate. There were hints of autochthonous transmission. Conclusions. Multiplex real-time PCR proved to be suitable for diarrhea surveillance on deployment. Etiological attribution is challenging in cases of detection of multiple pathogens. PMID- 26525955 TI - Comparing the Coronal Flaring Efficacy of Five Different Instruments Using Cone Beam Computed Tomography. AB - INTRODUCTION: Fearless removal of tooth structure during canal preparation and shaping has negative effects on the prognosis of treatment. On the other hand, sufficient pre-enlargement facilitates exact measurement of the apical size. The present in vitro study aimed to compare the efficacy of Gates-Glidden drills, K3, ProTaper, FlexMaster and RaCe instruments in dentin removal during coronal flaring using cone-beam computed tomography (CBCT). METHODS AND MATERIALS: A total of 40 mandibular molars were selected and the coronal areas of their mesiobuccal and mesiolingual root canals were randomly prepared with either mentioned instruments. Pre- and post-instrumentation CBCT images were taken and the thickness of canal walls was measured in 1.5- and 3-mm distances from the furcation area. Data were analyzed using the one-way ANOVA. Tukey's post hoc tests were used for two-by-two comparisons. RESULTS: At 1.5-mm distance, there was no significant difference between different instruments. However, at 3-mm distances, Gates-Glidden drills removed significantly more dentin compared to FlexMaster files (mean=0.18 mm) (P<0.02); however, two-by-two comparisons did not reveal any significant differences between the other groups. CONCLUSION: All tested instruments can be effectively used in clinical settings for coronal pre enlargement. PMID- 26525956 TI - Severe eosinophilic fasciitis: comparison of treatment with D-penicillamine plus corticosteroids vs. corticosteroids alone. AB - OBJECTIVES: To compare the therapeutic effectiveness of corticosteroids (CS) alone vs. CS plus d-penicillamine (d-Pen) in severe eosinophilic fasciitis. METHOD: A long-term prospective non-randomized trial of d-Pen plus CS vs. CS alone in patients with severe eosinophilic fasciitis, defined as clinically apparent cutaneous fibrotic involvement affecting more than 15% body surface area (BSA) or more than 10% BSA with joint flexion contractures. RESULTS: Sixteen patients with severe eosinophilic fasciitis entered the study. Ten patients received d-Pen plus CS and six received CS alone. Affected BSA decreased from an average of 29% to 8.9% in the d-Pen plus CS group compared to a decrease in affected BSA from 28% to 22.83% in the CS-alone group. The reduction in affected BSA in the d-Pen plus CS group was significantly greater than in the CS-alone group (p = 0.038). Clinical improvement occurred in all d-Pen plus CS patients compared to only 33.3% of CS-alone patients (p = 0.008). There was no difference in overall frequency of adverse events between the groups (p = 0.60). The most common adverse event in the d-Pen plus CS group was proteinuria (33.3%). However, proteinuria also occurred in 16.6% in the CS-alone group. CONCLUSIONS: Treatment with CS alone failed to induce clinical improvement in the majority of the severe eosinophilic fasciitis patients. By contrast, d-Pen plus CS resulted in significantly greater clinical improvement. These results suggest that initial treatment of severe eosinophilic fasciitis with CS alone is not sufficient for optimal therapeutic response and that addition of an antifibrotic agent results in an improved outcome. PMID- 26525958 TI - One day CRIKC workshop on Technical Advances in Retinal Imaging. PMID- 26525957 TI - Bioinspired Reductionistic Peptide Engineering for Exceptional Mechanical Properties. AB - A simple solution-processing and self-assembly approach that exploits the synergistic interactions between multiple hydrogen bonded networks and aromatic interactions was utilized to synthesize molecular crystals of cyclic dipeptides (CDPs), whose molecular weights (~0.2 kDa) are nearly three orders of magnitude smaller than that of natural structural proteins (50-300 kDa). Mechanical properties of these materials, measured using the nanoindentation technique, indicate that the stiffness and strength are comparable and sometimes better than those of natural fibres. The measured mechanical responses were rationalized by recourse to the crystallographic structural analysis and intermolecular interactions in the self-assembled single crystals. With this work we highlight the significance of developing small molecule based bioinspired design strategies to emulate biomechanical properties. A particular advantage of the successfully demonstrated reductionistic strategy of the present work is its amenability for realistic industrial scale manufacturing of designer biomaterials with desired mechanical properties. PMID- 26525959 TI - Tamsulosin Treatment Affecting Patient-reported Outcomes in Benign Prostatic Hyperplasia-associated Depressive Symptoms. AB - OBJECTIVE: To investigate the effect of tamsulosin on LUTS and depressive symptoms among depressed and nondepressed individuals previously diagnosed with benign prostatic hyperplasia. MATERIALS AND METHODS: The study conducted from July 2013 to June 2014 included outpatient participants with benign prostatic hyperplasia presenting with lower urinary tract symptoms (LUTS). One tablet of tamsulosin (0.2 mg) was administered to patients daily. We divided participants with geriatric depression scale (GDS) scores of 0-17 into the nondepressive symptom group (group 1) and those with GDS scores of 18-30 into the depressive symptom group (group 2). At the first visit (V1), 4th week (V2), and 12th week (V3), the International Prostate Symptom Score (IPSS), quality of life (QoL), patient perception of bladder condition, overactive bladder syndrome symptom score, and GDS questionnaires were administered. RESULTS: IPSS (17.35 +/- 7.11 vs 14.61 +/- 6.04, P = .10) as well as GDS scores (20.97 +/- 3.07 vs 8.84 +/- 4.50, P < .01) were higher among those with depressive symptoms than those without, and difference between the two groups was not represented. After taking tamsulosin, on the V2 and V3, both groups had improved overactive bladder syndrome symptom scores, patient perception of bladder condition, IPSS, QoL, and GDS. Comparing the first visit with the V2 and V3, group 2 showed significant changes in GDS, but group 1 did not. CONCLUSION: Treatment with tamsulosin is associated with improved LUTS and decreased depressive symptoms, which could enhance QoL. PMID- 26525960 TI - The Effect of Disease Severity on 24-Hour Urine Parameters in Kidney Stone Patients With Type 2 Diabetes. AB - OBJECTIVE: To characterize the changes in urine composition associated with increasing severity of diabetes, we analyzed urine composition relative to glycated hemoglobin (HbA1c) and treatment strategy in a largely minority population. METHODS: Patients treated for kidney stones between 2001 and 2013 at a single tertiary institution and had 24-hour urine collections were included in the study. Patients with type 1 diabetes or taking either thiazide diuretics or alkalinizing agents were excluded. Analysis was performed in IBM SPSS Statistics version 20 using multivariate regression, and Kruskal-Wallis testing was used. RESULTS: Nine hundred fifty-five patients were included in this study-268 (28%) with type 2 diabetes mellitus, of whom 53 (19.8%) used insulin. Patients with diabetes had lower urine pH, calcium, and phosphate when compared with the control group, but no significant differences were found between the diabetes groups. Multivariate analysis found that HbA1c had a positive correlation with citrate (P = .008), creatinine (P = .037), urine volume (P = .044), and a trend toward a positive association with urinary calcium calcium (P = .064). Insulin use did not have a significant relationship with urinary parameters but trended toward an inverse relationship with calcium (P = .051). pH was not a significant predictor of any urine constituent. CONCLUSION: In an ethnically diverse inner city patient population, patients with diabetes mellitus type 2 who use insulin have no significant differences in urine parameters when compared with those on oral hypoglycemics. Worsening glucose control as measured by HbA1c levels predicts increased urine citrate and volume. PMID- 26525961 TI - Nutritional Interventions in Heart Failure: A Systematic Review of the Literature. AB - BACKGROUND: Heart failure (HF) is a major health care burden and there is a growing need to develop strategies to maintain health and sustain quality of life in persons with HF. The purpose of this review is to critically appraise the components of nutrition interventions and to establish an evidence base for future advances in HF nutrition research and practice. METHODS AND RESULTS: Cinahl, Pubmed, and Embase were searched to identify articles published from 2005 to 2015. A total of 17 randomized controlled trials were included in this review. Results were divided into 2 categories of nutrition-related interventions: (1) educational and (2) prescriptive. Educational interventions improved patient outcomes such as adherence to dietary restriction in urine sodium levels and self reported diet recall. Educational and prescriptive interventions resulted in decreased readmission rates and patient deterioration. Adherence measurement was subjective in many studies. Evidence showed that a normal-sodium diet and 1-liter fluid restriction along with high diuretic dosing enhanced B-type natriuretic peptide, aldosterone, tumor necrosis factor alpha, and interleukin-6 markers. CONCLUSIONS: Educational nutrition interventions positively affect patient clinical outcomes. Although clinical practice guidelines support a low-sodium diet and fluid restriction, research findings have revealed that a low-sodium diet may be harmful. Future research should examine the role of macronutrients, food quality, and energy balance in HF nutrition. PMID- 26525962 TI - Switching from usual brand cigarettes to a tobacco-heating cigarette or snus: Part 3. Biomarkers of biological effect. AB - A randomized, multi-center study of adult cigarette smokers switched to tobacco heating cigarettes, snus or ultra-low machine yield tobacco-burning cigarettes (50/group) for 24 weeks was conducted. Evaluation of biomarkers of biological effect (e.g. inflammation, lipids, hypercoaguable state) indicated that the majority of consistent and statistically significant improvements over time within each group were observed in markers of inflammation. Consistent and statistically significant differences in pairwise comparisons between product groups were not observed. These findings are relevant to the understanding of biomarkers of biological effect related to cigarette smoking as well as the risk continuum across various tobacco products (ClinicalTrials.gov Identifier: NCT02061917). PMID- 26525963 TI - Pre-hypertension: Is it an inflammatory state? AB - Even though several studies have implicated the role of inflammation in the pathogenesis of hypertension and other cardiovascular disease, there are only limited studies about inflammatory markers in prehypertension. The objective of the present article was to review the role of markers like C-reactive protein, interleukin-6, tumor necrosis factor-alpha and sialic acid in prehypertension. An extensive literature search was made in Pubmed (http://www.ncbi.nlm.nih.gov/pubmed/) using phrases such as prehypertension, inflammation, C-reactive protein, cardiovascular disease, cytokines and sialic acid. Several investigators have reported increased inflammatory markers like C reactive protein, interleukin-6, tumor necrosis factor-alpha and sialic acid in prehypertension indicating the role of inflammation in the pathogenesis of prehypertension and its complications. Elevated inflammatory markers may enhance the risk for cardiovascular disease in subjects with prehypertension. PMID- 26525964 TI - High levels of serum mannose-binding lectins are associated with the severity and clinical outcomes of severe traumatic brain injury. AB - BACKGROUND: Mannose-binding lectin (MBL) is a key component of innate immunity. The expression of cortical MBL is up-regulated after clinical and experimental head trauma. This study aimed to assess the association of serum MBL levels with injury severity and long-term clinical outcomes after severe traumatic brain injury (STBI). METHODS: Serum MBL levels were measured in 122 patients and 100 healthy controls. Multivariate analyses were used to analyze the relationship between serum MBL levels and trauma severity reflected by Glasgow Coma Scale scores as well as between serum MBL levels and 6-month mortality and unfavorable outcome (Glasgow Outcome Scale score: 1-3). A receiver operating characteristic (ROC) curve was structured to evaluate the prognostic predictive performance of serum MBL levels. RESULTS: Compared with healthy controls, serum MBL levels of patients were markedly elevated. Using multivariate analyses, serum MBL levels were found to be associated closely with Glasgow Coma Scale (GCS) scores and MBL emerged as an independent predictor for 6-month mortality and unfavorable outcome. Under ROC curve, serum MBL levels and GCS scores possessed similar prognostic predictive values. CONCLUSION: Increased serum level of MBL was independently associated with head trauma severity and long-term clinical outcomes of STBI. PMID- 26525965 TI - Revisiting HELLP syndrome. AB - HELLP syndrome was first described in 1982 by Weinstein et al. and the term HELLP refers to an acronym used to describe the clinical condition that leads to hemolysis, elevated liver enzymes and low platelets. The syndrome frequency varies from 0.5 to 0.9% pregnancies and manifests preferentially between the 27th and 37th week of gestation. Approximately 30% of cases occur after delivery. Although the etiopathogenesis of this syndrome remains unclear, histopathologic findings in the liver include intravascular fibrin deposits that presumably may lead to hepatic sinusoidal obstruction, intrahepatic vascular congestion, and increased intrahepatic pressure with ensuing hepatic necrosis, intraparenchymal and subcapsular hemorrhage, and eventually capsular rupture. Typical clinical symptoms of HELLP syndrome are pain in the right upper quadrant abdomen or epigastric pain, nausea and vomiting. However, this syndrome can present nonspecific symptoms and the diagnosis may be difficult to be established. Laboratory tests and imaging exams are essential for differential diagnosis with other clinical conditions. Treatment of HELLP syndrome with corticosteroids, targeting both lung maturation of the fetus is still an uncertain clinical value. In conclusion, three decades after the tireless efforts of Dr. Weinstein to characterize HELLP syndrome, it remains a challenge to the scientific community and several questions need to be answered for the benefit of pregnant women. PMID- 26525966 TI - [Cutaneous diphtheria after a minor injury in Sri Lanka]. AB - Cutaneous dipththeria is an infectious bacterial disease endemic in tropical regions, but rarely diagnosed in Germany. Following travel in Sri Lanka, a 60 year-old German presented to our dermatological clinic with a skin ulcer and extensive erythematous erosive edema of his left foot. Corynebacterium diphtheriae was isolated from a swab of the lesion. There were no clinical signs of toxic diphtheria. The patient was treated with penicillin G and erythromycin, followed by a slow healing of the lesion. The isolated strain could be identified as toxigenic C. diphtheriae mitis. Due to increased travel activity, dermatologists should have uncommon infections like cutaneous diphtheria in mind. PMID- 26525967 TI - [Verrucous variant of porokeratosis of Mibelli as a differential diagnosis of psoriasis vulgaris]. AB - In a 37-year-old man, diagnosis of verrucous porokeratosis could only be made by histological examination. Previously, the skin lesions on the right buttock had been treated by several dermatologists as psoriasis vulgaris. The clinical picture of both dermatoses was characterized by sharply defined, erythematous papules and plaques. Precise evaluation of the clinical morphology was key for diagnosis. Moreover, in contrast to psoriasis, verrucous porokeratosis is characterized by a high degree of treatment resistance. PMID- 26525968 TI - Recovery of precious metals from low-grade automobile shredder residue: A novel approach for the recovery of nanozero-valent copper particles. AB - The presence of precious metals (PMs) in low-grade automobile shredder residue (ASR) makes it attractive for recycling. This study investigated the leaching and recovery characteristics of two PMs (Cu and Ag) and two heavy metals (Mn and Co) from ASR. The effects of H2O2, leaching temperature, liquid to solid (L/S) ratio, and particle size on metal leaching were determined in an aqueous solution of 0.5M nitric acid. The metal leaching rate was increased with increasing nitric acid concentration, amount of H2O2, L/S ratio and temperature. The leaching kinetics was analyzed by using a second-order reaction model. In the analysis of leaching kinetics, the metal leaching data were well fitted (R(2)?0.99) with the second-order reaction model. The activation energy (kJ/mol) for metal leaching was 39.6 for Cu, 17.1 for Ag, 17.3 for Mn and 29.2 for Co. Metal recovery was carried out by fractional precipitation with the addition of advanced Fenton's regent. Metal recovery efficiency was increased to 99.95% for Cu, 99.8% for Mn, 90.0% for Ag and 96.46% for Co with the advanced Fenton's regent. In particular, a novel finding of the PM recovery is that Cu can also be recovered directly from the leachate of ASR in the form of zero-valent copper (ZVC) nanoparticles (NPs). Hydrometallurgical recovery of the metals from ASR using nitric acid is highly efficient. PMID- 26525969 TI - Quantification of parameters influencing methane generation due to biodegradation of municipal solid waste in landfills and laboratory experiments. AB - The energy conversion potential of municipal solid waste (MSW) disposed of in landfills remains largely untapped because of the slow and variable rate of biogas generation, delayed and inefficient biogas collection, leakage of biogas, and landfill practices and infrastructure that are not geared toward energy recovery. A database consisting of methane (CH4) generation data, the major constituent of biogas, from 49 laboratory experiments and field monitoring data from 57 landfills was developed. Three CH4 generation parameters, i.e., waste decay rate (k), CH4 generation potential (L0), and time until maximum CH4 generation rate (tmax), were calculated for each dataset using U.S. EPA's Landfill Gas Emission Model (LandGEM). Factors influencing the derived parameters in laboratory experiments and landfills were investigated using multi-linear regression analysis. Total weight of waste (W) was correlated with biodegradation conditions through a ranked classification scheme. k increased with increasing percentage of readily biodegradable waste (Br0 (%)) and waste temperature, and reduced with increasing W, an indicator of less favorable biodegradation conditions. The values of k obtained in the laboratory were commonly significantly higher than those in landfills and those recommended by LandGEM. The mean value of L0 was 98 and 88L CH4/kg waste for laboratory and field studies, respectively, but was significantly affected by waste composition with ranges from 10 to 300L CH4/kg. tmax increased with increasing percentage of biodegradable waste (B0) and W. The values of tmax in landfills were higher than those in laboratory experiments or those based on LandGEM's recommended parameters. Enhancing biodegradation conditions in landfill cells has a greater impact on improving k and tmax than increasing B0. Optimizing the B0 and Br0 values of landfilled waste increases L0 and reduces tmax. PMID- 26525970 TI - MSW to synthetic natural gas: System modeling and thermodynamics assessment. AB - To achieve environmental-friendly and energy-efficiency synthetic natural gas (SNG) production routing from municipal solid waste (MSW), a MSW-to-SNG process is unprecedentedly presented in this work, of which the designed configuration is developed and simulated with the aid of Aspen Plus. In addition, sensitivity analyses on major operation parameters, such as equivalence volume ratio (ER), steam-to-MSW mass ratio (S/M) and methanation pressure, are performed with the discussion of process efficiencies and SNG quality. In parallel, the comparison analysis is considered by adopting various MSW material. In this work, the composition of SNG mainly consists of 87.7% CH4, 2.9% CO2, 2.3% H2 and 7.1% N2. And lower heating value (LHV) together with Wobbe index of SNG are separately 31.66MJ/Nm(3) and 45.90MJ/Nm(3). Moreover, the wood-to-SNG, MSW-to-SNG and coal to-SNG processes are carried out to demonstrate the superiority of the MSW-to-SNG process. The results reveal that the MSW-to-SNG process is a promising option to dispose MSW environmentally, meanwhile converting MSW to the valuable SNG. PMID- 26525971 TI - Are all models susceptible to dysfunctional cognitions about eating and body image? The moderating role of personality styles. AB - OBJECTIVE: We investigated dysfunctional cognitions about eating and body image in relation to personality styles in a group of professional models. METHOD: Dysfunctional cognitions in professional models (n = 43) and a control group (n = 43) were assessed with the 'Eating Disorder Cognition Questionnaire' (EDCQ), eating attitudes with the 'Eating Attitudes Test' (EAT), and personality with the 'Personality Styles and Disorders Inventory' (PSDI-S). RESULTS: Models had higher scores than controls on the EDCQ and EAT and on nine scales of the PSDI-S. Moderation analyses showed significant interactions between groups and personality styles in predicting EDCQ scales: The ambitious/narcissistic style was related to "negative body and self-esteem", the conscientious/compulsive style to "dietary restraint", and the spontaneous/borderline style to "loss of control in eating". CONCLUSIONS: The results indicate that not all models are susceptible to dysfunctional cognitions about eating and body image. Models are at a higher risk of developing negative automatic thoughts and dysfunctional assumptions relating to body size, shape and weight, especially if they have high scores on the above personality styles. PMID- 26525974 TI - Erratum to: Micafungin Elicits an Immunomodulatory Effect in Galleria mellonella and Mice. PMID- 26525973 TI - Outcomes of initial surgery in patients with clinical N2 non-small cell lung cancer who met 4 specific criteria. AB - PURPOSE: The role of surgery for patients with non-small cell lung cancer (NSCLC) with clinical mediastinal lymph node metastasis (N2) remains controversial. We specified 4 criteria for performing initial surgery in these patients (single station N2, non-bulky N2, N2 with regional mode of spread, and N2 without N1) and examined the outcomes to validate the treatment options. METHODS: Between September 2002 and December 2010, of 1290 patients who underwent complete resection for NSCLC, 808 patients underwent initial standard resection, including 779 patients with cN0-1 and 29 with cN2. We compared the outcomes, and evaluated patients with cN2-pN2. RESULTS: The median follow-up was 45.5 months (3-119 months). Seventy (9.0 %) and 24 (82.8 %) patients had p-N2 in the cN0-1 and cN2 groups, respectively (p < 0.0001). The 5-year disease-free survival (DFS) rates in the cN0-1 and cN2 groups were 73.3 and 50.6 %, respectively (p = 0.0053), and the 5-year overall survival (OS) rates were 81.3 and 71.1 %, respectively (p = 0.051). The 5-year DFS and OS of patients with cN2-pN2 were 52.5 and 72.6 %, respectively. CONCLUSIONS: Patients with clinical N2 disease based on our criteria represent a highly specific group with a favorable prognosis. Resection should therefore be the initial treatment for these patients. PMID- 26525975 TI - Synergic Effects of Doxorubicin and Melatonin on Apoptosis and Mitochondrial Oxidative Stress in MCF-7 Breast Cancer Cells: Involvement of TRPV1 Channels. AB - Transient receptor transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+) permeable channel gated by oxidative stress and capsaicin (CAP) and modulated by melatonin (MEL) and capsazepine (CPZ). A combination of doxorubicin (DOX) and MEL may offer a potential therapy for breast cancer by exerting antitumor and anti apoptotic effects and modulating Ca(2+) influx and TRPV1 activity. We aimed to investigate the effects of MEL and DOX on the oxidative toxicity of MCF-7 human breast cancer cells, in addition to the activity of the TRPV1 channel and apoptosis. The MCF-7 cells were divided into the following six treatment groups: control, incubated with MEL (0.3 mM), incubated with 0.5 MUM DOX, incubated with 1 MUM DOX, incubated with MEL + 0.5 MUM DOX, or incubated with MEL + 1 MUM DOX. The intracellular free Ca(2+) concentration was higher in the DOX groups than in the control, and the concentration was decreased by MEL. The intracellular free Ca(2+) concentration was further increased by treatment with the TRPV1 channel activator CAP (0.01 mM), and it was decreased by the CPZ (0.1 mM). The intracellular production of reactive oxygen species, mitochondrial membrane depolarization, apoptosis level, procaspase 9 and PARP activities, and caspase 3 and caspase 9 activities were higher in the DOX and MEL groups than in the control. Apoptosis and the activity of caspase 9 were further increased in the DOX plus MEL groups. Taken together, the findings indicate that MEL supported the effects of DOX by activation of TRPV1 and apoptosis, as well as by inducing MCF-7 cell death. As the apoptosis and caspase activity of cancer cells increase because of their elevated metabolism, MEL may be useful in supporting their apoptotic capacity. PMID- 26525976 TI - First-Trimester Maternal Abdominal Adiposity Predicts Dysglycemia and Gestational Diabetes Mellitus in Midpregnancy. AB - OBJECTIVE: This study assessed the association between first-trimester abdominal adiposity and dysglycemia and gestational diabetes mellitus (GDM) in midpregnancy. RESEARCH DESIGN AND METHODS: In a prospective cohort of 485 women, we measured subcutaneous (SAT), visceral (VAT), and total (TAT) adipose tissue depth, using ultrasound at 11-14 weeks' gestation. Logistic regression analysis assessed the relation between quartiles of SAT, VAT, or TAT depth and the composite outcome of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or GDM, based on a 75-g oral glucose tolerance test at 24-28 weeks. RESULTS: Adjusting for maternal age, ethnicity, family history of diabetes, and BMI, quartile 4 versus quartile 1 VAT (adjusted odds ratio [aOR] 3.1, 95% CI 1.1 9.5) and TAT (aOR 2.7, 95% CI 1.1-7.8) were significantly associated with the composite outcome, but SAT was not (aOR 1.8, 95% CI 0.70-4.8). The same was seen for GDM alone. CONCLUSIONS: Elevated first-trimester VAT and TAT depth independently predicted the risk of dysglycemia later in pregnancy. PMID- 26525972 TI - Telomere homeostasis in mammalian germ cells: a review. AB - Telomeres protect against genome instability and participate in chromosomal movements during gametogenesis, especially in meiosis. Thus, maintaining telomere structure and telomeric length is essential to both cell integrity and the production of germ cells. As a result, alteration of telomere homeostasis in the germ line may result in the generation of aneuploid gametes or gametogenesis disruption, triggering fertility problems. In this work, we provide an overview on fundamental aspects of the literature regarding the organization of telomeres in mammalian germ cells, paying special attention to telomere structure and function, as well as the maintenance of telomeric length during gametogenesis. Moreover, we discuss the different roles recently described for telomerase and TERRA in maintaining telomere functionality. Finally, we review how new findings in the field of reproductive biology underscore the role of telomere homeostasis as a potential biomarker for infertility. Overall, we anticipate that the study of telomere stability and equilibrium will contribute to improve diagnoses of patients; assess the risk of infertility in the offspring; and in turn, find new treatments. PMID- 26525977 TI - Genotypic differences in photosynthetic performance, antioxidant capacity, ultrastructure and nutrients in response to combined stress of salinity and Cd in cotton. AB - Combined stress of salinity and heavy metal is a serious problem for crop production; however, physiological mechanisms of tolerance to such condition remain elusive in cotton. Here, we used two cotton genotypes differing in salt tolerance, to understand their response to salinity (NaCl) and cadmium (Cd) either alone or in combination (Cd + Na) via hydroponics. Results showed that salinity and/or Cd drastically reduced plant growth, chlorophyll content and photosynthesis, with greater effect observed in Zhongmian 41 (sensitive) than Zhong 9806 (tolerant). Although salinity and/or Cd induced malondialdehyde (MDA) accumulation in Zhongmian 41 at 5 and 10 days after treatment, MDA content remained unchanged in Zhong 9806, implying that Zhongmian 41 but not Zhong 9806 faced oxidative stress following exposure to salinity and/or Cd. Differential responses of antioxidant enzymes such as superoxide dismutase, guaiacol peroxidase, catalase and ascorbate peroxidase to Cd, NaCl and Cd + Na indicate genotype- and time course- dependent variations. In both genotypes, Cd content was decreased while Na concentration was increased under combined stress compared with Cd alone. Importantly, NaCl addition in Cd-containing medium caused remarkable reduction in Cd concentration, with the extent of reduction being also dependent on genotypes. The salt-tolerant genotypes had lower Na concentration than sensitive ones. Furthermore, obvious changes in leaf and root ultrastructure was observed under Cd, Na and Cd + Na stress, however Zhong 9806 was less affected compared with Zhongmian 41. These results may provide novel insight into the physiological mechanisms of Cd + Na stress tolerance in various cotton genotypes. PMID- 26525979 TI - Reply to the Letter to the Editor Submitted by Michel Gagner (Publish with OBSU-D 15-00482). PMID- 26525978 TI - A bioinformatic survey of RNA-binding proteins in Plasmodium. AB - BACKGROUND: The malaria parasites in the genus Plasmodium have a very complicated life cycle involving an invertebrate vector and a vertebrate host. RNA-binding proteins (RBPs) are critical factors involved in every aspect of the development of these parasites. However, very few RBPs have been functionally characterized to date in the human parasite Plasmodium falciparum. METHODS: Using different bioinformatic methods and tools we searched P. falciparum genome to list and annotate RBPs. A representative 3D models for each of the RBD domain identified in P. falciparum was created using I-TESSAR and SWISS-MODEL. Microarray and RNAseq data analysis pertaining PfRBPs was performed using MeV software. Finally, Cytoscape was used to create protein-protein interaction network for CITH-Dozi and Caf1-CCR4-Not complexes. RESULTS: We report the identification of 189 putative RBP genes belonging to 13 different families in Plasmodium, which comprise 3.5% of all annotated genes. Almost 90% (169/189) of these genes belong to six prominent RBP classes, namely RNA recognition motifs, DEAD/H-box RNA helicases, K homology, Zinc finger, Puf and Alba gene families. Interestingly, almost all of the identified RNA-binding helicases and KH genes have cognate homologs in model species, suggesting their evolutionary conservation. Exploration of the existing P. falciparum blood-stage transcriptomes revealed that most RBPs have peak mRNA expression levels early during the intraerythrocytic development cycle, which taper off in later stages. Nearly 27% of RBPs have elevated expression in gametocytes, while 47 and 24% have elevated mRNA expression in ookinete and asexual stages. Comparative interactome analyses using human and Plasmodium protein-protein interaction datasets suggest extensive conservation of the PfCITH/PfDOZI and PfCaf1-CCR4-NOT complexes. CONCLUSIONS: The Plasmodium parasites possess a large number of putative RBPs belonging to most of RBP families identified so far, suggesting the presence of extensive post transcriptional regulation in these parasites. Taken together, in silico identification of these putative RBPs provides a foundation for future functional studies aimed at defining a unique network of post-transcriptional regulation in P. falciparum. PMID- 26525980 TI - Erratum to: Intermittent Vagal Nerve Block for Improvements in Obesity, Cardiovascular Risk Factors, and Glycemic Control in Patients with Type 2 Diabetes Mellitus: 2-Year Results of the VBLOC DM2 Study. PMID- 26525981 TI - Identification of novel tylosin analogues generated by a wblA disruption mutant of Streptomyces ansochromogenes. AB - BACKGROUND: Streptomyces, as the main source of antibiotics, has been intensively exploited for discovering new drug candidates to combat the evolving pathogens. Disruption of wblA, an actinobacteria-specific gene controlling major developmental transition, can cause the alteration of phenotype and morphology in many species of Streptomyces. One wblA homologue was found in Streptomyces ansochromogenes 7100 by using the Basic Local Alignment Search Tool. It is interesting to identify whether novel secondary metabolites could be produced by the wblA disruption mutant as evidenced in other Streptomyces. RESULTS: The wblA disruption mutant of S. ansochromogenes 7100 (DeltawblA) was constructed by homologous recombination. DeltawblA failed to produce spores and nikkomycin, the major product of S. ansochromogenes 7100 (wild-type strain) during fermentation. Antibacterial activity against Staphylococcus aureus and Bacillus cereus was observed with fermentation broth of DeltawblA but not with that of the wild-type strain. To identify the antibacterial compounds, the two compounds (compound 1 and compound 2) produced by DeltawblA were characterized as 16-membered macrolides by mass spectrometry and nuclear magnetic resonance spectroscopy. The chemical structure of these compounds shows similarity with tylosin, and the bioassays indicated that the two compounds inhibited the growth of a number of gram-positive bacteria. It is intriguing that they displayed much higher activity than tylosin against Streptococcus pneumoniae. CONCLUSIONS: Two novel tylosin analogues (compound 1 and 2) were generated by DeltawblA. Bioassays showed that compound 1 and 2 displayed much higher activity than tylosin against Streptococcus pneumoniae, implying that these two compounds might be used to widen the application of tylosin. PMID- 26525982 TI - Rapid Evidence Assessment of the Literature (REAL((c))): streamlining the systematic review process and creating utility for evidence-based health care. AB - BACKGROUND: Systematic reviews (SRs) are widely recognized as the best means of synthesizing clinical research. However, traditional approaches can be costly and time-consuming and can be subject to selection and judgment bias. It can also be difficult to interpret the results of a SR in a meaningful way in order to make research recommendations, clinical or policy decisions, or practice guidelines. Samueli Institute has developed the Rapid Evidence Assessment of the Literature (REAL) SR process to address these issues. REAL provides up-to-date, rigorous, high quality SR information on health care practices, products, or programs in a streamlined, efficient and reliable manner. This process is a component of the Scientific Evaluation and Review of Claims in Health Care (SEaRCHTM) program developed by Samueli Institute, which aims at answering the question of "What works?" in health care. METHODS/DESIGN: The REAL process (1) tailors a standardized search strategy to a specific and relevant research question developed with various stakeholders to survey the available literature; (2) evaluates the quantity and quality of the literature using structured tools and rulebooks to ensure objectivity, reliability and reproducibility of reviewer ratings in an independent fashion and; (3) obtains formalized, balanced input from trained subject matter experts on the implications of the evidence for future research and current practice. RESULTS: Online tools and quality assurance processes are utilized for each step of the review to ensure a rapid, rigorous, reliable, transparent and reproducible SR process. CONCLUSIONS: The REAL is a rapid SR process developed to streamline and aid in the rigorous and reliable evaluation and review of claims in health care in order to make evidence-based, informed decisions, and has been used by a variety of organizations aiming to gain insight into "what works" in health care. Using the REAL system allows for the facilitation of recommendations on appropriate next steps in policy, funding, and research and for making clinical and field decisions in a timely, transparent, and cost-effective manner. PMID- 26525983 TI - Anti-inflammatory effects of novel sinomenine derivatives. AB - Sinomenine is an isoquinoline-type alkaloid found in Sinomenium acutum (Thunb.) Rehd. et Wils and S. acutum (Thunb.) Rehd. et Wils var. cinereum Rehd. et Wils. When used as a medicine, this compound exhibits anti-inflammatory properties; however, sinomenine's use as a medication is limited by side effects, a short half-life, and low efficacy. Owing to these limits, attempts have been made to synthesize sinomenine derivatives with enhanced efficacy. In this study, the anti inflammatory effects of novel sinomenine derivatives (S1a-S1f) were examined on the basis of lipopolysaccharide-induced inflammatory factor expression in Raw264.7 cells, dimethylbenzene-induced ear oedema, and Evan's blue leakage in mice, and carrageenan-induced paw oedema in rats. Compared with sinomenine, the derivatives significantly inhibited the expression of the inflammatory factors IL 1beta and IL-6 at the transcriptional and translational levels. Topical application of 3.250mg/kg of the derivatives also alleviated ear oedema. Compared with the vehicle, the derivatives significantly inhibited carrageenan-induced rat paw oedema after 6h. Among the derivatives, S1a exhibited the most potent anti inflammatory activity. S1a also significantly increased the sinomenine-induced inhibition of Evan's blue leakage. Thus, S1a may elicit the strongest anti inflammatory effects of the tested compounds. Based on these results, further development of this compound may be warranted. PMID- 26525984 TI - Focusing on rare diseases in China: are we there yet? AB - The Chinese researchers have made significant progress in studying rare diseases in the recent years. From 2000 to 2014, 269 out of 1892 clinically relevant original research papers published on high impact journals by Chinese institutions, and 2678 out of 6040 clinical trials conducted by Chinese institutions and registered at ClinicalTrial.gov are focused on rare diseases. The number of research papers and of clinical trials has shown a steady trend of increase. Creating public databases for rare disease will escalate progress in rare disease and enable multicenter studies. PMID- 26525986 TI - Using mobile technologies for immunization: Predictors of uptake of a pan Canadian immunization app (ImmunizeCA). PMID- 26525985 TI - Risk of fracture in men with prostate cancer on androgen deprivation therapy: a population-based cohort study in New Zealand. AB - BACKGROUND: Androgen deprivation therapy (ADT) administered as a prostate cancer treatment is known to exert multiple side effects including bone deterioration leading to bone fracture. The current analysis is to evaluate the burden of fracture risk in the New Zealand prostate cancer (PCa) population treated with ADT, and to understand the subsequent risk of mortality after a fracture. METHODS: Using datasets created through linking records from the New Zealand Cancer Registry, National Minimal Dataset, Pharmaceutical Collection and Mortality Collection, we studied 25,544 men (aged >=40 years) diagnosed with PCa between 2004 and 2012. ADT was categorised into the following groups: gonadotropin-releasing hormone (GnRH) agonists, anti-androgens, combined androgen blockade (GnRH agonists plus anti-androgens), bilateral orchiectomy, and bilateral orchiectomy plus pharmacologic ADT (anti-androgens and/or GnRH agonists). RESULTS: Among patients receiving ADT, 10.8 % had a fracture compared to 3.2 % of those not receiving ADT (p < 0.0001). After controlling for age and ethnicity, the use of ADT was associated with a significantly increased risk of any fracture (OR = 2.83; 95 % CI 2.52-3.17) and of hip fracture requiring hospitalisation (OR = 1.82; 95 % CI 1.44-2.30). Those who received combined androgen blockade (OR = 3.48; 95 % CI 3.07-3.96) and bilateral orchiectomy with pharmacologic ADT (OR = 4.32; 95 % CI 3.34-5.58) had the greatest risk of fracture. The fracture risk following different types of ADT was confounded by pathologic fractures and spinal cord compression (SCC). ADT recipients with fractures had a 1.83-fold (95 % CI 1.68-1.99) higher mortality risk than those without a fracture. However, after the exclusion of pathologic fractures and SCC, there was no increased risk of mortality. CONCLUSIONS: ADT was significantly associated with an increased risk of any fracture and hip fracture requiring hospitalisation. The excess risk was partly driven by pathologic fractures and SCC which are associated with decreased survival in ADT users. Identification of those at higher risk of fracture and close monitoring of bone health while on ADT is an important factor to consider. This may require monitoring of bone density and bone marker profiles. PMID- 26525987 TI - Children With Autism Spectrum Disorder and Screen Time: Results From a Large, Nationally Representative US Study. AB - OBJECTIVE: To test the hypotheses that children with autism spectrum disorder (ASD) have higher screen time than other children on a US nationally representative sample and that children with ASD are overrepresented among children who exceed the American Academy of Pediatrics (AAP) screen time recommendation (2 hours or less a day). METHODS: The National Survey of Children's Health 2011-2012, a nationally representative survey, asked parents to report their child's (aged 6-17 years) average daily media usage. The ASD subpopulation (n = 1393) was compared to children without ASD (non-ASD, n = 64,163). Differences were compared by design-corrected F tests. Regression models were estimated for both groups separately. Adjusted Wald tests were used to rigorously test the hypotheses. RESULTS: More than half of US children exceed the AAP screen time recommendation. Compared to non-ASD, children with ASD had similar amounts of total screen time (3.21 hours per day vs 3.46 hours per day; P > .05), media (TV/video) time, and computer/mobile device leisure time. Children with ASD have a milder age gradient than the general population on computer/mobile device usage. Children with ASD were proportionally represented among high users (more than 2 hours per day). Data did not support hypotheses. CONCLUSIONS: In a large, nationally representative US sample, there was no evidence that children with ASD differ in their screen time habits from other children. Both groups have high screen time use. Caution should be exercised before assuming that children with ASD are at higher risk of exceeding AAP screen time recommendations. Efforts to promote adherence to the recommendation are needed, but they should neither target nor exclude children with ASD. PMID- 26525988 TI - Provider Preferences and Experiences With a Countywide Centralized Collaborative Reminder/Recall for Childhood Immunizations. AB - OBJECTIVE: To assess among providers in 7 Colorado counties where a collaborative centralized reminder/recall (CC-R/R) using the Colorado Immunization Information System (CIIS) was performed: 1) preferences about CC-R/R conducted by the public health department (PHD); 2) preferences for future CC-R/R for different vaccines with and without practice names; and 3) experiences with including their name on CC-R/R notices. METHODS: A mailed survey was sent to all primary care sites where CC-R/R had been previously conducted. Respondents self-identified as the "the person in charge of immunization policy within the practice." RESULTS: Overall response rate was 69.9% (160 of 229). Twenty-one were removed because they did not provide immunizations to children. Among respondents, 65.0% were from family medicine and 26.3% from pediatric practices; 32.1% physicians or midlevel providers; 34.3% nurses or medical assistants; and 33.6% office managers. Taking into account all issues, 57.6% were "okay" with either the PHD or their practice conducting recall; 27.3% preferred the PHD; and 14.4% preferred their practice conduct R/R. Fifty-six percent of active CIIS practices (n = 95) included their practice's name on CC-R/R notices. Interest in future CC-R/R for different ages and vaccines was strongly related to whether reminders included the practice name: 77.8% for routine immunizations in 4- to 6-year-olds; 74.8% for immunizations for 0- to 3-year-olds; 73.3% for vaccines administered to adolescents; and 59.7% for influenza (P < .001). CONCLUSIONS: Most practices are accepting of the PHD centrally conducting R/R, but most prefer collaboration that includes their name. Given the success and support of this method, it should be more widely adopted. PMID- 26525989 TI - Association Between Bottle Size and Formula Intake in 2-Month-Old Infants. AB - OBJECTIVE: To determine range of bottle sizes used and examine the relationship between bottle size and total daily consumption of infant formula. METHODS: Cross sectional analysis of baseline data collected as part of Greenlight, a cluster randomized trial to prevent childhood obesity at 4 pediatric resident clinics. The Greenlight study included healthy, term infants. For our analysis, parents of exclusively formula-fed infants reported volume per feed, number of feeds per day, and bottle size, which was dichotomized into small (<6 oz) or large (>=6 oz). We identified determinants of bottle size, and then examined relationships between bottle size and volume fed with log-transformed ordinary least squares regression, adjusting for infant age, sex, birth weight, current weight, race/ethnicity, and enrollment in Special Supplemental Nutrition Program for Women, Infants, and Children. RESULTS: Of 865 participants in the Greenlight study, 44% (n = 378; 21.8% white, 40.6% black, 35.3% Hispanic, 2.4% other) of infants were exclusively formula fed at 2 months. Median volume per day was 30 oz (interquartile range 12), and 46.0% of infants were fed with large bottles. Adjusted for covariates, parents using larger bottles reported feeding 4 oz more formula per day (34.2 oz, 95% confidence interval 33.5-34.9 vs 29.7 oz, 95% confidence interval 29.2-30.3, P = .03). CONCLUSIONS: Among exclusively formula fed infants, use of a larger bottle is associated with parental report of more formula intake compared to infants fed with smaller bottles. If infants fed with larger bottles receive more formula, these infants may be overfed and consequently at risk for obesity. PMID- 26525990 TI - Provider Attitudes Regarding Vaccine Tracking Systems in Pediatric Practices. AB - OBJECTIVE: To assess among US pediatricians' systems for tracking vaccine administration and inventory and attitudes about these systems; and attitudes regarding and perceived barriers to adoption of a 2-dimensional bar code systems. METHODS: Internet and mail survey of a nationally representative network of pediatricians between September 2011 and January 2012. RESULTS: The response rate was 71% (288 of 408). The most common methods for recording vaccine information were manual entry into an electronic (52%) or paper (27%) record; 76% recorded information in >=2 places. Physicians reported ordering vaccine on the basis of seasonal increases in demand (55%), paper-based inventory (52%), or when stock looks low (47%); 79% reported it was time consuming to track inventory and 24% reported their practices frequently run out of vaccines. Among those participating in an immunization information system, 29% transmitted data by automatic uploads and 58% entered data manually. Physicians agreed that bar codes could facilitate tracking of vaccine inventory (96%), would improve patient safety (96%), would be more reliable and accurate than current systems (93%), and could improve the efficiency of vaccine administration (90%). Barriers to adoption of a bar code system included need for software (52%), information technology support (42%), and computer equipment (33%). The total cost at which >50% reported they would definitely or probably adopt a bar code system was between $1000 and $4999. CONCLUSIONS: Most pediatricians report using inefficient systems for tracking vaccine administration and inventory and recognize multiple potential benefits of incorporating vaccine bar coding into their practice. To facilitate adoption, costs will need to be contained and technological barriers addressed. PMID- 26525991 TI - Family-Centered Pediatric Emergency Care: A Framework for Measuring What Parents Want and Value. AB - OBJECTIVE: To identify and describe dimensions of family-centered care important to parents in pediatric emergency care and compare them to those currently defined in the literature. METHODS: A qualitative study was conducted involving 8 focus groups with parents who accompanied their child to an emergency department visit at a large tertiary-care pediatric health system. Participants were identified using purposive sampling to achieve representation across demographic characteristics including child's race, insurance status, severity, and participant's relationship to child. Focus groups were segmented by patient age and presence of a chronic condition. They were moderated by a facilitator experienced in health-related topics. A 6-member multidisciplinary team completed a content analysis. RESULTS: Sixty-eight parents participated. They were female (77%); aged 20 to 29 years (19%), 30 to 39 years (47%), more than 40 years (31%); black (44%), white (52%); and married (50%). Their child's characteristics were: public insurance (52%); black (46%), white (46%); and admitted as an inpatient (46%). The analysis resulted in 8 dimensions: 1) emotional support; 2) coordination; 3) elicit and respect preferences, and involve the patient and family in care decisions; 4) timely and attentive care; 5) information, communication, and education; 6) pain management; 7) safe and child-focused environment; and 8) continuity and transition. Compared to those published in the literature, the most notable differences were combining involving family and respect for preferences into a single dimension, and separating physical comfort into 2 dimensions: pain management and safe/child-focused environment. CONCLUSIONS: The resulting dimensions provide a framework for measuring and improving the delivery of family-centered pediatric emergency care. PMID- 26525992 TI - Tailoring open metal sites for selective capture of CO2 in isostructural metalloporphyrin porous organic networks. AB - Porphyrin-based isostructural porous organic networks have been synthesized by varying the central metal atoms to cobalt, nickel and copper. Their selectivities for CO2 capture over N2 and Ar are found to be enhanced as the heats of adsorption for CO2 are increased in the order of Co, Ni and Cu, while the pore structures are well maintained. PMID- 26525993 TI - Physical and Cognitive Activities as Deterrents of Cognitive Decline in a Biracial Population Sample. AB - OBJECTIVE: Physical and cognitive activities are associated with slower cognitive decline. Few studies have examined racial differences in these associations, however. The aim of this study was to examine the association of physical and cognitive activities with level and change in cognitive function among black and white participants. A secondary aim was to explore observed differences between black and white participants using post hoc analyses based on education and cognitive function levels. METHODS: Data came from a longitudinal study of 7,742 (63% black and 61% female) participants assessed three times over an average of 9.5 years. At baseline, each participant reported number of hours of leisure time physical activity (categorized using quartiles) and rated frequency of participation in cognitively stimulating activities (range: 0-4). A standardized measure of cognition was derived from tests of memory, perceptual speed, and orientation. RESULTS: Of the 7,742 participants, 2,322 (30%) reported no physical activity. Cognitive decline was slower by about 20% (95% CI: 13%-27%) among whites with physical activity above 1.25 hours compared with those with no physical activity, but showed no significant decrease in cognitive decline relative to those with no physical activity among blacks. Further post hoc analysis revealed cognitive decline to be slower by about 29% (95% CI: 20%-38%) among blacks and whites with higher education and above average baseline cognition. A 1-point increase in cognitive activity frequency decreased cognitive decline by 8% (95% CI: 3%-14%) among blacks and by 14% (95% CI: 7%-20%) among whites. CONCLUSIONS: The benefits of higher physical activity on cognitive decline was observed among whites, and among blacks with higher education and above average baseline cognitive function. Nevertheless, the protective effect of cognitive activity seems to be independent of education and baseline cognitive function among both blacks and whites. PMID- 26525994 TI - Proactive Semantic Interference is Associated with Total and Regional Abnormal Amyloid Load in Non-Demented Community-Dwelling Elders: A Preliminary Study. AB - OBJECTIVE: To evaluate the relationship between susceptibility to proactive semantic interference (PSI) and retroactive semantic interference (RSI) and brain amyloid load in non-demented elders. METHODS: 27 participants (11 cognitively normal [CN] with subjective memory complaints, 8 CN without memory complaints, and 8 with mild cognitive impairment [MCI]) underwent complete neurological and neuropsychological evaluations. Participants also received the Semantic Interference Test (SIT) and AV-45 amyloid PET imaging. RESULTS: High levels of association were present between total amyloid load, regional amyloid levels, and the PSI measure (in the entire sample and a subsample excluding MCI subjects). RSI and other memory measures showed much weaker associations or no associations with total and regional amyloid load. No associations between amyloid levels and non-memory performance were observed. CONCLUSIONS: In non-demented individuals, vulnerability to PSI was highly associated with total and regional beta-amyloid load and may be an early cognitive marker of brain pathology. PMID- 26525995 TI - Trajectories of Neuropsychiatric Symptoms and Cognitive Decline in Mild Cognitive Impairment. AB - OBJECTIVE: To characterize the course of neuropsychiatric symptoms (NPS) in adults with mild cognitive impairment (MCI), and to examine baseline individual level predictors and associated cognitive and functional outcomes. DESIGN: A 2 year prospective cohort study. SETTING: Multicenter clinical settings. PARTICIPANTS: Five hundred sixty individuals with MCI at baseline. MEASUREMENTS: NPS severity (measured using Neuropsychiatric Inventory Questionnaire) and cognitive and functional outcomes were assessed at baseline and every 6 months thereafter. Potential individual-level predictors were collected at baseline. RESULTS: Three latent classes of NPS courses were identified using growth mixture modeling: a stable class in which a low NPS burden remained relatively unchanged over time (N = 503, 89.8%); a worsened class in which an initially moderate NPS burden increased (N = 39, 7.0%); and an improved class in which an initially high NPS burden decreased (N = 18, 3.2%). There were no associations between class membership and baseline individual characteristics. Members of the worsened class were 1.74 times more likely to be diagnosed with incident Alzheimer disease (AD) than members of the stable class (95% confidence interval: 1.07-2.84). The worsened class also showed significantly more rapid declines in cognitive and functional outcomes than the stable class. Class membership did not predict rate of brain atrophy. CONCLUSIONS: Patients with MCI may experience different trajectories of NPS over time. Patients with worsening NPS may be at greater risk of developing AD and severe cognitive and functional impairment. PMID- 26525996 TI - Directions for Effectiveness Research to Improve Health Services for Late-Life Depression in the United States. AB - Considerable progress has been made in the treatment of late-life depression over the past 20 years, yet considerable gaps in care remain. Gaps in care are particularly pronounced for older men, certain racial and ethnic minority groups, and those with comorbid medical or mental disorders. We reviewed the peer reviewed literature and conducted interviews with experts in late-life depression to identify promising directions for effectiveness research to address these gaps in care. We searched the PubMed, PsychInfo, and CINHAL databases between January 1, 1998, through August 31, 2013, using terms related to late-life depression and any of the following: epidemiology, services organization, economics of care, underserved groups including health disparities, impact on caregivers, and interventions. The results of this selective review supplemented by more current recommendations from national experts highlight three priority research areas to improve health services for late-life depression: focusing on the unique needs of the patient through patient-centered care and culturally sensitive care, involving caregivers outside the traditional clinical care team, and involving alternate settings of care. We build on these results to offer five recommendations for future effectiveness research that hold considerable potential to advance intervention and health services development for late-life depression. PMID- 26525997 TI - Trends in Psychotropic Dispensing Among Older Adults with Dementia Living in Long Term Care Facilities: 2004-2013. AB - OBJECTIVE: Guidelines worldwide have cautioned against the use of antipsychotics as first-line agents to treat neuropsychiatric symptoms of dementia. We aimed to investigate the changes over time in the dispensing of antipsychotics and other psychotropics among older adults with dementia living in long-term care facilities. METHODS: We used drug claims data from Ontario, Canada, to calculate quarterly rates of prescription dispensing of six psychotropic drug classes among all elderly (>=65 years of age) long-term care residents with dementia from January 1, 2004, to March 31, 2013. Psychotropic drugs were classified into the following categories: atypical and conventional antipsychotics, non-sedative and sedative antidepressants, anti-epileptics, and benzodiazepines. We used time series analysis to assess trends over time. RESULTS: The study sample increased by 21% over the 10-year study period, from 49,251 patients to 59,785 patients. The majority of patients (within the range of 75%-79%) were dispensed at least one psychotropic medication. At the beginning of the study period atypical antipsychotics (38%) were the most frequently dispensed psychotropic, followed by benzodiazepines (28%), non-sedative antidepressants (27%), sedative antidepressants (17%), anti-epileptics (7%), and conventional antipsychotics (3%). Dispensing of anti-epileptics (2% increase) and conventional antipsychotics (1% decrease) displayed modest changes over time, but we observed more pronounced changes in dispensing of benzodiazepines (11% decrease) and atypical antipsychotics (4% decrease). Concurrently, we observed a substantial growth in the dispensing of both sedative (15% increase) and non-sedative (9% increase) antidepressants. The proportion of patients dispensed two or more psychotropic drug classes increased from 42% in 2004 to 50% in 2013. CONCLUSIONS: Utilization patterns of psychotropic drugs in institutionalized patients with dementia have changed over the past decade. Although their use declined slightly over the study period, atypical antipsychotics continue to be used at a high rate. A decline in the use of benzodiazepines along with an increased use of sedative and non sedative antidepressants suggests that the latter class of drugs is being substituted for the former in the management of neuropsychiatric symptoms. Psychotropic polypharmacy continues to be highly prevalent in these patient samples. PMID- 26525998 TI - Electrochemistry-based approaches to low cost, high sensitivity, automated, multiplexed protein immunoassays for cancer diagnostics. AB - Early detection and reliable diagnostics are keys to effectively design cancer therapies with better prognoses. The simultaneous detection of panels of biomarker proteins holds great promise as a general tool for reliable cancer diagnostics. A major challenge in designing such a panel is to decide upon a coherent group of biomarkers which have higher specificity for a given type of cancer. The second big challenge is to develop test devices to measure these biomarkers quantitatively with high sensitivity and specificity, such that there are no interferences from the complex serum or tissue matrices. Lastly, integrating all these tests into a technology that does not require exclusive training to operate, and can be used at point-of-care (POC) is another potential bottleneck in futuristic cancer diagnostics. In this article, we review electrochemistry-based tools and technologies developed and/or used in our laboratories to construct low-cost microfluidic protein arrays for the highly sensitive detection of a panel of cancer-specific biomarkers with high specificity which at the same time has the potential to be translated into POC applications. PMID- 26525999 TI - GDAP1 mutations in Italian axonal Charcot-Marie-Tooth patients: Phenotypic features and clinical course. AB - Mutations in the ganglioside-induced differentiation associated-protein 1 (GDAP1) gene have been associated with both autosomal recessive (AR) and dominant (AD) Charcot-Marie-Tooth (CMT) axonal neuropathy. The relative frequency of heterozygous, dominant mutations in Italian CMT is unknown. We investigated the frequency of dominant mutations in GDAP1 in a cohort of 109 axonal Italian patients by sequencing genomic DNA and search for copy number variations. We also explored correlations with clinical features. All cases had already been tested for variants in common axonal AD genes. Eight patients (7.3%) harbored five already reported heterozygous mutations in GDAP1 (p.Arg120Gly, p.Arg120Trp, p.His123Arg, p.Gln218Glu, p.Arg226Ser). Mutations had different penetrances in the families; the onset of symptoms is in the first decade and progression is slower than usually seen in GDAP1-related AR-CMT. We show that the relative frequency of mutations in GDAP was slightly higher than those observed in MFN2 and MPZ (7.3% vs 6.3% and 5.0%). The relatively milder clinical features and the quite indolent course observed are relevant for prognostic assessment. On the basis of our experience and the data reported here, we suggest GDAP1 as the first gene that should be analysed in Italian patients affected by CMT2. PMID- 26526000 TI - Acid ceramidase deficiency associated with spinal muscular atrophy with progressive myoclonic epilepsy. AB - Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is an extremely rare disorder related to the lysosomal storage disease, Farber lipogranulomatosis. Both disorders are autosomal recessive conditions caused by mutations in the ASAH1 gene encoding acid ceramidase. Farber disease is associated with joint deformities, lipomatous skin nodules, and often is fatal by 2-3 years of age; while SMA-PME is characterized by childhood-onset motor neuron disease and progressive myoclonic epilepsy. We report a case of SMA-PME with a novel mutation in the ASAH1 gene encoding acid ceramidase. The proband presented with childhood-onset of diffuse muscle atrophy and hypotonia. He also had diffuse weakness with greater proximal than distal involvement. Tongue fasciculations were present and his reflexes were either diminished or absent. He ambulated with an unsteady and hesitant gait. He subsequently developed myoclonic epilepsy along with other associated features including tremor, polymyoclonus, and sensorineural hearing loss. Neurophysiological studies revealed a motor neuron disorder and generalized epilepsy. Exome sequencing analysis identified compound heterozygous variants and biochemical analysis indicated acid ceramidase activity was approximately 12 percent of normal controls. Our proband was phenotypically similar to other cases of SMA-PME, albeit with somewhat lesser severity, slower progression, and greater longevity. As lysosomal disorders are sometimes amendable to early interventions, it is important to make early diagnoses in these cases. The combination of motor neuron disease and progressive myoclonic epilepsy should prompt genetic evaluation of ASAH1. PMID- 26526001 TI - No progressive brain changes during a 1-year follow-up of patients with first episode psychosis. AB - BACKGROUND: First-episode psychosis (FEP) patients show structural brain abnormalities. Whether the changes are progressive or not remain under debate, and the results from longitudinal magnetic resonance imaging (MRI) studies are mixed. We investigated if FEP patients showed a different pattern of regional brain structural change over a 1-year period compared with healthy controls, and if putative changes correlated with clinical characteristics and outcome. METHOD: MRIs of 79 FEP patients [SCID-I-verified diagnoses: schizophrenia, psychotic bipolar disorder, or other psychoses, mean age 27.6 (s.d. = 7.7) years, 66% male] and 82 healthy controls [age 29.3 (s.d. = 7.2) years, 66% male] were acquired from the same 1.5 T scanner at baseline and 1-year follow-up as part of the Thematically Organized Psychosis (TOP) study, Oslo, Norway. Scans were automatically processed with the longitudinal stream in FreeSurfer that creates an unbiased within-subject template image. General linear models were used to analyse longitudinal change in a wide range of subcortical volumes and detailed thickness and surface area estimates across the entire cortex, and associations with clinical characteristics. RESULTS: FEP patients and controls did not differ significantly in annual percentage change in cortical thickness or area in any cortical region, or in any of the subcortical structures after adjustment for multiple comparisons. Within the FEP group, duration of untreated psychosis, age at illness onset, antipsychotic medication use and remission at follow-up were not related to longitudinal brain change. CONCLUSIONS: We found no significant longitudinal brain changes over a 1-year period in FEP patients. Our results do not support early progressive brain changes in psychotic disorders. PMID- 26526002 TI - How do systematic reviews of acupuncture for pain relief incorporate risk of bias assessments into the synthesis? A methodological study. AB - OBJECTIVE: By reviewing the assessment of internal validity in relevant systematic reviews (SRs), the aim of this study was to identify how critical appraisals of risk of bias (RoB) inform the synthesis of evidence in SRs of acupuncture for pain relief. METHODS: SRs were searched in Medline, EMBASE, and the Cochrane Database of SRs from their inception to 30 December 2014. Only SRs of acupuncture for pain relief were included. Basic information, types of RoB appraisal tool, whether or not there was domain-level assessment of RoB, whether or not the reviews ranked studies by RoB, plus whether or not (and, if so, how) RoB appraisal was incorporated into the synthesis were determined. RESULTS: A total of 91 SRs met the inclusion criteria and were included in the final analysis. Over half of the SRs (85, 64.8%) used standard tools, such as the Jadad quality score and the Cochrane RoB tool, followed by adapted tools (n=23, 25.3%). Of the 85 SRs that assessed RoB, 29 (34.1%) presented domain-level assessment and 71 SRs (83.5%) included ranking of the studies based on RoB assessment. Of these 71, 35 (49.4%) used a cut-off threshold score and 26 (36.6%) required all criteria sum-up. Of the 85 SRs that assessed RoB, 48 (56.5%) incorporated RoB appraisal into the data synthesis. CONCLUSIONS: Although most SRs of acupuncture for pain relief conducted some form of RoB assessment, nearly half of them failed to incorporate the RoB assessment into the synthesis. PMID- 26526004 TI - Influence of pH on the Motion of Catalytic Janus Particles and Tubular Bubble Propelled Micromotors. AB - Self-propelled miniaturized machines harness the chemical potential of their environment for movement. Locomotion of chemically powered micromotors have been hugely dependent on the surroundings. The use of pH to alter the mobility of micromotors is demonstrated in this work through the manipulation of hydrogen peroxide chemistry in different acidity/alkalinity. The sequential addition of sodium hydroxide to increase the pH of the solution led to a consequent increase in activity of micromotors. Meanwhile, addition of hydrochloric acid compromised the structural integrity of the microstructures, culminating in locomotive changes. Such dramatic changes in activity and velocities of the micromotors allow the usage of this behavior for pH detection. This concept was illustrated with Janus silver micromotors and tubular bimetallic Cu/Pt micromotors. Alteration of pH serves as a useful general strategy for increasing hydrogen peroxide decomposition for enhanced oxygen-bubble propulsion in catalytic micromotors. PMID- 26526003 TI - Epithelial cell-derived micro RNA-146a generates interleukin-10-producing monocytes to inhibit nasal allergy. AB - The aberrant immunity plays an important role in the pathogenesis of allergic diseases. Micro RNAs (miR) are involved in regulating the immunity in the body. This study aims to test a hypothesis that miR-146a induces the expression of interleukin (IL)-10 in monocytes (Mos). In this study, the levels of miR-146a were determined by real time RT-PCR. The IL-10(+) Mos were evaluated by flow cytometry. The miR-146a-laden exosomes were generated with RPMI2650 cells (an airway epithelial cell line). An allergic rhinitis mouse model was developed. The results showed that nasal epithelial cells expressed miR-146a, which was markedly lower in the nasal epithelial cells of patients with nasal allergy than that in healthy controls. Exposure to T helper (Th)2 cytokines suppressed the levels of miR-146a in the nasal epithelial cells. The nasal epithelial cell-derived miR 146a up regulated the expression of IL-10 in Mos. The inducible IL-10(+) Mos showed an immune suppressor effect on the activities of CD4(+) effector T cells and the Th2 polarization in a mouse model of allergic rhinitis. In summary, nasal epithelial cells express miR-146a, the latter is capable of inducing IL-10 expression in Mos, which suppress allergic reactions in the mouse nasal mucosa. PMID- 26526005 TI - Air Pressure and Contact Quotient Measures During Different Semioccluded Postures in Subjects With Different Voice Conditions. AB - OBJECTIVE: The purpose of this study was to investigate the effect of phonation into tubes in air and tubes submerged in water on air pressure variables and vocal fold adduction in subjects with different voice conditions. METHODS: Forty five participants representing four vocal conditions were included: (1) subjects diagnosed with normal voice and without voice training, (2) subjects with normal voice with voice training, (3) subjects with muscle tension dysphonia, and (4) subjects with unilateral vocal fold paralysis. Participants phonated into different kinds of tubes (drinking straw, 5 mm in inner diameter; stirring straw, 2.7 mm in inner diameter; silicon tube, 10 mm in inner diameter) with the free end in air and in water. Aerodynamic, acoustic, and electroglottographic signals were captured simultaneously. Mean values of the following variables were considered: glottal contact quotient (CQ) measured by electroglottograph, fundamental frequency, subglottic pressure (Psub), oral pressure (Poral), and transglottal pressure. RESULTS: All exercises had a significant effect on Psub, Poral, transglottal pressure, and CQ (P < 0.05). Phonation into a 55-cm silicon tube submerged 10 cm in water and phonation into a stirring straw resulted in the highest values for CQ, Psub, and Poral compared with baseline (repetition of syllable [pa:]) for all vocal status. Poral and Psub correlated positively. CONCLUSION: During semioccluded exercises, most variables behaved in a similar way (same trend with a quite large individual variation) regardless of the vocal status of the participants. PMID- 26526006 TI - Profile and outcome of patients with post-neonatal tetanus in a tertiary centre in south west Nigeria: any remarkable reduction in the scourge? AB - INTRODUCTION: The incidence of tetanus has remained unacceptably high in developing countries. We aimed to describe the profile and outcome of children with tetanus admitted at the Lagos State University Teaching Hospital (LASUTH), Ikeja. METHODS: A prospective and cross-sectional study of children aged 1 month to 12 years of age admitted with clinical diagnosis of tetanus, between January 2011 and December 2013, at the Paediatric department of LASUTH. The age, sex, presenting complaint, immunization status, portal of entry, socio-economic class, complications, duration of admission and outcome of the subjects were analyzed using Microsoft Excel supplemented with Statistical Package for Social Sciences (SPSS) version 17.0. Level of significance set at p<0.05. RESULTS: A total of 49 subject participated in the study. Male: Female ratio was 1.7: 1.0. mean age+/-SD of 6.5+/-3.2 years. Only 24.5% of the subjects were fully immunized, lower limb injury was the most common portal of entry (34.7%). Majority (79.6) were of the middle and lower social classes. Most of the subjects (67.3%) presented with generalised spasm. Only 1 patient (2.0%) did not have trismus. Case fatality rate was 4.1%. CONCLUSION: Tetanus is still prevalent among children in our environment. It is commoner among those with no immunization or incomplete immunization, commoner in those in the middle and lower social class. Lower limb injury was the most common portal of entry. Trismus was a common presenting feature. There is a need to develop programmes with will help improve compliance to immunization. PMID- 26526008 TI - Effects of Prophylactic Antiepileptic Drugs on Clinical Outcomes in Patients with a Good Clinical Grade Suffering from Aneurysmal Subarachnoid Hemorrhage. AB - OBJECTIVE: Routine use of prophylactic antiepileptic drugs (AED) has been debated. We retrospectively evaluated the effects of prophylactic AED on clinical outcomes in patients with a good clinical grade suffering from aneurysmal subarachnoid hemorrhage (aSAH). MATERIALS AND METHODS: Between September 2012 and December 2014, 84 patients who met the following criteria were included: (1) presence of a ruptured aneurysm; (2) Hunt-Hess grade 1, 2, or 3; and (3) without seizure presentation. Patients were divided into two groups; the AED group (n = 44) and the no AED group (n = 40). Clinical data and outcomes were compared between the two groups. RESULTS: Prophylactic AEDs were used more frequently in patients who underwent microsurgery (84.1%) compared to those who underwent endovascular surgery (15.9%, p < 0.001). Regardless of prophylactic AED use, seizure episodes were not observed during the six-month follow-up period. No statistical difference in clinical outcomes at discharge (p = 0.607) and after six months of follow-up (p = 0.178) were between the two groups. After six months, however, favorable outcomes in the no AED group tended to increase and poor outcomes tended to decrease. CONCLUSION: No difference in the clinical outcomes and systemic complications at discharge and after six months of follow up was observed between the two groups. However, favorable outcomes in the no AED group showed a slight increase after six months. These findings suggest that discontinuation of the current practice of using prophylactic AED might be recommended in patients with a good clinical grade. PMID- 26526010 TI - Evolution: Filling gaps in early human history. PMID- 26526017 TI - Gene regulation: Nuclear seclusion--a novel mechanism of transcription factor regulation. PMID- 26526018 TI - Development of a methodology for electronic waste estimation: A material flow analysis-based SYE-Waste Model. AB - Improved living standards and the share of services sector to the economy in Asia, and the use of electronic equipment is on the rise and results in increased electronic waste generation. A peculiarity of electronic waste is that it has a 'significant' value even after its life time, and to add complication, even after its extended life in its 'dump' stage. Thus, in Indian situations, after its life time is over, the e-material changes hands more than once and finally ends up either in the hands of informal recyclers or in the store rooms of urban dwellings. This character makes it extremely difficult to estimate electronic waste generation. The present study attempts to develop a functional model based on a material flow analysis approach by considering all possible end uses of the material, its transformed goods finally arriving at disposal. It considers various degrees of uses derived of the e-goods regarding their primary use (life time), secondary use (first degree extension of life), third-hand use (second degree extension of life), donation, retention at the respective places (without discarding), fraction shifted to scrap vendor, and the components reaching the final dump site from various end points of use. This 'generic functional model' named SYE-Waste Model, developed based on a material flow analysis approach, can be used to derive 'obsolescence factors' for various degrees of usage of e-goods and also to make a comprehensive estimation of electronic waste in any city/country. PMID- 26526019 TI - Rapid reduction of lead leachate from hazardous fly ash using microwave treatment with acid combination. AB - The novelty of this study is to rapidly reduce hazardous lead leachates from solid waste using microwave digestion treatment, which is an energy-saving and low greenhouse gas emission technology. The article presents the reduction of toxic characteristic leaching procedure-extractable lead concentration in the municipal solid waste incineration fly ash by the microwave digestion treatment in HNO3/H2SO4 combination, and focuses on the effects of treatment time and temperature. The results obtained from this study indicated a significant reduction efficiency of toxic characteristic leaching procedure-extractable lead concentration and showed sufficient reduction in leaching levels to render the treated fly ash safe in lead compound leaching characteristics. The reduction efficiency of toxic characteristic leaching procedure-extractable lead concentration can reach 98% in 15 minutes of treatment time. This is equivalent to the original toxic characteristic leaching procedure-extractable lead concentration of 46.2 mg L(-1) in raw fly ash being reduced down to less than 1.0 mg L(-1). Based on the experimental data obtained in this study, a useful correlation between reduction efficiency and treatment conditions is proposed. For engineering applications, the necessary minimum treatment time is solved using a graphic illustration method, by which the minimum treatment time (t(min)) is obtained if the desired reduction efficiency (eta) and treatment temperature (T) are known. The effects of treatment time and temperature are discussed. Some problems caused by the microwave digestion treatment method are also delineated in this article. PMID- 26526020 TI - Exploring the techno-economic feasibility of mine rock waste utilisation in road works: The case of a mining deposit in Ghana. AB - Mine rock waste, which is the rock material removed in order to access and mine ore, is free from gold processing chemical contaminants but presents a significant environmental challenge owing to the large volumes involved. One way of mitigating the environmental and safety challenges posed by the large volume of mine rock waste stockpiled in mining communities is to find uses of this material as a substitute for rock aggregates in construction. This article reports on a study conducted to evaluate the engineering properties of such a mine deposit to determine its suitability for use as road pavement material. Samples of mine rock waste, derived from the granitic and granodioritic intrusive units overlying the gold-bearing metavolcanic rock and volcano-clastic sediments of a gold mining area in Ghana, were obtained from three mine rock waste disposal facilities and subjected to a battery of laboratory tests to determine their physical, mechanical, geotechnical, geometrical and durability properties. The overall conclusion was that the mine rock waste met all the requirements of the Ghana Ministry of Transportation specification for use as aggregates for crushed rock subbase, base and surface dressing chippings for road pavements. The recommendation is to process it into the required sizes for the various applications. PMID- 26526021 TI - Biowaste separate collection and composting in a Small Island Developing State: The case study of Sao Tome and Principe, West Africa. AB - Sao Tome and Principe archipelago in West Africa is a Small Island Developing State facing acute waste management problems. This article describes the implementation of selective collection of biowaste combined with composting in Sao Tome, as a case-study of an innovative action in the framework of a Small Island Developing State. Collection was designed to gather 225 t y(-1), targeting non-domestic biowaste producers, namely local businesses, municipal markets and municipal green waste. A municipal composting plant was built using basic facilities and windrow composting. The total investment amounted to ?50,000, mainly supported by external aid. Biowaste producers reacted very positively, source segregating enthusiastically. Irregular service - collection collapsed each time the old vehicle was repaired - together with political disengagement and unmotivated work force were the major constrains. Biowaste was intermittently delivered to the composting plant and yielded 2 t of compost from July to December 2013 and 10 t during 2014. Compost was sold as organic fertiliser to a touristic resource, to small farmers and to gardeners, at a market price slightly below production costs, meaning the process is not economically sustainable without support. Nevertheless, biowaste is one of the few waste fractions (other than glass) that can be turned into a product that has both market value and a real demand, showing the enormous potential of composting source-separated biowaste in this part of the world. PMID- 26526022 TI - Sex, Gender and Pain. PMID- 26526023 TI - The First Record of Aedes (Hulecoeteomyia) japonicus (Diptera: Culicidae) and Its Establishment in Western Canada. AB - The potential disease-carrying mosquito, Aedes japonicus (Theobald) (Diptera: Culicidae), was identified among larvae collected in suburban Vancouver, BC, in July 2014, and over 200 were found at the same site in February 2015 where it presumably had overwintered in the egg stage. In late May 2015, a female was captured taking a bloodmeal 13 km east of the larval site. This population and those in the Washington and Oregon states are clearly disjunct from those in eastern North America, and their origin, probably from one or more different introductions from Asia, is discussed. Key characters of those in British Columbia are examined and match the description of subspecies japonicus, presumably like the others in North America. PMID- 26526024 TI - Glucaric acids from Leonurus japonicus. AB - Three new glucaric acids, namely 2-feruloyl-4-syringoyl or 5-feruloyl-3-syringoyl glucaric acid (1), 2-syringoyl-4-feruloyl or 5-syringoyl-3-feruloyl glucaric acid (2), and 3-feruloyl-4-syringoyl or 4-feruloyl-3-syringoyl glucaric acid (3), were isolated from Leonurus japonicus Houtt. Their structures were elucidated by detailed spectroscopic means including UV, IR, HR-ESI-MS, 1D and 2D NMR data spectra. The bioactive assays of compounds 1-3 against hepatoprotection activity were determined. The result suggested that compound 2 exhibited a moderate hepatoprotection activity and the cell survival rate was 74% (10(-5)mol/L), using bicyclol (survival rate: 66%, 10(-5)mol/L) as a positive control. Furthermore, compounds 1-3 were evaluated cytotoxic activities in vitro using HCT-8, Bel-7402, BGC-823, A-549, and A2780 model and the results exhibited no obvious cytotoxicity activity. PMID- 26526025 TI - Management of Acute Pain in Cancer Patients. AB - The management of acute pain, especially post-operative pain, in patients on high dose opioids is a challenge that requires in-depth knowledge of pharmacokinetics and the formulation of a careful management plan in order to avoid withdrawal symptoms and inadequate pain management. PMID- 26526026 TI - Histologic spectrum of the cardiac conducting tissue in non-natural deaths under 30 years of age: an analysis of 43 cases with special implications for sudden cardiac death. AB - In the past, histological findings of the cardiac conduction system or its adjacent structures, such as filiform fibers at the transition from bundle of His to bundle branches, connective tissue at the apex of the ventricular septum, or fibromuscular alterations of the arteries has been considered as a cause of death. However, the prevalence of such findings in a healthy population has been rarely analyzed systematically. In the present study, the morphology of the cardiac conduction system of 43 heart-healthy individuals who died of non-natural causes (ages 0 to 30 years) was investigated. In a high percentage of cases, connective tissue at the apex of the ventricular septum (97.7%), filiform fibers at the transition from bundle of His to the bundle branches (27.9%), and fibromuscular proliferations of the sinoatrial node artery (41.9%), and the AV node artery (39.5%) could be detected. Based on our observations, these alterations should not be considered as a pathologic entity or as a cause of death. PMID- 26526027 TI - Muscle activity during daily life in the older people. AB - BACKGROUND: Daily muscle activity is important for functional independence. This study examined muscle activity patterns during normal daily life and simulated daily tasks and compared muscle activity and energy consumption during active and passive transport tasks in older adults. METHODS: Nine volunteers (70 +/- 6 years) were measured for quadriceps and hamstring muscle activity (EMG) during normal daily life, treadmill walking, and during passive and active transport tasks. EMG was normalized to that recorded during maximal voluntary contraction (MVC). Oxygen uptake (VO2) was measured during treadmill and transport tasks. RESULTS: During daily life the mean EMG amplitude was 5.9 +/- 2.4 % of EMGMVC, activity time was 187 +/- 43 min and the longest continuous inactivity periods were 20.9 +/- 10.0 min. During stair ascend the peak EMG activity was 120 % of EMGMVC and the peak VO2 values were only about 70 % of VO2max. One kilometer walk consumed 3.5 times more energy than passive transport by bus, and using stairs consumed 11.7 times more energy than using an elevator. CONCLUSIONS: In daily life, older adults use only a small fraction of muscle's maximal capacity and have long continuous inactivity periods. Negotiating stairs produce significant load to neuromuscular, but not to cardiovascular system, thus providing an effective strength training stimulus. PMID- 26526028 TI - p15(INK4b) regulates cell cycle signaling in hippocampal astrocytes of aged rats. AB - BACKGROUND AND AIMS: Cyclin-dependent kinase inhibitor p15(INK4b) is thought to be an important player in regulating astrocytic cell cycle. However, little is known with regard to the expression of p15(INK4b) and its function in hippocampal astrocytes. This study evaluated the expression of p15(INK4b) and its function during different development stages in hippocampal astrocytes. METHODS: In this study, we cultured hippocampal astrocytes from neonatal adult and aged rats. The expression of p15(INK4b) in neonatal, adult and aged astrocytes was examined. Short interfering RNA (siRNA) was then used to study the functional effects of p15(INK4b) down-regulation during cell cycle regulation. RESULTS: We found the expression of p15(INK4b) in hippocampal astrocytes was detectable on postnatal day 7, was expressed at moderate levels in adult mice (9 months old) astrocytes and peaked in aged rat (24 months old) astrocytes. Incubation with siRNA significantly suppressed p15(INK4b) expression at the mRNA and protein levels in astrocytes. Down-regulation of p15(INK4b) increased [(3)H]-thymidine incorporation into DNA and allowed cells to pass the G0/G1-S checkpoint in aged but not in neonatal or adult astrocytes. CONCLUSIONS: These observations suggest p15(INK4b) is expressed at a steady level in neonatal and adult rat hippocampal astrocytes with no effect on cell cycle regulation. Importantly, aged astrocyte cell cycle regulation was significantly affected by high expression levels of p15(INK4b) suggesting a role for p15(INK4b) in cell cycle regulation when it is expressed at high but not moderate or low levels in hippocampal astrocytes. PMID- 26526029 TI - Relation of ambulatory blood pressure measurement and cognitive functions in hypertensive elderly patients. AB - INTRODUCTION: Hypertension is an important risk factor for dementia as much as the morbidity and mortality of cardiovascular disease. Sustained hypertension is also more related to that risk. The aim of the study was to determine the relationship between 24-h ambulatory blood pressure monitoring (ABPM) and cognitive functions in elderly hypertensive patients without comorbid diseases which may deteriorate cognitive functions. MATERIALS AND METHODS: Ninety-one patients (21 male, 72.5 +/- 8.1;70 female, 71.7 +/- 7.7) above 60 years old previously diagnosed as hypertensive (HT) have been included to this study. The ABPM was performed after standardized mini mental test (sMMT) and geriatric depression scale (GDS) has been examined. The patients were divided into the groups as dipper/nondipper and regulated/nonregulated. The sMMT scores of the groups were compared. RESULTS: There was no statistical difference in average sMMT scores and distribution of mini mental groups between the dipper and nondipper groups. Hypertension regulation and mini mental measurements of the studied groups were moderately suggestive in the same direction (r = 0.333, p = 0.001). DISCUSSION AND CONCLUSION: There is an association between tension regulation and cognitive functions in elderly patients who have primary HT, but no relationship have been found between being nondipper and low cognitive function. Our results suggested that this study is critically important by means of revealing that the studies which are perceived distinctly about HT and cognitive functions need further evaluation with subgroup analyses in selected patient groups. PMID- 26526030 TI - Intravenous immunoglobulins for cutaneous polyarteritis nodosa resistant to conventional treatment. PMID- 26526031 TI - Low Fertility, Socioeconomic Development, and Gender Equity. AB - While new empirical findings and theoretical frameworks provide insight into the interrelations between socioeconomic development, gender equity, and low fertility, puzzling exceptions and outliers in these findings call for a more all encompassing framework to understand the interplay between these processes. We argue that the pace and onset of development are two important factors to be considered when analyzing gender equity and fertility. Within the developed world, "first-wave developers"-or countries that began socioeconomic development in the 19th/early 20th century - currently have much higher fertility levels than "late developers". We lay out a novel theoretical approach to explain why this is the case and provide empirical evidence to support our argument. Our approach not only explains historical periods of low fertility but also sheds light on why there exists such large variance in fertility rates among today's developed countries. PMID- 26526032 TI - Transcriptome analysis of genes involved in defence response in Polyporus umbellatus with Armillaria mellea infection. AB - Polyporus umbellatus, a species symbiotic with Armillaria mellea and it also exhibits substantial defence response to Armillaria mellea infection. There are no genomics resources databases for understanding the molecular mechanism underlying the infection stress of P. umbellatus. Therefore, we performed a large scale transcriptome sequencing of this fungus with A. mellea infection using Illumina sequencing technology. The assembly of the clean reads resulted in 120,576 transcripts, including 38,444 unigenes. Additionally, we performed a gene expression profiling analysis upon infection treatment. The results indicated significant differences in the gene expression profiles between the control and the infection group. In total, 10933 genes were identified between the two groups. Based on the differentially expressed genes, a Gene Ontology annotation analysis showed many defence-relevant categories. Meanwhile, the Kyoto Encyclopedia of Genes and Genomes pathway analysis uncovered some important pathways. Furthermore, the expression patterns of 13 putative genes that are involved in defence response resulting from quantitative real-time PCR were consistent with their transcript abundance changes as identified by RNA-seq. The sequenced genes covered a considerable proportion of the P. umbellatus transcriptome, and the expression results may be useful to strengthen the knowledge on the defence response of this fungus defend against Armillaria mellea invasion. PMID- 26526033 TI - ATP5A1 and ATP5B are highly expressed in glioblastoma tumor cells and endothelial cells of microvascular proliferation. AB - Glioblastoma (GBM) is the most common primary malignant brain tumor. Microvascular proliferation is one of the characteristic pathologic features of GBM. Mitochondrial dysfunction plays an important role in the pathogenesis of GBM. In this study, microvascular proliferation from GBM and normal brain blood vessels were laser microdissected and total RNA was isolated from these microvasculatures. The difference of mRNA expression profiles among GBM microvasculature, normal brain blood vessels and GBM tumor cells was evaluated by mitochondria and metabolism PCR gene arrays. It was found that the mRNA levels of ATP5A1 and ATP5B in GBM tumor cells as well as microvascular proliferation were significantly higher compared with normal brain blood vessels. Immunohistochemical stains with anti-ATP5A1 antibody or anti-ATP5B antibody were performed on tissue microarray, which demonstrated strongly positive expression of ATP5A1 and ATP5B in GBM tumor cells and GBM microvascular proliferation while normal blood vessels were negative. By analyzing The Cancer Genome Atlas data sets for GBM and other cancers, genomic DNA alterations (mutation, amplification or deletion) were less likely the reason for the high expression of ATP5A1 and ATP5B in GBM. Our miRNA microarray data showed that miRNAs that target ATP5A1 or ATP5B were down-regulated, which might be the most likely reason for the high expression of ATP5A1 and ATP5B in GBM tumor cells and microvascular proliferation. These findings help us better understand the pathogenesis of GBM, and agents against ATP5A1 and/or ATP5B might effectively kill both tumor cells and microvascular proliferation in GBM. MiRNAs, such as Let-7f, miR-16, miR-23, miR-100 and miR-101, that target ATP5A1 or ATP5B, might be potential therapeutic agents for GBM. PMID- 26526034 TI - CSF Nrf2 and HSPA8 in Parkinson's disease patients with and without LRRK2 gene mutations. AB - Leucine-rich repeat kinase 2 (LRRK2) gene mutations are the most common genetic cause of Parkinson's disease (PD). CSF specimens from LRRK2 + PD patients and healthy LRRK2 mutation carriers are, therefore, useful for biomarker studies. This study examined the hypothesis that differences are present between subjects with sporadic PD (sPD), PD carriers of LRRK2 mutations (LRRK2 + PD), healthy control subjects lacking LRRK2 mutations (CTL), and LRRK2 mutation-carrying healthy controls (LRRK2 + CTL) for CSF concentrations of six potential PD biomarkers. Two of these proteins, nuclear factor (erythroid-derived 2)-like 2 ("Nrf2") and heat shock 70 kDa protein 8 ("HSPA8"), were detected in preliminary ELISAs, then measured in a larger cohort (60 sPD, 10 LRRK2 + PD, 23 CTL, 31 LRRK2 + CTL). No statistically significant differences were found between the groups (Nrf2 p = 0.13, HSPA8 p = 0.21). Nrf2 concentrations in LRRK2 + PD subjects were strongly positively associated with Unified Parkinson's Disease Rating Scale (UPDRS) total and motor scores [Spearman rho = 0.77 (p = 0.012) and 0.83 (p = 0.005)] and negatively associated with Montreal Cognitive Assessment (MoCA) scores (rho = -0.57; p = 0.11). Partial correlation coefficient calculations indicated that disease duration contributed to the associations of Nrf2 levels with UPDRS scores and with MoCA scores in this group. While CSF Nrf2 and HSPA8 do not appear to offer diagnostic biomarkers for PD, the associations between Nrf2 levels and UPDRS scores in LRRK2 + PD patients merit further investigation. PMID- 26526035 TI - Evidence Underlying KDIGO (Kidney Disease: Improving Global Outcomes) Guideline Recommendations: A Systematic Review. AB - BACKGROUND: The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guidelines establish international recommendations for the definition and treatment of kidney disease. Our objective was to characterize the strength of evidence supporting the KDIGO guidelines, the class of recommendations made, and the relationship between these. STUDY DESIGN: We reviewed and abstracted the level of evidence and strength of recommendations in the currently available KDIGO guidelines. SETTING & POPULATION: KDIGO clinical practice guidelines target care of patients with kidney disease to improve outcomes. SELECTION CRITERIA FOR STUDIES: All KDIGO guidelines published on the KDIGO website as of November 2013 were included. PREDICTOR: Recommendations pertaining to disease, diagnosis, or treatment. OUTCOMES: Levels of evidence and strength of recommendations. RESULTS: Of 853 recommendations in 9 guidelines, 5% were supported by level A quality evidence; 17%, level B; 31%, level C; 18%, level D; and 20%, ungraded evidence. The strength of recommendations was class 1 for 25%, class 2 for 54%, and ungraded for 20%. Only 3% of recommendations were class 1 in strength and supported by level A evidence. Of the recommendations, 2% concerned disease definition and classification; 29%, diagnosis; and 69%, treatment. LIMITATIONS: Our study included only the KDIGO guidelines. We did not assess historical changes in nephrology guidelines recommendations. CONCLUSIONS: KDIGO recommendations were based largely on weak evidence, reflecting expert opinion. Few recommendations were both strong and supported by high-level evidence. PMID- 26526036 TI - Predictors of Early Discontinuation of Effective Contraception by Teens at High Risk of Pregnancy. AB - STUDY OBJECTIVE: In the United States, teen pregnancy rates are declining. However, the United States still has the highest teen pregnancy rate among high income countries. Understanding factors that predict discontinuation of effective contraception might help to further decrease teen pregnancy. We aimed to assess predictors of early discontinuation of effective contraception during typical use by high-risk teens. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We recruited 145 women aged 13-20 years (mean, 17.7 +/- 1.8 years); 68% (99/145) Hispanic; 26% (38/145) black; 14% (20/145) ever pregnant; and 4% (6/145) high school dropouts who chose an effective contraceptive method during a health care visit and we prospectively assessed use of the method after 6 months. Contraceptive choices of the 130 participants who were reassessed at 6 months (90% retention) were: intrauterine device (IUD), 26% (34/130); depot medroxyprogesterone acetate (DMPA), 8% (10/130); combined oral contraceptives (COCs), 48% (62/130); transdermal patch (Patch), 13% (17/130); and intravaginal ring (Ring), 5% (7/130). RESULTS: After 6 months, only 49 of 130 (38%) continued their chosen method; 28 of 130 (22%) never initiated the method; and 53 of 130 (40%) discontinued. Users and nonusers at 6 months did not differ according to cultural and/or social characteristics (age, ethnicity, acculturation, education, health literacy) but differed according to contraceptive method type. For the 102 of 130 who initiated a method, 88% continued use of the IUD, 20% DMPA, 43% COC, 17% Patch and Ring (P < .001). Using Cox proportional hazards multivariable analysis, compared with IUDs, all other methods predicted discontinuation: DMPA (hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.2-26.7; P < .05); COCs (HR, 6.6; 95% CI, 1.8-25; P < .01); Patch and Ring (HR, 12; 95% CI, 3.0-48; P < .001). Discontinuation was also predicted by past use of hormonal contraceptives (HR, 1.9; 95% CI, 1.0-3.6; P < .05) and high school dropout (HR, 8.2; 95% CI, 1.6 41; P < .01). CONCLUSION: Contraceptive method type is the strongest predictor of early discontinuation; compared with IUDs, all other methods are 6-12 times more likely to be discontinued. Cultural and/or social characteristics, with the exception of school dropout, are of little predictive value. Increasing the use of IUDs by high-risk teens could decrease discontinuation rates and possibly teen pregnancy rates. PMID- 26526037 TI - Cardiac computed tomography assessment of the near term impact of percutaneous ventricular restoration therapy (parachute((r)) ) on mitral valve geometry. AB - OBJECTIVES: The aim of current study is to assess the near term impact of percutaneous ventricular restoration therapy (PVR), Parachute((r)) on mitral valve (MV) geometry by cardiac computed tomography (CCT). BACKGROUND: Recent data demonstrates the feasibility of PVR for treatment of post anterior myocardial infarction (MI) heart failure. Little is known, however, about the interaction of the device and left ventricular structures, particularly the MV apparatus. METHODS: This is a retrospective Core Laboratory analysis of Parachute Trials' CCT data. Patients with paired (before and after Parachute implant) CCT acquisitions were included into analysis. MV geometric parameters were measured. RESULTS: Thirty-three patients were included in the analysis. The mean time of follow-up CCT post procedure was 188 +/- 52 days. There were significant reduction in tenting height (A1P1: -1.70 +/- 1.89 mm, -17.40 +/- 20.20%; A2P2: 1.43 +/- 1.89 mm, -12.10 +/- 15.00%; A3P3: -1.54 +/- 1.58 mm, -15.50 +/- 15.20%, P < 0.001), tenting volume (-0.93 +/- 0.60 mm3, -22.00 +/- 11.40%, P < 0.001), systolic interpapillary muscle distance (-2.22 +/- 2.11 mm, -7.51 +/- 7.23%, P < 0.001) and diastolic interpapillary muscle distance (-3.14 +/- 2.20 mm, -8.46 +/- 5.73%, P < 0.001) post PVR. CONCLUSIONS: In post anterior MI heart failure patients, PVR has favorable near term impact on MV geometry as assessed by CCT. (c) 2015 Wiley Periodicals, Inc. PMID- 26526038 TI - Body mass index, adipokines and insulin resistance in asthmatic children and adolescents. AB - OBJECTIVE: This study aimed to describe the body mass index, insulin resistance, levels of adipokines and inflammatory markers in Brazilian asthmatic children and adolescents and to investigate their possible association with the severity and control of asthma. METHODS: Cross-sectional study (n = 92; age: 3-18 years). Assessed data: Body weight and height, used to calculate the body mass index (BMIZ) and height-for-age (HAZ). Laboratory measurements: Lipid profile; glycemia and insulin for homeostasis model assessment (HOMA); adipokines; tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1); total immunoglobulin E (IgE) and specific IgE against aeroallergens. RESULTS: The median age was 9.6 years (3.0-16.6); most participants were male (n = 52, 56.5%), pre-pubertal (n = 54, 58.6%) and had atopic asthma (n = 85, 92.4%). Overweight/obesity (38%) showed an inverse correlation with age (adjusted odds ratio [OR] = 0.781; 95% confidence interval [CI] 0.66-0.92) and a direct correlation with the leptin concentration (adjusted OR = 1.13; 95% CI 1.04-1.22). Insulin concentration was independently associated with moderated persistent asthma (adjusted OR = 1.31; 95% CI 1.09-1.52). HOMA showed a direct correlation with the leptin (beta = 0.475; 95% CI 0.117-0.268) and total IgE (beta = 0.197; 95% CI 0.002-0.096) levels and an inverse correlation with the TNF-alpha levels (beta = -0.255; 95% CI;-0.366-0.055). CONCLUSIONS: Asthma was associated with insulin resistance and a systemic inflammatory response possibly mediated by adipokines, with leptin levels standing out among the participants with excess weight. PMID- 26526039 TI - Computational Fluid Dynamics-Based Design Optimization Method for Archimedes Screw Blood Pumps. AB - An optimization method suitable for improving the performance of Archimedes screw axial rotary blood pumps is described in the present article. In order to achieve a more robust design and to save computational resources, this method combines the advantages of the established pump design theory with modern computer-aided, computational fluid dynamics (CFD)-based design optimization (CFD-O) relying on evolutionary algorithms and computational fluid dynamics. The main purposes of this project are to: (i) integrate pump design theory within the already existing CFD-based optimization; (ii) demonstrate that the resulting procedure is suitable for optimizing an Archimedes screw blood pump in terms of efficiency. Results obtained in this study demonstrate that the developed tool is able to meet both objectives. Finally, the resulting level of hemolysis can be numerically assessed for the optimal design, as hemolysis is an issue of overwhelming importance for blood pumps. PMID- 26526040 TI - Surface heparin treatment of the decellularized porcine heart valve: Effect on tissue calcification. AB - Tissue calcification is a major cause of failure of bioprosthetic heart valves. Aim of this study was to examine whether surface heparin treatment of the decellularized porcine heart valve reduces tissue calcification. Fresh porcine aortic heart valves were dissected as tissue discs and divided into four groups. Group A: controls without treatment, Group B: decellularization only, Group C: decellularization and glutaraldehyde cross-linking, Group D: decellularization and glutaraldehyde cross-linking followed by surface heparin treatment. After implantation in New Zealand White rabbits for 60 days, the explanted heart valve discs from the different study groups underwent a series of histological examinations as well as determination of calcium content by the methyl thyme phenol blue colorimetric method. Results of the explanted heart valve discs for the Von Kossa staining demonstrated that in Group A the heart valve tissue was the most severely stained with black color, whereas in Group D there was hardly any area that was stained black after implantation indicating the least tissue calcification. Furthermore, the inflammatory cells identified by the Hematoxylin eosin staining appeared to be the least in Group D. The average tissue calcium content was highest in Group A (0.197 +/- 0.115 MUmol mg-1 ), modest in Group B (0.113 +/- 0.041 MUmol mg-1 ), and Group C (0.089 +/- 0.049 MUmol mg-1 ), and the lowest in Group D (0.019 +/- 0.019 MUmol mg-1 , p < 0.05). These results suggest that surface heparin treatment tends to reduce tissue calcification of the dellellularized porcine heart valve in a rabbit intramuscular implantation model. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 400-405, 2017. PMID- 26526041 TI - Mosaic patterns of diversification dynamics following the colonization of Melanesian islands. AB - The fate of newly settled dispersers on freshly colonized oceanic islands is a central theme of island biogeography. The emergence of increasingly sophisticated methods of macroevolutionary pattern inference paves the way for a deeper understanding of the mechanisms governing these diversification patterns on lineages following their colonization of oceanic islands. Here we infer a comprehensive molecular phylogeny for Melanesian Exocelina diving beetles. Recent methods in historical biogeography and diversification rate inference were then used to investigate the evolution of these insects in space and time. An Australian origin in the mid-Miocene was followed by independent colonization events towards New Guinea and New Caledonia in the late Miocene. One colonization of New Guinea led to a large radiation of >150 species and 3 independent colonizations of New Caledonia gave rise to about 40 species. The comparably late colonizations of Vanuatu, Hawaii and China left only one or two species in each region. The contrasting diversification trajectories of these insects on Melanesian islands are likely accounted for by island size, age and availability of ecological opportunities during the colonization stage. PMID- 26526042 TI - Corrigendum. PMID- 26526044 TI - Intraluminal measurement of papillary duct urine pH, in vivo: a pilot study in the swine kidney. AB - We describe the in vivo use of an optic-chemo microsensor to measure intraluminal papillary duct urine pH in a large mammal. Fiber-optic pH microsensors have a tip diameter of 140-um that allows insertion into papillary Bellini ducts to measure tubule urine proton concentration. Anesthetized adult pigs underwent percutaneous nephrolithotomy to access the lower pole of the urinary collecting system. A flexible nephroscope was advanced towards an upper pole papilla with the fiber optic microsensor contained within the working channel. The microsensor was then carefully inserted into Bellini ducts to measure tubule urine pH in real time. We successfully recorded tubule urine pH values in five papillary ducts from three pigs (1 farm pig and 2 metabolic syndrome Ossabaw pigs). Our results demonstrate that optical microsensor technology can be used to measure intraluminal urine pH in real time in a living large mammal. This opens the possibility for application of this optical pH sensing technology in nephrolithiasis. PMID- 26526045 TI - Attentional Network Differences Between Migraineurs and Non-migraine Controls: fMRI Evidence. AB - Migraine is a headache disorder characterized by sensitivity to light and sound. Recent research has revealed abnormal visual-spatial attention in migraineurs in between headache attacks. Here, we ask whether these attentional abnormalities can be attributed to specific regions of the known attentional network to help characterize the abnormalities in migraine. Specifically, the ventral frontoparietal network of attention is involved with assessing the behavioural relevance of unattended stimuli. Given the decreased suppression of unattended stimuli reported in migraineurs, we hypothesized that migraineurs would have abnormal processing in the ventral portion of the frontoparietal network of attention. To address this, we used functional magnetic resonance imaging to assess the attentional control networks during visual spatial-orienting tasks in migraineurs (N = 16) as compared to non-migraine controls (N = 16). We employed two visual orienting paradigms with target discrimination tasks: (1) voluntary orienting to central arrow cues, and (2) reflexive orienting to peripheral flash cues. While both groups showed activation in the key areas of attentional processing networks, migraineurs showed less activation than non-migraine controls in a key area of the ventral frontoparietal network of attention, the right temporal parietal junction (rTPJ), during both voluntary and reflexive visual spatial orienting. Given the role of rTPJ is to assess the visual environment for behaviorally relevant sensory stimuli outside the focus of attention and signal other attentional areas to reorient attention to behaviorally salient stimuli, our findings fit with previous research showing that migraineurs lack suppression of unattended events and have heightened orienting to sudden onset stimuli in peripheral locations. PMID- 26526043 TI - Structural and Computational Biology in the Design of Immunogenic Vaccine Antigens. AB - Vaccination is historically one of the most important medical interventions for the prevention of infectious disease. Previously, vaccines were typically made of rather crude mixtures of inactivated or attenuated causative agents. However, over the last 10-20 years, several important technological and computational advances have enabled major progress in the discovery and design of potently immunogenic recombinant protein vaccine antigens. Here we discuss three key breakthrough approaches that have potentiated structural and computational vaccine design. Firstly, genomic sciences gave birth to the field of reverse vaccinology, which has enabled the rapid computational identification of potential vaccine antigens. Secondly, major advances in structural biology, experimental epitope mapping, and computational epitope prediction have yielded molecular insights into the immunogenic determinants defining protective antigens, enabling their rational optimization. Thirdly, and most recently, computational approaches have been used to convert this wealth of structural and immunological information into the design of improved vaccine antigens. This review aims to illustrate the growing power of combining sequencing, structural and computational approaches, and we discuss how this may drive the design of novel immunogens suitable for future vaccines urgently needed to increase the global prevention of infectious disease. PMID- 26526046 TI - The Natural Time Course of Membrane Alterations During Peritoneal Dialysis Is Partly Altered by Peritonitis. AB - ? BACKGROUND: The quality of the peritoneal membrane can deteriorate over time. Exposure to glucose-based dialysis solutions is the most likely culprit. Because peritonitis is a common complication of peritoneal dialysis (PD), distinguishing between the effect of glucose exposure and a possible additive effect of peritonitis is difficult. The aim of the present study was to compare the time course of peritoneal transport characteristics in patients without a single episode of peritonitis-representing the natural course-and in patients who experienced 1 or more episodes of peritonitis during long-term follow-up. ? METHODS: This prospective, single-center cohort study enrolled incident adult PD patients who started PD during 1990-2010. A standard peritoneal permeability analysis was performed in the first year of PD treatment and was repeated every year. The results in patients without a single episode of peritonitis ("no peritonitis group") were compared with the results obtained in patients who experienced 1 or more peritonitis episodes ("peritonitis group") during a follow up of 4 years. ? RESULTS: The 124 patients analyzed included 54 in the no peritonitis group and 70 in the peritonitis group. The time-course of small solute transport was different in the groups, with the peritonitis group showing an earlier and more pronounced increase in the mass transfer area coefficient for creatinine (p = 0.07) and in glucose absorption (p = 0.048). In the no peritonitis group, the net ultrafiltration rate (NUFR) and the transcapillary ultrafiltration rate (TCUFR) both showed a steep increase from the 1st to the 2nd year of PD that was absent in the peritonitis group. Both groups showed a decrease in the NUFR after year 3. A decrease in the TCUFR occurred only in the peritonitis group. That decrease was already present after the year 1 in patients with severe peritonitis. The time-course of free water transport showed a continuous increase in the patients without peritonitis, but a decrease in the patients who experienced peritonitis (p < 0.01). No difference was observed in the time-course of the effective lymphatic absorption rate. The time-courses of immunoglobulin G and alpha2-macroglobulin clearances showed a decrease in both patient groups, with a concomitant increase of the restriction coefficient. Those changes were not evidently influenced by peritonitis. The two groups showed a similar decrease in the mesothelial cell mass marker cancer antigen 125 during follow-up. ? CONCLUSIONS: On top of the natural course of peritoneal function, peritonitis episodes to some extent influence the time-course of small-solute and fluid transport-especially the transport of solute-free water. Those modifications increase the risk for overhydration. PMID- 26526047 TI - Measurement and Correlation of Indices of Insulin Resistance in Patients on Peritoneal Dialysis. AB - ? BACKGROUND: Insulin resistance (IR) is common in maintenance dialysis patients and is associated with excess mortality. Hyperinsulinemic euglycemic glucose clamp (HEGC) is the gold standard for measuring IR. There are limited studies using HEGC for comparison to other indirect indices of IR in peritoneal dialysis (PD) patients, nor have there been direct comparisons between patients receiving PD and those on maintenance hemodialysis (MHD) with regard to severity of IR, methods of measurement, or factors associated with the development of IR. ? METHODS: This is a cross-sectional, single-center study performed in 10 prevalent PD patients of median age 48 years (range 41 - 54); 50% were female and 60% were African American. Insulin resistance was assessed by HEGC (glucose disposal rate [GDR]), homeostatic model assessment of IR (HOMA-IR), HOMA-IR corrected by adiponectin (HOMA-AD), leptin adiponectin ratio (LAR), quantitative insulin sensitivity check index (QUICKI), McAuley's index, and oral glucose tolerance test (OGTT) at each time point for a total of 18 studies. Retrospective analysis compared this cohort to 12 hemodialysis patients who had previously undergone similar testing. ? RESULTS: The median GDR was 6.4 mg/kg/min (interquartile range [IQR] 6.0, 7.8) in the PD cohort compared with the MHD group, which was 5.7 mg/kg/min (IQR 4.3, 6.6). For both the PD and MHD cohorts, the best predictors of GDR by HEGC after adjusting for age, gender, and body mass index (BMI), were HOMA AD (PD: r = -0.69, p = 0.01; MHD: r = -0.78, p = 0.03) and LAR (PD: r = -0.68, p < 0.001; MHD: r = -0.65, p = 0.04). In both groups, HOMA-IR and QUICKI failed to have strong predictive value. Eight of 10 PD patients had at least 1 abnormal OGTT, demonstrating impaired glucose tolerance. ? CONCLUSIONS: Insulin resistance is highly prevalent in PD patients. The adipokine based formulas, HOMA-AD and LAR, correlated well in both the PD and MHD populations in predicting GDR by HEGC, outperforming HOMA-IR. The use of these novel markers could be considered for large-scale, epidemiological outcome studies. PMID- 26526051 TI - Stability of Tigecycline in Different Types of Peritoneal Dialysis Solutions. AB - ? INTRODUCTION: Intraperitoneal tigecycline is a potential option for the treatment of peritoneal dialysis (PD)-associated peritonitis caused by microorganisms resistant to commonly used antibiotics. However, the stability of tigecycline must be assessed in the PD solution before evaluating its safety and therapeutic efficacy in PD-associated peritonitis. The objective of this study was to investigate the stability of tigecycline in 3 types of PD solutions at different temperatures for various time points. ? METHODS: A total of 27 PD bags (9 PD bags for each type of PD solution; 1.5% glucose, 7.5% icodextrin, and 1.5% glucose pH neutral) containing 2 MUg/mL of tigecycline were prepared and stored at either 4, 25, or 37 degrees C. An aliquot was withdrawn immediately before (0 hour) and after pre-defined time points. Each sample was analyzed in duplicate for the concentration of tigecycline using a stability-indicating high performance liquid chromatography (HPLC) technique. Samples were also assessed for pH, color changes, and evidence of precipitation immediately after preparation and on each day of analysis. ? RESULTS: Tigecycline in all 3 types of PD solutions retained more than 90% of its initial concentration for at least 216, 72, and 8 hours at 4, 25, and 37 degrees C, respectively. There was no evidence of precipitation at any time under the tested storage conditions. The pH and color of tigecycline admixed PD solutions stored at 4, 25, and 37 degrees C remained essentially unchanged for 336, 96, and 48 hours respectively. ? CONCLUSION: The results obtained from the study provide a platform for future clinical studies aiming to determine the safety and therapeutic efficacy of intraperitoneally administered tigecycline for the treatment of PD-associated peritonitis. PMID- 26526049 TI - The Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS): Unifying Efforts to Inform Practice and Improve Global Outcomes in Peritoneal Dialysis. AB - ? BACKGROUND: Extending technique survival on peritoneal dialysis (PD) remains a major challenge in optimizing outcomes for PD patients while increasing PD utilization. The primary objective of the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) is to identify modifiable practices associated with improvements in PD technique and patient survival. In collaboration with the International Society for Peritoneal Dialysis (ISPD), PDOPPS seeks to standardize PD-related data definitions and provide a forum for effective international collaborative clinical research in PD. ? METHODS: The PDOPPS is an international prospective cohort study in Australia, Canada, Japan, the United Kingdom (UK), and the United States (US). Each country is enrolling a random sample of incident and prevalent patients from national samples of 20 to 80 sites with at least 20 patients on PD. Enrolled patients will be followed over an initial 3-year study period. Demographic, comorbidity, and treatment-related variables, and patient reported data, will be collected over the study course. The primary outcome will be all-cause PD technique failure or death; other outcomes will include cause specific technique failure, hospitalizations, and patient-reported outcomes. ? RESULTS: A high proportion of the targeted number of study sites has been recruited to date in each country. Several ancillary studies have been funded with high momentum toward expansion to new countries and additional participation. ? CONCLUSION: The PDOPPS is the first large, international study to follow PD patients longitudinally to capture clinical practice. With data collected, the study will serve as an invaluable resource and research platform for the international PD community, and provide a means to understand variation in PD practices and outcomes, to identify optimal practices, and to ultimately improve outcomes for PD patients. PMID- 26526053 TI - Discussion. PMID- 26526050 TI - Predictors of Transfer to Home Hemodialysis after Peritoneal Dialysis Completion. AB - ? BACKGROUND: The aim of the present study was to evaluate the predictors of transfer to home hemodialysis (HHD) after peritoneal dialysis (PD) completion. ? METHODS: All Australian and New Zealand patients treated with PD on day 90 after initiation of renal replacement therapy between 2000 and 2012 were included. Completion of PD was defined by death, transplantation, or hemodialysis (HD) for 180 days or more. Patients were categorized as "transferred to HHD" if they initiated HHD fewer than 180 days after PD had ended. Multivariable logistic regression was used to evaluate predictors of transfer to HHD in a restricted cohort experiencing PD technique failure; a competing-risks analysis was used in the unrestricted cohort. ? RESULTS: Of 10 710 incident PD patients, 3752 died, 1549 underwent transplantation, and 2915 transferred to HD, among whom 156 (5.4%) started HHD. The positive predictors of transfer to HHD in the restricted cohort were male sex [odds ratio (OR): 2.81], obesity (OR: 2.20), and PD therapy duration (OR: 1.10 per year). Negative predictors included age (OR: 0.95 per year), infectious cause of technique failure (OR: 0.48), underweight (OR: 0.50), kidney disease resulting from hypertension (OR: 0.38) or diabetes (OR: 0.32), race being Maori (OR: 0.65) or Aboriginal and Torres Strait Islander (OR: 0.30). Comparable results were obtained with a competing-risks model. ? CONCLUSIONS: Transfer to HHD after completion of PD is rare and predicted by patient characteristics at baseline and at the time of PD end. Transition to HHD should be considered more often in patients using PD, especially when they fulfill the identified characteristics. PMID- 26526048 TI - (1->3)-beta-d-Glucan and Galactomannan for Differentiating Chemical "Black Particles" and Fungal Particles Inside Peritoneal Dialysis Tubing. AB - ? BACKGROUND: Aseptic, sheet-like foreign bodies observed inside Tenckhoff (TK) catheter lumens (referred to as "black particles") are, on gross morphology, hardly distinguishable from fungal colonization because these contaminants adhere tightly to the catheter. Detection of fungal cell wall components using (1->3) beta-d-glucan (BG) and galactomannan index (GMI) might be an alternative method for differentiating the particles. ? METHODS: Foreign particles retrieved from TK catheters in 19 peritoneal dialysis patients were examined microscopically and cultured for fungi and bacteria. Simultaneously, a Fungitell test (Associates of Cape Cod, Falmouth, MA, USA) and a Platelia Aspergillus ELISA assay (Bio-Rad Laboratories, Marnes-La-Coquette, France) were used to test the spent dialysate for BG and GMI respectively. ? RESULTS: Of the 19 patients, 9 had aseptic black particles and 10 had fungal particles in their tubing. The fungal particles looked grainy, were tightly bound to the catheter, and appeared more "colorful" than the black particles, which looked sheet-like and could easily be removed by milking the tubing. Compared with effluent from patients having aseptic particles, effluent from patients with fungal particles had significantly higher levels of BG (501 +/- 70 pg/mL vs. 46 +/- 10 pg/mL) and GMI (10.98 +/- 2.17 vs. 0.25 +/- 0.05). Most of the fungi that formed colonies inside the catheter lumen were molds not usually found in clinical practice, but likely from water or soil, suggesting environmental contamination. Interestingly, in all 10 patients with fungal colonization, visualization of black particles preceded a peritonitis episode and TK catheter removal by approximately 1-3 weeks; in patients with aseptic particles, a 17-week onset to peritonitis was observed. ? CONCLUSIONS: In all patients with particle-coated peritoneal dialysis tubing, spent dialysate should be screened for BG and GMI. Manipulation of the TK catheter by squeezing, hard flushing, or even brushing to dislodge black particles should be avoided. Replacement of the TK catheter should be suspended until a cause for the particles is determined. PMID- 26526052 TI - Beta-blocker use is associated with lower stroke and death after carotid artery stenting. AB - BACKGROUND: Proper selection of patients for carotid artery stenting (CAS) remains controversial despite multiple controlled trials. This relates in part to differences in interpretation of the relative importance of myocardial vs stroke complications after the procedure by different specialties and a lack of granular clinical data to analyze outcomes outside the large clinical trials. The objective of this study was to assess the effect of preoperative medications, procedure parameters, and patient characteristics on outcomes of CAS performed in a multispecialty national database. METHODS: We analyzed all patients who underwent CAS between 2005 and 2014 in the Vascular Quality Initiative. A multivariate logistic regression model was built to assess the effects of age, gender, comorbidities, smoking, preprocedure medications, procedure details, and hypotension or hypertension that required intravenous medication on 30-day death or stroke rates. RESULTS: A total of 5263 patients underwent CAS (mean age, 70 years; 63% male). The 30-day stroke/death rate was 3.4% (1.5% minor stroke, 0.9% major stroke, and 1.2% death; 40% of patients who had major strokes died within 30 days), and the myocardial infarction rate was 0.8%. Postprocedural hypertension requiring treatment occurred in 519 cases (9.9%), and it was associated with a 3.4-fold increase in stroke/death (odds ratio, 3.39; 95% confidence interval, 2.30-5.00; P < .0001). Preprocedural beta-blocker use for >30 days was associated with a 34% reduction in the stroke/death risk (odds ratio, 0.66; 95% confidence interval, 0.46-0.95; P = .025) compared with nonuse. Beta-blocker use was not associated with postprocedural hypotension. Other predictors of postoperative stroke and death included age, symptomatic status, diabetes (type 1 or type 2), and postprocedural hypotension, whereas prior carotid endarterectomy and distal embolic protection use were protective. CONCLUSIONS: Postprocedural hypertension and hypotension that require treatment are both strongly associated with periprocedural stroke/death after CAS. Beta blockers significantly reduce the stroke/death risk associated with carotid stenting and should be investigated prospectively for potential use during CAS. PMID- 26526054 TI - Discussion. PMID- 26526055 TI - Validated prediction model for severe groin wound infection after lower extremity revascularization procedures. AB - BACKGROUND: Groin wound infection is a costly and morbid event after lower extremity revascularization. To date, a comprehensive and validated method for identifying patients who are at greatest risk for this complication has yet to be developed. METHODS: Our retrospective analysis included all patients at a single institution who underwent lower extremity revascularization using a groin incision from 2009 through 2012. Patients were randomly assigned to one of two groups: a test group, which was used to develop a predictive model for our primary outcome; and a validation group, which was used to test that model. The primary outcome for our analysis was severe groin wound infection, which we defined as postoperative groin infection that required operative intervention. Multimodel inference methods were used to evaluate all possible combinations, interactions, and transformations of potential predictor variables from the test group of patients. The resulting model that exhibited the lowest Akaike information criterion was then selected for testing with the validation group of patients. RESULTS: A total of 284 patients who underwent lower extremity revascularization procedures were included in our study (140 in the test group, 144 in the validation group). In the test group, 17 patients (12.1%) developed severe groin wound infection requiring operative intervention. The best-fit predictive model developed from this group identified the following independent risk factors for severe groin wound infection: prior ipsilateral groin incision, female gender, body mass index, end-stage renal disease, malnutrition, and urgent or emergency procedure status. The correct classification rate of this model in the test group was 88.6%. The incidence of severe groin wound infection in the validation group was 13.9%, and application of our predictive model to this group yielded a correct classification rate of 86.1%. CONCLUSIONS: We have developed and validated a statistical model that accurately predicts those patients who are likely to sustain severe groin wound infection after lower extremity revascularization. PMID- 26526056 TI - Remarkable impairment of Wnt/beta-catenin signaling in the brains of the mice infected with scrapie agents. AB - Prion diseases are a group of neurodegenerative diseases characterized by neuronal loss and spongiform degeneration, astrogliosis and aggregation of scrapie prion protein (PrPSc ) in the central nervous system (CNS). The Wnt signaling pathway is a highly evolutionarily conserved pathway in eukaryotes that regulates cell proliferation, differentiation and survival. Impairment of Wnt/beta-catenin signaling has been reported in the CNS of various neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. To investigate the functional state of Wnt/beta-catenin signaling in the CNS tissues during the progression of prion disease, the components of Wnt/beta catenin signaling in the brains of the scrapie agents 139A- and ME7-infected mice were evaluated. Compared with the normal controls, the brain levels of phosphor beta-catenin (Ser33,37 and Thr41 ) in 139A- and ME7-infected mice were significantly increased, while those of cyclin D1, which is one of the target genes of Wnt signaling, were decreased. The levels of phosphor-glycogen synthase kinase-3beta (GSK-3beta) Ser9 were markedly reduced, representing an enhanced GSK 3beta activity in scrapie-infected mice. Both western blot and immunohistochemical assays revealed a remarkable increase of Dickkopf-1, the antagonist of Wnt/beta-catenin signaling, in the brains of scrapie-infected anim als, which co-localized well with the remaining neurons in the immunofluorescent tests. We also observed slightly decreased Wnt-3 and unchanged disheveled-3 (Dvl 3) in the brains of the infected mice. Our data, here, strongly indicate an impairment of Wnt/beta-catenin pathway in the brains of prion disease, which shows a time-dependent progression along with the incubation period. Schematic for the impairment of canonical Wnt signaling during prion infection. The left and right parts represent the normal and prion-infected situations, respectively. Prion infection or PrPSc accumulation triggers the over-expression of Dickkopf WNT signaling pathway inhibitor 1 (DKK-1) and the enhancement of glycogen synthase kinase 3beta (GSK-3beta) activity, which subsequently promotes the phosphorylation and degradation of beta-catenin. As a result, the impairment of beta-catenin signaling leads to the down-regulation of Wnt target genes. PMID- 26526057 TI - Covariate dimension reduction for survival data via the Gaussian process latent variable model. AB - The analysis of high-dimensional survival data is challenging, primarily owing to the problem of overfitting, which occurs when spurious relationships are inferred from data that subsequently fail to exist in test data. Here, we propose a novel method of extracting a low-dimensional representation of covariates in survival data by combining the popular Gaussian process latent variable model with a Weibull proportional hazards model. The combined model offers a flexible non linear probabilistic method of detecting and extracting any intrinsic low dimensional structure from high-dimensional data. By reducing the covariate dimension, we aim to diminish the risk of overfitting and increase the robustness and accuracy with which we infer relationships between covariates and survival outcomes. In addition, we can simultaneously combine information from multiple data sources by expressing multiple datasets in terms of the same low-dimensional space. We present results from several simulation studies that illustrate a reduction in overfitting and an increase in predictive performance, as well as successful detection of intrinsic dimensionality. We provide evidence that it is advantageous to combine dimensionality reduction with survival outcomes rather than performing unsupervised dimensionality reduction on its own. Finally, we use our model to analyse experimental gene expression data and detect and extract a low-dimensional representation that allows us to distinguish high-risk and low risk groups with superior accuracy compared with doing regression on the original high-dimensional data. PMID- 26526059 TI - A search for genetic diversity among Italian Greyhounds from Continental Europe and the USA and the effect of inbreeding on susceptibility to autoimmune disease. AB - BACKGROUND: Previous studies documented the problem of inbreeding among Italian Greyhounds (IG) from the USA and its possible role in a multiple autoimmune disease syndrome. The present study is an extension of these earlier experiments and had two objectives: 1) to identify pockets of additional genetic diversity that might still exist among IG from the USA and Continental Europe, and 2) to determine how loss of genetic diversity within the genome and in the dog leukocyte antigen (DLA) complex relates to the problem of autoimmune disease in IG from the USA. Genetic testing was conducted using 33 short tandem repeat (STR) loci across 25 chromosomes and 7 STR loci that associated with specific dog leukocyte antigen (DLA) class I and II haplotypes. Standard genetic assessment tests based on allele frequencies and internal relatedness (IR) were used as measures of breed-wide and individual heterozygosity. RESULTS: The results of these tests demonstrated that IG from the USA and Continental Europe belonged to a single breed but were genetically distinguishable by genomic allele frequencies, DLA class I and II haplotypes, and principal coordinate analysis (PCoA). In the second part of the study, 85 IG from the USA that had suffered various autoimmune disorders (case) and 104 healthy dogs (control) of comparable age were studied for genetic associations with disease. Case dogs were found to be significantly more homozygous in the DLA regions than control dogs. Principal coordinate analysis did not differentiate case from control populations. No specific STR-associated DLA-class I or II haplotype was associated with increased autoimmune disease risks. Reasons for the loss of genetic diversity and increased homozygosity among IG from the USA were studied using registration data and deep pedigrees. The breed in the USA started from a small number of founders from Europe and has remained relatively isolated and small in numbers, limiting breeding choices especially in the period before modern transportation and artificial insemination. An additional cause of lost diversity and increased homozygosity has been the influence of famous sires and their show-winning progeny. The most influential of these sires was Ch. Dasa's King of the Mountain (King) born in 1978. Virtually all contemporary IG from the USA have King at least once in 10 generation pedigrees and 18 % of the genome of contemporary IG from the USA is shared with King. CONCLUSIONS: It was concluded that artificial genetic bottlenecks have concentrated numerous genetic polymorphisms responsible for autoimmune disease and that these risk factors did not originate in a specific individual or bloodline of the breed. Rather, they were of ancestral origin in both purebred and random bred dogs and inherited by descent. Italian Greyhound breeders in the USA have several options to improve breed health: 1) breed against homozygosity within the genome and in the DLA region, 2) avoid breeding dogs that have suffered an autoimmune disorder, 3) increase diversity by incorporating the genetic differences that exist in IG from Continental Europe, or 4) outcross to other small sighthound breeds. The latter two approaches must be undertaken with care to avoid introduction of new deleterious traits and to maximize retention and dissemination of new genetic diversity. PMID- 26526058 TI - Larger differences in utilization of rarely requested tests in primary care in Spain. AB - INTRODUCTION: The study was performed to compare and analyze the inter departmental variability in the request of rarely requested laboratory tests in primary care, as opposed to other more common and highly requested tests. MATERIALS AND METHODS: Data from production statistics for the year 2012 from 76 Spanish laboratories was used. The number of antinuclear antibodies, antistreptolysin O, creatinine, cyclic citrullinated peptide antibodies, deaminated peptide gliadine IgA antibodies, glucose, protein electrophoresis, rheumatoid factor, transglutaminase IgA antibodies, urinalysis and uric acid tests requested was collected. The number of test requests per 1000 inhabitants was calculated. In order to explore the variability the coefficient of quartile dispersion was calculated. RESULTS: The smallest variation was seen for creatinine, glucose, uric acid and urinalysis; the most requested tests. The tests that were least requested showed the greatest variability. CONCLUSION: Our study shows through a very simplified approach, in a population close to twenty million inhabitants, how in primary care, the variability in the request of laboratory tests is inversely proportional to the request rate. PMID- 26526060 TI - Tissue Specific Effects of Dietary Carbohydrates and Obesity on ChREBPalpha and ChREBPbeta Expression. AB - Carbohydrate response element binding protein (ChREBP) regulates insulin independent de novo lipogenesis. Recently, a novel ChREBPbeta isoform was identified. The purpose of the current study was to define the effect of dietary carbohydrates (CHO) and obesity on the transcriptional activity of ChREBP isoforms and their respective target genes. Mice were subjected to fasting refeeding of high-CHO diets. In all three CHO-refeeding groups, mice failed to induce ChREBPalpha, yet ChREBPbeta increased 10- to 20-fold. High-fat fed mice increased hepatic ChREBPbeta mRNA expression compared to chow-fed along with increased protein expression. To better assess the independent effect of fructose on ChREBPalpha/beta activity, HepG2 cells were treated with fructose +/- a fructose-1,6-bisphosphatase inhibitor to suppress gluconeogenesis. Fructose treatment in the absence of gluconeogenesis resulted in increased ChREBP activity. To confirm the existence of ChREBPbeta in human tissue, primary hepatocytes were incubated with high-glucose and the expression of ChREBPalpha and -beta was determined. As with the animal models, glucose induced ChREBPbeta expression while ChREBPalpha was decreased. Taken together, ChREBPbeta is more responsive to changes in dietary CHO availability than the -alpha isoform. Diet induced obesity increases basal expression of ChREBPbeta, which may increase the risk of developing hepatic steatosis, and fructose-induced activation is independent of gluconeogenesis. PMID- 26526061 TI - Low n-6/n-3 PUFA Ratio Improves Lipid Metabolism, Inflammation, Oxidative Stress and Endothelial Function in Rats Using Plant Oils as n-3 Fatty Acid Source. AB - Lipid metabolism, inflammation, oxidative stress and endothelial function play important roles in the pathogenesis of cardiovascular disease (CVD), which may be affected by an imbalance in the n-6/n-3 polyunsaturated fatty acid (PUFA) ratio. This study aimed to investigate the effects of the n-6/n-3 PUFA ratio on these cardiovascular risk factors in rats fed a high-fat diet using plant oils as the main n-3 PUFA source. The 1:1 and 5:1 ratio groups had significantly decreased serum levels of total cholesterol, low-density lipoprotein cholesterol, and proinflammatory cytokines compared with the 20:1 group (p < 0.05). Additionally, the 20:1 group had significantly increased serum levels of E-Selectin, von Willebrand factor (vWF), and numerous markers of oxidative stress compared with the other groups (p < 0.05). The 1:1 group had a significantly decreased lipid peroxide level compared with the other groups (p < 0.05). Serum levels of malondialdehyde, reactive oxygen species and vWF tended to increase with n-6/n-3 PUFA ratios increasing from 5:1 to 20:1. We demonstrated that low n-6/n-3 PUFA ratio (1:1 and 5:1) had a beneficial effect on cardiovascular risk factors by enhancing favorable lipid profiles, having anti-inflammatory and anti-oxidative stress effects, and improving endothelial function. A high n-6/n-3 PUFA ratio (20:1) had adverse effects. Our results indicated that low n-6/n-3 PUFA ratios exerted beneficial cardiovascular effects, suggesting that plant oils could be used as a source of n-3 fatty acids to prevent CVD. They also suggested that we should be aware of possible adverse effects from excessive n-3 PUFA. PMID- 26526062 TI - Chronic Post Surgical Pain. AB - Chronic post-surgical pain (CPSP) is a recognised adverse consequence of surgery; surgery is common, therefore the population at risk is considerable.Putative risk factors for CPSP include genetic predisposition, demographic, clinical (pain history, type of surgery, anaesthesia, acute pain severity), and psychological factors (vulnerability vs resilience).Evidence of prevention is limited: long term benefit from pre-emptive/perioperative analgesia has not been demonstrated consistently.Large scale prospective studies with detailed pre, intra and postoperative multifactorial assessments are required to refine understanding of the aetiology and prognosis of CPSP. PMID- 26526063 TI - Social capital and active membership in the Ghana National Health Insurance Scheme - a mixed method study. AB - BACKGROUND: People's decision to enroll in a health insurance scheme is determined by socio-cultural and socio-economic factors. On request of the National health Insurance Authority (NHIA) in Ghana, our study explores the influence of social relationships on people's perceptions, behavior and decision making to enroll in the National Health Insurance Scheme. This social scheme, initiated in 2003, aims to realize accessible quality healthcare services for the entire population of Ghana. We look at relationships of trust and reciprocity between individuals in the communities (so called horizontal social capital) and between individuals and formal health institutions (called vertical social capital) in order to determine whether these two forms of social capital inhibit or facilitate enrolment of clients in the scheme. Results can support the NHIA in exploiting social capital to reach their objective and strengthen their policy and practice. METHOD: We conducted 20 individual- and seven key-informant interviews, 22 focus group discussions, two stakeholder meetings and a household survey, using a random sample of 1903 households from the catchment area of 64 primary healthcare facilities. The study took place in Greater Accra Region and Western Regions in Ghana between June 2011 and March 2012. RESULTS: While social developments and increased heterogeneity seem to reduce community solidarity in Ghana, social networks remain common in Ghana and are valued for their multiple benefits (i.e. reciprocal trust and support, information sharing, motivation, risk sharing). Trusting relations with healthcare and insurance providers are, according healthcare clients, based on providers' clear communication, attitude, devotion, encouragement and reliability of services. Active membership of the NHIS is positive associated with community trust, trust in healthcare providers and trust in the NHIS (p-values are .009, .000 and .000 respectively). CONCLUSION: Social capital can motivate clients to enroll in health insurance. Fostering social capital through improving information provision to communities and engaging community groups in health care and NHIS services can facilitate peoples' trust in these institutions and their active participation in the scheme. PMID- 26526064 TI - The Australian Pharmaceutical Benefits Scheme data collection: a practical guide for researchers. AB - BACKGROUND: The Pharmaceutical Benefits Scheme (PBS) is Australia's national drug subsidy program. This paper provides a practical guide to researchers using PBS data to examine prescribed medicine use. FINDINGS: Excerpts of the PBS data collection are available in a variety of formats. We describe the core components of four publicly available extracts (the Australian Statistics on Medicines, PBS statistics online, section 85 extract, under co-payment extract). We also detail common analytical challenges and key issues regarding the interpretation of utilisation using the PBS collection and its various extracts. CONCLUSIONS: Research using routinely collected data is increasing internationally. PBS data are a valuable resource for Australian pharmacoepidemiological and pharmaceutical policy research. A detailed knowledge of the PBS, the nuances of data capture, and the extracts available for research purposes are necessary to ensure robust methodology, interpretation, and translation of study findings into policy and practice. PMID- 26526065 TI - Ketamine administration diminishes operant responding but does not impair conditioned fear. AB - While not well understood, the NMDA (N-methyl-D-aspartate) antagonist ketamine, a dissociative anesthetic, has been reported to be efficacious in depression and related psychological disorders. Conditioned fear is a normal emotional conditioning process that is known to become dysfunctional in individuals suffering from Post-Traumatic Stress Disorder (PTSD) and related stress disorders. We examined the effects of ketamine to determine the potential modulation of the acquisition and extinction of a conditioned fear using a conditioned suppression procedure. Rats were trained on a variable interval (VI), food maintained, operant conditioning task to establish a general measure of performance. Rats were exposed to inescapable shock (IES, unconditioned stimulus) paired (*20) with an audio/visual conditioned stimulus (CS) to establish conditioning. Conditioning was quantified by measuring response suppression following CS presentation during subsequent extinction trials where the CS alone was presented. Ketamine or vehicle was administered either after initial conditioning or after each of the subsequent extinction trials. For each regimen, a series of four injections were administered 60 min apart (100, 50, 50, 50 mg/kg, respectively) in order to sustain a ketamine effect for a minimum of 4 h. Ketamine produced a general decrease in responding on the VI, relative to baseline, as response rates were slower on the operant task when tested 24 h later and longer. Ketamine did not affect the acquisition of the conditioned fear when the regimen was administered shortly after the initial pairings of IES and CS. Ketamine did not alter extinction to the conditioned fear when the regimen was administered following each CS only presentation following initial conditioning. Our conclusion from these findings is that while ketamine alters behavior on an appetitively motivated operant task it does not, however, appear to directly modulate learning and memory processes associated with conditioned fear. PMID- 26526066 TI - Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Abeta accumulation and memory deficits. AB - BACKGROUND: Preventing or reducing amyloid-beta (Abeta) accumulation in the brain is an important therapeutic strategy for Alzheimer's disease (AD). Recent studies showed that the water channel aquaporin-4 (AQP4) mediates soluble Abeta clearance from the brain parenchyma along the paravascular pathway. However the direct evidence for roles of AQP4 in the pathophysiology of AD remains absent. RESULTS: Here, we reported that the deletion of AQP4 exacerbated cognitive deficits of 12 moth old APP/PS1 mice, with increases in Abeta accumulation, cerebral amyloid angiopathy and loss of synaptic protein and brain-derived neurotrophic factor in the hippocampus and cortex. Furthermore, AQP4 deficiency increased atrophy of astrocytes with significant decreases in interleukin-1 beta and nonsignificant decreases in interleukin-6 and tumor necrosis factor-alpha in hippocampal and cerebral samples. CONCLUSIONS: These results suggest that AQP4 attenuates Abeta pathogenesis despite its potentially inflammatory side-effects, thus serving as a promising target for treating AD. PMID- 26526067 TI - Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride. AB - Gastrointestinal toxicity, such as late-onset diarrhea, is a significant concern in irinotecan hydrochloride (CPT-11)-containing regimens. Prophylaxis of late onset diarrhea has been reported with use of Japanese traditional (Kampo) medicine containing baicalin and with the antibiotic cefixime, and this has been explained in terms of inhibition of bacterial deconjugation of SN-38-glucuronide since unconjugated SN-38 (active metabolite of CPT-11) is responsible for the gastrointestinal toxicity. It is also prerequisite for SN-38 to be accumulated in intestinal tissues to exert toxicity. Based on the fact that liver-specific organic anion transporting polypeptide (OATP)1B1, a member of the same family as OATP2B1, is known to be involved in hepatic transport of SN-38, we hypothesized that intestinal transporter OATP2B1 contributes to the accumulation of SN-38 in gastrointestinal tissues, and its inhibition would help prevent associated toxicity. We found that uptake of SN-38 by OATP2B1-expressing Xenopus oocytes was significantly higher than that by control oocytes. OATP2B1-mediated uptake of SN 38 was saturable, pH dependent, and decreased in the presence of baicalin, cefixime, or fruit juices such as apple juice. In vivo gastrointestinal toxicity of SN-38 in mice caused by oral administration for consecutive 5 days was prevented by coingestion of apple juice. Thus, OATP2B1 contributes to the uptake of SN-38 by intestinal tissues, triggering gastrointestinal toxicity. So, in addition to the reported inhibition of bacterial beta-glucuronidase by cefixime or baicalin, inhibition of OATP2B1 may also contribute to prevention of gastrointestinal toxicity. Apple juice may be helpful for prophylaxis of late onset diarrhea observed in CPT-11 therapy without disturbance of the intestinal microflora. PMID- 26526069 TI - The Effect of Fragaria vesca Extract on Smear Layer Removal: A Scanning Electron Microscopic Evaluation. AB - INTRODUCTION: Successful endodontic treatment depends on elimination of the microorganisms through chemomechanical debridement. The aim of this in vitro study was to evaluate the effectiveness of Fragaria vesca (wild strawberry) extract (FVE) on the removal of smear layer (SL). METHODS AND MATERIALS: In this analytical-observational study, 40 extracted mandibular and maxillary human teeth were selected. After canal preparation with standard step-back technique, the teeth were randomly divided into 4 groups according to the irrigation solution: saline (negative control), 5.25% NaOCl+EDTA (positive control), FVE and FVE+EDTA. The teeth were split longitudinally so that scanning electron microscopy (SEM) photomicrographs could be taken to evaluate the amount of remnant SL in coronal, middle and apical thirds. The data were analyzed statistically by the Kruskal Wallis and Mann Whitney U tests and the level of significance was set at 0.05. RESULTS: Significant differences were found among the groups (P<0.001). The use of NaOCl+EDTA was the most effective regimen for removing the SL followed by FVE+EDTA. FVE alone was significantly more effective than saline (P<0.001). CONCLUSION: FVE with and without EDTA could effectively remove the smear layer; however, compared to NaOCl group it was less effective. PMID- 26526068 TI - Molecular detection of pancreatic neoplasia: Current status and future promise. AB - Pancreatic cancer is usually diagnosed at an advanced stage and curative resection is feasible in only a small minority of patients at the time of diagnosis. Diagnosis at an early stage is unequivocally associated with better long-term survival. Several candidate molecular markers for early detection are currently under investigation in different phases of discovery and validation. Recent advances in the technology for whole genome, methylome, ribonucleome, and proteome interrogation has enabled rapid advancements in the field of biomarker discovery. In this review we discuss the current status of molecular markers for detection of pancreatic cancer in blood, pancreatic cyst fluid, pancreatic juice and stool and briefly highlight some promising preliminary results of new approaches that have the potential of advancing this field in the near future. PMID- 26526070 TI - Determining multiallelic complex copy number and sequence variation from high coverage exome sequencing data. AB - BACKGROUND: Copy number variation (CNV) is a major component of genomic variation, yet methods to accurately type genomic CNV lag behind methods that type single nucleotide variation. High-throughput sequencing can contribute to these methods by using sequence read depth, which takes the number of reads that map to a given part of the reference genome as a proxy for copy number of that region, and compares across samples. Furthermore, high-throughput sequencing also provides information on the sequence differences between copies within and between individuals. METHODS: In this study we use high-coverage phase 3 exome sequences of the 1000 Genomes project to infer diploid copy number of the beta defensin genomic region, a well-studied CNV that carries several beta-defensin genes involved in the antimicrobial response, signalling, and fertility. We also use these data to call sequence variants, a particular challenge given the multicopy nature of the region. RESULTS: We confidently call copy number and sequence variation of the beta-defensin genes on 1285 samples from 26 global populations, validate copy number using Nanostring nCounter and triplex paralogue ratio test data. We use the copy number calls to verify the genomic extent of the CNV and validate sequence calls using analysis of cloned PCR products. We identify novel variation, mostly individually rare, predicted to alter amino-acid sequence in the beta-defensin genes. Such novel variants may alter antimicrobial properties or have off-target receptor interactions, and may contribute to individuality in immunological response and fertility. CONCLUSIONS: Given that 81% of identified sequence variants were not previously in dbSNP, we show that sequence variation in multiallelic CNVs represent an unappreciated source of genomic diversity. PMID- 26526071 TI - The effects of pulmonary diseases on histologic types of lung cancer in both sexes: a population-based study in Taiwan. AB - BACKGROUND: The associations between pulmonary diseases (asthma, chronic obstructive pulmonary disease [COPD], and tuberculosis [TB]) and subsequent lung cancer risk have been reported, but few studies have investigated the association with different histologic types of lung cancer. METHODS: Patients newly diagnosed with lung cancer from 2004 to 2008 were identified from the National Health Insurance Research Database in Taiwan. Histologic types of lung cancer were further confirmed using the Taiwan Cancer Registry Database. Cox proportional hazards regression was used to calculate the hazard ratio (HR) of asthma, COPD, and TB and to estimate the risk of specific types of lung cancer. RESULTS: During the study period, 32,759 cases of lung cancer were identified from 15,219,024 insurants aged 20 years and older. In men and women, the adjusted HR estimates of squamous cell carcinoma were respectively 1.37 (95 % confidence interval [CI], 1.21-1.54) and 2.10 (95 % CI, 1.36-3.23) for TB, 1.52 (95 % CI, 1.42-1.64) and 1.50 (95 % CI, 1.21-1.85) for asthma, and 1.66 (95 % CI, 1.56-1.76) and 1.44 (95 % CI, 1.19-1.74) for COPD. Similarly, the adjusted HR estimates of adenocarcinoma were respectively 1.33 (95 % CI, 1.19-1.50) and 1.86 (95 % CI, 1.57-2.19) for TB, 1.13 (95 % CI, 1.05-1.21) and 1.18 (95 % CI, 1.09-1.28) for asthma, and 1.50 (95 % CI, 1.42-1.59) and 1.33 (95 % CI, 1.25-1.42) for COPD. The HRs of small cell carcinoma were respectively 1.24 (95 % CI, 1.01-1.52) and 2.23 (95 % CI, 1.17 4.25) for TB, 1.51 (95 % CI, 1.35-1.69) and 1.63 (95 % CI, 1.16-2.27) for asthma, and 1.39 (95 % CI, 1.26-1.53) and 1.78 (95 % CI, 1.33-2.39) for COPD. CONCLUSIONS: Asthma, COPD, and TB were associated with an increased risk of all major subtypes of lung cancer. The risk was the highest among women with TB. PMID- 26526072 TI - Differences in neural activity when processing emotional arousal and valence in autism spectrum disorders. AB - Individuals with autism spectrum disorders (ASD) often have difficulty recognizing and interpreting facial expressions of emotion, which may impair their ability to navigate and communicate successfully in their social, interpersonal environments. Characterizing specific differences between individuals with ASD and their typically developing (TD) counterparts in the neural activity subserving their experience of emotional faces may provide distinct targets for ASD interventions. Thus we used functional magnetic resonance imaging (fMRI) and a parametric experimental design to identify brain regions in which neural activity correlated with ratings of arousal and valence for a broad range of emotional faces. Participants (51 ASD, 84 TD) were group matched by age, sex, IQ, race, and socioeconomic status. Using task-related change in blood-oxygen-level-dependent (BOLD) fMRI signal as a measure, and covarying for age, sex, FSIQ, and ADOS scores, we detected significant differences across diagnostic groups in the neural activity subserving the dimension of arousal but not valence. BOLD-signal in TD participants correlated inversely with ratings of arousal in regions associated primarily with attentional functions, whereas BOLD-signal in ASD participants correlated positively with arousal ratings in regions commonly associated with impulse control and default-mode activity. Only minor differences were detected between groups in the BOLD signal correlates of valence ratings. Our findings provide unique insight into the emotional experiences of individuals with ASD. Although behavioral responses to face-stimuli were comparable across diagnostic groups, the corresponding neural activity for our ASD and TD groups differed dramatically. The near absence of group differences for valence correlates and the presence of strong group differences for arousal correlates suggest that individuals with ASD are not atypical in all aspects of emotion-processing. Studying these similarities and differences may help us to understand the origins of divergent interpersonal emotional experience in persons with ASD. Hum Brain Mapp 37:443-461, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26526073 TI - Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug-drug interactions. AB - The SCL22A1 gene encodes the broad selectivity transporter hOCT1. hOCT1 is expressed in most epithelial barriers thereby contributing to drug pharmacokinetics. It is also expressed in different drug target cells, including immune system cells and others. Thus, this membrane protein might also contribute to drug pharmacodynamics. Up to 1000 hOCT1 polymorphisms have been identified so far, although only a small fraction of those have been mechanistically studied. A paradigm in the field of drug transporter pharmacogenetics is the impact of hOCT1 gene variability on metformin clinical parameters, affecting area under the concentration-time curve, Cmax and responsiveness. However, hOCT1 also mediates the translocation of a variety of drugs used as anticancer, antiviral, anti inflammatory, antiemetic agents as well as drugs used in the treatment of neurological diseases among. This review focuses exclusively on those drugs for which some pharmacogenetic data are available, and aims at highlighting the need for further clinical research in this area. PMID- 26526074 TI - A new allele of gamma-kafirin gene coding for a protein with high lysine content in Mexican white sorghum germplasm. AB - BACKGROUND: Low protein digestibility and lysine content of white sorghum grain limit its use as a foodstuff. The increase in gamma-kafirin cross-linking, has an important role in the reduction of protein digestibility. The objective of this study was to characterize the gamma-kafirin gene in 12 Mexican tannin-free white sorghum genotypes and its relationship with protein digestibility and lysine content. RESULTS: Two alleles of gamma-kafirin gene were identified: alleles 1 and 7. The predicted amino acid sequence of allele 7 showed seven point mutations; six were silent, and one missense (C235G), causing the substitution P79A in the deduced amino acid sequence. In silico analysis showed that gamma kafirin codified by allele 1 has five alpha-helixes without disulfide bonds, while gamma-kafirin coding by allele 7 has four alpha-helixes and three disulfide bonds. Genotypes with allele 7 had higher lysine content than those with allele 1, showing no differences in the kafirin electrophoretic profile, neither a correlation with the protein content nor the in vitro pepsin digestibility. CONCLUSIONS: Mexican tannin-free white sorghum genotypes showed two gamma-kafirin alleles, 1 and 7. Allele 7 was associated with higher lysine content; in silico analysis showed that the substitution of P79A in this allele could modify gamma kafirin secondary structure. (c) 2015 Society of Chemical Industry. PMID- 26526075 TI - Amyl nitrite inhalation, a "volatile" anemia. PMID- 26526076 TI - Photocrosslinking of styrene-butadiene-styrene (SBS) networks formed by thiol-ene reactions and their influence on cell survival. AB - Styrene-butadiene-styrene (SBS) triblock copolymer has been conventionally used as synthetic rubber. However, the potential of SBS for biomedical applications has only been considered in limited earlier reports. Here, we demonstrate an effective approach to designing a photocrosslinked SBS network. Rheological analysis has been conducted for the investigation of the storage modulus of the resultant network. Crosslinked SBS networks were synthesized and characterized through optical and electron microscope imaging. The crosslink density of the network, calculated from swelling experiments, was 643 mol m(-3), where higher swelling in a hydrophobic medium was observed compared to the swelling measured in water. Cell survival analysis with HeLa cells and NIH/3T3 fibroblasts revealed that these networks are non-toxic, and that they could be considered for a variety of biomedical applications. PMID- 26526077 TI - Development and validation of molecular methodologies to assess PALB2 expression in sporadic breast cancer. AB - OBJECTIVES: Recent reports have included PALB2 (Partner and localizer of BRCA2) in the growing list of hereditary cancer genes. PALB2 mutations confer a moderate breast cancer risk in heterozygotes and Fanconi anemia in biallelic mutation carriers. PALB2 protein co-localizes with BRCA2 and BRCA1 in nuclear structures and enables error-free homologous recombination repair of double-stranded DNA breaks. This important contribution could be severely diminished if affected by epigenetic mechanisms such as promoter CpG island methylation. The aim of our study was to develop molecular methodologies in order to assess accurately PALB2 expression in breast cancer tissues. DESIGN AND METHODS: DNA and RNA were extracted from 91 sporadic fresh-frozen breast tissues with known histopathological data. DNA was subjected to sodium bisulfite conversion reaction and the CpG island of the PALB2 promoter was analyzed by pyrosequencing. RNA was converted to cDNA and analyzed by a newly developed and validated RT-qPCR assay based on a hydrolysis probe (TaqMan) in the Light Cycler. RESULTS: PALB2 promoter was not methylated in any of the samples tested. 87 out of 91 (95.6%) primary tumors were positive for PALB2 expression, as checked at the mRNA level. When levels of PALB2 mRNA were compared to histopathological data (tumor size, grade, lymph node involvement, metastasis, hormone receptors and HER2 overexpression), no significant statistical correlation was found. CONCLUSIONS: DNA methylation is an unlike mechanism for PALB2 transcriptional regulation. PALB2 mRNA expression does not seem be a promising prognostic biomarker for sporadic breast cancer. PMID- 26526078 TI - Cell-free DNA as a prognostic marker in stage I non-small-cell lung cancer patients undergoing stereotactic body radiotherapy. AB - OBJECTIVE: To evaluate whether plasma cell-free DNA (cfDNA) was related to clinical outcome in inoperable stage I non-small cell lung cancer (NSCLC) patients undergoing stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: Plasma cfDNA was assessed at baseline, before the last day and 45 days after the end of SBRT, in 22 NSCLC patients. Twenty-two healthy controls were also evaluated. RESULTS: Plasma cfDNA was higher in patients than in controls. An association with unfavourable disease-free survival was found for continuous baseline cfDNA increments (HR = 5.9, 95%CI: 1.7-19.8, p = 0.04). CONCLUSION: Plasma cfDNA may be a promising prognostic biomarker in high-risk NSCLC patients. PMID- 26526080 TI - Adherence to Competing Strategies for Colorectal Cancer Screening Over 3 Years. AB - OBJECTIVES: We have shown that, in a randomized trial comparing adherence to different colorectal cancer (CRC) screening strategies, participants assigned to either fecal occult blood testing (FOBT) or given a choice between FOBT and colonoscopy had significantly higher adherence than those assigned to colonoscopy during the first year. However, how adherence to screening changes over time is unknown. METHODS: In this trial, 997 participants were cluster randomized to one of the three screening strategies: (i) FOBT, (ii) colonoscopy, or (iii) a choice between FOBT and colonoscopy. Research assistants helped participants to complete testing only in the first year. Adherence to screening was defined as completion of three FOBT cards in each of 3 years after enrollment or completion of colonoscopy within the first year of enrollment. The primary outcome was adherence to assigned strategy over 3 years. Additional outcomes included identification of sociodemographic factors associated with adherence. RESULTS: Participants assigned to annual FOBT completed screening at a significantly lower rate over 3 years (14%) than those assigned to colonoscopy (38%, P<0.001) or choice (42%, P<0.001); however, completion of any screening test fell precipitously, indicating the strong effect of patient navigation. In multivariable logistic regression analysis, being randomized to the choice or colonoscopy group, Chinese language, homosexuality, being married/partnered, and having a non-nurse practitioner primary care provider were independently associated with greater adherence to screening (P<0.01). CONCLUSIONS: In a 3-year follow-up of a randomized trial comparing competing CRC screening strategies, participants offered a choice between FOBT and colonoscopy continued to have relatively high adherence, whereas adherence in the FOBT group fell significantly below that of the choice and colonoscopy groups. Patient navigation is crucial to achieving adherence to CRC screening, and FOBT is especially vulnerable because of the need for annual testing. PMID- 26526079 TI - ACG Clinical Guideline: Diagnosis and Management of Barrett's Esophagus. AB - Barrett's esophagus (BE) is among the most common conditions encountered by the gastroenterologist. In this document, the American College of Gastroenterology updates its guidance for the best practices in caring for these patients. These guidelines continue to endorse screening of high-risk patients for BE; however, routine screening is limited to men with reflux symptoms and multiple other risk factors. Acknowledging recent data on the low risk of malignant progression in patients with nondysplastic BE, endoscopic surveillance intervals are attenuated in this population; patients with nondysplastic BE should undergo endoscopic surveillance no more frequently than every 3-5 years. Neither routine use of biomarker panels nor advanced endoscopic imaging techniques (beyond high definition endoscopy) is recommended at this time. Endoscopic ablative therapy is recommended for patients with BE and high-grade dysplasia, as well as T1a esophageal adenocarcinoma. Based on recent level 1 evidence, endoscopic ablative therapy is also recommended for patients with BE and low-grade dysplasia, although endoscopic surveillance continues to be an acceptable alternative. Given the relatively common recurrence of BE after ablation, we suggest postablation endoscopic surveillance intervals. Although many of the recommendations provided are based on weak evidence or expert opinion, this document provides a pragmatic framework for the care of the patient with BE. PMID- 26526081 TI - Extensive Modulation of the Fecal Metagenome in Children With Crohn's Disease During Exclusive Enteral Nutrition. AB - OBJECTIVES: Exploring associations between the gut microbiota and colonic inflammation and assessing sequential changes during exclusive enteral nutrition (EEN) may offer clues into the microbial origins of Crohn's disease (CD). METHODS: Fecal samples (n=117) were collected from 23 CD and 21 healthy children. From CD children fecal samples were collected before, during EEN, and when patients returned to their habitual diets. Microbiota composition and functional capacity were characterized using sequencing of the 16S rRNA gene and shotgun metagenomics. RESULTS: Microbial diversity was lower in CD than controls before EEN (P=0.006); differences were observed in 36 genera, 141 operational taxonomic units (OTUs), and 44 oligotypes. During EEN, the microbial diversity of CD children further decreased, and the community structure became even more dissimilar than that of controls. Every 10 days on EEN, 0.6 genus diversity equivalents were lost; 34 genera decreased and one increased during EEN. Fecal calprotectin correlated with 35 OTUs, 14 of which accounted for 78% of its variation. OTUs that correlated positively or negatively with calprotectin decreased during EEN. The microbiota of CD patients had a broader functional capacity than healthy controls, but diversity decreased with EEN. Genes involved in membrane transport, sulfur reduction, and nutrient biosynthesis differed between patients and controls. The abundance of genes involved in biotin (P=0.005) and thiamine biosynthesis decreased (P=0.017), whereas those involved in spermidine/putrescine biosynthesis (P=0.031), or the shikimate pathway (P=0.058), increased during EEN. CONCLUSIONS: Disease improvement following treatment with EEN is associated with extensive modulation of the gut microbiome. PMID- 26526082 TI - Colonic Diverticula Are Not Associated With an Increased Risk of Colorectal Adenomas. AB - OBJECTIVES: Patients with missed colorectal cancer have been reported to be more likely to have colonic diverticulosis. Such an association could be due to either higher risk of neoplasia or difficulty examining the colon in patients with diverticulosis. The aim of this study was to determine whether colonic diverticula are associated with an increased risk for colonic neoplasia. METHODS: We analyzed data from a prospective study of patients undergoing screening colonoscopy that included detailed assessment of all colonic diverticula and colorectal polyps. We used logistic regression to estimate odds ratios and 95% confidence intervals while adjusting for confounding variables. RESULTS: Our analyses included 624 participants. Of these, 216 (35%) had one or more colorectal adenomas. Diverticula on colonoscopy were not associated with an increased risk of adenomas (odds ratio (OR) 1.0, 95% confidence interval (CI) 0.7 1.4) or advanced adenomas (OR 0.8, 95% CI 0.4-1.5). Those with the greatest burden of diverticula (10 or more) did not have an increased risk of adenomas (OR 1.1, 95% CI 0.7-1.8) compared with no diverticula. Colonic diverticula were not associated with an increased risk of proximal (OR 1.0, 95% CI 0.6-1.6) or distal adenomas (OR 1.0, 95% CI 0.6-1.7). CONCLUSIONS: Patients with colonic diverticula do not have an increased risk of colorectal adenomas or advanced adenomas. PMID- 26526083 TI - Cost Utility of Competing Strategies to Prevent Endoscopic Transmission of Carbapenem-Resistant Enterobacteriaceae. AB - OBJECTIVES: Prior reports have linked patient transmission of carbapenem resistant Enterobacteriaceae (CRE, or "superbug") to endoscopes used during endoscopic retrograde cholangiopancreatography (ERCP). We performed a decision analysis to measure the cost-effectiveness of four competing strategies for CRE risk management. METHODS: We used decision analysis to calculate the cost effectiveness of four approaches to reduce the risk of CRE transmission among patients presenting to the hospital for symptomatic common bile duct stones. The strategies included the following: (1) perform ERCP followed by US Food and Drug Administration (FDA)-recommended endoscope reprocessing procedures; (2) perform ERCP followed by "endoscope culture and hold"; (3) perform ERCP followed by ethylene oxide (EtO) sterilization of the endoscope; and (4) stop performing ERCP in lieu of laparoscopic cholecystectomy (LC) with common bile duct exploration (CBDE). Our outcome was incremental cost per quality-adjusted life year (QALY) gained. RESULTS: In the base-case scenario, ERCP with FDA-recommended endoscope reprocessing was the most cost-effective strategy. Both the ERCP with culture and hold ($4,228,170/QALY) and ERCP with EtO sterilization ($50,572,348/QALY) strategies had unacceptable incremental costs per QALY gained. LC with CBDE was dominated, being both more costly and marginally less effective vs. the alternatives. In sensitivity analysis, ERCP with culture and hold became the most cost-effective approach when the pretest probability of CRE exceeded 24%. CONCLUSIONS: In institutions with a low CRE prevalence, ERCP with FDA-recommended reprocessing is the most cost-effective approach for mitigating CRE transmission risk. Only in settings with an extremely high CRE prevalence did ERCP with culture and hold become cost-effective. PMID- 26526084 TI - Risk of Diabetes Mellitus after First-Attack Acute Pancreatitis: A National Population-Based Study. AB - OBJECTIVES: Population-based data on the risk of diabetes mellitus onset after acute pancreatitis (AP) are lacking. We assessed the incidence of diabetes in AP survivors compared with matched controls. METHODS: The study cohort, drawn from Taiwan National Health Insurance claims data, included 2,966 first-attack AP patients and 11,864 non-AP general controls individually matched on age and sex, with an AP/non-AP ratio of 1:4. Incidence rate was estimated under Poisson assumption. Relative risks of diabetes were indicated by hazard ratios (HRs) estimated from Cox proportional hazard regression models with a partitioning of time at 3 months to account for proportionality. RESULTS: In the first partition of time (<3 months), the incidences of diabetes were 60.8 and 8.0 per 1,000 person-years in AP and control groups, respectively; representing a covariate adjusted HR of 5.90 (95% confidence interval (CI) 3.37-10.34). In the second partition (>=3 months), the incidences of diabetes were 22.5 and 6.7 per 1,000 person-years in AP and control groups, respectively (adjusted HR 2.54, 95% CI 2.13-3.04). In the second partition, the risk of diabetes was greater in men than in women (HR 3.21 vs. 1.58, P=0.0004). When the analyses were stratified by severity of AP, the results for mild AP were similar to those for all AP. CONCLUSIONS: The risk of diabetes increases by twofold after AP; therefore, a long-term screening is necessary to evaluate diabetes after an attack regardless of severity. Further research should be conducted to develop cost-effective follow-up strategies, and to elucidate the underlying mechanisms of the relationship between diabetes and AP. PMID- 26526085 TI - Effect of Dynamic Position Changes on Adenoma Detection During Colonoscope Withdrawal: A Randomized Controlled Multicenter Trial. AB - OBJECTIVES: Adequate luminal distension is essential for improving adenoma detection during colonoscope withdrawal. A few crossover studies have reported that dynamic position changes maximize luminal distension and increase adenoma detection rates (ADR). We designed a multicenter, randomized, parallel-group trial to verify the effect of dynamic position changes on colonic adenoma detection. METHODS: This study was conducted at the six hospitals of the Catholic University of Korea. Patients aged 45-80 years who underwent a colonoscopy for the first time were included. In the position change group, the position changes during colonoscope withdrawal were as follows: cecum, ascending colon, and hepatic flexure: left lateral position; transverse colon: supine position; splenic flexure, descending colon, sigmoid colon, and rectum: right lateral position. In the control group, the examinations were performed entirely in the left lateral position during colonoscope withdrawal. The primary outcome measure was the ADR, which was defined as the proportion of patients with >=1 adenoma. RESULTS: A total of 1,072 patients were randomized into the position change group (536 patients) or the control group (536 patients). The ADR was higher in the position change group than in the control group (42.4 vs. 33.0%, P=0.002). More adenomas were detected per subject in the position change group (0.90 vs. 0.67, P=0.01). Increases in the number of adenomas were observed in examinations of the transverse colon (0.22 vs. 0.13, P=0.016) and the left colon (0.37 vs. 0.27, P=0.045). A significant increase in the ADR was observed for endoscopists with a relatively low detection rate. For endoscopists with a high detection rate, non significant changes in the ADR were observed. CONCLUSIONS: Dynamic position changes during colonoscope withdrawal increased the ADR. PMID- 26526086 TI - Hyperin attenuates inflammation by activating PPAR-gamma in mice with acute liver injury (ALI) and LPS-induced RAW264.7 cells. AB - Hyperin (HP) is a flavonoid compound found in various plants like Ericaceae, Guttifera and Celastraceae. The present study has revealed that HP has a variety of pharmacological effects including anti-oxidant, anticancer, and anti coagulant, especially anti-inflammatory. However, the potential molecular mechanism of anti-inflammatory is still unrevealed. In this study, HP not only significantly attenuated inflammation in C57BL/6J mice with acute liver injury (ALI), but also reduced the expression of TNF-alpha and IL-6 in lipopolysaccharide (LPS)-induced RAW264.7 cells. Furthermore, our findings showed that HP remarkably induced the expression of PPAR-gamma in vivo and in vitro. Interestingly, compared with the HP treatment group, a specific blocking agent of PPAR-gamma T0070907 and PPAR-gamma small interfering (si)-RNA-mediated silencing in RAW264.7 cells were used to evaluate the involvement of HP in alleviating LPS induced inflammation. More importantly, over-expression of PPAR-gamma had an opposite effect on the expression of TNF-alpha and IL-6 in LPS-induced RAW264.7 cells after treatment with HP. In addition, HP remarkably inhibited the expression of P-ERK1/2 and P-P38 MAPK. Taken together, all the above results indicate that HP may serve as an effective modulator of PPAR-gamma, further down regulating ERK1/2 and p38 MAPK during the pathogenesis of inflammation. PMID- 26526087 TI - Cardiovascular protective effect of glabridin: Implications in LDL oxidation and inflammation. AB - Atherosclerosis is one of the most common causes of death in Western countries and now considered as a chronic inflammatory disease in broad outline. Glaridin, a flavonoid isolated from licorice root, has been shown to exert a variety of biological activities, including antimicrobial, antioxidant, anti-inflammatory and cardiovascular protective effects. Among these, the most extensive research area in the past two decades was a cardiovascular protection-related activity of glabridin. The protective effect of glabridin on LDL oxidation, which is one of the important processes involved in the development of atherosclerosis, was demonstrated in vitro and in vivo and the mechanisms involved in this process were established well. Structure-activity relationship of glabridin derivatives on LDL oxidation was also reported. In addition, the inhibitory effects of glabridin on early inflammatory processes, including the expression of adhesion molecules on endothelial cells and the activation of macrophages and dendritic cells, were also demonstrated previously. In this review, we summarized the cardiovascular protection-related activities of glabridin and the mechanism of action involved in these activities. Collectively, it is hoped that glabridin or glabridin derivatives might be used as a therapeutic agent for the treatment of cardiovascular diseases in the future. PMID- 26526089 TI - treatment cost audits in medical institutes: neuroeconomics of affordable healthcare. PMID- 26526088 TI - The association between sociodemographic and clinical characteristics and poor glycaemic control: a longitudinal cohort study. AB - AIMS: People with diabetes and poor glycaemic control are at higher risk of diabetes-related complications and incur higher healthcare costs. An understanding of the sociodemographic and clinical characteristics associated with poor glycaemic control is needed to overcome the barriers to achieving care goals in this population. METHODS: We used linked administrative and laboratory data to create a provincial cohort of adults with prevalent diabetes, and a measure of HbA1c that occurred at least 1 year following the date of diagnosis. The primary outcome was poor glycaemic control, defined as at least two consecutive HbA1c measurements >= 86 mmol/mol (10%), not including the index measurement, spanning a minimum of 90 days. We used multivariable Cox proportional hazards models to evaluate the association between baseline sociodemographic and clinical factors and poor glycaemic control. RESULTS: In this population-based cohort of 169 890 people, younger age was significantly associated with sustained poor glycaemic control, with a hazard ratio (HR) of 3.08, 95% CI (2.79-3.39) for age 18-39 years compared with age >= 75 years. Longer duration of diabetes, First Nations status, lower neighbourhood income quintile, history of substance abuse, mood disorder, cardiovascular disease, albuminuria and high LDL cholesterol were also associated with poor glycaemic control. CONCLUSIONS: Although our results may be limited by the observational nature of the study, the large geographically defined sample size, longitudinal design and robust definition of poor glycaemic control are important strengths. These findings demonstrate the complexity associated with poor glycaemic control and indicate a need for tailored interventions. PMID- 26526090 TI - Late complications after percutaneous tracheostomy and oral intubation: Evaluation of 1,628 procedures. AB - OBJECTIVES/HYPOTHESIS: In large international studies, upper airway-related stenosis, granulomas, malacias, and laryngeal nerve palsies following percutaneous tracheostomy have an estimated incidence of 6% to 31%. The incidence following prolonged oral intubation is estimated to be 10% to 22%. The purpose of this study was to assess the incidence of late complications in our unit. STUDY DESIGN: Retrospective search of a single-unit intensive care patient population. METHODS: Patient records for a defined period were searched using a predefined search string, identifying those who received invasive mechanical ventilation and split in subgroups by orotracheal tube or tracheostomy tube. This search was cross-linked with the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes associated with recognized complications (J38.0, J38.3,J38.6, J38.7, J39.8, J39.9, J95.0, J95.5, J95.8, J95.9, J99, R04.8,S27.5). RESULTS: During the period January 1, 1997 to December 31, 2013, 32,852 patients were admitted to the intensive care unit. Of these, 1,620 patients received invasive mechanical ventilation. Out of this group, 519 had a tracheostomy and 1,109 were orally intubated. Four tracheostomized and zero orotracheally intubated patients had ICD-10 codes related to complications. From the patient records it became clear that three of four patients with tracheostomy had airway symptoms before being tracheostomized, and the fourth patient had her tracheostomy following a postintubation airway stenosis. CONCLUSIONS: Spanning a 17-year period, our study did not show any long-term symptomatic upper airway complications following tracheostomy and only one following orotracheal intubation. This contrasts the internationally estimated incidence. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1077-1082, 2016. PMID- 26526091 TI - Reply to the letter by D. Ollat and F. Chaise. PMID- 26526092 TI - Is hospital information system relevant to detect surgical site infection? Findings from a prospective surveillance study in posterior instrumented spinal surgery. AB - OBJECT: Spinal instrumentation has a high rate of surgical site infection (SSI), but results greatly vary depending on surveillance methodology, surgical procedures, or quality of follow-up. Our aim was to study true incidence of SSI in spinal surgery by significant data collection, and to compare it with the results obtained through the hospital information system. METHODS: This work is a single center prospective cohort study that included all patients consecutively operated on for spinal instrumentation by posterior approach over a six-month period regardless the etiology. For all patients, a "high definition" prospective method of surveillance was performed by the infection control (IC) department during at least 12 months after surgery. Results were then compared with findings from automatic surveillance though the hospital information system (HIS). RESULTS: One hundred and fifty-four patients were included. We found no hardly difference between "high definition" and automatic surveillance through the HIS, even if HIS tended to under-estimate the infection rate: rate of surgical site infection was 2.60% and gross SSI incidence rate via the hospital information system was 1.95%. Smoking and alcohol consumption were significantly related to a SSI. CONCLUSION: Our SSI rates to reflect the true incidence of infectious complications in posterior instrumented adult spinal surgery in our hospital and these results were consistent with the lower levels of published infection rate. In-house surveillance by surgeons only is insufficiently sensitive. Further studies with more patients and a longer inclusion time are needed to conclude if SSI case detection through the HIS could be a relevant and effective alternative method. PMID- 26526094 TI - Study of aerobic granular sludge stability in a continuous-flow membrane bioreactor. AB - A granular continuous-flow membrane bioreactor with a novel hydrodynamic configuration was developed to evaluate the stability of aerobic granular sludge (AGS). Under continuous-flow operation (Period I), AGS rapidly lost their structural integrity resulting in loose and fluffy microbial aggregates in which filamentous bacteria were dominant. The intermittent feeding (Period II) allowed obtaining the succession of feast and famine conditions that favored the increase in AGS stability. Although no further breakage occurred, the formation of new granules was very limited, owing to the absence of the hydraulic selection pressure. These results noted the necessity to ensure, on the one hand the succession of feast/famine conditions, and on the other, the hydraulic selection pressure that allows flocculent sludge washout. This preliminary study shows that the proposed configuration could meet the first aspect; in contrast, biomass selection needs to be improved. PMID- 26526093 TI - Enhancement in ionic liquid tolerance of cellulase immobilized on PEGylated graphene oxide nanosheets: Application in saccharification of lignocellulose. AB - The objective of the present work was to improve ionic liquid (IL) tolerance of cellulase based on the exploration of functional nanoscale carriers for potential application in lignocellulosic biorefinery. PEGylated graphene oxide (GO) composite was successfully fabricated by chemical binding of 4-arm-PEG-NH2 and GO and applied to the immobilization of cellulase. The PEGylated GO-Cellulase retained 61% of the initial activity in 25% (w/v) 1-butyl-3-methylimidazolium chloride ([Bmim][Cl]) while free cellulase only retained 2%. The IL stability was enhanced more than 30 times. The relatively minor change in Km value (from 2.7 to 3.2mgmL(-1)) after the immobilization suggested that PEGylated GO-Cellulase was capable of closely mimicking the performance of free enzyme. After treating rice straw with [Bmim][Cl] and dilution to a final IL concentration of 15% (w/v), the slurry was directly hydrolyzed using PEGylated GO-Cellulase without IL removing and a high hydrolysis rate of 87% was achieved. PMID- 26526095 TI - Diagnosis and management of asthma in preschoolers: A Canadian Thoracic Society and Canadian Paediatric Society position paper. AB - Asthma often starts before six years of age. However, there remains uncertainty as to when and how a preschool-age child with symptoms suggestive of asthma can be diagnosed with this condition. This delays treatment and contributes to both short- and long-term morbidity. Members of the Canadian Thoracic Society Asthma Clinical Assembly partnered with the Canadian Paediatric Society to develop a joint working group with the mandate to develop a position paper on the diagnosis and management of asthma in preschoolers. In the absence of lung function tests, the diagnosis of asthma should be considered in children one to five years of age with frequent (>=8 days/month) asthma-like symptoms or recurrent (>=2) exacerbations (episodes with asthma-like signs). The diagnosis requires the objective document of signs or convincing parent-reported symptoms of airflow obstruction (improvement in these signs or symptoms with asthma therapy), and no clinical suspicion of an alternative diagnosis. The characteristic feature of airflow obstruction is wheezing, commonly accompanied by difficulty breathing and cough. Reversibility with asthma medications is defined as direct observation of improvement with short-acting beta2-agonists (SABA) (with or without oral corticosteroids) by a trained health care practitioner during an acute exacerbation (preferred method). However, in children with no wheezing (or other signs of airflow obstruction) on presentation, reversibility may be determined by convincing parental report of a symptomatic response to a three-month therapeutic trial of a medium dose of inhaled corticosteroids with as-needed SABA (alternative method), or as-needed SABA alone (weaker alternative method). The authors provide key messages regarding in whom to consider the diagnosis, terms to be abandoned, when to refer to an asthma specialist and the initial management strategy. Finally, dissemination plans and priority areas for research are identified. PMID- 26526096 TI - Real-time PCR/DNA melting curve-based assay to identify individual strongylid larvae recovered from ovine faecal cultures. AB - A closed-tube real-time PCR (RT PCR) method was developed to identify individual strongylid nematode larvae recovered from ovine faecal cultures. The method builds on an earlier conventional PCR assay established by our group and similarly targets species-specific sequence motifs in the ITS-2 region of ribosomal DNA. The new procedure combines RT PCR with DNA melting curve analyses to identify species-specific amplicons, thus avoiding the need to undertake gel electrophoresis. As with the earlier method, it involves two sets of species specific reactions. The first targets Haemonchus contortus, Teladorsagia circumcincta, Trichostrongylus colubriformis, Nematodirus spathiger and Oesophagostomum venulosum while the second targets Trichostrongylus axei, Trichostrongylus vitrinis, Cooperia curticei and Chabertia ovina. With two exceptions, all the DNA primers employed in the new assay were among those described and tested in developing the earlier assay. The exceptions are the forward "generic" primer, which was re-designed to generate smaller amplicon sizes more suitable for melting curve analyses, and the T. axei-specific primer, which was modified to achieve a higher amplicon melt temperature to enable larvae of this species to be more readily differentiated from those of C. curticei. The melt temperature range for amplicons representing each of the species targeted was determined using lysates derived from both microscopically identified adult male worms (2-12/species), as well as 30 larvae of each of the species which were derived from at least 6 different geographical locations throughout New Zealand. The new assay potentially provides a simpler, faster method to identify individual ovine strongylid larvae for downstream applications than was provided by the earlier conventional PCR assay. PMID- 26526097 TI - Shear-Thinning Supramolecular Hydrogels with Secondary Autonomous Covalent Crosslinking to Modulate Viscoelastic Properties In Vivo. AB - Clinical percutaneous delivery of synthetically engineered hydrogels remains limited due to challenges posed by crosslinking kinetics - too fast leads to delivery failure, too slow limits material retention. To overcome this challenge, we exploit supramolecular assembly to localize hydrogels at the injection site and introduce subsequent covalent crosslinking to control final material properties. Supramolecular gels were designed through the separate pendant modifications of hyaluronic acid (HA) by the guest-host pair cyclodextrin and adamantane, enabling shear-thinning injection and high target site retention (>98%). Secondary covalent crosslinking occurred via addition of thiols and Michael-acceptors (i.e., methacrylates, acrylates, vinyl sulfones) on HA and increased hydrogel moduli (E=25.0+/-4.5kPa) and stability (>3.5 fold in vivo at 28 days). Application of the dual-crosslinking hydrogel to a myocardial infarct model showed improved outcomes relative to untreated and supramolecular hydrogel alone controls, demonstrating its potential in a range of applications where the precise delivery of hydrogels with tunable properties is desired. PMID- 26526098 TI - Application of novel anodized titanium for enhanced recruitment of H9C2 cardiac myoblast. AB - OBJECTIVES: Anodized treated titanium surfaces, have been proposed as potential surfaces with better cell attachment capacities. We have investigated the adhesion and proliferation properties of H9C2 cardiac myoblasts on anodized treated titanium surface. MATERIALS AND METHODS: Surface topography and anodized tubules were examined by high-resolution scanning electron microscopy (SEM). Control and test substrates were inserted to the bottom of 24-well tissue culture plates. Culture media including H9C2 cells were loaded on the surface of substrate and control wells at the second passage. Evaluation of cell growth, proliferation, viability and surface cytotoxicity was performed using MTT test. After 48 hr, some samples were inspected by SEM. DAPI-staining was used to count attached cells. RESULTS: MTT results for cells cultured on anodized titanium and unanodized titanium surfaces was equal to 1.56 and 0.55 fold change compared to tissue culture polystyrene (TCPS). The surface had no cytotoxic effects on cells. The average cell attachment to TCPS, unanodized and anodized titanium surface was 2497+/-40.16, 1250+/-20.11 and 4859.5+/-54.173, respectively. Cell adhesion to anodized titanium was showed 1.95 and 3.89 fold increase compared to TCPS and unanodized titanium, respectively (P<0.05). CONCLUSION: Anodized titanium surfaces can be potentially applied for enhanced recruitment of H9C2 cells. This unique property makes these inexpensive anodized surfaces as a candidate surface for attachment of cardiac cells and consequently for cardiac regeneration purposes. PMID- 26526099 TI - Polygenic interactions with environmental adversity in the aetiology of major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD. METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them. RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 * 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 * 10(-4) and p = 5.12 * 10( 20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples. CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits. PMID- 26526100 TI - Development of a Clickable Probe for Profiling of Protein Glutathionylation in the Central Cellular Metabolism of E. coli and Drosophila. AB - Protein glutathionylation is an important post-translational modification that regulates many cellular processes, including energy metabolism, signal transduction, and protein homeostasis. Global profiling of glutathionylated proteins (denoted as glutathionylome) is crucial for understanding redox regulated signal transduction. Here, we developed a novel method based on click reaction and proteomics to enrich and identify the glutathionylated peptides in Escherichia coli and Drosophila lysates, in which 937 and 1,930 potential glutathionylated peptides were identified, respectively. Bioinformatics analysis showed that the cysteine residue next to negatively charged amino acid residues has a higher frequency of glutathionylation. Importantly, we found that most proteins associated with metabolic pathways were glutathionylated and that the glutathionylation sites of metabolic enzymes were highly conserved among different species. Our results indicate that the glutathione analog is a useful tool to characterize protein glutathionylation, and glutathionylation of metabolic enzymes, which play important roles in regulating cellular metabolism, is conserved. PMID- 26526101 TI - Probing the Substrate Specificity and Protein-Protein Interactions of the E. coli Fatty Acid Dehydratase, FabA. AB - Microbial fatty acid biosynthetic enzymes are important targets for areas as diverse as antibiotic development to biofuel production. Elucidating the molecular basis of chain length control during fatty acid biosynthesis is crucial for the understanding of regulatory processes of this fundamental metabolic pathway. In Escherichia coli, the acyl carrier protein (AcpP) plays a central role by sequestering and shuttling the growing acyl chain between fatty acid biosynthetic enzymes. FabA, a beta-hydroxyacyl-AcpP dehydratase, is an important enzyme in controlling fatty acid chain length and saturation levels. FabA-AcpP interactions are transient in nature and thus difficult to visualize. In this study, four mechanistic crosslinking probes mimicking varying acyl chain lengths were synthesized to systematically probe for modified chain length specificity of 14 FabA mutants. These studies provide evidence for the AcpP-interacting "positive patch," FabA mutations that alter substrate specificity, and the roles that the FabA "gating residues" play in chain length control. PMID- 26526102 TI - Substrate Flexibility of a Mutated Acyltransferase Domain and Implications for Polyketide Biosynthesis. AB - Polyketides are natural products frequently used for the treatment of various diseases, but their structural complexity hinders efficient derivatization. In this context, we recently introduced enzyme-directed mutasynthesis to incorporate non-native extender units into the biosynthesis of erythromycin. Modeling and mutagenesis studies led to the discovery of a variant of an acyltransferase domain in the erythromycin polyketide synthase capable of accepting a propargylated substrate. Here, we extend molecular rationalization of enzyme substrate interactions through modeling, to investigate the incorporation of substrates with different degrees of saturation of the malonic acid side chain. This allowed the engineered biosynthesis of new erythromycin derivatives and the introduction of additional mutations into the AT domain for a further shift of the enzyme's substrate scope. Our approach yields non-native polyketide structures with functional groups that will simplify future derivatization approaches, and provides a blueprint for the engineering of AT domains to achieve efficient polyketide synthase diversification. PMID- 26526103 TI - Biochemical Studies of Mycobacterial Fatty Acid Methyltransferase: A Catalyst for the Enzymatic Production of Biodiesel. AB - Transesterification of fatty acids yields the essential component of biodiesel, but current processes are cost-prohibitive and generate waste. Recent efforts make use of biocatalysts that are effective in diverting products from primary metabolism to yield fatty acid methyl esters in bacteria. These biotransformations require the fatty acid O-methyltransferase (FAMT) from Mycobacterium marinum (MmFAMT). Although this activity was first reported in the literature in 1970, the FAMTs have yet to be biochemically characterized. Here, we describe several crystal structures of MmFAMT, which highlight an unexpected structural conservation with methyltransferases that are involved in plant natural product metabolism. The determinants for ligand recognition are analyzed by kinetic analysis of structure-based active-site variants. These studies reveal how an architectural fold employed in plant natural product biosynthesis is used in bacterial fatty acid O-methylation. PMID- 26526104 TI - A nitrogen-doped mesoporous carbon containing an embedded network of carbon nanotubes as a highly efficient catalyst for the oxygen reduction reaction. AB - A nitrogen-doped mesoporous carbon containing a network of carbon nanotubes (CNTs) was produced for use as a catalyst for the oxygen reduction reaction (ORR). SiO2 nanoparticles were decorated with clusters of Fe atoms to act as catalyst seeds for CNT growth, after which the material was impregnated with aniline. After polymerization of the aniline, the material was pyrolysed and the SiO2 was removed by acid treatment. The resulting carbon-based hybrid also contained some Fe from the CNT growth catalyst and was doped with N from the aniline. The Fe-N species act as active catalytic sites and the CNT network enables efficient electron transport in the material. Mesopores left by the removal of the SiO2 template provide short transport pathways and easy access to ions. As a result, the catalyst showed not only excellent ORR activity, with 59 mV more positive onset potential and 30 mV more positive half-wave potential than a Pt/C catalyst, but also much longer durability and stronger tolerance to methanol crossover than a Pt/C catalyst. PMID- 26526105 TI - Nanoparticles can cross mouse placenta and induce trophoblast apoptosis. AB - INTRODUCTION: The effects of nanoparticles on pregnancy remain unclear. In this study, we investigate whether nanoparticles of a specific size can cross the placenta and affect trophoblast function. METHODS: Fluorescently labelled carboxylate-modified polystyrene beads with diameters of 20, 40, 100, 200, and 500 nm were chosen as model particles. In vitro, trophoblast cell line (3A-Sub-E) or primary culture of term trophoblasts was used for nanoparticle uptake analysis using flow cytometry, confocal microscopy, BrdU proliferation assay and analysis of cell apoptosis using Western blot. Intravenous injection of nanoparticles into pregnant mice at embryonic day 17 was used to study whether nanoparticles can cross the placenta. The mouse placentas were collected and quantitatively analyzed using high-performance liquid chromatography for nanoparticle uptake. RESULTS: Fluorescent polystyrene particles with diameters of up to 500 nm were taken up by the placenta and were able to cross the placental barrier. The fluorescent polystyrene particles were observed in various organs of fetuses after 4 h of administration to pregnant mice. The nanoparticle uptake by placental tissue was significantly increased in nanoparticles with a diameter of 40 nm. No linear association was evident between nanoparticle size and uptake. Nanoparticles with diameters of 20 nm (200 MUg/ml) and 40 nm (500 MUg/ml) could induce trophoblast cell apoptosis with increased cleaved caspase 3 and reduced cell proliferation. DISCUSSION: Our findings suggest that nanoparticles can cross the placenta and be taken up by fetal organs. Certain concentrations of carboxylate-modified polystyrene nanoparticles may be cytotoxic to trophoblasts, which could alter placental function. PMID- 26526107 TI - O-shaped, Non-pulsatile Distal Superficial Femoral Artery Pseudoaneurysm in the Presence of Proximal Occlusion. PMID- 26526106 TI - Making a Hematopoietic Stem Cell. AB - Previous attempts to either generate or expand hematopoietic stem cells (HSCs) in vitro have involved either ex vivo expansion of pre-existing patient or donor HSCs or de novo generation from pluripotent stem cells (PSCs), comprising both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). iPSCs alleviated ESC ethical issues but attempts to generate functional mature hematopoietic stem and progenitor cells (HSPCs) have been largely unsuccessful. New efforts focus on directly reprogramming somatic cells into definitive HSCs and HSPCs. To meet clinical needs and to advance drug discovery and stem cell therapy, alternative approaches are necessary. In this review, we synthesize the strategies used and the key findings made in recent years by those trying to make an HSC. PMID- 26526108 TI - Commentary on 'Carotid Anatomy Does Not Predict the Risk of New Ischaemic Brain Lesions on Diffusion Weighted Imaging After Carotid Artery Stenting in the ICSS MRI Substudy'. PMID- 26526109 TI - Commentary on 'Risk Stratification of Ruptured Abdominal Aortic Aneurysms in Patients Treated by Open Surgical Repair'. PMID- 26526110 TI - Re: 'Management of Extracranial Carotid Artery Aneurysm'. PMID- 26526112 TI - Re: 'Editor's Choice-Management of Chronic Venous Disease: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS)'. PMID- 26526111 TI - Effect of CYP2C19 Polymorphisms on the Platelet Response to Clopidogrel and Influence on the Effect of High Versus Standard Dose Clopidogrel in Carotid Artery Stenting. AB - OBJECTIVES: Genetic background has been identified to be a major predictor of post-clopidogrel platelet inhibition in patients undergoing coronary stenting. However, there is a lack of data on clopidogrel response regarding genotype in patients undergoing carotid artery stenting (CAS). The influence of the most common allelic variants of CYP2C19 phenotypes and genotypes on response to baseline clopidogrel and on the pharmacodynamic effect of dose adjustment (high or standard dose of clopidogrel) in patients with high on-treatment reactivity after CAS was investigated. METHODS: Platelet reactivity was assessed before and 30 days after carotid stenting using the VerifyNow P2Y12 assay to obtain P2Y12 reactivity unit (PRU) values. RESULTS: A total of 209 patients (79.4% male, 44.1% currents smokers) were treated by CAS. Smokers improved responsiveness to clopidogrel (p = .034). With respect to CYP2C19 enzymatic function, 61 subjects (29.1%) were ultra-rapid metabolizers, 95 patients (45.5%) were extensive metabolizers, 51 (24.4%) were intermediate metabolizers, and two (0.96%) were poor metabolizers. Baseline PRU was significantly higher among intermediate-poor metabolizers compared with ultra-rapid (p = .001) or extensive metabolizers (p = .005). At 30 days follow up, in non-responding patients with the intermediate poor metabolizer phenotype, the PRU value and inhibition percentage were significantly reduced with standard dose (p = .008; p = .0029) and high dose of clopidogrel (p = .00 0; p = .000). However, high dose clopidogrel did not achieve a more intense pharmacodynamic effect at 30 days (p = .994) compared with standard dose. CONCLUSIONS: In patients undergoing carotid stenting, those with the CYP2C19*2 allele had increased basal PRU values and in fact clopidogrel non responders increased significantly among intermediate-poor metabolizers. Although high dose and standard dose clopidogrel therapy was effective in lowering the 30 day PRU values in patients with high on-treatment reactivity who are intermediate poor metabolizers, the use of high dose clopidogrel did not result in statistically significantly greater reductions in reactivity compared with the standard dose. PMID- 26526114 TI - Comparison of key modalities of micro-scale spatially offset Raman spectroscopy. AB - We compare several basic embodiments of a recently proposed and demonstrated micrometer-scale Spatially Offset Raman Spectroscopy (micro-SORS). Micro-SORS is a recently introduced analytical method for noninvasive characterisation of the chemical composition of subsurface, micrometre-scale-thick diffusely scattering layers at depths beyond the reach of conventional confocal Raman microscopy. The technique is applicable, for example, in nondestructive subsurface analysis of highly scattering stratified matrices such as painted layers in cultural heritage or in noninvasive analysis of stratified polymer systems or biological samples. Using Monte Carlo simulations, we analysed two defocusing variants of micro-SORS and a variant involving a full separation of illumination and collection zones on the sample surface. Both the penetration depth into the sample and relative enhancement of sublayer Raman signals were studied as a function of layer thickness and type of technique and their parameters. The model predicts that the most effective method by far is the variant with fully spatially separated illumination and collection zones. On the other hand, the defocusing micro-SORS, where both the laser and Raman collection zones are defocussed and overlapped, yielded the lowest performance although its key benefit lies in its simplicity as the concept can be practiced on existing conventional Raman microscopes without any modifications. A basic experimental verification of the theoretical findings contrasting two extreme modalities, the fully separated micro-SORS variant with the defocusing one, is also presented. PMID- 26526113 TI - Mouse adaptation of influenza B virus increases replication in the upper respiratory tract and results in droplet transmissibility in ferrets. AB - To investigate the molecular changes that allow influenza B viruses to adapt to new mammalian hosts, influenza B/Florida/04/2006 was serially passaged in BALB/c mice until highly virulent. The viral factors underlying this transition were then investigated in mice and ferrets. Five viruses, including the wild-type virus (P0), three intermediate viruses (P5, P9, and P12), and a lethal mouse adapted virus (P17 (MA)), harbored one to five amino acid substitutions in the hemagglutinin, M, NP, and PA segments suggesting that these mutations enhance virulence. The P17 (MA) virus replicated significantly more efficiently than the P0 virus both in vitro and in vivo (P < 0.0001), and was highly virulent (MLD50: 10(5.25)TCID50) while the P0, P5, and P9 viruses did not kill any infected mice (MLD50 > 10(6.0)TCID50). Furthermore, the P17 (MA) virus grew to greater titers in the ferret upper respiratory tract compared with the P0 and intermediate viruses, and only the P17 (MA) virus was transmissible between ferrets via both direct and aerosol contact. To our knowledge, this is the first study to demonstrate ferret-to-ferret transmission of influenza B virus and to delineate factors that may affect its transmission. PMID- 26526115 TI - Dual Catalytic Decarboxylative Allylations of alpha-Amino Acids and Their Divergent Mechanisms. AB - The room temperature radical decarboxylative allylation of N-protected alpha amino acids and esters has been accomplished via a combination of palladium and photoredox catalysis to provide homoallylic amines. Mechanistic investigations revealed that the stability of the alpha-amino radical, which is formed by decarboxylation, dictates the predominant reaction pathway between competing mechanisms. PMID- 26526116 TI - The localisation of the apical Par/Cdc42 polarity module is specifically affected in microvillus inclusion disease. AB - BACKGROUND INFORMATION: Microvillus inclusion disease (MVID) is a genetic disorder affecting intestinal absorption. It is caused by mutations in MYO5B or syntaxin 3 (STX3) affecting apical membrane trafficking. Morphologically, MVID is characterised by a depletion of apical microvilli and the formation of microvillus inclusions inside the cells, suggesting a loss of polarity. To investigate this hypothesis, we examined the location of essential apical polarity determinants in five MVID patients. RESULTS: We found that the polarity determinants Cdc42, Par6B, PKCzeta/iota and the structural proteins ezrin and phospho-ezrin were lost from the apical membrane and accumulated either in the cytoplasm or on the basal side of enterocytes in patients, which suggests an inversion of cell polarity. Moreover, microvilli-like structures were observed at the basal side as per electron microscopy analysis. We next performed Myo5B depletion in three dimensional grown human Caco2 cells forming cysts and found a direct link between the loss of Myo5B and the mislocalisation of the same apical proteins; furthermore, we observed that a majority of cysts displayed an inverted polarity phenotype as seen in some patients. Finally, we found that this loss of polarity was specific for MVID: tissue samples of patients with Myo5B-independent absorption disorders showed normal polarity but we identified Cdc42 as a potentially essential biomarker for trichohepatoenteric syndrome. CONCLUSION: Our findings indicate that the loss of Myo5B induces a strong loss of enterocyte polarity, potentially leading to polarity inversion. SIGNIFICANCE: Our results show that polarity determinants could be useful markers to help establishing a diagnosis in patients. Furthermore, they could be used to characterise other rare intestinal absorption diseases. PMID- 26526117 TI - Testicular cytological profiles of apparently healthy male dromedary camels during rutting and non-rutting periods. AB - The aim of this study was to evaluate testicular cytological profiles of apparently healthy dromedary bulls during rutting and non-rutting periods. Pairs of testes from 26 (18 non-rutting and 8 rutting seasons) dromedary bulls 6-12 years old that were slaughtered at Akaki, Addis Ababa abattoir were sampled. A 21 gauge needle attached to 20mL syringe was used to collect Testicular Fine Needle Aspiration (TFNA) samples and five aspiration smears were prepared from each testis. A total of 312 slides (260 Testicular fine Needle Aspiration and 52 imprints) were examined. The mod ified May-Grunwald Giemsa (mMGG) technique and a light microscope were used to assess cellularity, morphology and quantification of the testicular. Sertoli and spermatogenic cells were identified and counted. The spermatic index (SI), Sertoli cell index (SEI) and the relationship between SI and SEI indexes (SSEI) were used to assess the ratio between mature spermatozoa and nursing cells. There were differences (P<0.05) between the rutting and non-rutting seasons among the spermatogenic and Sertoli cells. There were no differences between groups for primary spermatocyte numbers, early spermatid numbers and SSEI. There was no differences (P>0.05) between TFNA and imprint smear slides of the testicular cells except for Sertoli cell count and SEI. Filarial worm larvae were present on the TFNA smear slides of four animals. Imprint and TFNA smear slides had comparable cytological profiles in dromedary bulls and significant differences were observed between rutting and non-rutting periods. PMID- 26526118 TI - Ocelot and oncilla spermatozoa can bind hen egg perivitelline membranes. AB - We evaluated the capacity of ocelot and oncilla spermatozoa to bind to the perivitelline membranes (PVMs) of hen eggs in a sperm binding assay (S-PVM). In addition, a device that improves the standardization of the assay was developed. The number of sperm bound to the PVM in fresh (T1) and frozen-thawed (T2) semen from both species was compared to the sperm quality observed in routine tests. The PVM was stretched on a circular silicone device to create a standardized area for analysis. In both treatments and for both species, the spermatozoa were able to bind to the PVM, indicating that PVM may be used for a sperm binding assay in ocelot and oncilla. The S-PVM assay did not differ in fresh and frozen-thawed ocelot sperm (p>0.05). However, fewer oncilla sperm (p<0.05) were bound to the PVM in T2, indicating that the proposed test may be able to detect injuries that compromise sperm binding abilities. The device maintained the PVM stretched during the processing and defined the evaluation area. PMID- 26526119 TI - Ovarian vein thrombosis. AB - Ovarian vein thrombosis (OVT) is a rare cause of abdominal pain that may mimic a surgical abdomen. It is most often diagnosed during the postpartum period. In this report, we present four cases of postoperative ovarian vein thrombosis. The complications of OVT can be significant, and the diagnosis relies on a careful examination of the radiographic findings. It can occur with lower quadrant abdominal pain, especially in the setting of recent pregnancy, abdominal surgery, pelvic inflammatory disease, or malignancy. Diagnosis can be made with confidence using ultrasound, computed tomography or magnetic resonance imaging. Treatment of ovarian vein thrombosis is particularly important in the post-partum patients, with anticoagulation therapy being the current recommendation. PMID- 26526120 TI - Practical Incidence and Risk Factors of Terson's Syndrome: A Retrospective Analysis in 322 Consecutive Patients with Aneurysmal Subarachnoid Hemorrhage. AB - OBJECTIVE: Terson's syndrome, a complication of visual function, has occasionally been reported in patients with aneurysmal subarachnoid hemorrhage (SAH), however the factors responsible for Terson's syndrome in aneurysmal SAH patients have not yet been fully clarified. In this study, we report on potential risk factors for prediction and diagnosis of Terson's syndrome in the earlier stage of the disease course in patients with aneurysmal SAH. MATERIALS AND METHODS: The authors retrospectively analyzed the data of 322 consecutive patients who suffered from aneurysmal SAH in a single institution between Jan. 2007 and Dec. 2013. Medical records including demographics, neurologic examination, and radiologic images were collected to clarify the risk factors of Terson's syndrome. Patients with visual problem were consulted to the Department of Ophthalmology. RESULTS: Among 332 patients with aneurysmal SAH, 34 patients were diagnosed as Terson's syndrome. Four individual factors, including World Federation of Neurosurgical Societies (WFNS) grade at admission, aneurysm size, method of operation, and Glasgow outcome scale showed statistically significant association with occurrence of Terson's syndrome. Of these, WFNS grade at admission, aneurysm size, and method of operation showed strong association with Terson's syndrome in multivariate analysis. Terson's syndrome accompanied by papilledema due to increased intracranial pressure led to permanent visual complication. CONCLUSION: In patients with aneurysmal SAH, the patients' WFNS grade at admission, the size of the aneurysms, particularly the diameter of the aneurysm dome, and the method of operation might influence development of Terson's syndrome. PMID- 26526121 TI - Modeling K-Ras-driven lung adenocarcinoma in mice: preclinical validation of therapeutic targets. AB - Lung cancer is the leading cause of cancer-related deaths worldwide, and even today, the 5-year survival rate is still below 15%. Lung adenocarcinoma is the most frequent subtype, and approximately 25% of the cases harbor activating mutations in the KRAS gene. To date, there is no effective treatment for patients carrying KRAS mutations due, at least in part, to the challenge posed by direct targeting of the KRAS oncoprotein. During the last decade, scientists have developed genetically engineered mouse models that faithfully recapitulate the natural history of the human tumors. These models have been used as a preclinical platform to validate a number of relevant downstream effectors of KRAS signaling. Targets displaying synthetic lethality with the KRAS oncoprotein have also been validated in these models. Here, we review these studies and discuss their potential value in the clinical setting. We also provide an outlook as of how to improve the significance of target validation studies in preclinical platforms. PMID- 26526123 TI - Liver: New genetic insights into the development of alcohol-related cirrhosis. PMID- 26526124 TI - Surgery: Gut metabolism differentially altered by bariatric surgeries. PMID- 26526122 TI - Evaluation of indeterminate biliary strictures. AB - Biliary strictures frequently present a diagnostic challenge during pre-operative evaluation to determine their benign or malignant nature. A variety of benign conditions, such as primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis, frequently mimic malignancies. In addition, PSC and other chronic biliary diseases increase the risk of cholangiocarcinoma and so require ongoing vigilance. Although traditional methods of evaluation including imaging, detection of circulating tumour markers, and sampling by endoscopic ultrasound and endoscopic retrograde cholangiopancreatography have a high specificity, they suffer from low sensitivity. Currently, up to 20% of biliary strictures remain indeterminate after pre-operative evaluation and necessitate surgical intervention for a definitive diagnosis. The discovery of novel biomarkers, new imaging modalities and advanced endoscopic techniques suggests that a multimodality approach might lead to better diagnostic accuracy. PMID- 26526125 TI - IBD: Genotypes and phenotypes of IBD. PMID- 26526126 TI - Biochemistry of the cingulate cortex in autism: An MR spectroscopy study. AB - Neuroimaging studies have uncovered structural and functional alterations in the cingulate cortex in individuals with autism spectrum disorders (ASD). Such abnormalities may underlie neurochemical imbalance. In order to characterize the neurochemical profile, the current study examined the concentration of brain metabolites in dorsal ACC (dACC) and posterior cingulate cortex (PCC) in high functioning adults with ASD. Twenty high-functioning adults with ASD and 20 age and-IQ-matched typically developing (TD) peers participated in this Proton magnetic resonance spectroscopy (1H-MRS) study. LCModel was used in analyzing the spectra to measure the levels of N-Acetyl aspartate (NAA), choline (Cho), creatine (Cr), and glutamate/glutamine (Glx) in dACC and PCC. Groups were compared using means for the ratio of each metabolite to their respective Cr levels as well as on absolute internal-water-referenced measures of each metabolite. There was a significant increase in Cho in PCC for ASD adults, with a marginal increase in dACC. A reduction in NAA/Cr in dACC was found in ASD participants, compared to their TD peers. No significant differences in Glx/Cr or Cho/Cr were found in dACC. There were no statistically significant group differences in the absolute concentration of NAA, Cr, Glx, or NAA/Cr, Cho/Cr, and Glx/Cr in the PCC. Differences in the metabolic properties of dACC compared to PCC were also found. Results of this study provide evidence for possible cellular and metabolic differences in the dACC and PCC in adults with ASD. This may suggest neuronal dysfunction in these regions and may contribute to the neuropathology of ASD. Autism Res 2016, 9: 643-657. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26526127 TI - Chronic Urogenital Pain in Men. AB - Current terminology uses the 2008 European Association of Urology guidelines, but variably used historical terms suggest inflammation or infection that is rarely found.Central sensitisation is important in causing visceral and muscle hyperalgesia throughout the pelvis.There can be considerable overlap between urogenital pain conditions.Men who have a chronic urological pain condition often have a disturbance of urinary, bowel and sexual function.Working with urologists as well as a multidisciplinary team is essential. PMID- 26526128 TI - Oral lesions, chronic diseases and the risk of head and neck cancer. AB - OBJECTIVES: The aim of our study is to explore the role of the history of oral lesions and chronic diseases on the risk of head and neck cancer in a Chinese population. MATERIALS AND METHODS: Our case-control study included 921 head and neck cancer cases and 806 controls. We obtained medical history information by administering questionnaires to both cases and controls. We used unconditional logistic regression to estimate odds ratios for oral lesions and chronic conditions. RESULTS: Oral submucous fibrosis (OR=24.24, 95% CI=7.39-79.52), oral leukoplakia (OR=4.05, 95% CI=2.44-6.71) and repetitive dental ulcers (OR=5.12, 95% CI=3.17-8.28) increased the risk of HNC. Depression was associated with HNC risk when adjusted for several covariates (OR=2.10, 95% CI=1.06-4.15), but the association was not statistically significant after adjusting for smoking and alcohol drinking (OR=1.53, 95% CI=0.72-3.25). Also, the crude OR suggested an association between diabetes and HNC risk (OR=1.51, 95% CI=1.09-2.11), but it was not significant after adjusting for confounders. CONCLUSION: Our study reported on strong associations between HNC risk and oral leukoplakia, oral submucous fibrosis, which is consistent with prior research. We also observed repetitive dental ulcer to be associated with HNC risk. Future studies may focus on studying the association between depression and HNC, using medical records or psychological evaluation results to get more accurate information about depression, with careful assessment of tobacco and alcohol history. PMID- 26526129 TI - Molecular cloning and sequence analysis of two carbonic anhydrase in the swimming crab Portunus trituberculatus and its expression in response to salinity and pH stress. AB - Carbonic anhydrase (CA) is involved in ion transport, acid-base balance and pH regulation by catalyzing the interconversion of CO2 and HCO3(-). In this study, full-length cDNA sequences of two CA isoforms were identified from Portunus trituberculatus. One was Portunus trituberculatus cytoplasmic carbonic anydrase (PtCAc) and the other one was Portunus trituberculatus glycosyl phosphatidylinositol-linked carbonic anhydrase (PtCAg). The sequence of PtCAc was formed by an ORF of 816 bp, encoding a protein of 30.18 kDa. The PtCAg was constituted by an ORF of 927 bp, encoding a protein of 34.09 kDa. The deduced amino acid sequences of the two CA isoforms were compared to other crustacean' CA sequences. Both of them reflected high conservation of the residues and domains essential to the function of the two enzymes. The tissue expression analysis of PtCAc and PtCAg were detected in gill, muscle, hepatopancreas, hemocytes and gonad. PtCAc and PtCAg gene expressions were studied under salinity and pH challenge. The results showed that when salinity decreased (30 to 20 ppt), the mRNA expression of PtCAc increased significantly at 24 and 48 h, and the highest value appeared at 24h. The mRNA expression of PtCAg had the same situation with PtCAc. However, when salinity increased (30 to 35 ppt), only the mRNA expression of PtCAc increased significantly at 48 h. When pH changed, only the mRNA expression of PtCAc increased significantly at 12h, which was under low pH situation. The mRNA expression of PtCAg increased significantly at 12-48 h, and there was no significant difference of the expression between the pH challenged group and the control group in other experimental time. The results provided the base of understanding CA' function and the underlying mechanism in response to environmental changes in crustaceans. PMID- 26526130 TI - Overexpression of lycopene epsilon-cyclase gene from lycium chinense confers tolerance to chilling stress in Arabidopsis thaliana. AB - Lutein plays an important role in protecting the photosynthetic apparatus from photodamage and eliminating ROS to render normal physiological function of cells. As a rate-limiting step for lutein synthesis in plants, lycopene epsilon-cyclase catalyzes lycopene to delta-carotene. We cloned a lycopene epsilon-cyclase gene (Lcepsilon-LYC) from Lycium chinense (L. chinense), a deciduous woody perennial halophyte growing in various environmental conditions. The Lcepsilon-LYC gene has an ORF of 1569bp encoding a protein of 522 aa. The deduced amino acid sequence of Lcepsilon-LYC gene has higher homology with LycEs in other plants, such as Nicotiana tabacum and Solanum tuberosum. When L. chinense was exposed to chilling stress, relative expression of Lcepsilon-LYC increased. To study the protective role of Lcepsilon-LYC against chilling stress, we overexpressed the Lcepsilon-LYC gene in Arabidopsis thaliana. Lcepsilon-LYC overexpression led to an increase of lutein accumulation in transgenic A. thaliana, and the content of lutein decreased when transgenics were under cold conditions. In addition, the transgenic plants under chilling stress displayed higher activities of superoxide dismutase (SOD) and peroxidase (POD) and less H2O2 and malondialdehyde (MDA) than the control. Moreover, the photosynthesis rate, photosystem II activity (Fv/fm), and Non-photochemical quenching (NPQ) also increased in the transgenetic plants. On the whole, overexpression of Lcepsilon-LYC ameliorates photoinhibition and photooxidation, and decreases the sensitivity of photosynthesis to chilling stress in transgenic plants. PMID- 26526131 TI - Expression profile of micro-RNAs and functional annotation analysis of their targets in human chorionic villi from early recurrent miscarriage. AB - Aberrant expressions of some miRNAs were reported in the placenta from compromised pregnancies, suggesting that the miRNA profiling of chorionic villi could be related with early recurrent miscarriage (RM). This study was designed to investigate the miRNA expression profile, and to predict their potential target genes and signal pathways. The chorionic villi tissues were collected from 15 early RM cases and 15 controls. We focused on investigating the biological pathways and their potential functions in order to explore what is the likely association and how they are possibly involved in the development of early RM. The chorionic villi tissues were collected from 15 early RM cases and 15 controls. A total of 155 differentially expressed miRNAs over 2-fold changes in expression levels (P<0.05), including 98 up-regulated and 57 down-regulated expressions. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the target genes of those miRNAs were mainly involved in the pathways of MAPK, B cell receptor, T cell receptor and tumor-associated signaling in the development of early RM. Those target genes of differentially expressed miRNAs, coupled with multiple biological processes and pathways, would be beneficial to understand the etiology and pathophysiological mechanism of early RM. PMID- 26526132 TI - Metagenomic studies of the Red Sea. AB - Metagenomics has significantly advanced the field of marine microbial ecology, revealing the vast diversity of previously unknown microbial life forms in different marine niches. The tremendous amount of data generated has enabled identification of a large number of microbial genes (metagenomes), their community interactions, adaptation mechanisms, and their potential applications in pharmaceutical and biotechnology-based industries. Comparative metagenomics reveals that microbial diversity is a function of the local environment, meaning that unique or unusual environments typically harbor novel microbial species with unique genes and metabolic pathways. The Red Sea has an abundance of unique characteristics; however, its microbiota is one of the least studied among marine environments. The Red Sea harbors approximately 25 hot anoxic brine pools, plus a vibrant coral reef ecosystem. Physiochemical studies describe the Red Sea as an oligotrophic environment that contains one of the warmest and saltiest waters in the world with year-round high UV radiations. These characteristics are believed to have shaped the evolution of microbial communities in the Red Sea. Over representation of genes involved in DNA repair, high-intensity light responses, and osmoregulation were found in the Red Sea metagenomic databases suggesting acquisition of specific environmental adaptation by the Red Sea microbiota. The Red Sea brine pools harbor a diverse range of halophilic and thermophilic bacterial and archaeal communities, which are potential sources of enzymes for pharmaceutical and biotechnology-based application. Understanding the mechanisms of these adaptations and their function within the larger ecosystem could also prove useful in light of predicted global warming scenarios where global ocean temperatures are expected to rise by 1-3 degrees C in the next few decades. In this review, we provide an overview of the published metagenomic studies that were conducted in the Red Sea, and the bio-prospecting potential of the Red Sea microbiota. Furthermore, we discuss the limitations of the previous studies and the need for generating a large and representative metagenomic database of the Red Sea to help establish a dynamic model of the Red Sea microbiota. PMID- 26526133 TI - Field application of safe chemical elicitors induced the expression of some resistance genes against grey mold and cottony rot diseases during snap bean pods storage. AB - Phaseolus vulgaris is subjected to serious post-harvest diseases such as grey mold and cottony rot diseases caused by Botrytis cinerea and Pythium aphanidermatum, respectively. In current study, potassium silicate (KSi), potassium thiosulfate (KTS) and potassium sulfate (KS) suppressed moderately the growth of B. cinerea and P. aphanidermatum in vitro. The applied treatments significantly suppressed grey mold and cottony rot of Xera and Valentino snap beans varieties' pods stored at 7 +/- 1 degrees C and 90-95% RH for 20 days. Ethylene responsive factor (ERF), polygalacturonase inhibitor protein (PGIP), phosphatase associated to defense (PA) and pathogenesis-related protein (PR1) defense genes were over-expressed in leaves tissue of both bean varieties responding positively to potassium salts field application. The expression of these genes was influenced by plant genotype and environment as it varied by snap bean varieties. Accumulation of ERF, GIP, PA and PR1 genes transcript under KTS at 4000 ppm treatment were the highest in Xera tissues (3.5-, 4.8-, 4- and 4.8 fold, respectively). In conclusion, pre-harvest potassium salt in vivo application could be used as effective safe alternatives to fungicides against grey mold and cottony rot diseases of snap beans during storage for up to 20 days at 7 +/- 1 degrees C. PMID- 26526135 TI - Over-expressed RPL34 promotes malignant proliferation of non-small cell lung cancer cells. AB - Ribosomal protein L34 (RPL34) was reported to be involved in the regulation of cell proliferation of prokaryotes, plant and animal cells. In the present study, we analyze the expression and function of RPL34 in NSCLC. Immunohistochemical analysis, qPCR and Western blot were used to detect the expression of RPL34 in NSCLC tissues and cells lines. Flow cytometry was used to detect cell activity of NSCLC cell line H1299 under lentivirus-mediated RNAi on RPL34. Cell proliferation and colony formation assays were used to analyze the role of RPL34 in NSCLC cell proliferation. We found that expression of ribosomal protein RPL34 was significantly up-regulated in NSCLC tissues compared to adjacent normal tissues. Lentivirus-mediated shRNA knockdown of RPL34 in NSCLC cell line H1299 resulted in a strong decrease of proliferation, and a moderate but significant increase of apoptosis and S-phase arrest. These data indicate that over-expressed RPL34 may promote malignant proliferation of NSCLC cells, thus playing an important role in development and progress of NSCLC. PMID- 26526136 TI - Recent and Upcoming Approaches in the Management of Cancer Breakthrough Pain. AB - The pharmacokinetics of the traditional oral opioids do not match the time course of breakthrough cancer pain, a common and distinct component of cancer pain which has a negative impact on quality of life for the patient.Fentanyl and alfentanil are potent, lipophilic, fast acting opioids with short durations of action and consequently more appropriate for the treatment of breakthrough cancer pain. These agents are ideal for oral transmucosal or nasal transmucosal administration.There are now four licensed preparations of fentanyl in the UK for the treatment of cancer breakthrough pain; lozenge, buccal tablet, sublingual tablet and nasal spray. They are not interchangeable and all require titration using the lowest dose.Alfentanil is available as a buccal or nasal spray. It is an unlicensed product and is available as a special order from Torbay Pharmacy Manufacturing Unit.There is a paucity of comparator studies for these new modes of administration.Further innovative delivery systems of fentanyl are on the horizon. PMID- 26526137 TI - Haem oxygenase-1 deficiency: a mimicker of childhood vasculitis. PMID- 26526134 TI - TNNI1, TNNI2 and TNNI3: Evolution, regulation, and protein structure-function relationships. AB - Troponin I (TnI) is the inhibitory subunit of the troponin complex in the sarcomeric thin filament of striated muscle and plays a central role in the calcium regulation of contraction and relaxation. Vertebrate TnI has evolved into three isoforms encoded by three homologous genes: TNNI1 for slow skeletal muscle TnI, TNNI2 for fast skeletal muscle TnI and TNNI3 for cardiac TnI, which are expressed under muscle type-specific and developmental regulations. To summarize the current knowledge on the TnI isoform genes and products, this review focuses on the evolution, gene regulation, posttranslational modifications, and structure function relationship of TnI isoform proteins. Their physiological and medical significances are also discussed. PMID- 26526138 TI - A systematic approach to assess locoregional differences in angiogenesis. AB - Skeletal muscle tissue differs with regard to the abundance of glycolytic and oxidative fiber types. In this context, capillary density has been described to be higher in muscle tissue with more oxidative metabolism as compared to that one with more glycolytic metabolism, and the highest abundance of capillaries has been found in boneward-oriented moieties of skeletal muscle tissue. Importantly, capillary formation is often analyzed as a measure for angiogenesis, a process that describes neo-vessel formation emanating from preexisting vessels, occurring, i.e., after arterial occlusion. However, a standardized way for investigation of calf muscle capillarization after surgically induced unilateral hind limb ischemia in mice, especially considering these locoregional differences, has not been provided so far. In this manuscript, a novel, methodical approach for reliable analysis of capillary density was established using anatomic-morphological reference points, and a software-assisted way of capillary density analysis is described. Thus, the systematic approach provided conscientiously considers intra-layer differences in capillary formation and therefore guarantees for a robust, standardized analysis of capillary density as a measure for angiogenesis. The significance of the methodology is further supported by the observation that capillary density in the calf muscle layers analyzed negatively correlates with distal lower limb perfusion measured in vivo. PMID- 26526140 TI - A novel approach combining self-organizing map and parallel factor analysis for monitoring water quality of watersheds under non-point source pollution. AB - High content of organic matter in the downstream of watersheds underscored the severity of non-point source (NPS) pollution. The major objectives of this study were to characterize and quantify dissolved organic matter (DOM) in watersheds affected by NPS pollution, and to apply self-organizing map (SOM) and parallel factor analysis (PARAFAC) to assess fluorescence properties as proxy indicators for NPS pollution and labor-intensive routine water quality indicators. Water from upstreams and downstreams was sampled to measure dissolved organic carbon (DOC) concentrations and excitation-emission matrix (EEM). Five fluorescence components were modeled with PARAFAC. The regression analysis between PARAFAC intensities (Fmax) and raw EEM measurements indicated that several raw fluorescence measurements at target excitation-emission wavelength region could provide similar DOM information to massive EEM measurements combined with PARAFAC. Regression analysis between DOC concentration and raw EEM measurements suggested that some regions in raw EEM could be used as surrogates for labor intensive routine indicators. SOM can be used to visualize the occurrence of pollution. Relationship between DOC concentration and PARAFAC components analyzed with SOM suggested that PARAFAC component 2 might be the major part of bulk DOC and could be recognized as a proxy indicator to predict the DOC concentration. PMID- 26526139 TI - Studies of drug interactions with glycated human serum albumin by high performance affinity chromatography. AB - Diabetes is a health condition associated with elevated levels of glucose in the bloodstream and affects 366 million people worldwide. Type II diabetes is often treated with sulfonylurea drugs, which are known to bind tightly in blood to the transport protein human serum albumin (HSA). One consequence of the elevated levels of glucose in diabetes is the non-enzymatic glycation of proteins such as HSA. Several areas of HSA are now known to be affected by glycation-related modifications, which may in turn affect the binding of sulfonylurea drugs and other solutes to this protein. This review discusses some recent studies that have examined these changes in drug-protein binding by employing high-performance affinity chromatography (HPAC). A description of the theoretical and experimental techniques that were used in these studies is given. The information on drug interactions with glycated HSA, as obtained through this method, is also summarized. In addition, the potential advantages of this approach in the areas of biointeraction analysis and personalized medicine are considered. PMID- 26526142 TI - Qualitative content analysis of psychologic discomfort and coping process after needlestick injuries among health care workers. AB - BACKGROUND: This study was designed to survey psychologic discomfort and coping processes of health care workers that suffered needlestick injuries (NSIs). METHODS: This qualitative analysis was performed with 15 health care workers who experienced NSIs. Data were collected using face-to-face interviews. The study subjects were asked the following: please describe the psychologic discomfort that you experienced after the NSI incidence. Data were evaluated by qualitative content analysis. RESULTS: Types of psychologic discomfort after NSI among health care workers included anxiety, anger, and feelings of guilt. Some personnel adopted active coping strategies, such as seeking first aid or reporting the incident to a monitoring system, whereas others used passive coping methods, such as avoidance of reporting the incident, vague expectancy to have no problems, and reliance on religious beliefs. Recommended support strategies to improve the prevention of NSIs were augmenting employee education and increasing recognition of techniques for avoiding NSIs. CONCLUSION: Medical institutions need to provide employees with repeated education so that they are familiar with guidelines for preventing NSIs and to stimulate their alertness to the risk of injuries at any time, in any place, and to anybody. PMID- 26526144 TI - Role of Muscarinic Acetylcholine Receptor-2 in the Cerebellar Cortex in Cardiovascular Modulation in Anaesthetized Rats. AB - Our previous investigations have demonstrated that microinjection of acetylcholine (ACh) or muscarinic ACh receptor activation in the cerebellar cortex induces a systemic blood pressure depressor response. This study aimed to determine the role of muscarinic ACh receptor-2 (M2 receptor) in the cerebellar cortex in cardiovascular function regulation in rats. A nonselective muscarinic receptor agonist (oxotremorine M, OXO; 30 mM), a selective M2 receptor agonist (arecaidine but-2-ynyl ester tosylate, ABET; 3, 10, and 30 mM), 30 mM OXO mixed with a selective M2 receptor antagonist (methoctramine hydrate, MCT; 0.3, 1, and 3 mM), and normal saline (0.9 % NaCl) were separately microinjected (0.5 ul/5 s) into the cerebellar cortex (lobule VI) of anaesthetized rats. We measured the mean arterial pressure (MAP), maximum change in MAP, and reactive time (RT; the duration required for the blood pressure to return to basal levels), heart rate (HR) and the maximum change in HR during the RT in response to drug activation. The results demonstrated that ABET dose-dependently decreased MAP and HR, increased the maximum change in MAP and the maximum change in HR, and prolonged the RT. Furthermore, MCT dose-dependently blocked the OXO-mediated cardiovascular depressor response. This study provides the first evidence that M2 receptors in the cerebellar cortex are involved in cardiovascular regulation, the activation of which evokes significant depressor and bradycardic responses. PMID- 26526145 TI - Human sex-determination and disorders of sex-development (DSD). AB - Several new genes and pathways have been identified in recent years associated with human errors of sex-determination or DSD. SOX family gene mutations, as well as mutations involving GATA4, FOG2 and genes involved in MAP kinase signaling have been associated with virilization in 46,XX individuals or with 46,XY gonadal dysgenesis. Furthermore, mutations involving another key gene in sex determination, NR5A1, are now known to be an important cause spermatogenic failure in the male and ovarian insufficiency in the female. These new findings offer insights into human sex-determination and highlight important differences between the human and mouse model. This review will critically examine the evidence linking gene mutations, especially MAP3K1, to non-syndromic forms of human 46,XY gonadal dysgenesis or XX testicular/ovotesticular. PMID- 26526143 TI - Cerebral Response to Peripheral Challenge with a Viral Mimetic. AB - It has been well established that peripheral inflammation resulting from microbial infections profoundly alters brain function. This review focuses on experimental systems that model cerebral effects of peripheral viral challenge. The most common models employ the induction of the acute phase response via intraperitoneal injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC). The ensuing transient surge of blood-borne inflammatory mediators induces a "mirror" inflammatory response in the brain characterized by the upregulated expression of a plethora of genes encoding cytokines, chemokines and other inflammatory/stress proteins. These inflammatory mediators modify the activity of neuronal networks leading to a constellation of behavioral traits collectively categorized as the sickness behavior. Sickness behavior is an important protective response of the host that has evolved to enhance survival and limit the spread of infections within a population. However, a growing body of clinical data indicates that the activation of inflammatory pathways in the brain may constitute a serious comorbidity factor for neuropathological conditions. Such comorbidity has been demonstrated using the PIC paradigm in experimental models of Alzheimer's disease, prion disease and seizures. Also, prenatal or perinatal PIC challenge has been shown to disrupt normal cerebral development of the offspring resulting in phenotypes consistent with neuropsychiatric disorders, such as schizophrenia and autism. Remarkably, recent studies indicate that mild peripheral PIC challenge may be neuroprotective in stroke. Altogether, the PIC challenge paradigm represents a unique heuristic model to elucidate the immune-to brain communication pathways and to explore preventive strategies for neuropathological disorders. PMID- 26526146 TI - Diversity and evolutionary history of lettuce necrotic yellows virus in Australia and New Zealand. AB - Lettuce necrotic yellows virus (LNYV) is the type member of the genus Cytorhabdovirus, family Rhabdoviridae, and causes a severe disease of lettuce (Lactuca sativa L.). This virus has been described as endemic to Australia and New Zealand, with sporadic reports of a similar virus in Europe. Genetic variability studies of plant-infecting rhabdoviruses are scarce. We have extended a previous study on the variability of the LNYV nucleocapsid gene, comparing sequences from isolates sampled from both Australia and New Zealand, as well as analysing symptom expression on Nicotiana glutinosa. Phylogenetic and BEAST analyses confirm separation of LNYV isolates into two subgroups (I and II) and suggest that subgroup I is slightly older than subgroup II. No correlation was observed between isolate subgroup and disease symptoms on N. glutinosa. The origin of LNYV remains unclear; LNYV may have moved between native and weed hosts within Australia or New Zealand before infecting lettuce or may have appeared as a result of at least two incursions, with the first coinciding with the beginning of European agriculture in the region. The apparent extinction of subgroup I in Australia may have been due to less-efficient dispersal than that which has occurred for subgroup II - possibly a consequence of suboptimal interactions with plant and/or insect hosts. Introduction of subgroup II to New Zealand appears to be more recent. More-detailed epidemiological studies using molecular tools are needed to fully understand how LNYV interacts with its hosts and to determine where the virus originated. PMID- 26526147 TI - Single-step concentration and purification of adenoviruses by coxsackievirus adenovirus receptor-binding capture and elastin-like polypeptide-mediated precipitation. AB - A single-step method for quick concentration and purification of adenoviruses (Ads) was established by combining coxsackievirus and adenovirus receptor (CAR) binding capture with elastin-like polypeptide (ELP)-mediated precipitation. The soluble ELP-CAR fusion protein was expressed in vector-transformed E. coli and purified to high purity by two rounds of inverse transition cycling (ITC). After demonstration of the specific binding of fusion protein, a recombinant Ad (rAd), namely rAd/GFP, was pulled down from the culture medium and extract of rAd transduced cells using ELP-CAR protein, with recovery of 76.2 % and 73.3 %, respectively. The rAd was eluted from the ELP-CAR protein and harvested by one round of ITC, with recoveries ranging from 30.6 % to 34.5 % (virus titration assay). Both ELP-CAR-bound and eluted rAds were able to transduce CAR-positive cells, but not CAR-negative cells (fluorescent microscopy). A further viral titration assay showed that the ELP-CAR-bound rAd/GFP had significantly lower transduction efficiency than the eluted rAd, and there was less of a decrease when tested in the presence of fetal bovine serum. In addition, rAd/GFP was efficiently recovered from the "spiked" PBS and tap water with recovery of ~74 % or ~60 %. This work demonstrates the usefulness of the ELP-CAR-binding capture method for concentration and/or purification of Ads in cellular and environmental samples. PMID- 26526148 TI - Phylogenetic and biological characterization of three K1203 (H5N8)-like avian influenza A virus reassortants in China in 2014. AB - Three H5N8 avian influenza viruses isolated from domestic geese in China in 2014 were characterized phylogenetically and biologically. Phylogenetic analysis of the complete genomic sequences of the three isolates from this study and those of 61 other H5N8 viruses retrieved from the GISAID platform indicated that, chronologically and geographically, all H5N8 viruses of the Asian H5N1 HA lineage of clade 2.3.4.4 are the direct descendents of the K1203 (H5N8)-like viruses first isolated in China in 2010. The three viruses from this study shared high sequence similarity in all eight gene segments with three other isolates from China in 2013, and two Korean isolates were distinct from the recently circulating reassortants causing outbreaks in Asia, Europe and the United States in 2014 and 2015. In vitro viral growth curves indicated that these H5N8 viruses replicated to high titers in CEF, DEF, MDCK and A549 cells but to significantly lower titers in Vero cells. Pathogenicity studies in vivo indicated that these viruses were all highly virulent to chickens and mallard ducks, while they varied from moderate to high virulence in mice. Additionally, hemagglutination assays using alpha-2,3-sialidase-treated goose red blood cells and solid-phase direct binding assays with different glycans demonstrated that the three viruses could bind to both avian-type SAalpha-2,3Gal and human-type SAalpha-2,6Gal receptors. Our findings confirmed the progenitor nature of the K1203-like viruses in generating recent prevalent clade 2.3.4.4 H5N8 reassortants, which have caused tremendous damage to the poultry industry and are a potential threat to public health. PMID- 26526149 TI - Functional characterization of a new promoter isolated from torque teno sus virus 1. AB - Torque teno sus virus 1 (TTSuV1) has a non-enveloped, single-stranded, negative sense circular DNA genome, and it is widely distributed in pigs. Open reading frame 1 (ORF1) of TTSuV1 can be transcribed into mRNA and then translated into protein; however, its promoter has not yet been identified. We used a dual luciferase reporter system, involving pGL3-Basic and pRL-TK, to identify the promoter of TTSuV1 ORF1. Our results revealed that the sequence between nucleotides 196 and 525 promoted the transcription of the firefly luciferase gene. The core sequence of the promoter was between nucleotides 250 and 400. A comparison of the identified TTSuV1 ORF1 promoter with that from cytomegalovirus (CMV) suggested that the two promoters were similar in strength. Our findings provide new information regarding the molecular biology of TTSuV1 and have revealed a new promoter that can be used in plasmids for numerous applications. PMID- 26526150 TI - Experimental infection with cytopathic bovine viral diarrhea virus in mice induces megakaryopoiesis in the spleen and bone marrow. AB - Here, we infected mice with cytopathic bovine viral diarrhea virus 1 (cp BVDV1) by oral inoculation and investigated the effects of infection by histopathological, immunohistochemical (IHC), hematological methods. Twelve mice were infected, and samples were obtained at day 2, 5, and 9 postinfection (pi). Most of the infected mice exhibited clinical signs of illness such as reduced movement, crouching, loose feces, loss of appetite, and reduced water intake. Blood samples from six mice were positive for BVDV based on reverse transcription polymerase chain reaction (RT-PCR). Blood analysis also revealed thrombocytopenia and lymphopenia. Viral antigens were detected in the spleen (12/12), bone marrow (12/12), and/or mesenteric lymph nodes (4/12) of all infected mice by IHC analysis. The spleens showed significant histopathological changes including (i) substantially increased numbers of megakaryocytes, (ii) lymphocyte depletion, and (iii) hemorrhages. The bone marrow also had an increased number of megakaryocytes, although this increase was not as strong as it was in the spleen. Severe lymphoid depletion was observed in the mesenteric lymph nodes. Viral infections were present in the lymphocytes but not detected in megakaryocytes of the spleen, bone marrow, or mesenteric lymph nodes. These results suggest that the increased numbers of megakaryocytes may be a direct result of BVDV infection. BVDV infection in mice following oral inoculation of cp BVDV1 leads to megakaryopoiesis in the spleen and bone marrow to replenish the platelets. PMID- 26526151 TI - Genomic characterization of Ralstonia solanacearum phage phiRS138 of the family Siphoviridae. AB - phiRS138, a bacteriophage of the family Siphoviridae that lyses Ralstonia solanacearum, was isolated. The genomic DNA of phiRS138 was 41,941 bp long with a GC content of 65.1 % and contained 56 putative open reading frames. The phiRS138 genome could be divided into three regions based on similarities to other genomes: (1) a region containing genes encoding a putative transcriptional regulator and an integrase, similar to the prophage genes in Ralstonia solanacearum K60-1; (2) a region encoding proteins related to structural modules and virion morphogenesis, similar to genes in the Pseudomonas phages of the family Siphoviridae; and (3) a region highly similar to the genomes of other Ralstonia solanacearum strains. PMID- 26526152 TI - A New Absorbable Synthetic Substitute With Biomimetic Design for Dural Tissue Repair. AB - Dural repair products are evolving from animal tissue-derived materials to synthetic materials as well as from inert to absorbable features; most of them lack functional and structural characteristics compared with the natural dura mater. In the present study, we evaluated the properties and tissue repair performance of a new dural repair product with biomimetic design. The biomimetic patch exhibits unique three-dimensional nonwoven microfiber structure with good mechanical strength and biocompatibility. The animal study showed that the biomimetic patch and commercially synthetic material group presented new subdural regeneration at 90 days, with low level inflammatory response and minimal to no adhesion formation detected at each stage. In the biological material group, no new subdural regeneration was observed and severe adhesion between the implant and the cortex occurred at each stage. In clinical case study, there was no cerebrospinal fluid leakage, and all the postoperation observations were normal. The biomimetic structure and proper rate of degradation of the new absorbable dura substitute can guide the meaningful reconstruction of the dura mater, which may provide a novel approach for dural defect repair. PMID- 26526153 TI - Boron nitride nanotubes and nanoplatelets as reinforcing agents of polymeric matrices for bone tissue engineering. AB - This study investigates the mechanical properties and in vitro cytotoxicity of one- and two-dimensional boron nitride nanomaterials-reinforced biodegradable polymeric nanocomposites. Poly(propylene fumarate) (PPF) nanocomposites were fabricated using crosslinking agent N-vinyl pyrrolidone and inorganic nanomaterials: boron nitride nanotubes (BNNTs) and boron nitride nanoplatelets (BNNPs) dispersed at 0.2 wt % in the polymeric matrix. The incorporation of BNNPs and BNNTs resulted in a ~38 and ~15% increase in compressive (Young's) modulus, and ~31 and ~6% increase in compressive yield strength compared to PPF control, respectively. The nanocomposites showed a time-dependent increased protein adsorption for collagen I protein. The cytotoxicity evaluation of aqueous BNNT and BNNP dispersions (at 1-100 MUg/mL concentrations) using murine MC3T3 preosteoblast cells showed ~73-99% viability. The cytotoxicity evaluation of media extracts of nanocomposites before crosslinking, after crosslinking, and upon degradation (using 1*-100* dilutions) showed dose-dependent cytotoxicity responses. Crosslinked nanocomposites showed excellent (~79-100%) cell viability, cellular attachment (~57-67%), and spreading similar to cells grown on the surface of tissue culture polystyrene control. The media extracts of degradation products showed a dose-dependent cytotoxicity. The favorable cytocompatibility results in combination with improved mechanical properties of BNNT and BNNP nanocomposites opens new avenues for further in vitro and in vivo safety and efficacy studies towards bone tissue engineering applications. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 406-419, 2017. PMID- 26526155 TI - Editorial for the Third Pangu Stroke Conference. AB - The Pangu Stroke Conference has been held annually in China since 2012 and is based on the successful templates of the Princeton Stroke Conference in the United States and the Marburg Conference on Cerebral Ischemia in Germany. All participants in the Pangu Stroke Conference are expert stroke clinicians or stroke basic science researchers of Chinese origin. This conference promotes collaboration between clinicians and basic science researchers and between stroke researchers in mainland China and other parts of the world. The Pangu Stroke Conference fosters translational stroke research, discussions of stroke research milestones, and proposals for future directions. Some of the keynote presentations in the third Pangu Stroke Conference are included in this special issue. PMID- 26526154 TI - Identification of the active components in Bone Marrow Soup: a mitigator against irradiation-injury to salivary glands. AB - In separate studies, an extract of soluble intracellular contents from whole bone marrow cells, named "Bone Marrow (BM) Soup", was reported to either improve cardiac or salivary functions post-myocardial infarction or irradiation (IR), respectively. However, the active components in BM Soup are unknown. To demonstrate that proteins were the active ingredients, we devised a method using proteinase K followed by heating to deactivate proteins and for safe injections into mice. BM Soup and "deactivated BM Soup" were injected into mice that had their salivary glands injured with 15Gy IR. Control mice received either injections of saline or were not IR. Results at week 8 post-IR showed the 'deactivated BM Soup' was no better than injections of saline, while injections of native BM Soup restored saliva flow, protected salivary cells and blood vessels from IR-damage. Protein arrays detected several angiogenesis-related factors (CD26, FGF, HGF, MMP-8, MMP-9, OPN, PF4, SDF-1) and cytokines (IL-1ra, IL 16) in BM Soup. In conclusion, the native proteins (but not the nucleic acids, lipids or carbohydrates) were the therapeutic ingredients in BM Soup for functional salivary restoration following IR. This molecular therapy approach has clinical potential because it is theoretically less tumorigenic and immunogenic than cell therapies. PMID- 26526156 TI - Risk assessment of medically assisted reproduction and advanced maternal ages in the development of Prader-Willi syndrome due to UPD(15)mat. AB - Recent studies have suggested that disomic oocyte-mediated uniparental disomy 15 (UPD(15)mat) is increased in patients with Prader-Willi syndrome (PWS) born after medically assisted reproduction (MAR). However, it remains unknown whether the increase is primarily due to MAR procedure itself or advanced maternal childbearing ages as a predisposing factor for the disomic oocyte production. To examine this matter, we studied 122 naturally conceived PWS patients (PWS-NC group) and 13 MAR-conceived patients (PWS-MAR group). The relative frequency of disomic oocyte-mediated UPD(15)mat was significantly higher in PWS-MAR group than in PWS-NC group (7/13 vs 20/122, p = 0.0045), and the maternal childbearing ages were significantly higher in PWS-MAR group than in PWS-NC group [median (range), 38 (26-45) vs 30 (19-42), p = 0.0015]. However, the logistic regression analysis revealed no significant association between the occurrence of disomic oocyte mediated UPD(15)mat and MAR, after adjusting for childbearing age (p = 0.25). Consistent with this, while the frequency of assisted reproductive technology (ART)-conceived livebirths was higher in the PWS patients than in the Japanese general population (6.4% vs 1.1%, p = 0.00018), the distribution of childbearing ages was significantly skewed to the increased ages in the PWS patients (p < 2.2 * 10(-16) ). These results argue against a positive association of MAR procedure itself with the development of UPD(15)mat. PMID- 26526157 TI - Prognostic Value of High CXCR4 Expression in Renal Cell Carcinoma: A System Review and Meta-Analysis. AB - BACKGROUND: Recent studies have shown that CXC chemokine receptor 4 (CXCR4) is involved in the progression and metastasis of renal cell carcinoma (RCC). However, the prognostic value of CXCR4 expression in RCC remains controversial. The aim of our meta-analysis is to evaluate the prognostic value of high CXCR4 expression in RCC. METHODS: Relevant studies focused on the relationship between high CXCR4 expression and the outcome of RCC were searched in PubMed and EMBASE/Cochrane Library database. Hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were our evaluation index. The individual and pooled HRs with 95% confidence intervals (CIs) were analyzed. RESULTS: A total of 1068 patients from 7 studies were included in our meta-analysis. The results suggested that high CXCR4 expression predicted a poor OS (random effect model (REM) HR = 2.77, 95% CI = 1.80-4.27) and PFS (REM HR = 4.83, 95% CI = 2.30-10.15) for RCC patients. CONCLUSION: The results of meta-analysis indicated that high CXCR4 expression was correlated with worse OS and PFS for patients with RCC. However, some larger samples and well-matched studies should be designed to estimate the potential prognosis of RCC patients. PMID- 26526158 TI - Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice. AB - Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease. We utilized apoE4-targeted replacement mice (approved by the Tel Aviv University Animal Care Committee) to investigate whether cholinergic dysfunction, which increases during aging and is a hallmark of Alzheimer's disease, is accentuated by apoE4. This revealed that levels of the pre-synaptic cholinergic marker, vesicular acetylcholine transporter in the hippocampus and the corresponding electrically evoked release of acetylcholine, are similar in 4 month-old apoE4 and apolipoprotein E3 (apoE3) mice. Both parameters decrease with age. This decrease is, however, significantly more pronounced in the apoE4 mice. The levels of cholinacetyltransferase (ChAT), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were similar in the hippocampus of young apoE4 and apoE3 mice and decreased during aging. For ChAT, this decrease was similar in the apoE4 and apoE3 mice, whereas it was more pronounced in the apoE4 mice, regarding their corresponding AChE and BuChE levels. The level of muscarinic receptors was higher in the apoE4 than in the apoE3 mice at 4 months and increased to similar levels with age. However, the relative representation of the M1 receptor subtype decreased during aging in apoE4 mice. These results demonstrate impairment of the evoked release of acetylcholine in hippocampus by apoE4 in 12-month-old mice but not in 4-month-old mice. The levels of ChAT and the extent of the M2 receptor mediated autoregulation of ACh release were similar in the adult mice, suggesting that the apoE4-related inhibition of hippocampal ACh release in these mice is not driven by these parameters. Evoked ACh release from hippocampal and cortical slices is similar in 4-month-old apoE4 and apoE3 mice but is specifically and significantly reduced in hippocampus, but not cortex, of 12-month-old apoE4 mice. This effect is accompanied by decreased VAChT levels. These findings show that the hipocampal cholinergic nerve terminals are specifically affected by apoE4 and that this effect is age dependent. PMID- 26526159 TI - Influenza Vaccination During Pregnancy: Influenza Seasons 2002-2012, Vaccine Safety Datalink. AB - INTRODUCTION: Pregnant women are at risk for influenza-related complications and have been recommended for vaccination by the Advisory Committee on Immunization Practices (ACIP) since 1990. Annual rates of influenza coverage of pregnant women have been consistently low. The Vaccine Safety Datalink was used to assess influenza vaccine coverage over 10 consecutive years (2002-2012); assess patterns related to changes in ACIP recommendations; identify predictors of vaccination; and compare the results with those published by national U.S. surveys. METHODS: Retrospective cohort study of 721,898 pregnancies conducted in 2014. Coverage rates were assessed for all pregnancies and for live births only. Multivariate regression analysis identified predictors associated with vaccination. RESULTS: Coverage increased from 8.8% to 50.9% in 2002-2012. Seasonal coverage rates increased slowly following the 2004 ACIP influenza vaccine recommendation (to remove the first trimester restriction), but spiked significantly during the 2009 H1N1 influenza pandemic. Significant predictors of vaccination during pregnancy included older age; vaccination in a previous season; high-risk conditions in addition to pregnancy; pregnancy during either the 2004-2005 or 2009-2010 seasons; entering the influenza season after the first trimester of pregnancy; and a pregnancy with longer overlap with the influenza season (p<0.001 for each). CONCLUSIONS: Influenza vaccination coverage among pregnant women increased between the 2002-2003 and 2011-2012 seasons, although it was still below the developmental Healthy People 2020 goal of 80%. The 2004 ACIP language change positively impacted first-trimester vaccination uptake. Vaccine Safety Datalink data estimates were consistent with U.S. estimates. PMID- 26526160 TI - Efficacy of the Type 2 Diabetes Prevention Using LifeStyle Education Program RCT. AB - INTRODUCTION: Self-administered lifestyle interventions have been suggested as an alternative to face-to-face delivery modes, although their efficacy remains uncertain. The aim of this study was to evaluate the efficacy of the Type 2 diabetes mellitus Prevention Using LifeStyle Education (PULSE) Program, a self administered and gender-tailored lifestyle intervention for men at high risk for developing Type 2 diabetes mellitus. DESIGN/SETTING: A 6-month, assessor-blinded, parallel-group RCT was conducted at the University of Newcastle, Australia in 2012-2013. PARTICIPANTS: Men (aged 18-65 years, BMI 25-40 kg/m(2), high risk for developing Type 2 diabetes mellitus) were stratified by age (<50 and >50 years) and BMI category (25.0-29.9, 30.0-35.9, and 35.0-40 kg/m(2)) and individually randomized (1:1 ratio) to the intervention (n=53) or waitlist control groups (n=48). INTERVENTION: The intervention group received the PULSE Program, which contained print and video resources on weight loss (Self-Help, Exercise and Diet using Internet Technology [SHED-IT] Weight Loss Program), diet modification, and exercise for Type 2 diabetes mellitus prevention. The waitlist control group received no information until 6 months. MAIN OUTCOME MEASURES: Data were collected from September 2012 to September 2013 and analyzed in 2014-2015. Linear mixed models (intention-to-treat) were used to determine group X time interactions (differences between groups in changes over time) at 6 months for the primary outcome (weight), glycated hemoglobin, and several secondary outcomes (significance level, p<0.05). RESULTS: Differences between groups in mean changes from baseline to 6 months (group * time interaction) favored the intervention over control group for weight loss (-5.50 kg, 95% CI=-7.40 kg, -3.61 kg, p<0.001, Cohen's d=1.15), glycated hemoglobin (-0.2%, 95% CI=-0.3%, -0.1%, p=0.002, d=0.64), and BMI, waist circumference, body fat percentage, aerobic fitness, and lower body muscular fitness (all p<0.05). No group * time effects were observed for fasting plasma glucose, upper body muscular fitness, physical activity, or energy intake. CONCLUSIONS: The PULSE Program improved several Type 2 diabetes mellitus risk factors in men, including weight and glycated hemoglobin. These findings provide evidence for a self-administered and gender-tailored lifestyle intervention, which has potential for dissemination in community settings. PMID- 26526161 TI - Social Differentiation of Sun-Protection Behaviors: The Mediating Role of Cognitive Factors. AB - INTRODUCTION: Adherence to sun-protection guidelines in developed countries is low, especially among people of low SES. Mechanisms underlying this social differentiation are poorly understood. This study aimed to examine the social differentiation of sun-protection behaviors and of two cognitive factors (knowledge about both sun health and behavioral risk factors for cancer) and to determine if these cognitive factors mediate the association between SES and sun protection behaviors. METHODS: Data came from the 2010 Barometre Cancer survey (analyzed in 2014), a random cross-sectional telephone survey conducted among the French general population (n=3,359 individuals aged 15-75 years). First, bivariate associations between a composite individual SES indicator (based on education level, occupation, and income) and both sun-protection behaviors and cognitive factors were tested with chi-square tests and ANOVA. Then, confirmatory factor analysis and structural equation modeling were used to test the mediating role of cognitive factors with a multiple mediation model including four latent variables. RESULTS: In bivariate analyses, the individual SES indicator was positively associated with sun-protection behaviors and both cognitive factors. Multiple mediation analyses showed that both cognitive factors partially mediated the effect of individual SES on sun-protection behaviors. The overall proportion of mediated effects was 48%. The direct effect of SES remained significant. CONCLUSIONS: These results suggest that interventions aimed at modifying the knowledge and perceptions of people of low SES might help to reduce social differentiation of sun-protection behaviors. Further qualitative research is needed to better understand these cognitive factors and develop suitable prevention messages. PMID- 26526162 TI - Tobacco Product Use Among Sexual Minority Adults: Findings From the 2012-2013 National Adult Tobacco Survey. AB - INTRODUCTION: A growing body of evidence reveals higher rates of tobacco use among sexual minority populations relative to non-minority ("straight") populations. This study seeks to more fully characterize this disparity by examining tobacco use by distinct sexual identities and gender to better understand patterns of: (1) cigarette smoking and smoking history; and (2) use of other tobacco products including cigars, pipes, hookah, e-cigarettes, and smokeless tobacco. METHODS: Data from the 2012-2013 National Adult Tobacco Survey, a random-digit dialed landline and cellular telephone survey of U.S. adults aged >=18 years, were analyzed in 2014. A sexual minority category was created by combining gay, lesbian, and bisexual responses, along with those who selected an option for other non-heterosexual identities. RESULTS: Smoking prevalence was higher among sexual minority adults (27.4%) than straight adults (17.3%). Cigarette smoking was particularly high among bisexual women (36.0%). Sexual minority women started smoking and transitioned to daily smoking earlier than their straight peers. Use of other tobacco products was higher among sexual minority women: prevalence of e-cigarette (12.4%), hookah (10.3%), and cigar use (7.2%) was more than triple that of their straight female peers (3.4%, 2.5%, and 1.3%, respectively). Likewise, prevalence of sexual minority men's e-cigarette (7.9%) and hookah (12.8%) use exceeded that of straight men (4.7% and 4.5%, respectively). CONCLUSIONS: Tobacco use is significantly higher among sexual minority than straight adults, particularly among sexual minority women. These findings underscore the importance of tobacco control efforts designed to reach sexual minorities and highlight the heterogeneity of tobacco use within this population. PMID- 26526163 TI - Medication Adherence and Incident Preventable Hospitalizations for Hypertension. AB - INTRODUCTION: Potentially preventable hospitalizations (PPHs) for hypertension (HTN) is one indicator of possible failed ambulatory care. Rates of PPHs for HTN have remained fairly level since the late 1980s, which may reflect a lack of understanding of the drivers of these hospitalizations. Anti-HTN medication non adherence has been studied as a potential risk factor for other cardiovascular disease outcomes but not for PPHs for HTN. METHODS: A cohort analysis was conducted during 2005-2012 of people with HTN enrolled in commercial and employee health plans with claims in the MarketScan database. PPH for HTN was defined according to specifications published by the Agency for Healthcare Research and Quality. The proportion of days covered (PDC) algorithm was used to assess adherence to antihypertensives. Crude- and multivariate-adjusted incident PPHs for HTN rates were calculated, as well as third-party payments for selected PPH for HTN-related expenses. RESULTS: During 9,344,528 person-years of follow-up (mean=3 years), 6,008 incident PPHs for HTN were identified among 3,099,291 people. The crude rate for good adherence (PDC >=80%) was 23.2 per 100,000 person years compared with 102.6 per 100,000 person-years for poor adherence (PDC <40%). Over the 8-year study, PPH for HTN-associated payments equaled $41 million. Payments for those with poor adherence were four times higher than for those with good adherence. CONCLUSIONS: Poor anti-HTN medication adherence is strongly associated with PPHs for HTN. Improving the percentage of people who achieve good medication adherence is one possible approach to reducing the burden of PPHs for HTN in the U.S. PMID- 26526164 TI - County Health Rankings: Relationships Between Determinant Factors and Health Outcomes. AB - INTRODUCTION: The County Health Rankings (CHR) provides data for nearly every county in the U.S. on four modifiable groups of health factors, including healthy behaviors, clinical care, physical environment, and socioeconomic conditions, and on health outcomes such as length and quality of life. The purpose of this study was to empirically estimate the strength of association between these health factors and health outcomes and to describe the performance of the CHR model factor weightings by state. METHODS: Data for the current study were from the 2015 CHR. Thirty-five measures for 45 states were compiled into four health factors composite scores and one health outcomes composite score. The relative contributions of health factors to health outcomes were estimated using hierarchical linear regression modeling in March 2015. County population size; rural/urban status; and gender, race, and age distributions were included as control variables. RESULTS: Overall, the relative contributions of socioeconomic factors, health behaviors, clinical care, and the physical environment to the health outcomes composite score were 47%, 34%, 16%, and 3%, respectively. Although the CHR model performed better in some states than others, these results provide broad empirical support for the CHR model and weightings. CONCLUSIONS: This paper further provides a framework by which to prioritize health-related investments, and a call to action for healthcare providers and the schools that educate them. Realizing the greatest improvements in population health will require addressing the social and economic determinants of health. PMID- 26526165 TI - Optimal adaptive two-stage designs for early phase II clinical trials. AB - Simon's optimal two-stage design has been widely used in early phase clinical trials for Oncology and AIDS studies with binary endpoints. With this approach, the second-stage sample size is fixed when the trial passes the first stage with sufficient activity. Adaptive designs, such as those due to Banerjee and Tsiatis (2006) and Englert and Kieser (2013), are flexible in the sense that the second stage sample size depends on the response from the first stage, and these designs are often seen to reduce the expected sample size under the null hypothesis as compared with Simon's approach. An unappealing trait of the existing designs is that they are not associated with a second-stage sample size, which is a non increasing function of the first-stage response rate. In this paper, an efficient intelligent process, the branch-and-bound algorithm, is used in extensively searching for the optimal adaptive design with the smallest expected sample size under the null, while the type I and II error rates are maintained and the aforementioned monotonicity characteristic is respected. The proposed optimal design is observed to have smaller expected sample sizes compared to Simon's optimal design, and the maximum total sample size of the proposed adaptive design is very close to that from Simon's method. The proposed optimal adaptive two stage design is recommended for use in practice to improve the flexibility and efficiency of early phase therapeutic development. PMID- 26526167 TI - Acute Pain Multiple Choice Questions. PMID- 26526166 TI - Possibility to predict early postpartum glucose abnormality following gestational diabetes mellitus based on the results of routine mid-gestational screening. AB - INTRODUCTION: Women with previous gestational diabetes mellitus (GDM) have increased risk of developing glucose abnormality, but current diagnostic criteria are evidence-based for adverse pregnancy outcome. THE AIMS OF OUR STUDY WERE: (i) to ascertain a frequency of early conversion of GDM into permanent glucose abnormality, (ii) to determine predictive potential of current GDM diagnostic criteria for prediction of postpartum glucose abnormality and (iii) to find optimal cut-off values of oral glucose tolerance test (oGTT) to stratify GDM population according to postpartum risk. MATERIALS AND METHODS: Electronic medical records of an ethnically homogenous cohort of women diagnosed and treated for GDM in a single medical centre during the period 2005-2011 who completed postpartum oGTT up to 1 year after the index delivery were retrospectively analysed (N=305). RESULTS: Postpartum glucose abnormality was detected in 16.7% subjects. Mid-trimester oGTT values, respective area under the curve and HbA1c were significantly associated with early postpartum glucose abnormality (P<0.05, Mann-Whitney) and exhibited significant predictive potential for postpartum glucose abnormality risk assessment. Optimal cut-off values for discrimination of at-risk sub-population were identified using ROC analysis and their comparison with WHO and IADPSG criteria exhibited superiority of IADPSG for risk stratification of GDM population. CONCLUSION: Risk-based stratification at the time of GDM diagnosis could improve efficiency of the post-gestational screening for diabetes. IADPSG criteria seem to optimally capture both perinatal and maternal metabolic risks and are therefore medically and economically justified. PMID- 26526168 TI - Assessment of functioning in patients with schizophrenia and schizoaffective disorder with the Mini-ICF-APP: a validation study in Italy. AB - BACKGROUND: The aim of the study was to evaluate validity of the Italian Mini-ICF APP (Mini-ICF Rating for Limitations of Activities and Participation in Psychological Disorders) in schizophrenia and related disorders. METHODS: 74 outpatients affected by schizophrenia or schizoaffective disorders attending a University-based community mental health centre were recruited to the study. All participants underwent comprehensive evaluation using standardized instruments to assess clinical, neurocognitive and functional status. Concurrent validity of Mini-ICF-APP was evaluated and compared to severity scores obtained using the Clinical Global Impression-Schizophrenia scale (CGI-SCH), Positive and Negative Syndrome scale (PANSS), Mini Mental State Examination test (MMSE), Brief Assessment of Cognition in Schizophrenia scale (BACS) and Personal and Social Performance scale (PSP). Construct validity was evaluated by comparing scores obtained at Mini-ICF-APP by remitted versus non-remitted patients, and by recovered versus unrecovered patients. Discriminant validity was evaluated comparing scores on Mini-ICF-APP and Subjective Well-being (SWN) scale. RESULTS: the total score and 12 out of the 13 Mini-ICF-APP items correlated significantly with total score at PSP; Mini-ICF-App total score was moreover significantly correlated with total scores at CGI-SCH, PANSS, MMSE, as well as with several BACS items. Total scores obtained at Mini-ICF-APP were significantly higher among remitted and recovered patients. No relevant correlations were found between scores of Mini-ICF-APP and SWN scales. RESULTS: The total score and 12 out of the 13 Mini-ICF-APP items correlated significantly with total score at PSP; Mini-ICF App total score was moreover significantly correlated with total scores at CGI SCH, PANSS, MMSE, as well as with several BACS items. Total scores obtained at Mini-ICF-APP were significantly higher among remitted and recovered patients. No relevant correlations were found between scores of Mini-ICF-APP and SWN scales. CONCLUSION: the Italian version of Mini-ICF-APP is a valid instrument for use in evaluating functioning in chronic patients with schizophrenia and related disorders. PMID- 26526169 TI - DNA shuffling of uricase gene leads to a more "human like" chimeric uricase with increased uricolytic activity. AB - Urate oxidase (Uox) is the enzyme involved in purine metabolism. Pseudogenization of Uox gene is the underlying mechanism of hyperuricemia and gout in human. Although Uox from various microorganisms has been used in clinical practice for many years, its application is limited by potential immunogenicity. In order to develop a more "human like" uricase, DNA shuffling was used to create chimeric uricase with both improved enzymatic activity and increased homology with deduced human uricase (dHU) gene. By using wild porcine uricase (wPU) gene and dhu as parental genes, a diverse chimeric library was generated. After preliminary screening by a "homebrew" high throughput protocol, approximately 100 chimeras with relatively high enzymatic activity were obtained. By further activity comparison of the purified enzymes, chimera-62 with increase in both activity and homology with dHU compared with wPU was selected. Its Km and catalytic efficiency were determined as 9.43+/-0.04MUM and 2.67s(-1)MUM(-1) respectively. There were 33 amino acid substitutions in chimera-62 when compared with dHU and 5 substitutions when compared with wPU. By homology modeling and 3-D structure analysis, it was speculated that mutations G248S and L266F contributed to the increased activity of chimera-62 by increasing the stability of alpha-helix and surface polarity respectively. PMID- 26526170 TI - Identification of a novel alkaline amylopullulanase from a gut metagenome of Hermetia illucens. AB - A novel pullulanase gene, PulSS4, was identified from the gut microflora of Hermetia illucens by a function-based metagenome screening. The PulSS4 gene had an open reading frame of 4455 base pairs, and encoded a mature protein of 1484 amino acids, with a signal peptide sequence of 44 amino acids. The deduced amino acid sequence of PulSS4 gene showed 51% identity with that of the amylopullulanase of Amphibacillus xylanus, exhibiting no significant sequence homology to already known pullulanases. A conserved domain analysis revealed it to be a pullulanase type II with respective active sites at the N-terminal pullulanase and C-terminal amylase domain. PulSS4 was active in the temperature range of 10-50 degrees C, with an optimum activity at 40 degrees C. It was active in the pH range of 6.5-10.5, with optimum pH at 9.0, and retained more than 80% of its original activity in a broad pH range of 5-11 for 24h at 30 degrees C. Also, PulSS4 was highly stable against many different chemical reagents, including 10% polar organic solvents and 1% non-ionic detergents. Overall, PulSS4 is expected to have the strong potential for application in biotechnological industries that require high activity at moderate temperature and alkaline conditions. PMID- 26526171 TI - Biocompatible and biodegradable poly(Tannic Acid) hydrogel with antimicrobial and antioxidant properties. AB - A novel resourceful bulk poly(Tannic Acid) (p(TA)) hydrogel was prepared by crosslinking TA molecules with an epoxy crosslinker, trimethylolpropane triglycidyl ether (TMPGDE), in an autoclave at 90 degrees C for 2h. The obtained p(TA) hydrogels were in disk form and have highly porous morphology. The swelling characteristics of p(TA) hydrogels were investigated in wound healing pH conditions of pH 5.4, 7.4, and 9 at 37.5 degrees C, and the hydrogels showed good swelling and moisture content behavior. Especially, p(TA) hydrogels were found to be sensitive to pH 9 with 1669% maximum swelling. P(TA) hydrogels were completely degraded at pH 9 hydrolytically in 9 days. Total phenol contents and the effects of scavenging ABTS(+) radicals of degraded p(TA) hydrogels at pH 5.4, 7.4, and 9 were evaluated and calculated in terms of gallic acid equivalent and trolox equivalent antioxidant capacity, respectively, and found to be very effective. Moreover, degraded p(TA) hydrogels display strong antimicrobial behavior against gram positive Staphylococcus aureus, Bacillus subtilis, gram negative Pseudomonas aeruginosa bacteria strains and Candida albicans fungus strain. The WST-1 results indicated that bulk p(TA) hydrogels have no cyctotoxicity to the L929 fibroblast cell line in vitro. PMID- 26526172 TI - Preparation and characterization of carboxymethylated carrageenan modified with collagen peptides. AB - The preparation of carboxymethyl kappa-carrageenan collagen peptide (CMKC-COP) was via an imide-bond forming reaction between carboxyl groups in carboxymethyl kappa-carrageenan (CMKC) and amino groups in collagen peptide in the presence of 1-ethyl-(dimethylaminopropyl) carbodiimide (EDC) and N-hydroxy sulfosuccinimide (NHS). CMKC-COP products were verified with infrared spectroscopy (FT-IR). The results of degree of substitution (DS) of CMKC-COP was presented, which are depended on reaction time, molar ratio of collagen peptide to carboxymethyl kappa carrageenan and reaction temperature. The optimal reaction conditions were studied by means of single factor experiment. Also MTT assay was applied to evaluate the effects of CMKC-COP on proliferation of chick embryo fibroblasts. The animal experiment results indicated that the wound covered with CMKC-COP were completely filled with new epithelium within 2 weeks without any significant adverse side reactions. Therefore, the CMKC-COP showed the potentiality to repair skin in cosmetic, biomedical and pharmaceutical fields. PMID- 26526173 TI - Production of xanthan gum by free and immobilized cells of Xanthomonas campestris and Xanthomonas pelargonii. AB - Production of xanthan gum using immobilized cells of Xanthomonas campestris and Xanthomonas pelargonii grown on glucose or hydrolyzed starch as carbon sources was investigated. Calcium alginate (CA) and calcium alginate-polyvinyl alcohol boric acid (CA-PVA) beads were used for the immobilization of cells. Xanthan titers of 8.2 and 9.2g/L were obtained for X. campestris cells immobilized in CA PVA beads using glucose and hydrolyzed starch, respectively, whereas those for X. pelargonii were 8 and 7.9 g/L, respectively. Immobilized cells in CA-PVA beads were successfully employed in three consecutive cycles for xanthan production without any noticeable degradation of the beads whereas the CA beads were broken after the first cycle. The results of this study suggested that immobilized cells are advantageous over the free cells for xanthan production. Also it was shown that the cells immobilized in CA-PVA beads are more efficient than cells immobilized in CA beads for xanthan production. PMID- 26526174 TI - Gellan gum-graft-polyaniline--An electrical conducting biopolymer. AB - Grafting of polyaniline (PANI) on to gellan gum (GG) was carried out in the presence of catalytic amount of ammonium peroxydisulfate (APS) as oxidant/initiator under mild acidic conditions by microwave irradiation technique. The grafting condition was optimized by varying the microwave power, exposure time and the composition of the reaction mixture. The graft copolymer GG g-PANI was characterized by FTIR, TGA, UV/vis, (1)H NMR and SEM techniques. The characteristic peaks at 1506, 1462, 1070 and 830 cm(-1) in the IR spectrum and signals at 7.3, 7.2, 7.1 and 4.0 delta in the (1)H NMR spectrum confirms the grafting process. The TGA data reveals GG-g-PANI to be thermally less stable than GG. The optimum grafting was observed when the reaction mixture containing 0.066 mmol APS, 0.1M aniline, 1M hydrochloric acid and 0.1g/dL GG was exposed to 80 W microwave power for 40s. The DC and AC conductivity of the GG-g-PANI were measured using the 'Two-point probe' method based on which the dielectric properties were evaluated. GG-g-PANI exhibited appreciable electrical conductivity, which increased with the extent of grafting. The results indicate threefold increase in DC conductivity of graft copolymer as compared to GG. PMID- 26526175 TI - Diagnosis of pelvic lymph node metastasis in prostate cancer using single optical fiber probe. AB - Elastic light single-scattering spectroscopy system (ELSSS) is a biomedical tool which is used for detection of cancerous tissues ex-vivo. ELSSS spectra depend primarily on the size of scatterers in the tissue and are not directly related to changes in the absorption which are caused by variations of the biological macromolecules. In the present study, we aimed to detect metastasis in the pelvic lymph node by using combination of Principal Components Analysis (PCA) and Linear Discriminant Analysis (LDA). Single-scattering spectra in the 450-750nm wavelength regions were obtained from the total of 83 reactive lymph node and 12 metastatic lymph node samples from 10 prostatic cancer patients. The ELSSS spectral data were compared against the "gold standard" histopathology results. Data analyses were done via using PCA, followed by LDA. Receiver Operating Characteristic (ROC) curve analysis was employed for differentiating performance. The classification based on discriminant score provided sensitivity of 100% and specificity of 96.4%, in differentiating non-metastatic (reactive) from metastatic pelvic lymph nodes, with a Positive Predictive Value (PPV) of 0.8, a Negative Predictive Value (NPV) of 0.99 and the area under the ROC curve (AUC) of 0.99, respectively. In this study, it was shown that ELSSS system can accurately distinguish reactive and metastatic pelvic lymph nodes of prostate cancer with high PPV and NPV. It can be concluded that diagnostic accuracy of ELSSS system allows detecting metastatic tissues during operation. PMID- 26526176 TI - Different intracellular signalling pathways triggered by an anti-prolactin receptor (PRLR) antibody: Implication for a signal-specific PRLR agonist. AB - In this work, we prepared a panel of monoclonal antibodies directed against prolactin receptor (PRLR) using the hybridoma technique. Of these monoclonal antibodies (Mabs), the Mab designated B6 was chosen for further characterization based on its biological activity. We first demonstrated that B6 can specifically bind to the prolactin receptor (PRLR) expressed on target cells by immunoprecipitation and Western blotting analysis. Subsequently, epitope mapping studies using a competitive receptor-binding assay indicated that B6 epitopes partially overlapped with those of prolactin (PRL). We then examined the resulting signal transduction pathways activated by this antibody in T-47D and CHO-PRLR cells and found that B6 induced different intracellular signalling compared with prolactin, which activates serine-threonine kinase (AKT), extracellular signal-regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription1 (STAT1) and STAT3 but not STAT5. The present study suggests that: (a) B6 may be a signal-specific prolactin receptor (PRLR) agonist; (b) B6 may be a biological reagent that can be used to explore the mechanism of PRLR-mediated intracellular signalling. In addition, this work also implies a strategy for preparing signal-specific cytokine agonists. PMID- 26526177 TI - Optimised extraction of Erythronium sibiricum bulb polysaccharides and evaluation of their bioactivities. AB - In this study, the extraction of Erythronium sibiricum bulb polysaccharides (ESBP) through hot water decoction was optimised using response surface methodology (RSM) and a three-level, four-factor Box-Behnken design. The optimum extraction conditions were as follows: extraction time of 4.28h, extraction temperature of 90 degrees C, ratio of liquid to raw material of 37 mL/g and extraction cycle number of three. The experimental yield (37.25%+/-0.17%) agreed with the predicted value of the RSM model (37.465%). Preliminary ESBP characterisation was conducted through physicochemical analysis. Biological activity test results showed that ESBP exhibited antioxidant activities and excellent anti-inflammatory and analgesic activities, indicating its potential as an anti-inflammatory and analgesic agent. PMID- 26526178 TI - Beta-chitosan extracted from Loligo Japonica for a potential use to inhibit Newcastle disease. AB - Beta-chitosan has a parallel structure, which differs from alpha-chitosan's antiparallel structure while producing different properties and difficulties. In this paper, we prepared the beta-chitosan through acid and alkali methods and the resultant material was characterized by elemental analysis, FT-IR, HPLC, XRD, NMR and AFS. To increase the solubility and biological activity of the beta-chitosan, we degraded it through microwave-assisted process. After characterization, we determined that the chitosan had not changed its configuration during the reaction with H2O2 under microwave irradiation. The inhibitory activity of the degraded chitosan for Newcastle disease was revealed by a hemagglutination test and RT-PCR. The yield of the beta-chitosan was approximately 30%, and its molecular weight can be degraded to 1000 to 10,000g/mol. Moreover, the degraded beta-chitosan has higher antiviral activity, reducing the hemagglutination titre to zero, compared with alpha-chitosan. Therefore, beta-chitosan has good development prospects during the development of veterinary drugs for Newcastle disease. PMID- 26526179 TI - Novel alkali-thermostable xylanase from Thielaviopsis basicola (MTCC 1467): Purification and kinetic characterization. AB - A novel extracellular alkali-thermostable xylanase was purified to an apparent homogeneity from the submerged fermented culture filtrate of Thielaviopsis basicola MTCC 1467, wherein, the fungus was fed with rice straw as prime carbon source. SDS-PAGE analysis of the xylanase showcased molecular weight of ~ 32 kDa. This extracellular protein macromolecule had maximum xylanolytic activity at pH 5.5 and 60 degrees C, and was stable in the range of pH 5.0-10.0 for 5 days retaining >70% activity. The enzyme was stable at 30-50 degrees C for 5h retaining >85% activity and further by retaining 70% activity at 60 degrees C for 2h. The enzyme deactivation constants (kd) were in range of 0.41-1.3. The kinetic experiments specified that the enzyme had Km and Vmax values of 1.447 +/- 0.22 mg mL(-1) and 60.04 +/- 1.25 IU mL(-1), respectively, for xylan. The purified xylanase was significantly inhibited by Cu(2+) and Zn(2+) (~ 58%), whilst Ca(2+) and Na(+) ions displayed partial inhibition (<8%) Intriguingly, the K(+) and Mn(2+) ions enhanced the activity by about ~ 10%. Both SDS and EDTA reduced its activity by ~ 20%. PMID- 26526180 TI - Compliance monitor for scoliosis braces in clinical practice. PMID- 26526181 TI - Optimizing Radiation Safety in the Cardiac Catheterization Laboratory: A Practical Approach. AB - Reducing radiation exposure during cardiovascular catheterization is of paramount importance for both patient and staff safety. Over the years, advances in equipment and application of radiation safety protocols have significantly reduced patient dose and operator exposure. This review examines the current status of radiation protection in the cardiac and vascular catheterization laboratory and summarizes best practices for minimizing radiation exposure. PMID- 26526182 TI - Jerry can carriage is an effective predictor of stretcher carry performance. AB - Carrying a casualty on a stretcher is a critical task conducted in a range of occupations. To ensure that personnel have the requisite physical capacity to conduct this task, two bilateral jerry can carries were used to predict individual performance in a four-person stretcher carry. Results demonstrated a bilateral 22-kg jerry can carry (R(2) = 0.59) had superior predictive ability of stretcher carry performance than a bilateral 15-kg jerry can carry (R(2) = 0.46). Pre- to post-carry changes in grip endurance (p > 0.05), back-leg isometric strength (p > 0.05) and leg power (p > 0.05) were not significantly different between carry tasks. There was no significant difference in heart rate (p > 0.05) and oxygen consumption (p > 0.05) between the stretcher carry and either jerry can carry. Thus, on the basis of performance correlations and physiological measures, the 22-kg jerry can carry is an appropriate predictive assessment of four-person stretcher carriage. Practitioner Summary: This study investigated the ability of a jerry can carry to predict individual performance on a four-person stretcher carry. Performance correlations were substantiated with physiological measures to demonstrate similar physical requirements between task and test. These results can be used to set physical employment standards to assess stretcher carriage. PMID- 26526183 TI - The spread of bla OXA-48 and bla OXA-244 carbapenemase genes among Klebsiella pneumoniae, Proteus mirabilis and Enterobacter spp. isolated in Moscow, Russia. AB - BACKGROUND: The spread of carbapenemase-producing Enterobacteriaceae (CPE) is a great problem of healthcare worldwide. Study of the spread for bla OXA-48-like genes coding epidemically significant carbapenemases among hospital pathogens is important for the regional and global epidemiology of antimicrobial resistance. METHODS: Antibacterial resistant isolates of Klebsiella pneumoniae (n = 95) from 54 patients, P. mirabilis (n = 32) from 20 patients, Enterobacter aerogenes (n = 6) from four patients, and Enterobacter cloacae (n = 4) from four patients were collected from January, 2013 to October, 2014 in neurosurgical intensive care unit (ICU) of the Burdenko Neurosurgery Institute, Moscow. Characteristics of the isolates were done using susceptibility tests, PCR detection of the resistance genes, genotyping, conjugation, DNA sequencing, and bioinformatic analysis. RESULTS: Major strains under study were multi drug resistant (MDR), resistant to three or more functional classes of drugs simultaneously-98.9 % K. pneumoniae, 100 % P. mirabilis, one E. aerogenes isolate, and one E. cloacae isolate. Molecular-genetic mechanism of MDR in K. pneumoniae and P. mirabilis isolates were based on carrying of epidemic extended-spectrum beta-lactamase bla CTX-M-15 gene (87.2 and 90.6 % accordingly), carbapenemase bla OXA-48-like gene (55.3 and 23.3 % accordingly), and class 1 (54.8 and 31.3 % accordingly) and class 2 (90.6 % P. mirabilis) integrons. The bla OXA-48-like-positive K. pneumoniae were collected during whole two-year surveillance period, while P. mirabilis and Enterobacter spp. carrying bla OXA-48-like genes were detected only after four and 18 months after the research start, respectively. The bla OXA-48-like gene acquisition was shown for P. mirabilis isolates collected from five patients and for E. cloacae isolate collected from one patient during their stay in the ICU, presumably from bla OXA-48-like-positive K. pneumoniae. The source of the bla OXA 244 gene acquired by E. aerogenes isolates and the time of this event were not recognized. CONCLUSIONS: The expanding of CPE in the surveyed ICU was associated with the spread of bla OXA-48 and bla OXA-244 carbapenemase genes documented not only among K. pneumoniae, well-known bacterial host for such genes, but among P. mirabilis, E. aerogenes, and E. cloacae. PMID- 26526184 TI - Determinants of demand for condoms to prevent HIV infections among barmaids and guesthouse workers in two districts, Tanzania. AB - BACKGROUND: Condoms are scientifically recommended as potential products for preventing infections attributable to human immuno-deficiency viruses (HIV). However, evidence on factors leading to their inadequate use in developing countries is still scanty. This paper reports an exploratory study of factors constraining condoms use in Tanzania from the perspectives of barmaids, guest house workers and retailers. METHODS: Data were collected in two districts Mpwapwa in Dodoma Region and Mbeya Rural in Mbeya Region-between October and December 2011, using structured interviews with 238 individuals including barmaids, guesthouse workers and 145 retailers. Data analysis was performed using STATA 11 software. RESULTS: Awareness about condoms was high among all study groups. Male condoms were more popular and available than female ones. A considerable proportion of the barmaids and guesthouses were disappointed with condoms being promoted and distributed to young children and disliked condom use during sexual intercourse. Accessibility of condoms was reported as being lowered by condom prices, shortage of information concerning their availability; short supply of condoms; some people shying away to be watched by children or adult people while purchasing condoms; retailers' using bad languages to condom customers; occasionally condom shops/kiosks found closed when they are urgently needed; and prevailing social perception of condoms to have low/no protective efficacy. Regression analysis of data from barmaids and guesthouse-workers indicated variations in the degree of condom acceptability and methods used to promote condoms among respondents with different demographic characteristics. CONCLUSION: A combination of psychosocial and economic factors was found contributing to lower the demand for and actual use of condoms in study communities. Concerted measures for promoting condom use need to address the demand challenges and making operational research an integral element of monitoring and evaluation of the launched interventions, hence widening the evidence for informed policy decisions. PMID- 26526185 TI - How neurologists are paid: Part 3: Hospital support, Veterans Administration, and neurohospitalists. AB - Part 1 of this series focused on factors influencing payment for patient care services and Part 2 described compensation plans for neurologists in private practice and in academic medicine. In Part 3, we review how hospital salary support and appointments to Veterans Administration hospitals contribute to the salary structure of neurologists. We also discuss neurohospitalist care and ways neurologists can potentially increase compensation from on-call pay, telemedicine, and the use of new transitional care and complex chronic care codes. We conclude with an emphasis on the important role of neurologists as team players in a health care system that will rely on efficient coordination of care among many health care workers. PMID- 26526186 TI - The development and delivery of a female chronic pelvic pain management programme: a specialised interdisciplinary approach. AB - CONTEXT/BACKGROUND: Chronic pelvic pain (CPP) is a physically and psychologically debilitating condition. European Association of Urology (EAU) Guidelines (2013) and Royal College of Obstetricians and Gynaecologists (RCOG) guidelines (2012) place strong emphasis upon multi-speciality assessment and liaison, as well as interdisciplinary assessment and intervention in reference to the management of CPP. OBJECTIVES: The aim was to introduce and describe the development and delivery of an interdisciplinary pain management programme (PMP), at a Specialised Pain Management Centre in Liverpool, United Kingdom, for women diagnosed with CPP. METHOD: The format and content of the CPP PMP at The Walton Centre, Liverpool, is described and the preliminary results from the CPP PMP are presented. RESULTS: Preliminary data suggest that outcomes on the specialised CPP PMP indicate that patients are able to make clinically important change across a range of outcome measures. Moreover, these results compare favourably to the established PMP for generalised chronic pain when comparing clinically significant outcomes with the Walton Centre's (a tertiary-level pain management centre) 2013 PMP Audit document. Patients attending the CPP PMP positively appraised the PMP and felt it was useful and supportive to be in a group dedicated to CPP. CONCLUSIONS: This article presents some preliminary results that suggest there is value in delivering a specialised multidisciplinary PMP for this group. There is a clear need for further clinical research into the effectiveness of similar interventions for CPP, including the early identification of those CPP patients who may benefit from both multi-specialty and interdisciplinary management. PMID- 26526187 TI - Gray matter structural compromise is equally distributed in left and right temporal lobe epilepsy. AB - In drug-resistant temporal lobe epilepsy (TLE), MRI studies have shown consistent mesiotemporal and neocortical structural alterations when comparing patients to healthy controls. It remains, however, relatively unclear whether the side of seizure focus differentially impacts the degree of structural damage. This work performed a comprehensive surface-based analysis of mesiotemporal and neocortical morphology on preoperative 1.5 T MRI in 25/35 LTLE/RTLE patients that achieved seizure freedom after surgery (i.e., Engel-I outcome; 7 +/- 2 years follow-up), an imaging-independent confirmation of focus lateralization. Compared to 46 age- and sex-matched controls, both TLE groups displayed marked ipsilateral atrophy in mesiotemporal regions, while cortical thinning was bilateral. Direct contrasts between LTLE and RTLE did not reveal significant differences. Bootstrap simulations indicated low reproducibility of observing a between-cohort difference; power analysis revealed that more than 110 patients would be necessary to detect subtle differences. No difference between LTLE and RTLE was confirmed when using voxel-based morphometry, an independent proxy of gray matter volume. Similar results were obtained analyzing a separate 3 T dataset (15/15 LTLE/RTLE patients; Engel-I after 4 +/- 2 years follow-up; 42 controls). Our results strongly support equivalent gray matter compromise in left and right TLE. The morphological profile of seizure-free patients, presenting with ipsilateral mesiotemporal and bilateral cortical atrophy, motivates the development of neuromarkers of outcome that consider both mesiotemporal and neocortical structures. Hum Brain Mapp 37:515-524, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26526188 TI - Carriage of CTX-M type extended spectrum beta-lactamases (ESBLs) in gulls across Europe. AB - BACKGROUND: Extended spectrum beta-lactamases (ESBLs), a group of enzymes conferring resistance to third generation cephalosporins have rapidly increased in Enterobacteriacae and pose a major challenge to human health care. Resistant isolates are common in domestic animals and clinical settings, but prevalence and genotype distribution varies on a geographical scale. Although ESBL genes are frequently detected in bacteria isolated from wildlife samples, ESBL dissemination of resistant bacteria to the environment is largely unknown. To address this, we used three closely related gull species as a model system and collected more than 3000 faecal samples during breeding times in nine European countries. Samples were screened for ESBL-producing bacteria, which were characterized to the level of ESBL genotype groups (SHV, TEM), or specific genotypes (CTX-M). RESULTS: ESBL-producing bacteria were frequently detected in gulls (906 of 3158 samples, 28.7 %), with significant variation in prevalence rates between countries. Highest levels were found in Spain (74.8 %), The Netherlands (37.8 %) and England (27.1 %). Denmark and Poland represented the other extreme with no, or very few positive samples. Genotyping of CTX-M isolates identified 13 different variants, with bla CTX-M-1 and bla CTX-M-14 as the most frequently detected. In samples from England, Spain and Portugal, bla CTX-M-14 dominated, while in the rest of the sampled countries bla CTX-M-1 (except Sweden where bla CTX-M-15 was dominant) was the most frequently detected genotype, a pattern similar to what is known from studies of human materials. CONCLUSIONS: CTX-M type ESBLs are common in the faecal microbiota from gulls across Europe. The gull ESBL genotype distribution was in large similar to published datasets from human and food-production animals in Europe. The data suggests that the environmental dissemination of ESBL is high from anthropogenic sources, and widespread occurrence of resistant bacteria in common migratory bird species utilizing urban and agricultural areas suggests that antibiotic resistance genes may also be spread through birds. PMID- 26526189 TI - Serum levels of valproic acid during delivery in mothers and in umbilical cord - correlation with birth length and weight. AB - AIMS: The data on the valproic acid transplacental transfer and risk to the fetus of exposure, remain sparse and only a limited number of studies have reported umbilical cord blood levels. MATERIALS AND METHODS: Maternal and umbilical cord serum levels were analyzed at delivery in a cohort of 58 women, between the years 1991 - 2013. The request forms for routine therapeutic drug monitoring were used as the data source. Maternal levels and dosing information were used for estimating the maternal apparent oral clearance and the paired umbilical cord and maternal levels for estimation of umbilical cord/maternal level ratios. RESULTS: The levels varied from 5.3 - 59.5 mg/L in maternal and 5.4 - 72.1 mg/L in umbilical cord serum. The umbilical cord/maternal level ratios ranged from 0.64 - 2.49. Significant correlation was found between maternal and umbilical cord levels. Significant inverse correlations were found between birth length, and both maternal and umbilical cord levels in monotherapy. CONCLUSIONS: There were large individual variations in umbilical cord/maternal level ratios of valproic acid. Neonatal length and weight were inversely related to maternal and umbilical cord levels, but not to dose. Therefore, therapeutic drug monitoring in mothers is more useful than the given dose for the estimation of fetal exposure and minimization of the risk of fetal effects. PMID- 26526190 TI - Patient survival, predictive factors and disease course of severe sepsis in Czech intensive care units: A multicentre, retrospective, observational study. AB - BACKGROUND: Severe sepsis/septic shock is associated with high mortality. In Central Europe, there is a dearth of information on the prevalence and treatment of severe sepsis. The EPOSS (Data-based Evaluation and Prediction of Outcome in Severe Sepsis) project launched in 2011 was aimed at collecting data on patients with severe sepsis/septic shock. METHODS: The EPOSS study processes data from the EPOSS project database, and is a retrospective, multicentre, observational study. This included all consecutive patients aged 18 and over who were admitted to participating ICUs from 1 January 2011 to 5 November 2013 and met the inclusion criteria of severe sepsis/septic shock. The primary endpoint was to analyse the relationship between in-hospital mortality (either in ICU or after discharge from ICU) and the type and number of fulfilled diagnostic and treatment interventions during the first 6 h after the diagnosis of severe sepsis/septic shock. RESULTS: The collected dataset involved 1082 patients meeting the criteria of severe sepsis/septic shock. Following data validation, a final dataset of 897 patients was obtained. The average age of the patient group was 64.7 years; mortality at discharge from EPOSS ICUs was 35.5% and from hospital 40.7%. Of the 10 evaluated diagnostic and treatment interventions within the initial 6 hours of identifying severe sepsis/septic shock (i.e. fulfilment of SSC bundles), four or five diagnostic and treatment interventions were administered to 58.4% patients. Combined diagnostic and treatment interventions associated with the lowest in hospital mortality were: CVP of >=8-12 mm Hg & MAP of >=65 mm Hg & Urine output at >=0.5 mL/kg/h & Lactate of <=4.0 mmol/L & Initial lactate measured & Antibiotics in the first hour. Lactate at <4 mmol/L and MAP of >=65 mm Hg remained statistically significant even after adjustment for patient age and APACHE II score. Statistically significantly increased in-hospital mortality was found in patients admitted from general departments (45.7%) or from other ICUs (41.6%), compared to a lower in-hospital mortality of patients transferred from outpatient clinics (26.5%) or Emergency (38.0%). Severe sepsis/septic shock patients transferred from the department of internal medicine were associated with a higher in-hospital mortality (45.1%) than surgical patients (35.5%). CONCLUSIONS: The most effective measures associated with the lowest in-hospital mortality in septic shock patients were CVP of >=8-12 mm Hg, MAP of >=65 mm Hg, urine output at >=0.5 mL/kg/h, initial lactate level of <=4.0 mmol/L and administration of antibiotics within the first hour. PMID- 26526191 TI - Relationship between obesity and clinical outcome in adults with acute myeloid leukemia: A pooled analysis from four CALGB (alliance) clinical trials. AB - Obesity has been previously suggested as an adverse prognostic marker in patients with acute leukemia. To evaluate the relationship between obesity and clinical outcome, disease-free survival (DFS) and overall survival (OS), in patients with acute myelogenous leukemia (AML), including acute promyelocytic leukemia (APL), we performed a pooled analysis of four CALGB (Alliance) clinical trials. Our study included 446 patients with APL from CALGB 9710, and 1,648 patients between 18 and 60 years of age with non-APL AML from CALGB 9621, 10503, and 19808. Obesity was defined as BMI >=30 kg/m(2). Multivariate Cox proportional-hazard regression models were fitted for DFS and OS. Obesity was seen in 50% and 38% of APL and non-APL AML patients, respectively. In APL patients, obesity was associated with worse DFS (HR 1.53, 95% CI 1.03-2.27; P = 0.04) and OS (HR 1.72, 95% CI 1.15-2.58; P = 0.01) after adjusting for age, sex, performance status, race, ethnicity, treatment arm and baseline white blood cell count. Obesity was not significantly associated with DFS or OS in the non-APL AML patients. In conclusion, our study indicates that obesity has significant prognostic value for DFS and OS in APL patients, but not for non-APL AML patients. PMID- 26526192 TI - Proteome analysis of the almond kernel (Prunus dulcis). AB - BACKGROUND: Almond (Prunus dulcis) is a popular tree nut worldwide and offers many benefits to human health. However, the importance of almond kernel proteins in the nutrition and function in human health requires further evaluation. The present study presents a systematic evaluation of the proteins in the almond kernel using proteomic analysis. RESULTS: The nutrient and amino acid content in almond kernels from Xinjiang is similar to that of American varieties; however, Xinjiang varieties have a higher protein content. Two-dimensional electrophoresis analysis demonstrated a wide distribution of molecular weights and isoelectric points of almond kernel proteins. A total of 434 proteins were identified by LC MS/MS, and most were proteins that were experimentally confirmed for the first time. Gene ontology (GO) analysis of the 434 proteins indicated that proteins involved in primary biological processes including metabolic processes (67.5%), cellular processes (54.1%), and single-organism processes (43.4%), the main molecular function of almond kernel proteins are in catalytic activity (48.0%), binding (45.4%) and structural molecule activity (11.9%), and proteins are primarily distributed in cell (59.9%), organelle (44.9%), and membrane (22.8%). CONCLUSION: Almond kernel is a source of a wide variety of proteins. This study provides important information contributing to the screening and identification of almond proteins, the understanding of almond protein function, and the development of almond protein products. (c) 2015 Society of Chemical Industry. PMID- 26526194 TI - Blood glucose monitoring had no impact on distress or self-efficacy in people with non-insulin-treated type 2 diabetes. PMID- 26526193 TI - Immunogenicity of twenty peptides representing epitopes of the hepatitis B core and surface antigens by IFN-gamma response in chronic and resolved HBV. AB - BACKGROUND: Patients with chronic hepatitis B virus infection (CHB) usually mount a modest T cell response against HBV epitopes. In order to determine immunogenic epitopes of HBV recognized by HBV-specific T cells, previous studies focused on previously confirmed HBV epitopes and assessed the T cell response by the number of HBV-specific T cells by IFN-gamma ELISPOT. METHODS: We studied T cell functionality by combined in silico methods predicting HBV-specific epitopes and experimental investigations on the recognition of these epitopes. 30 chronic CHB patients and 10 patients with resolved HBV (RHB) were included in the study. We identified epitopes from the literature and by in silico analysis. These were evaluated for immunogenicity by use of synthetic peptides representing the epitopes through exposure to PBMCs from patients with CHB or RHB by IFN-gamma ELISPOT. The number of IFN-gamma producing cells (SFC), mean spot size (MSS) and stimulation index (SI) were recorded. RESULTS: The frequency of HBV-specific T cells producing IFN-gamma after stimulation with HBV epitopes was similar in CHB and RHB patients. CHB patients had a higher MSS SI than RHB patients. Patients not carrying the HLA-A2 genotype had higher SFC SI and MSS SI. Patients with HLA A11 had higher MSS SI compared to non- HLA-A11 allele patients. HBeAg-positive patients had a lower MSS SI, and none of the HBeAg positive patients had the HLA A11 genotype. We found 3 immunogenic epitopes not described previously. CONCLUSION: IFN-gamma ELISPOT-determined MSS is an efficient marker for T cell recognition of epitopes. This experimental measure showed the in silico analysis for epitope prediction to be a valuable tool in future studies on HLA genotypes and HBV epitopes. This way our study now points to previously unappreciated consequences of carrying the HLA-A11 allele in terms of stronger immunity to HBV. PMID- 26526195 TI - Chitosan membranes for tissue engineering: comparison of different crosslinkers. AB - Chitosan (CS), a derivative of the naturally occurring biopolymer chitin, is an attractive material for biomedical applications thanks to its biocompatibility, biodegradability, antibacterial properties and ability to enhance cell adhesion and growth compared to other biopolymers. However, the physical and mechanical stability of CS based materials in aqueous solutions is limited and crosslinking agents are required to increase CS performances in a biological environment. In this work, the effect of three highly-biocompatible crosslinkers as genipin (GP), gamma-glycidoxypropyltrimethoxysilane (GPTMS), dibasic sodium phosphate (DSP) and a combination of GPTMS and DSP (GPTMS_DSP) on CS physicochemical, thermal, morphological, mechanical properties, swelling and degradation behavior was investigated. Infrared spectroscopy and thermogravimetric analyses confirmed the chemical reaction between CS and the different crosslinkers. CS wettability was enhanced when CS was DSP ionically crosslinked showing contact angle values of about 65 degrees and exhibiting a higher swelling behavior compared to covalently crosslinked films. Moreover, all the crosslinking methods analyzed improved the stability of CS in aqueous media, showed model molecule permeation in time and increased the mechanical properties when compared with non crosslinked films. The possibility to tailor the final properties of CS scaffolds through crosslinking is a key strategy in applying CS in different biomedical and tissue engineering applications. The obtained results reveal that the optimization of the crosslinking mechanism provides CS membrane properties required in different biomedical applications. PMID- 26526196 TI - Targeting glycolysis by 3-bromopyruvate improves tamoxifen cytotoxicity of breast cancer cell lines. AB - BACKGROUND: Tamoxifen is the standard endocrine therapy for ER+ breast cancer; however, many women still relapse after long-term therapy. 3-Bromopyruvate, a glycolytic inhibitor, has shown high selective anti-tumor activity in vitro, and in vivo. The aim of this study was to evaluate the possible augmentation of the effect of tamoxifen via reprograming cancer cell metabolism using 3 bromopyruvate. METHODS: An in vitro screening of antitumor activity as well as the apoptotic, anti-metastatic, and anti-angiogenic potentials of the combination therapy were carried out using different techniques on breast cancer cell lines MCF7and T47D. In addition the antitumor effect of the combined therapy was done on mice bearing tumor. RESULTS: Our results showed modulation in apoptosis, angiogenesis and metastatic potential by either drug alone; however, their combination has surpassed that of the individual one. Combination regimen enhanced activated caspases-3, 7 and 9, as well as oxidative stress, signified by increased malondialdehyde and decreased glutathione level. Additionally, the angiogenesis and metastasis markers, including hypoxia inducing factor-1alpha, vascular endothelia growth factor, and metaloproteinases-2 and 9 were decreased after using the combination regimen. These results were further confirmed by the in vivo study, which depicted a decrease in the tumor volume and angiogenesis and an increase in oxidative stress as well. CONCLUSION: 3-bromopyruvate could be a valuable compound when added with tamoxifen in breast cancer treatment. PMID- 26526199 TI - The cell factory approach toward biotechnological production of high-value chitosan oligomers and their derivatives: an update. AB - Chitin is one of the most abundant renewable resources, and chitosans, the partially deacetylated derivatives of chitin, are among the most promising functional biopolymers, with superior material properties and versatile biological functionalities. Elucidating molecular structure-function relationships and cellular modes of action of chitosans, however, it is challenging due to the micro-heterogeneity and structural complexity of polysaccharides. Lately, it has become apparent that many of the biological activities of chitosan polymers, such as in agricultural plant disease protection or in mediating scar-free wound healing, may be attributed to oligomeric break down products generated by the action of chitosanolytic hydrolases present in the target tissues, such as human chitotriosidase. Consequently, the focus of current research is shifting toward chitosan oligomers so that the availability of well defined chitosan oligosaccharides (COS) becomes a bottleneck. Well-known ways of producing COS use physical and/or chemical means for the partial depolymerization of chitosan polymers, typically leading to broad mixtures of COS varying in their degrees of polymerization (DP) and acetylation (DA), and with more or less random patterns of acetylation (PAs). Even after chromatographic separation according to DP and DA, such mixtures are of limited value to elucidate structure-function relationships and modes of action. More recently, enzymatic means using chitinases and/or chitosanases, and sometimes chitin deacetylases, have been proposed as these can be more tightly controlled and yield slightly better defined mixtures of COS. An alternative would be chemical synthesis of COS which in principle would allow for full structural control, but protocols for it are lengthy, costly, and not yet well developed, and yields are low. Synthetic biology now allows to develop today's in vitro bio-refinery approaches into in vivo cell factory approaches for the biotechnological production of defined COS using recombinant microbial strains expressing chitin oligomer synthases and chitin oligomer deacetylases. In this review, we will describe the state-of-the art of this cell factory approach, as a basis for upcoming developments. We will briefly describe traditional chemical protocols and enzymatic production of COS as a background to the more detailed presentation of what has been achieved through in vivo biosynthesis. We will only briefly describe those as a background to the more detailed presentation of what has been achieved through in vivo biosynthesis. We will also touch on the production of COS derivatives that has been achieved in this way, as these oligomers open up another plethora of potential applications when used as building blocks for defined biomaterials. PMID- 26526197 TI - DAAM1 and DAAM2 are co-required for myocardial maturation and sarcomere assembly. AB - Wnt ligands regulate heart morphogenesis but the underlying mechanisms remain unclear. Two Formin-related proteins, DAAM1 and 2, were previously found to bind the Wnt effector Disheveled. Here, since DAAM1 and 2 nucleate actin and mediate Wnt-induced cytoskeletal changes, a floxed-allele of Daam1 was used to disrupt its function specifically in the myocardium and investigate Wnt-associated pathways. Homozygous Daam1 conditional knockout (CKO) mice were viable but had misshapen hearts and poor cardiac function. The defects in Daam1 CKO mice were observed by mid-gestation and were associated with a loss of protrusions from cardiomyocytes invading the outflow tract. Further, these mice exhibited noncompaction cardiomyopathy (NCM) and deranged cardiomyocyte polarity. Interestingly, Daam1 CKO mice that were also homozygous for an insertion disrupting Daam2 (DKO) had stronger NCM, severely reduced cardiac function, disrupted sarcomere structure, and increased myocardial proliferation, suggesting that DAAM1 and DAAM2 have redundant functions. While RhoA was unaffected in the hearts of Daam1/2 DKO mice, AKT activity was lower than in controls, raising the issue of whether DAAM1/2 are only mediating Wnt signaling. Daam1-floxed mice were thus bred to Wnt5a null mice to identify genetic interactions. The hearts of Daam1 CKO mice that were also heterozygous for the null allele of Wnt5a had stronger NCM and more severe loss of cardiac function than Daam1 CKO mice, consistent with DAAM1 and Wnt5a acting in a common pathway. However, deleting Daam1 further disrupted Wnt5a homozygous-null hearts, suggesting that DAAM1 also has Wnt5a-independent roles in cardiac development. PMID- 26526198 TI - PTEN is required to maintain luminal epithelial homeostasis and integrity in the adult mammary gland. AB - In the mammary gland, PTEN loss in luminal and basal epithelial cells results in differentiation defects and enhanced proliferation, leading to the formation of tumors with basal epithelial characteristics. In breast cancer, PTEN loss is associated with a hormone receptor-negative, basal-like subtype that is thought to originate in a luminal epithelial cell. Here, we show that luminal-specific PTEN loss results in distinct effects on epithelial homeostasis and mammary tumor formation. Luminal PTEN loss increased proliferation of hormone receptor-negative cells, thereby decreasing the percentage of hormone receptor-positive cells. Moreover, luminal PTEN loss led to misoriented cell divisions and mislocalization of cells to the intraluminal space of mammary ducts. Despite their elevated levels of activated AKT, Pten-null intraluminal cells showed increased levels of apoptosis. One year after Pten deletion, the ducts had cleared and no palpable mammary tumors were detected. These data establish PTEN as a critical regulator of luminal epithelial homeostasis and integrity in the adult mammary gland, and further show that luminal PTEN loss alone is not sufficient to promote the progression of mammary tumorigenesis. PMID- 26526200 TI - Shenqi fuzheng injection attenuates irradiation-induced brain injury in mice via inhibition of the NF-kappaB signaling pathway and microglial activation. AB - AIM: Radiation-induced brain injury (RIBI) is the most common and severe adverse effect induced by cranial radiation therapy (CRT). In the present study, we examined the effects of the traditional Chinese medicine Shenqi Fuzheng Injection (SFI) on RIBI in mice, and explored the underlying mechanisms. METHODS: C57BL/6J mice were subjected to a single dose of 20-Gy CRT. The mice were treated with SFI (20 mL.kg(-1).d(-1), ip) for 4 weeks. Morris water maze test was used to assess the cognitive changes. Evans blue leakage and a horseradish peroxidase (HRP) assay were used to evaluate the integrity of the blood-brain barrier (BBB). The expression of inflammatory factors and microglial activation in brain tissues were detected using RT-PCR, Western blotting and immunofluorescence staining. RESULTS: CRT caused marked reductions in the body weight and life span of the mice, and significantly impaired their spatial learning. Furthermore, CRT significantly increased the BBB permeability, number of activated microglia, expression levels of TNF-alpha and IL-1beta, and the levels of phosphorylated p65 and PIDD-CC (the twice-cleaved fragment of p53-induced protein with a death domain) in the brain tissues. Four-week SFI treatment (administered for 2 weeks before and 2 weeks after CRT) not only significantly improved the physical status, survival, and spatial learning in CRT-treated mice, but also attenuated all the CRT-induced changes in the brain tissues. Four-week SFI pretreatment (administered for 4 weeks before CRT) was less effective. CONCLUSION: Administration of SFI effectively attenuates irradiation-induced brain injury via inhibition of the NF-kappaB signaling pathway and microglial activation. PMID- 26526201 TI - Metabolic alterations in the sera of Chinese patients with mild persistent asthma: a GC-MS-based metabolomics analysis. AB - AIM: To character the specific metabolomics profiles in the sera of Chinese patients with mild persistent asthma and to explore potential metabolic biomarkers. METHODS: Seventeen Chinese patients with mild persistent asthma and age- and sex-matched healthy controls were enrolled. Serum samples were collected, and serum metabolites were analyzed using GC-MS coupled with a series of multivariate statistical analyses. RESULTS: Clear intergroup separations existed between the asthmatic patients and control subjects. A list of differential metabolites and several top altered metabolic pathways were identified. The levels of succinate (an intermediate in tricarboxylic acid cycle) and inosine were highly upregulated in the asthmatic patients, suggesting a greater effort to breathe during exacerbation and hypoxic stress due to asthma. Other differential metabolites, such as 3,4-dihydroxybenzoic acid and phenylalanine, were also identified. Furthermore, the differential metabolites possessed higher values of area under the ROC curve (AUC), suggesting an excellent clinical ability for the prediction of asthma. CONCLUSION: Metabolic activity is significantly altered in the sera of Chinese patients with mild persistent asthma. The data might be helpful for identifying novel biomarkers and therapeutic targets for asthma. PMID- 26526202 TI - tRNA methyltransferase homologue gene TRMT10A mutation in young adult-onset diabetes with intellectual disability, microcephaly and epilepsy. AB - BACKGROUND: A syndrome of young-onset diabetes mellitus associated with microcephaly, epilepsy and intellectual disability caused by mutations in the tRNA methyltransferase 10 homologue A (TRMT10A) gene has recently been described. CASE REPORT: We report two siblings from the fourth family reported to have diabetes mellitus as a result of a TRMT10A mutation. A homozygous nonsense mutation p.Glu27Ter in TRMT10A was identified using targeted next-generation sequencing and confirmed by PCR/Sanger sequencing. Diabetes was diagnosed while the subjects were in their 20s and was characterized by insulin resistance. Epilepsy and intellectual disability were features in common. Mild microcephaly was present at birth but their final head circumferences were normal. CONCLUSION: Our report provides independent confirmation of the role of TRMT10A mutations in this syndrome and expands its phenotypic description. TRMT10A sequencing should be considered in children or adults with young-onset diabetes who have a history of intellectual disability, microcephaly and epilepsy. This report also shows the advantages of using a targeted panel to identify previously unsuspected monogenic diabetes among young-onset non-insulin-dependent diabetes in the absence of obesity and autoimmunity. PMID- 26526203 TI - Enteric glia: A new player in inflammatory bowel diseases. AB - In addition to the well-known involvement of macrophages and neutrophils, other cell types have been recently reported to substantially contribute to the onset and progression of inflammatory bowel diseases (IBD). Enteric glial cells (EGC) are the equivalent cell type of astrocyte in the central nervous system (CNS) and share with them many neurotrophic and neuro-immunomodulatory properties. This short review highlights the role of EGC in IBD, describing the role played by these cells in the maintenance of gut homeostasis, and their modulation of enteric neuronal activities. In pathological conditions, EGC have been reported to trigger and support bowel inflammation through the specific over-secretion of S100B protein, a pivotal neurotrophic factor able to induce chronic inflammatory changes in gut mucosa. New pharmacological tools that may improve the current therapeutic strategies for inflammatory bowel diseases (IBD), lowering side effects (i.e. corticosteroids) and costs (i.e. anti-TNFalpha monoclonal antibodies) represent a very important challenge for gastroenterologists and pharmacologists. Novel drugs capable to modulate enteric glia reactivity, limiting the pro-inflammatory release of S100B, may thus represent a significant innovation in the field of pharmacological interventions for inflammatory bowel diseases. PMID- 26526204 TI - Increased serum IgM, immunodeficiency, and autoimmunity: A clinical series. AB - BACKGROUND: Primary immunodeficiencies (PIDs) are generally characterized by recurrent infections; however they may be complicated by other clinical disorders such as allergy, autoimmunity, and lymphoproliferation. In particular, autoimmunity may be the first manifestation of the disease in patients with low serum immunoglobulins (Ig) levels. Here we describe a group of patients that share features of immunodeficiency and autoimmunity. MATERIALS AND METHODS: All patients went through a complete T and B cell subset characterization and a B cell function analysis in the peripheral blood by flow-cytometry. B cell proliferation and plasma cell differentiation was measured, in vitro, after CpG stimulation for 7 days as previously described. Semi-quantitative PCR analysis for AID and UNG expression as well as serum levels of BAFF were carried out in order to better define the diagnosis. RESULTS: Immunological and molecular analysis did not lead to the identification of known molecular defect typical of Hyper IgM syndrome. A comparative study of the peripheral blood B cell subsets between patients and healthy donors showed that in patients with autoimmune manifestations all circulating B cells expressed high amounts of surface IgM. CONCLUSIONS: These results suggest that the increased IgM expression on circulating B cells, reflecting B cell activation, might identify a clinical condition characterized by hyper IgM serum levels of unknown molecular defects, associated with susceptibility to infections and autoimmunity. PMID- 26526205 TI - In vitro activity of Aloe vera inner gel against microorganisms grown in planktonic and sessile phases. AB - The failure of traditional antimicrobial treatments is becoming a worldwide problem. The use of Aloe vera is of particular interest for its role as curative agent and its efficacy in complementary therapies for a variety of illnesses. This study evaluated the antimicrobial activity of A. vera inner gel against a panel of microorganisms, Gram-positive and -negative bacteria, and Candida albicans. In addition to A. vera inner gel being used in the treatment of peptic ulcers, in dermatological treatments, and wound healing, it was also tested on the sessile phase of clinical Helicobacter pylori strains (including multi-drug resistant strains) and on planktonic and sessile phase of Staphylococcus aureus/Pseudomonas aeruginosa clinical isolates from venous leg ulcers.A. vera inner gel expresses its prevalent activity against Gram-negative bacteria and C. albicans in respect to Gram-positive bacteria. The results of the A. vera antibiofilm activity showed a decrease of the produced biomass in a concentration dependent-way, in each analyzed microorganism. The data obtained show that A. vera inner gel has both an antimicrobial and antibiofilm activity suggesting its potential use for the treatment of microbial infections, in particular for H. pylori gastric infection, especially in case of multi-drug-resistance, as well as for an effective wound dressing. PMID- 26526206 TI - Preliminary study of efficacy of cup suction in the correction of typical pectus excavatum. AB - OBJECTIVE: This preliminary qualitative study evaluates the efficacy of cup suction in the correction of pectus excavatum (PE), and examines the place of this system as a strategic treatment and as an alternative to surgery. MATERIALS AND METHODS: Between October 2011 and June 2014, a total of 84 patients (children and adult) presenting with PE were treated by cup suction, in our chest wall deformities unit. On first consultation, the patients with typical PE and with at least partial correction during the first application of cup suction and a maximal suction pressure for correction of less than 300 mbar (millibars) were included in this study. 11 patients were excluded from the present study as they presented with a complex carinatum/excavatum. The remaining 73 patients were divided into two groups: Group I, adult patients >= 18 year old, 17 patients. The mean age was 22.8 years old. Group II, pediatric patients <18 years old, 56 patients. The mean age was 11.5 years old. Medical photographic documentation was collected systematically. In addition, the depth of PE was measured. The management protocol involved: adjustment of cup suction, strengthening exercises, and clinical follow-up every two to three months. The evaluation criteria during, and on the completion of the trial were: depth of the PE, morbidity and treatment compliance. Partial and final results were evaluated by the patients, their parents, and doctor, using a qualitative scoring scale. RESULTS: A total of 73 patients presenting typical PE (symmetric in 52 cases and asymmetric in 21 cases) were treated by cup suction. The mean depth of PE was 23 mm (9-44). Of the 73 patients, one adult abandoned treatment and three children abandoned follow-up. The mean time of use of the device was 4h daily. At six months of treatment, the mean depth of PE was 9 mm (0-30) across all patients. 23 patients completed the treatment and exhibited flattening of the sternum. These patients were considered to have an excellent aesthetic result. The mean treatment duration to normal reshape was achieved at 10 months (4-21). The remaining patients are improving under continuing active treatment. The mean depth of PE in this group was 12 mm (4-30), after a mean treatment duration of 9 months (2-22). CONCLUSIONS: Treatment using cup suction is a promising useful alternative in selected cases of symmetric and asymmetric PE, providing that the thorax is flexible. Treatment duration is directly linked to age, severity and the frequency of use. It is becoming a well-recognized therapy, which improves the self-image of those patients whose anterior chest wall is still pliable. The cup suction can be used for pediatrics and young adults waiting for a treatment, possibly surgery, however, the long-term effect of this procedure remains unclear. PMID- 26526207 TI - Long-term outcomes of gastric electrical stimulation in children with gastroparesis. AB - BACKGROUND: Gastric electrical stimulation (GES) has been used in adults with gastroparesis. However its use has been limited in children. We describe the largest experience with GES in children with long-term outcomes. METHODS: Data were collected on children who underwent GES over a 10-year period. Data regarding demographics, medical history, hospital course, and outcomes were collected and analyzed. Symptom scores (validated Likert scores) were compared using a paired Student's t test. RESULTS: Overall, 97 patients underwent GES, and a majority were teenage Caucasian girls. Ninety-six had temporary GES (tGES), and 66 had improvement in their symptoms. A total of 67 underwent permanent implantation (pGES), and there was significant reduction in all individual symptoms (p<0.001) as well as the total symptom score (TSS) (p<0.0001) at 1, 6, 12, and >12 months. Recurrence of symptoms leading to device removal occurred in 7 cases. Forty-one patients had continued improvement in symptoms for over 12 months, with a mean follow-up of 3.5 years (range 1-9 years). CONCLUSIONS: This study represents the largest experience of systematic application of GES in children. GES is a safe and effective therapy for selected children with intractable GP with continued symptomatic improvement at 1 year and beyond. PMID- 26526208 TI - Effect of single and multiple courses of maternal betamethasone on prenatal congenital lung lesion growth and fetal survival. AB - PURPOSE: Administration of maternal betamethasone (BMZ) is a therapeutic option for fetuses with large microcystic congenital lung lesions at risk for, or causing, hydrops. Not all fetuses respond to a single course of BMZ. We review our experience with the use of single and multiple courses of maternal BMZ for the management of these patients. METHODS: A retrospective review of fetuses with congenital lung lesions managed with maternal BMZ from 2003 to 2014 was performed. RESULTS: Forty-three patients were managed with prenatal steroids (28 single course, 15 multiple courses). Single course recipients demonstrated a reduction in lesion size and resolution of hydrops in 82% and 88% of patients respectively compared to 47% and 56% in recipients of multiple steroid courses. Survival of multiple course patients (86%) was comparable to that of single course patients (93%) and improved compared to non-treated historical controls. Multiple course recipients demonstrated an increased need for open fetal surgery and postnatal surgery at a younger age. CONCLUSION: Fetuses who fail to respond to a single course of BMZ may benefit, as indicated by hydrops resolution and improved survival, from additional courses. However, failure to respond is indicative of a lesion which may require fetal or immediate neonatal resection. PMID- 26526209 TI - Modeling transient retinal ischemia in mouse by ligation of pterygopalatine artery. AB - BACKGROUND: Retinal ischemia is a major cause of visual impairment and blindness worldwide. The available therapeutic strategies have limited potential. PURPOSE: In order to understand the pathophysiology and validating therapies for retinal ischemia, establishment of reproducible animal models is necessary. METHODS: In the model discussed in this article, the pterygopalatine artery (PPA) is ligated along with the external carotid artery for 3.5 hours and thereafter allowed to reperfuse. Because PPA supplies the blood to the ophthalmic artery, the ligation of this artery causes retinal ischemia. RESULTS: This article describes the validation of retinal ischemia-reperfusion model in mouse through PPA ligation and its validation through fluorescein fundus angiography (FFA) and immunofluorescence staining for glial fibrillary acidic protein (GFAP), a glial injury marker. CONCLUSIONS: In conclusion this article describes the creation of mouse model of retinal ischemia-reperfusion injury which can be reproduced in a shorter time duration resulting in reduced mortality. PMID- 26526210 TI - Falciform ligament flap for the protection of the gastroduodenal artery stump after pancreaticoduodenectomy: A single center experience. AB - AIM OF THE STUDY: Delayed hemorrhage, though rare, remains a significant source of morbidity and mortality after pancreaticoduodenectomy (PD). An important cause of this delayed hemorrhage is erosion or pseudoaneurysm formation of the gastroduodenal artery (GDA) by pancreatic enzymes and adjacent intra-abdominal sepsis. So protection of the GDA stump may avoid this devastating complication. PATIENTS AND METHODS: This is a retrospective observational study. All patients, who underwent a PD between August 2007 and December 2014, were included in the study. We used pedicled falciform ligament flap to protect the GDA stump. After PD, pedicled falciform ligament flap was spread widely over the skeletonized hepatic artery including the GDA stump and was fixed to the surrounding retroperitoneal connective tissue. This procedure allowed complete separation of the GDA stump from the pancreatic stump. RESULTS: We performed 182 cases of PD during the study period. Although, 27 (15%) patients developed pancreatic fistula and six patients developed intra-abdominal abscess, no one experienced hemorrhage due to erosion or pseudoaneurysm formation of the GDA. CONCLUSION: The present surgical option seems to be an effective measure for the prevention of erosion and pseudoaneurysm formation of the GDA after PD. PMID- 26526211 TI - Randomization in surgical research: Still a matter of debate in 2015? PMID- 26526212 TI - Mechanical bowel preparation before colorectal surgery. Where do we stand? PMID- 26526213 TI - Inhibitory kinetics of novel 2,3-dihydro-1H-inden-1-one chalcone-like derivatives on mushroom tyrosinase. AB - In this study, novel 2,3-dihydro-1H-inden-1-one chalcone-like compounds and their hydroxyl derivatives were synthesized, and their inhibitory effects on mushroom tyrosinase activity were evaluated. Two of the compounds synthesized inhibited the diphenolase activity of tyrosinase in a dose dependent manner and exhibited much higher tyrosinase inhibitory activities (IC50 values of 12.3 MUM and 8.2 MUM, respectively) than the positive control, kojic acid (IC50: 27.5 MUM). Kinetic analysis showed that their inhibition was reversible. Both the novel compounds displayed competitive inhibition with their Ki values of 10.3 MUM and 8.7 MUM, respectively. This study suggests hydroxy substituted 2,3-dihydro-1H inden-1-one chalcone-like compounds to serve as promising candidates for use as depigmentation agents. PMID- 26526214 TI - Discovery of potent, selective, and orally bioavailable inhibitors of interleukin 1 receptor-associate kinase-4. AB - In this Letter, we report the continued optimization of the N-acyl-2 aminobenzimidazole series, focusing in particular on the N-alkyl substituent and 5-position of the benzimidazole based on the binding mode and the early SAR. These efforts led to the discovery of 16, a highly potent, selective, and orally bioavailable inhibitor of IRAK-4. PMID- 26526215 TI - Geographic trends in management of early-stage laryngeal cancer. AB - OBJECTIVES/HYPOTHESIS: The goal of the study was to identify geographic trends in the primary treatment of early-stage glottic cancer. STUDY DESIGN: Retrospective analysis of the United States National Cancer Institute's Surveillance, Epidemiology, and End-Results (SEER) database. METHODS: Using the most up-to-date November 2014 submission of the SEER database in addition to SEER-18 data files, a cohort was created of stage I to II squamous cell glottic cancer from 2004 to 2012. The treatment groups (radiation and surgery) were compared with respect to several pretreatment covariates including age, race, gender, state where they received treatment, year of diagnosis, and American Joint Committee on Cancer (AJCC) stage. RESULTS: In analyzing geographic trends, a statistically significant difference in treatment received by region and state was found (P < .0001.). When examining patient demographics, there was no statistically significant difference in treatment by age (P = .5206), AJCC stage (P = .4922), or year of diagnosis (P = .6593). There was a significant difference in racial distribution by treatment (P = .0038), with patients receiving surgery more likely to be black than patients receiving radiation (12% vs. 10%). In analyzing overall survival (OS), there was no significant difference in OS among the four US treatment regions (P = .2508). CONCLUSIONS: Geographic factors impact overall treatment of early-stage glottic cancer. In addition, it was determined that race was a factor that correlated to differences in treatment modality. Finally, overall survival across the United States was determined to be significantly better in patients receiving radiation therapy. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:880-884, 2016. PMID- 26526216 TI - IVIVC of parenteral PLGA microspheres. PMID- 26526217 TI - Competitive active video games: Physiological and psychological responses in children and adolescents. AB - BACKGROUND: Recent strategies to reduce sedentary behaviour in children include replacing sedentary screen time for active video games. Active video game studies have focused principally on the metabolic consumption of a single player, with physiological and psychological responses of opponent-based multiplayer games to be further evaluated. OBJECTIVE: To determine whether adding a competitive component to playing active video games impacts physiological and psychological responses in players. METHODS: Sixty-two healthy Caucasian children and adolescents, nine to 14 years years of age, completed three conditions (8 min each) in random order: treadmill walking, and single and opponent-based Kinect active video games. Affect, arousal, rate of perceived exertion, heart rate and percentage of heart rate reserve were measured for each participant and condition. RESULTS: Kinect conditions revealed significantly higher heart rate, percentage of heart rate reserve, rate of perceived exertion and arousal when compared with treadmill walking (P<0.001). Opponent-based condition revealed lower values for the rate of perceived exertion (P=0.02) and higher affect (P=0.022) when compared with single play. CONCLUSION: Competitive active video games improved children's psychological responses (affect and rate of perceived exertion) compared with single play, providing a solution that may contribute toward improved adherence to physical activity. PMID- 26526219 TI - HbA1c: An effective screening tool for cystic fibrosis related diabetes? PMID- 26526218 TI - Comparing and Validating Simple Measures of Patient-Reported Peripheral Neuropathy for Oncology Clinical Trials: NCCTG N0897 (Alliance) A Pooled Analysis of 2440 Patients. AB - INTRODUCTION: Current standard evaluation of Peripheral Neuropathy (PN) is based on an investigator-reported classification system that is commonly unable to correctly reflect the subjective symptoms for patients. Thus more reliable methods to assess PN are needed. This study assessed alternative methods of assessing patient-reported PN in 5 North Central Cancer Treatment Group (NCCTG) clinical trials. METHOD: Two single-item assessments relating to numbness and tingling were used to measure PN. Patients' Quality Of Life (QOL) was also assessed using the Uniscale, Symptom Distress Scale (SDS), Profile of Mood States (POMS), Brief Pain Inventory (BPI) and Subject Global Impression of Change (SGIC). Wilcoxon tests compared QOL scores between patients with PN (score > 50) vs. no PN (score <= 50). Changes from baseline in QOL were compared by Wilcoxon rank sum test with a 20-point change in PN defined as clinically meaningful. Both distribution-based and anchor-based approaches were used to derive estimates of Minimal Important Differences (MID). Standardized Response Means (SRM), Effect Sizes (ES) and Guyatt's responsiveness statistic were used to measure responsiveness. RESULTS: The proportion of patients reporting numbness (tingling) at baseline was 10.7% (10.0%) and 18.4% (17.8%) at last assessment. The correlation between numbness and tingling at baseline was 0.81, and at last assessment was 0.83. Patients with substantial PN reported an average of 10 points lower overall QOL, mood and worse symptom distress and 20 points lower in the BPI interference items. Patients having a <= 20 point worsening in PN score reported significantly worse in symptom distress and BPI worst pain, but not in POMS or overall QOL. The MID estimates were similar between numbness and tingling items but varied depending on the approach used. Responsiveness statistics indicated that the two PN assessments are sensitive and responsive instruments for cancer patients with PN. CONCLUSIONS: The two PN items for numbness and tingling were redundant. Evidence of criterion validity and responsiveness indicates that these simple measures of PN can be used successfully in cancer clinical trials. PMID- 26526220 TI - Non-allergic asthma as a CFTR-related disorder. AB - BACKGROUND: CFTR dysfunction can be involved in CBAVD, pancreatitis or bronchiectasis. METHODS: Subjects with cystic fibrosis-like disease, equivocal sweat chloride concentrations and no or one disease-causing CFTR mutation were investigated by intestinal current and/or nasal potential difference measurements. RESULTS: A subgroup of female patients who had been diagnosed to suffer from non-allergic asthma showed intermediary chloride concentrations in sweat test, normal chloride secretory responses in the intestine and an abnormal nasal potential difference with Sermet scores in the cystic fibrosis range. CONCLUSION: Non-allergic asthma is a clinical entity that may be associated with CFTR dysfunction of the respiratory epithelium. PMID- 26526221 TI - Latent variable mixture modeling in psychiatric research--a review and application. AB - Latent variable mixture modeling represents a flexible approach to investigating population heterogeneity by sorting cases into latent but non-arbitrary subgroups that are more homogeneous. The purpose of this selective review is to provide a non-technical introduction to mixture modeling in a cross-sectional context. Latent class analysis is used to classify individuals into homogeneous subgroups (latent classes). Factor mixture modeling represents a newer approach that represents a fusion of latent class analysis and factor analysis. Factor mixture models are adaptable to representing categorical and dimensional states of affairs. This article provides an overview of latent variable mixture models and illustrates the application of these methods by applying them to the study of the latent structure of psychotic experiences. The flexibility of latent variable mixture models makes them adaptable to the study of heterogeneity in complex psychiatric and psychological phenomena. They also allow researchers to address research questions that directly compare the viability of dimensional, categorical and hybrid conceptions of constructs. PMID- 26526222 TI - Inkjet printed fluorescent nanorod layers exhibit superior optical performance over quantum dots. AB - Semiconductor nanocrystals exhibit unique fluorescence properties which are tunable in size, shape and composition. The high quantum yield and enhanced stability have led to their use in biomedical imaging and flat panel displays. Here, semiconductor nanorod based inkjet inks are presented, overcoming limitations of the commonly reported quantum dots in printing applications. Fluorescent seeded nanorods were found to be outstanding candidates for fluorescent inks, due to their low particle-particle interactions and negligible self-absorption. This is manifested by insignificant emission shifts upon printing, even in highly concentrated printed layers and by maintenance of a high fluorescence quantum yield, unlike quantum dots which exhibit fluorescence wavelength shifts and quenching effects. This behavior results from the reduced absorption/emission overlap, accompanied by low energy transfer efficiencies between the nanorods as supported by steady state and time resolved fluorescence measurements. The new seeded nanorod inks enable patterning of thin fluorescent layers, for demanding light emission applications such as signage and displays. PMID- 26526223 TI - The reliability of the quantitative timed up and go test (QTUG) measured over five consecutive days under single and dual-task conditions in community dwelling older adults. AB - The timed up and go (TUG) test is a commonly used assessment in older people with variations including the addition of a motor or cognitive dual-task, however in high functioning older adults it is more difficult to assess change. The quantified TUG (QTUG) uses inertial sensors to detect test and gait parameters during the test. If it is to be used in the longitudinal assessment of older adults, it is important that we know which parameters are reliable and under which conditions. This study aims to examine the relative reliability of the QTUG over five consecutive days under single, motor and cognitive dual-task conditions. Twelve community dwelling older adults (10 females, mean age 74.17 (3.88)) performed the QTUG under three conditions for five consecutive days. The relative reliability of each of the gait parameters was assessed using intra class correlation coefficient (ICC 3,1) and standard error of measurement (SEM). Five of the measures demonstrated excellent reliability (ICC>0.70) under all three conditions (time to complete test, walk time, number of gait cycles, number of steps and return from turn time). Measures of variability and turn derived parameters demonstrated weak reliability under all three conditions (ICC=0.05 0.49). For the most reliable parameters under single-task conditions, the addition of a cognitive task resulted in a reduction in reliability suggesting caution when interpreting results under these conditions. Certain sensor derived parameters during the QTUG test may provide an additional resource in the longitudinal assessment of older people and earlier identification of falls risk. PMID- 26526224 TI - A polydopamine nanosphere based highly sensitive and selective aptamer cytosensor with enzyme amplification. AB - With CCRF-CEM as the model cell, a highly sensitive and selective cytosensor was developed by taking advantage of polydopamine nanospheres for the first time. The strategies of aptamer/membrane protein recognition and Exonuclease III assisted cycle amplification were used for improving selectivity and sensitivity. The detection of limit reached was as low as 15 cells per mL. PMID- 26526225 TI - The effect of 17beta-estradiol on gene expression of calcitonin gene-related peptide and some pro-inflammatory mediators in peripheral blood mononuclear cells from patients with pure menstrual migraine. AB - OBJECTIVES: The neuropeptide calcitonin gene-related peptide (CGRP) has long been postulated to play an integral role in the pathophysiology of migraine. Earlier studies showed that CGRP can stimulate the synthesis and release of nitric oxide (NO) and cytokines from trigeminal ganglion glial cells. The purpose of this study was to determine the effect of 17beta-estradiol in regulation of CGRP expression, inducible nitric oxide synthase (iNOS) activity, and NO and interleukin-1beta (IL-1beta) release in cultured peripheral blood mononuclear cells (PBMCs) from patients with pure menstrual migraine and healthy individuals. MATERIALS AND METHODS: This study was performed on twelve patients with pure menstrual migraine and twelve age-and sex-matched healthy individuals. PBMCs treated with 17beta-estradiol for 24 hr at physiological and pharmacological doses. Gene expression was evaluated by real time-PCR. CGRP and IL-1beta proteins in culture supernatant were determined by ELISA method. Activity of iNOS in PBMCs and total nitrite in the culture supernatant were measured by colorimetric assays. RESULTS: Treatment with 17beta-estradiol had a biphasic effect on expression of CGRP. We found that 17beta-estradiol treatment at pharmacological dose significantly increases mRNA expression of CGRP in both groups (P<0.001), whereas at physiological dose it could significantly decrease CGRP mRNA expression (P<0.001), CGRP protein levels, IL-1beta release, NO production and iNOS activity only in patient groups (P<0.05). CONCLUSION: Collectively, it appears that 17beta-estradiol can exert protective effect on decrease of inflammation in migraine via decrease in levels of CGRP, IL-1beta and iNOS activity; however, more studies are necessary in this regard. PMID- 26526226 TI - Role of leptin in body temperature regulation and lipid metabolism following splenectomy. AB - OBJECTIVE: The physiological changes in serum triglycerides and body temperature that are induced by splenectomy are poorly understood. Therefore, the aim of this study was to investigate parameters related to lipid and glucose metabolism, as well as thermoregulation, in splenectomized mice. DESIGN AND METHODS: Splenectomized and sham-operated WT mice (C57Bl/6) and ob/ob mice were randomly divided and treated with a standard or high fat diet, and several metabolic parameters and the body temperature were investigated. RESULTS: Splenectomy induced a significant increase in triglyceride levels regardless of the diet. It was found that the splenectomized WT mice showed greater serum leptin and insulin levels compared with the sham-operated mice. Additionally, the body temperatures of the splenectomized WT mice were greater than the body temperatures of the control animals regardless of diet; this result too was observed without any significant change in the temperature of the splenectomized ob/ob animals. CONCLUSION: The results suggest that splenectomy interferes with serum triglyceride metabolism and body temperature regardless of the fat content in the diet and that leptin is involved in the regulation of body temperature related to splenectomy. PMID- 26526227 TI - Mystixin-7 mini-peptide protects ionotropic glutamatergic mechanisms against oxygen-glucose deprivation in vitro. AB - The aim of the present study was to explore the neuroprotective effects of the mystixin-7 mini-peptide (MTX, a synthetic corticotropin-releasing-factor-like, 7 amino-acid peptide) on an in vitro oxygen glucose deprivation model (OGD, 10min). The study used a technique of on-line monitoring of changes in alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and N-methyl-d-aspartic acid receptor (NMDAR)-mediated field excitatory postsynaptic potentials (fEPSPs) in the olfactory cortex slices in the OGD model. OGD resulted in an irreversible blockade of both AMPAR and NMDAR activity. Pretreatment of slices by MTX and their subsequent exposure to OGD resulted in decreased activity of these postsynaptic mechanisms (AMPARs, 71%; NMDARs, 68% as compared to baseline), but they were not blocked altogether. The degree protection of activity of both AMPARs and NMDARs had dose-dependent manner, with a maximal effect at 100mg/mL. These protective effects were retained after the removal of MTX from the bathing medium. To evaluate the protective efficacy of MTX on NMDARs, the slices were pretreated by MTX and exposed to OGD and then treated with l-glutamate (1mM). NMDARs' response to application of l-glutamate was minimal at higher concentrations of MTX and maximal at lower concentrations. These findings indicate that the molecules of MTX interact with a certain amount of NMDARs, and thereby protect them from the OGD. Pretreatment of slices with MTX contributed to the protection of network activity against OGD and promoted the development of the learning process in the form of long-term potentiation. To specify the protective effects of MTX, it was denatured by trypsin. The proteolytic cleavage of MTX resulted to a significant decrease in the activity of both AMPARs and NMDARs against OGD as compared with that of the native peptide. Together, these findings provide further insight into the protective potential of the MTX mini peptide. We believe that the data presented can be the basis for the development of therapeutics MTX-based medications for the treatment of the ischemic stroke. PMID- 26526228 TI - Neural Reactivity to Emotional Stimuli Prospectively Predicts the Impact of a Natural Disaster on Psychiatric Symptoms in Children. AB - BACKGROUND: Natural disasters expose entire communities to stress and trauma, leading to increased risk for psychiatric symptoms. Yet, the majority of exposed individuals are resilient, highlighting the importance of identifying underlying factors that contribute to outcomes. METHODS: The current study was part of a larger prospective study of children in Long Island, New York (n = 260). At age 9, children viewed unpleasant and pleasant images while the late positive potential (LPP), an event-related potential component that reflects sustained attention toward salient information, was measured. Following the event-related potential assessment, Hurricane Sandy, the second costliest hurricane in United States history, hit the region. Eight weeks after the hurricane, mothers reported on exposure to hurricane-related stress and children's internalizing and externalizing symptoms. Symptoms were reassessed 8 months after the hurricane. RESULTS: The LPP predicted both internalizing and externalizing symptoms after accounting for prehurricane symptomatology and interacted with stress to predict externalizing symptoms. Among children exposed to higher levels of hurricane related stress, enhanced neural reactivity to unpleasant images predicted greater externalizing symptoms 8 weeks after the disaster, while greater neural reactivity to pleasant images predicted lower externalizing symptoms. Moreover, interactions between the LPP and stress continued to predict externalizing symptoms 8 months after the hurricane. CONCLUSIONS: Results indicate that heightened neural reactivity and attention toward unpleasant information, as measured by the LPP, predispose children to psychiatric symptoms when exposed to higher levels of stress related to natural disasters, while greater reactivity to and processing of pleasant information may be a protective factor. PMID- 26526229 TI - Ontogenetic development of the auditory sensory organ in zebrafish (Danio rerio): changes in hearing sensitivity and related morphology. AB - Zebrafish (Danio rerio) is an important model organism in hearing research. However, data on the hearing sensitivity of zebrafish vary across different reports. In the present study, the hearing sensitivity of zebrafish was examined by analysing the auditory evoked potentials (AEPs) over a range of total lengths (TLs) from 12 to 46 mm. Morphological changes in the hair cells (HCs) of the saccule (the main auditory end organ) and their synapses with primary auditory neurons were investigated. The AEPs were detected up to a much higher frequency limit (12 kHz) than previously reported. No significant difference in the frequency response range was observed across the TL range examined. However, the AEP thresholds demonstrated both developmental improvement and age-related loss of hearing sensitivity. The changes in hearing sensitivity were roughly consistent with the morphological changes in the saccule including (1) the number and density of HCs, (2) the organization of stereocilia, and (3) the quantity of a main ribbon protein, Ribeye b. The results of this study established a clear baseline for the hearing ability of zebrafish and revealed that the changes in the saccule contribute to the observed changes in TL (age)-related hearing sensitivity. PMID- 26526230 TI - Novel intramolecular photoinduced electron transfer-based probe for the Human Ether-a-go-go-Related Gene (hERG) potassium channel. AB - Drug induced long QT syndrome is a high risk event in clinic, which mainly results from their high affinity to the Human Ether-a-go-go-Related Gene (hERG) potassium channel. Therefore, evaluation of the drug's inhibitory activity against the hERG potassium channel is a required step in drug discovery and development. In this study, we developed a series of novel conformation-mediated intramolecular photoinduced electron transfer fluorogenic probes for the hERG potassium channel. After careful evaluation, probes N4 and N6 showed good activity and may have a promising application in the cell-based hERG potassium channel inhibitory activity assay, as well as potential hERG-associated cardiotoxicity evaluation. Compared with other assay methods, such as patch clamp assay, radio-ligand competitive binding assay, fluorescence polarization and potential-sensitive fluorescent probes, this method is convenient and can also selectively measure the inhibitory activity in the native state of the hERG potassium channel. Meanwhile, these probes can also be used for hERG potassium channel imaging without complex washing steps. PMID- 26526231 TI - Automated estimation of choroidal thickness distribution and volume based on OCT images of posterior visual section. AB - A variety of vision ailments are indicated by anomalies in the choroid layer of the posterior visual section. Consequently, choroidal thickness and volume measurements, usually performed by experts based on optical coherence tomography (OCT) images, have assumed diagnostic significance. Now, to save precious expert time, it has become imperative to develop automated methods. To this end, one requires choroid outer boundary (COB) detection as a crucial step, where difficulty arises as the COB divides the choroidal granularity and the scleral uniformity only notionally, without marked brightness variation. In this backdrop, we measure the structural dissimilarity between choroid and sclera by structural similarity (SSIM) index, and hence estimate the COB by thresholding. Subsequently, smooth COB estimates, mimicking manual delineation, are obtained using tensor voting. On five datasets, each consisting of 97 adult OCT B-scans, automated and manual segmentation results agree visually. We also demonstrate close statistical match (greater than 99.6% correlation) between choroidal thickness distributions obtained algorithmically and manually. Further, quantitative superiority of our method is established over existing results by respective factors of 27.67% and 76.04% in two quotient measures defined relative to observer repeatability. Finally, automated choroidal volume estimation, being attempted for the first time, also yields results in close agreement with that of manual methods. PMID- 26526232 TI - Gender differences in scalp hair growth rates are maintained but reduced in pattern hair loss compared to controls. AB - BACKGROUND: Hair loss is related to follicular density, programmed regrowth and hair productivity. OBJECTIVE: The dissatisfaction with hair growth in patients experiencing hair loss might be due to slower linear hair growth rate (LHGR). METHODS: LHGR and hair diameter was evaluated in Caucasian controls and patients with patterned hair loss employing the validated non-invasive, contrast-enhanced phototrichogram with exogen collection. RESULTS: We evaluated 59,765 anagen hairs (controls 24,609, patients 35,156) and found thinner hairs grew slower than thicker hairs. LHGR in normal women was generally higher than in normal men. LHGR correlates with hair diameter (P < 0.006) and global thinning is associated with slower growth rates. Compared with hair of equal thickness in controls, subjects affected with patterned hair loss showed reduced hair growth rates, an observation found in both male and female patients. Males with pattern hair loss showed further reduction in growth rates as clinical severity worsened. However, sample size limitations prevented statistical evaluation of LHGR in severely affected females. LIMITATIONS: Caucasian ethnicity. CONCLUSION: In pattern hair loss, LHGR significantly contributes to the apparent decrease in hair volume in affected areas. In early onset, LHRG might have a prognostic value in females but not in males. PMID- 26526234 TI - Do hot flashes induce insomnia? PMID- 26526233 TI - Role of GPER on proliferation, migration and invasion in ligand-independent manner in human ovarian cancer cell line SKOV3. AB - G protein-coupled estrogen receptor (GPER) is identified as a critical estrogen receptor, in addition to the classical estrogen receptors ERalpha and ERbeta. In ERalpha-negative ovarian cancer cells, our previous studies have found that estrogen stimulated cell proliferation and metastasis via GPER. However, the ligand-independent function of GPER in ovarian cancer cells is still not clear. Herein, we describe that GPER has a co-expression with ERalpha and ERbeta, which are first determined in SKOV3 ovarian cancer cell line. In the absence of estrogen, GPER depletion by specific siRNA inhibits the proliferation, migration and invasion of SKOV3 cells. Whereas abrogation of ERalpha or ERbeta by specific antagonist MPP and PHTPP has the opposite effects for stimulation of cell growth. Markedly, GPER knockdown attenuates MPP or PHTPP-induced cell proliferation, migration and invasion. Furthermore, GPER modulates protein expression of the cell cycle critical components, c-fos and cyclin D1 and factors for cancer cell invasion and metastasis, matrix metalloproteinase 2 (MMP-2) and MMP-9. These findings establish that GPER ligand-independently stimulates the proliferation, migration and invasion of SKOV3 cells. Knockdown of GPER attenuates the progression of ovarian cancer that caused by functional loss of ERalpha or ERbeta. Targeting GPER provides new aspect as a potential therapeutic strategy in ovarian cancer. PMID- 26526235 TI - Food And Health. PMID- 26526237 TI - From Lab Bench To Kitchen Table. AB - As the environmental impact of large-scale animal farming increasingly threatens global health, the hunt is on for new sources of protein. PMID- 26526238 TI - The Complex Relationship Between Diet And Health. AB - The relationship between food and health is complex. Everyone needs food to live, but too little food, too much food, or the wrong type of food has negative consequences for health. To increase understanding of this relationship, we describe trends and patterns in food-related diseases among both adults and children. Using an ecological framework, we then describe why food intake is complex with a discussion of three broad levels--macro (including policy and social-cultural norms), local community, and individual environments--and their relationship to food consumption. Given the strong relationship between an individual's food choice and his or her surrounding environment, we end with examples of policy responses that aim to help people overcome environmental disincentives toward healthy eating. Finding ways to make eating healthfully easier and affordable for all populations is essential to shifting the average American diet toward one that promotes health. PMID- 26526239 TI - Reducing Food Loss And Waste While Improving The Public's Health. AB - An estimated 30 percent of the global food supply is lost or wasted, as is about 40 percent of the US food supply. There are valuable synergies between efforts to reduce food loss and waste and those promoting public health. To demonstrate the potential impact of building upon these synergies, we present an analysis of policies and interventions addressing food loss and waste, food security, food safety, and nutrition. We characterize as opportunities the policies and interventions that promote synergistic relationships between goals in the fields of food loss and waste and of public health. We characterize as challenges the policies and interventions that may reduce food loss and waste but compromise public health, or improve public health but increase food loss and waste. Some interventions are both opportunities and challenges. With deliberate planning and action, challenges can often be addressed and turned into opportunities. In other cases, it may be necessary to strike a balance between potential benefit in one area and risk of harm in the other. To help policy makers make the best use of the opportunities while tackling the challenges, it is essential to consider public health in efforts to reduce food loss and waste. PMID- 26526240 TI - Food Insecurity And Health Outcomes. AB - Almost fifty million people are food insecure in the United States, which makes food insecurity one of the nation's leading health and nutrition issues. We examine recent research evidence of the health consequences of food insecurity for children, nonsenior adults, and seniors in the United States. For context, we first provide an overview of how food insecurity is measured in the country, followed by a presentation of recent trends in the prevalence of food insecurity. Then we present a survey of selected recent research that examined the association between food insecurity and health outcomes. We show that the literature has consistently found food insecurity to be negatively associated with health. For example, after confounding risk factors were controlled for, studies found that food-insecure children are at least twice as likely to report being in fair or poor health and at least 1.4 times more likely to have asthma, compared to food-secure children; and food-insecure seniors have limitations in activities of daily living comparable to those of food-secure seniors fourteen years older. The Supplemental Nutrition Assistance Program (SNAP) substantially reduces the prevalence of food insecurity and thus is critical to reducing negative health outcomes. PMID- 26526241 TI - US Household Food Shopping Patterns: Dynamic Shifts Since 2000 And Socioeconomic Predictors. AB - Under the assumption that differential food access might underlie nutritional disparities, programs and policies have focused on the need to build supermarkets in underserved areas, in an effort to improve dietary quality. However, there is limited evidence about which types of stores are used by households of different income levels and differing races/ethnicities. We used cross-sectional cluster analysis to derive shopping patterns from US households' volume food purchases by store from 2000 to 2012. Multinomial logistic regression identified household socioeconomic characteristics that were associated with shopping patterns in 2012. We found three food shopping patterns or clusters: households that primarily shopped at grocery stores, households that primarily shopped at mass merchandisers, and a combination cluster in which households split their purchases among multiple store types. In 2012 we found no income or race/ethnicity differences for the cluster of households that primarily shopped at grocery stores. However, low-income non-Hispanic blacks (versus non-Hispanic whites) had a significantly lower probability of belonging to the mass merchandise cluster. These varied shopping patterns must be considered in future policy initiatives. Furthermore, it is important to continue studying the complex rationales for people's food shopping patterns. PMID- 26526242 TI - Baltimore City Stores Increased The Availability Of Healthy Food After WIC Policy Change. AB - As part of a 2009 revision to the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) program, the Department of Agriculture required WIC-authorized stores to stock additional varieties of healthy food. The long-term effects of this policy on access to healthy food are unknown. Using surveys conducted in 118 Baltimore City, Maryland, food stores in 2006 and 2012, we examined associations of the change in healthy food availability with store type, neighborhood demographics, and the 2009 WIC policy change. Overall, healthy food availability improved significantly between 2006 and 2012, with the greatest increases in corner stores and in census tracts with more than 60 percent black residents. On an 11-point scale measuring availability of fruit (3 points), vegetables (4 points), bread (2 points), and milk (2 points), the WIC policy change was associated with a 0.72-point increase in WIC-relevant healthy food availability, while joining WIC was associated with a 0.99-point increase. Stores that carry a limited variety of food items may be more receptive to stocking healthier food than previously thought, particularly within neighborhoods with a majority of black residents. Policies targeting healthy food availability have the potential to increase availability and decrease health disparities. PMID- 26526243 TI - Diet And Perceptions Change With Supermarket Introduction In A Food Desert, But Not Because Of Supermarket Use. AB - Placing full-service supermarkets in food deserts--areas with limited access to healthy food--has been promoted as a way to reduce inequalities in access to healthy food, improve diet, and reduce the risk of obesity. However, previous studies provide scant evidence of such impacts. We surveyed households in two Pittsburgh, Pennsylvania, neighborhoods in 2011 and 2014, one of which received a new supermarket in 2013. Comparing trends in the two neighborhoods, we obtained evidence of multiple positive impacts from new supermarket placement. In the new supermarket neighborhood we found net positive changes in overall dietary quality; average daily intakes of kilocalories and added sugars; and percentage of kilocalories from solid fats, added sugars, and alcohol. However, the only positive outcome in the recipient neighborhood specifically associated with regular use of the new supermarket was improved perceived access to healthy food. We did not observe differential improvement between the neighborhoods in fruit and vegetable intake, whole grain consumption, or body mass index. Incentivizing supermarkets to locate in food deserts is appropriate. However, efforts should proceed with caution, until the mechanisms by which the stores affect diet and their ability to influence weight status are better understood. PMID- 26526244 TI - Gains Made By Walmart's Healthier Food Initiative Mirror Preexisting Trends. AB - Healthier food initiatives conducted by national food retailers may offer opportunities to improve the nutritional profile of food purchases. Using a longitudinal data set of packaged food purchases made by US households, we examined the effect of a healthier food initiative officially launched by Walmart in 2011. From 2000 to 2013, household-level purchases of packaged foods at Walmart showed major declines in energy, sodium, and total sugar density, as well as in quantities of sugary beverages, grain-based desserts, snacks, and candy. These trends in packaged food purchases were more pronounced than similar concurrent trends seen at other major food retailers. However, the declines seen at Walmart after the initiative's official implementation did not exceed what would have been expected had pre-implementation trends continued, and therefore they cannot be attributed to the initiative. These results suggest that food retailer-based initiatives that purportedly create a healthier food environment may not suffice to improve the nutritional profile of food purchases. More systemic shifts in consumers' characteristics and preferences may be needed. PMID- 26526245 TI - Restaurants With Calories Displayed On Menus Had Lower Calorie Counts Compared To Restaurants Without Such Labels. AB - Beginning in December 2016, calorie labeling on menus will be mandatory for US chain restaurants and many other establishments that serve food, such as ice cream shops and movie theaters. But before the federal mandate kicks in, several large chain restaurants have begun to voluntarily display information about the calories in the items on their menus. This increased transparency may be associated with lower overall calorie content of offered items. This study used data for the period 2012-14 from the MenuStat project, a data set of menu items at sixty-six of the largest US restaurant chains. We compared differences in calorie counts of food items between restaurants that voluntarily implemented national menu labeling and those that did not. We found that the mean per item calorie content in all years was lower for restaurants that voluntarily posted information about calories (the differences were 139 calories in 2012, 136 in 2013, and 139 in 2014). New menu items introduced in 2013 and 2014 showed a similar pattern. Calorie labeling may have important effects on the food served in restaurants by compelling the introduction of lower-calorie items. PMID- 26526246 TI - Orders Of Healthier Children's Items Remain High More Than Two Years After Menu Changes At A Regional Restaurant Chain. AB - In a previous study we showed that customers ordered healthier food following the April 2012 implementation of a healthier children's menu at Silver Diner, a regional restaurant chain. In this study we used newly available data to assess orders of children's menu items both one and two years after our last assessment. Previous assessments took place in September 2011-March 2012 and in September 2012-March 2013, before and after implementation of the new menu, respectively. Orders were abstracted from the restaurant's central database. We found that the overarching changes from the previous study were sustained during the two follow up periods, with some small fluctuations (for example, the prevalence of healthy side dish orders changed from 38 percent of children's meals ordered to 74 percent, then 76 percent, and then 75 percent in the successive study periods). Ordering patterns at follow-up remained healthier than before the menu change and in some cases continued to improve. Similar interventions have the potential to promote sustainable healthier ordering patterns and inform policy. PMID- 26526247 TI - Five Years Later: Awareness Of New York City's Calorie Labels Declined, With No Changes In Calories Purchased. AB - To follow up on a previous study that examined how the mandated displaying of calorie information on menu boards in fast-food restaurants in New York City influenced consumers' behavior, we analyzed itemized cash register receipts and survey responses from 7,699 consumers at four fast-food chains. Using a difference-in-differences study design, we found that consumers exposed to menu labeling immediately after the mandate took effect in 2008 and at three points in 2013-14 reported seeing and using the information more often than their counterparts at fast-food restaurants without menu labeling. In each successive period of data collection, the percentage of respondents noticing and using the information declined, while remaining above the prelabeling baseline. There were no statistically significant changes over time in levels of calories or other nutrients purchased or in the frequency of visits to fast-food restaurants. Menu labeling at fast-food chain restaurants, which the Affordable Care Act requires to be implemented nationwide in 2016, remains an unproven strategy for improving the nutritional quality of consumer food choices at the population level. Additional policy efforts that go beyond labeling and possibly alter labeling to increase its impact must be considered. PMID- 26526248 TI - Infographics And Public Policy: Using Data Visualization To Convey Complex Information. AB - Data visualization combines principles from psychology, usability, graphic design, and statistics to highlight important data in accessible and appealing formats. Doing so helps bridge knowledge producers with knowledge users, who are often inundated with information and increasingly pressed for time. PMID- 26526249 TI - A Food Systems Approach To Healthy Food And Agriculture Policy. AB - Food has become a prominent focus of US public health policy. The emphasis has been almost exclusively on what Americans eat, not what is grown or how it is grown. A field of research, policy, and practice activities addresses the food health-agriculture nexus, yet the work is still often considered "alternative" to the mainstream. This article outlines the diverse ways in which agriculture affects public health. It then describes three policy issues: farm-to-school programming, sustainability recommendations in the Dietary Guidelines for Americans, and antibiotic use in animal agriculture. These issues illustrate the progress, challenges, and public health benefits of taking a food systems approach that brings together the food, agriculture, and public health fields. PMID- 26526250 TI - Improvements In US Diet Helped Reduce Disease Burden And Lower Premature Deaths, 1999-2012; Overall Diet Remains Poor. AB - Evaluation of time trends in dietary quality and their relation to disease burden provides essential feedback for policy making. We used an index titled the Alternate Healthy Eating Index 2010 to evaluate trends in dietary quality among 33,885 US adults. From 1999 to 2012 the index increased from 39.9 to 48.2 (perfect score = 110). Gaps in performance on the index across socioeconomic groups persisted or widened. Using data relating index scores to health outcomes in two large cohorts, we estimated that the improvements in dietary quality from 1999 to 2012 prevented 1.1 million premature deaths. Also, this improvement in diet quality resulted in 8.6 percent fewer cardiovascular disease cases, 1.3 percent fewer cancer cases, and 12.6 percent fewer type 2 diabetes cases. Although the steady improvement in dietary quality likely accounted for substantial reductions in disease burden from 1999 to 2012, overall dietary quality in the United States remains poor. Policy initiatives are needed to ensure further improvements. PMID- 26526251 TI - Severe Obesity In Adults Cost State Medicaid Programs Nearly $8 Billion In 2013. AB - Efforts to expand Medicaid while controlling spending must be informed by a deeper understanding of the extent to which the high medical costs associated with severe obesity (having a body mass index of [Formula: see text] or higher) determine spending at the state level. Our analysis of population-representative data indicates that in 2013, severe obesity cost the nation approximately $69 billion, which accounted for 60 percent of total obesity-related costs. Approximately 11 percent of the cost of severe obesity was paid for by Medicaid, 30 percent by Medicare and other federal health programs, 27 percent by private health plans, and 30 percent out of pocket. Overall, severe obesity cost state Medicaid programs almost $8 billion a year, ranging from $5 million in Wyoming to $1.3 billion in California. These costs are likely to increase following Medicaid expansion and enhanced coverage of weight loss therapies in the form of nutrition consultation, drug therapy, and bariatric surgery. Ensuring and expanding Medicaid-eligible populations' access to cost-effective treatment for severe obesity should be part of each state's strategy to mitigate rising obesity related health care costs. PMID- 26526252 TI - Three Interventions That Reduce Childhood Obesity Are Projected To Save More Than They Cost To Implement. AB - Policy makers seeking to reduce childhood obesity must prioritize investment in treatment and primary prevention. We estimated the cost-effectiveness of seven interventions high on the obesity policy agenda: a sugar-sweetened beverage excise tax; elimination of the tax subsidy for advertising unhealthy food to children; restaurant menu calorie labeling; nutrition standards for school meals; nutrition standards for all other food and beverages sold in schools; improved early care and education; and increased access to adolescent bariatric surgery. We used systematic reviews and a microsimulation model of national implementation of the interventions over the period 2015-25 to estimate their impact on obesity prevalence and their cost-effectiveness for reducing the body mass index of individuals. In our model, three of the seven interventions--excise tax, elimination of the tax deduction, and nutrition standards for food and beverages sold in schools outside of meals--saved more in health care costs than they cost to implement. Each of the three interventions prevented 129,000-576,000 cases of childhood obesity in 2025. Adolescent bariatric surgery had a negligible impact on obesity prevalence. Our results highlight the importance of primary prevention for policy makers aiming to reduce childhood obesity. PMID- 26526253 TI - Consumption Of Specific Foods And Beverages And Excess Weight Gain Among Children And Adolescents. AB - Efforts are under way to identify successful strategies to reduce long-term childhood obesity risk, such as ways to improve diet quality. To identify foods and beverages associated with excess weight gain, we used cohort data from the Avon Longitudinal Study of Parents and Children in the United Kingdom. We quantified the associations between changes in or levels of consumption of twenty seven food and beverage groups and excess weight gain in three-year periods among youth ages 7-13. When we considered all dietary factors and physical activity levels simultaneously, we found that foods with the largest positive associations with three-year excess weight gain were fat spread (butter or margarine), coated (breaded or battered) poultry, potatoes cooked in oil (French fries, roasted potatoes, and potato chips), coated fish, processed meats, other meats, desserts and sweets, milk, and sugar-sweetened beverages. Foods associated with weight loss were whole grains and high-fiber cereals. These results provide evidence for targeting specific food and beverage groups in efforts to influence weight outcomes. PMID- 26526254 TI - Transitions Into Food Insecurity Associated With Behavioral Problems And Worse Overall Health Among Children. AB - Children living in food-insecure households face myriad challenges to their well being. The Great Recession of December 2007-June 2009 increased food insecurity to the highest levels ever measured in the United States. Using nationally representative data from the period 2010-12 for 6,300 children in the Early Childhood Longitudinal Study, Kindergarten Class of 2010-11, with household incomes below 300 percent of the federal poverty level and a dynamic measure of food insecurity transitions, we assessed the impact of transitions into and out of household food insecurity on the academic achievement, behavioral problems, and health status of young children. We found negligible impacts of food insecurity transitions on academic achievement in first grade. However, we found consistent negative impacts of the transitions on teachers' reports of children's externalizing behaviors, self-control, and interpersonal skills and on parents' reports of children's overall health status. Taken together, our findings underline the importance of food security for children's healthy development. PMID- 26526255 TI - A Pilot Food Bank Intervention Featuring Diabetes-Appropriate Food Improved Glycemic Control Among Clients In Three States. AB - Food insecurity--defined as not having adequate quantity and quality of food at all times for all household members to have an active, healthy life--is a risk factor for poor diabetes control, yet few diabetes interventions address this important factor. Food pantries, which receive food from food banks and distribute it to clients in need, may be ideal sites for diabetes self-management support because they can provide free diabetes-appropriate food to people in low income communities. Between February 2012 and March 2014, we enrolled 687 food pantry clients with diabetes in three states in a six-month pilot intervention that provided them with diabetes-appropriate food, blood sugar monitoring, primary care referral, and self-management support. Improvements were seen in pre post analyses of glycemic control (hemoglobin A1c decreased from 8.11 percent to 7.96 percent), fruit and vegetable intake (which increased from 2.8 to 3.1 servings per day), self-efficacy, and medication adherence. Among participants with elevated HbA1c (at least 7.5 percent) at baseline, HbA1c improved from 9.52 percent to 9.04 percent. Although food pantries are nontraditional settings for diabetes support, this pilot study suggests a promising health promotion model for vulnerable populations. Policies supporting such interventions may be particularly effective because of food pantries' food access and distribution capacity. PMID- 26526256 TI - China's Left-Behind Children: Impact Of Parental Migration On Health, Nutrition, And Educational Outcomes. AB - China's rapid development and urbanization have induced large numbers of rural residents to migrate from their homes to urban areas in search of better job opportunities. Parents typically leave their children behind with a caregiver, creating a new, potentially vulnerable subpopulation of left-behind children in rural areas. A growing number of policies and nongovernmental organization efforts target these children. The primary objective of this study was to examine whether left-behind children are really the most vulnerable and in need of special programs. Pulling data from a comprehensive data set covering 141,000 children in ten provinces (from twenty-seven surveys conducted between 2009 and 2013), we analyzed nine indicators of health, nutrition, and education. We found that for all nine indicators, left-behind children performed as well as or better than children living with both parents. However, both groups of children performed poorly on most of these indicators. Based on these findings, we recommend that special programs designed to improve health, nutrition, and education among left-behind children be expanded to cover all children in rural China. PMID- 26526257 TI - Guiding Principles And A Decision-Making Framework For Stakeholders Pursuing Healthy Food Environments. AB - To address obesity and diet-related chronic diseases in the United States, organizations such as the Robert Wood Johnson Foundation and the Institute of Medicine have encouraged the use of voluntary engagement strategies among stakeholders. By using public-private partnerships as well as networks, alliances, and coalitions, voluntary engagement can translate evidence-informed dietary recommendations into effective policies and actions and into innovative products and services. We offer six guiding principles and a decision-making framework that stakeholders can use to ensure that partnerships are accountable and effective in their pursuit of health-related goals. We apply the principles and framework to four national partnerships of US food, beverage, and food retail industry stakeholders working to prevent child obesity and to promote healthy food environments through product reformulation and healthy food retail incentives. We conclude that partnerships should be evaluated for their synergy, accountability, and effectiveness at achieving the partners' objectives. Independent evaluations will help build credibility and public trust in the capacity of voluntary engagement strategies to promote healthy food environments and positively influence public health. PMID- 26526258 TI - Challenges And Lessons Learned From Communities Using Evidence To Adopt Strategies To Improve Healthy Food Environments. AB - Communities across the United States are increasingly tackling the complex task of changing their local environments and cultures to improve access to and consumption of healthy food. Communities that have received the Robert Wood Johnson Foundation Culture of Health Prize have deployed numerous evidence informed strategies to enhance their local food environments. Their experiences can provide lessons for other communities working to improve health. In this article we examine how the prize-winning communities worked in a multidisciplinary collective manner to implement evidence-based strategies, deployed suites of strategies to expand the reach of food-related work, balanced evidence against innovation, and measured their own progress. Most of the communities also faced challenges in using evidence effectively to implement strategies to promote healthy food environments. Policy makers can accelerate the adoption of evidence-informed approaches related to food and health by embedding them in program standards and funding requirements. Establishing opportunities for ongoing training to enhance community practitioners' evaluation skills and collaborative leadership would also improve the effectiveness of community implementation of these strategies. PMID- 26526259 TI - Outstanding Questions In First Amendment Law Related To Food Labeling Disclosure Requirements For Health. AB - The federal and state governments are increasingly focusing on food labeling as a method to support good health. Many such laws are opposed by the food industry and may be challenged in court, raising the question of what is legally feasible. This article analyzes outstanding questions in First Amendment law related to commercial disclosure requirements and conducts legal analysis and policy evaluation for three current policies. These include the Food and Drug Administration's draft regulation requiring an added sugar disclosure on the Nutrition Facts panel, California's proposed sugar-sweetened beverage safety warning label bill, and Vermont's law requiring labels of genetically engineered food to disclose this information. I recommend several methods for policy makers to enact food labeling laws within First Amendment parameters, including imposing factual commercial disclosure requirements, disclosing the government entity issuing a warning, collecting evidence, and identifying legitimate governmental interests. PMID- 26526260 TI - Bearing Fruit: The Fight For The FDA's Food Safety Reforms. AB - A food safety advocate recounts one long road to the passage of the FDA Food Safety Modernization Act of 2011. PMID- 26526261 TI - Food And Health: What Foundations Are Funding. PMID- 26526263 TI - An Interdisciplinary Team To Inform Patients' Decisions. PMID- 26526264 TI - A Team To Inform Patients' Decisions: The Authors Reply. PMID- 26526265 TI - Noncommunicable Diseases And Essential Medicines. PMID- 26526266 TI - Noncommunicable Diseases: The Authors Reply. PMID- 26526267 TI - Low-Income Countries And Repurposed Drugs. PMID- 26526268 TI - Nonprofit Hospitals And Community Health. PMID- 26526269 TI - End-Stage Kidney Disease Without Dialysis. PMID- 26526270 TI - End-Stage Kidney Disease: The Author Replies. PMID- 26526272 TI - Rebleeding of Ruptured Intracranial Aneurysms in the Immediate Postoperative Period after Coil Embolization. AB - OBJECTIVE: Early rebleeding after coil embolization of ruptured intracranial aneurysms is rare, however serious and fatal results of rebleeding have been reported. We studied the incidence and angiographic and clinical characteristics of rebleeding of ruptured aneurysms occurring in the immediate postoperative period after coil embolization. MATERIALS AND METHODS: We analyzed patients who had aneurysmal subarachnoid hemorrhage and underwent coil embolization. Patients with dissecting aneurysms, blood blister-like aneurysms, fusiform aneurysms, and pseudoaneurysms were excluded. This study included 330 consecutive patients. The clinical and radiological data of 7 of these patients with acute rebleeding after coil embolization were reviewed. RESULTS: The incidence of rebleeding of ruptured aneurysms after coil embolization was 2.1% (7/330), and all cases of rebleeding occurred in the immediate postoperative period within 3 days after coiling. The radiological characteristics were as follows: anterior communicating artery (ACoA) aneurysm (71.4%, 5/7); presence of intracerebral hemorrhage (ICH, 71.4%, 5/7); dome-to-neck ratio < 2 (42.9%, 3/7); presence of bleb (42.9%, 3/7); and subtotal occlusion of aneurysm after coiling (14.3%, 1/7). A thrombolytic agent was administered in 1 patient and continued anticoagulation was performed in 2 patients. Rebleeding patients showed a very poor outcome (Glasgow Outcome Scale 1, 85.7%, 6/7). CONCLUSION: The prognosis of early rebleeding was very poor. Location of aneurysms on ACoA, the unilateral hypoplasia of A1 segment, presence of ICH and bleb, and adverse events during the procedure were probably associated with early rebleeding of ruptured intracranial aneurysms in the immediate postoperative period after coil embolization. PMID- 26526273 TI - Prediction of designer drugs: synthesis and spectroscopic analysis of synthetic cannabinoid analogues of 1H-indol-3-yl(2,2,3,3-tetramethylcyclopropyl)methanone and 1H-indol-3-yl(adamantan-1-yl)methanone. AB - In this work, emergence patterns of synthetic cannabinoids were utilized in an attempt to predict those that may appear on the drug market in the future. Based on this information, two base structures of the synthetic cannabinoid analogues - (1H-indol-3-yl(2,2,3,3-tetramethylcyclopropyl)methanone and 1H-indol-3 yl(adamantan-1-yl)methanone) - together with three substituents - butyl, 4 fluorobutyl and ethyl tetrahydropyran - were selected for synthesis. This resulted in a total of six synthetic cannabinoid analogues that to the authors' knowledge have not yet appeared on the drug market. Spectroscopic data, including nuclear magnetic resonance (NMR), mass spectrometry (MS), and Fourier transform infrared (FTIR) spectroscopy (solid and gas phase), are presented for the synthesized analogues and some additional related cannabinoids. In this context, the suitability of the employed techniques for the identification of unknowns is discussed and the use of GC-FTIR as a secondary complementary technique to GC-MS is addressed. Examples of compounds that are difficult to differentiate by their mass spectra, but can be distinguished based upon their gas phase FTIR spectra are presented. Conversely, structural homologues where mass spectra are more powerful than gas phase FTIR spectra for unambiguous assignments are also exemplified. This work further emphasizes that a combination of several techniques is the key to success in structural elucidations. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26526274 TI - [Annular lipoatrophy of the ankle of fortuitous discovery]. PMID- 26526275 TI - Chronic Pelvic and Vulvar Pain in Women. AB - Peripheral generators and the central nervous system have a role in the production of visceral and somatic hypersensivities and hyperalgesias.More generalised symptoms often exist and efferent activity from the CNS may also be responsible for abnormal visceral and muscular function.It is important to dissect out the symptoms and as well as treating peripheral generators to consider interventions of the central mechanisms aimed at the cognitive behavioural aspects of the patients' condition. PMID- 26526276 TI - Electrophysiological and psychophysical asymmetries in sensitivity to interaural correlation gaps and implications for binaural integration time. AB - Brief deviations of interaural correlation (IAC) can provide valuable cues for detection, segregation and localization of acoustic signals. This study investigated the processing of such "binaural gaps" in continuously running noise (100-2000 Hz), in comparison to silent "monaural gaps", by measuring late auditory evoked potentials (LAEPs) and perceptual thresholds with novel, iteratively optimized stimuli. Mean perceptual binaural gap duration thresholds exhibited a major asymmetry: they were substantially shorter for uncorrelated gaps in correlated and anticorrelated reference noise (1.75 ms and 4.1 ms) than for correlated and anticorrelated gaps in uncorrelated reference noise (26.5 ms and 39.0 ms). The thresholds also showed a minor asymmetry: they were shorter in the positive than in the negative IAC range. The mean behavioral threshold for monaural gaps was 5.5 ms. For all five gap types, the amplitude of LAEP components N1 and P2 increased linearly with the logarithm of gap duration. While perceptual and electrophysiological thresholds matched for monaural gaps, LAEP thresholds were about twice as long as perceptual thresholds for uncorrelated gaps, but half as long for correlated and anticorrelated gaps. Nevertheless, LAEP thresholds showed the same asymmetries as perceptual thresholds. For gap durations below 30 ms, LAEPs were dominated by the processing of the leading edge of a gap. For longer gap durations, in contrast, both the leading and the lagging edge of a gap contributed to the evoked response. Formulae for the equivalent rectangular duration (ERD) of the binaural system's temporal window were derived for three common window shapes. The psychophysical ERD was 68 ms for diotic and about 40 ms for anti- and uncorrelated noise. After a nonlinear Z-transform of the stimulus IAC prior to temporal integration, ERDs were about 10 ms for reference correlations of +/-1 and 80 ms for uncorrelated reference. Hence, a physiologically motivated peripheral nonlinearity changed the rank order of ERDs across experimental conditions in a plausible manner. PMID- 26526277 TI - Clustering of elderly patient subgroups to identify medication-related readmission risks. AB - INTRODUCTION: High Risk Medication Regimen (HRMR) scores are weakly predictive of hospital readmissions for elderly home health care patients. HRMR is composed of three elements related to drug risks: polypharmacy (number of medications); Potentially Inappropriate Medications (PIM) known to be harmful to the elderly; and the Medication Regimen Complexity Index (MRCI) that weighs drugs by the complexity of their dosing and instructions. In this paper, we hypothesized that HRMR scores are more predictive for demographic subgroups of elderly patients. The study used Outcome and Assessment Information Set (OASIS) variables to identify subgroups of patients for whom the HRMR measures appeared more predictive for hospital readmissions. METHODS: OASIS and medication data were reused from a study of 911 patients (355 males, 556 females; mean age 78.9) from 15 Medicare-certified home health care agencies that established the relationship between HRMR and hospital readmissions. Hierarchical agglomerative clustering using the Jaccard distance measure and average-link method identified patient subgroups based on the OASIS data. Receiver operating curve (ROC) analyses evaluated the predictive strength of the HRMR variables for each subgroup. Additional False Discovery Rate (FDR) analyses assessed whether the clustered relationships were chance. RESULTS: Clustering of OASIS data for 911 patients identified six subgroups: patients with Good Functional Status (n=382); Females with Moderate to Severe Pain (n=354); patients with poor prognosis needing functional status assistance (n=419); patients with Poor Functional Status (n=287); Males with Adult Children as Caregiver (n=198); adults living alone with spouses as primary caregiver (n=127). ROC results relating these subgroups to HRMR risks were strongest for Males with Adult Children as Caregivers (AUC: polypharmacy, 0.73; PIM, 0.64; MRCI, 0.77). The findings for this subgroup also met the FDR analysis threshold (<=0.20). CONCLUSIONS: A risk of medication related readmissions in elderly men with adult children as caregivers is consistent with research showing problems in medication adherence when seniors are supported by informal caregivers. The results from clustering analysis present a hypothesis for research on HRMR and on the relationship between adult caregivers and their fathers. PMID- 26526278 TI - Criterion validity of a computer-assisted instrument of self-triage (ca-ISET) compared to the validity of regular triage in an ophthalmic emergency department. AB - OBJECTIVES: The computer-assisted version of a self-triage tool (ca-ISET) for an ophthalmic emergency department (ED) was developed to increase the validity of the triage procedure when trained ED staff is absent. METHODS: We tested whether sensitivity, specificity, Negative Predictive Value (NPV) and Positive Predictive Value (PPV) of the ca-ISET deviated from regular triage. Patients >=18 years visiting the ED of the Rotterdam Eye Hospital in the Netherlands were invited to participate in this prospective study. This ED focuses on eye-related problems. Patient recruitment was carried out during working hours. The ca-ISET is a touch operated software application and the algorithm of the triage is based in the Manchester triage system. For all participants three triage scores were determined by (1) the participant using the ca-ISET; (2) triage by a regular, trained triage assistant and (3) triage by one physician who was specially trained in ophthalmic triage. The diagnosis of the physician was chosen as the reference standard to define criterion validity. The order of triage administration was alternated per patient. Only cases with triage scores from the two triage systems and the reference standard were included. The outcome variables, four triage colours, were transformed into a binary score: high urgent and low urgent. The difference between the ca-ISET and regular triage in terms of sensitivity, specificity, NPV and PPV was tested by Z-scores. RESULTS: Of 247 eligible patients, data was elicited from 189 patients (average age 54 years, range 18-89). The sensitivity of the ca-ISET (0.89, CI: 0.75-0.96) did not differ from the sensitivity of the regular triage (0.69, CI: 0.53-0.82, Z=1.74, p=0.08). The ca-ISET was less specific (0.78, CI: 0.71-0.84) than the regular triage (0.92, CI=0.86-0.95, Z=3.04, p=0.00). We found no significant difference between the ca-ISET and regular triage for PPV (Z=0.19, p=0.85) and NPV (Z=0.03, p=0.98). CONCLUSIONS: The sensitivity, PPV and NPV of the ca-ISET does not differ from the sensitivity of the regular triage, while the ca-ISET retained a reasonable level of specificity. Therefore the ca-ISET can be recommended as a tool for ophthalmic emergency departments, and could be used when trained ED staff is absent. PMID- 26526279 TI - Anticipating mismatches of HIT investments: Developing a viability-fit model for e-health services. AB - OBJECTIVES: Albeit massive investments in the recent years, the impact of health information technology (HIT) has been controversial and strongly disputed by both research and practice. While many studies are concerned with the development of new or the refinement of existing measurement models for assessing the impact of HIT adoption (ex post), this study presents an initial attempt to better understand the factors affecting viability and fit of HIT and thereby underscores the importance of also having instruments for managing expectations (ex ante). METHODS: We extend prior research by undertaking a more granular investigation into the theoretical assumptions of viability and fit constructs. In doing so, we use a mixed-methods approach, conducting qualitative focus group discussions and a quantitative field study to improve and validate a viability-fit measurement instrument. RESULTS: Our findings suggest two issues for research and practice. First, the results indicate that different stakeholders perceive HIT viability and fit of the same e-health services very unequally. Second, the analysis also demonstrates that there can be a great discrepancy between the organizational viability and individual fit of a particular e-health service. CONCLUSION: The findings of this study have a number of important implications such as for health policy making, HIT portfolios, and stakeholder communication. PMID- 26526280 TI - [Bone metabolism and fracture treatment]. PMID- 26526282 TI - Exploring classical conditioning for strengthening the links between semantic and lexical representations in pure anomia: Preliminary findings from a single case study. AB - The same language symptom might arise at different functional loci in people with aphasia. Therefore, it is plausible that different therapeutic interventions should be adopted to approach the same difficulties in different patients. Although this point of view is still widely accepted, recently the focus has shifted from the functional locus of a rehabilitative intervention to the mechanisms of action underlying the relearning process. We maintain that both aspects should be taken into account when programming a rehabilitative intervention; furthermore, investigating relearning mechanisms might shed new light on the functional architecture of the disrupted processes. Here, we investigated, in a single case study, whether classical conditioning was a suitable relearning paradigm for targeting word-finding difficulties in pure anomia, that is in a patient with an impairment in accessing intact output lexical representations from a spared semantic system. Using a word-repetition task on picture presentation, we contrasted a condition in which the stimulus onset asynchrony between word and picture stimuli was well suited to produce classical conditioning with a condition in which repetition training could not benefit from this learning mechanism. Only classical conditioning training exerted a significant, long-lasting effect on our patient's naming skill. Tentative implications of our results for the functional architecture of single word processing are discussed. PMID- 26526283 TI - Complex relationship between sex hormones, insulin resistance and leptin in men with and without prostatic disease. AB - OBJECTIVES: To assess sex hormones, leptin and insulin-resistance in men with prostate cancer (PCa) and benign prostatic hyperplasia (BPH) and to study associations between androgens and histologic score of prostate tissue in PCa. SUBJECTS AND METHODS: Two hundred ten men older than 45 years selected from 2906 participants of a population screening for PCa were studied: 70 with PCa, 70 with BPH and 70 controls (CG), matched by body mass index and age. Insulin, IGF-1, PSA, leptin, total, free (fT) and bioavailable testosterone (bT) and estradiol were measured. Each group was subdivided into two subgroups considering the presence of metabolic syndrome (MS); androgens and leptin levels were analyzed in the subgroups. RESULTS: Prostate cancer and BPH patients presented higher total, fT and bT levels than CG. IGF-1, insulin and HOMA index were higher in BPH than in the other two groups. PCa presented higher leptin [median (range) 6.5 (1.3 28.0) versus 4.8 (1.1-12.3) ng/ml; p < 0.01] and estradiol [median (range) 37.0 (20-90) versus 29.0 (20-118) pg/ml; p = 0.025] levels than CG. After dividing men considering the presence of MS, leptin was higher and total testosterone was lower in MS patients in all the groups. CONCLUSIONS: It was observed a coexistence of an altered hormone profile with increased sex hormones and leptin in PCa patients, in accordance with the new perspective of PCa pathogenesis. PMID- 26526284 TI - Pain, Cancer and Palliative Care. PMID- 26526281 TI - A history of spine biomechanics. Focus on 20th century progress. AB - The application of mechanical principles to problems of the spine dates to antiquity. Significant developments related to spinal anatomy and biomechanical behaviour made by Renaissance and post-Renaissance scholars through the end of the 19th century laid a strong foundation for the developments since that time. The objective of this article is to provide a historical overview of spine biomechanics with a focus on the developments in the 20th century. The topics of spine loading, spinal posture and stability, spinal kinematics, spinal injury, and surgical strategies were reviewed. PMID- 26526285 TI - Biotechnologies for gaseous emissions and by-products management in waste treatment facilities. PMID- 26526287 TI - Coastal sea level projections with improved accounting for vertical land motion. AB - Regional and coastal mean sea level projections in the Intergovernmental Panel for Climate Change (IPCC) Fifth Assessment Report (AR5) account only for vertical land motion (VLM) associated with glacial isostatic adjustment (GIA), which may significantly under- or over-estimate sea level rise. Here we adjust AR5-like regional projections with the VLM from Global Positioning Satellite (GPS) measurements and/or from a combination of altimetry and tide-gauge data, which include both GIA and non-GIA VLM. Our results at selected tide-gauge locations on the North American and East Asian coasts show drastically different projections with and without non-GIA VLM being accounted for. The present study points to the importance of correcting IPCC AR5 coastal projections for the non-GIA VLM in making adaptation decisions. PMID- 26526286 TI - Feasibility of an exercise programme in elderly patients undergoing allogeneic stem cell transplantation - a pilot study. AB - It has been demonstrated that physical exercise benefits younger patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). We designed a prospective pilot study investigating whether elderly patients (>60 years) would also be able to participate in such a programme. It consisted of physiotherapist-supervised alternating endurance and resistance workouts on 6 of 7 days a week. Sixteen consecutive patients undergoing allo-HSCT were enrolled into the study. The median age was 64.5 years. Twelve patients participated in the programme until the time of discharge (75%) from the transplant unit. Therefore, the predefined criteria regarding feasibility were met. The reason for drop out was transplantation associated mortality in all patients (n = 4). Adherence was very good with a median of 85% attended training sessions. No adverse events were recorded. The endurance capacity dropped by 7% and lower extremity strength improved by 2% over time. Quality of life decreased during the study period, with global health being significantly worse at the time of discharge. In conclusion, a combined and intensified strength and endurance exercise programme is feasible and safe in a population of elderly patients undergoing allo-HSCT. Further research should focus on exploring effect sizes of such an intervention by conducting randomised controlled trials. PMID- 26526288 TI - The experience of participatory research: Perceptions of oncology employees participating in a workplace study. AB - Participatory research, a concept developed in the Third World, has been increasingly applied to community and health research in developed countries. However, little is known about attitudes to the participatory process in the context of workplace research, especially that carried out in health care settings. In this qualitative study, employees participating in a quality of work life (QWL) project at a Canadian cancer centre were asked about their perceptions of the participatory research process. Using a phenomenological approach, the author interviewed 12 employees. The following themes emerged from the analysis of interview data: 1) The role of management and senior management was viewed as being important but employees were uncomfortable with the presence of management at meetings; 2) The desired composition of the committee was more complex than ensuring representation from workers and there may have been a natural process by which this composition was attained; 3) Participatory research without action was unacceptable; and 4) Full participation in all aspects of the project was difficult to achieve. These findings have important implications because they challenge some existing notions in the literature about participatory research. Recommendations regarding trust issues, membership recruitment, and the role of members in the participatory process are outlined. PMID- 26526290 TI - Electrode position markedly affects knee torque in tetanic, stimulated contractions. AB - PURPOSE: The purpose of this study was to investigate how much the distance between stimulation electrodes affects the knee extension torque in tetanic, electrically elicited contractions. METHODS: Current pulses of progressively larger amplitude, from 0 mA to maximally tolerated intensities, were delivered at 20 pps to the vastus medialis, rectus femoris and vastus lateralis muscles of ten, healthy male subjects. Four inter-electrode distances were tested: 32.5% (L1), 45.0% (L2), 57.5% (L3) and 70% (L4) of the distance between the patella apex and the anterior superior iliac spine. The maximal knee extension torque and the current leading to the maximal torque were measured and compared between electrode configurations. RESULTS: The maximal current tolerated by each participant ranged from 60 to 100 mA and did not depend on the inter-electrode distance. The maximal knee extension torque elicited did not differ between L3 and L4 (P = 0.15) but, for both conditions, knee torque was significantly greater than for L1 and L2 (P < 0.024). On average, the extension torque elicited for L3 and L4 was two to three times greater than that obtained for L1 and L2. The current leading to maximal torque was not as sensitive to inter-electrode distance. Except for L1 current intensity did not change with electrode configuration (P > 0.16). CONCLUSIONS: Key results presented here revealed that for a given stimulation intensity, knee extension torque increased dramatically with the distance between electrodes. The distance between electrodes seems therefore to critically affect knee torque, with potential implication for optimising exercise protocols based on electrical stimulation. PMID- 26526291 TI - Interactions of mean body and local skin temperatures in the modulation of human forearm and calf blood flows: a three-dimensional description. AB - AIM: The inter-relationships between mean body and local skin temperatures have previously been established for controlling hand and foot blood flows. Since glabrous skin contains many arteriovenous anastomoses, it was important to repeat those experiments on non-glabrous regions using the same sample and experimental conditions. METHODS: Mild hypothermia (mean body temperature 31.4 degrees C), normothermia (control: 36.0 degrees C) and moderate hyperthermia (38.3 degrees C) were induced and clamped (climate chamber and water-perfusion garment) in eight males. Within each condition, five localised thermal treatments (5, 15, 25, 33, 40 degrees C) were applied to the left forearm and right calf. Steady-state forearm and calf blood flows were measured (venous occlusion plethysmography) for each of the resulting 15 combinations of clamped mean body and local skin temperatures. RESULTS: Under the normothermic clamp, cutaneous blood flows averaged 4.2 mL 100 mL(-1) min(-1) (+/-0.28: forearm) and 5.4 mL 100 mL(-1) min( 1) (+/-0.27: calf). When mildly hypothermic, these segments were unresponsive to localised thermal stimuli, but tracked those changes when normothermic and moderately hyperthermic. For deep-body (oesophageal) temperature elevations, forearm blood flow increased by 5.1 mL 100 mL(-1) min(-1) degrees C(-1) (+/-0.9) relative to normothermia, while the calf was much less responsive: 3.3 mL 100 mL( 1) min(-1) degrees C(-1) (+/-1.5). Three-dimensional surfaces revealed a qualitative divergence in the control of calf blood flow, with vasoconstrictor tone apparently being released more gradually. CONCLUSION: These descriptions reinforce the importance of deep-tissue temperatures in controlling cutaneous perfusion, with this modulation being non-linear at the forearm and appearing linear for the calf. PMID- 26526292 TI - Prevalence of Influenza Vaccination in Chronic Obstructive Pulmonary Disease Patients and Impact on the Risk of Severe Exacerbations. AB - OBJECTIVE: To determine the prevalence of influenza vaccination in chronic obstructive pulmonary disease (COPD) patients, and the effectiveness of the procedure. METHODS: Retrospective population-based cohort study. On 31 December 2011, influenza vaccination history was retrieved from 899 patients with confirmed COPD selected by simple random sampling from all COPD patients in Cantabria (northern Spain). Severe exacerbations (hospitalization due to COPD exacerbation) and overall mortality during 2012 were treated as dependent variables. Odds ratios (OR) were estimated by logistic regression, adjusting for age, sex, smoking status, severity of COPD, and frequency of exacerbations during the previous year. Prevented fraction among the exposed (PFe-adjusted) was determined as a measure of impact. RESULTS: Overall prevalence of influenza vaccination was 62.7%, but this rate fell in patients classified as more severe according to FEV1 (52.0%). Influenza vaccination showed a statistically significant protective effect against severe exacerbations in the following year: Ora: 0.54 (95%CI: 0.35-0.84); FPe-adjusted: 0.46 (95%CI: 0.16-0.65). A non significant protective effect for overall mortality was observed: Ora: 0.76 (95%CI: 0.41-1.40). When stratified according to COPD severity (FEV1), the protective effect against risk of hospitalization was higher in more severe COPD patients: Ora: 0.23 (95%CI: 0.11-0.48); FPe-adjusted: 0.77 (95%CI: 0.52-0.89). CONCLUSIONS: We found that influenza vaccination has a protective effect and reduces the risk of hospitalization due to exacerbations in the following year. Despite the evidence for protection, prevalence of vaccination was not optimal, especially in more severe COPD patients. PMID- 26526293 TI - Pulmonary dirofilariasis: A diagnostic pitfall in clinical practice. PMID- 26526294 TI - Mentors in waiting. AB - A four stage framework, developed by the Nursing and Midwifery Council for the preparation of nurses and midwives who support learners within practice and educational settings was implemented in the United Kingdom in September 2007. Since then the focus of debate and discussion within the literature has centred on stage 2 of the developmental framework i.e. the mentor role. The three other stages of registrant, practice teacher and teacher have received little attention. This paper argues that currently, the provisions made within the developmental framework in relation to the stage 1 registrant's role in supporting students within practice settings, has yet to be realised. The paper begins by contemplating both the pros and cons of the 'should all nurses be mentors' debate. The argument for embracing and utilising the stage 1 role more fully in practice is then presented. The paper concludes by underlining the need to recognise the stage 1 registrants as 'mentors in waiting' and the need to support the full potential of their contribution to students' learning and assessment in practice. PMID- 26526295 TI - Non-medical prescribing assessment - An evaluation of a nationally agreed multi method approach. AB - In the United Kingdom, legislation permits nurses and allied health professionals to prescribe for patients within their care. Preparation for this role includes learning, teaching and assessment that is embedded in practice, supervised by a designated medical practitioner (DMP) and evidenced in a reflective learning in practice portfolio. AIM: The objectives were to explore; (1) which assessment in the practice portfolio was ranked most valuable in terms of achieving safe, effective prescribing practice and, (2) whether a practice based assessment (SDEP) was an acceptable alternative to an Observed Simulated Clinical Examination (OSCE). METHODS: Online surveys were conducted and follow up semi structured telephone interviews were conducted across 5 universities in Scotland with students, DMPs and line managers. RESULTS: Students ranked the learning log most valuable and DMPs and line managers ranked the SDEP most valuable. Survey and follow up interviews suggested that the portfolio provided the opportunity to develop prescribing skills and knowledge relevant to their specific clinical speciality. There was agreement amongst all participants that clinical assessment in the practice portfolio effectively enable non-medical prescribing students to evidence prescribing competence. SUMMARY: The novel use of the SDEP and reflective summary offers a viable alternative to an OSCE and was viewed as one of the most valued components of the assessment strategy. PMID- 26526296 TI - Abiotic Hydrolysis of Fluorotelomer-Based Polymers as a Source of Perfluorocarboxylates at the Global Scale. AB - Fluorotelomer-based polymers (FTPs) are the main product of the fluorotelomer industry. For nearly 10 years, whether FTPs degrade to form perfluorooctanoate (PFOA) and perfluorocarboxylate (PFCA) homologues has been vigorously contested. Here we show that circum-neutral abiotic hydrolysis of a commercial FTP proceeds with half-life estimates of 55-89 years and that base-mediated hydrolysis overtakes neutral hydrolysis at about pH = 10, with a half-life of ~0.7 years at pH ~ 12. Considered in light of the large production volume of FTPs and the poor efficacy of conventional treatments for recovery of PFCAs from waste streams, these results suggest that FTPs manufactured to date potentially could increase PFCAs 4- to 8-fold over current oceanic loads, largely depending on the integrity of disposal units to contain PFCAs upon hydrolytic generation from FTPs. PMID- 26526297 TI - Analysis of Imprinted Gene Regulation. AB - Genetic studies have been well established for identifying sequence variants associated with phenotypes. With the expanding field of epigenetics, and the growing understanding of epigenetic regulation of gene expression, similar studies can be undertaken to also define associations between epigenetic variation and phenotypes. Of particular interest are imprinted genes, which have parent-of-origin specific regulation and expression, and are key regulators of early development. Herein, we describe methods for examining epigenetic regulation by the two major hallmarks of imprinted genes: differentially methylated regions (DMRs), regulatory DNA sequences with allele specific methylation; and monoallelic expression, the silencing and transcription of opposite alleles in a parent-of-origin specific manner. PMID- 26526298 TI - Colistin-resistant Enterobacteriaceae bacteraemia: real-life challenges and options. PMID- 26526299 TI - A meta analysis of current status of alcohol septal ablation and surgical myectomy for obstructive hypertrophic cardiomyopathy. AB - OBJECTIVE: Our objective was to perform an updated systematic review to compare the efficacy and short- and long-term mortality of surgical myectomy (SM) and alcohol septal ablation (ASA) by including most recent and largest cohort studies published in last few years. BACKGROUND: SM and ASA are the two invasive strategies used to relieve left ventricular outflow tract obstruction (LVOTO) in patients with drug refractory symptomatic hypertrophic cardiomyopathy (HCM). In the absence of a randomized trial, we tried to compare the pros and cons of the two procedures using a systematic review and meta-analysis. METHOD: A comprehensive search of three major databases was performed. We included original research studies comparing data on ASA and SM. Of 1,143 citations, 10 studies were included in the analysis. RESULTS: A total of 805 patients underwent ASA and 1,019 underwent SM. Patients undergoing SM were younger (MD 6.3, P = 0.0001) and had higher reduction in the LVOT gradient (MD -9.56, P = 0.05). However, there was similar resolution of class III and IV symptoms between the two groups (P = 0.56). There was no difference in sudden cardiac death (SCD) (P = 0.93), short term (P = 0.36), long-term all cause (P = 0.27), and long-term cardiac mortality (P = 0.58). Patients undergoing ASA had higher incidence of post procedure device implantation (OR 3.09, P < 0.00001). CONCLUSION: No significant difference in symptom relief was noted between the two approaches. ASA was as safe a myectomy with regards to SCD, short-term, and long-term mortality. (c) 2015 Wiley Periodicals, Inc. PMID- 26526300 TI - Topical tranexamic acid as an adjuvant treatment in melasma: Side-by-side comparison clinical study. AB - BACKGROUND: Tranexamic acid (TNA) is a novel therapeutic agent for hyperpigmented skin disorders. The efficacy and safety of topical TNA in patients with melasma has not been heretofore studied. The main objective of this study is to evaluate the efficacy and safety of topical TNA combined with intense pulsed light (IPL) treatment in Asians with melasma. METHODS: A randomized, split-face (internally controlled) study was conducted in 15 women who received four monthly sessions of IPL to both sides of the face. Topical TNA or vehicle was applied to a randomly assigned side during and after IPL treatment. Patients were followed up for 12 weeks after completing the IPL treatments. Baseline and follow-up melanin index (MI; measured by Mexameter(r), Courage and Khazaka, Cologne, Germany) and modified melasma area and severity index (mMASI) scores were determined. RESULTS: Thirteen subjects completed the study without serious adverse events. MI and mMASI decreased significantly from baseline to 12 weeks after the last IPL treatment on the topical TNA side but not on the vehicle side. The efficacy of topical TNA in preventing rebound pigmentation after IPL treatment was also statistically significant. CONCLUSION: Topical TNA can be considered an effective and safe adjuvant to conventional treatment for melasma. PMID- 26526301 TI - Enhanced Fibroblast Cellular Ligamentization Process to Polyethylene Terepthalate Artificial Ligament by Silk Fibroin Coating. AB - Artificial ligaments utilized in reconstruction of anterior cruciate ligament (ACL) are usually made of polyethylene terepthalate (PET) because of its good mechanical properties in vivo. However, it was found that the deficiencies in hydrophilicity and biocompatibility of PET hindered the process of ligamentization. Therefore, surface modification of the PET is deemed as a solution in resolving such problem. Silk fibroin (SF), which is characterized by good biocompatibility and low immunogenicity in clinical applications, was utilized to prepare a coating on the PET ligament (PET+SF) in this work. At first, decrease of hydrophobicity and appearance of amino groups were found on the surface of artificial PET ligament after coating with SF. Second, mouse fibroblasts were cultured on the two different kinds of ligament in order to clarify the possible effect of SF coating. It was proved that mouse fibroblasts display better adhesion and proliferation on PET+SF than PET ligament according to the results of several technical methods including SEM observation, cell adhesive force and spread area test, and mRNA analysis. Meanwhile, methylthiazolyldiphenyl-tetrazolium bromide and DNA content tests showed that biocompatibility of PET+SF is better than PET ligament. In addition, collagen deposition tests also indicated that the quantity of collagen in PET+SF is higher than PET ligament. Based on these results, it can be concluded that SF coating is suggested to be an effective approach to modify the surface of PET ligament and enhance the "ligamentization" process in vivo accordingly. PMID- 26526302 TI - Preface for the Special Issue Prof. Lynn Wecker. PMID- 26526303 TI - Cloning, expression of, and evidence of positive selection for, the prolactin receptor gene in Chinese giant salamander (Andrias davidianus). AB - Prolactin receptor (PRLR) is a protein associated with reproduction in mammals and with osmoregulation in fish. In this study, the complete length of Chinese giant salamander Andrias davidianus prolactin receptor (AD-prlr) was cloned. Andrias davidianus prlr expression was high in the kidney, pituitary, and ovary and low in other examined tissues. The AD-prlr levels were higher in ovary than in testis, and increased in ovaries with age from 1 to 6 years. To determine effect of exogenous androgen and aromatase inhibitor on AD-prlr expression, methyltestosterone (MT) and letrozole (LE) were injected, resulting in decreased AD-prlr in both brain and ovary, with MT repressing prlr transcription more rapidly than did LE. The molecular evolution of prlr was assessed, and found to have undergone a complex evolution process. The obranch-site test detected four positively selected sites in ancestral lineages prior to the separation of mammals and birds. Fourteen sites underwent positive selection in ancestral lineages of birds and six were positively selected in amphibians. The site model showed that 16, 7, and 30 sites underwent positive selection in extant mammals, amphibians, and birds, respectively. The positively selected sites in amphibians were located outside the transmembrane domain, with four in the extracellular and three in the intracellular domain, indicating that the transmembrane region might be conserved and essential for protein function. Our findings provide a basis for further studies of AD-prlr function and molecular evolution in Chinese giant salamander. J. Exp. Zool. (Mol. Dev. Evol.) 324B: 707-719, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26526304 TI - Diallyl disulfide attenuated carbon ion irradiation-induced apoptosis in mouse testis through changing the ratio of Tap73/DeltaNp73 via mitochondrial pathway. AB - Diallyl disulfide (DADS), a major organosulfur compound derived from garlic, has various biological properties, including anti-cancer effects. However, the protective mechanism of DADS against radiation-induced mouse testis cell apoptosis has not been elucidated. In this study, the magnitude of radiation effects evoked by carbon ion irradiation was marked by morphology changes, significant rise in apoptotic cells, activation expression of p53, up regulation the ratio of pro-apoptotic Tap73/anti-apoptotic DeltaNp73, as well as alterations of crucial mediator of the mitochondrial pathway. Interestingly, pretreatment with DADS attenuated carbon ion irradiation-induced morphology damages and apoptotic cells. Additionally, DADS elevated radiation-induced p53 and p21 expression, suggesting that p53 might be involved in the inhibition of cell cycle progression through up regulation of p21. Furthermore, administration with DADS prevented radiation-induced Tap73/DeltaNp73 expression and consequently down regulated Bax/Bcl-2 ratio, cytochrome c release and caspase-3 expression, indicating that the balance between Tap73 and DeltaNp73 had potential to activate p53 responsive genes. Thus, our results showed that radio protection effect of DADS on mouse testis is mediated by blocking apoptosis through changing the ratio of Tap73/DeltaNp73 via mitochondrial pathway, suggesting that DADS could be used as a potential radio protection agent for the testis against heavy-ion radiation. PMID- 26526306 TI - Three job stress models and their relationship with musculoskeletal pain in blue- and white-collar workers. AB - OBJECTIVES: Musculoskeletal pain has been found to co-occur with psychosocial job stress. However, different conceptualizations of job stress exist, each emphasizing different aspects of the work environment, and it is unknown which of these aspects show the strongest associations with musculoskeletal pain. Further, these associations may differ for white-collar vs. blue-collar job types, but this has not been tested. The present study examined the independent and combined contributions of Effort-RewardImbalance (ERI), Job-Demand-Control (JDC) and Organizational Justice (OJ) to musculoskeletal pain symptoms among white- and blue-collar workers. METHODS: Participants of a cross-sectional study (n=1634) completed validated questionnaires measuring ERI, JDC, and OJ, and reported the frequency of pain during the previous year at four anatomical locations (lower back, neck or shoulder, arms and hands, and knees/feet). Pain reports were summarized into a single musculoskeletal symptom score (MSS). Analyses were stratified for white- and blue-collar workers. RESULTS: Among white-collar workers, ERI and OJ were independently associated with MSS. In addition to these additive effects, significant 2-way and 3-way interactions indicated a synergistic effect of job stressors in relation to reported pain. In blue-collar workers, ERI and JDC independently associated with MSS, and a significant 3-way interaction was observed showing that the combination of job stressors exceeded an additive effect. CONCLUSION: ERI influences pain symptoms in both occupational groups. OJ was independent significant predictor only among white-collar workers, whereas JDC had additive predictive utility exclusively among blue-collar workers. Simultaneous exposure to multiple job stress factors appeared to synergize pain symptom reporting. PMID- 26526305 TI - Associations between DSM-IV mental disorders and subsequent COPD diagnosis. AB - OBJECTIVES: COPD and mental disorder comorbidity is commonly reported, although findings are limited by substantive weaknesses. Moreover, few studies investigate mental disorder as a risk for COPD onset. This research aims to investigate associations between current (12-month) DSM-IV mental disorders and COPD, associations between temporally prior mental disorders and subsequent COPD diagnosis, and cumulative effect of multiple mental disorders. METHODS: Data were collected using population surveys of 19 countries (n=52,095). COPD diagnosis was assessed by self-report of physician's diagnosis. The World Mental Health Composite International Diagnostic Interview (WMH-CIDI) was used to retrospectively assess lifetime prevalence and age at onset of 16 DSM-IV disorders. Adjusting for age, gender, smoking, education, and country, survival analysis estimated associations between first onset of mental disorder and subsequent COPD diagnosis. RESULTS: COPD and several mental disorders were concurrently associated across the 12-month period (ORs 1.5-3.8). When examining associations between temporally prior disorders and COPD, all but two mental disorders were associated with COPD diagnosis (ORs 1.7-3.5). After comorbidity adjustment, depression, generalized anxiety disorder, and alcohol abuse were significantly associated with COPD (ORs 1.6-1.8). There was a substantive cumulative risk of COPD diagnosis following multiple mental disorders experienced over the lifetime. CONCLUSIONS: Mental disorder prevalence is higher in those with COPD than those without COPD. Over time, mental disorders are associated with subsequent diagnosis of COPD; further, the risk is cumulative for multiple diagnoses. Attention should be given to the role of mental disorders in the pathogenesis of COPD using prospective study designs. PMID- 26526308 TI - The relationship of modern health worries to non-specific physical symptoms and perceived environmental sensitivity: A study combining self-reported and general practice data. AB - OBJECTIVE: The present study investigates the association of modern health worries (MHW) with self-reported as well as general practitioner (GP)-registered non-specific physical symptoms (NSPS), medication use, alternative therapy consultations, sleep quality and quality of life. The interrelation between MHW, general environmental sensitivity and the aforementioned outcomes is also explored. METHODS: Self-reported questionnaires and data from electronic medical records from 21 general practices in The Netherlands were combined in a sample of 5933 adult participants. RESULTS: The majority of the participants reported increased worries about potential health effects from environmental exposures. The highest worry scores were reported by people who perceived themselves as more vulnerable to environmental stressors. After adjustment for socio-demographic characteristics and diagnosed psychiatric morbidity, higher MHW were significantly associated with increased self-reported prevalence and duration of NSPS, symptom-related healthcare utilization, GP-registered NSPS, alternative therapy consultations and lower sleep quality and quality of life. These associations were statistically mediated by perceived environmental sensitivity. No association was observed between worries and GP-registered medication prescriptions. CONCLUSION: Modern health worries are very common in the general population. They are associated with self-reported as well as clinically defined NSPS and as such might play a key role in the process of developing and maintaining environmental sensitivities and related symptoms. A large cross cultural longitudinal study would help to determine important aspects such as temporal precedence and stability of MHW and the relevant psychosocial context within which symptomatic conditions occur. PMID- 26526309 TI - Still modern? Developing the biopsychosocial model for the 21st century. PMID- 26526307 TI - Correlates of diabetes-related distress in type 2 diabetes: Findings from the benchmarking network for clinical and humanistic outcomes in diabetes (BENCH-D) study. AB - OBJECTIVE: To evaluate correlates of high diabetes-related distress (HD) among individuals with type 2 diabetes mellitus (T2DM). METHODS: The study involved a sample of patients with T2DM who filled in the Problem Areas in Diabetes questionnaire (PAID-5); a score >= 40 indicates HD. Additional instruments included: SF12 health survey (SF12), Well-Being Index (WHO-5), Diabetes Empowerment Scale-Short Form (DES-SF), Patient Assessment of Chronic Illness Care Short Form (PACIC-SF), Health Care Climate-Short Form (HCC-SF), Global Satisfaction with Diabetes Treatment (GSDT), Summary of Diabetes Self-Care Activities (SDSCA-6); Barriers to Medications (BM), Perceived Social Support (PSS). Clinical data were extracted from computerized medical records. Multivariable logistic regression analyses were performed to identify correlates of HD. RESULTS: Of 2374 patients (mean age 65.0+/-10.2 years, diabetes duration 14.0+/-15.3 years, 59.9% males), 1429 (60.2%) had HD. Compared to patients with a PAID-5 score<40 those with HD were more often female, living alone, had a lower level of education, higher HbA1c levels, a greater perceived impact of hyperglycemic and hypoglycemic symptoms, a greater number of diabetes-related complications, lower scores of WHO-5, DES-SF, PSS, GSDT, SF-12 PCS, SDSCA-healthy diet and physical activity subscales, higher scores of BM and SDSCA-SMBG component. Multivariable analyses confirmed the relationship between HD and symptoms of hyperglycemia, levels of empowerment, global satisfaction with treatment, perception of barriers to medication, and psychological well-being. Conclusion HD is extremely common among people with T2DM, affecting almost two thirds of patients. High levels of distress are associated with worse clinical and psychosocial outcomes and should be considered as a key patient-centered indicator. PMID- 26526310 TI - Physician reported adherence to immunosuppressants in renal transplant patients: Prevalence, agreement, and correlates. AB - OBJECTIVE: Adherence to immunosuppressants (IS) is crucial to prevent allograft rejection. Even though there is evidence that non-adherence to IS among kidney transplant recipients is common, it is rarely routinely assessed in clinical practice. Especially, little is known about how physicians estimate patients' adherence to IS medication. METHODS: In a single center, cross-sectional study adult patients at least 1 year after kidney transplantation were asked to complete measures of adherence (BAASIS(c), Transplant Effect Questionnaire) and of general psychopathology (anxiety, depression, perceived social support). Also the physicians were asked to estimate their patients' adherence. Medical data (time since transplantation, treatment for rejection, IS serum trough levels and target levels) were taken from the patients' charts. RESULTS: Physicians rated 22 of 238 (9.2%) patients as non-adherent. Physicians' estimations of non-adherence were lower compared to the results of the self-ratings and biopsy-proven rejections. No association was found between physicians' estimates and the variability of IS through levels. Significantly more women and patients who reported that their native language was not German were rated as non-adherent by the physicians. Also, physician-rated non-adherent patients reported significantly higher depression and anxiety scores as well as less social support compared to adherent patients. CONCLUSION: Our results suggest that physicians tend to underestimate patient non-adherence to IS medication. They appear to use observable cues such as sex, language skills, and elevated anxiety and depression scores in particular, to make inferences about an individual patient's adherence. Underestimation of medication non-adherence may impede physicians' ability to provide high quality care. PMID- 26526311 TI - Somatic disorders and antidepressant use in suicides: A population-based study from the Friuli Venezia Giulia region, Italy, 2003-2013. AB - BACKGROUND: Many somatic disorders are complicated by depression and increase the risk of suicide. Little is known about whether antidepressants might reduce the suicidal risk in patients with somatic disorders. METHODS: Data on diagnoses and antidepressant prescriptions were derived from the Social and Health Information System of the Friuli Venezia Giulia Region. Cases were all suicides that occurred in the region during the years 2003-2013 and were sex- and age-matched to controls from the general population. Conditional logistic regression analysis was used to assess the association between suicide and somatic disorders. RESULTS: The suicide rate in Friuli Venezia Giulia decreased from 11.3 to 10.7 per 100,000 inhabitants during the years 2003-2013, however patients with somatic disorder had a three times increased risk of suicide. Elderly somatic patients' suicide risk was twice as high as younger patients. The risk increased from 2.6 to 9.8 times as the number of comorbid disorders increased from 1 to 4 and over. Although no significant risk of suicide in patients with somatic disorders was found when patients were adherent to antidepressants, only 11.5% of the suicides was adherent in the year prior to death. CONCLUSIONS: Medical illnesses and underlying depressive symptoms may have a synergy effect on the risk of suicide, particularly in older patients and in patients with multiple morbidities. Since medically ill subjects adherent to antidepressants did not show a significant risk of suicide, early identification and adequate treatment of depression in somatic patients should be considered in order to prevent suicide. PMID- 26526312 TI - Somatic symptom reports in the general population: Application of a bi-factor model to the analysis of change. AB - OBJECTIVE: To investigate the latent structure of somatic symptom reports in the general population with a bi-factor model and apply the structure to the analysis of change in reported symptoms after the emergence of an uncertain environmental health risk. METHODS: Somatic symptoms were assessed in two general population environmental health cohorts (AMIGO, n=14,829 & POWER, n=951) using the somatization scale of the four-dimensional symptom questionnaire (4DSQ-S). Exploratory bi-factor analysis was used to determine the factor structure in the AMIGO cohort. Multi-group and longitudinal models were applied to assess measurement invariance. For a subsample of residents living close to a newly introduced power line (n=224), we compared a uni- and multidimensional method for the analysis of change in reported symptoms after the power line was put into operation. RESULTS: We found a good fit (RMSEA=0.03, CFI=0.98) for a bi-factor model with one general and three symptom specific factors (musculoskeletal, gastrointestinal, cardiopulmonary). The latent structure was found to be invariant between cohorts and over time. A significant increase (p<.05) was found only for musculoskeletal and gastrointestinal symptoms after the power line was put into operation. CONCLUSIONS: In our study we found that a bi-factor structure of somatic symptoms reports was equivalent between cohorts and over time. Our findings suggest that taking this structure into account can lead to a more informative interpretation of a change in symptom reports compared to a unidimensional approach. PMID- 26526313 TI - Physical injury and posttraumatic stress reactions. A study of the survivors of the 2011 shooting massacre on Utoya Island, Norway. AB - OBJECTIVE: The objective of the study was to investigate the relationship between physical injury (no, moderate and severe) and posttraumatic stress reactions (PTSR) at 4-5 months after the attack in survivors of the terror attack at Utoya Island, Norway, 22 July 2011, adjusting for sociodemographic, psychosocial and trauma-related factors. METHODS: Overall, 325 young survivors (47% women, mean age 19.4 years) were interviewed 4-5 months (T1) and 14-15 months (T2) after the attack. Variables concerning physical injury, PTSR (UCLA PTSD-RI scale, 0-4), peritraumatic exposure, sociodemographic and psychosocial backgrounds were measured. To evaluate the role of injury, multiple linear regression analyses were conducted. RESULTS: The physically injured (n=60) reported higher levels of PTSR than did the non-injured. The difference was statistically significant between the moderately injured (n=37, mean 1.9) and the non-injured (n=265, mean 1.5). No significant differences were found between the moderately and the severely (n=23, mean 1.8) injured. Higher levels of peritraumatic events, peritraumatic reactions and loss of close, female sex and non-Norwegian ethnicity were significantly related to higher levels of PTSR in the full regression model. CONCLUSION: Physical injury was associated with higher PTSR after the terror attack. Moderately injured survivors may, as those severely injured, exhibit high levels of PTSR, and this should be taken into account when targeting early psychosocial health care after terror. PMID- 26526314 TI - Bidirectional relations between work-related stress, sleep quality and perseverative cognition. AB - OBJECTIVE: In this longitudinal two-wave study, bidirectional relations between work-related stress and sleep quality were examined. Moreover, it was investigated whether perseverative cognition is a potential underlying mechanism in this association, related to both work-related stress and sleep quality. METHODS: A randomly selected sample of Dutch employees received an online survey in 2012 and 2013. Of all invited employees, 877 participated in both waves. Structural equation modeling was performed to analyze the data. RESULTS: We found evidence for reversed relations between work-related stress and sleep quality. Specifically, when controlling for perseverative cognition, work-related stress was not directly related to subsequent sleep quality, but low sleep quality was associated with an increase in work-related stress over time. Moreover, negative bidirectional associations over time were found between perseverative cognition and sleep quality, and positive bidirectional associations were found between work-related stress and perseverative cognition. Lastly, a mediation analysis showed that perseverative cognition fully mediated the relationship between work related stress and sleep quality. CONCLUSION: The study findings suggest that perseverative cognition could be an important underlying mechanism in the association between work-related stress and sleep quality. The bidirectionality of the studied relationships could be an indication of a vicious cycle, in which work-related stress, perseverative cognition, and sleep quality mutually influence each other over time. PMID- 26526315 TI - Effectiveness of an Internet-based preparation for psychosomatic treatment: Results of a controlled observational study. AB - OBJECTIVE: Patients often have to sustain long waiting periods between the time they first apply for psychotherapy and the actual uptake of the treatment. To support patients who are on a wait-list for inpatient psychosomatic treatment an Internet-based preparatory treatment (VORSTAT) was developed. In a randomized controlled trial, VORSTAT proved to increase treatment motivation prior to intake and to accelerate the accommodation phase at the beginning of inpatient treatment. No impact of VORSTAT on inpatient treatment outcome was found. The aim of the present study was to investigate the effectiveness of VORSTAT after implementing the service into routine care. METHODS: A large naturalistic observational study comparing VORSTAT participants (N=911) against non participants (N=1721) was conducted. Propensity scores were used to control for potential confounding variables due to the non-randomized group allocation. Reliable improvement of self-reported impairment achieved during inpatient treatment was used as outcome measure. RESULTS: VORSTAT participants showed higher rates of reliable improvement in physical impairment (50.8% vs. 44.9%), psychological impairment (41.2% vs. 29.9%), and social problems (22.3% vs. 15.2%). CONCLUSION: An Internet-based preparation for psychotherapy is an effective approach to improve outcome of inpatient psychosomatic treatment. PMID- 26526316 TI - Predictive validity of a frailty measure (GFI) and a case complexity measure (IM E-SA) on healthcare costs in an elderly population. AB - OBJECTIVES: Measures of frailty (Groningen Frailty Indicator, GFI) and case complexity (INTERMED for the Elderly, IM-E-SA) may assist healthcare professionals to allocate healthcare resources. Both instruments have been evaluated with good psychometric properties. Limited evidence has been published about their predictive validity. Thus, our aim is to evaluate the predictive validity of both instruments on healthcare costs. METHODS: Multivariate linear regression models were developed to estimate associations between the predictors frailty (GFI) and/or case complexity (IM-E-SA) and the healthcare costs (in ? log transformed) in the following year. All models were adjusted for demographics and the presence of morbidity. RESULTS: In the multivariate regression analyses the continuous scores of the GFI and IM-E-SA remained significant predictors for total healthcare costs. Adjusted betas for GFI and IM-E-SA were respectively 0.14 (95% CI 0.10-0.18) and 0.06 (95% CI 0.04-0.07). The corresponding explained variance (R(2)) for both models was 0.40. Frailty remained a significant predictor of long-term care costs (adjusted beta 0.13 [95% CI 0.09-0.16]), while case complexity was a significant predictor of curative care costs (adjusted beta 0.03 [95% CI 0.02-0.05]). CONCLUSIONS: The GFI and IM-E-SA both accurately predict total healthcare costs in the following year. PMID- 26526318 TI - The impact of receiving a diagnosis of Non-Epileptic Attack Disorder (NEAD): A systematic review. AB - BACKGROUND: Clinicians have reported observations of the immediate cessation of non-epileptic attacks after the diagnosis of NEAD is presented. OBJECTIVE: The purpose of this systematic review was to examine the impact of receiving a diagnosis of NEAD. SEARCH STRATEGY: A literature search across the databases Medline, PsycINFO, EMBASE, and CINAHL, and additional hand searching, identified six original studies meeting criteria for the review. SELECTION CRITERIA: Included studies were original peer-reviewed articles investigating the impact of receiving a diagnosis of NEAD on adult populations with at least one outcome measured pre- and post-diagnosis. ANALYSIS: The studies were assessed for methodological quality, including biases. This assessment was developed to include criteria specific to research regarding NEAD and diagnosis. RESULTS: Six identified studies, with a total of 153 NEAD participants, examined the impact of receiving a diagnosis on seizure frequency. Two of the six also examined the impact on health-related quality of life. The findings were inconsistent, with approximately half the participants experiencing seizure reduction or cessation post-diagnosis. Diagnosis appeared to have no significant impact on health related quality of life. The overall evidence lacked quality, particularly in study design and statistical rigour. CONCLUSIONS: Mixed results and a lack of high quality evidence were found. Concerns are considered regarding the appropriateness of seizure frequency as the primary outcome measure and the use of epilepsy control groups. Indications for future research include: measuring more meaningful outcomes, using larger samples and power calculations, and ensuring consistent and standard methods for communicating the diagnosis and recording outcomes. PMID- 26526317 TI - Stress management reduces intraindividual cortisol variability, while not impacting other measures of cortisol rhythm, in a group of women at risk for breast cancer. AB - OBJECTIVE: The stress hormone cortisol exhibits a diurnal rhythm throughout the day, as well as within person variability. Recent statistical approaches allow for the estimation of intraindividual cortisol variability ("ICV") and a greater ICV has been observed in some mood disorders (major depression, remitted bipolar disorder); however, ICV has not been examined following stress management. In this secondary analyses of an efficacious randomized clinical trial, we examine how ICV may change after cognitive behavioral stress management (CBSM) among healthy stressed women at risk for breast cancer. Second, we concurrently compare other calculations of cortisol that may change following CBSM. METHODS: Multilevel modeling (MLM) was applied to estimate ICV and to test for a group by time interaction from baseline, post-intervention, to 1 month following CBSM. Forty-four women were randomized to the CBSM; 47 to the comparison group; mean age of the entire group was 44.2 (SD=10.27). RESULTS: After controlling for relevant covariates, a significant time by group interaction emerged (beta estimate=-.070; p<.05), such that CBSM participants demonstrated a lower ICV following CBSM compared to the comparison group. The interaction for cortisol slope and cortisol output (area under the curve) approached significance (beta estimates=-.10 and -.062, respectively; p's<.08), while other cortisol outcomes tested were not significantly changed following CBSM. CONCLUSION: ICV may represent a novel index of cortisol dysregulation that is impacted by CBSM and may represent a more malleable within-person calculation than other, widely applied cortisol outcomes. Future research should examine these relationships in larger samples, and examine ICV and health outcomes. CLINICAL TRIALS IDENTIFIER: NCT01048528. PMID- 26526319 TI - Bidirectional relationship between sleep and optimism with depressive mood as a mediator: A longitudinal study of Chinese working adults. AB - OBJECTIVE: Sleep and optimism are important psycho-biological and personality constructs, respectively. However, very little work has examined the causal relationship between them, and none has examined the potential mechanisms operating in the relationship. This study aimed to understand whether sleep quality was a cause or an effect of optimism, and whether depressive mood could explain the relationship. METHOD: Internet survey data were collected from 987 Chinese working adults (63.4% female, 92.4% full-time workers, 27.0% married, 90.2% Hong Kong residents, mean age=32.59 at three time-points, spanning about 19 months). Measures included a Chinese attributional style questionnaire, the Pittsburgh Sleep Quality Index, and the Depression Anxiety Stress Scale. RESULTS: Cross-sectional analyses revealed moderate correlations among sleep quality, depressive mood, and optimism. Cross-lagged analyses showed a bidirectional causality between optimism and sleep. Path analysis demonstrated that depressive mood fully mediated the influence of optimism on sleep quality, and it partially mediated the influence of sleep quality on optimism. CONCLUSION: Optimism improves sleep. Poor sleep makes a pessimist. The effects of sleep quality on optimism could not be fully explained by depressive mood, highlighting the unique role of sleep on optimism. Understanding the mechanisms of the feedback loop of sleep quality, mood, and optimism may provide insights for clinical interventions for individuals presented with mood-related problems. PMID- 26526320 TI - Are changes in workplace bullying status related to changes in salivary cortisol? A longitudinal study among Danish employees. AB - OBJECTIVES: This study aims to investigate whether incident workplace bullying and its dicontinuance is related to subsequent change in morning and evening saliva cortisol concentrations. METHODS: Participants came from two Danish cohort studies, the PRISME cohort (n=4489) and the Workplace Bullying and Harassment Cohort (n=3707). At baseline and follow-up exposure to bullying was measured by a single question on bullying (preceded by a definition). Two saliva samples to measure cortisol were collected during a work-day (30 min after awakening and at 8 p.m.). All participants responding to the item on workplace bullying, giving saliva samples and participated at both baseline and follow-up were included. The reference group consisted of non-bullied respondents at both baseline and follow up. Multilevel mixed-effects linear regressions were used to test for changes in salivary cortisol after newly onset of and discontinuance of workplace bullying. All analyses were adjusted for the potentially confounding effect of differences from baseline to follow-up in education, smoking, alcohol consumption, body mass index, cohort, sampling waves, time of awakening, and time of sampling. RESULTS: We found no indication of statistically significant difference in saliva cortisol, neither when participants changed their self-labelling from not bullied at baseline to being bullied at follow-up, nor when they at follow-up two years later reported discontinuance of bullying. CONCLUSION: This longitudinal study on the impact of changes in bullying status on change in cortisol levels showed consistent lack of associations with onset and discontinuance of workplace bullying. PMID- 26526321 TI - Circadian rhythm disruption as a link between Attention-Deficit/Hyperactivity Disorder and obesity? AB - OBJECTIVE: Patients with Attention-Deficit/Hyperactivity Disorder (ADHD) have a high prevalence of obesity. This is the first study to investigate whether circadian rhythm disruption is a mechanism linking ADHD symptoms to obesity. METHODS: ADHD symptoms and two manifestations of circadian rhythm disruption: sleep problems and an unstable eating pattern (skipping breakfast and binge eating later in the day) were assessed in participants with obesity (n= 114), controls (n= 154), and adult ADHD patients (n= 202). RESULTS: Participants with obesity had a higher prevalence of ADHD symptoms and short sleep on free days as compared to controls, but a lower prevalence of ADHD symptoms, short sleep on free days, and an unstable eating pattern as compared to ADHD patients.We found that participants with obesity had a similar prevalence rate of an unstable eating pattern when compared to controls. Moreover, mediation analyses showed that both sleep duration and an unstable eating pattern mediated the association between ADHD symptoms and body mass index (BMI). CONCLUSION: Our study supports the hypothesis that circadian rhythm disruption is a mechanism linking ADHD symptoms to obesity. Further research is needed to determine if treatment of ADHD and circadian rhythm disruption is effective in the prevention and treatment of obesity in patients with obesity and/or ADHD. PMID- 26526322 TI - Purpose in life predicts allostatic load ten years later. AB - OBJECTIVE: Living a purposeful life is associated with better mental and physical health, including longevity. Accumulating evidence shows that these associations might be explained by the association between life purpose and regulation of physiological systems involved in the stress response. The aim of this study was to investigate the prospective associations between life purpose and allostatic load over a 10-year period. METHODS: Analyses were conducted using data from the Midlife in the United States (MIDUS) survey. Assessment of life purpose, psychological covariates and demographics were obtained at baseline, while biomarkers of allostatic load were assessed at the 10-year follow-up. RESULTS: We found that greater life purpose predicted lower levels of allostatic load at follow-up, even when controlling for other aspects of psychological well-being potentially associated with allostatic load. Further, life purpose was also a strong predictor of individual differences in self-health locus of control-i.e., beliefs about how much influence individuals can exert on their own health-which, in turn, partially mediated the association between purpose and allostatic load. Although life purpose was also negatively linked to other-health locus of control i.e., the extent to which individuals believe their health is controlled by others/chance-this association did not mediate the impact of life purpose on allostatic load. CONCLUSION: The current study provides the first empirical evidence for the long-term physiological correlates of life purpose and supports the hypothesis that self-health locus of control acts as one proximal psychological mechanism through which life purpose may be linked to positive biological outcomes. PMID- 26526323 TI - Symptom dimensions of affective disorders in migraine patients. AB - OBJECTIVE: A strong association has been established between migraine and depression. However, this is the first study to differentiate in a large sample of migraine patients for symptom dimensions of the affective disorder spectrum. METHODS: Migraine patients (n=3174) from the LUMINA (Leiden University Medical Centre Migraine Neuro-analysis Program) study and patients with current psychopathology (n=1129), past psychopathology (n=477), and healthy controls (n=561) from the NESDA (Netherlands Study of Depression and Anxiety) study, were compared for three symptom dimensions of depression and anxiety. The dimensions lack of positive affect (depression specific); negative affect (nonspecific); and somatic arousal (anxiety specific)- were assessed by a shortened adaptation of the Mood and Anxiety Symptom Questionnaire (MASQ-D30). Within the migraine group, the association with migraine specific determinants was established. Multivariate regression analyses were conducted. RESULTS: Migraine patients differed significantly (p<0.001) from healthy controls for all three dimensions: Cohen's d effect sizes were 0.37 for lack of positive affect, 0.68 for negative affect, and 0.75 for somatic arousal. For the lack of positive affect and negative affect dimensions, migraine patients were predominantly similar to the past psychopathology group. For the somatic arousal dimension, migraine patients scores were more comparable with the current psychopathology group. Migraine specific determinants for high scores on all dimensions were high frequency of attacks and cutaneous allodynia during attacks. CONCLUSION: This study shows that affective symptoms in migraine patients are especially associated with the somatic arousal component. PMID- 26526324 TI - The impact of sexual behavior on oral HPV infections in young unvaccinated adults. AB - OBJECTIVE: Different authors hypothesized an important impact of sexual behavior on the prevalence of oral human papillomavirus (HPV) infections. In order to investigate this relationship more in detail and in contrast to most other studies, the present work focused on the population group with the highest risk for sexually transmitted infections: young and sexual active adults. MATERIALS AND METHODS: Three hundred and ten men and women aged 18-30 years could be recruited. After the completion of a risk-factor survey, brush smear samples for oral HPV detection were taken in every participant. RESULTS: In 18.1 %, oral HPV could be detected. Overall, smoking (p = 0.0074) and a high number of different sexual partners (vaginal: p = 0.0001; oral: p < 0.0001) were significantly correlated with a positive HPV testing. In case of high risk HPV infections, besides tobacco and sexual behavior, alcohol consumption showed a significant association with a positive testing (p = 0.0212). CONCLUSIONS: Overall, the prevalence of oral HPV seems to be higher in young, sexual active adults compared to other population groups. Tobacco and alcohol may facilitate an oral HPV infection. Sexual behavior, especially oral sex practices, seems to play a crucial role in the transmission of oral HPV. CLINICAL RELEVANCE: The presented data, especially the association of oral high risk HPV positivity and promiscuity, may lead to improvements in the existing oral HPV prevention strategies like a HPV vaccination for both genders. PMID- 26526325 TI - Reliability and failure modes of narrow implant systems. AB - OBJECTIVES: Narrow implants are indicated in areas of limited bone width or when grafting is nonviable. However, the reduction of implant diameter may compromise their performance. This study evaluated the reliability of several narrow implant systems under fatigue, after restored with single-unit crowns. MATERIALS AND METHODS: Narrow implant systems were divided (n = 18 each), as follows: Astra (ASC); BioHorizons (BSC); Straumann Roxolid (SNC), Intra-Lock (IMC), and Intra Lock one-piece abutment (ILO). Maxillary central incisor crowns were cemented and subjected to step-stress accelerated life testing in water. Use level probability Weibull curves and reliability for a mission of 100,000 cycles at 130- and 180-N loads (90 % two-sided confidence intervals) were calculated. Scanning electron microscopy was used for fractography. RESULTS: Reliability for 100,000 cycles at 130 N was ~99 % in group ASC, ~99 % in BSC, ~96 % in SNC, ~99 % in IMC, and ~100 % in ILO. At 180 N, reliability of ~34 % resulted for the ASC group, ~91 % for BSC, ~53 % for SNC, ~70 % for IMC, and ~99 % for ILO. Abutment screw fracture was the main failure mode for all groups. CONCLUSIONS: Reliability was not different between systems for 100,000 cycles at the 130-N load. A significant decrease was observed at the 180-N load for ASC, SNC, and IMC, whereas it was maintained for BSC and ILO. CLINICAL RELEVANCE: The investigated narrow implants presented mechanical performance under fatigue that suggests their safe use as single crowns in the anterior region. PMID- 26526327 TI - Heading Disorientation after Right Posteromedial Infarction. AB - We report the case of heading disorientation following ischemic stroke involving the right posteromedial areas. The patient was administered a new test named the Card Placing Test during which a subject was required to recreate an array of three cards, each of which was randomly placed on eight grids around the subject, before and after the subject's rotation. Qualitative analysis of his performance after rotation revealed that over half of the errors comprised transposition and rotational offset. His score on the Card Placing Test was compared with those of normal controls (n = 11). The results showed that his score on Card Placing Test after rotation was significantly lower than those of controls, whereas there was no significant difference between the case and controls in profile of error types. We infer that the heading disorientation observed in the present case was a result of a derangement of a short-term buffer that integrated information on spatial locations of objects with changes in body directions. PMID- 26526326 TI - Functional interplay between ganglioside GM1 and cross-linking galectin-1 induces axon-like neuritogenesis via integrin-based signaling and TRPC5-dependent Ca2+ influx. AB - Axon-like neuritogenesis in neuroblastoma (NG108-15) cells and primary cerebellar granular neurons is furthered by the presence of ganglioside GM1. We describe here that galectin-1 (Gal-1), a homobivalent endogenous lectin, is an effector by cross-linking the ganglioside and its associated glycoprotein alpha5 beta1 integrin. The thereby triggered signaling cascade involves autophosphorylation of focal adhesion kinase and activation of phospholipase Cgamma and phosphoinositide 3 kinase. This leads to a transient increase in the intracellular Ca(2+) concentration by opening of TRPC5 channels, which belong to the signal transduction-gated cation channels. Controls with GM1-defective cells (NG-CR72 and neurons from ganglio-series KO mice) were retarded in axonal growth, underscoring the relevance of GM1 as functional counterreceptor for Gal-1. The lectin's presence was detected in the NG108-15 cells, suggesting an autocrine mechanism of action, and in astrocytes in situ. Gal-1, as cross-linking lectin, can thus translate metabolic conversion of ganglioside GD1a to GM1 by neuraminidase action into axon growth. Galectin-1 (Gal-1) was shown an effector of axonogenesis in cerebellar granule neurons (CGNs) and NG108-15 cells by cross linking GM1 ganglioside and its associated glycoprotein alpha5 beta1 -integrin. The resulting signaling led to a transient increase in intracellular Ca(2+) by opening TRPC5 channels. CGNs deficient in GM1 showed retarded axonogenesis, underscoring the relevance of GM1 as functional counterreceptor for Gal-1 in this process. This Gal-1/GM1-induced signaling was manifest only at the earliest, initiating stage of axon development. PMID- 26526328 TI - Autologous Pericardial Reconstruction of Ruptured Salmonella Mycotic Aortic Arch Aneurysm. AB - The primary goals of surgery for mycotic thoracic aortic aneurysms include control of sepsis, radical debridement of infected tissue, anatomic or extra anatomic aortic reconstruction, and prevention of recurrent infection. Patients with Salmonella aortitis are a challenging subgroup of patients with aggressive infection and very poor prognosis, because bacterial eradication is difficult and risk of recurrent infection is high. We report the successful surgical management of a patient who presented with a ruptured Salmonella aortic arch aneurysm with extensive debridement and near circumferential autologous pericardial patch reconstruction of the aortic arch. PMID- 26526329 TI - Antibiotics alone versus appendectomy to treat uncomplicated acute appendicitis in adults: what do meta-analyses say? AB - BACKGROUND: Primary appendectomy is the current standard of care for treating uncomplicated acute appendicitis, but interest in conservative treatment with antibiotics alone has been increasing in recent years. Clinical trials so far have shown controversial results. METHODS: A series of meta-analyses were reviewed. Studies comparing surgery versus antibiotics alone for treating uncomplicated acute appendicitis in adults were included. Descriptive statistics and data on treatment effects were retrieved and summarized. RESULTS: The conservative approach has a success rate of around 60 % and is associated with shorter pain duration, reduced analgesic medication, faster resolution of the inflammation process, lower expenses and quicker return to work. On the other hand, medical treatment leads to high (up to 20 %) readmission rates and more often requires surgery. An operative approach is associated with higher treatment success rates (>90 %) and very a low mortality rate. CONCLUSION: Based on the current body of evidence, the use of antibiotics for primary treatment of uncomplicated acute appendicitis cannot be routinely recommended. Appendectomy remains the gold-standard treatment. PMID- 26526330 TI - Diagnostic accuracy of urinary prostate protein glycosylation profiling in prostatitis diagnosis. AB - INTRODUCTION: Although prostatitis is a common male urinary tract infection, clinical diagnosis of prostatitis is difficult. The developmental mechanism of prostatitis is not yet unraveled which led to the elaboration of various biomarkers. As changes in asparagine-linked-(N-)-glycosylation were observed between healthy volunteers (HV), patients with benign prostate hyperplasia and prostate cancer patients, a difference could exist in biochemical parameters and urinary N-glycosylation between HV and prostatitis patients. We therefore investigated if prostatic protein glycosylation could improve the diagnosis of prostatitis. MATERIALS AND METHODS: Differences in serum and urine biochemical markers and in total urine N-glycosylation profile of prostatic proteins were determined between HV (N=66) and prostatitis patients (N=36). Additionally, diagnostic accuracy of significant biochemical markers and changes in N glycosylation was assessed. RESULTS: Urinary white blood cell (WBC) count enabled discrimination of HV from prostatitis patients (P<0.001). Urinary bacteria count allowed for discriminating prostatitis patients from HV (P<0.001). Total amount of biantennary structures (urinary 2A/MA marker) was significantly lower in prostatitis patients compared to HV (P<0.001). Combining the urinary 2A/MA marker and urinary WBC count resulted in an AUC of 0.79, 95% confidence interval (CI)=(0.70-0.89) which was significantly better than urinary WBC count (AUC=0.70, 95% CI=[0.59-0.82], P=0.042) as isolated test. CONCLUSIONS: We have demonstrated the diagnostic value of urinary N-glycosylation profiling, which shows great potential as biomarker for prostatitis. Further research is required to unravel the developmental course of prostatic inflammation. PMID- 26526331 TI - Procedural Pain Management in Neonates, Infants and Children. AB - Neonates, infants and children all feel pain and require analgesia for painful procedures.Many painful procedures are associated with medical interventions, including immunisation, heel lance, venesection, IV cannulation and dressing change.Untreated pain can have short and long term effects, including sensitisation to pain episodes in later life.A range of non-pharmacological and pharmacological interventions have been shown to be effective for procedural pain management in infants and children, and are most effective when used in combination.Developmental changes in pain responses, analgesic response and drug pharmacokinetics need to be taken into account when planning procedural pain management for neonates.Comprehensive evidence based guidelines are available to guide effective procedural pain management in neonates, infants and older children. PMID- 26526332 TI - Mosquito hemocytes preferentially aggregate and phagocytose pathogens in the periostial regions of the heart that experience the most hemolymph flow. AB - When a mosquito acquires an infection in the hemocoel, dedicated immune cells called hemocytes aggregate around the valves of the heart. These sessile hemocytes are called periostial hemocytes. In the present study we scrutinized the immune response mounted by the periostial hemocytes of the malaria mosquito, Anopheles gambiae, against bacterial pathogens, and tested the relationship between periostial hemocyte aggregation, immune activity, and hemolymph flow. Initially, we quantified the process of periostial hemocyte aggregation and found that hemocytes migrate to the periostial regions in response to infection with Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, and Micrococcus luteus (all infections tested). Then, we investigated whether the periostial hemocytes are evenly distributed along the six periostial regions of the heart, and found that they preferentially aggregate in the periostial regions of the mid-abdominal segments (4, 5 and 6). This distribution perfectly correlates with the spatial distribution of phagocytic activity along the surface of the heart, and to a lesser extent, with the distribution of melanin deposits. Finally, experiments measuring circulatory physiology found that the majority of hemolymph enters the heart through the ostia located in the periostial regions of abdominal segments 4, 5, and 6. These data show that periostial hemocytes aggregate on the surface of the heart in response to diverse foreign stimuli, and that both hemocytes and immune activity preferentially occur in the regions that experience the swiftest hemolymph flow. Thus, these data show that two major organ systems - the immune and circulatory systems - interact to control infections. PMID- 26526333 TI - Expression of Aquaporin-6 in Rat Retinal Ganglion Cells. AB - Several aquaporins (AQPs) have been identified to be present in the eyes, and it has been suggested that they are involved in the movement of water and small solutes. AQP6, which has low water permeability and transports mainly anions, was recently discovered in the eyes. In the present study, we investigate the localization of AQP6 in the rat retina and show that AQP6 is selectively localized to the ganglion cell layer and the outer plexiform layer. Along with the gradual decrease in retinal ganglion cells after a crushing injury of optic nerve, immunofluorescence signals of AQP6 gradually decreased. Confocal microscope images confirmed AQP6 expression in retinal ganglion cells and Muller cells in vitro. Therefore, AQP6 might participate in water and anion transport in these cells. PMID- 26526334 TI - Ischemia-Induced Changes of PRAS40 and p-PRAS40 Immunoreactivities in the Gerbil Hippocampal CA1 Region After Transient Cerebral Ischemia. AB - Proline-rich Akt substrate of 40-kDa (PRAS40) is one of the important interactive linkers between Akt and mTOR signaling pathways. The increase of PRAS40 is related with the reduction of brain damage induced by cerebral ischemia. In the present study, we investigated time-dependent changes in PRAS40 and phospho PRAS40 (p-PRAS40) immunoreactivities in the hippocampal CA1 region of the gerbil after 5 min of transient cerebral ischemia. PRAS40 immunoreactivity in the CA1 region was decreased in pyramidal neurons from 12 h after ischemic insult in a time-dependent manner, and, at 5 days post-ischemia, PRAS40 immunoreactivity was newly expressed in astrocytes. p-PRAS40 immunoreactivity in the CA1 pyramidal neurons was hardly found 12 h and apparently detected again 1 and 2 days after ischemic insult. At 5 days post-ischemia, p-PRAS40 immunoreactivity in the CA1 pyramidal neurons was not found. These results indicate that ischemia-induced changes in PRAS40 and p-PRAS40 immunoreactivities in CA1 pyramidal neurons and astrocytes may be closely associated with delayed neuronal death in the hippocampal CA1 region following transient cerebral ischemia. PMID- 26526335 TI - Predictors of Long-Term Outcome in Children with Hypertrophic Cardiomyopathy. AB - To date limited data are available to predict the progression to end-stage heart failure (HF) with subsequent death (non-SCD), need for heart transplantation, or sudden cardiac death (SCD) in children with hypertrophic cardiomyopathy (HCM). We aimed to determine predictors of long-term outcome in children with HCM. A total of 112 children (median 14.1, IQR 7.8-16.6 years) were followed up for the median of 6.5 years for the development of morbidity and mortality, including arrhythmic and HF-related secondary end points. HF end point included HF-related death or heart transplant, and arrhythmic end point included resuscitated cardiac arrest, appropriate ICD discharge, or SCD. Overall, 23 (21 %) patients reached the pre defined composite primary end point. At 10-year follow-up, the event-free survival rate was 76 %. Thirteen patients (12 %) reached the secondary arrhythmic end point, and 10 patients (9 %) reached the secondary HF end point. In multivariate model, prior cardiac arrest (r = 0.658), QTc dispersion (r = 0.262), and NSVT (r = 0.217) were independent predictors of the arrhythmic secondary end point, while HF (r = 0.440), LV posterior wall thickness (r = 0.258), LA size (r = 0.389), and decreased early transmitral flow velocity (r = 0.202) were all independent predictors of the secondary HF end point. There are differences in the risk factors for SCD and for HF-related death in childhood HCM. Only prior cardiac arrest, QTc dispersion, and NSVT predicted arrhythmic outcome in patients aged <18 years. LA size, LV posterior wall thickness, and decreased early transmitral flow velocity were strong independent predictors of HF-related events. PMID- 26526336 TI - Distortion of the left anterior descending coronary artery after pulmonary valve replacement. AB - Injury of the left main coronary artery may sometimes complicate a pulmonary valve replacement (PVR). We present the case of a 39-year-old man, with post operative distortion of the left anterior descending coronary artery, which caused onset of ventricular arrhythmia associated with electrocardiographic signs of myocardial ischemia. A coronary angiogram revealed the cause of the lesion. Stenting the coronary artery restored normal coronary blood flow and improved the patient's condition. Through this case, we describe a new life-threatening complication after PVR. (c) 2015 Wiley Periodicals, Inc. PMID- 26526337 TI - The cation-dependent structural phase transition and dielectric response in a family of cyano-bridged perovskite-like coordination polymers. AB - A family of cyano-bridged perovskite-like coordination polymers (CPs), [(CH3)nNH(4-n)]2[KFe(CN)6] (n = 1 (1), 2 (2), 3 (3), and 4 (4)), were synthesized and characterized. The differential scanning calorimetry measurements and variable-temperature single-crystal X-ray structural analyses revealed that, owing to the deformation of the host framework as well as the dynamic transition of the guest cation between the static/ordered and dynamic/disordered states, the four CPs undergo structural phase transitions (at 429, 226, 316, and 350 K, respectively) with the symmetry breakings dependent on the symmetries of the encapsulated guest cations. The modulated differential scanning calorimetry measurement suggested that the phase transitions of 1 and 3 have more striking kinetic processes related to their drastic deformation of the host framework as well as a very significant alteration of the host-guest interaction during the phase transition. Moreover, accompanying the transitions between low- and high temperature phases, the step-like transitions between low and high dielectric states were observed in 1-3, and the corresponding change in amplitude of the dielectric constant is dependent on the total dipole moment of each cage in the high-temperature phase. The investigation on these host-guest CPs deepens the understanding of the relationship between the dipole moment of guest cations and the dielectric behaviour of materials, shedding light on the search for new switchable molecular dielectrics. PMID- 26526339 TI - Selective reduction of fMRI responses to transient achromatic stimuli in the magnocellular layers of the LGN and the superficial layer of the SC of early glaucoma patients. AB - Glaucoma is now viewed not just a disease of the eye but also a disease of the brain. The prognosis of glaucoma critically depends on how early the disease can be detected. However, early glaucomatous loss of the laminar functions in the human lateral geniculate nucleus (LGN) and superior colliculus (SC) remains difficult to detect and poorly understood. Using functional MRI, we measured neural signals from different layers of the LGN and SC, as well as from the early visual cortices (V1, V2 and MT), in patients with early-stage glaucoma and normal controls. Compared to normal controls, early glaucoma patients showed more reduction of response to transient achromatic stimuli than to sustained chromatic stimuli in the magnocellular layers of the LGN, as well as in the superficial layer of the SC. Magnocellular responses in the LGN were also significantly correlated with the degree of behavioral deficits to the glaucomatous eye. Finally, early glaucoma patients showed no reduction of fMRI response in the early visual cortex. These findings demonstrate that 'large cells' in the human LGN and SC suffer selective loss of response to transient achromatic stimuli at the early stage of glaucoma. Hum Brain Mapp 37:558-569, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26526338 TI - Cardiac Rehabilitation: Underrecognized/Underutilized. AB - OPINION STATEMENT: Unfortunately, too many patients continue to rely on costly coronary revascularization procedures, cardioprotective medications, or both, as first-line strategies to stabilize the course of coronary heart disease. However, these palliative therapies do not address the foundational or most proximal risk factors for coronary disease, that is, unhealthy dietary habits, physical inactivity, and cigarette smoking. Because most acute myocardial infarctions evolve from mild-to-moderate coronary artery stenosis (<70 % obstruction), rather than at the more severe obstructions that are commonly treated with coronary revascularization, these findings help explain the inability to demonstrate a reduction in acute cardiac events in most studies examining coronary artery bypass graft surgery and/or percutaneous coronary interventions. The delivery of comprehensive cardiovascular risk reduction, including exercise-based cardiac rehabilitation as an integral component, offers patients a bona fide treatment intervention to prevent recurrent cardiovascular events and the need for repeated revascularization procedures, while simultaneously providing referring physicians with ongoing surveillance data to potentially enhance their medical management. PMID- 26526340 TI - Intensified low-density lipoprotein-cholesterol target of statin therapy and cancer risk: a meta-analysis. AB - BACKGROUND: This study aimed to investigate the relationship between an intensified low-density lipoprotein-cholesterol (LDL-c) target of statin therapy and cancer risk. METHODS: Data from PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials as of September 2014 were searched for randomized controlled trials on statins. An intensified LDL-c target of <2.59 mmol/L (100 mg/dL) or a relative LDL-c reduction by at least 30% of the baseline was the primary criterion for all the trials that were included in this meta-analysis. The I(2) statistic was used to measure heterogeneity among the trials, and risk estimates were calculated for cancer incidence in this random-effect meta analysis. RESULTS: Nine eligible studies were identified with 59,571 participants, of whom 5379 developed cancer during the follow-up period (2691 were given statins and 2688 were given control treatment). The intensified LDL-c target of statin therapy did not affect cancer incidence (odds ratio, 1.00; 95% confidence interval, 0.94 - 1.06; I(2) = 1.6%, p = 0.42), which included some common cancers. Subgroup analysis showed that neither the chemical properties nor the variety of the statins accounted for the residual variation in risk. CONCLUSIONS: The intensified LDL-c target of statin therapy had no effect on the overall incidence of cancer, including some common cancers. Therefore, intensified statin therapy does not need to be changed among adult clinical patients. PMID- 26526341 TI - Can large surveys conducted on highly selected populations provide valid information on the epidemiology of common health conditions? An analysis of UK Biobank data on musculoskeletal pain. AB - INTRODUCTION: Biobank-type studies are typically large but have very low participation rates. It has been suggested that these studies may provide biased estimates of prevalence but are likely to provide valid estimates of association. We test these hypotheses using data collected on pain in a large Biobank study in the United Kingdom. METHODS: UK Biobank recruited 503,325 persons aged 40-69 years (participation rate 5.5%). Participants completed questionnaires, including pain, lifestyle and environment factors. As a comparison, we used both a large population study of pain (MUSICIAN: n = 8847, aged: 40-69 years) conducted 2008 2009 and the National Child Development study (NCDS) which recruited all persons in Great Britain born during one week of 1958 and followed them up at age 44 years (n = 9377). RESULTS: 'Any pain' (UK Biobank 61.0%; MUSICIAN 63.9%), chronic pain (42.9%, 52.2%) and site-specific musculoskeletal pain (back 26.2%, 29.7%; shoulder/neck 23.3%, 25.3%) were generally similar in UK Biobank and MUSICIAN. The prevalence of chronic pain and most regional musculoskeletal pains in UK Biobank were all within 2% of that in NCDS. CONCLUSION: UK Biobank has provided estimates of the prevalence of pain which are similar to those from previous large-scale studies, although a formal comparison of the estimates cannot be made. It has also confirmed known associations with the reporting of pain. Despite its very low participation rate, such a study provides the opportunity to investigate novel exposure-pain relationships and investigate rarer exposures and characteristics to further our knowledge of the epidemiology of pain. PMID- 26526342 TI - Neurology Choosing Wisely recommendations: 74 and growing. AB - To increase neurologist awareness and inform future efficiency efforts, we identified all neurology-related Choosing Wisely items. Items were categorized by neurologic specialty, disease/symptom, and test/treatment. Of 370 items provided by 65 medical societies, 74 (20%) items were relevant to neurologists. Twelve were duplicated by multiple societies. Items pertaining to 10 neurologic subspecialties were identified, but none for movement disorders and neuromuscular disease. While many recommendations question the use of imaging, few address other high-cost neurologic tests such as EMG/nerve conduction studies and EEG. A rapidly growing number of neurology-related Choosing Wisely recommendations exist including areas of consensus and areas with few recommendations despite high costs. Consensus items should be prioritized for near-term interventions, while areas with few recommendations represent opportunities for future research. PMID- 26526343 TI - The in vivo disposition and in vitro transmembrane transport of two model radiometabolites of DOTA-conjugated receptor-specific peptides labelled with (177) Lu. AB - In vivo metabolism of the radiolabelled receptor-specific peptides has been described; however, information regarding the pharmacokinetic behaviour of the degradation products within the body is very scarce. The present study was designed to obtain new knowledge on the disposition and elimination of low molecular radiometabolites of receptor-specific peptides in the organism and to reveal the potential involvement of selected membrane transport mechanisms in the cellular uptake of radiometabolites, especially in the kidney. The study compared pharmacokinetics of two radiometabolites: a final metabolite of somatostatin analogues, (177)Lu-DOTA-DPhe, and a tripeptide metabolite of (177)Lu-DOTA minigastrin 11, (177)Lu-DOTA-DGlu-Ala-Tyr. Their pharmacokinetics was compared with that of respective parent (177)Lu-radiopeptide. Both radiometabolites exhibited relative rapid clearing from most body tissues in rats in vivo along with predominant renal excretion. The long-term renal retention of the smaller radiometabolite (177)Lu-DOTA-DPhe was lower than that of (177)Lu-DOTA-DGlu-Ala Tyr. An uptake of (177)Lu-DOTA-DPhe by human renal influx transporter organic cation transporter 2 was found in vitro in a cellular model. The study brings the first experimental data on the in vivo pharmacokinetics of radiometabolites of receptor-specific somatostatin and gastrin analogues. The found results may indicate a negative correlation between the degree of decomposition of the parent peptide chain and the renal retention of the metabolite. PMID- 26526344 TI - WeBIAS: a web server for publishing bioinformatics applications. AB - BACKGROUND: One of the requirements for a successful scientific tool is its availability. Developing a functional web service, however, is usually considered a mundane and ungratifying task, and quite often neglected. When publishing bioinformatic applications, such attitude puts additional burden on the reviewers who have to cope with poorly designed interfaces in order to assess quality of presented methods, as well as impairs actual usefulness to the scientific community at large. RESULTS: In this note we present WeBIAS-a simple, self contained solution to make command-line programs accessible through web forms. It comprises a web portal capable of serving several applications and backend schedulers which carry out computations. The server handles user registration and authentication, stores queries and results, and provides a convenient administrator interface. WeBIAS is implemented in Python and available under GNU Affero General Public License. It has been developed and tested on GNU/Linux compatible platforms covering a vast majority of operational WWW servers. Since it is written in pure Python, it should be easy to deploy also on all other platforms supporting Python (e.g. Windows, Mac OS X). Documentation and source code, as well as a demonstration site are available at http://bioinfo.imdik.pan.pl/webias . CONCLUSIONS: WeBIAS has been designed specifically with ease of installation and deployment of services in mind. Setting up a simple application requires minimal effort, yet it is possible to create visually appealing, feature-rich interfaces for query submission and presentation of results. PMID- 26526345 TI - Production of wheat gluten hydrolysates with reduced antigenicity employing enzymatic hydrolysis combined with downstream unit operations. AB - BACKGROUND: Due to allergies or other health disorders a certain segment of the population is not able to safely consume some plant proteins, which are the main protein support in human nutrition. Coeliac disease is a prominent autoimmune disorder and requires a strict adherence to a gluten-free diet. The aim of this study was to identify suitable combinations of enzymatic hydrolysis and common unit operations in food processing (centrifugation, ultra-filtration) to produce gluten-free wheat gluten hydrolysates for food application. To analyse the hydrolysates, a simple and cheap competitive ELISA protocol was designed and validated in this study as well. RESULTS: The competitive ELISA was validated using gliadin spiked skim milk protein hydrolysates, due to the latter application of the assay. The limit of quantification was 4.19 mg kg(-1) , which allowed the identification of gluten-free (<20 mg kg(-1) ) hydrolysates. Enzymatic hydrolysis, including the type of peptidase, and the downstream processing greatly affected the antigenicity of the hydrolysates. CONCLUSION: Enzymatic hydrolysis and downstream processing operations, such as centrifugation and ultra-filtration, reduced the antigenicity of wheat gluten hydrolysates. Gluten-free hydrolysates were obtained with Flavourzyme after centrifugation (25 g L(-1) substrate) and after 1 kDa ultra-filtration (100 g L(-1) substrate). A multiple peptidase complex, such as Flavourzyme, seems to be required for the production of gluten-free hydrolysates. (c) 2015 Society of Chemical Industry. PMID- 26526346 TI - Visualization of in vivo degradation of aliphatic polyesters by a fluorescent dendritic star macromolecule. AB - In tissue engineering, most polymeric scaffolds should degrade along with the formation of the new tissues. Therefore, it is necessary to look into the in vivo degradation of scaffolds. In this study, a fluorescent perylenediimide-cored (PDI cored) dendritic star macromolecule bearing multiple amines (d-p48) was incorporated into biodegradable polyester nanofibrous scaffolds by eletrospinning as an indicator. The polyester/d-p48 blend nanofibers could emit strong red fluorescence when they were irradiated under exciting light. Initially, using slowly degradable polyester, poly(L-lactide) (PLLA)/d-p48 nanofibers were soaked in phosphate buffered saline for various lengths of time to determine the possible diffusing release of d-p48 macromolecule from nanofibers. The PLLA/d-p48 nanofibers were then implanted subcutaneously into mice and left for up to 2 weeks. In both cases, no undesirable release of the incorporated d-p48 macromolecule was detected, and the nanofibers were clearly visualized in vivo by fluorescence microscopy. Using a fast degradable polyester, poly(lactide-co glycolide) (PLGA)/d-p48 nanofibers were electrospun and implanted subcutaneously to determine the possibility of monitoring in vivo degradation by fluorescence during 12 weeks. The results showed that the location and the contour of PLGA/d p48 nanofibrous scaffolds could be clearly visualized using an animal fluorescent imaging system. The fluorescent intensities decreased gradually with the degradation of the scaffolds. No side effects on liver and kidney were found during the detection. This study indicates that the fluorescent PDI-cored dendritic star macromolecule can be used as a stable bioimaging indicator for biodegradable aliphatic polyesters in vivo. PMID- 26526347 TI - Mast cells and eosinophils in allergy: Close friends or just neighbors. AB - Mast cells are mostly known for their role in allergic diseases although in recent years it has become clear that they have a role in other diseases and in the body's defense against microbes. In most cases, but especially in allergy, eosinophils are present in the tissue within proximity of mast cells. Due to this spatio-temporal correlation we and others have postulated and described a crosstalk between these two cells, mediated via their released mediators and physical interactions, that is able to modulate each other's function and ultimately the outcome of the allergic inflammatory reaction. This review will focus on the functional unit between mast cells and eosinophils that we have named the "Allergic Effector Unit" and specifically highlight its role in allergy. PMID- 26526348 TI - Effects of harmine, an acetylcholinesterase inhibitor, on spatial learning and memory of APP/PS1 transgenic mice and scopolamine-induced memory impairment mice. AB - Harmine, a beta-carboline alkaloid present in Peganum harmala with a wide spectrum of pharmacological activities, has been shown to exert strong inhibition against acetylcholinesterase in vitro. However, whether it can rescue the impaired cognition has not been elucidated yet. In current study, we examined its effects on scopolamine-induced memory impairment mice and APP/PS1 transgenic mice, one of the models for Alzheimer's disease, using Morris Water Maze test. In addition, whether harmine could penetrate blood brain barrier, interact with and inhibit acetylcholinesterase, and activate downstream signaling network was also investigated. Our results showed that harmine (20mg/kg) administered by oral gavage for 2 weeks could effectively enhance the spatial cognition of C57BL/6 mice impaired by intraperitoneal injection of scopolamine (1mg/kg). Meanwhile, long-term consumption of harmine (20mg/kg) for 10 weeks also slightly benefited the impaired memory of APP/PS1 mice. Furthermore, harmine could pass through blood brain barrier, penetrate into the brain parenchyma shortly after oral administration, and modulate the expression of Egr-1, c-Jun and c-Fos. Molecular docking assay disclosed that harmine molecule could directly dock into the catalytic active site of acetylcholinesterase, which was partially confirmed by its in vivo inhibitory activity on acetylcholinesterase. Taken together, all these results suggested that harmine could ameliorate impaired memory by enhancement of cholinergic neurotransmission via inhibiting the activity of acetylcholinesterase, which may contribute to its clinical use in the therapy of neurological diseases characterized with acetylcholinesterase deficiency. PMID- 26526349 TI - Inhibition of leucine aminopeptidase 3 suppresses invasion of ovarian cancer cells through down-regulation of fascin and MMP-2/9. AB - Leucine aminopeptidase 3 (LAP3) is a cell surface aminopeptidase that catalyzes the hydrolysis of leucine residues from the amino termini of protein or peptide substrates. The over-expression of LAP3 correlates with prognosis and malignant development of several human cell carcinomas. However, the molecular mechanism remains unknown. In this study, we used ES-2 ovarian cancer cell line as a model system to explore the role of LAP3 in regulation of cancer cell invasion by employing a natural LAP3 inhibitor bestatin and LAP3 siRNA. Bestatin inhibited tumor cell migration and invasion in a dose-dependent manner. More interestingly, bestatin down-regulated expression of fascin protein and inhibited activity of fascin promoter luciferase reporter. Both proteome profiler array and Western blot assay showed that bestatin up-regulated the phosphorylation of Hsp27. Furthermore, LAP3 siRNA could up-regulate the phosphorylation of Hsp27 and down regulate the expression of fascin. Meanwhile, LAP3 siRNA could also down-regulate the phosphorylation of Akt and the expression of MMP-2/9. Taken together, LAP3 could affect the expression of fascin and MMP-2/9 and may act as a potential anti metastasis therapeutic target. PMID- 26526350 TI - Agonists and protein kinase C-activation induce phosphorylation and internalization of FFA1 receptors. AB - FFA1 (previously known as GPR40) is a free fatty acid receptor involved in the regulation of inflammatory processes and insulin secretion. The cellular actions resulting from FFA1 activation have received considerable attention. However, little is known on the regulation of the receptor function. In the present work, using cells transfected with this receptor, docosahexaenoic acid and alpha linolenic acid increased intracellular calcium concentration and ERK 1/2 phosphorylation. It was also observed that FFA1 is a phosphoprotein whose phosphorylation state was increased (2- to 3-fold) by agonists (i.e., free fatty acids) and also by phorbol myristate acetate. Agonist- and phorbol ester-mediated FFA1 phosphorylation was markedly reduced by inhibitors of protein kinase C. Receptor stimulation by free fatty acids and protein kinase C activation also induced receptor internalization as evidenced by confocal microscopy. In summary, our data show that FFA1 is a phosphoprotein whose phosphorylation state is modulated by agonists and protein kinase C activation; such covalent modification is associated with receptor internalization. PMID- 26526351 TI - Endothelin receptor-antagonists suppress lipopolysaccharide-induced cytokine release from alveolar macrophages of non-smokers, smokers and COPD subjects. AB - Smoking-induced COPD is characterized by chronic airway inflammation, which becomes enhanced by bacterial infections resulting in accelerated disease progression called exacerbation. Alveolar macrophages (AM) release endothelin-1 (ET-1), IL-6, CCL-2 and MMP-9, all of which are linked to COPD pathogenesis and exacerbation. ET-1 signals via ETA- and ETB-receptors (ETAR, ETBR). This is blocked by endothelin receptor antagonists (ERAs), like bosentan, which targets both receptors, ETAR-selective ambrisentan and ETBR-specific BQ788. Therefore, ERAs could have anti-inflammatory potential, which might be useful in COPD and other inflammatory lung diseases. We hypothesized that ERAs suppress cytokine release from AM of smokers and COPD subjects induced by lipopolysaccharide (LPS), the most important immunogen of gram-negative bacteria. AM were isolated from the broncho-alveolar lavage (BAL) of n=29 subjects (11 non-smokers, 10 current smokers without COPD, 8 smokers with COPD), cultivated and stimulated with LPS in the presence or absence of ERAs. Cytokines were measured by ELISA. Endothelin receptor expression was investigated by RT-PCR and western blot. AM expressed ETAR and ETBR mRNA, but only ETBR protein was detected. LPS and ET-1 both induced IL-6, CCL-2 and MMP-9. LPS-induced IL-6 release was increased in COPD versus non smokers and smokers. Bosentan, ambrisentan and BQ788 all partially reduced all cytokines without differences between cohorts. Specific ETBR inhibition was most effective. LPS induced ET-1, which was exclusively blocked by BQ788. In conclusion, LPS induces ET-1 release in AM, which in turn leads to CCL-2, IL-6 and MMP-9 expression rendering AM sensitive for ERAs. ERAs could have anti inflammatory potential in smoking-induced COPD. PMID- 26526352 TI - EGFR is not a major driver for osteosarcoma cell growth in vitro but contributes to starvation and chemotherapy resistance. AB - BACKGROUND: Enhanced signalling via the epidermal growth factor receptor (EGFR) is a hallmark of multiple human carcinomas. However, in recent years data have accumulated that EGFR might also be hyperactivated in human sarcomas. Aim of this study was to investigate the influence of EGFR inhibition on cell viability and its interaction with chemotherapy response in osteosarcoma cell lines. METHODS: We have investigated a panel of human osteosarcoma cell lines regarding EGFR expression and downstream signalling. To test its potential applicability as therapeutic target, inhibition of EGFR by gefitinib was combined with osteosarcoma chemotherapeutics and cell viability, migration, and cell death assays were performed. RESULTS: Osteosarcoma cells expressed distinctly differing levels of functional EGFR reaching in some cases high amounts. Functionality of EGFR in osteosarcoma cells was proven by EGF-mediated activation of both MAPK and PI3K/AKT pathway (determined by phosphorylation of ERK1/2, AKT, S6, and GSK3beta). The EGFR-specific inhibitor gefitinib blocked EGF-mediated downstream signal activation. At standard in vitro culture conditions, clinically achievable gefitinib doses demonstrated only limited cytotoxic activity, however, significantly reduced long-term colony formation and cell migration. In contrast, under serum-starvation conditions active gefitinib doses were distinctly reduced while EGF promoted starvation survival. Importantly, gefitinib significantly supported the anti-osteosarcoma activities of doxorubicin and methotrexate regarding cell survival and migratory potential. CONCLUSION: Our data suggest that EGFR is not a major driver for osteosarcoma cell growth but contributes to starvation- and chemotherapy-induced stress survival. Consequently, combination approaches including EGFR inhibitors should be evaluated for treatment of high grade osteosarcoma patients. PMID- 26526353 TI - Harnessing biodiesel-producing microbes: from genetic engineering of lipase to metabolic engineering of fatty acid biosynthetic pathway. AB - Microbial production routes, notably whole-cell lipase-mediated biotransformation and fatty-acids-derived biosynthesis, offer new opportunities for synthesizing biodiesel. They compare favorably to immobilized lipase and chemically catalyzed processes. Genetically modified whole-cell lipase-mediated in vitro route, together with in vivo and ex vivo microbial biosynthesis routes, constitutes emerging and rapidly developing research areas for effective production of biodiesel. This review presents recent advances in customizing microorganisms for producing biodiesel, via genetic engineering of lipases and metabolic engineering (including system regulation) of fatty-acids-derived pathways. Microbial hosts used include Escherichia coli, Saccharomyces cerevisiae, Pichia pastoris and Aspergillus oryzae. These microbial cells can be genetically modified to produce lipases under different forms: intracellularly expressed, secreted or surface displayed. They can be metabolically redesigned and systematically regulated to obtain balanced biodiesel-producing cells, as highlighted in this study. Such genetically or metabolically modified microbial cells can support not only in vitro biotransformation of various common oil feedstocks to biodiesel, but also de novo biosynthesis of biodiesel from glucose, glycerol or even cellulosic biomass. We believe that the genetically tractable oleaginous yeast Yarrowia lipolytica could be developed to an effective biodiesel-producing microbial cell factory. For this purpose, we propose several engineered pathways, based on lipase and wax ester synthase, in this promising oleaginous host. PMID- 26526355 TI - Sanofi-Cell Research outstanding paper award of 2014. PMID- 26526354 TI - Identification and functional analysis of two Golgi-localized UDP-galactofuranose transporters with overlapping functions in Aspergillus niger. AB - BACKGROUND: Galactofuranose (Galf)-containing glycoconjugates are present in numerous microbes, including filamentous fungi where they are important for morphology, virulence and maintaining cell wall integrity. The incorporation of Galf-residues into galactomannan, galactomannoproteins and glycolipids is carried out by Golgi-localized Galf transferases. The nucleotide sugar donor used by these transferases (UDP-Galf) is produced in the cytoplasm and has to be transported to the lumen of the Golgi by a dedicated nucleotide sugar transporter. METHODS: Based on homology with recently identified UDP-Galf transporters in A. fumigatus and A. nidulans, two putative UDP-Galf-transporters in A. niger were found. Their function and localization was determined by gene deletions and GFP-tagging studies, respectively. RESULTS: The two putative UDP Galf-transporters in A. niger are homologous to each other and are predicted to contain eleven transmembrane domains (UgtA) or ten transmembrane domains (UgtB) due to a reduced length of the C-terminal part of the UgtB protein. The presence of two putative UDP-Galf-transporters in the genome was not unique for A. niger. From the twenty Aspergillus species analysed, nine species contained two additional putative UDP-Galf-transporters. Three of the nine species were outside the Aspergillus section nigri, indication an early duplication of UDP-Galf transporters and subsequent loss of the UgtB copy in several aspergilli. Deletion analysis of the single and double mutants in A. niger indicated that the two putative UDP-Galf-transporters (named UgtA and UgtB) have a redundant function in UDP-Galf-transport as only the double mutant displayed a Galf-negative phenotype. The Galf-negative phenotype of the double mutant could be complemented by expressing either CFP-UgtA or CFP-UgtB fusion proteins from their endogenous promoters, indicating that both CFP-tagged proteins are functional. Both Ugt proteins co-localize with each other as well as with the GDP-mannose nucleotide transporter, as was demonstrated by fluorescence microscopy, thereby confirming their predicted localization in the Golgi. CONCLUSION: A. niger contains two genes encoding UDP-Galf-transporters. Deletion and localization studies indicate that UgtA and UgtB have redundant functions in the biosynthesis of Galf containing glycoconjugates. PMID- 26526356 TI - A Her2-let-7-beta2-AR circuit affects prognosis in patients with Her2-positive breast cancer. AB - BACKGROUND: Our previous studies show that beta2-adrenergic receptor (beta2-AR) is highly expressed in most Her2-overexpressing breast cancers. However, the mechanisms underlying upregulation of the beta2-AR expression in Her2 overexpressing breast cancer cells are not fully understood. The clinical significance of the beta2-AR overexpression in breast cancer is unclear. METHODS: Human breast cancer cells MCF-7 and MCF-7/Her2 were transfected with the let-7 mimics or inhibitors. The expression of beta2-AR was analyzed by Western blot. The beta2-AR status in primary and metastatic sites of breast cancer and the human breast cancer tissue microarrays containing 49 primary tumors and 50 metastatic lymph node tissues was analyzed by immunohistochemistry. The correlation of lymph node metastasis with the beta2-AR level was determined in 59 primary tumor tissues from the patients with Her2-positive breast cancer. The clinical prognostic significance of the beta2-AR overexpression in the patients with Her2-positive breast cancers was evaluated by a retrospective study. RESULTS: The let-7f level in Her2-overexpressing breast cancer cells SKBR3 and BT474 was significantly lower than that in MCF-7 cells, which express low level of Her2. Ectopic expression of Her2 in MCF-7 cells (MCF-7/Her2) represses the expression of microRNA let-7f, which is previously identified to regulate baseline beta2-AR expression. The treatment with MEK1/2 inhibitors PD98059 or PD184352 effectively restored the let-7f level, suggesting that Her2 overexpression-mediated ERK constitutive activation inhibited let-7f, leading to the upregulation of the beta2-AR expression. The transfection with the let-7f mimics markedly downregulated the beta2-AR level, whereas the let-7 inhibitor significantly upregulated the beta2-AR expression in both parental MCF-7 and MCF 7/Her2 cells. In addition, treatment of MCF-7/Her2 cells with isoproterenol resulted in a concentration-dependent reduction of the let-7f expression, demonstrating that the inhibitory effect of Her2 overexpression on let-7f can be reinforced by agonist-triggered beta2-AR activation. We further demonstrate that high level of beta2-AR associates with lymph node metastasis and poor outcome in the patients with Her2-positive breast cancer. CONCLUSIONS: The mutual and reciprocal interaction between Her2, beta2-AR, and let-7f may maintain a high level of beta2-AR in breast cancer cells. Our data suggest that beta2-AR may be a new useful biomarker for predicting prognosis in Her2-positive breast cancer and may also be a promising selective therapeutic target for the aggressive subtype of breast cancer. PMID- 26526357 TI - Characterization of Intestinal Microbiota in Ulcerative Colitis Patients with and without Primary Sclerosing Cholangitis. AB - BACKGROUND AND AIMS: There is an unexplained association between ulcerative colitis [UC] and primary sclerosing cholangitis [PSC], with the intestinal microbiota implicated as an important factor. The study aim was to compare the structure of the intestinal microbiota of patients with UC with and without PSC. METHODS: UC patients with PSC [PSC-UC] and without PSC [UC] were identified from biobanks at Oslo University Hospital, Foothills Hospital Calgary and Mount Sinai Hospital Toronto. Microbial DNA was extracted from colonic tissue and sequencing performed of the V4 region of the 16S rRNA gene on Illumina MiSeq. Sequences were assigned to operational taxonomic units [OTUs] using Quantitative Insights Into Microbial Ecology [QIIME]. Microbial alpha diversity, beta diversity, and relative abundance were compared between PSC-UC and UC phenotypes. RESULTS: In all, 31 PSC-UC patients and 56 UC patients were included. Principal coordinate analysis [PCoA] demonstrated that city of sample collection was the strongest determinant of taxonomic profile. In the Oslo cohort, Chao 1 index was modestly decreased in PSC-UC compared with UC [p = 0.04] but did not differ significantly in the Calgary cohort. No clustering by PSC phenotype was observed using beta diversity measures. For multiple microbial genera there were nominally significant differences between UC and PSC-UC, but results were not robust to false-discovery rate correction. CONCLUSIONS: No strong PSC-specific microbial associations in UC patients consistent across different cohorts were identified. Recruitment centre had a strong effect on microbial composition. Future studies should include larger cohorts to increase power and the ability to control for confounding factors. PMID- 26526358 TI - A small molecule neutrophil elastase inhibitor, KRP-109, inhibits cystic fibrosis mucin degradation. AB - BACKGROUND: Neutrophil elastase (NE) rapidly degrades gel-forming airway mucins in cystic fibrosis (CF) sputum. We hypothesized that KRP-109, a small molecule NE inhibitor, would inhibit CF mucin degradation in vitro. METHODS: Sputa were collected from CF patients (n=5) chronically or intermittently infected with Pseudomonas aeruginosa (P.a.). Mucin degradation was analyzed using western blot. Protease inhibitor studies were performed using alpha1-proteinase inhibitor (A1 PI Prolastin(r)) and KRP-109. Elastase activity assays were performed using spectrophotometry. RESULTS: There were significant differences in the amount of active NE in different CF sputum samples. KRP-109 decreased the NE driven mucin degradation in vitro. Pseudomonas elastases appeared to blunt elastase inhibition by A1-PI or KRP-109. CONCLUSION: Inhibitors of neutrophil and Pseudomonas-derived elastases might rescue mucus clearance and reverse airway obstruction in CF. PMID- 26526360 TI - Using HbA1c as a screening tool for Cystic Fibrosis Related Diabetes. PMID- 26526361 TI - Health Services and Health Care Needs Fulfilled by Structured Clinical Programs for Children with Medical Complexity. AB - OBJECTIVE: To describe family-reported health service needs of children with medical complexity (CMC) and to assess which needs are more often addressed in a tertiary care center-based structured clinical program for CMC. STUDY DESIGN: Mailed survey to families of CMC enrolled in a structured-care program providing care coordination and oversight at 1 of 3 children's hospitals. Outcomes included receipt of 14 specific health service needs. Paired t tests compared unmet health care needs prior to and following program enrollment. RESULTS: Four hundred forty one of 968 (46%) surveys were returned and analyzed. Respondents reported their children had a mean age of 7 (SD 5) years. A majority of respondents reported the child had developmental delay (79%) and feeding difficulties (64%). Of the respondents, 56% regarded the primary care provider as the primary point of contact for medical issues. Respondents reported an increase in meeting all 14 health services needs after enrollment in a tertiary care center-based structured clinical program, including primary care checkups (82% vs 96%), therapies (78% vs 91%), mental health care (34% vs 58%), respite care (56% vs 75%), and referrals (51% vs 83%) (all P < .001). CONCLUSIONS: Tertiary care center-based structured clinical care programs for CMC may address and fulfill a broad range of health service needs that are not met in the primary care setting. PMID- 26526359 TI - Hallmarks of therapeutic management of the cystic fibrosis functional landscape. AB - The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein does not operate in isolation, rather in a dynamic network of interacting components that impact its synthesis, folding, stability, intracellular location and function, referred to herein as the 'CFTR Functional Landscape (CFFL)'. For the prominent F508del mutation, many of these interactors are deeply connected to a protein fold management system, the proteostasis network (PN). However, CF encompasses an additional 2000 CFTR variants distributed along its entire coding sequence (referred to as CFTR2), and each variant contributes a differential liability to PN management of CFTR and to a protein 'social network' (SN) that directs the probability of the (patho)physiologic events that impact ion transport in each cell, tissue and patient in health and disease. Recognition of the importance of the PN and SN in driving the unique patient CFFL leading to disease highlights the importance of precision medicine in therapeutic management of disease progression. We take the view herein that it is not CFTR, rather the PN/SN, and their impact on the CFFL, that are the key physiologic forces driving onset and clinical progression of CF. We posit that a deep understanding of each patients PN/SN gained by merging genomic, proteomic (mass spectrometry (MS)), and high-content microscopy (HCM) technologies in the context of novel network learning algorithms will lead to a paradigm shift in CF clinical management. This should allow for generation of new classes of patient specific PN/SN directed therapeutics for personalized management of the CFFL in the clinic. PMID- 26526362 TI - Commercial Television Exposure, Fast Food Toy Collecting, and Family Visits to Fast Food Restaurants among Families Living in Rural Communities. AB - OBJECTIVE: To assess the associations between children's exposure to television (TV) networks that aired child-directed advertisements for children's fast food meals with the collection of fast food meal toy premiums and frequency of family visits to those restaurants. STUDY DESIGN: One hundred parents of children 3-7 years old were recruited from a rural pediatrics clinic during 2011; families receiving Medicaid were oversampled. Parents reported the child's TV viewing habits and family visit frequency to the fast food restaurants participating in child-directed TV marketing at the time, and their child's requests for visits to and the collecting of toy premiums from those restaurants. Logistic regression models assessed adjusted associations between a child's TV viewing with more frequent restaurant visits (>=monthly in this population). Structural equation modeling assessed if child requests or toy collecting mediated that association. RESULTS: Thirty-seven percent of parents reported >=monthly visits to the select fast food restaurants. Among children, 54% requested visits to and 29% collected toys from those restaurants. Greater child commercial TV viewing was significantly associated with more frequent family visits to those fast food restaurants (aOR 2.84 for each 1-unit increase in the child's commercial TV viewing scale, P < .001); toy collecting partially mediated that positive association. CONCLUSIONS: Higher exposure among children to commercial TV networks that aired child-directed ads for children's fast food meals was associated with more frequent family visits to those fast food restaurants. Child desire for toy premiums may be a mediating factor. PMID- 26526363 TI - Brain Connectomics of Visual-Motor Deficits in Children with Developmental Coordination Disorder. AB - OBJECTIVE: To extend preliminary findings on associated white matter deficits and structural connectivity in children with developmental coordination disorder (DCD). STUDY DESIGN: Diffusion magnetic resonance imaging-based tractography was used to identify abnormal microstructural properties of specific sensorimotor white matter tracts in 21 children with DCD between 8 and 10 years of age and 20 age- and sex-matched typically developing controls. Graph theoretical analyses were applied to evaluate whole brain connectomics. Associations were also calculated between the tractography/connectome results and visual-motor performance, as measured with the Beery-Buktenica Developmental Test of Visual Motor Integration. RESULTS: Significant positive correlations were obtained between visual-motor trace scores and fractional anisotropy (FA) in the retrolenticular limb of the internal capsule within the group with DCD. Moreover, lower FA in sensorimotor tracts and altered structural connectivity were observed for children with DCD. Compared with controls, subjects with DCD showed decreases in clustering coefficient, and global and local efficiency, suggesting weaker structural network segregation and integration. The degree of decreased global efficiency was significantly associated with poor visual-motor tracing outcomes, above and beyond FA reductions. Specifically, nodal efficiency at the cerebellar lobule VI and right parietal superior gyrus were found significant predictors to discriminate between children with DCD and those with typical development. CONCLUSIONS: Specific white matter alterations and network topology features associate with visual-motor deficits and DCD diagnosis indicating the clinical potential of diffusion magnetic resonance imaging-based metrics for diagnosing DCD. PMID- 26526364 TI - Effects of Posthemorrhagic Ventricular Dilatation in the Preterm Infant on Brain Volumes and White Matter Diffusion Variables at Term-Equivalent Age. AB - OBJECTIVE: To evaluate the differential impact of germinal matrix intraventricular hemorrhage (GMH-IVH) and posthemorrhagic ventricular dilatation (PHVD) on brain and cerebrospinal fluid (CSF) volumes and diffusion variables in preterm born infants at term-equivalent age (TEA). STUDY DESIGN: Nineteen infants (gestational age <31 weeks) with GMH-IVH grade II-III according to Papile et al and subsequent PHVD requiring intervention were matched against 19 controls with GMH-IVH grade II but no PHVD and 19 controls without GMH-IVH. Outcome variables on magnetic resonance imaging (MRI) including diffusion weighted imaging at TEA were volumes of white matter, cortical gray matter, deep gray matter, brainstem, cerebellum, ventricles, extracerebral CSF, total brain tissue, and intracranial volume (ICV), as well as white matter and cerebellar apparent diffusion coefficients (ADCs). Effects of GMH-IVH and PHVD on TEA-MRI measurements were evaluated using multivariable regression analysis. Brain and CSF volumes were adjusted for ICV to account for differences in bodyweight at TEA-MRI and ICV between cases and controls. RESULTS: PHVD was independently associated with volumes of deep gray matter (beta [95% CI]: -1.4 cc [-2.3; -.5]), cerebellum ( 2.7 cc [-3.8; -1.6]), ventricles (+12.7 cc [7.9; 17.4]), and extracerebral CSF ( 11.2 cc [-19.2; -3.3]), and with ADC values in occipital, parieto-occipital, and parietal white matter (beta: +.066-.119*10(-3) mm(2)/s) on TEA-MRI (P < .05). No associations were found between GMH-IVH grade II-III and brain and CSF volumes or ADC values at TEA. CONCLUSIONS: PHVD was negatively related to deep gray matter and cerebellar volumes and positively to white matter ADC values on TEA-MRI, despite early intervention for PHVD in the majority of the infants. These relationships were not observed for GMH-IVH. PMID- 26526365 TI - Intercostal Lung Herniation. PMID- 26526366 TI - Honey-Comb Lungs in Langerhans Cell Histiocytosis. PMID- 26526367 TI - Prognostic Impact of Primary Percutaneous Coronary Intervention in the Very Elderly STEMI Patient: Insights From the Codi Infart Registry. PMID- 26526368 TI - Lack of association of polymorphisms in six candidate genes in colombian adhd patients. AB - BACKGROUND: Attention Deficit and Hyperactivity Disorder (ADHD) is a common childhood neuropsychiatric condition. The disorder has a multifactorial background, with heritability estimates of around 76%, suggesting an important role of genetic factors. Candidate genes include those related to dopaminergic (e.g. DRD4, DRD5, SLC6A3 and DBH)and serotoninergic (e.g.HTR1B and SLC6A4) pathways. PURPOSE: To explore the association of common polymorphisms in six genes (DRD4, DRD5, SLC6A3, DBH, HTR1B and SLC6A4) and the susceptibility to ADHD in a Colombian sample population. METHODS: trios and 152 healthy controls were recruited. Genotyping of the six polymorphisms was performed using described PCR based protocols. A TDT analysis was used to test if there was preferential allelic transmission for any of the six polymorphisms. Additionally, a case control analysis was performed to test for association of the serotoninergic (HTR1B and SLC6A4) polymorphisms with ADHD. RESULTS: Through the TDT analysis there was no preferential allelic transmission for any of the studied variants. Case-control analysis did not show association. CONCLUSION: This is the first study in Latin America to describe six polymorphisms in a group of patients with ADHD. There was no evidence of association for any of the studied polymorphic variants in this Colombian ADHD sample. Further research, with larger sample sizes and study of endophenotypes, is needed in this population to confirm and extend the results. PMID- 26526369 TI - TGF-beta-Induced Transcription Sustains Amoeboid Melanoma Migration and Dissemination. AB - Cell migration underlies metastatic dissemination of cancer cells, and fast "amoeboid" migration in the invasive fronts of tumors is controlled by high levels of actomyosin contractility. How amoeboid migration is regulated by extracellular signals and sustained over time by transcriptional changes is not fully understood. Transforming growth factor beta (TGF-beta) is well known to promote epithelial-to-mesenchymal transition (EMT) and contribute to metastasis, but melanocytes are neural crest derivatives that have undergone EMT during embryonic development. Surprisingly, we find that in melanoma, TGF-beta promotes amoeboid features such as cell rounding, membrane blebbing, high levels of contractility, and increased invasion. Using genome-wide transcriptomics, we find that amoeboid melanoma cells are enriched in a TGF-beta-driven signature. We observe that downstream of TGF-beta, SMAD2 and its adaptor CITED1 control amoeboid behavior by regulating the expression of key genes that activate contractile forces. Moreover, CITED1 is highly upregulated during melanoma progression, and its high expression is associated with poor prognosis. CITED1 is coupled to a contractile-rounded, amoeboid phenotype in a panel of 16 melanoma cell lines, in mouse melanoma xenografts, and in 47 human melanoma patients. Its expression is also enriched in the invasive fronts of lesions. Functionally, we show how the TGF-beta-SMAD2-CITED1 axis promotes different steps associated with progression: melanoma detachment from keratinocytes, 2D and 3D migration, attachment to endothelial cells, and in vivo lung metastatic initial colonization and outgrowth. We propose a novel mechanism by which TGF-beta-induced transcription sustains actomyosin force in melanoma cells and thereby promotes melanoma progression independently of EMT. PMID- 26526370 TI - The Speed of Alpha-Band Oscillations Predicts the Temporal Resolution of Visual Perception. AB - Evidence suggests that scalp-recorded occipital alpha-band (8-13 Hz) oscillations reflect phasic information transfer in thalamocortical neurons projecting from lateral geniculate nucleus to visual cortex. In animals, the phase of ongoing alpha oscillations has been shown to modulate stimulus discrimination and neuronal spiking. Human research has shown that alpha phase predicts visual perception of near-threshold stimuli and subsequent neural activity and that the frequency of these oscillations predicts reaction times, as well as the maximum temporal interval necessary for perceived simultaneity. These phasic effects have led to the hypothesis that conscious perception occurs in discrete temporal windows, clocked by the frequency of alpha oscillations. Under this hypothesis, variation in the frequency of occipital alpha oscillations should predict variation in the temporal resolution of visual perception. Specifically, when two stimuli fall within the same alpha cycle, they may be perceived as a single stimulus, resulting in perception with lower temporal resolution when alpha frequency is lower. We tested this by assessing the relationship between two flash fusion thresholds (a measure of the temporal resolution of visual perception) and the frequency of eyes-closed and task-related alpha rhythms. We found, both between and within subjects, that faster alpha frequencies predicted more accurate flash discrimination, providing novel evidence linking alpha frequency to the temporal resolution of perception. PMID- 26526371 TI - Queen Killing Is Linked to High Worker-Worker Relatedness in a Social Wasp. AB - Social insect colonies are pinnacles of evolved altruism but also exhibit dramatic conflict among relatives. In many species, a colony's workers compete with the queen and each other over the production of males. Interspecific comparisons demonstrate the importance of within-colony relatedness in determining the outcome of such conflicts, but facultative responses to within colony relatedness are rarely reported. Here, I report facultative matricide (worker killing of a colony's queen) in the social wasp Dolichovespula arenaria. Matricide is strongly associated with high worker-worker relatedness, as predicted by theory, because closely related workers value nephews more than brothers. This pattern is the result of variation in both paternity frequency and the paternity skew of colonies with multiple patrilines, implicating worker worker relatedness rather than a direct effect of multiple mating on queen survival. Furthermore, occasional inbreeding can explain why some multiple patriline colonies exhibit high paternity skew associated with matricide. In general, these results support the hypothesis that workers can facultatively respond to intracolony relatedness determined by queen mating behavior and demonstrate a novel benefit of polyandry in annual social insects. Facultative matricide shows dramatically how workers are evolutionary actors with interests that can diverge from the queen's, rather than being "extrasomatic projections of her personal genome". PMID- 26526372 TI - Identification of Neurons with a Privileged Role in Sleep Homeostasis in Drosophila melanogaster. AB - Sleep is thought to be controlled by two main processes: a circadian clock that primarily regulates sleep timing and a homeostatic mechanism that detects and responds to sleep need. Whereas abundant experimental evidence suggests that sleep need increases with time spent awake, the contributions of different brain arousal systems have not been assessed independently of each other to determine whether certain neural circuits, rather than waking per se, selectively contribute to sleep homeostasis. Using the fruit fly, Drosophila melanogaster, we found that sustained thermogenetic activation of three independent neurotransmitter systems promoted nighttime wakefulness. However, only sleep deprivation resulting from activation of cholinergic neurons was sufficient to elicit subsequent homeostatic recovery sleep, as assessed by multiple behavioral criteria. In contrast, sleep deprivation resulting from activation of octopaminergic neurons suppressed homeostatic recovery sleep, indicating that wakefulness can be dissociated from accrual of sleep need. Neurons that promote sleep homeostasis were found to innervate the central brain and motor control regions of the thoracic ganglion. Blocking activity of these neurons suppressed recovery sleep but did not alter baseline sleep, further differentiating between neural control of sleep homeostasis and daily fluctuations in the sleep/wake cycle. Importantly, selective activation of wake-promoting neurons without engaging the sleep homeostat impaired subsequent short-term memory, thus providing evidence that neural circuits that regulate sleep homeostasis are important for behavioral plasticity. Together, our data suggest a neural circuit model involving distinct populations of wake-promoting neurons, some of which are involved in homeostatic control of sleep and cognition. PMID- 26526373 TI - Preservational Pathways of Corresponding Brains of a Cambrian Euarthropod. AB - The record of arthropod body fossils is traceable back to the "Cambrian explosion," marked by the appearance of most major animal phyla. Exceptional preservation provides crucial evidence for panarthropod early radiation. However, due to limited representation in the fossil record of internal anatomy, particularly the CNS, studies usually rely on exoskeletal and appendicular morphology. Recent studiesshow that despite extreme morphological disparities, euarthropod CNS evolution appears to have been remarkably conservative. This conclusion is supported by descriptions from Cambrian panarthropods of neural structures that contribute to understanding early evolution of nervous systems and resolving controversies about segmental homologies. However, the rarity of fossilized CNSs, even when exoskeletons and appendages show high levels of integrity, brought into question data reproducibility because all but one of the aforementioned studies were based on single specimens. Foremost among objections is the lack of taphonomic explanation for exceptional preservation of a tissue that some see as too prone to decay to be fossilized. Here we describe newly discovered specimens of the Chengjiang euarthropod Fuxianhuia protensa with fossilized brains revealing matching profiles, allowing rigorous testing of the reproducibility of cerebral structures. Their geochemical analyses provide crucial insights of taphonomic pathways for brain preservation, ranging from uniform carbon compressions to complete pyritization, revealing that neural tissue was initially preserved as carbonaceous film and subsequently pyritized. This mode of preservation is consistent with the taphonomic pathways of gross anatomy, indicating that no special mode is required for fossilization of labile neural tissue. PMID- 26526374 TI - Active Control of Cell Size Generates Spatial Detail during Plant Organogenesis. AB - How cells regulate their dimensions is a long-standing question. In fission and budding yeast, cell-cycle progression depends on cell size, although it is still unclear how size is assessed. In animals, it has been suggested that cell size is modulated primarily by the balance of external signals controlling growth and the cell cycle, although there is evidence of cell-autonomous control in cell cultures. Regardless of whether regulation is external or cell autonomous, the role of cell-size control in the development of multicellular organisms remains unclear. Plants are a convenient system to study this question: the shoot meristem, which continuously provides new cells to form new organs, maintains a population of actively dividing and characteristically small cells for extended periods. Here, we used live imaging and quantitative, 4D image analysis to measure the sources of cell-size variability in the meristem and then used these measurements in computer simulations to show that the uniform cell sizes seen in the meristem likely require coordinated control of cell growth and cell cycle in individual cells. A genetically induced transient increase in cell size was quickly corrected by more frequent cell division, showing that the cell cycle was adjusted to maintain cell-size homeostasis. Genetically altered cell sizes had little effect on tissue growth but perturbed the establishment of organ boundaries and the emergence of organ primordia. We conclude that meristem cells actively control their sizes to achieve the resolution required to pattern small scale structures. PMID- 26526375 TI - Thyroplasty in the previously irradiated neck: A case series and short-term outcomes. AB - OBJECTIVES/HYPOTHESIS: External beam radiation to the neck is widely considered a contraindication for thyroplasty due to concern for infection and implant extrusion. We present a case series of our experience regarding thyroplasty performed in a previously radiated field. STUDY DESIGN: Retrospective case study at a tertiary academic referral center. METHODS: Using the institution's clinical notes search tool, records from 1999 through 2014 documenting thyroplasty and radiation were identified and reviewed. Patients who received external beam radiation to the operative field prior to thyroplasty were included. Data including duration of radiation, timing and specifics of thyroplasty, postoperative complications, risk factors, clinical voice outcomes, and length of follow-up were collected. RESULTS: Fourteen patients met criteria for the study. Of all thyroplasty performed, 11 were Silastic implants, two were Gore-Tex implants, six had concurrent arytenoid adduction, and one was a midline type II thyroplasty. In terms of risk factors for postoperative complications, two were diabetic, none were active smokers, and one had a splenectomy. All patients were given postoperative antibiotics. The median duration of follow-up after surgery was 14.2 months. No patients were found to have postoperative complications. Pre- and postoperative voice data were assessed. Overall, there was improvement in voice outcomes. CONCLUSIONS: Thyroplasty may be an option for patients who have previously undergone external beam radiation. Short-term and intermediate outcomes in our patients showed no postoperative complications, and generally voice or dysphagia improved. Careful selection is still warranted when considering thyroplasty in a previously irradiated neck, and long-term outcomes need further study. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1849-1853, 2016. PMID- 26526377 TI - Experience in managing an urban massive burn incident: The Hangzhou bus attack on 5 July 2014. AB - BACKGROUND: On 5 July 2014, a suicide terrorist set a crowded bus on fire in Hangzhou, injuring 33 passengers. Among these, 19 adult victims with the most severe burns were triaged to our center. This is a single-center, descriptive study recording the prehospital response and in-hospital treatment of these patients. METHODS: Information on the attack, on-scene rescue, and patient triage was collected from public media, governmental, and hospital reports. Information on patient injury and our in-hospital procedures was collected from the emergency registry and patient records. RESULTS: Of the 80 passengers in the burning bus, 33 were injured. The total burn surface area (TBSA) of the 19 most severely injured patients triaged to our hospital ranged from 25% to 95% (mean 48.3 +/- 2.08%). Two patients had a TBSA of >90% (92% and 95%) and eight had a TBSA of >60%. Nineteen cases of inhalation injury were diagnosed, eight of which were severe. The emergency center performed 14 bedside escharotomies, 14 central venous catheter (CVC) implantations, and one cardiopulmonary resuscitation (CPR). Approximately 131000 ml of resuscitation fluid was infused within the first 24h and 111000 ml within the second; further, 160230 ml of plasma and 4100 ml of red blood cells were infused during the antishock stage. All victims were transported to the burn ward to receive burn-centered multidisciplinary care. The respiratory team conducted 121 bronchoscopies. A total of 89 operations were performed, and the residual wound area decreased dramatically. After 124 days of extensive therapy, complete wound healing was observed and all patients entered the rehabilitation stage. CONCLUSION: Adequate preparation, including planning and disaster drills, is crucial for handling mass casualty events. Efficient and precise first rescue and triage can reduce prehospital mortality, and burn centered multidisciplinary care and hospital-government cooperation helps reduce in-hospital mortality. Nevertheless, lessons can be drawn from this incident to be better prepared for future disasters. PMID- 26526376 TI - Burns in Baghdad from 2003 to 2014: Results of a randomized household cluster survey. AB - PURPOSE: Civilians living amid conflict are at high-risk of burns. However, the epidemiology of burns among this vulnerable group is poorly understood, yet vital for health policy and relief planning. To address this gap, we aimed to determine the death and disability, healthcare needs and household financial consequences of burns in post-invasion Baghdad. METHODS: A two-stage, cluster randomized, community-based household survey was performed in May 2014 to determine the civilian burden of injury from 2003 to 2014 in Baghdad. In addition to questions about cause of household member death, households were interviewed regarding burn specifics, healthcare required, disability, relationship to conflict and resultant financial hardship. RESULTS: Nine-hundred households, totaling 5148 individuals, were interviewed. There were 55 burns, which were 10% of all injuries reported. There were an estimated 2340 serious burns (39 per 100,000 persons) in Baghdad in 2003. The frequency of serious burns generally increased post-invasion to 8780 burns in 2013 (117 per 100,000 persons). Eight burns (15%) were the direct result of conflict. Individuals aged over 45 years had more than twice the odds of burn than children aged less than 13 years (aOR 2.42; 95%CI 1.08-5.44). Nineteen burns (35%) involved >= 20% body surface area. Death (16% of burns), disability (40%), household financial hardship (48%) and food insecurity (50%) were common after burn. CONCLUSION: Civilian burn in Baghdad is epidemic, increasing in frequency and associated with household financial hardship. Challenges of healthcare provision during prolonged conflict were evidenced by a high mortality rate and likelihood of disability after burn. Ongoing conflict will directly and indirectly generates more burns, which mandates planning for burn prevention and care within local capacity development initiatives, as well as humanitarian assistance. PMID- 26526378 TI - Clinical characteristics, treatment and outcome of children with Lyme arthritis in Nova Scotia. AB - BACKGROUND: Lyme disease is an emerging problem in Nova Scotia. Lyme arthritis is a late manifestation of Lyme disease. OBJECTIVE: To describe the demographic characteristics, referral patterns and clinical course of children diagnosed with Lyme arthritis in a tertiary care pediatric rheumatology clinic in Nova Scotia. METHODS: In the present retrospective chart review, subjects diagnosed with Lyme arthritis between 2006 and 2013 were identified through the clinic database. Demographic variables, referral patterns, clinical presentation and information regarding treatment course and outcome were collected. RESULTS: Seventeen patients were identified; 76% presented in 2012 and 2013. In 37.5% of cases, the referring physician suspected Lyme disease. Most patients presented with one or more painful and/or swollen joints; 94% had knee involvement. Only three of 17 patients had a history of erythema migrans and four of 17 recalled a tick bite. Five patients had a history of neurological manifestations consistent with Lyme disease, although, none had a diagnosis made at the time. Arthritis usually resolved after treatment with standard antibiotics; however, at last follow-up, two patients had antibiotic refractory Lyme arthritis, with one having joint damage despite aggressive arthritis treatment. CONCLUSION: A significant increase in cases of Lyme arthritis has recently been recognized in a pediatric rheumatology clinic in Nova Scotia. A history of a tick bite or erythema migrans were not sensitive markers of Lyme arthritis, and this diagnosis was often not considered by the referring physician. Educational initiatives should be undertaken to increase local awareness of this treatable cause of arthritis in children. PMID- 26526379 TI - Preventive Home Visits for Older People: A Systematic Review. AB - RESUME L'augmentation du nombre de personnes agees presentant des incapacites et ayant des maladies chroniques entraine une hausse des besoins en services de sante a domicile. Le nombre d'etudes et de revues systematiques traitant des approches preventives pour cette clientele a prolifere, generant un besoin de synthese des connaissances. Nous avons mene une revue systematique de revues systematiques evaluant l'effet des programmes de visite preventive pour les personnes agees. Des 5 973 citations identifiees dans plus de 30 bases de donnees de litterature grise et scientifique, 10 articles repondaient a tous les criteres d'inclusion. Les revues systematiques etaient retenues si elles comprenaient des essais randomises controles comparant des interventions de soins a domicile offerts par un professionnel de la sante et ceux sans professionnels. Les interventions sont souvent des evaluations geriatriques globales et s'accompagnent de visites de suivi. Il ressort que les visites preventives multidimensionnelles a domicile ont le potentiel de diminuer la mortalite, en particulier chez les personnes agees plus jeunes, et offrent aussi un potentiel d'amelioration de l'autonomie fonctionnelle. Toutefois, ces resultats doivent etre interpretes avec prudence vue la diversite des interventions analysees. PMID- 26526381 TI - Enabling high solubility of ZnO in TiO2 by nanolamination of atomic layer deposition. AB - Zn-doped TiO2 nanotubes were fabricated by nanolaminated packing of alternating layers of TiO2 and ZnO by atomic layer deposition (ALD) using a polycarbonate (PC) membrane as a template. With 400 cycles of ALD, the nanotubes with a thickness of 28 nm and an outer diameter of 220 nm were obtained after removing the PC membrane by annealing at 450 degrees C. The doping concentration of ZnO in TiO2 depends on the precursor cycle ratio of ZnO to TiO2. With the precursor cycle ratio of ZnO : TiO2 at 0.04, a uniform bulk solubility of ~8 at% is obtained, and the surface concentration of Zn is even higher, ~16 at%. From the depth profiles measured by secondary ion mass spectrometry, Zn is uniformly distributed across the thickness, which is further confirmed by analyses of X-ray photoelectron spectroscopy, X-ray diffraction, and Raman spectroscopy. Additionally, from the transmission electron microscopic observation, the highly doped anatase TiO2 exhibits some regions of severe deformation that results in localized solid-state amorphization. PMID- 26526380 TI - Mesenchymal progenitor cells for the osteogenic lineage. AB - Mesenchymal progenitors of the osteogenic lineage provide the flexibility for bone to grow, maintain its function and homeostasis. Traditionally, colony forming-unit fibroblasts (CFU-Fs) have been regarded as surrogates for mesenchymal progenitors; however, this definition cannot address the function of these progenitors in their native setting. Transgenic murine models including lineage-tracing technologies based on the cre-lox system have proven to be useful in delineating mesenchymal progenitors in their native environment. Although heterogeneity of cell populations of interest marked by a promoter-based approach complicates overall interpretation, an emerging complexity of mesenchymal progenitors has been revealed. Current literatures suggest two distinct types of bone progenitor cells; growth-associated mesenchymal progenitors contribute to explosive growth of bone in early life, whereas bone marrow mesenchymal progenitors contribute to the much slower remodeling process and response to injury that occurs mainly in adulthood. More detailed relationships of these progenitors need to be studied through further experimentation. PMID- 26526382 TI - Can people with multiple sclerosis actually understand what they read in the Internet age? AB - People with multiple sclerosis (MS) frequently report difficulties in finding personally relevant information on the Internet. With this in mind, the Google top-ten patient-oriented results were analysed for their overall level of readability. The most commonly visited websites required an average grade level of 11.74 +/- 1.54, and an average number of years of formal education of 12.78 +/ 1.82, to be easily understood. The average Flesch Reading Ease readability index is 45.26 +/- 7.35, a difficult-to-read score. The high educational level required to easily understand most websites worsens health inequalities, not allowing a full participation in health information and decision making. PMID- 26526383 TI - Stage at presentation and survival outcomes of patients with Gleason 8-10 prostate cancer and low prostate-specific antigen. AB - OBJECTIVE: To evaluate outcomes for men with high Gleason score and low prostate specific antigen (PSA) prostate cancer. Low PSA levels among men with Gleason 8 10 prostate cancer may be owing to cellular dedifferentiation rather than low disease burden. We hypothesized that men with Gleason 8-10 prostate cancer and low PSA levels have increased risk for advanced disease and worse survival. MATERIALS AND METHODS: Men diagnosed from 2004 to 2007 with Gleason 8-10 prostate adenocarcinoma in the National Cancer Data Base were included. Patients were stratified by PSA levels at diagnosis: 0.1 to 3.9, 4.0 to 9.9, 10.0 to 19.9, and>=20.0ng/ml. Outcomes were clinical TNM category, pathologic stage (for prostatectomy patients), and overall survival (OS). Kaplan-Meier analysis and Cox proportional hazards models were used. RESULTS: A total of 37,283 patients were included. Men with PSA levels of<4.0ng/ml were more likely than those with PSA levels of 4 to 9.9ng/ml to present with clinical T3-4 disease (15% vs. 10%, P<0.001), nodal (4% vs. 2%, P<0.001) and distant (5% vs. 3%, P<0.001) metastasis. However, among patients treated with prostatectomy, lower PSA levels were not associated with increased likelihood of pathologic T3-4 disease or nodal metastasis. Six-year OS was 89.1% (PSA: 0.1-3.9ng/ml) vs. 91.0% (PSA: 4.0 9.9ng/ml) for prostatectomy (log-rank P<0.001), and 75.8% vs. 81.0% for radiotherapy (P<0.001). Multivariable analyses showed OS of patients with PSA levels of 0.1 to 3.9ng/ml to be similar to those with PSA levels of 10 to 19.9ng/ml. CONCLUSIONS: Patients with Gleason 8-10 cancer and PSA levels of<4.0ng/ml have more aggressive disease than those with PSA levels of 4 to 9.9ng/ml; these low PSA cancers behave more like those with PSA levels of 10 to 19.9ng/ml. Further study is needed to evaluate potential biological differences in these patients with low PSA-producing cancers. PMID- 26526384 TI - Towards an all-copper redox flow battery based on a copper-containing ionic liquid. AB - The first redox flow battery (RFB), based on the all-copper liquid metal salt [Cu(MeCN)4][Tf2N], is presented. Liquid metal salts (LMS) are a new type of ionic liquid that functions both as solvent and electrolyte. Non-aqueous electrolytes have advantages over water-based solutions, such as a larger electrochemical window and large thermal stability. The proof-of-concept is given that LMSs can be used as the electrolyte in RFBs. The main advantage of [Cu(MeCN)4][Tf2N] is the high copper concentration, and thus high charge and energy densities of 300 kC l(-1) and 75 W h l(-1) respectively, since the copper(i) ions form an integral part of the electrolyte. A Coulombic efficiency up to 85% could be reached. PMID- 26526385 TI - Relapses Requiring Intravenous Steroid Use and Multiple-Sclerosis-related Hospitalizations: Integrated Analysis of the Delayed-release Dimethyl Fumarate Phase III Studies. AB - PURPOSE: The purpose was to report the effects of delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on the number of relapses requiring intravenous (IV) steroids and multiple sclerosis (MS)-related hospitalizations using integrated data from the Phase III DEFINE and CONFIRM studies. METHODS: DEFINE and CONFIRM were randomized, double-blind, placebo controlled, multicenter studies that evaluated the efficacy and safety of DMF over a 2-year period in patients with relapsing-remitting MS (RRMS). Patients were randomized (1:1:1) to receive oral DMF 240 mg BID or TID, placebo, or glatiramer acetate (CONFIRM only). Eligible subjects (aged 18-55 years) had an EDSS score of 0-5.0 and experienced either >=1 relapse in the 12 months or had >=1 gadolinium-enhanced lesion on brain MRI in the 6 weeks, before randomization. Data DEFINE and CONFIRM were pooled and analyzed using a negative binomial regression model (adjusted for study and region). Data obtained after subjects switched to an alternative MS therapy were not included in the analysis. Only relapses confirmed by the Independent Neurology Evaluation Committee were included in the analysis of relapses requiring IV steroids. FINDINGS: The study population (intention-to-treat) comprised 2301 patients who received either placebo (n = 771), DMF BID (n = 769), or DMF TID (n = 761). Baseline demographic and disease characteristics were generally well balanced among treatment groups. Throughout the 2-year studies, the total number of relapses treated with methylprednisolone was 402, 221, and 209 in the placebo, DMF BID, and DMF TID groups, respectively. A smaller proportion of patients in the DMF BID (168 of 769 [21.8%]) and DMF TID (151 of 761 [19.8%]) groups experienced >=1 relapse requiring IV steroids compared with the placebo group (284 of 771 [36.8%]). The total number of MS-related hospitalizations over 2 years was 136, 94, and 74 in the placebo, DMF BID, and DMF TID groups. A smaller proportion of patients in the DMF BID (73 of 769 [9.5%]) and DMF TID (57 of 761 [7.5%]) groups had >=1 MS related hospitalization compared with the placebo group (104 of 771 [13.5%]). IMPLICATIONS: DMF is an effective and well tolerated therapy for RRMS. In addition to clinical benefits, the use of DMF may be associated with reduced patient burden and health economic savings, resulting from a decrease in resource utilization associated with relapses. ClinicalTrials.gov identifiers: NCT00420212 and NCT00451451. PMID- 26526386 TI - Age impact on human papillomavirus vaccination in France in 2014: A study from the National Health Insurance Database. AB - INTRODUCTION: Human papillomavirus (HPV) is the main cause of cervical cancer. In France, since March 2007, HPV vaccination has been recommended for girls aged 14, in addition to a catch-up program for girls aged 15 to 23. In October 2012, the target population was changed to 11- to 14-year-old girls. The main objective of the present study was to evaluate the impact of the recommendation change on HPV vaccination coverage and compliance. METHODS: We conducted a descriptive study of the Echantillon Generaliste des Beneficiaires (EGB), which is a random 1/97 permanent sample from the French National Health Insurance Database. We focused our analyses on girls aged 11 to 17 years who were covered by the main insurance scheme (which covers 77% of the French population). RESULTS: We included 16,195 girls in this analysis. At the last update of the database (06/15/2014), 42% of 17-year-old girls had been vaccinated, with more than 50% of them having been vaccinated at age 14. Between January 2012 and June 2014, patients were reimbursed for a total of 7698 doses of the HPV vaccine. During the first trimester of 2013, the number of vaccinated 11- to 13-year-old girls increased, growing by more than 20-fold between the last trimester of 2012 (n=8) and the last trimester of 2013 (n=178). Less than 60% of the vaccinated patients received 3 injections. DISCUSSION: Implementation of the new recommendations was rapid but had only a slight impact on vaccination coverage. PMID- 26526387 TI - The trophic effect of ciliary neurotrophic factor on injured masseter muscle in rat. AB - OBJECTIVES: Occlusal trauma is one of the most common forms of oral biting dysfunction. Long-term occlusal trauma could weaken the stomatognathic system; especially damage one's masticatory muscle. Through using the rat model, this study investigated the trophic effect of ciliary neurotrophic factor (CNTF) on injured masseter muscle. MATERIALS AND METHODS: Male Wistar rats (n=36) were randomly divided into five experimental groups and one control group (6 rats per group). Animals in the experimental group were cemented modified crowns on their mandibular first molars to artificially induce occlusal trauma in 1, 3, 7, 14, and 28 days. Control group was sham-treated with forced mouth-opening for about 5 min, while no crowns were placed. After 28 days of treatment, all rats were euthanized and their masseter muscle was collected. Through immunofluorescence and real-time quantitative PCR, the expression of desmin, CNTF, and CNTFRalpha was investigated in rat masseter muscle. The microstructure of masseter muscle was observed by transmission electron microscope. RESULTS: The expression of desmin showed a time-dependent decrease on traumatic and non-traumatic sides masseter, until reached the nadir at the 14(th) day, then restored to its normal level at the 28(th) day; however, the expression of CNTF and CNTFRalpha on the traumatic and non-traumatic sides increased from day 7, reached the peak at the 14(th) day, and returned to normal level on the 28(th) day. CONCLUSION: CNTF, as an important neurotrophic factor, was tightly associated to the restoring of rat injured masseter muscle, which provides new target and treatment method for clinical application. PMID- 26526389 TI - Terminus-free siRNA prepared by photo-crosslinking activated via slicing by Ago2. AB - We report the development of photo-crosslinked siRNA strands modified at each terminus with p-cyanostilbene. The siRNA was nuclease resistant and retained RNAi activity. We further studied the activation mechanism of the covalently crosslinked siRNA. Interestingly Dicer, which is known to generate siRNA with overhanging 3' ends from the precursor siRNA, did not cleave the crosslinked siRNA at all. Our results suggest that the activation of the crosslinked siRNAs required cleavage by Argonaute2. PMID- 26526388 TI - CD11b deficiency suppresses intestinal tumor growth by reducing myeloid cell recruitment. AB - Mac-1 (CD11b) is expressed on bone marrow-derived immune cells. CD11b binds to ligands to regulate leukocyte adhesion and migration across the endothelium or epithelium. Here, we employed CD11b knockout mice and an Apc(Min/+) spontaneous intestinal adenoma mouse model to clarify the function of CD11b in intestinal tumorigenesis. We showed that CD11b deficiency may contribute to the inhibition of myeloid cell trafficking to the tumor microenvironment and inactivated Wnt/beta-catenin pathway to suppress tumor growth. This effect was partly mediated by inhibiting the myeloid cell-mediated decrease in TNF-alpha secretion, which inhibits the recruitment of myeloid-derived suppressor cells to the tumor microenvironment and subsequently induces IFN-gamma and CXCL9 production. This work provides evidence for the mechanism by which CD11b may function as an important oncogene and highlights the potential of CD11b as a therapeutic target in CRC. PMID- 26526390 TI - Activating Injury-Responsive Genes with Hypoxia Enhances Axon Regeneration through Neuronal HIF-1alpha. AB - Injured peripheral neurons successfully activate a proregenerative transcriptional program to enable axon regeneration and functional recovery. How transcriptional regulators coordinate the expression of such program remains unclear. Here we show that hypoxia-inducible factor 1alpha (HIF-1alpha) controls multiple injury-induced genes in sensory neurons and contribute to the preconditioning lesion effect. Knockdown of HIF-1alpha in vitro or conditional knock out in vivo impairs sensory axon regeneration. The HIF-1alpha target gene Vascular Endothelial Growth Factor A (VEGFA) is expressed in injured neurons and contributes to stimulate axon regeneration. Induction of HIF-1alpha using hypoxia enhances axon regeneration in vitro and in vivo in sensory neurons. Hypoxia also stimulates motor neuron regeneration and accelerates neuromuscular junction re innervation. This study demonstrates that HIF-1alpha represents a critical transcriptional regulator in regenerating neurons and suggests hypoxia as a tool to stimulate axon regeneration. PMID- 26526391 TI - Doublecortin-Like Kinases Promote Neuronal Survival and Induce Growth Cone Reformation via Distinct Mechanisms. AB - After axotomy, neuronal survival and growth cone re-formation are required for axon regeneration. We discovered that doublecortin-like kinases (DCLKs), members of the doublecortin (DCX) family expressed in adult retinal ganglion cells (RGCs), play critical roles in both processes, through distinct mechanisms. Overexpression of DCLK2 accelerated growth cone re-formation in vitro and enhanced the initiation and elongation of axon re-growth after optic nerve injury. These effects depended on both the microtubule (MT)-binding domain and the serine-proline-rich (S/P-rich) region of DCXs in-cis in the same molecules. While the MT-binding domain is known to stabilize MT structures, we show that the S/P-rich region prevents F-actin destabilization in injured axon stumps. Additionally, while DCXs synergize with mTOR to stimulate axon regeneration, alone they can promote neuronal survival possibly by regulating the retrograde propagation of injury signals. Multifunctional DCXs thus represent potential targets for promoting both survival and regeneration of injured neurons. PMID- 26526392 TI - A Source for Feature-Based Attention in the Prefrontal Cortex. AB - In cluttered scenes, we can use feature-based attention to quickly locate a target object. To understand how feature attention is used to find and select objects for action, we focused on the ventral prearcuate (VPA) region of prefrontal cortex. In a visual search task, VPA cells responded selectively to search cues, maintained their feature selectivity throughout the delay and subsequent saccades, and discriminated the search target in their receptive fields with a time course earlier than in FEF or IT cortex. Inactivation of VPA impaired the animals' ability to find targets, and simultaneous recordings in FEF revealed that the effects of feature attention were eliminated while leaving the effects of spatial attention in FEF intact. Altogether, the results suggest that VPA neurons compute the locations of objects with the features sought and send this information to FEF to guide eye movements to those relevant stimuli. PMID- 26526394 TI - Andrew E. Czeizel, 3 April 1935-10 August 2015. PMID- 26526393 TI - ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function. AB - The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins. PMID- 26526395 TI - Serum interferon-inducible protein 10 levels predict hepatitis B s antigen seroclearance in patients with chronic hepatitis B. AB - BACKGROUND: Hepatitis B s antigen (HBsAg) seroclearance is regarded as the optimal virological end-point. AIM: To investigate the dynamic changes in serum cytokine levels around the time of HBsAg seroclearance. METHODS: This was a case control study. Consecutive patients with chronic hepatitis B (CHB) who lost HBsAg were matched with those remained positive for HBsAg with same age, gender, HBeAg status and presence of cirrhosis in 1:2 ratio. Relevant serum cytokines [interleukin (IL)-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, IL-15, IL-21 interferon-gamma, tumour necrosis factor-alpha (TNF-alpha), granulocyte macrophage colony-stimulating factor (GM-CSF) and interferon-inducible protein 10 (IP-10)] were assayed at the time (Year 0) and 3 years before (Year -3) HBsAg seroclearance. RESULTS: Seventy-one and 142 CHB patients who did and did not achieve HBsAg seroclearance were included. Mean age was 48 +/- 11 years; 76% were male, 20% had positive HBeAg, 99 (46%) patients received anti-viral therapy, and mean baseline HBV DNA was 3.78 +/- 2.28 log IU/mL vs. 4.36 +/- 2.13 log IU/mL respectively (P = 0.05). In those who achieved HBsAg seroclearance, serum IL-15 and GM-CSF levels decreased significantly from Year -3 to Year 0 (P = 0.017 and 0.05 respectively). When compared to controls, only serum IP-10 level was significantly lower at Year 0 than at Year -3 in patients with HBsAg seroclearance. Lower serum IP-10 level at Year 0 was the only factor associated with HBsAg seroclearance. There was no correlation between serum IP-10 and HBsAg levels around the time of HBsAg seroclearance. CONCLUSION: Lower serum IP-10 level at Year 0 was the only factor associated with HBsAg seroclearance. PMID- 26526396 TI - Psychiatric and neuropsychological issues in Marfan syndrome: A critical review of the literature. AB - The cooccurrence of Marfan syndrome and psychiatric disorders has been reported for many years. Furthermore, neuropsychological deficits have been shown to be associated with Marfan syndrome. The aim of the present article is to summarize findings from the sparse studies and case reports available. The results hold clinical and therapeutic implications and suggest that psychological and neuropsychological domains in Marfan syndrome patients should be carefully assessed. In particular, some patients may require specific rehabilitation programs. On this basis, a multidisciplinary approach to Marfan syndrome treatment seems mandatory. PMID- 26526397 TI - Improving the assessment of depression remission with the Remission Evaluation and Mood Inventory Tool. AB - OBJECTIVE: The Remission Evaluation and Mood Inventory Tool (REMIT) is a practical 5-item self-report measure of key positive mood states associated with recovering from depression, as distinct from depressive symptoms per se. The study goal was to identify a clinically useful threshold for interpreting REMIT responses in the context of mild to moderate depressive symptoms. METHODS: This was a secondary analysis of a cross-sectional dataset initially used to develop and validate the REMIT. Primary care patients being treated for depressive symptoms of either mild or moderate severity (n = 247 and 240, respectively) rated their perceived degree of depression remission prior to completing the Patient Health Questionnaire-8 (PHQ-8) and the REMIT. We summed the totals of the latter two measures to form the PHQ + REMIT index. RESULTS: Receiver Operating Characteristics analysis indicated that the PHQ + REMIT threshold >= 13 was associated with good sensitivity (92%) and acceptable specificity (43%) to the absence of patient-perceived remission. In contrast, the PHQ had only 21% specificity at this sensitivity level. Area under the curve was 0.815 (95% C.I.: 0.765-0.865), which was significantly greater than that of the PHQ-8 alone (area under the curve = 0.745, 95% C.I.: 0.691-0.805, p(diff) = 0.0002). Threshold performance was unaffected by adjustment for demographic characteristics and variation in remission percentage. Compared with standard symptom-based classification, using the REMIT reclassified 27% of mildly symptomatic patients as remitted. CONCLUSIONS: Using the REMIT with patients who have mild to moderate depressive symptoms improves the assessment of patient-perceived remission, which is indicated by a summed PHQ + REMIT index of less than 13. Longitudinal research is needed to test whether this broadened patient-centered approach to assessing remission improves clinical decision making and long-term outcomes. PMID- 26526398 TI - Drug-induced parkinsonism following chronic methamphetamine use by a patient on haloperidol decanoate. AB - This report attempts to highlight that use of an antipsychotic and concurrent chronic use of methamphetamine can cause drug-induced parkinsonism. Methamphetamine is usually not encountered in the list of agents that induce drug induced parkinsonism and so its consideration particularly during chronic use by a patient who is also on an antipsychotic is worthwhile because of its popularity as an illegal narcotic. This case report describes just such a case of drug induced parkinsonism which is a subacute syndrome that mimics Parkinson's disease. Although less alarming than dystonia, it is more common, more difficult to treat and can be the cause of significant disability during maintenance treatment especially in the elderly. In most cases, symptoms are reversible in days or weeks, but occasionally, especially in the elderly, or if long-acting injectable antipsychotics are used-as in this case-symptoms may last for weeks or months. The report also illustrates the neuronal workings due to chronic methamphetamine-use and the additive effects of dopamine blockade by antipsychotics such as haloperidol. PMID- 26526399 TI - Self-reported side-effects associated with use of dietary supplements in an armed forces population. AB - Approximately 60-70% of Armed Forces personnel consume a dietary supplement (DS) at least once a week and there have been numerous reports of severe adverse events among DS users. This study assessed patterns of DS use and self-reported side-effects among 4400 Armed Forces personnel using a paper-and-pencil survey. Multivariable logistic regression was used to examine associations between patterns of DS use and self-reported side-effects. Sixty-nine percent of personnel surveyed reported using a DS. Seven percent of DS users reported experiencing abnormal heart beats, 6% tremors, 5% stomach pain, 3% dizziness, and 3% numbness/tingling and they believed these symptoms were associated with the use of DS. After adjustment for use of other DS classes, total supplement use, and demographic characteristics, protein supplement users were more likely than non-users to report numbness/tingling; combination product users were more likely to report experiencing abnormal heart beats, stomach pain, dizziness, tremors, and numbness/tingling; and users of purported steroid analogues were more likely to report dizziness. Use of more than one DS per week was associated with an increased likelihood of reporting side-effects. Respondents with a higher body mass index were more likely to report side-effects. Further research is necessary to determine whether self-reported side-effects associated with multiple DS use and some DS classes impact the long-term health or performance of service members. Surveillance of military populations using surveys like this one may provide a method for detecting adverse health events of DS before they are apparent in the civilian population. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26526400 TI - [Gastric leiomyosarcoma simulating splenic hilum tumor: report of a case]. PMID- 26526401 TI - Rupture of Very Small Intracranial Aneurysms: Incidence and Clinical Characteristics. AB - OBJECTIVE: Unruptured intracranial aneurysms are now being detected with increasing frequency in clinical practice. Results of the largest studies, including those of the International Study of Unruptured Intracranial Aneurysms, indicate that surgical and endovascular treatments are rarely justified in small aneurysms. However, we have encountered several cases of rupture of small and very small aneurysms in our clinical practice. This retrospective study analyzed the incidence and clinical characteristics of very small ruptured aneurysms. MATERIALS AND METHODS: A total of 200 patients with aneurysmal subarachnoid hemorrhage between January 2012 and December 2014 were reviewed. Various factors were analyzed, including the aneurysm location and size as well as the associated risk factors. RESULTS: The mean age of patients was 56.31 +/- 13.78 (range, 25 89) years, and the male to female ratio was 1:2.1. There were 94 (47%) small sized (< 5 mm), 91 (45.5%) medium-sized (5-9.9 mm), and 15 large-sized (> 10 mm) aneurysms. Of these, 30 (15%) aneurysms were very small-sized (< 3 mm). The most frequent site of aneurysms was the anterior communicating artery (ACoA). However, the proportion of aneurysms at the ACoA was significantly high in very small aneurysms (53.3%, p = 0.013). Hypertension was a significant risk factor for rupture of very small aneurysms (p < 0.001). CONCLUSION: About half of our cases of ruptured aneurysms involved the rupture of small and very small aneurysms. The most common site of rupture of very small aneurysm was the ACoA. Rupture of small and very small aneurysms is unpredictable, and treatment may be considered in selected high-risk patients according to factors such as young age, ACoA location, and hypertension. PMID- 26526402 TI - Stem cells: Young nephron progenitors might extend the lifespan of old progenitors. PMID- 26526403 TI - Plasma miR-1, miR-208, miR-499 as potential predictive biomarkers for acute myocardial infarction: An independent study of Han population. AB - BACKGROUND: It has been demonstrated that circulating muscle-enriched miR-1 and the cardiac-specific miR-208 and miR-499 might leak out of the necrotic myocardium and release into the circulation during the early stages of acute myocardial infarction (AMI). This study aims to investigate potential predictive value of the three miRNAs in AMI. METHODS: Plasma samples were taken from 70 AMI patients and 72 healthy controls. The expression levels of target miRNAs were measured by qRT-PCR. Student's t test and chi(2) test were applied to test the significance of the differences between AMI patients and controls. Additionally, a meta-analysis about the prediction accuracy of the three miRNAs in AMI was performed to summarize all the results from available studies. RESULTS: The expression of plasma miR-1, miR-208 and miR-499 were all significantly elevated in AMI patients compared with controls. By receiver operating characteristic (ROC) curve analysis, plasma miR-1, miR-208 and miR-499 were demonstrated to be potential biomarkers for the prediction of AMI with AUC values of 0.81, 0.72, and 0.88, respectively. The meta-analysis consisted of nine studies for miR-1, eight studies for miR-208 and eight studies for miR-499. The summary estimates of miR 1, miR-208 and miR-499 were 0.73, 0.80 and 0.83 for sensitivity, 0.82, 0.95 and 0.90 for specificity, 0.84, 0.89 and 0.91 for AUC, respectively. CONCLUSION: In summary, we confirmed the predictive values of plasma miR-1, miR-208 and miR-499 in AMI. In contrast to miR-1, the cardiac-specific miR-208 and miR-499 were supposed to be more reliable as biomarkers in AMI screening and prediction. PMID- 26526404 TI - The Pain of Labour. AB - Labour is an emotional experience and involves both physiological and psychological mechanisms.The pain of labour is severe but despite this its memory diminishes with time.Labour pain has two components: visceral pain which occurs during the early first stage and the second stage of childbirth, and somatic pain which occurs during the late first stage and the second stage.The pain of labour in the first stage is mediated by T10 to L1 spinal segments, whereas that in the second stage is carried by T12 to L1, and S2 to S4 spinal segments.Pain relief in labour is complex and often challenging without regional analgesia.Effective management of labour pain plays a relatively minor role in a woman's satisfaction with childbirth. PMID- 26526405 TI - Agricultural land usage transforms nitrifier population ecology. AB - Application of nitrogen fertilizer has altered terrestrial ecosystems. Ammonia is nitrified by ammonia and nitrite-oxidizing microorganisms, converting ammonia to highly mobile nitrate, contributing to the loss of nitrogen, soil nutrients and production of detrimental nitrogen oxides. Mitigating these costs is of critical importance to a growing bioenergy industry. To resolve the impact of management on nitrifying populations, amplicon sequencing of markers associated with ammonia and nitrite-oxidizing taxa (ammonia monooxygenase-amoA, nitrite oxidoreductase nxrB, respectively) was conducted from long-term managed and nearby native soils in Eastern Washington, USA. Native nitrifier population structure was altered profoundly by management. The native ammonia-oxidizing archaeal community (comprised primarily by Nitrososphaera sister subclusters 1.1 and 2) was displaced by populations of Nitrosopumilus, Nitrosotalea and different assemblages of Nitrososphaera (subcluster 1.1, and unassociated lineages of Nitrososphaera). A displacement of ammonia-oxidizing bacterial taxa was associated with management, with native groups of Nitrosospira (cluster 2 related, cluster 3A.2) displaced by Nitrosospira clusters 8B and 3A.1. A shift in nitrite-oxidizing bacteria (NOB) was correlated with management, but distribution patterns could not be linked exclusively to management. Dominant nxrB sequences displayed only distant relationships to other NOB isolates and environmental clones. PMID- 26526407 TI - Tissue-specific regulation of CYP3A by hydrolysable tannins in male pigs. AB - 1. Little is known about the activities and regulation of cytochrome P4503A (CYP3A) enzymes in porcine colon in response to specific feeding components. 2. We added hydrolyzable tannins to the diet of fattening boars and studied its effect on the expression of hepatic and intestinal CYP3A. 3. In total, 51 Landrace * Large White boars were assigned to the following treatment groups: control (without the addition of hydrolysable tannins), T1 (diet-containing 1% hydrolysable tannin extract), T2 (diet-containing 2% hydrolysable tannin extract) and T3 (diet-containing 3% hydrolysable tannin extract). CYP3A expression and activity were measured in microsomes prepared from liver and colon tissue. 4. CYP3A protein expression and activity were increased in the colon of pigs fed 2% and 3% tannins, while no changes were observed with lower tannin concentrations, or in the liver of any treatment groups. Also, it was demonstrated that colon mucosa possess CYP3A activity similar to that measured in the liver. 5. The present results provide the first evidence that tannin supplementation can modulate CYP3A in porcine colon mucosa in vivo. The physiological significance of this finding for the health status of the individual animal needs further investigation. PMID- 26526406 TI - Impact of a large deletion in the neuraminidase protein identified in a laninamivir-selected influenza A/Brisbane/10/2007 (H3N2) variant on viral fitness in vitro and in ferrets. AB - Viral fitness of a laninamivir-selected influenza A/Brisbane/10/2007-like (H3N2) isolate (LRVp9) containing a 237-amino acid neuraminidase deletion and a P194L hemagglutinin mutation was evaluated in vitro and in ferrets. LRVp9 and the wild type (WT) virus showed comparable replication kinetics in MDCK-ST6GalI cells. Cultured virus was recovered between days 2 and 5 post-infection in nasal washes (NW) from the 4 WT-infected ferrets whereas no virus was recovered from the LRVp9 infected animals. There was a >=1 log reduction in viral RNA copies/MUl of NW for LRVp9 compared to WT at most time points. The large neuraminidase deletion compromises viral infectivity in vivo. PMID- 26526409 TI - Multiple Choice Questions. PMID- 26526408 TI - [Intestinal wall edema and echo-free abdominal fluid in abdominal sonography after blunt force abdominal trauma]. PMID- 26526410 TI - 3D tracking of single nanoparticles and quantum dots in living cells by out-of focus imaging with diffraction pattern recognition. AB - Live cells are three-dimensional environments where biological molecules move to find their targets and accomplish their functions. However, up to now, most single molecule investigations have been limited to bi-dimensional studies owing to the complexity of 3d-tracking techniques. Here, we present a novel method for three-dimensional localization of single nano-emitters based on automatic recognition of out-of-focus diffraction patterns. Our technique can be applied to track the movements of single molecules in living cells using a conventional epifluorescence microscope. We first demonstrate three-dimensional localization of fluorescent nanobeads over 4 microns depth with accuracy below 2 nm in vitro. Remarkably, we also establish three-dimensional tracking of Quantum Dots, overcoming their anisotropic emission, by adopting a ligation strategy that allows rotational freedom of the emitter combined with proper pattern recognition. We localize commercially available Quantum Dots in living cells with accuracy better than 7 nm over 2 microns depth. We validate our technique by tracking the three-dimensional movements of single protein-conjugated Quantum Dots in living cell. Moreover, we find that important localization errors can occur in off-focus imaging when improperly calibrated and we give indications to avoid them. Finally, we share a Matlab script that allows readily application of our technique by other laboratories. PMID- 26526411 TI - Pre-operative serum albumin level substantially predicts post-operative morbidity and mortality among patients with colorectal cancer who undergo elective colectomy. AB - The quantitative relationship between serum albumin level and surgical outcomes has not been clearly established. This study included 3732 patients with colon cancer who underwent a potentially curative colectomy. Post-operative mortality and morbidity were analysed according to the patients' demographic data, pre operative comorbidities, and tumour-related factors. Age, asthma, renal impairment, and albumin level were significantly associated with post-operative morbidity and mortality in the multivariate analyses. Logistic regression analysis revealed linear relationships of post-operative morbidity and mortality with albumin level. The morbidity and mortality rates decreased by 7.3% and 15.6%, respectively, for each 0.1 g/dL increase in albumin level. This finding remained significant in the hypoalbuminaemia subgroup but not in the normoalbuminaemia subgroup. That is, the morbidity and mortality rates significantly decreased by 8.7% and 17.7%, respectively (both P < 0.001), in the former group and decreased by 2.7% (P = 0.112) and 11.6% (P = 0.092), respectively, in the latter group. This study demonstrated that serum albumin level linearly predicted the post-operative morbidity and mortality among the colorectal cancer patients. Pre-operative serum albumin level may therefore be used as a continuous rather than a categorical marker of disease severity, especially among patients with hypoalbuminaemia. PMID- 26526412 TI - A Strategy to Identify Critical Appraisal Criteria for Primary Mixed-Method Studies. AB - The practice of mixed-methods research has increased considerably over the last 10 years. While these studies have been criticized for violating quantitative and qualitative paradigmatic assumptions, the methodological quality of mixed-method studies has not been addressed. The purpose of this paper is to identify criteria to critically appraise the quality of mixed-method studies in the health literature. Criteria for critically appraising quantitative and qualitative studies were generated from a review of the literature. These criteria were organized according to a cross-paradigm framework. We recommend that these criteria be applied to a sample of mixed-method studies which are judged to be exemplary. With the consultation of critical appraisal experts and experienced qualitative, quantitative, and mixed-method researchers, further efforts are required to revise and prioritize the criteria according to importance. PMID- 26526413 TI - Gibberellin-like effects of KAR1 on dormancy release of Avena fatua caryopses include participation of non-enzymatic antioxidants and cell cycle activation in embryos. AB - MAIN CONCLUSION: The induction of dormancy release and germination of Avena fatua caryopses by KAR 1 involves ABA degradation to phaseic acid. Both, KAR 1 and GA 3 , control the AsA-GSH cycle, DNA replication and accumulation of beta-tubulin in embryos before caryopses germination. Avena fatua caryopses cannot germinate in darkness at 20 degrees C because of dormancy, but karrikinolide-1 (KAR1), a compound in plant-derived smoke, and gibberellic acid (GA3) induced an almost complete germination. The radicle protrusion through the coleorhiza was preceded by increased water uptake, rupture of coat, increased embryo size and coleorhiza length as well as coleorhiza protrusion through covering structures. The stimulatory effect of KAR1 was correlated with the reduced content of abscisic acid (ABA) and an increase in phaseic acid (PA) in embryos from caryopses before coleorhiza protrusion. Two non-enzymatic antioxidants, ascorbate (AsA) and reduced glutathione (GSH), did not affect the germination of dormant caryopses, but in the presence of KAR1 or GA3 they only slightly delayed the germination. The stimulatory effect of KAR1 or GA3 on the final germination percentage was markedly antagonized by lycorine, an AsA biosynthesis inhibitor. KAR1 and GA3 applied during caryopses imbibition resulted in increases of AsA, dehydroascorbate (DHA) and GSH, but reduced the embryos' oxidized glutathione (GSSG) content. Furthermore, both KAR1 and GA3 induced an additional ascorbate peroxidase (APX) isoenzyme and increased the glutathione reductase (GR) activity. Both compounds stimulated beta-tubulin accumulation in radicle+coleorhiza (RC) and plumule+coleoptile (PC), and enhanced the transition from G1 to S and also from S to G2 phases. The comparison of the effects produced by KAR1 and GA3 shows a similar action; thus the KAR1 effect may not be specific. The study provides new data regarding the mechanism with which KAR1, a representative of a novel class of plant growth regulators, regulates dormancy and germination of caryopses. PMID- 26526414 TI - What's in a name? Variations in terminology of third-party reproduction. AB - The terminology used to discuss third-party reproduction, as with other new biomedical processes, can ease or impede communication and even influence behaviour. In an effort to sensitize analysts and stakeholders to variations in terminology and to facilitate communication on issues arising from international surrogacy arrangements, this paper examines variations in terms used. We introduce some of the issues previously raised by scholars concerned with analysis of discourse related to third-party reproduction. We then survey the terms used in English-language discussions to denote specific actors, including 'surrogates,' 'intended parents,' gamete providers and children, as well as terms used to describe 'surrogacy arrangements.' We conclude with a discussion on navigating and negotiating the use of these various and value-laden terms. PMID- 26526416 TI - Molecular characterization by MLVA of Coxiella burnetii strains infecting dairy cows and goats of north-eastern Italy. AB - Q fever is a worldwide zoonotic disease caused by Coxiella burnetii (C. burnetii), an obligate intracellular bacterium. In ruminants, shedding into the environment mainly occurs during parturition or abortion, but the bacterium is shed also in milk, vaginal mucus, stools and urine. In Italy few surveys have been conducted and reported seroprevalence values ranged between 10% and 60%, even if few human cases have been described. Genotyping of bacteria is crucial for enhancing diagnostic methods and for epidemiological surveillance. The objective of this study was to investigate genotypic differences of C. burnetii genotypes directly in 34 samples, collected during a 3-years survey among 11 dairy cattle and 11 goat farms in the north-eastern part of Italy using a 6-locus multiple loci variable number of tandem repeat analysis (MLVA) method. The samples analysed included 13 bulk tank milk (BTM), 6 individual milk, 11 vaginal swabs and 4 foetal spleens. MLVA-type 2 was determined as the most prevalent in cattle in this study. C. burnetii strains circulating in the studied cattle population are very similar to genotypes previously described, while genotypes from goats showed an important variability. Further investigation are needed to understand the reason of this pattern. PMID- 26526417 TI - The Potential Application of Pulsed Ultrasound on Bone Defect Repair via Developmental Engineering: An In Vitro Study. AB - Repairing bone defect by recapitulation of endochondral bone formation, known as developmental engineering, has been a promising approach in bone tissue engineering. The critical issue in this area is how to effectively construct the hypertrophic cartilaginous template in vitro and enhance in vivo endochondral ossification process after implantation. Pulsed ultrasound stimulation has been widely used in the clinic for accelerating bone healing in fractures and nonunions. The aim of this study was to investigate whether ultrasound (US) could accelerate in vitro chondrogenesis and the hypertrophic process in certain microenvironments. Rat bone marrow mesenchymal stem cells were chondrogenic or hypertrophic differentiated in a three-dimensional pellet culture system with different media, and treated with different intensities of US. US exposure promoted chondrogenic differentiation of stem cells and inhibited their transition into the hypertrophic stage in a chondrogenic-friendly microenvironment. US significantly advanced hypertrophic differentiation of bone marrow stem cell pellets in hypertrophic medium after chondrogenesis. Our data indicated that pulsed US promoted in vitro chondrogenic and hypertrophic differentiation of stem cell pellets in specific culture conditions. The present study proves the potential application of US in the in vitro stage of "developmental engineering" for bone development and repair. PMID- 26526418 TI - The relationship between sweetened beverage consumption and risk of heart failure in men. AB - OBJECTIVES: To investigate whether sweetened beverage consumption is associated with risk of heart failure (HF) in a large prospective population-based study of men. METHODS AND RESULTS: A population-based cohort comprising 42,400 men, 45-79 years of age, was followed from 1998 through 2010. Sweetened beverage consumption was assessed by utilising a food frequency questionnaire. Incident events of HF were identified through linkage to the Swedish National Patient Register and the Cause of Death Register. Cox regression analyses were implemented to investigate the association between sweetened beverage consumption and HF. During a mean follow-up time of 11.7 years, a total of 4113 HF events were identified. We observed a positive association between sweetened beverage consumption and risk of HF after adjustment for other risk factors (p for trend <0.001). Men who consumed two or more servings of sweetened beverages per day had a statistically significant higher risk of developing HF (23%, 95% CI 1.12 to 1.35) compared to men who were non-consumers. CONCLUSIONS: Our finding that sweetened beverage consumption is associated with higher risk of HF could have implications for HF prevention strategies. Additional prospective studies investigating the link between sweetened beverage consumption and HF are therefore needed. PMID- 26526419 TI - Preventing heart failure: sweetened beverages and healthy lifestyles. PMID- 26526420 TI - When to consider an implantable cardioverter defibrillator following myocardial infarction? AB - After reading this article the reader should be familiar with: Current guidelines for implantable cardioverter defibrillator (ICD) use post myocardial infarction (MI) and ischaemic cardiomyopathy. Primary prevention ICD guidelines. Secondary prevention ICD guidelines. Non-sustained ventricular tachycardia in patients post MI and the use of ICDs. Programming ICDs. PMID- 26526421 TI - Completeness of revascularization and its impact on the outcomes of a staged approach of percutaneous coronary intervention followed by minimally invasive valve surgery for patients with concomitant coronary artery and valvular heart disease. AB - BACKGROUND: A staged approach of percutaneous coronary intervention (PCI) followed by minimally invasive valve surgery (MIVS) is an alternative to the conventional combined coronary artery bypass and valve surgery for patients with concomitant coronary artery and valve disease. Limited data exist on degree of the completeness of revascularization achieved with this approach and its impact on outcomes. METHODS: A total of 138 patients, who underwent a staged approach between January 2009 and June 2013, were retrospectively evaluated. Coronary angiograms were reviewed by two cardiologists blinded to outcomes and were then categorized into two groups: complete or incomplete revascularization, which was defined as >=1 major epicardial coronary arteries of at least 2.0 mm diameter with >=70% untreated obstruction after the index PCI and before MIVS. RESULTS: Complete and incomplete revascularization was achieved in 105 (76%) and 33 (24%) patients, respectively. The patients with incomplete revascularization had a lower ejection fraction, a higher STS score, and more prior myocardial infarctions and multi-vessel coronary artery disease. There were no differences in the post-operative complications, 30-day mortality, or 3-year survival (84 vs. 83%, P = 0.68). After a median follow-up of 29 months, incompletely revascularized patients had a higher incidence of acute coronary syndrome (2.9 vs. 12.9%, P = 0.05). CONCLUSIONS: In patients undergoing a staged approach of PCI followed by MIVS, incomplete revascularization did not significantly impact the short or mid-term survival, but was associated with an increased incidence of acute coronary syndrome at follow-up. (c) 2015 Wiley Periodicals, Inc. PMID- 26526422 TI - Normoglycemic Ketonemia as Biochemical Presentation in Ketotic Glycogen Storage Disease. AB - BACKGROUND: According to the textbooks, the ketotic glycogen storage disease (GSD) types 0, III, VI, IX, and XI are associated with fasting ketotic hypoglycemia and considered milder as gluconeogenesis is intact. METHODS: A retrospective cohort study of biochemical profiles from supervised clinical fasting studies is performed in ketotic GSD patients in our metabolic center. For data analysis, hypoglycemia was defined as plasma glucose concentration <2.6 mmol/L. Total KB was defined as the sum of blood acetoacetate and beta hydroxybutyrate concentrations. If the product of glucose and KB concentrations was greater than 10, a ketolysis defect was suspected. RESULTS: Data could be collected from 13 fasting studies in 12 patients with GSD III (n = 4), GSD VI (n = 3), and GSD IX (n = 5). Six patients remained normoglycemic with median glucose concentration of 3.9 mmol/L (range, 2.8-4.6 mmol/L) and median total KB concentration of 1.9 mmol/L (range, 0.6-5.1 mmol/L). The normoglycemic patients included type VI (3 out of 3) and type IX (3 out of 5) patients. All type III patients developed ketotic hypoglycemia. Interestingly, in five patients (one GSD III, one GSD VI, and three GSD IX), the biochemical profile suggested a ketolysis defect. CONCLUSION: Normoglycemic ketonemia is a common biochemical presentation in patients with GSD types VI and IX, and ketonemia can precede hypoglycemia in all studied GSD types. Therefore, GSD VI and GSD IX should be added to the differential diagnosis of ketotic normoglycemia, and KB concentrations should be routinely measured in ketotic GSD patients. PMID- 26526423 TI - Incorporating metacognition into morbidity and mortality rounds: The next frontier in quality improvement. AB - This Perspective proposes the introduction of metacognition (thinking about thinking) into the existing format of hospital-based morbidity and mortality rounds. It is placed in the context of historical movements to advance quality improvement by expanding the spectrum of the causes of medical error from systems based issues to flawed human decision-making capabilities. We suggest that the current approach that focuses on systems-based issues can be improved by exploiting the opportunities to educate physicians about predictable errors committed by reliance on cognitive heuristics. In addition, because the field of educating clinicians about cognitive heuristics has shown mixed results, this proposal represents fertile ground for further research. Educating clinicians about cognitive heuristics may improve metacognition and perhaps be the next frontier in quality improvement. PMID- 26526424 TI - Graft-versus-host disease (GVHD) prophylaxis by using methotrexate decreases pre engraftment syndrome and severe acute GVHD, and accelerates engraftment after cord blood transplantation. AB - GVHD and graft failure are serious problems in CBT. PES after CBT also occurs frequently and is associated with transplantation-related complications such as acute GVHD. We reviewed medical records for 70 consecutive child CBT recipients between December 1997 and April 2015. Forty-nine patients received prophylaxis against GVHD with CsA or Tac in combination with mPSL from day +7 (mPSL group), and 21 patients received CsA or Tac with MTX on day +1 and day +3 (MTX group). Neutrophil engraftment was detected in 59 patients (84.3%). Neutrophil engraftment rate in the MTX group was significantly higher than that in the mPSL group (21/21 (100%) and 38/49 (77.6%), respectively, p = 0.027). PES developed in 35 patients, and the incidence of PES in the mPSL group was significantly higher than that in the MTX group (p = 0.036). The incidence of severe acute GVHD (grade III or IV) in the MTX group was significantly lower than that in the mPSL group (p = 0.049). Although this study was a small-scale study, the results showed that increase in the rate of engraftment and decrease in the incidence of early immune reactions such as PES and severe acute GVHD could be achieved by early commencement of immunosuppression using MTX. PMID- 26526425 TI - Characterisation of Growth and Ultrastructural Effects of the Xanthoria elegans Photobiont After 1.5 Years of Space Exposure on the International Space Station. AB - The lichen Xanthoria elegans has been exposed to space and simulated Mars analogue environment in the Lichen and Fungi Experiment (LIFE) on the EXPOSE-E facility at the International Space Station (ISS). This long-term exposure of 559 days tested the ability of various organisms to cope with either low earth orbit (LEO) or Mars-analogue conditions, such as vacuum, Mars-analogue atmosphere, rapid temperature cycling, cosmic radiation of up to 215 +/- 16 mGy, and insolation of accumulated doses up to 4.87 GJm(-2), including up to 0.314 GJm(-2) of UV irradiation. In a previous study, X. elegans demonstrated considerable resistance towards these conditions by means of photosynthetic activity as well as by post-exposure metabolic activity of 50-80% in the algal and 60-90% in the fungal symbiont (Brandt et al. Int J Astrobiol 14(3):411-425, 2015). The two objectives of the present study were complementary: First, to verify the high post-exposure viability by using a qualitative cultivation assay. Second, to characterise the cellular damages by transmission electron microscopy (TEM) which were caused by the space and Mars-analogue exposure conditions of LIFE. Since the algal symbiont of lichens is considered as the more susceptible partner (de Vera and Ott 2010), the analyses focused on the photobiont. The study demonstrated growth and proliferation of the isolated photobiont after all exposure conditions of LIFE. The ultrastructural analysis of the algal cells provided an insight to cellular damages caused by long-term exposure and highlighted that desiccation induced breakdown of cellular integrity is more pronounced under the more severe space vacuum than under Mars-analogue atmospheric conditions. In conclusion, desiccation-induced damages were identified as a major threat to the photobiont of X. elegans. Nonetheless, a fraction of the photobiont cells remained cultivable after all exposure conditions tested in LIFE. PMID- 26526426 TI - Electron-Selective TiO2 Contact for Cu(In,Ga)Se2 Solar Cells. AB - The non-toxic and wide bandgap material TiO2 is explored as an n-type buffer layer on p-type Cu(In,Ga)Se2 (CIGS) absorber layer for thin film solar cells. The amorphous TiO2 thin film deposited by atomic layer deposition process at low temperatures shows conformal coverage on the CIGS absorber layer. Solar cells from non-vacuum deposited CIGS absorbers with TiO2 buffer layer result in a high short-circuit current density of 38.9 mA/cm(2) as compared to 36.9 mA/cm(2) measured in the reference cell with CdS buffer layer, without compromising open circuit voltage. The significant photocurrent gain, mainly in the UV part of the spectrum, can be attributed to the low parasitic absorption loss in the ultrathin TiO2 layer (~10 nm) with a larger bandgap of 3.4 eV compared to 2.4 eV of the traditionally used CdS. Overall the solar cell conversion efficiency was improved from 9.5% to 9.9% by substituting the CdS by TiO2 on an active cell area of 10.5 mm(2). Optimized TiO2/CIGS solar cells show excellent long-term stability. The results imply that TiO2 is a promising buffer layer material for CIGS solar cells, avoiding the toxic CdS buffer layer with added performance advantage. PMID- 26526427 TI - SimPhy: Phylogenomic Simulation of Gene, Locus, and Species Trees. AB - We present a fast and flexible software package--SimPhy--for the simulation of multiple gene families evolving under incomplete lineage sorting, gene duplication and loss, horizontal gene transfer--all three potentially leading to species tree/gene tree discordance--and gene conversion. SimPhy implements a hierarchical phylogenetic model in which the evolution of species, locus, and gene trees is governed by global and local parameters (e.g., genome-wide, species specific, locus-specific), that can be fixed or be sampled from a priori statistical distributions. SimPhy also incorporates comprehensive models of substitution rate variation among lineages (uncorrelated relaxed clocks) and the capability of simulating partitioned nucleotide, codon, and protein multilocus sequence alignments under a plethora of substitution models using the program INDELible. We validate SimPhy's output using theoretical expectations and other programs, and show that it scales extremely well with complex models and/or large trees, being an order of magnitude faster than the most similar program (DLCoal Sim). In addition, we demonstrate how SimPhy can be useful to understand interactions among different evolutionary processes, conducting a simulation study to characterize the systematic overestimation of the duplication time when using standard reconciliation methods. SimPhy is available at https://github.com/adamallo/SimPhy, where users can find the source code, precompiled executables, a detailed manual and example cases. PMID- 26526429 TI - Evaluating Patients with Right Upper Quadrant Pain. AB - Many disorders of the liver, gallbladder, and biliary tree may cause right upper quadrant pain and clinical diagnosis may be challenging. Imaging plays a key role in establishing a prompt diagnosis and guiding appropriate management. Although ultrasonography is the initial imaging modality of choice for most hepatobiliary disorders, radionuclide imaging, computed tomography (CT), and MR imaging also play important roles. Acute cholecystitis may be associated with many complications that have characteristic imaging features. MR cholangiopancreatography achieves high accuracy in diagnosis of choledocholithiasis and allows for noninvasive imaging when ultrasonography and CT are indeterminate. PMID- 26526428 TI - Genealogical Working Distributions for Bayesian Model Testing with Phylogenetic Uncertainty. AB - Marginal likelihood estimates to compare models using Bayes factors frequently accompany Bayesian phylogenetic inference. Approaches to estimate marginal likelihoods have garnered increased attention over the past decade. In particular, the introduction of path sampling (PS) and stepping-stone sampling (SS) into Bayesian phylogenetics has tremendously improved the accuracy of model selection. These sampling techniques are now used to evaluate complex evolutionary and population genetic models on empirical data sets, but considerable computational demands hamper their widespread adoption. Further, when very diffuse, but proper priors are specified for model parameters, numerical issues complicate the exploration of the priors, a necessary step in marginal likelihood estimation using PS or SS. To avoid such instabilities, generalized SS (GSS) has recently been proposed, introducing the concept of "working distributions" to facilitate--or shorten--the integration process that underlies marginal likelihood estimation. However, the need to fix the tree topology currently limits GSS in a coalescent-based framework. Here, we extend GSS by relaxing the fixed underlying tree topology assumption. To this purpose, we introduce a "working" distribution on the space of genealogies, which enables estimating marginal likelihoods while accommodating phylogenetic uncertainty. We propose two different "working" distributions that help GSS to outperform PS and SS in terms of accuracy when comparing demographic and evolutionary models applied to synthetic data and real-world examples. Further, we show that the use of very diffuse priors can lead to a considerable overestimation in marginal likelihood when using PS and SS, while still retrieving the correct marginal likelihood using both GSS approaches. The methods used in this article are available in BEAST, a powerful user-friendly software package to perform Bayesian evolutionary analyses. PMID- 26526430 TI - Evaluating Patients with Left Upper Quadrant Pain. AB - Imaging plays a major role in the evaluation of patients who present to the emergency department with acute left upper quadrant (LUQ) pain. Multidetector computed tomography is currently the primary modality used for imaging these patients. The peritoneal reflections, subperitoneal compartment, and peritoneal spaces of the LUQ are key anatomic features in understanding the imaging appearance of acute diseases in this area. Diseases of the stomach, spleen, pancreas, and splenic flexure are encountered in patients with acute LUQ pain. Optimization of the imaging protocol is vital for accurate diagnosis and characterization of these diseases in the acute setting. PMID- 26526431 TI - Evaluating the Patient with Right Lower Quadrant Pain. AB - Right lower quadrant pain is one of the most common indications for imaging evaluation of the abdomen in the emergency department setting. This article reviews important imaging findings associated with acute appendicitis as well as major differential considerations including: mesenteric adenitis, Meckel diverticulum, neutropenic colitis, right-sided diverticulitis, epiploic appendagitis, omental infarction, and inflammatory bowel diseaseRight lower quadrant pain is one of the most common indications for imaging evaluation of the abdomen in the emergency department setting. This article reviews important imaging findings associated with acute appendicitis as well as major differential considerations including: mesenteric adenitis, Meckel diverticulum, neutropenic colitis, right-sided diverticulitis, epiploic appendagitis, omental infarction, and inflammatory bowel disease. PMID- 26526432 TI - Evaluating the Patient with Left Lower Quadrant Abdominal Pain. AB - Left lower quadrant pain is a frequent indication for imaging in the emergency department. Most causes of pain originate from the colon, including diverticulitis, colitis, fecal impaction, and epiploic appendagitis. Left-sided urolithiasis and spontaneous hemorrhage in the retroperitoneum or rectus sheath are additional causes of pain. Computed tomography is the preferred imaging modality in the emergent setting for all of these pathologic conditions. Gynecologic, testicular, and neoplastic pathology may also cause left lower quadrant pain but are not discussed in this article. PMID- 26526433 TI - Imaging of Acute Pancreatitis. AB - Acute pancreatitis is an acute inflammation of the pancreas. Several classification systems have been used in the past but were considered unsatisfactory. A revised Atlanta classification of acute pancreatitis was published that assessed the clinical course and severity of disease; divided acute pancreatitis into interstitial edematous pancreatitis and necrotizing pancreatitis; discerned an early phase (first week) from a late phase (after the first week); and focused on systemic inflammatory response syndrome and organ failure. This article focuses on the revised classification of acute pancreatitis, with emphasis on imaging features, particularly on newly-termed fluid collections and implications for the radiologist. PMID- 26526434 TI - The Acute Abdominal Aorta. AB - Acute disorders of the abdominal aorta are potentially lethal conditions that require prompt evaluation and treatment. Computed tomography (CT) is the primary imaging method for evaluating these conditions because of its availability and speed. Volumetric CT acquisition with multiplanar reconstruction and three dimensional analysis is now the standard technique for evaluating the aorta. MR imaging may be useful for select applications in stable patients in whom rupture has been excluded. Imaging is indispensable for diagnosis and treatment planning, because management has shifted toward endoluminal repair. Acute abdominal aortic conditions most commonly are complications of aneurysms and atherosclerosis. PMID- 26526435 TI - Bowel Obstruction. AB - Small bowel obstruction and large bowel obstruction account for approximately 20% of cases of acute abdominal surgical conditions. The role of the radiologist is to answer several key questions: Is obstruction present? What is the level of the obstruction? What is the cause of the obstruction? What is the severity of the obstruction? Is the obstruction simple or closed loop? Is strangulation, ischemia, or perforation present? In this presentation, the radiologic approach to and imaging findings of patients with known or suspected bowel obstruction are presented. PMID- 26526437 TI - Acute Infectious and Inflammatory Enterocolitides. AB - Infectious and inflammatory enterocolitides can present with an acute abdomen. The most common entities are ulcerative colitis, Crohn disease, and Clostridium difficile colitis. This article reviews the clinical and imaging findings of patients who present acutely with infectious and inflammatory enterocolitides. The acute abdomen can be defined as the sudden onset (generally <24 hours) of severe localized or generalized abdominal pain that prompts the patient to seek immediate medical assistance; most often a visit to the emergency department. PMID- 26526436 TI - Radiological Evaluation of Bowel Ischemia. AB - Intestinal ischemia, which refers to insufficient blood flow to the bowel, is a potentially catastrophic entity that may require emergent intervention or surgery in the acute setting. Although the clinical signs and symptoms of intestinal ischemia are nonspecific, computed tomography (CT) findings can be highly suggestive in the correct clinical setting. In our article, we review the CT diagnosis of arterial, venous, and nonocclusive intestinal ischemia. We discuss the vascular anatomy, pathophysiology of intestinal ischemia, CT techniques for optimal imaging, key and ancillary radiological findings, and differential diagnosis. PMID- 26526438 TI - Acute Urinary Tract Disorders. AB - Acute urinary tract disorders often manifest as flank pain and are a common complaint of patients who present to the emergency department. The pain is often a vague, poorly localized sensation that may have a variety of causes. Laboratory and clinical findings, such as hematuria, are neither sensitive nor specific for determining the cause of the flank pain. Accordingly, imaging is an important tool in determining a diagnosis and management plan. Patients with acute urinary tract disorders who present with pain include those with calculi as well as renal infection, vascular disorders, and hemorrhage. PMID- 26526439 TI - Acute Gynecologic Disorders. AB - Premenopausal women with acute pelvic pain comprise a significant percentage of patients who present to the emergency room. Etiologies can be gynecologic, urologic, gastrointestinal, or vascular. Signs and symptoms are often nonspecific and overlapping. The choice of imaging modality is determined by the clinically suspected differential diagnosis. Ultrasound (US) is the preferred imaging modality for suspected obstetric or gynecologic disorders. CT is more useful when gastrointestinal or urinary tract pathology is likely. MR imaging is rarely used in the emergent setting, except to exclude appendicitis in pregnant women. This article presents a comprehensive review of imaging of acute gynecologic disorders. PMID- 26526440 TI - Evaluating the Acute Abdomen in the Pregnant Patient. AB - Acute abdominal pain in pregnancy presents diagnostic and therapeutic challenges. Ultrasound remains the primary imaging investigation of the pregnant abdomen because of its availability, portability, and lack of ionizing radiation. MR imaging has been shown to be useful in the diagnosis of gynecologic and obstetric problems and in the setting of acute abdomen during pregnancy. MR imaging is often used when ultrasound is inconclusive. Computed tomography is the investigation of choice when there is a life-threatening situation and in case of traumatic injuries, when a rapid diagnosis is required. PMID- 26526441 TI - MR Evaluation of the Nontraumatic Acute Abdomen with CT Correlation. AB - Cross-sectional imaging plays a crucial role in the triage of patients with acute abdominal pain. Ionizing radiation exposure is a recognized drawback of computed tomography (CT), the primary imaging technique. MR imaging is a promising alternative to CT; it provides excellent image quality with high-contrast resolution without the disadvantages of ionizing radiation and iodinated contrast. This article provides a basic overview of the typical MR findings of the most frequent disease entities encountered in the setting of the nontraumatic acute abdomen, including direct comparison with CT findings to familiarize the readers with these same findings on MR. PMID- 26526442 TI - Imaging of the Acute Abdomen. PMID- 26526443 TI - Plasmatic retinol-binding protein 4 and glial fibrillary acidic protein as biomarkers to differentiate ischemic stroke and intracerebral hemorrhage. AB - A rapid differentiation of acute ischemic stroke and intracerebral hemorrhage (ICH) is essential for an adequate treatment and to promote a better outcome. Our aim was to identify new plasma biomarkers to differentiate stroke subtypes and to combine their diagnostic ability with other biomarkers already described for this clinical indication. Plasma samples of ischemic stroke patients (36) and ICH patients (10) were screened using a 177 antibodies library, and 11 showed different concentrations among stroke subtypes (p < 0.05), mainly chemokines, growth factors and angiogenic factors. Five proteins were selected for replication in 16 ischemic stroke patients and 16 ICH patients, and retinol binding protein 4 (RPB4), apolipoprotein B100 and pigment epithelial-derived factor were replicated (p < 0.05). These proteins, together with glial fibrillary acidic protein (GFAP) and receptor for advanced glycation end product, were tested in 38 ischemic stroke and 28 ICH samples. Finally, RBP4 >61 MUg/mL and GFAP <0.07 ng/mL showed a specificity of 100% for both subtypes. Moreover, after multivariate logistic regression analysis, RBP4 >48.75 MUg/mL (ORadj : 6.09 (1.3 28.57), p = 0.02) and GFAP <0.07 ng/mL (ORadj : 0.03 (0.003-0.31), p = 0.003) resulted in independent predictors of stroke subtype, improving discrimination by 29% (p < 0.0001). Both biomarkers might be useful as diagnostic biomarkers to differentiate ischemic stroke and ICH. A rapid differentiation of ischemic stroke from intracerebral hemorrhage is essential to provide the appropriate treatment. We describe the discovery and subsequent replications of RBP4 and its combination with circulating GFAP as plasmatic biomarkers for hyperacute stroke subtype differentiation. The combination of these biomarkers and others might aid to speed up the discrimination of both stroke subtypes improving the outcome of patients. PMID- 26526445 TI - Environment-Living Organism's Interactions from Physiology to Genomics. PMID- 26526444 TI - A 2-year longitudinal study of prospective predictors of pathological Internet use in adolescents. AB - Longitudinal studies of prospective predictors for pathological Internet use (PIU) in adolescents as well as its course are lacking. This three-wave longitudinal study was conducted within the framework of the European Union funded project "Saving and Empowering Young Lives in Europe" over a 2-year period. The sample consisted of 1444 students at the baseline investigation (T0); 1202 students after 1 year (T1); and 515 students after 2 years (T2). Structured self-report questionnaires were administered at all three time points. PIU was assessed using the Young Diagnostic Questionnaire (YDQ). In addition, demographic (i.e., gender), social (i.e., parental involvement), psychological (i.e., emotional problems), and Internet use-related factors (i.e., online activities) were assessed as prospective predictors. The prevalence of PIU was 4.3 % at T0, 2.7 % at T1 and 3.1 % at T2. However, only 3 students (0.58 %) had persistent categorical PIU (YDQ score of >=5) over the 2-year period. In univariate models, a variety of variables that have been previously identified in cross-sectional investigations predicted PIU at T2. However, multivariate regression demonstrated that only previous PIU symptoms and emotional problems were significant predictors of PIU 2 years later (adjusted R (2) 0.23). The stability of categorical PIU in adolescents over 2 years was lower than previously reported. However, current PIU symptoms were the best predictor of later PIU; emotional symptoms also predicted PIU over and above the influence of previous problematic Internet use. Both PIU symptoms and emotional problems may contribute to the vicious cycle that supports the perpetuation of PIU. PMID- 26526447 TI - A not so random walk through space, time and spirit. PMID- 26526448 TI - Letter from the editors. PMID- 26526449 TI - Quantification of diagnostic biomarkers to detect multiple sclerosis lesions employing (1)H-MRSI at 3T. AB - Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) enables the quantification of metabolite concentration ratios in the brain. The major purpose of the current work is to characterize NAA/Cho, NAA/Cr and Myo/Cr in multiple sclerosis (MS) patients, and to estimate their reproducibility in healthy controls. Twelve MS patients and five healthy volunteers were imaged using (1)H MRSI at 3T. Eddy current correction was performed using a single-voxel non-water suppressed acquisition on an external water phantom. Time-domain quantification was carried out using subtract-QUEST technique, and based on an optimal simulated metabolite database. Reproducibility was evaluated on the same quantified ratios in five normal subjects. An optimal database was created for the quantification of the MRSI data, consisting of choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), lactate (Lac), lipids, myo-inositol (Myo) and glutamine + glutamate (Glx). Decreasing of NAA/Cr and NAA/Cho ratios, as well as an increase in Myo/Cr ratio were observed for MS patients in comparison with control group. Reproducibility of NAA/Cr, NAA/Cho and Myo/Cr in control group was 0.98, 0.87 and 0.64, respectively, expressed as the squared correlation coefficient R (2) between duplicate experiments. We showed that MRSI alongside the time-domain quantification of spectral ratios offers a sensitive and reproducible framework to differentiate MS patients from normals. PMID- 26526450 TI - Karyopherin Alpha 2 Promotes the Inflammatory Response in Rat Pancreatic Acinar Cells Via Facilitating NF-kappaB Activation. AB - BACKGROUND: Activation of the transcription factor NF-kappaB and expression of pro-inflammatory mediators have been considered as major events of acute pancreatitis (AP). Karyopherin alpha 2 (KPNA2), a member of the importin alpha family, reportedly modulates p65 subcellular localization. AIM: This study aimed to investigate the expression and possible functions of KPNA2 in the AP cell and animal model, focusing on its association with NF-kappaB activation. METHODS: An AP cell model was established with the cerulein-stimulated AR42J and isolated rat pancreatic acinar cells. The AP rat model was induced by the intraperitoneal injection of cerulein. The secretion of TNF-alpha, IL-6, and LDH was detected by ELISA kits and the production of NO using nitric oxide kit. Expression of KPNA2 was measured by RT-PCR and Western blot. Expression levels of IKKalpha, phosphorylation of p65, and total p65 were detected by Western blot. Co localization of KPNA2 with p65 was observed by immunofluorescence assay. To determine the biological functions of KPNA2 in cerulein-induced inflammatory response, RNA interference was employed to knockdown KPNA2 expression in AR42J and isolated pancreatic acini cells. RESULTS: Cerulein stimulated KPNA2 expression and IL-6, TNF-alpha, NO, and LDH production in rat pancreatic acinar cells. Cerulein triggered the phosphorylation and nuclear translocation of NF kappaB p65 subunit, indicating the NF-kappaB activation. The co-localization and nuclear accumulation of KPNA2 and p65 were detected in cerulein-treated cells. Knocking down KPNA2 hindered cerulein-induced nuclear transportation of p65 and alleviated the subsequent inflammatory response in rat pancreatic acinar cells. Additionally, KPNA2 expression was significantly up-regulated in cerulein-induced AP rat model. CONCLUSIONS: KPNA2-facilitated p65 nuclear translocation promotes NF-kappaB activation and inflammation in acute pancreatitis. PMID- 26526452 TI - Advances in applications, metabolism, and biotechnological production of L xylulose. AB - L-Xylulose is an intermediate in certain metabolic pathways and is classified as a rare sugar. It shows important physiological effects such as acting as an inhibitor of alpha-glucosidase and decreasing blood glucose, and it can be employed to produce other significant rare sugars, such as L-ribose and L-xylose which contribute to the production of antiviral drugs. Chemical synthesis of L xylulose was performed, but it is difficult and low yielding. The biotransformation from xylitol to L-xylulose by xylitol 4-dehydrogenase was studied intensively. This review describes the occurrence of L-xylulose in certain metabolic pathways, its bioproduction, and application potential. PMID- 26526451 TI - Incidence and Progression of Chronic Kidney Disease After Hepatitis C Seroconversion: Results from ERCHIVES. AB - BACKGROUND AND AIMS: We aimed to assess the incidence and progression of chronic kidney disease (CKD) following hepatitis C virus (HCV) seroconversion. METHODS: This retrospective cohort study included Veterans with a confirmed HCV seroconversion between 2001 and 2014 and Veterans with negative HCV testing over the same time period. The outcomes included development of advanced CKD (eGFR < 60 mL/min/1.73 m(2) on two separate occasions at least 90 days apart, plus a >= 10 mL/min/1.73 m(2) decline from baseline) and progressive CKD (decline in eGFR of >= 30 mL/min/1.73 m(2) from baseline). Multivariable Cox proportional hazards models were used to evaluate the association between HCV and incident advanced and progressive CKD. RESULTS: The final cohort consisted of 71,528 Veterans, including 2589 with recently seroconverted HCV. Over a mean follow-up of 6 years, 36% of patients with and 31% without HCV developed advanced CKD (p < 0.001), and 35% of patients with vs. 26% without HCV developed progressive CKD (p < 0.001). After controlling for traditional risk factors, recently seroconverted HCV+ patients were significantly less likely to develop advanced CKD (HR 0.86; 95% CI 0.79, 0.92), and HCV status was not significantly associated with progressive CKD (HR 0.93; 95% CI 0.86, 1.00). Factors associated with developing advanced and progressive CKD included older age, female sex, diabetes, hypertension, development of cirrhosis, and substance abuse. CONCLUSIONS: In this cohort of newly infected US Veterans, HCV infection was associated with decreased incidence of advanced and unchanged risk of progressive CKD, suggesting a larger role for traditional risk factors in the development of CKD after HCV seroconversion. PMID- 26526453 TI - Inhibition of Streptococcus mutans biofilm formation, extracellular polysaccharide production, and virulence by an oxazole derivative. AB - Dental caries, a biofilm-related oral disease, is a result of disruption of the microbial ecological balance in the oral environment. Streptococcus mutans, which is one of the primary cariogenic bacteria, produces glucosyltransferases (Gtfs) that synthesize extracellular polysaccharides (EPSs). The EPSs, especially water insoluble glucans, contribute to the formation of dental plaque, biofilm stability, and structural integrity, by allowing bacteria to adhere to tooth surfaces and supplying the bacteria with protection against noxious stimuli and other environmental attacks. The identification of novel alternatives that selectively inhibit cariogenic organisms without suppressing oral microbial residents is required. The goal of the current study is to investigate the influence of an oxazole derivative on S. mutans biofilm formation and the development of dental caries in rats, given that oxazole and its derivatives often exhibit extensive and pharmacologically important biological activities. Our data shows that one particular oxazole derivative, named 5H6, inhibited the formation of S. mutans biofilms and prevented synthesis of extracellular polysaccharides by antagonizing Gtfs in vitro, without affecting the growth of the bacteria. In addition, topical applications with the inhibitor resulted in diminished incidence and severity of both smooth and sulcal surface caries in vivo with a lower percentage of S. mutans in the animals' dental plaque compared to the control group (P < 0.05). Our results showed that this oxazole derivative has the capacity to inhibit biofilm formation and cariogenicity of S. mutans. PMID- 26526454 TI - Engineering Rhodosporidium toruloides with a membrane transporter facilitates production and separation of carotenoids and lipids in a bi-phasic culture. AB - The oleaginous yeast Rhodosporidium toruloides has great biotechnological potential. It accumulates a high amount of lipids which can be used for biofuels and also produces carotenoids which are valuable in the food and pharmaceutical industry. However, the location of these two hydrophobic products in the cell membrane prohibits its efficient harvesting and separation. Here, the transporter Pdr10 was engineered into R. toruloides and cultured in two-phase media containing oil. This enabled the production and in situ export of carotenoids into the oil and concurrent separation from intracellular lipids in the cells. When Pdr10 strain was cultured in the two-phase media, carotenoids and fatty acids yield increased from 1.9 to 2.9 MUg/mg and 0.07 to 0.09 mg/mg, respectively. A total of 1.8 MUg/mg carotenoids was exported by Pdr10 strain, as compared to 0.3 MUg/mg in the wild type. In the Pdr10 strain, the composition of carotenoids and fatty acid it produced also changed. Torulene became the major carotene produced instead of torularhodin. Also, the unsaturated fatty acid C18:2 became the dominant fatty acid produced instead of the saturated C16:0, which was similar to the grape seed oil used in the two-phase media. This indicated that oil was being consumed by the cells, which was supported by the increased intracellular glycerol levels detected by gas chromatography-mass spectrometry (GC-MS). Our approach represents an easy and greener extraction method which could serve to increase the yield and facilitate separation of carotenoids and fatty acids. PMID- 26526455 TI - Eukaryotic aggresomes: from a model of conformational diseases to an emerging type of immobilized biocatalyzers. AB - Unraveling the characteristics and putative applications of naturally occurring protein aggregates has received an increasing interest during the last years. For example, the finding that the proteins embedded within bacterial inclusion bodies are, at least partially, biologically functional opened new opportunities for their rational design and application as naturally self-immobilized biocatalysts or as new drug delivery systems ("nanopills"). In another scenario, it is well established that "conformational diseases" are caused by misfolding and protein aggregation in different cells and tissues. The presence of such protein aggregates is a hallmark of these conditions, therefore becoming an excellent target for new therapeutic approaches for such devastating pathologies. Aggresomes are protein aggregates found in eukaryotic cells when the intracellular protein degradation machinery is overtitered. These protein-based nanoparticles are increasingly becoming excellent models in studies aimed to obtain a better understanding and control over protein aggregation processes in eukaryotic cells. In this work, we focus on some of the latest findings in the field of putative aggresome applications in biotechnology, as a new type of self assembled immobilized biocatalysts, and in nanomedicine, mainly on their relationship with conformational diseases and the rational design of better therapeutics through a deeper understanding of protein aggregation processes. PMID- 26526456 TI - The activity and community structure of total bacteria and denitrifying bacteria across soil depths and biological gradients in estuary ecosystem. AB - The distribution of soil microorganisms often shows variations along soil depth, and even in the same soil layer, each microbial group has a specific niche. In particular, the estuary soil is intermittently flooded, and the characteristics of the surface soil layer are different from those of other terrestrial soils. We investigated the microbial community structure and activity across soil depths and biological gradients composed of invasive and native plants in the shallow surface layer of an estuary ecosystem by using molecular approaches. Our results showed that the total and denitrifying bacterial community structures of the estuarine wetland soil differed according to the short depth gradient. In growing season, gene copy number of 16S rRNA were 1.52(+/-0.23) * 10(11), 1.10(+/-0.06) * 10(11), and 4.33(+/-0.16) * 10(10) g(-1) soil; nirS were 5.41(+/-1.25) * 10(8), 4.93(+/-0.94) * 10(8), and 2.61(+/-0.28) * 10(8) g(-1) soil; and nirK were 9.67(+/-2.37) * 10(6), 3.42(+/-0.55) * 10(6), and 2.12(+/-0.19) * 10(6) g(-1) soil in 0 cm, 5 cm, and 10 cm depth layer, respectively. The depth-based difference was distinct in the vegetated sample and in the growing season, evidencing the important role of plants in structuring the microbial community. In comparison with other studies, we observed differences in the microbial community and functions even across very short depth gradients. In conclusion, our results suggested that (i) in the estuary ecosystem, the denitrifying bacterial community could maintain its abundance and function within shallow surface soil layers through facultative anaerobiosis, while the total bacterial community would be both quantitatively and qualitatively affected by the soil depth, (ii) the nirS gene community, rather than the nirK one, should be the first candidate used as an indicator of the microbial denitrification process in the estuary system, and (iii) as the microbial community is distributed and plays a certain niche role according to biogeochemical factors, the study of the microbial community even in surface soil should be performed in detail by considering the soil depth. PMID- 26526457 TI - Mechanisms and microbial structure of partial denitrification with high nitrite accumulation. AB - Nitrite (NO2 (-)-N) accumulation in denitrification can provide the substrate for anammox, an efficient and cost-saving process for nitrogen removal from wastewater. This batch-mode study aimed at achieving high NO2 (-)-N accumulation over long-term operation with the acetate as sole organic carbon source and elucidating the mechanisms of NO2 (-)-N accumulation. The results showed that the specific nitrate (NO3 (-)-N) reduction rate (59.61 mg N VSS(-1) h(-1) at NO3 (-) N of 20 mg/L) was much higher than specific NO2 (-)-N reduction rate (7.30 mg N VSS(-1) h(-1) at NO3 (-)-N of 20 mg/L), and the NO2 (-)-N accumulation proceeded well at the NO3 (-)-N to NO2 (-)-N transformation ratio (NTR) as high as 90 %. NO2 (-)-N accumulation was barely affected by the ratio of chemical oxygen demand (COD) to NO3 (-)-N concentration (C/N). With the addition of NO3 (-)-N, NO2 (-)-N accumulation occurred and the specific NO2 (-)-N reduction rate declined to a much lower level compared with the value in the absence of NO3 (-)-N. This indicated that the denitrifying bacteria in the system preferred to use NO3 (-)-N as electron acceptor rather than use NO2 (-)-N. In addition, the Illumina high throughput sequencing analysis revealed that the genus of Thauera bacteria was dominant in the denitrifying community with high NO2 (-)-N accumulation and account for 67.25 % of total microorganism. This bacterium might be functional for high NO2 (-)-N accumulation in the presence of NO3 (-)-N. PMID- 26526458 TI - Acute Pain in the Emergency Department: The Challenges. AB - Acute pain is the reason that the majority of patients present to the emergency department.Failure to adequately treat acute pain in the emergency department has been labelled a public health problem.The College of Emergency Medicine has set standards for the timelines and adequacy in management of pain in both adults and children.Joint Care Quality Commission and College of Emergency Medicine national audit demonstrates the gap between standards and current practice.The new Department of Health clinical quality indicators for emergency medicine do not include a measure of pain.Untreated pain can have short and long term effects, including sensitisation to pain episodes in later life.A range of non pharmacological and pharmacological interventions have been shown to be effective for procedural pain management in infants and children, and are most effective when used in combination.Developmental changes in pain responses, analgesic response and drug pharmacokinetics need to be taken into account when planning procedural pain management for neonates.Comprehensive evidence based guidelines are available to guide effective procedural pain management in neonates, infants and older children. PMID- 26526460 TI - Relative longevity among retired military personnel: a historical-cohort study. AB - BACKGROUND: Occupation is a significant factor affecting life, health and well being. Long-term military service is a unique career path that may have an influence on life expectancy, even after excluding obvious risks such as battlefield mortality. However, it remains unclear what the effects of a military career are on the life trajectory of personnel after retiring from service. This study compared life expectancy among retired military personnel (RMP) to their sex and birth cohort-specific reference populations. METHODS: For this historical cohort study, we collected data on the sex, year of birth, year of death, time in service, and rank at end of service for 4862 Israeli RMPs. Data on reference populations were provided by the Israel Central Bureau of Statistics by birth decade from 1900 to 1989. We calculated the difference between each individual RMP's age at death and the "expected" age at death, based on sex and birth cohort specific means in the reference populations. RESULTS: Overall, 67.9 % of RMPs lived longer than average relative to their sex-specific birth cohort. This difference in life expectancy was more pronounced among women than among men. There was a significant trend of increasing differences between RMP males and reference males over time (P < 0.002), whereas no significant trend was identified among females. Length of service and rank were not associated with relative longevity for RMPs. CONCLUSIONS: The mechanism of the protective effect of military service on life expectancy remains unknown, but our findings indicate that it affects men and women differently, with women being more likely to benefit from the potential protective effect of military service. The healthy worker effect is known to vary from one occupation to another, and to the best of our knowledge, this is the first attempt to quantify the magnitude of the healthy worker effect among career military servicemen and women. PMID- 26526461 TI - Perspectives of Benzimidazole Derivatives as Anticancer Agents in the New Era. AB - Cancer is one of the deadliest diseases nowadays and is a great topic for research as the challenging task is to develop new entities with selectivity towards cancerous cells. Heterocyclic compounds are of great importance in medicinal chemistry as they possess an extensive range of therapeutic applications. Benzimidazole is one such important heterocyclic organic compound having structural analogy to nucleotides found in human body and hence is an important pharmacophore in medicinal chemistry. A variety of marketed drugs containing benzimidazole are thiabendazole, flubendazole (anthelmintic), astmizole (antihistaminic), lansoprazole and omeprazole (antiulcerative). In the light of the above facts, this review is an attempt to summarize the collective contributions from the authors around the world in the field of anticancer agents. This review highlights synthetic schemes and anticancer activity results of the research done in the past years. PMID- 26526459 TI - Two-photon imaging of chronically implanted neural electrodes: Sealing methods and new insights. AB - BACKGROUND: Two-photon microscopy has enabled the visualization of dynamic tissue changes to injury and disease in vivo. While this technique has provided powerful new information, in vivo two-photon chronic imaging around tethered cortical implants, such as microelectrodes or neural probes, present unique challenges. NEW METHOD: A number of strategies are described to prepare a cranial window to longitudinally observe the impact of neural probes on brain tissue and vasculature for up to 3 months. RESULTS: It was found that silastic sealants limit cell infiltration into the craniotomy, thereby limiting light scattering and preserving window clarity over time. In contrast, low concentration hydrogel sealants failed to prevent cell infiltration and their use at high concentration displaced brain tissue and disrupted probe performance. COMPARISON WITH EXISTING METHOD(S): The use of silastic sealants allows for a suitable imaging window for long term chronic experiments and revealed new insights regarding the dynamic leukocyte response around implants and the nature of chronic BBB leakage in the sub-dural space. CONCLUSION: The presented method provides a valuable tool for evaluating the chronic inflammatory response and the performance of emerging implantable neural technologies. PMID- 26526462 TI - A comparison between two different automated total 25-hydroxyvitamin D immunoassay methods using liquid chromatography-tandem mass spectrometry. AB - INTRODUCTION: Total 25-hydroxyvitamin D [25(OH)D] is the most reliable indicator of vitamin D status. In this study, we compared two automated immunoassay methods, the Abbott Architect 25-OH Vitamin D assay and the Roche Cobas Vitamin D total assay, with the liquid chromatography-tandem mass spectrometry (LC-MS/MS). MATERIALS AND METHODS: One hundred venous blood samples were randomly selected from routine vitamin D tests. Two of the serum aliquots were analyzed at the Abbott Architect i2000 and the Roche Cobas 6000's module e601 in our laboratory within the same day. The other serum aliquots were analyzed at the LC-MS/MS in different laboratory. Passing-Bablok regression analysis and Bland-Altman plot were used to compare methods. Inter-rater agreement was analyzed using kappa (kappa) analysis. RESULTS: The Roche assay showed acceptable agreement with the LC-MS/MS based on Passing-Bablok analysis (intercept: -5.23 nmol/L, 95% CI: -8.73 to 0.19; slope: 0.97, 95% CI: 0.77 to 1.15). The Abbott assay showed proportional (slope: 0.77, 95% CI: 0.67 to 0.85) and constant differences (intercept: 17.08 nmol/L; 95% CI: 12.98 to 21.39). A mean bias of 15.1% was observed for the Abbott and a mean bias of -14.1% was observed for the Roche based on the Bland-Altman plots. We found strong to nearly perfect agreement in vitamin D status between the immunoassays and LC-MS/MS. (kappa: 0.83 for Abbott, kappa: 0.93 for Roche) using kappa analysis. CONCLUSION: Both immunoassays demonstrated acceptable performance, but the Roche Cobas assay demonstrated better performance than the Abbott Architect in the studied samples. PMID- 26526464 TI - Cloning, Purification and Characterization of a Highly Thermostable Amylase Gene of Thermotoga petrophila into Escherichia coli. AB - A putative alpha-amylase gene of Thermotoga petrophila was cloned and expressed in Escherichia coli BL21 (DE3) using pET-21a (+), as an expression vector. The growth conditions were optimized for maximal expression of the alpha-amylase using various parameters, such as pH, temperature, time of induction and addition of an inducer. The optimum temperature and pH for the maximum expression of alpha amylase were 22 degrees C and 7.0 pH units, respectively. Purification of the recombinant enzyme was carried out by heat treatment method, followed by ion exchange chromatography with 34.6-fold purification having specific activity of 126.31 U mg(-1) and a recovery of 56.25%. Molecular weight of the purified alpha amylase, 70 kDa, was determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The enzyme was stable at 100 degrees C temperature and at pH of 7.0. The enzyme activity was increased in the presence of metal ions especially Ca(+2) and decreased in the presence of EDTA indicating that the alpha amylase was a metalloenzyme. However, addition of 1% Tween 20, Tween 80 and beta mercaptoethanol constrained the enzyme activity to 87, 96 and 89%, respectively. No considerable effect of organic solvents (ethanol, methanol, isopropanol, acetone and n-butanol) was observed on enzyme activity. With soluble starch as a substrate, the enzyme activity under optimized conditions was 73.8 U mg(-1). The alpha-amylase enzyme was active to hydrolyse starch forming maltose. PMID- 26526465 TI - How neurologists are paid: Part 1: The Medicare payment system. AB - Neurologists are facing yearly reductions in reimbursement for rendered services. These reductions arise from changes by Medicare, Medicaid, and third-party payers to achieve cost savings. In Part 1, we discuss reimbursement for office visits and procedures, the relative value scale, the conversion factor used by Medicare to transform work into payments, and the recently repealed sustainable growth rate. The establishment of new codes for transitional care and chronic care management may augment the salaries of neurologists who care for patients with chronic conditions. Medicare's recent elimination of payment for consultations and the bundling of nerve conduction studies have dramatically affected reimbursement. Large discrepancies remain between compensation for procedures and office visits. PMID- 26526466 TI - A systematic review of prognostic factors for distal upper limb pain. AB - BACKGROUND: Musculoskeletal pain in the distal upper limb is relatively common, can be a cause of disability, presents a high cost to society and is clinically important. Previous reviews of prognostic factors have focused on pain in the proximal upper limb, whole upper extremity or isolated regions of the distal upper limb. AIM: To identify factors that predict outcome of distal upper limb pain. STUDY DESIGN: Systematic review. METHOD: Eight bibliographic databases were searched from inception to March 2014. Eligible articles included adults with pain anywhere in the distal upper limb at baseline from randomised controlled trials with a waiting list, expectant policy or usual care group, or observational studies where no treatment or usual care was provided. Data describing the association between a putative prognostic factor and pain or functional outcome at follow-up were required. Quality was assessed using the Quality in Prognostic Studies tool. RESULTS: Seven articles reporting on six studies were identified. Heterogeneity of study populations and outcome measures prevented a meta-analysis so a narrative synthesis of results was undertaken. Three factors (being female, a longer duration of the complaint at initial presentation and having musculoskeletal pain in multiple locations) were significantly associated with poor pain outcome in more than one study. Being female was the only factor significantly associated with poor functional outcome in more than one study. CONCLUSIONS: A range of sociodemographic, pain-related, occupational and psychosocial prognostic factors for distal upper limb pain outcomes were investigated in studies included in the review. However, due to the lack of commonality of factors investigated and lack of consistency of results across studies, there is limited evidence for predictors of distal upper limb pain outcomes. Further research is required to identify prognostic factors of distal upper limb pain, particularly modifiable factors that may influence management. PMID- 26526468 TI - [Jean Francois Marie Aicardi (1926-2015)]. PMID- 26526467 TI - Combined effects of education level and perceived social class on self-rated health and life satisfaction: Results of Korean labor and income panel study wave 8-wave 15. AB - BACKGROUND: To examine the combined effects of education level and perceived social class on self-rated health and life satisfaction in South Korea. METHODS: We used data drawn from the 8 to 15th wave of the Korean Labor and Income Panel Study (KLIPS). Using wave 8 at baseline, data included 11,175 individuals. We performed a longitudinal analysis at baseline estimating the prevalence of self rated health and life satisfaction among individuals by education level (high, middle, and low education level) and perceived social class (high, middle, and low social class). RESULTS: For self-rated health, odds ratio (OR) of individuals with low education and low perceived social class was 0.604 times lower (95% CI: 0.555-0.656) and the OR of individuals with low education and middle perceived social class was 0.853 time lower (95% CI: 0.790-0.922) when compared to individuals with high education and high perceived social class. For life satisfaction, OR of individuals with low education and low perceived social class was 0.068 times lower (95% CI: 0.063-0.074) and the OR of individuals with middle education and middle perceived social class was 0.235 time lower (95% CI: 0.221 0.251) compared to individuals with high education and high perceived social class. CONCLUSIONS: This study shows that the combined effects of education level and perceived social class associated with self-rated health and life satisfaction. Our study suggests increasing education level and perceived social class. Additionally, it will be important to develop multi-dimensional measurement tools including education level and subjective social class. PMID- 26526469 TI - [Level of knowledge of and capability for application of isolation precautions in a tertiary-level pediatric hospital]. AB - OBJECTIVE: To assess the level of knowledge of and capability for application of isolation precautions. MATERIALS AND METHODS: A cross-sectional study was conducted at a tertiary-level pediatric hospital, and a questionnaire including structured questions and clinical scenarios was applied to healthcare personnel. Descriptive and inferential statistics were performed with the chi-squared test and odds ratios were obtained. RESULTS: A total of 131 healthcare workers participated in the study, including 34 (26%) attending physicians, 47 (36%) medical residents, 48 (37%) nurses, and 2 (1%) physicians who were heads of the department. According to our definition, 99 (75%) had poor, 22 (17%) had fair, and 10 (8%), good knowledge. With regard to the capability for application of isolation precautions, 66 (51%), 33 (25%), and 32 (24%) possessed poor, fair, and good levels, respectively. Association with poor knowledge was exhibited as follows: physicians, OR: 0.17 (0.005-0.54), p = 0.001; undergraduate degree in medicine, OR: 0.37 (0.16-0.83), p = 0.01; seniority < 5 years, OR: 0.35 (0.14 0.86), p = 0.019, and training during previous year, OR: 0.09 (0.03-0.24), p = 0.005, while association with poor capability was the following; physician, OR: 0.25 (0.12-0.55), p = 0.005; undergraduate degree in medicine, OR: 0.38 (0.18 0.80), p = 0.009; seniority < 5 years, OR: 0.90 (0.45-1.81), p = 0.78, and training during previous year, OR: 0.23 (0.10-0.51), p = 0.005. CONCLUSIONS: Being a physician, having an undergraduate degree in medicine, < 5 years working at the hospital, and having received training in the previous year were positively associated with knowledge and application of isolation precautions. PMID- 26526470 TI - [Expression of the concept of death by residents of a tertiary hospital]. AB - INTRODUCTION: Attitudes of health professionals are based on their conditions and personal life experiences about life and death and are part of their professional behavior. Medical training relies mainly on physical-biological sciences and, to a lesser extent, on social-medical aspects, thus forming the physician's concept about death. These concepts may present themselves as a result of culture and as factors that model or limit the cognitive development of the physicians. OBJECTIVE: To determine the concept of death of medical residents in a high specialty hospital. METHODS: A cross-sectional, prospective survey of physicians in training from the first to the sixth year from different specialties. Descriptive statistical analysis was carried out. RESULTS: We made 174 surveys; 61% were in the first year of the specialty; 149 practiced some religion. Women were 3.5 times more likely to have a concept of death that was not that of a biologist, unlike men. Women were 25% more likely to have had an influence of religion on their concept of death. CONCLUSIONS: The personality of the physician is versatile. It has a relationship with professional and human experiences. As training progresses, medical influence transforms biological or religious views. The concept of death and its influence on the idea appeared to be different between male and female physicians. PMID- 26526471 TI - [Donor cell leukemia (DCL): A prospective study of its identification and treatment]. AB - Donor-derived malignancies after allogeneic hematopoietic stem cell transplantation and after solid organ transplantation are considered as rare diseases. We have prospectively searched for donor cell leukemia in a 12-year period, in a single institution, in a group of 106 consecutive patients allografted because of leukemia. We have identified seven cases of donor cell leukemia; six were allografted because of relapsed acute lymphoblastic leukemia and one because of paroxysmal nocturnal hemoglobinuria/aplastic anemia. These figures suggest that the real incidence of donor cell leukemia has been underestimated. The six patients with lymphoblastic donor cell leukemia were treated prospectively with a pediatric-inspired combined chemotherapy schedule designed for de novo acute leukemia. A complete response was obtained in three out of six patients with lymphoblastic donor cell leukemia. It is possible to obtain favorable responses in donor cell leukemia patients employing combined chemotherapy. The long-term donor cell leukemia survivors remain as full chimeras and have not needed a second transplant. PMID- 26526472 TI - [Electroencephalographic and neurodevelopmental disorders in severe congenital heart disease: A follow-up study]. AB - Congenital heart defects are the most common malformations at birth. Due to the fact that the developmental windows at early stages close rapidly, the aim of this study was to determine the impact of congenital heart defects on the central nervous system at short and medium terms after applying traditional and quantitative electroencephalography techniques and a test of neurodevelopment. Twenty-one patients (8-27 months, x = 14.8) with severe congenital heart defects who had been studied previously, and a control group of 19 healthy children (8-29 months, x = 14.6) were included. In all of them traditional electroencephalography, quantitative electroencephalography, and a test of neurodevelopment were performed. The results between groups (control vs. congenital heart defects) and between congenital heart defects (previous vs. present) were compared. In the second evaluation, congenital heart defect children maintained abnormal quantitative and traditional electroencephalography recordings. Comparing quantitative electroencephalography among congenital heart defects (previous vs. present) and between controls and congenital heart defects, significant differences of theta band activity in frontal, central, and temporal leads were found (p < 0.05). Upon assessing neurodevelopment, 86% of the previously studied congenital heart defect cases kept the same diagnosis of abnormality, of which mild-to-moderate hypotone was the most frequently observed. As hypothesized, congenital heart defect diseases have a very important impact on central nervous system function as determined by neurodevelopmental testing and traditional and quantitative electroencephalography recordings. The alterations observed persisted throughout the period studied. PMID- 26526473 TI - [Diagnostic utility of the hyomental distance ratio as predictor of difficult intubation at UMAE 25]. AB - BACKGROUND: The hyomental distance ratio is defined as the ratio of the hyomental distances in neutral position and at head extension. The aim of the study was to establish the diagnostic utility as predictor of difficult intubation. METHODS: In a cross-sectional study, the assessment of the airway was performed in 70 patients (35 male and 35 female, 15-75 years old) undergoing general anesthesia with endotracheal intubation for elective surgery. We assessed Mallampati, Patil Aldreti, interincisive distance, Bellhouse Dore scales and hyomental distance ratio. Subsequently, laryngoscopy was performed and the view graded with Cormack scale. We define "difficult intubation" as Cormack III and IV. We determined the diagnostic utility of the scales and the hyomental distance ratio. RESULTS: For hyomental distance ratio of <= 1.2 we calculated sensitivity, 60%; specificity, 20%; positive predictive value, 5%; negative predictive value, 86%; positive likelihood ratio of 0.75 and negative likelihood ratio of 2. CONCLUSIONS: The hyomental distance ratio, as predictor of difficult intubation, has little utility. PMID- 26526474 TI - [Prevalence of severe periodontal disease and its association with respiratory disease in hospitalized adult patients in a tertiary care center]. AB - BACKGROUND: Severe periodontal disease is a chronic inflammatory gingival process associated with systemic diseases. OBJECTIVE: To determine the prevalence of severe periodontal disease and its association with respiratory diseases among hospitalized patients at the Institute of Respiratory Diseases "Ismael Cosio Villegas" (INER) in 2011. MATERIAL AND METHODS: A cross-sectional study was developed. The severe periodontal disease was diagnosed by the Department of Stomatology. The International Classification of Diseases 10th revision was used. A multinomial logistic was fit to estimate relative-risk. RESULTS: Three thousand and fifty-nine patients were included; 772/3,059 (25.2%) had severe periodontal disease. After controlling for age, sex, inpatient days, death, and socioeconomic status, the infectious respiratory diseases that were significantly associated with severe periodontal disease were: HIV/AIDS (RR: 10.6; 95% CI: 9.1-23.3; p < 0.0001); pneumonia (RR: 2.6; 95% CI: 2.2-5.7; p < 0.0001); pulmonary tuberculosis and its sequels (RR: 2.1; 95% CI: 1.6-4.9; p < 0.0001); and lung abscess (RR: 2.6; 95% CI: 1.6-7.8; p = 0.002). Lung cancer and pleural diseases were also significantly associated with severe periodontal disease. CONCLUSIONS: High prevalence of severe periodontal disease was observed in the different respiratory diseases. Severe periodontal disease was associated with both infectious and non-infectious respiratory diseases. It is important to study an oral health intervention. PMID- 26526475 TI - [Nail changes associated with distal renal tubular acidosis in pediatric patients]. AB - Renal tubular acidosis is a disease prevalent in childhood, responsible for a decrease in growth due inadequate acid-base levels regulation. It is well known that systemic conditions can generate or accompany nail changes by different pathophysiologic mechanisms, however no one has ever found or reported any association of onychopathy with renal tubular acidosis so far. That is why we would like to share our experience on this topic. PMID- 26526476 TI - [Comparison of the tests polymerase chain reaction, serology, and blood culture with respect to sensitivity and specificity for detection of Brucella spp in human samples]. AB - OBJECTIVE: The aim of this study was to evaluate the sensitivity and specificity of polymerase chain reaction for detection of Brucella spp in human blood samples compared with the serological tests and blood culture. MATERIAL AND METHODS: In 2005, a total of 92 people were sampled from the towns of Anahuac and Sabinas Hidalgo, Nuevo Leon, where an outbreak of human cases had taken place in the same year as this study. The sera collected were analyzed by serological tests according to the NOM 022-SS2-1994. DNA was obtained using CTAB extraction method and it was used to amplify a fragment of 223 bp of the coding sequence for a protein of 31 kDa present in all Brucella species. RESULTS: The polymerase chain reaction test detected 23 positive samples. The sensitivity and specificity compared with RB was 44.68 and 95.56%, respectively. Compared with mouse antibody production, it was 51.61 and 88.52%, and 2-mercaptoethanol was 53.57 and 87.50%. When isolation (positives cultures) was compared with polymerase chain reaction, we obtained 100.0% sensitivity and 80.23% specificity, taking into account people with positive and negative serology. CONCLUSIONS: The polymerase chain reaction test can be an alternative tool to bacterial culture in human brucellosis diagnosis. PMID- 26526477 TI - [The process of death in the intensive care unit (ICU). From a medical, thanatological and legislative point of view]. AB - Traditional goals in the intensive care unit are to reduce morbidity and mortality. Despite medical and technological advances, death in the intensive care unit remains commonplace and the modern critical care team should be familiar with palliative care and legislation in Mexico. Preserving the dignity of patients, avoiding harm, and maintaining communication with the relatives is fundamental. There is no unique, universally accepted technical approach in the management of the terminal critical care patient, so it is important to individualize each case and define objectives together under the legal framework in Mexico. PMID- 26526478 TI - [Heart failure with preserved ejection fraction (HFPEF). Impact of change in the paradigm of isolated diastolic dysfunction]. AB - Heart failure with preserved ejection fraction is a significant and growing public health problem, since it currently represents half of all patients with heart failure. Despite improvements in the understanding of the disease, there is no benefit form treatments tested at all. Advances in diagnostic imaging and invasive evaluation algorithms will allow a more accurate and early diagnosis so that treatment of earliest forms in the progression of the disease are applied since the potential for benefit may be higher. Although important progress has been made in our understanding of the pathophysiology, cardiac catheterization, and cellular of diastolic failure mechanisms and not diastolic mechanisms of disease, further research is required promptly to determine how best to address these anomalies to reduce the significant burden of morbidity and mortality in this form of heart failure, which is reaching pandemic proportions. PMID- 26526479 TI - [Hyaline-vascular Multicentric Castleman's Disease in an immunocompetent patient]. AB - A previously healthy, immunocompetent 67-year-old female presented with a one month history of general symptoms, weight loss, night fevers, and bilateral lower extremity edema. On admission she had severe anemia, acute kidney injury, and multiple lymphadenopathies. An excisional biopsy of one of the axillary lymphadenopathies confirmed hyaline-vascular Castleman's disease. This rare disease is a polyclonal lymphoproliferative disorder that affects the normal lymph node architecture. According to its location it can be divided in unicentric (localized) or multicentric disease; it can be further divided according to histopathology in hyaline-vascular or plasmatic cells variety. Clinical presentation relates more to histopathological variety than to centricity. Human herpes virus 8 is ubiquitous in this disease and, along with interleukin 6, plays an important role in pathogenesis and symptoms presentation. Surgery is the go-to treatment of localized disease, while systemic chemotherapy is the option in multicentric disease. Communication between the clinical and anatomopathological teams is crucial; lag in diagnosis can lead to futile investigations in search of other diseases and delay in treatment. PMID- 26526480 TI - [Vertebral-subclavian bifurcation treatment. "The wedding ring technique" for a vertebral in-stent restenosis associated with stent fracture]. AB - This report describes a solution for a restenosis and for the fracture of a stent in the vertebral artery in a patient suffering from vertebrobasilar symptoms. Angiography demonstrates restenosis of a vertebral stent as well as its fracture and migration into the subclavian artery. This complication was managed percutaneously by passing a guide wire through the fractured stent. Pre dilatation and kissing balloon techniques were applied in both the vertebral and subclavian arteries to modify the stent's dimensions and shape it into the form of a "ring." Postprocedural angiography demonstrated an excellent final result with the assistance of StentBoost visualization. Control angiography at six months also utilized StentBoost imaging and confirmed the patency of the bifurcation and that the stent was not displaced. PMID- 26526481 TI - [A tribute to the memory of the illustrious maestro and academic Dr. Rafael Mendez Martinez, pioneer in the pharmacological studies of digitalis and digitalis glycosides]. AB - Since the end of the XVIII century, digitalis glycosides were employed in heart failure. They were considered initially as diuretics and later as cardiotonic agents or as positive inotropics. At the present time there are varied groups of positive inotropic agents, which have a beneficial action on the failing human myocardium. For example, the beta adrenergics, the phosphodiesterase III inhibitors such as milrinone, or the sensibilizers of myocardial proteins to Ca++ such as levosimendan and omecamtiv mecarbil. However, following the opinion of distinguished cardiologists, in the case of heart failure associated to atrial fibrillation, digitalis cannot be substituted. PMID- 26526482 TI - [VI Symposium: Some global health problems with local impact: Great challenges for Public Health]. AB - The objective of the symposium was to emphasize the great public health challenges that we are facing today; such is the case of dementia, which is one of the main causes of disability and dependence among older adults. Another important issue is antibiotic resistance; even though it has played a key role in the health of humanity, its indiscriminate use has resulted in increased bacterial resistance. Therefore, health regulations in the rational use of prescribed drugs in our country are part of the actions taken in order to not only control the use of such drugs, but also regulate different areas related to health in order to avoid health risks. Finally, a current challenge is emerging and reemerging diseases that have caused various epidemics such as influenza, Ebola virus disease, binomial tuberculosis and HIV, and Chikungunya that is currently affecting the Region of the Americas. PMID- 26526483 TI - [Dementia in Mexico: The need for a National Alzheimer's Plan]. AB - Dementia is one of the facts than most contributes to the disability and dependence in elderly people. Alzheimer's disease is the cause more common of dementia in the world. In Mexico, the prevalence of Alzheimer's disease is 7.3% and incidence of 27.3 per 1,000 people/year. Mexican population studies have determined that Alzheimer's disease is highly associated to women and their risk to develop it is increased with metabolic syndrome, cardiovascular disease, or depression. The projections are that there will be 3.5 million elderly people affected by Alzheimer's disease by 2050 in Mexico; this will have a major impact on the healthcare system. The National Institute of Geriatrics from Mexico's Ministry of Health has released a first proposal for a National Alzheimer and Other Dementias' Plan. The central aim of this plan is to promote the well being of people affected by Alzheimer's disease and their families through of the strengthening of the Mexican healthcare system and the support of other responsible institutions. PMID- 26526484 TI - [Emerging and reemerging diseases]. AB - Emerging and reemerging diseases are the result of the interaction of multiple factors, such as social determinants of health, climate change, and conditions that prevail and are identifiable in some populations. As a consequence, there may be situations that by their nature are defined as a health emergency, impacting directly on the health of a population, either because they are not known or due to their rapid spread, resulting in a health security problem. Examples of these diseases are described in this article, starting with their origin, their impact on the population, and the response necessary in order to contain or prevent damage of a greater magnitude. The presence of these agents and their consequent damage to the population should lead efforts towards comprehensive prevention and appropriate containment strategies to ensure the protection of public health. Endeavors should be directed not only to a specific agent, but rather to factors that determine their reemergence, such as Ebola, or their permanence, such as the binomial infection of tuberculosis-AIDS. In order to correctly implement strategies, training and availability of supplies play a crucial role in facing the challenges that lie ahead. PMID- 26526485 TI - [Resistance to antibiotic: A serious global problem]. AB - An important piece of improvement in public health standards, medicine achievements, and development is based on the impressive effect of vaccines and antibiotics on infectious diseases. However, the last three or so decades have witnessed how an unsound use of antibiotics has resulted in antibiotic multi resistant clones in hospitals and community environments. It also has been said that antibiotic research and the development pipeline has crashed, leading to no new antibiotic molecules to be tested at a time of treatment failure, manifest with unacceptable frequency as an increased economic and human cost in lives. Like the name of the series, antibiotic resistance is a global problem with clear evolutionary roots and a broad local impact. In that sense, this review explores the interaction among resistant mechanisms, underlying motives of expansion and actual trends in antibiotic resistance upgrade to limit the problem. Conceivably, only the involvement of players at every level, and coordinated actions accordingly constitute the necessary elements for effectively intervention. PMID- 26526486 TI - [The role of health regulations in the rational use of medicines]. AB - The Federal Commission for the Protection against Sanitary Risk (COFEPRIS by its initials in Spanish) is the state body responsible for transversely regulating various sectors of the Mexican economy, among them health services and inputs. Both cases are related to the rational use of medicines. The pharmaceutical policy of the Mexican Government is to prevent health risks by strengthening the effective and timely access to a market supplied with safe, effective, and quality products at the lowest possible prices. To date, the regulatory mechanisms used by COFEPRIS to ensure access to medicines and quality health services have been effective. With the implemented measures, self-medication has been reduced and medical services provided by pharmaceutical clinics comply with the best practices. Finally, the regulatory framework has been strengthened to fight the illegal drug market and "miracle" products. So far, the present administration has increased seizures of illegal substances and, as of today, all advertising guidelines for health-related products comply with the regulations. PMID- 26526487 TI - [Why must we celebrate the 150 years from the National Academy of Medicine of Mexico foundation?]. PMID- 26526488 TI - [Anastomosis dehiscence or enteric fistula? Need for precise definitions in the description of surgical complications, even in pediatric surgery]. PMID- 26526489 TI - An improved synthesis of [26-(2)H3]castasterone. AB - Commercially available epicastasterone has been employed as a starting material for the preparation of [26-(2)H3 ]castasterone. The chemical synthesis has been realized in 13 chemical steps and 4.6% total yield. The target compound is intended to be used as internal standard for the quantitative analysis of brassinosteroids. PMID- 26526490 TI - Modelling postharvest quality of blueberry affected by biological variability using image and spectral data. AB - BACKGROUND: Hyperspectral reflectance and transmittance sensing as well as near infrared (NIR) spectroscopy were investigated as non-destructive tools for estimating blueberry firmness, elastic modulus and soluble solid content (SSC). Least squares-support vector machine models were established from these three spectra based on samples from three cultivars viz. Bluecrop, Duke and M2 and two harvest years viz. 2014 and 2015 for predicting blueberry postharvest quality. RESULTS: One-cultivar reflectance models (establishing model using one cultivar) derived better results than the corresponding transmittance and NIR models for predicting blueberry firmness with few cultivar effects. Two-cultivar NIR models (establishing model using two cultivars) proved to be suitable for estimating blueberry SSC with correlations over 0.83. Rp (RMSEp ) values of the three cultivar reflectance models (establishing model using 75% of three cultivars) were 0.73 (0.094) and 0.73 (0.186), respectively , for predicting blueberry firmness and elastic modulus. For SSC prediction, the three-cultivar NIR model was found to achieve an Rp (RMSEp ) value of 0.85 (0.090). Adding Bluecrop samples harvested in 2014 could enhance the three-cultivar model robustness for firmness and elastic modulus. CONCLUSION: The above results indicated the potential for using spatial and spectral techniques to develop robust models for predicting blueberry postharvest quality containing biological variability. (c) 2015 Society of Chemical Industry. PMID- 26526491 TI - (Super)hydrophobic coating of orthodontic dental devices and reduction of early oral biofilm retention. AB - This study was designed to apply (super)hydrophobic crosslinked coatings by means of a sol-gel process on the surface of orthodontic devices and investigate the potential effect of these coatings in reducing the early retention of oral biofilm. Two organosilane-based hydrophobic solutions (HSs) were prepared containing hexadecyltrimethoxysilane diluted in ethanol (HS1) or 1H, 1H, 2H, 2H perfluorodecyltriethoxysilane diluted in dimethyl sulfoxide (HS2). Stainless steel plates and ceramic discs were coated with HS1 or HS2 and heated at 150 degrees C for 2 h for condensation of a crosslinked SiO x network. Organosilane coatings were applied after previous, or no, surface sandblasting. Commercial stainless steel and ceramic brackets were used to evaluate oral biofilm retention after 12 h or 24 h of biofilm growth, using a microcosm model with human saliva as the inoculum. Surface roughness analysis (Ra, MUm) indicated that sandblasting associated with organosilane coatings increased roughness for stainless steel brackets only. Analysis of the water contact angle showed that the stainless steel surface treated with HS1 was hydrophobic (~123 degrees ), while the ceramic surface treated with HS2 was superhydrophobic (~155 degrees ). Biofilm retention after 24 h was significantly lower in groups treated with hydrophobic coatings. An exponential reduction in biofilm accumulation was associated with increased water contact angle for both stainless steel and ceramic at 24 h. Application of (super)hydrophobic coatings on the surface of stainless steel and ceramic orthodontic devices might reduce the retention of oral biofilm. PMID- 26526492 TI - CARMA3 regulates the invasion, migration, and apoptosis of non-small cell lung cancer cells by activating NF-kB and suppressing the P38 MAPK signaling pathway. AB - In our previous study, CARMA3 overexpression in lung cancer cells promoted cell proliferation and invasion; however, the mechanism underlying the role of CARMA3 in cancer cell invasion remained unclear. In the present study, knockdown of CARMA3 in A549 and H1299 cells suppressed cell invasion and migration, and downregulated matrix metalloprotease 9 expression at the protein and mRNA levels, as shown by Western blotting and real-time PCR. CARMA3 knockdown increased cell apoptosis, as shown by flow cytometry, increased the mRNA and protein expression levels of Bax and Caspase3, and downregulated Bcl-2 in A549 and H1299 cells. Phosphorylated P38 levels increased and NF-kB activation decreased following knockdown of CARMA3. SB203580, a P38 MAPK inhibitor, activated NF-kB, increased cell migration, and inhibited cell apoptosis after knockdown of CARMA3 compared to knockdown of CARMA3 without SB203580. These findings indicate that CARMA3 may suppress the activation of the P38 MAPK signaling pathway to regulate invasion, migration and apoptosis of lung cancer cells by activating NF-kB (P65) in the nucleus. PMID- 26526493 TI - Natural polyphenols based new therapeutic avenues for advanced biomedical applications. AB - Polyphenols are naturally occurring, synthetic or semisynthetic organic compounds that offer a vast array of advanced biomedical applications. The mostly researched polyphenolic compounds are resveratrol and flavanols, notably (-) epicatechin. The ongoing research on clinically important resveratrol and flavanols has revealed their potentials as extremely efficient drug agents that can be leveraged for new therapeutic designs for combating stroke related injuries, cancer and renal failures. Here, we have highlighted recent developments in this area with an emphasis on the biomedical applications of polyphenols. Also, a perspective on the future research directions has been discussed. We believe that this review would facilitate further research and development of polyphenols as a therapeutic avenue in medical science. PMID- 26526494 TI - Randomized control trial of high fidelity vs low fidelity simulation for training undergraduate students in neonatal resuscitation. AB - BACKGROUND: Knowledge acquisition and skill maintenance are important in learning neonatal resuscitation. Traditionally this is taught by using low fidelity mannequins. Technological advancement enabled a move towards high fidelity mannequins. In a low resources setting, it is incumbent to ensure reasonable cost benefit ratio before investing in technology. METHODS: A randomized control trial was conducted in 101 undergraduate students who were assigned to conventional Resusci((r)) Baby Basic or SimNewB group over a period of 3 days. The lectures were the same for both groups but the hands on training was on different mannequins. There were five experienced and accredited teachers who were standardized for training the students. Both the groups received a written test and a Megacode before and after the training, and 3 months later a post-test. RESULTS: The baseline written exam score (p = 0.07), Megacode assessment score (p = 0.19) and sex distribution (p = 0.17) were similar in both groups. Both groups showed significant improvement in the written exam score as well as in the Megacode assessment score at post-test and 3 months (retention) period. However there was no significant difference in the "improvement" between both the groups with respect to written exam (p = 0.38) or Megacode assessment (p = 0.92). Further the post-test and 3 month scores were comparable for the skills as well as content components suggesting that the skills were retained in 3 months with an opportunity of self learning them. CONCLUSIONS: Due diligence is a caveat before contemplating the acquisition of high fidelity mannequins by educational centers for neonatal resuscitation. PMID- 26526495 TI - Application of immunoaffinity purification technology as the pretreatment technology for traditional Chinese medicine: Its application to analysis of hesperidin and narirutin in traditional Chinese medicine preparations containing Citri reticulatae Pericarpium. AB - In the present study, the feasibility of immunoaffinity chromatography (IAC) as a purification technology for the analysis of bioactive components in Traditional Chinese Medicine (TCM) was evaluated. IAC was used to analyze hesperidin (HP) and narirutin (NR) in TCM preparations containing Citri reticulatae Pericarpium (CRP, Chenpi in Chinese). An IAC column for the specific extraction and enrichment of HP and NR from TCM preparations containing CRP was developed and characterized. After HP reacted with carbonyl diimidazole and coupled to protein, it was used to immune mice for the generation of antibody. Through cell fusion, cloning and screening, monoclonal antibody was obtained. The IAC column was constructed by covalently coupling specific monoclonal antibody against HP and NR to CNBr activated Sepharose 4B and packed into a common solid phase extraction cartridge. The extraction conditions including loading, washing and eluting, as well as flow rate for the extraction of HP and NR were optimized. Under optimal conditions, the maximum capacity, extraction recovery rate and stability of IAC column was also characterized. Results revealed that the maximum capacity of IAC column for HP and NR was approximately 16MUg and the relative binding capacity per 1mL of the column volume was 27MUg. The extraction recovery rate of IAC column for HP and NR at three spiked levels was in the range of 94.05-109.15%. After the repeated application for 5 times, no significant loss of specific recognition was observed. Using high performance liquid chromatography (HPLC) as an effective analytic tool, HP and NR could be successfully separated via IAC column without the inference from impurities, suggesting that the extraction of HP and NR using the prepared IAC column is feasible. The application of IAC can solve the problem of quantitative analysis due to severe interference or low content. Furthermore, pretreatment methods in different matrixes can be unified. The IAC purification procedure can be used as an alternative effective analytical method for the pretreatment of bioactive components in TCM. PMID- 26526496 TI - How to understand the results of studies of glutamine supplementation. AB - The lack of understanding of the mechanisms behind possible beneficial and possible harmful effects of glutamine supplementation makes the design of interventional studies of glutamine supplementations difficult, perhaps even hazardous. What is the interventional target, and how might it relate to outcomes? Taking one step further and aggregating results from interventional studies into meta-analyses does not diminish the difficulties. Therefore, conducting basic research seems to be a better idea than groping in the dark and exposing patients to potential harm in this darkness. PMID- 26526497 TI - The predicted sigma(54)-dependent regulator EtpR is essential for expression of genes for anaerobic p-ethylphenol and p-hydroxyacetophenone degradation in "Aromatoleum aromaticum" EbN1. AB - BACKGROUND: The denitrifying betaproteobacterium "Aromatoleum aromaticum" EbN1 anaerobically utilizes a multitude of aromatic compounds via specific peripheral degradation routes. Compound-specific formation of these catabolic modules is assumed to be mediated by specific transcriptional activators. In case of the recently elucidated p-ethylphenol/p-hydroxyacetophenone pathway, the highly substrate-specific regulation was implicated to involve the predicted sigma(54) dependent, NtrC-type regulator EbA324. The latter was suggested to control the expression of the two neighboring gene clusters encoding the catabolic enzymes as well as a corresponding putative solvent efflux system. In the present study, a molecular genetic approach was used to study the predicted function of EbA324. RESULTS: An unmarked in frame DeltaebA324 (here renamed as DeltaetpR; p ethylphenol regulator) deletion mutation was generated. The DeltaetpR mutant was unable to grow anaerobically with either p-ethylphenol or p-hydroxyacetophenone. Growth similar to the wild type was restored in the DeltaetpR mutant background by in trans expression of plasmid-born etpR. Furthermore, expression of the "p ethylphenol" gene clusters as well as corresponding protein formation was shown to depend on the presence of both, EtpR and either p-ethylphenol or p hydroxyacetophenone. In the wild type, the etpR gene appears to be constitutively expressed and its expression level not to be modulated upon effector presence. Comparison with the regulatory domains of known phenol- and alkylbenzene responsive NtrC-type regulators of Pseudomonas spp. and Thauera aromatica allowed identifying >60 amino acid residues in the regulatory domain (in particular positions 149 to 192 of EtpR) that may contribute to the effector specificity viz. presumptively restricted effector spectrum of EtpR. CONCLUSIONS: This study provides experimental evidence for the genome predicted sigma(54)-dependent regulator EtpR (formerly EbA324) of "A. aromaticum" EbN1 to be responsive to p ethylphenol, as well as its degradation intermediate p-hydroxyacetophenone, and to control the expression of genes involved in the anaerobic degradation of these two aromatic growth substrates. Overall, the presented results advance our understanding on the regulation of anaerobic aromatic compound catabolism, foremost based on the sensory discrimination of structurally similar substrates. PMID- 26526498 TI - Changing circumstances drive changing attendance: A longitudinal cohort study of time varying predictors of frequent attendance in primary health care. AB - OBJECTIVE: To investigate risk factors for frequent attendance in primary care over time, contrasting models based on baseline and time-varying characteristics. METHODS: Analysis of data from the Personality and Total Health (PATH) Through Life Project: a representative community cohort study from the Canberra region of Australia. A balanced sample of 1734 respondents, initially aged in their early 40s, were assessed on three occasions over 8 years. The survey assessed respondents' experience of chronic physical conditions, self-reported health, depression symptoms, personality, life events, socio-demographic characteristics and self-reported medication use. Survey data were linked to respondent's own administrative health service use data, and used to generate an objective measure of general practitioner (GP) consultations over a 12-month period. For each gender, respondents in the (approximate) highest decile of GP consultations at each time point were defined as frequent attenders (FAs). RESULTS: Analysis showed chronic health conditions, self- reported health, mental health and medication use measured at baseline was associated with FA status, with some gender differences evident. However taking into account of changing circumstances improved the model fit and the prediction over FA status over time. CONCLUSIONS: The study showed that there is considerable variability in frequent attender status over the study period. While baseline characteristics can predict current and future frequent attender status, it is clear that frequent attender in primary care does reflect changing circumstances over time. PMID- 26526499 TI - Normalization of Host Intestinal Mucus Layers Requires Long-Term Microbial Colonization. AB - The intestinal mucus layer provides a barrier limiting bacterial contact with the underlying epithelium. Mucus structure is shaped by intestinal location and the microbiota. To understand how commensals modulate gut mucus, we examined mucus properties under germ-free (GF) conditions and during microbial colonization. Although the colon mucus organization of GF mice was similar to that of conventionally raised (Convr) mice, the GF inner mucus layer was penetrable to bacteria-sized beads. During colonization, in which GF mice were gavaged with Convr microbiota, the small intestine mucus required 5 weeks to be normally detached and colonic inner mucus 6 weeks to become impenetrable. The composition of the small intestinal microbiota during colonization was similar to Convr donors until 3 weeks, when Bacteroides increased, Firmicutes decreased, and segmented filamentous bacteria became undetectable. These findings highlight the dynamics of mucus layer development and indicate that studies of mature microbe mucus interactions should be conducted weeks after colonization. PMID- 26526500 TI - Cholelithiasis and the risk of intrahepatic cholangiocarcinoma: a meta-analysis of observational studies. AB - BACKGROUND: The etiological factor for intrahepatic cholangiocarcinoma (ICC) is not clear. Although it has been widely accepted that intrahepatic biliary tree stone is associated with increased risk of ICC, the role of extrahepatic biliary tree stone in the incidence of ICC is controversial. In the present study we aim to evaluate the association between pre-existing choledocholithiasis and cholecystolithiasis and the risk of ICC. METHODS: PubMed, Embase, and Web of Science were searched to identify cohort and case-control studies on the association between choledocholithiasis or cholecystolithiasis and the risk of ICC. Studies that met the inclusion criteria were subjected to a meta-analysis performed with Stata statistical software. Either a fixed or random effect model was used, depending on the heterogeneity within the studies. Egger's test was performed to assess publication bias. RESULTS: Seven case-control studies met our inclusion criteria. Of the 123,771 participants, 4763 (3.85 %) were patients with ICC, and 119,008 were tumor-free controls. The presence of pre-existing bile duct stones (choledocholithiasis alone or choledocholithiasis accompanied by hepatolithiasis) was associated with the risk of ICC (odds ratio [OR] 17.64, 95 % confidence interval [CI] 11.14-27.95). Even the presence of choledocholithiasis alone (in the absence of hepatolithiasis) was associated with a high risk of ICC (OR 11.79, 95 % CI 4.17-33.35). Cholecystolithiasis may possibly contributed to the incidence of ICC (OR 2.00, 95 % CI 1.16-3.42), with large heterogeneity within studies (I (2) = 78.5 %). CONCLUSIONS: Bile duct stones including choledocholithiasis are important risk factors for ICC. Careful surveillance of patients with extrahepatic biliary tree stone should be considered. PMID- 26526501 TI - Cerebral ganglionic variations and movement behaviors of Lumbricus terrestris on exposure to neurotoxin. AB - BACKGROUND: Invertebrate worms serve as models for understanding the features of neurological functions. Acrylamide (ACR), the well-known neurotoxin, is a water soluble chemical widely used in various industrial and laboratory processes. ACR is also found in food items which are cooked under high temperature. PURPOSE: The study attempts to assess the neuropathological changes in cerebral ganglions along with the locomotion and neuronal behavior of Lumbricus terrestris on ACR intoxication. METHODS: The dosage of acrylamide induced neurotoxicity ranged from 0-17.5 mg/kg body weight for 7 days. The time/dose dependent changes in the oxidant and antioxidant status, activities of Na(+)/K(+)ATPase, Ca(2+)/Mg(2+) ATPase and 5' Nucleotidase were assessed along with the locomotor behavioral analysis. RESULT: The activities of super oxidase dismutase and catalases were not altered appreciably. However, the glutathione family, lipid peroxide, protein carbonyl content and vitamin C did show significant variations (p<0.001) in a dose-dependent manner, depicting more of oxidative stress, when compared to control worms. The activities of Na(+)/K(+) ATPase was significantly affected (p<0.001) at 3.5 mg/kg bw itself while those of both Ca(2+) and 5' Nucleotidase were found to be affected at 7.0 mg/kg bw of ACR. Mg(2+) ATPase showed significant reduction (p<0.001) in its activity only at 10.5 mg/kg bw of ACR. These dose dependent biochemical variations observed were found to be linked with the behavior of the worms as evident from the latency of movement in a dose dependent manner which is less pronounced at 7.0 mg and more pronounced at 17.5 mg/kg bw of ACR. CONCLUSION: The study suggests that ACR disrupts GSSS/GSH balance and perturbs ionic homeostasis in worms and thus affect the motor function highlighting their (GSH-ions) interrelationship in influencing neuromuscular activity. These simple analyses implicate that the cerebral ganglionic variations in the worms may be useful to appreciate the pathology of the neurological diseases (provided sophisticated analyses are employed) especially which involve movement dysfunction, where the brain tissue samples from the affected human patients are scarce. PMID- 26526502 TI - Programming Bacteriophages by Swapping Their Specificity Determinants. AB - Bacteriophages, bacteria's natural enemies, may serve as potent antibacterial agents. Their specificity for certain bacterial sub-species limits their effectiveness, but allows selective targeting of bacteria. Lu and colleagues present a platform for such targeting through alteration of bacteriophages' host specificity by swapping specificity domains in their host-recognition ligand. PMID- 26526504 TI - Vinca alkaloids in the therapeutic management of malignant pleural mesothelioma. AB - Therapeutic options for malignant pleural mesothelioma (MPM) are limited. Most patients are treated with chemotherapy during the course of their disease. The combination of pemetrexed with a platinum compound is the standard of care in the first-line setting, while no established treatment exists in the second and beyond-line setting. Vinca alkaloids are chemotherapeutic agents that have demonstrated clinical efficacy both as single agents and in combination in a broad spectrum of cancers, including MPM. Vinorelbine has shown activity in MPM patients as neoadjuvant therapy, first-line treatment, and in the second and third-line setting. Vinflunine is a derivative of vinorelbine that has been studied in MPM as first-line agent. While the role of vinca alkaloids in the first-line treatment of MPM seems marginal, treatment with vinorelbine remains a reasonable option for pemetrexed-pretreated patients in clinical practice, based on an acceptable rate of stable disease, confirmed by several trials. Ongoing studies on predictive biomarkers for vinorelbine will hopefully be able to individualize treatment, increasing response rates and survival outcomes. PMID- 26526503 TI - Game of 'Somes: Protein Destruction for Mycobacterium tuberculosis Pathogenesis. AB - The proteasome system of Mycobacterium tuberculosis is required for causing disease. Proteasomes are multisubunit chambered proteases and, until recently, were only known to participate in adenosine triphosphate (ATP)-dependent proteolysis in bacteria. In this review, we discuss the latest advances in understanding how both ATP-dependent and ATP-independent proteasome-regulated pathways contribute to M. tuberculosis virulence. PMID- 26526505 TI - Perception vs Reality: Methicillin-Resistant Staphylococcus aureus Carriage Among Healthcare Workers at a Veterans Affairs Medical Center. AB - In a prevalence study of 209 healthcare workers, 18 (8.6%) and 13 (6.2%) carried methicillin-resistant Staphylococcus aureus in their nares or on their hands, respectively. However, 100 (62%) of 162 workers completing an associated survey believed themselves to be colonized, revealing a knowledge deficit about methicillin-resistant Staphylococcus aureus epidemiology. Infect. Control Hosp. Epidemiol. 2015;37(1):110-112. PMID- 26526506 TI - Childhood exposure to ionizing radiation from computed tomography imaging in Nova Scotia. AB - BACKGROUND: Examining radiation dose in the paediatric population is particularly important due to the vulnerability of paediatric patients (increased radiosensitive tissues and postexposure life-years) and risk for future radiogenic malignancy. OBJECTIVES: To evaluate trends in paediatric computed tomography (CT) use and ionizing radiation exposure using population-based data from Nova Scotia. METHODS: A retrospective, population-based cohort study of CT use in patients <20 years of age, from January 1, 2004 to December 31, 2011, was performed in Nova Scotia. CT examination data were retrieved from a provincial imaging repository. Trends in CT use were described, and both annual and cumulative effective dose exposures were calculated. RESULTS: In total, 29,452 CT events, involving up to 22,867 individuals were retrieved. Overall annual paediatric CT examination rates remained static (range 17.4 to 18.8 per 1000 per year). However, use in children <10 years of age decreased by >50% (P<0.001); this was counterbalanced by a steady increase among 15- to 19-year-olds (P<0.0001). Overall, 15.4% of scanned patients underwent >=2 examinations, of which 58 patients (1.6%) exceeded 50 mSv of exposure. CONCLUSIONS: Despite a static rate in CT imaging among the entire cohort, children <15 years of age and, particularly, those <10 years of age displayed marked reductions in CT use. This may reflect increased awareness of campaigns emphasizing judicious CT use, revised clinical practice guidelines and increased availability of alternative modalities. A small subgroup demonstrated high-dose exposure (>50 mSv), and rates in individuals >15 years of age steadily increased, suggesting further exposure reduction efforts are necessary. PMID- 26526507 TI - Low dose ribavirin has been effective in the treatment of incapacitating muco cutaneous extrahepatic manifestations in patients with hepatitis C with contraindication or no access for approved antiviral treatment. AB - BACKGROUND AND STUDY AIMS: Chronic hepatitis C virus (HCV) is a major public health problem and represents a common cause of chronic liver disease worldwide. The Egyptian Demographic Health Survey (EDHS) has estimated HCV prevalence in Egypt to be 14.7%. HCV can affect multiple organ systems and cause a variety of extrahepatic manifestations. Most of extrahepatic manifestations affect the skin and mucous membranes; such as lichen planus (LP), psoriasis, and leucocytoclastic vasculitis. The treatment of extrahepatic manifestations has been disappointing in patients not indicated for interferon with no access for the new costly all oral treatments. PATIENTS AND METHODS: In 2014, thirty Egyptian patients with incapacitating mucocutaneous extrahepatic manifestations due to chronic HCV infection, not indicated for interferon, have been randomised into two groups; group I treated with ribavirin (5-10mg/kg daily divided into 2 doses), and group II treated with local steroids for 3months. Patients were followed up for 3months. Dermatology life quality index score has been measured before and after treatment for all patients. RESULTS: A significant improvement of mucocutaneous lesions has been accomplished in group I in comparison to group II (p<0.01). All lesions in group I showed a significant improvement except psoriasis (p>0.05). A significant improvement of dermatology life quality index score has been found in patients in group I when compared to group II (p<0.05). CONCLUSION: We conclude that low dose ribavirin was effective in the treatment of incapacitating mucocutaneous extrahepatic manifestations of chronic HCV infection in patients with contraindication or no access to the approved antiviral treatments. PMID- 26526508 TI - Complications of blind versus ultrasound-guided percutaneous liver biopsy in children. AB - BACKGROUND AND STUDY AIMS: Liver biopsy is a well-established procedure in the diagnosis and follow-up of liver diseases. Complications of liver biopsy are rare but potentially lethal. The aim of this study was to evaluate the complications of percutaneous liver biopsy and to compare the complications of blind and ultrasound-guided percutaneous liver biopsy in paediatric wards of Nemazee Hospital of Shiraz in the south of Iran. PATIENT AND METHOD: To complete the questionnaire, registered information of liver biopsies due to different causes in paediatric patients between 2008 and 2012 was retrospectively reviewed. All children aged between 0 and 18years, who underwent liver biopsy (due to any indication), participated in this study. RESULTS: Liver biopsies were obtained from 210 patients. Seven of 210 cases were excluded due to unreliable data. A total of 209 liver biopsies were done in the rest of the cases (n=203). Of all cases of liver biopsies, 22 (10.5%) experienced complications after biopsy. Pain (n=7) was the most frequent complication in 22 cases of liver biopsy. Mortality rate was one (0.5%) due to rupture of subcapsular haematoma. In terms of complication (p=0.592), there was no significant difference statistically between patients with blind liver biopsy (n=16) and patients with ultrasound-guided liver biopsy (n=6). CONCLUSION: In terms of complications, there was no significant difference when the patients were evaluated with and without ultrasound-guided biopsy. PMID- 26526509 TI - Type 1 diabetic adults should be screened for coeliac autoimmunity. PMID- 26526510 TI - Epstein-Barr virus and Interleukin-28B polymorphism in the prediction of response to interferon therapy in hepatitis C patients. AB - BACKGROUND AND STUDY AIMS: In chronic hepatitis C virus (HCV), viral and host factors are known to be predictors for anti-viral therapy. IL-28B genotype strongly influences treatment outcome, while Epstein-Barr virus (EBV) co infection could accelerate the course of chronic HCV infection. This study was conducted to assess whether EBV co-infection adds to the predictive value of IL 28B. PATIENTS AND METHODS: A total of 105 patients with chronic HCV were classified according to their response to treatment into two groups: 38 sustained virological responders (SVRs) and 67 nonresponders (NRs). Collected sera at baseline and follow-up (FUP) were used for assessing EBV antibodies by enzyme linked immunosorbent assay (ELISA) and the expression of EBV genes (BNLF-1, BZLF 1, and EBER-2) by polymerase chain reaction (PCR). Collected peripheral blood was used for detecting IL-28B rs.12979860 single-nucleotide polymorphism. RESULTS: Regarding IL-28B genotype frequencies, a significant difference (p=0.003) was observed between SVRs (C/C=51.4%, C/T=48.6%, T/T=0%) and NRs (C/C=25%, C/T=55%, T/T=20%). On assessing EBV infection at baseline and FUP, it was found that 61% and 55% were positive, respectively, with no significant difference between SVRs and NRs. As for anti-viral capsid antigen (VCA) antibodies, the NRs had significantly higher baseline anti-VCA immunoglobulin M (IgM) levels than SVRs (p=0.01). While FUP anti-Epstein-Barr nuclear antigen-1 (EBNA-1) IgG reported a significant decline within SVR patients (p=0.02), neither baseline nor FUP anti VCA IgG levels showed a statistically significant viral response. Finally, on comparing EBV markers with CC versus CT and TT genotypes, it was found that FUP anti-VCA IgG levels were significantly increased in CC genotype (p=0.003). CONCLUSION: Interleukin-28B polymorphism could be a possible predictor of response to pegylated interferon/ribavirin therapy (PEG-IFN/RBV). Furthermore, co infection with EBV did not affect the response to IFN-based therapy in HCV infected patients. PMID- 26526511 TI - Acute mesenteroaxial gastric volvulus: A rare cause of haematemesis. AB - Gastric volvulus is a rare condition that is typically characterised by abdominal pain and unproductive retching. The volvulus occurs around an axis formed by two fixed points, organoaxial or mesenteroaxial. Although a rare diagnosis, primary care providers and emergency room physicians should be aware of the telltale signs of gastric volvulus, and endoscopists should be able to recognise the endoscopic features that are suggestive of this diagnosis. Although haematemesis is a commonly encountered emergency, acute mesenteroaxial gastric volvulus is an uncommon cause. PMID- 26526512 TI - Reporting of the circumferential tumour margin involvement and preoperative levels of carcinoembryonic antigen as prognostic risk factors in colorectal cancer patients. AB - BACKGROUND AND STUDY AIMS: The two very important prognostic risk factors of colorectal cancer are circumferential tumour margin (CTM) involvement and preoperative levels of carcinoembryonic antigen (CEA). The aim of this study is to monitor the frequency of reporting of the CTM in the postoperative pathology reports after colorectal cancer resection in addition to monitoring the frequency of reporting of preoperative levels of CEA and exploring the possibility of improving the frequency of reporting of both. PATIENTS AND METHODS: Reports of the CTM and preoperative level of CEA were found in 730 (664 retrospective and 66 prospective) patients with colorectal cancer. The possibility of improving the incidence of reporting was estimated by comparing the reporting frequency of both (retrospective and prospective) groups. RESULTS: The percentage of reporting the involvement of the CTM was 46.08% and 81.81% for the retrospective group and the prospective group, respectively. The percentage of reporting the preoperative CEA levels was 40.9% and 68.7% for the retrospective and the prospective groups, respectively. There was a statistically significant difference in reporting both CTMs and the preoperative level of CEA between retrospective and prospective groups to the side of prospective group in which the p-value was <0.0001 for both groups. CONCLUSION: There was inadequate reporting of both the CTM involvement and preoperative levels of CEA in the retrospective patients with statistically significant improvement of this reporting in patients in the prospective group. This may point to the unawareness of the importance of both in the prognosis of colorectal cancer, which may be because both are not involved in the widely used tumour, node, metastasis (TNM) staging system. PMID- 26526513 TI - Tight junction protein claudin 4 in gastric carcinoma and its relation to lymphangiogenic activity. AB - BACKGROUND AND STUDY AIMS: Gastric cancer is the second most common cause of cancer-related death worldwide. Claudins are a family of tight junction proteins that are biologically relevant in many cancer progression steps. This study aimed to investigate the expression of the intestinal claudin (claudin 4) in gastric carcinoma and to evaluate its relation to the different clinicopathologic prognostic parameters, especially lymphangiogenesis (production of new lymphatic vessels, measured by lymphovascular density (LVD)) and lymphovascular invasion (LVI). PATIENTS AND METHODS: Fifty-five gastric carcinoma specimens were immunohistochemically stained for claudin 4 and D2-40 (for detection of lymphatic vessel endothelium). RESULTS: High expression of claudin 4 was detected in 26 of 55 (47.3%) cases. Low expression of claudin 4 was related to poorly differentiated type (p=0.001), non-intestinal (diffuse) type (p=0.001), deeper tumour invasion (p<0.001), lymph node metastasis (p=0.001), and higher stage (p=0.001). In addition, higher LVD was related to poorly differentiated types (p=0.001), non-intestinal type (p=0.001), lymph node metastasis (p=0.015), and higher tumour, node, metastasis (TNM) stage (p=0.001). LVI was related to lymph node metastasis (p=0.025), higher TNM stage (p=0.001), and LVD (p=0.001). Claudin 4 significantly correlated with both LVD (p=0.009) and LVI (p=0.009). CONCLUSIONS: High expression of claudin 4 was associated with the more differentiated intestinal-type gastric carcinoma and lost in poorly differentiated diffuse type. So, claudin 4 may be used as one of the differentiating markers between the two major types of gastric carcinoma (intestinal vs. diffuse). LVD and LVI were related to higher incidence of lymph node metastasis and therefore could be used as predictive markers for lymph node metastasis in limited specimens during early gastric carcinoma to determine the need for more invasive surgery. Low expression of claudin 4 was related to lymphangiogenesis. This may shed light on the relation of tight junction protein expression and lymphangiogenesis. PMID- 26526514 TI - Correction: The energetic viability of an unexpected skeletal rearrangement in cyclooctatin biosynthesis. AB - Correction for 'The energetic viability of an unexpected skeletal rearrangement in cyclooctatin biosynthesis' by Young J. Hong and Dean J. Tantillo, Org. Biomol. Chem., 2015, 13, 10273-10278. PMID- 26526515 TI - Quantification of 1H NMR Spectra from Human Plasma. AB - Human plasma is a biofluid that is high in information content, making it an excellent candidate for metabolomic studies. 1H NMR has been a popular technique to detect several dozen metabolites in blood plasma. In order for 1H NMR to become an automated, high-throughput method, challenges related to (1) the large signal from lipoproteins and (2) spectral overlap between different metabolites have to be addressed. Here diffusion-weighted 1H NMR is used to separate lipoprotein and metabolite signals based on their large difference in translational diffusion. The metabolite 1H NMR spectrum is then quantified through spectral fitting utilizing full prior knowledge on the metabolite spectral signatures. Extension of the scan time by 3 minutes or 15% per sample allowed the acquisition of a 1H NMR spectrum with high diffusion weighting. The metabolite 1H NMR spectra could reliably be modeled with 28 metabolites. Excellent correlation was found between results obtained with diffusion NMR and ultrafiltration. The combination of minimal sample preparation together with minimal user interaction during processing and quantification provides a metabolomics technique for automated, quantitative 1H NMR of human plasma. PMID- 26526516 TI - Synthesis at the Speed of Codons. AB - The possibility that different mRNA sequences encoding identical peptides are translated dissimilarly has long been of great interest. Recent work by Yu and co workers provides striking evidence that mRNA sequences influence the rate of protein synthesis, and lends support to the emerging idea that mRNA sequence informs protein folding. PMID- 26526517 TI - Reflections on the process of using systematic review techniques to evaluate the literature regarding the neurotoxicity of low level exposure to organophosphate pesticides. AB - We undertook a systematic review (incorporating meta-analysis) of the literature concerning the neurotoxicity of cumulative low level occupational exposure to organophosphate pesticides, which was published online by the journal Critical Reviews in Toxicology in 2012. As far as we are aware, we were the first research team to attempt quantitative evaluation of study findings on this topic, using meta-analysis. We wish to encourage others to apply systematic review techniques in chemical risk assessment to reduce bias, increase transparency and better inform public policy. We thought it would be useful to share our experience of undertaking a systematic review in the hope of dispelling misconceptions about the complexity, time and resource issues involved along with the view that meta analysis is meaningless when studies are not homogeneous. In this commentary paper we reflect on aspects of the process which were relatively straightforward; aspects which were more challenging; the advantages of using systematic review techniques; and the advantages and limitations of using statistical techniques such as meta-analysis in this context. PMID- 26526518 TI - Hospital variability in postoperative mortality after rectal cancer surgery in the Spanish Association of Surgeons project: The impact of hospital volume. AB - OBJECTIVE: This multicentre observational study examines variation between hospitals in postoperative mortality after elective surgery in the Rectal Cancer Project of the Spanish Society of Surgeons and explores whether hospital volume and patient characteristics contribute to any variation between hospitals. METHODS: Hospital variation was quantified using a multilevel approach on prospective data derived from the multicentre database of all rectal adenocarcinomas operated by an anterior resection or an abdominoperineal excision at 84 surgical departments from 2006 to 2013. The following variables were included in the analysis; demographics, American Society of Anaesthesiologists classification, tumour location and stage, administration of neoadjuvant treatment, and annual volume of surgical procedures. RESULTS: A total of 9809 consecutive patients were included. The rate of 30-day postoperative mortality was 1.8% Stratified by annual surgical volume hospitals varied from 1.4 to 2.0 in 30-day mortality. In the multilevel regression analysis, male gender (OR 1.623 [1.143; 2.348]; P<.008), increased age (OR: 5.811 [3.479; 10.087]; P<.001), and ASA score (OR 10.046 [3.390; 43.185]; P<.001) were associated with 30-day mortality. However, annual surgical volume was not associated with mortality (OR 1.309 [0.483; 4.238]; P=.619). Besides, there was a statistically significant variation in mortality between all departments (MOR 1.588 [1.293; 2.015]; P<.001). CONCLUSION: Postoperative mortality varies significantly among hospitals included in the project and this difference cannot be attributed to the annual surgical volume. PMID- 26526519 TI - Understanding the structural transformation, stability of medium-sized neutral and charged silicon clusters. AB - The structural and electronic properties for the global minimum structures of medium-sized neutral, anionic and cationic Sin(MU) (n = 20-30, MU = 0, -1 and +1) clusters have been studied using an unbiased CALYPSO structure searching method in conjunction with first-principles calculations. A large number of low-lying isomers are optimized at the B3PW91/6-311 + G* level of theory. Harmonic vibrational analysis has been performed to assure that the optimized geometries are stable. The growth behaviors clearly indicate that a structural transition from the prolate to spherical-like geometries occurs at n = 26 for neutral silicon clusters, n = 27 for anions and n = 25 for cations. These results are in good agreement with the available experimental and theoretical predicted findings. In addition, no significant structural differences are observed between the neutral and cation charged silicon clusters with n = 20-24, both of them favor prolate structures. The HOMO-LUMO gaps and vertical ionization potential patterns indicate that Si22 is the most chemical stable cluster, and its dynamical stability is deeply discussed by the vibrational spectra calculations. PMID- 26526520 TI - Tadalafil attenuates graft arteriosclerosis of aortic transplant in a rat model. AB - OBJECTIVES: Tadalafil can restore endothelial function and treat atherosclerosis. However, the effect of tadalafil on transplant arteriosclerosis remains unclear. In this study, we explore the effects of tadalafil on allograft vasculopathy. MATERIALS AND METHODS: Male Brow-Norway rats supplied aorta grafts for Male Lewis rats. All recipients were divided into 3 groups: saline as placebo (control) treated group, low dose tadalafil (0.5 mg/kg/day) treated group, and high dose tadalafil (1.0 mg/kg/day) treated group. Eight weeks after transplantation, the grafts were harvested at and analyzed by histological and Western blot analysis. An enzyme-linked immunosorbent assay (ELISA) was used for measure of plasma cyclic guanylate monophosphate (cGMP). RESULTS: the treatment with tadalafil significantly alleviated the neointimal thickness of aortas compared with the control group (P<0.05). Tadalafil also remarkably enhanced the production of cGMP in plasma and expression of cGMP-dependent kinase I (PKG-I) and RhoA compared with control group (P<0.05). CONCLUSION: These results showed that tadalafil can attenuate graft arteriosclerosis by cGMP -PKG-I pathway. PMID- 26526521 TI - Safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells for treatment of dogs with inflammatory bowel disease: Endoscopic and histological outcomes. AB - Systemic administration of mesenchymal stem cells (MSCs) has been shown to be safe and efficacious in humans with Crohn's disease. The aim of this study was to evaluate the safety of an intravenous (IV) infusion of adipose tissue-derived mesenchymal stem cells (ASCs) and to assess macroscopic and histological effects in the digestive tract of dogs with inflammatory bowel disease (IBD). Eleven dogs with confirmed IBD received a single ASC infusion (2 * 10(6) cells/kg bodyweight). Full digestive endoscopic evaluation was performed pre-treatment and between 90 and 120 days post-treatment with mucosal changes being assessed using a fit-for-purpose endoscopic scale. Endoscopic biopsies from each digestive section were evaluated histologically according to the World Small Animal Veterinary Association (WSAVA) Gastrointestinal Standardization Group criteria. The pre- and post-treatment canine IBD endoscopic index (CIBDEI) and histological score (HS) were calculated and compared using the Wilcoxon test. Remission was defined as a reduction of >75% of the CIBDEI and HS compared with pre-treatment. No acute reactions to ASC infusion or side effects were reported in any dog. Significant differences between pre- and post-treatment were found in both the CIBDEI (P = 0.004) and HS (P = 0.004). Endoscopic remission occurred in 4/11 dogs with the remaining dogs showing decreased CIBDEI (44.8% to 73.3%). Histological remission was not achieved in any dog, with an average reduction of the pre treatment HS of 27.2%. In conclusion, a single IV infusion of allogeneic ASCs improved gastrointestinal lesions as assessed macroscopically and slightly reduced gastrointestinal inflammation as evaluated by histopathology in dogs with IBD. PMID- 26526522 TI - Safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells for treatment of dogs with inflammatory bowel disease: Clinical and laboratory outcomes. AB - Mesenchymal stem cells (MSCs) have shown immunomodulatory and anti-inflammatory effects in experimental colitis, and promising clinical results have been obtained in humans with Crohn's disease and ulcerative colitis. The aim of this study was to determine the safety and feasibility of adipose tissue-derived MSC (ASC) therapy in dogs with inflammatory bowel disease (IBD). Eleven dogs with confirmed IBD received one ASC intravascular (IV) infusion (2 * 10(6) cells/kg bodyweight). The outcome measures were clinical response based on percentage reduction of the validated Clinical Inflammatory Bowel Disease Activity Index (CIBDAI) and Canine Chronic Enteropathy Clinical Activity Index (CCECAI), as well as normalisation of C-reactive protein (CRP), albumin, folate and cobalamin serum concentrations at day 42 post-treatment. The Wilcoxon test was used to compare variables before and after treatment. No acute reaction to ASC infusion and no side effects were reported during follow-up in any dog. Six weeks post-treatment, the CIBDAI and CCECAI decreased significantly and albumin, cobalamin and folate concentrations increased substantially. Differences in CRP concentrations pre- and post-treatment were not significant (P = 0.050). Clinical remission (defined by a reduction of initial CIBDAI and CCECAI >75%) occurred in 9/11 dogs at day 42. The two remaining dogs showed a partial response with reduction percentages of 69.2% and 71.4%. In conclusion, a single IV infusion of allogeneic ASCs was well tolerated and appeared to produce clinical benefits in dogs with severe IBD. PMID- 26526523 TI - Mechanisms of tumour resistance against chemotherapeutic agents in veterinary oncology. AB - Several classes of chemotherapy drugs are used as first line or adjuvant treatment of the majority of tumour types in veterinary oncology. However, some types of tumour are intrinsically resistant to several anti-cancer drugs, and others, while initially sensitive, acquire resistance during treatment. Chemotherapy often significantly prolongs survival or disease free interval, but is not curative. The exact mechanisms behind intrinsic and acquired chemotherapy resistance are unknown for most animal tumours, but there is increasing knowledge on the mechanisms of drug resistance in humans and a few reports on molecular changes in resistant canine tumours have emerged. In addition, approaches to overcome or prevent chemotherapy resistance are becoming available in humans and, given the overlaps in molecular alterations between human and animal tumours, these may also be relevant in veterinary oncology. This review provides an overview of the current state of research on general chemotherapy resistance mechanisms, including drug efflux, DNA repair, apoptosis evasion and tumour stem cells. The known resistance mechanisms in animal tumours and the potential of these findings for improving treatment efficacy in veterinary oncology are also explored. PMID- 26526524 TI - Canine intracranial meningiomas: Immunohistochemical evaluation of tissue factor, fibrin/fibrinogen and D-dimers. AB - The haemostatic system influences angiogenesis, cell growth and metastasis in solid tumours. The aim of this study was to investigate tissue factor (TF) expression, fibrin/fibrinogen and D-dimer deposition, as well as the occurrence of intravascular thrombosis (IVT) in canine intracranial meningiomas using immunohistochemistry. All but three (26/29) meningiomas expressed TF. TF immunolabelling was significantly higher in high-grade (grades II and III) than in low-grade (grade I) meningiomas. Fibrin/fibrinogen and D-dimer deposits were detected in all meningiomas and staining scores were statistically different between different meningioma grades. IVT was detected in 19/29 specimens, but no statistical differences were observed between different malignancy grades. In conclusion, the haemostatic system may be involved in meningioma pathobiology and may be a potential therapeutic target for canine meningiomas, as also suggested for human meningiomas. PMID- 26526525 TI - Prognostic potential of amniotic fluid analysis at birth on canine neonatal outcomes. AB - Glucose, lactate and cortisol concentrations in amniotic fluid were measured at birth in 95 pups and related to neonatal viability based on Apgar scoring and to neonatal mortality. Neither amniotic parameters nor neonatal mortality were associated with the Apgar score. Stillborn pups showed high lactate (P < 0.001) and cortisol (P < 0.05) but low glucose amniotic concentrations (P < 0.001). No amniotic fluid differences were observed between normal and malformed pups. Amniotic glucose (P < 0.001), lactate (P < 0.05) and cortisol (P < 0.05) concentrations were higher in pups delivered by vaginal parturition than by Caesarean section. Birth weight was higher in live pups than in pups dying within 48 h (P < 0.05). Although these are preliminary results, the analysis of amniotic fluid collected at birth could be a valuable predictor of neonatal outcomes in dogs. PMID- 26526526 TI - Monitoring acute equine visceral pain with the Equine Utrecht University Scale for Composite Pain Assessment (EQUUS-COMPASS) and the Equine Utrecht University Scale for Facial Assessment of Pain (EQUUS-FAP): A scale-construction study. AB - Although recognition of equine pain has been studied extensively over the past decades there is still need for improvement in objective identification of pain in horses with acute colic. This study describes scale construction and clinical applicability of the Equine Utrecht University Scale for Composite Pain Assessment (EQUUS-COMPASS) and the Equine Utrecht University Scale for Facial Assessment of Pain (EQUUS-FAP) in horses with acute colic. A cohort follow-up study was performed using 50 adult horses (n = 25 with acute colic, n = 25 controls). Composite pain scores were assessed by direct observations, Visual Analog Scale (VAS) scores were assessed from video clips. Colic patients were assessed at arrival, and on the first and second mornings after arrival. Both the EQUUS-COMPASS and EQUUS-FAP scores showed high inter-observer reliability (ICC = 0.98 for EQUUS-COMPASS, ICC = 0.93 for EQUUS-FAP, P <0.001), while a moderate inter-observer reliability for the VAS scores was found (ICC = 0.63, P <0.001). The cut-off value for differentiation between healthy and colic horses for the EQUUS-COMPASS was 5, and for differentiation between conservatively treated and surgically treated or euthanased patients it was 11. For the EQUUS-FAP, cut-off values were 4 and 6, respectively. Internal sensitivity and specificity were good for both EQUUS-COMPASS (sensitivity 95.8%, specificity 84.0%) and EQUUS-FAP (sensitivity 87.5%, specificity 88.0%). The use of the EQUUS-COMPASS and EQUUS FAP enabled repeated and objective scoring of pain in horses with acute colic. A follow-up study with new patients and control animals will be performed to further validate the constructed scales that are described in this study. PMID- 26526528 TI - Towards Clarifying the Role of O2 during the Phthalocyanine Synthesis. AB - The role of O2 within the synthesis of phthalocyanines (Pcs) has remained unclear in the past century. Here, we demonstrate that O2 , in cooperation with the solvent n-pentanol, participates in the cyclic tetramerization of phthalonitriles over the half-sandwich complex template [Lu(Pc)(acac)] (acac=acetylacetonate) and terminates the reaction at the stage of uncyclized isoindole oligomeric derivatives rather than the phthalocyanine chromophores, resulting in the isolation of the heteroleptic (phthalocyaninato)(triisoindole-1-one) lutetium double-decker complexes [(Pc)Lu(TIO-I)] (TIO-I=3,4,7,8,11,12-sexi(2,6 diisopropylphenoxy)-15-[4,5-di(2,6-diisopropylphenoxy)-2 cyanobenzimidamido]triisoindole-1-one) and [(Pc)Lu(TIO-II)] (TIO-II=3,4,7,8,11,12 sexi(2,6-dimethylphenoxy)-15-[4,5-di(2,6-dimethylphenoxy)-2 cyanobenzimidamido]triisoindole-1-one) with the help of bulky substituents at the phthalonitrile periphery and an unsubstituted phthalocyanine ligand in the double decker skeleton. Nevertheless, the cyclic tetramerization of the phthalonitriles was revealed to be sensitive to O2 with the reaction progression also depending on the oxygen concentration/content, leading to the O2 -senstive and -dependent nature for the isolation of phthalocyanine derivatives. PMID- 26526527 TI - Detection of different kidney stone types: an ex vivo comparison of ultrashort echo time MRI to reference standard CT. AB - BACKGROUND AND PURPOSE: With the development of ultrashort echo time (UTE) sequences, it may now be possible to detect kidney stones by using magnetic resonance imaging (MRI). In this study, kidney stones of varying composition and sizes were imaged using both UTE MRI as well as the reference standard of computed tomography (CT), with different surrounding materials and scan setups. METHODS: One hundred and fourteen kidney stones were inserted into agarose and urine phantoms and imaged both on a dual-energy CT (DECT) scanner using a standard renal stone imaging protocol and on an MRI scanner using the UTE sequence with both head and body surface coils. A subset of the stones representing all composition types and sizes was then inserted into the collecting system of porcine kidneys and imaged in vitro with both CT and MRI. RESULTS: All of the stones were visible on both CT and MRI imaging. DECT was capable of differentiating between uric acid and nonuric acid stones. In MRI imaging, the choice of coil and large field of view (FOV) did not affect stone detection or image quality. The MRI images showed good visualization of the stones' shapes, and the stones' dimensions measured from MRI were in good agreement with the actual values (R(2)=0.886, 0.895, and 0.81 in the agarose phantom, urine phantom, and pig kidneys, respectively). The measured T2 relaxation times ranged from 4.2 to 7.5ms, but did not show significant differences among different stone composition types. CONCLUSIONS: UTE MRI compared favorably with the reference standard CT for imaging stones of different composition types and sizes using body surface coil and large FOV, which suggests potential usefulness of UTE MRI in imaging kidney stones in vivo. PMID- 26526529 TI - d-Alanine metabolism is essential for growth and biofilm formation of Streptococcus mutans. AB - Part of the d-alanine (d-Ala) metabolic pathway in bacteria involves the conversion of l-alanine to d-Ala by alanine racemase and the formation of d alanyl-d-alanine by d-alanine-d-alanine ligase, the product of which is involved in cell wall peptidoglycan synthesis. At present, drugs that target the metabolic pathway of d-Ala are already in clinical use - e.g. d-cycloserine (DCS) is used as an antibiotic against Mycobacterium tuberculosis. Streptococcus mutans is the main cariogenic bacterium in the oral cavity. Its d-Ala metabolism-associated enzymes alanine racemase and d-alanine-d-alanine ligase are encoded by the genes smu.1834 and smu.599, respectively, which may be potential targets for inhibitors. In this study, the addition of DCS blocked the d-Ala metabolic pathway in S. mutans, leading to bacterial cell wall defects, significant inhibition of bacterial growth and biofilm formation, and reductions in extracellular polysaccharide production and bacterial adhesion. However, the exogenous addition of d-Ala could reverse the inhibitory effect of DCS. Through the means of drug regulation, our study demonstrated, for the first time, the importance of d-Ala metabolism in the survival and biofilm formation of S. mutans. If the growth of S. mutans can be specifically inhibited by designing drugs that target d-Ala metabolism, then this may serve as a potential new treatment for dental caries. PMID- 26526530 TI - Bumetanide for neonatal seizures-back from the cotside. PMID- 26526531 TI - Nonconventional MRI and microstructural cerebral changes in multiple sclerosis. AB - MRI has become the most important paraclinical tool for diagnosing and monitoring patients with multiple sclerosis (MS). However, conventional MRI sequences are largely nonspecific in the pathology they reveal, and only provide a limited view of the complex morphological changes associated with MS. Nonconventional MRI techniques, such as magnetization transfer imaging (MTI), diffusion-weighted imaging (DWI) and susceptibility-weighted imaging (SWI) promise to complement existing techniques by revealing more-specific information on microstructural tissue changes. Past years have witnessed dramatic advances in the acquisition and analysis of such imaging data, and numerous studies have used these tools to probe tissue alterations associated with MS. Other MRI-based techniques-such as myelin-water imaging, (23)Na imaging, magnetic resonance elastography and magnetic resonance perfusion imaging-might also shed new light on disease associated changes. This Review summarizes the rapid technical progress in the use of MRI in patients with MS, with a focus on nonconventional structural MRI. We critically discuss the present utility of nonconventional MRI in MS, and provide an outlook on future applications, including clinical practice. This information should allow appropriate selection of advanced MRI techniques, and facilitate their use in future studies of this disease. PMID- 26526532 TI - Neurodegenerative disease: C9orf72 repeats compromise nucleocytoplasmic transport. PMID- 26526533 TI - Stroke: Preventive antibiotics for stroke-associated pneumonia. PMID- 26526534 TI - Alzheimer disease: Evidence for trans-synaptic and exo-synaptic tau propagation in Alzheimer disease. PMID- 26526535 TI - Neurosurgery: Quick check for tumour infiltration. PMID- 26526537 TI - Alzheimer disease: Solanezumab-prospects for meaningful interventions in AD? PMID- 26526538 TI - Neurodevelopmental disorders: Deep brain stimulation alleviates hippocampal memory deficit in a mouse model of Rett syndrome. PMID- 26526539 TI - Determination of airborne wood dust in Button samples by diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). AB - Emerging concerns regarding the toxicity of inhaled wood dust support the need for techniques to quantitate wood content of mixed industrial dusts. The diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) analysis technique was applied to the determination of wood content of 181 inhalable dust samples (geometric mean concentration: 0.895 mg/m(3); geometric standard deviation: 2.73) collected from six wood product industry factories using 25mm glass fibre filters with the Button aerosol sampler. Prior to direct DRIFTS analysis the filter samples were treated with ethyl acetate and re-deposited uniformly. Standards ranging from 125 MUg to 4000 MUg were prepared for red oak, southern yellow pine, and red cedar and used for quantitation of samples depending upon the wood materials present at a given factory. The oak standards spectra were quantitated by linear regression of response in Kubelka-Munk units at 1736 cm(-1), whereas the pine standards and the cedar standards spectra were quantitated by polynomial regression of response in log 1/R units at 1734 cm(-1), with the selected wavenumbers corresponding to stretching vibration of free C=O from cellulose and hemicelluloses. For one factory which used both soft- and hardwoods, a separate polynomial standard curve was created by proportionally combining the oak and pine standards polynomial regression equations based on response (log 1/R) at 1734 cm(-1). The analytical limits of detection were approximately 52 MUg of oak, 20 MUg of pine, 30 MUg of cedar, and 16 MUg of mixed oak and pine for the factory with mixed woods. Overall, the average of dry wood dust percentage of inhalable dust was approximately 56% and the average dry wood dust weight was 0.572mg for the Button samples. Across factories, there were statistically significant differences (p<0.001) for the percentage of dry wood dust in inhalable dust with factory averages ranging from 33.5 to 97.6%. PMID- 26526540 TI - [Grade III acromioclavicular dislocation in the elderly]. PMID- 26526541 TI - Metagenomics for the discovery of pollutant degrading enzymes. AB - Organic pollutants, including xenobiotics, are often persistent and toxic organic compounds resulting from human activities and released in large amounts into terrestrial, fluvial and marine environments. However, some microbial species which are naturally exposed to these compounds in their own habitat are capable of degrading a large range of pollutants, especially poly-aromatic, halogenated and polyester molecules. These microbes constitute a huge reservoir of enzymes for the diagnosis of pollution and for bioremediation. Most are found in highly complex ecosystems like soils, activated sludge, compost or polluted water, and more than 99% have never been cultured. Meta-omic approaches are thus well suited to retrieve biocatalysts from these environmental samples. In this review, we report the latest advances in functional metagenomics aimed at the discovery of enzymes capable of acting on different kinds of polluting molecules. PMID- 26526542 TI - Cloning and characterization of GST fusion tag stabilized large subunit of Escherichia coli acetohydroxyacid synthase I. AB - There are three acetohydroxyacid synthase (AHAS, EC 4.1.3.18) isozymes (I, II, and III) in the enterobacteria Escherichia coli among which AHAS I is the most active. Its large subunit (LSU) possesses full catalytic machinery, but is unstable in the absence of the small subunit (SSU). To get applicable LSU of AHAS I, we prepared and characterized in this study the polypeptide as a His-tagged (His-LSU) and a glutathione S-transferase (GST)-tagged (GST-LSU) fusion protein, respectively. The results showed that the His-LSU is unstable, whereas the GST LSU displays excellent stability. This phenomenon suggests that the GST polypeptide fusion tag could stabilize the target protein when compared with histidine tag. It is the first time that the stabilizing effect of the GST tag was observed. Further characterization of the GST-LSU protein indicated that it possesses the basic functions of AHAS I with a specific activity of 20.8 MUmol min(-1) mg(-1) and a Km value for pyruvate of 0.95 mM. These observations imply that introduction of the GST fusion tag to LSU of AHAS I does not affect the function of the protein. The possible reasons that the GST fusion tag could make the LSU stable are initially discussed. PMID- 26526543 TI - Impacts of inoculum pre-treatments on enzyme activity and biochemical methane potential. AB - Biochemical methane potential (BMP) tests were carried out to investigate the influence of inoculum pre-treatments (filtration and pre-incubation) on methane production from cellulose and wheat straw. First-order model and Monod model were used to evaluate the kinetic constants of the BMP assays. The results demonstrated that fresh inoculum was the best option to perform BMP tests. This was evidenced by highest enzyme activity (0.11 U/mL) and highest methane yields for cellulose (356 NmL CH4/gVS) as well as wheat straw (261 NmL CH4/gVS). Besides, high biodegradability (85.8% for cellulose and 61.3% for wheat straw) was also obtained when the fresh inoculum was used. Moreover, a kinetic evaluation showed that inoculum pre-incubation at 37 degrees C or storage at 4 degrees C introduced a lag-time whereas the effects on hydrolysis rate were less consequent. In summary, pre-treatments affected the enzyme activity of the inoculum, and further on, significantly influenced the methane production and the degradation kinetics of the investigated substrates. It is recommended that filtration of inoculum should be avoided unless in case too large particles therein. PMID- 26526544 TI - The Evolution of Suidae. AB - The Suidae are a family of Cetartiodactyla composed of 17 species classified in a minimum of five extant genera that originated at least 20 million years ago. Their success is evident in the multitude of habitats in which they are found as both natural and feral populations in tropical Island Southeast Asia, the high plateau of the Himalayas, Siberia, North Africa, the Pacific Islands, Australia, and the Americas. Morphological and molecular analyses of these species have revealed numerous aspects of their biology, including the ease with which many lineages have and continue to hybridize. This trait has made them an ideal model for evolutionary biologists. Suid species have also shared a deep history with humans, from their association with early hominids in Africa to their domestication. Here we review the current knowledge of this fascinating group and provide a comprehensive evolutionary history from the Oligocene to the present day. PMID- 26526545 TI - Sperm Storage in the Female Reproductive Tract. AB - The capacity for sperm storage within the female reproductive tract occurs widely across all groups of vertebrate species and is exceptionally well developed in some reptiles (maximum duration seven years) and fishes (maximum duration >1 year). Although there are many reports on both the occurrence of female sperm storage in diverse species and its adaptive benefits, few studies have been directed toward explaining the mechanisms involved. In this article we review recent findings in birds and mammals in an effort to develop hypotheses that could be translated into research applications in animal breeding technologies. There are pockets of evidence to suggest that the local epithelial cells, sometimes arranged as sperm storage tubules, can respond to spermatozoa by producing heat shock proteins as well as providing an environment rich in antioxidants. Moreover, the local immune system seems to tolerate the arrival of spermatozoa, while retaining the ability to combat the arrival of infectious microorganisms. PMID- 26526546 TI - Milk Production and Fertility in Cattle. AB - Evolutionary biology provides reasons for why the intensive selection for milk production reduces reproductive success rates. There is considerable exploitable genetic variation in reproductive performance in both dairy and beef cattle, and examination of national genetic trends demonstrates that genetic gain for both reproductive performance and milk production is possible in a well-structured breeding program. Reproductive failure is often postulated to be a consequence of the greater negative energy balance associated with the genetic selection for increased milk production. However, experimental results indicate that the majority of the decline in reproductive performance cannot be attributed to early lactation energy balance, per se; reproductive success will, therefore, not be greatly improved by nutritional interventions aimed at reducing the extent of negative energy balance. Modeling can aid in better pinpointing the key physiological components governing reproductive success and, also, the impact of individual improvements on overall fertility, helping to prioritize variables for inclusion in breeding programs. PMID- 26526547 TI - Molecular Epidemiology of Mycobacterium avium subsp. paratuberculosis on Dairy Farms. AB - Mycobacterium avium subspecies paratuberculosis (MAP) is the etiological agent of severe chronic intestinal inflammatory disease in ruminants, termed Johne's disease, and can infect many other animal species, including humans. MAP has a long incubation period prior to manifestation of clinical signs including diarrhea, weight loss, and loss of production. MAP has a high prevalence in dairy herds and results in considerable adverse impacts on animal health and productivity throughout the world. Recent investigations have leveraged the characterization of the MAP genome for the development of powerful new molecular techniques for MAP strain differentiation. These approaches are providing key insights into the epidemiology and transmission of MAP on and between dairy herds. We summarize the state of the art for MAP diagnostics and strain differentiation and our current knowledge of mechanisms of within- and between herd transmission of MAP, along with future needs for the development of rational MAP infection control programs. PMID- 26526548 TI - Defining the Urological Chronic Pelvic Pain Syndromes. AB - From an international symposium by the National Institutes of Health, June 16-17, 2008, the mechanisms around urogenital pain (UGP) are now much more clearly understood, with a move away from considering the 'end-organ' as being responsible towards a central neuroplasticity theory and as a consequence both a multidisciplinary and interdisciplinary approach to management. PMID- 26526549 TI - JAK2/STAT3 Pathway Mediates Protection of Metallothionein Against Doxorubicin Induced Cytotoxicity in Mouse Cardiomyocytes. AB - Doxorubicin (Dox) is one of the most important anticancer agents; however, its clinical application is limited by its severe cardiotoxicity. In our previous study, we found that the gene expression levels of the Janus-activated kinase/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway were different between MT(-/-) cardiomyocytes and MT(+/+) cardiomyocytes when they were treated with Dox. Thus, this study was intended to investigate the role of JAK2/STAT3 pathway in metallothionein (MT) protection of Dox-induced cardiotoxicity. Tyrphostin AG490 (alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide) is a synthetic protein tyrosine kinase inhibitor which at first has been considered as a specific JAK2 inhibitor and can inhibit the JAK2/STAT3 signaling pathway. In the present study, AG490 was used to assess the role of JAK2/STAT3 in MT protection against Dox-induced cardiotoxicity. The AG490 can attenuate the MT protection by increasing lactate dehydrogenase and the number of apoptotic cells. Interestingly, pretreated with AG490, MT(-/-) cardiomyocytes were more sensitive than MT(+/+) to Dox-induced cytotoxicity as measured by reactive oxygen species generation, lipid peroxidation, and protein carbonylation. Metallothionein 1 and MT-2 messenger RNA were upregulated by Dox, and AG490 decreased the protein expression of MT-1 and MT-2. After Dox treatment, the protein expression of p Jak2 and p-Stat3 levels was significantly increased in MT(+/+) cardiomyocytes, suggesting that the JAK2/STAT3 pathway was partially involved in MT protection against Dox-induced cardiotoxicity. PMID- 26526550 TI - Species and tissue differences in serotonin glucuronidation. AB - 1. Serotonin is a UGT1A6 substrate that is mainly found in the extrahepatic tissues where some UGT1As are expressed. The aim of the present study was to characterize serotonin glucuronidation in various tissues of humans and rodents. 2. Serotonin glucuronidation in the human liver and kidney fitted to the Michaelis-Menten model, and the Km values were similar to that of recombinant UGT1A6. However, serotonin glucuronidation in the human intestine fitted to the Hill equation, indicating that it is likely catalyzed not only by UGT1A6, but also by another UGT1A isoform. Serotonin glucuronidation in the rat liver, intestine and kidney fitted well to the Michaelis-Menten model and exhibited monophasic kinetics in the kidney, but biphasic kinetics in the liver and intestine. Furthermore, serotonin glucuronidation in the rat brain fitted best to the Hill equation. Serotonin glucuronidation in the mouse tissues fitted to the Michaelis-Menten model and exhibited monophasic kinetics in the liver and intestine microsomes, but biphasic kinetics in the kidney and brain microsomes. 3. In conclusion, we clarified that tissue and species differences exist in serotonin glucuronidation. It is necessary to take these potential differences into account when considering the pharmacodynamics and pharmacokinetics of serotonin. PMID- 26526551 TI - Psychological Aspects and Approaches to Pain Management in Cancer Survivors. AB - Psychological distress increases with the intensity of cancer pain. Cancer pain is often under-reported and under-treated for a variety of complex reasons, including a number of beliefs held by patients, families and healthcare professionals. There is evidence that cognitive behavioural techniques that address catastrophising and promote self-efficacy lead to improved pain management. Group format pain management programmes could contribute to the care of cancer survivors with persistent pain. PMID- 26526552 TI - Taxonomic, spatial and adaptive genetic variation of Beta section Beta. AB - KEY MESSAGE: The genetic variation of Beta section Beta is structured into four taxonomic and spatial clusters. There are significant associations between molecular markers and environmental variables. ABSTRACT: We investigated the genetic diversity of Beta section Beta, which includes the wild and cultivated relatives of the sugar beet. The taxa included in the study were: Beta vulgaris subsp. maritima, B. vulgaris subsp. adanensis, B. macrocarpa, B. patula and B. vulgaris subsp. vulgaris (garden beet, leaf beet and swiss chards). We collected 1264 accessions originating from the entire distribution area of these taxa and genotyped them for 4436 DArT markers (DArTs). We showed that the genetic variation of these accessions is structured into four taxonomic and spatial clusters: (1) samples of Beta macrocarpa, (2) samples of Beta vulgaris subsp. adanensis, (3) Mediterranean and Asian samples and (4) Atlantic and Northern European samples. These last two clusters were mainly composed of samples of Beta vulgaris subsp. maritima. We investigated in deeper detail the genetic structure of B. vulgaris subsp. maritima, which constituted the majority (80%) of the wild samples. This subspecies exhibited a clinal genetic variation from South-East to North-West. We detected some markers significantly associated to environmental variables in B. vulgaris subsp. maritima. These associations are interpreted as results of natural selection. The variable most often involved in the associations was annual mean temperature. Therefore, these markers can be useful for the development of frost-tolerant winter beets and drought-tolerant rain-fed beets. PMID- 26526553 TI - Interactions between uncoupling protein 2 gene polymorphisms, obesity and alcohol intake on liver function: a large meta-analysed population-based study. AB - BACKGROUND AND OBJECTIVE: Given the role of uncoupling protein 2 (UCP2) in the accumulation of fat in the hepatocytes and in the enhancement of protective mechanisms in acute ethanol intake, we hypothesised that UCP2 polymorphisms are likely to cause liver disease through their interactions with obesity and alcohol intake. To test this hypothesis, we investigated the interaction between tagging polymorphisms in the UCP2 gene (rs2306819, rs599277 and rs659366), alcohol intake and obesity traits such as BMI and waist circumference (WC) on alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) in a large meta analysis of data sets from three populations (n=20 242). DESIGN AND METHODS: The study populations included the Northern Finland Birth Cohort 1966 (n=4996), Netherlands Study of Depression and Anxiety (n=1883) and LifeLines Cohort Study (n=13 363). Interactions between the polymorphisms and obesity and alcohol intake on dichotomised ALT and GGT levels were assessed using logistic regression and the likelihood ratio test. RESULTS: In the meta-analysis of the three cohorts, none of the three UCP2 polymorphisms were associated with GGT or ALT levels. There was no evidence for interaction between the polymorphisms and alcohol intake on GGT and ALT levels. In contrast, the association of WC and BMI with GGT levels varied by rs659366 genotype (Pinteraction=0.03 and 0.007, respectively; adjusted for age, gender, high alcohol intake, diabetes, hypertension and serum lipid concentrations). CONCLUSION: In conclusion, our findings in 20 242 individuals suggest that UCP2 gene polymorphisms may cause liver dysfunction through the interaction with body fat rather than alcohol intake. PMID- 26526554 TI - Epigenetic stability in the adult mouse cortex under conditions of pharmacologically induced histone acetylation. AB - Histone acetylation is considered a major epigenetic process that affects brain development and synaptic plasticity, as well as learning and memory. The transcriptional effectors and morphological changes responsible for plasticity as a result of long-term modifications to histone acetylation are not fully understood. To this end, we pharmacologically inhibited histone deacetylation using Trichostatin A in adult (6-month-old) mice and found significant increases in the levels of the acetylated histone marks H3Lys9, H3Lys14 and H4Lys12. High resolution transcriptome analysis of diverse brain regions uncovered few differences in gene expression between treated and control animals, none of which were plasticity related. Instead, after increased histone acetylation, we detected a large number of novel transcriptionally active regions, which correspond to long non-coding RNAs (lncRNAs). We also surprisingly found no significant changes in dendritic spine plasticity in layers 1 and 2/3 of the visual cortex using long-term in vivo two-photon imaging. Our results indicate that chronic pharmacologically induced histone acetylation can be decoupled from gene expression and instead, may potentially exert a post-transcriptional effect through the differential production of lncRNAs. PMID- 26526555 TI - Doxorubicin-Bound Albumin Nanoparticles Containing a TRAIL Protein for Targeted Treatment of Colon Cancer. AB - PURPOSE: We developed a new nanoparticle formulation comprised of human serum albumin (HSA) for co-delivery of doxorubicin (Dox) and tumor necrosis factor related apoptosis-inducing ligand (TRAIL) with the goal of apoptotic synergy in the treatment of colon cancer. METHODS: TRAIL (0.2, 0.4, 1.0%)- and Dox-loaded HSA nanoparticles (TRAIL/Dox HSA NPs) were prepared by using the nab(TM) technology. Morphological and physicochemical characterizations were investigated by dynamic light scattering and transmission electron microscopy. Synergistic cytotoxicity, apoptotic activity, and potential penetration into mass tumor were determined in HCT116 cell-based systems. Furthermore, antitumor efficacy and tumor targeting were also investigated. RESULTS: TRAIL/Dox HSA NPs were uniformly spherical with sizes of 60 ~ 120 nm. The encapsulation efficacy of Dox and TRAIL was 68.9-77.2% and 80.4-86.0%, respectively. TRAIL 1.0%/Dox HSA NPs displayed the best inhibition of HCT116 colon cancer cells; inhibition was 6 times higher than achieved with Dox HSA NPs. The TRAIL 1.0%/Dox HSA NPs formulation was studied further. Flow cytometry analysis and TUNEL assay revealed that TRAIL 1.0%/Dox HSA NPs had markedly greater apoptotic activity than Dox HSA NPs. In HCT116 tumor bearing BALB/c nu/nu mice, TRAIL 1.0%/Dox HSA NPs had significantly higher antitumor efficacy than Dox HSA NPs (tumor volume; 933.4 mm(3) vs. 3183.7 mm(3), respectively). TRAIL 1.0%/Dox HSA NPs penetrated deeply into tumor masses in a HCT116 spheroid model and localized in tumor sites after tail vein injection. CONCLUSIONS: Data indicate that TRAIL 1.0%/Dox HSA NPs offer advantages of co delivery of Dox and TRAIL in tumors, with potential synergistic apoptosis-based anticancer therapy. PMID- 26526556 TI - New reference ranges for interpreting forced expiratory manoeuvres in infants and implications for clinical interpretation: a multicentre collaboration. AB - The raised volume rapid thoracoabdominal compression (RVRTC) technique is commonly used to obtain full forced expiratory manoeuvres from infants, but reference equations derived from 'in-house' equipment have been shown to be inappropriate for current commercially available devices. AIM: To explore the impact of equipment differences on RVRTC outcomes, derive robust equipment specific RVRTC reference ranges and investigate their potential clinical impact on data interpretation. METHOD: RVRTC data from healthy subjects using Jaeger BabyBody or the 'Respiratory Analysis Software Program, RASP' systems were collated from four centres internationally. Data were excluded if gestational age <37 weeks or birth weight <2.5 kg. Reference equations for RVRTC outcomes were constructed using the LMS (lambda-mu-sigma) method, and compared with published equations using data from newborn screened infants with cystic fibrosis (CF). RESULTS: RVRTC data from 429 healthy infants (50.3% boys; 88% white infants) on 639 occasions aged 4-118 weeks were available. When plotted against length, flows were significantly higher with RASP than Jaeger, requiring construction of separate equipment-specific regression equations. When comparing results derived from the new equations with those from widely used published equations based on different equipments, discrepancies in forced expiratory volumes and flows of up to 2.5 z-scores were observed, the magnitude of which increased with age. According to published equations, 25% of infants with CF fell below the 95% limits of normal for FEV0.5, compared with only 10% when using the new equations. CONCLUSIONS: Use of equipment-specific prediction equations for RVRTC outcomes will enhance interpretation of infant lung function results; particularly during longitudinal follow-up. PMID- 26526560 TI - Investigation of Aerosol Surface Area Estimation from Number and Mass Concentration Measurements: Particle Density Effect. AB - For nanoparticles with nonspherical morphologies, e.g., open agglomerates or fibrous particles, it is expected that the actual density of agglomerates may be significantly different from the bulk material density. It is further expected that using the material density may upset the relationship between surface area and mass when a method for estimating aerosol surface area from number and mass concentrations (referred to as "Maynard's estimation method") is used. Therefore, it is necessary to quantitatively investigate how much the Maynard's estimation method depends on particle morphology and density. In this study, aerosol surface area estimated from number and mass concentration measurements was evaluated and compared with values from two reference methods: a method proposed by Lall and Friedlander for agglomerates and a mobility based method for compact nonspherical particles using well-defined polydisperse aerosols with known particle densities. Polydisperse silver aerosol particles were generated by an aerosol generation facility. Generated aerosols had a range of morphologies, count median diameters (CMD) between 25 and 50 nm, and geometric standard deviations (GSD) between 1.5 and 1.8. The surface area estimates from number and mass concentration measurements correlated well with the two reference values when gravimetric mass was used. The aerosol surface area estimates from the Maynard's estimation method were comparable to the reference method for all particle morphologies within the surface area ratios of 3.31 and 0.19 for assumed GSDs 1.5 and 1.8, respectively, when the bulk material density of silver was used. The difference between the Maynard's estimation method and surface area measured by the reference method for fractal-like agglomerates decreased from 79% to 23% when the measured effective particle density was used, while the difference for nearly spherical particles decreased from 30% to 24%. The results indicate that the use of particle density of agglomerates improves the accuracy of the Maynard's estimation method and that an effective density should be taken into account, when known, when estimating aerosol surface area of nonspherical aerosol such as open agglomerates and fibrous particles. PMID- 26526558 TI - Comparison between Ultrasound Guided Transperineal and Transrectal Prostate Biopsy: A Prospective, Randomized, and Controlled Trial. AB - This prospective study of comparing transperineal prostate biopsy (TPBx) with transrectal prostate biopsy (TRBx) was aimed to provide evidence for clinicians to select the appropriate biopsy approach under different conditions. TPBx (n = 173) and TRBx (n = 166) were performed randomly for 339 patients who were suspicious of prostate cancer (PCa). The cancer detection rate (CDR), complication rate, visual analogue scale (VAS) score, most painful procedure, number of repeated biopsy and additional anesthesia, and operating time (starting from lying down on the operating table to getting up) were recorded. The results showed that TPBx and TRBx were equivalent in CDR (35.3% vs. 31.9%) and minor complication rate (44.9% vs. 41.0%) (both P > 0.05). The major complication rate was lower in TPBx than in TRBx (0.6% vs. 4.3%, P < 0.05). TPBx was more time consuming (17.51 +/- 3.33 min vs. 14.73 +/- 3.25 min) and painful (VAS score: 4.0 vs. 2.0); and it had higher rates of repeated biopsy (3.2% vs. 1.1%) and additional anesthesia (15.0% vs. 1.2%) (all P < 0.05). In summary, both TPBx and TRBx are effective to detect PCa. The major complication rate for TRBx is higher, whereas TPBx procedure is more complex and painful. PMID- 26526561 TI - Hydrodynamic evaluation of a new dispersive aortic cannula (Stealthflow). AB - The aim of this study was to evaluate flow from a new dispersive aortic cannula (Stealthflow) in the aortic arch using flow visualization methods. Particle image velocimetry was used to analyze flow dynamics in the mock aortic model. Flow patterns, velocity distribution, and streamlines with different shape cannulas were evaluated in a glass aortic arch model. We compared flow parameters in two different dispersive type cannulas: the Stealthflow and the Soft-flow cannula. A large vortex and regurgitant flow were observed in the aortic arch with both cannulas. With the Stealthflow cannula, a high-velocity area with a maximum velocity of 0.68 m/s appeared on the ostium of the cannula in the longitudinal plane. With the Soft-flow cannula, 'multiple jet streams, each with a velocity less than 0.60 m/s, were observed at the cannula outlet. Regurgitant flow from the cannula to the brachiocephalic artery and to the ascending aorta on the greater curvature was specific to the Soft-flow cannula. The degree of regurgitation on the same site was lower with the Stealthflow cannula than with the Soft-flow cannula. The Stealthflow cannula has similar flow properties to those of the Soft-flow cannula according to glass aortic model analysis. It generates gentle flow in the aortic arch and slow flow around the ostia of the aortic arch vessels. The Stealthflow cannula is as effective as the Soft-flow cannula. Care must be taken when the patient has thick atheromatous plaque or frail atheroma on the lesser curvature of the aortic arch. PMID- 26526557 TI - The TB-specific CD4(+) T cell immune repertoire in both cynomolgus and rhesus macaques largely overlap with humans. AB - Non-human primate (NHP) models of tuberculosis (TB) immunity and pathogenesis, especially rhesus and cynomolgus macaques, are particularly attractive because of the high similarity of the human and macaque immune systems. However, little is known about the MHC class II epitopes recognized in macaques, thus hindering the establishment of immune correlates of immunopathology and protective vaccination. We characterized immune responses in rhesus macaques vaccinated against and/or infected with Mycobacterium tuberculosis (Mtb), to a panel of antigens currently in human vaccine trials. We defined 54 new immunodominant CD4(+) T cell epitopes, and noted that antigens immunodominant in humans are also immunodominant in rhesus macaques, including Rv3875 (ESAT-6) and Rv3874 (CFP10). Pedigree and inferred restriction analysis demonstrated that this phenomenon was not due to common ancestry or inbreeding, but rather presentation by common alleles, as well as, promiscuous binding. Experiments using a second cohort of rhesus macaques demonstrated that a pool of epitopes defined in the previous experiments can be used to detect T cell responses in over 75% of individual monkeys. Additionally, 100% of cynomolgus macaques, irrespective of their latent or active TB status, responded to rhesus and human defined epitope pools. Thus, these findings reveal an unexpected general repertoire overlap between MHC class II epitopes recognized in both species of macaques and in humans, showing that epitope pools defined in humans can also be used to characterize macaque responses, despite differences in species and antigen exposure. The results have general implications for the evaluation of new vaccines and diagnostics in NHPs, and immediate applicability in the setting of macaque models of TB. PMID- 26526562 TI - Enjoyment in nursing--experiences from the clinical milieu. AB - AIMS AND OBJECTIVES: To present findings from a qualitative study which aimed to explore and describe experiences of enjoyment in nursing. BACKGROUND: The topic of 'enjoying nursing' is often part of job satisfaction surveys conducted in the workplace and in some studies it has been found to be the prime reason that nurses stay in the workforce. However, there is little research which explores the concept fully. DESIGN: Qualitative in-depth interviews. METHOD: Semi structured individual interviews were conducted with 17 nurses in a local health district in Sydney, Australia. Data from digitally recorded individual interviews were transcribed and the content was analysed for themes relating to aspects of nursing that were enjoyable and others that were not. RESULTS: The major themes to emerge from the data describing enjoyment of nursing were: doing for others, supporting others and educating others. Themes that identified not enjoying nursing were related to the aggression of others, i.e. patients/clients, families or other staff in the workplace, as well as system issues. System issues referred mainly to the need for support from other nurses and management. CONCLUSION: Nurses still enjoy caring for patients and teaching others to care. This is the reason they remain in nursing even though the system and people are not always supportive or encouraging. RELEVANCE TO CLINICAL PRACTICE: Managers and educators can use these results to assist them to understand the importance of giving support to nursing staff to optimise their enjoyment of caring for their patients/clients. PMID- 26526563 TI - A team-based approach to patients in cardiogenic shock. AB - Cardiogenic shock is a common clinical condition with high in-hospital mortality. Early application of appropriate interventions for cardiogenic shock-including medical therapies, revascularization, temporary hemodynamic support devices, and durable mechanical circulatory support-may improve outcomes. The number and complexity of therapies for cardiogenic shock are increasing, making time dependent decision-making more challenging. A multidisciplinary cardiogenic shock team is recommended to guide the rapid and efficient use of these available treatments. (c) 2015 Wiley Periodicals, Inc. PMID- 26526564 TI - [Longitudinal analysis of nutrition parameters in a cohort of elderly people with and without dementia]. AB - INTRODUCTION: It is important to assess longitudinal nutritional parameters during the ageing process in order to determine body composition changes. This procedure is more relevant when dealing with institutionalised geriatric patients suffering from cognitive impairment. The aim of this study was to assess the interactions, if any, between mental status and several nutritional parameters in a cohort of elderly people. MATERIAL AND METHODS: A longitudinal prospective two years follow-up evaluation was performed on 301 elderly residents (233 females and 68 males) in a nursing home, of whom 51 of them fulfilled the clinical criteria for dementia. Both anthropometric and biochemical parameters were obtained annually, according to standard procedures. RESULTS: The dementia group had lower values when compared to the non-dementia group. Furthermore, nutritional values remained constant in the group with cognitive impairment (no significant differences were observed throughout the study period). BMI 24.5+/ 4.9 vs 24.2+/-4.1; tricipital skinfold 15.0+/-6.0 vs 14.7+/-6.9; brachial circumference 25.9+/-3.3 vs 25.7+/-3.5, and albumin 3.7+/-0.3 vs 3.7+/-0.3. At the end of the study, the group without cognitive impairment showed lower values in all the parameters analysed when compared to the baseline ones, except for bicipital fold and plasma triglycerides. CONCLUSIONS: Our study shows that there are no variations in the elderly with cognitive impairment, as regards the nutritional, anthropometric and biochemist parameters analysed. On the contrary, the group with normal cognitive status showed a reduction in most of the parameters. Further studies analysing larger populations of elderly people and over longer periods of time will provide more information to improve our knowledge on this important issue. PMID- 26526565 TI - [Impact of a multidimensional intervention in elderly patients with community acquired pneumonia: IMIEPCAP clinical trial]. AB - INTRODUCTION: The main objective of this study is to determine whether a multidimensional intervention applied to elderly patients admitted to hospital due to pneumonia reduces re-admissions and emergency department visits in the year after the intervention. METHODOLOGY: This is a single-centre non pharmacological randomised clinical trial with a parallel design. Three hundred and fourteen patients will be included (157 in each arm). Eligible patients will be >=65 years old and with a Barthel index >=60 that are admitted to hospital due to pneumonia. Participants will be randomised to multidimensional intervention or to control group. Two months after hospital discharge the intervention group will receive a geriatric intervention, carried out by a nurse and a physician. It will include assessment of co-morbidities, nutritional, functional and cognitive status, and immunisation. The control group will receive conventional follow-up. The number of re-admissions, visits to the emergency department, functional status, survival, and institutionalisation will be evaluated one year after intervention. If the intervention shows an improvement in the studied outcomes, it would allow us to improve individual outcomes, and indirectly reduce healthcare costs using a relatively simple, standardised tool. PMID- 26526567 TI - In Vitro Hemodynamic Evaluation of Five 6 Fr and 8 Fr Arterial Cannulae in Simulated Neonatal Cardiopulmonary Bypass Circuits. AB - The objective of this study was to evaluate five small-bore arterial cannulae (6Fr and 8Fr) in terms of pressure drop and hemodynamic performance in simulated neonatal cardiopulmonary bypass (CPB) circuits. The experimental circuits consisted of a Jostra HL-20 roller pump, a Terumo Capiox Baby FX05 oxygenator with integrated arterial filter, an arterial and a venous tubing (1/4, 3/16, or 1/8 in * 150 cm), and an arterial cannula (Medtronic Bio-Medicus 6Fr and 8Fr, Maquet 6Fr and 8Fr, or RMI Edwards 8Fr). The circuit was primed using lactated Ringer's solution and heparinized packed human red blood cells (hematocrit 30%). Trials were conducted at different flow rates (6Fr: 200-400 mL/min; 8Fr: 200-600 mL/min) and temperatures (35 and 28 degrees C). Flow and pressure data were collected using a custom-based data acquisition system. Higher circuit pressure, circuit pressure drop, and hemodynamic energy loss across the circuit were recorded when using small-bore arterial cannula and small inner diameter arterial tubing in a neonatal CPB circuit. The maximum preoxygenator pressures reached 449.7 +/- 1.0 mm Hg (Maquet 6Fr at 400 mL/min), and 395.7 +/- 0.4 mm Hg (DLP 8Fr at 600 mL/min) when using 1/8 in ID arterial tubing at 28 degrees C. Hypothermia further increased circuit pressure drop and hemodynamic energy loss. Compared with the others, the RMI 8Fr arterial cannula had significantly lower pressure drop and energy loss. Maquet 6Fr arterial cannula had a greater pressure drop than the DLP 6Fr. A small-bore arterial cannula and arterial tubing created high circuit pressure drop and hemodynamic energy loss. Appropriate arterial cannula and arterial tubing should be considered to match the expected flow rate. Larger cannula and tubing are recommended for neonatal CPB. Low-resistance neonatal arterial cannulae need to be developed. PMID- 26526568 TI - Is maternal anxiety a barrier to exclusive breastfeeding? AB - OBJECTIVE: To assess the association of maternal anxiety with nonadherence to exclusive breastfeeding. METHODS: This questionnaire-based study was conducted at a tertiary care teaching hospital in South India mothers with infants less than 6 months of age and not exclusively breastfeeding were interviewed and their demographic and clinical details were noted. The Iowa Infant Feeding Attitude Scale (IIFAS) and Hospital Anxiety and Depression Scale (HADS) were administered to these mothers. RESULTS: A total of 85 mother-infant dyads were included. The mean age of the mothers was 26 years and 57% were from urban areas. Among the additional feeds given, cow's milk was the commonest (57.6%), followed by gripe water (28.2%) and formula feeds (16.5%). The mean HADS anxiety subscale score was 12.2 (+/-5.3) and HADS depression subscale score was 9.5 (+/-3.8). The mean score on IIFAS was 58.4 (+/-3.6) suggesting a relatively favorable attitude toward breastfeeding. On linear regression analysis, higher HADS depression score, lower birth weight and lower per capita income were independent predictors of poorer attitudes toward breastfeeding. CONCLUSION: Maternal anxiety may be an independent risk factor for nonadherence to exclusive breastfeeding for the initial six months. PMID- 26526569 TI - Steroidogenesis: The Classics and Beyond. PMID- 26526566 TI - Immunocytokines: a novel class of products for the treatment of chronic inflammation and autoimmune conditions. AB - Antibody-cytokine fusion proteins, often referred to as immunocytokines, represent a novel class of biopharmaceutical agents that combine the disease homing activity of certain antibodies with the immunomodulatory properties of cytokine payloads. Originally, immunocytokines were mainly developed for cancer therapy applications. More recently, however, the use of anti-inflammatory cytokines for the treatment of chronic inflammatory conditions and to treat autoimmune diseases has been considered. This review analyzes basic principles in the design of immunocytokines and describes the most advanced products in preclinical and clinical development. PMID- 26526570 TI - The Construct and Measurement of Perceived Risk of Nonremunerated Blood Donation: Evidence from the Chinese Public. AB - The perceived risk of nonremunerated blood donation (NRBD) is one of the most important factors which hinder the Chinese public from donating blood. To understand deeply and measure scientifically the public's perceived risk of NRBD, in this paper the qualitative and quantitative methods were used to explore the construct of perceived risk of NRBD in Chinese context. Firstly, the preliminary construct of perceived risk of NRBD was developed based on the grounded theory. Then, a measurement scale of perceived risk of NRBD was designed. Finally, the exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were adopted for testing and verifying the construct. The results show that the construct of perceived risk of NRBD has three core dimensions, namely, trust risk, psychological risk, and health risk, which provides a clear construct and concise scale to better capture the Chinese public's perceived risk of NRBD. Blood collection agencies can strategically make polices about perceived risk reduction to maximize the public's NRBD behavior. PMID- 26526571 TI - Pipette vial dispersive liquid-liquid microextraction combined with high performance liquid chromatography for the determination of benzoylurea insecticide in fruit juice. AB - A simple, sensitive, and efficient method of using a pipette vial to perform dispersive liquid-liquid microextraction based on the solidification of floating organic droplets was coupled with high-performance liquid chromatography (HPLC) and a diode array detector for the preconcentration and analysis of four benzoylurea insecticides in fruit juice. In this method, 1-dodecanol was used as an extractant, and a snipped pipette was used as an experimental vial to simplify the procedure of collecting and separating solidified extractant. The experimental parameters were optimized using a Plackett-Burman design and one factor-at-a-time method. Under the optimal conditions in the water model, the limits of detection for analytes varied from 0.03 to 0.28 MUg/L, and the enrichment factors ranged from 147 to 206. Linearity was achieved for diflubenzuron and flufenoxuron in a range of 0.5-500 MUg/L, for hexaflumuron in a range of 1-500 MUg/L, and for triflumuron in a range of 5-500 MUg/L. The correlation coefficients for the analytes ranged from 0.9986 to 0.9994 with recoveries of 91.4-110.9%. Finally, the developed technique was successfully applied to fruit juice samples with acceptable results. The relative standard deviations of the analytes at two spiking levels (50 and 200 MUg/L) varied between 0.2 and 4.5%. PMID- 26526572 TI - Natural transformation occurs independently of the essential actin-like MreB cytoskeleton in Legionella pneumophila. AB - Natural transformation is the process by which bacteria can actively take up and integrate exogenous DNA thereby providing a source of genetic diversity. Under specific growth conditions the coordinated expression of several genes--a situation referred to as "competence"--allows bacteria to assemble a highly processive and dedicated system that can import high molecular weight DNA. Within the cell these large imported DNA molecules are protected from degradation and brought to the chromosome for recombination. Here, we report elevated expression of mreB during competence in the Gram-negative pathogen Legionella pneumophila. Interestingly a similar observation had previously been reported in the distantly related Gram-positive organism Bacillus subtilis. MreB is often viewed as the bacterial actin homolog contributing to bacterial morphogenesis by coordinating peptidoglycan-synthesising complexes. In addition MreB is increasingly found to be involved in a growing number of processes including chromosome segregation and motor-driven motility. Using genetic and pharmacological approaches, we examined the possible role of MreB during natural transformation in L. pneumophila. Our data show that natural transformation does not require MreB dynamics and exclude a direct role of MreB filaments in the transport of foreign DNA and its recombination in the chromosome. PMID- 26526573 TI - Deregulation of miR-1, miR486, and let-7a in cytogenetically normal acute myeloid leukemia: association with NPM1 and FLT3 mutation and clinical characteristics. AB - Cytogenetically normal acute myeloid leukemia (CN-AML) constitutes the largest subgroup of AML patients that is associated with molecular alteration. MiRNAs have been shown to be aberrantly expressed in CN-AML. In addition, specific miRNA (miR) expression patterns were found to be associated with certain genetic alterations in these patients. This study investigated the expression level of miR-1, miR-486, and let-7a in 45 CN-AML patients well characterized for FLT3 and/or NPM1 mutations using real-time quantitative RT-PCR and evaluated the association between candidate miRs expression and clinical features. Our data revealed that miR-1 was significantly overexpressed in CN-AML patients, and increasing expression of miR-1 correlated with NPM1 mutation (P < 0.05) and lower hemoglobin level was also observed in patients with miR-1 overexpression (P < 0.05). The expression of miR-1 was much higher in AML-M2 compared with other subtypes. Further, we found significantly increasing miR-486 expression in 40 of 45 (89 %) CN-AML patients. There was no significant association of upregulation of miR-486 with clinical parameters. The expression level of miR-486 was increased in AML-M2 subtype. The levels of let-7a were significantly increased in CN-AML patients compared to the healthy control and significantly higher in the NPM1 +/- CN-AML patients. There was no correlation detected between the level of let-7a and FLT3+. An increasing expression level of let-7a was demonstrated in M2 subtype. In addition, our data showed no significant association between increasing let-7a and clinical characteristic. Comparison of peripheral blood and bone marrow results in 30 CN-AML patients showed that there is a considerable concordance between PB and BM in the results of candidate miR levels (P < 0.001). In conclusion, further studies should also be performed to detect functional mechanism of these miRs. PMID- 26526574 TI - Predictive significance of combined LAPTM4B and VEGF expression in patients with cervical cancer. AB - Lysosome-associated protein transmembrane 4beta-35 (LAPTM4B-35) is overexpressed in several solid malignancies. This study determines the expression level of LAPTM4B-35 in the cervical cancer during tumor development and progression. The present study investigated the clinicopathological significance of the coexpression of LAPTM4B-35 and VEGF in patients with cervical cancer. Immunohistochemistry was used to evaluate the expression of LAPTM4B-35 and VEGF in 62 cervical intraepithelial neoplasia (CIN) and 226 cervical carcinoma in comparison with 45 normal cervical specimens. The correlation of combined LAPTM4B 35 and VEGF with clinicopathologic characteristics was analyzed using a chi squared test. Patient survival was determined using Kaplan-Meier method and log rank test. A Cox regression analysis was performed to determine the prognostic significance of the factors. Combined LAPTM4B-35 and VEGF expression was significantly associated with FIGO stage (P = 0.014), tumor histologic grade (P = 0.033), lymph node metastasis (P = 0.045), and recurrence (P = 0.010). Kaplan Meier survival analysis showed that patients with cervical cancer expressing both LAPTM4B-35 and VEGF exhibited both poor overall survival (OS) and disease-free survival (DFS) (P = 0.015 and P = 0.016, respectively). Cox analysis demonstrated that combined LAPTM4B-35 and VEGF expression was an independent factor for both OS and DFS (P = 0.015 and P = 0.016, respectively). Overexpression of LAPTM4B 35combined with positive VEGF expression may serve as a new biological marker to predict the prognosis of cervical carcinoma patients. PMID- 26526575 TI - Effects of the GSK-3beta inhibitor (2Z,3E)-6-bromoindirubin-3'-oxime upon ovarian cancer cells. AB - Ovarian cancer (OC) is a deadly disease, and despite improvements in treatment, overall 5-year survival is low. Glycogen synthase kinase (GSK)-3beta is a multifunctional serine/threonine kinase. We wished to ascertain if the GSK-3beta inhibitor (2Z,3E)-6-bromoindirubin-3'-oxime, known as "BIO," can suppress OC development. The OC cell lines A2780 and OVCAR3 were exposed to BIO. At different time points, cell proliferation, apoptosis, cell cycle, and cell invasion/cell migration assays were carried out. Phalloidin staining was undertaken to observe lamellipodia formation. Real-time reverse transcription-polymerase chain reaction and western blotting were used to assess expression of messenger RNA (mRNA) and protein of GSK-3beta, cyclin D1, matrix metalloproteinase (MMP)-9, and p21. BIO suppressed the proliferation, invasion, and migration of OC cells; reduced lamellipodia formation; and induced G1 arrest of the cell cycle. BIO exposure led to a significant downregulation of mRNA and protein expression of cyclin D1 and MMP9 in comparison with untreated control cells. In contrast, BIO exposure upregulated mRNA and protein expression of p21 in comparison with untreated control cells. Besides, GSK-3beta small interfering RNA (siRNA) transfection in ovarian cancer cells also downregulated GSK-3beta, cyclin D1, and MMP9 protein expression while upregulated p21 expression. These data suggest that BIO, as an inhibitor of GSK-3beta, can suppress OC development. Therefore, BIO could be a candidate drug for the treatment of OC. PMID- 26526576 TI - RASSF4 is downregulated in nonsmall cell lung cancer and inhibits cancer cell proliferation and invasion. AB - RASSF4 has been implicated as a tumor suppressor in several human cancers. Its clinical significance and biological characteristics in human nonsmall cell lung cancer (NSCLC) have not been explored yet. In this study, we explored expression pattern of RASSF4 in 89 NSCLC specimens. The results showed that RASSF4 was downregulated in 36/89 NSCLC tissues compared with normal tissue. RASSF4 downregulation significantly associated with advanced TNM stage, positive nodal status, and poor prognosis. We examined RASSF4 protein expression in normal lung epithelial cell line and lung cancer lines. We found that RASSF4 expression was downregulated in four of seven lung cancer cell lines compared with normal bronchial epithelial cells. RASSF4 plasmid transfection was performed in H460 and A549 cell lines. RASSF4 overexpression inhibited proliferation, colony formation, and invading ability. In addition, we identified that RASSF4 could inhibit cell cycle progression with downregulation of cyclin D1. Expression of invasion related protein MMP2, MMP9 was also decreased. In conclusion, the present study suggested that RASSF4 serves as an important tumor suppressor in NSCLC. PMID- 26526577 TI - Nuclear Gli1 expression is associated with pathological complete response and event-free survival in HER2-positive breast cancer treated with trastuzumab-based neoadjuvant therapy. AB - Aberrant activation of the hedgehog (Hh) signaling pathway has shown predictive significance for treatment response and prognostic effect for survival in human tumors. However, the associations of the Hh signaling pathway with response to neoadjuvant therapy (NAT) and survival after NAT in breast cancer are unknown. Therefore, we investigated the correlation of pretherapeutic nuclear expression of glioma-associated oncogene homolog 1 (Gli1), a key transcriptional factor of the Hh signaling pathway, with pathological complete response (pCR) and event free survival (EFS) in HER2-positive breast cancer treated with trastuzumab-based NAT. High nuclear Gli1 expression (OR 0.19; 95 % CI 0.07-0.54; P = 0.002) and positive hormone receptor (HR) status (OR 0.36; 95 % CI 0.14-0.90; P = 0.028) were independent and negative predictors of pCR in multivariate analysis. High nuclear Gli1 expression was significantly associated with lower pCR rates in both HR-positive and HR-negative tumors (P = 0.014 and 0.024, respectively). For survival analyses, multivariate analysis indicated that high nuclear Gli1 expression was the only independent predictor of poorer EFS in both the entire population (hazard ratio 2.97; 95 % CI 1.18-7.44; P = 0.020) and patients with non-pCR (hazard ratio 3.98; 95 % CI 1.35-11.68; P = 0.012). Our study is the first to demonstrate the associations of high nuclear Gli1 expression with resistance to trastuzumab-based NAT and subsequent worse prognosis in HER2 positive disease. These findings suggest that the nuclear Gli1 protein may be a novel target of NAT for HER2-positive breast cancer. PMID- 26526578 TI - Genetic polymorphisms in MMP 2, 3, 7, and 9 genes and the susceptibility and clinical outcome of cervical cancer in a Chinese Han population. AB - Matrix metalloproteases (MMPs) are proteolytic enzymes that contribute to all stages of tumor progression, including the invasion and metastasis. However, there are no data about the role of MMP polymorphism in the development of cervical cancer. A hospital-based case-control study was conducted in 230 patients with cervical cancer and 230 healthy controls to investigate the possible association between the MMP2 rs243865, MMP3 rs3025058, MMP7 rs11568818, and MMP9 rs3918242 polymorphisms, respectively, and the risk of cervical cancer. Our results suggested that the MMP2 rs243865-1306 C/T was significantly associated with an increased risk of cervical cancer (CT vs. CC, OR = 1.46; 95 % CI 1.18-3.55; P = 0.032; TT vs. CC, OR = 1.72; 95 % CI 1.28-4.02; P = 0.031; CT + TT vs. CC, OR = 1.43; 95 % CI 1.21-3.44; P = 0.029). Similarly, the MMP7 rs11568818-181A/G genotypes can also elevate the risk of cervical cancer in all genetic models. However, the genotype and allele frequencies of MMP3 rs3025058 and MMP9 rs3918242 polymorphisms in cervical cancer patients were not significantly different from controls. Further analysis showed MMP2 rs243865 and MMP7 rs11568818 genotypes were associated with advanced tumor stages of cervical cancer patients. More interestingly, the MMP2 rs243865 and MMP7 rs11568818 genotype was statistically significantly associated with a poor survival in cervical cancer patients. Our results showed that the MMP2 rs243865 and MMP7 rs11568818 genotypes e were associated with increased susceptibility and development of cervical cancer in Chinese Han population. PMID- 26526579 TI - Mammary serine protease inhibitor and CD138 immunohistochemical expression in ovarian serous and clear cell carcinomas. AB - This study aims to investigate the immunohistochemical expression of mammary serine protease inhibitor (maspin) and CD138 in primary ovarian high-grade serous carcinomas (HGSC) as compared to low-grade serous carcinomas (LGSC) and clear cell carcinomas and investigate if the studied markers have a correlation to International Federation of Gynaecology and Obstetrics (FIGO) stage, Ki67 proliferation index, and to each other. Maspin cellular location varied significantly between studied groups with only nuclear expression seen in 46.7 % of LGSC group, mixed nuclear and cytoplasmic in 13.3, 28.6, and 20 % of LGSC, HGSC, and clear cell carcinoma, respectively, and was only cytoplasmic in 26.7, 71.4, and 80 % of LGSC, HGSC, and clear cell carcinoma, respectively. Mean maspin and CD138 counts were significantly higher in HGSC and clear cell carcinoma compared to LGSC. Both maspin and CD138 scores varied significantly between studied groups and were positively correlated with adverse prognostic factors in studied carcinomas including FIGO stage and Ki67 proliferation index. Besides, both maspin and CD138 had significant correlation to each other. These findings suggest that epithelial cytoplasmic expression of maspin and CD138 may have a significant role in tumorigenesis in ovarian high-grade serous carcinomas and clear cell carcinomas; these markers may regulate tumor cell proliferation, and their significant correlation to each other may suggest that CD138 probably induces maspin expression to protect tumor growth factors from being lysed by proteolytic enzymes. PMID- 26526580 TI - Hotspot TERT promoter mutations are rare events in testicular germ cell tumors. AB - The abnormal activation of telomerase, codified by the telomerase reverse transcriptase (TERT) gene, is related to one of cancer hallmarks. Hotspot somatic mutations in the promoter region of TERT, specifically the c.-124:C>T and c. 146:C>T, were recently identified in a range of human cancers and have been associated with a more aggressive behavior. Testicular germ cell tumors frequently exhibit a good prognosis; however, the development of refractory disease is still a clinical challenge. In this study, we aim to evaluate for the first time the presence of the hotspot telomerase reverse transcriptase gene promoter mutations in testicular germ cell tumors. A series of 150 testicular germ cell tumor cases and four germ cell tumor cell lines were evaluated by PCR followed by direct Sanger sequencing and correlated with patient's clinical pathological features. Additionally, we genotyped the telomerase reverse transcriptase gene promoter single nucleotide polymorphism rs2853669 (T>C) located at -245 position. We observed the presence of the TERT promoter mutation in four patients, one exhibited the c.-124:C>T and three the c.-146:C>T. No association between TERT mutation status and clinicopathological features could be identified. The analysis of the rs2853669 showed that variant C was present in 22.8 % of the cases. In conclusion, we showed for the first time that TERT promoter mutations occur in a small subset (~3 %) of testicular germ cell tumors. PMID- 26526581 TI - Radiosensitisation of human glioma cells by inhibition of beta1,6-GlcNAc branched N-glycans. AB - Gliomas are the most prevalent type of primary brain tumors and are resistant to radiation therapy. beta1,6-GlcNAc branched N-glycans, which are encoded by N acetylglucosaminyltransferase V (GnT-V), play important roles in glioma progression. However, the relationship between beta1,6-GlcNAc branched expression and radiosensitivity in glioma cells is still unknown. In this study, the expression of beta1,6-GlcNAc branched N-glycans in nonneoplastic brain and glioma samples was characterized by lectin histochemistry. The radiosensitivity of glioma cells was evaluated by colony formation assay. We found that beta1,6 GlcNAc branches were highly expressed in glioblastoma specimens, compared with diffuse astrocytomas and nonneoplastic brain. In addition, beta1,6-GlcNAc branched expression was negatively correlated with the radiosensitivity of glioblastoma cells. Furthermore, the inhibition of N-linked beta1,6-GlcNAc branches by GnT-V silencing in U251 cells could reduce the cell clonogenic survival after X-irradiation. Meanwhile, the G2/M checkpoint was impaired and there was an increase in the number of apoptotic cells. Tunicamycin, an inhibitor of N-glycan biosynthesis, was also able to enhance the radiosensitivity of U251 cells. Thus, our results suggest that development of therapeutic approaches targeting N-linked beta1,6-GlcNAc branches may be a promising strategy in glioblastoma treatment. PMID- 26526582 TI - Prognostic tissue biomarker exploration for patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors. AB - In metastatic renal cell carcinoma (mRCC), the prognostic role of several tumor tissue biomarkers has been evaluated, but the results were controversial. This study aims to verify the prognostic importance of selected tumor tissue biomarkers in patients with mRCC. The clinicopathological features, immunohistochemical staining and scoring for select tissue biomarkers, treatment, and outcome of patients with mRCC treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) between July 2006 and March 2011 at Asan Medical Center in Seoul, South Korea, were reviewed. In total, 123 patients met the inclusion criteria. Most patients had clear-cell carcinoma (107 patients, 87.0 %). First-line VEGFR TKIs were sunitinib (97 patients, 78.9 %), sorafenib (23 patients, 18.7 %), and pazopanib (3 patients, 2.4 %). With a median follow-up period of 60.0 months (95 % confidence interval (CI), 56.3-63.6), median overall survival (OS) and progression-free survival (PFS) were 25.6 months (95 % CI, 19.2-32.0) and 12.2 months (95 % CI, 8.1-16.3), respectively. In the multivariable analysis for OS, carbonic anhydrase IX (CAIX; 47.5 % or less vs. more than 47.5 %, p = 0.014), sarcomatoid change (40 % or less vs. more than 40 %, p < 0.001), tumor necrosis (20 % or less vs. more than 20 %, p = 0.006), and Heng's risk group (good vs. intermediate vs. poor, p = 0.011) were identified as independent prognostic factors. In the multivariable analysis for PFS, CAIX (p < 0.001), phosphatase and tensin homolog (PTEN; 45 % or less vs. more than 45 %, p = 0.004), sarcomatoid change (p = 0.002), and tumor necrosis (p = 0.001) were identified as independent factors affecting PFS. CAIX and PTEN had prognostic importance for mRCC patients receiving first-line VEGFR TKI. Future validation and mechanistic studies are required. PMID- 26526583 TI - Rapamycin inhibited the function of lung CSCs via SOX2. AB - The presence of cancer stem cells (CSCs) is the source of occurrence, aggravation, and recurrence of lung cancer. Accordingly, targeting killing the lung CSCs has been suggested to be an effective approach for lung cancer treatment. In this study, we showed that rapamycin inhibited the mammalian target of rapamycin (mTOR) signal transduction in A549 cells and improved the sensitivity to cisplatin (DDP). The mechanisms involve inhibition of the SOX2 expression, cell proliferation, epithelial-mesenchymal transition (EMT) phenotype, and sphere formation. Interestingly, knocked down SOX2 was a similar effect with rapamycin in A549 sphere. Furthermore, we showed that ectopic expression of Sox2 in A549 cells was sufficient to render them more resistant to rapamycin treatment in vitro. These data suggested that rapamycin inhibited the function of lung CSCs via SOX2. It will be of great interest to further explore the therapeutic strategies of lung cancer. PMID- 26526584 TI - No improvement of neuronal metabolism in the reperfusion phase with melatonin treatment after hypoxic-ischemic brain injury in the neonatal rat. AB - Mitochondrial impairment is a key feature underlying neonatal hypoxic-ischemic (HI) brain injury and melatonin is potentially neuroprotective through its effects on mitochondria. In this study, we have used (1) H and (13) C NMR spectroscopy after injection of [1-(13) C]glucose and [1,2-(13) C]acetate to examine neuronal and astrocytic metabolism in the early reperfusion phase after unilateral HI brain injury in 7-day-old rat pups, exploring the effects of HI on mitochondrial function and the potential protective effects of melatonin on brain metabolism. One hour after hypoxia-ischemia, astrocytic metabolism was recovered and glycolysis was normalized, whereas mitochondrial metabolism in neurons was clearly impaired. Pyruvate carboxylation was also lower in both hemispheres after HI. The transfer of glutamate from neurons to astrocytes was higher whereas the transfer of glutamine from astrocytes to neurons was lower 1 h after HI in the contralateral hemisphere. Neuronal metabolism was equally affected in pups treated with melatonin (10 mg/kg) immediately after HI as in vehicle treated pups indicating that the given dose of melatonin was not capable of protecting the neuronal mitochondria in this early phase after HI brain injury. However, any beneficial effects of melatonin might have been masked by modulatory effects of the solvent dimethyl sulfoxide on cerebral metabolism. Neuronal and astrocytic metabolism was examined by (13) C and (1) H NMR spectroscopy in the early reperfusion phase after unilateral hypoxic-ischemic brain injury and melatonin treatment in neonatal rats. One hour after hypoxia-ischemia astrocytic mitochondrial metabolism had recovered and glycolysis was normalized, whereas mitochondrial metabolism in neurons was impaired. Melatonin treatment did not show a protective effect on neuronal metabolism. PMID- 26526585 TI - Opinion: Labour Analgesia in the Developing World; Why Not. AB - The provision of western-style safe, highly effective labour analgesia requires levels of training, staffing and technology that make its applicability in the developing world in current circumstances questionable. This review examines the reasons. PMID- 26526586 TI - The lipid moiety of brincidofovir is required for in vitro antiviral activity against Ebola virus. AB - Brincidofovir (BCV) is the 3-hexadecyloxy-1-propanol (HDP) lipid conjugate of the acyclic nucleoside phosphonate cidofovir (CDV). BCV has established broad spectrum activity against double-stranded DNA (dsDNA) viruses; however, its activity against RNA viruses has been less thoroughly evaluated. Here, we report that BCV inhibited infection of Ebola virus in multiple human cell lines. Unlike the mechanism of action for BCV against cytomegalovirus and other dsDNA viruses, phosphorylation of CDV to the diphosphate form appeared unnecessary. Instead, antiviral activity required the lipid moiety and in vitro activity against EBOV was observed for several HDP-nucleotide conjugates. PMID- 26526587 TI - Requirement of the eukaryotic translation initiation factor 4F complex in hepatitis E virus replication. AB - Hepatitis E virus (HEV) infection, one of the foremost causes of acute hepatitis, is becoming a health problem of increasing magnitude. As other viruses, HEV exploits elements from host cell biochemistry, but we understand little as to which components of the human hepatocellular machinery are perverted for HEV multiplication. It is, however, known that the eukaryotic translation initiation factors 4F (eIF4F) complex, the key regulator of the mRNA-ribosome recruitment phase of translation initiation, serves as an important component for the translation and replication of many viruses. Here we aim to investigate the role of three subunits of the eIF4F complex: eukaryotic translation initiation factor 4A (eIF4A), eukaryotic translation initiation factor 4G (eIF4G) and eukaryotic translation initiation factor 4E (eIF4E) in HEV replication. We found that efficient replication of HEV requires eIF4A, eIF4G and eIF4E. Consistently, the negative regulatory factors of this complex: programmed cell death 4 (PDCD4) and eIF4E-binding protein 1 (4E-BP1) exert anti-HEV activities, which further illustrates the requirement for eIF4A and eIF4E in supporting HEV replication. Notably, phosphorylation of eIF4E induced by MNK1/2 activation is not involved in HEV replication. Although ribavirin and interferon-alpha (IFN-alpha), the most often-used off-label drugs for treating hepatitis E, interact with this complex, their antiviral activities are independent of eIF4E. In contrast, eIF4E silencing provokes enhanced anti-HEV activity of these compounds. Thus, HEV replication requires eIF4F complex and targeting essential elements of this complex provides important clues for the development of novel antiviral therapy against HEV. PMID- 26526588 TI - Targeting host lipid synthesis and metabolism to inhibit dengue and hepatitis C viruses. AB - Lipids are necessary for every step in the replication cycle of hepatitis C virus (HCV) and dengue virus (DENV), members of the family Flaviviridae. Recent studies have demonstrated that discrete steps in the replication cycles of these viruses can be inhibited by pharmacological agents that target host factors mediating lipid synthesis, metabolism, trafficking, and signal transduction. Despite this, targeting host lipid metabolism and trafficking as an antiviral strategy by blockade of entire pathways may be limited due to host toxicity. Knowledge of the molecular details of lipid structure and function in replication and the mechanisms whereby specific lipids are generated and trafficked to the relevant sites may enable more targeted antiviral strategies without global effects on the host cell. In this review, we discuss lipids demonstrated to be critical to the replication cycles of HCV and DENV and highlight potential areas for anti-viral development. This review article forms part of a symposium on flavivirus drug discovery in Antiviral Research. PMID- 26526589 TI - Synergistic antiviral activity of gemcitabine and ribavirin against enteroviruses. AB - Enteroviruses are major causative agents of various human diseases, and some of them are currently considered to be an enormous threat to public health. However, no effective therapy is currently available for the treatment of these infections. We identified gemcitabine, a nucleoside-analog drug used for cancer treatment, from a screen of bioactive chemicals as a novel inhibitor of coxsackievirus B3 (CVB3) and enterovirus 71 (EV71). Gemcitabine potently inhibited the proliferation of CVB3 and EV71, as well as the replication of CVB3 and EV71 replicons, in cells with a low micromolar IC50 (1-5 MUM). Its strong inhibitory effect was also observed in cells infected with human rhinoviruses, demonstrating broad-spectrum antiviral effects on enteroviruses. Mechanistically, an extensive analysis excluded the involvement of 2C, 3A, IRES-dependent translation, and also that of polyprotein processing in the antiviral effects of gemcitabine. Importantly, gemcitabine in combination with ribavirin, an antiviral drug currently being used against a few RNA viruses, exhibited a synergistic antiviral effect on the replication of CVB3 and EV71 replicons. Consequently, our results clearly demonstrate a new indication for gemcitabine as an effective broad-spectrum inhibitor of enteroviruses and strongly suggest a new therapeutic strategy using gemcitabine alone or in combination with ribavirin for the treatment of various diseases associated with enterovirus infection. PMID- 26526590 TI - The non-pathogenic Henipavirus Cedar paramyxovirus phosphoprotein has a compromised ability to target STAT1 and STAT2. AB - Immune evasion by the lethal henipaviruses, Hendra (HeV) and Nipah virus, is mediated by its interferon (IFN) antagonist P gene products, phosphoprotein (P), and the related V and W proteins, which can target the signal transducer and activator of transcription 1 (STAT1) and STAT2 proteins to inhibit IFN/STAT signaling. However, it is not clear if the recently identified non-pathogenic Henipavirus, Cedar paramyxovirus (CedPV), is also able to antagonize the STAT proteins. We performed comparative studies between the HeV P gene products (P/V/W) and CedPV-P (CedPV does not encode V or W) and demonstrate that differences exist in their ability to engage the STAT proteins using immunoprecipitation and quantitative confocal microscopic analysis. In contrast to HeV-P gene encoded proteins, the ability of CedPV-P to interact with and relocalize STAT1 or STAT2 is compromised, correlating with a reduced capacity to inhibit the mRNA synthesis of IFN-inducible gene MxA. Furthermore, infection studies with HeV and CedPV demonstrate that HeV is more potent than CedPV in inhibiting the IFN-alpha-mediated nuclear accumulation of STAT1. These results strongly suggest that the ability of CedPV to counteract the IFN/STAT response is compromised compared to HeV. PMID- 26526591 TI - Brachytelephalangic chondrodysplasia punctata caused by new small hemizygous deletion in a boy presenting with hearing loss. AB - X-linked recessive type chondrodysplasia punctata (CDPX1) is a congenital disorder of cartilage and bone development with typical findings of stippled epyphises, nasomaxillary hypoplasia and short distal phalanges in a male patient. Disease is caused due to the loss of arylsulfatase E activity and only 55 patients with genetically confirmed disease have been reported so far. In 60-75 % of all patients the mutation in ARSE gene is detected by sequence analysis and in further 25 % of patients Xp deletions or rearrangements are causative and may be identified by classical chromosome studies. We report on a male patient refered to clinical geneticist for congenital hearing loss and mild dysplastic signs, both phenotypic features being relatively unspecific and non suggestive of CDPX1 in first instance. Array comparative genomic hybridisation showed approximatelly 3 kb big deletion, spaning intron and exon 7 of arylsulfatase E gene located in Xp22.33. This explained the cause of hearing loss, being present in 26-89 % od CDPX1 patients, as well as additional non prominent skeletal characteristics described by geneticist in our patient - mild midface hypoplasia and mild brachytelephalangy. Reported case introduces different presenting clinical phenotype for CDPX1, emphasizing different expressivity in this disorder. PMID- 26526592 TI - Selective Control of the Upper Extremity Scale: validation of a clinical assessment tool for children with hemiplegic cerebral palsy. AB - AIM: The ability to determine the relationship between selective motor control and upper extremity function in children with unilateral cerebral palsy (CP), and to measure the functional outcome and efficacy of interventions designed to improve selective motor control, has been limited by the lack of an objective, validated tool. The primary objective of this study is to describe the development of a clinical tool entitled Selective Control of the Upper Extremity Scale (SCUES), and present evidence of its validity and reliability. METHOD: Content validity was established through an expert panel (eight clinicians, mean and median of 17y of clinical experience, range 2-30y). Intra- and interrater reliability was determined by six occupational therapists who scored 10 participant studies. Construct validity of the SCUES was established by comparison to the spontaneous functional analysis section of the Shriners Hospitals Upper Extremity Evaluation, the Manual Ability Classification System, and the Box and Block test for 25 children with unilateral CP. RESULTS: The content validity ratio values were greater than 0 (indicating >50% agreement) for 33 of the 34 items (97%), and equal or greater than 0.5 (indicating >=75% agreement) for 26 of the 34 items (76%). Intrarater reliability was excellent (intraclass correlation coefficient [ICC] >0.75) for all segments and joints of the affected extremity. Interrater reliability was excellent for all segments and joints of the affected extremity except the shoulder (ICC=0.72). The SCUES was strongly correlated with the SHUEE (Spearman's rho=0.69, p=0.003). The SCUES was not correlated with the Manual Ability Classification System (rho=-0.24, p=0.369) or the Box and Block test (rho=0.47, p=0.066). INTERPRETATION: Psychometric analysis of the SCUES revealed comparable validity to other accepted video-based clinical assessment tools for the upper extremity in children with CP. PMID- 26526594 TI - Erratum to: Difficulties in deciding whether to ablate patients with putatively "low-intermediate-risk" differentiated thyroid carcinoma: do guidelines mainly apply in the centres that produce them? Results of a retrospective, two-centre quality assurance study. PMID- 26526593 TI - Linezolid induced retinopathy. AB - PURPOSE: While optic neuropathy is a well-known cause of visual disturbances in linezolid-treated patients, the possibility of linezolid-related retinopathy has not been investigated. Here, we report a case of retinopathy demonstrated by multifocal electroretinogram (mfERG) in a linezolid-treated patient. METHOD AND RESULTS: A 61-year-old man with extensively drug-resistant pulmonary tuberculosis treated with linezolid for 5 months presented with painless loss of vision in both eyes. The patient's best corrected visual acuity was 20/50 in the right eye and 20/100 in the left eye. Fundus examination revealed mild disc edema, and color vision was defective in both eyes. Humphrey visual field tests showed a superotemporal field defect in the right eye and central and pericentral field defect in the left eye. Optical coherence tomography (OCT) revealed only mild optic disc swelling. In mfERG, central amplitudes were depressed in both eyes. Four months after the cessation of linezolid, visual acuity was restored to 20/20 right eye and 20/25 left eye. The color vision and visual field had improved. The OCT and mfEFG findings improved as well. CONCLUSIONS: Although the clinical features were similar to linezolid-induced optic neuropathy, the mfERG findings suggest the possibility of a retinopathy through cone dysfunction. PMID- 26526595 TI - The Young EANM Committee survey. PMID- 26526596 TI - Comparative Effectiveness of Oral Versus Outpatient Parenteral Antibiotic Therapy for Empyema. AB - BACKGROUND: Treatment of pediatric parapneumonic empyema (PPE) requires several weeks of antibiotic therapy that is typically completed in the outpatient setting. The route of outpatient therapy can be oral or intravenous (outpatient parenteral antibiotic therapy [OPAT]). No studies have compared outcomes between oral therapy and OPAT for PPE. METHODS: We identified children <18 years hospitalized from 2005 to 2014 at Primary Children's Hospital with PPE and discharged with oral therapy or OPAT. The primary outcome was the percentage of children who experienced all-cause complications after discharge. Complications included those that were related to pneumonia (including treatment failure, defined as readmission with reaccumulation of pleural fluid or abscess requiring drainage) or antibiotic therapy (eg, allergy, line clot) resulting in either a hospital readmission or emergency department/urgent care visit. All-cause complications were compared between oral therapy and OPAT by using propensity score-weighted logistic regression. RESULTS: A total of 391 children were hospitalized with PPE; 337 (86%) were discharged with OPAT; 35 (9%) children experienced an all-cause complication, including 5 with oral (9.3%) and 30 (8.9%) with OPAT. Pneumonia and treatment-related complications were comparable (P = .25 and .78, respectively). Two patients treated with OPAT (1%) experienced treatment failure. After adjustment using propensity score weighting, the frequency of complications was similar between groups (adjusted odds ratio 0.97, 95% confidence interval 0.23-4.65). CONCLUSIONS: The frequency of complications was similar with oral therapy and OPAT for children with PPE. Oral antibiotics may be considered safe and effective for children with PPE who will be discharged to complete therapy in the outpatient setting. PMID- 26526597 TI - Toward Optimal Outpatient Therapy for Pediatric Parapneumonic Empyema. PMID- 26526598 TI - Cerebrospinal fluid protein and glucose examinations and tuberculosis:?Will laboratory safety regulations force a change of practice? AB - Cerebrospinal fluid (CSF) protein and glucose examinations are usually performed in chemical pathology departments on autoanalysers. Tuberculosis (TB) is a group 3 biological agent under Directive 2000/54/EC of the European Parliament but in the biochemistry laboratory, no extra precautions are taken in its analysis in possible TB cases. The issue of laboratory practice and safety in the biochemical analyses of CSF specimens, when tuberculosis infection is in question is addressed in the context of ambiguity in the implementation of current national and international health and safety regulations. Additional protective measures for laboratory staff during the analysis of CSF TB samples should force a change in current laboratory practice and become a regulatory issue under ISO 15189. Annual Mantoux skin test or an interferon-gamma release assay for TB should be mandatory for relevant staff. This manuscript addresses the issue of biochemistry laboratory practice and safety in the biochemical analyses of CSF specimens when tuberculosis infection is in question in the context of the ambiguity of statutory health and safety regulations. PMID- 26526600 TI - Novel 4- Aryl-2(1H)-phthalazinone Derivatives as Cyclooxygenase-2 Inhibitors: Synthesis, Molecular Modeling Study and Evaluation as Promising Anti-inflammatory Agents. AB - BACKGROUND: Inflammation is a natural reaction of our body in response to infection or any other injury to renovate that damage. The majority of the available Non-steroidal anti-inflammatory drugs is nonselective and consequently, causes gastric irritation and ulceration. Therefore, it is a beard to design and synthesize a new series of Non-steroidal anti-inflammatory drugs with minimal gastric complications. METHODS: A series of novel 4-(3,4-dimethylphenyl)-2(1H) phthalazinone derivatives were designed, synthesized and evaluated for their in vivo anti-inflammatory activity. The compounds that showed powerful anti inflammatory activities were assessed for their in vitro COX-1/COX-2 inhibitory activity and their in vivo ulcerogenic profile. The interaction between the designated compounds and the binding pocket of the COX-2 enzyme was predicted by molecular docking stimulation. RESULTS: Six compounds, 2, 4, 5, 7a, 7b, and 8b showed significant anti-inflammatory activities at 4h compared to standard drug celecoxib. Compounds 4, 5, and 8b were the most potent and selective COX-2 inhibitors. Moreover, all the screened compounds demonstrated higher gastric safety profile compared to celecoxib particularly compound 8b displayed the highest safety profile. Among the tested compounds, 8b displayed the best fitting score, the highest antiinflammatory activity and COX-2 selectivity with minimal ulcer score. CONCLUSION: A new series of phthalazinone derivatives were successfully synthesized and were evaluated for their in vivo anti-inflammatory activity. Six compounds (2, 4, 5, 7a, 7b, and 8b) presented powerful anti inflammatory activity compared to celecoxib. Moreover, compounds 4, 5 and 8b were the most potent inhibitors to COX-2 and were inactive to COX-1. The screened compounds showed better ulcer protection and less gastric lesion compared to celecoxib. Compound 8b was the most promising candidate with more gastric safety. PMID- 26526601 TI - Use of a new low profile Occlutech PLD device for closure of Fontan fenestrations. AB - For some higher risk patients, fenestrations are still created in total cavopulmonary connection conduits completing the Fontan circulation for univentricular hearts. If these fenestrations remain patent and hemodynamics are favorable, they are closed to improve oxygenation and exercise tolerance and to decrease the risk of paradoxical emboli. Depending on the type of fenestration, different devices are used. Unfortunately, the search for the ideal device is still ongoing. We propose the first experience with the off-label use of the new Occlutech paravalvular leak device. This device offers the combination of a small delivery sheath size, high flexibility, less material, and a low profile. The low profile in particular could be an advantage in order to reduce the risk of thrombus formation in the low velocity flow environment of the Fontan circulation. (c) 2015 Wiley Periodicals, Inc. PMID- 26526599 TI - Walker 256 tumor-bearing rats demonstrate altered interstitial cells of Cajal. Effects on ICC in the Walker 256 tumor model. AB - BACKGROUND: Cachexia is a significant problem in patients with cancer. The effect of cancer on interstitial cells of Cajal (ICC) and neurons of the gastrointestinal tract have not been studied previously. Although supplementation with L-glutamine 2% may have beneficial effects in cancer-related cachexia, and be protective of ICC in models of oxidative stress such as diabetes, its effects on ICC in cancer have also not been studied. METHODS: Twenty-eight male Wistar rats were divided into four groups: control (C), control supplemented with L glutamine (CG), Walker 256 tumor (WT), and Walker 256 tumor supplemented with L glutamine (WTG). Rats were implanted with tumor cells or injected with saline in the right flank. After 14 days, the jejunal tissues were collected and processed for immunohistochemical techniques including whole mounts and cryosections and Western blot analysis. KEY RESULTS: Tumor-bearing rats demonstrate reduced numbers of Myenteric ICC and deep muscular plexus ICC and yet increased Ano1 protein expression and enhanced ICC networks. In addition, there is more nNOS protein expressed in tumor-bearing rats compared to controls. L-glutamine treatment had a variety of effects on ICC that may be related to the disease state and the interaction of ICC and nNOS neurons. Regardless, L-glutamine reduced the size of tumors and also tumor-induced cachexia that was not due to altered food intake. CONCLUSIONS & INFERENCES: There are significant effects on ICC in the Walker 256 tumor model. Although supplementation with L-glutamine has differential and complex effects of ICC, it reduces tumor size and tumor associated cachexia, which supports its beneficial therapeutic role in cancer. PMID- 26526602 TI - Chronic care management coding for neurologists. AB - Chronic care management provides a way for neurologists to code for time spent by clinical office staff who coordinate services for patients with major chronic illnesses. Medicare allows payment for one such code; some third party payers accept 2 additional codes. When using these codes, the physician develops a Care Plan that organizes the patient's medical and psychosocial needs. Clinical office staff communicates among the patient's physicians, therapists, community services, the patient, family, and caregiver. The patient chooses only one physician whose office provides these coordination services. Rules include 24/7 access for urgent phone contact and use of an electronic health record system. PMID- 26526603 TI - 3D high-density localization microscopy using hybrid astigmatic/ biplane imaging and sparse image reconstruction. AB - Localization microscopy achieves nanoscale spatial resolution by iterative localization of sparsely activated molecules, which generally leads to a long acquisition time. By implementing advanced algorithms to treat overlapping point spread functions (PSFs), imaging of densely activated molecules can improve the limited temporal resolution, as has been well demonstrated in two-dimensional imaging. However, three-dimensional (3D) localization of high-density data remains challenging since PSFs are far more similar along the axial dimension than the lateral dimensions. Here, we present a new, high-density 3D imaging system and algorithm. The hybrid system is implemented by combining astigmatic and biplane imaging. The proposed 3D reconstruction algorithm is extended from our state-of-the art 2D high-density localization algorithm. Using mutual coherence analysis of model PSFs, we validated that the hybrid system is more suitable than astigmatic or biplane imaging alone for 3D localization of high density data. The efficacy of the proposed method was confirmed via simulation and real data of microtubules. Furthermore, we also successfully demonstrated fluorescent-protein-based live cell 3D localization microscopy with a temporal resolution of just 3 seconds, capturing fast dynamics of the endoplasmic recticulum. PMID- 26526604 TI - Systematic review of cognitive behavioural therapy for the management of headaches and migraines in adults. AB - AIM: This systematic review aimed to establish if cognitive behavioural therapy (CBT) can reduce the physical symptoms of chronic headache and migraines in adults. METHODS: Evidence from searches of eight databases was systematically sought, appraised and synthesised. Screening of title and abstracts was conducted independently by two reviewers. Full papers were screened, data extracted and quality assessed by one reviewer and checked by a second. Data were synthesised narratively by intervention due to the heterogeneity of the studies. The inclusion criteria specified randomised controlled trials with CBT as an intervention in adults suffering from chronic headaches/migraines not associated with an underlying pathology/medication overuse. CBT was judged on the basis of authors describing the intervention as CBT. The diagnosis of the condition had to be clinician verified. Studies had to include a comparator and employ headache/migraine-specific outcomes such as patient-reported headache days. RESULTS: Out of 1126 screened titles and abstracts and 20 assessed full papers, 10 studies met the inclusion criteria of the review. Some studies combined CBT with another intervention, as well as employing varying numbers of comparators. CBT was statistically significantly more effective in improving some headaches related outcomes in CBT comparisons with waiting lists (three studies), in combination with relaxation compared with relaxation only (three studies) or antidepressant medication (one study), with no statistically significant differences in three studies. CONCLUSIONS: The findings of this review were mixed, with some studies providing evidence in support of the suggestion that people experiencing headaches or migraines can benefit from CBT, and that CBT can reduce the physical symptoms of headache and migraines. However, methodology inadequacies in the evidence base make it difficult to draw any meaningful conclusions or to make any recommendations. PMID- 26526605 TI - Post-glucose-load urinary C-peptide and glucose concentration obtained during OGTT do not affect oral minimal model-based plasma indices. AB - The purpose of this study was to investigate how renal loss of both C-peptide and glucose during oral glucose tolerance test (OGTT) relate to and affect plasma derived oral minimal model (OMM) indices. All individuals were recruited during family screening between August 2007 and January 2011 and underwent a 3.5-h OGTT, collecting nine plasma samples and urine during OGTT. We obtained the following three subgroups: normoglycemic, at risk, and T2D. We recruited South Asian and Caucasian families, and we report separate analyses if differences occurred. Plasma glucose, insulin, and C-peptide concentrations were analyzed as AUCs during OGTT, OMM estimate of renal C-peptide secretion, and OMM beta-cell and insulin sensitivity indices were calculated to obtain disposition indices. Post glucose load glucose and C-peptide in urine were measured and related to plasma based indices. Urinary glucose corresponded well with plasma glucose AUC (Cau r = 0.64, P < 0.01; SA r = 0.69, P < 0.01), S I (Cau r = -0.51, P < 0.01; SA r = 0.41, P < 0.01), Phi dynamic (Cau r = -0.41, P < 0.01; SA r = -0.57, P < 0.01), and Phi oral (Cau r = -0.61, P < 0.01; SA r = -0.73, P < 0.01). Urinary C-peptide corresponded well to plasma C-peptide AUC (Cau r = 0.45, P < 0.01; SA r = 0.33, P < 0.05) and OMM estimate of renal C-peptide secretion (r = 0.42, P < 0.01). In general, glucose excretion plasma threshold for the presence of glucose in urine was ~10-10.5 mmol L(-1) in non-T2D individuals, but not measurable in T2D individuals. Renal glucose secretion during OGTT did not influence OMM indices in general nor in T2D patients (renal clearance range 0-2.1 %, with median 0.2 % of plasma glucose AUC). C-indices of urinary glucose to detect various stages of glucose intolerance were excellent (Cau 0.83-0.98; SA 0.75-0.89). The limited role of renal glucose secretion validates the neglecting of urinary glucose secretion in kinetic models of glucose homeostasis using plasma glucose concentrations. Both C-peptide and glucose in urine collected during OGTT might be used as non-invasive measures for endogenous insulin secretion and glucose tolerance state. PMID- 26526606 TI - Radiosynthesis and 'click' conjugation of ethynyl-4-[(18)F]fluorobenzene--an improved [(18)F]synthon for indirect radiolabeling. AB - Reproducible methods for [(18)F]radiolabeling of biological vectors are essential for the development of new [(18)F]radiopharmaceuticals. Molecules such as carbohydrates, peptides and proteins are challenging substrates that often require multi-step indirect radiolabeling methods. With the goal of developing more robust, time saving, and less expensive procedures for indirect [(18)F]radiolabeling of such molecules, our group has synthesized ethynyl-4 [(18)F]fluorobenzene ([(18)F]2, [(18)F]EYFB) in a single step (14 +/- 2% non decay corrected radiochemical yield (ndc RCY)) from a readily synthesized, shelf stable, inexpensive precursor. The alkyne-functionalized synthon [(18)F]2 was then conjugated to two azido-functionalized vector molecules via CuAAC reactions. The first 'proof of principle' conjugation of [(18)F]2 to 1-azido-1-deoxy-beta-D glucopyranoside (3) gave the desired radiolabeled product [(18)F]4 in excellent radiochemical yield (76 +/- 4% ndc RCY (11% overall)). As a second example, the conjugation of [(18)F]2 to matrix-metalloproteinase inhibitor (5), which has potential in tumor imaging, gave the radiolabeled product [(18)F]6 in very good radiochemical yield (56 +/- 12% ndc RCY (8% overall)). Total preparation time for [(18)F]4 and [(18)F]6 including [(18)F]F(-) drying, two-step reaction (nucleophilic substitution and CuAAC conjugation), two HPLC purifications, and two solid phase extractions did not exceed 70 min. The radiochemical purity of synthon [(18)F]2 and the conjugated products, [(18)F]4 and [(18)F]6, were all greater than 98%. The specific activities of [(18)F]2 and [(18)F]6 were low, 5.97 and 0.17 MBq nmol(-1), respectively. PMID- 26526607 TI - Inhibition of lipid oxidation in frozen farmed ovate pompano (Trachinotus ovatus L.) fillets stored at -18 degrees C by chitosan coating incorporated with citric acid or licorice extract. AB - BACKGROUND: Lipid oxidation can occur in fish fillets during long-term frozen storage and cause quality and nutrition loss, which is a major concern in the seafood industry. Our previous study showed that chitosan combined with citric acid or licorice extract can have a preserving effect on fresh fish fillets stored at 4 degrees C. It is of interest to further study their antioxidant effects on fish fillets during frozen storage. RESULTS: Chitosan, chitosan and citric acid, chitosan and licorice extract can inhibit primary and secondary lipid oxidation, as indicated by lower peroxide value (PV) and thiobarbituric acid reactive substances (TBARS) values compared to the control samples. In addition, drip loss was decreased in the treatment samples. Both citric acid and licorice extract enhanced the antioxidant effects of chitosan. Among all the three treatments, chitosan and licorice extract showed the best antioxidant effects, reducing both PV and TBARS significantly at the end of storage. CONCLUSION: The combination of chitosan and citric acid or licorice extract showed significant antioxidant effects on ovate pompano fillets at -18 degrees C during 6 months of storage. They could be applied as natural antioxidant preservatives for use in seafood products or other meat products. (c) 2015 Society of Chemical Industry. PMID- 26526608 TI - Enhanced cell apoptosis triggered by a multi modal mesoporous amphiphilic drug delivery system. AB - Mesoporous magnetic nanoparticles (MMNPs) have been synthesized through a facile soft chemical route and are conjugated with multiple therapeutic agents. These MMNPs have the ability to contain and deliver both hydrophilic and hydrophobic drugs simultaneously with the mediation of an AC magnetic field (ACMF). Furthermore, the synthesis and characterization of doxorubicin hydrochloride:paclitaxel (DOX:TXL) and doxorubicin hydrochloride:cisplatin (DOX:Cis-Pt) conjugates are demonstrated. MMNPs show an excellent loading efficiency of ~96:83% (DOX:TXL) and ~93:83% (DOX:Cis-Pt) along with a loading capacity of ~0.002:0.002 mg mg(-1) (DOX:TXL) and ~0.002:0.002 mg mg(-1) (DOX:Cis Pt), respectively. Over a period of 180 h, a sustained release of drugs is observed and shows a better efficiency at pH 4.3 (~85:63%-DOX:TXL and ~86:73% DOX:Cis-Pt) compared to that under physiological pH conditions (~28:22%-DOX:TXL and ~26:22%-DOX:Cis-Pt). The MMNPs can release ~37:22% (DOX:TXL) and ~34:25% (DOX:Cis-Pt) within 30 min when triggered by an ACMF (at ~43 degrees C). The in vitro cytotoxic effect, the ROS generation level and cell cycle distribution analysis of DOX:TXL-MMNPs and DOX:Cis-Pt-MMNPs treated MDA-MB231, MCF-7 and PC3 cancer cells are demonstrated. Enhanced cell apoptosis is observed by thermo chemotherapy which includes application of an ACMF for 15 min. Specifically, DOX:TXL-MMNPs are more effective than DOX:Cis-Pt-MMNPs towards the PC3 cell line. The internalization of multiple drug loaded MMNPs by cells and their morphological changes due to thermo-chemotherapy are confirmed through confocal microscopy. From the present results, it is observed that the DOX:TXL and DOX:Cis Pt conjugated MMNPs, under an ACMF, can readily minimize drug resistance. This has significantly enhanced the cell apoptosis of target cancer cells. PMID- 26526609 TI - An analysis of discrepancies between United Kingdom cancer research funding and societal burden and a comparison to previous and United States values. AB - BACKGROUND: Ideally, the allocation of research funding for each specific type of cancer should be proportional to its societal burden. This burden can be estimated with the metric 'years of life lost' (YLL), which combines overall mortality and age at death. METHODS: Using United Kingdom data from 2010, we compared research funding from the National Cancer Research Institute to this YLL burden metric for 26 types of cancers in order to identify the discrepancies between cancer research funding allocation and societal burden. We also compared these values to United States data from 2010 and United Kingdom data published in 2005. RESULTS: Our study revealed a number of discrepancies between cancer research funding and burden. Some cancers are funded at levels far higher than their relative burden suggests (testicular, leukaemia, Hodgkin's lymphoma, breast, cervical, ovarian, prostate) while other cancers appear under-funded (gallbladder, lung, nasopharyngeal, intestine, stomach, pancreatic, thyroid, oesophageal, liver, kidney, bladder, and brain/central nervous system). United Kingdom funding patterns over the past decade have generally moved to increase funding to previously under-funded cancers with one notable exception showing a converse trend (breast cancer). The broad relationship between United Kingdom and United States funding patterns is similar with a few exceptions (e.g. leukaemia, Hodgkin's lymphoma, prostate, testicular cancer). CONCLUSIONS: There are discrepancies between cancer research funding allocation and societal burden in the United Kingdom. These discrepancies are broadly similar in both the United Kingdom and the United States and, while they appear to be improving, this is not consistent across all types of cancer. PMID- 26526610 TI - Cell fate determination, neuronal maintenance and disease state: The emerging role of transcription factors Lmx1a and Lmx1b. AB - LIM-homeodomain (LIM-HD) proteins are evolutionary conserved developmental transcription factors. LIM-HD Lmx1a and Lmx1b orchestrate complex temporal and spatial gene expression of the dopaminergic pathway, and evidence shows they are also involved in adult neuronal homeostasis. In this review, the multiple roles played by Lmx1a and Lmx1b will be discussed. Controlled Lmx1a and Lmx1b expression and activities ensure the proper formation of critical signaling centers, including the embryonic ventral mesencephalon floor plate and sharp boundaries between lineage-specific cells. Lmx1a and Lmx1b expression persists in mature dopaminergic neurons of the substantia nigra pars compacta and the ventral tegmental area, and their role in the adult brain is beginning to be revealed. Notably, LMX1B expression was lower in brain tissue affected by Parkinson's disease. Actual and future applications of Lmx1a and Lmx1b transcription factors in stem cell production as well as in direct conversion of fibroblast into dopaminergic neurons are also discussed. A thorough understanding of the role of LMX1A and LMX1B in a number of disease states, including developmental diseases, cancer and neurodegenerative diseases, could lead to significant benefits for human healthcare. PMID- 26526611 TI - The closed conformation of the LDL receptor is destabilized by the low Ca(++) concentration but favored by the high Mg(++) concentration in the endosome. AB - The LDL receptor (LDLR) internalizes LDL and VLDL particles. In the endosomes, it adopts a closed conformation important for recycling, by interaction of two modules of the ligand binding domain (LR4-5) and a beta-propeller motif. Here, we investigate by SPR the interactions between those two modules and the beta propeller. Our results indicate that the two modules cooperate to bind the beta propeller. The binding is favored by low pH and by high [Ca(++)]. Our data show that Mg(++), at high concentration in the endosome, favors the formation of the closed conformation by replacing the structuring effect of Ca(++) in LR5. We propose a sequential model of LDL release where formation of the close conformation follows LDL release. PMID- 26526612 TI - Co-silencing of human Bub3 and dynein highlights an antagonistic relationship in regulating kinetochore-microtubule attachments. AB - We previously reported that the spindle assembly checkpoint protein Bub3 is involved in regulating kinetochore-microtubule (KT-MT) attachments. Also, Bub3 was reported to interact with the microtubule motor protein dynein. Here we examined how this interaction contributes to KT-MT attachments. Depletion of Bub3 or dynein induced misaligned chromosomes, consistent with their role in KT-MT attachments. Unexpectedly, co-silencing of both proteins partially suppressed the misalignment phenotype and restored chromosome congression. Consistent with these observations, KT-MT attachments in co-depleted cells were stable, able to drive chromosome congression, and produce inter- and intra-kinetochore stretch, indicating they are functional. We suggest that a mutual antagonism exists between Bub3 and dynein to ensure optimal KT-MT attachments. PMID- 26526614 TI - PIP1 aquaporins: Intrinsic water channels or PIP2 aquaporin modulators? AB - The highly conserved plant aquaporins, known as Plasma membrane Intrinsic Proteins (PIPs), are the main gateways for cell membrane water exchange. Years of research have described in detail the properties of the PIP2 subfamily. However, characterizing the PIP1 subfamily has been difficult due to the failure to localize to the plasma membrane. In addition, the discovery of the PIP1-PIP2 interaction suggested that PIP1 aquaporins could be regulated by a complex posttranslational mechanism that involves trafficking, heteromerization and fine tuning of channel activity. This review not only considers the evidence and findings but also discusses the complexity of PIP aquaporins. To establish a new benchmark in PIP regulation, we propose to consider PIP1-PIP2 pairs as functional units for the purpose of future research into their physiological roles. PMID- 26526615 TI - Caspase-3 cleaved p65 fragment dampens NF-kappaB-mediated anti-apoptotic transcription by interfering with the p65/RPS3 interaction. AB - Caspase-3-mediated p65 cleavage is believed to suppress nuclear factor-kappa B (NF-kappaB)-mediated anti-apoptotic transactivation in cells undergoing apoptosis. However, only a small percentage of p65 is cleaved during apoptosis, not in proportion to the dramatic reduction in NF-kappaB transactivation. Here we show that the p65(1-97) fragment generated by Caspase-3 cleavage interferes with ribosomal protein S3 (RPS3), an NF-kappaB "specifier" subunit, and selectively retards the nuclear translocation of RPS3, thus dampening the RPS3/NF-kappaB dependent anti-apoptotic gene expression. Our findings reveal a novel cell fate determination mechanism to ensure cells undergo programed cell death through interfering with RPS3/NF-kappaB-conferred anti-apoptotic transcription by the fragment from partial p65 cleavage by activated Caspase-3. PMID- 26526616 TI - Rapid and direct spectrophotometric method for kinetics studies and routine assay of peroxidase based on aniline diazo substrates. AB - Peroxidases are ubiquitous enzymes that play an important role in living organisms. Current spectrophotometrically based peroxidase assay methods are based on the production of chromophoric substances at the end of the enzymatic reaction. The ambiguity regarding the formation and identity of the final chromophoric product and its possible reactions with other molecules have raised concerns about the accuracy of these methods. This can be of serious concern in inhibition studies. A novel spectrophotometric assay for peroxidase, based on direct measurement of a soluble aniline diazo substrate, is introduced. In addition to the routine assays, this method can be used in comprehensive kinetics studies. 4-[(4-Sulfophenyl)azo]aniline (lambdamax = 390 nm, E = 32 880 M(-1) cm( 1) at pH 4.5 to 9) was introduced for routine assay of peroxidase. This compound is commercially available and is indexed as a food dye. Using this method, a detection limit of 0.05 nmol mL(-1) was achieved for peroxidase. PMID- 26526613 TI - Understanding the susceptibility of dopamine neurons to mitochondrial stressors in Parkinson's disease. AB - Mitochondria are undoubtedly changed in Parkinson's disease (PD), and mitochondrial functions are disrupted in genetic and pharmacologic models of PD. However, many of these changes might not truly drive neurodegeneration. PD is defined by the particular susceptibility of nigrostriatal dopamine (DA) neurons, but little is understood about the mitochondria in these cells. Here, we critically review the evidence that mitochondrial stressors cause PD. We then consider how changes in the intrinsic function of mitochondria and in their mass, distribution, and dynamics might synergize with an increased need for mitochondria and produce PD, and the importance of understanding how mitochondria contribute to its pathogenesis. PMID- 26526618 TI - Anatomical variation in bifurcation and trifurcations of sciatic nerve and its clinical implications: in selected university in Ethiopia. AB - BACKGROUND: The Sciatic nerve is the widest nerve of the body. It consists of two components, namely: the tibia and the common peroneal components derived from the ventral rami of L4 to S3 spinal nerves of the lumbosacral plexus. It exits the pelvis through the greater sciatic foramen below the Piriformis muscle and descends between the greater trochanter of the femur and ischial tuberosity of the pelvis to the knee. The purpose of this study is to identify the course and variations in branching pattern of the sciatic nerve which may lead to various clinical manifestations. METHODS: Twenty-eight formalin fixed cadavers comprising of 56 lower limbs are used for this study, of which six specimens were female cadavers. Dissection of gluteal region and posterior compartment of the thigh was done to expose the sciatic nerve. Variations in the sciatic nerve anatomy; their relationship to Piriformis muscle and a point of bifurcation and trifurcation were noted and recorded. RESULTS: Forty-two lower limbs (75 %) showed normal anatomy of sciatic nerve. Fourteen regions (25 %) showed variations in the sciatic nerve, of which six regions (11 %) showed a variation of the sciatic nerve in relation to Piriformis muscle, three regions (5 %) showed trifurcation of the sciatic nerve and five regions (9 %) showed variation in the origin of the sural nerve. CONCLUSION: The knowledge regarding the level of division and distribution of the sciatic nerve and its location is of great importance. The sciatic nerve is frequently involved in daily medical practice of neurology, orthopedics, rehabilitation and anesthesia. Its long course makes it vulnerable to nerve injury. Even in this era the cadaver is the best means to study anatomy. It emphasizes proper clinical implications, for the surgeons to practice efficient surgical recombination and avoid errors. PMID- 26526617 TI - The canonical Wnt pathway regulates the metastasis-promoting mucin MUC4 in pancreatic ductal adenocarcinoma. AB - Aberrant Wnt signaling frequently occurs in pancreatic cancer (PC) and contributes to disease progression/metastases. Likewise, the transmembrane-mucin MUC4 is expressed de novo in early pancreatic intraepithelial neoplasia (PanINs) and incrementally increases with PC progression, contributing to metastasis. To determine the mechanism of MUC4 upregulation in PC, we examined factors deregulated in early PC progression, such as Wnt/beta-catenin signaling. MUC4 promoter analysis revealed the presence of three putative TCF/LEF-binding sites, leading us to hypothesize that MUC4 can be regulated by beta-catenin. Immunohistochemical (IHC) analysis of rapid autopsy PC tissues showed a correlation between MUC4 and cytosolic/nuclear beta-catenin expression. Knock down (KD) of beta-catenin in CD18/HPAF and T3M4 cell lines resulted in decreased MUC4 transcript and protein. Three MUC4 promoter luciferase constructs, p3778, p3000, and p2700, were generated. The construct p3778, encompassing the entire MUC4 promoter, elicited increased luciferase activity in the presence of stabilized beta-catenin. Mutation of the TCF/LEF site closest to the transcription start site (i.e., -2629/-2612) and furthest from the start site (i.e., -3425/-3408) reduced MUC4 promoter luciferase activity. Transfection with dominant negative TCF4 decreased MUC4 transcript and protein levels. Chromatin immunoprecipitation confirmed enrichment of beta-catenin on -2629/-2612 and 3425/-3408 of the MUC4 promoter in CD18/HPAF. Functionally, CD18/HPAF and T3M4 beta-catenin KD cells showed decreased migration and decreased Vimentin, N cadherin, and pERK1/2 expression. Tumorigenicity studies in athymic nude mice showed CD18/HPAF beta-catenin KD cells significantly reduced primary tumor sizes and metastases compared to scrambled control cells. We show for the first time that beta-catenin directly governs MUC4 in PC. PMID- 26526619 TI - Mechanisms of fate decision and lineage commitment during haematopoiesis. AB - Blood stem cells need to both perpetuate themselves (self-renew) and differentiate into all mature blood cells to maintain blood formation throughout life. However, it is unclear how the underlying gene regulatory network maintains this population of self-renewing and differentiating stem cells and how it accommodates the transition from a stem cell to a mature blood cell. Our current knowledge of transcriptomes of various blood cell types has mainly been advanced by population-level analysis. However, a population of seemingly homogenous blood cells may include many distinct cell types with substantially different transcriptomes and abilities to make diverse fate decisions. Therefore, understanding the cell-intrinsic differences between individual cells is necessary for a deeper understanding of the molecular basis of their behaviour. Here we review recent single-cell studies in the haematopoietic system and their contribution to our understanding of the mechanisms governing cell fate choices and lineage commitment. PMID- 26526620 TI - Inflammation during skeletal muscle regeneration and tissue remodeling: application to exercise-induced muscle damage management. AB - Increase in the practice of sport by more and more numerous people in the Western countries is associated with an increase in muscle injuries, and in demand for improving muscle function and acceleration of muscle recovery after damage. Most of the treatments used target inflammation. Indeed, several lines of experimental evidence in animal models that are supported by human studies identify inflammatory cells, and particularly macrophages, as essential players in skeletal muscle regeneration. Macrophages act not only through their immune functions, but also control myogenesis and extracellular matrix remodeling by directly acting on myogenic precursors and fibro-adipogenic precursors. In light of these recent biological advances, the question of early treatment aiming at blunting inflammation after exercise-induced muscle injury is discussed. PMID- 26526621 TI - Cryopreservation of virulent Acinetobacter baumannii to reduce variability of in vivo studies. AB - BACKGROUND: Microbiological assays require accurate and reproducible preparation of bacterial inocula. Inocula prepared on different days by different individuals can vary significantly from experiment to experiment. This variance is particularly problematic for Gram-negative bacterial infections, for which threshold effects can result in marked variations in host outcome with minor differences in inocula. RESULTS: We compared the accuracy of traditional methods versus using frozen stocks for preparing Acinetobacter baumannii inocula for infection in mice. Standard inoculum preparation resulted in substantial variability, both with respect to the actual inocula achieved compared to the targeted inocula, and with respect to the in vivo outcome resulting from similar inocula. Cryopreservation of the bacteria resulted in no significant decrement in growth of the bacteria. Furthermore, preparation of multiple infectious inocula from a frozen stock significantly improved the accuracy of the achieved inocula, and resulted in more reproducible in vivo outcomes from infection. Frozen stocks reduced inter-experiment variability associated with inoculum preparation, displayed no significant loss of growth capacity, and maintained virulence, increasing the reliability of infection. CONCLUSIONS: Frozen stocks require considerably less time to prepare and enhance reproducibility of in vivo experimental results when infecting with A. baumannii. PMID- 26526622 TI - Long-term mortality and risk factors for development of end-stage renal disease in critically ill patients with and without chronic kidney disease. AB - INTRODUCTION: Prevalence of chronic kidney disease (CKD) amongst intensive care unit (ICU) admissions is rising. How mortality and risk of end-stage renal disease (ESRD) differs between those with and without CKD and with acute kidney injury (AKI) is unclear. Determining factors that increase the risk of ESRD is essential to optimise treatment, identify patients requiring nephrological surveillance and for quantification of dialysis provision. METHOD: This cohort study used the Swedish intensive care register 2005-2011 consisting of 130,134 adult patients. Incomplete cases were excluded (26,771). Patients were classified (using diagnostic and intervention codes as well as admission creatinine values) into the following groups: ESRD, CKD, AKI, acute-on-chronic disease (AoC) or no renal dysfunction (control). Primary outcome was all-cause mortality. Secondary outcome was ESRD incidence. RESULTS: Of 103,363 patients 4,192 had pre-existing CKD; 1389 had ESRD; 5273 developed AKI and 998 CKD patients developed AoC. One year mortality was greatest in AoC patients (54 %) followed by AKI (48.7 %), CKD (47.6 %) and ESRD (40.3 %) (P < 0.001). Five-year mortality was highest for the CKD and AoC groups (71.3 % and 68.2 %, respectively) followed by AKI (61.8 %) and ESRD (62.9 %) (P < 0.001). ESRD incidence was greatest in the AoC and CKD groups (adjusted incidence rate ratio (IRR) 259 (95 % confidence interval (CI) 156.9 429.1) and 96.4, (95 % CI 59.7-155.6) respectively) and elevated in AKI patients compared with controls (adjusted IRR 24 (95 % CI 3.9-42.0); P < 0.001). Risk factors independently associated with ESRD in 1-year survivors were, according to relative risk ratio, AoC (356; 95 % CI 69.9-1811), CKD (267; 95 % CI 55.1-1280), AKI (30; 95 % CI 5.98-154) and presence of elevated admission serum potassium (4.6; 95 % CI 1.30-16.40) (P < 0.001). CONCLUSIONS: Pre-ICU renal disease significantly increases risk of death compared with controls. Subjects with AoC disease had extreme risk of developing ESRD. All patients with CKD who survive critical care should receive a nephrology referral. TRIAL REGISTRATION: CLINICAL TRIALS REGISTRATION NUMBER: NCT02424747 April 20th 2015. PMID- 26526623 TI - Toremifene, a selective estrogen receptor modulator, significantly improved biochemical recurrence in bone metastatic prostate cancer: a randomized controlled phase II a trial. AB - BACKGROUNDS: Durability of androgen-deprivation therapy (ADT) for prostate cancer (PC) is limited. Additional selective estrogen receptor modulators (SERMs) may prolong the durability of ADT, because androgen and estrogen signaling drive PC progression. METHODS: Men with treatment-naive bone metastatic PC were randomly assigned in 1:1:1 fashion to receive ADT, toremifene 60 mg plus ADT (TOPADT), or raloxifene 60 mg plus ADT (RAPADT). The primary endpoint was the biochemical recurrence (BCR) rate, and secondary endpoints were changes of scores of the visual analogue scale (VAS) and the functional assessment of cancer therapy (FACT). RESULTS: A total of 15 men, 5 each, were allocated to one of the three treatment arms. The basal serum prostate-specific antigen (PSA) level was 198 ng/mL (median, range; 30-8428). Bone metastases were graded as 1 (n = 11), 2 (n = 3), and 3 (n = 1) by the extent of disease. During the median follow-up period of 1370 days (range; 431-1983), BCR occurred in 3, 0 and 2 men in ADT, TOPADT and RAPADT group, respectively. The 5-year BCR-free rate was 30, 100 and 53 %, in ADT, TOPADT and RAPADT group, respectively (p = 0.04, ADT v.s. TOPADT, p = 0.48, ADT v.s. RAPADT and p = 0.12, TOPADT v.s. RAPADT). Scores of VAS improved in all groups and remained stable throughout the study. This analysis is limited as a preliminary result in a single center. CONCLUSIONS: Toremifene with conventional ADT significantly improved the BCR rate in treatment-naive bone metastatic PC. Further clinical trials are warranted to confirm the promising clinical efficacy of this combination therapy. TRIAL REGISTRATION: The protocol was registered at the University Hospital Medical Information Network ( UMIN ID;0,000,064,000 ) in Sep 25, 2011. PMID- 26526624 TI - Clinical validation of the C-VAT 2.0 assessment tool for gaming disorder: A sensitivity analysis of the proposed DSM-5 criteria and the clinical characteristics of young patients with 'video game addiction'. AB - AIMS: Clinicians struggle with the identification of video gaming problems. To address this issue, a clinical assessment tool (C-VAT 2.0) was developed and tested in a clinical setting. The instrument allows exploration of the validity of the DSM-5 proposal for 'internet gaming disorder'. METHOD: Using C-VAT 2.0, the current study provides a sensitivity analysis of the proposed DSM-5 criteria in a clinical youth sample (13-23years old) in treatment for video gaming disorder (N=32). The study also explores the clinical characteristics of these patients. RESULTS: The patients were all male and reported spending extensive amounts of time on video games. At least half of the patients reported playing online games (n=15). Comorbid problems were common (n=22) and included (social) anxiety disorders, PDD NOS, ADHD/ADD, Parent-Child relationship problem, and various types of depressive mood problems. The sensitivity of the test was good: results further show that the C-VAT correctly identified 91% of the sample at the proposed cut-off score of at least 5 out of 9 of the criteria. As our study did not include healthy, extreme gamers, we could not assess the specificity of the tool: future research should make this a priority. CONCLUSION: Using the proposed DSM-5 cut-off score, the C-VAT 2.0 shows preliminary validity in a sample of gamers in treatment for gaming disorder, but the discriminating value of the instrument should be studied further. In the meantime, it is crucial that therapists try to avoid false positives by using expert judgment of functional impairment in each case. PMID- 26526625 TI - From understanding to action: interventions for surgical disparities. AB - BACKGROUND: Health care disparities are a well-documented phenomenon. Despite the development and implementation of multiple interventions, disparities in surgery have proven persistent. Thought to arise from a combination of patient, provider, and system-level factors, the objective of this study was to identify what is currently known about factors that influence surgical disparities and elucidate possible interventions to address them across four intervention-based themes: (1) condition-specific targeted interventions; (2) increased reliance on quantitative factors; (3) doctor-patient communication; and (4) cultural humility. DATA SOURCES: Articles were abstracted from PubMed, EMBASE, and the Cochrane Library using controlled keyword vocabulary. CONCLUSIONS: There are various forms of interventions to address surgical disparities, spanning knowledge from disparate fields. Promising efforts have emerged towards the successful alleviation of disparities. In order to move the field of surgery from understanding of disparities towards actions to mitigate them, continued development of meaningful quality improvement initiatives are needed. PMID- 26526626 TI - Congenital fiber type disproportion. AB - Type I muscle fiber atrophy in childhood can be encountered in a variety of neuromuscular disorders. Congenital fiber type disproportion (CFTD) is one such condition which presents as a nonprogressive muscle weakness. The diagnosis is often made after excluding other differential diagnostic considerations. We present a 2-year-9-month-old full term boy who presented at 2 months with an inability to turn his head to the right. Over the next couple of years, he showed signs of muscle weakness, broad based gait and a positive Gower's sign. He had normal levels of creatine kinase and normal electromyography. A biopsy of the vastus lateralis showed a marked variation in muscle fiber type. The adenosine triphosphate (ATP)-ase stains highlighted a marked type I muscle atrophy with rare scattered atrophic type II muscle fibers. No abnormalities were observed on the nicotinamide adenine dinucleotide (NADH), succinate dehydrogenase (SDH) or cytochrome oxidase stained sections. Ragged red fibers were not present on the trichrome stain. Abnormalities of glycogen or lipid deposition were not observed on the periodic acid-Schiff or Oil-Red-O stains. Immunostaining for muscular dystrophy associated proteins showed normal staining. Ultrastructural examination showed a normal arrangement of myofilaments, and a normal number and morphology for mitochondria. A diagnosis of CFTD was made after excluding other causes of type I atrophy including congenital myopathy. The lack of specific clinical and genetic disorder associated with CFTD suggests that it is a spectrum of a disease process and represents a diagnosis of exclusion. PMID- 26526627 TI - Human embryonic stem cells in the treatment of patients with spinal cord injury. AB - BACKGROUND: Spinal cord injury (SCI) is a neurological condition which paralyses the patient below the level of injury and could occur due to damage, infection and tumors. Presently, there is no cure for SCI. The treatment options used for SCI include corticosteroid (methylprednisolone sodium succinate), surgical interventions, and physiotherapy and lowering of body temperature. The research on treatment options for SCI has been shifted to cell-based therapies. Use of human embryonic stem cells (hESCs) have been explored in animal models in which these cells have been found to hold a potential to repair and regenerate. PURPOSE: We wanted to assess the safety and efficacy of hESCs in the treatment of patients with spinal cord injury. METHODS: Five patients who were either paraplegic or quadriplegic were treated with hESC therapy. RESULTS: Following the treatment, all patients showed significant improvement in their sitting balance, control and sensation of bowel and bladder, power and movement of limbs (lower limbs and upper limbs). No adverse events were reported. CONCLUSION: In conclusion, hESC is safe and effective therapy for SCI. PMID- 26526628 TI - Letters to the Editor. PMID- 26526629 TI - [T3-predominant Graves' disease in paediatric patients]. PMID- 26526630 TI - The twisted tauopathies: surface interactions of helically patterned filaments seen in alzheimer's disease and elsewhere. AB - This paper broadly examines the dynamics of helically patterned filaments interacting with a surface and focuses on the surface interaction of amyloid fibrils formed by tau protein. Two structures are addressed in detail: cylindrical filaments with periodic thinning (CF-PT) and paired helical filaments (PHFs). PHFs are observed in neural tissue affected by Alzheimer's disease and may aggregate to form the pathological neurofibrillary tangles associated with the illness. Work using electron microscopy has demonstrated the conversion of CF PT into PHFs in vitro, suggesting CF-PT to be a PHF precursor in vivo. Here we model CF-PT as a patterned elastic rod placed on a flat surface (characteristic of the environment during microscopy) and examine the conformational changes resulting in stable surface bonding. Analysis of this conformational space reveals structures resembling PHFs and thus provides a mechanistic explanation of the CF-PT to PHF transition. We develop a general phase diagram of the filament conformation as a function of filament twist and bend rigidity. Results of this work also suggest that we can obtain desired filament conformations by patterning interactions of elastic filaments with a substrate, and therefore can be used as a method in microfabrication. PMID- 26526631 TI - Impact of Hospital Operating Margin on Central Line-Associated Bloodstream Infections Following Medicare's Hospital-Acquired Conditions Payment Policy. AB - In October 2008, Medicare ceased additional payment for hospital-acquired conditions not present on admission. We evaluated the policy's differential impact in hospitals with high vs low operating margins. Medicare's payment policy may have had an impact on reducing central line-associated bloodstream infections in hospitals with low operating margins. Infect. Control Hosp. Epidemiol. 2015;37(1):100-103. PMID- 26526632 TI - Diagnostic Accuracy of the Spectralis and Cirrus Reference Databases in Differentiating between Healthy and Early Glaucoma Eyes. AB - PURPOSE: To evaluate and compare the diagnostic accuracy of global and sector analyses for detection of early visual field (VF) damage using the retinal nerve fiber layer (RNFL) reference databases of the Spectralis (Heidelberg Engineering, Heidelberg, Germany) and Cirrus (Carl Zeiss Meditec, Dublin, CA) spectral-domain optical coherence tomography (SD OCT) devices. METHODS: Healthy subjects and glaucoma suspects from the Diagnostic Innovations in Glaucoma Study (DIGS) and African Descent and Glaucoma Evaluation Study (ADAGES) with at least 2 years of follow-up were included. Global and sectoral RNFL measures were classified as within normal limits, borderline (BL), and outside normal limits (ONL) on the basis of the device reference databases. The sensitivity of ONL classification was estimated in glaucoma suspect eyes that developed repeatable VF damage. RESULTS: A total of 353 glaucoma suspect eyes and 279 healthy eyes were included. A total of 34 (9.6%) of the glaucoma suspect eyes developed VF damage. In glaucoma suspect eyes, Spectralis and Cirrus ONL classification was present in 47 eyes (13.3%) and 24 eyes (6.8%), respectively. The sensitivity of the global RNFL ONL classification among eyes that developed VF damage was 23.5% for Cirrus and 32.4% for Spectralis. The specificity of within-normal-limits global classification in healthy eyes was 100% for Cirrus and 99.6% for Spectralis. There was moderate to substantial agreement between Cirrus and Spectralis classification as ONL. CONCLUSIONS: The Spectralis and Cirrus reference databases have a high specificity for identifying healthy eyes and good agreement for detection of eyes with early glaucoma damage. PMID- 26526633 TI - Comparative Effectiveness of First-Line Medications for Primary Open-Angle Glaucoma: A Systematic Review and Network Meta-analysis. AB - TOPIC: Primary open-angle glaucoma (POAG) is a highly prevalent condition worldwide and the most common cause of irreversible sight loss. The objective is to assess the comparative effectiveness of first-line medical treatments in patients with POAG or ocular hypertension through a systematic review and network meta-analysis, and to provide relative rankings of these treatments. CLINICAL RELEVANCE: Treatment for POAG currently relies completely on lowering the intraocular pressure (IOP). Although topical drops, lasers, and surgeries can be considered in the initial treatment of glaucoma, most patients elect to start treatment with eye drops. METHODS: We included randomized controlled trials (RCTs) that compared a single active topical medication with no treatment/placebo or another single topical medication. We searched CENTRAL, MEDLINE, EMBASE, and the Food and Drug Administration's website. Two individuals independently assessed trial eligibility, abstracted data, and assessed the risk of bias. We performed Bayesian network meta-analyses. RESULTS: We included 114 RCTs with data from 20 275 participants. The overall risk of bias of the included trials is mixed. The mean reductions (95% credible intervals) in IOP in millimeters of mercury at 3 months ordered from the most to least effective drugs were as follows: bimatoprost 5.61 (4.94; 6.29), latanoprost 4.85 (4.24; 5.46), travoprost 4.83 (4.12; 5.54), levobunolol 4.51 (3.85; 5.24), tafluprost 4.37 (2.94; 5.83), timolol 3.70 (3.16; 4.24), brimonidine 3.59 (2.89; 4.29), carteolol 3.44 (2.42; 4.46), levobetaxolol 2.56 (1.52; 3.62), apraclonidine 2.52 (0.94; 4.11), dorzolamide 2.49 (1.85; 3.13), brinzolamide 2.42 (1.62; 3.23), betaxolol 2.24 (1.59; 2.88), and unoprostone 1.91 (1.15; 2.67). CONCLUSIONS: All active first line drugs are effective compared with placebo in reducing IOP at 3 months. Bimatoprost, latanoprost, and travoprost are among the most efficacious drugs, although the within-class differences were small and may not be clinically meaningful. All factors, including adverse effects, patient preferences, and cost, should be considered in selecting a drug for a given patient. PMID- 26526634 TI - A Comparative Cohort Study of Visual Outcomes in Femtosecond Laser-Assisted versus Phacoemulsification Cataract Surgery. AB - PURPOSE: To evaluate visual outcomes after femtosecond laser-assisted cataract surgery (LCS) with phacoemulsification cataract surgery (PCS). DESIGN: Prospective, multicenter, comparative case series. PARTICIPANTS: Consecutive patients undergoing femtosecond LCS or PCS with intraocular lens insertion. METHODS: A total of 1876 eyes of 1238 patients (422 male and 772 female) who underwent cataract surgery between January 2012 and June 2014 were included in the study: 1017 eyes from center A and 859 eyes from center B. Cases underwent clinico-socioeconomic selection. Patients with absolute LCS contraindications were assigned to PCS; otherwise, all patients were offered LCS and elected on the basis of their decision to pay (the out-of-pocket cost for LCS). Demographic and postoperative data were collected to determine differences between groups. MAIN OUTCOME MEASURES: Six-month postoperative visual and refractive outcomes. Masked subjective refractions were performed 2 to 6 months postoperatively. RESULTS: There were 988 eyes in the LCS group and 888 eyes in the PCS group. Baseline best corrected visual acuity (BCVA) was better in LCS compared with PCS (20/44.0 vs. 20/51.5; P < 0.0003). Preoperative surgical refractive aim differed significantly between groups (LCS -0.28 vs. PCS -0.23; P < 0.0001). More patients who received LCS had Toric lenses implanted compared with PCS (47.4% vs. 34.8%; P < 0.0001). Postoperative BCVA was better after LCS (20/24.5 vs. 20/26.4; P = 0.0003) with a greater proportion of LCS cases achieving BCVA >20/30 (LCS 89.7% vs. PCS 84.2%; P = 0.0006) and 20/40 (LCS 96.6% vs. PCS 93.9%; P = 0.0077). However, PCS cases had more letters gained compared with LCS cases (13.5 vs. 12.5 letters; P = 0.0088), reflecting baseline BCVA differences. Mean absolute error was higher in LCS compared with PCS (0.41 diopters [D] vs. 0.35 D; P < 0.0011). The percentage of eyes within 0.5 D of error from preoperative aim refraction was higher in the PCS group (LCS 72.2% vs. PCS 82.6%; P < 0.0001). CONCLUSIONS: Femtosecond LCS did not demonstrate clinically meaningful improvements in visual outcomes over conventional PCS. PMID- 26526636 TI - Outcomes after Total Knee Arthroplasty for post-traumatic arthritis. AB - INTRODUCTION: Total Knee Arthroplasty (TKA) is an important treatment for posttraumatic arthritis (PTA), but evidence on outcomes is sparse. The purpose of this study was to evaluate the impact of PTA versus primary osteoarthritis (OA) on postoperative outcomes after TKA. METHODS: We queried the entire Medicare database from 2005 to 2012. International Classification of Diseases, 9th revision and Current Procedural Terminology codes were used to identify the procedure, indication, and complications. Patients with minimum two-years follow up were selected. Odds ratios (ORs), confidence intervals, and p-values (p) were calculated. RESULTS: For PTA, 3509 patients had TKA. For OA, 257,611 patients with TKA served as controls. The average Charlson Comorbidity Index for both groups was five. PTA patients were younger; only eight out of 29 Elixhauser comorbidities were higher. PTA patients had higher incidence of periprosthetic infection (OR 1.72, p<0.001), cellulitis or seroma (OR 1.19, p<0.001), knee wound complications (OR 1.80, p<0.001), TKA revision (OR 1.23, p=0.01), and arthrotomy/incision and drainage (OR 1.55, p<0.001). Blood transfusion rate was lower in PTA patients. There were no significant differences in bleeding complications, prosthetic dislocation, broken prostheses, periprosthetic fracture, osteolysis and polywear, neurovascular injury, and extensor mechanism rupture. DISCUSSION AND CONCLUSION: This study represents, to our knowledge, TKA outcomes in the largest cohort of PTA patients to date. Our findings indicate that these patients are at higher risk for many, but not all, postoperative surgical complications despite being as healthy as patients receiving TKA for primary OA. PMID- 26526635 TI - Construction and analysis of dynamic transcription factor regulatory networks in the progression of glioma. AB - The combinatorial cross-regulation of transcription factors (TFs) plays an important role in cellular identity and function; however, the dynamic regulation of TFs during glioma progression remains largely unknown. Here, we used the genome-wide expression of TFs to construct an extensive human TF network comprising interactions among 513 TFs and to analyse the dynamics of the TF-TF network during glioma progression. We found that the TF regulatory networks share a common architecture and that the topological structures are conserved. Strikingly, despite the conservation of the network architecture, TF regulatory networks are highly grade specific, and TF circuitry motifs are dynamically rewired during glioma progression. In addition, the most frequently observed structure in the grade-specific TF networks was the feedforward loop (FFL). We described applications that show how investigating the behaviour of FFLs in glioblastoma can reveal FFLs (such as RARG-NR1I2-CDX2) that are associated with prognosis. We constructed comprehensive TF-TF networks and systematically analysed the circuitry, dynamics, and topological principles of the networks during glioma progression, which will further enhance our understanding of the functions of TFs in glioma. PMID- 26526637 TI - Blood-based Biomarkers at Large Bowel Endoscopy and Prediction of Future Malignancies. AB - Soluble cancer-related protein biomarker levels may be increased in subjects without findings at large bowel endoscopy performed due to symptoms associated with colorectal cancer. The present study focused on a possible association between increased biomarker levels in such subjects and subsequent development of malignant diseases. In a major study of 4,990 subjects undergoing large bowel endoscopy, 691 were without pathology and comorbidity. Plasma levels of TIMP-1, CEA, CA19-9, and YKL-40 were determined in samples collected just before endoscopy and compared with subsequent development of a malignant disease within a period of 7-8 years. The upper 90% limits of the reference levels of every single protein were used to differentiate between normal and increased levels. The levels were separated into three groups: 0, none of the biomarkers increased; 1, one biomarker increased; 2, two or more biomarkers increased. A total of 43 subjects developed a primary malignant disease in the observation period. Univariatly, increase of all four biomarkers was significantly associated with subsequent development of a malignant disease. A multivariate analysis showed that increased biomarker levels were associated with subsequent development of a malignant disease (P = 0.002). The cumulative risk of developing malignant disease within the first 5 years after endoscopy was group 0, 3.3%; group 1, 5.8%; group 2, 7.8%. It is concluded that increased levels of plasma TIMP-1, CEA, CA19-9, and serum YKL-40 at large bowel endoscopy without findings may be associated with an increased risk of developing a subsequent malignant disease. PMID- 26526638 TI - Does market integration buffer risk, erode traditional sharing practices and increase inequality? A test among Bolivian forager-farmers. AB - Sharing and exchange are common practices for minimizing food insecurity in rural populations. The advent of markets and monetization in egalitarian indigenous populations presents an alternative means of managing risk, with the potential impact of eroding traditional networks. We test whether market involvement buffers several types of risk and reduces traditional sharing behavior among Tsimane Amerindians of the Bolivian Amazon. Results vary based on type of market integration and scale of analysis (household vs. village), consistent with the notion that local culture and ecology shape risk management strategies. Greater wealth and income were unassociated with the reliance on others for food, or on reciprocity, but wealth was associated with a greater proportion of food given to others (i.e., giving intensity) and a greater number of sharing partners (i.e., sharing breadth). Across villages, greater mean income was negatively associated with reciprocity, but economic inequality was positively associated with giving intensity and sharing breadth. Incipient market integration does not necessarily replace traditional buffering strategies but instead can often enhance social capital. PMID- 26526639 TI - Population-based epidemiology of primary biliary cirrhosis in South Korea. AB - BACKGROUND: As a rare disease, only a few population-based epidemiology studies of primary biliary cirrhosis (PBC) have been reported. AIMS: To elucidate the nationwide prevalence, incidence, complications, fatality and direct medical costs of PBC in South Korea. METHODS: The nationwide Health Insurance Review and Assessment Service claims data and Rare Intractable Disease registration data on PBC, identified with the International Classification of Diseases (ICD) 10 code of K74.3, were obtained from 2009 to 2013. Age- and gender-specific prevalence and incidence rates of PBC were calculated, and data on complications, comorbidities, prescribed drugs, therapeutic procedures and direct medical costs were analysed. RESULTS: A total of 2824 patients over 20 years old with PBC were identified in 2009-2013 (female-to-male ratio 6.2, median age 57 years old). The average age- and sex-adjusted incidence from 2011 to 2013 was 8.57 per million per year, and the average age- and sex-adjusted prevalence from 2009 to 2013 was 47.50 per million population. About 10% of patients presented with complications such as ascites (10.3%), variceal bleeding (5.8%) and/or hepatocellular carcinoma (HCC) (1.3%). Liver transplantation was undertaken in 71 patients (2.5%) for 5 years. Case fatality was 2.2% and the transplantation-free survival was 95.4% for 5 years. CONCLUSIONS: This is the first report on the nationwide epidemiology of primary biliary cirrhosis in South Korea, demonstrating lower incidence and prevalence rates than those of Western countries, but a considerable disease burden, representing at least 10% were complicated with decompensated cirrhosis or hepatocellular carcinoma requiring liver transplantation. PMID- 26526640 TI - Overweight, but not obesity, paradox on mortality following coronary artery bypass grafting. AB - OBJECTIVES: To determine whether an "obesity paradox" on post-coronary artery bypass grafting (CABG) mortality exists, we abstracted exclusively adjusted odds ratios (ORs) and/or hazard ratios (HRs) for mortality from each study, and then combined them in a meta-analysis. METHODS: MEDLINE and EMBASE were searched through April 2015 using PubMed and OVID, to identify comparative studies, of overweight or obese versus normal weight patients undergoing CABG, reporting adjusted relative risk estimates for short-term (30-day or in-hospital) and/or mid-to-long-term all-cause mortality. RESULTS: Our search identified 14 eligible studies. In total our meta-analysis included data on 79,140 patients undergoing CABG. Pooled analyses in short-term mortality demonstrated that overweight was associated with a statistically significant 15% reduction relative to normal weight (OR, 0.85; 95% confidence interval [CI], 0.74-0.98; p=0.03) and no statistically significant differences between mild obesity, moderate/severe obesity, or overall obesity and normal weight. Pooled analyses in mid-to-long term mortality demonstrated that overweight was associated with a statistically significant 10% reduction relative to normal weight (HR, 0.90; 95% CI, 0.84 to 0.96; p=0.001); and no statistically significant differences between mild obesity, moderate/severe obesity, or overall obesity and normal weight. CONCLUSIONS: Overweight, but not obesity, may be associated with better short term and mid-to-long-term post-CABG survival relative to normal weight. An overweight, but not obesity, paradox on post-CABG mortality appears to exist. PMID- 26526641 TI - Narrow band CE-Chirp auditory steady-state response is more reliable than the conventional ASSR in predicting the behavioral hearing threshold. AB - OBJECTIVE: We evaluated conventional ASSR (Bio-logic MASTER II) and NB CE-Chirp ASSR thresholds as objective hearing measures in both normal and hearing loss subjects. METHODS: Patients with sensorineural hearing loss and volunteer normal hearing subjects were enrolled. Pure tone thresholds at 0.5, 1, 2 and 4 kHz were compared with the corresponding thresholds measured using Bio-logic MASTER II and the Eclipse ASSR systems. The threshold differences and correlation with pure tone were measured and reliability was evaluated with Cronbach's alpha. In part I of the study, all subjects were included, in part II of the study, only mild hearing loss and normal hearing subjects were included. RESULTS: In part I, NB CE Chirp ASSR revealed a significantly smaller difference in threshold than conventional ASSR, a better correlation and better reliability. However, lower frequencies of NB CE-Chirp tended to be less reliable than higher frequencies. In part II, NB CE-Chirp revealed smaller threshold differences than conventional ASSR. Both correlation scores and reliability values were generally lower in the part II results. CONCLUSION: NB CE-Chirp ASSR generally revealed more favorable outcomes. However, its reliability was reduced at lower frequencies and in patients with milder hearing loss. PMID- 26526642 TI - Extranodal soft tissue Rosai-Dorfman disease of the head and neck and its diagnostic difficulty. AB - Rosai-Dorfman disease (RDD) is a rare proliferative histiocytic disorder that is characterized by persistent massive lymphadenopathy mimicking malignant tumors. Extranodal RDD is uncommon, and more severe fibrosis and fewer histiocytes in lesions make the diagnosis of RDD more difficult than that of nodal RDD. We herein described a 31-year-old male patient with isolated soft tissue RDD of the head and neck. The patient was referred to our hospital with a right neck mass. Computed tomography (CT) scans showed a diffuse enhanced tumor with an unclear border in the right side of the neck. 18F-fluorodeoxyglucose positron emission tomography (PET)/CT revealed high uptake in the corresponding lesion. Second wide local excisional biopsy led to a diagnosis of RDD, and immunohistochemistry was useful for diagnosing RDD. A systemic treatment with steroids improved his symptoms, including the neck mass. Physicians need to consider the diagnostic difficulty associated with extranodal soft tissue RDD as well as its rarity. PMID- 26526643 TI - Parotid gland metastases of distant primary tumours: A diagnostic challenge. AB - OBJECTIVE: Metastatic disease is common among parotid malignancies. The majority of primary tumours are located in the head and neck, but primary tumours below the clavicle must also be considered, especially in histological types not usually found in primary parotid or skin tumours. METHODS: We performed 644 consecutive parotidectomies between 1980 and 2012. Benign tumours were found in 555 patients (86%) and malignant tumours in 89 patients (14%). RESULTS: Of 89 malignant tumours, 39 were metastases (44%). In 5 cases, the primary tumour was located below the clavicle (6% of malignant tumours). A carcinoma of the bronchus was subsequently diagnosed in three patients: one patient had breast carcinoma and one renal cell carcinoma. CONCLUSION: The majority of metastases in the parotid gland arise from primary tumours of the head and neck. In 10-20% of metastases, the primary tumour arises below the clavicle. Parotid metastases can be the first clinical manifestation of a malignant tumour, and can also occur years after curative intent treatment. Histopathology and immunohistochemistry will offer clues to a possible metastatic process and to primary tumour location. Parotidectomy with complete excision of the tumour can be a curative measure or form an essential part of symptom control and should be considered in all but the most moribund patients. PMID- 26526645 TI - Connective tissue diseases: ApoER2 linked to pregnancy complications in APS. PMID- 26526644 TI - 'MHC-I-opathy'-unified concept for spondyloarthritis and Behcet disease. AB - The spondyloarthropathies comprise ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis (PsA) and arthritis associated with inflammatory bowel disease. In this Perspectives article, we describe how Behcet disease and several clinically distinct spondyloarthropathies-all associated with MHC class I (MHC-I) alleles such as HLA-B(*)51, HLA-C(*)0602 and HLA-B(*)27 and epistatic ERAP-1 interactions-have a shared immunopathogenetic basis. As a unifying concept, we propose that barrier dysfunction in environmentally exposed organs such as the skin, and aberrant innate immune reactions at sites of mechanical stress, can often trigger secondary adaptive immune CD8(+) T-cell responses with prominent neutrophilic inflammation that culminate in exacerbation and recurrence of these diseases. Of note, these 'MHC-I-opathies' show a differential immunopathology, probably reflecting antigenic differences within target tissues: HLA-B(*)51 is linked to ocular and mucocutaneous disease but not gut involvement, and HLA-C(*)0602 is linked to type I psoriasis but not scalp or nail disease. PMID- 26526646 TI - Therapy: HSCT-resetting immune tolerance by boosting TREG cell diversity. PMID- 26526647 TI - Trait reflection predicts interleukin-6 response to a social-evaluative stressor. AB - Past work has linked negative repetitive thought (worry, rumination) about stressors to sustained stress responses. Less is known about the effects of neutral types of repetitive thought (e.g., reflection) on physiological stress responses. The present study examined whether greater trait reflection was associated with a lower inflammatory response to an acute psychosocial stressor. Thirty-four healthy undergraduate women completed a speech stressor, and plasma interleukin-6 (IL-6), C-reactive protein, and tumor necrosis factor-alpha levels were assessed before and after the stressor. Higher levels of reflection predicted lower IL-6 responses 1h after the stressor. Stressor appraisal was not a significant mediator. These preliminary findings stand in contrast to existing evidence that other forms of repetitive thought like worry and rumination may exacerbate or prolong the inflammatory stress response and indicate that reflection is a notable factor worth considering when examining the relationship between stress, inflammation, and health. PMID- 26526648 TI - Microglial toll-like receptors and Alzheimer's disease. AB - Microglial activation represents an important pathological hallmark of Alzheimer's disease (AD), and emerging data highlight the involvement of microglial toll-like receptors (TLRs) in the course of AD. TLRs have been observed to exert both beneficial and detrimental effects on AD-related pathologies, and transgenic animal models have provided direct and credible evidence for an association between TLRs and AD. Moreover, analyses of genetic polymorphisms have suggested interactions between genetic polymorphisms in TLRs and AD risk, further supporting the hypothesis that TLRs are involved in AD. In this review, we summarize the key evidence in this field. Future studies should focus on exploring the mechanisms underlying the potential roles of TLRs in AD. PMID- 26526649 TI - Response to the Letter "Opioid-induced hyperalgesia and dopamine-induced augmentation in an intractable and refractory case of RLS". PMID- 26526650 TI - Chemical derivatization in bioanalysis. PMID- 26526651 TI - Gene therapy for spinal fusion using an insect vector. AB - COMMENTARY ON: Fu T-S, Chang Y-H, Wong C-B, Wang I-C, Tsai T-T, Lai P-L, et al. Mesenchymal stem cells expressingbaculovirus-engineered BMP-2 and VEGF enhance posterolateral spine fusion in a rabbit model. Spine J 2015;15(9):2036-44. PMID- 26526652 TI - Assessing calibration in an external validation study. PMID- 26526653 TI - Reply to the letter to the editor regarding "A clinical prediction model to assess surgical outcome in patients with cervical spondylotic myelopathy: internal and external validation using the prospective multicenter AOSpine North American and International datasets of 743 patients." Spine J 2015;15:388-397. PMID- 26526654 TI - Letter to the editor: "A meta-analysis of open versus minimally invasive foraminotomy for cervical herniated disc" Spine J 2015;15:849-856. PMID- 26526655 TI - Reply to letter to the editor regarding "A meta-analysis of open versus minimally invasive foraminotomy for cervical herniated disc". PMID- 26526656 TI - Predators and the public trust. AB - Many democratic governments recognize a duty to conserve environmental resources, including wild animals, as a public trust for current and future citizens. These public trust principles have informed two centuries of U.S.A. Supreme Court decisions and environmental laws worldwide. Nevertheless numerous populations of large-bodied, mammalian carnivores (predators) were eradicated in the 20th century. Environmental movements and strict legal protections have fostered predator recoveries across the U.S.A. and Europe since the 1970s. Now subnational jurisdictions are regaining management authority from central governments for their predator subpopulations. Will the history of local eradication repeat or will these jurisdictions adopt public trust thinking and their obligation to broad public interests over narrower ones? We review the role of public trust principles in the restoration and preservation of controversial species. In so doing we argue for the essential roles of scientists from many disciplines concerned with biological diversity and its conservation. We look beyond species endangerment to future generations' interests in sustainability, particularly non consumptive uses. Although our conclusions apply to all wild organisms, we focus on predators because of the particular challenges they pose for government trustees, trust managers, and society. Gray wolves Canis lupus L. deserve particular attention, because detailed information and abundant policy debates across regions have exposed four important challenges for preserving predators in the face of interest group hostility. One challenge is uncertainty and varied interpretations about public trustees' responsibilities for wildlife, which have created a mosaic of policies across jurisdictions. We explore how such mosaics have merits and drawbacks for biodiversity. The other three challenges to conserving wildlife as public trust assets are illuminated by the biology of predators and the interacting behavioural ecologies of humans and predators. The scientific community has not reached consensus on sustainable levels of human caused mortality for many predator populations. This challenge includes both genuine conceptual uncertainty and exploitation of scientific debate for political gain. Second, human intolerance for predators exposes value conflicts about preferences for some wildlife over others and balancing majority rule with the protection of minorities in a democracy. We examine how differences between traditional assumptions and scientific studies of interactions between people and predators impede evidence-based policy. Even if the prior challenges can be overcome, well-reasoned policy on wild animals faces a greater challenge than other environmental assets because animals and humans change behaviour in response to each other in the short term. These coupled, dynamic responses exacerbate clashes between uses that deplete wildlife and uses that enhance or preserve wildlife. Viewed in this way, environmental assets demand sophisticated, careful accounting by disinterested trustees who can both understand the multidisciplinary scientific measurements of relative costs and benefits among competing uses, and justly balance the needs of all beneficiaries including future generations. Without public trust principles, future trustees will seldom prevail against narrow, powerful, and undemocratic interests. Without conservation informed by public trust thinking predator populations will face repeated cycles of eradication and recovery. Our conclusions have implications for the many subfields of the biological sciences that address environmental trust assets from the atmosphere to aquifers. PMID- 26526657 TI - Genetic polymorphisms of the drug-metabolizing enzyme CYP2C19 in the Uyghur population in northwest China. AB - 1. CYP2C19 is a clinically important enzyme and is involved in the metabolism of approximately 10% of drugs used in daily clinical practice. Previous studies mainly focused on Chinese Han populations or other ethnic groups, little is known about Uyghur populations. 2. The present study was designed to determine the genetic basis of CYP2C19 polymorphisms. 3. We used direct sequencing to investigate the promoter, exons and surrounding introns, and 3'-untranslated region of the CYP2C19 gene in 96 unrelated healthy Uyghur individuals. 4. A total of 31 different CYP2C19 polymorphisms were identified in the Uyghur population, three of which were novel, including two nonsynonymous variants (57807A > M, Gln279Pro and 19257G > R, Asp262Asn) and one synonymous variants in exon 5 (19184T > Y, Leu237Leu). In addition, CYP2C19*1, *2 and *3 alleles showed frequencies of 83.34%, 14.06% and 2.08%, respectively. 5. This is the first study that systematically screened the polymorphisms of the whole CYP2C19 gene in Uyghur population. Hence, our results provided important information on CYP2C19 polymorphisms in Uyghur population and could be helpful for future personalized medicine studies in Uyghur population generally. PMID- 26526658 TI - Recent Taxonomic Developments with Candida and Other Opportunistic Yeasts. AB - Increases in susceptible patient populations and advances in identification methods have resulted in the continued recognition of novel yeasts as agents of human infection. Most of these agents are members of the well-recognized genera Candida, Cryptococcus, Trichosporon, and Rhodotorula. Some of these agents are "cryptic species," members of species complexes, and may not be detectable using classical carbohydrate assimilation-based methods of yeast identification. Such species require DNA- or MALDI-based methods for correct identification, although sporadic isolates may not routinely require delineation to the individual species level. The coming end of the fungal taxonomy rules requiring separate names for sexual and asexual forms of the same fungus will hopefully allow greater clarity, as names for medically important yeast can now be based on the needs of the medical mycology community and the common goal of better communication between laboratory and clinician. PMID- 26526659 TI - [Orbital cystic hygroma invading the eyeball: report of a case]. PMID- 26526660 TI - Back Pain in Malignant Disease - Metastatic Spinal Cord Compression? AB - Be alert to possible spinal cord compression in patients who are at risk and who present with warning signs and symptomsMaintain a low threshold for further investigation of such patients and for discussing them with specialist colleaguesIf MSCC is suspected, commence high dose steroids (16mg dexamethasone orally in the morning) immediatelyEnsure imaging to confirm diagnosis of MSCC is carried out within 24 hours of clinical suspicionEnsure prompt treatment within 24 hours of diagnosis. PMID- 26526661 TI - Sex Differences in Pain. AB - There is good evidence that men and women differ with respect to the perception and experience of pain.Women on average report more pain when compared to men, and there seem to be more painful conditions where women exhibit a greater prevalence than where men do.Sex differences in pain vary according to age, with many differences occurring during the reproductive years.The sex of an individual is still not routinely investigated in many studies.There are a range of mechanisms that may be involved in explaining these sex differences, from sex hormones to health seeking behaviours. PMID- 26526662 TI - Cardiac (82)Rb PET/CT for fast and non-invasive assessment of microvascular function and structure in asymptomatic patients with type 2 diabetes. AB - AIMS/HYPOTHESIS: Coronary flow reserve (CFR) and coronary artery calcium (CAC) represent functional and structural aspects of atherosclerosis. We examined the prevalence of reduced CFR and high CAC scores in three predefined groups of participants without known cardiovascular disease: (1) patients with type 2 diabetes and albuminuria; (2) patients with type 2 diabetes and normoalbuminuria; and (3) non-diabetic controls. METHODS: In a cross-sectional design, cardiac (82)Rb positron emission tomography/computed tomography was conducted in 60 patients with type 2 diabetes who were free of overt cardiovascular disease and who were stratified by normoalbuminuria (<30 mg/24 h) (n = 30; age [mean +/- SD] 60.9 +/- 10.1 years) and albuminuria (>= 30 mg/24 h) (n = 30; age 65.6 +/- 4.8 years), and in 30 healthy, non-diabetic controls (age 59.8 +/- 9.9 years). RESULTS: In controls, normoalbuminuric and albuminuric patients, CFR was 3.0 +/- 0.8, 2.6 +/- 0.8 and 2.0 +/- 0.5, respectively. Reduced CFR (<2.5) was observed in 16.7%, 40.0% and 83.3% of participants, respectively, and median (interquartile range) CAC scores were 0 (0-81), 36 (1-325) and 370 (152-1,025), respectively (p for trend <0.01). After adjustment, the difference in CFR and CAC between albuminuric patients and controls remained significant (p <= 0.001). There were trends towards lower CFR and higher CAC scores in normoalbuminuric patients vs controls (p <= 0.023) and towards higher CAC scores in albuminuric vs normoalbuminuric patients (p = 0.026). In multivariate regression analysis, a higher urinary albumin excretion rate (UAER) tended to predict reduced CFR in the total population (p = 0.045). When the CAC score was added, there was also a trend (p = 0.032) towards an inverse association with reduced CFR. CONCLUSIONS/INTERPRETATION: Type 2 diabetic patients who were free of overt cardiovascular disease had a high prevalence of coronary microvascular dysfunction, especially with concomitant albuminuria, suggesting a common microvascular impairment occurring in multiple microvascular beds. Prospective studies are needed to show the prognostic significance of this finding. PMID- 26526663 TI - Pelvic floor muscle training added to another active treatment versus the same active treatment alone for urinary incontinence in women. AB - BACKGROUND: Pelvic floor muscle training (PFMT) is a first-line conservative treatment for urinary incontinence in women. Other active treatments include: physical therapies (e.g. vaginal cones); behavioural therapies (e.g. bladder training); electrical or magnetic stimulation; mechanical devices (e.g. continence pessaries); drug therapies (e.g. anticholinergics (solifenacin, oxybutynin, etc.) and duloxetine); and surgical interventions including sling procedures and colposuspension. This systematic review evaluated the effects of adding PFMT to any other active treatment for urinary incontinence in women OBJECTIVES: To compare the effects of pelvic floor muscle training combined with another active treatment versus the same active treatment alone in the management of women with urinary incontinence. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE in process, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 5 May 2015), and CINAHL (January 1982 to 6 May 2015), and the reference lists of relevant articles. SELECTION CRITERIA: We included randomised or quasi-randomised trials with two or more arms, of women with clinical or urodynamic evidence of stress urinary incontinence, urgency urinary incontinence or mixed urinary incontinence. One arm of the trial included PFMT added to another active treatment; the other arm included the same active treatment alone. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and methodological quality and resolved any disagreement by discussion or consultation with a third party. We extracted and processed data in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. Other potential sources of bias we incorporated into the 'Risk of bias' tables were ethical approval, conflict of interest and funding source. MAIN RESULTS: Thirteen trials met the inclusion criteria, comprising women with stress urinary incontinence (SUI), urgency urinary incontinence (UUI) or mixed urinary incontinence (MUI); they compared PFMT added to another active treatment (585 women) with the same active treatment alone (579 women). The pre-specified comparisons were reported by single trials, except bladder training, which was reported by two trials, and electrical stimulation, which was reported by three trials. However, only two of the three trials reporting electrical stimulation could be pooled, as one of the trials did not report any relevant data. We considered the included trials to be at unclear risk of bias for most of the domains, predominantly due to the lack of adequate information in a number of trials. This affected our rating of the quality of evidence. The majority of the trials did not report the primary outcomes specified in the review (cure or improvement, quality of life) or measured the outcomes in different ways. Effect estimates from small, single trials across a number of comparisons were indeterminate for key outcomes relating to symptoms, and we rated the quality of evidence, using the GRADE approach, as either low or very low. More women reported cure or improvement of incontinence in two trials comparing PFMT added to electrical stimulation to electrical stimulation alone, in women with SUI, but this was not statistically significant (9/26 (35%) versus 5/30 (17%); risk ratio (RR) 2.06, 95% confidence interval (CI) 0.79 to 5.38). We judged the quality of the evidence to be very low. There was moderate-quality evidence from a single trial investigating women with SUI, UUI or MUI that a higher proportion of women who received a combination of PFMT and heat and steam generating sheet reported a cure compared to those who received the sheet alone: 19/37 (51%) versus 8/37 (22%) with a RR of 2.38, 95% CI 1.19 to 4.73). More women reported cure or improvement of incontinence in another trial comparing PFMT added to vaginal cones to vaginal cones alone, but this was not statistically significant (14/15 (93%) versus 14/19 (75%); RR 1.27, 95% CI 0.94 to 1.71). We judged the quality of the evidence to be very low. Only one trial evaluating PFMT when added to drug therapy provided information about adverse events (RR 0.84, 95% CI 0.45 to 1.60; very low-quality evidence).With regard to condition-specific quality of life, there were no statistically significant differences between women (with SUI, UUI or MUI) who received PFMT added to bladder training and those who received bladder training alone at three months after treatment, on either the Incontinence Impact Questionnaire-Revised scale (mean difference (MD) -5.90, 95% CI -35.53 to 23.73) or on the Urogenital Distress Inventory scale (MD -18.90, 95% CI -37.92 to 0.12). A similar pattern of results was observed between women with SUI who received PFMT plus either a continence pessary or duloxetine and those who received the continence pessary or duloxetine alone. In all these comparisons, the quality of the evidence for the reported critical outcomes ranged from moderate to very low. AUTHORS' CONCLUSIONS: This systematic review found insufficient evidence to state whether or not there were additional effects by adding PFMT to other active treatments when compared with the same active treatment alone for urinary incontinence (SUI, UUI or MUI) in women. These results should be interpreted with caution as most of the comparisons were investigated in small, single trials. None of the trials in this review were large enough to provide reliable evidence. Also, none of the included trials reported data on adverse events associated with the PFMT regimen, thereby making it very difficult to evaluate the safety of PFMT. PMID- 26526664 TI - The Ebola Vaccine Team B: a model for promoting the rapid development of medical countermeasures for emerging infectious disease threats. AB - In support of accelerated development of Ebola vaccines from preclinical research to clinical trials, in November, 2014, the Wellcome Trust and the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota established the Wellcome Trust-CIDRAP Ebola Vaccine Team B initiative. This ongoing initiative includes experts with global experience in various phases of bringing new vaccines to market, such as funding, research and development, manufacturing, determination of safety and efficacy, regulatory approval, and vaccination delivery. It also includes experts in community engagement strategies and ethical issues germane to vaccination policies, including eight African scientists with direct experience in developing and implementing vaccination policies in Africa. Ebola Vaccine Team B members have worked on a range of vaccination programmes, such as polio eradication (Africa and globally), development of meningococcal A disease vaccination campaigns in Africa, and malaria and HIV/AIDS vaccine research. We also provide perspective on how this experience can inform future situations where urgent development of vaccines is needed, and we comment on the role that an independent, expert group such as Team B can have in support of national and international public health authorities toward addressing a public health crisis. PMID- 26526665 TI - Atomic mapping of Ruddlesden-Popper faults in transparent conducting BaSnO3-based thin films. AB - Doped BaSnO3 has arisen many interests recently as one of the promising transparent conducting oxides for future applications. Understanding the microstructural characteristics are crucial for the exploration of relevant devices. In this paper, we investigated the microstructural features of 0.001% La doped BaSnO3 thin film using both conventional and aberration corrected transmission electron microscopes. Contrast analysis shows high densities of Ruddlesden-Popper faults in the film, which are on {100} planes with translational displacements of 1/2a < 111 > . Atomic EELS element mappings reveal that the Ruddlesden-Popper faults are Ba-O layer terminated, and two kinds of kink structures at the Ruddlesden-Popper faults with different element distributions are also demonstrated. Quantitative analysis on lattice distortions of the Ruddlesden-Popper faults illustrates that the local lattice spacing poses a huge increment of 36%, indicating that large strains exist around the Ruddlesden-Popper faults in the film. PMID- 26526666 TI - Hodgkin lymphoma as a novel presentation of familial DICER1 syndrome. AB - DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly presenting with pleuropulmonary blastoma (PPB), ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. We describe the occurrence of a Hodgkin lymphoma (HL) of the T cell phenotype in a family with DICER1 syndrome. The patient presented with PPB Type I and HL. Immunohistochemical staining of the Hodgkin and Reed-Sternberg cells revealed CD30, TGP, CD2, CD3, CD15, and IRF4 positivity and weekly positivity of PAX5. T cell receptor repertoire analysis suggested HL of T cell origin, which is in contrast to common B cell-derived HL. The mother had been diagnosed with thyroid cysts, one sister had died from a primitive neuroectodermal tumor, and a brother had died from PPB Type III. Two mutational events were revealed in all affected family members; a single bp deletion, c.5299delC, leading to a frameshift and premature stop in exon 24 and a heterozygous variant (c.4616C>T; p.Thr1539Met) located in exon 23 of the DICER1 gene. This variant is predicted to be benign by in silico analysis. CONCLUSION: Future studies looking for DICER1 mutations in HL cases of the T cell phenotype will be important to confirm its association with constitutional DICER1 syndrome. WHAT IS KNOWN: * DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly pleuropulmonary blastoma, ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. * Hodgkin lymphoma is one of the most frequent types of malignant lymphomas and typically arises sporadically. T cell derived Hodgkin lymphomas are exceptionally rare. What is New: * DICER1 syndrome may have an even broader phenotypic spectrum and seems to be associated with rare forms of T cell Hodgkin lymphoma. PMID- 26526668 TI - Crystal structure and biochemical characterization of Chlamydomonas FDX2 reveal two residues that, when mutated, partially confer FDX2 the redox potential and catalytic properties of FDX1. AB - The green alga Chlamydomonas reinhardtii contains six plastidic [2Fe2S]-cluster ferredoxins (FDXs), with FDX1 as the predominant isoform under photoautotrophic growth. FDX2 is highly similar to FDX1 and has been shown to interact with specific enzymes (such as nitrite reductase), as well as to share interactors with FDX1, such as the hydrogenases (HYDA), ferredoxin:NAD(P) reductase I (FNR1), and pyruvate:ferredoxin oxidoreductase (PFR1), albeit performing at low catalytic rates. Here we report the FDX2 crystal structure solved at 1.18 A resolution. Based on differences between the Chlorella fusca FDX1 and C. reinhardtii FDX2 structures, we generated and purified point-mutated versions of the FDX2 protein and assayed them in vitro for their ability to catalyze hydrogen and NADPH photo production. The data show that structural differences at two amino acid positions contribute to functional differences between FDX1 and FDX2, suggesting that FDX2 might have evolved from FDX1 toward a different physiological role in the cell. Moreover, we demonstrate that the mutations affect both the midpoint potentials of the FDX and kinetics of the FNR reaction, possibly due to altered binding between FDX and FNR. An effect on H2 photo-production rates was also observed, although the kinetics of the reaction were not further characterized. PMID- 26526669 TI - The development of a questionnaire to evaluate rheumatoid arthritis patient's knowledge about methotrexate. AB - AIMS AND OBJECTIVES: Assess knowledge concerning methotrexate in rheumatoid arthritis patients by means of a questionnaire. BACKGROUND: Methotrexate is the standard drug for rheumatoid arthritis treatment. It has potentially serious side effects that can be largely prevented by making sure that patients are well informed and comply with prescription guidelines. DESIGN: Cross-sectional survey. METHODS: A questionnaire on methotrexate (mode of action, administration, drug interactions), side effects, monitoring and lifestyle implications was offered to all the rheumatoid arthritis patients treated with the drug seen between March and September 2013 in a large hospital in France. RESULTS: One hundred and eighty three patients (143 women), mean age 60 (13.5) years, with a median disease duration of 12 years [7-20] and treated with methotrexate for eight years [5-13] took part. Methotrexate was identified as a disease-modifying antirheumatic drug by 78% of the patients. The weekly administration method was well assimilated (97%); 67% indicated that the rationale for folic acid was to reduce treatment toxicity. Only 21% knew that trimethoprim was contraindicated. Half were aware of the haematologic risk and 36% were aware of the risk of hypersensitivity pneumonitis. There was knowledge concerning laboratory testing (80%), but 54% thought they were only being monitored for rheumatoid arthritis activity. Only 13% of the men, but 90% of the women, of childbearing age knew that contraception was essential, and 75% indicated that alcohol consumption should be limited. A low knowledge score correlated significantly with age and low educational level. It was independent of sex, duration of treatment for rheumatoid arthritis. CONCLUSIONS: Rheumatoid arthritis patient's knowledge concerning methotrexate is poor, particularly for the most serious side effects (haematologic and hypersensitivity pneumonitis), interactions with trimethoprim, and in men, the need for contraception. RELEVANCE TO CLINICAL PRACTICE: Patient knowledge concerning methotrexate should be regularly checked and supported using the different therapeutic education tools available, especially when patients are older people and have had limited schooling. PMID- 26526671 TI - More tobacco is used in cigarette tubes than is taxed as roll-your-own tobacco in the USA. PMID- 26526670 TI - Effective utilization of genetic information for athletes and coaches: focus on ACTN3 R577X polymorphism. AB - Training variants (type, intensity, and duration of exercise) can be selected according to individual aims and fitness assessment. Recently, various methods of resistance and endurance training have been used for muscle hypertrophy and VO2max improvement. Although several genetic variants are associated with elite athletic performance and muscle phenotypes, genetic background has not been used as variant for physical training. ACTN3 R577X is a well-studied genetic polymorphism. It is the only genotype associated with elite athletic performance in multiple cohorts. This association is strongly supported by mechanistic data from an Actn3-knockout mouse model. In this review, possible guidelines are discussed for effective utilization of ACTN3 R577X polymorphism for physical training. PMID- 26526672 TI - Electronically Stabilized Nonplanar Phenalenyl Radical and Its Planar Isomer. AB - Stable phenalenyl radicals have great potential as the basis for new materials for applications in the field of molecular electronics. In particular, electronically stabilized phenalenyl species that do not require steric shielding are molecules of fundamental interest, but are notoriously difficult to synthesize. Herein, the synthesis and characterization of two phenalenyl-type cations is reported: planar benzo[i]naphtho[2,1,8-mna]xanthenium (8(+)) and helical benzo[a]naphtho[8,1,2-jkl]xanthenium (9(+)), which can be reduced to the corresponding radicals. Radical 9 represents the first stable, helical phenalenyl radical which does not rely on bulky substituents to ensure its stability. Both cations are water-soluble, and the radicals are stable for weeks at room temperature under air. These compounds were characterized crystallographically, and also by NMR, EPR, electrochemistry, and electronic spectra. The synthesis of the previously reported compound benzo[5,6]naphthaceno[1,12,11,10 jklmna]xanthylium (5(+)), the largest oxygen-containing polycyclic hydrocarbon, was undertaken for comparison with 8(+) and 9(+), allowing us to report its crystal structure here for the first time. The different properties of these compounds and their radicals are explained by considering their differing aromaticities using in-depth computational methods. PMID- 26526673 TI - Aortic regurgitation following transcatheter aortic valve replacement: Impact of preprocedural left ventricular diastolic filling patterns on late clinical outcomes. AB - OBJECTIVES: To investigate the impact of preprocedural left ventricular (LV) diastolic function on outcomes of patients with postprocedural aortic regurgitation (ARpost ) following transcatheter aortic valve replacement (TAVR). BACKGROUND: The predictors and mechanisms of the increased mortality in patients with ARpost are inadequately defined. METHODS: Baseline clinical and echocardiographic variables from a prospective TAVR registry were analyzed. Preprocedural correlates of late outcomes (all-cause mortality and the composite of mortality, stroke, heart failure, and new-onset atrial fibrillation) were examined according to the presence and severity of ARpost . RESULTS: Of the 418 patients undergoing TAVR, ARpost was present in 212 (51%): mild 36%, moderate severe 15%. Mean follow-up was 909 +/- 489 days. All-cause mortality and composite endpoint rates were significantly increased in patients with moderate severe ARpost compared with patients with either none or only mild ARpost (38, 22, 21%, P = 0.02; and, 56, 35, 40%, P = 0.01; respectively). Moderate-severe (though not mild) ARpost was independently associated with mortality and the composite endpoint (HR = 1.93 [95%CI 1.15-3.14], P = 0.01; HR = 1.85 [95%CI 1.22 2.77], P = 0.004], respectively). By multivariate analysis, preprocedural LV deceleration time (DT) < 160 ms was independently associated with the risk of all cause mortality and the composite endpoint among patients with mild AR (HR = 1.74 [95%CI 1.14-2.60], P = 0.01; and, HR = 1.73 [95%CI 1.23-2.41], P = 0.002, respectively) and moderate-severe ARpost (HR = 1.81 [95%CI 1.28-2.51], P < 0.001; HR = 1.86 [95%CI 0.22-2.80], P = 0.004, respectively). CONCLUSIONS: Preprocedural impairment of LV filling, reflected by short DT, portends an adverse prognosis in TAVR patients who develop ARpost independently of other clinical and echocardiocardigraphic measures including AS severity and systolic LV function. (c) 2015 Wiley Periodicals, Inc. PMID- 26526674 TI - Differential diagnosis and prognosis for longitudinally extensive myelitis in Buenos Aires, Argentina. AB - INTRODUCTION: Longitudinally extensive myelitis (LETM) has classically been grouped with the full or limited neuromyelitis optica spectrum disorders (NMOSD). However, differential diagnosis reveals a wide range of aetiologies. OBJECTIVE: To report on differential diagnosis and prognosis for LETM observed in a group of patients in Buenos Aires, Argentina. PATIENTS AND METHODS: Cross-sectional and retrospective multicentre study in two hospitals in Buenos Aires from June 2008 to June 2014. INCLUSION CRITERIA: medullary syndrome associated with spinal cord lesion extending for 3 or more contiguous spinal segments in magnetic resonance imaging (MRI). Clinical, radiological, and biochemical data were collected and subjects were rated on the Hughes functional disability scale (WHFDS) at 3 months. RESULTS: We evaluated 27 patients, 74% of whom were women; mean age was 35.22 years. The NMO-IgG antibody test was performed in 66.6% and oligoclonal band testing in 71%. NMO-IgG seropositivity was found exclusively in NMOSD patients (75%). Brain MRI was normal in 59.2% and revealed a mean of 7.9 affected spinal segments. Differential diagnoses revealed NMOSD (37%), idiopathic LETM (22.2%), lupus (11.1%), tumour (11.1%), dural fistula (7.4%), acute disseminated encephalomyelitis (7.4%), and a single case of multiple sclerosis (3.7%). Patients with lesions to >= 7 spinal segments showed poor recovery at 3 months (P<.001); these cases were associated with neoplastic, vascular, idiopathic, and lupus-related aetiologies. CONCLUSIONS: The most frequent causes of LETM in our cohort were NMOSD followed by idiopathic cases. Neoplastic, vascular, lupus related, and idiopathic LETM may constitute a critical group with a distinct prognosis and other treatment needs. PMID- 26526675 TI - Activity, stability and folding analysis of the chitinase from Entamoeba histolytica. AB - Human amebiasis, caused by the parasitic protozoan Entamoeba histolytica, remains as a significant public health issue in developing countries. The life cycle of the parasite compromises two main stages, trophozoite and cyst, linked by two major events: encystation and excystation. Interestingly, the cyst stage has a chitin wall that helps the parasite to withstand harsh environmental conditions. Since the amebic chitinase, EhCHT1, has been recognized as a key player in both encystation and excystation, it is plausible to consider that specific inhibition could arrest the life cycle of the parasite and, thus, stop the infection. However, to selectively target EhCHT1 it is important to recognize its unique biochemical features to have the ability to control its cellular function. Hence, to gain further insights into the structure-function relationship, we conducted an experimental approach to examine the effects of pH, temperature, and denaturant concentration on the enzymatic activity and protein stability. Additionally, dependence on in vivo oxidative folding was further studied using a bacterial model. Our results attest the potential of EhCHT1 as a target for the design and development of new or improved anti-amebic therapeutics. Likewise, the potential of the oxidoreductase EhPDI, involved in oxidative folding of amebic proteins, was also confirmed. PMID- 26526676 TI - Interleukin-6 promoter haplotypes are associated with etanercept response in patients with rheumatoid arthritis. AB - Indices prognosticating anti-tumor necrosis factor (TNF) response in patients with rheumatoid arthritis are a matter of interest. Differential outcome under anti-TNF and anti-interleukin-6 (IL-6) therapy raises the question whether genetic polymorphisms that have previously been linked to IL-6 production are associated with response to anti-TNF therapy. Fifty (50) rheumatoid arthritis (RA) patients were treated with etanercept (median 36 weeks, range 4-52). In terms of the EULAR response criteria, 25 patients responded well, 17 patients moderately and 8 patients not. By direct sequencing, the patients and 91 matched healthy controls were genotyped for the IL-6 promoter SNPs -597G > A (rs1800797), -572G > C (rs1800796) and -174G > C (rs1800795) and for an AnTn microsatellite tract at -373. Alleles and haplotypes were tested for association with disease susceptibility and therapy response. No significant difference was seen in the genotype distribution between patients and healthy controls. Confirming the results of previous studies, we observed a trend of -174G being more frequent in patients with a good or moderate therapy response. Beyond that, carriage of the A9T11 microsatellite allele within the -174G haplotype was associated most closely with a favourable response (relative risk 1.31; 95 % confidence interval 1.02-1.68). A subtle analysis of the IL-6 promoter giving respect to its complex haplotypic structure results in more precise information as to the association of genotypes with the long-term etanercept response. Despite a conclusive hypothesis that a genetically determined IL-6-dominated RA responds less well to anti-TNF, more work has to be done to provide us with reliable information regarding the functional aspects of these genetic polymorphisms. PMID- 26526677 TI - Insulin resistance and levels of adipokines in patients with untreated early rheumatoid arthritis. AB - The aim of this study is to investigate the presence of insulin resistance (IR) in patients with untreated early rheumatoid arthritis (ERA) and its relationship with adipokines, inflammatory cytokines, and treatment. In this prospective study, we enrolled 46 ERA patients with a disease duration of <1 year, and 45 sex , age-, race-, and body mass index (BMI)-matched controls. Patients and controls with diabetes or a history of glucocorticoid (GC) or disease-modifying antirheumatic drugs (DMARDs) use were excluded. Patients were assessed at the time of diagnosis (visit 1) and after 6 months of treatment (visit 2). The main outcomes were homeostatic model assessment of IR (HOMA-IR) and beta-cell function (HOMA-beta) and quantitative insulin sensitivity check index (QUICKI). A multivariate regression analysis was performed to analyze IR adjusting according to lipids, body composition, physical activity, nutrition, and inflammatory cytokine and adipokine levels. The baseline HOMA-IR, HOMA-beta, and QUICKI values were similar in both groups. However, patients showed lower levels of physical activity, total cholesterol, and high-density lipoprotein. Moreover, the inflammatory cytokines and resistin concentrations were higher in patients than controls. Multivariate analysis indicated that BMI and baseline rheumatoid factor levels were positively associated with HOMA-IR and HOMA-beta, and negatively with QUICKI. After DMARD treatment, patients showed improvements in inflammatory parameters and lipids whereas IR remained stable. Furthermore, adiponectin and resistin concentrations decreased slightly. Our data suggest that IR is not present in ERA patients either at diagnosis or at 6 months after treatment. However, symptom duration and fat mass appear to be related. PMID- 26526678 TI - Three Preservation Solutions for Cold Storage of Heart Allografts: A Systematic Review and Meta-Analysis. AB - Organ preservation solution has been designed to attenuate the detrimental effects during the ischemic period. The aim of this study was to systematically evaluate the evidence comparing preservation solutions for heart preservation. Studies were searched in PubMed, Embase, the Cochrane Library, the Transplant Library, and the International Clinical Trials Registry Platform. The primary outcomes were patient survival and donor heart dysfunction. The secondary outcomes were in-hospital mortality and enzyme gene expression. The University of Wisconsin solution (UW) was associated with a significantly improved survival at 30 days and 90 days (hazard ratio = 1.16, 95% confidence interval [CI] = 1.11 1.22, P < 0.00001; risk difference [RD] = 0.03, 95% CI = 0.01-0.05, P = 0.002), compared with Celsior. Hearts preserved with UW exhibited less ischemic necrosis than those preserved with Celsior (RD = -0.07, 95% CI = -0.08 to 0.05, P < 0.00001). UW was associated with better survival compared with histidine tryptophan-ketoglutarate solution (HTK). There was no statistical difference in donor heart dysfunction and in-hospital mortality outcomes when comparing HTK with Celsior solution. During static cold storage preservation, this study suggests that UW solution has better clinical outcomes for heart transplantation compared with the other two organ preservation solutions. Besides, the protective effect of Celsior solution is similar to HTK solution in donor heart preservation. PMID- 26526679 TI - Making CMAM relevant in India: the letter and the spirit. PMID- 26526680 TI - Reply to R Dasgupta et al. PMID- 26526682 TI - An Association between Single Nucleotide Polymorphisms of Lys751Gln ERCC2 Gene and Ovarian Cancer in Polish Women. AB - Aim. The aim of this study was to evaluate the role of the Lys751Gln (rs13181) ERCC2 gene polymorphism in clinical parameters and the risk for development of ovarian cancer. Material and Methods. The study consisted of 430 patients with ovarian cancer (mean age: 53.2 +/- 10.11) and 430 healthy subjects (mean age: 50.31 +/- 18.21). Analysis of the gene polymorphisms was performed using the PCR based restriction fragment length polymorphism (PCR-RFLP). The odds ratios (ORs) and 95% confidence intervals (CIs) for each genotype and allele were calculated. Results. The results obtained indicate that the genotype Gln/Gln is associated with an increased risk of ovarian cancer (OR 5.01; 95% CI 3.37-7.43; p < 0.0001). Association of Lys751Gln polymorphism with histological grading showed increased ERCC2 Gln/Gln (OR = 6.96; 95% CI 3.41-14.21; p < 0.0001) genotype in grading 1 as well as Gln allele overrepresentation (OR = 4.98; 95% CI 3.37-7.40; p < 0.0001) in G1 ovarian patients. Finally, with clinical FIGO staging under evaluation, an increase in ERCC2 Gln/Gln homozygote frequencies in staging I and Gln allele frequencies in SI were observed. Conclusion. On the basis of these results, we conclude that ERCC2 gene polymorphism Lys751Gln may be associated with an increased risk of ovarian carcinoma. PMID- 26526683 TI - Bacillus cereus AR156 primes induced systemic resistance by suppressing miR825/825* and activating defense-related genes in Arabidopsis. AB - Small RNAs play an important role in plant immune responses. However, their regulatory function in induced systemic resistance (ISR) is nascent. Bacillus cereus AR156 is a plant growth-promoting rhizobacterium that induces ISR in Arabidopsis against bacterial infection. Here, by comparing small RNA profiles of Pseudomonas syringae pv. tomato (Pst) DC3000-infected Arabidopsis with and without AR156 pretreatment, we identified a group of Arabidopsis microRNAs (miRNAs) that are differentially regulated by AR156 pretreatment. miR825 and miR825* are two miRNA generated from a single miRNA gene. Northern blot analysis indicated that they were significantly downregulated in Pst DC3000-infected plants pretreated with AR156, in contrast to the plants without AR156 pretreatment. miR825 targets two ubiquitin-protein ligases, while miR825* targets toll-interleukin-like receptor (TIR)-nucleotide binding site (NBS) and leucine rich repeat (LRR) type resistance (R) genes. The expression of these target genes negatively correlated with the expression of miR825 and miR825*. Moreover, transgenic plants showing reduced expression of miR825 and miR825* displayed enhanced resistance to Pst DC3000 infection, whereas transgenic plants overexpressing miR825 and miR825* were more susceptible. Taken together, our data indicates that Bacillus cereus AR156 pretreatment primes ISR to Pst infection by suppressing miR825 and miR825* and activating the defense related genes they targeted. PMID- 26526684 TI - The Plasmodium palmitoyl-S-acyl-transferase DHHC2 is essential for ookinete morphogenesis and malaria transmission. AB - The post-translational addition of C-16 long chain fatty acids to protein cysteine residues is catalysed by palmitoyl-S-acyl-transferases (PAT) and affects the affinity of a modified protein for membranes and therefore its subcellular localisation. In apicomplexan parasites this reversible protein modification regulates numerous biological processes and specifically affects cell motility, and invasion of host cells by Plasmodium falciparum merozoites and Toxoplasma gondii tachyzoites. Using inhibitor studies we show here that palmitoylation is key to transformation of zygotes into ookinetes during initial mosquito infection with P. berghei. We identify DHHC2 as a unique PAT mediating ookinete formation and morphogenesis. Essential for life cycle progression in asexual blood stage parasites and thus refractory to gene deletion analyses, we used promoter swap (ps) methodology to maintain dhhc2 expression in asexual blood stages but down regulate expression in sexual stage parasites and during post-fertilization development of the zygote. The ps mutant showed normal gamete formation, fertilisation and DNA replication to tetraploid cells, but was characterised by a complete block in post-fertilisation development and ookinete formation. Our report highlights the crucial nature of the DHHC2 palmitoyl-S-acyltransferase for transmission of the malaria parasite to the mosquito vector through its essential role for ookinete morphogenesis. PMID- 26526685 TI - Striatal adenosine-cannabinoid receptor interactions in rats over-expressing adenosine A2A receptors. AB - Adenosine A2A receptors (A2 A Rs) and cannabinoid CB1 receptors (CB1 Rs) are highly expressed in the striatum, where they functionally interact and form A2A /CB1 heteroreceptor complexes. We investigated the effects of CB1 R stimulation in a transgenic rat strain over-expressing A2 A Rs under the control of the neural-specific enolase promoter (NSEA2A rats) and in age-matched wild-type (WT) animals. The effects of the CB1 R agonist WIN 55,212-2 (WIN) were significantly lower in NSEA2A rats than in WT animals, as demonstrated by i) electrophysiological recordings of synaptic transmission in corticostriatal slices; ii) the measurement of glutamate outflow from striatal synaptosomes and iii) in vivo experiments on locomotor activity. Moreover, while the effects of WIN were modulated by both A2 A R agonist (CGS 21680) and antagonists (ZM 241385, KW-6002 and SCH-442416) in WT animals, the A2 A R antagonists failed to influence WIN-mediated effects in NSEA2A rats. The present results demonstrate that in rats with genetic neuronal over-expression of A2 A Rs, the effects mediated by CB1 R activation in the striatum are significantly reduced, suggesting a change in the stoichiometry of A2A and CB1 receptors and providing a strategy to dissect the involvement of A2 A R forming or not forming heteromers in the modulation of striatal functions. These findings add additional evidence for the existence of an interaction between striatal A2 A Rs and CB1 Rs, playing a fundamental role in the regulation of striatal functions. We studied A2A -CB1 receptor interaction in transgenic rats over-expressing adenosine A2A receptors under the control of the neuron-specific enolase promoter (NSEA2A ). In these rats, we demonstrated a reduced effect of the CB1 receptor agonist WIN 55,212-2 in the modulation of corticostriatal synaptic transmission and locomotor activity, while CB1 receptor expression level did not change with respect to WT rats. A reduction in the expression of A2A -CB1 receptor heteromers is postulated. PMID- 26526687 TI - Acute Pain. PMID- 26526686 TI - Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies. AB - The best-known peripheral neuropathies are those affecting the large, myelinated motor and sensory fibers. These have well-established immunological causes and therapies. Far less is known about the somatic and autonomic "small fibers"; the unmyelinated C-fibers, thinly myelinated A-deltas, and postganglionic sympathetics. The small fibers sense pain and itch, innervate internal organs and tissues, and modulate the inflammatory and immune responses. Symptoms of small fiber neuropathy include chronic pain and itch, sensory impairment, edema, and skin color, temperature, and sweating changes. Small-fiber polyneuropathy (SFPN) also causes cardiovascular, gastrointestinal, and urological symptoms, the neurologic origin of which often remains unrecognized. Routine electrodiagnostic study does not detect SFPN, so skin biopsies immunolabeled to reveal axons are recommended for diagnostic confirmation. Preliminary evidence suggests that dysimmunity causes some cases of small-fiber neuropathy. Several autoimmune diseases, including Sjogren and celiac, are associated with painful small-fiber ganglionopathy and distal axonopathy, and some patients with "idiopathic" SFPN have evidence of organ-specific dysimmunity, including serological markers. Dysimmune SFPN first came into focus in children and teenagers as they lack other risk factors, for example diabetes or toxic exposures. In them, the rudimentary evidence suggests humoral rather than cellular mechanisms and complement consumption. Preliminary evidence supports efficacy of corticosteroids and immunoglobulins in carefully selected children and adult patients. This paper reviews the evidence of immune causality and the limited data regarding immunotherapy for small-fiber-predominant ganglionitis, regional neuropathy (complex regional pain syndrome), and distal SFPN. These demonstrate the need to develop case definitions and outcome metrics to improve diagnosis, enable prospective trials, and dissect the mechanisms of small-fiber neuropathy. PMID- 26526688 TI - Mitogen Activated Protein Kinase (MPK) Interacts With Auxin Influx Carrier (OsAux/LAX1) Involved in Auxin Signaling in Plant. AB - BACKGROUND: Mitogen activated protein kinases (MPKs) are serine/threonine protein kinases that contain characteristic T-x-Y motif in the activation loop region. MPKs are important signaling molecules involved in diverse signaling cascades that regulate plant growth, development and stress responses by conducting phosphorylation events in their target proteins. MPKs phosphorylate their target proteins at either S-P/T-P (Serine/Proline/Threonine) amino acid. To understand, if MPKs are involved in the auxin signaling cascade, we identified probable target proteins of MPKs involved in auxin signaling or transport processes. RESULTS: A genome-wide search of the rice genome database led us to identification of the OsAux/LAX1 gene as a potential downstream target protein of MPKs. In-silico analysis predicted that MPKs interact with OsAux/LAX1 proteins which were validated by a yeast two-hybrid assay that showed OsMPK3, OsMPK4 and OsMPK6 are physically interact with OsAux/LAX1 protein. CONCLUSION: The yeast two hybrid interaction showed that MPKs are directly involved in auxin signaling events in plants. This is the first study to report direct involvement of MPKs in the auxin signaling pathway. PMID- 26526690 TI - Life course health and healthcare utilization among adults with spina bifida. AB - AIM: To evaluate the prevalence of organ system disorders and describe healthcare utilization among adults with spina bifida at a regional clinic. METHOD: This study was a structured chart review using the Rochester Health Status Survey-IV. 65 males, 57 females aged 16 to 59 years were seen at the Spina Bifida Center of Central New York between January 2007 and December 2008 (annual hospitalization rate was 15 out of 100). RESULTS: Hospitalizations and acute outpatient visits were associated with having shunted hydrocephalus, whereas visits to the emergency department were associated with having a decubitus ulcer. Logistic regression models revealed that older adults made proportionately fewer visits to primary care providers than younger adults (odds ratio 0.919; p=0.02). Yet for every 1-year increase in age, the odds of being hospitalized increased by 5% (odds ratio 1.051; p=0.03). INTERPRETATION: Adults with spina bifida have multiple organ-system disorders. They have greater difficulty accessing services, and utilize emergency and inpatient healthcare at higher rates than the general population. In the future, adults with spina bifida will require access to more medical care and preventive services if they are to have optimal health, well being, and functioning. PMID- 26526693 TI - Drug-Resistant Brain Metastases: A Role for Pharmacology, Tumor Evolution, and Too-Late Therapy. AB - Two recent studies report deep molecular profiling of matched brain metastases and primary tumors. In both studies, somatic alterations in the brain metastases were frequently discordant with those in the primary tumor, suggesting divergent evolution at metastatic sites and raising questions about the use of biomarkers in patients in clinical trials with targeted therapies. PMID- 26526689 TI - The "tail" of Connexin43: An unexpected journey from alternative translation to trafficking. AB - With each heartbeat, Connexin43 (Cx43) cell-cell communication gap junctions are needed to rapidly spread and coordinate excitation signals for an effective heart contraction. The correct formation and delivery of channels to their respective membrane subdomain is referred to as protein trafficking. Altered Cx43 trafficking is a dangerous complication of diseased myocardium which contributes to the arrhythmias of sudden cardiac death. Cx43 has also been found to regulate many other cellular processes that cannot be explained by cell-cell communication. We recently identified the existence of up to six endogenous internally translated Cx43 N-terminal truncated isoforms from the same full length mRNA molecule. This is the first evidence that alternative translation is possible for human ion channels and in human heart. Interestingly, we found that these internally translated isoforms, more specifically the 20 kDa isoform (GJA1 20k), is important for delivery of Cx43 to its respective membrane subdomain. This review covers recent advances in Cx43 trafficking and potential importance of alternatively translated Cx43 truncated isoforms. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26526694 TI - The SIN1-PH Domain Connects mTORC2 to PI3K. AB - The mTOR complex 2, mTORC2, is a critical downstream effector of PI3K that stimulates AGC kinase members, including AKT, PKC, and SGK. Liu and colleagues reported that the pleckstrin homology domain of SIN1, an essential component of mTORC2, directly binds the PI3K product PtdIns(3,4,5)P3 to promote mTORC2 kinase activation and membrane localization, thereby revealing a mechanistic link between PI3K and mTORC2. Cancer Discov; 5(11); 1127-9. (c)2015 AACR.See related article by Liu and colleagues, p. 1194. PMID- 26526695 TI - Large-Scale Drug Screens Support Precision Medicine. AB - The major challenge underlying the emerging precision medicine initiative is to make links between cancer subsets and drugs that can be used to guide treatment of individual patients, leading to improved outcomes and decreased toxicity. Seashore-Ludlow and colleagues support this effort by reporting measurements of responses of 664 adherent cancer cell lines to 70 FDA-approved drugs, 100 experimental compounds, and 311 small-molecule probes. They use a novel Annotated Cluster Multidimensional Enrichment algorithm to identify drug mechanisms of action, molecular markers of response, responsive cancer subtypes, and compounds that produce synergistic cell inhibition. PMID- 26526696 TI - All the World's a Stage: Facilitating Discovery Science and Improved Cancer Care through the Global Alliance for Genomics and Health. AB - The recent explosion of genetic and clinical data generated from tumor genome analysis presents an unparalleled opportunity to enhance our understanding of cancer, but this opportunity is compromised by the reluctance of many in the scientific community to share datasets and the lack of interoperability between different data platforms. The Global Alliance for Genomics and Health is addressing these barriers and challenges through a cooperative framework that encourages "team science" and responsible data sharing, complemented by the development of a series of application program interfaces that link different data platforms, thus breaking down traditional silos and liberating the data to enable new discoveries and ultimately benefit patients. PMID- 26526697 TI - Synthesis of water-soluble silicon-porphyrin: protolytic behaviour of axially coordinated hydroxy groups. AB - A new water-soluble silicon(IV)-tetra(4-carboxyphenyl)porphyrin (SiTCPP) with silicon(iv), the second most abundant element on Earth, in the center of porphyrin was synthesized. Fundamental properties including protolytic behaviour of axially coordinating hydroxy groups, and electrochemical behaviour were characterized. The properties were compared with those of silicon(IV)-tetra(2,4,6 trimethylphenyl)porphyrin (SiTMP) and silicon(IV)-tetra(4 trifluoromethylphenyl)porphyrin (SiTFMPP) and discussed in respect to the electron donating/withdrawing effect of the substituents. Two axially coordinating hydroxy groups of SiTCPP exhibit a four-step protolytic behaviour under the acidic conditions along with a single step protolysis of peripheral carboxyl groups. Though SiTCPP and SiTFMPP did not show any reactivity in the photochemical oxygenation of a substrate with K2PtCl6 as a sacrificial electron acceptor, the first oxidation wave in the electrochemical process of SiTCPP and SiTFMPP showed catalytic behaviour in aqueous acetonitrile solution at any pH condition, in contrast to SiTMP which has only a reversible oxidation wave under neutral and weakly acidic conditions. The criteria for the electrochemical oxidative activation of water and the photooxygenation of the substrate were obtained. The higher oxidation wave of Si-porphyrins than ~0.86 volt vs. SHE is required for the electrochemical oxidation of water, while suitable protecting groups such as a methyl substituent is a requisite for the photochemical oxygenation with K2PtCl6 as a sacrificial electron acceptor. PMID- 26526699 TI - A new method for separation and determination of Cr(III) and Cr(VI) in water samples by high-performance liquid chromatography based on anion exchange stationary phase of ionic liquid modified silica. AB - In this work, N-methylimidazolium-chloride ionic liquid functionalized silica was prepared and used as an anion-exchange stationary phase for separation of chromium species by high-performance liquid chromatography (HPLC) with UV detection at 200 nm. The Cr(VI) as HCr2O7(-) and chelated Cr(III) with potassium hydrogen phthalate (PHP) as Cr(PHP)2 (-) was retained on the prepared column and separated using a mobile phase composed of 5% methanol in 25 mM phosphate buffer at pH 6.5. Several variables affecting the chelation/separation steps were modeled by response surface methodology (RSM) using Box-Behnken (BBD) design. The significance of the independent variables and their interactions were tested by the analysis of variances (ANOVA) with 95% confidence limit. Under the optimized conditions, the Cr(III) and Cr(VI) anionic species were well separated with a single peak for each Cr species at retention times of 2.3 and 4.3 min, respectively. The relationship between the peak area and concentration was linear in the range of 0.025-30 for Cr(III) and 0.5-20 mg L(-1) for Cr(VI) with detection limits of 0.010 and 0.210 mg L(-1) for Cr(III) and Cr(VI), respectively. The proposed method was validated by simultaneous separation and determination of the Cr species in tap and underground water samples without impose to any pretreatment. PMID- 26526700 TI - ICMJE authorship criteria are not met in a substantial proportion of manuscripts submitted to Biochemia Medica. AB - INTRODUCTION: Our aim was to investigate if: (a) authors of Biochemia Medica meet authorship criteria given by International Committee of Medical Journal Editors (ICMJE), (b) authorship violations are more frequent in submissions containing some type of scientific misconduct. MATERIALS AND METHODS: Self-reported authorship contributions regarding the three ICMJE criteria were analysed for all submissions to Biochemia Medica (February 2013-April 2015) which were forwarded to peer-review. To test the differences in frequencies we used Chi-squared test. P<0.05 was considered statistically significant. RESULTS: 186 manuscripts were authored by 804 authors. All ICMJE criteria were met by 487/804 (61%) authors. The first and the last author met all the criteria more frequently than those authors in between (P<0.001). The degree to which ICMJE criteria was met for the first author did not differ between manuscripts authored by only one author and those authored by >1 author (P=0.859). In 9% of the manuscripts ICMJE criteria were not met by a single author. Authors of the 171/186 manuscripts declared that all persons qualify for authorship but only 49% of them satisfied all ICMJE criteria. Authors have failed to acknowledge contributors in 88/186 (47%) manuscripts; instead these contributors have been listed as authors without fulfilling ICMJE criteria. Authorship violation was not more common in 42 manuscripts with some type of scientific misconduct (P=0.135). CONCLUSION: Large proportion of authors of the manuscripts submitted to Biochemia Medica do not fulfil ICMJE criteria. Violation of authorship criteria is not more common for manuscripts with some type of scientific misconduct. PMID- 26526698 TI - Altered brain responses in subjects with irritable bowel syndrome during cued and uncued pain expectation. AB - BACKGROUND: A majority of the subjects with irritable bowel syndrome (IBS) show increased behavioral and brain responses to expected and delivered aversive visceral stimuli during controlled rectal balloon distension, and during palpation of the sigmoid colon. We aimed to determine if altered brain responses to cued and uncued pain expectation are also seen in the context of a noxious somatic pain stimulus applied to the same dermatome as the sigmoid colon. METHODS: A task-dependent functional magnetic resonance imaging technique was used to investigate the brain activity of 37 healthy controls (18 females) and 37 IBS subjects (21 females) during: (i) a cued expectation of an electric shock to the abdomen vs a cued safe condition; and (ii) an uncued cross-hair condition in which the threat is primarily based on context vs a cued safe condition. KEY RESULTS: Regions within the salience, attention, default mode, and emotional arousal networks were more activated by the cued abdominal threat condition and the uncued condition than in the cued safe condition. During the uncued condition contrasted to the cued safe condition, IBS subjects (compared to healthy control subjects) showed greater brain activations in the affective (amygdala, anterior insula) and attentional (middle frontal gyrus) regions, and in the thalamus and precuneus. These disease-related differences were primarily seen in female subjects. CONCLUSIONS & INFERENCES: The observed greater engagement of cognitive and emotional brain networks in IBS subjects during contextual threat may reflect the propensity of IBS subjects to overestimate the likelihood and severity of future abdominal pain. PMID- 26526701 TI - Allergic reactions in arthroplasty: myth or serious problem? AB - PURPOSE: The purpose of this study was to determine the prevalence of sensitisation to chromium, cobalt, nickel, or a cement component in patients who received endoprosthetic surgery at our institution. Also, we aimed to assess the portion related to allergic reactions in endoprosthetic revisions and to follow up those patients after allergic reaction related revisions. METHODS: We selected patients with a pre-operative known sensitisation to chromium, cobalt, nickel, or a cement component for a post-operative allergic reaction. All patients who received revision surgery because of a potential allergic reaction were followed up post revision surgery. RESULTS: Eight hundred fifty-five patients were pre operative known to have a sensitisation to chromium, cobalt, nickel, or a cement component. Six hundred eighty-two patients (79.8 %) received a primary arthroplasty, and 173 patients (20.2 %) received a revision surgery. Seventeen patients (2.0 %) were revised because of allergic reactions. Allergic reactions were the cause for approximately 0.2 % of all endoprosthetic revisions and for 9.8 % of revisions in patients with sensitisation to one of the reviewed components. Potential allergens were strictly avoided in the replaced prosthesis. Outcome scores improved post-operatively. CONCLUSIONS: The allergic patient should be thoroughly informed about potential reactions resulting from implant choice. Our study can serve as risk assessments by quantifying the incidence of allergic reactions due to endoprosthetic treatment. PMID- 26526702 TI - Increased bleeding risk during percutaneous coronary interventions by arterial hypertension. AB - OBJECTIVES: We aimed to assess the association between arterial hypertension and bleeding in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: The impact of arterial hypertension on bleeding risk of patients with coronary artery disease undergoing PCI is unknown. METHODS: This study included 14,180 patients who underwent PCI. Bleeding was defined using the Bleeding Academic Research Consortium (BARC) criteria. Arterial hypertension was defined as treatment with antihypertensive drugs or a systolic blood pressure >140 mm Hg and/or diastolic blood pressure value >90 mm Hg documented on at least 2 occasions. The primary outcome was bleeding rate within 30 days of PCI. RESULTS: Overall, 11,066 patients (78.0%) had arterial hypertension. Bleeding events occurred in 1,232 patients with arterial hypertension and 278 patients without arterial hypertension (11.1% vs 8.9%; odds ratio [OR] = 1.28, 95% confidence interval [CI] 1.11-1.46, P < 0.001). Access-site bleeding occurred in 730 patients with arterial hypertension and 175 patients without arterial hypertension (6.6% vs 5.6%: OR = 1.19 [1.01-1.41], P = 0.049). Non-access-site bleeding occurred in 502 patients with and 103 patients without arterial hypertension (4.5% vs 3.3%; OR = 1.39 [1.12-1.72], P = 0.003). After adjustment, arterial hypertension was significantly associated with any bleeding (adjusted OR = 1.41 [1.19-1.67], P < 0.001), access-site bleeding (adjusted OR = 1.36 [1.10 1.68], P = 0.005) and non-access-site bleeding (adjusted OR = 1.42 [1.09-1.83], P = 0.008). A history of arterial hypertension increased the risk of non-access site bleeding (P = 0.002), whereas systolic blood pressure at the time of PCI increased the risk of access site bleeding (P = 0.018). CONCLUSIONS: Arterial hypertension is associated with increased risk of bleeding during PCI procedures. (c) 2015 Wiley Periodicals, Inc. PMID- 26526703 TI - How neurologists are paid: Part 2: Private practice, research grants, academic and nonclinical activities. AB - Part 1 of this series focused on factors influencing payment for patient care services. In Part 2, we review compensation models for nonpatient activity such as medical legal reviews, committee participation, and collaboration with the pharmaceutical industry. Compensation to neurologists in private practice is commonly in the form of guaranteed salary and bonuses. Salary for neurologists in academic medicine has changed considerably over the past 3 decades, from small departments with faculty supported by grants and volunteer faculty, to large departments with faculty split between those with research grant support and those focusing on patient care and teaching. Compensation models in academic medicine range from straight salary without bonus to straight salary with personal or shared bonus and salary based on relative value units. PMID- 26526704 TI - Pain in Older Adults: Epidemiology, Impact and Barriers to Management. AB - There will be increased numbers of older adults in society in the next few decades.Older adults are more likely to have pain problems and other co morbidities.Generally pain is poorly managed in older adults and this becomes worse when cognitive impairment exists.The impact of chronic pain on older adults will be greater than that of their younger counterparts in terms of social isolation.Attitudes and barriers exist in both the older adults themselves and their younger counterparts. PMID- 26526705 TI - Prescribing opioid analgesics for chronic non-malignant pain in general practice a survey of attitudes and practice. AB - BACKGROUND: This study replicates a previous postal survey of general practitioners (GPs) to explore whether attitudes to opioid prescribing have changed at a time when the number of opioid prescriptions issued in primary care has increased. METHODS: With permission, a 57-item survey instrument previously utilised with GPs in the South-west of England was circulated to 214 GPs in city centre practices in the East Midlands. The survey instrument included items relating to practice context, prescribing patterns and attitudes about analgesic medication, perceived prescribing frequency and reluctance to prescribe. RESULTS: Responses were received from 94 GPs (45%). Almost three-quarters (72.7%) of GPs reported that they sometimes or frequently prescribed strong opioids for chronic non-cancer pain. Over two-thirds (67.8%) reported that they were sometimes or frequently reluctant to prescribe strong opioids for chronic non-cancer pain. No significant relationships were observed between perceived frequency of prescribing and a range of demographic factors; however, concerns about 'physical dependence', 'long-term commitment to prescribing' and 'media reports' were associated with less frequent reported prescribing of, and greater reluctance to prescribe, strong opioids. DISCUSSION: Given the national trend for increased opioid prescriptions, it is unsurprising that more frequent self-reported prescribing is reported here; however, increased frequency does not translate into less reluctance about prescribing. The effectiveness of strong opioids for chronic pain is recognised, but concerns about addiction, dependence and misuse inform a reluctance to use strong opioids. These juxtapositions highlight a continued need for clearer understanding of GPs' perceptions of strong opioids and point to the potential benefit of dedicated guidelines or specialist education and training to address their uncertainties. PMID- 26526706 TI - Efficient and facile synthesis of novel stable monodeuterium labeled ractopamine. AB - A novel synthetic route to stable deuterium labeled ractopamine was disclosed with 6.49% total yield and 97.7% isotopic abundance. Its structure and the isotope-abundance were confirmed according to (1)H-NMR and high-resolution mass spectrometry. PMID- 26526707 TI - The impact of resident involvement on otolaryngology surgical outcomes. AB - OBJECTIVES/HYPOTHESIS: Intraoperative experience is an essential element of surgical training, but has the potential to impact patient outcomes. The purpose of this study was two-fold: 1) to evaluate the effect of resident involvement on morbidity and mortality following otolaryngology procedures and 2) to examine the influence of resident training level on the same outcomes. STUDY DESIGN: Retrospective cohort study. METHODS: This study reviewed 2,320,920 patients captured in the 2005 to 2012 National Surgical Quality Improvement Program databases to identify surgical otolaryngology cases. Outcomes of interest included surgical complications, medical complications, and mortality. Cases with and without resident involvement were propensity matched (caliper = 0.2) to account for nonrandomized assignment, and data were subject to multivariate logistic regression analyses. RESULTS: Residents participated in 38.4% of the 20,307 cases identified. Cases with resident involvement demonstrated longer operative duration (178.8 minutes vs. 80.1 minutes, P < .001), increased surgical complexity (23.5 relative value units [RVU] vs. 12.4 RVU, P < .001) and greater overall morbidity burden. Logistic regression analyses of the matched cohort revealed that resident participation did not independently increase morbidity (odds ratio [OR] = 0.969, P = .751) or mortality (OR = 0.893, P = .758). A separate logistic regression analysis of the unmatched cohort using resident postgraduate year showed that training level did not confer differential risk to patients. CONCLUSIONS: Our data indicate that resident involvement does not increase the risk of morbidity or mortality, and that trainees are being assigned to appropriate cases for their level of experience. These findings suggest that the contemporary paradigm of graduate otolaryngology surgical education does not negatively impact patient outcomes. LEVEL OF EVIDENCE: 2c Laryngoscope, 126:602 607, 2016. PMID- 26526708 TI - Polymer waveguide couplers based on metal nanoparticle-polymer nanocomposites. AB - In this work Au nanoparticles (AuNPs) are incorporated into poly(methyl methacrylate) (PMMA) waveguides to develop optical couplers that are compatible with planar organic polymer photonics. A method for growing AuNPs (of 10 to 100 nm in size) inside the commercially available Novolak resist is proposed with the intention of tuning the plasmon resonance and the absorption/scattering efficiencies inside the patterned structures. The refractive index of the MNP Novolak nanocomposite (MNPs: noble metal nanoparticles) is carefully analysed both experimentally and numerically in order to find the appropriate fabrication conditions (filling factor and growth time) to optimize the scattering cross section at a desired wavelength. Then the nanocomposite is patterned inside a PMMA waveguide to exploit its scattering properties to couple and guide a normal incident laser light beam along the polymer. In this way, light coupling is experimentally demonstrated in a broad wavelength range (404-780 nm). Due to the elliptical shape of the MNPs the nanocomposite demonstrates a birefringence, which enhances the coupling to the TE mode up to efficiencies of around 1%. PMID- 26526709 TI - FERN Ethnomedicinal Plant Database: Exploring Fern Ethnomedicinal Plants Knowledge for Computational Drug Discovery. AB - Fern plants are known for their ethnomedicinal applications. Huge amount of fern medicinal plants information is scattered in the form of text. Hence, database development would be an appropriate endeavor to cope with the situation. So by looking at the importance of medicinally useful fern plants, we developed a web based database which contains information about several group of ferns, their medicinal uses, chemical constituents as well as protein/enzyme sequences isolated from different fern plants. Fern ethnomedicinal plant database is an all embracing, content management web-based database system, used to retrieve collection of factual knowledge related to the ethnomedicinal fern species. Most of the protein/enzyme sequences have been extracted from NCBI Protein sequence database. The fern species, family name, identification, taxonomy ID from NCBI, geographical occurrence, trial for, plant parts used, ethnomedicinal importance, morphological characteristics, collected from various scientific literatures and journals available in the text form. NCBI's BLAST, InterPro, phylogeny, Clustal W web source has also been provided for the future comparative studies. So users can get information related to fern plants and their medicinal applications at one place. This Fern ethnomedicinal plant database includes information of 100 fern medicinal species. This web based database would be an advantageous to derive information specifically for computational drug discovery, botanists or botanical interested persons, pharmacologists, researchers, biochemists, plant biotechnologists, ayurvedic practitioners, doctors/pharmacists, traditional medicinal users, farmers, agricultural students and teachers from universities as well as colleges and finally fern plant lovers. This effort would be useful to provide essential knowledge for the users about the adventitious applications for drug discovery, applications, conservation of fern species around the world and finally to create social awareness. PMID- 26526710 TI - Novel Thiosemicarbazide Hybrids with Amino Acids and Peptides Against Hepatocellular Carcinoma: A Molecular Designing Approach Towards Multikinase Inhibitor. AB - Hepatocellular Carcinoma is the most common primary malignant tumor of the liver. Development of multidrug resistance is the main obstacle to the success of anticancer drugs. In this study, designing and docking study of thiosemicarbazide hybrids with amino acids or peptides against hepatocellular carcinoma was performed since hybrids of biologically active compounds with amino acids or peptides may show target specificity and lower toxicity. All the structures were drawn in 2D platform and converted to the 3D platform using ChemDraw 10.0. Evaluations of ADME properties were done by using QikProp 3.0 to check for the possibility of oral delivery. In silico prediction of LD50 values were performed using Pro-Tox webserver. Interestingly, it was found that conjugation with amino acids decreases toxicity and increases the therapeutic index of thiosemicarbazide. Finally, all the compounds were docked to the crystal structure of the Vascular Endothelial Growth Factor Receptor-2 and Checkpoint kinase-1 utilizing Glide 5.0, Schrodinger 8.5, to understand the interaction of ligands with the receptor. A significant number of derivatives have been found active in both the receptors and also displayed multikinase inhibitory activity similar to Sorafenib, against hepatocellular carcinoma. Further, wet lab synthesis, in vitro ADMET and biological screening studies need to be performed to prove that designed compounds are effective against hepatocellular carcinoma as predicted by molecular modeling. However, as predicted by molecular modeling, the efficacy of designed compounds against hepatocellular carcinoma, needs to be confirmed by wet lab synthesis, in vitro ADMET and biological screening studies. PMID- 26526711 TI - Rational Design and Optimization of Trypsin Inhibitory Peptides with Antibacterial Activity. AB - Small natural or synthetic peptides have been reported to exhibit potent inhibitory capability against trypsin, some of which were also found to have antibacterial potency. Here, we described a successful application of in silico in vitro integrated approach to rationally design and optimize bifunctional peptides with both trypsin inhibitory and antimicrobial activities. In the procedure, computer-aided methods including protein docking, peptide redocking, molecular dynamics simulations and binding free energy calculations were employed to model and analyze the intermolecular interaction between human trypsin (hT) and natural trypsin inhibitors (TIs). Based on the modeled hT-TI complex structures a number of promising peptide fragments were derived from the trypsin inhibitory loop of TIs, which were then tested experimentally to determine their inhibitory potency on recombinant hT protein as well as their antibacterial potency against three clinical strains. Consequently, few peptides were found to possess a good profile of trypsin inhibitory and antibacterial bi-functionality. Structural visualization and noncovalent examination of hT complex with a potent peptide revealed that the hydrophobic forces and van der Waals contacts between the peptide nonpolar residues and the hydrophobic pocket around hT active site confer significant stability to the complex architecture, while few specific hydrogen bonds and cation-pi interactions at the complex interface contribute to peptide selectivity for hT. PMID- 26526712 TI - Veterans Affairs Office of Research and Development: Research Programs and Emerging Opportunities in Digestive Diseases Research. PMID- 26526713 TI - Agreement Between Rectosigmoidoscopy and Colonoscopy Analyses of Disease Activity and Healing in Patients With Ulcerative Colitis. AB - BACKGROUND & AIMS: Endoscopy limited to the rectosigmoid colon is the standard technique used to measure endoscopic healing in ulcerative colitis (UC) clinical trials. We evaluated whether rectosigmoidoscopy adequately measures UC activity in the more proximal colon. METHODS: We analyzed data from a phase 2, placebo controlled study that evaluated the efficacy and safety of etrolizumab in patients with moderate to severely active UC who had not responded to standard therapy. Central readers determined Mayo Clinic endoscopic subscores (MCSe) and ulcerative colitis endoscopic index of severity (UCEIS) scores from the rectosigmoid and proximal colon in videos of 331 examinations performed at baseline, week 6, and week 10. Rates of endoscopic healing (MCSe <= 1, MCSe = 0) and scores from rectosigmoidoscopy and colonoscopy analyses were compared among 239 examinations with endoscopic assessment proximal to the rectosigmoid colon. RESULTS: There was a high degree of correlation between findings from rectosigmoidoscopy vs colonoscopy in assessment of disease activity based on MCSe of 2 or higher (r = 0.84) or MCSe of 1 or higher (r = 0.96), or the UCEIS score (r = 0.92). In 230 of 239 videos, findings from rectosigmoidoscopy agreed with those from colonoscopy in the detection of active disease (MCSe >= 2; n = 205) or healing (MCSe <= 1; n = 25). In 9 videos (2 taken at baseline, 7 taken after treatment), colonoscopy found proximal disease activity not detected by rectosigmoidoscopy. Post-treatment discordance was more frequent in the placebo group, affecting assessment of efficacy at week 10. When endoscopic healing was defined as MCSe of 0, there were discordant findings from only 1 video. CONCLUSIONS: There is a high degree of correlation in assessments of UC activity made by rectosigmoidoscopy vs colonoscopy. For detection of endoscopic healing (MCSe <= 1), colonoscopy found persistent proximal lesions in the placebo group, which affected efficacy analyses. When endoscopic healing was defined as MCSe of 0, the concordance between rectosigmoidoscopy and colonoscopy was nearly perfect. PMID- 26526714 TI - A New Scalpel for the Treatment of Pancreatic Cancer: Targeting Stromal-Derived STAT3 Signaling. PMID- 26526715 TI - Hirschsprung Disease and Activation of Hedgehog Signaling via GLI1-3 Mutations. PMID- 26526717 TI - Library of diversely substituted 2-(quinolin-4-yl)imidazolines delivers novel non cytotoxic antitubercular leads. AB - A novel library based on quinolin-4-ylimidazoline core was designed to incorporate a general quinoline antimicrobial pharmacophore. A synthesis of the well-characterized library of 36 compounds was achieved using the Pd-catalyzed Buchwald-Hartwig-type imidazoline arylation chemistry developed earlier. Compounds were tested for biological activity and were found to possess no antimalarial activity. However, the library delivered two promising antitubercular leads, which are non-cytotoxic and can be further optimized with respect to antimycobacterial potency. PMID- 26526716 TI - BCL3 Reduces the Sterile Inflammatory Response in Pancreatic and Biliary Tissues. AB - BACKGROUND & AIMS: Under conditions of inflammation in the absence of micro organisms (sterile inflammation), necrotic cells release damage-associated molecular patterns that bind to Toll-like receptors on immune cells to activate a signaling pathway that involves activation of IkappaB kinase and nuclear factor kappaB (NF-kappaB). Little is known about the mechanisms that control NF-kappaB activity during sterile inflammation. We analyzed the contribution of B-cell CLL/lymphoma 3 (BCL3), a transcription factor that associates with NF-kappaB, in control of sterile inflammation in the pancreas and biliary system of mice. METHODS: Acute pancreatitis (AP) was induced in C57BL/6 (control) and Bcl3(-/-) mice by intraperitoneal injection of cerulein or pancreatic infusion of sodium taurocholate. We also studied Mdr2(-/-) mice, which develop spontaneous biliary inflammation, as well as Bcl3(-/-)Mdr2(-/-) mice. We performed immunohistochemical analyses of inflamed and noninflamed regions of pancreatic tissue from patients with AP or primary sclerosing cholangitis (PSC), as well as from mice. Immune cells were characterized by fluorescence-activated cell sorting analysis. Control or Bcl3(-/-) mice were irradiated, injected with bone marrow from Bcl3(-/-) or control mice, and AP was induced. RESULTS: Pancreatic or biliary tissues from patients with AP or PSC had higher levels of BCL3 and phosphorylated RelA and IkappaBalpha in inflamed vs noninflamed regions. Levels of BCL3 were higher in pancreata from control mice given cerulein than from mice without AP, and were higher in biliary tissues from Mdr2(-/-) mice than from control mice. Bcl3(-/-) mice developed more severe AP after administration of cerulein or sodium taurocholate than control mice; pancreata from the Bcl3(-/-) mice with AP had greater numbers of macrophages, myeloid-derived suppressor cells, dendritic cells, and granulocytes than control mice with AP. Activation of NF-kappaB was significantly prolonged in Bcl3(-/-) mice with AP, compared with control mice with AP. Bcl3(-/-)Mdr2(-/-) mice developed more severe cholestasis and had increased markers of liver injury and increased proliferation of biliary epithelial cells and hepatocytes than Mdr2(-/-) mice. In experiments with bone marrow chimeras, expression of BCL3 by acinar cells, but not myeloid cells, was required for reduction of inflammation during development of AP. BCL3 inhibited ubiquitination and proteasome-mediated degradation of p50 homodimers, which prolonged binding of NF-kappaB heterodimers to DNA. CONCLUSIONS: BCL3 is up regulated in inflamed pancreatic or biliary tissues from mice and patients with AP or cholangitis. Its production appears to reduce the inflammatory response in these tissues via blocking ubiquitination and proteasome-mediated degradation of p50 homodimers. PMID- 26526718 TI - The need of travelling to another city to be attended in a Hospital Clinic for obesity. Does it affect to the adequacy of referrals from Primary Care? PMID- 26526719 TI - Risk of malignancy in thyroid nodules with atipia of undetermined significance. AB - INTRODUCTION: Prevalence of malignancy among cytologies with atypia of undetermined significance (Bethesda category III) is variable, ranging from 5% 37% in the different studies. There is thus no agreement on whether FNA should be repeated or surgery should be performed in these cases. The aim of this paper was to analyze the risk of malignancy in order to establish the most adequate clinical approach. MATERIAL AND METHODS: We analyzed 431 thyroid cytologies performed at our hospital since the introduction of Bethesda System (from January 2011 to September 2014), of which 32 (7.1%) were labeled as category III. The second FNA, when performed, and the histological results after surgery were reviewed. RESULTS: Twenty-three patients (82.1%) underwent thyroidectomy, while repeat FNA was performed in the remaining 5 patients (17.9%). Cytology was reported as benign (category II) in 3 (60%) and as unsatisfactory (category I) in 2 (40%), who underwent thyroidectomy. Thirteen of the 25 (52%) surgical thyroid specimens showed no malignancy, while differentiated thyroid carcinomas were found in 12 (48%): papillary cancer in 10 (83.3%), follicular cancer in 1 (8.3%), and papillary cancer with follicular areas in 1 (8.3%). The risk of malignancy of Bethesda category III in our patients was 42.9%-48.0%. CONCLUSION: We recommend thyroidectomy for all patients with of cytological Bethesda category III. PMID- 26526720 TI - Are there any new insights for G-CSF and/or AMD3100 in chemotherapy of haematological malignants? AB - AML is a common life-threatening blood system malignancy. The treatment of AML continues to face greater challenges. An abnormal haematopoietic niche with high adhesion and proliferation might be the root cause of resistance and relapse. Most leukaemia cells are stored in the endosteal niche and recess in the G0 phase, and they are not sensitive to varieties of radiotherapies and chemotherapies. G-CSF and AMD3100 are increasingly used in priming chemotherapy. G-CSF can promote leukaemia cells to the cell cycle, which improves the complete remission rate of leukaemia patients. AMD3100, the novel CXCR4 antagonist, could also potentially promote leukaemia cells to cell cycle and improve the susceptibility of leukaemia cells to chemotherapeutic agents. The combination of them enhances anti-leukaemia effect. So in this review, we explore the function of G-CSF and/or AMD3100 in the priming chemotherapy of haematological malignants. PMID- 26526721 TI - Autologous immuno magnetically selected CD133+ stem cells in the treatment of no option critical limb ischemia: clinical and contrast enhanced ultrasound assessed results in eight patients. AB - OBJECTIVES: Demonstrate the safety and effectiveness of highly purified CD133+ autologous stem cells in critical limb ischemia (CLI). DESIGN: Prospective single center not randomized. Clinicaltrials.gov identifier: NCT01595776 METHODS: Eight patients with a history of stable CLI were enrolled in a period of 2 years. After bone marrow stimulation and single leukapheresis collection, CD133+ immunomagnetic cell selection was performed. CD133+ cells in buffer phosphate suspension was administered intramuscularly. Muscular and arterial contrast enhanced ultra sound (CEUS), lesion evolution and pain management were assessed preoperatively and 3, 6 and 12 months after the implant. RESULTS: No patient had early or late complications related to the procedure. Two patients (25 %) didn't get any relief from the treatment and underwent major amputation. Six patients (75 %) had a complete healing of the wounds, rest pain cessation and walking recovery. An increase in CEUS values was shown in all eight patients at 6 months and in the six clinical healed patients at 12 months and had statistical relevance. CONCLUSIONS: Highly purified autologous CD133+ cells can stimulate neo angiogenesis, as based on clinical and CEUS data. PMID- 26526722 TI - Survival of Bacillus spp. SUBB01 at high temperatures and a preliminary assessment of its ability to protect heat-stressed Escherichia coli cells. AB - BACKGROUND: The bacterial stressed state upon temperature raise has widely been observed especially in Escherichia coli cells. The current study extended such physiological investigation on Bacillus spp. SUBB01 under aeration at 100 rpm on different culture media along with the high temperature exposure at 48, 50, 52, 53 and 54 degrees C. Bacterial growth was determined through the enumeration of the viable and culturable cells; i.e., cells capable of producing the colony forming units on Luria-Bertani and nutrient agar plates up to 24 h. Microscopic experiments were conducted to scrutinize the successive physiological changes. Suppression of bacterial growth due to the elevated heat was further confirmed by the observation of non-viability through spot tests. RESULTS: As expected, a quick drop in both cell turbidity and colony forming units (~10(4)) along with spores were observed after 12-24 h of incubation period, when cells were grown at 54 degrees C in both Luria-Bertani and nutrient broth and agar. The critical temperature (the temperature above which it is no longer possible to survive) of Bacillus spp. SUBB01 was estimated to be 53 degrees C. Furthermore, a positive impact was observed on the inhibited E. coli SUBE01 growth at 45 and 47 degrees C, upon the supplementation of the extracellular fractions of Bacillus species into the growing culture. CONCLUSIONS: Overall the present analysis revealed the conversion of the culturable cells into the viable and nonculturable (VBNC) state as a result of heat shock response in Bacillus spp. SUBB01 and the cellular adaptation at extremely high temperature. PMID- 26526724 TI - Polycomb Complex PRC1 Preserves Intestinal Stem Cell Identity by Sustaining Wnt/beta-Catenin Transcriptional Activity. AB - Polycomb repressive complexes (PRCs) are among the most important gatekeepers of establishing and maintaining cell identity in metazoans. PRC1, which plays a dominant role in this context, executes its functions via multiple subcomplexes, which all contribute to H2AK119 mono-ubiquitination (H2Aubq). Despite our comprehensive knowledge of PRC1-dependent H2Aubq in embryonic stem cells and during early development, its role in adult stem cells still remains poorly characterized. Here we show that PRC1 activity is required for the integrity of the intestinal epithelium, regulating stem cell self-renewal via a cell autonomous mechanism that is independent from Cdkn2a expression. By dissecting the PRC1-dependent transcription program in intestinal stem cells, we demonstrate that PRC1 represses a large number of non-lineage-specific transcription factors that directly affect beta-catenin/Tcf transcriptional activity. Our data reveal that PRC1 preserves Wnt/beta-catenin activity in adult stem cells to maintain intestinal homeostasis and supports tumor formation induced by the constitutive activation of this pathway. PMID- 26526723 TI - Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming. AB - Epigenetic and epitranscriptomic networks have important functions in maintaining the pluripotency of embryonic stem cells (ESCs) and somatic cell reprogramming. However, the mechanisms integrating the actions of these distinct networks are only partially understood. Here we show that the chromatin-associated zinc finger protein 217 (ZFP217) coordinates epigenetic and epitranscriptomic regulation. ZFP217 interacts with several epigenetic regulators, activates the transcription of key pluripotency genes, and modulates N6-methyladenosine (m(6)A) deposition on their transcripts by sequestering the enzyme m(6)A methyltransferase-like 3 (METTL3). Consistently, Zfp217 depletion compromises ESC self-renewal and somatic cell reprogramming, globally increases m(6)A RNA levels, and enhances m(6)A modification of the Nanog, Sox2, Klf4, and c-Myc mRNAs, promoting their degradation. ZFP217 binds its own target gene mRNAs, which are also METTL3 associated, and is enriched at promoters of m(6)A-modified transcripts. Collectively, these findings shed light on how a transcription factor can tightly couple gene transcription to m(6)A RNA modification to ensure ESC identity. PMID- 26526725 TI - Histone Demethylase Expression Enhances Human Somatic Cell Nuclear Transfer Efficiency and Promotes Derivation of Pluripotent Stem Cells. AB - The extremely low efficiency of human embryonic stem cell (hESC) derivation using somatic cell nuclear transfer (SCNT) limits its potential application. Blastocyst formation from human SCNT embryos occurs at a low rate and with only some oocyte donors. We previously showed in mice that reduction of histone H3 lysine 9 trimethylation (H3K9me3) through ectopic expression of the H3K9me3 demethylase Kdm4d greatly improves SCNT embryo development. Here we show that overexpression of a related H3K9me3 demethylase KDM4A improves human SCNT, and that, as in mice, H3K9me3 in the human somatic cell genome is an SCNT reprogramming barrier. Overexpression of KDM4A significantly improves the blastocyst formation rate in human SCNT embryos by facilitating transcriptional reprogramming, allowing efficient derivation of SCNT-derived ESCs using adult Age-related Macular Degeneration (AMD) patient somatic nuclei donors. This conserved mechanistic insight has potential applications for improving SCNT in a variety of contexts, including regenerative medicine. PMID- 26526727 TI - Possible scenarios of the influence of low-dose ionizing radiation on neural functioning. AB - Possible scenarios of the influence of ionizing radiation on neural functioning and the CNS are suggested. We argue that the radiation-induced bystander mechanisms associated with Ca(2+) flows, reactive nitrogen and oxygen species, and cytokines might lead to modulation of certain neuronal signaling pathways. The considered scenarios of conjugation of the bystander signaling and the neuronal signaling might result in modulation of certain synaptic receptors, neurogenesis, neurotransmission, channel conductance, synaptic signaling, different forms of neural plasticity, memory formation and storage, and learning. On this basis, corresponding new possible strategies for treating neurodegenerative deceases and mental disorders are proposed. The mechanisms considered might also be associated with neuronal survival and relevant to the treatment for brain injuries. At the same time, these mechanisms might be associated with detrimental effects and might facilitate the development of some neurological and psychiatric disorders. PMID- 26526726 TI - Rapid Conversion of Fibroblasts into Functional Forebrain GABAergic Interneurons by Direct Genetic Reprogramming. AB - Transplantation of GABAergic interneurons (INs) can provide long-term functional benefits in animal models of epilepsy and other neurological disorders. Whereas GABAergic INs can be differentiated from embryonic stem cells, alternative sources of GABAergic INs may be more tractable for disease modeling and transplantation. We identified five factors (Foxg1, Sox2, Ascl1, Dlx5, and Lhx6) that convert mouse fibroblasts into induced GABAergic INs (iGABA-INs) possessing molecular signatures of telencephalic INs. Factor overexpression activates transcriptional networks required for GABAergic fate specification. iGABA-INs display progressively maturing firing patterns comparable to cortical INs, form functional synapses, and release GABA. Importantly, iGABA-INs survive and mature upon being grafted into mouse hippocampus. Optogenetic stimulation demonstrated functional integration of grafted iGABA-INs into host circuitry, triggering inhibition of host granule neuron activity. These five factors also converted human cells into functional GABAergic INs. These properties suggest that iGABA INs have potential for disease modeling and cell-based therapeutic approaches to neurological disorders. PMID- 26526728 TI - Development of a questionnaire to measure primary care physicians' scope of practice. AB - BACKGROUND: Despite an increase in research devoted to primary care attributes, the patient benefits and educational aspects of broad scope practice of primary care physicians (PCPs) have not been well studied, due to a lack of validated measurement in each country. The objective of this study was to develop and validate the Scope of Practice Inventory (SPI) to measure physicians' scope of practice within the Japanese primary care setting. METHODS: The questionnaire was developed in seven phases: 1) item generation, 2) consensus method for necessity of each item, 3) Delphi process for the importance of each item, 4) pilot tests to limit the number of items, 5) preliminary cross-sectional study to examine factor structure and to validate the construct validity, 6) evaluation of internal consistency and intra-class reliability, and 7) evaluation of external validity. To confirm the interpretability of the SPI, the determinants of the SPI using a generalized linear model were evaluated. RESULTS: Among 359 items generated by a focus group, 180 reached a defined consensus on face and content validity after the Delphi process. After deletion of items with Kappa values less than 0.6, 120 items were selected for the preliminary study. The principle component analysis using responses from 451 PCPs eliminated 52 items. The final 68-point SPI had three subdomains: Inpatient care, 25 items; Urgent care and minor procedures, 27 items; and Ambulatory care, 16 items. Internal consistency and test-retest reliability for total SPI and each subdomain revealed acceptable reliability. Male sex, less years since graduation, working in a hospital, sub urban or rural setting, having remote experience, and having board certification as a PCP were positively associated with higher SPI. CONCLUSIONS: We developed a self-administered 68-point scale, the SPI, which had satisfactory validity and reliability. Primary care quality and educational research using SPI are expected to contribute to comprehensive and efficient health care systems in the future. PMID- 26526729 TI - Novel derivatives of nitro-substituted salicylic acids: Synthesis, antimicrobial activity and cytotoxicity. AB - Inspired by the high antituberculous activity of novel nitro-substituted derivatives and based on promising predicted ADMET properties we have synthesized a series of 33 salicylanilides containing nitro-group in their salicylic part and evaluated them for their in vitro antimycobacterial, antimicrobial and antifungal activities. The presence of nitro-group in position 4 of the salicylic acid was found to be beneficial and the resulting molecules exhibited minimum inhibitory concentrations (MICs) ranging from 2 to 32 MUM against Mycobacterium tuberculosis. The best activity was found for 2-hydroxy-4-nitro-N-[4 (trifluoromethyl)phenyl]benzamide (MIC=2 MUM). 4-Nitrosalicylanilides were also found to be active against all Staphylococcus species tested while for MRSA strain 2-hydroxy-4-nitro-N-[4-(trifluoromethyl)phenyl]benzamide's MIC was 0.98 MUM. None of the nitrosalicylanilides was active against Enterococcus sp. J 14365/08 and no considerable activity was found against Gram-negative bacteria or fungi. The hepatotoxicity of all nitrosalicylanilides was found to be in the range of their MICs for HepG2 cells. PMID- 26526730 TI - Mechanical circulatory assistance: A growing and expanding field in cardiac surgery. PMID- 26526731 TI - Erratum to: the role of previously unmeasured organic acids in the pathogenesis of severe malaria. PMID- 26526732 TI - Intraocular foreign bodies extracted by pars plana vitrectomy: clinical characteristics, management, outcomes and prognostic factors. AB - BACKGROUND: Intraocular foreign bodies (IOFBs) are an important cause of visual loss within the group of working age population. We aim to present the clinical features and the algorithm according to which we manage the foreign bodies that are located in the posterior segment of the eye. We define the outcomes and the prognostic factors that influenced the final visual acuity and globe survival in patients with IOFBs that we extracted by pars plana vitrectomy (PPV) over a 5 year period. METHODS: We reviewed the medical records of all the cases with IOFBs that we removed by PPV, over 5 years (2009-2013). We extracted the following parameters: age, gender, wound anatomy, IOFB characteristics, ocular lesions, initial and final visual acuities. We used the program SPSS version 20.0.0. for the statistical analysis of our data. RESULTS: During 5 years, we treated 21 IOFBs by PPV, representing 12.20 % of all the open globe injuries. All the patients were males with the median age of 36 years. The foreign body was located in the vitreous - 11 cases (52.38 %), retina--seven cases (33.33 %) and perforating--three cases (14.28 %). Retinal detachment (RD) at presentation was identified in eight cases (38.09 %) and endophthalmitis, in six cases (28.57 %). The visual outcome was significantly worse in patients with RD at presentation (p = 0.012) and with IOFBs larger than 3 mm (p = 0.042). Endophthalmitis did not influence the visual outcome. CONCLUSIONS: The worse prognostic factors were: RD at presentation and large foreign body. TRIAL REGISTRATION NUMBER: IRCT2015040418966N3 / Apr. 9/2015. PMID- 26526733 TI - Frequency of full, partial and no recovery from subsyndromal deliriumin older hospital inpatients. AB - OBJECTIVES: To determine the frequencies of full, partial and no recovery from subsyndromal delirium (SSD) in older hospital inpatients. A secondary objective was to compare the recovery status of patients with SSD or delirium. METHODS: SSD was defined as acute onset of one or more Confusion Assessment Method core symptoms of delirium (fluctuation, inattention, disorganized thinking and altered level of consciousness) not meeting criteria for delirium and not progressing to delirium. The recovery status of medical or surgical inpatients aged 65 and older with SSD was assessed approximately 1 and 3 months after enrolment. Primary outcome categories were full recovery (no core symptoms of delirium), partial recovery (presence of one or more core symptoms but fewer symptoms than at enrolment), no recovery (same number of core symptoms as at enrolment) or death. Nominal logistic regression was used to compare the recovery status of patients with SSD or delirium. RESULTS: Twenty-eight patients with SSD were enrolled. At the first follow-up, the frequencies of full, partial and no recovery and death were 40%, 12%, 32% and 16%, respectively; at the second follow-up, the frequencies were 54%, 8%, 21% and 17%, respectively. The frequency of full recovery was much higher in patients with SSD than delirium. CONCLUSION: Small study sample size notwithstanding, the majority (54%) of patients with SSD recovered fully, but a substantial proportion (29%) had a protracted course. It may be important to monitor the longer-term course of SSD and develop strategies to ensure full recovery in all patients. PMID- 26526734 TI - Letters to the Editor. PMID- 26526735 TI - [Pneumothorax during right-sided nephrectomy in a heifer]. AB - A 250-kg heifer had signs of colic attributable to urolithiasis of the right kidney. Medical treatment did not result in resolution of clinical signs, and nephrectomy was carried out. The surgery was started with the heifer standing, and the 13th rib was resected. However, during blunt dissection of the kidney, air suddenly entered the pleural space and the heifer had acute severe dyspnoea. The hole in the pleural cavity was sutured and a chest drain was placed. Inhalation anaesthesia was then induced and nephrectomy could be completed without further complications. The heifer was discharged 11 days postoperatively, and was healthy and had been integrated into the herd 12 months after surgery. Pneumothorax must be considered a possible complication of rib resection in right sided nephrectomy in cattle. PMID- 26526736 TI - Exploring the role of VEGF in Indian Age related macular degeneration. AB - BACKGROUND: Age related macular degeneration (AMD) is major devastating neurodegenerative disorder characterized by progressive irreversible vision loss in the elderly persons. In spite of several genetic and environmental factors, the role of VEGF and CFH predispose the pathological phenomenon in the AMD patients. PURPOSE: The aim of the study was to estimate the VEGF levels in the serum of AMD patients and its correlation with co-morbidity of the participants. METHODS: The study recruited the 98 AMD patients and 59 controls with proper consent of the participants as per the exclusion-inclusion criteria. The co morbidity and socio-economic details were obtained by introducing the standard questionnaire amongst the participants. Serum levels of vascular endothelial growth factor (VEGF) was estimated by ELISA and compared with the control population of the study. The levels of VEGF in the serum of AMD patients and controls were compared with Mann-Whitney U-test. Kruskal Wallis one-way analysis of variance (ANOVA) was employed to analyze more than two variables in the study. RESULTS: Elevated level of VEGF was found in AMD patients as compared to controls. Surprisingly, we did not find significant changes among wet AMD subtypes i.e. minimal, predominant and classic wet AMD. However, we have demonstrated the intravitreal anti-VEGF treatment (avastin) in AMD patients could reduce the systemic VEGF levels although it was not significant. Moreover, the heart ailment in the AMD patients could also influence the VEGF levels. CONCLUSION: Our study is consistent with previous studies describing the imperative significance of VEGF in AMD pathology. However, our study did not reveal the role of VEGF in wet AMD progression but it is well established causative agent for the same. The increased levels of VEGF in heart ailment among AMD patients are significant. PMID- 26526737 TI - Objective Sepsis Surveillance Using Electronic Clinical Data. AB - OBJECTIVE: To compare the accuracy of surveillance of severe sepsis using electronic health record clinical data vs claims and to compare incidence and mortality trends using both methods. DESIGN: We created an electronic health record-based surveillance definition for severe sepsis using clinical indicators of infection (blood culture and antibiotic orders) and concurrent organ dysfunction (vasopressors, mechanical ventilation, and/or abnormal laboratory values). We reviewed 1,000 randomly selected medical charts to characterize the definition's accuracy and stability over time compared with a claims-based definition requiring infection and organ dysfunction codes. We compared incidence and mortality trends from 2003-2012 using both methods. SETTING: Two US academic hospitals. PATIENTS: Adult inpatients. RESULTS: The electronic health record based clinical surveillance definition had stable and high sensitivity over time (77% in 2003-2009 vs 80% in 2012, P=.58) whereas the sensitivity of claims increased (52% in 2003-2009 vs 67% in 2012, P=.02). Positive predictive values for claims and clinical surveillance definitions were comparable (55% vs 53%, P=.65) and stable over time. From 2003 to 2012, severe sepsis incidence imputed from claims rose by 72% (95% CI, 57%-88%) and absolute mortality declined by 5.4% (95% CI, 4.6%-6.7%). In contrast, incidence using the clinical surveillance definition increased by 7.7% (95% CI, -1.1% to 17%) and mortality declined by 1.7% (95% CI, 1.1%-2.3%). CONCLUSIONS: Sepsis surveillance using clinical data is more sensitive and more stable over time compared with claims and can be done electronically. This may enable more reliable estimates of sepsis burden and trends. PMID- 26526740 TI - Synthesis and biological evaluation of di-aryl urea derivatives as c-Kit inhibitors. AB - Inhibition of receptor tyrosine kinases (RTKs) continued to be a successful approach for the treatment of many types of human cancers and many potent small molecules kinase inhibitors have been discovered the last decade. In the present study, we describe the synthesis of thienopyrimidine derivatives and their pharmacological evaluation against nine kinases (EGFR, PDGFR-beta, c-Kit, c-Met, Src, Raf, VEGFR-1, -2 and -3). Most of the synthesized compounds showed from moderate to potent activities against c-Kit with IC50 values in the nanomolar range. Among them, 4-anilino(urea)thienopyrimidine analogs showed selectivity and potent c-Kit inhibition with IC50 values less than 6 nM. Docking simulation was performed for the most promising compound 9 into the c-Kit active site to determine the potential binding mode. This study reveal that the 4 anilino(urea)thienopyrimidine is an interesting scaffold to design novel potent and selective c-Kit inhibitors which may make promising candidates for cancers where c-Kit receptors are overexpressed. PMID- 26526739 TI - Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships. AB - In this study, a series of catechol-based amides (8a-n) with different amide linkers linking the catecholic moiety to the terminal phenyl ring was designed and synthesized as potent phosphodiesterase (PDE) 4D inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4B1 and PDE4D7 enzymes, and other PDE family members. The results indicated the majority of compounds 8a-n displayed moderate to good inhibitory activities against PDE4CAT. Among these compounds, compound 8 j with a short amide linker (-CONHCH2-) displayed comparable PDE4CAT inhibitory activity (IC50=410 nM) with rolipram. More interestingly, compound 8 g, a potent and selective PDE4D inhibitor (IC50=94 nM), exhibited a 10-fold selectivity over the PDE4B subtypes and an over 1000-fold selectivity against other PDE family members. Docking simulations suggested that 8 g forms three extra H-bonds with the N-H of residue Asn487 and two water molecules. PMID- 26526738 TI - Glucocorticoid (dexamethasone)-induced metabolome changes in healthy males suggest prediction of response and side effects. AB - Glucocorticoids are indispensable anti-inflammatory and decongestant drugs with high prevalence of use at (~)0.9% of the adult population. Better holistic insights into glucocorticoid-induced changes are crucial for effective use as concurrent medication and management of adverse effects. The profiles of 214 metabolites from plasma of 20 male healthy volunteers were recorded prior to and after ingestion of a single dose of 4 mg dexamethasone (+20 mg pantoprazole). Samples were drawn at three predefined time points per day: seven untreated (day 1 midday - day 3 midday) and four treated (day 3 evening - day 4 evening) per volunteer. Statistical analysis revealed tremendous impact of dexamethasone on the metabolome with 150 of 214 metabolites being significantly deregulated on at least one time point after treatment (ANOVA, Benjamini-Hochberg corrected, q < 0.05). Inter-person variability was high and remained uninfluenced by treatment. The clearly visible circadian rhythm prior to treatment was almost completely suppressed and deregulated by dexamethasone. The results draw a holistic picture of the severe metabolic deregulation induced by single-dose, short-term glucocorticoid application. The observed metabolic changes suggest a potential for early detection of severe side effects, raising hope for personalized early countermeasures increasing quality of life and reducing health care costs. PMID- 26526741 TI - Inhibition of human topoisomerase I and II and anti-proliferative effects on MCF 7 cells by new titanocene complexes. AB - The antitumor activity shown by many platinum complexes has produced a strong interest in research of new organometallic compounds having anticancer action. Among the many metal compounds synthesized and tested, those based on titanium have received considerable attention because of their cytotoxic activity against solid tumors. Particularly, new titanocene compounds containing aromatic groups linked to the Cp (cyclopentadienyl ring, C5H5) have been synthetized, such as the titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl]titanium dichloride) that displayed promising medium-high cytotoxic activity on breast cancer cell lines. Other titanocene complexes recently synthesized, obtained by replacing the substituent methoxy-aryl of cyclopentadienes of titanocene Y with ethenyl methoxide or ethenyl-phenoxide, showed increased cytotoxic activity on breast cancer cell lines being more stable compounds. In this paper, we report that new titanocene complexes holding lipophilic groups, for instance a methyl group on benzyl carbon, exhibit improved antiproliferative effect on breast cancer cell line MCF-7. Similar results have been obtained introducing a 5-methoxy naphthyl group to further stabilize the titanocene complexes. These inhibitory effects on breast cancer cells have been ascribed to human topoisomerase I and II inhibition as demonstrated by specific enzymatic assays. PMID- 26526742 TI - Bivalent ligands incorporating curcumin and diosgenin as multifunctional compounds against Alzheimer's disease. AB - In an effort to combat the multifaceted nature of Alzheimer's disease (AD) progression, a series of multifunctional, bivalent compounds containing curcumin and diosgenin were designed, synthesized, and biologically characterized. Screening results in MC65 neuroblastoma cells established that compound 38 with a spacer length of 17 atoms exhibited the highest protective potency with an EC50 of 111.7 +/- 9.0 nM. A reduction in protective activity was observed as spacer length was increased up to 28 atoms and there is a clear structural preference for attachment to the methylene carbon between the two carbonyl moieties of curcumin. Further study suggested that antioxidative ability and inhibitory effects on amyloid-beta oligomer (AbetaO) formation may contribute to the neuroprotective outcomes. Additionally, compound 38 was found to bind directly to Abeta, similar to curcumin, but did not form complexes with the common biometals Cu, Fe, and Zn. Altogether, these results give strong evidence to support the bivalent design strategy in developing novel compounds with multifunctional ability for the treatment of AD. PMID- 26526743 TI - Synthesis of novel benzohydrazone-oxadiazole hybrids as beta-glucuronidase inhibitors and molecular modeling studies. AB - A series of compounds consisting of 25 novel oxadiazole-benzohydrazone hybrids (6 30) were synthesized through a five-step reaction sequence and evaluated for their beta-glucuronidase inhibitory potential. The IC50 values of compounds 6-30 were found to be in the range of 7.14-44.16MUM. Compounds 6, 7, 8, 9, 11, 13, 18, and 25 were found to be more potent than d-saccharic acid 1,4-lactone (48.4+/ 1.25MUM). These compounds were further subjected for molecular docking studies to confirm the binding mode towards human beta-d-glucuronidase active site. Docking study for compound 13 (IC50=7.14+/-0.30MUM) revealed that it adopts a binding mode that fits within the entire pocket of the binding site of beta-d glucuronidase. Compound 13 has the maximum number of hydrogens bonded to the residues of the active site as compared to the other compounds, that is, the ortho-hydroxyl group forms hydrogen bond with carboxyl side chain of Asp207 (2.1A) and with hydroxyl group of Tyr508 (2.6A). The other hydroxyl group forms hydrogen bond with His385 side chain (2.8A), side chain carboxyl oxygen of Glu540 (2.2A) and Asn450 side-chain's carboxamide NH (2.1A). PMID- 26526744 TI - Synthesis and activities of new indolopyrrolobenzodiazepine derivatives toward acute myeloid leukemia cells. AB - The synthesis of new indolopyrrolobenzodiazepine derivatives is described. Six compounds were selected for evaluation of cytotoxicity towards acute myeloid leukemia (AML) cells and normal fibroblasts. One compound (29) showed selective AML cell death induction. Its action was only partly overcome by knock-down of p53 or Bcl-2 overexpression, suggesting a strong activation of intrinsic apoptotic pathways. PMID- 26526745 TI - Landscape genetics, adaptive diversity and population structure in Phaseolus vulgaris. AB - Here we studied the organization of genetic variation of the common bean (Phaseolus vulgaris) in its centres of domestication. We used 131 single nucleotide polymorphisms to investigate 417 wild common bean accessions and a representative sample of 160 domesticated genotypes, including Mesoamerican and Andean genotypes, for a total of 577 accessions. By analysing the genetic spatial patterns of the wild common bean, we documented the existence of several genetic groups and the occurrence of variable degrees of diversity in Mesoamerica and the Andes. Moreover, using a landscape genetics approach, we demonstrated that both demographic processes and selection for adaptation were responsible for the observed genetic structure. We showed that the study of correlations between markers and ecological variables at a continental scale can help in identifying local adaptation genes. We also located putative areas of common bean domestication in Mesoamerica, in the Oaxaca Valley, and the Andes, in southern Bolivia-northern Argentina. These observations are of paramount importance for the conservation and exploitation of the genetic diversity preserved within this species and other plant genetic resources. PMID- 26526747 TI - Design and fabrication of a flexible MEMS-based electromechanical sensor array for breast cancer diagnosis. AB - The use of flexible micro-electro-mechanical systems (MEMS) based device provides a unique opportunity in bio-medical robotics such as characterization of normal and malignant tissues. This paper reports on design and development of a flexible MEMS-based sensor array integrating mechanical and electrical sensors on the same platform to enable the study of the change in electro-mechanical properties of the benign and cancerous breast tissues. In this work, we present the analysis for the electrical characterization of the tissue specimens and also demonstrate the feasibility of using the sensor for mechanical characterization of the tissue specimens. Eight strain gauges acting as mechanical sensors were fabricated using poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT:PSS) conducting polymer on poly(dimethylsiloxane) (PDMS) as the substrate material. Eight electrical sensors were fabricated using SU-8 pillars on gold (Au) pads which were patterned on the strain gauges separated by a thin insulator (SiO2 1.0MUm). These pillars were coated with gold to make it conducting. The electromechanical sensors are integrated on the same substrate. The sensor array covers 180MUm * 180MUm area and the size of the complete device is 20mm in diameter. The diameter of each breast tissue core used in the present study was 1mm and the thickness was 8MUm. The region of interest was 200MUm * 200MUm. Microindentation technique was used to characterize the mechanical properties of the breast tissues. The sensor is integrated with conducting SU-8 pillars to study the electrical property of the tissue. Through electro-mechanical characterization studies using this MEMS-based sensor, we were able to measure the accuracy of the fabricated device and ascertain the difference between benign and cancer breast tissue specimens. PMID- 26526746 TI - Application of Functional Genomics for Bovine Respiratory Disease Diagnostics. AB - Bovine respiratory disease (BRD) is the most common economically important disease affecting cattle. For developing accurate diagnostics that can predict disease susceptibility/resistance and stratification, it is necessary to identify the molecular mechanisms that underlie BRD. To study the complex interactions among the bovine host and the multitude of viral and bacterial pathogens, as well as the environmental factors associated with BRD etiology, genome-scale high throughput functional genomics methods such as microarrays, RNA-seq, and proteomics are helpful. In this review, we summarize the progress made in our understanding of BRD using functional genomics approaches. We also discuss some of the available bioinformatics resources for analyzing high-throughput data, in the context of biological pathways and molecular interactions. Although resources for studying host response to infection are avail-able, the corresponding information is lacking for majority of BRD pathogens, impeding progress in identifying diagnostic signatures for BRD using functional genomics approaches. PMID- 26526748 TI - Harmonizing Measures of Cognitive Performance Across International Surveys of Aging Using Item Response Theory. AB - OBJECTIVE: To harmonize measures of cognitive performance using item response theory (IRT) across two international aging studies. METHOD: Data for persons >=65 years from the Health and Retirement Study (HRS, N = 9,471) and the English Longitudinal Study of Aging (ELSA, N = 5,444). Cognitive performance measures varied (HRS fielded 25, ELSA 13); 9 were in common. Measurement precision was examined for IRT scores based on (a) common items, (b) common items adjusted for differential item functioning (DIF), and (c) DIF-adjusted all items. RESULTS: Three common items (day of date, immediate word recall, and delayed word recall) demonstrated DIF by survey. Adding survey-specific items improved precision but mainly for HRS respondents at lower cognitive levels. DISCUSSION: IRT offers a feasible strategy for harmonizing cognitive performance measures across other surveys and for other multi-item constructs of interest in studies of aging. Practical implications depend on sample distribution and the difficulty mix of in common and survey-specific items. PMID- 26526749 TI - Radioprotective activity of Polyalthia longifolia standardized extract against X ray radiation injury in mice. AB - The radioprotective effect of Polyalthia longifolia was studied in mice. P. longifolia treatment showed improvement in mice survival compared to 100% mortality in the irradiated mice. Significant increases in hemoglobin concentration, and red blood cell, white blood cell and platelet counts were observed in the animals pretreated with leaf extract. Pre-irradiation administration of P. longifolia leaf extract also increased the CFU counts of the spleen colony and increased the relative spleen size. A dose-dependent decrease in lipid peroxidation levels was observed in the animals pretreated with P. longifolia. However, although the animals pretreated with P. longifolia exhibited a significant increase in superoxide dismutase and catalase activity, the values remained below normal in both liver and the intestine. Pre-irradiation administration of P. longifolia also resulted in the regeneration of the mucosal crypts and villi of the intestine. Moreover, pretreatment with P. longifolia leaf extract also showed restoration of the normal liver cell structure and a significant reduction in the elevated levels of ALT, AST and bilirubin. These results suggested the radioprotective ability of P. longifolia leaf extract, which is significant for future investigation for human applications in developing efficient, economically viable, non-toxic natural and clinically acceptable novel radioprotectors. PMID- 26526750 TI - The association of neurocognitive impairment with diminished expression and apathy in schizophrenia. AB - Negative symptoms can be grouped into the two dimensions of diminished expression and apathy, which have been shown to be dissociable regarding external validators, such as functional outcome. Here, we investigated whether these two dimensions differentially relate to neurocognitive impairment in schizophrenia. 47 patients with schizophrenia or schizoaffective disorder and 33 healthy control participants were subjected to a neurocognitive test battery assessing multiple cognitive domains (processing speed, working memory, verbal fluency, verbal learning and memory, mental planning), which are integrated into a composite cognition score. Negative symptoms in patients were assessed using the Brief Negative Symptom Scale. We found that diminished expression significantly related to neurocognitive impairment, while severity of apathy symptoms was not directly associated with neurocognition. Other assessed clinical variables include chlorpromazine equivalents, positive symptoms, and depressive symptoms and did not influence the results. Our results are in line with a cognitive resource limitation model of diminished expression in schizophrenia and indicate that cognitive remediation therapy might be helpful to ameliorate expressive deficits. PMID- 26526751 TI - Twelve-month psychosis-predictive value of the ultra-high risk criteria in children and adolescents. AB - OBJECTIVE: The validity of current ultra-high risk (UHR) criteria is under examined in help-seeking minors, particularly, in children below the age of 12 years. Thus, the present study investigated predictors of one-year outcome in children and adolescents (CAD) with UHR status. METHOD: Thirty-five children and adolescents (age 9-17 years) meeting UHR criteria according to the Structured Interview for Psychosis-Risk Syndromes were followed-up for 12 months. Regression analyses were employed to detect baseline predictors of conversion to psychosis and of outcome of non-converters (remission and persistence of UHR versus conversion). RESULTS: At one-year follow-up, 20% of patients had developed schizophrenia, 25.7% had remitted from their UHR status that, consequently, had persisted in 54.3%. No patient had fully remitted from mental disorders, even if UHR status was not maintained. Conversion was best predicted by any transient psychotic symptom and a disorganized communication score. No prediction model for outcome beyond conversion was identified. CONCLUSIONS: Our findings provide the first evidence for the predictive utility of UHR criteria in CAD in terms of brief intermittent psychotic symptoms (BIPS) when accompanied by signs of cognitive impairment, i.e. disorganized communication. However, because attenuated psychotic symptoms (APS) related to thought content and perception were indicative of non-conversion at 1-year follow-up, their use in early detection of psychosis in CAD needs further study. Overall, the need for more in depth studies into developmental peculiarities in the early detection and treatment of psychoses with an onset of illness in childhood and early adolescence was further highlighted. PMID- 26526753 TI - Mapping the course after CHAARTED. PMID- 26526752 TI - A river model to map convergent cancer evolution and guide therapy in RCC. AB - Intratumoural heterogeneity in clear cell renal cell carcinoma (ccRCC) complicates identification and validation of biomarkers and thwarts attempts to improve precision medicine. Efforts to depict intratumoural heterogeneity and to pinpoint strategies for disease control resulted in the creation of the trunk branch model of mutational cancer evolution, which emphasizes targeting trunk mutations. However, most patients with ccRCC receiving current therapeutics that target these mutations, such as inhibitors of vascular endothelial growth factors, eventually develop resistance. A novel paradigm might improve depiction of cancer evolution and advise therapeutic selection: the river model is based on findings from multiregion sequencing in samples from exceptional responders to mTOR inhibitors. The accumulating data on genotypic and phenotypic convergence in renal cell carcinoma and other malignancies can be used to examine how a mutable river model might best describe clinically significant phenotype-convergent events that could guide effective cancer control. This model originates from studying exceptional responders and its generalizability awaits validation. PMID- 26526754 TI - Feasibility of water ablation for removal of prostate tissue. PMID- 26526755 TI - CCH injections regarded effective by men with Peyronie's disease. PMID- 26526756 TI - Organoid model shows effect of BPA on prostate development. PMID- 26526757 TI - Lenvatinib shows promise. PMID- 26526759 TI - ODM-201 tablets complete phase I. PMID- 26526758 TI - Voluntary medical male circumcision in resource-constrained settings. AB - Throughout East and Southern Africa, the WHO recommends voluntary medical male circumcision (VMMC) to reduce heterosexual HIV acquisition. Evidence has informed policy and the implementation of VMMC programmes in these countries. VMMC has been incorporated into the HIV prevention portfolio and more than 9 million VMMCs have been performed. Conventional surgical procedures consist of forceps-guided, dorsal slit or sleeve resection techniques. Devices are also becoming available that might help to accelerate the scale-up of adult VMMC. The ideal device should make VMMC easier, safer, faster, sutureless, inexpensive, less painful, require less infrastructure, be more acceptable to patients and should not require follow up visits. Elastic collar compression devices cause vascular obstruction and necrosis of foreskin tissue and do not require sutures or injectable anaesthesia. Collar clamp devices compress the proximal part of the foreskin to reach haemostasis; the distal foreskin is removed, but the device remains and therefore no sutures are required. Newer techniques and designs, such as tissue adhesives and a circular cutter with stapled anastomosis, are improvements, but none of these methods have achieved all desirable characteristics. Further research, design and development are needed to address this gap to enable the expansion of the already successful VMMC programmes for HIV prevention. PMID- 26526760 TI - Isometric and isokinetic hip strength and agonist/antagonist ratios in symptomatic femoroacetabular impingement. AB - OBJECTIVES: This study investigated isometric and isokinetic hip strength in individuals with and without symptomatic femoroacetabular impingement (FAI). The specific aims were to: (i) determine whether differences exist in isometric and isokinetic hip strength measures between groups; (ii) compare hip strength agonist/antagonist ratios between groups; and (iii) examine relationships between hip strength and self-reported measures of either hip pain or function in those with FAI. DESIGN: Cross-sectional. METHODS: Fifteen individuals (11 males; 25+/-5 years) with symptomatic FAI (clinical examination and imaging (alpha angle >55 degrees (cam FAI), and lateral centre edge angle >39 degrees and/or positive crossover sign (combined FAI))) and 14 age- and sex-matched disease-free controls (no morphological FAI on magnetic resonance imaging) underwent strength testing. Maximal voluntary isometric contraction strength of hip muscle groups and isokinetic hip internal (IR) and external rotation (ER) strength (20 degrees /s) were measured. Groups were compared with independent t-tests and Mann-Whitney U tests. RESULTS: Participants with FAI had 20% lower isometric abduction strength than controls (p=0.04). There were no significant differences in isometric strength for other muscle groups or peak isokinetic ER or IR strength. The ratio of isometric, but not isokinetic, ER/IR strength was significantly higher in the FAI group (p=0.01). There were no differences in ratios for other muscle groups. Angle of peak IR torque was the only feature correlated with symptoms. CONCLUSIONS: Individuals with symptomatic FAI demonstrate isometric hip abductor muscle weakness and strength imbalance in the hip rotators. Strength measurement, including agonist/antagonist ratios, may be relevant for clinical management of FAI. PMID- 26526761 TI - Overall conceptual framework for studying the genetics of autoimmune diseases following vaccination: a regulatory perspective. AB - The US Vaccine Adverse Event Reporting System contains case reports of autoimmune diseases (ADs) occurring following vaccinations. ADs are rare and occur in unvaccinated people, making the potential association between vaccines and ADs challenging to evaluate. Developing mechanistic pathways that link genes, immune mediators, vaccine components and ADs would be helpful for hypothesis generation, enhancing theories of biologic plausibility and grouping rare autoimmune adverse events to increase the ability to detect and evaluate safety signals. Here, we propose a conceptual framework for investigating the genetics of ADs as safety signals following vaccination, potentially contributing to the identification of relevant biomarkers. We also discuss a study design that incorporates genetic information into postmarket clinical evaluation of autoimmune adverse events following vaccination. PMID- 26526762 TI - A ruptured superficial femoral artery aneurysm: A case report. AB - True atherosclerotic aneurysms of superficial femoral artery (SFA) are rare and often associated with other peripheral or aortic aneurysms. We are reporting the case of a 78-year-old man who has been admitted with a ruptured superficial femoral artery aneurysm associated with bilateral popliteal artery aneurysm. The patient underwent successful aneurysm resection and bypass grafting. PMID- 26526763 TI - [Search for circulating tumor cells: Seriously, a real cancer screening tool?]. PMID- 26526765 TI - Fecundity selection theory: concepts and evidence. AB - Fitness results from an optimal balance between survival, mating success and fecundity. The interactions between these three components of fitness vary depending on the selective context, from positive covariation between them, to antagonistic pleiotropic relationships when fitness increases in one reduce the fitness of others. Therefore, elucidating the routes through which selection shapes life history and phenotypic adaptations via these fitness components is of primary significance to understanding ecological and evolutionary dynamics. However, while the fitness components mediated by natural (survival) and sexual (mating success) selection have been debated extensively from most possible perspectives, fecundity selection remains considerably less studied. Here, we review the theoretical basis, evidence and implications of fecundity selection as a driver of sex-specific adaptive evolution. Based on accumulating literature on the life-history, phenotypic and ecological aspects of fecundity, we (i) suggest a re-arrangement of the concepts of fecundity, whereby we coin the term 'transient fecundity' to refer to brood size per reproductive episode, while 'annual' and 'lifetime fecundity' should not be used interchangeably with 'transient fecundity' as they represent different life-history parameters; (ii) provide a generalized re-definition of the concept of fecundity selection as a mechanism that encompasses any traits that influence fecundity in any direction (from high to low) and in either sex; (iii) review the (macro)ecological basis of fecundity selection (e.g. ecological pressures that influence predictable spatial variation in fecundity); (iv) suggest that most ecological theories of fecundity selection should be tested in organisms other than birds; (v) argue that the longstanding fecundity selection hypothesis of female-biased sexual size dimorphism (SSD) has gained inconsistent support, that strong fecundity selection does not necessarily drive female-biased SSD, and that this form of SSD can be driven by other selective pressures; and (vi) discuss cases in which fecundity selection operates on males. This conceptual analysis of the theory of fecundity selection promises to help illuminate one of the central components of fitness and its contribution to adaptive evolution. PMID- 26526764 TI - Role of NOS2 in pulmonary injury and repair in response to bleomycin. AB - Nitric oxide (NO) is derived from multiple isoforms of the Nitric Oxide Synthases (NOSs) within the lung for a variety of functions; however, NOS2-derived nitrogen oxides seem to play an important role in inflammatory regulation. In this study, we investigate the role of NOS2 in pulmonary inflammation/fibrosis in response to intratracheal bleomycin instillation (ITB) and to determine if these effects are related to macrophage phenotype. Systemic NOS2 inhibition was achieved by administration of 1400W, a specific and potent NOS2 inhibitor, via osmotic pump starting six days prior to ITB. 1400W administration attenuated lung inflammation, decreased chemotactic activity of the broncheoalveolar lavage (BAL), and reduced BAL cell count and nitrogen oxide production. S-nitrosylated SP-D (SNO-SP-D), which has a pro-inflammatory function, was formed in response to ITB; but this formation, as well as structural disruption of SP-D, was inhibited by 1400W. mRNA levels of IL-1beta, CCL2 and Ptgs2 were decreased by 1400W treatment. In contrast, expression of genes associated with alternate macrophage activation and fibrosis Fizz1, TGF-beta and Ym-1 was not changed by 1400W. Similar to the effects of 1400W, NOS2-/- mice displayed an attenuated inflammatory response to ITB (day 3 and day 8 post-instillation). The DNA-binding activity of NF-kappaB was attenuated in NOS2-/- mice; in addition, expression of alternate activation genes (Fizz1, Ym-1, Gal3, Arg1) was increased. This shift towards an increase in alternate activation was confirmed by western blot for Fizz-1 and Gal-3 that show persistent up-regulation 15 days after ITB. In contrast arginase, which is increased in expression at 8 days post ITB in NOS2-/ , resolves by day 15. These data suggest that NOS2, while critical to the development of the acute inflammatory response to injury, is also necessary to control the late phase response to ITB. PMID- 26526766 TI - Importance of Nucleic Acid Recognition in Inflammation and Autoimmunity. AB - An important concept in immunology is the classification of immune responses as either innate or adaptive, based on whether the antigen receptors are encoded in the germline or generated somatically by gene rearrangement. The innate immune system is an ancient mode of immunity, and by being a first layer in our defense against infectious agents, it is essential for our ability to develop rapid and sustained responses to pathogens. We discuss the importance of nucleic acid recognition by the innate immune system to mounting an appropriate immune response to pathogens and also how inflammation driven by uncontrolled recognition of self-nucleic acids can lead to autoimmune diseases. We also summarize current efforts to either harness the immune system using agonists of nucleic acid-specific innate sensors or, on the contrary, by using inhibitors in autoimmune situations. PMID- 26526767 TI - Progress Toward HIV Eradication: Case Reports, Current Efforts, and the Challenges Associated with Cure. AB - An estimated 35 million people worldwide are infected with HIV, yet a widely applicable cure strategy remains elusive. Recent case reports have suggested that curing HIV infection is possible, renewing excitement about research efforts. We describe those cases and discuss their relevance to the global HIV epidemic. We also review ongoing cure strategies that are transitioning from the lab to the clinic, and the assays and clinical assessments that can be used to evaluate cure interventions. PMID- 26526768 TI - Validity of the 6min walk test in outpatients with bipolar disorder. AB - Cardiorespiratory fitness is a major modifiable risk factor for cardiovascular diseases. People with bipolar disorder have a reduced cardiorespiratory fitness and its assessment within a multidisciplinary treatment therefore is necessary. We investigated the validity of the 6min walk test in people with bipolar disorder. A secondary aim was to assess clinical and demographic characteristics that might interfere with cardiorespiratory fitness performance. 19 (5?) outpatients (47.1+/-8.3 years) underwent a 6min walk test and a maximal cardiopulmonary exercise test on a cycle ergometer and completed the Positive-and Negative-Affect-Schedule (PANAS) and Beck Depression Inventory (BDI). The distance achieved on the 6min walk test correlated moderately with peak oxygen uptake obtained during the maximal cardiopulmonary exercise test. The variance in age, weight and the PANAS negative score explained 70% of the variance in the distance achieved on the 6min walk test. The 6min walk test can be used as a measure-of-proxy to gauge cardiorespiratory fitness in people with bipolar disorder when maximal cardiopulmonary exercise test equipment is not available. Negative mood should be considered when evaluating the cardiorespiratory fitness of this vulnerable population. PMID- 26526769 TI - Airborne exposure patterns from a passenger source in aircraft cabins. AB - Airflow is a critical factor that influences air quality, airborne contaminant distribution, and disease transmission in commercial airliner cabins. The general aircraft-cabin air-contaminant transport effect model seeks to build exposure spatial relationships between contaminant sources and receptors, quantify the uncertainty, and provide a platform for incorporation of data from a variety of studies. Knowledge of infection risk to flight crews and passengers is needed to form a coherent response to an unfolding epidemic, and infection risk may have an airborne pathogen exposure component. The general aircraf-tcabin air-contaminant transport effect model was applied to datasets from the University of Illinois and Kansas State University and also to case study information from a flight with probable severe acute respiratory syndrome transmission. Data were fit to regression curves, where the dependent variable was contaminant concentration (normalized for source strength and ventilation rate), and the independent variable was distance between source and measurement locations. The data-driven model showed exposure to viable small droplets and post-evaporation nuclei at a source distance of several rows in a mock-up of a twin-aisle airliner with seven seats per row. Similar behavior was observed in tracer gas, particle experiments, and flight infection data for severe acute respiratory syndrome. The study supports the airborne pathway as part of the matrix of possible disease transmission modes in aircraft cabins. PMID- 26526770 TI - Transdermal Opioids for Cancer Pain Management. AB - The prevalence of pain in cancer is up to 90%, more than 45% of this can be adequately managed using the World Health Organisation three step analgesic ladder.Transdermal opioids are safe, effective, and produce significantly fewer side effects than oral morphine when used for moderate to severe cancer pain.Transdermal buprenorphine has a lower incidence of systemic side effects than transdermal fentanyl and it is indicated for use in cancer patients with neuropathic pain and renal dysfunction.Transdermal opioids require a long lag period for dose stabilisation and elimination, hence are unsuitable for acute or unstable pain, and may result in prolonged side effects.Transdermal analgesics reduce the need for frequent dosing, clock watching and are more convenient for patients, physicians and carers, hence increasing treatment compliance. PMID- 26526771 TI - Electrodeposited Ultrathin TiO2 Blocking Layers for Efficient Perovskite Solar Cells. AB - In this study, the electrodeposition (ED) of ultrathin, compact TiO2 blocking layers (BLs) on fluorine-doped tin oxide (FTO) glass for perovskite solar cells (PSCs) is evaluated. This bottom-up method allows for controlling the morphology and thickness of TiO2 films by simply manipulating deposition conditions. Compared with BLs produced using the spin-coating (SC) method, BLs produced using ED exhibit satisfactory surface coverage, even with a film thickness of 29 nm. Evidence from cyclic voltammetry shows that an ED BL suppresses interfacial recombination more profoundly than an SC BL does, consequently improving the photovoltaic properties of the PSC significantly. A PSC equipped with an ED TiO2 BL having a 13.6% power conversion efficiency is demonstrated. PMID- 26526772 TI - [Paraneoplastic bullous pemphigoid associated with lung cancer]. PMID- 26526773 TI - Hormones and their Interaction with the Pain Experience. AB - Sex differences in the prevalence of painful conditions appear after pubertyVariation in symptom severity across the menstrual cycle occurs in a number of clinical pain conditionsSex steroid hormones act at a number of sites in both the peripheral and central nervous systems and in both reproductive and non-reproductive tissuesSex steroid hormones have traditionally been thought to alter transcription; however, there is evidence that there are also non-genomic effectsSex steroid hormones can have organisational effects from as early as in uteroThe relationship between sex hormones and pain is complex. PMID- 26526774 TI - The elderly, the young and the pregnant traveler -- A retrospective data analysis from a large Swiss Travel Center with a special focus on malaria prophylaxis and yellow fever vaccination. AB - BACKGROUND: Vulnerable individuals such as elderly, children/adolescents and pregnant/breastfeeding women increasingly travel overseas. We describe the travel and vaccination patterns of these groups at the largest Travel Clinic in Switzerland especially focusing on travel to yellow fever and malaria-endemic countries, and yellow fever vaccination (YFV) and malaria medications. METHOD: An analysis of pre-travel visits between 2010 and 2012 at the Travel Clinic of the University of Zurich, was performed assessing differences between the elderly, young and middle-aged travelers as well as between pregnant/breastfeeding and other female travelers. RESULTS: Overall, the vulnerable groups did not differ from other travelers regarding their travel patterns. YFV was the most often administered vaccine to elderly travelers; half of them received it for the first time. More than 30% of children/adolescents received YFV, but no child below six months was vaccinated. 80% of young travelers and a similar percentage of pregnant women went to malaria-endemic regions. Twenty-five pregnant/breastfeeding women traveled to YF endemic areas. CONCLUSIONS: Travel patterns of vulnerable travelers are comparable to those of other travelers. In view of the limited data on malaria medications and precautions against YFV during pregnancy and at the extreme ages of life, giving travel advice to these groups is challenging. PMID- 26526775 TI - Resistance exercise training increase activation of AKT-eNOS and Ref-1 expression by FOXO-1 activation in aorta of F344 rats. AB - PURPOSE: This study investigated the effects of resistance exercise on the Akt eNOS, the activation of antioxidant protein and FOXO1 in the aorta of F344 rats. METHODS: Male 7 week-old F344 rats were randomly divided into 2 groups: a climbing group (n = 6) and a sedentary group (n = 6). H&E staining and western blotting were used to analyze the rat aortas and target proteins. RESULTS: Resistance exercise training did not significantly affect aortic structure. Phosphorylation of AKT and eNOS and expression of MnSOD and Ref-1 were significantly increased while FOXO1 phosphorylation was significantly decreased in the resistance exercise group compared with the sedentary group. CONCLUSION: We demonstrate that resistance exercise activates the Akt-eNOS and Ref-1 protein without changes to aortic thickness via FOXO-1 activation in the aorta of F344 rats. PMID- 26526776 TI - [The use of the new direct oral anticoagulants among older subjects: The limits of the evidence-based medicine?]. AB - The growing use of direct oral anticoagulants, in particular among older subjects, raises questions about the limits of the evidence-based medicine. The phase III studies that have validated the efficacy and the safety profile of these molecules (dabigatran, rivaroxaban, apixaban, edoxaban) in their both indications, the venous thromboembolic disease and the non-valvular atrial fibrillation raise concerns in four major fields: the financial support of pharmaceutical companies, the links of interest for many authors with the industry, the study design (exclusively non-inferiority studies), and the poor representativeness of the older subjects included. All these points are discussed, using data of sub-groups studies, post-marketing studies and recent meta-analysis. The lack of data for the very old subjects, with frailty or comorbidities, remains the main concern from these phase III studies. PMID- 26526777 TI - [Immunogenicity of biopharmaceuticals: Which consequences during the treatment of rheumatoid arthritis?]. AB - The biopharmaceuticals used in rheumatology are monoclonal antibodies, chimeric ( ximab), humanized (-zumab) or fully human (-[m]umab), or fusion proteins. The immunogenicity, that is the ability to develop an immune response towards biopharmaceuticals and leading to the production of anti-drug antibodies (ADA), may be observed in nearly 30% of patients with monoclonal antibodies, more rarely with fusion proteins. The immunogenicity may lead to an increase of clearance, a reduction of half-life and serum concentration of biopharmaceuticals, a decrease of clinical response and therapeutic maintenance, as well as the occurrence of immuno-allergic reactions. However, we must relativize the importance of this phenomenon because in registers with anti-TNFalpha, the survival curve of monoclonal antibodies is much closed to that of fusion proteins. The immunogenicity is only one of the factors allowing to explain the clinical response, or the lack of response, with biopharmaceuticals. This phenomenon may explain some clinical situations (secondary failures, adverse reactions), but other factors (weight, inflammatory activity, combination with an immunosuppressive agent, etc.) may influence, more importantly than immunogenicity, the dose-response relationship with biopharmaceuticals. PMID- 26526779 TI - Highly Selective Formation of n-Butanol from Ethanol through the Guerbet Process: A Tandem Catalytic Approach. AB - A highly selective (>99%) tandem catalytic system for the conversion of ethanol (up to 37%) to n-butanol, through the Guerbet process, has been developed using a bifunctional iridium catalyst coupled with bulky nickel or copper hydroxides. These sterically crowded nickel and copper hydroxides catalyze the key aldol coupling reaction of acetaldehyde to exclusively yield the C4 coupling product, crotonaldehyde. Iridium-mediated dehydrogenation of ethanol to acetaldehyde has led to the development of an ethanol-to-butanol process operated at a lower temperature. PMID- 26526778 TI - [Malignant hypertension and cardiac decompensation after overuse of nasal decongestant: A case report and literature review]. AB - INTRODUCTION: Vasoconstrictors, widely prescribed in the congestive states during acute rhinitis, are responsible for many cases of drug-related iatrogenic disease. CASE REPORT: We report the case of a 40-year-old man, who presented with an episode of malignant hypertensive crisis associated with life-threatening congestive heart decompensation. The patient interview revealed consumption to supra-therapeutic dosage of an association of naphazoline and prednisolone nasal sprays. The diagnostic work-up allowed to rule out disease-related causes of secondary hypertension. The drug-related disease was thus retained. CONCLUSION: The results of the literature review showed many cases of vasoconstrictor poisoning responsible for central nervous system and cardiovascular involvement, especially in young children. This first case of heart failure related to nasal decongestant administration increases the scope of potentially serious risks of these drugs and demonstrates the outreach needs for health professionals and patients about their proper use. PMID- 26526780 TI - Osteoporotic vertebral compression fracture located adjacent to the fused segments in an ankylosing spondylitis patient. PMID- 26526781 TI - A huge retropharyngeal abscess causing airway and esophageal obstruction associated with cervical spine tuberculosis. PMID- 26526782 TI - Design and Characterization of Fibrin-Based Acoustically Responsive Scaffolds for Tissue Engineering Applications. AB - Hydrogel scaffolds are used in tissue engineering as a delivery vehicle for regenerative growth factors. Spatiotemporal patterns of growth factor signaling are critical for tissue regeneration, yet most scaffolds afford limited control of growth factor release, especially after implantation. We previously found that acoustic droplet vaporization can control growth factor release from a fibrin scaffold doped with a perfluorocarbon emulsion. This study investigates properties of the acoustically responsive scaffold (ARS) critical for further translation. At 2.5 MHz, acoustic droplet vaporization and inertial cavitation thresholds ranged from 1.5 to 3.0 MPa and from 2.0 to 7.0 MPa peak rarefactional pressure, respectively, for ARSs of varying composition. Viability of C3H/10T1/2 cells, encapsulated in the ARS, did not decrease significantly for pressures below 4 MPa. ARSs with perfluorohexane emulsions displayed higher stability versus those with perfluoropentane emulsions, while surrogate payload release was minimal without ultrasound. These results enable the selection of ARS compositions and acoustic parameters needed for optimized spatiotemporally controlled release. PMID- 26526783 TI - Early healing assessment with optical coherence tomography of everolimus-eluting stents with bioabsorbable polymer (synergyTM) at 3 and 6 months after implantation. AB - OBJECTIVES: In this study we sought to evaluate coverage and apposition of SynergyTM stent at 3 and 6 months after implantation. BACKGROUND: The Pt-Cr everolimus-eluting stent with abluminal bioabsorbable polymer (SynergyTM) is a new generation drug-eluting stent with features potentially favoring an early healing process which could make safe a shorter period of dual antiplatelet therapy treatment. METHODS: Prospective, two-centers study enrolling patients with similar lesions treated with SynergyTM stents undergoing examination with OCT at 3 and 6 months in the respective centers. Blinded analysis was done at a core lab. Co-primary endpoints were proportion of struts with coverage and with apposition at 3 and 6 months. RESULTS: Finally, 22 patients (30 stents) in the 3 months group and 20 patients (30 stents) in the 6 months group were included. There were no significant differences between groups regarding clinical, angiographic measurements, and procedural data. The rate of strut coverage was 94.5% at 3 months and 96.6% at 6 months (P < 0.001), the rates of apposition were 93.8% and 96.2%, respectively, (P < 0.001), the proportion of uncovered but apposed struts was 2.5% and 1.9% (P = 0.03) and the proportion of uncovered and malapposed struts was 3% and 1.8%, respectively (P < 0.001). The maximal area of malapposition related with uncovered struts was 0.43 +/- 0.4 mm(2) at 3 months and 0.14 +/- 0.2 mm(2) at 6 months (P = 0.001). CONCLUSIONS: The everolimus eluting stent with absorbable polymer, SynergyTM, is associated to a high degree of intimal coverage and apposition at 3 months after implantation with additional increase at 6 months. (c) 2015 Wiley Periodicals, Inc. PMID- 26526784 TI - Effect of the Pulsatile Extracorporeal Membrane Oxygenation on Hemodynamic Energy and Systemic Microcirculation in a Piglet Model of Acute Cardiac Failure. AB - The objective of this study was to compare the effects of pulsatile and nonpulsatile extracorporeal membrane oxygenation (ECMO) on hemodynamic energy and systemic microcirculation in an acute cardiac failure model in piglets. Fourteen piglets with a mean body weight of 6.08 +/- 0.86 kg were divided into pulsatile (N = 7) and nonpulsatile (N = 7) ECMO groups. The experimental ECMO circuit consisted of a centrifugal pump, a membrane oxygenator, and a pneumatic pulsatile flow generator system developed in-house. Nonpulsatile ECMO was initiated at a flow rate of 140 mL/kg/min for the first 30 min with normal heart beating, with rectal temperature maintained at 36 degrees C. Ventricular fibrillation was then induced with a 3.5-V alternating current to generate a cardiac dysfunction model. Using this model, we collected the data on pulsatile and nonpulsatile groups. The piglets were weaned off ECMO at the end of the experiment (180 min after ECMO was initiated). The animals did not receive blood transfusions, inotropic drugs, or vasoactive drugs. Blood samples were collected to measure hemoglobin, methemoglobin, blood gases, electrolytes, and lactic acid levels. Hemodynamic energy was calculated using the Shepard's energy equivalent pressure. Near infrared spectroscopy was used to monitor brain and kidney perfusion. The pulsatile ECMO group had a higher atrial pressure (systolic and mean), and significantly higher regional saturation at the brain level, than the nonpulsatile group (for both, P < 0.05). Additionally, the pulsatile ECMO group had higher methemoglobin levels within the normal range than the nonpulsatile group. Our study demonstrated that pulsatile ECMO produces significantly higher hemodynamic energy and improves systemic microcirculation, compared with nonpulsatile ECMO in acute cardiac failure. PMID- 26526785 TI - A case-control study of caesarean delivery on maternal request: who and why? AB - OBJECTIVE: The current study aimed to evaluate the profile of women who are most likely to undergo caesarean delivery on maternal request (CDMR) and clarify their reasons for this decision. METHODS: For this multicentre case-control study, data were collected from 429 women who underwent CDMR and 429 matched controls who delivered vaginally from June, 2008 through February, 2009. Participants were interviewed by telephone regarding sociodemographic variables, health and lifestyle. RESULTS: CDMR predictors were as follows: increasing age (OR = 1.09/year; 95%CI: 1.05-1.14), family status (unmarried without a steady partner versus married - OR = 3.60; 95%CI: 1.08-11.97), decreasing level of religiosity (secular versus ultra-orthodox - OR = 11.82; 95%CI: 3.75-37.21), and never having engaged, or ceasing sports activity during pregnancy (OR = 1.79; 95%CI: 1.09-2.91 and 2.38; 95%CI: 1.28-4.43, respectively). Above average income reduced the probability of CDMR (OR = 0.56; 95%CI: 0.33-0.94). The most frequent reasons for choosing CDMR were concern for pain (21.9%), concern for their own or baby's health (20.4% and 16.5%, respectively) and emotional aspects (10.0%). CONCLUSIONS: Older, unmarried and/or secular women had increased probability of CDMR. Addressing specific concerns regarding vaginal delivery may provide the basis for a patient-oriented intervention for preventing unnecessary surgery. PMID- 26526786 TI - Opportunity Knocks: Organic Chemistry for Fragment-Based Drug Discovery (FBDD). PMID- 26526787 TI - Efficacy of oral moxifloxacin for aerobic vaginitis. AB - The purpose of this study was to investigate the therapeutic efficacy of oral moxifloxacin for aerobic vaginitis (AV). We also identified factors that are associated with therapeutic efficacy. This prospective study enrolled general gynecological outpatients at Tianjin Medical University General Hospital between September 2012 and May 2014. Women diagnosed with AV (n = 102) were recruited. All enrolled women were treated with oral moxifloxacin, 400 mg once daily for 6 days (one course). Therapeutic efficacy was evaluated based on microscopic criteria, and cure rates were calculated. Women who were microscopically improved (but not cured) received a second course of therapy. Women classified with microscopic failure were treated using other strategies. Univariate and multivariate logistic regression analysis was used to identify factors that may be associated with a cure after one course of therapy. After one course of therapy, 65.7 % (67/102) of women were cured, 29.4 % (30/102) of women were improved (but not cured), 4.9 % (5/102) of women failed to respond to the therapy. After two courses of therapy, 85.3 % (87/102) of women were cured, 9.8 % (10/102) of women were improved, 4.9 % (5/102) of women failed to respond to the therapy, and clinical improvement was achieved in additional women. In the multivariate logistic regression analysis, women with a baseline vaginal pH value of <5.0 had a 3.5-times higher chance of being cured, compared with those with a baseline vaginal pH value of >=5.0 (OR, 3.503; 95 % CI, 1.278-9.601). Moxifloxacin is an effective therapeutic option for patients with AV. Most women with AV were cured with one course of moxifloxacin. For those with a higher vaginal pH value of >=5.0 before treatment, two courses of therapy should be considered. PMID- 26526788 TI - Ciliated pancreatic foregut cyst: MRI, EUS, and cytologic features. AB - Ciliated foregut cysts are extremely uncommon pancreatic cystic lesions, with-to the best of our knowledge-only five cases previously reported in the English literature. We report herein on a case of a ciliated foregut cyst of the pancreas connected with the duct of Wirsung. The magnetic resonance imaging, endoultrasonographic, and cytologic features are described and a brief review of literature is also presented. PMID- 26526789 TI - Brain MRI findings with vigabatrin therapy: case report and literature review. AB - Infantile spasm or West syndrome is a pediatric epileptic disorder characterized by flexor and/or extensor spasms beginning in childhood. Vigabatrin is an effective medical therapy for infantile spasm but has pronounced, potentially worrisome imaging findings in patients receiving therapy. We present the case of an 8-month-old infant with such brain magnetic resonance imaging findings after treatment initiation. In this article, we highlight the imaging changes and discuss the differential diagnosis along with the required follow-up. PMID- 26526790 TI - miR-193b Modulates Resistance to Doxorubicin in Human Breast Cancer Cells by Downregulating MCL-1. AB - MicroRNAs (miRNAs) family, which is involved in cancer development, proliferation, apoptosis, and drug resistance, is a group of noncoding RNAs that modulate the expression of oncogenes and antioncogenes. Doxorubicin is an active cytotoxic agent for breast cancer treatment, but the acquisition of doxorubicin resistance is a common and critical limitation to cancer therapy. The aim of this study was to investigate whether miR-193b mediated the resistance of breast cancer cells to doxorubicin by targeting myeloid cell leukemia-1 (MCL-1). In this study, we found that miR-193b levels were significantly lower in doxorubicin resistant MCF-7 (MCF-7/DOXR) cells than in the parental MCF-7 cells. We observed that exogenous miR-193b significantly suppressed the ability of MCF-7/DOXR cells to resist doxorubicin. It demonstrated that miR-193b directly targeted MCL-1 3' UTR (3'-Untranslated Regions). Further studies indicated that miR-193b sensitized MCF-7/DOXR cells to doxorubicin through a mechanism involving the downregulation of MCL-1. Together, our findings provide evidence that the modulation of miR-193b may represent a novel therapeutic target for the treatment of breast cancer. PMID- 26526792 TI - Erratum. PMID- 26526795 TI - From the ABNM: Practice of Nuclear Medicine. PMID- 26526791 TI - Family history of esophageal cancer increases the risk of esophageal squamous cell carcinoma. AB - A population-based case-control was performed to explore familial aggregation of esophageal squamous cell carcinoma (ESCC). Family history of cancer was assessed by a structured questionnaire, and from which 2 cohorts of relatives of cases and controls were reconstructed. Unconditional logistic regression and Cox proportional hazards regression were applied for case-control design and reconstructed cohort design, respectively. We observed a close to doubled risk of ESCC associated with a positive family history of esophageal cancer among first degree relatives (odds ratio [OR] = 1.85, 95% confidence interval [CI]: 1.42 2.41), after adjusting age, sex, family size and other confounders. The excess risks of ESCC increased with the increasing of first-degree relatives affected by esophageal cancer (p < 0.001). In particular, those individuals whose both parents with esophageal cancer had an 8-fold excess risk of ESCC (95% CI: 1.74 36.32). The reconstructed cohort analysis showed that the cumulative risk of esophageal cancer to age 75 was 12.2% in the first-degree relatives of cases and 7.0% in those of controls (hazard ratio = 1.91, 95% CI: 1.54-2.37). Our results suggest family history of esophageal cancer significantly increases the risk for ESCC. Future studies are needed to understand how the shared genetic susceptibility and/or environmental exposures contribute to the observed excess risk. PMID- 26526797 TI - SNMMI Leadership Update: Developing Evidence-Based Appropriate Use Criteria under the Protecting Access to Medicare Act of 2014. PMID- 26526798 TI - 2015 SNMMI Highlights Lecture: Oncology, Part I. PMID- 26526799 TI - Indication for mild therapeutic hypothermia based on an initial Glasgow Coma Scale motor score. AB - Although neurological evaluation using the Glasgow Coma Scale motor score is mandatory for post-cardiac arrest patients, further study is required to determine if this score can be used as an indicator for mild therapeutic hypothermia. Although the current study conducted by Natsukawa et al. presents interesting data, there are some critical issues regarding study design, selection bias, and interpretation of study results that should be pointed out. PMID- 26526800 TI - Persistent Pain after Dental Surgery. AB - This article aims to cover post surgical trigeminal neuropathy and other conditions related to chronic trigeminal pain not specifically covered elsewhere in this series.Is estimated to occur in 4-5% of patients overall, considerably less compared with other site surgeries.Due to the high volume surgery undertaken in this region chronic post surgical pain remains common.Relatively few clinicians are aware of this condition and as a result it is frequently poorly managed. PMID- 26526801 TI - Parent and Provider Perspectives on Pediatric Readmissions: What Can We Learn About Readiness for Discharge? AB - BACKGROUND: Readmissions are an increasingly recognized quality metric that will likely affect payments to children's hospitals. Our aim was to inform future efforts to reduce readmissions by eliciting parent and provider perceptions of pediatric readmissions. METHODS: We interviewed English- and Spanish-speaking parents and inpatient providers of children with medical diagnoses who had unplanned readmissions (<=7 days). Parents were interviewed one-on-one during the readmission. Providers were interviewed in person or by phone within 1 week of the patient's second discharge. Interviewees were queried about their perceptions of the reason for readmission and whether the readmission was preventable. Interview transcripts were analyzed using qualitative content methods. Code categories were developed and emergent themes independently identified by 2 analysts. RESULTS: The study included 30 readmitted children (median age 17 months, 70% male, 80% White or Hispanic, and 66% publically insured). We interviewed 30 parents (23% Spanish speaking) and 27 discharging or readmitting providers. Parents and providers identified several major factors as causing readmissions, including child related (health and symptoms), parent/family related (adherence to recommended care), provider/team related (medical management), communication difficulties, home supports, and quality of discharge teaching. Parents and providers had differing interpretations of the role or magnitude of these factors. Lack of shared understanding between parents and providers emerged as a potentially important cause of readmissions. CONCLUSIONS: We identified lack of shared understanding and communication difficulties between parents and providers as potential causes of readmission. Further research is needed to determine if improvements in identifying and addressing such problems can reduce pediatric readmissions. PMID- 26526802 TI - An Examination of Physician-, Caregiver-, and Disease-Related Factors Associated With Readmission From a Pediatric Hospital Medicine Service. AB - OBJECTIVES: The purpose of this study was to describe the characteristics and reasons for pediatric hospital medicine readmissions. We also aimed to describe characteristics of potentially preventable cases and the reliability of classification. METHODS: Retrospective descriptive study from December 2008 through June 2010 in a large academic tertiary care children's hospital in Houston, Texas. Children were included if they were readmitted to the hospital within 30 days of discharge from the pediatric hospital medicine service. Reasons for readmission were grouped into three categories: physician-related, caretaker related, and disease-related. Readmissions with physician- or caretaker-related reasons were considered potentially preventable. RESULTS: The overall readmission rate was 3.1%, and a total of 204 subjects were included in the analysis. Lymphadenitis and failure to thrive had the highest readmission rates with 21%, and 13%, respectively. Twenty percent (n=41/204) of readmissions were preventable with 24% (n=10/41) being physician-related, 12% (n=5/41) caregiver-related, and 63% (n=26/41) for mixed reasons. When comparing classification of readmissions into preventable status, there was moderate agreement between 2 reviewers (K=0.44, 95% confidence interval: 0.28-0.60). Among patients with preventable readmission, the probability of having had a readmission by 7 days and 15 days was 73% and 78%, respectively. CONCLUSIONS: Reliable identification of preventable pediatric readmissions using individual reviewers remains a challenge. Additional studies are needed to develop a reliable approach to identify preventable readmissions and underlying modifiable factors. A focused review of 7-day readmissions and diagnoses with high readmission rates may allow use of fewer resources. PMID- 26526803 TI - The Med-Peds Hospitalist Workforce: Results From the American Academy of Pediatrics Workforce Survey. AB - OBJECTIVE: There is no published literature about the med-peds hospitalist workforce, physicians dually trained in internal medicine and pediatrics. Our objective was to analyze this subset of physicians by using data from the American Academy of Pediatrics (AAP) workforce survey to assess practice patterns and workforce demographics. We hypothesized that demographic differences exist between hospitalists and nonhospitalists. METHODS: The AAP surveyed med-peds physicians from the Society of Hospital Medicine and the AAP to define workforce demographics and patterns of practice. We compared self-identified hospitalists with nonhospitalist physicians on multiple characteristics. Almost one-half of the hospitalists self-identified as being both primary care physicians and hospitalists; we therefore also compared the physicians self-identifying as being both primary care physicians and hospitalists with those who identified themselves solely as hospitalists. RESULTS: Of 1321 respondents, 297 physicians (22.4%) self-reported practicing as hospitalists. Hospitalists were more likely than nonhospitalists to have been practicing<10 years (P<.001), be employed by a health care organization (P<.001), work>50 hours per week (P<.001), and see only adults (P<.001) or children (P=.03) in their practice rather than a mix of both groups. Most, 191/229 (83.4%), see both adults and children in practice, and 250/277 (90.3%) stated that their training left them well prepared to practice both adult and pediatric medicine. CONCLUSIONS: Med-peds hospitalists are more likely to be newer to practice and be employed by a health care organization than nonhospitalists and to report satisfaction that their training sufficiently prepared them to see adults and children in practice. PMID- 26526804 TI - Outcomes After Skin and Soft Tissue Infection in Infants 90 Days Old or Younger. AB - BACKGROUND AND OBJECTIVES: Skin and soft tissue infections (SSTIs) are an increasingly common cause of pediatric hospital visits among infants. The optimal evaluation strategy for younger infants with SSTI is unknown because there is little information about outcomes including risks of concomitant bacterial infections and treatment failure. This study was designed to determine rates of concomitant invasive bacterial infection and hospital revisits for treatment failure as well as factors associated with treatment failure in infants presenting with SSTI. METHODS: Retrospective study of patients<=90 days of age who received care from the 22 emergency departments and hospitals in the Intermountain Healthcare system from July 1, 2004 to December 31, 2011, with a primary discharge diagnosis of SSTI. Concomitant bacterial infections were defined as urinary tract infection (UTI; culture-confirmed) or invasive bacterial infection (IBI; culture-confirmed bacteremia and/or meningitis). Treatment failure was defined as any unplanned change in care at hospital revisit within 14 days of discharge. RESULTS: The study included 172 infants; 29 (17%) were febrile, and 91 (53%) had >=1 sterile site culture performed. One case of bacteremia in a febrile infant was identified giving an overall proportion with UTI/IBI of 0.58% (95% confidence interval 0.01%-3.2%). Sixteen infants (9.3%; 95% confidence interval 5.4%-14.7%) returned for treatment failure. Perianal location (P=.03) and private insurance status (P=.01) were associated with more treatment failures compared with other locations or payer types. No patients returned for missed UTI/IBI. CONCLUSIONS: Concomitant bacterial infections were rare in infants with SSTI, with none identified in afebrile infants. Treatment failure of SSTI leading to hospital revisit was common. PMID- 26526805 TI - A Pilot Study of the Pediatric Oral Medications Screener (POMS). AB - OBJECTIVE: Oral medications are commonly used to treat acute and chronic conditions, but formal evaluation of a child's pill-swallowing ability rarely occurs. In this pilot study, the Pediatric Oral Medication Screener (POMS) was used to physically assess a child's pill swallowing ability and identify children who would benefit from a targeted intervention. METHODS: We identified children 3 to 17 years old admitted to a general pediatric service over a 3-month period in 2014. Patients were asked to swallow several different-sized placebo formulations. If subjects did not meet age-based goals, they were referred for pill swallowing interventions (POMS+). Follow-up parental surveys were performed for patients completing the intervention. RESULTS: The prospective pilot study recruited 34 patients. Twenty-eight patients (82%) passed the screening, and a majority of this group started or continued taking pill medications. Six did not pass the screen. Three of the 6 completed the intervention, improved their pill swallowing ability, and were taking oral pill medications at discharge. Parent prediction of pill swallowing was accurate only 56% of the time. Follow-up survey of the 3 families who completed POMS+ reported satisfaction with the program, and 2 of the patients had continued success with swallowing pills 5 months later. CONCLUSIONS: The POMS was effective at identifying children who could benefit from an intervention to improve pill-swallowing ability. Our analysis demonstrated that POMS has the potential to improve patient satisfaction and discharge planning. PMID- 26526806 TI - Weighing Evidence and Art: A Challenging Case of Early-Onset Atypical Kawasaki Disease. PMID- 26526807 TI - The Cost of a Culture and Doctoring at a Distance. PMID- 26526808 TI - European Insights. PMID- 26526809 TI - Preventing Readmissions in Children: How Do We Do That? PMID- 26526810 TI - 14,15-epoxyeicosatrienoic acid promotes production of brain derived neurotrophic factor from astrocytes and exerts neuroprotective effects during ischaemic injury. AB - AIMS: 14,15-Epoxyeicosatrienoic acid (14,15-EET) is abundantly expressed in brain and exerts protective effects against ischaemia. 14,15-EET is hydrolysed by soluble epoxide hydrolase (sEH). sEH-/- mice show a higher level of 14,15-EET in the brain. Astrocytes play a pivotal role in neuronal survival under ischaemic conditions. However, it is unclear whether the neuroprotective effect of 14,15 EET is associated with astrocytes. METHODS: A mouse model of focal cerebral ischaemia was induced by middle cerebral artery occlusion. Oxygen-glucose deprivation/reoxygenation (OGD/R) was performed on cultured murine astrocytes, neurons and a human cell line. Cell viabilities were measured by 3-(4, 5-dimethyl 2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) assay. The mRNA expressions were quantified by real-time PCR. Brain derived neurotrophic factor (BDNF) concentration was measured by ELISA. Protein expressions were quantified by Western blotting. BDNF and peroxisome proliferators-activated receptor gamma (PPAR-gamma) expressions were analysed by confocal microscopy. RESULTS: Decreased infarct volumes, elevated BDNF expression and increased numbers of BDNF/GFAP Glial Fibrillary Acidic Protein double-positive cells were observed in the ischaemic penumbra of sEH-/- mice. The decreased infarct volumes of sEH-/- mice were diminished by intracerebroventricular injection of a blocker of BDNF receptor. 14,15-EET increases BDNF expression and cell viability of murine astrocytes and U251 cells by BDNF-TrkB Tyrosine receptor kinase-B-extracellular signal-regulated kinase 1/2 signalling during OGD/R. 14,15-EET protects neurons from OGD/R by stimulating the production of astrocyte-derived BDNF. 14,15-EET stimulates the production of astrocyte-derived BDNF through PPAR-gamma/p-cAMP response element binding protein signal pathways. CONCLUSIONS: Our study demonstrates the importance of 14,15-EET-mediated production of astrocyte-derived BDNF for enhancing viability of astrocytes and protecting neurons from the ischaemic injury and provides insights into the mechanism by which 14,15-EET is involved in neuroprotection. PMID- 26526811 TI - DBD-F induces apoptosis in gastric cancer-derived cells through suppressing HIF2alpha expression. AB - PURPOSE: Gastric cancer is the third leading cause of cancer-related death in China. Accumulating evidence indicates that HIF2alpha may affect the aggressiveness of gastric cancer. It has also been found that HIF2alpha C terminal PAS domains can form complexes with inactive benzoxadiazole antagonists. Here, the anti-tumor effect of 4-(N,Ndimethylaminosulphonyl)-7-fluoro-1,2,3 benzoxadiazole (DBD-F) on human gastric cancer cells was examined using both in vitro and in vivo assays. METHODS AND RESULTS: We found that DBD-F can induce apoptosis and inhibit the mobility of MKN28 and MKN45 gastric cancer-derived cells in vitro. We also found that DBD-F can suppress tumor growth in established gastric cancer-derived xenograft models in vivo. Finally, we found that DBD-F can inhibit HIF2alpha expression in gastric cancer-derived cells. CONCLUSIONS: From our findings we conclude that DBD-F (i) is cytotoxic to gastric cancer-derived cells and (ii) can induce apoptosis in these cells via the MEK/ERK signaling pathway. In addition, our findings strongly indicate that DBD-F can inhibit HIF2alpha expression by affecting the phosphorylation status of MEK/ERK in gastric cancer-derived cells. PMID- 26526812 TI - Development of role-differentiated bimanual manipulation in infancy: Part 2. Hand preferences for object acquisition and RDBM--continuity or discontinuity? AB - This second paper in a series of three investigated the development of hand preference for role-differentiated bimanual manipulation (RDBM) relative to the infant's hand preference for object acquisition and to the infant's hand-use for acquiring the objects used to assess RDBM. The same 90 infants (30 with a right preference, 30 with a left preference, and 30 with no preference to acquire objects) from the first paper were tested from 9 to 14 months for hand preference for acquiring those objects used to assess RDBM and for a hand preference for RDBM. Multilevel analysis revealed that infants with a hand preference for acquiring objects decreased in their use of the preferred hand for object acquisition during the 11 to 14 month interval, which coincided with the development of a hand preference for RDBM. These results are discussed in relation to the cascade theory of hand preference development. PMID- 26526813 TI - Chloroplasts in anther endothecium of Zea mays (Poaceae). AB - PREMISE OF THE STUDY: Although anthers of Zea mays, Oryza sativa, and Arabidopsis thaliana have been studied intensively using genetic and biochemical analyses in the past 20 years, few updates to anther anatomical and ultrastructural descriptions have been reported. For example, no transmission electron microscopy (TEM) images of the premeiotic maize anther have been published. Here we report the presence of chloroplasts in maize anthers. METHODS: TEM imaging, electron acceptor photosynthesis assay, in planta photon detection, microarray analysis, and light and fluorescence microscopy were used to investigate the presence of chloroplasts in the maize anther. KEY RESULTS: Most cells of the maize subepidermal endothecium have starch-containing chloroplasts that do not conduct measurable photosynthesis in vitro. CONCLUSIONS: The maize anther contains chloroplasts in most subepidermal, endothecial cells. Although maize anthers receive sufficient light to photosynthesize in vivo and the maize anther transcribes >96% of photosynthesis-associated genes found in the maize leaf, no photosynthetic light reaction activity was detected in vitro. The endothecial cell layer should no longer be defined as a complete circle viewed transversely in anther lobes, because chloroplasts are observed only in cells directly beneath the epidermis and not those adjacent to the connective tissue. We propose that chloroplasts be a defining characteristic of differentiated endothecial cells and that nonsubepidermal endothecial cells that lack chloroplasts be defined as a separate cell type, the interendothecium. PMID- 26526814 TI - Flowers of the early-branching papilionoid legume Petaladenium urceoliferum display unique morphological and ontogenetic features. AB - PREMISE OF THE STUDY: Floral development can help to shed light on puzzling features across flowering plants. The enigmatic Amazonian monospecific genus Petaladenium of the legume family (Leguminosae) had rarely been collected and only recently became available for ontogenetic studies. The fimbriate-glandular wing petals of P. urceoliferum are unique among the more than 19000 legume species. Ontogenetic data illuminate the systematic position of the genus and foster our understanding on floral evolution during the early diversification of the papilionoid legumes. METHODS: Flower buds were collected in the field, fixed in 70% ethanol, and investigated using scanning electron microscopy (SEM). Results were compared with existing material from early-diverging papilionoid legumes. KEY RESULTS: Formation of sepals and petals shows bidirectional tendencies. Stamens arise in two whorls, and the single carpel arises concomitantly with the outer stamen whorl. Gland formation starts early on the edges of the wing petals. The carpel reopens for a short time when the initiation of ovules is visible. Stomata at the base of the hypanthium indicate that the flower functions like other standard flag blossoms. CONCLUSIONS: The floral ontogeny confirms the close affinity of P. urceoliferum with the florally heterogeneous, early-diverging papilionoid Amburaneae clade. The results strengthen the theory of a distinct experimental phase among early-branching papilionoid legumes during which a wider range of floral morphologies arose. Polysymmetry, monosymmetry, variable organ numbers, and a wide range of ontogenetic patterns laid the foundation for a successful canalization toward the more restricted but well-adapted dorsiventral papilionoid flag blossom. PMID- 26526815 TI - 24-hour pH-impedance monitoring on therapy to select patients with refractory reflux symptoms for antireflux surgery. A single center retrospective study. AB - BACKGROUND: Treatment of gastro-esophageal reflux refractory symptoms is challenging. This monocenter retrospective study assessed the value of preoperative pH-impedance monitoring 'on' therapy to predict functional outcome after laparoscopic fundoplication in patients with refractory reflux symptoms. METHODS: Patients with a preoperative pH-impedance monitoring 'on' proton pump inhibitors (PPIs) twice daily were assessed at least 6 months after a laparoscopic fundoplication for refractory reflux symptoms. Failure of fundoplication was defined by a Visick score > 2. Postoperative symptoms were assessed by the reflux disease questionnaire (RDQ). The pH-impedance parameters analyzed were the number of reflux events (total, acid, non-acid), esophageal acid exposure time, esophageal bolus exposure time, and symptom-reflux association defined by symptom index (SI) >50% and symptom association probability (SAP) >95%. KEY RESULTS: Thirty-three patients (18 female patients, median age 46 years) were assessed after a mean follow-up of 41.3 (range 7-102.2) months. Seven (21.2%) patients were considered as failures. Compared to patients with favorable outcome, these patients were more often 'on' PPI therapy (86% vs 23%, p < 0.05) and had higher RDQ scores in each domain: heartburn (p < 0.05), regurgitation (p < 0.05) and dyspepsia (p < 0.05). A positive SAP was the only pH impedance parameter statistically associated with successful postoperative outcome (p = 0.004). CONCLUSIONS & INFERENCES: On therapy, a preoperative positive symptom association probability is the only pH-impedance parameter associated with favorable outcome after laparoscopic fundoplication for refractory reflux symptoms. These results should be confirmed by prospective studies. PMID- 26526816 TI - Morphological, Functional, and Biological Vascular Healing Response 6 Months After Drug-Eluting Stent Implantation: A Randomized Comparison of Three Drug Eluting Stents. AB - OBJECTIVES: This study evaluated coronary endothelial function after the implantation of sirolimus-eluting stents (SESs), everolimus-eluting stents (EESs), and zotarolimus-eluting stents (ZES) by a different methodology, and also analyzed whether optical coherence tomography (OCT) findings represent endothelial healing after stenting. BACKGROUND: It is unclear whether OCT assessment of stent strut coverage represents endothelial healing after drug eluting stent implantation. METHODS: Thirty patients with a left anterior descending artery lesion were randomized 1:1:1 to receive an SES, EES, or ZES. The vascular response was evaluated 6 months after stenting by three methods: the functional response by acetylcholine infusion, the morphological response by OCT, and the biological response by measuring vascular endothelial growth factor (VEGF) levels. RESULTS: The proportion of uncovered struts by OCT at 6 months was significantly higher in both SES and EES than in ZES. However, the vasomotor response was impaired and the VEGF level of the coronary sinus was significantly lower in SES than in EES and ZES. There were no relationships between the OCT findings and vasomotor response to acetylcholine and VEGF levels in all cohorts. CONCLUSIONS: The vascular response at 6 months was more preserved in ZES and EES than in SES. Our results suggest that the morphological assessment with OCT may not always be used as a surrogate for functional and biological healing response after stenting. (c) 2015 Wiley Periodicals, Inc. PMID- 26526817 TI - How compliant are technicians with universal safety measures in medical laboratories in Croatia?--A pilot study. AB - INTRODUCTION: This pilot study aimed to investigate the use of personal protective equipment (PPE) and compliance to the code of conduct (rules defined in institutional, governmental and professional guidelines) among laboratory technicians in Croatian medical laboratories. In addition, we explored the differences in compliance between participants of different age groups, laboratory ownership and accreditation status. MATERIALS AND METHODS: An anonymous and voluntary survey with 15 questions was conducted among Croatian medical laboratory technicians (N=217). The questions were divided into two groups: demographic characteristics and the use of PPE. The questions of the second part were graded according to the Likert scale (1-4) and an overall score, shown as median and range (min-max), was calculated for each participant. Differences between the overall scores were tested for each group of participants. RESULTS: The majority of participants always wear protective clothes at work, 38.7% of them always wear gloves in daily routine, more than 30.0% consume food and almost half of them drink beverages at workplace. A significantly lower overall score was found for participants working in public compared to private laboratories (36 (16-40) vs. 40 (31-40), P<0.001). There were no statistically significant differences in overall scores for participants of different age groups (P=0.456) and laboratory accreditation status (P=0.081). CONCLUSION: A considerable percentage of laboratory technicians in Croatian medical laboratories do not comply with safety measures. Lack of compliance is observed in all personnel regardless laboratory accreditation and participants' age. However, those working in private laboratories adhere more to the code of conduct. PMID- 26526818 TI - P53 expression in hepatocellular carcinoma: influence on the radiotherapeutic response of the hepatocellular carcinoma. PMID- 26526819 TI - Normal Pain Transmission. AB - Acute (normal) pain transmission is part of a survival response to prevent tissue damage and attend to and protect damaged tissue.A cycle of afferent transmission, response to stimuli, followed by temporary hypersensitivity, then attenuation and resolution occurs.Primary afferent, spinal cord ascending and descending pathways are fixed; however the response elicited is highly dynamic and not a linear relationship with input intensity.Somatic inputs are topographically accurate, in contrast to diffuse visceral inputs.Primary afferents code differentially for stimuli (heat, acid, pressure etc) and intensity.The dorsal horn allows extensive modulation of initial inputs, either excitation or inhibition.Higher CNS areas allow extensive modulation of inputs, account for the conscious recognition of pain: the intensity, location, emotional and memory aspects.Descending pathways arising from midbrain regions can be inhibitory or excitatory. PMID- 26526820 TI - Technical difficulties of left colic artery preservation during left colectomy for colon cancer. AB - PURPOSE: Low-tie ligation in colorectal cancer surgery is associated with technical difficulties in left colic artery preservation. We aimed to evaluate and classify the anatomical and technical difficulties of left colic artery (LCA) preservation at its origin and along its route at the inferior border of the pancreas. METHODS: A vascular reconstruction computed tomography prospective series of 113 patients was analyzed. The inferior mesenteric artery (IMA) branching pattern according to Latarjet's classification (Type I, separate LCA origin, Type II, fan-shaped branching pattern) and the distances between the IMA and the LCA origins and between the LCA and the Inferior mesenteric vein (IMV) at the inferior border of the pancreas were measured. RESULTS: The IMA branching pattern was Type I in 80 (71 %) patients and Type II in 33 (29 %) patients. The IMA-LCA distance was 39.8 +/- 12.2 mm. The LCA-IMV distance at the inferior border of the pancreas was 20.5 +/- 21.7 mm. When classified based on this distance, 75 (66 %) patients were classified into the Near subgroup (<20 mm) (7.7 +/- 4.1 mm) and 38 (34 %) into the Far subgroup (>=20 mm) (45.6 +/- 20.4 mm, p < 0.001). A Type I subgroup F accounted for 27 % of the patients. CONCLUSIONS: Left colic artery preservation is highly feasible at its origin in more than two thirds of cases due to the separate origin. The addition of a high IMV ligation increases the risk of damage to the LCA at the inferior border of the pancreas because the distance to the IMV is less than 20 mm in two-thirds of cases. PMID- 26526821 TI - Approach to en bloc resection and reconstruction of primary masticator space malignancies. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to present our experience with management of malignant lesions arising within the masticator space, and to describe a technique of en bloc resection and reconstruction. STUDY DESIGN: Case series and case report. METHODS: Eight cases of masticator space malignancies treated surgically with en bloc resection and free flap reconstruction were retrospectively reviewed. RESULTS: Tumor extirpation was carried out through a parotidectomy approach with mobilization and protection of the facial nerve. Primary reconstruction was accomplished with vascularized bone containing free flaps, fibula (n = 4), scapula (n = 2), and scapula with latissimus dorsi muscle (n = 2). Mean follow-up was 62.5 months (range, 18-132 months). CONCLUSIONS: En bloc resection of masticator space malignancies can be consistently accomplished through an extended parotidectomy approach. The defect is best reconstructed with a vascularized bone and soft tissue free flap. Favorable functional and aesthetic outcomes can be successfully achieved using the techniques described in this series. LEVEL OF EVIDENCE: 4. PMID- 26526822 TI - Editorial. PMID- 26526823 TI - Prevalence of oro-dental pathology in a working horse population in Egypt and its relation to equine health. AB - REASONS FOR PERFORMING STUDY: Oro-dental disease can have a significant impact on equine welfare. OBJECTIVES: To determine the prevalence of oro-dental disease and to identify risk factors for oro-dental disorders and poor body condition scores (BCS) in a working horse population in Egypt. STUDY DESIGN: Cross-sectional survey. METHODS: Oro-dental examination was performed on 450 working horses in 2 Egyptian provinces. Horse and management historical data were collected and horses were assigned to no/mild, moderate and severe dental disease categories based on findings on examination. Multivariable logistic regression and generalised additive models were used to identify risk factors for oral mucosal injuries and very poor/poor BCS, and to explore the relationship between age and different oro-dental disorders. RESULTS: Oro-dental disease was common, with 45.3% and 8.4% of horses considered to have moderate and severe oro-dental disease, respectively. None of these horses had previously undergone any form of proper dental examination and treatment by trained personnel. Oral mucosal injuries (64.2%) and sharp enamel points (79.8%) were most common. Oral mucosal injuries were significantly associated with increasing age (odds ratio (OR) 1.1, 95% confidence interval (CI) 1.01-1.1, P = 0.03), focal dental overgrowths (OR 2.4, 95% CI 1.4-4.0, P = 0.002) and sharp enamel points (OR 6.3, 95% CI 3.5-11.0, P<0.001). Very poor and poor BCS were significantly associated with severe dental disease (OR 2.6, 95% CI 1.2-5.8, P = 0.02), horses aged 16-30 years (OR 3.5, 95% CI 1.7-7.0, P = 0.001), height (OR 0.9, 95% CI 0.9-0.97, P = 0.001) and packed cell volume (OR 0.9, 95% CI 0.85-0.95, P<0.001). CONCLUSIONS: There is a need for education of working horse-owners in Egypt about the importance of oro-dental disease and for greater availability of veterinarians with suitable training and equipment to perform dental prophylaxis and treatment. Even simple dental prophylaxis could have a significant impact on the health and welfare of this population of working horses. PMID- 26526824 TI - Foldable and portable triboelectric-electromagnetic generator for scavenging motion energy and as a sensitive gas flow sensor for detecting breath personality. AB - An easily foldable and portable triboelectric-electromagnetic generator (TEMG) based on two polymer/Al layers and one copper coil has been designed to harvest ambient mechanical energy, where the copper coil is used both as a spring to achieve contact and separation of triboelectric layers and as a circuit to collect electromagnetic-induced electricity. The output performance of the TEMG is approximately reproducible after being folded many times. The working mechanism is discussed. The output performance of individual triboelectric generator (TEG) and electromagnetic generator (EMG) are systematically investigated. The maximum output current, voltage, and power are obtained to be 32.2 MUA, 500 V, and 2 mW for the TEG, and 4.04 mA, 30 mV, and 15.8 MUW for the EMG, respectively. The TEG with a higher internal resistance can be used as a current source, while the EMG with a lower resistance can be used as a voltage source. It can be used as a mobile light source via integrating the TEMG in clothes or bags, and as a self-powered gas flow sensor for detecting respiratory rate, which has a potential application in medical diagnoses. The simple structure and easy portability of the TEMG could be used widely in daily life to harvest ambient energy for electronic devices. PMID- 26526825 TI - Intraluminal water filling technique to prevent double mucosal puncture during EUS-guided choledochoduodenostomy. PMID- 26526826 TI - Synthesis and biological evaluation of esters of 16-formyl-17-methoxy dehydroepiandrosterone derivatives as inhibitors of 5alpha-reductase type 2. AB - In this study, we investigated the in vitro effect of 16-formyl-17-methoxy dehydroepiandrosterone derivatives on the activity of 5alpha-reductase type 2 (5alpha-R2) obtained from human prostate. The activity of different concentrations of these derivatives was determined for the conversion of labelled testosterone to dihydrotestosterone. The results indicated that an aliphatic ester moiety at the C-3 position of these derivatives increases their in vitro potency as inhibitors of 5alpha-R2 activity compared to finasteride(r), which is considered to be a potent inhibitor of 5alpha-R2. In this case, the augmentation of the lipophilicity of these dehydroepiandrosterone derivatives increased their potency as inhibitors of 5alpha-R2. However, the presence of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings as the cycloaliphatic ester moiety at C-3 of the formyl methoxy dehydroepiandrosterone scaffold did not inhibit the activity of this enzyme. This may be due to the presence of steric factors between the enzyme and the spatial structure of these derivatives. PMID- 26526827 TI - [Assessing the use of procalcitonin in the hospitalised young febrile infant]. AB - INTRODUCTION: The use of procalcitonin (PCT) in the evaluation of the febrile infant in the emergency care unit has been widespread. The aim of this study is to assess whether the introduction of PCT has changed the management of hospitalised febrile infants and the cost/effectiveness of this marker. MATERIALS AND METHODS: A retrospective study was performed comparing 2 periods: January December 2009 (without PCT) and January-December 2011 (routine use of PCT). Infants aged 7 to 90 days with fever who were admitted to a university hospital and had a blood test performed were included in the study. Bacterial infection rate, antibiotic use, hospitalisation days, and analytical costs were compared. Evaluations were made using PCT, C-reactive protein (CRP), white cell count, Rochester score, and the lab-score proposed by Galetto-Lacour for the diagnosis of bacterial infection. RESULTS: A total of 109 patients were included in period 1, and 111 in period 2 (87 of which had a PCT value). The prevalence of bacterial infection, use of antibiotics, number of blood tests, and days of hospital admission was similar in both periods. The blood test cost was significantly higher in the second period. Sensitivity, specificity, positive predictive value and negative predictive value were 70.6, 58.1, 52.6 and 75%, respectively for the CRP (cut-off 1mg/dL) and 41.7; 78.4; 57.7, and 65.6% for the PCT (cut-off value 0.5ng/ml). CONCLUSIONS: The use of PCT does not seem to have a significant impact on the management of the hospitalised febrile infant. PMID- 26526828 TI - [Chromosomal anomalies: The experience of the Congenital Anomalies Registry of the Valencia Region]. AB - OBJECTIVE: To describe the temporal trend and distribution of chromosomal congenital abnormalities (CA) in the Valencia Region, in less than one year olds, during the period 2007-2011. METHODOLOGY: Live births, still births and termination of pregnancy due to foetal anomaly between 2007 and 2011 with chromosomal CA (Q90-Q99.9 codes of the 10th International Classification of Diseases -British Paediatric Association) were selected from the CA population based Registry of Valencia Region The prevalence per 10,000 births for the chromosomal CA and for the different types of chromosomal syndromes with 95% confidence intervals was calculated. The analysis was performed by calculating prevalences and data were compared using Pearson Chi-squared test. RESULTS: A total of 895 cases were found, representing a prevalence of 33.5 per 10,000 births (95% CI: 31.0-35.9), highlighting five syndromes: Down's, Edward's, Patau, Turner and Klinefelter. The prevalence of chromosomal CA and Down's syndrome were stable over the period, except in 2010. Down's was the most frequent chromosomal CA (67% of the cases), and the most frequent termination of pregnancy type was for foetal anomaly (69%). Cardiac heart defects represented 70.3% of the associated congenital anomalies. Mothers of children with chromosomal CA were mainly Spanish (73.3%). The age group of mothers over 39 years had a higher prevalence (133.0 per 10,000 births). The province of Castellon had the highest prevalence, 39.1 per 10,000 births. CONCLUSIONS: The prevalence has remained stable over the five years, excluding the significant decline in 2010, for chromosomal CA detected and two of the major syndromes. The chromosomal CA are an important public health problem as they represent 15% of all CA identified in the Valencia Region, and agrees with the European data. PMID- 26526829 TI - Prediction of Metabolism of Drugs using Artificial Intelligence: How far have we reached? AB - Information about drug metabolism is an essential component of drug development. Modeling the drug metabolism requires identification of the involved enzymes, rate and extent of metabolism, the sites of metabolism etc. There has been continuous attempts in the prediction of metabolism of drugs using artificial intelligence in effort to reduce the attrition rate of drug candidates entering to preclinical and clinical trials. Currently, there are number of predictive models available for metabolism using Support vector machines, Artificial neural networks, Bayesian classifiers etc. There is an urgent need to review their progress so far and address the existing challenges in prediction of metabolism. In this attempt, we are presenting the currently available literature models and some of the critical issues regarding prediction of drug metabolism. PMID- 26526830 TI - UGT1A1 Mediated Drug Interactions and its Clinical Relevance. AB - BACKGROUND: The administration of multiple drugs for the treatment of diseases is an integral aspect of modern medicine. Though its purpose is to create the intended therapeutic effect, the unintended consequences of drug interactions can cause severe side effects and subsequent economic losses. Likewise, herbal extracts and supplements with pharmacologically active moieties also have the potential to interact with medications. There are many possible mechanisms on how these moieties could potentially interact, one of which is mediated by modulation of the activity of metabolizing enzymes. One such enzyme of high clinical significance is uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphism of UGT1A1 has been found to affect the plasma concentrations of many drugs, and may even be linked to treatment outcome. OBJECTIVE: This mini-review summarized the potential in vitro and in vivo interactions mediated by UGT1A1. METHOD: Firstly, literature search was conducted using the Web of Knowledge database. No date limitation was applied to the search. Following which, the interactions were stratified into 3 main categories based on its clinical significance. Both herbal and pharmacological drug moieties are covered within the scope of this mini-review. RESULTS: Of 35 UGT1A1 induced drug interactions, likely and unlikely to be clinically significant interactions are 11 and 6 respectively. The rest of them are inconclusive. CONCLUSION: We hope that this secondary literature can broaden and update the perspective of clinicians, pharmacists and academics on the interactions mediated by UGT1A1. PMID- 26526831 TI - Ceramide: Therapeutic Potential in Combination Therapy for Cancer Treatment. AB - Combination therapy has become an important strategy for treating cancer in recent years. Ceramide, which is a powerful tumor suppressor, regulating the processes of cell proliferation, differentiation, senescence and apoptosis, has attracted tremendous attention in combination therapy for cancer treatment. It has been demonstrated that combination of chemotherapeutic drugs and ceramide led to a reversion of multidrug resistance (MDR), synergistic tumor inhibition while simultaneously reducing systemic toxicity in cancer treatment. In this review, we aim to reveal the interactions between some anticancer drugs and ceramide, and summarize the research progress in combination therapies based on ceramide. Synthesis, metabolism and anticancer mechanisms of ceramide were described. Furthermore, the advantages of combination of chemotherapeutic drugs and exogenous ceramide, cerami-degenerating agents or modulators of ceramide metabolism were highlighted. Future perspective and problems to solve before the extension of ceramide's applications were also discussed. It is hoped that this review will provide new ideas for combination therapies in cancer treatment. PMID- 26526832 TI - Patients' Induced Pluripotent Stem Cells to Model Drug Induced Adverse Events: A Role in Predicting Thiopurine Induced Pancreatitis? AB - Induced pluripotent stem cells (iPSC) can be produced from adult cells by transfecting them with a definite set of pluripotency-associated genes. Under adequate growth conditions and stimulation iPSC can differentiate to almost every somatic lineage in the body. Patients' derived iPSC are an innovative model to study mechanisms of adverse drug reactions in individual patients and in cell types that cannot be easily obtained from human subjects. Proof-of concept studies with known toxicants have been performed for liver, cardiovascular and central nervous system cells: neurons obtained from iPSC have been used to elucidate the mechanism of chemotherapy-induced peripheral neuropathy by evaluating the effects of neurotoxic drugs such as vincristine. However, no study has been performed yet on pancreatic tissue and drug induced pancreatitis. Thiopurines (azathioprine and mercaptopurine) are immunosuppressive antimetabolite drugs, commonly used to treat Crohn's disease. About 5% of Crohn's disease patients treated with thiopurines develop pancreatitis, a severe idiosyncratic adverse event; these patients have to stop thiopurine administration and may require medical treatment, with significant personal and social costs. Molecular mechanism of thiopurine induced pancreatitis (TIP) is currently unknown and no fully validated biomarker is available to assist clinicians in preventing this adverse event. Hence, in this review we have reflected upon the probable research applications of exocrine pancreatic cells generated from patient specific iPS cells. Such pancreatic cells can provide excellent insights into the molecular mechanism of TIP. In particular three hypotheses on the mechanism of TIP could be explored: drug biotransformation, innate immunity and adaptative immunity. PMID- 26526833 TI - Recent Advances of Poly(ether-ether) and Poly(ether-ester) Block Copolymers in Biomedical Applications. AB - BACKGROUND: Poly(ether-ether) and poly(ether-ester) block copolymers have been widely applied in biomedical fields over two decades due to their good safety and biocompatibility. Poly(ethylene glycol), poly(ethylene glycol)-poly(propylene glycol) and poly(lactic-co-glycolic acid) have been approved as excipients by Food and Drug Administration. Because of the broad perspective in biomedical fields, many novel poly(etherether) and poly(ether-ester) block copolymers have been developed for drug delivery, gene therapy and tissue engineering in recent years. This review focuses on active targeting theranostic systems, gene delivery systems and tissue engineering based on poly(ether-ether) and poly(ether-ester) block copolymers. METHODS: We perform a structured search of bibliographic databases for peer-reviewed scientific reports using a focused review question and inclusion/exclusion criteria. The literatures related to the topics of this review are cataloged according to the developed copolymers or their applications such as active targeting theranostic systems, gene delivery systems and tissue engineering. Some important advances and new trends are summarized in this review. RESULTS: Some commercial poly(ether-ether) copolymers have been used as excipients for drug research and development. Amphiphilic and biodegradable poly(ether-ester) diblock copolymers are capable of formulating biomedical nanoparticulate theranostic systems, and targeting moiety-functionalized poly(ether-ester) diblock copolymers will be further developed and applied in biomedical nanotechnology fields in the near future. Meanwhile, triblock or multiblock poly(ether-ether) and poly(ether-ester) copolymers with environmentsensitive properties are suitable for gene delivery and tissue engineering. Poly(ether-ether) and poly(ether-ester) copolymers are being extensively applied in active targeting theranostic systems, gene delivery systems and tissue engineering. CONCLUSIONS: Biodegradable, environment-sensitive and targeting moiety-functionalized block copolymers, which are being applied in active targeting theranostic systems, gene delivery systems and tissue engineering, are promising candidates for treatment of various diseases. PMID- 26526834 TI - Cunninghamella Biotransformation--Similarities to Human Drug Metabolism and Its Relevance for the Drug Discovery Process. AB - BACKGROUND: Studies of drug metabolism are one of the most significant issues in the process of drug development, its introduction to the market and also in treatment. Even the most promising molecule may show undesirable metabolic properties that would disqualify it as a potential drug. Therefore, such studies are conducted in the early phases of drug discovery and development process. Cunninghamella is a filamentous fungus known for its catalytic properties, which mimics mammalian drug metabolism. It has been proven that C. elegans carries at least one gene coding for a CYP enzyme closely related to the CYP51 family. The transformation profile of xenobiotics in Cunninghamella spp. spans a number of reactions catalyzed by different mammalian CYP isoforms. OBJECTIVE: This paper presents detailed data on similar biotransformation drug products in humans and Cunninghamella spp. and covers the most important aspects of preparative biosynthesis of metabolites, since this model allows to obtain metabolites in sufficient quantities to conduct the further detailed investigations, as quantification, structure analysis and pharmacological activity and toxicity testing. CONCLUSION: The metabolic activity of three mostly used Cunninghamella species in obtaining hydroxylated, dealkylated and oxidated metabolites of different drugs confirmed its convergence with human biotransformation. Though it cannot replace the standard methods, it can provide support in the field of biotransformation and identifying metabolic soft spots of new chemicals and in predicting possible metabolic pathways. Another aspect is the biosynthesis of metabolites. In this respect, techniques using Cunninghamella spp. seem to be competitive to the chemical methods currently used. PMID- 26526835 TI - Coenzyme Q10 Supplementation and Exercise in Healthy Humans: A Systematic Review. AB - OBJECTIVE: Coenzyme Q10 (CoQ10) is an endogenous lipid-soluble benzoquinone compound that functions as a diffusible electron carrier in the electron transport chain. It is prevalent in all human tissues and organs, although it is mainly biosynthesised and concentrated in tissues with high energy turnover. The aim of this review was to perform an exhaustive analysis of the influence and effects of CoQ10 supplementation on parameters related to exercise in healthy humans, and to clarify the current state of knowledge of this field of study, presenting the relevant data in a systematic manner. METHOD: This paper describes a transversal descriptive systematic review of published research in this field; the study was conducted using a method adapted from the PRISMA guidelines. The inclusion criteria applied were based on the PICO (population, intervention, comparison, and outcome) model. RESULTS: The database search performed yielded 372 citations. Finally, 13 studies met all the inclusion criteria and were incorporated in the present review. CONCLUSION: CoQ10 has properties related to bioenergetic and antioxidant activity; thus, it is intimately involved in energy production and in the prevention of peroxidative damage to membrane phospholipids and of free radical-induced oxidation. These properties make it suitable as a dietary supplement to improve cellular bioenergetics and to inhibit certain age related pathologies. PMID- 26526836 TI - Bile Acids in Physiology, Pathology and Pharmacology. AB - Bile acids, synthesized by hepatocytes from cholesterol, are specific and quantitatively important organic components of bile, where they are the main driving force of the osmotic process that generates bile flow toward the canaliculus. The bile acid pool comprises a variety of species of amphipathic acidic steroids. They are not mere detergent molecules that play a key role in fat digestion and the intestinal absorption of hydrophobic compounds present in the intestinal lumen after meals, including liposoluble vitamins. They are now known to be involved in the regulation of multiple functions in liver cells, mainly hepatocytes and cholangiocytes, and also in extrahepatic tissues. The identification of nuclear receptors, such as farnesoid X receptor (FXR or NR1H4), and plasma membrane receptors, such as the G protein-coupled bile acid receptor (TGR5, GPBAR1 or MBAR), which are able to trigger specific and complex responses upon activation (with dissimilar sensitivities) by different bile acid molecular species and synthetic agonists, has opened a new and promising field of research whose implications extend to physiology, pathology and pharmacology. In addition, pharmacological development has taken advantage of advances in the understanding of the chemistry and biology of bile acids and the biological systems that interact with them, which in addition to the receptors include several families of transporters and export pumps, to generate novel bile acid derivatives aimed at treating different liver diseases, such as cholestasis, biliary diseases, metabolic disorders and cancer. This review is an update of the role of bile acids in health and disease. PMID- 26526837 TI - Cytochrome P450-Mediated Estrogen Metabolites and Autoimmunity: Relationship and Link to Free Radicals. AB - Cytochrome P450 enzymes are responsible for the hydroxylation of various endogenous estrogens of the Phase I metabolic pathway. Cytochrome P450s produce hormonally active estrogen metabolites that are typically reactive and mutagenic. Although these metabolites are known to have important roles in autoimmunity, the underlying mechanism of this remains unknown. Here we report that cytochrome P450 mediated estrogen metabolites produce high ROS concentrations that can result in DNA damage. Such DNA damage can alter its immunogenicity, resulting in the induction and elevation of autoantibody concentrations, thus generating various autoimmune conditions. Here we focus on the mechanisms through which cytochrome P450-catalyzed estrogen metabolites induce immune responses and subsequently produce the autoimmune phenomenon. PMID- 26526838 TI - Clinically Relevant Pharmacokinetic Herb-drug Interactions in Antiretroviral Therapy. AB - For healthcare professionals, the volume of literature available on herb-drug interactions often makes it difficult to separate experimental/potential interactions from those deemed clinically relevant. There is a need for concise and conclusive information to guide pharmacotherapy in HIV/AIDS. In this review, the bases for potential interaction of medicinal herbs with specific antiretroviral drugs are presented, and several botanicals are discussed for which clinically relevant interactions in humans are established. Such studies have provided, in most cases, sufficient ground to warrant the avoidance of concurrent administration of antiretroviral (ARVs) drugs with St John's wort (Hypericum perforatum), black pepper (Piper species) and grapefruit juice. Other botanicals that require caution in the use with antiretrovirals include African potato (Hypoxis hemerocallidea), ginkgo (Ginkgo biloba), ginseng (Panax species), garlic (Allium sativum), goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum). The knowledge of clinically significant herb-drug interaction will be important in order to avoid herb-induced risk of sub-therapeutic exposure to ARVs (which can lead to viral resistance) or the precipitation of toxicity (which may lead to poor compliance and/or discontinuation of antiretroviral therapy). PMID- 26526839 TI - The Role of the Metabolism of Anticancer Drugs in Their Induced-Cardiotoxicity. AB - Cardioncology is a major topic of the day, since cardiotoxicity of chemotherapy agents can limit its real use and it can also become a clinical problem years after the end of anticancer therapy. These cardiac problems largely increase the mortality and morbidity of cancer-treated patients. Actually, as the number of cancer survivors is increasing each decade, late cardiotoxicity related to anticancer therapy is expected to grow exponentially in the fore coming years. The mechanisms of cardiotoxicity of anticancer drugs are still largely unknown. The metabolism of some drugs can lead to more active anticancer metabolites but those metabolites can likewise contribute to the observed cardiotoxicity. The alcohols and aglycone metabolites of anthracyclines are known to be cardiotoxic, while regarding 5-fluorouracil, fluoroacetate is considered one of the major metabolites responsible for its cardiotoxicity. Regarding mitoxantrone, the toxicity of the majority of the metabolites has not been assessed so far and concerning cyclophosphamide metabolites, both hydroxycyclophosphamide and acrolein are shown to be more cardiotoxic than the parent drug. Still, the contribution of drug metabolism to the cardiotoxicity of chemotherapy agents is largely unknown and poorly discussed. This review presents a new link between several cardiotoxic anticancer drugs and their drug metabolites, as they can play an important role in the widely reported heart damage inflicted by chemotherapy. Anthracyclines, cyclophosphamide, mitoxantrone, and 5- fluorouracil will be mainly focused, given the vast literature and clinical use. The current knowledge shows the possible involvement of drug metabolism in bioactivation mechanisms that can contribute to their cardiotoxicity. PMID- 26526840 TI - Decreased Poly(ADP-Ribose) Polymerase 1 Expression Attenuates Glucose Oxidase Induced Damage in Rat Cochlear Marginal Strial Cells. AB - Oxidative damage to the inner ear is responsible for several types of sensorineural deafness. Cochlear stria marginal cells (MCs) are thought to be vulnerable to such oxidative stress. Activated poly(ADP-ribose) polymerase 1 (PARP1) has been implicated in several diseases, but the effect of PARP1 on MCs subjected to oxidative stress remains elusive. In this study, we established an in vitro cellular oxidative stress model using glucose oxidase (GO) and attempted to explore the role that PARP1 plays in the oxidative damage of MCs. In this study, PARP1 and poly-ADP-ribose (PAR) were highly expressed in GO-treated MCs, and this was accompanied by loss of MC viability, excessive generation of reactive oxygen species (ROS), collapse of mitochondria membrane potential (DeltaPsim), and redistribution of the mitochondrial downstream pathway-related molecules Bax and cytochrome c, eventually causing MC death. These effects were almost completely counteracted by suppressing PARP1 expression with small interfering RNA (siRNA). We also found that caspase-3 activation was a downstream event of PARP activation and that apoptosis of MCs was suppressed, although not completely, by pretreatment with the pan-caspase inhibitor z-VAD-fmk. The suppression was less than that when PARP1 expression was inhibited. We conclude that GO treatment induces activation of PARP1, which causes MC damage via mitochondrial mediation. PARP1 plays a pivotal role in GO-induced MC death, at least in part, via the caspase-3 cascade. Our study might provide a new cellular and molecular approach for the treatment of oxidative stress-related sensorineural deafness. PMID- 26526841 TI - Modulation of BAG3 Expression and Proteasomal Activity by sAPPalpha Does Not Require Membrane-Tethered Holo-APP. AB - Maintenance of intracellular proteostasis is essential for neuronal function, and emerging data support the view that disturbed proteostasis plays an important role in brain aging and the pathogenesis of age-related neurodegenerative disorders such as Alzheimer's disease (AD). sAPPalpha (sAPPalpha), the extracellularly secreted N-terminal alpha secretase cleavage product of the amyloid precursor protein (APP), has an established function in neuroprotection. Recently, we provided evidence that membrane-bound holo-APP functionally cooperates with sAPPalpha to mediate neuroprotection via activation of the Akt survival signaling pathway and sAPPalpha directly affects proteostasis. Here, we demonstrate that in addition to its anti-apoptotic function, sAPPalpha has effects on neuronal proteostasis under conditions of proteasomal stress. In particular, recombinant sAPPalpha significantly suppressed MG132-triggered expression of the co-chaperone BAG3 and aggresome formation, and it partially rescued proteasomal activity in a dose-dependent manner in SH-SY5Y neuroblastoma cells. In analogy, sAPPalpha was able to inhibit MG132-induced BAG3 expression in primary hippocampal neurons. Strikingly, these sAPPalpha-induced changes were unaltered in APP-depleted SH-SY5Y cells and APP-deficient neurons, demonstrating that holo-APP is not required for this particular function of sAPPalpha. Importantly, recombinant sAPPbeta (sAPPbeta) failed to modulate BAG3 expression and proteostasis in APP-proficient wild-type (wt) cells, indicating that these biological effects are highly selective for sAPPalpha. In conclusion, we demonstrate that modulation of proteostasis is a distinct biological function of sAPPalpha and does not require surface-bound holo-APP. Our data shed new light on the physiological functions of APP and the interplay between APP processing and proteostasis during brain aging. PMID- 26526842 TI - Evaluation of Anti-Inflammatory Effects of Helminthostachys zeylanica Extracts via Inhibiting Bradykinin-Induced MMP-9 Expression in Brain Astrocytes. AB - Phytochemicals present in vegetables, fruits, and herbs are believed to reduce the risk of several major diseases including cardiovascular or neurodegenerative disorders. The roots of the fern Helminthostachys zeylanica (L.) Hook. (Ophioglossaceae) have been used for centuries in the treatment of inflammation and as a folk medicine in several countries. The plant has been shown to possess an array of medicinal properties, including antioxidants and anti-inflammatory activities. Moreover, a rising level of matrix metalloproteinase-9 (MMP-9) has been found in blood fluid of these patients suffering from brain inflammatory diseases, which may be considered an inflammatory biomarker in several inflammatory diseases including the central nervous system (CNS) inflammation. Previously, we have demonstrated the signaling mechanisms of bradykinin (BK) induced MMP-9 expression in brain astrocytes. Herein, we evaluate the effects of H. zeylanica extracts on BK-induced MMP-9 expression in brain astrocytes and its influencing mechanism. The results showed that H. zeylanica extracts, including E0, E1, and E2 significantly reduce MMP-9 induced by BK in brain astrocytes (RBA 1 cells). These H. zeylanica extracts can inhibit BK-stimulated phosphorylation of c-Src, Pyk2, and PKC(alpha/delta). Moreover, BK-stimulated NADPH oxidase (Nox) derived reactive oxygen species (ROS) generation has also been attenuated by pretreatment with these extracts, suggesting that the H. zeylanica extracts have an antioxidative activity. We further demonstrated that the H. zeylanica extracts blocked activation of MAPKs (e.g., ERK1/2 and p38 MAPK) by BK. These data indicated that the H. zeylanica extracts may be has anti-inflammatory activity by reducing BK-induced ROS-dependent MMP-9 expression via these related pathways in brain astrocytes. PMID- 26526843 TI - L-carnitine Prevents Oxidative Stress in the Brains of Rats Subjected to a Chemically Induced Chronic Model of MSUD. AB - Maple syrup urine disease (MSUD), or branched-chain alpha-keto aciduria, is an inherited disorder that is caused by a deficiency in branched-chain alpha-keto acid dehydrogenase complex (BCKAD) activity. Blockade of this pathway leads to the accumulation of the branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, and their respective ketoacids in tissues. The main clinical symptoms presented by MSUD patients include ketoacidosis, hypoglycemia, opisthotonos, poor feeding, apnea, ataxia, convulsions, coma, psychomotor delay, and mental retardation. Although increasing evidence indicates that oxidative stress is involved in the pathophysiology of this disease, the mechanisms of the brain damage caused by this disorder remain poorly understood. In the present study, we investigated the effect of BCAAs on some oxidative stress parameters and evaluated the efficacy of L-carnitine (L-car), an efficient antioxidant that may be involved in the reduction of oxidative damage observed in some inherited neurometabolic diseases, against these possible pro-oxidant effects of a chronic MSUD model in the cerebral cortex and cerebellum of rats. Our results showed that chronic BCAA administration was able to promote both lipid and protein oxidation, impair brain antioxidant defenses, and increase reactive species production, particularly in the cerebral cortex, and that L-car was able to prevent these effects. Taken together, the present data indicate that chronic BCAA administration significantly increased oxidative damage in the brains of rats subjected to a chronic model of MSUD and that L-car may be an efficient antioxidant in this disorder. PMID- 26526844 TI - Microtubule-Actin Crosslinking Factor 1 Is Required for Dendritic Arborization and Axon Outgrowth in the Developing Brain. AB - Dendritic arborization and axon outgrowth are critical steps in the establishment of neural connectivity in the developing brain. Changes in the connectivity underlie cognitive dysfunction in neurodevelopmental disorders. However, molecules and associated mechanisms that play important roles in dendritic and axon outgrowth in the brain are only partially understood. Here, we show that microtubule-actin crosslinking factor 1 (MACF1) regulates dendritic arborization and axon outgrowth of developing pyramidal neurons by arranging cytoskeleton components and mediating GSK-3 signaling. MACF1 deletion using conditional mutant mice and in utero gene transfer in the developing brain markedly decreased dendritic branching of cortical and hippocampal pyramidal neurons. MACF1 deficient neurons showed reduced density and aberrant morphology of dendritic spines. Also, loss of MACF1 impaired the elongation of callosal axons in the brain. Actin and microtubule arrangement appeared abnormal in MACF1-deficient neurites. Finally, we found that GSK-3 is associated with MACF1-controlled dendritic differentiation. Our findings demonstrate a novel role for MACF1 in neurite differentiation that is critical to the creation of neuronal connectivity in the developing brain. PMID- 26526845 TI - Postnatal Excitability Development and Innervation by Functional Transient Receptor Potential Vanilloid 1 (TRPV1) Terminals in Neurons of the Rat Spinal Sacral Dorsal Commissural Nucleus: an Electrophysiological Study. AB - The sacral dorsal commissural nucleus (SDCN) in the spinal cord receives both somatic and visceral primary afferents. Transient receptor potential vanilloid 1 (TRPV1) channels are preferentially expressed in certain fine primary afferents. However, knowledge of the SDCN neurons postnatal excitability development and their contacts with TRPV1 fibers remains elusive. Here, whole-cell recordings were conducted in spinal cord slices to evaluate the postnatal development of SDCN neurons and their possible contacts with functional TRPV1-expressing terminals. SDCN neurons in neonatal (postnatal day (P) 1-2), young (P8-10), and adult rats (P35-40) have different electrophysiological properties. SDCN neurons in neonatal rats have higher frequency of spontaneous firing, higher resting membrane potential, and lower presynaptic glutamate release probability. However, no difference in quantal release was found. At all developmental stages, TRPV1 activation with the selective agonist capsaicin increases glutamate release in the presence of tetrodotoxin, which blocks action potential-dependent and polysynaptic neurotransmission, indicating that functional TRPV1 fibers innervate SDCN neurons directly. Capsaicin-induced presynaptic glutamate release onto SDCN neurons depends on external Ca2+ influx through TRPV1 channels; voltage-dependent calcium channels had a slighter impact. In contrast, capsaicin blocked C fiber evoked synaptic transmission, indicating that TRPV1 activation has opposite effects on spontaneous asynchronous and action potential-dependent synchronous glutamate release. These data indicate that excitability of SDCN neurons undergoes a developmental shift, and these neurons receive functional TRPV1 terminals from early postnatal stage. The opposite action of capsaicin on asynchronous and synchronous glutamate release should be taken into account when TRPV1 channels are considered as therapeutic targets. PMID- 26526847 TI - Nonalcoholic steatohepatitis cirrhosis and type 1 refractory celiac disease: More than a fortuitous association? PMID- 26526846 TI - Lentiviral Vector-Mediated p27kip1 Expression Facilitates Recovery After Spinal Cord Injury. AB - Traumatic spinal cord injury (SCI) causes tissue loss and associated neurological dysfunction attributable to both mechanical damage and secondary biochemical and physiological responses. Upregulation of cell cycle proteins occurs in both neurons and glia after SCI and may contribute to these changes. Increased cell cycle protein is associated with neuronal and oligodendroglial apoptosis, reactive astrogliosis, glial scar formation, and microglial activation. Here, using lentiviral vectors (LV), we induced the expression of the cyclin-dependent kinase (CDK) inhibitor p27kip1 in the lesioned spinal cord of adult rat. Treatment with LV-p27kip1 significantly reduced the expression of cell cycle proteins and improved functional recovery. In addition, p27kip1 overexpression also reduced lesion volume, decreased astrocytic reactivity, attenuated microglial activation, reduced cell death, and improved the local microenvironment. We suggest that these effects reflect the ability of p27kip1 to inhibit cell cycle pathways. Thus, the present study provides further support for the therapeutic potential of cell cycle inhibitors in the treatment of SCI. PMID- 26526848 TI - Early activation of CD4+ and CD8+ T lymphocytes by myelin basic protein in subjects with MS. AB - BACKGROUND: Multiple sclerosis is the most common autoimmune disorder affecting the central nervous system. In this study, whole blood samples were analyzed for activation capacity and the activatability of CD4+ and CD8+ T-lymphocytes by human total myelin basic protein (MBP), human MBP 104-118 fragment, and guinea pig MBP 68-82 fragment. METHODS: Whole blood samples from healthy human subjects were compared with samples from patients with multiple sclerosis (MS). In particular, the expression of CD69, a surface marker of T-lymphocyte activity, was measured via flow cytometry before and after 14 h of incubation with human total MBP, MBP 104-118 fragment and/or guinea pig MBP 68-82 fragment. The results were compared between 15 patients with MS and 15 healthy subjects. RESULTS: In response to all three MBP forms, CD4+ and CD8+ T-lymphocytes from patients with MS demonstrated greater activatability than those from healthy subjects. These results indicate that in patients with MS, latent pre-activation to MBP epitopes results in an increased activation capacity of T-lymphocytes. CONCLUSION: This effect may occur because immunization against MBP (at least in a subset of patients) plays a pathophysiological role in MS pathogenesis. Alternatively, this result may represent a non-specific, bystander autoimmune phenomenon. PMID- 26526849 TI - Mutation-Guided Unbiased Modeling of the Fat Sensor GPR119 for High-Yield Agonist Screening. AB - Recent benchmark studies have demonstrated the difficulties in obtaining accurate predictions of ligand binding conformations to comparative models of G-protein coupled receptors. We have developed a data-driven optimization protocol, which integrates mutational data and structural information from multiple X-ray receptor structures in combination with a fully flexible ligand docking protocol to determine the binding conformation of AR231453, a small-molecule agonist, in the GPR119 receptor. Resulting models converge to one conformation that explains the majority of data from mutation studies and is consistent with the structure activity relationship for a large number of AR231453 analogs. Another key property of the refined models is their success in separating active ligands from decoys in a large-scale virtual screening. These results demonstrate that mutation-guided receptor modeling can provide predictions of practical value for describing receptor-ligand interactions and drug discovery. PMID- 26526850 TI - Structural Basis for Cyclopropanation by a Unique Enoyl-Acyl Carrier Protein Reductase. AB - The natural product curacin A, a potent anticancer agent, contains a rare cyclopropane group. The five enzymes for cyclopropane biosynthesis are highly similar to enzymes that generate a vinyl chloride moiety in the jamaicamide natural product. The structural biology of this remarkable catalytic adaptability is probed with high-resolution crystal structures of the curacin cyclopropanase (CurF ER), an in vitro enoyl reductase (JamJ ER), and a canonical curacin enoyl reductase (CurK ER). The JamJ and CurK ERs catalyze NADPH-dependent double bond reductions typical of enoyl reductases (ERs) of the medium-chain dehydrogenase reductase (MDR) superfamily. Cyclopropane formation by CurF ER is specified by a short loop which, when transplanted to JamJ ER, confers cyclopropanase activity on the chimeric enzyme. Detection of an adduct of NADPH with the model substrate crotonyl-CoA provides indirect support for a recent proposal of a C2-ene intermediate on the reaction pathway of MDR enoyl-thioester reductases. PMID- 26526851 TI - Dynamic Short Hydrogen Bonds in Histidine Tetrad of Full-Length M2 Proton Channel Reveal Tetrameric Structural Heterogeneity and Functional Mechanism. AB - The tetrameric M2 protein from influenza A conducts protons into the virus upon acid activation of its His37 tetrad and is a proven drug target. Here, in studies of full-length M2 protein solubilized in native-like liquid-crystalline lipid bilayers, a pH titration monitored by solid-state nuclear magnetic resonance revealed a clustering of the first three His37 pKas (6.3, 6.3, and 5.5). When the +2 state of the tetrad accepts a third proton from the externally exposed portion of the channel pore and releases a proton to the internally exposed pore, successful proton conductance is achieved, but more frequently the tetrad accepts and returns the proton to the externally exposed pore, resulting in a futile cycle. Both dynamics and conformational heterogeneity of the His37 tetrad featuring short hydrogen bonds between imidazolium-imidazole pairs are characterized, and the heterogeneity appears to reflect oligomeric helix packing and the extent of transmembrane helical bending around Gly34. PMID- 26526852 TI - The High-Resolution Structure of Activated Opsin Reveals a Conserved Solvent Network in the Transmembrane Region Essential for Activation. AB - Rhodopsin, a light-activated G protein coupled receptor (GPCR), has been the subject of numerous biochemical and structural investigations, serving as a model receptor for GPCRs and their activation. We present the 2.3-A resolution structure of native source rhodopsin stabilized in a conformation competent for G protein binding. An extensive water-mediated hydrogen bond network linking the chromophore binding site to the site of G protein binding is observed, providing connections to conserved motifs essential for GPCR activation. Comparison of this extensive solvent-mediated hydrogen-bonding network with the positions of ordered solvent in earlier crystallographic structures of rhodopsin photointermediates reveals both static structural and dynamic functional water-protein interactions present during the activation process. When considered along with observations that solvent occupies similar positions in the structures of other GPCRs, these analyses strongly support an integral role for this dynamic ordered water network in both rhodopsin and GPCR activation. PMID- 26526853 TI - The Importance of Ligand-Receptor Conformational Pairs in Stabilization: Spotlight on the N/OFQ G Protein-Coupled Receptor. AB - Understanding the mechanism by which ligands affect receptor conformational equilibria is key in accelerating membrane protein structural biology. In the case of G protein-coupled receptors (GPCRs), we currently pursue a brute-force approach for identifying ligands that stabilize receptors and facilitate crystallogenesis. The nociceptin/orphanin FQ peptide receptor (NOP) is a member of the opioid receptor subfamily of GPCRs for which many structurally diverse ligands are available for screening. We observed that antagonist potency is correlated with a ligand's ability to induce receptor stability (Tm) and crystallogenesis. Using this screening strategy, we solved two structures of NOP in complex with top candidate ligands SB-612111 and C-35. Docking studies indicate that while potent, stabilizing antagonists strongly favor a single binding orientation, less potent ligands can adopt multiple binding modes, contributing to their low Tm values. These results suggest a mechanism for ligand aided crystallogenesis whereby potent antagonists stabilize a single ligand receptor conformational pair. PMID- 26526854 TI - Prevalence and correlates of HIV-risky sexual behaviors among students attending the Medical and Social Welfare Center of the University of Maroua, Cameroon. AB - BACKGROUND: Data on sexual behaviors in Cameroonian youths are needed to design and implement effective preventive strategies against HIV/AIDS. This study aimed at assessing sociodemographic and religious factors associated with sexual behaviors among university students in Cameroon. METHODS: In 2011, 411 university students were surveyed by a self-administered questionnaire at the Medical and Social Welfare Center of the University of Maroua. Logistic regression analyses were used to determine correlates of sexual behaviors. RESULTS: 80.8 % of students were sexually active. The mean age at sexual debut was 18.1 years (SD = 3.1). The frequency of premarital sex was 92.8 %. Pornography viewing [adjusted odds ratio (aOR): 4.0, 95 % CI 2.1-7.6; p < 0.0001] and an increased age of 1 year (aOR: 1.3, 95 % CI 2.0-7.6; p < 0.0001) were significantly associated with having previously had sex. The likelihood to have a lower (<18) age at sexual debut was increased by male gender (aOR: 2.5, 95 % CI 1.7-5; p < 0.001), and urban origin (aOR: 2.9, 95 % CI 1.5-5.7; p < 0.01). The probability to have a high number (#3) of lifetime sexual partners was increased by age (aOR: 1.1, 95 % CI 1.0-1.2; p < 0.001), pornography viewing (aOR: 4.3, 95 % CI 1.9-9.5; p < 0.001), an early sexual debut (aOR: 2.8, 95 % CI 1.6-5.0; p < 0.001), having had occasional sexual partners (aOR: 7.0, 95 % CI 3.7-13.1; p < 0.0001), and was decreased by Muslim religious affiliation (aOR: 0.2, 95 % CI 0.1-0.9; p < 0.05). Having had casual sexual partners was associated with less inconsistent condom use (aOR: 0.5, 95 % CI 0.2-0.9; p < 0.05). CONCLUSIONS: Our findings indicate that there is an alarming level of risky sexual behaviors among the study population. Strong and efficient measures should be undertaken to handle such harmful behaviors, this for the prevention and control of HIV/AIDS and other STIs in this vulnerable population. PMID- 26526855 TI - Heavy metal contamination and ecological risk assessment in the surface sediments of the coastal area surrounding the industrial complex of Gabes city, Gulf of Gabes, SE Tunisia. AB - In the present study, the concentrations of 6 trace metals (Hg, Cd, Cu, Pb, Cr and Zn) were assessed in the surface sediments of the central coastal area of Gabes Gulf to determine their contamination status, source, spatial distribution and ecological risks. The ranking of metal contents was found to be Zn>Cd>Cr>Pb>Cu>Hg. Correlation analysis indicated that Cd and Zn derived mainly from the Tunisian Chemical Group phosphogypsum. The other pollutants may originate from other industrial wastes. Metallic contamination was detected in the south of chemical complex, especially in the inter-harbor zone, where the ecological risk of surface sediments is the highest, implying potential negative impacts of industrial pollutants. The spatial distribution of pollutants seems to be due to the effect of harbor installations and coastal currents. The metallic pollution status of surface sediments of Gabes Gulf is obvious, very worrying and requires rapid intervention. PMID- 26526856 TI - Prevalence of pseudobulbar affect symptoms and clinical correlates in nursing home residents. AB - OBJECTIVE: Pseudobulbar affect (PBA) is a neurological disorder of emotional expression, characterized by uncontrollable episodes of crying or laughing in patients with certain neurological disorders affecting the brain. The purposes of this study were to estimate the prevalence of PBA in US nursing home residents and examine the relationship between PBA symptoms and other clinical correlates, including the use of psychopharmacological medications. METHODS: A retrospective study was conducted between 2013 and 2014 with a convenience sample of residents from nine Michigan nursing homes. Chronic-care residents were included in the "predisposed population" if they had a neurological disorder affecting the brain and no evidence of psychosis, delirium, or disruptive behavior (per chart review). Residents were screened for PBA symptoms by a geropsychologist using the Center for Neurologic Study-Lability Scale (CNS-LS). Additional clinical information was collected using a diagnostic evaluation checklist and the most recent Minimum Data Set 3.0 assessment. RESULTS: Of 811 residents screened, complete data were available for 804, and 412 (51%) met the criteria for the "predisposed population." PBA symptom prevalence, based on having a CNS-LS score >=13, was 17.5% in the predisposed population and 9.0% among all nursing home residents. Those with PBA symptoms were more likely to have a documented mood disorder and be using a psychopharmacological medication, including antipsychotics, than those without PBA symptoms. CONCLUSIONS: Pseudobulbar affect symptoms were present in 17.5% of nursing home residents with neurological conditions, and 9.0% of residents overall. Increasing awareness and improving diagnostic accuracy of PBA may help optimize treatment. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26526857 TI - Highest power magnification with narrow-band imaging is useful for improving diagnostic performance for endoscopic delineation of early gastric cancers. AB - BACKGROUND AND STUDY AIMS: Magnifying endoscopy with narrow-band imaging (ME-NBI) is more reliable than chromoendoscopy (CE) for delineating the horizontal extent of early gastric cancers prior to endoscopic submucosal dissection (ESD). However, the added benefits of ME-NBI over CE in terms of the difference in magnification level have yet to be elucidated. The aim of this study was to investigate the improvement in diagnostic accuracy for tumor delineation obtained with different magnification levels of ME-NBI following CE. PATIENTS AND METHODS: This was a retrospective study, performed at a single tertiary referral center. A series of 158 consecutive patients with 161 early gastric cancers resected en bloc using ESD was included in the study. The margins of each lesion were examined in their entirety using CE, followed by low power optical magnifying endoscopy with narrow-band imaging (LM-NBI), and finally the highest power optical magnifying endoscopy with narrow-band imaging (HM-NBI). The primary endpoint was the added benefit, as measured using the successful delineation rate, for the delineation of gastric cancer margins using CE + LM-NBI vs CE, and for CE + LM-NBI + HM-NBI vs CE + LM-NBI. RESULTS: The successful delineation rates (95 % CI) using CE, CE + LM-NBI and CE + LM-NBI + HM-NBI were 72.7 % (68.5 79.9 %), 88.9 % (84.2-93.8 %), and 98.1 % (95.8-100 %). The diagnostic accuracy improved significantly for CE + LM-NBI compared with CE (P < 0.001), and for HM NBI compared with LM-NBI (P < 0.001). CONCLUSIONS: HM-NBI is useful for improving diagnostic performance for endoscopic delineation of early gastric cancers, following CE and LM-NBI. PMID- 26526858 TI - Puberty-specific promotion of mammary tumorigenesis by a high animal fat diet. AB - INTRODUCTION: Increased animal fat consumption is associated with increased premenopausal breast cancer risk in normal weight, but not overweight, women. This agrees with our previous findings in obesity-resistant BALB/c mice, in which exposure to a high saturated animal fat diet (HFD) from peripuberty through adulthood promoted mammary tumorigenesis. Epidemiologic and animal studies support the importance of puberty as a life stage when diet and environmental exposures affect adult breast cancer risk. In this study, we identified the effects of peripubertal exposure to HFD and investigated its mechanism of enhancing tumorigenesis. METHODS: Three-week-old BALB/c mice fed a low-fat diet (LFD) or HFD were subjected to 7,12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis. At 9 weeks of age, half the mice on LFD were switched to HFD (LFD HFD group) and half the mice on HFD were switched to LFD (HFD-LFD group). Tumor gene expression was evaluated in association with diet and tumor latency. RESULTS: The peripubertal HFD reduced the latency of DMBA-induced mammary tumors and was associated with tumor characteristics similar to those in mice fed a continuous HFD. Notably, short-latency tumors in both groups shared gene expression characteristics and were more likely to have adenosquamous histology. Both HFD-LFD and continuous HFD tumors showed similar gene expression patterns and early latency. Adult switch from HFD to LFD did not reverse peripubertal HFD tumor promotion. Increased proliferation, hyperplasia, and macrophages were present in mammary glands before tumor development, implicating these as possible effectors of tumor promotion. Despite a significant interaction between pubertal diet and carcinogens in tumor promotion, peripubertal HFD by itself produced persistent macrophage recruitment to mammary glands. CONCLUSIONS: In obesity resistant mice, peripubertal HFD is sufficient to irreversibly promote carcinogen induced tumorigenesis. Increased macrophage recruitment is likely a contributing factor. These results underscore the importance of early life exposures to increased adult cancer risk and are consistent with findings that an HFD in normal weight premenopausal women leads to increased breast cancer risk. Notably, short-latency tumors occurring after peripubertal HFD had characteristics similar to human basal-like breast cancers that predominantly develop in younger women. PMID- 26526860 TI - Timing of radiation and outcomes in implant-based breast reconstruction. AB - OBJECTIVE: Limited data exist regarding the effect of radiation timing on complications of tissue expander/implant-based breast reconstruction. This study seeks to compare outcomes of tissue expander/implant reconstruction in patients undergoing postmastectomy radiotherapy, those with previous radiation therapy following breast conservation therapy, and those who did not receive radiation therapy. METHODS: The records of the patients of a single surgeon were reviewed from January 2007 to July 2013. All patients undergoing tissue expander/implant breast reconstruction were placed into one of three groups based on the timing of radiation therapy: postmastectomy (Current), previously following breast conservation therapy (Prior), and no radiotherapy (No XRT). Medical records were reviewed for any reported complications, and statistical analysis was performed. RESULTS: A total of 210 patients (265 breasts) were included in the analysis. Current patients were more likely than No XRT patients to experience expander infection (20% vs. 2.6%, p = 0.001) and expander removal (26% vs. 8.3%, p = 0.007). Prior patients were more likely than No XRT patients to undergo conversion to tissue flap reconstruction (10.5% vs. 0.6%, p = 0.031). No significant differences were found between groups with respect to cellulitis, abscess formation, hematoma, seroma, skin flap necrosis, expander exposure, implant exposure, or implant infection. CONCLUSIONS: This study supports the relative safety of tissue expander/implant breast reconstruction in selected groups of patients who have received radiation therapy. Differences in rates of expander infection, expander removal, and conversion to tissue flap reconstruction represent potential areas for further research. PMID- 26526859 TI - Comparison of tobacco and alcohol use in films produced in Europe, Latin America, and the United States. AB - BACKGROUND: Studies that have evaluated tobacco and alcohol portrayals in films have mainly focused on US films. Our aim is to describe tobacco and alcohol portrayals in nationally produced films from six European and two Latin American countries, and compare them with US produced films. METHODS: A sample of 337 nationally produced and 502 US produced films, consisting of top grossing films from 2004 to 2009 in each country, was content coded for presence of tobacco or alcohol and seconds of tobacco or alcohol use. Logistic and linear regression models were estimated for all films and youth-rated films (Ages 0-14) to assess cross country differences in tobacco and alcohol content, with US films as the reference category. RESULTS: Domestically produced films from several countries were more likely than US films to contain any tobacco use both overall (Iceland (OR = 9.29, CI: 1.22-70.89), Italy (OR = 3.58, CI: 1.72-7.43), Argentina (OR = 5.06, CI: 2.13-12.03), Mexico (OR = 4.87, CI: 2.17-10.90)) and for youth-rated films (Germany (OR = 2.24, CI: 1.21-4.16), Iceland (OR = 13.79, CI: 1.80-105.5), Italy (OR = 5.31, CI: 2.54-11.1), and Argentina (OR = 6.9, CI: 0.88-1.34)). Models for alcohol showed few differences compared to US, regardless of rating. Linear regression models for seconds of use in films with tobacco indicated that only Argentine films had more seconds of smoking than US films, regardless of the rating category. For films with alcohol use, Mexican films had higher seconds of alcohol use than US films. CONCLUSIONS: Smoking was more commonly depicted in films produced outside the US, however there were few differences in the means for smoking screen time in films that contained smoking. This may be partly explained by the prohibition of tobacco product placement in the US. Countries should consider banning paid placement of both products and eliminating subsidies for films with content that promotes tobacco and alcohol use. PMID- 26526861 TI - Modified 'Mustarde' suture technique: Novel way of inserting mattress sutures to create the antihelical fold. PMID- 26526862 TI - Vaccine recommendations for children and youth for the 2015/2016 influenza season. AB - The Canadian Paediatric Society continues to encourage annual influenza vaccination for ALL children and youth >=6 months of age. Recommendations from the National Advisory Committee on Immunization for the 2015/2016 influenza season include some important changes: Children and adolescents with neurological or neurodevelopmental disorders were added to the list of individuals considered to be at high risk for severe influenza.Quadrivalent influenza vaccines are recommended preferentially over trivalent vaccines for use in children and youth.An adjuvanted trivalent inactivated influenza vaccine is now available for use in children six to 23 months of age. PMID- 26526863 TI - Treatment of a periorbital cyst in a dog by creation of a permanent drainage opening. AB - An inflammatory periorbital cyst with secondary pressure atrophy of the maxilla was treated by surgical creation of a drainage opening to the nasal cavity in a 4 year-old Yorkshire Terrier. Following treatment, clinical signs resolved and computed tomography 5 weeks after surgery confirmed the permanence of the drainage opening. Eight months later, the dog showed no clinical abnormalities. Therefore, the procedure described in this report may offer a suitable treatment option in cases where the cyst's size or localization prevents complete excision. PMID- 26526864 TI - Milk metabolites and neurodegeneration: Is there crosstalk? AB - Milk has been considered as a natural source of nutrition for decades. Milk is known to be nutrient-rich which aids the growth and development of the human body. Milk contains both macro- and micronutrients. Breast milk is widely regarded as the optimal source of neonatal nutrition due to its composition of carbohydrates, proteins, minerals and antibodies. However, despite the wide use of milk products, investigations into the role of milk in degenerative diseases have been limited. This review will examine the relationship between the beta casein gene found in bovine milk and disease states by using age-related macular degeneration as an example. PMID- 26526865 TI - Insights into erythropoietin in veterinary oncology: The other side of the coin. PMID- 26526866 TI - Diagnostic imaging and other disciplines: The importance of quality review articles in veterinary medicine. PMID- 26526867 TI - It is time to establish a better connection between reporting individual studies and research synthesis. PMID- 26526868 TI - In vivo assessment of an industrial waste product as a feed additive in dairy cows: Effects of larch (Larix decidua L.) sawdust on blood parameters and milk composition. AB - When larch (Larix spp.) is processed in the wood industry, the sawdust is currently disposed of as waste or used as combustible material, even though it is rich in biologically active compounds. In this study the effect of larch sawdust supplementation on blood parameters as well as milk composition was examined in healthy mid-lactating dairy cows. Twenty-four multiparous Italian Friesian dairy cows were assigned to groups receiving either 300 g/day/cow of larch sawdust or a control diet, and treatments were continued for a 20 day period. Milk parameters were unaffected by treatment. A lower plasma total protein concentration was observed and can be attributed to a decrease in globulin concentration. A lower plasma urea concentration was also detected in the larch group. Moreover, biomarkers of liver function were influenced by the treatment. Total bilirubin was lower in larch-treated animals, and cholesterol tended to be lower. In addition, an interaction between day and treatment was observed for very low density lipoprotein. The concentration of other parameters, including reactive oxygen metabolites, superoxide dismutase, glutathione peroxidase and nitrotyrosine, did not differ between treatments. The observed benefits, together with the good palatability, make larch sawdust a promising candidate for the development of beneficial feed supplements for livestock. Further studies will be useful, particularly to evaluate its efficacy in different health conditions. PMID- 26526869 TI - Linking the relevance of microbiota composition shifts with intestinal health disorders: A complex issue. PMID- 26526870 TI - Emergency Department Catheter-Associated Urinary Tract Infection Prevention: Multisite Qualitative Study of Perceived Risks and Implemented Strategies. AB - BACKGROUND: Existing knowledge of emergency department (ED) catheter-associated urinary tract infection (CAUTI) prevention is limited. We aimed to describe the motivations, perceived risks for CAUTI acquisition, and strategies used to address CAUTI risk among EDs that had existing CAUTI prevention programs. METHODS: In this qualitative comparative case study, we enrolled early-adopting EDs, that is, those using criteria for urinary catheter placement and tracking the frequency of catheters placed in the ED. At 6 diverse facilities, we conducted 52 semistructured interviews and 9 focus groups with hospital and ED participants. RESULTS: All ED CAUTI programs originated from a hospitalwide focus on CAUTI prevention. Staff were motivated to address CAUTI because they believed program compliance improved patient care. ED CAUTI prevention was perceived to differ from CAUTI prevention in the inpatient setting. To identify areas of ED CAUTI prevention focus, programs examined ED workflow and identified 4 CAUTI risks: (1) inappropriate reasons for urinary catheter placement; (2) physicians' limited involvement in placement decisions; (3) patterns of urinary catheter overuse; and (4) poor insertion technique. Programs redesigned workflow to address risks by (1) requiring staff to specify the medical reason for catheter at the point of order entry and placement; (2) making physicians responsible for determining catheter use; (3) using catheter alternatives to address patterns of overuse; and (4) modifying urinary catheter insertion practices to ensure proper placement. CONCLUSIONS: Early-adopting EDs redesigned workflow to minimize catheter use and ensure proper insertion technique. Assessment of ED workflow is necessary to identify and modify local practices that may increase CAUTI risk. PMID- 26526871 TI - Micro-structural Change During Nucleation: From Nucleus To Bicontinuous Morphology. AB - Although the microstructure of coexistence phase provides direct insights of the nucleation mechanism and their change is substantial in the phase transition, their study is limited due to the lack of suitable tools capturing the thermodynamically unstable transient states. We resolve this problem in computational study by introducing a generalized canonical ensemble simulation and investigate the morphological change of the nucleus during the water evaporation and condensation. We find that at very low pressure, where the transition is first order, classical nucleation theory holds approximately. A main nucleus is formed in the supersaturation near spinodal, and the overall shape of the nucleus is finite and compact. On increasing the pressure of the system, more nuclei are formed even before spinodal. They merge into a larger nuclei with a smaller free energy penalty to form ramified shapes. We suggest order parameters to describe the extent of fluctuation, and their relation to the free energy profile. PMID- 26526872 TI - Effects of anesthetics on vesicular monoamine transporter type 2 binding to 18F FP-(+)-DTBZ: a biodistribution study in rat brain. AB - OBJECTIVES: The in vivo binding analysis of vesicular monoamine transporter type 2 (VMAT2) to radioligand has provided a means of investigating related disorders. Anesthesia is often inevitable when the investigations are performed in animals. In the present study, we tested effects of four commonly-used anesthetics: isoflurane, pentobarbital, chloral hydrate and ketamine, on in vivo VMAT2 binding to (18)F-FP-(+)-DTBZ, a specific VMAT2 radioligand, in rat brain. METHODS: The transient equilibrium time window for in vivo binding of (18)F-FP-(+)-DTBZ after a bolus injection was firstly determined. The brain biodistribution studies under anesthetized and awake rats were then performed at the equilibrium time. Standard uptake values (SUVs) of the interest brain regions: the striatum (ST), hippocampus (HP), cortex (CX) and cerebellum (CB) were obtained; and ratios of tissue to cerebellum were calculated. RESULTS: Isoflurane and pentobarbital did not alter distribution of (18)F-FP-(+)-DTBZ in the brain relative to the awake group; neither SUVs nor ratios of ST/CB and HP/CB were altered significantly. Chloral hydrate significantly increased SUVs of all the brain regions, but did not significantly alter ratios of ST/CB and HP/CB. Ketamine significantly increased SUVs of the striatum, hippocampus and cortex, and insignificantly increased the SUV of the cerebellum; consequently, ketamine significantly increased ratios of ST/CB and HP/CB. CONCLUSIONS: It is concluded that in vivo VMAT2 binding to (18)F-FP-(+)-DTBZ are not altered by isoflurane and pentobarbital, but altered by chloral hydrate and ketamine. Isoflurane and pentobarbital may be promising anesthetic compounds for investigating in vivo VMAT2 binding. Further studies are warranted to investigate the interactions of anesthetics with VMAT2 binding potential with in vivo PET studies. PMID- 26526873 TI - Drought * CO2 interactions in trees: a test of the low-intercellular CO2 concentration (Ci ) mechanism. AB - Models of tree responses to climate typically project that elevated atmospheric CO2 concentration (eCa ) will reduce drought impacts on forests. We tested one of the mechanisms underlying this interaction, the 'low Ci effect', in which stomatal closure in drought conditions reduces the intercellular CO2 concentration (Ci ), resulting in a larger relative enhancement of photosynthesis with eCa , and, consequently, a larger relative biomass response. We grew two Eucalyptus species of contrasting drought tolerance at ambient and elevated Ca for 6-9 months in large pots maintained at 50% (drought) and 100% field capacity. Droughted plants did not have significantly lower Ci than well-watered plants, which we attributed to long-term changes in leaf area. Hence, there should not have been an interaction between eCa and water availability on biomass, and we did not detect one. The xeric species did have higher Ci than the mesic species, indicating lower water-use efficiency, but both species exhibited similar responses of photosynthesis and biomass to eCa , owing to compensatory differences in the photosynthetic response to Ci . Our results demonstrate that long-term acclimation to drought, and coordination among species traits may be important for predicting plant responses to eCa under low water availability. PMID- 26526874 TI - Preparation of Poly(ionic liquid)s-Supported Recyclable Organocatalysts for the Asymmetric Nitroaldol (Henry) Reaction. AB - A novel strategy for the embedding of quinine-based organocatalysts in polymerized ionic liquids-based hydrogels is presented. With this technique, the encapsulated organocatalyst was successfully recovered and reused for four cycles without any loss of enantioselectivity (up to 91% ee) for the asymmetric nitroaldol (Henry) reaction. In this study, high catalyst leaching was significantly reduced (<0.01%) by controlling the water content. After catalyst removal, evaporation of the solvent affords the product in 98% purity without any further purification. PMID- 26526875 TI - Adipose Tissue Residing Progenitors (Adipocyte Lineage Progenitors and Adipose Derived Stem Cells (ADSC). AB - The formation of brown, white and beige adipocytes have been a subject of intense scientific interest in recent years due to the growing obesity epidemic in the United States and around the world. This interest has led to the identification and characterization of specific tissue resident progenitor cells that give rise to each adipocyte population in vivo. However, much still remains to be discovered about each progenitor population in terms of their "niche" within each tissue and how they are regulated at the cellular and molecular level during healthy and diseased states. While our knowledge of brown, white and beige adipose tissue is rapidly increasing, little is still known about marrow adipose tissue and its progenitor despite recent studies demonstrating possible roles for marrow adipose tissue in regulating the hematopoietic space and systemic metabolism at large. This chapter focuses on our current knowledge of brown, white, beige and marrow adipose tissue with a specific focus on the formation of each tissue from tissue resident progenitor cells. PMID- 26526876 TI - In Silico Gene Regulatory Network of the Maurer's Cleft Pathway in Plasmodium falciparum. PMID- 26526877 TI - Publishing interdisciplinary research--a perspective from the Croatian Medical Journal. PMID- 26526879 TI - Causes of chest pain in primary care--a systematic review and meta-analysis. AB - AIM: To investigate the frequencies of different and relevant underlying etiologies of chest pain in general practice. METHODS: We systematically searched PubMed and EMBASE. Two reviewers independently rated the eligibility of publications and assessed the risk of bias of included studies. We extracted data to calculate the relative frequencies of different underlying conditions and investigated the variation across studies using forest plots, I(2), tau(2), and prediction intervals. With respect to unexplained heterogeneity, we provided qualitative syntheses instead of pooled estimates. RESULTS: We identified 11 eligible studies comprising about 6500 patients. The overall risk of bias was rated as low in 6 studies comprising about 3900 patients. The relative frequencies of different conditions as the underlying etiologies of chest pain reported by these studies ranged from 24.5 to 49.8% (chest wall syndrome), 13.8 to 16.1% (cardiovascular diseases), 6.6 to 11.2% (stable coronary heart disease), 1.5 to 3.6% (acute coronary syndrome/myocardial infarction), 10.3 to 18.2% (respiratory diseases), 9.5 to 18.2% (psychogenic etiologies), 5.6 to 9.7% (gastrointestinal disorders), and 6.0 to 7.1% (esophageal disorders). CONCLUSION: This information may be of practical value for general practitioners as it provides the pre-test probabilities for a range of underlying diseases and may be suitable to guide the diagnostic process. PMID- 26526878 TI - Dynamic regulation of aquaporin-4 water channels in neurological disorders. AB - Aquaporin-4 water channels play a central role in brain water regulation in neurological disorders. Aquaporin-4 is abundantly expressed at the astroglial endfeet facing the cerebral vasculature and the pial membrane, and both its expression level and subcellular localization significantly influence brain water transport. However, measurements of aquaporin-4 levels in animal models of brain injury often report opposite trends of change at the injury core and the penumbra. Furthermore, aquaporin-4 channels play a beneficial role in brain water clearance in vasogenic edema, but a detrimental role in cytotoxic edema and exacerbate cell swelling. In light of current evidence, we still do not have a complete understanding of the role of aquaporin-4 in brain water transport. In this review, we propose that the regulatory mechanisms of aquaporin-4 at the transcriptional, translational, and post-translational levels jointly regulate water permeability in the short and long time scale after injury. Furthermore, in order to understand why aquaporin-4 channels play opposing roles in cytotoxic and vasogenic edema, we discuss experimental evidence on the dynamically changing osmotic gradients between blood, extracellular space, and the cytosol during the formation of cytotoxic and vasogenic edema. We conclude with an emerging picture of the distinct osmotic environments in cytotoxic and vasogenic edema, and propose that the directions of aquaporin-4-mediated water clearance in these two types of edema are distinct. The difference in water clearance pathways may provide an explanation for the conflicting observations of the roles of aquaporin 4 in edema resolution. PMID- 26526880 TI - Effects of d- and l-limonene on the pregnant rat myometrium in vitro. AB - AIM: To study the effects of d- and l-limonene on pregnant rat myometrial contractility in vitro, and investigate how these effects are modified by other agents. D- and l-limonene (10(-13)-10(-8) M) caused myometrial contraction in a dose-dependent manner. METHODS: Contractions of uterine rings from 22-day pregnant rats were measured in an organ bath in the presence of d- or l-limonene (10(-13)-10(-8) M) and nifedipine (10(-8) M), tetraethyl-ammonium (10(-3) M), theophylline (10(-5) M), or paxilline (10(-5) M). Uterine cyclic adenosine monophosphate (cAMP) level was detected by enzyme immunoassay. Oxidative damage was induced by methylglyoxal (3*10(-2) M) and the alteration was measured via noradrenaline (1*10(-9) to 3*10(-5) M) -induced contractions. RESULTS: Pre treatment with nifedipine (10(-8) M), tetraethylammonium (10(-3) M), and theophylline (10(-5) M) attenuated the contracting effect of d- and l-limonene, while in the presence of paxilline (10(-5) M) d- and l-limonene were ineffective. The two enantiomers decreased the myometrial cAMP level, but after paxilline pretreatment the cAMP level was not altered compared with the control value. Additionally, l-limonene (10(-6) M) diminished consequences of oxidative damage caused by methylglyoxal (3*10(-2) M) on contractility, whereas d-limonene was ineffective. CONCLUSION: Our findings suggest that l-limonene has an antioxidant effect and that both d-and l-limonene cause myometrial contraction through activation of the A2A receptor and opening of the voltage-gated Ca(2+) channel. It is possible that limonene-containing products increase the pregnant uterus contractility and their use should be avoided during pregnancy. PMID- 26526881 TI - A new Agkistrodon halys venom-purified protein C activator prevents myocardial fibrosis in diabetic rats. AB - AIM: To assess the effects of protein C activator (PCA) from Agkistrodon halys snake venom on cardiac fibrosis in streptozotocin (STZ) induced diabetic rat model, and investigate the mechanisms of its action. METHODS: PCA was identified by one-dimensional reversed phase liquid chromatography - mass spectrometry/mass spectrometry. Male Sprague-Dawley rats (120-140 g) were randomly assigned to negative control (NC) and diabetic group. Diabetes was induced by STZ in high-fat diet fed rats. Diabetic group was subdivided into three groups: diabetic group (DM), diabetic group treated with PCA (0.5, 2, and 8 mg/kg), and diabetic group treated with metformin (5 mg/kg, positive control). NC and DM groups received the same volume of distilled water. Left ventricular mass index (LVWI) and collagen volume fraction were measured by hematoxylin and eosin and Masson staining. Transforming growth factor beta-1 (TGF-beta1) and interleukin 1 beta (IL-1beta) levels were determined by enzyme-linked immunosorbent assay. RESULTS: The diabetic rat model was successfully established by STZ induction and high-fat diet. Glucose level, LVWI, TGF-beta1 and IL-1beta level, and collagen volume fraction were significantly reduced in diabetic rats treated by PCA in a dose dependent manner (P<0.050), especially in the high dose (8 mg/kg) group (P<0.010), compared to diabetes group. The high dose PCA had the same effect as metformin positive control in reducing the level of fasting blood glucose. PCA decreased the expression of MMP-2 and reduced that of TIMP-2. CONCLUSION: Our results indicate that PCA has anti-fibrotic effects and that it may be used to treat myocardial fibrosis. PMID- 26526883 TI - Apparent diffusion coefficient measurement covering complete tumor area better predicts rectal cancer response to neoadjuvant chemoradiotherapy. AB - AIM: To determine the impact of two apparent diffusion coefficient (ADC) measurement techniques on diffusion-weighted magnetic resonance images (DW MRI) on the assessment of rectal cancer response to neoadjuvant chemoradiotherapy (CRT). METHODS: ADC values were measured prospectively with two different techniques - the first, which measures ADCs in the most cellular tumor parts, and the second, which measures the entire tumor area, in 58 patients with locally advanced rectal cancer on pre-CRT and post-CRT image sets. Areas under the receiver operating characteristic curves (AUCs) and parameters of diagnostic accuracy were calculated for pre- and post-CRT ADC values and numeric and percent ADC change for each technique to determine their performance in tumor response evaluation using histopathological tumor-regression grade as the reference standard. RESULTS: The second technique yielded higher AUCs (0.935 vs 0.704, P<.001), percent-change (0.828 vs 0.636, P<0.001), and numeric-change (0.866 vs 0.653, P<0.001) than the first technique for post-CRT ADC. Accuracies for post CRT ADC assessment were 62% for the first and 88% for the second technique (cut off values: 0.98 and 1.29*10(-3) mm2/s, respectively) and for ADC change assessment, both numeric and percent, 59% and 74%, respectively (cut-off values: increase of 0.18 and 0.28*10(-3) mm(2)/s; increase of 24% and 37%, respectively). CONCLUSIONS: The type of measurement technique significantly affected ADC results. ADC measurements covering a larger area better predicted tumor response to therapy. Post-CRT ADCs, regardless of the measurement technique, and numeric ADC change measured in the whole tumor volume accurately identified non-complete responders. Post-CRT ADCs measured in the entire tumor area yielded the highest accuracy level in tumor response evaluation. PMID- 26526882 TI - In female rats, ethylene glycol treatment elevates protein expression of hepatic and renal oxalate transporter sat-1 (Slc26a1) without inducing hyperoxaluria. AB - AIM: To investigate whether the sex-dependent expression of hepatic and renal oxalate transporter sat-1 (Slc26a1) changes in a rat model of ethylene glycol (EG)-induced hyperoxaluria. METHODS: Rats were given tap water (12 males and 12 females; controls) or EG (12 males and 12 females; 0.75% v/v in tap water) for one month. Oxaluric state was confirmed by biochemical parameters in blood plasma, urine, and tissues. Expression of sat-1 and rate-limiting enzymes of oxalate synthesis, alcohol dehydrogenase 1 (Adh1) and hydroxy-acid oxidase 1 (Hao1), was determined by immunocytochemistry (protein) and/or real time reverse transcription polymerase chain reaction (mRNA). RESULTS: EG-treated males had significantly higher (in MUmol/L; mean+/-standard deviation) plasma (59.7+/-27.2 vs 12.9+/-4.1, P<0.001) and urine (3716+/-1726 vs 241+/-204, P<0.001) oxalate levels, and more abundant oxalate crystaluria than controls, while the liver and kidney sat-1 protein and mRNA expression did not differ significantly between these groups. EG-treated females, in comparison with controls had significantly higher (in MUmol/L) serum oxalate levels (18.8+/-2.9 vs 11.6+/-4.9, P<0.001), unchanged urine oxalate levels, low oxalate crystaluria, and significantly higher expression (in relative fluorescence units) of the liver (1.59+/-0.61 vs 0.56+/ 0.39, P=0.006) and kidney (1.77+/-0.42 vs 0.69+/-0.27, P<0.001) sat-1 protein, but not mRNA. The mRNA expression of Adh1 was female-dominant and that of Hao1 male-dominant, but both were unaffected by EG treatment. CONCLUSIONS: An increased expression of hepatic and renal oxalate transporting protein sat-1 in EG-treated female rats could protect from hyperoxaluria and oxalate urolithiasis. PMID- 26526884 TI - Real-time two-dimensional shear wave ultrasound elastography of the liver is a reliable predictor of clinical outcomes and the presence of esophageal varices in patients with compensated liver cirrhosis. AB - AIM: Primary: to evaluate predictivity of liver stiffness (LS), spleen stiffness (SS), and their ratio assessed by real-time 2D shear wave elastography (RT-2D SWE) for adverse outcomes (hepatic decompensation, hepatocellular carcinoma or death; "event") in compensated liver cirrhosis (LC) patients. Secondary: to evaluate ability of these measures to discriminate between cirrhotic patients with/without esophageal varices (EV). METHODS: Predictivity of LS, SS, and LS/SS was assessed in a retrospectively analyzed cohort of compensated LC patients (follow-up cohort) and through comparison with incident patients with decompensated cirrhosis (DC) (cross-sectional cohort). Both cohorts were used to evaluate diagnostic properties regarding EV. RESULTS: In the follow-up cohort (n=44) 18 patients (40.9%) experienced an "event" over a median period of 28 months. LS>=21.5 kPa at baseline was independently associated with 3.4-fold (95% confidence interval [CI] 1.16-10.4, P=0.026) higher risk of event. Association between SS and outcomes was weaker (P=0.056), while there was no association between LS/SS ratio and outcomes. Patients with DC (n=43) had higher LS (35.3 vs 18.3 kPa, adjusted difference 65%, 95% CI 43%-90%; P<0.001) than compensated patients at baseline. Adjusted odds of EV increased by 13% (95% CI 7.0%-20.0%; Plt;0.001) with 1 kPa increase in LS. At cut-offs of 19.7 and 30.3 kPa, LS and SS had 90% and 86.6% negative predictive value, respectively, to exclude EV in compensated patients. CONCLUSION: This is the first evaluation of RT-2D-SWE as a prognostic tool in LC. Although preliminary and gathered in a limited sample, our data emphasize the potential of LS to be a reliable predictor of clinical outcomes and the presence of EV in LC patients. PMID- 26526886 TI - How much precision in reporting statistics is enough? PMID- 26526885 TI - Identification and characterization of the highly polymorphic locus D14S739 in the Han Chinese population. AB - AIM: To systemically select and evaluate short tandem repeats (STRs) on the chromosome 14 and obtain new STR loci as expanded genotyping markers for forensic application. METHODS: STRs on the chromosome 14 were filtered from Tandem Repeats Database and further selected based on their positions on the chromosome, repeat patterns of the core sequences, sequence homology of the flanking regions, and suitability of flanking regions in primer design. The STR locus with the highest heterozygosity and polymorphism information content (PIC) was selected for further analysis of genetic polymorphism, forensic parameters, and the core sequence. RESULTS: Among 26 STR loci selected as candidates, D14S739 had the highest heterozygosity (0.8691) and PIC (0.8432), and showed no deviation from the Hardy-Weinberg equilibrium. 14 alleles were observed, ranging in size from 21 to 34 tetranucleotide units in the core region of (GATA)9-18 (GACA)7-12 GACG (GACA)2 GATA. Paternity testing showed no mutations. CONCLUSION: D14S739 is a highly informative STR locus and could be a suitable genetic marker for forensic applications in the Han Chinese population. PMID- 26526887 TI - Translation of the focus toward excellence in translational science: comment on "TDP-43 Repression of Nonconserved Cryptic Exons is Compromised in ALS-FTD". PMID- 26526888 TI - The communication aspects of the Ebola virus disease outbreak in Western Africa- do we need to counter one, two, or many epidemics? PMID- 26526889 TI - The "Brain to Behavior Approach" to diagnosis and treatment. PMID- 26526890 TI - Psychoanalysis has its place in modern medicine, and neuropsychoanalysis is here to support it. PMID- 26526891 TI - [Qualitative research about euthanasia concept, between Spanish doctors]. AB - BACKGROUND AND OBJECTIVES: The decriminalisation of euthanasia and assisted medical suicide has generated a continuous debate. The terminological confusion is one of the main difficulties in obtaining medical practice consensus. The objective of this study was to determine whether the terms of Euthanasia and physician assisted suicide are used with the same meaning by doctors in Extremadura (Spain). MATERIAL AND METHOD: A qualitative study was conducted using two focus groups in which doctors from different specialties who attended a large number of terminal patients participated. No other focus group was required due to saturation. The sessions were tape recorded and transcribed by two experts in qualitative methodology. Atlas.ti software was used for the analysis. We were advised by the "Health Care at the end of life" Group of the Organizacion Medica Colegial of Spain. RESULTS: Terminological confusion was verified in: 1) The mixture of etymological, functional and social concepts, 2) the term Passive Euthanasia, 3) the association between euthanasia and physician assisted suicide, 4) the confusion with the equivalent "wish to hasten death", and 5) the difficulty of differentiating sedation with Euthanasia. There was consensus on some aspects: a) Full voluntariness, b) the condition of terminal illness, and c) the condition of unbearable symptoms. CONCLUSIONS: Conceptual variability persists in relation to the concept of Euthanasia, and is particularly noticeable in the persistence of the concept of passive euthanasia. It would be desirable to achieve a common language to assign a precise meaning to these words to help doctors in their professional practice. PMID- 26526892 TI - The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study. AB - BACKGROUND: Pruritus is a common symptom associated with cholestatic liver diseases. To date only small single centre case series have suggested efficacy of nasobiliary drainage in relieving cholestatic pruritus. AIM: To perform a multicentre study to evaluate the safety and efficacy of nasobiliary drainage in cholestatic pruritus. METHODS: This was a retrospective study of all patients treated with nasobiliary drainage for refractory cholestatic pruritus between 2006 and 2015 at five European centres. Pruritus was quantified using a visual analogue scale (VAS) and liver enzymes, serum bilirubin and total serum bile salts (TBS) were measured before (pre-NBD) and after nasobiliary drainage (post NBD). We analysed the duration of treatment response and associated complications. RESULTS: In total, 27 patients (59% females) underwent 29 nasobiliary drainage procedures. The median duration of NBD was 7 days. NBD decreased pruritus in 89.6% of cases (VAS from 10.0 to 0.3, P < 0.0001). The median percentage decline in pruritus VAS was 94% and 33% of patients were free of pruritus within 24 h of starting drainage. The duration of treatment response was independent of duration of drainage (P = 0.12) and bile output. Significant improvements were seen in the median levels of serum alkaline phosphatase (P = 0.001) and serum bilirubin (P = 0.03) but not in serum TBS (P = 0.07). Mild post endoscopic retrograde cholangiopancreatography pancreatitis (31%) was the most frequent complication. CONCLUSIONS: Nasobiliary drainage is effective in relieving cholestatic pruritus in most patients and has favourable effect on biomarkers of cholestasis. Nasobiliary drainage may be associated with high risk of adverse events, especially pancreatitis. Prospective studies are needed to confirm our findings. PMID- 26526893 TI - Influence of antibiotic pressure on bacterial bioluminescence, with emphasis on Staphylococcus aureus. AB - Bioluminescence imaging is used for longitudinal evaluation of bacteria in live animals. Clear relations exist between bacterial numbers and their bioluminescence. However, bioluminescence images of Staphylococcus aureus Xen29, S. aureus Xen36 and Escherichia coli Xen14 grown on tryptone soy agar in Etests demonstrated increased bioluminescence at sub-MICs of different antibiotics. This study aimed to further evaluate the influence of antibiotic pressure on bioluminescence in S. aureus Xen29. Bioluminescence of S. aureus Xen29, grown planktonically in tryptone soy broth, was quantified in the absence and presence of different concentrations of vancomycin, ciprofloxacin, erythromycin or chloramphenicol and was related to expression of the luxA gene under antibiotic pressure measured using real-time PCR. In the absence of antibiotics, staphylococcal bioluminescence increased over time until a maximum after ca. 6h of growth, and subsequently decreased to the detection threshold after 24h of growth owing to reduced bacterial metabolic activity. Up to MICs of the antibiotics, bioluminescence increased according to a similar pattern up to 6h of growth, but after 24h bioluminescence was higher than in the absence of antibiotics. Contrary to expectations, bioluminescence per organism (CFU) after different growth periods in the absence and at MICs of different antibiotics decreased with increasing expression of luxA. Summarising, antibiotic pressure impacts the relation between CFU and bioluminescence. Under antibiotic pressure, bioluminescence is not controlled by luxA expression but by co-factors impacting the bacterial metabolic activity. This conclusion is of utmost importance when evaluating antibiotic efficacy in live animals using bioluminescent bacterial strains. PMID- 26526894 TI - Linezolid-related adverse events predictive score (LAPS): Usefulness in clinical practice. PMID- 26526895 TI - Apigenin as an anti-quinolone-resistance antibiotic. AB - We previously reported the first 'reverse antibiotic' (RA), nybomycin (NYB), which showed a unique antimicrobial activity against Staphylococcus aureus strains. NYB specifically suppressed the growth of quinolone-resistant S. aureus strains but was not effective against quinolone-susceptible strains. Although NYB was first reported in 1955, little was known about its unique antimicrobial activity because it was before the synthesis of the first quinolone ('old quinolone'), nalidixic acid, in 1962. Following our re-discovery of NYB, we looked for other RAs among natural substances that act on quinolone-resistant bacteria. Commercially available flavones were screened against S. aureus, including quinolone-resistant strains, and their minimum inhibitory concentrations (MICs) were compared using the microbroth dilution method. Some of the flavones screened showed stronger antimicrobial activity against quinolone resistant strains than against quinolone-susceptible ones. Amongst them, apigenin (API) was the most potent in its RA activity. DNA cleavage assay showed that API inhibited DNA gyrase harbouring the quinolone resistance mutation gyrA(Ser84Leu) but did not inhibit 'wild-type' DNA gyrase that is sensitive to levofloxacin. An API-susceptible S. aureus strain Mu50 was also selected using agar plates containing 20mg/L API. Whole-genome sequencing of selected mutant strains was performed and frequent back-mutations (reverse mutations) were found among API resistant strains derived from the API-susceptible S. aureus strains. Here we report that API represents another molecular class of natural antibiotic having RA activity against quinolone-resistant bacteria. PMID- 26526896 TI - Co-transplantation of autologous bone marrow mesenchymal stem cells and Schwann cells through cerebral spinal fluid for the treatment of patients with chronic spinal cord injury: safety and possible outcome. AB - STUDY DESIGN: This is a clinical trial (phase 1). OBJECTIVES: The objective of this study was to asses the safety and feasibility of bone marrow mesenchymal stem cell (MSC) and Schwann cell (SC) co-injection through cerebral spinal fluid (CSF) for the treatment of patients with chronic spinal cord injury. METHODS: Six subjects with complete spinal cord injury due to trauma according to International Standard of Neurological Classification for Spinal Cord Injury (ISNCSCI) developed by the American Spinal Injury Association were enrolled. They received autologous co-transplantation of MSC and SC through lumbar puncture. Neurological status of the patients was determined by ISNCSCI, as well as by assessment of functional status by Spinal Cord Independent Measure. Before and after cell transplantation, magnetic resonance imaging (MRI) was performed for all the patients. Before the procedure, all the patients underwent electromyography, urodynamic study (UDS) and MRI tractograghy. After transplantation, these assessments were performed in special cases when the patients reported any changes in motor function or any changes in urinary sensation. RESULTS: Over the mean 30 months of follow-up, the radiological findings were unchanged without any evidence of neoplastic tissue overgrowth. American Spinal Injury Association class in one patient was changed from A to B, in addition to the improvement in indexes of UDS, especially bladder compliance, which was congruous with axonal regeneration detected in MRI tractography. No motor score improvement was observed among the patients. CONCLUSION: No adverse findings were detected at a mean of 30 months after autologous transplantation of the combination of MSCs and SCs through CSF. It may suggest the safety of this combination of cells for spinal cord regeneration. PMID- 26526897 TI - Building a roadmap to biomarker qualification: challenges and opportunities. AB - The traditional route for regulatory acceptance of biomarkers in drug development is through submission of biomarker data in drug approval submissions in the context of a single drug development program. The US FDA's Critical Path Initiative called for establishment of a biomarker qualification process to enable progress in the drug development paradigm. In response to this, the Center for Drug Evaluation and Research (CDER) established a Biomarker Qualification Program (BQP) to qualify a biomarker for a specific context of use (COU). The qualified biomarker can then be used in multiple drug development programs for this COU without re-review. Here, we describe some of the features of the BQP and two new initiatives that have the potential to aid biomarker development through early interactions with the FDA. Finally, we discuss some of the feedback the FDA has received from submitters and the BQP's actions to strengthen the program. PMID- 26526898 TI - Nicotinamide yields impressive results in skin cancer. PMID- 26526899 TI - Physicians' recommendation affects HPV vaccination uptake. PMID- 26526900 TI - CT enterography: Diagnostic value of 4th generation iterative reconstruction algorithm in low dose studies in comparison with standard dose protocol for follow-up of patients with Crohn's disease. AB - PURPOSE: To compare radiation dose, image quality and diagnostic performance of low dose CT enterography (CTE) protocol combined with iterative reconstruction algorithm (iDose(4)) with standard dose CTE in follow-up of patients with known Crohn's disease (CD). MATERIALS AND METHOD: Thirty-six patients (12 females), with CD underwent a low-dose CTE scan during single venous phase on 256 MDCT scanner, with the following parameters: 120 kV, automated mAs dose-modulation, slice thickness 2mm and iDose(4) iterative reconstruction algorithm. A control group of thirty-seven patients underwent standard dose CTE examination on the same CT scanner. Two radiologists, blinded to clinical and pathological findings, independently evaluated in each scan, HU values in bowel wall and any presence of CD activity features and disease complications. Image noise and diagnostic quality were evaluated using a 4-point scale. Dose-length product (DLP) and CT dose-index (CTDI) were recorded and data from both examinations were compared and statistically analyzed. RESULTS: Low-dose CTE protocol showed high diagnostic quality in assessment of Crohn's disease obtaining significantly (p <= 0.001) lower values of DLP and CTDI (604.98 mGy*cm and 12.29 mGy) as compared to standard dose examinations (974.85 mGy*cm and 19.71 mGy), with an overall dose reduction of 37.6%. Noise resulted slightly higher in iDose(4) images (SD=15.97) than in standard dose ones (SD=13.61) but this difference was not statistically significant (p=0.064). CONCLUSION: Low-dose CTE combined with iDose(4) reconstruction algorithm offers high quality images with significant reduction of radiation dose, and therefore can be considered a useful tool in the management of CD patients, considering their young age and the frequent imaging follow-up required. PMID- 26526901 TI - Prostate cancer on computed tomography: A direct comparison with multi-parametric magnetic resonance imaging and tissue pathology. AB - OBJECTIVES: Multi-parametric prostate magnetic resonance imaging (MRI) is considered the current imaging standard for detection and staging of prostate cancer. The combination of anatomical and functional imaging provided in this exam significantly increases the accuracy of prostate cancer detection. Computed tomography (CT) imaging has so far been found to be lacking in this regard, however observations at our academic institution as well as evidence present in the literature support the proposition that CT could indeed be helpful in detecting prostate abnormalities that correspond to neoplasm. The purpose of this study was to prove that areas of focal mass-like enhancement on CT imaging directly correlate with prostate neoplasms as revealed on multi-parametric MRI and follow-up targeted biopsy. MATERIALS AND METHODS: This was a single institution retrospective study with 27 male subjects. Inclusion criteria required subjects to have a multi-parametric MRI of the prostate between January 1, 2014 and June 1, 2015 and a pelvic venous phase contrast-enhanced CT study between January 1, 2000 and June 1, 2015. Two blinded Radiologists read subjects' CT scans for any abnormalities of the prostate. CT and multi-parametric MRI results were compared and were considered concordant if focal or mass like enhancement to a greater degree than the background parenchyma was detected in the same areas of the prostate on CT scan as areas of decreased T2 signal, perfusion abnormalities, and restricted diffusion on multi-parametric MRI. RESULTS: CT results were directly compared to multi-parametric MRI findings and biopsy results. The overall agreement of MRI and CT is 85.19% (95% CI: 67.52 94.08%). The positive percent agreement is 78.95% (95% CI: 54.43-93.95%) and the negative percent agreement is 100.0% (95% CL: 63.06-100.0%). When CT results are directly compared to biopsy results, sensitivity and specificity of CT are 63.64% (95% CI: 30.79-89.07%) and 100.0% (95% CI: 47.82-100.0%). The positive predictive value (PPV) is 100.0% (95% CI: 59.04-100.0%) and the negative predictive value (NPV) is 55.56% (95% CI: 21.2-86.3%). When compared to MRI, CT has a lower sensitivity and a higher specificity, as well as a higher PPV and NPV. Logistic regression analysis did not show a significant relationship between concordance of MRI and CT and Gleason score, time between studies, age, and Prostate-specific antigen (PSA) level. CONCLUSION: Incidental focal areas of mass-like enhancement in the peripheral prostate detected on venous phase contrast-enhanced CT imaging may indeed correlate with prostate neoplasm and it would be prudent to suggest further work-up with PSA and perhaps multi-parametric MRI, especially in high risk patients. PMID- 26526902 TI - Rapid acquisition axial and coronal T2 HASTE MR in the evaluation of acute abdominal pain. AB - PURPOSE: To assess T2 HASTE MR in acute abdominal imaging and ascertain if it is a reliable alternative to CT in patients under 60. METHOD AND MATERIALS: In a prospective diagnostic performance study from January 2009 to December 2013, patients under 60 presenting with acute abdominal pain, that required imaging following surgical review, were imaged with T2 HASTE MR. Rapid acquisition HASTE (Half Fourier Acquisition Single Shot Turbo Spin Echo) coronal and axial sequences were obtained, without intravenous contrast. Patients were followed up clinically for a minimum of 3 months. RESULTS: 468 cases included in the study. 349 were negative for acute abdominal pathology, 116 positive for acute abdominal pathology and 3 were indeterminate. In the MR positive group (n=116), 64 had surgery confirming findings (34 appendicitis, 14 SBO, 3 ovarian torsion, 3 LBO, intussusception, ovarian carcinoma, ovarian dermoid, 2 pelvic inflammatory disease, diverticular abscess, crohns, 4 endoscopy for acute bowel pathology) while 51 were managed conservatively with concordant follow up (4 SBO, 11 diverticulitis, 6 pelvic inflammatory disease, 7 inflammatory bowel disease, 7 colitis, 6 pyelonephritis, 2 cholecystitis, renal abscess, pseudomembranous colitis, splenic haematoma, mesenteric adenitis, 2 pancreatitis, lymphoma, epiploic appendagitis). 1 patient had an MR diagnosis of appendicitis but at laparoscopy a sigmoid diverticular perforation was diagnosed and the appendix was normal. In the MR negative group (n=349), 324 had uneventful follow-up, 22 had negative laparoscopies, while 3 had subsequent appendectomies, with appendicitis on histology (3 days, 10 days and 2 months post scan). In the MR indeterminate group (n=3), one was treated conservatively with uneventful follow up, one had laparoscopic appendectomy with normal appendix on histology, one had laparoscopic appendectomy with acute appendicitis on histology. When MR correlated with clinical follow up (n=468), overall diagnostic accuracy is 99% (463/468). When MR findings correlated with direct visualisation at surgery/endoscopy (n=90), sensitivity is 98% (95% CI) and specificity is 92% (95% CI). CONCLUSION: This study demonstrates that rapid acquisition axial and coronal T2 HASTE MR is a practical, safe and effective method in the diagnosis of acute abdominal pain. MR is the preferred option to CT in patients of an age prone to radiation with a potential surgical diagnosis. CLINICAL RELEVANCE/APPLICATION: MRI in acute abdominal imaging is both effective and practical and is the preferred imaging option in patients of an age prone to radiation with a potential surgical diagnosis. PMID- 26526903 TI - Assessment of learning, memory, and attention in developmental neurotoxicity regulatory studies: synthesis, commentary, and recommendations. AB - Cognitive tests of learning and memory (L&M) have been required by U.S. Environmental Protection Agency (EPA) developmental neurotoxicity test (DNT) guidelines for more than two decades. To evaluate the utility of these guidelines, the EPA reviewed 69 pesticide DNT studies. This review found that the DNT provided or could provide the point-of-departure for risk assessment by showing the Lowest Observable Adverse Effect Level (LOAEL) in 28 of these studies in relation to other reported end points. Among the behavioral tests, locomotor activity and auditory/acoustic startle provided the most LOAELs, and tests of cognitive function and the Functional Observational Battery (FOB) the fewest. Two issues arose from the review: (1) what is the relative utility of cognitive tests versus tests of unconditioned behavior, and (2) how might cognitive tests be improved? The EPA sponsored a symposium to address this. Bushnell reviewed studies in which both screening (locomotor activity, FOB, reflex ontogeny, etc.) and complex tests (those requiring training) were used within the same study; he found relatively little evidence that complex tests provided a LOAEL lower than screening tests (with exceptions). Levin reviewed reasons for including cognitive tests in regulatory studies and methods and evidence for the radial arm maze and its place in developmental neurotoxicity assessments. Driscoll and Strupp reviewed the value of serial reaction time operant methods for assessing executive function in developmental neurotoxicity studies. Vorhees and Williams reviewed the value of allocentric (spatial) and egocentric cognitive tests and presented methods for using the Morris water maze for spatial and the Cincinnati water maze for egocentric cognitive assessment. They also reviewed the possible use of water radial mazes. The relatively lower impact of cognitive tests in previous DNT studies in the face of the frequency of human complaints of chemical induced cognitive dysfunction indicates that animal cognitive tests need improvement. The contributors to this symposium suggest that if the guidelines are updated, they be made more specific by recommending preferred tests and providing greater detail on key characteristics of such tests. Additionally, it is recommended that guidance be developed to address important issues with cognitive tests and to provide the information needed to improve the design, conduct, and interpretation of tests of higher function within a regulatory context. These steps will maximize the value of cognitive tests for use in hazard evaluation and risk assessment. PMID- 26526905 TI - Analytical approaches for arsenic determination in air: A critical review. AB - This review describes the different steps involved in the determination of arsenic in air, considering the particulate matter (PM) and the gaseous phase. The review focuses on sampling, sample preparation and instrumental analytical techniques for both total arsenic determination and speciation analysis. The origin, concentration and legislation concerning arsenic in ambient air are also considered. The review intends to describe the procedures for sample collection of total suspended particles (TSP) or particles with a certain diameter expressed in microns (e.g. PM10 and PM2.5), or the collection of the gaseous phase containing gaseous arsenic species. Sample digestion of the collecting media for PM is described, indicating proposed and established procedures that use acids or mixtures of acids aided with different heating procedures. The detection techniques are summarized and compared (ICP-MS, ICP-OES and ET-AAS), as well those techniques capable of direct analysis of the solid sample (PIXE, INAA and XRF). The studies about speciation in PM are also discussed, considering the initial works that employed a cold trap in combination with atomic spectroscopy detectors, or the more recent studies based on chromatography (GC or HPLC) combined with atomic or mass detectors (AFS, ICP-MS and MS). Further trends and challenges about determination of As in air are also addressed. PMID- 26526904 TI - Developmental origin of abnormal dendritic growth in the mouse brain induced by in utero disruption of aryl hydrocarbon receptor signaling. AB - Increased prevalence of mental disorders cannot be solely attributed to genetic factors and is considered at least partly attributable to chemical exposure. Among various environmental chemicals, in utero and lactational dioxin exposure has been extensively studied and is known to induce higher brain function abnormalities in both humans and laboratory animals. However, how the perinatal dioxin exposure affects neuromorphological alterations has remained largely unknown. Therefore, in this study, we initially studied whether and how the over expression of aryl hydrocarbon receptor (AhR), a dioxin receptor, would affect the dendritic growth in the hippocampus of the developing brain. Transfecting a constitutively active AhR plasmid into the hippocampus via in utero electroporation on gestational day (GD) 14 induced abnormal dendritic branch growth. Further, we observed that 14-day-old mice born to dams administered with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dose: 0, 0.6, or 3.0 MUg/kg) on GD 12.5 exhibited disrupted dendritic branch growth in both the hippocampus and amygdala. Finally, we observed that 16-month-old mice born to dams exposed to perinatal TCDD as described above exhibited significantly reduced spine densities. These results indicated that abnormal micromorphology observed in the developing brain may persist until adulthood and may induce abnormal higher brain function later in life. PMID- 26526906 TI - Determination of refractive and volatile elements in sediment using laser ablation inductively coupled plasma mass spectrometry. AB - Wet-milling protocol was employed to produce pressed powder tablets with excellent cohesion and homogeneity suitable for laser ablation (LA) analysis of volatile and refractive elements in sediment. The influence of sample preparation on analytical performance was also investigated, including sample homogeneity, accuracy and limit of detection. Milling in volatile solvent for 40 min ensured sample is well mixed and could reasonably recover both volatile (Hg) and refractive (Zr) elements. With the exception of Cr (-52%) and Nb (+26%) major, minor and trace elements in STSD-1 and MESS-3 could be analysed within +/-20% of the certified values. Comparison of the method with total digestion method using HF was tested by analysing 10 different sediment samples. The laser method recovers significantly higher amounts of analytes such as Ag, Cd, Sn and Sn than the total digestion method making it a more robust method for elements across the periodic table. LA-ICP-MS also eliminates the interferences from chemical reagents as well as the health and safety risks associated with digestion processes. Therefore, it can be considered as an enhanced method for the analysis of heterogeneous matrices such as river sediments. PMID- 26526907 TI - In situ dsDNA-bevacizumab anticancer monoclonal antibody interaction electrochemical evaluation. AB - The interaction of the anticancer monoclonal antibody bevacizumab (BEVA) with double-stranded DNA (dsDNA) was studied by voltammetry and gel-electrophoresis in incubated samples and using the dsDNA-electrochemical biosensor. The voltammetric results revealed a decrease and disappearance of the dsDNA oxidation peaks with increasing incubation time, showing that BEVA binds to the dsDNA but no DNA oxidative damage was detected electrochemically. Non denaturing agarose gel electrophoresis experiments were in agreement with the voltammetric results showing the formation of compact BEVA-dsDNA adduct. The dsDNA-electrochemical biosensor in incubated solutions showed that BEVA also undergoes structural modification upon binding dsDNA, and BEVA electroactive amino acid residues oxidation peaks were detected. PMID- 26526908 TI - Real-time tracking of hydrogen peroxide secreted by live cells using MnO2 nanoparticles intercalated layered doubled hydroxide nanohybrids. AB - We report a facile and green method for the fabrication of new type of electrocatalysts based on MnO2 nanoparticles incorporated on MgAl LDH P-type semiconductive channel and explore its practical applications as high-performance electrode materials for electrochemical biosensor. A series of MgAl layered doubled hydroxide (LDH) nanohybrids with fixed Mg/Al (M(2+)/M(3+) atomic ratio of 3) and varied amount of MnCl2.4H2O are fabricated by a facile co-precipitation method. This approach demonstrates the combination of distinct properties including excellent intercalation features of LDH for entrapping nanoparticles and high loading of MnO2 nanoparticles in the host layers of LDH. Among all samples, Mn5-MgAl with 0.04% loaded manganese has a good crystalline morphology. A well-dispersed MnO2 nanoparticles encapsulated into the host matrix of hydrotalcite exhibit enhanced electrocatalytic activity towards the reduction of H2O2 as well as excellent stability, selectivity and reproducibility due to synergistic effect of good catalytic ability of MnO2 and conductive MgAl LDH. Glass carbon electrode (GCE) modified with Mn5-MgAl possesses a wide linear range of 0.05-78 mM, lowest detection limit 5 MUM (S/N = 3) and detection sensitivity of 0.9352 MUAmM(-1). This outstanding performance enables it to be used for real time tracking of H2O2 secreted by live HeLa cells. This work may provide new insight in clinical diagnosis, on-site environmental analysis and point of care testing devices. PMID- 26526909 TI - A new effective on chip electromembrane extraction coupled with high performance liquid chromatography for enhancement of extraction efficiency. AB - In the present research, an effective on chip electromembrane extraction (CEME) coupled with high performance liquid chromatography was presented for analysis of nortriptyline (NOR) and amitriptyline (AMI) as basic model analytes from urine samples. The chip consists of two polymethyl methacrylate (PMMA) parts with two craved microfluidic channels in each part. These channels were used as flow path for the sample solution and a thin compartment for the acceptor phase. A porous polypropylene sheet membrane impregnated with an organic solvent was placed between two parts of chip device to separate the channels. Two platinum electrodes were mounted at the bottom of these channels that were connected to a power supply providing the electrical driving force for migration of ionized analytes from sample solution through the porous sheet membrane into the acceptor phase. This new setup provides effective and reproducible extractions with low volume of sample solution. Efficient parameters on CEME of the model analytes were optimized using one variable at a time method. Under the optimized conditions, the calibration curve was linear in the range of 10.0-500 MUg L(-1) with coefficient of determination (r(2)) more than 0.9902. The relative standard deviations (RSDs %) for extraction and determination of the analytes were less than 6.8% based on six replicate measurements. LODs less than 4.0 MUg L(-1) were obtained for both of the model analytes. The preconcentration factors higher than 17.0-fold were obtained. The results demonstrated that CEME would be used efficiently for extraction and determination of AMI and NOR from urine samples. PMID- 26526910 TI - Porous membrane-protected molecularly imprinted polymer micro-solid-phase extraction for analysis of urinary cocaine and its metabolites using liquid chromatography - Tandem mass spectrometry. AB - Porous membrane-protected micro-solid phase extraction (MU-SPE) using a molecularly imprinted polymer (MIP) as an adsorbent has been proposed as an integrated extraction-cleanup procedure for isolating cocaine (COC) and its metabolites [benzoylecgonine (BZE), ecgonine methyl ester (EME), and cocaethylene (CE)] from human urine. MIP beads have been synthesized using COC as a template molecule, ethylene dimethacrylate (EDMA) as a functional monomer, divinylbenzene (DVB) as a cross-linker, and 2,2'-azobisisobutyronitrile (AIBN) as an initiator. High performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS) has been used for quantifying the analytes after MIP-MU-SPE. Variables such as urine pH, adsorption temperature and time, mechanical (orbital-horizontal) stirring; and composition of the eluting solution and eluting time, were evaluated. The proposed method was shown to be precise and accurate [relative standard deviations (RSDs) of intra- and inter-day tests ranging from 3 to 8% and from 2 to 10%, respectively]; and analytical recoveries in the range of 89-100%). In addition, excellent accuracy was also verified after analyzing a FDT +25% control material for BZE. The detection limits were in the range of 0.16-1.7 ng L(-1), low enough for confirmative conclusions regarding cocaine abuse. The method was finally applied for screening/quantifying cocaine and metabolites in urine samples from poly-drug abusers. PMID- 26526911 TI - Analytical capabilities of high performance liquid chromatography - Atmospheric pressure photoionization - Orbitrap mass spectrometry (HPLC-APPI-Orbitrap-MS) for the trace determination of novel and emerging flame retardants in fish. AB - A new analytical method was established and validated for the analysis of 27 brominated flame retardants (BFRs), including so called "emerging" and "novel" BFRs (EBFRs and NBFRs) in fish samples. High performance liquid chromatography (HPLC) coupled to Orbitrap mass spectrometry (Orbitrap-MS) employing atmospheric pressure photoionization (APPI) interface operated in negative mode was used for the identification/quantitation of contaminants. HPLC-Orbitrap-MS analysis provided a fast separation of selected analytes within 14 min, thus demonstrating a high throughput processing of samples. The developed methodology was tested by intralaboratory validation in terms of recovery, repeatability, linear calibration ranges, instrumental and method limits of quantitation (i-LOQ and m LOQ), and where possible, trueness was verified by analysis of certified reference materials (CRMs). Recoveries of analytes were between 80 and 119%, while the repeatability in terms of relative standard deviations (RSDs) was in the range from 1.2 to 15.5%. The measured values for both analyzed CRMs agreed with the provided consensus values, revealing the recovery of reference concentrations in 72-119% range. The elaborated method met the sensitivity criterion according to Commission Recommendation 2014/118/EU on monitoring of BFRs in food products for majority of the compounds. The concentrations of polybrominated diphenyl ethers (PBDEs) in real samples determined by HPLC-APPI Orbitrap-MS method and validated gas chromatography-high-resolution mass spectrometry (GC-HRMS) method were found to be in a good agreement. PMID- 26526912 TI - A novel approach for LC-MS/MS-based chiral metabolomics fingerprinting and chiral metabolomics extraction using a pair of enantiomers of chiral derivatization reagents. AB - Chiral metabolites are found in a wide variety of living organisms and some of them are understood to be physiologically active compounds and biomarkers. However, the overall analysis of chiral metabolomics is quite difficult due to the high number of metabolites, the significant diversity in their physicochemical properties, and concentration range from metabolite-to metabolite. To solve this difficulty, we developed a novel approach for chiral metabolomics fingerprinting and chiral metabolomics extraction, which is based on the labeling of a pair of enantiomers of chiral derivatization reagents (i.e., DMT-(S,R)-Pro-OSu and DMT-3(S,R)-Apy) and precursor ion scan chromatography of the derivatives. The multivariate statistics is also required for this strategy. The proposed procedures were evaluated by the detection of a diagnostic marker (i.e., d-lactic acid) using the saliva of diabetic patients. This method was used for the determination of biomarker candidates of chiral amines and carboxyls in Alzheimer's disease (AD) brain homogenates. As the results, l-phenylalanine (L Phe) and l-lactic acid (L-LA) were identified as the decreased and increased biomarker candidates in the AD brain, respectively. Therefore, the proposed approach seems to be helpful for the determination of non-target chiral metabolomics possessing amines and carboxyls. PMID- 26526913 TI - Drug cytotoxicity and signaling pathway analysis with three-dimensional tumor spheroids in a microwell-based microfluidic chip for drug screening. AB - Currently, there has been a growing need for developing in vitro models to better reflect organism response to chemotherapy at tissue level. For this reason, a microfluidic platform was developed for mimicking physiological microenvironment of solid tumor with multicellular tumor spheroids (MTS) for anticancer drug screening. Importantly, the power of this system over traditional systems is that it is simple to operate and high integration in a more physiologically relevant context. As a proof of concept, long-term MTS cultures with uniform structure were realized on the microfluidic based platform. The response of doxorubicin and paclitaxel on different types of spheroids were simultaneously performed by in situ Live/Dead fluorescence stain to provide spatial distribution of dead cells as well as cytotoxicity information. In addition, the established platform combined with microplate reader was capable to determine the cytotoxicity of different sized MTS, showing a more powerful tool than cell staining examination at the end-point of assay. The HCT116 spheroids were then lysed on chip followed by signaling transduction pathway analysis. To our knowledge, the on chip drug screening study is the first to address the drug susceptibility testing and the offline detailed drug signaling pathway analysis combination on one system. Thus, this novel microfluidic platform provides a useful tool for drug screening with tumor spheroids, which is crucial for drug discovery and development. PMID- 26526914 TI - Circular dichroism sensor based on cadmium sulfide quantum dots for chiral identification and detection of penicillamine. AB - A new chemical sensor based on the measuring of circular dichroism signal (CD) was fabricated from cysteamine capped cadmium sulfide quantum dots (Cys-CdS QDs). The chiral-thiol molecules, d-penicillamine (DPA) and l-penicillamine (LPA), were used to evaluate potentials of this sensor. Basically, DPA and LPA provide very low CD signals. However, the CD signals of DPA and LPA can be enhanced in the presence of Cys-CdS QDs. The CD spectra of DPA and LPA exhibited a mirror image profile. Parameters affecting the determination of DPA and LPA were thoroughly investigated in details. Under the optimized condition, the CD signals of DPA and LPA displayed a linear relationship with the concentrations of both enantiomers, ranging from 1 to 35 MUM. Detection limits of this sensor were 0.49 and 0.74 MUM for DPA and LPA, respectively. To demonstrate a potential application of this sensor, the proposed sensor was used to determine DPA and LPA in real urine samples. It was confirmed that the proposed detection technique was reliable and could be utilized in a broad range of applications. PMID- 26526915 TI - Poly (N-Isopropylacrylamide) microgel-based optical devices for humidity sensing. AB - Optical sensors for environmental humidity have been constructed from poly (N isopropylacrylamide)-co-acrylic acid (pNIPAm-co-AAc) microgels. The devices were constructed by first depositing a monolithic layer of pNIPAm-co-AAc microgels on a Au-coated glass substrate followed by the addition of another Au layer on top. The resultant assembly showed visual color, and exhibited multipeak reflectance spectra. We found that the thickness of the device's microgel layer depended on environmental humidity, which corresponded to a change in the device's optical properties. Specifically, at low humidity the microgel layer was collapsed, while it absorbed water from the atmosphere (and swelled) as the humidity increased. Additionally, we investigated how the deposition of the hygroscopic polymer poly (diallyldimethylammonium chloride) (pDADMAC) onto the microgel layer (prior to final Au layer deposition) influenced the devices humidity response. We found that the devices were more sensitive to humidity as the number of pDADMAC layers in the device increased. Finally, we evaluated the device performance at various temperatures, and found that the sensitivity was enhanced at low temperature, although the response was more linear at elevated temperature. PMID- 26526916 TI - A nonenzymatic optical immunoassay strategy for detection of Salmonella infection based on blue silica nanoparticles. AB - A novel nonenzymatic optical immunoassay strategy was for the first time designed and utilized for sensitive detection of antibody to Salmonella pullorum and Salmonella gallinarum (S. pullorum and S. gallinarum) in serum. The optical immunoassay strategy was based on blue silica nanoparticles (Blue-SiNps) and magnetic beads (MB). To construct such an optical immunoassay system, the Blue SiNPs were first synthesized by inverse microemulsion method, characterized by SEM, Zeta potential and FTIR. Two nanostructures including Blue-SiNPs and MB were both functionalized with antibody against S. pullorum and S. gallinarum (anti-PG) without using enzyme labeled antibody. Anti-PG functionalized blue silica nanoparticles (IgG-Blue-SiNps) were used as signal transduction labels, while anti-PG functionalized magnetic beads (IgG-MB) were selected to separate and enrich the final sandwich immune complexes. In the process of detecting negative serum, a sandwich immunocomplex is formed between the IgG-MB and IgG-Blue-SiNPs. With the separation of the immunocomplex using an external magnetic field, the final plaque displayed bright blue color. While in the detection of infected serum, IgG-MB and anti-PG formed sandwich immunocomplexes, IgG-Blue-SiNPs were unable to bind to the limited sites of the antigen, and a light brown plaque was displayed in the bottom of microplate well. Stable results were obtained with an incubation time of 60 min at room temperature, and different colors corresponding to different results can be directly detected with naked eye. The reaction of IgG Blue-SiNPs with S. pullorum was inhibited by 1:100 dilution of positive chicken serum. Such a simple immunoassay holds great potential as sensitive, selective and point-of-care (POC) tool for diagnosis of other biological molecules. PMID- 26526917 TI - Comparative study for N and S doped carbon dots: Synthesis, characterization and applications for Fe(3+) probe and cellular imaging. AB - A facile and eco-friendly approach to prepare nitrogen(N)- and sulfur(S)-doped carbon dots (CDs) by one step microwave-assisted pyrolysis of the precursors with dl-malic acid as carbon source, ethanolamine and ethane-sulfonic acid as N and S dopants, respectively, was reported. Through the extensive investigation on morphology, chemical structures and optical properties of the carbon dots, it was found that the obtained CDs exhibited good luminescence stability, high resistance to photo bleaching and favorite solubility. Compared with undoped CDs, adding the N or S dopant could give rise to a slightly smaller particle size and a long fluorescence lifetime of CDs. Moreover, the optimal N-CDs was successfully employed as good multicolor cell imaging probes due to its fine dispersion in water, excitation-dependent emission, excellent biocompatibility and low toxicity. Besides, such N-CDs showed a wide detection range and excellent accuracy as fluorescent probe for Fe(3+) ions. This probe enabled the selective detection of Fe(3+) ions with a linear range of 6.0-200 MUM and a limit of detection of 0.80 MUM. PMID- 26526918 TI - High efficiency, narrow particle size distribution, sub-2 MUm based macrocyclic glycopeptide chiral stationary phases in HPLC and SFC. AB - State of the art chiral chromatography still employs 3-5 MUm bonded or immobilized chiral selectors in 10-25 cm columns. With the availability of 1.9 MUm narrow particle size distribution (NPSD) silica, it is now possible to make ever shorter, high efficiency columns practical for sub-minute chiral separations. Three macrocyclic glycopeptides (teicoplanin, teicoplanin aglycone, and vancomycin) were bonded onto 1.9 MUm NPSD particles. Such packed columns had ~80% lower backpressure as compared to polydisperse (PD) 1.7 MUm silica materials when using the same mobile phase. The decreased backpressure allowed for diminution of frictional heating and allowed for the use of the 1.9 MUm NPSD particle based columns at high flow rates. The 1.9 MUm NPSD particle based columns showed up to 190,000 plates m(-1) for chiral molecules and 210,000 plates m(-1) for achiral probes. Representative enantiomeric separations are shown for wide classes of compounds, including different types of amino acids, beta blockers, and pharmaceutically important heterocyclic compounds such as oxazolidinones. Applications in three liquid chromatography modes, namely, reversed phase, polar organic mode and normal phase chiral separations were shown with resolution values ranging from 1.5 to 5.7. Additionally, the same columns were used with supercritical fluid chromatography (SFC) for ultrafast separations. PMID- 26526919 TI - Trapping devices of nematode-trapping fungi: formation, evolution, and genomic perspectives. AB - Nematode-trapping fungi (NTF) are potential biological control agents against plant- and animal-parasitic nematodes. These fungi produce diverse trapping devices (traps) to capture, kill, and digest nematodes as food sources. Most NTF can live as both saprophytes and parasites. Traps are not only the weapons that NTF use to capture and infect nematodes, but also an important indicator of their switch from a saprophytic to a predacious lifestyle. Formation of traps and their numbers are closely related to the nematicidal activity of NTF, so the mechanisms governing trap formation have become a focus of research on NTF. Recently, much progress has been made in our understanding of trap formation, evolution, and the genome, proteome and transcriptome of NTF. Here we provide a comprehensive overview of recent advances in research on traps of NTF. Various inducers of trap formation, trap development, structural properties and evolution of traps are summarized and discussed. We specifically discuss the latest studies of NTF based on genomic, proteomic and transcriptomic analyses. PMID- 26526920 TI - Real-Time Polymerase Chain Reaction Detection of Angiostrongylus cantonensis DNA in Cerebrospinal Fluid from Patients with Eosinophilic Meningitis. AB - Angiostrongylus cantonensis is the most common infectious cause of eosinophilic meningitis. Timely diagnosis of these infections is difficult, partly because reliable laboratory diagnostic methods are unavailable. The aim of this study was to evaluate the usefulness of a real-time polymerase chain reaction (PCR) assay for the detection of A. cantonensis DNA in human cerebrospinal fluid (CSF) specimens. A total of 49 CSF specimens from 33 patients with eosinophilic meningitis were included: A. cantonensis DNA was detected in 32 CSF specimens, from 22 patients. Four patients had intermittently positive and negative real time PCR results on subsequent samples, indicating that the level of A. cantonensis DNA present in CSF may fluctuate during the course of the illness. Immunodiagnosis and/or supplemental PCR testing supported the real-time PCR findings for 30 patients. On the basis of these observations, this real-time PCR assay can be useful to detect A. cantonensis in the CSF from patients with eosinophilic meningitis. PMID- 26526921 TI - Predictive Time Series Analysis Linking Bengal Cholera with Terrestrial Water Storage Measured from Gravity Recovery and Climate Experiment Sensors. AB - Outbreaks of diarrheal diseases, including cholera, are related to floods and droughts in regions where water and sanitation infrastructure are inadequate or insufficient. However, availability of data on water scarcity and abundance in transnational basins, are a prerequisite for developing cholera forecasting systems. With more than a decade of terrestrial water storage (TWS) data from the Gravity Recovery and Climate Experiment, conditions favorable for predicting cholera occurrence may now be determined. We explored lead-lag relationships between TWS in the Ganges-Brahmaputra-Meghna basin and endemic cholera in Bangladesh. Since bimodal seasonal peaks in cholera in Bangladesh occur during spring and autumn seasons, two separate logistical models between TWS and disease time series (2002-2010) were developed. TWS representing water availability showed an asymmetrical, strong association with cholera prevalence in the spring (tau = -0.53; P < 0.001) and autumn (tau = 0.45; P < 0.001) up to 6 months in advance. One unit (centimeter of water) decrease in water availability in the basin increased odds of above normal cholera by 24% (confidence interval [CI] = 20-31%; P < 0.05) in the spring, while an increase in regional water by 1 unit, through floods, increased odds of above average cholera in the autumn by 29% (CI = 22-33%; P < 0.05). PMID- 26526922 TI - Evidence for an Overwintering Population of Aedes aegypti in Capitol Hill Neighborhood, Washington, DC. AB - Aedes aegypti is an invasive, highly anthropophilic mosquito and a major vector for dengue and chikungunya. Population persistence in the continental United States is reportedly limited to southward of the average 10 degrees C winter isotherm, which in the east, bisects Alabama, Mississippi, Georgia, and South Carolina. We report on summer collections and genotypic analyses of Ae. aegypti collected in the Capitol Hill neighborhood in Washington, DC (WDC). Analysis of a 441-bp fragment of the mitochondrial cytochrome oxidase I gene sequence identified the same two haplotype sequences during 2011-2014, and placed these within two discrete groups known to be derived from lineages resident in the Americas. Analysis of 10 microsatellite loci for specimens collected during 2011 2014 revealed no evidence for introgression of new alleles across years. Overall, our data support a conclusion that this represents a resident WDC population, likely maintained during winter months in a subterranean habitat that facilitates year-round survival. PMID- 26526923 TI - Diagnosis of Opisthorchis viverrini Infection with Handheld Microscopy in Lao People's Democratic Republic. AB - Opisthorchiasis is a neglected tropical disease, yet it is of considerable public health importance in Southeast Asia given the predilection for chronically infected persons to develop cholangiocarcinoma. We evaluated a handheld microscope for the diagnosis of Opisthorchis viverrini in a community-based setting in Lao People's Democratic Republic in comparison with conventional light microscopy. In stool samples collected from 104 individuals, handheld microscopy revealed a sensitivity of 70.6% and a specificity of 89.5% for O. viverrini infection. Pearson's correlation for quantitative fecal egg counts between the two devices was 0.98 (95% confidence interval: 0.98-0.99). With small adjustments to further increase diagnostic sensitivity, a handheld microscope may become a helpful tool to screen for O. viverrini and other helminth infections in public health settings. PMID- 26526924 TI - Acute Abdomen Caused by Brucellar Hepatic Abscess. AB - Brucellosis, a zoonosis that is common worldwide, is endemic in many countries, primarily those of the Mediterranean region (including Turkey). Human brucellosis is a systemic infection with a wide clinical spectrum. Although hepatic involvement is very common during the course of chronic brucellosis, hepatic abscess is a very rare complication of Brucella spp. infection. We present a case of hepatic abscess caused by Brucella melitensis, which resembled the clinical presentation of surgical acute abdomen. PMID- 26526925 TI - Burkholderia pseudomallei Genotype Distribution in the Northern Territory, Australia. AB - Melioidosis is a tropical disease of high mortality caused by the environmental bacterium, Burkholderia pseudomallei. We have collected clinical isolates from the highly endemic Northern Territory of Australia routinely since 1989, and animal and environmental B. pseudomallei isolates since 1991. Here we provide a complete record of all B. pseudomallei multilocus sequence types (STs) found in the Northern Territory to date, and distribution maps of the eight most common environmental STs. We observed surprisingly restricted geographic distributions of STs, which is contrary to previous reports suggesting widespread environmental dissemination of this bacterium. Our data suggest that B. pseudomallei from soil and water does not frequently disperse long distances following severe weather events or by migration of infected animals. PMID- 26526926 TI - Short-Course Treatment Regimen of Indian Visceral Leishmaniasis with an Indian Liposomal Amphotericin B Preparation (FungisomeTM). AB - India bears the burden of about half of global visceral leishmaniasis (VL) cases with emerging problems of stibanate resistance. Liposomal preparations have improved treatment outcome through shorter duration of therapy and lower toxicity compared with conventional amphotericin B. We report the efficacy of two short course regimens of an Indian preparation of liposomal amphotericin B (FungisomeTM) for VL caused by Leishmania donovani in India. An open-label, randomized, single-center comparative study was undertaken from 2008 to 2011, involving 120 treatment naive non-human immunodeficiency virus VL patients randomly allocated to two groups. FungisomeTM was given, in groups A (N = 60), 5 mg/kg daily for 2 days and B (N = 60), 7.5 mg/kg daily for 2 days, as intravenous infusion. Initial cure rate was 100% in both the groups after 1 month posttreatment. At 6 months after completion of treatment, definitive cure rate was group A 90% (54/60, 95% confidence interval (CI): 80.55-95.72%); group B: 100% (95% CI: 95.92-100%); (P = 0.027). No serious adverse events occurred in either group. The short-course, 2-day regimen of 15 mg/kg FungisomeTM infusion is easy to administer, effective, and safe for treatment of VL caused by L. donovani in India. PMID- 26526928 TI - Extracts from the British Pain Society Cancer Pain Management Publication. PMID- 26526927 TI - Experimental Survival of Mycobacterium ulcerans in Watery Soil, a Potential Source of Buruli Ulcer. AB - The reservoir of Mycobacterium ulcerans causing Buruli ulcer (BU) remains unknown. Here, sterilized watery soil was mixed with 2 * 10(6) colony-forming units (CFU)/g of M. ulcerans Agy99 or M. ulcerans ATCC 33728 and incubated in a microaerophilic atmosphere in the presence of negative controls. Both M. ulcerans strains survived in soil for 4 months with a final inoculum of 300-440 CFU/g. Further, three groups of five mice with and without footpad scarification were exposed to control soil or M. ulcerans-inoculated soil. Although no specific clinical and histopathological lesions were observed in control animals, red spots observed on 8/20 scarified feet in 8/10 challenged mice yielded inflammatory infiltrates and positive real-time polymerase chain reaction detection of M. ulcerans DNA in five mice. BU can be acquired as an inoculation infection with watery soil as a transient source of infection. These experimental observations warrant additional field observations. PMID- 26526929 TI - Tamm plasmon- and surface plasmon-coupled emission from hybrid plasmonic-photonic structures. AB - Photonic and plasmon-coupled emissions present new opportunities for control on light emission from fluorophores, and have many applications in the physical and biological sciences. The mechanism of and the influencing factors for the coupling between the fluorescent molecules and plasmon and/or photonic modes are active areas of research. In this paper, we describe a hybrid photonic-plasmonic structure that simultaneously contains two plasmon modes: surface plasmons (SPs) and Tamm plasmons (TPs), both of which can modulate fluorescence emission. Experimental results show that both SP-coupled emission (SPCE) and TP-coupled emission (TPCE) can be observed simultaneously with this hybrid structure. Due to the different resonant angles of the TP and SP modes, the TPCE and SPCE can be beamed in different directions and can be separated easily. Back focal plane images of the fluorescence emission show that the relative intensities of the SPCE and TPCE can be changed if the probes are at different locations inside the hybrid structure, which reveals the probe location-dependent different coupling strengths of the fluorescent molecules with SPs and TPs. The different coupling strengths are ascribed to the electric field distribution of the two modes in the structure. Here, we present an understanding of these factors influencing mode coupling with probes, which is vital for structure design for suitable applications in sensing and diagnostics. PMID- 26526930 TI - Metabolomics Identifies Biomarker Pattern for Early Diagnosis of Hepatocellular Carcinoma: from Diethylnitrosamine Treated Rats to Patients. AB - Early diagnosis of hepatocellular carcinoma (HCC) remains challenging to date. Characteristic metabolic deregulations of HCC may enable novel biomarkers discovery for early diagnosis. A capillary electrophoresis-time of flight mass spectrometry (CE-TOF/MS)-based metabolomics approach was performed to discover and validate potential biomarkers for HCC from the diethylnitrosamine-induced rat hepatocarcinogenesis model to human subjects. Time series sera from the animal model were evaluated using multivariate and univariate analyses to reveal dynamic metabolic changes. Two independent human cohorts (populations I and II) containing 122 human serum specimens were enrolled for validations. A novel biomarker pattern of ratio creatine/betaine which reflects the balance of methylation was identified. This biomarker pattern achieved effective classification of pre-HCC and HCC stages in animal model. It was still effective in the diagnosis of HCC from high-risk patients with cirrhotic nodules, achieving AUC values of 0.865 and 0.905 for two validation cohorts, respectively. The diagnosis of small HCC from cirrhosis with an AUC of 0.928 highlighted the potential for early diagnosis. This ratio biomarker can also improve the diagnostic performance of alpha-fetoprotein (AFP). This study demonstrates the efficacy of present strategy for biomarker discovery, and the potential of metabolomics approach to provide novel insights for disease study. PMID- 26526931 TI - Function of sustained released resveratrol on IL-1beta-induced hBMSC MMP13 secretion inhibition and chondrogenic differentiation promotion. AB - Metalloproteinase-13 is the major type II collagenase that directly implicates cartilage matrix destruction. Metalloproteinase-13 is inducted and activated by interleukin-1beta, which is a commonly observed proinflammatory cytokine in the joint cavity of arthritic patients. Depression of interleukin-1beta function can inhibit metalloproteinase-13 expression and protect the cartilage extracellular matrix. In this study, resveratrol release microspheres were developed, and the direct function of the released resveratrol on the interleukin-1beta was discussed. The resveratrol-loaded microspheres were fabricated using oil-in-water emulsion and solution-evaporation methods. The particle size and the encapsulation efficiency for the techniques, which used different fabrication conditions, were within 8.3-63.9 MUm and 37%-82%, respectively. The effect of drug release lasted for more than 650 h in a PBS solution at 37C. Human bone mesenchymal stem cells were chosen for cell experiments. Interleukin-1beta was used to induce an inflammatory condition. The effect of sustained resveratrol release from the microspheres on the cells' gene expression was observed using the transwell co-culturing method. The results indicated that metalloproteinase 13 mRNA expression was upregulated after interleukin-1beta induction. The released resveratrol directly inhibited the function of interleukin-1beta and thus downregulated metalloproteinase-13 mRNA expression. Moreover, the upregulation of Col2, aggrecan and Sox9 mRNA expressions, which are major chondrocyte markers, was observed after resveratrol was released into the culture medium. Resveratrol was observed to maintain the cells' chondrogenic gene expression when subject to the inflammation condition. The sustained released resveratrol inhibited interleukin-1beta-inducted metalloproteinase-13 activation and promoted chondrocyte differentiation. This drug-loading microsphere is a promising candidate for arthritis therapy. PMID- 26526932 TI - Microstructure and in vitro cellular response to novel soy protein-based porous structures for tissue regeneration applications. AB - Interest in the development of new bioresorbable structures for various tissue engineering applications is on the rise. In the current study, we developed and studied novel soy protein-based porous blends as potential new scaffolds for such applications. Soy protein has several advantages over the various types of natural proteins employed for biomedical applications due to its low price, non animal origin and relatively long storage time and stability. In the present study, blends of soy protein with other polymers (gelatin, pectin and alginate) were added and chemically cross-linked using the cross-linking agents carbodiimide or glyoxal, and the porous structure was obtained through lyophilization. The resulting blend porous structures were characterized using environmental scanning microscopy, and the cytotoxicity of these scaffolds was examined in vitro. The biocompatibility of the scaffolds was also evaluated in vitro by seeding and culturing human fibroblasts on these scaffolds. Cell growth morphology and adhesion were examined histologically. The results show that these blends can be assembled into porous three-dimensional structures by combining chemical cross-linking with freeze-drying. The achieved blend structures combine suitable porosity with a large pore size (100-300 um). The pore structure in the soy-alginate scaffolds possesses adequate interconnectivity compared to that of the soy-gelatin scaffolds. However, porous structure was not observed for the soy pectin blend, which presented a different structure with significantly lower porosities than all other groups. The in vitro evaluation of these porous soy blends demonstrated that soy-alginate blends are advantageous over soy-gelatin blends and exhibited adequate cytocompatibility along with better cell infiltration and stability. These soy protein scaffolds may be potentially useful as a cellular/acellular platform for skin regeneration applications. PMID- 26526933 TI - [Lipoma of the corpus callosum: about a case with literature review]. PMID- 26526934 TI - The feasibility of using 'bring your own device' (BYOD) technology for electronic data capture in multicentre medical audit and research. AB - Large-scale audit and research projects demand robust, efficient systems for accurate data collection, handling and analysis. We utilised a multiplatform 'bring your own device' (BYOD) electronic data collection app to capture observational audit data on theatre efficiency across seven hospital Trusts in South Yorkshire in June-August 2013. None of the participating hospitals had a dedicated information governance policy for bring your own device. Data were collected by 17 investigators for 392 individual theatre lists, capturing 14,148 individual data points, 12, 852 (91%) of which were transmitted to a central database on the day of collection without any loss of data. BYOD technology enabled accurate collection of a large volume of secure data across multiple NHS organisations over a short period of time. Bring your own device technology provides a method for collecting real-time audit, research and quality improvement data within healthcare systems without compromising patient data protection. PMID- 26526935 TI - Structural phases of adsorption for flexible polymers on nanocylinder surfaces. AB - By means of generalized-ensemble Monte Carlo simulations, we investigate the thermodynamic behavior of a flexible, elastic polymer model in the presence of an attractive nanocylinder. We systematically identify the structural phases that are formed by competing monomer-monomer and monomer-substrate interactions. The influence of the relative surface attraction strength on the structural phases in the hyperphase diagram, parameterized by cylinder radius and temperature, is discussed as well. In the limiting case of the infinitely large cylinder radius, our results coincide with previous outcomes of studies of polymer adsorption on planar substrates. PMID- 26526936 TI - [Epidemiology and prevention of prosthetic joint infection]. AB - BACKGROUND: Prosthetic joint infection (PJI) is challenging for patients and orthopedic surgeons and represents a great economic burden to the health care system. The growing number of primary and revision arthroplasty procedures in an aging society with demographic changes will increase the number of PJIs in the future. AIM: This article presents an overview of the epidemiology and prevention of PJI. METHOD: A selective literature review was performed focusing on evidence based epidemiology, risk factors, and prevention of PJI. RESULTS: The total number of primary arthroplasty and septic revision procedures is increasing. The incidence of PJI is constant, although surgical techniques have improved over the years, with a multitude of possible preventive procedures for use before surgical treatment. This is most likely due to the increasing comorbidities and individual risk factors of the patient. Both endogenous and exogenous risk factors are known to be associated with PJI. Endogenous risk factors include diabetes, obesity, immunosuppression, oncological diseases, rheumatoid arthritis, previous or chronic infections, and bacteriuria. Exogenous risk factors include the extended duration of the operation, blood transfusion, and hypothermia. However, the facilities in the operating theatre or the use of iodine-impregnated incision drape seem to have no influence on the incidence of PJI. PROSPECT: The increasing number of arthroplasty procedures and the static incidence of PJI will result in an increase in the total number of PJIs in the next few years. In particular, the costs to the health care system of the treatment of PJI will emphasize further the need for the prevention of PJI. Individual risk factors should be optimized before arthroplasty requiring a close cooperation between the general practitioner and the orthopedic specialist. PMID- 26526937 TI - [Update on implant-associated infections]. PMID- 26526938 TI - The Endo-Model((r)) rotating hinge for rheumatoid knees : Functional results in primary and revision surgery. AB - BACKGROUND: Major joints of the lower limbs are commonly affected by rheumatoid arthritis (RA), with consequent pain, loss of function, and progressive disability. Knee replacement represents a useful solution, but a highly constrained implant design is often needed in order to face the severe anatomical deformities and the gross instability that the surgeon may encounter in the rheumatoid knee. OBJECTIVES: The aim of this work was to evaluate the Endo Model((r)) rotating hinge knee prosthesis implanted in patients affected by RA and severely damaged knees. PATIENTS AND METHODS: We retrospectively evaluated a series of 38 patients with RA implanted with the Endo-Model((r)) rotating hinge knee prosthesis for primary or revision surgery (mean follow-up 6.1 years; mean age at surgery 71.5 years). At the time of surgery, the mean duration of RA was 13.2 years. Patients were evaluated clinically and radiographically and the Knee Society Score (KSS) was used. RESULTS: Implant survival at most recent follow-up was 91.7 %. Mean final knee flexion was 102.7 degrees . The mean KSS was 93.5 (excellent) and 67.1 (good) for clinical and functional score, respectively. Mild pain was present in 10 patients. No sign of malalignment or residual instability was found. No evidence of loosening or implant failure was observed in x-rays. CONCLUSION: The Endo-Model((r)) rotating hinge knee prosthesis provides excellent pain relief, functional recovery, and intrinsic knee stability both in complex primary and in revision knee arthroplasty in the majority of patients with severely affected rheumatoid knees. PMID- 26526939 TI - Vulval and vaginal cancer in pregnancy. AB - Lower genital tract malignancy during pregnancy is rare. Due to the rarity of this condition, the best evidence in its management is based on case reports. The management of the lower genital tract malignancy is influenced by factors including oncological factors, maternal and foetal effect of treatment, and other religious and ethical issues in a multidisciplinary approach. In most cases, the woman can continue with the pregnancy. This chapter describes the management of vaginal and vulval cancer during pregnancy based on available case reports. PMID- 26526940 TI - The Cost and Burden of Chronic Pain. AB - There are enormous costs which society has to bear as a result of the burden of chronic pain and its suffering.Policy makers at governmental level and commissioners, and health care decision-makers alike should adopt a broad, strategic and coherent perspective in determining issues relating to service provision and resource allocation. PMID- 26526942 TI - Metabolic Reprogramming in Brain Cancer: A Coordinated Effort. PMID- 26526941 TI - The interaction effects of aerobic exercise training and vitamin D supplementation on plasma lipid profiles and insulin resistance in ovariectomized rats. AB - PURPOSE: The purpose of this study was to determine the interaction effects of aerobic exercise training and vitamin D supplementation on indices of obesity and plasma lipid profiles in ovariectomized (OVX) rats. METHODS: Forty female Wistar rats were divided into 5 groups: aerobic training (3 days/week for 8 weeks; AT; n = 8), aerobic training and vitamin D supplementation (OVX + AT + Vit D; n = 8), vitamin D supplementation (OVX + Vit D; n = 8), ovariectomized control (OVX + C, n = 8) and SHAM (n = 8). After blood sampling, visceral fat was taken from the abdominal cavity and weighed immediately. Data was statistically analyzed by One way ANOVA and Repeated measure ANOVA tests with a 0.05 significance level. RESULTS: Body weight, visceral fat, BMI and food intake decreased significantly in OVX + AT + Vit D (P < 0.001); whereas these variables increased significantly in OVX + C (P < 0.001) and SHAM (P < 0.023) groups. At the end of two-months of follow-up, we observed significant differences in TC, TG, HDL-C, LDL-C, glucose, insulin, and HOMA-IR in all groups. CONCLUSION: It seems that aerobic training with vitamin D, due to the involvement of muscle mass and exposure to dynamic pressure on the bones and muscles, increased energy expenditure, stimulated insulin exudation and glucose homeostasis, decreased insulin resistance and improved the lipid profile in ovariectomized rats. PMID- 26526943 TI - mTORC2 and Metabolic Reprogramming in GBM: at the Interface of Genetics and Environment. AB - Metabolic reprogramming is a central hallmark of cancer, enabling tumor cells to obtain the macromolecular precursors and energy needed for rapid tumor growth. Understanding how oncogenes coordinate altered signaling with metabolic reprogramming and how cancer cells harness cellular metabolism and its metabolites for their survival may yield new insights into tumor pathogenesis. Here, we review the recently identified central regulatory role for mTORC2, a downstream effector of many cancer-causing mutations, in metabolic reprogramming and cancer drug resistance in glioblastoma. We further consider the emerging concept that mTORC2 may connect genetics with environmental alterations in brain cancer. PMID- 26526945 TI - Magnetic Resonance (MR) Metabolic Imaging in Glioma. AB - This review is focused on describing the use of magnetic resonance (MR) spectroscopy for metabolic imaging of brain tumors. We will first review the MR metabolic imaging findings generated from preclinical models, focusing primarily on in vivo studies, and will then describe the use of metabolic imaging in the clinical setting. We will address relatively well-established (1) H MRS approaches, as well as (31) P MRS, (13) C MRS and emerging hyperpolarized (13) C MRS methodologies, and will describe the use of metabolic imaging for understanding the basic biology of glioma as well as for improving the characterization and monitoring of brain tumors in the clinic. PMID- 26526946 TI - The Role of Pyruvate Kinase M2 in Cancer Metabolism. AB - The M2 isoform of pyruvate kinase is expressed preferentially in cancer cells over other pyruvate kinase isoforms. PKM2 is unique in its ability to be regulated allosterically by nutrients and growth signaling pathways, allowing cells to adapt their metabolic program to match physiological needs in different environments. Here, we discuss the role of pyruvate kinase M2 in glioma and in cancer metabolism. PMID- 26526944 TI - 2-Hydoxyglutarate: D/Riving Pathology in gLiomaS. AB - Common pathways and mechanisms can be found in both cancers and inborn errors of metabolism. 2-Hydroxyglutarate (2-HG) acidurias and isocitrate dehydrogenase (IDH) 1/2 mutant tumors are examples of this phenomenon. 2-HG can exist in two chiral forms, D(R)-2-HG and L(S)-2-HG, which are elevated in D- and L-acidurias, respectively. D-2-HG was subsequently discovered to be synthesized in IDH 1/2 mutant tumors including ~70% of intermediate-grade gliomas and secondary glioblastomas (GBM). Recent studies have revealed that L-2-HG is generated in hypoxia in IDH wild-type tumors. Both 2-HG enantiomers have similar structures as alpha-ketoglutarate (alpha-KG) and can competitively inhibit alpha-KG-dependent enzymes. This inhibition modulates numerous cellular processes, including histone and DNA methylation, and can ultimately impact oncogenesis. D-2-HG can be detected in vivo in glioma patients and animal models using advanced imaging modalities. Finally, pharmacologic inhibitors of mutant IDH 1/2 attenuate the production of D-2-HG and show great promise as therapeutic agents. PMID- 26526947 TI - Unusual Spinal Cord Tumor in A 16-Month-Old Child. PMID- 26526948 TI - 24-Year-Old Woman with Recent Onset Back Pain. PMID- 26526949 TI - A 59-Year-Old Man with History of Renal Transplantation. PMID- 26526950 TI - A 59-Year-Old Man with Two Cerebellar Lesions and Disturbed Cerebellar Morphology. PMID- 26526952 TI - Deletion of mitogen-activated protein kinase 1 inhibits development and growth of Toxoplasma gondii. AB - Mitogen-activated protein kinases (MAPKs) regulate key signaling events in a variety of eukaryotic cells. Toxoplasma gondii, the causative agents of toxoplasmosis, possesses a p38alpha MAPK homologue, MAPK1, which is an important manipulator of host immunity and virulence in mice. In this work, we showed an increased transcript level of MAPK1 in T. gondii during bradyzoite differentiation induced by alkaline treatment and heat shock in vitro, suggesting that MAPK1 may be associated with bradyzoite differentiation. The biological roles of MAPK1 of T. gondii were investigated by construction of a MAPK1 deletion mutant (Deltamapk1) and a complementation mutant with restored MAPK1 expression using a type I strain. Knockout of MAPK1 resulted in markedly defective bradyzoite differentiation, host-cell attachment and parasite replication in vitro, and the inability to cause lethal infection in a murine model of acute toxoplasmosis, with lower parasite burden in infected tissues, showing that MAPK1 is associated with the acute virulence of parasite in mice. Complementation of MAPK1-deficient parasites restored bradyzoite development, attachment, replication, and virulence. Our findings demonstrate that MAPK1 is involved in asexual development and growth of T. gondii. PMID- 26526953 TI - Trypanosoma cruzi infection induces the expression of CD40 in murine cardiomyocytes favoring CD40 ligation-dependent production of cardiopathogenic IL 6. AB - The inflammatory response in the myocardium is an important aspect of the pathogenesis of Chagas' heart disease raised by Trypanosoma cruzi. CD40, a transmembrane type I receptor belonging to the tumor necrosis factor receptor (TNFR) family, is expressed in a broad spectrum of cell types and is crucial in several inflammatory and autoimmune diseases. Activation of CD40 through ligation to CD40L (CD154) induces multiple effects, including the secretion of proinflammatory molecules. In the present study, we examined the ability of T. cruzi to trigger the expression of CD40 in cardiac myocytes in vitro and in a murine model of chagasic cardiomyopathy. Our results indicate, for the first time, that T. cruzi is able to induce the expression of CD40 in HL-1 murine cardiomyocytes. Moreover, ligation of CD40 receptor upregulated interleukin-6 (IL 6), associated with inflammation. Furthermore, the induction of this costimulatory molecule was demonstrated in vivo in myocardium of mice infected with T. cruzi. This suggests that CD40-bearing cardiac muscle cells could interact with CD40L-expressing lymphocytes infiltrating the heart, thus contributing to inflammatory injury in chagasic cardiomyopathy. PMID- 26526954 TI - Implementation of an innovative hands-on training to improve adherence to hygiene rules: A feasibility Study. AB - BACKGROUND: Hospital-acquired infections (HAI) still pose a major problem in inpatient care. The single most important measure for preventing HAIs is to improve adherence to hand hygiene among health care professionals. OBJECTIVE: To assess the feasibility of an innovative hands-on training to improve adherence to hygiene rules under standardized and under real life conditions. DESIGN: Before after controlled cohort trial to assess the feasibility of implementing an innovative hands-on training to improve hand hygiene adherence. SETTING: Large university hospital in Germany. PARTICIPANTS: Fifty trained nurses from three wards with an average age of 32years (+/-10.22years) and an average vocational experience of 6.85years (+/-7.54years). METHODS: The intervention consisted of a hands-on training in the skills lab of the University of Cologne complemented by a 12-week observation period before and after the training on participating wards. The training comprised important skills with respect to hand hygiene, venipuncture, dressing changes of central venous catheters, preparation of IV infusions, and donning of gloves using sterile technique. A communication training was included to enable nurses to enforce hygiene rules in their collaboration with peers and physicians. The intervention was taught in small groups with a wide array of interactive teaching methods. It was evaluated using the objective structured clinical examination (OSCE) format. Observations were conducted by a trained infection control nurse. RESULTS: Before (after) the intervention 622 (612) occasions of hand hygiene were documented. A highly significant improvement in hygiene compliance was observed pre- and post intervention (64.3% vs. 79.2%; p<=0.0001). The OSCE evaluation showed significant improvements in all subscales. CONCLUSION: The developed and conducted hands-on training seems feasible and is successful in significantly improving adherence to hygiene rules under standardized and real life conditions. Whether the effect is stable over time is subject to further investigation. PMID- 26526955 TI - Antimicrobials in animal production: usage and practices among livestock farmers in Oyo and Kaduna States of Nigeria. AB - Antimicrobials have proven to be important for sustainable livestock production by their use as growth promoters and in the control of animal infections. However, injudicious use of antimicrobials could accelerate the emergence and spread of resistant bacterial strains with attendant socioeconomic and public health issues. This work assessed antimicrobial usage in animal production with emphasis on usage and practices by livestock producers in Oyo and Kaduna States of Nigeria. Data on antimicrobial usage were collected through interviews, questionnaire and focus group discussions. Four hundred and fifty-four farmers in 11 communities within 11 Local Government Areas of Oyo and Kaduna States of Nigeria were sampled in a multi-stage sampling procedure. The study showed that antimicrobial agents were widely distributed, readily accessible and commonly used in animal production. Fluoroquinolones and other critically important antimicrobials for human medicine were widely used in animals as prophylactics. Potentially harmful antimicrobials including furazolidones and chloramphenicol already banned for use in humans and animals were freely marketed and used in livestock production. Most of the respondents believed that veterinarians should be responsible for the administration of antimicrobials to animals, but in practice, they buy and administer antimicrobials without consulting veterinary professionals. It was observed that the ready availability of antimicrobial agents promoted the use of antimicrobials in livestock production and may encourage non-adherence to hygienic principles and management laxity in farm operations. The non-involvement of veterinary professionals and laboratory investigations in disease diagnosis prior to antimicrobial use could lead to improper usage that contribute to the development of antimicrobial resistance in bacterial strains. Responsible antimicrobial stewardship and strict regulations are vital to prolonging the benefits derivable from the use of antimicrobials. PMID- 26526956 TI - Prevalence and risk factors of Echinococcus granulosus infection in dogs in Moroto and Bukedea districts in Uganda. AB - A cross sectional study was conducted in Moroto and Bukedea districts of Uganda from May to September 2013 to determine the prevalence and risk factors of Echinococcus granulosus infection in dogs. Fresh dog faecal samples were collected, preserved in 70 % ethanol, and later screened for presence of taeniid eggs using zinc chloride floatation method. Positive samples were confirmed by a copro-PCR (polymerase chain reaction) for E. granulosus using NADH dehydrogenase sub-unit 1 gene (NADH1) as a target molecular marker. Structured questionnaires and focus group discussions were used to collect quantitative and qualitative data for risk factor identification. Study sub-counties were selected by simple random sampling. Overall apparent prevalence of taeniid infection in dogs of 14.9 % (39/261, confidence interval 10.6-19.2) in both districts was recorded using the faecal floatation test. The sensitivity of the faecal floatation test was found to be 78 % (25/32), while the specificity was 93 % (215/229). Copro-PCR results revealed a true prevalence of 14.4 % (9.91-19.0, 95 % CI) in dogs in Moroto district and 7.4 % (2.14-12.60, 95 % CI) in Bukedea district. The overall true prevalence of cystic echinococcosis (CE) was 12.2 % (8.70-15.76, 95 % CI) in both districts. The major risk factors identified using logistic regression were uncontrolled access of dogs to animal slaughter facilities, higher cattle herd sizes and lack of knowledge about the disease. It was recommended that restricting dog access to infected tissues and public health education about epidemiology of CE should be done. PMID- 26526957 TI - Seroprevalence and molecular characterization of Chlamydia abortus in frozen fetal and placental tissues of aborting ewes in northeastern Algeria. AB - Enzootic abortion of ewes is one of the most serious health problems in sheep flocks worldwide. It has a significant economic impact because abortion, decrease in milk production and weak lambs. Besides, the bacteria is zoonotic. A cross sectional study was conducted to determine the seroprevalence and risk factors associated with Chlamydia abortus infection in 552 ewes in Constantine using a C. abortus-specific indirect ELISA kit. Chlamydial DNA was investigated in ten ovine fetuses and eight placentas using PCR- restriction fragment length polymorphism (RFLP) and DNA sequencing. The study concluded that 7.2 % of ewes were seropositive and 33.3 % of sheep flocks had at least one seropositive ewe. Adjacent farmworker visits (OR = 7.667, 95 % CI (OR) = 2.307; 27.203) was defined as a risk factor. Deliveries of weak lambs (OR = 2.920, 95 % CI (OR) = 1.022; 8.342) and septicemia in lambs (OR = 9.971, 95 % CI (OR) = 2.383; 41.713) were significantly associated with chlamydial infection. PCR-RFLP analysis revealed positive signals to C. abortus in six fetuses and four placentas. Sequencing of the omp2 gene revealed that the Algerian strain is 96 % similar with C. abortus FAS strain. C. abortus plays a major role in abortion in northeastern Algeria. Appropriate control measures must be implemented to reduce economic losses and to avoid human contamination. PMID- 26526958 TI - Perforation Risk Associated With Percutaneous Endoscopic Gastrostomy-Jejunal Tube Feeding in Pancreatic Walled Off Necrosis. PMID- 26526959 TI - Hemodynamic Effects of Ventricular Assist Device Implantation on Norwood, Glenn, and Fontan Circulation: A Simulation Study. AB - The growing population of failing single-ventricle (SV) patients might benefit from ventricular assist device (VAD) support as a bridge to heart transplantation. However, the documented experience is limited to isolated case reports. Considering the complex and different physiopathology of Norwood, Glenn, and Fontan patients and the lack of established experience, the aim of this work is to realize and test a lumped parameter model of the cardiovascular system able to simulate SV hemodynamics and VAD implantation effects to support clinical decision. Hemodynamic and echocardiographic data of 30 SV patients (10 Norwood, 10 Glenn, and 10 Fontan) were retrospectively collected and used to simulate patients' baseline. Then, the effects of VAD implantation were simulated. Simulation results suggest that the implantation of VAD: (i) increases the cardiac output and the mean arterial systemic pressure in all the three palliation conditions (Norwood 77.2 and 19.7%, Glenn 38.6 and 32.2%, and Fontan 17.2 and 14.2%); (ii) decreases the SV external work (Norwood 55%, Glenn 35.6%, and Fontan 41%); (iii) decreases the pressure pulsatility index (Norwood 65.2%, Glenn 81.3%, and Fontan 64.8%); (iv) increases the pulmonary arterial pressure in particular in the Norwood circulation (Norwood 39.7%, Glenn 12.1% and Fontan 3%); and (v) decreases the atrial pressure (Norwood 2%, Glenn 10.6%, and Fontan 8.6%). Finally, the VAD work is lower in the Norwood circulation (30.4 mL.mm Hg) in comparison with Fontan (40.3 mL.mm Hg) and to Glenn (64.5 mL.mm Hg) circulations. The use of VAD in SV physiology could be helpful to bridge patients to heart transplantations by increasing the CO and unloading the SV with a decrement of the atrial pressure and the SV external work. The regulation of the pulmonary flow is challenging because the Pap is increased by the presence of VAD. The hemodynamic changes are different in the different SV palliation step. The use of numerical models could be helpful to support patient and VAD selection to optimize the clinical outcome. PMID- 26526960 TI - Adeno-associated Virus Serotype Vectors Efficiently Transduce Normal Prostate Tissue and Prostate Cancer Cells. PMID- 26526961 TI - Intra-pulpal temperature rise of different tooth types during dental bleaching supported by an Er,Cr:YSGG laser. A pilot study. AB - The purpose of this pilot in vitro study was to evaluate the temperature increase in the pulp chamber of the teeth, during Er,Cr:YSGG bleaching, as well as to show which teeth are the most susceptible in terms of pulp temperature increase during laser-activated bleaching treatment. Although Er:YAG studies have been published on this subject, it is the first time Er,Cr:YSGG wavelength is tested. Fifteen teeth were tested--3 each of the following--(maxillary central incisors, lateral incisors, canines, premolars and mandibular incisors). The bleaching procedure comprised an Er,Cr:YSGG laser (2780 nm, Waterlase MD, Biolase, USA) and a yellow coloured bleaching agent with a concentration of 38 % H2O2 (Power whitening, WHITEsmile GmbH, Germany). The tip used was a 6-mm long Z-type glass tip (MZ8) of a 800 MUm diameter. Average output power was set to 1.25 W, pulse duration 700 MUs (S-mode), whilst the pulse repetition rate was 10 Hz. The results showed that the most susceptible teeth in terms of pulp temperature increase were the lateral maxillary incisors and the mandibular incisors. The mean temperature increase on these teeth was 1.06 and 1.00 degrees C, respectively, on 60 s Er,Cr:YSGG supported bleaching. PMID- 26526962 TI - Oxygen-Controlled Catalysis by Vitamin B12 -TiO2 : Formation of Esters and Amides from Trichlorinated Organic Compounds by Photoirradiation. AB - An oxygen switch in catalysis of the cobalamin derivative (B12 )-TiO2 hybrid catalyst for the dechlorination of trichlorinated organic compounds has been developed. The covalently bound B12 on the TiO2 surface transformed trichlorinated organic compounds into an ester and amide by UV light irradiation under mild conditions (in air at room temperature), while dichlorostilbenes (E and Z forms) were formed in nitrogen from benzotrichloride. A benzoyl chloride was formed as an intermediate of the ester and amide, which was detected by GC MS. The substrate scope of the synthetic strategy is demonstrated with a range of various trichlorinated organic compounds. A photo-duet reaction utilizing the hole and conduction band electron of TiO2 in B12 -TiO2 for the amide formation was also developed. PMID- 26526963 TI - Heterobimetallic Zeolite, InV-ZSM-5, Enables Efficient Conversion of Biomass Derived Ethanol to Renewable Hydrocarbons. AB - Direct catalytic conversion of ethanol to hydrocarbon blend-stock can increase biofuels use in current vehicles beyond the ethanol blend-wall of 10-15%. Literature reports describe quantitative conversion of ethanol over zeolite catalysts but high C2 hydrocarbon formation renders this approach unsuitable for commercialization. Furthermore, the prior mechanistic studies suggested that ethanol conversion involves endothermic dehydration step. Here, we report the complete conversion of ethanol to hydrocarbons over InV-ZSM-5 without added hydrogen and which produces lower C2 (<13%) as compared to that over H-ZSM-5. Experiments with C2H5OD and in situ DRIFT suggest that most of the products come from the hydrocarbon pool type mechanism and dehydration step is not necessary. Thus, our method of direct conversion of ethanol offers a pathway to produce suitable hydrocarbon blend-stock that may be blended at a refinery to produce fuels such as gasoline, diesel, JP-8, and jet fuel, or produce commodity chemicals such as BTX. PMID- 26526964 TI - High homocysteine, low vitamin B-6, and increased oxidative stress are independently associated with the risk of chronic kidney disease. AB - OBJECTIVE: Hyperhomocysteinemia, increased oxidative stress, and decreased antioxidant defense function have been found to be associated with the risk of chronic kidney disease (CKD). Deficiencies of folate and vitamin B-6 (pyridoxal 5'-phosphate, PLP) may cause hyperhomocysteinemia and increased oxidative stress. The purpose of this study was to determine the associations among homocysteine, folate, PLP, oxidative stress indicator, and antioxidant capacities in patients with stage 2 to 3 CKD, and to further analyze these relationships with respect to risk for CKD. METHODS: Ninety-seven patients with CKD and 135 healthy subjects were recruited. RESULTS: Patients with CKD had significantly higher levels of malondialdehyde and total antioxidant capacities, but had significantly lower antioxidant enzyme activities compared with healthy subjects. Serum folate but not plasma PLP was significantly negatively associated with plasma homocysteine. There were no significant associations of homocysteine, PLP, and folate with oxidative stress indicator and antioxidant capacities. High homocysteine (odds ratio [OR] = 1.11; 95% confidence interval [CI], 1.02-1.22) and malondialdehyde (OR = 34.24; 95% CI, 4.44-264.40) level increased the risk of CKD, whereas high plasma PLP (OR = 0.98; 95% CI, 0.97-0.99) and superoxide dismutase activity (OR = 0.82; 95% CI, 0.74-0.91) decreased the risk of CKD after adjusting all potential confounders. CONCLUSION: High homocysteine, low PLP, increased oxidative stress, and decreased antioxidant enzyme activity (superoxide dismutase activity) were independent contributing factors in the development of early stage CKD. PMID- 26526965 TI - Immunologic and metabolic effects of high-refined carbohydrate-containing diet in food allergic mice. AB - OBJECTIVE: Allergic mice show a reduction in body weight and adiposity with a higher inflammatory response in the adipose tissue similar to obese fat tissue. This study aimed to evaluate whether the low-grade inflammatory milieu of mice with diet-induced mild obesity interferes with the allergic response induced by ovalbumin (OVA). METHODS: BALB/c mice were divided into four groups: 1) non allergic (OVA-) mice fed chow diet, 2) allergic (OVA+) mice fed chow diet, 3) OVA mice fed high-refined carbohydrate-containing (HC) diet, and 4) OVA+ mice fed HC diet. After 5 wk, allergic groups were sensitized with OVA and received a booster 14 d later. All groups received an oral OVA challenge 7 d after the booster. RESULTS: Allergic groups showed increased serum levels of total IgE, anti-OVA IgE, and IgG1; a high disease activity index score; aversion to OVA; and increased intestinal eosinophil infiltration. Non-allergic mild-obese mice also showed aversion to OVA and an increased number of eosinophils in the proximal jejunum. After the allergic challenge, OVA+ mice fed chow diet showed weight loss and lower adiposity in several adipose tissue depots. OVA+ mice fed HC diet showed a loss of fat mass only in the mesenteric adipose tissue. Furthermore, increased levels of TNF, IL-6, and IL-10 were observed in this tissue. CONCLUSIONS: Our data show that mild-obese allergic mice do not present severe pathologic features of food allergy similar to those exhibited by lean allergic mice. Mild obesity promoted by HC diet ingestion causes important intestinal disorders that appear to modulate the inflammatory response during the antigen challenge. PMID- 26526967 TI - Orofacial Pain. PMID- 26526966 TI - Testosterone Depletion Induces Demethylation of Murine Reelin Promoter CpG Dinucleotides: A Preliminary Study. AB - Schizophrenia (SZ) is a debilitating mental disorder characterized by psychotic events, abnormal social behavior, false beliefs, and auditory hallucinations. Hypermethylation of the promoter region of reelin (RELN), a gene involved in regulation of neuronal positioning during telencephalic development, is strongly associated with low protein expression in several cortical structures and promoter hypermethylation in brain from postmortem SZ subjects. Recent experimental data suggests that testosterone is able to promote RELN demethylation, although no direct evidence of hormonal influence on reelin promoter methylation was obtained. We investigated if reduced levels of plasma testosterone in adult male mice lead to Reln promoter demethylation. Animals were administered with flutamide, an antiandrogenic compound, and reelin promoter methylation was assessed using methylationspecific PCR using bisulfite DNA from cerebellum. We found that flutamide was able to significantly lower plasma testosterone when compared to control mice, and treatment did not influence animal survival and body weight. We also show that low plasma testosterone was associated with demethylation of a cytosine residue located at -860 in reelin promoter region. These preliminary data suggest that androgenic hormones can influence cerebral reelin demethylation. To our knowledge, this is the first experimental approach directly linking testosterone depletion and RELN promoter methylation. PMID- 26526968 TI - A family caregiver's relaxation enhances the gastric motility function of the patient: a crossover study. AB - BACKGROUND: The primary purpose of this study was to assess the effect of a caregiver's relaxation on the gastric motility function of the patient. The secondary purpose was to evaluate changes in the caregiver's willingness to perform self-care following feedback on the results of the primary purpose. METHODS: Subjects were 26 patients with a decreased level of consciousness who received gastrostomy tube feeding and their 26 family caregivers. We compared the patient's gastric motility under the condition of having his or her hand held with and without caregiver relaxation (crossover study). Changes in the caregiver's willingness to perform self-care following feedback on the results was evaluated using self-administered questionnaires. Hypnosis was used for relaxation. The outcomes assessed for gastric motility function were the motility index and gastric emptying rate by ultrasonography examination. RESULTS: Hand holding by the family caregiver while he or she was receiving relaxation enhanced the patient's gastric motility function. By giving feedback on the results, the caregiver's willingness to adopt self-care was increased and his or her sense of guilt was reduced. CONCLUSIONS: This study suggested that a caregiver's relaxation increases the gastric motility function of the patient and that gettinng feedback including the positive results increases the caregiver's willingness to perform self-care, which consequently reduce the caregiver burden. PMID- 26526969 TI - Comparative effect of gold nanorods and nanocages for prostate tumor hyperthermia. AB - Gold nanoparticles have been investigated as photothermal agents, drug delivery carriers, diagnostics, and theranostics. As long-term accumulation of nanoparticles in nontarget tissues is a growing concern, it is vital to establish biodistribution profiles, tumor uptake, and tissue residence times for each nano based system. This study aimed to investigate the prostate tumor uptake, photothermal therapy mediated macromolecular delivery, acute and chronic biodistribution profiles, and organ residence time differences between two nanoparticles, i.e., gold nanocages and gold nanorods. These particles have tunable surface plasmon resonances in the near infrared, but dissimilar shapes. Gold nanocages and nanorods had very different light to heat transduction efficiencies, with gold nanocages requiring 18.4 times fewer particles and approximately half the gold mass of gold nanorods to achieve the same heating profile given a constant laser intensity. It was also observed that while the photothermal macromolecular delivery enhancements were similar for the two systems when dosed by optical density, the tumoral uptake and biodistribution profiles for each of these shapes differed, with the nanocages residing in the liver, kidneys and spleen for less time than the nanorods. Additionally, it was observed that the nanocages were excreted from the body at a higher percentage of injected dose than the nanorods at both the 7 and 28 day time points. These findings have implications for the use of these constructs in diagnostic and therapeutic applications. PMID- 26526970 TI - Development of a novel cyclic RGD peptide for multiple targeting approaches of liposomes to tumor region. AB - Liposomes containing cytotoxic agents and targeted with Arg-Gly-Asp based peptides have frequently been used against alphavbeta3 integrin on tumor neovasculature. However, like many other ligand modified liposomes these preparations suffered from enhanced uptake by the reticulo endothelial system (RES) and off-targeted interaction with integrin receptors vastly expressed in normal organs causing poor biodistribution and toxic effects. Here we mainly focus on development of a RGD-modified liposomal delivery system to enhance both targeting selectivity and tumor uptake. First, sterically stabilized liposomal doxorubicin (SSLD) prepared and decorated with cRGDfK and RGDyC peptides differ in their physical properties. Stability assessments as well as in vitro and in vivo studies revealed that increasing the peptide hydrophobicity promotes the therapeutic efficacy of RGD-SSLD in a C-26 tumor model due to decreased recognition by RES and opsonization and limited off-targeted interactions. Then a novel N-methylated RGD peptide was designed and its capability in targeting integrin presenting cells was comprehensively assessed both in vitro and in vivo. RGDf[N-methyl]C promotes the liposome internalization by HUVEC via integrin mediated endocytosis. Intravital microscopy in window chamber bearing mice illustrated the capability of RGDf[N-methyl]C-liposomes in targeting both tumor vasculature and tumor cells in murine B16F0 and human BLM tumor models. Quantitative biodistribution in mice bearing B16F0 tumor revealed its high affinity to tumor with no considerable affinity to normal organs. Treatment by high dose of RGDf[N-methyl]C-SSLD was found more effective than non-targeted SSLD and no toxic side effect was observed. In conclusion, the RGDf[N-methyl]C liposome was found promising in targeting tumor vasculature as well as other cells inside the tumor. PMID- 26526971 TI - A noninterventional study evaluating the effectiveness and safety of lacosamide added to monotherapy in patients with epilepsy with partial-onset seizures in daily clinical practice: The VITOBA study. AB - OBJECTIVE: Evidence for the efficacy and safety of adjunctive lacosamide in the treatment of partial-onset seizures (POS) was gained during placebo-controlled clinical trials in patients with treatment-resistant seizures who were taking one to three concomitant antiepileptic drugs (AEDs). The VITOBA study (NCT01098162) evaluated the effectiveness and tolerability of adjunctive lacosamide added to one baseline AED in real-world clinical practice. METHODS: We conducted a 6-month observational study at 112 sites across Germany. Adult patients (>= 16 years) with POS received lacosamide adjunctive to only one baseline AED. Seizure frequency reduction at the end of the observation period was compared with a 3 month retrospective baseline period. RESULTS: Five hundred seventy-one patients received lacosamide at least once (Safety Set [SS]); 520 provided evaluable seizure records (Full Analysis Set [FAS]); and 499 took in-label dosages of lacosamide (up to 400 mg) and were evaluated for effectiveness (modified FAS). Median baseline seizure frequency was 2.0 per 28 days: 47.1% of patients (235/499, mFAS) took a concomitant sodium channel-blocking (SCB) AED; 38.1% (190/499) had only one lifetime AED; and 18.4% (92/499) were aged >= 65 years (mFAS). At the final visit, 72.5% (358/494) of patients showed a >= 50% reduction in seizure frequency from baseline, 63.8% (315/494) showed a >= 75% reduction, and 45.5% (225/494) were seizure-free. Seizure freedom rates were higher in patients aged >= 65 years (56.7%) compared with patients aged <65 years (43.1%), in patients with <= 5 years epilepsy duration (52.5%) versus >5 years duration (41.0%), and when added to first monotherapy (60.5%) rather than as a later therapy option. Treatment-emergent adverse events (TEAEs) were reported by 48.5% (277/571) of patients (SS), with a profile similar to that observed in pivotal trials; 466 of patients (81.6%, SS) continued lacosamide therapy after the trial. SIGNIFICANCE: These results suggest that lacosamide use, added to one concomitant AED, was effective at improving seizure control and was well tolerated in patients treated in routine clinical practice. PMID- 26526973 TI - Mixed-linker solid solutions of functionalized pillared-layer MOFs - adjusting structural flexibility, gas sorption, and thermal responsiveness. AB - Flexible metal-organic frameworks (MOFs) can undergo fascinating structural transitions triggered by external stimuli, such as adsorption/desorption of specific guest molecules or temperature changes. In this detailed study we investigate the potentials and limitations of tuning framework flexibility systematically by exploiting the powerful concept of mixed-linker solid solutions. We chose the prototypical family of functionalized pillared-layer MOFs of the general type Zn2(fu(1)-bdc)2x(fu(2)-bdc)(2-2x)dabco (with x = 1.00, 0.75, 0.50, 0.25 and 0.00; fu-bdc = 2,5-dialkoxy-1,4-benzenedicarboxylate with varying alkoxy chain length, dabco = 1,4-diazabicyclo[2.2.2]octane) and examined their guest responsive, as well as intrinsic temperature dependent structural flexibility by X-ray diffraction, gas physisorption and calorimetric measurements. The ratio of the different fu-bdc linkers can be adjusted freely, offering opportunity for a targeted design of these functional materials by modulating their key features, such as magnitude of framework contraction upon guest removal, breathing behaviour upon CO2 adsorption/desorption, thermoresponsive phase behaviour, and their general thermal expansivity, by the careful choice of fu-bdc linkers and their combination. PMID- 26526972 TI - Bringing CLARITY to the human brain: visualization of Lewy pathology in three dimensions. AB - AIMS: CLARITY is a novel technique which enables three-dimensional visualization of immunostained tissue for the study of circuitry and spatial interactions between cells and molecules in the brain. In this study, we aimed to compare methodological differences in the application of CLARITY between rodent and large human post mortem brain samples. In addition, we aimed to investigate if this technique could be used to visualize Lewy pathology in a post mortem Parkinson's brain. METHODS: Rodent and human brain samples were clarified and immunostained using the passive version of the CLARITY technique. Samples were then immersed in different refractive index matching media before mounting and visualizing under a confocal microscope. RESULTS: We found that tissue clearing speed using passive CLARITY differs according to species (human vs. rodents), brain region and degree of fixation (fresh vs. formalin-fixed tissues). Furthermore, there were advantages to using specific refractive index matching media. We have applied this technique and have successfully visualized Lewy body inclusions in three dimensions within the nucleus basalis of Meynert, and the spatial relationship between monoaminergic fibres and Lewy pathologies among nigrostriatal fibres in the midbrain without the need for physical serial sectioning of brain tissue. CONCLUSIONS: The effective use of CLARITY on large samples of human tissue opens up many potential avenues for detailed pathological and morphological studies. PMID- 26526974 TI - Tobacco Use Is Associated With Increased Complications After Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: The use of tobacco is a well-established cause of preventable morbidity and mortality. There have been few studies examining the effect of tobacco use on outcomes and complications after arthroscopic knee procedures such as anterior cruciate ligament (ACL) reconstruction. PURPOSE: To investigate the relationship between tobacco use and rates of postoperative infection, venous thromboembolism (VTE), arthrofibrosis, and subsequent ACL reconstruction after primary ACL reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A national insurance database was queried for patients who underwent arthroscopic-assisted ACL reconstruction using Current Procedural Terminology code 29888. Patients underage for tobacco use in all regions of the United States (age <20 years), those with prior ACL reconstruction, and those with the following concomitant procedures were excluded: open cruciate or collateral ligament reconstruction, open or arthroscopic cartilage procedures, patellar stabilization, extra-articular ligamentous reconstruction, and posterior cruciate ligament reconstruction. Tobacco use and non-tobacco use cohorts were queried using International Classification of Diseases-9th Revision coding. The non tobacco use patients were then matched to the patients with coded tobacco use by age, sex, obesity, diabetes, meniscal repair, and meniscectomy. Complications within 90 days postoperatively were assessed for both cohorts, including infection, VTE, arthrofibrosis, and subsequent ipsilateral or contralateral ACL reconstruction after the index procedure. RESULTS: A total of 13,358 patients who underwent ACL reconstruction met inclusion and exclusion criteria, including 1659 patients with documented tobacco use and 11,699 matched controls. The incidence of infection was significantly higher in patients who use tobacco (2.0%) versus matched controls (0.9%; odds ratio [OR], 2.3; P < .0001). The rate of VTE was also significantly higher in patients who use tobacco (1.0%) compared with matched controls (0.5%; OR, 1.9; P = .035). The rate of subsequent ACL reconstruction was significantly higher in the tobacco use cohort (12.6%) compared with matched controls (7.8%; OR, 1.7; P < .0001). There was no significant difference in the rate of postoperative stiffness after ACL reconstruction between patients who use tobacco (2.0%) and matched controls (2.3%; OR, 0.9; P = .656). CONCLUSION: ACL reconstruction in patients who use tobacco is associated with significantly increased rates of infection, VTE, and subsequent ACL reconstruction compared with controls. There was no association between tobacco use and postoperative arthrofibrosis after primary ACL reconstruction. PMID- 26526975 TI - Glycated nail proteins as a new biomarker in management of the South Kivu Congolese diabetics. AB - INTRODUCTION: Diagnosis and monitoring of diabetes mellitus in sub-Saharan Africa, based on blood analyses, are hampered by infrastructural and cultural reasons. The first aim of this study was to evaluate the diagnostic accuracy of glycated nail proteins for diabetes mellitus. The second aim was to compare the course of short- and long-term glycemic biomarkers after 6 months of antidiabetic treatment. These objectives should support our hypothesis that glycated nail proteins could be used as an alternative glycemic biomarker. MATERIALS AND METHODS: This case-control study consisted of 163 black diabetics and 67 non diabetics of the South Kivu (Democratic Republic of Congo). Diagnostic accuracy of glycated nail proteins was evaluated using ROC curve analysis. At the start of the study, glycated nail protein concentrations were compared between diabetics and non-diabetics, using a nitro blue tetrazolium (NBT) colorimetric method. In a subgroup of 30 diabetics, concentrations of glycated nail proteins, fasting glucose (Accu-Chek(r) Aviva), serum fructosamine (NBT) and HbA1c (DCA-2000+(r)) were measured at start and after 6 months. RESULTS: ROC analysis yielded an AUC of 0.71 (95% confidence interval (CI): 0.65-0.76) and a cut-off point of 3.83 MUmol/g nail. Concentration of glycated nail proteins was significantly higher (P<0.001) in diabetics in comparison with non-diabetics. After 6 months of antidiabetic treatment, a significant drop in the fasting glucose concentration (P=0.017) and concentration of glycated nail proteins (P=0.008) was observed in contrast to serum fructosamine and HbA1c. CONCLUSIONS: Measurement of glycated nail proteins could be used to diagnose and monitor diabetes mellitus in sub Saharan Africa. PMID- 26526976 TI - Transcutaneous Electrical Nerve Stimulation: Mechanisms, Clinical Application and Evidence. AB - Transcutaneous electrical nerve stimulation (TENS) is a non-invasive, inexpensive, self-administered technique to relieve pain.There are few side effects and no potential for overdose so patients can titrate the treatment as required.TENS techniques include conventional TENS, acupuncture-like TENS and intense TENS. In general, conventional TENS is used in the first instance.The purpose of conventional TENS is to selectively activate large diameter non noxious afferents (A-beta) to reduce nociceptor cell activity and sensitization at a segmental level in the central nervous system.Pain relief with conventional TENS is rapid in onset and offset and is maximal when the patient experiences a strong but non-painful paraesthesia beneath the electrodes. Therefore, patients may need to administer TENS throughout the day.Clinical experience suggests that TENS may be beneficial as an adjunct to pharmacotherapy for acute pain although systematic reviews are conflicting. Clinical experience and systematic reviews suggest that TENS is beneficial for chronic pain. PMID- 26526977 TI - Comparison and analysis of the prevalence of hepatitis C virus infection by region in the Republic of Korea during 2005-2012. AB - BACKGROUND/AIMS: This study compared the prevalence of hepatitis C virus (HCV) infection in the Republic of Korea and estimated the high-risk regions and towns. METHODS: National Health Insurance Service data for 8 years from 2005 to 2012 were used. The subjects of the study had visited medical facilities and been diagnosed with or received treatment for acute or chronic HCV as a primary or secondary disease according to ICD-10 codes of B17.1 or B18.2, respectively. Any patient who received treatment for the same disease multiple times during 1 year was counted as one patient in that year. To correct for the effect of the age structure of the population by year and region, the age-adjusted prevalence was calculated using the direct method based on the registered population in 2010. RESULTS: The overall prevalence of HCV infection among Korean adults (>20 years old) increased from 0.14% in 2005 to 0.18% in 2012. The sex-, age-, and region adjusted prevalence in 2012 was 0.18%. The prevalence was highest in Busan, Jeonnam, and Gyeongnam, and there were towns with noticeably higher prevalences within these regions: Jindo (0.97%) in Jeonnam, Namhae (0.90%) in Gyeongnam, and Seo-gu (0.86%) in Busan. CONCLUSIONS: The prevalence of HCV infection differs by regions as well as towns in the Republic of Korea, and is highest in Busan, Jeonnam, and Gyeongnam. The reasons for the high prevalence in these specific regions should be identified, since this could help prevent HCV infections in the future. In addition, active surveillance and treatment policies should be introduced to stop any further spread of infection in these high-prevalence regions. PMID- 26526978 TI - Severe bradycardia associated with suspension laryngoscopy. AB - Suspension laryngoscopy is one of the most common procedures performed for visualizing and diagnosing diseases of the larynx. A relatively uncommon yet potentially life-threatening complication is that of severe bradycardia or asystole during manipulation of the larynx. This case report highlights the occurrence of this complication during a routine removal of a true vocal fold lesion at a tertiary medical center and discusses the potential pathophysiological mechanisms and proposed management options for this phenomenon. PMID- 26526979 TI - Comprehensive review of several surfactants in marine environments: Fate and ecotoxicity. AB - Surfactants are a commercially important group of chemicals widely used on a global scale. Despite high removal efficiencies during wastewater treatment, their high consumption volumes mean that a certain fraction will always enter aquatic ecosystems, with marine environments being the ultimate sites of deposition. Consequently, surfactants have been detected within marine waters and sediments. However, aquatic environmental studies have mostly focused on the freshwater environment, and marine studies are considerably underrepresented by comparison. The present review aims to provide a summary of current marine environmental fate (monitoring, biodegradation, and bioconcentration) and effects data of 5 key surfactant groups: linear alkylbenzene sulfonates, alcohol ethoxysulfates, alkyl sulfates, alcohol ethoxylates, and ditallow dimethyl ammonium chloride. Monitoring data are currently limited, especially for alcohol ethoxysulfates and alkyl sulfates. Biodegradation was shown to be considerably slower under marine conditions, whereas ecotoxicity studies suggest that marine species are approximately equally as sensitive to these surfactants as freshwater species. Marine bioconcentration studies are almost nonexistent. Current gaps within the literature are presented, thereby highlighting research areas where additional marine studies should focus. PMID- 26526980 TI - Biotechnology in Environmental Monitoring and Pollution Abatement 2015. PMID- 26526981 TI - In vitro effects of somatostatin on the growth hormone-insulin-like growth factor axis in orange-spotted grouper (Epinephelus coioides). AB - Growth in vertebrates is mainly mediated by the growth hormone (GH)-insulin-like growth factor (IGF) axis, and somatostatin (SRIF) inhibits growth by decreasing GH release at the pituitary level and antagonizing the release and action of GHRH in the hypothalamus. However, the effects of SRIF on the regulation of growth at levels other than GH release from the pituitary gland are less well known. In the present study, we comprehensively examined the pituitary and peripheral actions of SRIF on the GH-IGF axis in grouper using a primary pituitary and hepatocyte cell culture system. Our results showed that SRIF inhibited GH release at the pituitary level, but had no influence on GH mRNA expression. Basal hepatic GH receptor 1 (GHR1), IGF-I and IGF-II mRNA levels declined over time, whereas GHR2 mRNA levels remained stable throughout the culture period. GH stimulated the hepatic expression of GHR and IGF mRNAs in a dose-dependent manner, while SRIF suppressed both basal and GH-stimulated expression of GHR and IGF mRNAs in primary cultured hepatocytes. The inhibition of GHR and IGF mRNA levels by SRIF was not attributed to the rate of mRNA degradation. To the best of our knowledge, we demonstrated the effects of SRIF on basal and GH-stimulated IGF-II mRNA levels in teleosts for the first time. These results indicate that SRIF regulates growth at the level of the pituitary and peripheral liver. PMID- 26526982 TI - Modulation of expression of 17-Hydroxylase/17,20 lyase (CYP17) and P450 aromatase (CYP19) by inhibition of MEK1 in a human ovarian granulosa-like tumor cell line. AB - The differential steroid production in the theca and granulosa cells in ovary are resulted from unique enzyme expression profiles. Among them, c-fos, a downstream target of mitogen and extracellular signal-regulated kinases (MEK/ERK) signaling, takes part in this compartment. In this study, we investigated the effect of c fos on the steady-state levels of CYP17 and CYP19 in human ovarian granulosa-like tumor cell line (KGN) by inhibiting MEK/ERK pathway with PD98059. As a result, our finding demonstrated the distinct distribution patterns of CYP17 and CYP19 in KGN. Moreover, the MEK/ERK pathway functions to inhibit the production of CYP17, while enhance the production of CYP19 in granulosa cells, probably involving a c fos-dependent mechanism. In conclusion, factors such as c-fos may play a crucial role in the down-regulation of CYP17 and up-regulation of CYP19 in granulosa cells, thereby suppressing androstenedione synthesis. PMID- 26526983 TI - The pharmacokinetics and safety of idelalisib in subjects with severe renal impairment. AB - PURPOSE: Idelalisib is a novel, potent inhibitor of phosphatidylinositol 3-kinase delta (PI3Kdelta), which is prominently expressed in cells of hematopoietic origin. Renal excretion plays a minor role in elimination of idelalisib in humans (~15 % of the dose is excreted in urine). This study evaluated the pharmacokinetics (PK) and safety of idelalisib and GS-563117 (its inactive primary metabolite) in subjects with severe renal impairment and healthy subjects. METHODS: Subjects with severe renal impairment were matched in age, sex, and body mass index with healthy subjects who had normal renal function. Each subject received a single oral dose of idelalisib at 150 mg, and safety assessments and PK analyses were performed. RESULTS: Compared with healthy subjects, the geometric least-squares mean ratio of area under the concentration time curve from zero to last PK observation (AUC(last)), area under the concentration-time curve from zero to infinity (AUC(inf)), and maximum observed plasma concentration (C(max)) were 127, 127, and 105 % for idelalisib and 124, 124, and 96 % for GS-563117, respectively, in subjects with severe renal impairment. CONCLUSIONS: There were no clinically relevant changes of idelalisib or GS-563117 PK in subjects with severe renal impairment versus matched healthy controls. No relevant relationships were identified between idelalisib or GS 563117 exposures and baseline creatinine clearance. Idelalisib dosing was generally well tolerated with most treatment-emergent adverse events and laboratory abnormalities assessed as grade 1 or 2 in severity. Accordingly, dose adjustments for idelalisib are not necessary in subjects with mild, moderate, or severe renal impairment. PMID- 26526984 TI - Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors. AB - PURPOSE: Inhibition of transforming growth factor-beta receptor I (TGF-beta RI) mediated signaling pathways blocks tumor growth and metastases in nonclinical studies. Galunisertib (LY2157299), a small molecule inhibitor of TGF-beta RI serine/threonine kinase, had antitumor effects with acceptable safety/tolerability in a first-in-human dose (FHD) study conducted mainly in Caucasian patients with glioma. In this nonrandomized, open-label, dose escalation study, we assessed safety/tolerability, pharmacokinetics (PK), and tumor response in Japanese patients. METHODS: Patients with advanced and/or metastatic disease refractory were assigned sequentially to Cohort-1 (80 mg) or Cohort-2 (150 mg) of galunisertib, administered twice daily and treated using 2 week on, 2-week off treatment cycles. Dose escalation was guided by predefined PK criteria and dose-limiting toxicities (DLT). Safety assessments included treatment-emergent adverse events (TEAEs) and cardiac safety (ultrasound cardiography/Doppler imaging, electrocardiogram, chest computed tomography, and cardiotoxicity serum biomarkers). RESULTS: Twelve patients (Cohort-1, n = 3; Cohort-2, n = 9) were enrolled and the most common types of cancer were pancreatic (n = 5) and lung cancer (n = 3). Seven patients (Cohort-1, n = 2; Cohort-2, n = 5) experienced possibly galunisertib-related TEAEs. The most frequent related TEAEs were brain natriuretic peptide increased (n = 2), leukopenia (n = 2), and rash (n = 2). No cardiovascular toxicities or other DLTs were reported. PK profile of galunisertib was consistent with the FHD study. Maximum plasma concentration was reached within 2 h post-dose, and the mean elimination half-life was 9 h. CONCLUSIONS: Galunisertib had an acceptable tolerability and safety profile in Japanese patients with advanced cancers. CLINICATRIALS.GOV. IDENTIFIER: NCT01722825. PMID- 26526985 TI - Coincidence of tuberous sclerosis and systemic lupus erythematosus-a case report. AB - Tuberous sclerosis, also called Bourneville Pringle disease, is a phakomatosis with potential dermal, nerve, kidney and lung damage. It is characterized by the development of benign proliferations in many organs, which result in different clinical manifestations. It is associated with the mutation of two genes: TSC1 (hamartin) and TSC2 (tuberin), with the change in the functionality of the complex target of rapamycin (mTOR). MTOR activation signal has been recently described in systemic lupus erythematosus (SLE) and its inhibition could be beneficial in patients with lupus nephritis. We report the case of a patient who began with clinical manifestations of tuberous sclerosis complex (TSC) 30 years after the onset of SLE with severe renal disease (tipe IV nephritis) who improved after treatment with iv pulses of cyclophosphamide. We found only two similar cases in the literature, and hence considered the coexistence of these two entities of great interest. PMID- 26526986 TI - Efficacy of ruxolitinib on hepatomegaly in patients with myelofibrosis. PMID- 26526987 TI - Clinical value of molecular subtyping multiple myeloma using gene expression profiling. AB - Using a data set of 1217 patients with multiple myeloma enrolled in Total Therapies, we have examined the impact of novel therapies on molecular and risk subgroups and the clinical value of molecular classification. Bortezomib significantly improved the progression-free survival (PFS) and overall survival (OS) of the MMSET (MS) subgroup. Thalidomide and bortezomib positively impacted the PFS of low-risk (LoR) cases defined by the GEP70 signature, whereas high-risk (HiR) cases showed no significant changes in outcome. We show that molecular classification is important if response rates are to be used to predict outcomes. The t(11;14)-containing CD-1 and CD-2 subgroups showed clear differences in time to response and cumulative response rates but similar PFS and OS. Furthermore, complete remission was not significantly associated with the outcome of the MAF/MAFB (MF) subgroup or HiR cases. HiR cases were enriched in the MF, MS and proliferation subgroups, but the poor outcome of these groups was not linked to subgroup-specific characteristics such as MAF overexpression per se. It is especially important to define risk status if HiR cases are to be managed appropriately because of their aggressive clinical course, high rates of early relapse and the need to maintain therapeutic pressure on the clone. PMID- 26526989 TI - Uninterrupted Sedentary Behavior Downregulates BRCA1 Gene Expression. AB - BRCA1 mutation carriers face a high lifetime risk of developing breast cancer. Physical activity induces broad transcriptional changes, and multiple studies have documented its beneficial effects across cancers. Because haploinsufficiency predisposes to breast cancer in these women, factors that increase BRCA1 levels may mitigate the effect of the mutation. Whether physical activity modulates BRCA1 expression and whether lifestyle factors could benefit women with a mutation remain unclear. The objective of this study was to systematically evaluate whether physical activity or sedentary behavior affects BRCA1 mRNA expression. Activity levels were assessed in 50 female participants (14 BRCA1 mutation carriers and 36 noncarriers) using the GT3X Actigraph accelerometer, and BRCA1 mRNA expression was quantified from peripheral blood lymphocytes using the Nanostring nCounter Analysis System. There was a significant negative correlation between the longest sedentary bout and BRCA1 mRNA expression (rho = -0.32; P = 0.02). Women below the median for the longest sedentary bout had significantly higher BRCA1 mRNA levels compared with women above the median (161 vs. 132 counts; P = 0.04; one-sided Mann-Whitney U test). There was no significant relationship between mean metabolic equivalents of task rate or mean sedentary time and BRCA1 mRNA expression (Spearman correlation P >= 0.75; P >= 0.14; Mann Whitney U test). These findings suggest that prolonged periods of sedentary behavior are associated with significantly lower BRCA1 mRNA expression. Whether this translates into a potentially more harmful effect in BRCA1 mutation carriers warrants further investigation. PMID- 26526988 TI - Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells. AB - Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro. CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs. PMID- 26526990 TI - A Presurgical Study of Oral Silybin-Phosphatidylcholine in Patients with Early Breast Cancer. AB - Silybin-phosphatidylcholine is an orally bioavailable complex of silybin, a polyphenolic flavonolignan derived from milk thistle, endowed with potential anticancer activity in preclinical models. The purpose of this window of opportunity trial was to determine, for the first time in early breast cancer patients, the breast tissue distribution of silybin. Twelve breast cancer patients received silybin-phosphatidylcholine, 2.8 g daily for 4 weeks prior to surgery. Silybin levels were measured before (SIL) and after (TOT-SIL) enzymatic hydrolysis by high-performance liquid chromatography (HPLC)-MS/MS in biologic samples (plasma, urine, breast cancer, and surrounding normal tissue). Fasting blood samples were taken at baseline, before the last administration, and 2 hours later. All patients were fully compliant and completed the treatment program. No toxicity was observed. SIL and TOT-SIL were undetectable in baseline samples. Despite a high between-subject variability, repeated administration of Siliphos achieved levels of TOT-SIL of 31,121 to 7,654 ng/mL in the plasma and up to 1,375 ng/g in breast cancer tissue. SIL concentrations ranged from 10,861 to 1,818 ng/mL in plasma and up to 177 ng/g in breast cancer tissue. Median TOT-SIL concentration was higher in the tumor as compared with the adjacent normal tissue (P = 0.018). No significant change in either blood levels of IGF-I and nitric oxide or Ki-67 in tumors was noted. Silybin-phosphatidylcholine, taken orally, can deliver high blood concentrations of silybin, which selectively accumulates in breast tumor tissue. These findings provide the basis for a future phase II biomarker trial in breast cancer prevention. PMID- 26526991 TI - Re-examination of Dietary Amino Acid Sensing Reveals a GCN2-Independent Mechanism. AB - Animals cannot synthesize nine essential amino acids (EAAs) and must therefore obtain them from food. Mice reportedly reject food lacking a single EAA within the first hour of feeding. This remarkable phenomenon is proposed to involve post ingestive sensing of amino acid imbalance by the protein kinase GCN2 in the brain. Here, we systematically re-examine dietary amino acid sensing in mice. In contrast to previous results, we find that mice cannot rapidly identify threonine or leucine-deficient food in common feeding paradigms. However, mice attain the ability to identify EAA-deficient food following 2 days of EAA deprivation, suggesting a requirement for physiologic need. In addition, we report that mice can rapidly identify lysine-deficient food without prior EAA deficit, revealing a distinct sensing mechanism for this amino acid. These behaviors are independent of the proposed amino acid sensor GCN2, pointing to the existence of an undescribed mechanism for rapid sensing of dietary EAAs. PMID- 26526992 TI - MicroRNA-223 Regulates the Differentiation and Function of Intestinal Dendritic Cells and Macrophages by Targeting C/EBPbeta. AB - Dendritic cells (DCs) and macrophages play important roles in maintaining intestinal homeostasis. However, the molecular mechanisms that regulate the differentiation and responses of intestinal DCs and macrophages remain poorly understood. Here, we have identified microRNA miR-223 as a key molecule for regulating these processes. Deficiency of miR-223 led to a significantly decreased number of intestinal CX3CR1(hi) macrophages at steady state. Both intestinal CX3CR1(hi) macrophages and CD103(+) conventional DCs (cDCs) in miR-223 deficient mice exhibited a strong pro-inflammatory phenotype. Moreover, miR-223 deficient monocytes gave rise to more monocyte-derived DCs (moDCs) and produced more pro-inflammatory cytokines upon stimulation. Using a mouse model of colitis, we demonstrated that the miR-223 deficiency resulted in more severe colitis. Target gene analysis further identified that the effects of miR-223 on DCs and macrophages were mediated by directly targeting C/EBPbeta. Taken together, our study identifies a role for miR-223 as a critical regulator of intestinal homeostasis. PMID- 26526994 TI - Age-Associated Methylation Suppresses SPRY1, Leading to a Failure of Re quiescence and Loss of the Reserve Stem Cell Pool in Elderly Muscle. AB - The molecular mechanisms by which aging affects stem cell number and function are poorly understood. Murine data have implicated cellular senescence in the loss of muscle stem cells with aging. Here, using human cells and by carrying out experiments within a strictly pre-senescent division count, we demonstrate an impaired capacity for stem cell self-renewal in elderly muscle. We link aging to an increased methylation of the SPRY1 gene, a known regulator of muscle stem cell quiescence. Replenishment of the reserve cell pool was modulated experimentally by demethylation or siRNA knockdown of SPRY1. We propose that suppression of SPRY1 by age-associated methylation in humans inhibits the replenishment of the muscle stem cell pool, contributing to a decreased regenerative response in old age. We further show that aging does not affect muscle stem cell senescence in humans. PMID- 26526993 TI - Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus. AB - Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype. PMID- 26526995 TI - Rapid Modulation of Axon Initial Segment Length Influences Repetitive Spike Firing. AB - Neurons implement a variety of plasticity mechanisms to alter their function over timescales ranging from seconds to days. One powerful means of controlling excitability is to directly modulate the site of spike initiation, the axon initial segment (AIS). However, all plastic structural AIS changes reported thus far have been slow, involving days of neuronal activity perturbation. Here, we show that AIS plasticity can be induced much more rapidly. Just 3 hr of elevated activity significantly shortened the AIS of dentate granule cells in a calcineurin-dependent manner. The functional effects of rapid AIS shortening were offset by dephosphorylation of voltage-gated sodium channels, another calcineurin dependent mechanism. However, pharmacological separation of these phenomena revealed a significant relationship between AIS length and repetitive firing. The AIS can therefore undergo a rapid form of structural change over timescales that enable interactions with other forms of activity-dependent plasticity in the dynamic control of neuronal excitability. PMID- 26526997 TI - The Salivary Gland Acts as a Sink for Tissue-Resident Memory CD8(+) T Cells, Facilitating Protection from Local Cytomegalovirus Infection. AB - Tissue-resident memory T cells (TRM) reside in barrier tissues and provide local immediate protective immunity. Here, we show that the salivary gland (SG) most effectively induces CD8(+) and CD4(+) TRM cells against murine cytomegalovirus (MCMV), which persists in and spreads from this organ. TRM generation depended on local antigen for CD4(+), but not CD8(+), TRM cells, highlighting major differences in T cell subset-specific demands for TRM development. CMV-specific CD8(+) T cells fail to control virus replication upon primary infection in the SG due to CMV-induced MHC I downregulation in glandular epithelial cells. Using intraglandular infection, we challenge this notion and demonstrate that memory CD8(+) T cells confer immediate protection against locally introduced MCMV despite active viral immune evasion, owing to early viral tropism to cells that largely withstand MHC I downregulation. Thus, we unravel a yet-unappreciated role for memory CD8(+) T cells in protecting mucosal tissues against CMV infection. PMID- 26526996 TI - Murine CMV Infection Induces the Continuous Production of Mucosal Resident T Cells. AB - Cytomegalovirus (CMV) is a herpesvirus that persists for life and maintains extremely large numbers of T cells with select specificities in circulation. However, it is unknown how viral persistence impacts T cell populations in mucosal sites. We found that many murine (M)CMV-specific CD8s in mucosal tissues became resident memory T cells (TRM). These cells adopted an intraepithelial localization in the salivary gland that correlated with, but did not depend on, expression of the integrin CD103. MCMV-specific TRM cells formed early after infection, and spleen-localized cells had reduced capacities to become TRM at late times. Surprisingly, however, small numbers of new TRM cells were formed from the circulating pool throughout infection, favoring populations maintained at high levels in the blood and shifting the immunodominance within the TRM populations over time. These data show that mucosal TRM populations can be dynamically maintained by a persistent infection. PMID- 26526998 TI - Piezo1 in Smooth Muscle Cells Is Involved in Hypertension-Dependent Arterial Remodeling. AB - The mechanically activated non-selective cation channel Piezo1 is a determinant of vascular architecture during early development. Piezo1-deficient embryos die at midgestation with disorganized blood vessels. However, the role of stretch activated ion channels (SACs) in arterial smooth muscle cells in the adult remains unknown. Here, we show that Piezo1 is highly expressed in myocytes of small-diameter arteries and that smooth-muscle-specific Piezo1 deletion fully impairs SAC activity. While Piezo1 is dispensable for the arterial myogenic tone, it is involved in the structural remodeling of small arteries. Increased Piezo1 opening has a trophic effect on resistance arteries, influencing both diameter and wall thickness in hypertension. Piezo1 mediates a rise in cytosolic calcium and stimulates activity of transglutaminases, cross-linking enzymes required for the remodeling of small arteries. In conclusion, we have established the connection between an early mechanosensitive process, involving Piezo1 in smooth muscle cells, and a clinically relevant arterial remodeling. PMID- 26526999 TI - Apical versus Basal Neurogenesis Directs Cortical Interneuron Subclass Fate. AB - Fate determination in the mammalian telencephalon, with its diversity of neuronal subtypes and relevance to neuropsychiatric disease, remains a critical area of study in neuroscience. Most studies investigating this topic focus on the diversity of neural progenitors within spatial and temporal domains along the lateral ventricles. Often overlooked is whether the location of neurogenesis within a fate-restricted domain is associated with, or instructive for, distinct neuronal fates. Here, we use in vivo fate mapping and the manipulation of neurogenic location to demonstrate that apical versus basal neurogenesis influences the fate determination of major subgroups of cortical interneurons derived from the subcortical telencephalon. Somatostatin-expressing interneurons arise mainly from apical divisions along the ventricular surface, whereas parvalbumin-expressing interneurons originate predominantly from basal divisions in the subventricular zone. As manipulations that shift neurogenic location alter interneuron subclass fate, these results add an additional dimension to the spatial-temporal determinants of neuronal fate determination. PMID- 26527001 TI - APOBEC-Induced Cancer Mutations Are Uniquely Enriched in Early-Replicating, Gene Dense, and Active Chromatin Regions. AB - An antiviral component of the human innate immune system-the APOBEC cytidine deaminases-was recently identified as a prominent source of mutations in cancers. Here, we investigated the distribution of APOBEC-induced mutations across the genomes of 119 breast and 24 lung cancer samples. While the rate of most mutations is known to be elevated in late-replicating regions that are characterized by reduced chromatin accessibility and low gene density, we observed a marked enrichment of APOBEC mutations in early-replicating regions. This unusual mutagenesis profile may be associated with a higher propensity to form single-strand DNA substrates for APOBEC enzymes in early-replicating regions and should be accounted for in statistical analyses of cancer genome mutation catalogs aimed at understanding the mechanisms of carcinogenesis as well as highlighting genes that are significantly mutated in cancer. PMID- 26527000 TI - Dorsal Horn Parvalbumin Neurons Are Gate-Keepers of Touch-Evoked Pain after Nerve Injury. AB - Neuropathic pain is a chronic debilitating disease that results from nerve damage, persists long after the injury has subsided, and is characterized by spontaneous pain and mechanical hypersensitivity. Although loss of inhibitory tone in the dorsal horn of the spinal cord is a major contributor to neuropathic pain, the molecular and cellular mechanisms underlying this disinhibition are unclear. Here, we combined pharmacogenetic activation and selective ablation approaches in mice to define the contribution of spinal cord parvalbumin (PV) expressing inhibitory interneurons in naive and neuropathic pain conditions. Ablating PV neurons in naive mice produce neuropathic pain-like mechanical allodynia via disinhibition of PKCgamma excitatory interneurons. Conversely, activating PV neurons in nerve-injured mice alleviates mechanical hypersensitivity. These findings indicate that PV interneurons are modality specific filters that gate mechanical but not thermal inputs to the dorsal horn and that increasing PV interneuron activity can ameliorate the mechanical hypersensitivity that develops following nerve injury. PMID- 26527002 TI - The Crystal Structure of the NHL Domain in Complex with RNA Reveals the Molecular Basis of Drosophila Brain-Tumor-Mediated Gene Regulation. AB - TRIM-NHL proteins are conserved among metazoans and control cell fate decisions in various stem cell linages. The Drosophila TRIM-NHL protein Brain tumor (Brat) directs differentiation of neuronal stem cells by suppressing self-renewal factors. Brat is an RNA-binding protein and functions as a translational repressor. However, it is unknown which RNAs Brat regulates and how RNA-binding specificity is achieved. Using RNA immunoprecipitation and RNAcompete, we identify Brat-bound mRNAs in Drosophila embryos and define consensus binding motifs for Brat as well as a number of additional TRIM-NHL proteins, indicating that TRIM-NHL proteins are conserved, sequence-specific RNA-binding proteins. We demonstrate that Brat-mediated repression and direct RNA-binding depend on the identified motif and show that binding of the localization factor Miranda to the Brat-NHL domain inhibits Brat activity. Finally, to unravel the sequence specificity of the NHL domain, we crystallize the Brat-NHL domain in complex with RNA and present a high-resolution protein-RNA structure of this fold. PMID- 26527003 TI - Sorting of Dendritic and Axonal Vesicles at the Pre-axonal Exclusion Zone. AB - Polarized sorting of newly synthesized proteins to the somatodendritic and axonal domains of neurons occurs by selective incorporation into distinct populations of vesicular transport carriers. An unresolved issue is how the vesicles themselves are sorted to their corresponding neuronal domains. Previous studies concluded that the axon initial segment (AIS) is an actin-based filter that selectively prevents passage of somatodendritic vesicles into the axon. We find, however, that most somatodendritic vesicles fail to enter the axon at a more proximal region in the axon hillock, herein referred to as the pre-axonal exclusion zone (PAEZ). Forced coupling of a somatodendritic cargo protein to an axonally directed kinesin is sufficient to drive transport of whole somatodendritic vesicles through the PAEZ toward the distal axon. Based on these findings, we propose that polarized sorting of transport vesicles occurs at the PAEZ and depends on the ability of the vesicles to acquire an appropriately directed microtubule motor. PMID- 26527004 TI - Rhythmic Working Memory Activation in the Human Hippocampus. AB - Working memory (WM) maintenance is assumed to rely on a single sustained process throughout the entire maintenance period. This assumption, although fundamental, has never been tested. We used intracranial electroencephalography (EEG) recordings from the human hippocampus in two independent experiments to investigate the neural dynamics underlying WM maintenance. We observed periodic fluctuations between two different oscillatory regimes: Periods of "memory activation" were reflected by load-dependent alpha power reductions and lower levels of cross-frequency coupling (CFC). They occurred interleaved with periods characterized by load-independent high levels of alpha power and CFC. During memory activation periods, a relevant CFC parameter (load-dependent changes of the peak modulated frequency) correlated with individual WM capacity. Fluctuations between these two periods predicted successful performance and were locked to the phase of endogenous delta oscillations. These results show that hippocampal maintenance is a dynamic rather than constant process and depends critically on a hierarchy of oscillations. PMID- 26527005 TI - SPOP E3 Ubiquitin Ligase Adaptor Promotes Cellular Senescence by Degrading the SENP7 deSUMOylase. AB - The SPOP gene, which encodes an E3 ubiquitin ligase adaptor, is frequently mutated in a number of cancer types. However, the mechanisms by which SPOP functions as a tumor suppressor remain poorly understood. Here, we show that SPOP promotes senescence, an important tumor suppression mechanism, by targeting the SENP7 deSUMOylase for degradation. SPOP is upregulated during senescence. This correlates with ubiquitin-mediated degradation of SENP7, which promotes senescence by increasing HP1alpha sumoylation and the associated epigenetic gene silencing. Ectopic wild-type SPOP, but not its cancer-associated mutants, drives senescence. Conversely, SPOP knockdown overcomes senescence. These phenotypes correlate with ubiquitination and degradation of SENP7 and HP1alpha sumoylation, subcellular re-localization, and its associated gene silencing. Furthermore, SENP7 is expressed at higher levels in prostate tumor specimens with SPOP mutation (n = 13) compared to those with wild-type SPOP (n = 80). In summary, SPOP acts as a tumor suppressor by promoting senescence through degrading SENP7. PMID- 26527006 TI - TRIM28 Controls Genomic Imprinting through Distinct Mechanisms during and after Early Genome-wide Reprogramming. AB - Genomic imprinting depends on the establishment and maintenance of DNA methylation at imprinting control regions. However, the mechanisms by which these heritable marks influence allele-specific expression are not fully understood. By analyzing maternal, zygotic, maternal-zygotic, and conditional Trim28 mutants, we found that the transcription factor TRIM28 controls genomic imprinting through distinct mechanisms at different developmental stages. During early genome-wide reprogramming, both maternal and zygotic TRIM28 are required for the maintenance of methylation at germline imprints. However, in conditional Trim28 mutants, Gtl2 imprinted gene expression was lost despite normal methylation levels at the germline IG-DMR. These results provide evidence that TRIM28 controls imprinting after early embryonic reprogramming through a mechanism other than the maintenance of germline imprints. Additionally, our finding that secondary imprints were hypomethylated in TRIM28 mutants uncovers a requirement of TRIM28 after genome-wide reprogramming for interpreting germline imprints and regulating DNA methylation at imprinted gene promoters. PMID- 26527007 TI - Transcriptomics Identify CD9 as a Marker of Murine IL-10-Competent Regulatory B Cells. AB - Regulatory B cells (Breg) have immune suppressive functions in various autoimmune/inflammation models and diseases and are found to be enriched in diverse B cell subsets. The lack of a unique marker or set of markers efficiently identifying Breg cells impedes detailed investigation into their origin, development, and immunological roles. Here, we perform transcriptome analysis of IL-10-expressing B cells to identify key regulators for Breg biogenesis and function and identify CD9, a tetraspanin-family transmembrane protein, as a key surface marker for most mouse IL-10(+) B cells and their progenitors. CD9 plays a role in the suppressive function of IL-10(+) B cells in ex vivo T cell proliferation assays through a mechanism that is dependent upon B/T cell interactions. CD9(+) B cells also demonstrate inhibition of Th1-mediated contact hypersensitivity in an in vivo model system. Taken together, our findings implicate CD9 in the immunosuppressive activity of regulatory B cells. PMID- 26527008 TI - A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control. AB - Control of chronic viral infections by CD8 T cells is critically dependent on CD4 help. In particular, helper-derived IL-21 plays a key role in sustaining the CD8 T cell response; however, the molecular pathways by which IL-21 sustains CD8 T cell immunity remain unclear. We demonstrate that IL-21 causes a phenotypic switch of transcription factor expression in CD8 T cells during chronic viral infection characterized by sustained BATF expression. Importantly, BATF expression during chronic infection is both required for optimal CD8 T cell persistence and anti-viral effector function and sufficient to rescue "unhelped" CD8 T cells. Mechanistically, BATF sustains the response by cooperating with IRF4, an antigen-induced transcription factor that is also critically required for CD8 T cell maintenance, to preserve Blimp-1 expression and thereby sustain CD8 T cell effector function. Collectively, these data suggest that CD4 T cells "help" the CD8 response during chronic infection via IL-21-induced BATF expression. PMID- 26527009 TI - Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF kappaB and Interferon Signaling: Implications for Paget's Disease. AB - Paget's disease of bone (PDB) is a common disease characterized by osteoclast activation that leads to various skeletal complications. Susceptibility to PDB is mediated by a common variant at the optineurin (OPTN) locus, which is associated with reduced levels of mRNA. However, it is unclear how this leads to the development of PDB. Here, we show that OPTN acts as a negative regulator of osteoclast differentiation in vitro and that mice with a loss-of-function mutation in Optn have increased osteoclast activity and bone turnover. Osteoclasts derived from Optn mutant mice have an increase in NF-kappaB activation and a reduction in interferon beta expression in response to RANKL when compared to wild-type mice. These studies identify OPTN as a regulator of bone resorption and are consistent with a model whereby genetically determined reductions in OPTN expression predispose to PDB by enhancing osteoclast differentiation. PMID- 26527011 TI - [Exploration of breast inflammation excluding pregnancy and breastfeeding: Guidelines]. AB - Breast inflammation, excluding breast-feeding and pregnancy, is a rare breast pathology. We conducted a PubMed database search of all studies focusing on mastitis or breast inflammation exploration. While the most frequent aetiologies are infectious and inflammatory, inflammatory breast cancer can be diagnosed (LE2). Aetiologic diagnostic is difficult due to the absence of any clinical and imaging specific signs (LE3). The presence of mass, suspect lymph nodes or skin thickening in a woman older than 40 years old should orient toward inflammatory breast cancer (LE3). A suspect lesion must lead to perform a biopsy under sonography (grade A). In the absence of evidence for a malignant pathology after initial evaluation, we recommend starting an antibiotic treatment (grade C) with a clinical follow-up at the end of the treatment (grade B). If the symptoms persist, we recommend a new imaging (+/- MRI) (grade C) and a biopsy (grade C). Benign inflammatory pathologies may require a biopsy to exclude an inflammatory breast cancer and precise the diagnosis. Their specific management and treatment are presented in detail in the following chapters and may involve steroids. PMID- 26527010 TI - Origin of a Non-Clarke's Column Division of the Dorsal Spinocerebellar Tract and the Role of Caudal Proprioceptive Neurons in Motor Function. AB - Proprioception, the sense of limb and body position, is essential for generating proper movement. Unconscious proprioceptive information travels through cerebellar-projecting neurons in the spinal cord and medulla. The progenitor domain defined by the basic-helix-loop-helix (bHLH) transcription factor, ATOH1, has been implicated in forming these cerebellar-projecting neurons; however, their precise contribution to proprioceptive tracts and motor behavior is unknown. Significantly, we demonstrate that Atoh1-lineage neurons in the spinal cord reside outside Clarke's column (CC), a main contributor of neurons relaying hindlimb proprioception, despite giving rise to the anatomical and functional correlate of CC in the medulla, the external cuneate nucleus (ECu), which mediates forelimb proprioception. Elimination of caudal Atoh1-lineages results in mice with relatively normal locomotion but unable to perform coordinated motor tasks. Altogether, we reveal that proprioceptive nuclei in the spinal cord and medulla develop from more than one progenitor source, suggesting an avenue to uncover distinct proprioceptive functions. PMID- 26527012 TI - [Epidemiology of shoulder dystocia]. AB - OBJECTIVES: To synthetize the available evidence regarding the incidence and risk factors of shoulder dystocia (SD). METHODS: Consultation of the Medline database, and of national guidelines. RESULTS: Shoulder dystocia is defined as a vaginal delivery that requires additional obstetric manoeuvres to deliver the foetus after the head has delivered and gentle traction has failed. With this definition, the incidence of SD in population-based studies is about 0.5-1% of vaginal deliveries. Many risk factors have been described but most associations are not independent, or have not been constantly found. The 2 characteristics consistently found as independent risk factors for SD in the literature are previous SD (incidence of SD of about 10% in parturients with previous SD) and foetal macrosomia. Maternal diabetes and obesity also are associated with a higher risk of SD (2 to 4 folds) but these associations may be completely explained by foetal macrosomia. However, even factors independently and constantly associated with SD do not allow a valid prediction of SD because they are not discriminant; 50 to 70% of SD cases occur in their absence, and the great majority of deliveries when they are present is not associated with SD. CONCLUSION: Shoulder dystocia is defined by the need for additional obstetric manoeuvres to deliver the foetus after the head has delivered and gentle traction has failed, and complicates 0.5-1% of vaginal deliveries. Its main risk factors are previous SD and macrosomia, but they are poorly predictive. SD remains a non predictable obstetrics emergency. Knowledge of SD risk factors should increase the vigilance of clinicians in at-risk contexts. PMID- 26527013 TI - [Neonatal complications related to shoulder dystocia]. AB - OBJECTIVE: To describe neonatal complications related to shoulder dystocia. METHODS: This systematic evidence review is based on PubMed search, Cochrane library and experts' recommendations. RESULTS: The risks of brachial plexus birth injury, clavicle and humeral fracture, perinatal asphyxia, hypoxic-ischemic encephalopathy and perinatal mortality are increased after shoulder dystocia. The medical team should be able to provide neonatal resuscitation in the delivery room in case of perinatal asphyxia following shoulder dystocia, according to national and international guidelines. The initial clinical examination should search for complications such as brachial plexus birth injury or clavicle fracture. CONCLUSION: The risk of perinatal complications is increased in newborn after shoulder dystocia. The medical team should be able to manage these complications. PMID- 26527014 TI - [Impact of simulation to reduce neonatal and maternal morbidity of shoulder dystocia]. AB - OBJECTIVE: To assess the role of simulation in reducing morbidity and mortality of shoulder dystocia. METHODS: A systematic literature review was conducted in the Medline database. RESULTS: Regarding the prevention of complications of shoulder dystocia, practical training using mannequin is associated with improvements in management shoulder dystocia than training using video tutorial (EL2). Practical training using simulation for shoulder dystocia allows an improvement for manoeuvres mainly for trainees, but simulation seems to benefit to all caregivers for the communication (EL3). The effect of training sessions using simulation for learning writing the medical observation allows only a modest improvement in the medical record transcription (EL3). The interest of a specific grid for reporting shoulder dystocia seems interesting to increase the amount of information transcribed by the caregiver (EL3). The establishment of a practical training using simulation and concerning all caregivers of the delivery room is associated with a significant reduction in neonatal injury (EL3). The establishment of a training program using simulation does not seem to decrease maternal morbidity in case of shoulder dystocia (EL3). CONCLUSION: A teaching using simulation for the management of shoulder dystocia is encouraged for the initial and continuing formation of different actors in the delivery room (professional agreement). PMID- 26527016 TI - [Guidelines for clinical practice: Shoulder dystocia--Method and organization]. PMID- 26527015 TI - [Clinical practice guidelines: Benign breast tumor--Aims, methods and organization]. AB - Conversely to breast cancer, few data and guidelines are available to explore and manage benign breast disorders. Therefore, the College national des gynecologues et obstetriciens francais (CNGOF - French College of Gynaecologists and Obstetricians) decided to establish clinical practice guidelines for benign breast tumour (BBT). CNGOF appointed a committee with responsibility for selecting experts, compiling questions and summarizing the recommendations. The summary of valid scientific data for each question analyzed by the experts included a level of evidence, based on the quality of the data available and defined accordingly rating scheme developed by the Haute Autorite de sante (French National Authority for Health). PMID- 26527017 TI - [Post-partum: Guidelines for clinical practice--Short text]. AB - OBJECTIVE: To determine the post-partum management of women and their newborn whatever the mode of delivery. MATERIAL AND METHODS: The PubMed database, the Cochrane Library and the recommendations from the French and foreign obstetrical societies or colleges have been consulted. RESULTS: Because breastfeeding is associated with a decrease in neonatal morbidity (lower frequency of cardiovascular diseases, infectious, atopic or infantile obesity) (EL2) and an improvement in the cognitive development of children (EL2), exclusive and extended breastfeeding is recommended (grade B) between 4 to 6 months (Professional consensus). In order to increase the rate of breastfeeding initiation and its duration, it is recommended that health professionals work closely with mothers in their project (grade A) and to promote breastfeeding on demand (grade B). There is no scientific evidence to recommend non pharmacological measures of inhibition of lactation (Professional consensus). Pharmacological treatments for inhibition of lactation should not be given routinely to women who do not wish to breastfeed (Professional consensus). Because of potentially serious adverse effects, bromocriptin is contraindicated in inhibiting lactation (Professional consensus). For women aware of the risks of pharmacological treatment of inhibition of lactation, lisuride and cabergolin are the preferred drugs (Professional consensus). Whatever the mode of delivery, numeration blood count is not systematically recommended in a general population (Professional consensus). Anemia must be sought only in women with bleeding or symptoms of anemia (Professional consensus). The only treatment of post-dural puncture headache is the blood patch (EL2), it must not be carried out before 48 h (Professional consensus). Women vaccination status and their family is to be assessed in the early post-partum (Professional consensus). Immediate postoperative monitoring after caesarean delivery should be performed in the recovery room, but in exceptional circumstances, it may be performed in the delivery unit provided safety rules are maintained and regulatory authorities are informed (Professional consensus). An analgesic multimodal protocol developed by the medical team should be available and oral way should be favored (Professional consensus) (grade B). For every cesarean delivery, thromboprophylaxis with elastic stockings applied on the morning of the surgery and kept for at least 7 postoperative days is recommended (Professional consensus) with or without the addition of LMWH according to the presence or not of additional risk factors, and depending on the risk factor (major, minor). Early postoperative rehabilitation is encouraged (Professional consensus). Postpartum visit should be planned 6 to 8 weeks after delivery and can be performed by an obstetrician, a gynecologist, a general practitioner or a midwife, after normal pregnancy and delivery (Professional consensus). Starting effective contraception later 21 days after delivery in women who do not want closely spaced pregnancy is recommended (grade B), and to prescribe it at the maternity (Professional consensus). According to the postpartum risk of venous thromboembolism, the combined hormonal contraceptive use before six postpartum weeks is not recommended (grade B). Rehabilitation in asymptomatic women in order to prevent urinary or anal incontinence in medium or long-term is not recommended (Expert consensus). Pelvic floor rehabilitation using pelvic-floor muscle contraction exercises is recommended to treat persistent urinary incontinence at 3 months postpartum (grade A), regardless of the type of incontinence. Postpartum pelvic-floor rehabilitation is recommended to treat anal incontinence (grade C). Postpartum pelvic-floor rehabilitation is not recommended to treat or prevent prolapse (grade C) or dyspareunia (grade C). The optimal time for maternity discharge for low risk newborn depends more on the organisation of the post-discharge follow up (Professional consensus). The months following the birth are a transitional period, and psychological alterations concern all parents (EL2). It is more difficult in case of psychosocial risk factors (EL2). In situations of proven psychological difficulties, the impact on the psycho-emotional development of children can be important (EL3). Among these difficulties, postpartum depression is the most common situation. However, the risk is generally higher in the perinatal period for all mental disorders (EL3). CONCLUSION: Postpartum is, for clinicians, a unique and privileged opportunity to address the physical, psychological, social and somatic health of their patients. PMID- 26527018 TI - [Hysterectomy for benign gynaecological disease: Surgical approach, vaginal suture method and morcellation: Guidelines]. AB - OBJECTIVE: To provide clinical practice guidelines from the French college of obstetrics and gynaecology (CNGOF), based on the best evidence available, concerning the surgical approach, the vaginal suture method, the surgeon's experience and morcellation to avoid complications with hysterectomy for benign gynaecological disease. MATERIAL AND METHODS: English and French review of literature about complications with hysterectomy for benign gynaecological disease, excluding cancer. RESULTS AND CONCLUSION: For benign gynaecological disease, vaginal (VH) or laparoscopic (LH) hysterectomy are recommended (grade B). In case of big uterus, VH or LH are recommended (grade C). VH is not contraindicated in nulliparous (Grade C). VH is not contraindicated in case of previous caesarean (grade C). In obese women, VH and LH are recommended (grade C). It should be recommended to perform at least 30 hysterectomies during learning curve (grade C). Hysterectomy should be performed by surgeon doing at least 10 hysterectomies each year (grade C). No vaginal suture method is recommended (grade C). It is recommended to assess cancer risk before (histological sample and/or imagery) when morcellation is planned (expert opinion). PMID- 26527019 TI - [Post-partum management after cesarean delivery. Guidelines for clinical practice]. AB - OBJECTIVE: To determine guidelines for post-partum management after cesarean delivery regarding patient monitoring, organization, postoperative analgesia, time of urinary catheter removal, resumption of feeding and drinking, timing of ambulation, indication and modalities of thromboprophylaxis. METHODS: The PubMed database, the Cochrane Library and the recommendations from the French and foreign obstetrical societies or colleges have been consulted. RESULTS: Immediate postoperative monitoring after caesarean delivery should be performed in the recovery room, but in exceptional circumstances, it may be performed in the delivery unit provided safety rules are maintained and regulatory authorities are informed (professional consensus). Specific surveillance including emergency call procedures must be performed (professional consensus). Systematic blood count performed immediately after cesarean delivery is not recommended in the general population (professional consensus). An analgesic protocol developed by the medical team should be available for each patient (professional consensus). An indwelling bladder catheter should be inserted before and maintained during surgery (professional consensus). The bladder catheter should be preferentially removed in the first 12 hours after cesarean delivery (professional consensus). It is recommended to check that spontaneous voiding has occurred in the 4-6 hours after the removal of the bladder catheter. The physician in charge should be alerted if the patient has failed to void within 6 hours after catheter removal (grade C). Early ambulation on day 1 (or earlier from the 6th to 8th hour) with help is advised and encouraged (professional consensus). Early feeding and drinking after elective or emergency cesarean delivery, performed under regional or general anesthesia, is recommended (grade A). Administration of a prophylactic treatment using two antiemetic medications is recommended during cesarean delivery (grade B). For every cesarean delivery, thromboprophylaxis with elastic stockings applied on the morning of the surgery and kept for at least 7 postoperative days is recommended (professional consensus) with or without the addition of LMWH according to the presence or not of additional risk factors, and depending on the risk factor (major, minor). In obese patient, LMWH dose needs to be weight-adapted (grade C). CONCLUSION: Harmonization of care according to these recommendations is expected to enhance recovery after cesarean delivery. PMID- 26527020 TI - [Postpartum psychological disorders: Screening and prevention after birth. Guidelines for clinical practice]. AB - OBJECTIVES: Focusing on the mother's postpartum psychological and psychiatric disorders. METHOD: Bibliographic research carried out by the data banks and the recommendations of learned societies from the following French words translated into English: postpartum, perinatal, postpartum, breastfeeding, birth, weaning, peripartum, lactation, postnatal, mood disorders, anxiety disorders, depression, anxiety, psychosis. These keywords were combined with the following words: prevalence, incidence, recurrence, development, identification, scale, assessment, test, father, man, husband, partner, hormones, treatment, intervention, prevention, testing, therapy, medicine, medication, to prescribe, prescription. RESULTS: The months following the birth are a transitional period, and psychological alterations concern all parents (LE2). It is more difficult in case of psychosocial risk factors (LE2). In situations of proven psychological difficulties, the impact on the psycho-emotional development of children can be important (LE3). Among these difficulties, postpartum depression is the most common situation. Given its prevalence (about 13 %) and because of its implications for the entire family, it's an important health issue (LE2). However, the risk is generally higher in the perinatal period for all mental disorders (LE3). Pregnancy and postpartum are periods favorable to develop links with health professionals. New parents are often looking for support to deal with the upheavals associated with the birth. The postpartum period is thus for clinicians a unique opportunity to address the mental, social and somatic aspects of the health of their patients (professional agreement). Early detection and treatment of mental disorders are essential for family functioning and parent child relationship (professional agreement). CONCLUSION: The issue of screening and prevention of postpartum mental disorders is fundamental and requires involvement of all professional receiving parents and babies in the aftermath of the birth. PMID- 26527021 TI - [Post-partum contraception: Guidelines for clinical practice]. AB - OBJECTIVE: Establishment of guidelines for post-partum contraception. MATERIAL AND METHODS: Systematic review of publications between 1960 and 2015 from database Medline, Embase, Cochrane Library and recommendations of international societies. RESULTS: The most recent French data show that approximately 2% of women with induced abortion have deliver within 6 months before this abortion and 4% had a child six to twelve months earlier (Evidence Level [EL] 3). A contraceptive counseling is ideally recommended after delivery to avoid unplanned pregnancies (grade C). Among non-breastfeeding women, the shorter median delay for recovery ovulation is 39 days after delivery (EL4). Starting effective contraception later 21 days after delivery in women who does not want closely spaced pregnancy is recommended (grade B), and to prescribe it at the maternity (Professional consensus). In breastfeeding women, the recovery of ovarian activity is dependent on breastfeeding characteristics. Only exclusive breastfeeding with very specific conditions can be used for contraception over a six months period (EL2). For all other breastfeeding conditions, contraceptive strategies are the same than without breastfeeding (grade B). According to the post-partum risk of venous thromboembolism, the combined hormonal contraceptive use before six post-partum weeks is not recommended (grade B). In women with vascular risk factors, the evaluation of benefit risk balance of this use between 6th and 12th post-partum weeks is recommended (Professional consensus). Progestin only contraceptives with low dose are allowed in earlier post-partum (grade B), except at the acute phase of severe thromboembolic event (Professional consensus). In women who want intra-uterine device (IUD) as contraception, it is recommended to prescribe IUD at the hospital and to insert the IUD during the postnatal consultation (grade B). In breastfeeding women, progestin contraception's (oral or subcutaneous) are permitted immediately after delivery (grade B). For women at short interpregnancy interval risk, long acting reversible contraceptives (implant or IUD) started at the hospital is suggested (grade B). CONCLUSION: The wide contraceptive choice permits to find the best strategy for each woman while respecting post-partum period specificities. PMID- 26527022 TI - [Clinical practice guidelines: Benign breast tumor--Introduction]. AB - The benign breast tumors cover a wide clinical spectrum ranging from stromal epithelial tumors to breast abscess and epithelial hyperplasia with atypia. Their management has a major medical and economic impact and requires a rational use of paraclinical investigations. PMID- 26527023 TI - [Explorations of breast microcalcifications: Guidelines]. AB - OBJECTIVES: To assess imaging performances for the detection, characterization and biopsy of breast microcalcifications and make recommendations. MATERIALS AND METHODS: French and English publications were searched using PubMed, Cochrane Library and international learned societies recommendations. RESULTS: Digital mammography (DR [Direct Radiography] and CR [Computed Radiography]) and screen film mammography demonstrate good performances for the detection and the characterization of breast microcalcifications. Systematic use of the 2013 edition of the BI-RADS lexicon is recommended for description and characterization of microcalcifications. Faced with BI-RADS 4 or 5 microcalcifications, breast ultrasound is recommended but a normal result does not eliminate the diagnosis of cancer and other examination should be performed. Literature review does not allow recommending digital breast tomosynthesis, elastography or MRI to analyze microcalcifications. In case of probably benign microcalcifications (BI-RADS 3), six months, one year and at least two years follow-up are recommended. In case a biopsy is indicated, it is recommended to use a vacuum-assisted macrobiopsy system with 11-gauges needles or bigger. If no calcification is visible on the radiography of the specimen, it is recommended to obtain additional samples. PMID- 26527024 TI - [Urinary, infectious and digestive adverse events related to benign hysterectomy and the associated surgery on the Fallopian tube: Guidelines]. AB - OBJECTIVES: To provide clinical practice guidelines from the French College of Obstetrics and Gynecology (CNGOF) based on the best evidence available, concerning the urinary, infectious and digestive adverse events related to benign hysterectomy and the associated surgery including opportunistic salpingectomy and adnexectomy. MATERIAL AND METHOD: Review of literature using following keywords: benign hysterectomy; urinary injury; bladder injury; ureteral injury; vesicovaginal fistula; infection; bowel injury; salpingectomy. RESULTS: Urinary catheter should be removed before 24h following uncomplicated hysterectomy (grade B). In case of urinary catheter during hysterectomy, immediate postoperative removal is possible (grade C). No hemostasis technics can be recommended to avoid urinary injury (grade C). There is not any evidence to recommend to perform a window in the broad ligament or an ureterolysis, to put ureteral stent or a uterine manipulator in order to avoid ureteral injury. An antibiotic prophylaxis by a cephalosporin is always recommended (grade B). Mechanical bowel preparation before hysterectomy is not recommended (grade B). If there is no ovarian cyst/disease and no familial or personal history of ovarian/breast cancer, ovarian conservation is recommended in premenopausal women (grade B). In postmenopausal women, informed consent and surgical approach should be taken in account to perform a salpingo-oophorectomy. Since the association salpingectomy and hysterectomy is not assessed in the prevention of ovarian cancer, systematic bilateral salpingectomy is not recommended (expert consensus). CONCLUSIONS: Practical application of these guidelines should decrease the prevalence of visceral complications associated with benign hysterectomy. PMID- 26527025 TI - [Postnatal visit: Routine and particularity after complicated pregnancy- Guidelines for clinical practice]. AB - OBJECTIVES: To propose guidelines for clinical practice for routine postnatal visit and after pathological pregnancies. MATERIALS AND METHODS: Bibliographic searches were performed with PubMed and Cochrane databases, and within international guidelines references. RESULTS: Postpartum visit should be planned 6 to 8 weeks after delivery and can be performed by an obstetrician, a gynecologist, a general practitioner or a midwife, when after normal pregnancy and delivery (Professional consensus). If any complication occurred, this visit should be handled by an obstetrician (Professional consensus). Physical examination should focus on patient symptoms and pregnancy complications (Professional consensus). Gynecological examination is not systematic (Professional consensus). Pap smear should be performed if previous exam was done more than 2years ago or when the previous exam was abnormal (Professional consensus). Weight should be measured to encourage weight loss (Professional consensus), with the aim to catch up preconceptional weight within 6 months after delivery (gradeC). Professional intervention may reduce weight retention (professional consensus). Tobacco, alcohol and illicit drugs cessation should be promoted (grade B) and supported by a professional (grade A). Obstetrical risks consecutive to short interval between pregnancies should be explained (evidence level [EL]: 3) and contraception discussed regarding family project (Professional consensus). Mother mood, mother to child relationship and breastfeeding troubles should be systematically evaluated (professional consensus). Pelvic-floor rehabilitation should be performed only when urinary of fecal incontinence persist 3 months after delivery (Professional consensus). Serological screening for toxoplamosis (grade B) and blood hemoglobin concentration should not be systematically performed (gradeC). After spontaneous preterm birth, women should be screened for uterine anomalies and treatment should be discussed (Professional consensus). Evidence is lacking to recommend any exploration to diagnose cervical incompetence (Professional consensus). When investigations are performed, there is no argument to recommend a specific exam (Professional consensus). Women should be screened for antiphospholipid antibodies after severe or early pre eclampsia, IUGR or intra-uterine fetal death (Professional consensus) but screening for inherited thrombophilia is not recommended (grade B). Women with persistent proteinuria and/or hypertension 3 months after pre-eclampsia should be referred to a nephrologist (Professional consensus). Normalization of liver enzymes should be checked 8 to 12 weeks after intrahepatic cholestasis of pregnancy (Professional consensus). A synthetic document should be send to the women corresponding physicians (Professional consensus). Preconceptional counseling is recommended (Professional consensus). CONCLUSION: A postpartum visit is recommended 6 to 8 weeks after delivery, including mother physical and psychological evaluation and information about contraception, short interval between pregnancy, weight loss, smoking cessation (Professional consensus). To ensure continuity in the management of women health, relevant medical elements will be pass on to the corresponding physicians (Professional consensus). PMID- 26527026 TI - [Prevention of shoulder dystocia risk factors before delivery]. AB - OBJECTIVE: To determine whether it is possible to prevent the occurrence of risk factors for shoulder dystocia before or during pregnancy. METHODS: The PubMed database, the Cochrane Library and the recommendations from the French and foreign obstetrical societies or colleges have been consulted. Studied measures were exercise before or during pregnancy, dietary management, and gestational diabetes management in obese and non-obese patients. RESULTS: No study has proven that the correction of these risk factors (except gestational diabetes) would reduce the risk of shoulder dystocia. In the general population, physical exercise is recommended either before or during pregnancy to reduce the risk of gestational diabetes (physical activity before pregnancy) (grade B), fetal macrosomia (grade C) or maternal weight gain during pregnancy (grade C). No dietary regimen is recommended to reduce these issues (grade B). In overweight or obese (body mass index [BMI]>25), physical activity coupled with dietary management is recommended (grade A) because it reduces fetal macrosomia (EL1). In addition, it allows a modest reduction in maternal weight gain during pregnancy (EL2), but did have an effect on the occurrence of gestational diabetes (EL1). In case of gestational diabetes, diabetes care is recommended (diabetic diet, glucose monitoring, insulin if needed) (grade A) as it reduces the risk of macrosomia and shoulder dystocia (EL1). The recommended weight gain during pregnancy is 11.5 kg to 16 kg for normal BMI patients (grade B). Obese patients should be aware of the importance of controlling their weight gain during pregnancy (professional consensus). It is recommended that patients regain their pre-conception weight, and ideally a BMI between 18 and 25 kg/m(2), 6 months postpartum (grade B) to reduce the risk of gestational diabetes and macrosomia in a subsequent pregnancy (EL2). CONCLUSION: Physical activity is recommended before and during pregnancy to reduce the occurrence of risk factors for shoulder dystocia. In obese patients, physical activity should be coupled with dietary measures to reduce fetal macrosomia and weight gain during pregnancy. PMID- 26527027 TI - [Breast-feeding (part II): Lactation inhibition--Guidelines for clinical practice]. AB - OBJECTIVE: Provide guidelines for clinical use of non-pharmacological and pharmacological treatments of inhibition of lactation and the management of the weaning. MATERIALS AND METHODS: Systematically review of the literature between 1972 and May 2015 from the databases Medline, Google Scholar, Cochrane Library, and the international recommendations about inhibition of lactation with establishment of levels of evidence (LE) and grades of recommendation. RESULTS: The available data on the effectiveness of non-pharmacological measures are limited, with very low levels of evidence that fail to make recommendations (Professional consensus). Pharmacological treatments for inhibition of lactation should not be given routinely to women who do not wish to breast-feed (Professional consensus). For women aware of the risks of pharmacological treatments of inhibition of lactation, lisuride and cabergolin are the preferred drugs (Professional consensus). Because of potentially serious adverse effects, bromocriptin is contraindicated in inhibiting lactation (Professional consensus). Available data on management of lactation weaning fail to provide recommendation and no treatment is recommended (Professional consensus). CONCLUSION: Bromocriptin is contraindicated in the treatment of inhibiting lactation. Women who do not wish to breast-feed have to be informed of the benefits and disadvantages of the pharmacological treatment for inhibition of lactation. PMID- 26527028 TI - [Management of a breast cystic syndrome: Guidelines]. AB - OBJECTIVE: Breast cysts are common, often discovered incidentally or subsequently to pain or palpable mass. The purpose of these recommendations is to describe the sonographic findings for classifying breast cystic lesions, to analyze the value and contribution of various imaging techniques and sampling and to provide a management strategy. MATERIALS AND METHODS: Literature review conducted by a small group and then reviewed and validated by the group designated by the College national des gynecologues et obstetriciens francais (CNGOF) to make recommendations for clinical practice for benign breast lesions. RESULTS: Breast cysts are classified in 3 categories: simple cysts, complicated cysts and complex cysts. For simple cysts, after ultrasound, no further imaging is necessary, cytology is to consider only as analgesic. For complicated cysts, a control at 4 6 months is recommended; the use of cytology depends on the context (familial risk, difficulty of follow-up). In case of complex cyst, sampling by cytology or biopsy is recommended. More assessments of other imaging tests are reported. CONCLUSION: The sonographic characterization is essential for management of breast cyst. PMID- 26527029 TI - [How to explore breast skin lesion?: Guidelines]. AB - A change in the shape or appearance of the nipple-areola complex, especially if it is unilateral and recent appearance, is a sign of underlying breast tumor. Breast imaging is then required (grade C). Any erythematous lesion of the nipple or nipple-areola can be a Paget's disease, an adenoma of the nipple or a nipple eczema. Clinical course and pattern can point to a diagnosis without sufficient specificity (LE4). If nipple eczema is suspected, it is recommended to perform a test treatment with topical corticosteroids. In case of failure or if a Paget's disease of the breast is suspected, a biopsy must be done. When indicated, it is not possible to recommend a biopsy modality (scrape cytology, punch biopsy, nipple core biopsy and surgical excision) compared to another. When imaging exploration of the nipple-areola complex is necessary, ultrasound and mammography are recommended as first-line. In the absence of signal, an MRI is recommended as second-line (grade C). PMID- 26527030 TI - Toward realization of 'mix-and-use' approach in 68Ga radiopharmacy: preparation, evaluation and preliminary clinical utilization of 68Ga-labeled NODAGA-coupled RGD peptide derivative. AB - INTRODUCTION: The present article demonstrates a 'mix-and-use' approach for radiolabeling RGD peptide derivative with (68)Ga, which is easily adaptable in hospital radiopharmacy practice. The radiotracer thus formulated was successfully used for positron emission tomography (PET) imaging of breast cancer in human patients. METHODS: The conditions for radiolabeling NODAGA-coupled dimeric cyclic RGD peptide derivative [NODAGA-(RGD)2] with (68)Ga were optimized using (68)Ga obtained from a (68)Ge/(68)Ga generator developed in-house with CeO2-PAN composite sorbent as well as from a commercial (68)Ge/(68)Ga generator obtained from ITG, Germany. Preclinical studies were carried out in C57BL/6 mice bearing melanoma tumors. The radiotracer was prepared in a hospital radiopharmacy using (68)Ga obtained from ITG generator and used for monitoring breast cancer patients by positron emission tomography (PET) imaging. RESULTS: (68)Ga-NODAGA-(RGD)2 could be prepared with high radiolabeling yield (>98%) and specific activity (~50 GBq/MUmol) within 10 min at room temperature by mixing (68)Ga with the solution of the peptide conjugate. In vivo biodistribution studies showed significant uptake (5.24+/-0.39% ID/g) in melanoma tumor at 30 min post-injection, with high tumor-to-background contrast. The integrin alphavbeta3 specificity of the tracer was corroborated by blocking study. Preliminary clinical studies in locally advanced breast cancer (LABC) patients indicated specifically high tumor uptake (SUVmax 10-15) with good contrast. CONCLUSIONS: This is one of the very few reports which presents preliminary clinical data on use of (68)Ga-NODAGA-(RGD)2 and the developed 'mix-and-use' holds tremendous prospect in clinical PET imaging using (68)Ga. PMID- 26527031 TI - Can tumor regression grade influence survival outcome in ypT3 rectal cancer? AB - PURPOSE: Locally advanced rectal cancer (LARC) patients achieving ypT3 status following neoadjuvant chemoradiation are considered to have poor response with minimal downstaging. However, residual cancer cell amounts vary in the subserosa/perirectal fat. Tumor regression grading (TRG) is an evaluation method based on the proportion of fibrosis and residual cancer cells. The aim of this study is to assess the influence of TRG in ypT3 rectal cancer patients who received neoadjuvant chemoradiation. METHODS: We retrospectively reviewed 325 LARC patients who received neoadjuvant chemoradiation and surgery. TRG scores were recorded by two independent pathologists. Among these patients, 143 were staged as ypT3. We analyzed TRG and other clinicopathological factors and their relationship with survival outcome including overall survival (OS) and disease free survival (DFS). RESULTS: Among 143 ypT3 patients, 44 (30.8 %) were TRG1, 84 (58.7 %) were TRG2 and 15 (10.5 %) were TRG3. Seventy-nine (55.3 %) of these patients had metastatic lymph nodes. In univariate analysis, TRG was not associated with DFS (TRG2 vs TRG1, P = 0.852; TRG3 vs TRG1, P = 0.593) or OS (TRG2 vs TRG1, P = 0.977; TRG3 vs TRG1, P = 0.665). Palliative surgery (HR 3.845; 95 % CI 1.670-8.857; P = 0.002) and metastatic lymph nodes after surgery (HR 5.894; 95 % CI 1.142-3.48; P = 0.015) were significantly associated with decreased DFS, while palliative surgery was the only factor associated with worse OS (HR 6.011; 95 % CI 2.150-16.810; P = 0.001). Palliative surgery (HR 3.923; 95 % CI 1.696-9.073; P = 0.001) and metastatic lymph nodes (HR 2.011; 95 % CI 1.152 3.512; P = 0.014) also showed prognostic significance for DFS in multivariate analysis. CONCLUSIONS: Residual cancer cells evaluated by TRG score after neoadjuvant chemoradiation do not influence survival outcome in ypT3 rectal cancer patients. However, lymph node status is a significant prognostic factor in ypT3 patients. PMID- 26527032 TI - ATAD2 is overexpressed in gastric cancer and serves as an independent poor prognostic biomarker. AB - OBJECTIVE: ATPase family, AAA domain containing 2 (ATAD2) has been found overexpressed in various cancer types and correlated with malignant status and poor prognosis. However, little is known about the clinical significance of ATAD2 in gastric cancer patients. The aim of this study was to explore the clinical and prognostic significance of ATAD2 in gastric cancer. METHODS: The mRNA and protein levels expression of ATAD2 were detected in clinical tissue samples by qRT-PCR and immunohistochemistry, respectively. We examined the ATAD2 protein expression by immunohistochemistry. Furthermore, we analyzed the association between ATAD2 expression and clinicopathological features including prognosis in 166 gastric cancer samples. RESULTS: In our results, ATAD2 mRNA and protein were highly expressed in gastric cancer samples. ATAD2 overexpression was correlated with advanced clinical stage, tumor depth, lymph node metastasis, and distant metastasis. According to the survival analysis, ATAD2 protein overexpression was a poor independent prognostic factor for gastric cancer patients. CONCLUSIONS: In summary, ATAD2 could serve as a prognostic biomarker for gastric cancer patients. PMID- 26527033 TI - Dual inhibiting EGFR and VEGF pathways versus EGFR-TKIs alone in the treatment of advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The strategy of dual inhibiting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways has been extensively investigated in advanced non-small-cell lung cancer (NSCLC), but the benefit-to-risk ratio of dual-targeted regimen versus EGFR-tyrosine kinase inhibitors (TKIs) alone is still unclear. We thus perform this meta-analysis to assess the efficacy and safety of this regimen versus EGFR-TKIs alone in those patients. METHODS: Databases from PubMed, Web of Science and the Cochrane Library up to March 31, 2015 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials (RCTs) evaluating dual inhibiting EGFR and VEGF pathways versus EGFR-TKIs alone in advanced NSCLC. The endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and grade 3 or 4 adverse events. Statistical analyses were conducted by using either random effects or fixed effect models according to the heterogeneity of included studies. RESULTS: A total of 1918 patients with advanced NSCLC from 4 RCTs were identified for the analysis. The pooled results demonstrated that dual inhibiting EGFR and VEGF pathways significantly improved the PFS (HR 0.71, 95 % CI 0.58-0.86, p < 0.001) and ORR (OR 1.54, 95 % CI 1.14 2.08, p = 0.005) in unselected NSCLC when compared to EGFR-TKIs alone, but it did not translate into OS benefit (HR 0.94, 95 % CI 0.84-1.05, p = 0.24). No evidence of publication bias was observed. CONCLUSIONS: Our study suggests that dual inhibition of EGFR and VEGF pathways significantly improves PFS and ORR, but it does not translate into survival benefit in unselected NSCLC patients. Prospective clinical trials investigating the role of this regimen in EGFR mutation-positive NSCLC are still warranted. PMID- 26527035 TI - Impact of Atrial Fibrillation and Sinus Rhythm Restoration on Reticulated Platelets. AB - OBJECTIVE: To assess the impact of nonvalvular atrial fibrillation (NVAF) and sinus rhythm restoration on the distribution of reticulated platelets (RPs), which are known to be associated with thrombotic propensity and have a greater predilection for thrombus participation. PARTICIPANTS AND METHODS: The RP content was assessed by flow cytometry (thiazole orange/CD61) in 110 consecutive patients with NVAF before and 3 to 4 months after catheter ablation of the pulmonary veins. Results were compared with those of 55 age- and sex-matched controls with normal sinus rhythm. RESULTS: The mean +/- SD percentage of RPs was higher in patients with NVAF compared with controls (28.5%+/-7.3% vs 6.4%+/-5.3%; P<.001). The RP content did not vary by CHA2DS2-VASc score. After catheter ablation of the pulmonary veins, 63 patients were available for follow-up assessment. A significant reduction of RPs was observed compared with preintervention values (29.85%+/-7.1% vs 20.79%+/-7.6%; P<.001). During follow-up, 19% of patients (12 of 63) had confirmed AF recurrence. The mean +/- SD percentage of RPs was higher in this group than in those without a recurrence (24.7%+/-6.5% vs 18.9%+/-7.5%; P=.01). CONCLUSION: Nonvalvular atrial fibrillation affects the percentage of RPs, independent of the CHA2DS2-VASc score. After ablation, RP content dropped significantly. High RP content in patients with NVAF may explain the potential mechanism of thromboembolic complications and the lack of efficacy of currently available antiplatelet therapy for stroke prevention in this dysrhythmia. PMID- 26527034 TI - Decreased progranulin levels in patients and rats with subarachnoid hemorrhage: a potential role in inhibiting inflammation by suppressing neutrophil recruitment. AB - BACKGROUND: Subarachnoid hemorrhage (SAH) is a devastating neurological injury with high morbidity and mortality that is mainly caused by early brain injury (EBI). Progranulin (PGRN) is known to be involved in various biological functions, such as anti-inflammation and tissue repair. This study aimed to investigate the change of PGRN in the brain after SAH and its role on EBI. METHODS: The levels of PGRN, myeloperoxidase (MPO), interleukin1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) were detected in the cerebrospinal fluid (CSF) from SAH patients by enzyme-linked immunosorbent assay (ELISA). In addition, PGRN levels were also detected in the cerebral cortex after experimental SAH in rats by western blotting and immunohistochemistry (IHC). Recombinant human PGRN (r-PGRN) or an equal volume of phosphate-buffered saline (PBS) was administrated at 30 min after SAH. All rats were subsequently sacrificed at 24 h after SAH. Neurological score and brain water content were assessed. For mechanistic studies, the changes of MPO, matrix metalloproteinase-9 (MMP-9), zonula occludens 1 (ZO-1), Bcl-2, and cleaved caspase-3 were examined by western blotting and the levels of pro-inflammatory cytokines (IL-1beta and TNF alpha) were determined by ELISA. In addition, neuronal apoptosis and blood brain barrier (BBB) permeability were examined. RESULTS: The levels of PGRN significantly decreased, and the levels of MPO, IL-1beta, and TNF-alpha were markedly elevated in the CSF from SAH patients. In rats, PGRN levels in the brain also decreased after SAH. Administration of r-PGRN decreased brain water content and improved neurological scores at 24 h after SAH. These changes were associated with marked reductions in MPO, MMP-9, and proinflammation cytokine levels, as well as increased levels of Bcl-2 and ZO-1. In addition, neuronal apoptosis and BBB permeability were alleviated by r-PGRN. CONCLUSIONS: These results indicate that the levels of PGRN decreased after SAH and that r-PGRN alleviates EBI after SAH possibly via inhibition of neutrophil recruitment, providing a new target for the treatment of SAH. PMID- 26527036 TI - Soft tissue regeneration using leukocyte-platelet rich fibrin after exeresis of hyperplastic gingival lesions: two case reports. AB - INTRODUCTION: Leukocyte-platelet rich fibrin belongs to a second generation of platelet concentrates that does not need biochemical blood manipulation. It is used for tissue healing and regeneration in periodontal and oral-maxillofacial surgery. We report two cases of hyperplastic gingival lesions treated by exeresis and application of leukocyte-platelet rich fibrin membranes in order to improve and accelerate tissue healing. CASE PRESENTATION: Two patients (a 78-year-old Caucasian woman and a 30-year-old Caucasian man) were treated for hyperplastic gingival lesions. They underwent to exeresis of lesions and application of leukocyte-platelet rich fibrin membranes. Tissue healing was clinically evaluated after 1, 3, 7, 14 and 30 postoperative days. No recurrences were observed after 2 years of semi-annual follow up. CONCLUSIONS: We obtained rapid and good healing of soft tissues probably due to the elevated content of leukocytes, platelets and growth factors in the leukocyte-platelet rich fibrin. Based on our results we suggest the use of leukocyte-platelet rich fibrin to cover wounds after exeresis of oral neoformations such as hyperplastic gingival lesions. PMID- 26527037 TI - Agenesis of lateral incisors: A fresh look at our practice. AB - In cases involving compensation treatment for edentulousness related to agenesis of the lateral incisors, the transition phase between the orthodontic and the prosthetic stages is tricky. Using clinical illustrations, we will demonstrate that it is time we took a fresh look at our practices. The aim will be to shorten this phase either by postponing the orthodontic stage into adulthood or by placing the prosthesis as quickly as possible on completion of the orthodontic stage, a process which is now feasible, thanks to advances in the designing of bonded bridges and notably of cantilever bonded bridges. PMID- 26527039 TI - Laparoscopy shows superiority over endoscopy for early detection of malignant atrophic papulosis gastrointestinal complications: a case report and review of literature. AB - BACKGROUND: The malignant form of atrophic papulosis (Kohlmeier-Degos disease) is a rare thrombo-occlusive vasculopathy that can affect multiple organ systems. Patients typically present with distinctive skin lesions reflective of vascular drop out. The small bowel is the most common internal organ involved, resulting in considerable morbidity and mortality attributable to ischemic microperforations. Determination of the presence of gastrointestinal lesions is critical in distinguishing systemic from the benign, cutaneous only disease and in identifying candidates for treatment. CASE PRESENTATION: We describe an 18 year old male who first presented with cutaneous atrophic papulosis but became critically ill from small bowel microperforations. He had an almost immediate and dramatic response to treatment. Prior to his presentation with acute abdomen he had upper and lower endoscopy showing areas of nonspecific patchy erythema. At laparotomy, innumerable characteristic lesions with central pearly hue and erythematous border were seen. PubMed was used for a literature search using the keywords malignant atrophic papulosis, Degos disease, endoscopy, laparoscopy and laparotomy. This search yielded 200 articles which were further analyzed for diagnostic procedures and findings. Among the 200 articles we identified only 11 cases in which endoscopy was performed. Results of endoscopy and laparotomy in our patient with malignant atrophic papulosis were compared to those in the literature. Endoscopy of the gastrointestinal tract has shown gastritis and non specific inflammation whereas laparoscopy shows white plaques with red borders on the serosal surface of the small bowel and the peritoneum. From personal communications with other physicians worldwide, we identified three additional unpublished cases in which endoscopy revealed only minimal changes while laparoscopy showed dramatic lesions. From our experience the endoscopic findings are often subtle and nonspecific, whereas laparascopy or laparotomy will reveal pathognomic lesions on the serosal surface of the intestine. CONCLUSION: Our report contrasts the endoscopic and laparoscopic findings in malignant atrophic papulosis which suggest laparoscopy is the more powerful means of detecting gastrointestinal involvement. Imaging studies may serve as a key indicator of systemic progression. Based on our experience, laparoscopy should be performed when there is a high index of suspicion for gastrointestinal malignant atrophic papulosis, even if endoscopic examination is non-diagnostic or normal. PMID- 26527040 TI - Pathological alterations due to motile Aeromonas infection in red swordtail fish (Xiphophorus helleri). AB - A herd of red swordtail fish (Xiphophorus helleri) was reared in outdoor concrete ponds and suffered from occasional mortality. Moribund fishes showing abdominal dropsy and fin rots were sent for diagnosis. Gross necropsy findings showed enlargement of liver, spleen, and kidney in concurrence with congestion, and a severe accumulation of peritoneal fluid. Histopathological findings revealed an alteration of hepatocytes, with a severe diffuse accumulation of fat vacuoles in the cytoplasm. In the trunk kidney, severe accumulation of mononuclear cells together with cloudy swelling of the renal tubular epithelium was observed. From internal organs of the fish motile Aeromonas spp. were identified. The pathological findings might be associated with a long-term infection of affected fish fostered by common stressors such as improper feeding and poor pond environment condition (water temperature). Effective therapeutic measures comprised an advancement of keeping conditions and appropriate feeding to improve the health status in combination with the application of antibiotic substances. PMID- 26527041 TI - Scabies. AB - Scabies is a contagious skin infestation caused by a mite. It causes significant global morbidity, with an estimated 300 million cases annually. Although it can affect individuals at any socioeconomic level, individuals who live in poverty or in overcrowded conditions are at much higher risk for scabies. Lack of local expertise can result in failure to recognize scabies, leading to delayed diagnosis and inadequate treatment of cases and contacts. Scabies disproportionately affects many Indigenous (First Nations, Inuit, Metis) communities where risk factors are present. Scabies risk is also higher in young children, the elderly and immunocompromised individuals. Institutional outbreaks of scabies have also been reported. Apart from a very itchy rash, scabies can lead to secondary bacterial infections and related complications, as well as to stigmatization, depression, insomnia and significant financial costs. Topical antiscabies lotions are still the mainstay of treatment, but oral ivermectin has also proven effective under certain circumstances. Asymptomatic and symptomatic household members should all be treated at the same time. In Canada and globally, the presence of scabies is usually a symptom of poor living conditions and a sign that basic necessities need improvement. Clinicians who work with Indigenous communities can improve their ability to diagnose and treat scabies, and should advocate for better living conditions where scabies is prevalent. PMID- 26527042 TI - Redundant anomalous vertebral artery in a case of congenital irreducible atlantoaxial dislocation: Emphasizing on the differences from the first intersegemental artery and operative steps to prevent injury while performing C1 2 joint manipulation. AB - Anomalous vertebral artery (VA), commonly the persistent first intersegmental artery (FIA) is often seen with congenital atlantoaxial dislocations (AAD). An unusual redundant/ectatic loop of VA passing below the C1 (upside down VA) has been described below and appears to be different from FIA. The operative technique to protect it while C1-2 joint manipulation has been described. A 35 year old male presented with progressive spastic quadriparesis after trivial trauma. Radiology showed irreducible atlantoaxial dislocation with occipitalised C1 and C2-3 fusion. The left VA was anomalous passing beneath the C1 arch with a redundant loop lying posterior to the C1-2 joint. This was unlike the persistent first intersegmental artery (FIA) and was safeguarded while dissecting the C1-2 facet. The artery was dissected and safeguarded while performing C1-2 joint manipulation. A redundant/ectatic loop lying posterior to C1-2 joint is an unusual variant of anomalous VA. Evaluation of preoperative radiology helps in diagnosing such anomalous VA. Dissection of the entire redundant loop of the anomalous artery is important in opening the C1-2 joint required for reduction and placement of spacer/ bone grafts to achieve good bony fusion. Also mobilizing the loop allows safe insertion of lateral mass screw. Care needs to be taken while fastening screws to prevent compression of the loop. PMID- 26527043 TI - Creating a safe space: A qualitative inquiry into the way doctors discuss spirituality. AB - OBJECTIVE: Spiritual history taking by physicians is recommended as part of palliative care. Nevertheless, very few studies have explored the way that experienced physicians undertake this task. METHOD: Using grounded theory, semistructured interviews were conducted with 23 physicians who had experience in caring for advanced cancer patients. They were asked to describe the way they discuss spirituality with their patients. RESULTS: We have described a delicate, skilled, tailored process whereby physicians create a space in which patients feel safe enough to discuss intimate topics. Six themes were identified: (1) developing the self: physicians describe the need to understand and be secure in one's own spirituality and be comfortable with one's own mortality before being able to discuss spirituality; (2) developing one's attitude: awareness of the importance of spirituality in the life of a patient, and the need to respect each patient's beliefs is a prerequisite; (3) experienced physicians wait for the patient to give them an indication that they are ready to discuss spiritual issues and follow their lead; (4) what makes it easier: spiritual discussion is easier when doctor and patient share spiritual and cultural backgrounds, and the patient needs to be physically comfortable and willing to talk; (5) what makes it harder: experienced physicians know that they will find it difficult to discuss spirituality when they are rushed and when they identify too closely with a patient's struggles; and (6) an important and effective intervention: exploration of patient spirituality improves care and enhances coping. SIGNIFICANCE OF RESULTS: A delicate, skilled, tailored process has been described whereby doctors endeavor to create a space in which patients feel sufficiently safe to discuss intimate topics. PMID- 26527044 TI - Thickness effect of ultra-thin Ta2O5 resistance switching layer in 28 nm-diameter memory cell. AB - Resistance switching (RS) devices with ultra-thin Ta2O5 switching layer (0.5-2.0 nm) with a cell diameter of 28 nm were fabricated. The performance of the devices was tested by voltage-driven current-voltage (I-V) sweep and closed-loop pulse switching (CLPS) tests. A Ta layer was placed beneath the Ta2O5 switching layer to act as an oxygen vacancy reservoir. The device with the smallest Ta2O5 thickness (0.5 nm) showed normal switching properties with gradual change in resistance in I-V sweep or CLPS and high reliability. By contrast, other devices with higher Ta2O5 thickness (1.0-2.0 nm) showed abrupt switching with several abnormal behaviours, degraded resistance distribution, especially in high resistance state, and much lower reliability performance. A single conical or hour-glass shaped double conical conducting filament shape was conceived to explain these behavioural differences that depended on the Ta2O5 switching layer thickness. Loss of oxygen via lateral diffusion to the encapsulating Si3N4/SiO2 layer was suggested as the main degradation mechanism for reliability, and a method to improve reliability was also proposed. PMID- 26527045 TI - Advantages and limitations of virtual reality for balance assessment and rehabilitation. AB - Virtual reality (VR) is now commonly used in many domains because of its ability to provide a standardized, reproducible and controllable environment. In balance assessment, it can be used to control stimuli presented to patients and thus accurately evaluate their progression or compare them to different populations in standardized situations. In balance rehabilitation, VR allows the creation of new generation tools and at the same time the means to assess the efficiency of each parameter of these tools in order to optimize them. Moreover, with the development of low-cost devices, this rehabilitation can be continued at home, making access to these tools much easier, in addition to their entertaining and thus motivating properties. Nevertheless, and even more with low-cost systems, VR has limits that can alter the results of the studies that use it: the latency of the system (the delay cumulated on each step of the process from data acquisition on the patients to multimodal outputs); and distance perception, which tends to be underestimated in VR. After having described why VR is an essential tool for balance assessment and rehabilitation and illustrated this statement with a case study, this review discusses the previous works in the domain with regards to the technological limits of VR. PMID- 26527046 TI - Long-Term Stroke Risk Due to Partial White-Coat or Masked Hypertension Based on Home and Ambulatory Blood Pressure Measurements: The Ohasama Study. AB - The prognostic significance of white-coat hypertension (WCHT) is controversial, and different findings on self-measured home measurements and 24-h ambulatory monitoring make identifying WCHT difficult. We examined whether individuals with partially or completely defined WCHT, as well as masked hypertension, as determined by different out-of-office blood pressure measurements, have a distinct long-term stroke risk. We followed 1464 participants (31.8% men; mean age, 60.6+/-10.8 years) in the general population of Ohasama, Japan, for a median of 17.1 years. A first stroke occurred in 212 subjects. Using sustained normal blood pressure (events/n=61/776) as a reference, adjusted hazard ratios for stroke (95% confidence intervals; events/n) were 1.38 (0.82-2.32; 19/137) for complete WCHT (isolated office hypertension), 2.16 (1.36-3.43; 29/117) for partial WCHT (either home or ambulatory normotension with office hypertension), 2.05 (1.24-3.41; 23/100) for complete masked hypertension (both home and ambulatory hypertension with office normotension), 2.08 (1.37-3.16; 38/180) for partial masked hypertension (either home or ambulatory hypertension with office normotension), and 2.46 (1.61-3.77; 42/154) for sustained hypertension. When partial WCHT and partial masked hypertension groups were further divided into participants only with home hypertension and those only with ambulatory hypertension, all subgroups had a significantly higher stroke risk (adjusted hazard ratio >=1.84, P<=0.04). In conclusion, impacts of partial WCHT as well as partial masked hypertension for long-term stroke risk were comparable to those of complete masked hypertension or sustained hypertension. We need both home and 24 h ambulatory blood pressure measurements to evaluate stroke risk accurately. PMID- 26527047 TI - Increased Arterial Stiffness Trumps on Blood Pressure in Predicting Cognitive Decline in Low-Risk Populations. PMID- 26527048 TI - Cost-Effectiveness of a Physician-Pharmacist Collaboration Intervention to Improve Blood Pressure Control. AB - Previous studies have demonstrated the cost-effectiveness of physician-pharmacist collaborations to improve hypertension control. However, most studies have limited generalizability, lacking minority and low-income populations. The Collaboration Among Pharmacist and Physicians to Improve Blood Pressure Now (CAPTION) trial randomized 625 patients from 32 medical offices in 15 states. Each office had an existing clinical pharmacist on staff. Pharmacists in intervention offices communicated with patients and made recommendations to physicians about changes in therapy. Demographic information, blood pressure (BP), medications, and physician visits were recorded. In addition, pharmacists tracked time spent with each patient. Costs were assigned to medications and pharmacist and physician time. Cost-effectiveness ratios were calculated based on changes in BP measurements and hypertension control rates. Thirty-eight percent of patients were black, 14% were Hispanic, and 49% had annual income <$25 000. At 9 months, average systolic BP was 6.1 mm Hg lower (+/-3.5), diastolic was 2.9 mm Hg lower (+/-1.9), and the percentage of patients with controlled hypertension was 43% in the intervention group and 34% in the control group. Total costs for the intervention group were $1462.87 (+/-132.51) and $1259.94 (+/-183.30) for the control group, a difference of $202.93. The cost to lower BP by 1 mm Hg was $33.27 for systolic BP and $69.98 for diastolic BP. The cost to increase the rate of hypertension control by 1 percentage point in the study population was $22.55. Our results highlight the cost-effectiveness of a clinical pharmacy intervention for hypertension control in primary care settings. PMID- 26527049 TI - Roles of Arterial Stiffness and Blood Pressure in Hypertension-Associated Cognitive Decline in Healthy Adults. AB - Although there is strong evidence that hypertension leads to cognitive decline, especially in the executive domain, the relationship between blood pressure and cognition has been conflicted. Hypertension is characterized by blood pressure elevation and increased arterial stiffness. We aimed at investigating whether arterial stiffness would be superior to blood pressure in predicting cognitive decline and explaining the hypertension-executive decline association. A randomly selected asymptomatic population (n=591, age=49.2 years, 70% women, 27% black, and education=18 years) underwent annual vascular and cognitive assessments. Cognition was assessed using computerized versions commonly used cognitive tests, and principal component analysis was used for deriving cognitive scores for executive function, memory, and working memory. Arterial stiffness was measured by carotid-femoral pulse wave velocity (PWV). Higher PWV, but not blood pressure, was associated with a steeper decline in executive (P=0.0002), memory (P=0.05), and working memory (P=0.02) scores after adjusting for demographics, education, and baseline cognitive performance. This remained true after adjusting for hypertension. Hypertension was associated with greater decline in executive score (P=0.0029) and those with combined hypertension and elevated PWV (>7 m/s) had the greatest decline in executive score (P value hypertension*PWV=0.02). PWV explained the association between hypertension and executive function (P value for hypertension=0.0029 versus 0.24 when adjusting for PWV). In healthy adults, increased arterial stiffness is superior to blood pressure in predicting cognitive decline in all domains and in explaining the hypertension-executive function association. Arterial stiffness, especially in hypertension, may be a target in the prevention of cognitive decline. PMID- 26527050 TI - Modern Hypertension Management: The Who and the Where. PMID- 26527051 TI - Rac1-Mediated Activation of Mineralocorticoid Receptor in Pressure Overload Induced Cardiac Injury. AB - There is increasing evidence for a crucial role of aberrant mineralocorticoid receptor (MR) activation in heart failure, with clinical studies showing beneficial effects of MR blockade. However, the mechanisms of MR activation in heart failure remain unclear. In this study, we observed that the small GTPase Rac1 contributes to myocardial MR activation, whereas Rac1-MR pathway activation leads to cardiac dysfunction. Mouse hearts subjected to chronic pressure overload induced by transverse aortic constriction showed Rac1 activation and increased nuclear accumulation of MR and expression of MR target genes, suggesting MR activation. Pharmacological inhibition of Rac1 and heterozygous deletion of Rac1 in cardiomyocytes suppressed Rac1-induced MR signaling and reduced NADPH oxidase 4 gene induction and reactive oxygen species overproduction, which attenuated transverse aortic constriction-induced cardiac hypertrophy and dysfunction. Consistently, treatment with the selective MR antagonist eplerenone blocked transverse aortic constriction-induced MR signaling and NADPH oxidase 4 gene upregulation, which improved cardiac hypertrophy and dysfunction. These findings suggest that Rac1-MR pathway activation in the myocardium is involved in development of heart failure induced by pressure load via recruitment of the responsible isoform of NADPH oxidase. Thus, the cardiac Rac1-MR-NADPH oxidase 4 pathway may be a therapeutic target for treatment of the pressure-overloaded heart. PMID- 26527052 TI - Copper-Catalyzed Double Additions and Radical Cyclization Cascades in the Re Engineering of the Antibacterial Pleuromutilin. AB - A general synthetic sequence involving simply prepared starting materials provides rapid access to diverse, novel tricyclic architectures inspired by pleuromutilin. Sm(II) -mediated radical cyclization cascades of dialdehydes, prepared using a new, one-pot, copper-catalyzed double organomagnesium addition to beta-chlorocyclohexenone, proceed with complete sequence selectivity and typically with high diastereocontrol to give analogues of the target core. Our expedient approach (ca. 7 steps) allows non-traditional, de novo synthetic access to analogues of the important antibacterial that can't be prepared from the natural product by semisynthesis. PMID- 26527053 TI - Evaluating Linearly Interpolated Intercensal Estimates of Demographic and Socioeconomic Characteristics of U.S. Counties and Census Tracts 2001-2009. AB - The American Community Survey (ACS) multiyear estimation program has greatly advanced opportunities for studying change in the demographic and socioeconomic characteristics of U.S. communities. Challenges remain, however, for researchers studying years prior to the full implementation of the ACS or areas smaller than the thresholds for ACS annual estimates (i.e., small counties and census tracts). We evaluate intercensal estimates of the demographic and socioeconomic characteristics of U.S. counties and census tracts produced via linear interpolation between the 2000 census and both the 2010 census and 2005-2009 ACS. Discrepancies between interpolated estimates and reference estimates from the Population Estimates Program, the Small Area Income and Poverty Estimates, and ACS are calculated using several measures of error. Findings are discussed in relation to the potential for measurement error to bias longitudinal estimates of linearly interpolated neighborhood change, and alternative intercensal estimation models are discussed, including those that may better capture non-linear trends in economic conditions over the 21st century. PMID- 26527054 TI - Factors Influencing Short-term Synaptic Plasticity in the Avian Cochlear Nucleus Magnocellularis. AB - Defined as reduced neural responses during high rates of activity, synaptic depression is a form of short-term plasticity important for the temporal filtering of sound. In the avian cochlear nucleus magnocellularis (NM), an auditory brainstem structure, mechanisms regulating short-term synaptic depression include pre-, post-, and extrasynaptic factors. Using varied paired pulse stimulus intervals, we found that the time course of synaptic depression lasts up to four seconds at late-developing NM synapses. Synaptic depression was largely reliant on exogenous Ca(2+)-dependent probability of presynaptic neurotransmitter release, and to a lesser extent, on the desensitization of postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor (AMPA-R). Interestingly, although extrasynaptic glutamate clearance did not play a significant role in regulating synaptic depression, blocking glutamate clearance at early-developing synapses altered synaptic dynamics, changing responses from depression to facilitation. These results suggest a developmental shift in the relative reliance on pre-, post-, and extrasynaptic factors in regulating short-term synaptic plasticity in NM. PMID- 26527055 TI - A review of the current nomenclature for psychotropic agents and an introduction to the Neuroscience-based Nomenclature. AB - Neuroscience based Nomenclature (NbN) is a new system of classifying psychotropic drugs by their pharmacological profile. The NbN was developed to replace the current indication-based nomenclature and to provide an up-to-date and more useful framework to better inform pharmacological decisions. NbN provides updated relevant and specific scientific, regulatory and clinical information, aiming to support rational and lucid prescribing. This pharmacologically driven nomenclature, which highlights pharmacological domains and modes of action, may also increase drug adherence as it clarifies the rationale for selecting a specific psychotropic agent. PMID- 26527056 TI - Older adults' perceptions of ageing and their health and functioning: a systematic review of observational studies. AB - Many older people perceive ageing negatively, describing it in terms of poor or declining health and functioning. These perceptions may be related to older adults' health. The aim of this review was to synthesise existing research on the relationship between older adults' perceptions of ageing and their health and functioning. A systematic search was conducted of five electronic databases (ASSIA, CINAHL, IBSS, MEDLINE and PsycINFO). Citations within identified reports were also searched. Observational studies were included if they included perceptions of ageing and health-related measures involving participants aged 60 years and older. Study selection, data extraction and quality appraisal were conducted using predefined criteria. Twenty-eight reports met the criteria for inclusion. Older adults' perceptions of ageing were assessed with a variety of measures. Perceptions were related to health and functioning across seven health domains: memory and cognitive performance, physical and physiological performance, medical conditions and outcomes, disability, care-seeking, self rated health, quality of life and death. How ageing is perceived by older adults is related to their health and functioning in multiple domains. However, higher quality and longitudinal studies are needed to further investigate this relationship. PMID- 26527058 TI - Active involvement of learning disabilities service users in the development and delivery of a teaching session to pre-registration nurses: Students' perspectives. AB - A teaching session about service users' experiences of accessing and receiving health and social care was designed and delivered by service users to first year BSc Nursing students. The aim was to enhance students' knowledge, skills and confidence in caring for people with a learning disability. An evaluation research study was undertaking at one university in London into the perceived effectiveness of the teaching session, including students' perceptions of the extent to which the service users' teaching session was useful, the impact of the session, its benefits and challenges and the sustainability of teaching sessions delivered by service users. Data were collected through an online questionnaire. Quantitative analysis was undertaken of Likert-style questions and qualitative analysis was undertaken using the Framework Method. The session impacted on students' knowledge and understanding of people with a learning disability. Students reported that they felt more comfortable and confident interacting with people with a learning disability. In addition, they reflected on their feelings about caring for people with a learning disability. PMID- 26527057 TI - NFAT isoforms play distinct roles in TNFalpha-induced retinal leukostasis. AB - The objective of this study was to determine the role of individual NFAT isoforms in TNFalpha-induced retinal leukostasis. To this end, human retinal microvascular endothelial cells (HRMEC) transfected with siRNA targeting individual NFAT isoforms were treated with TNFalpha, and qRT-PCR was used to examine the contribution of each isoform to the TNFalpha-induced upregulation of leukocyte adhesion proteins. This showed that NFATc1 siRNA increased ICAM1 expression, NFATc2 siRNA reduced CX3CL1, VCAM1, SELE, and ICAM1 expression, NFATc3 siRNA increased CX3CL1 and SELE expression, and NFATc4 siRNA reduced SELE expression. Transfected HRMEC monolayers were also treated with TNFalpha and assayed using a parallel plate flow chamber, and both NFATc2 and NFATc4 knockdown reduced TNFalpha-induced cell adhesion. The effect of isoform-specific knockdown on TNFalpha-induced cytokine production was also measured using protein ELISAs and conditioned cell culture medium, and showed that NFATc4 siRNA reduced CXCL10, CXCL11, and MCP-1 protein levels. Lastly, the CN/NFAT-signaling inhibitor INCA-6 was shown to reduce TNFalpha-induced retinal leukostasis in vivo. Together, these studies show a clear role for NFAT-signaling in TNFalpha-induced retinal leukostasis, and identify NFATc2 and NFATc4 as potentially valuable therapeutic targets for treating retinopathies in which TNFalpha plays a pathogenic role. PMID- 26527059 TI - Performance of Vitek MS in identifying nontuberculous mycobacteria from MGIT liquid medium and Lowenstein-Jensen solid medium. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry is a fast and inexpensive method for bacterial identification. The aim of this study was to analyze the performance of Vitek MS in identifying 160 nontuberculous mycobacterial isolates of 24 species from Lowenstein-Jensen solid medium and BACTEC MGIT 960 liquid medium using a bead-based method. The system correctly identified 76.9% of the isolates (123 of 160) cultivated on solid medium and 76.9% (123 of 160) of positive liquid cultures. None of the isolates included in the study was misidentified. Although the overall performance of Vitek MS with the SARAMIS 4.12 database was comparable in identifying mycobacterial species grown on solid medium and in liquid medium, the identification rate varied notably between the various species analyzed, which currently limits the utility for identification in routine diagnostics for some species. PMID- 26527060 TI - Selection of KPC-2-producing Providencia stuartii during treatment for septicemia. PMID- 26527061 TI - cAMP/PKA enhances interleukin-1beta-induced interleukin-6 synthesis through STAT3 in glial cells. AB - We previously reported that interleukin (IL)-1beta induces IL-6 synthesis via activation of the IkappaB/NFkappaB pathway, p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and signal transducer and activator of transcription (STAT)3, but not p44/p42 MAP kinase in rat glioma cell line, C6 cells and that cAMP enhances the IL-6 synthesis. However, the details behind enhancement of IL-1beta-induced IL-6 synthesis by cAMP remain to be elucidated. In the present study, we investigated the exact mechanism of cAMP underlying the amplification of IL-1beta-induced IL-6 synthesis in C6 cells. 8-Bromo cAMP significantly enhanced IL-1beta-induced STAT3 phosphorylation without affecting phosphorylation of IkappaB, p38 MAP kinase or SAPK/JNK. In addition, we found that forskolin, a direct activator of adenylyl cyclase, significantly enhanced IL-1beta-induced STAT3 phosphorylation. Janus family of tyrosine kinase (JAK) inhibitor I markedly suppressed the amplification by 8-bromo cAMP of IL-1beta-induced IL-6 release. IL-1beta induced JAK2 phosphorylation, and FLLL32, a specific JAK2 inhibitor, significantly reduced IL 1beta-stimulated IL-6 release. 4-Cyano-3-methylisoquinoline, an inhibitor of protein kinase A (PKA), significantly attenuated the enhancing effect of 8-bromo cAMP on IL-1beta-induced STAT3 phosphorylation. 8-Bromo cAMP markedly induced JAK2 phosphorylation. PKA siRNA transfection reduced enhancement of IL-1beta induced IL-6 release by 8-bromo cAMP. In conclusion, our results strongly suggest that the adenylyl cyclase/cAMP/PKA pathway upregulates IL-1beta-induced IL-6 synthesis through enhancement of the JAK2/STAT3 pathway in C6 glioma cells. PMID- 26527062 TI - A novel method of preparing the monoform structure of catalytic antibody light chain. AB - Along with the development of antibody drugs and catalytic antibodies, the structural diversity (heterogeneity) of antibodies has been given attention. For >20 yr, detailed studies on the subject have not been conducted, because the phenomenon presents many difficult and complex problems. Structural diversity provides some (or many) isoforms of an antibody distinguished by different charges, different molecular sizes, and modifications of amino acid residues. For practical use, the antibody and the subunits must have a defined structure. In recent work, we have found that the copper (Cu) ion plays a substantial role in solving the diversity problem. In the current study, we used several catalytic antibody light chains to examine the effect of the Cu ion. In all cases, the different electrical charges of the molecule converged to a single charge, giving 1 peak in cation-exchange chromatography, as well as a single spot in 2 dimensional gel electrophoresis. The Cu-binding site was investigated by using mutagenesis, ultraviolet-visible spectroscopy, atomic force microscope analysis, and molecular modeling, which suggested that histidine and cysteine residues close to the C-terminus are involved with the binding site. The constant region domain of the antibody light chain played an important role in the heterogeneity of the light chain. Our findings may be a significant tool for preparing a single defined, not multiple, isoform structure. PMID- 26527063 TI - Leukotriene B4 receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins. AB - GPCRs are involved in numerous physiologic functions and are important drug targets. Although the epithelial barrier is important for protection from invading pathogens, the correlation between GPCRs and epithelial barrier function remains unknown. Leukotriene B4 (LTB4) receptor type 2 (BLT2), mainly expressed in epithelial cells, is a GPCR for 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and LTB4. In our study, BLT2 localized at the lateral membrane in BLT2 overexpressing Madin-Darby canine kidney (MDCK) II cells and in the small intestine of BLT2-transgenic mice. BLT2-deficient mice exhibited higher transepidermal water loss and were more sensitive to epicutaneous sensitization. MDCK-BLT2 cells recovered transepithelial electrical resistance (TER) after a calcium switch faster than did MDCK-Mock cells, and 12-HHT stimulation accelerated TER recovery only in MDCK-BLT2 cells. Quantitative PCR and immunoblot analyses revealed that the 12-HHT/BLT2 axis up-regulated claudin-4 (CLDN4) expression in MDCK-BLT2 cells and human primary keratinocytes, and CLDN4 knockdown abolished 12-HHT-dependent TER recovery. Acceleration of TER recovery and induction of CLDN4 expression by 12-HHT stimulation were abolished by inhibition of Galphai protein or p38 MAPK. These results show that 12-HHT/BLT2 enhances epithelial barrier function by increasing CLDN4 expression via the Galphai protein-p38 MAPK pathway. PMID- 26527064 TI - Gain-of-function somatic mutations contribute to inflammation and blood vessel damage that lead to Alzheimer dementia: a hypothesis. AB - Amyloid deposits are a characteristic feature of advanced Alzheimer dementia (AD), but whether they initiate the disease or are a consequence of it remains an unsettled question. To explore an alternative pathogenic mechanism, I propose that the triggering events that begin the pathogenic cascade are not amyloid deposits but damaged blood vessels caused by inflammatory reactions that lead to ischemia, amyloid accumulation, axonal degeneration, synaptic loss, and eventually irreversible neuronal cell death. Inflammation and blood vessel damage are well recognized complications of AD, but what causes them and why the cerebral microvasculature is affected have never been adequately addressed. Because heritable autosomal dominant mutations of NLRP3, APP, TREX1, NOTCH3, and Col4A1 are known to provoke inflammatory reactions and damage the brain in a wide variety of diseases, I propose that one or more low abundant, gain-of-function somatic mutations of the same 5 gene families damage the microvasculature of the brain that leads to dementia. This implies that the pathogenic triggers that lead to AD are derived not from external invaders or amyloid but from oxidative damage of our own genes. PMID- 26527065 TI - Cathelicidins positively regulate pancreatic beta-cell functions. AB - Cathelicidins are pleiotropic antimicrobial peptides largely described for innate antimicrobial defenses and, more recently, immunomodulation. They are shown to modulate a variety of immune or nonimmune host cell responses. However, how cathelicidins are expressed by beta cells and modulate beta-cell functions under steady-state or proinflammatory conditions are unknown. We find that cathelicidin related antimicrobial peptide (CRAMP) is constitutively expressed by rat insulinoma beta-cell clone INS-1 832/13. CRAMP expression is inducible by butyrate or phenylbutyric acid and its secretion triggered upon inflammatory challenges by IL-1beta or LPS. CRAMP promotes beta-cell survival in vitro via the epidermal growth factor receptor (EGFR) and by modulating expression of antiapoptotic Bcl-2 family proteins: p-Bad, Bcl-2, and Bcl-xL. Also via EGFR, CRAMP stimulates glucose-stimulated insulin secretion ex vivo by rat islets. A similar effect is observed in diabetes-prone nonobese diabetic (NOD) mice. Additional investigation under inflammatory conditions reveals that CRAMP modulates inflammatory responses and beta-cell apoptosis, as measured by prostaglandin E2 production, cyclooxygenases (COXs), and caspase activation. Finally, CRAMP-deficient cnlp(-/-) mice exhibit defective insulin secretion, and administration of CRAMP to prediabetic NOD mice improves blood glucose clearance upon glucose challenge. Our finding suggests that cathelicidins positively regulate beta-cell functions and may be potentially used for intervening beta cell dysfunction-associated diseases. PMID- 26527066 TI - Enhanced FGF23 production in mice expressing PI3K-insensitive GSK3 is normalized by beta-blocker treatment. AB - Glycogen synthase kinase (GSK)-3 is a ubiquitously expressed kinase inhibited by insulin-dependent Akt/PKB/SGK. Mice expressing Akt/PKB/SGK-resistant GSK3alpha/GSK3beta (gsk3(KI)) exhibit enhanced sympathetic nervous activity and phosphaturia with decreased bone density. Hormones participating in phosphate homeostasis include fibroblast growth factor (FGF)-23, a bone-derived hormone that inhibits 1,25-dihydroxyvitamin D3 (1,25(OH)2D3; calcitriol) formation and phosphate reabsorption in the kidney and counteracts vascular calcification and aging. FGF23 secretion is stimulated by the sympathetic nervous system. We studied the role of GSK3-controlled sympathetic activity in FGF23 production and phosphate metabolism. Serum FGF23, 1,25(OH)2D3, and urinary vanillylmandelic acid (VMA) were measured by ELISA, and serum and urinary phosphate and calcium were measured by photometry in gsk3(KI) and gsk3(WT) mice, before and after 1 wk of oral treatment with the beta-blocker propranolol. Urinary VMA excretion, serum FGF23, and renal phosphate and calcium excretion were significantly higher, and serum 1,25(OH)2D3 and phosphate concentrations were lower in gsk3(KI) mice than in gsk3(WT) mice. Propranolol treatment decreased serum FGF23 and loss of renal calcium and phosphate and increased serum phosphate concentration in gsk3(KI) mice. We conclude that Akt/PKB/SGK-sensitive GSK3 inhibition participates in the regulation of FGF23 release, 1,25(OH)2D3 formation, and thus mineral metabolism, by controlling the activity of the sympathetic nervous system. PMID- 26527067 TI - The K+ channel TASK1 modulates beta-adrenergic response in brown adipose tissue through the mineralocorticoid receptor pathway. AB - Brown adipose tissue (BAT) is essential for adaptive thermogenesis and dissipation of caloric excess through the activity of uncoupling protein (UCP)-1. BAT in humans is of great interest for the treatment of obesity and related diseases. In this study, the expression of Twik-related acid-sensitive K(+) channel (TASK)-1 [a pH-sensitive potassium channel encoded by the potassium channel, 2-pore domain, subfamily K, member 3 (Kcnk3) gene] correlated highly with Ucp1 expression in obese and cold-exposed mice. In addition, Task1-null mice, compared with their controls, became overweight, mainly because of an increase in white adipose tissue mass and BAT whitening. Task1(-/-)-mouse-derived brown adipocytes, compared with wild-type mouse-derived brown adipocytes, displayed an impaired beta3-adrenergic receptor response that was characterized by a decrease in oxygen consumption, Ucp1 expression, and lipolysis. This phenotype was thought to be caused by an exacerbation of mineralocorticoid receptor (MR) signaling, given that it was mimicked by corticoids and reversed by an MR inhibitor. We concluded that the K(+) channel TASK1 controls the thermogenic activity in brown adipocytes through modulation of beta-adrenergic receptor signaling. PMID- 26527068 TI - Extracellular adenosine levels are associated with the progression and exacerbation of pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis is a devastating lung disease with limited treatment options. The signaling molecule adenosine is produced in response to injury and serves a protective role in early stages of injury and is detrimental during chronic stages of disease such as seen in lung conditions such as pulmonary fibrosis. Understanding the association of extracellular adenosine levels and the progression of pulmonary fibrosis is critical for designing adenosine based approaches to treat pulmonary fibrosis. The goal of this study was to use various models of experimental lung fibrosis to understand when adenosine levels are elevated during pulmonary fibrosis and whether these elevations were associated with disease progression and severity. To accomplish this, extracellular adenosine levels, defined as adenosine levels found in bronchioalveolar lavage fluid, were determined in mouse models of resolvable and progressive pulmonary fibrosis. We found that relative bronchioalveolar lavage fluid adenosine levels are progressively elevated in association with pulmonary fibrosis and that adenosine levels diminish in association with the resolution of lung fibrosis. In addition, treatment of these models with dipyridamole, an inhibitor of nucleoside transporters that potentiates extracellular adenosine levels, demonstrated that the resolution of lung fibrosis is blocked by the failure of adenosine levels to subside. Furthermore, exacerbating adenosine levels led to worse fibrosis in a progressive fibrosis model. Increased adenosine levels were associated with elevation of IL-6 and IL-17, which are important inflammatory cytokines in pulmonary fibrosis. These results demonstrate that extracellular adenosine levels are closely associated with the progression of experimental pulmonary fibrosis and that this signaling pathway may mediate fibrosis by regulating IL-6 and IL-17 production. PMID- 26527069 TI - Drugging Undruggable Molecular Cancer Targets. AB - Cancer, more than any other human disease, now has a surfeit of potential molecular targets poised for therapeutic exploitation. Currently, a number of attractive and validated cancer targets remain outside of the reach of pharmacological regulation. Some have been described as undruggable, at least by traditional strategies. In this article, we outline the basis for the undruggable moniker, propose a reclassification of these targets as undrugged, and highlight three general classes of this imposing group as exemplars with some attendant strategies currently being explored to reclassify them. Expanding the spectrum of disease-relevant targets to pharmacological manipulation is central to reducing cancer morbidity and mortality. PMID- 26527070 TI - Sleep Pharmacogenetics: Personalized Sleep-Wake Therapy. AB - Research spanning (genetically engineered) animal models, healthy volunteers, and sleep-disordered patients has identified the neurotransmitters and neuromodulators dopamine, serotonin, norepinephrine, histamine, hypocretin, melatonin, glutamate, acetylcholine, gamma-amino-butyric acid, and adenosine as important players in the regulation and maintenance of sleep-wake-dependent changes in neuronal activity and the sleep-wake continuum. Dysregulation of these neurochemical systems leads to sleep-wake disorders. Most currently available pharmacological treatments are symptomatic rather than causal, and their beneficial and adverse effects are often variable and in part genetically determined. To evaluate opportunities for evidence-based personalized medicine with present and future sleep-wake therapeutics, we review here the impact of known genetic variants affecting exposure of and sensitivity to drugs targeting the neurochemistry of sleep-wake regulation and the pathophysiology of sleep-wake disturbances. Many functional polymorphisms modify drug response phenotypes relevant for sleep. To corroborate the importance of these and newly identified variants for personalized sleep-wake therapy, human sleep pharmacogenetics should be complemented with pharmacogenomic investigations, research about sleep-wake dependent pharmacological actions, and studies in mice lacking specific genes. These strategies, together with future knowledge about epigenetic mechanisms affecting sleep-wake physiology and treatment outcomes, may lead to potent and safe novel therapies for the increasing number of sleep-disordered patients (e.g., in aged populations). PMID- 26527071 TI - Immunohistochemical analysis of orbicularis oris muscle fiber distribution at the philtrum in healthy infants. AB - OBJECTIVE: To characterize the fiber-type distribution of the orbicularis oris muscle at the philtrum in healthy infants by immunohistochemistry and examine the relationship between orbicularis oris and philtrum structure. METHODS: Samples of the upper lip were obtained from two infant cadavers. Serial sagittal sections were obtained at the midline of the philtral dimple, unilateral philtral ridge, and the lateral side. Three sections from each site were prepared for immunohistochemical staining using myosin heavy chain fast fiber (MHCf) and myosin heavy chain slow fiber (MHCs) antibodies to determine the ratio of fast to slow skeletal muscle fibers. RESULTS: The ratio of fast to slow muscle fibers differed significantly among the superficial orbicularis oris muscle (98.30%:1.13%), deep pars peripheralis (95.30%:3.14%), and deep pars marginalis (91.31%:5.74%), with a significantly higher percentage of slow fibers in the pars marginalis compared to pars peripheralis (P=0.002) and fast fibers in the superficial muscle compared to pars marginalis and peripheralis (both P=0.000). Similarly, the fast:slow fiber ratio differed among the superficial philtral dimple (95.88%:2.41%), superficial philtral ridge (98.52%:1.11%), and superficial midlateral philtral ridge (99.07%:0.66%), with a higher percentage of fast fibers higher on the lateral side of the superficial philtral ridge than at the philtral ridge (P=0.030) and higher at the philtral ridge than the philtral dimple (P=0.001). The fast:slow fiber ratio did not differ within the pars peripheralis at the philtral dimple (93.94%:4.19%), philtral ridge (94.49%:3.84%), and lateral philtral ridge (95.79%:2.70%) (all P>0.05). CONCLUSIONS: Philtum structure is likely determined in part by the distribution of muscle fiber types among philtral dimple, ridge, and lateral side. These differences should be considered in cleft lip repair. PMID- 26527072 TI - Transcanal endoscopic ear surgery for pediatric population with a narrow external auditory canal. AB - OBJECTIVES: To retrospectively determine the size of the external auditory canal (EAC) in a pediatric population and to describe our experience with transcanal endoscopic ear surgery (TEES) in this pediatric population which had been successfully treated for middle ear disease using TEES. METHODS: We analyzed 31 patients ranging in age from 2 to 13 years old (median: 7.6 years) with middle ear disease who underwent TEES between November 2011 and August 2014. Sixteen of these patients had surgery for cholesteatomas; 11 for chronic otitis media; and 4 for malformation of the middle ear. A preoperative CT scan was performed to evaluate the middle ear disease. Transcanal endoscopic tympanoplasty was performed using a rigid endoscope with a 2.7mm outer diameter. Transcanal endoscopic atticoantrotomy was also performed, as necessary, on some patients to access pathologies in the antrum. The values of anterior-posterior diameters and superior-inferior diameters of the bony parts of EAC were measured retrospectively based on the preoperative CT scan data. RESULTS: TEES was successfully performed in all 31 pediatric patients without resorting to a retroauricular incision. Twenty-seven patients were evaluated for postoperative hearing levels which were found to fall within an acceptable range and for postoperative air-bone gap (ABG) by pure tone audiometry with a resulting mean of 8.6dB. The smallest anterior-posterior diameters of the external ear canal ranged from 3.2 to 7.1mm (5.0+/-1.0mm) and the smallest superior-inferior diameters ranged from 3.4 to 10.3mm (5.9+/-1.3mm). CONCLUSION: TEES can be used to safely and effectively treat middle ear disease even in the pediatric population in its narrow EAC. PMID- 26527073 TI - Parotid abscess in children - A tertiary rural hospital experience. AB - Parotid abscess is a rare complication of acute parotitis in children. Acute parotitis occurs due to infection of intra-parotid or para-parotid lymph nodes or glandular parenchyma of the parotid gland which may progress to parotid abscess. OBJECTIVES: To document the causative organism, clinical behaviour and response to treatment in paediatric parotid abscess. MATERIALS AND METHODS: A retrospective study was done in our tertiary rural hospital from May 2007 to May 2015 to identify and analyse paediatric parotid abscess in 80 unilateral parotitis cases. RESULTS: 7 cases of parotid abscess were identified. 4 cases were diagnosed clinically and in 3 cases ultrasound was done showing heterogenous, hyperechoic, solid and cystic areas. In 2 patients, abscess was extending to the submandibular space. Incision and drainage was done in all patients. The most common bacteria was Methicillin Sensitive Staphylococcus aureus. Escherichia coli was reported in one patient, and was rare in parotid region. 2 patients had House Brackmann grade 2 marginal mandibular nerve palsy, and they recovered within 41/2 months. CONCLUSION: Parotid abscess is an uncommon but life-threatening condition in paediatric age group. Poor orodental hygiene was most important predisposing factor. Abscess can be diagnosed clinically and ultrasound scan is also an important diagnostic tool. It is commonly caused by Gram positive cocci and responds well to incision and drainage followed by appropriate antibiotics. No fistula may result if treated early. PMID- 26527074 TI - Establishment of reference intervals of clinical chemistry analytes for the adult population in Saudi Arabia: a study conducted as a part of the IFCC global study on reference values. AB - BACKGROUND: This study is a part of the IFCC-global study to derive reference intervals (RIs) for 28 chemistry analytes in Saudis. METHOD: Healthy individuals (n=826) aged >=18 years were recruited using the global study protocol. All specimens were measured using an Architect analyzer. RIs were derived by both parametric and non-parametric methods for comparative purpose. The need for secondary exclusion of reference values based on latent abnormal values exclusion (LAVE) method was examined. The magnitude of variation attributable to gender, ages and regions was calculated by the standard deviation ratio (SDR). Sources of variations: age, BMI, physical exercise and smoking levels were investigated by using the multiple regression analysis. RESULTS: SDRs for gender, age and regional differences were significant for 14, 8 and 2 analytes, respectively. BMI related changes in test results were noted conspicuously for CRP. For some metabolic related parameters the ranges of RIs by non-parametric method were wider than by the parametric method and RIs derived using the LAVE method were significantly different than those without it. RIs were derived with and without gender partition (BMI, drugs and supplements were considered). CONCLUSIONS: RIs applicable to Saudis were established for the majority of chemistry analytes, whereas gender, regional and age RI partitioning was required for some analytes. The elevated upper limits of metabolic analytes reflects the existence of high prevalence of metabolic syndrome in Saudi population. PMID- 26527076 TI - Pain Challenges at the End of Life - Pain and Palliative Care Collaboration. AB - Pain and symptom management at the end of life remains suboptimal.Pain physicians are uniquely placed to provide interventions for patients with difficult to manage pain.Interventions such as acupuncture, radiofrequency ablation, neurolysis together with regional analgesia including neuraxial techniques and spinal cordotomy may provide the patient with improved analgesia. PMID- 26527075 TI - Antinociceptive effects of incarvillateine, a monoterpene alkaloid from Incarvillea sinensis, and possible involvement of the adenosine system. AB - Incarvillea sinensis is a Bignoniaceae plant used to treat rheumatism and relieve pain in traditional Chinese medicine. As a major component of I. sinensis, incarvillateine has shown analgesic activity in mice formalin tests. Using a series of animal models, this study further evaluated the effects of incarvillateine against acute, inflammatory, and neuropathic pain. Incarvillateine (10 or 20 mg/kg, i.p.) dose-dependently attenuated acetic acid induced writhing, but did not affect thermal threshold in the hot plate test. In a Complete Freund's Adjuvant model, incarvillateine inhibited both thermal hyperalgesia and paw edema, and increased interleukin-1beta levels. Additionally, incarvillateine attenuated mechanical allodynia induced by spared nerve injury or paclitaxel, whereas normal mechanical sensation was not affected. Incarvillateine did not affect locomotor activity and time on the rotarod at analgesic doses, and no tolerance was observed after 7 consecutive daily doses. Moreover, incarvillateine-induced antinociception was attenuated by theophylline, 1,3 dipropyl-8-cyclopentylxanthine, and 3,7-dimethyl-1-propargylxanthine, but not naloxone, indicating that the effects of incarvillateine on chronic pain were related to the adenosine system, but not opioid system. These results indicate that incarvillateine is a novel analgesic compound that is effective against inflammatory and neuropathic pain, and that its effects are associated with activation of the adenosine system. PMID- 26527077 TI - Persistent syndrome of inappropriate antidiuretic hormone secretion following traumatic brain injury. AB - The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can occur following traumatic brain injury (TBI), but is usually transient. There are very few case reports describing chronic SIADH and all resolved within 12 months, except for one case complicated by meningo-encephalitis. Persistent symptomatic hyponatremia due to chronic SIADH was present for 4 years following a TBI in a previously well 32-year-old man. Hyponatremia consistent with SIADH initially occurred in the immediate period following a high-speed motorbike accident in 2010. There were associated complications of post-traumatic amnesia and mild cognitive deficits. Normalization of serum sodium was achieved initially with fluid restriction. However, this was not sustained and he subsequently required a permanent 1.2 l restriction to maintain near normal sodium levels. Multiple episodes of acute symptomatic hyponatremia requiring hospitalization occurred over the following years when he repeatedly stopped the fluid restriction. Given the ongoing nature of his hyponatremia and difficulties complying with strict fluid restriction, demeclocycline was commenced in 2014. Normal sodium levels without fluid restriction have been maintained for 6 months since starting demeclocycline. This case illustrates an important long-term effect of TBI, the challenges of complying with permanent fluid restrictions and the potential role of demeclocycline in patients with chronic hyponatremia due to SIADH. LEARNING POINTS: Hyponatraemia due to SIADH commonly occurs after TBI, but is usually mild and transient.Chronic hyponatraemia due to SIADH following TBI is a rare but important complication.It likely results from damage to the pituitary stalk or posterior pituitary causing inappropriate non-osmotic hypersecretion of ADH.First line management of SIADH is generally fluid restriction, but hypertonic saline may be required in severe cases. Adherence to long-term fluid restriction is challenging. Other options include oral urea, vasopressin receptor antagonists and demeclocycline.While effective, oral urea is poorly tolerated and vasopressin receptor antagonists are currently not licensed for use in Australia or the USA beyond 30 days due to insufficient long-term safety data and specific concerns of hepatotoxicity.Demeclocycline is an effective, well-tolerated and safe option for management of chronic hyponatraemia due to SIADH. PMID- 26527079 TI - Spontaneous spinal subdural hematoma in a geriatric patient under anticoagulant. PMID- 26527080 TI - Sign change of magnetoresistance in Gd-doped amorphous carbon granular films. AB - Gd/C granular films with 11% Gd were fabricated by facing-target magnetron sputtering at room temperature and then annealed at 300-650 degrees C for 1.5 h. A magnetoresistance of -82% was obtained in the Gd/C films annealed at 650 degrees C at 3 K under a magnetic field of 50 kOe. A sign change of the magnetoresistance from negative to positive and then back to negative was observed in all samples as the temperature decreases. Grain boundary scattering effects, wave-function-shrinkage, cotunneling and Gd-Gd interactions account for the mechanisms of the magnetoresistance effects in different temperature regions. The sign of the magnetoresistance also varies as the magnetic field increases. At the transition temperature of 25 K, the wave-function-shrinkage effect competes with cotunneling and Gd-Gd interactions at different magnetic fields. The competition between the wave-function-shrinkage effect and the grain boundary scattering effect is approximately at the transition temperature of 100 K. The temperature range of positive magnetoresistance expands and transition temperatures are changed as the annealing temperature increases. It is related to the expansion of the temperature region for the wave-function-shrinkage effect which occurs in the Mott variable range hopping conduction mechanism. PMID- 26527081 TI - [Not Available]. PMID- 26527082 TI - Genomic survey and expression analysis of DNA repair genes in the genus Leptospira. AB - Leptospirosis is an emerging zoonosis with important economic and public health consequences and is caused by pathogenic leptospires. The genus Leptospira belongs to the order Spirochaetales and comprises saprophytic (L. biflexa), pathogenic (L. interrogans) and host-dependent (L. borgpetersenii) members. Here, we present an in silico search for DNA repair pathways in Leptospira spp. The relevance of such DNA repair pathways was assessed through the identification of mRNA levels of some genes during infection in animal model and after exposition to spleen cells. The search was performed by comparison of available Leptospira spp. genomes in public databases with known DNA repair-related genes. Leptospires exhibit some distinct and unexpected characteristics, for instance the existence of a redundant mechanism for repairing a chemically diverse spectrum of alkylated nucleobases, a new mutS-like gene and a new shorter version of uvrD. Leptospira spp. shares some characteristics from Gram-positive, as the presence of PcrA, two RecQ paralogs and two SSB proteins; the latter is considered a feature shared by naturally competent bacteria. We did not find a significant reduction in the number of DNA repair-related genes in both pathogenic and host-dependent species. Pathogenic leptospires were enriched for genes dedicated to base excision repair and non-homologous end joining. Their evolutionary history reveals a remarkable importance of lateral gene transfer events for the evolution of the genus. Up regulation of specific DNA repair genes, including components of SOS regulon, during infection in animal model validates the critical role of DNA repair mechanisms for the complex interplay between host/pathogen. PMID- 26527083 TI - Metastatic renal cell carcinoma without evidence of a renal primary. AB - PURPOSE: Metastatic renal cell carcinoma (RCC), without an identified kidney primary, has been reported rarely. We report a patient with RCC metastatic to bilateral adrenal glands and liver, without an apparent renal primary. We detail the immunohistochemical and molecular studies employed to substantiate the diagnosis of RCC and direct therapy. METHODS: Histopathologic findings were correlated with imaging data and supplemented by a panel of immunohistochemical stains, as well as tumor sequence analysis. RESULTS: Despite the presence of bilateral adrenal masses and lack of tumor within kidney parenchyma, the diagnosis of RCC was substantiated by immunohistochemistry (RCC+/PAX2+/PAX8+/Melan-A-/SF-1- among others) and molecular genetic analysis, harboring mutations in VHL, TP53, KDM5C, and PBRM1. After debulking surgery, based on the diagnosis of RCC and the molecular profile, the patient was treated with a tyrosine kinase inhibitor (sunitinib), resulting in stablilization of disease. CONCLUSIONS: This case illustrates the role of mutational analysis in carcinomas with rare or unusual presentations, such as metastatic RCC without a renal primary. PMID- 26527084 TI - Schematic interpretation of lateral neck radiographs of adults in the emergency department: a pictorial review. AB - The lateral neck radiograph is widely utilized for the evaluation of common neck conditions in the emergency department. The anatomy of the neck is complex and it can be difficult to differentiate between soft tissue structures on a lateral radiograph. We suggest a schematic pattern of interpreting the lateral neck radiograph with case images of various pathologies that can present in the emergency setting. PMID- 26527085 TI - A Critical Appraisal of the PETITE Study Report: Topical Corticosteroids Are Safe and Effective in the Long-term Treatment of Infantile Atopic Dermatitis. PMID- 26527086 TI - Authors' Response. PMID- 26527087 TI - Ethics Rounds Needs to Consider Evidence for Listening and Spoken Language for Deaf Children. PMID- 26527088 TI - Ethics Rounds Was Right On Point. PMID- 26527089 TI - Ethics Rounds Needs to Consider Current Population of Deaf Children. PMID- 26527090 TI - Author's Response: Deaf Children, Cochlear Implants, and Language Acquisition. PMID- 26527091 TI - Stratifying Cystic Fibrosis Risk for Newborn Screen Infants With Equivocal Sweat Chloride Levels. PMID- 26527092 TI - Author's Response: Re: Stratifying Cystic Fibrosis Risk for Newborn Screen Infants With Equivocal Sweat Chloride Levels. PMID- 26527093 TI - Corrigendum. AB - Margot JL (2015) Insufficient evidence of purported lunar effect on pollination in Ephedra. J Biol Rhythms 30(5): 454-456. DOI: 10.1177/0748730415591662. PMID- 26527095 TI - Dissecting Daily and Circadian Expression Rhythms of Clock-Controlled Genes in Human Blood. AB - The identification and investigation of novel clock-controlled genes (CCGs) has been conducted thus far mainly in model organisms such as nocturnal rodents, with limited information in humans. Here, we aimed to characterize daily and circadian expression rhythms of CCGs in human peripheral blood during a sleep/sleep deprivation (S/SD) study and a constant routine (CR) study. Blood expression levels of 9 candidate CCGs (SREBF1, TRIB1, USF1, THRA1, SIRT1, STAT3, CAPRIN1, MKNK2, and ROCK2), were measured across 48 h in 12 participants in the S/SD study and across 33 h in 12 participants in the CR study. Statistically significant rhythms in expression were observed for STAT3, SREBF1, TRIB1, and THRA1 in samples from both the S/SD and the CR studies, indicating that their rhythmicity is driven by the endogenous clock. The MKNK2 gene was significantly rhythmic in the S/SD but not the CR study, which implies its exogenously driven rhythmic expression. In addition, we confirmed the circadian expression of PER1, PER3, and REV-ERBalpha in the CR study samples, while BMAL1 and HSPA1B were not significantly rhythmic in the CR samples; all 5 genes previously showed significant expression in the S/SD study samples. Overall, our results demonstrate that rhythmic expression patterns of clock and selected clock controlled genes in human blood cells are in part determined by exogenous factors (sleep and fasting state) and in part by the endogenous circadian timing system. Knowledge of the exogenous and endogenous regulation of gene expression rhythms is needed prior to the selection of potential candidate marker genes for future applications in medical and forensic settings. PMID- 26527094 TI - The Circadian Clock in the Regulation of Renal Rhythms. AB - Since the kidney is integral to maintenance of fluid and ion homeostasis, and therefore blood pressure regulation, its proper function is paramount. Circadian fluctuations in blood pressure, renal blood flow, glomerular filtration rate, and sodium and water excretion have been documented for decades, if not longer. Recent studies on the role of circadian clock proteins in the regulation of a variety of renal transport genes suggest that the molecular clock in the kidney controls circadian fluctuations in renal function. The circadian clock appears to be a critical regulator of renal function with important implications for the treatment of renal pathologies, which include chronic kidney disease and hypertension. The development, regulation, and mechanism of the kidney clock are reviewed here. PMID- 26527096 TI - Face-induced expectancies influence neural mechanisms of performance monitoring. AB - In many daily situations, the consequences of our actions are predicted by cues that are often social in nature. For instance, seeing the face of an evaluator (e.g., a supervisor at work) may activate certain evaluative expectancies, depending on the history of prior encounters with that particular person. We investigated how such face-induced expectancies influence neurocognitive functions of performance monitoring. We recorded an electroencephalogram while participants completed a time-estimation task, during which they received performance feedback from a strict and a lenient evaluator. During each trial, participants first saw the evaluator's face before performing the task and, finally, receiving feedback. Therefore, faces could be used as predictive cues for the upcoming evaluation. We analyzed electrocortical signatures of performance monitoring at the stages of cue processing, task performance, and feedback reception. Our results indicate that, at the cue stage, seeing the strict evaluator's face results in an anticipatory preparation of fronto-medial monitoring mechanisms, as reflected by a sustained negative-going amplitude shift (i.e., the contingent negative variation). At the performance stage, face-induced expectancies of a strict evaluation rule led to increases of early performance monitoring signals (i.e., frontal-midline theta power). At the final stage of feedback reception, violations of outcome expectancies differentially affected the feedback-related negativity and frontal-midline theta power, pointing to a functional dissociation between these signatures. Altogether, our results indicate that evaluative expectancies induced by face-cues lead to adjustments of internal performance monitoring mechanisms at various stages of task processing. PMID- 26527097 TI - Weight Loss from Green Tea Extracts. PMID- 26527098 TI - Protective effect of branched chain amino acids on hindlimb suspension-induced muscle atrophy in growing rats. AB - PURPOSE: The effect of BCAA (branched chain amino acid) administration on muscle atrophy during growth phases is not well known. We investigated whether BCAA administration can prevent the muscle atrophy induced by hindlimb suspension in growing male rats. METHODS: Male Wistar rats were assigned to 1 of 2 groups (n = 7/group): hindlimb suspension and hindlimb suspension with oral BCAA administration (600 mg.kg(-1).day(-1), valine 1: leucine 2: isoleucine 1). After 14 days of hindlimb suspension, the weight and mRNA levels of the soleus muscle were measured. RESULTS: BCAA administration prevented a decrease in soleus muscle weight. BCAA administration attenuated atrogin-1 and MuRF1 mRNA expression, which has been reported to play a pivotal role in muscle atrophy. CONCLUSION: BCAA could serve as an effective supplement for the prevention or treatment of muscle atrophy, especially atrophy caused by weightlessness. PMID- 26527099 TI - Non-Contact Measurement of Thermal Diffusivity in Ion-Implanted Nuclear Materials. AB - Knowledge of mechanical and physical property evolution due to irradiation damage is essential for the development of future fission and fusion reactors. Ion irradiation provides an excellent proxy for studying irradiation damage, allowing high damage doses without sample activation. Limited ion-penetration-depth means that only few-micron-thick damaged layers are produced. Substantial effort has been devoted to probing the mechanical properties of these thin implanted layers. Yet, whilst key to reactor design, their thermal transport properties remain largely unexplored due to a lack of suitable measurement techniques. Here we demonstrate non-contact thermal diffusivity measurements in ion-implanted tungsten for nuclear fusion armour. Alloying with transmutation elements and the interaction of retained gas with implantation-induced defects both lead to dramatic reductions in thermal diffusivity. These changes are well captured by our modelling approaches. Our observations have important implications for the design of future fusion power plants. PMID- 26527100 TI - The Quantified Level of Circulating Prostate Stem Cell Antigen mRNA relative to GAPDH Level Is a Clinically Significant Indictor for Predicting Biochemical Recurrence in Prostate Cancer Patients after Radical Prostatectomy. AB - The study quantified the relative absolute PSCA level in relation to the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) level in the peripheral blood of 478 hormone-naive prostate cancer (PC) patients who underwent radical prostatectomy from 2005 to 2012 and evaluated its prognostic significance as a risk factor for predicting biochemical recurrence (BCR), compared to known parameters. Nested real-time polymerase chain reaction (RT-PCR) and gel electrophoresis detected PSCA levels and measured the PSCA/GAPDH ratio. Clinicopathological data from the institutional database were examined to determine the adequate cut-off level to predict postoperative BCR. A total of 110 patients had a positive PSCA result (23.0%) via RT-PCR (mean blood ratio 1.1 +/- 0.4). The BCR was significantly higher in the PSCA-positive detection group (p = 0.009). A multivariate model was created to show that a PSCA/GAPDH ratio between 1.0 and 1.5 (HR 12.722), clinical T2c stage (HR 0.104), preoperative PSA (HR 1.225), extraprostatic capsule extension (HR 0.006), lymph node dissection (HR 16.437), and positive resection margin (HR 27.453) were significant predictive factors for BCR (p < 0.05). The study showed successful quantification of PSCA with its significance for BCR-related risk factor; however, further studies are needed to confirm its clinical predictive value. PMID- 26527102 TI - Multiple Choice Questions. PMID- 26527101 TI - Geographical miss is associated with vulnerable plaque and increased major adverse cardiovascular events in patients with myocardial infarction. AB - OBJECTIVES: To determine the incidence, characteristics, and outcomes associated with geographical miss (GM) of plaque. BACKGROUND: GM describes plaques that are incompletely covered following stenting, with GM thought to be associated with worse clinical outcomes. However, the incidence and characteristics of intravascular ultrasound (IVUS)-defined GM plaques have never been studied and the relationship between GM with both short and long-term clinical events is unknown. METHODS: One hundred and seventy patients with stable angina (n = 100) or myocardial infarction (MI) (n = 70) underwent virtual-histology IVUS (VH-IVUS) prior to, and following, percutaneous coronary intervention (PCI). GM was defined as three consecutive uncovered VH frames, either proximal or distal to the stented segment with plaque burden >40%. MACE was defined as a composite of death, myocardial infarction, unplanned revascularization, or hospitalization for angina. RESULTS: In total, 245 plaques underwent PCI with 80 (32.7%) displaying evidence of GM (69 patients). GM was associated with increased plaque volume (p < 0.001), % necrotic core, and dense calcium (both p < 0.001) and VH-defined thin cap fibroatheroma (VH-TCFA) (p = 0.01). GM was not associated with increased periprocedural MI (p = 0.15) or inflammatory cytokine release. At follow-up, 42 MACE occurred in 28 patients (median 1,115 days). MACE was attributable to 8/80 (10%) plaques with and 7/165 (4.2%) plaques without GM (log-rank p = 0.11). GM was associated with increased MACE in patients presenting with MI (p = 0.015), but not for those with stable angina (p = 0.94). CONCLUSIONS: GM is common after PCI and associated with more vulnerable plaque composition/subtype. GM may confer a worse prognosis in patients undergoing PCI for MI. (c) 2015 Wiley Periodicals, Inc. PMID- 26527103 TI - Successful Repeat Catheter Ablation of Recurrent Longstanding Persistent Atrial Fibrillation With Rotor Elimination as the Procedural Endpoint: A Case Series. AB - BACKGROUND: There remains a lack of consensus regarding the ideal ablation strategy for atrial fibrillation (AF), particularly in patients with persistent or longstanding persistent AF. Given increasing evidence from clinical imaging studies that rotors sustain AF, rotor elimination may be a desirable procedural endpoint. However, there is no description to date of the clinical outcomes using rotor elimination during ablation as the procedural endpoint. Moreover, a series of studies question whether procedural AF termination is a desirable endpoint for ablation after many forms of AF ablation. METHODS AND RESULTS: We report a single center experience of rotor elimination during AF ablation using Focal Impulse and Rotor Mapping (FIRM), describing 20 consecutive patients with case descriptions of 3 patients with recurrent longstanding persistent AF after prior ablation. In all cases, endocardial mapping using a 64-electrode basket catheter was performed to identify rotors, which were eliminated using radiofrequency catheter ablation. After it was verified that all identified rotors were eliminated, standard ablation consisting of PV isolation was performed. Notably, persistent AF terminated in only 1/20 (5%) patients. However, after a follow-up of 6 months, single-procedure freedom from AF was 80% (16/20 patients) with only 1 patient on antiarrhythmic drugs. All three patients in the highlighted series are AF free despite the lack of acute procedural AF termination. CONCLUSIONS: Patients with persistent AF including those with unsuccessful prior ablation can be treated successfully by rotor targeted ablation, using the elimination of all rotors rather than acute AF termination as the procedural endpoint. PMID- 26527104 TI - Sensory properties of the PII signalling protein family. AB - PII signalling proteins constitute one of the largest families of signalling proteins in nature. An even larger superfamily of trimeric sensory proteins with the same architectural principle as PII proteins appears in protein structure databases. Large surface-exposed flexible loops protrude from the intersubunit faces, where effector molecules are bound that tune the conformation of the loops. Via this mechanism, PII proteins control target proteins in response to cellular ATP/ADP levels and the 2-oxoglutarate status, thereby coordinating the cellular carbon/nitrogen balance. The antagonistic (ATP versus ADP) and synergistic (2-oxoglutarate and ATP) mode of effector molecule binding is further affected by PII -receptor interaction, leading to a highly sophisticated signalling network organized by PII . Altogether, it appears that PII is a multitasking information processor that, depending on its interaction environment, differentially transmits information on the energy status and the cellular 2-oxoglutarate level. In addition to the basic mode of PII function, several bacterial PII proteins may transmit a signal of the cellular glutamine status via covalent modification. Remarkably, during the evolution of plant chloroplasts, glutamine signalling by PII proteins was re-established by acquisition of a short sequence extension at the C-terminus. This plant-specific C-terminus makes the interaction of plant PII proteins with one of its targets, the arginine biosynthetic enzyme N-acetyl-glutamate kinase, glutamine-dependent. PMID- 26527106 TI - Honoring Our Past, Building Our Future. PMID- 26527105 TI - Cortical Lewy bodies and Abeta burden are associated with prevalence and timing of dementia in Lewy body diseases. AB - AIMS: Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. METHODS: One hundred and twenty-one cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Abeta plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. RESULTS: The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, P < 0.001). The total cortical Abeta plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (P = 0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE epsilon4 allele was associated with a higher cortical LB burden (P = 0.02), particularly in the neocortical frontal, parietal and temporal regions. CONCLUSIONS: High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Abeta plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE epsilon4 allele. PMID- 26527107 TI - Developing Items to Measure Theory of Planned Behavior Constructs for Opioid Administration for Children: Pilot Testing. AB - The Theory of Planned Behavior (TpB) is useful to direct nursing research aimed at behavior change. As proposed in the TpB, individuals' attitudes, perceived norms, and perceived behavior control predict their intentions to perform a behavior and subsequently predict their actual performance of the behavior. Our purpose was to apply Fishbein and Ajzen's guidelines to begin development of a valid and reliable instrument for pediatric nurses' attitudes, perceived norms, perceived behavior control, and intentions to administer PRN opioid analgesics when hospitalized children self-report moderate to severe pain. Following Fishbein and Ajzen's directions, we were able to define the behavior of interest and specify the research population, formulate items for direct measures, elicit salient beliefs shared by our target population and formulate items for indirect measures, and prepare and test our questionnaire. For the pilot testing of internal consistency of measurement items, Cronbach alphas were between 0.60 and 0.90 for all constructs. Test-retest reliability correlations ranged from 0.63 to 0.90. Following Fishbein and Ajzen's guidelines was a feasible and organized approach for instrument development. In these early stages, we demonstrated good reliability for most subscales, showing promise for the instrument and its use in pain management research. Better understanding of the TpB constructs will facilitate the development of interventions targeted toward nurses' attitudes, perceived norms, and/or perceived behavior control to ultimately improve their pain behaviors toward reducing pain for vulnerable children. PMID- 26527108 TI - Chiral Sulfinamide Bisphosphine Catalysts: Design, Synthesis, and Application in Highly Enantioselective Intermolecular Cross-Rauhut-Currier Reactions. AB - A novel type of highly efficient chiral sulfinamide bisphosphine catalysts (Wei Phos) were developed. These could be easily prepared from commercially available starting materials. Wei-Phos has shown good performance in the very challenging intermolecular cross-Rauhut-Currier reactions of vinyl ketones and 3-acyl acrylates or 2-ene-1,4-diones, leading to the R-C products in high yields with up to 99% ee under 2.5-5 mol% catalyst loading. The highly regio- and enantio selective cross-Rauhut-Currier reactions of 2-ene-1,4-diones and vinyl ketone have yet reported so far. PMID- 26527109 TI - Relationship Between Self-Reported Health and Stress in Mothers of Children with Autism Spectrum Disorders. AB - The current study explore the relationship between various forms of experienced stress (general stress and parenting stress) and both health-related quality of life (QoL) and reported physical health symptoms. One hundred and twenty-two mothers of children with autism spectrum disorder responded to an online survey included questionnaires on general stress, parenting stress, health-related QoL, and physical symptoms. The results suggested that perceived general stress as associated with both a reduced health-related QoL and more physical symptoms. However, parenting stress was only associated with a reduced health-related QoL, and not with physical health. These results are discussed in relation to the complex impact of prolonged and predictable parenting stress on the cortisol response and immune system. PMID- 26527111 TI - A meta-analysis of case-control studies of the association of migraine and patent foramen ovale. AB - OBJECTIVES: To establish quantitative evidence, we performed the first meta analysis of case-control studies assessing the relationship between migraine and patent foramen ovale (PFO). METHODS: MEDLINE and EMBASE were searched through April 2015 using PubMed and OVID. Eligible studies were case-control studies reporting PFO (or migraine) prevalence in migraine patients versus no-migraine subjects (or PFO patients versus no-PFO subjects). RESULTS: Of 395 potentially relevant articles screened initially, 21 eligible studies enrolling a total of 5572 participants were identified and included. Pooled analyses demonstrated statistically significant 3.36-fold migraine-with-aura [odds ratio (OR), 3.36; 95% confidence interval (CI), 2.04-5.55; p<0.00001] and 2.46-fold migraine with/without-aura prevalence (OR, 2.46; 95% CI, 1.55-3.91; p=0.0001) but statistically non-significant 1.30-fold migraine-without-aura prevalence (OR, 1.30; 95% CI, 0.85-1.99; p=0.22) in PFO patients relative to no-PFO subjects. CONCLUSIONS: PFO is associated with 3.4-fold migraine-with-aura and 2.5-fold migraine-with/without-aura prevalence but unassociated with migraine-without-aura prevalence. PMID- 26527110 TI - Brief Report: Whole Blood Serotonin Levels and Gastrointestinal Symptoms in Autism Spectrum Disorder. AB - Elevated whole blood serotonin levels are observed in more than 25% of children with autism spectrum disorder (ASD). Co-occurring gastrointestinal (GI) symptoms are also common in ASD but have not previously been examined in relationship with hyperserotonemia, despite the synthesis of serotonin in the gut. In 82 children and adolescents with ASD, we observed a correlation between a quantitative measure of lower GI symptoms and whole blood serotonin levels. No significant association was seen between functional constipation diagnosis and serotonin levels in the hyperserotonemia range, suggesting that this correlation is not driven by a single subgroup. More specific assessment of gut function, including the microbiome, will be necessary to evaluate the contribution of gut physiology to serotonin levels in ASD. PMID- 26527112 TI - Associations of residual left ventricular and left atrial remodeling with clinical outcomes in patients after aortic valve replacement for severe aortic stenosis. AB - BACKGROUND: Aortic valve replacement (AVR) is currently the standard therapy for severe aortic stenosis (AS), and regression of left ventricular (LV) hypertrophy after AVR has been reported. However, data regarding a temporal relation between LV mass and left atrial (LA) volume are limited, and their prognostic impacts have not been fully elucidated. We aimed to clarify the temporal patterns of LA and LV reverse remodeling and their associations with clinical outcomes. METHODS: We retrospectively reviewed 198 consecutive patients who underwent AVR for severe AS. After excluding patients with prior cardiac surgery, atrial fibrillation, concomitant moderate to severe aortic regurgitation, or concurrent mitral valve surgery, 83 patients with echocardiographic LV mass index (LVMI) and LA volume index (LAVI) data before and 1 year after AVR were eligible for the outcome analysis and 29 patients with these 2 measures before surgery, 1 month, 1 year, and 3 years after surgery were eligible for the analysis of time-dependent change of LVMI and LAVI. RESULTS: Significant reductions in LVMI and LAVI (both p<0.001) after surgery were observed over time. LA dilatation improved and reached a plateau 1 month after surgery, whereas LV hypertrophy improved more gradually and reached a plateau at 1 year. The presence of both LV hypertrophy and LA dilatation 1 year after surgery was associated with significantly higher mortality (patients with both conditions vs. patients with neither or one condition=22.6% vs. 7.3% at 3 years; p=0.031) and major adverse cardiac and cerebrovascular events (38.9% vs. 12.6% at 3 years; p=0.021). CONCLUSIONS: LA reverse remodeling occurred rapidly after AVR for severe AS, and regression of LV hypertrophy was more gradual. The presence of both residual LV hypertrophy and LA dilatation 1 year after AVR was associated with poor long-term outcomes. PMID- 26527113 TI - Clinical characteristics of hemodialysis patients with atrial fibrillation: The RAKUEN (Registry of atrial fibrillation in chronic kidney disease under hemodialysis from Niigata) study. AB - BACKGROUND: Clinical characteristics, management, and outcomes in hemodialysis patients with atrial fibrillation (AF) remain unclear. METHODS AND RESULTS: We studied 423 Japanese patients undergoing maintenance hemodialysis (age 65.2+/ 12.4 years, male 70%, mean duration of hemodialysis 139+/-124 months). AF was present in 19% (n=82) and was independently related to increased age (odds ratio 1.070, 95% confidence interval 1.043-1.098), longer hemodialysis duration (odds ratio 1.006, 95% confidence interval 1.004-1.008), and congestive heart failure (odds ratio 2.749, 95% confidence interval 1.546-4.891). During observations lasting a mean of 36 months, the incidences of all-cause death, cardiovascular death, and major bleeding, in particular gastrointestinal bleeding, were significantly higher in the AF (n=82) than the non-AF (n=341) patients (p<0.001, p=0.004, p=0.002, p=0.027, respectively), but the incidence of ischemic stroke/systemic embolism was similar in the AF and non-AF patients. AF was independently associated with all-cause death (hazard ratio 1.728, 95% confidence interval 1.123-2.660) and major bleeding (hazard ratio 1.984, 95% confidence interval 1.010-3.896). Warfarin was prescribed in 33% of the AF patients, but the rates of all-cause death, ischemic stroke, and major bleeding during the study period were not significantly different between warfarin (n=27) and non-warfarin (n=55) groups. CONCLUSIONS: In our hemodialysis patients, AF was a common comorbidity and was independently associated with all-cause death and major bleeding, but not with increased risk of ischemic stroke. PMID- 26527114 TI - The postnatal morbidity associated with second-trimester miscarriage. AB - OBJECTIVE(S): To describe the complications, and their incidence, associated with the management and delivery of a distinct second-trimester miscarriage cohort. METHODS: A retrospective cohort study was undertaken in a large, tertiary referral university hospital (8500 deliveries per annum). All cases of pregnancy loss occurring between 14(+0) and 23(+6) were identified from July 2009 to June 2013 (n = 181). Medical notes were reviewed and the number of complications among this cohort was identified. Logistic regression was conducted to assess associations with clinical presentation and management. RESULTS: The mean gestation of loss was 18(+2) weeks (SD: 2(+2)). 64.6% (n = 117) of the total losses were of intrauterine fetal demise (IUFD) with 17.7% (n = 32) following preterm premature rupture of membranes (PPROM) and 17.7% (n = 32) following preterm labour (PTL). All women required inpatient admission with 59.1% (n = 107) undergoing medical induction of labour. PPROM cases, compared with cases of IUFD, had increased odds of requiring antibiotic therapy (OR 13.75, 95% CI: 4.88-38.72) and readmission (OR OR 4.15, 95% CI 1.12-15.36). CONCLUSION: These women represent a small proportion of the obstetric population but remain a distinct cohort whose management is complicated by high rates of morbidity requiring medical intervention. An awareness of these risks should inform future clinical practice. PMID- 26527115 TI - Fungal chitinases: function, regulation, and potential roles in plant/pathogen interactions. AB - In the past decades our knowledge about fungal cell wall architecture increased tremendously and led to the identification of many enzymes involved in polysaccharide synthesis and remodeling, which are also of biotechnological interest. Fungal cell walls play an important role in conferring mechanic stability during cell division and polar growth. Additionally, in phytopathogenic fungi the cell wall is the first structure that gets into intimate contact with the host plant. A major constituent of fungal cell walls is chitin, a homopolymer of N-acetylglucosamine units. To ensure plasticity, polymeric chitin needs continuous remodeling which is maintained by chitinolytic enzymes, including lytic polysaccharide monooxygenases N-acetylglucosaminidases, and chitinases. Depending on the species and lifestyle of fungi, there is great variation in the number of encoded chitinases and their function. Chitinases can have housekeeping function in plasticizing the cell wall or can act more specifically during cell separation, nutritional chitin acquisition, or competitive interaction with other fungi. Although chitinase research made huge progress in the last decades, our knowledge about their role in phytopathogenic fungi is still scarce. Recent findings in the dimorphic basidiomycete Ustilago maydis show that chitinases play different physiological functions throughout the life cycle and raise questions about their role during plant-fungus interactions. In this work we summarize these functions, mechanisms of chitinase regulation and their putative role during pathogen/host interactions. PMID- 26527116 TI - Characterization of complete mitochondrial genome of Dezhou donkey (Equus asinus) and evolutionary analysis. AB - Mitochondrial DNA (mtDNA) has been widely used in species identification and genetic diversification. Comparisons among mtDNAs of closely related species are valuable for phylogenetic studies. However, only the partial mtDNA Cytb gene and the D-loop sequences were used to analysis the phylogenetic relationship between donkey breeds due to lack of complete mitochondrial genome. Dezhou donkey, as a bigger somatotype ass, is one of Chinese domestic donkey breeds, and used by many places as breeding stock. To further investigate the phylogenetic relationship of Dezhou donkey with other breeds, the complete mtDNA was firstly sequenced and de novo assembled using next generation sequence data from total genomic DNA. The genome was 16,813 bp in length (NCBI submission number: KT182635) and contained 13 protein coding genes, 2 ribosomal RNA genes, 25 transfer RNA genes, and 1 control region. Based on the novel complete mtDNA sequence, the sequences of 13 protein coding genes and 2 ribosomal RNA genes were amplifying in other 2 Dezhou donkeys and 3 Yunnan donkeys, respectively. The pattern of genetic variation in horse, wild ass and domestic donkeys among these 15 genes indicated the sequence polymorphisms. The more accurate phylogenetic relationships of donkey species (Dezhou donkey, Yunnan donkey and previously published donkeys) were first obtained using the combined sequences of 12S rRNA+16S rRNA+13 protein-coding genes. Molecular-based phylogeny supported the hypothesis that Chinese domestic donkey breeds may have originated from Somali wild ass, not from Asian wild ass by analyzing mitochondrial genomes. PMID- 26527117 TI - Response to letter entitled Plasma MMPs in CAD patients by Ceron CS et al. PMID- 26527118 TI - Musical Sequence Learning and EEG Correlates of Audiomotor Processing. AB - Our motor and auditory systems are functionally connected during musical performance, and functional imaging suggests that the association is strong enough that passive music listening can engage the motor system. As predictive coding constrains movement sequence selections, could the motor system contribute to sequential processing of musical passages? If this is the case, then we hypothesized that the motor system should respond preferentially to passages of music that contain similar sequential information, even if other aspects of music, such as the absolute pitch, have been altered. We trained piano naive subjects with a learn-to play-by-ear paradigm, to play a simple melodic sequence over five days. After training, we recorded EEG of subjects listening to the song they learned to play, a transposed version of that song, and a control song with different notes and sequence from the learned song. Beta band power over sensorimotor scalp showed increased suppression for the learned song, a moderate level of suppression for the transposed song, and no suppression for the control song. As beta power is associated with attention and motor processing, we interpret this as support of the motor system's activity during covert perception of music one can play and similar musical sequences. PMID- 26527119 TI - CRISP: Catheterization RISk score for Pediatrics: A Report from the Congenital Cardiac Interventional Study Consortium (CCISC). AB - OBJECTIVES: We sought to develop a scoring system that predicts the risk of serious adverse events (SAE's) for individual pediatric patients undergoing cardiac catheterization procedures. BACKGROUND: Systematic assessment of risk of SAE in pediatric catheterization can be challenging in view of a wide variation in procedure and patient complexity as well as rapidly evolving technology. METHODS: A 10 component scoring system was originally developed based on expert consensus and review of the existing literature. Data from an international multi institutional catheterization registry (CCISC) between 2008 and 2013 were used to validate this scoring system. In addition we used multivariate methods to further refine the original risk score to improve its predictive power of SAE's. RESULTS: Univariate analysis confirmed the strong correlation of each of the 10 components of the original risk score with SAE attributed to a pediatric cardiac catheterization (P < 0.001 for all variables). Multivariate analysis resulted in a modified risk score (CRISP) that corresponds to an increase in value of area under a receiver operating characteristic curve (AUC) from 0.715 to 0.741. CONCLUSION: The CRISP score predicts risk of occurrence of an SAE for individual patients undergoing pediatric cardiac catheterization procedures. PMID- 26527120 TI - Trigeminal Neuralgia - A Debilitating Facial Pain. AB - Trigeminal neuralgia (TN) is characterised by sudden usually unilateral severe, brief, stabbing, recurrent episodes of pain in the distribution of one or more branches of the trigeminal nerve.Diagnosis is largely based on clinical history due to the current lack of objective investigations.MRI can identify those patients who have TN secondary to an underlying pathology such as multiple sclerosis.The first line medical management remains carbamazepine, with oxcarbazepine being the second choice medication.Both percutaneous techniques targeting the Gasserian ganglion and microvascular decompression can be considered effective in the management of TN. Microvascular decompression is considered to provide on average, the longest pain free period post surgery.There are a number of TN associations and support groups which provide a valued service to patients and clinicians.Due to a dearth of high quality studies in many aspects of the condition, TN requires further research to be conducted. PMID- 26527123 TI - Editorial. PMID- 26527121 TI - Influence of P53 on the radiotherapy response of hepatocellular carcinoma. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and it has a poor prognosis and few therapeutic options. Radiotherapy is one of the most effective forms of cancer treatment, and P53 protein is one of the key molecules determining how a cell responds to radiotherapy. The aim of this study was to determine the therapeutic efficacy of iodine-131 in three human HCC cell lines. METHODS: Western blotting was used to measure P53 expression. The effects of radiotherapy with iodine-131 were assessed by using the clonogenic assay to evaluate cell survival. Flow cytometry was carried out to examine the effects of iodine-131 on cell death, oxidative stress, reduced intracellular glutathione expression, the mitochondrial membrane potential, and the cell cycle. RESULTS: The P53 protein was not expressed in Hep3B2.1-7 cells, was expressed at normal levels in HepG2 cells, and was overexpressed in HuH7 cells. P53 expression in the HuH7 and HepG2 cell lines increased after internal and external irradiation with iodine-131. Irradiation induced a decrease in cell survival and led to a decrease in cell viability in all of the cell lines studied, accompanied by cell death via late apoptosis/necrosis and necrosis. Irradiation with 131 iodine induced mostly cell-cycle arrest in the G0/G1 phase. CONCLUSIONS: These results suggest that P53 plays a key role in the radiotherapy response of HCC. PMID- 26527122 TI - Serial full-thickness excision of dysplastic vocal fold leukoplakia: Diagnostic or therapeutic? AB - OBJECTIVES/HYPOTHESIS: A previous study proposed that serial full-thickness excisional biopsies of vocal fold leukoplakia therapeutically decreased dysplasia grade. The current investigation aimed to 1) analyze the pathological evolution and natural history of these lesions and 2) re-examine the role of serial excisions in dysplasia grade regression in long-term follow-up. STUDY DESIGN: Retrospective case series. METHODS: Patients treated for vocal fold dysplasia (1994-2013) with serial full-thickness microflap-type excisions were identified and followed longitudinally. Excluded were those with one excision, invasive cancer at initial excision, or history of laryngeal cancer or radiation. Data from surgical procedures, associated pathology, and patient characteristics were recorded. Weighted repeated measures ordinal logistic regression measured associations with pathology findings. RESULTS: Of 55 patients (median age = 65 years, interquartile range = 54-73 years, 89% male, 63% ever smokers, 27% alcohol users), 31 met inclusion criteria. During the study period, patients had two to 44 excisions, with a median time between excisions of 4.0 months. Each additional excision increased odds of higher-grade pathology by 4% (odds ratio = 1.04, 95% confidence interval = 1.01-1.06; P = .007). A transition model demonstrated that patients with moderate dysplasia, severe dysplasia, or carcinoma in situ on a prior biopsy had 2.64-, 5.64-, and 8.73-times increased odds of the same or higher pathology grade at the next excision, respectively. CONCLUSIONS: Data do not support the hypothesis that serial full-thickness excisions decrease dysplasia grade. Progression of dysplasia appears to be nonlinear, but higher grade dysplasia is more likely to progress to malignancy. LEVEL OF EVIDENCE: 4. PMID- 26527125 TI - Perspectives and visions on CO2 capture and utilisation. AB - This article summarises and contextualises the debates which occurred during the Carbon Dioxide Utilisation Faraday Discussion meeting. The utilisation of carbon dioxide is discussed in terms of both conversion to fuel, with a potential impact on atmospheric carbon dioxide levels, and conversion to chemicals with a potential impact on sustainability. PMID- 26527124 TI - Confidence level in venipuncture and knowledge on causes of in vitro hemolysis among healthcare professionals. AB - INTRODUCTION: This study aimed to assess confidence level of healthcare professionals in venipuncture and their knowledge on the possible causes of in vitro hemolysis. MATERIALS AND METHODS: A sample of 94 healthcare professionals (nurses and laboratory technicians) participated in this survey study. A four section questionnaire was used as a research instrument comprising general information for research participants, knowledge on possible causes of in vitro hemolysis due to type of material used and venipuncture technique and specimen handling, as well as assessment of healthcare professionals' confidence level in their own ability to perform first and last venipuncture. RESULTS: The average score on the knowledge test was higher in nurses' than in laboratory technicians (8.11+/-1.7, and 7.4+/-1.5, respectively). The difference in average scores was statistically significant (P=0.035) and Cohen's d in the range of 0.4 indicates that there is a moderate difference on the knowledge test among the health care workers. Only 11/94 of healthcare professionals recognized that blood sample collection from cannula and evacuated tube is method which contributes most to the occurrence of in vitro hemolysis, whereas most risk factors affecting occurrence of in vitro hemolysis during venipuncture were recognized. There were no significant differences in mean score on the knowledge test in relation to the confidence level in venipuncture (P=0.551). CONCLUSION: Confidence level at last venipuncture among both profiles of healthcare staff was very high, but they showed insufficient knowledge about possible factors affecting hemolysis due to materials used in venipuncture compared with factors due to venipuncture technique and handling of blood sample. PMID- 26527126 TI - Breath Analysis Using a Time-of-Flight Camera and Pressure Belts. AB - The proper way of breathing is important for everyone. Healthy people often do not follow respiration until breathing problems start-during stress or during sport activity in physiological cases. More serious cases are stroke, injury, or surgery of the chest and others. So, learning to breathe correctly and/or breathing diagnosis is considerable for many reasons. Two novel methods of breath analysis suitable for diagnostics and rehabilitation are presented. The first technique utilizes pressure belts fastened to the patient's belly and chest, and the second method relies on a SwissRanger SR-4000 time-of-flight camera. The measurement principles are described together with the advantages and disadvantages of the applied techniques. The SwissRanger camera depth calibration is proposed to facilitate better results during the breath analysis. The methods are tested on a group of students to provide a comparison of their individual performances. As it was demonstrated, presented methods proved to work reliably. The method based on time-of-flight camera seems to be more suitable for diagnosis, while the method based on pressure belts is more suitable for rehabilitation and biofeedback applications. PMID- 26527127 TI - Bioengineering Hematopoietic Stem Cell Niche toward Regenerative Medicine. AB - The scope of this chapter is to introduce the current consensus of hematopoietic stem cell (HSC) niche biology to bioengineering field so that can apply to regenerative medicine. A decade of research has been addressing "what is HSC niche", then next step is "how it advances medicine". The demand to improve HSC transplantation has advanced the methodology to expand HSC in vitro. Still precise modeling of bone marrow (BM) is demanded by bioengineering HSC niche in vitro. Better understanding of HSC niche is essential toward this progress. Now it would be the time to apply the knowledge of HSC niche field to the venue of bioengineering, so that a promising new approach to regenerative medicine might appear. This chapter describes the current consensus of niche that endothelial cell and perivascular mesenchymal stromal cell maintain HSC, expansion of cord blood HSC by small molecules, bioengineering efforts to model HSC niche by microfluidics chip, organoids, and breakthroughs to induce HSC from heterologous types of cells. PMID- 26527128 TI - Emotional and psychological trauma in refugees arriving in Germany in 2015. PMID- 26527129 TI - Entomopathogenic and plant pathogenic nematodes as opposing forces in agriculture. AB - Plant-parasitic nematodes are responsible for substantial damages within the agriculture industry every year, which is a challenge that has thus far gone largely unimpeded. Chemical nematicides have been employed with varying degrees of success, but their implementation can be cumbersome, and furthermore they could potentially be neutralising an otherwise positive effect from the entomopathogenic nematodes that coexist with plant-parasitic nematodes in soil environments and provide protection for plants against insect pests. Recent research has explored the potential of employing entomopathogenic nematodes to protect plants from plant-parasitic nematodes, while providing their standard degree of protection against insects. The interactions involved are highly complex, due to both the three-organism system and the assortment of variables present in a soil environment, but a strong collection of evidence has accumulated regarding the suppressive capacity of certain entomopathogenic nematodes and their mutualistic bacteria, in the context of limiting the infectivity of plant-parasitic nematodes. Specific factors produced by certain entomopathogenic nematode complexes during the process of insect infection appear to have a selectively nematicidal, or at least repellant, effect on plant parasitic nematodes. Using this information, an opportunity has formed to adapt this relationship to large-scale, field conditions and potentially relieve the agricultural industry of one of its most substantial burdens. PMID- 26527130 TI - A virtual ward for home hemodialysis patients - a pilot trial. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) have a high rate of hospitalization and are prone to care gaps that may occur during the transition from hospital to home. The virtual ward (VW) is an innovative model that provides short-term transitional care to patients upon hospital discharge. The VW may be an effective intervention to address care gaps. OBJECTIVES: The primary objective of the pilot study was to assess the feasibility and practicality of implementing the Home Dialysis VW (HDVW) on a broader scale. DESIGN: The HDVW Pilot Study enrolled home hemodialysis patients following one of four inclusion criteria: 1. Discharge from hospital, 2. Completion of an in-hospital medical procedure, 3. Prescription of an antibiotic, 4. Completion of home hemodialysis training. Patients were followed in the HDVW for 14 days and during this time were assessed serially with a clinician-led telephone interview for one of three transitional care gaps: 1. Requirement for change in hemodialysis prescription, 2. Requirement for coordination of follow-up care, 3. Requirement for medication change. SETTING: The study was conducted in Toronto, Ontario, Canada at a quaternary care academic teaching hospital from 2012-2013. PATIENTS: This study included 52 HDVW admissions among 35 patients selected from the existing home hemodialysis program. MEASUREMENTS: The primary outcome was the identification of the number of care gaps at each HDVW admission. Secondary outcomes included the identification of potential predictors of care gaps and description of clinical adverse events following HDVW admission (readmissions, emergency department visits, unplanned visits to the home hemodialysis in-center). RESULTS: The implementation and execution of the HDVW Pilot Study proved to be technically feasible and practical. A care gap was identified in 35 (67 %) of the HDVW admissions. In total, the cohort experienced 85 care gaps. There were no baseline demographic characteristics predictive of experiencing a care gap. In the total cohort observed for 2912 patient days, there were 9 readmissions, 13 visits to the emergency department, and 7 unplanned visits to the home hemodialysis in center unit. LIMITATIONS: The results of this study are limited by the small study size and single-center experience. CONCLUSION: The implementation of a virtual ward for home hemodialysis patients is practical, feasible and identifies many care gaps which have the potential to result in subsequent adverse events. A larger, multi-center prospective clinical trial is justified to identify if the HDVW can prevent adverse events among home dialysis patients. PMID- 26527131 TI - The impact of maternal hypothyroidism during pregnancy on neonatal outcomes: a systematic review and meta-analysis. AB - The effects of maternal hypothyroidism on neonatal outcomes were not definitely confirmed. We conduct a systematic review of the literatures on the impact of maternal hypothyroidism on neonatal outcomes. We searched Pubmed, Embase and the Cochrane Controlled Trials Register databases complemented by manual searches in article references without language restrictions published from 1946 to April 2015. Nine trials are included. For preterm birth in pregnancies of hypothyroidism women, there is an increased tendency (RR 1.18; 95% CI 0.99 to 1.40; p = 0.06). The same result is seen relating to the low birth weight (RR 1.31; 95% CI 1.00 to 1.72; p = 0.05). Regarding small for gestational age there is no significant increase. Children who were born from mothers with hypothyroidism during pregnancy have increased birth weight (MD 32.35, 95% CI 7.46 to 57.24; p = 0.01). The impact of maternal hypothyroidism shows a trend of reduced risk of large for gestational age (RR 1.17; 95% CI 0.99 to 1.38; p = 0.06). Our review suggests that mothers with hypothyroidism during pregnancy are more likely to give birth to children with higher birth weight or LGA, and L-T4 supplementation should be recommended. The risk of preterm birth and low birth weight also tends to be higher in children with hypothyroidism mothers. PMID- 26527132 TI - CHK1 and replicative stress in T-cell leukemia: Can an irreverent tumor suppressor end up playing the oncogene? AB - Replicative stress (RS) is a cell-intrinsic phenomenon enhanced by oncogenic transformation. Checkpoint kinase 1 (CHK1) is a key component of the ATR dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair. Taking this knowledge into account, one would predict CHK1 behaves strictly as a tumor suppressor. However, the reality seems far more complex. CHEK1 loss-of-function mutations have not been found in human tumors, and transgenic expression of Chek1 in mice promotes oncogene-induced transformation through RS inhibition. Moreover, CHK1 is overexpressed in various human cancers and CHK1 inhibitors have been developed as sensitizers to enhance the cytotoxicity of DNA damage-inducing chemotherapies. Here, we summarize the literature on the involvement of CHK1 in cancer progression, including our recent observation that CHK1 sustains T-cell acute lymphoblastic leukemia (T-ALL) cell viability. We also debate the importance of identifying patients that could benefit the most from treatment with CHK1 inhibitors, taking T-ALL as a model, and propose possible markers of therapeutic response. PMID- 26527133 TI - Effect of sensorial stimulations on postural disturbances related to spatial cognition disorders after stroke. AB - Balance disorders related to disturbances in perception of spatial reference systems are common especially after right hemispheric stroke. Mental misrepresentation of bodily orientation in space is then often superimposed upon other factors affecting imbalance such as motor and sensory impairments. Traditional rehabilitation for balance recovery has not been specifically designed to improve balance disorders related to spatial cognition. The traditional approach, consisting of stimulating the conscious perception of body orientation in space, is demanding and laborious. The approach based on sensorial stimulation is completely different. The relevance of this method lies in the fact that, firstly it is specifically active in the cognitive component of balance disorders; and secondly, it can passively be applied with minimal patient participation, which is of particular importance for this patient group characterized by disorders of attention and concentration. These techniques, such as proprioceptive, visual or vestibular stimulation, have been found to correct spatial neglect but also postural bias. Clinical and data from functional neuro imaging suggest a direct central action on cortical structures involved in the elaboration of spatial representation. These are promising techniques for the rehabilitation of postural disturbances related to spatial cognition disorders but are as yet at the stage of preliminary results. PMID- 26527134 TI - Deformable complex network for refining low-resolution X-ray structures. AB - In macromolecular X-ray crystallography, building more accurate atomic models based on lower resolution experimental diffraction data remains a great challenge. Previous studies have used a deformable elastic network (DEN) model to aid in low-resolution structural refinement. In this study, the development of a new refinement algorithm called the deformable complex network (DCN) is reported that combines a novel angular network-based restraint with the DEN model in the target function. Testing of DCN on a wide range of low-resolution structures demonstrated that it constantly leads to significantly improved structural models as judged by multiple refinement criteria, thus representing a new effective refinement tool for low-resolution structural determination. PMID- 26527135 TI - Structural analysis of an oxygen-regulated diguanylate cyclase. AB - Cyclic di-GMP is a bacterial second messenger that is involved in switching between motile and sessile lifestyles. Given the medical importance of biofilm formation, there has been increasing interest in understanding the synthesis and degradation of cyclic di-GMPs and their regulation in various bacterial pathogens. Environmental cues are detected by sensing domains coupled to GGDEF and EAL or HD-GYP domains that have diguanylate cyclase and phosphodiesterase activities, respectively, producing and degrading cyclic di-GMP. The Escherichia coli protein DosC (also known as YddV) consists of an oxygen-sensing domain belonging to the class of globin sensors that is coupled to a C-terminal GGDEF domain via a previously uncharacterized middle domain. DosC is one of the most strongly expressed GGDEF proteins in E. coli, but to date structural information on this and related proteins is scarce. Here, the high-resolution structural characterization of the oxygen-sensing globin domain, the middle domain and the catalytic GGDEF domain in apo and substrate-bound forms is described. The structural changes between the iron(III) and iron(II) forms of the sensor globin domain suggest a mechanism for oxygen-dependent regulation. The structural information on the individual domains is combined into a model of the dimeric DosC holoprotein. These findings have direct implications for the oxygen dependent regulation of the activity of the cyclase domain. PMID- 26527136 TI - Structures of yeast peroxisomal Delta(3),Delta(2)-enoyl-CoA isomerase complexed with acyl-CoA substrate analogues: the importance of hydrogen-bond networks for the reactivity of the catalytic base and the oxyanion hole. AB - Delta(3),Delta(2)-Enoyl-CoA isomerases (ECIs) catalyze the shift of a double bond from 3Z- or 3E-enoyl-CoA to 2E-enoyl-CoA. ECIs are members of the crotonase superfamily. The crotonase framework is used by many enzymes to catalyze a wide range of reactions on acyl-CoA thioesters. The thioester O atom is bound in a conserved oxyanion hole. Here, the mode of binding of acyl-CoA substrate analogues to peroxisomal Saccharomyces cerevisiae ECI (ScECI2) is described. The best defined part of the bound acyl-CoA molecules is the 3',5'-diphosphate adenosine moiety, which interacts with residues of loop 1 and loop 2, whereas the pantetheine part is the least well defined. The catalytic base, Glu158, is hydrogen-bonded to the Asn101 side chain and is further hydrogen-bonded to the side chain of Arg100 in the apo structure. Arg100 is completely buried in the apo structure and a conformational change of the Arg100 side chain appears to be important for substrate binding and catalysis. The oxyanion hole is formed by the NH groups of Ala70 (loop 2) and Leu126 (helix 3). The O atoms of the corresponding peptide units, Gly69 O and Gly125 O, are both part of extensive hydrogen-bond networks. These hydrogen-bond networks are a conserved feature of the crotonase oxyanion hole and their importance for catalysis is discussed. PMID- 26527137 TI - Structure of the ordered hydration of amino acids in proteins: analysis of crystal structures. AB - Crystallography provides unique information about the arrangement of water molecules near protein surfaces. Using a nonredundant set of 2818 protein crystal structures with a resolution of better than 1.8 A, the extent and structure of the hydration shell of all 20 standard amino-acid residues were analyzed as function of the residue conformation, secondary structure and solvent accessibility. The results show how hydration depends on the amino-acid conformation and the environment in which it occurs. After conformational clustering of individual residues, the density distribution of water molecules was compiled and the preferred hydration sites were determined as maxima in the pseudo-electron-density representation of water distributions. Many hydration sites interact with both main-chain and side-chain amino-acid atoms, and several occurrences of hydration sites with less canonical contacts, such as carbon-donor hydrogen bonds, OH-pi interactions and off-plane interactions with aromatic heteroatoms, are also reported. Information about the location and relative importance of the empirically determined preferred hydration sites in proteins has applications in improving the current methods of hydration-site prediction in molecular replacement, ab initio protein structure prediction and the set-up of molecular-dynamics simulations. PMID- 26527138 TI - Structural basis for the slow photocycle and late proton release in Acetabularia rhodopsin I from the marine plant Acetabularia acetabulum. AB - Although many crystal structures of microbial rhodopsins have been solved, those with sufficient resolution to identify the functional water molecules are very limited. In this study, the Acetabularia rhodopsin I (ARI) protein derived from the marine alga A. acetabulum was synthesized on a large scale by the Escherichia coli cell-free membrane-protein production method, and crystal structures of ARI were determined at the second highest (1.52-1.80 A) resolution for a microbial rhodopsin, following bacteriorhodopsin (BR). Examinations of the photochemical properties of ARI revealed that the photocycle of ARI is slower than that of BR and that its proton-transfer reactions are different from those of BR. In the present structures, a large cavity containing numerous water molecules exists on the extracellular side of ARI, explaining the relatively low pKa of Glu206(ARI), which cannot function as an initial proton-releasing residue at any pH. An interhelical hydrogen bond exists between Leu97(ARI) and Tyr221(ARI) on the cytoplasmic side, which facilitates the slow photocycle and regulates the pKa of Asp100(ARI), a potential proton donor to the Schiff base, in the dark state. PMID- 26527139 TI - On the accuracy of unit-cell parameters in protein crystallography. AB - The availability in the Protein Data Bank (PDB) of a number of structures that are presented in space group P1 but in reality possess higher symmetry allowed the accuracy and precision of the unit-cell parameters of the crystals of macromolecules to be evaluated. In addition, diffraction images from crystals of several proteins, previously collected as part of in-house projects, were processed independently with three popular software packages. An analysis of the results, augmented by published serial crystallography data, suggests that the apparent precision of the presentation of unit-cell parameters in the PDB to three decimal points is not justified, since these parameters are subject to errors of not less than 0.2%. It was also noticed that processing data including full crystallographic symmetry does not lead to deterioration of the refinement parameters; thus, it is not beneficial to treat the crystals as belonging to space group P1 when higher symmetry can be seen. PMID- 26527140 TI - Selecting soluble/foldable protein domains through single-gene or genomic ORF filtering: structure of the head domain of Burkholderia pseudomallei antigen BPSL2063. AB - The 1.8 A resolution crystal structure of a conserved domain of the potential Burkholderia pseudomallei antigen and trimeric autotransporter BPSL2063 is presented as a structural vaccinology target for melioidosis vaccine development. Since BPSL2063 (1090 amino acids) hosts only one conserved domain, and the expression/purification of the full-length protein proved to be problematic, a domain-filtering library was generated using beta-lactamase as a reporter gene to select further BPSL2063 domains. As a result, two domains (D1 and D2) were identified and produced in soluble form in Escherichia coli. Furthermore, as a general tool, a genomic open reading frame-filtering library from the B. pseudomallei genome was also constructed to facilitate the selection of domain boundaries from the entire ORFeome. Such an approach allowed the selection of three potential protein antigens that were also produced in soluble form. The results imply the further development of ORF-filtering methods as a tool in protein-based research to improve the selection and production of soluble proteins or domains for downstream applications such as X-ray crystallography. PMID- 26527141 TI - Superoxide reductase from Giardia intestinalis: structural characterization of the first SOR from a eukaryotic organism shows an iron centre that is highly sensitive to photoreduction. AB - Superoxide reductase (SOR), which is commonly found in prokaryotic organisms, affords protection from oxidative stress by reducing the superoxide anion to hydrogen peroxide. The reaction is catalyzed at the iron centre, which is highly conserved among the prokaryotic SORs structurally characterized to date. Reported here is the first structure of an SOR from a eukaryotic organism, the protozoan parasite Giardia intestinalis (GiSOR), which was solved at 2.0 A resolution. By collecting several diffraction data sets at 100 K from the same flash-cooled protein crystal using synchrotron X-ray radiation, photoreduction of the iron centre was observed. Reduction was monitored using an online UV-visible microspectrophotometer, following the decay of the 647 nm absorption band characteristic of the iron site in the glutamate-bound, oxidized state. Similarly to other 1Fe-SORs structurally characterized to date, the enzyme displays a tetrameric quaternary-structure arrangement. As a distinctive feature, the N terminal loop of the protein, containing the characteristic EKHxP motif, revealed an unusually high flexibility regardless of the iron redox state. At variance with previous evidence collected by X-ray crystallography and Fourier transform infrared spectroscopy of prokaryotic SORs, iron reduction did not lead to dissociation of glutamate from the catalytic metal or other structural changes; however, the glutamate ligand underwent X-ray-induced chemical changes, revealing high sensitivity of the GiSOR active site to X-ray radiation damage. PMID- 26527142 TI - The putative role of some conserved water molecules in the structure and function of human transthyretin. AB - Human transthyretin (hTTR) is a multifunctional protein that is involved in several neurodegenerative diseases. Besides the transportation of thyroxin and vitamin A, it is also involved in the proteolysis of apolipoprotein A1 and Abeta peptide. Extensive analyses of 32 high-resolution X-ray and neutron diffraction structures of hTTR followed by molecular-dynamics simulation studies using a set of 15 selected structures affirmed the presence of 44 conserved water molecules in its dimeric structure. They are found to play several important roles in the structure and function of the protein. Eight water molecules stabilize the dimeric structure through an extensive hydrogen-bonding network. The absence of some of these water molecules in highly acidic conditions (pH <= 4.0) severely affects the interfacial hydrogen-bond network, which may destabilize the native tetrameric structure, leading to its dissociation. Three pairs of conserved water molecules contribute to maintaining the geometry of the ligand-binding cavities. Some other water molecules control the orientation and dynamics of different structural elements of hTTR. This systematic study of the location, absence, networking and interactions of the conserved water molecules may shed some light on various structural and functional aspects of the protein. The present study may also provide some rational clues about the conserved water-mediated architecture and stability of hTTR. PMID- 26527143 TI - Structure of AadA from Salmonella enterica: a monomeric aminoglycoside (3'')(9) adenyltransferase. AB - Aminoglycoside resistance is commonly conferred by enzymatic modification of drugs by aminoglycoside-modifying enzymes such as aminoglycoside nucleotidyltransferases (ANTs). Here, the first crystal structure of an ANT(3'')(9) adenyltransferase, AadA from Salmonella enterica, is presented. AadA catalyses the magnesium-dependent transfer of adenosine monophosphate from ATP to the two chemically dissimilar drugs streptomycin and spectinomycin. The structure was solved using selenium SAD phasing and refined to 2.5 A resolution. AadA consists of a nucleotidyltransferase domain and an alpha-helical bundle domain. AadA crystallizes as a monomer and is a monomer in solution as confirmed by small angle X-ray scattering, in contrast to structurally similar homodimeric adenylating enzymes such as kanamycin nucleotidyltransferase. Isothermal titration calorimetry experiments show that ATP binding has to occur before binding of the aminoglycoside substrate, and structure analysis suggests that ATP binding repositions the two domains for aminoglycoside binding in the interdomain cleft. Candidate residues for ligand binding and catalysis were subjected to site directed mutagenesis. In vivo resistance and in vitro binding assays support the role of Glu87 as the catalytic base in adenylation, while Arg192 and Lys205 are shown to be critical for ATP binding. PMID- 26527144 TI - The structure of the GemC1 coiled coil and its interaction with the Geminin family of coiled-coil proteins. AB - GemC1, together with Idas and Geminin, an important regulator of DNA-replication licensing and differentiation decisions, constitute a superfamily sharing a homologous central coiled-coil domain. To better understand this family of proteins, the crystal structure of a GemC1 coiled-coil domain variant engineered for better solubility was determined to 2.2 A resolution. GemC1 shows a less typical coiled coil compared with the Geminin homodimer and the Geminin-Idas heterodimer structures. It is also shown that both in vitro and in cells GemC1 interacts with Geminin through its coiled-coil domain, forming a heterodimer that is more stable that the GemC1 homodimer. Comparative analysis of the thermal stability of all of the possible superfamily complexes, using circular dichroism to follow the unfolding of the entire helix of the coiled coil, or intrinsic tryptophan fluorescence of a unique conserved N-terminal tryptophan, shows that the unfolding of the coiled coil is likely to take place from the C-terminus towards the N-terminus. It is also shown that homodimers show a single-state unfolding, while heterodimers show a two-state unfolding, suggesting that the dimer first falls apart and the helices then unfold according to the stability of each protein. The findings argue that Geminin-family members form homodimers and heterodimers between them, and this ability is likely to be important for modulating their function in cycling and differentiating cells. PMID- 26527145 TI - Crystallographic study of a MATE transporter presents a difficult case in structure determination with low-resolution, anisotropic data and crystal twinning. AB - NorM from Neisseria gonorrhoeae (NorM-NG) belongs to the multidrug and toxic compound extrusion (MATE) family of membrane-transport proteins, which can extrude cytotoxic chemicals across cell membranes and confer multidrug resistance. Here, the structure determination of NorM-NG is described, which had been hampered by low resolution (~ 4 A), data anisotropy and pseudo-merohedral twinning. The crystal structure was solved using molecular replacement and was corroborated by conducting a difference Fourier analysis. The NorM-NG structure displays an extracellular-facing conformation, similar to that of NorM-NG bound to a crystallization chaperone. The approaches taken to determine the NorM-NG structure and the lessons learned from this study are discussed, which may be useful for analyzing X-ray diffraction data with similar shortcomings. PMID- 26527146 TI - Structure and inhibition of subunit I of the anthranilate synthase complex of Mycobacterium tuberculosis and expression of the active complex. AB - The tryptophan-biosynthesis pathway is essential for Mycobacterium tuberculosis (Mtb) to cause disease, but not all of the enzymes that catalyse this pathway in this organism have been identified. The structure and function of the enzyme complex that catalyses the first committed step in the pathway, the anthranilate synthase (AS) complex, have been analysed. It is shown that the open reading frames Rv1609 (trpE) and Rv0013 (trpG) encode the chorismate-utilizing (AS-I) and glutamine amidotransferase (AS-II) subunits of the AS complex, respectively. Biochemical assays show that when these subunits are co-expressed a bifunctional AS complex is obtained. Crystallization trials on Mtb-AS unexpectedly gave crystals containing only AS-I, presumably owing to its selective crystallization from solutions containing a mixture of the AS complex and free AS-I. The three dimensional structure reveals that Mtb-AS-I dimerizes via an interface that has not previously been seen in AS complexes. As is the case in other bacteria, it is demonstrated that Mtb-AS shows cooperative allosteric inhibition by tryptophan, which can be rationalized based on interactions at this interface. Comparative inhibition studies on Mtb-AS-I and related enzymes highlight the potential for single inhibitory compounds to target multiple chorismate-utilizing enzymes for TB drug discovery. PMID- 26527147 TI - Structural insight and flexible features of NS5 proteins from all four serotypes of Dengue virus in solution. AB - Infection by the four serotypes of Dengue virus (DENV-1 to DENV-4) causes an important arthropod-borne viral disease in humans. The multifunctional DENV nonstructural protein 5 (NS5) is essential for capping and replication of the viral RNA and harbours a methyltransferase (MTase) domain and an RNA-dependent RNA polymerase (RdRp) domain. In this study, insights into the overall structure and flexibility of the entire NS5 of all four Dengue virus serotypes in solution are presented for the first time. The solution models derived revealed an arrangement of the full-length NS5 (NS5FL) proteins with the MTase domain positioned at the top of the RdRP domain. The DENV-1 to DENV-4 NS5 forms are elongated and flexible in solution, with DENV-4 NS5 being more compact relative to NS5 from DENV-1, DENV-2 and DENV-3. Solution studies of the individual MTase and RdRp domains show the compactness of the RdRp domain as well as the contribution of the MTase domain and the ten-residue linker region to the flexibility of the entire NS5. Swapping the ten-residue linker between DENV-4 NS5FL and DENV-3 NS5FL demonstrated its importance in MTase-RdRp communication and in concerted interaction with viral and host proteins, as probed by amide hydrogen/deuterium mass spectrometry. Conformational alterations owing to RNA binding are presented. PMID- 26527148 TI - MeshAndCollect: an automated multi-crystal data-collection workflow for synchrotron macromolecular crystallography beamlines. AB - Here, an automated procedure is described to identify the positions of many cryocooled crystals mounted on the same sample holder, to rapidly predict and rank their relative diffraction strengths and to collect partial X-ray diffraction data sets from as many of the crystals as desired. Subsequent hierarchical cluster analysis then allows the best combination of partial data sets, optimizing the quality of the final data set obtained. The results of applying the method developed to various systems and scenarios including the compilation of a complete data set from tiny crystals of the membrane protein bacteriorhodopsin and the collection of data sets for successful structure determination using the single-wavelength anomalous dispersion technique are also presented. PMID- 26527149 TI - The oxygenating constituent of 3,6-diketocamphane monooxygenase from the CAM plasmid of Pseudomonas putida: the first crystal structure of a type II Baeyer Villiger monooxygenase. AB - The three-dimensional structures of the native enzyme and the FMN complex of the overexpressed form of the oxygenating component of the type II Baeyer-Villiger 3,6-diketocamphane monooxygenase have been determined to 1.9 A resolution. The structure of this dimeric FMN-dependent enzyme, which is encoded on the large CAM plasmid of Pseudomonas putida, has been solved by a combination of multiple anomalous dispersion from a bromine crystal soak and molecular replacement using a bacterial luciferase model. The orientation of the isoalloxazine ring of the FMN cofactor in the active site of this TIM-barrel fold enzyme differs significantly from that previously observed in enzymes of the bacterial luciferase-like superfamily. The Ala77 residue is in a cis conformation and forms a beta-bulge at the C-terminus of beta-strand 3, which is a feature observed in many proteins of this superfamily. PMID- 26527152 TI - NMR assignments of the peptidyl-prolyl cis-trans isomerase domain of trigger factor from E. coli. AB - Trigger factor (TF) is a highly conserved multi-domain molecular chaperone in bacteria. It binds via its ribosome binding domain (RBD) to the ribosomal tunnel exit and facilitates co-translational folding of a broad range of protein substrates primarily through interactions with the substrate binding domain (SBD) adjacent to the RBD. Within the SBD, a peptidyl-prolyl cis-trans isomerase (PPIase) domain is inserted leading to an unusual domain insertion, which may provide stabilizing effect to the highly plastic SBD. Here we report the near complete NMR assignments of TF PPIase providing the basis for subsequent structural and folding in the context of the chaperone activity of TF. PMID- 26527150 TI - Structural insights into the interaction of human IgG1 with FcgammaRI: no direct role of glycans in binding. AB - The three-dimensional structure of a human IgG1 Fc fragment bound to wild-type human FcgammaRI is reported. The structure of the corresponding complex was solved at a resolution of 2.4 A using molecular replacement; this is the highest resolution achieved for an unmutated FcgammaRI molecule. This study highlights the critical structural and functional role played by the second extracellular subdomain of FcgammaRI. It also explains the long-known major energetic contribution of the Fc 'LLGG' motif at positions 234-237, and particularly of Leu235, via a 'lock-and-key' mechanism. Finally, a previously held belief is corrected and a differing view is offered on the recently proposed direct role of Fc carbohydrates in the corresponding interaction. Structural evidence is provided that such glycan-related effects are strictly indirect. PMID- 26527154 TI - Withanolides: Biologically Active Constituents in the Treatment of Alzheimer's Disease. AB - The use of natural products in drug discovery and development have an important history. Several therapeutic agents have been investigated during the biological screenings of natural compounds. It is well documented that plants are possibly the core of novel substances that led to the discovery of new, novel, and effective therapeutic agents. Therefore, in the last few decades, scientists were thoroughly attempting for the search of benevolent drugs to protect mankind from various diseases and discomforts. The diverse chemical structures of natural products are the key element of their success in modern drug discovery. Cholinesterase enzyme inhibitors (ChEI) are chemicals which inhibit the splitting of cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase). Acetyl cholinesterase (AChE) and butyrylcholinesterase (BChE) are two types of cholinesterase enzymes that have been identified in vertebrates that are responsible for Alzheimer's disease and related dementia. Withanolides are affective plant secondary metabolites which inhibit acetylcholinesterase and butyrylcholinesterase enzyme and thus possibly will be the future drug for Alzheimer's disease. By viewing the importance of natural products in drug discovery and development, we present here, the importance of withanolides in the treatment of Alzheimer's disease. In this article, we also describe the classification and structural characterization of withanolides. This review comprises of 114 compounds. PMID- 26527153 TI - Targeting translocator protein (18 kDa) (TSPO) dampens pro-inflammatory microglia reactivity in the retina and protects from degeneration. AB - BACKGROUND: Reactive microglia are commonly seen in retinal degenerative diseases, and neurotoxic microglia responses can contribute to photoreceptor cell death. We and others have previously shown that translocator protein (18 kDa) (TSPO) is highly induced in retinal degenerations and that the selective TSPO ligand XBD173 (AC-5216, emapunil) exerts strong anti-inflammatory effects on microglia in vitro and ex vivo. Here, we investigated whether targeting TSPO with XBD173 has immuno-modulatory and neuroprotective functions in two mouse models of acute retinal degeneration using bright white light exposure. METHODS: BALB/cJ and Cx3cr1(GFP/+) mice received intraperitoneal injections of 10 mg/kg XBD173 or vehicle for five consecutive days, starting 1 day prior to exposure to either 15,000 lux white light for 1 h or 50,000 lux focal light for 10 min, respectively. The effects of XBD173 treatment on microglia and Muller cell reactivity were analyzed by immuno-stainings of retinal sections and flat mounts, fluorescence-activated cell sorting (FACS) analysis, and mRNA expression of microglia markers using quantitative real-time PCR (qRT-PCR). Optical coherence tomography (OCT), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stainings, and morphometric analyses were used to quantify the extent of retinal degeneration and photoreceptor apoptosis. RESULTS: Four days after the mice were challenged with bright white light, a large number of amoeboid-shaped alerted microglia appeared in the degenerating outer retina, which was nearly completely prevented by treatment with XBD173. This treatment also down-regulated the expression of TSPO protein in microglia but did not change the TSPO levels in the retinal pigment epithelium (RPE). RT-PCR analysis showed that the microglia/macrophage markers Cd68 and activated microglia/macrophage whey acidic protein (Amwap) as well as the pro-inflammatory genes Ccl2 and Il6 were reduced after XBD173 treatment. Light-induced degeneration of the outer retina was nearly fully blocked by XBD173 treatment. We further confirmed these findings in an independent mouse model of focal light damage. Retinas of animals receiving XBD173 therapy displayed significantly more ramified non-reactive microglia and more viable arrestin-positive cone photoreceptors than vehicle controls. CONCLUSIONS: Targeting TSPO with XBD173 effectively counter-regulates microgliosis and ameliorates light-induced retinal damage, highlighting a new pharmacological concept for the treatment of retinal degenerations. PMID- 26527156 TI - Recent Updates on the Association Between Alzheimer's Disease and Vascular Dementia. AB - The two most common forms of dementia are Alzheimer's disease (AD) followed by vascular dementia (VaD), together accounting for a whopping 60-80% of total dementia cases worldwide. Even though these diseases are recognized as 'common', they still remain underdiagnosed. Recent research suggests that AD and VaD are closely intertwined. The symptoms of AD and VaD can be similar and the two conditions can occur simultaneously. A large number of patients diagnosed with AD have also been reported with VaD-caused brain damage. Moreover, both the diseases have been reported to have similar risk factors. The overlap between these diseases is important because the lifestyle changes and medications prescribed to curb one of these diseases may also help curb the other. In the present review, we present an inclusive outline of parallelism between AD and VaD by exploring the potential commonalities at the mechanistic and therapeutic levels. PMID- 26527155 TI - miRNAs as Circulating Biomarkers for Alzheimer's Disease and Parkinson's Disease. AB - Detection of biomarkers for neurodegenerative disorders (NDDs) within brain tissues of Alzheimer's disease (AD) and Parkinson's disease (PD) patients has always been hampered by our inability to access and biopsy tissue of key brain regions implicated in disease occurrence and progression. Currently, diagnosis of NDDs is principally based on clinical observations of symptoms that present at later stages of disease progression, followed by neuroimaging and, possibly, CSF evaluation. One way to potentially detect and diagnose NDDs at a far earlier stage is to screen for abnormal levels of specific disease markers within the peripheral circulation of patients with NDDs. Increasing evidence suggests that there is dysregulation of microRNAs (miRNAs) in NDDs. Peripheral blood mononuclear cells, as well as biofluids, such as plasma, serum, urine and cerebrospinal fluid, contain miRNAs that can be identified and quantified. Circulating miRNAs within blood and other biofluids may thus be characterized and used as non-invasive, diagnostic biomarkers that facilitate the early detection of disease and potentially the continual monitoring of disease progression for NDDs such as AD and PD. Plainly, such a screen is only possible with a clear understanding of which miRNAs change with disease, and when these changes occur during the progression of AD and PD. Such information is becoming increasingly available and, in the near future, may not only support disease diagnosis, but provide the opportunity to evaluate therapeutic interventions earlier in the disease process. PMID- 26527157 TI - Special Section Guest Editorial: Protein Photonics for Imaging, Sensing, and Manipulation: Honoring Prof. Osamu Shimomura, a Pioneer of Photonics for Biomedical Research. PMID- 26527158 TI - An epidemiological investigation to reconstruct a probable human immunodeficiency virus-1 transmission network: a case report. AB - BACKGROUND: Recently published studies have highlighted the importance of phylogenetic and phylodynamic analyses in supporting epidemiological investigations to reconstruct the transmission network of human immunodeficiency virus. Here, we report a case of sexual transmission of human immunodeficiency virus type 1 between a man and a woman that marks once more the importance of a tightened collaboration between phylogeny and epidemiology. CASE PRESENTATION: We describe a case of human immunodeficiency virus type 1 subtype B transmission in a stable Caucasian heterosexual couple. The man was 30 years old and the woman was 21 years old at the time of their presentation to the Department of Public Health and Infectious Diseases of the University of Rome "Sapienza". The couple reported a history of drug abuse. CONCLUSION: Phylogenetic analysis is a powerful technique that if properly used can prove valuable in research investigations. In the case presented here, a phylogenetic analysis alongside epidemiological evidence allowed us to determine the most probable source of the human immunodeficiency virus infection. The dated tree allowed us to date the transmission event, the time point, and the direction of transmission based on the phylogeny, which agreed with the presumptive time of infection determined from clinical history-taking. PMID- 26527159 TI - Living at the farm, innovative nursing home care for people with dementia - study protocol of an observational longitudinal study. AB - BACKGROUND: In nursing home care, new care environments directed towards small scale and homelike environments are developing. The green care farm, which provides 24-h nursing home care for people with dementia, is one such new care environment. Knowledge is needed on the relation between environmental features of green care farms such as nature, domesticity and offering care in small groups and the influence on the daily lives of residents. The aim of this study is to explore (1) the daily lives of residents, (2) the quality of care and (3) the experiences of caregivers on green care farms compared with other nursing home care environments. METHODS/DESIGN: An observational longitudinal study including a baseline and a six-month follow-up measurement is carried out. Four types of nursing home care environments are included: (1) large scale nursing home ward, (2) small scale living facility on the terrain of a larger nursing home (3) stand alone small scale living facility and (4) green care farm. Quality of care is examined through structure, process and outcome indicators. The primary outcome measure is the daily life of residents, assessed by ecological momentary assessments. Aspects of daily life include (1) activity (activity performed by the resident, the engagement in this activity and the degree of physical effort); (2) physical environment (the location of the resident and the interaction with the physical environment); (3) social environment (the level and type of social interaction, and with whom this social interaction took place) and (4) psychological well-being (mood and agitation). In addition, social engagement, quality of life, behavioral symptoms and agitation are evaluated through questionnaires. Furthermore, demographics, cognitive impairment, functional dependence and the severity of dementia are assessed. Semi-structured interviews are performed with caregivers regarding their experiences with the different nursing home care environments. DISCUSSION: This is the first study investigating green care farms providing 24-h nursing home care for people with dementia. The study provides valuable insight into the daily lives of residents, the quality of care, and the experiences of caregivers at green care farms in comparison with other nursing home care environments including small-scale care environments and large scale nursing home wards. PMID- 26527160 TI - Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency. AB - BACKGROUND: The etiology of liver disease remains elusive in some adults presenting with severe hepatic dysfunction. METHODS AND RESULTS: Here we describe a woman of Pakistani descent who had elevated aminotransferases at age 23. She developed muscle weakness in her mid-20s, and was diagnosed with hepatocellular carcinoma at age 29. She died without a diagnosis at age 32 after having a liver transplant. Exome sequencing revealed that she was homozygous for a missense mutation (R49H) in AHCY, the gene encoding S-adenosylhomocysteine (SAH) hydrolase. SAH hydrolase catalyzes the final step in conversion of methionine to homocysteine and inactivating mutations in this enzyme cause a rare autosomal recessive disorder, SAH hydrolase deficiency, that typically presents in infancy. An asymptomatic 7-year old son of the proband is also homozygous for the AHCY R49H mutation and has elevated serum aminotransferase levels, as well as markedly elevated serum levels of SAH, S-adenosylmethionine (SAM), and methionine, which are hallmarks of SAH hydrolase deficiency. CONCLUSION: This report reveals several new aspects of SAH hydrolase deficiency. Affected women with SAH hydrolase deficiency can give birth to healthy children. SAH hydrolase deficiency can remain asymptomatic in childhood, and the disorder can be associated with early onset hepatocellular carcinoma. The measurement of serum amino acids should be considered in patients with liver disease or hepatocellular carcinoma of unknown etiology. PMID- 26527161 TI - Subtractive assembly for comparative metagenomics, and its application to type 2 diabetes metagenomes. AB - Comparative metagenomics remains challenging due to the size and complexity of metagenomic datasets. Here we introduce subtractive assembly, a de novo assembly approach for comparative metagenomics that directly assembles only the differential reads that distinguish between two groups of metagenomes. Using simulated datasets, we show it improves both the efficiency of the assembly and the assembly quality of the differential genomes and genes. Further, its application to type 2 diabetes (T2D) metagenomic datasets reveals clear signatures of the T2D gut microbiome, revealing new phylogenetic and functional features of the gut microbial communities associated with T2D. PMID- 26527163 TI - clinical audits and the state of record keeping in india. PMID- 26527162 TI - Biodegradable magnesium screws and vascularized iliac grafting for displaced femoral neck fracture in young adults. AB - OBJECTIVE: Avascular necrosis of femoral head and nonunion is a major complication after the treatment of displaced femoral neck fracture in young adults. The purpose of this study was to introduce a new technique using biodegradable magnesium screws and vascularised iliac grafting for displaced femoral neck fracture in young adults. METHODS: Totally 19 patients with displaced femoral neck fracture treated with this technique were retrospectively reviewed. The major steps of this technique included the harvesting of vascularized iliac graft, fixing of the fracture and biodegradable magnesium screws combined with vascularized iliac grafting implantation. RESULTS: All patients were followed for an average of 16 months (range: 8-24 months). Clinical and radiological outcomes were evaluated. In 18 cases (94.7 %), the hip union was achieved at an average duration of 4.1 months (range: 3.6-5 months). The nonunion was observed in 1 hip (5.3 %) and the revision to a hip replacement was conducted after twelve months of the operation. According to the Harris hip score (HHS) that was available for 17 hips with satisfactory union, excellent results were achieved in 14 cases (HHS >= 90), fair results in 3 cases (HHS: 80-90), and poor result in 1 hip (HHS < 80). No patient developed avascular necrosis of femoral head after operation. CONCLUSION: Biodegradable magnesium screws and vascularized iliac grafting based on the ascending branch of lateral femoral circumflex artery for displaced femoral neck fracture in young adults can provide the satisfactory results with a low rate of complications including avascular necrosis and nonunion. TRIAL REGISTRATION: This prospective and randomized controlled study was registered in the Chinese Clinical Trial Registry ( ChiCTR-TRC-13003238). Date of registration: 2013-3-21. PMID- 26527164 TI - Housing need in Canada: Healthy lives start at home. AB - Housing affects the health of children and youth. One-third of households in Canada live in substandard conditions or in housing need. The present statement reviews the literature documenting the impacts of housing on personal health and the health care system. Types of housing need are defined, including unsuitable or crowded housing, unaffordable housing and inadequate housing, or housing in need of major repairs. The health effects of each type of housing need, as well as of unsafe neighbourhoods, infestations and other environmental exposures are outlined. Paediatricians and other physicians caring for children need to understand the housing status of patients to fully determine their health issues and ability to access and engage in health care. Recommendations and sample tools to assess and address housing need at the patient, family, community and policy levels are described. Canada is the only G8 country without a national housing strategy. Recommendations also include advocating for enhanced action at all levels of government and for housing-supportive policies, including a national housing strategy. PMID- 26527165 TI - Continuous light after a long-day treatment is equivalent to melatonin implants to stimulate testosterone secretion in Alpine male goats. AB - In rams, artificial long days followed by continuous light stimulate testosterone secretion during the non-breeding season. The objective of this study was to determine whether artificial long days followed by continuous light could stimulate testosterone secretion in Alpine bucks as well as in those exposed to long days followed by a melatonin treatment. All bucks were kept in shaded open pens. Control males were exposed to natural photoperiod conditions (n=5). Males of the two experimental groups were exposed to 2.5 months of long days from 1 December (n=5 each). On 16 February, one group of males was exposed to 24 h of light per day until 30 June; the other group was exposed to natural variations of photoperiod and received two s.c. melatonin implants. Testicular weight was determined every 2 weeks, and the plasma testosterone concentrations once a week. In the control and the two photoperiodic-treated groups, a treatment*time interaction was detected for testicular weight and plasma testosterone concentrations (P<0.001). In control bucks, testicular weight increased from January and peaked in June, whereas in both photoperiodic-treated groups, this variable increased from January, but peaked in April, when the values were higher than in controls (P<0.05). In the control group, plasma testosterone concentrations remained low from January to June, whereas in both photoperiodic treated groups, this variable remained low from January to March; thereafter, these levels increased in both photoperiodic-treated groups, and were higher than controls in April and May (P<0.05). We conclude that continuous light after a long-day treatment stimulate testosterone secretion in Alpine male goats during the non-breeding season as well as the long days followed by a melatonin treatment. Therefore, continuous light could replace the implants of melatonin. PMID- 26527167 TI - Aquaporin8 regulates cellular development and reactive oxygen species production, a critical component of virulence in Botrytis cinerea. AB - Aquaporins (AQPs) are ubiquitous in nearly all organisms, mediating selective and rapid flux of water across biological membranes. The role of AQPs in phytopathogenic fungi is poorly understood. Orthologs of AQP genes in Botrytis cinerea were identified and knocked out. The effects of AQPs on hyphal growth and conidiation, formation of infection structures and virulence on plant hosts were examined. The role of AQP8 in reactive oxygen species (ROS) production, distribution and transport were further determined. Among eight AQPs, only AQP8 was essential for the ability of B. cinerea to infect plants. AQP8 was demonstrated to be an intrinsic plasma membrane protein, which may function as a channel and mediate hydrogen peroxide uptake. Deletion of AQP8 in B. cinerea completely inhibited the development of conidia and infection structures, and significantly affected noxR expression. Further observations revealed that both AQP8 and noxR impacted ROS distribution in the hyphal tips of B. cinerea. Moreover, AQP8 affected the expression of a mitochondrial protein, NQO1. A knockout mutant of NQO1 was observed to display reduced virulence. These data lead to a better understanding of the important role of AQP8 in the development and pathogenesis of plant pathogens. PMID- 26527166 TI - E. adenophorum induces Cell Cycle Arrest and Apoptosis of Splenocytes through the Mitochondrial Pathway and Caspase Activation in Saanen Goats. AB - The precise cytotoxicity of E. Adenophorum in relation to the cell cycle and apoptosis of splenocytes in Saanen goats remains unclear. In the present study, 16 Saanen goats were randomly divided into four groups, which were fed on 0%, 40%, 60% and 80% E. adenophorum diets. The results of TUNEL, DAPI and AO/EB staining, flow cytometry analysis and DNA fragmentation assays showed that E. adenophorum induced typical apoptotic features in splenocytes, suppressed splenocyte viability, and caused cell cycle arrest in a dose-dependent manner. However, westernblot, ELISA, qRT-PCR and caspase activity analyses showed that E. adenophoruminhibited Bcl-2 expression, promoted Bax translocation to the mitochondria, triggered the release of Cytc from the mitochondria into the cytosol, and activated caspase-9 and -3 and the subsequent cleavage of PARP. Moreover, in E. adenophorum-induced apoptosis, the protein levels of Fas, Bid, FasL and caspase-8 showed no significant changes. E. adenophorum treatment induced the collapse of DeltaPsim. Moreover, these data suggested that E. adenophorum induces splenocyte apoptosis via the activation of the mitochondrial apoptosis pathway in splenocytes. These findings provide new insights into the mechanisms underlying the effects of E. adenophorum cytotoxicity on splenocytes. PMID- 26527168 TI - Direct Photoredox-Catalyzed Reductive Difluoromethylation of Electron-Deficient Alkenes. AB - Photoredox-catalyzed reductive difluoromethylation of electron-deficient alkenes was achieved in one step under tin-free, mild and neutral conditions. This protocol affords a facile method to introduce RCF2 (R=H, Ph, Me, and CH2N3) groups at sites beta to electron-withdrawing groups. It was found that TTMS (tris(trimethylsilyl)silane) served nicely as both the H-atom donor and the electron donor in the catalytic cycle. Experimental and DFT computational results provided evidence that RCF2 (R=H, Ph, Me) radicals are nucleophilic in nature. PMID- 26527169 TI - Review article: insights into colonic protein fermentation, its modulation and potential health implications. AB - BACKGROUND: Beneficial effects of carbohydrate fermentation on gastrointestinal health are well established. Conversely, protein fermentation generates harmful metabolites but their relevance to gastrointestinal health is poorly understood. AIM: To review the effects of increased protein fermentation on biomarkers of colonic health, factors influencing fermentative activity and potential for dietary modulation to minimise detrimental effects. METHODS: A literature search was performed in PubMed, Medline, EMBASE and Google scholar for clinical and pre clinical studies using search terms - 'dietary protein', 'fermentation', 'putrefaction', 'phenols', 'sulphide', 'branched-chain fatty acid', 'carbohydrate fermentation', 'gastrointestinal'. RESULTS: High protein, reduced carbohydrate diets alter the colonic microbiome, favouring a potentially pathogenic and pro inflammatory microbiota profile, decreased short-chain fatty acid production and increased ammonia, phenols and hydrogen sulphide concentrations. These metabolites largely compromise the colonic epithelium structure, causing mucosal inflammation but may also directly modulate the enteric nervous system and intestinal motility. Increased protein fermentation as a result of a high-protein intake can be attenuated by addition of oligosaccharides, resistant starch and nonstarch polysaccharides and a reduction in total protein or specifically, aromatic and sulphur-containing amino acids. These factors may have clinical importance as novel therapeutic approaches to problems, in which protein fermentation may be implicated, such as malodorous flatus, irritable bowel syndrome, ulcerative colitis and prevention of colorectal cancer. CONCLUSIONS: The direct clinical relevance of excessive protein fermentation in the pathogenesis of irritable bowel syndrome, malodorous flatus and ulcerative colitis are underexplored. Manipulating dietary carbohydrate and protein intake have potential therapeutic applications in such settings and warrant further clinical studies. PMID- 26527171 TI - Investigation of terpinolene + ozone or terpinolene + nitrate radical reaction products using denuder/filter apparatus. AB - Terpinolene's (1-methyl-4-(propan-2-ylidene)cyclohexene) reaction with ozone or the nitrate radical was investigated using a denuder/filter apparatus in order to characterize gas-phase and particulate reaction products. Identification of the reaction products (i.e., aldehydes, ketones, dicarbonyls and carboxylic acids) was made using two derivatization methods; O-(2,3,4,5,6 pentafluorobenzyl)hydroxylamine (PFBHA) to derivatize the carbonyl products or 3 Ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC) and 2,2,2 trifluoroethylamine hydrochloride (TFEA) to derivatize the carboxylic acid products. Proposed carbonyl products for ozonolysis of terpinolene are: 4 methylcyclohex-3-en-1-one, 2-hydroxy-4-methylcyclohex-3-en-1-one, glyoxal, methyl glyoxal, 3-oxobutanal, and 6-oxo-3-(propan-2-ylidene)heptanal. Proposed carbonyl products for nitrate radical reaction of terpinolene are: 2-hydroxy-4 methylcyclohex-3-en-1-one, glyoxal, methyl glyoxal, and 4-oxopentanal. No carboxylic acid products were detected with either oxidizing reactant. PMID- 26527170 TI - Roles of lipoprotein receptors in the entry of hepatitis C virus. AB - Infection by hepatitis C virus (HCV), a plus-stranded RNA virus that can cause cirrhosis and hepatocellular carcinoma, is one of the major health problems in the world. HCV infection is considered as a multi-step complex process and correlated with abnormal metabolism of lipoprotein. In addition, virus attacks hepatocytes by the initial attaching viral envelop glycoprotein E1/E2 to receptors of lipoproteins on host cells. With the development of HCV model system, mechanisms of HCV cell entry through lipoprotein uptake and its receptor have been extensively studied in detail. Here we summarize recent knowledge about the role of lipoprotein receptors, scavenger receptor class B type I and low density lipoprotein receptor in the entry of HCV, providing a foundation of novel targeting therapeutic tools against HCV infection. PMID- 26527172 TI - Differential neural processing of unpleasant haptic sensations in somatic and affective partitions of the insula in non-suicidal self-injury (NSSI). AB - Altered perception and neural processing of pain have been observed during non suicidal self-injury (NSSI). Evidence suggests that this phenomenon could be associated with the affective rather than the somatosensory dimension of pain. Sub-partitions of the insula have been suggested to process these different aspects differentially. In the present study, activation within the posterior, middle, and anterior partitions of the insula upon unpleasant electric stimulation was compared between subjects with a history of NSSI and healthy controls. Using functional magnetic resonance imaging (fMRI), we investigated a sample of 30 subjects, 14 of them with a lifetime history of NSSI. Unpleasant electric stimulation to the dorsum of the non-dominant hand was performed at four levels of increasing intensity. Significantly increasing posterior insula activation, which is likely to reflect the somatosensory aspects of unpleasant haptic sensations, was found upon parametrically increasing electric stimulation in both groups. By contrast, activation of the anterior insula, rather related to the more affective aspects of distressing stimuli, was significantly modulated only in the control group, but not in subjects with NSSI. These findings may support present hypotheses of altered processing of the more affective aspects of unpleasant or distressing experiences in NSSI, as a putatively relevant factor for understanding the etiology of this behavior. PMID- 26527174 TI - A neurology revival in Latin America. PMID- 26527173 TI - UV-Enhanced Sacrificial Layer Stabilised Graphene Oxide Hollow Fibre Membranes for Nanofiltration. AB - Graphene oxide (GO) membranes have demonstrated great potential in gas separation and liquid filtration. For upscale applications, GO membranes in a hollow fibre geometry are of particular interest due to the high-efficiency and easy-assembly features at module level. However, GO membranes were found unstable in dry state on ceramic hollow fibre substrates, mainly due to the drying-related shrinkage, which has limited the applications and post-treatments of GO membranes. We demonstrate here that GO hollow fibre membranes can be stabilised by using a porous poly(methyl methacrylate) (PMMA) sacrificial layer, which creates a space between the hollow fibre substrate and the GO membrane thus allowing stress-free shrinkage. Defect-free GO hollow fibre membrane was successfully determined and the membrane was stable in a long term (1200 hours) gas-tight stability test. Post-treatment of the GO membranes with UV light was also successfully accomplished in air, which induced the creation of controlled microstructural defects in the membrane and increased the roughness factor of the membrane surface. The permeability of the UV-treated GO membranes was greatly enhanced from 0.07 to 2.8 L m(-2) h(-1) bar(-1) for water, and 0.14 to 7.5 L m(-2) h(-1) bar(-1) for acetone, with an unchanged low molecular weight cut off (~250 Da). PMID- 26527175 TI - Double-lumen tube tracheal intubation in a manikin model using the VivaSight Double Lumen: a randomized controlled comparison with the Macintosh laryngoscope. PMID- 26527176 TI - Overcoming the difficulties of bougie-assisted endotracheal intubation. PMID- 26527177 TI - Prolonged length of stay in ED psychiatric patients: a multivariable predictive model. AB - BACKGROUND: We aimed to evaluate factors associated with prolonged emergency department (ED) length of stay (LOS) among psychiatric patients and to develop a multivariable predictive model to guide future interventions to reduce ED LOS. METHODS: Electronic health records of ED patients receiving a psychiatric consultation and providing research authorization were reviewed from September 14, 2010, through September 13, 2013, at an academic hospital with approximately 73000 visits annually. Prolonged LOS was defined as >=8 hours. RESULTS: We identified 9247 visits among 6335 patients; median LOS was 4.1 hours, with 1424 visits (15%) with prolonged LOS. In the multivariable model, characteristics associated with an increased risk of a prolonged LOS included patient age 12 to 17 years (odds ratio [OR], 2.43; P<.001) or >=65 years (OR, 1.46; P=.007); male gender (OR, 1.24; P=.002); Medicare insurance coverage (OR, 1.34; P=.008); use of restraints (OR, 2.25; P=.006); diagnoses of cognitive disorder (OR, 4.62; P<.001) or personality disorder (OR, 3.45; P<.001); transfer to an unaffiliated psychiatric hospital (OR, 22.82; P<.001); ED arrival from 11 pm through 6:59 am (OR, 1.53; P<.001) or on a Sunday (OR, 1.76; P<.001); or ED evaluation in February (OR, 1.59; P=.006), April (OR, 1.66; P=.002), and May (OR, 1.54; P=.007). CONCLUSIONS: Many psychiatric patients had a prolonged ED LOS. Understanding the multiple, patient-specific, ED operational, and seasonal factors that predict an increased LOS will help guide allocation of resources to improve overall ED processes and patient care. PMID- 26527178 TI - South African flag sign: a teaching tool for easier ECG recognition of high lateral infarct. PMID- 26527179 TI - Bougie-assisted tube thoracostomy placement: a novel technique. PMID- 26527180 TI - Are junior doctors trained to use to use intraosseous access? PMID- 26527181 TI - Increases in intracellular calcium perturb blood-brain barrier via protein kinase C-alpha and apoptosis. AB - An increase in intracellular calcium represents one of the early events during an ischaemic stroke. It triggers many downstream processes which promote the formation of brain oedema, the leading cause of death after an ischaemic stroke. As impairment of blood-brain barrier (BBB) accounts for much of oedema formation, the current study explored the impact of intracellular calcium on barrier integrity in relation to protein kinase C, caspase-3/7, plasminogen activators and the pro-oxidant enzyme NADPH oxidase. Human brain microvascular endothelial cells alone or in co-culture with human astrocytes were subjected to 4h of oxygen glucose deprivation alone or followed by 20h of reperfusion (OGD+/-R) in the absence or presence of inhibitors for urokinase plasminogen activator (amiloride), NADPH oxidase (apocynin), intracellular calcium (BAPTA-AM) and protein kinase C-alpha (RO-32-0432). Endothelial cells with protein kinase C alpha knockdown, achieved by siRNA, were also exposed to the above conditions. BBB permeability was measured by transendothelial electrical resistance and Evan's blue-albumin and sodium fluorescein flux. Intracellular calcium and total superoxide anion levels, caspase-3/7, NADPH oxidase, plasminogen activator and protein kinase C activities, stress fibre formation, the rate of apoptosis and BBB permeability were increased by OGD+/-R. Treatment with the specific inhibitors or knockdown of protein kinase C-alpha attenuated them. This study reveals successive increases in intracellular calcium levels and protein kinase C alpha activity are key mechanisms in OGD+/-R-mediated impairment of BBB. Furthermore inhibition of protein kinase C-alpha may be therapeutic in restoring BBB function by reducing the rate of cytoskeletal reorganisation, oxidative stress and apoptosis. PMID- 26527182 TI - Myeloid derived suppressor cells in inflammatory conditions of the central nervous system. AB - The knowledge of the immune system elements and their relationship with other tissues, organs and systems are key approximations for the resolution of many immune-related disorders. The control of the immune response and/or its modulation from the pro-inflammatory to the anti-inflammatory response is being deeply studied in the field. In the last years, the study of myeloid-derived suppressor cells (MDSCs), a group of immature myeloid cells with a high suppressive activity on T cells has been extensively addressed in cancer. In contrast, their role in neuroimmune diseases is far from being totally understood. In this review, we will summarize data about MDSCs coming from the study of neuroinflammatory diseases in general and their potential role in multiple sclerosis, in order to introduce the putative use of this extraordinary promising cell type for future cell-based therapies. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID- 26527183 TI - Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. AB - Each year about 650,000 Europeans die from stroke and a similar number lives with the sequelae of multiple sclerosis (MS). Stroke and MS differ in their etiology. Although cause and likewise clinical presentation set the two diseases apart, they share common downstream mechanisms that lead to damage and recovery. Demyelination and axonal injury are characteristics of MS but are also observed in stroke. Conversely, hallmarks of stroke, such as vascular impairment and neurodegeneration, are found in MS. However, the most conspicuous common feature is the marked neuroinflammatory response, marked by glia cell activation and immune cell influx. In MS and stroke the blood-brain barrier is disrupted allowing bone marrow-derived macrophages to invade the brain in support of the resident microglia. In addition, there is a massive invasion of auto-reactive T cells into the brain of patients with MS. Though less pronounced a similar phenomenon is also found in ischemic lesions. Not surprisingly, the two diseases also resemble each other at the level of gene expression and the biosynthesis of other proinflammatory mediators. While MS has traditionally been considered to be an autoimmune neuroinflammatory disorder, the role of inflammation for cerebral ischemia has only been recognized later. In the case of MS the long track record as neuroinflammatory disease has paid off with respect to treatment options. There are now about a dozen of approved drugs for the treatment of MS that specifically target neuroinflammation by modulating the immune system. Interestingly, experimental work demonstrated that drugs that are in routine use to mitigate neuroinflammation in MS may also work in stroke models. Examples include Fingolimod, glatiramer acetate, and antibodies blocking the leukocyte integrin VLA-4. Moreover, therapeutic strategies that were discovered in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, turned out to be also effective in experimental stroke models. This suggests that previous achievements in MS research may be relevant for stroke. Interestingly, the converse is equally true. Concepts on the neurovascular unit that were developed in a stroke context turned out to be applicable to neuroinflammatory research in MS. Examples include work on the important role of the vascular basement membrane and the BBB for the invasion of immune cells into the brain. Furthermore, tissue plasminogen activator (tPA), the only established drug treatment in acute stroke, modulates the pathogenesis of MS. Endogenous tPA is released from endothelium and astroglia and acts on the BBB, microglia and other neuroinflammatory cells. Thus, the vascular perspective of stroke research provides important input into the mechanisms on how endothelial cells and the BBB regulate inflammation in MS, particularly the invasion of immune cells into the CNS. In the current review we will first discuss pathogenesis of both diseases and current treatment regimens and will provide a detailed overview on pathways of immune cell migration across the barriers of the CNS and the role of activated astrocytes in this process. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID- 26527184 TI - The Neural Basis of Long-Distance Navigation in Birds. AB - Migratory birds can navigate over tens of thousands of kilometers with an accuracy unobtainable for human navigators. To do so, they use their brains. In this review, we address how birds sense navigation- and orientation-relevant cues and where in their brains each individual cue is processed. When little is currently known, we make educated predictions as to which brain regions could be involved. We ask where and how multisensory navigational information is integrated and suggest that the hippocampus could interact with structures that represent maps and compass information to compute and constantly control navigational goals and directions. We also suggest that the caudolateral nidopallium could be involved in weighing conflicting pieces of information against each other, making decisions, and helping the animal respond to unexpected situations. Considering the gaps in current knowledge, some of our suggestions may be wrong. However, our main aim is to stimulate further research in this fascinating field. PMID- 26527185 TI - Systemic Nutrient and Stress Signaling via Myokines and Myometabolites. AB - Homeostatic systems mount adaptive responses to meet the energy demands of the cell and to compensate for dysfunction in cellular compartments. Such surveillance systems are also active at the organismal level: Nutrient and stress sensing in one tissue can lead to changes in other tissues. Here, we review the emerging understanding of the role of skeletal muscle in regulating physiological homeostasis and disease progression in other tissues. Muscle-specific genetic interventions can induce systemic effects indirectly, via changes in the mass and metabolic demand of muscle, and directly, via the release of muscle-derived cytokines (myokines) and metabolites (myometabolites) in response to nutrients and stress. In turn, myokines and myometabolites signal to various target tissues in an autocrine, paracrine, and endocrine manner, thereby determining organismal resilience to aging, disease, and environmental challenges. We propose that tailoring muscle systemic signaling by modulating myokine and myometabolite levels may combat many degenerative diseases and delay aging. PMID- 26527187 TI - Thioredoxin-1 (Trx1) engineered mesenchymal stem cell therapy is a promising feasible therapeutic approach for myocardial infarction. PMID- 26527186 TI - The Microbiome and the Respiratory Tract. AB - Although the notion that "the normal lung is free from bacteria" remains common in textbooks, it is virtually always stated without citation or argument. The lungs are constantly exposed to diverse communities of microbes from the oropharynx and other sources, and over the past decade, novel culture-independent techniques of microbial identification have revealed that the lungs, previously considered sterile in health, harbor diverse communities of microbes. In this review, we describe the topography and population dynamics of the respiratory tract, both in health and as altered by acute and chronic lung disease. We provide a survey of current techniques of sampling, sequencing, and analysis of respiratory microbiota and review technical challenges and controversies in the field. We review and synthesize what is known about lung microbiota in various diseases and identify key lessons learned across disease states. PMID- 26527189 TI - GITIRBio: A Semantic and Distributed Service Oriented-Architecture for Bioinformatics Pipeline. AB - The need to process large quantities of data generated from genomic sequencing has resulted in a difficult task for life scientists who are not familiar with the use of command-line operations or developments in high performance computing and parallelization. This knowledge gap, along with unfamiliarity with necessary processes, can hinder the execution of data processing tasks. Furthermore, many of the commonly used bioinformatics tools for the scientific community are presented as isolated, unrelated entities that do not provide an integrated, guided, and assisted interaction with the scheduling facilities of computational resources or distribution, processing and mapping with runtime analysis. This paper presents the first approximation of a Web Services platform-based architecture (GITIRBio) that acts as a distributed front-end system for autonomous and assisted processing of parallel bioinformatics pipelines that has been validated using multiple sequences. Additionally, this platform allows integration with semantic repositories of genes for search annotations. GITIRBio is available at: http://c-head.ucaldas.edu.co:8080/gitirbio. PMID- 26527188 TI - Adrenergic stimulation sensitizes TRPV1 through upregulation of cystathionine beta-synthetase in a rat model of visceral hypersensitivity. AB - The pathogenesis of pain in irritable bowel syndrome (IBS) is poorly understood and treatment remains difficult. The present study was designed to investigate roles of adrenergic signaling and the endogenous hydrogen sulfide producing enzyme cystathionine beta-synthetase (CBS) in a previously validated rat model of IBS induced by neonatal colonic inflammation (NCI). Here we showed that NCI induced visceral hypersensitivity (VH) was significantly attenuated by beta2 subunit inhibitor but not by beta1 or beta3 or alpha subunit inhibitor. NCI markedly elevated plasma norepinephrine (NE) concentration without alteration in expression of beta2 subunit receptors in dorsal root ganglion (DRGs) innervating the colon. In addition, NCI markedly enhanced TRPV1 and CBS expression in the colon DRGs. CBS inhibitor AOAA reversed the upregulation of TRPV1 in NCI rats. In vitro experiments showed that incubation of DRG cells with NE markedly enhanced expression of TRPV1, which was reversed by application of AOAA. Incubation of DRG cells with the H2S donor NaHS greatly enhanced TRPV1 expression. Collectively, these data suggest that activation of adrenergic signaling by NCI sensitizes TRPV1 channel activity, which is likely mediated by upregulation of CBS expression in peripheral sensory neurons, thus contributing to chronic visceral hypersensitivity. PMID- 26527190 TI - Web application for automatic prediction of gene translation elongation efficiency. AB - Expression efficiency is one of the major characteristics describing genes in various modern investigations. Expression efficiency of genes is regulated at various stages: transcription, translation, posttranslational protein modification and others. In this study, a special EloE (Elongation Efficiency) web application is described. The EloE sorts the organism's genes in a descend order on their theoretical rate of the elongation stage of translation based on the analysis of their nucleotide sequences. Obtained theoretical data have a significant correlation with available experimental data of gene expression in various organisms. In addition, the program identifies preferential codons in organism's genes and defines distribution of potential secondary structures energy in 5' and 3' regions of mRNA. The EloE can be useful in preliminary estimation of translation elongation efficiency for genes for which experimental data are not available yet. Some results can be used, for instance, in other programs modeling artificial genetic structures in genetically engineered experiments. PMID- 26527191 TI - Shared bioinformatics databases within the Unipro UGENE platform. AB - Unipro UGENE is an open-source bioinformatics toolkit that integrates popular tools along with original instruments for molecular biologists within a unified user interface. Nowadays, most bioinformatics desktop applications, including UGENE, make use of a local data model while processing different types of data. Such an approach causes an inconvenience for scientists working cooperatively and relying on the same data. This refers to the need of making multiple copies of certain files for every workplace and maintaining synchronization between them in case of modifications. Therefore, we focused on delivering a collaborative work into the UGENE user experience. Currently, several UGENE installations can be connected to a designated shared database and users can interact with it simultaneously. Such databases can be created by UGENE users and be used at their discretion. Objects of each data type, supported by UGENE such as sequences, annotations, multiple alignments, etc., can now be easily imported from or exported to a remote storage. One of the main advantages of this system, compared to existing ones, is the almost simultaneous access of client applications to shared data regardless of their volume. Moreover, the system is capable of storing millions of objects. The storage itself is a regular database server so even an inexpert user is able to deploy it. Thus, UGENE may provide access to shared data for users located, for example, in the same laboratory or institution. UGENE is available at: http://ugene.net/download.html. PMID- 26527193 TI - Depression and Anxiety in Pain. AB - Mood disorders, especially depression and anxiety, play an important role in the exacerbation of pain perception in all clinical settings.Depression commonly occurs as a result of chronic pain and needs treating to improve outcome measures and quality of life.Anxiety negatively affects thoughts and behaviours which hinders rehabilitation.Anxiety and depression in acute hospital settings also negatively affect pain experience and should be considered in both adults and children.Poor pain control and significant mood disorders perioperatively contribute to the development of chronic postoperative pain. PMID- 26527192 TI - Trends in maternal and newborn health characteristics and obstetric interventions among Aboriginal and Torres Strait Islander mothers in Western Australia from 1986 to 2009. AB - BACKGROUND: Detailed analyses of long-term trends in Aboriginal maternal and newborn health characteristics are lacking. AIM: To examine trends in maternal and newborn health characteristics for all mothers who were recorded as Aboriginal in the Western Australian Midwives' Notification System from 1986 to 2009. MATERIALS AND METHODS: Births were categorised into four-year time intervals (1986-1989, 1990-1993, 1994-1997, 1998-2001, 2002-2005, 2006-2009). Trends in maternal demographic characteristics, pre-existing medical conditions, pregnancy complications and neonatal characteristics were examined. RESULTS: For 37 424 births recorded from 1986 to 2009, the proportion of births to mothers aged <=19 years decreased (31-22%, P < 0.001) along with the prevalence of pre eclampsia (6.8-4.0%, P < 0.001) and antepartum haemorrhage (4.8-3.2%, P < 0.001). There were increases in the prevalence of diabetes in pregnancy (3.8-6.6%, P < 0.001), induction of labour (17.8-21.4%, P < 0.001), elective caesarean (6.6 8.2%, P < 0.001) and emergency caesarean (9.5-14.9%, P < 0.001) deliveries. There were no changes in the overall prevalence of preterm births (15.4-15.9%, P = 0.32). However, increases were observed in the prevalence of medically indicated preterm births with and without prelabour rupture of membranes (1.0-1.7%; P < 0.001 and 3.3-4.3%; P = 0.005, respectively). There were no significant changes in the rates of smoking during pregnancy (51-52% from 1998 to 2009, P = 0.18), small-for-gestational age (16.9-17.2%, P = 0.07), suboptimal-birthweight (20.4 20.1%, P = 0.92), stillbirths (14.7 per 1000-12.1 per 1000, P = 0.22) and neonatal deaths (6.2 per 1000-5.5 per 1000, P = 0.68). CONCLUSION: Encouraging trends include reduced rates of teenage pregnancy, pre-eclampsia and antepartum haemorrhage. The persistent high rates of smoking during pregnancy, preterm births, stillbirths, neonatal deaths and increasing rates of diabetes in pregnancy are of concern. PMID- 26527194 TI - Resistant hypertension with adrenal nodule: are we removing the right gland? AB - Resistant hypertension is often difficult to treat and may be associated with underlying primary aldosteronism (PA). We describe the case of an elderly gentleman who presented with severe and resistant hypertension and was found to have a left adrenal incidentaloma during evaluation but had aldosterone excess secondary to unilateral adrenal hyperplasia (UAH) of the contralateral gland, which needed surgical intervention. A 65-year-old gentleman was evaluated for uncontrolled high blood pressure (BP) in spite of taking four antihypertensive medications. The high BP was confirmed on a 24-h ambulatory reading, and further biochemical evaluation showed an elevated serum aldosterone renin ratio (ARR) (1577 pmol/l per ng per ml per h). Radiological evaluation showed an adrenal nodule (15 mm) in the left adrenal gland but an adrenal vein sampling demonstrated a lateralization towards the opposite site favouring the right adrenal to be the source of excess aldosterone. A laparoscopic right adrenalectomy was performed and the histology of the gland confirmed nodular hyperplasia. Following surgery, the patient's BP improved remarkably although he remained on antihypertensives and under regular endocrine follow-up. PA remains the most common form of secondary and difficult-to-treat hypertension. Investigations may reveal incidental adrenal lesions, which may not be the actual source of excess aldosterone, but UAH may be a contributor and may coexist and amenable to surgical treatment. An adrenal vein sampling should be undertaken for correct lateralization of the source, otherwise a correctable diagnosis may be missed and the incorrect adrenal gland may be removed. LEARNING POINTS: Severe and resistant hypertension can often be associated with underlying PA.ARR is an excellent screening tool in patients with suspected PA.Lateralization with adrenal venous sampling is essential to isolate the source and differentiate between unilateral and bilateral causes of hyperaldosteronism.Adrenal incidentalomas and UAH may coexist and the latter may often be the sole cause of excess aldosterone secretion.Decisions about adrenalectomy should be made only after integrating and interpreting radiological and biochemical test findings properly. PMID- 26527195 TI - Revealing the working mechanism of polymer photodetectors with ultra-high external quantum efficiency. AB - We report polymer photodetectors (PPDs) with an evident photomultiplication (PM) phenomenon, based on a sandwich structure ITO/PEDOT:PSS/P3HT:PC71BM(100:1)/Al. A similar device structure has been reported in our previous work, showing great potential as a new type of high performance PPD. However, we found more interesting new phenomena from these PPDs. Solid evidence is provided to prove the existence of photogenerated electron transport in the almost hole-only active layer under an applied bias. The transport of photogenerated electrons leads to electron accumulation near the Al electrode and the electron redistribution, which strongly affect the EQE spectral shape and the transient response of the PPDs. Our conclusion is further confirmed by confirmatory devices with a structure of Al(1)/P3HT:PC71BM(100:1)/Al(2). EQE spectra and transient Jph curves of the confirmatory devices accord well with our speculation. This discovery may provide a new insight to increase the response speed of PM type PPDs by adjusting the photogenerated electron distribution in the active layer. Considering that the PM type PPDs have much higher EQE than the traditional organic photodetectors, the improvement may further extend its potential applications with low cost. PMID- 26527196 TI - Evaluation of hearing among kindergarten children in Jazan (Kingdom of Saudi Arabia). AB - INTRODUCTION: Hearing loss among kindergarten children is considered as a major health problem especially when there is a deficiency in routine hearing screening during the clinical examination. The aim of the study was to detect any pattern of hearing loss among kindergarten children in Jazan (Kingdom of Saudi Arabia). METHODS: A total of 1220 kindergarten students in Jazan (Kingdom of Saudi Arabia) were subjected to meticulous hearing evaluation using otological examination, Tuning fork tests, pure tone audiometry (PTA), speech audiometry, and tympanometry. RESULTS: We found that 18 kindergarten students had type C tympanogram (Eustachian tube dysfunction), 28 had type B tympanogram (secretory otitis media with conductive hearing loss), 4 had chronic otitis media with conductive hearing loss, and 6 had mild sensorineural hearing loss. CONCLUSIONS: Early detection and eradication of hearing loss improves quality of life outcomes of children which reduces the incidence of social burden from unrecognized hearing loss. PMID- 26527197 TI - Does this comatose survivor of cardiac arrest have a poor prognosis? PMID- 26527200 TI - Meeting report--Imaging the Cell. AB - Every two years, the French Society for Cell Biology (SBCF) organises an international meeting called 'Imaging the Cell'. This year, the 8th edition was held on 24-26 June 2015 at University of Bordeaux Campus Victoire in the city of Bordeaux, France, a UNESCO World Heritage site. Over the course of three days, the meeting provided a forum for experts in different areas of cell imaging. Its unique approach was to combine conventional oral presentations during morning sessions with practical workshops at hosting institutes and the Bordeaux Imaging Center during the afternoons. The meeting, co-organised by Violaine Moreau and Frederic Saltel (both INSERM U1053, Bordeaux, France), Christel Poujol and Fabrice Cordelieres (both Bordeaux Imaging Center, Bordeaux, France) and Isabelle Sagot (Institut de Biochimie et Genetique Cellulaires, Bordeaux, France), brought together about 120 scientists including 16 outstanding speakers to discuss the latest advances in cell imaging. Thanks to recent progress in imaging technologies, cell biologists are now able to visualise, follow and manipulate cellular processes with unprecedented accuracy. The meeting sessions and workshops highlighted some of the most exciting developments in the field, with sessions dedicated to optogenetics, high-content screening, in vivo and live-cell imaging, correlative light and electron microscopy, as well as super-resolution imaging. PMID- 26527198 TI - Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes. AB - Over 800 mutations in the ABCA4 gene cause autosomal recessive Stargardt disease. Due to extensive genetic heterogeneity, observed variant-associated phenotypes can manifest tremendous variability of expression. Furthermore, the high carrier frequency of pathogenic ABCA4 alleles in the general population (~1:20) often results in pseudo-dominant inheritance patterns further complicating the diagnosis and characterization of affected individuals. This study describes a genotype/phenotype analysis of an unusual family with multiple macular disease phenotypes spanning across two generations and segregating four distinct ABCA4 mutant alleles. Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Array comparative genomic hybridization revealed a large novel deletion combined with a small insertion, c.6148 698_c.6670del/insTGTGCACCTCCCTAG, and complete sequencing of the entire ABCA4 genomic locus uncovered a new deep intronic variant, c.302+68C>T. Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. This family epitomizes the clinical and genetic complexity of ABCA4-associated diseases. It contained variants from all classes of mutations, in the coding region, deep intronic, both single nucleotide variants and copy number variants that accounted for varying phenotypes segregating in an apparent dominant fashion. Unequivocally defining disease-associated alleles in the ABCA4 locus requires a multifaceted approach that includes advanced mutation detection methods and a thorough analysis of clinical phenotypes. PMID- 26527201 TI - Reliability of ROS and RNS detection in hematopoietic stem cells--potential issues with probes and target cell population. AB - Many studies have provided evidence for the crucial role of the reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the regulation of differentiation and/or self-renewal, and the balance between quiescence and proliferation of hematopoietic stem cells (HSCs). Several metabolic regulators have been implicated in the maintenance of HSC redox homeostasis; however, the mechanisms that are regulated by ROS and RNS, as well as their downstream signaling are still elusive. This is partially owing to a lack of suitable methods that allow unequivocal and specific detection of ROS and RNS. In this Opinion, we first discuss the limitations of the commonly used techniques for detection of ROS and RNS, and the problem of heterogeneity of the cell population used in redox studies, which, together, can result in inaccurate conclusions regarding the redox biology of HSCs. We then propose approaches that are based on single-cell analysis followed by a functional test to examine ROS and RNS levels specifically in HSCs, as well as methods that might be used in vivo to overcome these drawbacks, and provide a better understanding of ROS and RNS function in stem cells. PMID- 26527202 TI - Robust hematopoietic progenitor cell commitment in the presence of a conflicting cue. PMID- 26527203 TI - APC16 is a conserved subunit of the anaphase-promoting complex/cyclosome. PMID- 26527204 TI - Long-term efficacy of an oral appliance in early treated patients with obstructive sleep apnea. AB - PURPOSE: The purpose of the present study was to evaluate the long-term efficacy of oral appliances (OAs) in early treated patients with obstructive sleep apnea (OSA). METHOD AND PATIENTS: Polysomnographic sleep recordings without and with an OA were performed at treatment start and in patients who had been continuously treated with OAs for at least 15 years. RESULTS: Nine patients (eight men) with a median age of 68.1 years (interquartile range (IQR) 60.0 to 76.3 years) and a median treatment time of 16.5 years (IQR 16.3 to 18.0 years) were included. The apnea-hypopnea index decreased from a median of 17.3 (IQR 9.7 to 26.5) to 7.2 (IQR 4.0 to 9.6; p = 0.03) at the short-term follow-up. After long-term use, the apnea-hypopnea index was 32.4 (IQR 22.2 to 58.8) without the device and 35.1 (IQR 13.6 to 46.2) with it (p = 0.08). There were increases in the apnea-hypopnea index, both without the device (p = 0.02) and with it (p = 0.008). The degree of mandibular advancement did not differ between the two study occasions (p = 1.0). CONCLUSIONS: Patients treated with oral appliances may experience deteriorations in disease severity and treatment efficacy during continuous long-term OA treatment. Regular follow-up schedules with renewed sleep apnea recordings should be considered for these patients in order to avoid suboptimal or a total loss of effects on sleep apneas. PMID- 26527205 TI - Sleep bruxism frequency and platelet serotonin transporter activities in young adult subjects. AB - PURPOSE: To evaluate correlations between serotonin transporter (SERT) uptake ability in human peripheral platelets and sleep bruxism (SB) frequency. METHODS: Subjects were consecutively recruited from sixth-year students at Okayama University Dental School. Subjects were excluded if they (1) were receiving orthodontic treatment, (2) had a dermatological disease, (3) had taken an antidepressant within 6 months, or (4) had used an oral appliance within 6 months. SB frequency was determined as the summary score of three consecutive night assessments using a self-contained electromyography detector/analyzer in their home. Fasting peripheral venous blood samples were collected in the morning following the final SB assessment. SERT amount and platelet number were quantified via an ELISA assay and flow cytometry, respectively. Functional SERT characterization, 5-hydroxytryptamine (5-HT) uptake, maximum velocity (V max), and an affinity constant (K m ) were assessed with a [(3)H] 5-HT uptake assay. The correlations between these variables and SB level were evaluated. RESULTS: Among 50 eligible subjects (26 males, mean age 25.4 +/- 2.41 years), 7 were excluded because of venipuncture failure, smoking, and alcohol intake during the experimental period. A small but significant negative correlation between SB level and [(3)H] 5-HT uptake was observed (Spearman's correlation R (2) = 0.063, p = 0.04). However, there were no significant correlations between SB level and total platelet amount, SERT, V max, and K m values (p = 0.08, 0.12, 0.71, and 0.68, respectively). CONCLUSIONS: Platelet serotonin uptake is significantly associated with SB frequency, yet only explains a small amount of SB variability. PMID- 26527206 TI - Diagnostic validity of the use of a portable single-channel electromyography device for sleep bruxism. AB - PURPOSE: The aim of this study was to determine an appropriate cutoff value and the number of nights of sleep with the portable single-channel EMG device (GrindCare) necessary for a valid sleep bruxism (SB) diagnosis. METHODS: Twenty consecutive post-graduate students and staff at Bauru School of Dentistry composed the sample. Each participant underwent the GrindCare for five consecutive nights and the polysomnography (PSG). The discrimination between bruxers and non-bruxers was based only on the PSG analysis. Data about electromyography per hour with GrindCare (EMG/h) and PSG (bursts/h) were scored. RESULTS: There were positive correlations between the two devices for EMG/h and bursts/h in three and five consecutive nights. Bland-Altman analysis of the EMG bursts/h showed positive agreement between the methods. The receiver operating characteristic (ROC) analyses also showed that using a minimum of 18 EMG/h for three nights and 19 EMG/h for five nights in GrindCare as cutoffs resulted in a 90 % specificity and positive likelihood ratio equal to 5. CONCLUSIONS: GrindCare is able to discriminate SB diagnosed by PSG and gold standard criteria, when used for three or five consecutive nights, and it may be a valid choice in clinical practice for SB assessment. PMID- 26527207 TI - Genetic variation in V gene of class II Newcastle disease virus. AB - The genetic variation and molecular evolution of the V gene of the class II Newcastle disease virus (NDV) isolates with genotypes I-XVIII were determined using bioinformatics. Results indicated that low homology existed in different genotype viruses, whereas high homology often for the same genotypes, exception may be existed within genotypes I, V, VI, and XII. Sequence analysis showed that the genetic variation of V protein was consistent with virus genotype, and specific signatures on the V protein for nine genotypes were identified. Phylogenetic analysis demonstrated that the phylogenetic trees were highly consistent between the V and F genes, with slight discrepancies in the sub genotypes. Evolutionary rate analyses based on V and F genes revealed the evolution rates varied in genotypes. These data indicate that the genetic variation of V protein is genotype-related and will help in elucidating the molecular evolution of NDV. PMID- 26527208 TI - Increased storage and secretion of phosphatidylcholines by senescent human peritoneal mesothelial cells. AB - BACKGROUND/AIMS: Human peritoneal mesothelial cells (HPMC) secrete phosphatidylcholines (PC) which form a lipid bilayer lining the peritoneum. They prevent frictions and adhesions and act as a barrier to the transport of water soluble solutes while permitting water flux. PC may play an essential role in peritoneal integrity and function, the role of PD induced HPMC senescence on PC homeostasis, however, is unknown. METHODS: HPMC cell lines were isolated from four non-uremic patients. Expression of the three PC synthesis genes (rt-PCR), and cellular storage and secretion of PC (ESI-mass-spectrometry) were analyzed in young and senescent HPMC (>Hayflick-limit). RESULTS: Senescent cells displayed significantly altered morphology; flow cytometry demonstrated extensive staining for senescence-associated beta galactosidase. Nine different PC were detected in HPMC with palmitoyl-myristoyl phosphatidylcholine (PMPC) being most abundant. In senescent HPMC mRNA expression of the three key PC synthesis genes was 1.5-, 2.4- and 6-fold increased as compared to young HPMC, with the latter, phosphatidylcholine cytidylyltransferase, being rate limiting. Intracellular storage of the nine PC was 75-450 % higher in senescent vs. young HPMC, PC secretion rates were 100-300 % higher. Intracellular PC concentrations were not correlated with the PC secretion rates. Electron microscopy demonstrated lamellar bodies, the primary storage site of PC, in senescent but not in young cells. CONCLUSION: Senescent HPMC store and secrete substantially more PC than young cells. Our findings indicate a novel protective mechanism, which should counteract peritoneal damage induced by chronic exposure to PD fluids. PMID- 26527209 TI - Exercise copes with prolonged stress-induced impairment of spatial memory performance by endoplasmic reticulum stress. AB - The present study demonstrates that prolonged restraint administration for 21 days caused memory impairment and induced hippocampal endoplasmic reticulum (ER) stress-mediated apoptosis. On the contrary, this change was revered by treadmill running for 8 weeks. Repeated psychological stress caused an increase in escape latency time in the water maze test, accompanied by the induction of glucose regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), and cleaved/active caspase-12 protein in the hippocampus. The expression pattern of ER stress response-related proteins were counter-regulated by chronic exercise, as indicated by a reduction in GRP78, CHOP, and cleaved caspase-12, along with a decrease in escape latency time. In addition, the hippocampal expression pattern of phospho-cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) opposed that of ER stress response components. Accordingly, chronic exercise may attenuate prolonged stress-induced hippocampal ER stress and memory deficit, likely through CREB/BDNF signaling. PMID- 26527210 TI - Flexible or leaky attention in creative people? Distinct patterns of attention for different types of creative thinking. AB - Creativity has been putatively linked to distinct forms of attention, but which aspects of creativity and which components of attention remains unclear. Two experiments examined how divergent thinking and creative achievement relate to visual attention. In both experiments, participants identified target letters (S or H) within hierarchical stimuli (global letters made of local letters), after being cued to either the local or global level. In Experiment 1, participants identified the targets more quickly following valid cues (80% of trials) than following invalid cues. However, this smaller validity effect was associated with higher divergent thinking, suggesting that divergent thinking was related to quicker overcoming of invalid cues, and thus to flexible attention. Creative achievement was unrelated to the validity effect. Experiment 2 examined whether divergent thinking (or creative achievement) is related to "leaky attention," so that when cued to one level of a stimulus, some information is still processed, or leaks in, from the non-cued level. In this case, the cued stimulus level always contained a target, and the non-cued level was congruent, neutral, or incongruent with the target. Divergent thinking did not relate to stimulus congruency. In contrast, high creative achievement was related to quicker responses to the congruent than to the incongruent stimuli, suggesting that real world creative achievement is indeed associated with leaky attention, whereas standard laboratory tests of divergent thinking are not. Together, these results elucidate distinct patterns of attention for different measures of creativity. Specifically, creative achievers may have leaky attention, as suggested by previous literature, whereas divergent thinkers have selective yet flexible attention. PMID- 26527211 TI - Cognitive impairment in a young marmoset reveals lateral ventriculomegaly and a mild hippocampal atrophy: a case report. AB - The number of studies that use the common marmoset (Callithrix jacchus) in various fields of neurosciences is increasing dramatically. In general, animals enter the study when their health status is considered satisfactory on the basis of classical clinical investigations. In behavioral studies, variations of score between individuals are frequently observed, some of them being considered as poor performers or outliers. Experimenters rarely consider the fact that it could be related to some brain anomaly. This raises the important issue of the reliability of such classical behavioral approaches without using complementary imaging, especially in animals lacking striking external clinical signs. Here we report the case of a young marmoset which presented a set of cognitive impairments in two different tasks compared to other age-matched animals. Brain imaging revealed a patent right lateral ventricular enlargement with a mild hippocampal atrophy. This abnormality could explain the cognitive impairments of this animal. Such a case points to the importance of complementing behavioral studies by imaging explorations to avoid experimental bias. PMID- 26527212 TI - Divergence between the Highly Virulent Zoonotic Pathogen Helicobacter heilmannii and Its Closest Relative, the Low-Virulence "Helicobacter ailurogastricus" sp. nov. AB - Helicobacter heilmannii naturally colonizes the stomachs of dogs and cats and has been associated with gastric disorders in humans. Nine feline Helicobacter strains, classified as H. heilmannii based on ureAB and 16S rRNA gene sequences, were divided into a highly virulent and a low-virulence group. The genomes of these strains were sequenced to investigate their phylogenetic relationships, to define their gene content and diversity, and to determine if the differences in pathogenicity were associated with the presence or absence of potential virulence genes. The capacities of these helicobacters to bind to the gastric mucosa were investigated as well. Our analyses revealed that the low-virulence strains do not belong to the species H. heilmannii but to a novel, closely related species for which we propose the name Helicobacter ailurogastricus. Several homologs of H. pylori virulence factors, such as IceA1, HrgA, and jhp0562-like glycosyltransferase, are present in H. heilmannii but absent in H. ailurogastricus. Both species contain a VacA-like autotransporter, for which the passenger domain is remarkably larger in H. ailurogastricus than in H. heilmannii. In addition, H. ailurogastricus shows clear differences in binding to the gastric mucosa compared to H. heilmannii. These findings highlight the low virulence character of this novel Helicobacter species. PMID- 26527213 TI - Pneumococcal 6-Phospho-beta-Glucosidase (BglA3) Is Involved in Virulence and Nutrient Metabolism. AB - For the generation of energy, the important human pathogen Streptococcus pneumoniae relies on host-derived sugars, including beta-glucoside analogs. The catabolism of these nutrients involves the action of 6-phospho-beta-glucosidase to convert them into usable monosaccharaides. In this study, we characterized a 6 phospho-beta-glucosidase (BglA3) encoded by SPD_0247. We found that this enzyme has a cell membrane localization and is active only against a phosphorylated substrate. A mutated pneumococcal DeltaSPD0247 strain had reduced 6-phospho glucosidase activity and was attenuated in growth on cellobiose and hyaluronic acid compared to the growth of wild-type D39. DeltaSPD0247-infected mice survived significantly longer than the wild-type-infected cohort, and the colony counts of the mutant were lower than those of the wild type in the lungs. The expression of SPD_0247 in S. pneumoniae harvested from infected tissues was significantly increased relative to its expression in vitro on glucose. Additionally, DeltaSPD0247 is severely impaired in its attachment to an abiotic surface. These results indicate the importance of beta-glucoside metabolism in pneumococcal survival and virulence. PMID- 26527214 TI - New Role of Nod Proteins in Regulation of Intestinal Goblet Cell Response in the Context of Innate Host Defense in an Enteric Parasite Infection. AB - Mucins secreted by intestinal goblet cells are considered an important component of innate defense in a number of enteric infections, including many parasitic infections, but also likely provide protection against the gut microbiota. Nod proteins are intracellular receptors that play key roles in innate immune response and inflammation. Here, we investigated the role of Nod proteins in regulation of intestinal goblet cell response in naive mice and mice infected with the enteric parasite Trichuris muris. We observed significantly fewer periodic acid-Schiff (PAS)-stained intestinal goblet cells and less mucin (Muc2) in Nod1 and Nod2 double-knockout (Nod DKO) mice after T. muris infection than in wild-type (WT) mice. Expulsion of parasites from the intestine was significantly delayed in Nod DKO mice. Treatment of naive WT mice with Nod1 and Nod2 agonists simultaneously increased numbers of PAS-stained goblet cells and Muc2-expressing cells, whereas treatment with Nod1 or Nod2 separately had no significant effect. Stimulation of mucin-secreting LS174T cells with Nod1 and Nod2 agonists upregulated core 3 beta1,3-N-acetylglucosaminyltransferase (C3GnT; an important enzyme in mucin synthesis) and MUC2. We also observed lower numbers of PAS stained goblet cells and less Muc2 in germfree mice. Treatment with Nod1 and Nod2 agonists enhanced the production of PAS-stained goblet cells and Muc2 in germfree mice. These data provide novel information on the role of Nod proteins in goblet cell response and Muc2 production in relation to intestinal innate defense. PMID- 26527215 TI - Interaction of Mycoplasma gallisepticum with Chicken Tracheal Epithelial Cells Contributes to Macrophage Chemotaxis and Activation. AB - Mycoplasma gallisepticum colonizes the chicken respiratory mucosa and mediates a severe inflammatory response hallmarked by subepithelial leukocyte infiltration. We recently reported that the interaction of M. gallisepticum with chicken tracheal epithelial cells (TECs) mediated the upregulation of chemokine and inflammatory cytokine genes in these cells (S. Majumder, F. Zappulla, and L. K. Silbart, PLoS One 9:e112796, http://dx.doi.org/10.1371/journal.pone.0112796). The current study extends these observations and sheds light on how this initial interaction may give rise to subsequent inflammatory events. Conditioned medium from TECs exposed to the virulent Rlow strain induced macrophage chemotaxis to a much higher degree than the nonvirulent Rhigh strain. Coculture of chicken macrophages (HD-11) with TECs exposed to live mycoplasma revealed the upregulation of several proinflammatory genes associated with macrophage activation, including interleukin-1beta (IL-1beta), IL-6, IL-8, CCL20, macrophage inflammatory protein 1beta (MIP-1beta), CXCL-13, and RANTES. The upregulation of these genes was similar to that observed upon direct contact of HD-11 cells with live M. gallisepticum. Coculture of macrophages with Rlow-exposed TECs also resulted in prolonged expression of chemokine genes, such as those encoding CXCL 13, MIP-1beta, RANTES, and IL-8. Taken together, these studies support the notion that the initial interaction of M. gallisepticum with host respiratory epithelial cells contributes to macrophage chemotaxis and activation by virtue of robust upregulation of inflammatory cytokine and chemokine genes, thereby setting the stage for chronic tissue inflammation. PMID- 26527216 TI - All Three TonB Systems Are Required for Vibrio vulnificus CMCP6 Tissue Invasiveness by Controlling Flagellum Expression. AB - TonB systems actively transport iron-bound substrates across the outer membranes of Gram-negative bacteria. Vibrio vulnificus CMCP6, which causes fatal septicemia and necrotizing wound infections, possesses three active TonB systems. It is not known why V. vulnificus CMCP6 has maintained three TonB systems throughout its evolution. The TonB1 and TonB2 systems are relatively well characterized, while the pathophysiological function of the TonB3 system is still elusive. A reverse transcription-PCR (RT-PCR) study showed that the tonB1 and tonB2 genes are preferentially induced in vivo, whereas tonB3 is persistently transcribed, albeit at low expression levels, under both in vitro and in vivo conditions. The goal of the present study was to elucidate the raison d'etre of these three TonB systems. In contrast to previous studies, we constructed in-frame single-, double-, and triple-deletion mutants of the entire structural genes in TonB loci, and the changes in various virulence-related phenotypes were evaluated. Surprisingly, only the tonB123 mutant exhibited a significant delay in killing eukaryotic cells, which was complemented in trans with any TonB operon. Very interestingly, we discovered that flagellum biogenesis was defective in the tonB123 mutant. The loss of flagellation contributed to severe defects in motility and adhesion of the mutant. Because of the difficulty of making contact with host cells, the mutant manifested defective RtxA1 toxin production, which resulted in impaired invasiveness, delayed cytotoxicity, and decreased lethality for mice. Taken together, these results indicate that a series of virulence defects in all three TonB systems of V. vulnificus CMCP6 coordinately complement each other for iron assimilation and full virulence expression by ensuring flagellar biogenesis. PMID- 26527217 TI - Erythrocyte Catalase Activity in More Frequent Microcytic Hypochromic Anemia: Beta-Thalassemia Trait and Iron Deficiency Anemia. AB - Most common microcytic hypochromic anemias are iron deficiency anemia (IDA) and beta-thalassemia trait (BTT), in which oxidative stress (OxS) has an essential role. Catalase causes detoxification of H2O2 in cells, and it is an indispensable antioxidant enzyme. The study was designed to measure erythrocyte catalase activity (ECAT) in patients with IDA (10) or BTT (21), to relate it with thalassemia mutation type (beta (0) or beta (+)) and to compare it with normal subjects (67). Ninety-eight individuals were analyzed since September 2013 to June 2014 in Tucuman, Argentina. Total blood count, hemoglobin electrophoresis at alkaline pH, HbA2, catalase, and iron status were performed. beta-thalassemic mutations were determined by real-time PCR. Normal range for ECAT was 70,0-130,0 MU/L. ECAT was increased in 14% (3/21) of BTT subjects and decreased in 40% (4/10) of those with IDA. No significant difference (p = 0,245) was shown between normal and BTT groups, while between IDA and normal groups the difference was proved to be significant (p = 0,000). In beta (0) and beta (+) groups, no significant difference (p = 0,359) was observed. An altered ECAT was detected in IDA and BTT. These results will help to clarify how the catalase activity works in these anemia types. PMID- 26527218 TI - IAPAC Guidelines for Optimizing the HIV Care Continuum for Adults and Adolescents. AB - BACKGROUND: An estimated 50% of people living with HIV (PLHIV) globally are unaware of their status. Among those who know their HIV status, many do not receive antiretroviral therapy (ART) in a timely manner, fail to remain engaged in care, or do not achieve sustained viral suppression. Barriers across the HIV care continuum prevent PLHIV from achieving the therapeutic and preventive effects of ART. METHODS: A systematic literature search was conducted, and 6132 articles, including randomized controlled trials, observational studies with or without comparators, cross-sectional studies, and descriptive documents, met the inclusion criteria. Of these, 1047 articles were used to generate 36 recommendations to optimize the HIV care continuum for adults and adolescents. RECOMMENDATIONS: Recommendations are provided for interventions to optimize the HIV care environment; increase HIV testing and linkage to care, treatment coverage, retention in care, and viral suppression; and monitor the HIV care continuum. PMID- 26527219 TI - Coinfection of Sexually Transmitted Infections among HIV-Positive Individuals: Cross-Sectional Results of a Community-Based Positive Living with HIV (POLH) Study in Nepal. AB - In Asian concentrated HIV epidemics, data on coinfection of sexually transmitted infections (STIs) among HIV-positive individuals are limited. The authors measured the prevalence of Chlamydia trachomatis (CT), Neisseria gonorrhea (NG), and syphilis, and their correlates among 319 HIV-positive individuals in Kathmandu, Nepal. The authors tested blood samples for syphilis and urine samples for CT and NG. Overall, 17 (5.3%) participants had at least 1 STI (CT: 1.3%, NG: 2.8%, and syphilis: 1.2%). Of 226 participants who had sex in past 6 months, 51.3% did not always use condoms. Older (aged 35-60 years) participants were more likely (adjusted odds ratio [AOR] = 3.83; 95% confidence interval [CI] = 1.19 12.33; P = .024) and those who were currently married (AOR = 0.30; 95% CI = 0.09 0.97; P = .046) or on antiretroviral therapy (AOR = 0.21; 95% CI = 0.06-0.71; P = .012) were less likely to have at least 1 STI. Our results suggest the need to strengthen the efforts to screen and treat STIs and to promote safer sexual practices among Nepalese HIV-positive individuals. PMID- 26527220 TI - Splenectomy increases the subsequent risk of systemic lupus erythematosus. AB - Splenectomy may be necessary to treat systemic lupus erythematosus (SLE) patients with thrombocytopenia; however, whether performing a splenectomy on patients without SLE increases the subsequent risk of SLE remains unknown. Therefore, this study was conducted to determine the association between splenectomy and SLE. We conducted a cohort study by using data from the Taiwan National Health Institute Research Database to identify 10,298 patients with received a splenectomy between 2000 and 2006 and 41,192 participants without received a splenectomy who were selected by frequency matched based on sex, age, and the index year. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95 % confidence intervals (CIs) of developing SLE associated with splenectomy compared with patients who did not receive a splenectomy. During the study period, the overall incidence density rate of SLE was higher in the splenectomy cohort than in the non-splenectomy cohort (adjusted HR 10.55; 95 % CI 50.55 20.05). The incidence density rates of SLE in women and men who received a splenectomy were higher than those of patients who did not receive a splenectomy. Non-traumatic splenectomy increases the subsequent risk of SLE. The risk of SLE should be considered before performing a splenectomy, particularly in women and younger patients. PMID- 26527221 TI - An Efficient and Sensitive Optical Sensor Based on Furosemide as a new Fluoroionophore for Determination of Uranyl ion. AB - A new, simple and sensitive optical sensor for determination of uranyl ion (UO2 (2+)) in aqueous solutions by spectrofluorimetric technique was introduced. The fluorescence spectra and response characteristics of 4-chloro-2 (furan-2 ylmethylamino) - 5-sulfamoylbenzoic acid (Furosemide) to UO2 (2+) was investigated. It showed preferable fluorescence response to UO2 (2+). Thereby, an efficient and sensitive optical sensor based on the fluorescence enhancement of Furosemide as a new fluoroionophore for UO2 (2+) determination at low concentration levels has been developed. The reaction was extremely rapid at room temperature, and the fluorescence intensity remains unchanged for at least 24 h. Also, the response mechanism of the present sensor is discussed. This optical sensor is useful owing to the sufficient capability for determination of UO2 (2+) in various real samples. Apart from the high sensitivity, the procedure is very simple, fast, wider linear range and gains a low detection limit without any complicated equipment. The present sensor has been successfully tested for determination of UO2 (2+) in real samples and the results obtained are comparable to inductively coupled plasma optical emission spectrometry (ICP-OES) measured which could be used as a promising tool in nuclear safeguards material accountability measurements. PMID- 26527222 TI - Non-Invasive Detection of Lung Inflammation by Near-Infrared Fluorescence Imaging Using Bimodal Liposomes. AB - Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome results in respiratory obstruction and severe lung inflammation. Critical characteristics of ALI are alveolar edema, infiltration of leukocytes (neutrophils and monocytes), release of pro-inflammatory cytokines and chemokines into broncho-alveolar lavage fluid, and activation of integrin receptors. The purpose of the study was to demonstrate non-invasive detection of lung inflammation using integrin receptor targeted fluorescence liposomes. An inflammation similar to that observed in ALI was elicited in rodents by intra tracheal instillation of interleukin-1beta (IL-1beta). Cyclic arginine glycine (D)-aspartic acid-peptide (cRGD-peptide) grafted fluorescence liposomes were administered to ALI induced male Sprague-Dawley rats for targeting lung integrin receptors. Near-infrared fluorescence imaging (NIRFI) was applied for visualization and quantitation of lung inflammation. NIRFI signals were correlated with inflammatory cellular and biochemical markers of lungs. A positive correlation was observed between NIRF signals and lung inflammation markers. Compared to control group, an intense NIRF signal was observed in ALI induced rats in the window 6-24 h post-IL-1beta instillation. Interaction of integrin receptors with targeted liposomes was assumed to contribute to intense NIRF signal. RT-PCR studies showed an elevated lung expression of alphavbeta5 integrin receptors, 12 h post-IL-1beta instillation. In vitro studies demonstrated integrin receptor specificity of targeted liposomes. These targeted liposomes showed binding to alphavbeta5 integrin receptors expressed on alveolar cells. Non-invasive detection of lung inflammation was demonstrated using a combination of integrin receptor targeting and NIRFI. PMID- 26527223 TI - Implications of IASP Core Curriculum for Pre-Registration Physiotherapy Education. AB - There are concerns about the effectiveness of health professionals when they are working with people who have pain.Health professionals have reported a lack of confidence when working with people with complex pain conditions.Review of pain education in health professional training may improve clinical practice.The International Association for the Study of Pain curricula can be useful in developing pain education initiatives.The up-dated IASP core curriculum appears to be a useful resource for curriculum designers of pre-registration physiotherapy programmes, while the IASP discipline-specific curriculum is in need of revision. PMID- 26527224 TI - Dental (Odontogenic) Pain. AB - This article provides a simple overview of acute trigeminal pain for the non dentist.This article does not cover oral mucosal diseases (vesiculobullous disorders) that may cause acute pain.Dental pain is the most common in this group and it can present in several different ways.Of particular interest for is that dental pain can mimic both trigeminal neuralgia and other chronic trigeminal pain disorders.It is crucial to exclude these disorders whilst managing patients with chronic trigeminal pain. PMID- 26527225 TI - Clinical and Safety Outcomes of Oral Antithrombotics for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Network Meta-analysis. AB - INTRODUCTION: Novel oral anticoagulants (NOACs) expanded the options for stroke prevention in atrial fibrillation (AF). Earlier studies comparing their relative effectiveness and safety typically do not incorporate age-related differences or postmarketing studies. This study aimed to summarize and compare clinical and safety outcomes of oral antithrombotics for stroke prevention in AF in younger (65-74 years) and older (>=75 years) elderly. METHODS: We searched PubMed, Embase, and The Cochrane Library from inception through May 1, 2015, for randomized and nonrandomized studies comparing NOACs, warfarin, and aspirin in elderly with AF. Stroke and systemic embolism (SSE) and major bleeding (MB) are the main outcomes. We also studied secondary outcomes of ischemic stroke, all cause mortality, intracranial bleeding, and gastrointestinal bleeding. RESULTS: Of 5255 publications identified, 25 randomized controlled trials and 24 nonrandomized studies of 897,748 patients were included. NOACs reduced the risk of SSE compared with warfarin (rate ratios [RRs] range from 0.78-0.82). Relative to SSE, NOACs demonstrated a smaller benefit for ischemic stroke (dabigatran 110 mg, RR 1.08; edoxaban, 1.00; apixaban, 0.99). On the contrary, aspirin was associated with a significantly higher risk of SSE, ischemic stroke, and mortality than warfarin or NOACs (RR > 1), particularly in older elderly. Regarding safety, medium-dose aspirin (100-300 mg daily) and aspirin/clopidogrel combination showed an increased risk of MB compared with warfarin (RR 1.17 and 1.15, respectively), as per dabigatran 150 mg and rivaroxaban in older elderly (RR 1.17 and 1.12, respectively). Among the NOACs, dabigatran 150 mg conferred greater gastrointestinal bleeding risk compared with warfarin (RR 1.51), whereas rivaroxaban (RR 0.73) demonstrated less benefit of reduced intracranial bleeding than other NOACs (RRs range 0.39-0.46). CONCLUSIONS: Lower rates of SSE and intracranial bleeding were observed with the NOACs compared with warfarin. Dabigatran 150 mg and rivaroxaban were associated with higher rates of MB in older elderly. PMID- 26527226 TI - Pre-delivery remifentanil infusion for placenta accreta cesarean delivery under general anesthesia: an observational study. AB - OBJECTIVE: General anesthesia may be required for placenta accreta cesarean delivery. Intrauterine fetal anesthetic exposure should be minimized to avoid neonatal respiratory depression; opioids are often delayed until post-delivery. METHODS: In this observational study, we compared neonatal outcome using pre delivery remifentanil versus post-delivery (deferred) opioids for placenta accreta cesarean delivery. Choice of anesthesia was discretionary. The primary outcome was Apgar score at 5 min comparing women who received pre-delivery remifentanil versus deferred opioid administration. We recorded maternal/obstetric characteristics, surgical characteristics, maternal hemodynamic data, neonatal outcomes: Apgar scores, umbilical vein pH and respiratory interventions at birth. RESULTS: Between February 2007 and April 2014 we identified 40 general anesthesia placenta accreta cesarean deliveries. The remifentanil dose rate ranged from 0.06 to 0.46 mcg kg(-1 )min(-1). Obstetric and maternal characteristics were similar. Neonatal Apgar, umbilical pH and respiratory intervention outcomes were similar in both groups; Apgar scores median (interquartile range IQR [range]) at 5 min were 9 (8-10) for pre-delivery remifentanil versus 9 (9-10) for deferred opioid administration, p = 0.18. CONCLUSIONS: We did not observe a significant effect on neonatal Apgar scores at 1 and 5 min, or respiratory interventions at birth when remifentanil infusion was administered pre-delivery. PMID- 26527228 TI - Dental Management of a Patient with Nager Acrofacial Dysostosis. AB - Nager syndrome is a rare syndrome resulting from developmental abnormalities of the first and second branchial arches. Nager syndrome is rare and mostly sporadic. The main clinical features consist of craniofacial, limb, and musculoskeletal morphogenesis. These findings included malar hypoplasia, maxillomandibular hypoplasia, micrognathia, downslanting palpebral fissures, cleft palate, ear anomalies, hypoplastic thumb, short forearm, proximal radioulnar synostosis, atrial septal defect, lower limb deformities, and flat nasal bridge. The prevalence is unknown; about 100 cases of Nager syndrome have been published up to now. Patients with Nager syndrome are found worldwide among all racial and ethnic groups. Trismus and glossoptosis resulting in oropharyngeal airway narrowing cause life-threatening respiratory distress for patients with Nager syndrome. In this case report, dental rehabilitation of a 10-year-old child with Nager syndrome is presented. PMID- 26527227 TI - Voltage-Based Ablation: The Growing Evidence for the Role of Individually Tailored Substrate Modification for Atrial Fibrillation. PMID- 26527229 TI - When LVAD Patients Die: The Caregiver's Mourning. AB - Left ventricular assist devices (LVADs) have progressively evolved, particularly in the last 10 years, to serve patients affected by severe heart failure as a bridge to transplant or destination therapy. The survival rate and quality of life of pre- and postimplant patients, as well as caregivers' perceptions and distress, are under investigation by the scientific community. But what caregivers think and feel after the loss of their loved one has not so far been examined. We contacted 16 principal caregivers of deceased LVAD patients by telephone. They were asked to evaluate their experience with LVADs and were administered a specific questionnaire about their mourning, the Caregiver Mourning Questionnaire (CMQ), to evaluate their perceptions of the physical, emotional, and social support-related problems that they had experienced during the previous 3 months. Positive aspects reported by the caregivers were the patient's overall subjective well-being and increased survival. Negative aspects were the difficulty to manage infections and the driveline, and the incomplete autonomy of the patient. Half of the caregivers reported not being preadvised about many of the problems they would face. The CMQ revealed that numerous caregivers had health problems, difficulty in sleeping, eating disorders, lack of energy, and loneliness. Use of psychotropic drugs and regrets about how they assisted their loved one also emerged. In conclusion, caregivers of LVAD patients may experience complicated mourning. Our data support in particular the need for an early intervention of palliative care which could prevent or reduce complicated mourning. PMID- 26527230 TI - Determination of the Gelation Mechanism of Freeze-Thawed Hen Egg Yolk. AB - A study of yolks stored up to 168 d at -20 degrees C was conducted to determine the gelation behavior and mechanism of freeze-thawed yolk. Methods used were rheology, native and sodium dodecyl sulfate polyacrylamide gel electrophoresis (native- and SDS-PAGE), differential scanning calorimetry (DSC), transmission electron microscopy (TEM), particle size analysis, and proton nuclear magnetic resonance ((1)H NMR) spectroscopy for matrix mobility. Results indicate that both constituents of plasma and granules contributed to gelation of yolk under freezing. PAGE analyses suggest that granular proteins participated in aggregation during freeze-thaw. Increasing gel strength and particle size and decreasing water and lipid-water mobility indicate that lipoproteins or apolipoproteins aggregated. At storage times >=84 d, increased protein and lipid mobility, the detection of smaller particles, and secondarily increased gel strength suggest the liberation of protein or lipoprotein components from previously formed aggregates and further aggregation of these constituents. Disruption of the gelled yolk matrix observed with TEM supported that ice crystal formation was required for gelation to occur. A two-stage dynamic gelation model is thus proposed. PMID- 26527231 TI - Specimen rejection in laboratory medicine: Necessary for patient safety? AB - INTRODUCTION: The emergency laboratory in Hacettepe University Hospitals receives specimens from emergency departments (EDs), inpatient services and intensive care units (ICUs). The samples are accepted according to the rejection criteria of the laboratory. In this study, we aimed to evaluate the sample rejection ratios according to the types of pre-preanalytical errors and collection areas. MATERIALS AND METHODS: The samples sent to the emergency laboratory were recorded during 12 months between January to December, 2013 in which 453,171 samples were received and 27,067 specimens were rejected. RESULTS: Rejection ratios was 2.5% for biochemistry tests, 3.2% for complete blood count (CBC), 9.8% for blood gases, 9.2% for urine analysis, 13.3% for coagulation tests, 12.8% for therapeutic drug monitoring, 3.5% for cardiac markers and 12% for hormone tests. The most frequent rejection reasons were fibrin clots (28%) and inadequate volume (9%) for biochemical tests. Clotted samples (35%) and inadequate volume (13%) were the major causes for coagulation tests, blood gas analyses and CBC. The ratio of rejected specimens was higher in the EDs (40%) compared to ICUs (30%) and inpatient services (28%). The highest rejection ratio was observed in neurology ICU (14%) among the ICUs and internal medicine inpatient service (10%) within inpatient clinics. CONCLUSIONS: We detected an overall specimen rejection rate of 6% in emergency laboratory. By documentation of rejected samples and periodic training of healthcare personnel, we expect to decrease sample rejection ratios below 2%, improve total quality management of the emergency laboratory and promote patient safety. PMID- 26527232 TI - A Shape-Memory Supercapacitor Fiber. AB - A shape-memory, fiber-shaped supercapacitor is developed by winding aligned carbon nanotube sheets on a shape-memory polyurethane substrate. Despite its flexibility and stretchability, the deformed shapes under bending and stretching can be "frozen" as expected and recovered to the original state when required. Its electrochemical performances are well-maintained during deformation, at the deformed state and after the recovery. PMID- 26527233 TI - What is the role of intralesional corticosteroid injections for keloids before considering surgery? PMID- 26527234 TI - Energy metabolism, liver and kidney function in adolescent marathon runners. AB - BACKGROUND: To study parameters of energy metabolism, liver and kidney function in adolescent runners completing a standard 42.2-km marathon run. DESIGN: Observational field study. MATERIALS AND METHODS: Fifty adolescents (30 healthy males and 20 healthy females) aged between 13 and 17 years participated in the study. All participants underwent routine medical screening. Blood samples were taken before, at the end and 24 h after a competitive marathon to investigate parameters of metabolism, liver and kidney function. RESULTS: Forty-seven runners completed the race with a mean finishing time of 4 h 57 min 24 s (range: 3 h 17 min 09 s to 6 h 14 min 01 s). None of the participants experienced an adverse medical event during or postmarathon. Findings indicate predominant lipid oxidation during and postmarathon, signs of minor hepatic injury and only transiently reduced kidney function caused by marathon running in adolescents. CONCLUSION: The observed findings are very similar to those reported in healthy adults. There is no evidence of liver or kidney injury in adolescent runners participating in a standard marathon run. PMID- 26527236 TI - Multiple Choice Questions. PMID- 26527235 TI - Anxiolytic effects of ACE inhibitory peptides on the behavior of rats in an elevated plus-maze. AB - Three novel egg white-derived peptides were demonstrated to display in vitro activities against the angiotensin converting enzyme (ACE). A further study was conducted to assess their anxiolytic-like effects upon spontaneously hypertensive rats (SHRs) after an oral administration of the peptides, which showed the same behavioral performance as that using an elevated plus maze (EPM). In the EPM experiment, the behavioral effects of peptides TNGIIR, RVPSL, and QIGLF were investigated at doses ranging from 5 to 50 mg kg(-1), with records of the number of entries by the rats into the open arms, the time the rats spent in the open arms, and the total amount of entries into the open + closed arms. The results showed that the peptides TNGIIR and RVPSL, in a range of 5-50 mg kg(-1), exerted an anxiolytic effect on the SHRs. These results suggested that the egg white derived peptides TNGIIR and RVPSL could be considered as possible functional food or food ingredients due to their in vivo anti-stress and anti-anxiety effects on the SHRs. PMID- 26527237 TI - Comparison of cerebral and non-cerebral coenurosis by genetic markers of glycolytic enzyme (enolase) and mitochondrial sequences in sheep and goats. AB - Coenurosis is a debilitating disease caused by the larval stage of Taenia multiceps. The larval stage of T. multiceps appears in two cerebral and non cerebral forms known as Coenurus cerebralis and Coenurus gaigeri,respectively. This leads to the hypothesis that there are genetic intraspecific variabilities within this species. Molecular analysis in the present study showed that C. cerebralis and C. gaigeri were 100% genetically identical based on exonic region of enolase (ENO) gene and both mitochondrial (cox1 and nad1) markers. In addition, an intronic mutation at ENO gene (position: 1171) was detected in the Iranian C. cerebralis. The phylogenetic analyses based on the ENO, cox1, nad1 sequence data also suggest that T. gaigeri may not be distinct from T. multiceps and there is only one single valid species within T. multiceps. PMID- 26527238 TI - Genetic diversity of Cryptosporidium in fish at the 18S and actin loci and high levels of mixed infections. AB - Cryptosporidium is an enteric parasite that infects humans and a wide range of animals. Relatively little is known about the epidemiology and taxonomy of Cryptosporidium in fish. In the present study, a total of 775 fish, belonging to 46 species and comprising ornamental fish, marine fish and freshwater fish were screened for the prevalence of Cryptosporidium by PCR. The overall prevalence of Cryptosporidium in fish was 5.3% (41/775), with prevalences ranging from 1.5 to 100% within individual host species. Phylogenetic analysis of these Cryptosporidium isolates as well as 14 isolates from previous studies indicated extensive genetic diversity as well as evidence for mixed infections. At the 18S locus the following species were identified; Cryptosporidium molnari-like genotype (n=14), Cryptosporidium huwi (n=8), piscine genotype 2 (n=4), piscine genotype 3-like (n=1), piscine genotype 4 (n=2), piscine genotype 5 (n=13), piscine genotype 5-like (n=1) and five novel genotypes (n=5). At the actin locus, species identification agreed with the 18S locus for only 52.3% of isolates sequenced, indicating high levels of mixed infections. Future studies will need to employ both morphological characterization and deep sequencing amplicon-based technologies to better understand the epidemiological and phylogenetic relationships of piscine-derived Cryptosporidium species and genotypes, particularly when mixed infections are detected. PMID- 26527239 TI - Reduction of atherothrombotic burden before stent deployment in non-ST elevation acute coronary syndromes: Reduction of myocardial necrosis achieved with nose dive manual thrombus aspiration (REMNANT) trial. A volumetric intravascular ultrasound study. AB - OBJECTIVES: To test whether thrombus aspiration (TA) reduces the atherosclerotic burden in culprit lesions and "facilitate" percutaneous coronary intervention with stent (S-PCI) among patients with non-ST elevation acute coronary syndromes (NSTE-ACS). BACKGROUND: Evidence on the effects of TA adjunctive to S-PCI in NSTE ACS is limited and controversial. METHODS: TA was defined "aggressive" when using 7F devices or a catheter/artery ratio >0.6, "conservative" with 6F, and a catheter/artery ratio <=0.6. Angiography and intravascular ultrasound (IVUS) were performed at baseline, after TA and after stent deployment. RESULTS: TA was accomplished in 61/76 patients (80%) with NSTE-ACS. The aspirated material was red thrombus in 23% and plaque fragments in 49% of cases. Compared with baseline, TA was associated with an 82% increase in minimal lumen diameter and a 15% reduction in diameter stenosis (P < 0.001 for both). After TA, IVUS documented a 24 and 16% increase in minimal lumen area and lumen volume, respectively (P < 0.001 for both), a 7% decrease in area stenosis through an 11% reduction of plaque + media volume (P < 0.001). When compared with "conservative", an "aggressive" TA was associated with a more pronounced reduction in percent area stenosis (P < 0.05) and an increase in percent stent expansion (P < 0.001). The plaque + media volume reduction after TA was correlated with stent expansion (r = 0.261, P = 0.046). CONCLUSIONS: Manual TA reduces atherothrombotic burden in culprit lesions of NSTE-ACS patients before S-PCI and, when deep plaque removal is obtained, TA optimizes subsequent stent expansion. (c) 2015 Wiley Periodicals, Inc. PMID- 26527242 TI - The Bilingual Switching Advantage: Sometimes Related to Bilingual Proficiency, Sometimes Not. AB - This study investigated the relationship between bilingualism and task switching ability using a standardized measure of switching and an objective measure of bilingual language proficiency. Heritage Language (HL) speaking Spanish-English and Mandarin-English bilinguals and English speaking monolinguals completed all four subtests of the Color-Word Interference Test (CWIT), an English verbal fluency task, and a picture naming test (the Multilingual Naming Test) in English. Bilinguals also named pictures in their HL to assess HL proficiency. Spanish-English bilinguals were advantaged in task switching, exhibiting significantly smaller switching cost than monolinguals, but were disadvantaged in verbal fluency and picture naming. Additionally, performance on these cognitive and linguistic tasks was related to degree of HL proficiency, so that increased ability to name pictures in Spanish was associated with greater switching advantage, and greater disadvantage in both verbal fluency and picture naming. Mandarin-English bilinguals, who differed from the Spanish-English bilinguals on several demographic and language-use characteristics, exhibited a smaller but statistically significant switching advantage, but no linguistic disadvantage, and no clear relationship between HL proficiency and the switching advantage. Together these findings demonstrate an explicit link between objectively measured bilingual language proficiency and both bilingual advantages and disadvantages, while also showing that consequences of bilingualism for cognitive and linguistic task performance can vary across different language combinations. PMID- 26527240 TI - Predictors of Retest Effects in a Longitudinal Study of Cognitive Aging in a Diverse Community-Based Sample. AB - Better performance due to repeated testing can bias long-term trajectories of cognitive aging and correlates of change. We examined whether retest effects differ as a function of individual differences pertinent to cognitive aging: race/ethnicity, age, sex, language, years of education, literacy, and dementia risk factors including apolipoprotein E epsilon4 status, baseline cognitive performance, and cardiovascular risk. We used data from the Washington Heights Inwood Columbia Aging Project, a community-based cohort of older adults (n=4073). We modeled cognitive change and retest effects in summary factors for general cognitive performance, memory, executive functioning, and language using multilevel models. Retest effects were parameterized in two ways, as improvement between the first and subsequent testings, and as the square root of the number of prior testings. We evaluated whether the retest effect differed by individual characteristics. The mean retest effect for general cognitive performance was 0.60 standard deviations (95% confidence interval [0.46, 0.74]), and was similar for memory, executive functioning, and language. Retest effects were greater for participants in the lowest quartile of cognitive performance (many of whom met criteria for dementia based on a study algorithm), consistent with regression to the mean. Retest did not differ by other characteristics. Retest effects are large in this community-based sample, but do not vary by demographic or dementia related characteristics. Differential retest effects may not limit the generalizability of inferences across different groups in longitudinal research. PMID- 26527241 TI - The Association between High Neuroticism-Low Extraversion and Dual-Task Performance during Walking While Talking in Non-demented Older Adults. AB - The Walking While Talking (WWT) dual-task paradigm is a mobility stress test that predicts major outcomes, including falls, frailty, disability, and mortality in aging. Certain personality traits, such as neuroticism, extraversion, and their combination, have been linked to both cognitive and motor outcomes. We examined whether individual differences in personality dimensions of neuroticism and extraversion predicted dual-task performance decrements (both motor and cognitive) on a WWT task in non-demented older adults. We hypothesized that the combined effect of high neuroticism-low extraversion would be related to greater dual-task costs in gait velocity and cognitive performance in non-demented older adults. Participants (N=295; age range,=65-95 years; female=164) completed the Big Five Inventory and WWT task involving concurrent gait and a serial 7's subtraction task. Gait velocity was obtained using an instrumented walkway. The high neuroticism-low extraversion group incurred greater dual-task costs (i.e., worse performance) in both gait velocity {95% confidence interval (CI) [-17.68 to -3.07]} and cognitive performance (95% CI [-19.34 to -2.44]) compared to the low neuroticism-high extraversion group, suggesting that high neuroticism-low extraversion interferes with the allocation of attentional resources to competing task demands during the WWT task. Older individuals with high neuroticism-low extraversion may be at higher risk for falls, mobility decline and other adverse outcomes in aging. PMID- 26527245 TI - The relationship between clinical and recovery dimensions of outcome in mental health. AB - BACKGROUND: Little is known about the empirical relationship between clinical and personal recovery. AIMS: To examine whether there are separate constructs of clinical recovery and personal recovery dimensions of outcome, how they change over time and how they can be assessed. METHOD: Standardised outcome measures were administered at baseline and one-year follow-up to participants in the REFOCUS Trial (ISRCTN02507940). An exploratory factor analysis was conducted and a confirmatory factor analysis assessed change across time. RESULTS: We identified three factors: patient-rated personal recovery, patient-rated clinical recovery and staff-rated clinical recovery. Only the personal recovery factor improved after one year. HHI, CANSAS-P and HoNOS were the best measures for research and practice. CONCLUSIONS: The identification of three rather than two factors was unexpected. Our findings support the value of concurrently assessing staff and patient perceptions of outcome. Only the personal recovery factor changed over time, this desynchrony between clinical and recovery outcomes providing empirical evidence that clinical recovery and personal recovery are not the same. We did not find evidence of a trade-off between clinical recovery and personal recovery outcomes. Optimal assessment based on our data would involve assessment of hope, social disability and patient-rated unmet need. PMID- 26527246 TI - Baseline putamen volume as a predictor of positive symptom reduction in patients at clinical high risk for psychosis: A preliminary study. AB - OBJECTIVES: Illness course in individuals at clinical high risk (CHR) status for psychosis is heterogeneous, which limits effective treatment for all CHR subgroups. Baseline predictors of positive symptom trajectory in the CHR group will reduce such limitations. We singled out the putamen, thought to be involved in the generation of the key schizophrenia symptoms early in the course of disease, as a potential predictor of positive symptom trajectory in CHR patients. METHOD: We recruited 45 CHR patients and 29 age- and gender-matched healthy controls (HC). The CHR group was divided into patients with positive symptom reduction (CHR-R) and patients without positive symptom reduction (CHR-NR) at 6 months. Comparisons were made between the baseline putamen volumes of CHR-R, CHR NR and HC groups. The relationship between baseline putamen volumes and clinical measures was investigated. RESULTS: Left putamen volumes of CHR-R patients were significantly smaller than those of HCs (p=0.002) and of CHR-NR patients (p=0.024). CHR-R patients had significantly reduced leftward laterality compared to HCs (p=0.007). In the CHR-R group, bilateral putamen volumes were correlated with positive symptom severity at baseline (r=-0.552, p=0.001) and at 6 months (r=-0.360, p=0.043), and predicted positive symptom score change in 6 months at a trend level (p=0.092). CONCLUSION: Smaller left putamen volumes in CHR-R patients, and the correlation between positive symptom severity and putamen volumes suggest that putamen volume is a possible risk-stratifier and predictor of clinical course in the CHR population. PMID- 26527247 TI - Loneliness in psychotic disorders and its association with cognitive function and symptom profile. AB - BACKGROUND: Loneliness involves subjective, rather than objective, social isolation and has a range of negative effects on mental and physical functioning. The purpose of this study was to examine the prevalence of loneliness in psychotic disorders and its association with symptoms and cognitive performance. METHOD: Data were drawn from the second Australian National Survey of Psychosis and comprised responses from 1642 participants with an International Classification of Diseases 10 diagnosis of psychotic disorder who had completed a semi-structured interview of symptoms and social functioning (including loneliness), along with standardized assessments of current (digit symbol coding; DSC) and premorbid (National Adult Reading Test) cognitive ability. We examined the prevalence of loneliness across the diagnostic categories of psychosis, and its association with psychotic and non-psychotic symptoms and digit symbol coding scores. RESULTS: The prevalence of loneliness was high, ranging from 74.75% in participants with delusional disorders to 93.8% in depressive psychosis, and was significantly higher than in the general population. Loneliness was also significantly associated with anhedonia and subjective thought disorder. Participants feeling socially isolated/lonely for company had significantly lower DSC scores than those who only felt lonely occasionally. Unexpectedly, participants who reported not feeling lonely had the lowest DSC scores. CONCLUSIONS: Loneliness is common across all psychotic disorders, particularly in depressive psychosis. It is specifically associated with ongoing loss of pleasure and disordered thoughts as well as impairment in current cognitive functioning. However, poor cognitive functioning is not inevitably associated with loneliness. Implications for personalized treatment of psychosis are discussed. PMID- 26527248 TI - A case control study of association between cognition and functional capacity in schizophrenia. AB - BACKGROUND: Cognitive functions are important prognostic factors for schizophrenia (SZ), while ability to perform activities of daily living are important measures of functional capacity. The relationship between cognition and functional capacity has not been tested extensively in India. OBJECTIVE: To compare persons with SZ with controls on measures of cognition and functional capacity, and evaluate correlations between cognitive performance and functional capacity. METHOD: Schizophrenia outpatients and controls without psychiatric illness (DSM IV) who completed the MATRICS Consensus Cognitive Battery and Functional Assessment Battery comprised of two tests from University of California San Diego (UCSD) Performance Based Skill Assessment (UPSA), one Test of Adaptive Behavior in Schizophrenia (TABS) and one test from University of California San Diego Performance Based Skill Assessment Brief edition (UPSA-B). Cognitive and functional domains were examined using regression analyses, with relevant covariates. RESULTS: Cases (N=51) though younger, were more educated than controls (N=41). Adjusting for education, controls performed better than cases in 3/7 cognitive and 4/5 domains of functional capacity but similarly in 'household management'. Among both cases and controls, cognitive measures of verbal learning and speed of processing overlapped with functional capacity (3 domains). Working memory was associated with one functional domain. CONCLUSIONS: Consistent with other studies, Indian patients with schizophrenia performed worse than controls on several domains of cognition and functional capacity; these domains were correlated. Speed of processing and verbal learning are most frequently associated with functional capacity indices and should be targeted to improve skills of daily living among persons with SZ. PMID- 26527249 TI - Cerebellar activity in young people with familial risk for psychosis--The Oulu Brain and Mind Study. AB - OBJECTIVE: The cerebellum plays a critical role in cognition and behavior. Altered function of the cerebellum has been related to schizophrenia and psychosis but it is not known how this applies to spontaneous resting state activity in young people with familial risk for psychosis. METHODS: We conducted resting-state functional MRI (R-fMRI) in 72 (29 male) young adults with a history of psychosis in one or both parents (FR) but without their own psychosis, and 72 (29 male) similarly healthy control subjects without parental psychosis. Both groups in the Oulu Brain and Mind Study were drawn from the Northern Finland Birth Cohort 1986. Participants were 20-25 years old. Parental psychosis was established using the Care Register for Health Care. R-fMRI data pre-processing was conducted using independent component analysis with 30 and 70 components. A dual regression technique was used to detect between-group differences in the cerebellum with p<0.05 threshold corrected for multiple comparisons. RESULTS: FR participants demonstrated statistically significantly increased activity compared to control subjects in the anterior lobe of the right cerebellum in the analysis with 70 components. The volume of the increased activity was 73 mm(3). There was no difference between the groups in the analysis with 30 components. CONCLUSION: The finding suggests that increased activity of the anterior lobe of the right cerebellum may be associated with increased vulnerability to psychosis. The finding is novel, and needs replication to be confirmed. PMID- 26527250 TI - Long-term outcomes of patients with advanced hepatocellular carcinoma who achieved complete remission after sorafenib therapy. AB - BACKGROUND/AIMS: Sorafenib is currently the sole molecular targeted agent that improves overall survival in advanced hepatocellular carcinoma (HCC). Despite the efficacy of sorafenib, the response rate varies in patients with advanced HCC. We retrospectively analyzed a series of Korean patients with advanced HCC with complete remission (CR) after sorafenib therapy. METHODS: In total, 523 patients with advanced HCC were treated with sorafenib in 3 large tertiary referral hospitals in Korea. A survey was conducted to collect data on patients who experienced CR after sorafenib monotherapy, and their medical records and follow up data were analyzed. The tumor response and recurrence rates were assessed by radiologic study, based on modified response evaluation criteria in solid tumors. RESULTS: Seven patients with advanced HCC experienced CR after sorafenib therapy. The median time to tumor disappearance and the median disease-free survival time were 3 months and 9 months, respectively. HCC recurrence was identified in three cases (42.9%). Of these, two patients discontinued sorafenib before or after achieving CR and the other patient continued sorafenib after achieving CR. HCC recurred at 3, 10, and 42 months after CR in these three patients. Three patients needed dose reduction for toxicity and adverse events. CONCLUSIONS: Though CR was achieved after sorafenib therapy in patients with advanced HCC, the recurrence rate was relatively high. Subsequent strategies to reduce a chance of recurrence after sorafenib therapy are required to investigate. PMID- 26527251 TI - Outpatient hysteroscopic polypectomy: bipolar energy system (Versapoint(r)) versus diode laser - randomized clinical trial. AB - OBJECTIVE: To compare the resection of endometrial polyps with two different devices: the Versapoint biopolar electrode and the Diode Laser. METHODS: One hundred and two patients diagnosed with endometrial polyps were randomly assigned to undergo hysteroscopic polypectomy: one group (n = 52) performed with Versapoint bipolar electrode through a 5Fr working channel and the other group with Biolitec Diode Laser (n = 50) using a specific fiber for polyps in a 7Fr working channel. All cases were managed on an outpatient basis, without anesthesia and using a rigid 30(o) hysteroscope and saline solution as a distention medium. MAIN OUTCOME MEASURES: Complete resection rate, operative time, complications, intraoperative pain and relapse rate after three months. RESULTS: Intraoperative pain and polyp resection time was similar in both groups. Upon second look hysteroscopy at 3-month, a higher percentage of women of the Versapoint group presented polyp relapse (32.6 versus 2.2%, p = 0.001). Elimination of the polyp after incomplete resection was higher in the Laser group. A significantly higher number of patients in the Laser group considered the procedure to be highly recommendable (p = 0.02). CONCLUSION: Polypectomy with Diode Laser resulted in fewer relapses and a higher procedure satisfaction rate as compared to Versapoint. PMID- 26527252 TI - Intubation after rapid sequence induction performed by non-medical personnel during space exploration missions: a simulation pilot study in a Mars analogue environment. AB - BACKGROUND: The question of the safety of anaesthetic procedures performed by non anaesthetists or even by non physicians has long been debated. We explore here this question in the hypothetical context of an exploration mission to Mars. During future interplanetary space missions, the risk of medical conditions requiring surgery and anaesthetic techniques will be significant. On Earth, anaesthesia is generally performed by well accustomed personnel. During exploration missions, onboard medical expertise might be lacking, or the crew doctor could become ill or injured. Telemedical assistance will not be available. In these conditions and as a last resort, personnel with limited medical training may have to perform lifesaving procedures, which could include anaesthesia and surgery. The objective of this pilot study was to test the ability for unassisted personnel with no medical training to perform oro-tracheal intubation after a rapid sequence induction on a simulated deconditioned astronaut in a Mars analogue environment. The experiment made use of a hybrid simulation model, in which the injured astronaut was represented by a torso manikin, whose vital signs and hemodynamic status were emulated using a patient simulator software. Only assisted by an interactive computer tool (PowerPoint((r)) presentation), five participants with no previous medical training completed a simplified induction of general anaesthesia with intubation. RESULTS: No major complication occurred during the simulated trials, namely no cardiac arrest, no hypoxia, no cardiovascular collapse and no failure to intubate. The study design was able to reproduce many of the constraints of a space exploration mission. CONCLUSIONS: Unassisted personnel with minimal medical training and familiarization with the equipment may be able to perform advanced medical care in a safe and efficient manner. Further studies integrating this protocol into a complete anaesthetic and surgical scenario will provide valuable input in designing health support systems for space exploration missions. PMID- 26527253 TI - Nutritional value of foods sold in vending machines in a UK University: Formative, cross-sectional research to inform an environmental intervention. AB - Vending machine use has been associated with low dietary quality among children but there is limited evidence on its role in food habits of University students. We aimed to examine the nutritional value of foods sold in vending machines in a UK University and conduct formative research to investigate differences in food intake and body weight by vending machine use among 137 University students. The nutrient content of snacks and beverages available at nine campus vending machines was assessed by direct observation in May 2014. Participants (mean age 22.5 years; 54% males) subsequently completed a self-administered questionnaire to assess vending machine behaviours and food intake. Self-reported weight and height were collected. Vending machine snacks were generally high in sugar, fat and saturated fat, whereas most beverages were high in sugar. Seventy three participants (53.3%) used vending machines more than once per week and 82.2% (n 60) of vending machine users used them to snack between meals. Vending machine accessibility was positively correlated with vending machine use (r = 0.209, P = 0.015). Vending machine users, compared to non-users, reported a significantly higher weekly consumption of savoury snacks (5.2 vs. 2.8, P = 0.014), fruit juice (6.5 vs. 4.3, P = 0.035), soft drinks (5.1 vs. 1.9, P = 0.006), meat products (8.3 vs. 5.6, P = 0.029) and microwave meals (2.0 vs. 1.3, P = 0.020). No between group differences were found in body weight. Most foods available from vending machines in this UK University were of low nutritional quality. In this sample of University students, vending machine users displayed several unfavourable dietary behaviours, compared to non-users. Findings can be used to inform the development of an environmental intervention that will focus on vending machines to improve dietary behaviours in University students in the UK. PMID- 26527255 TI - Detection of undescribed ostreid herpesvirus 1 (OsHV-1) specimens from Pacific oyster, Crassostrea gigas. AB - The ostreid herpesvirus 1 (OsHV-1) and variants were implicated in mass mortality affecting the young Pacific cupped oysters, Crassostrea gigas, in European countries and those around the world. From 2008 onwards, oyster mortality had greatly increased on the French coast and was associated with the detection of a new OsHV-1 variant, entitled OsHV-1 MUVar. The OsHV-1 MUVar is predominant in oysters; however, other OsHV-1 variants have been detected in samples collected during mortality periods or collected out of mortality periods in France, Ireland, Spain, Portugal, Italy, Mexico, United States, South Korea, Australia, and New Zealand. A retrospective study conducted on 1047 OsHV-1 specimens sampled mainly in France between 2009 and 2012, revealed 17 undescribed OsHV-1 variants found in 65 oyster samples. These specimens presented point mutations situated downstream and upstream from the microsatellite area in the C region (ORF 4/5) which were different from the OsHV-1 reference and the OsHV-1 MUVar. In the present work, investigation was performed to further characterize these OsHV-1 specimens by sequencing two habitually targeted regions to study genetic polymorphism of the virus: ORF 41/42 and ORF 35-38. An OsHV-1 variant detected in six oyster samples, contained a nucleotide substitution in the C region which impacted the amino acid sequence and might modify the function of the unknown protein encoding by ORF 4. For the ORF 41/42 region, only two specimens presented a synonymous mutation in comparison with the OsHV-1 MUVar. All specimens contained the same deletion with the OsHV-1 MUVar in ORF 35-38. Then, a phylogenetic analysis based on the C region was performed to investigate the distribution of undescribed specimens among 21 OsHV-1 DNA sequences notified in GenBank and collected from different countries (France, Japan, New Zealand, China, Ireland, and United States) between 1995 and 2012. All analyzed samples and the OsHV-1 MUVar were placed in the same group, excepted for a Japan specimen. Our results contribute to improve the description of the genetic diversity of the OsHV-1 and the C region (ORF 4/5) appears to be a better target than ORF 42/42 and 35-38 to distinguish variants between themselves. PMID- 26527254 TI - Home food environment factors associated with the presence of fruit and vegetables at dinner: A direct observational study. AB - BACKGROUND: Little research exists about the factors influencing the foods available at family meals. This study examines the home food environment factors contributing to the presence of fruit and vegetables at family meals. METHODS: Home food inventory (HFI) and survey data were collected from low-income, minority families (n = 120) with children 6-12 years old. Observations from video recorded family dinner meals, totaling 800 videos, were used to measure the frequency at which fruit and vegetables were served. Multiple regression was used to investigate how the fruit and vegetables in the HFI and other home food environment factors were related to the number of days fruit and vegetables were served at dinner during the observation period. RESULTS: Availability and accessibility of fruit and vegetables in the home were each found to be significantly associated with the presence of fruits and vegetables at family dinners. Of the fruit and vegetable categories (i.e., fresh, canned, or frozen), having fresh fruit and vegetables available in the home was found to be most strongly associated with serving fruit and vegetables at dinner, respectively. Higher parent intake of vegetables was associated with the presence of vegetables at dinners, and parent meal planning was associated with the presence of fruit at dinners. CONCLUSIONS: Increasing the availability and accessibility of fresh fruit and vegetables in the home may be an effective approach to increasing the presence of fruits and vegetables at family dinners, especially among low-income, minority households. It is also essential to understand why families are not using all fruits and vegetables (e.g., canned and frozen) available in the home for family meals. Family meals are a place to promote the increased presence of both fruit and vegetables. PMID- 26527256 TI - Jonas Salk. PMID- 26527257 TI - Is transmission electron microscopy (TEM) a promising approach for qualitative and quantitative investigations of polymyxin B and miconazole interactions with cellular and subcellular structures of Staphylococcus pseudintermedius, Escherichia coli, Pseudomonas aeruginosa and Malassezia pachydermatis? AB - Antimicrobial therapy using a combination of polymyxin B and miconazole is effective against the main bacterial pathogens associated with otitis externa in dogs, and a synergistic effect of both drugs has been shown previously. The objective of the present investigation was to visualize ultrastructural changes after exposure of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus pseudintermedius and Malassezia pachydermatis to polymyxin B and miconazole by transmission electron microscopic (TEM). For this, cultures of E. coli, P. aeruginosa, S. pseudintermedius and M. pachydermatis were exposed to polymyxin B and miconazole, alone or in combination for 24 h. Ultrastructural changes were observed most frequently in the cell envelope of the four microorganisms. Exposure to polymyxin B seemed to cause more damage than miconazole within the range of concentrations applied. Treatment resulted in changes of the cell size: in E. coli, cell size increased significantly after treatment with either compound alone; in P. aeruginosa, cell size decreased significantly after treatment with polymyxin B and with miconazole; exposure of S. pseudintermedius to miconazole caused a decrease in cell size; in M. pachydermatis, cell size increased significantly after treatment with polymyxin B.; in E.coli, S. pseudintermedius and M. pachydermatis, cell size changed highly significant, in P. aeruginosa significantly after exposure to the combination of both compounds. In conclusion, by using a different approach than previous investigations, this study confirmed a clear combinatory effect of polymyxin B and miconazole against the tested microorganisms involved in canine otitis externa. It is the first time that visualization technologies were applied to compare the effect of single drugs to their combinatory effects on cellular and subcellular entities of selected bacterial and yeast species. PMID- 26527259 TI - Imaging of non-traumatic abdominal emergencies in adults. AB - Non-traumatic abdominal pathology is one of the most common reasons for consultation in emergency care services. Abdominal pain is the presenting symptom for many diseases, which often requires urgent care. Clinical history and physical examination are rarely sufficient to establish a definite diagnosis and imaging is usually necessary. The choice of imaging modality is oriented by the clinical context and guided by the institutional capabilities, safety and cost effectiveness of the available tests. Plain radiographs have little or no place in the evaluation of the acute abdomen. Magnetic resonance imaging (MRI) still has limited availability in many hospitals, thus narrowing the imaging choice to ultrasound (US) and computerized tomography (CT). No scientific evidence exists to allow the imposition of one single strategy. At the present time, the clinician may choose either routine US evaluation complemented by CT in case the US is inconclusive or first-line CT (except for the evaluation of right lower quadrant [RLQ] pain, right upper quadrant [RUQ] pain and in pregnant women where ultrasound is the first-line study). PMID- 26527258 TI - Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes. AB - Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)-synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA-responsive gene Cyp26b1. To explore the actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice culture method was developed in which the Raldh1 expressing tanycytes were maintained. These slice cultures confirmed that TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems has the capability to mediate some of the functions of TH in the hypothalamus. PMID- 26527260 TI - Re-admission after gastro-intestinal surgery. AB - Re-admission is a new concept in France, born with the advent of day-case surgery, and defined as any re-admission occurring within 30 days after surgery. The re-admission rate has increasingly come to be considered a criterion of the quality of medical care, by both the medical profession and by insurance companies. This report outlines the generalities and definitions related to re admission after gastro-intestinal surgery, describes the current situation, rationalizes the value of re-admission rates as a measure of quality of care, details the risk factors for re-admission according to the type of intervention, exposes the possible means of prevention and what to do when a patient comes to the emergency room within 30 days after an operation. PMID- 26527261 TI - Abdominal emergencies during pregnancy. AB - Abdominal emergencies during pregnancy (excluding obstetrical emergencies) occur in one out of 500-700 pregnancies and may involve gastrointestinal, gynecologic, urologic, vascular and traumatic etiologies; surgery is necessary in 0.2-2% of cases. Since these emergencies are relatively rare, patients should be referred to specialized centers where surgical, obstetrical and neonatal cares are available, particularly because surgical intervention increases the risk of premature labor. Clinical presentations may be atypical and misleading because of pregnancy-associated anatomical and physiologic alterations, which often result in diagnostic uncertainty and therapeutic delay with increased risks of maternal and infant morbidity. The most common abdominal emergencies are acute appendicitis (best treated by laparoscopic appendectomy), acute calculous cholecystitis (best treated by laparoscopic cholecystectomy from the first trimester through the early part of the third trimester) and intestinal obstruction (where medical treatment is the first-line approach, just as in the non-pregnant patient). Acute pancreatitis is rare, usually resulting from trans ampullary passage of gallstones; it usually resolves with medical treatment but an elevated risk of recurrent episodes justifies laparoscopic cholecystectomy in the 2nd trimester and endoscopic sphincterotomy in the 3rd trimester. The aim of the present work is to review pregnancy-induced anatomical and physiological modifications, to describe the main abdominal emergencies during pregnancy, their specific features and their diagnostic and therapeutic management. PMID- 26527262 TI - Structure of a fungal form of aspartate semialdehyde dehydrogenase from Cryptococcus neoformans. AB - Aspartate semialdehyde dehydrogenase (ASADH) functions at a critical junction in the aspartate-biosynthetic pathway and represents a valid target for antimicrobial drug design. This enzyme catalyzes the NADPH-dependent reductive dephosphorylation of beta-aspartyl phosphate to produce the key intermediate aspartate semialdehyde. Production of this intermediate represents the first committed step in the biosynthesis of the essential amino acids methionine, isoleucine and threonine in fungi, and also the amino acid lysine in bacteria. The structure of a new fungal form of ASADH from Cryptococcus neoformans has been determined to 2.6 A resolution. The overall structure of CnASADH is similar to those of its bacterial orthologs, but with some critical differences both in biological assembly and in secondary-structural features that can potentially be exploited for the development of species-selective drugs. PMID- 26527263 TI - Crystallization and crystallographic analysis of an Arabidopsis nuclear proteinaceous RNase P. AB - RNase P activity is ubiquitous and involves the 5' maturation of precursor tRNAs. For a long time, it was thought that all RNases P were ribonucleoproteic enzymes. However, the characterization of RNase P in human mitochondria and in plants revealed a novel kind of RNase P composed of protein only, called PRORP for 'proteinaceous RNase P'. Whereas in human mitochondria PRORP has two partners that are required for RNase P activity, PRORP proteins are active as single subunit enzymes in plants. Three paralogues of PRORP are found in Arabidopsis thaliana. PRORP1 is responsible for RNase P in mitochondria and chloroplasts, while PRORP2 and PRORP3 are nuclear enzymes. Here, the purification and crystallization of the Arabidopsis PRORP2 protein are reported. Optimization of the initial crystallization conditions led to crystals that diffracted to 3 A resolution. PMID- 26527264 TI - Structure of Escherichia coli tryptophanase purified from an alkaline-stressed bacterial culture. AB - Tryptophanase is a bacterial enzyme involved in the degradation of tryptophan to indole, pyruvate and ammonia, which are compounds that are essential for bacterial survival. Tryptophanase is often overexpressed in stressed cultures. Large amounts of endogenous tryptophanase were purified from Escherichia coli BL21 strain overexpressing another recombinant protein. Tryptophanase was crystallized in space group P6522 in the apo form without pyridoxal 5'-phosphate bound in the active site. PMID- 26527265 TI - Structure of the HIV-1 reverse transcriptase Q151M mutant: insights into the inhibitor resistance of HIV-1 reverse transcriptase and the structure of the nucleotide-binding pocket of Hepatitis B virus polymerase. AB - Hepatitis B virus polymerase (HBV Pol) is an important target for anti-HBV drug development; however, its low solubility and stability in vitro has hindered detailed structural studies. Certain nucleotide reverse transcriptase (RT) inhibitors (NRTIs) such as tenofovir and lamivudine can inhibit both HBV Pol and Human immunodeficiency virus 1 (HIV-1) RT, leading to speculation on structural and mechanistic analogies between the deoxynucleotide triphosphate (dNTP)-binding sites of these enzymes. The Q151M mutation in HIV-1 RT, located at the dNTP binding site, confers resistance to various NRTIs, while maintaining sensitivity to tenofovir and lamivudine. The residue corresponding to Gln151 is strictly conserved as a methionine in HBV Pol. Therefore, the structure of the dNTP binding pocket of the HIV-1 RT Q151M mutant may reflect that of HBV Pol. Here, the crystal structure of HIV-1 RT Q151M, determined at 2.6 A resolution, in a new crystal form with space group P321 is presented. Although the structure of HIV-1 RT Q151M superimposes well onto that of HIV-1 RT in a closed conformation, a slight movement of the beta-strands (beta2-beta3) that partially create the dNTP binding pocket was observed. This movement might be caused by the introduction of the bulky thioether group of Met151. The structure also highlighted the possibility that the hydrogen-bonding network among amino acids and NRTIs is rearranged by the Q151M mutation, leading to a difference in the affinity of NRTIs for HIV-1 RT and HBV Pol. PMID- 26527266 TI - Production, crystallization and neutron diffraction of fully deuterated human myelin peripheral membrane protein P2. AB - The molecular details of the formation of the myelin sheath, a multilayered membrane in the nervous system, are to a large extent unknown. P2 is a peripheral membrane protein from peripheral nervous system myelin, which is believed to play a role in this process. X-ray crystallographic studies and complementary experiments have provided information on the structure-function relationships in P2. In this study, a fully deuterated sample of human P2 was produced. Crystals that were large enough for neutron diffraction were grown by a ten-month procedure of feeding, and neutron diffraction data were collected to a resolution of 2.4 A from a crystal of 0.09 mm(3) in volume. The neutron crystal structure will allow the positions of H atoms in P2 and its fatty-acid ligand to be visualized, as well as shedding light on the fine details of the hydrogen-bonding networks within the P2 ligand-binding cavity. PMID- 26527267 TI - Cloning, expression, purification, characterization, crystallization and X-ray crystallographic analysis of recombinant Der f 21 (rDer f 21) from Dermatophagoides farinae. AB - Dermatophagoides farinae is one of the major house dust mite (HDM) species that cause allergic diseases. N-terminally His-tagged recombinant Der f 21 (rDer f 21), a group 21 allergen, with the signal peptide truncated was successfully overexpressed in an Escherichia coli expression system. The purified rDer f 21 protein was initially crystallized using the sitting-drop vapour-diffusion method. Well diffracting protein crystals were obtained after optimization of the crystallization conditions using the hanging-drop vapour-diffusion method with a reservoir solution consisting of 0.19 M Tris-HCl pH 8.0, 32% PEG 400 at 293 K. X ray diffraction data were collected to 1.49 A resolution using an in-house X-ray source. The crystal belonged to the C-centered monoclinic space group C2, with unit-cell parameters a = 123.46, b = 27.71, c = 90.25 A, beta = 125.84 degrees . The calculated Matthews coefficient (VM) of 2.06 A(3) Da(-1) suggests that there are two molecules per asymmetric unit, with a solvent content of 40.3%. Despite sharing high sequence identity with Blo t 5 (45%) and Blo t 21 (41%), both of which were determined to be monomeric in solution, size-exclusion chromatography, static light scattering and self-rotation function analysis indicate that rDer f 21 is likely to be a dimeric protein. PMID- 26527268 TI - Crystallization and X-ray diffraction studies of a complete bacterial fatty-acid synthase type I. AB - While a deep understanding of the fungal and mammalian multi-enzyme type I fatty acid synthases (FAS I) has been achieved in recent years, the bacterial FAS I family, which is narrowly distributed within the Actinomycetales genera Mycobacterium, Corynebacterium and Nocardia, is still poorly understood. This is of particular relevance for two reasons: (i) although homologous to fungal FAS I, cryo-electron microscopic studies have shown that bacterial FAS I has unique structural and functional properties, and (ii) M. tuberculosis FAS I is a drug target for the therapeutic treatment of tuberculosis (TB) and therefore is of extraordinary importance as a drug target. Crystals of FAS I from C. efficiens, a homologue of M. tuberculosis FAS I, were produced and diffracted X-rays to about 4.5 A resolution. PMID- 26527269 TI - Phosphate binding in the active centre of tomato multifunctional nuclease TBN1 and analysis of superhelix formation by the enzyme. AB - Tomato multifunctional nuclease TBN1 belongs to the type I nuclease family, which plays an important role in apoptotic processes and cell senescence in plants. The newly solved structure of the N211D mutant is reported. Although the main crystal packing motif (the formation of superhelices) is conserved, the details differ among the known structures. A phosphate ion was localized in the active site of the enzyme. The binding of the surface loop to the active centre is stabilized by the phosphate ion, which correlates with the observed aggregation of TBN1 in phosphate buffer. The conserved binding of the surface loop to the active centre suggests biological relevance of the contact in a regulatory function or in the formation of oligomers. PMID- 26527270 TI - Cloning, expression, crystallization and crystallographic analysis of CouR from Rhodopseudomonas palustris. AB - CouR from Rhodopseudomonas palustris is a member of the MarR transcriptional regulator family. It regulates the expression of CouA and CouB, enzymes that are involved in the degradation of p-coumarate. In vivo, CouR binds to a DNA fragment containing the couAB promoter and suppresses the expression of CouA and CouB, while binding of p-coumaroyl-CoA attenuates its affinity towards DNA and activates the expression of CouA and CouB. Here, the crystallization and X-ray diffraction analyses of CouR alone and in complex with p-coumaroyl-CoA are reported. Apo and ligand-complexed CouR crystals diffracted to 2.5 and 3.3 A resolution, respectively. The crystals of apo CouR belonged to space group P22121, with unit-cell parameters a = 62.78, b = 76.15, c = 87.38 A, whereas the crystals of the CouR-ligand complex belonged to space group P212121, with unit cell parameters a = 61.37, b = 69.82, c = 70.32 A. The crystals were predicted to contain two CouR molecules or CouR-ligand complexes per asymmetric unit. PMID- 26527271 TI - Crystallization and biochemical characterization of the human spliceosomal Aar2 Prp8(RNaseH) complex. AB - In eukaryotes, the removal of nuclear noncoding sequences (pre-mRNA splicing) is catalyzed by the spliceosome, which consists of five ribonucleoprotein particles (U1, U2, U4, U5 and U6 snRNPs, each with a respective snRNA) and a plethora of protein factors that aid spliceosomal maturation, assembly, activation and disassembly. Recently, the U5 snRNP maturation factor Aar2p from baker's yeast has been characterized structurally and biochemically. Aar2p binds to the RNaseH (RH) and Jab1/MPN domains of the highly conserved U5-specific Prp8p, which forms a framework for the spliceosomal catalytic centre. Thereby, Aar2p sterically excludes Brr2p, a helicase essential for the catalytic activation of the spliceosome, from Prp8p binding. At the same time, Aar2p blocks U4/U6 di-snRNA binding to Prp8p. Aar2p therefore prevents premature spliceosome activation and its functions are regulated by reversible phosphorylation. To date, little is known about the hypothetical human Aar2 (hsAar2) orthologue C20ORF4. This study identifies C20ORF4 (i) as part of the HeLa proteome by Western blotting and (ii) as a true Aar2 orthologue which binds to the RH domain (hsRH) of Prp8 and corroborates an evolutionary link between yeast and human Aar2 function. An elaborate strategy was devised to crystallize hsAar2 in complex with hsRH. The analysis of initial weakly diffracting crystals obtained by in situ proteolysis and homology modelling guided the design of an hsAar2 construct in which an internal loop was replaced by three serines (hsAar2(Deltaloop)). A complex of hsAar2(Deltaloop) and hsRH crystallized in space group C2; the crystals diffracted to 2.35 A resolution and were suitable for structure determination by molecular-replacement approaches. The study presented here suggests a connection between Aar2 and the spliceosome in human cells and paves the way for structural studies of human Aar2. PMID- 26527272 TI - Structure of a lectin from the sea mussel Crenomytilus grayanus (CGL). AB - CGL is a 150 amino-acid residue lectin that was originally isolated from the sea mussel Crenomytilus grayanus. It is specific for binding GalNAc/Gal-containing carbohydrate moieties and in general does not share sequence homology with other known galectins or lectins. Since CGL displays antibacterial, antifungal and antiviral activities, and interacts with high affinity with mucin-type receptors, which are abundant on some cancer cells, knowledge of its structure is of significant interest. Conditions have been established for the expression, purification and crystallization of a recombinant variant of CGL. The crystal structure of recombinant CGL was determined and refined at a resolution of 2.12 A. The amino-acid sequence of CGL contains three homologous regions (73% similarity) and the folded protein has a beta-trefoil topology. Structural comparison of CGL with the closely related lectin MytiLec allowed description of the glycan-binding pockets. PMID- 26527273 TI - Crystallization and X-ray diffraction analysis of the HMG domain of the chondrogenesis master regulator Sox9 in complex with a ChIP-Seq-identified DNA element. AB - Sox9 is a fundamental sex-determining gene and the master regulator of chondrogenesis, and is involved in the development of various vital organs such as testes, kidney, heart and brain, and in skeletal development. Similar to other known Sox transcription factors, Sox9 recognizes and binds DNA with the consensus sequence C(T/A)TTG(T/A)(T/A) through the highly conserved HMG domain. Nonetheless, the molecular basis of the functional specificity of Sox9 in key developmental processes is still unclear. As an initial step towards a mechanistic understanding of Sox9 transcriptional regulation, the current work describes the details of the purification of the mouse Sox9 HMG domain (mSox9HMG), its crystallization in complex with a ChIP-Seq-identified FOXP2 promoter DNA element and the X-ray diffraction data analysis of this complex. The mSox9HMG-FOXP2 promoter DNA complex was crystallized by the hanging-drop vapour diffusion method using 20% PEG 3350 in 200 mM sodium/potassium phosphate with 100 mM bis-tris propane at pH 8.5. The crystals diffracted to 2.7 A resolution and the complex crystallized in the tetragonal space group P41212, with unit-cell parameters a = b = 99.49, c = 45.89 A. Crystal-packing parameters revealed that asymmetric unit contained one mSox9HMG-FOXP2 promoter DNA complex with an estimated solvent content of 64%. PMID- 26527274 TI - Expression and crystallographic studies of the ligand-binding region of the human endocytic collagen receptor uPARAP. AB - Urokinase plasminogen activator receptor-associated protein (uPARAP) is an endocytic receptor that internalizes collagen for lysosomal degradation and plays an important role in matrix remodelling. Previous recombinant protein production of uPARAP in Pichia pastoris generated protein with highly heterogeneous glycans that was prone to proteolytic degradation, resulting in highly twinned crystals. In this study, the uPARAP ligand-binding region was expressed in stably transfected Drosophila S2 insect cells. The recombinant protein was homogeneous after purification by metal-affinity and anion-exchange chromatography. Crystals were obtained at two different pH values (5.3 and 7.4) and diffracted to 2.44 and 3.13 A resolution, respectively. A model of the ligand-binding region of uPARAP was obtained by molecular replacement combined with autobuilding. As the first multidomain crystal structure of the mannose receptor family, structural characterization of the uPARAP ligand-binding region will provide insight into the pH-induced conformational rearrangements of the mannose receptor family. PMID- 26527275 TI - Neutron and high-resolution room-temperature X-ray data collection from crystallized lytic polysaccharide monooxygenase. AB - Bacteria and fungi express lytic polysaccharide monooxgyenase (LPMO) enzymes that act in conjunction with canonical hydrolytic sugar-processing enzymes to rapidly convert polysaccharides such as chitin, cellulose and starch to single monosaccharide products. In order to gain a better understanding of the structure and oxidative mechanism of these enzymes, large crystals (1-3 mm(3)) of a chitin processing LPMO from the Gram-positive soil bacterium Jonesia denitrificans were grown and screened for their ability to diffract neutrons. In addition to the collection of neutron diffraction data, which were processed to 2.1 A resolution, a high-resolution room-temperature X-ray diffraction data set was collected and processed to 1.1 A resolution in space group P212121. To our knowledge, this work marks the first successful neutron crystallographic experiment on an LPMO. Joint X-ray/neutron refinement of the resulting data will reveal new details of the structure and mechanism of this recently discovered class of enzymes. PMID- 26527276 TI - Serine and SAM Responsive Complex SESAME Regulates Histone Modification Crosstalk by Sensing Cellular Metabolism. AB - Pyruvate kinase M2 (PKM2) is a key enzyme for glycolysis and catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate, which supplies cellular energy. PKM2 also phosphorylates histone H3 threonine 11 (H3T11); however, it is largely unknown how PKM2 links cellular metabolism to chromatin regulation. Here, we show that the yeast PKM2 homolog, Pyk1, is a part of a novel protein complex named SESAME (Serine-responsive SAM-containing Metabolic Enzyme complex), which contains serine metabolic enzymes, SAM (S-adenosylmethionine) synthetases, and an acetyl-CoA synthetase. SESAME interacts with the Set1 H3K4 methyltransferase complex, which requires SAM synthesized from SESAME, and recruits SESAME to target genes, resulting in phosphorylation of H3T11. SESAME regulates the crosstalk between H3K4 methylation and H3T11 phosphorylation by sensing glycolysis and glucose-derived serine metabolism. This leads to auto-regulation of PYK1 expression. Thus, our study provides insights into the mechanism of regulating gene expression, responding to cellular metabolism via chromatin modifications. PMID- 26527277 TI - CTCF Binding Polarity Determines Chromatin Looping. AB - CCCTC-binding factor (CTCF) is an architectural protein involved in the three dimensional (3D) organization of chromatin. In this study, we assayed the 3D genomic contact profiles of a large number of CTCF binding sites with high resolution 4C-seq. As recently reported, our data also suggest that chromatin loops preferentially form between CTCF binding sites oriented in a convergent manner. To directly test this, we used CRISPR/Cas9 genome editing to delete core CTCF binding sites in three loci, including the CTCF site in the Sox2 super enhancer. In all instances, CTCF and cohesin recruitment were lost, and chromatin loops with distal, convergent CTCF sites were disrupted or destabilized. Re insertion of oppositely oriented CTCF recognition sequences restored CTCF and cohesin recruitment, but did not re-establish chromatin loops. We conclude that CTCF binding polarity plays a functional role in the formation of higher-order chromatin structure. PMID- 26527278 TI - Mitotic Transcriptional Activation: Clearance of Actively Engaged Pol II via Transcriptional Elongation Control in Mitosis. AB - Although it is established that some general transcription factors are inactivated at mitosis, many details of mitotic transcription inhibition (MTI) and its underlying mechanisms are largely unknown. We have identified mitotic transcriptional activation (MTA) as a key regulatory step to control transcription in mitosis for genes with transcriptionally engaged RNA polymerase II (Pol II) to activate and transcribe until the end of the gene to clear Pol II from mitotic chromatin, followed by global impairment of transcription reinitiation through MTI. Global nascent RNA sequencing and RNA fluorescence in situ hybridization demonstrate the existence of transcriptionally engaged Pol II in early mitosis. Both genetic and chemical inhibition of P-TEFb in mitosis lead to delays in the progression of cell division. Together, our study reveals a mechanism for MTA and MTI whereby transcriptionally engaged Pol II can progress into productive elongation and finish transcription to allow proper cellular division. PMID- 26527280 TI - Robust Ordering of Anaphase Events by Adaptive Thresholds and Competing Degradation Pathways. AB - The splitting of chromosomes in anaphase and their delivery into the daughter cells needs to be accurately executed to maintain genome stability. Chromosome splitting requires the degradation of securin, whereas the distribution of the chromosomes into the daughter cells requires the degradation of cyclin B. We show that cells encounter and tolerate variations in the abundance of securin or cyclin B. This makes the concurrent onset of securin and cyclin B degradation insufficient to guarantee that early anaphase events occur in the correct order. We uncover that the timing of chromosome splitting is not determined by reaching a fixed securin level, but that this level adapts to the securin degradation kinetics. In conjunction with securin and cyclin B competing for degradation during anaphase, this provides robustness to the temporal order of anaphase events. Our work reveals how parallel cell-cycle pathways can be temporally coordinated despite variability in protein concentrations. PMID- 26527279 TI - Analysis of the Histone H3.1 Interactome: A Suitable Chaperone for the Right Event. AB - Despite minimal disparity at the sequence level, mammalian H3 variants bind to distinct sets of polypeptides. Although histone H3.1 predominates in cycling cells, our knowledge of the soluble complexes that it forms en route to deposition or following eviction from chromatin remains limited. Here, we provide a comprehensive analysis of the H3.1-binding proteome, with emphasis on its interactions with histone chaperones and components of the replication fork. Quantitative mass spectrometry revealed 170 protein interactions, whereas a large scale biochemical fractionation of H3.1 and associated enzymatic activities uncovered over twenty stable protein complexes in dividing human cells. The sNASP and ASF1 chaperones play pivotal roles in the processing of soluble histones but do not associate with the active CDC45/MCM2-7/GINS (CMG) replicative helicase. We also find TONSL-MMS22L to function as a H3-H4 histone chaperone. It associates with the regulatory MCM5 subunit of the replicative helicase. PMID- 26527281 TI - A model with combined viral and metabolic factors effectively predicts HBeAg status under long term entecavir therapy: a prospective cohort study. AB - BACKGROUND & AIM: The aim was to extract factors from virologic and biochemical profiles at baseline and 24 weeks of treatment to predict HBeAg seroconversion in patients treated with ETV. METHODS: HBeAg positive chronic hepatitis B patients receiving ETV naive-treatment were enrolled. HBV DNA, ALT, and serological markers were prospectively monitored every 6 months for 240 weeks. The cumulative rates of virologic response (VR), biochemical response (BR), and HBeAg seroconversion were determined, and potential predictors for HBeAg seroconversion were identified through uni/multivariate analysis. RESULT: Two hundred twenty nine patients were eligible for this study. The cumulative rates of VR, BR, and HBeAg seroconversion at 240 weeks were 88.4 %, 100 %, and 36.7 %, respectively. Multivariate analysis showed that HBV DNA (OR, 2.8, p = 0.003), ALT (OR, 2.6, p = 0.005) at baseline, undetectable HBV DNA within 24 weeks (OR = 3.2, p < 0.001), and body mass index (BMI) >=24kg/m(2) (OR = 0.038, p = 0.013) were associated with HBeAg seroconversion. A prediction model for probability of HBeAg seroconversion was constructed. Patients can be classified into high (>40 %), intermediate (20-40 %), or low (<=20 %) groups based on the calculated probability of HBeAg seroconversion. The cumulative rates of HBeAg seroconversion were different among the three groups (p < 0.001). About 58 % patients in the high probability group achieved HBeAg seroconversion while almost 90 % patients within the low group remained HBeAg positive. CONCLUSION: A combination of HBV DNA, ALT and BMI values at baseline, and undetectable HBV DNA level within 24 weeks can predict HBeAg seroconversion. Both viral and metabolic factors likely determine HBeAg status with ETV treatment. TRIAL REGISTRATION: CTR20132358. PMID- 26527282 TI - A protocol for a systematic review of the diagnostic accuracy of blood markers, synovial fluid, and tissue testing in periprosthetic joint infections (PJI). AB - BACKGROUND: Total joint replacement (TJR) procedures have been one of the most rewarding interventions for treating patients suffering from joint disease. However, developing a periprosthetic joint infection (PJI) is a serious complication that is associated with the highest burden of cost and reduction in patients' quality of life compared to other complications following TJRs. One of the main challenges facing clinicians who are treating PJIs is accurately diagnosing infection in a timely fashion. Multiple orthopedic associations have published clinical guidelines for diagnosing PJI which are based solely on consensus approaches, expert opinions, and narrative reviews. We believe that a higher quality of scientific rigor is necessary to establish a diagnostic guideline that represents current evidence more accurately and that identifies important knowledge gaps in PJI diagnosis. Therefore, we will conduct a systematic review on diagnostic performance of blood markers, synovial fluids, and tissue tests for diagnosing PJI. METHODS/DESIGN: Electronic search strategies will be developed and tested by an experienced medical information specialist in consultation with the review team, and gray literature will be searched using the checklist from CADTH's Grey Matters Light. Two reviewers will independently screen the literature for inclusion using the prespecified eligibility criteria. Non-English language and animal-only studies will be excluded. Quality assessment and data extractions by reviewers will be verified, and disagreements will be resolved through consensus or third party adjudication. We will assess the quality of individual studies using the QUADAS-2 tool and use GRADE to summarize the strength of body of evidence. Analyses of evidence will be conducted in accordance with the Cochrane Handbook for Diagnostic Test Accuracy Reviews. DISCUSSION: We will conduct a systemic review of tests (blood markers, synovial fluids, and tissue testing) for diagnosing PJI in patients' knee, hip, and shoulder joint replacements. This will be the first scientifically rigorous and comprehensive systematic review in the field and may feed into an evidence-based clinical practice guideline. We will compare the findings of this review with the consensus-based guides and discuss the differences, similarities, and knowledge gaps. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015023768. PMID- 26527283 TI - One-step real-time RT-PCR assays for serotyping dengue virus in clinical samples. AB - BACKGROUND: Dengue is one of the leading causes of morbidity in tropical and subtropical regions and infection with any of the four dengue virus serotypes (DENV1-4) result in a wide range of clinical manifestations. Given the geographic expansion of DENV1-4, assays for serotyping are needed to be able to perform surveillance and epidemiological studies. In this study, we describe the design and validation of one-step real-time serotype-specific DENV RT-PCR assays. METHODS: The DENV1, DENV2, DENV3, and DENV4 RT-PCR assays were designed using all available whole genome DENV sequences in the NCBI nucleotide collection. Because of the high mutation rates of RNA viruses, the assays were performed in singleplex format to enable quick modifications to the primer and probe sequences when new genetic variants emerge. The analytical performance of the RT-PCR assays were evaluated using in vitro transcribed RNA and their specificity was determined by testing 24 DENV isolates, external DENV control panels and RNA preparation of non-DENV flaviviruses and non-dengue clinical samples. Additionally, the clinical performance of the serotype-specific DENV RT-PCR were compared to that of the CDC DENV-1-4 RT-PCR using 85 clinical samples collected from patients presenting with acute dengue. RESULTS: The RT-PCR assays were found to be specific for their respective serotype and did not cross-react with other flaviviruses or human mRNA. All assays had a linear dynamic range of 10(2) to 10(6) copies/reaction with detection limits between 12 and 44 copies/reaction. When testing sera from 85 confirmed acute dengue cases, the serotype-specific DENV RT-PCR assays had 100 % positive agreement with the FDA-approved CDC DENV-1 4 RT-PCR assay performed in a singleplex format. Additionally 15 samples that tested negative in the CDC DENV-1-4- RT-PCR assay were found positive using the serotype-specific DENV RT-PCR assays. CONCLUSIONS: Our results suggest that these RT-PCR assays are useful alternatives to existing methods for serotyping DENV in clinical sera. PMID- 26527284 TI - Obesity Associated Modulation of miRNA and Co-Regulated Target Transcripts in Human Adipose Tissue of Non-Diabetic Subjects. AB - OBJECTIVE: Micro RNAs (miRNAs) are a class of non-coding regulatory RNAs. We performed a transcriptome-wide analysis of subcutaneous adipose tissue and in vitro studies to identify miRNAs and co-regulated target transcripts associated with insulin sensitivity (SI) and obesity in human. METHODS: We selected 20 insulin-resistant (IR, SI=2.0+/-0.7) and 20 insulin-sensitive (IS, SI=7.2+/-2.3) subjects from a cohort of 117 metabolically characterized non-diabetic Caucasians for comparison. RESULTS: After global profiling, 3 miRNAs had marginally different expressions between IR and IS subjects. A total of 14 miRNAs were significantly correlated with %fat mass, body mass index (BMI), or SI. The qRT PCR validated the correlation of miR-148a-3p with BMI (r=-0.70, P=2.73X10(-6)). MiRNA target filtering analysis identified DNA methyltransferase 1 (DNMT1) as one of the target genes of miR-148a-3p. DNMT1 expression in adipose tissue was positively correlated with BMI (r=0.47, p=8.42X10(-7)) and was inversely correlated with miR-148a-3p (r=-0.34). Differentiation of SGBS preadipocytes showed up-regulation of miR-148a-3p and down-regulation of DNMT1 in differentiated adipocytes. After transfecting miR-148a-3p mimics into HeLa-S3 cells, DNMT1 was down-regulated, while transfection of adipose stem cells with miR-148a-3p inhibitor up-regulated DNMT1. CONCLUSIONS: Our results indicate that miR-148a-3pmediated regulation of DNMT1 expression may play a mechanistic role in obesity. PMID- 26527285 TI - MicroRNAs: An Apparent Switch for High-Altitude Pulmonary Edema. AB - BACKGROUND: High-altitude (HA) attracts people for its beauty and adventure. Interestingly, however, it affects the normal physiology and health due to the hypobaric hypoxic environment. Normal individuals acclimatize efficiently, but susceptible individuals encounter HA related disorders. Among these disorders, high-altitude pulmonary edema (HAPE) results into casualties. During acclimatization, body makes sequential changes in the expression of genes to counterbalance the hypobaric hypoxia induced stress. In this context, gene regulatory elements, such as transcription factors, DNA methylation and microRNAs (miRNAs) become relevant. This review, however, will primarily focus on miRNAs because of its decisive role in maintaining physiological homeostasis, both under normoxic and hypoxic conditions. METHODS: Availing the literature, an in-silico study was performed to explore the anticipated role of miRNAs in HAPE pathophysiology. RESULTS: We observed robust target based networking among the miRNAs. miR-16, 20b, 22, 206 and 17/92 were reported to have decreased expression in response to hypoxia and inhibit ion channels and increase pulmonary arterial pressure leading to vascular dysfunction and loss of cellular integrity. Whereas, miR-23b, 26a and 155 inhibit TGF signaling and contribute to increased pulmonary pressure, while miR-210 inhibits mitochondrial function. Incidentally, these physiological func- tions associate with HAPE, favoring possible role of miRNAs. CONCLUSION: It is concluded that the expression of individual/groups of miRNAs may change differentially under hypobaric hypoxia to modulate human physiology; however, this needs to be validated for HAPE pathophysiology. PMID- 26527287 TI - Understanding the Unique Attributes of MUC16 (CA125): Potential Implications in Targeted Therapy. AB - CA125, the most widely used ovarian cancer biomarker, was first identified approximately 35 years ago in an antibody screen against ovarian cancer antigen. Two decades later, it was cloned and characterized to be a transmembrane mucin, MUC16. Since then, several studies have investigated its expression, functional, and mechanistic involvement in multiple cancer types. Antibody-based therapeutic approaches primarily using antibodies against the tandem repeat domains of MUC16 (e.g., oregovomab and abagovomab) have been the modus operandi for MUC16-targeted therapy, but have met with very limited success. In addition, efforts have been also made to disrupt the functional cooperation of MUC16 and its interacting partners; for example, use of a novel immunoadhesin HN125 to interfere MUC16 binding to mesothelin. Since the identification of CA125 to be MUC16, it is hypothesized to undergo proteolytic cleavage, a process that is considered to be critical in determining the kinetics of MUC16 shedding as well as generation of a cell-associated carboxyl-terminal fragment with potential oncogenic functions. In addition to our experimental demonstration of MUC16 cleavage, recent studies have demonstrated the functional importance of carboxyl terminal fragments of MUC16 in multiple tumor types. Here, we provide how our understanding of the basic biologic processes involving MUC16 influences our approach toward MUC16-targeted therapy. PMID- 26527286 TI - A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution. AB - Genome-wide association studies (GWAS) have identified SNPs in six genes that are associated with childhood acute lymphoblastic leukemia (ALL). A lead SNP was found to occur on chromosome 9p21.3, a region that is deleted in 30% of childhood ALLs, suggesting the presence of causal polymorphisms linked to ALL risk. We used SNP genotyping and imputation-based fine-mapping of a multiethnic ALL case control population (Ncases = 1,464, Ncontrols = 3,279) to identify variants of large effect within 9p21.3. We identified a CDKN2A missense variant (rs3731249) with 2% allele frequency in controls that confers three-fold increased risk of ALL in children of European ancestry (OR, 2.99; P = 1.51 * 10(-9)) and Hispanic children (OR, 2.77; P = 3.78 * 10(-4)). Moreover, of 17 patients whose tumors displayed allelic imbalance at CDKN2A, 14 preferentially retained the risk allele and lost the protective allele (PBinomial = 0.006), suggesting that the risk allele provides a selective advantage during tumor growth. Notably, the CDKN2A variant was not significantly associated with melanoma, glioblastoma, or pancreatic cancer risk, implying that this polymorphism specifically confers ALL risk but not general cancer risk. Taken together, our findings demonstrate that coding polymorphisms of large effect can underlie GWAS "hits" and that inherited polymorphisms may undergo directional selection during clonal expansion of tumors. PMID- 26527288 TI - Application of Evolutionary Principles to Cancer Therapy. AB - The dynamic cancer ecosystem, with its rich temporal and spatial diversity in environmental conditions and heritable cell phenotypes, is remarkably robust to therapeutic perturbations. Even when response to therapy is clinically complete, adaptive tumor strategies almost inevitably emerge and the tumor returns. Although evolution of resistance remains the proximate cause of death in most cancer patients, a recent analysis found that evolutionary terms were included in less than 1% of articles on the cancer treatment outcomes, and this has not changed in 30 years. Here, we review treatment methods that attempt to understand and exploit intratumoral evolution to prolong response to therapy. In general, we find that treating metastatic (i.e., noncurable) cancers using the traditional strategy aimed at killing the maximum number of tumor cells is evolutionarily unsound because, by eliminating all treatment-sensitive cells, it enables rapid proliferation of resistant populations-a well-known evolutionary phenomenon termed "competitive release." Alternative strategies, such as adaptive therapy, "ersatzdroges," and double-bind treatments, shift focus from eliminating tumor cells to evolution-based methods that suppress growth of resistant populations to maintain long-term control. PMID- 26527289 TI - Amphiregulin Is a Critical Downstream Effector of Estrogen Signaling in ERalpha Positive Breast Cancer. AB - Estrogen stimulation promotes epithelial cell proliferation in estrogen receptor (ERalpha)-positive breast cancer. Many ERalpha target genes have been enumerated, but the identities of the key effectors mediating the estrogen signal remain obscure. During mouse mammary gland development, the estrogen growth factor receptor (EGFR) ligand amphiregulin acts as an important stage-specific effector of estrogen signaling. In this study, we investigated the role of amphiregulin in breast cancer cell proliferation using human tissue samples and tumor xenografts in mice. Amphiregulin was enriched in ERalpha-positive human breast tumor cells and required for estrogen-dependent growth of MCF7 tumor xenografts. Furthermore, amphiregulin levels were suppressed in patients treated with endocrine therapy. Suppression of EGF receptor signaling appeared necessary for the therapeutic response in this setting. Our findings implicate amphiregulin as a critical mediator of the estrogen response in ERalpha-positive breast cancer, emphasizing the importance of EGF receptor signaling in breast tumor pathogenesis and therapeutic response. PMID- 26527290 TI - Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1. AB - The urokinase-type plasminogen activator receptor (uPAR) has a well-established role in cancer progression, but it has been little studied at earlier stages of cancer initiation. Here, we show that uPAR deficiency in the mouse dramatically reduces susceptibility to the classical two-stage protocol of inflammatory skin carcinogenesis. uPAR genetic deficiency decreased papilloma formation and accelerated keratinocyte differentiation, effects mediated by Notch1 hyperactivation. Notably, Notch1 inhibition in uPAR-deficient mice rescued their susceptibility to skin carcinogenesis. Clinically, we found that human differentiated keratoacanthomas expressed low levels of uPAR and high levels of activated Notch1, with opposite effects in proliferating tumors, confirming the relevance of the observations in mice. Furthermore, we found that TACE-dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR. Mechanistically, uPAR sequestered TACE within lipid rafts to prevent Notch1 activation, thereby promoting cell proliferation and tumor formation. Given that uPAR signaling is nonessential for normal epidermal homeostasis, our results argue that uPAR may present a promising disease-specific target for preventing skin cancer development. PMID- 26527291 TI - ZIFA: Dimensionality reduction for zero-inflated single-cell gene expression analysis. AB - Single-cell RNA-seq data allows insight into normal cellular function and various disease states through molecular characterization of gene expression on the single cell level. Dimensionality reduction of such high-dimensional data sets is essential for visualization and analysis, but single-cell RNA-seq data are challenging for classical dimensionality-reduction methods because of the prevalence of dropout events, which lead to zero-inflated data. Here, we develop a dimensionality-reduction method, (Z)ero (I)nflated (F)actor (A)nalysis (ZIFA), which explicitly models the dropout characteristics, and show that it improves modeling accuracy on simulated and biological data sets. PMID- 26527292 TI - Focal concavity of posterior superior acetabulum and its relation with acetabular dysplasia and retroversion in adults without advanced hip osteoarthritis. AB - BACKGROUND: Although little is known, a limited number of three-dimensional computed tomography (CT) images of the pelvis present focal concavity of posterior superior acetabulum. The purpose of the present study was to investigate this morphologic deformity and its relation with dysplasia and retroversion in adults who were expected to have the original morphology of the acetabulum after growth. METHODS: Consecutive adult patients with hip pain who visited our hospital and had three-dimensional pelvic CT images were retrospectively analyzed after approval of the institutional review board; exclusion criterions included diseases, injuries and operations that affect the morphology of the hip including radiographic osteoarthritis Tonnis grades 2 and 3. Focal concavity of posterior superior acetabulum was evaluated by three dimensional CT image. Acetabular dysplasia was determined by lateral center edge (LCE) angle <25 degrees , Tonnis angle >10 degrees , and anterior center edge (ACE) angle <25 degrees on standing hip radiographs. Acetabular version angle was measured at the one-fourth cranial level of axial CT image. A subgroup analysis included only younger adult patients up to 50 years. RESULTS: The subjects analyzed were 46 men (92 hips) and 54 women (108 hips) with a median age of 57.5 (21-79) and 51.0 (26-77) years, respectively. Focal concavity of posterior superior acetabulum was observed in 13 hips; 7 patients had unilaterally, while 3 patients showed bilaterally. Among these hips, pain was observed in 8 hips but 4 hips (2 patients) were associated with injuries. This morphologic abnormality was not associated with acetabular dysplasia determined by LCE angle <25 degrees , Tonnis angle >10 degrees or ACE angle <25 degrees . Of note, no acetabulum with the deformity plus dysplasia was retroverted. These findings were confirmed in a subgroup analysis including 22 men (44 hips) and 27 women (54 hips) with a median age of 31.0 (21-50) and 41.0 (26-50) years, respectively. CONCLUSIONS: Focal concavity of posterior superior acetabulum could be a rare morphologic abnormality of acetabular formation independent of lateral or anterior dysplasia or retroversion. PMID- 26527293 TI - Large Area MEMS Based Ultrasound Device for Cancer Detection. AB - We present image results obtained using a prototype ultrasound array which demonstrates the fundamental architecture for a large area MEMS based ultrasound device for detection of breast cancer. The prototype array consists of a tiling of capacitive Micro-Machined Ultrasound Transducers (cMUTs) which have been flip chip attached to a rigid organic substrate. The pitch on the cMUT elements is 185 um and the operating frequency is nominally 9 MHz. The spatial resolution of the new probe is comparable to production PZT probes, however the sensitivity is reduced by conditions that should be correctable. Simulated opposed-view image registration and Speed of Sound volume reconstruction results for ultrasound in the mammographic geometry are also presented. PMID- 26527294 TI - Corrigendum. AB - [This corrects the article on p. e30 in vol. 20, PMID: 26435675.]. PMID- 26527295 TI - Genetic and Environmental Causes of Variation in the Difference Between Biological Age Based on DNA Methylation and Chronological Age for Middle-Aged Women. AB - The disease- and mortality-related difference between biological age based on DNA methylation and chronological age (Deltaage) has been found to have approximately 40% heritability by assuming that the familial correlation is only explained by additive genetic factors. We calculated two different Deltaage measures for 132 middle-aged female twin pairs (66 monozygotic and 66 dizygotic twin pairs) and their 215 sisters using DNA methylation data measured by the Infinium HumanMethylation450 BeadChip arrays. For each Deltaage measure, and their combined measure, we estimated the familial correlation for MZ, DZ and sibling pairs using the multivariate normal model for pedigree analysis. We also pooled our estimates with those from a former study to estimate weighted average correlations. For both Deltaage measures, there was familial correlation that varied across different types of relatives. No evidence of a difference was found between the MZ and DZ pair correlations, or between the DZ and sibling pair correlations. The only difference was between the MZ and sibling pair correlations (p < .01), and there was marginal evidence that the MZ pair correlation was greater than twice the sibling pair correlation (p < .08). For weighted average correlation, there was evidence that the MZ pair correlation was greater than the DZ pair correlation (p < .03), and marginally greater than twice the sibling pair correlation (p < .08). The varied familial correlation of Deltaage is not explained by additive genetic factors alone, implying the existence of shared non-genetic factors explaining variation in Deltaage for middle-aged women. PMID- 26527296 TI - pH and redox sensitive albumin hydrogel: A self-derived biomaterial. AB - Serum albumin can be transformed to a stimuli (pH and redox) responsive hydrogel using the reduction process followed by oxidative refolding. The preparation of albumin hydrogel involves a range of concentrations (75, 150, 300, 450, 600 and 750 MUM) and pH (2.0-10.0) values and the gelation begins at a concentration of 150 MUM and 4.5-8.0 pH value. The hydrogel shows maximum swelling at alkali pH (pH > 9.0). The increase in albumin concentration increases hydrogel stability, rheological property, compressive strength, proteolytic resistance and rate of in vivo biodegradation. Based on the observed physical and biological properties of albumin hydrogel, 450 MUM was determined to be an optimum concentration for further experiments. In addition, the hemo- and cytocompatibility analyses revealed the biocompatibility nature of albumin hydrogel. The experiments on in vitro drug (Tetracycline) delivery were carried out under non reducing and reducing conditions that resulted in the sustained and fast release of the drug, respectively. The methodology used in the preparation of albumin hydrogel may lead to the development of autogenic tissue constructs. In addition, the methodology can have various applications in tissue engineering and drug delivery. PMID- 26527297 TI - Ectomycorrhizal fungi decompose soil organic matter using oxidative mechanisms adapted from saprotrophic ancestors. AB - Ectomycorrhizal fungi are thought to have a key role in mobilizing organic nitrogen that is trapped in soil organic matter (SOM). However, the extent to which ectomycorrhizal fungi decompose SOM and the mechanism by which they do so remain unclear, considering that they have lost many genes encoding lignocellulose-degrading enzymes that are present in their saprotrophic ancestors. Spectroscopic analyses and transcriptome profiling were used to examine the mechanisms by which five species of ectomycorrhizal fungi, representing at least four origins of symbiosis, decompose SOM extracted from forest soils. In the presence of glucose and when acquiring nitrogen, all species converted the organic matter in the SOM extract using oxidative mechanisms. The transcriptome expressed during oxidative decomposition has diverged over evolutionary time. Each species expressed a different set of transcripts encoding proteins associated with oxidation of lignocellulose by saprotrophic fungi. The decomposition 'toolbox' has diverged through differences in the regulation of orthologous genes, the formation of new genes by gene duplications, and the recruitment of genes from diverse but functionally similar enzyme families. The capacity to oxidize SOM appears to be common among ectomycorrhizal fungi. We propose that the ancestral decay mechanisms used primarily to obtain carbon have been adapted in symbiosis to scavenge nutrients instead. PMID- 26527300 TI - Off-resonance effects in (14)N NQR signals from the pulsed spin-locking (PSL) and three-pulse echo sequence; a study for monoclinic TNT. AB - In NQR detection applications signal averaging by the summation of rapidly regenerated signals from multiple pulse sequences of the pulsed spin-locking (PSL) type is often used to improve sensitivity. It is important to characterise and if possible minimise PSL sequence off-resonance effects since they can make it difficult to optimise detection performance. We illustrate this with measurements of the variation of the decay time T2e and the amplitude of PSL signal trains with pulse spacing and excitation offset frequency for the 870 kHz nu+(14)N NQR line of monoclinic TNT under carefully stabilised temperature conditions. We have also carried out a similar study of signals from monoclinic TNT and 1H-1,2,3-triazole generated by a three-pulse echo sequence and the results are shown to agree well with a theoretical treatment appropriate to polycrystalline NQR samples such as TNT for which spin I=1, asymmetry parameter eta?0 and T1?T2. Based on this theory we derive simple models for calculating TNT PSL signal trains and hence the pulse spacing and off-resonance dependence of signal amplitude and T2e which we compare to our experimental data. We discuss the influence of PSL echo summation on off-resonance effects in detected signal intensity and show how a phase-alternated multiple pulse sequence can be used in combination with the PSL sequence to eliminate variation in detection performance due to off-resonance effects. PMID- 26527298 TI - Evaluation of bound and pore water in cortical bone using ultrashort-TE MRI. AB - Bone water exists in different states with the majority bound to the organic matrix and to mineral, and a smaller fraction in 'free' form in the pores of cortical bone. In this study, we aimed to develop and evaluate ultrashort-TE (UTE) MRI techniques for the assessment of T2*, T1 and concentration of collagen bound and pore water in cortical bone using a 3-T clinical whole-body scanner. UTE MRI, together with an isotope study using tritiated and distilled water (THO H2O) exchange, as well as gravimetric analysis, were performed on ten sectioned bovine bone samples. In addition, 32 human cortical bone samples were prepared for comparison between the pore water concentration measured with UTE MRI and the cortical porosity derived from micro-computed tomography (MUCT). A short T2* of 0.27 +/- 0.03 ms and T1 of 116 +/- 6 ms were observed for collagen-bound water in bovine bone. A longer T2* of 1.84 +/- 0.52 ms and T1 of 527 +/- 28 ms were observed for pore water in bovine bone. UTE MRI measurements showed a pore water concentration of 4.7-5.3% by volume and collagen-bound water concentration of 15.7-17.9% in bovine bone. THO-H2O exchange studies showed a pore water concentration of 5.9 +/- 0.6% and collagen-bound water concentration of 18.1 +/- 2.1% in bovine bone. Gravimetric analysis showed a pore water concentration of 6.3 +/- 0.8% and collagen-bound water concentration of 19.2 +/- 3.6% in bovine bone. A mineral water concentration of 9.5 +/- 0.6% was derived in bovine bone with the THO-H2O exchange study. UTE-measured pore water concentration is highly correlated (R(2) = 0.72, p < 0.0001) with MUCT porosity in the human cortical bone study. Both bovine and human bone studies suggest that UTE sequences could reliably measure collagen-bound and pore water concentration in cortical bone using a clinical scanner. PMID- 26527301 TI - The Sensory Ecology of Ant Navigation: From Natural Environments to Neural Mechanisms. AB - Animals moving through the world are surrounded by potential information. But the components of this rich array that they extract will depend on current behavioral requirements and the animal's own sensory apparatus. Here, we consider the types of information available to social hymenopteran insects, with a specific focus on ants. This topic has a long history and much is known about how ants and other insects use idiothetic information, sky compasses, visual cues, and odor trails. Recent research has highlighted how insects use other sensory information for navigation, such as the olfactory cues provided by the environment. These cues are harder to understand because they submit less easily to anthropomorphic analysis. Here, we take an ecological approach, considering first what information is available to insects, then how different cues might interact, and finally we discuss potential neural correlates of these behaviors. PMID- 26527302 TI - Invasion and Management of Agricultural Alien Insects in China. AB - China is the world's fourth-largest country in terms of landmass. Its highly diverse biogeography presents opportunities for many invasive alien insects. However, physical and climate barriers sometimes prevent locally occurring species from spreading. China has 560 confirmed invasive alien species; 125 are insect pests, and 92 of these damage the agricultural ecosystem. The estimated annual economic loss due to alien invasive species is more than $18.9 billion. The most harmful invasive insects exhibit some common characteristics, such as high reproduction, competitive dominance, and high tolerance, and benefit from mutualist facilitation interactions. Regional cropping system structure adjustments have resulted in mono-agricultural ecosystems in cotton and other staple crops, providing opportunities for monophagous insect pests. Furthermore, human dietary shifts to fruits and vegetables and smallholder-based farming systems result in highly diverse agricultural ecosystems, which provide resource opportunities for polyphagous insects. Multiple cropping and widespread use of greenhouses provide continuous food and winter habitats for insect pests, greatly extending their geographic range. The current management system consists of early warning, monitoring, eradication, and spread blocking technologies. This review provides valuable new synthetic information on integrated management practices based mainly on biological control for a number of invasive species. We encourage farmers and extension workers to be more involved in training and further research for novel protection methods that takes into consideration end users' needs. PMID- 26527303 TI - Genome-wide identification and characterization of reference genes with different transcript abundances for Streptomyces coelicolor. AB - The lack of reliable reference genes (RGs) in the genus Streptomyces hampers effort to obtain the precise data of transcript levels. To address this issue, we aimed to identify reliable RGs in the model organism Streptomyces coelicolor. A pool of potential RGs containing 1,471 genes was first identified by determining the intersection of genes with stable transcript levels from four time-series transcriptome microarray datasets of S. coelicolor M145 cultivated in different conditions. Then, following a strict rational selection scheme including homology analysis, disturbance analysis, function analysis and transcript abundance analysis, 13 candidates were selected from the 1,471 genes. Based on real-time quantitative reverse transcription PCR assays, SCO0710, SCO6185, SCO1544, SCO3183 and SCO4758 were identified as the top five genes with the most stable transcript levels among the 13 candidates. Further analyses showed these five genes also maintained stable transcript levels in different S. coelicolor strains, as well as in Streptomyces avermitilis MA-4680 and Streptomyces clavuligerus NRRL 3585, suggesting they could fulfill the requirements of accurate data normalization in streptomycetes. Moreover, the systematic strategy employed in this work could be used for reference in other microorganism to select reliable RGs. PMID- 26527304 TI - Perinatal outcomes among migrant mothers in the United Kingdom: Is it a matter of biology, behaviour, policy, social determinants or access to health care? AB - This paper examines trends in perinatal outcomes among migrant mothers in the UK, and it explores potential contributors to disparities focusing on pregnancy, birth and the first year of life. Trends in perinatal outcomes indicate that ethnic minority grouping, regardless of migrant status, is a significant risk factor for unfavourable outcomes. It is unclear whether migrant status per se adds to this risk as within-group comparisons between UK-born and foreign-born women show variable findings. The role of biological and behavioural factors in producing excess unfavourable outcomes among ethnic minority mothers, although indicated, is yet to be fully understood. UK policies have salient aspects that address ethnic inequalities, but their wide focus obscures provisions for migrant mothers. Direct associations between socio-economic factors, ethnicity and adverse infant outcomes are evident. Evidence is consistent about differential access to and utilisation of health services among ethnic minority mothers, in particular recently arrived migrants, refugees and asylum seekers. PMID- 26527305 TI - Growth factors and pathogenesis. AB - Growth factors are relatively small and stable, secreted or membrane-bound polypeptide ligands, which play an important role in proliferation, differentiation, angiogenesis, survival, inflammation, and tissue repair, or fibrosis. They exert multiple effects through the activation of signal transduction pathways by binding to their receptors on the surface of target cells. A number of studies have demonstrated the central role of growth factors and their signaling pathways in the pathogenesis of uterine leiomyomas. Numerous differentially expressed growth factors have been identified in leiomyoma and myometrial cells. These growth factors can activate multiple signaling pathways (Smad 2/3, ERK 1/2, PI3K, and beta-catenin) and regulate major cellular processes, including inflammation, proliferation, angiogenesis, and fibrosis which are linked to uterine leiomyoma development and growth. In this chapter, we discuss the role of growth factors and their signaling pathways in the pathogenesis of uterine leiomyomas. PMID- 26527306 TI - Cell-based strategies to reconstitute vital functions in preterm infants with organ failure. AB - Infants born preterm face a number of challenges. Depending on the degree of prematurity, they are at a risk of developing several specific conditions and diseases related to organ immaturity and complications of long-term neonatal intensive care. Various organ systems are affected, such as the lung, resulting in bronchopulmonary dysplasia (BPD); the vascular system, resulting in pulmonary hypertension; the brain, with the risk of intracranial hemorrhage; the eye with retinopathy of prematurity; and the gut, manifesting in the severe complication of necrotizing enterocolitis. A common hallmark for all these prematurity-related conditions is that inflammation seems to be a major driving force in the pathogenesis, and that injury repair is essential for recovery and long-term health. In addition, the available treatment options are often only supportive, not curative. This chapter reviews the recent advances of stem cell therapy that have opened up new possibilities to restore organ function following prematurity. PMID- 26527307 TI - Shared decision-making in chronic kidney disease: A retrospection of recently initiated dialysis patients in Germany. AB - OBJECTIVE: To compare differences in shared decision-making (SDM) and treatment satisfaction (TS) between haemodialysis (HD) and peritoneal dialysis (PD) patients. METHODS: 6-24 months after initiation of dialysis, we surveyed 780 patients from throughout Germany (CORETH-project) regarding SDM, the reason for modality choice and TS. Data were compared between two age-, comorbidity-, education-, and employment status-matched groups (n=482). RESULTS: PD patients rated all aspects of SDM more positively than did HD patients (total score: MPD=84.6, SD=24.1 vs. MHD=61.9, SD=37.3; p<=0.0001). The highest difference occurred for the item "announcement of a necessary decision" (delta=1.3 points on a 6-point Likert-scale). PD patients indicated their desire for independence as a motivator for choosing PD (65%), whereas HD patients were subject to medical decisions (23%) or wanted to rely on medical support (20%). We found positive correlations between SDM and TS (0.16<=r<=0.48; p<=0.0001). CONCLUSION: Our findings increase awareness of a participatory nephrological counseling-culture and imply that SDM can pave the way for quality of life and treatment success for dialysis patients. PRACTICE IMPLICATIONS: Practitioners can facilitate SDM by screening patient preferences at an early stage, being aware of biases in consultation, using easy terminology and encouraging passive patients to participate in the choice. PMID- 26527308 TI - Gremlin1 induces anterior-posterior limb bifurcations in developing Xenopus limbs but does not enhance limb regeneration. AB - Gremlin1 (grem1) has been previously identified as being significantly up regulated during regeneration of Xenopus laevis limbs. Grem1 is an antagonist of bone morphogenetic proteins (BMPs) with a known role in limb development in amniotes. It forms part of a self-regulating feedback loop linking epithelial (FGF) and mesenchymal (shh) signalling centres, thereby controlling outgrowth, anterior posterior and proximal distal patterning. Spatiotemporal regulation of the same genes in developing and regenerating Xenopus limb buds supports conservation of this mechanism. Using a heat shock inducible grem1 (G) transgene to created temperature regulated stable lines, we have shown that despite being upregulated in regeneration, grem1 overexpression does not enhance regeneration of tadpole hindlimbs. However, both the regenerating and contralateral, developing limb of G transgenics developed skeletal defects, suggesting that overexpressing grem1 negatively affects limb patterning. When grem1 expression was targeted earlier in limb bud development, we saw dramatic bifurcations of the limbs resulting in duplication of anterior posterior (AP) pattern, forming a phenotypic continuum ranging from duplications arising at the level of the femoral head to digit bifurcations, but never involving the pelvis. Intriguingly, the original limbs have AP pattern inversion due to de-restricted Shh signalling. We discuss a possible role for Grem1 regulation of limb BMPs in regulation of branching pattern in the limbs. PMID- 26527309 TI - Unusual case of drug-induced cholestasis due to glucosamine and chondroitin sulfate. AB - Glucosamine (GS) and chondroitin sulfate (CS) are common over-the-counter (OTC) supplements used in the treatment of osteoarthritis. These medications are seemingly safe, but there are increasing reports of hepatotoxicity with these supplements. We reported a unique case of drug-induced cholestasis caused by GS and CS in a combination tablet. The etiology of the jaundice was overlooked despite extensive investigations over a three-month period. Unlike drug-induced hepatocellular injury, drug-induced cholestatic jaundice with GS and CS has only been reported twice before. This case emphasizes the importance of a complete medication history, especially OTC supplements, in the assessment of cholestasis. PMID- 26527310 TI - HPV testing alone is not as safe as cytology and selective HPV testing: FOR: The sensitivity of HPV testing is not high enough. PMID- 26527311 TI - Joint engagement modulates object discrimination in toddlers: a pilot electrophysiological investigation. AB - Joint engagement (JE) is a state in which two people attend to a common target. By supporting an infant's attention to the target, JE promotes encoding of information. This process has not been studied in toddlers despite the fact that language and social interaction develop rapidly in this period. We asked whether JE modulates object discrimination in typically developing toddlers. In a pilot evaluation of a novel, naturalistic paradigm, toddlers (n = 11) were introduced to toys by an examiner with or without JE. Toddlers then viewed images of the toys while high-density electroencephalography (EEG) was recorded. Analysis focused on the differential neural response to objects presented in the two conditions. EEG components of interest included frontal positive component (Pb), negative component (Nc), and positive slow wave. Toddlers discriminated between conditions with a larger Pb peak amplitude to stimuli presented with JE and a larger Nc mean amplitude to the stimuli presented without JE, reflecting greater familiarity with the toys presented socially. Our findings suggest that JE supports object learning in toddlers, and supports the potential utility of this novel paradigm in both the assessment and the potential to detect impairment in social learning among toddlers. PMID- 26527312 TI - Using participatory epidemiology to investigate management options and relative importance of tick-borne diseases amongst transhumant zebu cattle in Karamoja Region, Uganda. AB - A participatory epidemiological (PE) study was conducted with livestock keepers in Moroto and Kotido districts, Karamoja Region, Uganda, between October and December 2013 to determine the management options and relative importance of tick borne diseases (TBDs) amongst transhumant zebu cattle. Data collection involved 24 focus group discussions (each comprising 8-12 people) in 24 settlement areas (manyattas), key informant interviews (30), direct observation, a review of surveillance data, clinical examination, and laboratory confirmation of cases of TBDs. Methods used in group discussions included semi-structured interviews, simple ranking, pairwise ranking, matrix scoring, proportional piling and participatory mapping. The results of pairwise comparison showed the Ngakarimojong-named diseases, lokit (East Coast fever, ECF), lopid (anaplasmosis), loukoi (contagious bovine pleuropneumonia, CBPP), lokou (heartwater) and lokulam (babesiosis), were considered the most important cattle diseases in Moroto in that order, while ECF, anaplasmosis, trypanosomosis (ediit), CBPP and nonspecific diarrhoea (loleo) were most important in Kotido. Strong agreement between informant groups (Kendall's coefficient of concordance W=0.568 and 0.682; p<0.001) in pairwise ranking indicated that the diseases were a common problem in selected districts. East Coast fever had the highest median score for incidence (18% [range: 2, 33]) in Moroto, followed by anaplasmosis (17.5% [8,32]) and CBPP (9% [1,21]). Most animals that suffered from ECF, anaplasmosis, heartwater and babesiosis died, as the respective median scores for case fatality rates (CFR) were 89.5% (42, 100), 82.8% (63, 100), 66.7% (20, 100) and 85.7% (0, 100). In Kotido, diseases with high incidence scores were ECF (21% [6,32]), anaplasmosis (17% [10,33]) and trypanosomosis (8% [2,18]). The CFRs for ECF and anaplasmosis were 81.7% (44, 100) and 70.7% (48, 100), respectively. Matrix scoring revealed that disease indicators showed strong agreement (W=0.382 0.659, p<0.05-p<0.001) between informant groups. Inadequate knowledge, poor veterinary services and limited availability of drugs were the main constraints that hindered the control of TBDs. Hand picking of ticks was done by all pastoralists while hand spraying with acaricides was irregular, often determined by availability of drug supplies and money. It was concluded that TBDs, particularly ECF and anaplasmosis were important diseases in this pastoral region. Results from this study may assist in the design of feasible control strategies. PMID- 26527313 TI - Calibrating physical activity intensity for hip-worn accelerometry in women age 60 to 91 years: The Women's Health Initiative OPACH Calibration Study. AB - OBJECTIVE: We conducted a laboratory-based calibration study to determine relevant cutpoints for a hip-worn accelerometer among women >=60 years, considering both type and filtering of counts. METHODS: Two hundred women wore an ActiGraph GT3X+ accelerometer on their hip while performing eight laboratory based activities. Oxygen uptake was measured using an Oxycon portable calorimeter. Accelerometer data were analyzed in 15-second epochs for both normal and low frequency extension (LFE) filters. Receiver operating characteristic (ROC) curve analyses were used to calculate cutpoints for sedentary, light (low and high), and moderate to vigorous physical activity (MVPA) using the vertical axis and vector magnitude (VM) counts. RESULTS: Mean age was 75.5 years (standard deviation 7.7). The Spearman correlation between oxygen uptake and accelerometry ranged from 0.77 to 0.85 for the normal and LFE filters and for both the vertical axis and VM. The area under the ROC curve was generally higher for VM compared to the vertical axis, and higher for cutpoints distinguishing MVPA compared to sedentary and light low activities. The VM better discriminated sedentary from light low activities compared to the vertical axis. The area under the ROC curves were better for the LFE filter compared to the normal filter for the vertical axis counts, but no meaningful differences were found by filter type for VM counts. CONCLUSION: The cutpoints derived for this study among women >=60 years can be applied to ongoing epidemiologic studies to define a range of physical activity intensities. PMID- 26527314 TI - Proteoglycan expression correlates with the phenotype of malignant and non malignant EBV-positive B-cell lines. AB - The involvement of proteoglycans (PGs) in EBV-host interactions and lymphomagenesis remains poorly investigated. In this study, expression of major proteoglycans (syndecan-1, glypican-1, perlecan, versican, brevican, aggrecan, NG2, serglycin, decorin, biglycan, lumican, CD44), heparan sulphate (HS) metabolic system (EXT1/2, NDST1/2, GLCE, HS2ST1, HS3ST1/2, HS6ST1/2, SULF1/2, HPSE) and extracellular matrix (ECM) components (collagen 1A1, fibronectin, elastin) in primary B cells and EBV carrying cell lines with different phenotypes, patterns of EBV-host cell interaction and viral latency stages (type I-III) was investigated. Primary B cells expressed a wide repertoire of PGs (dominated by serglycin and CD44) and ECM components. Lymphoblastoid EBV+ B cell lines (LCLs) showed specific PG expression with down-regulation of CD44 and ECM components and up-regulation of serglycin and perlecan/HSPG2. For Burkitt's lymphoma cells (BL), serglycin was down-regulated in BL type III cells and perlecan in type I BL cells. The biosynthetic machinery for HS was active in all cell lines, with some tendency to be down-regulated in BL cells. 5'-aza-dC and/or Trichostatin A resulted in transcriptional upregulation of the genes, suggesting that low expression of ECM components, proteoglycan core proteins and HS biosynthetic system is due to epigenetic suppression in type I cells. Taken together, our data show that proteoglycans are expressed in primary B lymphocytes whereas they are not or only partly expressed in EBV-carrying cell lines, depending on their latency type program. PMID- 26527315 TI - 5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits. AB - Despite marked tumor shrinkage after 5-FU treatment, the frequency of colon cancer relapse indicates that a fraction of tumor cells survives treatment causing tumor recurrence. The majority of cancer cells divert metabolites into anabolic pathways through Warburg behavior giving an advantage in terms of tumor growth. Here, we report that treatment of colon cancer cell with 5-FU selects for cells with mesenchymal stem-like properties that undergo a metabolic reprogramming resulting in addiction to OXPHOS to meet energy demands. 5-FU treatment-resistant cells show a de novo expression of pyruvate kinase M1 (PKM1) and repression of PKM2, correlating with repression of the pentose phosphate pathway, decrease in NADPH level and in antioxidant defenses, promoting PKM2 oxidation and acquisition of stem-like phenotype. Response to 5-FU in a xenotransplantation model of human colon cancer confirms activation of mitochondrial function. Combined treatment with 5-FU and a pharmacological inhibitor of OXPHOS abolished the spherogenic potential of colon cancer cells and diminished the expression of stem-like markers. These findings suggest that inhibition of OXPHOS in combination with 5-FU is a rational combination strategy to achieve durable treatment response in colon cancer. PMID- 26527316 TI - IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival. AB - The chromatin-binding DEK protein was recently reported to promote the growth of HPV+ and HPV- head and neck squamous cell carcinomas (HNSCCs). Relevant cellular and molecular mechanism(s) controlled by DEK in HNSCC remain poorly understood. While DEK is known to regulate specific transcriptional targets, global DEK dependent gene networks in HNSCC are unknown. To identify DEK transcriptional signatures we performed RNA-Sequencing (RNA-Seq) in HNSCC cell lines that were either proficient or deficient for DEK. Bioinformatic analyses and subsequent validation revealed that IRAK1, a regulator of inflammatory signaling, and IRAK1 dependent regulatory networks were significantly repressed upon DEK knockdown in HNSCC. According to TCGA data, 14% of HNSCC specimens overexpressed IRAK1, thus supporting possible oncogenic functions. Furthermore, genetic or pharmacologic inhibition of IRAK1 in HNSCC cell lines was sufficient to attenuate downstream signaling such as ERK1/2 and to induce HNSCC cell death by apoptosis. Finally, targeting DEK and IRAK1 simultaneously enhanced cell death as compared to targeting either alone. Our findings reveal that IRAK1 promotes cell survival and is an attractive therapeutic target in HNSCC cells. Thus, we propose a model wherein IRAK1 stimulates tumor signaling and phenotypes both independently and in conjunction with DEK. PMID- 26527317 TI - Mutational profiling of brain metastasis from breast cancer: matched pair analysis of targeted sequencing between brain metastasis and primary breast cancer. AB - Although breast cancer is the second most common cause of brain metastasis with a notable increase of incidence, genes that mediate breast cancer brain metastasis (BCBM) are not fully understood. To study the molecular nature of brain metastasis, we performed gene expression profiling of brain metastasis and matched primary breast cancer (BC). We used the Ion AmpliSeq Cancer Panel v2 covering 2,855 mutations from 50 cancer genes to analyze 18 primary BC and 42 BCBM including 15 matched pairs. The most common BCBM subtypes were triple negative (42.9%) and basal-like (36.6%). In a total of 42 BCBM samples, 32 (76.2%) harbored at least one mutation (median 1, range 0-7 mutations). Frequently detected somatic mutations included TP53 (59.5%), MLH1 (14.3%), PIK3CA (14.3%), and KIT (7.1%). We compared BCBM with patient-matched primary BC specimens. There were no significant differences in mutation profiles between the two groups. Notably, gene expression in BCBM such as TP53, PIK3CA, KIT, MLH1, and RB1 also seemed to be present in primary breast cancers. The TP53 mutation frequency was higher in BCBM than in primary BC (59.5% vs 38.9%, respectively). In conclusion, we found actionable gene alterations in BCBM that were maintained in primary BC. Further studies with functional testing and a delineation of the role of these genes in specific steps of the metastatic process should lead to a better understanding of the biology of metastasis and its susceptibility to treatment. PMID- 26527318 TI - Mutations in epigenetic regulators are involved in acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation. AB - Although steady improvements to chemotherapeutic treatments has helped cure 80% of childhood acute lymphoblastic leukemia (ALL) cases, chemotherapy has proven to be less effective in treating the majority of adult patients, leaving allogeneic hematopoietic stem cell transplantation (allo-HSCT) as the primary adult treatment option. Nevertheless relapse are the leading cause of death following allo-HSCT. The genetic pathogenesis of relapse following allo-HSCT in Philadelphia chromosome- negative ALL (Ph- ALL) remains unexplored. We performed longitudinal whole-exome sequencing analysis in three adult patients with Ph- B cell ALL (Ph- B-ALL) on samples collected from diagnosis to relapse after allo HSCT. Based on these data, we performed target gene sequencing on 23 selected genes in 58 adult patients undergoing allo-HSCT with Ph- B-ALL. Our results revealed a significant enrichment of mutations in epigenetic regulators from relapsed samples, with recurrent somatic mutations in SETD2, CREBBP, KDM6A and NR3C1. The relapsed samples were also enriched in signaling factor mutations, including KRAS, PTPN21, MYC and USP54. Furthermore, we are the first to reveal the clonal evolution patterns during leukemia relapse after allo-HSCT. Cells present in relapsed specimens were genetically related to the diagnosed tumor, these cells therefore arose from either an existing subclone that was not eradicated by allo-HSCT therapy, or from the same progenitor that acquired new mutations. In some cases, however, it is possible that leukemia recurrence following allo-HSCT could result from a secondary malignancy with a distinct set of mutations. We identified novel genetic causes of leukemia relapse after allo HSCT using the largest generated data set to date from adult patients with Ph- B ALL. PMID- 26527319 TI - Tamoxifen therapy benefit predictive signature coupled with prognostic signature of post-operative recurrent risk for early stage ER+ breast cancer. AB - Two types of prognostic signatures for predicting recurrent risk of ER+ breast cancer patients have been developed: one type for patients accepting surgery only and another type for patients receiving post-operative tamoxifen therapy. However, the first type of signature cannot distinguish high-risk patients who cannot benefit from tamoxifen therapy, while the second type of signature cannot identify patients who will be at low risk of recurrence even if they accept surgery only. In this study, we proposed to develop two coupled signatures to solve these problems based on within-sample relative expression orderings (REOs) of gene pairs. Firstly, we identified a prognostic signature of post-operative recurrent risk using 544 samples of ER+ breast cancer patients accepting surgery only. Then, applying this drug-free signature to 840 samples of patients receiving post-operative tamoxifen therapy, we recognized 553 samples of patients who would have been at high risk of recurrence if they had accepted surgery only and used these samples to develop a tamoxifen therapy benefit predictive signature. The two coupled signatures were validated in independent data. The signatures developed in this study are robust against experimental batch effects and applicable at the individual levels, which can facilitate the clinical decision of tamoxifen therapy. PMID- 26527321 TI - Giant myelolipomas and inadvertent bilateral adrenalectomy in classic congenital adrenal hyperplasia. AB - Myelolipomas have been reported in patients with congenital adrenal hyperplasia (CAH). ACTH excess, as seen with non-adherence to glucocorticoid therapy, may be responsible for tumor development. We report a case of a 51-year-old man with classic salt-wasting CAH managed on prednisone 7.5 mg daily and fludrocortisone who presented with chronic back pain and was found to have giant bilateral retroperitoneal masses. On computed tomography (CT) imaging, the masses were heterogeneous, but contained predominantly low-density fat attenuation. The tumors were resected due to concern for malignancy and mass symptoms. Pathologic examination identified both retroperitoneal masses as myelolipomas. The left tumor was 34*20*13 cm and weighed 4.7 kg and the right tumor was 20 cm in the largest dimension. Adrenal tissue was present in the specimen. The patient reported long-term compliance with glucocorticoid treatment. However, no biochemical monitoring of ACTH levels had occurred. Therefore, it is unclear if ACTH excess contributed to the development of these large tumors in this patient. It was presumed that both adrenal glands were inadvertently removed during surgery and the patient was treated with physiologic replacement doses of hydrocortisone and fludrocortisone postoperatively. In this case, the bilateral adrenalectomy was inadvertent. However, adrenalectomy can be considered as a treatment option in patients with classical CAH under certain circumstances to avoid complications of glucocorticoid excess. LEARNING POINTS: Myelolipomas should be considered in the differential diagnosis of adrenal or retroperitoneal masses in patients with CAH.On CT imaging, myelolipomas are seen as heterogeneous masses with low-density mature fat interspersed with more dense myeloid tissue.Myelolipomas are usually unilateral and measure <4 cm; however, very large and bilateral tumors have been reported.Treatment of CAH typically involves using supraphysiologic doses of glucocorticoid to suppress adrenal hyperandrogenism. Bilateral adrenalectomy is an alternative treatment option in patients with CAH.There is an association between ACTH excess and increased incidence of adrenal myelolipoma but the direct causal link remains to be established. PMID- 26527320 TI - Tumorsphere as an effective in vitro platform for screening anti-cancer stem cell drugs. AB - Cancer stem cells (CSCs) are a sub-population of cells within cancer tissues with tumor initiation, drug resistance and metastasis properties. CSCs also have been considered as the main cause of cancer recurrence. Targeting CSCs have been suggested as the key for successful treatment against cancer. Tumorsphere cultivation is based on culturing cancer cells onto ultralow attachment surface in serum-free media under the supplementation with growth factors such as epidermal growth factor and basic fibroblast growth factor. Tumorsphere cultivation is widely used to analyze the self-renewal capability of CSCs and to enrich these cells from bulk cancer cells. This method also provides a reliable platform for screening potential anti-CSC agents. The in vitro anti-proliferation activity of potential agents selected from tumorsphere assay is more translatable into in vivo anti-tumorigenic activity compared with general monolayer culture. Tumorsphere assay can also measure the outcome of clinical trials for potential anti-cancer agents. In addition, tumorsphere assay may be a promising strategy in the innovation of future cancer therapeutica and may help in the screening of anti-cancer small-molecule chemicals. PMID- 26527322 TI - Three-dimensional tracking of plus-tips by lattice light-sheet microscopy permits the quantification of microtubule growth trajectories within the mitotic apparatus. AB - Mitotic apparatus, which comprises hundreds of microtubules, plays an essential role in cell division, ensuring the correct segregation of chromosomes into each daughter cell. To gain insight into its regulatory mechanisms, it is essential to detect and analyze the behavior of individual microtubule filaments. However, the discrimination of discrete microtubule filaments within the mitotic apparatus is beyond the capabilities of conventional light microscopic technologies. Recently, we detected three-dimensional (3-D) microtubule growth dynamics within the cellular cytoplasmic space using lattice light-sheet microscopy in conjunction with microtubule growth marker protein end-binding 1, a microtubule plus-end tracking protein, which was fused to green fluorescent protein (EB1-GFP). This technique enables high-resolution 3-D imaging at subsecond intervals. We adapted mathematical computing and geometric representation techniques to analyze spatial variations in microtubule growth dynamics within the mitotic spindle apparatus. Our analytical approach enabled the different dynamic properties of individual microtubules to be determined, including the direction and speed of their growth, and their growth duration within a 3-D spatial map. Our analysis framework provides an important step toward a more comprehensive understanding of the mechanisms driving cellular machinery at the whole-cell level. PMID- 26527324 TI - Dissecting cellulitis of the scalp treated with tumour necrosis factor-alpha inhibitors: experience with two agents. PMID- 26527323 TI - Echocardiographic assessment of right ventricular functions in nondiabetic normotensive hemodialysis patients. AB - PURPOSE: Heart is affected structurally and functionally in end-stage renal disease (ESRD). However, the data available about adverse effects of ESRD on right ventricle (RV) is scarce. We aimed to evaluate echocardiographic parameters of RV in nondiabetic, normotensive patients with ESRD undergoing hemodialysis (HD). METHODS: A total of 45 (24 women; mean age 52.4 +/- 12.4 years) consecutive nondiabetic, normotensive patients with ESRD undergoing HD and 39 healthy age and sex-matched control subjects (22 women; mean age 50.3 +/- 6.6 years) were enrolled in the study. M-mode and two dimensional images, color, pulsed and continuous wave Doppler, and tissue Doppler measurements were acquired from all subjects. Echocardiographic evaluation was performed in the days between HD dates of the patients. RESULTS: RV fractional area change, tricuspid annular plane systolic excursion, tricuspid E velocity, E/A ratio, tricuspid annular E' velocity, and E'/A' ratio were lower in patients than controls (p < 0.001, p = 0.003, p = 0.007, p = 0.005, p < 0.001, and p = 0.034, respectively). However, RV diastolic area, RV myocardial performance index, E/E' ratio, and mean and systolic pulmonary artery pressure were higher in patients than controls (p < 0.001, p = 0.007, p = 0.005, p < 0.001, p = 0.006, respectively). CONCLUSIONS: RV systolic and diastolic functions of nondiabetic, normotensive HD patients are deteriorated as compared to healthy controls. PMID- 26527325 TI - Characterising the bacterial microbiota across the gastrointestinal tracts of dairy cattle: membership and potential function. AB - The bacterial community composition and function in the gastrointestinal tracts (GITs) of dairy cattle is very important, since it can influence milk production and host health. However, our understanding of bacterial communities in the GITs of dairy cattle is still very limited. This study analysed bacterial communities in ten distinct GIT sites (the digesta and mucosa of the rumen, reticulum, omasum, abomasum, duodenum, jejunum, ileum, cecum, colon and rectum) in six dairy cattle. The study observed 542 genera belonging to 23 phyla distributed throughout the cattle GITs, with the Firmicutes, Bacteroidetes and Proteobacteria predominating. In addition, data revealed significant spatial heterogeneity in composition, diversity and species abundance distributions of GIT microbiota. Furthermore, the study inferred significant differences in the predicted metagenomic profiles among GIT regions. In particular, the relative abundances of the genes involved in carbohydrate metabolism were overrepresented in the digesta samples of forestomaches, and the genes related to amino acid metabolism were mainly enriched in the mucosal samples. In general, this study provides the first deep insights into the composition of GIT microbiota in dairy cattle, and it may serve as a foundation for future studies in this area. PMID- 26527326 TI - An exploration of the effects of clinical negligence litigation on the practice of midwives in England: A phenomenological study. AB - OBJECTIVE: to explore how midwives' personal involvement in clinical negligence litigation affects their midwifery practice. DESIGN: descriptive phenomenological study using semi-structured interviews. SETTING: in 2006-2007 in-depth interviews were conducted in participants' homes or at their place of work and focused on participants' experience of litigation. Participants were recruited from various regions of England. PARTICIPANTS: 22 National Health Service (NHS) midwives who had been alleged negligent. FINDINGS: clinical practice affected was an increase in documentation, fear of practising outside clinical guidelines and electronic fetal monitoring of women at low obstetric risk; these changes were not widespread. Changes in practice were sometimes perceived negatively and sometimes positively. Forming a good relationship with childbearing women was judged to promote effective midwifery care but litigation had affected the ability of a minority of midwives to advocate for women if this relationship had not been established. Litigation could result in loss of confidence leading to self-doubt, isolation, increased readiness to seek medical assistance and avoidance of working in the labour ward, perceived as an area with a high risk of litigation. A blame culture in the NHS was perceived by several midwives. In contrast an open non-punitive culture resulted in midwives readily reporting mistakes to risk managers. Litigation lowered midwifery morale and damaged professional reputations, particularly when reported in the newspapers. Some midwives expressed thoughts of leaving midwifery or taking time off work because of litigation but only one was actively seeking other employment, another took sick leave and one had left midwifery and returned to nursing. KEY CONCLUSIONS: litigation can have a negative effect on midwives' clinical practice and morale and fosters a culture of blame within the NHS. IMPLICATIONS FOR PRACTICE: education regarding appropriate documentation, use or non-use of electronic fetal monitoring and the legal status of clinical guidelines will enable midwives to respond proportionately to the threat of litigation. A culture of openness and sharing the problem when adverse events occur would help to extinguish the current blame culture in the National Health Service. Litigation must be recognised by management as capable of inducing loss of confidence and reluctance to work in the labour ward. Promoting teamwork will help support these midwives. The potential for litigation in maternity care could affect retention of the midwifery workforce. PMID- 26527327 TI - Insights into Pain: A Review of Qualitative Research. AB - Qualitative research exposes and explores important aspects of the pain experience that are inaccessible to other approaches.Qualitative work adopts a different epistemological and ontological perspective to quantitative work.Qualitative research is not well established in the field of pain, but is growing.More interpretative engagement with qualitative data is required. PMID- 26527328 TI - A pyridyl-decorated MOF-505 analogue exhibiting hierarchical porosity, selective CO2 capture and catalytic capacity. AB - An expanded pyridyl-decorated MOF-505 analogue[Cu2(L)(H2O)2].G(x) (H4L = 5,5' (pyridine-2,5-diyl)diisophthalic acid, G = solvent molecule) has been solvothermally synthesized and reported. It exhibited rare hierarchical meso- and microporosity. With exposed unsaturated Cu(II) sites and Lewis basic pyridyl sites, the material shows both large CO2-uptake capacity (123.4 cm(3) g(-1) at 273 K, 1 bar) and high selectivity for CO2 over N2 (55.7) at 273 K. Furthermore, for the first time the compound has been exploited for its heterogeneous catalytic performance toward the cyanosilylation reaction under solvent-free conditions. The compound can be recycled up to five times with only a minor loss of activity. PMID- 26527329 TI - Clinical usefulness of autoantibodies to M-type phospholipase A2 receptor (PLA2R) for monitoring disease activity in idiopathic membranous nephropathy (IMN). AB - Autoantibodies to M-type phospholipase A2 receptor (PLA2R) are specific markers of idiopathic membranous nephropathy (IMN). They can differentiate IMN from other glomerular diseases and primary from secondary forms of MN. Preliminary data suggest that anti-PLA2R antibody titer correlates with disease activity but more solid evidence is needed. To evaluate the performance of anti-PLA2R antibody for monitoring nephropathy activity, 149 anti-PLA2R antibody measurements were performed during the follow-up of 42 biopsy proven IMN consecutive patients. Patients were enrolled either at time of diagnosis (33 cases, inception cohort) or after diagnosis (9 patients, non-inception cohort). Anti-PLA2R detection was performed using the highly sensitive transfected cell-based indirect immunofluorescence (IIFT). Over the follow-up there was a linear time-trend of decreasing proteinuria (P<0.001), increasing serum albumin (P<0.001) and decreasing PLA2R antibody levels (P=0.002). There was a statistically significant association between changes in PLA2R antibody levels and the clinical course of PLA2R-positive IMN. The positive PLA2R serum antibody status was linearly associated with increasing proteinuria and decreasing serum albumin over time, compared with negative antibody status. Moreover, the strong correlation between the clinical conditions and PLA2R antibody levels allowed the prediction of prevalence distribution of patients with active disease, partial and complete remission. Over the course of the follow-up, the probability of halving proteinuria increased 6.5 times after disappearance of PLA2R antibodies. Our data suggest that the serial evaluation of anti-PLA2R antibodies could help in optimal timing and duration of the immunosuppressive therapy, reducing over(under) treatment and associated side-effects. PMID- 26527330 TI - Experimental simulation of decoherence in photonics qudits. AB - We experimentally perform the simulation of open quantum dynamics in single-qudit systems. Using a spatial light modulator as a dissipative optical device, we implement dissipative-dynamical maps onto qudits encoded in the transverse momentum of spontaneous parametric down-converted photon pairs. We show a well controlled technique to prepare entangled qudits states as well as to implement dissipative local measurements; the latter realize two specific dynamics: dephasing and amplitude damping. Our work represents a new analogy-dynamical experiment for simulating an open quantum system. PMID- 26527331 TI - Effect of treadmill exercise on PI3K/AKT/mTOR, autophagy, and Tau hyperphosphorylation in the cerebral cortex of NSE/htau23 transgenic mice. AB - PURPOSE: Neurofibrillary tangles, one of pathological features of Alzheimer's disease, are produced by the hyperphosphorylation and aggregation of tau protein. This study aimed to investigate the effects of treadmill exercise on PI3K/AKT/mTOR signal transmission, autophagy, and cognitive ability that are involved in the hyperphosphorylation and aggregation of tau protein. METHODS: Experimental animals (NSE/htau23 mice) were divided into non-transgenic control group (Non-Tg-Control; CON; n = 7), transgenic control group (Tg-CON; n = 7), and transgenic exercise group (Tg-Treadmill Exercise; TE; n = 7). The Tg-TE group was subjected to treadmill exercise for 12 weeks. After the treadmill exercise was completed, the cognitive ability was determined by conducting underwater maze tests. Western blot was conducted to determine the phosphorylation status of PI3K/AKT/mTOR proteins and autophagy-related proteins (Beclin-1, p62, LC3-B); hyperphosphorylation and aggregation of tau protein (Ser199/202, Ser404, Thr231, PHF-1); and phosphorylation of GSK-3beta, which is involved in the phosphorylation of tau protein in the cerebral cortex of experimental animals. RESULTS: In the Tg-TE group that was subjected to treadmill exercise for 12 weeks, abnormal mTOR phosphorylation of PI3K/AKT proteins was improved via increased phosphorylation and its activity was inhibited by increased GSK-3beta phosphorylation compared with those in the Tg-CON group, which was used as the control group. In addition, the expression of Beclin-1 protein involved in autophagosome formation was increased in the Tg-TE group compared with that in the Tg-CON group, whereas that of p62 protein was reduced in the Tg-TE group compared with that in the Tg-CON group. Autophagy was activated owing to the increased expression of LC3-B that controls the completion of autophagosome formation. The hyperphosphorylation and aggregation (Ser199/202, Ser404, Thr231, PHF-1) of tau protein was found to be reduced in the Tg-TE group compared with that in the Tg-CON group. Furthermore, in the underwater maze test, the Tg-TE group showed a reduced escape time and distance compared with those of the Tg-CON group, suggesting that learning and cognitive ability were improved. CONCLUSION: These findings suggest that aerobic exercise such as treadmill exercise might be an effective approach to ameliorate the pathological features (or neurofibrillary tangles) of Alzheimer's disease. PMID- 26527332 TI - Studies on the effects of zerovalent iron nanoparticles on bacteria from the mangrove ecosystem. AB - Zerovalent iron (ZVI) nanoparticles are gaining popularity in bioremediation of contaminated ground water and antimicrobial studies. In this study, ZVI nanoparticles were synthesized by borohydride method. The effect of these nanoparticles to alter the cell surface hydrophobicity of mangrove bacteria was studied by bacterial adhesion to hydrocarbon assay. The effect of these nanoparticles on the growth and extracellular polymeric substances (EPS) of a novel bacterial strain Halobacillus trueperi MXM-16 from mangroves was evaluated by growing the culture in the presence of ZVI nanoparticles and SEM. The change in the emulsifying ability of the cell-free supernatant of Halobacillus trueperi MXM-16 when grown in media amended with ZVI nanoparticles was also investigated by spectrophotometric analysis. PMID- 26527333 TI - The use of ALS, botanical, and soil data to monitor the environmental hazards and regeneration capacity of areas devastated by highway construction. AB - The impact of viaduct construction on the vegetation of a river valley was studied in Central Poland (Natura 2000 site PLH100006). The research aimed at assessing the suitability of ALS (airborne laser scanning), soil, and botanical data for monitoring the environmental effects of right-of-way reclamation 1 year after the road construction. Based on the data mentioned above, the following problems were identified: changes in topography and hydrological conditions of the valley as a result of improper land levelling, the use of inadequate soil for reclamation, no spontaneous regeneration of natural vegetation along the entire right-of-way, as well as the abundant occurrence of invasive species. The results of analysis were used to define strategies for mitigation of adverse impacts of the viaduct construction. PMID- 26527334 TI - Screening of environmental contaminants in honey bee wax comb using gas chromatography-high-resolution time-of-flight mass spectrometry. AB - This study reports an analytical approach intended to be used for investigation of non-targeted environmental contaminants and to characterize the organic pollution pattern of bee wax comb samples. The method comprises a generic extraction followed by detection with gas chromatography coupled to high resolution time-of-flight mass spectrometry (GC-TOF-MS), operated in electron impact ionization (EI) mode. The screening approach for the investigation of non targeted contaminants consisted of initial peak detection by deconvolution and matching the first-stage mass spectra EI-MS(1) with a nominal mass spectral library. To gain further confidence in the structural characterization of the contaminants under investigation, the molecular formula of representative ions (molecular ion when present in the EI spectrum) and, for at least other two fragment ions, was provided for those with an accurate mass scoring (mass error < 5 ppm). This methodology was applied for screening environmental contaminants in 50 samples of bee wax comb. This approach has allowed the tentative identification of some GC-amenable contaminants belonging to different chemical groups, among them, phthalates and polycyclic aromatic hydrocarbons (PAHs), along with residues of veterinary treatments used in apiculture. PMID- 26527335 TI - Environmental management in North American mining sector. AB - This paper reviews the environmental issues and management practices in the mining sector in the North America. The sustainable measures on waste management are recognized as one of the most serious environmental concerns in the mining industry. For mining activities, it will be no surprise that the metal recovery reagents and acid effluents are a threat to the ecosystem as well as hazards to human health. In addition, poor air quality and ventilation in underground mines can lead to occupational illness and death of workers. Electricity usage and fuel consumption are major factors that contribute to greenhouse gases. On the other hand, many sustainability challenges are faced in the management of tailings and disposal of waste rock. This paper aims to highlight the problems that arise due to poor air quality and acid mine drainage. The paper also addresses some of the advantages and limitations of tailing and waste rock management that still have to be studied in context of the mining sector. This paper suggests that implementation of suitable environmental management tools like life cycle assessment (LCA), cleaner production technologies (CPTs), and multicriteria decision analysis (MCD) are important as it ultimately lead to improve environmental performance and enabling a mine to focus on the next stage of sustainability. PMID- 26527336 TI - Assessment of temporal and spatial differences of source apportionment of nitrate in an urban river in China, using delta(15)N and delta(18)O values and an isotope mixing model. AB - Nitrate contamination in surface water has become an environmental problem widespread concern. In this study, environmental isotopes (delta(15)N-NO3 (-) and delta(18)O-NO3 (-)) and the chemical compositions of water samples from an urban river in Chongqing, China, were analyzed to evaluate the primary sources of nitrate pollution. A Bayesian isotope mixing model was applied to estimate the relative contributions of five potential NO3 (-) sources to river pollution (sewage/manure, soil N, NH4 (+) in fertilizer and precipitation, NO3 (-) fertilizer, and NO3 (-) in precipitation). The results show that the urban river was affected by NO3 (-) pollution from multiple sources. The major sources of NO3 (-) pollution in the dry season were sewage/manure (38-50 %) and soil N (22-26 %); in the wet season, the major sources of NO3 (-) pollution were sewage/manure (30-37 %), soil N (16-25 %), and precipitation (14-24 %). The higher contribution of N to the river water by precipitation indicates that atmospheric N deposition has become an important source of pollution in surface water in China. We conclude that domestic sewage is still the main contributor to NO3 (-) pollution in urban rivers in China. The discharge of domestic sewage into rivers should be prohibited as a priority measure to prevent NO3 (-) contamination. PMID- 26527337 TI - Changes of lead speciation and microbial toxicity in soil treated with repeated Pb exposure in the presence of BDE209. AB - Lead (Pb) and decabromodiphenyl ether (BDE209) are main pollutants at electric waste (e-waste) recycling sites (EWRSs), and their joint toxicological effects have received extensive attention. Frequently, soil pollution at EWRSs usually results from the occurrence of repeated single or multiple pollution events, with continuous impacts on soil microorganisms. Therefore, a laboratory incubation study was conducted to determine Pb bioavailability and microbial toxicity in repeated Pb-polluted soil in the presence of BDE209 for the first time. We evaluated the impacts of repetitive exposure trials on chemical fractions of Pb, and the results showed that repeated single Pb pollution event resulted in an increase of carbonates fraction of Pb, which was different from one-off single Pb exposure. Moreover, one-off Pb-treated groups exhibited higher I R (reduced partition index) values on day 30 and all treatments remained the same I R level at the end of incubation period. The parameters of microbial toxicity were well reflected by soil enzymes. During the entire incubation, the dehydrogenase and urease activities were significantly inhibited by Pb (P < 0.01), and BDE209 supply could weaken the adverse influence. Additionally, significant correlations between available or metastable Pb and the two soil enzymes were clearly observed (P < 0.05 or 0.01). Such observations would provide useful information for ecological effects of Pb and BDE209 at EWRSs. PMID- 26527338 TI - Effects of surfactants on low-molecular-weight organic acids to wash soil zinc. AB - Soil washing is an effective approach to the removal of heavy metals from contaminated soil. In this study, the effects of the surfactants sodium dodecyl sulfate, Triton X-100, and non-ionic polyacrylamide (NPAM) on oxalic acid, tartaric acid, and citric acid used to remove zinc from contaminated soils were investigated. The Zn removal efficiencies of all washing solutions showed a logarithmic increase with acid concentrations from 0.5 to 10.0 g/L, while they decreased as pH increased from 4 to 9. Increasing the reaction time enhanced the effects of surfactants on Zn removal efficiencies by the acids during washing and significantly (P < 0.05) improved the removal under some mixed cases. Oxalic acid suffered antagonistic effects from the three surfactants and seriously damaged soil nutrients during the removal of soil Zn. Notably, the three surfactants caused synergistic effects on tartaric and citric acid during washing, with NPAM leading to an increase in Zn removal by 5.0 g/L citric acid of 10.60 % (P < 0.05) within 2 h. NPAM also alleviated the loss of cation exchange capacity of washed soils and obviously improved soil nitrogen concentrations. Overall, combining citric acid with NPAM offers a promising approach to the removal of zinc from contaminated soil. PMID- 26527339 TI - Soil quality assessment of urban green space under long-term reclaimed water irrigation. AB - Reclaimed water is widely used for landscape irrigation with the benefits of saving fresh water and ameliorating soil quality. Field samples were collected from seven parks in Beijing irrigated reclaimed water with different irrigation history in 2011 and 2014 to evaluate the long-term impacts of reclaimed water irrigation on soil quality. Soil quality index method was used to assess the comprehensive effects of reclaimed water irrigation on soil. Results showed that the effects of reclaimed water irrigation on the soil nutrient conditions were limited. Compared with tap water irrigation, soil salinity was significantly higher in 2011, while the difference was insignificant in 2014; soil heavy metals were slightly higher by 0.5-10.6 % in 2011 and 2014, while the differences were insignificant. Under reclaimed water irrigation, soil biological activities were significantly improved in both years. Total nitrogen in reclaimed water had a largest effect on soil quality irrigated reclaimed water. Soil quality irrigated with reclaimed water increased by 2.6 and 6.8 % respectively in 2011 and 2014, while the increases were insignificant. Soil quality of almost half samples was more than or closed to soil quality of natural forest in Beijing. Soil quality was ameliorated at some extent with long-term reclaimed water irrigation. PMID- 26527340 TI - Ammonium removal of drinking water at low temperature by activated carbon filter biologically enhanced with heterotrophic nitrifying bacteria. AB - We sought to confirm whether use of Acinetobacter strains Y7 and Y16, both strains of heterotrophic nitrifying bacteria, was practical for removing ammonium (NH4 (+)-N) from drinking water at low temperatures. To test this, ammonium containing drinking water was treated with strains Y7 and Y16 at 8 and 2 degrees C. Continuous ammonium treatment was conducted in order to evaluate the performance of three biologically enhanced activated carbon (BEAC) filters in removing ammonium. The three BEAC filters were inoculated with strain Y7, strain Y16, and a mixture of strains Y7 and Y16, respectively. A granular activated carbon (GAC) filter, without inoculation by any strains, was tested in parallel with the BEAC filters as control. The results indicated that NH4 (+)-N removal was significant when a BEAC filter was inoculated with the mixture of strains Y7 and Y16 (BEAC-III filter). Amounts of 0.44 +/- 0.05 and 0.25 +/- 0.05 mg L(-1) NH4 (+)-N were removed using the BEAC-III filter at 8 and 2 degrees C, respectively. These values were 2.8-4.0-fold higher than the values of ammonium removal acquired using the GAC filter. The synergistic effect of using strains Y7 and Y16 in concert was the cause of the high-ammonium removal efficiency achieved by using the BEAC-III filter at low temperatures. In addition, a high C/N ratio may promote NH4 (+)-N removal efficiency by improving biomass and microbial activity. This study provides new insight into the use of biofilters to achieve biological removal of ammonium at low temperature. PMID- 26527341 TI - Effect of clay nanoparticles on model lung surfactant: a potential marker of hazard from nanoaerosol inhalation. AB - This work investigates influence of different aluminosillicate nanoparticles (NPs) which are found in air in selected workplaces on the properties of the phospholipid (DPPC) monolayer at air-saline interface considered as ex vivo model of the lung surfactant (LS). The measurements were done under physiological-like conditions (deformable liquid interface at 37 degrees C) for NP concentrations matching the calculated lung doses after exposure in the working environment. Measured surface pressure-area (pi-A) isotherms and compressibility curves demonstrated NP-induced changes in the structure and mechanical properties of the lipid monolayer. It was shown that hydrophilic nanomaterials (halloysite and bentonite) induced concentration-dependent impairment of DPPC's ability of attaining high surface pressures on interfacial compression, suggesting a possibility of reduction of physiological function of natural LS. Hydrophobic montmorillonites affected DPPC monolayer in the opposite way; however, they significantly changed the mechanical properties of the air-liquid interface during compression. The results support the hypothesis of possible reduction or even degradation of the natural function of the lung surfactant induced by particle-phospholipid interactions after inhalation of nanoclays. Presented data do not only supplement the earlier results obtained with another LS model (animal derived surfactant in oscillating bubble experiments) but also offer an explanation of physicochemical mechanisms responsible for detrimental effects which arise after deposition of inhaled nanomaterials on the surface of the respiratory system. PMID- 26527342 TI - Constructed wetlands as sustainable ecotechnologies in decentralization practices: a review. AB - Recently, a range of novel and cost-effective engineered wetland technologies for decentralization practices of domestic wastewater treatment have been developed with ecological process modification, the use of functionalized plants, and advanced biofilm formation. However, selecting the one that can be more appreciated for on-site sanitation is still uncertain. This paper reviews the role of plants, media materials, microorganisms, and oxygen transfer in domestic wastewater purification through constructed wetlands (CWs). The effectiveness of traditional and recently developed CWs and the necessity of an induced biofilm attachment surface (BAS) in these systems for the treatment of domestic sewage are presented. This review also elucidates the idea of CWs for domestic wastewater characteristics highly stressed by total dissolved solids and the adaptive strategies in mitigating the cold climate impacts on their efficiencies. Further research needed to enhance the stability and sustainability of CWs is highlighted. By a more advanced investigation, BAS CWs can be specified as an ideal treatment process in decentralization. PMID- 26527343 TI - An analysis of the impact on land use and ecological vulnerability of the policy of returning farmland to forest in Yan'an, China. AB - During the past decades, land use change has taken place around the Loess Plateau at unprecedented rates. Due to the impact of existing land use policy, great changes have taken place in the land use types in this ecologically vulnerable area. Taking eight counties in Yan'an, Shaanxi province, China, as the study area, this study analyzed the long-term (from 1997 to 2011) changes in land use and ecological vulnerability. Based on thematic mapper (TM) images of Yan'an in 1997, 2004, and 2011, the dynamic changes in land use are analyzed with the application software for remote sensing (RS) and geographic information system (GIS) since the implementation of the policy of returning farmland to forest. Combined with the land use data, the local socio-economic data, and natural resources condition, ecological vulnerability is evaluated using the spatial principal component analysis (SPCA) model in Yan'an region. Using the natural breaks classification (NBC), the evaluation results are divided into five categories: potential, slight, light, medium, and heavy. The results show that although the regional land use types changed markedly, the ecological vulnerability in the study shows greater than average optimism, and the ecological vulnerability index of the southern four counties is lower than that of the northern four counties. In 1997-2011, the eco-environmental quality gradually improved in most areas. However, it gradually deteriorated in some regions. PMID- 26527344 TI - Farm and product carbon footprints of China's fruit production--life cycle inventory of representative orchards of five major fruits. AB - Understanding the environmental impacts of fruit production will provide fundamental information for policy making of fruit consumption and marketing. This study aims to characterize the carbon footprints of China's fruit production and to figure out the key greenhouse gas emissions to cut with improved orchard management. Yearly input data of materials and energy in a full life cycle from material production to fruit harvest were obtained via field visits to orchards of five typical fruit types from selected areas of China. Carbon footprint (CF) was assessed with quantifying the greenhouse gas emissions associated with the individual inputs. Farm and product CFs were respectively predicted in terms of land use and of fresh fruit yield. Additionally, product CFs scaled by fruit nutrition value (vitamin C (Vc) content) and by the economic benefit from fruit production were also evaluated. The estimated farm CF ranged from 2.9 to 12.8 t CO2-eq ha(-1) across the surveyed orchards, whereas the product CF ranged from 0.07 to 0.7 kg CO2-eq kg(-1) fruit. While the mean product CFs of orange and pear were significantly lower than those of apple, banana, and peach, the nutrition scaled CF of orange (0.5 kg CO2-eq g(-1) Vc on average) was significantly lower than others (3.0-5.9 kg CO2-eq g(-1) Vc). The income-scaled CF of orange and pear (1.20 and 1.01 kg CO2-eq USD(-1), respectively) was higher than apple, banana, and peach (0.87~0.39 kg CO2-eq USD(-1)). Among the inputs, synthetic nitrogen fertilizer contributed by over 50 % to the total greenhouse gas (GHG) emissions, varying among the fruit types. There were some tradeoffs in product CFs between fruit nutrition value and fruit growers' income. Low carbon production and consumption policy and marketing mechanism should be developed to cut down carbon emissions from fruit production sector, with balancing the nutrition value, producer's income, and climate change mitigation. PMID- 26527345 TI - How to measure the agroecological performance of farming in order to assist with the transition process. AB - The use of plant protection products enables farmers to maximize economic performance and yields, but in return, the environment and human health can be greatly affected because of their toxicity. There are currently strong calls for farmers to reduce the use of these toxic products for the preservation of the environment and the human health, and it has become urgent to invest in more sustainable models that help reduce these risks. One possible solution is the transition toward agroecological production systems. These new systems must be beneficial economically, socially, and environmentally in terms of human health. There are many tools available, based on a range of indicators, for assessing the sustainability of agricultural systems on conventional farm holdings. These methods are little suitable to agroecological farms and do not measure the performance of agroecological transition farms. In this article, we therefore develop a model for the strategic definition, guidance, and assistance for a transition to agroecological practices, capable of assessing performance of this transition and simulating the consequences of possible changes. This model was built by coupling (i) a decision-support tool and a technico-economic simulator with (ii) a conceptual model built from the dynamics of agroecological practices. This tool is currently being tested in the framework of a Compte d'Affectation Speciale pour le Developpement Agricole et Rural (CASDAR) project (CASDAR: project launched in 2013 by the French Ministry of Agriculture, Food and Forestry, on the theme "collective mobilisation for agroecology," http://agriculture.gouv.fr/Appel-a-projets-CASDAR ) using data from farms, most of which are engaged in agroenvironmental process and reducing plant protection treatments since 2008. PMID- 26527346 TI - A method for monitoring mass concentration of black carbon particulate matter using photothermal interferometry. AB - A method for measurements of mass concentration of black carbon particulate matter (PM) is proposed based on photothermal interferometry (PTI). A folded Jamin photothermal interferometer was used with a laser irradiation of particles deposited on a filter paper. The black carbon PM deposited on the filter paper was regarded as a film while the quartz filter paper was regarded as a substrate to establish a mathematical model for measuring the mass concentration of PM using a photothermal method. The photothermal interferometry system was calibrated and used to measure the atmospheric PM concentration corresponding to different dust-treated filter paper. The measurements were compared to those obtained using beta ray method and were found consistent. This method can be particularly relevant to polluted atmospheres where PM is dominated by black carbon. PMID- 26527347 TI - Is rapid growth in Internet usage environmentally sustainable for Australia? An empirical investigation. AB - This study estimates the short- and long-run effects of Internet usage and economic growth on carbon dioxide (CO2) emissions using annual time series macro data for Australia for the period 1985-2012. Autoregressive distributive lag (ARDL) bounds and Gregory-Hansen structural break cointegration tests are applied. ARDL estimates indicate no significant long-run relationship between Internet usage and CO2 emissions, which implies that the rapid growth in Internet usage is still not an environmental threat for Australia. The study further indicates that higher level of economic growth is associated with lower level of CO2 emissions; however, Internet usage and economic growth have no significant short-run relationship with CO2 emissions. Financial development has both short run and long-run significant positive association with CO2 emissions. The findings offer support in favor of energy efficiency gains and a reduction in energy intensity in Australia. However, impulse response and variance decomposition analysis suggest that Internet usage, economic growth and financial development will continue to impact CO2 emissions in the future, and as such, this study recommends that in addition to the existing measures to combat CO2 emissions, Australia needs to exploit the potential of the Internet not only to reduce its own carbon footprint but also to utilize information and communication technology (ICT)-enabled emissions abatement potential to reduce emissions in various other sectors across the economy, such as, power, renewable energy especially in solar and wind energy, agriculture, transport and service. PMID- 26527348 TI - Visual evoked potentials in subgroups of migraine with aura patients. AB - BACKGROUND: Patients suffering from migraine with aura can have either pure visual auras or complex auras with sensory disturbances and dysphasia, or both. Few studies have searched for possible pathophysiological differences between these two subgroups of patients. METHODS: Methods - Forty-seven migraine with aura patients were subdivided in a subgroup with exclusively visual auras (MA, N = 27) and another with complex neurological auras (MA+, N = 20). We recorded pattern-reversal visual evoked potentials (VEP: 15 min of arc cheques, 3.1 reversal per second, 600 sweeps) and measured amplitude and habituation (slope of the linear regression line of amplitude changes from the 1st to 6th block of 100 sweeps) for the N1-P1 and P1-N2 components in patients and, for comparison, in 30 healthy volunteers (HV) of similar age and gender distribution. RESULTS: VEP N1 P1 habituation, i.e. amplitude decrement between 1st and 6th block, which was obvious in most HV (mean slope -0.50), was deficient in both MA (slope +0.01, p = 0.0001) and MA+ (-0.0049, p = 0.001) patients. However, VEP N1-P1 amplitudes across blocks were normal in MA patients, while they were significantly greater in MA+ patients than in HVs. CONCLUSIONS: Our findings suggest that in migraine with aura patients different aura phenotypes may be underpinned by different pathophysiological mechanisms. Pre-activation cortical excitability could be higher in patients with complex neurological auras than in those having pure visual auras or in healthy volunteers. PMID- 26527349 TI - Subclinical vestibular dysfunction in migraine patients: a preliminary study of ocular and rectified cervical vestibular evoked myogenic potentials. AB - BACKGROUND: Many studies have identified various vestibular symptoms and laboratory abnormalities in migraineurs. Although the vestibular tests may be abnormal, the changes may exist without vestibular symptoms. To date, vestibular evoked myogenic potential (VEMP) has been the easiest and simplest test for measuring vestibular function in clinical practice. Cervical VEMP (cVEMP) represents a vestibulo-collic reflex, whereas ocular VEMP (oVEMP) reflects a vestibulo-ocular pathway. Therefore, we determined whether ocular and rectified cervical VEMPs differed in patients with migraine or tension type headache (TTH) and compared the results to controls with no accompanying vestibular symptoms. METHODS: The present study included 38 females with migraine without aura, 30 with episodic TTH, and 50 healthy controls without vestibular symptoms. oVEMP and cVEMP using a blood pressure manometer were recorded during a headache-free period. From the VEMP graphs, latency and amplitude parameters were analyzed, especially following EMG rectification in cVEMP. RESULTS: With respect to oVEMP, the migraine group exhibited significantly longer mean latencies of bilateral n1 and left p1 than the other groups (p < 0.05). Amplitudes of n1-p1 were lower than in other groups, but the difference did not reach statistical significance. In regards to cVEMP, p13 and n23 latencies and amplitudes after rectification did not differ significantly among groups. CONCLUSIONS: An abnormal interictal oVEMP profile was associated with subclinical vestibular dysfunction in migraineurs, suggesting pathology within the vestibulo-ocular reflex. oVEMP is a more reliable measure than cVEMP to evaluate vestibular function in migraineurs, although results from the two tests in patients with migraine are complementary. PMID- 26527350 TI - New Biomaterials in Drug Delivery and Wound Care. PMID- 26527351 TI - Toward an evolutionary-predictive foundation for creativity : Commentary on "Human creativity, evolutionary algorithms, and predictive representations: The mechanics of thought trials" by Arne Dietrich and Hilde Haider, 2014 (Accepted pending minor revisions for publication in Psychonomic Bulletin & Review). AB - Dietrich and Haider (Psychonomic Bulletin & Review, 21 (5), 897-915, 2014) justify their integrative framework for creativity founded on evolutionary theory and prediction research on the grounds that "theories and approaches guiding empirical research on creativity have not been supported by the neuroimaging evidence." Although this justification is controversial, the general direction holds promise. This commentary clarifies points of disagreement and unresolved issues, and addresses mis-applications of evolutionary theory that lead the authors to adopt a Darwinian (versus Lamarckian) approach. To say that creativity is Darwinian is not to say that it consists of variation plus selection - in the everyday sense of the term - as the authors imply; it is to say that evolution is occurring because selection is affecting the distribution of randomly generated heritable variation across generations. In creative thought the distribution of variants is not key, i.e., one is not inclined toward idea A because 60 % of one's candidate ideas are variants of A while only 40 % are variants of B; one is inclined toward whichever seems best. The authors concede that creative variation is partly directed; however, the greater the extent to which variants are generated non-randomly, the greater the extent to which the distribution of variants can reflect not selection but the initial generation bias. Since each thought in a creative process can alter the selective criteria against which the next is evaluated, there is no demarcation into generations as assumed in a Darwinian model. We address the authors' claim that reduced variability and individuality are more characteristic of Lamarckism than Darwinian evolution, and note that a Lamarckian approach to creativity has addressed the challenge of modeling the emergent features associated with insight. PMID- 26527352 TI - Revascularization heart team recommendations as an adjunct to appropriate use criteria for coronary revascularization in patients with complex coronary artery disease. AB - OBJECTIVES: To evaluate how a comprehensive evidence-based clinical review by a multidisciplinary revascularization heart team on treatment decisions for revascularization in patients with complex coronary artery disease using SYNTAX scores combined with Society of Thoracic Surgeons-derived clinical variables can be additive to the utilization of Appropriate Use Criteria for coronary revascularization. BACKGROUND: Decision-making regarding the use of revascularization for coronary artery disease has come under major scrutiny due to inappropriate overuse of revascularization. There is little data in routine clinical practice evaluating how a structured, multidisciplinary heart team approach may be used in combination with the Appropriate Use Criteria for revascularization. METHODS: From May 1, 2012 to January 1, 2015, multidisciplinary revascularization heart team meetings were convened to discuss evidence-based management of 301 patients with complex coronary artery disease. Heart team recommendations were adjudicated with the Appropriate Use Criteria for coronary revascularization for each clinical scenario using the Society for Cardiovascular Angiography and Interventions' Quality Improvement Toolkit (SCAI QIT) Appropriate Use Criteria App. RESULTS: Concordance of the Heart Team to Appropriate Use Criteria had a 99.3% appropriate primary indication for coronary revascularization. Among patients who underwent percutaneous revascularization, 34.9% had an inappropriate or uncertain indication as recommended by the Heart Team. Patients with uncertain or inappropriate percutaneous coronary interventions had significantly higher SYNTAX score (27.3 +/- 6.6; 28.5 +/- 5.5; 19.2 +/- 6; P < 0.0001) and Society of Thoracic Surgeons-Predicted Risk of Mortality (6.1% +/- 4.7%; 8.1% +/- 6.3%; 3.7% +/- 4.1%; P < 0.0081) compared to appropriate indications, frequently had concomitant forms of advanced comorbidities and frailty in the setting of symptomatic coronary artery disease. CONCLUSIONS: A formal, multidisciplinary revascularization heart team can provide proper validation for clinical decisions and should be considered in combination with the Appropriate Use Criteria for coronary revascularization to formulate revascularization strategies for individuals in a patient-centered fashion. (c) 2015 Wiley Periodicals, Inc. PMID- 26527353 TI - Working with Musculoskeletal Pain. AB - Pain has a significant impact on work in terms of presenteeism, sickness absence, and long-term incapacity for workA bio-psychosocial approach is required in understanding pain-related disability and incapacity for workLong-term absence from work is associated with a number of negative outcomes including; poverty, social exclusion and poorer physical and psychosocial well-beingReturn to work can improve recovery for people with musculoskeletal complaints and painInterventions to reduce the impact of pain on work can operate at clinical, worker, workplace, and wider systems levelsA broader whole systems approach to pain management needs to be adopted, with a greater focus on work retention as well as rehabilitation. PMID- 26527354 TI - Orofacial Pain Multiple Choice Questions. PMID- 26527355 TI - Pleural effusions in children from Southern Brazil. AB - Parapneumonic pleural effusions (PPE) are a relatively common (5-40%) complication of paediatric pneumonia. However, in clinical practice the majority of the effusions are small and do not need any further investigation or specific treatment apart from antibiotic therapy. A small number require drainage or surgical intervention. Rarely, significant effusions are associated with non bacterial pneumonia in the paediatric population. Pleural tuberculosis in our hospital is the second highest cause of pleural effusions related to the high incidence of TB in our city. In the last 3 years we have had around 50 cases of pleural TB in children. PMID- 26527356 TI - Research is the Future, the Future is....... AB - Over the past two decades, Professor Lenney has established the Paediatric Respiratory Department at the Royal Stoke University Hospital as a centre recognised for high quality research. A broad portfolio of clinical and laboratory based research is in progress. Four research areas are discussed that are likely to contribute to the continued academic output from the unit. These are the use of selected ion flow tube mass spectrometry for the detection of biomarkers associated with pulmonary pathogens, the measurement of lung clearance index in preschool children, structured light plethysmography in children and the use of oral prednisolone for asthma exacerbations in children. PMID- 26527357 TI - Poetry, Music, Writing and Painting; Developing the artistic talents of Adults with Cystic Fibrosis. AB - Art is an expressive outlet for the physical limitations and emotional frustrations of living with a life limiting condition such cystic fibrosis. In the Manchester Adult Cystic Fibrosis Centre we have facilitated the sharing of the inherent artistic talent of our patients with the support of painters, musicians, potters, creative writers, photographers and textile specialists and our own ward staff in our dedicated 22 bed CF inpatient unit. The programme has provided some splendid works that enliven our ward and, more importantly, continue to inspire our patients as they attempt to overcome the socially limiting consequences of hospital admission. PMID- 26527358 TI - Ventilator Associated Pneumonia in Children. AB - Ventilator associated pneumonia (VAP) is a common complication in mechanically ventilated children and adults. There remains much controversy in the literature over the definition, treatment and prevention of VAP. The incidence of VAP is variable, depending on the definition used and can effect up to 12% of ventilated children. For the prevention and reduction of the incidence of VAP, ventilation care bundles are suggested, which include vigorous hand hygiene, head elevation and use of non-invasive ventilation strategies. Diagnosis is mainly based on the clinical presentation with a lung infection occurring after 48hours of mechanical ventilation requiring a change in ventilator settings (mainly increased oxygen requirement, a positive culture of a specimen taken preferentially using a sterile sampling technique either using a bronchoscope or a blind lavage of the airways). A new infiltrate on a chest X ray supports the diagnosis of VAP. For the treatment of VAP, initial broad-spectrum antibiotics should be used followed by a specific antibiotic therapy with a narrow target once the bacterium is confirmed. PMID- 26527359 TI - Cystic Fibrosis Nutrition--Chewing the Fat. AB - Survival data for successive birth cohorts of cystic fibrosis infants born in the twentieth century have shown consistent improvements. More recent UK and US data suggest a plateau in improvements for clinically relevant outcomes. Better treatment of malnutrition has arguably been the most important advance in CF care, but despite this nearly a half of the UK CF population has a sub-optimal BMI. Nutritional decline typically occurs in late childhood and early adult life. Addressing poor adherence and more targeted multi-disciplinary interventions to prevent or reverse this pattern are key to achieving better outcomes for CF patients in the future. PMID- 26527360 TI - Elevated plasma aldosterone is an independent risk factor for erectile dysfunction in men. AB - INTRODUCTION: Erectile dysfunction (ED) and cardiovascular disease (CVD) share a great number of common risk factors. There is growing evidence that aldosterone, an independent CVD risk factor, is associated with ED. AIMS: The purpose of this study was to determine the relationship between plasma aldosterone and erectile dysfunction. METHODS: This study recruited 287 participants, ranging from 18 to 84 years old; 217 were suffering from ED, diagnosed by the International Index of Erectile Function 5 (IIEF-5) scores. Based on IIEF-5 scores, patients were divided into one control group and three ED groups (mild ED; moderate ED; severe ED). MAIN OUTCOME MEASURES: The differences in principal characteristics, blood routine, sexual hormone, adrenal hormone, thyroid hormone, renal function, liver function and blood lipid were compared between ED and control groups. RESULTS: Our study demonstrated that the difference of mean plasma aldosterone levels between ED group and the control group was statistically significant (P < 0.05). Stepwise logistic regression analysis of all the possible factors support the role of aldosterone as an independent risk factor for ED (OR 1.011; 95 % CI 1.003 1.018; P = 0.004). Similar statistical methods were applied to the comparison between moderate to severe ED group and control to mild ED group (OR 1.017; 95 % CI 1.009-1.024; P < 0.001). ROC curve and the area under the curve (0.718; 95 % CI 0.643-0.794; P < 0.001) were performed to assess the diagnostic effect and to compare the severity of risk with the known independent risk factors, such as age and cholesterol (0.704; 95 % CI 0.631-0.778; P < 0.001). When using a 374 pg/mL cut-off value from Youden index, the OR of ED group versus controls is 3.106 (95 % CI 1.458-6.617), while the OR of moderate to severe ED versus control and mild ED is 5.480 (95 % CI 3.108-9.662). CONCLUSIONS: We determined that elevated plasma aldosterone concentration is an independent risk factor for ED. Our findings also indicate that the aldosterone, a well-recognized contributor to vascular injury, might be a potential bond between ED and CVD. PMID- 26527361 TI - Repetitive Hypershear Activates and Sensitizes Platelets in a Dose-Dependent Manner. AB - Implantation of mechanical circulatory support (MCS) devices-ventricular assist devices and the total artificial heart-has emerged as a vital therapy for advanced and end-stage heart failure. Unfortunately, MCS patients face the requirement of life-long antiplatelet and anticoagulant therapy to combat thrombotic complications resulting from the dynamic and supraphysiologic shear stress conditions associated with such devices, whose effect on platelet activation is poorly understood. We developed a syringe-capillary viscometer-the "platelet hammer"-that repeatedly exposed platelets to average shear stresses up to 1000 dyne/cm(2) for as short as 25 ms. Platelet activation state was measured using a modified prothrombinase assay, with morphological changes analyzed using scanning electron microscopy. We observed an increase in platelet activation state and post-high shear platelet activation rate, or sensitization, with an increase in stress accumulation (SA), the product of shear stress and exposure time. A significant increase in platelet activation state was observed beyond an SA of 1500 dyne-s/cm(2) , with a marked increase in pseudopod length visible beyond an SA of 1000 dyne-s/cm(2) . Utility of the platelet hammer extends to studies of other shear-dependent pathologies, and may assist development of approaches to enhance the safety and effectiveness of MCS devices and objective antithrombotic pharmacotherapy management. PMID- 26527362 TI - Comparison of Repellency Effect of Mosquito Repellents for DEET, Citronella, and Fennel Oil. AB - To confirm that Korean Food and Drug Administration (KFDA) guidelines are applicable to test the efficacy of mosquito repellents, these guidelines were used to test the efficacy and complete protection times (CPTs) of three representative mosquito repellents: N,N-diethyl-3-methylbenzamide (DEET), citronella, and fennel oil. The repellency of citronella oil decreased over time, from 97.9% at 0 h to 71.4% at 1 h and 57.7% at 2 h, as did the repellency of fennel oil, from 88.6% at 0 h to 61.2% at 1 h and 47.4% at 2 h. In contrast, the repellency of DEET remained over 90% for 6 h. The CPT of DEET (360 min) was much longer than the CPTs of citronella (10.5 min) and fennel oil (8.4 min). These results did not differ significantly from previous findings, and hence confirm that the KFDA guidelines are applicable for testing the efficacy of mosquito repellents. PMID- 26527363 TI - Maternal Betaine Supplementation during Gestation Enhances Expression of mtDNA Encoded Genes through D-Loop DNA Hypomethylation in the Skeletal Muscle of Newborn Piglets. AB - Betaine has been widely used in animal and human nutrition to promote muscle growth and performance, yet it remains unknown whether maternal betaine supplementation during gestation affects the metabolic characteristics of neonatal skeletal muscles. In the present study, feeding sows with betaine supplemented diets throughout gestation significantly upregulated the expression of mtDNA-encoded OXPHOS genes (p < 0.05), including COX1, COX2, and ND5, in the muscle of newborn piglets, which was associated with enhanced mitochondrial COX enzyme activity (p < 0.05). Concurrently, maternal betaine supplementation increased the plasma betaine concentration and muscle expression of methyl transfer enzymes (p < 0.05), BHMT and GNMT, in offspring piglets. Nevertheless, Dnmt3a was downregulated at the level of both mRNA and protein, which was associated with a hypomethylated mtDNA D-loop region (p < 0.05). These results suggest that maternal betaine supplementation during gestation enhances expression of mtDNA-encoded genes through D-loop DNA hypomethylation in the skeletal muscle of newborn piglets. PMID- 26527364 TI - Enzymatic Synthesis of Nucleic Acids with Defined Regioisomeric 2'-5' Linkages. AB - Information-bearing nucleic acids display universal 3'-5' linkages, but regioisomeric 2'-5' linkages occur sporadically in non-enzymatic RNA synthesis and may have aided prebiotic RNA replication. Herein we report on the enzymatic synthesis of both DNA and RNA with site-specific 2'-5' linkages by an engineered polymerase using 3'-deoxy- or 3'-O-methyl-NTPs as substrates. We also report the reverse transcription of the resulting modified nucleic acids back to 3'-5' linked DNA with good fidelity. This enables a fast and simple method for "structural mutagenesis" by the position-selective incorporation of 2'-5' linkages, whereby nucleic acid structure and function may be probed through local distortion by regioisomeric linkages while maintaining the wild-type base sequence as we demonstrate for the 10-23 RNA endonuclease DNAzyme. PMID- 26527365 TI - Sulcus vocalis: A new clinical paradigm based on a re-evaluation of histology. AB - OBJECTIVES/HYPOTHESIS: Sulcus vocalis is an epithelial invagination adherent to deep tissues of the vocal fold. Traditionally, dysphonia is believed to result from attenuation or absence of lamina propria and consequent alteration of mucosal dynamics. This conception does not account for several clinical features of the lesion, most notably inflammation. The goal of this study is to elucidate the clinical nature of sulcus by re-examination of its histopathology. STUDY DESIGN: Retrospective review. METHODS: Clinical features, including stroboscopic examination, and hematoxylin and eosin sections of 19 lesions in 15 patients who underwent surgery were reviewed. RESULTS: Epithelial change was found uniformly in all specimens, consisting of parakeratosis (78.9%), epithelial thickening (77.8%), dyskeratosis (63.2%), basement membrane thickening (47%), epithelial inflammation (52.6%), and retention of keratin debris (36.8%). In contrast, submucosal findings were less prevalent. Seven patients (36.8%) had essentially normal subepithelial tissues. Submucosal inflammation was present in seven (36.8%), and other submucosal changes in four of 17 (23.5%). Clinical characteristics demonstrated general improvement after surgical intervention in most cases. CONCLUSIONS: Sulcus vocalis appears to have an important component of epithelial pathology, with especially high prevalence of parakeratosis, dyskeratosis, and epithelial thickening. Clinical changes may result from prominent perilesional inflammation related to epithelial changes instead of or in addition to any alteration of the lamina propria. Surgical treatment, when necessary, should refocus on removal of pathologic epithelium as a source of inflammation independent of reconstructive considerations. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1397-1403, 2016. PMID- 26527366 TI - Resampling methods in Microsoft Excel(r) for estimating reference intervals. AB - Computer-intensive resampling/bootstrap methods are feasible when calculating reference intervals from non-Gaussian or small reference samples. Microsoft Excel(r) in version 2010 or later includes natural functions, which lend themselves well to this purpose including recommended interpolation procedures for estimating 2.5 and 97.5 percentiles. ?The purpose of this paper is to introduce the reader to resampling estimation techniques in general and in using Microsoft Excel(r) 2010 for the purpose of estimating reference intervals in particular.? Parametric methods are preferable to resampling methods when the distributions of observations in the reference samples is Gaussian or can transformed to that distribution even when the number of reference samples is less than 120. Resampling methods are appropriate when the distribution of data from the reference samples is non-Gaussian and in case the number of reference individuals and corresponding samples are in the order of 40. At least 500-1000 random samples with replacement should be taken from the results of measurement of the reference samples. PMID- 26527367 TI - Immunoproteasomes edit tumors, which then escapes immune recognition. AB - In 1985, John Monaco--the discoverer of LMP-2 and -7, the inducible components of the immunoproteasome--asked his advanced immunology class as to why the MHC region contained not only structural genes, but several others as well, whose functions were then unknown. As we drew a blank, he quipped: perchance because many of the MHC genes are induced by IFN-gamma! The ensuing three decades have witnessed the unveiling of the profound fundamental and clinical implications of that classroom tete-a-tete. Amongst its multitudinous effects, IFN-gamma induces genes enhancing antigen processing and presentation to T cells; such as those encoding cellular proteases and activators of proteases. In this issue, Keller et al. [Eur. J. Immunol. 2015. 45: 3257-3268] demonstrate that the limited success of MART-1/Melan-A-targeted immunotherapy in melanoma patients could be due to inefficient MART-1(26-35) presentation, owing to the proteolytic activities of IFN-gamma-inducible beta2i/MECL-1, proteasome activator 28 (PA28), and endoplasmic reticulum-associated aminopeptidase-associated with antigen processing (ERAP). Specifically, whilst beta2i and PA28 impede MART-1(26-35) liberation from its precursor protein, ERAP-1 degrades this epitope. Hence, critical to effective cancer immunotherapy is deep knowledge of T-cell-targeted tumor antigens and how cellular proteases generate protective epitope(s) from them, or destroy them. PMID- 26527368 TI - Relevant pH and lipase for in vitro models of gastric digestion. AB - The development of in vitro digestion models relies on the availability of in vivo data such as digestive enzyme levels and pH values recorded in the course of meal digestion. The variations of these parameters along the GI tract are important for designing dynamic digestion models but also static models for which the choice of representative conditions of the gastric and intestinal conditions is critical. Simulating gastric digestion with a static model and a single set of parameters is particularly challenging because the variations in pH and enzyme concentration occurring in the stomach are much broader than those occurring in the small intestine. A review of the literature on this topic reveals that most models of gastric digestion use very low pH values that are not representative of the fed conditions. This is illustrated here by showing the variations in gastric pH as a function of meal gastric emptying instead of time. This representation highlights those pH values that are the most relevant for testing meal digestion in the stomach. Gastric lipolysis is still largely ignored or is performed with microbial lipases. In vivo data on gastric lipase and lipolysis have however been collected in humans and dogs during test meals. The biochemical characterization of gastric lipase has shown that this enzyme is rather unique among lipases: (i) stability and activity in the pH range 2 to 7 with an optimum at pH 4-5.4; (ii) high tensioactivity that allows resistance to bile salts and penetration into phospholipid layers covering TAG droplets; (iii) sn-3 stereospecificity for TAG hydrolysis; and (iv) resistance to pepsin. Most of these properties have been known for more than two decades and should provide a rational basis for the replacement of gastric lipase by other lipases when gastric lipase is not available. PMID- 26527369 TI - Using the IRB Researcher Assessment Tool to Guide Quality Improvement. AB - Institutional Review Boards (IRBs) are intended to protect those who participate in research. However, because there is no established measure of IRB quality, it is unclear whether these committees achieve their goal. The IRB Researcher Assessment Tool is a previously validated, internally normed, proxy measure of IRB quality that assesses 45 distinct IRB activities and functions. We administered this instrument to a sample of investigators and IRB members at a large urban VA Medical Center. We describe a systematic approach to analyze and interpret survey responses that can identify the IRB activities and functions most in need of quality improvement. The proposed approach to empirical data analysis and presentation could inform local initiatives to improve the quality of IRB review. PMID- 26527370 TI - Are Research Ethics Committees Prepared for Community-Based Participatory Research? AB - Community-based participatory research (CBPR) is challenging to research ethics committees (RECs). We reviewed the REC preparedness when reviewing CBPR projects. We searched the MEDLINE database and included qualitative studies of CBPR researchers or REC members about their experiences with RECs. The search yielded 107 studies, of which 10 met our criteria. Barriers were that the community is not prepared to conduct research, the reluctance of RECs to work outside the university, the difficulty RECs have understanding CBPR, and that REC forms evaluate individual rather than community risk. Facilitators were having a CBPR expert as an REC member and educating RECs. Therefore, RECs are not prepared to evaluate CBPR projects leading to unnecessary delays in the approval process. PMID- 26527371 TI - Vascular hamartoma in the right ventricle of a dog: Diagnosis and treatment. AB - A 6-month old Labrador retriever was presented with an acute history of collapse during exercise. A grade III/VI left basilar systolic murmur and thoracic radiographs showing severe right heart enlargement with an enlarged main pulmonary artery were most consistent with a clinical diagnosis of pulmonic stenosis. Echocardiography revealed an intracardiac mass partially obstructing the right ventricular outflow tract. The mass was surgically excised, and histopathology diagnosed a benign vascular hamartoma of the right ventricle. Short-term follow-up showed resolution of clinical signs with no evidence of local recurrence. Intracardiac masses should be considered a differential diagnosis for patients with acute-onset syncope. PMID- 26527372 TI - Adult survivors' lived experience of burns and post-burn health: A qualitative analysis. AB - INTRODUCTION: The individual implications of major burns are likely to affect the full spectrum of patients' physical, emotional, psychological, social, environmental, spiritual and vocational health. Yet, not all of the post-burn health implications are inevitably negative. Utilizing a qualitative approach, this heuristic phenomenological study explores the experiences and perceptions early (ages 18-35) and midlife (ages 36-64) adults providing insight for how participants perceived their burns in relationship to their post-burn health. METHODS: Participants were interviewed using semi-structured interview questions framed around seven domains of health. Interview recordings were transcribed verbatim then coded line by line, identifying dominant categories related to health. Categories were analyzed identifying shared themes among the study sample. RESULTS: Participants were Caucasian, seven males and one female. Mean age at time of interviews was 54.38 and 42.38 at time of burns. Mean time since burns occurred was 9.38 years with a minimum of (20%) total body surface area (TBSA) burns. Qualitative content analysis rendered three emergent health-related categories and associated themes that represented shared meanings within the participant sample. The category of "Physical Health" reflected the theme physical limitations, pain and sensitivity to temperature. Within the category of "Intellectual Health" were themes of insight, goal setting and self-efficacy, optimism and humor and within "Emotional Health" were the themes empathy and gratitude. CONCLUSIONS: By exploring subjective experiences and perceptions of health shared through dialog with experienced burned persons, there are opportunities to develop a more complete picture of how holistic health may be affected by major burns that in turn could support future long-term rehabilitative trajectories of early and midlife adult burn patients. PMID- 26527373 TI - Multiple Choice Questions. PMID- 26527374 TI - Balloon-expandable transcatheter aortic valve replacement in patients with extreme aortic valve calcification. AB - OBJECTIVES: To assess the procedural and short-term clinical outcome of performing balloon-expandable TAVR in patients with extremely calcified aortic valves. BACKGROUND: Quantity of aortic valve calcification predicts rates of paravalvular regurgitation (PVR) post transcatheter aortic valve replacement (TAVR). Nonetheless, short-term outcomes of balloon-expandable TAVR in patients with extremely high calcified aortic valves have not been previously described. METHODS: We studied patients with severe aortic stenosis that underwent balloon expandable TAVR and had a pre-procedural non-contrast CT. Twenty patients that had aortic valve calcification score (AVCS) of more than 8,000 Agatston Units were compared to 279 patients with lower calcification scores. TAVR endpoints, device success and adverse events were considered according to the Valve Academic Research Consortium-2 definitions. RESULTS: Device success was 80% in the extremely high calcification group compared to 95.3% in patients with less calcified aortic valves (P = 0.004). There was significantly more postprocedural PVR in the extreme calcification group: 50%, 35%, 10%, 5% vs. 72.4%, 25.8%, 1.8%, 0% for no/trace, mild, moderate and severe PVR, respectively (P < 0.001). There was one case of ascending aortic perforation resulting in intramural hematoma that resolved with no treatment. In-hospital mortality, new pacemaker implantation and major complications were similar between groups. CONCLUSIONS: Balloon-expandable TAVR in patients with extremely calcified aortic valve is associated with lower device success and greater risk of PVR. (c) 2015 Wiley Periodicals, Inc. PMID- 26527376 TI - Corrigendum. PMID- 26527375 TI - Novel wildlife in the Arctic: the influence of changing riparian ecosystems and shrub habitat expansion on snowshoe hares. AB - Warming during the 20th century has changed the arctic landscape, including aspects of the hydrology, vegetation, permafrost, and glaciers, but effects on wildlife have been difficult to detect. The primary aim of this study is to examine the physical and biological processes contributing to the expanded riparian habitat and range of snowshoe hares (Lepus americanus) in northern Alaska. We explore linkages between components of the riparian ecosystem in Arctic Alaska since the 1960s, including seasonality of stream flow, air temperature, floodplain shrub habitat, and snowshoe hare distributions. Our analyses show that the peak discharge during spring snowmelt has occurred on average 3.4 days per decade earlier over the last 30 years and has contributed to a longer growing season in floodplain ecosystems. We use empirical correlations between cumulative summer warmth and riparian shrub height to reconstruct annual changes in shrub height from the 1960s to the present. The effects of longer and warmer growing seasons are estimated to have stimulated a 78% increase in the height of riparian shrubs. Earlier spring discharge and the estimated increase in riparian shrub height are consistent with observed riparian shrub expansion in the region. Our browsing measurements show that snowshoe hares require a mean riparian shrub height of at least 1.24-1.36 m, a threshold which our hindcasting indicates was met between 1964 and 1989. This generally coincides with observational evidence we present suggesting that snowshoe hares became established in 1977 or 1978. Warming and expanded shrub habitat is the most plausible reason for recent snowshoe hare establishment in Arctic Alaska. The establishment of snowshoe hares and other shrub herbivores in the Arctic in response to increasing shrub habitat is a contrasting terrestrial counterpart to the decline in marine mammals reliant on decreasing sea ice. PMID- 26527378 TI - Mapping areas of spatial-temporal overlap from wildlife tracking data. AB - BACKGROUND: The study of inter-individual interactions (often termed spatial temporal interactions, or dynamic interactions) from remote tracking data has focused primarily on identifying the presence of such interactions. New datasets and methods offer opportunity to answer more nuanced questions, such as where on the landscape interactions occur. In this paper, we provide a new approach for mapping areas of spatial-temporal overlap in wildlife from remote tracking data. The method, termed the joint potential path area (jPPA) builds from the time geographic movement model, originally proposed for studying human movement patterns. RESULTS: The jPPA approach can be used to delineate sub-areas of the home range where inter-individual interaction was possible. Maps of jPPA regions can be integrated with existing geographic data to explore landscape conditions and habitat associated with spatial temporal-interactions in wildlife. We apply the jPPA approach to simulated biased correlated random walks to demonstrate the method under known conditions. The jPPA method is then applied to three dyads, consisting of fine resolution (15 minute sampling interval) GPS tracking data of white-tailed deer (Odocoileus virginianus) collected in Oklahoma, USA. Our results demonstrate the ability of the jPPA to identify and map jPPA sub-areas of the home range. We show how jPPA maps can be used to identify habitat differences (using percent tree canopy cover as a habitat indicator) between areas of spatial temporal overlap and the overall home range in each of the three deer dyads. CONCLUSIONS: The value of the jPPA approach within current wildlife habitat analysis workflows is highlighted along with its simple and straightforward implementation and interpretation. Given the current emphasis on remote tracking in wildlife movement and habitat research, new approaches capable of leveraging both the spatial and temporal information content contained within these data are warranted. We make code (in the statistical software R) for implementing the jPPA approach openly available for other researchers. PMID- 26527377 TI - CRISPR/dCas9-mediated Transcriptional Inhibition Ameliorates the Epigenetic Dysregulation at D4Z4 and Represses DUX4-fl in FSH Muscular Dystrophy. AB - Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent myopathies, affecting males and females of all ages. Both forms of the disease are linked by epigenetic derepression of the D4Z4 macrosatellite repeat array at chromosome 4q35, leading to aberrant expression of D4Z4-encoded RNAs in skeletal muscle. Production of full-length DUX4 (DUX4-fl) mRNA from the derepressed D4Z4 array results in misexpression of DUX4-FL protein and its transcriptional targets, and apoptosis, ultimately leading to accumulated muscle pathology. Returning the chromatin at the FSHD locus to its nonpathogenic, epigenetically repressed state would simultaneously affect all D4Z4 RNAs, inhibiting downstream pathogenic pathways, and is thus an attractive therapeutic strategy. Advances in CRISPR/Cas9-based genome editing make it possible to target epigenetic modifiers to an endogenous disease locus, although reports to date have focused on more typical genomic regions. Here, we demonstrate that a CRISPR/dCas9 transcriptional inhibitor can be specifically targeted to the highly repetitive FSHD macrosatellite array and alter the chromatin to repress expression of DUX4-fl in primary FSHD myocytes. These results implicate the promoter and exon 1 of DUX4 as potential therapeutic targets and demonstrate the utility of CRISPR technology for correction of the epigenetic dysregulation in FSHD. PMID- 26527379 TI - Adoptive transfer of Aspergillus-specific T cells as a novel anti-fungal therapy for hematopoietic stem cell transplant recipients: Progress and challenges. AB - Although newer antifungal drugs have substantially altered the natural history of invasive aspergillosis, the disease still accounts for significant morbidity and mortality in hematopoietic stem cell transplant recipients. Both the evidence supporting a protective role of T cells against this fungal pathogen and the documented efficacy of adoptive transfer of antigen-specific T cells for prophylaxis and treatment of viral infections post-transplant have stimulated much interest towards development of Aspergillus-specific T cells (Asp-STs) for adoptive immunotherapy in the allogeneic transplant setting. In contrast to the remarkable progress with virus-specific T cells, clinical development of fungus specific T cells is still in its infancy. Several groups have characterized Asp STs in healthy individuals and patients with malignant hematological diseases, while others sought to develop GMP-compliant methods of expanding or bioengineering Asp-STs ex vivo as immunotherapy. This review highlights the recent advances in this field, and discusses critical issues involved in development and protocol design of Asp-ST immunotherapy. PMID- 26527380 TI - Melatonin protects the brain from apoptosis by enhancement of autophagy after traumatic brain injury in mice. AB - Melatonin has been proven to possess neuroprotection property against various neurological diseases by decreasing cerebral oxidative stress and inhibiting inflammatory process. However, whether administration of melatonin influences the autophagy pathway, which has recently been reported playing a pivotal role in traumatic brain injury, is yet not fully understood. We supposed that treatment of melatonin enhances the autophagy pathway after traumatic brain injury (TBI) in mice and subsequently inhibited the mitochondrion apoptotic pathway. Firstly, we investigated the neurological severity score, brain water content and neuronal apoptosis in mice cortex to demonstrate the neuroprotection of melatonin. Then we determined the autophagy markers, namely Beclin1 and LC3-II, using western blot and immunofluorescence. Next, we evaluated the mitochondrial apoptotic pathway in the presence or absence of melatonin. More significantly, we employed 3 methyladenine (3-MA) to inhibit the autophagy pathway, to further confirm our hypothesis. The results showed that melatonin significantly ameliorated secondary brain injury induced by TBI. In addition, melatonin enhanced autophagy after TBI, which was accompanied by a decrease in both the translocation of Bax to mitochondria and the release of cytochrome C to cytoplasm. Furthermore, simultaneous treatment of 3-MA reversed the beneficial effects of melatonin on mitochondrial apoptotic pathway. Taken together, we conclude that melatonin enhances autophagy, which inhibits mitochondrial apoptotic pathway, thus protecting mice from secondary brain injury after TBI. PMID- 26527381 TI - The epicardium as modulator of the cardiac autonomic response during early development. AB - The cardiac autonomic nervous system (cANS) modulates heart rate, contraction force and conduction velocity. The embryonic chicken heart already responds to epinephrine prior to establishment of the cANS. The aim of this study was to define the regions of the heart that might participate in modulating the early autonomic response to epinephrine. Immunofluorescence analysis reveals expression of neural markers tubulin beta-3 chain and neural cell adhesion molecule in the epicardium during early development. In addition, expression of the beta2 adrenergic receptor, the receptor for epinephrine, was found in the epicardium. Ex-ovo micro-electrode recordings in hearts with inhibition of epicardial outgrowth showed a significantly reduced response of the heart rate to epinephrine compared to control hearts. This study suggests a role for the epicardium as autonomic modulator during early cardiac development. PMID- 26527382 TI - Atypical PKC-iota Controls Stem Cell Expansion via Regulation of the Notch Pathway. AB - The number of stem/progenitor cells available can profoundly impact tissue homeostasis and the response to injury or disease. Here, we propose that an atypical PKC, Prkci, is a key player in regulating the switch from an expansion to a differentiation/maintenance phase via regulation of Notch, thus linking the polarity pathway with the control of stem cell self-renewal. Prkci is known to influence symmetric cell division in invertebrates; however a definitive role in mammals has not yet emerged. Using a genetic approach, we find that loss of Prkci results in a marked increase in the number of various stem/progenitor cells. The mechanism used likely involves inactivation and symmetric localization of NUMB, leading to the activation of NOTCH1 and its downstream effectors. Inhibition of atypical PKCs may be useful for boosting the production of pluripotent stem cells, multipotent stem cells, or possibly even primordial germ cells by promoting the stem cell/progenitor fate. PMID- 26527383 TI - Characterization of Epithelial Progenitors in Normal Human Palatine Tonsils and Their HPV16 E6/E7-Induced Perturbation. AB - Human palatine tonsils are oropharyngeal lymphoid tissues containing multiple invaginations (crypts) in which the continuity of the outer surface epithelium is disrupted and the isolated epithelial cells intermingle with other cell types. We now show that primitive epithelial cells detectable in vitro in 2D colony assays and in a 3D culture system are CD44(+)NGFR(+) and present in both surface and crypt regions. Transcriptome analysis indicated a high similarity between CD44(+)NGFR(+) cells in both regions, although those isolated from the crypt contained a higher proportion of the most primitive (holo)clonogenic cells. Lentiviral transduction of CD44(+)NGFR(+) cells from both regions with human papillomavirus 16-encoded E6/E7 prolonged their growth in 2D cultures and caused aberrant differentiation in 3D cultures. Our findings therefore reveal a shared, site-independent, hierarchical organization, differentiation potential, and transcriptional profile of normal human tonsillar epithelial progenitor cells. They also introduce a new model for investigating the mechanisms of their transformation. PMID- 26527384 TI - Stroma-Derived Connective Tissue Growth Factor Maintains Cell Cycle Progression and Repopulation Activity of Hematopoietic Stem Cells In Vitro. AB - Hematopoietic stem cells (HSCs) are preserved in co-cultures with UG26-1B6 stromal cells or their conditioned medium. We performed a genome-wide study of gene expression changes of UG26-1B6 stromal cells in contact with Lineage- SCA-1+ KIT+ (LSK) cells. This analysis identified connective tissue growth factor (CTGF) to be upregulated in response to LSK cells. We found that co-culture of HSCs on CTGF knockdown stroma (shCtgf) shows impaired engraftment and long-term quality. Further experiments demonstrated that CD34- CD48- CD150+ LSK (CD34- SLAM) cell numbers from shCtgf co-cultures increase in G0 and senescence and show delayed time to first cell division. To understand this observation, a CTGF signaling network model was assembled, which was experimentally validated. In co-culture experiments of CD34- SLAM cells with shCtgf stromal cells, we found that SMAD2/3 dependent signaling was activated, with increasing p27(Kip1) expression and downregulating cyclin D1. Our data support the view that LSK cells modulate gene expression in the niche to maintain repopulating HSC activity. PMID- 26527385 TI - Cloning-free CRISPR. AB - We present self-cloning CRISPR/Cas9 (scCRISPR), a technology that allows for CRISPR/Cas9-mediated genomic mutation and site-specific knockin transgene creation within several hours by circumventing the need to clone a site-specific single-guide RNA (sgRNA) or knockin homology construct for each target locus. We introduce a self-cleaving palindromic sgRNA plasmid and a short double-stranded DNA sequence encoding the desired locus-specific sgRNA into target cells, allowing them to produce a locus-specific sgRNA plasmid through homologous recombination. scCRISPR enables efficient generation of gene knockouts (~88% mutation rate) at approximately one-sixth the cost of plasmid-based sgRNA construction with only 2 hr of preparation for each targeted site. Additionally, we demonstrate efficient site-specific knockin of GFP transgenes without any plasmid cloning or genome-integrated selection cassette in mouse and human embryonic stem cells (2%-4% knockin rate) through PCR-based addition of short homology arms. scCRISPR substantially lowers the bar on mouse and human transgenesis. PMID- 26527386 TI - Intrauterine Bone Marrow Transplantation in Osteogenesis Imperfecta Mice Yields Donor Osteoclasts and Osteomacs but Not Osteoblasts. AB - In this article, Millard and colleagues show that intrauterine bone marrow transplantation in the oim/oim mouse model of osteogenesis imperfecta yields hematopoietic microchimerism in the absence of donor osteopoiesis or phenotypic improvement. Bone-associated donor cells were not bone-forming osteoblasts, but osteoclasts (bone resorbing cells of the hematopoietic lineage) and osteal macrophages (bone regulatory cells of the hematopoietic lineage). PMID- 26527387 TI - Cell Division Mode Change Mediates the Regulation of Cerebellar Granule Neurogenesis Controlled by the Sonic Hedgehog Signaling. AB - Symmetric and asymmetric divisions are important for self-renewal and differentiation of stem cells during neurogenesis. Although cerebellar granule neurogenesis is controlled by sonic hedgehog (SHH) signaling, whether and how this process is mediated by regulation of cell division modes have not been determined. Here, using time-lapse imaging and cell culture from neuronal progenitor-specific and differentiated neuron-specific reporter mouse lines (Math1-GFP and Dcx-DsRed) and Patched +/- mice in which SHH signaling is activated, we find evidence for the existence of symmetric and asymmetric divisions that are closely associated with progenitor proliferation and differentiation. While activation of the SHH pathway enhances symmetric progenitor cell divisions, blockade of the SHH pathway reverses the cell division mode change in Math1-GFP; Dcx-DsRed; Patched +/- mice by promoting asymmetric divisions or terminal neuronal symmetric divisions. Thus, cell division mode change mediates the regulation of cerebellar granule neurogenesis controlled by SHH signaling. PMID- 26527388 TI - Strategy Approach for Direct Enantioseparation of Hyoscyamine Sulfate and Zopiclone on a Chiral alphal-Acid Glycoprotein Column and Determination of Their Eutomers: Thermodynamic Study of Complexation. AB - Rapid and simple isocratic high-performance liquid chromatographic methods with UV detection were developed and validated for the direct resolution of racemic mixtures of hyoscyamine sulfate and zopiclone. The method involved the use of alphal -acid glycoprotein (AGP) as chiral stationary phase. The stereochemical separation factor (alpha) and the stereochemical resolution factor (Rs ) obtained were 1.29 and 1.60 for hyoscyamine sulfate and 1.47 and 2.45 for zopiclone, respectively. The method was used for determination of chiral switching (eutomer) isomers: S-hyoscyamine sulfate and eszopiclone. Several mobile phase parameters were investigated for controlling enantioselective retention and resolution on the chiral AGP column. The influence of mobile phase, concentration and type of uncharged organic modifier, ionic strength, and column temperature on enantioselectivity were studied. Calibration curves were linear in the ranges of 1-10 ug mL(-1) and 0.5-5 ug mL(-1) for S-hyoscyamine sulfate and eszopiclone, respectively. The method is specific and sensitive, with lower limits of detection and quantifications of 0.156, 0.515 and 0.106, 0.349 for S-hyoscyamine sulfate and eszopiclone, respectively. The method was used to identify quantitatively the enantiomers profile of the racemic mixtures of the studied drugs in their pharmaceutical preparations. Thermodynamic studies were performed to calculate the enthalpic DeltaH and entropic DeltaS terms. The results showed that enantiomer separation of the studied drugs were an enthalpic process. PMID- 26527389 TI - Secular trends and geographical variations in sex ratio at birth. AB - Numerous studies have established the presence of secular trends and geographical variations in sex ratio at birth, albeit with mixed and often contradictory results. In addition, a multitude of environmental, social, economic, demographic and other factors has been proposed to influence the sex ratio at birth, thus complicating the interpretation of both secular trends and geographical variations. In this paper, the current state of knowledge on these issues is presented and critically assessed. Analyzing longer time series of sex ratio at birth with possible cycles and random components is given priority over establishing simple linear trends in the data. In analyzing the geographical variation in the sex ratio at birth, two different levels of analysis are distinguished (global and local), and two different sets of factors affecting the sex ratio at birth are proposed accordingly. Some key guidelines and future research directions are also proposed. PMID- 26527390 TI - Evidence of economic deprivation and female foeticide in a United Nations global births by gender data set. AB - INTRODUCTION: The male-to-female ratio of live births is expressed as the ratio of male births divided by total births (M/F). Males are produced approximately 3% in excess. A large number of factors have been found to influence M/F. Stress and privation reduces M/F. Gender preference (which almost invariably favours males) with selective female foetal abortion increases M/F. This study was carried out in order to assess a United Nations data set for evidence of global trends in M/F in relation to broad socioeconomic conditions and male preference. METHODS: Data (M/F and total births, 1955-2009) was obtained from the United Nations (UN) Department of Economic and Social Affairs, Population Division, Population Estimates and Projection Section. The following regions were analysed: more developed countries, less developed countries and least developed countries (as defined by the UN General Assembly). RESULTS: More developed countries: M/F was initially stable at 0.53 up to 1979 then fell to 0.525. Less developed countries: M/F was initially stable at 0.53 then rose after 1984 to 0.545 with a rise in male births and a fall in female births (estimated female birth deficit=48734993). Least developed countries: exhibited a stable M/F of 0.52 (all p<<0.001). DISCUSSION: This study has confirmed, on a global scale, that least developed countries have the lowest M/F. The rise in M/F in developed countries (which includes Asia) confirms widespread selective female foeticide due to cultural male preference. The declining trend in M/F in developed countries has been previously noted and remains unexplained. PMID- 26527391 TI - The male to female ratio at birth. PMID- 26527392 TI - Ionizing radiation and the human gender proportion at birth--A concise review of the literature and complementary analyses of historical and recent data. AB - It has long been known that ionizing radiation causes genetic mutations and that nuclear bomb testing, nuclear accidents, and the regular and incidental emissions of nuclear facilities enhance environmental radioactivity. For this reason, the carcinogenic and genetic impact of ionizing radiation has been an escalating issue for environmental health and human health studies in the past decades. The Windscale fire (1957) and the Chernobyl accident (1986) caused alterations to the human birth sex ratio at national levels across Europe, and childhood cancer and childhood leukemia are consistently elevated near nuclear power plants. These findings are generalized and corroborated by the observation of increased sex ratios near nuclear facilities in Austria, France, Germany, Luxembourg, Switzerland, and The Netherlands. We present a concise review of the pertinent literature and we complement our review by spatiotemporal analyses of historical and most recent data. Evidence of genetic damage by elevated environmental radioactivity is provided. PMID- 26527393 TI - Inverse characterization of plates using zero group velocity Lamb modes. AB - In the presented work, the characterization of plates using zero group velocity Lamb modes is discussed. First, analytical expressions are shown for the determination of the k-omega location of the zero group velocity Lamb modes as a function of the Poisson's ratio. The analytical expressions are solved numerically and an inverse problem is formulated to determine the unknown wave velocities in plates of known thickness. The analysis is applied to determine the elastic properties of tungsten and aluminum plates based on the experimentally measured frequency spectra. PMID- 26527394 TI - Comorbidity, age, and mortality among adults treated intensively for acute myeloid leukemia (AML). AB - INTRODUCTION: Our goal was to characterize comorbidities among adults receiving intensive therapy for AML, and investigate their association with outcomes. METHODS: We retrospectively analyzed 277 consecutive patients with newly diagnosed AML treated intensively at the Comprehensive Cancer Center of Wake Forest University from 2002 to 2009. Pretreatment comorbidities were identified by ICD-9 codes and chart review. Comorbidity burden (modified Charlson Comorbidity Index [CCI]) and specific conditions were analyzed individually. Outcomes were overall survival (OS), remission, and 30-day mortality. Covariates included age, gender, cytogenetic characteristics, hemoglobin, white cell count, lactate dehydrogenase, body mass index, and insurance type. Cox proportional hazards models were used to evaluate OS; logistic regression was used for remission and 30-day mortality. RESULTS: In this series, 144 patients were >= 60 years old (median age 70 years, median survival 8.7 months) and 133 were <60 years (median age 47 years, median survival 23.1 months). Older patients had a higher comorbidity burden (CCI>=1 58% versus 26%, P<0.001). Prevalent comorbid conditions differed by age (diabetes 19.2% versus 7.5%; cardiovascular disease 12.5% versus 4.5%, for older versus younger patients, respectively). The CCI was not independently associated with OS or 30-day mortality in either age group. Among older patients, diabetes was associated with higher 30-day mortality (33.3% vs. 12.0% in diabetic vs. non-diabetic patients, p=0.006). Controlling for age, cytogenetic characteristics and other comorbidities, the presence of diabetes increased the odds of 30-day mortality by 4.9 (CI 1.6-15.2) times. DISCUSSION: Diabetes is adversely associated with 30-day survival in older AML patients receiving intensive therapy. PMID- 26527395 TI - Dragon's blood extracts reduce radiation-induced peripheral blood injury and protects human megakaryocyte cells from GM-CSF withdraw-induced apoptosis. AB - PURPOSE: Dragon's blood (DB), a Chinese traditional herb, was shown to have certain protective effects on radiation-induced bone marrow injury due to the presence of several phenolic compounds. The 50% ethanol extracts (DBE) were separated from DB by the methods of alcohol extracting-water precipitating. The protective effects of DBE on hematopoiesis were studied, particularly on megakaryocytes. MATERIALS AND METHODS: In this study, we investigated the in vivo radioprotective effects of DBE on hematopoiesis and pathological changes using an irradiated-mouse model. Moreover, the protective effects and potential molecular mechanisms of DBE on megakaryocytopoiesis in vitro were explored in GM-CSF depletion-induced Mo7e cell model. RESULTS: DBE significantly promoted the recovery of peripheral blood cells in irradiated mice. Histology bone marrow confirmed the protective effect of DBE, as shown by an increased number of hematopoietic cells and a reduction of apoptosis. In a megakaryocytic apoptotic model, DBE (50 ug/mL) markedly alleviated GM-CSF withdrawal-induced apoptosis and cell-cycle arrest of Mo7e cells. DBE (50 ug/mL) also significantly decreased the ratio of Bax to Bcl-2 expression, inhibited the active caspase-3 expression. In addition, DBE could induce ERK1/2 phosphorylation in GM-CSF-depleted Mo7e cell, but not Akt. CONCLUSIONS: Our data demonstrated that DBE could effectively accelerate the recovery of peripheral blood cells, especially platelet. DBE attenuated cell apoptosis and cell cycle arrest through the decrease of Bax/Bcl-2 ratio and the reduction of active caspase-3 expression. The effect of DBE on Mo7e cells survival and proliferation is likely associated with the activation of ERK, but not Akt. PMID- 26527396 TI - The cytolinker plectin regulates nuclear mechanotransduction in keratinocytes. AB - The transmission of mechanical forces to the nucleus is important for intracellular positioning, mitosis and cell motility, yet the contribution of specific components of the cytoskeleton to nuclear mechanotransduction remains unclear. In this study, we examine how crosstalk between the cytolinker plectin and F-actin controls keratin network organisation and the 3D nuclear morphology of keratinocytes. Using micro-patterned surfaces to precisely manipulate cell shape, we find that cell adhesion and spreading regulate the size and shape of the nucleus. Disruption of the keratin cytoskeleton through loss of plectin facilitated greater nuclear deformation, which depended on acto-myosin contractility. Nuclear morphology did not depend on direct linkage of the keratin cytoskeleton with the nuclear membrane, rather loss of plectin reduced keratin filament density around the nucleus. We further demonstrate that keratinocytes have abnormal nuclear morphologies in the epidermis of plectin-deficient, epidermolysis bullosa simplex patients. Taken together, our data demonstrate that plectin is an essential regulator of nuclear morphology in vitro and in vivo and protects the nucleus from mechanical deformation. PMID- 26527397 TI - Interaction between CHL1 and serotonin receptor 2c regulates signal transduction and behavior in mice. AB - The serotonergic system plays important roles in multiple functions of the nervous system and its malfunctioning leads to neurological and psychiatric disorders. Here, we show that the cell adhesion molecule close homolog of L1 (CHL1), which has been linked to mental disorders, binds to a peptide stretch in the third intracellular loop of the serotonin 2c (5-HT2c) receptor through its intracellular domain. Moreover, we provide evidence that CHL1 deficiency in mice leads to 5-HT2c-receptor-related reduction in locomotor activity and reactivity to novelty, and that CHL1 regulates signaling pathways triggered by constitutively active isoforms of the 5-HT2c receptor. Furthermore, we found that the 5-HT2c receptor and CHL1 colocalize in striatal and hippocampal GABAergic neurons, and that 5-HT2c receptor phosphorylation and its association with phosphatase and tensin homolog (PTEN) and beta-arrestin 2 is regulated by CHL1. Our results demonstrate that CHL1 regulates signal transduction pathways through constitutively active 5-HT2c receptor isoforms, thereby altering 5-HT2c receptor functions and implicating CHL1 as a new modulator of the serotonergic system. PMID- 26527398 TI - CENP-C and CENP-I are key connecting factors for kinetochore and CENP-A assembly. AB - Although it is generally accepted that chromatin containing the histone H3 variant CENP-A is an epigenetic mark maintaining centromere identity, the pathways leading to the formation and maintenance of centromere chromatin remain unclear. We previously generated human artificial chromosomes (HACs) whose centromeres contain a synthetic alpha-satellite (alphoid) DNA array containing the tetracycline operator (alphoid(tetO)). We also obtained cell lines bearing the alphoid(tetO) array at ectopic integration sites on chromosomal arms. Here, we have examined the regulation of CENP-A assembly at centromeres as well as de novo assembly on the ectopic arrays by tethering tetracycline repressor (tetR) fusions of substantial centromeric factors and chromatin modifiers. This analysis revealed four classes of factors that influence CENP-A assembly. Interestingly, many kinetochore structural components induced de novo CENP-A assembly at the ectopic site. We showed that these components work by recruiting CENP-C and subsequently recruiting M18BP1. Furthermore, we found that CENP-I can also recruit M18BP1 and, as a consequence, enhances M18BP1 assembly on centromeres in the downstream of CENP-C. Thus, we suggest that CENP-C and CENP-I are key factors connecting kinetochore to CENP-A assembly. PMID- 26527399 TI - ATF6a, a Runx2-activable transcription factor, is a new regulator of chondrocyte hypertrophy. AB - Our previous research has shown that the spliced isoform of XBP1 (XBP1s) is an important downstream mediator of BMP2 and is involved in BMP2-stimulated chondrocyte differentiation. Herein, we report that ATF6 and its cleaved N terminal cytoplasmic domain (known as ATF6a) are expressed in growth plate chondrocytes. We find that these proteins are differentially induced during BMP2 triggered chondrocyte differentiation. This differential expression probably results from the activation of the ATF6 gene by Runx2 and its repression by the Sox6 transcription factor. Runx2 and Sox6 act through their respective binding elements on the ATF6 gene. When overexpressed, ATF6 and ATF6a intensify chondrogenesis; our studies demonstrate that under the stimulation of ATF6 and ATF6a, chondrocytes tend to be hypertrophied and mineralized, a process leading to bone formation. By contrast, lowering expression of ATF6a by use of its specific siRNA suppresses chondrocyte differentiation. Moreover, ATF6a interacts with Runx2 and augments the Runx2-mediated hypertrophication of chondrocytes. Importantly, overexpression and knockdown of ATF6a during the chondrocyte hypertrophy process also led to altered expressions of IHH and PTHrP (also known as PTHLH). Taken together, these findings indicate that ATF6a favorably controls chondrogenesis and bone formation (1) by acting as a co-factor of Runx2 and enhancing Runx2-incited hypertrophic chondrocyte differentiation, and (2) by affecting IHH and PTHrP signaling. PMID- 26527400 TI - AP-2-complex-mediated endocytosis of Drosophila Crumbs regulates polarity by antagonizing Stardust. AB - Maintenance of epithelial polarity depends on the correct localization and levels of polarity determinants. The evolutionarily conserved transmembrane protein Crumbs is crucial for the size and identity of the apical membrane, yet little is known about the molecular mechanisms controlling the amount of Crumbs at the surface. Here, we show that Crumbs levels on the apical membrane depend on a well balanced state of endocytosis and stabilization. The adaptor protein 2 (AP-2) complex binds to a motif in the cytoplasmic tail of Crumbs that overlaps with the binding site of Stardust, a protein known to stabilize Crumbs on the surface. Preventing endocytosis by mutation of AP-2 causes expansion of the Crumbs positive plasma membrane domain and polarity defects, which can be partially rescued by removing one copy of crumbs. Strikingly, knocking down both AP-2 and Stardust leads to the retention of Crumbs on the membrane. This study provides evidence for a molecular mechanism, based on stabilization and endocytosis, to adjust surface levels of Crumbs, which are essential for maintaining epithelial polarity. PMID- 26527401 TI - The murine cytomegalovirus immunoevasin gp40 binds MHC class I molecules to retain them in the early secretory pathway. AB - In the presence of the murine cytomegalovirus (mCMV) gp40 (m152) protein, murine major histocompatibility complex (MHC) class I molecules do not reach the cell surface but are retained in an early compartment of the secretory pathway. We find that gp40 does not impair the folding or high-affinity peptide binding of the class I molecules but binds to them, leading to their retention in the endoplasmic reticulum (ER), the ER-Golgi intermediate compartment (ERGIC) and the cis-Golgi, most likely by retrieval from the cis-Golgi to the ER. We identify a sequence in gp40 that is required for both its own retention in the early secretory pathway and for that of class I molecules. PMID- 26527402 TI - Avian influenza virus H9N2 infections in farmed minks. AB - BACKGROUND: The prevalence of avian H9N2 viruses throughout Asia, along with their demonstrated ability to infect mammals, puts them high on the list of influenza viruses with pandemic potential for humans. In this study, we investigated whether H9N2 viruses could infect farmed minks. METHODS: First, we conducted a serological survey for avian influenza virus antibodies on a random sample of the field-trial population of farmed minks. Then we inoculated farmed minks with A/Chicken/Hebei/4/2008 H9N2 viruses and observed the potential pathogenicity of H9N2 virus and virus shedding in infected minks. RESULTS: H9 influenza antibodies could be detected in most farmed minks with a higher seropositivity, which indicated that farmed minks had the high prevalence of exposure to H9 viruses. After infection, the minks displayed the slight clinical signs including lethargy and initial weight loss. The infected lungs showed the mild diffuse pneumonia with thickened alveolar walls and inflammatory cellular infiltration. Influenza virus detection showed that viruses were detected in the allantoic fluids inoculated supernatant of lung tissues at 3 and 7 days post infection (dpi), and found in the nasal swabs of H9N2-infected minks at 3-11 dpi, suggesting that H9N2 viruses replicated in the respiratory organ, were then shed outwards. HI antibody test showed that antibody levels began to rise at 7 dpi. CONCLUSIONS: Our data provided the serological and experimental evidences that strongly suggested farmed minks under the natural state were susceptible to H9N2 viral infection and might be the H9N2 virus carriers. It is imperative to strengthen the H9N2 viral monitoring in farmed minks and pay urgent attention to prevent and control new influenza viruses pandemic prevalence. PMID- 26527403 TI - Effect of stigma reduction intervention strategies on HIV test uptake in low- and middle-income countries: a realist review protocol. AB - BACKGROUND: Several stigma reduction intervention strategies have been developed and tested for effectiveness in terms of increasing human immunodeficiency virus (HIV) test uptake. These strategies have been more effective in some contexts and less effective in others. Individual factors, such as lack of knowledge and fear of disclosure, and social-contextual factors, such as poverty and illiteracy, might influence the effect of stigma reduction intervention strategies on HIV test uptake in low- and middle-income countries. So far, it is not clearly known how the stigma reduction intervention strategies interact with these contextual factors to increase HIV test uptake. Therefore, we will conduct a review that will synthesize existing studies on stigma reduction intervention strategies to increase HIV test uptake to better understand the mechanisms underlying this process in low- and middle-income countries. METHODS: A realist review will be conducted to unpack context-mechanism-outcome configurations of the effect of stigma reduction intervention strategies on HIV test uptake. Based on a scoping review, we developed a preliminary theoretical framework outlining a potential mechanism of how the intervention strategies influence HIV test uptake. Our realist synthesis will be used to refine the preliminary theoretical framework to better reflect mechanisms that are supported by existing evidence. Journal articles and grey literature will be searched following a purposeful sampling strategy. Data will be extracted and tested against the preliminary theoretical framework. Data synthesis and analysis will be performed in five steps: organizing extracted data into evidence tables, theming, formulating chains of inference from the identified themes, linking the chains of inference and developing generative mechanisms, and refining the framework. DISCUSSION: This will be the first realist review that offers both a quantitative and a qualitative exploration of the available evidence to develop and propose a theoretical framework that explains why and how HIV stigma reduction intervention strategies influence HIV test uptake in low- and middle-income countries. Our theoretical framework is meant to provide guidance to program managers on identifying the most effective stigma reduction intervention strategies to increase HIV test uptake. We also include advice on how to effectively implement these strategies to reduce the rate of HIV transmission. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015023687. PMID- 26527404 TI - Health system delay among patients with tuberculosis in Taiwan: 2003-2010. AB - BACKGROUND: Taiwan has integrated the previous vertical tuberculosis (TB) control system into the general health care system. With the phase out of the specialized TB care system and the declining TB incidence, it is likely that clinical workers become less familiar with the presentation of TB, resulting in delay in TB diagnosis and treatment. METHODS: We used the detailed information of health care visits in the Taiwan National Health Insurance database to analyze the temporal pattern of the health system delay (HSD) among 3,117 patients with TB between 2003 and 2010. RESULTS: The median HSD was 29 days (interquartile range 5-73 days), and the median delay increased from 26 days in 2003 to 33.5 days in 2008, thereafter slightly decreased to 32 days in 2010. Patient factors associated with a longer HSD included: aged 45-64 and ?65 years (as compared to aged <30 years); females (as compared to males); an initial visit as an outpatient (as compared to an inpatient). Provider factors were an initial visit to a provider not specialized in TB (as compared to a TB-related provider), to a primary care clinic or to a medical center (as compared to a district hospital), and in Central region, Northern region, KaoPing region, Southern region and Taipei region (as compared to in Eastern region). Longer distances from the point of initial visit to that of treatment were associated with longer HSD. Patients who switched among different levels or different types of medical care services during their illness exhibited the longest HSD. CONCLUSIONS: In countries where the TB care systems are being restructured from a vertical to a horizontal system, it is critical to monitor HSD and be aware of its increase. The potential increase in the HSD from 2003 to 2008 observed in this study is concerning and the decline of HSD after 2008 might be attributed to the launch of contact investigation. Our results call for actions to improve the efficiency of TB diagnosis in the health care system and to increase the awareness of TB among physicians and the general public. PMID- 26527406 TI - Evaluating soil metallic pollution and consequent human health hazards in the vicinity of an industrialized zone, case study of Mubarakeh steel complex, Iran. AB - BACKGROUND: Being established in 1988 in the vicinity of Isfahan city, Mubarakeh Steel complex has imposed adverse environmental and health effects within the area. The study area is covered by lots of farms through which major crops like wheat and rice are provided. METHODS: Considering the imposed pollution load of the complex, the current study has monitored the concentration of metals Fe, Al, Cd, Cr, Ni, Pb, Cu, Zn, Mn, Co, Mo, As in 14 soil samples within the study area. Furthermore, human health hazards of mentioned metals due to consumption of domestic rice and wheat have also been evaluated through different scenarios. In order to evaluate the mobility of metals in soil samples the sequential chemical analysis is performed. RESULTS: Regarding the accumulation of metals in loose phases the order of metals bioavailability risk level is estimated to be as follows: Co > Cd > Mo > Ba > As > Pb > Mn > Cu > V > Zn > Cr > Ni. DISCUSSION: An index approach is also considered to evaluate the severity of metal contamination. Regarding geochemical accumulation index, only cadmium is detected to be in a moderately contaminated status while other metals declare an unpolluted condition. Index of pollution pays more attention to mobility potential of metals and accordingly detects metals Co, Mn, As, Pb, Cd, Ba and Mo to be in a moderately contaminated level. On the other hand, enrichment factor declares all toxic metals except for Co, Ba and V to be enriched. CONCLUSIONS: Considering human health hazard assessment, except for Fe, Ba, Cu and Zn, all metals intakes in different scenarios are considered as hazardous while their CDI values are much more than the respective oral reference doses. PMID- 26527405 TI - Fast-Response Calmodulin-Based Fluorescent Indicators Reveal Rapid Intracellular Calcium Dynamics. AB - Faithful reporting of temporal patterns of intracellular Ca(2+) dynamics requires the working range of indicators to match the signals. Current genetically encoded calmodulin-based fluorescent indicators are likely to distort fast Ca(2+) signals by apparent saturation and integration due to their limiting fluorescence rise and decay kinetics. A series of probes was engineered with a range of Ca(2+) affinities and accelerated kinetics by weakening the Ca(2+)-calmodulin-peptide interactions. At 37 degrees C, the GCaMP3-derived probe termed GCaMP3fast is 40 fold faster than GCaMP3 with Ca(2+) decay and rise times, t1/2, of 3.3 ms and 0.9 ms, respectively, making it the fastest to-date. GCaMP3fast revealed discreet transients with significantly faster Ca(2+) dynamics in neonatal cardiac myocytes than GCaMP6f. With 5-fold increased two-photon fluorescence cross-section for Ca(2+) at 940 nm, GCaMP3fast is suitable for deep tissue studies. The green fluorescent protein serves as a reporter providing important novel insights into the kinetic mechanism of target recognition by calmodulin. Our strategy to match the probe to the signal by tuning the affinity and hence the Ca(2+) kinetics of the indicator is applicable to the emerging new generations of calmodulin-based probes. PMID- 26527407 TI - Developing a Nuclear Global Health Workforce Amid the Increasing Threat of a Nuclear Crisis. AB - This study argues that any nuclear weapon exchange or major nuclear plant meltdown, in the categories of human systems failure and conflict-based crises, will immediately provoke an unprecedented public health emergency of international concern. Notwithstanding nuclear triage and management plans and technical monitoring standards within the International Atomic Energy Agency and the World Health Organization (WHO), the capacity to rapidly deploy a robust professional workforce with the internal coordination and collaboration capabilities required for large-scale nuclear crises is profoundly lacking. A similar dilemma, evident in the early stages of the Ebola epidemic, was eventually managed by using worldwide infectious disease experts from the Global Outbreak Alert and Response Network and multiple multidisciplinary WHO-supported foreign medical teams. This success has led the WHO to propose the development of a Global Health Workforce. A strategic format is proposed for nuclear preparedness and response that builds and expands on the current model for infectious disease outbreak currently under consideration. This study proposes the inclusion of a nuclear global health workforce under the technical expertise of the International Atomic Energy Agency and WHO's Radiation Emergency Medical Preparedness and Assistance Network leadership and supported by the International Health Regulations Treaty. Rationales are set forth for the development, structure, and function of a nuclear workforce based on health outcomes research that define the unique health, health systems, and public health challenges of a nuclear crisis. Recent research supports that life-saving opportunities are possible, but only if a rapidly deployed and robust multidisciplinary response component exists. PMID- 26527408 TI - Editorial: The Role of Creatine on Disease-Related Conditions. PMID- 26527409 TI - Novel Benzo[d]imidazole-based Heterocycles as Broad Spectrum Anti-viral Agents: Design, Synthesis and Exploration of Molecular Basis of Action. AB - The design and synthesis of a novel series of benzo[d]imidazole-based heterocycles and their biological evaluation as antiviral agents are reported herein. 1-(1-Methyl-1H-benzo[d]imidazol- 2-yl)-2-thiocyanatoethanone 2 was used as a key intermediate for the synthesis of the thiazolylhydrazine 4, the thiazolylamine 5 and the methylthiazole 7. Coupling of compounds 5 or 7 with the appropriate diazotized aromatic amines gave the diazenyl derivatives 6a-c and 8a c, respectively. The quinazoline derivative 12 was also synthesized. On the other hand, the phenylthio 20 and the phenylsulphonyl 22 bioisosteresand their respective diazenyl derivatives 21a-c and 23a-c were prepared. The synthesized compounds were evaluated for their HIV-1, HCV, SSPE and H1N1 inhibitory activities and were found to display very promising results. Furthermore, to investigate the underlying possible mechanism of action, in vitro and in silico screening of this series of benzo[d]imidazoles was performed against the viral enzymes HIV-1 RT, HCV NS3/4A serine protease and H1N1 NA1. Overall findings of the executed investigations highlight these novel compounds as very promising potent, broad spectrum antiviral agents. PMID- 26527410 TI - Stable Freestanding Thin Films of Copolymer Melts Far from the Glass Transition. AB - Thin polymer films have attracted attention because of both their broad range of applications and of the fundamental questions they raise regarding the dynamic response of confined polymers. These films are unstable if the temperature is above their glass transition temperature Tg. Here, we describe freestanding thin films of centimetric dimensions made of a comb copolymer melt far from its glass transition that are stable for more than a day. These long lifetimes allowed us to characterize the drainage dynamics and the thickness profile of the films. Stratified regions appear as the film drains. We have evidence that the stability, thinning dynamics, and thickness profile of the films result from structural forces in the melt. Understanding the key mechanisms behind our observations may lead to new developments in polymeric thin films, foams, and emulsions without the use of stabilizing agents. PMID- 26527411 TI - Bacterial calpains and the evolution of the calpain (C2) family of peptidases. AB - Homologues of calpain, often thought to be an essential, cytoplasmic, calcium dependent cysteine endopeptidase found exclusively in eukaryotes, have been found in bacterial proteomes. The homologues lack calcium-binding sites, have differing domain architectures, and can be secreted or membrane-associated. Homologues are rare and occur in a minority of bacterial phyla and often in a minority of species in a genus. However, the differences in domain architecture argue against a recent, horizontal gene transfer from a eukaryote. From analysis of a phylogenetic tree and absence of homologues in archaea, calpains in eukaryotes may be derived from genes horizontally transferred from a bacterium. PMID- 26527412 TI - The Effect of Age and Sex on Clinical Outcome after Intravenous Recombinant Tissue Plasminogen Activator Treatment in Patients with Acute Ischemic Stroke. AB - BACKGROUND: There are conflicting results regarding the effect of intravenous (IV) recombinant tissue plasminogen activator (rtPA) stroke treatment between men and women. Studies evaluating the impact of sex differences on functional outcome in relation to different age groups are nonexistent. AIM: The objective of the study is to examine the influence of sex differences in relation to age on the prognosis after IV rtPA treatment in acute stroke patients. METHODS: In this cohort study, 887 patients with acute ischemic stroke were treated with rtPA. Functional outcome after 3 months was determined with the modified Rankin Scale (mRS). Good outcome was defined as an mRS score of 2 or lower. Age was stratified in decades (41-50, 51-60, 61-70, 71-80, and >80 years). Multivariable analyses were performed with adjustment for age, sex, stroke severity (National Institutes of Health Stroke Scale [NIHSS]), and stroke subtype (Trial of Org 10172 in Acute Stroke Treatment). RESULTS: Fifty-five percent of the patients were men. The mean age was 67.4 (men) and 72.0 (women) years. Fifty-six percent of the men and 45% of the women had a favorable outcome (P = .001). After adjustment for NIHSS score and stroke subtype, the women had a better outcome in the age group 51-60 years compared with men (odds ratio [OR] .38, 95% confidence interval [CI] .15-.96). In the age group >80 years, men had a better outcome than women (OR 2.69, 95% CI 1.21-5.96). There were no significant differences in the other age groups. CONCLUSION: Men and women have different prognoses after IV rtPA treatment for acute ischemic stroke, which also depends on age. Women in middle age appear to have a better outcome than men, whereas at a more advanced age men appear to have a better outcome than women. PMID- 26527413 TI - Characteristics and outcomes of patients with type 2 diabetes mellitus treated with canagliflozin: a real-world analysis. AB - BACKGROUND: Canagliflozin, an oral agent that inhibits sodium glucose co transporter 2, improves glycemic control, body weight, and blood pressure and is generally well tolerated in patients with type 2 diabetes mellitus (T2DM). This study extends the scope of previous analyses by evaluating outcomes associated with the use of canagliflozin over a 6-month period in a real-world setting. METHODS: This retrospective cohort study used data obtained from a large health plan database for patients (>=18 years) with a diagnosis of T2DM who filled at least one canagliflozin prescription between April 1, 2013 and October 30, 2013 (first 7 months canagliflozin was commercially available in the USA) and were continuously enrolled in the health plan for 6 months prior to (baseline) and 6 months following the first canagliflozin prescription claim (follow-up). Changes in glycemic control were evaluated, along with characteristics of enrolled patients and changes in treatment patterns. RESULTS: 4017 patients (mean age 56 years, 43 % female) met the study inclusion criteria. Of these, at the time of first canagliflozin claim, 21 % used canagliflozin concomitantly with three or more other antihyperglycemic agents (AHAs), 29 % with two other AHAs, 30 % with one other AHA, and 20 % without other AHAs. During follow-up, patients received 3.4 (average) canagliflozin prescription fills and a mean of 148 total days of supply; median adherence (interquartile range [IQR]) was 86 % (66-98 %) for patients with >=2 fills. Among patients with available glycated hemoglobin (A1C) measurements at baseline and follow-up (n = 826, baseline A1C 8.59 %), mean A1C reduction was 0.81 % (P < 0.001). Mean A1C reduction during the follow-up period was greatest in patients with the highest baseline A1C levels. Of the patients who used canagliflozin concomitantly with other AHAs, 20 % were observed to discontinue one or more other AHAs during follow-up. The most commonly discontinued baseline AHAs were: glucagon-like peptide-1 receptor agonists (16 %), dipeptidyl peptidase-4 inhibitors (15 %), insulin (13 %), sulfonylureas (13 %), and metformin (11 %). CONCLUSIONS: This real-world study on canagliflozin use in a range of patients with T2DM demonstrated significant improvements in mean A1C from baseline following the first canagliflozin prescription. In patients concomitantly using one or more additional AHAs at baseline, there appears to be a trend toward lower other AHA use after canagliflozin initiation. PMID- 26527414 TI - Functional ratios among leaf, xylem and phloem areas in branches change with shade tolerance, but not with local light conditions, across temperate tree species. AB - Leaf, xylem and phloem areas drive the water and carbon fluxes within branches and trees, but their mutual coordination is poorly understood. We test the hypothesis that xylem and phloem areas increase relative to leaf area when species are selected for, or branches are exposed to, higher levels of light intensity. Trees of 10 temperate, broadleaved and deciduous, tree species were selected. Fifty-centimetre-long branches were collected from shaded and exposed conditions at a height of 3-4 m. We measured the total leaf area, xylem area, phloem area and leaf traits, as well as the area of the constituent cell types, for a stem section at the branch base. Xylem area : leaf area and phloem area : leaf area ratios did not differ consistently between sun and shade branches, but, as expected, they decreased with species' shade tolerance. Similar trends were observed for conductive cell areas in xylem and phloem. Trees of light-demanding species maintain higher water loss and carbon gain rates per leaf area by producing more xylem area and phloem area than shade-tolerant species. We call for more comparative branch studies as they provide an integrated biological perspective on functional traits and their role in the ecology of tree species. PMID- 26527415 TI - Long-term, calorie-restricted intake of a high-fat diet in rats reduces impulse control and ventral striatal D2 receptor signalling - two markers of addiction vulnerability. AB - High impulsivity, mediated through ventral striatal dopamine signalling, represents an established risk factor for substance abuse, and may likewise confer vulnerability to pathological overeating. Mechanistically, the assumption is that trait impulsivity facilitates the initiation of maladaptive eating styles or choices. However, whether consumption of appetitive macronutrients themselves causes deficits in impulse control and striatal signalling, thereby contributing to cognitive changes permissive of overeating behaviour, has yet to be considered. We examined the effects of chronic maintenance on restricted equicaloric, but high-fat or high-sugar, diets (48 kcal/day; 60 kcal% fat or sucrose) on rats' performance in the five-choice serial reaction time task, indexing impulsivity and attention. Markers of dopamine signalling in the dorsal and ventral striatum, and plasma insulin and leptin levels, were also assessed. Rats maintained on the high-fat diet (HFD) were more impulsive, whereas the high sugar diet (HSD) did not alter task performance. Importantly, body weight and hormone levels were similar between groups when behavioural changes were observed. Maintenance on HFD, but not on HSD, reduced the levels of dopamine D2 receptor (D2 R), cAMP response element-binding protein (CREB) and phosphophorylated CREB (Ser133) proteins in the ventral, but not dorsal, striatum. D2 R expression in the ventral striatum also negatively correlated with impulsive responding, independently of diet. These data indicate that chronic exposure to even limited amounts of high-fat foods may weaken impulse control and alter neural signalling in a manner associated with vulnerability to addictions - findings that have serious implications for the propagation of uncontrolled eating behaviour in obesity and binge-eating disorder. PMID- 26527416 TI - [Contraception and obesity]. AB - The prevalence of obesity is increasing massively over several decades in industrialized countries. Obese women are sexually active but they use fewer contraceptive methods and are at high risk of unintended pregnancy. In addition, obesity is an important risk factor for venous thromboembolism events and arterial thrombosis (myocardial infarction and ischemic stroke). All of these data are to be considered in choosing a contraceptive method for obese women. Except depot medroxyprogesterone acetate injection, the progestin-only contraceptives (progestin only pills and etonogestrel subdermal implant) and the intra-uterine devices are the preferred contraceptive methods in obese women. The combined estrogen-progestin contraceptives (pill, patch and vaginal ring) may be proposed in very strict conditions (no other associated vascular risk factor). Obesity does not increase the risk of failure of most contraceptive methods. Bariatric surgery is a complex situation. It requires to program a possible pregnancy and contraception is needed for several months. Some bariatric surgical techniques such as by-pass can induce gastrointestinal malabsorption. In this situation, all oral contraceptives are not recommended because of a higher risk of failure. PMID- 26527417 TI - The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation. AB - BACKGROUND: Reabsorption of bile acids from the intestine by ileal bile acid transporter is pivotal for the enterohepatic circulation of BAs and sterol homoeostasis. AIM: To assess tolerability and study, bile acid metabolism in a phase 1 trial with the selective ileal bile acid transporter inhibitor A4250. METHODS: A randomised double-blind, single-ascending dose (SAD) and multiple ascending-dose study consisting of five cohorts comprising 40 individuals with a single administration of A4250 (0.1, 0.3, 1, 3, or 10 mg) or placebo and three cohorts comprising 24 individuals with a 1-week administration of A4250 (1 or 3 mg once daily or 1.5 mg twice daily) or placebo. For the multiple-ascending-dose study, bile acids were measured by HPLC-MS in plasma and faeces, and fibroblast growth factor 19 (FGF19) and 7alpha-hydroxy-4-cholesten-3-one (C4) were measured in plasma. RESULTS: No serious adverse events occurred and all participants finished the trial per protocol. At the end of the multiple-ascending-dose study, plasma total bile acids and FGF19 decreased by 47% and 76%, respectively, at 3 mg/day (P < 0.01), and by 15% and 16%, respectively, at 1.5 mg twice daily (P < 0.05). Plasma C4 and faecal bile acids increased at all dose regimens, by 555%, 664%, 292% and 338%, 421%, 420%, respectively (P < 0.01-0.05). The primary bile acids cholic and chenodeoxycholic acids constituted the majority of faecal bile acids in the A4250-treated groups. CONCLUSIONS: A4250 is well tolerated. By blocking ileal bile acid transporter in the terminal ileum, it highly efficiently interrupts the enterohepatic circulation of BAs, and should be of benefit to patients with cholestatic liver diseases. Clinical Trial registration EudraCT 2013-001175-21. PMID- 26527418 TI - The Synthesis and Characterization of Aromatic Hybrid Anderson-Evans POMs and their Serum Albumin Interactions: The Shift from Polar to Hydrophobic Interactions. AB - Four aromatic hybrid Anderson polyoxomolybdates with Fe(3+) or Mn(3+) as the central heteroatom have been synthesized by using a pre-functionalization protocol and characterized by using single-crystal X-ray diffraction, FTIR, ESI MS, (1) H NMR spectroscopy, and elemental analysis. Structural analysis revealed the formation of (TBA)3 [FeMo6 O18 {(OCH2 )3 CNHCOC6 H5 }2 ]?3.5 ACN (TBA-FeMo6 bzn; TBA=tetrabutylammonium, ACN=acetonitrile, bzn=TRIS-benzoic acid alkanolamide, TRIS?R=(HOCH2 )3 C?R)), (TBA)3 [FeMo6 O18 {(OCH2 )3 CNHCOC8 H7 }2 ]?2.5 ACN (TBA-FeMo6 -cin; cin=TRIS-cinnamic acid alkanolamide), (TBA)3 [MnMo6 O18 {(OCH2 )3 CNHCOC6 H5 }2 ]?3.5 ACN (TBA-MnMo6 -bzn), and (TBA)3 [MnMo6 O18 {(OCH2 )3 CNHCOC8 H7 }2 ]?2.5 ACN (TBA-MnMo6 -cin). To make these four compounds applicable in biological systems, an ion exchange was performed that gave the water-soluble (up to 80 mM) sodium salts Na3 [FeMo6 O18 {(OCH2 )3 CNHCOC6 H5 }2 ] (Na-FeMo6 -bzn), Na3 [FeMo6 O18 {(OCH2 )3 CNHCOC8 H7 }2 ] (Na-FeMo6 -cin), Na3 [MnMo6 O18 {(OCH2 )3 CNHCOC6 H5 }2 ] (Na-MnMo6 -bzn), and Na3 [MnMo6 O18 {(OCH2 )3 CNHCOC8 H7 }2 ] (Na-MnMo6 -cin). The hydrolytic stability of the sodium salts was examined by applying ESI-MS in the pH range of 4 to 9. Sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) showed that human and bovine serum albumin (HSA and BSA) remain intact in solutions that contain up to 100 equivalents of the sodium salts over more than 4 d at 20 degrees C. Tryptophan (Trp) fluorescence quenching was applied to study the interactions between the sodium salts and HSA and BSA at pH 5.5 and 7.4. The quenching constants were extracted by using Stern-Volmer analysis, which suggested the formation of a 1:1 POM-protein complex in all samples. It is suggested that the aromatic hybrid POM approaches subdomain IIA of HSA and exhibits hydrophobic interactions with its hydrophobic tails, whereas the Anderson core is stabilized through electrostatic interactions with polar amino acid side chains from, for example, subdomain IB. PMID- 26527419 TI - Synergistic effect of (+)-pinitol from Saraca asoca with beta-lactam antibiotics and studies on the in silico possible mechanism. AB - Saraca asoca bark has been used in the Ayurvedic system of medicine for female urino-genital disorders. We have recently reported the isolation and characterization of several compounds as markers to develop HPLC profiling of its methanol and aqueous methanol extracts. Now, a HPLC-PDA inactive compound, (+) pinitol has been isolated and characterized from the bark of this medicinally important tree. Pinitol is a well known bioactive compound for a variety of biological activities, including hypoglycemic and anti-inflammatory activities. A process for the isolation of relatively good concentration of (+)-pinitol from S. asoca bark has been developed and its in vitro anti TNF-alpha and anti inflammatory activities against carragenan-induced edema confirmed. While conducting experiments on the possible agonistic activity, it was found that (+) pinitol showed up to eight fold reduction in the doses of beta-lactam antibiotics. The mechanism of its agonistic activity was studied by docking experiments which showed that different conformations of (+)-pinitol and antibiotics were actually in the same binding site with no significant change in the binding energy. These docking simulations, thus predict the possible binding mode of studied compounds and probable reason behind the synergistic effect of (+)-pinitol along with beta-lactam antibiotics. PMID- 26527420 TI - Dual-channel near-field control by polarizations using isotropic and inhomogeneous metasurface. AB - We propose a method for dual-channel near-field manipulations by designing isotropic but inhomogeneous metasurfaces. As example, we present a dual-channel near-field focusing metasurface device. When the device is driven by surface waves from different channels on the metasurface, the near fields will be focused at the same spatial point with different polarizations. Conversely, if a linearly polarized source is radiated at the spatial focal point, different channels will be evoked on the metasurface controlled by polarization. We fabricated and measured the metasurface device in the microwave frequency. Well agreements between the simulation and measurement results are observed. The proposed method exhibits great flexibility in controlling the surface waves and spatial waves simultaneously. It is expected that the proposed method and dual-channel device will facilitate the manipulation of near electromagnetic or optical waves in different frequency regimes. PMID- 26527421 TI - Lessons to Exchange: A Comparison of Long-Term Care Between Two Cultures: Uganda and Singapore. AB - Today, both the developed and developing world are facing fast-aging populations. Projections show that by 2050, 80% of the world's older persons will live in low and middle-income countries. As developed countries look to institutionalization as one of the means to cope with the challenges of long-term care of seniors, the developing world, with a different cultural, socioeconomic, and environmental context, may yet offer insights that instruct and inspire. By analyzing and comparing the approaches, context, and progress of Singapore and Uganda in coping with frail and dependent seniors, this article provides lessons about what the developing and developed world can offer each other, and in turn, teach us about long-term care of seniors. PMID- 26527422 TI - Tetrandrine prevents monocrotaline-induced pulmonary arterial hypertension in rats through regulation of the protein expression of inducible nitric oxide synthase and cyclic guanosine monophosphate-dependent protein kinase type 1. AB - OBJECTIVE: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a persistent elevation of pulmonary artery pressure and ventricular hypertrophy. Tetrandrine is a bisbenzylisoquinoline alkaloid that can decrease blood pressure, inhibit the proliferation of vascular smooth muscle cells, and block cardiac hypertrophy, but whether it has a therapeutic effect on PAH remains poorly defined. This study was undertaken to investigate the efficacy of tetrandrine on PAH. METHODS: Forty-eight male Sprague-Dawley rats were randomly and equally divided into four groups. The control group was injected with normal saline; the others were injected with monocrotaline (MCT) to induce PAH, then treated with saline, tetrandrine, and vardenafil, respectively, from day 21 to day 42. On day 43, we measured the mean pulmonary artery pressure under general anesthesia, dissected the rat, and calculated the right ventricular hypertrophy index [right ventricle/(left ventricle plus septum)]. Later we observed the changes in the pulmonary vascular wall; measured the expression of cyclic guanosine monophosphate-dependent protein kinase type 1 and inducible nitric oxide synthase; measured the levels of superoxide dismutase, glutathione, malondialdehyde, and catalase; and then compared the results among groups. RESULTS: Compared with the MCT group, rats treated with tetrandrine had attenuated mean pulmonary artery pressure (20.48 +/- 1.49 vs 30.07 +/- 1.51; P < .01) and right ventricular hypertrophy index (49.19 +/- 2.45 vs 68.50 +/- 1.95; P < .01), inhibited proliferation of pulmonary artery smooth muscle cells, and improved endothelial function. Tetrandrine also upregulated the expression of protein kinase type 1 (90.86 +/- 1.95 vs 67.34 +/- 1.50; P < .01); downregulated the expression of inducible nitric oxide synthase (74.76 +/- 1.48 vs 80.19 +/- 0.28; P < .01); increased levels of superoxide dismutase (245.54 +/- 12.98 vs 166.16 +/- 21.42; P < .01), glutathione (0.699 +/- 0.032 vs 0.514 +/- 0.056; P < .01), and catalase (32.13 +/- 2.33 vs 27.19 +/- 2.72; P < .01); and decreased malondialdehyde (1.027 +/- 0.039 vs 1.462 +/- 0.055; P < .01). CONCLUSIONS: Tetrandrine alleviated MCT-induced PAH through regulation of nitric oxide signaling pathway and antioxidant and antiproliferation effects. PMID- 26527423 TI - Outcome of visceral chimney grafts after urgent endovascular repair of complex aortic lesions. AB - OBJECTIVE: Endovascular abdominal aortic repair requires an adequate sealing zone. The chimney graft (CG) technique may be the only option for urgent high risk patients who are unfit for open repair and have no adequate sealing zone. This single-center experience provides long-term results of CGs with endovascular repair for urgent and complex aortic lesions. METHODS: Between July 2006 and October 2012, 51 patients (16 women) with a median age of 77 years (interquartile range, 72-81 years), were treated urgently (within 24 hours [61%]) or semiurgently (within 3 days [39%]) with endovascular aortic repair and visceral CGs (n = 73). Median follow-up was 2.3 years (interquartile range, 0.8-5.0 years) for the whole cohort, 3 years for 30-day survivors, and 4.8 years for patients who are still alive. RESULTS: Five patients (10%) died within 30 days. All of them had a sacrificed kidney. All-cause mortality was 57% (n = 29), but the chimney- and procedure-related mortality was 6% (n = 3) and 16% (n = 8), respectively. Chimney-related death was due to bleeding, infection, renal failure, and multiple organ failure. There were two postoperative ruptures; both were fatal although not related to the treated disease. The primary and secondary long-term CG patencies were 89% (65 of 73) and 93% (68 of 73), respectively. Primary type I endoleak (EL-I) occurred in 10% (5 of 51) of the patients, and only one patient had recurrent EL-I (2%; 1 of 51). No secondary endoleak was observed. Chimney-related reintervention was required in 16% (8 of 51) of the patients because of EL-I (n = 3), visceral ischemia (n = 4), and bleeding (n = 2). The reinterventions included stenting (n = 5), embolization (n = 3), and laparotomy (n = 2). Thirty-one visceral branches were sacrificed (9 celiac trunks, 9 right, and 13 left renal arteries). Among the 30-day survivors, 8 of 17 patients (47%) with a sacrificed kidney required permanent dialysis; of these, seven underwent an urgent index operation. The aneurysm sac shrank in 63% (29 of 46) of cases. CONCLUSIONS: The 6% chimney-related mortality and 93% long-term patency seem promising in urgent, complex aortic lesions of a high-risk population and may justify a continued yet restrictive applicability of this technique. Most endoleaks could be sealed endovascularly. However, sacrifice of a kidney in this elderly cohort was associated with permanent dialysis in 47% of patients. PMID- 26527424 TI - Feasibility and accuracy of fusion imaging during thoracic endovascular aortic repair. AB - OBJECTIVE: To evaluate accuracy and feasibility of fusion imaging during thoracic endovascular aortic repair (TEVAR). METHODS: From January 2013 to January 2015 fusion imaging was used in 18 TEVAR procedures. Patients were prospectively enrolled for the survey and informed consent was obtained. Planning of the procedure and computed tomography (CT) angiography (CTA) segmentation with determination of all relevant surgical landmarks that should be displayed on fusion imaging was done using the preoperative CTA data. The registration was done with an intraoperative noncontrast-enhanced cone beam CT and CTA (three dimensional [3D]-3D registration; n = 15) or with two fluoroscopic images in anteroposterior and lateral projection and the CTA (two-dimensional-3D registration; n = 3). An intraoperative digital subtraction angiography was performed to adjust fusion imaging and to allow accuracy measurement. RESULTS: Fusion imaging was possible in all included patients. The median dose for noncontrast-enhanced cone beam CT imaging was 28.6 Gy/cm(2) (range, 17.9-43.3) and 0.46 Gy cm(2) for two fluoroscopic images in the two-dimensional-3D group. Full accuracy was achieved in two cases (11%), with a median deviation of 11.7 mm (range, 0.0-37.2). Manual realignment was possible in all cases. CONCLUSIONS: This early experience shows that fusion imaging is feasible in TEVAR procedures using different registration methods. However, it shows a significant deviation in thoracic procedures because of different sources of error, making confirmation of fusion overlay with a digital subtraction angiography necessary in any case. PMID- 26527425 TI - Unplanned return to operating room after lower extremity arterial bypass is an independent predictor for hospital readmission. AB - OBJECTIVE: Hospital readmissions after surgical operations are considered serious complications and have an impact on health care-associated costs. The Centers for Medicare and Medicaid Services strongly encourage identification and ramification of factors associated with hospital readmissions after operations. Despite advances in endovascular surgery, lower extremity arterial bypass remains the "gold standard" treatment for severe, symptomatic peripheral arterial disease. The purpose of this study was to retrospectively review the factors associated with hospital readmission after lower extremity bypass surgery. METHODS: The 2013 lower extremity revascularization-targeted American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database and generalized 2013 general and vascular surgery NSQIP Participant Use Data File were used for this study. Patient, diagnosis, and procedure characteristics of patients undergoing lower extremity bypass surgery were assessed. Multivariate logistic regression analysis was used to determine independent risk factors for hospital readmission within 30 days after surgery. RESULTS: A total of 2646 patients (65% male, 35% female) were identified in the NSQIP database who underwent lower extremity open revascularization during the year 2013. Indications for operations included tissue loss (39%), rest pain (32%), and severe claudication (25%). Preoperative ankle-brachial indices were 0.4 to 0.9 (32%) and <0.4 (16.5%). A total of 425 patients (16%) were readmitted within 30 days of index operation. Risk factors associated with readmission included wound complication (odds ratio [OR], 8.54; 95% confidence interval [CI], 6.68-10.92; P < .001), need for reoperation (OR, 5.95; 95% CI, 4.45-7.97; P < .001), postoperative myocardial infarction (OR, 2.19; 95% CI, 1.25-3.83; P = .006), wound dehiscence (OR, 8.45; 95% CI, 4.54 15.71; P < .001), organ or space surgical site infection (OR, 7.62; 95% CI, 2.89 20.14; P < .001), postoperative pneumonia (OR, 2.66; 95% CI, 1.28-5.52; P = .009), progressive renal insufficiency (OR, 4.12; 95% CI, 1.52-11.11; P = .005), superficial surgical site infection (OR, 7.37; 95% CI, 5.31-10.23; P < .001), urinary tract infection (OR, 2.67; 95% CI, 1.42-5.01; P = .002), and deep wound infection (OR, 14.0; 95% CI, 7.62-24.80; P < .001). CONCLUSIONS: Readmission after lower extremity bypass surgery is a serious complication. Various factors put a patient at high risk for readmission. Return to the operating room, wound infection, amputation, deep venous thrombosis, and major reintervention on bypass are independent risk factors for hospital readmission. Return to the operating room is associated with a 5.95-fold increase in hospital readmission. PMID- 26527426 TI - Controlled therapeutic gas delivery systems for quality-improved transplants. AB - Therapeutic gases enriched into perfusion solutions have been effectively used for the improvement of organ transplant quality. At present, the enrichment of perfusion solutions with gases requires complex machinery/containers and handling precautions. Alternatively, the gas is generated within the perfusion solution by supplemented carbonylated transition metal complexes with associated toxicological concerns when these metals contact the transplant. Therefore, we developed therapeutic gas releasing systems (TGRSs) allowing for the controlled generation and release of therapeutic gases (carbon monoxide and hydrogen sulfide) from otherwise hermetically sealed containers, such that the perfusion solution for the transplant is saturated with the gas but no other components from the TGRS are liberated in the solution. The release from the TGRS into the perfusion solution can be tailored as a function of the number and thickness of gas permeable membranes leading to release patterns having been linked to therapeutic success in previous trials. Furthermore, the surrogate biomarker HMGB1 was significantly downregulated in ischemic rat liver transplants perfused with enriched CO solution as compared to control. In conclusion, the TGRS allows for easy, reliable, and controlled generation and release of therapeutic gases while removing safety concerns of current approaches, thereby positively impacting the risk benefit profile of using therapeutic gases for transplant quality improvement in the future. PMID- 26527427 TI - HPV testing alone is not as safe as cytology and selective HPV testing: AGAINST: There is powerful evidence for primary cervical screening. PMID- 26527428 TI - Iatrogenic bile duct injury with loss of confluence. AB - AIM: To describe our experience concerning the surgical treatment of Strasberg E 4 (Bismuth IV) bile duct injuries. METHODS: In an 18-year period, among 603 patients referred to our hospital for surgical treatment of complex bile duct injuries, 53 presented involvement of the hilar confluence classified as Strasberg E4 injuries. Imagenological studies, mainly magnetic resonance imaging showed a loss of confluence. The files of these patients were analyzed and general data were recorded, including type of operation and postoperative outcome with emphasis on postoperative cholangitis, liver function test and quality of life. The mean time of follow-up was of 55.9 +/- 52.9 mo (median = 38.5, minimum = 2, maximum = 181.2). All other patients with Strasberg A, B, C, D, E1, E2, E3, or E5 biliary injuries were excluded from this study. RESULTS: Patients were divided in three groups: G1 (n = 21): Construction of neoconfluence + Roux-en-Y hepatojejunostomy. G2 (n = 26): Roux-en-Y portoenterostomy. G3 (n = 6): Double (right and left) Roux-en-Y hepatojejunostomy. Cholangitis was recorded in two patients in group 1, in 14 patients in group 2, and in one patient in group 3. All of them required transhepatic instrumentation of the anastomosis and six patients needed live transplantation. CONCLUSION: Loss of confluence represents a surgical challenge. There are several treatment options at different stages. Roux en-Y bilioenteric anastomosis (neoconfluence, double-barrel anastomosis, portoenterostomy) is the treatment of choice, and when it is technically possible, building of a neoconfluence has better outcomes. When liver cirrhosis is shown, liver transplantation is the best choice. PMID- 26527429 TI - Mu opioid receptor polymorphism, early social adversity, and social traits. AB - A polymorphism in the mu opioid receptor gene OPRM1 (rs1799971) has been investigated for its role in sensitivity to social contexts. Evidence suggests that the G allele of this polymorphism is associated with higher levels of sensitivity. This study tested for main effects of the polymorphism and its interaction with a self-report measure of childhood adversity as an index of negative environment. Outcomes were several personality measures relevant to social connection. Significant interactions were obtained, such that the negative impact of childhood adversity on personality was greater among G carriers than among A homozygotes on measures of agreeableness, interdependence, anger proneness, hostility, authentic pride, life engagement, and an index of (mostly negative) feelings coloring one's world view. Findings support the role of OPRM1 in sensitivity to negative environments. Limitations are noted, including the lack of a measure of advantageous social environment to assess sensitivity to positive social contexts. PMID- 26527430 TI - Survival and toxicity following sequential multimodality treatment including whole abdominopelvic radiotherapy for patients with desmoplastic small round cell tumor. AB - BACKGROUND AND PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive malignancy. We report survival rates and toxicity associated with sequential multimodality treatment including whole abdominopelvic radiation therapy (WART). MATERIAL AND METHODS: Medical records of 32 patients with DSRCT treated at our institution were reviewed. Patients underwent chemotherapy, cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (HIPEC), followed by WART with intensity-modulated radiation or volumetric-modulated arc therapy. RESULTS: Median overall survival (OS) was 60months. After 18months of follow-up, 20 patients (62.5%) had disease recurrence and median disease-free survival (DFS) was 10months. Median time to extrahepatic abdominal failure was 19.4months. Factors affecting time to local progression included liver metastases at diagnosis, and an interval of greater than 5.6months between diagnosis and HIPEC or greater than 2.1months between HIPEC and WART. None of these factors altered OS. Grade 3 or higher toxicities occurred in 84% of patients. CONCLUSIONS: WART following chemotherapy, surgical cytoreduction and HIPEC is an aggressive treatment for DSRCT patients and can result in severe side effects. Our median OS of 5years is favorable compared to prior studies, despite a median DFS of only 10months, which may be due to improved salvage therapies. PMID- 26527431 TI - Rare association of insulin autoimmune syndrome with ankylosing spondylitis. AB - Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinemic hypoglycaemia, which is known to occur in association with the use of sulfhydryl containing drugs and autoimmune disorders. We describe a patient with hitherto an unreported association of IAS with ankylosing spondylitis. We have also performed and described a simplified method of polyethylene glycol (PEG) precipitation of an insulin bound antibody in the serum. LEARNING POINTS: IAS should be considered in differential diagnosis of endogenous hyperinsulinemic hypoglycaemia.Ankylosing spondylitis can be associated with IAS apart from several other autoimmune diseases.Very high serum insulin levels (100-10 000 MUU/ml) are frequently seen in IAS.When faced with very high serum insulin before suspecting insulinoma, it is advisable that PEG precipitation of serum be done to identify antibody bound insulin.A clinical suspicion of IAS can avoid expensive imaging and unnecessary surgery in affected patients. PMID- 26527432 TI - Dynamic Heterogeneity of the Heart Valve Interstitial Cell Population in Mitral Valve Health and Disease. AB - The heart valve interstitial cell (VIC) population is dynamic and thought to mediate lay down and maintenance of the tri-laminar extracellular matrix (ECM) structure within the developing and mature valve throughout life. Disturbances in the contribution and distribution of valve ECM components are detrimental to biomechanical function and associated with disease. This pathological process is associated with activation of resident VICs that in the absence of disease reside as quiescent cells. While these paradigms have been long standing, characterization of this abundant and ever-changing valve cell population is incomplete. Here we examine the expression pattern of Smooth muscle alpha-actin, Periostin, Twist1 and Vimentin in cultured VICs, heart valves from healthy embryonic, postnatal and adult mice, as well as mature valves from human patients and established mouse models of disease. We show that the VIC population is highly heterogeneous and phenotypes are dependent on age, species, location, and disease state. Furthermore, we identify phenotypic diversity across common models of mitral valve disease. These studies significantly contribute to characterizing the VIC population in health and disease and provide insights into the cellular dynamics that maintain valve structure in healthy adults and mediate pathologic remodeling in disease states. PMID- 26527434 TI - Giants in Chest Medicine: John F. Murray, MD. PMID- 26527433 TI - Neural influences on human intestinal epithelium in vitro. AB - KEY POINTS: We present the first systematic and, up to now, most comprehensive evaluation of the basic features of epithelial functions, such as basal and nerve evoked secretion, as well as tissue resistance, in over 2200 surgical specimens of human small and large intestine. We found no evidence for impaired nerve evoked epithelial secretion or tissue resistance with age or disease pathologies (stomach, pancreas or colon cancer, polyps, diverticulitis, stoma reversal). This indicates the validity of future studies on epithelial secretion or resistance that are based on data from a variety of surgical specimens. ACh mainly mediated nerve-evoked and basal secretion in the small intestine, whereas vasoactive intestinal peptide and nitric oxide were the primary pro-secretory transmitters in the large intestine. The results of the present study revealed novel insights into regional differences in nerve-mediated secretion in the human intestine and comprise the basis by which to more specifically target impaired epithelial functions in the diseased gut. ABSTRACT: Knowledge on basic features of epithelial functions in the human intestine is scarce. We used Ussing chamber techniques to record basal tissue resistance (R-basal) and short circuit currents (ISC; secretion) under basal conditions (ISC-basal) and after electrical field stimulation (ISC-EFS) of nerves in 2221 resectates from 435 patients. ISC-EFS was TTX-sensitive and of comparable magnitude in the small and large intestine. ISC EFS or R-basal were not influenced by the patients' age, sex or disease pathologies (cancer, polyps, diverticulitis). Ion substitution, bumetanide or adenylate cyclase inhibition studies suggested that ISC-EFS depended on epithelial cAMP-driven chloride and bicarbonate secretion but not on amiloride sensitive sodium absorption. Although atropine-sensitive cholinergic components prevailed for ISC-EFS of the duodenum, jejunum and ileum, PG97-269-sensitive [vasoactive intestinal peptide (VIP) receptor 1 antagonist] VIPergic together with L-NAME-sensitive nitrergic components dominated the ISC-EFS in colonic preparations. Differences in numbers of cholinergic or VIPergic neurons, sensitivity of epithelial muscarinic or VIP receptors, or stimulus frequency dependent transmitter release were not responsible for the region-specific transmitter contribution to ISC-EFS. Instead, the low atropine-sensitivity of ISC EFS in the colon was the result of high cholinesterase activity because neostigmine revealed cholinergic components. Colonic ISC-EFS remained unchanged after tachykinin, P2X, P2Y or A1 and A2 receptor blockade. R-basal was smaller and ISC-basal was higher in the small intestine. TTX and bumetanide decreased ISC basal in all regions, suggesting nerve-dependent secretory tone. ISC-basal was atropine-sensitive in the small intestine and PG97-269-sensitive in the large intestine. This comprehensive study reveals novel insights into region-specific nerve-mediated secretion in the human small and large intestine. PMID- 26527435 TI - Smoking and Emphysema: Looking Beyond the Cigarette. PMID- 26527436 TI - The Weighty Issue of Obesity Management in Sleep Apnea. PMID- 26527438 TI - Correction to Table in: Dosing Frequency of Unfractionated Heparin Thromboprophylaxis: A Meta-analysis. PMID- 26527437 TI - Childhood OSA Syndrome: Patience for Your Patients Is a Virtue. PMID- 26527439 TI - Unusual Acute Sequelae of alpha1-Antitrypsin Deficiency: A Myriad of Symptoms With One Common Cure. AB - Panniculitis associated with alpha1-antitrypsin deficiency (AATD) is well documented but rare. We report the first case, to our knowledge, of successful induction of clinical remission of AATD-related panniculitis following a single 120-mg/kg dose administration of plasma-purified alpha1-antitrypsin (AAT). A 23 year-old man with known PiZZ AATD presented to the hospital with a diffusely swollen and tender right upper limb. This was associated with subcutaneous induration, and a discrepancy of 5 cm in upper limb circumference at the mid arm was noted. There was no convincing precipitant for cellulitis or an infectious cause, and inflammatory markers were raised, with a C-reactive protein (CRP) level of 93.9 mg/L and erythrocyte sedimentation rate (ESR) of 71 mm/h. Doppler ultrasonography ruled out DVT. No antimicrobials or antiinflammatory medications were administered during or prior to admission. Biopsy specimens of the right upper limb revealed extensive panniculitis with neutrophils, foamy macrophages, and fat necrosis. A diagnosis of AATD-associated panniculitis was made. Following this, a single IV dose of 120 mg/kg of plasma-purified AAT was administered. By day 7 post AAT infusion, CRP level had normalized to 4.6 mg/L and ESR had dropped to 22 mm/h. Limb circumference discrepancy on day 7 was 1 cm. There was no tenderness to palpation or induration, and a clinical remission of panniculitis was observed. We report the first case, to our knowledge, of clinical remission following a single treatment with IV AAT at a dose of 120 mg/kg. This opens avenues to more timely and effective treatment of the more severe presentations of AAT-associated panniculitis. PMID- 26527440 TI - A 69-Year-Old Man With Dyspnea Following Lung Biopsy. PMID- 26527441 TI - A 66-Year-Old Man With a Past History of Relapsing Polychondritis Presented With Right Upper Lobe Consolidation, Nodular Airway Lesions, and a Corticosteroid Responsive Chronic Cough. AB - A 66-year-old male nonsmoker from Arizona was referred to our practice for evaluation of chronic cough. He had a history of biopsy-proven relapsing polychondritis manifesting as right auricular and nasal pain and swelling 9 months prior to presentation. The onset of his cough coincided with the diagnosis of relapsing polychondritis, and he was prescribed prednisone 90 mg/d, which promptly relieved his rheumatologic and respiratory symptoms. A chest radiograph, obtained prior to the initiation of therapy, was normal. Any attempts at decreasing the dose of the glucocorticoid to < 30 mg/d resulted in recurrence of the cough but not of the auricular or nasal symptoms. A second chest radiograph done 6 months before presentation, while the patient was receiving prednisone 20 mg/d, was normal as well. In anticipation of our evaluation, he stopped all glucocorticoids for 7 days. He was not receiving any other medications, and he had no history of an atopic diathesis. PMID- 26527442 TI - A 34-Year-Old Woman With Recurrent Right-Sided Chest Pain and Dyspnea. AB - A 34-year-old woman presented with her third episode of acute-onset right-sided chest pain and dyspnea. She had two prior similar occurrences of right-sided sharp, pleuritic chest pain with radiation to the back and dyspnea. Chest radiographs during these presentations revealed a small apical right-sided pneumothorax that was managed conservatively with high-flow oxygen. All three presentations were associated with vigorous exercise and the first day of her menses. She denied cough, hemoptysis, fever, smoking history, airplane travel, scuba diving, or trauma during these presentations. The patient has been trying to conceive for the past year but has been unsuccessful because of uterine fibroids but no history of endometriosis. PMID- 26527443 TI - A 23-Year-Old Man With Recurrent Hemoptysis. AB - A 23-year-old white man was admitted to the hospital for evaluation of recurrent hemoptysis. He denied any other associated symptoms, including dyspnea, chest pain, productive cough, wheezing, fever, or weight loss. He had no significant past medical history and was not taking any medication. He had no significant family history for cardiopulmonary diseases. PMID- 26527444 TI - A 21-Year-Old Woman With Cystic Fibrosis, Abdominal Pain, and Recent Weight Loss. AB - A 21-year-old woman with cystic fibrosis (CF) was seen in the pulmonary clinic complaining of abdominal pain. Her past medical history included bilateral lung transplantation for CF pulmonary disease 26 months previously, as well as gastroesophageal reflux disease and pancreatic insufficiency. Her baseline weight was 49.1 kg (BMI, 19.4 kg/m2). PMID- 26527445 TI - Therapeutic Bronchoscopy: "Can" Does Not Necessarily Mean "Should". PMID- 26527446 TI - Response. PMID- 26527447 TI - Biomass Pollution, Chimney Stove Interventions, and Discrepant Outcomes. PMID- 26527448 TI - Upper Lobe or Upper Division Bronchus. PMID- 26527449 TI - Response. PMID- 26527450 TI - OSA and Work-Related Injuries: Searching for Evidence. PMID- 26527451 TI - Response. PMID- 26527452 TI - Predictors of in-hospital mortality following redo cardiac surgery: Single center experience. AB - PURPOSE: Redo cardiac operations represent one of the main challenges in heart surgery. The purpose of the study was to analyze the predictors of in-hospital mortality in patients undergoing reoperative cardiac surgery by a single surgical team. METHODS: A total of 1367 patients underwent cardiac surgical procedures and prospectively entered into a computerized database. Patients were divided into 2 groups based on the reoperative cardiac surgery (n = 109) and control group (n = 1258). Uni- and multivariate logistic regression analysis were performed to evaluate the possible predictors of hospital mortality. RESULTS: Mean age was 56 +/- 13, and 46% were female in redo group. In-hospital mortality was 4.6 vs. 2.2%, p = 0.11. EuroSCORE (6 vs. 3; p < 0.01), cardiopulmonary bypass time (90 vs. 71 min; p < 0.01), postoperative bleeding (450 vs. 350 ml; p < 0.01), postoperative atrial fibrillation (AF) (29 vs. 16%; p < 0.01), and inotropic support (58 vs. 31%; p = 0.001) were significantly different. These variables were entered into uni- and multivariate regression analysis. Postoperative AF (OR1.76, p = 0.007) and EuroSCORE (OR 1.42, p < 0.01) were significant risk factors predicting hospital mortality. CONCLUSIONS: Reoperative cardiac surgery can be performed under similar risks as primary operations. Postoperative AF and EuroSCORE are predictors of in-hospital mortality for redo cases. PMID- 26527453 TI - The role of knee joint moments and knee impairments on self-reported knee pain during gait in patients with knee osteoarthritis. AB - BACKGROUND: The association between high mechanical knee joint loading during gait with onset and progression of knee osteoarthritis has been extensively studied. However, less attention has been given to risk factors related to increased pain during gait. The purpose of this study was to evaluate knee joint moments and clinical characteristics that may be associated with gait-related knee pain in patients with knee osteoarthritis. METHODS: Sixty-seven participants with knee osteoarthritis were stratified into three groups of no pain (n=18), mild pain (n=27), or moderate/severe pain (n=22) based on their self-reported symptoms during gait. All participants underwent three-dimensional gait analysis. Quadriceps strength, knee extension range of motion, radiographic knee alignment and self-reported measures of global pain and function were also quantified. FINDINGS: The moderate/severe pain group demonstrated worse global pain (P<0.01) and physical function scores (P<0.01) compared to the no pain and the mild pain groups. The moderate/severe pain group also walked with greater knee flexion moments during the midstance phase of gait compared to the no pain group (P=0.02). Additionally, the moderate/severe pain group demonstrated greater varus knee malalignment (P=0.009), which was associated with higher weight acceptance peak knee adduction moments (P=0.003) and worse global pain (P=0.003) and physical function scores (P=0.006). INTERPRETATION: Greater knee flexion moment is present during the midstance phase of gait in patients with knee osteoarthritis and moderate/severe pain during gait. Additionally, greater varus malalignment may be a sign of increased global knee joint dysfunction that can influence many activities of daily living beyond gait. PMID- 26527455 TI - The Self in Pain. AB - The self is not a unitary concept but has different facets, encompassing potentially contradictory states, intentions or desires.The ensuing contradictory facets of the self lead to internal discrepancies which can have both motivational and emotional consequences.Self-Discrepancy Theory (SDT) explains emotional consequences by considering discrepancies between the actual, ideal or ought self.Depression can be part predicted by considering the extent an individual regards their self as enmeshed with their pain.Individuals who place a high value on independence or social interaction are more likely to experience a high anxious state in the presence of the "mere threat" of pain enmeshment.Consequently pain can rapidly come to infiltrate and affect a person's sense of self. PMID- 26527454 TI - Neurotoxicity induced by zinc oxide nanoparticles: age-related differences and interaction. AB - This study mainly investigated the neurotoxicity induced by zinc oxide nanoparticle (ZnO NP) in different-aged mice and the interaction between age and ZnO NP exposure. Sixty adult and old male C57BL/6J mice were assigned to four groups based on a two-factor (age and ZnO NP exposure) design. Results showed that ZnO NPs (5.6 mg/kg, intraperitoneal) induced increased production of pro inflammatory cytokines in the serum and the brain of mice. A synergistic reaction between aging and ZnO NP exposure occurred regarding serum interleukin 1 (IL-1) and interleukin 6 (IL-6). In the brain, increased oxidative stress level, impaired learning and memory abilities, and hippocampal pathological changes were identified, especially in old mice, following ZnO NP exposure. Then, a potential mechanism of cognitive impairment was examined. The contents of hippocampal cAMP response element binding protein (CREB), phosphorylated CREB, synapsin I, and cAMP were decreased in an age-dependent manner, and the most substantial decrease occurred in old mice treated with ZnO NPs. These findings demonstrated for the first time that aging and ZnO NP exposure synergistically influenced systemic inflammation, and indicated old individuals were more susceptible to ZnO NP induced neurotoxicity. One of the mechanisms might due to the supression of cAMP/CREB signaling. PMID- 26527456 TI - Influence of para substituents in controlling photophysical behavior and different non-covalent weak interactions in zinc complexes of a phenol based "end off" compartmental ligand. AB - Three dinuclear zinc(II) complexes with "end-off" compartmental ligands, namely 2,6-bis(N-ethylmorpholine-iminomethyl)-4-R-phenol (R = -CH3, Cl, (t)Bu) have been synthesized with the aim of exploring the role of the para substituent present in the ligand backbone in controlling the structural diversity, photophysical properties and different weak interactions of the complexes. All three species, with the general formula {2[Zn2L(CH3COO)2][Zn(NCS)4]}, show the complex anion Zn(NCS)4(2-) as a common structural feature decisive for crystallization. Interestingly, all of them possess several non-covalent weak interactions where the nature of the "R" group plays an essential role as exposed by DFT study. Besides exhibiting fluorescence behavior, the complexes also show para substitution controlled phosphorescence both at room and low temperature. Anisotropy studies suggest the existence of complexes 2 and 3 as dimers in solution. The origins of the unusual room temperature phosphorescence and fluorescence behavior of the complexes have been rationalized in the light of theoretical calculations. PMID- 26527457 TI - Trypanosoma cruzi mitochondrial tryparedoxin peroxidase is located throughout the cell and its pull down provides one step towards the understanding of its mechanism of action. AB - Trypanosoma cruzi depends on the effectiveness of redox metabolism to survive and ensure infection in the host. Homeostasis of redox metabolism in T. cruzi is achieved by the actions of several proteins that differ in many aspects from host proteins. Although extensive research has been performed examining hydroperoxide cytosolic antioxidant defense centered on trypanothione, the mechanisms of mitochondrial antioxidant defense are not yet known. The aim of this study was to elucidate the partners of TcMPx antioxidant pathway and to determine the influence of the cellular context (physiological versus oxidative stress). Through co-precipitation coupled with a mass spectrometry approach, a variety of proteins were detected under physiological and oxidative stress conditions. Interestingly, functional category analysis of the proteins identified under physiological conditions showed that they were involved in the stress response, oxidoreduction, thiol transfer, and metabolic processes; this profile is distinct under oxidative stress conditions likely due to structural alterations. Our findings help to elucidate the reactions involving TcMPx and most importantly also reveal that this protein is present throughout the cell and that its interaction partners change following oxidative stress exposure. The involvement and significance of the proteins found to interact with TcMPx and other possible functions for this protein are discussed widening our knowledge regarding T. cruzi mitochondrial antioxidant defenses. PMID- 26527458 TI - Urinary diversion for patients with inoperable obstetric vesicovaginal fistula: the Jos, Nigeria experience. AB - INTRODUCTION: Repair of obstetric urinary fistula may result in successful fistula closure, but often incontinence persists. Our goal was to review our experience with continent urinary diversion in our patients with inoperable vesicovaginal fistula (VVF). METHODS: The database of patients who underwent urinary diversion at ECWA Evangel VVF Centre in Jos, Nigeria, between 1996 and 2012, was reviewed. Complications and surgical outcomes were noted. The earlier patients (1996-2002) and the later patients (2003-2012) were compared. RESULTS: Urinary diversions were performed on 118 patients. Compared with the earlier patients, the later patients more often underwent modified Mainz II diversions, had similar complication rates, but had better outcomes. The use of ureteric catheters intraoperatively and the performance of modified Mainz II pouch were associated with a better outcome. Overall perioperative mortality was 2.5 %. CONCLUSIONS: Urinary diversion is feasible in a low-resource setting. Use of modified Mainz II pouch diversion and intraoperative ureteric catheters were associated with a better outcome. Urinary diversion should be undertaken only after the careful counseling of each patient, and by an experienced surgeon. PMID- 26527459 TI - Intron V, not intron I of human thrombopoietin, improves expression in the milk of transgenic mice regulated by goat beta-casein promoter. AB - Introns near 5' end of genes generally enhance gene expression because of an enhancer /a promoter within their sequence or as intron-mediated enhancement. Surprisingly, our previous experiments found that the vector containing the last intron (intron V) of human thromobopoietin (hTPO) expressed higher hTPO in cos-1 cell than the vector containing intron I regulated by cytomegalovirus promoter. Moreover, regulated by 1.0 kb rat whey acidic protein promoter, hTPO expression was higher in transgenic mice generated by intron V-TPOcDNA than in transgenic mice generated by TPOcDNA and TPOgDNA. However, it is unknown whether the enhancement of hTPO expression by intron I is decreased by uAUG7 at 5'-UTR of hTPO in vivo. Currently, we constructed vectors regulated by stronger 6.5 kb beta casein promoter, including pTPOGA (containing TPOcDNA), pTPOGB (containing TUR TPOcDNA, TUR including exon1, intron I and non-coding exon2 of hTPO gene), pTPOGC (containing DeltaTUR-TPOcDNA, nucleotides of TUR from uAUG7 to physiological AUG were deleted), pTPOGD (containing intron V-TPOcDNA) and pTPOGE (containing TPOgDNA), to evaluate the effect of intron I on hTPO expression and to further verify whether intron V enhances hTPO expression in the milk of transgenic mice. The results demonstrated that intron V, not intron I improved hTPO expression. PMID- 26527460 TI - A study on verifying the effectiveness of 4-week composite weight-loss dietary supplement ingestion on body composition and blood lipid changes in middle-aged women. AB - PURPOSE: The purpose of this study was to investigate the effectiveness of a composite weight-loss dietary supplement on body composition and blood lipid changes in middle-aged women. METHODS: Thirty seven middle-aged women living in the Kyunggi area participated in this study and they were randomly divided into 2 groups (Dietary supplement ingestion group; DG, n = 20 and Placebo group; PG, n = 17). Blood draw and dual energy x-ray (DEXA) measurements were conducted to examine changes in body composition and blood lipids. RESULTS: There were no significant changes in weight and BMI in both groups. There was an interaction between the composite weight-loss dietary supplement intake and lean body mass in DG and there was a significant decrease in percent body fat in DG. Blood lipid changes in the study results showed that there was no significant difference in TC, TG, and LDL in both groups; however, there was a significant interaction between the composite weight-loss dietary supplement intake and HDL-C as well as an increase in the HDL-C of DG. CONCLUSION: In conclusion, it seems that 4-week ingestion of the composite weight-loss dietary supplement decreased body fat, increased lean body mass, and increased HDL-C. Therefore, the composite weight loss dietary supplement is expected to prevent obesity and induce health improvements in middle-aged women. PMID- 26527461 TI - Erratum to: Combined effects of climatic gradient and domestic livestock grazing on reptile community structure in a heterogeneous agroecosystem. PMID- 26527462 TI - The relative contribution of short-term versus long-term effects in shrub understory species interactions under arid conditions. AB - Plant-plant interactions (competition and facilitation) in terrestrial ecosystems include: (1) short-term effects, primarily quantified with experimental removals; and (2) long-term effects, mostly due to soil weathering processes, primarily quantified with observational methods. It has been argued that these effects are likely to vary in contrasting directions with increasing drought stress in arid systems. However, few studies have used appropriate methodology to assess both types of effects and their variation across nurse species and environmental conditions, in particular in arid systems. This knowledge is crucial for predicting variation in the mediating role of facilitation with climate change and assessing the importance of nurse effects in ecological restoration. In the arid climate of central-south Tunisia, understory species' biomass, abundance and composition and soil parameters were compared in shrub-control, shrub-removed and open areas for three shrub species and in two habitats with contrasting soil moisture conditions. Long-term effects were dominant, positive for all three shrub species and associated with increasing nutrient content in shrub patches. Short-term effects, mainly related to water consumption, were weaker, mostly negative and dependent on shrub species. Additionally, long-term effects were less positive and short-term effects more negative in the dry habitat than in the wet habitat. Our study provides evidence of the primary influence of positive (facilitative) long-term effects in this arid system. However, the net effects of shrubs could be less beneficial for other species with increasing aridity under climate change, due to both a decrease in positive long-term effects and an increase in negative short-term effects. PMID- 26527463 TI - Degradation of soil fertility can cancel pollination benefits in sunflower. AB - Pollination and soil fertility are important ecosystem services to agriculture but their relative roles and potential interactions are poorly understood. We explored the combined effects of pollination and soil fertility in sunflower using soils from a trial characterized by different long-term input management in order to recreate plausible levels of soil fertility. Pollinator exclusion was used as a proxy for a highly eroded pollination service. Pollination benefits to yield depended on soil fertility, i.e., insect pollination enhanced seed set and yield only under higher soil fertility indicating that limited nutrient availability may constrain pollination benefits. Our study provides evidence for interactions between above- and belowground ecosystem services, highlighting the crucial role of soil fertility in supporting agricultural production not only directly, but also indirectly through pollination. Management strategies aimed at enhancing pollination services might fail in increasing yield in landscapes characterized by high soil service degradation. Comprehensive knowledge about service interactions is therefore essential for the correct management of ecosystem services in agricultural landscapes. PMID- 26527464 TI - Late tissue erosion after transcatheter closure of an atrial septal defect. AB - We present the case of a 27-year-old male presenting with sudden-onset retrosternal chest pain, dyspnea, and cardiac tamponade due to erosion of an Amplatzer Atrial Septal Occluder (ASO) through the left atrial wall 4 years after placement. Emergent surgical management of the hemopericardium, followed by surgical removal of the device, repair of the left atrial wall perforation, and patch closure of the atrial septal defect (ASD) were performed successfully. Tissue erosion leading to hemopericardium and cardiac tamponade should be suspected in subjects with a history of transcatheter ASD closure who present with acute chest pain or dyspnea and signs of hemodynamic instability (c) 2015 Wiley Periodicals, Inc. PMID- 26527465 TI - Role and timing of endoscopy in acute biliary pancreatitis. AB - The role and timing of endoscopy in the setting of acute biliary pancreatitis (ABP) is still being debated. Despite numerous randomized trials have been published, there is an obvious lack of consensus on the indications and timing of endoscopic retrograde cholangiopancreatography (ERCP) in ABP in meta-analyses and nationwide guidelines. The present editorial has been written to clarify the role of endoscopy in ABP. In clinical practice the decision to perform an ERCP is often based on biochemical and radiological criteria despite they already have been shown to be unreliable predictors of common bile duct stone presence. Endoscopic ultrasonography (EUS) is not currently a worldwide standard diagnostic procedure early in the course of acute biliary pancreatitis, but it has been shown to be accurate, safe and cost effective in diagnosing biliary obstructions compared with magnetic resonance cholangiopancreatography and ERCP and therefore in preventing unnecessary ERCP and its related complications. Early EUS in ABP allows, if appropriate, immediate endoscopic treatment and significant spare of unnecessary operative procedures thus reducing possible related complications. PMID- 26527467 TI - Chronic Pain and Icebergs. PMID- 26527466 TI - The effects of water-based exercise in combination with blood flow restriction on strength and functional capacity in post-menopausal women. AB - Water-based exercise and low-intensity exercise in combination with blood flow restriction (BFR) are two methods that have independently been shown to improve muscle strength in those of advancing age. The objective of this study was to assess the long-term effect of water-based exercise in combination with BFR on maximum dynamic strength and functional capacity in post-menopausal women. Twenty eight women underwent an 8-week water-based exercise program. The participants were randomly allocated to one of the three groups: (a) water exercise only, (b) water exercise + BFR, or (c) a non-exercise control group. Functional capacity (chair stand test, timed up and go test, gait speed, and dynamic balance) and strength testing were tested before and after the 8-week aquatic exercise program. The main findings were as follows: (1) water-based exercise in combination with BFR significantly increased the lower limb maximum strength which was not observed with water-based exercise alone and (2) water-based exercise, regardless of the application of BFR, increased functional performance measured by the timed up and go test over a control group. Although we used a healthy population in the current study, these findings may have important implications for those who may be contraindicated to using traditional resistance exercise. Future research should explore this promising modality in these clinical populations. PMID- 26527468 TI - Recent Advancements in Temporomandibular Disorders (TMDs). AB - TMDs are a group of conditions affecting the joint and or the muscles of mastication.TMDs consist of three main groups of conditions: myofascial pain; disc disorders; TMJ arthritides.The gold standard diagnostic criteria for research involving TMDs are the Research Diagnostic Criteria for TMDs (RDC/TMD). A pragmatic clinically applicable alternative is the Clinical examination protocol for TMDs (CEP-TMD).Signs and symptoms can include: pain in masticatory musculature and or the joint; noises associated with joint movements; locking; headache; otalgia.TMDs' aetiology is multifactorial and biopsychosocial in nature.Reversible conservative management as defined by the American Association of Dental Research is the initial management of choice for all subgroups of TMDs. PMID- 26527469 TI - Storage of Fractional Flow Reserve Hemodynamic Waveforms Using Semantic Extension of the DICOM Standard. AB - Visual assessment of coronary stenoses by coronary angiography remains widely used but correlates poorly with ischemia, particularly for moderate lesions. Fractional flow reserve (FFR) is a cardiac catheterization procedure that aims to provide objective measures of coronary lesion hemodynamic significance and involves the acquisition of phasic pressure and electrocardiographic waveforms. The dataset from these procedures currently remains in proprietary systems with restricted data access, inability for data exchange, and often inadequate archiving. Digital Imaging and Communications in Medicine (DICOM) includes a waveform information object definition. We describe the method of encapsulating FFR procedural information into a DICOM waveform file. We define private data elements to capture modality-specific data that is not represented by standard DICOM data elements. We propose the adoption of this semantic extension of the DICOM waveform information object for exchange and archiving of data from studies of pressure-derived indices of coronary stenoses. PMID- 26527470 TI - Sex Differences in Early-Age Mortality: The Preconception Origins Hypothesis. PMID- 26527471 TI - Reproductive History and Later-Life Comorbidity Trajectories: A Medicare-Linked Cohort Study From the Utah Population Database. AB - Reproductive lives of men and women may provide significant insight into later life morbidity and mortality. Sociological, biological, and evolutionary theories predict a relationship between reproductive history and later-life health; however, current research is lacking consensus on the direction of the relationship. Parity, early age at first birth and last birth, birth weight of offspring, having a child die as an infant, and having a preterm birth may have long-term effects on health for both men and women. In this study, the relationship between these measures of reproductive history and later-life health is examined using the Utah Population Database (a rich source of longitudinal data), and Medicare claims data from 1992-2009. Later-life health is measured using annual Charlson comorbidity index scores, a construct that summarizes most serious illnesses afflicting older individuals. Group-based trajectory modeling that accounts for nonrandom attrition due to death is used to identify the number and types of morbidity trajectories by sex and age for 52,924 individuals aged 65 84 in 1992. For females, early age at first birth, high parity, and having a preterm or high-birth-weight baby are associated with increased risks of comorbidity; later age at last birth is associated with a decreased risk of comorbidity. For males, early age at first birth and having a child with an abnormal birth weight leads to increased risk of comorbidity. The results suggest that both biological and social factors play important roles in the relationships between fertility and morbidity profiles at older ages. PMID- 26527472 TI - Clinical and pathogenetic features of early- and late-onset pre-eclampsia. AB - BACKGROUND: PE is present in ~2-8% of all pregnant women worldwide. Placental bed disorders at early and late PE have been not carried out yet. However, these studies help to explore details of the pathogenesis of PE, and to optimize the prognosis and obstetric management. OBJECTIVE: To identify clinical and morphological differences between early- and late-onset PE based on a comprehensive observation of pregnant women with regard to morphological and immunohistochemical characteristics of the placental bed. MATERIALS AND METHODS: One hundred fifty patients aged 18-43 years old delivered by cesarean section due to severe PE. The samples of placental bed tissue were studied by morphological and immunohistochemical methods. RESULTS: The violation of invasion trophoblast, remodeling of spiral arteries were expressed in early onset PE; the degree of compensation of chronic hypoxia tissue in the area of the placental site was typical for late PE and was absent of an early onset PE. CONCLUSION: Our studies confirm the need for separation of early- and late-onset PE, being justified in terms of different pathogenetic mechanisms of formation, and therefore the possibility of therapeutic effects, duration of pregnancy prolongation, forecasting, search early diagnostic markers of the disease, and personalized approaches. PMID- 26527473 TI - Noninvasive measurement of lower extremity muscle oxygen extraction fraction under cuff compression paradigm. AB - BACKGROUND: To demonstrate the feasibility of using a susceptibility-based MRI technique with asymmetric spin-echo (ASE) sequence to assess the lower extremity muscle oxygen extraction fraction (OEF) alternations under cuff compression paradigm. METHODS: Approved by the local institutional human study committee, nine healthy young volunteers participated in this study. All the ASE scans were conducted using a 3 Tesla clinical MRI scanner during resting state (pre), 1-3 min (post1) and 3-5 min (post2) after a pressure of 50 mmHg above individual systolic blood pressure imposed on the thigh. Moreover, near-infrared spectroscopy (NIRS) measurements were performed on the same day under the same cuff compression protocol to verify the accuracy of this susceptibility-based method. RESULTS: In all volunteers, the mean MRI based OEF in gastrocnemius (GAS) muscle increased significantly from 0.28 +/- 0.02 (pre) to 0.31 +/- 0.03 (post1, P < 0.05) and 0.31 +/- 0.03 (post2, P < 0.05). In addition, mean OEF in soleus (SOL) muscle went up from 0.31 +/- 0.01 (pre) to 0.33 +/- 0.03 (post1, P = 0.14) and 0.37 +/- 0.04 (post2, P < 0.05). For comparison, NIRS measured 1-%HbO2 (percentage of deoxyhemoglobin concentration within total hemoglobin) in GAS rose significantly from 0.29 +/- 0.03 (pre) to 0.31 +/- 0.04 (post1, P < 0.05) and 0.31 +/- 0.04 (post2, P < 0.05), which confirmed the accuracy of the MRI-based OEF. CONCLUSION: This susceptibility-based OEF quantification technique together with cuff compression paradigm could provide a noninvasive, quantifiable and effective tool for measuring skeletal muscle oxygenation. PMID- 26527474 TI - Response to: Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication - A Systematic Review with Meta-Analyses of Randomised Trials. PMID- 26527475 TI - Conductive Gel Increases the Small Tumor Treatment With Electrochemotherapy Using Needle Electrodes. AB - The combination of chemotherapy drugs and high electric field treatment in local cancer is named electrochemotherapy. The European Standard Operation Procedure of Electrochemotherapy (ESOPE) provides guidelines for treatment of cutaneous and subcutaneous tumors. The electrochemotherapy of numerous tumors varying in sizes is more convenient using needle electrodes. However, ESOPE recommends that needle electrodes are applied to deeper tumors. The application of needle electrodes to treatment of superficial small tumors seems to be practical in electrochemotherapy. Plate electrodes and gel improve the electrochemotherapy efficacy. This technique provides electric field homogeneity in irregularly shaped tissue structures (bulk tumors). We propose an investigation of needle electrode and gel in electrochemotherapy of superficial tumors. In vivo experiment with squamous cell carcinoma (SCC) spontaneous nodules in dog was used to validate the mathematical tissue model. The numerical model considers the tissue conductivity dependent on local electric field. Our studies demonstrated that conductive gel is important for effective treatment of superficial tumors with needle electrodes. The needle electrodes and gel presented reduction of medium current, increased the tumor-free margin, and improved the practical application in relation to plate electrode. PMID- 26527476 TI - One-stage posterior focus debridement, fusion, and instrumentation in the surgical treatment of lumbar spinal tuberculosis with kyphosis in children. AB - OBJECTIVE: The purpose of this study is to investigate the clinical efficacy and feasibility of one-stage posterior focus debridement, fusion, and instrumentation in the surgical treatment of lumbar spinal tuberculosis with kyphosis in children. METHODS: From December 2007 to May 2012, 13 patients (six males and seven females) suffering from lumbar spinal tuberculosis with kyphosis were admitted. All patients were treated with one-stage posterior focus debridement, fusion, and instrumentation. Then, the clinical efficacy was estimated by statistical analysis based on the data about Frankel grade, the Cobb angle of kyphosis, and erythrocyte sedimentation rate (ESR), which were collected at certain time. RESULTS: The age of all patients ranged from 5 to 13 years (average, 8.8 years). Operation time ranged from 120 to 190 min (average, 165 min). Intraoperative blood loss ranged from 200 to 800 ml (average, 460 ml). All patients were followed up for 24 to 57 months postoperatively (average, 33.5 months). The Cobb angle was changed significantly between preoperation and postoperation (P < 0.05), and there was no significant loss at the last follow up. The preoperation ESR (62.5 +/- 15.7) returned to normal (16.6 +/- 8.1) within 3 months postoperatively in all patients (P < 0.05). Bone fusion was achieved within 3-5 months (average, 3.5 months). In the 13 cases, no postoperative severe complications occurred and neurologic function improved in various degrees. CONCLUSION: The outcomes of follow-up showed that one-stage posterior focus debridement, fusion, and instrumentation can be an effective treatment method for the lumbar spinal tuberculosis with kyphosis in children. PMID- 26527477 TI - Solitary Langerhans cell histiocytosis located in the neurohypophysis with a positive titer HCG-beta in the cerebrospinal fluid. AB - INTRODUCTION: Beta-human chorionic gonadotropin (HCG-beta) is considered to be a useful tumor marker for germ cell tumors (GCTs); however, various tumors other than GCTs, including cystic pituitary adenomas, Rathke's cleft cysts, and craniopharyngiomas, were reported to express HCG-beta. CASE REPORT: We herein present the case of a 5-year-old boy who presented with polyuria and had a solitary lesion in the neurohypophysis with a positive HCG-beta titer in the cerebrospinal fluid. Under a preoperative diagnosis of germinoma, a biopsy was performed from the posterior pituitary lobe via the transsphenoidal endoscopic approach and the histological diagnosis was revealed to be Langerhans cell histiocytosis (LCH). CONCLUSIONS: The finding of a slightly positive HCG-beta titer in the cerebrospinal fluid (CSF) cannot exclude the possibility of LCH, and we strongly recommend a histological diagnosis for the diagnosis of a solitary neurohypophysial lesion. PMID- 26527478 TI - Purification and Characterization of a Novel Redox-Regulated Isoform of Myrosinase (beta-Thioglucoside Glucohydrolase) from Lepidium latifolium L. AB - Myrosinase (ExPASy entry EC 3.2.1.147) is involved in the hydrolysis of glucosinolates to isothiocyanates, nitriles, and thiocyanates that are responsible for various ecological and health benefits. Myrosinase was purified from the leaves of Lepidium latifolium, a high-altitude plant, to homogeneity in a three-step purification process. Purified enzyme exists as dimer in native form (~160 kDa) with a subunit size of ~70 kDa. The enzyme exhibited maximum activity at pH 6.0 and 50 degrees C. With sinigrin as substrate, the enzyme showed Km and Vmax values of 171 +/- 23 MUM and 0.302 MUmol min(-1) mg(-1), respectively. The enzyme was found to be redox-regulated, with an increase in Vmax and Kcat in the presence of GSH. Reduced forms of the enzyme were found to be more active. This thiol-regulated kinetic behavior of myrosinase signifies enzyme's strategy to fine-tune its activity in different redox environments, thus regulating its biological effects. PMID- 26527479 TI - A Comparison Effect of Copper Nanoparticles versus Copper Sulphate on Juvenile Epinephelus coioides: Growth Parameters, Digestive Enzymes, Body Composition, and Histology as Biomarkers. AB - Copper nanoparticles (Cu-NPs) are components in numerous commercial products, but little is known about their potential hazard in the marine environments. In this study the effects of Cu-NPs and soluble Cu on juvenile Epinephelus coioides were investigated. The fish were exposed in triplicate to control, 20 or 100 ug Cu L( 1) as either copper sulphate (CuSO4) or Cu-NPs for 25 days. The growth performance decreased with increasing CuSO4 or Cu-NPs dose, more so in the CuSO4 than Cu-NPs treatment. Both forms of Cu exposure inhibited activities of digestive enzymes (protease, amylase, and lipase) found in liver, stomach, and intestine. With an increase in CuSO4 and Cu-NPs dose, crude protein and crude lipid decreased, but ash and moisture increased, more so in the CuSO4 than Cu-NPs treatment. The Cu-NPs treatment caused pathologies in liver and gills, and the kinds of pathologies were broadly of the same type as with CuSO4. With an increase in CuSO4 or Cu-NPs dose, the total polyunsaturated fatty acids decreased, but total monounsaturated fatty acids and total saturated fatty acids increased compared to control. Overall, these data showed that Cu-NPs had a similar type of toxic effects as CuSO4, but soluble Cu was more toxic than Cu NPs. PMID- 26527480 TI - Using Lean Thinking at an otorhinolaryngology outpatient clinic to improve quality of care. AB - OBJECTIVES/HYPOTHESIS: Although Lean Thinking has led to considerable improvement in a variety of healthcare settings, its effects on otorhinolaryngology remain underexposed. This study reports on how the implementation of Lean Thinking at an otorhinolaryngology outpatient clinic has affected patient and provider satisfaction, waste reduction, and organizational culture. STUDY DESIGN: Prospective before-and-after design. METHODS: The 18-month prospective before-and after design used mixed methods for data collection and analysis. A survey was conducted to measure satisfaction among patients and providers. Semistructured interviews were conducted to evaluate the effect of Lean Thinking on waste and organizational culture. RESULTS: During the project, 69 issues were posted on the Lean board. Improvements were made on 36 inefficiency issues, not all concerning a specific type of waste. Employees reported considerable improvement in transportation, motion, and waiting. Patient satisfaction was high both at baseline and follow-up and did not change significantly. The effects on provider satisfaction were slight; satisfaction with autonomy and participation decreased significantly, but satisfaction with communication increased significantly. CONCLUSIONS: The implementation of Lean Thinking at an otorhinolaryngology outpatient clinic reduced waste and increased provider satisfaction with communication. Although patient satisfaction did not change significantly, it cannot be concluded that the intervention had no effect on perceived quality of care. Other approaches to measure patients' perceptions should be considered. LEVEL OF EVIDENCE: NA. PMID- 26527481 TI - Hierarchical beta-Mo2 C Nanotubes Organized by Ultrathin Nanosheets as a Highly Efficient Electrocatalyst for Hydrogen Production. AB - Production of hydrogen by electrochemical water splitting has been hindered by the high cost of precious metal catalysts, such as Pt, for the hydrogen evolution reaction (HER). In this work, novel hierarchical beta-Mo2 C nanotubes constructed from porous nanosheets have been fabricated and investigated as a high performance and low-cost electrocatalyst for HER. An unusual template-engaged strategy has been utilized to controllably synthesize Mo-polydopamine nanotubes, which are further converted into hierarchical beta-Mo2 C nanotubes by direct carburization at high temperature. Benefitting from several structural advantages including ultrafine primary nanocrystallites, large exposed surface, fast charge transfer, and unique tubular structure, the as-prepared hierarchical beta-Mo2 C nanotubes exhibit excellent electrocatalytic performance for HER with small overpotential in both acidic and basic conditions, as well as remarkable stability. PMID- 26527482 TI - Problem Gambling Family Impacts: Development of the Problem Gambling Family Impact Scale. AB - Although family members of problem gamblers frequently present to treatment services, problem gambling family impacts are under-researched. The most commonly endorsed items on a new measure of gambling-related family impacts [Problem Gambling Family Impact Measure (PG-FIM: Problem Gambler version)] by 212 treatment-seeking problem gamblers included trust (62.5 %), anger (61.8 %), depression or sadness (58.7 %), anxiety (57.7 %), distress due to gambling related absences (56.1 %), reduced quality time (52.4 %), and communication breakdowns (52.4 %). The PG-FIM (Problem Gambler version) was comprised of three factors: (1) financial impacts, (2) increased responsibility impacts, and (3) psychosocial impacts with good psychometric properties. Younger, more impulsive, non-electronic gaming machine (EGM) gamblers who had more severe gambling problems reported more financial impacts; non-EGM gamblers with poorer general health reported more increased responsibility impacts; and more impulsive non-EGM gamblers with more psychological distress and higher gambling severity reported more psychosocial impacts. The findings have implications for the development of interventions for the family members of problem gamblers. PMID- 26527483 TI - Hepatic fat fraction and visceral adipose tissue fatty acid composition in mice: Quantification with 7.0T MRI. AB - PURPOSE: To develop an MRI method for quantifying hepatic fat content and visceral adipose tissue fatty acid composition in mice on a 7.0T preclinical system. METHODS: MR acquisitions were performed with a multiple echo spoiled gradient echo with bipolar readout gradients. After phase correction, the number of double bounds (ndb) and the number of methylene interrupted double bounds (nmidb) were quantified with a model including eight fat components, and parametric maps of saturated, monounsaturated, and polyunsaturated fatty acids were derived. The model included a complex error map to correct for the phase errors and the amplitude modulation caused by the bipolar acquisition. Validations were performed in fat-water emulsions and vegetable oils. In vivo, the feasibility was evaluated in mice receiving a high-fat diet containing primarily saturated fatty acids and a low-fat diet containing primarily unsaturated fatty acids. RESULTS: Linear regressions showed strong agreements between ndb and nmidb quantified with MRI and the theoretical values calculated using oil compositions, as well as between the proton density and the fat fractions in the emulsions. At MRI, the mouse liver fat fraction was smaller in mice fed the low-fat diet compared with mice fed the high-fat diet. In visceral adipose tissue, saturated fatty acids were significantly higher, whereas monounsaturated and polyunsaturated fatty acids were significantly lower in mice fed the low-fat diet compared with mice fed the high-fat diet. CONCLUSION: It is feasible to simultaneously quantify hepatic fat content and visceral adipose tissue fatty acid composition with 7.0T MRI in mice. Magn Reson Med 76:510-518, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 26527484 TI - Intraguild predation leads to genetically based character shifts in the threespine stickleback. AB - Intraguild predation is a common ecological interaction that occurs when a species preys upon another species with which it competes. The interaction is potentially a mechanism of divergence between intraguild prey (IG-prey) populations, but it is unknown if cases of character shifts in IG-prey are an environmental or evolutionary response. We investigated the genetic basis and inducibility of character shifts in threespine stickleback from lakes with and without prickly sculpin, a benthic intraguild predator (IG-predator). Wild populations of stickleback sympatric with sculpin repeatedly show greater defensive armor and water column height preference. We laboratory-raised stickleback from lakes with and without sculpin, as well as marine stickleback, and found that differences between populations in armor, body shape, and behavior persisted in a common garden. Within the common garden, we raised stickleback half-families from multiple populations in the presence and absence of sculpin. Although the presence of sculpin induced trait changes in the marine stickleback, we did not observe an induced response in the freshwater stickleback. Behavioral and morphological trait differences between freshwater populations thus have a genetic basis and suggest an evolutionary response to intraguild predation. PMID- 26527485 TI - "Real life use" of troponin in the emergency department: a survey of over 3000 cases. AB - INTRODUCTION: The aim of this study was to identify clinical variables which may be independently associated with positivity of a cardiac troponin I (cTnI) assay in a large population of patients admitted to the emergency department (ED). MATERIALS AND METHODS: 3166 subjects, with at least two troponin I tests ordered within 6 hours in the ED, were studied. Patient data were statistically analyzed to identify clinical associations with increased values of Troponin I. RESULTS: Although patients with diagnosis of acute coronary syndrome displayed troponin I values significantly higher than those of other groups, positivity to troponin I (>40 ng/L) was also observed in patients with other clinical conditions. In multivariate analysis, age, elevated heart rate and electrocardiographic changes were independently associated with troponin I positivity at admission. In the whole study population troponin I positivity exhibited high sensitivity and negative predictive value, counterbalanced by low specificity and limited positive predictive value. CONCLUSIONS: Troponin I positivity should be combined with history and clinical evaluation and cautiously interpreted in the ED, especially in patients exhibiting factors associated with higher troponin I levels such as older age, elevated heart rate or ECG changes. PMID- 26527486 TI - Versatile multiple protein nanopatterning within a microfluidic channel for cell recruitment studies. AB - A novel approach combining self-assembly-based colloidal lithography and polydimethylsiloxane (PDMS) micromolding to generate complex protein nanopatterns for studying the mechanisms of leukocyte extravasation within microchannels is presented. Nanostructured surfaces sealed onto PDMS-molded microchannels are chemically functionalized in situ in an all-aqueous process to generate bi functional chemical nanopatterns. Subsequent co-immobilization with proteins makes use of common non-covalent coupling (e.g. HIS-tags, FC-tags and biotin tags), giving nanopatterns of arbitrary combinations of oriented, functional proteins. Up to three different proteins were simultaneously co-immobilized into the microchannel with nanoscale precision, demonstrating the complex patterns. As a proof-of-principle, a mimic of an inflamed endothelium was constructed using a macro- and nanoscale pattern of intercellular adhesion molecule 1 (ICAM1) and P selectin, and the response of leukocytes through live cell imaging was measured. A clear result on the rolling behavior of the cells was observed with rolling limited to areas where ICAM1 and P-selectin are present. This micro/nano interface will open new doors to investigations of how spatial distributions of proteins control cellular activity. PMID- 26527487 TI - QUESTION 2: Are intravenous fluid boluses beneficial in late preterm or term infants with suspected haemodynamic compromise? PMID- 26527488 TI - European College of Orthodontics: Commission of affiliation and titularisation. AB - Date of birth: 5/6/1998; sex: male. A. PRETREATMENT RECORDS: 11.11 years; 5/2010. DIAGNOSIS: Molar Class II in a fairly brachyfacial setting; maxillary incisor alveolar retrusion, tendency to bimaxillary alveolar retrusion; TSALD; crossbite of 12/42 and almost a scissor bite at 24/34; incisor deep bite. Mixed dentition stage with persistence of 53-55-63-65-75-85 during early treatment. Teeth missing prior to treatment: none. TREATMENT PLAN: Molar retraction, repositioning of 12, alignment and leveling; arch coordination and correction of the premolar quasi scissor bite. Cl.II mechanics. Retention using bonded lingual wire on the 6 mandibular anterior teeth and maxillary splint. Extraction of the third molars. Appliances or methods: EOF; straightwire multibracket; Cl.II mechanics. Beginning of treatment: 12.4 years; 10/2010. B. POSTTREATMENT RECORDS: 15.4 years; 10/2013. Twelve was repositioned. Dental Cl.I was achieved. The incisors were torqued. The deep bite was reduced. DURATION OF ACTIVE TREATMENT: 36 months. C. POSTRETENTION RECORDS (1YEAR MINIMUM): 16.6 years; 12/2014. The molar occlusion remains stable. The patient must continue to wear his splint and keep the bonded wire. Extraction of the 3rd molars is scheduled. Date of end of retention: 12/2014. Duration of retention: 14 months. PMID- 26527490 TI - Effectiveness and efficiency in clinical orthodontic practice. AB - Proffitt et al. have described "effectiveness and efficiency" (E&E) as achieving desired results without wasting the orthodontist's and patients' time. In 1972, Archibald Cochrane published a monograph entitled "Effectiveness and Efficiency," which challenged the medical community to use medical protocols that were evidence-based. As a possible starting point for E&E, the orthodontist could consider an "Evidence-based clinical practice" (EBCP) model, which integrates the best research evidence with clinical expertise and patient values. This model considers scientific or evidence-based orthodontics (EBO) together with patient preferences and patient autonomy, clinical or patient circumstances, and clinical experience and judgment. In this paper, therefore, E&E will be discussed from an EBCP perspective which, for our purposes, includes relevant evidence but also our clinical experience and rationale. We will discuss: wire sequence; NiTi Wire types; space closure by sliding; canine retraction versus en masse retraction, 18" slot versus 22" slot, the Bidimensional System; self-ligating brackets (SL); vertical slot; economic aspects. PMID- 26527492 TI - Somatic cognition - Body talk and body language. PMID- 26527493 TI - Protective effects of exercise in metabolic disorders are mediated by inhibition of mitochondrial-derived sterile inflammation. AB - While beneficial properties of physical activity and exercise on human health have been extensively reported in literature, the exact mechanism(s) underpinning impacts of exercise are not well understood. Focusing on metabolic disorders, as the main causes of social and economic burden in current century, exercise exhibited promising effects in prevention, alleviation and retardation of these disorders including, type 2 diabetes (T2D), Alzheimer's disease (AD), major depressive disorder (MDD) and obesity. Recent evidence has unmasked the role of mitochondrial dysfunction and chronic inflammation in pathophysiology of these disorders. Despite of the wealth of research on the etiology of metabolic disorders, intimate connections between these diseases, complex pathophysiology and their comorbidity still remains a challenging dilemma. In addition, although physical activity has improving effects on human health, it is not clear that how exercise is able to exert its modulatory effects on outcomes of metabolic disorders. Among several mechanisms, we assumed the hypothesis that exercise mitigates the production of mitochondrial-induced reactive oxygen species (ROS) and danger associated molecular patterns (DAMPs) as the main triggering factors for inflammasome formation. Since inflammasomes are of highly deleterious molecules relevant to pathogenesis of metabolic disorders, we hypothesized that beneficial effects of exercise may be associated with its ability to enhance the mitochondrial biogenesis and glucose transportation through generation of brain derived neurotrophic factor (BDNF). Also, we proposed that boosting impact of exercise on autophagy process accelerates the elimination of damaged mitochondria and thus, results in considerable decrease in production of ROS and DAMPs and consequently sterile inflammation. PMID- 26527494 TI - A hypothesis about how to achieve anticoagulation without bleeding. AB - The hypothesis is set forth that a prothrombotic state is frequently caused by epinephrine-activated platelets initiating the intrinsic coagulation cascade by binding factor XII, a pathway which is enhanced by stasis. This pathway explains spontaneous non-injury related thrombosis in atrial fibrillation on the arterial side of the circulation and deep vein thrombosis/pulmonary embolism on the venous side of the circulation. Pharmacological interventions directed against targets in this pathway, for example factor XII, the putative factor XII receptor on activated platelets, and the alpha2-adrenoceptor on platelets, would be expected to provide effective anticoagulation for most clinical indications for anticoagulation without incurring the bleeding risk associated with pharmacological blockade of the extrinsic pathway, which is the limiting factor for conventional anticoagulants. Thrombotic stroke is another possible indication for such a treatment. PMID- 26527495 TI - "Cystic fibrotics could survive cholera, choleraics could survive cystic fibrosis"; hypothesis that explores new horizons in treatment of cystic fibrosis. AB - Cystic fibrosis, the most common inherited disease of white population, is a disease of CFTR channels, in which mucosal function of many organs especially respiratory tract is impaired. Decreased mucociliary clearance and accumulation of mucus in airways facilitates colonization of infectious microorganisms, followed by infection. Following chronic infection, persistent inflammation ensues, which results in airway remodeling and deterioration of mucociliary clearance and result in a vicious cycle. Here, it is hypothesized that cholera toxin (CT) could ameliorate symptoms of cystic fibrosis as CT could dilute the thickened mucus, improve mucociliary clearance and alleviate airway obstruction. CT strengthens immunity of airway mucosa and it could attenuates bacterial growth and reduce persistency of infection. CT also modulates cellular immune response and it could decrease airway inflammation, hinder airway remodeling and prevent respiratory deterioration. Thereby it is hypothesized that CT could target and ameliorate many of pathophysiologic steps of the disease and it explores new horizons in treatment of CF. PMID- 26527496 TI - Effect of protein arginine methyltransferase-1 inhibition on hypoxia-induced vasoconstriction. AB - Hypoxia is defined as a decrease in the oxygen supply to a level below physiological levels which is insufficient to maintain cellular function, in the presence of unrestricted coronary inflow. It is one of the leading causes of global mortality and morbidity, due to its association with the pathology of cancer, cardiovascular disease and stroke. The common feature in these pathologies is the limitation of oxygen availability that participates in the development of these conditions. The pulmonary response to hypoxia, when hypoxia is localized, is hypoxic pulmonary vasoconstriction (HPV). HPV is a physiological and self-regulatory mechanism by which pulmonary capillary blood flow is automatically adjusted to alveolar ventilation for maintaining the optimal balance of ventilation and perfusion. In pathological conditions, HPV occurs as an acute episode during progressive critical illness or as a sustained response with vascular remodeling and pulmonary hypertension. Inspite of the hypoxia induced shift in the redox status to a more oxidized state, the endothelium dependent mediators of HPV that cause vasoconstrictor response to hypoxia include nitric oxide (NO), endothelin-1 and angiotensin-II. Indeed, in chronic hypoxia, due to the enhanced reactive oxygen species (ROS) generation, inhibition of endothelial nitric oxide synthase (eNOS) activity and reduced nitric oxide (NO) production there is an imbalance in the vasoconstriction-vasodilation status toward constriction. It is our hypothesis that, in hypoxic stress, a key player in initiating this imbalance is the enzyme, protein arginine methyltransferase-1 (PRMT1) which indirectly affects eNOS activity by increased production of asymmetric dimethylarginine (ADMA), a NOS-inhibitor. Thus, pharmacological inhibition of PRMT1 should restore the cellular and vascular homeostasis in hypoxic conditions. PMID- 26527497 TI - Identification of the specific epigenetic alterations associated with chemo resistance via reprogramming of cancer cells. AB - BACKGROUND: Chemo-resistance is the main obstacle in cancer therapy, limiting the effectiveness of drug treatment. Epigenetics-mediated changes are suggested as a critical factor paying the chemo-resistance phenotype. Since epigenetic modulations are a reversible phenomenon, reversion of epigenetic changes represents a promising therapeutic approach for cancer. However, heterogeneity in epigenetic marks in tumor cells makes it difficult to identify the specific epigenetic aberrations contributing to chemo-resistance. Our hypothesis aimed to explore this issue to add therapeutic options for cancer. PRESENTATION OF THE HYPOTHESIS: Epigenetic alterations, the main mediator of cellular reprogramming, occur rapidly upon exposure to chemotherapy. Recent studies have demonstrated that reprogramming resets/erases the epigenetic marks established during differentiation to specific somatic cell types. To overcome the heterogeneous nature of cancer cells, we will attempt to make homogenous cancer cell colonies by reprogramming. Comparison of the drug-resistant cancer cells obtained from these colonies to parent cancer cells and reprogrammed cancer cells is an effective way to determine the precise epigenetic alterations underlying specific chemo-resistance. TESTING THE HYPOTHESIS: Cellular reprogramming of cancer cells led to generation of homogenous colonies. Following lineage specification and long term drug treatment, the obtained drug resistance cells will be compared with parent cancer cells for whole genome epigenetic signature. IMPLICATIONS OF THE HYPOTHESIS: A key implication of this hypothesis is that determination of the usefulness of cellular reprogramming of cancer cells enabling the identification of specific epigenetic modulation associated with particular drug resistance will enable exploration of new research avenues for cancer treatment. PMID- 26527498 TI - A suggestion about the cause of inflammation in acute atherosis complicating poor placentation in preeclampsia. AB - The hypothesis is set forth that maternal release of epinephrine in the adrenal medulla causes systemic platelet activation (SPA) which, in turn, initiates coagulation via the intrinsic pathway and leads to thrombin generation. Thrombin causes inflammation, which is the underlying cause of acute atherosis in preeclampsia (PE). Each step of this cascade is examined in detail and supporting literature documented. SPA is associated with migraine headaches, which are a prominent clinical feature of PE and may help explain why PE is a risk factor for future maternal cardiovascular disease. PMID- 26527500 TI - Editorial. PMID- 26527499 TI - Development of a novel hybrid strategy for transcatheter pulmonary valve placement in patients following transannular patch repair of tetralogy of fallot. AB - BACKGROUND: Transcatheter pulmonary valve replacement (tPVR) is an accepted therapy for treatment of dysfunctional right ventricular outflow tract (RVOT) conduits. At present, the majority of Fallot patients who undergo transannular patch (TAP) repair are not candidates for tPVR due to the large irregular nature of their RVOT. Herein, we describe a novel approach to assessing the RVOT in this group, which may then be used to design, test, and carry out hybrid RVOT modification and transcatheter valve implantation in this population. METHODS: A retrospective analysis of TAP patients who underwent 3D modeling of the RVOT which was then used to develop individualized hybrid procedures designed to modify the RVOT, thereby rendering patients suitable for transcatheter valve implantation. RESULTS: Eight consecutive patients underwent 3D RVOT modeling followed by hybrid implantation of a transcatheter valve via a perventricular approach. A landing zone stent was placed in all and four required additional intravascular geometric remodeling of the RVOT prior to valve implant. Transcatheter valves were successfully implanted in all. There were no instances of valve malposition, embolization, or death. There was one minor procedural complication. No patient had more than trivial pulmonary regurgitation at follow up. CONCLUSIONS: Using a hybrid approach to remodel the RVOT in TAP patients supported by preprocedural 3D-model planning allows for successful tPVR implantation in this population. A larger cohort and longer follow-up will be needed to determine the ultimate utility of this approach. PMID- 26527501 TI - [Effectiveness of a nutritional program based upon a ready-to-use therapeutic food in Chad]. AB - OBJECTIVE: In the health district of Goundi in Chad, 6.7% of children were affected by acute malnutrition in 2011. The purpose of this study was to evaluate the efficacy of a locally made ready-to-use therapeutic food (RUTF). METHODS: One hundred sixty-eight children were suffering from severe acute malnutrition (weight-for-height status less than -3 SD or mid-upper arm circumference less than 115mm). The RUTF was made in a specific laboratory. The product consisted of 49% carbohydrates, 33% lipids, 16% proteins, and 1.5% vitamins. Children received daily one packet of RUTF containing 500kcal as outpatient care. RESULTS: At inclusion, the average age was 17.4+/-8.7 months, and the weight-for-height status -3.8+/-0.9 SD. At the end of the program, we noted recovery in 58.3% of the children, 2.4% unsuccessful treatment, 21.4% lost to follow-up, and 17.9% deaths (60% of which occurred during the first 2 weeks). At the end of the program, the weight-for-height status had increased by 2.1 SD. At recovery, children treated for tuberculosis had a higher weight-for-height status (-1.2+/ 1.5 SD) than the children who were not infected by tuberculosis (-2+/-1.9 SD) (P<0.005). CONCLUSION: Nutritional treatment using RUTF was effective. To improve treatment, early case detection should be improved, as should management of associated infectious diseases. PMID- 26527502 TI - Agronomic improvements can make future cereal systems in South Asia far more productive and result in a lower environmental footprint. AB - South Asian countries will have to double their food production by 2050 while using resources more efficiently and minimizing environmental problems. Transformative management approaches and technology solutions will be required in the major grain-producing areas that provide the basis for future food and nutrition security. This study was conducted in four locations representing major food production systems of densely populated regions of South Asia. Novel production-scale research platforms were established to assess and optimize three futuristic cropping systems and management scenarios (S2, S3, S4) in comparison with current management (S1). With best agronomic management practices (BMPs), including conservation agriculture (CA) and cropping system diversification, the productivity of rice- and wheat-based cropping systems of South Asia increased substantially, whereas the global warming potential intensity (GWPi) decreased. Positive economic returns and less use of water, labor, nitrogen, and fossil fuel energy per unit food produced were achieved. In comparison with S1, S4, in which BMPs, CA and crop diversification were implemented in the most integrated manner, achieved 54% higher grain energy yield with a 104% increase in economic returns, 35% lower total water input, and a 43% lower GWPi. Conservation agriculture practices were most suitable for intensifying as well as diversifying wheat-rice rotations, but less so for rice-rice systems. This finding also highlights the need for characterizing areas suitable for CA and subsequent technology targeting. A comprehensive baseline dataset generated in this study will allow the prediction of extending benefits to a larger scale. PMID- 26527503 TI - Ovulation induction and luteal support with GnRH agonist in patients at high risk for hyperstimulation syndrome. AB - The aim of this study was to compare GnRHa trigger and luteal addition of triptorelin to hCG trigger for final oocyte maturation in women at high risk for OHSS undergoing IVF. A total of 423 patients were divided in two groups both stimulated using antagonist short protocol. Gonadotropins 75-150 UI/day were started on day 2-5, GnRH antagonist was added when the lead follicle was >14 mm and the final trigger was obtained with hCG 250 ug or triptorelin 0.2 mg. The luteal phase was supported with progesterone alone in the hCG group, with progesterone plus triptorelin 0.1 every other day from embryo transfer in the triptorelin group. In the triptorelin group we did neither have to suspend any embryo transfer, nor we have any early clinical OHSS. In the control group, 13 patients were suspended due to symptomatic high risk for OHSS and two patients developed a clinically significant OHSS. No statistically significant difference was observed in terms of clinical and ongoing pregnancy rates and implantation rates. Our results indicate that a protocol including GnRHa as trigger and an intensive luteal phase supported with GnRHa is safer than a standard antagonist protocol using hCG as trigger. It displays similar results, therefore it can be used as the first choice in patients at high risk for OHSS. PMID- 26527504 TI - Psychological distress in corticosteroid-naive patients with systemic lupus erythematosus: A prospective cross-sectional study. AB - OBJECTIVE: Psychological distress, such as depression and anxiety, has been intensively studied in patients with systemic lupus erythematosus (SLE). However, those studies have mostly included patients who were treated with corticosteroids, which might themselves induce mood disturbances. We investigated psychological distress in corticosteroid-naive patients with SLE who did not exhibit any overt neuropsychiatric manifestations. METHODS: Forty-three SLE in patients with no current or past abnormal neuropsychiatric history participated in the study. Patients and 30 healthy control subjects with similar demographic and personality characteristics were administered a comprehensive battery of psychological/neuropsychological tests. The Profile of Mood States (POMS) was used to assess depression and anxiety. Results of clinical, laboratory, and neurological tests were compared with regard to their presence. RESULTS: Prevalence of depression was higher in patients (n = 11, 25.6%) than in controls (n = 2, 6.7%; p = 0.035), although prevalence of anxiety did not differ across groups (patients: 34.9%, n = 15; controls: 16.7%, n = 5; p = 0.147). Using multiple logistic regression analysis, we identified avoidance coping methods (OR, 1.3; 95% CI 1.030-1.644; p = 0.027) as an independent risk factor for depression. CONCLUSION: Our results indicate that depression presents more frequently in corticosteroid-naive patients with early-stage, active SLE than in the normal population, but anxiety does not. Depression may be related to psychological reactions to suffering from the disease. PMID- 26527506 TI - Corrigendum: Circadian control of bile acid synthesis by a KLF15-Fgf15 axis. PMID- 26527505 TI - Expanding the Catalytic Triad in Epoxide Hydrolases and Related Enzymes. AB - Potato epoxide hydrolase 1 exhibits rich enantio- and regioselectivity in the hydrolysis of a broad range of substrates. The enzyme can be engineered to increase the yield of optically pure products as a result of changes in both enantio- and regioselectivity. It is thus highly attractive in biocatalysis, particularly for the generation of enantiopure fine chemicals and pharmaceuticals. The present work aims to establish the principles underlying the activity and selectivity of the enzyme through a combined computational, structural, and kinetic study using the substrate trans-stilbene oxide as a model system. Extensive empirical valence bond simulations have been performed on the wild-type enzyme together with several experimentally characterized mutants. We are able to computationally reproduce the differences between the activities of different stereoisomers of the substrate and the effects of mutations of several active-site residues. In addition, our results indicate the involvement of a previously neglected residue, H104, which is electrostatically linked to the general base H300. We find that this residue, which is highly conserved in epoxide hydrolases and related hydrolytic enzymes, needs to be in its protonated form in order to provide charge balance in an otherwise negatively charged active site. Our data show that unless the active-site charge balance is correctly treated in simulations, it is not possible to generate a physically meaningful model for the enzyme that can accurately reproduce activity and selectivity trends. We also expand our understanding of other catalytic residues, demonstrating in particular the role of a noncanonical residue, E35, as a "backup base" in the absence of H300. Our results provide a detailed view of the main factors driving catalysis and regioselectivity in this enzyme and identify targets for subsequent enzyme design efforts. PMID- 26527507 TI - Nutritional control of immunity: Balancing the metabolic requirements with an appropriate immune function. AB - The immune system is a highly integrated network of cells sensitive to a number of environmental factors. Interestingly, recent years have seen a dramatic increase in our understanding of how diet makes a crucial contribution to human health, affecting the immune system, secretion of adipocytokines and metabolic pathways. Recent experimental evidence indicates that diet and its components are able to profoundly influence immune responses, thus affecting the development of inflammatory and autoimmune diseases. This review aims to discuss some of the main topics concerning the impact of nutrients and their relative composition on immune cell development and function that may be particularly important for regulating the balance between inflammatory and tolerogenic processes. We also highlight the effects of diet on commensal bacteria and how changes in the composition of the microbiota alter intestinal and systemic immune homeostasis. Finally, we summarize the effects of dietary compounds on epigenetic mechanisms involved in the regulation of several immune related genes. PMID- 26527508 TI - Aberrant frequency of IL-10-producing B cells and its association with Treg and MDSC cells in Non Small Cell Lung Carcinoma patients. AB - OBJECTIVES: B regulatory cells (Bregs) are a newly described subpopulation of B cells that play important roles in autoimmunity, however, whether play an important role in cancer is relatively unknown. Herein, we investigated the role of IL-10 producing B cells in Non Small Cell Lung Carcinoma (NSCLC). METHODS: 18 healthy controls (HC) and 66 untreated patients with NSCLC were enrolled. Next to IL-10 producing B cells, CD4(+)CD25(+/high)CD127(low/-) regulatory T (Treg) cells and CD14(+)HLA-DR(low/-) myeloid-derived suppressor cells (MDSCs) were determined via flow cytometry. RESULTS: Upregulation of IL-10 producing B cells was associated with the NSCLC progression. Furthermore, this B cell subset was positively correlated with the frequency of CD4(+)CD25(+/high)CD127(low/-) Treg cells, also with the frequency of CD14(+)HLA-DR(low/-) MDSCs in these NSCLC patients. CONCLUSIONS: Together, IL-10 producing B cells are significantly elevated in NSCLC patients, indicating this B cell subset might play an important role in the clinical progression of NSCLC. PMID- 26527509 TI - Cushing's conundrum: an unusual case of primary pigmented nodular adrenal disease in a 60-year-old woman. PMID- 26527510 TI - Prescribing low-fat diets: useless for long-term weight loss? PMID- 26527511 TI - Effect of low-fat diet interventions versus other diet interventions on long-term weight change in adults: a systematic review and meta-analysis. AB - BACKGROUND: The effectiveness of low-fat diets for long-term weight loss has been debated for decades, with many randomised controlled trials (RCTs) and recent reviews giving mixed results. We aimed to summarise the large body of evidence from RCTs to determine whether low-fat diets contribute to greater weight loss than participants' usual diet, low-carbohydrate diets, and other higher-fat dietary interventions. METHODS: We did a systematic review and random effects meta-analysis of RCTs comparing the long-term effect (>=1 year) of low-fat and higher-fat dietary interventions on weight loss by searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Database of Systematic Reviews to identify eligible trials published from database inception up until July 31, 2014. We excluded trials if one intervention group included a non-dietary weight loss component but the other did not, and trials of dietary supplements or meal replacement drink interventions. Data including the main outcome measure of mean difference in weight change between interventions, and whether interventions were intended to lead to weight loss, weight maintenance, or neither, were extracted from published reports. We estimated the pooled weighted mean difference (WMD) with a DerSimonian and Laird random effects method. FINDINGS: 3517 citations were identified by the search and 53 studies met our inclusion criteria, including 68 128 participants (69 comparisons). In weight loss trials, low-carbohydrate interventions led to significantly greater weight loss than did low-fat interventions (18 comparisons; WMD 1.15 kg [95% CI 0.52 to 1.79]; I(2)=10%). Low-fat interventions did not lead to differences in weight change compared with other higher-fat weight loss interventions (19 comparisons; WMD 0.36 kg [-0.66 to 1.37; I(2)=82%), and led to a greater weight decrease only when compared with a usual diet (eight comparisons; -5.41 kg [-7.29 to -3.54]; I(2)=68%). Similarly, results of non-weight-loss trials and weight maintenance trials, for which no low-carbohydrate comparisons were made, showed that low-fat versus higher-fat interventions have a similar effect on weight loss, and that low-fat interventions led to greater weight loss only when compared with usual diet. In weight loss trials, higher-fat weight loss interventions led to significantly greater weight loss than low-fat interventions when groups differed by more than 5% of calories obtained from fat at follow-up (18 comparisons; WMD 1.04 kg [95% CI 0.06 to 2.03]; I(2)=78%), and when the difference in serum triglycerides between the two interventions at follow-up was at least 0.06 mmol/L (17 comparisons; 1.38 kg [0.50 to 2.25]; I(2)=62%). INTERPRETATION: These findings suggest that the long-term effect of low-fat diet intervention on bodyweight depends on the intensity of the intervention in the comparison group. When compared with dietary interventions of similar intensity, evidence from RCTs does not support low-fat diets over other dietary interventions for long-term weight loss. FUNDING: National Institutes of Health and American Diabetes Association. PMID- 26527512 TI - Changing Default Fluoroscopy Equipment Settings Decreases Entrance Skin Dose in Patients. AB - PURPOSE: Proper fluoroscopic education and protocols may reduce the patient radiation dose but few prospective studies in urology have been performed. Using optically stimulated luminescent dosimeters we tested whether fluoroscopy time and/or entrance skin dose would decrease after educational and radiation reduction protocols. MATERIALS AND METHODS: At default manufacturer settings fluoroscopy time and entrance skin dose were prospectively measured using optically stimulated luminescent dosimeters in patients undergoing ureteroscopy, retrograde pyelogram/stent or percutaneous nephrolithotomy with access for stone disease. A validated radiation safety competency test was administered to urology faculty and residents before and after web based, hands-on fluoroscopy training. Default fluoroscopy settings were changed from continuous to intermittent pulse rate and from standard to half-dose output. Fluoroscopy time and entrance skin dose were then measured again. RESULTS: The cohorts of 44 pre-protocol and 50 post-protocol patients with stones were similarly matched. The change in mean fluoroscopy time and entrance skin dose from pre-protocol to post-protocol was 0.6 minutes and -11.6 mGy (33%) for percutaneous nephrolithotomy (p = 0.62 and <0.001), 0.5 minutes and -0.1 mGy (34%) for ureteroscopy (p = 0.42 and 0.31), and 0.1 minute and -0.1 mGy (29%) for retrograde pyelogram/stent (p = 0.85 and 0.49, respectively). Urologist post-training test scores increased 30% from pretraining scores (p = 0.1). CONCLUSIONS: Radiation safety training protocols improved clinical knowledge but did not significantly alter fluoroscopy time. Changing equipment default settings to intermittent pulse rate (12 frames per second) and half-dose lowered the entrance skin dose by 30% across all endourology patients but most significantly during percutaneous nephrolithotomy. To limit patient radiation exposure fluoroscopy default settings should be decreased before all endourology procedures and image equipment manufacturers should consider lowering standard default renal settings. PMID- 26527513 TI - Evaluation of Urinary Tract Dilation Classification System for Grading Postnatal Hydronephrosis. AB - PURPOSE: We assessed the reliability and validity of the Urinary Tract Dilation classification system as a new grading system for postnatal hydronephrosis. MATERIALS AND METHODS: We retrospectively reviewed charts of patients who presented with hydronephrosis from 2008 to 2013. We included patients diagnosed prenatally and those with hydronephrosis discovered incidentally during the first year of life. We excluded cases involving urinary tract infection, neurogenic bladder and chromosomal anomalies, those associated with extraurinary congenital malformations and those with followup of less than 24 months without resolution. Hydronephrosis was graded postnatally using the Society for Fetal Urology system, and then the management protocol was chosen. All units were regraded using the Urinary Tract Dilation classification system and compared to the Society for Fetal Urology system to assess reliability. Univariate and multivariate analyses were performed to assess the validity of the Urinary Tract Dilation classification system in predicting hydronephrosis resolution and surgical intervention. RESULTS: A total of 490 patients (730 renal units) were eligible to participate. The Urinary Tract Dilation classification system was reliable in the assessment of hydronephrosis (parallel forms 0.92). Hydronephrosis resolved in 357 units (49%), and 86 units (12%) were managed by surgical intervention. The remainder of renal units demonstrated stable or improved hydronephrosis. Multivariate analysis revealed that the likelihood of surgical intervention was predicted independently by Urinary Tract Dilation classification system risk group, while Society for Fetal Urology grades were predictive of likelihood of resolution. CONCLUSIONS: The Urinary Tract Dilation classification system is reliable for evaluation of postnatal hydronephrosis and is valid in predicting surgical intervention. PMID- 26527514 TI - Validation of the AUA BLUS Tasks. AB - PURPOSE: Standardized assessment of laparoscopic skill in urology is lacking. We investigated whether the AUA (American Urological Association) BLUS (Basic Laparoscopic Urologic Skills) skill tasks are valid to address this need. MATERIALS AND METHODS: This institutional review board approved study included 27 medical students, 42 urology residents, 18 fellows and 37 faculty urologists across 8 sites. Using the EDGE (Electronic Data Generation and Evaluation) device (Simulab, Seattle, Washington) 454 recordings were collected on peg transfer, pattern cutting, suturing and clip applying tasks, which together comprise the expert determined BLUS tasks. We collected synchronized video and tool motion data for each trial. For each task errors, time, path length, economy of motion, peak grasp force and EDGE score were collected. An expert panel of 5 faculty members performed GOALS (Global Objective Assessment of Laparoscopic Skills) evaluations on a representative subset of peg transfer and suturing skill tasks performed by 24 participants (IRR = 0.95). RESULTS: Demographically derived skill levels proved unsuitable to evaluate construct validity. Separation of mean scores by grouped skill levels was strongest for the suturing task. Objective motion metrics and errors supported construct validity vis-a-vis correlation with blinded expert video ratings (motion metrics R(2) = 0.95, p <0.01). Expert scores appeared to reward errors in suturing but not in block transfer. CONCLUSIONS: BLUS skill task performance scoring can discriminate among basic laparoscopic technical skill levels. Self-reported demographics are an unreliable source of determining laparoscopic technical skill. PMID- 26527515 TI - Progression of mouse skin carcinogenesis is associated with the orchestrated deregulation of mir-200 family members, mir-205 and their common targets. AB - MicroRNAs are small, non-coding RNAs which regulate post-transcriptionally hundreds of target mRNAs. Given that their expression is deregulated in several cancer types, they represent potential diagnostic, prognostic, and predictive biomarkers, as well as next-generation therapeutic targets. Nevertheless, the involvement of miRNAs in non-melanoma skin cancer, a cancer type with increasing prevalence, is not extensively studied, and their comprehensive characterization as regard to the initiation, promotion, and progression stages is missing. To this end, we exploited a well-established multistage mouse skin carcinogenesis model in order to identify miRNAs consistently implicated in different stages of skin carcinogenesis. The cell lines comprising this model were subjected to miRNA expression profiling using microarrays, followed by bioinformatics analysis and validation with Q-PCR, as well as treatment with miRNA modulators. We showed that among all deregulated miRNAs in our system, only a functionally coherent group consisting of the miR-200 family members and miR-205-5p displays a pattern of progressive co-downregulation from the early toward the most aggressive stages of carcinogenesis. Their overlapping, co-regulated putative targets are potentially inter-associated and, of these, the EMT-related Rap1a is overexpressed toward aggressive stages. Ectopic expression of miR-205-5p in spindle cancer cells reduces Rap1a, mitigates cell invasiveness, decreases proliferation, and delays tumor onset. We conclude that deregulation of this miRNA group is primarily associated with aggressive phenotypes of skin cancer cells. Restoration of the miR-205-5p member of this group in spindle cells reduces the expression of critical, co-regulated targets that favor cancer progression, thus reversing the EMT characteristics. (c) 2015 Wiley Periodicals, Inc. PMID- 26527516 TI - Recent advances in primary ciliary dyskinesia. AB - Primary ciliary dyskinesia (PCD) is a genetic disease inherited in an autosomal recessive manner. The prevalence of PCD is estimated to be 1 in 20,000 live births. Congenital abnormality of the primary cilia results in situs inversus in 50% of patients. Decreased function of motile cilia causes chronic rhinosinusitis, otitis media with effusion, bronchiectasis and infertility. Cases with situs inversus are considered to show "Kartagener's syndrome", and diagnosis is not difficult. However, in cases without situs inversus, the diagnosis is much more troublesome. PCD without situs inversus is thus probably underdiagnosed. Prolonged chronic cough represents an important symptom that is seen in most patients. The diagnosis of PCD requires the presence of the characteristic clinical phenotypes and either: (1) specific ciliary ultrastructural defects identified by transmission electron microscopy in biopsy samples of respiratory epithelium; or (2) identification of mutation in one of the genes known to be associated with PCD. Nasal nitric oxide concentration is extremely low in PCD, and this could be useful for screening of the disease. At present, no fundamental therapies are available for PCD. Diagnosis in the early stages is important to prevent progression of bronchiectasis and deterioration of lung function by guidance for daily life, immunization, cessation of smoking and prompt therapy at the time of respiratory tract infection. Since PCD is inherited in an autosomal recessive manner, genetic counseling is necessary after definite diagnosis. PMID- 26527517 TI - Differences in urinary leukotriene E4 levels and distribution of eosinophils between chronic rhinosinusitis patients with aspirin-intolerant and -tolerant asthma. AB - OBJECTIVE: Urinary leukotriene E4 (U-LTE4) concentrations are significantly elevated in patients with aspirin-intolerant asthma (AIA). However, the relationship between the clinicopathogenetic features of eosinophilic rhinosinusitis and U-LTE4 concentration remains unknown. Here we examined the relationship between U-LTE4 level and eosinophil in chronic rhinosinusitis. METHODS: We measured the U-LTE4 concentrations and eosinophil counts in ethmoidal and maxillary sinuses and peripheral blood in 30 asthmatic patients (including 15 AIA patients). RESULTS: Eosinophil counts in ethmoidal sinuses and peripheral blood were markedly higher in asthmatic patients than in controls. Although there were no significant differences between eosinophil counts in maxillary and ethmoidal sinuses for ATA group, eosinophil counts were higher in ethmoidal sinus compared to that in maxillary sinus in the AIA group (P<.05). Eosinophil counts were higher in the maxillary than in ethmoidal sinuses for control patients (P<.05). Despite low correlation between eosinophil counts in peripheral blood and eosinophil counts in maxillary sinus (rs=0.4323, P<.001), moderate correlation was observed between eosinophil counts in peripheral blood and eosinophil counts in ethmoidal sinus (rs=0.5249, P<.0001). Basal U-LTE4 concentrations were higher in AIA patients than in those with aspirin-tolerant asthma. Despite low correlation between eosinophil counts and U-LTE4 concentration in maxillary sinus (rs=0.3849, P<.01), moderate correlation was observed between eosinophil counts and U-LTE4 concentrations in ethmoidal sinus (rs=0.4736, P<.001). CONCLUSION: We describe the differences in U-LTE4 and other parameters in AIA compared to ATA, and correlation among parameters. We demonstrate that eosinophil-dominant inflammation starts in ethmoidal sinus clinicopathogenetically in CRS with asthma. U-LTE4 concentration was not exclusively associated with eosinophil counts in ethmoidal sinus. Eosinophils in ethmoidal sinus may be a major production site for CysLTs, particularly in AIA. CRS with AIA is assumed to be characterized by leukotriene-eosinophil cross interaction in ethmoidal sinus. PMID- 26527518 TI - Clinical classification of peritonsillar abscess based on CT and indications for immediate abscess tonsillectomy. AB - OBJECTIVE: To clarify indications for immediate abscess tonsillectomy (IAT) for peritonsillar abscess (PTA). METHODS: A retrospective study was performed on 99 patients who were diagnosed with PTA on the basis of computed tomography (CT). Based on CT findings, PTA patients were classified into two categories by abscess shape: Oval type and Cap type. Furthermore, abscess location was differentiated into superior and inferior, resulting in a final classification of 4 categories: superior Oval type; superior Cap type; inferior Oval type; and inferior Cap type. In addition, the proportion of PTA patients showing extraperitonsillar spread into parapharyngeal spaces in each category was examined. RESULTS: Superior Oval type PTA was the most common. Thirteen patients showed extraperitonsillar spread. When CT classifications were compared with clinical findings, patients with inferior Cap-type abscess displayed extraperitonsillar spread more frequently than the other categories of PTA. In all 13 patients, the parapharyngeal space was involved. In addition, 3 patients displayed retropharyngeal space involvement. In all 13 cases, abscess remained above the hyoid bone. CONCLUSIONS: Inferior Cap-type PTA may need more intensive and reliable treatment, such as IAT, which might be effective for PTA showing extraperitonsillar spread. PMID- 26527519 TI - Study of hemostasis procedures for posterior epistaxis. AB - OBJECTIVE: Hemostasis is difficult in patients with bleeding emanating from the deep regions in the nasal cavity; however, there is no standard treatment method. We studied hemostasis procedures in patients who visited our outpatient department and presented with idiopathic epistaxis extending from the posterior nasal cavity to Kiesselbach's area. METHODS: The subjects were patients with epistaxis who visited our hospital between June 2008 and May 2010. We asked specific questions at the time of the hospital visit and examined patients using a nasal speculum, a flexible endoscope, and a rigid endoscope (0 or 70 degree) to identify bleeding sites. Hemostasis using electrocoagulation was selected as the first-line therapy for patients in whom a bleeding point had been identified, whereas hemostasis using a gauze tampon was performed in patients in whom the bleeding point was unknown. The subjects were analyzed by multivariate logistic regression analysis. RESULTS: The bleeding point was unknown in most cases of recurrent posterior epistaxis. Electrocoagulation was the best hemostasis procedure. Identifying the bleeding points as much as possible and performing electrocoagulation at these sites was the preferred procedures. CONCLUSION: We propose the treatment procedure for refractory epistaxis. When it is difficult to identify a bleeding point in a patient with refractory epistaxis due to a deviated nasal septum, a bleeding point should be identified after septoplasty; for bleeding from the sphenopalatine artery region, electrocoagulation or endoscopic cauterization of the sphenopalatine artery should be performed. PMID- 26527520 TI - Reproducibility between messenger RNA real-time polymerase chain reaction and messenger RNA in situ hybridization in oropharyngeal squamous cell carcinoma patients. PMID- 26527521 TI - Primary salivary duct carcinoma of the lung, mucin-rich variant. AB - Primary salivary gland-type lung cancer is a heterogeneous group of neoplasms arising from the seromucinous glands of the respiratory tract. Histopathologically, they are identical to salivary gland neoplasms of the head and neck. While mucoepidermoid carcinoma and adenoid cystic carcinoma are overwhelmingly the most common subtypes found in the lung, reports of uncommon subtypes can be found in the literature. We report a case of a 73-year-old woman with primary lung salivary duct carcinoma, mucin-rich variant--an exceedingly rare subtype of an already rare malignant salivary-type neoplasm. One case of primary lung salivary duct carcinoma has been reported in the literature; however, the mucin-rich variant has never been described in the lung. Furthermore, the tumor in our case bears a rare BRAF G464V mutation. To our knowledge, this is the first reported case of a BRAF G464V mutation detected in a salivary duct carcinoma or any other salivary-type neoplasm. PMID- 26527522 TI - PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. AB - Programmed death ligand 1 (PD-L1) expression by tumor-infiltrating lymphocytes (TILs) and tumor cells in breast cancer has been reported, but the relationships between PD-L1 expression by TIL, carcinoma cells, and other immunologic features of the breast tumor microenvironment remain unclear. We therefore evaluated the interrelationships between tumor cell surface and TIL PD-L1 expression, lymphocyte subpopulations, and patterns of immune cell infiltration in cohorts of treatment-naive, primary breast cancers (PBCs) (n = 45) and matched PBC and metastatic breast cancers (MBC) (n = 26). Seventy-eight percent of untreated PBCs contained PD-L1(+) TILs, but only 21% had PD-L1(+) carcinoma cells. Carcinoma PD L1 expression localized to the tumor invasive front and was associated with high tumor grade (P = .04). Eighty-nine percent of PD-L1(+) carcinomas contained brisk TIL infiltrates, compared to only 24% of PD-L1(-) carcinomas; this included CD3(+) (P = .02), CD4(+) (P = .04), CD8(+) (P = .002), and FoxP3(+) T cells (P = .02). PD-L1(+) PBCs were more likely to contain PD-L1(+) TIL than PD-L1(-) PBCs (P = .04). Peripheral lymphoid aggregates were present in 100% of PD-L1(+) compared to 41% of PD-L1(-) PBC (P < .001). No patient with PD-L1(+) PBC developed distant recurrence, compared to 15% of patients with PD-L1(-) PBC. For the matched PBC and MBC cohort, 2 patients (8%) had PD-L1(+) tumors, with 1 case concordant and 1 case discordant for carcinoma PD-L1 expression in the PBC and MBC. Our data support PD-L1 expression by tumor cells as a biomarker of active breast tumor immunity and programmed death 1 blockade as a therapeutic strategy for breast cancer. PMID- 26527526 TI - "OMICS" technologies and their role in foregut primary malignancies. PMID- 26527523 TI - GATA-3 and FOXA1 expression is useful to differentiate breast carcinoma from other carcinomas. AB - GATA-3, a member of the GATA family of zinc-finger DNA binding proteins, and FOXA1, a member of the forkhead transcription factor family, are both associated with estrogen receptor expression. Both GATA-3 and FOXA1 are useful markers for breast carcinoma, but their expression in the different breast cancer subtypes and other neoplasms has not been thoroughly evaluated. We examined the expression of GATA-3 and FOXA1 in estrogen receptor-positive, Her2/neu-positive, and triple negative breast carcinomas as well as in 10 other common carcinomas, including hepatocellular, colonic, pancreatic, gastric, endometrial (endometrioid), lung, prostatic, renal cell, urothelial, and ovarian serous carcinomas. Primary and metastatic melanomas and mesotheliomas were also evaluated. GATA-3 and FOXA1 staining of estrogen receptor-positive breast carcinomas was seen in 96.6% and 96.2%, respectively. In triple-negative breast carcinomas, GATA-3 and FOXA1 staining was seen in 21.6% and 15.9%, respectively. Among the other tumors, GATA 3 staining was only seen in urothelial carcinoma (70.9%) and FOXA1 staining was only seen in prostatic (87.5%), urothelial (5.1%) carcinomas, and mesotheliomas (40.0%). In conclusion, GATA-3 and FOXA1 are excellent breast carcinoma markers; however, their utility is limited in the triple-negative subtype. The utility of FOXA1 in diagnosing prostatic carcinoma and mesothelioma warrants further investigation. PMID- 26527527 TI - [Quality of life from the perspective of addiction]. AB - INTRODUCTION: Quality of life (QoL) is a concept that incorporates an individual's perception of health status, style and life satisfaction, mental state or well-being, and helps identify gaps in areas of functioning, facilitating the identification of risk groups and planning of preventive measures. The aim of the study is to assess the quality of life related to health (HRQOL) in patients treated for substance use in the Drug Dependency Care Unit of Monforte de Lemos (Lugo). METHODS: Sociodemographic variables, health, consumer and other related QoL measured by the SF-36 questionnaire were studied in a sample of 100 users. Data were analysed with SPSS 15. RESULTS: There were differences in the means in most of the eight dimensions analysed, with higher scores generally by men, although these differences did not reach statistical significance except for physical role (P=.03). A meaningful data analysis is presented based on the work situation, primary drug, and infectious and somatic diseases. CONCLUSIONS: Overall HRQOL is lower in our users than in the general population, and it is higher in men than in women, with the most compromised area being vitality. In the present circumstances, being in active employment leads to a better HRQOL. PMID- 26527528 TI - The K167I variant of DNA polymerase beta that is found in Esophageal Carcinoma patients impairs polymerase activity and BER. AB - DNA polymerase beta (pol beta) is a key enzyme in DNA base excision repair, and an important factor for maintaining genomic integrity and stability. Esophageal carcinoma (EC) patients who have been identified as carrying the K167I variant of pol beta have been shown to have decreased life expectancy. However, it is unknown if the variant affects pol beta's functions and/or how it contributes to the initiation and progression of cancer. In this study, we expressed and purified the K167I variant. Moreover, we found that K167I significantly reduced polymerase activity. As a result, the K167I substitution reduced base excision repair (BER) efficiency when assayed in a reconstitution assay or when using cellular extracts. Finally, we observed EC cells expressing the K167I variant to be sensitive to DNA damaging agents. These results suggest the K167I variant affected pol beta biochemical activity resulting in impaired BER function, which might subsequently contribute to genomic instability and cancer development. PMID- 26527529 TI - Combination effects of ribavirin and interferons on severe fever with thrombocytopenia syndrome virus infection. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an acute infectious disease caused by SFTS virus and characterized by a high case fatality rate. Currently, there is no effective therapy for the disease. While the administration of ribavirin does not improve the case fatality rate or viral load in patient blood, it can inhibit viral infection in vitro. METHODS: Vero cells were pre-treated with interferons (IFNs) alpha, beta, and gamma alone and in combination with ribavirin drugs and inoculated with SFTS virus. Three days later, supernatants were harvested and subjected to virus titration. An unpaired t-test was used for statistical analysis of the drugs' effects. RESULTS: While the effects of IFNgamma at high concentrations were slightly weaker than those of the other IFNs, all IFNs showed dose-dependent inhibitory effects. The combined usage of IFNs with ribavirin at 90 % effective concentrations showed large inhibitory effects, with over a 3 log10 reduction in viral titers. CONCLUSIONS: The combined usage of one of type-I/II IFNs with ribavirin drastically reduced SFTS virus infection and therefore may be useful in the treatment of SFTS. PMID- 26527531 TI - Peripheral Ulcerative Keratitis with Pyoderma Gangrenosum. AB - Pyoderma gangrenosum is an unusual necrotizing noninfective and ulcerative skin disease whose cause is unknown. Ophthalmic involvement in pyoderma gangrenosum is an unusual event. Only a few cases have been reported, from which we can highlight scleral, corneal, and orbital cases. Peripheral ulcerative keratitis is a process which destroys the peripheral cornea. Its cause is still unknown although it is often associated with autoimmune conditions. Pyoderma gangrenosum should be included in the differential diagnosis of peripheral ulcerative keratitis. Early recognition of these manifestations can vary the prognosis by applying the appropriate treatment. We introduce a 70-year-old woman who suffered pyoderma gangrenosum associated with peripheral ulcerative keratitis in her left eye. The patient's skin lesions and peripheral keratitis responded successfully to systemic steroids and cyclosporine A. PMID- 26527530 TI - Altered social behavior and ultrasonic communication in the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy. AB - BACKGROUND: The Duchenne and Becker muscular dystrophies (DMD, BMD) show significant comorbid diagnosis for autism, and the genomic sequences encoding the proteins responsible for these diseases, the dystrophin and associated proteins, have been proposed as new candidate risk loci for autism. Dystrophin is expressed not only in muscles but also in central inhibitory synapses in the cerebellum, hippocampus, amygdala, and cerebral cortex, where it contributes to the organization of autism-associated trans-synaptic neurexin-neuroligin complexes and to the clustering of synaptic gamma-aminobutyric acid (GABA)A receptors. While brain defects due to dystrophin loss are associated with deficits in cognitive and executive functions, communication skills and social behavior, only a subpopulation of DMD patients meet the criteria for autism, suggesting that mutations in the dystrophin gene may confer a vulnerability to autism. The loss of dystrophin in the mdx mouse model of DMD has been associated with cognitive and emotional alterations, but social behavior and communication abilities have never been studied in this model. METHODS: Here, we carried out the first in depth analysis of social behavior and ultrasonic communication in dystrophin deficient mdx mice, using a range of socially relevant paradigms involving various degrees of executive and cognitive demands, from simple presentation of sexual olfactory stimuli to social choice situations and direct encounters with female and male mice of various genotypes. RESULTS: We identified context specific alterations in social behavior and ultrasonic vocal communication in mdx mice during direct encounters in novel environments. Social behavior disturbances depended on intruders' genotype and behavior, suggesting alterations in executive functions and adaptive behaviors, and were associated with selective alterations of the development, rate, acoustic properties, and use of the ultrasonic vocal repertoire. CONCLUSIONS: This first evidence that a mutation impeding expression of brain dystrophin affects social behavior and communication sheds new light on critical cognitive, emotional, and conative factors contributing to the development of autistic-like traits in this disease model. PMID- 26527532 TI - Anticoagulation in patients with pulmonary arterial hypertension: An update on current knowledge. AB - Pulmonary hypertension is a severe clinical condition characterized by molecular and anatomic changes in pulmonary circulation. It is associated with increased pulmonary vascular resistance, which leads to right-sided heart failure if left untreated and, ultimately, death. Treatment of patients with pulmonary arterial hypertension (PAH) involves a complex strategy that takes into consideration disease severity, general and supportive measures, and combination drug regimens. Abnormalities of blood coagulation factors, anti-thrombotic factors, and the fibrinolytic system may contribute to a prothrombotic state in patients with idiopathic PAH. These physiologic changes, in concert with the presence of non specific risk factors for venous thromboembolism such as heart failure and immobility, are thought to be the basis for oral anticoagulation in PAH. Several observational studies provide helpful information in favor of anticoagulation use in idiopathic PAH but not in other pulmonary hypertension etiologies. Guideline recommendations are based on the lack of prospective comparative trials in this regard. For that reason, large differences exist in the use of anticoagulants in different countries and centers. More studies should be carried out to clarify the risks and the potential benefits of anticoagulant use in a heterogeneous population of patients who are already at considerable life risk. PMID- 26527533 TI - Model for end-stage liver disease excluding international normalized ratio (MELD XI) score predicts heart transplant outcomes: Evidence from the registry of the United Network for Organ Sharing. AB - BACKGROUND: Hepato-renal function is a valuable predictor of success after left ventricular assist device therapy and heart transplantation. Hence, we analyzed the importance of the Model for End-stage Liver Disease excluding international normalized ratio (MELD-XI) score to outcomes after heart transplant. METHODS: Adults undergoing heart transplant from the United Network for Organ Sharing (UNOS) database were identified (1994 to 2014). Individual MELD-XI scores were calculated; patients were stratified by MELD-XI quartiles (Q1 to Q4). Multivariate logistic regression and the Cox proportional hazard model were implemented to determine any association between MELD-XI scores, survival and other outcomes. RESULTS: From 39,711 patients undergoing OHT during the study period, MELD-XI score [median 10.7 (interquartile range 7.0 to 14.4)] was calculated for 36,005 patients (76% male and 75% white, 34% Status 1A). Higher MELD-XI scores had higher rates of pre-transplant extracorporeal membrane oxygenation, intra-aortic balloon pump, inotrope use and mechanical ventilation (p < 0.001 for all). Adjusted long-term mortality (median follow-up 8.1 years) was associated with MELD-XI score (hazard ratio [HR] 1.021 [1.016 to 1.026], p < 0.001). The highest MELD-XI quartile was associated with an HR 1.364 [1.255 to 1.482] risk of mortality compared with Q1. MELD-XI score was also associated with increased post-transplant infections (adjusted HR Q4 vs Q1: 1.364 [1.153 to 1.614], p < 0.001), stroke (adjusted HR Q4 vs Q1: 1.410 [1.074 to 1.852], p = 0.013), dialysis (adjusted HR Q4 vs Q1: 3.982 [3.386 to 4.683], p < 0.001), rejection (adjusted HR Q4 vs Q1: 1.519 [1.286 to 1.795], p = 0.003) and prolonged hospitalization (adjusted HR Q4 vs Q1: 1.635 [1.429 to 1.871], p < 0.001). CONCLUSION: Hepato-renal dysfunction, measured with MELD-XI score, predicts morbidity and mortality in patients undergoing orthotopic heart transplantation. Etiology of hepato-renal dysfunction should be sought and treated before heart transplantation. PMID- 26527534 TI - The effects of culture on guideline discordant gestational weight gain: a systematic review protocol. AB - BACKGROUND: A significant proportion of women exceeds or does not meet the Institute of Medicine's gestational weight gain (GWG) guidelines. Inadequate, excessive GWG or weight loss during pregnancy is associated with an increased risk of negative maternal and fetal outcomes. Among the many determinants of GWG identified in the 2009 Institute of Medicine guidelines, culture was named as one of the few whose influence has not been fully explored. Some cultural beliefs may erroneously promote overeating as "eating for two" and discourage physical activity during pregnancy, but there is lack of empirical evidence on how culture affects GWG. The purpose of this systematic review is to examine the effects of culture on GWG. METHODS/DESIGN: Ten electronic databases will be searched to identify studies reporting on the effects of culture on GWG. Grey literature, published conference abstracts, websites of relevant organizations and reference lists of included studies will also be searched. Studies that report on effects of culture, acculturation, ethnicity, race, nationality, ancestry and identity on GWG in adult women will be included. Quality of evidence will be evaluated using the grading of recommendations, assessment, development and evaluations (GRADE) approach to rating evidence. Study selection, data extraction and risk of bias assessment will be conducted by two independent reviewers, with disagreements being resolved by consensus or third party adjudication as needed. Formal meta analyses will be conducted among included studies that are sufficiently statistically and clinically homogeneous. DISCUSSION: This review will provide a comprehensive assessment and synthesis of current evidence and will draw attention to potential gaps where future research on the effects of culture on guideline discordant gestational weight gain remains to be conducted. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015023399. PMID- 26527535 TI - Potential of selected Senegalese Aedes spp. mosquitoes (Diptera: Culicidae) to transmit Zika virus. AB - BACKGROUND: Zika virus (ZIKV; genus Flavivirus, family Flaviviridae) is an emerging virus of medical importance maintained in a zoonotic cycle between arboreal Aedes spp. mosquitoes and nonhuman primates in African and Asian forests. Serological evidence and virus isolations have demonstrated widespread distribution of the virus in Senegal. Several mosquito species have been found naturally infected by ZIKV but little is known about their vector competence. METHODS: We assessed the vector competence of Ae. aegypti from Kedougou and Dakar, Ae. unilineatus, Ae. vittatus and Ae. luteocephalus from Kedougou in Senegal for 6 ZIKV strains using experimental oral infection. Fully engorged female mosquitoes were maintained in an environmental chamber set at 27 +/- 1 degrees C and 80 +/- 5% Relative humidity. At day 5, 10 and 15 days post infection (dpi), individual mosquito saliva, legs/wings and bodies were tested for the presence of ZIKV genome using real time RT-PCR to estimate the infection, dissemination, and transmission rates. RESULTS: All the species tested were infected by all viral strains but only Ae. vittatus and Ae. luteocephalus were potentially capable of transmitting ZIKV after 15 dpi with 20 and 50% of mosquitoes, respectively, delivering epidemic (HD 78788) and prototype (MR 766) ZIKV strains in saliva. CONCLUSION: All the species tested here were susceptible to oral infection of ZIKV but only a low proportion of Ae. vittatus and Ae. luteocephalus had the viral genome in their saliva and thus the potential to transmit the virus. Further investigations are needed on the vector competence of other species associated with ZIKV for better understanding of the ecology and epidemiology of this virus in Senegal. PMID- 26527536 TI - Kava for the treatment of generalised anxiety disorder (K-GAD): study protocol for a randomised controlled trial. AB - BACKGROUND: Generalised anxiety disorder (GAD) is a chronic and pervasive condition that generates high levels of psychological stress, and it is difficult to treat in the long term. Current pharmacotherapeutic options for GAD are in some cases only modestly effective, and may elicit undesirable side effects. Through targeted actions on the gamma-aminobutyric acid (GABA) pathway, the South Pacific medicinal plant kava (Piper methysticum) is a non-addictive, non-hypnotic anxiolytic with the potential to treat GAD. The evidence for the efficacy of kava for treating anxiety has been affirmed through clinical trials and meta-analyses. Recent research has also served to lessen safety concerns regarding the use of kava due to hepatotoxic risk, which is reflected in a recent German court overturning the previous kava ban in that country (which may in turn influence a reinstatement by the European Union). The aim of current research is to assess the efficacy of an 'aqueous noble cultivar rootstock extract' of kava in GAD in a larger longer term study. In addition, we plan to investigate the pharmacogenomic influence of GABA transporters on response, effects of kava on gene expression, and for the first time, the neurobiological correlates of treatment response via functional and metabolic imaging. METHODS/DESIGN: This clinical trial is funded by the Australian National Health and Medical Research Council (APP1063383) and co-funded by MediHerb (Integria Healthcare (Australia) Pty. Ltd). The study is a phase III, multi-site, two-arm, 18-week, randomised, double-blind, placebo controlled study using an aqueous extract of noble kava cultivar (standardised to 240 mg of kavalactones per day) versus matching placebo in 210 currently anxious participants with diagnosed GAD who are non-medicated. The study takes place at two sites: the Centre for Human Psychopharmacology (Swinburne University of Technology), Hawthorn, Melbourne, Australia; and the Academic Discipline of Psychiatry (The University of Queensland) based at the Royal Brisbane and Women's Hospital, Herston, Brisbane, Australia. Written informed consent will be obtained from each participant prior to commencement in the study. The primary outcome is the Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A). The secondary outcomes involve a range of scales that assess affective disorder symptoms and quality of life outcomes, in addition to the study of mediating biomarkers of response (assessed via genomics and neuroimaging). DISCUSSION: If this study demonstrates positive findings in support of the superiority of kava over placebo in the treatment of GAD, and also is shown to be safe, then this plant-medicine can be considered a 'first-line' therapy for GAD. Genomic and neuroimaging data may reveal clinical response patterns and provide more evidence of the neurobiological activity of the plant extract. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT02219880 Date: 13 August 2014:. PMID- 26527538 TI - COBAS(r) TaqMan(r) MTB, smear positivity grade and MGIT culture; correlation analyses of three methods for bacillary quantification. AB - We investigated the correlation between the cycle threshold (Ct) value of the COBAS((r)) TaqMan((r)) MTB (TaqMan MTB), the mycobacterial smear positivity grade, and the time to detection (TTD) in the Mycobacteria Growth Indicator Tube (MGIT) for quantification of Mycobacterium tuberculosis (MTB). For 57 sputum samples, significant correlations were observed between the Ct value, the smear positivity grade, and the MGIT TTD (Spearman's rank correlation coefficient: r(s) = -0.940, P < 0.001 and Pearson's correlation coefficient: r(p) = 0.737, P < 0.001). In addition, a correlation was observed between the number of bacteria estimated based on the smear positivity grade and the number of MTB bacilli calculated by the Ct value (r(s) = 0.930, P < 0.001). This study has demonstrated the possible estimation of the smear positivity grade and MGIT TTD using the Ct value of TaqMan MTB, which is based on a real-time PCR system, for diagnostic samples. PMID- 26527539 TI - Editorial: Management of Gynaecological Cancers - An Update. PMID- 26527537 TI - The role of the cannabinoid receptor in adolescents' processing of facial expressions. AB - The processing of emotional faces is an important prerequisite for adequate social interactions in daily life, and might thus specifically be altered in adolescence, a period marked by significant changes in social emotional processing. Previous research has shown that the cannabinoid receptor CB1R is associated with longer gaze duration and increased brain responses in the striatum to happy faces in adults, yet, for adolescents, it is not clear whether an association between CBR1 and face processing exists. In the present study we investigated genetic effects of the two CB1R polymorphisms, rs1049353 and rs806377, on the processing of emotional faces in healthy adolescents. They participated in functional magnetic resonance imaging during a Faces Task, watching blocks of video clips with angry and neutral facial expressions, and completed a Morphed Faces Task in the laboratory where they looked at different facial expressions that switched from anger to fear or sadness or from happiness to fear or sadness, and labelled them according to these four emotional expressions. A-allele versus GG-carriers in rs1049353 displayed earlier recognition of facial expressions changing from anger to sadness or fear, but not for expressions changing from happiness to sadness or fear, and higher brain responses to angry, but not neutral, faces in the amygdala and insula. For rs806377 no significant effects emerged. This suggests that rs1049353 is involved in the processing of negative facial expressions with relation to anger in adolescence. These findings add to our understanding of social emotion-related mechanisms in this life period. PMID- 26527540 TI - Knowledge about permanent tooth avulsion and its management among dentists in Riyadh, Saudi Arabia. AB - BACKGROUND: There is a lack of adequate information on dentists' knowledge about tooth avulsion and its management in Saudi Arabia. The aim of this study was to evaluate the level of knowledge about permanent tooth avulsion and its management among dentists working in Riyadh, Saudi Arabia. METHODS: A total of 550 dentists were contacted to request their participation in this 19-item questionnaire survey over a three-month period starting in January 2015 using convenience sampling methodology. A questionnaire consisting of demographic items and multiple-choice questions regarding knowledge of avulsion and its management was used. The level of knowledge was assessed using a scoring system that assigned one point for each correct answer and zero points for wrong answers, with a maximum possible score of ten points. An independent t-test was used to compare the level of knowledge (mean score) based on particular variables, such as sex, nationality, type of practice, current employment, working hours and whether the respondents had attended a continuing dental education (CDE) programme on avulsion management. The level of significance was set at P< 0.05. RESULTS: A total of 470 completed questionnaires were collected with data suitable for statistical analysis. The majority of the respondents were Saudi (n = 331; 72.1 %) and general practitioners (n = 278; 59.3 %). Most of the participants correctly responded to the knowledge-based questions, except the questions regarding the best storage medium (milk: 24.1 %) and the duration of follow-up by clinical and radiographic examination (5 years: 15.6 %). The mean knowledge score was 5.94 +/- 1.57. Gender (P = 0.001), current employment (P = 0.045) and working hours per day (P = 0.020) had a significant effect on the mean knowledge score. CONCLUSIONS: The surveyed dentists were found to have a moderate knowledge of avulsion and its management, although a relative lack of knowledge was observed regarding the duration of follow-up after replantation. PMID- 26527541 TI - Supramolecular Protein Immobilization on Lipid Bilayers. AB - Protein immobilization on surfaces, and on lipid bilayers specifically, has great potential in biomolecular and biotechnological research. Of current special interest is the immobilization of proteins using supramolecular noncovalent interactions. This allows for a reversible immobilization and obviates the use of harsh ligation conditions that could denature fragile proteins. In the work presented here, reversible supramolecular immobilization of proteins on lipid bilayer surfaces was achieved by using the host-guest interaction of the macrocyclic molecule cucurbit[8]uril. A fluorescent protein was successfully immobilized on the lipid bilayer by making use of the property of cucurbit[8]uril to host together a methylviologen and the indole of a tryptophan positioned on the N-terminal of the protein. The supramolecular complex was anchored to the bilayer through a cholesterol moiety that was attached to the methylviologen tethered with a small polyethylene glycol spacer. Protein immobilization studies using a quartz crystal microbalance (QCM) showed the assembly of the supramolecular complexes on the bilayer. Specific immobilization through the protein N-terminus is more efficient than through protein side-chain events. Reversible surface release of the proteins could be achieved by washing with cucurbit[8]uril or buffer alone. The described system shows the potential of supramolecular assembly of proteins and provides a method for site-specific protein immobilization under mild conditions in a reversible manner. PMID- 26527542 TI - [Bariatric surgery in obese adolescents: When and how should the transition from pediatric to adult medical management be made?]. AB - INTRODUCTION: In young obese patients, the transition from adolescence to adulthood, i.e., the transition from the pediatric to the adult medical team, is a new issue. In particular, it is important to define when and how this transition should be made in the setting of bariatric surgery. MATERIALS AND METHODS: Fourteen young obese patients (under the age of 20), who underwent bariatric surgery, were included in the study (nine cases of Roux-en-Y gastric by pass, three sleeve gastrectomy, one gastric banding). After surgery, the patients were followed in both the pediatric and adult departments (protocol 1) or only in the pediatric department during the 1st year and then in the adult department afterwards (protocol 2). Anthropometric and metabolic data, before and after surgery, and compliance monitoring were analyzed using a retrospective design. Twelve patients completed a questionnaire assessing how they experienced the transition. RESULTS: Before surgery, mean age+/-SD was 16.3+/-1.8 years old and mean body mass index (BMI) 55.0+/-8.6kg/m(2). At 1 year after surgery, mean weight loss was -32.1+/-8.2% of initial body weight. Adherence to vitamin supplementation was judged to be adequate (vitamins were not taken less than once a week) for only 57.5% patients. Mean follow-up was 34.8+/-25.1 months [95% CI, 9.5-78.4]. None of the patients was lost to follow-up. Compliance was significantly better for patients following protocol 2. Adolescents reported being satisfied with meetings and newsletters about surgery, specific to this age group (91.7%). They also reported that information on the adult department was sufficient and 91.7% of them expressed satisfaction on the first outpatient visit in the adult department. However, all patients spontaneously reported having difficulties identifying members of the different teams: nutritionist pediatrician, nutritionist, and adult surgeon. DISCUSSION: These preliminary data suggest that, in obese adolescents, it is important to differentiate the transition period and the time and preparation for bariatric surgery. A prospective follow-up with a larger number of subjects and recommendations are needed to better define and improve the specific clinical management of obese adolescents transitioning to adulthood. PMID- 26527543 TI - [Sacral dimple: What form of management is best?]. AB - A sacral dimple measuring less than 5mm, within 25mm of the anus on the median line, with no other cutaneous anomaly, does not require any complementary examination. Parents can be reassured. However, any cutaneous depression in the sacrolumbar region not respecting these criteria must be considered as an occult dysraphism until proved otherwise. A medullary ultrasound examination and a consultation with a specialist (pediatric neurosurgeon) are necessary. The dermic sinus is the main differential diagnosis, with favorable outcome in case of early treatment before any infectious complication arises. Conversely, the risk of permanent sequelae is high if neglected or in case of late diagnosis. PMID- 26527545 TI - Risk factors associated with malignancy and with triage to surgery in thyroid nodules classified as Bethesda category III (AUS/FLUS). AB - BACKGROUND: Selection of nodules for surgery diagnosed as Bethesda category III [atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) category] is very important. We aimed at to define the predictive factors for malignancy and factors associated with triage to surgery. METHODS: The records of all patients with nodules who underwent fine needle aspiration biopsy (FNAB) and classified by Bethesda reporting system as AUS/FLUS between 2011 and 2015 at our institution were reviewed. Univariate and multivariate analysis were performed to select independent factors associated with thyroid cancer and with triage to surgery. Using independent risk factors for malignancy predictive index categories were created. RESULTS: Of the 485 patients who were classified as AUS/FLUS on initial FNAB, 153 underwent surgery with the associated malignancy rate of 22.8%. The malignancy rates for AUS/FLUS patients with and without repeat FNAB were 37.5% and 16.2%, respectively. Multivariate logistic regression analysis revealed that solid structure, microcalcification, hypoechogenicity, increased vascularization, and irregular margin were found to be significant and independent risk factors associated for malignancy, and solid structure, microcalcifications, increased nodule size (>=2 cm) and younger patient age (<65 years) were associated with triage to surgery. CONCLUSIONS: Our findings showed that using predictive factors for malignancy in AUS/FLUS category as risk indices, an important proportion of patients (35%) who had nodules without any risk factors could be spared unnecessary surgery. We suggest that predictive indices should be considered for selection of the patients to triage to surgery. PMID- 26527547 TI - Insurance Coverage of Puberty Blocker Therapies for Transgender Youth. PMID- 26527544 TI - Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway. AB - Lipopolysaccharide (LPS) derived from Gram-negative bacteria activates plasma membrane signaling via Toll-like receptor 4 (TLR4) on host cells and triggers innate inflammatory responses, but the underlying mechanisms remain to be fully elucidated. Here we reveal a role for annexin A2 (AnxA2) in host defense against infection as anxa2(-/-) mice were highly susceptible to Gram-negative bacteria induced sepsis with enhanced inflammatory responses. Computing analysis and biochemical experiments identified that constitutive AnxA2 expression facilitated TLR4 internalization and its subsequent translocation into early endosomal membranes. It activated the TRAM-dependent endosomal signaling, leading to the release of anti-inflammatory cytokines. Importantly, AnxA2 deficiency prolonged TLR4-mediated signaling from the plasma membrane, which was attributable to pro inflammatory cytokine production (IL-6, TNFalpha and IL-1beta). Thus, AnxA2 directly exerted negative regulation of inflammatory responses through TLR4 initiated TRAM-TRIF pathway occurring on endosomes. This study reveals AnxA2 as a critical regulator in infection-initiated inflammation, which protects the host from excessive inflammatory damage. PMID- 26527546 TI - Rab9A is required for delivery of cargo from recycling endosomes to melanosomes. AB - Melanosomes are a type of lysosome-related organelle that is commonly defective in Hermansky-Pudlak syndrome. Biogenesis of melanosomes is regulated by BLOC-1, 2, -3, or AP-1, -3 complexes, which mediate cargo transport from recycling endosomes to melanosomes. Although several Rab GTPases have been shown to regulate these trafficking steps, the precise role of Rab9A remains unknown. Here, we found that a cohort of Rab9A associates with the melanosomes and its knockdown in melanocytes results in hypopigmented melanosomes due to mistargeting of melanosomal proteins to lysosomes. In addition, the Rab9A-depletion phenotype resembles Rab38/32-inactivated or BLOC-3-deficient melanocytes, suggesting that Rab9A works in line with BLOC-3 and Rab38/32 during melanosome cargo transport. Furthermore, silencing of Rab9A, Rab38/32 or its effector VARP, or BLOC-3 deficiency in melanocytes decreased the length of STX13-positive recycling endosomal tubules and targeted the SNARE to lysosomes. This result indicates a defect in directing recycling endosomal tubules to melanosomes. Thus, Rab9A and its co-regulatory GTPases control STX13-mediated cargo delivery to maturing melanosomes. PMID- 26527548 TI - Exposure and Use of Mobile Media Devices by Young Children. AB - BACKGROUND AND OBJECTIVES: Research on children's use of mobile media devices lags behind its adoption. The objective of this study was to examine young children's exposure to and use of mobile media devices. METHODS: Cross-sectional study of 350 children aged 6 months to 4 years seen October to November 2014 at a pediatric clinic in an urban, low-income, minority community. The survey was adapted from Common Sense Media's 2013 nationwide survey. RESULTS: Most households had television (97%), tablets (83%), and smartphones (77%). At age 4, half the children had their own television and three-fourths their own mobile device. Almost all children (96.6%) used mobile devices, and most started using before age 1. Parents gave children devices when doing house chores (70%), to keep them calm (65%), and at bedtime (29%). At age 2, most children used a device daily and spent comparable screen time on television and mobile devices. Most 3- and 4-year-olds used devices without help, and one-third engaged in media multitasking. Content delivery applications such as YouTube and Netflix were popular. Child ownership of device, age at first use, and daily use were not associated with ethnicity or parent education. CONCLUSIONS: Young children in an urban, low-income, minority community had almost universal exposure to mobile devices, and most had their own device by age 4. The patterns of use suggest early adoption, frequent and independent use, and media multitasking. Studies are urgently needed to update recommendations for families and providers on the use of mobile media by young children. PMID- 26527549 TI - X-linked Agammaglobulinemia With Normal Immunoglobulin and Near-Normal Vaccine Seroconversion. AB - We present a 22-month-old boy with X-linked agammaglobulinemia masked by normal immunoglobulin levels and vaccine seroconversion. Diagnosis was made after strong clinical suspicion of immune deficiency led to identification of markedly reduced B-cell numbers and confirmation with identification of a novel Bruton tyrosine kinase gene mutation. He was commenced on replacement immunoglobulin therapy with excellent clinical improvement. This case highlights the variability of phenotypic presentation and apparent disunity between routine immunologic investigations and severe disease in X-linked agammaglobulinemia, necessitating clinical acumen to make the diagnosis. PMID- 26527550 TI - Testing and Treating Sexually Assaulted Adolescents: What Are We Waiting For? PMID- 26527551 TI - Obesity and Autism. AB - OBJECTIVE: Overweight and obesity are increasingly prevalent in the general pediatric population. Evidence suggests that children with autism spectrum disorders (ASDs) may be at elevated risk for unhealthy weight. We identify the prevalence of overweight and obesity in a multisite clinical sample of children with ASDs and explore concurrent associations with variables identified as risk factors for unhealthy weight in the general population. METHODS: Participants were 5053 children with confirmed diagnosis of ASD in the Autism Speaks Autism Treatment Network. Measured values for weight and height were used to calculate BMI percentiles; Centers for Disease Control and Prevention criteria for BMI for gender and age were used to define overweight and obesity (>=85th and >=95th percentiles, respectively). RESULTS: In children age 2 to 17 years, 33.6% were overweight and 18% were obese. Compared with a general US population sample, rates of unhealthy weight were significantly higher among children with ASDs ages 2 to 5 years and among those of non-Hispanic white origin. Multivariate analyses revealed that older age, Hispanic or Latino ethnicity, lower parent education levels, and sleep and affective problems were all significant predictors of obesity. CONCLUSIONS: Our results indicate that the prevalence of unhealthy weight is significantly greater among children with ASD compared with the general population, with differences present as early as ages 2 to 5 years. Because obesity is more prevalent among older children in the general population, these findings raise the question of whether there are different trajectories of weight gain among children with ASDs, possibly beginning in early childhood. PMID- 26527552 TI - Characteristics of Physicians Who Dismiss Families for Refusing Vaccines. AB - BACKGROUND AND OBJECTIVES: Physicians dismissing families who refuse vaccines from their practices is controversial. We assessed the following among pediatricians (Peds) and family physicians (FPs): (1) reported prevalence of parental refusal of 1 or more vaccines in the infant series; (2) physician response to refusal; and (3) the association between often/always dismissing families and provider/practice characteristics and state exemption laws. METHODS: Nationally representative survey conducted June to October 2012. A multivariable analysis assessed association of often/always dismissing families with physician/practice characteristics, state philosophical exemption policy, and degree of difficulty obtaining nonmedical exemptions. RESULTS: The response rate was 66% (534/815). Overall, 83% of physicians reported that in a typical month, >=1% of parents refused 1 or more infant vaccines, and 20% reported that >5% of parents refused. Fifty-one percent reported always/often requiring parents to sign a form if they refused (Peds 64%, FP 29%, P < .0001); 21% of Peds and 4% of FPs reported always/often dismissing families if they refused >=1 vaccine. Peds only were further analyzed because few FPs dismissed families. Peds who dismissed families were more likely to be in private practice (adjusted odds ratio [aOR] 4.90, 95% confidence interval [CI] 1.40-17.19), from the South (aOR 4.07, 95% CI 1.08-15.31), and reside in a state without a philosophical exemption law (aOR 3.70, 95% CI 1.74-7.85). CONCLUSIONS: Almost all physicians encounter parents who refuse infant vaccines. One-fifth of Peds report dismissing families who refuse, but there is substantial variation in this practice. Given the frequency of dismissal, the impact of this practice on vaccine refusers and on pediatric practices should be studied. PMID- 26527553 TI - Improving Pediatric Asthma Care and Outcomes Across Multiple Hospitals. AB - BACKGROUND AND OBJECTIVES: Gaps exist in inpatient asthma care. Our aims were to assess the impact of an evidence-based care process model (EB-CPM) 5 years after implementation at Primary Children's Hospital (PCH), a tertiary care facility, and after its dissemination to 7 community hospitals. METHODS: Participants included asthmatics 2 to 17 years admitted at 8 hospitals between 2003 and 2013. The EB-CPM was implemented at PCH between January 2008 and March 2009, then disseminated to 7 community hospitals between January and June 2011. We measured compliance using a composite score (CS) for 8 quality measures. Outcomes were compared between preimplementation and postimplementation periods. Confounding was addressed through multivariable regression analyses. RESULTS: At PCH, the CS increased and remained at >90% for 5 years after implementation. We observed sustained reductions in asthma readmissions (P = .026) and length of stay (P < .001), a trend toward reduced costs (P = .094), and no change in hospital resource use, ICU transfers, or deaths. The CS also increased at the 7 community hospitals, reaching 80% to 90% and persisting >2 years after dissemination, with a slight but not significant readmission reduction (P = .119), a significant reduction in length of stay (P < .001) and cost (P = .053), a slight increase in hospital resource use (P = .032), and no change in ICU transfers or deaths. CONCLUSIONS: Our intervention resulted in sustained, long-term improvement in asthma care and outcomes at the tertiary care hospital and successful dissemination to community hospitals. PMID- 26527554 TI - Testing and Treatment After Adolescent Sexual Assault in Pediatric Emergency Departments. AB - OBJECTIVE: To examine rates of recommended of testing and prophylaxis for chlamydia, gonorrhea, and pregnancy in adolescents diagnosed with sexual assault across pediatric emergency departments (EDs) and to determine whether specialized sexual assault pathways and teams are associated with performance of recommended testing and prophylaxis. METHODS: In this retrospective study of 12- to 18-year old adolescents diagnosed with sexual assault at 38 EDs in the Pediatric Hospital Information System database from 2004 to 2013, information regarding routine practice for sexual assault evaluations and presence and year of initiation of specialized ED sexual assault pathways and teams was collected via survey. We examined across-hospital variation and identified patient- and hospital-level factors associated with testing and prophylaxis using logistic regression models, accounting for clustering by hospital. RESULTS: Among 12,687 included cases, 93% were female, 79% were <16 years old, 34% were non-Hispanic white, 38% were non Hispanic black, 21% were Hispanic, and 52% had public insurance. Overall, 44% of adolescents received recommended testing (chlamydia, gonorrhea, pregnancy) and 35% received recommended prophylaxis (chlamydia, gonorrhea, emergency contraception). Across EDs, unadjusted rates of testing ranged from 6% to 89%, and prophylaxis ranged from 0% to 57%. Presence of a specialized sexual assault pathway was associated with increased rates of prophylaxis even after adjusting for case-mix and temporal trends (odds ratio 1.46, 95% confidence interval 1.15 to 1.86). CONCLUSIONS: Evaluation and treatment of adolescent sexual assault victims varied widely across pediatric EDs. Adolescents cared for in EDs with specialized sexual assault pathways were more likely to receive recommended prophylaxis. PMID- 26527555 TI - The Medical Home and Hospital Readmissions. AB - BACKGROUND AND OBJECTIVE: Despite considerable attention, little is known about the degree to which primary care medical homes influence early postdischarge utilization. We sought to test the hypothesis that patients with medical homes are less likely to have early postdischarge hospital or emergency department (ED) encounters. METHODS: This prospective cohort study enrolled randomly selected patients during an acute hospitalization at a children's hospital during 2012 to 2014. Demographic and clinical data were abstracted from administrative sources and caregiver questionnaires on admission through 30 days postdischarge. Medical home experience was assessed by using Maternal and Child Health Bureau definitions. Primary outcomes were 30-day unplanned readmission and 7-day ED visits to any hospital. Logistic regression explored relationships between outcomes and medical home experiences. RESULTS: We followed 701 patients, 97% with complete data. Thirty-day unplanned readmission and 7-day ED revisit rates were 12.4% and 5.6%, respectively. More than 65% did not have a medical home. In adjusted models, those with medical home component "having a usual source of sick and well care" had fewer readmissions than those without (adjusted odds ratio 0.54, 95% confidence interval 0.30-0.96). Readmissions were higher among those with less parent confidence in avoiding a readmission, subspecialist primary care providers, longer length of index stay, and more hospitalizations in the past year. ED visits were associated with lack of parent confidence but not medical home components. CONCLUSIONS: Lacking a usual source for care was associated with readmissions. Lack of parent confidence was associated with readmissions and ED visits. This information may be used to target interventions or identify high risk patients before discharge. PMID- 26527556 TI - Case Reports of Aripiprazole Causing False-Positive Urine Amphetamine Drug Screens in Children. AB - Urine drug screens (UDSs) are used to identify the presence of certain medications. One limitation of UDSs is the potential for false-positive results caused by cross-reactivity with other substances. Amphetamines have an extensive list of cross-reacting medications. The literature contains reports of false positive amphetamine UDSs with multiple antidepressants and antipsychotics. We present 2 cases of presumed false-positive UDSs for amphetamines after ingestion of aripiprazole. Case 1 was a 16-month-old girl who accidently ingested 15 to 45 mg of aripiprazole. She was lethargic and ataxic at home with 1 episode of vomiting containing no identifiable tablets. She remained sluggish with periods of irritability and was admitted for observation. UDS on 2 consecutive days came back positive for amphetamines. Case 2 was of a 20-month-old girl who was brought into the hospital after accidental ingestion of an unknown quantity of her father's medications which included aripiprazole. UDS on the first day of admission came back positive only for amphetamines. Confirmatory testing with gas chromatography-mass spectrometry (GC-MS) on the blood and urine samples were also performed for both patients on presentation to detect amphetamines and were subsequently negative. Both patients returned to baseline and were discharged from the hospital. To our knowledge, these cases represent the first reports of false-positive amphetamine urine drug tests with aripiprazole. In both cases, aripiprazole was the drug with the highest likelihood of causing the positive amphetamine screen. The implications of these false-positives include the possibility of unnecessary treatment and monitoring of patients. PMID- 26527557 TI - Anatomical features for an adequate choice of experimental animal model in biomedicine: II. Small laboratory rodents, rabbit, and pig. AB - The anatomical features distinctive to each of the very large array of species used in today's biomedical research must be born in mind when considering the correct choice of animal model(s), particularly when translational research is concerned. In this paper we take into consideration and discuss the most important anatomical and histological features of the commonest species of laboratory rodents (rat, mouse, guinea pig, hamster, and gerbil), rabbit, and pig related to their importance for applied research. PMID- 26527558 TI - Type I diabetes in paediatric age in Apulia (Italy): Incidence and associations with outdoor air pollutants. AB - AIM: This study aimed to explore Type 1 diabetes (T1D) incidence and possible relations with specific air pollutants in a large population of children, during a wide time period. METHODS: T1D rates and trends were examined (2001-2013, GAM and Joinpoint Regression analysis) by data on the first hospitalization in all children (0-14 years) living in Apulia (Southern Italy, average yearly population aged 0-14 years in the examined period: 631,275 subjects), and linked with levels of PM10, NOx, CO and ozone. RESULTS: A total of 1501 children were first discharged in the selected area with a diagnosis of T1D. Incidence decreased from 48.5 (95% CI 43.3; 54.0, 2001) to 16.9 per 100,000 (95% CI 13.7; 20.6, 2013), with differences according to age at onset (constant at 0-4 years, continuously decreasing at 5-9 years, decreasing until 2003 at 10-14 years), and with a positive relation with PM10--but not ozone, NOx and CO average air levels. The OR was 1.037 (1.002; 1.074) in the high tertile of PM10 concentrations, and mean incidence was higher with PM10 levels in the highest, than in the medium/reference tertile. Mean age at T1D onset was linked with yearly PM10 and ozone air levels. CONCLUSIONS: On a wide period, a stable or decreased incidence of T1D was evident in children with early- or later onset of disease, respectively. PM10 exposure significantly affects the incidence of T1D, which might be considered, at least in part, a preventable condition. PMID- 26527559 TI - Chinese Erdheim-Chester disease: clinical-pathology-PET/CT updates. AB - Erdheim-Chester disease (ECD), one type of systemic non-Langerhans cell histiocytosis, has been rarely seen and is characterized by the accumulation of foamy CD68+CD1a- histiocytes. We reported a case of ECD and reviewed the clinical features of 13 cases of ECD reported so far in China. A 53-year-old male was diagnosed with central diabetes insipidus in March 2014, followed by fever, splenomegaly and anemia in July 2014. His initial pituitary magnetic resonance imaging (MRI) revealed the absence of high signal at T1-weighted image in posterior pituitary without any lesion. A further positron emission tomography/computer tomography (PET/CT) images showed elevated metabolic activity of (18)F-2-fluro-D-deoxy-glucose (FDG) and low (13)N-NH3 uptake in the posterior pituitary, and multi-organ involvement. Biopsy at right femur lesion revealed that granulomatous infiltration of foamy histiocytes and Touton giant cells surrounded by fibrosis tissues. Immunohistochemistry stain was positive for CD68, negative for CD207/Langerin and S-100. The diagnosis of ECD was confirmed and the treatment with pegylated interferon was effective. ECD was a possible immune related disorder concluding from the IgG4 immunohistochemistry results. We summarized the pathological manifestations for ECD and its differential diagnosis from Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD). ECD should be considered by both pathologists and clinicians in the differential diagnosis when central diabetes insipidus is accompanied with multi-organ involvement, especially skeletal system involvement, or recurrent fever. LEARNING POINTS: ECD should be considered when central diabetes insipidus is accompanied with multisystem involvement, especially symmetric/asymmetric bone lesions, or recurrent fever.PET/CT scanning was helpful for locating pituitary lesion, discovering multiple system involvement and indicating the biopsy sites.Conducting proper immunohistochemistry stains was important for diagnosing ECD. ECD might be correlated with immune disorder. PMID- 26527560 TI - Obese patients have similar short-term outcomes to non-obese in laparoscopic colorectal surgery. AB - AIM: To determine whether obese patients undergoing laparoscopic surgery within an enhanced recovery program had worse short-term outcomes. METHODS: A prospective study of consecutive patients undergoing laparoscopic colorectal resection was carried out between 2008 and 2011 in a single institution. Patients were divided in groups based on body mass index (BMI). Short-term outcomes including operative data, length of stay, complications and readmission rates were recorded and compared between the groups. Continuous data were analysed using t-test or one-way Analysis of Variance. chi(2) test was used to compare categorical data. RESULTS: Two hundred and fifty four patients were included over the study period. The majority of individuals (41.7%) recruited were of a healthy weight (BMI < 25), whilst 50 patients were classified as obese (19.6%). Patients were matched in terms of the presence of co-morbidities and previous abdominal surgery. Obese patients were found to have a statistically significant difference in The American Society of Anesthesiologists grade. Length of surgery and intra operative blood loss were no different according to BMI. CONCLUSION: Obesity (BMI > 25) does not lead to worse short-term outcomes in laparoscopic colorectal surgery and therefore such patients should not be precluded from laparoscopic surgery. PMID- 26527561 TI - Cord blood mononuclear cells prevent neuronal apoptosis in response to perinatal asphyxia in the newborn lamb. AB - Perinatal asphyxia is a significant cause of death or long-term neurodevelopmental impairment. Hypothermia, currently the only effective treatment, leads to modest improvements, but new therapeutic strategies are required. Umbilical cord blood (UCB) mononuclear cells have potent anti inflammatory properties and may reduce neuropathology. This study examined whether autologous UCB mononuclear cells were neuroprotective when administered to newborn lambs at 12 h after birth asphyxia. At caesarean section, birth asphyxia was induced by clamping the umbilical cord until mean arterial blood pressure decreased to 18-20 mmHg. Asphyxia (n = 20) or control (n = 11) lambs were resuscitated and maintained, with magnetic resonance spectroscropy (MRS) performed at 12 and 72 h, and were then killed at 72 h. Cord blood was collected once the cord was clamped, and mononuclear cells were isolated and labelled fluorescently and administered to control (n = 3) or asphyxia (n = 8) lambs. Asphyxia induced a significant increase in cellular apoptosis (caspase-3 immunopositive) within all brain regions examined, including cortex, hippocampus, thalamus, striatum and subcortical white matter (P < 0.01 vs. control). Additionally, asphyxia induced significant and widespread astrogliosis and increased inflammatory cells (activated microglia and macrophages). The administration of UCB mononuclear cells (asphyxia+UCB) significantly decreased neuronal apoptosis, astrogliosis and inflammation (P < 0.05 vs. asphyxia alone). Asphyxia+UCB lambs also demonstrated decreased brain metabolites lactate:choline (P = 0.01) and lactate:N-acetylaspartate (P < 0.01) from 12 to 72 h, detected using MRS. Autologous UCB mononuclear cell treatment restores normal brain metabolism following perinatal asphyxia, and reduces brain inflammation, astrogliosis and neuronal apoptosis, supporting its use as a neuroprotective therapy following asphyxia. PMID- 26527562 TI - Sensitive Detection of Cardiac Biomarkers Using a Magnetic Microbead Immunoassay. AB - To achieve improved sensitivity in cardiac biomarker detection, a batch incubation magnetic microbead immunoassay was developed and tested on three separate human protein targets: myoglobin, heart-type fatty acid binding protein, and cardiac troponin I. A sandwich immunoassay was performed in a simple micro centrifuge tube allowing full dispersal of the solid capture surface during incubations. Following magnetic bead capture and wash steps, samples were analyzed in the presence of a manipulated magnetic field utilizing a modified microscope slide and fluorescent inverted microscope to collect video data files. Analysis of the video data allowed for the quantitation of myoglobin, heart-type fatty acid binding protein and cardiac troponin I to levels of 360 aM, 67 fM, and 42 fM, respectively. Compared to the previous detection limit of 50 pM for myoglobin, this offers a five-fold improvement in sensitivity. This improvement in sensitivity and incorporation of additional markers, along with the small sample volumes required, suggest the potential of this platform for incorporation as a detection method in a total sample analysis device enabling multiplexed detection for the analysis of clinical samples. PMID- 26527563 TI - Selective downregulation of HLA-C and HLA-E in childhood acute lymphoblastic leukaemia. PMID- 26527564 TI - Anti-pruritic Effect of Sertaconazole 2% Cream in Atopic Dermatitis Subjects: A Prospective, Randomized, Double-blind, Vehicle-controlled, Multi-centre Clinical Trial of Efficacy, Safety and Local Tolerability. AB - This study was a prospective, parallel-group, randomized, double-blind, vehicle controlled, multi-centre clinical trial to compare the efficacy of topical sertaconazole 2% cream with vehicle in reducing chronic pruritus in subjects with atopic dermatitis, and to assess its safety and local tolerability. A total of 70 subjects applied either of the 2 treatments twice daily for a period of 4 weeks on affected, itchy skin areas. Treatment efficacy was evaluated primarily considering the item itch intensity on a 5-point verbal rating scale. Insomnia, state of atopic dermatitis (Scoring Atopic Dermatitis; SCORAD), quality of life and therapy benefit were also assessed. No significant difference between active treatment and vehicle was found at any of the time-points for any of the investigated parameters. Under the experimental conditions of the study, sertaconazole 2% cream did not exert anti-pruritic effects that were better than vehicle in subjects with atopic dermatitis who had chronic pruritus. Trial registration ClinicalTrials.gov #NCT01792713. PMID- 26527565 TI - Regulation of TRH neurons and energy homeostasis-related signals under stress. PMID- 26527566 TI - 60 YEARS OF NEUROENDOCRINOLOGY: TRH, the first hypophysiotropic releasing hormone isolated: control of the pituitary-thyroid axis. PMID- 26527567 TI - Pregnancy outcome of 149 pregnancies in women with epilepsy: Experience from a tertiary care hospital. AB - INTRODUCTION: Epilepsy has a prevalence of 1.65% in adults, and every 1 in 200 pregnancies encounters its complications. We aimed to present the existing condition of and our experience with epileptic pregnant women for whom the prepregnancy counseling is inadequate in Turkey. METHODS: We evaluated 149 epileptic pregnant women between March 2009 and January 2015. Demographic features of the patients, along with type and duration of epileptic seizure, time of diagnosis, date of last seizure prior to pregnancy, number and duration of seizures during pregnancy, type of AEDs, result and week of termination of pregnancy, and birth weight were registered, and also, we evaluated perinatal complications and fetal malformations. RESULTS: Mean age of the patients was 27.12 +/- 5.4 years, and mean duration from the diagnosis of epilepsy to pregnancy was 9.68 +/- 5.91 years. Twenty-seven (18.12%) and 101 (67.78%) patients had polytherapy and monotherapy, respectively. We observed epileptic seizures in 103 (69.12%) patients during pregnancy, and seizures mostly occurred in the first and third trimesters. Forty-one (39.80%) patients had seizures in all three trimesters. Forty-two (28.18%) patients among all patients who had seizures during pregnancy had 5 or more seizures. Major malformations, namely, cleft lip and palate, ventriculoseptal defect, and spina bifida were observed in the patients. Mean birth week was 38.43 +/- 1.68 weeks, and mean birth weight was 2965.31 +/- 453.94 grams. Twenty-two patients had normal spontaneous vaginal delivery whereas 118 patients had cesarean section. CONCLUSIONS: Pregnant women with epilepsy have their own risks. These women should be followed by experienced obstetricians and neurologists during their pregnancies. Appropriate management and follow-up lead to good results almost the same as general population. PMID- 26527568 TI - Editorial. PMID- 26527569 TI - Osteoporosis, Sarcopenia, Falls and Fractures: In This Issue. PMID- 26527570 TI - Welding of Semiconductor Nanowires by Coupling Laser-Induced Peening and Localized Heating. AB - We demonstrate that laser peening coupled with sintering of CdTe nanowire films substantially enhances film quality and charge transfer while largely maintaining basic particle morphology. During the laser peening phase, a shockwave is used to compress the film. Laser sintering comprises the second step, where a nanosecond pulse laser beam welds the nanowires. Microstructure, morphology, material content, and electrical conductivities of the films are characterized before and after treatment. The morphology results show that laser peening can decrease porosity and bring nanowires into contact, and pulsed laser heating fuses those contacts. Multiphysics simulations coupling electromagnetic and heat transfer modules demonstrate that during pulsed laser heating, local EM field enhancement is generated specifically around the contact areas between two semiconductor nanowires, indicating localized heating. The characterization results indicate that solely laser peening or sintering can only moderately improve the thin film quality; however, when coupled together as laser peen sintering (LPS), the electrical conductivity enhancement is dramatic. LPS can decrease resistivity up to a factor of ~10,000, resulting in values on the order of ~10(5) Omega-cm in some cases, which is comparable to CdTe thin films. Our work demonstrates that LPS is an effective processing method to obtain high-quality semiconductor nanocrystal films. PMID- 26527571 TI - Predictors of survival following trans-catheter aortic valve closure for left ventricular assist device associated aortic insufficiency. AB - OBJECTIVE: This study sought to assess the long-term clinical benefits and predictors of survival of trans-catheter aortic valve closure in left ventricular assist device (LVAD) patients. BACKGROUND: LVADs have been shown to increase survival and quality of life in patients with end-stage heart failure. However, severe aortic insufficiency (AI) can develop in up to 50% of patients at 12 months resulting in significant morbidity and mortality. Trans-catheter treatment of LVAD associated AI has emerged as a potential alternative to surgical treatment. METHODS: We conducted a retrospective analysis of all patients undergoing trans-catheter aortic valve closure using an Amplatzer Multi Fenestrated Septal Occluder "Cribriform" device to assess potential clinical and procedural factors associated with survival. Student's t-tests were used to compare baseline patient demographics and procedural characteristics, as well as patient outcomes immediately post procedure and at 6 months. A P-value of less than 0.05 was considered statistically significant. RESULTS: A total of 10 patients (70% male, median age 59 years) were included. Technical success was accomplished in 100% of patients with a 6 month survival rate of 30% (3/10). Compared with survivors, non-survivors had a higher rate of pre-procedural clinical co-morbidities, an increased likelihood of right ventricular failure, and received larger occluder devices. CONCLUSIONS: Trans-catheter aortic valve closure successfully treats late severe AI in LVAD patients, however, the presence or development of right heart failure portends a worse prognosis. Further studies are needed to investigate the factors involved in the development of right ventricular failure, and potential treatment, in patients undergoing trans-catheter aortic valve closure. PMID- 26527573 TI - Dynamics of yeast immobilized-cell fluidized-bed bioreactors systems in ethanol fermentation from lactose-hydrolyzed whey and whey permeate. AB - We studied the dynamics of ethanol production on lactose-hydrolyzed whey (LHW) and lactose-hydrolyzed whey permeate (LHWP) in batch fluidized-bed bioreactors using single and co-cultures of immobilized cells of industrial strains of Saccharomyces cerevisiae and non-industrial strains of Kluyveromyces marxianus. Although the co-culture of S. cerevisiae CAT-1 and K. marxianus CCT 4086 produced two- to fourfold the ethanol productivity of single cultures of S. cerevisiae, the single cultures of the K. marxianus CCT 4086 produced the best results in both media (Y EtOH/S = 0.47-0.49 g g(-1) and Q P = 1.39-1.68 g L(-1) h(-1), in LHW and LHWP, respectively). Ethanol production on concentrated LHWP (180 g L( 1)) reached 79.1 g L(-1), with yields of 0.46 g g(-1) for K. marxianus CCT 4086 cultures. Repeated batches of fluidized-bed bioreactor on concentrated LHWP led to increased ethanol productivity, reaching 2.8 g L(-1) h(-1). PMID- 26527572 TI - Immunogenicity and mechanisms impairing the response to vaccines in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is an immunological disorder that is usually treated with immunosuppressive therapy, potentially leading to increases in vulnerability to infections. Although many infections can be prevented by vaccination, vaccination coverage in these patients in clinical practice is insufficient. Therefore, the seroprotection condition should be verified, even for routine vaccines, such as hepatitis B or pneumococcus. Response to vaccines in IBD patients is thought to be impaired due to the immunological alterations generated by the disease and to the immunomodulatory treatments. The immunogenicity of hepatitis B, influenza, and pneumococcal vaccines is impaired in IBD patients, whereas the response to papillomavirus vaccine seems similar to that observed in the healthy population. On the other hand, data on the immunogenicity of tetanus vaccine in IBD patients are conflicting. Studies assessing the response to measles-mumps-rubella, varicella, and herpes zoster vaccines in IBD patients are scarce. The cellular and molecular mechanisms responsible for the impairment of the response to vaccination in IBD patients are poorly understood. Studies aiming to assess the response to vaccines in IBD patients and to identify the mechanisms involved in their immunogenicity are warranted. A better understanding of the immune response, specifically to vaccines, in patients with immune-mediated diseases (such as IBD), is crucial when developing vaccines that trigger more potent immunologic responses. PMID- 26527574 TI - Neuroimaging of Visceral Pain. AB - Functional neuroimaging allows conscious reporting by human subjects to be related to changes in brain activation during painful stimulation.Brain regions thought to be involved in the perception of pain include the primary and secondary somatosensory cortex, the anterior cingulate cortex, the prefrontal cortex, the insula and the thalamus.There are major similarities in how visceral pain and somatic pain are processed by the brain.No single brain region has been found to be responsible for visceral pain.Patients with IBS often activate the same brain regions as healthy controls in response to pain, but with differing intensities.Functional neuroimaging studies have failed to reach a consensus opinion on how the brain processes pain in Irritable Bowel Syndrome. PMID- 26527575 TI - Molecular Biology of the Gene: by James D. Watson: W. A. Benjamin (1965): New York, New York. PMID- 26527576 TI - ERRATUM. PMID- 26527578 TI - Antibiotics and evolution: food for thought. AB - The role of secondary metabolites in effecting and modulating reactions during early biochemical evolution has been largely unappreciated. It is possible that low molecular weight effectors were gradually replaced by polypeptides as polymerizing reactions became more complex, but retained some ability to interact with original receptor sites. Indeed, by reviewing the era of antibiotics in this light we can begin to reconcile the ancient and contemporary activities of these molecules. The corollary being that secondary metabolites participate in a vast array of interactions in nature and investigating their intended receptors will be revealing in both pharmacological and evolutionary terms. PMID- 26527579 TI - A normalization method for combination of laboratory test results from different electronic healthcare databases in a distributed research network. AB - PURPOSE: Distributed research networks (DRNs) afford statistical power by integrating observational data from multiple partners for retrospective studies. However, laboratory test results across care sites are derived using different assays from varying patient populations, making it difficult to simply combine data for analysis. Additionally, existing normalization methods are not suitable for retrospective studies. We normalized laboratory results from different data sources by adjusting for heterogeneous clinico-epidemiologic characteristics of the data and called this the subgroup-adjusted normalization (SAN) method. METHODS: Subgroup-adjusted normalization renders the means and standard deviations of distributions identical under population structure-adjusted conditions. To evaluate its performance, we compared SAN with existing methods for simulated and real datasets consisting of blood urea nitrogen, serum creatinine, hematocrit, hemoglobin, serum potassium, and total bilirubin. Various clinico-epidemiologic characteristics can be applied together in SAN. For simplicity of comparison, age and gender were used to adjust population heterogeneity in this study. RESULTS: In simulations, SAN had the lowest standardized difference in means (SDM) and Kolmogorov-Smirnov values for all tests (p < 0.05). In a real dataset, SAN had the lowest SDM and Kolmogorov Smirnov values for blood urea nitrogen, hematocrit, hemoglobin, and serum potassium, and the lowest SDM for serum creatinine (p < 0.05). CONCLUSION: Subgroup-adjusted normalization performed better than normalization using other methods. The SAN method is applicable in a DRN environment and should facilitate analysis of data integrated across DRN partners for retrospective observational studies. PMID- 26527577 TI - Harnessing natural product assembly lines: structure, promiscuity, and engineering. AB - Many therapeutically relevant natural products are biosynthesized by the action of giant mega-enzyme assembly lines. By leveraging the specificity, promiscuity, and modularity of assembly lines, a variety of strategies has been developed that enables the biosynthesis of modified natural products. This review briefly summarizes recent structural advances related to natural product assembly lines, discusses chemical approaches to probing assembly line structures in the absence of traditional biophysical data, and surveys efforts that harness the inherent or engineered promiscuity of assembly lines for the synthesis of non-natural polyketides and non-ribosomal peptide analogues. PMID- 26527580 TI - (13) C Breath Tests Are Feasible in Patients With Extracorporeal Membrane Oxygenation Devices. AB - Temporary extracorporeal membrane oxygenation (ECMO) has been established as an essential part of therapy in patients with pulmonary or cardiac failure. As physiological gaseous exchange is artificially altered in this patient group, it is debatable whether a (13) C-breath test can be carried out. In this proof of technical feasibility report, we assess the viability of the (13) C-breath test LiMAx (maximum liver function capacity) in patients on ECMO therapy. All breath probes for the test device were obtained directly via the membrane oxygenator. Data of four patients receiving liver function assessment with the (13) C-breath test LiMAx while having ECMO therapy were analyzed. All results were compared with validated scenarios of the testing procedures. The LiMAx test could successfully be carried out in every case without changing ECMO settings. Clinical course of the patients ranging from multiorgan failure to no sign of liver insufficiency was in accordance with the results of the LiMAx liver function test. The (13) C-breath test is technically feasible in the context of ECMO. Further evaluation of (13) C-breath test in general would be worthwhile. The LiMAx test as a (13) C-breath test accessing liver function might be of particular predictive interest if patients with ECMO therapy develop multiorgan failure. PMID- 26527581 TI - Congenital-infantile fibrosarcoma of the ileocecal region: the first case presentation. AB - Infantile fibrosarcoma is a very rare soft tissue tumor that originates most commonly in the body and extremities. We present a neonate with an infantile fibrosarcoma that originated in the ileocecal region and was detected incidentally without symptoms. This is the first case of fibrosarcoma reported in the ileocecal region. PMID- 26527582 TI - Aganglionosis with the absence of hypertrophied nerve fibres predicts disease proximal to rectosigmoid colon. AB - PURPOSE: The gold standard for the diagnosis of Hirschsprung's disease (HSCR) is the pathologic evaluation of a rectal biopsy that demonstrates the absence of ganglion cells and nerve fibre hypertrophy. However, it has been frequently reported that hypertrophic nerves may not be present in some variants like long segment HSCR, total colonic aganglionosis, premature and very young infants. The aim of this study was to determine this association. METHODS: We performed a retrospective review of the HSCR database at our tertiary care children's hospital from 2000 to 2013. In order to analyse the relationship between the diameter of the nerve fibres and the level of aganglionosis, we classified the patient sample into two groups-fibres <=40 and >40 MUm. The groups were statistically compared with P < 0.05 being significant. RESULTS: Rectal biopsies of 92 patients confirmed as HSCR with definitive operation performed at the same institution were reviewed. The mean nerve diameter was 50.1 MUm (range 20-87.5 MUm). Nerve fibre diameter <=40 MUm was predictive of transition zone above the sigmoid colon. A specificity of 77.3 % and a likelihood ratio of 2.03 supported this perception. No correlation was noted between nerve fibre diameter and gestational age at birth, birth weight or age at biopsy. CONCLUSION: The absence of nerve fibre hypertrophy in the presence of aganglionosis on rectal biopsy specimens is predictive of long-segment HSCR. PMID- 26527583 TI - Functional and Clinical Outcomes of Upper Extremity Amputation. AB - Upper extremity amputation is an uncommon but often necessary procedure. It can be required as a result of trauma, infection, or malignancy. Amputation is a life changing procedure. Careful planning for it must not only include the level of amputation and assurance of durable soft-tissue coverage of the amputation site, but it must also consider patients' goals and occupations, as well as social factors affecting amputees. The choice of prosthesis is an individual matter, but new technology permits lighter and more multifunctional prostheses. Targeted muscle reinnervation can be used to achieve improved myoelectric signaling and possibly decrease limb pain following amputation. Rehabilitation is crucial to achieving favorable results. PMID- 26527584 TI - Personal characteristics of residents may predict competency improvement. AB - OBJECTIVES/HYPOTHESIS: We hypothesized that personal characteristics of residents may affect how well competency is attained in a surgical residency. To this end, we examined two concepts of global trait emotional intelligence and learner autonomy profile and their factor relationship with competency outcomes in a residency program in otolaryngology-head and neck surgery. STUDY DESIGN: A cohort study prospectively gathered competency change scores for 1 year and retrospectively analyzed the factor associations. METHODS: We measured two personal characteristics using the Trait Emotional Intelligence Questionnaire Short Form and Learner Autonomy Profile-Short Form between 2013 and 2014 in a tertiary otolaryngology-head and neck residency program. We prospectively examined faculty-rated resident competency scores monitored in the same time period and correlated the personal attributes with cumulative competency improvement scores. Statistical analyses included factor correlations and univariate regression. RESULTS: With a response rate of 64% (N = 16/25), we identified two statically significant predictors of competency improvement outcome attained by the end of the year. Regression analyses showed that emotionality factor of global trait emotional intelligence (P = .04) and learner autonomy profile (P < .01) were significant predictors for the higher improvement of aggregate competency outcome. CONCLUSIONS: Personal factors of individual residents can affect their improvement of overall competency. Practicing competency-based education should, therefore, include assessing individual resident factors as well as teaching clinical knowledge and technical skills. LEVEL OF EVIDENCE: NA Laryngoscope, 126:1746-1752, 2016. PMID- 26527586 TI - Redesign of the Active Site of Sucrose Phosphorylase through a Clash-Induced Cascade of Loop Shifts. AB - Sucrose phosphorylases have been applied in the enzymatic production of glycosylated compounds for decades. However, several desirable acceptors, such as flavonoids or stilbenoids, that exhibit diverse antimicrobial, anticarcinogenic or antioxidant properties, remain poor substrates. The Q345F exchange in sucrose phosphorylase from Bifidobacterium adolescentis allows efficient glucosylation of resveratrol, (+)-catechin and (-)-epicatechin in yields of up to 97 % whereas the wild-type enzyme favours sucrose hydrolysis. Three previously undescribed products are made available. The crystal structure of the variant reveals a widened access channel with a hydrophobic aromatic surface that is likely to contribute to the improved activity towards aromatic acceptors. The generation of this channel can be explained in terms of a cascade of structural changes arising from the Q345F exchange. The observed mechanisms are likely to be relevant for the design of other tailor-made enzymes. PMID- 26527585 TI - Utilities for High-Throughput Analysis of B-Cell Clonal Lineages. AB - There are at present few tools available to assist with the determination and analysis of B-cell lineage trees from next-generation sequencing data. Here we present two utilities that support automated large-scale analysis and the creation of publication-quality results. The tools are available on the web and are also available for download so that they can be integrated into an automated pipeline. Critically, and in contrast to previously published tools, these utilities can be used with any suitable phylogenetic inference method and with any antibody germline library and hence are species-independent. PMID- 26527587 TI - Health Literacy in Unauthorized Mexican Immigrant Mothers and Risk of Developmental Delay in their Children. AB - The incidence of developmental delay and early intervention (EI) service utilization is not well documented among unauthorized Mexican immigrants, a vulnerable population. Individual interviews were conducted in Spanish with Mexican born women receiving maternal health care. Children 12-60 months of age were screened for developmental delay using the Ages and Stages Questionnaire. 12 % (n = 8) of children assessed (n = 65) were at risk for developmental delay. Of those at risk 38 % (n = 3) participated in EI. An additional 26 % of the children (n = 17) qualified for further monitoring, and of those 59 % (n = 10) received EI. Women with low health literacy had more than four times the odds of having a child with risk of developmental delay (aOR 4.4; 95 % CI 1.3-15.4). Developmental delay was associated with low maternal health literacy in unauthorized Mexican immigrants; however, rates of self-reported EI use in this population are higher than those seen nationally. PMID- 26527588 TI - Health Status of North Korean Refugees in Toronto: A Community Based Participatory Research Study. AB - Increasing numbers of North Koreans are fleeing their country due to economic insecurity and political persecution, with over 1000 North Koreans Refugee (NKR) claims in Canada in the past decade. There is little published on their health. Using a Community-Based Participatory Research (CBPR) methodology, we investigated NKR health status through a retrospective chart review of 1022 patients rostered at a Toronto refugee clinic between December 2011 and June 2014. The health status of 117 NKRs was compared to that of 905 other refugees seen during the same period. There were lower rates of chronic diseases, including obesity and elevated blood pressure, among NKRs. Conversely, some infectious diseases were more prevalent, including hepatitis B and chlamydia. Female NKRs had higher rates of abnormal cervical cytology. This study uniquely uses CBPR methodology to examine the health of NKRs, and can help guide targeted interventions in this population. PMID- 26527589 TI - Neighborhood Social Cohesion and Prevalence of Hypertension and Diabetes in a South Asian Population. AB - South Asians have a high burden of cardiovascular disease compared to other racial/ethnic groups in the United States. Little has been done to evaluate how neighborhood environments may influence cardiovascular risk factors including hypertension and type 2 diabetes in this immigrant population. We evaluated the association of perceived neighborhood social cohesion with hypertension and type 2 diabetes among 906 South Asian adults who participated in the Mediators of Atherosclerosis in South Asians Living in America Study. Multivariable logistic regression adjusted for demographic, socioeconomic, psychosocial, and physiologic covariates. Subgroup analyses examined whether associations differed by gender. South Asian women living in neighborhoods with high social cohesion had 46 % reduced odds of having hypertension than those living in neighborhoods with low social cohesion (OR 0.54, 95 % CI 0.30-0.99). Future research should determine if leveraging neighborhood social cohesion prevents hypertension in South Asian women. PMID- 26527590 TI - Fast three-dimensional inner volume excitations using parallel transmission and optimized k-space trajectories. AB - PURPOSE: To design short parallel transmission (pTx) pulses for excitation of arbitrary three-dimensional (3D) magnetization patterns. METHODS: We propose a joint optimization of the pTx radiofrequency (RF) and gradient waveforms for excitation of arbitrary 3D magnetization patterns. Our optimization of the gradient waveforms is based on the parameterization of k-space trajectories (3D shells, stack-of-spirals, and cross) using a small number of shape parameters that are well-suited for optimization. The resulting trajectories are smooth and sample k-space efficiently with few turns while using the gradient system at maximum performance. Within each iteration of the k-space trajectory optimization, we solve a small tip angle least-squares RF pulse design problem. Our RF pulse optimization framework was evaluated both in Bloch simulations and experiments on a 7T scanner with eight transmit channels. RESULTS: Using an optimized 3D cross (shells) trajectory, we were able to excite a cube shape (brain shape) with 3.4% (6.2%) normalized root-mean-square error in less than 5 ms using eight pTx channels and a clinical gradient system (Gmax = 40 mT/m, Smax = 150 T/m/s). This compared with 4.7% (41.2%) error for the unoptimized 3D cross (shells) trajectory. Incorporation of B0 robustness in the pulse design significantly altered the k-space trajectory solutions. CONCLUSION: Our joint gradient and RF optimization approach yields excellent excitation of 3D cube and brain shapes in less than 5 ms, which can be used for reduced field of view imaging and fat suppression in spectroscopy by excitation of the brain only. Magn Reson Med 76:1170-1182, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26527591 TI - Application of sigma metrics for the assessment of quality assurance using the MQ 2000 PT HbA1c analyzer. AB - INTRODUCTION: Glycosylated hemoglobin (HbA1c) concentrations measured in clinical chemistry laboratories show large differences between their interlaboratory reported values. Laboratory measurements of quality performance should be based on quantitative data. The sigma metrics model provides an objective method for the assessment of current HbA1c assays and is useful in quality management planning. The aim of our study was to evaluate the analytical performance of the MQ-2000 PT HbA1c analyzer test results in the context of our operating conditions on the sigma scale. MATERIALS AND METHODS: The coefficient of variation was determined from the calculated mean and standard deviation evaluated from internal quality control (QC) (N=168 days) (Shanghai Huachen Biological Reagent Co. Ltd, China) data, and records of external quality data (KBUDEK, Istanbul, Turkey) measured in the period from May to November 2013 were used to determine the bias. The resulting data and total allowable error rate (TEA=10%) from the Clinical Laboratory Improvement Amendments of 1988 (CLIA'88) were used to calculate the sigma level. RESULTS: The calculated coefficient of variations (CVs) at the two levels, normal (QC1=36.6+/-2.38 mmol/mol) and pathological (QC2=84.7+/-2.68 mmol/mol), were 6.5% and 3.1%, respectively. The average bias between the external QC and MQ-2000 PT during the study period was 4.3%. The calculated average sigma value was 1.19. CONCLUSIONS: The MQ-2000 PT HbA1c is a new analyser in the market; there is need for improvement and the method should be controlled with greater attention to ensure quality. PMID- 26527592 TI - Accuracy of Visual Estimates of Partial Flexor Tendon Lacerations. AB - PURPOSE: To determine whether hand surgeons could accurately and consistently estimate the size of partial flexor tendon lacerations. MATERIALS AND METHODS: Thirty-two partial flexor tendon lacerations were made in the flexor digitorum profundus tendons of a fresh-frozen cadaveric hand. Four hand surgeons and 5 residents estimated the size of the lacerations. Estimates were repeated 3 days later. Magnified images of the laceration cross-section were used to calculate the true size of each laceration. Inter- and intrarater reliability were calculated using the intraclass correlation coefficient. Accuracy was measured with the mean bias error and the mean absolute error. RESULTS: Interrater and intrarater reliabilities were both high. There was a high level of consistency for both surgeons and residents. In terms of accuracy, there was a 3% bias toward underestimation. The mean absolute error was 11%. There was no statistically significant difference between the accuracy of attending hand surgeons and that of residents. Participants were less accurate when estimating lacerations close to a 60% laceration threshold for surgical repair (lacerations in the 50%-70% range). For lacerations within this range, an incorrect management decision would have been made 17% of the time, compared with 7% of the time for lacerations outside that range. CONCLUSIONS: The accuracy and reliability of surgeon estimates of partial flexor tendon laceration size were high for surgeons and residents. Accuracy was lower for lacerations close to the threshold for repair. CLINICAL RELEVANCE: Visual estimation is acceptable for evaluating partial flexor tendon lacerations, but it may be less reliable for lacerations near the threshold for repair. Therefore, surgeons should be cautious when deciding whether or not to repair partial lacerations in the borderline range. PMID- 26527593 TI - Selective Nerve Block Combined With Tumescent Anesthesia. AB - PURPOSE: To evaluate the effect of selective nerve blocks before tumescent anesthesia on the pain and anxiety levels of patients. METHODS: A prospective study was performed with 80 patients. Forty consecutive patients received tumescent anesthesia, and 40 consecutive patients received selective nerve blocks followed by tumescent anesthesia. Patients filled out a questionnaire regarding their preoperative, intraoperative, and postoperative pain and anxiety levels. The results of the questionnaire were evaluated with an independent samples t test. RESULTS: The 2 study groups showed similar distribution in age, sex, and diagnosis. No complications related to tumescent anesthesia or nerve blocks were observed. The group that received tumescent anesthesia with selective nerve blocks reported lower pain scores in anesthesia injections than the group that received tumescent anesthesia alone. The intraoperative and postoperative pain and anxiety levels between the groups were not different. CONCLUSION: Tumescent anesthesia combined with selective nerve blocks in hand surgery decreased the pain associated with injections and increased patient satisfaction. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I. PMID- 26527594 TI - Incidence of Hardware Removal Following Volar Plate Fixation of Distal Radius Fracture. AB - PURPOSE: To assess the risk of tendon rupture or plate removal after volar plate fixation of distal radius fractures and to determine the incidence of hardware removal. METHODS: We searched the surgical database of 5 attending hand surgeons at a single institution from 2009 to 2014. All patients who had undergone volar plate fixation were included. Patients were excluded if they underwent an alternate form of fixation, had less than 1 year of follow-up, or could not be reached for follow-up. Postoperative radiographs were examined for Soong grade, plate distance to the critical line, and plate distance to the volar rim. If patients had hardware removed, the reason for plate removal was identified. For all patients who did not have documented hardware removal at our institution, we placed a follow-up call to determine whether they had hardware removed elsewhere. RESULTS: A total of 517 patients underwent volar plate fixation, 143 of whom did not have their hardware removed at our institution but could not be reached for follow-up. Of the remaining 374 patients, 37 (10%) had hardware removed. For group 1 (hardware retained), Soong grades were 13% grade 0, 85% grade 1, and 2% grade 2. For group 2 (hardware removed) the proportions were 11%, 76%, and 5%, respectively, and 8% undetermined. Mean plate distance to the critical line was significantly greater for group 2 (1.9 mm) compared with group 1 (1.2 mm). Mean plate distance to the volar rim did not differ (5.1 mm vs 5.3 mm). CONCLUSIONS: The incidence of hardware removal in our series was 10%. The vast majority of patients had Soong grade 1 prominence. Patients who had hardware removed had a greater plate prominence volar to the critical line. Plate distance to the volar rim was not associated with removal. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 26527595 TI - Innervated Digital Artery Perforator Flap: A Versatile Technique for Fingertip Reconstruction. AB - PURPOSE: To demonstrate the advanced use of innervated digital artery perforator (IDAP) flaps for fingertip reconstruction. METHODS: From August 2011 to May 2014, 65 fingers (59 patients) underwent fingertip or finger stump reconstruction using IDAP flaps. Sixty-one fingers from 55 patients who were followed up for more than 6 months were included in this study. The objective outcomes of patient evaluations consisted of the results of static 2-point discrimination tests, Semmes Weinstein monofilament tests, and extension loss tests. The subjective patient outcome evaluations consisted of the results of hypersensitivity and cold intolerance tests and patient satisfaction. RESULTS: All flaps survived completely, and no patients required early secondary interventions. The mean follow-up period was 18 months (range, 6-36 months). The static 2-point discrimination in the flaps ranged from 2 to 6 mm (mean, 3.5 mm) compared with a range of 2 to 3 mm (mean, 2.5 mm) in the contralateral hands. The Semmes Weinstein monofilament test results ranged from 0.07 to 1.4 g compared with 0.04 to 0.4 g for the contralateral hand. One patient exhibited mild extension loss in the reconstructed finger, 4 patients experienced mild cold intolerance, and 2 patients exhibited mild hypersensitivity. CONCLUSIONS: The IDAP flaps are sensitive, reliable, and versatile and should be considered for reconstructing acute fingertip defects. The use of IDAP flaps for revisions of previously reconstructed defects is also possible. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26527596 TI - Regional Variations in Cartilage Thickness of the Radial Head: Implications for Prosthesis Design. AB - PURPOSE: To characterize the regional variations in cartilage thickness around the radial head. METHODS: We dissected 27 cadaveric radii and scanned them with computed tomography in neutral position. Three-dimensional cartilage and subchondral bone surface models were generated from computed tomography scans and 2 independent observers processed them through a computer program to obtain cartilage thickness measurements. These measurements were taken at 41 predetermined landmarks around the periphery of the radial head and within the articular dish. RESULTS: At the periphery of the radial head, cartilage was thickest in the posteromedial region. Thickness values within the articular dish were similar but increased toward the rim. Regional variations within the rim (range, 0.76-1.73 mm) were also detected with the thickest region located anteriorly and thinnest region laterally. In addition, cartilage was significantly thicker in male relative to female specimens. CONCLUSIONS: Regional variations in cartilage thickness are present around the periphery and rim and within the articular dish of the radial head. CLINICAL RELEVANCE: Cartilage thickness across the articular dish may contribute to dish depth and the radius of curvature. This may be clinically important for the design of anatomic implants, because accounting for such subtle contours could help to restore radiocapitellar concavity-compression stability better. PMID- 26527597 TI - Metacarpophalangeal Joint Arthroplasty in the Setting of Trauma. AB - PURPOSE: To report the outcome of pyrocarbon metacarpophalangeal (MCP) joint implants with traumatic nonreconstructible articular cartilage loss. METHODS: We performed a review of all patients at a single institution who underwent a pyrocarbon MCP joint arthroplasty performed after an acute injury. Of 820 MCP joint arthroplasties performed, 10 were performed in 7 patients for open MCP joint trauma within 24 hours of the initial injury. Six were hemi- and 4 were total arthroplasties. The mean follow-up was 4 years. All injuries were the result of a direct laceration over the MCP joint. RESULTS: There were no cases of revision or postoperative infection. Mean total arc of motions for the MCP, proximal interphalangeal, and distal interphalangeal joints were 56 degrees (30 degrees to 70 degrees ), 76 degrees (40 degrees to 100 degrees ), and 50 degrees (21 degrees to 70 degrees ), respectively. Postoperative mean grip, oppositional pinch, and appositional pinch strengths were 28, 9, and 11 kg, respectively. All patients except one reported no or mild pain at the last follow up. Half of the patients required a tenolysis. CONCLUSIONS: MCP joint arthroplasty was performed safely in the setting of acute complex open MCP joint trauma. Patients had preservation of adequate MCP joint motion and experienced little pain. MCP arthroplasty should be a consideration in cases of open MCP joint trauma to preserve motion, prevent pain, and avoid fusion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26527598 TI - Hand Problems Related to Chemotherapeutic Agents. PMID- 26527599 TI - Utilization of Post-Acute Care Following Distal Radius Fracture Among Medicare Beneficiaries. AB - PURPOSE: To examine the utilization and cost of post-acute care following isolated distal radius fractures (DRFs) among Medicare beneficiaries. METHODS: We examined utilization of post-acute care among Medicare beneficiaries who experienced an isolated DRF (n = 38,479) during 2007 using 100% Medicare claims data. We analyzed the effect of patient factors on hospital admission following DRF and the receipt of post-acute care delivered by skilled nursing facilities, inpatient rehabilitation facilities, home health care agencies, and outpatient occupational therapy/physical therapy for the recovery of DRF. RESULTS: In this cohort of isolated DRF patients, 1,694 (4.4%) were admitted to hospitals following DRF, and 20% received post-acute care. Women and patients with more comorbid conditions were more likely to require hospital admission. The utilization of post-acute care was higher among women, patients who resided in urban areas, and patients of higher socioeconomic status. The average cost per patient of post-acute care services from inpatient rehabilitation facilities and skilled nursing facilities ($15,888/patient) was significantly higher than the average cost other aspects of DRF care and accounted for 69% of the total DRF related expenditure among patients who received inpatient rehabilitation. CONCLUSIONS: Sociodemographic factors, including sex, socioeconomic status, and age, were significantly correlated with the use of post-acute care following isolated DRFs, and post-acute care accounted for a substantial proportion of the total expenditures related to these common injuries among the elderly. Identifying patients who will derive the greatest benefit from post-acute care can inform strategies to improve the cost efficiency of rehabilitation and optimize scarce health care resources. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 26527600 TI - Transcatheter closure of coronary artery fistulas in infants and children: A French multicenter study. AB - OBJECTIVES: The short-term efficacy and safety of transcatheter closure (TCC) for the management of coronary artery fistulas (CAFs) was investigated in pediatric patients. BACKGROUND: CAFS are rare with potentially severe complications and their management is still a matter of debate. Percutaneous closure appears to be the treatment of choice in anatomically suitable vessels but limited data are available in the pediatric population. METHODS: This retrospective, observational, multicenter, national study included patients under 16 years of age who underwent TCC of a congenital CAF. Patients with additional congenital heart defect were excluded. RESULTS: 61 patients (36 girls, 25 boys) with a median age of 0.6 year [0-15.4] at diagnosis and 3.9 years [0-16] at procedure were included. The CAF was large in 48 patients (79%); it was distal in 23 (38%) and proximal in 22 (36%). Most patients (77%) were asymptomatic at diagnosis. Clinical signs of congestive heart failure were present in seven patients (11%). Perioperative complications included three cases of ST elevation myocardial infarction (exclusively during attempted closure of a distal CAF), three devices migrations, and one case of leg ischemia. One patient died after surgical closure of a large distal CAF that could not be closed by TCC. Follow-up data were collected for 43 patients (70%) for a median of 91 days [0-4,824]. The Kaplan Meyer estimate for complete occlusion at 2 years was 73 +/- 7.6%. CONCLUSION: TCC in the pediatric population appears to be effective and associated with few complications. PMID- 26527601 TI - Non-Obstetric Pain in Pregnancy. AB - The hormonal and mechanical changes which result from pregnancy have the capacity to exacerbate existing chronic pain conditions as well as produce pain unique to this physiological and anatomical state.Pain in pregnancy is very common and can impact negatively on maternal satisfaction with the pregnancy.Management of pain requires a multidisciplinary, biopsychosocial approach. The possible presence of co-existing pathology and obstetric conditions must be borne in mind when assessing pain in pregnancy.Treatment of pain in pregnancy should focus on non pharmacological interventions in the first instance with due consideration of the risk of medications to the mother, fetus and the course of the pregnancy. PMID- 26527602 TI - The relevance of food peak architecture in trophic interactions. AB - Phenological shifts and associated changes in the temporal match between trophic levels have been a major focus of the study of ecological consequences of climate change. Previously, the food peak has been thought to respond as an entity to warming temperatures. However, food peak architecture, that is, timings and abundances of prey species and the level of synchrony between them, determines the timing and shape of the food peak. We demonstrate this with a case example of three passerine prey species and their predator. We explored temporal trends in the timing, height, width, and peakedness of prey availabilities and explained their variation with food peak architecture and ambient temperatures of prebreeding and breeding seasons. We found a temporal match between the predator's breeding schedule and food availability. Temporal trends in the timing of the food peak or in the synchrony between the prey species were not found. However, the food peak has become wider and more peaked over time. With more peaked food availabilities, predator's breeding success will depend more on the temporal match between its breeding schedule and the food peak, ultimately affecting the timing of breeding in the predator population. The height and width of the food peak depended on the abundances and breeding season lengths of individual prey species and their reciprocal synchronies. Peakednesses of separate prey species' availability distributions alone explained the peakedness of the food peak. Timing and quantity of food production were associated with temperatures of various time periods with variable relevance in different prey species. Alternating abundances of early and late breeding prey species caused high annual fluctuation in the timing of the food peak. Interestingly, the food peak may become later even when prey species' schedules are advanced. Climate warming can thus produce unexpected changes in the food availabilities, intervening in trophic interactions. PMID- 26527604 TI - NUP160-SLC43A3 is a novel recurrent fusion oncogene in angiosarcoma. AB - Angiosarcoma is a malignant vascular tumor originating from endothelial cells of blood vessels or lymphatic vessels. The specific driver mutations in angiosarcoma remain unknown. In this study, we investigated this issue by transcriptome sequencing of patient-derived angiosarcoma cells (ISO-HAS), identifying a novel fusion gene NUP160-SLC43A3 found to be expressed in 9 of 25 human angiosarcoma specimens that were examined. In tumors harboring the fusion gene, the duration between the onset of symptoms and the first hospital visit was significantly shorter, suggesting more rapid tumor progression. Stable expression of the fusion gene in nontransformed human dermal microvascular endothelial cells elicited a gene-expression pattern mimicking ISO-HAS cells and increased cell proliferation, an effect traced in part to NUP160 truncation. Conversely, RNAi-mediated attenuation of NUP160 in ISO-HAS cells decreased cell number. Confirming the oncogenic effects of the fusion protein, subcutaneous implantation of NUP160 SLC43A3-expressing fibroblasts induced tumors resembling human angiosarcoma. Collectively, our findings advance knowledge concerning the genetic causes of angiosarcoma, with potential implications for new diagnostic and therapeutic approaches. PMID- 26527605 TI - Urokinase exerts antimetastatic effects by dissociating clusters of circulating tumor cells. AB - Clusters of circulating tumor cells (CTC) exhibit more robust metastatic properties than single CTC. Thus, understanding the distinct behaviors of CTC clusters and how CTC clustering is regulated may offer new insights into how to limit metastasis. In this study, we utilized an in vivo confocal system to observe the clustering behavior of CTC in real time, finding that the number of clusters increased proportionally with the growth of the primary tumor. Our experiments also indicated that the flow rate of the CTC clusters in blood vessels was relatively slower than single CTC due to increased vessel wall adhesion. Depending on disease stage, 5% to 10% of total CTC in circulation were in clusters, with this proportion increasing to >24% within lung metastases examined. Notably, in the 4T1 mouse model of breast cancer metastasis, we found that injecting host animals with urokinase-type plasminogen activator, a clinical thrombolytic agent, was effective at preventing the assembly of CTC clusters and prolonging overall host survival by approximately 20% relative to control animals. Our results suggest a tractable approach to limit metastasis by suppressing the formation or stability of CTC clusters circulating in the blood of cancer patients. PMID- 26527606 TI - QbD-Oriented Development and Characterization of Effervescent Floating Bioadhesive Tablets of Cefuroxime Axetil. AB - The objective of the present studies was systematic development of floating bioadhesive gastroretentive tablets of cefuroxime axetil employing rational blend of hydrophilic polymers for attaining controlled release drug delivery. As per the QbD-based approach, the patient-centric target product profile and quality attributes of tablet were earmarked, and preliminary studies were conducted for screening the suitability of type of polymers, polymer ratio, granulation technique, and granulation time for formulation of tablets. A face-centered cubic design (FCCD) was employed for optimization of the critical material attributes, i.e., concentration of release controlling polymers, PEO 303 and HPMC K100 LV CR, and evaluating in vitro buoyancy, drug release, and ex vivo mucoadhesion strength. The optimized formulation was embarked upon through numerical optimization, which yield excellent floatation characteristic with drug release control (i.e., T 60% > 6 h) and bioadhesion strength. Drug-excipient compatibility studies through FTIR and P-XRD revealed the absence of any interaction between the drug and polymers. In vivo evaluation of the gastroretentive characteristics through X-ray imaging and in vivo pharmacokinetic studies in rabbits revealed significant extension in the rate of drug absorption (i.e., T max, K a, and MRT) from the optimized tablet formulation as compared to the marketed formulation. Successful establishment of various levels of in vitro/in vivo correlations (IVIVC) substantiated high degree of prognostic ability of in vitro dissolution conditions in predicting the in vivo performance. In a nutshell, the studies demonstrate successful development of the once-a-day gastroretentive formulations of cefuroxime axetil with controlled drug release profile and improved compliance. PMID- 26527607 TI - Biomarkers in traumatic brain injury: a review. AB - Biomarkers allow physiological processes to be monitored, in both health and injury. Multiple attempts have been made to use biomarkers in traumatic brain injury (TBI). Identification of such biomarkers could allow improved understanding of the pathological processes involved in TBI, diagnosis, prognostication and development of novel therapies. This review article aims to cover both established and emerging TBI biomarkers along with their benefits and limitations. It then discusses the potential value of TBI biomarkers to military, civilian and sporting populations and the future hopes for developing a role for biomarkers in head injury management. PMID- 26527608 TI - The role of sub-ventricular zone in gliomagenesis. PMID- 26527609 TI - miR-181 suppresses metastasis via MMP-14. PMID- 26527610 TI - A jejunal GIST presenting with obscure gastrointestinal bleeding and small bowel obstruction secondary to intussusception. AB - A 68-year-old man with episodes of overt obscure gastrointestinal (GI) bleeding was investigated with multiple upper and lower GI endoscopies, CT enterography and capsule endoscopy, but no cause was found. He then presented acutely with small bowel obstruction. A laparotomy revealed complete small bowel obstruction secondary to jejunal intussusception over a 4 cm intraluminal polyp. Following resection and primary anastomosis, histology revealed that the polyp was a GI stromal tumour (GIST). This is an exceptionally uncommon presentation of a rare tumour. It is surprising that this tumour was not detected by CT enterography and not seen on capsule endoscopy. Immunohistochemistry and mutation analysis of the GIST suggested that it had a low risk of metastatic disease, but a high risk of recurrence. Staging CT scans did not reveal evidence of distal spread. The patient is currently receiving 3 years of chemotherapy with imatinib. PMID- 26527611 TI - Reflection: The Early Career Surgeon-Scientist's Pathway to Independence. AB - The surgeon-scientist offers a unique perspective as one who can arguably best comprehend clinical needs, identify areas ripe for research, and translate discoveries from bench to bedside. However, the long transition from postdoc to independent investigator can prove to be quite challenging. Surgeons have long been described as having results-oriented personalities, and so the long road to independence can be fraught with frustration at times. It requires humility in seeking scientific direction and mentorship, institutional support, and ultimately extramural funding. This reflection piece examines some hallmark steps along the pathway to independence for one otolaryngology-head and neck surgeon scientist in her early academic career. PMID- 26527612 TI - Systematic Review of Endoscopic Obliteration Techniques for Managing Congenital Piriform Fossa Sinus Tracts in Children. AB - BACKGROUND: Piriform fossa sinus tracts (PFSTs) are a recognized cause of recurrent deep neck infections in the pediatric population. Conventional management has historically required open resection, but over recent years minimally invasive endoscopic approaches to obliterate the pharyngeal opening of the sinus have been performed in many centers. However, there is a lack of clear evidence regarding the success rate and safety of these approaches. OBJECTIVE: To determine the success rate of endoscopic management of PFST through a systematic review of the existing literature. DATA SOURCES: MEDLINE (1964-2014) and bibliographies of identified papers. REVIEW METHODS: Two authors independently reviewed 170 abstracts and identified relevant studies for full-text review. Data were independently extracted from those studies, and the Oxford Centre for Evidence-Based Medicine guidelines were used to classify the level of evidence. RESULTS: Thirteen studies met the inclusion criteria, comprising a total of 84 patients. All included studies were evidence level 4 (case series). Various methods of obliterating the PFST were described: electrocautery (n = 39), laser (n = 19), trichloroacetic acid (n = 19), silver nitrate (n = 4), combination of silver nitrate and laser (n = 2), and fibrin glue (n = 1). The success rate for endoscopic management of PFST was 89.3% overall (90.5% in primary cases and 85.7% in revision cases). The only adverse event reported was temporary vocal cord immobility in 2.4% (n = 2) of cases. CONCLUSION: Endoscopic management of pediatric PFST appears to be safe and effective, as a primary option and for revision after open surgery. PMID- 26527613 TI - A Systematic Review of Non-Echo Planar Diffusion-Weighted Magnetic Resonance Imaging for Detection of Primary and Postoperative Cholesteatoma. AB - OBJECTIVE: To investigate the diagnostic value of non-echo planar diffusion weighted magnetic resonance imaging (DW-MRI) for primary and recurrent/residual (postoperative) cholesteatoma in adults (>=18 years) after canal wall up surgery. DATA SOURCES: We conducted a systematic search in PubMed, Embase, and Cochrane up to October 22, 2014. REVIEW METHODS: All studies investigating non-echo planar DW MRI for primary and postoperative cholesteatoma were selected and critically appraised for relevance and validity. RESULTS: In total, 779 unique articles were identified, of which 23 articles were included for critical appraisal. Seven articles met our criteria for relevance and validity for postoperative cholesteatoma. Four studies were additionally included for subgroup analysis of primary cases only. Ranges of sensitivity, specificity, positive predictive value, and negative predictive value yielded 43%-92%, 58%-100%, 50%-100% and 64% 100%, respectively. Results for primary subgroup analysis were 83%-100%, 50% 100%, 85%-100%, and 50%-100%, respectively. Results for subgroup analysis for only postoperative cases yielded 80%-82%, 90%-100%, 96%-100%, 64%-85%, respectively. Despite a higher prevalence of cholesteatoma in the primary cases, there was no clinical difference in added value of DW-MRI between primary and postoperative cases. CONCLUSION: We found a high predictive value of non-echo planar DW-MRI for the detection of primary and postoperative cholesteatoma. Given the moderate quality of evidence, we strongly recommend both the use of non-echo planar DW-MRI scans for the follow-up after cholesteatoma surgery, and when the correct diagnosis is questioned in primary preoperative cases. PMID- 26527614 TI - Shortening Tuberculosis Treatment With Fluoroquinolones: Lost in Translation? AB - The disappointing recent failure of fluoroquinolone-containing regimens to shorten the duration of tuberculosis treatment in costly phase 3 trials has raised serious questions about the reliability of preclinical tuberculosis models, especially mice, and the current paradigm of regimen development. Therefore we re-examined data from murine models and early-stage clinical trials on which the pivotal trials were based, concluding that phase 3 trial results were in line with preceding studies. Finally, we offer suggestions for a more efficient and integrated preclinical and clinical regimen development program where quantitative pharmacokinetic and pharmacodynamic models more predictive of curative treatment durations are set forth. PMID- 26527615 TI - Clinical Consensus Statement Development Manual. AB - Clinical consensus statements reflect opinions drafted by content experts for which consensus is sought using explicit methodology to identify areas of agreement and disagreement. In contrast to clinical practice guidelines, which are based primarily on high-level evidence, clinical consensus statements are more applicable to situations where evidence is limited or lacking, yet there are still opportunities to reduce uncertainty and improve quality of care. This manual describes methodology used by the American Academy of Otolaryngology-Head and Neck Surgery Foundation to promote rapid and consistent development of clinical consensus statements for its membership. Although the manual contains specific practices relevant to the Academy, the principles are also explained and may help other organizations create similar products. PMID- 26527616 TI - Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response. AB - The Keap1-Nrf2 system plays a central role in cytoprotection against electrophilic/oxidative stresses. Although Cys151, Cys273, and Cys288 of Keap1 are major sensor cysteine residues for detecting these stresses, it has not been technically feasible to evaluate the functionality of Cys273 or Cys288, since Keap1 mutants that harbor substitutions in these residues and maintain the ability to repress Nrf2 accumulation do not exist. To overcome this problem, we systematically introduced amino acid substitutions into Cys273/Cys288 and finally identified Cys273Trp and Cys288Glu mutations that do not affect Keap1's ability to repress Nrf2 accumulation. Utilizing these Keap1 mutants, we generated stable murine embryonic fibroblast (MEF) cell lines and knock-in mouse lines. Our analyses with the MEFs and peritoneal macrophages from the knock-in mice revealed that three major cysteine residues, Cys151, Cys273, and Cys288, individually and/or redundantly act as sensors. Based on the functional necessity of these three cysteine residues, we categorized chemical inducers of Nrf2 into four classes. Class I and II utilizes Cys151 and Cys288, respectively, while class III requires all three residues (Cys151/Cys273/Cys288), while class IV inducers function independently of all three of these cysteine residues. This study thus demonstrates that Keap1 utilizes multiple cysteine residues specifically and/or collaboratively as sensors for the detection of a wide range of environmental stresses. PMID- 26527617 TI - Sorbs1 and -2 Interact with CrkL and Are Required for Acetylcholine Receptor Cluster Formation. AB - Crk and CrkL are noncatalytic adaptor proteins necessary for the formation of neuromuscular synapses which function downstream of muscle-specific kinase (MuSK), a receptor tyrosine kinase expressed in skeletal muscle, and the MuSK binding protein Dok-7. How Crk/CrkL regulate neuromuscular endplate formation is not known. To better understand the roles of Crk/CrkL, we identified CrkL binding proteins using mass spectrometry and have identified Sorbs1 and Sorbs2 as two functionally redundant proteins that associate with the initiating MuSK/Dok 7/Crk/CrkL complex, regulate acetylcholine receptor (AChR) clustering in vitro, and are localized at synapses in vivo. PMID- 26527618 TI - The Poly(C) Binding Protein Pcbp2 and Its Retrotransposed Derivative Pcbp1 Are Independently Essential to Mouse Development. AB - RNA-binding proteins participate in a complex array of posttranscriptional controls essential to cell type specification and somatic development. Despite their detailed biochemical characterizations, the degree to which each RNA binding protein impacts mammalian embryonic development remains incompletely defined, and the level of functional redundancy among subsets of these proteins remains open to question. The poly(C) binding proteins, PCBPs (alphaCPs and hnRNP E proteins), are encoded by a highly conserved and broadly expressed gene family. The two major Pcbp isoforms, Pcbp2 and Pcbp1, are robustly expressed in a wide range of tissues and exert both nuclear and cytoplasmic controls over gene expression. Here, we report that Pcbp1-null embryos are rendered nonviable in the peri-implantation stage. In contrast, Pcbp2-null embryos undergo normal development until midgestation (12.5 to 13.5 days postcoitum), at which time they undergo a dramatic loss in viability associated with combined cardiovascular and hematopoietic abnormalities. Mice heterozygous for either Pcbp1 or Pcbp2 null alleles display a mild and nondisruptive defect in initial postpartum weight gain. These data reveal that Pcbp1 and Pcbp2 are individually essential for mouse embryonic development and have distinct impacts on embryonic viability and that Pcpb2 has a nonredundant in vivo role in hematopoiesis. These data further provide direct evidence that Pcbp1, a retrotransposed derivative of Pcpb2, has evolved an essential function(s) in the mammalian genome. PMID- 26527619 TI - A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes. AB - Cholesterol synthesis and lipoprotein uptake are tightly coordinated to ensure that the cellular level of cholesterol is adequately maintained. Hepatic dysregulation of these processes is associated with pathological conditions, most notably cardiovascular disease. Using a genetic approach, we have recently identified the E3 ubiquitin ligase MARCH6 as a regulator of cholesterol biosynthesis, owing to its ability to promote degradation of the rate-limiting enzymes 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR) and squalene epoxidase (SQLE). Here, we present evidence for MARCH6 playing a multifaceted role in the control of cholesterol homeostasis in hepatocytes. We identify MARCH6 as an endogenous inhibitor of the sterol regulatory element binding protein (SREBP) transcriptional program. Accordingly, loss of MARCH6 increases expression of SREBP-regulated genes involved in cholesterol biosynthesis and lipoprotein uptake. Unexpectedly, this is associated with a decrease in cellular lipoprotein uptake, induced by enhanced lysosomal degradation of the low-density lipoprotein receptor (LDLR). Finally, we provide evidence that induction of the E3 ubiquitin ligase IDOL represents the molecular mechanism underlying this MARCH6-induced phenotype. Our study thus highlights a MARCH6-dependent mechanism to direct cellular cholesterol accretion that relies on uncoupling of cholesterol synthesis from lipoprotein uptake. PMID- 26527621 TI - Selective distribution of Pseudomonas aeruginosa O-antigen among strains producing group I pilin. AB - Strains of Pseudomonas aeruginosa that produce type IVa pili categorized as group I have the potential to covalently attach an O-antigen repeating unit to the pilin C-terminal residue. PCR, employing primers targeting a conserved region of a group-I-specific gene, was used to provide evidence that 110 of 206 clinical isolates studied had the capability of producing this type of pilus. The potential of P. aeruginosa to produce a particular O-antigen type is determined by the presence of a specific biosynthetic gene cluster. The distribution of these gene clusters among the isolates studied was determined using a second PCR procedure. The results of these studies showed that the O-antigen repeating unit types associated with group I pilin producers were significantly different from those found in the non-group I pilin strains. In addition, the predicted ability to express O-antigen repeating units composed of four sugars, and the ability of the glycan to express a negative charge were associated with group I pilin producing strains. The results presented suggest that these properties specifically enhance group I pilus function and that the commonality of pilus and O-antigen types may be useful as targets in disease intervention. PMID- 26527620 TI - Coordination of RNA Polymerase II Pausing and 3' End Processing Factor Recruitment with Alternative Polyadenylation. AB - Most mammalian genes produce transcripts whose 3' ends are processed at multiple alternative positions by cleavage/polyadenylation (CPA). Poly(A) site cleavage frequently occurs cotranscriptionally and is facilitated by CPA factor binding to the RNA polymerase II (Pol II) C-terminal domain (CTD) phosphorylated on Ser2 residues of its heptad repeats (YS2PTSPS). The function of cotranscriptional events in the selection of alternative poly(A) sites is poorly understood. We investigated Pol II pausing, CTD Ser2 phosphorylation, and processing factor CstF recruitment at wild-type and mutant IgM transgenes that use alternative poly(A) sites to produce mRNAs encoding the secreted and membrane-bound forms of the immunoglobulin (Ig) heavy chain. The results show that the sites of Pol II pausing and processing factor recruitment change depending on which poly(A) site is utilized. In contrast, the extent of Pol II CTD Ser2 phosphorylation does not closely correlate with poly(A) site selection. We conclude that changes in properties of the transcription elongation complex closely correlate with utilization of different poly(A) sites, suggesting that cotranscriptional events may influence the decision between alternative modes of pre-mRNA 3' end processing. PMID- 26527622 TI - Elution of antibiotics from poly(methyl methacrylate) bone cement after extended implantation does not necessarily clear the infection despite susceptibility of the clinical isolates. AB - Chronic orthopedic infections are commonly caused by bacterial biofilms, which are recalcitrant to antibiotic treatment. In many cases, the revision procedure for periprosthetic joint infection or trauma cases includes the implantation of antibiotic-loaded bone cement to kill infecting bacteria via the elution of a strong local dose of antibiotic(s) at the site. While many studies have addressed the elution kinetics of both non-absorbable and absorbable bone cements both in vitro and in vivo, the potency of ALBC against pathogenic bacteria after extended implantation time is not clear. In this communication, we use two case studies, a Viridans streptococci infected total knee arthroplasty (TKA) and a MRSA polymicrobial osteomyelitis of a distal tibial traumatic amputation (TA) to demonstrate that an antibiotic-loaded poly(methyl methacrylate) (ALPMMA) coated intermedullary rod implanted for 117 days (TKA) and three ALPMMA suture-strung beads implanted for 210 days (TA) retained killing ability against Pseudomonas aeruginosa and Staphylococcus aureus in vitro, despite different clinical efficacies. The TKA infection resolved and the patient progressed to an uneventful second stage. However, the TA infection only resolved after multiple rounds of debridement, IV vancomycin and removal of the PMMA beads and placement of vancomycin and tobramycin loaded calcium sulfate beads. PMID- 26527623 TI - Translating Proteomic Into Functional Data: An High Mobility Group A1 (HMGA1) Proteomic Signature Has Prognostic Value in Breast Cancer. AB - Cancer is a very heterogeneous disease, and biological variability adds a further level of complexity, thus limiting the ability to identify new genes involved in cancer development. Oncogenes whose expression levels control cell aggressiveness are very useful for developing cellular models that permit differential expression screenings in isogenic contexts. HMGA1 protein has this unique property because it is a master regulator in breast cancer cells that control the transition from a nontumorigenic epithelial-like phenotype toward a highly aggressive mesenchymal-like one. The proteins extracted from HMGA1-silenced and control MDA-MB-231 cells were analyzed using label-free shotgun mass spectrometry. The differentially expressed proteins were cross-referenced with DNA microarray data obtained using the same cellular model and the overlapping genes were filtered for factors linked to poor prognosis in breast cancer gene expression meta-data sets, resulting in an HMGA1 protein signature composed of 21 members (HRS, HMGA1 reduced signature). This signature had a prognostic value (overall survival, relapse-free survival, and distant metastasis-free survival) in breast cancer. qRT-PCR, Western blot, and immunohistochemistry analyses validated the link of three members of this signature (KIFC1, LRRC59, and TRIP13) with HMGA1 expression levels both in vitro and in vivo and wound healing assays demonstrated that these three proteins are involved in modulating tumor cell motility. Combining proteomic and genomic data with the aid of bioinformatic tools, our results highlight the potential involvement in neoplastic transformation of a restricted list of factors with an as-yet-unexplored role in cancer. These factors are druggable targets that could be exploited for the development of new, targeted therapeutic approaches in triple-negative breast cancer. PMID- 26527624 TI - On the Quest for the Best Freeze: Predictors of Late Pulmonary Vein Reconnections After Second-Generation Cryoballoon Ablation. AB - BACKGROUND: The second-generation cryoballoon is effective in achieving acute pulmonary vein isolation (PVI) and favorable clinical outcome. To date, no data are available on factors affecting late PV reconnection after second-generation cryoballoon ablation. METHODS AND RESULTS: A total of 29 consecutive patients (25 male, 86.2%; mean age 57.8+/-13.8 years) underwent a repeat procedure, after a mean 11.6+/-4.5 months (range, 3.5-19.7 months), after index ablation using the 28-mm second-generation cryoballoon. All repeat ablations were performed using a 3-dimensional electroanatomical mapping system. Among all 115 PVs, including 1 left common ostiums (LCOs), 25 (21.7%) showed a PV reconnection in 20 patients (1.25 per patient). Persistent PVI could be documented in 90 of 115 PVs (78.2%). In 9 of 29 patients (31%), all PVs were electrically isolated. In the multivariable analysis, time to PVI (P=0.03) and failure to achieve -40 degrees C within 60 s (P=0.05) independently predicted late PV reconnection. At receiver operator curve analysis, time to PVI <60 s identified the absence of PV reconduction (sensitivity, 86.7%; specificity, 86.2%; positive predictive value, 59.1%; and negative predictive value, 96.4%; area under the curve, 0.85; confidence interval, 0.73-0.97; P<0.001). CONCLUSIONS: The rate of late PV reconnection after second-generation cryoballoon ablation is low (1.25 PVs/patient). Faster time to isolation and achievement of -40 degrees C within 60 s independently predict durable PVI. In addition, 60-s cut-off for time to PVI indicates persistent isolation with 96.4% negative predictive value. These parameters might guide the operator whether to perform further applications to ensure a long-lasting PVI. PMID- 26527625 TI - Epicardial Radiofrequency Ablation Failure During Ablation Procedures for Ventricular Arrhythmias: Reasons and Implications for Outcomes. AB - BACKGROUND: Radiofrequency ablation (RFA) from the epicardial space for ventricular arrhythmias is limited or impossible in some cases. Reasons for epicardial ablation failure and the effect on outcome have not been systematically analyzed. METHODS AND RESULTS: We assessed reasons for epicardial RFA failure relative to the anatomic target area and the type of heart disease and assessed the effect of failed epicardial RFA on outcome after ablation procedures for ventricular arrhythmias in a large single-center cohort. Epicardial access was attempted during 309 ablation procedures in 277 patients and was achieved in 291 procedures (94%). Unlimited ablation in an identified target region could be performed in 181 cases (59%), limited ablation was possible in 22 cases (7%), and epicardial ablation was deemed not feasible in 88 cases (28%). Reasons for failed or limited ablation were unsuccessful epicardial access (6%), failure to identify an epicardial target (15%), proximity to a coronary artery (13%), proximity to the phrenic nerve (6%), and complications (<1%). Epicardial RFA was impeded in the majority of cases targeting the left ventricular summit region. Acute complications occurred in 9%. The risk for acute ablation failure was 8.3* higher (4.5-15.0; P<0.001) after no or limited epicardial RFA compared with unlimited RFA, and patients with unlimited epicardial RFA had better recurrence-free survival rates (P<0.001). CONCLUSIONS: Epicardial RFA for ventricular arrhythmias is often limited even when pericardial access is successful. Variability of success is dependent on the target area, and the presence of factors limiting ablation is associated with worse outcomes. PMID- 26527626 TI - Acute Otitis Media Perspectives in Israel. PMID- 26527627 TI - Otitis Media: To Treat, To Refer, To Do Nothing: A Review for the Practitioner. AB - .On the basis of research evidence, a recommended strategy for improving the care of middle ear infections is to identify the subset of patients least likely to benefit from antibiotic therapy. They include children ages 6 months to 23 months with unilateral disease without severe signs and symptoms (moderate or severe otalgia, otalgia lasting more than 48 hours,or temperature of 39 degrees C [102.2 degrees F]), and those older than 2 years ofage with unilateral or bilateral disease who have mild signs andsymptoms.(9) On the basis of research evidence, the initial treatment of otitis media with effusion is watchful observation. There is little harm in observing a child who is not at risk for speech, language, or learning difficulties compared to medical or surgical intervention.(4) On the basis of research evidence, administration of the annual influenza vaccine and the conjugated pneumococcal vaccination has been shown to have a small but statistically significant impact on the frequency of middle ear disease. (7)(8) On the basis of expert opinion, optimal outcomes depend oncommunication between clinicians and parents. At a minimum , primary care clinicians should state their reasons for their own clinical judgment about appropriate management and for referral to otolaryngology if necessary. PMID- 26527628 TI - Autoimmunity and Immunodeficiency. AB - The references provided include data from evidence A and B studies based on the relevant populations. Because many primary immunodeficiencies associated with autoimmune diseases are rare, illustrative cases (evidence D) also are referenced. On the basis of level A evidence, immunoglobulin A deficiency is the most common primary immunodeficiency and is associated with defective mucosal immunity and autoimmune disease. On the basis of strong evidence (level A), Wiskott Aldrich syndrome presents early in life and is associated with autoimmune arthritis and anemia. On the basis of strong evidence in the literature, a number of primary immunodeficiencies are associated with defects in T regulatory cell number and development, cytokine aberrancies, and, as a consequence, production of autoantibodies. On the basis of strong evidence (level A) and case reports (level D), complement deficiency can be associated with autoimmune disease, most notably systemic lupus erythematosus. PMID- 26527629 TI - Laboratory Evaluation in Pediatric Autoimmune Diseases. AB - Pediatric autoimmune diseases are chronic lifelong disorders associated with potential disability and increased morbidity and mortality if not properly recognized and treated. On the basis of largely expert opinion in addition to observational studies, children with suspected autoimmune disease should undergo general laboratory and autoantibody screening. (1)(2)(4)(6)(7)(11) There can be many causes of positive antinuclear antibody test results, including, but not limited to, autoimmune disease. On the basis of expert opinion and observational studies, a thorough history and physical examination as well as laboratory evaluation is recommended (often in consultation with a pediatric rheumatologist) to elucidate the cause for a positive test result. (4) (6)(11) PMID- 26527630 TI - Case 1: Alopecia in a Healthy 9-year-old Girl. PMID- 26527631 TI - Case 2: Bilateral Thumbnail Abnormalities in a 9-year-old Boy. PMID- 26527632 TI - Case 3: Fatigue, Weight Loss, Pallor, and Polydipsia in 12-year-old Girl. PMID- 26527633 TI - Infectious Disease Prevention: Hospital and Office. PMID- 26527634 TI - Visual Diagnosis: An Adolescent Male With Severe Facial Swelling and Scalp Infection. AB - Scalp eruptions are common in infants, children, and adolescents and the etiology can be broad. Allergic contact dermatitis can result after multiple non eventful uses of a hair care product, including shampoo, relaxers, and coloring agents. Symptoms of allergic contact dermatitis include intense pruritus with weeping, pain, and stinging sensations. Signs on physical examination include swelling with scaly erythematous plaques as well as bullae with vesicles and pustules in severe cases. The forehead, eyelids, and postauricular areas also are subject to swelling. Definitive diagnosis of allergic dermatitis involves patch testing to determine the specific allergen. Education about avoidance of the allergen and recommendations for allergen-free products are the most important aspects of managing patients with allergic contact dermatitis. Treatment depends on the severity and extent of involvement. First-line treatment is topical corticosteroids, followed by topical calcineurin inhibitors. For more extensive dermatitis, systemic corticosteroids are beneficial. PMID- 26527635 TI - Sustained lung inflation at birth: what do we know, and what do we need to know? AB - A sustained inflation has been advocated as a potential method of augmenting lung aeration at birth. Clinical trials have suggested that a sustained inflation may lead to a reduced need for intubation and ventilation in the first few days of life, without cardiovascular compromise or increased lung injury. Despite this, a sustained inflation is not currently a standard of practice, mainly due to a lack of clarity regarding the optimal delivery method. Animal trials have sought to refine delivery techniques. This review will outline current recommendations regarding a sustained inflation, discuss potential strategies for its optimal delivery and suggest priorities for future research. PMID- 26527636 TI - The MBRRACE-UK perinatal surveillance report. PMID- 26527637 TI - Seroprevalence of histoplasmosis in Kampala, Uganda. AB - Histoplasmosis is endemic to the Midwestern United States, but cases have been reported nearly worldwide. A 1970 study found 3.8% skin test sensitivity to Histoplasma capsulatum in Uganda but no systemic study of histoplasmosis exposure has occurred since the onset of the human immunodeficiency virus (HIV) pandemic. This study investigated the seroprevalence of H. capsulatum and sought previously undetected cases of histoplasmosis in Kampala, Uganda. Serum, cerebrospinal fluid (CSF) and/or urine specimens were obtained from HIV-infected persons with suspected meningitis. Specimens were tested for H. capsulatum IgG and IgM by enzyme immune assay and Histoplasma antigen. 147 of the 257 subjects who were enrolled had cryptococcal meningitis. Overall, 1.3% (2/151) of subjects were serum Histoplasma IgG positive, and zero of 151 were IgM positive. Antigen was not detected in any serum (n = 57), urine (n = 37, or CSF (n = 63) samples. Both subjects with serum Histoplasma IgG positivity had cryptococcal meningitis. Histoplasma capsulatum IgG was detected at low levels in persons with HIV/AIDS in Kampala, Uganda. Histoplasmosis is not widespread in Uganda but microfoci do exist. There appears to be no cross-reactivity between Cryptococcus neoformans and Histoplasma antigen testing, and cryptococcosis appears to be at most, a rare cause of positive Histoplasma IgG. PMID- 26527638 TI - Clinical utility of panfungal polymerase chain reaction for the diagnosis of invasive fungal disease: a single center experience. AB - The role of panfungal polymerase chain reaction (PCR) assays for diagnosis of invasive fungal disease (IFD) is inadequately defined. We describe the use of an internal transcribed spacer 1 (ITS-1) region-directed panfungal PCR in this context at a tertiary referral transplant center. A retrospective review of patients at Alfred Health, Melbourne, Australia (2009-2014) who had clinical samples referred for panfungal PCR testing was conducted. Baseline patient characteristics, antifungal drug history, fungal culture/histopathology, and radiology results were recorded. For bronchoalveolar lavage (BAL) fluid samples, identification of a fungus other than a Candida spp. was defined as a potential pathogen.Of 138 panfungal PCR tests (108 patients), 41 (30%) were positive for a fungal product. Ninety-seven percent (134/138) of specimens were from immunocompromised hosts. Thirteen percent (19/138) of panfungal PCR positive results were for potential pathogens and potential pathogens were detected more frequently in tissue as compared with BAL (12/13 vs. 6/26; P = .0001). No positive panfungal PCR results were obtained from CSF specimens. If histopathology examination was negative, panfungal PCR identified a potential pathogen in only 12% (11/94) of specimens. For the 20 culture negative/histopathology positive specimens, diagnosis of IFD to causative species level by panfungal PCR occurred in 35% (6/20).Sterile site specimens, in particular tissue, were more frequently panfungal PCR positive for potential pathogens than BAL. The utility of panfungal PCR appears greatest in tissue specimens, as an adjunct to histopathology to improve diagnostic sensitivity and specificity. Based on the results of this study we are now only testing tissue specimens by panfungal PCR. PMID- 26527639 TI - Glutamate Limitation, BvgAS Activation, and (p)ppGpp Regulate the Expression of the Bordetella pertussis Type 3 Secretion System. AB - Bordetella pertussis is a bacterium that is considered to be highly adapted to humans, and it has not been isolated from the environment. As this bacterium does not utilize sugars, the abundant supply of glutamate in Stainer Scholte (SS) medium enables B. pertussis to grow efficiently in liquid culture in vitro, and as such, SS medium is a popular choice for laboratory experiments. However, the concentration of glutamate in the in vivo niche of B. pertussis is quite low. We investigated the bacterial response to low concentrations of glutamate to elucidate bacterial physiology via the expression of the type 3 secretion system (T3SS), and we discuss its relationship to the Bvg mode in which the two component regulator of pathogenesis (BvgAS) is activated. Glutamate limitation induced the expression of both the T3SS apparatus and effector genes at the transcriptional level. (p)ppGpp, a modulator of the stringent response, was necessary for maximum expression of the T3SS genes. These observations indicate that the expression of the T3SS is managed by nutrient starvation. In addition, the autoaggregation ability was high in the absence of glutamate and no autoaggregation was observed in glutamate-replete medium. Taken together, glutamate-limited conditions in Bvg(+) mode elicit the high expression of T3SS genes in B. pertussis and promotes its sessile form. IMPORTANCE: Bordetella pertussis is a highly contagious pathogen that causes respiratory infectious disease. In spite of the increasing use of vaccination, the number of patients with pertussis is increasing. The proteins produced in vivo often are different from the protein profile under laboratory conditions; therefore, the development of conditions reflecting the host environment is important to understand native bacterial behavior. In the present study, we examined the effect of glutamate limitation, as its concentration in vivo is much lower than that in the culture medium currently used for B. pertussis experiments. As predicted, the T3SS was induced by glutamate limitation. These results are suggestive of the importance of regulation by nutrient conditions and in the pathogenicity of B. pertussis. PMID- 26527640 TI - Identification and Characterization of a New 7-Aminocephalosporanic Acid Deacetylase from Thermophilic Bacterium Alicyclobacillus tengchongensis. AB - Deacetylation of 7-aminocephalosporanic acid (7-ACA) at position C-3 provides valuable starting material for producing semisynthetic beta-lactam antibiotics. However, few enzymes have been characterized in this process before now. Comparative analysis of the genome of the thermophilic bacterium Alicyclobacillus tengchongensis revealed a hypothetical protein (EstD1) with typical esterase features. The EstD1 protein was functionally cloned, expressed, and purified from Escherichia coli BL21(DE3). It indeed displayed esterase activity, with optimal activity at around 65 degrees C and pH 8.5, with a preference for esters with short-chain acyl esters (C2 to C4). Sequence alignment revealed that EstD1 is an SGNH hydrolase with the putative catalytic triad Ser15, Asp191, and His194, which belongs to carbohydrate esterase family 12. EstD1 can hydrolyze acetate at the C 3 position of 7-aminocephalosporanic acid (7-ACA) to form deacetyl-7-ACA, which is an important starting material for producing semisynthetic beta-lactam antibiotics. EstD1 retained more than 50% of its initial activity when incubated at pH values ranging from 4 to 11 at 65 degrees C for 1 h. To the best of our knowledge, this enzyme is a new SGNH hydrolase identified from thermophiles that is able to hydrolyze 7-ACA. IMPORTANCE: Deacetyl cephalosporins are highly valuable building blocks for the industrial production of various kinds of semisynthetic beta-lactam antibiotics. These compounds are derived mainly from 7 ACA, which is obtained by chemical or enzymatic processes from cephalosporin C. Enzymatic transformation of 7-ACA is the main method because of the adverse effects chemical deacylation brought to the environment. SGNH hydrolases are widely distributed in plants. However, the tools for identifying and characterizing SGNH hydrolases from bacteria, especially from thermophiles, are rather limited. Here, our work demonstrates that EstD1 belongs to the SGNH family and can hydrolyze acetate at the C-3 position of 7-ACA. Moreover, this study can enrich our understanding of the functions of these enzymes from this family. PMID- 26527642 TI - Controlling the Connections of Cells to the Biofilm Matrix. AB - The importance of cyclic di-GMP (c-di-GMP) and its control of biofilm matrix assembly and production has been a focal point of researchers in recent history. In this issue, Cooley et al. (Cooley RB, Smith TJ, Leung W, Tierney V, Borlee BR, O'Toole GA, Sondermann H, J Bacteriol 198:66-77, http://dx.doi.org/10.1128/JB.00369-15) demonstrate that two c-di-GMP controlled features of Pseudomonas aeruginosa, the periplasmic protease LapG and the surface adhesin CdrA, are linked. CdrA is shown to be a substrate of LapG, with LapG activity controlled by intracellular c-di-GMP levels. This commentary discusses the significance of this finding. PMID- 26527641 TI - Mutation of the Thiol-Disulfide Oxidoreductase SdbA Activates the CiaRH Two Component System, Leading to Bacteriocin Expression Shutdown in Streptococcus gordonii. AB - Streptococcus gordonii is a commensal inhabitant of the human oral cavity. To maintain its presence as a major component of oral biofilms, S. gordonii secretes inhibitory molecules such as hydrogen peroxide and bacteriocins to inhibit competitors. S. gordonii produces two nonmodified bacteriocins (i.e., Sth1 and Sth2) that are regulated by the Com two-component regulatory system, which also regulates genetic competence. Previously we found that the thiol-disulfide oxidoreductase SdbA was required for bacteriocin activity; however, the role of SdbA in Com signaling was not clear. Here we demonstrate that DeltasdbA mutants lacked bacteriocin activity because the bacteriocin gene sthA was strongly repressed and the peptides were not secreted. Addition of synthetic competence stimulating peptide to the medium reversed the phenotype, indicating that the Com pathway was functional but was not activated in the DeltasdbA mutant. Repression of bacteriocin production was mediated by the CiaRH two-component system, which was strongly upregulated in the DeltasdbA mutant, and inactivation of CiaRH restored bacteriocin production. The CiaRH-induced protease DegP was also upregulated in the DeltasdbA mutant, although it was not required for inhibition of bacteriocin production. This establishes CiaRH as a regulator of Sth bacteriocin activity and links the CiaRH and Com systems in S. gordonii. It also suggests that either SdbA or one of its substrates is an important factor in regulating activation of the CiaRH system. IMPORTANCE: Streptococcus gordonii is a noncariogenic colonizer of the human oral cavity. To be competitive in the oral biofilm, S. gordonii secretes antimicrobial peptides called bacteriocins, which inhibit closely related species. Our previous data showed that mutation of the disulfide oxidoreductase SdbA abolished bacteriocin production. In this study, we show that mutation of SdbA generates a signal that upregulates the CiaRH two component system, which in turn downregulates a second two-component system, Com, which regulates bacteriocin expression. Our data show that these systems are also linked in S. gordonii, and the data reveal that the cell's ability to form disulfide bonds is sensed by the CiaRH system. PMID- 26527643 TI - A DinB Ortholog Enables Mycobacterial Growth under dTTP-Limiting Conditions Induced by the Expression of a Mycobacteriophage-Derived Ribonucleotide Reductase Gene. AB - Mycobacterium species such as M. smegmatis and M. tuberculosis encode at least two translesion synthesis (TLS) polymerases, DinB1 and DinB2, respectively. Although predicted to be linked to DNA repair, their role in vivo remains enigmatic. M. smegmatis mc(2)155, a strain commonly used to investigate mycobacterial genetics, has two copies of dinB2, the gene that codes for DinB2, by virtue of a 56-kb chromosomal duplication. Expression of a mycobacteriophage D29 gene (gene 50) encoding a class II ribonucleotide reductase in M. smegmatis DeltaDRKIN, a strain derived from mc(2)155 in which one copy of the duplication is lost, resulted in DNA replication defects and growth inhibition. The inhibitory effect could be linked to the deficiency of dTTP that resulted under these circumstances. The selective inhibition observed in the DeltaDRKIN strain was found to be due solely to a reduced dosage of dinB2 in this strain. Mycobacterium bovis, which is closely related to M. tuberculosis, the tuberculosis pathogen, was found to be highly susceptible to gene 50 overexpression. Incidentally, these slow-growing pathogens harbor one copy of dinB2. The results indicate that the induction of a dTTP-limiting state can lead to growth inhibition in mycobacteria, with the effect being maximum in cells deficient in DinB2. IMPORTANCE: Mycobacterium species, such as M. tuberculosis, the tuberculosis pathogen, are known to encode several Y family DNA polymerases, one of which is DinB2, an ortholog of the DNA repair-related protein DinP of Escherichia coli. Although this protein has been biochemically characterized previously and found to be capable of translesion synthesis in vitro, its in vivo function remains unknown. Using a novel method to induce dTTP deficiency in mycobacteria, we demonstrate that DinB2 can aid mycobacterial survival under such conditions. Apart from unraveling a specific role for the mycobacterial Y family DNA polymerase DinB2 for the first time, this study also paves the way for the development of drugs that can kill mycobacteria by inducing a dTTP-deficient state. PMID- 26527644 TI - Regulation of Chlamydia Gene Expression by Tandem Promoters with Different Temporal Patterns. AB - Chlamydia is a genus of pathogenic bacteria with an unusual intracellular developmental cycle marked by temporal waves of gene expression. The three main temporal groups of chlamydial genes are proposed to be controlled by separate mechanisms of transcriptional regulation. However, we have noted genes with discrepancies, such as the early gene dnaK and the midcycle genes bioY and pgk, which have promoters controlled by the late transcriptional regulators EUO and sigma(28). To resolve this issue, we analyzed the promoters of these three genes in vitro and in Chlamydia trachomatis bacteria grown in cell culture. Transcripts from the sigma(28)-dependent promoter of each gene were detected only at late times in the intracellular infection, bolstering the role of sigma(28) RNA polymerase in late gene expression. In each case, however, expression prior to late times was due to a second promoter that was transcribed by sigma(66) RNA polymerase, which is the major form of chlamydial polymerase. These results demonstrate that chlamydial genes can be transcribed from tandem promoters with different temporal profiles, leading to a composite expression pattern that differs from the expression profile of a single promoter. In addition, tandem promoters allow a gene to be regulated by multiple mechanisms of transcriptional regulation, such as DNA supercoiling or late regulation by EUO and sigma(28). We discuss how tandem promoters broaden the repertoire of temporal gene expression patterns in the chlamydial developmental cycle and can be used to fine-tune the expression of specific genes. IMPORTANCE: Chlamydia is a pathogenic bacterium that is responsible for the majority of infectious disease cases reported to the CDC each year. It causes an intracellular infection that is characterized by coordinated expression of chlamydial genes in temporal waves. Chlamydial transcription has been shown to be regulated by DNA supercoiling, alternative forms of RNA polymerase, and transcription factors, but the number of transcription factors found in Chlamydia is far fewer than the number found in most bacteria. This report describes the use of tandem promoters that allow the temporal expression of a gene or operon to be controlled by more than one regulatory mechanism. This combinatorial strategy expands the range of expression patterns that are available to regulate chlamydial genes. PMID- 26527645 TI - AcrB-AcrA Fusion Proteins That Act as Multidrug Efflux Transporters. AB - The AcrAB-TolC system in Escherichia coli is an intrinsic RND-type multidrug efflux transporter that functions as a tripartite complex of the inner membrane transporter AcrB, the outer membrane channel TolC, and the adaptor protein AcrA. Although the crystal structures of each component of this system have been elucidated, the crystal structure of the whole complex has not been solved. The available crystal structures have shown that AcrB and TolC function as trimers, but the number of AcrA molecules in the complex is now under debate. Disulfide chemical cross-linking experiments have indicated that the stoichiometry of AcrB AcrA-TolC is 1:1:1; on the other hand, recent cryo-electron microscopy images of AcrAB-TolC suggested a 1:2:1 stoichiometry. In this study, we constructed 1:1 fixed AcrB-AcrA fusion proteins using various linkers. Surprisingly, all the 1:1 fixed linker proteins showed drug export activity under both acrAB-deficient conditions and acrAB acrEF double-pump-knockout conditions regardless of the lengths of the linkers. Finally, we optimized a shorter linker lacking the conformational freedom imparted by the AcrB C terminus. These results suggest that a complex with equal amounts of AcrA and AcrB is sufficient for drug export function. IMPORTANCE: The structure and stoichiometry of the RND-type multidrug exporter AcrB-AcrA-TolC complex are still under debate. Recently, electron microscopic images of the AcrB-AcrA-TolC complex have been reported, suggesting a 1:2:1 stoichiometry. However, we report here that the AcrB-AcrA 1:1 fusion protein is active for drug export under acrAB-deficient conditions and also under acrAB acrEF double-deficient conditions, which eliminate the aid of free AcrA and its close homolog AcrE, indicating that the AcrB-AcrA 1:1 stoichiometry is enough for drug export function. In addition, the AcrB-AcrA fusion protein can function without the aid of free AcrA. We believe that these results are very important for considering the structure and mechanism of AcrAB-TolC-mediated multidrug export. PMID- 26527646 TI - Identification of the Key Sequence in the FliK C-Terminal Domain for Substrate Specificity Switching in the Flagellar Protein Secretion. AB - The flagellar hook is a short tubular structure located between the external filament and the membrane-bound basal body. The average hook length is 55 nm and is determined by the soluble protein FliK and the integral membrane protein FlhB. Hook elongation is terminated by FliK-mediated cessation of hook protein secretion, followed by the secretion of filamentous proteins. This process is referred to as the substrate specificity switch. Switching of the secretion modes results from a direct interaction between the FliK C-terminal domain (FliKC) and the secretion gate in FlhB. FliKC consists of two alpha-helices and four beta strands. Loop 2 connects the first two beta-sheets and contains a conserved sequence of 9 residues. Genetic and physiological analyses of various fliK partial deletion mutants pointed to loop 2 as essential for induction of a conformational change in the FlhB gate. We constructed single-amino-acid substitutions in the conserved region of loop 2 of FliK and discovered that the loop sequence LRL is essential for the timely switching of secretion modes. IMPORTANCE: Flagellar protein secretion is controlled by the soluble protein FliK. We discovered that the loop 2 sequence LRL in the FliK C terminus was essential for timely switching of secretion modes. This mechanism is applicable to type three secretions systems that secrete virulence factors in bacterial pathogens. PMID- 26527647 TI - Reciprocal Regulation of l-Arabinose and d-Xylose Metabolism in Escherichia coli. AB - Glucose is known to inhibit the transport and metabolism of many sugars in Escherichia coli. This mechanism leads to its preferential consumption. Far less is known about the preferential utilization of nonglucose sugars in E. coli. Two exceptions are l-arabinose and d-xylose. Previous studies have shown that l arabinose inhibits d-xylose metabolism in Escherichia coli. This repression results from l-arabinose-bound AraC binding to the promoter of the d-xylose metabolic genes and inhibiting their expression. This mechanism, however, has not been explored in single cells. Both the l-arabinose and d-xylose utilization systems are known to exhibit a bimodal induction response to their cognate sugar, where mixed populations of cells either expressing the metabolic genes or not are observed at intermediate sugar concentrations. This suggests that l-arabinose can only inhibit d-xylose metabolism in l-arabinose-induced cells. To understand how cross talk between these systems affects their response, we investigated E. coli during growth on mixtures of l-arabinose and d-xylose at single-cell resolution. Our results showed that mixed, multimodal populations of l-arabinose- and d xylose-induced cells occurred at intermediate sugar concentrations. We also found that d-xylose inhibited the expression of the l-arabinose metabolic genes and that this repression was due to XylR. These results demonstrate that a strict hierarchy does not exist between l-arabinose and d-xylose as previously thought. The results may also aid in the design of E. coli strains capable of simultaneous sugar consumption. IMPORTANCE: Glucose, d-xylose, and l-arabinose are the most abundant sugars in plant biomass. Developing efficient fermentation processes that convert these sugars into chemicals and fuels will require strains capable of coutilizing these sugars. Glucose has long been known to repress the expression of the l-arabinose and d-xylose metabolic genes in Escherichia coli. Recent studies found that l-arabinose also represses the expression of the d xylose metabolic genes. In the present study, we found that d-xylose also represses the expression of the l-arabinose metabolic genes, leading to mixed populations of cells capable of utilizing l-arabinose and d-xylose. These results further our understanding of mixed-sugar utilization and may aid in strain design. PMID- 26527648 TI - Phenotypes Associated with the Essential Diadenylate Cyclase CdaA and Its Potential Regulator CdaR in the Human Pathogen Listeria monocytogenes. AB - Cyclic diadenylate monophosphate (c-di-AMP) is a second messenger utilized by diverse bacteria. In many species, including the Gram-positive human pathogen Listeria monocytogenes, c-di-AMP is essential for growth. Here we show that the single diadenylate cyclase of L. monocytogenes, CdaA, is an integral membrane protein that interacts with its potential regulatory protein, CdaR, via the transmembrane protein domain. The presence of the CdaR protein is not required for the membrane localization and abundance of CdaA. We have also found that CdaR negatively influences CdaA activity in L. monocytogenes and that the role of CdaR is most evident at a high growth temperature. Interestingly, a cdaR mutant strain is less susceptible to lysozyme. Moreover, CdaA contributes to cell division, and cells depleted of CdaA are prone to lysis. The observation that the growth defect of a CdaA depletion strain can be partially restored by increasing the osmolarity of the growth medium suggests that c-di-AMP is important for maintaining the integrity of the protective cell envelope. Overall, this work provides new insights into the relationship between CdaA and CdaR. IMPORTANCE: Cyclic diadenylate monophosphate (c-di-AMP) is a recently identified second messenger that is utilized by the Gram-positive human pathogen Listeria monocytogenes. Here we show that the single diadenylate cyclase of L. monocytogenes, CdaA, is an integral membrane protein that interacts with CdaR, its potential regulatory protein. We show that CdaR is not required for membrane localization or abundance of the diadenylate cyclase, but modulates its activity. Moreover, CdaA seems to contribute to cell division. Overall, this work provides new insights into the relationship between CdaA and CdaR and their involvement in cell growth. PMID- 26527650 TI - Comparative Genomics of Sibling Fungal Pathogenic Taxa Identifies Adaptive Evolution without Divergence in Pathogenicity Genes or Genomic Structure. AB - It has been estimated that the sister plant pathogenic fungal species Heterobasidion irregulare and Heterobasidion annosum may have been allopatrically isolated for 34-41 Myr. They are now sympatric due to the introduction of the first species from North America into Italy, where they freely hybridize. We used a comparative genomic approach to 1) confirm that the two species are distinct at the genomic level; 2) determine which gene groups have diverged the most and the least between species; 3) show that their overall genomic structures are similar, as predicted by the viability of hybrids, and identify genomic regions that instead are incongruent; and 4) test the previously formulated hypothesis that genes involved in pathogenicity may be less divergent between the two species than genes involved in saprobic decay and sporulation. Results based on the sequencing of three genomes per species identified a high level of interspecific similarity, but clearly confirmed the status of the two as distinct taxa. Genes involved in pathogenicity were more conserved between species than genes involved in saprobic growth and sporulation, corroborating at the genomic level that invasiveness may be determined by the two latter traits, as documented by field and inoculation studies. Additionally, the majority of genes under positive selection and the majority of genes bearing interspecific structural variations were involved either in transcriptional or in mitochondrial functions. This study provides genomic-level evidence that invasiveness of pathogenic microbes can be attained without the high levels of pathogenicity presumed to exist for pathogens challenging naive hosts. PMID- 26527649 TI - Global Regulator of Virulence A (GrvA) Coordinates Expression of Discrete Pathogenic Mechanisms in Enterohemorrhagic Escherichia coli through Interactions with GadW-GadE. AB - Global regulator of virulence A (GrvA) is a ToxR-family transcriptional regulator that activates locus of enterocyte effacement (LEE)-dependent adherence in enterohemorrhagic Escherichia coli (EHEC). LEE activation by GrvA requires the Rcs phosphorelay response regulator RcsB and is sensitive to physiologically relevant concentrations of bicarbonate, a known stimulant of virulence systems in intestinal pathogens. This study determines the genomic scale of GrvA-dependent regulation and uncovers details of the molecular mechanism underlying GrvA dependent regulation of pathogenic mechanisms in EHEC. In a grvA-null background of EHEC strain TW14359, RNA sequencing analysis revealed the altered expression of over 700 genes, including the downregulation of LEE- and non-LEE-encoded effectors and the upregulation of genes for glutamate-dependent acid resistance (GDAR). Upregulation of GDAR genes corresponded with a marked increase in acid resistance. GrvA-dependent regulation of GDAR and the LEE required gadE, the central activator of GDAR genes and a direct repressor of the LEE. Control of gadE by GrvA was further determined to occur through downregulation of the gadE activator GadW. This interaction of GrvA with GadW-GadE represses the acid resistance phenotype, while it concomitantly activates the LEE-dependent adherence and secretion of immune subversion effectors. The results of this study significantly broaden the scope of GrvA-dependent regulation and its role in EHEC pathogenesis. IMPORTANCE: Enterohemorrhagic Escherichia coli (EHEC) is an intestinal human pathogen causing acute hemorrhagic colitis and life-threatening hemolytic-uremic syndrome. For successful transmission and gut colonization, EHEC relies on the glutamate-dependent acid resistance (GDAR) system and a type III secretion apparatus, encoded on the LEE pathogenicity island. This study investigates the mechanism whereby the DNA-binding regulator GrvA coordinates activation of the LEE with repression of GDAR. Investigating how these systems are regulated leads to an understanding of pathogenic behavior and novel strategies aimed at disease prevention and control. PMID- 26527651 TI - Impacts of Whole-Genome Triplication on MIRNA Evolution in Brassica rapa. AB - MicroRNAs (miRNAs) are a class of short non-coding, endogenous RNAs that play essential roles in eukaryotes. Although the influence of whole-genome triplication (WGT) on protein-coding genes has been well documented in Brassica rapa, little is known about its impacts on MIRNAs. In this study, through generating a comprehensive annotation of 680 MIRNAs for B. rapa, we analyzed the evolutionary characteristics of these MIRNAs from different aspects in B. rapa. First, while MIRNAs and genes show similar patterns of biased distribution among subgenomes of B. rapa, we found that MIRNAs are much more overretained than genes following fractionation after WGT. Second, multiple-copy MIRNAs show significant sequence conservation than that of single-copy MIRNAs, which is opposite to that of genes. This indicates that increased purifying selection is acting upon these highly retained multiple-copy MIRNAs and their functional importance over singleton MIRNAs. Furthermore, we found the extensive divergence between pairs of miRNAs and their target genes following the WGT in B. rapa. In summary, our study provides a valuable resource for exploring MIRNA in B. rapa and highlights the impacts of WGT on the evolution of MIRNA. PMID- 26527652 TI - Determining the Position of Storks on the Phylogenetic Tree of Waterbirds by Retroposon Insertion Analysis. AB - Despite many studies on avian phylogenetics in recent decades that used morphology, mitochondrial genomes, and/or nuclear genes, the phylogenetic positions of several birds (e.g., storks) remain unsettled. In addition to the aforementioned approaches, analysis of retroposon insertions, which are nearly homoplasy-free phylogenetic markers, has also been used in avian phylogenetics. However, the first step in the analysis of retroposon insertions, that is, isolation of retroposons from genomic libraries, is a costly and time-consuming procedure. Therefore, we developed a high-throughput and cost-effective protocol to collect retroposon insertion information based on next-generation sequencing technology, which we call here the STRONG (Screening of Transposons Obtained by Next Generation Sequencing) method, and applied it to 3 waterbird species, for which we identified 35,470 loci containing chicken repeat 1 retroposons (CR1). Our analysis of the presence/absence of 30 CR1 insertions demonstrated the intra- and interordinal phylogenetic relationships in the waterbird assemblage, namely 1) Loons diverged first among the waterbirds, 2) penguins (Sphenisciformes) and petrels (Procellariiformes) diverged next, and 3) among the remaining families of waterbirds traditionally classified in Ciconiiformes/Pelecaniformes, storks (Ciconiidae) diverged first. Furthermore, our genome-scale, in silico retroposon analysis based on published genome data uncovered a complex divergence history among pelican, heron, and ibis lineages, presumably involving ancient interspecies hybridization between the heron and ibis lineages. Thus, our retroposon-based waterbird phylogeny and the established phylogenetic position of storks will help to understand the evolutionary processes of aquatic adaptation and related morphological convergent evolution. PMID- 26527653 TI - p53 Activity Dominates That of p73 upon Mdm4 Loss in Development and Tumorigenesis. AB - Mdm4 negatively regulates the p53 tumor suppressor. Mdm4 loss in mice leads to an embryonic lethal phenotype that is p53-dependent. Biochemical studies indicate that Mdm4 also binds p73, a member of the p53 family, with higher affinity than p53. In this study, the significance of the Mdm4 and p73 interaction in vivo during embryogenesis and tumorigenesis was examined. The data revealed that p73 loss did not rescue either the early Mdm4-deficient embryonic lethality or the runted phenotype of Mdm4(Delta2/Delta2) p53(+/-) embryos. Furthermore, studies in the developing central nervous system wherein both genes have prominent roles indicated that loss of p73 also did not rescue the Mdm4-null brain phenotype as did p53 loss. This p53 dependency occurred despite evidence for p73-specific transcriptional activity. In tumor studies, the combination of Mdm4 overexpression and p73 loss did not alter survival of mice or the tumor spectrum as compared with Mdm4 overexpression alone. In summary, these data demonstrate that the Mdm4-p73 axis cannot override the dominant role of p53 in development and tumorigenesis. IMPLICATIONS: Genetic characterization of the Mdm4 and p73 interaction during development and tumorigenesis suggests new insight into the role of p53 family members, which may influence treatment options for patients. PMID- 26527654 TI - Phytochrome A and B Function Antagonistically to Regulate Cold Tolerance via Abscisic Acid-Dependent Jasmonate Signaling. AB - Light signaling and phytohormones both influence plant growth, development, and stress responses; however, cross talk between these two signaling pathways in response to cold remains underexplored. Here, we report that far-red light (FR) and red light (R) perceived by phytochrome A (phyA) and phyB positively and negatively regulated cold tolerance, respectively, in tomato (Solanum lycopersicum), which were associated with the regulation of levels of phytohormones such as abscisic acid (ABA) and jasmonic acid (JA) and transcript levels of ABA- and JA-related genes and the C-REPEAT BINDING FACTOR (CBF) stress signaling pathway genes. A reduction in the R/FR ratio did not alter cold tolerance, ABA and JA accumulation, and transcript levels of ABA- and JA-related genes and the CBF pathway genes in phyA mutant plants; however, those were significantly increased in wild-type and phyB plants with the reduction in the R/FR ratio. Even though low R/FR treatments did not confer cold tolerance in ABA deficient (notabilis [not]) and JA-deficient (prosystemin-mediated responses2 [spr2]) mutants, it up-regulated ABA accumulation and signaling in the spr2 mutant, with no effect on JA levels and signaling in the not mutant. Foliar application of ABA and JA further confirmed that JA functioned downstream of ABA to activate the CBF pathway in light quality-mediated cold tolerance. It is concluded that phyA and phyB function antagonistically to regulate cold tolerance that essentially involves FR light-induced activation of phyA to induce ABA signaling and, subsequently, JA signaling, leading to an activation of the CBF pathway and a cold response in tomato plants. PMID- 26527655 TI - Noninvasive Measurement of Vulnerability to Drought-Induced Embolism by X-Ray Microtomography. AB - Hydraulic failure induced by xylem embolism is one of the primary mechanisms of plant dieback during drought. However, many of the methods used to evaluate the vulnerability of different species to drought-induced embolism are indirect and invasive, increasing the possibility that measurement artifacts may occur. Here, we utilize x-ray computed microtomography (microCT) to directly visualize embolism formation in the xylem of living, intact plants with contrasting wood anatomy (Quercus robur, Populus tremula * Populus alba, and Pinus pinaster). These observations were compared with widely used centrifuge techniques that require destructive sampling. MicroCT imaging provided detailed spatial information regarding the dimensions and functional status of xylem conduits during dehydration. Vulnerability curves based on microCT observations of intact plants closely matched curves based on the centrifuge technique for species with short vessels (P. tremula * P. alba) or tracheids (P. pinaster). For ring porous Q. robur, the centrifuge technique significantly overestimated vulnerability to embolism, indicating that caution should be used when applying this technique to species with long vessels. These findings confirm that microCT can be used to assess the vulnerability to embolism on intact plants by direct visualization. PMID- 26527656 TI - C4 Photosynthesis in the Rice Paddy: Insights from the Noxious Weed Echinochloa glabrescens. AB - The C4 pathway is a highly complex trait that increases photosynthetic efficiency in more than 60 plant lineages. Although the majority of C4 plants occupy disturbed, arid, and nutrient-poor habitats, some grow in high-nutrient, waterlogged conditions. One such example is Echinochloa glabrescens, which is an aggressive weed of rice paddies. We generated comprehensive transcriptome datasets for C4 E. glabrescens and C3 rice to identify genes associated with adaption to waterlogged, nutrient-replete conditions, but also used the data to better understand how C4 photosynthesis operates in these conditions. Leaves of E. glabrescens exhibited classical Kranz anatomy with lightly lobed mesophyll cells having low chloroplast coverage. As with rice and other hygrophytic C3 species, leaves of E. glabrescens accumulated a chloroplastic phosphoenolpyruvate carboxylase protein, albeit at reduced amounts relative to rice. The arid-grown species Setaria italica (C4) and Brachypodium distachyon (C3) were also found to accumulate chloroplastic phosphoenolpyruvate carboxylase. We identified a molecular signature associated with C4 photosynthesis in nutrient-replete, waterlogged conditions that is highly similar to those previously reported from C4 plants that grow in more arid conditions. We also identified a cohort of genes that have been subjected to a selective sweep associated with growth in paddy conditions. Overall, this approach highlights the value of using wild species such as weeds to identify adaptions to specific conditions associated with high yielding crops in agriculture. PMID- 26527657 TI - Xyloglucan Deficiency Disrupts Microtubule Stability and Cellulose Biosynthesis in Arabidopsis, Altering Cell Growth and Morphogenesis. AB - Xyloglucan constitutes most of the hemicellulose in eudicot primary cell walls and functions in cell wall structure and mechanics. Although Arabidopsis (Arabidopsis thaliana) xxt1 xxt2 mutants lacking detectable xyloglucan are viable, they display growth defects that are suggestive of alterations in wall integrity. To probe the mechanisms underlying these defects, we analyzed cellulose arrangement, microtubule patterning and dynamics, microtubule- and wall integrity-related gene expression, and cellulose biosynthesis in xxt1 xxt2 plants. We found that cellulose is highly aligned in xxt1 xxt2 cell walls, that its three-dimensional distribution is altered, and that microtubule patterning and stability are aberrant in etiolated xxt1 xxt2 hypocotyls. We also found that the expression levels of microtubule-associated genes, such as MAP70-5 and CLASP, and receptor genes, such as HERK1 and WAK1, were changed in xxt1 xxt2 plants and that cellulose synthase motility is reduced in xxt1 xxt2 cells, corresponding with a reduction in cellulose content. Our results indicate that loss of xyloglucan affects both the stability of the microtubule cytoskeleton and the production and patterning of cellulose in primary cell walls. These findings establish, to our knowledge, new links between wall integrity, cytoskeletal dynamics, and wall synthesis in the regulation of plant morphogenesis. PMID- 26527658 TI - Roles of Arabidopsis PARC6 in Coordination of the Chloroplast Division Complex and Negative Regulation of FtsZ Assembly. AB - Chloroplast division is driven by the simultaneous constriction of the inner FtsZ ring (Z ring) and the outer DRP5B ring. The assembly and constriction of these rings in Arabidopsis (Arabidopsis thaliana) are coordinated partly through the inner envelope membrane protein ACCUMULATION AND REPLICATION OF CHLOROPLASTS6 (ARC6). Previously, we showed that PARC6 (PARALOG OF ARC6), also in the inner envelope membrane, negatively regulates FtsZ assembly and acts downstream of ARC6 to position the outer envelope membrane protein PLASTID DIVISION1 (PDV1), which functions together with its paralog PDV2 to recruit DYNAMIN-RELATED PROTEIN 5B (DRP5B) from a cytosolic pool to the outer envelope membrane. However, whether PARC6, like ARC6, also functions in coordination of the chloroplast division contractile complexes was unknown. Here, we report a detailed topological analysis of Arabidopsis PARC6, which shows that PARC6 has a single transmembrane domain and a topology resembling that of ARC6. The newly identified stromal region of PARC6 interacts not only with ARC3, a direct inhibitor of Z-ring assembly, but also with the Z-ring protein FtsZ2. Overexpression of PARC6 inhibits FtsZ assembly in Arabidopsis but not in a heterologous yeast system (Schizosaccharomyces pombe), suggesting that the negative regulation of FtsZ assembly by PARC6 is a consequence of its interaction with ARC3. A conserved carboxyl-terminal peptide in FtsZ2 mediates FtsZ2 interaction with both PARC6 and ARC6. Consistent with its role in the positioning of PDV1, the intermembrane space regions of PARC6 and PDV1 interact. These findings provide new insights into the functions of PARC6 and suggest that PARC6 coordinates the inner Z ring and outer DRP5B ring through interaction with FtsZ2 and PDV1 during chloroplast division. PMID- 26527660 TI - Correction to Supporting Information for Kowalewski et al., HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL). PMID- 26527661 TI - Schizophrenia and bipolar disorder: no recovery without suicide prevention. AB - Suicide prevention for people with schizophrenia or bipolar disorder warrants an evidence-based approach to service design as well as clinical practice. The issue of personal responsibility (diminished when mental capacity is impaired) contributing to reduction of suicide risk has, arguably, been neglected. PMID- 26527659 TI - Hormone-regulated defense and stress response networks contribute to heterosis in Arabidopsis F1 hybrids. AB - Plant hybrids are extensively used in agriculture to deliver increases in yields, yet the molecular basis of their superior performance (heterosis) is not well understood. Our transcriptome analysis of a number of Arabidopsis F1 hybrids identified changes to defense and stress response gene expression consistent with a reduction in basal defense levels. Given the reported antagonism between plant immunity and growth, we suggest that these altered patterns of expression contribute to the greater growth of the hybrids. The altered patterns of expression in the hybrids indicate decreases to the salicylic acid (SA) biosynthesis pathway and increases in the auxin [indole-3-acetic acid (IAA)] biosynthesis pathway. SA and IAA are hormones known to control stress and defense responses as well as plant growth. We found that IAA-targeted gene activity is frequently increased in hybrids, correlating with a common heterotic phenotype of greater leaf cell numbers. Reduced SA concentration and target gene responses occur in the larger hybrids and promote increased leaf cell size. We demonstrated the importance of SA action to the hybrid phenotype by manipulating endogenous SA concentrations. Increasing SA diminished heterosis in SA-reduced hybrids, whereas decreasing SA promoted growth in some hybrids and phenocopied aspects of hybrid vigor in parental lines. Pseudomonas syringae infection of hybrids demonstrated that the reductions in basal defense gene activity in these hybrids does not necessarily compromise their ability to mount a defense response comparable to the parents. PMID- 26527662 TI - Are neurological and psychiatric disorders different? AB - There have been recent calls to abandon the distinction between neurological and psychiatric disorders on philosophical and moral grounds. Crossley and colleagues, in this issue, meta-analyse published structural brain imaging data and prove that they are different after all--or do they? PMID- 26527663 TI - Old age psychiatry in the modern age. AB - Old age psychiatry services globally are under threat. The discipline enjoyed its heyday in the two decades bridging the millennium. More recently there has been a move to integrate old age services with those of working age adults, to create 'ageless' services. Evidence is beginning to accumulate that this is a bad idea. PMID- 26527665 TI - Psychiatric expertise. PMID- 26527666 TI - How could it happen? The killing of people in mental hospitals in Germany under the Third Reich. PMID- 26527664 TI - Evidence for effective interventions to reduce mental health-related stigma and discrimination in the medium and long term: systematic review. AB - BACKGROUND: Most research on interventions to counter stigma and discrimination has focused on short-term outcomes and has been conducted in high-income settings. AIMS: To synthesise what is known globally about effective interventions to reduce mental illness-based stigma and discrimination, in relation first to effectiveness in the medium and long term (minimum 4 weeks), and second to interventions in low- and middle-income countries (LMICs). METHOD: We searched six databases from 1980 to 2013 and conducted a multi-language Google search for quantitative studies addressing the research questions. Effect sizes were calculated from eligible studies where possible, and narrative syntheses conducted. Subgroup analysis compared interventions with and without social contact. RESULTS: Eighty studies (n = 422 653) were included in the review. For studies with medium or long-term follow-up (72, of which 21 had calculable effect sizes) median standardised mean differences were 0.54 for knowledge and -0.26 for stigmatising attitudes. Those containing social contact (direct or indirect) were not more effective than those without. The 11 LMIC studies were all from middle income countries. Effect sizes were rarely calculable for behavioural outcomes or in LMIC studies. CONCLUSIONS: There is modest evidence for the effectiveness of anti-stigma interventions beyond 4 weeks follow-up in terms of increasing knowledge and reducing stigmatising attitudes. Evidence does not support the view that social contact is the more effective type of intervention for improving attitudes in the medium to long term. Methodologically strong research is needed on which to base decisions on investment in stigma-reducing interventions. PMID- 26527667 TI - High Royds Hospital, Menston, Ilkley. PMID- 26527668 TI - On Madness and Civilisation: A History of Insanity in the Age of Reason (1961), by Michel Foucault. PMID- 26527669 TI - Do micronutrients help in ADHD? PMID- 26527671 TI - Kaleidoscope. PMID- 26527670 TI - Authors' reply. PMID- 26527674 TI - Poor oral health including active caries in 187 UK professional male football players: clinical dental examination performed by dentists. AB - BACKGROUND: The few studies that have assessed oral health in professional/elite football suggest poor oral health with minimal data on impact on performance. The aim of this research was to determine oral health in a representative sample of professional footballers in the UK and investigate possible determinants of oral health and self-reported impact on well-being, training and performance. METHODS: Clinical oral health examination of senior squad players using standard methods and outcomes carried out at club training facilities. Questionnaire data were also collected. 8 teams were included, 5 Premier League, 2 Championship and 1 League One. RESULTS: 6 dentists examined 187 players who represented >90% of each senior squad. Oral health was poor: 37% players had active dental caries, 53% dental erosion and 5% moderate-severe irreversible periodontal disease. 45% were bothered by their oral health, 20% reported an impact on their quality of life and 7% on training or performance. Despite attendance for dental check-ups, oral health deteriorated with age. CONCLUSIONS: This is the first large, representative sample study in professional football. Oral health of professional footballers is poor, and this impacts on well-being and performance. Successful strategies to promote oral health within professional football are urgently needed, and research should investigate models based on best evidence for behaviour change and implementation science. Furthermore, this study provides strong evidence to support oral health screening within professional football. PMID- 26527675 TI - The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. AB - There are >24 million registered adult donors, and the numbers of unrelated donor transplantations are increasing. The optimal strategy for prioritizing among comparably HLA-matched potential donors has not been established. Therefore, the objective of the current analyses was to study the association between donor characteristics (age, sex, parity, cytomegalovirus serostatus, HLA match, and blood group ABO match) and survival after transplantation for hematologic malignancy. The association of donor characteristics with transplantation outcomes was examined using either logistic or Cox regression models, adjusting for patient disease and transplantation characteristics associated with outcomes in 2 independent datasets: 1988 to 2006 (N = 6349; training cohort) and 2007 to 2011 (N = 4690; validation cohort). All donor-recipient pairs had allele-level HLA typing at HLA-A, -B, -C, and -DRB1, which is the current standard for selecting donors. Adjusting for patient disease and transplantation characteristics, survival was better after transplantation of grafts from young donors (aged 18-32 years) who were HLA matched to recipients (P < .001). These findings were validated for transplantations that occurred between 2007 and 2011. For every 10-year increment in donor age, there is a 5.5% increase in the hazard ratio for overall mortality. Increasing HLA disparity was also associated with worsening survival. Donor age and donor-recipient HLA match are important when selecting adult unrelated donors. Other donor characteristics such as sex, parity, and cytomegalovirus serostatus were not associated with survival. The effect of ABO matching on survival is modest and must be studied further before definitive recommendations can be offered. PMID- 26527676 TI - Predictors of survival, nonrelapse mortality, and failure-free survival in patients treated for chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (GVHD) is a pleotropic syndrome that lacks validated methods of measuring response in clinical trials, although several end points have been proposed. To investigate the prognostic significance of these proposed end points, such as the 2005 National Institutes of Health (NIH) response measures, 2014 NIH response measures, clinician-reported response, and patient-reported response, we tested their ability to predict subsequent overall survival (OS), nonrelapse mortality (NRM), and failure-free survival (FFS). Patients (n = 575) were enrolled on a prospective chronic GVHD observational trial. At 6 months, clinician-reported response (P = .004) and 2014 NIH calculated response (P = .001) correlated with subsequent FFS, and clinician reported response predicted OS (P = .007). Multivariate models were used to identify changes in organ involvement, laboratory values, and patient-reported outcomes that were associated with long-term outcomes. At 6 months, a change in the 2005 NIH 0 to 3 clinician-reported skin score and 0 to 10 patient-reported itching score predicted subsequent FFS. Change in the Lee skin symptom score and Functional Assessment of Cancer Therapy-Bone Marrow Transplant score predicted subsequent OS. Change in the Lee skin symptom score predicted subsequent NRM. This study provides evidence that clinician-reported response and patient reported outcomes are predictive of long-term survival. The trial was registered at www.clinicaltrials.gov as #NCT00637689. PMID- 26527677 TI - Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels. PMID- 26527678 TI - The C-terminal Cytosolic Region of Rim21 Senses Alterations in Plasma Membrane Lipid Composition: INSIGHTS INTO SENSING MECHANISMS FOR PLASMA MEMBRANE LIPID ASYMMETRY. AB - Yeast responds to alterations in plasma membrane lipid asymmetry and external alkalization via the sensor protein Rim21 in the Rim101 pathway. However, the sensing mechanism used by Rim21 remains unclear. Here, we found that the C terminal cytosolic domain of Rim21 (Rim21C) fused with GFP was associated with the plasma membrane under normal conditions but dissociated upon alterations in lipid asymmetry or external alkalization. This indicates that Rim21C contains a sensor motif. Rim21C contains multiple clusters of charged residues. Among them, three consecutive Glu residues (EEE motif) were essential for Rim21 function and dissociation of Rim21C from the plasma membrane in response to changes in lipid asymmetry. In contrast, positively charged residues adjacent to the EEE motif were required for Rim21C to associate with the membrane. We therefore propose an "antenna hypothesis," in which Rim21C moves to or from the plasma membrane and functions as the sensing mechanism of Rim21. PMID- 26527679 TI - Loss of Scribble Promotes Snail Translation through Translocation of HuR and Enhances Cancer Drug Resistance. AB - Drug resistance of cancer cells to various therapeutic agents and molecular targets is a major problem facing current cancer research. The tumor suppressor gene Scribble encodes a polarity protein that is conserved between Drosophila and mammals; loss of the locus disrupts cell polarity, inhibits apoptosis, and mediates cancer process. However, the role of Scribble in drug resistance remains unknown. We show here that knockdown of Scribble enhances drug resistance by permitting accumulation of Snail, which functions as a transcription factor during the epithelial-mesenchymal transition. Then, loss of Scribble activates the mRNA-binding protein human antigen R (HuR) by facilitating translocation of HuR from the nucleus to the cytoplasm. Furthermore, we demonstrate HuR can recognize AU-rich elements of the Snail-encoding mRNA, thereby regulating Snail translation. Moreover, loss of Scribble-induced HuR translocation mediates the accumulation of Snail via activation of the p38 MAPK pathway. Thus, this work clarifies the role of polarity protein Scribble, which is directly implicated in the regulation of developmental transcription factor Snail, and suggesting a mechanism for Scribble mediating cancer drug resistance. PMID- 26527680 TI - Streptococcal 5'-Nucleotidase A (S5nA), a Novel Streptococcus pyogenes Virulence Factor That Facilitates Immune Evasion. AB - Streptococcus pyogenes is an important human pathogen that causes a wide range of diseases. Using bioinformatics analysis of the complete S. pyogenes strain SF370 genome, we have identified a novel S. pyogenes virulence factor, which we termed streptococcal 5'-nucleotidase A (S5nA). A recombinant form of S5nA hydrolyzed AMP and ADP, but not ATP, to generate the immunomodulatory molecule adenosine. Michaelis-Menten kinetics revealed a Km of 169 MUm and a Vmax of 7550 nmol/mg/min for the substrate AMP. Furthermore, recombinant S5nA acted synergistically with S. pyogenes nuclease A to generate macrophage-toxic deoxyadenosine from DNA. The enzyme showed optimal activity between pH 5 and pH 6.5 and between 37 and 47 degrees C. Like other 5'-nucleotidases, S5nA requires divalent cations and was active in the presence of Mg(2+), Ca(2+), or Mn(2+). However, Zn(2+) inhibited the enzymatic activity. Structural modeling combined with mutational analysis revealed a highly conserved catalytic dyad as well as conserved substrate and cation-binding sites. Recombinant S5nA significantly increased the survival of the non-pathogenic bacterium Lactococcus lactis during a human whole blood killing assay in a dose-dependent manner, suggesting a role as an S. pyogenes virulence factor. In conclusion, we have identified a novel S. pyogenes enzyme with 5'-nucleotidase activity and immune evasion properties. PMID- 26527681 TI - Glut4 Is Sorted from a Rab10 GTPase-independent Constitutive Recycling Pathway into a Highly Insulin-responsive Rab10 GTPase-dependent Sequestration Pathway after Adipocyte Differentiation. AB - The RabGAP AS160/TBC1D4 controls exocytosis of the insulin-sensitive glucose transporter Glut4 in adipocytes. Glut4 is internalized and recycled through a highly regulated secretory pathway in these cells. Glut4 also cycles through a slow constitutive endosomal pathway distinct from the fast transferrin (Tf) receptor recycling pathway. This slow constitutive pathway is the only Glut4 cycling pathway in undifferentiated fibroblasts. The alpha2-macroglobulin receptor LRP1 cycles with Glut4 and the Tf receptor through all three exocytic pathways. To further characterize these pathways, the effects of knockdown of AS160 substrates on the trafficking kinetics of Glut4, LRP1, and the Tf receptor were measured in adipocytes and fibroblasts. Rab10 knockdown decreased cell surface Glut4 in insulin-stimulated adipocytes by 65%, but not in basal adipocytes or in fibroblasts. This decrease was due primarily to a 62% decrease in the rate constant of Glut4 exocytosis (kex), although Rab10 knockdown also caused a 1.4-fold increase in the rate constant of Glut4 endocytosis (ken). Rab10 knockdown in adipocytes also decreased cell surface LRP1 by 30% by decreasing kex 30-40%. There was no effect on LRP1 trafficking in fibroblasts or on Tf receptor trafficking in either cell type. These data confirm that Rab10 is an AS160 substrate that limits exocytosis through the highly insulin-responsive specialized secretory pathway in adipocytes. They further show that the slow constitutive endosomal (fibroblast) recycling pathway is Rab10-independent. Thus, Rab10 is a marker for the specialized pathway in adipocytes. Interestingly, mathematical modeling shows that Glut4 traffics predominantly through the specialized Rab10-dependent pathway both before and after insulin stimulation. PMID- 26527682 TI - Novel UDP-GalNAc Derivative Structures Provide Insight into the Donor Specificity of Human Blood Group Glycosyltransferase. AB - Two closely related glycosyltransferases are responsible for the final step of the biosynthesis of ABO(H) human blood group A and B antigens. The two enzymes differ by only four amino acid residues, which determine whether the enzymes transfer GalNAc from UDP-GalNAc or Gal from UDP-Gal to the H-antigen acceptor. The enzymes belong to the class of GT-A folded enzymes, grouped as GT6 in the CAZy database, and are characterized by a single domain with a metal dependent retaining reaction mechanism. However, the exact role of the four amino acid residues in the specificity of the enzymes is still unresolved. In this study, we report the first structural information of a dual specificity cis-AB blood group glycosyltransferase in complex with a synthetic UDP-GalNAc derivative. Interestingly, the GalNAc moiety adopts an unusual yet catalytically productive conformation in the binding pocket, which is different from the "tucked under" conformation previously observed for the UDP-Gal donor. In addition, we show that this UDP-GalNAc derivative in complex with the H-antigen acceptor provokes the same unusual binding pocket closure as seen for the corresponding UDP-Gal derivative. Despite this, the two derivatives show vastly different kinetic properties. Our results provide a important structural insight into the donor substrate specificity and utilization in blood group biosynthesis, which can very likely be exploited for the development of new glycosyltransferase inhibitors and probes. PMID- 26527683 TI - Integrin alphaVbeta5-mediated Removal of Apoptotic Cell Debris by the Eye Lens and Its Inhibition by UV Light Exposure. AB - Accumulation of apoptotic material is toxic and associated with cataract and other disease states. Identification of mechanisms that prevent accumulation of apoptotic debris is important for establishing the etiology of these diseases. The ocular lens is routinely assaulted by UV light that causes lens cell apoptosis and is associated with cataract formation. To date, no molecular mechanism for removal of toxic apoptotic debris has been identified in the lens. Vesicular debris within lens cells exposed to UV light has been observed raising speculation that lens cells themselves could act as phagocytes to remove toxic apoptotic debris. However, phagocytosis has not been confirmed as a function of the intact eye lens, and no mechanism for lens phagocytosis has been established. Here, we demonstrate that the eye lens is capable of phagocytizing extracellular lens cell debris. Using high throughput RNA sequencing and bioinformatics analysis, we establish that lens epithelial cells express members of the integrin alphaVbeta5-mediated phagocytosis pathway and that internalized cell debris co localizes with alphaVbeta5 and with RAB7 and Rab-interacting lysosomal protein that are required for phagosome maturation and fusion with lysosomes. We demonstrate that the alphaVbeta5 receptor is required for lens epithelial cell phagocytosis and that UV light treatment of lens epithelial cells results in damage to the alphaVbeta5 receptor with concomitant loss of phagocytosis. These data suggest that loss of alphaVbeta5-mediated phagocytosis by the eye lens could result in accumulation of toxic cell debris that could contribute to UV light induced cataract formation. PMID- 26527684 TI - Regulation of Focal Adhesion Dynamics and Cell Motility by the EB2 and Hax1 Protein Complex. AB - Cell migration is a fundamental cellular process requiring integrated activities of the cytoskeleton, membrane, and cell/extracellular matrix adhesions. Many cytoskeletal activities rely on microtubule filaments. It has been speculated that microtubules can serve as tracks to deliver proteins essential for focal adhesion turnover. Three microtubule end-binding proteins (EB1, EB2, and EB3) in mammalian cells can track the plus ends of growing microtubules. EB1 and EB3 together can regulate microtubule dynamics by promoting microtubule growth and suppressing catastrophe, whereas, in contrast, EB2 does not play a direct role in microtubule dynamic instability, and little is known about the cellular function of EB2. By quantitative proteomics, we identified mammalian HCLS1-associated protein X-1 (HAX1) as an EB2-specific interacting protein. Knockdown of HAX1 and EB2 in skin epidermal cells stabilizes focal adhesions and impairs epidermal migration in vitro and in vivo. Our results further demonstrate that cell motility and focal adhesion turnover require interaction between Hax1 and EB2. Together, our findings provide new insights for this critical cellular process, suggesting that EB2 association with Hax1 plays a significant role in focal adhesion turnover and epidermal migration. PMID- 26527686 TI - Chemical Modulation of Endocytic Sorting Augments Adeno-associated Viral Transduction. AB - Intracellular trafficking of viruses can be influenced by a variety of inter connected cellular sorting and degradation pathways involving endo-lysosomal vesicles, the ubiquitin-proteasome system, and autophagy-based or endoplasmic reticulum-associated machinery. In the case of recombinant adeno-associated viruses (AAV), proteasome inhibitors are known to prevent degradation of ubiquitinated AAV capsids, thereby leading to increased nuclear accumulation and transduction. However, the impact of other cellular degradation pathways on AAV trafficking is not well understood. In the current study, we screened a panel of small molecules focused on modulating different cellular degradation pathways and identified eeyarestatin I (EerI) as a novel reagent that enhances AAV transduction. EerI improved AAV transduction by an order of magnitude regardless of vector dose, genome architecture, cell type, or serotype. This effect was preceded by sequestration of AAV within enlarged vesicles that were dispersed throughout the cytoplasm. Specifically, EerI treatment redirected AAV particles toward large vesicles positive for late endosomal (Rab7) and lysosomal (LAMP1) markers. Notably, MG132 and EerI (proteasomal and endoplasmic reticulum associated degradation inhibitors, respectively) appear to enhance AAV transduction by increasing the intracellular accumulation of viral particles in a mutually exclusive fashion. Taken together, our results expand on potential strategies to redirect recombinant AAV vectors toward more productive trafficking pathways by deregulating cellular degradation mechanisms. PMID- 26527685 TI - Structural Basis of Ribosomal S6 Kinase 1 (RSK1) Inhibition by S100B Protein: MODULATION OF THE EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) SIGNALING CASCADE IN A CALCIUM-DEPENDENT WAY. AB - Mitogen-activated protein kinases (MAPK) promote MAPK-activated protein kinase activation. In the MAPK pathway responsible for cell growth, ERK2 initiates the first phosphorylation event on RSK1, which is inhibited by Ca(2+)-binding S100 proteins in malignant melanomas. Here, we present a detailed in vitro biochemical and structural characterization of the S100B-RSK1 interaction. The Ca(2+) dependent binding of S100B to the calcium/calmodulin-dependent protein kinase (CaMK)-type domain of RSK1 is reminiscent of the better known binding of calmodulin to CaMKII. Although S100B-RSK1 and the calmodulin-CAMKII system are clearly distinct functionally, they demonstrate how unrelated intracellular Ca(2+)-binding proteins could influence the activity of the CaMK domain containing protein kinases. Our crystallographic, small angle x-ray scattering, and NMR analysis revealed that S100B forms a "fuzzy" complex with RSK1 peptide ligands. Based on fast-kinetics experiments, we conclude that the binding involves both conformation selection and induced fit steps. Knowledge of the structural basis of this interaction could facilitate therapeutic targeting of melanomas. PMID- 26527687 TI - E2F1 Transcription Factor Regulates O-linked N-acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Expression. AB - Protein O-GlcNAcylation, which is controlled by O-GlcNAc transferase (OGT) and O GlcNAcase (OGA), has emerged as an important posttranslational modification that may factor in multiple diseases. Until recently, it was assumed that OGT/OGA protein expression was relatively constant. Several groups, including ours, have shown that OGT and/or OGA expression changes in several pathologic contexts, yet the cis and trans elements that regulate the expression of these enzymes remain essentially unexplored. Here, we used a reporter-based assay to analyze minimal promoters and leveraged in silico modeling to nominate several candidate transcription factor binding sites in both Ogt (i.e. the gene for OGT protein) and Mgea5 (i.e. the gene for OGA protein). We noted multiple E2F binding site consensus sequences in both promoters. We performed chromatin immunoprecipitation in both human and mouse cells and found that E2F1 bound to candidate E2F binding sites in both promoters. In HEK293 cells, we overexpressed E2F1, which significantly reduced OGT and MGEA5 expression. Conversely, E2F1-deficient mouse fibroblasts had increased Ogt and Mgea5 expression. Of the known binding partners for E2F1, we queried whether retinoblastoma 1 (Rb1) might be involved. Rb1 deficient mouse embryonic fibroblasts showed increased levels of Ogt and Mgea5 expression, yet overexpression of E2F1 in the Rb1-deficient cells did not alter Ogt and Mgea5 expression, suggesting that Rb1 is required for E2F1-mediated suppression. In conclusion, this work identifies and validates some of the promoter elements for mouse Ogt and Mgea5 genes. Specifically, E2F1 negatively regulates both Ogt and Mgea5 expression in an Rb1 protein-dependent manner. PMID- 26527688 TI - Hepatocyte Nuclear Factor 4alpha Controls Iron Metabolism and Regulates Transferrin Receptor 2 in Mouse Liver. AB - Iron is an essential element in biological systems, but excess iron promotes the formation of reactive oxygen species, resulting in cellular toxicity. Several iron-related genes are highly expressed in the liver, a tissue in which hepatocyte nuclear factor 4alpha (HNF4alpha) plays a critical role in controlling gene expression. Therefore, the role of hepatic HNF4alpha in iron homeostasis was examined using liver-specific HNF4alpha-null mice (Hnf4a(DeltaH) mice). Hnf4a(DeltaH) mice exhibit hypoferremia and a significant change in hepatic gene expression. Notably, the expression of transferrin receptor 2 (Tfr2) mRNA was markedly decreased in Hnf4a(DeltaH) mice. Promoter analysis of the Tfr2 gene showed that the basal promoter was located at a GC-rich region upstream of the transcription start site, a region that can be transactivated in an HNF4alpha independent manner. HNF4alpha-dependent expression of Tfr2 was mediated by a proximal promoter containing two HNF4alpha-binding sites located between the transcription start site and the translation start site. Both the GC-rich region of the basal promoter and the HNF4alpha-binding sites were required for maximal transactivation. Moreover, siRNA knockdown of HNF4alpha suppressed TFR2 expression in human HCC cells. These results suggest that Tfr2 is a novel target gene for HNF4alpha, and hepatic HNF4alpha plays a critical role in iron homeostasis. PMID- 26527690 TI - Diabetic ketoacidosis in adults. PMID- 26527689 TI - MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages. AB - Membrane-coated extracellular vesicles (EVs) released by cells can serve as vehicles for delivery of biological materials and signals. Recently, we demonstrated that alcohol-treated hepatocytes cross-talk with immune cells via exosomes containing microRNA (miRNAs). Here, we hypothesized that alcohol-exposed monocytes can communicate with naive monocytes via EVs. We observed increased numbers of EVs, mostly exosomes, secreted by primary human monocytes and THP-1 monocytic cells in the presence of alcohol in a concentration- and time-dependent manner. EVs derived from alcohol-treated monocytes stimulated naive monocytes to polarize into M2 macrophages as indicated by increased surface expression of CD68 (macrophage marker), M2 markers (CD206 (mannose receptor) and CD163 (scavenger receptor)), secretion of IL-10, and TGFbeta and increased phagocytic activity. miRNA profiling of the EVs derived from alcohol-treated THP-1 monocytes revealed high expression of the M2-polarizing miRNA, miR-27a. Treatment of naive monocytes with control EVs overexpressing miR-27a reproduced the effect of EVs from alcohol treated monocytes on naive monocytes and induced M2 polarization, suggesting that the effect of alcohol EVs was mediated by miR-27a. We found that miR-27a modulated the process of phagocytosis by targeting CD206 expression on monocytes. Importantly, analysis of circulating EVs from plasma of alcoholic hepatitis patients revealed increased numbers of EVs that contained high levels of miR-27a as compared with healthy controls. Our results demonstrate the following: first, alcohol increases EV production in monocytes; second, alcohol-exposed monocytes communicate with naive monocytes via EVs; and third, miR-27a cargo in monocyte derived EVs can program naive monocytes to polarize into M2 macrophages. PMID- 26527691 TI - DNA-binding activity of rat DNA topoisomerase II alpha C-terminal domain contributes to efficient DNA catenation in vitro. AB - DNA topoisomerase IIalpha (topo IIalpha) is an essential enzyme for resolution of DNA topologies arising in DNA metabolic reactions. In proliferating cells, topo II activities of DNA catenation or decatenation are required for condensation of chromosomes and segregation of chromatids. Recent studies suggest that the C terminal domain (CTD) of human topo IIalpha is required for localization to mitotic chromosomes. Here, we show that the CTD of topo IIalpha is also associated with efficient DNA catenation in vitro, based on comparison of wild type (WT) rat topo IIalpha and its deletion mutants. Unlike WT, the CTD truncated mutant (DeltaCTD) lacked linear DNA binding activity, but could bind to negatively supercoiled DNA similarly to WT. The CTD alone showed linear DNA binding activity. DeltaCTD mediated formation of a DNA catenane in the presence of polyethylene glycol, which enhances macromolecular association. These results indicate that DNA-binding activity in the CTD of topo IIalpha concentrates the enzyme in the vicinity of condensed DNA and allows topo IIalpha to efficiently form a DNA catenane. PMID- 26527694 TI - Anomaly of the Descending Aorta: Multifurcation and Reunion. PMID- 26527692 TI - Molecular Mechanisms of Right Ventricular Failure. AB - An abundance of data has provided insight into the mechanisms underlying the development of left ventricular (LV) hypertrophy and its progression to LV failure. In contrast, there is minimal data on the adaptation of the right ventricle (RV) to pressure and volume overload and the transition to RV failure. This is a critical clinical question, because the RV is uniquely at risk in many patients with repaired or palliated congenital heart disease and in those with pulmonary hypertension. Standard heart failure therapies have failed to improve function or survival in these patients, suggesting a divergence in the molecular mechanisms of RV versus LV failure. Although, on the cellular level, the remodeling responses of the RV and LV to pressure overload are largely similar, there are several key differences: the stressed RV is more susceptible to oxidative stress, has a reduced angiogenic response, and is more likely to activate cell death pathways than the stressed LV. Together, these differences could explain the more rapid progression of the RV to failure versus the LV. This review will highlight known molecular differences between the RV and LV responses to hemodynamic stress, the unique stressors on the RV associated with congenital heart disease, and the need to better understand these molecular mechanisms if we are to develop RV-specific heart failure therapeutics. PMID- 26527695 TI - Transthyretin-Derived (ATTR) Amyloidotic Cardiomyopathy After Receiving a Domino Liver Allograft. PMID- 26527696 TI - Cardiology Patient Page. ABCDE Steps for Heart and Vascular Wellness Following a Prostate Cancer Diagnosis. PMID- 26527697 TI - Letter by Escudero et al Regarding Article, "Elevated Placental Adenosine Signaling Contributes to the Pathogenesis of Preeclampsia". PMID- 26527699 TI - Letter by Lin et al Regarding Article, "Frequent Physical Activity May Not Reduce Vascular Disease Risk as Much as Moderate Activity: Large Prospective Study of Women in the United Kingdom". PMID- 26527698 TI - Response to Letter Regarding Article, "Elevated Placental Adenosine Signaling Contributes to the Pathogenesis of Preeclampsia". PMID- 26527700 TI - Response to Letter Regarding Article, "Frequent Physical Activity May Not Reduce Vascular Disease Risk as Much as Moderate Activity: Large Prospective Study of Women in the United Kingdom". PMID- 26527701 TI - Pakistan mounts first mass antismoking campaign. PMID- 26527702 TI - Immune effects of chicken non-MHC alloantigens. AB - Alloantigen systems are a broad group of molecules found on various cell types, including erythrocytes and lymphocytes. These alloantigens, identified via specific polyclonal or monoclonal antibodies or molecular methods, have demonstrated effects on immune responses. Erythrocyte alloantigens include the A, B, C, D, E, H, I, J, K, L, N, P, and R systems. Highly polymorphic alloantigen B has been identified as the chicken major histocompatibility complex (MHC). The other twelve systems have a variable degree of polymorphism as well as impact on immune measurements or responses against pathogens. Selection for immune characters altered allele frequencies for particular alloantigen systems. Three lymphocyte alloantigens, Bu-1, Ly-4 and Th-1 have more limited polymorphism but still influence responses against viral pathogens, Rous sarcoma virus and Marek's disease. Together, these erythrocyte and lymphocyte systems contribute to the overall immunity. Identification of the specific alloantigen proteins remains crucial to understanding their immune contribution. PMID- 26527703 TI - Failed landings after laying hen flight in a commercial aviary over two flock cycles. AB - Many egg producers are adopting alternative housing systems such as aviaries that provide hens a tiered cage and a litter-covered open floor area. This larger, more complex environment permits expression of behaviors not seen in space limited cages, such as flight. Flight is an exercise important for strengthening bones; but domestic hens might display imperfect flight landings due to poor flight control. To assess the potential implications of open space, we evaluated the landing success of Lohmann white laying hens in a commercial aviary. Video recordings of hens were taken from 4 aviary sections at peak lay, mid lay and end lay across two flock cycles. Observations were made in each focal section of all flights throughout the day noting flight origin and landing location (outer perch or litter) and landing success or failure. In Flock 1, 9.1% of all flights failed and 21% failed in Flock 2. The number of flights decreased across the laying cycle for both flocks. Proportionally more failed landings were observed in the double row sections in Flock 2. Collisions with other hens were more common than slipping on the ground or colliding with aviary structures across sections and flocks. More hens slipped on the ground and collided with physical structures at peak lay for Flock 2 than at other time points. More collisions with other hens were seen at mid and end lay than at peak lay for Flock 2. Landings ending on perches failed more often than landings on litter. These results indicate potential for flight-related hen injuries in aviary systems resulting from failed landings, which may have implications for hen welfare and optimal system design and management. PMID- 26527704 TI - The apparent metabolizable energy requirement of male Korean native ducklings from hatch to 21 days of age. AB - A study was conducted to determine the apparent metabolizable energy (AME) requirement of Korean native ducklings for hatch to 21 d of age. A total of 336 one-day-old male Korean native ducklings were used in a completely randomized design having 8 dietary treatments to provide a range of AME content from 2,600 to 3,300 kcal/kg (i.e., 100 kcal/kg disparity). Eight experimental diets containing varying levels of AME were formulated to meet the NRC (1994) nutrient specifications. Ducklings were randomly allocated to 48 pens (6 replicates per treatment and 7 ducklings per pen) and were offered their respective diets on an ad libitum basis for the period of study. Body weight and feed intake were measured weekly to calculate feed conversion ratio, energy intake, and protein intake. Two ducklings per pen (n = 6) were euthanized via cervical dislocation to weigh empty body and drumsticks at the conclusion of the experiment. Data were fitted to both linear-plateau and quadratic-plateau models for estimation of the AME requirements for Korean native ducklings for hatch to 21 d of age. The estimated AME requirements were 2,953, 3,007, and 2,950 kcal AME/kg diet for maximum daily gain, daily feed intake, and for minimum feed conversion ratio, respectively. PMID- 26527705 TI - Effect of in ovo-delivered prebiotics and synbiotics on the morphology and specific immune cell composition in the gut-associated lymphoid tissue. AB - The purpose of this study was to examine how pre- and synbiotic administration in ovo into the air chamber at d 12 of egg incubation influenced the specific immune cell composition and distribution in the ileum, cecal tonsils (CT) and bursa of Fabricius of broilers. The experiment was performed on 800 hatching eggs of the meat-type chickens (Ross 308). Hatching eggs were treated with: prebiotic, consisting of inulin (Pre1) or Bi(2)tos((r)) (Pre2); symbiotic, composed of inulin and Lactococcus lactis subsp. lactis IBB SL1 (Syn1) or Bi(2)tos and Lactococcus lactis subsp. cremoris IBB SC1 (Syn2); or physiological saline as a control group. Seven chickens from each treatment group were randomly selected on , 1, 7, and 21 after hatch for tissue collection. Ileum, cecal tonsil and bursa of Fabricius samples were immunohistochemically stained and the proportions of Bu 1(+), CD3(+), CD4(+), CD8alpha(+) and TCRgammadelta(+) cells were estimated. It was indicated that the pre- and synbiotics do not adversely affect the development of the GALT of the chicken. The temporary decrease in B-cell number in bursa on d 7 after hatch suggested an increased colonization rate of the peripheral lymphoid organs by these cells after Pre1, Pre2, and Syn2 treatment. In CT at d 7 after hatch more potent colonization of the GALT by T cells was observed in all pre- and synbiotic treated groups and by B cells in both synbiotic-treated groups than those in respective controls. Then, on d 21 in both synbiotic-treated groups, an increase in T-cell number in ileum was also noticed with faster colonization of the CT by B cells. In 21-day-old chickens, both synbiotics exerted stronger stimulatory effect on the GALT colonization by T cells then prebiotics respectively. Similarly, the colonization by B cells was more pronounced in the Syn2 than in the Pre2 group. The data obtained in this study indicated that prebiotics and particularly synbiotics administrated in ovo stimulated GALT development after hatch. PMID- 26527706 TI - Assessment of cecal microbiota, integron occurrence, fermentation responses, and Salmonella frequency in conventionally raised broilers fed a commercial yeast based prebiotic compound. AB - Prebiotics are defined as nondigestible food ingredients that can stimulate the growth of one or more beneficial bacteria in the gastrointestinal tract. The Biolex((r)) MB40 is a commercial prebiotic that contains mannanoligosaccharides. The aims of this study were to evaluate the effects of prebiotic Biolex((r)) MB40 on cecal microbiota of conventionally raised chickens using PCR-based denaturing gradient gel electrophoresis (DGGE) and assessing Salmonella prevalence. Chickens were randomly selected and distributed into three groups; a negative control (NC) and two treatment groups (T1 and T2). The NC group was fed a non-medicated feed, while the treatment groups were fed either T1 or T2, 0.05% antibiotic (BMD50) or 0.2% Biolex((r)) MB40 respectively. During the study, cecal contents and bird feed were plated on selective media for Salmonella, yeast and mold prevalence analysis. Ten chickens from each group were randomly selected at 1, 2, 4 and 6 wk and ceca were extracted for DNA isolation for PCR-based DGGE. Also, short-chain fatty acids (SCFAs) were analyzed from collected cecal material by gas chromatography. Only 4.2% of the samples were Salmonella positive. Presence of class 1 integron from cecal material were analyzed by PCR and 97.5% of the cecal samples were positive for integron presence, but no class I integrons were detected in the Salmonella isolates. According to the PCR-based DGGE analysis, the T2 group exhibited a cecal microbial population pattern that was similar to the T1 group prior to wk 4 and the T2 group appeared to be almost identical with the NC group after wk 4 but T2 exhibited less Bacteroides rodentium prior to wk 4. Overall results showed that the commercial prebiotic, MB40 did not lead to a detectable reduction of Salmonella but the general frequency of Salmonella was minimal in all treatments. However, feeding an MB40 supplement did result in similar DGGE band patterns as the T1 group indicating that cecal microbiotia were potentially similar in these 2 groups. Overall, it appears that MB40 (T2) exhibited similar DGGE-cecal population patterns as BMD50 (T1) which suggests that these treatments may have influenced the populations in a comparable fashion. PMID- 26527707 TI - Bacterial chondronecrosis with osteomyelitis and lameness in broilers: a review. AB - This review focuses on a specific cause of lameness known as bacterial chondronecrosis with osteomyelitis (BCO) in broilers. Rapid increases in body weight impose excessive torque and shear stress on structurally immature epiphyseal and physeal cartilage, primarily in the proximal femora, proximal tibiae, and flexible thoracic vertebrae. Excessive mechanical stress creates osteochondrotic clefts among the chondrocytes of susceptible growth plates. These wound sites are colonized by hematogenously distributed opportunistic bacteria, culminating in the gross abscesses and necrotic voids that are pathognomonic for terminal BCO. Lameness attributable to characteristic BCO lesions can be reproduced by rearing broilers on wire flooring to create persistent footing instability and physiological stress, without the need to inoculate the birds with pathogenic bacteria that presumably are present but quiescent within the bird's microbial communities or in the environment. Experiments using the wire flooring model revealed innate differences in the susceptibility of broiler lines to BCO, and demonstrated that BCO incidences can be reduced by prophylactically providing probiotics in the feed, by prophylactically adding 25-hydroxy vitamin D3 to the drinking water, or by therapeutically adding the antibiotic enrofloxacin to the drinking water. Hatchery and chick quality issues clearly influence the susceptibility of broilers to BCO. When broilers remain in a sitting posture for prolonged periods, the major arteries supplying their legs may be compressed. These episodes of inadequate blood flow may prevent chondrocyte maturation and trigger focal necrosis, thereby making the epiphyseal and physeal cartilage highly susceptible to osteochondrosis and BCO. Much remains to be revealed regarding the pathogenesis of BCO. Further revelations will be facilitated by the availability of the now-validated wire-flooring models that consistently trigger high incidences of BCO in experimental flocks. PMID- 26527708 TI - Incubation temperature manipulation during fetal development reduces adiposity of broiler hatchlings. AB - Broilers are known as an efficient source of lean meat. Genetic selection resulted in broiler strains with large body size and fast growth, but a concomitant increase in fat deposition also occurred. Other than reducing nutrient intake, there is a lack of alternative methods to control body fat composition of broilers. The present study assessed whether incubation temperature (machine temperatures: 36oC, 37.5oC, and 39oC; eggshell temperatures: 37.4 +/- 0.08 degrees C, 37.8 +/- 0.15oC, and 38.8 +/- 0.33 degrees C, respectively.) from d 13 affects broiler hatchling fat deposition. We analyzed adipocyte hypertrophy and proliferation in 3 body regions; weight and chemical composition of yolk-free chicks and yolk sacs; and serum lipid profile. Increased incubation temperature reduced abdominal and cervical adipocyte size. Independently of temperature, cervical adipocytes were smaller and showed higher proliferation than adipocytes in the abdominal and thigh regions. Smaller cervical adipocytes were observed in birds from eggs incubated at 36oC and 39oC. With regard to weight and composition of chicks, ash content as a percentage of dry matter was the only variable affected by temperature; it was higher in chicks from eggs incubated at 36oC than at 39oC and showed no significant difference between chicks incubated at 39oC and 37.5oC. Absolute and relative weights of yolk sacs were higher from eggs incubated at 39oC than at 36oC, and these two treatments did not differ from the 37.5oC control. Absolute measures of yolk sac lipids, moisture, dry matter, and crude protein content were lower in chicks from eggs incubated at 36oC, and no significant differences were found for these variables between chicks from eggs incubated at 37.5oC and 39oC. Hatchlings from eggs incubated at 36 degrees C had significantly higher cholesterol levels than chicks incubated at the other 2 temperatures, but no additional effects on blood lipids were detected. Incubation temperature manipulation during fetal development altered cervical and abdominal adipocyte size in broiler hatchlings and could become a tool in hatcheries to manipulate chick quality, although further studies are needed to evaluate its long-term effects. PMID- 26527709 TI - Improvement of turkey breast meat quality and cooked gel functionality using hot boning, quarter sectioning, crust-freeze-air-chilling and cold-batter-mincing technologies. AB - The effect of rapid carcass chilling on breast meat quality was evaluated using commercial (COMM) and random-bred (RB) turkeys. Immediately after slaughter, 48 turkeys from COMM or RB line were randomly subjected to one of four chilling methods: 1) water-immersion chilling (WIC) of the carcasses at 0 degrees C ice slurry, 2) WIC after temperature abuse (TA) of the carcasses at 40 degrees C for 30 min (TA-WIC), 3) hot-boning, quarter sectioning, and crust-freeze-air-chilling (HB-(1)/4CFAC) of breast fillets at -12 degrees C, and 4) HB-(1)/4CFAC of fillets after TA of carcasses (TA-HB-(1)/4CFAC). The TA increased carcass and fillet temperatures by ~1.3 and ~4.1 degrees C, respectively, regardless of turkey line, whereas HB-(1)/4CFAC of fillets required 28 and 33% of carcass chilling time for COMM and RB, respectively. During chilling, COMM breast pH rapidly reduced from 6.04 to 5.82, resulting in a significantly lower pH than RB after chilling (P < 0.05), whereas COMM R-value sharply increased from 1.17 to 1.43, causing no difference from RB (P > 0.05). Significantly higher L* value and cooking yield (P < 0.05) were seen in the samples of TA and WIC than those of no TA and HB (1)/4CFAC, respectively, with no difference observed between COMM and RB fillets (P > 0.05). Higher values of hardness, gumminess, and chewiness were found for RB, no TA, and HB-(1)/4CFAC gels than COMM, TA, and WIC, respectively. These results generally indicated that protein quality and textural properties of turkey fillets were improved, regardless of strains or temperature abuse, using HB-(1)/4CFAC technology. PMID- 26527710 TI - Effects of season on the reproductive organ and plasma testosterone concentrations in guinea cocks (Numida meleagris). AB - The physiological basis of seasonal breeding in the guinea fowl (Numida meleagris) still remains unknown, despite the socioeconomic importance of these birds, particularly in Ghana. A study involving a total of 50 local guinea cocks was conducted, and documented gross anatomical and histological differences in the reproductive organs of breeding and non-breeding male guinea fowls. The study also compared peripheral testosterone concentrations in breeding and non-breeding cocks. Seasonal differences in variables measured were determined using two tailed t-test/Mann-Whitney U-test. All comparisons were made at 5% level of significance. Breeding males had significantly (P = 0.000) higher anatomical biometric parameters than their non-breeding counterparts. Also, breeding birds had thicker (P = 0.000) phalli than their non-breeding counterparts. Histologically, regressing testis was characterized by the presence of sloughed off cells and increased debris in the tubular lumen and within the excurrent duct system, collapsed tubules and reduction in tubular lumen. Germ and Sertoli cell populations and nuclear diameters and actual seminiferous tubular diameter and length in regressing testes were significantly (P = 0.000) lower than in active testes. Leydig cell nuclear diameters and populations were also significantly (P = 0.000) reduced. Relative volume of seminiferous tubules in the testis, testicular sperm production/mg testis and per testis and peripheral testosterone concentrations were all higher (P < 0.05) in breeding than non-breeding testis. The ducts in the epididymal region also saw significant (P < 0.05) reductions in luminal diameters in non-breeding birds. Significant regression in anatomical and histological structures of the guinea cock reproductive tract occurred during the non-breeding season, and lower peripheral testosterone concentrations may be responsible for this phenomenon. PMID- 26527711 TI - Two Turkish doctors who went to aid of protesters are sentenced to prison. PMID- 26527712 TI - Effects of conjugated linoleic acid and lutein on the growth performance and immune response of broiler chickens. AB - The effects of lutein and conjugated linoleic acid (CLA) on growth performance and immune response of broiler chickens were evaluated in the presence and absence of Salmonella lipopolysaccharide (LPS) immune challenge. Cobb chicks (360; 1 to 22 d of age) were used in a 3 * 2 factorial arrangement of CLA (0, 1, and 2%) and lutein (0 and 50 mg/kg) dietary levels. At d 8 and 15, birds were injected with BSA to assess IgY production. At d 20, birds were injected with LPS. Samples of liver, spleen, and duodenum were collected at 3 and 16 h post-LPS challenge for RT-qPCR analysis of RXRalpha, RXRgamma, PPARalpha, PPARgamma, TLR 4, IL-1beta, IL-2, IL-10, and IL-12 gene expression. CLA decreased BW, BW gain (BWG), and G:F from d 1 to 20, but these effects were reversed when lutein was included in the 1% CLA diet (P < 0.001). The production of IgY anti-BSA increased following a 2% CLA supplementation (P < 0.01). LPS increased the liver:BW ratio at 3 h post-injection (P < 0.001) and decreased BWG at 3, 16, and 40 h (P < 0.001). Lutein decreased plasmatic nitric oxide levels (P < 0.01). LPS downregulated PPARalpha mRNA in the duodenum (P = 0.02) and liver (P = 0.04), and PPARgamma (P = 0.01) and RXRalpha (P = 0.08) in the spleen; these effects were not reversed by CLA or lutein as initially hypothesized. Although LPS upregulated IL-1beta (P = 0.02) and IL-12 (P = 0.07) expression, lutein downregulated these pro-inflammatory cytokines in the liver (P = 0.03 and P = 0.07, respectively). Lutein decreased splenic (P = 0.09) but increased hepatic (P = 0.06) TLR-4 mRNA. A dietary CLA supplementation of 2% increased hepatic RXRalpha (P = 0.10). In conclusion, CLA decreased broiler chicken growth performance, but lutein could prevent this negative effect (depending on CLA dose). Lutein had an anti inflammatory effect, and a 2% CLA supplementation improved the humoral immune response. PMID- 26527713 TI - Margaret McCartney: Nits--no hiding from head lice. PMID- 26527714 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 2: Preparticipation Screening for Cardiovascular Disease in Competitive Athletes: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26527715 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 14: Sickle Cell Trait: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26527716 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 10: The Cardiac Channelopathies: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26527717 TI - Twenty years of the MEROPS database of proteolytic enzymes, their substrates and inhibitors. AB - The MEROPS database (http://merops.sanger.ac.uk) is an integrated source of information about peptidases, their substrates and inhibitors, which are of great relevance to biology, medicine and biotechnology. The hierarchical classification of the database is as follows: homologous sets of sequences are grouped into a protein species; protein species are grouped into a family; families are grouped into clans. There is a type example for each protein species (known as a 'holotype'), family and clan, and each protein species, family and clan has its own unique identifier. Pages to show the involvement of peptidases and peptidase inhibitors in biological pathways have been created. Each page shows the peptidases and peptidase inhibitors involved in the pathway, along with the known substrate cleavages and peptidase-inhibitor interactions, and a link to the KEGG database of biological pathways. Links have also been established with the IUPHAR Guide to Pharmacology. A new service has been set up to allow the submission of identified substrate cleavages so that conservation of the cleavage site can be assessed. This should help establish whether or not a cleavage site is physiologically relevant on the basis that such a cleavage site is likely to be conserved. PMID- 26527718 TI - Computational learning on specificity-determining residue-nucleotide interactions. AB - The protein-DNA interactions between transcription factors and transcription factor binding sites are essential activities in gene regulation. To decipher the binding codes, it is a long-standing challenge to understand the binding mechanism across different transcription factor DNA binding families. Past computational learning studies usually focus on learning and predicting the DNA binding residues on protein side. Taking into account both sides (protein and DNA), we propose and describe a computational study for learning the specificity determining residue-nucleotide interactions of different known DNA-binding domain families. The proposed learning models are compared to state-of-the-art models comprehensively, demonstrating its competitive learning performance. In addition, we describe and propose two applications which demonstrate how the learnt models can provide meaningful insights into protein-DNA interactions across different DNA binding families. PMID- 26527720 TI - MetaNetX/MNXref--reconciliation of metabolites and biochemical reactions to bring together genome-scale metabolic networks. AB - MetaNetX is a repository of genome-scale metabolic networks (GSMNs) and biochemical pathways from a number of major resources imported into a common namespace of chemical compounds, reactions, cellular compartments--namely MNXref- and proteins. The MetaNetX.org website (http://www.metanetx.org/) provides access to these integrated data as well as a variety of tools that allow users to import their own GSMNs, map them to the MNXref reconciliation, and manipulate, compare, analyze, simulate (using flux balance analysis) and export the resulting GSMNs. MNXref and MetaNetX are regularly updated and freely available. PMID- 26527719 TI - CEGA--a catalog of conserved elements from genomic alignments. AB - By identifying genomic sequence regions conserved among several species, comparative genomics offers opportunities to discover putatively functional elements without any prior knowledge of what these functions might be. Comparative analyses across mammals estimated 4-5% of the human genome to be functionally constrained, a much larger fraction than the 1-2% occupied by annotated protein-coding or RNA genes. Such functionally constrained yet unannotated regions have been referred to as conserved non-coding sequences (CNCs) or ultra-conserved elements (UCEs), which remain largely uncharacterized but probably form a highly heterogeneous group of elements including enhancers, promoters, motifs, and others. To facilitate the study of such CNCs/UCEs, we present our resource of Conserved Elements from Genomic Alignments (CEGA), accessible from http://cega.ezlab.org. Harnessing the power of multiple species comparisons to detect genomic elements under purifying selection, CEGA provides a comprehensive set of CNCs identified at different radiations along the vertebrate lineage. Evolutionary constraint is identified using threshold-free phylogenetic modeling of unbiased and sensitive global alignments of genomic synteny blocks identified using protein orthology. We identified CNCs independently for five vertebrate clades, each referring to a different last common ancestor and therefore to an overlapping but varying set of CNCs with 24 488 in vertebrates, 241 575 in amniotes, 709 743 in Eutheria, 642 701 in Boreoeutheria and 612 364 in Euarchontoglires, spanning from 6 Mbp in vertebrates to 119 Mbp in Euarchontoglires. The dynamic CEGA web interface displays alignments, genomic locations, as well as biologically relevant data to help prioritize and select CNCs of interest for further functional investigations. PMID- 26527721 TI - PGSB PlantsDB: updates to the database framework for comparative plant genome research. AB - PGSB (Plant Genome and Systems Biology: formerly MIPS) PlantsDB (http://pgsb.helmholtz-muenchen.de/plant/index.jsp) is a database framework for the comparative analysis and visualization of plant genome data. The resource has been updated with new data sets and types as well as specialized tools and interfaces to address user demands for intuitive access to complex plant genome data. In its latest incarnation, we have re-worked both the layout and navigation structure and implemented new keyword search options and a new BLAST sequence search functionality. Actively involved in corresponding sequencing consortia, PlantsDB has dedicated special efforts to the integration and visualization of complex triticeae genome data, especially for barley, wheat and rye. We enhanced CrowsNest, a tool to visualize syntenic relationships between genomes, with data from the wheat sub-genome progenitor Aegilops tauschii and added functionality to the PGSB RNASeqExpressionBrowser. GenomeZipper results were integrated for the genomes of barley, rye, wheat and perennial ryegrass and interactive access is granted through PlantsDB interfaces. Data exchange and cross-linking between PlantsDB and other plant genome databases is stimulated by the transPLANT project (http://transplantdb.eu/). PMID- 26527722 TI - 2016 update of the PRIDE database and its related tools. AB - The PRoteomics IDEntifications (PRIDE) database is one of the world-leading data repositories of mass spectrometry (MS)-based proteomics data. Since the beginning of 2014, PRIDE Archive (http://www.ebi.ac.uk/pride/archive/) is the new PRIDE archival system, replacing the original PRIDE database. Here we summarize the developments in PRIDE resources and related tools since the previous update manuscript in the Database Issue in 2013. PRIDE Archive constitutes a complete redevelopment of the original PRIDE, comprising a new storage backend, data submission system and web interface, among other components. PRIDE Archive supports the most-widely used PSI (Proteomics Standards Initiative) data standard formats (mzML and mzIdentML) and implements the data requirements and guidelines of the ProteomeXchange Consortium. The wide adoption of ProteomeXchange within the community has triggered an unprecedented increase in the number of submitted data sets (around 150 data sets per month). We outline some statistics on the current PRIDE Archive data contents. We also report on the status of the PRIDE related stand-alone tools: PRIDE Inspector, PRIDE Converter 2 and the ProteomeXchange submission tool. Finally, we will give a brief update on the resources under development 'PRIDE Cluster' and 'PRIDE Proteomes', which provide a complementary view and quality-scored information of the peptide and protein identification data available in PRIDE Archive. PMID- 26527723 TI - The role of topoisomerase I in suppressing genome instability associated with a highly transcribed guanine-rich sequence is not restricted to preventing RNA:DNA hybrid accumulation. AB - Highly transcribed guanine-run containing sequences, in Saccharomyces cerevisiae, become unstable when topoisomerase I (Top1) is disrupted. Topological changes, such as the formation of extended RNA:DNA hybrids or R-loops or non-canonical DNA structures including G-quadruplexes has been proposed as the major underlying cause of the transcription-linked genome instability. Here, we report that R-loop accumulation at a guanine-rich sequence, which is capable of assembling into the four-stranded G4 DNA structure, is dependent on the level and the orientation of transcription. In the absence of Top1 or RNase Hs, R-loops accumulated to substantially higher extent when guanine-runs were located on the non-transcribed strand. This coincides with the orientation where higher genome instability was observed. However, we further report that there are significant differences between the disruption of RNase Hs and Top1 in regards to the orientation specific elevation in genome instability at the guanine-rich sequence. Additionally, genome instability in Top1-deficient yeasts is not completely suppressed by removal of negative supercoils and further aggravated by expression of mutant Top1. Together, our data provide a strong support for a function of Top1 in suppressing genome instability at the guanine-run containing sequence that goes beyond preventing the transcription-associated RNA:DNA hybrid formation. PMID- 26527724 TI - RegulonDB version 9.0: high-level integration of gene regulation, coexpression, motif clustering and beyond. AB - RegulonDB (http://regulondb.ccg.unam.mx) is one of the most useful and important resources on bacterial gene regulation,as it integrates the scattered scientific knowledge of the best-characterized organism, Escherichia coli K-12, in a database that organizes large amounts of data. Its electronic format enables researchers to compare their results with the legacy of previous knowledge and supports bioinformatics tools and model building. Here, we summarize our progress with RegulonDB since our last Nucleic Acids Research publication describing RegulonDB, in 2013. In addition to maintaining curation up-to-date, we report a collection of 232 interactions with small RNAs affecting 192 genes, and the complete repertoire of 189 Elementary Genetic Sensory-Response units (GENSOR units), integrating the signal, regulatory interactions, and metabolic pathways they govern. These additions represent major progress to a higher level of understanding of regulated processes. We have updated the computationally predicted transcription factors, which total 304 (184 with experimental evidence and 120 from computational predictions); we updated our position-weight matrices and have included tools for clustering them in evolutionary families. We describe our semiautomatic strategy to accelerate curation, including datasets from high throughput experiments, a novel coexpression distance to search for 'neighborhood' genes to known operons and regulons, and computational developments. PMID- 26527726 TI - MouseNet v2: a database of gene networks for studying the laboratory mouse and eight other model vertebrates. AB - Laboratory mouse, Mus musculus, is one of the most important animal tools in biomedical research. Functional characterization of the mouse genes, hence, has been a long-standing goal in mammalian and human genetics. Although large-scale knockout phenotyping is under progress by international collaborative efforts, a large portion of mouse genome is still poorly characterized for cellular functions and associations with disease phenotypes. A genome-scale functional network of mouse genes, MouseNet, was previously developed in context of MouseFunc competition, which allowed only limited input data for network inferences. Here, we present an improved mouse co-functional network, MouseNet v2 (available at http://www.inetbio.org/mousenet), which covers 17 714 genes (>88% of coding genome) with 788 080 links, along with a companion web server for network-assisted functional hypothesis generation. The network database has been substantially improved by large expansion of genomics data. For example, MouseNet v2 database contains 183 co-expression networks inferred from 8154 public microarray samples. We demonstrated that MouseNet v2 is predictive for mammalian phenotypes as well as human diseases, which suggests its usefulness in discovery of novel disease genes and dissection of disease pathways. Furthermore, MouseNet v2 database provides functional networks for eight other vertebrate models used in various research fields. PMID- 26527725 TI - Highly efficient homology-driven genome editing in human T cells by combining zinc-finger nuclease mRNA and AAV6 donor delivery. AB - The adoptive transfer of engineered T cells for the treatment of cancer, autoimmunity, and infectious disease is a rapidly growing field that has shown great promise in recent clinical trials. Nuclease-driven genome editing provides a method in which to precisely target genetic changes to further enhance T cell function in vivo. We describe the development of a highly efficient method to genome edit both primary human CD8 and CD4 T cells by homology-directed repair at a pre-defined site of the genome. Two different homology donor templates were evaluated, representing both minor gene editing events (restriction site insertion) to mimic gene correction, or the more significant insertion of a larger gene cassette. By combining zinc finger nuclease mRNA delivery with AAV6 delivery of a homologous donor we could gene correct 41% of CCR5 or 55% of PPP1R12C (AAVS1) alleles in CD8(+) T cells and gene targeting of a GFP transgene cassette in >40% of CD8(+) and CD4(+) T cells at both the CCR5 and AAVS1 safe harbor locus, potentially providing a robust genome editing tool for T cell-based immunotherapy. PMID- 26527727 TI - ENCODE data at the ENCODE portal. AB - The Encyclopedia of DNA Elements (ENCODE) Project is in its third phase of creating a comprehensive catalog of functional elements in the human genome. This phase of the project includes an expansion of assays that measure diverse RNA populations, identify proteins that interact with RNA and DNA, probe regions of DNA hypersensitivity, and measure levels of DNA methylation in a wide range of cell and tissue types to identify putative regulatory elements. To date, results for almost 5000 experiments have been released for use by the scientific community. These data are available for searching, visualization and download at the new ENCODE Portal (www.encodeproject.org). The revamped ENCODE Portal provides new ways to browse and search the ENCODE data based on the metadata that describe the assays as well as summaries of the assays that focus on data provenance. In addition, it is a flexible platform that allows integration of genomic data from multiple projects. The portal experience was designed to improve access to ENCODE data by relying on metadata that allow reusability and reproducibility of the experiments. PMID- 26527728 TI - SATPdb: a database of structurally annotated therapeutic peptides. AB - SATPdb (http://crdd.osdd.net/raghava/satpdb/) is a database of structurally annotated therapeutic peptides, curated from 22 public domain peptide databases/datasets including 9 of our own. The current version holds 19192 unique experimentally validated therapeutic peptide sequences having length between 2 and 50 amino acids. It covers peptides having natural, non-natural and modified residues. These peptides were systematically grouped into 10 categories based on their major function or therapeutic property like 1099 anticancer, 10585 antimicrobial, 1642 drug delivery and 1698 antihypertensive peptides. We assigned or annotated structure of these therapeutic peptides using structural databases (Protein Data Bank) and state-of-the-art structure prediction methods like I TASSER, HHsearch and PEPstrMOD. In addition, SATPdb facilitates users in performing various tasks that include: (i) structure and sequence similarity search, (ii) peptide browsing based on their function and properties, (iii) identification of moonlighting peptides and (iv) searching of peptides having desired structure and therapeutic activities. We hope this database will be useful for researchers working in the field of peptide-based therapeutics. PMID- 26527729 TI - sORFs.org: a repository of small ORFs identified by ribosome profiling. AB - With the advent of ribosome profiling, a next generation sequencing technique providing a "snap-shot'' of translated mRNA in a cell, many short open reading frames (sORFs) with ribosomal activity were identified. Follow-up studies revealed the existence of functional peptides, so-called micropeptides, translated from these 'sORFs', indicating a new class of bio-active peptides. Over the last few years, several micropeptides exhibiting important cellular functions were discovered. However, ribosome occupancy does not necessarily imply an actual function of the translated peptide, leading to the development of various tools assessing the coding potential of sORFs. Here, we introduce sORFs.org (http://www.sorfs.org), a novel database for sORFs identified using ribosome profiling. Starting from ribosome profiling, sORFs.org identifies sORFs, incorporates state-of-the-art tools and metrics and stores results in a public database. Two query interfaces are provided, a default one enabling quick lookup of sORFs and a BioMart interface providing advanced query and export possibilities. At present, sORFs.org harbors 263 354 sORFs that demonstrate ribosome occupancy, originating from three different cell lines: HCT116 (human), E14_mESC (mouse) and S2 (fruit fly). sORFs.org aims to provide an extensive sORFs database accessible to researchers with limited bioinformatics knowledge, thus enabling easy integration into personal projects. PMID- 26527730 TI - Automated design of hammerhead ribozymes and validation by targeting the PABPN1 gene transcript. AB - We present a new publicly accessible web-service, RiboSoft, which implements a comprehensive hammerhead ribozyme design procedure. It accepts as input a target sequence (and some design parameters) then generates a set of ranked hammerhead ribozymes, which target the input sequence. This paper describes the implemented procedure, which takes into consideration multiple objectives leading to a multi objective ranking of the computer-generated ribozymes. Many ribozymes were assayed and validated, including four ribozymes targeting the transcript of a disease-causing gene (a mutant version of PABPN1). These four ribozymes were successfully tested in vitro and in vivo, for their ability to cleave the targeted transcript. The wet-lab positive results of the test are presented here demonstrating the real-world potential of both hammerhead ribozymes and RiboSoft. RiboSoft is freely available at the website http://ribosoft.fungalgenomics.ca/ribosoft/. PMID- 26527731 TI - Allosteric ring assembly and chemo-mechanical melting by the interaction between 5'-phosphate and lambda exonuclease. AB - Phosphates along the DNA function as chemical energy frequently used by nucleases to drive their enzymatic reactions. Exonuclease functions as a machine that converts chemical energy of the phosphodiester-chain into mechanical work. However, the roles of phosphates during exonuclease activities are unknown. We employed lambda exonuclease as a model system and investigated the roles of phosphates during degradation via single-molecule fluorescence resonance energy transfer (FRET). We found that 5' phosphates, generated at each cleavage step of the reaction, chemo-mechanically facilitate the subsequent post-cleavage melting of the terminal base pairs. Degradation of DNA with a nick requires backtracking and thermal fraying at the cleavage site for re-initiation via the formation of a catalytically active complex. Unexpectedly, we discovered that a phosphate of a 5' recessed DNA acts as a hotspot for an allosteric trimeric-ring assembly without passing through the central channel. Our study provides new insight into the versatile roles of phosphates during the processive enzymatic reaction. PMID- 26527732 TI - The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. AB - The MetaCyc database (MetaCyc.org) is a freely accessible comprehensive database describing metabolic pathways and enzymes from all domains of life. The majority of MetaCyc pathways are small-molecule metabolic pathways that have been experimentally determined. MetaCyc contains more than 2400 pathways derived from >46,000 publications, and is the largest curated collection of metabolic pathways. BioCyc (BioCyc.org) is a collection of 5700 organism-specific Pathway/Genome Databases (PGDBs), each containing the full genome and predicted metabolic network of one organism, including metabolites, enzymes, reactions, metabolic pathways, predicted operons, transport systems, and pathway-hole fillers. The BioCyc website offers a variety of tools for querying and analyzing PGDBs, including Omics Viewers and tools for comparative analysis. This article provides an update of new developments in MetaCyc and BioCyc during the last two years, including addition of Gibbs free energy values for compounds and reactions; redesign of the primary gene/protein page; addition of a tool for creating diagrams containing multiple linked pathways; several new search capabilities, including searching for genes based on sequence patterns, searching for databases based on an organism's phenotypes, and a cross-organism search; and a metabolite identifier translation service. PMID- 26527733 TI - Norine, the knowledgebase dedicated to non-ribosomal peptides, is now open to crowdsourcing. AB - Since its creation in 2006, Norine remains the unique knowledgebase dedicated to non-ribosomal peptides (NRPs). These secondary metabolites, produced by bacteria and fungi, harbor diverse interesting biological activities (such as antibiotic, antitumor, siderophore or surfactant) directly related to the diversity of their structures. The Norine team goal is to collect the NRPs and provide tools to analyze them efficiently. We have developed a user-friendly interface and dedicated tools to provide a complete bioinformatics platform. The knowledgebase gathers abundant and valuable annotations on more than 1100 NRPs. To increase the quantity of described NRPs and improve the quality of associated annotations, we are now opening Norine to crowdsourcing. We believe that contributors from the scientific community are the best experts to annotate the NRPs they work on. We have developed MyNorine to facilitate the submission of new NRPs or modifications of stored ones. This article presents MyNorine and other novelties of Norine interface released since the first publication. Norine is freely accessible from the following URL: http://bioinfo.lifl.fr/NRP. PMID- 26527734 TI - Proposed ban on foreigners using Indian surrogacy services sparks protests. PMID- 26527736 TI - Structural basis for the regulatory role of the PPxY motifs in the thioredoxin interacting protein TXNIP. AB - TXNIP (thioredoxin-interacting protein) negatively regulates the antioxidative activity of thioredoxin and participates in pleiotropic cellular processes. Its deregulation is linked to various human diseases, including diabetes, acute myeloid leukaemia and cardiovascular diseases. The E3 ubiquitin ligase Itch (Itchy homologue) polyubiquitinates TXNIP to promote its degradation via the ubiquitin-proteasome pathway, and this Itch-mediated polyubiquitination of TXNIP is dependent on the interaction of the four WW domains of Itch with the two PPxY motifs of TXNIP. However, the molecular mechanism of this interaction of TXNIP with Itch remains elusive. In the present study, we found that each of the four WW domains of Itch exhibited different binding affinities for TXNIP, whereas multivalent engagement between the four WW domains of Itch and the two PPxY motifs of TXNIP resulted in their strong binding avidity. Our structural analyses demonstrated that the third and fourth WW domains of Itch were able to recognize both PPxY motifs of TXNIP simultaneously, supporting a multivalent binding mode between Itch and TXNIP. Interestingly, the phosphorylation status on the tyrosine residue of the PPxY motifs of TXNIP serves as a molecular switch in its choice of binding partners and thereby downstream biological signalling outcomes. Phosphorylation of this tyrosine residue of TXNIP diminished the binding capability of PPxY motifs of TXNIP to Itch, whereas this phosphorylation is a prerequisite to the binding activity of TXNIP to SHP2 [SH2 (Src homology 2) domain-containing protein tyrosine phosphatase 2] and their roles in stabilizing the phosphorylation and activation of CSK (c-Src tyrosine kinase). PMID- 26527735 TI - Epilepsy in glioma patients: mechanisms, management, and impact of anticonvulsant therapy. AB - Seizures are a well-recognized symptom of primary brain tumors, and anticonvulsant use is common. This paper provides an overview of epilepsy and the use of anticonvulsants in glioma patients. Overall incidence and mechanisms of epileptogenesis are reviewed. Factors to consider with the use of antiepileptic drugs (AEDs) including incidence during the disease trajectory and prophylaxis along with considerations in the selection of anticonvulsant use (ie, potential side effects, drug interactions, adverse effects, and impact on survival) are also reviewed. Finally, areas for future research and exploring the pathophysiology and use of AEDs in this population are also discussed. PMID- 26527737 TI - The intrinsically disordered tails of PTEN and PTEN-L have distinct roles in regulating substrate specificity and membrane activity. AB - Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid and protein phosphatase, and both activities are necessary for its role as a tumour suppressor. PTEN activity is controlled by phosphorylation of its intrinsically disordered C-terminal tail. A recently discovered variant of PTEN, PTEN-long (PTEN-L), has a 173-residue N-terminal extension that causes PTEN-L to exhibit unique behaviour, such as movement from one cell to another. Using hydrogen/deuterium exchange mass spectrometry (HDX-MS) and biophysical assays, we show that both the N-terminal extension of PTEN-L and C-terminal tail of PTEN affect the phosphatase activity using unique mechanisms. Phosphorylation of six residues in the C-terminal tail of PTEN results in auto-inhibitory interactions with the phosphatase and C2 domains, effectively blocking both the active site and the membrane-binding interface of PTEN. Partially dephosphorylating PTEN on pThr(366)/pSer(370) results in sufficient exposure of the active site to allow a selective activation for soluble substrates. Using HDX-MS, we identified a membrane-binding element in the N-terminal extension of PTEN-L, termed the membrane-binding helix (MBH). The MBH radically alters the membrane binding mechanism of PTEN-L compared with PTEN, switching PTEN-L to a 'scooting' mode of catalysis from the 'hopping' mode that is characteristic of PTEN. PMID- 26527738 TI - Characterization of alpha-taxilin as a novel factor controlling the release of hepatitis C virus. AB - Although it is well established that the release of HCV (hepatitis C virus) occurs through the secretory pathway, many aspects concerning the control of this process are not yet fully understood. alpha-Taxilin was identified as a novel binding partner of syntaxin-4 and of other members of the syntaxin family, which are part of SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) complexes and so are involved in intracellular vesicle traffic. Since alpha-taxilin prevents t-SNARE (target SNARE) formation by binding exclusively to free syntaxin-4, it exerts an inhibitory effect on the vesicular transport. HCV-replicating Huh7.5 cells and HCV-infected primary human hepatocytes and liver samples of patients suffering from chronic HCV contain significantly less alpha-taxilin compared with the controls. HCV impairs the expression of alpha-taxilin via NS5A-dependent interruption of the Raf/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] signal transduction cascade. Moreover, the half-life of alpha-taxilin is significantly reduced in HCV-replicating cells. Whereas modulation of alpha taxilin expression does not significantly affect genome replication, the overexpression of alpha-taxilin prevents the release of HCV. In contrast with this, silencing of alpha-taxilin expression leads to increased release of infectious viral particles. This is due to the negative effect of alpha-taxilin on t-SNARE formation that leads to impaired vesicular trafficking. Accordingly, overexpression of the t-SNARE component syntaxin-4 increases release of HCV, whereas silencing leads to an impaired release. These data identify alpha-taxilin as a novel factor that controls the release of HCV and reveal the mechanism by which HCV controls the activity of alpha-taxilin. PMID- 26527739 TI - Evidence for caspase-dependent programmed cell death along with repair processes in affected skeletal muscle fibres in patients with mitochondrial disorders. AB - Mitochondrial disorders are heterogeneous multisystemic disorders due to impaired oxidative phosphorylation causing defective mitochondrial energy production. Common histological hallmarks of mitochondrial disorders are RRFs (ragged red fibres), muscle fibres with abnormal focal accumulations of mitochondria. In contrast with the growing understanding of the genetic basis of mitochondrial disorders, the fate of phenotypically affected muscle fibres remains largely unknown. We investigated PCD (programmed cell death) in muscle of 17 patients with mitochondrial respiratory chain dysfunction. We documented that in affected muscle fibres, nuclear chromatin is condensed in lumpy irregular masses and cytochrome c is released into the cytosol to activate, along with Apaf-1 (apoptotic protease-activating factor 1), caspase 9 that, in turn, activates effector caspase 3, caspase 6, and caspase 7, suggesting the execution of the intrinsic apoptotic pathway. Whereas active caspase 3 underwent nuclear translocation, AIF (apoptosis-inducing factor) mainly stayed within mitochondria, into which an up-regulated Bax is relocated. The significant increase in caspase 2, caspase 3 and caspase 6 activity strongly suggest that the cell death programme is caspase-dependent and the activation of caspase 2 together with PUMA (p53 up-regulated modulator of apoptosis) up-regulation point to a role for oxidative stress in triggering the intrinsic pathway. Concurrently, in muscle of patients, the number of satellite cells was significantly increased and myonuclei were detected at different stages of myogenic differentiation, indicating that a reparative programme is ongoing in muscle of patients with mitochondrial disorders. Together, these data suggest that, in patients with mitochondrial disorders, affected muscle fibres are trapped in a mitochondria-regulated caspase dependent PCD while repairing events take place. PMID- 26527740 TI - Membrane-anchored ubiquitin ligase complex is required for the turnover of lysosomal membrane proteins. AB - Cells must regulate the abundance and activity of numerous nutrient transporters in different organelle membranes to achieve nutrient homeostasis. As the recycling center and major storage organelle, lysosomes are essential for maintaining nutrient homeostasis. However, very little is known about mechanisms that govern the regulation of its membrane proteins. In this study, we demonstrated that changes of Zn(2+) levels trigger the downregulation of vacuolar Zn(2+) transporters. Low Zn(2+) levels cause the degradation of the influx transporter Cot1, whereas high Zn(2+) levels trigger the degradation of the efflux channel Zrt3. The degradation process depends on the vacuole membrane recycling and degradation pathway. Unexpectedly, we identified a RING domain containing E3 ligase Tul1 and its interacting proteins in the Dsc complex that are important for the ubiquitination of Cot1 and partial ubiquitination of Zrt3. Our study demonstrated that the Dsc complex can function at the vacuole to regulate the composition and lifetime of vacuolar membrane proteins. PMID- 26527741 TI - Modifiers of solid RNP granules control normal RNP dynamics and mRNA activity in early development. AB - Ribonucleoproteins (RNPs) often coassemble into supramolecular bodies with regulated dynamics. The factors controlling RNP bodies and connections to RNA regulation are unclear. During Caenorhabditis elegans oogenesis, cytoplasmic RNPs can transition among diffuse, liquid, and solid states linked to mRNA regulation. Loss of CGH-1/Ddx6 RNA helicase generates solid granules that are sensitive to mRNA regulators. Here, we identified 66 modifiers of RNP solids induced by cgh-1 mutation. A majority of genes promote or suppress normal RNP body assembly, dynamics, or metabolism. Surprisingly, polyadenylation factors promote RNP coassembly in vivo, suggesting new functions of poly(A) tail regulation in RNP dynamics. Many genes carry polyglutatmine (polyQ) motifs or modulate polyQ aggregation, indicating possible connections with neurodegenerative disorders induced by CAG/polyQ expansion. Several RNP body regulators repress translation of mRNA subsets, suggesting that mRNAs are repressed by multiple mechanisms. Collectively, these findings suggest new pathways of RNP modification that control large-scale coassembly and mRNA activity during development. PMID- 26527742 TI - GRHL2 coordinates regeneration of a polarized mucociliary epithelium from basal stem cells. AB - Pseudostratified airway epithelium of the lung is composed of polarized ciliated and secretory cells maintained by basal stem/progenitor cells. An important question is how lineage choice and differentiation are coordinated with apical basal polarity and epithelial morphogenesis. Our previous studies indicated a key integrative role for the transcription factor Grainyhead-like 2 (Grhl2). In this study, we present further evidence for this model using conditional gene deletion during the regeneration of airway epithelium and clonal organoid culture. We also use CRISPR/Cas9 genome editing in primary human basal cells differentiating into organoids and mucociliary epithelium in vitro. Loss of Grhl2 inhibits organoid morphogenesis and the differentiation of ciliated cells and reduces the expression of both notch and ciliogenesis genes (Mcidas, Rfx2, and Myb) with distinct Grhl2 regulatory sites. The genome editing of other putative target genes reveals roles for zinc finger transcription factor Znf750 and small membrane adhesion glycoprotein in promoting ciliogenesis and barrier function as part of a network of genes coordinately regulated by Grhl2. PMID- 26527743 TI - Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic gamma-actin levels. AB - Synaptic plasticity requires remodeling of the actin cytoskeleton. Although two actin isoforms, beta- and gamma-actin, are expressed in dendritic spines, the specific contribution of gamma-actin in the expression of synaptic plasticity is unknown. We show that synaptic gamma-actin levels are regulated by the E3 ubiquitin ligase TRIM3. TRIM3 protein and Actg1 transcript are colocalized in messenger ribonucleoprotein granules responsible for the dendritic targeting of messenger RNAs. TRIM3 polyubiquitylates gamma-actin, most likely cotranslationally at synaptic sites. Trim3(-/-) mice consequently have increased levels of gamma-actin at hippocampal synapses, resulting in higher spine densities, increased long-term potentiation, and enhanced short-term contextual fear memory consolidation. Interestingly, hippocampal deletion of Actg1 caused an increase in long-term fear memory. Collectively, our findings suggest that temporal control of gamma-actin levels by TRIM3 is required to regulate the timing of hippocampal plasticity. We propose a model in which TRIM3 regulates synaptic gamma-actin turnover and actin filament stability and thus forms a transient inhibitory constraint on the expression of hippocampal synaptic plasticity. PMID- 26527745 TI - Photoreceptor disc morphogenesis: The classical evagination model prevails. AB - Vision begins in photoreceptor outer segments with light captured by opsins in continually synthesized disc membranes. The process by which rod photoreceptor discs are formed has been controversial. In this issue, Ding et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201508093) show conclusively that rod discs are formed by plasma membrane evagination. PMID- 26527744 TI - TRIP13PCH-2 promotes Mad2 localization to unattached kinetochores in the spindle checkpoint response. AB - The spindle checkpoint acts during cell division to prevent aneuploidy, a hallmark of cancer. During checkpoint activation, Mad1 recruits Mad2 to kinetochores to generate a signal that delays anaphase onset. Yet, whether additional factors contribute to Mad2's kinetochore localization remains unclear. Here, we report that the conserved AAA+ ATPase TRIP13(PCH-2) localizes to unattached kinetochores and is required for spindle checkpoint activation in Caenorhabditis elegans. pch-2 mutants effectively localized Mad1 to unattached kinetochores, but Mad2 recruitment was significantly reduced. Furthermore, we show that the C. elegans orthologue of the Mad2 inhibitor p31(comet)(CMT-1) interacts with TRIP13(PCH-2) and is required for its localization to unattached kinetochores. These factors also genetically interact, as loss of p31(comet)(CMT 1) partially suppressed the requirement for TRIP13(PCH-2) in Mad2 localization and spindle checkpoint signaling. These data support a model in which the ability of TRIP13(PCH-2) to disassemble a p31(comet)/Mad2 complex, which has been well characterized in the context of checkpoint silencing, is also critical for spindle checkpoint activation. PMID- 26527746 TI - Discs of mammalian rod photoreceptors form through the membrane evagination mechanism. AB - Photoreceptor discs are membrane organelles harboring components of the visual signal transduction pathway. The mechanism by which discs form remains enigmatic and is the subject of a major controversy. Classical studies suggest that discs are formed as serial plasma membrane evaginations, whereas a recent alternative postulates that discs, at least in mammalian rods, are formed through intracellular vesicular fusion. We evaluated these models in mouse rods using methods that distinguish between the intracellular vesicular structures and plasma membrane folds independently of their appearance in electron micrographs. The first differentiated membranes exposed to the extracellular space from intracellular membranes; the second interrogated the orientation of protein molecules in new discs. Both approaches revealed that new discs are plasma membrane evaginations. We further demonstrated that vesiculation and plasma membrane enclosure at the site of new disc formation are artifacts of tissue fixation. These data indicate that all vertebrate photoreceptors use the evolutionary conserved membrane evagination mechanism to build their discs. PMID- 26527747 TI - Elevated Coexpression of KITENIN and the ErbB4 CYT-2 Isoform Promotes the Transition from Colon Adenoma to Carcinoma Following APC loss. AB - PURPOSE AND EXPERIMENTAL DESIGN: The molecular events in the malignant progression of colon adenoma after loss of adenomatous polyposis coli (APC) are not fully understood. KITENIN (KAI1 C-terminal interacting tetraspanin) increases the invasiveness of colorectal cancer cells, and we identified a novel EGFR independent oncogenic signal of EGF that works under coexpressed KITENIN and ErbB4. Here we tested whether elevated KITENIN and ErbB4 contribute to further progression of intestinal adenoma following APC loss. RESULTS: The intestinal tissues of villin-KITENIN transgenic mice in which villin-driven KITENIN expression induces increased c-Jun expression exhibit mild epithelial cell proliferation but no epithelial lineage changes compared with those of nontransgenic mice. Among the four ErbB4 isoforms, JM-a/CYT-2 and JM-b/CYT-2 exhibited the highest AP-1 activity when cells coexpressing KITENIN and each isoform were stimulated by EGF. Interestingly, predominant overexpression of the ErB4-CYT-2 mRNA as well as increased EGFR expression were observed in intestinal adenoma of APC(min/+) mice, which makes the microenvironment of activated EGF signaling. When we crossed villin-KITENIN mice with APC(min/+) mice, intestinal tumor tissues in the crossed mice showed the characteristics of early-stage invading adenocarcinoma. In patients with colorectal cancer, ErbB4-CYT-2 mRNA expression was significantly greater in tumor tissues than in normal adjacent tissues, but no significant differences in tumor tissue expression were found between different colorectal cancer stages. Furthermore, the mRNA expression of KITENIN and that of ErbB4-CYT-2 were positively correlated in human colorectal cancer tissue. CONCLUSIONS: Elevated coexpression of KITENIN and ErbB4-CYT-2 promotes the transition of colon adenoma to adenocarcinoma within an APC loss associated tumor microenvironment. PMID- 26527749 TI - Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling. AB - PURPOSE: Flightless I (FLII), member of the gelsolin superfamily of actin remodeling proteins, functions as a transcriptional coregulator. We aim to evaluate a tumor-suppressive function of FLII in regulating androgen receptor (AR) in prostate cancer progression. EXPERIMENTAL DESIGN: We examined FLII protein and mRNA expression in clinical prostate cancer specimens by immunohistochemistry. Kaplan-Meier analysis was conducted to evaluate the difference in disease-overall survival associated with the expression levels of FLII and AR. Prostate cancer cells stably expressing FLII or shRNA knockdown were used for functional analyses. Immunoprecipitation, Luciferase reporter, and immunofluorescence staining assays were performed to examine the functional interaction between FLII and AR. RESULTS: Our analysis of the expression levels of FLII in a clinical gene expression array dataset showed that the expression of FLII was positively correlated with the overall survival of prostate cancer patients exhibiting high levels of AR expression. Examination of protein and mRNA levels of FLII showed a significant decrease of FLII expression in human prostate cancers. AR and FLII formed a complex in a ligand-dependent manner through the ligand-binding domain (LBD) of AR. Subsequently, we observed a competitive binding to AR between FLII and the ligand. FLII inhibited AR transactivation and decreased AR nuclear localization. Furthermore, FLII contributed to castration sensitive and castration-resistant prostate cancer cell growth through AR dependent signaling, and reintroduction of FLII in prostate cancer cells sensitized the cells to bicalutamide and enzalutamide treatment. CONCLUSIONS: FLII plays a tumor-suppressive role and serves as a crucial determinant of resistance of prostate cancer to endocrine therapies. PMID- 26527750 TI - Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer. AB - PURPOSE: Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. EXPERIMENTAL DESIGN: In ARMOR1, 49 patients received increasing doses (650-2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700-3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. RESULTS: In ARMOR1, across all doses, 49.0% (24/49) achieved a >=30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a >=50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events. CONCLUSIONS: The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition. PMID- 26527748 TI - A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan Refractory Multiple Myeloma Cells. AB - PURPOSE: The onset of drug resistance is a major cause of treatment failure in multiple myeloma. Although increasing evidence is defining the role of miRNAs in mediating drug resistance, their potential activity as drug-sensitizing agents has not yet been investigated in multiple myeloma. EXPERIMENTAL DESIGN: Here we studied the potential utility of miR-221/222 inhibition in sensitizing refractory multiple myeloma cells to melphalan. RESULTS: miR-221/222 expression inversely correlated with melphalan sensitivity of multiple myeloma cells. Inhibition of miR-221/222 overcame melphalan resistance and triggered apoptosis of multiple myeloma cells in vitro, in the presence or absence of human bone marrow (BM) stromal cells. Decreased multiple myeloma cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ABC transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory multiple myeloma xenografts with systemic locked nucleic acid (LNA) inhibitors of miR-221 (LNA-i-miR-221) plus melphalan overcame drug resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice. CONCLUSIONS: Taken together, our findings provide the proof of concept that LNA-i-miR-221 can reverse melphalan resistance in preclinical models of multiple myeloma, providing the framework for clinical trials to overcome drug resistance, and improve patient outcome in multiple myeloma. PMID- 26527752 TI - Clinical Consensus Statement: Septoplasty with or without Inferior Turbinate Reduction. AB - OBJECTIVE: To develop a clinical consensus statement on septoplasty with or without inferior turbinate reduction. METHODS: An expert panel of otolaryngologists with no relevant conflicts of interest was assembled to represent general otolaryngology and relevant subspecialty societies. A working definition of septoplasty with or without inferior turbinate reduction and the scope of pertinent otolaryngologic practice were first established. Patients 18 years and older were defined as the targeted population of interest. A modified Delphi method was then used to distill expert opinion into clinical statements that met a standardized definition of consensus. RESULTS: The group defined nasal septoplasty as a surgical procedure designed to correct a deviated nasal septum for the purpose of improving nasal function, form, or both. After 2 iterative Delphi method surveys, 20 statements met the standardized definition of consensus, while 13 statements did not. The clinical statements were grouped into 8 categories for presentation and discussion: (1) definition and diagnosis, (2) imaging studies, (3) medical management prior to septoplasty, (4) perioperative management, (5) surgical considerations, (6) adjuvant procedures, (7) postoperative care, and (8) outcomes. CONCLUSION: This clinical consensus statement was developed by and for otolaryngologists and is intended to promote appropriate and, when possible, evidence-based care for patients undergoing septoplasty with or without inferior turbinate reduction. A complete definition of septoplasty with or without inferior turbinate reduction was first developed, and additional statements were subsequently produced and evaluated addressing diagnosis, medical management prior to septoplasty, and surgical considerations, as well as the appropriate role of perioperative, postoperative, and adjuvant procedures, in addition to outcomes. Additionally, a series of clinical statements were developed, such as "Computed tomography scan may not accurately demonstrate the degree of septal deviation," "Septoplasty can assist delivery of intranasal medications to the nasal cavity," "Endoscopy can be used to improve visualization of posterior-based septal deviation during septoplasty," and "Quilting sutures can obviate the need for nasal packing after septoplasty." It is anticipated that the application of these principles will result in decreased variations in the care of septoplasty patients and an increase in the quality of care. PMID- 26527753 TI - Re: "Symptom Resolution Rates of Posttraumatic versus Nontraumatic Benign Paroxysmal Positional Vertigo: A Systematic Review". PMID- 26527754 TI - Position of Styloid Process in Eagle's Syndrome. PMID- 26527755 TI - In Reply to: "Position of the Styloid Process in Eagle's Syndrome". PMID- 26527756 TI - Cycling with an amputation: A systematic review. AB - BACKGROUND: Cycling with any form of limb amputation has progressed from an activity of leisure or rehabilitation to elite level competition as part of the Paralympic Games programme. OBJECTIVE: While it is often proposed that research into sport with an amputation can be extremely limited, this study intended to identify the volume, type and historical strategy in this area. STUDY DESIGN: This study comprises a documented systematic literature review of cycling undertaken with any form of limb amputation. METHOD: This study used four online search engines to identify relevant peer-reviewed literature. These included SPORTDiscus, CINAHL, Scopus and MEDLINE. Google Scholar was also used as a secondary source. The initial results were then subjected to a set of pre-defined inclusion criteria. The resulting publications were then analysed for content and thematic commonality. RESULTS: The review identified 20 articles which met pre defined inclusion criteria. The identified peer-reviewed publications were dated from the period 2004 to 2014. CONCLUSIONS: Three clear themes emerged from the historical research. There was both a paucity of peer-reviewed literature with respect to cycling with an amputation and the design of adaptive or assistive technology to replace limb loss. However, publications have been rising substantially over the last 5 years. CLINICAL RELEVANCE: This review study established the historical strategy and content of cycling with an amputation and identified the existing research themes. This will assist in summarising the current level of knowledge and help signpost such work in the future. PMID- 26527757 TI - Successful management of iliocostal impingement syndrome: A case series. AB - BACKGROUND: Iliocostal impingement syndrome is a rare, painful, and disabling condition associated with thoracic hyperkyphosis and kyphoscoliosis. There is little published literature regarding management of this syndrome. The purpose of this case series is to report treatment outcomes for iliocostal impingement syndrome with improving posture and back muscle strength. CASE DESCRIPTION AND METHODS: Thirty-eight women with thoracic hyperkyphosis or kyphoscoliosis and back and/or flank pain were diagnosed with iliocostal impingement syndrome on the basis of symptoms and spine radiographs. They were instructed in weighted kypho orthosis use and taught a home back-extensor strengthening program. Outcome measures included posture evaluation and pain level. FINDINGS AND OUTCOMES: All patients reported immediate pain reduction with weighted kypho-orthosis trial. Nineteen patients returned within 2 years, and all had continued pain relief and posture improvement. CONCLUSIONS: Our findings suggest that successful management of iliocostal impingement syndrome is possible with a weighted kypho-orthosis and back strengthening program focusing on posture improvement. CLINICAL RELEVANCE: Iliocostal syndrome is a rare, painful, and disabling condition that severely affects quality of life. This report discusses our diagnostic and treatment approach to this syndrome, which has proven successful in our patient population. PMID- 26527758 TI - Marker-based method to measure movement between the residual limb and a transtibial prosthetic socket. AB - BACKGROUND: Limb movement between the residuum and socket continues to be an underlying factor in limb health, prosthetic comfort, and gait performance yet techniques to measure this have been underdeveloped. OBJECTIVES: Develop a method to measure motion between the residual limb and a transtibial prosthetic socket. STUDY DESIGN: Single subject, repeated measures with mathematical modeling. METHODS: The gait of a participant with transtibial amputation was recorded using a motion capture system using a marker set that included arrays on the anterior distal tibia and the lateral epicondyle of the femur. The proximal or distal translation, anterior or posterior translation, and angular movements were quantified. A random Monte Carlo simulation based on the precision of the motion capture system and a model of the bone moving under the skin explored the technique's accuracy. Residual limb tissue stiffness was modeled as a linear spring based on data from Papaioannou et al. RESULTS: Residuum movement relative to the socket went through ~30 mm, 18 mm, and 15 degrees range of motion. Root mean squared errors were 5.47 mm, 1.86 mm, and 0.75 degrees when considering the modeled bone-skin movement in the proximal or distal, anterior or posterior, and angular directions, respectively. CONCLUSION: The measured movement was greater than the root mean squared error, indicating that this method can measure motion between the residuum and socket. CLINICAL RELEVANCE: The ability to quantify movement between the residual limb and the prosthetic socket will improve prosthetic treatment through the evaluation of different prosthetic suspensions, socket designs, and motor control of the prosthetic interface. PMID- 26527759 TI - Preparation of Urogenital Sinus Mesenchymal Cells for Prostate Tissue Recombination Models. AB - An appropriate microenvironment provided by the mesenchyme is important for establishing tissue recombination models for epithelial cancer. Urogenital sinus mesenchymal (UGSM) cells derived from embryonic rodent show potent inductive effects for prostate regeneration. Genetic manipulation of these mesenchymal cells allows us to define the contribution of the tumor microenvironment to prostate cancer development. This protocol describes preparation and propagation of murine UGSM cells in culture. PMID- 26527760 TI - Dissociated Prostate Regeneration under the Renal Capsule. AB - Tissue recombination models are useful for studying cancer initiation, progression, and metastasis. They also provide an in vivo environment in which to investigate the functional role of stem cells in tissue repair. In this protocol, we describe in detail the dissociated prostate regeneration assay. Dissociated adult murine prostate cells are combined with embryonic urogenital sinus mesenchymal cells and implanted under the renal capsule. Morphological tissue structures with appropriate epithelial-stroma interactions are reconstituted in the grafts. PMID- 26527761 TI - Homogenization of Mammalian Cells. AB - Homogenization is the name given to the methodological steps necessary for releasing organelles and other cellular constituents as a free suspension of intact individual components. Most homogenization procedures used for mammalian cells (e.g., cavitation pump and Dounce homogenizer) rely on mechanical force to break the plasma membrane and may be supplemented with osmotic or temperature alterations to facilitate membrane disruption. In this protocol, we describe a syringe-based homogenization method that does not require specialized equipment, is easy to handle, and gives reproducible results. The method may be adapted for cells that require hypotonic shock before homogenization. We routinely use it as part of our workflow to isolate endocytic organelles from mammalian cells. PMID- 26527762 TI - Isolation of Early and Late Endosomes by Density Gradient Centrifugation. AB - Density gradient centrifugation is a common method for separating intracellular organelles. During centrifugation, organelles float or sediment until they reach their isopycnic position within the gradient. The density of an organelle depends on its content, size, shape, and the lipid:protein ratio. The degree of separation between different organelles will therefore be highly dependent on how different their isopycnic points are in a given buffer. Separation will also depend on the medium used to prepare the gradient, whether it is sucrose (the most common) or an alternative. Here we describe the use of both continuous and discontinuous (step) gradients to isolate endocytic organelles. PMID- 26527763 TI - Analysis of Yeast Sporulation Efficiency, Spore Viability, and Meiotic Recombination on Solid Medium. AB - Under conditions of nutrient deprivation, yeast cells initiate a differentiation program in which meiosis is induced and spores are formed. During meiosis, one round of genome duplication is followed by two rounds of chromosome segregation (meiosis I and meiosis II) to generate four haploid nuclei. Meiotic recombination occurs during prophase I. During sporogenesis, each nucleus becomes surrounded by an individual spore wall, and all four haploid spores become contained as a tetrad within an ascus. Important insights into the meiotic function(s) of a gene of interest can be gained by observing the effects of gene mutations on spore viability and viability patterns among tetrads. Moreover, recombination frequencies among viable spores can reveal potential involvement of the gene during meiotic exchange between homologous chromosomes. Here, we describe methods for inducing spore formation on solid medium, determining spore viability, and measuring, via tetrad analysis, frequencies of crossing over and gene conversion as indicators of meiotic chromosome exchange. PMID- 26527764 TI - Quantification of Lysosomal Membrane Permeabilization by Cytosolic Cathepsin and beta-N-Acetyl-Glucosaminidase Activity Measurements. AB - Programmed cell death involving lysosomal membrane permeabilization (LMP) is an alternative cell death pathway induced under various cellular conditions and by numerous cytotoxic stimuli. The method presented here to quantify LMP takes advantage of the detergent digitonin, which creates pores in cellular membranes by replacing cholesterol. The difference in cholesterol content between the plasma membrane (high) and lysosomal membrane (low) allows titration of digitonin to a concentration that permeabilizes the plasma membrane but leaves lysosomal membranes intact. The extent of LMP is determined by measuring the cytosolic activity of lysosomal hydrolases (e.g., cysteine cathepsins) and/or beta-N-acetyl glucosaminidase in the digitonin-extracted cytoplasm and comparing it to the total cellular enzyme activity. Digitonin extraction of the cytosol can be combined with precipitation of protein and/or western blot analysis for detection of lysosomal proteins (e.g., cathepsins). PMID- 26527765 TI - Assembling the MUs-ALEX Setup. AB - This protocol describes the construction of a microsecond-alternating laser excitation (MUs-ALEX) using two lasers, a green 532-nm acousto-optically modulated laser and a red 635-nm directly modulated laser. PMID- 26527766 TI - Aligning the MUs-ALEX Setup. AB - To achieve single-molecule sensitivity and thus have the ability to detect single diffusing fluorophores, careful alignment of the microsecond-alternating laser excitation (MUs-Alex) setup is crucial. The following protocol describes routine alignment for 2c-ALEX (532 nm/635 nm) with spectral windows G(550-620)R(650-750). PMID- 26527767 TI - Sample Preparation and Data Acquisition for MUs-ALEX. AB - This protocol describes the preparation of samples and data acquisition for microsecond-alternating laser excitation. Sample preparation requires a dilution that ensures the detection of single events. PMID- 26527768 TI - Voltage-Sensitive Dye Imaging of Population Signals in Brain Slices. AB - In a bright-field measurement from a vertebrate brain stained by superfusing a solution of the dye over the surface, each pixel in a camera receives light from a substantial number (thousands) of neurons and neuronal processes (population signals). Because of scattering and out-of-focus light, this will be true even if the pixel size corresponds to a small area of the brain. In this situation, the voltage-sensitive dye signal will be a population average of the change in membrane potential of all of these neurons and processes. Many investigators have published voltage-sensitive dye imaging studies of population activities in brain slices. Their methods, including choice of dyes, illumination intensity, and imaging device, vary across a large spectrum. Here we present a protocol for visualizing spatiotemporal patterns in rodent neocortex in vitro. Detecting these patterns requires high-sensitivity imaging in single trials, because averaging will obscure the complex dynamics of the spatiotemporal patterns. PMID- 26527769 TI - In Vivo Voltage-Sensitive Dye Imaging of Mammalian Cortex Using "Blue" Dyes. AB - Optical recording of membrane potential allows simultaneous measurements to be taken from many different locations in the nervous system. This is important in studies of the nervous system in which simultaneous activity can occur at the regional, cellular, and subcellular levels. New "blue" dyes, developed by Amiram Grinvald's group, are a great advance for in vivo voltage-sensitive dye imaging of mammalian cortex. The blue dyes are excited by red light (630 nm) that does not overlap with light absorption of hemoglobin (510-590 nm). This virtually eliminates the heart pulsation artifact. PMID- 26527770 TI - Methods for Probing Lysosomal Membrane Permeabilization. AB - Cell death triggered by lysosomal membrane permeabilization (LMP) is gaining increased interest as target for cancer therapy, but the death pathway also plays an important role in normal physiology (e.g., during involution of the mammary gland). LMP-induced cell death is triggered by release of hydrolases including cysteine cathepsin proteases from the lysosomal lumen into the cytosol. Limited release of proteases to the cytoplasm induces apoptosis or apoptosis-like cell death, whereas massive LMP results in rapid cellular necrosis. Here we introduce three complementary methods for quantifying and visualizing LMP: (i) monitoring LMP by immunocytochemistry, (ii) visualizing LMP by fluorescent dextran release, and (iii) quantification of LMP by activity measurements of lysosomal enzymes in digitonin-extracted cytosol. PMID- 26527771 TI - Analysis of Recombination and Chromosome Structure during Yeast Meiosis. AB - Meiosis is a diploid-specific differentiation program that consists of a single round of genome duplication followed by two rounds of chromosome segregation. These events result in halving of the genetic complement, which is a requirement for formation of haploid reproductive cells (i.e., spores in yeast and gametes in animals and plants). During meiosis I, homologous maternal and paternal chromosomes (homologs) pair and separate, whereas sister chromatids remain connected at the centromeres and separate during the second meiotic division. In most organisms, accurate homolog disjunction requires crossovers, which are formed as products of meiotic recombination. For the past two decades, studies of yeast meiosis have provided invaluable insights into evolutionarily conserved mechanisms of meiosis. PMID- 26527772 TI - Alternating Laser Excitation for Solution-Based Single-Molecule FRET. AB - Single-molecule fluorescence resonance energy transfer (smFRET) has been widely applied to the study of fluorescently labeled biomolecules on surfaces and in solution. Sorting single molecules based on fluorescent dye stoichiometry provides one with further layers of information and also enables "filtering" of unwanted molecules from the analysis. We accomplish this sorting by using alternating laser excitation (ALEX) in combination with smFRET measurements; here we describe the implementation of these methodologies for the study of biomolecules in solution. PMID- 26527773 TI - Changing guards: time to move beyond body mass index for population monitoring of excess adiposity. AB - With the obesity epidemic, and the effects of aging populations, human phenotypes have changed over two generations, possibly more dramatically than in other species previously. As obesity is an important and growing hazard for population health, we recommend a systematic evaluation of the optimal measure(s) for population-level excess body fat. Ideal measure(s) for monitoring body composition and obesity should be simple, as accurate and sensitive as possible, and provide good categorization of related health risks. Combinations of anthropometric markers or predictive equations may facilitate better use of anthropometric data than single measures to estimate body composition for populations. Here, we provide new evidence that increasing proportions of aging populations are at high health-risk according to waist circumference, but not body mass index (BMI), so continued use of BMI as the principal population-level measure substantially underestimates the health-burden from excess adiposity. PMID- 26527774 TI - Acute Toxicity and Quality of Life After Dose-Intensified Salvage Radiation Therapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: First Results of the Randomized Trial SAKK 09/10. AB - PURPOSE: Patients with biochemical failure (BF) after radical prostatectomy may benefit from dose-intensified salvage radiation therapy (SRT) of the prostate bed. We performed a randomized phase III trial assessing dose intensification. PATIENTS AND METHODS: Patients with BF but without evidence of macroscopic disease were randomly assigned to either 64 or 70 Gy. Three-dimensional conformal radiation therapy or intensity-modulated radiation therapy/rotational techniques were used. The primary end point was freedom from BF. Secondary end points were acute toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) and quality of life (QoL) according to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and PR25. RESULTS: Three hundred fifty patients were enrolled between February 2011 and April 2014. Three patients withdrew informed consent, and three patients were not eligible, resulting in 344 patients age 48 to 75 years in the safety population. Thirty patients (8.7%) had grade 2 and two patients (0.6%) had grade 3 genitourinary (GU) baseline symptoms. Acute grade 2 and 3 GU toxicity was observed in 22 patients (13.0%) and one patient (0.6%), respectively, with 64 Gy and in 29 patients (16.6%) and three patients (1.7%), respectively, with 70 Gy (P = .2). Baseline grade 2 GI toxicity was observed in one patient (0.6%). Acute grade 2 and 3 GI toxicity was observed in 27 patients (16.0%) and one patient (0.6%), respectively, with 64 Gy, and in 27 patients (15.4%) and four patients (2.3%), respectively, with 70 Gy (P = .8). Changes in early QoL were minor. Patients receiving 70 Gy reported a more pronounced and clinically relevant worsening in urinary symptoms (mean difference in change score between arms, 3.6; P = .02). CONCLUSION: Dose-intensified SRT was associated with low rates of acute grade 2 and 3 GU and GI toxicity. The impact of dose-intensified SRT on QoL was minor, except for a significantly greater worsening in urinary symptoms. PMID- 26527775 TI - Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib. AB - PURPOSE: Dual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (pCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features. PATIENTS AND METHODS: Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was pCR in the breast; correlative end points focused on molecular features identified by gene expression-based assays. RESULTS: Among 305 randomly assigned patients (THL, n = 118; TH, n = 120; TL, n = 67), the pCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P = .13), with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in pCR with dual therapy in those with hormone receptor negative disease (P = .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). pCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P < .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with pCR. Post-treatment residual disease was largely luminal A (69%). CONCLUSION: pCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pCR rates. These factors should be considered when interpreting and designing trials in HER2-positive disease. PMID- 26527776 TI - Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. AB - PURPOSE: The MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation. METHODS: Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens. RESULTS: After a median follow-up of 9.5 years, 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX4) arms were 67.1% versus 71.7% (hazard ratio [HR], 0.85; P = .043) in the whole population, 79.5% versus 78.4% for stage II (HR, 1.00; P = .980), and 59.0% versus 67.1% for stage III (HR, 0.80; P = .016) disease. Ninety five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR and 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation. CONCLUSION: The OS benefit of oxaliplatin-based adjuvant chemotherapy, increasing over time and with the disease severity, was confirmed at 10 years in patients with stage II to III colon cancer. These updated results support the use of FOLFOX in patients with stage III disease, including those with dMMR or BRAF mutation. PMID- 26527777 TI - Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer. AB - PURPOSE: Sonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models. PATIENTS AND METHODS: Patients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score >= 80 were enrolled. Patients were randomly assigned in a one to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (Kras(G12D); p16/p19(fl/fl); Pdx1-Cre and Kras(G12D); p53(R270H/wt); Pdx1-Cre) were studied. RESULTS: No safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model. CONCLUSION: The addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant differences with respect to drug delivery or treatment efficacy using vismodegib. PMID- 26527778 TI - Barriers to a Career Focus in Cancer Prevention: A Report and Initial Recommendations From the American Society of Clinical Oncology Cancer Prevention Workforce Pipeline Work Group. AB - PURPOSE: To assist in determining barriers to an oncology career incorporating cancer prevention, the American Society of Clinical Oncology (ASCO) Cancer Prevention Workforce Pipeline Work Group sponsored surveys of training program directors and oncology fellows. METHODS: Separate surveys with parallel questions were administered to training program directors at their fall 2013 retreat and to oncology fellows as part of their February 2014 in-training examination survey. Forty-seven (67%) of 70 training directors and 1,306 (80%) of 1,634 oncology fellows taking the in-training examination survey answered questions. RESULTS: Training directors estimated that <= 10% of fellows starting an academic career or entering private practice would have a career focus in cancer prevention. Only 15% of fellows indicated they would likely be interested in cancer prevention as a career focus, although only 12% thought prevention was unimportant relative to treatment. Top fellow-listed barriers to an academic career were difficulty in obtaining funding and lower compensation. Additional barriers to an academic career with a prevention focus included unclear career model, lack of clinical mentors, lack of clinical training opportunities, and concerns about reimbursement. CONCLUSION: Reluctance to incorporate cancer prevention into an oncology career seems to stem from lack of mentors and exposure during training, unclear career path, and uncertainty regarding reimbursement. Suggested approaches to begin to remedy this problem include: 1) more ASCO-led and other prevention educational resources for fellows, training directors, and practicing oncologists; 2) an increase in funded training and clinical research opportunities, including reintroduction of the R25T award; 3) an increase in the prevention content of accrediting examinations for clinical oncologists; and 4) interaction with policymakers to broaden the scope and depth of reimbursement for prevention counseling and intervention services. PMID- 26527779 TI - Female Estrogen-Related Factors and Incidence of Basal Cell Carcinoma in a Nationwide US Cohort. AB - PURPOSE: UV radiation exposure is the primary risk factor for basal cell carcinoma (BCC), the most common human malignancy. Although the photosensitizing properties of estrogens have been recognized for decades, few studies have examined the relationship between reproductive factors or exogenous estrogen use and BCC. METHODS: Using data from the US Radiologic Technologists Study, a large, nationwide, prospective cohort, we assessed the relationship between reproductive factors, exogenous estrogen use, and first primary BCC while accounting for sun exposure, personal sun sensitivity, and lifestyle factors for geographically dispersed women exposed to a wide range of ambient UV radiation. RESULTS: Elevated risk of BCC was associated with late age at natural menopause (hazard ratio [HR] for >= 55 years v 50 to 54 years, 1.50; 95% CI, 1.04 to 2.17) and any use of menopausal hormone therapy (MHT; HR, 1.16; 95% CI, 1.03 to 1.30; P for trend for duration = .001). BCC risk was most increased among women reporting natural menopause who used MHT for 10 or more years versus women who never used MHT (HR, 1.97; 95% CI, 1.35 to 2.87). Risk of BCC was not associated with age at menarche, parity, age at first birth, infertility, use of diethylstilbestrol by participant's mother, age at hysterectomy, or use of oral contraceptives. CONCLUSION: These analyses confirm a previous finding of increased risk of BCC associated with MHT. Novel findings of increased BCC risk associated with MHT in women experiencing natural menopause and for late age at natural menopause warrant further investigation. Users of MHT may constitute an additional high risk group in need of more frequent skin cancer screening. PMID- 26527780 TI - Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. AB - PURPOSE: Long-term survival rates for older patients with newly diagnosed acute myeloid leukemia (AML) are extremely low. Previous observational studies suggest that allogeneic hematopoietic stem-cell transplantation (HSCT) may improve overall survival (OS) because of lower rates of relapse. We sought to prospectively determine the value of HSCT for older patients with AML in first complete remission. PATIENTS AND METHODS: We conducted a prospective multicenter phase II study to assess the efficacy of reduced-intensity conditioning HSCT for patients between the ages of 60 and 74 years with AML in first complete remission. The primary end point was disease-free survival at 2 years after HSCT. Secondary end points included nonrelapse mortality (NRM), graft-versus-host disease (GVHD), relapse, and OS. RESULTS: In all, 114 patients with a median age of 65 years received transplantations. The majority (52%) received transplantations from unrelated donors and were given antithymocyte globulin for GVHD prophylaxis. Disease-free survival and OS at 2 years after transplantation were 42% (95% CI, 33% to 52%) and 48% (95% CI, 39% to 58%), respectively, for the entire group and 40% (95% CI, 29% to 55%) and 50% (95% CI, 38% to 64%) for the unrelated donor group. NRM at 2 years was 15% (95% CI, 8% to 21%). Grade 2 to 4 acute GVHD occurred in 9.6% (95% CI, 4% to 15%) of patients, and chronic GVHD occurred in 28% (95% CI, 19% to 36%) of patients. The cumulative incidence of relapse at 2 years was 44% (95% CI, 35% to 53%). CONCLUSION: Reduced-intensity conditioning HSCT to maintain remission in selected older patients with AML is relatively well tolerated and appears to provide superior outcomes when compared with historical patients treated without HSCT. GVHD and NRM rates were lower than expected. Future transplantation studies in these patients should focus on further reducing the risk of relapse. PMID- 26527781 TI - Double-Blind Phase III Randomized Trial of the Antiprogestin Agent Mifepristone in the Treatment of Unresectable Meningioma: SWOG S9005. AB - PURPOSE: Progesterone receptors are expressed in approximately 70% of meningiomas. Mifepristone is an oral antiprogestational agent reported to have modest activity in a phase II study. This multicenter, prospective, randomized, placebo-controlled phase III trial conducted by SWOG was planned to define the role of mifepristone in the treatment of unresectable meningioma. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive either mifepristone or placebo for 2 years unless disease progressed. Patients who were stable or responding to protocol therapy after 2 years had the option to continue with the same blinded therapy. Serial follow-up allowed assessment of efficacy and toxicity. Time to treatment failure and overall survival were ascertained for all randomly assigned patients. On progression, patients receiving placebo could cross over and receive active drug. RESULTS: Among 164 eligible patients, 80 were randomly assigned to mifepristone and 84 to placebo. Twenty-four patients (30%) were able to complete 2 years of mifepristone without disease progression, adverse effects, or other reasons for discontinuation. Twenty-eight patients (33%) in the placebo arm completed the 2-year study. There was no statistical difference between the arms in terms of failure-free or overall survival. CONCLUSION: Long-term administration of mifepristone was well tolerated but had no impact on patients with unresectable meningioma. PMID- 26527782 TI - Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial. AB - PURPOSE: Three years of adjuvant imatinib therapy are recommended for patients with GI stromal tumor (GIST) with high-risk features, according to survival findings in the Scandinavian Sarcoma Group XVIII/AIO (Arbeitsgemeinschaft Internistische Onkologie) trial. To investigate whether the survival benefits have persisted, we performed the second planned analysis of the trial. PATIENTS AND METHODS: Eligible patients had macroscopically completely excised, KIT positive GIST with a high risk of recurrence, as determined by using the modified National Institutes of Health criteria. After surgery, the patients were randomly assigned to receive imatinib for either 1 or 3 years. The primary objective was recurrence-free survival (RFS), and the secondary objectives included survival. RESULTS: A total of 400 patients were entered onto this open-label study between February 4, 2004, and September 29, 2008. During a median follow-up of 90 months, 171 recurrences and 69 deaths were detected. Patients assigned to the 3-year group had longer RFS than those assigned to the 1- year group; 5-year RFS was 71.1% versus 52.3%, respectively (hazard ratio [HR], 0.60; 95% CI 0.44 to 0.81; P < .001), and survival was 91.9% versus 85.3% (HR, 0.60; 95% CI, 0.37 to 0.97; P = .036). Patients in the 3-year group survived longer in the subset with centrally confirmed GIST and without macroscopic metastases at study entry (93.4% v 86.8%; HR, 0.53; 95% CI, 0.30 to 0.93; P = .024). Similar numbers of cardiac events and second cancers were recorded in the groups. CONCLUSION: Three years of adjuvant imatinib therapy results in longer survival than 1 year of imatinib. High 5-year survival rates are achievable in patient populations with high-risk GIST. PMID- 26527783 TI - Reply to A. Fiorentino et al. PMID- 26527784 TI - Antiemetics: American Society of Clinical Oncology Focused Guideline Update. AB - PURPOSE: To update a key recommendation of the American Society of Clinical Oncology antiemetic guideline. This update addresses the use of the oral combination of netupitant (a neurokinin 1 [NK1] receptor antagonist) and palonosetron (a 5-hydroxytryptamine-3 [5-HT3] receptor antagonist) for the prevention of acute and delayed nausea and vomiting in patients receiving chemotherapy. METHODS: An update committee conducted a targeted systematic literature review and identified two phase III clinical trials and a randomized phase II dose-ranging study. RESULTS: In one phase III trial, the oral combination of netupitant and palonosetron was associated with higher complete response rates (no emesis and no rescue medications) compared with palonosetron alone in patients treated with anthracycline plus cyclophosphamide chemotherapy (74% v 67% overall; P = .001). In another phase III trial, the oral combination of netupitant and palonosetron was safe and effective across multiple cycles of moderately or highly emetogenic chemotherapies. In the phase II dose-ranging study, each dose of netupitant (coadministered with palonosetron 0.50 mg) produced higher complete response rates than palonosetron alone among patients receiving cisplatin-based chemotherapy. The highest dose of netupitant (ie, 300 mg) was most effective. RECOMMENDATIONS: All patients who receive highly emetogenic chemotherapy regimens (including anthracycline plus cyclophosphamide) should be offered a three-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone. The oral combination of netupitant and palonosetron plus dexamethasone is an additional treatment option in this setting. The remaining recommendations from the 2011 ASCO guideline are unchanged pending a full update. Additional information is available at www.asco.org/guidelines/antiemetics and www.asco.org/guidelineswiki. PMID- 26527785 TI - Cognitive Function in Patients With Colorectal Cancer Who Do and Do Not Receive Chemotherapy: A Prospective, Longitudinal, Controlled Study. AB - PURPOSE: Cognitive dysfunction is reported in people with cancer. Therefore, we evaluated longitudinal changes in cognitive function and underlying mechanisms in people with colorectal cancer (CRC) and healthy controls (HCs). PATIENTS AND METHODS: Participants completed cognitive assessments and questionnaires reporting cognitive symptoms, fatigue, quality of life, and anxiety/depression at baseline (before chemotherapy, if given) and 6, 12, and 24 months. Blood tests included cytokines, clotting factors, apolipoprotein E genotype, and sex hormones. Primary end point was overall cognitive function measured by the Global Deficit Score at 12 months. RESULTS: We recruited 289 patients with localized CRC (173 received chemotherapy; median age, 59 years; 63% male), 73 patients with limited metastatic/recurrent CRC, and 72 HCs. Cognitive impairment was more frequent in patients with localized CRC than HCs at baseline (43% v 15%, respectively; P < .001) and 12 months (46% v 13%, respectively; P < .001), with no significant effect of chemotherapy. Attention/working memory, verbal learning/memory, and complex processing speed were most affected. Cognitive impairment was similar in patients with localized and metastatic CRC. Cytokine levels were elevated in patients with CRC compared with HCs. There was no association between overall cognitive function and fatigue, quality of life, anxiety/depression, or any blood test. Cognitive symptoms at 12 months were reported in 25% of patients with localized CRC versus 17% of HCs (P = .19). More participants who received chemotherapy had cognitive symptoms at 6 months (32%) versus those who did not (16%; P = .007), with no significant difference at 12 months (29% v 21%, respectively; P = .19). Objective cognitive function was only weakly associated with cognitive symptoms. CONCLUSION: Patients with CRC had substantially more cognitive impairment at every assessment than HCs, with no significant added effect of chemotherapy. Mechanisms of cognitive impairment remain unknown. PMID- 26527786 TI - Cerebral Perfusion and Gray Matter Changes Associated With Chemotherapy-Induced Peripheral Neuropathy. AB - PURPOSE: To investigate the longitudinal relationship between chemotherapy induced peripheral neuropathy (CIPN) symptoms (sx) and brain perfusion changes in patients with breast cancer. Interaction of CIPN-sx perfusion effects with known chemotherapy-associated gray matter density decrease was also assessed to elucidate the relationship between CIPN and previously reported cancer treatment related brain structural changes. METHODS: Patients with breast cancer treated with (n = 24) or without (n = 23) chemotherapy underwent clinical examination and brain magnetic resonance imaging at the following three time points: before treatment (baseline), 1 month after treatment completion, and 1 year after the 1 month assessment. CIPN-sx were evaluated with the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity four-item sensory-specific scale. Perfusion and gray matter density were assessed using voxel-based pulsed arterial spin labeling and morphometric analyses and tested for association with CIPN-sx in the patients who received chemotherapy. RESULTS: Patients who received chemotherapy reported significantly increased CIPN-sx from baseline to 1 month, with partial recovery by 1 year (P < .001). CIPN-sx increase from baseline to 1 month was significantly greater for patients who received chemotherapy compared with those who did not (P = .001). At 1 month, neuroimaging showed that for the group that received chemotherapy, CIPN-sx were positively associated with cerebral perfusion in the right superior frontal gyrus and cingulate gyrus, regions associated with pain processing (P < .001). Longitudinal magnetic resonance imaging analysis in the group receiving chemotherapy indicated that CIPN-sx and associated perfusion changes from baseline to 1 month were also positively correlated with gray matter density change (P < .005). CONCLUSION: Peripheral neuropathy symptoms after systemic chemotherapy for breast cancer are associated with changes in cerebral perfusion and gray matter. The specific mechanisms warrant further investigation given the potential diagnostic and therapeutic implications. PMID- 26527787 TI - Personalized--Not Omitted--Radiation Oncology for Breast Cancer. PMID- 26527788 TI - Randomized Comparison of Surveillance Intervals in Familial Colorectal Cancer. AB - PURPOSE: Colonoscopic surveillance is recommended for individuals with familial colorectal cancer (CRC). However, the appropriate screening interval has not yet been determined. The aim of this randomized trial was to compare a 3-year with a 6-year screening interval. PATIENTS AND METHODS: Individuals between ages 45 and 65 years with one first-degree relative with CRC age < 50 years or two first degree relatives with CRC were selected. Patients with zero to two adenomas at baseline were randomly assigned to one of two groups: group A (colonoscopy at 6 years) or group B (colonoscopy at 3 and 6 years). The primary outcome measure was advanced adenomatous polyps (AAPs). Risk factors studied included sex, age, type of family history, and baseline endoscopic findings. RESULTS: A total of 528 patients were randomly assigned (group A, n = 262; group B, n = 266). Intention to-treat analysis showed no significant difference in the proportion of patients with AAPs at the first follow-up examination at 6 years in group A (6.9%) versus 3 years in group B (3.5%). Also, the proportion of patients with AAPs at the final follow-up examination at 6 years in group A (6.9%) versus 6 years in group B (3.4%) was not significantly different. Only AAPs at baseline was a significant predictor for the presence of AAPs at first follow-up. After correction for the difference in AAPs at baseline, differences between the groups in the rate of AAPs at first follow-up and at the final examination were statistically significant. CONCLUSION: In view of the relatively low rate of AAPs at 6 years and the absence of CRC in group A, we consider a 6-year surveillance interval appropriate. A surveillance interval of 3 years might be considered in patients with AAPs and patients with >= three adenomas. PMID- 26527789 TI - Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). AB - PURPOSE: Concurrent chemoradiotherapy with or without surgery are options for stage IIIA(N2) non-small-cell lung cancer. Our previous phase II study had shown the efficacy of induction chemotherapy followed by chemoradiotherapy and surgery in patients with IIIA(N2) disease and with selected IIIB disease. Here, we compared surgery with definitive chemoradiotherapy in resectable stage III disease after induction. PATIENTS AND METHODS: Patients with pathologically proven IIIA(N2) and selected patients with IIIB disease that had medical/functional operability received induction chemotherapy, which consisted of three cycles of cisplatin 50 mg/m(2) on days 1 and 8 and paclitaxel 175 mg/m(2) on day 1 every 21 days, as well as concurrent chemoradiotherapy to 45 Gy given as 1.5 Gy twice daily, concurrent cisplatin 50 mg/m(2) on days 2 and 9, and concurrent vinorelbine 20 mg/m(2) on days 2 and 9. Those patients whose tumors were reevaluated and deemed resectable in the last week of radiotherapy were randomly assigned to receive a chemoradiotherapy boost that was risk adapted to between 65 and 71 Gy in arm A or to undergo surgery (arm B). The primary end point was overall survival (OS). RESULTS: After 246 of 500 planned patients were enrolled, the trial was closed after the second scheduled interim analysis because of slow accrual and the end of funding, which left the study underpowered relative to its primary study end point. Seventy-five patients had stage IIIA disease and 171 had stage IIIB disease according to the Union for International Cancer Control TNM classification, sixth edition. The median age was 59 years (range, 33 to 74 years). After induction, 161 (65.4%) of 246 patients with resectable tumors were randomly assigned; strata were tumor-node group, prophylactic cranial irradiation policy, and region. Patient characteristics were balanced between arms, in which 81 were assigned to surgery and 80 were assigned to a chemoradiotherapy boost. In arm B, 81% underwent R0 resection. With a median follow-up after random assignment of 78 months, 5-year OS and progression-free survival (PFS) did not differ between arms. Results were OS rates of 44% for arm B and 40% for arm A (log-rank P = .34) and PFS rates of 32% for arm B and 35% for arm A (log-rank P = .75). OS at 5 years was 34.1% (95% CI, 27.6% to 40.8%) in all 246 patients, and 216 patients (87.8%) received definitive local treatment. CONCLUSION: The 5-year OS and PFS rates in randomly assigned patients with resectable stage III non-small-cell lung cancer were excellent with both treatments. Both are acceptable strategies for this good-prognosis group. PMID- 26527790 TI - Postoperative Adjuvant Lapatinib and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib Monotherapy in High-Risk Patients With Resected Squamous Cell Carcinoma of the Head and Neck: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study. AB - PURPOSE: This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with resected stage II to IVA SCCHN, with a surgical margin <= 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m(2) per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy. RESULTS: Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342). With a median follow-up time of 35.3 months, the study ended early because of the apparent plateauing of disease-free survival (DFS) events. Median DFS assessed by an independent review committee was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95% CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee assessment. No significant differences in DFS by human papillomavirus status or overall survival were observed between treatment arms. Similar numbers of patients in both treatment arms experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-related AEs were diarrhea and rash, both predominantly in the lapatinib arm. CONCLUSION: Addition of lapatinib to chemoradiotherapy and its use as long term maintenance therapy does not offer any efficacy benefits and had additional toxicity compared with placebo in patients with surgically treated high-risk SCCHN. PMID- 26527791 TI - Complete kinetic mechanism for recycling of the bacterial ribosome. AB - How EF-G and RRF act together to split a post-termination ribosomal complex into its subunits has remained obscure. Here, using stopped-flow experiments with Rayleigh light scattering detection and quench-flow experiments with radio detection of GTP hydrolysis, we have clarified the kinetic mechanism of ribosome recycling and obtained precise estimates of its kinetic parameters. Ribosome splitting requires that EF-G binds to an already RRF-containing ribosome. EF-G binding to RRF-free ribosomes induces futile rounds of GTP hydrolysis and inhibits ribosome splitting, implying that while RRF is purely an activator of recycling, EF-G acts as both activator and competitive inhibitor of RRF in recycling of the post-termination ribosome. The ribosome splitting rate and the number of GTPs consumed per splitting event depend strongly on the free concentrations of EF-G and RRF. The maximal recycling rate, here estimated as 25 sec(-1), is approached at very high concentrations of EF-G and RRF with RRF in high excess over EF-G. The present in vitro results, suggesting an in vivo ribosome recycling rate of ~5 sec(-1), are discussed in the perspective of rapidly growing bacterial cells. PMID- 26527792 TI - The Impact of Inter-Kernel Movement in the Evolution of Resistance to Dual-Toxin Bt-Corn Varieties in Helicoverpa zea (Lepidoptera: Noctuidae). AB - Seeds or kernels on hybrid plants are primarily F(2) tissue and will segregate for heterozygous alleles present in the parental F(1) hybrids. In the case of plants expressing Bt-toxins, the F(2) tissue in the kernels will express toxins as they would segregate in any F(2) tissue. In the case of plants expressing two unlinked toxins, the kernels on a Bt plant fertilized by another Bt plant would express anywhere from 0 to 2 toxins. Larvae of corn earworm [Helicoverpa zea (Boddie)] feed on a number of kernels during development and would therefore be exposed to local habitats (kernels) that varied in their toxin expression. Three models were developed for plants expressing two Bt-toxins, one where the traits are unlinked, a second where the traits were linked and a third model assuming that maternal traits were expressed in all kernels as well as paternally inherited traits. Results suggest that increasing larval movement rates off of expressing kernels tended to increase durability while increasing movement rates off of nonexpressing kernels always decreased durability. An ideal block refuge (no pollen flow between blocks and refuges) was more durable than a seed blend because the refuge expressed no toxins, while pollen contamination from plants expressing toxins in a seed blend reduced durability. A linked-trait model in an ideal refuge model predicted the longest durability. The results suggest that using a seed-blend strategy for a kernel feeding insect on a hybrid crop could dramatically reduce durability through the loss of refuge due to extensive cross pollination. PMID- 26527793 TI - The Discovery of Resistant Sources of Spring Barley, Hordeum vulgare ssp. spontaneum, and Unique Greenbug Biotypes. AB - The genetic sources for host-plant resistance to the greenbug (Schizaphis graminum Rondani) in barley (Hordeum vulgare ssp. spontaneum) are limited in that only two single dominant genes Rsg1 and Rsg2 are available for the complex of greenbug biotypes. We evaluated four new barley lines from the Wild Barley Diversity Collection (WBDC) that previously showed potential for greenbug resistance. Three of those entries, WBDC 53, WBDC 117, WBDC 336, exhibited very dominant sources of resistance to older known biotypes B, C, E, F, H, I, and TX1, which also add to the host-plant differentials used to separate these greenbug biotypes. We also re-evaluated the earlier known set of greenbug biotypes that have been in culture for several years against the known host-plant differentials, and included seven newer greenbug isolates collected from Wyoming to the full complement of small grain differentials. This resulted in the discovery of five new greenbug biotypes, WY10 MC, WY81, WY10 B, WY12 MC, and WY86. Wyoming isolates WY4 A and WY4 B were identical in their phenotypic profile, and should be combined as a single unique greenbug biotype. These barley trials resulted in finding new sources of host-plant resistance, although more research needs to be conducted on what type of resistance was found, and how it can be used. We also document that the Wheatland, Wyoming area serves as a very conducive environment for the development of new greenbug biotypes. PMID- 26527794 TI - Evolution of brain lesions in a patient with TREX1 cerebroretinal vasculopathy. PMID- 26527795 TI - Extensive stretching of intracranial aneurysm coil causing TIAs. PMID- 26527796 TI - Shining light on Medicare's values: The Medicare physician data release. PMID- 26527797 TI - Cluster randomized controlled trial of TIA electronic decision support in primary care. PMID- 26527798 TI - Clinical Reasoning: A 72-year-old man with nocturnal stridor. PMID- 26527799 TI - Teaching NeuroImages: Obstructive sleep apnea triggered by vagus nerve stimulation. PMID- 26527800 TI - Identification of a novel cis-regulatory element essential for immune tolerance. AB - Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. Here, we identify a highly conserved noncoding DNA element that is essential for Aire expression. This element shows enrichment of enhancer associated histone marks in mTECs and also has characteristics of being an NF kappaB-responsive element. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance. PMID- 26527801 TI - Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance. AB - Improving the functional avidity of effector T cells is critical in overcoming inhibitory factors within the tumor microenvironment and eliciting tumor regression. We have found that Cish, a member of the suppressor of cytokine signaling (SOCS) family, is induced by TCR stimulation in CD8(+) T cells and inhibits their functional avidity against tumors. Genetic deletion of Cish in CD8(+) T cells enhances their expansion, functional avidity, and cytokine polyfunctionality, resulting in pronounced and durable regression of established tumors. Although Cish is commonly thought to block STAT5 activation, we found that the primary molecular basis of Cish suppression is through inhibition of TCR signaling. Cish physically interacts with the TCR intermediate PLC-gamma1, targeting it for proteasomal degradation after TCR stimulation. These findings establish a novel targetable interaction that regulates the functional avidity of tumor-specific CD8(+) T cells and can be manipulated to improve adoptive cancer immunotherapy. PMID- 26527804 TI - CCR 20th Anniversary Commentary: Gene-Expression Signature in Breast Cancer- Where Did It Start and Where Are We Now? AB - Desmedt and colleagues published two articles, one in the June 1, 2007 issue, and the other in the August 15, 2008, issue of Clinical Cancer Research, that showed gene-expression signatures to be proliferation driven and time dependent, with their prognostic power decreasing with increasing follow-up years. Moreover, the articles showed that immune response is a crucial determinant of prognosis in the HER2-positive and estrogen receptor-negative/HER2-negative subtypes, providing a rationale to further explore the role of the antitumor immune response in these breast cancer subtypes. PMID- 26527802 TI - Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine. AB - Tumor initiation in the intestine can rapidly occur from Lgr5(+) crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required for Wnt-driven intestinal tumor initiation and radiation-induced regeneration by maintaining a subpool of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Elp3 deficiency dramatically delayed tumor appearance in Apc-mutated intestinal epithelia and greatly prolonged mice survival without affecting the normal epithelium. Specific ablation of Elp3 in Lgr5(+) cells resulted in marked reduction of polyp formation upon Apc inactivation, in part due to a decreased number of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Mechanistically, Elp3 is induced by Wnt signaling and promotes Sox9 translation, which is needed to maintain the subpool of Lgr5(+)/Dclk1(+) cancer stem cells. Consequently, Elp3 or Sox9 depletion led to similar defects in Dclk1(+) cancer stem cells in ex vivo organoids. Finally, Elp3 deficiency strongly impaired radiation-induced intestinal regeneration, in part because of decreased Sox9 protein levels. Together, our data demonstrate the crucial role of Elp3 in maintaining a subpopulation of Lgr5-derived and Sox9-expressing cells needed to trigger Wnt-driven tumor initiation in the intestine. PMID- 26527805 TI - Circulating Tumor Cells and Circulating Tumor DNA: Challenges and Opportunities on the Path to Clinical Utility. AB - Recent technological advances have enabled the detection and detailed characterization of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in blood samples from patients with cancer. Often referred to as a "liquid biopsy," CTCs and ctDNA are expected to provide real-time monitoring of tumor evolution and therapeutic efficacy, with the potential for improved cancer diagnosis and treatment. In this review, we focus on these opportunities as well as the challenges that should be addressed so that these tools may eventually be implemented into routine clinical care. PMID- 26527806 TI - AMER1 Is a Frequently Mutated Gene in Colorectal Cancer--Letter. PMID- 26527807 TI - Transition from non-periodic to periodic explosions. AB - We show the existence of periodic exploding dissipative solitons. These non chaotic explosions appear when higher-order nonlinear and dispersive effects are added to the complex cubic-quintic Ginzburg-Landau equation modelling soliton transmission lines. This counterintuitive phenomenon is the result of period halving bifurcations leading to order (periodic explosions), followed by period doubling bifurcations (or intermittency) leading to chaos (non-periodic explosions). PMID- 26527808 TI - Weighting dissimilarities to detect communities in networks. AB - Many complex systems can be described as networks exhibiting inner organization as communities of nodes. The identification of communities is a key factor to understand community-based functionality. We propose a family of measures based on the weighted sum of two dissimilarity quantifiers that facilitates efficient classification of communities by tuning the quantifiers' relative weight to the network's particularities. Additionally, two new dissimilarities are introduced and incorporated in our analysis. The effectiveness of our approach is tested by examining the Zachary's Karate Club Network and the Caenorhabditis elegans reactions network. The analysis reveals the method's classification power as confirmed by the efficient detection of intrapathway metabolic functions in C. elegans. PMID- 26527809 TI - Topics on non-equilibrium statistical mechanics and nonlinear physics (II). PMID- 26527810 TI - Effect of the vibration profile on shallow granular systems. AB - We describe the collective behaviour of a system of many inelastic spherical particles inside a box which is being periodically vibrated. The box is shallow, with large horizontal dimensions, while the height is less than two particle diameters. The vibrations are not symmetric: the time the box is moving up is, in general, different from the time it is moving down. The limit cycles of isolated grains are largely affected by the asymmetry of the vibration mode, increasing the size in phase space of the chaotic regions. When many grains are placed in the box, the phase separation between dense, solid-like regions, coexisting with fluid-like regions takes place at smaller global densities for asymmetric vibration profiles. Besides, the order parameter of the transition takes larger values when asymmetric forcing is used. PMID- 26527811 TI - Layer-layer competition in multiplex complex networks. AB - The coexistence of multiple types of interactions within social, technological and biological networks has moved the focus of the physics of complex systems towards a multiplex description of the interactions between their constituents. This novel approach has unveiled that the multiplex nature of complex systems has strong influence in the emergence of collective states and their critical properties. Here we address an important issue that is intrinsic to the coexistence of multiple means of interactions within a network: their competition. To this aim, we study a two-layer multiplex in which the activity of users can be localized in each of the layers or shared between them, favouring that neighbouring nodes within a layer focus their activity on the same layer. This framework mimics the coexistence and competition of multiple communication channels, in a way that the prevalence of a particular communication platform emerges as a result of the localization of user activity in one single interaction layer. Our results indicate that there is a transition from localization (use of a preferred layer) to delocalization (combined usage of both layers) and that the prevalence of a particular layer (in the localized state) depends on the structural properties. PMID- 26527812 TI - Community control in cellular protein production: consequences for amino acid starvation. AB - Deprivation of essential nutrients can have stark consequences for many processes in a cell. We consider amino acid starvation, which can result in bottlenecks in mRNA translation when ribosomes stall due to lack of resources, i.e. tRNAs charged with the missing amino acid. Recent experiments also show less obvious effects such as increased charging of other (non-starved) tRNA species and selective charging of isoaccepting tRNAs. We present a mechanism which accounts for these observations and shows that production of some proteins can actually increase under starvation. One might assume that such responses could only be a result of sophisticated control pathways, but here we show that these effects can occur naturally due to changes in the supply and demand for different resources, and that control can be accomplished through selective use of rare codons. We develop a model for translation which includes the dynamics of the charging and use of aminoacylated tRNAs, explicitly taking into account the effect of specific codon sequences. This constitutes a new control mechanism in gene regulation which emerges at the community level, i.e. via resources used by all ribosomes. PMID- 26527813 TI - Non-unique results of collisions of quasi-one-dimensional dissipative solitons. AB - We investigate collisions of quasi-one-dimensional dissipative solitons (DSs) for a large class of initial conditions, which are not temporally asymptotic quasi one-dimensional DSs. For the case of sufficiently small approach velocity and sufficiently large values of the dissipative cross-coupling between the counter propagating DSs, we find non-unique results for the outcome of collisions. We demonstrate that these non-unique results are intrinsically related to a modulation instability along the crest of the quasi-one-dimensional objects. As a model, we use coupled cubic-quintic complex Ginzburg-Landau equations. Among the final results found are stationary and oscillatory compound states as well as more complex assemblies consisting of quasi-one-dimensional and localized states. We analyse to what extent the final results can be described by the solutions of one cubic-quintic complex Ginzburg-Landau equation with effective parameters. PMID- 26527814 TI - Experimental dynamics in magnetic field-driven flows compared to thermoconvective convection. AB - We compare the dynamics obtained in two intermediate aspect ratio (diameter over height) experiments. These systems have rotational symmetry and consist of fluid layers that are destabilized using two different methods. The first one is a classical Benard-Marangoni experiment, where the destabilizing forces, buoyancy and surface tension, are created by temperature gradients. The second system consists of a large drop of liquid metal destabilized using oscillating magnetic fields. In this configuration, the instability is generated by a radial Lorentz force acting on the conducting fluid. Although there are many important differences between the two configurations, the dynamics are quite similar: the patterns break the rotational symmetry, and different azimuthal and radial wavenumbers appear depending on the experimental control parameters. These patterns in most cases are stationary, but for some parameters they exhibit different dynamical behaviours: rotations, transitions between different solutions or cyclic connections between different patterns. PMID- 26527815 TI - Classification of complex Wishart matrices with a diffusion-reaction system guided by stochastic distances. AB - We propose a new method for polarimetric synthetic aperture radar (PolSAR) imagery classification based on stochastic distances in the space of random matrices obeying complex Wishart distributions. Given a collection of prototypes [Formula: see text] and a stochastic distance d(.,.), we classify any random matrix X using two criteria in an iterative set-up. First, we associate X with the class which minimizes the weighted stochastic distance w(m)d(X,Z(m)), where the positive weights w(m) are computed to max- imize the class discrimination power. Second, we improve the result by embedding the classification problem into a diffusion-reaction partial differential system where the diffusion term smooths the patches within the image, and the reaction term tends to move the pixel values towards the closest class prototype. In particular, the method inherits the benefits of speckle reduction by diffusion-like methods. Results on synthetic and real PolSAR data show the performance of the method. PMID- 26527816 TI - Two-phase fluid flow in geometric packing. AB - We investigate how a plug of obstacles inside a two-dimensional channel affects the drainage of high viscous fluid (oil) when the channel is invaded by a less viscous fluid (water). The plug consists of an Apollonian packing with, at most, 17 circles of different sizes, which is intended to model an inhomogeneous porous region. The work aims to quantify the amount of retained oil in the region where the flow is influenced by the packing. The investigation, carried out with the help of the computational fluid dynamics package ANSYS-FLUENT, is based on the integration of the complete set of equations of motion. The study considers the effect of both the injection speed and the number and size of obstacles, which directly affects the porosity of the system. The results indicate a complex dependence in the fraction of retained oil on the velocity and geometric parameters. The regions where the oil remains trapped is very sensitive to the number of circles and their size, which influence in different ways the porosity of the system. Nevertheless, at low values of Reynolds and capillary numbers Re<4 and n(c)?10(-5), the overall expected result that the volume fraction of oil retained decreases with increasing porosity is recovered. A direct relationship between the injection speed and the fraction of oil is also obtained. PMID- 26527817 TI - A permutation information theory tour through different interest rate maturities: the Libor case. AB - This paper analyses Libor interest rates for seven different maturities and referred to operations in British pounds, euros, Swiss francs and Japanese yen, during the period 2001-2015. The analysis is performed by means of two quantifiers derived from information theory: the permutation Shannon entropy and the permutation Fisher information measure. An anomalous behaviour in the Libor is detected in all currencies except euros during the years 2006-2012. The stochastic switch is more severe in one, two and three months maturities. Given the special mechanism of Libor setting, we conjecture that the behaviour could have been produced by the manipulation that was uncovered by financial authorities. We argue that our methodology is pertinent as a market overseeing instrument. PMID- 26527818 TI - A symbolic information approach to determine anticipated and delayed synchronization in neuronal circuit models. AB - The phenomenon of synchronization between two or more areas of the brain coupled asymmetrically is a relevant issue for understanding mechanisms and functions within the cerebral cortex. Anticipated synchronization (AS) refers to the situation in which the receiver system synchronizes to the future dynamics of the sender system while the intuitively expected delayed synchronization (DS) represents exactly the opposite case. AS and DS are investigated in the context of causal information formalism. More specifically, we use a multi-scale symbolic information-theory approach for discriminating the time delay displayed between two areas of the brain when they exchange information. PMID- 26527819 TI - Causal information quantification of prominent dynamical features of biological neurons. AB - Neurons tend to fire a spike when they are near a bifurcation from the resting state to spiking activity. It is a delicate balance between noise, dynamic currents and initial condition that determines the phase diagram of neural activity. Many possible ionic mechanisms can be accounted for as the source of spike generation. Moreover, the biophysics and the dynamics behind it can usually be described through a phase diagram that involves membrane voltage versus the activation variable of the ionic channel. In this paper, we present a novel methodology to characterize the dynamics of this system, which takes into account the fine temporal 'structures' of the complex neuronal signals. This allows us to accurately distinguish the most fundamental properties of neurophysiological neurons that were previously described by Izhikevich considering the phase-space trajectory, using a time causal space: statistical complexity versus Fisher information versus Shannon entropy. PMID- 26527822 TI - The yellow folder. PMID- 26527821 TI - Difficulty with right-left discrimination: A clinical problem? PMID- 26527823 TI - Syrian refugees' mental health is top priority. PMID- 26527820 TI - Anti-HIV-1 activity determined by beta-galactosidase activity in the multinuclear activation of an indicator assay is comparable with that by a conventional focus counting method. AB - BACKGROUND: Direct comparison of enzymatic and original blue cell-counting detections with the multinuclear activation of an indicator (MAGI) cells, so far, remains to be performed in parallel. Although inhibitors for reverse transcription solely inhibit the reverse transcription step, those for HIV-1 entry block syncytium formation of HIV-1-infected MAGI cells in addition to the entry (dual inhibition). It raises a concern that reduction of enzymatic activity is artificially influenced by syncytium-blocking activity of inhibitors for entry. METHODS: The MAGI cells with a syncytium inducible strain, HIV-1IIIB, were used for anti-HIV activity determination both with conventional counting with X Gal staining and measurement of chlorophenol red beta-d-galactopyranoside conversion with a plate reader. RESULTS: Infectivity of HIV-1 in the MAGI cells was highly correlated with both methods. In microscopic observation, small blue cells with single or a couple of nuclei were dominantly observed in the presence of inhibitors for entry, but not in the presence of those for reverse transcription. Actual anti-HIV-1 activities were comparable or moderately sensitive in the chlorophenol red beta-d-galactopyranoside method. CONCLUSIONS: Antiviral activities of inhibitors for entry obtained from both enzymatic and counting methods appear to be comparable, even in infection of a highly syncytia inducible HIV-1IIIB strain. PMID- 26527825 TI - Calls for independent inquiry into bombing. PMID- 26527824 TI - Differences in obstetric care among nulliparous First Nations and non-First Nations women in British Columbia, Canada. AB - BACKGROUND: Canada's Aboriginal population faces significantly higher rates of stillbirth and neonatal and postnatal death than those seen in the general population. The objective of this study was to compare indicators of obstetric care quality and use of obstetric interventions between First Nations and non First Nations mothers in British Columbia, Canada. METHODS: We linked obstetrical medical records with the First Nations Client File for all nulliparous women who delivered single infants in British Columbia from 1999 to 2011. Using logistic regression models, we examined differences in the proportion of women who received services aligned with best practice guidelines, as well as the overall use of obstetric interventions among First Nations mothers compared with the general population, controlling for geographic barriers (distance to hospital) and other relevant confounders. RESULTS: During the study period, 215,993 single births occurred in nulliparous women in British Columbia, 9152 of which were to members of our First Nations cohort. First Nations mothers were less likely to have early ultrasonography (adjusted risk difference = 10.2 fewer women per 100 deliveries [95% confidence interval {CI} -11.3 to -9.3]), to have at least 4 antenatal care visits (3.6 fewer women per 100 deliveries [95% CI -4.6 to -2.6]), and to undergo labour induction after prolonged (> 24 hours) prelabour rupture of membranes (-5.9 [95% CI -11.8 to 0.1]) or at post-dates gestation (-10.6 [95% CI 13.8 to -7.5]). Obstetric interventions including epidural, labour induction, instrumental delivery and cesarean delivery were used less often in First Nations mothers. INTERPRETATION: We identified differences in the obstetric care received by First Nations mothers compared with the general population. Such differences warrant further investigation, given increases in perinatal mortality that are consistently shown and that may be a downstream consequence of differences in care. PMID- 26527826 TI - Nunavut acts on recommendations for suicide prevention. PMID- 26527827 TI - Federal inmates treated for hep C drop 29%. PMID- 26527828 TI - Survey aims to capture patient experience. PMID- 26527830 TI - Minister in charge of suicide prevention knows the crisis intimately. PMID- 26527829 TI - Internet-delivered cognitive behavioural therapy in the treatment of psychiatric illness. PMID- 26527831 TI - Muir-Torre syndrome. PMID- 26527833 TI - Nitrofurantoin and older women. PMID- 26527834 TI - Animal visitation in acute care medical facilities. PMID- 26527835 TI - Health professionals' perspectives on exercise referral and physical activity promotion in primary care: Findings from a process evaluation of the National Exercise Referral Scheme in Wales. AB - BACKGROUND AND OBJECTIVES: Referring clinicians' experiences of exercise referral schemes (ERS) can provide valuable insights into their uptake. However, most qualitative studies focus on patient views only. This paper explores health professionals' perceptions of their role in promoting physical activity and experiences of a National Exercise Referral Scheme (NERS) in Wales. DESIGN: Qualitative semi-structured group interviews. SETTING: General practice premises. METHODS: Nine semi-structured group interviews involving 46 health professionals were conducted on general practice premises in six local health board areas. Purposive sampling taking into account area deprivation, practice size and referral rates was employed. Interviews were transcribed verbatim and analysed using the Framework method of thematic analysis. RESULTS: Health professionals described physical activity promotion as important, although many thought it was outside of their expertise and remit, and less important than other health promotion activities such as smoking cessation. Professionals linked decisions on whether to advise physical activity to patients to their own physical activity levels and to subjective judgements of patient motivation. While some described ERS as a holistic alternative to medication, with potential social benefits, others expressed concerns regarding their limited reach and potential to exacerbate inequalities. Barriers to referral included geographic isolation and uncertainties about patient selection criteria, medico-legal responsibilities and a lack of feedback about patient progress. CONCLUSION: Clinicians' concerns about expertise, priority setting and time constraints should be addressed to enhance physical activity promotion in primary care. Further research is needed to fully understand decision making relating to provision of physical activity advice and use of ERS. PMID- 26527836 TI - First Report of Korean Cyst Nematode, Heterodera koreana, Parasitic on Bamboo, Phyllostachys nigra, from Iran. AB - Bamboo is grown sporadically in the north of Iran and is confined to very limited areas. The history of growing bamboo was to some extent simultaneous with the entrance, commencement, and growth of the tea industry in the north about a century ago. The bamboo was used for making baskets to transfer the harvested tea foliage from farm to the factory and other linked functions. A main area allocated for bamboo growing is located in Lahidjan Agricultural Research Station (LARS) in the north of Iran, where several species of bamboo were cultivated in an area of 5 ha. The species include five species of Phyllostachys (viz., P. aurea, P. bambusoides, P. decora, P. nigra, P. vivax) and one species of Arundinaria gigantean, Pleioblastus fortune, and Semiarundinaria fastuosa; however, only P. aurea and P. nigra have been precisely identified. A survey on plant parasitic nematodes associated with bamboo mainly on P. nigra in LARS revealed second-stage juveniles of cyst forming nematode in soil samples. Further analysis of root and soil samples led to recovery of a cyst nematode belonging to the genus Heterodera and the Afenestrata group. Cysts, vulval cone, and second stage juveniles were studied for morphological and morphometric features. The classical identification was followed by amplification of the ribosomal RNA-ITS region and the D2-D3 expansion segments of 28S large-subunit rRNA gene; the amplified fragments were sequenced, edited, and compared with those of the corresponding published gene sequences. New D2-D3 and rRNA-ITS gene sequences were deposited in the GenBank database under the accession numbers KR818910 and KR818911, respectively. Based on the morphological and molecular data, the species of the cyst-forming nematode was identified as H. koreana (Vovlas et al., 1992; Mundo-Ocampo et al., 2008). The body contour of cysts was mainly subspherical, vey often with irregular shape (Fig. 1A), yellowish to light brown, thin cuticle with fine zigzag pattern, without fenestration, lacking bulla, and underbridge. Vulval lips protruded, cuticular pattern of vulval cone with a tuberculate area (Fig. 2B), and vagina embedded into vulval lips. The second stage juveniles cylindrical and slender, hemispherical cephalic framework, with three lines in lateral field, well-developed rounded stylet knobs, tail conoid tapring to fine rounded terminus, phasmids posterior to anus. The cyst measurements were (n = 21) length 502 +/- 70 (420 to 640) um; width = 408 +/- 60 (320 to 520) um; length/width = 1.23 +/- 0.09 (1.07 to 1.5) um. The morphometric characters of vulval cone were measured (n = 7): fenestral length = 62.4 +/- 6.5 (51 to 71) um; fenestral width = 50.7 +/- 3.2 (45 to 54) um; vulval slit = 51.9 +/- 4.3 (46 to 59) um; distance from vulva to anus = 51.3 +/- 4.4 (43 to 56) um. Second-stage juveniles showed the following morphometric characters (n = 14): L = 455 +/- 11.3 (437 to 472) um; a = 29.9 +/- 0.9 (28.3 to 31.5); b? = 2.7 +/- 0.4 (2.2 to 3.5); c = 7.4 +/- 0.9 (6 to 8.9); c = 6.1 +/- 0.4 (5.1 to 6.7); lip region height = 3 um; lip region width = 7.5 +/- 0.5 (7 to 8) um; stylet length = 18.1 +/- 0.5 (17 to 19) um; anterior end to median bulb = 72.2 +/- 1.7 (70 to 75) um; anterior end to secretory-excretory pore = 99.7 +/- 2.5 (96 to 103) um; maximum body width = 15.2 +/- 0.4 (15 to 16) um; body width at anus = 10.1 +/- 1 (8 to 11) um; tail length = 62.0 +/- 6.9 (51 to 74) um; hyaline part of tail = 44.0 +/- 1.8 (40 to 47) um. The egg measurements for 11 individuals were length = 102.5 +/- 7.9 (93 to 119) um; width = 39.3 +/- 4.2 (33 to 46) um; length/width = 2.6 +/- 0.3 (2.0 to 3.1). The morphology, morphometric characters and molecular data of the population of H. koreana isolated from bamboo in Iran are in agreement with those previously reported for this species (Vovlas et al., 1992; Mundo-Ocampo et al., 2008). At present, five species of Heterodera belonging to the Cyperi and Afenestrata groups were reported from bamboo, H. bamboosi (Kaushal and Swarup, 1988; Wouts and Baldwin, 1998) on Bambusa sp. from India; H. koreana on P. pubescence, P. aurea, and P. nigra from South Korea and the United States; and H. hainanensis (Zhuo et al., 2013), H. fengi (Wang et al., 2013), and H. guangdongensis (Zhuo et al., 2014) on P. pubescence from China; thus showing host suitability of bamboo for at least five species of cyst-forming nematodes. A greenhouse test performed by planting rice seed cv. Hashemi in soil containing H. koreana showed successful multiplication of Korean cyst nematode on rice seedlings after 2 mon. The exact date of the establishment of bamboo plantation in LARS is not precisely clear, but it indicates that the Korean cyst nematode was most likely brought with the imported bamboo seedlings from unknown origin several decades ago. According to our best knowledge, this is the first report of occurrence of H. koreana from Iran. So far the Korean cyst nematode was reported from South Korea, Thailand, and the United States, Florida (from nurseries); this study includes the distribution of this cyst-forming nematode in Iran and expands the information of the occurrence of H. koreana for the world. PMID- 26527837 TI - Molecular Characterization of Meloidogyne christiei Golden and Kaplan, 1986 (Nematoda, Meloidogynidae) Topotype Population Infecting Turkey Oak (Quercus laevies) in Florida. AB - Meloidogyne christiei isolated from turkey oak, Quercus laevies, from the type locality in Florida was characterized using isozyme profiles and ribosomal and mitochondrial gene sequences. The phenotype N1a detected from a single egg-laying female of M. christiei showed one very strong band of malate dehydrogenase (MDH) activity; however, no esterase (EST) activity was identified from macerate of one or even 20 females per well. Phylogenetic relationships within the genus Meloidogyne as inferred from Bayesian analysis of partial 18S ribosomal RNA (rRNA), D2-D3 of 28S rRNA, internal transcribed spacer (ITS) rRNA, and cytochrome oxidase subunit II (COII)-16S rRNA of mitochondrial DNA (mtDNA) gene fragments showed that M. christiei formed a separate lineage within the crown group of Meloidogyne and its relationships with any of three Meloidogyne clades were not resolved. PMID- 26527838 TI - Sex Attraction and Mating in Bursaphelenchus okinawaensis and B. xylophilus. AB - The fungal feeding, hermaphroditic Bursaphelenchus okinawaensis is a laboratory model to understand the biology of Bursaphelenchus. The extent to which B. okinawaensis can be used to model Bursaphelenchus xylophilus mating was investigated. A chemotaxis assay was conducted to examine whether B. xylophilus and B. okinawaensis produce and respond to volatile sex attractants. Unmated B. xylophilus females were found to attract B. xylophilus males. Similarly, old (sperm depleted) but not young (sperm repleted) B. okinawaensis hermaphrodites attract B. okinawaensis males. Thus, in both species, sperm status corresponds to its ability to attract males. B. xylophilus males also produce a volatile pheromone that attracts both mated and unmated females. A second assay, in which the behavior of males on petri plates in the presence of different females or hermaphrodites of Bursaphelenchus was observed, revealed that B. xylophilus unmated females attract B. okinawaensis males, and B. okinawaensis old hermaphrodites attract B. xylophilus males. These observations suggested that the pheromones of Bursaphelenchus work to some extent across species. Mating behavior through spicule insertion occurs across species, suggesting that postcopulatory mechanisms prevent production of interspecific progeny. The hermaphroditic B. okinawaensis will be a useful model to conduct genetic studies for the understanding of the molecular mechanisms underlying mating behavior in Bursaphelenchus nematodes. PMID- 26527839 TI - Viability and Virulence of Entomopathogenic Nematodes Exposed to Ultraviolet Radiation. AB - Entomopathogenic nematodes (EPNs) can be highly effective biocontrol agents, but their efficacy can be reduced due to exposure to environmental stress such as from ultraviolet (UV) radiation. Our objectives were to 1) compare UV tolerance among a broad array of EPN species, and 2) investigate the relationship between reduced nematode viability (after exposure to UV) and virulence. Nematodes exposed to a UV radiation (254 nm) for 10 or 20 min were assessed separately for viability (survival) and virulence to Galleria mellonella. We compared 9 different EPN species and 15 strains: Heterorhabditis bacteriophora (Baine, fl11, Oswego, and Vs strains), H. floridensis (332), H. georgiana (Kesha), H. indica (HOM1), H. megidis (UK211), Steinernema carpocapsae (All, Cxrd, DD136, and Sal strains), S. feltiae (SN), S. rarum (17C&E), and S. riobrave (355). In viability assessments, steinernematids, particularly strains of S. carpocapsae, generally exhibited superior UV tolerance compared with the heterorhabditids. However, some heterorhabditids tended to be more tolerant than others, e.g., H. megidis and H. bacteriophora (Baine) were most susceptible and H. bacteriophora (Vs) was the only heterorhabditid that did not exhibit a significant effect after 10 min of exposure. All heterorhabditids experienced reduced viability after 20 min exposure though several S. carpocapsae strains did not. In total, after 10 or 20 min exposure, the viability of seven nematode strains did not differ from their non-UV exposed controls. In virulence assays, steinernematids (particularly S. carpocapsae strains) also tended to exhibit higher UV tolerance. However, in contrast to the viability measurements, all nematodes experienced a reduction in virulence relative to their controls. Correlation analysis revealed that viability among nematode strains is not necessarily related to virulence. In conclusion, our results indicate that the impact of UV varies substantially among EPNs, and viability alone is not a sufficient measure for potential impact on biocontrol efficacy as other characters such as virulence may be severely affected even when viability remains high. PMID- 26527840 TI - A New Species of Pristionchus (Rhabditida: Diplogastridae) and Its Bacterial Symbiont from Yixing, China. AB - A new nematode species, Pristionchus entomophilus n. sp., was collected during a soil sample survey in Yixing of Jiangsu province, eastern China. P. entomophilus n. sp. is distinguished by its unique characteristics. This new species is mainly hermaphroditic, with males seldom found. The new nematode has a similar body length but has much narrower body width compared with P. pacificus. Its body is covered with longitudinal ridges: 12 ridges on head, 13 or 14 ridges in the middle, 11 and 7 ridges in front and rear of the anus, respectively. The eurystomatous form mouth includes a triangular dorsal tooth, a large claw-like right subventral tooth, and a row of five ventral denticles placed opposite the dorsal tooth. Only eight pairs of genital papillae and a pair of phasmids are present in the tail of the male as the sixth pair of papillae having seemingly been degenerated and lost. Molecular phylogenetic trees based on 18S rDNA confirmed that the new species belongs to the genus Pristionchus and is most closely related to P. pacificus. Moreover, the new species was found to be occasionally associated with the entomopathogenic bacterial strain 09FLYB1 of Serratia nematodophila and be able to stably transfer the bacterial strain for several generations. PMID- 26527842 TI - Pasteuria penetrans for Control of Meloidogyne incognita on Tomato and Cucumber, and M. arenaria on Snapdragon. AB - Meloidogyne incognita and Meloidogyne arenaria are important parasitic nematodes of vegetable and ornamental crops. Microplot and greenhouse experiments were conducted to test commercial formulations of the biocontrol agent Pasteuria penetrans for control of M. incognita on tomato and cucumber and M. arenaria on snapdragon. Three methods of application for P. penetrans were assessed including seed, transplant, and post-plant treatments. Efficacy in controlling galling and reproduction of the two root-knot nematode species was evaluated. Seed treatment application was assessed only for M. incognita on cucumber. Pasteuria treatment rates of a granular transplant formulation ranged from 1.5 * 10(5) endospores/cm(3) to 3 * 10(5) endospores/cm(3) of transplant mix applied at seeding. Additional applications of 1.5 * 10(5) endospores/cm(3) of soil were applied as a liquid formulation to soil post-transplant for both greenhouse and microplot trials. In greenhouse cucumber trials, all Pasteuria treatments were equivalent to steamed soil for reducing M. incognita populations in roots and soil, and reducing nematode reproduction and galling. In cucumber microplot trials there were no differences among treatments for M. incognita populations in roots or soil, eggs/g root, or root condition ratings. Nematode reproduction on cucumber was low with Telone II and with the seed treatment plus post-plant application of Pasteuria, which had the lowest nematode reproduction. However, galling for all Pasteuria treatments was higher than galling with Telone II. Root knot nematode control with Pasteuria in greenhouse and microplot trials varied on tomato and snapdragon. Positive results were achieved for control of M. incognita with the seed treatment application on cucumber. PMID- 26527841 TI - Marine Nematode Taxonomy in Africa: Promising Prospects Against Scarcity of Information. AB - From the late 19th century, Africa has faced heavy exploitation of its natural resources with increasing land/water pollution, and several described species have already become extinct or close to extinction. This could also be the case for marine nematodes, which are the most abundant and diverse benthic group in marine sediments, and play major roles in ecosystem functioning. Compared to Europe and North America, only a handful of investigations on marine nematodes have been conducted to date in Africa. This is due to the scarcity of experienced taxonomists, absence of identification guides, as well as local appropriate infrastructures. A pivotal project has started recently between nematologists from Africa (Tunisia), India, and Europe (Italy) to promote taxonomic study and biodiversity estimation of marine nematodes in the African continent. To do this, as a first step, collection of permanent slides of marine nematodes (235 nominal species and 14 new to science but not yet described) was recently established at the Faculty of Sciences of Bizerte (Tunisia). Capacity building of next generation of African taxonomists have been carried out at level of both traditional and molecular taxonomy (DNA barcoding and next-generation sequencing [NGS]), but they need to be implemented. Indeed, the integration of these two approaches appears crucial to overcome lack of information on the taxonomy, ecology, and biodiversity of marine nematodes from African coastal waters. PMID- 26527843 TI - Potential of Sahelian Native Shrub Materials to Suppress the Spiral Nematode Helicotylenchus dihystera. AB - Pearl millet (Pennisetum glaucum) is a drought-tolerant cereal commonly grown for grain and fodder in arid areas throughout the world. Senegalese millet fields are infested with Helicotylenchus. The native evergreen woody shrub Piliostigma reticulatum is widely distributed in sub-Saharan Africa. Its coppiced residues are used by small farmers as mulch in crop fields. The shrub's nematicidal effect on the spiral nematode Helicotylenchus dihystera was evaluated in a pearl millet pot experiment. The abundance of nematodes decreased by 64% after application of either leaf powder or a pulverized mixing of leaves and stems, suggesting the use of aboveground materials of P. reticulatum as a potential nematicide. The results show promise for use of a local resource by subsistence farmers in the Sahel. Further research is needed on application to fully develop this approach as a biopesticide. PMID- 26527845 TI - Incomplete Categorical Data Design: Nonrandomized Response Techniques for Sensitive Questions in Surveys. PMID- 26527844 TI - SPReM: Sparse Projection Regression Model For High-dimensional Linear Regression. AB - The aim of this paper is to develop a sparse projection regression modeling (SPReM) framework to perform multivariate regression modeling with a large number of responses and a multivariate covariate of interest. We propose two novel heritability ratios to simultaneously perform dimension reduction, response selection, estimation, and testing, while explicitly accounting for correlations among multivariate responses. Our SPReM is devised to specifically address the low statistical power issue of many standard statistical approaches, such as the Hotelling's T2 test statistic or a mass univariate analysis, for high-dimensional data. We formulate the estimation problem of SPREM as a novel sparse unit rank projection (SURP) problem and propose a fast optimization algorithm for SURP. Furthermore, we extend SURP to the sparse multi-rank projection (SMURP) by adopting a sequential SURP approximation. Theoretically, we have systematically investigated the convergence properties of SURP and the convergence rate of SURP estimates. Our simulation results and real data analysis have shown that SPReM out-performs other state-of-the-art methods. PMID- 26527846 TI - Sociology of Low Expectations: Recalibration as Innovation Work in Biomedicine. AB - Social scientists have drawn attention to the role of hype and optimistic visions of the future in providing momentum to biomedical innovation projects by encouraging innovation alliances. In this article, we show how less optimistic, uncertain, and modest visions of the future can also provide innovation projects with momentum. Scholars have highlighted the need for clinicians to carefully manage the expectations of their prospective patients. Using the example of a pioneering clinical team providing deep brain stimulation to children and young people with movement disorders, we show how clinicians confront this requirement by drawing on their professional knowledge and clinical expertise to construct visions of the future with their prospective patients; visions which are personalized, modest, and tainted with uncertainty. We refer to this vision constructing work as recalibration, and we argue that recalibration enables clinicians to manage the tension between the highly optimistic and hyped visions of the future that surround novel biomedical interventions, and the exigencies of delivering those interventions in a clinical setting. Drawing on work from science and technology studies, we suggest that recalibration enrolls patients in an innovation alliance by creating a shared understanding of how the "effectiveness" of an innovation shall be judged. PMID- 26527847 TI - Chicago Residents' Perceptions of Air Quality: Objective Pollution, the Built Environment, and Neighborhood Stigma Theory. AB - Substantial research documents higher pollution levels in minority neighborhoods, but little research evaluates how residents perceive their own communities' pollution risks. According to "Neighborhood stigma" theory, survey respondents share a cultural bias that minorities cause social dysfunction, leading to over reports of dysfunction in minority communities. This study investigates perceptions of residential outdoor air quality by linking objective data on built and social environments with multiple measures of pollution and a representative survey of Chicago residents. Consistent with the scholarly narrative, results show air quality is rated worse where minorities and poverty are concentrated, even after extensive adjustment for objective pollution and built environment measures. Perceptions of air pollution may thus be driven by neighborhood socioeconomic position far more than by respondents' ability to perceive pollution. The finding that 63.5% of the sample reported excellent or good air quality helps to explain current challenging in promoting environmental action. PMID- 26527848 TI - Local Variability in the Impacts of Residential Particulate Matter and Pest Exposure on Children's Wheezing Severity: A Geographically Weighted Regression Analysis of Environmental Health Justice. AB - Two assumptions have underpinned environmental justice over the past several decades: 1) uneven environmental exposures yield correspondingly unequal health impacts and 2) these effects are stable across space. To test these assumptions, relationships for residential pest and PM2.5 exposures with children's wheezing severity are examined using global (ordinary least squares) and local (geographically weighted regression [GWR]) models using cross-sectional observational survey data from El Paso (Texas) children. In the global model, having pests and higher levels of PM2.5 were weakly associated with greater wheezing severity. The local model reveals two types of asthmogenic socio environments where environmental exposures more powerfully predict greater wheezing severity. The first is a lower-income context where children are disproportionately exposed to pests and PM2.5 and the second is a higher-income socio-environment where children are exposed to lower levels of PM2.5, yet PM2.5is counterintuitively associated with more severe wheezing. Findings demonstrate that GWR is a powerful tool for understanding relationships between environmental conditions, social characteristics and health inequalities. PMID- 26527849 TI - Expression of Concern. PMID- 26527850 TI - SynRio: R and Shiny based application platform for cyanobacterial genome analysis. AB - SynRio is a Shiny and R based web analysis portal for viewing Synechocystis PCC 6803 genome, a cyanobacterial genome with data analysis capabilities. The web based user interface is created using R programming language powered by Shiny package. This web interface helps in creating interactive genome visualization based on user provided data selection along with selective data download options. AVAILABILITY: SinRio is available to download freely from Github - https://github.com/NFMC/SynRio or from http://www.nfmc.res.in/synrio/. In addition an online version of the platform is also hosted at nfmc.res.in/synrio, using shiny server (open source edition) installation. PMID- 26527851 TI - Molecular docking studies of phytochemicals from Phyllanthus niruri against Hepatitis B DNA Polymerase. AB - Hepatitis B virus (HBV) infection is the leading cause for liver disorders and can lead to hepatocellular carcinoma, cirrhosis and liver damage which in turn can cause death of patients. HBV DNA Polymerase is essential for HBV replication in the host and hence is used as one of the most potent pharmacological target for the inhibition of HBV. Chronic hepatitis B is currently treated with nucleotide analogues that suppress viral reverse transcriptase activity and most of them are reported to have viral resistance. Therefore, it is of interest to model HBV DNA polymerase to dock known phytochemicals. The present study focuses on homology modeling and molecular docking analysis of phytocompounds from the traditional antidote Phyllanthus niruri and other nucleoside analogues against HBV DNA Polymerase using the software Discovery studio 4.0. 3D structure of HBV DNA Polymerase was predicted based on previously reported alignment. Docking studies revealed that a few phytochemicals from Phyllanthus niruri had good interactions with HBV DNA Polymerase. These compounds had acceptable binding properties for further in vitro validation. Thus the study puts forth experimental validation for traditional antidote and these phytocompounds could be further promoted as potential lead molecule. PMID- 26527852 TI - Modular organization of the human disease genes: a text-based network inference. AB - The analysis of disease phenotype data with genetic information indicated that genes associated with clinically similar diseases tend to be functionally related and work together to perform a specific biological function. Therefore, it is of interest to relate disease phenotype data to mirror modular property implied in the association map of disease genes. Hence, we constructed a textbased human disease gene network (HDGN) by using the phenotypic similarity of their associated disease phenotype records in the OMIM database. Analysis shows that the network is highly modular and it is highly correlated with the physiological classification of genetic diseases. Using a graph clustering algorithm, we found 139 gene modules in the network of 1,865 genes and their gene products (proteins) in these gene modules tend to interact with each other via the computation of PPI intensity. Genes in such gene modules are functionally related and may represent the shared genetic basis of their corresponding diseases. These genes, alone or in combination, could be considered as potential therapeutic targets in future clinical therapy. PMID- 26527853 TI - Identification and molecular docking analysis of active ingredients with medicinal properties from edible Baccaurea sapida. AB - Underutilized plant species has started changing the conception of plants by expanding the use well beyond from foods and fibers to rich source of medicinally important secondary metabolites. Bioactive compounds from natural sources are gaining importance as potential drug candidates towards many inflammatory conditions like Rheumatoid Arthritis (RA). The focus of the present study has been centred to reveal the anti-inflammatory potential of an underutilized fruits of B. sapida. Further efforts towards its medicinal significance may provide relieve from symptoms of RA by reducing the side effects that are observed in available medications. Total 10 compounds in fruit crude methanol extract were identified and quantified by LC-MS/MS analysis followed by the agar well diffusion method for their anti microbial activity. Among all studied micro organism S. aureus was found to surmount the inflammation in RA through domain B of surface protein A (Staphylococcal surface protein A). Identified compounds (having anti-inflammatory properties) were scrutinized for their toxicity and quantitative structure-activity relationship (QSAR) using lazer toxicity and Molinspiration servers respectively. Further, docking studies have been carried out between domain B and studied compounds using AutoDock. Out of 6 anti inflammtory compounds, quercetin has been identified as the most potent compound in reference to its inhibitory constant (47.01) and binding energy (-5.90 kcal/mol) to bacterial protein. Our data suggest that methanol extract of B. sapida fruit posses medicinally significant anti-inflammatory compounds and thus justifies the use of this fruit as folklore medicine for preventing inflammation related diseases. PMID- 26527854 TI - Molecular marker database for efficient use in agricultural breeding programs. AB - The National Agricultural Biotechnology Information Center (NABIC) constructed a web-based molecular marker database to provide information about 7,847 sequence tagged site (STS) markers identified in the 11 species using a next generation sequencing (NGS) technologies. The database consists of three major functional categories: keyword search, detailed viewer and download function. The molecular marker annotation table provides detailed information such as ownership information, basic information, and STS-related characterization information. AVAILABILITY: The database is available for free at http://nabic.rda.go.kr/Molecularmarker. PMID- 26527856 TI - Multiple Family Groups for Child Behavior Difficulties Retention Among Child Welfare-Involved Caregivers. AB - : Among children who remain at home with their permanent caregivers following a child welfare investigation, few who manifest emotional and behavioral difficulties actually engage in mental health treatment. The Multiple Family Group service delivery model to reduce childhood disruptive behavior disorders (MFG) has shown promise in engaging child welfare-involved families. This qualitative study examines caregiver perceptions of factors that influence retention in MFGs among child welfare-involved families. METHODS: Twenty-five predominantly Black and Hispanic adult (ages 26-57) female caregivers with child welfare services involvement participated in individual, in-depth interviews about their experience with MFGs. Transcribed interview data were thematically coded guided by grounded theory methodology. Emergent themes were subsequently organized into a conceptual framework. RESULTS: Within the overarching influence of child welfare services involvement, specific components of MFGs influencing retention included the quality of interaction among group members, group facilitators' attentive approach with caregivers, supports designed to overcome logistical barriers (i.e., child care, transportation expenses, meals), and perceptions of MFG content and activities as fun and helpful. Caregiver factors, including their mental health and personal characteristics, as well as children's behavior, (i.e., observed changes in behavioral difficulties) were also associated with retention. CONCLUSIONS: High acceptability suggest utility for implementing MFGs within settings serving child welfare involved families, with additional modifications to tailor to setting and client features. PMID- 26527857 TI - Addressing Parental Mental Health Within Interventions for Children: A Review. AB - PURPOSE: Untreated parent mental health problems have deleterious effects upon the family, yet caregivers are unlikely to receive services for their emotional health. We conducted a review of treatments and services for children and adolescents that also offered services to parents. METHODS: Child treatment and service studies were included in the present study if they analyzed parent symptoms or diagnoses over time, and the intervention contained a parent component. RESULTS: Of 200 studies reviewed, 20 contained a component for the parent and assessed the parent's emotional health at multiple time points. Depression and anxiety were the most commonly studied parental mental health problem; most parent components consisted of behavioral strategies in service of the child's psychological health. CONCLUSION: Major shifts in health care policy affecting mental health services provide an opportunity to create integrated and coordinated health and behavioral health systems. Attention must be given to ensure that the workforce of providers, the administrative structures, and the reimbursement strategies are strengthened and connected to serve the needs of parents/caregivers and children in order to enhance family outcomes. PMID- 26527858 TI - Implementation of a Cross-specialty Training Program in Basic Laparoscopy. AB - BACKGROUND AND OBJECTIVES: Several surgical specialties use laparoscopy and share many of the same techniques and challenges, such as entry approaches, equipment, and complications. However, most basic training programs focus on a single specialty. The objective of this study was to describe the implementation of a regional cross-specialty training program for basic laparoscopy, to increase the flexibility of educational courses, and to provide a more efficient use of simulation equipment. METHODS: Using a regional training program in basic laparoscopy for gynecology as a model, we developed a cross-specialty training program for residents in surgery, gynecology, urology, and thoracic surgery. We reviewed data on training for the first year of the program and evaluated the program by using a scoring system for quality criteria for laparoscopic curricula and skills. RESULTS: We held 6 full-day theoretical courses involving 67 residents between September 1, 2013, and August 31, 2014. In the weeks following each course, residents practiced in a self-directed, distributed, and proficiency based manner at a simulation center and in local hospital departments. A total of 57 residents completed the self-practice and a subsequent practical animal laboratory-based course. The structure of the training program was evaluated according to identified quality criteria for a skills laboratory, and the program scored 38 of a maximum 62 points. DISCUSSION: Implementation of a regional cross specialty training program in basic laparoscopy is feasible. There are several logistic benefits of using a cross-specialty approach; however, it is important that local departments include specialty-specific components, together with clinical departmental follow-up. PMID- 26527859 TI - A review of the efficacy of mitomycin C in glaucoma filtration surgery. AB - The success of trabeculectomy, which is considered the gold standard in the surgical treatment of glaucoma, depends on the wound healing response. The introduction of antiproliferative agents such as mitomycin C (MMC) has increased the success rates of trabeculectomy. However, complications due to these agents can be challenging to manage. Hence, it is important to determine the most efficacious dose and duration of exposure. Multiple studies suggest that many factors, including but not limited to MMC preparation, different concentrations, different exposure times, and method of application may affect success rate, and these factors were reviewed in this article. We concluded that lower concentrations of MMC that are prepared and applied in a standardized fashion, such as that using the Mitosol((r)) kit (for 2-3 minutes) during trabeculectomy, could potentially provide trabeculectomy success rates similar to that reported with off-label preparations, and that such a treatment regime could result in in lower complication rates than higher doses of MMC. PMID- 26527861 TI - Erratum: The role of taxanes in triple-negative breast cancer: literature review [Corrigendum]. PMID- 26527860 TI - Adenoviral delivery of truncated MMP-8 fused with the hepatocyte growth factor mutant 1K1 ameliorates liver cirrhosis and promotes hepatocyte proliferation. AB - Liver cirrhosis is a chronic liver disease caused by chronic liver injury, which activates hepatic stellate cells (HSCs) and the secretion of extracellular matrix (ECM). Cirrhosis accounts for an extensive level of morbidity and mortality worldwide, largely due to lack of effective treatment options. In this study, we have constructed a fusion protein containing matrix metal-loproteinase 8 (MMP-8) and the human growth factor mutant 1K1 (designated cMMP8-1K1) and delivered it into hepatocytes and in vivo and in cell culture via intravenous injection of fusion protein-harboring adenovirus. In doing so, we found that the cMMP8-1K1 fusion protein promotes the proliferation of hepatocytes, likely resulting from the combined inhibition of type I collagen secretion and the degradation of the ECM in the HSCs. This fusion protein was also observed to ameliorate liver cirrhosis in our mouse model. These changes appear to be linked to changes in downstream gene expression. Taken together, these results suggest a possible strategy for the treatment of liver cirrhosis and additional work is warranted. PMID- 26527862 TI - Bifunctional fused polypeptide inhibits the growth and metastasis of breast cancer. AB - Breast cancer is the most common cancer and the leading cause of cancer-related death among women worldwide, with urgent need to develop new therapeutics. Targeted therapy is a promising strategy for breast cancer therapy. Stromal derived factor-1/CXC chemokine receptor 4 (CXCR4) has been implicated in the metastasis of breast cancer, which renders it to be therapeutic target. This study aimed to evaluate the anticancer effect of fused TAT- DV1-BH3 polypeptide, an antagonist of CXCR4, and investigate the underlying mechanism for the cancer cell-killing effect in the treatment of breast cancer in vitro and in vivo. This results in a potent inhibitory effect of fused TAT-DV1-BH3 polypeptide on tumor growth and metastasis in nude mice bearing established MDA-MB-231 tumors. Fused TAT-DV1-BH3 polypeptide inhibited the proliferation of MDA-MB-231 and MCF-7 cells but did not affect that of HEK-293 cells. The fused TAT-DV1-BH3 polypeptide colocalized with mitochondria and exhibited a proapoptotic effect through the regulation of caspase-9 and -3. Furthermore, the fused TAT-DV1-BH3 polypeptide suppressed the migration and invasion of the highly metastatic breast cancer cell line MDA-MB-231 in a concentration-dependent manner. Notably, the DV1-mediated inhibition of the stromal-derived factor-1/CXCR4 pathway contributed to the antimetastasis effect, evident from the reduction in the level of phosphoinositide 3 kinase and matrix metalloproteinase 9 in MDA-MB-231 cells. Collectively, these results indicate that the apoptosis-inducing effect and migration- and invasion-suppressing effect explain the tumor regression and metastasis inhibition in vivo, with the involvement of caspase- and CXCR4 mediated signaling pathway. The data suggest that the fused TAT-DV1-BH3 polypeptide is a promising agent for the treatment of breast cancer, and more studies are warranted to fully elucidate the therapeutic targets and molecular mechanism. PMID- 26527863 TI - Safety and pharmacokinetics of dicloxacillin in healthy Chinese volunteers following single and multiple oral doses. AB - BACKGROUND: Dicloxacillin, a semisynthetic isoxazolyl penicillin antibiotic, has antimicrobial activity against a wide variety of gram-positive bacteria including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumonia, Streptococcus epidermidis, Streptococcus viridans, Streptococcus agalactiae, and Neisseria meningitidis. The objective of this study was to evaluate the safety and pharmacokinetic profile of dicloxacillin after single and multiple oral dose in healthy Chinese volunteers. METHODS: A single-center, open-label, randomized, two-phase study was conducted in 16 subjects. In the single-dose phase, subjects were randomly assigned to receive single doses of 0.25, 0.5, 1.0, and 2.0 g of dicloxacillin sodium capsule in a 4-way crossover design with a 5-day washout period between administrations. In the multiple-dose phase, subjects were assigned to receive 0.25 or 0.5 g every 6 hours for 3 days in a 2-way crossover design. Plasma and urine pharmacokinetic samples were assayed by a validated high performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated and analyzed statistically. Safety assessments were conducted throughout the study. RESULTS: Following a single oral dose of 0.25-2.0 g dicloxacillin sodium, the maximum plasma drug concentration (Cmax) and the corresponding values for the area under the concentration- time curve from 0 to 10 hours (AUC0-10 h) increased in a dose-proportional manner. The mean elimination half-life (t1/2) was in the range of 1.38-1.71 hours. Dicloxacillin was excreted in its unchanged form via the kidney, with no tendency of accumulation, and varied from 38.65% to 50.10%. No appreciable accumulation of drug occurred with multiple oral doses of dicloxacillin. No serious adverse events were reported. Adverse events were generally mild. CONCLUSION: Dicloxacillin was safe and well tolerated in the volunteers and displayed linear increases in the Cmax and AUC0-10 h values. PMID- 26527864 TI - 4-Hydroxyisoleucine ameliorates an insulin resistant-like state in 3T3-L1 adipocytes by regulating TACE/TIMP3 expression. AB - BACKGROUND: Obesity-associated insulin resistance (IR) is highly correlated with soluble tumor necrosis factor-alpha (sTNF-alpha), which is released from transmembranous TNF-alpha by TNF-alpha converting enzyme (TACE). In vivo, TACE activity is suppressed by tissue inhibitor of metalloproteinase 3 (TIMP3). Agents that can interact with TACE/TIMP3 to improve obesity-related IR would be highly valuable. In the current study, we assessed whether (2S,3R,4S)-4 hydroxyisoleucine (4-HIL) could modulate TACE/TIMP3 and ameliorate an obesity induced IR-like state in 3T3-L1 adipocytes. MATERIALS AND METHODS: 3T3-L1 adipocytes were incubated in the presence of 25 mM glucose and 0.6 nM insulin to induce an IR-like state, and were then treated with different concentrations of 4 HIL or 10 uM pioglitazone (positive control). The glucose uptake rate was determined using the 2-deoxy-[(3)H]-D-glucose method, and the levels of sTNF alpha in the cell supernatant were determined using ELISA. The protein expression of TACE, TIMP3, and insulin signaling-related molecules was measured using western blotting. RESULTS: Exposure to high glucose and insulin for 18 hours increased the levels of sTNF-alpha in the cell supernatant. The phosphorylation of insulin receptor substrate-1 (IRS-1) Ser(307) and Akt Ser(473) was increased, whereas the protein expression of IRS-1, Akt, and glucose transporter-4 was decreased. The insulin-induced glucose uptake was reduced by 67% in 3T3-L1 adipocytes, which indicated the presence of an IR-like state. The above indexes, which demonstrated the successful induction of an IR-like state, were reversed by 4-HIL in a dose-dependent manner by downregulating and upregulating the protein expression of TACE and TIMP3 proteins, respectively. CONCLUSION: 4-HIL improved an obesity-associated IR-like state in 3T3-L1 adipocytes by targeting TACE/TIMP3 and the insulin signaling pathway. PMID- 26527865 TI - Health-related quality of life in patients with depression treated with duloxetine or a selective serotonin reuptake inhibitor in a naturalistic outpatient setting. AB - PURPOSE: To assess the levels of quality of life (QoL) in major depressive disorder (MDD) patients treated with either duloxetine or a selective serotonin reuptake inhibitor (SSRI) as monotherapy for up to 6 months in a naturalistic clinical setting mostly in the Middle East, East Asia, and Mexico. PATIENTS AND METHODS: Data for this post hoc analysis were taken from a 6-month prospective observational study involving 1,549 MDD patients without sexual dysfunction. QoL was measured using the EQ-5D instrument. Depression severity was measured using the Clinical Global Impression of Severity and the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16), while pain severity was measured using the pain items of the Somatic Symptom Inventory. Regression analyses were performed to compare the levels of QoL between duloxetine-treated (n=556) and SSRI-treated (n=776) patients, adjusting for baseline patient characteristics. RESULTS: These MDD patients, on average, had moderately impaired QoL at baseline, and the level of QoL impairment was similar between the duloxetine and SSRI groups (EQ-5D score of 0.46 [SD =0.32] in the former and 0.47 [SD =0.33] in the latter, P=0.066). Both descriptive and regression analyses confirmed QoL improvements in both groups during follow-up, but duloxetine treated patients achieved higher QoL. At 24 weeks, the estimated mean EQ-5D score was 0.90 in the duloxetine cohort, which was statistically significantly higher than that of 0.83 in the SSRI cohort (P<0.001). Notably, pain severity at baseline was also statistically significantly associated with poorer QoL during follow-up (P<0.001). In addition, this association was observed in the subgroup of SSRI-treated patients (P<0.001), but not in that of duloxetine-treated patients (P=0.479). CONCLUSION: Depressed patients treated with duloxetine achieved higher QoL, compared to those treated with SSRIs, possibly in part due to its moderating effect on the link between pain and poorer QoL. PMID- 26527866 TI - Repeated vertebral augmentation for new vertebral compression fractures of postvertebral augmentation patients: a nationwide cohort study--how useful is the current clinical gold standard for fracture risk? PMID- 26527867 TI - Is it the resistance training itself or the combined associated weight loss that improves the metabolic syndrome-related phenotypes in postmenopausal women? PMID- 26527868 TI - Body composition as a frailty marker for the elderly community. AB - BACKGROUND: Body composition (BC) in the elderly has been associated with diseases and mortality; however, there is a shortage of data on frailty in the elderly. OBJECTIVE: To investigate the association between BC and frailty, and identify BC profiles in nonfrail, prefrail, and frail elderly people. METHODS: A cross-sectional study comprising 235 elderly (142 females and 93 males) aged >=65 years, from the city of Amparo, State of Sao Paulo, Brazil, was undertaken. Sociodemographic and cognitive features, comorbidities, medication, frailty, body mass index (BMI), muscle mass, fat mass, bone mass, and fat percent (%) data were evaluated. Aiming to examine the relationship between BC and frailty, the Mann Whitney and Kruskal-Wallis nonparametric tests were applied. The statistical significance level was P<0.05. RESULTS: The nonfrail elderly showed greater muscle mass and greater bone mass compared with the prefrail and frail ones. The frail elderly had greater fat % than the nonfrail elderly. There was a positive association between grip strength and muscle mass with bone mass (P<0.001), and a negative association between grip strength and fat % (P<0.001). Gait speed was positively associated with fat mass (P=0.038) and fat % (P=0.002). The physical activity level was negatively associated with fat % (P=0.022). The weight loss criterion was positively related to muscle mass (P<0.001), bone mass (P=0.009), fat mass (P=0.018), and BMI (P=0.003). There was a negative association between fatigue and bone mass (P=0.008). DISCUSSION: Frailty in the elderly was characterized by a BC profile/phenotype with lower muscle mass and lower bone mass and with a higher fat %. The BMI was not effective in evaluating the relationship between BC and frailty. The importance of evaluating the fat % was verified when considering the tissue distribution in the elderly BC. PMID- 26527869 TI - The inevitable drift to triple therapy in COPD: an analysis of prescribing pathways in the UK. AB - BACKGROUND: Real-world prescription pathways leading to triple therapy (TT) (inhaled corticosteroid [ICS] plus long-acting beta2-agonist bronchodilator [LABA] plus long-acting muscarinic antagonist) differ from Global initiative for chronic Obstructive Lung Disease [GOLD] and National Institute for Health and Care Excellence treatment recommendations. This study sets out to identify COPD patients without asthma receiving TT, and determine the pathways taken from diagnosis to the first prescription of TT. METHODS: This was a historical analysis of COPD patients without asthma from the Optimum Patient Care Research Database (387 primary-care practices across the UK) from 2002 to 2010. Patient disease severity was classified using GOLD 2013 criteria. Data were analyzed to determine prescribing of TT before, at, and after COPD diagnosis; the average time taken to receive TT; and the impact of lung function grade, modified Medical Research Council dyspnea score, and exacerbation history on the pathway to TT. RESULTS: During the study period, 32% of patients received TT. Of these, 19%, 28%, 37%, and 46% of patients classified as GOLD A, B, C, and D, respectively, progressed to TT after diagnosis (P<0.001). Of all patients prescribed TT, 25% were prescribed TT within 1 year of diagnosis, irrespective of GOLD classification (P=0.065). The most common prescription pathway to TT was LABA plus ICS. It was observed that exacerbation history did influence the pathway of LABA plus ICS to TT. CONCLUSION: Real life UK prescription data demonstrates the inappropriate prescribing of TT and confirms that starting patients on ICS plus LABA results in the inevitable drift to overuse of TT. This study highlights the need for dissemination and implementation of COPD guidelines to physicians, ensuring that patients receive the recommended therapy. PMID- 26527870 TI - Candidate genes for COPD: current evidence and research. AB - COPD is a common complex disease characterized by progressive airflow limitation. Several genome-wide association studies (GWASs) have discovered genes that are associated with COPD. Recently, candidate genes for COPD identified by GWASs include CHRNA3/5 (cholinergic nicotine receptor alpha 3/5), IREB2 (iron regulatory binding protein 2), HHIP (hedgehog-interacting protein), FAM13A (family with sequence similarity 13, member A), and AGER (advanced glycosylation end product-specific receptor). Their association with COPD susceptibility has been replicated in multiple populations. Since these candidate genes have not been considered in COPD, their pathological roles are still largely unknown. Herein, we review some evidences that they can be effective drug targets or serve as biomarkers for diagnosis or subtyping. However, more study is required to understand the functional roles of these candidate genes. Future research is needed to characterize the effect of genetic variants, validate gene function in humans and model systems, and elucidate the genes' transcriptional and posttranscriptional regulatory mechanisms. PMID- 26527871 TI - Respiratory infectious phenotypes in acute exacerbation of COPD: an aid to length of stay and COPD Assessment Test. AB - PURPOSE: To investigate the respiratory infectious phenotypes and their impact on length of stay (LOS) and the COPD Assessment Test (CAT) Scale in acute exacerbation of COPD (AECOPD). PATIENTS AND METHODS: We categorized 81 eligible patients into bacterial infection, viral infection, coinfection, and non infectious groups. The respiratory virus examination was determined by a liquid bead array xTAG Respiratory Virus Panel in pharyngeal swabs, while bacterial infection was studied by conventional sputum culture. LOS and CAT as well as demographic information were recorded. RESULTS: Viruses were detected in 38 subjects, bacteria in 17, and of these, seven had both. Influenza virus was the most frequently isolated virus, followed by enterovirus/rhinovirus, coronavirus, bocavirus, metapneumovirus, parainfluenza virus types 1, 2, 3, and 4, and respiratory syncytial virus. Bacteriologic analyses of sputum showed that Pseudomonas aeruginosa was the most common bacteria, followed by Acinetobacter baumannii, Klebsiella, Escherichia coli, and Streptococcus pneumoniae. The longest LOS and the highest CAT score were detected in coinfection group. CAT score was positively correlated with LOS. CONCLUSION: Respiratory infection is a common causative agent of exacerbations in COPD. Respiratory coinfection is likely to be a determinant of more severe acute exacerbations with longer LOS. CAT score may be a predictor of longer LOS in AECOPD. PMID- 26527872 TI - Lipid nanoparticles for cyclosporine A administration: development, characterization, and in vitro evaluation of their immunosuppression activity. AB - Cyclosporine A (CsA) is an immunosuppressant commonly used in transplantation for prevention of organ rejection as well as in the treatment of several autoimmune disorders. Although commercial formulations are available, they have some stability, bioavailability, and toxicity related problems. Some of these issues are associated with the drug or excipients and others with the dosage forms. With the aim of overcoming these drawbacks, lipid nanoparticles (LN) have been proposed as an alternative, since excipients are biocompatible and also a large amount of surfactants and organic solvents can be avoided. CsA was successfully incorporated into LN using the method of hot homogenization followed by ultrasonication. Three different formulations were optimized for CsA oral administration, using different surfactants: Tween((r)) 80, phosphatidylcholine, taurocholate and Pluronic((r)) F127 (either alone or mixtures). Freshly prepared Precirol nanoparticles showed mean sizes with a narrow size distribution ranging from 121 to 202 nm, and after freeze-drying were between 163 and 270 nm, depending on the stabilizer used. Surface charge was negative in all LN developed. High CsA entrapment efficiency of approximately 100% was achieved. Transmission electron microscopy was used to study the morphology of the optimized LN. Also, the crystallinity of the nanoparticles was studied by X-ray powder diffraction and differential scanning calorimetry. The presence of the drug in LN surfaces was confirmed by X-ray photoelectron spectroscopy. The CsA LN developed preserved their physicochemical properties for 3 months when stored at 4 degrees C. Moreover, when the stabilizer system was composed of two surfactants, the LN formulations were also stable at room temperature. Finally, the new CsA formulations showed in vitro dose-dependent immuno-suppressive effects caused by the inhibition of IL-2 levels secreted from stimulated Jurkat cells. The findings obtained in this paper suggest that new lipid nanosystems are a good alternative to produce physicochemically stable CsA formulations for oral administration. PMID- 26527874 TI - A new method of wound treatment: targeted therapy of skin wounds with reactive oxygen species-responsive nanoparticles containing SDF-1alpha. AB - OBJECTIVE: To accelerate wound healing through promoting vascularization by using reactive oxygen species (ROS)-responsive nanoparticles loaded with stromal cell derived factor-1alpha(SDF-1alpha). METHODS: The ROS-reactive nanomaterial poly (1,4-phenyleneacetone dimethylene thioketal) was synthesized, and its physical and chemical properties were characterized. ROS-responsive nanoparticles containing SDF-1alpha were prepared through a multiple emulsion solvent evaporation method. The loading capacity, stability, activity of the encapsulated protein, toxicity, and in vivo distribution of these nanoparticles were determined. These nanoparticles were administered by intravenous infusion to mice with full-thickness skin defects to study their effects on the directed chemotaxis of bone marrow mesenchymal stem cells, wound vascularization, and wound healing. RESULTS: The synthesized ROS-reactive organic polymer poly-(1,4 phenyleneacetone dimethylene thioketal) possessed a molecular weight of approximately 11.5 kDa with a dispersity of 1.97. ROS-responsive nanoparticles containing SDF-1alpha were prepared with an average diameter of 110 nm and a drug loading capacity of 1.8%. The encapsulation process showed minimal effects on the activity of SDF-1alpha, and it could be effectively released from the nanoparticles in the presence of ROS. Encapsulated SDF-1alpha could exist for a long time in blood. In mice with full-thickness skin defects, SDF-1alpha was effectively released and targeted to the wounds, thus promoting the chemotaxis of bone marrow mesenchymal stem cells toward the wound and its periphery, inducing wound vascularization, and accelerating wound healing. PMID- 26527875 TI - Neuropsychological and neuroimaging markers in prediction of cognitive impairment after ischemic stroke: a prospective follow-up study. AB - BACKGROUND: There are few longitudinal studies with controversial results examining delayed changes in cognition after ischemic stroke and predictive values of neuropsychological and neuroimaging markers. OBJECTIVE: The objectives of this study were to evaluate the delayed changes in cognition in poststroke patients and their relationship to the neuropsychological and neuroimaging markers measured during the acute poststroke phase. METHODS: Eighty-five first ever stroke inpatients (mean age 65.6+/-5.6 years) without previous cognitive complaints were prospectively evaluated with a comprehensive neuropsychological battery at the 5th day and the 1st, 6th, and 12th months. A wide range of clinical, radiological, and neuropsychological variables were examined. RESULTS: Our results showed significantly poorer performance on mini-mental state examination, memory, attention/executive functions, and processing speed in patients with stroke in comparison with stroke-free cognitively intact controls. Multiple regression analysis revealed that hippocampal atrophy is the strongest predictor of delayed cognitive impairment. Secondary divided subgroups according to Isaacs Set Test (IST) score showed that patients with IST score <=28 had different patterns of cognitive and neurological impairment after 1 year. Baseline impairments in attention/executive functions and memory were associated with development of dementia in poststroke patients. CONCLUSION: Executive functioning deficit appears to have a predictive power for cognitive impairment progression. The study suggests that IST as a screening test has a potential to be a reliable and quick tool for poststroke cognitive impairment evaluation and delayed cognitive and neurological outcome. Hippocampal atrophy was the strongest predictor for cognitive impairment outcome, even in poststroke cognitive impairment. The findings may set the stage for better poststroke management. PMID- 26527873 TI - Diagnosis of prostate cancer via nanotechnological approach. AB - Prostate cancer is one of the leading causes of cancer-related deaths among the Caucasian adult males in Europe and the USA. Currently available diagnostic strategies for patients with prostate cancer are invasive and unpleasant and have poor accuracy. Many patients have been overly or underly treated resulting in a controversy regarding the reliability of current conventional diagnostic approaches. This review discusses the state-of-the-art research in the development of novel noninvasive prostate cancer diagnostics using nanotechnology coupled with suggested diagnostic strategies for their clinical implication. PMID- 26527876 TI - Symptomatic flexible flatfoot in adults: subtalar arthroereisis. AB - Flexible flatfoot is a common deformity in pediatric and adult populations. In this study, we aimed to evaluate the functional and radiographic results of subtalar arthroereisis in adult patients with symptomatic flexible flatfoot. We included 26 feet in 16 patients who underwent subtalar arthroereisis for symptomatic flexible flatfoot. Radiographic examination included calcaneal inclination angle, lateral talocalcaneal angle, Meary's angle, anteroposterior talonavicular angle, and Kite's angle. The clinical assessment was based on the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot scale and a visual analog scale (VAS). The mean follow-up was 15.1+/-4.7 months. The mean preoperative AOFAS score was 53+/-6.6, while the mean AOFAS score at the last follow-up visit was 75+/-11.2 (P<0.05). The mean visual analog scale score was 6.9+/-0.6 preoperatively and 4.1+/-1.4 at the last follow-up visit (P<0.05). The mean preoperative and postoperative values measured were 13.4 degrees +/-3.3 degrees and 14.6 degrees +/-2.7 degrees for calcaneal inclination angles (P<0.05); 35.7 degrees +/-6.9 degrees and 33.2 degrees +/-5.3 degrees for lateral talocalcaneal angles (P>0.05); 8 degrees +/-5.3 degrees and 3.3+/-3 for Meary's angles (P<0.05); 5.6 degrees +/-3.5 degrees and 2.6 degrees +/-1.5 degrees for anteroposterior talonavicular angles (P<0.05); and 23.7 degrees +/ 6.1 degrees and 17.7 degrees +/-5 degrees for Kite's angles, respectively (P<0.05). Implants were removed in three feet (11.5%). Subtalar arthroereisis is a minimally invasive procedure that can be used in the surgical treatment of adults with symptomatic flexible flatfoot. This procedure provided radiological and functional recovery in our series of patients. PMID- 26527877 TI - Patterns of treatment and costs of intermediate and advanced hepatocellular carcinoma management in four Italian centers. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a severe health condition associated with high hospitalizations and mortality rates, which also imposes a relevant economic burden. PURPOSE: The aim of the present survey is to investigate treatment strategies and related costs for HCC in the intermediate and advanced stages of the disease. PATIENTS AND METHODS: The survey was conducted in four Italian centers through structured interviews with physicians. Information regarding the stage of disease, treatments performed, and related health care resource consumption was included in the questionnaire. Direct health care cost per patient associated with the most relevant treatments such as sorafenib, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE) was evaluated. RESULTS: Between 2013 and 2014, 285 patients with HCC were treated in the four participating centers; of these, 80 were in intermediate stage HCC (Barcelona Clinic Liver Cancer Classification [BCLC] B), and 57 were in the advanced stage of the disease (BCLC C). In intermediate stage HCC, the most frequent first-line treatment was TACE (63%) followed by sorafenib (15%), radiofrequency ablation (14%), and TARE (1.3%). In the advanced stage of HCC, the most frequently used first-line therapy was sorafenib (56%), followed by best supportive care (21%), TACE (18%), and TARE (3.5%). The total costs of treatment per patient amounted to ?12,214.54 with sorafenib, ?13,418.49 with TACE, and ?26,106.08 with TARE. Both in the intermediate and in the advanced stage of the disease, variability in treatment patterns among centers was observed. CONCLUSION: The present analysis raises for the first time the awareness of the overall costs incurred by the Italian National Healthcare System for different treatments used in intermediate and advanced HCC. Further investigations would be important to better understand the effective health care resource usage. PMID- 26527878 TI - The role of blood groups in the development of diabetes mellitus after gestational diabetes mellitus. AB - INTRODUCTION: Gestational diabetes mellitus (GDM) is a common condition that is defined as glucose intolerance of varying degree with onset or first recognition during pregnancy and it affects approximately 5% of all pregnancies all over the world. GDM is not only associated with adverse pregnancy outcomes such as macrosomia, dystocia, birth trauma, and metabolic complications in newborns, but it is also a strong predictor of transitioning to overt DM postpartum. The association of ABO blood groups with DM has been observed before in several epidemiological and genetic studies and resulted with inconsistent findings, but still there are not enough studies in the literature about the association of ABO blood groups with GDM. In this study, we aimed at investigating any possible relationship between the ABO blood group system and GDM and also the transitioning of GDM to overt DM postpartum, in Turkey. PATIENTS AND METHODS: A total of 233 patients with GDM from Kayseri Training and Research Hospital between 2002 and 2012 were included in the study. The cases that have serologically determined blood groups and Rh factor in the hospital records were included in the study, and the patients with unknown blood groups were excluded. Patients were classified according to blood groups (A, B, AB, and O) and Rh status (+/-). GDM was diagnosed based on the glucose cut-points of the International Association of the Diabetes and Pregnancy Society Groups. The distributions of blood groups of the patients with GDM were compared with the distribution of blood groups of 17,314 healthy donors who were admitted to the Turkish Red Crescent Blood Service in our city in 2012. RESULTS: There was a significant difference between the patients with GDM and control group in terms of distribution of ABO blood groups. Blood group AB was found to be higher in the patients with GDM compared to the control group (P=0.029). When the patients were compared according to the development of DM, the ratio of group O was higher than others, while the ratio of group B was lower in the group developing DM (P=0.001). There was a significant difference between the groups - GDM patients with or without DM - in terms of distribution of ABO blood groups with Rh factor and the ratio of developing DM is found to be higher in patients with +Rh factor among all the blood groups except for group B (P=0.008). CONCLUSION: In this study, we found a higher risk of GDM for the patients with blood group AB, which means that we have to be more careful on the follow-up of pregnant women with blood group AB. The patients with GDM of blood group O are under a higher risk of developing DM and also +Rh factor must be considered as another risk factor, so these patients should be closely followed postpartum by the oral glucose tolerance tests. To our knowledge, this is the first analysis that investigates the association between the ABO blood groups and transitioning to DM after GDM. PMID- 26527879 TI - Effect of fluid loading on left ventricular volume and stroke volume variability in patients with end-stage renal disease: a pilot study. AB - PURPOSE: The aim of this study was to investigate fluid loading-induced changes in left ventricular end-diastolic volume (LVEDV) and stroke volume variability (SVV) in patients with end-stage renal disease (ESRD) using real-time three dimensional transesophageal echocardiography and the Vigileo-FloTrac system. PATIENTS AND METHODS: After obtaining ethics committee approval and informed consent, 28 patients undergoing peripheral vascular procedures were studied. Fourteen patients with ESRD on hemodialysis (HD) were assigned to the HD group and 14 patients without ESRD were assigned to the control group. Institutional standardized general anesthesia was provided in both groups. SVV was measured using the Vigileo-FloTrac system. Simultaneously, a full-volume three-dimensional transesophageal echocardiography dataset was acquired to measure LVEDV, left ventricular end-systolic volume, and left ventricular ejection fraction. Measurements were obtained before and after loading 500 mL hydroxyethyl starch over 30 minutes in both groups. RESULTS: In the control group, intravenous colloid infusion was associated with a significant decrease in SVV (13.8%+/-2.6% to 6.5%+/-2.6%, P<0.001) and a significant increase in LVEDV (83.6+/-23.4 mL to 96.1+/-28.8 mL, P<0.001). While SVV significantly decreased after infusion in the HD group (16.2%+/-6.0% to 6.2%+/-2.8%, P<0.001), there was no significant change in LVEDV. CONCLUSION: Our preliminary data suggest that fluid responsiveness can be assessed not by LVEDV but also by SVV due to underlying cardiovascular pathophysiology in patients with ESRD. PMID- 26527880 TI - Progression of carotid-artery disease in type 2 diabetic patients: a cohort prospective study. AB - In order to assess the progression of carotid-artery disease in type 2 diabetic cohort (n=207 patients), the dynamic change in carotid intima-media thickness (CIMT) and the occurrence of plaques were followed for a period of 31.35+/-10.59 months. The mean CIMT at the beginning of the study was 0.9178+/-0.1447 mm, with a maximal value of 1.1210+/-0.2366 mm. The maximal value of CIMT changed by 0.07 mm/year. Progression of CIMT was noted in 86.8% and its regression in 7.8% of patients. The occurrence of carotid plaques was detected in 41.8% of patients. Multiple regression analysis revealed the maximal value of CIMT to be associated with diastolic blood pressure, despite mean CIMT being predicted by body mass index. The presence of peripheral arterial disease and hypo-high-density lipoproteinemia were found to be predictors for the occurrence of carotid plaques. Our data have clinical implications in predicting risk factors for the progression of carotid-artery disease in type 2 diabetic patients for their appropriate management. PMID- 26527881 TI - Differential regulation of human Eag1 channel expression by serum and epidermal growth factor in lung and breast cancer cells. AB - Oncogenic ether a-go-go-1 (Eag1) potassium channels are overexpressed in most primary human solid tumors. Low oxygen and nutrient/growth factor concentrations play critical roles in tumorigenesis. However, the mechanisms by which tumor cells survive and proliferate under growth factor-depleted conditions remain elusive. Here, we investigated whether serum-deprived conditions and epidermal growth factor (EGF) regulate Eag1 expression in human lung and breast cancer cells. The human cancer cell lines A549 and MCF-7 (from the lungs and breast, respectively) were obtained from the American Type Culture Collection and cultured following the manufacturer's recommendations. Eag1 gene and protein expression were studied by real-time PCR and immunocytochemistry, respectively. Cell proliferation was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, and ERK1/2 phosphorylation was investigated by Western blot. Serum-deprived conditions increased Eag1 mRNA and protein expression in both cell lines. This Eag1 upregulation was prevented by EGF and the ERK1/2 inhibitor U0126 in only lung cancer cells; vascular endothelial growth factor did not prevent Eag1 upregulation. Our results suggest that Eag1 may act as a survival and mitogenic factor under low-serum and nutrient conditions and may be a clinical target during the early stages of tumor development. PMID- 26527882 TI - Mutation analysis underlying the downregulation of the thyroid hormone receptor beta1 gene in the Chinese breast cancer population. AB - PURPOSE: There are a growing number of reports suggesting that the aberrant expression and mutation of the thyroid hormone receptor beta1 (TRbeta1) gene is associated with the development of human neoplasms. However, its exact role in the pathogenesis of breast cancer remains elusive. In the present study, we analyzed the mRNA expression and mutations of the TRbeta1 gene in the Chinese breast cancer population. METHODS: The expression of TRbeta1 mRNA was examined by real-time quantitative reverse transcription polymerase chain reaction, and mutations in the TRbeta1 gene in the hotspot region that spans exons 7-10 were analyzed by polymerase chain reaction single-strand conformation polymorphism and automated DNA sequencing. RESULTS: TRbeta1 mRNA expression was significantly reduced in all 105 breast cancer specimens examined. A total of 20 samples showed truncating mutations within the exons 7-10 of the TRbeta1 gene, where eight cases harbored a frame shift mutation (five cases of c.850insA in exon 7 and three cases c.1028delA in exon 8), whereas missense mutations were observed in 12 breast cancer cases. The 20 cases with mutation in the TRbeta1 gene showed a reduction in TRbeta1 mRNA expression compared with that observed in matched normal tissues. The mutation was also correlated with menopausal stage and estrogen receptor status. CONCLUSION: The findings of the present study suggest that the aberrant expression and mutations of the TRbeta1 gene are associated with the development of breast cancer and that the mutations in the TRbeta1 gene partly serve as the underlying mechanism for TRbeta1 inactivation in the Chinese breast cancer population. PMID- 26527883 TI - Links between cancer stem cells and epithelial-mesenchymal transition. AB - The epithelial-mesenchymal transition (EMT) has been reported to be an important program that is often activated during the process of cancer invasion and metastasis. Cancer stem cells (CSCs) that can initiate and maintain cancer are also involved in invasion and metastasis of cancer. Recently, insights into the molecular mechanisms and functional features of mesenchymal cells have been greatly colored by findings that some of them have been endowed with the self renewal trait associated with normal tissue stem cells and CSCs. Among cancer cells experiencing EMT, only some of the most competent CSCs will succeed in planting in another organ. In this paper, we review the molecular mechanism behind the link of EMT and CSCs in cancer progression. PMID- 26527884 TI - Luteolin decreases invasiveness, deactivates STAT3 signaling, and reverses interleukin-6 induced epithelial-mesenchymal transition and matrix metalloproteinase secretion of pancreatic cancer cells. AB - Luteolin, a flavone, has been shown to exhibit anticancer properties. Here, we investigated whether luteolin affects epithelial-mesenchymal transition (EMT) and invasiveness of pancreatic cancer cell lines and their underlying mechanism. Pancreatic cancer cell lines PANC-1 and SW1990 were used in our study, and their EMT characters, matrix metalloproteinase (MMP) expression level, invasiveness, and signal transducer and activator of transcription 3 (STAT3) activity were determined after luteolin treatment. We also treated pancreatic cancer cells with interleukin-6 (IL-6) to see whether IL-6-induced activation of STAT3, EMT, and MMP secretion was affected by luteolin. We found that luteolin inhibits EMT and MMP2, MMP7, and MMP9 expression in a dose-dependent manner, similar to STAT3 signaling. Through Transwell assay, we found that invasiveness of pancreatic cancer cells was inhibited by luteolin. EMT characters and MMP secretion increase with STAT3 activity after IL-6 treatment and these effects, caused by IL-6, were inhibited by luteolin. We concluded that luteolin inhibits invasiveness of pancreatic cancer cells, and we speculated that luteolin inhibits EMT and MMP secretion likely through deactivation of STAT3 signaling. Luteolin has potential antitumor effects and merits further investigation. PMID- 26527885 TI - Association between pre-miR-27a functional polymorphism and risk of colorectal cancer in north Chinese Han population. AB - MicroRNA-27a (miR-27a) is deemed as an oncogene in malignancies including colorectal cancer (CRC), and rs895819 within pre-miR-27a may affect its secondary structure, leading to its aberrant expression and dysfunction of its targeted gene. We investigated genotype and allele frequencies of the locus in 412 I-III stage CRC cases and 412 age- and sex-matched healthy individuals to explore the possible association between them in the north of Chinese population. The results showed that frequencies of alleles A and G and genotypes GG, AG, and AA of the locus were 65.7%, 34.3%, 17.0%, 34.7%, and 48.3% in cases and 69.9%, 30.1%, 9.9%, 40.2%, and 49.8% in controls, respectively. GG genotype of the locus was positively associated with an increased risk of CRC in codominant (P=0.01, adjusted odds ratio =1.541, 95% confidence interval =1.110-2.239 for genotype GG vs AA) and recessive (P=0.003, adjusted odds ratio =1.855, 95% confidence interval =1.221-2.786 for genotype GG vs AA/GA) models, indicating that GG genotype of the locus might increase susceptibility to CRC. Moreover, genotypes AG and GG and allele G were significantly associated with III stage (P<0.001, P<0.001, and P=0.001, respectively), suggesting that the locus was associated with the progression of CRC. These results suggested that rs895819 within pre-miR 27a was involved in colorectal carcinogenesis and progression, genotype GG of the locus might be a susceptible factor for CRC, and allele G and allele G carrier (genotypes AG and GG) could predict CRC progression in north Chinese Han population. PMID- 26527886 TI - SOX2 expression is associated with FGFR fusion genes and predicts favorable outcome in lung squamous cell carcinomas. AB - OBJECTIVES: SOX2 is a gene that encodes for a transcription factor, which functions as an activator or suppressor of gene transcription. SOX2 amplification and overexpression have been found in various types of tumors and play important roles in cancer cells. The aim of the study was to evaluate SOX2 expression and amplification in lung squamous cell carcinomas (SCCs) and to determine the relationship with main clinicopathologic features, patient prognosis, and common driver mutations. MATERIALS AND METHODS: SOX2 protein levels were measured by immunohistochemistry, while SOX2 copy numbers were measured by fluorescence in situ hybridization in resected samples from 162 Chinese lung SCC patients. All patients were also analyzed for mutations in EGFR, HER2, BRAF, PIK3CA, NFE2L2, and FGFR fusion genes. Clinical characteristics, including age, sex, smoking status, stage, relapse-free survival (RFS), and overall survival (OS), were collected. RESULTS: SOX2 overexpression and amplification were observed in 58.6% and 45.9% of lung SCCs. Lung SCC patients with SOX2 overexpression were significantly associated with absence of malignant tumor family history (P=0.021), FGFR fusion gene (P=0.046), longer RFS (P=0.041), and OS (P=0.025). No correlation was found between SOX2 gene amplification and main clinicopathologic features, patient prognosis, or common driver mutations. CONCLUSION: SOX2 overexpression and amplification are common in lung SCCs. SOX2 over-expression was associated with FGFR fusion genes and predicted favorable outcome in lung SCCs. The underlying relationship of SOX2 and FGFR still needs further investigation. PMID- 26527887 TI - EGFR gene-mutation status correlated with therapeutic decision making in lung adenocarcinoma. AB - The purpose of this study was to investigate the correlation between EGFR mutation status and treatment efficacy for advanced lung adenocarcinoma patients. A total of 47 patients receiving erlotinib as first-line therapy were divided into two groups: the EGFR gene mutation group included 19 patients with known EGFR-sensitive mutations, and the EGFR-mutation status-unknown group comprised 28 patients with unknown EGFR-mutation status. Both objective response rate and disease-control rate were significantly higher in the EGFR-mutation group compared with the EGFR-unknown group (42.1% vs 14.2%, P=0.032; 94.7% vs 57.1%, P=0.005). Age, sex, smoking history, stage of disease, and tissue-sample source were not significantly correlated with the distributions of mutation status. In conclusion, it is important for advanced lung adenocarcinoma patients to undergo gene analysis before being assigned a molecularly targeted drug as first-line treatment. PMID- 26527888 TI - miR-195 is a key regulator of Raf1 in thyroid cancer. AB - Proto-oncogene Raf1 serves as a part of the mitogen-activated protein kinases/extracellular signal-regulated kinase signal transduction pathway and regulates cell migration, apoptosis, and differentiation. Although a large number of studies have shown that Raf1 is overexpressed in various kinds of cancer, little is known about the association between Raf1 and miRNAs in thyroid carcinoma. This study proves that Raf1 is overexpressed in thyroid cancer, which has been confirmed by many other studies. Besides, we identify that Raf1 is a direct target of miR-15a/b, miR-16, and miR-195 by dual luciferase reporter assay. We also find that the expression of miR-195 is downregulated in 50 pairs of thyroid tumor tissues compared to the adjacent nontumor tissues, while there is no difference in the expression of miR-15a/b and miR-16 between the groups. Furthermore, exogenous overexpression of miR-195 significantly inhibits the protein expression of Raf1 and blocks the thyroid cancer cell proliferation. Our findings delineate a novel mechanism for the regulation of Raf1 in thyroid cancer, which may help to provide a new direction for the treatment of thyroid cancer. PMID- 26527889 TI - Forkhead box protein A1 is a prognostic predictor and promotes tumor growth of gastric cancer. AB - Previous studies have demonstrated the cancer-type specific role of forkhead box protein A1 (FOXA1) in human malignancies. However, the clinical significance of FOXA1 and its biological function in gastric cancer remain unknown. In this study, the expression of FOXA1 in 80 pairs of gastric cancer tissues and corresponding non-tumor tissues was analyzed using immunohistochemistry and quantitative real-time polymerase chain reaction. We found that the levels of FOXA1 protein and mRNA in gastric cancer tissues were significantly higher than those in matched tumor-adjacent tissues. Furthermore, clinical association analysis indicated that the positive expression of FOXA1 was associated with adverse clinicopathological characteristics of gastric cancer patients including poor tumor differentiation, large tumor size, and advanced tumor-node-metastasis tumor stage. Notably, gastric cancer patients with positive expression of FOXA1 had a poorer 5-year overall survival and recurrence-free survival. In addition, FOXA1 knockdown remarkably inhibited cell proliferation and induced apoptosis in both SGC-7901 and MGC-803 cells. In vivo studies indicated that FOXA1 knockdown prominently suppressed tumor growth of gastric cancer in a nude mouse xenograft model. Mechanistically, we disclosed that the expression of Yes-associated protein was decreased accordingly after FOXA1 knockdown in both SGC-7901 and MGC 803 cells. Taken together, our data suggest that FOXA1 may serve as a promising prognostic indicator and an attractive therapeutic target of gastric cancer. PMID- 26527890 TI - Clinical ineffectiveness of latamoxef for Stenotrophomonas maltophilia infection. AB - OBJECTIVES: Stenotrophomonas maltophilia shows wide-spectrum resistance to antimicrobials and causes various infections in immunocompromised or critically ill patients with high mortality. In this era of antibiotics resistance, a revival of old antibiotics is now featured. We examined the clinical usefulness of latamoxef (LMOX) for the treatment of S. maltophilia infection. PATIENTS AND METHODS: The observational study was retrospectively performed at Okayama University Hospital (Okayama, Japan) from January 2011 to December 2013. LMOX was administered to 12 patients with S. maltophilia infection, with eleven of those patients being admitted to the intensive care unit. RESULTS: Underlying conditions of the patients included postoperation, hematological transplantation, hepatic transplantation, and burn. Major infectious foci were surgical site infection (six cases), respiratory infection (four cases), blood stream infection (three cases), and burn site infection (one case). The doses of LMOX administered ranged from 1 g/d to 3 g/d for ten adult patients and from 40 mg/kg/d to 80 mg/kg/d for two pediatric patients. Microbiologic failure was seen in five (41.7%) of 12 cases, and 30-day and hospital mortality rates were 25% and 50%, respectively. Minimum inhibitory concentrations of LMOX were higher in the deceased group (4-64 ug/mL) than in the surviving group (1-4 ug/mL). CONCLUSION: LMOX treatment is not recommended for the treatment of S. maltophilia infection. Further investigation would be needed before its clinical use. PMID- 26527891 TI - Emerging utility of once-weekly exenatide in patients with type 2 diabetes. AB - Type 2 diabetes mellitus (T2DM) is a major risk factor for the development of cardiovascular disease (CVD). Due to the ever increasing incidence of both T2DM and CVD and coexistence of these disorders, numerous agents have been developed over the years to target complications. We focus on the efficacy and safety perspective of a long-acting formulation of the glucagon-like peptide-1 analog exenatide. Our review focuses on the various landmark trials, efficacy, safety profile, and patient perspectives of weekly exenatide that delineates its current and future role in the treatment of patients with T2DM and CVD. PMID- 26527892 TI - Exploring the translational disconnect between the murine and human inflammatory response: analysis of LPS dose-response relationship in murine versus human cell lines and implications for translation into murine models of sepsis. AB - BACKGROUND: Inflammation forms an important part of the human innate immune system and is largely dependent on the activation of the "classical" NF-kappaB pathway through Toll-like receptors (TLRs). Understanding this has allowed researchers to explore roles of therapeutic targets in managing conditions such as sepsis. Recapitulating an inflammatory response using lipopolysaccharide (LPS), a "sterile" technique, can provide information that is dissimilar to the clinical condition. By examining NF-kappaB activation (through immunoblotting of the p65 subunit) in two separate cell lines (murine and human) and analyzing two murine models of sepsis (intraperitoneal [IP] LPS and IP stool inoculation), an evaluation of the translational disconnect between experimental and clinical sepsis can be made. METHODS: THP-1 (human) cells and RAW 264.7 (murine) cells were dosed with concentrations of LPS (human, 1 pg/mL to 100 ng/mL; murine, 30 pg/mL to 1,000 ng/mL) and nuclear actin and p65 were immunoblotted to measure changes in nuclear density. In vivo, C57BL/6 mice received either IP injection of stool suspension (5 uL/g) or LPS (25 mg/kg) or saline (1 mL/kg). Animals were culled at 6 hours and tissues were analyzed. RESULTS: An increase in basal p65:actin density in THP-1 cells (mean 0.214, standard error of the mean 0.024) was seen at doses as small as 0.1 ng/mL (0.519+/-0.064). In contrast to RAW 264.7 cells, basal increases (0.170+/-0.025) were only seen when a dose of 3 ng/mL (0.387+/-0.078) was used. Dose-response analysis of p65:actin ratio showed that THP-1 cells respond to lower doses of LPS than RAW 264.7 cells and lower doses produce a greater fold increase in the nuclear p65 density. Both in vivo models showed evidence of neutrophil (NL) recruitment into tissues (which was more intense after LPS treatment). IP stool inoculation resulted in an acute suppurative peritonitis and more substantial evidence of NL recruitment into adipose tissue and skeletal muscle. CONCLUSION: Our results support previous observations that translation of murine models into the human clinical setting suffers from considerable limitations including species-associated differences in LPS response seen at a molecular level. Furthermore, the histopathological changes during clinical sepsis cannot be adequately reproduced by injection of LPS. Therefore, the so-called translational disconnect that exists between murine LPS models and human sepsis involves NF-kappaB activation at a molecular level and is further augmented by the use of LPS as a stimulus for infectious responses in vivo. PMID- 26527894 TI - Performance of the estimated glomerular filtration rate creatinine and cystatin C based equations in Thai patients with chronic glomerulonephritis. AB - BACKGROUND: Glomerular filtration rate (GFR) is considered the indicator of overall kidney function, and therefore, its assessment has become an important clinical tool in the daily care of chronic glomerulonephritis (CGN) patients. Currently, practical guidelines recommend using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations to assess GFR in CKD patients. METHODS: A cross-sectional study was performed in CGN patients. Standard GFR was measured using 24-hour urine creatinine clearance. GFR was estimated using the Cockcroft-Gault, Modification of Diet in Renal Disease, CKD-EPI equation based creatinine, cystatin C, and combined creatinine and cystatin C. The performance of GFR estimation equations were examined using bias, precision and accuracy and agreement between standard GFR and estimated GFR by calculating Cohen's k. RESULTS: A total of 125 patients (74 male, 59.2%) with mean age 56.1+/-18.1 years were included. Mean standard GFR was 51.6+/-32.2 mL/min per 1.73 m(2). A significant correlation was found between standard GFR and all estimated GFRs (r=0.573 to 0.660, P<0.001). CKD-EPI-creatinine-cystatin C equation had the smallest absolute bias and the significantly highest accuracy, although it was not significantly different from CKD-EPI-cystatin C equation (P=0.523). CKD-EPI creatinine-cystatin C equation had the highest accuracy to classify CKD staging (Cohen's k=0.345), but it underestimated GFR in 32% and overestimated GFR in 18% of the CGN patients. CONCLUSION: CKD-EPI-creatinine-cystatin C equation estimated GFR with little bias, and the highest accuracy among CGN patients. This equation gave a better estimate of GFR than the equation based on serum creatinine. PMID- 26527893 TI - The genetics of Charcot-Marie-Tooth disease: current trends and future implications for diagnosis and management. AB - Charcot-Marie-Tooth (CMT) disease is the most common hereditary polyneuropathy and is classically associated with an insidious onset of distal predominant motor and sensory loss, muscle wasting, and pes cavus. Other forms of hereditary neuropathy, including sensory predominant or motor predominant forms, are sometimes included in the general classification of CMT, but for the purpose of this review, we will focus primarily on the forms associated with both sensory and motor deficits. CMT has a great deal of genetic heterogeneity, leading to diagnostic considerations that are still rapidly evolving for this disorder. Clinical features, inheritance pattern, gene mutation frequencies, and electrodiagnostic features all are helpful in formulating targeted testing algorithms in practical clinical settings, but these still have shortcomings. Next-generation sequencing (NGS), combined with multigene testing panels, is increasing the sensitivity and efficiency of genetic testing and is quickly overtaking targeted testing strategies. Currently, multigene panel testing and NGS can be considered first-line in many circumstances, although obtaining initial targeted testing for the PMP22 duplication in CMT patients with demyelinating conduction velocities is still a reasonable strategy. As technology improves and cost continues to fall, targeted testing will be completely replaced by multigene NGS panels that can detect the full spectrum of CMT mutations. Nevertheless, clinical acumen is still necessary given the variants of uncertain significance encountered with NGS. Despite the current limitations, the genetic diagnosis of CMT is critical for accurate prognostication, genetic counseling, and in the future, specific targeted therapies. Although whole exome and whole genome sequencing strategies have the power to further elucidate the genetics of CMT, continued technological advances are needed. PMID- 26527896 TI - A case of polymyalgia rheumatica following influenza B infection. AB - Polymyalgia rheumatica (PMR) is relatively common among the elderly, and is characterized by multiple body aches with an elevated erythrocyte sedimentation rate. Even though the etiology of PMR remains unknown, a number of infectious agents have been suggested to cause PMR. Also, there are reports of PMR after influenza vaccination. The exact role of influenza vaccination on the development of PMR remains unknown, but may be associated with specific human leukocyte antigens (HLAs), such as HLA-DRB1 and HLA-DQB1. Whether postvaccination PMR is caused by influenza virus antigen or adjuvants in the vaccine is another unanswered question. We herein report a case of an 85-year-old woman who developed PMR shortly after contracting influenza virus B. Even though infections are hypothesized to be one of the causes of PMR, this is the first-ever case of PMR following influenza virus infection. Further studies may elucidate the exact role of influenza virus infection on the etiology and pathogenesis of PMR. PMID- 26527895 TI - Managing neurocysticercosis: challenges and solutions. AB - Taenia solium neurocysticercosis (NCC) is a major cause of neurological morbidity in the world. Variability in the neuropathology and clinical presentation of NCC often make it difficult to diagnose and manage. Diagnosis of NCC can be challenging especially in endemic and resource-limited countries where laboratory and imaging techniques are often lacking. NCC management can also be challenging as current treatment options are limited and involve symptomatic agents, antiparasitic agents, or surgery. Although antiparasitic treatment probably reduces the number of active lesions and long-term seizure frequency, its efficacy is limited and strategies to improve treatment regimens are warranted. Treatment decisions should be individualized in relation to the type of NCC. Initial measures should focus on symptomatic management, with antiparasitic therapy only to be considered later on, when appropriate. Symptomatic treatment remains the cornerstone in NCC management which should not only focuses on epilepsy, but also on other manifestations that cause considerable burden (recurrent headaches, cognitive decline). Accurate patients' categorization, better antiparasitic regimens, and definition of new clinical outcomes for trials on NCC could improve management quality and prognosis of NCC. Prevention strategies targeting tapeworm carriers and infected pigs are yielding good results in local models. If local elimination of transmission is confirmed and replicated, this will open the door to cysticercosis eradication efforts worldwide. PMID- 26527898 TI - Profile of extended-release oxycodone/acetaminophen for acute pain. AB - This article provides a historical and pharmacological overview of a new opioid analgesic that boasts an extended-release (ER) formulation designed to provide both immediate and prolonged analgesia for up to 12 hours in patients who are experiencing acute pain. This novel medication, ER oxycodone/acetaminophen, competes with current US Food and Drug Administration (FDA)-approved opioid formulations available on the market in that it offers two benefits concurrently: a prolonged duration of action, and multimodal analgesia through a combination of an opioid (oxycodone) with a nonopioid component. Current FDA-approved combination analgesics, such as Percocet (oxycodone/acetaminophen), are available solely in immediate-release (IR) formulations. PMID- 26527897 TI - Exposure to general anesthesia and the risk of dementia. AB - Exposure to anesthesia and surgery has been hypothesized to increase the risk of developing Alzheimer's disease (AD). While the exact pathogenesis of AD remains unknown, it potentially involves specific proteins (eg, amyloid beta and tau) and neuroinflammation. A growing body of preclinical evidence also suggests that anesthetic agents interact with the components that mediate AD neuropathology at multiple levels. However, it remains unclear whether anesthesia and surgery are associated with an increased risk of AD in humans. To date, there have not been randomized controlled trials to provide evidence for such a causal relationship. Besides, observational studies showed inconsistent results. A meta-analysis of 15 case-control studies revealed no statistically significant association between general anesthesia and the development of AD (pooled odds ratio [OR] =1.05; P=0.43). However, a few retrospective cohort studies have demonstrated that exposure to anesthesia and surgery is associated with an increased risk of AD. Thus, well-designed studies with longer follow-up periods are still needed to define the role of anesthesia in relation to the development of AD. PMID- 26527899 TI - Symptom report in detecting breast cancer-related lymphedema. AB - Breast cancer-related lymphedema is a syndrome of abnormal swelling coupled with multiple symptoms resulting from obstruction or disruption of the lymphatic system associated with cancer treatment. Research has demonstrated that with increased number of symptoms reported, breast cancer survivors' limb volume increased. Lymphedema symptoms in the affected limb may indicate a latent stage of lymphedema in which changes cannot be detected by objective measures. The latent stage of lymphedema may exist months or years before overt swelling occurs. Symptom report may play an important role in detecting lymphedema in clinical practice. The purposes of this study were to: 1) examine the validity, sensitivity, and specificity of symptoms for detecting breast cancer-related lymphedema and 2) determine the best clinical cutoff point for the count of symptoms that maximized the sum of sensitivity and specificity. Data were collected from 250 women, including healthy female adults, breast cancer survivors with lymphedema, and those at risk for lymphedema. Lymphedema symptoms were assessed using a reliable and valid instrument. Validity, sensitivity, and specificity were evaluated using logistic regression, analysis of variance, and areas under receiver operating characteristic curves. Count of lymphedema symptoms was able to differentiate healthy adults from breast cancer survivors with lymphedema and those at risk for lymphedema. A diagnostic cutoff of three symptoms discriminated breast cancer survivors with lymphedema from healthy women with a sensitivity of 94% and a specificity of 97% (area under the curve =0.98). A diagnostic cutoff of nine symptoms discriminated at-risk survivors from survivors with lymphedema with a sensitivity of 64% and a specificity of 80% (area under the curve =0.72). In the absence of objective measurements capable of detecting latent stages of lymphedema, count of symptoms may be a cost-effective initial screening tool for detecting lymphedema. PMID- 26527901 TI - Calvarium and dura mater as delayed sites of distant metastasis from papillary thyroid carcinoma. AB - BACKGROUND: Skull calvarium and dura mater are rare sites of distant metastasis, and mostly have been reported in lung, breast, and prostate malignancies. However, the calvarial and dural metastases from papillary thyroid cancer (PTC) are rare entities and pose diagnostic and therapeutic challenges. To date, only seven cases of calvarial metastasis with intracranial extension from PTC have been reported in literature. However, true dural metastasis from PTC has not yet been reported. CASE PRESENTATION: A 65-year-old Saudi woman presented with 6 months history of painful posterior scalp lump, 7 years after initial diagnosis of PTC. Computed tomography and magnetic resonance imaging showed occipitoparietal calvarial lesion with massive intracranial extension. Another para-sagittal lesion was found at the top of corpus callosum mimicking a meningioma. Histopathology of para-sagittal lesion and the biopsy of calvarial mass confirmed the diagnosis of metastatic PTC. After surgical resection, residual tumors were treated with postoperative intensity-modulated radiation therapy. At 13 months of follow-up, patient was alive and without any signs of recurrence. CONCLUSION: Calvarial and dural metastases from PTC are extremely rare clinical entities. Surgical resection followed by postoperative radiotherapy is the treatment of choice. However, for such cases, multidisciplinary approach can prolong the treatment outcome and survival. PMID- 26527900 TI - Epidemiology and treatment of osteoporosis in women: an Indian perspective. AB - The number of women with osteoporosis, ie, with reduced bone mass and the disruption of bone architecture, is increasing in India. While data on prevalence of osteoporosis among women in India come from studies conducted in small groups spread across the country, estimates suggest that of the 230 million Indians expected to be over the age of 50 years in 2015, 20%, ie, ~46 million, are women with osteoporosis. Thus, osteoporosis is a major public health problem in Indian women. Low calcium intakes with extensive prevalence of vitamin D deficiency, increasing longevity, sex inequality, early menopause, genetic predisposition, lack of diagnostic facilities, and poor knowledge of bone health have contributed toward the high prevalence of osteoporosis. Bone health may be optimized by creating an environment to achieve peak bone mass during adolescence, maintenance of healthy bone throughout the life cycle, and prevention of bone loss postmenopausal. In Indian women, calcium, vitamin D, and bisphosphonates are the commonest first-line therapies used. The use of other drugs such as hormone replacement therapy, estrogen agonists, calcitonin, parathyroid hormone, and denosumab is decided as per the affordability and availability of treatment options. Major gaps still remain in the diagnosis and management of osteoporosis, thus highlighting the need for more structured research in this area. This review focuses on the epidemiology of osteoporosis in Indian women and available treatments. PMID- 26527902 TI - Neuroretinitis with dual infections. AB - A 22-year-old Malay female presented with left eye floaters for 2 weeks, associated with temporal visual field defect and metamorphopsia for 3 days. She has a guinea pig and a hedgehog at home, but denied being bitten or scratched by them. Her visual acuity at presentation was 6/12 on the left eye and 6/6 on the right eye. Her left eye relative afferent pupillary defect was barely positive with mild anterior chamber reaction. Fundus examination of the left eye showed mild vitritis, swollen optic disc with macular star, crops of active choroidal lesions at superonasal retina with a linear arrangement in the form of migratory track nasally. However, there were no nematodes seen on fundus examination. Investigations showed normal full blood count with no eosinophilia and positive serology test for Bartonella henselae. She was diagnosed to have dual infection - diffuse unilateral subacute neuroretinitis (DUSN), based on the presence of crops of choroidal lesions with migratory track, and cat scratch disease (CSD) based on a positive serological test. She was treated with oral albendazole 400 mg 12 hourly for 6 weeks for DUSN and oral doxycycline 100 mg 12 hourly for 4 weeks for CSD. Focal laser had been applied to the area of migratory track in the left eye. Her left eye vision improved to 6/6 at 1 month after treatment, with resolution of neuroretinitis. PMID- 26527903 TI - Incidental detection of a small solid pseudopapillary neoplasm of the pancreas after a traffic accident in a 12-year-old girl: a case report. AB - Solid pseudopapillary neoplasm (SPN) is a rare tumor of the pancreas that tends to grow silently in patients at a young age, to a large size and mass. We report here a case of a small-sized SPN detected incidentally in a 12-year-old girl following a traffic accident. The tumor was 3.5 cm in maximal diameter and was found to have hemorrhagic necrosis without a solid component. Laparoscopic spleen preserving distal pancreatectomy was performed which cured the patient. SPN is generally accepted to be a low grade malignant tumor, but its clinical behavior is sometimes unpredictable. Tumor size and the proportion of solid portion of the tumor have both recently been identified as predictors of malignancy. Although the initial presentation in this case was that of the traffic accident, the subsequent detection of a small, totally cystic SPN, and then the complete eradication of the lesion, led to a favorable outcome for the patient. Long-term monitoring should prevent any chance of recurrence. PMID- 26527904 TI - A pilot study: portable out-of-center sleep testing as an early sleep apnea screening tool in acute ischemic stroke. AB - INTRODUCTION: Prompt diagnosis of obstructive sleep apnea (OSA) after acute ischemic stroke (AIS) is critical for optimal clinical outcomes, but in laboratory conventional polysomnograms (PSG) are not routinely practical. Though portable out-of-center type III cardiopulmonary sleep studies (out-of-center cardiopulmonary sleep testing [OCST]) are widely available, these studies have not been validated in patients who have recently suffered from AIS. We hypothesized that OCST in patients with AIS would yield similar results when compared to conventional PSG. METHODS: Patients with AIS had simultaneous type III OCST and PSG studies performed within 72 hours from symptom onset. The accuracy of OCST was compared to PSG using: chi-square tests, receiver operatory characteristic curves, Bland-Altman plot, paired Student's t-test/Wilcoxon signed rank test, and calculation of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Twenty-one out of 23 subjects with AIS (age 61+/-9.4 years; 52% male; 58% African-American) successfully completed both studies (9% technical failure). Nearly all (95%) had Mallampati IV posterior oropharynx; the mean neck circumference was 16.8+/-1.6 in. and the mean body mass index (BMI) was 30+/-7 kg/m(2). The apnea hypopnea index (AHI) provided by OCST was similar to that provided by PSG (19.8+/-18.0 vs 22.0+/-22.7, respectively; P=0.49). On identifying subjects by OCST with an AHI >=5 on PSG, OCST had the following parameters: sensitivity 100%, specificity 85.7%, PPV 93%, and NPV 100%. On identifying subjects with an AHI >=15 on PSG, OCST parameters were as follows: sensitivity 100%, specificity 83.3%, PPV 81.8%, and NPV 100%. Bland-Altman plotting showed an overall diagnostic agreement between OCST and PSG modalities for an AHI cutoff >5, despite fine-grained differences in estimated AHIs. CONCLUSION: Compared with PSG, OCST provides similar diagnostic information when run simultaneously in AIS patients. OCST is a reliable screening tool for early diagnosis of OSA in AIS patients. PMID- 26527905 TI - Can the transition process from foundation doctor to neurosurgical specialty trainee be improved through "learner-centered induction programs"? AB - The transition period from foundation program doctor to specialty trainee can be difficult for junior doctors. This difficult period often acts as a major obstacle for learning in the workplace. Existing induction programs are commonly seen as inadequate at easing this transition, and therefore, a pilot study intervention was undertaken to assess if the initiation of "learner-centered induction programs" could help improve the confidence, knowledge acquisition, and satisfaction of junior doctors as they begin specialty training in neurosurgery. Ethnographic and anecdotal evidences were collated from junior doctors, specialty trainees, and consultants in order to investigate if further work on this subject would be beneficial. All participants were working in the Department of Neurosurgery at University Hospital Coventry and Warwickshire, Coventry, UK, over a 4-week period in March/April 2015. A review of the relevant literature was also undertaken. This report found that despite the reservations around the increased organizational demands of induction programs of this nature, as well as concerns around a single junior doctor covering the ward alone during the induction period, feedback following the intervention was largely positive. Junior doctors appreciated being taught about their roles and responsibilities from their predecessors as well as deciding among themselves what topics they wanted covering. As a result, the induction sessions tended to focus on clinical skills rather than theoretical knowledge, which most of the junior doctors believed they could cover adequately in their own time. The junior doctors felt that they benefited from learning/refreshing their relevant practical skills in a safe environment under senior supervision, prior to starting on the wards. Finally, as the induction program was of a greater duration than the traditional half day, they felt they had sufficient time to ask questions and address concerns while "on the job". Overall, "learner-centered induction programs" did appear to show promise in this pilot study with regards to increasing the confidence of junior doctors starting a neurosurgical placement and helped ease the transition process from foundation doctor to specialty trainee in neurosurgery. We believe further work to formalize and quantify these findings using questionnaires and a larger sample group as well as across successive is indicated and may help junior doctor learning and transition processes in future practice. PMID- 26527906 TI - What is the impact of age on adult patients with inflammatory bowel disease? AB - Inflammatory bowel disease (IBD) is a chronic disease that affects both young adults and also the elderly. This article emphasises the particularities related to age in the epidemiology, diagnosis, natural course of the disease, prognosis and therapy of adult patients with IBD. Even though the main characteristics in geriatric populations with IBD may not differ much from those in younger patients, distinct problems exist. The majority of IBD studies were performed on young subjects, younger than 40 years of age. The optimal therapeutic choice in young individuals with IBD is a challenge for the physician who needs to take in account the risk of untreated or suboptimally treated chronic intestinal inflammation, long term prognosis, quality of life, the impact of side-effects of aggressive therapeutic approaches, the impact on pregnancy, as well as personal and healthcare costs. The diagnosis in elderly patients can be challenging due to the large number of conditions that mimic IBD. The treatment options are those used in younger patients, but a series of considerations related to potential pharmacological interactions and side effects of the drugs must be taken in account. The risks associated with the use of some IBD medications may be increased in older patients, but so is the risk of under-treated IBD and surgery. PMID- 26527907 TI - Modern and multidimensional approach of sleep apneea as a public health problem. AB - The obstructive sleep apnea syndrome (OSAS) is a highly prevalent disorder, associated with recurring episodes of partial or complete upper airway occlusion during sleep, which results in marked sleep disturbance, excessive daytime sleepiness, irritability and morning headache, among other symptoms. Sleep apnea is strongly associated with impaired neuropsychological function and reduced quality of life and social functioning. Daytime sleepiness leads to an increased risk for traffic and industrial accidents. OSAS is also independently associated with several cardiovascular complications: not only systemic hypertension but also ischaemic heart disease and stroke. Identifying patients "at risk" and treating them is very important, but at the same time it is time consuming and expensive. Nevertheless, treatment with continuous positive airway pressure (CPAP) has been shown to improve symptoms and quality of life, decrease traffic accidents and may have a positive effect on cardiovascular morbidity. That is why the economic aspects of sleep apnea and the current legislation are an important issue to discuss and manage, for both the patients and the society they live in. PMID- 26527908 TI - Endocrine disrupting effects of butylated hydroxyanisole (BHA - E320). AB - Butylated hydroxyanisole (BHA) is extensively used as antioxidant in foods, food packaging, cosmetics and pharmaceuticals. In the past years, it raised concerns regarding its possible endocrine disrupting effect. The existing in vitro studies indicate that BHA presents a weak estrogenic effect and also anti-androgenic properties while an in vivo study found it to have antiestrogenic properties. There is no sufficient data available at the moment to draw a conclusion regarding the safety of BHA when referring to its endocrine disrupting effect. Since a fraction of the population might be exposed to doses superior to the acceptable daily intake (ADI), it is important to gather more in vitro and in vivo data concerning the potential effects that BHA might have alone, but also in mixtures with natural hormones or other endocrine disrupting compounds. PMID- 26527909 TI - The etiology of upper gastrointestinal bleeding in cirrhotic patients. AB - AIMS: To investigate the etiology of upper digestive hemorrhage in cirrhotic patients. PATIENTS AND METHODS: From November 2004 to December 2006, we performed a prospective study at the Regional Institute of Gastroenterology and Hepatology "O. Fodor" Cluj-Napoca. The study was performed on 1,284 patients with esophageal varices from the endoscopy records, diagnosed with liver cirrhosis based on clinical, biochemical and endoscopic information, documented from the observation sheet. During the periodical examinations, we observed and monitored the patients' variceal and non-variceal bleedings. RESULTS: Out of the 1,284 patients included in this study, there were 297 cases of upper digestive hemorrhage, the dominant etiology being the variceal bleeding (217 cases - 73%), and 80 (27%) cases of upper non-variceal digestive hemorrhage. Duodenal ulcer was the main cause for upper non-variceal digestive hemorrhage in case of cirrhotic patients considered for this study (33.75%), followed by gastric ulcer (21.25%), portal hypertensive gastropathy (17.5%), acute erosive gastritis (11.25%), Mallory-Weiss syndrome (6.25%), esophageal ulcer (5%), antral vascular ectasia (1.25%), duodenal polyps (1.25%) and exulcerated gastric tumor (1.25%). We also observed the cases of hemorrhagic relapse in the group of patients with variceal hemorrhages. Variceal bleedings are predominant in each Child-Pugh clinical category, but one must mention that the risk of variceal rupture increases with the severity of the hepatic disease. There were 8 deaths, all caused by esophageal variceal hemorrhages. CONCLUSIONS: In our study, almost 27% of cirrhotic patients with upper gastrointestinal hemorrhage had bleeding from a non variceal source, the most common etiology being peptic ulcer. Variceal bleeding is more severe and bears a higher mortality rate than non-variceal bleeding. PMID- 26527910 TI - Use of alternative therapies in patients submitted to anorectal manometry. AB - BACKGROUND AND AIM: Anorectal manometry is used in the evaluation of disorders of the lower gastrointestinal tract: constipation, incontinence, anorectal pain. Most of these conditions are invalidating. Moreover, the patients do not benefit from a perfect therapy. Therefore many of them also use alternative therapies, but we still miss data on the use of alternative therapies in anorectal disorders. Therefore we looked for the use of alternative therapies in patients submitted to anorectal manometry. MATERIAL AND METHODS: 60 consecutive patients submitted to anorectal manometry were questioned about the use of alternative therapy by a specially developed structured questionnaire. All of them accepted to answer the questionnaire after careful instruction. The questions were administered by a qualified staff and filled before the investigation. RESULTS: The indication for anorectal manometry was: incontinence 18 cases (20%), constipation 33 cases (55%), anorectal pain 9 cases (15%). 44 out of 60 (73%) patients admitted to have used one or more alternative therapies, usually together with the observance of medical dietary or pharmacological prescriptions. These were: homeopathy 10 (17%), herbal therapy 36 (60%), acupuncture 1 (0.02%), bioenergy resonance 11 (18%). Users were mainly females with a low level of education. The use of alternative therapy was similar in all three subgroups of patients. CONCLUSION: These data emphasizes the importance of the use of alternative therapies in patients with anorectal disorders submitted to anorectal manometry. PMID- 26527911 TI - Cell proliferation and apoptosis in urinary bladder urothelium of rats following ovariectomy and chronic estrogen replacement therapy. AB - AIMS: In this study we followed the effect of menopause and estrogenic replacement therapy on the proliferative and apoptotic activity of the bladder urothelial cells. METHODS: The experimental model of menopause was reproduced using a standard protocol of bilateral ovariectomy in rats, estrogen replacement therapy being achieved by systemic administration of hexestrol diacetate for six weeks. Proliferative and apoptotic activity was monitored by quantifying the urothelium imunoexpression for PCNA antigen as a marker of S phase of the cell cycle and Cleaved Caspase 3 for monitoring apoptotic activity. RESULTS: Following ovariectomy, the main changes were urothelial atrophy associated with intensification of the apoptotic activity at these level. Estrogen therapy managed to improve the urothelium activity by reducing the Apoptotic Index and by increasing urothelial proliferative activity. CONCLUSIONS: The results show the important role of estrogens in maintaining urothelial activities, highlighting their potential use in the treatment of urothelium atrophic and degenerative processes associated with menopause. PMID- 26527912 TI - Contrast-enhanced ultrasound in ovarian tumors - diagnostic parameters: method presentation and initial experience. AB - The aim of this paper is to discuss and illustrate the use of contrast-enhanced ultrasound in evaluating ovarian tumors compared to conventional ultrasound, Doppler ultrasound and the histopathological analysis and suggest how this technique may best be used to distinguish benign from malignant ovarian masses. We present the method and initial experience of our center by analyzing the parameters used in contrast-enhanced ultrasound in 6 patients with ovarian tumors of uncertain etiology. For examination we used a Siemens ultrasound machine with dedicated contrast software and the contrast agent SonoVue, Bracco. The patients underwent conventional ultrasound, Doppler ultrasound and i.v. administration of the contrast agent. The parameters studied were: inflow of contrast (rise time), time to peak enhancement, mean transit time. The series of patients is part of an extensive prospective PhD study aimed at elaborating a differential diagnosis protocol for benign versus malignant ovarian tumors, by validating specific parameters for contrast-enhanced ultrasound. Although the method is currently used with great success in gastroenterology, urology and senology, its validation in gynecology is still in the early phases. Taking into consideration that the method is minimally invasive and much less costly that CT/MRI imaging, demonstrating its utility in oncologic gynecology would be a big step in preoperative evaluation of these cases. PMID- 26527913 TI - A study of the Achilles tendon while running. AB - The following study attempts to elaborate a model of the Achilles tendon while in the process of running, specifically during a step that is part of a running sequence. Data are collected with the help of a force plate and then is processed and modeled to serve as a starting point and comparison to a mathematical model using polynomial functions. The data collected were filtered to diminish recording of "noise" and an empirical model was established. Mathematical models using second order and fourth order polynomials were employed, as well as an approximation using known maximal force. The increase in the accuracy of modeling was determined as the order of the polynomial function increased. Achieving an accurate predictor function is essential in understanding the biomechanics of the Achilles tendon. PMID- 26527914 TI - Minimally invasive treatment of trochanteric fractures with intramedullary nails. Technique and results. AB - The aim of the study was to evaluate the results of minimally invasive treatment of trochanteric fractures with the use of intramedullary nails. PATIENTS AND METHODS: From September 2010 to September 2012 we treated 21 patients with pertrochanteric fractures by a minimally invasive technique using the Gamma 3 (Stryker, Howmedica) nail. There were 13 females and 8 men with a mean age of 74.1 years, ranging from 58 to 88 years. Fractures were classified as being stable (AO type 31-A1) in 5 cases and unstable (AO type 31-A2 and A3) in the rest of 16 cases. Patients were reviewed at 6 weeks and 3 months postoperatively. RESULTS: Mean surgery time was 46.8 minutes and mean hospital stay was 14.9 days. No patients required blood transfusions. During the hospital stay all the patients were mobilized with weight bearing as tolerated. All patients were available for review at 6 weeks, and 2 were lost to the 3 months follow up. 16 patients regained the previous level of activity. CONCLUSIONS: This minimally invasive technique using a gamma nail device for pertrochanteric fractures gives reliable good results with excellent preservation of hip function. PMID- 26527915 TI - Intratracheal fiber glass instillation in rats: IL8 and lymphocytes levels in bronchoalveolar lavage, correlation with the histopathological findings. AB - INTRODUCTION: Fiberglass (FG) is the largest category of man -made mineral fibers. Many types of FG are manufactured for specific uses building insulation, air handling, and sound absorption. Because of increasing use and potential for widespread human exposure, a chronic toxicity instillation study was conducted in Wistar rats, which were found to be sensitive to the induction of mesotheliomas with another MMVF. AIM: The present study is focused on the effect of fiber glass on lung through intratracheal exposure, the analysis of bronchoalveolar lavage and measurement of IL 8 levels, lymphocytes number and histopathological finding after the exposure period. MATERIAL AND METHOD: Four groups of 8 female Wistar rats were included in the study. The animals were divided into three groups of 8 each, exposed to different doses of FG and one control group. The first group (1 8) was exposed to 6 mg dose/0.2 ml saline 5 days/week for 10 weeks, the second (9 16) group was exposed to 10 mg/0.2 ml saline 5 days/week 10 weeks, the third group (17-24) was exposed to 12 mg FG/0.2 ml saline solution 5 days/week 10 weeks and the control group (25-32) was exposed to the same volume of saline. The fibers had been size selected to be rat respirable. At the end of the exposure period of 10 weeks the rats were killed one week after the last exposure. Following preparation of the lungs, they were lavaged with 2x5 ml saline without massage. The lavage fluid was collected in calibrated tubes and harvested volume was recorded. Supernatant was obtained after centrifugation at 1,500 r.p.m for 5 minutes and IL8 levels and lymphocytes number were measured. RESULTS: The IL8 levels were found to be dose related; the first group had values ranging from 10 to 19.8 pg/ml and the total lymphocytes number in the bronchoalveolar lavage fluid ranging from 1,500-1,900 and minimal/slight inflammatory lesions. The second group had the IL8 levels ranging between 60.4-80.4 pg/ml, lymphocytes number between 680-881 and moderate to marked inflammatory lesions. For the third group the IL8 values ranged between 88.3-113.2, the lymphocytes number ranged between 241-342 and the histopathological findings were marked and severe including emphysema, lung and pleural fibrosis. The control group had IL8 values between 10-19.4, there were no lymphocytes in the bronchoalveolar lavage and no histopathological findings. CONCLUSION: These findings indicate that IL8 levels were dose related and IL8 levels have an inverse correlation with lymphocytes count in BAL, also correlated with the histopathological findings for the studied groups. PMID- 26527916 TI - The impact of depression and anxiety on the quality of life in nonmetastatic breast cancer patients in postoperative evaluation. AB - AIMS: To evaluate the impact of psychiatric comorbidities on the quality of life of early stage breast cancer subjects, in the first post-surgery week, the prevalence of those psychiatric disorders in this group, the correlation between pain and adjustment disorders and between the STAI-X1 (State Trait Anxiety Inventory 1) and BDI (Beck Depression Inventory) scales and the psychopathological findings. PATIENTS AND METHODS: We conducted a clinical study at the Ocological Institute "Ioan Chiricuta" Cluj-Napoca on a group of 56 patients (mean age 53.51 years old) with nonmetastatic breast cancer, who underwent surgical intervention in the week prior to the psychiatric evaluation. Patients received a complete psychiatric evaluation during their hospitalization. The STAI-X1, BDI, Numeric Rating Scale and QLQ 30 (Quality of Life Questionnaire 30) plus BR 23 (Breast 23) questionnaires were administered. RESULTS: The prevalence of adjustment disorders in the group was 28.58%. The psychiatric diagnosis significantly and inversely correlated with the emotional functioning, the cognitive functioning and future perspective. The existence of psychiatric disorders significantly and directly correlated with fatigue, pain, insomnia, appetite loss, constipation, arm symptoms and global health status. CONCLUSIONS: Depression and anxiety have an important prevalence in the breast cancer population and they significantly alter the quality of life of these patients and caregivers by reducing their functional abilities and by generating a higher level of symptomatology and subjective sufferance. PMID- 26527917 TI - Perceived discrimination, a risk factor for developing psychoses in Romanian emigrants? AB - AIM: Investigating the relationship between the perceived discrimination and the psychotic symptom severity as well as the level of social functioning in Romanian migrants with psychotic disorders, considering that this is a major stressor which contributes to the feeling of alienation from the majority culture. MATERIALS AND METHODS: The assessment included 70 patients admitted to the Cluj Psychiatric Hospital, from January 2007 to April 2010, diagnosed with acute psychotic disorder, schizophrenia and other schizophrenia-spectrum disorders, according to ICD 10 diagnosis criteria. The patients completed the migration questionnaire for socio-demographic variables and the level of discrimination perceived, the psychotic symptom severity being assessed through PANNS and GAF scales. RESULTS: The level of discrimination perceived by the subjects correlated neither with PANNS symptoms (r=-0.051, p>0.05) nor with the social functioning level (r=0.029, p>0.05). The social functioning level had significant negative correlations with the PANNS level of general symptoms(r=-0.41, p>0.05). There are no differences between PANNS symptoms, social functioning and perceived discrimination according to age, gender or illness onset country. There are significantly statistical differences between education categories concerning the general symptoms on PANNS scale, respectively the level of discrimination perceived, the lower level of education being associated with a highly perceived discrimination level. The subjects of rural origin perceived discrimination at a higher level than those from urban area (t=2.31, p<0.05). CONCLUSIONS: Discrimination is perceived more intensely by the subjects from the rural area and with a poorer educational level but this doesn't correlate with psychotic symptom severity. PMID- 26527918 TI - Influence of risk factors and comorbidities on the successful therapy and survival of patients with critical limb ischemia. AB - BACKGROUND: Critical limb ischemia (CLI) is associated with an increased risk of limb amputation, low quality of life and cardiovascular death. The aim of this study is to identify the prognostic factors of mortality, revascularization failure and amputation failure, as part of risk factors for athero-sclerosis and comorbidities. PATIENTS AND METHODS: We examined 198 patients operated for CLI. Cox analysis was performed to discern the factors that were associated with failure of initial surgical therapy and death. RESULTS: For survival analysis, a significant model emerged with hypertension (p=0.00), cardiac comorbidities (p=0.00), renal comorbidities (p=0.04) and respiratory comorbidities (p=0.02) as significant predictors. Regarding the time to amputation failure, there was a significant model with insulin treated diabetes (p=0.00), coronary artery disease (p=0.02) and cerebrovascular disease (p=0.05) as significant predictors. CONCLUSIONS: Significant predictors for mortality in CLI patients are high risk hypertension, severe coronary artery disease, renal failure requiring dialysis and chronic obstructive pulmonary disease. The association of these prognostic factors results in a proportional decrease of survival. The predictors for amputation failure were, in addition to local factors, insulin treated diabetes, coronary artery disease and cerebrovascular disease. The revascularization for limb salvage depends on the correct indication and accurate surgical technique. PMID- 26527919 TI - Isolation, culture and detection of mesenchymal stem cells in tissues from critical limb ischemia model in rat. AB - INTRODUCTION: Rat mesenchymal stem cells (MSCs) represent a small portion of the cells in the stromal compartment of bone marrow and have the potential to differentiate into new blood vessel and other tissues. MSCs transplantation in tissues from critical limb ischemia model in rat may represent a therapeutic applications of vascular regeneration. AIM: The aim of this study was to isolate with a simple method the rat bone marrow stromal cells. Then the adherent cells were labeled with 5-bromo-2-deoxyuridine (BrdU, Sigma) and injected in the gastrocnemius and adductor muscle of ischemic hind limbs in order to demonstrate their presence in the critical limb ischemia model in rat. MATERIAL AND METHODS: MSCs were isolated from Wistar rats, 8 weeks of age. The MSCs were labeled in vitro for later identification by adding 10 MUg/mL 5-bromo-2 -deoxyuridine (BrdU, Sigma). RESULTS: Small colonies of fibroblast-like cells were seen after several days of primary culture. These colonies increased in size and were subcultured after 15-18 days. CONCLUSION: The MSCs obtained in this study presented a stable undifferentiated phenotype under normal culture conditions. MSCs are easy to isolate, culture, and detect in in vivo culture. These cells are characterized by high plasticity and could have an important role in angiogenesis. PMID- 26527920 TI - Gingival recession in postmenopausal women with and without osteoporosis. AB - BACKGROUND: The periodontal disease is a complex chronic progressive inflammatory and destructive process of the tooth attachment apparatus: gingiva, alveolar bone, desmodontium, cementum. Systemic osteoporosis has a potential influence on both the periodontal and gingival inflammation indices, on the gingival recession (GR) and teeth mobility. The aim of this study was to investigate the possible relationship between the menopause osteoporosis and gingival recession, by studying the correlations between osteoporosis and gingival recession, and between the bone mineral density (BMD) at the level of L1-L4, femur, hip, mandible and gum recession. MATERIALS AND METHODS: The present study included a total of 97 postmenopausal patients. The diagnosis of osteoporosis was made based on the WHO definition. The results were expressed as absolute BMD values in g/cm(2) and as T score form. We used dual x-ray absortiometry (DXA) measurements in assessing the lumbar column, proximal femur and mandible and we calculated the T scores. The gingival recession, which is an indicator of ligament tissue lysis and apical migration of the periodontal tissue, was measured as the distance between the anatomical tooth neck and the gumline. For the statistical analysis the Medcalc program version 12.3 was used. RESULTS: We found statistically significant differences between the two groups of women, with and without osteoporosis, in terms of the distribution of the cases of GR (p=0.003). The only parameter with statistical significance of the differences between the three categories of gingival recessions (absent, moderate, major), was p=0.034 for the femoral neck BMD. There were significant differences between the mean values of lumbar column L1-L4 BMD according to the presence or absence of recession signs. CONCLUSIONS: 1) The prevalence of moderate and major gingival recession was statistically significantly higher in the group of postmenopausal women with osteoporosis. 2) In postmenopausal women, statistically significant differences were found between the femoral neck BMD values according to the three types of gingival recession. 3) The mean L1-L4 BMD values and the femoral neck BMD were significantly lower in the women with GR compared to those without gingival recession. PMID- 26527921 TI - High-pressure injection injury of the finger - a case presentation. AB - High-pressure injection injuries are uncommon traumas characterized by a great discrepancy between a deceptively small entrance site and the extensive and underestimated subcutaneous tissue injury and destruction. Without early and correct treatment these lesions lead to disability and local extensive destruction. This paper presents a case of high-pressure injection injury to the metacarpal-phalangeal articulation of the finger from industrial paint; the extent of the injury was underestimated at presentation and improperly treated. This case required surgical staged management, with a total time of medical leave of three months. PMID- 26527922 TI - Ovarian pregnancy associated with pelvic adhesions. AB - Ovarian pregnancy is a rare entity. Making a definitive preoperative or even intraoperative diagnosis of ovarian pregnancy is difficult and the diagnosis is usually established by the pathologist. Rupture in the first trimester is the usual rule in ovarian ectopy. Thus, it continues to challenge practicing clinicians. The literature shows an association between intrauterine device usage and ovarian gestation. We present a case of ovarian pregnancy in a secundipara complaining of abdominal pain that also has pelvic adhesions. This case meets the four criteria of Spiegelberg and is interesting because of its rarity and association with adhesions, which makes diagnosis more difficult. PMID- 26527924 TI - Centennial Victor Preda (1912-1982). PMID- 26527923 TI - Cases of injustice done to prominent figures of the Cluj Medical School. AB - This is a presentation of few cases in the history of the Medical School of Cluj, when outstanding figures were victims of injustice, with respect to the acknowledgement of their priority works. PMID- 26527925 TI - The methodology of glucose monitoring in type 2 diabetes mellitus. AB - Type 2 diabetes is a chronic disease and maintaining a tight glycemic control is essential to prevent both microvascular and macrovascular complications, as demonstrated in previous studies. It is essential to monitor the glucose levels in order to achieve the targets. The blood glucose monitoring can be done by different methods: glycated haemoglobin A1c, self-monitoring of blood glucose (before and after meals) with a glucometer and continuous glucose monitoring with a system that measures interstitial glucose concentrations. Even though glycated haemoglobin A1c is considered the "gold standard" of diabetes care, it does not provide complete information about the magnitude of the glycemic disequilibrium. Therefore the self-monitoring and continuous monitoring of blood glucose are considered an important adjunct for achieving and maintaining optimal glycemic control. The three methods of assessing glycemic control: HbA1c, SMBG and CGMS provide distinct but at the same time complementary information. PMID- 26527926 TI - Cytoarchitectonic study of the trigeminal ganglion in humans. AB - The trigeminal ganglion (TG), a cluster of pseudounipolar neurons, is located in the trigeminal impression of the temporal pyramid. It is covered by a sheath of the dura mater and arachnoid and is near the rear end of the cavernous sinus. The peripheral processes of the pseudounipolar cells are involved in the formation of the first and second branch and the sensory part of the third branch of the fifth cranial nerve, and the central ones form the sensory root of the nerve, which penetrates at the level of the middle cerebellar peduncle, aside from the pons, and terminate in the sensory nuclei of the trigeminal complex. We found that the primary sensory neurons involved in sensory innervation of the orofacial complex are a diverse group. Although they possess the general structure of pseudounipolar neurons, there are significant differences among them, seen in varying intensities of staining. Based on our investigations we classified the neurons into 7 groups, i.e. large, subdivided into light and dark, medium, also light and dark, and small light and dark, and, moreover, neurons with an irregular shape of their perikarya. Further research by applying various immunohistochemical methods will clarify whether differences in the morphological patterns of the neurons are associated with differences in the neurochemical composition of various neuronal types. PMID- 26527927 TI - Results of faecal immunochemical test for colorectal cancer screening, in average risk population, in a cohort of 1389 subjects. AB - AIM: The aim of this study is to evaluate the usefulness of the fecal immunochemical test (FIT) in colorectal cancer screening, detection of precancerous lesions and early colorectal cancer. MATERIAL AND METHODS: The study evaluated asymptomatic patients with average risk (no personal or family antecedents of polyps or colorectal cancer), aged between 50 and 74 years. The presence of the occult haemorrhage was tested with the immunochemical faecal test Hem Check 1 (Veda Lab, France). The subjects were not requested to have any dietary or drug restrictions. Colonoscopy was recommended in all subjects that tested positive. RESULTS: In our study, we had a total of 1389 participants who met the inclusion criteria, with a mean age of 61.2 +/- 12.8 years, 565 (40.7%) men and 824 (59.3%) women. FIT was positive in 87 individuals (6.3%). In 57/87 subjects (65.5%) with positive FIT, colonoscopy was performed, while the rest of the subjects refused or delayed the investigation. A number of 5 (8.8%) patients were not able to have a complete colonoscopy, due to neoplastic stenosis. The colonoscopies revealed in 10 cases (0.7%) cancer, in 29 cases (2.1%) advanced adenomas and in 15 cases (1.1%) non advanced adenomas from the total participants in the study. The colonoscopies performed revealed a greater percentage of advanced adenomas in the left colon compared to the right colon, 74.1% vs. 28.6% (p<0.001). CONCLUSIONS: In our study, FIT had a positivity rate of 6.3%. The detection rate for advanced neoplasia was 2.8% (0.7% for cancer, 2.1% for advanced adenomas) in our study group. Adherence to colonoscopy for FIT-positive subjects was 65.5%. PMID- 26527928 TI - Variceal bleeding in cirrhotic patients: risk factors, evolution, treatment. AB - OBJECTIVES: The aim of this study was to monitor the risk factors that trigger variceal bleeding in cirrhotic patients, assess the severity of the bleeding and the efficacy of the endoscopic hemostasis techniques, as well as the recurrence of bleeding episodes and the mortality rate. MATERIALS AND METHODS: The current study was a prospective one, and it was conducted in the period November 2004 - December 2006 in the "O. Fodor" Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca. It included 273 patients with upper gastrointestinal bleeding because of variceal rupture, assessed by emergency endoscopy. The patients included in the study met the clinical, biochemical, endoscopic and ultrasound criteria for liver cirrhosis. Its etiology and staging were documented from the patients' observation charts. RESULTS: Out of the 273 cases of variceal bleeding there were 255 (93.4%) cases of bleeding from esophageal varices and 18 (6.6%) from gastric varices. Variceal bleeding episodes were more frequent in patients with alcoholic liver cirrhosis (51.28%). Most patients with variceal bleeding were in Child class B or C (77%). Mortality because of variceal hemorrhage was 2.93% in the study group. A number of 148 patients were treated by sclerotherapy and 125 patients with elastic ligatures. Bleeding relapses occurred in 65 (23.8%) patients within the study group, 43 men and 22 women. Variceal bleeding relapses were more frequent after sclerotherapy than after elastic ligatures. CONCLUSIONS: Variceal bleeding occurred more frequently in patients with alcoholic cirrhosis stage Child C. In the current study mortality was relatively low. The treatment of bleeding recurrence is more difficult, hence variceal rupture prevention and application of elastic ligatures represent a therapeutic necessity. PMID- 26527929 TI - Liraglutide and DPP-4 inhibitors - side effects comparative clinical study. AB - The objective of this study was to monitor the side effects of the GLP-1 receptor agonist liraglutide in comparison to those of DPP-4 inhibitors (sitagliptin and vildagliptin), in order to determine their safety, tolerability and therapeutic efficiency. The study was carried out in the "Heart and Diabetes Center NRW" and included overweight patients with type 2 diabetes whose therapeutic regimen was switched to liraglutide or DPP-4 inhibitors. A validated questionnaire method was used to monitor the side effects during the hospitalization period, then again at 3, and 6 months after the beginning of the therapy. The therapy with liraglutide was associated with more side effects than the one with DPP-4 inhibitors. In general, side effects were declining with time, thus only few patients stopped therapy. The incretin therapy turned out to be a safe and effective therapeutic option for patients with type 2 diabetes mellitus. PMID- 26527930 TI - Assessment of health effects related to fiber glass exposure in fiber glass workers: exhaled biomarkers eCO, FENO and their usefulness in the occupational environment testing. AB - INTRODUCTION: Numerous epidemiological animal model studies have been conducted in order to assess the health effects of man-made vitreous fibers. They have been shown to be responsible for producing lung fibrosis and lung and peritoneal cancer in animal models. A few large cohort studies were conducted in Europe and the US to assess the health effects of fiber glass in production workers and a higher cancer incidence was evidenced. AIM: The aim of the study is to assess the usefulness of exhaled biomarkers measurements: exhaled nitric oxide and exhaled carbon monoxide in fiber glass workers as indicators of an inflammatory airway response. MATERIAL AND METHOD: A total of 42 fiber glass workers were included in this study with a minimum of 5 year exposure period in which FENO and eCO values were measured. Also spirometry chest X ray, C reactive protein, fibrinogen, total IgE serum and IL8 serum levels were determined. RESULTS: Increased values of exhaled nitric oxide (over 25 ppb) were found in 43% of the fiber glass workers and increased values of exhaled carbon monoxide (over 6 ppm) were determined in 26% of the fiber glass workers. A positive correlation was found between the exposure period and FENO values and total IgE values (p<0.05). A negative correlation coefficient was found between FEF 25-75 predictive values and FENO and total IgE values. CONCLUSION: These results suggest that exhaled biomarkers can be useful to assess an inflammatory airway response in the occupational environment. PMID- 26527931 TI - Effects of corticosteroids on hyposmia in persistent allergic rhinitis. AB - OBJECTIVE: To asses the effects of two topical nasal corticosteroids sprays on hyposmia in patients with persistent allergic rhinitis. MATERIAL AND METHODS: The study was a prospective clinical trial and it included twenty four patients with persistent allergic rhinitis (PER) and hyposmia (H). The patients were divided into two groups depending on the type of corticosteroid topical nasal spray treatment: group A, 200 micrograms dose of mometasone furoate (MF) and group B, 110 micrograms dose of fluticasone furoate (FF) both administered in the morning for 4 weeks. The olfactory function of the patients was evaluated with the extended Test battery "Sniffin' Sticks". The visual analogue scale (VAS) was used for the assessment of hyposmia, nasal discharge. The level of the nasal obstruction, before and after the treatment, was evaluated through the anterior rhinomanometry. RESULTS: The comparisons between the two types of topical corticosteroids showed a significant improvement separately between scores of the odor threshold (OT), odor discrimination (OD) and odor identification (OI) and also on the final olfactory score (SDI) before and after 4 weeks of the treatment. The comparisons of the VAS scores pre and post treatment showed a significant improvement in hyposmia and nasal obstruction. The nasal airflow and the nasal discharge scores were improved, but the differences were not statistically significant between the groups. The final statistical analysis found no significant differences between the two patients groups. CONCLUSION: The study concludes that fluticasone furoate and mometasone furoate have quite the same effects on hyposmia and on the classical symptoms from PER. PMID- 26527932 TI - Factors that may influence the functional outcome after primary total hip arthroplasty. AB - AIM: The present paper aims to decipher the multiple factors occurring in patients on the recovery program, in order to obtain an optimal functional outcome after the implantation of a primary total hip prosthesis. MATERIAL AND METHOD: One hundred patients operated with primary total hip prosthesis, consecutively included in this study, underwent an immediate postoperative recovery program, with an integrative aspect, over the entire duration of hospitalization. The program was individualized according to the specific features of the patients, such as gender, age, Body Mass Index (BMI), type of diagnosis that required the prosthesis implantation, type of prosthesis implanted and functional status of the opposite hip, and it was continued at home. At 3 months postoperatively, the Harris hip score (in comparison with the preoperative one) and the quality of life were calculated. RESULTS: At 3 months post-surgery and post-recovery, the average Harris hip score was more than double in comparison with the preoperative one (85.89 as compared to 40.06), and on average the patients considered the quality of life as good. The preoperative Harris hip score had no statistically significant differences in different patient groups, except for the ones aged over 75, for whom it was statistically significantly lower than the score of other age groups. Three months after surgery, the statistically significant differences between different groups of patients disappeared. At 3 months postoperatively, the average perceived quality of life was good. There were statistically significant differences only in obese patients, who considered it to be very good. DISCUSSION: Correlations are sought between different categories of patients and the obtained results, to be compared with the data in specialized literature. CONCLUSIONS: The factors contributing to a good functional outcome after primary total hip arthroplasty are the following: rehabilitation program beginning immediately after surgery, its performance gradually reaching exercises against resistance and its integrative aspect being mainly oriented towards obtaining movement independence and walking recovery, careful adaptation to the specific features of the patient, related to age, weight condition, opposite hip condition and, within each group, related to the physical possibilities of the person submitted to surgery, as well as the continuation of the rehabilitation program at home. Factors such as gender, old age, the cause requiring prosthesis implantation, obesity or unoperated hip with functional impairment are not limitative and do not prevent obtaining satisfactory results. PMID- 26527933 TI - The traumatic rupture of the Achilles' tendon - an analysis of the modern methods of evaluation and treatment. AB - AIMS: The main aim of this article is an analysis of both advantages and disadvantages of the modern solutions of treatment - percutaneous surgery, in comparison with the classic methods of treatments described in the surgery of Achilles' tendon. PATIENTS AND METHOD: The study was conducted on 23 patients admitted to the Orthopedics and Traumatology Clinic of Cluj-Napoca between January 2011-June 2012. Nineteen (19) patients were diagnosed with a complete rupture of the Achilles tendon and 4 patients with a partial rupture. The diagnosis of traumatic Achilles tendon ruptures was usually clinical, the Ultrasound (common or 3D) and the MRI confirmed the lesion and determined its location and extension. We analyzed the diagnostic methods, the elapsed time before surgery, the treatment options depending on lesion's location, technical difficulties, costs, postoperative care, the average healing time, complications. RESULTS: The Ultrasound was performed in 65.2% of the patients (15 patients) for confirming the extension of the lesion and it served for pre-operative planning. In most of the cases, the classical methods of Achilles tendon reconstruction were used (18 cases). The complications rate was about 8%. We diagnosed an iterative Achilles tendon rupture (the patient was initially treated using the percutaneous methods) and a delay in cicatrisation. CONCLUSIONS: The percutaneous surgical techniques are a viable alternative for the acute ruptures of Achilles tendon, the classic intervention has clear indications in lesions diagnosed late, in the recurrent tendon ruptures. PMID- 26527934 TI - Prostate cancer - peculiarities of the process of adaptation to the disease. AB - AIM: Psycho-social adaptation to the diagnosis of cancer is a dynamic process, different from one patient to another, depending on many factors (location, stage, treatment, personality of each individual, environment - family, professional background, social-economic-cultural status). The aim of this study is to analyze the process of adaptation of patients with prostate cancer. PATIENTS AND METHOD: Thirty six patients diagnosed with prostate cancer, admitted in the Department of Oncology, Palliative Care for Chronic Patients within Chronic Disease Hospital "St. Luke" from Bucharest, Romania, over a period of six months, answered the Illness Cognition Questionnaire (ICQ), in order to assess adaptation to the disease (helplessness, acceptance, perceived benefits). RESULTS: Results of the study showed that feelings of helplessness were expressed at a high level in 22.2% patients, medium level in 55.6% cases and low level 22.2%. The feelings of acceptance were the following: 61.1% of patients had a high level, 33.3% of them a medium level, while only 5.6% had a low level of acceptance. Regarding perceived benefits due to the disease, the following results have been obtained: 22.2% had a high level, 77.8% a medium level and no patient reported low level benefit. CONCLUSION: The results of this study indicate that patients diagnosed with prostate cancer adapt well to the disease, accept it and even obtain benefits from it. PMID- 26527935 TI - Atrophic gastritis: Helicobacter pylori versus duodenogastric reflux. AB - OBJECTIVES: The objective of this study was to asses the prevalence of atrophic gastritis in children. We also wanted to compare the clinical manifestation, endoscopic appearance and the degree of the gastric atrophy in children and to identify the possible causes which determine gastric atrophy. METHODS: We evaluated 247 children with chronic gastritis (153 female/94 male, mean age 12.32 years). Atrophy was defined as the loss of normal glandular components, including replacement with fibrosis and/or intestinal metaplasia. RESULTS: The prevalence of the atrophic gastritis was 16.6% (41 cases), mean age 11.59+/-1.75 years, male to-female ratio 16:25. The clinical manifestations were correlated with the patient age (infants and toddlers were evaluated mostly for weight loss - 4 cases, and older children for abdominal pain - 22 cases). The endoscopic appearance was described as either nodular (15 cases), or erythematous gastritis (10 cases), or normal (10 cases). According to the Sydney System, the degree of atrophy was found to be mild in 3 patients, moderate in 25, and severe in 13 patients; 14 cases were associated with duodenogastric reflux, 5 with Helicobacter pylori and 2 with Helicobacter heilmannii infection, but in 17 cases the etiology was unknown. CONCLUSIONS: Atrophic gastritis is present in childhood, even at very young ages (infants, toddlers). The endoscopic appearance is not characteristic for the presence of atrophy. The degree of the atrophy is not correlated with the age of the children. Because of the relatively high number of duodenogastric reflux associated with gastric atrophy, further studies need to evaluate the potential causes and clinical course. PMID- 26527936 TI - Traumatic exposure and posttraumatic symptoms for train drivers involved in railway incidents. AB - AIMS: International research highlights the occupational risk of train drivers of being exposed to work related traumatic incidents and subsequently developing posttraumatic symptoms or other comorbid dysfunctions. PARTICIPANTS AND METHODS: The article focuses on investigating the effects of repeated traumatic exposure on posttraumatic reactions in a sample of 193 Romanian train drivers. We used the Impact of Event Scale-Revised (IES-R) to retrospectively evaluate symptoms of Posttraumatic Stress Disorder (PTSD), The General Health Questionnaire to investigate related mental health symptoms, and a demographic questionnaire to assess contextual factors like frequency or severity of exposure. RESULTS: Sample reports of exposure to PUT ("person under train") incidents were high. An interesting finding was that train drivers exposed to just one or two PUT incidents reported significantly more posttraumatic symptoms than train drivers with more PUT experiences, accounting for a habituation effect of repeated traumatic exposure. CONCLUSIONS: Reported posttraumatic reactions to PUT incidents and influencing factors provide evidence recommending systematic screening of train drivers for posttraumatic symptoms, general emotional distress and further elaborating prevention and treatment strategies for specific risk categories of these professionals. PMID- 26527937 TI - Role of medical rehabilitation in postpoliomyelitis syndrome. A case report. AB - Postpoliomyelitis syndrome is characterized by a sudden or progressive loss of muscle strength, muscle atrophy, muscle pain, fatigue, intolerance to cold, after a period of at least 15 years from the acute polio virus infection, a period of neurological and functional stability. No therapeutic benefit of the evaluated drug agents (pyridostigmine, steroids, amantadine) has been reported. The reason for this presentation results from the fact that clinical studies have demonstrated that isokinetic and isometric muscle training can prevent the loss of muscle strength and reduce muscle fatigue. Rehabilitation programs through physical-kinetic therapy are the only way to limit functional deficit, playing an important role in the long-term management and care of patients. The particularity of this case is the fact that the symptoms occurred after a 40 year period of neurological stability. The regular monitoring and inclusion of the patient in complex medical rehabilitation programs are important in order to limit the functional deficit and increase the quality of life of these patients. PMID- 26527938 TI - Unusual presentation of endocarditis with nutritional variant Streptococci. AB - Patients presenting with endocarditis often will give clues to the diagnosis within the history and the physical exam. A history of valvular heart disease and obvious signs of bacteriemia are classical stigmata of infective endocarditis. However, we should keep in mind that endocarditis can present with unusual signs and symptoms that can mislead to the wrong diagnosis and if unrecognized it can lead to severe complications. PMID- 26527939 TI - Case report of primary small cell neuroendocrine breast cancer. AB - Primary neuroendocrine cancer of the breast (NECB) is an extremely rare tumor. In 2003, the World Health Organization (WHO) recognized this category with three well-described subtypes: small cell, large cell, and carcinoid-like carcinoma; very few peer-review publications based on the WHO definition were encountered in the literature, and we conducted a literature search to investigate the reported incidence, diagnosis, prognosis, hormone receptor status, and treatment options for this rare tumor. Confirming the breast as an origin of neuroendocrine tumor represents a challenge. The diagnosis is mainly dependent on the exclusion of other extra-mammary organs based on clinical, radiological, and pathological data. Primary neuroendocrine carcinoma of the breast is rare - only about 30 cases have been reported in literature. Immunohistochemical examination showing expression of chromogranin and/or synaptophysin confirms evidence of neuroendocrine differentiation. Usually foci of neuroendocrine differentiation can be seen in breast carcinoma and are reported to be present in about 2-5% of breast cancer cases. Here, we report a case of breast carcinoma in which most of the areas studied on the tissue section showed neuroendocrine differentiation. Primary neuroendocrine carcinoma of the breast is a group that exhibits morphological features similar to those of neuroendocrine tumors of both the gastrointestinal tract and the lung. CASE PRESENTATION: We report the case of a 50-year-old Caucasian woman with primary small cell neuroendocrine cancer of the breast, which we characterized with immunohistochemical techniques. A palpable and mobile 3.0 cm tumor was located in the upper-outer quadrant of her right breast. After pathological confirmation the patient underwent 8 cycles of chemotherapy, and subsequent radical mastectomy with axillary lymph node resection were performed. Microscopically, the tumor consisted predominantly of a diffuse proliferation of small oat cells. The tumor cells were positive for neuroendocrine markers; 21 of 30 lymph nodes were metastatic. Local recurrence with multiple lung metastases developed only 5 weeks after surgery, despite of the transient tumor regression achieved by chemotherapy. This case reinforces the importance of an early correct diagnosis and the standardization of a treatment regimen for this very rare tumor. A correct treatment needs to be chosen. PMID- 26527940 TI - Vintila Ciocalteu (1891-1947): physician, biochemist, poet and professor. AB - Among the ambassadors of Romanian science and culture, we include the doctor Vintila Ciocalteu. Along with Victor Babes, Nicolae Paulescu and George Emil Palade, Vintila Ciocalteu contributed further, by the reagent which he prepared together with Otto Folin, to the completion and deepening of the knowledge of cell biology within the medical agricultural, horticultural research or industrial chemistry. A multi-faceted personality, V. Ciocalteu was also a remarkable poet, who entered into an unjust and hopeless conflict with the communist regime. Just like many of his compatriots, he was deleted from medical or literature books, was expelled from the department of Medicine in Bucharest and was charged with offences that he did not commit. But his name could not be deleted from the laboratory methods which used - the Reagent Folin-Ciocalteu! Today, doctor Vintila Ciocalteu continues to promote the fame of the Romanian medicine in the world. PMID- 26527941 TI - The foundation of the first amphitheatre of the Faculty of Pharmacy in Cluj. AB - The Faculty of Pharmacy of Cluj was created in 1948. The first dean was Erwin Popper (1906-1974) - professor of analytical chemistry. At the beginning of the activity the didactic spaces in this institution were not sufficient. Consequently, Prof. Popper tried and succeeded in solving this problem. In 1955 1957, despite financial and economic difficulties, he succeeded in raising a new building for the departments of Analytical Chemistry and Physical Chemistry. The most important part of this edifice was a modern, large and elegant amphitheatre of 200 places. This was the first lecture hall of the Faculty. The historical value of this amphitheatre was completed in 1957 with bass relief carvings, representing important pharmacists and chemists, such as Carol Davila, Stefan Minovici, Constantin I. Istrati, Nicolae Teclu, Ion Vintilescu and Gheorghe Spacu. The artistic representations of these Romanian scientists were created by Virgil Fulicia (1907-1979) - professor of the Fine Arts Academy in Cluj. PMID- 26527942 TI - Immunosuppression in kidney transplantation. AB - For most patients with chronic kidney failure, kidney transplantation has the greatest potential for restoring a healthy and productive life. The risk of acute rejection is the highest in the first months after transplantation (induction phase) and diminishes afterwards (maintenance phase). Immunosuppression should be at the highest level in the early period and reduced for long-term therapy. At present, conventional immunosuppressive protocols consist of the triple therapy: a calcineurin inhibitor, an adjunctive agent, corticosteroids. The development of new immunosuppressives drugs is aimed not only at improving short-term outcomes, but also achieving better safety, less nephrotoxicity and minimal side effects. PMID- 26527943 TI - A better communcation with the patients improves the management of HIV disease: a nonsystematic review. AB - The human immunodeficiency virus (HIV) is a blood-borne, sexually transmissible virus which belongs to a subset of viruses called retroviruses. Patients with HIV disease face problems like stigma, discrimination, poverty and marginalization. These problems also affect the physician-patient communication in HIV disease. Learning to conduct a consultation is a complex skill which is gradually learned and perfected during training and career. Good physician-patient communication in HIV disease demands medical professional competence, good communication skills, ethical behaviour, respect of patient's dignity, good teamwork skills and maintaining confidentiality. The most important aspect of patient care is education, which should include empowering patients with basic knowledge about HIV infection, methods of transmission, progression, prognosis, and prevention. A multidisciplinary approach that uses the special skills of nurses, pharmacists, nutritionists, social workers, and case managers is desirable. Effective methods for clinicians to support such development are needed. PMID- 26527944 TI - An overview of pharmacology and clinical aspects concerning the therapy of cochleo-vestibular syndromes by intratympanic drug delivery. AB - Intratympanic drug delivery refers to drug administration in the middle ear, the main advantage being direct diffusion of substances in the inner ear through the round window membrane with subsequent high intralabiryntine drug concentration and very low systemic side effects. The article is a review of literature concerning the inner ear barrier systems, the physiology of inner ear fluids, intralabirinthine pharmacokinetics and the commonest drugs applied in the middle ear for the treatment of cochleo-vestibular syndromes. PMID- 26527945 TI - The management of biofilm formation after hyaluronic acid gel filler injections: a review. AB - BACKGROUND AND AIM: One of the most popular procedures of facial fillers in recent years has become the use of hyaluronic acid (HA). However, this method may be associated with local side effects of different severity. Many of them are not due to allergies, as previously believed, but to the formation of biofilm. We review the current knowledge on biofilm after HA. METHODS: All pertinent full text papers retrieved from PubMed under search words: "biofilm", "hyaluronic acid", "dermal fillers", "hyaluronic acid complications" and "hyaluronic acid side effects" were analyzed; 29 of 60 articles were selected fro analysis. RESULTS: Local infections were reported: 13 cases are attributable to the activation of the biofilm. Clinical evolution is generally mild. Therapy should avoid NSAID and is based on the administration of antibiotics, oral corticosteroids, or 5-Flourouracil. Removal of HA with hyaluronidase has also been proposed. CONCLUSIONS: The use of HA in cosmetic procedures might be accompanied by local adverse effects attributable to biofilm formation. This usually has a mild evolution, but in special cases requires specific therapy. PMID- 26527947 TI - Abnormal attachments between a plantar aponeurosis and calcaneus. AB - BACKGROUND AND AIMS: The plantar aponeurosis or fascia is a thick fascial seal located on the lower surface of the sole. It consists of three parts central, lateral, and medial. The central portion is the thickest. It is narrow behind and wider in front. The central portion has two strong vertical intermuscular septa which are directed upward into the foot. The lateral and medial portions are thinner. The medial portion is thinnest. The lateral portion is thin in front and thick behind. The main function of the plantar fascia is to support the longitudinal arch of the foot. In May 2013 during a routine dissection in the section hall of the Department of Anatomy and Histology in Medical University - Sofia, Bulgaria we came across a very interesting variation of the plantar aponeurosis. MATERIALS AND METHODS: For the present morphological study tissues from a human corpse material were used. This unusual anatomical variation was photographed using a Nikon Coolpix 995 camera with a 3.34 Megapixels. RESULTS: We found some fibrous strands which started from the proximal portion of the plantar aponeurosis on the left foot. The fibrous strands resembled the tentacles of an octopus and started from the proximal portion of the aponeurosis. Two of fibrous strands were directed laterally to adipose tissue and one was directed medially and backward. The first lateral fibrous strand was divided into several fascicles. We found very few data in literature about the varieties of the plantar fascia. CONCLUSION: It is very important to consider the occurrence of above mentioned variations in the plantar aponeurosis when surgical procedures are performed on the sole. PMID- 26527946 TI - Genes and dental disorders. AB - In recent decades with the advancement of molecular research, information regarding specific molecular mechanisms has exploded. In the present review we present the molecular basis of dental pathologies that are of particular interest to clinicians. PMID- 26527948 TI - Neuroprotective strategy in an experimental newborn rat model of brain ischemia and hypoxia: effects of Resveratrol and hypothermia. AB - INTRODUCTION: Cerebral hypoxia and ischemia are the major causes of perinatal mortality resulting in central nervous system injury. Hypoxia and ischemia produce massive brain damage and one of the most important mechanisms in the lesion pattern is oxidative stress. AIMS: The objectives of this study are to assess the effects of resveratrol pretreatment in a cerebral hypoxic-ischemic (HI) newborn rat model as well as the influence that hypothermia has on redox parameters in this experimental model and the effects of the combined therapy from the oxidative stress perspective. MATERIAL AND METHOD: The experiment was performed on eighty newborn Wistar rats of both genders, weighing about 10 grams, placed into eight groups: control, treated with resveratrol (RES), RES+HI insult, RES+hypothermia, subjected to hypothermia only, HI insult+normothermia, HI insult+hypothermia. Resveratrol was administrated in a dose of 20 mg/kg/day for seven days as premedication. At the end of this period the animals were exposed to hypobaric hypoxia (9% O(2+) for 90 minutes) and ischemia (by clamping the right carotid artery). In order to test the effect of combined therapy of resveratrol with hypothermia, several animals were exposed after HI injury to whole body moderate hypothermia (with 4 degrees C) for 3h. After recovery the malondialdehyde level and the activities of superoxide dismutase and glutathione peroxidase were determined in the brain tissue of the newborn rats. RESULTS: MDA levels were increased in the groups receiving resveratrol pretreatment. In the group subjected to simple hypothermia MDA levels were also increased. In the group subjected to HI insult and then to hypothermia, MDA levels were significantly lower. MDA levels were lower also in the group where RES was associated with hypothermia in HI insult context. GPx levels were decreased in groups pretreated with RES and subjected to HI, hypothermia, the same effect in case of hypothermia alone. Only in the group treated with RES was the GPx level higher than in controls. SOD levels were high in the RES pretreated group, but decreased in HI insult. In the group subjected to hypothermia after HI, SOD was significantly higher. CONCLUSION: The results of this study prove that hypothermia offers better neuroprotection in ischemic brain injuries than resveratrol. The combined therapy influenced the oxidative stress parameters. Hypothermia is a stress factor, but when applied in post-lesion condition, offers protection for the brain. PMID- 26527949 TI - An expert system for the diagnosis of irritable bowel syndrome. AB - For a long time functional digestive disorders (FGIDs), including irritable bowel syndrome (IBS), were described based on what they are not, without considering them real entities. Although IBS evolution is benign, it has major effects on the quality of life, it determines a higher number of days of sick leave or days when work activities had to be interrupted, thus increasing the expenses for the society. Our system, developed using CORVID Exsys, is called IBS Expert and addresses both patients and physicians. Answering some simple questions, patients will receive information about their diagnosis, together with additional recommendations. Non-expert physicians will have rapid access to the algorithm of IBS diagnosis, and could use recommendations for future investigations. This expert system is based on the information provided by the most complete collection of data about FGIDs, created by an international group of experts, who elaborated Rome III criteria. The system consists of three sub-systems, including a set of eighteen questions and the diagnosis of IBS, as well as additional recommendations, established using confidence variables. The evaluation of the system consisted of verification (determining the accuracy of the results to ensure the delivery of diagnosis and recommendations as it was intended), validation of knowledge (met through the use of the gold standard in the field) and assessment of the impact on users, either patients or physicians (measuring overall satisfaction and the user effort score in using the system). The system is available online at www.gastroterra.ro and can be accessed by using any Java enabled device, from standard computers to mobile devices. PMID- 26527950 TI - Toxicosis in Helicobacter Pylori infection - a hypothesis. AB - BACKGROUND AND AIM: We present a new clinical entity in relation to the Helicobacter pylori infection characterized by complex and varied clinical extra digestive manifestations. Clinical findings such as asthenia, adynamia, sleep disorders, hair and nails modifications, digestive symptoms and heart rhythm disorders describe the clinical aspect of toxicosis associated with Helicobacter pylori infection. METHODS: The clinical presentation and therapy of patients with Helicobacter pylori infection were analyzed. RESULTS: Combined drug therapy: antibiotics + proton pump inhibitors + colloidal bismuth compound determinate remission of the symptoms in the first 3 to 5 days. The characteristic of the relation between Helicobacter pylori and the mucus-epithelial cell complex, the properties of the bacterial cell components, and the inflammatory and immunological response targeting other organs describe the immuno-pathological outbreak of Helicobacter pylori. CONCLUSION: We support the term of toxicosis associated with Helicobacter pylori infection in selected cases. PMID- 26527951 TI - Inflammatory markers in paroxysmal atrial fibrillation and the protective role of renin-angiotensin-aldosterone system inhibitors. AB - BACKGROUND: Experimental and clinical studies have shown the importance of inflammation in the pathophysiology of atrial fibrillation (AF). The renin angiotensin-aldosterone system (RAAS) may play an important role in the pathogenesis of AF in correlation with the inflammatory process. RAAS inhibition may have important therapeutic value in limiting AF. The aim of this study was the correlation between inflammatory markers and recurrent episodes of AF in patients with known paroxysmal atrial fibrillation, with and without treatment with RAAS inhibitors. METHODS AND RESULTS: We studied 82 patients with paroxysmal AF recorded at "Niculae Stancioiu" Heart Institute Cluj-Napoca, divided into two groups: group A treated with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) and group B without this medication. All patients underwent clinical examination, ECG, echocardiography and determination of plasma levels of inflammatory markers represented by high sensitivity C reactive protein (hs-CRP) and interleukin 6 (IL-6). In the group treated with ACE inhibitors/ARBs, AF burden was significantly lower than in patients without treatment. We obtained a strong positive correlation between blood levels of high sensitivity CRP and those of IL-6 (r=0.64, p<0.001), the number of yearly AF episodes (r=0.570, p<0.001), LA diameter (r=0.5, p<0.001) and LA volume (r=0.5, p<0.001). We found moderate positive correlations between blood levels of IL-6 and LA diameter (r=0.305, p=0.01), LA volume (r=0.314, p=0.01), the number of yearly AF episodes (r=0.489, p<0.001), the total number of AF episodes (r=0.304, p<0.001), BMI (r=0.473, p<0.001), LA area (r=0.458, p<0.001), LA area index (r=0.334, p=0.007) and LA volume index (r=0.304, p=0.01). The number of yearly AF episodes and BMI values influenced IL-6 blood levels (t=3.46, p=0.001, respectively t=2.17, p=0.03). CONCLUSIONS: Inflammation is present in patients with AF, with or without treatment with RAAS inhibitors and is correlated with longer duration of AF, left atrial diameter and left atrial volume. ACE inhibitors and ARBs, acting on cardiac substrate and reducing the inflammatory process, may have a therapeutic protective role of decreasing AF burden. PMID- 26527952 TI - The association between arterial stiffness and carotid intima-media thickness in patients with known cardiovascular risk factors. AB - OBJECTIVES: The aim of this study was to evaluate the relationship between pulse wave velocity and carotid intima-media thickness (IMT) in patients with different cardiovascular risk factors. MATERIAL AND METHODS: This prospective study included 223 patients with at least 2 risk factors for atherosclerosis, divided based on the presence of coronary artery disease (CAD): 140 patients with angiographically documented CAD and 83 patients without CAD. The patients were compared with a control group of 74 healthy age-matched subjects (CON). We determined the following parameters: blood pressure, total cholesterol (TC), triglycerides (TG), LDL-cholesterol, HDL-cholesterol, fasting serum glucose and renal parameters: blood urea nitrogen, serum creatinine, and uric acid levels in all patients. Arterial stiffness was measured with non-invasive oscillometric Arteriograph device (Tensiomed Ltd., Budapest, Hungary) and carotid scan was performed with B-mode ultrasound. RESULTS: Patients with CAD had increased values of aortic PWV compared with patients without CAD and CON group (12.5+/-0.7 vs 10.9+/-0.6 vs 8.5+/-0.6 m/s, all p<0.001). The values of carotid IMT were significantly higher in CAD patients as compared to patients without CAD and CON group (1+/-0.05 versus 1.0+/-0.07 versus 0.7+/-0.08 mm, all p<0.001). The carotid IMT significantly correlated with aortic PWV (r=0.787, p<0.001). CONCLUSIONS: Carotid IMT and aortic PWV are useful non-invasive methods for atherosclerosis detection in patients with known cardiovascular risk factors. Both determinations in the same patient will increase the clinical relevance. PMID- 26527953 TI - Systemic markers of oxidative stress in relation to metabolic syndrome components. AB - INTRODUCTION: The potential role of oxidative stress (OS) in metabolic syndrome (MetS) is rapidly evolving. Reported results support the concept that increased OS may play a key role in the development of atherosclerosis, hypertension and diabetes. STUDY AIM: The purpose of this study was to analyze the clinical correlates of systemic OS markers in a well characterized group of patients with MetS. MATERIAL AND METHOD: 72 hospitalized patients with a mean age 59.19+/-5.26 years were studied between October 2010 and June 2011. MetS was diagnosed based on the AHA/NHLBI/IDF 2009 definition. OS was assessed by urinary 8 isoprostaglandinF2alpha (8-isoPGF2alpha) (immunometric assays) and plasmatic uric acid (UA). Antioxidant status was evaluated by plasmatic glutathione peroxidase (GPx). These data were compared to those of 100 subjects without MetS (mean age 59.93+/-4.7 years). RESULTS: All biomarkers were significantly higher in MetS patients as compared with healthy individuals (p<0.05), except GPx which was significantly lower (p<0.001). GPx and UA were statistically significant correlated. In multivariate analysis 8-isoPGF2alpha concentrations were influenced by hypertension, fasting glucose and triglycerides, UA levels were directly influenced by hypertension, waist circumference, fasting glucose and triglycerides. GPx levels were inversely correlated with blood pressure (all p<0.05). Only GPx was influenced by the number of MetS components. Subjects with a lower level of GPx had a significantly greater risk of MetS (OR 0.85). CONCLUSIONS: Higher 8-isoPGF2alpha and uric acid and lower GPx levels are associated with MetS. The OS biomarkers are differently influenced by each component of the MetS. High blood pressure seems to be the key component linking OS to MetS. Antioxidant status is influenced by the number of MetS components with GPx being a risk factor for MetS. PMID- 26527954 TI - Magnesium and selenium in diabetics with peripheral artery disease of the lower limbs. AB - BACKGROUND AND AIMS: Knowing that diabetes mellitus (DM) often leads to cardiovascular injury such as peripheral artery disease (PAD) of the lower limbs and that some microelements like magnesium (Mg) and Selenium (Se) might be involved in the alterations entailed by these complications, we aimed to investigate the behavior of those microelements in these diseases. METHODS: We studied 114 patients with type 2 DM, treated not with insulin but only by diet or oral antidiabetics, mean aged 56.6 having a mean duration of the diabetes of 14.5 years, mostly men (80), 64 of them (40 men) having also PAD stage 2 without severe complications. We had a control group of 40 similarly-aged subjects without DM or PAD. The measurements were performed on a Konelab 30I device and serum selenium was quantified by atomic absorption spectroscopy. All patients underwent clinical, paraclinical and arterial Doppler echography for establishing the diagnosis of PAD. RESULTS: The results for controls were 2.2+/-0.4 mg/dl for Mg, 130+/-6 MUg/dl for Se; diabetics had 1.68+/-0.4 mg/dl Mg, 88+/-6 MUg/dl Se; diabetics with PAD had significantly lower levels: 1.36+/-0.6 mg/dl Mg, 66+/-6 MUg/dl Se (p<0.05). Age inversely correlated with the values of both microelements especially in women. Mixed dysipidemia, present in DM, correlated with PAD. Blood pressure also inversely correlated with Mg and Se. Coronary heart disease (ischemia) linked to lower blood values of Mg and Se. Left Ventricle Hypertrophy (as proved by echography) also correlated to lower blood values of Mg and Se, as did glycated hemoglobin (HbA1c). CONCLUSION: We may conclude that in DM there is a Mg deficit which becomes significant in DZ+PAD especially in forms with high blood pressure (HBP), severe dyslipidemia and in the presence of early microvascular complications, our paper suggesting the opportunity of a substitutive treatment with Mg and Se in selected cases. PMID- 26527955 TI - Ways to prevent infection after open fracture of the lower limb. AB - BACKGROUND AND AIMS: Despite the great effectiveness of antibiotics, no principle is more important in the care of open fractures than aggressive irrigation and debridement. Fixation of open fractures has a number of beneficial effects, including even the reduction of the risk of infection. MATERIALS AND METHODS: This prospective study of the treatment of 116 open fractures of the lower limb offered us the possibility to determine the ways to prevent the infection. All the patients were studied prospectively and the type of treatment and the rate of infection were evaluated. RESULTS: In the course of the treatment, 96 wounds were closed by primary closure (82.8%) and 2 wounds were closed by secondary closure on the 5(th) postoperative day (1.7%). There were 14 skin grafts (12.1%), 2 muscle flap closures (1.7%) and 2 healings by granulation (1.7%). The antibiotics used were ceftriaxone + gentamycin for type I, II fractures; metronidazole was added for type III fractures. The duration of the antibiotic therapy was 7-10 days, according to the severity of the fracture. The infection rate was 0% for type I, 0% for type II and 5.17% for type III fractures (6/116). CONCLUSIONS: The treatment of open fractures by intensive debridement of the wound and immediate fixation, as well as by primary closure of the wound with prolonged use of antibiotics, led to a dramatic decrease of the rate of infections. PMID- 26527956 TI - The role and prognostic impact of lymph node ratio on stage III colorectal cancer. AB - AIM: The aim of this study was to evaluate the prognostic significance of the lymph node ratio (LNR) in patients with stage III colorectal cancer. MATERIALS AND METHODS: We included 35 stage III colorectal cancer patients who underwent a curative resection at the County Clinic Hospital, Cluj-Napoca, 5(th) Surgical Clinic between January 2006-July2008. Patients were categorized into LNR groups 1 to 5 according to cut-off points: <0.1; 0.21; 0.36; 0.6; >0.61. The Kaplan-Meier and the Cox proportional hazard models were used to evaluate the prognostic effect according to the LNR. RESULTS: From one hundred forty-eight patients who underwent colorectal cancer resection, 33.1 % were stage III and 35 patients met the study inclusion criteria. The five-year survival rate in N1 group was 64.62% compared to the N2 group, where it was 8.57% (p<0.001) The lymph node ratio (LNR) groups consisted of 5 cases (14.2%) in LNR1 group (<0.1), five-year survival rate 100%, 6 cases (17.14%) in LNR2 group (0.11-0.21), five-year survival rate 83.33%, 8 cases (22.8%) in LNR3 group (0.22-0.36), five-year survival rate 37.5%, 12 cases (34.28%) in LNR4 group (0.37-0.60), survival rate 0%, and LNR5 group (>0.6). The relationship between the five-year survival rates in the five LNR groups results in a statistically significant proportionality (p<0.001). CONCLUSION: Lymph node ratio can be considered a more accurate and potent modality for prognosis in stage III colorectal cancer and may improve stratification in this heterogenous group of patients. PMID- 26527957 TI - Influence of sildenafil and donepezil administration on the serum redox balance in experimentally induced lower limb critical ischemia. AB - INTRODUCTION: Chronic lower limb ischemia (CLLI) leads to endothelial cell dysfunctions and endothelial lesions. The use of substances that release nitric oxide and activate endothelial nitric oxide synthase has proved to be useful in increasing angiogenesis and arteriogenesis under critical ischemia conditions. OBJECTIVES: To investigate the therapeutic effect of Sildenafil and Donepezil with a vasodilating action in experimentally induced CLLI and on serum redox homeostasis. MATERIAL AND METHOD: The research was performed in 3 groups of rats (n=10 animals/group) with experimentally induced CLLI: group I - control group; group II - animals treated postoperatively with a therapeutic dose of sildenafil, and group III - animals treated postoperatively with a therapeutic dose of donepezil. Oxidative stress (OS) indicators (malondialdehyde - MDA, protein carbonyls - PC), antioxidant (AO) defense indicators (reduced glutathione - GSH and oxidized glutathione - GSSH), and ceruloplasmin (CP) were determined on days 7, 14, 21 and 30. Statistical processing was performed using the Excel application (Microsoft Office 2007), with the StatsDirect v.2.7.2 software. RESULTS: Changes in OS were evidenced in all groups on account of a decrease in MDA and PC. The greatest OS decrease in all groups was on day 30. AO defence changes were represented by decreased levels of GSH and GSSG in all groups, at the studied moments. Intracellular AO defense in the cytosol, nucleus and mitochondria was similar in all groups, (decreased GSH, GSSG and GSH/GSSG ratio). We found increased extracellular levels of GSH, GSSG, and CP and increased extracellular GSH/GSSG ratio at level compared to values on day 7. CONCLUSIONS: 1) The administration of sildenafil (group II) and donepezil (group III) has favorable effects on reducing OS in experimentally induced CLLI. 2) Sildenafil and Donepezil administration stimulates extracellular AO defense on account of CP. 3) Sildenafil and Donepezil administration influences intracellular redox homeostasis on account of the GSH/GSSG couple, the major redox buffer in the body. PMID- 26527958 TI - Maternal obesity - a risk factor for metabolic syndrome in children. AB - OBJECTIVE: To determine the association between the metabolic syndrome in children (MS) and the pre-pregnancy nutritional status of the mother. DESIGN AND METHODS: A total number of 180 children aged between 6-19 years were examined. Self reported data about parents and their children were collected. The children underwent physical examination; weight, height, waist circumference, blood pressure (BP) were measured. The nutritional status of the children was assessed by body mass index (BMI) and laboratory tests needed to diagnose MS were performed. IDF criteria for MS were used in children 10 years and older, and age and gender specific cut-off points in children younger than 10 years. The mothers were classified in the normal weight, overweight and obese categories according to the pre-pregnancy BMI. The statistical analysis of the data was descriptive and inferential analysis. In the bivariate analysis of the association between qualitative variables, we used the Chi-Square test and the exact Fisher test. The statistical analysis was performed with SPSS v 13.0. RESULTS: 73 (40.55%) children were normal weight, 54 (30%) were overweight and 53 (29.44%) were obese. None of the normal weight children, 16 (29.60%) of the overweight and 23 (43.40%) of the obese ones had MS; 125 (69.44%) of the mothers were normal weight, 44 (24.44%) were overweight and 11 (6.11%) were obese. Pre-pregnancy maternal BMI was significantly associated with offspring MS in both genders, obese children and in the 10-16 age group. CONCLUSIONS: Pre-pregnancy maternal overweight/obesity represents a risk factor for offspring MS. The results are very difficult to compare between studies because of different cut-off values and definition of MS in children. If prevention is the goal rather than treatment, the perinatal period may be an important focus for future research. PMID- 26527959 TI - Surgical management of complicated parapneumonic pleural effusion in children. AB - AIMS: We analyzed and examined the effect of different management strategies on short term outcomes for pediatric patients with parapneumonic pleural effusions. PATIENTS AND METHODS: We retrospectively reviewed 16 cases of children admitted and treated in our department of pediatric surgery for empyema or pleural effusions for a period of 30 months. RESULTS: When chest drains are used alone, patients can make a complete recovery, even with the cost of longer hospital stay. Furthermore, some patients often require extensive surgical treatment as open thoracotomy with decortication due to failure to respond to chest-tube drainage. CONCLUSIONS: Because of the relatively small number of patients with parapneumonic effusions and because of lack of modern possibilities that require expensive equipment, like VATS or fybrinolitic therapy, our study results are limited and need to be reviewed in time. Even so, results on short outcome are good, with low morbidity and mortality, but with higher costs. PMID- 26527960 TI - Osteoarthropathy in mucopolysaccharidosis type II. AB - INTRODUCTION: Mucopolysaccharidosis type II (MPS type II, Hunter syndrome) is a rare (~ 1/1500.000), X-linked inherited disorder (affects boys) due to deficiency of the lysosomal enzyme iduronate sulfatase (Xq.28). The complex clinical picture includes osteoarthropathy with a tendency to flexion stiffness and disability. In our country, the specific diagnosis and enzyme replacement therapy (ERT), are recently available in the Center for Genetic Pathology Cluj. OBJECTIVES: Assessment of clinical features, radiological and imaging of osteoarthropathy in MPS type II and their evolution under ERT. MATERIAL AND METHODS: The study included 9 male patients with a suggestive clinical picture of MPS type II; the diagnosis was confirmed by enzymatic assay and the patients were treated with ERT. Osteoarthropathy was assessed before treatment: a) clinical tests (joint goniometry, walking test) and b) radiology (X-rays of the hand and wrist, spine and pelvis), bone densitometry in five patients. Clinical tests were repeated after therapy. RESULTS: Chronic osteoarthropathy was present in all patients. Joint mobility was reduced with quasi stationary trend after 12 months of treatment. The walking test was improved after treatment. Radiological assessment revealed: hand bones changes, delayed bone age, vertebral changes, pelvis changes, kipho-scoliosis and aseptic necrosis of the femoral head in 100%, 88%, 88%, 55% and 11% respectively. Bone mineral density was normal in five of the nine patients evaluated. CONCLUSIONS: Chronic osteoarthropathy with flexion stiffness is an essential component of the clinical picture of MPS type II. ERT allows an improvement/arrest of evolution (depending on disease severity and time of initiating therapy). PMID- 26527963 TI - History of the pharmacies in the town of Alesd, Bihor county. AB - In 1848 pharmacist Horvath Mihaly established the first pharmacy in Alesd, called Speranta (Remeny). Following the brief history of this pharmacy we will notice that in 1874 the pharmacy comes into the possession of Kocsiss Jozsef. In 1906 the personal rights of the pharmacy are transcribed to Kocsiss Bela, and since 1938 the his son, Kocsiss Dezso, pharmacist, became the new owner. In 1949 the pharmacy was nationalized and became the property of the Pharmaceutical Office Oradea, the pharmacy got the name Farmacia nr. 22 of Alesd, and continued its activity throughout the whole communist period. Starting with the year 1991 it entered into private system as Angefarm, as the property of Mermeze Gheorghe, pharmacist, and from 2003 until now works under the name Vitalogy 3, as the property of Ghitea Sorin. A second pharmacy, Sfantul Anton was founded in 1937 by pharmacist Herceg Dobreanu Atena, which however had no continuity during the communist period. PMID- 26527961 TI - Quality of life in metastatic breast cancer: comparing patients with major depressive episodes with patients without M.I.N.I. diagnosis. AB - AIM: To compare the quality of life indicators in patients with metastatic breast cancer diagnosed with major depressive episodes with those in patients with no psychiatric diagnosis. PATIENTS AND METHODS: We conducted a cross-sectional, observational study at the Day Care Unit of the Oncology Institute "Ioan Chiricuta" Cluj-Napoca in a group of 100 patients with metastatic breast cancer, during chemotherapy. General data were collected and the patients received a complete psychiatric evaluation, in conjunction with a structured interview and an oncology designed quality of life questionnaire. RESULTS: The rate of major depressive episodes in the group was 29.30%. The patients with major depressive episodes had lower adjusted mean scores for physical, emotional, social and role functioning and higher adjusted mean scores for fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss and constipation than those without diagnosis. The quality of life/global health status scores were significantly lower in the depressive patients group, and the same results were noted for sexual functioning and enjoyment mean scores, as well as for the future perspective. CONCLUSIONS: These results suggest that patients with metastatic breast cancer and major depressive episodes have an impaired quality of life as compared to those without psychiatric diagnosis. PMID- 26527962 TI - A fatal case of Taxus poisoning. AB - CONTEXT: Taxine-derived alkaloids, taxane-derived substances, and glycosides seem to be responsible for the toxicity of Taxus spp. by blocking microtubule, sodium and calcium channels causing conduction abnormalities. Cases with Taxus baccata acute intoxication have rarely been reported. CASE DETAILS: We report the case of a 43-year-old man who ingested, for suicidal purposes, common (or European) yew leaves (Taxus baccata) and presented severe hypokalemia, ventricular arrhythmias with hemodynamic instability accompanied by severe multiple organ dysfunction syndrome, including respiratory insufficiency, renal failure, acid-base imbalance with severe hypokalemia, hepatic dysfunction and coma, which led to death 12 hours after Taxus baccata ingestion. CONCLUSION: In this particular case, the cardiac electrical instability was definitely maintained by several causes, including severe hypokalemia, which has not been previously reported as related to Taxus poisoning. The metabolic acidosis associated with severe hypokalemia definitely contributed to the complex arrhythmias. The occurrence of severe hypokalemia needs further attention in cases with Taxus poisoning as its immediate treatment might increase survival chances. PMID- 26527964 TI - Memories of the first President of the Academy of Medical Sciences - Professor Aurel Moga. PMID- 26527965 TI - The recognition of Gheorghe Bilascu's contributions in the Romanian history of dentistry. AB - Prof. Dr. Gheorghe Bilascu (1863-1926) was one of the founders of the Romanian Faculty of Medicine in Cluj. At this Faculty, in 1919/1920 he created the department and the clinic of dentistry. These two achievements were accomplished for the first time in Romania. Normally, his contribution should have been appreciated both during his life and after his death. Also, his name would be expected to be present in the large majority of Romanian medico-historians dictionaries, treatises, papers etc. Unfortunately, his posthumous appreciation was not as Bilascu would have deserved. In our paper we present the recognition of Gh. Bilascu's contributions in the Romanian history of dentistry between 1926 2013. We divided this period into three intervals: from 1926 to 1948, the communist era, and after the anticommunist revolution (1990-present). In the first interval the achievements of Bilascu in the field of dentistry were very much appreciated and they were mentioned in a correct way in different medico historical sources of information. During the communist era the name of Bilascu was omitted in some dictionaries, courses etc. After 1990, the important role of Bilascu in Romanian dentistry was put into its important place in the majority of Romanian history of medicine sources of information. PMID- 26527966 TI - Medical ethics and the Romanian law. Surrogate decisions regarding life-saving medical interventions. AB - Romanian doctors who encounter controversial surrogate decisions such as refusal of life-saving interventions react differently from an ethical perspective. Some do not take into account the surrogates' rejection of treatment, while others respect and abide by the surrogates' decision and withhold the refused procedures, forgoing their ethical responsibilities. In this article we will defend the ethical position that doctors should consider and, therefore, thoroughly evaluate the surrogate decisions in cases where the medical intervention is life-saving and the benefits for the patient are significant and certain. The doctors who choose to obey the controversial decisions of surrogates usually invoke the Romanian medical law. In the following we argue that in today's Romanian medical framework there is a conflict between ethical (professional) obligations and the some of the legal provisions and we provide two ethical arguments, one principlist and one contractualist, that prompt for the overriding of refusals which concern life-saving interventions. PMID- 26527967 TI - Dilated cardiomyopathy produced by lamin A/C gene mutations. AB - Lamin A/C gene (LMNA) associated cardiomyopathy is a form of dilated cardiomyopathy with poor prognosis and high mortality, and a rapid evolution toward end-stage heart failure and malignant ventricular arrhythmias associated with increased risk of sudden cardiac death. It is transmitted in a autosomal dominant manner and is characterized by age-dependent high penetrance and variable expression. Screening of first degree relatives of proband patients by means of clinical evaluation, electrocardiogram, echocardiography and genetic analysis is useful for the early diagnosis of the disease. Drug therapy and non pharmacological measures in the early stages of the disease seem to improve the prognosis of these patients. PMID- 26527969 TI - Psychiatric Adverse Effects Of Interferon Therapy. AB - A number of data support the involvement of immunological mechanisms in the etiology of psychiatric disorders. The nervous and immune systems are physiologically integrated and influence each other's functioning. Clinical studies have reported a larger number of psychiatric symptoms consecutive to immunomodulating interferon therapy. The most frequent are depression, suicidal behavior, manic syndrome, anxiety disorders, psychotic disorders and delirium associated with an array of unspecific psychiatric symptoms: fatigue, irritability, psycho-motor retardation, decreased libido, insomnia, concentration difficulties and attention deficit. Another undesired consequence of interferon therapy is the worsening of a preexistent psychiatric disorder. Thus, a history of psychiatric disorder is currently one of the contraindications of interferon therapy. Psychiatric adverse events may occur either shortly after the initiation of therapy, or as a result of ongoing treatment, but most adverse events occur after 3 weeks of treatment. Although there are relatively few studies on statistically significant patient samples, current data underline the importance of managing these effects and also the most indicated treatment strategies. Therefore, an improved psychiatric management of these adverse effects may change the gastroenterologist's decision to exclude from treatment high - risk patient categories such as those with mood disorders, alcohol or drug abuse, or other addiction. PMID- 26527970 TI - Epidemiology of self-reported drug-induced immediate-type hypersensitivity reactions in the surgical population: a 5-year single-center survey in a romanian allergo-anaesthesia center. AB - AIM: Immediate-type hypersensitivity drug reactions are frequently under reported, epidemiological data being imprecise. The aim of our study was to identify the drugs involved and to describe the clinical characteristics of previous immediate-type hypersensitivity reactions in a large series of Romanian surgical patients, and to establish the concordance between in vivo and in vitro tests. METHODS: Of the 807 surgical patients referred to our outpatient department of allergo-anaesthesia, we retrospectively enrolled 632 patients with previous drug-induced hypersensitivity reactions. The allergological work-up included a complete allergological history, allergological skin tests and in vitro tests. RESULTS: The drugs involved were: antibiotics in 68% of our patients (with 83.02% being beta-lactams), followed by NSAIDs in 43.28% (50.24% of them being metamizol), general anaesthetics in 9.33%, and local anaesthetics or other drugs, each in 6.32% of the 632 patients. The clinical features reported were urticaria in 63.13%, angioedema in 41.77%, bronchospasm in 15.82%, hypotension in 16.61% and cardiovascular collapse in 21.51% of our patients; 31.80% of the referred patients were confirmed as being positive by at least one diagnostic test. The agreement between in vivo tests and BAT was fair (k=0.35), while between in vivo tests and IgE, the concordance was poor (k=0.12). CONCLUSIONS: The data obtained from the patients referred to our clinic without any filters and restrictions indicates the pattern of drug-induced immediate-type hypersensitivity reactions and the most frequently involved drugs in Romania. At the end of the allergological work-up we confirmed 31.80% of our patients as having drug-induced hypesensitivity. PMID- 26527968 TI - Ear keloids: a review and update of treatment options. AB - Ear keloids are among the most challenging plastic surgery conditions and may have significant psychosocial impact for the patient. Their aesthetic considerations are serious and despite a variety of treatment options, they often proved to be recurrent. This paper reviews the management options of ear keloids available in literature up to date. Multiple therapeutic options are discussed, such as: surgical treatment, corticosteroid injections, laser therapy, cryotherapy, radiotherapy, pressure therapy, therapy with antitumor or immunosuppressive agents. PMID- 26527971 TI - A rare variation of the digastric muscle. AB - The digastric muscle is composed by two muscle bellies: an anterior and a posterior, joined by an intermediate tendon. This muscle is situated in the anterior region of the neck. The region between the hyoid bone and the mandible is divided by an anterior belly into two triangles: the submandibular situated laterally and the submental triangle which is located medially. We found that the anatomical variations described in the literature relate mainly to the anterior belly and consist of differences in shape and attachment of the muscle. During routine dissection in February 2013 in the section hall of the Department of Anatomy and Histology in Medical University - Sofia we came across a very interesting variation of the digastric muscle. The digastric muscles that presented anatomical variations were photographed using a Sony Cyber-shot DSC-T1 camera, with a Carl Zeiss Vario-Tessar lens. We found out bilateral variation of the digastric muscle in one cadaver. The anterior bellies were very thin and insert to the hyoid bone. Two anterior bellies connect each other and thus they formed a loop. The anatomical variations observed of our study related only to the anterior belly, as previously described by other authors. It is very important to consider the occurrence of the above mentioned variations in the digastric muscle when surgical procedures are performed on the anterior region of the neck. PMID- 26527972 TI - Physical and biological properties of Bazna waters. AB - The healing properties of Bazna waters and their therapeutic indications have been well known since the 18(th) century. The objective of the present study was to characterize these waters from physical and biological points of view, and to further analyze the nitrogen compounds, especially NH4+. The following physical parameters of the water were analyzed: density (g/cm(3)), electric resistivity (Omega.m), electric conductivity (cm(-1)o(-1)), salinity, The pH analysis of the biological component was performed on samples from 4 basins. Nitrogen compounds were dosed in the form of ammonium ion (NH(4+)). The physical and chemical proprieties are similar across the basins. Flora and fauna biological components were identified. Ammonium ions were identified in large quantities, but this did not lead to hygienicaly unclean waters. PMID- 26527973 TI - Induction of a chronic myocardial infarction in the laboratory animal - experimental model. AB - INTRODUCTION: Ischemic heart disease is a major public health problem in western countries. Appropriate animal experimental models of chronic myocardial infarction is an essential first step in order to investigate and develop new therapeutic interventions. AIM: The aim of this study was to find an optimal place for a coronary artery ligation to induce an optimal chronic myocardial infarction and also a new heart approach that will not require oro-tracheal intubation. MATERIAL AND METHODS: To achieve these goals we used a group of rabbits and after induction of anesthesia and cardiac exposure by rib osteotomy (rib III, IV and V) at the costo-sternal junction level on the right side we performed three different left anterior descending artery (LAD) ligation at different distances (5, 10 and 15 mm) in relation to the apex. Thirty days after the acute myocardial infarction, we correlated laboratory investigations (serology, ECG, cardiac ultrasound) with histopathological findings. RESULTS: Heart approach achieved by rib osteotomy (rib III, IV and V) at the costo-sternal junction level on the right side, maintains the integrity of the ribcage, allowing it to take part in respiratory movements and the animal model does not need oro-tracheal intubation. Ligation of LAD at 15 mm from the apex was incompatible with life; ligation of LAD at 5 mm from the apex does not achieved transmural myocardial infarction and ligation of LAD at 10 mm from the apex achieved a transmural myocardial infarction of the left ventricle which also involved the distal part of the interventricular septum. CONCLUSION: Ligation of LAD at 10 mm from the apex achieved a transmural myocardial infarction of the left ventricle, is in an easily accessible area from technical point of view, it is sufficiently expanded to induce hemodynamic effects that can be quantified with paraclinical examination and also it is compatible with the experimental animal life. If the heart is approached by rib III, IV and V osteotomy at the costo-sternal junction level on the right side combined with neuroleptic anaesthesia, the animal does not need assisted ventilation. PMID- 26527974 TI - Non-variceal upper gastrointestinal bleeding: clinical, therapeutic and evolution aspects. Comparison between a tertiary medical center and a municipal hospital. AB - Upper gastrointestinal bleeding (UGIB) is one of the most common emergencies in gastroenterology practice. In recent years, the introduction of urgent upper gastrointestinal endoscopy (UGIE) and of the treatment with proton pump inhibitors (PPIs) in high doses has resulted in an improvement of the treatment outcome in patients with UGIB, but without a significant improvement in mortality rates. In our study we compared the epidemiological, clinical, therapeutic, and prognostic aspects in patients with non-variceal UGIB admitted over a period of one year in a tertiary center where urgent UGIE is a routine procedure and in a municipal hospital where UGIE with endoscopic hemostasis is not available. Patients admitted to the tertiary medical center had more clinical and endoscopic severity factors compared to those from the municipal hospital: they were older, with more frequent intake of NSAIDs, several comorbidities, some of them severe, and more severe posthemorrhagic anemia. The endoscopic examination revealed that active bleeding and stigmata of recent hemorrhage were more frequent in these patients. Urgent UGIE and, where necessary because of lesions, endoscopic hemostasis were performed in most of these patients. Patients admitted to the municipal hospital were treated more frequently with high-dose intravenous PPIs. Patients undergoing urgent UGIE and endoscopic therapy had a shorter duration of hospitalization. However, there were no differences regarding the need for surgery or mortality rates. The results of our study are consistent with the literature. PMID- 26527975 TI - Prevalence of dental erosions in GERD: a pilot study. AB - BACKGROUND: Dental erosions are determined by a mechanism involving increased oral acidity. Gastro-esophageal reflux disease (GERD) represents the pathological reflux of gastric content into the oral cavity, affecting the hard dental tissues integrity, with a major risk of advanced tooth wear. AIM: This study aims to investigate the prevalence of dental erosions in GERD patients, in order to obtain a basis for therapeutic strategies and specific prophylactic measures. METHODS: We incorporated a mandatory dental consultation in the therapeutic protocol of GERD patients. The study was carried out in a group of 60 patients with GERD. Dental examination of these patients revealed 21 cases showing visible dental erosions. The control group included 60 patients, without GERD, age and sex matched. All examinations were carried out in a tertiary center by the same team of dentists, instructed in dental erosion recognition and questionnaire administration. RESULTS: The dental erosion prevalence in patients with GERD was 35%. In the control group, erosions were 13% (OR: 3.6); 67% of patients with dental erosions were females and 33% were males. Middle age showed the highest risk for dental erosions, with peaks in the fourth and sixth decades. CONCLUSIONS: The risk of dental erosion was significantly higher in GERD patients as compared to the control group. The sex ratio shows a higher prevalence of erosion in females. PMID- 26527976 TI - Evaluation of serum beta-hCG and PAPP-A levels in pregnant women at risk of developing preeclampsia. AB - BACKGROUND AND AIM: Preeclampsia remains a major problem of modern obstetrics with insufficiently elucidated etiology; early detection would diminish maternal and fetal mortality and morbidity. The aim of this study was to determine the serum values of beta-hCG in the first and second trimesters of pregnancy and PAPP A values in the first trimester of pregnancy in pregnant women with risk factors for preeclampsia, in order to evaluate their relevance in the prediction of this disorder. MATERIAL AND METHODS: We performed a prospective longitudinal study on 120 pregnant women divided into two groups according to the evolution of pregnancy: group I - 26 pregnant women who developed preeclampsia and group II - 94 pregnant women who did not develop preeclampsia and had a physiological evolution of pregnancy. RESULTS: Our results indicate the association between high beta-hCG levels in the first and second trimesters of pregnancy and the development of PE, beta-hCG having the highest predictive power in the second trimester. We also obtained a positive association between low serum levels in PAPP-A in the first trimester and onset of PE. The predictive power of conjugated beta-hCG and PAPP-A values in the first trimester of pregnancy was better that any other marker analyzed separately. CONCLUSIONS: Increased beta-hCG levels in the first and second trimesters of pregnancy and low PAPP-A levels in the second trimester of pregnancy are associated with a higher risk for PE, the study providing only a modest efficiency of the prediction capacity. PMID- 26527977 TI - Anatomical variants of tympanic compartments and their aeration pathways involved in the pathogenesis of middle ear inflammatory disease. AB - AIM: The aim of this article is to review the anatomy of middle ear compartments and folds and to demonstrate through anatomical evidence their presence at birth. Additionally, their role in the obstructions of middle ear ventilatory pathway is highlighted. METHODS: Ninety-eight adult temporal bones, with no history of auricular disease and fifteen newborn temporal bones were studied by micro dissection. Documentation was done by color photography using the operation microscope. RESULTS: Our micro-dissections have showed that mucosal folds from the middle ear are steadily present since birth, given that they were found in all newborn temporal bones. The mucosal folds in our normal adult material, showed some variations including membrane defects but they were constantly present. Our micro dissections showed that the epitympanic diaphragm consisted, in addition to malleal ligamental folds and ossicles, of only two constantly present folds: the tensor tympani fold and the incudomalleal fold. When the tensor fold is complete the only ventilation pathway to the anterior epitympanic space is through the isthmus, whereas its absence creates an efficient additional aeration route from the Eustachian tube to the epitympanum. CONCLUSIONS: The goal of surgery in the chronic pathology of the middle ear should be restoration of normal ventilation of the attical-mastoid area. This is possible by removing the tensor fold and restoring the functionality of the isthmus tympani. PMID- 26527978 TI - The role of exhaled nitric oxide assessment in children with bronchial asthma. AB - BACKGROUND: Exhaled nitric oxide (eNO) assessment in children with bronchial asthma (BA) is an easy and non-invasive test that provides informations on the presence of bronchial inflammation. METHODS: The study included 110 children aged between 5-18 years with a diagnosis of BA. The patients were assessed clinically (objective examination, questionnaire regarding the disease control) and by medical tests (exhaled breath analysis for nitric oxide, induced sputum, spirometry). RESULTS: Of the 33 patients with non-atopic BA, 9 (27.27%) presented normal eNO values, and 24 (72.72%) had higher than normal levels. There were 26 patients with controlled BA, 59 with partially controlled BA and 25 with uncontrolled BA, the levels of eNO demonstrating the existence of the statistically significant differences between the mean values of the variables obtained in the studied groups (p=0.003). Increased individual values were more frequently noted in patients with an exacerbation of asthma in the last month (70% vs 56.6%), but the differences were not statistically significant. Of the 77 patients with atopic BA, 35 (45.45%) had normal eNO, while 42 (54.54%) had increased values. The normal values of the eNO were most frequently noted in patients undergoing treatment with inhaled glucocorticoids (IGC). Patients with low percent of eosinophils in sputum had increased eNO values (p=0.03). CONCLUSIONS: The investigation of the airways by measuring the eNO levels is a useful method of assessing bronchial inflammation in children with bronchial asthma, in order to establish the disease responsiveness and therapy. PMID- 26527979 TI - Predictors of limph node metastasis in endometrial cancer. AB - INTRODUCTION: Endometrial cancer is the most common gynecologic malignancy in developed countries. The adequate surgical staging proposed by FIGO (International Federation for Gynaecology and Obstetrics) advocates lymphadenectomy; however, it does not establish the indications, the type and the extent of lymphadenectomy, thus generating multiple controversies. METHODS: Retrospective, analytical study of patients treated surgically for endometrial adenocarcinoma in the Oncological Institute "Prof. Dr. Ion Chiricuta" Cluj-Napoca (IOCN) between January 2008 and December 2012 - 709 cases eligible for the study. RESULTS: 206 pelvic and/or paraaortic lymphadenectomies were performed, the average number of excised lymph nodes being 15.6. Overall in 4.4% of patients the lymph nodes were affected by metastases. The presence of each risk factor analysed was statistically significantly associated with lymph node metastasis (p<0.05). Age above 55 years was statistically significantly associated (p<0.05) with the presence of negative prognostic factors in the study. CONCLUSIONS: The analysed histopathological and clinical prognostic factors were statistically significantly associated with lymphatic dissemination in endometrial cancer. We recommend treating endometrial cancer in tertiary centres by surgeons or gynaecologists-oncologists with experience in extensive peritoneal and retroperitoneal surgery. PMID- 26527980 TI - Clinical experience with induction therapy in renal transplantation. AB - INTRODUCTION: Acute rejection (AR) is a major determinant of renal allograft survival. The incorporation of new immunosuppressive agents explains the improvement seen in the results of transplantation in recent years. OBJECTIVE: To assess the optimal immunosuppression regimen according to the immunological risk of renal transplant patients. METHOD: We performed a retrospective study of 977 consecutive patients transplanted in our institution between January 2000 and December 2011. Recipients were classified according to the immunological risk (high, intermediate and low) and the type of induction therapy received. We evaluated the incidence of early acute rejection (eAR) and late acute rejection (lAR) and their influence on graft and patients survival in relation to the immunological risk and induction regimen used. RESULTS: The incidence of eAR was 5.4%, 6.4% and 1.4% in relation with the immunological risk, high, intermediate and low respectively. The most commonly used induction immunosuppression was rabbit antithymocyte globulin (ATG), followed by methylprednisolone and basiliximab. No statistical difference was found between the incidence of eAR according to the type of induction therapy and immunological risk. The graft survival was significantly better for the cases without eAR at 1 year (98.6% versus 94.4%, p=0.019), and 3 years (94.9% versus 88.9%, p=0.056). The patients survival was significantly better for those without eAR at 1 year after transplant (95.7% vs. 88.9%, p=0.051), 3 years (93.1% vs. 83.3%, p=0.008) and 5 years (92.2% vs. 79.6%, p=0.001). The incidence of lAR was between 0 and 7.1% according to the induction therapy, lacking any statistical significance (p=0.450). CONCLUSION: Tailoring the induction immunosuppression according to the immunological risk reduces the incidence of early acute rejection. PMID- 26527981 TI - In-vivo assessment of barbed suturing thread with regard to tissue reaction and material absorption in a rat model. AB - AIM: The laparoscopic approach in urological surgery demands a high degree of skill in intracorporeal suturing and knot tying. In an effort to reduce the amount of time required to perform a suture, new materials have been developed that through selfanchorage distribute tension more evenly across the suture and also eliminate the need of knot tying. The goal of this study was to assess the in vivo tissue response to a novel material (V-Loc tm; Covidien) in comparison to established materials (Vicryl, PDS II), in the case of bladder suturing, in a rat model. METHODS: The study included 48 male Wistar rats. All underwent a median abdominal incision, with a 1cm cystotomy, followed by a running suture. The suture material used was either V-Loc absorbable self anchoring thread, Vicryl threaded absorbable suture or monofilament absorbable suture. The abdominal cavity and the bladder suture were macroscopically evaluated at the rats' scheduled death at 3 and 6 weeks. The bladder wall was microscopically assessed by a pathologist, with regard to tissue reaction and suture material degradation. RESULTS: All rats survived the procedure, with the abdominal scar fully healed at week 2. There were no signs of infection or lithiasis during the observation. Macroscopically, at 3 weeks, the suture material was recognizable and visible in all cases, with special mention that the V-Loc thread was considerably more rigid, retaining its shape almost entirely, and provoked more adhesion of the surrounding tissue. At 6 weeks, the suture was indistinguishable in the bladder wall in the case of monofilament absorbable material, barely visible in the case of Vicryl, while the aspect of the V-Loc suture resembled the one at 3 weeks, with the material still clearly visible in the bladder wall, shape almost entirely maintained, and surrounding tissue adherence. Microscopically, at 3 weeks and 6 weeks, all bladder walls examined had regained their structure. At 3 weeks, the monofilament absorbable suture showed intense tissue reaction, with the material already in phagocytosis; at 6 weeks, no clear evidence of leftover material was observed. At 3 weeks, the Vicryl material showed moderate tissue reaction, with phagocytosis initiated between the strands of the material; at 6 weeks, the material was almost entirely absorbed, but with a clear leftover tissue reaction. In the case of the V-Loc suture, due to the hardness of the thread, the material itself could not be cut for analysis with the bladder wall, and the examination could only involve the bladder wall and marks of the thread. Thus, the tissue reaction was minimal, as was the presence of phagocytes at the suture site. The material showed little, if any, signs of absorption after 6 weeks. CONCLUSION: The materials tested all proved equally effective in suturing the bladder wall in a rat model. However, the novel barbed thread proved a consistently low in-vivo absorption rate, while maintaining its rigidity over time. More research is needed to assess the possible clinical implications of these findings. PMID- 26527982 TI - Pancreatic insulinoma. Case report and review of the literature. AB - Insulinoma is a rare pancreatic islet cell tumor, the most common cause of hypoglycemia related to endogenous hyperinsulinism. We present the case of an adult patient with pancreatic insulinoma. The patient presented to our clinic after prior hospitalizations in diabetes and psychiatry hospital units for repeated episodes of loss of consciousness, sweating and tonic-clonic seizures. Early detection of the cause is important for prompt initiation of therapy and to reduce symptoms. We describe our diagnostic and therapeutic strategies with references to previously published reports. PMID- 26527983 TI - Primary non-Hodgkin lymphoma of the orbit presenting with massive bilateral periorbital tumors. AB - Extranodal onset can be seen in approximately 25-40% of the cases of non- Hodgkin lymphomas and diagnosis is often difficult due to nonspecific symptoms. Orbital lymphomas represent approximately 50% of the orbital malignancies. Common symptoms and signs at presentation are: palpable tumor, exophtalmia, dyplopia and decreased vision. Diagnosis can be made only by biopsy and early treatment is important in order to increase the chance of cure. We present the case of a patient whose diagnosis and treatment were delayed due to refusal of biopsy and, although complete remission of lymphoma was obtained, the vision loss was permanent because of prolonged compression on the optic nerves. A particularity of this case is the presence of massive periorbital tumors on admission to the hospital, incorporating the eye globes completely and causing impressive facial deformity. PMID- 26527984 TI - Biliary Hamartoma. AB - Biliary hamartoma or von Mayenburg complex (VMCs) is a rare benign congenital malformation of the biliary duct. Patients are usually asymptomatic. Hepatic lesions are incidentally discovered on ultrasonography (US) and subsequent radiological methods are necessary for confirmation. A correct diagnosis is established when typical imaging findings are present, otherwise histological confirmation might be needed. PMID- 26527985 TI - Frontal fixed prosthetic restoration in edentulous space modification. AB - This study case presents a 53 years old patient with severe aesthetic dysfunctions due to an ectopic maxillary canine associated with a frontal edentulous space. Orthodontic treatment proposition was refused by the patient. After canine extraction, metalo-ceramic fixed partial prosthesis successfully restored the aesthetic damage in the conditions of a non-gingival smile. Adapted abutment teeth preparations were made in order to provide necessary space for aesthetic alignment of artificial teeth in the pontic. PMID- 26527986 TI - Testimonials about the life of prof. Ion Manta (1900-1979) A victim of the communist regim. AB - Ion Manta was the first Romanian professor and director of the Department of Biochemistry in the Cluj Faculty of Medicine and one of the most endowed biochemists in Romania. He was considered one of the founders of didactic medical biochemistry in our country. His scientific activity, his teaching talent, capacity of work, his character and personal charm were much appreciated by his colleagues, by different scientists and students. Our paper presents some important testimonials about the life and achievements of Ion Manta. The paper contains also some testimonials which put into evidence the fact that at the beginning of the '50 he was an innocent victim of the communist regime. PMID- 26527987 TI - The impact of stress and glucocorticoids on memory. AB - Responses to stress are mediated by a complex network of the nervous and endocrine systems. Glucocorticoids, which are among the most important "players" in stress resilience, may have important implications in the cognitive functions, particularly in the modulation of memory. Declarative memory, the memory for facts, events and word meaning is the most studied type of memory on which glucocorticoids exert an influence, both positively through consolidation and negatively through impairment. These effects depend on the receptor type, dose, time of exposure, memory component and the salience of stimuli, retrieval being generally affected and storage being facilitated, especially for emotionally relevant events. Glucocorticoids also induce hippocampal atrophy, which is a hallmark seen in various diseases accompanied by a chronic high level of cortisol, such as the Cushing syndrome, major depression, post-traumatic stress disorder. Also, chronic stress might be a risk factor for the development of Alzheimer's disease, especially when a genetic background and other environmental influences are present. PMID- 26527988 TI - Is there any interplay between incretins and bile acids? What is the role of bariatric surgery? AB - Obesity and type 2 diabetes are associated with the impairment of the incretin effect. Evidence has revealed that bile acids are involved in glucose homeostasis. Bariatric surgery, referred also as metabolic surgery, exerts beyond weight loss an important metabolic effect by inducing amelioration or remission of type 2 diabetes. Surgical procedures that involve rearrangements of the gastrointestinal tract and therefore rerouting of the food such as laparoscopic Roux en Y gastric by pass (LRYGB), induce an increase in glucagon-like peptide 1 (GLP-1) levels and of bile acids, which will both promote an early improvement of glycemic control. Emerging data have revealed that there might be an interplay between GLP-1 and bile acids regarding glycemic control, raising the question about considering bile acids as the new gut hormones. PMID- 26527989 TI - Suckling and non-nutritive sucking habit: what should we know? AB - Correct breast feeding can be considered a tool for the post-natal prophylaxis of craniofacial abnormalities, or at least a way of reducing their extent. Inadequate bottle feeding forces the tongue and cheek muscles to develop a compensating and atypical function, in order to obtain the milk. As a result, there can be an adaptation change of the dental and bone structures, leading to malocclusions. Finger-sucking is normal in the first two-three years of life. It gives the child a feeling of relaxation; that is why it is usually practiced before sleeping. The effects of non-nutritive sucking on the developing dentition are minor in the child under 3 years of age and are usually limited to changes in the incisor position. Some upper or lower incisors (depend on how the finger has been sucked) become spontaneously tipped toward the lips, and/or others are prevented from erupting. Normally children abandon this habit between 2 and 4 years of age. If it persists after this age, it will be the cause for some dental maxillary anomalies: open-bite, narrow maxilla with upper protrusion, cross-bite; all these could be accompanied by retrognathic mandible. PMID- 26527990 TI - Pill -Induced Erosive Esophagitis in Children. AB - AIMS: Pill-induced esophagitis has been recognized in adults, but rarely in children. The aim of this article is to discuss endoscopic features, drugs implicated, prevention and treatment in pill-induced esophagitis in children. PATIENTS AND METHODS: Over a period of 4 years, 26 patients presented at our clinic with drug-induced esophageal ulcerations. All patients were diagnosed by means of endoscopy and treated with proton-pump inhibitors and prokinetics. The mean age of the children was 10.76 years. RESULTS: The ulcers were frequently located at the mid-esophagus. Odynophagea, retrosternal pain and dysphagia were the most common presenting symptoms. All children took pills (non-steroidal anti inflammatory drugs, antibiotics - Doxycycline and ferrous sulfate) with little water and at bed time. The mean elapse between the drug intake and endoscopy was 4.96 days. The symptoms resolved within a maximum of one week of antireflux therapy. CONCLUSIONS: In pediatric cases treated by tablets or capsules, the possibility of medication-induced esophagitis should always be considered. The drug-induced esophagitis should be suspected in all patients presenting with chest pain and dysphagia. Physicians must warn the patients to take the pills and capsules with enough water and in the upright position. PMID- 26527991 TI - Increased chemerin and decreased omentin-1 levels in morbidly obese patients are correlated with insulin resistance, oxidative stress and chronic inflammation. AB - BACKGROUND AND AIM: Morbid obesity represents a proinflammatory and pro-oxidative state associated with dysregulation of adipokines. We aimed to evaluate the circulating levels of chemerin and omentin-1 in morbidly obese (MO) patients and to investigate the relationship between these two adipokines and between each of them and anthropometric, metabolic, oxidative stress and chronic inflammatory parameters. MATERIAL AND METHODS: 32 MO patients and 20 controls were investigated in this study. Anthropometric, metabolism parameters, inflammatory markers, oxidative stress indicators as well as chemerin and omentin-1 were measured. RESULTS: Serum levels of chemerin were increased while omentin-1 levels were decreased in MO patients when compared with controls. Chemerin correlated positively with insulin, HOMA-IR, LDL cholesterol and negatively with total antioxidant response. Omentin-1 correlated negatively with tumor necrosis factor alpha and total cholesterol. In a multiple linear stepwise regression analysis we learnt that only HOMA-IR (beta=0.70, p<0.001), total cholesterol (beta=0.42, p<0.001) and triglycerides (beta=0.31, p<0.05) remained significantly associated with chemerin changes. Using the same analysis we noticed that total cholesterol (beta=-0.71, p<0.001), fasting glucose (beta= -0.40, p<0.05) and body mass index (BMI) (beta= -0.38, p<0.05) were considered to be significant predictors for omentin-1 changes. CONCLUSIONS: Chemerin and omentin-1 synthesis was dysregulated in MO patients. Chemerin might play a role in insulin resistance and oxidative stress. Chemerin changes seemed to be predicted mainly by insulin resistance. Omentin-1 levels were inversely associated with chronic inflammation and dyslipidemia while the main modulating factors seemed to be dyslipidemia, hyperglycemia and BMI. PMID- 26527992 TI - Ex-vivo perfusion machines in kidney transplantation. The significance of the resistivity index. AB - INTRODUCTION: With a growing shortage of organs for transplantation, finding ways of increasing the donor organ pool remains of utmost importance. Perfusion machines (PM) have been proven to enhance the potential for kidney transplants to function sooner, last longer, giving patients the opportunity for a better life quality. OBJECTIVE: The aim of this study is to evaluate the relation between the resistance index provided by the PM, the postoperative resistance index measured by Doppler ultrasound and the initial graft outcome. MATERIAL AND METHOD: Between January 2012-December 2012, clinical data obtained from 82 consecutive renal transplants from brain death donors (BDD) which underwent PM maintenance were analyzed in a transversal study. Prior transplantation we recorded the solution temperature, filtration rate and the resistance index provided by PM. After the surgical intervention, each patient had standard follow-up. Doppler ultrasound resistivity index (RI) was recorded on the first postoperative day. RESULTS: Out of 115 renal transplants, 98 (85.21%) were performed with grafts from BDD. The PM was used for 82 renal grafts. The Doppler resistance index in relation to the resistance index shows a highly statistical correlation by linear regression (R=0.813, p<0.0001). Primary graft function was recorded in 74 patients (90.24%) and it was highly statistically significant correlated with the resistance index measured by PM. Out of 8 patients with primary non-function, 6 patients recovered with normal graft function at one year. CONCLUSION: The resistivity index recorded by the life-port machine is correlated with the vascular resistivity index measured by Doppler ultrasound and thus it may predicts the primary graft outcome. PMID- 26527993 TI - Influence of light source and clinical experience on shade matching. AB - INTRODUCTION: Shade is one of the most important attributes when evaluating the success of a restoration. Several factors can influence the visual shade matching process, and therefore the outcome of the final restoration. OBJECTIVES: 1. to assess the importance of clinical experience on shade matching accuracy; 2. to assess the influence of two standard light sources on the ability to match shade tabs; 3. to identify the area in a VITA Classical shade guide where matching errors are most likely to appear. METHODS: 28 subjects were enrolled in the study: 14 undergraduate dental students and 14 dentists. All subjects had passed the Ishihara blindness test previously. Participants had to match 16 pairs of tabs from two shade guides, under two versions of illuminants of a viewing booth: D50 and D65, on a neutral background, 0 degrees /45 degrees viewing geometry. Paired and independent samples t tests were used to investigate the significant differences between the groups. RESULTS: The clinical experience had no significant influence on shade matching (p>0.05). According to participants' color discrimination competency, three groups were formed: superior competency, average competency and poor competency. The light source did not significantly influence the matching scores of subjects with superior or average color discrimination competency (p>0.05). However, in the group of subjects with poor competency the light source significantly influenced the results (p<0.05). Moreover, for the group of students the light source also influenced shade matching results (p<0.05). The most frequently mismatched tabs were C2 with D4 (11 subjects - 39.28%), B3 with B4 (11 subjects - 39.28%), B3 with A3.5 (8 subjects - 28.57%). CONCLUSIONS: The light source was proved to influence the shade matching results for subjects with a low level of clinical experience and for subjects with poor competency in color discrimination. PMID- 26527994 TI - Saliva characteristics, diet and carioreceptivity in dental students. AB - BACKGROUND AND AIMS: The use of sugar by dental plaque microorganisms leads to acid formation from the bacteria metabolism, which determines a decrease of pH onto teeth surfaces. The value of the critical pH is 5.2-5.5. We aimed to evaluate the capacity of patients to change their diet towards caries prevention after acknowledging the values of saliva parameters (pH, buffer capacity). MATERIAL AND METHODS: A group of 52 subjects were clinically examined according to the International Caries Assessment and Detection System protocol. They were required to complete a diet questionnaire and salivary tests were made for the oral mucosa hydration level, pH, buffer capacity, salivary flow rate at rest and upon stimulation. 4 pre-calibrated 6th year students and 2 dentists performed the tests and the ICDAS examination. One week after the tests, the subjects were asked to complete the diet questionnaire again. The studied group consisted of students aged between 23-26 years, randomly selected among 6(th) year students of the Faculty of Dentistry from Cluj-Napoca. RESULTS AND DISCUSSION: The mean DMF-S index was 18.39. Most of the patients (65%) had a DMF-S index between 9 and 21. Just 2.5% had an index of 3, which was the lowest value recorded. 5% of the patients had a DMFS of 35, which was the maximal value recorded. The distribution of DMF-S was normal. 50% of the patients had no active caries. Even though most subjects (19.23%) had a pH within the normal interval, most of them were at the bottom value of the interval (6.8). Most subjects had a pH of 6.4, which is moderately acid. The mean pH was 6.7, therefore, a moderately acid one. The Pearson correlation coefficient between DMFS and pH was 0.255. A mild negative correlation (-0.275) was found between the cariogenic food and buffer capacity. A week later we noticed a statistically significant decrease of cariogenic foods and drinks in students with acid pH and with low buffer capacity. CONCLUSIONS: A regular intake of cakes, bonbons and chocolate was reported by subjects who had a high DMF-S value and a low saliva buffer capacity. Only after the patients were aware of their caries risk, did they change their diet towards a non-cariogenic one, even though they had had the theoretical knowledge regarding caries prevention for at least 3 years. We conclude that the use of the chair-side salivary test should be highly recommended for cario-receptive patients. PMID- 26527995 TI - Change in the lower limb deep venous flow in peripheral atherosclerotic arterial disease. AB - AIM: This prospective study was undertaken to determine how peripheral atherosclerotic disease influences the flow in the deep veins of the leg. MATERIAL AND METHOD: Thirty one subjects with peripheral atherosclerotic disease and 23 age matched control subjects were studied. The popliteal vein flow velocity was measured at rest and during reactive hyperemia by means of color duplex ultrasound scanning. Patient age, ankle-brachial index (ABI) and the presence of risk factors for venous thrombosis were also recorded. RESULTS: There was a negative correlation between the ankle-brachial index and venous flow velocity among subjects with peripheral arterial disease (p=0.001). There was a negative correlation between dyslipidemia and resting venous flow velocity (p=0.049). During reactive hyperemia, venous flow velocity increased less in subjects with peripheral arterial disease than it did in control subjects (p=0.007). The subjects with dyslipidemia showed no changes in venous flow velocity in reactive hyperemia measurements (p=0.908). CONCLUSION: Increasing the venous flow velocity in peripheral arterial disease, may confer some protection against the deep venous thrombosis. PMID- 26527996 TI - Considerations on the surgical treatment of Duct Carcinoma in Situ (DCIS) of the breast from DRG system perspective. AB - Medical services for the treatment of Duct Carcinoma In Situ (DCIS) may be delivered in inpatient or outpatient care conditions. The aim of this study was to identify services recommended during patient hospitalization, and those more suitable for outpatient health care services, as well as measures to optimize the management of these cases from the reimbursement of medical services system perspective. PATIENTS AND METHODS: We conducted our study on the case records of the Oncological Institute "Prof. Dr. Ion Chiricuta" Cluj-Napoca (IOCN) over a period of five years (2008-2012). RESULTS: Analysis of the 129 cases of patient hospitalization showed that for the mastectomies performed the mean relative value (VR) for the discharged cases was slightly greater that the referential VR stated in the reimbursement framework contract (VR for IOCN discharged case was 1.2529 vs. 1.2097 referential VR in the contract). VR for the cases discharged after hospitalization in which a local excision had been performed was 0.6778 compared to 0.5482 the referential VR from the reimbursement contract. In the same period, the entity-specific flat-rate reimbursement for local excisions varied from 539 RON to 360 RON, depending on the year. CONCLUSIONS: Our study concludes that the treatment of DCIS cases did not negatively influence IOCN funding. In addition, it recommends the negotiation of combined services packages for the lesions that require imaging localization. PMID- 26527997 TI - A doctoral thesis about Carol Davila written in Paris in 1936. AB - Carol Davila, the father of the Romanian modern medicine, made decisive contributions to the development of health sciences in the Romanian Principalities in the last decades of the nineteenth century. The merit of his scientific work was recognized beyond the borders of his country. His life (not devoid of anecdotic instances and unknown episodes) and especially his work have aroused considerable interest among numerous medical historians. This paper presents a historical study elaborated in France, but until recently ignored, dedicated to the biography of Carol Davila. It concerns the medical doctoral thesis (State Diploma) elaborated by Joseph Adler (born 1910 in Botosani, Romania) under the supervision of professor Maxime Laignel-Lavastine, whose interest in Romania is well-known. Professor Laignel-Lavastine held the office of Secretary General of the International Society of History of Medicine (ISHM), founded in 1921, (replaced in this position by another French professor with links to Romania: Jules Guiart). The thesis comprises 48 pages and an exhaustive bibliography. It represents a token of the appreciation given to Davila's achievements by Europe's medical community. PMID- 26527998 TI - Memories of Nicolae Cajal - an emblematic personality of the Romanian Academy of Medical Sciences. AB - The Romanian Academy of Medical Sciences is the institution that includes the elite of the Romanian medical and pharmaceutical professionals. This is an article of recollection of one of the most outstanding presidents of the Romanian Academy of Medical Sciences, Nicolae Cajal. A distinguished scientist, Cajal accepted not only the task of president of this forum, but was also involved in social and political projects, as chairman of the Jewish Community of Romania, gaining the respect of both his colleagues and the general population. His activity is put in the context of the period in which he lived. PMID- 26527999 TI - The pathophysiological mechanisms of the onset of death through accidental hypothermia and the presentation of "The little match girl" case. AB - Hypothermia and death caused by hypothermia may be found in a number of fiction works, mainly in novels. In the well-known story "The Little Match Girl" by Hans Christian Andersen, one can notice that the descriptions of the phenomena occurring before the girl's death are in fact a literary presentation of the pathophysiological mechanisms of the onset of death through accidental hypothermia. This essay presents the medical aspects of the story written by Andersen. PMID- 26528000 TI - The Rehabilitation of Oncological Patients Presenting Neuropathies. AB - The International Association for the Study of Pain (IASP 2011) defines neuropathic pain as "the pain caused by an injury or disease of the somatosensory portion of the nervous system". The central neuropathic pain is defined as "the pain caused by an injury or disease of the central somatosensory central nervous system", whereas the peripheral neuropathic pain is defined as "the pain caused by an injury or disease of the peripheral somatosensory nervous system" [1]. The peripheral neuropathy describes any affection of the peripheral nervous system. The etiology is vast, there being a number of over 100 possible causes, which causes the global morbidity rate to reach approximately 2.4%. The chronic nature of the pain superposes the everyday routine and leads to the high intake of medication for pain alleviation. The number of cases of neuroplasia has always increased today. This disturbing diagnosis which can potentiate the signs and symptoms of peripheral neuropathy as well as reduce and limit the treatment options associated with neuropathies. The treatment presupposes a multidisciplinary approach, while the solution to prevent complications involves the control of risk factors and pathophysiological treatment. Chemotherapy induced peripheral neuropathy (CPIN) is a significant disabling symptom that is tightly connected to the administration of neurotoxic cytostatic agents used for the treatment of neoplasia. CPIN compromises the quality of life and produces pain or discomfort [2]. I have sought to produce a presentation of the medicated and physical-kinetic treatment options that have proved their effectiveness during clinical studies or random trials and can be applied to cancer patients presenting with symptoms associated with peripheral neuropathy, namely with neuropathic pain, and support it with arguments. PMID- 26528001 TI - Irritable Bowel Syndrome: Peripheral Mechanisms and Therapeutic Implications. AB - Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder, affecting about 10 to 20% of the population in developed countries. The mechanisms underlying the symptoms of this condition are poorly understood. Considered initially as the consequence of abnormal gut motility, visceral hypersensitivity, psychosocial factors and brain-gut axis dysfunction, IBS is now acknowledged as a multifactorial disorder. Specific peripheral mechanisms are involved, including mucosal immune activation, increased intestinal permeability, entero-endocrine cell products, an excess of bile acids, gut dysbiosis. A better understanding of these mechanisms could help develop new and specific therapeutic pathways in patients suffering from IBS. PMID- 26528002 TI - From NAFLD to Cardiovascular Disease. Is it (Still) the Metabolic Syndrome? AB - Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in developed countries. The incidence of NAFLD in the general population is 30-38% deppending on the geographical area and the diagnostic method used. NAFLD is considered to be the liver manifestation of the metabolic syndrome. A better understanding of the natural evolution would have practical consequences related mainly to the need of early and aggressive diagnosis, active monitoring and therapeutic solutions. Cardiovascular disease appears to be the main cause of death in these patients. The mechanisms linking NAFLD with cardiovascular disease are not fully understood yet, but attention was focused primarily on insulin resistance. The visceral adipose tissue, the epicardial adipose tissue, the systemic inflammatory response syndrome, the lipid profile, the procoagulants factors, the oxidative stress, and type 2 diabetes mellitus, they all might play a role in the link between NAFLD and cardiovascular disease. Currently, there isn't any medication specifically recommended for the treatment of NAFLD. Although the mechanisms underlying the association between NAFLD and cardiovascular disease are not fully known, attention must be paid to this association, given that these patients are more likely to die due to heart disease rather than liver disease. PMID- 26528003 TI - MicroRNAs with Specific Roles in Diabetes and Psychiatric Diseases. AB - Diabetes mellitus is one of the most cited non communicable diseases and the most common metabolic disorder. Epigenetics represents the field of study of heritable changes in gene expression which are not directly related to DNA. Epigenetics is concerned, alongside histone modifications, short interfering RNAs etc., with microRNAs (miRNAs) as well. These are small noncoding RNAs, 21 to 23 nucleotides in length, which either inhibit translation or affect mRNA stability and degradation. At present, there are dozens of miRNAs which have been proven to be involved in the animal and human pathology of diabetes (type 1 or 2). This review focuses on the miRNAs which have been identified as playing a role in both psychiatric diseases and diabetes. PMID- 26528004 TI - Elastic Stable Intramedullary Nailing for Fractures in Children - Principles, Indications, Surgical Technique. AB - Elastic stable intramedullary nailing (ESIN) is a minimally invasive technique. According to this technique, two elastic nails are introduced through the metaphysis into the medullary canal, advanced through the fracture site and impacted into the opposite metaphysis. These nails are preformed in a C-shaped manner, which allows for their precise orientation and the creation of an elastic system that resists deformation. PMID- 26528005 TI - Biopsychosocial Approach of Gastrointestinal Disorders. AB - Gastrointestinal disorders represent are conditions frequently seen in primary care, usually associated with a poor quality of life, entailing increased direct and indirect costs. Disorders of the digestive tract frequently coexist with psychological impairment. Even in early times scientists were concerned about the influence of the mind over body, and that there are many theories that explain the interaction between psychological factors and the physical status. At the present time the most comprehensive theory is the biopsychosocial model. There are four categories of factors that have to be addressed by the physician (or the integrated team that manages the patient): disease-related, therapeutic-regimen related, individual factors and psychopathological comorbidities. In the following paper we discuss these factors and their importance in clinical management of gastrointestinal disorders. PMID- 26528006 TI - Experience of anger in patients with irritable bowel syndrome in Romania. AB - BACKGROUND AND AIMS: Anger is strongly associated with the coping style, personality, interpersonal conflicts and quality of life. Increased research is being focused on the negative impact of anger on irritable bowel syndrome (IBS). Certain psychological areas such as anger have not been investigated in Romanian patients. The present study aims to determine the basal differences in experiencing anger between IBS patients and controls. METHOD: We examined the State-Trait anger in 60 subjects with IBS and 45 controls. The socio-demographic data and the State-Trait Anger Inventory were administered in individual sessions. RESULTS: evidenced that the IBS group had high mean scores for trait anger. No significant differences between the groups were detected on state anger. CONCLUSION: Higher levels of trait anger characterize IBS patients when compared to controls and this may be associated with symptoms. These findings are discussed within the context of other data suggesting that trait anger contributes to development and evolution of IBS, perhaps through modulation of the colonic motor activity. PMID- 26528007 TI - Role of comorbidities in caring for chronicly ill elderly patients with and without dementia. AB - BACKGROUND AND AIM: The aim of this study is to highlight the presence of co morbidities and their role in caring for chronicly ill patients with and without dementia. PATIENTS AND METHODS: The study was performed on a group of 213 chronic patients. We used CIRS-G (Cumulative Illness Rating Scale in Geriatric Population) and IADL (Instrumental Activity Daily Living) scales. We compared the scores of severity and dependency. RESULTS: The most frequent co-morbidities in the study group were cardiac, vascular, locomotor, sensory organs and metabolic diseases. For the study group, the highest medium score of severity according to the CIRS-G scale was represented by cardiovascular diseases. For patients with dementia, psychiatric, cardiac, vascular, metabolic, genitourinary, sensory organs and locomotion domains had the highest score of severity and dependency. CONCLUSIONS: The health status of chronic patients with and without dementia is characterized by multiple pathologies with various degrees of severity and dependency. PMID- 26528008 TI - Incidence and treatment of intra-articular lesions associated with anterior cruciate ligament tears. AB - The aim of the study is to retrospectively review the patients admitted and treated in the "Alexandru Radulescu" Orthopedics and Traumatology Clinic, Cluj Napoca for an anterior cruciate ligament tear over a 2-year period and document the intra-articular lesions found at arthroscopy as well as the treatment used for these associated lesions. PATIENTS AND METHODS: The case records of 88 patients operated for anterior cruciate ligament tear over a period of 2 years were reviewed. There were 67 males and 21 females with a mean age of 28.9 years, ranging from 14 to 49 years. After recording the patient demographics, we documented all the intra-articular lesions found during knee arthroscopy, as well as all procedures undertaken concomitant with the ACL reconstruction. RESULTS: 50 of the 88 patients (56.8%) had associated intra-articular lesions at the time of anterior cruciate ligament reconstruction. The most common injury found was a meniscus tear, 48 patients (54.5%) had a meniscal pathology at the time of ligament reconstruction, medial meniscus being the most frequent injured one, found in 37 patients. Meniscectomy and meniscus suture were the procedures performed for these lesions, meniscectomy being more frequent. Chondral defects were the next associated injuries found with an incidence of 15.9% of the cases. The medial side of the knee was the most common site of chondral pathology. CONCLUSIONS: ACL tears are frequently associated with other intra-articular lesions, especially medial meniscus tears and chondral defects affecting the medial compartment. Such pathology most often needs surgical attention during the anterior cruciate ligament reconstruction. PMID- 26528009 TI - Treatment adherence and social functioning in patients diagnosed with schizophrenia and treated with antipsychotic depot medication. AB - BACKGROUND AND AIM: Some of the most significant problems encountered in the treatment of schizophrenia are non-adherence to the treatment with oral neuroleptics and difficult recovery of social functioning, after its impairment by negative psychotic symptoms and the progression of the disease with episodes of remission and relapse. METHODS: This study comparatively assesses the parameters "social functioning" and "treatment adherence" in 34 outpatients diagnosed with schizophrenia at the Adult Psychiatry Clinic III and the Adult Mental Health Center of Cluj-Napoca, using the "Medication Adherence Rating Scale" (MARS) and the "Social Adaptation Self-evaluation Scale". RESULTS: The two scales revealed that patients on depot medication tend to have better social functioning and social integration rates than patients for whom oral medication was prescribed. Despite the fact that most patients participating in the study had intellectual preoccupations and, to some extent, enjoyed working, 82% of them did not have a job. The percentage of those who did was higher in the cohort of patients on depot medication (63%) than in the cohort of patients for whom orally administered medication was prescribed (53%). CONCLUSIONS: Treatment adherence in patients with schizophrenia is thus significantly improved by depot medication, whereas treatment effectiveness and the frequency of adverse effects are similar for the two treatment options. PMID- 26528010 TI - Counseling provided by the pharmacist in Romanian community pharmacies: the patients' perspective. AB - BACKGROUND AND AIMS: Patient education is a critical task that may be carried out by the pharmacists, especially in the context of contemporary pharmacists' roles, which tend to be closer to patients and their needs. This study aimed to evaluate the counseling provided by the pharmacist in the community pharmacy, from the patient's perspective. PATIENTS AND METHODS: We conducted a prospective, non interventional study in 520 pharmacies from 10 Romanian counties across the country. The first 10 visitors of the pharmacy on a given day were asked to complete a questionnaire regarding the counseling provided by the pharmacist during the visit. RESULTS: More than 90% of patients received advice from the pharmacist on the route of administration, use in relation to meals, dosage and length of treatment. More than 80% of the patients were counseled on the medicine contraindications and precautions, interactions with other medicines and food, side effects, additional changes in lifestyle and diet appropriate to the condition and the necessity to immediately consult a doctor/pharmacist in case of adverse drug reactions. Lower percentages were registered for advising the patient on the obligation to return to pharmacy the unused psychotropic drugs (38.04%) and the ability of the drug to modify the laboratory results (47.66). CONCLUSIONS: The results of the present study showed that the counseling activity in the community pharmacy is carried out by the pharmacists in a high proportion, according to the patients' feedback. PMID- 26528011 TI - Description of a systematic pharmaceutical care approach intended to increase the appropriateness of medication use by elderly patients. AB - BACKGROUND & AIMS: The pharmaceutical care practice represents a model of responsible pharmacist involvement in the pharmacotherapy optimization of various population groups, including the elderly, known to be at risk for drug-related problems. Romanian pharmacists could use validated pharmaceutical care experiences to confirm their role as health-care professionals. This descriptive research presents the application in two real and different environments of practice of a structured pharmaceutical care approach conceived as the basis for a medication review activity and aiming at the identification and resolution of the drug related problems in the elderly. PATIENTS AND METHODS: Two patients with similar degree of disease-burden complexity, receiving care in different health care environments (The Geriatric Ward of the Royal Victoria Hospital from the McGill University Health Centre in Montreal, Quebec, Canada, in November 2010, and an urban nursing-home facility in Cluj-Napoca, Romania, in March 2011), were chosen for the analysis. One clinical pharmacist suggested solutions for the management of each of the active drug-related problems identified, using the systematic pharmaceutical care approach and specific published geriatric pharmacotherapy recommendations. The number of the drug-related problems identified and the degree of the care-team acceptance of the pharmacists' solutions were noted for each patient. RESULTS: The pharmacist found 6 active drug-related problems for the hospitalized patient (72 year-old, Chronic Disease Score 9) and 7 potential ones for the nursing-home resident (79 year-old, Chronic Disease Score 8), involving misuse, underuse and overuse of medications. Each patient had 3 geriatric syndromes at baseline. The therapy changes suggested by the pharmacist were implemented for the hospitalized patient, through collaboration with the health-care team. For the nursing home resident, the pharmacist identified the need for additional 6 medications and safety and efficacy arguments to cease 7 initial therapies, simplifying the therapeutic daily schedule (from 24 daily doses to 15). CONCLUSION: The pharmacist's potential contribution to the optimization of the Romanian elderly patients' pharmacotherapy needs further exploration, as potential drug related problems reported as characteristic for this population were easily identified. The presented structured and validated model of pharmaceutical care approach could be used to this end. Its dissemination and use could be encouraged along with the enhancement of pharmacotherapy information and care team collaboration skills. PMID- 26528013 TI - The Role of Oxidative Stress and Vascular Insufficiency in Primary Open Angle Glaucoma. AB - Primary Open Angle Glaucoma (POAG) is a chronic, irreversible optic neuropathy leading to the progressive death of retinal ganglion cells, clinically observed as silent visual field loss along with a decrease in colour and contrast sensitivity. Multiple pathogenic theories have been issued and some of them have proven their involvement in disease development: mechanical damage due to increased intraocular pressure, variable susceptibility of the optic nerve, mutation in specific nuclear genes, increased glutamate levels, alteration in nitric oxide (NO) metabolism, changes in the mitochondrial genome, vascular disturbances, and toxic effects and oxidative damage caused by reactive oxygen species [1]. The aim of this article is to highlight the pathogenic role of vascular disturbances and reactive oxygen species in POAG with the further possibilities for prevention and gene therapy. PMID- 26528012 TI - Chemotherapy-Induced Cardiotoxicity: Pathophysiology and Prevention. AB - Along with the remarkable progress registered in oncological treatment that led to increased survival of cancer patients, treatment-related comorbidities have also become an issue for these long-term survivors. Of particular interest is the development of cardiotoxic events, which, even when asymptomatic, not only have a negative impact on the patient's cardiac prognosis, but also considerably restrict therapeutic opportunities. The pathophysiology of cytostatic-induced cardiotoxicity implies a series of complex and intricate mechanisms, whose understanding enables the development of preventive and therapeutic strategies. Securing cardiac function is an ongoing challenge for the pharmaceutical industry and the physicians who have to deal currently with these adverse reactions. This review focuses on the main mechanism of cardiac toxicity induced by anticancer drugs and especially on the current strategies applied for preventing and minimizing the cardiac side effects. PMID- 26528014 TI - Elastic Stable Intramedullary Nailing for Fractures in Children - Specific Applications. AB - Elastic stable intramedullary nailing (ESIN) is a new minimally invasive technique for the treatment of pediatric fractures. It approximates the physiological healing process of bone, without opening the fracture site. Also, the operative stress is minimal because of the minimally invasive nature of the procedure, and the volume of implants is small, offering a very good stability without plaster cast immobilization. PMID- 26528015 TI - The Relationship between Serum Lipid Fractions and Heart Rate Variability in Diabetic Patients with Statin Therapy. AB - BACKGROUND AND AIMS: The aim of this study is to identify and highlight the relationship between serum lipid fractions and heart rate variability in diabetic patients receiving statin therapy. PATIENTS AND METHODS: The study was performed in a group of 87 type 2 diabetic patients on statin associated therapy. All patients were on Holter ECG 24 hours monitored with three channel monitor (Labtech ECG Holter monitor), and data were analyzed on a commercially available software (Cardiospy PC SW/EV 5.02.06.02). Concentrations of biochemical parameters were determined using specific enzymatic assays on an autoanalyzer Olympus AU 680. In the studied patients, we analyzed Holter/24 hours monitoring reports with respect to heart rate variability indexes, arrhythmic events and myocardial ischemia. RESULTS: It was noticed that the mean values of serum TG were slightly elevated, TC levels were close to the limits specified by the guidelines for diabetic patients and for patients with cardiovascular diseases, with no significant differences between males and females. After analyzing the HRV in both time and frequency domains, we found no strong correlations between any of the HRV indexes and any of the lipid fractions. CONCLUSIONS: The results suggest that statin therapy may reduce the autonomic impairment secondary to dyslipidemia. PMID- 26528016 TI - HCV Infection Frequency and Trends Among Voluntary Blood Donors in Cluj County (Romania) Between 2006 and 2011. AB - BACKGROUND AND AIMS: In Europe a wide variation in HCV prevalence between countries was described, ranging from 0.1 to 6.0%, higher in Eastern Europe than in Western Europe, which may threaten the biological safety of donated blood. The HCV frequency among blood donors in Romania has has made the object of only very few published studies. The aim of this study was to analyze the frequency of anti HCV antibodies in blood donors from Cluj County (Romania) and its trend, in the period 2006-2011. PATIENTS AND METHODS: Between 2006-2011 all donors, new and repeat donors were screened for hepatitis C virus infections using enzyme-linked immunosorbent assay (ELISA). Reactive results were confirmed using radioimmunoblotting assay (RIBA). The frequency and trends were analyzed using the T-test and X(2)-test. RESULTS: There were 95,181 donors tested in the blood transfusion centre (BTC) laboratories between 2006-2011. The overall prevalence was 0.254 % (95% CI 0.222-0.286). The prevalence rates of anti-HCV antibodies increased with age between both genders, being higher among women, starting to decrease after the age of 51. CONCLUSIONS: The results of this study demonstrate a high HCV prevalence in donations from 2006 to 2011, as compared to other countries in Europe, especially among first time blood donors, an infection that might be a potential threat to blood safety. PMID- 26528017 TI - Small Intestinal Bacterial Overgrowth is Associated with Intestinal Inflammation in the Irritable Bowel Syndrome. AB - BACKGROUND AND AIM: Small intestinal bacterial overgrowth is encountered in bowel disorders, including irritable bowel symptoms. Low degrees of inflammation have been recently reported in the irritable bowel syndrome. We looked for the association between intestinal inflammation and small intestinal bacterial overgrowth in irritable bowel syndrome. METHODS: Small intestinal bacterial overgrowth was assessed by the H2 glucose breath test in 90 consecutive patients with irritable bowel syndrome. A check-up of the oral cavity was carried out before the breath testing. Further on, the patients were classified into two groups, positive and negative, at the breath test. Then they were tested for intestinal inflammation with a fecal test for calprotectin. We used a semiquantitative test for this study. Both groups were compared for the association of intestinal inflammation with small intestinal bacterial overgrowth. RESULTS: A number of 24/90 (26.7%) patients with irritable bowel syndrome had small intestinal bacterial overgrowth. A positive test for intestinal inflammation was significantly more frequent in patients with irritable bowel syndrome and small intestinal bacterial overgrowth (chi(2): p<0.05). CONCLUSIONS: Small intestinal bacterial overgrowth is present in almost one quarter of patients with irritable bowel syndrome. It is significantly associated with intestinal inflammation. PMID- 26528018 TI - Correlations Among Parental and Neonatal Anthropometric Parameters, Feeding Practices and Infant Obesity. AB - BACKGROUND AND AIMS: Infant and adult obesity is becoming a real public health concern in Romania, similar to other countries of the European Union. Maternal obesity and excessive weight gain during pregnancy are proven risk factors for the obesity of the child. The protective role of the breastfeeding against obesity has also been demonstrated. The most important issue is whether the choice of a milk formula with the right protein composition could or not protect the newborn from becoming a future obese infant and child. Our study aims to describe the characteristics of a group of macrosomic newborns, in relation to the mothers' weight gain during pregnancy, mode of delivery, birth weight, complications at birth, time of first feeding and type of feeding during maternity stay. PATIENTS AND METHODS: We conducted a retrospective study on 179 newborns with birth weights >4000 grams, born over a period of three months (March-May) in 6 large maternity hospitals in Romania. RESULTS: the newborns had a mean gestational age of 39.5 weeks and a mean birth weight of 4195 grams. Male newborns were prevalent (74%). More than half were born by Cesarian section and had Apgar scores with a median of 9. Macrosomes are prone to complications at birth and in our study those were mainly hypoglycemia and birth trauma. Time at first feeding was 95 minutes (mean), with a high percentage of formula/mixed feeding (68%). CONCLUSION: Macrosomia itself attracts the risk of birth by cesarean section (54% of study group), birth trauma and a low rate of exclusive breast milk feeding (32% of study group) at discharge. PMID- 26528019 TI - The Value of Induced Sputum in the Diagnosis and Management of Children with Bronchial Asthma. AB - BACKGROUND: Induced sputum in children with bronchial asthma represents a non invasive method of bronchial inflammation assessment. The main objective of our study was to analyze the cellularity of sputum in patients with bronchial asthma according to the level of disease control and the controlling therapy (with/without inhaled glucocorticoids). The second objective was to establish the correlation between sputum cellularity and other indirect parameters used to evidence bronchial inflammation (exhaled nitric oxide) and obstruction (forced expiratory volume in 1 second). METHODS: The study included children with bronchial asthma that were assessed clinically (physical exam, questionnaire on the control of bronchial asthma in children) and by medical tests (induced sputum, exhaled nitric oxide, spirometry). RESULTS: In patients with partially controlled asthma and those with uncontrolled asthma, the eosinophils percentage in the sputum was higher than in patients with controlled asthma (19.8+/-26.4% respectively 9.2+/-20.5% versus 4.5+/-14.6%, p<0.001). Higher percentage of neutrophils in the sputum was found in the partially controlled and uncontrolled asthma than in the controlled asthma (43.9+/-20.1% respectively 51.6+/-38.3% versus 35+/-19.7%, p=0.009). We also evidenced a direct and statistically significant correlation between the exhaled nitric oxide and the neutrophils percentage in the sputum (r=0.67, p=0.0003). Also, an indirect, moderate to good correlation (r=-0.56, p=0.005) was evidenced between the values of the forced expiratory volume in 1 second and the high eosinophils percentage in the sputum. CONCLUSIONS: In partially controlled and uncontrolled bronchial asthma the eosinophils and neutrophils count in the sputum is significantly higher than in patients with controlled asthma. There is an indirect correlation between the high eosinophils count in the sputum and the forced expiratory volume in 1 second, as well as a direct correlation between the neutrophils count and the exhaled nitric oxide, suggesting that induced sputum should be used in combination with other indirect parameters for the evidence of bronchial inflammation. PMID- 26528020 TI - Effect of Cimetidine on Nitro-Oxidative Stress in a Rat Model of Periodontitis. AB - BACKGROUND AND AIMS: Periodontitis is a chronic inflammation that involves nitro oxidative stress with damaging periodontal structural effects. We aimed to evaluate the consequences of low-dose cimetidine on nitro-oxidative stress in periodontitis. METHODS: A rat model of ligature-induced periodontitis was used. After two weeks, the periodontitis groups were treated with cimetidine, aminoguanidine, N-nitro-L-arginine methyl ester and trolox for one week. On day 21, blood was drawn and the serum analyzed for measurement of total nitrites and nitrates, total oxidative status, total antioxidant response, and oxidative stress index. RESULTS: Cimetidine had an inhibitory effect on the synthesis of nitric oxide (p=0.001), total oxidative status (p=0.01) and oxidative stress index (p=0.01). Total antioxidant reactivity was increased by cimetidine (p=0.01). The effects of cimetidine were almost like those of aminoguanidine, NG nitro-L-arginine methyl ester, and trolox. CONCLUSIONS: Low-dose cimetidine can be used as adjunctive host modulatory therapy in chronic periodontitis because it reduces nitro-oxidative stress. PMID- 26528021 TI - The Use of Dental Sealing in Cluj, Romania: Frequency, Materials and Techniques - A Questionnaire Study. AB - AIMS: Dental decay is a condition that affects both temporary and permanent dentitions. Prophylactic methods for dental decays consist of: dental sealing, use of fluorides, oral hygiene and healthy diet habits. This article focuses on the frequency, dental materials and techniques of dental sealing used for caries prophylaxis in the Cluj County. MATERIALS AND METHODS: The study used a set of questionnaires that was applied to 175 doctors/dentists from Cluj. The questionnaire contained 11 questions and was delivered to the doctors personally or by the internet. RESULTS: From the interviewed dentists 85.7% use dental sealing and 86.7% use materials based on composite resins in this respect. For diagnostic purposes,76% of the dentists use inspection and palpation, 68.66% use cotton rolls and aspiration for isolation, 74% use professional brushing, 74% call back the patient after 6 months for a check-up and 60% of the doctors redo the sealing if the sealant is partially or entirely lost or they perform a filling if a secondary decay appeared. CONCLUSIONS: Most of the interviewed dentists perform dental sealing and consider it as a good caries prophylaxis method. Also, most of them use a material based on composite resins as pit and fissure sealant. The techniques for this procedure are different among the interviewed dentists. PMID- 26528022 TI - Short-Term Results in Evaluating a Gingiva-Adhesive Hydrophobic-Chlorhexidine-Gel for Chronic Periodontitis. AB - BACKGROUND AND AIMS: Oral mucosa and interproximal spaces of the teeth could favor the colonization of periodontopathogenic bacteria, which could be targeted by chemical antiplaque agents such as chlorhexidine, present in different oral hygiene products, thus improving the control of biofilm growth and delaying microbial accumulation. The study aimed to evaluate whether the use of a hydrophobic gel with good gingival adhesion for 14 days after the scaling and root planing of patients with chronic periodontitis would improve the treatment outcome, when compared with the use of a regular hydrophyllic gel. MATERIAL AND METHODS: Patients with moderate disease were included in two study groups. At baseline and 3 months after the treatment the following parameters were recorded: pocket depth, Approximal Plaque Index, Modified Gingival Index, Simplified Oral Hygiene Index, bleeding on probing. Patients received scaling and root planing in two sessions at 24 hours interval. After the treatment, patients in the test group applied the hydrophobic adhesive chlorhexidine gel once a day, every other day, while in the control group the gel was used twice daily. RESULTS: Both treatments resulted in significant improvement in all clinical indices, except Approximal Plaque Index, which deteriorated significantly in both groups. Three months after mechanical treatment, the mean probing depth changed in the test group from 4.16+/-0.45 mm to 2.80+/-0.42 mm, and in the control group from 4.16+/ 0.30 to 2.69+/-0.19. CONCLUSIONS: Both adjunctive anti-infective therapies induced clinical improvement 3 months from baseline. The differences between the two treatments were not statistically significant. PMID- 26528023 TI - Castleman Disease. A Report of Six Cases. AB - BACKGROUND AND AIMS: Castleman's disease is a rare disorder situated at the boundary between reactive and neoplastic conditions. The pathogenesis is a subject of debate and the limited number of cases renders the study of the disease difficult. In our paper we present a series of six cases of Castleman disease with emphasis on the clinical presentation, pathology examination and the use of immunohistochemistry in the final diagnosis of the cases. PATIENTS AND METHOD: The classification of the disease was based on clinical, imaging and pathological assessment. Specimens were obtained by surgical excision and were routinely processed for the pathology examination. RESULTS: All cases were unicentric disease. Two cases were locally extensive. The clinical symptoms were related mostly to compression effects. Five case were of the hyaline-vascular type and one was included in the plasma cell variant. One case showed angiomyoid differentiation. CONCLUSIONS: We strongly believe that by understanding the pathogenesis of the precursor lesions we will gain better understanding of the pathways that lead to neoplasia and that Castleman disesase is a very interesting "natural experiment" illustrating the progression from chronic antigen stimulation to reactive lymphoid hyperplasia and finally to overt lymphoid neoplasia. PMID- 26528024 TI - Localized Juvenile Spongiotic Gingival Inflammation: A Report on 3 Cases. AB - BACKGROUND AND AIMS: A new pathological entity with distinct clinicopathological features has been recently described and termed as juvenile spongiotic gingivitis. Histopathological associated features are unique and characterized by prominent intercellular edema (spongiosis) and neutrophil infiltrate. The aims of this paper were to: introduce juvenile spongiotic gingivitis to the dental and pediatric communities, to report three cases based on clinical and histopathological findings, and to discuss the most common clinical differential diagnoses. The cases were documented at baseline and follow-ups. The clinical appearance of the lesions described in this paper correspond to the pattern described by the literature: 1) localized lesions as bright red slightly raised overgrowths, most often with a subtle papillary or finely granular surface; or 2) multifocal masses or raised papular lesions with a pebbly texture. The first intention treatment approach was personal and professional plaque control. Because of the lack of a good clinical response to conventional therapy, excisional biopsies were performed, which helped establish the diagnosis. The plaque control was reinforced and additional antiseptic local treatment was administered. A real improvement in the local gingival conditions was recorded for all the patients. However, because of the persistence of some bright reddish gingival masses in one of the patients these lesions were treated by surgical excision. The overall clinical outcome was good and stable after one year. CONCLUSIONS: The presented cases might raise awareness of this condition among orthodontic specialists because orthodontic treatment could not be applied until the gingival gum disease was resolved. PMID- 26528025 TI - Prosthetic Rehabilitation in Partially Edentulous Elders - A Case Report. AB - Complex treatment involving removable articulated to fixed prostheses is indicated in extended edentulous areas, which represent clinical conditions more frequently encountered in elderly patients. A number of aspects must be considered in elderly patients before starting the therapy: physical and mental condition, self-care capacity, time and cost of treatment, predictability. In institutionalized elders, suffering of systemic diseases, the therapy of choice should be the least invasive and able to restore function at an acceptable level. Active healthy elders can be beneficiaries of complex prosthetic treatments involving many long sessions and difficult treatments. We present a case of a 74 year-old male with extended maxillary edentulous areas, in whom a complex prosthetic treatment was performed. PMID- 26528026 TI - Aspect on Health Sociology and Social Medicine Reflected in the Studies of Constantin Stanca (1889-1969). AB - Constantin Stanca (1889-1969) was the first director of the Institute for the Study and Prevention of Cancer from Cluj between 1929 and 1940 and the founder of the Gynecologic Oncology Surgery Department of this Institute. During his important career in gynecology and surgical oncology, which took place in Cluj and in Bucharest, he was also interested in medical sociology and in social medicine. Our paper presents some of Stanca's objectives in these domains: to increase the health status of women, to prevent gynecological diseases and to improve women's working conditions, especially in factories. PMID- 26528027 TI - Bovine Serum Albumin Interactions with Metal Complexes. AB - The continuous search for new molecules with therapeutic abilities has led to the synthesis and characterization of a large number of metal complexes, proven to exhibit potential as pharmacological agents through their antibacterial, antiviral, antifungal and antineoplastic properties. As serum albumins play a key role in drug pharmacokinetics and pharmacodynamics, the study of coordination compounds affinity towards this class of proteins, as well as understanding the mechanism through which they interact is crucial. The aim of this review is to focus on the structure and biological functions of bovine serum albumin, the design of metal complexes that are able to bind to the biomolecule, as well as the experimental techniques employed in the study and evaluation of these interactions. PMID- 26528028 TI - Heart Rate Recovery in Patients with Ischemic Heart Disease - Risk Factors. AB - BACKGROUND AND AIM: Central nervous system dysfunction is associated with mortality and morbidity in patients with cardiovascular disease, post-workout recovery and faster heart rate being mediated by the dynamic interaction between the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS), as components of the autonomic nervous system. Heart rate recovery is the decline in heart rate after exercise. The aim of the study was to determine the influence of certain clinical and paraclinical parameters on heart rate recovery after exercise in patients with ischemic heart disease. METHODS: The study included 260 patients who were subjected to cardiovascular stress test. The following parameters were measured in each patient: blood pressure and pulse rate prior to exercise, during exercise and at protocol-established time intervals, as well as 1 and 3 minutes after the end of the stress test. Statistical analysis was performed using MedCalc software version 14.8.1. RESULTS: Elderly patients had slower heart rate recovery at 1 minute after effort. Female patients have recovered significantly better the heart rate, at 1 minute and 3 minutes after effort compared to the males. This difference was maintained in multivariate analysis, independent of age or comorbidities of patients. The presence of ischemic heart disease was the most important factor independently associated with HRR1. Triglyceride values were negatively correlated with both HRR3 and HRR1 and independent of other factors present in the multivariate analysis. CONCLUSIONS: Autonomic dysfunction is involved in the development of cardiovascular risk factors like hypertension, diabetes, dyslipidemia and was directly correlated with morbidity and mortality caused by coronary heart disease. PMID- 26528029 TI - Antiandrogenic Therapy with Ciproterone Acetate in Female Patients Who Suffer from Both Androgenetic Alopecia and Acne Vulgaris. AB - BACKGROUND: Androgenetic Alopecia in Women (AGA) occurs due to an underlying susceptibility of hair follicles to androgenic miniaturization, caused by androgens. Clinically, AGA is characterized by progressive hair loss, with a marked hair thinning in the fronto-parietal area so that the scalp can be easily seen. Acne vulgaris is androgen-dependent and often affects the skin that has an increased number of oil glands: face, back and chest. Although the sebaceous glands are present on the scalp too, it is very rare to get acne at this site, as the hair acts as a wig and allows the sebum to drain and does not block the pores. Both AGA and Acne Vulgaris are signs of hyperandrogenism. Cyproterone acetate/ethinyl estradiol (2mg/0.035mg) products are authorized for the treatment of androgenetic symptoms in women, such as acne, seborrhea, mild forms of hirsutism and androgenetic alopecia. Our study had a double purpose: - To evaluate the result of the study regimen Melleva 35 (one pill per day, for 3 consecutive months) in patients with moderate to severe acne, suffering also from Androgenetic Alopecia;- To establish the efficacy of the drug on acne and alopecia improvement, both from the doctor's and patient's point of view. PATIENTS AND METHODS: After being informed of the aims and procedures of the study, participants provided a written informed consent. A number of 35 female subjects with moderate to severe acne vulgaris remained in the study. The subjects had also been diagnosed as suffering from AGA, on the basis of clinical criteria, including the pattern of hair loss and trichoscopy assessment. RESULTS: 83% of study subjects reported that their hair did not continue to fall after 3 months of antiandrogen therapy. The females were evaluated using trichoscopy and the doctor noticed hair regrowth in 77% of the cases. Regarding the improvement of acne lesions after the treatment, 40% of study subjects recorded good improvement and 26% recorded excellent results with Melleva 35. The acceptance of the treatment was very high, 86% patients were compliant with the study therapy. The rate of adverse events (5 cases) was within the limits of the treatment tested by the study. Almost a third of the total number of subjects (28.5%) reached a good satisfaction level after the treatment, while 37.1% claimed moderate satisfaction. CONCLUSION: There was no correlation between the age of the subjects and the treatment for acne therefore our first hypothesis was rejected. As a conclusion, antiandrogenic therapy with Melleva 35, 1 pill per day, for 3 consecutive months, shows good results for patients who suffer from both Androgenetic Alopecia and Acne Vulgaris. PMID- 26528030 TI - Carbapenem Resistance in Non-Fermentative Bacterial Species and in Enterobacteriaceae Isolates from Hospitalized Patients in Different Health-Care Settings. AB - AIM: Carbapenem-resistant strains have been increasingly reported over the last few years. In this study we used laboratory records to determine the occurrence of carbapenem-resistant strains from hospitalized patients with emphasis on the comparative analysis of the incidence in various health-care settings. MATERIALS AND METHODS: From January 2012 to November 2012 and from May 2013 to November 2013, we evaluated 566 strains (Acinetobacter spp., Pseudomonas aeruginosa, Escherichia coli, and Klebsiella spp.). All isolates were tested and analyzed according to their antibiotic resistance phenotypic pattern. Laboratory results were correlated with data regarding admission in different clinical wards. RESULTS: Among 566 isolates, 191 carbapenem-resistant or carbapenem-intermediate strains (33.74%) were detected. Non-fermentative species were the most prevalent carbapenem-resistant organisms, 80.62% of 191 carbapenem-resistant or carbapenem intermediate strains isolated were Acinetobacter spp., and 17.27% of 191 were Pseudomonas aeruginosa. Apart from that, only 4 (2.09%) carbapenem-resistant Enterobacteriaceae (CRE) strains were identified. We identified 59.30% of 172 strains isolated from patients hospitalized in anesthesia and intensive care units non-susceptible to carbapenems. The main mechanism associated with carbapenem resistance could be the production of carbapenemase in combination with impermeability. CONCLUSIONS: Our study demonstrates that infections with carbapenem-resistant strains are correlated with hospitalization in intensive care units. Our data showed a predominant carbapenem-resistant Acinetobacter spp. strain in intensive care units. PMID- 26528031 TI - Circadian Variation of Stroke Onset: A Hospital-Based Study. AB - AIMS AND BACKGROUND: The circadian pattern of stroke occurrence variation has been recognized with certain differences between authors and stroke types. The underlying reason may be related to exogenous factors (cyclic physical activity, including sleep-awake cycles and assuming the up-right posture) and endogenous factors, with their diurnal variation (blood pressure, hemostatic balance, autonomic system activity). The aims of the present study are to investigate the existence of a circadian variation of stroke and the possible differences between stroke subtypes in the Cluj Napoca area. MATERIALS AND METHOD: The stroke event data were acquired from the Patient Records of a consecutive series of 1083 patients admitted through the Emergency Room at Neurology Departments I and II of the District Hospital of Cluj Napoca, between 1 January 2012 and 31 December 2012. The classifiable onset time was assigned to one of four six-hour intervals: 00.01-06.00 (night), 06.01-12.00 (morning), 12.01-18.00 (afternoon) and 18.01 24.00 (evening). Demographic data and vascular risk factors were recorded. RESULTS: All three stroke types (ischemic stroke, hemorrhagic stroke and subarachnoid hemorrhage) have shown a circadian variation regarding their occurrence, with the peak of incidence in the morning and the nadir during nighttime. This circadian pattern is independent by demographic factors and vascular risk factors. CONCLUSION: Our study confirmed the circadian variation of onset occurrence for all stroke subtypes. Some triggering factors promote ischemic stroke and prevent hemorrhagic stroke. The diurnal pattern of variation with the higher incidence in the morning and the lower in the night may lead to chrono-therapeutic and preventive approach (chrono-therapy of the risk factors), which targets the period of the highest vulnerability after awaking. PMID- 26528032 TI - Breast Diagnosis: Concordance Analysis Between the BI-RADS Classification and Tsukuba Sonoelastography Score. AB - AIMS: To establish the correlations between the ultrasound (US) BI-RADS classification and Tsukuba elastography score when assessing breast lesions. To determine which type of breast lesion (BI-RADS category) would benefit most from an elastographic assessment. PATIENTS AND METHODS: The investigated sample of imaging comprised a number of 129 images belonging to 92 subjects examined with a Hitachi 8500 US device. Each lesion was assessed according to the BI-RADS and Tsukuba elastography score. Histopathology was obtained by means of percutaneous biopsy or post-surgery. Fibroadenoma-like lesions unchanged over a period of 3 years were considered benign. RESULTS: The 1, 2 and BGR Tsukuba scores mostly correlated with BI-RADS II and III lesions such as cysts, hamartomas, lipomas, hematomas, non-palpable fibroadenomas. Palpable fibroadenomas initially included in BI-RADS IVa/b category, usually received benign elasticity scores (1 or 2), the exception being represented by a minority of cases of old, fibrotic or calcified lesions (elastic score 3 or 4). Non-specific BI-RADS IVa/b lesions, such as mastopathic nodules demonstrated rather soft, elastic properties on elastogram (score 1 or 2). The 4 and 5 Ueno-Itoh scores were predominantly correlated with BI-RADS IVc and V categories represented by high risk lesions (radial scar, papillomas, atypical epithelial ductal hyperplasia) and in situ or invasive carcinomas. CONCLUSIONS: Generally the BI-RADS classification correlates well with the Tsukuba elasticity score, the main exception being represented by fibrotic, calcified lesions which falsely appear more suspicious post elastography. BI-RADS III and IV lesions would benefit most from an elastographic assessment, a low Tsukuba score allowing a less invasive approach, while a high score imposes histopathological evaluation. PMID- 26528033 TI - Evaluation of Rapigest Efficacy for the Digestion of Proteins from Cell Cultures and Heart Tissue. AB - INTRODUCTION: Rapigest is an acid-labile detergent used in proteomics for the improvement of protein digestion. MATERIALS AND METHOD: To test the efficacy of Rapigest for proteomics analysis of different sample types we used protein extracts from S9 cell line and mouse heart tissue and performed protein isolation, digestion and mass spectrometry analysis. RESULTS: For the S9 cell line, there was no significant difference concerning the number of identifications (peptides, proteins) between Rapigest and No Rapigest samples, though slightly more peptides and proteins were identified in the Rapigest samples. For the mouse heart tissue samples, Rapigest use resulted in the identification of a higher number of proteins. Rapigest did not modify the protein profile with respect to the biological compartments covered by the identified proteins in S9 cell line samples, but produced a small increase in the representation of cytoplasm proteins and a small decrease in the representation of membrane proteins in the mouse heart tissue samples. DISCUSSIONS: Results are comparable to other studies that evaluated the efficacy of Rapigest for the analysis of tissue samples, recommending Rapigest for the improvement of protein digestion and implicitly identification, without the modification of the protein profile in the samples. CONCLUSION: Rapigest may be successfully used for the improvement of protein identification from heart tissue samples using mass spectrometry. PMID- 26528034 TI - The Influence of Root-End Filling Materials on Bone Healing - An Experimental Study. AB - AIMS: The aim of this experimental study is to assess the bone healing phenomenon produced in the presence of several dental materials: a polycarboxylate cement, a glass-ionomer cement, a composite resin and MTA (mineral trioxide aggregate) based cement. METHODS: The biocompatibility of four root-end fillings materials, used in periapical surgery was investigated after intra-osseous implantation of the materials in rats' calvaria. Tissue reaction was studied at 2, 4, 6, 8, 10 and 12 weeks after implantation. We took into consideration the presence of inflammatory cells (polymorphonuclear leukocytes, macrophages, plasma cells, lymphocytes and giant cells) and classified the aspects of the histological samples according to the following scale: 0 - no inflammation, 1 - mild, isolated inflammation, 2 - moderate, localized inflammatory reaction, 3 - severe, diffuse and intense inflammatory reaction. RESULTS: The inflammatory reaction was present at the six intervals for all the tested materials, but at 12 week interval, the reaction was minimal in all cases. Also, a dissolution reaction was observed for all the materials, less intense for glass-ionomer cement and polycarboxilate cement. CONCLUSIONS: At the end of the experimental period, glass-ionomer cement and polycarboxilate cement suffered a lesser dissolution reaction as compared to the second group of tested materials. PMID- 26528035 TI - The Study of Oral Liquid Microcrystallization in Children with Gastro-Esophageal Reflux Disease. AB - BACKGROUND AND AIM: Patients with disabilities have a higher prevalence of caries and dental erosions than general population. This particularity may be assessed by the study of microcrystallization of saliva. We investigated the oral liquid microcrystallization in children with gastroesophageal reflux disease (GERD), a condition associated with dental erosions. MATERIAL AND METHODS: 54 children have been clinically examined: 27 children suffering from GERD with ages between 13 and 15, were included in the study group, and 27 healthy children - the control group. The study of crystallographic changes of the oral liquid was performed using the method developed by Shatohina, Razumov SN, Shabalin VN (2006) with the scanning electron microscope VEGA TESCAN TS 5130 MM. RESULTS: The degree of microcrystalization of the oral liquid in children with GERD was considerably reduced, (1.73+/-0.11 points) and was lower than in children in the control group (3.22+/-0.16 points) (p<0.01, RR=2). The degree of microcrystallization of oral liquid in children with GERD was 1.86 times lower than in healthy children. This was correlated with the duration of gastroesophageal reflux. CONCLUSION: The study of structural particularities of dehydrated droplet of oral liquid in children with GERD has elucidated a number of markers of the changes produced in the oral cavity. These can be used in the screening research in prevention of caries and dental erosions. PMID- 26528036 TI - Surgical Treatment of Dermatofibrosarcoma Protuberans Using a Reversed Adipofascial Sural Flap - Case Report. AB - Dermatofibrosarcoma protuberans is a rare superficial tumor characterized by high rates of local recurrence and low risk of metastasis. Dermatofibrosarcoma protuberans occurs most commonly on the trunk and proximal extremities, it affects all races, and often develops between the second and the fifth decade of life. The tumor grows slowly, typically over years. We present a rare case of a young male patient, 21 years old, with an asymptomatic calf tumor which was suspected to be an angioma, but after the initial excision histology and imunohistochemistry proved to be a Dermatofibrosarcoma protuberans without safety limits. After 2 weeks, we excised the remaining scar with 4 cm tissue limit and the defect was covered using an adipofascial reversed sural flap from the posterior part of the left calf and after another 2 weeks we applied a skin graft from the thigh. The patient had a good evolution, with full recovery, without local recurrences or metastasis, and the histology was within good safety limits. PMID- 26528037 TI - Dental Erosion in a Partially Edentulous Patient with Gastroesophageal Reflux Disease: A Case Report. AB - Diseases such as gastroesophageal reflux disease (GERD), bulimia, anorexia, and extrinsic alimentary factors may cause dental erosion (DE). The minimally invasive therapeutic attitude preserves the remaining healthy tooth structure. In the earlier stages, the direct restoration of dental lesions is possible, using composite materials. In advanced stages of DE, prosthetic treatments are recommended for stable esthetic and functional results. We present a case of DE in a partially edentulous patient who benefited from a complex therapy. The prosthetic project of the case involves ceramic veneers associated with dental and implant supported fixed prosthesis for the restoration of esthetics, mastication, phonetics and their maintenance. PMID- 26528038 TI - Alcoholism in Romania in the Late Nineteenth Century and at the Beginning of the Twentieth Century. AB - Although alcohol consumption has been described from the earliest times, alcohol abuse has grown significantly since the mid-nineteenth century as a consequence of the industrialization progress. Due to the socio-economic profile of Romania, which was considered to be agrarian, the idea of developing mainly the industry branches belonging to agriculture was considered. Amongst these branches, the production of alcohol appeared to be the most appropriate. The political state leaders from Romania enjoyed the taxes collected from alcohol commercialization, disregarding the costs involved in alcoholism which went far beyond them. PMID- 26528039 TI - The Biography of Doctor Charles Laugier (1875-1830). AB - This paper presents the life and works of the famous doctor, hygienist, folklore researcher and sanitary mentor, Charles Laugier, whose contribution to the development of the medical system of Oltenia marked the beginning of the 20th century. He is noted for his research in hygiene, in the treatment of some diseases like: tuberculosis, malaria, pellagra, and also as the founder of numerous societies which contributed to the cultural and scientific development of the region of Oltenia and even of its small localities. PMID- 26528040 TI - The Apelin-APJ System in the Evolution of Heart Failure. AB - Heart failure is a chronic, progressive disease in which the overexpression of biologically active molecules and neurohomonal activation are the key factors of the evolution and natural history. The apelin-APJ system is a newly discovered molecular pathway and the RAAS counterbalance is its principal effect. The apelin is a potent inotrope, vasodilator and diuretic with crucial cardioprotective effects against angiotensin and aldosterone injuries. Intense and prolonged RAAS induces the downregulation of the apelin and its receptor at myocardial level and cancels their protection. Compared to the vasoactive agents used in the treatment of acute heart failure, exogen apelin has unique intropic and vasodilatory effects without deleterious consequences, being a promising therapeutic option. PMID- 26528041 TI - The Importance of Ubiquitin E3 Ligases, SCF and APC/C, in Human Cancers. AB - A normal evolution of the cell-cycle phases consists of multiple consecutive events, which makes it a highly complex process. Its preservation is regulated by Cyclin-Cdks (cyclin-dependent kinases) interactions and protein degradation, which is often controlled by the ubiquitin-mediated proteolysis. The goal of this review is to emphasize the most important features of the regulation of the cell cycle involved in cancerogenesis, by presenting the involvement of E3 ubiquitin ligases SCF (Skp1-Cul1-F-box protein) and APC/C (Anaphase-promoting complex/cyclosome) in human malignancies. Also, we discuss the importance of the ubiquitin proteasome pathway blockade in cancer treatment. We know that a better understanding of the regulatory biology of the cell cycle can lead to the development of new target therapies for cancer. PMID- 26528043 TI - Infantile Hemangioma: A Brief Review. AB - Infantile hemangiomas as frequent infancy tumors have been a controversial issue of medical scientists worldwide. Their clinical aspects are various and their physiopathology is yet to be fully understood. Numerous publications outline the characteristics, causes, evolution possibilities and therapeutic approaches. Deciding whether to treat or not is the main question of this kind of pathology. Hemangiomas that have complications or can cause irreversible damage need therapy. This is a brief review of up-to-date information regarding the presentation of infantile hemangiomas and target-therapies. PMID- 26528042 TI - On the Collagen Mineralization. A Review. AB - Collagen mineralization (CM) is a challenging process that has received a lot of attention in the past years. Among the reasons for this interest, the key role is the importance of collagen and hydroxyapatite in natural bone, as major constituents. Different protocols of mineralization have been developed, specially using simulated body fluid (SBF) and many methods have been used to characterize the systems obtained, starting with methods of determining the mineral content (XRD, FTIR, Raman, High-Resolution Spectral Ultrasound Imaging), continuing with imaging methods (AFM, TEM, SEM, Fluorescence Microscopy), thermal analysis (DSC and TGA), evaluation of the mechanical and biological properties, including statistical methods and molecular modeling. In spite of the great number of studies regarding collagen mineralization, its mechanism, both in vivo and in vitro, is not completely understood. Some of the methods used in vitro and investigation methods are reviewed here. PMID- 26528044 TI - The Relationship Between Left Ventricular Fractional Shortening and Intravenous Administration of Stem Cells in Laboratory Rabbits Presenting Chronic Myocardial Infarction. AB - BACKGROUND AND AIMS: The present study conducted from March 2012 to July 2013 aimed to evaluate from echocardiographic point of view the effects of peripheral intravenous administration of mesenchymal stem cells (MSCs) in laboratory rabbits presenting 30 days old chronic myocardial infarction. MATERIAL AND METHODS: 30 days after the induction of an acute myocardial infarction in 40 laboratory rabbits by direct ligation of the left anterior descending coronary artery at about 10 mm from the apex, we injected 1*106 MSCs in the auricular vein in a group of 30 rabbits, and a group of 10 rabbits were used as controls. 30 days after the injection of stem cells the left ventricular (LV) fractional shortening (FS) was evaluated by echocardiography and compared with the control rabbits. RESULTS: In control rabbits, echocardiography revealed akinesis of apex, interventricular septum kinetics was also impaired, FS being approximately 6%. In 80% (24 rabbits) of the injected rabbits the FS of the LV was significantly greater than in the witness group (26+/-2%, p<0.0001). At 13.3% (4 rabbits) of the injected rabbits the FS of the LV showed no improvement in comparison with the control group (6.5+/-1%). CONCLUSION: An improvement of LV SF 30 days after MSCs were injected(p<0.0001) was noted. We have to further determine if this improvement of the LV function is correlated with any histopathological changes and if it is not lost in time. Also, further studies needs to evaluate if there is any significant change in the overall mortality. PMID- 26528045 TI - Polymerase Chain Reaction as a Diagnostic Tool for Six Sexually Transmitted Infections - Preliminary Results. AB - BACKGROUND AND AIM: Sexually transmitted infections are a very frequent and under diagnosed cause of illness worldwide. A high number of detection methods and a large range of specimens in which sexually transmitted infections can be determined are available at the moment. Polymerase chain reaction performed on first void urine offers the advantage of being non-invasive, self-collectable and has high sensitivity and specificity. We looked to determine the frequency of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Mycoplasma hominis, Mycoplasma genitalium and Ureaplasma urealyticum in symptomatic and asymptomatic patients. METHODS: Six sexually transmitted infections were determined in the first void urine of 15 symptomatic and asymptomatic patients by polymerase chain reaction. We used "Epicenter MasterPureTM Complete DNA and RNA Purification Kit" for the DNA purification and "Seeplex(r) STD6 ACE Detection" for the DNA amplification. The results were examined in UV light. RESULTS: A number of 5 patients had positive results for Chlamydia trachomatis or Neisseria gonorrhoeae. Sexually transmitted infections are more frequent in men between 27 and 40 years old. CONCLUSIONS: Polymerase chain reaction is a good diagnostic tool for sexually transmitted infections because it has a high sensitivity and specificity. Chlamydia trachomatis is the most frequent sexually transmitted infection, followed by Neisseria gonorrhoeae. PMID- 26528046 TI - Patterns of Change During the Dermoscopic Follow-Up of Melanocytic Lesions in High Risk Patients. AB - BACKGROUND: Melanomas and melanocytic nevi that change over time display different change patterns, correlated with histopathological features. METHODS: We performed a retrospective analysis of the dermoscopic images corresponding to 86 lesions excised due to the changes occurred during the follow-up period in patients at high risk for melanoma, and we drew a comparison between the changes occurring in melanomas and those occurring in melanocytic nevi. RESULTS: There were significant differences between the models of dermoscopic change characteristic to melanoma and those characteristic to melanocytic nevi. We observed changes with high specificity for the diagnosis of melanoma - asymmetric growth (Sp=90%), new structureless grey-blue areas (Sp=97.5%) or new grey-blue network (Sp=96.25%), new pseudopods or radial streaks (Sp=95%). CONCLUSION: Our study highlights highly specific changes whose presence should raise the suspicion of melanoma and lead to the excision of the lesion. PMID- 26528047 TI - Late Responses in the Electrodiagnosis of Cervical Radiculopathies. AB - BACKROUND AND AIM: This paper aims to assess the parameters of late responses and then determine their usefulness in patients with cervical radiculopathy. PATIENTS AND METHODS: We studied a total of 114 patients with bilateral assessment of median and ulnar nerves and of F and A waves parameters. RESULTS: We draw attention to the need of bilateral electrodiagnostic examination due to changes occurring in a third of cases also in the asymptomatic limb. Pluriradicular injuries occurred in one third of cases. The root that was most commonly affected in cases of uniradicular lesion was C7. The parameters with the most important alterations were persistence, tacheodispersion and chronodispersion, which were changed in about a half of the patients. With regard to the A wave, it occurred in a small number of cases, about 10%, with an average amplitude of about 120 MUV and an average latency of 15ms. The distance from the point of stimulation where the collateral branch appeared was calculated to be approximately 35 cm. CONCLUSIONS: Among the F wave parameters, persistence, tacheodispersion and chronodispersion are recommended to be studied; these parameters were also included in the composite score along with the AAEM recommendations. PMID- 26528048 TI - The Added Value of Color Parameters in Analyzing Elastographic Images of Ultrasound Detected Breast Focal Lesions. AB - AIMS: The purpose of the study was to determine if the color quantitative analysis obtained on elastographic images of breast lesions could improve the benign-malignant differentiation, and also to identify some of the circumstances which would benefit most from such an analysis. PATIENTS AND METHODS: The study design was a longitudinal prospective one, all data being acquired between May 2007 and September 2008. The US device used: Hitachi 8500 EUB machine with elastography option. For suspicious breast lesions histopathology was obtained by means of percutaneous biopsy or post-surgery. Studied color parameters (numeric values): average color (red, green, blue), color dispersion, average intensity, average hue, hue dispersion. Calculus modality: Image Processing Version 1.3, a program developed in collaboration with the Technical University of Cluj Napoca. RESULTS: Seventy-one (71) women were selected for the study. A hundred and six circumscribed breast lesions were detected by means of ultrasound in the studied group. Five color parameters were independently associated with the histological diagnosis (AvgBlue, AvgGreen and AvgRed; DispRed and DispIntensity) with AvgBlue parameter making the most important contribution (p<0.0001); the greater the values of AvgBlue (more than 92), the higher the chances of malignancy and the greater the values of AvgGreen (more than 88), the higher the chances for a benign lesion. CONCLUSION: High numeric values for Avg Blue (more than 92) would increase the probability of malignancy and thus recommend a more aggressive diagnostic management (biopsy), while high numeric values for AvgGreen (more than 88) would reassure the examiner to proceed conservatively with short interval or routine follow-ups. PMID- 26528049 TI - The Surgical Treatment of Inguinal Hernia Using the Laparoscopic Totally Extra Peritoneal (TEP) Technique. AB - The surgical repair of inguinal hernia represents one of the most frequent procedures used in general surgery. The new surgical techniques are simpler, with a lower morbidity and recurrence of less than 2%. The laparoscopic totally extra peritoneal (TEP) technique is contraindicated in complicated hernias (occlusion, incarceration) and in voluminous inguino-scrotal hernias. PURPOSE: The evaluation of the TEP technique, of the risk factors and of the postoperative results on the group of patients who have undergone surgery in the Surgical Clinic 2 Cluj Napoca. MATERIAL AND METHOD: The study is prospective, on a group of 40 patients operated with the TEP technique in the Surgical Clinic 2 during the period May 2013 - July 2014. The following have been assessed: the demographic data, the risk factors, the immediate complications, the recurrence of the hernias. RESULTS: The average duration of hospitalization was 6.79 days. The intraoperative incidents were: 7 minimal peritoneal lesions with pneumoperitoneum and a hemorrhagic lesion of the epigastric vessels repaired endoscopically by the clipping of the lesion. There were 2 recurrences, 24 hours and 1 year after surgery, solved by the Lichtenstein technique. After 30 interventions, the average duration of the surgery was of 64 minutes, being longer in the case of bilateral hernias and being influenced by the team's learning curve. CONCLUSIONS: The TEP technique is a safe option followed by a low rate of complications, a low recurrence rate and low intensity postoperative pain. PMID- 26528050 TI - Efficiency of Empirically Administered Antibiotics in Patients with Cervical Infections of Odontogenic Origin. AB - BACKGROUND AND AIMS: Odontogenic infections are among the main types of disorders located in the cephalic extremity. The aim of this study was to determine the efficiency of empirically administered antibiotics on the bacterial strains identified at the infection sites. PATIENTS AND METHOD: The study included 10 randomly selected patients with odontogenic cervical soft tissue infections, who received antibiotic treatment prescribed by the family doctor or the dentist. The bacterial flora involved in the development of the septic process, the type of antibiotic administered to the patient and the sensitivity of the identified bacterial flora to the administered antibiotic were determined. RESULTS: In the 10 selected patients, 14 bacterial strains were detected; 7 patients had a single bacterial strain, and 3 patients had two or three types of bacteria. Of the administered antibiotics, amoxicillin was the most widely used (33.3% of the cases), followed by amoxicillin with beta-lactamase inhibitors (25% of the cases). In half of the patients, there was no sensitivity of the bacteria detected in the septic focus to the empirically administered antibiotic, and in 10% of the cases, partial sensitivity was evidenced. CONCLUSIONS: Empirical administration of antibiotics without the association of surgery did not prove to be effective in the treatment of cervical infections of odontogenic origin. PMID- 26528051 TI - Subantral Augmentation with a 1/1 Alloplastic and Autologous Material Mixture. Histological Characteristics and Dimensional Stability of the Newly Formed Bone. AB - BACKGROUND AND AIM: The maxillary sinus augmentation procedure is the most frequent method used to prepare the posterior maxillary area, with bone deficit, for the placement of dental implants. For this purpose, several types of materials have been used as bone grafts, each of these materials having a number of advantages and disadvantages. The present study is aimed at evaluating the histological and volumetric properties of an alloplastic and autologous material mixture. PATIENTS AND METHODS: The study included 7 selected patients who underwent subantral bone augmentation with a 1/1 autologous and alloplastic material mixture. Subsequently, at the time of dental implant placement, biological samples were taken from the bone augmentation area and were histologically analyzed. The subantral bone resorption rate was also evaluated in parallel. RESULTS: Histological examination evidenced the presence of residual amorphous material in the bone augmentation area. The mean bone resorption rate was 15.15%. The presence of a high bone resorption rate was correlated with the presence of a smaller residual amorphous material amount in the subantral bone augmentation area. CONCLUSIONS: The association of autologous and alloplastic material for subantral bone augmentation improves the characteristics of the two material types. PMID- 26528052 TI - Facial Attractiveness Assessment using Illustrated Questionnairers. AB - INTRODUCTION: An attractive facial appearance is considered nowadays to be a decisive factor in establishing successful interactions between humans. In relation to this topic, scientific literature states that some of the facial features have more impact then others, and important authors revealed that certain proportions between different anthropometrical landmarks are mandatory for an attractive facial appearance. AIM: Our study aims to assess if certain facial features count differently in people's opinion while assessing facial attractiveness in correlation with factors such as age, gender, specific training and culture. MATERIAL AND METHODS: A 5-item multiple choice illustrated questionnaire was presented to 236 dental students. The Photoshop CS3 software was used in order to obtain the sets of images for the illustrated questions. The original image was handpicked from the internet by a panel of young dentists from a series of 15 pictures of people considered to have attractive faces. For each of the questions, the images presented were simulating deviations from the ideally symmetric and proportionate face. The sets of images consisted in multiple variations of deviations mixed with the original photo. Junior and sophomore year students from our dental medical school, having different nationalities were required to participate in our questionnaire. Simple descriptive statistics were used to interpret the data. RESULTS: Assessing the results obtained from the questionnaire it was observed that a majority of students considered as unattractive the overdevelopment of the lower third, while the initial image with perfect symmetry and proportion was considered as the most attractive by only 38.9% of the subjects. Likewise, regarding the symmetry 36.86% considered unattractive the canting of the inter-commissural line. The interviewed subjects considered that for a face to be attractive it needs to have harmonious proportions between the different facial elements. CONCLUSIONS: Considering an evaluation of facial attractiveness it is important to keep in mind that such assessment is subjective and influenced by multiple factors, among which the most important are cultural background and specific training. PMID- 26528053 TI - Coronary-Subclavian Steal: Case Series and Review of the Literature. AB - Coronary subclavian steal syndrome (CSSS) is a relatively uncommon entity, and its clinical spectrum is characterized by stable exertional angina and rarely as acute coronary syndrome. The diagnosis can be established easily by angiography. We report a case series of three patients with CSSS and acute coronary syndrome and we review the literature in the attempt to understand the nature of symptomatology and the mechanisms of ischemia in this condition. Our study raised some questions about the correct definition of this entity, the pathophysiology of coronary steal and the mechanisms of ischemia, in the setting of unstable angina and acute myocardial infarction. PMID- 26528054 TI - Typhus Exanthematicus in Romania During the Second World War (1940-1945) Reflected by Romanian Medical Journals of the Time. AB - This article provides a picture of exanthematic Typhus in Romania during the Second World War: epidemiological aspects of this disease in the inner zone and in the zone of military operations, as well as information about the diagnosis, treatment and prophylaxis of the Typhus in our country during this period. PMID- 26528055 TI - Theodor I. Preda Hospital from Craiova Between the Years 1870-1910. AB - One of the most important hospitals in Craiova, hospital Theodor I. Preda, was the result of private initiatives in health care. It was founded in 1870 by the Municipality of Craiova, according to the request expressed by Theodore I. Preda in his will. Until 1910 it functioned in the homes of the donor and the money necessary for the activity came from leasing out the Starcovita and Cearangul estates that belonged to Theodor I. Preda and were donated to the town hall in order to maintain the hospital that would bear his name. Thanks to the efforts of the city hall but also of accrued income, it was possible to put up another building. The new premises of the hospital, which was opened in 1910, improved work and turned it into a modern hospital. PMID- 26528057 TI - Classic tumor markers in gastric cancer. Current standards and limitations. AB - The progress made in the last few years made available a large amount of information that needs to be integrated and ordered by oncologists. Tumor markers are one of the pieces that physicians need to fit into the bigger puzzle. This article will detail the most frequent etiologies for the surges in the carcinoembryonic antigen (CEA), cancer-related antigen 72-4 (CA 72-4), cancer related antigen 19-9 (CA 19-9) serum levels and their indications. Although tumor markers are an invaluable asset to medical practice, their role in screening, diagnosis and oncologic treatment remains poorly standardized. Ongoing or future clinical trials will shed light on pending problems. PMID- 26528056 TI - Management of endometrial modifications in perimenopausal women. AB - Perimenopause has a variable length and time of onset and is characterized by its variability in hormonal levels. The histological changes in the perimenopausal endometrium may be represented by nonproliferative or proliferative benign or malignant lesions. A commonly encountered manifestation of endometrium lesions during menopausal transition is the abnormal uterine bleeding (AUB). The clinical management of AUB must follow a standardized classification system for optimal results. The medical and surgical treatment must be adapted according to age, risk factors, symptoms, and cycle irregularities. Use of alternative therapies and proper diet may result in improved long-term outcomes. PMID- 26528058 TI - State of the art in the diagnosis and management of interstitial lung disease. AB - The interstitial lung diseases (ILDs) are a diverse group of disorders characterized by a varying combination of inflammation and fibrosis of the pulmonary parenchyma. Treatment and prognosis of ILD typically depend on the underlying ILD subtype, highlighting the importance of accurate classification and diagnosis. Besides a thorough history and clinical examination, the protocol should include a 6-minute walk test, chest radiography, high-resolution computed tomography, biochemical analysis, pulmonary function tests, blood gas analysis, bronchoalveolar lavage, and, when necessary, a lung biopsy. The final diagnosis of ILD entities requires dynamic interaction between clinicians, radiologists and pathologists to reach a clinico-radiologic-pathologic diagnosis, the gold standard no longer being the histology but rather a multidisciplinary approach. PMID- 26528059 TI - Operator-related risk factors of anastomotic leaks after colorectal surgery: an up-to-date. AB - Digestive fistulas are a major complication after digestive surgery. Anastomotic leakage increases the hospitalization time, the prognosis and survival rate after colorectal surgical interventions. The factors involved are either systemic (determined by the patients' co-morbidities), or local (vicious surgical technique or the injuries produced by the disease that requires the anastomosis). Although there are many studies regarding the risk factors of anastomotic leaks, there is no consensus for the role played by each one of them in the healing process of digestive sutures. Most authors sustain that the importance of systemic factors is secondary, the main role being played by the surgeon and the local conditions of the anastomosis. Knowledge of the risk factors can lead to new methods of reducing the incidence of anastomotic leaks by improving vascularization, limiting the tension and the duration of surgery, and by new surgical techniques used for digestive sutures. PMID- 26528061 TI - Modern management of dental decay in children and adolescents - a review. AB - Health is a right that requires responsible individual actions. Oral health corresponds to an important part of general health, even if for a large majority of people healthy teeth are equal with beautiful teeth. For children and adolescents "having an attractive smile" is synonymous with social acceptance and success. Dental decay has a high incidence in children in our country and progress in decay prevention, diagnosis and treatment is not reflected in children and adolescents' oral health. It is established by studies conducted by dentists and psychologists that dental decay can affect the quality of life by engendering specific eating behaviors, particular ways of speech or smile and unfortunately pain. The aim of this article is to emphasize the modern approach of dental decay in line with principles of non-invasive strategies. An important element to be considered - prophylactic methods - must be included in every treatment plan, in order to control individual caries risk. The time invested in prevention during childhood represents a real benefit for the future adult's oral health. Many a dental problems can be avoided if dental decay management relies on the link between medical science and every day practice. PMID- 26528060 TI - Safety issues of current analgesics: an update. AB - Pain represents a complex experience which can be approached by various medicines. Non-opioid and opioid analgesics are the most common drugs used to manage different types of pain. The increased attention nowadays to pain management entailed concomitantly more frequent adverse drug reactions (ADRs) related to analgesic use. Drug-drug interactions can be sometimes responsible for the adverse effects. However, a significant proportion of analgesic ADRs are preventable, which would avoid patient suffering. In order to draw the attention to analgesics risks and to minimize the negative consequences related to their use, the present review comprises a synthesis of the most important safety issues described in the scientific literature. It highlights the potential risks of the most frequently used analgesic medicines: non-opioid (paracetamol, metamizole, non-steroidal anti-inflammatory drugs) and opioid analgesics. Even if there is a wide experience in their use, they continue to capture attention with safety concerns and with potential risks recently revealed. Acknowledging potential safety problems represents the first step for health professionals in assuring a safe and efficient analgesic treatment with minimum risks to patients. Taking into consideration all medical and environmental factors and carefully monitoring the patients are also essential in preventing and early detecting analgesic ADRs. PMID- 26528062 TI - Nitro-oxidative stress, VEGF and MMP-9 in patients with cirrhotic and non cirrhotic portal hypertension. AB - BACKGROUND AND AIMS: Nitro-oxidative stress may have pathophysiological consequences. The study aimed to assess the nitro-oxidative stress, the vascular growth factor, and metalloproteinase-9 levels in patients with noncirrohic and cirrhotic portal hypertension. METHODS: Patients with noncirrhotic portal hypertension (n=50) and cirrhotic portal hypertension (n=50) from the 3rd Medical Clinic in Cluj-Napoca Romania were prospectively enrolled between October 2004 and October 2006. A control group of healthy volunteers (n=50) was also evaluated. Nitro-oxidative stress was assessed by measuring serum concentration of nitrites and nitrate, 3-nitrotyrosine, total oxidative status, total antioxidant reactivity, and oxidative stress index. Serum vascular growth factor and matrix metalloproteinase-9 were also determined. RESULTS: Serum nitrites and nitrate levels significantly increased in both noncirrhotic (p<0.001) and cirrhotic portal hypertension (p=0.057). 3-nitrotyrosine also increased in noncirrhotic (p=0.001) and cirrhotic portal hypertension patients (p=0.014). Total oxidative status showed a significant increase in noncirrhotic (p<0.001) and in cirrhotic portal hypertension (p<0.001), but total antioxidant reactivity did not change significantly. The oxidative stress index increased in both noncirrhotic (p <0.001) and cirrhotic portal hypertension (p<0.001), as well as the serum vascular growth factor (p=0.005 and p=0.01, respectively). In NCPHT patients serum MMP-9 was significantly lower than in the healthy controls (p=0.03) and CPHT patients (p=0.05). CONCLUSION: In patients with noncirrhotic and cirrhotic portal hypertension a significant systemic nitro-oxidative stress was found, correlated with an increase of VEGF. MMP-9 decreased in noncirrhotic portal hypertension. PMID- 26528063 TI - Epidemiology of irritable bowel syndrome in the former communist countries from Eastern Europe: a systematic review. AB - BACKGROUND AND AIM: The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder frequently encountered in clinical practice in Eastern Europe. Epidemiological data are diverging on this condition. Our objective was to assess the prevalence of IBS in the former communist countries from Eastern Europe (EE). METHODS: We performed a systematic review study using data from PubMed. Many languages, some having only local spreading, are spoken in EE, so we decided to look only for papers indexed in PubMed, which have at least an English summary or title. We searched PubMed using the following keywords: irritable bowel syndrome, functional digestive disorders, prevalence, EE. Only relevant studies were selected for analysis. RESULTS: From more than 4000 papers retrieved by this search, we identified a few papers appropriate to this survey. The spectrum of prevalence values is wide in IBS. Prevalence of IBS varies in different studies from 28% in a Croatian study, to 14% in Romania. Most studies report a higher prevalence in females. Stressful events are linked to the impairment of symptoms. Anxiety and depression are common in IBS patients, showing similar expression of functional symptoms. Quality of life is impaired. The role of abuse (physical, sexual) is not commonly investigated and when it was, the importance of this factor was revealed to be much less important than in Western Europe or North America. General practitioners seem to be well trained to recognize IBS, to make correct interpretations of the disease and to use the correct therapy. It seems that the Rome criteria are known and applied by general practitioners. Several epidemiological studies on IBS exist in most EE countries. Usually they look for self-reporting symptoms, or reports from endoscopy units. Psychosomatic approach of IBS was taken into consideration in several countries (Poland, Hungary, Romania), mainly by psychologists and psychotherapists rather than by gastroenterologists. CONCLUSIONS: There are few epidemiological studies on the epidemiology of IBS in EE. The majority of studies used Rome criteria. Several studies used small groups of patients. Some of the smaller studies have methodological flaws. The effect of stress and psychological factors are often investigated and analyzed with different methods of different accuracy. Some doctors used knowledge gained in EE in order to disseminate or to investigate further in more economically developed countries with a higher level of health. PMID- 26528064 TI - Transvaginal three-dimensional sonographic assessment of the embryonic brain: a pilot study. AB - AIMS: A very good knowledge of human embryology is mandatory not only for the correct sonographic assessment of the developing brain, but also for better understanding the origins of congenital anomalies involving the central nervous system. 3D transvaginal sonography may be an effective technique for imaging the developing brain. The aims of this explorative study are to demonstrate the feasibility of imaging the embryonic brain between 7 and 10 weeks of gestation for clinical studies by using a 3D high-frequency vaginal ultrasound transducer and to provide a reference for the morphology of the brain in the embryonic period. MATERIALS AND METHODS: Four embryos of 9 mm, 17 mm, 23 mm and 31 mm crown rump length respectively were assessed in vivo by transvaginal sonography. We gave a special attention to the embryonic brain. All patients were examined with a Voluson E10, BT 15 ultrasound scanner (GE Healthcare, Zipf, Austria), using a high-frequency 6-12 MHz/ 256-element 3D/4D transvaginal transducer. Three dimensional sonography was performed routinely as the patients were scanned. The multiplanar display was used after selecting the best volume. The Omni view(r) software was used for digitally slicing the selected volumes. RESULTS: We describe the morphological details of the developing brains of four embryos ranging from 7 to 10 gestational weeks. In the human embryo 9 mm CRL the hypoechogenic cavities of the three primary vesicles (prosencephalon, mesencephalon, rhombencephalon) could be observed on a sagittal section. In the human embryo 17 mm CRL the prosencephalon was divided into the median diencephalon and two telencephalic vesicles, which were partially separated by the falx cerebri. In the human embryo 23 mm CRL the cerebral hemispheres developed and they were completely separated by the falx cerebri. The choroid plexus was evident inside the lateral ventricles and the fourth ventricle. In the human embryo 31 mm CRL the ventral thalamus was evident, and the ganglionic eminence, as the precursor of the basal ganglia, was well seen on the floor of the cerebral hemispheres. CONCLUSIONS: Studies of embryology are still needed for a complete understanding of the developing brain. 3D sonography using a high frequency vaginal ultrasound transducer is feasible for imaging the embryonic brain with an acceptable quality for clinical studies. PMID- 26528065 TI - Combined glutathione S transferase M1/T1 null genotypes is associated with type 2 diabetes mellitus. AB - BACKGROUND: Due to new genetic insights, a considerably large number of genes and polymorphic gene variants are screened and linked with the complex pathogenesis of type 2 diabetes (DM). Our study aimed to investigate the association between the two isoforms of the glutathione S-transferase genes (Glutathione S transferase isoemzyme type M1- GSTM1 and Glutathione S transferase isoemzyme type T1-GSTT1) and the prevalence of DM in the Northern Romanian population. METHODS: We conducted a cross-sectional, randomized, case-control study evaluating the frequency of GSTM1 and GSTT1 null alleles in patients diagnosed with DM. A total of 106 patients diagnosed with DM and 124 healthy controls were included in the study. GSTM1 and GSTT1 null alleles genotyping was carried out using Multiplex PCR amplification of relevant gene fragments, followed by gel electrophoresis analysis of the resulting amplicons. RESULTS: Molecular analysis did not reveal an increased frequency of the null GSTM1 and GSTT1 alleles (mutant genotypes) respectively in the DM group compared to controls (p=0.171, OR=1.444 CI=0.852 2.447; p=0.647, OR=0.854, CI=0.436-1.673). Nevertheless, the combined GSTM1/GSTT1 null genotypes were statistically significantly higher in DM patients compared to control subjects (p=0.0021, OR=0.313, CI=0.149-0.655). CONCLUSIONS: The main finding of our study is that the combined, double GSTM1/GSTT1 null genotypes are to be considered among the polymorphic genetic risk factors for type 2 DM. PMID- 26528066 TI - Evaluation of interleukin-10 levels in the plasma of patients with various stages of tuberculosis. AB - Mycobacterium tuberculosis (Mtb) infection remains one of the world's major causes of illness and mortality. A clear understanding of the host defense against Mtb is imperatively needed forthe control of this epidemic. When tuberculosis (TB) infection occurs, a variety of pro and anti-inflammatory cytokines play a vital role in the pathogenesis of this disease. Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokines reported to suppress the protective immune response against tuberculosis. AIM: The aim of the present study was to evaluate the association of plasma IL-10 levels with various disease stages of TB and the possible effects of treatment on these levels. MATERIALS AND METHODS: A group of 30 patients with active pulmonary TB and a control group of 21 healthy individuals were enrolled in this study. The levels of IL-10 were measured before, during, and after treatment using commercially available enzyme-linked immune-sorbent assay (ELISA). Data were analyzed using GraphPad Prism version 5.0. RESULTS: The results showed that the levels of IL-10 had significant differences between the TB and control groups (p<0.05). The patients with abnormal chest X-Ray findings had higher IL-10 levels when compared to patients with normal X-Rays (p=0.03). A subgroup of 18 patients were followed during the treatment and the mean plasma concentration of IL-10 in patients before therapy was higher than in patients at 3 months of therapy and in patients after 6 months of therapy (p=0.01). However, the IL-10 level remained significantly higher in patients at the end of treatment compared with controls. These findings could be used in follow-up as clinical biomarker of the success of tuberculosis therapy. PMID- 26528067 TI - Effect of the early intensive multifactorial therapy on the cardiovascular risk in patients with newly diagnosed type 2 diabetes: an observational, prospective study. AB - BACKGROUND AND AIMS: We assessed if early intensive interventions improve the glycemic control and the modifiable cardiovascular diseases risk factors in Romanian patients with newly diagnosed type-2 diabetes during the first year follow-up period. PATIENTS AND METHODS: This was an observational, prospective study: 69 subjects were included in the analysis; each of them received intensive multi-factorial pharmacologic treatment and therapeutic education targeting hyperglycemia, weight, hypertension and dyslipidemia. Disease monitoring was done at months 0, 1, 3, 6 and 12 by assessment of anthropometric measurements, arterial blood pressure and biochemical parameters. The cardiovascular diseases risk factors were calculated using the United Kingdom Prospective Diabetes Study Risk Engine. RESULTS: The mean age at diagnosis was 53.61+/-10.66 years. All anthropometric variables (body weight, body mass index, waist circumference, visceral fat area, percentage of body fat), except for skeletal muscle mass, significantly decreased overtime. The majority of the biochemical parameters significantly decreased overtime. The non-fatal/fatal coronary heart disease risk significantly decreased at month 12 (9.74 [p<0.05] and 4.84 [p<0.05], respectively) compared to month 0 (19.66 and 11.10, respectively); a similar trend of the non-fatal/fatal stroke (risk at month 12, 8.30 [p<0.05] and 1.04 [p<0.05], respectively, while at month 0, 7.89 and 1.38, respectively) was recorded. CONCLUSIONS: Early multi-factorial treatment and intensive lifestyle interventions in patients newly diagnosed with type-2 diabetes could decrease with approximately 50% the rate of cardiovascular disease risk. PMID- 26528068 TI - Photodynamic therapy of melanoma using new, synthetic porphyrins and phthalocyanines as photosensitisers - a comparative study. AB - Melanoma, a cancer that arises from melanocytes, is one of the most unresponsive cancers to known therapies and has a tendency to produce early metastases. Several studies showed encouraging results of the efficacy of photodynamic therapy (PDT) in melanoma, in different experimental settings in vitro and in vivo, as well as several clinical reports. AIMS: Our study focuses on testing the antimelanoma efficacy of several new, synthetic photosensitisers (PS), from two different chemical classes, respectively four porphyrins and six phthalocyanines. METHODS: These PS were tested in terms of cell toxicity and phototoxicity against a radial growth phase melanoma cell line (WM35), in vitro. Cells were exposed to different concentrations of the PS for 24h, washed, then irradiatied with red light (630 nm) 75 mJ/cm(2) for the porphyrins and 1 J/cm(2) for the phthalocyanines. Viability was measured using the MTS method. RESULTS: Two of the synthetic porphyrins, TTP and THNP, were active photosensitizers against WM35 melanoma in vitro. Phthalocyanines were effective in producing a dose dependent PDT-induced decrease in viability in a dose-dependent manner. The most efficient was Indium (III) Phthalocyanine chloride, a metal substituted phthalocyanine. CONCLUSIONS: The most efficient photosensitizers for PDT in melanoma cells were the phthalocyanines in terms of tumor cell photokilling and decreased dark toxicity. PMID- 26528069 TI - Unilateral peripheral vestibular disorders in the emergency room of the ENT Department of Cluj-Napoca, Romania. AB - OBJECTIVE: To asses the management of unilateral peripheral vestibular disorders in the emergency room of the ENT Department of Cluj-Napoca, Romania. MATERIAL AND METHOD: The study was prospective, non-randomized, and included the patients presented for dizziness or balance disorders at the emergency room of the ENT Department between March 2012 and March 2013. Demographic characteristics, specific clinical history, the onset of peripheral vestibular disorders, and co morbidities were recorded. The patients charts included the type of onset and the treatment (medical, surgical, and rehabilitation) performed in the emergency room or, in case of hospital admission, the relieving measures for the vestibular symptoms with or without hearing recovery. RESULTS: One hundred and fifty-two subjects were included in our study, 97 with pure peripheral vestibular dysfunction (VD), 34 with cochlear-vestibular dysfunction (CVD), and 21 with Meniere's disease (MD). No significant differences were identified when the proportion of patients with a certain onset (acute, subacute or chronic) were compared. Hypertension was the most frequent co-morbidity in all investigated groups. No significant difference was observed when the relief of vertigo or hearing recovery were compared between all groups. CONCLUSION: This first Romanian report on the management of unilateral peripheral vestibular disorders showed that early corticosteroids treatment associated with electrolytes, antiemetic, and vasodilation drugs led to the recovery of the vestibular function without any differences between the types of peripheral vestibular dysfunction. In addition, we obtained the complete recovery of the vestibular and acoustic dysfunction in the cases treated with metylprednisolone intratympanic injection. PMID- 26528070 TI - Intra-abdominal hypertension in the ICU - a prospective epidemiological study. AB - The aim of this prospective study is to examine the frequency and the severity of intra-abdominal hypertension in a mixed ICU of the University hospital. METHODS: A closed system for intravesical intermittent measurement of IAP was constructed. RESULTS: The frequency and the severity of IAH were examined in the period from June 2009 to December 2012 in 240 ICU patients divided into 3 groups (patients submitted to elective surgery, emergency surgery, and medical patients) in the University Hospital. In the elective surgery group there was 12.5% IAH, while in the emergency group IAH was 43.75%, and in the medical patients it was 42.5%. There was no statistical significant difference in the frequency of IAH among the mixed population of patients we examined and those studied by other authors with the same type of population. CONCLUSIONS: The standardized measurement of intra abdominal pressure is fundamental for defining intra-abdominal hypertension and abdominal compartment syndrome. The measurement of intra-abdominal pressure should be a part of the basic monitoring of patients at risk of intra-abdominal hypertension. Our point of view is that before there are indications for a surgical decompression, less invasive treatment options should be optimized. PMID- 26528071 TI - Evaluation of a training course on open vascular surgical techniques in aortoiliac pathology - 5 years of experience. AB - INTRODUCTION: The aim of this prospective study was to assess the efficacy of a vascular surgery course (2008-2012), and to verify the viability and the feasibility of vascular anastomoses. MATERIAL AND METHOD: The vascular surgical techniques performed simultaneously on pigs were: enlargement prosthetic angioplasty, abdominal aortic interposition graft and aortoiliac bypass. The endpoints of the study were the surgical skills and the technical quality, assessed on a scale ranging from 1 (satisfactory) to 3 (very good) for our participants. RESULTS: A significant improvement in vascular surgical skills tasks was observed during the study years and we also found a significant statistical association between the quality of the suture and the surgical technique used (Kendall coefficient=0.71, p=0.001<0.05). CONCLUSIONS: Our course contributed to the improvement of the technical vascular surgical skills of the operator teams, reproducing in vivo, in pigs, the intraoperative environment of human patients. PMID- 26528072 TI - The multimodal treatment of central and peripheral cholangiocarcinoma - analysis based on a single center experience. AB - The hilar and intrahepatic location represents the most frequent positioning of cholangiocarcinoma. Late diagnosis, tumour resection - as the sole method of radical treatment require a multimodal approach of this form of malignancy. MATERIAL AND METHODS: The paper is based on a retrospective study conducted on a series of 56 patients diagnosed with hilar and peripheral cholangiocarcinoma admitted and treated in the 3rd Surgical Clinic Cluj-Napoca between September 2004 - December 2010. The series included patients treated with radical or palliative surgical treatment, or patients who underwent minimally invasive treatment of biliary endoscopic or percutaneous drainage followed or not by surgery. We analyzed the data on the postoperative morbidity and mortality, surgical re-interventions, the percentage of patients who received curative resection with radical intention or palliative treatment. CONCLUSIONS: Cholangiocarcinoma is an aggressive form of cancer and commonly diagnosed late. The cholangiocarcinoma resectability results are comparable to those in literature and may be improved by increasing the number of tumor resections with negative resection margins. The main goal of the palliative procedures is the improvement and remission of the obstructive jaundice, in most cases being successful. The multimodality of the cholangiocarcinoma treatment is a reality, but also a goal in the group of patients studied, the number of patients in which the sequential treatment biliary drainage - surgical treatment were applied being still low. PMID- 26528073 TI - Phenotypic differences in nebivolol metabolism and bioavailability in healthy volunteers. AB - INTRODUCTION: Nebivolol, a third-generation beta-blocker, is subject to extensive first-pass metabolism and produces active beta-blocking hydroxylated metabolites, like 4-OH-nebivolol. It is primarily a substrate of CYP2D6, a metabolic pathway that is under polymorphic genetic regulation. The objective of this study was to assess the metabolizer phenotype and to evaluate the interphenotype bioavailability and metabolism of nebivolol. MATERIAL AND METHODS: Forty-three healthy volunteers were included in this open-label, non-randomized clinical trial and each volunteer received a single dose of 5 mg nebivolol. Non compartmental pharmacokinetic analysis was performed to determine the pharmacokinetic parameters of nebivolol and its active metabolite. The phenotypic distribution was assessed based on the AUC (aria under the curve) metabolic ratio of nebivolol/4-OH-nebivolol and statistical analysis. An interphenotype comparison of nebivolol metabolism and bioavailability was performed based on the pharmacokinetic parameters of nebivolol and its active metabolite. RESULTS: Nebivolol/4-OH-nebivolol AUC metabolic ratios were not characterized by a standard normal distribution. The unique distribution emphasized the existence of two groups and the 43 healthy volunteers were classified as follows: poor metabolizers (PMs)=3, extensive metabolizers (EMs)=40. The phenotype had a marked impact on nebivolol metabolism. The exposure to nebivolol was 15-fold greater for PMs in comparison to EMs. CONCLUSION: 40 EMs and 3 PMs were differentiated by using the pharmacokinetic parameters of nebivolol and its active metabolite. The study highlighted the existence of interphenotype differences regarding nebivolol metabolism and bioavailability. PMID- 26528074 TI - Development and optimization of quercetin-loaded PLGA nanoparticles by experimental design. AB - BACKGROUND AND AIMS: Quercetin is a flavonoid with good antioxidant activity, and exhibits various important pharmacological effects. The aim of the present work was to study the influence of formulation factors on the physicochemical properties of quercetin-loaded polymeric nanoparticles in order to optimize the formulation. MATERIALS AND METHODS: The nanoparticles were prepared by the nanoprecipitation method. A 3-factor, 3-level Box-Behnken design was employed in this study considering poly(D,L-lactic-co-glycolic) acid (PLGA) concentration, polyvinyl alcohol (PVA) concentration and the stirring speed as independent variables. The responses were particle size, polydispersity index, zeta potential and encapsulation efficiency. RESULTS: The PLGA concentration seemed to be the most important factor influencing quercetin-nanoparticle characteristics. Increasing PLGA concentration led to an increase in particle size, as well as encapsulation efficiency. On the other hand, it exhibited a negative influence on the polydispersity index and zeta potential. The PVA concentration and the stirring speed had only a slight influence on particle size and polydispersity index. However, PVA concentration had an important negative effect on the encapsulation efficiency. Based on the results obtained, an optimized formulation was prepared, and the experimental values were comparable to the predicted ones. CONCLUSIONS: The overall results indicated that PLGA concentration was the main factor influencing particle size, while entrapment efficiency was predominantly affected by the PVA concentration. PMID- 26528075 TI - The influence of laser radiation on human osteoblasts cultured on nanostructured composite substrates. AB - BACKGROUND AND AIMS: Carbon-based nanomaterials such as carbon nanotubes, graphene oxide and graphene have been explored by researchers as well as the industry. Graphene is a new nanomaterial which has commercial and scientific advantages. Laser therapy has proven highly useful in biomedicine, with the use of different laser types and energies for distinct purposes. The low level laser therapy (LLLT) can have anti-inflammatory, analgesic and biostimulant effects. Recent research has shown that laser radiation has different effects on osteoblasts. The aim of this study was to identify the influence of laser radiation on human osteoblastic cells cultured on nanostructured composite substrates. MATERIALS AND METHODS: Four types of substrates were created using colloidal suspensions of nanostructured composites in PBS at a concentration of 30 MUg/ml. We used human osteoblasts isolated from patella bone pieces harvested during arthroplasty. Irradiation of osteoblasts cultured on nanostructured composite substrates was made with a semiconductor laser model BTL-10 having a wavelength of 830 nm. The proliferation activity of osteoblast cells was assessed using the MTT assay. After laser irradiation procedure the viability and proliferation of osteoblast cells were analyzed using fluorescein diacetate (FDA) staining. RESULTS: The osteoblast cells viability and proliferation were evaluated with MTT assay at 30 minutes, 24 hours, 5 days and 10 days after laser irradiation. In the first 30 minutes there were no significant differences between the irradiated and non-irradiated cells. At 24 hours after laser irradiation procedure a significant increase of MTT values in case of irradiated osteoblasts cultivated on nanostructured hydroxyapatite, nanostructured hydroxyapatite with gold nanoparticles and 1.6% and 3.15% graphenes composites substrates was observed. A more marked proliferation rate was observed after 10 days of irradiation for irradiated osteoblasts seeded on nanostructured hydroxyapatite with gold nanoparticles and graphenes containing substrate. Using FDA staining we obtained very similar results with MTT test. CONCLUSIONS: The association between the 830 nm laser irradiation of osteoblasts and their long term cultivation of the nanostructured composite substrates induces the cell proliferation and differentiation and therefore it will be a useful alternative for bone regeneration therapy. PMID- 26528076 TI - Arthroscopic management of proximal tibial fractures: technical note and case series presentation. AB - BACKGROUND AND AIMS: The purpose of this article is to describe a new surgical method of arthroscopy assisted treatment of intraarticular proximal tibial fractures (ARIF - arthroscopic reduction and internal fixation), analyzing its efficiency and safety on a series of patients. Tibial plateau fractures affect the proximal tibial metaphyseal and articular surface, representing 1.2% of all fractures and up to 8% of all fractures in elderly. PATIENTS AND METHOD: Our case series consists of 6 patients with Schatzker types I-III tibial plateau fractures, treated in the Orthopedic and Traumatology Clinic of Cluj-Napoca from July 2012 to August 2014. Patients included in the study presented Schatzker type I-III tibial plateau fracture. RESULTS: The results obtained with the arthroscopic method were excellent in 5 cases (mean Rasmussen score 27.60 points) and good in 1 case (mean score 23.75). The radiological consolidation appeared after a mean of 12 weeks. No major complication was noted. CONCLUSIONS: Diagnosis and treatment of associated lesions, shortening of hospitalization length and postoperative rehabilitation, but also the lower rate of complications, can make arthroscopic reduction and internal fixation the method of choice for the operative treatment of selected Schatzker I-III types of proximal tibial fractures. PMID- 26528077 TI - Unusual skin metastasis in a patient with recurrent micropapillary serous ovarian carcinoma - a case report and review of the literature. AB - The presence of skin metastasis in ovarian cancer patients is uncommon and related with poor prognosis. We report a 49-year-old patient with recurrent ovarian cancer presented with extensive skin metastasis on the anterior chest (including bilateral breast skin), lower abdomen, vulva and the upper part of the lower limbs at 21 months after initial diagnosis of ovarian cancer. The skin biopsy revealed metastasis of adenocarcinoma in the dermis. The patient underwent palliative chemotherapy and she died after 2 months of the diagnosis of the skin metastasis. It is the first case of skin metastasis from a micropapillary serous ovarian carcinoma published in Romania. PMID- 26528078 TI - On rate-dependent polycrystal deformation: the temperature sensitivity of cold dwell fatigue. AB - A temperature and rate-dependent crystal plasticity framework has been used to examine the temperature sensitivity of stress relaxation, creep and load shedding in model Ti-6Al polycrystal behaviour under dwell fatigue conditions. A temperature close to 120 degrees C is found to lead to the strongest stress redistribution and load shedding, resulting from the coupling between crystallographic slip rate and slip system dislocation hardening. For temperatures in excess of about 230 degrees C, grain-level load shedding from soft to hard grains diminishes because of the more rapid stress relaxation, leading ultimately to the diminution of the load shedding and hence, it is argued, the elimination of the dwell debit. Under conditions of cyclic stress dwell, at temperatures between 20 degrees C and 230 degrees C for which load shedding occurs, the rate-dependent accumulation of local slip by ratcheting is shown to lead to the progressive cycle-by-cycle redistribution of stress from soft to hard grains. This phenomenon is termed cyclic load shedding since it also depends on the material's creep response, but develops over and above the well known dwell load shedding, thus providing an additional rationale for the incubation of facet nucleation. PMID- 26528079 TI - Quantum speedup of Monte Carlo methods. AB - Monte Carlo methods use random sampling to estimate numerical quantities which are hard to compute deterministically. One important example is the use in statistical physics of rapidly mixing Markov chains to approximately compute partition functions. In this work, we describe a quantum algorithm which can accelerate Monte Carlo methods in a very general setting. The algorithm estimates the expected output value of an arbitrary randomized or quantum subroutine with bounded variance, achieving a near-quadratic speedup over the best possible classical algorithm. Combining the algorithm with the use of quantum walks gives a quantum speedup of the fastest known classical algorithms with rigorous performance bounds for computing partition functions, which use multiple-stage Markov chain Monte Carlo techniques. The quantum algorithm can also be used to estimate the total variation distance between probability distributions efficiently. PMID- 26528080 TI - Elastodynamic image forces on dislocations. AB - The elastodynamic image forces on edge and screw dislocations in the presence of a planar-free surface are derived. The explicit form of the elastodynamic fields of an injected, quiescent screw dislocation are also derived. The resulting image forces are affected by retardation effects: the dislocations experience no image force for a period of time defined by the arrival and reflection at the free surface of the dislocation fields. For the case of injected, stationary dislocations, it is shown that the elastodynamic image force tends asymptotically to the elastotatic prediction. For the case of injected, moving dislocations, it is shown that the elastodynamic image force on both the edge and the screw dislocations is magnified by inertial effects, and becomes increasingly divergent with time; this additional effect, missing in the elastostatic description, is shown to be substantial even for slow moving dislocations. Finally, it is shown that the elastodynamic image force of an edge dislocation moving towards the surface at the Rayleigh wave speed becomes repulsive, rather than attractive; this is suggestive of instabilities at the core of the dislocation, and likely resonances with the free surface. PMID- 26528082 TI - Rodger H. Brown, MD. PMID- 26528083 TI - Techniques in Breast Reduction and Mastopexy. PMID- 26528081 TI - 360 degree perspective on allergic rhinitis management in Italy: a survey of GPs, pharmacists and patients. AB - BACKGROUND: General practitioners (GPs), community pharmacists and allergic rhinitis (AR) patients in Italy were surveyed in order to gain insight from all three perspectives into the diagnosis, management and burden of AR in Italy. METHODS: General practitioners and pharmacists (n = 100 for each) were surveyed by telephone; questions related to overall practice and to last AR patient seen. Patients (n = 552) completed a questionnaire after visiting specialist allergy centres. Questions related to diagnosis and treatment, degree of everyday limitation from AR, and satisfaction with treatment. The data were analysed descriptively. RESULTS: Allergic rhinitis was managed mainly by GPs, who reported making the diagnosis themselves in 68 % of cases; rhinorrhea (64 %), sneezing (57 %) and congestion (49 %) were the symptoms most frequently taken into account. Limitation from AR on everyday life was rated 6.2 out of 10 by GPs. Pharmacists most often considered eye tearing (54 %) in their diagnosis. Almost half of GPs (49 %) and 87 % of pharmacists were unaware of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines. The most commonly reported prescribed treatments by GPs were branded mometasone furoate, desloratadine, ebastine and generic mometasone; 21 % prescribed homeopathic products occasionally. On average, GPs remembered that their last patient case had moderate/severe disease, was prescribed anti-histamine monotherapy (37 % of cases), and did not change prescription (78 %). Pharmacists recommended an antihistamine for 56 % of clients who asked for advice, and a nasal decongestant for 21 %. Patients rated limitation from AR on everyday life as 5.7/10. 55 % reported using multiple therapies, and 43 % were not satisfied or weakly satisfied with their current treatment. Patients' main expectation for the future was to succeed in managing their AR symptoms (45 %), while 22 % hoped for a definitive cure. Many patients (61 %) were concerned their health would deteriorate. CONCLUSIONS: Allergic rhinitis is largely managed by GPs in Italy, with pharmacists also playing a role, yet awareness of the ARIA guidelines among these groups is low. Patient satisfaction with treatment is moderate or low. New more effective treatments are needed to improve AR management in Italy. Allergy education programs need to be better targeted to GPs and pharmacists, and communication with patients regarding symptom control must be improved. PMID- 26528084 TI - The Delay Fill Technique: A Safer Approach to Combination Augmentation Mastopexy. AB - Combining breast augmentation with mastopexy is a challenging procedure that has a relatively high revision rate in the literature. Some surgeons prefer a two stage procedure to avoid the potential for skin flap or nipple-areolar complex necrosis that can occur with a one-stage procedure. The authors compared 101 patients who had subpectoral breast augmentation with immediate implant fill and mastopexy with 203 patients who had subpectoral breast augmentation with delayed (10-14 days) implant fill and mastopexy. They found the revision rate for immediate implant fill was 24%; in the delayed implant fill group, the revision rate was 10.3%. Patients had soft tissue-related complications in 16% of the immediate fill group and in 2% of the delayed fill group. Delaying implant fill in combined breast augmentation mastopexy significantly reduces the risk of soft tissue-related complications and revision procedures; the delay flap phenomenon is responsible for fewer wound-healing complications when implant fill is delayed during a combined augmentation mastopexy procedure. PMID- 26528085 TI - The Superomedial Pedicle Wise-Pattern Breast Reduction: Reproducible, Reliable, and Resilient. AB - The combination of the superomedial pedicle with the traditional Wise-pattern skin resection has gained increasing popularity for its versatility and ability to achieve significant reduction of breast parenchyma and skin envelope with improved contour and lasting results. Here the authors review the pertinent anatomy and discuss their surgical technique and its benefits. In addition, a retrospective chart review of 80 patients (151 breasts) who underwent superomedial pedicle Wise-pattern breast reduction between 2010 and 2014 was performed. Mean specimen weights and complication rates, including seroma, delayed wound healing, nipple loss, infection, and reoperation were calculated for the cohort. PMID- 26528086 TI - Reduction and Mastopexy Techniques for Optimal Results in Oncoplastic Breast Reconstruction. AB - Breast conservation therapy has emerged as an important option for select cancer patients as survival rates are similar to those after mastectomy. Large tumor size and the effect of radiation create cosmetic deformities in the shape of the breast after lumpectomy alone. Volume loss, nipple displacement, and asymmetry of the contralateral breast are just a few concerns. Reconstruction of lumpectomy defects with local tissue rearrangement in concert with reduction and mastopexy techniques have allowed for outstanding aesthetic results. In patients who have a reasonable tumor- to breast-size ratio, this oncoplastic surgery can successfully treat the patient's cancer while often improving upon preoperative breast shape. Specific surgical guidelines in reduction and mastopexy help achieve predictable aesthetic results, despite the effects of radiation, and can allow for a single surgical procedure for cancer removal, reconstruction, and contralateral symmetry in one stage. PMID- 26528087 TI - Reduction and Mastopexy of the Reconstructed Breast: Special Considerations in Free Flap Reconstruction. AB - Autologous breast reconstruction is capable of creating a breast that closely resembles a natural breast. Reduction and mastopexy in this type of reconstruction yields several challenges to the reconstructive surgeon. Revision surgery is common to achieve symmetry; however, reduction, mastopexy, and other revision techniques are sparse in the current literature. Often, these techniques are passed from mentor to student during plastic surgery training or are learned with experience in managing one's own patients. Reviewing anatomical principles unique to this subset of patients is essential. We must also consider factors unique to this group including the effects of delayed reconstruction, radiation, skin paddle size, and flap volume. In this article, the authors describe some of the common principles used by experienced reconstructive surgeons to perform reduction and mastopexy in autologous breast reconstruction to achieve a natural, aesthetically pleasing breast reconstruction. In addition, they have included several case examples to further illustrate these principles. PMID- 26528088 TI - Trends in the Surgical Correction of Gynecomastia. AB - Gynecomastia refers to the enlargement of the male breast due to a proliferation of ductal, stromal, and/or fatty tissue. Although it is a common condition affecting up to 65% of men, not all cases require surgical intervention. Contemporary surgical techniques in the treatment of gynecomastia have become increasingly less invasive with the advent of liposuction and its variants, including power-assisted and ultrasound-assisted liposuction. These techniques, however, have been largely limited in their inability to address significant skin excess and ptosis. For mild to moderate gynecomastia, newer techniques using arthroscopic morcellation and endoscopic techniques promise to address the fibrous component, while minimizing scar burden by utilizing liposuction incisions. Nevertheless, direct excision through periareolar incisions remains a mainstay in treatment algorithms for its simplicity and avoidance of additional instrumentation. This is particularly true for more severe cases of gynecomastia requiring skin resection. In the most severe cases with significant skin redundancy and ptosis, breast amputation with free nipple grafting remains an effective option. Surgical treatment should be individualized to each patient, combining techniques to provide adequate resection and optimize aesthetic results. PMID- 26528089 TI - What we are like when we are at our best: Appreciative stories of staff in a community mental health center. AB - Appreciative Inquiry is an organizational change methodology that discovers what works well in an organization and then pursues strategies to enhance those factors. The initial discovery process itself provides data ripe for qualitative analysis. Narratives were collected from 27 community mental health staff about times when they were at their best. An emergent, consensus-based analysis was used to understand the stories and exemplary work -- with competent, caring staff and elements needed to support them. Findings are discussed in light of self determination theory that people are at their best with a sense of mastery, connection, and autonomy. PMID- 26528092 TI - Continuing efforts to integrate care can benefit from cross-jurisdictional comparisons. PMID- 26528091 TI - Problems of robustness in Poisson-Boltzmann binding free energies. AB - Although models based on the Poisson-Boltzmann (PB) equation have been fairly successful at predicting some experimental quantities, such as solvation free energies (DeltaG), these models have not been consistently successful at predicting binding free energies (DeltaDeltaG). Here we found that ranking a set of protein-protein complexes by the electrostatic component (DeltaDeltaGel) of DeltaDeltaG was more difficult than ranking the same molecules by the electrostatic component (DeltaGel) of DeltaG. This finding was unexpected because DeltaDeltaGel can be calculated by combining estimates of DeltaGel for the complex and its components with estimates of the DeltaDeltaGel in vacuum. One might therefore expect that if a theory gave reliable estimates of DeltaGel, then its estimates of DeltaDeltaGel would be reliable. However, DeltaDeltaGel for these complexes were orders of magnitude smaller than DeltaGel, so although estimates of DeltaGel obtained with different force fields and surface definitions were highly correlated, similar estimates of DeltaDeltaGel were often not correlated. PMID- 26528090 TI - Modeling molecular kinetics with tICA and the kernel trick. AB - The allure of a molecular dynamics simulation is that, given a sufficiently accurate force field, it can provide an atomic-level view of many interesting phenomena in biology. However, the result of a simulation is a large, high dimensional time series that is difficult to interpret. Recent work has introduced the time-structure based Independent Components Analysis (tICA) method for analyzing MD, which attempts to find the slowest decorrelating linear functions of the molecular coordinates. This method has been used in conjunction with Markov State Models (MSMs) to provide estimates of the characteristic eigenprocesses contained in a simulation (e.g., protein folding, ligand binding). Here, we extend the tICA method using the kernel trick to arrive at nonlinear solutions. This is a substantial improvement as it allows for kernel-tICA (ktICA) to provide estimates of the characteristic eigenprocesses directly without building an MSM. PMID- 26528093 TI - The Norrtaelje model: a unique model for integrated health and social care in Sweden. AB - Many countries organise and fund health and social care separately. The Norrtaelje model is a Swedish initiative that transformed the funding and organisation of health and social care in order to better integrate care for older people with complex needs. In Norrtaelje model, this transformation made it possible to bringing the team together, to transfer responsibility to different providers, to use care coordinators, and to develop integrated pathways and plans around transitions in and out of hospital and from nursing homes to hospital. The Norrtaelje model operates in the context of the Swedish commitment to universal coverage and public programmes based on tax-funded resources that are pooled and redistributed to citizens on the basis of need. The experience of Norrtaelje model suggests that one way to promote integration of health and social care is to start with a transformation that aligns these two sectors in terms of high level organisation and funding. This transformation then enables the changes in operations and management that can be translated into changes in care delivery. This "top-down" approach must be in-line with national priorities and policies but ultimately is successful only if the culture, resource allocation and management are changed throughout the local system. PMID- 26528094 TI - Implementing integrated models of care: the importance of the macro-level context. AB - Reports of how different countries are responding to the need to develop more integrated health and social care services for older adults can provide useful lessons for other health systems. However an understanding of how the wider structural, political, economic and cultural context affects implementation of these models of care is essential when considering the potential for models to be scaled up or transferred to other jurisdictions. PMID- 26528095 TI - Integrated community-based dementia care: the Geriant model. AB - This article gives an in-depth description of the service delivery model of Geriant, a Dutch organization providing community-based care services for people suffering from dementia. Core to its model is the provision of clinical case management, embedded in multidisciplinary dementia care teams. As Geriant's client group includes people from the first presumption of dementia until they can no longer live at home, its care model provides valuable lessons about how different mechanisms of integration are flexibly put to use if the complexity of clients" care needs increases. It showcases how the integration of services for a specific sub-population is combined with alignment of these services with generalist network partners. After a detailed description of the programme and its results, this article builds on the work of Walter Leutz for a conceptual discussion of Geriant's approach to care integration. PMID- 26528096 TI - Integrating care for older people with complex needs: key insights and lessons from a seven-country cross-case analysis. AB - BACKGROUND: To address the challenges of caring for a growing number of older people with a mix of both health problems and functional impairment, programmes in different countries have different approaches to integrating health and social service supports. OBJECTIVE: The goal of this analysis is to identify important lessons for policy makers and service providers to enable better design, implementation and spread of successful integrated care models. METHODS: This paper provides a structured cross-case synthesis of seven integrated care programmes in Australia, Canada, the Netherlands, New Zealand, Sweden, the UK and the USA. KEY FINDINGS: All seven programmes involved bottom-up innovation driven by local needs and included: (1) a single point of entry, (2) holistic care assessments, (3) comprehensive care planning, (4) care co-ordination and (5) a well-connected provider network. The process of achieving successful integration involves collaboration and, although the specific types of collaboration varied considerably across the seven case studies, all involved a care coordinator or case manager. Most programmes were not systematically evaluated but the two with formal external evaluations showed benefit and have been expanded. CONCLUSIONS: Case managers or care coordinators who support patient-centred collaborative care are key to successful integration in all our cases as are policies that provide funds and support for local initiatives that allow for bottom-up innovation. However, more robust and systematic evaluation of these initiatives is needed to clarify the 'business case' for integrated health and social care and to ensure successful generalization of local successes. PMID- 26528097 TI - Micro practices of coordination based on complex adaptive systems: user needs and strategies for coordinating public health in Denmark. AB - INTRODUCTION: Many highly formalised approaches to coordination poorly fit public health and recent studies call for coordination based on complex adaptive systems. Our contribution is two-fold. Empirically, we focus on public health, and theoretically we build on the patient perspective and treat coordination as a process of contingent, two-level negotiations of user needs. THEORY AND METHODS: The paper draws on the concept of user needs-based coordination and sees coordination as a process, whereby needs emerging from the life world of the user are made amenable to the health system through negotiations. The analysis is based on an explorative case study of a health promotion initiative in Denmark. It adopts an anthropological qualitative approach and uses a range of qualitative data. RESULTS: The analysis identifies four strategies of coordination: the coordinator focusing on the individual user or on relations with other professionals; and the manager coaching the coordinator or providing structural support. Crucially, the coordination strategies by management remain weak as they do not directly relate to specific user needs. DISCUSSION: In process of bottom up negotiations user needs become blurred and this is especially a challenge for management. The study therefore calls for an increased focus on the level nature of negotiations to bridge the gap that currently weakens coordination strategies by management. PMID- 26528098 TI - Parents' perspectives of the transition to home when a child has complex technological health care needs. AB - INTRODUCTION: There is an increasing number of children with complex care needs, however, there is limited evidence of the experience of families during the process of transitioning to becoming their child's primary care giver. The aim of this study was to explore parents' perspectives of the transition to home of a child with complex respiratory health care needs. METHODS: Parents of children with a tracheostomy with or without other methods of respiratory assistance, who had transitioned to home from a large children's hospital in the last 5 years, were invited to participate in the interviews. Voice-centred relational method of qualitative analysis was used to analyse parent responses. RESULTS: Four key themes emerged from the interviews including "stepping stones: negotiating the move to home", "fighting and frustration", "questioning competence" and "coping into the future". DISCUSSION: There is a need for clear and equitable assessments and shared policies and protocols for the discharge of children with complex care needs. Direction and support are required at the level of health service policy and planning to redress these problems. This study provides evidence that the transition of children with complex care needs from hospital to home is a challenging dynamic in need of further improvement and greater negotiation between the parent and health service provider. There are tangible issues that could be addressed including the introduction of a standardised approach to assessment of the needs of the child and family in preparation for discharge and for clear timelines and criteria for reassessment of needs once at home. PMID- 26528099 TI - Institutional framework for integrated Pharmaceutical Benefits Management: results from a systematic review. AB - OBJECTIVES: In this paper, we emphasised that effective management of health plans beneficiaries access to reimbursed medicines requires proper institutional set-up. The main objective was to identify and recommend an institutional framework of integrated pharmaceutical care providing effective, safe and equitable access to medicines. METHOD: The institutional framework of drug policy was derived on the basis of publications obtained by systematic reviews. A comparative analysis concerning adaptation of coordinated pharmaceutical care services in the USA, the UK, Poland, Italy, Denmark and Germany was performed. RESULTS: While most European Union Member States promote the implementation of selected e-Health tools, like e-Prescribing, these efforts do not necessarily implement an integrated package. There is no single agent who would manage an insured patients' access to medicines and health care in a coordinated manner, thereby increasing the efficiency and safety of drug policy. More attention should be paid by European Union Member States as to how to integrate various e Health tools to enhance benefits to both individuals and societies. One solution could be to implement an integrated "pharmacy benefit management" model, which is well established in the USA and Canada and provides an integrated package of cost containment methods, implemented within a transparent institutional framework and powered by strong motivation of the agent. PMID- 26528100 TI - How should integrated care address the challenge of people with complex health and social care needs? Emerging lessons from international case studies. PMID- 26528101 TI - Development and implementation of an integrated chronic disease model in South Africa: lessons in the management of change through improving the quality of clinical practice. AB - BACKGROUND: South Africa is facing a complex burden of disease arising from a combination of chronic infectious illness and non-communicable diseases. As the burden of chronic diseases (communicable and non-communicable) increases, providing affordable and effective care to the increasing numbers of chronic patients will be an immense challenge. METHODS: The framework recommended by the Medical Research Council of the United Kingdom for the development and evaluation of complex health interventions was used to conceptualise the intervention. The breakthrough series was utilised for the implementation process. These two frameworks were embedded within the clinical practice improvement model that served as the overarching framework for the development and implementation of the model. RESULTS: The Chronic Care Model was ideally suited to improve the facility component and patient experience; however, the deficiencies in other aspects of the health system building blocks necessitated a hybrid model. An integrated chronic disease management model using a health systems approach was initiated across 42 primary health care facilities. The interventions were implemented in a phased approach using learning sessions and action periods to introduce the planned and targeted changes. CONCLUSION: The implementation of the integrated chronic disease management model is feasible at primary care in South Africa provided that systemic challenges and change management are addressed during the implementation process. PMID- 26528102 TI - Pelvic organ prolapse in women: how is it diagnosed and treated currently? AB - The aim of the paper was to summarize the current opinions about the management of pelvic organ prolapse in women. Food and Drug Administration safety announcements from 2008 and 2011 triggered the discussion about the methods of treatment of pelvic organ prolapse and the used materials and a partial return to the methods which had been totally criticized before the implementation of meshes. The decrease in mesh usage is also observed. The studies did not demonstrate the prevalence of any particular surgical procedure. The amount of studies concerning the evaluation and the treatment of pelvic organ prolapse ensures that the quality of care provided to women with urogynecological problems is continuously increasing. PMID- 26528103 TI - Polymorphisms of estrogen metabolism-related genes ESR1, UGT2B17, and UGT1A1 are not associated with osteoporosis in surgically menopausal Japanese women. AB - INTRODUCTION: Bilateral salpingo-oophorectomy (BSO) is a risk factor for osteoporosis. Previous studies have reported an association between genetic polymorphisms and the risk of developing osteoporosis. However, the relationship between osteoporosis and genetic polymorphisms in Japanese women treated with BSO is not well understood. To improve the quality of life for post-BSO patients, it is important to determine the genetic factors that influence their risk for osteoporosis. The aim of this study was to investigate the association between gene variations of estrogen metabolism-related genes and osteoporosis in surgically menopausal patients, which may improve their quality of life. MATERIAL AND METHODS: This study included 203 menopausal women treated with BSO because of gynecologic disorders. One hundred and twenty-six women with artificial (surgical) menopause, who had undergone BSO in the premenopausal period, were compared with 77 women with natural menopause, who had undergone BSO in the postmenopausal period. The women were tested for bone mineral density to diagnose osteoporosis. Polymorphisms of estrogen receptor 1 (ESR1) and UDP-glucuronosyl transferase (UGT) genes UGT2B17 and UGT1A1 were analyzed, and their association with bone mass and osteoporosis was statistically evaluated. RESULTS: No significant association was found between osteoporosis and polymorphisms in ESR1, UGT2B17, or UGT1A1 in both groups, suggesting that BSO might be a more significant physiological factor in influencing bone mass density compared to genetic variations. CONCLUSIONS: These results suggest that the ESR1, UGT2B17, and UGT1A1 polymorphisms are not genetic factors affecting osteoporosis in postmenopausal Japanese women. PMID- 26528104 TI - Comparison of SCORE-predicted risk of death due to cardiovascular events in women before and after menopause. AB - INTRODUCTION: Approximately 55% of women in Europe die from cardiovascular events, mostly as a result of coronary diseases and cerebral stroke. There is a 10-year shift in the cardiovascular risk between women and men. The risk in a 55 year-old female patient is similar to that of a 45-year-old man, thus the risk among women increases rapidly around the age of 50, when menopause prevails to occur. The purpose of the study was to assess and compare the SCORE-predicted risk of a fatal cardiovascular incident in pre- and postmenopausal women. MATERIAL AND METHODS: The cross-sectional study was conducted as part of community nursing practice. It covered 219 women - inhabitants of Krakow, aged from 30 to 65, without clinically validated cardiovascular diseases of arteriosclerotic and/or diabetic origin, who volunteered to take part in the study. The group was divided into three subgroups: K1 - menstruating women (n = 113), K2a - women after natural menopause (n = 88), and K2b - women after surgical menopause (n = 18). The study made use of a lifestyle questionnaire, which concerned the social and economic status, and lifestyle habits including tobacco smoking. Arterial blood pressure was measured, and total cholesterol concentration in blood (mmol/l) was recorded. RESULTS: A high (>= 5%) level of the SCORE risk was discovered in 14.3% of postmenopausal women, as compared to 0.9% in the group of menstruating women. An average risk of a fatal cardiovascular incident during the following 10 years was significantly higher among women from groups K2a (2.61%) and K2b (2.32%) as compared to K1 - menstruating women (0.38%). No difference was, however, discovered between groups of naturally (K2a) and surgically menopausal women (K2b). CONCLUSIONS: A significantly higher risk of SCORE-predicted death caused by a cardiovascular incident, as compared to the group of women in the premenopausal period, is characteristic of women in the postmenopausal period. PMID- 26528105 TI - Risk factors for disease progression in HER2-positive breast cancer patients based on the location of metastases. AB - INTRODUCTION: Trastuzumab therapy significantly improves progression-free and overall survival in HER2-positive [HER2(+)] breast cancer (BC) patients. However, in most patients with HER2(+) metastatic BC, the disease progress occurred. The aim of this study was to evaluate the clinicopathological risk factors for progression in HER2-positive breast cancer patients during trastuzumab therapy. MATERIAL AND METHODS: The analysis included medical records of HER2(+) metastatic BC patients treated with trastuzumab between 2006 and 2013. RESULTS: The most common site of progression during trastuzumab therapy were lungs 25 (39%), central nervous system (CNS) 8 (13%), skin 9 (14%), locoregional lymph nodes 19 (30%), liver 18 (28%) and bone 17 (27%). Patients with lung metastases significantly more often had a history of cancer in the family than women with other metastasis sites (24% vs. 2.6%), p = 0.048. Metastases to lungs occurred also more often during therapy containing trastuzumab with chemotherapy than trastuzumab alone 17/8 (58% vs. 41%), p = 0.043. Central nervous system metastases were observed insignificantly more frequently in postmenopausal women than premenopausal patients 8/0 (22% vs. 0%), p = 0.093. There was reported a tendency to liver metastases in ER-negative tumors 13/20 (72% vs. 44%, p = 0.053). Bone metastases were associated with the positive steroid receptor status (p = 0.019) and second neoplasm in history (p = 0.06). CONCLUSIONS: Risk factors for disease progression were the menopausal status (CNS metastases), steroid receptor status (liver, lymph nodes and bone metastases), history of cancer in the family (lung metastases) and history of cigarette smoking (liver metastases). PMID- 26528106 TI - Coping with stress and quality of life in women with stress urinary incontinence. AB - INTRODUCTION: Urinary incontinence (UI) involves uncontrolled leakage of urine through the urethra as a result of damage to its sphincter muscle and a disturbed function of the urogenital diaphragm within the pelvis minor. The symptoms of UI radically impair psychological, somatic, and social functioning. The aim of each disease stress coping process is to reduce the impact of harmful agents as well as the acquisition of necessary preventive measures in order to combat the disorder. Aim of the study was to assess the relationship between coping styles used when dealing with stress associated with disease and the quality of life. MATERIAL AND METHODS: The study was carried out at an outpatients' clinic located in the Lublin Province (eastern Poland), covering 150 women with diagnosed stress urinary incontinence, aged between 32 and 79. The following methods were used: (a) Coping Inventory for Stressful Situations (Endler, Parker) to assess coping styles, (b) CASP-19 scale (Higgins, Hyde, Wiggins, Blade) to measure the overall quality of life, and (c) Urinary Incontinence Life Quality Scale (Szymona Palkowska, Kraczkowski). RESULTS: The preferred style in the studied group of women was Task-Oriented Coping. This style is associated with a low score on the Independence from Symptoms scale and low Control, being simultaneously correlated with Autonomy and Self-Realisation. Emotion-Oriented Coping is associated with low psychological, physical and social well-being, as well as with little independence from the disease symptoms, little pleasure and self-realisation, but it gives a sense of internal control. Avoidance-Oriented Coping does not significantly correlate with any of the Overall Quality of Life dimensions. CONCLUSIONS: Women suffering from UI tend to try to solve their problem by means of cognitive transformation. In their situation, clinging to the problem turns out to be a depressing factor and entails a lower quality of their life. PMID- 26528107 TI - Effects of selected factors on the osseointegration of dental implants. AB - INTRODUCTION: Osseointegration of dental implants with the maxillary and/or mandibular bone is the basis for implant prosthetic treatment. The aim of the study was to assess the influence of the patients' gender, age, and in the case of women, their menopausal status (before menopause/after menopause/during hormone replacement therapy) on the osseointegration of dental implants. MATERIAL AND METHODS: The study evaluated the bone loss after implant loading and the success rate of the procedure in 71 women and 30 men. In the postmenopausal group, 20 (28.1%) women were receiving hormone replacement therapy. The implants used in the treatment of the studied patients were the two-phase dental implants. The extent of bone loss was estimated by comparing the post-implantation radiographs and the post-loading ones. RESULTS: The implantation procedure was entirely successful in 81 patients (80.2%). The patients' age, gender and menopausal status did not significantly affect the implantation procedure success rate or bone loss (p > 0.05). A correlation between bone loss and hormone replacement therapy (p = 0.002) was found. CONCLUSIONS: The hormone replacement therapy contributes to a greater peri-implant bone loss. The patients receiving hormone replacement therapy who consider replacement of missing teeth with implants should be informed about a greater risk of osseointegration failure, which may affect the success of implant therapy. PMID- 26528108 TI - Unexpected premalignant gynecological lesions in women undergoing vaginal hysterectomy for utero-vaginal prolapse. AB - AIM OF THE STUDY: Aim of the study was to estimate the incidence of unexpected premalignant gynecological lesions in women undergoing vaginal hysterectomy for utero-vaginal prolapse. MATERIAL AND METHODS: Eighty women with asymptomatic utero-vaginal prolapse were included in this prospective study for vaginal hysterectomy after preoperative preparation and after written informed consent. Women included in this study were screened preoperatively by high vaginal swab, Pap smear, endometrial biopsy and trans-vaginal ultrasound. Surgically removed uteri and ovaries were sent for histopathological examination. Results of histopathological examination as gold standard were compared with conventional gynecological screening methods. RESULTS: Histopathological examination of surgically removed uteri and ovaries after vaginal hysterectomy for uterovaginal prolapse showed abnormal findings in 61.25% (49/80) of studied cases (10 chronic cervicitis; 20 cervical intra-epithelial neoplasia-1 [CIN-1]; 5 CIN-2; 2 CIN-3; 10 simple endometrial hyperplasia without atypia and 2 simple serous ovarian cyst). Also, histopathological examination showed premalignant changes in 33.75% (27/80) of studied cases (20 CIN-1; 5 CIN-2 and 2 CIN-3), which mean 50% sensitivity of pre-operative Pap smear to detect premalignant cervical changes. CONCLUSIONS: Asymptomatic women with utero-vaginal prolapse may have associated premalignant lesions which may not be detected by conventional screening methods, and this should be explained preoperatively for women undergoing surgery, especially if conservative management was considered. PMID- 26528109 TI - Endometrial and cervical cancer: incidence and mortality among women in the Lodz region. AB - INTRODUCTION: By the early 21(st) century the most common cancer of female genitals in Poland was cervical cancer. Now endometrial cancer ranks first. The aim of this study was to analyse the incidence and mortality of endometrial and cervical cancer among women in the Lodz region. MATERIAL AND METHODS: Data on the incidence and mortality of endometrial and cervical cancer among inhabitants of the Lodz region were obtained from the National Cancer Registry and Bulletin of Cancer Cases in the Lodz region. The analysis covered ten consecutive years beginning in 2001. RESULTS: The number of new cases reported in 2010 exceeded that observed in 2001 by 181. The standardized incidence rate of endometrial cancer increased by 6.3, while the standardized incidence rate of cervical cancer decreased by 1.4. CONCLUSIONS: In the years 2001-2010, the incidence of endometrial cancer increased by 88.3% and that of cervical cancer decreased by 6.5% among inhabitants of the Lodz region. In the years 2001-2010, mortality of endometrial cancer increased by 24.5% and that of cervical cancer decreased by 12.6%. In 2010, the highest crude incidence rates in the Lodz region of both endometrial and cervical cancer at 39.1 were recorded in the district town of Piotrkow. PMID- 26528110 TI - Breast cancer risk factors. AB - Breast cancer is the most frequently diagnosed neoplastic disease in women around menopause often leading to a significant reduction of these women's ability to function normally in everyday life. The increased breast cancer incidence observed in epidemiological studies in a group of women actively participating in social and professional life implicates the necessity of conducting multidirectional studies in order to identify risk factors associated with the occurrence of this type of neoplasm. Taking the possibility of influencing the neoplastic transformation process in individuals as a criterion, all the risk factors initiating the process can be divided into two groups. The first group would include inherent factors such as age, sex, race, genetic makeup promoting familial occurrence of the neoplastic disease or the occurrence of benign proliferative lesions of the mammary gland. They all constitute independent parameters and do not undergo simple modification in the course of an individual's life. The second group would include extrinsic factors conditioned by lifestyle, diet or long-term medical intervention such as using oral hormonal contraceptives or hormonal replacement therapy and their influence on the neoplastic process may be modified to a certain degree. Identification of modifiable factors may contribute to development of prevention strategies decreasing breast cancer incidence. PMID- 26528111 TI - Low back pain in women before and after menopause. AB - Low back pain is a massive problem in modern population, both in social and economic terms. It affects large numbers of women, especially those aged 45-60. Going through a perimenopausal period is associated with many symptoms, including low back pain. This paper is a review of published research on the association between the perimenopausal age and low back pain. PubMed databases were investigated. After the search was narrowed to "menopausal status, back pain", 35 studies were found. Seven studies, which suited our area of research best, were thoroughly analyzed. All studies show increased pain when women enter this period of their life. There is no agreement among researchers regarding which stage of menopause is the most burdensome. Examples of possible treatments and physiotherapeutic methods targeting low back pain are also presented. Physiotherapeutic procedures used to treat low back pain include exercises in safe positions, balance exercises, manual therapy, massage and physical measures. PMID- 26528112 TI - Vaginal foreign body mimicking cervical cancer in postmenopausal woman - case study. AB - We present a case report of a 73-year-old, postmenopausal woman with detailed history of breast cancer and oncology treatment including tamoxifen therapy. She presented at the clinic of gynecology and obstetrics with recurrent inflammation of the urinary and genital tract and suspicion of a cervical mass. She also presented occasional abdominal complaints and malodorous vaginal discharge. These symptoms were observed in the patient for several years. Before hospitalization she received many kinds of empirical, antimicrobial treatment such as chlorquinaldol, metronidazole, nifuratel, and nystatin. She did not receive further guidance from doctors about the causes of ailments and further diagnostic and treatment capabilities. In our clinic a detailed diagnostic process including ultrasound transvaginal examination and a minisurgical procedure revealed the presence of a vaginal foreign body (which turned out to be a plastic, shampoo bottle cap) surrounded by a mass of inflamed tissue mimicking a cervical tumor. All symptoms and complaints subsided after surgical removal of the foreign body and antibacterial therapy with metronidazole and cefuroxime. Our study draws attention to the need of thorough gynecological care including prophylaxis, especially in the case of complaints of an intimate nature. Even trivial, frequently occurring disorders can be dangerous and require proper and responsible doctor's supervision and management through the healing process. PMID- 26528113 TI - Reconstruction of audio waveforms from spike trains of artificial cochlea models. AB - Spiking cochlea models describe the analog processing and spike generation process within the biological cochlea. Reconstructing the audio input from the artificial cochlea spikes is therefore useful for understanding the fidelity of the information preserved in the spikes. The reconstruction process is challenging particularly for spikes from the mixed signal (analog/digital) integrated circuit (IC) cochleas because of multiple non-linearities in the model and the additional variance caused by random transistor mismatch. This work proposes an offline method for reconstructing the audio input from spike responses of both a particular spike-based hardware model called the AEREAR2 cochlea and an equivalent software cochlea model. This method was previously used to reconstruct the auditory stimulus based on the peri-stimulus histogram of spike responses recorded in the ferret auditory cortex. The reconstructed audio from the hardware cochlea is evaluated against an analogous software model using objective measures of speech quality and intelligibility; and further tested in a word recognition task. The reconstructed audio under low signal-to-noise (SNR) conditions (SNR < -5 dB) gives a better classification performance than the original SNR input in this word recognition task. PMID- 26528114 TI - Neuroprotective therapies in glaucoma: II. Genetic nanotechnology tools. AB - Neurotrophic factor genome engineering could have many potential applications not only in the deeper understanding of neurodegenerative disorders but also in improved therapeutics. The fields of nanomedicine, regenerative medicine, and gene/cell-based therapy have been revolutionized by the development of safer and efficient non-viral technologies for gene delivery and genome editing with modern techniques for insertion of the neurotrophic factors into clinically relevant cells for a more sustained pharmaceutical effect. It has been suggested that the long-term expression of neurotrophic factors is the ultimate approach to prevent and/or treat neurodegenerative disorders such as glaucoma in patients who do not respond to available treatments or are at the progressive stage of the disease. Recent preclinical research suggests that novel neuroprotective gene and cell therapeutics could be promising approaches for both non-invasive neuroprotection and regenerative functions in the eye. Several progenitor and retinal cell types have been investigated as potential candidates for glaucoma neurotrophin therapy either as targets for gene therapy, options for cell replacement therapy, or as vehicles for gene delivery. Therefore, in parallel with deeper understanding of the specific protective effects of different neurotrophic factors and the potential therapeutic cell candidates for glaucoma neuroprotection, the development of non-invasive and highly specific gene delivery methods with safe and effective technologies to modify cell candidates for life-long neuroprotection in the eye is essential before investing in this field. PMID- 26528115 TI - A method for electrophysiological characterization of hamster retinal ganglion cells using a high-density CMOS microelectrode array. AB - Knowledge of neuronal cell types in the mammalian retina is important for the understanding of human retinal disease and the advancement of sight-restoring technology, such as retinal prosthetic devices. A somewhat less utilized animal model for retinal research is the hamster, which has a visual system that is characterized by an area centralis and a wide visual field with a broad binocular component. The hamster retina is optimally suited for recording on the microelectrode array (MEA), because it intrinsically lies flat on the MEA surface and yields robust, large-amplitude signals. However, information in the literature about hamster retinal ganglion cell functional types is scarce. The goal of our work is to develop a method featuring a high-density (HD) complementary metal-oxide-semiconductor (CMOS) MEA technology along with a sequence of standardized visual stimuli in order to categorize ganglion cells in isolated Syrian Hamster (Mesocricetus auratus) retina. Since the HD-MEA is capable of recording at a higher spatial resolution than most MEA systems (17.5 MUm electrode pitch), we were able to record from a large proportion of RGCs within a selected region. Secondly, we chose our stimuli so that they could be run during the experiment without intervention or computation steps. The visual stimulus set was designed to activate the receptive fields of most ganglion cells in parallel and to incorporate various visual features to which different cell types respond uniquely. Based on the ganglion cell responses, basic cell properties were determined: direction selectivity, speed tuning, width tuning, transience, and latency. These properties were clustered to identify ganglion cell types in the hamster retina. Ultimately, we recorded up to a cell density of 2780 cells/mm(2) at 2 mm (42 degrees ) from the optic nerve head. Using five parameters extracted from the responses to visual stimuli, we obtained seven ganglion cell types. PMID- 26528116 TI - Divergent evolution of two corticotropin-releasing hormone (CRH) genes in teleost fishes. AB - Genome duplication, thought to have happened twice early in vertebrate evolution and a third time in teleost fishes, gives rise to gene paralogs that can evolve subfunctions or neofunctions via sequence and regulatory changes. To explore the evolution and functions of corticotropin-releasing hormone (CRH), we searched sequenced teleost genomes for CRH paralogs. Our phylogenetic and synteny analyses indicate that two CRH genes, crha and crhb, evolved via duplication of crh1 early in the teleost lineage. We examined the expression of crha and crhb in two teleost species from different orders: an African cichlid, Burton's mouthbrooder, (Astatotilapia burtoni; Order Perciformes) and zebrafish (Danio rerio; Order Cypriniformes). Furthermore, we compared expression of the teleost crha and crhb genes with the crh1 gene of an outgroup to the teleost clade: the spotted gar (Lepisosteus oculatus). In situ hybridization for crha and crhb mRNA in brains and eyes revealed distinct expression patterns for crha in different teleost species. In the cichlid, crha mRNA was found in the retina but not in the brain. In zebrafish, however, crha mRNA was not found in the retina, but was detected in the brain, restricted to the ventral hypothalamus. Spotted gar crh1 was found in the retina as well as the brain, suggesting that the ancestor of teleost fishes likely had a crh1 gene expressed in both retina and brain. Thus, genome duplication may have freed crha from constraints, allowing it to evolve distinct sequences, expression patterns, and likely unique functions in different lineages. PMID- 26528117 TI - Estimating multivariate similarity between neuroimaging datasets with sparse canonical correlation analysis: an application to perfusion imaging. AB - An increasing number of neuroimaging studies are based on either combining more than one data modality (inter-modal) or combining more than one measurement from the same modality (intra-modal). To date, most intra-modal studies using multivariate statistics have focused on differences between datasets, for instance relying on classifiers to differentiate between effects in the data. However, to fully characterize these effects, multivariate methods able to measure similarities between datasets are needed. One classical technique for estimating the relationship between two datasets is canonical correlation analysis (CCA). However, in the context of high-dimensional data the application of CCA is extremely challenging. A recent extension of CCA, sparse CCA (SCCA), overcomes this limitation, by regularizing the model parameters while yielding a sparse solution. In this work, we modify SCCA with the aim of facilitating its application to high-dimensional neuroimaging data and finding meaningful multivariate image-to-image correspondences in intra-modal studies. In particular, we show how the optimal subset of variables can be estimated independently and we look at the information encoded in more than one set of SCCA transformations. We illustrate our framework using Arterial Spin Labeling data to investigate multivariate similarities between the effects of two antipsychotic drugs on cerebral blood flow. PMID- 26528118 TI - Mild traumatic brain injury and delayed alteration of memory processing. PMID- 26528119 TI - Reconstruction of human brain spontaneous activity based on frequency-pattern analysis of magnetoencephalography data. AB - A new method for the analysis and localization of brain activity has been developed, based on multichannel magnetic field recordings, over minutes, superimposed on the MRI of the individual. Here, a high resolution Fourier Transform is obtained over the entire recording period, leading to a detailed multi-frequency spectrum. Further analysis implements a total decomposition of the frequency components into functionally invariant entities, each having an invariant field pattern localizable in recording space. The method, addressed as functional tomography, makes it possible to find the distribution of magnetic field sources in space. Here, the method is applied to the analysis of simulated data, to oscillating signals activating a physical current dipoles phantom, and to recordings of spontaneous brain activity in 10 healthy adults. In the analysis of simulated data, 61 dipoles are localized with 0.7 mm precision. Concerning the physical phantom the method is able to localize three simultaneously activated current dipoles with 1 mm precision. Spatial resolution 3 mm was attained when localizing spontaneous alpha rhythm activity in 10 healthy adults, where the alpha peak was specified for each subject individually. Co-registration of the functional tomograms with each subject's head MRI localized alpha range activity to the occipital and/or posterior parietal brain region. This is the first application of this new functional tomography to human brain activity. The method successfully provides an overall view of brain electrical activity, a detailed spectral description and, combined with MRI, the localization of sources in anatomical brain space. PMID- 26528120 TI - Benchmarking neuromorphic vision: lessons learnt from computer vision. AB - Neuromorphic Vision sensors have improved greatly since the first silicon retina was presented almost three decades ago. They have recently matured to the point where they are commercially available and can be operated by laymen. However, despite improved availability of sensors, there remains a lack of good datasets, while algorithms for processing spike-based visual data are still in their infancy. On the other hand, frame-based computer vision algorithms are far more mature, thanks in part to widely accepted datasets which allow direct comparison between algorithms and encourage competition. We are presented with a unique opportunity to shape the development of Neuromorphic Vision benchmarks and challenges by leveraging what has been learnt from the use of datasets in frame based computer vision. Taking advantage of this opportunity, in this paper we review the role that benchmarks and challenges have played in the advancement of frame-based computer vision, and suggest guidelines for the creation of Neuromorphic Vision benchmarks and challenges. We also discuss the unique challenges faced when benchmarking Neuromorphic Vision algorithms, particularly when attempting to provide direct comparison with frame-based computer vision. PMID- 26528121 TI - The effect of precision and power grips on activations in human auditory cortex. AB - The neuroanatomical pathways interconnecting auditory and motor cortices play a key role in current models of human auditory cortex (AC). Evidently, auditory motor interaction is important in speech and music production, but the significance of these cortical pathways in other auditory processing is not well known. We investigated the general effects of motor responding on AC activations to sounds during auditory and visual tasks (motor regions were not imaged). During all task blocks, subjects detected targets in the designated modality, reported the relative number of targets at the end of the block, and ignored the stimuli presented in the opposite modality. In each block, they were also instructed to respond to targets either using a precision grip, power grip, or to give no overt target responses. We found that motor responding strongly modulated AC activations. First, during both visual and auditory tasks, activations in widespread regions of AC decreased when subjects made precision and power grip responses to targets. Second, activations in AC were modulated by grip type during the auditory but not during the visual task. Further, the motor effects were distinct from the present strong attention-related modulations in AC. These results are consistent with the idea that operations in AC are shaped by its connections with motor cortical regions. PMID- 26528122 TI - Angiotensin II-superoxide-NFkappaB signaling and aortic baroreceptor dysfunction in chronic heart failure. AB - Chronic heart failure (CHF) affects approximately 5.7 million people in the United States. Increasing evidence from both clinical and experimental studies indicates that the sensitivity of arterial baroreflex is blunted in the CHF state, which is a predictive risk factor for sudden cardiac death. Normally, the arterial baroreflex regulates blood pressure and heart rate through sensing mechanical alteration of arterial vascular walls by baroreceptor terminals in the aortic arch and carotid sinus. There are aortic baroreceptor neurons in the nodose ganglion (NG), which serve as the main afferent component of the arterial baroreflex. Functional changes of baroreceptor neurons are involved in the arterial baroreflex dysfunction in CHF. In the CHF state, circulating angiotensin II (Ang II) and local Ang II concentration in the NG are elevated, and AT1R mRNA and protein are overexpressed in the NG. Additionally, Ang II-superoxide-NFkappaB signaling pathway regulates the neuronal excitability of aortic baroreceptors through influencing the expression and activation of Nav channels in aortic baroreceptors, and subsequently causes the impairment of the arterial baroreflex in CHF. These new findings provide a basis for potential pharmacological interventions for the improvement of the arterial baroreflex sensitivity in the CHF state. This review summarizes the mechanisms responsible for the arterial baroreflex dysfunction in CHF. PMID- 26528123 TI - Identification of functional networks in resting state fMRI data using adaptive sparse representation and affinity propagation clustering. AB - Human brain functional system has been viewed as a complex network. To accurately characterize this brain network, it is important to estimate the functional connectivity between separate brain regions (i.e., association matrix). One common approach to evaluating the connectivity is the pairwise Pearson correlation. However, this bivariate method completely ignores the influence of other regions when computing the pairwise association. Another intractable issue existed in many approaches to further analyzing the network structure is the requirement of applying a threshold to the association matrix. To address these issues, we develop a novel scheme to investigate the brain functional networks. Specifically, we first establish a global functional connection network by using the Adaptive Sparse Representation (ASR), adaptively integrating the sparsity of l1-norm and the grouping effect of l2-norm for linear representation and then identify connectivity patterns with Affinity Propagation (AP) clustering algorithm. Results on both simulated and real data indicate that the proposed scheme is superior to the Pearson correlation in connectivity quality and clustering quality. Our findings suggest that the proposed scheme is an accurate and useful technique to delineate functional network structure for functionally parsimonious and correlated fMRI data with a large number of brain regions. PMID- 26528124 TI - miRNAs: biological and clinical determinants in epilepsy. AB - Recently, microRNAs (miRNAs) are reported to be crucial modulators in the pathogenesis and potential treatment of epilepsies. To date, several miRNAs have been demonstrated to be significantly expressed in the epileptic tissues and strongly associated with the development of epilepsy. Specifically, miRNAs regulate synaptic strength, inflammation, neuronal and glial function, ion channels, and apoptosis. Furthermore, peripheral blood miRNAs can also be utilized as diagnostic biomarkers to assess disease risk and treatment responses. Here, we will summarize the recent available literature regarding the role of miRNAs in the pathogenesis and treatment of epilepsy. Moreover, we will provide brief insight into the potential of miRNA as diagnostic biomarkers for early diagnosis and prognosis of epilepsy. PMID- 26528125 TI - Ubiquitin-dependent trafficking and turnover of ionotropic glutamate receptors. AB - Changes in synaptic strength underlie the basis of learning and memory and are controlled, in part, by the insertion or removal of AMPA-type glutamate receptors at the postsynaptic membrane of excitatory synapses. Once internalized, these receptors may be recycled back to the plasma membrane by subunit-specific interactions with other proteins or by post-translational modifications such as phosphorylation. Alternatively, these receptors may be targeted for destruction by multiple degradation pathways in the cell. Ubiquitination, another post translational modification, has recently emerged as a key signal that regulates the recycling and trafficking of glutamate receptors. In this review, we will discuss recent findings on the role of ubiquitination in the trafficking and turnover of ionotropic glutamate receptors and plasticity of excitatory synapses. PMID- 26528126 TI - Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice. AB - Amyloidopathy involves the accumulation of insoluble amyloid beta (Abeta) species in the brain's parenchyma and is a key histopathological hallmark of Alzheimer's disease (AD). Work on transgenic mice that overexpress Abeta suggests that elevated Abeta levels in the brain are associated with aberrant epileptiform activity and increased intrinsic excitability (IE) of CA1 hippocampal neurons. In this study we examined if similar changes could be observed in hippocampal CA1 pyramidal neurons from aged PDAPP mice (20-23 month old, Indiana mutation: V717F on APP gene) compared to their age-matched wild-type littermate controls. Whole cell current clamp recordings revealed that sub-threshold intrinsic properties, such as input resistance, resting membrane potential and hyperpolarization activated "sag" were unaffected, but capacitance was significantly decreased in the transgenic animals. No differences between genotypes were observed in the overall number of action potentials (AP) elicited by 500 ms supra-threshold current stimuli. PDAPP neurons, however, exhibited higher instantaneous firing frequencies after accommodation in response to high intensity current injections. The AP waveform was narrower and shorter in amplitude in PDAPP mice: these changes, according to our in silico model of a CA1/3 pyramidal neuron, depended on the respective increase and reduction of K(+) and Na(+) voltage-gated channels maximal conductances. Finally, the after-hyperpolarization, seen after the first AP evoked by a +300 pA current injection and after 50 Hz AP bursts, was more pronounced in PDAPP mice. These data show that Abeta-overexpression in aged mice altered the capacitance, the neuronal firing and the AP waveform of CA1 pyramidal neurons. Some of these findings are consistent with previous work on younger PDAPP; they also show important differences that can be potentially ascribed to the interaction between amyloidopathy and ageing. Such a change of IE properties over time underlies that the increased incidence of seizure observed in AD patients might rely on different mechanistic pathways during progression of the disease. PMID- 26528127 TI - Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia. AB - Many encoded gene products responsible for neurodevelopmental disorders (NDs) like autism spectrum disorders (ASD), schizophrenia (SCZ), intellectual disability (ID), and idiopathic generalized epilepsy (IGE) converge on networks controlling synaptic function. An increase in KCC2 (SLC12A5) Cl(-) transporter activity drives the developmental GABA excitatory-inhibitory sequence, but the role of KCC2 in human NDs is essentially unknown. Here, we report two rare, non synonymous (NS), functionally-impairing variants in the KCC2 C-terminal regulatory domain (CTRD) in human ASD (R952H and R1049C) and SCZ (R952H) previously linked with IGE and familial febrile seizures, and another novel NS KCC2 variant in ASD (R1048W) with highly-predicted pathogenicity. Exome data from 2517 simplex families in the ASD Simon Simplex Collection (SSC) revealed significantly more KCC2 CTRD variants in ASD cases than controls, and interestingly, these were more often synonymous and predicted to disrupt or introduce a CpG site. Furthermore, full gene analysis showed ASD cases are more likely to contain rare KCC2 variants affecting CpG sites than controls. These data suggest genetically-encoded dysregulation of KCC2-dependent GABA signaling may contribute to multiple human NDs. PMID- 26528130 TI - Combination Low-Dose Tissue-Type Plasminogen Activator Plus Annexin A2 for Improving Thrombolytic Stroke Therapy. AB - Risk of hemorrhagic transformation, incomplete reperfusion, neurotoxicity, and a short treatment time window comprises major challenges for tissue plasminogen activator (tPA) thrombolytic stroke therapy. Improving tPA therapy has become one of the highest priorities in the stroke field. This mini review article focuses on our recent efforts aimed at evaluating a novel combination approach of low dose tPA plus recombinant annexin A2 (rA2, a tPA, and plasminogen co-receptor), which might enhance tPA thrombolytic efficacy, while reducing its associated complications related to intracerebral hemorrhagic transformation. Results of our experimental studies using a focal embolic stroke model in rats support the feasibility of the combination approach and suggest the potential for successful clinical translation. PMID- 26528129 TI - Physiological and pathological roles of tissue plasminogen activator and its inhibitor neuroserpin in the nervous system. AB - Although its roles in the vascular space are most well-known, tissue plasminogen activator (tPA) is widely expressed in the developing and adult nervous system, where its activity is believed to be regulated by neuroserpin, a predominantly brain-specific member of the serpin family of protease inhibitors. In the normal physiological state, tPA has been shown to play roles in the development and plasticity of the nervous system. Ischemic damage, however, may lead to excess tPA activity in the brain and this is believed to contribute to neurodegeneration. In this article, we briefly review the physiological and pathological roles of tPA in the nervous system, which includes neuronal migration, axonal growth, synaptic plasticity, neuroprotection and neurodegeneration, as well as a contribution to neurological disease. We summarize tPA's multiple mechanisms of action and also highlight the contributions of the inhibitor neuroserpin to these processes. PMID- 26528131 TI - Does non-invasive brain stimulation applied over the dorsolateral prefrontal cortex non-specifically influence mood and emotional processing in healthy individuals? AB - The dorsolateral prefrontal cortex (DLPFC) is often targeted with non-invasive brain stimulation (NIBS) to modulate in vivo human behaviors. This brain region plays a key role in mood, emotional processing, and attentional processing of emotional information. In this article, we ask the question: when we target the DLPFC with NIBS, do we modulate these processes altogether, non-specifically, or can we modulate them selectively? We thus review articles investigating the effects of NIBS applied over the DLPFC on mood, emotional processing, and attentional processing of emotional stimuli in healthy subjects. We discuss that NIBS over the DLPFC can modulate emotional processing and attentional processing of emotional stimuli, without specifically influencing mood. Indeed, there seems to be a lack of evidence that NIBS over the DLPFC influences mood in healthy individuals. Finally, there appears to be a hemispheric lateralization: when applied over the left DLPFC, NIBS improved processing of positive stimuli and reduced selective attention for stimuli expressing anger, whereas when applied over the right DLPFC, it increased selective attention for stimuli expressing anger. PMID- 26528132 TI - Editorial: Single membrane channels formed by connexins or pannexins: focus on the nervous system. PMID- 26528133 TI - Neuron-macrophage crosstalk in the intestine: a "microglia" perspective. AB - Intestinal macrophages are strategically located in different layers of the intestine, including the mucosa, submucosa and muscularis externa, where they perform complex tasks to maintain intestinal homeostasis. As the gastrointestinal tract is continuously challenged by foreign antigens, macrophage activation should be tightly controlled to prevent chronic inflammation and tissue damage. Unraveling the precise cellular and molecular mechanisms underlying the tissue specific control of macrophage activation is crucial to get more insight into intestinal immune regulation. Two recent reports provide unanticipated evidence that the enteric nervous system (ENS) acts as a critical regulator of macrophage function in the myenteric plexus. Both studies clearly illustrate that enteric neurons reciprocally interact with intestinal macrophages and are actively involved in shaping their phenotype. This concept has striking parallels with the central nervous system (CNS), where neuronal signals maintain microglia, the resident macrophages of the CNS, in a quiescent, anti-inflammatory state. This inevitably evokes the perception that the ENS and CNS share mechanisms of neuroimmune interaction. In line, intestinal macrophages, both in the muscularis externa and (sub)mucosa, express high levels of CX3CR1, a feature that was once believed to be unique for microglia. CX3CR1 is the sole receptor of fractalkine (CX3CL1), a factor mainly produced by neurons in the CNS to facilitate neuron microglia communication. The striking parallels between resident macrophages of the brain and intestine might provide a promising new line of thought to get more insight into cellular and molecular mechanisms controlling macrophage activation in the gut. PMID- 26528128 TI - Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. AB - The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress-related psychiatric disorders, but also their treatment. Thus the gut microbiome and its influence on host barrier function is positioned to be a critical node within the brain-gut axis. Mounting preclinical evidence broadly suggests that the gut microbiota can modulate brain development, function and behavior by immune, endocrine and neural pathways of the brain-gut-microbiota axis. Detailed mechanistic insights explaining these specific interactions are currently underdeveloped. However, the concept that a "leaky gut" may facilitate communication between the microbiota and these key signaling pathways has gained traction. Deficits in intestinal permeability may underpin the chronic low-grade inflammation observed in disorders such as depression and the gut microbiome plays a critical role in regulating intestinal permeability. In this review we will discuss the possible role played by the gut microbiota in maintaining intestinal barrier function and the CNS consequences when it becomes disrupted. We will draw on both clinical and preclinical evidence to support this concept as well as the key features of the gut microbiota which are necessary for normal intestinal barrier function. PMID- 26528134 TI - Investigating the cortical regions involved in MEP modulation in tDCS. AB - Transcranial magnetic stimulation (TMS) is used in several studies to evaluate cortical excitability changes induced by transcranial direct current stimulation (tDCS) of the primary motor cortex. Interpretation of these results, however, is hindered by the very different spatial distribution of the electric field (E field) induced by the two techniques and by the different target neurons that they might act upon. In this study we used the finite element method to calculate the E-field distribution induced by TMS and tDCS in a realistically shaped model of a human head. A model of a commercially available figure-8 coil was placed over a position above the identified hand knob (HK) region. We also modeled two configurations of bipolar tDCS montages with one of the electrodes placed over the HK and a return electrode over the contralateral orbital region. The electrodes over the HK were either rectangular in shape, with an area of 35 cm(2) or cylindrical with an area of pi cm(2) (1 cm radius). To compare the E-field distribution in TMS and the two tDCS models, average values of the E-field's magnitude as well as the polar and azimuthal angle were investigated in the HK region and premotor areas. The results show that both techniques induce fields with different magnitudes and directions in the HK: the field in tDCS is predominantly perpendicular to the cortical surface, contrary to what happens in TMS where the field is mostly parallel to it. In the premotor areas, the magnitude of the E-field induced in TMS was well below the accepted threshold for MEP generation, 100 V/m. In tDCS, the magnitude of the field in these areas was comparable to that induced at the HK with a significant component perpendicular to the cortical surface. These results indicate that tDCS and TMS target preferentially different neuronal structures at the HK. Besides, they show that premotor areas may play a role in the tDCS-induced after effects on motor cortex excitability. PMID- 26528135 TI - X MARCKS the spot: myristoylated alanine-rich C kinase substrate in neuronal function and disease. AB - Intracellular protein-protein interactions are dynamic events requiring tightly regulated spatial and temporal checkpoints. But how are these spatial and temporal cues integrated to produce highly specific molecular response patterns? A helpful analogy to this process is that of a cellular map, one based on the fleeting localization and activity of various coordinating proteins that direct a wide array of interactions between key molecules. One such protein, myristoylated alanine-rich C-kinase substrate (MARCKS) has recently emerged as an important component of this cellular map, governing a wide variety of protein interactions in every cell type within the brain. In addition to its well-documented interactions with the actin cytoskeleton, MARCKS has been found to interact with a number of other proteins involved in processes ranging from intracellular signaling to process outgrowth. Here, we will explore these diverse interactions and their role in an array of brain-specific functions that have important implications for many neurological conditions. PMID- 26528136 TI - Mechanosensitivity in the enteric nervous system. AB - The enteric nervous system (ENS) autonomously controls gut muscle activity. Mechanosensitive enteric neurons (MEN) initiate reflex activity by responding to mechanical deformation of the gastrointestinal wall. MEN throughout the gut primarily respond to compression or stretch rather than to shear force. Some MEN are multimodal as they respond to compression and stretch. Depending on the region up to 60% of the entire ENS population responds to mechanical stress. MEN fire action potentials after mechanical stimulation of processes or soma although they are more sensitive to process deformation. There are at least two populations of MEN based on their sensitivity to different modalities of mechanical stress and on their firing pattern. (1) Rapidly, slowly and ultra slowly adapting neurons which encode compressive forces. (2) Ultra-slowly adapting stretch-sensitive neurons encoding tensile forces. Rapid adaptation of firing is typically observed after compressive force while slow adaptation or ongoing spike discharge occurs often during tensile stress (stretch). All MEN have some common properties: they receive synaptic input, are low fidelity mechanoreceptors and are multifunctional in that some serve interneuronal others even motor functions. Consequently, MEN possess processes with mechanosensitive as well as efferent functions. This raises the intriguing hypothesis that MEN sense and control muscle activity at the same time as servo-feedback loop. The mechanosensitive channel(s) or receptor(s) expressed by the different MEN populations are unknown. Future concepts have to incorporate compressive and tensile-sensitive MEN into neural circuits that controls muscle activity. They may interact to control various forms of a particular motor pattern or regulate different motor patterns independently from each other. PMID- 26528137 TI - Basal adenosine modulates the functional properties of AMPA receptors in mouse hippocampal neurons through the activation of A1R A2AR and A3R. AB - Adenosine is a widespread neuromodulator within the CNS and its extracellular level is increased during hypoxia or intense synaptic activity, modulating pre- and postsynaptic sites. We studied the neuromodulatory action of adenosine on glutamatergic currents in the hippocampus, showing that activation of multiple adenosine receptors (ARs) by basal adenosine impacts postsynaptic site. Specifically, the stimulation of both A1R and A3R reduces AMPA currents, while A2AR has an opposite potentiating effect. The effect of ARs stimulation on glutamatergic currents in hippocampal cultures was investigated using pharmacological and genetic approaches. A3R inhibition by MRS1523 increased GluR1 Ser845 phosphorylation and potentiated AMPA current amplitude, increasing the apparent affinity for the agonist. A similar effect was observed blocking A1R with DPCPX or by genetic deletion of either A3R or A1R. Conversely, impairment of A2AR reduced AMPA currents, and decreased agonist sensitivity. Consistently, in hippocampal slices, ARs activation by AR agonist NECA modulated glutamatergic current amplitude evoked by AMPA application or afferent fiber stimulation. Opposite effects of AR subtypes stimulation are likely associated to changes in GluR1 phosphorylation and represent a novel mechanism of physiological modulation of glutamatergic transmission by adenosine, likely acting in normal conditions in the brain, depending on the level of extracellular adenosine and the distribution of AR subtypes. PMID- 26528138 TI - Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1 (G93A) mouse model of amyotrophic lateral sclerosis. AB - Astrocytes are key players in the progression of amyotrophic lateral sclerosis (ALS). Previously, gene expression profiling of astrocytes from the pre symptomatic stage of the SOD1(G93A) model of ALS has revealed reduced lactate metabolism and altered trophic support. Here, we have performed microarray analysis of symptomatic and late-stage disease astrocytes isolated by laser capture microdissection (LCM) from the lumbar spinal cord of the SOD1(G93A) mouse to complete the picture of astrocyte behavior throughout the disease course. Astrocytes at symptomatic and late-stage disease show a distinct up-regulation of transcripts defining a reactive phenotype, such as those involved in the lysosome and phagocytic pathways. Functional analysis of hexosaminidase B enzyme activity in the spinal cord and of astrocyte phagocytic ability has demonstrated a significant increase in lysosomal enzyme activity and phagocytic activity in SOD1(G93A) vs. littermate controls, validating the findings of the microarray study. In addition to the increased reactivity seen at both stages, astrocytes from late-stage disease showed decreased expression of many transcripts involved in cholesterol homeostasis. Staining for the master regulator of cholesterol synthesis, SREBP2, has revealed an increased localization to the cytoplasm of astrocytes and motor neurons in late-stage SOD1(G93A) spinal cord, indicating that down-regulation of transcripts may be due to an excess of cholesterol in the CNS during late-stage disease possibly due to phagocytosis of neuronal debris. Our data reveal that SOD1(G93A) astrocytes are characterized more by a loss of supportive function than a toxic phenotype during ALS disease progression and future studies should focus upon restorative therapies. PMID- 26528139 TI - Neural progenitor cells isolated from the subventricular zone present hemichannel activity and form functional gap junctions with glial cells. AB - The postnatal subventricular zone (SVZ) lining the walls of the lateral ventricles contains neural progenitor cells (NPCs) that generate new olfactory bulb interneurons. Communication via gap junctions between cells in the SVZ is involved in NPC proliferation and in neuroblast migration towards the olfactory bulb. SVZ NPCs can be expanded in vitro in the form of neurospheres that can be used for transplantation purposes after brain injury. We have previously reported that neurosphere-derived NPCs form heterocellular gap junctions with host glial cells when they are implanted after mechanical injury. To analyze functionality of NPC-glial cell gap junctions we performed dye coupling experiments in co cultures of SVZ NPCs with astrocytes or microglia. Neurosphere-derived cells expressed mRNA for at least the hemichannel/gap junction channel proteins connexin 26 (Cx26), Cx43, Cx45 and pannexin 1 (Panx1). Dye coupling experiments revealed that gap junctional communication occurred among neurosphere cells (incidence of coupling: 100%). Moreover, hemichannel activity was also detected in neurosphere cells as evaluated in time-lapse measurements of ethidium bromide uptake. Heterocellular coupling between NPCs and glial cells was evidenced in co cultures of neurospheres with astrocytes (incidence of coupling: 91.0 +/- 4.7%) or with microglia (incidence of coupling: 71.9 +/- 6.7%). Dye coupling in neurospheres and in co-cultures was inhibited by octanol, a gap junction blocker. Altogether, these results suggest the existence of functional hemichannels and gap junction channels in postnatal SVZ neurospheres. In addition, they demonstrate that SVZ-derived NPCs can establish functional gap junctions with astrocytes or microglia. Therefore, cell-cell communication via gap junctions and hemichannels with host glial cells might subserve a role in the functional integration of NPCs after implantation in the damaged brain. PMID- 26528140 TI - Role of satellite glial cells in gastrointestinal pain. AB - Gastrointestinal (GI) pain is a common clinical problem, for which effective therapy is quite limited. Sensations from the GI tract, including pain, are mediated largely by neurons in the dorsal root ganglia (DRG), and to a smaller extent by vagal afferents emerging from neurons in the nodose/jugular ganglia. Neurons in rodent DRG become hyperexcitable in models of GI pain (e.g., gastric or colonic inflammation), and can serve as a source for chronic pain. Glial cells are another element in the pain signaling pathways, and there is evidence that spinal glial cells (microglia and astrocytes) undergo activation (gliosis) in various pain models and contribute to pain. Recently it was found that satellite glial cells (SGCs), the main type of glial cells in sensory ganglia, might also contribute to chronic pain in rodent models. Most of that work focused on somatic pain, but in several studies GI pain was also investigated, and these are discussed in the present review. We have shown that colonic inflammation induced by dinitrobenzene sulfonic acid (DNBS) in mice leads to the activation of SGCs in DRG and increases gap junction-mediated coupling among these cells. This coupling appears to contribute to the hyperexcitability of DRG neurons that innervate the colon. Blocking gap junctions (GJ) in vitro reduced neuronal hyperexcitability induced by inflammation, suggesting that glial GJ participate in SGC-neuron interactions. Moreover, blocking GJ by carbenoxolone and other agents reduces pain behavior. Similar changes in SGCs were also found in the mouse nodose ganglia (NG), which provide sensory innervation to most of the GI tract. Following systemic inflammation, SGCs in these ganglia were activated, and displayed augmented coupling and greater sensitivity to the pain mediator ATP. The contribution of these changes to visceral pain remains to be determined. These results indicate that although visceral pain is unique, it shares basic mechanisms with somatic pain, suggesting that therapeutic approaches to both pain types may be similar. Future research in this field should include additional types of GI injury and also other types of visceral pain. PMID- 26528141 TI - Impacts of tissue-type plasminogen activator (tPA) on neuronal survival. AB - Tissue-type plasminogen activator (tPA) a serine protease is constituted of five functional domains through which it interacts with different substrates, binding proteins, and receptors. In the last years, great interest has been given to the clinical relevance of targeting tPA in different diseases of the central nervous system, in particular stroke. Among its reported functions in the central nervous system, tPA displays both neurotrophic and neurotoxic effects. How can the protease mediate such opposite functions remain unclear but several hypotheses have been proposed. These include an influence of the degree of maturity and/or the type of neurons, of the level of tPA, of its origin (endogenous or exogenous) or of its form (single chain tPA versus two chain tPA). In this review, we will provide a synthetic snapshot of our current knowledge regarding the natural history of tPA and discuss how it sustains its pleiotropic functions with focus on excitotoxic/ischemic neuronal death and neuronal survival. PMID- 26528142 TI - Spontaneous Up states in vitro: a single-metric index of the functional maturation and regional differentiation of the cerebral cortex. AB - Understanding the development and differentiation of the neocortex remains a central focus of neuroscience. While previous studies have examined isolated aspects of cellular and synaptic organization, an integrated functional index of the cortical microcircuit is still lacking. Here we aimed to provide such an index, in the form of spontaneously recurring periods of persistent network activity -or Up states- recorded in mouse cortical slices. These coordinated network dynamics emerge through the orchestrated regulation of multiple cellular and synaptic elements and represent the default activity of the cortical microcircuit. To explore whether spontaneous Up states can capture developmental changes in intracortical networks we obtained local field potential recordings throughout the mouse lifespan. Two independent and complementary methodologies revealed that Up state activity is systematically modified by age, with the largest changes occurring during early development and adolescence. To explore possible regional heterogeneities we also compared the development of Up states in two distinct cortical areas and show that primary somatosensory cortex develops at a faster pace than primary motor cortex. Our findings suggest that in vitro Up states can serve as a functional index of cortical development and differentiation and can provide a baseline for comparing experimental and/or genetic mouse models. PMID- 26528143 TI - Long-range recruitment of Martinotti cells causes surround suppression and promotes saliency in an attractor network model. AB - Although the importance of long-range connections for cortical information processing has been acknowledged for a long time, most studies focused on the long-range interactions between excitatory cortical neurons. Inhibitory interneurons play an important role in cortical computation and have thus far been studied mainly with respect to their local synaptic interactions within the cortical microcircuitry. A recent study showed that long-range excitatory connections onto Martinotti cells (MC) mediate surround suppression. Here we have extended our previously reported attractor network of pyramidal cells (PC) and MC by introducing long-range connections targeting MC. We have demonstrated how the network with Martinotti cell-mediated long-range inhibition gives rise to surround suppression and also promotes saliency of locations at which simple non uniformities in the stimulus field are introduced. Furthermore, our analysis suggests that the presynaptic dynamics of MC is only ancillary to its orientation tuning property in enabling the network with saliency detection. Lastly, we have also implemented a disinhibitory pathway mediated by another interneuron type (VIP interneurons), which inhibits MC and abolishes surround suppression. PMID- 26528144 TI - The maturation of auditory responses in infants and young children: a cross sectional study from 6 to 59 months. AB - BACKGROUND: An understanding of the maturation of auditory cortex responses in typically developing infants and toddlers is needed to later identify auditory processing abnormalities in infants at risk for neurodevelopmental disorders. The availability of infant and young child magnetoencephalography (MEG) systems may now provide near optimal assessment of left and right hemisphere auditory neuromagnetic responses in young populations. To assess the performance of a novel whole-head infant MEG system, a cross-sectional study examined the maturation of left and right auditory cortex responses in children 6- to 59 months of age. METHODS: Blocks of 1000 Hz (1st and 3rd blocks) and 500 Hz tones (2nd block) were presented while MEG data were recorded using an infant/young child biomagnetometer (Artemis 123). Data were obtained from 29 children (11 males; 6- to 59-months). Latency measures were obtained for the first positive-to negative evoked response waveform complex in each hemisphere. Latency and age associations as well as frequency and hemisphere latency differences were examined. For the 1000 Hz tone, measures of reliability were computed. RESULTS: For the first response-a response with a "P2m" topography-latencies decreased as a function of age. For the second response-a response with a "N2m" topography-no N2m latency and age relationships were observed. A main effect of tone frequency showed earlier P2m responses for 1st 1000 Hz (150 ms) and 2nd 1000 Hz (148 ms) vs. 500 Hz tones (162 ms). A significant main effect of hemisphere showed earlier N2m responses for 2nd 1000 Hz (226 ms) vs. 1st 1000 Hz (241 ms) vs. 500 Hz tones (265 ms). P2m and N2m interclass correlation coefficient latency findings were as follows: left P2m (0.72, p < 0.001), right P2m (0.84, p < 0.001), left N2m (0.77, p < 0.001), and right N2m (0.77,p < 0.01). CONCLUSIONS: Findings of strong age and latency associations, sensitivity to tone frequency, and good test-retest reliability support the viability of longitudinal infant MEG studies that include younger as well as older participants as well as studies examining auditory processing abnormalities in infants at risk for neurodevelopmental disorders. PMID- 26528145 TI - Noninvasive brain stimulation for the treatment of auditory verbal hallucinations in schizophrenia: methods, effects and challenges. AB - This mini-review focuses on noninvasive brain stimulation techniques as an augmentation method for the treatment of persistent auditory verbal hallucinations (AVH) in patients with schizophrenia. Paradigmatically, we place emphasis on transcranial magnetic stimulation (TMS). We specifically discuss rationales of stimulation and consider methodological questions together with issues of phenotypic diversity in individuals with drug-refractory and persistent AVH. Eventually, we provide a brief outlook for future investigations and treatment directions. Taken together, current evidence suggests TMS as a promising method in the treatment of AVH. Low-frequency stimulation of the superior temporal cortex (STC) may reduce symptom severity and frequency. Yet clinical effects are of relatively short duration and effect sizes appear to decrease over time along with publication of larger trials. Apart from considering other innovative stimulation techniques, such as transcranial Direct Current Stimulation (tDCS), and optimizing stimulation protocols, treatment of AVH using noninvasive brain stimulation will essentially rely on accurate identification of potential responders and non-responders for these treatment modalities. In this regard, future studies will need to consider distinct phenotypic presentations of AVH in patients with schizophrenia, together with the putative functional neurocircuitry underlying these phenotypes. PMID- 26528146 TI - The state of sleep and the current brain paradigm. AB - Up to the present time cerebral cortex was considered as substrate for realization of the highest psychical functions including consciousness. Cortical sensory areas were regarded as structures specialized for processing of information coming from one particular modality (visual, auditory, somatosensory, and so on). However, studies of cortical activity in sleep-wake cycle demonstrated that during sleep the same neurons in the same cortical areas switch to processing of signals coming from the various visceral systems. After awakening these visceral responses disappear and the neurons return to processing of the information coming from the exteroreceptors. These observations indicate that most likely cortical areas are universal processors, which perform particular operations with incoming information independent of its origin. During wakefulness, results of the information processing on the cortical level should be directed to structures connected with organization of behavior and consciousness, while during sleep cortical outputs should be redirected to structures performing integration of the visceral information. Thus, results of sleep studies indicate that current brain paradigm should be changed. PMID- 26528147 TI - Taste processing in Drosophila larvae. AB - The sense of taste allows animals to detect chemical substances in their environment to initiate appropriate behaviors: to find food or a mate, to avoid hostile environments and predators. Drosophila larvae are a promising model organism to study gustation. Their simple nervous system triggers stereotypic behavioral responses, and the coding of taste can be studied by genetic tools at the single cell level. This review briefly summarizes recent progress on how taste information is sensed and processed by larval cephalic and pharyngeal sense organs. The focus lies on several studies, which revealed cellular and molecular mechanisms required to process sugar, salt, and bitter substances. PMID- 26528148 TI - Support for the slip hypothesis from whisker-related tactile perception of rats in a noisy environment. AB - Rodents use active whisker movements to explore their environment. The "slip hypothesis" of whisker-related tactile perception entails that short-lived kinematic events (abrupt whisker movements, called "slips", due to bioelastic whisker properties that occur during active touch of textures) carry the decisive texture information. Supporting this hypothesis, previous studies have shown that slip amplitude and frequency occur in a texture-dependent way. Further, experiments employing passive pulsatile whisker deflections revealed that perceptual performance based on pulse kinematics (i.e., signatures that resemble slips) is far superior to the one based on time-integrated variables like frequency and intensity. So far, pulsatile stimuli were employed in a noise free environment. However, the realistic scenario involves background noise (e.g., evoked by rubbing across the texture). Therefore, if slips are used for tactile perception, the tactile neuronal system would need to differentiate slip-evoked spikes from those evoked by noise. To test the animals under these more realistic conditions, we presented passive whisker-deflections to head-fixed trained rats, consisting of "slip-like" events (waveforms mimicking slips occurring with touch of real textures) embedded into background noise. Varying the (i) shapes (ramp or pulse); (ii) kinematics (amplitude, velocity, etc.); and (iii) the probabilities of occurrence of slip-like events, we observed that rats could readily detect slip-like events of different shapes against noisy background. Psychophysical curves revealed that the difference of slip event and noise amplitude determined perception, while increased probability of occurrence (frequency) had barely any effect. These results strongly support the notion that encoding of kinematics dominantly determines whisker-related tactile perception while the computation of frequency or intensity plays a minor role. PMID- 26528149 TI - Marmosets treated with oxytocin are more socially attractive to their long-term mate. AB - Adult male-female bonds are partly characterized by initiating and maintaining close proximity with a social partner, as well as engaging in high levels of affiliative and sociosexual behavior. Oxytocin (OXT), a neuromodulatory nonapeptide, plays a critical role in the facilitation of social bonding and prosocial behavior toward a social partner (Feldman, 2012). However, less attention has been given to whether augmentation of OXT levels in an individual alters others' perceptions and behavior toward an OXT-treated social partner. We examined social dynamics in well-established male-female pairs of marmoset monkeys (Callithrix jacchus) in which one member of the pair was administered an intranasal OXT agonist, an OXT antagonist (OXTA), or saline. OXT treatment did not alter the expression of affiliative toward an untreated partner. However, OXT did significantly influence the expression of proximity and grooming behavior with a treated partner, as a function of OXT treatment and sex. Female interest in initiating and maintaining proximity with a pair-mate was altered by OXT treatment. Untreated female marmosets departed from their saline-treated partner more frequently than they approached them, as indicated by a low proximity index score. However, when males received an intranasal OXT agonist they had a significantly increased proximity index score relative to saline, indicating that their untreated partner approached them more often than they departed from them). Saline-treated females initiated and received equivalent levels of grooming behavior. However, when female marmosets were treated with an OXT agonist their untreated partner groomed them proportionately more often, for a greater total duration, and for more time per bout, than they initiated grooming behavior. These results suggest that intranasal OXT altered male and female marmosets' stimulus properties in such a way as to increase the amount of grooming behavior that females received from their long-term mate, as well as increase female interest in initiating and maintaining proximity with their long-term mate. Furthermore, these results support the notion that central OXT activity plays an important neuromodulatory role in the maintenance of long-lasting male-female relationships. PMID- 26528150 TI - Evidence for spatially-responsive neurons in the rostral thalamus. AB - Damage involving the anterior thalamic and adjacent rostral thalamic nuclei may result in a severe anterograde amnesia, similar to the amnesia resulting from damage to the hippocampal formation. Little is known, however, about the information represented in these nuclei. To redress this deficit, we recorded units in three rostral thalamic nuclei in freely-moving rats [the parataenial nucleus (PT), the anteromedial nucleus (AM) and nucleus reuniens NRe]. We found units in these nuclei possessing previously unsuspected spatial properties. The various cell types show clear similarities to place cells, head direction cells, and perimeter/border cells described in hippocampal and parahippocampal regions. Based on their connectivity, it had been predicted that the anterior thalamic nuclei process information with high spatial and temporal resolution while the midline nuclei have more diffuse roles in attention and arousal. Our current findings strongly support the first prediction but directly challenge or substantially moderate the second prediction. The rostral thalamic spatial cells described here may reflect direct hippocampal/parahippocampal inputs, a striking finding of itself, given the relative lack of place cells in other sites receiving direct hippocampal formation inputs. Alternatively, they may provide elemental thalamic spatial inputs to assist hippocampal spatial computations. Finally, they could represent a parallel spatial system in the brain. PMID- 26528152 TI - Increased perceived self-efficacy facilitates the extinction of fear in healthy participants. AB - Self-efficacy has been proposed as an important element of a successful cognitive behavioral treatment (CBT). Positive changes in perceived self-efficacy have been linked to an improved adaptive emotional and behavioral responding in the context of anxiety-provoking situations. Furthermore, a positive influence of increased self-efficacy on cognitive functions has been confirmed. The present study examined the effect of verbal persuasion on perceived self-efficacy and fear extinction. Healthy participants were subjected to a standardized differential fear conditioning paradigm. After fear acquisition, half of the participants received a verbal persuasion aimed at increasing perceived self-efficacy. The extinction of fear was assessed immediately thereafter on both the implicit and explicit level. Our results suggest that an increased perceived self-efficacy was associated with enhanced extinction, evidenced on the psychophysiological level and accompanied by more pronounced decrements in conditioned negative valence. Changes in extinction were not due to a decrease in overall emotional reactivity to conditioned stimuli (CS). In addition, debriefing participants about the false positive feedback did not affect the processing of already extinguished conditioned responses during a subsequent continued extinction phase. Our results suggest that positive changes in perceived self-efficacy can be beneficial for emotional learning. Findings are discussed with respect to strategies aimed at increasing extinction learning in the course of exposure-based treatments. PMID- 26528153 TI - Developmental role of acetylcholinesterase in impulse control in zebrafish. AB - Cellular and molecular processes that mediate individual variability in impulsivity, a key behavioral component of many neuropsychiatric disorders, are poorly understood. Zebrafish heterozygous for a nonsense mutation in ache (ache (sb55/+)) showed lower levels of impulsivity in a 5-choice serial reaction time task (5-CSRTT) than wild type and ache(+/+). Assessment of expression of cholinergic (nAChR), serotonergic (5-HT), and dopamine (DR) receptor mRNA in both adult and larval (9 dpf) ache (sb55/+) revealed significant downregulation of chrna2, chrna5, and drd2 mRNA in ache (sb55/+) larvae, but no differences in adults. Acute exposure to cholinergic agonist/antagonists had no effect on impulsivity, supporting the hypothesis that behavioral effects observed in adults were due to lasting impact of developmental alterations in cholinergic and dopaminergic signaling. This shows the cross-species role of cholinergic signaling during brain development in impulsivity, and suggests zebrafish may be a useful model for the role of cholinergic pathways as a target for therapeutic advances in addiction medicine. PMID- 26528154 TI - Changes in cortical activity associated with adaptive behavior during repeated balance perturbation of unpredictable timing. AB - The compensation for a sudden balance perturbation, unpracticed and unpredictable in timing and magnitude is accompanied by pronounced postural instability that is suggested to be causal to falls. However, subsequent presentations of an identical perturbation are characterized by a marked decrease of the amplitude of postural reactions; a phenomenon called adaptation or habituation. This study aimed to identify cortical characteristics associated with adaptive behavior during repetitive balance perturbations based on single-trial analyses of the P1 and N1 perturbation-evoked potentials. Thirty-seven young men were exposed to ten transient balance perturbations while balancing on the dominant leg. Thirty two channel electroencephalography (EEG), surface electromyography (EMG) of the ankle plantar flexor muscles and postural sway (i.e., Euclidean distance of the supporting platform) were recorded simultaneously. The P1 and N1 potentials were localized and the amplitude/latency was analyzed trial by trial. The best match sources for P1 and N1 potentials were located in the parietal (Brodmann area (BA) 5) and midline fronto-central cortex (BA 6), respectively. The amplitude and latency of the P1 potential remained unchanged over trials. In contrast, a significant adaptation of the N1 amplitude was observed. Similar adaptation effects were found with regard to postural sway and ankle plantarflexors EMG activity of the non-dominant (free) leg; i.e., an indicator for reduced muscular co-contraction and/or less temporary bipedal stance to regain stability. Significant but weak correlations were found between N1 amplitude and postural sway as well as EMG activity. These results highlight the important role of the midline fronto-central cortex for adaptive behavior associated with balance control. PMID- 26528155 TI - Severe dopaminergic neuron loss in rhesus monkey brain impairs morphine-induced conditioned place preference. AB - It is well known that dopamine (DA) is critical for reward, but the precise role of DA in reward remains uncertain. The aim of this study was to determine what percentage of dopaminergic neurons in the primate brain is required for the expression of conditioned reward by measuring the performance of DA-deficient rhesus monkeys in a morphine-induced conditioned place preference (CPP) paradigm. Animals with mild Parkinsonian symptoms successfully developed and retained a morphine preference that was equivalent to control monkeys. However, these monkeys could not maintain the preference as well as controls when they retained severe Parkinsonian symptoms. On the other hand, monkeys initially in a severe Parkinsonian state developed a preference for morphine, but this preference was weaker than that of the controls. Histological results showed that the loss of dopaminergic neurons in monkeys that had severe Parkinsonian symptoms was about 80% in comparison to the control monkeys. All these data suggest that a severely impaired DA system alters rewarding-seeking behavior in non-human primates. PMID- 26528151 TI - Dissecting Alzheimer disease in Down syndrome using mouse models. AB - Down syndrome (DS) is a common genetic condition caused by the presence of three copies of chromosome 21 (trisomy 21). This greatly increases the risk of Alzheimer disease (AD), but although virtually all people with DS have AD neuropathology by 40 years of age, not all develop dementia. To dissect the genetic contribution of trisomy 21 to DS phenotypes including those relevant to AD, a range of DS mouse models has been generated which are trisomic for chromosome segments syntenic to human chromosome 21. Here, we consider key characteristics of human AD in DS (AD-DS), and our current state of knowledge on related phenotypes in AD and DS mouse models. We go on to review important features needed in future models of AD-DS, to understand this type of dementia and so highlight pathogenic mechanisms relevant to all populations at risk of AD. PMID- 26528156 TI - Social interaction attenuates the extent of secondary neuronal damage following closed head injury in mice. AB - Recovery following Traumatic Brain Injury (TBI) can vary tremendously among individuals. Lifestyle following injury, including differential social interactions, may modulate the extent of secondary injury following TBI. To examine this possibility under controlled conditions, closed head injury (CHI) was induced in C57Bl6 mice using a standardized weight drop device after which mice were either housed in isolation or with their original cagemates ("socially housed") for 4 weeks. CHI transiently impaired novel object recognition (NOR) in both isolated and social mice, confirming physical and functional injury. By contrast, Y maze navigation was impaired in isolated but not social mice at 1-4 weeks post CHI. CHI increased excitotoxic signaling in hippocampal slices from all mice, which was transiently exacerbated by isolation at 2 weeks post CHI. CHI slightly increased reactive oxygen species and did not alter levels of amyloid beta (Abeta), total or phospho-tau, total or phosphorylated neurofilaments. CHI increased serum corticosterone in both groups, which was exacerbated by isolation. These findings support the hypothesis that socialization may attenuate secondary damage following TBI. In addition, a dominance hierarchy was noted among socially-housed mice, in which the most submissive mouse displayed indices of stress in the above analyses that were statistically identical to those observed for isolated mice. This latter finding underscores that the nature and extent of social interaction may need to vary among individuals to provide therapeutic benefit. PMID- 26528157 TI - Basal forebrain motivational salience signal enhances cortical processing and decision speed. AB - The basal forebrain (BF) contains major projections to the cerebral cortex, and plays a well-documented role in arousal, attention, decision-making, and in modulating cortical activity. BF neuronal degeneration is an early event in Alzheimer's disease (AD) and dementias, and occurs in normal cognitive aging. While the BF is best known for its population of cortically projecting cholinergic neurons, the region is anatomically and neurochemically diverse, and also contains prominent populations of non-cholinergic projection neurons. In recent years, increasing attention has been dedicated to these non-cholinergic BF neurons in order to better understand how non-cholinergic BF circuits control cortical processing and behavioral performance. In this review, we focus on a unique population of putative non-cholinergic BF neurons that encodes the motivational salience of stimuli with a robust ensemble bursting response. We review recent studies that describe the specific physiological and functional characteristics of these BF salience-encoding neurons in behaving animals. These studies support the unifying hypothesis whereby BF salience-encoding neurons act as a gain modulation mechanism of the decision-making process to enhance cortical processing of behaviorally relevant stimuli, and thereby facilitate faster and more precise behavioral responses. This function of BF salience-encoding neurons represents a critical component in determining which incoming stimuli warrant an animal's attention, and is therefore a fundamental and early requirement of behavioral flexibility. PMID- 26528159 TI - Evidence from neglect dyslexia for morphological decomposition at the early stages of orthographic-visual analysis. AB - This study examined whether and how the morphological structure of written words affects reading in word-based neglect dyslexia (neglexia), and what can be learned about morphological decomposition in reading from the effect of morphology on neglexia. The oral reading of 7 Hebrew-speaking participants with acquired neglexia at the word level-6 with left neglexia and 1 with right neglexia-was evaluated. The main finding was that the morphological role of the letters on the neglected side of the word affected neglect errors: When an affix appeared on the neglected side, it was neglected significantly more often than when the neglected side was part of the root; root letters on the neglected side were never omitted, whereas affixes were. Perceptual effects of length and final letter form were found for words with an affix on the neglected side, but not for words in which a root letter appeared in the neglected side. Semantic and lexical factors did not affect the participants' reading and error pattern, and neglect errors did not preserve the morpho-lexical characteristics of the target words. These findings indicate that an early morphological decomposition of words to their root and affixes occurs before access to the lexicon and to semantics, at the orthographic-visual analysis stage, and that the effects did not result from lexical feedback. The same effects of morphological structure on reading were manifested by the participants with left- and right-sided neglexia. Since neglexia is a deficit at the orthographic-visual analysis level, the effect of morphology on reading patterns in neglexia further supports that morphological decomposition occurs in the orthographic-visual analysis stage, prelexically, and that the search for the three letters of the root in Hebrew is a trigger for attention shift in neglexia. PMID- 26528158 TI - Incidental rewarding cues influence economic decisions in people with obesity. AB - Recent research suggests that obesity is linked to prominent alterations in learning and decision-making. This general difference may also underlie the preference for immediately consumable, highly palatable but unhealthy and high calorie foods. Such poor food-related inter-temporal decision-making can explain weight gain; however, it is not yet clear whether this deficit can be generalized to other domains of inter-temporal decision-making, for example financial decisions. Further, little is known about the stability of decision-making behavior in obesity, especially in the presence of rewarding cues. To answer these questions, obese and lean participants (n = 52) completed two sessions of a novel priming paradigm including a computerized monetary delay discounting task. In the first session, general differences between groups in financial delay discounting were measured. In the second session, we tested the general stability of discount rates. Additionally, participants were primed by affective visual cues of different contextual categories before making financial decisions. We found that the obese group showed stronger discounting of future monetary rewards than the lean group, but groups did not differ in their general stability between sessions nor in their sensitivity toward changes in reward magnitude. In the obese group, a fast decrease of subjective value over time was directly related to a higher tendency for opportunistic eating. Obese in contrast to lean people were primed by the affective cues, showing a sex-specific pattern of priming direction. Our findings demonstrate that environments rich of cues, aiming at inducing unhealthy consumer decisions, can be highly detrimental for obese people. It also underscores that obesity is not merely a medical condition but has a strong cognitive component, meaning that current dietary and medical treatment strategies may fall too short. PMID- 26528161 TI - Is it the picture or is it the frame? An fMRI study on the neurobiology of framing effects. AB - Using functional magnetic resonance imaging (fMRI) we investigated whether a culturally defined context modulates the neurocognitive processing of artworks. We presented subjects with paintings from the Museum of Modern Art (MoMA) in New York, and labeled them as being either from the MoMA or from an adult education center. Irrespective of aesthetic appreciation, we found higher neural activation in the left precuneus, superior and inferior parietal cortex for the MoMA condition compared to the control label condition. When taking the aesthetic preference for a painting into account, the MoMA condition elicited higher involvement of right precuneus, bilateral anterior cingulate cortex (ACC), and temporoparietal junction (TPJ). Our findings indicate that mental frames, in particular labels of social value, modulate both cognitive and affective aspects of sensory processing. PMID- 26528160 TI - The impact of expert visual guidance on trainee visual search strategy, visual attention and motor skills. AB - Minimally invasive and robotic surgery changes the capacity for surgical mentors to guide their trainees with the control customary to open surgery. This neuroergonomic study aims to assess a "Collaborative Gaze Channel" (CGC); which detects trainer gaze-behavior and displays the point of regard to the trainee. A randomized crossover study was conducted in which twenty subjects performed a simulated robotic surgical task necessitating collaboration either with verbal (control condition) or visual guidance with CGC (study condition). Trainee occipito-parietal (O-P) cortical function was assessed with optical topography (OT) and gaze-behavior was evaluated using video-oculography. Performance during gaze-assistance was significantly superior [biopsy number: (mean +/- SD): control = 5.6 +/- 1.8 vs. CGC = 6.6 +/- 2.0; p < 0.05] and was associated with significantly lower O-P cortical activity [DeltaHbO2 mMol * cm [median (IQR)] control = 2.5 (12.0) vs. CGC 0.63 (11.2), p < 0.001]. A random effect model (REM) confirmed the association between guidance mode and O-P excitation. Network cost and global efficiency were not significantly influenced by guidance mode. A gaze channel enhances performance, modulates visual search, and alleviates the burden in brain centers subserving visual attention and does not induce changes in the trainee's O-P functional network observable with the current OT technique. The results imply that through visual guidance, attentional resources may be liberated, potentially improving the capability of trainees to attend to other safety critical events during the procedure. PMID- 26528162 TI - Applying Emmert's Law to the Poggendorff illusion. AB - The Poggendorff illusion was approached with a novel perspective, that of applying Emmert's Law to the situation. The extensities between the verticals and the transversals happen to be absolutely equal in retinal image size, whereas the registered distance for the verticals must be smaller than that of the transversals due to the fact that the former is assumed to occlude the latter. This combination of facts calls for the operation of Emmert's Law, which results in the shrinkage of the occluding space between the verticals. Since the retinal image shows the transversals to be in contact with the verticals, the shrinkage must drag the transversals inwards in the cortical representation in order to eliminate the gaps. Such dragging of the transversals produces the illusory misalignment, which is a dictation of geometry. Some of the consequences of this new explanation were tested in four different experiments. In Experiment 1, a new illusion, the tilting of an occluded continuation of an oblique line, was predicted and achieved. In Experiments 2 and 3, perceived nearness of the occluding entity was manipulated via texture density variations and the predicted misalignment variations were confirmed by using a between-subjects and within subjects designs, respectively. In Experiment 4, tilting of the occluded segment of the transversal was found to vary in the predicted direction as a result of being accompanied by the same texture cues used in Experiments 2 and 3. PMID- 26528163 TI - Old-new ERP effects and remote memories: the late parietal effect is absent as recollection fails whereas the early mid-frontal effect persists as familiarity is retained. AB - Understanding the electrophysiological correlates of recognition memory processes has been a focus of research in recent years. This study investigated the effects of retention interval on recognition memory by comparing memory for objects encoded four weeks (remote) or 5 min (recent) before testing. In Experiment 1, event related potentials (ERPs) were acquired while participants performed a yes no recognition memory task involving remote, recent and novel objects. Relative to correctly rejected new items, remote and recent hits showed an attenuated frontal negativity from 300-500 ms post-stimulus. This effect, also known as the FN400, has been previously associated with familiarity memory. Recent and remote recognition ERPs did not differ from each other at this time-window. By contrast, recent but not remote recognition showed increased parietal positivity from around 500 ms post-stimulus. This late parietal effect (LPE), which is considered a correlate of recollection-related processes, also discriminated between recent and remote memories. A second, behavioral experiment confirmed that remote memories unlike recent memories were based almost exclusively on familiarity. These findings support the idea that the FN400 and LPE are indices of familiarity and recollection memory, respectively and show that remote and recent memories are functionally and anatomically distinct. PMID- 26528164 TI - Withholding planned speech is reflected in synchronized beta-band oscillations. AB - When engaged in a conversation, speakers sometimes have to withhold a planned response, for example, before it is their turn to speak. In the present study, using magnetoencephalography (MEG) outside of a conversational setting, we investigate the oscillatory brain mechanisms involved in the process of withholding a planned verbal response until it is time to speak. Our participants viewed a sequence of four random consonant strings and one pseudoword, which they had to pronounce when the fifth string (the imperative stimulus) was presented. The pseudoword appeared either as the fourth or fifth stimulus in the sequence, creating two conditions. In the withhold condition, the pseudoword was the fourth string and the verbal response was withheld until the imperative stimulus was presented. In the control condition, the fifth string was the pseudoword, so no response was withheld. We compared oscillatory responses to the withhold relative to the control condition in the time period preceding speech. Alpha-beta power (8 30 Hz) decreased over occipital sensors in the withhold condition relative to the control condition. Source-level analysis indicated a posterior source (i.e., occipital cortex) associated with the alpha-beta power decreases. This occipital alpha-beta desynchronization likely reflects attentional allocation to the upcoming imperative stimulus. Moreover, beta (12-20 Hz) power increased over frontal sensors. Source-level analysis indicated a frontal source (i.e., middle and superior frontal gyri) associated with the beta-power increases. We interpret the frontal beta synchronization to reflect a mechanism aiding the maintenance of the current motor or cognitive state. Our results provide a window into a possible oscillatory mechanism implementing the ability of speakers to withhold a planned verbal response until they have to speak. PMID- 26528165 TI - Visual aftereffects and sensory nonlinearities from a single statistical framework. AB - When adapted to a particular scenery our senses may fool us: colors are misinterpreted, certain spatial patterns seem to fade out, and static objects appear to move in reverse. A mere empirical description of the mechanisms tuned to color, texture, and motion may tell us where these visual illusions come from. However, such empirical models of gain control do not explain why these mechanisms work in this apparently dysfunctional manner. Current normative explanations of aftereffects based on scene statistics derive gain changes by (1) invoking decorrelation and linear manifold matching/equalization, or (2) using nonlinear divisive normalization obtained from parametric scene models. These principled approaches have different drawbacks: the first is not compatible with the known saturation nonlinearities in the sensors and it cannot fully accomplish information maximization due to its linear nature. In the second, gain change is almost determined a priori by the assumed parametric image model linked to divisive normalization. In this study we show that both the response changes that lead to aftereffects and the nonlinear behavior can be simultaneously derived from a single statistical framework: the Sequential Principal Curves Analysis (SPCA). As opposed to mechanistic models, SPCA is not intended to describe how physiological sensors work, but it is focused on explaining why they behave as they do. Nonparametric SPCA has two key advantages as a normative model of adaptation: (i) it is better than linear techniques as it is a flexible equalization that can be tuned for more sensible criteria other than plain decorrelation (either full information maximization or error minimization); and (ii) it makes no a priori functional assumption regarding the nonlinearity, so the saturations emerge directly from the scene data and the goal (and not from the assumed function). It turns out that the optimal responses derived from these more sensible criteria and SPCA are consistent with dysfunctional behaviors such as aftereffects. PMID- 26528166 TI - Motivated explanation. AB - Although motivation is a well-established field of study in its own right, and has been fruitfully studied in connection with attribution theory and belief formation under the heading of "motivated thinking," its powerful and pervasive influence on specifically explanatory processes is less well explored. Where one has a strong motivation to understand some event correctly, one is thereby motivated to adhere as best one can to normative or "epistemic" criteria for correct or accurate explanation, even if one does not consciously formulate or apply such criteria. By contrast, many of our motivations to explain introduce bias into the processes involved in generating, evaluating, or giving explanations. Non-epistemic explanatory motivations, or following Kunda's usage, "directional" motivations, include self-justification, resolution of cognitive dissonance, deliberate deception, teaching, and many more. Some of these motivations lead to the relaxation or violation of epistemic norms; others enhance epistemic motivation, so that one engages in more careful and thorough generational and evaluative processes. We propose that "real life" explanatory processes are often constrained by multiple goals, epistemic and directional, where these goals may mutually reinforce one another or may conflict, and where our explanations emerge as a matter of weighing and satisfying those goals. We review emerging evidence from psychology and neuroscience to support this framework and to elucidate the central role of motivation in human thought and explanation. PMID- 26528167 TI - Altered Basal Ganglia Network Integration in Schizophrenia. AB - The basal ganglia involve in a range of functions that are disturbed in schizophrenia patients. This study decomposed the resting-state data of 28 schizophrenia patients and 31 healthy controls with spatial independent component analysis and identified increased functional integration in the bilateral caudate nucleus in schizophrenia patients. Further, the caudate nucleus in patients showed altered functional connection with the prefrontal area and cerebellum. These results identified the importance of basal ganglia in schizophrenia patients. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry. Registration number ChiCTR-RCS-14004878. PMID- 26528168 TI - Brain state-dependent robotic reaching movement with a multi-joint arm exoskeleton: combining brain-machine interfacing and robotic rehabilitation. AB - While robot-assisted arm and hand training after stroke allows for intensive task oriented practice, it has provided only limited additional benefit over dose matched physiotherapy up to now. These rehabilitation devices are possibly too supportive during the exercises. Neurophysiological signals might be one way of avoiding slacking and providing robotic support only when the brain is particularly responsive to peripheral input. We tested the feasibility of three dimensional robotic assistance for reaching movements with a multi-joint exoskeleton during motor imagery (MI)-related desynchronization of sensorimotor oscillations in the beta-band. We also registered task-related network changes of cortical functional connectivity by electroencephalography via the imaginary part of the coherence function. Healthy subjects and stroke survivors showed similar patterns-but different aptitudes-of controlling the robotic movement. All participants in this pilot study with nine healthy subjects and two stroke patients achieved their maximum performance during the early stages of the task. Robotic control was significantly higher and less variable when proprioceptive feedback was provided in addition to visual feedback, i.e., when the orthosis was actually attached to the subject's arm during the task. A distributed cortical network of task-related coherent activity in the theta-band showed significant differences between healthy subjects and stroke patients as well as between early and late periods of the task. Brain-robot interfaces (BRIs) may successfully link three-dimensional robotic training to the participants' efforts and allow for task-oriented practice of activities of daily living with a physiologically controlled multi-joint exoskeleton. Changes of cortical physiology during the task might also help to make subject-specific adjustments of task difficulty and guide adjunct interventions to facilitate motor learning for functional restoration, a proposal that warrants further investigation in a larger cohort of stroke patients. PMID- 26528170 TI - Editorial: Bridging the gap before and after birth: methods and technologies to explore the functional neural development in humans. PMID- 26528171 TI - Theory-guided Therapeutic Function of Music to facilitate emotion regulation development in preschool-aged children. AB - Emotion regulation (ER) is an umbrella term to describe interactive, goal dependent explicit, and implicit processes that are intended to help an individual manage and shift an emotional experience. The primary window for appropriate ER development occurs during the infant, toddler, and preschool years. Atypical ER development is considered a risk factor for mental health problems and has been implicated as a primary mechanism underlying childhood pathologies. Current treatments are predominantly verbal- and behavioral-based and lack the opportunity to practice in-the-moment management of emotionally charged situations. There is also an absence of caregiver-child interaction in these treatment strategies. Based on behavioral and neural support for music as a therapeutic mechanism, the incorporation of intentional music experiences, facilitated by a music therapist, may be one way to address these limitations. Musical Contour Regulation Facilitation (MCRF) is an interactive therapist-child music-based intervention for ER development practice in preschoolers. The MCRF intervention uses the deliberate contour and temporal structure of a music therapy session to mirror the changing flow of the caregiver-child interaction through the alternation of high arousal and low arousal music experiences. The purpose of this paper is to describe the Therapeutic Function of Music (TFM), a theory-based description of the structural characteristics for a music-based stimulus to musically facilitate developmentally appropriate high arousal and low arousal in-the-moment ER experiences. The TFM analysis is based on a review of the music theory, music neuroscience, and music development literature and provides a preliminary model of the structural characteristics of the music as a core component of the MCRF intervention. PMID- 26528172 TI - Editorial: Mental practice: clinical and experimental research in imagery and action observation. PMID- 26528169 TI - Abnormal frontostriatal activity in recently abstinent cocaine users during implicit moral processing. AB - Investigations into the neurobiology of moral cognition are often done by examining clinical populations characterized by diminished moral emotions and a proclivity toward immoral behavior. Psychopathy is the most common disorder studied for this purpose. Although cocaine abuse is highly co-morbid with psychopathy and cocaine-dependent individuals exhibit many of the same abnormalities in socio-affective processing as psychopaths, this population has received relatively little attention in moral psychology. To address this issue, the authors used functional magnetic resonance imaging (fMRI) to record hemodynamic activity in 306 incarcerated male adults, stratified into regular cocaine users (n = 87) and a matched sample of non-cocaine users (n = 87), while viewing pictures that did or did not depict immoral actions and determining whether each depicted scenario occurred indoors or outdoors. Consistent with expectations, cocaine users showed abnormal neural activity in several frontostriatial regions during implicit moral picture processing compared to their non-cocaine using peers. This included reduced moral/non-moral picture discrimination in the vACC, vmPFC, lOFC, and left vSTR. Additionally, psychopathy was negatively correlated with activity in an overlapping region of the ACC and right lateralized vSTR. These results suggest that regular cocaine abuse may be associated with affective deficits which can impact relatively high-level processes like moral cognition. PMID- 26528173 TI - Solving difficult problems creatively: a role for energy optimised deterministic/stochastic hybrid computing. AB - How is the brain configured for creativity? What is the computational substrate for 'eureka' moments of insight? Here we argue that creative thinking arises ultimately from a synergy between low-energy stochastic and energy-intensive deterministic processing, and is a by-product of a nervous system whose signal processing capability per unit of available energy has become highly energy optimised. We suggest that the stochastic component has its origin in thermal (ultimately quantum decoherent) noise affecting the activity of neurons. Without this component, deterministic computational models of the brain are incomplete. PMID- 26528174 TI - Emergent gamma synchrony in all-to-all interneuronal networks. AB - We investigate the emergence of in-phase synchronization in a heterogeneous network of coupled inhibitory interneurons in the presence of spike timing dependent plasticity (STDP). Using a simple network of two mutually coupled interneurons (2-MCI), we first study the effects of STDP on in-phase synchronization. We demonstrate that, with STDP, the 2-MCI network can evolve to either a state of stable 1:1 in-phase synchronization or exhibit multiple regimes of higher order synchronization states. We show that the emergence of synchronization induces a structural asymmetry in the 2-MCI network such that the synapses onto the high frequency firing neurons are potentiated, while those onto the low frequency firing neurons are de-potentiated, resulting in the directed flow of information from low frequency firing neurons to high frequency firing neurons. Finally, we demonstrate that the principal findings from our analysis of the 2-MCI network contribute to the emergence of robust synchronization in the Wang-Buzsaki network (Wang and Buzsaki, 1996) of all-to-all coupled inhibitory interneurons (100-MCI) for a significantly larger range of heterogeneity in the intrinsic firing rate of the neurons in the network. We conclude that STDP of inhibitory synapses provide a viable mechanism for robust neural synchronization. PMID- 26528175 TI - NeuroManager: a workflow analysis based simulation management engine for computational neuroscience. AB - We developed NeuroManager, an object-oriented simulation management software engine for computational neuroscience. NeuroManager automates the workflow of simulation job submissions when using heterogeneous computational resources, simulators, and simulation tasks. The object-oriented approach (1) provides flexibility to adapt to a variety of neuroscience simulators, (2) simplifies the use of heterogeneous computational resources, from desktops to super computer clusters, and (3) improves tracking of simulator/simulation evolution. We implemented NeuroManager in MATLAB, a widely used engineering and scientific language, for its signal and image processing tools, prevalence in electrophysiology analysis, and increasing use in college Biology education. To design and develop NeuroManager we analyzed the workflow of simulation submission for a variety of simulators, operating systems, and computational resources, including the handling of input parameters, data, models, results, and analyses. This resulted in 22 stages of simulation submission workflow. The software incorporates progress notification, automatic organization, labeling, and time stamping of data and results, and integrated access to MATLAB's analysis and visualization tools. NeuroManager provides users with the tools to automate daily tasks, and assists principal investigators in tracking and recreating the evolution of research projects performed by multiple people. Overall, NeuroManager provides the infrastructure needed to improve workflow, manage multiple simultaneous simulations, and maintain provenance of the potentially large amounts of data produced during the course of a research project. PMID- 26528176 TI - Synaptic plasticity in a recurrent neural network for versatile and adaptive behaviors of a walking robot. AB - Walking animals, like insects, with little neural computing can effectively perform complex behaviors. For example, they can walk around their environment, escape from corners/deadlocks, and avoid or climb over obstacles. While performing all these behaviors, they can also adapt their movements to deal with an unknown situation. As a consequence, they successfully navigate through their complex environment. The versatile and adaptive abilities are the result of an integration of several ingredients embedded in their sensorimotor loop. Biological studies reveal that the ingredients include neural dynamics, plasticity, sensory feedback, and biomechanics. Generating such versatile and adaptive behaviors for a many degrees-of-freedom (DOFs) walking robot is a challenging task. Thus, in this study, we present a bio-inspired approach to solve this task. Specifically, the approach combines neural mechanisms with plasticity, exteroceptive sensory feedback, and biomechanics. The neural mechanisms consist of adaptive neural sensory processing and modular neural locomotion control. The sensory processing is based on a small recurrent neural network consisting of two fully connected neurons. Online correlation-based learning with synaptic scaling is applied to adequately change the connections of the network. By doing so, we can effectively exploit neural dynamics (i.e., hysteresis effects and single attractors) in the network to generate different turning angles with short-term memory for a walking robot. The turning information is transmitted as descending steering signals to the neural locomotion control which translates the signals into motor actions. As a result, the robot can walk around and adapt its turning angle for avoiding obstacles in different situations. The adaptation also enables the robot to effectively escape from sharp corners or deadlocks. Using backbone joint control embedded in the the locomotion control allows the robot to climb over small obstacles. Consequently, it can successfully explore and navigate in complex environments. We firstly tested our approach on a physical simulation environment and then applied it to our real biomechanical walking robot AMOSII with 19 DOFs to adaptively avoid obstacles and navigate in the real world. PMID- 26528177 TI - Cognitive training with and without additional physical activity in healthy older adults: cognitive effects, neurobiological mechanisms, and prediction of training success. AB - Data is inconsistent concerning the question whether cognitive-physical training (CPT) yields stronger cognitive gains than cognitive training (CT). Effects of additional counseling, neurobiological mechanisms, and predictors have scarcely been studied. Healthy older adults were trained with CT (n = 20), CPT (n = 25), or CPT with counseling (CPT+C; n = 23). Cognition, physical fitness, BDNF, IGF-1, and VEGF were assessed at pre- and post-test. No interaction effects were found except for one effect showing that CPT+C led to stronger gains in verbal fluency than CPT (p = 0.03). However, this superiority could not be assigned to additional physical training gains. Low baseline cognitive performance and BDNF, not carrying apoE4, gains in physical fitness and the moderation of gains in physical fitness * gains in BDNF predicted training success. Although all types of interventions seem successful to enhance cognition, our data do not support the hypotheses that CPT shows superior CT gains compared to CT or that CPT+C adds merit to CPT. However, as CPT leads to additional gains in physical fitness which in turn is known to have positive impact on cognition in the long-term, CPT seems more beneficial. Training success can partly be predicted by neuropsychological, neurobiological, and genetic parameters. Unique Identifier: WHO ICTRP (http://www.who.int/ictrp); ID: DRKS00005194. PMID- 26528179 TI - Alpha oscillatory correlates of motor inhibition in the aged brain. AB - Exerting inhibitory control is a cognitive ability mediated by functions known to decline with age. The goal of this study is to add to the mechanistic understanding of cortical inhibition during motor control in aged brains. Based on behavioral findings of impaired inhibitory control with age we hypothesized that elderly will show a reduced or a lack of EEG alpha-power increase during tasks that require motor inhibition. Since inhibitory control over movements has been shown to rely on prior motor memory formation, we investigated cortical inhibitory processes at two points in time-early after learning and after an overnight consolidation phase and hypothesized an overnight increase of inhibitory capacities. Young and elderly participants acquired a complex finger movement sequence and in each experimental session brain activity during execution and inhibition of the sequence was recorded with multi-channel EEG. We assessed cortical processes of sustained inhibition by means of task-induced changes of alpha oscillatory power. During inhibition of the learned movement, young participants showed a significant alpha power increase at the sensorimotor cortices whereas elderly did not. Interestingly, for both groups, the overnight consolidation phase improved up-regulation of alpha power during sustained inhibition. This points to deficits in the generation and enhancement of local inhibitory mechanisms at the sensorimotor cortices in aged brains. However, the alpha power increase in both groups implies neuroplastic changes that strengthen the network of alpha power generation over time in young as well as elderly brains. PMID- 26528178 TI - Frontotemporal lobar degeneration: old knowledge and new insight into the pathogenetic mechanisms of tau mutations. AB - Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative diseases which includes tauopathies. In the central nervous system (CNS) tau is the major microtubule-associated protein (MAP) of neurons, promoting assembly and stabilization of microtubules (MTs) required for morphogenesis and axonal transport. Primary tauopathies are characterized by deposition of abnormal fibrils of tau in neuronal and glial cells, leading to neuronal death, brain atrophy and eventually dementia. In genetic tauopathies mutations of tau gene impair the ability of tau to bind to MTs, alter the normal ratio among tau isoforms and favor fibril formation. Recently, additional functions have been ascribed to tau and different pathogenetic mechanisms are then emerging. In fact, a role of tau in DNA protection and genome stability has been reported and chromosome aberrations have been found associated with tau mutations. Furthermore, newly structurally and functionally characterized mutations have suggested novel pathological features, such as a tendency to form oligomeric rather than fibrillar aggregates. Tau mutations affecting axonal transport and plasma membrane interaction have also been described. In this article, we will review the pathogenetic mechanisms underlying tau mutations, focusing in particular on the less common aspects, so far poorly investigated. PMID- 26528180 TI - A probabilistic model of human variability in physiology for future application to dose reconstruction and QIVIVE. AB - The risk assessment of environmental chemicals and drugs is undergoing a paradigm shift in approach which seeks the full replacement of animal testing with high throughput, mechanistic, in vitro systems. This new approach will be reliant on the measurement in vitro, of concentration-dependent responses where prolonged excessive perturbations of specific biochemical pathways are likely to lead to adverse health effects in an intact organism. Such an approach requires a framework, into which disparate data generated by in vitro, in silico, and in chemico systems can be integrated and utilized for quantitative in vitro-to-in vivo extrapolation (QIVIVE), ultimately to the human population level. Physiologically based pharmacokinetic (PBPK) models are ideally suited to this and are needed to translate in vitro concentration- response relationships to an exposure or dose, route and duration regime in human populations. Thus, a realistic description of the variation in the physiology of the human population being modeled is critical. Whilst various studies in the past decade have made progress in describing human variability, the algorithms are typically coded in computer programs and as such are unsuitable for reverse dosimetry. In this report we overcome this limitation by developing a hierarchical statistical model using standard probability distributions for the specification of a virtual US and UK human population. The work draws on information from both population databases and cadaver studies. PMID- 26528181 TI - Antioxidant properties of HDL. AB - High-density lipoprotein (HDL) provides a pathway for the passage of lipid peroxides and lysophospholipids to the liver via hepatic scavenger receptors. Perhaps more importantly, HDL actually metabolizes lipid hydroperoxides preventing their accumulation on low-density lipoprotein (LDL), thus impeding its atherogenic structural modification. A number of candidates have been suggested to be responsible for HDL's antioxidant function, with paraoxonase-1 (PON1) perhaps the most prominent. Here we review the evidence for HDL anti-oxidative function and the potential contributions of apolipoproteins, lipid transfer proteins, paraoxonases and other enzymes associated with HDL. PMID- 26528182 TI - Bortezomib modulates CHIT1 and YKL40 in monocyte-derived osteoclast and in myeloma cells. AB - Osteolytic bone disease is a common manifestation of multiple myeloma (MM) that leads to progressive skeleton destruction and is the most severe cause of morbidity in MM patients. It results from increased osteolytic activity and decrease osteoblastic function. Activation of mammalian chitinases chitotriosidase (CHIT1) and YKL40 is associated with osteoclast (OCs) differentiation and bone digestion. In the current study, we investigated the effect of two Bortezomib's concentration (2.5 and 5 nM) on osteoclastogenesis by analyzing regulation of chitinase expression. OCs exposition to bortezomib (BO) was able to inhibit the expression of different OCs markers such as RANK, CTSK, TRAP, and MMP9. In addition BO-treatment reduced CHIT1 enzymatic activity and both CHIT1 and YKL40 mRNA expression levels and cytoplasmatic and secreted protein. Moreover, immunofluorescence evaluation of mature OCs showed that BO was able to translocate YKL40 into the nucleus, while CHIT1 remained into the cytoplasm. Since MM cell lines such as U266, SKM-M1 and MM1 showed high levels of CHIT1 activity, we analyzed bone resorption ability of U266 using dentin disk assay resorption pits. Silencing chitinase proteins in U266 cell line with specific small interfering RNA, resulted in pits number reduction on dentine disks. In conclusion, we showed that BO decreases osteoclastogenesis and reduces bone resorption in OCs and U266 cell line by modulating the chitinases CHIT1 and YKL40. These results indicate that chitinases may be a therapeutic target for bone disease in MM patients. PMID- 26528183 TI - Lactate does not activate NF-kappaB in oxidative tumor cells. AB - The lactate anion is currently emerging as an oncometabolite. Lactate, produced and exported by glycolytic and glutaminolytic cells in tumors, can be recycled as an oxidative fuel by oxidative tumors cells. Independently of hypoxia, it can also activate transcription factor hypoxia-inducible factor-1 (HIF-1) in tumor and endothelial cells, promoting angiogenesis. These protumoral activities of lactate depend on lactate uptake, a process primarily facilitated by the inward, passive lactate-proton symporter monocarboxylate transporter 1 (MCT1); the conversion of lactate and NAD(+) to pyruvate, NADH and H(+) by lactate dehydrogenase-1 (LDH-1); and a competition between pyruvate and alpha ketoglutarate that inhibits prolylhydroxylases (PHDs). Endothelial cells do not primarily use lactate as an oxidative fuel but, rather, as a signaling agent. In addition to HIF-1, lactate can indeed activate transcription factor nuclear factor-kappaB (NF-kappaB) in these cells, through a mechanism not only depending on PHD inhibition but also on NADH alimenting NAD(P)H oxidases to generate reactive oxygen species (ROS). While NF-kappaB activity in endothelial cells promotes angiogenesis, NF-kappaB activation in tumor cells is known to stimulate tumor progression by conferring resistance to apoptosis, stemness, pro-angiogenic and metastatic capabilities. In this study, we therefore tested whether exogenous lactate could activate NF-kappaB in oxidative tumor cells equipped for lactate signaling. We report that, precisely because they are oxidative, HeLa and SiHa human tumor cells do not activate NF-kappaB in response to lactate. Indeed, while lactate-derived pyruvate is well-known to inhibit PHDs in these cells, we found that NADH aliments oxidative phosphorylation (OXPHOS) in mitochondria rather than NAD(P)H oxidases in the cytosol. These data were confirmed using oxidative human Cal27 and MCF7 tumor cells. This new information positions the malate-aspartate shuttle as a key player in the oxidative metabolism of lactate: similar to glycolysis that aliments OXPHOS with pyruvate produced by pyruvate kinase and NADH produced by glyceraldehyde-3-phosphate dehydrogenase (GAPDH), oxidative lactate metabolism aliments OXPHOS in oxidative tumor cells with pyruvate and NADH produced by LDH1. PMID- 26528184 TI - Effect of cAMP signaling on expression of glucocorticoid receptor, Bim and Bad in glucocorticoid-sensitive and resistant leukemic and multiple myeloma cells. AB - Stimulation of cAMP signaling induces apoptosis in glucocorticoid-sensitive and resistant CEM leukemic and MM.1 multiple myeloma cell lines, and this effect is enhanced by dexamethasone in both glucocorticoid-sensitive cell types and in glucocorticoid-resistant CEM cells. Expression of the mRNA for the glucocorticoid receptor alpha (GR) promoters 1A3, 1B and 1C, expression of mRNA and protein for GR, and the BH3-only proapoptotic proteins, Bim and Bad, and the phosphorylation state of Bad were examined following stimulation of the cAMP and glucocorticoid signaling pathways. Expression levels of GR promoters were increased by cAMP and glucocorticoid signaling, but GR protein expression was little changed in CEM and decreased in MM.1 cells. Stimulation of these two signaling pathways induced Bim in CEM cells, induced Bad in MM.1 cells, and activated Bad, as indicated by its dephosphorylation on ser112, in both cell types. This study shows that leukemic and multiple myeloma cells, including those resistant to glucocorticoids, can be induced to undergo apoptosis by stimulating the cAMP signaling pathway, with enhancement by glucocorticoids, and the mechanism by which this occurs may be related to changes in Bim and Bad expression, and in all cases, to activation of Bad. PMID- 26528185 TI - Monoamine transporters: insights from molecular dynamics simulations. AB - The human monoamine transporters (MATs) facilitate the reuptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Imbalance in monoaminergic neurotransmission is linked to various diseases including major depression, attention deficit hyperactivity disorder, schizophrenia, and Parkinson's disease. Inhibition of the MATs is thus an important strategy for treatment of such diseases. The MATs are sodium-coupled transport proteins belonging to the neurotransmitter/Na(+) symporter (NSS) family, and the publication of the first high-resolution structure of a NSS family member, the bacterial leucine transporter LeuT, in 2005, proved to be a major stepping stone for understanding this family of transporters. Structural data allows for the use of computational methods to study the MATs, which in turn has led to a number of important discoveries. The process of substrate translocation across the membrane is an intrinsically dynamic process. Molecular dynamics simulations, which can provide atomistic details of molecular motion on ns to ms timescales, are therefore well-suited for studying transport processes. In this review, we outline how molecular dynamics simulations have provided insight into the large scale motions associated with transport of the neurotransmitters, as well as the presence of external and internal gates, the coupling between ion and substrate transport, and differences in the conformational changes induced by substrates and inhibitors. PMID- 26528186 TI - The role of macropinocytosis in the propagation of protein aggregation associated with neurodegenerative diseases. AB - With the onset of the rapidly aging population, the impact of age related neurodegenerative diseases is becoming a predominant health and economic concern. Neurodegenerative diseases such as Alzheimer's disease, Creutzfeldt-Jakob disease (CJD), Parkinson's disease, Huntington's disease, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) result from the loss of a specific subsets of neurons, which is closely associated with accumulation and deposition of specific protein aggregates. Protein aggregation, or fibril formation, is a well-studied phenomenon that occurs in a nucleation-dependent growth reaction. Recently, there has been a swell of literature implicating protein aggregation and its ability to propagate cell-to-cell in the rapid progression of these diseases. In order for protein aggregation to be kindled in recipient cells it is a requisite that aggregates must be able to be released from one cell and then taken up by others. In this article we will explore the relationship between protein aggregates, their propagation and the role of macropinocytosis in their uptake. We highlight the ability of neurons to undergo stimulated macropinocytosis and identify potential therapeutic targets. PMID- 26528187 TI - Polyamine regulates tolerance to water stress in leaves of white clover associated with antioxidant defense and dehydrin genes via involvement in calcium messenger system and hydrogen peroxide signaling. AB - Endogenous polyamine (PA) may play a critical role in tolerance to water stress in plants acting as a signaling molecule activator. Water stress caused increases in endogenous PA content in leaves, including putrescine (Put), spermidine (Spd), and spermine (Spm). Exogenous application of Spd could induce the instantaneous H2O2 burst and accumulation of cytosolic free Ca(2+), and activate NADPH oxidase and CDPK gene expression in cells. To a great extent, PA biosynthetic inhibitor reduced the water stress-induced H2O2 accumulation, free cytosolic Ca(2+) release, antioxidant enzyme activities and genes expression leading to aggravate water stress-induced oxidative damage, while these suppressing effects were alleviated by the addition of exogenous Spd, indicating PA was involved in water stress-induced H2O2 and cytosolic free Ca(2+) production as well as stress tolerance. Dehydrin genes (Y 2 SK, Y 2 K, and SK 2) were showed to be highly responsive to exogenous Spd. PA-induced antioxidant defense and dehydrin genes expression could be blocked by the scavenger of H2O2 and the inhibitors of H2O2 generation or Ca(2+) channels blockers, a calmodulin antagonist, as well as the inhibitor of CDPK. These findings suggested that PA regulated tolerance to water stress in white clover associated with antioxidant defenses and dehydrins via involvement in the calcium messenger system and H2O2 signaling pathways. PA induced H2O2 production required Ca(2+) release, while PA-induced Ca(2+) release was also essential for H2O2 production, suggesting an interaction between PA induced H2O2 and Ca(2+) signaling. PMID- 26528188 TI - Accuracy of prediction of infarct-related arrhythmic circuits from image-based models reconstructed from low and high resolution MRI. AB - Identification of optimal ablation sites in hearts with infarct-related ventricular tachycardia (VT) remains difficult to achieve with the current catheter-based mapping techniques. Limitations arise from the ambiguities in determining the reentrant pathways location(s). The goal of this study was to develop experimentally validated, individualized computer models of infarcted swine hearts, reconstructed from high-resolution ex-vivo MRI and to examine the accuracy of the reentrant circuit location prediction when models of the same hearts are instead reconstructed from low clinical-resolution MRI scans. To achieve this goal, we utilized retrospective data obtained from four pigs ~10 weeks post infarction that underwent VT induction via programmed stimulation and epicardial activation mapping via a multielectrode epicardial sock. After the experiment, high-resolution ex-vivo MRI with late gadolinium enhancement was acquired. The Hi-res images were downsampled into two lower resolutions (Med-res and Low-res) in order to replicate image quality obtainable in the clinic. The images were segmented and models were reconstructed from the three image stacks for each pig heart. VT induction similar to what was performed in the experiment was simulated. Results of the reconstructions showed that the geometry of the ventricles including the infarct could be accurately obtained from Med-res and Low-res images. Simulation results demonstrated that induced VTs in the Med-res and Low-res models were located close to those in Hi-res models. Importantly, all models, regardless of image resolution, accurately predicted the VT morphology and circuit location induced in the experiment. These results demonstrate that MRI-based computer models of hearts with ischemic cardiomyopathy could provide a unique opportunity to predict and analyze VT resulting for from specific infarct architecture, and thus may assist in clinical decisions to identify and ablate the reentrant circuit(s). PMID- 26528189 TI - Effect of oral nitrate supplementation on pulmonary hemodynamics during exercise and time trial performance in normoxia and hypoxia: a randomized controlled trial. AB - BACKGROUND: Hypoxia-induced pulmonary vasoconstriction increases pulmonary arterial pressure (PAP) and may impede right heart function and exercise performance. This study examined the effects of oral nitrate supplementation on right heart function and performance during exercise in normoxia and hypoxia. We tested the hypothesis that nitrate supplementation would attenuate the increase in PAP at rest and during exercise in hypoxia, thereby improving exercise performance. METHODS: Twelve trained male cyclists [age: 31 +/- 7 year (mean +/- SD)] performed 15 km time-trial cycling (TT) and steady-state submaximal cycling (50, 100, and 150 W) in normoxia and hypoxia (11% inspired O2) following 3-day oral supplementation with either placebo or sodium nitrate (0.1 mmol/kg/day). We measured TT time-to-completion, muscle tissue oxygenation during TT and systolic right ventricle to right atrium pressure gradient (RV-RA gradient: index of PAP) during steady state cycling. RESULTS: During steady state exercise, hypoxia elevated RV-RA gradient (p > 0.05), while oral nitrate supplementation did not alter RV-RA gradient (p > 0.05). During 15 km TT, hypoxia lowered muscle tissue oxygenation (p < 0.05). Nitrate supplementation further decreased muscle tissue oxygenation during 15 km TT in hypoxia (p < 0.05). Hypoxia impaired time-to completion during TT (p < 0.05), while no improvements were observed with nitrate supplementation in normoxia or hypoxia (p > 0.05). CONCLUSION: Our findings indicate that oral nitrate supplementation does not attenuate acute hypoxic pulmonary vasoconstriction nor improve performance during time trial cycling in normoxia and hypoxia. PMID- 26528190 TI - Dental pulp stem cells as a multifaceted tool for bioengineering and the regeneration of craniomaxillofacial tissues. AB - Dental pulp stem cells, or DPSC, are neural crest-derived cells with an outstanding capacity to differentiate along multiple cell lineages of interest for cell therapy. In particular, highly efficient osteo/dentinogenic differentiation of DPSC can be achieved using simple in vitro protocols, making these cells a very attractive and promising tool for the future treatment of dental and periodontal diseases. Among craniomaxillofacial organs, the tooth and salivary gland are two such cases in which complete regeneration by tissue engineering using DPSC appears to be possible, as research over the last decade has made substantial progress in experimental models of partial or total regeneration of both organs, by cell recombination technology. Moreover, DPSC seem to be a particularly good choice for the regeneration of nerve tissues, including injured or transected cranial nerves. In this context, the oral cavity appears to be an excellent testing ground for new regenerative therapies using DPSC. However, many issues and challenges need yet to be addressed before these cells can be employed in clinical therapy. In this review, we point out some important aspects on the biology of DPSC with regard to their use for the reconstruction of different craniomaxillofacial tissues and organs, with special emphasis on cranial bones, nerves, teeth, and salivary glands. We suggest new ideas and strategies to fully exploit the capacities of DPSC for bioengineering of the aforementioned tissues. PMID- 26528191 TI - Sensitive Periods for Developing a Robust Trait of Appetitive Aggression. AB - Violent behavior can be intrinsically rewarding; especially combatants fighting in current civil wars present with elevated traits of appetitive aggression. The majority of these fighters were recruited as children or adolescents. In the present study, we test whether there is a developmental period where combatants are sensitive for developing a robust trait of appetitive aggression. We investigated 95 combatants in their demobilization process that were recruited at different ages in the Kivu regions of the eastern Democratic Republic of Congo. Using random forest with conditional inference trees, we identified recruitment at the ages from 16 and 17 years as being predictive of the level of appetitive aggression; the number of lifetime, perpetrated acts was the most important predictor. We conclude that high levels of appetitive aggression develop in ex combatants, especially in those recruited during their middle to late teenage, which is a developmental period marked by a natural inclination to exercise physical force. Consequently, ex-combatants may remain vulnerable for aggressive behavior patterns and re-recruitment unless they are provided alternative strategies for dealing with their aggression. PMID- 26528192 TI - Challenges in the Treatment of Adolescent Anorexia Nervosa - Is Enhanced Cognitive Behavior Therapy The Answer? PMID- 26528194 TI - Complaints as starting point for vicious cycles in customer-employee interactions. AB - A ring-model of vicious cycles in customer-employee-interaction is proposed: service employees perceive complaints as a threat to their self-esteem resulting in defense responses such as an increased need for cognitive closure, a devaluation of the customer and their information and degrading service behavior. Confronted with such degrading service behavior, customers react defensively as well, by devaluing the employee for example with regard to his/her competence and by reducing repurchase and positive word-of-mouth (WOM). Three studies investigated each link in this ring-model. In study 1, participants were confronted with an aggressive or neutral customer complaint. Results show that motivated closed-mindedness (one aspect of the need for cognitive closure) increases after an aggressive complaint leading to a devaluation of the customer and their information, and in turn to a degrading service reaction. In study 2, participants were confronted with a degrading or favorable service reaction. Results show that they devaluate the employees' competence after receiving a degrading service reaction and thus reduce their intention to repurchase. In study 3, we finally examined our predictions investigating real customer-employee interactions: we analyzed data from an evaluation study in which mystery callers tested the service hotline of an airline. Results show that the employees' competence is devaluated after degrading behavior and thus reduces positive WOM. PMID- 26528193 TI - Evolution of tonal organization in music mirrors symbolic representation of perceptual reality. Part-1: Prehistoric. AB - This paper reveals the way in which musical pitch works as a peculiar form of cognition that reflects upon the organization of the surrounding world as perceived by majority of music users within a socio-cultural formation. The evidence from music theory, ethnography, archeology, organology, anthropology, psychoacoustics, and evolutionary biology is plotted against experimental evidence. Much of the methodology for this investigation comes from studies conducted within the territory of the former USSR. To date, this methodology has remained solely confined to Russian speaking scholars. A brief overview of pitch set theory demonstrates the need to distinguish between vertical and horizontal harmony, laying out the framework for virtual music space that operates according to the perceptual laws of tonal gravity. Brought to life by bifurcation of music and speech, tonal gravity passed through eleven discrete stages of development until the onset of tonality in the seventeenth century. Each stage presents its own method of integration of separate musical tones into an auditory-cognitive unity. The theory of "melodic intonation" is set forth as a counterpart to harmonic theory of chords. Notions of tonality, modality, key, diatonicity, chromaticism, alteration, and modulation are defined in terms of their perception, and categorized according to the way in which they have developed historically. Tonal organization in music, and perspective organization in fine arts are explained as products of the same underlying mental process. Music seems to act as a unique medium of symbolic representation of reality through the concept of pitch. Tonal organization of pitch reflects the culture of thinking, adopted as a standard within a community of music users. Tonal organization might be a naturally formed system of optimizing individual perception of reality within a social group and its immediate environment, setting conventional standards of intellectual and emotional intelligence. PMID- 26528195 TI - Cosmopolitan cities: the frontier in the twenty-first century? AB - People with independent (vs. interdependent) social orientation place greater priority on personal success, autonomy, and novel experiences over maintaining ties to their communities of origin. Accordingly, an independent orientation should be linked to a motivational proclivity to move to places that offer economic opportunities, freedom, and diversity. Such places are cities that can be called "cosmopolitan." In support of this hypothesis, Study 1 found that independently oriented young adults showed a preference to move to cosmopolitan rather than noncosmopolitan cities. Study 2 used a priming manipulation and demonstrated a causal impact of independence on residential preferences for cosmopolitan cities. Study 3 established ecological validity by showing that students who actually moved to a cosmopolitan city were more independent than those who either moved to a noncosmopolitan city or never moved. Taken together, the findings illuminate the role of cosmopolitan settlement in the contemporary cultural change toward independence and have implications for urban development and economic growth. PMID- 26528196 TI - Social and relational identification as determinants of care workers' motivation and well-being. AB - A growing body of research in the field of health and social care indicates that the quality of the relationship between the person giving care and the person receiving it contributes significantly to the motivation and well-being of both. This paper examines how care workers' motivation is shaped by their social and relational identification at work. Survey findings at two time points (T1, N = 643; T2, N = 1274) show that care workers' motivation increases to the extent that incentives, the working context (of residential vs. domiciliary care), and the professionalization process (of acquiring vs. not acquiring a qualification) serve to build and maintain meaningful identities within the organization. In this context care workers attach greatest importance to their relational identity with clients and the more they perceive this as congruent with their organizational identity the more motivated they are. Implications are discussed with regard to the need to develop and sustain a professional and compassionate workforce that is able to meet the needs of an aging society. PMID- 26528197 TI - Natural frequencies improve Bayesian reasoning in simple and complex inference tasks. AB - Representing statistical information in terms of natural frequencies rather than probabilities improves performance in Bayesian inference tasks. This beneficial effect of natural frequencies has been demonstrated in a variety of applied domains such as medicine, law, and education. Yet all the research and applications so far have been limited to situations where one dichotomous cue is used to infer which of two hypotheses is true. Real-life applications, however, often involve situations where cues (e.g., medical tests) have more than one value, where more than two hypotheses (e.g., diseases) are considered, or where more than one cue is available. In Study 1, we show that natural frequencies, compared to information stated in terms of probabilities, consistently increase the proportion of Bayesian inferences made by medical students in four conditions three cue values, three hypotheses, two cues, or three cues-by an average of 37 percentage points. In Study 2, we show that teaching natural frequencies for simple tasks with one dichotomous cue and two hypotheses leads to a transfer of learning to complex tasks with three cue values and two cues, with a proportion of 40 and 81% correct inferences, respectively. Thus, natural frequencies facilitate Bayesian reasoning in a much broader class of situations than previously thought. PMID- 26528198 TI - Beliefs about willpower moderate the effect of previous day demands on next day's expectations and effective goal striving. AB - Research suggests that beliefs about willpower affect self-regulation following previous self-regulatory demands (Job et al., 2010). Some people believe that their willpower is limited, meaning that after a demanding task it needs to be replenished (limited theory). By contrast, others believe that willpower is not limited and that previous self-control tasks even activate willpower (non-limited theory). We hypothesized that when people experience a demanding day their beliefs about willpower predict their expected capacity to self-regulate and their actual self-regulation on the following day. In a daily diary study (N = 157), we measured students' daily level of demands, their expected performance in unpleasant tasks, and their effective goal striving. Results showed that following a demanding day, students with a non-limited theory had higher expectations about their progress in unpleasant tasks and were striving more efficiently for their goals than students with a limited theory. These findings suggest that beliefs about willpower affect whether demands experienced on a previous day have positive or negative consequences on people's self-regulation. PMID- 26528199 TI - PsyAcoustX: A flexible MATLAB((r)) package for psychoacoustics research. AB - The demands of modern psychophysical studies require precise stimulus delivery and flexible platforms for experimental control. Here, we describe PsyAcoustX, a new, freely available suite of software tools written in the MATLAB((r)) environment to conduct psychoacoustics research on a standard PC. PsyAcoustX provides a flexible platform to generate and present auditory stimuli in real time and record users' behavioral responses. Data are automatically logged by stimulus condition and aggregated in an exported spreadsheet for offline analysis. Detection thresholds can be measured adaptively under basic and complex auditory masking tasks and other paradigms (e.g., amplitude modulation detection) within minutes. The flexibility of the module offers experimenters access to nearly every conceivable combination of stimulus parameters (e.g., probe-masker relations). Example behavioral applications are highlighted including the measurement of audiometric thresholds, basic simultaneous and non-simultaneous (i.e., forward and backward) masking paradigms, gap detection, and amplitude modulation detection. Examples of these measurements are provided including the psychoacoustic phenomena of temporal overshoot, psychophysical tuning curves, and temporal modulation transfer functions. Importantly, the core design of PsyAcoustX is easily modifiable, allowing users the ability to adapt its basic structure and create additional modules for measuring discrimination/detection thresholds for other auditory attributes (e.g., pitch, intensity, etc.) or binaural paradigms. PMID- 26528200 TI - Response inhibition of cigarette-related cues in male light smokers: behavioral evidence using a two-choice oddball paradigm. AB - Behavioral inhibitory control has been shown to play an important role in a variety of addictive behaviors. A number of studies involving the use of Go/NoGo and stop-signal paradigms have shown that smokers have reduced response inhibition for cigarette-related cues. However, it is not known whether male light smokers' response inhibition for cigarette-related cues is lower than that of non-smokers in the two-choice oddball paradigm. The objective of the current study was to provide further behavioral evidence of male light smokers' impaired response inhibition for cigarette-related cues, using the two-choice oddball paradigm. Sixty-two male students (31 smokers, 31 non-smokers), who were recruited via an advertisement, took part in this two-choice oddball experiment. Cigarette-related pictures (deviant stimuli) and pictures unrelated to cigarettes (standard stimuli) were used. Response inhibition for cigarette-related cues was measured by comparing accuracy (ACC) and reaction time (RT) for deviant and standard stimuli in the two groups of subjects. An analysis of variance (ANOVA) showed that in all the participants, ACC was significantly lower for deviant stimuli than for standard stimuli. For deviant stimuli, the RTs were significantly longer for male light smokers than for male non-smokers; however, there was no significant difference in RTs for standard stimuli. Compared to male non-smokers, male light smokers seem to have a reduced ability to inhibit responses to cigarette-related cues. PMID- 26528202 TI - Auditory scene analysis and sonified visual images. Does consonance negatively impact on object formation when using complex sonified stimuli? AB - A critical task for the brain is the sensory representation and identification of perceptual objects in the world. When the visual sense is impaired, hearing and touch must take primary roles and in recent times compensatory techniques have been developed that employ the tactile or auditory system as a substitute for the visual system. Visual-to-auditory sonifications provide a complex, feature-based auditory representation that must be decoded and integrated into an object-based representation by the listener. However, we don't yet know what role the auditory system plays in the object integration stage and whether the principles of auditory scene analysis apply. Here we used coarse sonified images in a two-tone discrimination task to test whether auditory feature-based representations of visual objects would be confounded when their features conflicted with the principles of auditory consonance. We found that listeners (N = 36) performed worse in an object recognition task when the auditory feature-based representation was harmonically consonant. We also found that this conflict was not negated with the provision of congruent audio-visual information. The findings suggest that early auditory processes of harmonic grouping dominate the object formation process and that the complexity of the signal, and additional sensory information have limited effect on this. PMID- 26528201 TI - The brain dynamics of linguistic computation. AB - Neural oscillations at distinct frequencies are increasingly being related to a number of basic and higher cognitive faculties. Oscillations enable the construction of coherently organized neuronal assemblies through establishing transitory temporal correlations. By exploring the elementary operations of the language faculty-labeling, concatenation, cyclic transfer-alongside neural dynamics, a new model of linguistic computation is proposed. It is argued that the universality of language, and the true biological source of Universal Grammar, is not to be found purely in the genome as has long been suggested, but more specifically within the extraordinarily preserved nature of mammalian brain rhythms employed in the computation of linguistic structures. Computational representational theories are used as a guide in investigating the neurobiological foundations of the human "cognome"-the set of computations performed by the nervous system-and new directions are suggested for how the dynamics of the brain (the "dynome") operate and execute linguistic operations. The extent to which brain rhythms are the suitable neuronal processes which can capture the computational properties of the human language faculty is considered against a backdrop of existing cartographic research into the localization of linguistic interpretation. Particular focus is placed on labeling, the operation elsewhere argued to be species-specific. A Basic Label model of the human cognome dynome is proposed, leading to clear, causally-addressable empirical predictions, to be investigated by a suggested research program, Dynamic Cognomics. In addition, a distinction between minimal and maximal degrees of explanation is introduced to differentiate between the depth of analysis provided by cartographic, rhythmic, neurochemical, and other approaches to computation. PMID- 26528203 TI - Mechanisms of embodiment. AB - This paper is a critical review of recent studies demonstrating the mechanism of sensorimotor simulation in different cognitive domains. Empirical studies that specify conditions under which embodiment occurs in different domains will be discussed and evaluated. Examples of relevant domains are language comprehension (Tucker and Ellis, 1998), autobiographical memory (Dijkstra et al., 2007), gestures (Alibali et al., 2014), facial mimicry (Stel and Vonk, 2010), and problem solving (Wiemers et al., 2014). The focus of the review is on supporting claims regarding sensorimotor simulation as well as on factors that modulate dynamic relationships between sensorimotor components in action and cognitive domains, such as expertise (Boschker et al., 2002). This discussion takes place within the context of currently debated issues, specifically the need to specify the underlying mechanisms of embodied representations (Zwaan, 2014; Korner et al., 2015). PMID- 26528204 TI - The effects of teachers' homework follow-up practices on students' EFL performance: a randomized-group design. AB - This study analyzed the effects of five types of homework follow-up practices (i.e., checking homework completion; answering questions about homework; checking homework orally; checking homework on the board; and collecting and grading homework) used in class by 26 teachers of English as a Foreign Language (EFL) using a randomized-group design. Once a week, for 6 weeks, the EFL teachers used a particular type of homework follow-up practice they had previously been assigned to. At the end of the 6 weeks students completed an EFL exam as an outcome measure. The results showed that three types of homework follow-up practices (i.e., checking homework orally; checking homework on the board; and collecting and grading homework) had a positive impact on students' performance, thus highlighting the role of EFL teachers in the homework process. The effect of EFL teachers' homework follow-up practices on students' performance was affected by students' prior knowledge, but not by the number of homework follow-up sessions. PMID- 26528205 TI - Ecological and cosmological coexistence thinking in a hypervariable environment: causal models of economic success and failure among farmers, foragers, and fishermen of southwestern Madagascar. AB - A fact of life for farmers, hunter-gatherers, and fishermen in the rural parts of the world are that crops fail, wild resources become scarce, and winds discourage fishing. In this article we approach subsistence risk from the perspective of "coexistence thinking," the simultaneous application of natural and supernatural causal models to explain subsistence success and failure. In southwestern Madagascar, the ecological world is characterized by extreme variability and unpredictability, and the cosmological world is characterized by anxiety about supernatural dangers. Ecological and cosmological causes seem to point to different risk minimizing strategies: to avoid losses from drought, flood, or heavy winds, one should diversify activities and be flexible; but to avoid losses caused by disrespected spirits one should narrow one's range of behaviors to follow the code of taboos and offerings. We address this paradox by investigating whether southwestern Malagasy understand natural and supernatural causes as occupying separate, contradictory explanatory systems (target dependence), whether they make no categorical distinction between natural and supernatural forces and combine them within a single explanatory system (synthetic thinking), or whether they have separate natural and supernatural categories of causes that are integrated into one explanatory system so that supernatural forces drive natural forces (integrative thinking). Results from three field studies suggest that (a) informants explain why crops, prey, and market activities succeed or fail with reference to natural causal forces like rainfall and pests, (b) they explain why individual persons experience success or failure primarily with supernatural factors like God and ancestors, and (c) they understand supernatural forces as driving natural forces, so that ecology and cosmology represent distinct sets of causes within a single explanatory framework. We expect that future cross-cultural analyses may find that this form of "integrative thinking" is common in unpredictable environments and is a cognitive strategy that accompanies economic diversification. PMID- 26528206 TI - Association between facial expression and PTSD symptoms among young children exposed to the Great East Japan Earthquake: a pilot study. AB - "Emotional numbing" is a symptom of post-traumatic stress disorder (PTSD) characterized by a loss of interest in usually enjoyable activities, feeling detached from others, and an inability to express a full range of emotions. Emotional numbing is usually assessed through self-report, and is particularly difficult to ascertain among young children. We conducted a pilot study to explore the use of facial expression ratings in response to a comedy video clip to assess emotional reactivity among preschool children directly exposed to the Great East Japan Earthquake. This study included 23 child participants. Child PTSD symptoms were measured using a modified version of the Parent's Report of the Child's Reaction to Stress scale. Children were filmed while watching a 2-min video compilation of natural scenes ('baseline video') followed by a 2-min video clip from a television comedy ('comedy video'). Children's facial expressions were processed the using Noldus FaceReader software, which implements the Facial Action Coding System (FACS). We investigated the association between PTSD symptom scores and facial emotion reactivity using linear regression analysis. Children with higher PTSD symptom scores showed a significantly greater proportion of neutral facial expressions, controlling for sex, age, and baseline facial expression (p < 0.05). This pilot study suggests that facial emotion reactivity, measured using facial expression recognition software, has the potential to index emotional numbing in young children. This pilot study adds to the emerging literature on using experimental psychopathology methods to characterize children's reactions to disasters. PMID- 26528208 TI - Attentional bias in math anxiety. AB - Cognitive theory from the field of general anxiety suggests that the tendency to display attentional bias toward negative information results in anxiety. Accordingly, the current study aims to investigate whether attentional bias is involved in math anxiety (MA) as well (i.e., a persistent negative reaction to math). Twenty seven participants (14 with high levels of MA and 13 with low levels of MA) were presented with a novel computerized numerical version of the well established dot probe task. One of six types of prime stimuli, either math related or typically neutral, was presented on one side of a computer screen. The prime was preceded by a probe (either one or two asterisks) that appeared in either the prime or the opposite location. Participants had to discriminate probe identity (one or two asterisks). Math anxious individuals reacted faster when the probe was at the location of the numerical related stimuli. This suggests the existence of attentional bias in MA. That is, for math anxious individuals, the cognitive system selectively favored the processing of emotionally negative information (i.e., math related words). These findings suggest that attentional bias is linked to unduly intense MA symptoms. PMID- 26528207 TI - The influence of object shape and center of mass on grasp and gaze. AB - Recent experiments examining where participants look when grasping an object found that fixations favor the eventual index finger landing position on the object. Even though the act of picking up an object must involve complex high level computations such as the visual analysis of object contours, surface properties, knowledge of an object's function and center of mass (COM) location, these investigations have generally used simple symmetrical objects - where COM and horizontal midline overlap. Less research has been aimed at looking at how variations in object properties, such as differences in curvature and changes in COM location, affect visual and motor control. The purpose of this study was to examine grasp and fixation locations when grasping objects whose COM was positioned to the left or right of the objects horizontal midline (Experiment 1) and objects whose COM was moved progressively further from the midline of the objects based on the alteration of the object's shape (Experiment 2). Results from Experiment 1 showed that object COM position influenced fixation locations and grasp locations differently, with fixations not as tightly linked to index finger grasp locations as was previously reported with symmetrical objects. Fixation positions were also found to be more central on the non-symmetrical objects. This difference in gaze position may provide a more holistic view, which would allow both index finger and thumb positions to be monitored while grasping. Finally, manipulations of COM distance (Experiment 2) exerted marked effects on the visual analysis of the objects when compared to its influence on grasp locations, with fixation locations more sensitive to these manipulations. Together, these findings demonstrate how object features differentially influence gaze vs. grasp positions during object interaction. PMID- 26528209 TI - Investigating the flow of information during speaking: the impact of morpho phonological, associative, and categorical picture distractors on picture naming. AB - In three experiments, participants named target pictures by means of German compound words (e.g., Gartenstuhl-garden chair), each accompanied by two different distractor pictures (e.g., lawn mower and swimming pool). Targets and distractor pictures were semantically related either associatively (garden chair and lawn mower) or by a shared semantic category (garden chair and wardrobe). Within each type of semantic relation, target and distractor pictures either shared morpho-phonological (word-form) information (Gartenstuhl with Gartenzwerg, garden gnome, and Gartenschlauch, garden hose) or not. A condition with two completely unrelated pictures served as baseline. Target naming was facilitated when distractor and target pictures were morpho-phonologically related. This is clear evidence for the activation of word-form information of distractor pictures. Effects were larger for associatively than for categorically related distractors and targets, which constitute evidence for lexical competition. Mere categorical relatedness, in the absence of morpho-phonological overlap, resulted in null effects (Experiments 1 and 2), and only speeded target naming when effects reflect only conceptual, but not lexical processing (Experiment 3). Given that distractor pictures activate their word forms, the data cannot be easily reconciled with discrete serial models. The results fit well with models that allow information to cascade forward from conceptual to word-form levels. PMID- 26528210 TI - The role of self-math overlap in understanding math anxiety and the relation between math anxiety and performance. AB - Recent work has demonstrated that math anxiety is more than just the product of poor math skills. Psychosocial factors may play a key role in understanding what it means to be math anxious, and hence may aid in attempts to sever the link between math anxiety and poor math performance. One such factor may be the extent to which individuals integrate math into their sense of self. We adapted a well established measure of this degree of integration (i.e., self-other overlap) to assess individuals' self-math overlap. This non-verbal single-item measure showed that identifying oneself with math (having higher self-math overlap) was strongly associated with lower math anxiety (r = -0.610). We also expected that having higher self-math overlap would leave one especially susceptible to the threat of poor math performance to the self. We identified two competing hypotheses regarding how this plays out in terms of math anxiety. Those higher in self-math overlap might be more likely to worry about poor math performance, exacerbating the negative relation between math anxiety and math ability. Alternatively, those higher in self-math overlap might exhibit self-serving biases regarding their math ability, which would instead predict a decoupling of the relation between their perceived and actual math ability, and in turn the relation between their math ability and math anxiety. Results clearly favored the latter hypothesis: those higher in self-math overlap exhibited almost no relation between math anxiety and math ability, whereas those lower in self-math overlap showed a strong negative relation between math anxiety and math ability. This was partially explained by greater self-serving biases among those higher in self math overlap. In sum, these results reveal that the degree to which one integrates math into one's self - self-math overlap - may provide insight into how the pernicious negative relation between math anxiety and math ability may be ameliorated. PMID- 26528211 TI - What is special about our own face? Commentary: Tuning of temporo-occipital activity by frontal oscillations during virtual mirror exposure causes erroneous self-recognition. PMID- 26528212 TI - Poor readers' retrieval mechanism: efficient access is not dependent on reading skill. AB - A substantial body of evidence points to a cue-based direct-access retrieval mechanism as a crucial component of skilled adult reading. We report two experiments aimed at examining whether poor readers are able to make use of the same retrieval mechanism. This is significant in light of findings that poor readers have difficulty retrieving linguistic information (e.g., Perfetti, 1985). Our experiments are based on a previous demonstration of direct-access retrieval in language processing, presented in McElree et al. (2003). Experiment 1 replicates the original result using an auditory implementation of the Speed Accuracy Tradeoff (SAT) method. This finding represents a significant methodological advance, as it opens up the possibility of exploring retrieval speeds in non-reading populations. Experiment 2 provides evidence that poor readers do use a direct-access retrieval mechanism during listening comprehension, despite overall poorer accuracy and slower retrieval speeds relative to skilled readers. The findings are discussed with respect to hypotheses about the source of poor reading comprehension. PMID- 26528213 TI - Emotion regulation in heavy smokers: experiential, expressive and physiological consequences of cognitive reappraisal. AB - Emotion regulation dysfunctions are assumed to contribute to the development of tobacco addiction and relapses among smokers attempting to quit. To further examine this hypothesis, the present study compared heavy smokers with non smokers (NS) in a reappraisal task. Specifically, we investigated whether non deprived smokers (NDS) and deprived smokers (DS) differ from non-smokers in cognitive emotion regulation and whether there is an association between the outcome of emotion regulation and the cigarette craving. Sixty-five participants (23 non-smokers, 22 NDS, and 20 DS) were instructed to down-regulate emotions by reappraising negative or positive pictorial scenarios. Self-ratings of valence, arousal, and cigarette craving as well as facial electromyography and electroencephalograph activities were measured. Ratings, facial electromyography, and electroencephalograph data indicated that both NDS and DS performed comparably to nonsmokers in regulating emotional responses via reappraisal, irrespective of the valence of pictorial stimuli. Interestingly, changes in cigarette craving were positively associated with regulation of emotional arousal irrespective of emotional valence. These results suggest that heavy smokers are capable to regulate emotion via deliberate reappraisal and smokers' cigarette craving is associated with emotional arousal rather than emotional valence. This study provides preliminary support for the therapeutic use of reappraisal to replace maladaptive emotion-regulation strategies in nicotine addicts. PMID- 26528214 TI - Modality use in joint attention between hearing parents and deaf children. AB - The present study examined differences in modality use during episodes of joint attention between hearing parent-hearing child dyads and hearing parent-deaf child dyads. Hearing children were age-matched to deaf children. Dyads were video recorded in a free play session with analyses focused on uni- and multimodality use during joint attention episodes. Results revealed that adults in hearing parent-deaf child dyads spent a significantly greater proportion of time interacting with their children using multiple communicative modalities than adults in hearing parent-hearing child dyads, who tended to use the auditory modality (e.g., oral language) most often. While these findings demonstrate that hearing parents accommodate their children's hearing status, we observed greater overall time spent in joint attention in hearing parent-hearing child dyads than hearing parent-deaf child dyads. Our results point to important avenues for future research on how parents can better accommodate their child's hearing status through the use of multimodal communication strategies. PMID- 26528216 TI - Statistician, heal thyself: fighting statophobia at the source. AB - Notwithstanding the popularity of psychology courses throughout the world, educators face a constant and difficult problem of overcoming the fear of and dislike for statistics which represents one of the pillars of modern psychological science. Although the issue is complex and multifaceted, here I argue that "statophobia" might represent a rational and justified response to the sense of unease felt in contact with abstract statistical concepts which are often vague, circular or ill-defined. I illustrate the problem by briefly discussing two myths about the nature of probability and statistics, namely that probability and statistics generate knowledge and that the fault for not understanding probability lies solely with the subjective cognition which is incapable of comprehending deeper mathematical truth. I argue that the confident presentation of statistical methods hides numerous conceptual blind spots that students might be aware of and that need to be addressed before other causes of statistics anxiety can be tackled successfully. PMID- 26528215 TI - Chronic care management of globesity: promoting healthier lifestyles in traditional and mHealth based settings. AB - Obesity and being overweight could be real chronic conditions above all if there are other complications such as type 2 diabetes, cardiovascular diseases, hypertension, dyslipidemia, hypercholesterolemia, cancer, and various psychosocial and psychopathological disorders. Due to the multifactorial etiology of obesity, evidence-based interventions to improve weight loss, maintain a healthy weight, and reduce related comorbidities combine different treatment approaches: dietetic, nutritional, physical, behavioral, psychological, and, in some situations, pharmacological and surgical. There are significant limitations in this multidisciplinary chronic care management of obesity, most notably those regarding costs and long-term adherence and efficacy. Programs including eHealth platforms and new technologies could overcome limitations connected to the traditional in-patient chronic care management of obesity, thus providing promising opportunities in enhancing weight reduction and reducing complications in terms of long-term efficacy and effectiveness across clinical, organizational, and economic perspectives. PMID- 26528217 TI - How is theory of mind useful? Perhaps to enable social pretend play. PMID- 26528218 TI - A commentary on theory of mind. PMID- 26528219 TI - Binding lies. AB - Do we feel bound by our own misrepresentations? Does one act of cheating compel the cheater to make subsequent choices that maintain the false image even at a cost? To answer these questions we employed a two-task paradigm such that in the first task the participants could benefit from false reporting of private observations whereas in the second they could benefit from making a prediction in line with their actual, rather than their previously reported observations. Thus, for those participants who inflated their report during the first task, sticking with that report for the second task was likely to lead to a loss, whereas deviating from it would imply that they had lied. Data from three experiments (total N = 116) indicate that, having lied, participants were ready to suffer future loss rather than admit, even if implicitly, that they had lied. PMID- 26528220 TI - Preliminary evaluation of an analog procedure to assess acceptability of intimate partner violence against women: the Partner Violence Acceptability Movie Task. AB - Acceptability of partner violence against women is a risk factor linked to its perpetration, and to public, professionals' and victims' responses to this behavior. Research on the acceptability of violence in intimate partner relationships is, however, limited by reliance solely on self-reports that often provide distorted or socially desirable accounts that may misrepresent respondents' attitudes. This study presents data on the development and initial validation of a new analog task assessing respondents' acceptability of physical violence toward women in intimate relationships: the Partner Violence Acceptability Movie Task (PVAM). This new analog task is intended to provide a more implicit measure of the acceptability of partner violence against women. For this analog task, clips were extracted from commercially available films (90-s segments) portraying partner violence. Two independent samples were used to develop and evaluate the PVAM: a sample of 245 undergraduate students and a sample of 94 male intimate partner violence offenders. This new analog task demonstrated acceptable internal consistency. Results also indicated adequate construct validity. Both perpetrators and undergraduates scoring high in the PVAM also scored higher in self-reported justifications of partner abuse. Perpetrators of partner violence scored significantly higher in acceptability of partner violence than the undergraduate sample (both male and female students), and male students scored higher than females. These preliminary results suggest that the PVAM may be a promising tool to assess the acceptability of violence in intimate partner relationships, highlighting the need to consider alternatives to self report to evaluate potential beliefs about partner violence. PMID- 26528221 TI - The effect of social categorization on trust decisions in a trust game paradigm. AB - This study investigates whether participants use categorical or individual knowledge about others in order to make cooperative decisions in an adaptation of the trust game paradigm. Concretely, participants had to choose whether to cooperate or not with black and white unknown partners as a function of expected partners' reciprocity rates. Reciprocity rates were manipulated by associating three out of four members of an ethnic group (blacks or whites consistent members) with high (or low) reciprocity rates, while the remaining member of the ethnic group is associated with the reciprocity of the other ethnic group (inconsistent member). Results show opposite performance's patterns for white and black partners. Participants seemed to categorize white partners, by making the same cooperation decision with all the partners, that is, they cooperated equally with consistent and inconsistent white partners. However, this effect was not found for black partners, suggesting a tendency to individuate them. Results are discussed in light of the implications of these categorization-individuation processes for intergroup relations and cooperative economic behavior. PMID- 26528222 TI - Genetic influences on insight problem solving: the role of catechol-O methyltransferase (COMT) gene polymorphisms. AB - People may experience an "aha" moment, when suddenly realizing a solution of a puzzling problem. This experience is called insight problem solving. Several findings suggest that catecholamine-related genes may contribute to insight problem solving, among which the catechol-O-methyltransferase (COMT) gene is the most promising candidate. The current study examined 753 healthy individuals to determine the associations between 7 candidate single nucleotide polymorphisms on the COMT gene and insight problem-solving performance, while considering gender differences. The results showed that individuals carrying A allele of rs4680 or T allele of rs4633 scored significantly higher on insight problem-solving tasks, and the COMT gene rs5993883 combined with gender interacted with correct solutions of insight problems, specifically showing that this gene only influenced insight problem-solving performance in males. This study presents the first investigation of the genetic impact on insight problem solving and provides evidence that highlights the role that the COMT gene plays in insight problem solving. PMID- 26528223 TI - Lexical frequency effects on articulation: a comparison of picture naming and reading aloud. AB - The present study investigated whether lexical frequency, a variable that is known to affect the time taken to utter a verbal response, may also influence articulation. Pairs of words that differed in terms of their relative frequency, but were matched on their onset, vowel, and number of phonemes (e.g., map vs. mat, where the former is more frequent than the latter) were used in a picture naming and a reading aloud task. Low-frequency items yielded slower response latencies than high-frequency items in both tasks, with the frequency effect being significantly larger in picture naming compared to reading aloud. Also, initial-phoneme durations were longer for low-frequency items than for high frequency items. The frequency effect on initial-phoneme durations was slightly more prominent in picture naming than in reading aloud, yet its size was very small, thus preventing us from concluding that lexical frequency exerts an influence on articulation. Additionally, initial-phoneme and whole-word durations were significantly longer in reading aloud compared to picture naming. We discuss our findings in the context of current theories of reading aloud and speech production, and the approaches they adopt in relation to the nature of information flow (staged vs. cascaded) between cognitive and articulatory levels of processing. PMID- 26528224 TI - Chinese adolescents' coping tactics in a parent-adolescent conflict and their relationships with life satisfaction: the differences between coping with mother and father. AB - The present study examined the differences of conflict coping tactics in adolescents' grade and gender and parents' gender and explored the relationships among conflict frequency, conflict coping tactics, and life satisfaction. A total of 1874 Chinese students in grades 7, 8, 10, and 11 completed surveys on conflict frequency, coping tactics, and life satisfaction. The results obtained by MANOVA suggested that the adolescents' reported use of assertion and avoidance with either mothers or fathers increased from Grade 7 to Grade 8 and did not change from Grade 8 to Grade 11 in parent-adolescent conflicts. The results of paired sample T-tests indicated that adolescents used more conciliation in Grade 7, more conciliation and assertion in Grade 8, and more conciliation and less avoidance in Grade 10 and 11 to cope with mothers than with fathers in parent-adolescent conflicts. Boys used more conciliation and less avoidance, while girls used more conciliation, assertion and third-party intervention to cope with mothers than with fathers in parent-adolescent conflicts. The results of the hierarchical regression analysis indicated the significance of the primary effects of conflict frequency and coping tactics on life satisfaction. Specifically, conflict frequency negatively predicted life satisfaction. Conciliation positively and avoidance negatively predicted life satisfaction when adolescents coped with either mothers or fathers in parent-adolescent conflicts. Assertion negatively predicted life satisfaction when adolescents coped with fathers. The moderating effects of conflict coping tactics on the relationship between parent-adolescent conflict frequency and life satisfaction were not significant. PMID- 26528225 TI - The possibility of a science of magic. PMID- 26528226 TI - Vection lies in the brain of the beholder: EEG parameters as an objective measurement of vection. PMID- 26528227 TI - Interaction effect of response medium and working memory capacity on creative idea generation. AB - This study aimed to examine the interaction effect of response medium (i.e., write down ideas and orally report ideas) and working memory capacity (WMC) on creative idea generation. Participants (N = 90) with higher or lower WMC were asked to solve Alternative Uses Task (AUT) problems in the condition of writing down or speaking out ideas. The results showed that fluency of AUT performance was higher in the writing than in the speaking condition. Additionally, participants with higher WMC performed better on AUT fluency than those with lower WMC in the writing condition, while they showed no difference in the speaking condition. Moreover, level of cognitive demand fully mediated the effect of response medium on AUT fluency. Theoretically, these findings indicated the importance of WMC in creative idea generation, which supported the controlled attention theory of creativity. Practical implications and future directions were discussed. PMID- 26528228 TI - Nurse managers' perceptions and experiences regarding staff nurse empowerment: a qualitative study. AB - AIM: To study nurse managers' perceptions and experiences of staff nurse structural empowerment and its impact on the nurse manager leadership role and style. BACKGROUND: Nurse managers' leadership roles may be viewed as challenging given the complex needs of patients and staff nurses' involvement in both clinical and organizational decision-making processes in interdisciplinary care settings. DESIGN: Qualitative phenomenological study. METHODS: Individual semi structured interviews were conducted with 8 medical or surgical nurse managers in a 600-bed Belgian university hospital between December 2013 and June 2014. This hospital was undergoing conversion from a classical hierarchical, departmental structure to a flat, interdisciplinary model. RESULTS: Nurse managers were found to be familiar with the structural empowerment of clinical nurses in the hospital and to hold positive attitudes toward it. They confirmed the positive impact of empowerment on their staff nurses, as evidenced by increased responsibility, autonomy, critical reflection and enhanced communication skills that in turn improved the quality and safety of patient care. Structural empowerment was being supported by several change initiatives at both the unit and hospital levels. Nurse managers' experiences with these initiatives were mixed, however, because of the changing demands with regard to their manager role and leadership style. In addition, pressure was being experienced by both staff nurses and nurse managers as a result of direct patient care priorities, tightly scheduled projects and miscommunication. CONCLUSION: Nurse managers reported that structural empowerment was having a favorable impact on staff nurses' professional attitudes and the safety and quality of care in their units. However, they also reported that the empowerment process had led to changes in the managers' roles as well as daily practice dilemmas related to the leadership styles needed. Clear organizational goals and dedicated support for both clinical nurses and nursing unit managers are imperative to maintaining an empowering practice environment which can ensure the best care and healthy, engaged staff. PMID- 26528229 TI - Behavioral and facial thermal variations in 3-to 4-month-old infants during the Still-Face Paradigm. AB - Behavioral and facial thermal responses were recorded in twelve 3- to 4-month-old infants during the Still-Face Paradigm (SFP). As in the usual procedure, infants were observed in a three-step, face-to-face interaction: a normal interaction episode (3 min); the "still-face" episode in which the mother became unresponsive and assumed a neutral expression (1 min); a reunion episode in which the mother resumed the interaction (3 min). A fourth step that consisted of a toy play episode (5 min) was added for our own research interest. We coded the behavioral responses through the Infant and Caregiver Engagement Phases system, and recorded facial skin temperature via thermal infrared (IR) imaging. Comparing still-face episode to play episode, the infants' communicative engagement decreased, their engagement with the environment increased, and no differences emerged in self regulatory and protest behaviors. We also found that facial skin temperature increased. For the behavioral results, infants recognized the interruption of the interactional reciprocity caused by the still-face presentation, without showing upset behaviors. According to autonomic results, the parasympathetic system was more active than the sympathetic, as usually happens in aroused but not distressed situations. With respect to the debate about the causal factor of the still-face effect, thermal data were consistent with behavioral data in showing this effect as related to the infants' expectations of the nature of the social interactions being violated. Moreover, as these are associated to the infants' subsequent interest in the environment, they indicate the thermal IR imaging as a reliable technique for the detection of physiological variations not only in the emotional system, as indicated by research to date, but also in the attention system. Using this technique for the first time during the SFP allowed us to record autonomic data in a more ecological manner than in previous studies. PMID- 26528230 TI - The role of experience in children's discrimination of unfamiliar languages. AB - Five- and six-year-old children (n = 160) participated in three studies designed to explore language discrimination. After an initial exposure period (during which children heard either an unfamiliar language, a familiar language, or music), children performed an ABX discrimination task involving two unfamiliar languages that were either similar (Spanish vs. Italian) or different (Spanish vs. Mandarin). On each trial, participants heard two sentences spoken by two individuals, each spoken in an unfamiliar language. The pair was followed by a third sentence spoken in one of the two languages. Participants were asked to judge whether the third sentence was spoken by the first speaker or the second speaker. Across studies, both the difficulty of the discrimination contrast and the relation between exposure and test materials affected children's performance. In particular, language discrimination performance was facilitated by an initial exposure to a different unfamiliar language, suggesting that experience can help tune children's attention to the relevant features of novel languages. PMID- 26528231 TI - Commentary: A crisis in comparative psychology: where have all the undergraduates gone? PMID- 26528232 TI - Better dual-task processing in simultaneous interpreters. AB - Simultaneous interpreting (SI) is a highly complex activity and requires the performance and coordination of multiple, simultaneous tasks: analysis and understanding of the discourse in a first language, reformulating linguistic material, storing of intermediate processing steps, and language production in a second language among others. It is, however, an open issue whether persons with experience in SI possess superior skills in coordination of multiple tasks and whether they are able to transfer these skills to lab-based dual-task situations. Within the present study, we set out to explore whether interpreting experience is associated with related higher-order executive functioning in the context of dual-task situations of the Psychological Refractory Period (PRP) type. In this PRP situation, we found faster reactions times in participants with experience in simultaneous interpretation in contrast to control participants without such experience. Thus, simultaneous interpreters possess superior skills in coordination of multiple tasks in lab-based dual-task situations. PMID- 26528233 TI - Insecure attachment is associated with math anxiety in middle childhood. AB - Children's anxiety for situations requiring mathematical problem solving, a concept referred to as math anxiety, has a unique and detrimental impact on concurrent and long-term mathematics achievement and life success. Little is known about the factors that contribute to the emergence of math anxiety. The current study builds on the hypothesis that math anxiety might reflect a maladaptive affect regulation mechanism that is characteristic for insecure attachment relationships. To test this hypothesis, 87 children primary school children (M age = 10.34 years; SD age = 0.63) filled out questionnaires measuring insecure attachment and math anxiety. They all completed a timed and untimed standardized test of mathematics achievement. Our data revealed that individual differences in math anxiety were significantly related to insecure attachment, independent of age, sex, and IQ. Both tests of mathematics achievement were associated with insecure attachment and this effect was mediated by math anxiety. This study is the first to indicate that math anxiety might develop in the context of insecure parent-child attachment relationships. PMID- 26528234 TI - Supplementary Motor Complex and Disturbed Motor Control - a Retrospective Clinical and Lesion Analysis of Patients after Anterior Cerebral Artery Stroke. AB - BACKGROUND: Both the supplementary motor complex (SMC), consisting of the supplementary motor area (SMA) proper, the pre-SMA, and the supplementary eye field, and the rostral cingulate cortex are supplied by the anterior cerebral artery (ACA) and are involved in higher motor control. The Bereitschaftspotential (BP) originates from the SMC and reflects cognitive preparation processes before volitional movements. ACA strokes may lead to impaired motor control in the absence of limb weakness and evoke an alien hand syndrome (AHS) in its extreme form. AIM: To characterize the clinical spectrum of disturbed motor control after ACA strokes, including signs attributable to AHS and to identify the underlying neuroanatomical correlates. METHODS: A clinical assessment focusing on signs of disturbed motor control including intermanual conflict (i.e., bilateral hand movements directed at opposite purposes), lack of self-initiated movements, exaggerated grasping, motor perseverations, mirror movements, and gait apraxia was performed. Symptoms were grouped into (A) AHS-specific and (B) non-AHS specific signs of upper limbs, and (C) gait apraxia. Lesion summation mapping was applied to the patients' MRI or CT scans to reveal associated lesion patterns. The BP was recorded in two patients. RESULTS: Ten patients with ACA strokes (nine unilateral, one bilateral; mean age: 74.2 years; median NIH-SS at admission: 13.0) were included in this case series. In the acute stage, all cases had marked difficulties to perform volitional hand movements, while movements in response to external stimuli were preserved. In the chronic stage (median follow-up: 83.5 days) initiation of voluntary movements improved, although all patients showed persistent signs of disturbed motor control. Impaired motor control is predominantly associated with damaged voxels within the SMC and the anterior and medial cingulate cortex, while lesions within the pre-SMA are specifically related to AHS. No BP was detected over the damaged hemisphere. CONCLUSION: ACA strokes involving the premotor cortices, particularly the pre-SMA, are associated with AHS-specific signs. In the acute phase, motor behavior is characterized by the inability to carry out self-initiated movements. Motor control deficits may persist to a variable degree beyond the acute phase. Alterations of the BP point to an underlying SMC dysfunction in AHS. PMID- 26528235 TI - A Thalamic-Fronto-Parietal Structural Covariance Network Emerging in the Course of Recovery from Hand Paresis after Ischemic Stroke. AB - AIM: To describe structural covariance networks of gray matter volume (GMV) change in 28 patients with first-ever stroke to the primary sensorimotor cortices, and to investigate their relationship to hand function recovery and local GMV change. METHODS: Tensor-based morphometry maps derived from high resolution structural images were subject to principal component analyses to identify the networks. We calculated correlations between network expression and local GMV change, sensorimotor hand function and lesion volume. To verify which of the structural covariance networks of GMV change have a significant relationship to hand function, we performed an additional multivariate regression approach. RESULTS: Expression of the second network, explaining 9.1% of variance, correlated with GMV increase in the medio-dorsal (md) thalamus and hand motor skill. Patients with positive expression coefficients were distinguished by significantly higher GMV increase of this structure during stroke recovery. Significant nodes of this network were located in md thalamus, dorsolateral prefrontal cortex, and higher order sensorimotor cortices. Parameter of hand function had a unique relationship to the network and depended on an interaction between network expression and lesion volume. Inversely, network expression is limited in patients with large lesion volumes. CONCLUSION: Chronic phase of sensorimotor cortical stroke has been characterized by a large scale co-varying structural network in the ipsilesional hemisphere associated specifically with sensorimotor hand skill. Its expression is related to GMV increase of md thalamus, one constituent of the network, and correlated with the cortico-striato thalamic loop involved in control of motor execution and higher order sensorimotor cortices. A close relation between expression of this network with degree of recovery might indicate reduced compensatory resources in the impaired subgroup. PMID- 26528236 TI - Role of the Contralesional Hemisphere in Post-Stroke Recovery of Upper Extremity Motor Function. AB - Identification of optimal treatment strategies to improve recovery is limited by the incomplete understanding of the neurobiological principles of recovery. Motor cortex (M1) reorganization of the lesioned hemisphere (ipsilesional M1) plays a major role in post-stroke motor recovery and is a primary target for rehabilitation therapy. Reorganization of M1 in the hemisphere contralateral to the stroke (contralesional M1) may, however, serve as an additional source of cortical reorganization and related recovery. The extent and outcome of such reorganization depends on many factors, including lesion size and time since stroke. In the chronic phase post-stroke, contralesional M1 seems to interfere with motor function of the paretic limb in a subset of patients, possibly through abnormally increased inhibition of lesioned M1 by the contralesional M1. In such patients, decreasing contralesional M1 excitability by cortical stimulation results in improved performance of the paretic limb. However, emerging evidence suggests a potentially supportive role of contralesional M1. After infarction of M1 or its corticospinal projections, there is abnormally increased excitatory neural activity and activation in contralesional M1 that correlates with favorable motor recovery. Decreasing contralesional M1 excitability in these patients may result in deterioration of paretic limb performance. In animal stroke models, reorganizational changes in contralesional M1 depend on the lesion size and rehabilitation treatment and include long-term changes in neurotransmitter systems, dendritic growth, and synapse formation. While there is, therefore, some evidence that activity in contralesional M1 will impact the extent of motor function of the paretic limb in the subacute and chronic phase post-stroke and may serve as a new target for rehabilitation treatment strategies, the precise factors that specifically influence its role in the recovery process remain to be defined. PMID- 26528237 TI - The Central Biobank and Virtual Biobank of BIOMARKAPD: A Resource for Studies on Neurodegenerative Diseases. AB - Biobanks are important resources for biomarker discovery and assay development. Biomarkers for Alzheimer's and Parkinson's disease (BIOMARKAPD) is a European multicenter study, funded by the EU Joint Programme-Neurodegenerative Disease Research, which aims to improve the clinical use of body fluid markers for the diagnosis and prognosis of Alzheimer's disease (AD) and Parkinson's disease (PD). The objective was to standardize the assessment of existing assays and to validate novel fluid biomarkers for AD and PD. To support the validation of novel biomarkers and assays, a central and a virtual biobank for body fluids and associated data from subjects with neurodegenerative diseases have been established. In the central biobank, cerebrospinal fluid (CSF) and blood samples were collected according to the BIOMARKAPD standardized pre-analytical procedures and stored at Integrated BioBank of Luxembourg. The virtual biobank provides an overview of available CSF, plasma, serum, and DNA samples at each site. Currently, at the central biobank of BIOMARKAPD samples are available from over 400 subjects with normal cognition, mild cognitive impairment (MCI), AD, frontotemporal dementia (FTD), vascular dementia, multiple system atrophy, progressive supranuclear palsy, PD, PD with dementia, and dementia with Lewy bodies. The virtual biobank contains information on over 8,600 subjects with varying diagnoses from 21 local biobanks. A website has been launched to enable sample requests from the central biobank and virtual biobank. PMID- 26528238 TI - The Therapeutic Potential of Brown Adipocytes in Humans. AB - Obesity and its metabolic consequences represent a significant clinical problem. From a thermodynamic standpoint, obesity results from a discord in energy intake and expenditure. To date, lifestyle interventions based on reducing energy intake and/or increasing energy expenditure have proved ineffective in the prevention and/or treatment of obesity, owing to poor long-term adherence to such interventions. Thus, an effective strategy to prevent or correct obesity is currently lacking. As the combustion engines of our cells, mitochondria play a critical role in energy expenditure. At a whole-body level, approximately 80% of mitochondrial membrane potential generated by fuel oxidation is used to produce ATP, and the remaining 20% is lost through heat-producing uncoupling reactions. The coupling of mitochondrial respiration to ATP production represents an important component in whole-body energy expenditure. Brown adipose tissue (BAT) is densely populated with mitochondria containing the inner mitochondrial proton carrier uncoupling protein 1 (UCP1). UCP1 uncouples oxidative phosphorylation, meaning that mitochondrial membrane potential is dissipated as heat. The recent rediscovery of BAT depots in adult humans has rekindled scientific interest in the manipulation of mitochondrial uncoupling reactions as a means to increase metabolic rate, thereby counteracting obesity and its associated metabolic phenotype. In this article, we discuss the evidence for the role BAT plays in metabolic rate and glucose and lipid metabolism in humans and the potential for UCP1 recruitment in the white adipose tissue of humans. While the future holds much promise for a therapeutic role of UCP1 expressing adipocytes in human energy metabolism, particularly in the context of obesity, tissue-specific strategies that activate or recruit UCP1 in human adipocytes represent an obligatory translational step for this early promise to be realized. PMID- 26528239 TI - Oxytocin and Estrogen Receptor beta in the Brain: An Overview. AB - Oxytocin (OT) is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons have axons that project into the posterior pituitary and release OT into the bloodstream to promote labor and lactation; however, OT neurons also project to other brain areas where it plays a role in numerous brain functions. OT binds to the widely expressed OT receptor (OTR), and, in doing so, it regulates homeostatic processes, social recognition, and fear conditioning. In addition to these functions, OT decreases neuroendocrine stress signaling and anxiety-related and depression-like behaviors. Steroid hormones differentially modulate stress responses and alter OTR expression. In particular, estrogen receptor beta activation has been found to both reduce anxiety-related behaviors and increase OT peptide transcription, suggesting a role for OT in this estrogen receptor beta mediated anxiolytic effect. Further research is needed to identify modulators of OT signaling and the pathways utilized and to elucidate molecular mechanisms controlling OT expression to allow better therapeutic manipulations of this system in patient populations. PMID- 26528240 TI - 3D Porous Architecture of Stacks of beta-TCP Granules Compared with That of Trabecular Bone: A microCT, Vector Analysis, and Compression Study. AB - The 3D arrangement of porous granular biomaterials usable to fill bone defects has received little study. Granular biomaterials occupy 3D space when packed together in a manner that creates a porosity suitable for the invasion of vascular and bone cells. Granules of beta-tricalcium phosphate (beta-TCP) were prepared with either 12.5 or 25 g of beta-TCP powder in the same volume of slurry. When the granules were placed in a test tube, this produced 3D stacks with a high (HP) or low porosity (LP), respectively. Stacks of granules mimic the filling of a bone defect by a surgeon. The aim of this study was to compare the porosity of stacks of beta-TCP granules with that of cores of trabecular bone. Biomechanical compression tests were done on the granules stacks. Bone cylinders were prepared from calf tibia plateau, constituted high-density (HD) blocks. Low density (LD) blocks were harvested from aged cadaver tibias. Microcomputed tomography was used on the beta-TCP granule stacks and the trabecular bone cores to determine porosity and specific surface. A vector-projection algorithm was used to image porosity employing a frontal plane image, which was constructed line by line from all images of a microCT stack. Stacks of HP granules had porosity (75.3 +/- 0.4%) and fractal lacunarity (0.043 +/- 0.007) intermediate between that of HD (respectively 69.1 +/- 6.4%, p < 0.05 and 0.087 +/- 0.045, p < 0.05) and LD bones (respectively 88.8 +/- 1.57% and 0.037 +/- 0.014), but exhibited a higher surface density (5.56 +/- 0.11 mm(2)/mm(3) vs. 2.06 +/- 0.26 for LD, p < 0.05). LP granular arrangements created large pores coexisting with dense areas of material. Frontal plane analysis evidenced a more regular arrangement of beta-TCP granules than bone trabecule. Stacks of HP granules represent a scaffold that resembles trabecular bone in its porous microarchitecture. PMID- 26528241 TI - Structure Model Index Does Not Measure Rods and Plates in Trabecular Bone. AB - Structure model index (SMI) is widely used to measure rods and plates in trabecular bone. It exploits the change in surface curvature that occurs as a structure varies from spherical (SMI = 4), to cylindrical (SMI = 3) to planar (SMI = 0). The most important assumption underlying SMI is that the entire bone surface is convex and that the curvature differential is positive at all points on the surface. The intricate connections within the trabecular continuum suggest that a high proportion of the surface could be concave, violating the assumption of convexity and producing regions of negative differential. We implemented SMI in the BoneJ plugin and included the ability to measure the amounts of surface that increased or decreased in area after surface mesh dilation, and the ability to visualize concave and convex regions. We measured SMI and its positive (SMI(+)) and negative (SMI(-)) components, bone volume fraction (BV/TV), the fraction of the surface that is concave (CF), and mean ellipsoid factor (EF) in trabecular bone using 38 X-ray microtomography (XMT) images from a rat ovariectomy model of sex steroid rescue of bone loss, and 169 XMT images from a broad selection of 87 species' femora (mammals, birds, and a crocodile). We simulated bone resorption by eroding an image of elephant trabecule and recording SMI and BV/TV at each erosion step. Up to 70%, and rarely <20%, of the trabecular surface is concave (CF 0.155-0.700). SMI is unavoidably influenced by aberrations induced by SMI(-), which is strongly correlated with BV/TV and CF. The plate-to rod transition in bone loss is an erroneous observation resulting from the close and artifactual relationship between SMI and BV/TV. SMI cannot discern between the distinctive trabecular geometries typical of mammalian and avian bone, whereas EF clearly detects birds' more plate-like trabecule. EF is free from confounding relationships with BV/TV and CF. SMI results reported in the literature should be treated with suspicion. We propose that EF should be used instead of SMI for measurements of rods and plates in trabecular bone. PMID- 26528242 TI - Downregulation of host tryptophan-aspartate containing coat (TACO) gene restricts the entry and survival of Leishmania donovani in human macrophage model. AB - Leishmania are obligate intracellular protozoan parasites of mammalian hosts. Promastigotes of Leishmania are internalized by macrophages and transformed into amastigotes in phagosomes, and replicate in phagolysosomes. Phagosomal maturation arrest is known to play a crucial role in the survival of pathogenic Leishmania within activated macrophages. Recently, tryptophan-aspartate containing coat (TACO) gene has been recognized as playing a central role in the survival of Mycobacterium tuberculosis within human macrophages by arresting the phagosome maturation process. We postulated that a similar association of TACO gene with phagosomes would prevent the vacuole from maturation in the case of Leishmania. In this study we attempted to define the effect of TACO gene downregulation on the entry/survival of Leishmania donovani intracellularly, by treatment with Vitamin D3 (Vit.D3)/Retinoic acid (RA) and chenodeoxycholic acid (CDCA)/RA combinations in human THP-1 macrophages (in vitro). Treatment with these molecules downregulated the TACO gene in macrophages, resulting in reduced parasite load and marked reduction of disease progression in L. donovani infected macrophages. Taken together, these results suggest that TACO gene downregulation may play a role in subverting macrophage machinery in establishing the L. donovani replicative niche inside the host. Our study is the first to highlight the important role of the TACO gene in Leishmania entry, survival and to identify TACO gene downregulation as potential drug target against leishmaniasis. PMID- 26528243 TI - Fungal association and utilization of phosphate by plants: success, limitations, and future prospects. AB - Phosphorus (P) is a major macronutrient for plant health and development. The available form of P is generally low in the rhizosphere even in fertile soils. A major proportion of applied phosphate (Pi) fertilizers in the soil become fixed into insoluble, unavailable forms, which restricts crop production throughout the world. Roots possess two distinct modes of P uptake from the soil, direct and indirect uptake. The direct uptake of P is facilitated by the plant's own Pi transporters while indirect uptake occurs via mycorrhizal symbiosis, where the host plant obtains P primarily from the fungal partner, while the fungus benefits from plant-derived reduced carbon. So far, only one Pi transporter has been characterized from the mycorrhizal fungus Glomus versiforme. As arbuscular mycorrhizal fungi cannot be cultured axenically, their Pi transporter network is difficult to exploite for large scale sustainable agriculture. Alternatively, the root-colonizing endophytic fungus Piriformospora indica can grow axenically and provides strong growth-promoting activity during its symbiosis with a broad spectrum of plants. P. indica contains a high affinity Pi transporter (PiPT) involved in improving Pi nutrition levels in the host plant under P limiting conditions. As P. indica can be manipulated genetically, it opens new vistas to be used in P deficient fields. PMID- 26528244 TI - The therapeutic effect of chlorogenic acid against Staphylococcus aureus infection through sortase A inhibition. AB - The emergence and wide spread of multi-drug resistant Staphylococcus aureus (S. aureus) requires the development of new therapeutic agents with alternative modes of action. Anti-virulence strategies are hoped to meet that need. Sortase A (SrtA) has attracted great interest as a potential drug target to treat infections caused by S. aureus, as many of the surface proteins displayed by SrtA function as virulence factors by mediating bacterial adhesion to specific organ tissues, invasion of host cells, and evasion of the host-immune responses. It has been suggested that inhibitors of SrtA might be promising candidates for the treatment and/or prevention of S. aureus infections. In this study, we report that chlorogenic acid (CHA), a natural compound that lacks significant anti-S. aureus activity, inhibit the activity of SrtA in vitro (IC50 = 33.86 +/- 5.55 MUg/ml) and the binding of S. aureus to fibrinogen (Fg). Using molecular dynamics simulations and mutagenesis assays, we further demonstrate that CHA binds to the binding sites of C184 and G192 in the SrtA. In vivo studies demonstrated that CHA prevent mice from S. aureus-induced renal abscess, resulting in a significant survival advantage. These findings indicate that CHA is a promising therapeutic compound against SrtA during S. aureus infections. PMID- 26528245 TI - An abundance of Epsilonproteobacteria revealed in the gut microbiome of the laboratory cultured sea urchin, Lytechinus variegatus. AB - In this study, we have examined the bacterial community composition of the laboratory cultured sea urchin Lytechinus variegatus gut microbiome and its culture environment using NextGen amplicon sequencing of the V4 segment of the 16S rRNA gene, and downstream bioinformatics tools. Overall, the gut and tank water was dominated by Proteobacteria, whereas the feed consisted of a co occurrence of Proteobacteria and Firmicutes at a high abundance. The gut tissue represented Epsilonproteobacteria as dominant, with order Campylobacterales at the highest relative abundance (>95%). However, the pharynx tissue was dominated by class Alphaproteobacteria. The gut digesta and egested fecal pellets had a high abundance of class Gammaproteobacteria, from which Vibrio was found to be the primary genus, and Epsilonproteobacteria, with genus Arcobacter occurring at a moderate level. At the class level, the tank water was dominated by Gammaproteobacteria, and the feed by Alphaproteobacteria. Multi-Dimensional Scaling analysis showed that the microbial community of the gut tissue clustered together, as did the pharynx tissue to the feed. The gut digesta and egested fecal pellets showed a similarity relationship to the tank water. Further analysis of Campylobacterales at a lower taxonomic level using the oligotyping method revealed 37 unique types across the 10 samples, where Oligotype 1 was primarily represented in the gut tissue. BLAST analysis identified Oligotype 1 to be Arcobacter sp., Sulfuricurvum sp., and Arcobacter bivalviorum at an identity level >90%. This study showed that although distinct microbial communities are evident across multiple components of the sea urchin gut ecosystem, there is a noticeable correlation between the overall microbial communities of the gut with the sea urchin L. variegatus culture environment. PMID- 26528247 TI - Patterns of benthic bacterial diversity in coastal areas contaminated by heavy metals, polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs). AB - Prokaryotes in coastal sediments are fundamental players in the ecosystem functioning and regulate processes relevant in the global biogeochemical cycles. Nevertheless, knowledge on benthic microbial diversity patterns across spatial scales, or as function to anthropogenic influence, is still limited. We investigated the microbial diversity in two of the most chemically polluted sites along the coast of Italy. One site is the Po River Prodelta (Northern Adriatic Sea), which receives contaminant discharge from one of the largest rivers in Europe. The other site, the Mar Piccolo of Taranto (Ionian Sea), is a chronically polluted area due to steel production plants, oil refineries, and intense maritime traffic. We collected sediments from 30 stations along gradients of contamination, and studied prokaryotic diversity using Illumina sequencing of amplicons of a 16S rDNA gene fragment. The main sediment variables and the concentration of eleven metals, polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) were measured. Chemical analyses confirmed the high contamination in both sites, with concentrations of PCBs particularly high and often exceeding the sediment guidelines. The analysis of more than 3 millions 16S rDNA sequences showed that richness decreased with higher contamination levels. Multivariate analyses showed that contaminants significantly shaped community composition. Assemblages differed significantly between the two sites, but showed wide within-site variations related with spatial gradients in the chemical contamination, and the presence of a core set of OTUs shared by the two geographically distant sites. A larger importance of PCB-degrading taxa was observed in the Mar Piccolo, suggesting their potential selection in this historically polluted site. Our results indicate that sediment contamination by multiple contaminants significantly alter benthic prokaryotic diversity in coastal areas, and suggests considering the potential contribution of the resident microbes to contaminant bioremediation actions. PMID- 26528246 TI - Mucociliary dysfunction in HIV and smoked substance abuse. AB - Impaired mucociliary clearance (MCC) is a hallmark of acquired chronic airway diseases like chronic bronchitis associated with chronic obstructive pulmonary disease (COPD) and asthma. This manifests as microbial colonization of the lung consequently leading to recurrent respiratory infections. People living with HIV demonstrate increased incidence of these chronic airway diseases. Bacterial pneumonia continues to be an important comorbidity in people living with HIV even though anti-retroviral therapy has succeeded in restoring CD4+ cell counts. People living with HIV demonstrate increased microbial colonization of the lower airways. The microbial flora is similar to that observed in diseases like cystic fibrosis and COPD suggesting that mucociliary dysfunction could be a contributing factor to the increased incidence of chronic airway diseases in people living with HIV. The three principal components of the MCC apparatus are, a mucus layer, ciliary beating, and a periciliary airway surface liquid (ASL) layer that facilitates ciliary beating. Cystic fibrosis transmembrane conductance regulator (CFTR) plays a pivotal role in regulating the periciliary ASL. HIV proteins can suppress all the components of the MCC apparatus by increasing mucus secretion and suppressing CFTR function. This can decrease ASL height leading to suppressed ciliary beating. The effects of HIV on MCC are exacerbated when combined with other aggravating factors like smoking or inhaled substance abuse, which by themselves can suppress one or more components of the MCC system. This review discusses the pathophysiological mechanisms that lead to MCC suppression in people living with HIV who also smoke tobacco or abuse illicit drugs. PMID- 26528248 TI - Rumen microbial communities influence metabolic phenotypes in lambs. AB - The rumen microbiota is an essential part of ruminants shaping their nutrition and health. Despite its importance, it is not fully understood how various groups of rumen microbes affect host-microbe relationships and functions. The aim of the study was to simultaneously explore the rumen microbiota and the metabolic phenotype of lambs for identifying host-microbe associations and potential biomarkers of digestive functions. Twin lambs, separated in two groups after birth were exposed to practices (isolation and gavage with rumen fluid with protozoa or protozoa-depleted) that differentially restricted the acquisition of microbes. Rumen microbiota, fermentation parameters, digestibility and growth were monitored for up to 31 weeks of age. Microbiota assembled in isolation from other ruminants lacked protozoa and had low bacterial and archaeal diversity whereas digestibility was not affected. Exposure to adult sheep microbiota increased bacterial and archaeal diversity independently of protozoa presence. For archaea, Methanomassiliicoccales displaced Methanosphaera. Notwithstanding, protozoa induced differences in functional traits such as digestibility and significantly shaped bacterial community structure, notably Ruminococcaceae and Lachnospiraceae lower up to 6 folds, Prevotellaceae lower by ~40%, and Clostridiaceae and Veillonellaceae higher up to 10 folds compared to microbiota without protozoa. An orthogonal partial least squares-discriminant analysis of urinary metabolome matched differences in microbiota structure. Discriminant metabolites were mainly involved in amino acids and protein metabolic pathways while a negative interaction was observed between methylotrophic methanogens Methanomassiliicoccales and trimethylamine N-oxide. These results stress the influence of gut microbes on animal phenotype and show the potential of metabolomics for monitoring rumen microbial functions. PMID- 26528249 TI - Bacillus cereus efflux protein BC3310 - a multidrug transporter of the unknown major facilitator family, UMF-2. AB - Phylogenetic classification divides the major facilitator superfamily (MFS) into 82 families, including 25 families that are comprised of transporters with no characterized functions. This study describes functional data for BC3310 from Bacillus cereus ATCC 14579, a member of the "unknown major facilitator family-2" (UMF-2). BC3310 was shown to be a multidrug efflux pump conferring resistance to ethidium bromide, SDS and silver nitrate when heterologously expressed in Escherichia coli DH5alpha DeltaacrAB. A conserved aspartate residue (D105) in putative transmembrane helix 4 was identified, which was essential for the energy dependent ethidium bromide efflux by BC3310. Transport proteins of the MFS comprise specific sequence motifs. Sequence analysis of UMF-2 proteins revealed that they carry a variant of the MFS motif A, which may be used as a marker to distinguish easily between this family and other MFS proteins. Genes orthologous to bc3310 are highly conserved within the B. cereus group of organisms and thus belong to the core genome, suggesting an important conserved functional role in the normal physiology of these bacteria. PMID- 26528250 TI - Multiple adaptations to polar and alpine environments within cyanobacteria: a phylogenomic and Bayesian approach. AB - Cyanobacteria are major primary producers in the polar and alpine regions contributing significantly to nitrogen and carbon cycles in the cryosphere. Recent advancements in environmental sequencing techniques have revealed great molecular diversity of microorganisms in cold environments. However, there are no comprehensive phylogenetic analyses including the entire known diversity of cyanobacteria from these extreme environments. We present here a global phylogenetic analysis of cyanobacteria including an extensive dataset comprised of available small subunit (SSU) rRNA gene sequences of cyanobacteria from polar and high altitude environments. Furthermore, we used a large-scale multi-gene (135 proteins and 2 ribosomal RNAs) genome constraint including 57 cyanobacterial genomes. Our analyses produced the first phylogeny of cold cyanobacteria exhibiting robust deep branching relationships implementing a phylogenomic approach. We recovered several clades common to Arctic, Antarctic and alpine sites suggesting that the traits necessary for survival in the cold have been acquired by a range of different mechanisms in all major cyanobacteria lineages. Bayesian ancestral state reconstruction revealed that 20 clades each have common ancestors with high probabilities of being capable of surviving in cold environments. PMID- 26528251 TI - Nitrate and ammonia as nitrogen sources for deep subsurface microorganisms. AB - We investigated the N-utilizing bacterial community in anoxic brackish groundwater of the low and intermediate level nuclear waste repository cave in Olkiluoto, Finland, at 100 m depth using (15)N-based stable isotope probing (SIP) and enrichment with (14/15)N-ammonium or (14/15)N-nitrate complemented with methane. Twenty-eight days of incubation at 12 degrees C increased the concentration of bacterial 16S rRNA and nitrate reductase (narG) gene copies in the substrate amended microcosms simultaneously with a radical drop in the overall bacterial diversity and OTU richness. Hydrogenophaga/Malikia were enriched in all substrate amended microcosms and Methylobacter in the ammonium and ammonium+methane supplemented microcosms. Sulfuricurvum was especially abundant in the nitrate+methane treatment and the unamended incubation control. Membrane-bound nitrate reductase genes (narG) from Polarimonas sp. were detected in the original groundwater, while Burkholderia, Methylibium, and Pseudomonas narG genes were enriched due to substrate supplements. Identified amoA genes belonged to Nitrosomonas sp. (15)N-SIP revealed that Burkholderiales and Rhizobiales clades belonging to the minority groups in the original groundwater used (15)N from ammonium and nitrate as N source indicating an important ecological function of these bacteria, despite their low number, in the groundwater N cycle in Olkiluoto bedrock system. PMID- 26528252 TI - Single cell PCR amplification of diatoms using fresh and preserved samples. AB - Single cell Chelex(r) DNA extraction and nested PCR amplification were used to examine partial gene sequences from natural diatom populations for taxonomic and phylogenetic studies at and above the level of species. DNA was extracted from cells that were either fresh collected or stored in RNAlater. Extractions from Lugol's fixation were also attempted with limited success. Three partial gene sequences (rbcL, 18S, and psbA) were recovered using existing and new primers with a nested or double nested PCR approach with amplification and success rates between 70 and 96%. An rbcL consensus tree grouped morphologically similar specimens and was consistent across the two primary sample treatments: fresh and RNAlater. This tool will greatly enhance the number of microscopic diatom taxa (and potentially other microbes) available for barcoding and phylogenetic studies. The near-term increase in sequence data for diatoms generated via routine single cell extractions and PCR will act as a multiproxy validation of longer-term next generation genomics. PMID- 26528253 TI - Metagenomic analysis of the rumen microbial community following inhibition of methane formation by a halogenated methane analog. AB - Japanese goats fed a diet of 50% Timothy grass and 50% concentrate with increasing levels of the anti-methanogenic compound, bromochloromethane (BCM) were investigated with respect to the microbial population and functional shifts in the rumen. Microbial ecology methods identified species that exhibited positive and negative responses to the increasing levels of BCM. The methane inhibited rumen appeared to adapt to the higher H2 levels by shifting fermentation to propionate which was mediated by an increase in the population of H2-consuming Prevotella and Selenomonas spp. Metagenomic analysis of propionate production pathways was dominated by genomic content from these species. Reductive acetogenic marker gene libraries and metagenomics analysis indicate that reductive acetogenic species do not play a major role in the BCM treated rumen. PMID- 26528254 TI - Application of modified-alginate encapsulated carbonate producing bacteria in concrete: a promising strategy for crack self-healing. AB - Self-healing concrete holds promising benefits to reduce the cost for concrete maintenance and repair as cracks are autonomously repaired without any human intervention. In this study, the application of a carbonate precipitating bacterium Bacillus sphaericus was explored. Regarding the harsh condition in concrete, B. sphaericus spores were first encapsulated into a modified-alginate based hydrogel (AM-H) which was proven to have a good compatibility with the bacteria and concrete regarding the influence on bacterial viability and concrete strength. Experimental results show that the spores were still viable after encapsulation. Encapsulated spores can precipitate a large amount of CaCO3 in/on the hydrogel matrix (around 70% by weight). Encapsulated B. sphaericus spores were added into mortar specimens and bacterial in situ activity was demonstrated by the oxygen consumption on the mimicked crack surface. While specimens with free spores added showed no oxygen consumption. This indicates the efficient protection of the hydrogel for spores in concrete. To conclude, the AM-H encapsulated carbonate precipitating bacteria have great potential to be used for crack self-healing in concrete applications. PMID- 26528255 TI - Ces locus embedded proteins control the non-ribosomal synthesis of the cereulide toxin in emetic Bacillus cereus on multiple levels. AB - The emetic toxin cereulide produced by Bacillus cereus is synthesized by the modular enzyme complex Ces that is encoded on a pXO1-like megaplasmid. To decipher the role of the genes adjacent to the structural genes cesA/cesB, coding for the non-ribosomal peptide synthetase (NRPS), gene inactivation- and overexpression mutants of the emetic strain F4810/72 were constructed and their impact on cereulide biosynthesis was assessed. The hydrolase CesH turned out to be a part of the complex regulatory network controlling cereulide synthesis on a transcriptional level, while the ABC transporter CesCD was found to be essential for post-translational control of cereulide synthesis. Using a gene inactivation approach, we show that the NRPS activating function of the phosphopantetheinyl transferase (PPtase) embedded in the ces locus was complemented by a chromosomally encoded Sfp-like PPtase, representing an interesting example for the functional interaction between a plasmid encoded NRPS and a chromosomally encoded activation enzyme. In summary, our results highlight the complexity of cereulide biosynthesis and reveal multiple levels of toxin formation control. ces operon internal genes were shown to play a pivotal role by acting at different levels of toxin production, thus complementing the action of the chromosomal key transcriptional regulators AbrB and CodY. PMID- 26528256 TI - Different Candida parapsilosis clinical isolates and lipase deficient strain trigger an altered cellular immune response. AB - Numerous human diseases can be associated with fungal infections either as potential causative agents or as a result of changed immune status due to a primary disease. Fungal infections caused by Candida species can vary from mild to severe dependent upon the site of infection, length of exposure, and past medical history. Patients with impaired immune status are at increased risk for chronic fungal infections. Recent epidemiologic studies have revealed the increasing incidence of candidiasis caused by non-albicans species such as Candida parapsilosis. Due to its increasing relevance we chose two distinct C. parapsilosis strains, to describe the cellular innate immune response toward this species. In the first section of our study we compared the interaction of CLIB 214 and GA1 cells with murine and human macrophages. Both strains are commonly used to investigate C. parapsilosis virulence properties. CLIB 214 is a rapidly pseudohyphae-forming strain and GA1 is an isolate that mainly exists in a yeast form. Our results showed, that the phagocyte response was similar in terms of overall uptake, however differences were observed in macrophage migration and engulfment of fungal cells. As C. parapsilosis releases extracellular lipases in order to promote host invasion we further investigated the role of these secreted components during the distinct stages of the phagocytic process. Using a secreted lipase deficient mutant strain and the parental strain GA1 individually and simultaneously, we confirmed that fungal secreted lipases influence the fungi's virulence by detecting altered innate cellular responses. In this study we report that two isolates of a single species can trigger markedly distinct host responses and that lipase secretion plays a role on the cellular level of host pathogen interactions. PMID- 26528257 TI - Environmental and microbial factors influencing methane and nitrous oxide fluxes in Mediterranean cork oak woodlands: trees make a difference. AB - Cork oak woodlands (montado) are agroforestry systems distributed all over the Mediterranean basin with a very important social, economic and ecological value. A generalized cork oak decline has been occurring in the last decades jeopardizing its future sustainability. It is unknown how loss of tree cover affects microbial processes that are consuming greenhouse gases in the montado ecosystem. The study was conducted under two different conditions in the natural understory of a cork oak woodland in center Portugal: under tree canopy (UC) and open areas without trees (OA). Fluxes of methane and nitrous oxide were measured with a static chamber technique. In order to quantify methanotrophs and bacteria capable of nitrous oxide consumption, we used quantitative real-time PCR targeting the pmoA and nosZ genes encoding the subunit of particulate methane mono-oxygenase and catalytic subunit of the nitrous oxide reductase, respectively. A significant seasonal effect was found on CH4 and N2O fluxes and pmoA and nosZ gene abundance. Tree cover had no effect on methane fluxes; conversely, whereas the UC plots were net emitters of nitrous oxide, the loss of tree cover resulted in a shift in the emission pattern such that the OA plots were a net sink for nitrous oxide. In a seasonal time scale, the UC had higher gene abundance of Type I methanotrophs. Methane flux correlated negatively with abundance of Type I methanotrophs in the UC plots. Nitrous oxide flux correlated negatively with nosZ gene abundance at the OA plots in contrast to that at the UC plots. In the UC soil, soil organic matter had a positive effect on soil extracellular enzyme activities, which correlated positively with the N2O flux. Our results demonstrated that tree cover affects soil properties, key enzyme activities and abundance of microorganisms and, consequently net CH4 and N2O exchange. PMID- 26528258 TI - Cell membrane fatty acid changes and desaturase expression of Saccharomyces bayanus exposed to high pressure homogenization in relation to the supplementation of exogenous unsaturated fatty acids. AB - AIMS: The aim of this work was to study the responses of Saccharomyces bayanus cells exposed to sub-lethal high-pressure homogenization (HPH) and determine whether the plasmatic membrane can sense HPH in the presence, or absence, of exogenous unsaturated fatty acids (UFAs) in the growth medium. METHODS AND RESULTS: High-pressure homogenization damaged and caused the collapse of cell walls and membranes of a portion of cells; however, HPH did not significantly affect S. bayanus cell viability (less than 0.3 Log CFU ml(-1)). HPH strongly affected the membrane fatty acid (FA) composition by increasing the percentage of total UFA when compared with saturated fatty acids. The gene expression showed that the transcription of OLE1, ERG3, and ERG11 increased after HPH. The presence of exogenous UFA abolished HPH-induced effects on the OLE1 and ERG3 genes, increased the percentage of membrane lipids and decreased the expression of OLE1 and ERG3 within 30 min of treatment. CONCLUSION: The results suggest a key role for UFA in the microbial cell response to sub-lethal stress. In addition, these data provide insight into the molecular basis of the response of S. bayanus to this innovative technology. SIGNIFICANCE AND IMPACT OF THE STUDY: Elucidation of the mechanism of action for sub-lethal HPH will enable the utilization of this technology to modulate the starter performance at the industrial scale. PMID- 26528259 TI - Microbial production of scleroglucan and downstream processing. AB - Synthetic petroleum-based polymers and natural plant polymers have the disadvantage of restricted sources, in addition to the non-biodegradability of the former ones. In contrast, eco-sustainable microbial polysaccharides, of low cost and standardized production, represent an alternative to address this situation. With a strong global market, they attracted worldwide attention because of their novel and unique physico-chemical properties as well as varied industrial applications, and many of them are promptly becoming economically competitive. Scleroglucan, a beta-1,3-beta-1,6-glucan secreted by Sclerotium fungi, exhibits high potential for commercialization and may show different branching frequency, side-chain length, and/or molecular weight depending on the producing strain or culture conditions. Water-solubility, viscosifying ability and wide stability over temperature, pH and salinity make scleroglucan useful for different biotechnological (enhanced oil recovery, food additives, drug delivery, cosmetic and pharmaceutical products, biocompatible materials, etc.), and biomedical (immunoceutical, antitumor, etc.) applications. It can be copiously produced at bioreactor scale under standardized conditions, where a high exopolysaccharide concentration normally governs the process optimization. Operative and nutritional conditions, as well as the incidence of scleroglucan downstream processing will be discussed in this chapter. The relevance of using standardized inocula from selected strains and experiences concerning the intricate scleroglucan scaling-up will be also herein outlined. PMID- 26528260 TI - Marine Group II Archaea, potentially important players in the global ocean carbon cycle. AB - Marine Group (MG) I (currently known as Thaumarchaeota) and MG II Archaea were first reported over two decades ago. While significant progress has been made on MG I microbiology and ecology, the progress on MG II has been noticeably slower. The common understanding is that while MG I mainly function as chemolithoautotrophs and occur predominantly in the deep ocean, MG II reside mostly in the photic zone and live heterotrophically. Studies to date have shown that MG II are abundant in the marine aquatic environment and display great seasonal and spatial variation and phylogenetic diversity. They also show unique patterns of organic carbon degradation and their energy requirements may be augmented by light in the photic zone. However, no pure culture of MG II has been obtained and thus their precise ecological role remains elusive. PMID- 26528261 TI - A combined bioinformatics and functional metagenomics approach to discovering lipolytic biocatalysts. AB - The majority of protein sequence data published today is of metagenomic origin. However, our ability to assign functions to these sequences is often hampered by our general inability to cultivate the larger part of microbial species and the sheer amount of sequence data generated in these projects. Here we present a combination of bioinformatics, synthetic biology, and Escherichia coli genetics to discover biocatalysts in metagenomic datasets. We created a subset of the Global Ocean Sampling dataset, the largest metagenomic project published to date, by removing all proteins that matched Hidden Markov Models of known protein families from PFAM and TIGRFAM with high confidence (E-value > 10(-5)). This essentially left us with proteins with low or no homology to known protein families, still encompassing ~1.7 million different sequences. In this subset, we then identified protein families de novo with a Markov clustering algorithm. For each protein family, we defined a single representative based on its phylogenetic relationship to all other members in that family. This reduced the dataset to ~17,000 representatives of protein families with more than 10 members. Based on conserved regions typical for lipases and esterases, we selected a representative gene from a family of 27 members for synthesis. This protein, when expressed in E. coli, showed lipolytic activity toward para-nitrophenyl (pNP) esters. The K m value of the enzyme was 66.68 MUM for pNP-butyrate and 68.08 MUM for pNP palmitate with k cat/K m values at 3.4 * 10(6) and 6.6 * 10(5) M(-1)s(-1), respectively. Hydrolysis of model substrates showed enantiopreference for the R form. Reactions yielded 43 and 61% enantiomeric excess of products with ibuprofen methyl ester and 2-phenylpropanoic acid ethyl ester, respectively. The enzyme retains 50% of its maximum activity at temperatures as low as 10 degrees C, its activity is enhanced in artificial seawater and buffers with higher salt concentrations with an optimum osmolarity of 3,890 mosmol/l. PMID- 26528262 TI - Effects of sludge inoculum and organic feedstock on active microbial communities and methane yield during anaerobic digestion. AB - Anaerobic digestion (AD) is a widespread microbial technology used to treat organic waste and recover energy in the form of methane ("biogas"). While most AD systems have been designed to treat a single input, mixtures of digester sludge and solid organic waste are emerging as a means to improve efficiency and methane yield. We examined laboratory anaerobic cultures of AD sludge from two sources amended with food waste, xylose, and xylan at mesophilic temperatures, and with cellulose at meso- and thermophilic temperatures, to determine whether and how the inoculum and substrate affect biogas yield and community composition. All substrate and inoculum combinations yielded methane, with food waste most productive by mass. Pyrosequencing of transcribed bacterial and archaeal 16S rRNA showed that community composition varied across substrates and inocula, with differing ratios of hydrogenotrophic/acetoclastic methanogenic archaea associated with syntrophic partners. While communities did not cluster by either inoculum or substrate, additional sequencing of the bacterial 16S rRNA gene in the source sludge revealed that the bacterial communities were influenced by their inoculum. These results suggest that complete and efficient AD systems could potentially be assembled from different microbial inocula and consist of taxonomically diverse communities that nevertheless perform similar functions. PMID- 26528263 TI - Stereoselective chemo-enzymatic oxidation routes for (1R,3E,7E,11S,12S)-3,7,18 dolabellatriene. AB - The diterpene (1R,3E,7E,11S,12S)-3,7,18-dolabellatriene from the marine brown alga Dilophus spiralis belongs to the dolabellanes natural product family and has antimicrobial activity against multi-drug resistant Staphylococcus aureus. Recently, we generated a CotB2 diterpene synthase mutant (W288G), which instead of its native product cyclooctat-9-en-7-ol, generates (1R,3E,7E,11S,12S)-3,7,18 dolabellatriene. In vivo CotB2 W288G reconstitution in an Escherichia coli based terpene production system, allowed efficient production of this olefinic macrocycle. To diversify the 3,7,18-dolabellatriene bioactivity we evaluated chemical and enzymatic methods for selective oxidation. Epoxidation by acetic peracid, which was formed in situ by a lipase catalyzed reaction of acetic acid with H2O2, provided efficient access to two monooxidized dolabellanes and to a novel di-epoxidated dolabellane species. These compounds could act as synthons en route to new dolabellanes with diversified bioactivities. Furthermore, we demonstrate the almost quantitative 3,7,18-dolabellatriene conversion into the new, non-natural compound (1R,3E,7E,11S,12S,18R)-dolabella-3,7-diene-20-ol by hydroboration-oxidation with an enantiomeric excess of 94%, for the first time. PMID- 26528264 TI - Regulation of fucose and 1,2-propanediol utilization by Salmonella enterica serovar Typhimurium. AB - After ingestion, Salmonella enterica serovar Typhimurium (S. Typhimurium) encounters a densely populated, competitive environment in the gastrointestinal tract. To escape nutrient limitation caused by the intestinal microbiota, this pathogen has acquired specific metabolic traits to use compounds that are not metabolized by the commensal bacteria. For example, the utilization of 1,2 propanediol (1,2-PD), a product of the fermentation of L-fucose, which is present in foods of herbal origin and is also a terminal sugar of gut mucins. Under anaerobic conditions and in the presence of tetrathionate, 1,2-PD can serve as an energy source for S. Typhimurium. Comprehensive database analysis revealed that the 1,2-PD and fucose utilization operons are present in all S. enterica serovars sequenced thus far. The operon, consisting of 21 genes, is expressed as a single polycistronic mRNA. As demonstrated here, 1,2-PD was formed and further used when S. Typhimurium strain 14028 was grown with L-fucose, and the gene fucA encoding L fuculose-1-phosphate aldolase was required for this growth. Using promoter fusions, we monitored the expression of the propanediol utilization operon that was induced at very low concentrations of 1,2-PD and was inhibited by the presence of D-glucose. PMID- 26528265 TI - Can the duration of tuberculosis treatment be shortened with higher dosages of rifampicin? PMID- 26528266 TI - Metabolic functions of Pseudomonas fluorescens strains from Populus deltoides depend on rhizosphere or endosphere isolation compartment. AB - The bacterial microbiota of plants is diverse, with 1000s of operational taxonomic units (OTUs) associated with any individual plant. In this work, we used phenotypic analysis, comparative genomics, and metabolic models to investigate the differences between 19 sequenced Pseudomonas fluorescens strains. These isolates represent a single OTU and were collected from the rhizosphere and endosphere of Populus deltoides. While no traits were exclusive to either endosphere or rhizosphere P. fluorescens isolates, multiple pathways relevant for plant-bacterial interactions are enriched in endosphere isolate genomes. Further, growth phenotypes such as phosphate solubilization, protease activity, denitrification and root growth promotion are biased toward endosphere isolates. Endosphere isolates have significantly more metabolic pathways for plant signaling compounds and an increased metabolic range that includes utilization of energy rich nucleotides and sugars, consistent with endosphere colonization. Rhizosphere P. fluorescens have fewer pathways representative of plant-bacterial interactions but show metabolic bias toward chemical substrates often found in root exudates. This work reveals the diverse functions that may contribute to colonization of the endosphere by bacteria and are enriched among closely related isolates. PMID- 26528267 TI - Amdoparvoviruses in small mammals: expanding our understanding of parvovirus diversity, distribution, and pathology. AB - Many new viruses have been discovered recently, thanks in part to the advent of next-generation sequencing technologies. Among the Parvoviridae, three novel members of the genus Amdoparvovirus have been described in the last 4 years, expanding this genus that had contained a single species since its discovery, Aleutian mink disease virus. The increasing number of molecular and epidemiological studies on these viruses around the world also highlights the growing interest in this genus. Some aspects of amdoparvoviruses have been well characterized, however, many other aspects still need to be elucidated and the most recent reviews on this topic are outdated. We provide here an up-to-date overview of what is known and what still needs to be investigated about these scientifically and clinically relevant animal viruses. PMID- 26528268 TI - Salt resistance genes revealed by functional metagenomics from brines and moderate-salinity rhizosphere within a hypersaline environment. AB - Hypersaline environments are considered one of the most extreme habitats on earth and microorganisms have developed diverse molecular mechanisms of adaptation to withstand these conditions. The present study was aimed at identifying novel genes from the microbial communities of a moderate-salinity rhizosphere and brine from the Es Trenc saltern (Mallorca, Spain), which could confer increased salt resistance to Escherichia coli. The microbial diversity assessed by pyrosequencing of 16S rRNA gene libraries revealed the presence of communities that are typical in such environments and the remarkable presence of three bacterial groups never revealed as major components of salt brines. Metagenomic libraries from brine and rhizosphere samples, were transferred to the osmosensitive strain E. coli MKH13, and screened for salt resistance. Eleven genes that conferred salt resistance were identified, some encoding for well known proteins previously related to osmoadaptation such as a glycerol transporter and a proton pump, whereas others encoded proteins not previously related to this function in microorganisms such as DNA/RNA helicases, an endonuclease III (Nth) and hypothetical proteins of unknown function. Furthermore, four of the retrieved genes were cloned and expressed in Bacillus subtilis and they also conferred salt resistance to this bacterium, broadening the spectrum of bacterial species in which these genes can function. This is the first report of salt resistance genes recovered from metagenomes of a hypersaline environment. PMID- 26528269 TI - Computational analysis of candidate prion-like proteins in bacteria and their role. AB - Prion proteins were initially associated with diseases such as Creutzfeldt Jakob and transmissible spongiform encephalopathies. However, deeper research revealed them as versatile tools, exploited by the cells to execute fascinating functions, acting as epigenetic elements or building membrane free compartments in eukaryotes. One of the most intriguing properties of prion proteins is their ability to propagate a conformational assembly, even across species. In this context, it has been observed that bacterial amyloids can trigger the formation of protein aggregates by interacting with host proteins. As our life is closely linked to bacteria, either through a parasitic or symbiotic relationship, prion like proteins produced by bacterial cells might play a role in this association. Bioinformatics is helping us to understand the factors that determine conformational conversion and infectivity in prion-like proteins. We have used PrionScan to detect prion domains in 839 different bacteria proteomes, detecting 2200 putative prions in these organisms. We studied this set of proteins in order to try to understand their functional role and structural properties. Our results suggest that these bacterial polypeptides are associated to peripheral rearrangement, macromolecular assembly, cell adaptability, and invasion. Overall, these data could reveal new threats and therapeutic targets associated to infectious diseases. PMID- 26528270 TI - Dissimilatory nitrogen reduction in intertidal sediments of a temperate estuary: small scale heterogeneity and novel nitrate-to-ammonium reducers. AB - The estuarine nitrogen cycle can be substantially altered due to anthropogenic activities resulting in increased amounts of inorganic nitrogen (mainly nitrate). In the past, denitrification was considered to be the main ecosystem process removing reactive nitrogen from the estuarine ecosystem. However, recent reports on the contribution of dissimilatory nitrate reduction to ammonium (DNRA) to nitrogen removal in these systems indicated a similar or higher importance, although the ratio between both processes remains ambiguous. Compared to denitrification, DNRA has been underexplored for the last decades and the key organisms carrying out the process in marine environments are largely unknown. Hence, as a first step to better understand the interplay between denitrification, DNRA and reduction of nitrate to nitrite in estuarine sediments, nitrogen reduction potentials were determined in sediments of the Paulina polder mudflat (Westerschelde estuary). We observed high variability in dominant nitrogen removing processes over a short distance (1.6 m), with nitrous oxide, ammonium and nitrite production rates differing significantly between all sampling sites. Denitrification occurred at all sites, DNRA was either the dominant process (two out of five sites) or absent, while nitrate reduction to nitrite was observed in most sites but never dominant. In addition, novel nitrate to-ammonium reducers assigned to Thalassospira, Celeribacter, and Halomonas, for which DNRA was thus far unreported, were isolated, with DNRA phenotype reconfirmed through nrfA gene amplification. This study demonstrates high small scale heterogeneity among dissimilatory nitrate reduction processes in estuarine sediments and provides novel marine DNRA organisms that represent valuable alternatives to the current model organisms. PMID- 26528271 TI - Heat Shock Protein 90 regulates encystation in Entamoeba. AB - Enteric protozoan Entamoeba histolytica is a major cause of debilitating diarrheal infection worldwide with high morbidity and mortality. Even though the clinical burden of this parasite is very high, this infection is categorized as a neglected disease. Parasite is transmitted through feco-oral route and exhibit two distinct stages namely - trophozoites and cysts. Mechanism and regulation of encystation is not clearly understood. Previous studies have established the role of Heat shock protein 90 (Hsp90) in regulating stage transition in various protozoan parasites like Giardia, Plasmodium, Leishmania, and Toxoplasma. Our study for the first time reports that Hsp90 plays a crucial role in life cycle of Entamoeba as well. We identify Hsp90 to be a negative regulator of encystation in Entamoeba. We also show that Hsp90 inhibition interferes with the process of phagocytosis in Entamoeba. Overall, we show that Hsp90 plays an important role in virulence and transmission of Entamoeba. PMID- 26528272 TI - Nonlinear temperature sensitivity of enzyme kinetics explains canceling effect-a case study on loamy haplic Luvisol. AB - The temperature sensitivity of enzymes responsible for organic matter decomposition in soil is crucial for predicting the effects of global warming on the carbon cycle and sequestration. We tested the hypothesis that differences in temperature sensitivity of enzyme kinetic parameters V max and K m will lead to a canceling effect: strong reduction of temperature response of catalytic reactions. Short-term temperature response of V max and K m of three hydrolytic enzymes responsible for decomposition of cellulose (beta-glucosidase, cellobiohydrolase) and hemicelluloses (xylanase) were analyzed in situ from 0 to 40 degrees C. The apparent activation energy varied between enzymes from 20.7 to 35.2 kJ mol(-1) corresponding to the Q 10 values of the enzyme activities of 1.4 1.9 (with V max - Q 10 1.0-2.5 and K m - Q 10 0.94-2.3). Temperature response of all tested enzymes fitted well to the Arrhenius equation. Despite that, the fitting of Arrhenius model revealed the non-linear increase of two cellulolytic enzymes activities with two distinct thresholds at 10-15 degrees C and 25-30 degrees C, which were less pronounced for xylanase. The nonlinearity between 10 and 15 degrees C was explained by 30-80% increase in V max . At 25-30 degrees C, however, the abrupt decrease of enzyme-substrate affinity was responsible for non linear increase of enzyme activities. Our study is the first demonstrating nonlinear response of V max and K m to temperature causing canceling effect, which was most strongly pronounced at low substrate concentrations and at temperatures above 15 degrees C. Under cold climate, however, the regulation of hydrolytic activity by canceling in response to warming is negligible because canceling was never observed below 10 degrees C. The canceling, therefore, can be considered as natural mechanism reducing the effects of global warming on decomposition of soil organics at moderate temperatures. The non-linearity of enzyme responses to warming and the respective thresholds should therefore be investigated for other enzymes, and incorporated into Earth system models to improve the predictions at regional and global levels. PMID- 26528273 TI - Synergistic anti-Campylobacter jejuni activity of fluoroquinolone and macrolide antibiotics with phenolic compounds. AB - The increasing resistance of Campylobacter to clinically important antibiotics, such as fluoroquinolones and macrolides, is a serious public health problem. The objective of this study is to investigate synergistic anti-Campylobacter jejuni activity of fluoroquinolones and macrolides in combination with phenolic compounds. Synergistic antimicrobial activity was measured by performing a checkerboard assay with ciprofloxacin and erythromycin in the presence of 21 phenolic compounds. Membrane permeability changes in C. jejuni by phenolic compounds were determined by measuring the level of intracellular uptake of 1-N phenylnaphthylamine (NPN). Antibiotic accumulation assays were performed to evaluate the level of ciprofloxacin accumulation in C. jejuni. Six phenolic compounds, including p-coumaric acid, sinapic acid, caffeic acid, vanillic acid, gallic acid, and taxifolin, significantly increased the susceptibility to ciprofloxacin and erythromycin in several human and poultry isolates. The synergistic antimicrobial effect was also observed in ciprofloxacin- and erythromycin-resistant C. jejuni strains. The phenolic compounds also substantially increased membrane permeability and antibiotic accumulation in C. jejuni. Interestingly, some phenolic compounds, such as gallic acid and taxifolin, significantly reduced the expression of the CmeABC multidrug efflux pump. Phenolic compounds increased the NPN accumulation in the cmeB mutant, indicating phenolic compounds may affect the membrane permeability. In this study, we successfully demonstrated that combinational treatment of C. jejuni with antibiotics and phenolic compounds synergistically inhibits C. jejuni by impacting both antimicrobial influx and efflux. PMID- 26528275 TI - Erratum: Glucose-tolerant beta-glucosidase retrieved from a Kusaya gravy metagenome. AB - [This corrects the article on p. 548 in vol. 6, PMID: 26136726.]. PMID- 26528274 TI - VarR controls colonization and virulence in the marine macroalgal pathogen Nautella italica R11. AB - There is increasing evidence to suggest that macroalgae (seaweeds) are susceptible to infectious disease. However, to date, little is known about the mechanisms that facilitate the colonization and virulence of microbial seaweed pathogens. One well-described example of a seaweed disease is the bleaching of the red alga Delisea pulchra, which can be caused by the bacterium Nautella italica R11, a member of the Roseobacter clade. This pathogen contains a unique luxR-type gene, varR, which we hypothesize controls its colonization and virulence. We show here that a varR knock-out strain is deficient in its ability to cause disease in D. pulchra and is defective in biofilm formation and attachment to a common algal polysaccharide. Moreover complementation of the varR gene in trans can restore these functions to the wild type levels. Proteomic analysis of bacterial cells in planktonic and biofilm growth highlight the potential importance of nitrogen scavenging, mobilization of energy reserves, and stress resistance in the biofilm lifestyle of N. italica R11. Moreover, we show that VarR regulates the expression of a specific subset of biofilm-associated proteins. Taken together these data suggest that VarR controls colonization and persistence of N. italica R11 on the surface of a macroalgal host and that it is an important regulator of virulence. PMID- 26528276 TI - Manipulating rumen microbiome and fermentation through interventions during early life: a review. AB - The nutritional manipulations of the rumen microbiome to enhance productivity and health are rather limited by the resilience of the ecosystem once established in the mature rumen. Based on recent studies, it has been suggested that the microbial colonization that occurs soon after birth opens a possibility of manipulation with potential to produce lasting effects into adult life. This paper presents the state-of-the-art in relation to early life nutritional interventions by addressing three areas: the development of the rumen as an organ in regards to the nutrition of the new-born, the main factors that determine the microbial population that first colonizes and establishes in the rumen, and the key immunity players that contribute to shaping the commensal microbiota in the early stage of life to understand host-microbiome specificity. The development of the rumen epithelium and muscularization are differently affected by the nature of the diet and special care should be taken with regards to transition from liquid (milk) to solid feed. The rumen is quickly colonized by all type of microorganisms straight after birth and the colonization pattern may be influenced by several factors such as presence/absence of adult animals, the first solid diet provided, and the inclusion of compounds that prevent/facilitate the establishment of some microorganisms or the direct inoculation of specific strains. The results presented show how early life events may be related to the microbial community structure and/or the rumen activity in the animals post weaning. This would create differences in adaptive capacity due to different early life experiences and leads to the idea of microbial programming. However, many elements need to be further studied such as: the most sensitive window of time for interventions, the best means to test long term effectiveness, the role of key microbial groups and host-immune regulations. PMID- 26528277 TI - Neutropenia exacerbates infection by Acinetobacter baumannii clinical isolates in a murine wound model. AB - The Gram negative coccobacillus Acinetobacter baumannii has become an increasingly prevalent cause of hospital-acquired infections in recent years. The majority of clinical A. baumannii isolates display high-level resistance to antimicrobials, which severely compromises our capacity to care for patients with A. baumannii disease. Neutrophils are of major importance in the host defense against microbial infections. However, the contribution of these cells of innate immunity in host resistance to cutaneous A. baumannii infection has not been directly investigated. Hence, we hypothesized that depletion of neutrophils increases severity of bacterial disease in an experimental A. baumannii murine wound model. In this study, the Ly-6G-specific monoclonal antibody (mAb), 1A8, was used to generate neutropenic mice and the pathogenesis of several A. baumannii clinical isolates on wounded cutaneous tissue was investigated. We demonstrated that neutrophil depletion enhances bacterial burden using colony forming unit determinations. Also, mAb 1A8 reduces global measurements of wound healing in A. baumannii-infected animals. Interestingly, histological analysis of cutaneous tissue excised from A. baumannii-infected animals treated with mAb 1A8 displays enhanced collagen deposition. Furthermore, neutropenia and A. baumannii infection alter pro-inflammatory cytokine release leading to severe microbial disease. Our findings provide a better understanding of the impact of these innate immune cells in controlling A. baumannii skin infections. PMID- 26528278 TI - Characterization of CTX-M-14-producing Escherichia coli from food-producing animals. AB - Bacterial resistance to the third-generation cephalosporin antibiotics has become a major concern for public health. This study was aimed to determine the characteristics and distribution of bla CTX-M-14, which encodes an extended spectrum beta-lactamase, in Escherichia coli isolated from Guangdong Province, China. A total of 979 E. coli isolates isolated from healthy or diseased food producing animals including swine and avian were examined for bla CTX-M-14 and then the bla CTX-M-14 -positive isolates were detected by other resistance determinants [extended-spectrum beta-lactamase genes, plasmid-mediated quinolone resistance, rmtB, and floR] and analyzed by phylogenetic grouping analysis, PCR based plasmid replicon typing, multilocus sequence typing, and plasmid analysis. The genetic environments of bla CTX-M-14 were also determined by PCR. The results showed that fourteen CTX-M-14-producing E. coli were identified, belonging to groups A (7/14), B1 (4/14), and D (3/14). The most predominant resistance gene was bla TEM (n = 8), followed by floR (n = 7), oqxA (n = 3), aac(6')-1b-cr (n = 2), and rmtB (n = 1). Plasmids carrying bla CTX-M-14 were classified to IncK, IncHI2, IncHI1, IncN, IncFIB, IncF or IncI1, ranged from about 30 to 200 kb, and with insertion sequence of ISEcp1, IS26, or ORF513 located upstream and IS903 downstream of bla CTX-M-14. The result of multilocus sequence typing showed that 14 isolates had 11 STs, and the 11 STs belonged to five groups. Many of the identified sequence types are reported to be common in E. coli isolates associated with extraintestinal infections in humans, suggesting possible transmission of bla CTX-M-14 between animals and humans. The difference in the flanking sequences of bla CTX-M-14 between the 2009 isolates and the early ones suggests that the resistance gene context continues to evolve in E. coli of food producing animals. PMID- 26528279 TI - Inactivation of the MAPK signaling pathway by Listeria monocytogenes infection promotes trophoblast giant cell death. AB - Listeria monocytogenes has a well-characterized ability to cross the placental barrier, resulting in spontaneous abortion and fetal infections. However, the mechanisms resulting in infection-associated abortion are not fully understood. In this study, we demonstrate that the dephosphorylation of MAPK family proteins caused by L. monocytogenes infection of trophoblast giant (TG) cells, which are placental immune cells, contributes to infectious abortion. Dephosphorylation of c-Jun, p38, and ERK1/2 was observed in infected TG cells, causing the downregulation of cytoprotective heme oxygenase (HO)-1. Blocking the dephosphorylation of proteins, including MAPK family proteins, inhibited the decrease in HO-1 expression. Treatment with MAPK inhibitors inhibited bacterial internalization into TG cells. Moreover, Toll-like receptor 2 involved in the expression of MAPK family proteins. Infection with a listeriolysin O-deleted mutant impaired dephosphorylation of MAPK family proteins in TG cells and did not induce infectious abortion in a mouse model. These results suggest that inactivation of the MAPK pathway by L. monocytogenes induces TG cell death and causes infectious abortion. PMID- 26528280 TI - Characterization of genetic structures of the QepA3 gene in clinical isolates of Enterobacteriaceae. AB - QepA is one of the genes that confer quinolone resistance in bacteria. The aim of this study was to analyze the genetic structures of plasmids that carry a qepA3, a recently discovered allele of qepA in Enterobacteriaceae clinical isolates. 656 non-redundant Enterobacteriaceae clinical isolates were screened for the qepA3 gene and five isolates were identified to carry the gene. Plasmids were isolated from these isolates and were found to increase antibiotic resistance once the plasmids were transferred to Escherichia coli. These plasmids were subcloned and sequenced to analyze the genetic structures surrounding the qepA3 gene. The results showed that the five plasmids had different genetic structures; two of the qepA3-containning isolates had either the bla CTX-M-14 or bla TEM-12 gene instead of the bla TEM-1 gene. The structures of both pKP3764 and pECL3786 have not been previously described. In comparison with pHPA, there were a number of changes in DNA sequences up- and down-stream of the qepA3 gene. These findings provide better understanding of the genetic variations in qepA3 and would be useful for diagnosis and control of quinolone resistance in clinical settings. PMID- 26528281 TI - Disruptions of the intestinal microbiome in necrotizing enterocolitis, short bowel syndrome, and Hirschsprung's associated enterocolitis. AB - Next generation sequencing techniques are currently revealing novel insight into the microbiome of the human gut. This new area of research seems especially relevant for neonatal diseases, because the development of the intestinal microbiome already starts in the perinatal period and preterm infants with a still immature gut associated immune system may be harmed by a dysproportional microbial colonization. For most gastrointestinal diseases requiring pediatric surgery there is very limited information about the role of the intestinal microbiome. This review aims to summarize the current knowledge and outline future perspectives for important pathologies like necrotizing enterocolitis (NEC) of the newborn, short bowel syndrome (SBS), and Hirschsprung's disease associated enterocolitis (HAEC). Only studies applying next generation sequencing techniques to analyze the diversity of the intestinal microbiome were included. In NEC patients intestinal dysbiosis could already be detected prior to any clinical evidence of the disease resulting in a reduction of the bacterial diversity. In SBS patients the diversity seems to be reduced compared to controls. In children with Hirschsprung's disease the intestinal microbiome differs between those with and without episodes of enterocolitis. One common finding for all three diseases seems to be an overabundance of Proteobacteria. However, most human studies are based on fecal samples and experimental data question whether fecal samples actually represent the microbiome at the site of the diseased bowel and whether the luminal (transient) microbiome compares to the mucosal (resident) microbiome. In conclusion current studies already allow a preliminary understanding of the potential role of the intestinal microbiome in pediatric surgical diseases. Future investigations could clarify the interface between the intestinal epithelium, its immunological competence and mucosal microbiome. Advances in this field may have an impact on the understanding and non-operative treatment of such diseases in infancy. PMID- 26528282 TI - Selective isolation of ammonia-oxidizing bacteria from autotrophic nitrifying granules by applying cell-sorting and sub-culturing of microcolonies. AB - Nitrification is a key process in the biogeochemical nitrogen cycle and biological wastewater treatment that consists of two stepwise reactions, ammonia oxidation by ammonia-oxidizing bacteria (AOB) or archaea followed by nitrite oxidation by nitrite-oxidizing bacteria. One of the representatives of the AOB group is Nitrosomonas mobilis species. Although a few pure strains of this species have been isolated so far, approaches to their preservation in pure culture have not been established. Here, we report isolation of novel members of the N. mobilis species from autotrophic nitrifying granules used for ammonia-rich wastewater treatment. We developed an isolation method focusing on microcolonies formation of nitrifying bacteria. Two kinds of distinctive light scattering signatures in a cell-sorting system enabled to separate microcolonies from single cells and heterogeneous aggregates within granule samples. Inoculation of a pure microcolony into 96-well microtiter plates led to successful sub-culturing and increased probability of isolation. Obtained strain Ms1 is cultivated in the liquid culture with relatively high ammonia or nitrite concentration, not extremely slow growing. Considering environmental clones that were closely related to N. mobilis and detected in various environments, the availability of this novel strain would facilitate to reveal this member's ecophysiology in a variety of habitats. PMID- 26528283 TI - Alloreactive Natural Killer Cells for the Treatment of Acute Myeloid Leukemia: From Stem Cell Transplantation to Adoptive Immunotherapy. AB - Natural killer (NK) cells express activating and inhibitory receptors, which recognize MHC class-I alleles, termed "Killer cell Immunoglobulin-like Receptors" (KIRs). Preclinical and clinical data from haploidentical T-cell-depleted stem cell transplantation have demonstrated that alloreactive KIR-L mismatched NK cells play a major role as effectors against acute myeloid leukemia (AML). Outside the transplantation setting, several reports have proven the safety and feasibility of NK cell infusion in AML patients and, in some cases, provided evidence that transferred NK cells are functionally alloreactive and may have a role in disease control. The aim of the present work is to briefly summarize the most recent advances in the field by moving from the first preclinical and clinical demonstration of donor NK alloreactivity in the transplantation setting to the most recent attempts at exploiting the use of alloreactive NK cell infusion as a means of adoptive immunotherapy against AML. Altogether, these data highlight the pivotal role of NK cells for the development of novel immunological approaches in the clinical management of AML. PMID- 26528284 TI - Real-Time Imaging of Resident T Cells in Human Lung and Ovarian Carcinomas Reveals How Different Tumor Microenvironments Control T Lymphocyte Migration. AB - T cells play a key role in the battle against cancer. To perform their antitumor activities, T cells need to adequately respond to tumor antigens by establishing contacts with either malignant cells or antigen-presenting cells. These latter functions rely on a series of migratory steps that go from entry of T cells into the tumor followed by their locomotion in the tumor stroma. Our knowledge of how T cells migrate within tumors mainly comes from experiments performed in mouse models. Whereas such systems have greatly advanced our understanding, they do not always faithfully recapitulate the disease observed in cancer patients. We previously described a technique based on tissue slices that enables to track with real-time imaging microscopy the motile behavior of fluorescent T cells plated onto fresh sections of human lung tumors. We have now refined this approach to monitor the locomotion of resident tumor-infiltrating CD8 T cells labeled with fluorescently coupled antibodies. Using this approach, our findings reveal that CD8 T cells accumulate in the stroma of ovarian and lung carcinomas but move slowly in this compartment. Conversely, even though less populated, tumors islets were found to be zones of faster migration for resident CD8 T cells. We also confirm the key role played by collagen fibers, which, by their orientation, spacing and density, control the distribution and migration of resident CD8 T cells within the tumor stroma. We have subsequently demonstrated that, under some physical tissue constraints, CD8 T cells exhibited a mode of migration characterized by alternate forward and backward movements. In sum, using an ex vivo assay to track CD8 T cells in fresh human tumor tissues, we have identified the extracellular matrix as a major stromal component in influencing T cell migration, thereby impacting the control of tumor growth. This approach will aid in the development and testing of novel immunotherapy strategies to promote T cell migration in tumors. PMID- 26528285 TI - Immune Response Modulation by Vitamin D: Role in Systemic Lupus Erythematosus. AB - Vitamin D plays key roles as a natural immune modulator and has been implicated in the pathophysiology of autoimmune diseases, including systemic lupus erythematosus (SLE). This review presents a summary and analysis of the recent literature regarding immunoregulatory effects of vitamin D as well as its importance in SLE development, clinical severity, and possible effects of supplementation in disease treatment. PMID- 26528286 TI - Paving the Road to Tumor Development and Spreading: Myeloid-Derived Suppressor Cells are Ruling the Fate. AB - Cancer development is dependent on intrinsic cellular changes as well as inflammatory factors in the tumor macro and microenvironment. The inflammatory milieu nourishes the tumor and contributes to cancer progression. Numerous studies, including ours, have demonstrated that the tumor microenvironment is immunosuppressive, impairing the anticancer immune responses. Chronic inflammation was identified as the key process responsible for this immunosuppression via induction of immature myeloid-derived suppressor cells (MDSCs). Upon a prolonged immune response, MDSCs are polarized toward immunosuppressive cells meant to control the exacerbated immune response. In cancer, the chronic inflammatory response renders the MDSCs harmful. Polarized MDSCs suppress T-cells and natural killer cells, as well as antigen-presenting cells, abrogating the beneficial immune response. These changes in the immunological milieu could also lead to high frequency of mutations, enhanced cancer cell stemness, and angiogenesis, directly supporting tumor initiation, growth, and spreading. The presence of MDSCs in cancer poses a serious obstacle in a variety of immune-based therapies, which rely on the stimulation of antitumor immune responses. Cumulative data, including our own, suggest that the selection of an appropriate and effective anticancer therapy must take into consideration the host's immune status as well as tumor-related parameters. Merging biomarkers for immune monitoring into the traditional patient's categorization and follow-up can provide new predictive and diagnostic tools to the clinical practice. Chronic inflammation and MDSCs could serve as novel targets for therapeutic interventions, which can be combined with conventional cancer treatments such as chemotherapy, radiotherapy, and cancer cell-targeted and immune-based therapies. Intervention in environmental and tumor-specific inflammatory mechanisms will allow better clinical management of cancer toward more efficient treatment. PMID- 26528287 TI - Kinetoplastid Membrane Protein-11 as a Vaccine Candidate and a Virulence Factor in Leishmania. AB - Kinetoplastid membrane protein-11 (KMP-11), a protein present in all kinetoplastid protozoa, is considered a potential candidate for a leishmaniasis vaccine. In Leishmania amazonensis, KMP-11 is expressed in promastigotes and amastigotes. In both stages, the protein was found in association with membrane structures at the cell surface, flagellar pocket, and intracellular vesicles. More importantly, its surface expression is higher in amastigotes than in promastigotes and increases during metacyclogenesis. The increased expression of KMP-11 in metacyclic promastigotes, and especially in amastigotes, indicates a role for this molecule in the parasite relationship with the mammalian host. In this connection, we have shown that addition of KMP-11 exacerbates L. amazonensis infection in peritoneal macrophages from BALB/c mice by increasing interleukin (IL)-10 secretion and arginase activity while reducing nitric oxide production. The doses of KMP-11, the IL-10 levels, and the intracellular amastigote loads were strongly, positively, and significantly correlated. The increase in parasite load induced by KMP-11 was inhibited by anti-KMP-11 or anti-IL-10-neutralizing antibodies, but not by isotype controls. The neutralizing antibodies, but not the isotype controls, were also able to significantly decrease the parasite load in macrophages cultured without the addition of KMP-11, demonstrating that KMP-11 induced exacerbation of the infection is not dependent on the addition of exogenous KMP-11 and that the protein naturally expressed by the parasite is able to promote it. All these data indicate that KMP-11 acts as a virulence factor in L. amazonensis infection. PMID- 26528288 TI - Predominant Role of Plasmacytoid Dendritic Cells in Stimulating Systemic Autoimmunity. AB - Plasmacytoid dendritic cells (pDCs), which are prominent type I interferon (IFN I)-producing immune cells, have been extensively implicated in systemic lupus erythematosus (SLE). However, whether they participate critically in lupus pathogenesis remains unknown. Recent studies using various genetic and cell type specific ablation strategies have demonstrated that pDCs play a pivotal role in the development of autoantibodies and the progression of lupus under diverse experimental conditions. The findings of several investigations highlight a notion that pDCs operate critically at the early stage of lupus development. In particular, pDCs have a profound effect on B-cell activation and humoral autoimmunity in vivo. This deeper understanding of the vital role of pDCs in lupus pathogenesis supports the therapeutic targeting of the pDC-IFN-I pathway in SLE. PMID- 26528290 TI - The Contribution of CD40/CD40L Axis in Inflammatory Bowel Disease: An Update. AB - Inflammatory bowel disease (IBD) is a chronic and multifactorial disease of the gastrointestinal tract. The exact etiology of IBD remains complex and unclear involving an inadequately defined relationship between microbial insult, genetic predisposition, altered intestinal barrier permeability, oxidative stress components and abnormal immune responses. The role of the co-stimulatory system made up of cluster of differentiation 40 protein (CD40) and its ligand (CD40L) in the response of the immune system to pathogens is now widely accepted. The implication of CD40/CD40L axis in immune system disorders due to its important role as signal transduction pathway among immune cells is well documented. Several studies have suggested that CD40/CD40L interactions regulate oxidative stress; this can affect various signaling pathways leading to IBD development. Hence, CD40/CD40L signaling pathway may become a new target for IBD treatment. This review will cover the general contribution of the CD40/CD40L dyad in the development of IBD in order to facilitate future approaches aiming to elucidate the immunological mechanisms that control gut inflammation. PMID- 26528289 TI - Immunity to Pathogens Taught by Specialized Human Dendritic Cell Subsets. AB - Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that have a key role in immune responses because they bridge the innate and adaptive arms of the immune system. They mature upon recognition of pathogens and upregulate MHC molecules and costimulatory receptors to activate antigen-specific CD4(+) and CD8(+) T cells. It is now well established that DCs are not a homogeneous population but are composed of different subsets with specialized functions in immune responses to specific pathogens. Upon viral infections, plasmacytoid DCs (pDCs) rapidly produce large amounts of IFN-alpha, which has potent antiviral functions and activates several other immune cells. However, pDCs are not particularly potent APCs and induce the tolerogenic cytokine IL-10 in CD4(+) T cells. In contrast, myeloid DCs (mDCs) are very potent APCs and possess the unique capacity to prime naive T cells and consequently to initiate a primary adaptive immune response. Different subsets of mDCs with specialized functions have been identified. In mice, CD8alpha(+) mDCs capture antigenic material from necrotic cells, secrete high levels of IL-12, and prime Th1 and cytotoxic T-cell responses to control intracellular pathogens. Conversely, CD8alpha(-) mDCs preferentially prime CD4(+) T cells and promote Th2 or Th17 differentiation. BDCA 3(+) mDC2 are the human homologue of CD8alpha(+) mDCs, since they share the expression of several key molecules, the capacity to cross-present antigens to CD8(+) T-cells and to produce IFN-lambda. However, although several features of the DC network are conserved between humans and mice, the expression of several toll-like receptors as well as the production of cytokines that regulate T-cell differentiation are different. Intriguingly, recent data suggest specific roles for human DC subsets in immune responses against individual pathogens. The biology of human DC subsets holds the promise to be exploitable in translational medicine, in particular for the development of vaccines against persistent infections or cancer. PMID- 26528291 TI - PKC-Theta in Regulatory and Effector T-cell Functions. AB - One of the major goals in immunology research is to understand the regulatory mechanisms that underpin the rapid switch on/off of robust and efficient effector (Teffs) or regulatory (Tregs) T-cell responses. Understanding the molecular mechanisms underlying the regulation of such responses is critical for the development of effective therapies. T-cell activation involves the engagement of T-cell receptor and co-stimulatory signals, but the subsequent recruitment of serine/threonine-specific protein Kinase C-theta (PKC-theta) to the immunological synapse (IS) is instrumental for the formation of signaling complexes, which ultimately lead to a transcriptional network in T cells. Recent studies demonstrated that major differences between Teffs and Tregs occurred at the IS where its formation induces altered signaling pathways in Tregs. These pathways are characterized by reduced recruitment of PKC-theta, suggesting that PKC-theta inhibits Tregs suppressive function in a negative feedback loop. As the balance of Teffs and Tregs has been shown to be central in several diseases, it was not surprising that some studies revealed that PKC-theta plays a major role in the regulation of this balance. This review will examine recent knowledge on the role of PKC-theta in T-cell transcriptional responses and how this protein can impact on the function of both Tregs and Teffs. PMID- 26528292 TI - In-Depth Assessment of Within-Individual and Inter-Individual Variation in the B Cell Receptor Repertoire. AB - High-throughput sequencing of the B cell receptor (BCR) repertoire can provide rapid characterization of the B cell response in a wide variety of applications in health, after vaccination and in infectious, inflammatory and immune-driven disease, and is starting to yield clinical applications. However, the interpretation of repertoire data is compromised by a lack of studies to assess the intra and inter-individual variation in the BCR repertoire over time in healthy individuals. We applied a standardized isotype-specific BCR repertoire deep sequencing protocol to a single highly sampled participant, and then evaluated the method in 9 further participants to comprehensively describe such variation. We assessed total repertoire metrics of mutation, diversity, VJ gene usage and isotype subclass usage as well as tracking specific BCR sequence clusters. There was good assay reproducibility (both in PCR amplification and biological replicates), but we detected striking fluctuations in the repertoire over time that we hypothesize may be due to subclinical immune activation. Repertoire properties were unique for each individual, which could partly be explained by a decrease in IgG2 with age, and genetic differences at the immunoglobulin locus. There was a small repertoire of public clusters (0.5, 0.3, and 1.4% of total IgA, IgG, and IgM clusters, respectively), which was enriched for expanded clusters containing sequences with suspected specificity toward antigens that should have been historically encountered by all participants through prior immunization or infection. We thus provide baseline BCR repertoire information that can be used to inform future study design, and aid in interpretation of results from these studies. Furthermore, our results indicate that BCR repertoire studies could be used to track changes in the public repertoire in and between populations that might relate to population immunity against infectious diseases, and identify the characteristics of inflammatory and immunological diseases. PMID- 26528293 TI - Evidence from Human and Animal Studies: Pathological Roles of CD8(+) T Cells in Autoimmune Peripheral Neuropathies. AB - Autoimmune peripheral neuropathies such as Guillain-Barre Syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) affect millions of people worldwide. Despite significant advances in understanding the pathology, the molecular and cellular mechanisms of immune-mediated neuropathies remain elusive. T lymphocytes definitely play an important role in disease pathogenesis and CD4(+) T cells have been the main area of research for decades. This is partly due to the fact that the most frequent animal model to study autoimmune peripheral neuropathy is experimental allergic neuritis (EAN). As it is induced commonly by immunization with peripheral nerve proteins, EAN is driven mainly by CD4(+) T cells. However, similarly to what has been reported for patients suffering from multiple sclerosis, a significant body of evidence indicates that CD8(+) T cells may play a pathogenic role in GBS and CIDP disease development and/or progression. Here, we summarize clinical studies pertaining to the presence and potential role of CD8(+) T cells in autoimmune peripheral neuropathies. We also discuss the findings from our most recent studies using a transgenic mouse line (L31 mice) in which the T cell co-stimulator molecule B7.2 (CD86) is constitutively expressed in antigen presenting cells of the nervous tissues. L31 mice spontaneously develop peripheral neuropathy, and CD8(+) T cells are found accumulating in peripheral nerves of symptomatic animals. Interestingly, depletion of CD4(+) T cells accelerates disease onset and increases disease prevalence. Finally, we point out some unanswered questions for future research to dissect the critical roles of CD8(+) T cells in autoimmune peripheral neuropathies. PMID- 26528294 TI - Seed germination strategies: an evolutionary trajectory independent of vegetative functional traits. AB - Seed germination strategies vary dramatically among species but relatively little is known about how germination traits correlate with other elements of plant strategy systems. Understanding drivers of germination strategy is critical to our understanding of the evolutionary biology of plant reproduction.We present a novel assessment of seed germination strategies focussing on Australian alpine species as a case study. We describe the distribution of germination strategies and ask whether these are correlated with, or form an independent axis to, other plant functional traits. Our approach to describing germination strategy mimicked realistic temperatures that seeds experience in situ following dispersal. Strategies were subsequently assigned using an objective clustering approach. We hypothesized that two main strategies would emerge, involving dormant or non dormant seeds, and that while these strategies would be correlated with seed traits (e.g., mass or endospermy) they would be largely independent of vegetative traits when analysed in a phylogenetically structured manner.Across all species, three germination strategies emerged. The majority of species postponed germination until after a period of cold, winter-like temperatures indicating physiological and/or morphological dormancy mechanisms. Other species exhibited immediate germination at temperatures representative of those at dispersal. Interestingly, seeds of an additional 13 species "staggered" germination over time. Germination strategies were generally conserved within families. Across a broad range of ecological traits only seed mass and endospermy showed any correlation with germination strategy when phylogenetic relatedness was accounted for; vegetative traits showed no significant correlations with germination strategy. The results indicate that germination traits correlate with other aspects of seed ecology but form an independent axis relative to vegetative traits. PMID- 26528295 TI - Sunflower: a potential fructan-bearing crop? AB - Grain filling in sunflower (Helianthus annuus L.) mainly depends on actual photosynthesis, being the contribution of stored reserves in stems (sucrose, hexoses, and starch) rather low. Drought periods during grain filling often reduce yield. Increasing the capacity of stem to store reserves could help to increase grain filling and yield stability in dry years. Fructans improve water uptake in soils at low water potential, and allow the storage of large amount of assimilates per unit tissue volume that can be readily remobilized to grains. Sunflower is a close relative to Jerusalem artichoke (H. tuberosus L.), which accumulates large amounts of fructan (inulin) in tubers and true stems. The reason why sunflower does not accumulate fructans is obscure. Through a bioinformatics analysis of a sunflower transcriptome database, we found sequences that are homologous to dicotyledon and monocotyledon fructan synthesis genes. A HPLC analysis of stem sugar composition revealed the presence of low amounts of 1 kestose, while a drastic enhancement of endogenous sucrose levels by capitulum removal did not promote 1-kestose accumulation. This suggests that the regulation of fructan synthesis in this species may differ from the currently best known model, mainly derived from research on Poaceae, where sucrose acts as both a signaling molecule and substrate, in the induction of fructan synthesis. Thus, sunflower might potentially constitute a fructan-bearing species, which could result in an improvement of its performance as a grain crop. However, a large effort is needed to elucidate how this up to now unsuspected potential could be effectively expressed. PMID- 26528297 TI - Transcriptome analysis of Phoenix canariensis Chabaud in response to Rhynchophorus ferrugineus Olivier attacks. AB - Red Palm Weevil (RPW, Rhynchophorus ferrugineus Olivier) threatens most palm species worldwide. Until now, no studies have analyzed the gene regulatory networks of Phoenix canariensis (Chabaud) in response to RPW attacks. The aim of this study was to fill this knowledge gap. Providing this basic knowledge is very important to improve its management. RESULTS: A deep transcriptome analysis was performed on fully expanded leaves of healthy non-infested trees and attacked trees at two symptom stages (middle and late infestation). A total of 54 genes were significantly regulated during middle stage. Pathway enrichment analysis showed that phenylpropanoid-related pathways were induced at this stage. More than 3300 genes were affected during late stage of attacks. Higher transcript abundances were observed for lipid fatty acid metabolism (fatty acid and glycerolipids), tryptophan metabolism, phenylpropanoid metabolism. Key RPW modulated genes involved in innate response mediated by hormone crosstalk were observed belonging to auxin, jasmonate and salicylic acid (SA) pathways. Among transcription factors, some WRKYs were clearly induced. qRT-PCR validation confirmed the upregulation of key genes chosen as validation of transcriptomic analysis. CONCLUSION: A subset of these genes may be further analyzed in future studies to confirm their specificity to be induced by RPW infestations. PMID- 26528296 TI - Abiotic stress responses in plants: roles of calmodulin-regulated proteins. AB - Intracellular changes in calcium ions (Ca(2+)) in response to different biotic and abiotic stimuli are detected by various sensor proteins in the plant cell. Calmodulin (CaM) is one of the most extensively studied Ca(2+)-sensing proteins and has been shown to be involved in transduction of Ca(2+) signals. After interacting with Ca(2+), CaM undergoes conformational change and influences the activities of a diverse range of CaM-binding proteins. A number of CaM-binding proteins have also been implicated in stress responses in plants, highlighting the central role played by CaM in adaptation to adverse environmental conditions. Stress adaptation in plants is a highly complex and multigenic response. Identification and characterization of CaM-modulated proteins in relation to different abiotic stresses could, therefore, prove to be essential for a deeper understanding of the molecular mechanisms involved in abiotic stress tolerance in plants. Various studies have revealed involvement of CaM in regulation of metal ions uptake, generation of reactive oxygen species and modulation of transcription factors such as CAMTA3, GTL1, and WRKY39. Activities of several kinases and phosphatases have also been shown to be modulated by CaM, thus providing further versatility to stress-associated signal transduction pathways. The results obtained from contemporary studies are consistent with the proposed role of CaM as an integrator of different stress signaling pathways, which allows plants to maintain homeostasis between different cellular processes. In this review, we have attempted to present the current state of understanding of the role of CaM in modulating different stress-regulated proteins and its implications in augmenting abiotic stress tolerance in plants. PMID- 26528298 TI - Down-regulation of multiple CDK inhibitor ICK/KRP genes promotes cell proliferation, callus induction and plant regeneration in Arabidopsis. AB - The ICK/KRP cyclin-dependent kinase (CDK) inhibitors are important plant cell cycle regulators sharing only limited similarity with the metazoan CIP/KIP family of CDK inhibitors. Information is still limited regarding the specific functions of different ICK/KRP genes in planta. We have shown previously that down regulation of multiple CDK inhibitor ICK/KRP genes up-regulates the E2F pathway and increases cell proliferation, and organ and seed sizes in Arabidopsis. In this study, we observed that the quintuple ick1/2/5/6/7 mutant had more cells in the cortical layer of the root apical meristem (RAM) than the wild type (Wt) while its RAM length was similar to that of the Wt, suggesting a faster cell cycle rate in the quintuple mutant. We further investigated the effects of down regulating ICK genes on tissue culture responses. The cotyledon explants of ick1/2/5/6/7 could form callus efficiently in the absence of cytokinin and also required a lower concentration of 2,4-D for callus induction compared to the Wt plants, suggesting increased competence for callus induction in the mutant. In addition, the quintuple ick mutant showed enhanced abilities to regenerate shoots and roots, suggesting that increased competence to enter the cell cycle in the quintuple mutant might make it possible for more cells to become proliferative and be utilized to form shoots or roots. These findings indicate that CDK activity is a major factor underlying callus induction and increased cell proliferation can enhance in vitro organogenesis. PMID- 26528299 TI - Integrative "omic" analysis reveals distinctive cold responses in leaves and roots of strawberry, Fragaria * ananassa 'Korona'. AB - To assess underlying metabolic processes and regulatory mechanisms during cold exposure of strawberry, integrative "omic" approaches were applied to Fragaria * ananassa Duch. 'Korona.' Both root and leaf tissues were examined for responses to the cold acclimation processes. Levels of metabolites, proteins, and transcripts in tissues from plants grown at 18 degrees C were compared to those following 1-10 days of cold (2 degrees C) exposure. When leaves and roots were subjected to GC/TOF-MS-based metabolite profiling, about 160 compounds comprising mostly structurally annotated primary and secondary metabolites, were found. Overall, 'Korona' showed a modest increase of protective metabolites such as amino acids (aspartic acid, leucine, isoleucine, and valine), pentoses, phosphorylated and non-phosphorylated hexoses, and distinct compounds of the raffinose pathway (galactinol and raffinose). Distinctive responses were observed in roots and leaves. By 2DE proteomics a total of 845 spots were observed in leaves; 4.6% changed significantly in response to cold. Twenty-one proteins were identified, many of which were associated with general metabolism or photosynthesis. Transcript levels in leaves were determined by microarray, where dozens of cold associated transcripts were quantitatively characterized, and levels of several potential key contributors (e.g., the dehydrin COR47 and GADb) to cold tolerance were confirmed by qRT-PCR. Cold responses are placed within the existing knowledge base of low temperature-induced changes in plants, allowing an evaluation of the uniqueness or generality of Fragaria responses in photosynthetic tissues. Overall, the cold response characteristics of 'Korona' are consistent with a moderately cold tolerant plant. PMID- 26528300 TI - Polyamines function in stress tolerance: from synthesis to regulation. AB - Plants are challenged by a variety of biotic or abiotic stresses, which can affect their growth and development, productivity, and geographic distribution. In order to survive adverse environmental conditions, plants have evolved various adaptive strategies, among which is the accumulation of metabolites that play protective roles. A well-established example of the metabolites that are involved in stress responses, or stress tolerance, is the low-molecular-weight aliphatic polyamines, including putrescine, spermidine, and spermine. The critical role of polyamines in stress tolerance is suggested by several lines of evidence: firstly, the transcript levels of polyamine biosynthetic genes, as well as the activities of the corresponding enzymes, are induced by stresses; secondly, elevation of endogenous polyamine levels by exogenous supply of polyamines, or overexpression of polyamine biosynthetic genes, results in enhanced stress tolerance; and thirdly, a reduction of endogenous polyamines is accompanied by compromised stress tolerance. A number of studies have demonstrated that polyamines function in stress tolerance largely by modulating the homeostasis of reactive oxygen species (ROS) due to their direct, or indirect, roles in regulating antioxidant systems or suppressing ROS production. The transcriptional regulation of polyamine synthesis by transcription factors is also reviewed here. Meanwhile, future perspectives on polyamine research are also suggested. PMID- 26528301 TI - Small RNA mediated regulation of seed germination. AB - Mature seeds of most of the higher plants harbor dormant embryos and go through the complex process of germination under favorable environmental conditions. The germination process involves dynamic physiological, cellular and metabolic events that are controlled by the interplay of several gene products and different phytohormones. The small non-coding RNAs comprise key regulatory modules in the process of seed dormancy and germination. Recent studies have implicated the small RNAs in plant growth in correlation with various plant physiological processes including hormone signaling and stress response. In this review we provide a brief overview of the regulation of seed germination or dormancy while emphasizing on the current understanding of the role of small RNAs in this regard. We have also highlighted specific examples of stress responsive small RNAs in seed germination and discussed their future potential. PMID- 26528302 TI - Exploring potential new floral organ morphogenesis genes of Arabidopsis thaliana using systems biology approach. AB - Flowering is one of the important defining features of angiosperms. The initiation of flower development and the formation of different floral organs are the results of the interplays among numerous genes. But until now, just fewer genes have been found linked with flower development. And the functions of lots of genes of Arabidopsis thaliana are still unknown. Although, the quartet model successfully simplified the ABCDE model to elaborate the molecular mechanism by introducing protein-protein interactions (PPIs). We still don't know much about several important aspects of flower development. So we need to discriminate even more genes involving in the flower development. In this study, we identified seven differentially modules through integrating the weighted gene co-expression network analysis (WGCNA) and Support Vector Machine (SVM) method to analyze co expression network and PPIs using the public floral and non-floral expression profiles data of Arabidopsis thaliana. Gene set enrichment analysis was used for the functional annotation of the related genes, and some of the hub genes were identified in each module. The potential floral organ morphogenesis genes of two significant modules were integrated with PPI information in order to detail the inherent regulation mechanisms. Finally, the functions of the floral patterning genes were elucidated by combining the PPI and evolutionary information. It was indicated that the sub-networks or complexes, rather than the genes, were the regulation unit of flower development. We found that the most possible potential new genes underlining the floral pattern formation in A. thaliana were FY, CBL2, ZFN3, and AT1G77370; among them, FY, CBL2 acted as an upstream regulator of AP2; ZFN3 activated the flower primordial determining gene AP1 and AP2 by HY5/HYH gene via photo induction possibly. And AT1G77370 exhibited similar function in floral morphogenesis, same as ELF3. It possibly formed a complex between RFC3 and RPS15 in cytoplasm, which regulated TSO1 and CPSF160 in the nucleus, to control the floral organ morphogenesis. This process might also be fine tuning by AT5G53360 in the nucleus. PMID- 26528303 TI - Priming maize resistance by its neighbors: activating 1,4-benzoxazine-3-ones synthesis and defense gene expression to alleviate leaf disease. AB - Plant disease can be effectively suppressed in intercropping systems. Our previous study demonstrated that neighboring maize plants can restrict the spread of soil-borne pathogens of pepper plants by secreting defense compounds into the soil. However, whether maize plant can receive benefits from its neighboring pepper plants in an intercropping system is little attention. We examined the effects of maize roots treated with elicitors from the pepper pathogen Phytophthora capsici and pepper root exudates on the synthesis of 1,4-benzoxazine 3-ones (BXs), the expression of defense-related genes in maize, and their ability to alleviate the severity of southern corn leaf blight (SCLB) caused by Bipolaris maydis. We found that SCLB was significantly reduced after the above treatments. The contents of 1,4-benzoxazine-3-ones (BXs: DIBOA, DIMBOA, and MBOA) and the expression levels of BX synthesis and defense genes in maize roots and shoots were up-regulated. DIMBOA and MBOA effectively inhibited the mycelium growth of Bipolaris maydis at physiological concentrations in maize shoots. Further studies suggested that the defense related pathways or genes in maize roots and shoots were activated by elicitors from the P. capsici or pepper root exudates. In conclusion, maize increased the levels of BXs and defense gene expression both in roots and shoots after being triggered by root exudates and pathogen from neighboring pepper plants, eventually enhancing its resistance. PMID- 26528304 TI - Review of functional markers for improving cooking, eating, and the nutritional qualities of rice. AB - After yield, quality is one of the most important aspects of rice breeding. Preference for rice quality varies among cultures and regions; therefore, rice breeders have to tailor the quality according to the preferences of local consumers. Rice quality assessment requires routine chemical analysis procedures. The advancement of molecular marker technology has revolutionized the strategy in breeding programs. The availability of rice genome sequences and the use of forward and reverse genetics approaches facilitate gene discovery and the deciphering of gene functions. A well-characterized gene is the basis for the development of functional markers, which play an important role in plant genotyping and, in particular, marker-assisted breeding. In addition, functional markers offer advantages that counteract the limitations of random DNA markers. Some functional markers have been applied in marker-assisted breeding programs and have successfully improved rice quality to meet local consumers' preferences. Although functional markers offer a plethora of advantages over random genetic markers, the development and application of functional markers should be conducted with care. The decreasing cost of sequencing will enable more functional markers for rice quality improvement to be developed, and application of these markers in rice quality breeding programs is highly anticipated. PMID- 26528305 TI - Combined effect of water loss and wounding stress on gene activation of metabolic pathways associated with phenolic biosynthesis in carrot. AB - The application of postharvest abiotic stresses is an effective strategy to activate the primary and secondary metabolism of plants inducing the accumulation of antioxidant phenolic compounds. In the present study, the effect of water stress applied alone and in combination with wounding stress on the activation of primary (shikimic acid) and secondary (phenylpropanoid) metabolic pathways related with the accumulation of phenolic compound in plants was evaluated. Carrot (Daucus carota) was used as model system for this study, and the effect of abiotic stresses was evaluated at the gene expression level and on the accumulation of metabolites. As control of the study, whole carrots were stored under the same conditions. Results demonstrated that water stress activated the primary and secondary metabolism of carrots, favoring the lignification process. Likewise, wounding stress induced higher activation of the primary and secondary metabolism of carrots as compared to water stress alone, leading to higher accumulation of shikimic acid, phenolic compounds, and lignin. Additional water stress applied on wounded carrots exerted a synergistic effect on the wound response at the gene expression level. For instance, when wounded carrots were treated with water stress, the tissue showed 20- and 14-fold increases in the relative expression of 3-deoxy-D-arabino-heptulosanate synthase and phenylalanine ammonia-lyase genes, respectively. However, since lignification was increased, lower accumulation of phenolic compounds was detected. Indicatively, at 48 h of storage, wounded carrots treated with water stress showed ~31% lower levels of phenolic compounds and ~23% higher lignin content as compared with wounded controls. In the present study, it was demonstrated that water stress is one of the pivotal mechanism of the wound-response in carrot. Results allowed the elucidation of strategies to induce the accumulation of specific primary or secondary metabolites when plants are treated with water stress alone or when additional water stress is applied on wounded tissue. If the accumulation of a specific primary or secondary metabolite were desirable, it would be recommended to apply both stresses to accelerate their biosynthesis. However, strategies such as the use of enzymatic inhibitors to block the carbon flux and enhance the accumulation of specific compounds should be designed. PMID- 26528306 TI - Dynamic transcription profiles of "Qinguan" apple (Malus * domestica) leaves in response to Marssonina coronaria inoculation. AB - Marssonina apple blotch, caused by the fungus Marssonina coronaria, is one of the most destructive apple diseases in China and East Asia. A better understanding of the plant's response to fungi during pathogenesis is urgently needed to improve plant resistance and to breed resistant cultivars. To address this, the transcriptomes of "Qinguan" (a cultivar with high resistance to M. coronaria) apple leaves were sequenced at 12, 24, 48, and 72 h post-inoculation (hpi) with Marssonina coronaria. The comparative results showed that a total of 1956 genes were differentially expressed between the inoculated and control samples at the 4 time points. Gene ontology (GO) term enrichment analysis of differentially expressed genes (DEGs) revealed changes in cellular component, secondary metabolism including chalcone isomerase activity, phytoalexin biosynthetic process, anthocyanin-containing compound biosynthetic process, lignin biosynthetic process, positive regulation of flavonoid biosynthetic process; and molecular functions or biological processes related to the defense response, biotic stimulus response, wounding response and fungus response. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that DEGs were significantly enriched in flavonoid biosynthesis, vitamin B6 metabolism, phenylpropanoid biosynthesis, and the stilbenoid, diarylheptanoid and gingerol biosynthesis pathways. Furthermore, the importance of changes in cellular components and partial polyphenol compounds when encountering M. coronaria are discussed. PMID- 26528307 TI - A method for the further assembly of targeted unigenes in a transcriptome after assembly by Trinity. AB - RNA-sequencing has been widely used to obtain high throughput transcriptome sequences in various species, but the assembly of a full set of complete transcripts is still a significant challenge. Judging by the number of expected transcripts and assembled unigenes in a transcriptome library, we believe that some unigenes could be reassembled. In this study, using the nitrate transporter (NRT) gene family and phosphate transporter (PHT) gene family in Salicornia europaea as examples, we introduced an approach to further assemble unigenes found in transcriptome libraries which had been previously generated by Trinity. To find the unigenes of a particular transcript that contained gaps, we respectively selected 16 NRT candidate unigene pairs and 12 PHT candidate unigene pairs for which the two unigenes had the same annotations, the same expression patterns among various RNA-seq samples, and different positions of the proteins coded as mapped to a reference protein. To fill a gap between the two unigenes, PCR was performed using primers that mapped to the two unigenes and the PCR products were sequenced, which demonstrated that 5 unigene pairs of NRT and 3 unigene pairs of PHT could be reassembled when the gaps were filled using the corresponding PCR product sequences. This fast and simple method will reduce the redundancy of targeted unigenes and allow acquisition of complete coding sequences (CDS). PMID- 26528308 TI - BABA-primed defense responses to Phytophthora infestans in the next vegetative progeny of potato. AB - The transcript of the PR1 gene accumulation as an informative marker of systemic acquired resistance (SAR) was analyzed in beta-aminobutyric acid (BABA) primed potato in the short-lasting (3 days) and long-lasting (28 days) time periods after induction and in the vegetative descendants of primed plants derived from tubers and from in vitro seedlings. BABA pretreatment resulted either in minimal or no PR1 gene expression, but sequential treatment with BABA followed by virulent Phytophthora infestans provided data on the imprint of post-stress information and its duration until fertilization, in the form of an enhanced PR1 transcript accumulation and a transient increase of basal resistance to the late blight disease. The primed state for defense of the susceptible potato cultivar was transmitted to its vegetative progeny as a potentiated PR1 mRNA accumulation following challenge inoculation. However, variation was observed between vegetative accessions of the BABA-primed potato genotype in responsiveness to disease. In contrast to plants derived from tubers, potato propagated through in vitro seedlings largely lost inducible resistance traits, although itretained primed PR1 gene expression. PMID- 26528309 TI - Proteomic analysis of differentially expressed proteins involved in ethylene induced chilling tolerance in harvested banana fruit. AB - To better understand the mechanism involved in ethylene-induced chilling tolerance in harvested banana fruit, a gel-based proteomic study followed by MALDI-TOF-TOF MS was carried out. Banana fruit were treated with 500 ppm ethylene for 12 h and then stored at 6 degrees C. During cold storage, the chilling tolerance was assessed and the proteins from the peel were extracted for proteomic analysis. It was observed that ethylene pretreatment significantly induced the chilling tolerance in harvested banana fruit, manifesting as increases in maximal chlorophyll fluorescence (Fv/Fm) and decreased electrolyte leakage. Sixty-four proteins spots with significant differences in abundance were identified, most of which were induced by ethylene pretreatment during cold storage. The up-regulated proteins induced by ethylene pretreatment were mainly related to energy metabolism, stress response and defense, methionine salvage cycle and protein metabolism. These proteins were involved in ATP synthesis, ROS scavenging, protective compounds synthesis, protein refolding and degradation, and polyamine biosynthesis. It is suggested that these up-regulated proteins might play a role in the ethylene-induced chilling tolerance in harvested banana fruit. PMID- 26528310 TI - Cytomixis doesn't induce obvious changes in chromatin modifications and programmed cell death in tobacco male meiocytes. AB - Cytomixis is a poorly studied process of nuclear migration between plant cells. It is so far unknown what drives cytomixis and what is the functional state of the chromatin migrating between cells. Using immunostaining, we have analyzed the distribution of posttranslational histone modifications (methylation, acetylation, and phosphorylation) that reflect the functional state of chromatin in the tobacco microsporocytes involved in cytomixis. We demonstrate that the chromatin in the cytomictic cells does not differ from the chromatin in intact microsporocytes according to all 14 analyzed histone modification types. We have also for the first time demonstrated that the migrating chromatin contains normal structures of the synaptonemal complex (SC) and lacks any signs of apoptosis. As has been shown, the chromatin migrating between cells in cytomixis is neither selectively heterochromatized nor degraded both before its migration to another cell and after it enters a recipient cell as micronuclei. We also showed that cytomictic chromatin contains marks typical for transcriptionally active chromatin as well as heterochromatin. Moreover, marks typical for chromosome condensation, SC formation and key proteins required for the formation of bivalents were also detected at migrated chromatin. PMID- 26528311 TI - Co-expression of G2-EPSPS and glyphosate acetyltransferase GAT genes conferring high tolerance to glyphosate in soybean. AB - Glyphosate is a widely used non-selective herbicide with broad spectrum of weed control around the world. At present, most of the commercial glyphosate tolerant soybeans utilize glyphosate tolerant gene CP4-EPSPS or glyphosate acetyltransferase gene GAT separately. In this study, both glyphosate tolerant gene G2-EPSPS and glyphosate degraded gene GAT were co-transferred into soybean and transgenic plants showed high tolerance to glyphosate. Molecular analysis including PCR, Sothern blot, qRT-PCR, and Western blot revealed that target genes have been integrated into genome and expressed effectively at both mRNA and protein levels. Furthermore, the glyphosate tolerance analysis showed that no typical symptom was observed when compared with a glyphosate tolerant line HJ06 698 derived from GR1 transgenic soybean even at fourfold labeled rate of Roundup. Chlorophyll and shikimic acid content analysis of transgenic plant also revealed that these two indexes were not significantly altered after glyphosate application. These results indicated that co-expression of G2-EPSPS and GAT conferred high tolerance to the herbicide glyphosate in soybean. Therefore, combination of tolerant and degraded genes provides a new strategy for developing glyphosate tolerant transgenic crops. PMID- 26528312 TI - Selection of reliable reference genes for quantitative real-time PCR gene expression analysis in Jute (Corchorus capsularis) under stress treatments. AB - To accurately measure gene expression using quantitative reverse transcription PCR (qRT-PCR), reliable reference gene(s) are required for data normalization. Corchorus capsularis, an annual herbaceous fiber crop with predominant biodegradability and renewability, has not been investigated for the stability of reference genes with qRT-PCR. In this study, 11 candidate reference genes were selected and their expression levels were assessed using qRT-PCR. To account for the influence of experimental approach and tissue type, 22 different jute samples were selected from abiotic and biotic stress conditions as well as three different tissue types. The stability of the candidate reference genes was evaluated using geNorm, NormFinder, and BestKeeper programs, and the comprehensive rankings of gene stability were generated by aggregate analysis. For the biotic stress and NaCl stress subsets, ACT7 and RAN were suitable as stable reference genes for gene expression normalization. For the PEG stress subset, UBC, and DnaJ were sufficient for accurate normalization. For the tissues subset, four reference genes TUBbeta, UBI, EF1alpha, and RAN were sufficient for accurate normalization. The selected genes were further validated by comparing expression profiles of WRKY15 in various samples, and two stable reference genes were recommended for accurate normalization of qRT-PCR data. Our results provide researchers with appropriate reference genes for qRT-PCR in C. capsularis, and will facilitate gene expression study under these conditions. PMID- 26528313 TI - Cloning and characterization of the CarbcL gene related to chlorophyll in pepper (Capsicum annuum L.) under fruit shade stress. AB - Light is an important environmental factor for fruit development and ripening in pepper plant. Fruit bagging is a significant agrotechnology practiced for the illumination regulation of fruits; some previous researches have shown that fruit bagging could improve the appearance and external quality of fruits and cause them to mature early. However, it would decrease the intrinsic qualities of fruits; especially, fruit bagging could decrease the content of capsanthin in peppers. On the basis of these details, fruit bagging was used as the method of fruit shade stress in this study to explore the characteristics and molecular mechanisms of pepper fruit's color change under shade stress. By using cDNA-AFLP under fruit shading, a fragment related to fruit color was obtained. Next, the full-length coding sequence of the gene was cloned from the pepper fruits. Homologous gene alignment confirmed that the gene has high homology with the rbcL gene, named CarbcL. The function of the CarbcL gene was identified through virus induced gene silencing (VIGS); it was found that the fruit color changed completely from green to red except for some residue of green fleck when CarbcL gene was silenced, and the green color of fruits had not fully faded in the control group and the empty vector group. The combine determination of chlorophyll content showed that CarbcL was involved in the metabolic control of chlorophyll in pepper fruits; subsequently, HPLC was used to determine the content of capsanthin in pepper fruit which the CarbcL gene was silencing, and it was also found that the content of capsanthin decreased appreciably. These results further confirmed that CarbcL gene was involved in the adjustment of chlorophyll and capsanthin. PMID- 26528314 TI - Cooperative control between AtRGS1 and AtHXK1 in a WD40-repeat protein pathway in Arabidopsis thaliana. AB - HEXOKINASE 1 (AtHXK1) and Regulator of G-protein Signaling 1 (AtRGS1) pathways, mediate D-glucose signaling in Arabidopsis. However, it is not known the degree, if any, that these pathways overlap and how. We show modest signaling crosstalk between these pathways, albeit complex with both epistatic interactions and additive effects that may be indirect. The action of HXK1 on AtRGS1 signaling lies downstream of the primary step in G protein-mediated sugar signaling in which the WD-repeat protein, AGB1, is the propelling signaling element. RHIP1, a previously unknown protein predicted here to have a 3-stranded helical structure, interacts with both AtRGS1 and AtHXK1 in planta and is required for some glucose regulated gene expression, providing a physical connection between these two proteins in sugar signaling. The rhip1 null mutant displays similar seedling growth phenotypes as rgs1-2 in response to glucose, further suggesting a role for RHIP1 in glucose signaling. In conclusion, glucose signaling is a complex hierarchical relationship which is specific to the target gene and sugar phenotype and suggests that there are two glycolysis-independent glucose signaling sensors: AtRGS1 and AtHXK1 that weakly communicate with each other via feed-back and feed-forward loops to fine tune the response to glucose. PMID- 26528315 TI - Somatic embryogenesis receptor-like kinase 5 in the ecotype Landsberg erecta of Arabidopsis is a functional RD LRR-RLK in regulating brassinosteroid signaling and cell death control. AB - In plants, LRR-RLKs play central roles in regulating perception of extracellular signals and initiation of cellular responses under various environmental challenges. Arabidopsis SERK genes, including SERK1 to SERK5, constitute a LRR RLK sub-family. SERK1, SERK2, SERK3/BAK1, and SERK4/BKK1 have been well characterized to function as crucial regulators in multiple physiological processes such as brassinosteroid signaling, cell death control, pathogenesis, and pollen development. Despite extremely high sequence identity with BKK1, SERK5 is reported to have no functional overlapping with BKK1, which is previously identified to regulate BR and cell death control pathways, probably due to a natural mutation in a highly conserved RD motif in the kinase domain of SERK5 in Col-0 ecotype. Through a gene sequencing analysis in several Arabidopsis accessions, we are able to identify SERK5 in Landsberg erecta (Ler) genome encoding a LRR-RLK with an intact RD motif. Overexpression of SERK5-Ler partially suppresses the BR defective phenotypes of bri1-5 and bak1-3 bkk1-1, indicating SERK5-Ler functions as a positive regulator in BR signaling. Furthermore, the interaction between SERK5-Ler and BRI1 is confirmed by yeast two-hybrid and BiFC assays, and the genetic result showing that elevated expression of a kinase-dead form of SERK5-Ler causes a dominant-negative phenotype in bri1-5. In addition, overexpression of SERK5-Ler is capable of delaying, not completely suppressing, the cell death phenotype of bak1-3 bkk1-1. In this study, we first reveal that SERK5-Ler is a biologically functional component in mediating multiple signaling pathways. PMID- 26528316 TI - Capturing spiral radial growth of conifers using the superellipse to model tree ring geometric shape. AB - Tree-rings are often assumed to approximate a circular shape when estimating forest productivity and carbon dynamics. However, tree rings are rarely, if ever, circular, thereby possibly resulting in under- or over-estimation in forest productivity and carbon sequestration. Given the crucial role played by tree ring data in assessing forest productivity and carbon storage within a context of global change, it is particularly important that mathematical models adequately render cross-sectional area increment derived from tree rings. We modeled the geometric shape of tree rings using the superellipse equation and checked its validation based on the theoretical simulation and six actual cross sections collected from three conifers. We found that the superellipse better describes the geometric shape of tree rings than the circle commonly used. We showed that a spiral growth trend exists on the radial section over time, which might be closely related to spiral grain along the longitudinal axis. The superellipse generally had higher accuracy than the circle in predicting the basal area increment, resulting in an improved estimate for the basal area. The superellipse may allow better assessing forest productivity and carbon storage in terrestrial forest ecosystems. PMID- 26528318 TI - Elevated air humidity affects hydraulic traits and tree size but not biomass allocation in young silver birches (Betula pendula). AB - As changes in air temperature, precipitation, and air humidity are expected in the coming decades, studies on the impact of these environmental shifts on plant growth and functioning are of major importance. Greatly understudied aspects of climate change include consequences of increasing air humidity on forest ecosystems, predicted for high latitudes. The main objective of this study was to find a link between hydraulic acclimation and shifts in trees' resource allocation in silver birch (Betula pendula Roth) in response to elevated air relative humidity (RH). A second question was whether the changes in hydraulic architecture depend on tree size. Two years of application of increased RH decreased the biomass accumulation in birch saplings, but the biomass partitioning among aboveground parts (leaves, branches, and stems) remained unaffected. Increased stem Huber values (xylem cross-sectional area to leaf area ratio) observed in trees under elevated RH did not entail changes in the ratio of non-photosynthetic to photosynthetic tissues. The reduction of stem-wood density is attributable to diminished mechanical load imposed on the stem, since humidified trees had relatively shorter crowns. Growing under higher RH caused hydraulic conductance of the root system (K R) to increase, while K R (expressed per unit leaf area) decreased and leaf hydraulic conductance increased with tree size. Saplings of silver birch acclimate to increasing air humidity by adjusting plant morphology (live crown length, slenderness, specific leaf area, and fine root traits) and wood density rather than biomass distribution among aboveground organs. The treatment had a significant effect on several hydraulic properties of the trees, while the shifts were largely associated with changes in tree size but not in biomass allocation. PMID- 26528319 TI - Detection of hydrogen peroxide in Photosystem II (PSII) using catalytic amperometric biosensor. AB - Hydrogen peroxide (H2O2) is known to be generated in Photosystem II (PSII) via enzymatic and non-enzymatic pathways. Detection of H2O2 by different spectroscopic techniques has been explored, however its sensitive detection has always been a challenge in photosynthetic research. During the recent past, fluorescence probes such as Amplex Red (AR) has been used but is known to either lack specificity or limitation with respect to the minimum detection limit of H2O2. We have employed an electrochemical biosensor for real time monitoring of H2O2 generation at the level of sub-cellular organelles. The electrochemical biosensor comprises of counter electrode and working electrodes. The counter electrode is a platinum plate, while the working electrode is a mediator based catalytic amperometric biosensor device developed by the coating of a carbon electrode with osmium-horseradish peroxidase which acts as H2O2 detection sensor. In the current study, generation and kinetic behavior of H2O2 in PSII membranes have been studied under light illumination. Electrochemical detection of H2O2 using the catalytic amperometric biosensor device is claimed to serve as a promising technique for detection of H2O2 in photosynthetic cells and subcellular structures including PSII or thylakoid membranes. It can also provide a precise information on qualitative determination of H2O2 and thus can be widely used in photosynthetic research. PMID- 26528317 TI - Beyond plant defense: insights on the potential of salicylic and methylsalicylic acid to contain growth of the phytopathogen Botrytis cinerea. AB - Using Botrytis cinerea we confirmed in the present work several previous studies showing that salicylic acid, a main plant hormone, inhibits fungal growth in vitro. Such an inhibitory effect was also observed for the two salicylic acid derivatives, methylsalicylic and acetylsalicylic acid. In marked contrast, 5 sulfosalicylic acid was totally inactive. Comparative proteomics from treated vs. control mycelia showed that both the intracellular and extracellular proteomes were affected in the presence of salicylic acid or methylsalicylic acid. These data suggest several mechanisms that could potentially account for the observed fungal growth inhibition, notably pH regulation, metal homeostasis, mitochondrial respiration, ROS accumulation and cell wall remodeling. The present observations support a role played by the phytohormone SA and derivatives in directly containing the pathogen. Data are available via ProteomeXchange with identifier PXD002873. PMID- 26528320 TI - Nodulation by Sinorhizobium meliloti originated from a mining soil alleviates Cd toxicity and increases Cd-phytoextraction in Medicago sativa L. AB - Besides their role in nitrogen supply to the host plants as a result of symbiotic N fixation, the association between legumes and Rhizobium could be useful for the rehabilitation of metal-contaminated soils by phytoextraction. A major limitation presents the metal-sensitivity of the bacterial strains. The aim of this work was to explore the usefulness of Sinorhizobium meliloti originated from a mining site for Cd phytoextraction by Medicago sativa. Inoculated and non-inoculated plants were cultivated for 60 d on soils containing 50 and/or 100 mg Cd kg(-1) soil. The inoculation hindered the occurrence of Cd- induced toxicity symptoms that appeared in the shoots of non-inoculated plants. This positive effect of S. meliloti colonization was accompanied by an increase in biomass production and improved nutrient acquisition comparatively to non-inoculated plants. Nodulation enhanced Cd absorption by the roots and Cd translocation to the shoots. The increase of plant biomass concomitantly with the increase of Cd shoot concentration in inoculated plants led to higher potential of Cd-phytoextraction in these plants. In the presence of 50 mg Cd kg(-1) in the soil, the amounts of Cd extracted in the shoots were 58 and 178 MUg plant(-1) in non-inoculated and inoculated plants, respectively. This study demonstrates that this association M. sativa-S. meliloti may be an efficient biological system to extract Cd from contaminated soils. PMID- 26528321 TI - Fructan synthesis, accumulation and polymer traits. II. Fructan pools in populations of perennial ryegrass (Lolium perenne L.) with variation for water soluble carbohydrate and candidate genes were not correlated with biosynthetic activity and demonstrated constraints to polymer chain extension. AB - Differences have been shown between ryegrass and fescue within the Festulolium subline introgression family for fructan synthesis, metabolism, and polymer-size traits. It is well-established that there is considerable variation for water soluble carbohydrate and fructan content within perennial ryegrass. However there is much still to be discovered about the fructan polymer pool in this species, especially in regard to its composition and regulation. It is postulated that similar considerable variation for polymer traits may exist, providing useful polymers for biorefining applications. Seasonal effects on fructan content together with fructan synthesis and polymer-size traits have been examined in diverse perennial ryegrass material comprising contrasting plants from a perennial ryegrass F2 mapping family and from populations produced by three rounds of phenotypic selection. Relationships with copy number variation in candidate genes have been investigated. There was little evidence of any variation in fructan metabolism across this diverse germplasm under these conditions that resulted in substantial differences in the complement of fructan polymers present in leaf tissue at high water-soluble carbohydrate concentrations. The importance of fructan synthesis during fructan accumulation was unclear as fructan content and polymer characteristics in intact plants during the growing season did not reflect the capacity for de novo synthesis. However, the retention of fructan in environmental conditions favoring high sink/low source demand may be an important component of the high sugar trait and the roles of breakdown and turnover are discussed. PMID- 26528322 TI - Composition of the SAGA complex in plants and its role in controlling gene expression in response to abiotic stresses. AB - Protein complexes involved in epigenetic regulation of transcription have evolved as molecular strategies to face environmental stress in plants. SAGA (Spt-Ada Gcn5 Acetyltransferase) is a transcriptional co-activator complex that regulates numerous cellular processes through the coordination of multiple post translational histone modifications, including acetylation, deubiquitination, and chromatin recognition. The diverse functions of the SAGA complex involve distinct modules that are highly conserved between yeast, flies, and mammals. In this review, the composition of the SAGA complex in plants is described and its role in gene expression regulation under stress conditions summarized. Some of these proteins are likely involved in the regulation of the inducible expression of genes under light, cold, drought, salt, and iron stress, although the functions of several of its components remain unknown. PMID- 26528323 TI - Species coexistence in a changing world. AB - The consequences of global change for the maintenance of species diversity will depend on the sum of each species responses to the environment and on the interactions among them. A wide ecological literature supports that these species specific responses can arise from factors related to life strategies, evolutionary history and intraspecific variation, and also from environmental variation in space and time. In the light of recent advances from coexistence theory combined with mechanistic explanations of diversity maintenance, we discuss how global change drivers can influence species coexistence. We revise the importance of both competition and facilitation for understanding coexistence in different ecosystems, address the influence of phylogenetic relatedness, functional traits, phenotypic plasticity and intraspecific variability, and discuss lessons learnt from invasion ecology. While most previous studies have focused their efforts on disentangling the mechanisms that maintain the biological diversity in species-rich ecosystems such as tropical forests, grasslands and coral reefs, we argue that much can be learnt from pauci-specific communities where functional variability within each species, together with demographic and stochastic processes becomes key to understand species interactions and eventually community responses to global change. PMID- 26528324 TI - Role of Trichoderma harzianum in mitigating NaCl stress in Indian mustard (Brassica juncea L) through antioxidative defense system. AB - Salinity stress affected crop production of more than 20% of irrigated land globally. In the present study the effect of different concentrations of NaCl (0, 100, and 200 mM) on growth, physio-biochemical attributes, antioxidant enzymes, oil content, etc. in Brassica juncea and the protective role of Trichoderma harzianum (TH) was investigated. Salinity stress deteriorates growth, physio biochemical attributes, that ultimately leads to decreased biomass yield in mustard seedlings. Higher concentration of NaCl (200 mM) decreased the plant height by 33.7%, root length by 29.7% and plant dry weight (DW) by 34.5%. On the other hand, supplementation of TH to NaCl treated mustard seedlings showed elevation by 13.8, 11.8, and 16.7% in shoot, root length and plant DW respectively as compared to plants treated with NaCl (200 mM) alone. Oil content was drastically affected by NaCl treatment; however, TH added plants showed enhanced oil percentage from 19.4 to 23.4% in the present study. NaCl also degenerate the pigment content and the maximum drop of 52.0% was recorded in Chl. 'a'. Enhanced pigment content was observed by the application of TH to NaCl treated plants. Proline content showed increase by NaCl stress and maximum accumulation of 59.12% was recorded at 200 mM NaCl. Further enhancement to 70.37% in proline content was recorded by supplementation of TH. NaCl stress (200 mM) affirms the increase in H2O2 by 69.5% and MDA by 36.5%, but reduction in the accumulation is recorded by addition of TH to mustard seedlings. 200 mM NaCl elevated SOD, POD, APX, GR, GST, GPX, GSH, and GSSG in the present study. Further enhancement was observed by the application of TH to the NaCl fed seedlings. NaCl stress suppresses the uptake of important elements in both roots and shoots, however, addition of TH restored the elemental uptake in the present study. Mustard seedlings treated with NaCl and TH showed restricted Na uptake as compared to seedlings treated with NaCl alone. In conclusion, TH proved to be very beneficial in imparting resistance to the mustard plants against NaCl stress through improved uptake of essential elements, modulation of osmolytes and antioxidants. PMID- 26528325 TI - A security network in PSI photoprotection: regulation of photosynthetic control, NPQ and O2 photoreduction by cyclic electron flow. AB - Cyclic electron flow (CEF) around PSI regulates acceptor-side limitations and has multiple functions in the green alga, Chlamydomonas reinhardtii. Here we draw on recent and historic literature and concentrate on its role in Photosystem I (PSI) photoprotection, outlining causes and consequences of damage to PSI and CEF's role as an avoidance mechanism. We outline two functions of CEF in PSI photoprotection that are both linked to luminal acidification: firstly, its action on Photosystem II with non-photochemical quenching and photosynthetic control and secondly, its action in poising the stroma to overcome acceptor-side limitation by rebalancing NADPH and ATP ratios for carbon fixation. PMID- 26528326 TI - Genetic markers as a predictive tool based on statistics in medical practice: ethical considerations through the analysis of the use of HLA-B(*)27 in rheumatology in France. AB - INTRODUCTION: The use of genetic predictive markers in medical practice does not necessarily bear the same kind of medical and ethical consequences than that of genes directly involved in monogenic diseases. However, the French bioethics law framed in the same way the production and use of any genetic information. It seems therefore necessary to explore the practical and ethical context of the actual use of predictive markers in order to highlight their specific stakes. In this study, we document the uses of HLA-B(*)27, which are an interesting example of the multiple features of genetic predictive marker in general medical practice. MATERIALS AND METHODS: The aims of this monocentric and qualitative study were to identify concrete and ethical issues of using the HLA-B(*)27 marker and the interests and limits of the legal framework as perceived by prescribers. In this regard, a thematic and descriptive analysis of five rheumatologists' semi structured and face-to-face interviews was performed. RESULTS: According to most of the interviewees, HLA-B(*)27 is an "overframed" test because they considered that this test is not really genetic or at least does not have the same nature as "classical genetic tests"; HLA-B(*)27 is not concerned by the ethical challenges of genetic test; the major ethics stake of this marker is not linked to its genetic nature but rather to the complexity of the probabilistic information. This study allows also showing that HLA-B(*)27, validated for a certain usage, may be used in different ways in practice. DISCUSSION: This marker and its clinical uses underline the challenges of translating both statistical concepts and unifying legal framework in clinical practice. This study allows identifying some new aspects and stakes of genetics in medicine and shows the need of additional studies about the use of predictive genetic markers, in order to provide a better basis for decisions and legal framework regarding these practices. PMID- 26528327 TI - Biological networks: the microscope of the twenty-first century? PMID- 26528329 TI - Defining order and timing of mutations during cancer progression: the TO-DAG probabilistic graphical model. AB - Somatic mutations arise and accumulate both during tumor genesis and progression. However, the order in which mutations occur is an open question and the inference of the temporal ordering at the gene level could potentially impact on patient treatment. Thus, exploiting recent observations suggesting that the occurrence of mutations is a non-memoryless process, we developed a computational approach to infer timed oncogenetic directed acyclic graphs (TO-DAGs) from human tumor mutation data. Such graphs represent the path and the waiting times of alterations during tumor evolution. The probability of occurrence of each alteration in a path is the probability that the alteration occurs when all alterations prior to it have occurred. The waiting time between an alteration and the subsequent is modeled as a stochastic function of the conditional probability of the event given the occurrence of the previous one. TO-DAG performances have been evaluated both on synthetic data and on somatic non-silent mutations from prostate cancer and melanoma patients and then compared with those of current well-established approaches. TO-DAG shows high performance scores on synthetic data and recognizes mutations in gatekeeper tumor suppressor genes as trigger for several downstream mutational events in the human tumor data. PMID- 26528330 TI - Association of SLC2A9 genotype with phenotypic variability of serum urate in pre menopausal women. AB - The SLC2A9 gene, that encodes a renal uric acid reuptake transporter, has genetic variants that explain ~3% of variance in urate levels. There are previous reports of non-additive interaction between SLC2A9 genotype and environmental factors which influence urate control. Therefore, our aim was to further investigate the general phenomenon that such non-additive interactions contribute to genotype specific association with variance at SLC2A9. Data from 14135 European individuals were used in this analysis. The measure of variance was derived from a ranked inverse normal transformation of residuals obtained by regressing known urate-influencing factors (sex, age, and body mass index) against urate. Variant rs6449173 showed the most significant effect on serum urate variance at SLC2A9 (P = 7.9 * 10(-14)), which was maintained after accounting for the effect on average serum urate levels (P = 0.022). Noting the stronger effect in a sub-cohort that consisted of pre-menopausal women and younger men, the participants were stratified into males and pre-menopausal and post-menopausal women. This revealed a strong effect on variance in pre-menopausal women (P = 3.7 * 10(-5)) with a weak effect in post-menopausal women (P = 0.032) and no effect in men (P = 0.22). The T-allele of rs6449173, which associates with increased urate levels, was associated with the greater variance in urate. There was a non-additive interaction between rs6449173 genotype and female gender in control of serum urate levels that was driven by a greater increase in urate levels associated with the T-allele in women. Female hormones, and/or other factors they influence or are associated with (such as iron levels, temperature, testosterone) interact with SLC2A9 genotype in women to determine urate levels. The association of SLC2A9 with greater variance in pre-menopausal women may reflect the cyclical changes resulting from menstruation. PMID- 26528331 TI - Sleep changes following statin therapy: a systematic review and meta-analysis of randomized placebo-controlled polysomnographic trials. AB - INTRODUCTION: Statin use might be associated with an increased risk of sleep disturbances including insomnia, but the evidence regarding sleep changes following statin therapy has not been conclusive. Therefore we assessed the impact of statin therapy on sleep changes through a systematic review and meta analysis of available randomized controlled trials (RCTs). MATERIAL AND METHODS: We searched MEDLINE and SCOPUS up to October 1, 2014 to identify placebo controlled RCTs investigating the effect of statin therapy on sleep changes. A meta-analysis was performed using either a fixed-effects or a random-effect model according to the I2 statistic. Effect size was expressed as weighted mean difference (WMD) and 95% confidence interval (CI). RESULTS: Overall, the impact of statin therapy on polysomnography (PSG) indices of sleep was reported in 5 trials comprising 9 treatment arms. Overall, statin therapy had no significant effect on total sleep duration (WMD: -7.75 min, 95% CI: -18.98, 3.48, p = 0.176), sleep efficiency (WMD: 0.09%, 95% CI: -2.27, 2.46, p = 0.940), entries to stage I (WMD: 0.36, 95% CI: -0.91, 1.63, p = 0.580), or latency to stage I (WMD: -1.92 min, 95% CI: -4.74, 0.89, p = 0.181). In contrast, statin therapy significantly reduced wake time (WMD: -4.43 min, 95% CI: -7.77, -0.88, p = 0.014) and number of awakenings (WMD: -0.40, 95% CI: -0.46, -0.33, p < 0.001). Meta-regression did not suggest any correlation between changes in wake time and awakening episodes with duration of treatment and LDL-lowering effect of statins. CONCLUSIONS: The results indicated that statins have no significant adverse effect on sleep duration and efficiency, entry to stage I, or latency to stage I sleep, but significantly reduce wake time and number of awakenings. PMID- 26528328 TI - Genetics of the ovarian reserve. AB - Primordial follicles or non-growing follicles (NGFs) are the functional unit of reproduction, each comprising a single germ cell surrounded by supporting somatic cells. NGFs constitute the ovarian reserve (OR), prerequisite for germ cell ovulation and the continuation of the species. The dynamics of the reserve is determined by the number of NGFs formed and their complex subsequent fates. During the reproductive lifespan, the OR progressively diminishes due to follicle atresia as well as recruitment, maturation, and ovulation. The depletion of the OR is the major determining driver of menopause, which ensues when the number of primordial follicles falls below a threshold of ~1,000. Therefore, genes and processes involved in follicle dynamics are particularly important to understand the process of menopause, both in the typical reproductive lifespan and in conditions like primary ovarian insufficiency, defined as menopause before age 40. Genes and their variants that affect the timing of menopause thereby provide candidates for diagnosis of and intervention in problems of reproductive lifespan. We review the current knowledge of processes and genes involved in the development of the OR and in the dynamics of ovarian follicles. PMID- 26528332 TI - Diagnostic accuracy of loop-mediated isothermal amplification in detection of Clostridium difficile in stool samples: a meta-analysis. AB - INTRODUCTION: Clostridium difficile infection (CDI) remains a diagnostic challenge for clinicians. More recently, loop-mediated isothermal amplification (LAMP) has become readily available for the diagnosis of CDI, and many studies have investigated the usefulness of LAMP for rapid and accurate diagnosis of CDI. However, the overall diagnostic accuracy of LAMP for CDI remains unclear. In this meta-analysis, our aim was to establish the overall diagnostic accuracy of LAMP in detection of Clostridium difficile (CD) in stool samples. MATERIAL AND METHODS: A search was done in PubMed, MEDLINE, EMBASE and Cochrane Library databases up to February 2014 to identify published studies that evaluated the diagnostic role of LAMP for CD. Methodological quality was assessed according to the quality assessment for studies of diagnostic accuracy (QUADAS) instrument. The sensitivities (SEN), specificities (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) were pooled statistically using random effects models. Statistical analysis was performed by employing Meta-Disc 1.4 software. Summary receiver operating characteristic (SROC) curves were used to summarize overall test performance. Funnel plots were used to test the potential publication bias. RESULT: A total of 9 studies met inclusion criteria for the present meta-analysis. The pooled SEN and SPE for diagnosing CD were 0.93 (95% CI: 0.91-0.95) and 0.98 (95% CI: 0.98-0.99), respectively. The PLR was 47.72 (95% CI: 15.10-150.82), NLR was 0.07 (95% CI: 0.04-0.14) and DOR was 745.19 (95% CI: 229.30-2421.72). The area under the ROC was 0.98. Meta-regression indicated that the total number of samples was a source of heterogeneity for LAMP in detection of CD. The funnel plots suggested no publication bias. CONCLUSIONS: The LAMP meets the minimum desirable characteristics of a diagnostic test of SEN, SPE and other measures of accuracy in the diagnosis of CD, and it is suitable as a rapid, effective and reliable stand-alone diagnostic test for diagnosis of CDI, potentially decreasing morbidity and nosocomial spread of CD. PMID- 26528333 TI - Association of polymorphism in adiponectin (+45 T/G) and leptin (-2548 G/A) genes with type 2 diabetes mellitus in male Egyptians. AB - INTRODUCTION: Adiponectin is an adipose tissue-specific protein with insulin sensitizing properties. Many investigators have explored the association between adiponectin single nucleotide polymorphisms (SNPs) and type 2 diabetes mellitus (T2DM) in different ethnic populations from different regions. Leptin is a protein hormone constituting an important signal in the regulation of adipose tissue mass and body weight. The aim of this study was to explore potential associations between SNP +45 T>G of the adiponectin gene and SNP 2548G/A of leptin with T2DM and the effect of SNPs on serum adiponectin and leptin levels. MATERIAL AND METHODS: From the Egyptian population, we enrolled 110 T2DM patients and 90 non-diabetic controls. Serum lipid profile, blood glucose, serum adiponectin, and leptin were measured. Genotyping for two common SNPs of the adiponectin and leptin genes was performed by polymerase chain reaction restriction fragment length polymorphism. RESULTS: The G allele and TG/GG genotype of SNP 45 occurred more frequently than the T allele and TT genotype in T2DM patients compares to the controls. Subjects with the GG + TG genotype of SNP 45 were at increased risk for T2DM (OR = 6.476; 95% CI: 3.401-12.33) and associated with a low serum adiponectin level compared with the TT genotype. The serum leptin concentration of GA + AA genotype carriers was not significantly different from that of the GG genotype in the diabetic group. CONCLUSIONS: The G allele carriers who have reduced plasma concentrations of adiponectin may have an association with T2DM, while leptin SNP 2548 G/A is not associated with the risk of development of T2DM in the Egyptian population. PMID- 26528334 TI - Usefulness of microvolt T-wave alternans testing in the assessment of all-cause mortality and life-threatening ventricular arrhythmia risk in patients with left ventricular dysfunction. AB - INTRODUCTION: Patients with left ventricular ejection fraction (LVEF) <= 35% are eligible for implantable cardioverter-defibrillator (ICD) placement in the primary prevention of sudden cardiac death. Nevertheless, other risk factors facilitating the selection of individuals with highest mortality are still sought. The aim of the study was to verify the usefulness of microvolt T-wave alternans (MTWA) testing in the assessment of all-cause mortality and life threatening ventricular arrhythmias (EVENTs) in these patients. Previous data from the literature are inconclusive. MATERIAL AND METHODS: Patients with LVEF <= 35% were eligible if they did not have a history of sustained ventricular arrhythmias, and were treated with beta-blockers. Participants underwent MTWA testing and were subsequently followed. RESULTS: The group consisted of 139 patients. MTWA results were classified as non-negative (MTWA_non-neg) in 93 and negative (MTWA_neg) in 46 patients. During the 14.3 +/-8.6 months of follow-up, EVENTs were observed in 21 patients. The 1-year EVENT rate was 16.4% among MTWA_non-neg patients, and 2.6% among MTWA_neg patients (p = 0.006). The sensitivity of the MTWA test was 95.24%, the specificity - 38.14%, the positive predictive value - 21.51% and the negative predictive value - 97.83%. CONCLUSIONS: In the group of patients with left ventricular systolic dysfunction, with the exclusion of patients with the history of life-threatening ventricular arrhythmia and individuals not being on chronic beta-adrenolytic therapy, the abnormal result of MTWA testing is associated with significantly increased risk of all-cause mortality and life-threatening ventricular arrhythmia during 1 year of follow-up, thus identifying the individuals at the highest risk. PMID- 26528335 TI - Aortic valve calcification in 499 consecutive patients referred for computed tomography. AB - INTRODUCTION: Aortic valve calcification (AVC) is the most common cause of aortic stenosis. The aim of the study was to assess the prevalence of aortic valve, coronary artery and aortic calcifications and to evaluate the correlation between calcification of the aortic valve, coronary arteries and aorta. MATERIAL AND METHODS: The study included 499 patients aged 60 years and over who underwent coronary computed tomography because of chest pain. Beside coronary artery calcium score (CAC), we evaluated AVC and ascending aorta calcifications (AAC). RESULTS: Aortic valve calcification was found in 144 subjects (28.9% of the whole study population). Prevalence of CAC and AAC was higher than AVC and amounted to 73.8% and 54.0%. Prevalence of AVC, CAC and AAC was significantly lower in the group of patients <= 70 years than in the group of patients > 70 years of age (p = 0.0002, p < 0.0001, p < 0.0001). Aortic valve calcification was more often observed in men than women (34.7% vs. 25.4%, p = 0.02). Degree of aortic valve calcification was also significantly higher among men than women (median score 4 vs. 0, p = 0.01). Similar observations were true for CAC and AAC, where both prevalence and degree of calcification was higher among men than women. In the whole study population no correlation was noted between AVC and CAC or AAC (p = 0.34, p = 0.85). There was a significant correlation between AAC and CAC (p < 0.0001). CONCLUSIONS: Despite some similarities in pathological mechanism and risk factors, a degenerative defect of the aortic valve could be independent of atheromatous lesions in the coronary arteries and aorta. PMID- 26528336 TI - Can we distinguish stroke and stroke mimics via red cell distribution width in young patients? AB - INTRODUCTION: Discrimination of stroke and stroke mimics is problematic in young patients. The aim of the study was to determine whether arterial ischemic stroke and stroke mimics can be differentiated via the red cell distribution width (RDW) value in young patients. MATERIAL AND METHODS: In this retrospective cross sectional study, a total of 236 patients hospitalized at the neurology ward were investigated. The patients were divided into 3 groups: the 1(st) group included young stroke patients, the 2(nd) group included patients with epilepsy, and the 3rd group included patients with multiple sclerosis (MS). Complete blood count and computed tomographic brain imaging tests were performed in all patients, and magnetic resonance imaging was done when necessary. RESULTS: A total of 236 patients were included in this study. Ninety-five (40%) patients were young stroke patients, 71 (30%) had epilepsy and 70 (30%) had MS. The mean RDW values of young patients with stroke were significantly higher than patients with epilepsy or MS (14.9 +/-1.2, 13.3 +/-1.2, 13.4 +/-0.6, p < 0.0001, respectively). The diagnostic power of RDW in the differentiation of patients with stroke is good (area under the curve (AUC) = 0.89). When an RDW cut-off value of 14.05% is accepted for differentiating young patients with stroke from other disorders, the sensitivity, specificity, positive predictive and negative predictive values were 73.7%, 87.9%, 6.1 and 0.043, respectively. CONCLUSIONS: Red cell distribution width is a promising, rapid, easy and inexpensive parameter to distinguish young stroke from stroke mimics (such as epilepsy and MS) in young patients. PMID- 26528337 TI - Effect of Helicobacter pylori eradication in Iranian patients with functional dyspepsia: a prospective, randomized, placebo-controlled trial. AB - INTRODUCTION: Whether patients with functional dyspepsia (FD) should receive Helicobacter pylori (H. pylori) eradication therapy remains controversial. The objective of this trial was to evaluate the effect of H. pylori eradication therapy on dyspeptic symptoms of patients with FD. MATERIAL AND METHODS: A prospective, randomized, placebo-controlled trial of H. pylori eradication for FD was conducted. A total of 720 FD patients diagnosed by Rome III criteria were consecutively enrolled. We randomly assigned 186 H. pylori infected patients with FD to receive quadruple therapy for 14 days and 173 such patients to receive identical-appearing placebos. Severity of abdominal symptoms was assessed with the Glasgow Dyspepsia Severity Score (GDSS), and eradication of H. pylori by (13)C-urea breath test was evaluated during one year. RESULTS: The rate of eradication of H. pylori infection was 87.1% in the treatment group and 2.9% in the placebo group at 6 weeks (p = 0.001). The mean GDSS at 12 months was 4.9 +/ 2.8 in the treatment group, as compared to 5.2 +/-3.4 in the placebo group (p = 0.064). The scores in both groups were lower than those at baseline. According to the intention-to-treat analysis, at 12 months, there was no significant difference between groups in the rate of successful treatment (48.6% in the treatment group and 51.2% in the placebo group; p = 0.84). There was no significant difference in mean symptom scores between the two treatment groups at any point during follow-up. CONCLUSIONS: The results of our study provide no evidence that H. pylori eradication leads to relief of symptoms 12 months after treatment, and there is a need for further studies. PMID- 26528338 TI - Evaluation of efficacy of endoscopic incision method in postoperative benign anastomotic strictures of gastrointestinal system. AB - INTRODUCTION: Postoperative benign anastomotic strictures (POBAS) which develop after surgical resections of the gastrointestinal system (GIS) present with symptoms depending on location of the stricture. Diagnosis is confirmed by endoscopic and radiological methods. Although bougie or balloon dilatation is preferred in management, the endoscopic incision method (EIM) is also used with considerable success. In this trial, we aimed to evaluate EIM, which is one of the endoscopic dilatation techniques used in postoperative anastomotic stricture of GIS. MATERIAL AND METHODS: A total of 20 POBAS patients, 12 men and 8 women, subjected to EIM intervention for strictures, were enrolled in the trial. The number of patients with upper GIS strictures was 6 (30%), while the number of cases with lower GIS strictures was 14 (70%). RESULTS: Dilatation of the stricture was achieved in 15 (75%) patients with one treatment session, while more than one session of EIM was needed in 5 (25%) cases. Mean duration of follow up of patients was 10.65 +/-5.86 (0-25) months. Procedure-related complications developed in 8 patients. Among them, 7 were minor complications and improved without any treatment. In only 1 (5%) patient, perforation was observed as a major complication. Following EIM, recurrence of POBAS was observed in 5 (25%) patients. The following parameters were found to have an impact on successful outcome in EIM: presence or absence of a tortuous lumen in POBAS (p = 0.035) and length of stricture (p = 0.02), complications during the procedure (if any), and presence of single or multiple strictures. CONCLUSIONS: Endoscopic incision method may be regarded as a favorable approach among first choice treatment alternatives in uncomplicated anastomotic strictures of GIS, or it may be used as an adjunctive dilatation method. PMID- 26528339 TI - Correlation of adrenomedullin with the erythropoietin receptor and microvessel density in hepatocellular carcinoma. AB - INTRODUCTION: Uncontrolled angiogenesis plays an essential role in the occurrence, metastasis and malignant progression of hepatocellular carcinoma (HCC). This study aimed to investigate the expression of adrenomedullin (ADM) in human HCC and its correlation with the expression of erythropoietin receptor (EPOR), microvessel density (MVD) and the tumor pathological characteristics. MATERIAL AND METHODS: Fresh tumor tissues were obtained from 30 HCC patients after hepatectomy. Ten cirrhotic and 10 normal liver tissues were included as controls. Expression of ADM and EPOR was determined by real-time PCR. The MVD was determined by counting the number of microvessels. RESULTS: The MVD and the mRNA levels of ADM and EPOR in cancer tissues were significantly higher than those in the non-cancer tissues (p < 0.05). Expression of ADM was significantly correlated with the MVD and EPOR (r = 0.68 and 0.74, p < 0.01). Adrenomedullin and EPOR mRNA levels in HCC tissues were correlated with capsule invasion, pathological differentiation and tumor metastasis (p < 0.05). CONCLUSIONS: Our findings suggest that ADM and EPOR may serve as new regulatory factors involved in angiogenesis of HCC and represent novel targets for the treatment of HCC. PMID- 26528340 TI - Vaginal excision of the sub-urethral sling: analysis of indications, safety and outcome. AB - INTRODUCTION: Sling techniques are the method of choice in stress urinary incontinence management, despite the high rates of complications leading sometimes to the necessity of re-operation, and the tape transection and resection are of the greatest importance. The study was aimed at analyzing the indications, technique and effects of transvaginal tape excision. MATERIAL AND METHODS: A retrospective study including 100 patients who underwent surgical removal of the sub-urethral sling in Evangelisches Krankenhaus Hagen-Haspe was conducted. The analyzed measures were: sling type, onset of symptoms, rates of particular complications, safety and outcome of the operative procedure. RESULTS: Most complications occurred in the first 2 years after surgery. The most common indications for re-operation were: overactive bladder (OAB) (64%), persistent stress urinary incontinence (SUI) (59%), pain (40%), urinary retention (40%), and erosion (29%). Some of the complications co-existed (i.e. vaginal erosion with postoperative pain, infections with urinary retention). During the procedure 1 bladder was injured and 1 patient had a hematoma. In women with OAB, 24-hour frequency decreased from 13.3 to 8.5 (p < 0.001), the mean voiding volume increased from 131.7 to 216.4 ml (p < 0.001), and nocturia increased from 3.28 to 1.19 (p < 0.001). Intensity of urgency decreased from 8.78 to 0.92 in the 10 point visual score (p < 0.001). Pain and urinary retention resolved in 39 out of 40 patients (p < 0.0001). The rate of SUI increased from 59% to 83% (p < 0.001). CONCLUSIONS: Sling removal is safe and associated with a minimal rate of complications. Removing the tape causes resolution of most of the complications, but SUI recurs or worsens. PMID- 26528341 TI - Relationship between mean platelet volume and recurrent miscarriage: a preliminary study. AB - INTRODUCTION: The aim of the study was to examine the relationship between mean platelet volume (MPV) and recurrent miscarriage in order to illuminate the etiopathogenesis of recurrent miscarriage. MATERIAL AND METHODS: We retrospectively investigated the data of 120 patients with unexplained recurrent miscarriage (group 1), and compared them with the data of 120 match-paired patients in the control group (group 2). The definition of recurrent miscarriage was accepted as two or more failed clinical pregnancies which were documented by ultrasonography or histopathologic examination. All patients in the recurrent miscarriage group were evaluated with diagnostic tests for the etiology of recurrent miscarriage. Total blood count parameters, including hemoglobin, mean corpuscular volume, red cell distribution width, white blood cells, platelets, and mean platelet volume, were compared. RESULTS: The average patient age at the time of examination was 29.07 +/-2.81 years in group I and 28.53 +/-3.5 years in group II (p > 0.05). Mean body mass index (BMI) was similar between group 1 and group 2, 22.54 +/-3.17 and 22.99 +/-2.38, respectively (p > 0.05). Mean hemoglobin, mean corpuscular volume, red cell distribution width, and white blood cell and platelet levels were similar in both groups (p > 0.05). Mean platelet volume levels were significantly higher in group I (9.45 +/-1.09 fl) than in group II (7.63 +/-0.52 fl) (p = 0.001). CONCLUSIONS: Higher MPV values in the study group suggest and support the importance of thromboembolic events in the etiology of recurrent miscarriage. PMID- 26528342 TI - A pilot study of the association of manganese superoxide dismutase and glutathione peroxidase 1 single gene polymorphisms with prostate cancer and serum prostate specific antigen levels. AB - INTRODUCTION: The aim of the study was to evaluate the potential association of single gene polymorphisms of the antioxidant enzymes manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPX1) with prostate cancer (PCa). MATERIAL AND METHODS: Manganese superoxide dismutase and glutathione peroxidase 1 genotypes and allele frequencies in 49 prostate cancer cases (PCa group) and 98 control subjects were determined. Analysis of genotypes in control group individuals were performed in two subgroups according to serum prostate-specific antigen levels: the control group (n = 49), with prostate specific antigen (PSA) level < 4 ng/ml; and the nonPCa-high PSA control group (n = 49), with serum PSA > 4 ng/ml. Determination of MnSOD Ala-9Val and GPX1 Pro198Leu polymorphisms was performed using real-time polymerase chain reaction amplification. RESULTS: No association was found between GPX1 polymorphisms and PCa in all groups (p > 0.05). In the PCa group, the frequency of homozygote Val allele carriers was significantly higher in comparison to nonPCa-high PSA control cases. Therefore, Val/Val genotype was found significantly suspicious for PCa risk (OR = 2.48; 95% CI: 1.37-4.48; p = 0.002). Furthermore, an overall protective effect of the Ala allele of the MnSOD polymorphism on PCa risk was detected. These findings in this small Turkish population suggested that individual risk of PCa may be modulated by MnSOD polymorphism especially in patients with high PSA, but GPX1 polymorphism seemed to have no effect on PCa risk. CONCLUSIONS: The presence of genetic variants of antioxidant enzymes could have a potential influence on genesis of prostatic malignancy. PMID- 26528343 TI - Ultrafiltration - an alternative method to polyethylene glycol precipitation for macroprolactin detection. AB - INTRODUCTION: The aim of the study was to evaluate two methods of macroprolactin (MaPRL) detection - precipitation with polyethylene glycol (PEG) and ultrafiltration and to compare these techniques with "gold standard" - gel filtration chromatography (GFC). MATERIAL AND METHODS: The study was conducted on 245 patients - 45 with organic and 200 with functional hyperprolactinaemia. In all the subjects MaPRL was detected by precipitation with PEG and ultrafiltration. Additionally, gel filtration chromatography was performed in some of the serum samples. RESULTS: Macroprolactinaemia was detected in 27 patients - 8 with prolactinoma and 19 with functional hyperprolactinaemia. Assessing positive and negative results for MaPRL, we observed high diagnostic agreement (95.9%) and positive correlation (r = 0.506, p < 0.001) between the methods. The results of precipitation and ultrafiltration positive for MaPRL were concordant in 63%. The dominance of MaPRL detected with precipitation and/or ultrafiltration was confirmed by GFC in 76% of cases (all patients with functional hyperprolactinaemia). Among 6 examined patients with prolactinoma, GFC showed four false-positive results - 1 case of precipitation and 3 cases of ultrafiltration. CONCLUSIONS: Efficacy of MaPRL detection with precipitation and ultrafiltration is comparable especially in cases of functional hyperprolactinaemia. In patients with prolactinoma, precipitation seems to be a more efficient separation method. PMID- 26528344 TI - Treatment of subclinical hypothyroidism does not affect bone mass as determined by dual-energy X-ray absorptiometry, peripheral quantitative computed tomography and quantitative bone ultrasound in Spanish women. AB - INTRODUCTION: The results of studies examining the influence of subclinical hypothyroidism (SCH) and levothyroxine (L-T4) replacement therapy on bone have generated considerable interest but also controversy. The present research aims to evaluate the effects of L-T4 treatment on different skeletal sites in women. MATERIAL AND METHODS: A group of 45 premenopausal (mean age: 43.62 +/-6.65 years) and 180 postmenopausal (mean age: 59.51 +/-7.90 years) women with SCH who were undergoing L-T4 replacement therapy for at least 6 months were compared to 58 pre and 180 postmenopausal women with SCH (untreated) matched for age. The mean doses of L-T4 were 90.88 +/-42.59 ug/day in the premenopausal women and 86.35 +/ 34.11 ug/day in the postmenopausal women. Bone measurements were obtained using quantitative bone ultrasound (QUS) for the phalanx, dual-energy X-ray absorptiometry (DXA) for the lumbar spine and hip, and peripheral quantitative computed tomography (pQCT) for the non-dominant distal forearm. RESULTS: No differences were observed between patients and untreated controls in these bone measurements except in the bone mineral density (BMD) of the spine (p = 0.0214) in postmenopausal women, which was greater in treated women than in untreated controls. CONCLUSIONS: Our results indicate that adequate metabolic control through replacement treatment with L-T4 in pre- and postmenopausal women does not affect bone mass. PMID- 26528345 TI - Application of plantography examination to the assessment of foot deformity in patients with rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a chronic, inflammatory and multiple system disorder of connective tissue. It frequently affects joints and periarticular structures of feet that constitute a significant supporting element underlying normal gait and motion of the body centre of gravity. The aim of the study was to evaluate foot deformities on the basis of plantography examination in RA patients according to the severity of the disease. MATERIAL AND METHODS: The study was performed on 54 RA patients. The control group consisted of 34 volunteers free of any disorders. Plantography examination was carried out by means of a CQ ST2K podoscope. The following parameters were applied to the assessment of the disturbances of foot statics: hallux valgus angle (alpha), Sztriter-Godunow index (KY), Wejsflog's index (Wwp) and Clarke's angle (CL). RESULTS: Markedly higher values of the alpha angle were noted in RA patients, reflecting the presence of hallux valgus. Moreover, values of the alpha angle were higher in patients in the third stage of radiological changes than those in the second one. On the other hand, values of Clarke's angle for the right foot were significantly higher in men in the second and third stage of RA compared to the control group. The most common deformities in RA patients include HV and transverse flat foot, more explicit in women in the third stage of RA. CONCLUSIONS: Plantography examination has been shown to constitute a useful diagnostic tool for assessment and monitoring of foot deformities in RA patients. PMID- 26528346 TI - A retrospective study of antihypertensives in pemphigus: a still unchartered odyssey particularly between thiols, amides and phenols. AB - INTRODUCTION: Autoimmune pemphigus diseases comprise several entities with serious prognoses, including the pemphigus vulgaris (PV) group and pemphigus foliaceus (PF) group. Antihypertensives are suspected to be one of the factors triggering/sustaining pemphigus. Here, the data of pemphigus patients regarding arterial hypertension (AH) and taking potentially noxious drugs were statistically analyzed in a setting of a Polish university dermatology department. MATERIAL AND METHODS: Medical histories of pemphigus patients (40 admissions of 24 female patients - 13 PV, 11 PF; and 102 admissions of 38 male patients - 24 PV, 14 PF), diagnosed at both immunopathological and biochemical molecular levels, were studied. RESULTS: Ten of 16 (62.50%) AH-positive PV patients received known PV triggers/sustainers 11 times (1-3 per patient). Fourteen of 15 (93.33%) AH-positive PF patients received known PF triggers/sustainers 21 times (1-3 per patient). No differences in numbers of patients taking potentially culprit drugs were shown between PV and PF (Fisher's exact test: p = 0.0829; Yates' chi(2) test: p = 0.1048). The most frequently used culprit drugs were ramipril in PV and enalapril in PF. On average, each PV/PF AH positive patient received 3.161 different antihypertensives in his/her history of admissions (2.155 antihypertensives per admission). CONCLUSIONS: Drug triggering should be suspected in every case of newly diagnosed or exacerbated pemphigus, as eliminating possible PV/PF triggers/sustainers may alleviate the clinical symptoms and enable the decrease of dose/range of immunosuppressants regardless of pemphigus form. Eliminating possible drug PV/PF triggers/sustainers may alleviate the clinical symptoms and enable the decrease of dose/range of immunosuppressants regardless of pemphigus form. PMID- 26528347 TI - The importance of vitamin D in the pathology of bone metabolism in inflammatory bowel diseases. AB - Etiological factors of bone metabolism disorders in inflammatory bowel diseases have been the subject of interest of many researchers. One of the questions often raised is vitamin D deficiency. Calcitriol acts on cells, tissues and organs through a vitamin D receptor. The result of this action is the multi-directional effect of vitamin D. The reasons for vitamin D deficiency are: decreased exposure to sunlight, inadequate diet, inflammatory lesions of the intestinal mucosa and post-gastrointestinal resection states. This leads not only to osteomalacia but also to osteoporosis. Of significance may be the effect of vitamin D on the course of the disease itself, through modulation of the inflammatory mechanisms. It is also necessary to pay attention to the role of vitamin D in skeletal pathology in patients with inflammatory bowel diseases and thus take measures aimed at preventing and treating these disorders through the supplementation of vitamin D. PMID- 26528348 TI - Lung cancer screening: history, current perspectives, and future directions. AB - Lung cancer has remained the leading cause of death worldwide among all cancers. The dismal 5-year survival rate of 16% is in part due to the lack of symptoms during early stages and lack of an effective screening test until recently. Chest X-ray and sputum cytology were studied extensively as potential screening tests for lung cancer and were conclusively proven to be of no value. Subsequently, a number of studies compared computed tomography (CT) with the chest X-ray. These studies did identify lung cancer in earlier stages. However, they were not designed to prove a reduction in mortality. Later trials have focused on low-dose CT (LDCT) as a screening tool. The largest US trial - the National Lung Screening Trial (NLST) - enrolled approximately 54,000 patients and revealed a 20% reduction in mortality. While a role for LDCT in lung cancer screening has been established, the issues of high false positive rates, radiation risk, and cost effectiveness still need to be addressed. The guidelines of the international organizations that now include LDCT in lung cancer screening are reviewed. Other methods that may improve earlier detection such as positron emission tomography, autofluorescence bronchoscopy, and molecular biomarkers are also discussed. PMID- 26528349 TI - The influence of infectious factors on dendritic cell apoptosis. AB - Pathogens can have a negative influence on dendritic cells (DCs), causing their apoptosis, which prevents active presentation of foreign antigens. It results in a state of immunosuppression which makes the body susceptible to secondary infections. Infected immature DCs have lower expression of co-stimulatory and adhesion molecules, reduced ability to secrete cytokines and an inhibited maturation process and are incapable of effective antigen presentation and activation of T-lymphocytes. In some cases, the ability of DCs to undergo rapid apoptosis is important for the body defense, which is probably because of DCs' ability to cross-present and cooperate with other cells. Apoptotic bodies released from the infected DCs are phagocytosed by other DCs, which then stimulate the effector cells and present antigens more efficiently than infected cells. The aim of this article is to review how the DCs respond to viral and bacterial factors and which biochemical mechanisms are responsible for their apoptosis. PMID- 26528350 TI - Evolution of the term and definition of dysplasia of the hip - a review of the literature. AB - There is no consensus on the definition of dysplasia of the hip (DH). Past and present concepts used to describe DH do not form a complete view of the pathology. Moreover, some authors still present the disease as congenital, not developmental. This prompted authors to analyze the evolution of the definition of DH. Based on the biomedical databases 500 articles and books in the field of hip dysplasia were found and analyzed. Fifteen definitions of hip dysplasia met inclusion criteria, subsequently were analyzed and presented in chronological order. The analysis revealed that currently there is no single, universal definition of hip dysplasia in the aspect of morphological, clinical, and radiological studies. Despite the widely-used term of DH, it is described imprecisely and in different ways. Therefore, it is necessary to develop a multidisciplinary definition of this pathology covering all aspects of hip disorders considered valid in modern orthopaedics. PMID- 26528351 TI - Early detection of idiopathic scoliosis - analysis of three screening models. AB - INTRODUCTION: The prevalence of lateral curvatures of the spine ranges from 0.3% to 15.3% in the general population. The aim of the study was to develop and compare three different screening tests for idiopathic scoliosis (IS) with respect to their effectiveness and costs. MATERIAL AND METHODS: The Delphi method was used to assess the efficacy of each screening algorithm in detecting IS in the population. An economic analysis was also performed. RESULTS: Diagnostic Algorithm 1 for IS comprised a screening examination performed by nurses and a general practitioner (GP) with verification by specialists. The unit cost of carrying out diagnostic work-up for IS in Algorithm 1 was ?94 per child. The second algorithm involved the use of the moire computer method, followed by verification by a specialist. The lower unit cost of ?86 per child of diagnostic work-up according to Algorithm 2 was due to fewer stages compared to Algorithm 1. The highest effectiveness with the highest costs were found for the third algorithm, with only one stage, a specialist's consultation (cost ?153 per child). CONCLUSIONS: The number of stages in an algorithm does not correlate positively with its efficacy or cost. The recommended scheme is Algorithm 3, where children are examined by rehabilitation specialists or a physiotherapist using a scoliometer and an inclinometer. The use of the apparently most expensive scheme (Algorithm 3) should result in lowering the costs of treatment of established idiopathic scoliosis and, in the long term, prove to be the most cost effective solution for the health care system. PMID- 26528352 TI - Apelin-13 protects the heart against ischemia-reperfusion injury through the RISK GSK-3beta-mPTP pathway. AB - INTRODUCTION: Apelin plays an important role in the protection against myocardial ischemia-reperfusion (I/R) injury, while the mechanism still remains unclear. In the current study, we aimed to evaluate the protective effect of apelin-13, and the main mechanism. MATERIAL AND METHODS: The in vivo I/R injury model (Sprague Dawley rat) was established, then infarct size, expression levels of phospho protein kinase B (p-Akt), phospho-extracellular signal-regulated kinase (p-ERK) and phospho-glycogen synthase kinase-3beta (p-GSK-3beta) were measured. The fluorescence intensity of tetramethylrhodamine ethyl ester perchlorate (TMRE) of the isolated myocardial cells was determined to evaluate the opening of the mitochondrial permeability transition pore (mPTP) caused by oxidant stress and hypoxia/reoxygenation. RESULTS: For the established I/R injury model, apelin-13 and SB216763 (GSK-3beta inhibitor) significantly reduced the infarct size (p < 0.05), which could be abolished by LY294002 (PI3K inhibitor), PD98059 (MEK inhibitor) and atractyloside (mPTP accelerator). The enhanced expression levels of p-Akt, p-ERK and p-GSK-3beta caused by apelin-13 (p < 0.05) could be counteracted by LY294002 and PD98059. The reduced fluorescence intensity of TMRE in the H2O2/apelin-13 and H2O2/SB216763 treated groups was significantly lower (p < 0.05), indicating that apelin-13 and SB216763 could reduce the decline in mitochondrial membrane potential caused by oxidant stress, and the fluorescence intensity in the hypoxia/reoxygenation + apelin-13 group was significantly lower (p < 0.05), which suggested that apelin-13 could inhibit the mitochondrial membrane potential changes induced by hypoxia/reoxygenation. CONCLUSIONS: The protective mechanism of apelin-13 might be that inactivation of GSK-3beta could inhibit the opening of mPTP by activating PI3K/Akt and ERK1/2 involved in the reperfusion injury salvage kinase (RISK) pathway. PMID- 26528354 TI - Polyunsaturated fatty acids trigger apoptosis of colon cancer cells through a mitochondrial pathway. AB - INTRODUCTION: Colorectal cancer is common in developed countries. Polyunsaturated fatty acids (PUFAs) have been reported to possess tumoricidal action, but the exact mechanism of their action is not clear. MATERIAL AND METHODS: In the present study, we studied the effect of various n-6 and n-3 fatty acids on the survival of the colon cancer cells LoVo and RKO and evaluated the possible involvement of a mitochondrial pathway in their ability to induce apoptosis. RESULTS: It was observed that n-3 alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid (ALA, EPA and DHA respectively) and n-6 linoleic acid, gamma linolenic acid and arachidonic acid (LA, GLA and AA respectively) induced apoptosis of the colon cancer cells LoVo and RKO at concentrations above 120 MUM (p < 0.01 compared to control). The semi-differentiated colon cancer cell line RKO was more sensitive to the cytotoxic action of PUFAs compared to the undifferentiated colon cancer cell line LoVo. PUFA-treated cells showed an increased number of lipid droplets in their cytoplasm. PUFA-induced apoptosis of LoVo and RKO cells is mediated through a mitochondria-mediated pathway as evidenced by loss of mitochondrial membrane potential, generation of ROS, accumulation of intracellular Ca(2+), activation of caspase-9 and caspase-3, decreased ATP level and increase in the Bax/Bcl2 expression ratio. CONCLUSIONS: PUFAs induced apoptosis of colon cancer cells through a mitochondrial dependent pathway. PMID- 26528353 TI - FK506-binding protein 5 inhibits proliferation and stimulates apoptosis of glioma cells. AB - INTRODUCTION: FK506-binding protein 5 (FKBP5) is reported to act as a scaffolding protein for Akt to promote the dephosphorylation of AKT Ser473 and suppress pancreatic cancer growth. However, other studies have shown that FKBP5 promotes tumor growth and chemoresistance through regulating NF-kappaB signaling in other cancers. In this study, we attempted to investigate the role and mechanism of action of FKBP5 in the regulation of proliferation and apoptosis of glioma cells. MATERIAL AND METHODS: The glioma U251 cell line was used as the model. Cell proliferation was detected by MTT assay. Cell apoptosis was detected by annexin-V staining. Protein expression was detected by Western blot analysis. RESULTS: FKBP5 overexpression inhibited the proliferation of U251 cells significantly (p < 0.05), and promoted the apoptosis of U251 cells significantly (p < 0.05). In addition, FKBP5 overexpression inhibited the phosphorylation of Akt at Ser743, decreased the level of Bcl-2, increased the level of Bax, and enhanced the cleavage of caspase-9 and caspase-3 (p < 0.05 compared to control). In contrast, FKBP5 knockdown enhanced the proliferation of U251 cells, increased the phosphorylation of Akt significantly (p < 0.05), increased the expression of Bcl 2 and decreased the expression of Bax, and decreased the cleavage of caspase-9 and caspase-3 significantly (p < 0.05). CONCLUSIONS: FKBP5 plays the role of a tumor suppressor in glioma by inhibiting the activation of Akt and stimulating the intrinsic mitochondrial apoptotic pathway, and could be used as a new target for gene therapy of glioma. PMID- 26528355 TI - Identification and analysis of the promoter region of the STGC3 gene. AB - INTRODUCTION: Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck. The STGC3 gene is related to development of nasopharyngeal cancer. The aim of this study is to explore the promoter region of the STGC3 gene. MATERIAL AND METHODS: The bioinformatic technique was applied to predict its promoter region and construct the gene promoter region luciferase for the gene vector and transfection of the human embryonic kidney epithelial 293T cell line, human nasopharyngeal carcinoma CNE2 cell line and immortalized nasopharyngeal epithelial NP69 cell line. The recombinant plasmid pGL3-en283, pGL3-en281, pGL3 en571, empty plasmid pGL3-control, negative control pGL3-enhance and internal control of marine intestine luciferase expression vector pRL-SV40 were transfected into NP69 cells, 293T cells and CNE2 cells. Dual luciferase activity detection showed luciferase luminescence values and marine intestine luciferase luminescence values. Relative luciferase activity (RLA) in each cell was calculated. RESULTS: We observed strong promoter activity of plasmid pGL3-en283, pGL3-en281 and pGL3-en571 in NP69, 293T and CNE2 cells compared with the negative control pGL3-enhance plasmid. Among them, pGL3-en281 showed the strongest promoter activity, and these three kinds of recombinant plasmids showed stronger promoter activity in 293T cells than in CNE2 cells. CONCLUSIONS: The pGL3-en281 plasmid showed stronger promoter activity than pGL3-en571 in the three cells, indicating that -11048 bp to -653 bp might be the core promoter region. PMID- 26528357 TI - The roles of pacing interval and pacing strength in ventricular fibrillation induced by rapid pacing with 1 : 1 capture. AB - INTRODUCTION: The roles of pacing interval (PI) and pacing strength (PS) in ventricular fibrillation (VF) induced by rapid pacing with 1 : 1 capture remain unclear. MATERIAL AND METHODS: Epicardial unipolar electrograms (UEs) were simultaneously recorded using contact mapping in 11 swine. Activation-recovery interval (ARI) restitution was constructed at 4 sites, i.e. the apex and base of the left and right ventricles, respectively. A steady state pacing (SSP) protocol was performed to induce VF. The longest PI and the lowest PS for inducing VF were recorded. Statistical correlation analysis was performed to determine the relationship between local ARI restitution properties and PI and PS for VF induction. RESULTS: Forty restitution curves were constructed from 11 SSP procedures. The maximal slope (Smax) of the ARI restitution curve of the right ventricular apex was positively correlated with the PI for VF induction (r = 0.761, p < 0.05). Spatial dispersions of ARI and Smax were negatively correlated with the PS for VF induction (r = -0.626 and r = -0.722, respectively, both p < 0.05). CONCLUSIONS: Ventricular fibrillation can be induced by rapid ventricular pacing with 1 : 1 capture. The PI for VF induction was related to the Smax of the ARI restitution curve of the right ventricular apex, while PS for VF induction was associated with the spatial dispersions of ARI and its restitution property. PMID- 26528356 TI - Lack of association between polymorphisms of the DNA base excision repair genes MUTYH and hOGG1 and keratoconus in a Polish subpopulation. AB - INTRODUCTION: Keratoconus (KC) is a non-inflammatory thinning of the cornea and a leading indication for corneal transplantation. Oxidative stress plays a role in the pathogenesis of this disease. The products of the hOGG1 and MUTYH genes play an important role in the repair of oxidatively modified DNA in the base excision repair pathway. We hypothesized that variability in these genes may change susceptibility to oxidative stress and predispose individuals to the development of KC. We investigated the possible association between the c.977C>G polymorphism of the hOGG1 gene (rs1052133) and the c.972G>C polymorphism of the MUTYH gene (rs3219489) and KC occurrence as well as the modulation of this association by some KC risk factors. MATERIAL AND METHODS: A total of 205 patients with KC and 220 controls were included in this study. The polymorphisms were genotyped with polymerase chain reaction (PCR) restriction fragment length polymorphism and PCR confronting two-pair primer techniques. Differences in genotype and allele frequency distributions were evaluated using the chi(2) test, and KC risk was estimated with an unconditional multiple logistic regression with and without adjustment for co-occurrence of visual impairment, allergies, sex and family history for KC. RESULTS: We did not find any association between the genotypes and combined genotypes of the c.977C>G polymorphism of the hOGG1 gene and the c.972G>C polymorphism of the MUTYH gene and the occurrence of KC. CONCLUSIONS: Our findings suggest that the c.977C>G-hOGG1 polymorphism and the c.972G>C-MUTYH polymorphism may not be linked with KC occurrence in this Polish subpopulation. PMID- 26528358 TI - Antioxidant and antiapoptotic effects of darbepoetin-alpha against traumatic brain injury in rats. AB - INTRODUCTION: In this study, we tried to determine whether darbepoetin-alpha would protect the brain from oxidative stress and apoptosis in a rat traumatic brain injury model. MATERIAL AND METHODS: The animals were randomized into four groups; group 1 (sham), group 2 (trauma), group 3 (darbepoetin alpha), group 4 (methylprednisolone). In the sham group only the skin incision was performed. In all the other groups, a moderate traumatic brain injury modelwas applied. RESULTS: Following trauma both glutathione peroxidase, superoxide dismutase levels decreased (p < 0.001 for both); darbepoetin-alpha increased the activity of both antioxidant enzymes (p = 0.001 and p < 0.001 respectively). Trauma caused significant elevation in the nitric oxide synthetase and xanthine oxidase levels (p < 0.001 for both). Administration of darbepoetin-alpha significantly decreased the levels of nitric oxide synthetase and xanthine oxidase (p < 0.001 for both). Also, trauma caused significant elevation in the nitric oxide levels (p < 0.001); darbepoetin-alpha administration caused statistically significant reduction in the nitric oxide levels (p < 0.001). On the other hand, malondialdehyde levels were increased following trauma (p < 0.001), and darbepoetin alpha significantly reduced the malondialdehyde levels (p < 0.001). Due to the elevated apoptotic activity following the injury, caspase-3 activity increased significantly. Darbepoetin-alpha treatment significantly inhibited apoptosis by lowering the caspase-3 activity (p < 0.001). In the darbepoetin group, histopathological score was lower than the trauma group (p = 0.016). CONCLUSIONS: In this study, darbepoetin-alpha was shown to be at least as effective as methylprednisolone in protecting brain from oxidative stress, lipid peroxidation and apoptosis. PMID- 26528359 TI - Melatonin is more effective than ascorbic acid and beta-carotene in improvement of gastric mucosal damage induced by intensive stress. AB - INTRODUCTION: Oxidative stress has been considered to play a primary role in the pathogenesis of stress-induced gastric damage. The aim of this study was to investigate the effects of melatonin, ascorbic acid and beta-carotene on stress induced gastric mucosal damage. MATERIAL AND METHODS: Fifty-six male Wistar albino rats were divided into control, stress, stress + standard diet, stress + saline, stress + melatonin, stress + ascorbic acid and stress + beta-carotene groups. The rats from stress groups were exposed to starvation, immobilization and cold by immobilizing for 8 h at +4 degrees C following 72-hour food restriction. Following stress application, melatonin, ascorbic acid and beta carotene were administered for 7 days. Specimens of gastric tissue were prepared for microscopic and biochemical examinations. RESULTS: Mean histopathological damage scores and mean tissue malondialdehyde levels were significantly decreased but mean tissue glutathione levels and glutathione peroxidase and superoxide dismutase activities were increased in treatment groups vs. stress groups in general. Mean histopathological damage scores of the stress + Mel group was lower than those of stress + D, stress + S, stress + beta-car (p < 0.05) and stress + Asc groups (p < 0.005). Additionally, mean tissue catalase activity of the stress + Mel group was higher than that of stress + S (p < 0.005), stress + D (p < 0.05) and stress + beta-car groups (p < 0.05). CONCLUSIONS: Melatonin is more effective than ascorbic acid and beta-carotene in improvement of gastric damage induced by intensive stress. We suggest that as well as the direct antioxidant and free radical scavenging potency of melatonin, its indirect effect via the brain-gut axis might account for its greater beneficial action against stress-induced gastric damage. PMID- 26528361 TI - Editorial Note. PMID- 26528360 TI - Pattern of neurobehavioral and organ-specific toxicities of beta, beta' iminodipropionitrile in mice. AB - INTRODUCTION: beta, beta'-iminodipropionitrile (IDPN) is a synthetic nitrile that produces a permanent movement disorder in rodents. Although IDPN-induced vestibular pathology is well documented, the mode of IDPN interaction with other organ systems is poorly understood. We examined the behavioral signs and histopathological changes in the vestibular labyrinth, brain, liver and kidneys of mice exposed to IDPN. MATERIAL AND METHODS: Adult male SWR/J mice were divided into 2 groups of 6 animals each. One group of mice received normal saline (control group) and the other group was treated with IDPN (400 mg/kg, i.p.) daily for 7 days. Dyskinetic movements including vertical and horizontal head weaving, circling and backward walking were quantified on days 7, 8 and 9. RESULTS: We observed a direct correlation between the severity of IDPN-induced behavioral deficits and the degeneration of vestibular hair cells in the crista ampullaris of mice. The brain cortex of both groups appeared similar, whereas the kidney histopathology revealed mild nephrotoxicity in some of the IDPN-treated mice. Administration of IDPN caused severe hepatotoxicity, but the intensity of hepatic damage was not correlated with the severity of behavioral deficits. CONCLUSIONS: Degeneration of vestibular sensory hair cells plays an important role in the development of IDPN-induced behavioral deficits in mice. Exposure to IDPN also caused severe hepatotoxicity which was independent of the behavioral symptoms. These findings could be of potential relevance to human health, particularly after the observation that IDPN not only causes a movement disorder but also produces acute liver injury. PMID- 26528363 TI - Can Procalcitonin Add to the Prognostic Power of the Severity Scoring System in Adults with Pneumonia? AB - BACKGROUND: The first decision confronting clinicians in the management of patients with community acquired pneumonia (CAP) is whether the patient is to be hospitalized or not. We sought to validate the pneumonia scoring system and assess the power of procalcitonin (PCT) level to predict in-hospital mortality (IHM) and intensive vasopressor and respiratory support (IVRS) requirements in patients with CAP. MATERIALS AND METHODS: A total of 120 patients with CAP were evaluated for severity of illness based on the defined scoring systems including pneumonia severity index (PSI), confusion, urea, respiratory rate, blood pressure, age>65 (CURB-65), confusion, respiratory rate, blood pressure, age>65 (CRB-65), infectious diseases society of America/American thoracic society 2007 criteria (IDSA/ATS 2007) and systolic blood pressure, multilobar infiltrate, albumin, respiratory rate, tachycardia, confusion, low oxygen, low pH (SMART COP). Demographic, clinical, laboratory and radiographic data were collected prospectively. The accuracy of each scoring system in predicting IVRS requirement and IHM was assessed from the area under the receiver operating characteristic (ROC) curve (AUC). Level of PCT was determined by semi-quantitative PCT-Q method (BRAHMS). The accuracy of the defined scoring systems, PCT levels and each scoring system plus PCT levels in prediction of IHM and IVRS requirement was analyzed. RESULTS: The accuracy of PCT levels in predicting IHM and IVRS requirement based on AUC was 0.542 and 0.658, respectively and the best threshold was >= 2ng/mL for both of them. Adding the level of procalcitonin to different scoring systems (based on the defined scoring systems) improved the accuracy of all systems. CONCLUSION: We do not suggest using the PCT level alone as a predictor for mortality and IVRS requirement. Instead, we suggest PSI plus PCT and IDSA/ATS 2007 plus PCT as accurate predictors for IHM and SMART-COP plus PCT for IVRS requirement in patients who presented with CAP. PMID- 26528364 TI - Relationship of Gingival Pigmentation with Passive Smoking in Women. AB - BACKGROUND: Oral mucosal pigmentation is among the most common findings in smokers, affecting smile esthetics. Passive smoking significantly compromises the health of non-smoker individuals particularly women. The purpose of this study was to assess the relationship of passive smoking with oral pigmentation in non smoker women. MATERIALS AND METHODS: This historical-cohort study was conducted on a case group of 50 married women who were unemployed, not pregnant, non smoker, had no systemic condition causing cutaneous or mucosal pigmentation, were not taking any medication causing cutaneous or mucosal pigmentation and had a heavy smoker husband. The control group comprised of 50 matched females with no smoker member in the family. Both groups were clinically examined for presence of gingival pigmentation and the results were analyzed using chi-square and logistic regression tests. RESULTS: Gingival pigmentation was found in 27 (54%) passive smokers and 14 (28%) controls (P=0.01). The odds ratio (OR) of gingival pigmentation in women exposed to secondhand smoke of their husbands (adjusted for education and having a smoker parent at childhood) was 3 (95% confidence interval; CI: 1.26 - 7.09). House floor area was correlated with gingival pigmentation in female passive smokers (P=0.025). CONCLUSION: This study was the first to describe the relationship between secondhand smoke and gingival pigmentation in women and this effect was magnified in smaller houses. PMID- 26528365 TI - Iranian Pulmonary Arterial Hypertension Registry. AB - BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disorder with a prevalence of 8.6 per million. We introduce a registry website for IPAH and PAH patients ( www.IPAH.ir) for access and efficient delivery of government aided and subsidized antihypertensive medications. MATERIALS AND METHODS: The IPAH registry was opened in November 2009. Information of IPAH and PAH patients with a username and password were uploaded in the site. Data entry was possible only via the physicians and healthcare organizations via internet that were given a personalized username and password for entry. Following the patients' profile submission, a scientific committee composed of a cardiologist and a pulmonologist who were selected by the Ministry of Health of Iran (MOH), evaluated the data. The eligibility of the patient to receive the medications was confirmed after evaluation. If the patient was eligible, 82% of the Bosentan cost was paid by MOH. RESULTS: To date, one hundred and sixteen patients (82 females, 34 males) have been registered. The mean pulmonary artery pressure by right heart catheterization was 69.24+/-17 mmHg (ranging from 35 to 110 mmHg). CONCLUSION: The first online Iranian registry program for IPAH and PAH patients is believed to supply essential information for health care providers in the field. PMID- 26528362 TI - Approach to Patients with Severe Asthma: a Consensus Statement from the Respiratory Care Experts' Input Forum (RC-EIF), Iran. AB - Challenges in the assessment, diagnosis and management of severe, difficult-to control asthma are increasingly regarded as clinical needs yet unmet. The assessments required to determine asthma severity, comorbidities and confounding factors, disease phenotypes and optimal treatment are among the controversial issues in the field. The respiratory care experts' input forum (RC-EIF), comprised of an Iranian panel of experts, reviewed the definition, appraised the available guidelines and provided a consensus for evaluation and treatment of severe asthma in adults. A systematic literature review followed by discussions during and after the forum, yielded the present consensus. The expert panel used the appraisal of guidelines for research and evaluation-II (AGREE-II) protocol to define an initial locally-adapted strategy for the management of severe asthma. Severe asthma is considered a heterogeneous condition with various phenotypes. Issues such as assessment of difficult-to-control asthma, phenotyping, the use of blood and sputum eosinophil count, exhaled nitric oxide to guide therapy, the position of anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty as well as the use of established, recently developed and evolving treatment approaches were discussed and unanimously agreed upon in the panel. A systematic approach is required to ensure proper diagnosis, evaluate compliance, and to identify comorbidities and triggering factors in severe asthma. Phenotyping helps select optimized treatment. The treatment approach laid down by the Global Initiative for Asthma (GINA) needs to be followed, while the benefit of using biological therapies should be weighed against the cost and safety concerns. PMID- 26528367 TI - Effect of Dialysis on Maximum Inspiratory and Expiratory Pressures in End Stage Renal Disease Patients. AB - BACKGROUND: Muscle weakness especially weakness of the respiratory muscles is a complication of chronic kidney disease. The cause of muscle weakness is the accumulation of excessive amounts of urea and other toxins. The aim of this study was to assess the effect of hemodialysis on respiratory muscle strength by measuring maximum inspiratory (PI max) and expiratory pressure (PE max). MATERIALS AND METHODS: A cross sectional study was carried out on 31 patients with chronic kidney disease at Modarres hospital in 2012. Before hemodialysis, patients had their PI max and PE max taken by using a manovacuometer. After that, the patients were connected to the dialysis machine. At the end of the hemodialysis, the patients had their PI max measured again. Data were assessed by the multivariate regression test. RESULTS: Before dialysis, PI max and PE max were lower than normal levels. After the hemodialysis session, repeat PFT revealed an increase in PE max and no significant change in PI max. There were strong correlations between hypoalbuminemia, anemia, hypercalcemia, hyperphosphatemia, hyperparathyroidism and decreased respiratory muscle strength. Also, the respiratory muscle strength decreased in the elderly and women. CONCLUSION: Respiratory muscle weakness is a complication of chronic kidney disease; hemodialysis can improve muscle strength and PI max. PMID- 26528366 TI - Reliability and Validity of the Iranian Version of Nijmegen Questionnaire in Iranians with Asthma. AB - BACKGROUND: The aim of this study was to assess the validity and reliability of Nijmegen questionnaire (NQ) translated to Farsi for diagnosis of the hyperventilation syndrome (HVS) in patients with asthma. MATERIALS AND METHODS: The original version of NQ was translated to Farsi and then back-translated to English again to assess its agreement with the original version. To determine its cultural adaptation, a pilot study was carried out. The mean score of the questionnaire and the mean pressure of end tidal carbon dioxide (PETCO2) were compared in 100 asthmatic patients to determine the validity of the questionnaire. For reliability, 52 out of 100 patients randomly filled out the questionnaire with an interval of 5 to 10 days. Internal consistency and content validity of the questionnaire were assessed by Cronbach's alpha coefficient and by calculating floor and ceiling effects respectively. The exploratory factor analysis was used to assess the factor structure. RESULTS: There was a significant inverse correlation between NQ scores and PETCO2 (P=-0.783). Cronbach's alpha coefficient was greater than 0.7, indicating good internal consistency of the questionnaire (P=0.702). The questionnaire had a good stability in an interval of 5 to 10 days (P=0.826). The NQ had no floor and ceiling effect. and also factor analysis of 16 scales showed that this questionnaire has a five-factor structure, which can describe 55% of data variance. CONCLUSION: The Iranian version of the Nijmegen questionnaire is a valid and reliable tool for detection of patients with HVS. In addition, the questionnaire can be used to evaluate the condition of respiratory function in people with asthma. PMID- 26528368 TI - Role of Serum Interleukin 6, Albumin and C-Reactive Protein in COPD Patients. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a non-specific inflammation, which involves the airways, lung parenchyma and pulmonary vessels. The inflammation causes the activation of inflammatory cells and the release of various inflammatory mediators such as interleukin-8 (IL-8), IL-6 and tumor necoris factor alpha (TNF-a). The purpose of the present study was to measure serum IL-6, C-reactive protein (CRP) (as a positive phase reactant) and albumin level (as a negative phase reactant) in COPD patients (only due to cigarette smoking not bio-mass), non COPD smokers and healthy subjects using enzyme-linked immunosorbent assay (ELISA); we compared the differences in inflammatory factors among groups. MATERIALS AND METHODS: A total of 180 males were enrolled in this study and divided into three equal groups. The first group was 60 smokers who had COPD. The second group included 60 smokers without COPD and the third group consisted of people who were not smokers and did not have COPD; 5 mL of venous blood was taken from all participants and it was collected in a test tube containing anticoagulant and then centrifuged at 3000 rpm for 10 minutes. Serum was separated and used to measure the amount of IL-6, CRP and albumin. Spirometry was performed according to the criteria set by the American Thoracic Society. RESULTS: The mean serum level of IL-6 was 83.2+/-7.5 pg/mL in group I, 54.9+/ 24.3 pg/mL in group II and 46.9+/-10.4 pg/mL in group III. There was a significant difference among the three groups (P<0.001). The mean serum level of CRP was 28.9+/-14.9 mg/dL in the first group, 19.9+/-8.5 mg/dL in the second group and 4.2+/-2.3 mg/dL in the third group (P=0.02). But by controlling the confounding effects of age, this difference was not significant (P=0.49). The mean serum level of albumin was I 4.1+/-0.57 mg/dL in group I, 4.3+/-0.56 mg/dL in group II and 4.1+/-0.53 mg/dL in group III. There was no significant difference among the three groups in this regard (P=0.099).There was a significant inverse relationship between serum levels of IL-6 and FEV 1 (r= 0.341, P<0.001). Moreover, there was a significant inverse relationship between serum levels of IL-6 and FEV1/FVC (r=-0.309, P<0.001). Serum albumin level was not different among various stages. Level of CRP and IL6 increased as the stage of COPD got worse in smokers. CONCLUSION: Our study showed that serum level of IL 6 predicts development of COPD in smokers with a high sensitivity among all inflammatory factors namely CRP, IL-6, and albumin. PMID- 26528370 TI - Pulmonary Mucormycosis in a Patient with Chronic Rejection of Kidney Transplant: A Case Report. AB - Pulmonary mucormycosis is a rare but fatal condition that frequently occurs in immunocompromised patients. Correct diagnosis and rapid start of preferred antifungal treatment need clinical suspicion. Patient's symptoms may be confluent with other conditions such as bacterial and other fungal infections. We present a case of pulmonary mucormycosis in a patient with end stage renal disease successfully treated with a long course of amphotericin B deoxycholate (AmB) and upper lobectomy of the left lung despite of low pulmonary capacity. PMID- 26528369 TI - Effect of Ventilation on Occupational Exposure to Airborne Biological Contaminants in an Isolation Room. AB - BACKGROUND: Airborne pathogens play an important role in a hospital air quality. Respiratory infections are the most common occupational disease among the health care staff. The aim of this study was to determine the effect of ventilation system parameters and patient bed arrangements on concentration of airborne pathogens in indoor air of an isolation room. MATERIALS AND METHODS: A single-bed room was considered in which a patient diagnosed with tuberculosis had been admitted. Five different ventilation types, each at four different capacities were installed in the room while two different locations for the patient's bed were assessed. A direct-impact sampling method (blood agar plate) was used in order to determine the intensity of the bio-aerosols in indoor air of the isolation room. RESULTS: The results showed that when the air was supplied through a circular vent located on the northern wall and the vented air was exhausted via a linear vent located on the southern wall, the average concentration of the bio-aerosols in the air, (with 12 air changes per hour) was reduced to 25 colonies per cubic meter (cfu/m(3)) (in the range of 25-88 cfu/m(3) and a 95 percent confidence interval). In accordance with the analysis applied upon the two different locations of the bed, no significant difference was observed (P>0.05). CONCLUSION: Installation of ventilation systems as determined by the study is recommended for tuberculosis isolation rooms. PMID- 26528371 TI - Lymphangiomatosis: The Cause of Refractory Pleural Effusion in a Patient with Lupus Erythematosus. AB - Mediastinal cavernous lymphangioma is a rare mediastinal lesion and its association with lupus erythematosus has not yet been reported in the literature. We present a 25 year-old female with lupus erythematosus who had bilateral massive refractory and recurrent pleural effusion as well as ascites for a long period of time. During surgery, a huge multicystic lesion with a thick wall, covering the entire parietal and visceral pleura was found, which was subsequently proven to be a cystic cavernous lymphangioma. PMID- 26528372 TI - Acremonium Pneumonia: Case Report and Literature Review. AB - Acremonium spp. cause human superficial infections including mycetoma, onychomycosis and keratitis. There are a few reports of systemic involvement in immunocompromised patients. However, isolated pulmonary infection in otherwise healthy hosts has never been reported in the literature. Herein, we report a 59 year-old diabetic man with non-resolving pneumonia due to Acremonium spp. and provide a consensus review of the published clinical cases of systemic and respiratory tract infections. PMID- 26528373 TI - Biosynthesis of silver nanoparticles using Artocarpus elasticus stem bark extract. AB - BACKGROUND: Green approach in synthesizing metal nanoparticles has gain new interest from the researchers as metal nanoparticles were widely applied in medical equipment and household products. The use of plants in the synthesis of nanoparticles emerges as a cost effective and eco-friendly approach. A green synthetic route for the production of stable silver nanoparticles (Ag-NPs) by using aqueous silver nitrate as metal precursor and Artocarpus elasticus stem bark extract act both as reductant and stabilizer is being reported for the first time. RESULTS: The resultant Ag-NPs were characterized by UV-vis spectroscopy, powder X-Ray diffraction, transmission electron microscopy (TEM), scanning electron microscopy (SEM), and Fourier-transform infra-red (FT-IR). The morphological study by TEM and SEM shows resultant Ag-NPs in spherical form with an average size of 5.81 +/- 3.80, 6.95 +/- 5.50, 12.39 +/- 9.51, and 19.74 +/- 9.70 nm at 3, 6, 24, and 48 h. Powder X-ray diffraction showed that the particles are crystalline in nature, with a face-centered cubic structure. The FT-IR spectrum shows prominent peaks appeared corresponds to different functional groups involved in synthesizing Ag-NPs. CONCLUSIONS: Ag-NPs were synthesized using a simple and biosynthetic method by using methanolic extract of A. elasticus under room temperature, at different reaction time. The diameters of the biosynthesis Ag-NPs depended on the time of reaction. Thus, with the increase of reaction time in the room temperature the size of Ag-NPs increases. From the results obtained in this effort, one can affirm that A. elasticus can play an important role in the bioreduction and stabilization of silver ions to Ag NPs.Graphical abstract:Figure illustrates stabilization of silver nanoparticles after formation by A. elasticus stem bark extract. PMID- 26528374 TI - Magnetically-actuated, bead-enhanced silicon photonic immunosensor. AB - Magnetic actuation has been introduced to an optical immunosensor technology resulting in improvements in both rapidity and limit of detection for an assay quantitating low concentrations of a representative protein biomarker. For purposes of demonstration, an assay was designed for monocyte chemotactic protein 1 (MCP-1), a small cytokine which regulates migration and infiltration of monocytes and macrophages, and is an emerging biomarker for several diseases. The immunosensor is based on arrays of highly multiplexed silicon photonic microring resonators. A one-step sandwich immunoassay was performed and the signal was further enhanced through a tertiary recognition event between biotinylated tracer antibodies and streptavidin-coated magnetic beads. By integrating a magnet under the sensor chip, magnetic beads were rapidly directed towards the sensor surface resulting in improved assay performance metrics. Notably, the time required in the bead binding step was reduced by a factor of 11 (4 vs 45 min), leading to an overall decrease in assay time from 73 min to 32 min. The magnetically-actuated assay also lowered the limit of detection (LOD) for MCP-1 from 124 pg mL-1 down to 57 pg mL-1. In sum, the addition of magnetic actuation into bead-enhanced sandwich assays on a silicon photonic biosensor platform might facilitate improved detection of biomarkers in point-of-care diagnostics settings. PMID- 26528375 TI - Single-Cell Migration as Studied by Scanning Electrochemical Microscopy. AB - Scanning electrochemical microscopy (SECM) was used to study the migration of single live head and neck cancer cells (SCC25). The newly developed graphite paste ultramicroelectrode (UME) showed significantly less fouling in comparison to a 10 MUm Pt-UME and thus could be used to monitor and track the migration pattern of a single cell. We also used SECM probe scan curves to measure the morphology (height and diameter) of a single live cancer cell during cellular migration and determined these dimensions to be 11 +/- 4 MUm and 40 +/- 10 MUm, respectively. The migration study revealed that cells within the same cell line had a heterogeneous migration pattern (migration and stationary) with an estimated migration speed of 8 +/- 3 MUm/h. However, serum-starved synchronized cells of the same line were found to have a non-heterogeneous cellular migration pattern with a speed of 9 +/- 3 MUm/h. Thus, this non-invasive SECM-based technique could potentially be expanded to other cell lines to study cellular biomechanics for improved understanding of the structure-function relationship at the level of a single cell. PMID- 26528376 TI - On Huberized calibration regression for censored medical cost data. AB - Authors have observed that the distribution of medical expenditures has features that do not lend it to parametric modeling and can present significant challenges for least-squares-type estimators, even on a logarithmic scale. In this note, we discuss caveats and extensions of coefficient estimation in the bivariate accelerated lifetime model of medical cost and survival time on covariates. We consider the setting where medical cost is observed only when the event occurs and potential right-censoring of the event time induces a dependent censoring mechanism on cost. We adopt Huang's (2002) estimation framework using the weighted log-rank estimating equations and investigate his proposal for robust mark-scale coefficient estimation. Due to modeling restrictions on the joint distribution of survival time and cost, we conclude that his robust mark-scale coefficient estimator would benefit from a time-scale adjustment. We use basic principles from robust estimation to define a new weighted marked process that subsequently leads to a new time-corrected robust regression calibration estimator. Our simulation studies illustrate how the proposed estimator has desirable operating characteristics, including reduced sensitivity to extreme values in the cost distribution, smaller finite sample bias and variance than earlier proposals. We illustrate the method in an analysis of lifetime medical cost data from a lung cancer study conducted by the Southwest Oncology Group. PMID- 26528378 TI - Corticosteroid Injection in the Management of Dupuytren Nodules: A Review of the Literature. PMID- 26528377 TI - TEAMS: Toxicity- and Efficacy-based Dose Insertion Design with Adaptive Model Selection for Phase I/II Dose-Escalation Trials in Oncology. AB - In many oncology clinical trials it is necessary to insert new candidate doses when the prespecified doses are poorly elicited. Formal statistical designs with dose insertion are lacking. We propose a dose insertion design for phase I/II clinical trials in oncology based on both efficacy and toxicity outcomes. We also implement Bayesian model selection during the course of the trial so that better models can be adaptively chosen to achieve more accurate inference. The new design, TEAMS, achieves great operating characteristics in extensive simulation studies due to its ability to adaptively insert new doses as well as perform model selection. As a result, appropriate doses are inserted when necessary and desirable doses are selected with higher probabilities at the end of the trial. PMID- 26528379 TI - Bowler's Thumb: Case Report and Review of the Literature. AB - OBJECTIVE: Traumatic neuropathy of the ulnar digital nerve of the thumb occurs in patients who undergo chronic frictional irritation of the nerve. The condition is aptly termed bowler's thumb, as it commonly afflicts patients who bowl and keep their thumb in the ball for an extended period of time. It is a pathology that rarely appears in the literature and for which standard treatment is unclear. METHODS: A 68-year-old man with a history of avid bowling presented with a chief complaint of left thumb numbness and tingling for several months. Physical examination demonstrated a small tender mass along the ulnar surface of the left thumb with a positive Tinel's sign and diminished 2-point discrimination distal to the mass. The patient's symptoms did not improve with conservative measures. Here, we describe his surgical treatment and review the current literature. RESULTS: Our patient underwent neurolysis of the ulnar digital nerve of the thumb, with placement of a porcine extracellular matrix nerve wrap. The patient reported improvement of symptoms within 2 weeks and was able to return to his previous level of activity. In the literature, treatment has included from conservative measures such as pressure relief and splinting to surgical intervention including neurolysis, transposition, or neurectomy with nerve grafting. CONCLUSIONS: We present neurolysis for treating bowler's thumb as a viable option that may relieve symptoms rapidly while obviating need for adductor transection. Porcine extracellular matrix nerve wrap can be placed in an attempt to prevent recurrence of neuroma, but long-term follow-up is necessary. PMID- 26528380 TI - Schwannoma in Digital Nerve: A Rare Case Report. PMID- 26528381 TI - Sonographic Evaluation of Cervical Lymphadenopathy; Comparison of Metastatic and Reactive Lymph Nodes in Patients With Head and Neck Squamous Cell Carcinoma Using Gray Scale and Doppler Techniques. AB - BACKGROUND: Cervical lymphadenopathy could be seen in several pathologic processes. An accurate differentiation between these conditions is of utmost importance to select an appropriate therapy and assess the prognosis. Gray scale and Doppler are appropriate sonographic techniques for evaluating internal and external features of lymph nodes. Although, various criteria have been proposed to differentiate metastatic lymph nodes from benign ones, the most valuable and specific sonographic features are still under dispute. OBJECTIVES: The present study was designed to determine valuable sonographic features for differentiating metastasis from benign nodes using gray scale and Doppler sonography. PATIENTS AND METHODS: A prospective diagnostic study was performed on 63 patients with head and neck squamous cell carcinoma (SCC) treated and referred to surgery clinic of Hazrat Rasoul Akram hospital from November 2010 to June 2012 with complaint of palpable cervical lymph node. All patients' necks were scanned multidirectionally by gray-scale and Doppler techniques. After sonography, lymph nodes were biopsied and investigated to find out whether they were metastatic or reactive. Finally, demographic, sonographic and pathologic data were statistically analyzed by SPSS ver. 16 software using t-test, a nonparametric test and ROC analysis. Ninety five percent confidence interval was considered for all parameters. RESULTS: The study included 41 males and 22 females with a mean age of 57.56 +/- 13.79 years. The number of metastatic lymph nodes was 47, while the remaining 16 were reactive. There were significant differences in length (P = 0.037), width (P = 0.001), resistance index (P < 0.001), pulsatility index (P < 0.001) and systolic velocity (P < 0.001) of metastatic and reactive lymph nodes. Cut points for resistive and pulsatility indexes and systolic velocity were calculated as 0.695, 1.35 and 16.5, respectively. The most valuable factor for defining a lymph node as metastatic was circulation pattern with accuracy, sensitivity and specificity of 94%, 85% and 93%, respectively. CONCLUSION: Gray scale sonography in combination with Doppler sonography could be a trustworthy technique in differentiating metastatic lymph nodes from reactive ones. Although, circulation pattern had a higher diagnostic accuracy in the present study, combination of sonographic characteristics could be more beneficial in differentiating metastatic cervical nodes from reactive ones. PMID- 26528382 TI - Primary Pulmonary Sequestration With Secondary Hamartomatosis Change. AB - The radiologic features of intralobar pulmonary sequestration (ILPS) have been describe and include the identification of a feeding systemic artery with venous drainage through pulmonary veins. Primary sequestration associated with typical hamartoma signs is really rare and has been described only once. We describe a patient with ILPS whose radiographic findings were unusual for two reasons. First, computed tomography (CT) demonstrated a bulky mass in the pulmonary sequestration. The size of lesion and histopathology made it an unusual presentation. Final histology study demonstrated pulmonary hamartoma with predominantly adipose and cartilage differentiation, which is an unusual complication originated from ILPS. Another sign also explains the second unusual feature, intracranial cholesteatoma, occurring concurrently with ILPS. PMID- 26528383 TI - Non Secretory Multiple Myeloma With Extensive Extramedullary Plasmacytoma: A Diagnostic Dilemma. AB - Multiple myeloma (MM) is characterized by progressive proliferation of malignant plasma cells, usually initiating in the bone marrow. MM can affect any organ; a total of 7 - 18% of patients with MM demonstrate extramedullary involvement at diagnosis. Non-secretory multiple myeloma (NSMM) is a rare variant that accounts for 1 - 5% of all cases of multiple myeloma. The disease is characterized by the absence of monoclonal gammopathy in serum and urine electrophoresis. Our case report highlights the diagnostic challenge of a case of NSMM with extensive extramedullary involvement in a young female patient who initially presented with right shoulder pain and bilateral breasts lumps. Skeletal survey showed multiple lytic bony lesions. The initial diagnosis was primary breast carcinoma with osseous metastases. No monoclonal gammopathy was found in the serum or urine electrophoresis. Bone marrow and breast biopsies revealed marked plasmacytosis. The diagnosis was delayed for a month in view of the lack of clinical suspicion of multiple myeloma in a young patient and scant biochemical expression of non secretory type of multiple myeloma. PMID- 26528384 TI - Sonographic Measurement of the Umbilical Cord and Its Vessels and Their Relation with Fetal Anthropometric Measurements. AB - BACKGROUND: It has been established that presence of lean umbilical cord with reduced Wharton's jelly in sonographic scans is a fetal marker for risk of small for gestational age at birth. With improvement of ultrasound techniques, more studies have been investigating the alterations of the umbilical cord on pregnancy outcomes. OBJECTIVES: To determine the reference ranges of the umbilical cord area during pregnancy and to find out the association between umbilical cord morphometry and fetal anthropometric measurements. PATIENTS AND METHODS: A cross sectional study was carried out on a study population of 278 low risk pregnant women between 15 and 41 weeks of gestational age. Fetal anthropometric measurements including biparietal diameter, abdominal circumference, and femur length were calculated. The measurements of the cross sectional area (CSA) and circumference of the umbilical cord, vein and arteries were done on an adjacent plane to the insertion of umbilical cord into the fetus's abdomen. The mean and standard deviation of the CSA of the umbilical cord and the 5th, 10th, 50th, 90th, 95th percentiles of it were calculated for each gestational age. Pearson correlation coefficient was used to assess the correlation between the measures of the cord and fetal anthropometric measurements. Polynomial regression analysis was performed for curves. RESULTS: The values of the CSA of the umbilical cord, umbilical vein and Wharton's jelly (WJ) increase consistently until 30 weeks of gestation, after which they reach a plateau. There was a significant correlation between anthropometric measurements and umbilical cord measurements especially with the CSA of the umbilical cord, umbilical vein and WJ. The regression equation for the umbilical cord CSA according to gestational age up to 30 weeks was y = -0.2159 x(2) + 23.828x-325.59 (R(2) = 0.6334) and for the WJ area according to gestational age up to 30 weeks, it was y = -0.2124 x (2) +17.613x-221.66 (R(2) = 0.4979). CONCLUSION: Reference ranges for umbilical cord CSA have been generated. The CSA of the umbilical cord and other components of it increase as a function of gestational age. These measurements correlate with fetal size. PMID- 26528385 TI - Iniencephaly Clausus: A New Case With Clinical and Imaging Findings. AB - Iniencephaly is a rare kind of neural tube defect that is classified into two types of iniencephaly apertus and iniencephaly clausus. This anomaly could be diagnosed prenatally by obstetric ultrasonography and terminated by therapeutic abortion; however, it could be undiagnosed until birth similar to our case due to the abnormal position of the fetus or lack of experience of the sonographer. Due to abnormality of the neural tube, which causes abnormal head and neck position, all these cases will die shortly after birth. We hereby introduce the photos and imaging findings of a case of an alive neonate with iniencephaly clausus. PMID- 26528386 TI - Endovascular Treatment of a Huge Hepatic Artery Aneurysm by Coil Embolization Method: A Case Report. AB - Hepatic artery aneurysms are rare but potentially life threatening. We describe a novel case of a successful endovascular coil embolization of a huge hepatic artery aneurysm. A 67-year-old woman presented with recent abdominal pain that had begun from 2 weeks before referring to our hospital. Sonographic and computerized tomographic (CT) findings revealed a huge hepatic artery aneurysm with 95 mm * 83 mm diameter. The patient underwent an endovascular technique. In aortic angiography, the celiac artery orifice and superior mesenteric artery were so narrow, so sonography was used in order to determine the exact position of the catheter in the celiac artery orifice. The aneurysm was thrombosed using coil embolization. Pulsation of the aneurysm immediately disappeared. Huge hepatic artery aneurysm can be safely treated using coil embolization. PMID- 26528387 TI - Presentation of Intrauterine Device in a Didelphic Uterus. PMID- 26528388 TI - Evaluating the Possibility of Defining Cut-Off Points for DeltaFA% in Order to Differentiate Four Major Types of Peri-Tumoral White Matter Tract Involvement. AB - BACKGROUND: Diffusion tensor imaging (DTI) and its different scalar values such as fractional anisotropy (FA) have recently been used for evaluation of peri tumoral white matter (WM) involvement to help define safer surgical excision margins. OBJECTIVES: The purpose of this study is to evaluate the possibility of defining diagnostic cut-off points for differentiating four major types of peri tumoral WM involvement using FA. PATIENTS AND METHODS: DTI was performed in 12 patients with high presumption of having brain tumors, on a 1.5 T MRI scanner. DTI data was processed by MedINRIA software. Two-hundred region of interests (ROI) were evaluated: 100 in the lesion zone and the rest in the normal WM in the contralateral hemisphere. FA value related to each ROI was measured, and the percentage of FA decrement (DeltaFAs%) was calculated. RESULTS: Of the 100 ROIs on the lesion side, 74 were related to high-grade lesions, 23 to low-grade ones, and three to "gliosis". There were 54 "infiltrated", 22 "displaced", 15 "disrupted", and 9 "edematous" tracts. The major type of fiber involvement, both in low-grade and high-grade tumors was "infiltrated, whereas "edematous" fibers comprised the minority. DeltaFA% was more than -35 for "displaced" and "edematous" fibers, and less than -35 for the majority of "disrupted" ones, but "infiltrated" fibers had scattered distribution. Mean DeltaFA% was the least for "disrupted", followed by "infiltrated", "edematous" and "displaced" parts. CONCLUSION: Introducing definite diagnostic cut-points was not possible, due to overlap. Based on the fact that "disruption" is the most aggressive process, a sensitivity analysis was carried out for "disrupted" fibers for several presumptive cut-off points. PMID- 26528389 TI - Coil Embolotherapy of Unilateral Diffuse Pulmonary Arteriovenous Malformations in a Nineteen-Year-Old Woman. AB - Pulmonary arteriovenous malformations (AVMs) are rare vascular malformations of the lung that usually led to a notable risk of serious and life-threatening complications. There is considerable debate about the best management of strategies for the group of patients with diffuse AVMs. Several therapeutic options have been reported for management of this abnormality among which coil embolization is currently the preferred ones. This report describes our experience with the use of coiling method for treatment of multiple AVMs in an adult patient. PMID- 26512320 TI - The ubiquitous and ancient ER membrane protein complex (EMC): tether or not? AB - The recently discovered endoplasmic reticulum (ER) membrane protein complex (EMC) has been implicated in ER-associated degradation (ERAD), lipid transport and tethering between the ER and mitochondrial outer membranes, and assembly of multipass ER-membrane proteins. The EMC has been studied in both animals and fungi but its presence outside the Opisthokont clade (animals + fungi + related protists) has not been demonstrated. Here, using homology-searching algorithms, I show that the EMC is truly an ancient and conserved protein complex, present in every major eukaryotic lineage. Very few organisms have completely lost the EMC, and most, even over 2 billion years of eukaryote evolution, have retained a majority of the complex members. I identify Sop4 and YDR056C in Saccharomyces cerevisiae as Emc7 and Emc10, respectively, subunits previously thought to be specific to animals. This study demonstrates that the EMC was present in the last eukaryote common ancestor (LECA) and is an extremely important component of eukaryotic cells even though its primary function remains elusive. PMID- 26528391 TI - Effect of health system reforms in Turkey on user satisfaction. AB - In 2003, the Turkish government introduced major health system changes, the Health Transformation Programme (HTP), to achieve universal health coverage (UHC). The HTP leveraged changes in all parts of the health system, organization, financing, resource management and service delivery, with a new family medicine model introducing primary care at the heart of the system. This article examines the effect of these health system changes on user satisfaction, a key goal of a responsive health system. Utilizing the results of a nationally representative yearly survey introduced at the baseline of the health system transformation, multivariate logistic regression analysis is used to examine the yearly effect on satisfaction with health services. During the 9-year period analyzed (2004-2012), there was a nearly 20% rise in reported health service use, coinciding with increased access, measured by insurance coverage. Controlling for factors known to contribute to user satisfaction in the literature, there is a significant (P < 0.001) increase in user satisfaction with health services in almost every year (bar 2006) from the baseline measure, with the odds of being satisfied with health services in 2012, 2.56 (95% confidence interval (CI) of 2.01-3.24) times that in 2004, having peaked at 3.58 (95% CI 2.82-4.55) times the baseline odds in 2011. Additionally, those who used public primary care services were slightly, but significantly (P < 0.05) more satisfied than those who used any other services, and increasingly patients are choosing primary care services rather than secondary care services as the provider of first contact. A number of quality indicators can probably help account for the increased satisfaction with public primary care services, and the increase in seeking first-contact with these providers. The implementation of primary care focused UHC as part of the HTP has improved user satisfaction in Turkey. PMID- 26528392 TI - Etiology of community acquired pneumonia among children in India: prospective, cohort study. AB - BACKGROUND: Childhood community acquired pneumonia (CAP) is a significant problem in developing countries, and confirmation of microbial etiology is important for individual, as well as public health. However, there is paucity of data from a large cohort, examining multiple biological specimens for diverse pathogens (bacteria and viruses). The Community Acquired Pneumonia Etiology Study (CAPES) was designed to address this knowledge gap. METHODS: We enrolled children with CAP (based on WHO IMCI criteria of tachypnea with cough or breathing difficulty) over 24 consecutive months, and recorded presenting symptoms, risk factors, clinical signs, and chest radiography. We performed blood and nasopharyngeal aspirate (NPA) bacterial cultures, and serology (Mycoplasma pneumoniae, Chlamydophila pneumoniae). We also performed multiplex PCR for 25 bacterial/viral species in a subgroup representing 20% of the cohort. Children requiring endotracheal intubation underwent culture and PCR of bronchoalveolar lavage (BAL) specimens. FINDINGS: We enrolled 2345 children. NPA and blood cultures yielded bacteria in only 322 (13.7%) and 49 (2.1%) children respectively. In NPA, Streptococcus pneumoniae (79.1%) predominated, followed by Haemophilus influenzae (9.6%) and Staphylococcus aureus (6.8%). In blood, S. aureus (30.6%) dominated, followed by S. pneumoniae (20.4%) and Klebsiella pneumoniae (12.2%). M. pneumoniae and C. pneumoniae serology were positive in 4.3% and 1.1% respectively. Multiplex PCR in 428 NPA specimens identified organisms in 422 (98.6%); of these 352 (82.2%) had multiple organisms and only 70 (16.4%) had a single organism viz. S. pneumoniae: 35 (50%), Cytomegalovirus (CMV): 13 (18.6%), Respiratory Syncytial Virus (RSV): 9 (12.9%), other viruses: 6 (8.7%), S. aureus: 5 (7.1%), and H. influenzae: 2 (2.9%). BAL PCR (n = 30) identified single pathogens in 10 (S. pneumoniae-3, CMV-3, S. aureus-2, H. influenzae-2) and multiple pathogens in 18 children. There were 108 (4.6%) deaths. The pattern of pathogens identified did not correlate with pneumonia severity or mortality. CONCLUSIONS: The majority of children with CAP have multiple pathogens (bacteria and viruses). S. pneumoniae and S. aureus predominate in NPA and blood respectively. CMV and RSV were the dominant respiratory viruses in NPA and BAL. The presence of multiple pathogens, especially organisms associated with nasopharyngeal carriage, precludes confirmation of a causal relationship in most cases. PMID- 26528393 TI - Using surveillance data to understand cancer trends: an overview in Morocco. AB - BACKGROUND: The aim was to use the existing surveillance data sources of cancer in Morocco that could be used to better describe cancer mortality and incidence trends in Morocco. METHODS: National incidence data were derived from population based cancer registries. Mortality data were collected from the international GLOBOCAN database. RESULTS: An overview of the main results was presented. In general, the most commonly diagnosed cancers in men are lung and prostates whereas in women, breast and cervical cancers are the pre-dominant cancers. Fifty nine percent and of breast and 65.7 % of cervical cancers in women are diagnosed at stages II and III. Cancer remains the second highest cause of mortality in Morocco. CONCLUSION: The data provides a description of the cancer incidence and trends in the Moroccan population. The Moroccan national cancer program should aim for more coherent, consistent and comparable incidence data between different cancer registries in the country, and develop uniform datasets with respect to quality. PMID- 26528394 TI - A multi-source dataset of urban life in the city of Milan and the Province of Trentino. AB - The study of socio-technical systems has been revolutionized by the unprecedented amount of digital records that are constantly being produced by human activities such as accessing Internet services, using mobile devices, and consuming energy and knowledge. In this paper, we describe the richest open multi-source dataset ever released on two geographical areas. The dataset is composed of telecommunications, weather, news, social networks and electricity data from the city of Milan and the Province of Trentino. The unique multi-source composition of the dataset makes it an ideal testbed for methodologies and approaches aimed at tackling a wide range of problems including energy consumption, mobility planning, tourist and migrant flows, urban structures and interactions, event detection, urban well-being and many others. PMID- 26528395 TI - A connectivity-based test-retest dataset of multi-modal magnetic resonance imaging in young healthy adults. AB - Recently, magnetic resonance imaging (MRI) has been widely used to investigate the structures and functions of the human brain in health and disease in vivo. However, there are growing concerns about the test-retest reliability of structural and functional measurements derived from MRI data. Here, we present a test-retest dataset of multi-modal MRI including structural MRI (S-MRI), diffusion MRI (D-MRI) and resting-state functional MRI (R-fMRI). Fifty-seven healthy young adults (age range: 19-30 years) were recruited and completed two multi-modal MRI scan sessions at an interval of approximately 6 weeks. Each scan session included R-fMRI, S-MRI and D-MRI data. Additionally, there were two separated R-fMRI scans at the beginning and at the end of the first session (approximately 20 min apart). This multi-modal MRI dataset not only provides excellent opportunities to investigate the short- and long-term test-retest reliability of the brain's structural and functional measurements at the regional, connectional and network levels, but also allows probing the test retest reliability of structural-functional couplings in the human brain. PMID- 26528396 TI - Australian sea-floor survey data, with images and expert annotations. AB - This Australian benthic data set (BENTHOZ-2015) consists of an expert-annotated set of georeferenced benthic images and associated sensor data, captured by an autonomous underwater vehicle (AUV) around Australia. This type of data is of interest to marine scientists studying benthic habitats and organisms. AUVs collect georeferenced images over an area with consistent illumination and altitude, and make it possible to generate broad scale, photo-realistic 3D maps. Marine scientists then typically spend several minutes on each of thousands of images, labeling substratum type and biota at a subset of points. Labels from four Australian research groups were combined using the CATAMI classification scheme, a hierarchical classification scheme based on taxonomy and morphology for scoring marine imagery. This data set consists of 407,968 expert labeled points from around the Australian coast, with associated images, geolocation and other sensor data. The robotic surveys that collected this data form part of Australia's Integrated Marine Observing System (IMOS) ongoing benthic monitoring program. There is reuse potential in marine science, robotics, and computer vision research. PMID- 26528397 TI - Population genomic datasets describing the post-vaccine evolutionary epidemiology of Streptococcus pneumoniae. AB - Streptococcus pneumoniae is common nasopharyngeal commensal bacterium and important human pathogen. Vaccines against a subset of pneumococcal antigenic diversity have reduced rates of disease, without changing the frequency of asymptomatic carriage, through altering the bacterial population structure. These changes can be studied in detail through using genome sequencing to characterise systematically-sampled collections of carried S. pneumoniae. This dataset consists of 616 annotated draft genomes of isolates collected from children during routine visits to primary care physicians in Massachusetts between 2001, shortly after the seven valent polysaccharide conjugate vaccine was introduced, and 2007. Also made available are a core genome alignment and phylogeny describing the overall population structure, clusters of orthologous protein sequences, software for inferring serotype from Illumina reads, and whole genome alignments for the analysis of closely-related sets of pneumococci. These data can be used to study both bacterial evolution and the epidemiology of a pathogen population under selection from vaccine-induced immunity. PMID- 26528398 TI - Peste des petits ruminants in Pakistan; past, present and future perspectives. AB - Peste des petits ruminants (PPR) is considered to be one of the main constraints to enhancing the productivity of goats and sheep in regions where it is present and becoming endemic. PPR was recognized in Pakistan in early 1990s but got importance during the Participatory Disease Surveillance (PDS) of Rinderpest Eradication Campaign. Lot of research work has been initiated during last decade towards disease epidemiology, risk factor recognition, laboratory diagnosis, vaccination and demonstration of control strategies. Although there are ongoing projects working towards the progressive control of the disease in country yet there is need to have a national level control program for PPR. Also there is need to have comprehensive social economic surveys, disease hot spot recognition and identification of role of other species in disease transmission. With combined efforts of local and national authorities and political will, there is high likelihood that this devastating disease can be controlled and eventually eradicated in near future. PMID- 26528399 TI - Haemostatic chitosan coated gauze: in vitro interaction with human blood and in vivo effectiveness. AB - BACKGROUND: Chitosan and its derivates are widely used for biomedical application due to antioxidative, anti-inflammatory, antimicrobial and tissue repair induced properties. Chitosan-based materials also used as a haemostatic agent but influence of different molecular weight and concentration of chitosan on biological response of blood cells is still not clear. The aim of this research was to evaluate interaction between human blood cells and various forms of chitosan-based materials with different molecular weight and chitosan concentration and prove their effectiveness on in-vivo model. METHODS: We used chitosan with molecular weight 200, 500 and 700 kDa and deacetylation rate 80-82 %. For chitosan impregnation of gauze chitosan solutions in 1 % acetic acid with different concentrations (1, 2, 3, 5 %) were used. We used scanning electron microscopy to obtain information about chitosan distribution on cotton surface; Erythrocyte agglutination test and Complete blood count test - for evaluation of interaction between blood cells and chitosan-based materials with different compound. In-vivo studies was performed in 20 Wistar rats to evaluate effectiveness of new dressing. RESULTS: Our data shown that chitosan can bind erythrocytes in concentration-depend manner that does not depend on its molecular weight. In addition, chitosan-based materials affect selectively human blood cells. Composition of chitosan with cotton materials does not change erythrocyte shape and does not cause agglutination. CONCLUSIONS: Sotton-chitosan materials have higher adhesive properties to platelets that depend on molecular weight and concentration of chitosan. These materials also change platelets' shape that probable is one of the most important mechanisms of haemostatic effect. In-vivo studies have shown high effectiveness of 2 % 200 kDa chitosan for stop bleeding from arteries of large diameter. PMID- 26528400 TI - Clinical Validation of Adjusted Corneal Power in Patients with Previous Myopic Lasik Surgery. AB - Purpose. To validate clinically a new method for estimating the corneal power (P c ) using a variable keratometric index (n kadj) in eyes with previous laser refractive surgery. Setting. University of Alicante and Medimar International Hospital (Oftalmar), Alicante, (Spain). Design. Retrospective case series. Methods. This retrospective study comprised 62 eyes of 62 patients that had undergone myopic LASIK surgery. An algorithm for the calculation of n kadj was used for the estimation of the adjusted keratometric corneal power (P kadj). This value was compared with the classical keratometric corneal power (P k ), the True Net Power (TNP), and the Gaussian corneal power (P cGauss). Likewise, P kadj was compared with other previously described methods. Results. Differences between P cGauss and P c values obtained with all methods evaluated were statistically significant (p < 0.01). Differences between P kadj and P cGauss were in the limit of clinical significance (p < 0.01, loA [-0.33,0.60] D). Differences between P kadj and TNP were not statistically and clinically significant (p = 0.319, loA [ 0.50,0.44] D). Differences between P kadj and previously described methods were statistically significant (p < 0.01), except with P cHaigisL (p = 0.09, loA [ 0.37,0.29] D). Conclusion. The use of the adjusted keratometric index (n kadj) is a valid method to estimate the central corneal power in corneas with previous myopic laser refractive surgery, providing results comparable to P cHaigisL. PMID- 26528401 TI - A comprehensive study of long-term skeletal changes after spinal cord injury in adult rats. AB - Spinal cord injury (SCI)-induced bone loss represents the most severe osteoporosis with no effective treatment. Past animal studies have focused primarily on long bones at the acute stage using adolescent rodents. To mimic chronic SCI in human patients, we performed a comprehensive analysis of long-term structural and mechanical changes in axial and appendicular bones in adult rats after SCI. In this experiment, 4-month-old Fischer 344 male rats received a clinically relevant T13 contusion injury. Sixteen weeks later, sublesional femurs, tibiae, and L4 vertebrae, supralesional humeri, and blood were collected from these rats and additional non-surgery rats for micro-computed tomography (uCT), micro-finite element, histology, and serum biochemical analyses. At trabecular sites, extreme losses of bone structure and mechanical competence were detected in the metaphysis of sublesional long bones after SCI, while the subchondral part of the same bones showed much milder damage. Marked reductions in bone mass and strength were also observed in sublesional L4 vertebrae but not in supralesional humeri. At cortical sites, SCI induced structural and strength damage in both sub- and supralesional long bones. These changes were accompanied by diminished osteoblast number and activity and increased osteoclast number and activity. Taken together, our study revealed site-specific effects of SCI on bone and demonstrated sustained inhibition of bone formation and elevation of bone resorption at the chronic stage of SCI. PMID- 26528402 TI - The nonlinear variation of drought and its relation to atmospheric circulation in Shandong Province, East China. AB - Considerable attention has recently been devoted to the linear trend of drought at the decadal to inter-decadal time scale; however, the nonlinear variation of drought at multi-decadal scales and its relation to atmospheric circulation need to be further studied. The linear and nonlinear variations of the Palmer drought severity index (PDSI) in Shandong from 1900 to 2012 and its relations to the Pacific decadal oscillation (PDO), El Nino-Southern Oscillation (ENSO), Siberian high (SH) and Southern Oscillation (SO) phase changes from multi-scale are detected using linear regression, the Mann-Kendall test, ensemble empirical mode decomposition (EEMD) and the Pearson correlation analysis method. The results indicate that the PDSI shows no statistically significant linear change trend from 1900 to 2012; however, before (after) the late 1950s, PDSI shows a significant upward (downward) trend (P < 0.01) with a linear rate of 0.28/decade (-0.48/decade). From 1900 to 2012, the PDSI also exhibits a nonlinear variation trend at the inter-annual scale (quasi-3 and quasi-7-year), inter-decadal scale (quasi-14-year) and multi-decadal scale (quasi-46 and quasi-65-year). The variance contribution rate of components from the inter-annual scale is the largest, reaching 38.7%, and that from the inter-decadal scale and multi-decadal scale are 18.9% and 19.0%, respectively, indicating that the inter-annual change exerts a huge influence on the overall PDSI change. The results also imply that the effect of the four atmospheric circulations (PDO, ENSO, SH, SO) on PDSI at the multi-decadal variability scale are more important than that at the other scales. Consequently, we state that PDSI variation at the inter-annual scale has more instability, while that at the inter-decadal and multi-decadal scale is more strongly influenced by natural factors. PMID- 26528403 TI - Effects of in situ climate warming on monarch caterpillar (Danaus plexippus) development. AB - Climate warming will fundamentally alter basic life history strategies of many ectothermic insects. In the lab, rising temperatures increase growth rates of lepidopteran larvae but also reduce final pupal mass and increase mortality. Using in situ field warming experiments on their natural host plants, we assessed the impact of climate warming on development of monarch (Danaus plexippus) larvae. Monarchs were reared on Asclepias tuberosa grown under 'Ambient' and 'Warmed' conditions. We quantified time to pupation, final pupal mass, and survivorship. Warming significantly decreased time to pupation, such that an increase of 1 degrees C corresponded to a 0.5 day decrease in pupation time. In contrast, survivorship and pupal mass were not affected by warming. Our results indicate that climate warming will speed the developmental rate of monarchs, influencing their ecological and evolutionary dynamics. However, the effects of climate warming on larval development in other monarch populations and at different times of year should be investigated. PMID- 26528404 TI - Is there a hybridization barrier between Gentiana lutea color morphs? AB - In Gentiana lutea two varieties are described: G. lutea var. aurantiaca with orange corolla colors and G. lutea var. lutea with yellow corolla colors. Both color varieties co-occur in NW Spain, and pollinators select flower color in this species. It is not known whether a hybridization barrier exists between these G. lutea color varieties. We aim to test the compatibility between flower color varieties in G. lutea and its dependence on pollen vectors. Within a sympatric population containing both flower color morphs, we analyzed differences in reproductive success (number, weight, viability and germinability of seeds) depending on fertilization treatments (autogamy and xenogamy within variety and among varieties). We found a 93% reduction in number of seeds and a 37% reduction in seed weight respectively of autogamy treatments compared to xenogamy crossings. Additionally, reproductive success is higher within color varieties than among varieties, due to a 45% seed viability reduction on hybrids from different varieties. Our results show that G. lutea reproductive success is strongly dependent on pollinators and that a partial hybridization barrier exists between G. lutea varieties. PMID- 26528405 TI - Genetic analysis of Thai cattle reveals a Southeast Asian indicine ancestry. AB - Cattle commonly raised in Thailand have characteristics of Bos indicus (zebu). We do not know when or how cattle domestication in Thailand occurred, and so questions remain regarding their origins and relationships to other breeds. We obtained genome-wide SNP genotypic data of 28 bovine individuals sampled from four regions: North (Kho-Khaolampoon), Northeast (Kho-Isaan), Central (Kho-Lan) and South (Kho-Chon) Thailand. These regional varieties have distinctive traits suggestive of breed-like genetic variations. From these data, we confirmed that all four Thai varieties are Bos indicus and that they are distinct from other indicine breeds. Among these Thai cattle, a distinctive ancestry pattern is apparent, which is the purest within Kho-Chon individuals. This ancestral component is only present outside of Thailand among other indicine breeds in Southeast Asia. From this pattern, we conclude that a unique Bos indicus ancestor originated in Southeast Asia, and native Kho-Chon Thai cattle retain the signal of this ancestry with limited admixture of other bovine ancestors. PMID- 26528406 TI - Intergenic incompatibilities reduce fitness in hybrids of extremely closely related bacteriophages. AB - Horizontal gene transfer and recombination occur across many groups of viruses and play key roles in important viral processes such as host-range expansion and immune-system avoidance. To have any predictive power regarding the ability of viruses to readily recombine, we must determine the extent to which epistasis restricts the success of recombinants, particularly as it relates to the genetic divergence between parental strains. In any hybridization event, the evolutionary success or failure of hybrids is largely determined by the pervasiveness of epistasis in the parental genomes. Recombination has previously been shown to incur steep fitness costs in highly divergent viruses as a result of disrupted epistatic interactions. We used a pair of bacteriophages of the family Microviridae to demonstrate that epistasis may evidence itself in the form of fitness costs even in the case of the exchange of alleles at a locus with amino acid divergence as low as 1%. We explored a possible biophysical source of epistasis in the interaction of viral coat and scaffolding proteins and examined a recovery mutation that likely repairs interactions disrupted by recombination. PMID- 26528407 TI - Local-scale topoclimate effects on treeline elevations: a country-wide investigation of New Zealand's southern beech treelines. AB - Although treeline elevations are limited globally by growing season temperature, at regional scales treelines frequently deviate below their climatic limit. The cause of these deviations relate to a host of climatic, disturbance, and geomorphic factors that operate at multiple scales. The ability to disentangle the relative effects of these factors is currently hampered by the lack of reliable topoclimatic data, which describe how regional climatic characteristics are modified by topographic effects in mountain areas. In this study we present an analysis of the combined effects of local- and regional-scale factors on southern beech treeline elevation variability at 28 study areas across New Zealand. We apply a mesoscale atmospheric model to generate local-scale (200 m) meteorological data at these treelines and, from these data, we derive a set of topoclimatic indices that reflect possible detrimental and ameliorative influences on tree physiological functioning. Principal components analysis of meteorological data revealed geographic structure in how study areas were situated in multivariate space along gradients of topoclimate. Random forest and conditional inference tree modelling enabled us to tease apart the relative effects of 17 explanatory factors on local-scale treeline elevation variability. Overall, modelling explained about 50% of the variation in treeline elevation variability across the 28 study areas, with local landform and topoclimatic effects generally outweighing those from regional-scale factors across the 28 study areas. Further, the nature of the relationships between treeline elevation variability and the explanatory variables were complex, frequently non-linear, and consistent with the treeline literature. To our knowledge, this is the first study where model-generated meteorological data, and derived topoclimatic indices, have been developed and applied to explain treeline variation. Our results demonstrate the potential of such an approach for ecological research in mountainous environments. PMID- 26528408 TI - Gluten-free food database: the nutritional quality and cost of packaged gluten free foods. AB - Notwithstanding a growth in popularity and consumption of gluten-free (GF) food products, there is a lack of substantiated analysis of the nutritional quality compared with their gluten-containing counterparts. To put GF foods into proper perspective both for those who need it (patients with celiac disease) and for those who do not, we provide contemporary data about cost and nutritional quality of GF food products. The objective of this study is to develop a food composition database for seven discretionary food categories of packaged GF products. Nutrient composition, nutritional information and cost of foods from 63 GF and 126 gluten-containing counterparts were systematically obtained from 12 different Austrian supermarkets. The nutrition composition (macro and micronutrients) was analyzed by using two nutrient composition databases in a stepwise approximation process. A total of 63 packaged GF foods were included in the analysis representing a broad spectrum of different GF categories (flour/bake mix, bread and bakery products, pasta and cereal-based food, cereals, cookies and cakes, snacks and convenience food). Our results show that the protein content of GF products is >2 fold lower across 57% of all food categories. In 65% of all GF foods, low sodium content was observed (defined as <120 mg/100 g). Across all GF products, 19% can be classified as source high in fiber (defined as >6g/100 g). On average, GF foods were substantially higher in cost, ranging from +205% (cereals) to +267% (bread and bakery products) compared to similar gluten containing products. In conclusion, our results indicate that for GF foods no predominant health benefits are indicated; in fact, some critical nutrients must be considered when being on a GF diet. For individuals with celiac disease, the GF database provides a helpful tool to identify the food composition of their medical diet. For healthy consumers, replacing gluten-containing products with GF foods is aligned with substantial cost differences but GF foods do not provide additional health benefits from a nutritional perspective. PMID- 26528409 TI - Evaluation of nutritional and economic feed values of spent coffee grounds and Artemisia princeps residues as a ruminant feed using in vitro ruminal fermentation. AB - Much research on animal feed has focused on finding alternative feed ingredients that can replace conventional ones (e.g., grains and beans) to reduce feed costs. The objective of this study was to evaluate the economic, as well as nutritional value of spent coffee grounds (SCG) and Japanese mugwort (Artemisia princeps) residues (APR) as alternative feed ingredients for ruminants. We also investigated whether pre-fermentation using Lactobacillus spp. was a feasible way to increase the feed value of these by-products. Chemical analyses and an in vitro study were conducted for SCG, APR, and their pre-fermented forms. All the experimental diets for in vitro ruminal fermentation were formulated to contain a similar composition of crude protein, neutral detergent fiber and total digestible nutrients at 1x maintenance feed intake based on the dairy National Research Council (NRC). The control diet was composed of ryegrass, corn, soybean meal, whereas the treatments consisted of SCG, SCG fermented with Lactobacillus spp. (FSCG), APR, and its fermented form (FAPR). The treatment diets replaced 100 g/kg dry matter (DM) of the feed ingredients in the control. Costs were lower for the all treatments, except FAPR, than that of the control. After 24-h incubation, the NDF digestibility of the diets containing SCG and its fermented form were significantly lower than those of the other diets (P < 0.01); pre-fermentation tended to increase NDF digestibility (P = 0.07), especially for APR. Supplementation of SCG significantly decreased total gas production (ml/g DM) after 24-h fermentation in comparison with the control (P < 0.05); however, there were no significant differences between the control and the SCG or the APR diets in total gas production, as expressed per Korean Won (KRW). Diets supplemented with SCG or FSCG tended to have a higher total volatile fatty acid (VFA) concentration, expressed as per KRW, compared with the control (P = 0.06). Conversely, the fermentation process of SCG and APR significantly decreased total gas production and VFA production as expressed per KRW (P < 0.05). Because of their nutrient composition and relatively lower cost, we concluded that SCG and APR could be used as alternative feed sources, replacing conventional feed ingredients. However, pre-fermentation of agricultural by-products, such as SCG and APR, may be inappropriate for improving their nutritive considering the increase in production costs. PMID- 26528410 TI - Cheetahs (Acinonyx jubatus) running the gauntlet: an evaluation of translocations into free-range environments in Namibia. AB - Following dramatic range and population declines, the cheetah is Africa's most endangered large felid. In Namibia, private land managers still trap cheetahs but increasingly consider moving animals instead of killing them. Across Africa, managers have translocated perceived conflict carnivores for decades, but rarely evaluated their actions. We analyse the outcomes of 15 cheetah translocations (for 23 adults and 10 dependent offspring) into free-range environments in Namibia. We released cheetahs at an average distance of 419.6 km +/- 216.1 km SD (range: 71-816 km) after captive periods ranging from 1-1,184 days (350.6 days +/ 439.0 days SD). An individual's ability to survive the first year predominantly determined the overall translocation success of 40%. Post-release conflict and homing had less impact on success. Cheetah survival was lowest in the first three months after release. Human persecution (50% of deaths) and spotted hyaenas (29% of deaths) had the highest effect on survival. The degree of habituation to humans acquired during captivity significantly influenced chances of survival. Cheetahs surviving the initial post-release period (~90 days) often settled into ranges and females reproduced successfully. However, all individuals exhibited extensive movements, frequently roaming >4,000 km(2) in the first six months after release (with a maximum of 19,743 km(2) in 112 days), resulting in low release site fidelity. Soft release and larger recipient area size did not improve site fidelity. Based on these outcomes, we evaluated which unfenced conservation areas in Namibia could potentially receive cheetahs. We found that there are currently few public and/or private reserves large enough to contain the movement profiles we observed in this study. This suggests that most translocations will result in cheetahs re-entering farmlands where they face a high risk of persecution. In conclusion, translocations into unconfined areas can successfully conserve individual cheetahs. Due to high mortality and unpredictable outcomes, however, conservation efforts need to focus on improving tolerance of cheetahs in commercial livestock and game farming areas in order to reduce the number of indiscriminately trapped animals. PMID- 26528411 TI - Person-centered osteopathic practice: patients' personality (body, mind, and soul) and health (ill-being and well-being). AB - Background. Osteopathic philosophy and practice are congruent with the biopsychosocial model, a patient-centered approach when treating disease, and the view of the person as a unity (i.e., body, mind, and soul). Nevertheless, a unity of being should involve a systematic person-centered understanding of the patient's personality as a biopsychosociospiritual construct that influences health (i.e., well-being and ill-being). We suggest Cloninger's personality model, comprising temperament (i.e., body) and character (i.e., mind and soul), as a genuine paradigm for implementation in osteopathic practice. As a first step, we investigated (1) the relationships between personality and health among osteopathic patients, (2) differences in personality between patients and a control group, and (3) differences in health within patients depending on the presenting problem and gender. Method. 524 osteopathic patients in Sweden (age mean = 46.17, SD = 12.54, 388 females and 136 males) responded to an online survey comprising the Temperament and Character Inventory and measures of health (well-being: life satisfaction, positive affect, harmony in life, energy, and resilience; ill-being: negative affect, anxiety, depression, stress, and dysfunction and suffering associated to the presenting problem). We conducted two structural equation models to investigate the association personality-health; graphically compared the patients' personality T-scores to those of the control group and compared the mean raw scores using t-tests; and conducted two multivariate analyses of variance, using age as covariate, to compare patients' health in relation to their presenting problem and gender. Results. The patients' personality explained the variance of all of the well-being (R (2) between .19 and .54) and four of the ill-being (R (2) between .05 and .43) measures. Importantly, self-transcendence, the spiritual aspect of personality, was associated to high levels of positive emotions and resilience. Osteopathic patients, compared to controls, scored higher in six of the seven personality dimensions. These differences were, however, not considerably large (divergences in T-scores were <1 SD, Cohen's d between 0.12 and 0.40). Presenting problem and gender did not have an effect on any of the health measures. Conclusion. The patient's personality as a ternary construct (i.e., body, mind, and soul), which is in line with osteopathy, is associated to both well-being and ill-being. The lack of substantial differences in personality between patients and controls implies that the patients had not any personality disorders. Hence, osteopaths might, with proper education, be able to coach their patients to self-awareness. The lack of differences in health variables between osteopathic patients with different presenting problems suggests that practitioners should focus on the person's health regardless of the type of presenting problem. PMID- 26528412 TI - Astrocyte activation in the anterior cingulate cortex and altered glutamatergic gene expression during paclitaxel-induced neuropathic pain in mice. AB - Spinal astrocyte activation contributes to the pathogenesis of paclitaxel-induced neuropathic pain (PINP) in animal models. We examined glial fibrillary acidic protein (GFAP; an astrocyte marker) immunoreactivity and gene expression of GFAP, glutamate transporters and receptor subunits by real time PCR in the anterior cingulate cortex (ACC) at 7 days post first administration of paclitaxel, a time point when mice had developed thermal hyperalgesia. The ACC, an area in the brain involved in pain perception and modulation, was chosen because changes in this area might contribute to the pathophysiology of PINP. GFAP transcripts levels were elevated by more than fivefold and GFAP immunoreactivity increased in the ACC of paclitaxel-treated mice. The 6 glutamate transporters (GLAST, GLT-1 EAAC1, EAAT4, VGLUT-1 and VGLUT-2) quantified were not significantly altered by paclitaxel treatment. Of the 12 ionotropic glutamate receptor subunits transcripts analysed 6 (GLuA1, GLuA3, GLuK2, GLuK3, GLuK5 and GLuN1) were significantly up-regulated, whereas GLuA2, GLuK1, GLuK4, GLuN2A and GLuN2B were not significantly altered and GLuA4 was lowly expressed. Amongst the 8 metabotropic receptor subunits analysed only mGLuR8 was significantly elevated. In conclusion, during PINP there is astrocyte activation, with no change in glutamate transporter expression and differential up-regulation of glutamate receptor subunits in the ACC. Thus, targeting astrocyte activation and the glutamatergic system might be another therapeutic avenue for management of PINP. PMID- 26528413 TI - Modeling the effects of cyclodextrin on intracellular membrane vesicles from Cos 7 cells prepared by sonication and carbonate treatment. AB - Cholesterol has important functions in the organization of membrane structure and this may be mediated via the formation of cholesterol-rich, liquid-ordered membrane microdomains often referred to as lipid rafts. Methyl-beta-cyclodextrin (cyclodextrin) is commonly used in cell biology studies to extract cholesterol and therefore disrupt lipid rafts. However, in this study we reassessed this experimental strategy and investigated the effects of cyclodextrin on the physical properties of sonicated and carbonate-treated intracellular membrane vesicles isolated from Cos-7 fibroblasts. We treated these membranes, which mainly originate from the trans-Golgi network and endosomes, with cyclodextrin and measured the effects on their equilibrium buoyant density, protein content, represented by the palmitoylated protein phosphatidylinositol 4-kinase type IIalpha, and cholesterol. Despite the reduction in mass stemming from cholesterol removal, the vesicles became denser, indicating a possible large volumetric decrease, and this was confirmed by measurements of hydrodynamic vesicle size. Subsequent mathematical analyses demonstrated that only half of this change in membrane size was attributable to cholesterol loss. Hence, the non-selective desorption properties of cyclodextrin are also involved in membrane size and density changes. These findings may have implications for preceding studies that interpreted cyclodextrin-induced changes to membrane biochemistry in the context of lipid raft disruption without taking into account our finding that cyclodextrin treatment also reduces membrane size. PMID- 26528414 TI - Migration in the social stage of Dictyostelium discoideum amoebae impacts competition. AB - Interaction conditions can change the balance of cooperation and conflict in multicellular groups. After aggregating together, cells of the social amoeba Dictyostelium discoideum may migrate as a group (known as a slug) to a new location. We consider this migration stage as an arena for social competition and conflict because the cells in the slug may not be from a genetically homogeneous population. In this study, we examined the interplay of two seemingly diametric actions, the solitary action of kin recognition and the collective action of slug migration in D. discoideum, to more fully understand the effects of social competition on fitness over the entire lifecycle. We compare slugs composed of either genetically homogenous or heterogeneous cells that have migrated or remained stationary in the social stage of the social amoeba Dictyostelium discoideum. After migration of chimeric slugs, we found that facultative cheating is reduced, where facultative cheating is defined as greater contribution to spore relative to stalk than found for that clone in the clonal state. In addition our results support previous findings that competitive interactions in chimeras diminish slug migration distance. Furthermore, fruiting bodies have shorter stalks after migration, even accounting for cell numbers at that time. Taken together, these results show that migration can alleviate the conflict of interests in heterogeneous slugs. It aligns their interest in finding a more advantageous place for dispersal, where shorter stalks suffice, which leads to a decrease in cheating behavior. PMID- 26528415 TI - Frailty severity is significantly associated with electrocardiographic QRS duration in chronic dialysis patients. AB - End-stage renal disease (ESRD) patients are at increased risk of sudden cardiac death, the risk of which is presumably related to arrhythmia. Electrocardiographic (ECG) parameters have been found to correlate with arrhythmia and predict cardiovascular outcomes in ESRD patients. Frailty is also a common feature in this population. We investigate whether the severity of dialysis frailty is associated with ECG findings, including PR interval, QRS duration, and QTc interval. Presence and severity of frailty was ascertained using six different self-report questionnaires with proven construct validity. Correlation analysis between frailty severity and ECG was made, and those with significant association entered into multiple regression analysis for confirmation. Among a cohort of chronic hemodialysis patients, we found that frailty severity, assessed by the Edmonton frailty scale, is significantly associated with QRS duration (r = - 0.3, p < 0.05). Dialysis patients with QRS longer than 120 ms had significantly lower severity of frailty than those with QRS less than 120 ms (p = 0.01 for the Edmonton frailty scale and 0.05 for simple FRAIL scale). Regression analysis showed that frailty severity, assessed by the Edmonton frailty scale and simple FRAIL scale, was significantly associated with QRS duration independent of serum electrolyte levels. In conclusion, a significant relationship exists between the severity of frailty and QRS duration in ESRD patients. This might be an under-recognized link between frailty and its adverse cardiovascular impact in these patients. PMID- 26528416 TI - Urban habitat complexity affects species richness but not environmental filtering of morphologically-diverse ants. AB - Habitat complexity is a major determinant of structure and diversity of ant assemblages. Following the size-grain hypothesis, smaller ant species are likely to be advantaged in more complex habitats compared to larger species. Habitat complexity can act as an environmental filter based on species size and morphological traits, therefore affecting the overall structure and diversity of ant assemblages. In natural and semi-natural ecosystems, habitat complexity is principally regulated by ecological successions or disturbance such as fire and grazing. Urban ecosystems provide an opportunity to test relationships between habitat, ant assemblage structure and ant traits using novel combinations of habitat complexity generated and sustained by human management. We sampled ant assemblages in low-complexity and high-complexity parks, and high-complexity woodland remnants, hypothesizing that (i) ant abundance and species richness would be higher in high-complexity urban habitats, (ii) ant assemblages would differ between low- and high-complexity habitats and (iii) ants living in high complexity habitats would be smaller than those living in low-complexity habitats. Contrary to our hypothesis, ant species richness was higher in low complexity habitats compared to high-complexity habitats. Overall, ant assemblages were significantly different among the habitat complexity types investigated, although ant size and morphology remained the same. Habitat complexity appears to affect the structure of ant assemblages in urban ecosystems as previously observed in natural and semi-natural ecosystems. However, the habitat complexity filter does not seem to be linked to ant morphological traits related to body size. PMID- 26528417 TI - Combining environmental suitability and population abundances to evaluate the invasive potential of the tunicate Ciona intestinalis along the temperate South American coast. AB - The tunicate Ciona intestinalis is an opportunistic invader with high potential for causing economic losses in aquaculture centers. Recent phylogenetic and population genetic analysis support the existence of a genetic complex described as C. intestinalis with two main dominant species (sp A and B) occurring worldwide. In Chile, the species has been observed around 30 degrees S of latitude, but no official reports exist for the presence of C. intestinalis in southern regions (above 40 degrees S), where most of the mollusk aquaculture centers are located. Here, we used occurrences from multiple invaded regions and extensive field sampling to model and validate the environmental conditions that allow the species to persist and to find the geographic areas with the most suitable environmental conditions for the spread of C. intestinalis in the Chilean coast. By studying the potential expansion of C. intestinalis southward in the Chilean Coast, we aimed to provide valuable information that might help the development of control plans before the species becomes a significant problem, especially above 40 degrees S. Our results highlight that, by using portions of the habitat that are apparently distinguishable, the species seem to be not only genetically distinct, but ecologically distinct as well. The two regional models fitted for sp A and for sp B showed disagreement on which sections of Chilean coastline are considered more suitable for these species. While the model for sp A identifies moderately to highly suitable areas between 30 degrees and 40 degrees S, the model for sp B classifies the areas around 45 degrees S as the most appropriate. Data from field sampling show a positive linear relationship between density of C. intestinalis and the index of suitability for sp A in aquaculture centers. Understanding the relation of the distinct species with the surrounding environment provided valuable insights about probable routes of dispersion in Chile, especially into those areas considered suitable for aquaculture activities but where the species has not yet been recorded. We discuss the implications of our findings as a useful tool to anticipate the invasion of such harmful invasive species with regard to the most relevant environmental variables. PMID- 26528418 TI - Mammalian bone palaeohistology: a survey and new data with emphasis on island forms. AB - The interest in mammalian palaeohistology has increased dramatically in the last two decades. Starting in 1849 via descriptive approaches, it has been demonstrated that bone tissue and vascularisation types correlate with several biological variables such as ontogenetic stage, growth rate, and ecology. Mammalian bone displays a large variety of bone tissues and vascularisation patterns reaching from lamellar or parallel-fibred to fibrolamellar or woven fibred bone, depending on taxon and individual age. Here we systematically review the knowledge and methods on cynodont and mammalian bone microstructure as well as palaeohistology and discuss potential future research fields and techniques. We present new data on the bone microstructure of two extant marsupial species and of several extinct continental and island placental mammals. Extant marsupials display mainly parallel-fibred primary bone with radial and oblique but mainly longitudinal vascular canals. Three juvenile specimens of the dwarf island hippopotamid Hippopotamus minor from the Late Pleistocene of Cyprus show reticular to plexiform fibrolamellar bone. The island murid Mikrotia magna from the Late Miocene of Gargano, Italy displays parallel-fibred primary bone with reticular vascularisation and strong remodelling in the middle part of the cortex. Leithia sp., the dormouse from the Pleistocene of Sicily, is characterised by a primary bone cortex consisting of lamellar bone and a high amount of compact coarse cancellous bone. The bone cortex of the fossil continental lagomorph Prolagus oeningensis and three fossil species of insular Prolagus displays mainly parallel-fibred primary bone and reticular, radial as well as longitudinal vascularisation. Typical for large mammals, secondary bone in the giant rhinocerotoid Paraceratherium sp. from the Late Oligocene of Turkey is represented by dense Haversian bone. The skeletochronological features of Sinomegaceros yabei, a large-sized deer from the Pleistocene of Japan closely related to Megaloceros, indicate a high growth rate. These examples and the synthesis of existing data show the potential of bone microstructure to reveal essential information on life history evolution. The bone tissue and the skeletochronological data of the sampled island species suggest the presence of various modes of bone histological modification and mammalian life history evolution on islands to depend on factors of island evolution such as island size, distance from mainland, climate, phylogeny, and time of evolution. PMID- 26528419 TI - Contributions to a neurophysiology of meaning: the interpretation of written messages could be an automatic stimulus-reaction mechanism before becoming conscious processing of information. AB - Background. Even though the interpretation of natural language messages is generally conceived as the result of a conscious processing of the message content, the influence of unconscious factors is also well known. What is still insufficiently known is the way such factors work. We have tackled interpretation assuming it is a process, whose basic features are the same for the whole humankind, and employing a naturalistic approach (careful observation of phenomena in conditions the closest to "natural" ones, and precise description before and independently of data statistical analysis). Methodology. Our field research involved a random sample of 102 adults. We presented them with a complete real world-like case of written communication using unabridged message texts. We collected data (participants' written reports on their interpretations) in controlled conditions through a specially designed questionnaire (closed and opened answers); then, we treated it through qualitative and quantitative methods. Principal Findings. We gathered some evidence that, in written message interpretation, between reading and the attribution of conscious meaning, an intermediate step could exist (we named it "disassembling") which looks like an automatic reaction to the text words/expressions. Thus, the process of interpretation would be a discontinuous sequence of three steps having different natures: the initial "decoding" step (i.e., reading, which requires technical abilities), disassembling (the automatic reaction, an unconscious passage) and the final conscious attribution of meaning. If this is true, words and expressions would firstly function like physical stimuli, before being taken into account as symbols. Such hypothesis, once confirmed, could help explaining some links between the cultural (human communication) and the biological (stimulus reaction mechanisms as the basis for meanings) dimension of humankind. PMID- 26528420 TI - Quotation accuracy in medical journal articles-a systematic review and meta analysis. AB - Background. Quotations and references are an indispensable element of scientific communication. They should support what authors claim or provide important background information for readers. Studies indicate, however, that quotations not serving their purpose-quotation errors-may be prevalent. Methods. We carried out a systematic review, meta-analysis and meta-regression of quotation errors, taking account of differences between studies in error ascertainment. Results. Out of 559 studies screened we included 28 in the main analysis, and estimated major, minor and total quotation error rates of 11,9%, 95% CI [8.4, 16.6] 11.5% [8.3, 15.7], and 25.4% [19.5, 32.4]. While heterogeneity was substantial, even the lowest estimate of total quotation errors was considerable (6.7%). Indirect references accounted for less than one sixth of all quotation problems. The findings remained robust in a number of sensitivity and subgroup analyses (including risk of bias analysis) and in meta-regression. There was no indication of publication bias. Conclusions. Readers of medical journal articles should be aware of the fact that quotation errors are common. Measures against quotation errors include spot checks by editors and reviewers, correct placement of citations in the text, and declarations by authors that they have checked cited material. Future research should elucidate if and to what degree quotation errors are detrimental to scientific progress. PMID- 26528421 TI - Differences in unilateral chest press muscle activation and kinematics on a stable versus unstable surface while holding one versus two dumbbells. AB - Training the bench press exercise on a traditional flat bench does not induce a level of instability as seen in sport movements and activities of daily living. Twenty participants were recruited to test two forms of instability: using one dumbbell rather than two and lifting on the COR bench compared to a flat bench. Electromyography (EMG) amplitudes of the pectoralis major, middle trapezius, external oblique, and internal oblique were recorded and compared. Differences in range of motion (ROM) were evaluated by measuring an angular representation of the shoulder complex. Four separate conditions of unilateral bench press were tested while lifting on a: flat bench with one dumbbell, flat bench with two dumbbells, COR Bench with one dumbbell, and COR Bench with two dumbbells. The results imply that there are no differences in EMG amplitude or ROM between the COR bench and traditional bench. However, greater ROM was found to be utilized in the single dumbbell condition, both in the COR bench and the flat bench. PMID- 26528422 TI - Taking account of uncertainties in digital land suitability assessment. AB - Simulations are used to generate plausible realisations of soil and climatic variables for input into an enterprise land suitability assessment (LSA). Subsequently we present a case study demonstrating a LSA (for hazelnuts) which takes into account the quantified uncertainties of the biophysical model input variables. This study is carried out in the Meander Valley Irrigation District, Tasmania, Australia. It is found that when comparing to a LSA that assumes inputs to be error free, there is a significant difference in the assessment of suitability. Using an approach that assumes inputs to be error free, 56% of the study area was predicted to be suitable for hazelnuts. Using the simulation approach it is revealed that there is considerable uncertainty about the 'error free' assessment, where a prediction of 'unsuitable' was made 66% of the time (on average) at each grid cell of the study area. The cause of this difference is that digital soil mapping of both soil pH and conductivity have a high quantified uncertainty in this study area. Despite differences between the comparative methods, taking account of the prediction uncertainties provide a realistic appraisal of enterprise suitability. It is advantageous also because suitability assessments are provided as continuous variables as opposed to discrete classifications. We would recommend for other studies that consider similar FAO (Food and Agriculture Organisation of the United Nations) land evaluation framework type suitability assessments, that parameter membership functions (as opposed to discrete threshold cutoffs) together with the simulation approach are used in concert. PMID- 26528423 TI - Biological Role of Anti-aging Protein Klotho. AB - Klotho-deficient mice have accelerated aging phenotypes, whereas overexpression of Klotho in mice extends lifespan. Klotho is an anti-aging single-pass membrane protein predominantly produced in the kidney, with shedding of the amino-terminal extracellular domain into the systemic circulation. Circulating levels of soluble Klotho decrease with age, and the klotho gene is associated with increased risk of age-related diseases. The three forms of Klotho protein have distinct functions. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors, functions as an obligatory co-receptor for FGF23, which is involved in aging and the development of chronic diseases via regulation of P i and vitamin D metabolism. Secreted Klotho functions as a humoral factor with pleiotropic activities including regulation of oxidative stress, growth factor signaling, and ion homeostasis. Secreted Klotho is also involved in organ protection. The intracellular form of Klotho suppresses inflammation-mediated cellular senescence and mineral metabolism. Herein we provide a brief overview of the structure and function and recent research about Klotho. PMID- 26528424 TI - Comorbidities and Metabolic Derangement of NAFLD. AB - Nonalcoholic fatty liver disease (NAFLD) is an increasingly common cause of chronic liver disease worldwide and is becoming a major public health problem. NAFLD has been recognized as a hepatic manifestation of metabolic syndrome linked with insulin resistance. Growing evidence supports that NAFLD is associated with systemic diseases such as cardiovascular disease (CVD), chronic kidney disease (CKD), type 2 diabetes, obesity, and metabolic syndrome. The majority of deaths in patients with NAFLD come from cardiovascular disease. These findings are strongly attributed to nonalcoholic steatohepatitis (NASH) rather than simple steatosis. NAFLD should be considered not only a liver specific disease but also an early mediator of systemic disease. The underlying mechanisms and pathogenesis of NAFLD with regard to other medical disorders are not yet fully understood. Further investigation is needed for future therapeutic strategies for NAFLD. This review focuses on the relationship between NAFLD and various comorbid diseases and metabolic derangement. PMID- 26528425 TI - What Do Very Low Plasma Concentrations of High-sensitivity C-reactive Protein (hs CRP) Mean among Healthy Middle-aged Koreans? AB - BACKGROUND: Systemic low-grade inflammation (SLGI), as assessed by measurements of high-sensitivity C-reactive protein (hs-CRP), is a strong independent risk factor for cardiovascular diseases (CVD). Although individuals with hs-CRP <= 1 mg/L have been defined as being at low risk according to AHA/CDC guidelines, the value of very low hs-CRP levels (<0.5 mg/L) for public health practices is unclear. METHODS: This cross-sectional cohort study assessed 104 healthy Koreans aged 34-60 years. Their anthropometric indices, results of computed tomography and bioelectrical impedance analysis, and biomarker concentrations in fasting venous blood samples were evaluated. RESULTS: Of 104 subjects, 88 (84.6%) had hs CRP concentrations <= 1.0 mg/L. When this low risk group was subdivided into subjects with hs-CRP <0.5 mg/L and hs-CRP levels between 0.5 and 1 mg/L, the former group showed better anthropometric profiles for central obesity and lipidemia. CONCLUSION: Even in low risk subjects, higher serum concentrations of hs-CRP may be associated with increased central obesity. Lifestyle modifications to lower hs-CRP should be recommended in public health practice, with hs-CRP viewed not as a risk marker, but rather as a marker of wellness. PMID- 26528427 TI - Suspected Anaphylactic Reaction Prior to Induction of Anesthesia. AB - Although uncommon, anaphylactic reactions during surgery are very dangerous and can result in serious morbidity. Various anesthetics can trigger anaphylactic reactions, and incidents with cephalosporin antibiotics are on the rise. In the case presented, an 84-year-old woman scheduled for calcaneus fracture surgery, was injected with cefbuperazone as a prophylactic antibiotic. On the way to the operating room, before induction of anesthesia, the patient lost consciousness and showed signs of hypoxemia, and anaphylactic reaction, which included hypotension, bronchospasm, and rash. Five hours after immediate intubation and fluid resuscitation, the patient was extubated and transferred to the general ward. Eight weeks later, the skin prick test confirmed a positive reaction to cefbuperazone. PMID- 26528426 TI - Intense Walking Exercise Affects Serum IGF-1 and IGFBP3. AB - BACKGROUND: Insulin-like growth factor (IGF-1) is associated with chronic diseases such as diabetes, cardiovascular disease, and hypertension, as well as muscle dysfunction. Previous studies of exercise interventions yield controversial results regarding plasma IGF-1, IGFBP3, and IGF-1/IGFBP3 ratio. In this study, we examined whether 100 km walking exercise affects serum levels of IGF-1 and IGFBP3 and IGF-1/IGFBP3 ratio. We also investigated several metabolic related blood parameters before and after walking. METHODS: Participants were 14 healthy middle aged men (41.0 +/- 6.78 years of age). We assessed body composition and measured metabolic-related blood indicators, such as such as lipid profiles, glucose, renal and hepatic metabolic bio-markers before and after a 100 km walking race. Blood samples from all participants were taken before and immediately after the walkathon. We also analyzed serum levels of IGF-1 and IGFBP3, and calculated the IGF-1/IGFBP3 ratio. RESULTS: After participants completed a 100 km walking race, some of their metabolic profiles were markedly changed. Serum levels of IGF-1 and IGFBP3 were significantly decreased, and therefore the IGF-1/IGFBP3 ratio also decreased before and after 100 km of walking. CONCLUSION: Our results indicate that intense walking exercise affects serum levels of IGF-1 and IGFBP3 as well as metabolic bio-markers including high density cholesterol, glucose and triglycerides. PMID- 26528428 TI - Difficult Intubation in Pediatric Patient with a Large Lymphangioma at the Tongue Base. AB - Lymphangioma is a congenital malformation of lymphatic system and often involves the oral cavity. When lymphangioma is located on the mouth floor and enlarges, it can compress the airway and make intubation difficult. The GlideScope((r)) video laryngoscope is sometimes used in routine intubation, but is most commonly used in difficult or failed intubation. We report a pediatric patient with a difficult intubation due to a large tongue base mass. The airway was compromised due to limited intraoral space, large mass at the tongue base, and glottis distortion. Oral approach was not successful with the Macintosh laryngoscope. In this case, a rigid stylet was made to match the GlideScope((r)) curve and the endo-tracheal tube was inserted through the glottis under GlideScope((r)) guidance. We believe that, even in pediatric patients, a rigid stylet is necessary when intubation at a sharp posterior angulation to the trachea is difficult during GlideScope((r)) approach. PMID- 26528430 TI - Association between CLN3 (Neuronal Ceroid Lipofuscinosis, CLN3 Type) Gene Expression and Clinical Characteristics of Breast Cancer Patients. AB - Breast cancer is the most common cancer in women worldwide. Elucidation of underlying biology and molecular pathways is necessary for improving therapeutic options and clinical outcomes. CLN3 protein (CLN3p), deficient in neurodegenerative CLN3 disease is anti-apoptotic, and defects in the CLN3 gene cause accelerated apoptosis of neurons in CLN3 disease and up-regulation of ceramide. Dysregulated apoptotic pathways are often implicated in the development of the oncogenic phenotype. Predictably, CLN3 mRNA expression and CLN3 protein were up-regulated in a number of human and murine breast cancer-cell lines. Here, we determine CLN3 expression in non-tumor vs. tumor samples from fresh and formalin-fixed/paraffin-embedded (FFPE) breast tissue and analyze the association between CLN3 overexpression and different clinicopathological characteristics of breast cancer patients. Additionally, gene expression of 28 enzymes involved in sphingolipid metabolism was determined. CLN3 mRNA is overexpressed in tumor vs. non-tumor breast tissue from FFPE and fresh samples, as well as in mouse MCF7 breast cancer compared to MCF10A normal cells. Of the clinicopathological characteristics of tumor grade, age, menopause status, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), only absence of HER2 expression correlated with CLN3 overexpression. Sphingolipid genes for ceramide synthases 2 and 6 (CerS2; CerS6), delta(4)-desaturase sphingolipid 2 (DEGS2), and acidic sphingomyelinase (SMPD1) displayed higher expression levels in breast cancer vs. control tissue, whereas ceramide galactosyltransferase (UGT8) was underexpressed in breast cancer samples. CLN3 may be a novel molecular target for cancer drug discovery with the goal of modulation of ceramide pathways. PMID- 26528429 TI - Remodeling Components of the Tumor Microenvironment to Enhance Cancer Therapy. AB - Solid tumor pathophysiology is characterized by an abnormal microenvironment that guides tumor progression and poses barriers to the efficacy of cancer therapies. Most common among tumor types are abnormalities in the structure of the tumor vasculature and stroma. Remodeling the tumor microenvironment with the aim to normalize any aberrant properties has the potential to improve therapy. In this review, we discuss structural abnormalities of the tumor microenvironment and summarize the therapeutic strategies that have been developed to normalize tumors as well as their potential to enhance therapy. Finally, we present different in vitro models that have been developed to analyze and better understand the effects of the tumor microenvironment on cancer cell behavior. PMID- 26528431 TI - The Role of Glycosylation in Breast Cancer Metastasis and Cancer Control. AB - Glycosylation and its correlation to the formation of remote metastasis in breast cancer had been an important scientific topic in the last 25 years. With the development of new analytical techniques, new insights were gained on the mechanisms underlying metastasis formation and the role of aberrant glycosylation within. Mucin-1 and Galectin were recognized as key players in glycosylation. Interestingly, aberrant carbohydrate structures seem to support the development of brain metastasis in breast cancer patients, as changes in glycosylation structures facilitate an overcoming of blood-brain barrier. Changes in the gene expression of glycosyltransferases are the leading cause for a modification of carbohydrate chains, so that also altered gene expression plays a role for glycosylation. In consequence, glycosylation and changes within can be useful for cancer diagnosis, determination of tumor stage, and prognosis, but can as well be targets for therapeutic strategies. Thus, further research on this topic would worthwhile for cancer combating. PMID- 26528432 TI - Factors Determining Colorectal Cancer: The Role of the Intestinal Microbiota. AB - The gastrointestinal tract, in particular the colon, holds a complex community of microorganisms, which are essential for maintaining homeostasis. However, in recent years, many studies have implicated microbiota in the development of colorectal cancer (CRC), with this disease considered a major cause of death in the western world. The mechanisms underlying bacterial contribution in its development are complex and are not yet fully understood. However, there is increasing evidence showing a connection between intestinal microbiota and CRC. Intestinal microorganisms cause the onset and progression of CRC using different mechanisms, such as the induction of a chronic inflammation state, the biosynthesis of genotoxins that interfere with cell cycle regulation, the production of toxic metabolites, or heterocyclic amine activation of pro-diet carcinogenic compounds. Despite these advances, additional studies in humans and animal models will further decipher the relationship between microbiota and CRC, and aid in developing alternate therapies based on microbiota manipulation. PMID- 26528433 TI - New Auroras on the Roles of the Chromosomal Passenger Complex in Cytokinesis: Implications for Cancer Therapies. AB - The chromosomal passenger complex (CPC), composed of a kinase component, Aurora B, the scaffolding subunit inner centromeric protein, Borealin, and Survivin, is a key regulator of cell division. It controls multiple events, from chromosome condensation in prophase to the final separation or abscission of the two daughter cells. The essential functions of the CPC during metaphase, however, have always hindered an accurate study of its role during cytokinesis. The recent development of small molecule inhibitors against Aurora B and the use of elegant technologies such as chemical genetics have offered new approaches to study the functions of the CPC at the end of cell division. Here, we review the recent findings about the roles of the CPC in controlling the assembly of the cleavage furrow, central spindle, and midbody. We will also discuss the crucial function of this complex in controlling abscission timing in order to prevent abscission when lagging chromatin is present at the cleavage site, thereby avoiding the formation of genetically abnormal daughter cells. Finally, we offer our perspective on how to exploit the potential therapeutic applications of inhibiting CPC activity during cytokinesis in cancer cells. PMID- 26528434 TI - Successes and Challenges of PARP Inhibitors in Cancer Therapy. PMID- 26528435 TI - Editorial: HPV-Associated Cancers, Socio-Economic Disparity, and Vaccination. PMID- 26528437 TI - Integrating Geriatric Assessment into Decision-Making after Prostatectomy: Adjuvant Radiotherapy, Salvage Radiotherapy, or None? AB - Despite current advancements in the field, management of older prostate cancer patients still remains a big challenge for Geriatric Oncology. The International Society of Geriatric Oncology (ISGO) has recently updated its recommendations in this area, and these have been widely adopted, notably by the European Association of Urology. This article outlines the principles that should be observed in the management of elderly patients who have recently undergone prostatectomy for malignancy or with a biochemical relapse following prostatectomy. Further therapeutic intervention should not be considered in those patients who are classified as frail in the geriatric assessment. In patients presenting better health conditions, salvage radiotherapy is to be preferred to adjuvant radiotherapy, which is only indicated in certain exceptional cases. Radiotherapy of the operative bed presents a higher risk to the elderly. Additionally, hormone therapy clearly shows higher side effects in older patients and therefore it should not be administered to asymptomatic patients. We propose a decision tree based on the ISGO recommendations, with specific modifications for patients in biochemical relapse. PMID- 26528438 TI - Opposing Effects of Inhibitors of Aurora-A and EGFR in Autosomal-Dominant Polycystic Kidney Disease. AB - Aurora-A kinase (AURKA) overexpression in numerous tumors induces aneuploidy, in part because of cytokinetic defects. Alisertib and other small-molecule inhibitors targeting AURKA are effective in some patients as monotherapies or combination therapies. Epidermal growth factor receptor (EGFR) pro-proliferative signaling activity is commonly elevated in cancer, and the EGFR inhibitor erlotinib is commonly used as a standard of care agent for cancer. An erlotinib/alisertib combination therapy is currently under assessment in clinical trials, following pre-clinical studies that indicated synergy of these drugs in cancer. We were interested in further exploring the activity of this drug combination. Beyond well-established functions for AURKA in mitotic progression, additional non-mitotic AURKA functions include control of ciliary stability and calcium signaling. Interestingly, alisertib exacerbates the disease phenotype in mouse models for autosomal-dominant polycystic kidney disease (ADPKD), a common inherited syndrome induced by aberrant signaling from PKD1 and PKD2, cilia localized proteins that have calcium channel activity. EGFR is also more active in ADPKD, making erlotinib also of potential interest in this disease setting. In this study, we have explored the interaction of alisertib and erlotinib in an ADPKD model. These experiments indicated erlotinib--restrained cystogenesis, opposing alisertib action. Erlotinib also interacted with alisertib to regulate proliferative signaling proteins, albeit in a complicated manner. Results suggest a nuanced role of AURKA signaling in different pathogenic conditions and inform the clinical use of AURKA inhibitors in cancer patients with comorbidities. PMID- 26528436 TI - The Aurora B Kinase in Chromosome Bi-Orientation and Spindle Checkpoint Signaling. AB - Aurora B, a member of the Aurora family of serine/threonine protein kinases, is a key player in chromosome segregation. As part of a macromolecular complex known as the chromosome passenger complex, Aurora B concentrates early during mitosis in the proximity of centromeres and kinetochores, the sites of attachment of chromosomes to spindle microtubules. There, it contributes to a number of processes that impart fidelity to cell division, including kinetochore stabilization, kinetochore-microtubule attachment, and the regulation of a surveillance mechanism named the spindle assembly checkpoint. In the regulation of these processes, Aurora B is the fulcrum of a remarkably complex network of interactions that feed back on its localization and activation state. In this review, we discuss the multiple roles of Aurora B during mitosis, focusing in particular on its role at centromeres and kinetochores. Many details of the network of interactions at these locations remain poorly understood, and we focus here on several crucial outstanding questions. PMID- 26528439 TI - The Insulin/IGF System in Colorectal Cancer Development and Resistance to Therapy. AB - The insulin/insulin-like growth factor (IGF) system is a major determinant in the pathogenesis and progression of colorectal cancer (CRC). Indeed, several components of this signaling network, including insulin, IGF-1, IGF-2, the IGF binding proteins, the insulin receptor (IR), the IGF-1 receptor (IGF-1R), and IR substrate proteins 1 and 2 contribute to the transformation of normal colon epithelial cells. Moreover, the insulin/IGF system is also implicated in the development of resistance to both chemotherapeutic drugs and epidermal growth factor receptor targeted agents. The identification of hybrid receptors comprising both the IR and IGF-1R adds further complexity to this signaling network. Thus, a comprehensive understanding of the biological functions performed by each component of the insulin/IGF system is required to design successful drugs for the treatment of CRC patients. PMID- 26528440 TI - Ionizing Particle Radiation as a Modulator of Endogenous Bone Marrow Cell Reprogramming: Implications for Hematological Cancers. AB - Exposure of individuals to ionizing radiation (IR), as in the case of astronauts exploring space or radiotherapy cancer patients, increases their risk of developing secondary cancers and other health-related problems. Bone marrow (BM), the site in the body where hematopoietic stem cell (HSC) self-renewal and differentiation to mature blood cells occurs, is extremely sensitive to low-dose IR, including irradiation by high-charge and high-energy particles. Low-dose IR induces DNA damage and persistent oxidative stress in the BM hematopoietic cells. Inefficient DNA repair processes in HSC and early hematopoietic progenitors can lead to an accumulation of mutations whereas long-lasting oxidative stress can impair hematopoiesis itself, thereby causing long-term damage to hematopoietic cells in the BM niche. We report here that low-dose (1)H- and (56)Fe-IR significantly decreased the hematopoietic early and late multipotent progenitor (E- and L-MPP, respectively) cell numbers in mouse BM over a period of up to 10 months after exposure. Both (1)H- and (56)Fe-IR increased the expression of pluripotent stem cell markers Sox2, Nanog, and Oct4 in L-MPPs and 10 months post IR exposure. We postulate that low doses of (1)H- and (56)Fe-IR may induce endogenous cellular reprogramming of BM hematopoietic progenitor cells to assume a more primitive pluripotent phenotype and that IR-induced oxidative DNA damage may lead to mutations in these BM progenitors. This could then be propagated to successive cell lineages. Persistent impairment of BM progenitor cell populations can disrupt hematopoietic homeostasis and lead to hematologic disorders, and these findings warrant further mechanistic studies into the effects of low-dose IR on the functional capacity of BM-derived hematopoietic cells including their self-renewal and pluripotency. PMID- 26528441 TI - Changes in protein abundance are observed in bacterial isolates from a natural host. AB - Bacterial proteomic studies frequently use strains cultured in synthetic liquid media over many generations. It is uncertain whether bacterial proteins expressed under these conditions will be the same as the repertoire found in natural environments, or when bacteria are infecting a host organism. Thus, genomic and proteomic characterization of bacteria derived from the host environment in comparison to reference strains grown in the lab, should aid understanding of pathogenesis. Isolates of Corynebacterium pseudotuberculosis were obtained from the lymph nodes of three naturally infected sheep and compared to a laboratory reference strain using bottom-up proteomics, after whole genome sequencing of each of the field isolates. These comparisons were performed following growth in liquid media that allowed us to reach the required protein amount for proteomic analysis. Over 1350 proteins were identified in the isolated strains, from which unique proteome features were revealed. Several of the identified proteins demonstrated a significant abundance difference in the field isolates compared to the reference strain even though there were no obvious differences in the DNA sequence of the corresponding gene or in nearby non-coding DNA. Higher abundance in the field isolates was observed for proteins related to hypoxia and nutrient deficiency responses as well as to thiopeptide biosynthesis. PMID- 26528443 TI - Pediatric Renal Biopsies in India: A Single-Centre Experience of Six Years. AB - BACKGROUND: Renal biopsy is a well-established diagnostic modality for the assessment of kidney diseases in children. It can provide diagnostic precision and prognostic value and guide in therapeutic options for many renal diseases. OBJECTIVES: This report describes the indication, histopathological patterns, and epidemiology of renal diseases in children in India. PATIENTS AND METHODS: This is a single-center study on renal biopsies performed between January 2008 and December 2013 in 346 children (age <= 14 years). RESULTS: Eleven (3.17%) biopsies were inadequate, and 335 biopsies were considered for analysis. The mean age was 7.91 +/- 3.04 years with a predominance of males (68.1%). Nephrotic syndrome (46.2%) was the most common indication, followed by urinary abnormality (41.19%), acute nephritic syndrome (10.74%), and chronic renal failure (1.79 %). Primary glomerulonephritis (GN) was predominant (81.79%), and secondary GN constituted 16.12% of the biopsies. Primary GN included mesangial proliferative GN (MePGN), IgM nephropathy, focal segmental glomerulosclerosis, minimal change disease, IgA nephropathy, membranoproliferative GN, membranous nephropathy, crescentic GN, and post-infectious GN. Secondary GN revealed lupus nephritis, hemolytic uremic syndrome, amyloidosis, and hypertensive nephropathy. Tubulointerstitial nephritis was observed in 2.08%. The most common histological pattern of primary GN was MePGN (20%) and in secondary GN it was lupus nephritis (7.76%). CONCLUSIONS: The present study provides data on the epidemiology of renal diseases in children in India and will be helpful for developing a national registry and devising therapeutic guidelines. PMID- 26528442 TI - Type IV secretion system of Brucella spp. and its effectors. AB - Brucella spp. are intracellular bacterial pathogens that cause infection in domestic and wild animals. They are often used as model organisms to study intracellular bacterial infections. Brucella VirB T4SS is a key virulence factor that plays important roles in mediating intracellular survival and manipulating host immune response to infection. In this review, we discuss the roles of Brucella VirB T4SS and 15 effectors that are proposed to be crucial for Brucella pathogenesis. VirB T4SS regulates the inflammation response and manipulates vesicle trafficking inside host cells. VirB T4SS also plays crucial roles in the inhibition of the host immune response and intracellular survival during infection. Here, we list the key molecular events in the intracellular life cycle of Brucella that are potentially targeted by the VirB T4SS effectors. Elucidating the functions of these effectors will help clarify the molecular role of T4SS during infection. Furthermore, studying the effectors secreted by Brucella spp. might provide insights into the mechanisms used by the bacteria to hijack the host signaling pathways and aid in the development of better vaccines and therapies against brucellosis. PMID- 26528444 TI - Arteriovenous Fistula Recirculation in Hemodialysis. PMID- 26528445 TI - Antiplatelet Therapy in Hemodialysis Patients Undergoing Percutaneous Coronary Interventions. AB - CONTEXT: Coronary artery disease is highly prevalent among patients with end stage renal disease/hemodialysis (ESRD/HD) and coronary percutaneous interventions (PCI) has been increased by nearly 50% over the past decade. After PCI with stent placement, guidelines recommend dual antiplatelet therapy (DAPT), but no specifically tailored pharmacotherapy approach is outlined for this frail population, mostly excluded from large randomized clinical trials (RCTs). EVIDENCE ACQUISITION: We reviewed current evidences on the use of antiplatelet therapy in patients with ESRD/HD undergoing PCI, focusing on the efficacy and safety of specific agents and their indications for detailed clinical settings. RESULTS: Clinical setting in HD patients is the principal determinant of the type, onset, combination and duration of the DAPT. However, irrespective clinical setting, in addition to aspirin, clopidogrel is currently the most used antiplatelet agent even if no information derived from RCTs are available in ESRD. Due to the large experience acquired in routine clinical practice, the awareness of safety is higher for clopidogrel than newer antiplatelet agents. Because of lack of data, the use of prasugrel and ticagrelor is actually not recommended. However, in case of high ischemic and acceptable bleeding risk, they may be selectively used in ESRD/HD. CONCLUSIONS: This investigation might contribute to delineate the best treatment options for this high risk population. PMID- 26528446 TI - Reporting Quality Assessment of Randomized Controlled Trials Published in Nephrology Urology Monthly Journal. AB - CONTEXT: Randomized controlled trials (RCTs) are important tools for evidence based health care decisions. It is, therefore, important that they be conducted and reported with the highest possible standards. The aim of this study was to evaluate the reporting quality of the RCTs published in nephrology urology monthly journal and to examine whether there was a change over time in the reporting quality. EVIDENCE ACQUISITION: The quality of each report was assessed using the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement checklist and a 5-point quality assessment instrument, i.e. the Jadad scale. RESULTS: Eighteen (14 Iranian and 4 non-Iranian) RCTs were published from 2012 to 2014 on topics including renal stone (16.6%), hemodialysis and transplantation (38.8%), and prostate conditions (11.1%). Interventions comprised surgery, drugs, and teaching method in 7 (38 %), 10 (55%), and 1 (5%) of them, respectively. According to the CONSORT checklist, the weakest reported items were registration number, identification as a randomized trial in the title, and settings and locations where the data were collected. The mean Jadad score of the reports was 2.72 +/- 1.36 (54% of their maximum possible total score). According to the Jadad and CONSORT scales, there was an increase in the quality of reporting from 2012 to 2014. CONCLUSIONS: This assessment shows low reporting quality scores in reports. Training courses for researchers, using standard reporting tools (e.g. CONSORT 2010 Statement checklist), and consultation with methodologists can improve the quality of published RCTs. PMID- 26528447 TI - Liver Enzymes and Uric acid in Acute Heart Failure. AB - BACKGROUND: Acute heart failure (AHF) is defined as the new onset or recurrence of gradual or rapidly worsening signs and symptoms of heart failure, requiring urgent or emergent therapy. OBJECTIVES: This study attempts to assess the association of liver function tests (LFT) and uric acid level with in hospital outcome and echocardiography parameters, in patients with acute decompensated heart failure. PATIENTS AND METHODS: A total of 100 patients (aged 16 - 90 years, 60% men) admitted with AHF were enrolled. LFTs and uric acid levels were assessed on first day and before discharge, and patients were followed for 3 months. RESULTS: In-hospital outcomes were considered. Mean Left Ventricular Ejection Fraction (LVEF) was 35% (20 - 45%). Mean Uric acid level was 8.4 mg/dL, significantly higher than chronic HF and normal groups (P < 0.02). Elevated liver enzymes were seen in 52% patients, mostly (87%) in transaminases. Liver enzymes were decreased in 85% patients before discharge. LFT and uric acid levels were inversely and significantly correlated with LVEF on echocardiography (P = 0.02), but not with diastolic parameters. Although there was no significant correlation between uric acid level and in-hospital mortality, risk of intubation and rehospitalization in 3 months, enzyme levels increased in these groups. Increased aspartate transaminase (AST level) was associated with inotrope infusion in AHF patients (42 vs. 82 mg/dL, P = 0.03). CONCLUSIONS: Abnormal transaminases and uric acid levels are seen in AHF patients. Increased AST levels may be a predictor of the need for inotrope during hospital course in these patients. PMID- 26528448 TI - Repair of Post-Infarction Ventricular Free Wall Rupture With TachoSil((r)). AB - INTRODUCTION: Left ventricular free wall rupture (LVFWR) is a frequent cause of death after acute myocardial infarction, and its repair remains a surgical challenge. CASE PRESENTATION: TachoSil((r)) is a ready-to-use equine collagen patch which has been successfully used for hemostasis in cardiovascular surgery. However, a limited number of studies have reported its application for LVFWR repair. In this study, we describe our initial experience using TachoSil((r)) for LVFWR repair. CONCLUSIONS: A hemodynamic study was acceptable at a 12-month follow-up, and no complication was seen. PMID- 26528449 TI - Age and the Head-Up Tilt Test Outcome in Syncope Patients. AB - BACKGROUND: The head-up tilt test (HUTT) is a useful diagnostic tool for syncope. OBJECTIVES: We sought to investigate the outcome of the HUTT in syncope patients and identify the relationship between age and different hemodynamic outcomes. PATIENTS AND METHODS: In this cross-sectional study, we prospectively enrolled consecutive patients who presented with syncope and underwent the HUTT with a clinical suspicion of neurocardiogenic syncope after the exclusion of orthostatic hypotension cases. The HUTT consisted of consecutive passive and active phases. In the passive phase, the patients were tilted at 70 degrees for 20 minutes; and if negative, the test was repeated with 400 micrograms of sublingual nitroglycerin for another 20 minutes. Positive responses were classified according to the classification of the vasovagal syncope international study (VASIS) and compared for age and gender. RESULTS: A total of 498 patients were enrolled (age = 44.93 +/- 18.77 years; male = 271 [54.4%]). Overall, 291 (58.4%) patients had a positive HUTT, while 256 (88.5%) patients had a positive result during the active phase. The test results were as follows: 107 (36.7%) mixed type (VASIS I), 103 (35.3%) cardioinhibitory (VASIS IIA = 44 [15.1%]; VASIS IIB = 59 [20.2%]), and 80 (27.4%) vasodepressive (VASIS III). There was no relationship between gender and syncope type. The trend of the HUTT result significantly changed with age, and the rate of cardioinhibitory syncope decreased after middle ages (P value for trend = 0.02). CONCLUSIONS: Hemodynamic response to the HUTT was associated with age. Cardioinhibitory response became less frequent with age due to exaggerated vagal activity in the younger patients as compared with the older subjects. PMID- 26528450 TI - Valsalva Maneuver and Strain-Related ECG Changes. AB - BACKGROUND: During the four steps of the Valsalva maneuver (VM), opposite changes can be observed in some physiologic parameters. Manifestations of the VM in the electrocardiogram (ECG) have been studied in detail, but there have been few reports comparing VM-related biochemical and hemodynamic changes with a focus on the strain phase of the VM. OBJECTIVES: We studied strain-related ECG changes during the VM. PATIENTS AND METHODS: This self-control descriptive study was conducted in 20 healthy male college students aged 20.12 +/- 2.23 years. They were well trained to perform the standard VM: maintenance of a 15-second expiratory pressure at 40 mmHg with open glottis. An ECG was continuously recorded in the supine position at (a) rest (before the VM) and at (b) the start and (c) end of strain maintenance in the second phase of the VM. The averages of four successive beats were computed for each set of (a), (b), and (c). Means +/- standard errors of the mean were used for comparison. RESULTS: Following the VM, the RR and PR intervals, corrected QT interval (QTc), P wave duration and amplitude, T wave amplitude, and the ratio of T/R amplitudes showed significant changes. The QRS duration and R wave amplitude did not show significant changes. CONCLUSIONS: The VM caused time and voltage changes in some ECG waves during the strain phase. Alterations in heart or lung volume, electrode-related alterations, and autonomic tone may cause these changes. PMID- 26528451 TI - The Relation of Respiratory Muscle Strength to Disease Severity and Abnormal Ventilation During Exercise in Chronic Heart Failure Patients. AB - BACKGROUND: Breathlessness is a common problem in chronic heart failure (CHF) patients, and respiratory muscle strength has been proposed to play an important role in causing breathlessness in these patients. OBJECTIVES: The aim of this study was to investigate the relation between respiratory muscle strength and the severity of CHF, and the influence of respiratory muscle strength on abnormal ventilation during exercise in CHF patients. PATIENTS AND METHODS: In this case series study, we assessed clinically stable CHF outpatients (N = 66, age: 57.7 +/ 14.6 years). The peak oxygen consumption (peak VO2), the slope relating minute ventilation to carbon dioxide production (VE/VCO2 slope), and the slope relating tidal volume to respiratory rate (TV/RR slope) were measured during cardiopulmonary exercise testing. Respiratory muscle strength was assessed by measuring the maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). RESULTS: The MIP and MEP decreased significantly as the New York Heart Association functional class increased (MIP, P = 0.021; MEP, P < 0.01). The MIP correlated with the TV/RR slope (r = 0.57, P < 0.001) and the VE/VCO2 slope (r = 0.44, P < 0.001), and the MEP also correlated with the TV/RR slope (r = 0.53, P < 0.001) and the VE/VCO2 slope (r = -0.25, P < 0.040). Stepwise multiple regression analysis revealed that age and MIP were statistically significant predictors of the TV/RR and VE/VCO2 slopes (both P < 0.05). CONCLUSIONS: Respiratory muscle strength is related to the severity of CHF, and associated with rapid and shallow ventilation or excessive ventilation during exercise. PMID- 26528452 TI - Pulmonary Vascular Capacitance as a Predictor of Vasoreactivity in Idiopathic Pulmonary Arterial Hypertension Tested by Adenosine. AB - BACKGROUND: Acute pulmonary vasoreactivity testing has been recommended in the diagnostic work-up of patients with idiopathic pulmonary arterial hypertension (IPAH). Pulmonary arteriolar capacitance (Cp) approximated by stroke volume divided by pulmonary pulse pressure (SV/PP) is considered as an independent predictor of mortality in patients with IPAH. OBJECTIVES: We sought to evaluate any differences in baseline and adenosine Cp between vasoreactive and non vasoreactive IPAH patients tested with adenosine. PATIENTS AND METHODS: Fourteen patients with IPAH and a vasoreactive adenosine vasoreactivity testing according to the ESC guidelines were compared with 24 IPAH patients with nonreactive adenosine test results. RESULTS: There were no statistical significant differences between the two groups regarding NYHA class, body surface area, heart rate, and systemic blood pressure during right heart catheterization. Hemodynamic study showed no statistical significant differences in cardiac output/Index, mean pulmonary artery pressure, pulmonary vascular resistance, and baseline Cp between the two groups. There was a statistical significant but weak increase in adenosine Cp in vasoreactive group compared to non-reactive group (P = 0.04). Multivariable analysis showed an association between Cp and vasoreactivity (Beta = 2, P = 0.04, OR = 0.05 (95%CI = 0.003 - 0.9). CONCLUSIONS: Cp could be considered as an index for the prediction of vasoreactivity in patients with IPAH. Prediction of long-term response to calcium channel blockers in patients with IPAH and a positive vasoreactive test by this index should be addressed in further studies. PMID- 26528453 TI - The Association of Subclinical Hypothyroidism and Pattern of Circulating Endothelial-Derived Microparticles Among Chronic Heart Failure Patients. AB - BACKGROUND: Subclinical hypothyroidism (SH) is diagnosed biochemically by the presence of normal serum free thyroxine concentration, in conjunction with an elevated serum thyroid-stimulating hormone level. Recent studies have demonstrated the frequent association between SH and cardiovascular diseases and risk factors. OBJECTIVES: To evaluate the impact of SH on patterns of circulating endothelial-derived microparticles, (EMPs) among chronic heart failure (CHF) patients. PATIENTS AND METHODS: This is a retrospective study involving a cohort of 388 patients with CHF. Fifty-three CHF subjects had SH and 335 patients were free from thyroid dysfunction. Circulating levels of N-terminal-pro brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), thyroid-stimulating hormone (TSH), total and free thyroxine (T4), and triiodothyronine (T3), and endothelial apoptotic microparticles (EMPs), were measured at baseline. SH was defined, according to contemporary clinical guidelines, as a biochemical state associated with an elevated serum TSH level of greater 10 MUU/L and normal basal free T3 and T4 concentrations. RESULTS: Circulating CD31+/annexin V+ EMPs were higher in patients with SH compared to those without SH. In contrast, activated CD62E+ EMP numbers were not significantly different between both patient cohorts. Using uni (bi) variate and multivariate age- and gender-adjusted regression analysis, we found several predictors that affected the increase of the CD31+/annexin V+ to CD62E+ ratio in the patient study population. The independent impact of TSH per 6.5 MUU/L (odds ratio [OR] = 1.23, P = 0.001), SH (OR = 1.22, P = 0.001), NT-proBNP (OR = 1.19, P = 0.001), NYHA class (OR = 1.09, P = 0.001), hs-CRP per 4.50 mg/L (OR = 1.05, P = 0.001), dyslipidemia (OR = 1.06, P = 0.001), serum uric acid per 9.5 mmol/L (OR = 1.04, P = 0.022) on the increase in the CD31+/annexin V+ to CD62E+ ratio, was determined. CONCLUSIONS: We believe that the SH state in CHF patients may be associated with the impaired pattern of circulating EMPs, with the predominantly increased number of apoptotic-derived microparticles. PMID- 26528454 TI - The Effect of Milk, Water and Lemon Juice on Various Subdiaphragmatic Activity Related Artifacts in Myocardial Perfusion Imaging. AB - BACKGROUND: Subdiaphragmatic activity can produce subdiaphragmatic-related artifacts, which can degrade the quality of myocardial perfusion imaging (MPI). OBJECTIVES: We examined the impact of drinking milk, water, and lemon juice on different subdiaphragmatic-related artifacts by using (99m)Tc-sestamibi myocardial single-photon emission computed tomography (SPECT) in order to determine a feasible method for improving the image quality. PATIENTS AND METHODS: A total of 179 patients (age 58 +/- 9.6 years) were enrolled in this study. The patients were randomly divided into five groups. Ten minutes after injection of 740 MBq 99mTc-sestamibi in both pharmacologic stress and rest phases, the individuals in group 1 were given water and milk (125 mL of each); those in group 2 were given lemon juice (250 mL); group 3 was given milk (250 mL); and group 4 was given water (250 mL), whereas no intervention was performed in group 5. The study was double-blind for both subjects and data collectors. MPI was performed for all patients and image quality was controlled by 2 experienced nuclear physicians. Interfering activity was determined visually on reconstructed images and categorized as extracardiac normalization artifact, overlapping of activity, scattering of activity, and ramp filter artifact. RESULTS: There were significant differences in terms of interfering activity among the five groups; group 3 (milk) had significantly lower interfering activity than other groups had, as defined by overlapping of activity (on both stress and rest images), ramp filter artifact (stress images), and scatter artifact (rest images) (P < 0.05). Furthermore, there was a significant difference in the incidence of good-quality images, with no interfering activity in group 3 in the resting state compared with the other groups in the study (P < 0.05). CONCLUSIONS: Drinking 250 mL of milk in either the stress phase or the rest phase of imaging diminishes interfering subdiaphragmatic-related artifacts, particularly overlapping of activity in MPI SPECT, resulting in better-quality images. PMID- 26528455 TI - Radiological findings and the clinical importance of megacalycosis. AB - OBJECTIVE: To describe the radiological findings and the clinical importance of megacalycosis. MATERIALS AND METHODS: On the basis of a case report and literature review, diagnostic criteria and clinical significance of megacalycosis are presented. RESULT: Megacalycosis is mostly asymptomatic and is usually discovered either accidentally or as a result of its complications, such as stone formation, flank pain, hematuria, infection, and fever. The renal pelvis, infundibulum, and ureter are not dilated. Calyces have a semilunar configuration rather than the conventional triangular or conical form. The tip of each pyramid is flat, and the calyces possess neither fornix nor papillae impressions. The number of calyces is increased compared to the healthy condition, typically from 20-25. The renal parenchyma has a normal width but with a slight narrowing of the renal medulla. The kidney exhibits normal function, in particular with respect to its ability to concentrate the urine. CONCLUSION: Megacalycosis is a rare, usually unilateral dilatation of the kidney calyces in the presence of a normal, undilated renal pelvis and ureter. Its pathological significance lies in the occurrence of complications. PMID- 26528456 TI - A Fixed Flow is More Effective than Titrated Flow during Bubble Nasal CPAP for Respiratory Distress in Preterm Neonates. AB - BACKGROUND: The clinical effects of a pre-fixed flow of air-oxygen versus a flow titrated according to visible bubbling are not well understood. OBJECTIVE: To compare the effects of a fixed flow (5 L/min) and titrated flow (flow just enough to ensure bubbling) at different set pressures on delivered intra-prong pressure, gas exchange and clinical parameters in preterm infants on bubble CPAP for respiratory distress. METHODS: Preterm infants <35 weeks gestational age on bubble CPAP and <96 h of age were enrolled in this crossover study. They were subjected to 30-min periods of titrated flow and fixed flow. At the end of both epochs, gas flow rate, set pressure, FiO2, SpO2, Silverman retraction score, respiratory rate, abdominal girth, and blood gases were recorded. The delivered intra-prong pressure was measured by an electronic manometer. RESULTS: 69 recordings were made in 54 infants. For each of the set CPAP pressures (4, 5, and 6 cm H2O), the mean delivered pressure with a fixed flow of 5 L/min was higher than that delivered by the titrated flow. During the fixed flow epoch, the delivered pressure was closer to and higher than the set pressure resulting in higher PaO2 and lower PaCO2 as compared to titrated flow epoch. In the titrated flow period, the delivered pressure was consistently lower than the set pressure. CONCLUSION: In preterm infants on bubble CPAP with set pressures of 4-6 cm H2O, a fixed flow of 5 L/min is more effective than a flow titrated to ensure adequate visible bubbling. It achieves higher delivered pressures, better oxygenation and ventilation. PMID- 26528457 TI - A Prospective Longitudinal Assessment of Medical Records for Diagnostic Substitution among Subjects Diagnosed with a Pervasive Developmental Disorder in the United States. AB - BACKGROUND: Previously, investigators suggested that diagnostic substitution from other diagnoses, e.g., mental retardation (MR) and/or cerebral palsy (CP) to pervasive developmental disorder (PDD) is a driving factor behind increases in autism. This study evaluated potential diagnostic substitution among subjects diagnosed with PDD vs. MR or CP by examining birth characteristic overlap. METHODS: SAS((r)) and StatsDirect software examined medical records for subjects within the Vaccine Safety Datalink database who were Health Maintenance Organization-enrolled from birth until diagnosed with an International Classification of Disease, 9th revision (ICD-9) outcome of PDD (299.xx, n = 84), CP (343.xx, n = 300), or MR (317.xx, 318.xx, or 319.xx, n = 51). RESULTS: Subjects with PDD had significantly (p < 0.01) increased: male/female ratio (PDD = 5.5 vs. CP = 1.5 or MR = 1.3), mean age of initial diagnosis in years (PDD = 3.13 vs. CP = 1.09 or MR = 1.62), mean gestational age in weeks at birth (PDD = 38.73 vs. CP = 36.20 or MR = 34.84), mean birth weight in grams (PDD = 3,368 vs. CP = 2,767 or MR = 2,406), and mean Appearance-Pulse-Grimace-Activity-Respiration scores at 1 min (PDD = 7.82 vs. CP = 6.37 or MR = 6.76) and 5 min (PDD = 8.77 vs. CP = 7.92 or MR = 8.04), as compared to subjects diagnosed with CP or MR. CONCLUSION: This study suggests diagnostic substitution cannot fully explain increased PDD prevalence during the 1990s within the United States. PMID- 26528458 TI - Balance is in the Moment. PMID- 26528459 TI - Commentary: Do the Benefits of Male Circumcision Outweigh the Risks? A Critique of the Proposed CDC Guidelines. PMID- 26528460 TI - Mapping of Networks to Detect Priority Zoonoses in Jordan. AB - Early detection of emerging disease events is a priority focus area for cooperative bioengagement programs. Communication and coordination among national disease surveillance and response networks are essential for timely detection and control of a public health event. Although systematic information sharing between the human and animal health sectors can help stakeholders detect and respond to zoonotic diseases rapidly, resource constraints, and other barriers often prevent efficient cross-sector reporting. The purpose of this research project was to map the laboratory and surveillance networks currently in place for detecting and reporting priority zoonotic diseases in Jordan in order to identify the nodes of communication, coordination, and decision-making where health and veterinary sectors intersect, and to identify priorities and gaps that limit information sharing for action. We selected three zoonotic diseases as case studies: highly pathogenic avian influenza (HPAI) H5N1, rabies, and brucellosis. Through meetings with government agencies and health officials, and desk research, we mapped each system from the index case through response - including both surveillance and laboratory networks, highlighting both areas of strength and those that would benefit from capacity-building resources. Our major findings indicate informal communication exists across sectors; in the event of emergence of one of the priority zoonoses studied, there is effective coordination across the Ministry of Health and Ministry of Agriculture. However, routine formal coordination is lacking. Overall, there is a strong desire and commitment for multi-sectoral coordination in detection and response to zoonoses across public health and veterinary sectors. Our analysis indicates that the networks developed in response to HPAI can and should be leveraged to develop a comprehensive laboratory and surveillance One Health network. PMID- 26528461 TI - Obesity-Related Behaviors among Poor Adolescents and Young Adults: Is Social Position Associated with Risk Behaviors? AB - HighlightsDifferent measures of social position capture unique dimensions of relative rank among youth.Youth-specific measures of social position may be important in identifying the most at-risk for obesity.Lower social status youth are more likely to be at-risk for obesity-related behaviors compared to those with a higher rank. This cross-sectional study examines multiple dimensions of social position in relation to obesity-related behaviors in an adolescent and young adult population. In addition to using conventional measures of social position, including parental education and household expenditures, we explore the usefulness of three youth-specific measures of social position - community and society subjective social status and school dropout status. Data are taken from a 2004 house-to-house survey of urban households within the bottom 20th percentile of income distribution within seven states in Mexico. A total of 5,321 Mexican adolescents, aged 12-22 years, provided information on obesity-related behaviors (e.g., diet, physical activity, sedentary behavior) and indicators of subjective and objective social position. A parent in each household provided information on socioeconomic status of the parent and household. Ordinal logistic regressions are used to estimate the associations of parental, household and adolescent indicators of social position and obesity-related risk behaviors. Those adolescents with the highest odds of adopting obesity risk behaviors were the ones who perceived themselves as lower in social status in reference to their peer community and those who had dropped out of school. We found no significant associations between parental education or household expenditures and obesity related risk behaviors. Immediate social factors in adolescents' lives may have a strong influence on their health-related behaviors. This study provides evidence for the usefulness of two particular measures, both of which are youth-specific. Adolescents and young adults who have dropped out of school and those with lower perceived relative social position within their community are more likely to be at-risk for obesity-related behaviors than those with higher relative social position. We conclude that youth-specific measures may be important in identifying the most at-risk among relatively homogeneous populations of youth. PMID- 26528462 TI - School Lunch Take up and Attainment in Primary and Secondary Schools in England. AB - HYPOTHESIS: Average levels of attainment in primary and secondary schools in England in 2010 and 2011 are positively associated with changes in average school lunch take up between 2008-2009 and 2010-2011. SUBJECTS/METHODS: Average school lunch take up and attainment data were available for 2009-2011 for primary and secondary sectors in a minimum of 106 local authorities (LAs) in England and 853 individual primary schools in six LAs. Associations between attainment at 11-12 years (primary) and 15-16 years (secondary) and changes in school lunch take up were tested using multilevel analysis, multiple regression, and cross-tabulation (chi-squared analysis). RESULTS: At school level, attainment at 11-12 years in 2010 and 2011 showed 9 positive and 12 negative associations with changes in school lunch take up between 2009 and 2011. At LA level, average attainment at 15 16 years in 2011 was associated with changes in total school lunch take up in 2010-2011 (p = 0.034). Cross-tabulation of changes in attainment 2010-2011 (above or below median) were positively associated with changes in total school lunch take up between 2009 and 2011, by quartiles (Chi-squared = 11.041, df = 3, p = 0.012). CONCLUSION: Attainment at secondary level in England is statistically significantly associated with increases in healthier school lunch take up. Results in the primary sector are not consistent. PMID- 26528463 TI - Implementation of the International Health Regulations (2005) Through Cooperative Bioengagement. AB - Cooperative bioengagement efforts, as practiced by U.S. government-funded entities, such as the Defense Threat Reduction Agency's Cooperative Biological Engagement Program, the State Department's Biosecurity Engagement Program, and parallel programs in other countries, exist at the nexus between public health and security. These programs have an explicit emphasis on developing projects that address the priorities of the partner country as well as the donor. While the objectives of cooperative bioengagement programs focus on reducing the potential for accidental or intentional misuse and/or release of dangerous biological agents, many partner countries are interested in bioengagement as a means to improve basic public health capacities. This article examines the extent to which cooperative bioengagement projects address public health capacity building under the revised International Health Regulations and alignment with the Global Health Security Agenda action packages. PMID- 26528464 TI - Occurrence and Diversity of Clinically Important Vibrio Species in the Aquatic Environment of Georgia. AB - Among the more than 70 different Vibrio species inhabiting marine, estuarine, and freshwater ecosystems, 12 are recognized as human pathogens. The warm subtropical climate of the Black Sea coastal area and inland regions of Georgia likely provides a favorable environment for various Vibrio species. From 2006 to 2009, the abundance, ecology, and diversity of clinically important Vibrio species were studied in different locations in Georgia and across seasons. Over a 33-month period, 1,595 presumptive Vibrio isolates were collected from the Black Sea (n = 657) and freshwater lakes around Tbilisi (n = 938). Screening of a subset of 440 concentrated and enriched water samples by PCR-electrospray ionization/mass spectrometry (PCR-ESI/MS) detected the presence of DNA from eight clinically important Vibrio species: V. cholerae, V. parahaemolyticus, V. vulnificus, V. mimicus, V. alginolyticus, V. harveyi, V. metschnikovii, and V. cincinnatiensis. Almost 90% of PCR/ESI-MS samples positive for Vibrio species were collected from June through November. Three important human-pathogenic Vibrio species (V. cholerae, V. parahaemolyticus, and V. vulnificus) were detected in 62.8, 37.8, and 21.4% of samples testing positive for Vibrios, respectively. The results of these activities suggest that natural reservoirs for human-pathogenic Vibrios exist in Georgian aquatic environments. Water temperature at all sampling sites was positively correlated with the abundance of clinically important Vibrio spp. (except V. metschnikovii), and salinity was correlated with species composition at particular Black Sea sites as well as inland reservoirs. PMID- 26528465 TI - Bigger, Brighter, Bluer-Better? Current Light-Emitting Devices - Adverse Sleep Properties and Preventative Strategies. AB - OBJECTIVE: In an effort to enhance the efficiency, brightness, and contrast of light-emitting (LE) devices during the day, displays often generate substantial short-wavelength (blue-enriched) light emissions that can adversely affect sleep. We set out to verify the extent of such short-wavelength emissions, produced by a tablet (iPad Air), e-reader (Kindle Paperwhite 1st generation), and smartphone (iPhone 5s) and to determine the impact of strategies designed to reduce these light emissions. SETTING: University of Surrey dedicated chronobiology facility. METHODS: First, the spectral power of all the LE devices was assessed when displaying identical text. Second, we compared the text output with that of "Angry Birds" - a popular top 100 "App Store" game. Finally, we measured the impact of two strategies that attempt to reduce the output of short-wavelength light emissions. The first strategy employed an inexpensive commercially available pair of orange-tinted "blue-blocking" glasses. The second strategy tested an app designed to be "sleep-aware" whose designers deliberately attempted to reduce short-wavelength light emissions. RESULTS: All the LE devices shared very similar enhanced short-wavelength peaks when displaying text. This included the output from the backlit Kindle Paperwhite device. The spectra when comparing text to the Angry Birds game were also very similar, although the text emissions were higher intensity. Both the orange-tinted glasses and the "sleep-aware" app significantly reduced short-wavelength emissions. CONCLUSION: The LE devices tested were all bright and characterized by short-wavelength enriched emissions. Since this type of light is likely to cause the most disruption to sleep as it most effectively suppresses melatonin and increases alertness, there needs to be the recognition that at night-time "brighter and bluer" is not synonymous with "better." Ideally future software design could be better optimized when night time use is anticipated, and hardware should allow an automatic "bedtime mode" that shifts blue and green light emissions to yellow and red as well as reduce backlight/light intensity. PMID- 26528466 TI - Corrigendum: Fomenting Sickness: Nocebo Priming of Residents about Wind Farm Health Harms. AB - [This corrects the article on p. 279 in vol. 2, PMID: 25566521.]. PMID- 26528467 TI - The Use of Nipple Shields: A Review. AB - INTRODUCTION: A nipple shield is a breastfeeding aid with a nipple-shaped shield that is positioned over the nipple and areola prior to nursing. Nipple shields are usually recommended to mothers with flat nipples or in cases in which there is a failure of the baby to effectively latch onto the breast within the first 2 days postpartum. The use of nipple shields is a controversial topic in the field of lactation. Its use has been an issue in the clinical literature since some older studies discovered reduced breast milk transfer when using nipple shields, while more recent studies reported successful breastfeeding outcomes. The purpose of this review was to examine the evidence and outcomes associated with nipple shield use. METHODS: A literature search was conducted in Ovid MEDLINE, OLDMEDLINE, EMBASE Classic, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL. The primary endpoint was any breastfeeding outcome following nipple shield use. Secondary endpoints included the reasons for nipple shield use and the average/median length of use. For the analysis, we examined the effect of nipple shield use on physiological responses, premature infants, mothers' experiences, and health professionals' experiences. RESULTS: The literature search yielded 261 articles, 14 of which were included in this review. Of these 14 articles, three reported on physiological responses, two reported on premature infants, eight reported on mothers' experiences, and one reported on health professionals' experiences. CONCLUSION: Through examining the use of nipple shields, further insight is provided on the advantages and disadvantages of this practice, thus allowing clinicians and researchers to address improvements on areas that will benefit mothers and infants the most. PMID- 26528468 TI - Universal Health Coverage as a Distinct Sustainable Development Goals Target: Dispelling Doubts and Underlining Implications. PMID- 26528470 TI - Radiopaque Strontium Fluoroapatite Glass-Ceramics. AB - The controlled precipitation of strontium fluoroapatite crystals was studied in four base glass compositions derived from the SiO2-Al2O3-Y2O3-SrO-Na2O K2O/Rb2O/Cs2O-P2O5-F system. The crystal phase formation of these glasses and the main properties of the glass-ceramics, such as thermal and optical properties and radiopacity were compared with a fifth, a reference glass-ceramic. The reference glass-ceramic was characterized as Ca-fluoroapatite glass-ceramic. The four strontium fluoroapatite glass-ceramics showed the following crystal phases: (a) Sr5(PO4)3F - leucite, KAlSi2O6, (b) Sr5(PO4)3F - leucite, KAlSi2O6, and nano sized NaSrPO4, (c) Sr5(PO4)3F - pollucite, CsAlSi2O6, and nano-sized NaSrPO4, and (d) Sr5(PO4)3F - Rb-leucite, RbAlSi2O6, and nano-sized NaSrPO4. The proof of crystal phase formation was possible by X-ray diffraction. The microstructures, which were studied using scanning electron microscopy, demonstrated a uniform distribution of the crystals in the glass matrix. The Sr-fluoroapatites were precipitated based on an internal crystallization process, and the crystals demonstrated a needle-like morphology. The study of the crystal growth of needle like Sr-fluoroapatites gave a clear evidence of an Ostwald ripening mechanism. The formation of leucite, pollucite, and Rb-leucite was based on a surface crystallization mechanism. Therefore, a twofold crystallization mechanism was successfully applied to develop these types of glass-ceramics. The main focus of this study was the controlled development of glass-ceramics exhibiting high radiopacity in comparison to the reference glass-ceramic. This goal could be achieved with all four glass-ceramics with the preferred development of the Sr fluoroapatite - pollucite-type glass-ceramic. In addition to this main development, it was possible to control the thermal properties. Especially the Rb leucite containing glass-ceramic showed the highest coefficient of thermal expansion (CTE). These glass-ceramics allow optical properties, especially the translucency and color, to be tailored to the needs of biomaterials for dental applications. The authors conclude that it is possible to use twofold crystallization processes to develop glass-ceramic biomaterials featuring different properties, such as specific radiopacity values, CTEs, and optical characteristics. PMID- 26528469 TI - Comparative Proteomic Studies of Yersinia pestis Strains Isolated from Natural Foci in the Republic of Georgia. AB - Yersinia pestis, the causative agent of plague, is a highly virulent bacterium responsible for millions of human deaths throughout history. In the last decade, two natural plague foci have been described in the Republic of Georgia from which dozens of Y. pestis strains have been isolated. Analyses indicate that there are genetic differences between these strains, but it is not known if these differences are also reflected in protein expression. We chose four strains of Y. pestis (1390, 1853, 2944, and 8787) from the National Center for Disease Control and Public Health collection for proteomic studies based on neighbor-joining tree genetic analysis and geographical loci of strain origin. Proteomic expression was analyzed using two-dimensional gel electrophoresis and mass spectrometry. Select Y. pestis strains were grown under different physiological conditions and their proteomes were compared: (1) 28 degrees C without calcium; (2) 28 degrees C with calcium; (3) 37 degrees C without calcium; and (4) 37 degrees C with calcium. Candidate proteins were identified and the differences in expression of F1 antigen, tellurium-resistance protein, and outer membrane protein C, porin were validated by Western blotting. The in vitro cytotoxicity activity of these strains was also compared. The results indicate that protein expression and cytotoxic activities differ significantly among the studied strains; these differences could contribute to variations in essential physiological functions in these strains. PMID- 26528471 TI - Development of a High Throughput Platform for Screening Glycoside Hydrolases Based on Oxime-NIMS. AB - Cost-effective hydrolysis of biomass into sugars for biofuel production requires high-performance low-cost glycoside hydrolase (GH) cocktails that are active under demanding process conditions. Improving the performance of GH cocktails depends on knowledge of many critical parameters, including individual enzyme stabilities, optimal reaction conditions, kinetics, and specificity of reaction. With this information, rate- and/or yield-limiting reactions can be potentially improved through substitution, synergistic complementation, or protein engineering. Given the wide range of substrates and methods used for GH characterization, it is difficult to compare results across a myriad of approaches to identify high performance and synergistic combinations of enzymes. Here, we describe a platform for systematic screening of GH activities using automatic biomass handling, bioconjugate chemistry, robotic liquid handling, and nanostructure-initiator mass spectrometry (NIMS). Twelve well-characterized substrates spanning the types of glycosidic linkages found in plant cell walls are included in the experimental workflow. To test the application of this platform and substrate panel, we studied the reactivity of three engineered cellulases and their synergy of combination across a range of reaction conditions and enzyme concentrations. We anticipate that large-scale screening using the standardized platform and substrates will generate critical datasets to enable direct comparison of enzyme activities for cocktail design. PMID- 26528472 TI - Using Ambulatory Voice Monitoring to Investigate Common Voice Disorders: Research Update. AB - Many common voice disorders are chronic or recurring conditions that are likely to result from inefficient and/or abusive patterns of vocal behavior, referred to as vocal hyperfunction. The clinical management of hyperfunctional voice disorders would be greatly enhanced by the ability to monitor and quantify detrimental vocal behaviors during an individual's activities of daily life. This paper provides an update on ongoing work that uses a miniature accelerometer on the neck surface below the larynx to collect a large set of ambulatory data on patients with hyperfunctional voice disorders (before and after treatment) and matched-control subjects. Three types of analysis approaches are being employed in an effort to identify the best set of measures for differentiating among hyperfunctional and normal patterns of vocal behavior: (1) ambulatory measures of voice use that include vocal dose and voice quality correlates, (2) aerodynamic measures based on glottal airflow estimates extracted from the accelerometer signal using subject-specific vocal system models, and (3) classification based on machine learning and pattern recognition approaches that have been used successfully in analyzing long-term recordings of other physiological signals. Preliminary results demonstrate the potential for ambulatory voice monitoring to improve the diagnosis and treatment of common hyperfunctional voice disorders. PMID- 26528473 TI - Transcriptional Network Growing Models Using Motif-Based Preferential Attachment. AB - Understanding relationships between architectural properties of gene-regulatory networks (GRNs) has been one of the major goals in systems biology and bioinformatics, as it can provide insights into, e.g., disease dynamics and drug development. Such GRNs are characterized by their scale-free degree distributions and existence of network motifs - i.e., small-node subgraphs that occur more abundantly in GRNs than expected from chance alone. Because these transcriptional modules represent "building blocks" of complex networks and exhibit a wide range of functional and dynamical properties, they may contribute to the remarkable robustness and dynamical stability associated with the whole of GRNs. Here, we developed network-construction models to better understand this relationship, which produce randomized GRNs by using transcriptional motifs as the fundamental growth unit in contrast to other methods that construct similar networks on a node-by-node basis. Because this model produces networks with a prescribed lower bound on the number of choice transcriptional motifs (e.g., downlinks, feed forward loops), its fidelity to the motif distributions observed in model organisms represents an improvement over existing methods, which we validated by contrasting their resultant motif and degree distributions against existing network-growth models and data from the model organism of the bacterium Escherichia coli. These models may therefore serve as novel testbeds for further elucidating relationships between the topology of transcriptional motifs and network-wide dynamical properties. PMID- 26528474 TI - Omega-3 Biotechnology: A Green and Sustainable Process for Omega-3 Fatty Acids Production. PMID- 26528475 TI - Enzymes from Extreme Environments and Their Industrial Applications. AB - This article will discuss the importance of specific extremophilic enzymes for applications in industrial biotechnology. It will specifically address those enzymes that have applications in the area of biocatalysis. Such enzymes now play an important role in catalyzing a variety of chemical conversions that were previously carried out by traditional chemistry. The biocatalytic process is carried out under mild conditions and with greater specificity. The enzyme process does not result in the toxic waste that is usually produced in a chemical process that would require careful disposal. In this sense, the biocatalytic process is referred to as carrying out "green chemistry" which is considered to be environmentally friendly. Some of the extremophilic enzymes to be discussed have already been developed for industrial processes such as an l-aminoacylase and a gamma-lactamase. The industrial applications of other extremophilic enzymes, including transaminases, carbonic anhydrases, dehalogenases, specific esterases, and epoxide hydrolases, are currently being assessed. Specific examples of these industrially important enzymes that have been studied in the authors group will be presented in this review. PMID- 26528476 TI - Corrigendum: Musculoskeletal Modeling of the Lumbar Spine to Explore Functional Interactions between Back Muscle Loads and Intervertebral Disk Multiphysics. AB - [This corrects the article on p. 111 in vol. 3, PMID: 26301218.]. PMID- 26528477 TI - Biomedical insights into cell adhesion and migration-from a viewpoint of central nervous system tumor immunology. PMID- 26528479 TI - Cognitive phylogenies, the Darwinian logic of descent, and the inadequacy of cladistic thinking. AB - There has been a reappraisal of phylogenetic issues in cognitive science, as reconstructing cognitive phylogenies has been considered a key for unveiling the cognitive novelties that set the stage for what makes humans special. In our opinion, the studies made until now have approached cognitive phylogenies in a non-optimal way, and we wish to both highlight their problems, drawing on recent considerations in philosophy of biology. The inadequacy of current visions on cognitive phylogenies stems from the influence of the traditional "linear cladograms," according to which every seemingly new or more sophisticated feature of a cognitive mechanism, viewed as a novelty, is represented as a node on top of the old and shared elements. We claim that this kind of cladograms does not succeed in depicting the complexity with which traits are distributed across species and, furthermore, that the labels of the nodes of these traditional representational systems fail to capture the "tinkering" nature of evolution. We argue that if we are to conceive of cognitive mechanisms in a multi-dimensional, bottom-up perspective, in accordance with the Darwinian logic of descent, we should rather focus on decomposing these mechanisms into lower-level, generic functions, which have the additional advantage of being implementable in neural matter, which ultimately produces cognition. Doing so renders current constructions of cognitive phylogenies otiose. PMID- 26528478 TI - Uncovering the dual role of RHAMM as an HA receptor and a regulator of CD44 expression in RHAMM-expressing mesenchymal progenitor cells. AB - The interaction of hyaluronan (HA) with mesenchymal progenitor cells impacts trafficking and fate after tissue colonization during wound repair and these events contribute to diseases such as cancer. How this interaction occurs is poorly understood. Using 10T1/2 cells as a mesenchymal progenitor model and fluorescent (F-HA) or gold-labeled HA (G-HA) polymers, we studied the role of two HA receptors, RHAMM and CD44, in HA binding and uptake in non-adherent and adherent mesenchymal progenitor (10T1/2) cells to mimic aspects of cell trafficking and tissue colonization. We show that fluorescent labeled HA (F-HA) binding/uptake was high in non-adherent cells but dropped over time as cells became increasingly adherent. Non-adherent cells displayed both CD44 and RHAMM but only function-blocking anti-RHAMM and not anti-CD44 antibodies significantly reduced F-HA binding/uptake. Adherent cells, which also expressed CD44 and RHAMM, primarily utilized CD44 to bind to F-HA since anti-CD44 but not anti-RHAMM antibodies blocked F-HA uptake. RHAMM overexpression in adherent 10T1/2 cells led to increased F-HA uptake but this increased binding remained CD44 dependent. Further studies showed that RHAMM-transfection increased CD44 mRNA and protein expression while blocking RHAMM function reduced expression. Collectively, these results suggest that cellular microenvironments in which these receptors function as HA binding proteins differ significantly, and that RHAMM plays at least two roles in F-HA binding by acting as an HA receptor in non-attached cells and by regulating CD44 expression and display in attached cells. Our findings demonstrate adhesion-dependent mechanisms governing HA binding/ uptake that may impact development of new mesenchymal cell-based therapies. PMID- 26528480 TI - Fish Oil-Derived Long-Chain n-3 Polyunsaturated Fatty Acids Reduce Expression of M1-Associated Macrophage Markers in an ex vivo Adipose Tissue Culture Model, in Part through Adiponectin. AB - Adipose tissue (AT) macrophages (ATM) play a key role in obesity-associated pathologies, and their phenotype can be influenced by the local tissue microenvironment. Interestingly, long-chain n-3 polyunsaturated fatty acids (LC n 3 PUFA) and the LC n-3 PUFA-upregulated adipokine, adiponectin (Ad), may mitigate excessive ATM inflammatory M1-polarization responses. However, to what extent LC n-3 PUFA and Ad work in concert to affect macrophage phenotype has not been examined. Thus, we used an established ex vivo AT organ culture model using visceral AT from mice fed a control (CON; 10% w/w safflower oil) n-6 PUFA-rich diet or an isocaloric fish oil (FO; 3% w/w menhaden oil + 7% w/w safflower oil) derived LC n-3 PUFA-rich diet to generate AT conditioned media (ACM). We then evaluated if CON or FO ACM affected macrophage polarization markers in a model designed to mimic acute [18 h ACM plus lipopolysaccharide (LPS) for the last 6 h] or chronic (macrophages treated with LPS-challenged CON or FO ACM for 24 h) inflammation +/- Ad-neutralizing antibody and the LPS-neutralizing agent, polymyxin B. In the acute inflammation model, macrophages treated with FO ACM had decreased lipid uptake and mRNA expression of M1 markers (Nos2, Nfkappab, Il6, Il18, Ccl2, and Ccl5) compared with CON ACM (p <= 0.05); however, these effects were largely attenuated when Ad was neutralized (p > 0.05). Furthermore, in the chronic inflammation model, macrophages treated with FO ACM had decreased mRNA expression of M1 markers (Nos2, Tnfalpha, Ccl2, and Il1beta) and IL-6 and CCL2 secretion (p <= 0.05); however, some of these effects were lost when Ad was neutralized, and were further exacerbated when both Ad and LPS were neutralized. Taken together, this work shows that LC n-3 PUFA and Ad work in concert to suppress certain M1 macrophage responses. Thus, future strategies to modulate the ATM phenotype should consider the role of both LC n-3 PUFA and Ad in mitigating obese AT inflammation. PMID- 26528481 TI - The Challenge for Reconstructive Surgeons in the Twenty-First Century: Manufacturing Tissue-Engineered Solutions. PMID- 26528482 TI - Treatment of Fistula-In-Ano with Fistula Plug - a Review Under Special Consideration of the Technique. AB - INTRODUCTION: In a recent Cochrane review, the authors concluded that there is an urgent need for well-powered, well-conducted randomized controlled trials comparing various modes of treatment of fistula-in-ano. Ten randomized controlled trials were available for analyses: There were no significant differences in recurrence rates or incontinence rates in any of the studied comparisons. The following article reviews the studies available for treatment of fistula-in-ano with a fistula plug with special attention paid to the technique. MATERIAL AND METHODS: PubMed, Medline, Embase, and the Cochrane medical database were searched up to July 2015. Sixty-four articles were relevant for this review. RESULTS: Healing rates of 50-60% can be expected for treatment of complex anal fistula with a fistula plug, with a plug-extrusion rate of 10-20%. Such results can be achieved not only with plugs made of porcine intestinal submucosa but also those made of other biological or synthetic bioabsorbable mesh materials. Important technical steps are firm suturing of the head of the plug in the primary opening and wide drainage of the secondary opening. DISCUSSION: Treatment of a complex fistula-in-ano with a fistula plug is an option with a success rate of 50-60% with low complication rate. Further improvements in technique and better studies are needed. PMID- 26528483 TI - A script to highlight hydrophobicity and charge on protein surfaces. AB - The composition of protein surfaces determines both affinity and specificity of protein-protein interactions. Matching of hydrophobic contacts and charged groups on both sites of the interface are crucial to ensure specificity. Here, we propose a highlighting scheme, YRB, which highlights both hydrophobicity and charge in protein structures. YRB highlighting visualizes hydrophobicity by highlighting all carbon atoms that are not bound to nitrogen and oxygen atoms. The charged oxygens of glutamate and aspartate are highlighted red and the charged nitrogens of arginine and lysine are highlighted blue. For a set of representative examples, we demonstrate that YRB highlighting intuitively visualizes segments on protein surfaces that contribute to specificity in protein protein interfaces, including Hsp90/co-chaperone complexes, the SNARE complex and a transmembrane domain. We provide YRB highlighting in form of a script that runs using the software PyMOL. PMID- 26528484 TI - Identification and functional studies of regulatory variants responsible for the association of NRG3 with a delusion phenotype in schizophrenia. AB - We previously reported genetic linkage for Schizophrenia (SZ) (NPL of 4.7) at 10q22 in the Ashkenazi Jewish (AJ) population. In follow up fine mapping we found strong evidence of association between three intronic single nucleotide variants (SNVs) in the 5' end of Neuregulin 3 (NRG3) and the delusion factor score of our phenotypic principal component analysis. Two independent groups replicated these findings, indicating that variants in NRG3 confer risk for a delusion-rich SZ subtype. To identify the causative variants, we sequenced the 162 kb linkage disequilibrium (LD) block covering the NRG3 5' end in 47 AJ SZ patients at the extremes of the delusion factor quantitative trait distribution. Among the identified variants we found 5 noncoding SNVs present on the high delusion factor haplotype and significantly overrepresented in high delusion factor subjects. We tested these for regulatory effects and found that risk alleles of rs10883866 and rs60827755 decreased and increased, respectively, the expression of a reporter gene as compared to the reference allele. In post-mortem brain RNA quantification experiments we found the same variants also perturb relative expression of alternative NRG3 isoforms. In summary, we have identified regulatory SNVs contributing to the association of NRG3 with delusion symptoms in SZ. PMID- 26528485 TI - Genetic and morphological features of human iPSC-derived neurons with chromosome 15q11.2 (BP1-BP2) deletions. AB - BACKGROUND: Copy number variation on chromosome 15q11.2 (BP1-BP2) causes deletion of CYFIP1, NIPA1, NIPA2 and TUBGCP5; it also affects brain structure and elevates risk for several neurodevelopmental disorders that are associated with dendritic spine abnormalities. In rodents, altered cyfip1 expression changes dendritic spine morphology, motivating analyses of human neuronal cells derived from iPSCs (iPSC-neurons). METHODS: iPSCs were generated from a mother and her offspring, both carrying the 15q11.2 (BP1-BP2) deletion, and a non-deletion control. Gene expression in the deletion region was estimated using quantitative real-time PCR assays. Neural progenitor cells (NPCs) and iPSC-neurons were characterized using immunocytochemistry. RESULTS: CYFIP1, NIPA1, NIPA2 and TUBGCP5 gene expression was lower in iPSCs, NPCs and iPSC-neurons from the mother and her offspring in relation to control cells. CYFIP1 and PSD95 protein levels were lower in iPSC neurons derived from the CNV bearing individuals using Western blot analysis. At 10 weeks post-differentiation, iPSC-neurons appeared to show dendritic spines and qualitative analysis suggested that dendritic morphology was altered in 15q11.2 deletion subjects compared with control cells. CONCLUSIONS: The 15q11.2 (BP1-BP2) deletion is associated with reduced expression of four genes in iPSC-derived neuronal cells; it may also be associated altered iPSC-neuron dendritic morphology. PMID- 26528486 TI - Association Study of Genotype by Depressive Response during Tryptophan Depletion in Subjects Recovered from Major Depression. AB - PURPOSE: The brief and reversible mood response to acute tryptophan (TRP) depletion (ATD) is being studied as a trait marker in subjects considered at risk for major depression (MD). PROCEDURES: ATD was administered to 64 subjects (54 European-Americans, and10 from other races) with personal and family history of MD. They were in remission and had been medication-free for at least three months. Subjects received an active and sham condition in a random assignment, double-blind crossover design. They were genotyped for serotonin-related candidate genes, and mood response was quantified with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using Poisson regression with repeated measures and latent trajectory models. RESULTS: Compared to the sham control, active ATD caused modest depressive changes showing significant main effects of test condition (chi2=5.14, df=1, p=0.023) and time (chi2=12.22, df=3, p=0.007), but no significant interaction of time and test condition. Latent trajectory analysis revealed two groups, identified as depletion responders and non responders. Those with the HTR2A rs6313 CC genotype had significantly higher HDRS scores during ATD (chi2=11.72, df=1, p=.0006). CONCLUSIONS AND MESSAGE: ATD may help the identification of biological subtypes of MD. These data are consistent with imaging reports implicating 5-HT2A receptor function in ATD phenotypes. PMID- 26528488 TI - Foreword. PMID- 26528487 TI - Highly efficient in vitro and in vivo delivery of functional RNAs using new versatile MS2-chimeric retrovirus-like particles. AB - RNA delivery is an attractive strategy to achieve transient gene expression in research projects and in cell- or gene-based therapies. Despite significant efforts investigating vector-directed RNA transfer, there is still a requirement for better efficiency of delivery to primary cells and in vivo. Retroviral platforms drive RNA delivery, yet retrovirus RNA-packaging constraints limit gene transfer to two genome-molecules per viral particle. To improve retroviral transfer, we designed a dimerization-independent MS2-driven RNA packaging system using MS2-Coat-retrovirus chimeras. The engineered chimeric particles promoted effective packaging of several types of RNAs and enabled efficient transfer of biologically active RNAs in various cell types, including human CD34(+) and iPS cells. Systemic injection of high-titer particles led to gene expression in mouse liver and transferring Cre-recombinase mRNA in muscle permitted widespread editing at the ROSA26 locus. We could further show that the VLPs were able to activate an osteoblast differentiation pathway by delivering RUNX2- or DLX5-mRNA into primary human bone-marrow mesenchymal-stem cells. Thus, the novel chimeric MS2-lentiviral particles are a versatile tool for a wide range of applications including cellular-programming or genome-editing. PMID- 26528490 TI - Morbidity and mortality of endoscopist-directed nurse-administered propofol sedation (EDNAPS) in a tertiary referral center. AB - BACKGROUND AND STUDY AIMS: Endoscopist-Directed Nurse-Administered Propofol Sedation (EDNAPS) has been evaluated in community settings rather than tertiary referral centers. PATIENTS AND METHODS: A hospital-wide prospectively collected database of Medical Emergency Team Calls (METCALL), emergency responses triggered by medically unstable patients, was reviewed. Responses that followed EDNAPS were extracted and compared with a prospectively entered database of all endoscopies performed using EDNAPS over the same period. RESULTS: A total of 33,539 endoscopic procedures (16,393 gastroscopies, 17,146 colonoscopies) were performed on 27,989 patients using EDNAPS. Intravenous drugs included midazolam (0 - 5 mg), fentanyl (0 - 100 mcg), and propofol (10 - 420 mg). Of 23 METCALLs (18 gastroscopies and 5 colonoscopies), there were 16 with ASA scores of III or higher. Indications for gastroscopy were gastrointestinal (GI) hemorrhage (n = 11; 8 variceal, 3 nonvariceal), dysphagia (n = 5), PEG removal (n = 1), and dyspepsia (n = 1). Fifteen of 22 patients, including all of those who had a colonoscopy, made a full recovery and returned to the ward or were discharged home. In the gastroscopy group, seven were intubated and admitted to Intensive Care, of whom six were emergency cases for gastrointestinal bleeding (n = 4 variceal, n = 2 non variceal) and one in which the indication was PEG removal. Two deaths occurred in the intubated group. CONCLUSIONS: In a tertiary referral center, EDNAPS for low-to-moderate risk (ASA <= 2) patients undergoing gastroscopy and colonoscopy is very safe. Gastroscopy is associated with greater anesthetic risk than colonoscopy and those with high ASA scores needing urgent endoscopy for upper gastrointestinal hemorrhage are at particular risk of cardiorespiratory decompensation. PMID- 26528489 TI - Biophotonic endoscopy: a review of clinical research techniques for optical imaging and sensing of early gastrointestinal cancer. AB - Detection, characterization, and staging constitute the fundamental elements in the endoscopic diagnosis of gastrointestinal diseases, but histology still remains the diagnostic gold standard. New developments in endoscopic techniques may challenge histopathology in the near future. An ideal endoscopic technique should combine a wide-field, "red flag" screening technique with an optical contrast or microscopy method for characterization and staging, all simultaneously available during the procedure. In theory, biophotonic advances have the potential to unite these elements to allow in vivo "optical biopsy." These techniques may ultimately offer the potential to increase the rates of detection of high risk lesions and the ability to target biopsies and resections, and so reduce the need for biopsy, costs, and uncertainty for patients. However, their utility and sensitivity in clinical practice must be evaluated against those of conventional histopathology. This review describes some of the most recent applications of biophotonics in endoscopic optical imaging and metrology, along with their fundamental principles and the clinical experience that has been acquired in their deployment as tools for the endoscopist. Particular emphasis has been placed on translational label-free optical techniques, such as fluorescence spectroscopy, fluorescence lifetime imaging microscopy (FLIM), two photon and multi-photon microscopy, second harmonic generation (SHG) and third harmonic generation (THG) imaging, optical coherence tomography (OCT), diffuse reflectance, Raman spectroscopy, and molecular imaging. PMID- 26528491 TI - Safety in numbers: the case for endoscopist-directed propofol sedation. PMID- 26528492 TI - Ultra-thin caliber endoscopes in daily practice: uses for therapeutic application and beyond on the basis of review of 1028 procedures. AB - BACKGROUND AND STUDY AIMS: Ultra-thin caliber endoscopes (UTCEs) are versatile and applicable in various conditions. However, only limited data exist on the actual daily clinical use of UTCEs. The aim of our study was to determine indications for UTCEs in a large patient cohort. In turn, our 2 main objectives were (1) to evaluate patient comfort and safety and (2) to determine benefits and potential advantages associated with the use of UTCEs in this same cohort. PATIENTS AND METHODS: We performed a retrospective analysis of our prospective database of 1028 procedures with UTCEs in 457 patients. All procedures were carried out in the Department of Gastroenterology and Hepatology, VU University Medical Center, in Amsterdam, the Netherlands, between May 2008 and May 2014. In these procedures, either the Fujinon (Tokyo, Japan) EG-530N UTCE or the Olympus (Tokyo, Japan) GIF N-180 UTCE was used. RESULTS: Mean (standard deviation [SD]) age of patients was 64 (20) years, and most (60 %) of the patients were men. Most (61 %) of the underlying diseases, requiring endoscopic procedures, were found in the esophagus. Of the procedures performed, 91 % were successful, and 82 % were therapeutic. In comparison with regular endoscopes, the most important advantage of the UTCE was the ability to pass a stenosis (37 %), followed by nasogastric feeding tube placement (13 %). Newer and more innovative uses of the UTCE were percutaneous endoscopic gastrostomy (PEG)-jejunal extension placement with endoscope introduction through existing PEG tract, retrograde esophageal introduction through existing PEG tract, inspection of colonic neovagina stenosis, and direct inspection of the common bile duct. CONCLUSIONS: In everyday clinical practice, the UTCE has specific advantages over conventional endoscopes because of its small caliber. The 3 main advantages are (1) introduction of high grade strictures; (2) introduction of fistulas, including PEG fistula; and (3) increased patient comfort. The endoscopist should appreciate these advantages and consider use of the UTCE accordingly. PMID- 26528493 TI - Use of autologous fibrin glue for endoscopic treatment of esophageal lesions. AB - BACKGROUND AND STUDY AIMS: Esophageal leaks are a potentially life-threatening condition. One treatment option is injection therapy with commercially available fibrin glue. We describe herein a method to close esophageal leaks by injecting autologous fibrin glue prepared exclusively with the patient's own blood. PMID- 26528494 TI - Low risk of bacteremia after endoscopic variceal therapy for esophageal varices: a systematic review and meta-analysis. AB - BACKGROUND AND STUDY AIMS: Endoscopic variceal ligation (EVL) and endoscopic variceal sclerotherapy (EVS) are the main therapeutic procedures for the emergency treatment and secondary prophylaxis of esophageal varices in cirrhotics. Post-endoscopic bacteremia has been reported after EVS and EVL, but data on the frequency of bacteremia are conflicting. This study aims to provide incidences of bacteremia after EVS and EVL in different settings through meta analysis. METHODS: Only prospective or randomized studies were included in this meta-analysis. Binomial distribution was used to compute variance for each study. Random effects models were used as the final model for estimating the effect size and 95 % confidence interval. Adjusted effects were obtained using meta regression analysis. RESULTS: Nineteen prospective studies involving 1001 procedures in 587 patients were included in the meta-analysis on the risk of bacteremia after EVS or EVL in cirrhotics with esophageal varices. The frequency of bacteremia after endoscopic variceal therapy was 13 %. The frequency of bacteremia after EVS (17 %) was higher than after EVL (6 %) with no statistically significant difference (P = 0.106). The frequency of bacteremia after elective EVS (14 %) was significantly less than after emergency EVS (22 %) (P < 0.001). The frequency of bacteremia after elective EVL (7.6 %) was not significantly different from after emergency EVL (3.2 %) (P = 0.850). CONCLUSIONS: The incidence of bacteremia is low in patients with cirrhosis and varices after esophageal variceal therapy. These results are consistent with our current guidelines that antibiotic prophylaxis before endoscopic variceal therapy is only necessary for bleeding patients. PMID- 26528495 TI - Circumferential distribution and location of Mallory-Weiss tears: recent trends. AB - BACKGROUND AND STUDY AIMS: Mallory-Weiss tears (MWTs) are not only a common cause of acute nonvariceal gastrointestinal bleeding but also an iatrogenic adverse event related to endoscopic procedures. However, changes in the clinical characteristics and endoscopic features of MWTs over the past decade have not been reported. The aim of this study was to investigate recent trends in the etiology and endoscopic features of MWTs. PATIENTS AND METHODS: We retrospectively reviewed the medical records of patients with a diagnosis of MWT at our university hospital between August 2003 and September 2013. The information regarding etiology, clinical parameters, endoscopic findings, therapeutic interventions, and outcome was reviewed. RESULTS: A total of 190 patients with MWTs were evaluated. More than half (n = 100) of the cases occurred during endoscopic procedures; cases related to alcohol consumption were less frequent (n = 13). MWTs were most frequently located in the lesser curvature of the stomach and right lateral wall (2 - to 4-o'clock position) of the esophagus, irrespective of the cause. The condition of more than 90 % of the patients (n = 179) was improved by conservative or endoscopic treatment, whereas 11 patients (5.8 %) required blood transfusion. Risk factors for blood transfusion were a longer laceration (odds ratio [OR] 2.3) and a location extending from the esophagus to the stomach (OR 5.3). CONCLUSIONS: MWTs were frequently found on the right lateral wall (2 - to 4-o'clock position) of the esophagus aligned with the lesser curvature of the stomach, irrespective of etiology. Longer lacerations extending from the esophagus to the gastric cardia were associated with an elevated risk for bleeding and requirement for blood transfusion. PMID- 26528496 TI - Novel strategy of endoscopic submucosal dissection using an insulation-tipped knife for early gastric cancer: near-side approach method. AB - BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) using insulation-tipped knives (IT knives) to treat gastric lesions located on the greater curvature of the gastric body remains technically challenging because of the associated bleeding, control of which can be difficult and time consuming. To eliminate these difficulties, we developed a novel strategy which we have called the "near-side approach method" and assessed its utility. PATIENTS AND METHODS: We reviewed patients who underwent ESD for solitary early gastric cancer located on the greater curvature of the gastric body from January 2003 to September 2014. The technical results of ESD were compared between the group treated with the novel near-side approach method and the group treated with the conventional method. RESULTS: This study included 238 patients with 238 lesions, 118 of which were removed using the near-side approach method and 120 of which were removed using the conventional method. The median procedure time was 92 minutes for the near-side approach method and 120 minutes for the conventional method. The procedure time was significantly shorter in the near-side approach method arm. Although, the procedure time required by an experienced endoscopist was not significantly different between the two groups (100 vs. 110 minutes), the near side approach group showed significantly shorter procedure time for a less experienced endoscopist (90 vs. 120 minutes). CONCLUSIONS: The near-side approach method appears to require less time to complete gastric ESD than the conventional method using IT knives for technically challenging lesions located on the greater curvature of the gastric body, especially if the procedure is performed by less experienced endoscopists. PMID- 26528497 TI - Endoscopic Submucosal Dissection for Early Gastric Cancer using the Clutch Cutter: a large single-center experience. AB - BACKGROUND AND STUDY AIMS: The Clutch Cutter (CC) was developed to reduce the risk of complications related to endoscopic submucosal dissection (ESD) using knives. The CC is able to grasp and coagulate and/or incise the targeted tissue using electrosurgical current, like a biopsy technique. The aim of this study was to evaluate the efficacy and safety of ESD using the CC (ESD-CC) for early gastric cancer (EGC). PATIENTS AND METHODS: From June 2007 to March 2014, 325 consecutive patients with a diagnosis of EGC were enrolled in this prospective study. They had all satisfied the Japanese gastric cancer treatment guidelines for ESD indication, namely confirmation by preliminary endoscopy, endoscopic ultrasound, and endoscopic biopsies. The CC was used for all steps of ESD (marking, circumferential marginal incision, submucosal dissection, and hemostatic treatment). The therapeutic efficacy and safety were assessed. RESULTS: The en-bloc resection rate was 99.7 % (324/325) and the R0 resection rate was 95.3 % (310/325). The mean operating time was 97.2 minutes. Perforation during ESD-CC occurred in one case (0.3 %), which was managed with conservative medical treatment after endoscopic closure of the perforation. Post-ESD-CC bleeding occurred in 11 cases (3.4 %), which were successfully treated by endoscopic hemostatic treatment. The R0 resection rate was significantly low in tumors > 20 mm (88.9 %), and in the exclusion indication group (73.7 %). Significant differences were seen in the mean operating time, depending upon tumor size, histologic type, location, and indication criteria. CONCLUSIONS: ESD CC is a technically efficient, safe, and easy method for resecting EGC. PMID- 26528498 TI - Enhancing proficiency in performing endoscopic submucosal dissection (ESD) by using a prototype robotic endoscope. AB - BACKGROUND AND STUDY AIMS: One of the challenges in performing endoscopic submucosal dissection (ESD) is the lack of counter traction during submucosal dissection. MASTER (Master and Slave Transluminal Endoscopic Robot) was designed to allow performance of complex endoluminal procedures using two arms with excellent control. This study aimed to compare the performance of ESD between endoscopists and novices using MASTER. METHODS: This is a prospective study comparing the differences in performing ESD using MASTER in an ex vivo porcine stomach model among individuals with or without experience in surgery and endoscopy. Multiple standardized lesions of 20 mm(2) were pre-marked on an ex vivo porcine stomach. Each participant received basic training in controlling MASTER before the ESD procedure. The operative time and size of specimen obtained by each participant were noted. RESULTS: Nine individuals (three ESD expert endoscopists, three ESD non-expert endoscopists, and three non-clinician novices) participated in the experiment. All participants completed the ESD procedure for en bloc resection of standardized lesions using EndoMASTER without perforation. The mean times (mean +/- SD) taken by ESD expert endoscopists, ESD non-expert endoscopists, and novices to complete Robotic ESD were 122 +/- 58 s, 203 +/- 150 s, and 561 +/- 496 s, respectively. There was no statistically significant difference in the mean operative time to complete the ESD between the three groups (P = 0.242). When the performance of the six endoscopists was compared to that of the three novices, the endoscopists took an average of 162 +/- 111 s to complete the ESD, while the non-clinicians required an average of 561 +/- 496 s (P = 0.085). CONCLUSIONS: There was a trend to shorter operative time when comparing endoscopists to non-endoscopists in performing ESD using MASTER. The use of MASTER enabled the novice without endoscopy experience to complete the ESD procedure. PMID- 26528499 TI - A new device to expedite endoscopic submucosal dissection procedures: a randomized animal study of efficacy and safety (with videos). AB - BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a recognized method for the curative treatment of superficial neoplasia, but its use is limited by lengthy procedures and the lack of versatility of existing knives. We developed a prototype ESD device with the ability to work as a needle, hook, or "scythe." This new device was compared to regular ESD knives in a randomized animal study. PATIENTS AND METHODS: Eight pigs underwent two gastric ESD procedures each, similar in size and difficulty, one with a regular ESD device and the other with the new device. The order and location of each ESD, as well as the performing operator, were randomized. Primary judgment criterion was safety of procedures. Overall and submucosal dissection procedure times were measured. Time-to-surface ratios were measured and estimated for ESDs larger than those performed. Histopathology of the resected tissue and remaining stomach was done after each experiment. RESULTS: No complications were observed throughout the study and all resections were completed en-bloc and uneventfully. The submucosal extension of resections was similar with both the standard and the new devices. A comparison of time-consumption between groups did not show statistically significant differences, but a dramatic reduction of procedure duration was observed in some procedures with the new device; based on observed data, a potential time-saving of up to 66 % was anticipated, with a relatively short learning curve. CONCLUSIONS: This new versatile device proved to be as safe as regular ESD knives, and seems likely to help reduce the duration of the procedure. PMID- 26528500 TI - Diagnostic values of dual focus narrow band imaging and probe-based confocal laser endomicroscopy in FAP-related duodenal adenoma. AB - BACKGROUND AND STUDY AIMS: Familial adenomatous polyposis (FAP) is associated with an increased risk of development of periampullary and nonampullary adenoma. Either routine biopsy or endoscopic removal of the lesion is generally required to identify the presence of adenoma. Because the risk of tissue sampling from the ampulla is high and nonampullary polyps are sometimes numerous, resection of all the lesions is time-consuming. This study aimed to evaluate the diagnostic values of duodenal adenoma by dual focus NBI (dNBI) and probe-based confocal endomicroscopy (pCLE) in FAP patients. PATIENTS AND METHODS: The authors conducted a diagnostic study in a single tertiary-care referral center. Surveillance esophagogastroduodenoscopy with dNBI and pCLE was performed on 26 patients with FAP for real-time adenoma diagnosis by two different endoscopists; one used dNBI and the other pCLE. Histology from the matched lesion was used as the gold standard. RESULTS: A total of 55 matched biopsies (25 ampullas, 30 nonampullas) were performed. The sensitivity, specificity, post predictive value (PPV), negative predictive value (NPV), and accuracy of dNBI vs. pCLE from all duodenal lesions were 96.9 % vs. 93.8 %, 78.3 % vs. 81 %, 86.1 % vs. 88.2 %, 94.7 vs. 89.5 %, and 92.4 % vs. 88.6 %, respectively. CONCLUSIONS: For surveillance of periampullary and nonampullary adenoma in patients with FAP, the real-time readings provided a high degree of diagnostic value when histology was used as the gold standard. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT02162173). PMID- 26528501 TI - Surveillance of duodenal adenomas in familial adenomatous polyposis patients: medical objectives and technical requirements. PMID- 26528502 TI - Laparoscopy-assisted transgastric endoscopic retrograde cholangiopancreatography in bariatric Roux-en-Y gastric bypass patients. AB - BACKGROUND: Performing endoscopic retrograde cholangiopancreatography in bariatric patients who underwent Roux-en-Y gastric bypass surgery is challenging due to the long anatomical route required to reach the biliopancreatic limb. AIM: Assessment of the feasibility and performance of laparoscopy-assisted transgastric endoscopic retrograde cholangiopancreatography. METHODS: A retrospective multicenter observational consecutive-patient cohort study of all patients in the period May 2008 to September 2014 with a history of Roux-en-Y gastric bypass who presented with complicated biliary disease and who underwent a laparoscopy-assisted transgastric endoscopic retrograde cholangiopancreatography. The laparoscopy-assisted transgastric endoscopic retrograde cholangiopancreatography procedure was similar in all centers and was performed through a 15 mm or 18 mm trocar that was inserted in the gastric remnant. Cholecystectomy was performed concomitantly when indicated. RESULTS: In total, 23 patients underwent a laparoscopy-assisted transgastric endoscopic retrograde cholangiopancreatography procedure. Two patients required a mini-laparotomy for transgastric access because of a complex surgical history resulting in multiple adhesions. Indications included ascending cholangitis, choledocholithiasis, and biliary pancreatitis. Of the 23 patients, 13 underwent concomitant cholecystectomy. All patients successfully underwent biliary cannulation and sphincterotomy. No endoscopic procedure-related complications (i. e. bleeding, pancreatitis or retroperitoneal perforation) occurred. Mean hospital stay was 2.8 days (range 2 - 4). CONCLUSIONS: Transgastric endoscopic retrograde cholangiopancreatography is a feasible approach in the treatment of pancreaticobiliary disease in Roux-en-Y gastric bypass patients, without major complications in our series and allows endoscopic treatment and cholecystectomy to be performed consecutively in a single procedure. In Roux-en-Y gastric bypass patients without a history of prior cholecystectomy presenting with complicated gallstone disease, combining cholecystectomy and transgastric endoscopic retrograde cholangiopancreatography as a first-line approach may be a valid treatment strategy. PMID- 26528503 TI - Comparison between loop-tip guidewire-assisted and conventional endoscopic cannulation in high risk patients. AB - BACKGROUND: The guidewire biliary cannulation (GWC) technique may increase the cannulation rate and decrease the risk for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. The aim of our multicenter prospective randomized controlled trial was to determine if the use of an atraumatic loop-tip guidewire reduces the rate of post-ERCP pancreatitis (PEP) compared with the standard contrast-assisted cannulation (CC) technique. METHODS: From June 2012 to December 2013, a total of 320 patients who had a naive papilla and were referred for ERCP were randomly assigned to the GWC group (n = 160) or the CC group (n = 160). GWC or CC was randomly used. In cases of failed cannulation in both arms after crossover, biliary access was attempted with alternative techniques (e. g., dual-wire technique, pancreatic duct stenting, precut). RESULTS: The biliary cannulation rates were 81 % in the GWC group and 73 % in the CC group (P = n. s.). Following crossover, cannulation was successful in 8 % and 11 % of patients in the GWC and CC groups, respectively. With use of an alternative technique, the cannulation rates were 98 % in the GWC group and 96 % in the CC group, respectively. The rates of PEP were 5 % in the GWC group and 12 % in the CC group (P = 0.027). The post-interventional complication rates did not differ between the two groups. CONCLUSION: GWC with the new wire guide is associated with a lower rate of PEP in comparison with the CC technique. Clinical trial reference number: NCT01771419. PMID- 26528504 TI - Comparison of EUS-guided tissue acquisition using two different 19-gauge core biopsy needles: a multicenter, prospective, randomized, and blinded study. AB - BACKGROUND AND STUDY AIMS: The optimal core biopsy needle for endoscopic ultrasound (EUS) is unknown. The principle aim of this study is to compare outcomes of EUS-fine-needle biopsy (EUS-FNB) with a new 19-gauge EUS histology needle (ProCore, Cook Medical Inc., Winston-Salem, North Carolina, United States) to a conventional 19-gauge Tru-Cut biopsy (EUS-TCB) needle (19G, Quick-Core, Cook Medical Inc.). PATIENTS AND METHODS: Patients referred for EUS who require possible histologic biopsy were prospectively randomized to EUS-FNB or EUS-TCB. With the initial needle, <= 3 biopsies were obtained until either technical failure or an adequate core was obtained. Patients with suspected inadequate biopsies were crossed over to the other needle and similarly <= 3 passes were obtained until adequate cores or technical failure occurred. Technical success, diagnostic histology, accuracy and complication rates were evaluated. RESULTS: Eighty-five patients (mean 58 years; 43 male) were randomized to FNB (n = 44) and TCB (n = 41) with seven patients excluded. Procedure indication, biopsy site, mass size, number of passes, puncture site, overall technical success and adverse events were similar between the two groups. FNB specimens had a higher prevalence of diagnostic histology (85 % vs. 57 %; P = 0.006), accuracy (88 % vs. 62 %; P = 0.02), mean total length (19.4 vs. 4.3 mm; P = 0.001), mean complete portal triads from liver biopsies (10.4 vs. 1.3; P = 0.0004) and required fewer crossover biopsies compared to those of TCB (2 % vs. 65 %; P = 0.0001). Overall technical success and complication rates were comparable. CONCLUSION: EUS-FNB using a 19-gauge FNB needle is superior to 19-gauge EUS-TCB needle. PMID- 26528505 TI - Managing incidental pancreatic cystic neoplasms with integrated molecular pathology is a cost-effective strategy. AB - BACKGROUND AND STUDY AIMS: Current guidelines recommend using endoscopic ultrasound (EUS), carcinoembryonic antigen (CEA) testing and cytology to manage incidental pancreatic cystic neoplasms (PCN); however, studies suggest a strategy including integrated molecular pathology (IMP) of cyst fluid may further aid in predicting risk of malignancy. Here, we evaluate several strategies for diagnosing and managing asymptomatic PCN using healthcare economic modeling. PATIENTS AND METHODS: A third-party-payer perspective Markov decision model examined four management strategies in a hypothetical cohort of 1000 asymptomatic patients incidentally found to have a 3 cm solitary pancreatic cystic lesion. Strategy I used cross-sectional imaging, recommended surgery only if symptoms or risk factors emerged. Strategy II considered patients for resection without initial EUS. Strategy III (EUS + CEA + Cytology) referred only those with mucinous cysts (CEA > 192 ng/mL) for resection. Strategy IV implemented IMP; a commercially available panel provided a "Benign," "Mucinous," or "Aggressive" classification based on the level of mutational change in cyst fluid. "Benign" and "Mucinous" patients were followed with surveillance; "Aggressive" patients were referred for resection. Quality-adjusted life-years (QALY), relative risk with 95 %CI, Number Needed to Treat (NNT), and incremental cost-effectiveness ratios were calculated. RESULTS: Strategy IV provided the greatest increase in QALY at nearly identical cost to the cheapest approach, Strategy I. Relative risk of malignancy compared to the current standard of care and nearest competing strategy, Strategy III, was 0.18 (95 %CI 0.06 - 0.53) with an NNT of 56 (95 %CI 34 - 120). CONCLUSIONS: Use of IMP was the most cost-effective strategy, supporting its routine clinical use. PMID- 26528506 TI - Portable inhaled methoxyflurane is feasible and safe for colonoscopy in subjects with morbid obesity and/or obstructive sleep apnea. AB - BACKGROUND AND STUDY AIMS: Colonoscopy with inhaled methoxyflurane (Penthrox) is well tolerated in unselected subjects and is not associated with respiratory depression. The aim of this prospective study was to compare the feasibility, safety, and post-procedural outcomes of portable methoxyflurane used as an analgesic agent during colonoscopy with those of anesthesia-assisted deep sedation (AADS) in subjects with morbid obesity and/or obstructive sleep apnea (OSA). PATIENTS AND METHODS: The outcomes of 140 patients with morbid obesity/OSA who underwent colonoscopy with either Penthrox inhalation (n = 85; 46 men, 39 women; mean age 57.2 +/- 1.1 years) or AADS (n = 55; 27 men, 28 women; mean age, 54.9 +/- 1.1 years) were prospectively assessed. RESULTS: All Penthrox-assisted colonoscopies were successful, without any requirement for additional intravenous sedation. Compared with AADS, Penthrox was associated with a shorter total procedural time (24 +/- 1 vs. 52 +/- 1 minutes, P < 0.001), a lower incidence of hypotension (3 /85 vs. 23 /55, P < 0.001), and a lower incidence of respiratory desaturation (0 /85 vs. 14 /55, P < 0.001). The patients in the Penthrox group recovered more rapidly and were discharged much earlier than those in the AADS group (27 +/- 2 vs. 97 +/- 5 minutes, P < 0.0001). Of those who underwent colonoscopy with Penthrox, 90 % were willing to receive Penthrox again for colonoscopy. More importantly, of the patients who underwent colonoscopy with Penthrox and had had AADS for previous colonoscopy, 82 % (28 /34) preferred to receive Penthrox for future colonoscopies. Penthrox-assisted colonoscopy cost significantly less than colonoscopy with AADS ($ 332 vs. $ 725, P < 0.001), with a cost saving of approximately $ 400 for each additional complication avoided. CONCLUSIONS: Compared with AADS, Penthrox is highly feasible and safe in patients with morbid obesity/OSA undergoing colonoscopy and is associated with fewer cardiorespiratory complications. Because of the advantages of this approach in regard to procedural time, recovery time, and cost benefit in comparison with AADS, further evaluation in a randomized trial is warranted. PMID- 26528507 TI - Colonoscopy performance is stable during the course of an extended three-session working day. AB - BACKGROUND: Three-session days were introduced in our endoscopy unit to accommodate the increased demand resulting from the introduction of the National Health Service Bowel Cancer Screening Programme (BCSP). Cecal intubation rate (CIR) and adenoma detection rate (ADR) may decline with time during a standard working day, but data are lacking for an extended three-session day. We assessed colonoscopy performance in an extended three-session day. METHODS: Colonoscopies performed during the year 2011 were retrospectively analyzed. The CIR and ADR were analyzed according to the time of day when procedures were done: morning (AM), afternoon (PM), or evening (EVE). Because of an expected higher incidence of adenomas in the BCSP patients, ADR was analyzed according to indication (BCSP or non-BCSP). RESULTS: Of the 2574 colonoscopies, 1328 (51.7 %) were in male patients and 1239 (48.3 %) in female patients with a median age of 63 years (interquartile range [IQR], 51 - 70). Of the 2574 colonoscopies, 1091 (42.4 %) were performed in AM lists, 994 (38.6 %) in PM lists, and 489 (19 %) in EVE lists. Time of day did not affect the CIRs for the AM, PM, and EVE lists (90.5 %, 90.1 %, and 89.9 %, respectively; chi (2) [2, N = 2540] = 0.15, P = 0.927). The CIR was reduced in female patients and those with poor bowel preparation (P < 0.05). After exclusion of the BCSP patients, the ADR was lower in the EVE lists than in the AM and PM lists on univariate analysis, but on multivariate analysis, this difference was not significant (P > 0.05). The ADR was significantly higher in patients older than 60 years and in men (P < 0.001). Queue position did not independently influence the CIR or ADR. CONCLUSIONS: Colonoscopy quality does not appear to depend on time of day or queue position in an extended three-session day. PMID- 26528508 TI - Clean Colon Software Program (CCSP), Proposal of a standardized Method to quantify Colon Cleansing During Colonoscopy: Preliminary Results. AB - BACKGROUND AND STUDY AIMS: Neoplastic lesions can be missed during colonoscopy, especially when cleansing is inadequate. Bowel preparation scales have significant limitations and no objective and standardized method currently exists to establish colon cleanliness during colonoscopy. The aims of our study are to create a software algorithm that is able to analyze bowel cleansing during colonoscopies and to compare it to a validate bowel preparation scale. PATIENTS AND METHODS: A software application (the Clean Colon Software Program, CCSP) was developed. Fifty colonoscopies were carried out and video-recorded. Each video was divided into 3 segments: cecum-hepatic flexure (1st Segment), hepatic flexure descending colon (2nd Segment) and rectosigmoid segment (3rd Segment). Each segment was recorded twice, both before and after careful cleansing of the intestinal wall. A score from 0 (dirty) to 3 (clean) was then assigned by CCSP. All the videos were also viewed by four endoscopists and colon cleansing was established using the Boston Bowel Preparation Scale. Interclass correlation coefficient was then calculated between the endoscopists and the software. RESULTS: The cleansing score of the prelavage colonoscopies was 1.56 +/- 0.52 and the postlavage one was 2,08 +/- 0,59 (P < 0.001) showing an approximate 33.3 % improvement in cleansing after lavage. Right colon segment prelavage (0.99 +/- 0.69) was dirtier than left colon segment prelavage (2.07 +/- 0.71). The overall interobserver agreement between the average cleansing score for the 4 endoscopists and the software pre-cleansing was 0.87 (95 % CI, 0.84 - 0.90) and post-cleansing was 0.86 (95 % CI, 0.83 - 0.89). CONCLUSIONS: The software is able to discriminate clean from non-clean colon tracts with high significance and is comparable to endoscopist evaluation. PMID- 26528509 TI - Cold snare piecemeal resection of colonic and duodenal polyps >=1 cm. AB - BACKGROUND: Endoscopic removal of duodenal and colorectal adenomas is currently considered to be the standard of care for prevention of adenocarcinoma. The use of cautery carries a risk of delayed bleeding, post-polypectomy syndrome, and perforation. We examined the safety and feasibility of removing colonic and duodenal polyps >= 1 cm using a piecemeal cold snare polypectomy technique. PATIENTS: The study included 15 patients with duodenal polyps >= 1 cm and 15 patients with colonic polyps >= 1 cm. MAIN OUTCOME MEASUREMENTS: Bleeding, perforation, abdominal pain, or hospitalization occurring within 2 weeks of polypectomy. RESULTS: Between 24 August 2011 and 29 April 2013, 15 patients had removal of duodenal polyps >= 1 cm. Mean patient age was 64 years and 9/15 patients were male. The mean polyp size was 24 mm (10 - 60 mm). All polyps were removed with a cold snare and some required cold biopsy forceps. One patient required hospitalization for gastrointestinal blood loss 7 days post-polypectomy; this patient was using Coumadin. Between 27 February 2012 and 30 May 2013, 15 patients underwent resection of a >= 1 cm colonic polyp. Mean patient age was 68 years and 9/15 were male. The mean polyp size was 20 mm (10 - 45 mm). All polyps were primarily removed with a cold snare. None of the patients required hemostatic clips for control of immediate bleeding. One patient presented to the emergency department with abdominal pain 1 day after initial endoscopy. CT scan showed no abnormalities and the patient was discharged. CONCLUSIONS: Cold snare polypectomy for large duodenal and colonic polyps is technically feasible and may have a favorable safety profile compared to standard electrocautery-based endoscopic resection. Comparative trials are required to determine the relative safety and efficacy of cold snare techniques for complete and durable resection of large polyps compared to standard hot snare methods. PMID- 26528510 TI - Expanding the field of cold snare polypectomy. PMID- 26528511 TI - Use of endoscopic distal attachment cap to enhance image stabilization in probe based confocal laser endomicroscopy in colorectal lesions. AB - BACKGROUND AND STUDY AIMS: Colorectal cancer can be prevented through the use of colonoscopy with polypectomy. Most colon polyps are benign or low grade adenomas. However, currently all lesions need histopathologic analysis, which increases diagnostic costs and delays the final diagnosis. Confocal laser endomicroscopy (CLE) is a new technology that enables real-time endomicroscopy. However, there are challenges to maintaining a stable image with currently available systems. We conducted a small study to obtain a preliminary assessment of whether the use of an endoscopic distal attachment cap may enhance image quality of CLE in comparison with images obtained with free-hand acquisition. PATIENTS AND METHODS: Forty outpatients underwent colonoscopy for evaluation of colon polyps in a single academic medical center. Patients were assigned randomly to 1 of 2 study arms on the basis of whether an endoscopic distal attachment cap was used (n = 21, Cap Used) or not used (n = 19, No Cap) in the procedure. The quality of confocal images and probe stabilization was summarized. RESULTS: A total of 81 polyps were identified. The proportion of polyps with images of high quality was 74 % (28/38) in the Cap Used group and 79 % (30/38) in the No Cap arm. Image stability was also similar with and without a cap. Diagnostic accuracy was estimated to be slightly higher in the Cap Used group for probe-based confocal laser endomicroscopy (pCLE; 78 % vs 70 %). This was also true for white-light and narrow-band imaging. CONCLUSIONS: This preliminary study did not yield any evidence to support that the use of an endoscopic distal attachment cap improves the quality of images obtained during CLE. PMID- 26528512 TI - Risk factors for early rebleeding after endoscopic band ligation for colonic diverticular hemorrhage. AB - BACKGROUND AND STUDY AIMS: Endoscopic band ligation (EBL) has been used for hemostasis of colonic diverticular hemorrhage. However, early rebleeding (< 30 days after EBL) has been reported in some cases. The aim of this study was to elucidate risk factors for early rebleeding after EBL in treatment of colonic diverticular hemorrhage. PATIENTS AND METHODS: A total of 101 patients with definite diverticular hemorrhage treated using EBL from June 2009 to October 2014 were included in the retrospective cohort study and divided into rebleeding and non-rebleeding groups, depending on the presence or absence of early rebleeding. Patients' ages, comorbid diseases, stigmata of recent hemorrhage (SRH) [active bleeding (AB), non-bleeding visible vessel (NBVV), or adherent clot (AC)], locations of bleeding diverticula, and eversions of the diverticula after EBL were retrospectively evaluated in each group. RESULTS: Early rebleeding occurred in 15 cases. The median time (range) of early rebleeding occurrence was 5 days (range, 2 h to 26 days). Early rebleeding could be managed conservatively and/or endoscopically, except in one case in which surgery was done. Multivariate analysis revealed that age under 50 (adjusted OR, 8.7; 95 % CI 1.6 - 52.5; P = 0.014) and AB (adjusted OR, 4.21; 95 % CI 1.15 - 18.1; P = 0.03) were shown to be significant risk factors. The right side of the colon carried less risk than did the left side (adjusted OR, 0.21; 95 % CI 0.04 - 0.84; P = 0.028). CONCLUSIONS: Younger age, AB of SRH, and leftsided lesions were identified as the risk factors for early rebleeding after EBL in the treatment of colonic diverticular hemorrhage. PMID- 26528513 TI - Comparison of long-term outcomes between endoscopic band ligation and endoscopic clipping for colonic diverticular hemorrhage. AB - BACKGROUND AND STUDY AIMS: Long-term outcomes of endoscopic band ligation (EBL) for colonic diverticular hemorrhage have not been reported to date. The aim of this study was to determine the long-term outcomes of EBL and to retrospectively compare them with those of endoscopic clipping (EC) in the treatment of colonic diverticular hemorrhage. PATIENTS AND METHODS: The study included patients with colonic diverticular hemorrhage who were treated with EBL or EC from January 2004 to November 2014 and followed up more than 1 year (61 patients in the EBL group and 39 patients in the EC group). Time-to-event analysis of rebleeding was performed with the Kaplan-Meier method. A follow-up colonoscopy was performed to confirm the disappearance of the banded diverticula in the EBL group. RESULTS: Rebleeding occurred in 21 patients in the EBL group and in 26 patients in the EC group. The cumulative incidence of rebleeding at 1, 12, 24, and 36 months after first treatments was 14 %, 23 %, 26 %, and 41 % in the EBL group and 38 %, 49 %, 59 %, and 68 % in the EC group, respectively. Time-to-event analysis revealed statistically significant data (Log-rank test, P = 0.0036). Scar formation with fold convergence at the previously banded site was observed in 11 of 24 patients who underwent follow-up colonoscopy (46 %). However, late rebleeding (rebleeding more than 30 days after EBL) occurred in five of these 11 cases. CONCLUSIONS: EBL was superior to EC in the treatment of colonic diverticular hemorrhage. However, the risk of rebleeding was not avoided even after the diverticula had been resolved using EBL. PMID- 26528514 TI - Is there an optimal technique to treat the bleeding diverticulum? Is diverticular bleeding a recurrent disease? PMID- 26528515 TI - High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study. PMID- 26528516 TI - Author's reply: To PMID 25179885. PMID- 26528517 TI - Author's reply. PMID- 26528518 TI - Author's reply. PMID- 26528519 TI - Author's reply. PMID- 26528520 TI - Fall Backward OR Move Forward With Full Practice Authority. PMID- 26528521 TI - Reflections: Neurology and the Humanities. The key. PMID- 26528522 TI - Placebo effect of medication cost in Parkinson disease: a randomized double-blind study. PMID- 26528524 TI - Lead insulation failure, a serious complication: risk factors and management. PMID- 26528523 TI - Author response. PMID- 26528525 TI - Release kinetics of circulating miRNA-208a in the early phase of myocardial infarction. AB - BACKGROUND: The biochemical confirmation of myocardial infarction is based on cardiac troponin (cTnI or cTnT) determination. Recent scientific results suggested that microRNAs (miRNAs) might become a new biomarker of tissue injury. AIM: To evaluate the release kinetics of circulating heart-specific miRNA-208a and also to test the hypothesis that miRNA-208a can serve as an accessible, diagnostically sensitive plasma biomarker of ST-elevation acute myocardial infarction (STEMI). METHODS: Nineteen STEMI patients (four women and 15 men, aged 44-85 years), 12 patients with stable coronary artery disease (CAD), and eight patients with a negative observation of CAD as a control group were studied. Blood samples were collected on admission and at three, six, 12, 24, and 48 h afterwards; in the CAD and control group blood samples were taken only once. Plasma levels of miRNA-208a determined by real-time polymerase chain reaction and their relative fold changes were calculated. cTnI and creatinine kinase (CK)-MB mass were also measured in the patients' serum samples. RESULTS: miRNA-208a was increased in STEMI patients at the time of admission and nearly undetectable in CAD patients and controls. The peak of miRNA-208a was observed at 3 h after reperfusion (p < 0.001). The traditional biomarkers (cTnI and CK-MBmass), which increase later in comparison to miRNA-208a reaching the maximum concentrations 6 h after reperfusion, were observed. Circulating miRNA-208a levels strongly correlated with cTnI and CK-MBmass released from the infarcted area. CONCLUSIONS: These results demonstrate that plasma miRNA-208a is an interesting and promising candidate for a new biomarker released early after onset of myocardial infarction. PMID- 26528526 TI - Histological assessment of myocardium in lethal ethanol intoxication. AB - BACKGROUND: The pathological mechanism of sudden death in healthy persons following incidental ethanol intoxication has not yet been fully elucidated and might be underlain by cardiogenic causes. AIM: Histological assessment of the myocardium in lethal ethanol intoxication. The analysis was based on a histological assessment of specimens of the myocardium obtained from the hearts of 30 deceased males within the age range 29-45 years. METHODS: The material for the study was taken from the myocardium of the anterior wall of the left ventricle and interventricular septum of the heart. The fixation material was first examined according to the standard histological procedure and subsequently subjected to a morphometric examination, which assessed the number of cardiomyocytes, their area, circumference, and circular deviation. RESULTS: The examination showed an increase in the area and circumference of cardiomyocytes, as well as fragmentation and segmentation of cardiomyocytes with a significant enlargement of cell nuclei. Additionally, it revealed the presence of lymphocytic cells in several cases.Conclusions: The obtained findings indicate a harmful influence of alcohol on the myocardium. PMID- 26528527 TI - Three-dimensional transoesophageal echocardiography as the ultimate diagnostic tool in a case of unintentional left ventricular pacing. PMID- 26528528 TI - Combined total aortic arch replacement associated with aortic valve replacement and subtotal thyroidectomy. PMID- 26528529 TI - Renal artery atherosclerotic plaque ruptures visualised with intravascular ultrasound. PMID- 26528531 TI - Inhibition of Bacillus cereus Growth and Toxin Production by Bacillus amyloliquefaciens RD7-7 in Fermented Soybean Products. AB - Bacillus cereus is a gram-positive, rod-shaped, spore-forming bacterium that has been isolated from contaminated fermented soybean food products and from the environment. B. cereus produces diarrheal and emetic toxins and has caused many outbreaks of foodborne diseases. In this study, we investigated whether B. amyloliquefaciens RD7-7, isolated from rice doenjang (Korean fermented soybean paste), a traditional Korean fermented soybean food, shows antimicrobial activity against B. cereus and regulates its toxin gene expression. B. amyloliquefaciens RD7-7 exhibited strong antibacterial activity against B. cereus and inhibited the expression of B. cereus toxin-related genes (groEL, nheA, nheC, and entFM). We also found that addition of water extracts of soybean and buckwheat soksungjang (Korean fermented soybean paste made in a short time) fermented with B. amyloliquefaciens RD7-7 significantly reduced the growth and toxin expression of B. cereus. These results indicate that B. amyloliquefaciens RD7-7 could be used to control B. cereus growth and toxin production in the fermented soybean food industry. Our findings also provide a basis for the development of candidate biological control agents against B. cereus to improve the safety of fermented soybean food products. PMID- 26528530 TI - Assessing Nephrological Competence among Geriatricians: A Proof of Concept Internet Survey. AB - Chronic kidney disease (CKD) is highly prevalent in the elderly and negatively impacts survival and health status. Thus, nephrological competence is mandatory for a skilled geriatrician. The present study aimed to assess nephrological competence in a sample of geriatricians recruited through a web survey. To this aim, a 12-items questionnaire was produced by an expert panel of nephrologists and geriatricians and was available online for members of the Italian Society of Gerontology and Geriatrics (SIGG). Two-hundred-eighty-seven geriatricians volunteered to fill in the questionnaire. The majority of them indirectly estimated the glomerular filtration rate (GFR) using mainly the Cockroft-Gault (C G) formula. Selected nephrological exams, such as urinary Na and serum D-vitamin measurements, did not qualify as routine exams although the majority of geriatricians supplemented their patients with fat-soluble secosteroids. Ten percent of geriatricians asked for nephrological consultation only for stage 5 CKD patients and 30,9% only for stage 4 or 5. Erythropoietin supplementation was common practice for the majority of geriatricians, while only one third of them systematically used a procedure intended to prevent the contrast induced nephropathy (CIN). Finally, an alleged 50% adherence to the international guidelines for the management of CKD patients emerged from the questionnaire. Overall, results from this survey strongly recommend promoting nephrological education among geriatricians. Didactic standards for in training geriatricians need to be updated and the cooperation between geriatrics and nephrological societies promoted. PMID- 26528532 TI - Purification and Characterization of a New kappa-Carrageenase from the Marine Bacterium Vibrio sp. NJ-2. AB - The carrageenan-degrading marine bacterium Vibrio sp. strain NJ-2 was isolated from rotten red algae, and kappa-carrageenase with high activity was purified from the culture supernatant. The purified enzyme with molecular mass of 33 kDa showed the maximal activity of 937 U/mg at 40 degrees C and pH 8.0. It maintained 80% of total activity below 40 degrees C and between pH 6.0 and 10.0. The kinetics experiment showed the Km and Vmax values were 2.54 mg/ml and 138.89 mmol/min/mg, respectively. The thin layer chromatography and ESI-MS analysis of hydrolysates indicated that the enzyme can endolytically depolymerize the kappa carrageenan into oligosaccharides with degrees of depolymerization of 2-8. Owing to its high activity, it could be a valuable tool to produce kappa-carrageenan oligosaccharides with various biological activities. PMID- 26528533 TI - Identification of a Bacteria-Specific Binding Protein from the Sequenced Bacterial Genome. AB - Novel and specific recognition elements are of central importance in the development of a pathogen detection method. Here, we describe a simple method for identifying the cell-wall binding domain (CBD) from a sequenced bacterial genome employing homology search for phage lysin genes. A putative CBD (CPF369_CBD) was identified from a genome of Clostridium perfringens type strain ATCC 13124, and its function was studied with the CBDGFP fusion protein recombinantly expressed in Escherichia coli. Fluorescence microscopy showed the specific binding of the fusion protein to C. perfringens cells, which demonstrates the potential of this method for the identification of novel bioprobes for specific detection of pathogenic bacteria. PMID- 26528534 TI - Process Performance and Bacterial Community Structure Under Increasing Influent Disturbances in a Membrane-Aerated Biofilm Reactor. AB - The membrane-aerated biofilm reactor (MABR) is a promising municipal wastewater treatment process. In this study, two cross-flow MABRs were constructed to explore the carbon and nitrogen removal performance and bacterial succession, along with changes of influent loading shock comprising flow velocity, COD, and NH4-N concentrations. Redundancy analysis revealed that the function of high flow velocity was mainly embodied in facilitating contaminants diffusion and biosorption rather than the success of overall bacterial populations (p > 0.05). In contrast, the influent NH4-N concentration contributed most to the variance of reactor efficiency and community structure (p < 0.05). Pyrosequencing results showed that Anaerolineae, and Beta- and Alphaproteobacteria were the dominant groups in biofilms for COD and NH4-N removal. Among the identified genera, Nitrosomonas and Nitrospira were the main nitrifiers, and Hyphomicrobium, Hydrogenophaga, and Rhodobacter were the key denitrifiers. Meanwhile, principal component analysis indicated that bacterial shift in MABR was probably the combination of stochastic and deterministic processes. PMID- 26528535 TI - High Concentration of Red Clay as an Alternative for Antibiotics in Aquaculture. AB - The use of antibiotics in aquaculture raises environmental and food safety concerns because chronic exposure of an aquatic ecosystem to antibiotics can result in the spread of antibiotic resistance, bioaccumulation of antibiotics in the organisms, and transfer of antibiotics to humans. In an attempt to overcome these problems, high-concentration red clay was applied as an alternative antibiotic against the following common fish pathogens: Aeromonas salmonicida, Vibrio alginolyticus, and Streptococcus equinus. The growth of A. salmonicida and V. alginolyticus was retarded by red clay, whereas that of S. equinus was promoted. Phase contrast and scanning electron microscopy analyses confirmed the attachment of red clay on cell surfaces, resulting in rapid gravitational removal and cell surface damage in both A. salmonicida and V. alginolyticus, but not in S. equinus. Different cell wall properties of grampositive species may explain the unharmed cell surface of S. equinus. Significant levels of oxidative stress were generated in only the former two species, whereas significant changes in membrane permeability were found only in S. equinus, probably because of its physiological adaptation. The bacterial communities in water samples from Oncorhynchus mykiss aquacultures supplemented with red clay showed similar structure and diversity as those from oxytetracycline-treated water. Taken together, the antibiotic effects of high concentrations of red clay in aquaculture can be attributed to gravitational removal, cell surface damage, and oxidative stress production, and suggest that red clay may be used as an alternative for antibiotics in aquaculture. PMID- 26528536 TI - Regulation of the Lactobacillus Strains on HMGCoA Reductase Gene Transcription in Human HepG2 Cells via Nuclear Factor-kappaB. AB - Lactic acid bacteria have been identified to be effective in reducing cholesterol levels. Most of the mechanistic studies were focused on the bile salt deconjugation ability of bile salt hydrolase in lactic acid bacteria. However, the mechanism by which Lactobacillus decreases cholesterol levels has not been thoroughly studied in intact primate cells. 3-Hydroxy-3- methyl-glutaryl-coenzyme A reductase (HMGCR) is the vital enzyme in cholesterol synthesis. To confirm the effect of probiotic Lactobacillus strains on HMGCR level, in the present study, human hepatoma HepG2 cells were treated with Lactobacillus strains, and then the HMGCR level was illustrated by luciferase reporter assay and RT-PCR. The results showed that the level of HMGCR was suppressed after being treated with the live Lactobacillus strains. These works might set a foundation for the following study of the antihyperlipidemic effects of L. acidophilus, and contribute to the development of functional foods or drugs that benefit patients suffering from hyperlipidemia diseases. PMID- 26528537 TI - Physiological Effects of GLT1 Modulation in Saccharomyces cerevisiae Strains Growing on Different Nitrogen Sources. AB - Saccharomyces cerevisiae is one of the most employed cell factories for the production of bioproducts. Although monomeric hexose sugars constitute the preferential carbon source, this yeast can grow on a wide variety of nitrogen sources that are catabolized through central nitrogen metabolism (CNM). To evaluate the effects of internal perturbations on nitrogen utilization, we characterized strains deleted or overexpressed in GLT1, encoding for one of the key enzymes of the CNM node, the glutamate synthase. These strains, together with the parental strain as control, have been cultivated in minimal medium formulated with ammonium sulfate, glutamate, or glutamine as nitrogen source. Growth kinetics, together with the determination of protein content, viability, and reactive oxygen species (ROS) accumulation at the single cell level, revealed that GLT1 modulations do not significantly influence the cellular physiology, whereas the nitrogen source does. As important exceptions, GLT1 deletion negatively affected the scavenging activity of glutamate against ROS accumulation, when cells were treated with H2O2, whereas Glt1p overproduction led to lower viability in glutamine medium. Overall, this confirms the robustness of the CNM node against internal perturbations, but, at the same time, highlights its plasticity in respect to the environment. Considering that side-stream protein-rich waste materials are emerging as substrates to be used in an integrated biorefinery, these results underline the importance of preliminarily evaluating the best nitrogen source not only for media formulation, but also for the overall economics of the process. PMID- 26528538 TI - Characterization of a Soil Metagenome-Derived Gene Encoding Wax Ester Synthase. AB - A soil metagenome contains the genomes of all microbes included in a soil sample, including those that cannot be cultured. In this study, soil metagenome libraries were searched for microbial genes exhibiting lipolytic activity and those involved in potential lipid metabolism that could yield valuable products in microorganisms. One of the subclones derived from the original fosmid clone, pELP120, was selected for further analysis. A subclone spanning a 3.3 kb DNA fragment was found to encode for lipase/esterase and contained an additional partial open reading frame encoding a wax ester synthase (WES) motif. Consequently, both pELP120 and the full length of the gene potentially encoding WES were sequenced. To determine if the wes gene encoded a functioning WES protein that produced wax esters, gas chromatography-mass spectroscopy was conducted using ethyl acetate extract from an Escherichia coli strain that expressed the wes gene and was grown with hexadecanol. The ethyl acetate extract from this E. coli strain did indeed produce wax ester compounds of various carbon chain lengths. DNA sequence analysis of the full-length gene revealed that the gene cluster may be derived from a member of Proteobacteria, whereas the clone does not contain any clear phylogenetic markers. These results suggest that the wes gene discovered in this study encodes a functional protein in E. coli and produces wax esters through a heterologous expression system. PMID- 26528539 TI - pCO2 Reveals Arteriovenous Fistula Recirculation in Bicarbonate Hemodialysis (RecirCO2lation Test). AB - We propose arterial pCO2 as test to discover vascular access recirculation (VAR) in bicarbonate hemodialysis (HD). We selected 30 HD patients with a ascertained well-functioning arteriovenous fistula (Control). In these patients, we artificially created VAR through the reversion of HD lines (Reversed). Results of the arterial gas analysis were collected at the start of HD (baseline) and after 5 min. At baseline, no differences of pH, pCO2 and HCO3 were found between the 2 groups. At 5 min, pCO2 increased from 38.1 +/- 3.3 to 47.2 +/- 6.3 mm Hg (p < 0.0001) in Reversed, whereas no increase was found in Control (p = 0.052). Areas under curve of pCO2-increase was 0.96 (0.91-1.00) and pCO2 at 5 min 0.92 (0.85 0.98). pCO2-increase >4.5 mm Hg showed sensitivity 86.7% and specificity 100% with positive predictive value (PPV) 100% and negative predictive value (NPV) 89%. A pCO2 value above 43 mm Hg at 5 min showed sensitivity 80%, specificity 90%, PPV 89%, NPV 82%. pCO2 increase >4.5 mm Hg and/or pCO2 at 5 min >43 mm Hg may accurately detect VAR. PMID- 26528540 TI - Identification of Pathways Mediating Growth Differentiation Factor5-Induced Tenogenic Differentiation in Human Bone Marrow Stromal Cells. AB - To date, the molecular signalling mechanisms which regulate growth factors induced MSCs tenogenic differentiation remain largely unknown. Therefore, a study to determine the global gene expression profile of tenogenic differentiation in human bone marrow stromal cells (hMSCs) using growth differentiation factor 5 (GDF5) was conducted. Microarray analyses were conducted on hMSCs cultures supplemented with 100 ng/ml of GDF5 and compared to undifferentiated hMSCs and adult tenocytes. Results of QuantiGene(r) Plex assay support the use and interpretation of the inferred gene expression profiles and pathways information. From the 27,216 genes assessed, 873 genes (3.21% of the overall human transcriptome) were significantly altered during the tenogenic differentiation process (corrected p<0.05). The genes identified as potentially associated with tenogenic differentiation were ARHGAP29, CCL2, integrin alpha 8 and neurofilament medium polypeptides. These genes, were mainly associated with cytoskeleton reorganization (stress fibers formation) signaling. Pathway analysis demonstrated the potential molecular pathways involved in tenogenic differentiation were: cytoskeleton reorganization related i.e. keratin filament signaling and activin A signaling; cell adhesion related i.e. chemokine and adhesion signaling; and extracellular matrix related i.e. arachidonic acid production signaling. Further investigation using atomic force microscopy and confocal laser scanning microscopy demonstrated apparent cytoskeleton reorganization in GDF5-induced hMSCs suggesting that cytoskeleton reorganization signaling is an important event involved in tenogenic differentiation. Besides, a reduced nucleostemin expression observed suggested a lower cell proliferation rate in hMSCs undergoing tenogenic differentiation. Understanding and elucidating the tenogenic differentiation signalling pathways are important for future optimization of tenogenic hMSCs for functional tendon cell-based therapy and tissue engineering. PMID- 26528541 TI - Extrapolation-Based References Improve Motion and Eddy-Current Correction of High B-Value DWI Data: Application in Parkinson's Disease Dementia. AB - PURPOSE: Conventional motion and eddy-current correction, where each diffusion weighted volume is registered to a non diffusion-weighted reference, suffers from poor accuracy for high b-value data. An alternative approach is to extrapolate reference volumes from low b-value data. We aim to compare the performance of conventional and extrapolation-based correction of diffusional kurtosis imaging (DKI) data, and to demonstrate the impact of the correction approach on group comparison studies. METHODS: DKI was performed in patients with Parkinson's disease dementia (PDD), and healthy age-matched controls, using b-values of up to 2750 s/mm2. The accuracy of conventional and extrapolation-based correction methods was investigated. Parameters from DTI and DKI were compared between patients and controls in the cingulum and the anterior thalamic projection tract. RESULTS: Conventional correction resulted in systematic registration errors for high b-value data. The extrapolation-based methods did not exhibit such errors, yielding more accurate tractography and up to 50% lower standard deviation in DKI metrics. Statistically significant differences were found between patients and controls when using the extrapolation-based motion correction that were not detected when using the conventional method. CONCLUSION: We recommend that conventional motion and eddy-current correction should be abandoned for high b value data in favour of more accurate methods using extrapolation-based references. PMID- 26528542 TI - PM2.5 Spatiotemporal Variations and the Relationship with Meteorological Factors during 2013-2014 in Beijing, China. AB - OBJECTIVE: Limited information is available regarding spatiotemporal variations of particles with median aerodynamic diameter < 2.5 MUm (PM2.5) at high resolutions, and their relationships with meteorological factors in Beijing, China. This study aimed to detect spatiotemporal change patterns of PM2.5 from August 2013 to July 2014 in Beijing, and to assess the relationship between PM2.5 and meteorological factors. METHODS: Daily and hourly PM2.5 data from the Beijing Environmental Protection Bureau (BJEPB) were analyzed separately. Ordinary kriging (OK) interpolation, time-series graphs, Spearman correlation coefficient and coefficient of divergence (COD) were used to describe the spatiotemporal variations of PM2.5. The Kruskal-Wallis H test, Bonferroni correction, and Mann Whitney U test were used to assess differences in PM2.5 levels associated with spatial and temporal factors including season, region, daytime and day of week. Relationships between daily PM2.5 and meteorological variables were analyzed using the generalized additive mixed model (GAMM). RESULTS: Annual mean and median of PM2.5 concentrations were 88.07 MUg/m3 and 71.00 MUg/m3, respectively, from August 2013 to July 2014. PM2.5 concentration was significantly higher in winter (P < 0.0083) and in the southern part of the city (P < 0.0167). Day to day variation of PM2.5 showed a long-term trend of fluctuations, with 2-6 peaks each month. PM2.5 concentration was significantly higher in the night than day (P < 0.0167). Meteorological factors were associated with daily PM2.5 concentration using the GAMM model (R2 = 0.59, AIC = 7373.84). CONCLUSION: PM2.5 pollution in Beijing shows strong spatiotemporal variations. Meteorological factors influence the PM2.5 concentration with certain patterns. Generally, prior day wind speed, sunlight hours and precipitation are negatively correlated with PM2.5, whereas relative humidity and air pressure three days earlier are positively correlated with PM2.5. PMID- 26528543 TI - Exocarp Properties and Transcriptomic Analysis of Cucumber (Cucumis sativus) Fruit Expressing Age-Related Resistance to Phytophthora capsici. AB - Very young cucumber (Cucumis sativus) fruit are highly susceptible to infection by the oomycete pathogen, Phytophthora capsici. As the fruit complete exponential growth, at approximately 10-12 days post pollination (dpp), they transition to resistance. The development of age-related resistance (ARR) is increasingly recognized as an important defense against pathogens, however, underlying mechanisms are largely unknown. Peel sections from cucumber fruit harvested at 8 dpp (susceptible) and 16 dpp (resistant) showed equivalent responses to inoculation as did whole fruit, indicating that the fruit surface plays an important role in defense against P. capsici. Exocarp from 16 dpp fruit had thicker cuticles, and methanolic extracts of peel tissue inhibited growth of P. capsici in vitro, suggesting physical or chemical components to the ARR. Transcripts specifically expressed in the peel vs. pericarp showed functional differentiation. Transcripts predominantly expressed in the peel were consistent with fruit surface associated functions including photosynthesis, cuticle production, response to the environment, and defense. Peel-specific transcripts that exhibited increased expression in 16 dpp fruit relative to 8 dpp fruit, were highly enriched (P<0.0001) for response to stress, signal transduction, and extracellular and transport functions. Specific transcripts included genes associated with potential physical barriers (i.e., cuticle), chemical defenses (flavonoid biosynthesis), oxidative stress, penetration defense, and molecular pattern (MAMP)-triggered or effector-triggered (R-gene mediated) pathways. The developmentally regulated changes in gene expression between peels from susceptible- and resistant- age fruits suggest programming for increased defense as the organ reaches full size. PMID- 26528544 TI - Lack of Improvement Over Time in Methodological Quality of Randomized Trials on Laparoscopic Surgery Training. PMID- 26528545 TI - Correction: Brivanib Attenuates Hepatic Fibrosis In Vivo and Stellate Cell Activation In Vitro by Inhibition of FGF, VEGF and PDGF Signaling. PMID- 26528546 TI - An Unprecedented High Incidence of Leptospirosis in Futuna, South Pacific, 2004 - 2014, Evidenced by Retrospective Analysis of Surveillance Data. AB - Futuna is a small Polynesian island in the South Pacific with a population of 3,612 in 2013. The first human leptospirosis case was confirmed in 1997. Active surveillance started in 2004. Cases were confirmed by PCR or real time PCR, or by serology using MAT or a combination of IgM-ELISA and MAT. A retrospective analysis of surveillance data shows that the disease was endemic with a mean annual incidence of 844 cases per 100,000 over an 11-year period from 2004 to 2014. An epidemic peak as high as 1,945 cases per 100,000 occurred in 2008. Serogroup Australis was predominant until 2007, Icterohaemorrhagiae was dominant afterwards. Cluster analysis revealed different hot spots over time. Lifestyle habits, such as walking barefoot in irrigated taro fields or pig pens probably contributed to contamination from the swine and rodent reservoirs to humans. Severe forms were rare, and the case fatality rate was 0.5%. The medical community and general population were aware of leptospirosis and rapid treatment with amoxycillin was the main treatment, probably contributing to this low fatality rate. PMID- 26528547 TI - Synthesis of 1,3,6-Trisubstituted Azulenes. AB - We have developed a short, general synthetic route to 1,3,6-trisubstituted azulenes. The key intermediate, 6-methylazulene, was synthesized from readily available and inexpensive starting materials in 63% yield over two steps. The methyl group of 6-methylazulene was then used as a synthetic handle to introduce different substituents at the 6-position via two different methods. Subsequently, the 1- and 3-positions were substituted with additional functional handles, such as formyl, chloromethylketone, and iodide. The efficiency of the synthetic route was demonstrated by preparing a collection of three different products with the best demonstrated yield 33% over seven steps. PMID- 26528549 TI - Trends in Extended Spectrum Beta-Lactamase (ESBL) Producing Enterobacteriaceae and ESBL Genes in a Dutch Teaching Hospital, Measured in 5 Yearly Point Prevalence Surveys (2010-2014). AB - This paper describes the trends in prevalence of ESBL producing Enterobacteriaceae (ESBL-E) and ESBL genes, measured in five consecutive yearly Point Prevalence Surveys (PPS). All patients present in the hospital and in a day care clinic (including patients on dialysis) on the day of the survey, were screened for perianal ESBL-E carriage. Perianal swabs were taken and cultured using an enrichment broth and a selective agar plate. Both phenotypic and genotypic methods were used to detect the production of ESBL, presence of ESBL genes and clonal relatedness. Out of 2,695 patients, 135 (5.0%) were tested ESBL E positive. The overall ESBL-E prevalence was stable over the years. Overall 5.2% of all ESBL-E were acquired by nosocomial transmission. A relative decrease of CTX-M-1-1-like ESBL genes (from 44 to 25%, p = 0.026) was observed, possibly related to the strong (>60%) decrease in antibiotic use in livestock in our country during the same period. PMID- 26528548 TI - Mathematical Modelling of Molecular Pathways Enabling Tumour Cell Invasion and Migration. AB - Understanding the etiology of metastasis is very important in clinical perspective, since it is estimated that metastasis accounts for 90% of cancer patient mortality. Metastasis results from a sequence of multiple steps including invasion and migration. The early stages of metastasis are tightly controlled in normal cells and can be drastically affected by malignant mutations; therefore, they might constitute the principal determinants of the overall metastatic rate even if the later stages take long to occur. To elucidate the role of individual mutations or their combinations affecting the metastatic development, a logical model has been constructed that recapitulates published experimental results of known gene perturbations on local invasion and migration processes, and predict the effect of not yet experimentally assessed mutations. The model has been validated using experimental data on transcriptome dynamics following TGF-beta dependent induction of Epithelial to Mesenchymal Transition in lung cancer cell lines. A method to associate gene expression profiles with different stable state solutions of the logical model has been developed for that purpose. In addition, we have systematically predicted alleviating (masking) and synergistic pairwise genetic interactions between the genes composing the model with respect to the probability of acquiring the metastatic phenotype. We focused on several unexpected synergistic genetic interactions leading to theoretically very high metastasis probability. Among them, the synergistic combination of Notch overexpression and p53 deletion shows one of the strongest effects, which is in agreement with a recent published experiment in a mouse model of gut cancer. The mathematical model can recapitulate experimental mutations in both cell line and mouse models. Furthermore, the model predicts new gene perturbations that affect the early steps of metastasis underlying potential intervention points for innovative therapeutic strategies in oncology. PMID- 26528550 TI - Photoacoustic and Colorimetric Visualization of Latent Fingerprints. AB - There is a high demand on a simple, rapid, accurate, user-friendly, cost effective, and nondestructive universal method for latent fingerprint (LFP) detection. Herein, we describe a combination imaging strategy for LFP visualization with high resolution using poly(styrene-alt-maleic anhydride)-b polystyrene (PSMA-b-PS) functionalized gold nanoparticles (GNPs). This general approach integrates the merits of both colorimetric imaging and photoacoustic imaging. In comparison with the previous methods, our strategy is single-step and does not require the signal amplification by silver staining. The PSMA-b-PS functionalized GNPs have good stability, tunable color, and high affinity for universal secretions (proteins/polypeptides/amino acids), which makes our approach general and flexible for visualizing LFPs on different substrates (presumably with different colors) and from different people. Moreover, the unique optical property of GNPs enables the photoacoustic imaging of GNPs deposited LFPs with high resolution. This allows observation of level 3 hyperfine features of LFPs such as the pores and ridge contours by photoacoustic imaging. This technique can potentially be used to identify chemicals within LFP residues. We believe that this dual-modality imaging of LFPs will find widespread use in forensic investigations and medical diagnostics. PMID- 26528551 TI - Expression of the Rice Arginase Gene OsARG in Cotton Influences the Morphology and Nitrogen Transition of Seedlings. AB - Arginase is the only enzyme capable of producing urea in plants. This enzyme also contributes to many important biological functions during plant growth and development, such as seed development, root development and plant nitrogen using. The unique rice arginase gene OsARG is known to affect nitrogen use efficiency and is also associated with higher yields in rice. In this study, we transformed OsARG into upland cotton R18 by Agrobacterium-mediated genetic transformation and analyzed the function of OsARG in transgenic cotton. Two independent OsARG expression transgenic cotton lines, ARG-26 and ARG-38, were obtained via transformation. Southern blot analysis indicated that two copies and one copy of the OsARG gene were integrated into the ARG-26 and ARG-38 genomes, respectively. Enzyme activity and RNA transcription analysis revealed that the OsARG gene is highly expressed in cotton. The nitric oxide content and the morphology of ARG-26 and ARG-38 seedlings were both affected by expression of the OsARG gene. Field experiments indicated that the polyamine and nitrogen content increased by more than two-fold in the T3 generation plants of the transgenic cotton lines ARG-26 2, ARG-26-7, ARG-38-8, and ARG-38-11, as compared with the control plants. After harvesting cotton fibers grown in field conditions, we analyzed the quality of fiber and found that the fiber length was increased in the transgenic lines. The average cotton fiber length for all of the transgenic cotton lines was two millimeters longer than the fibers of the control plants; the average cotton fiber lengths were 31.94 mm, 32.00 mm, 32.68 mm and 32.84 mm in the ARG-26ARG-26 2, ARG-26-7, ARG-38-8 and ARG-38-11 lines, respectively, but the average fiber length of the control plants was 29.36mm. Our results indicate that the OsARG gene could potentially be used to improve cotton fiber length traits. PMID- 26528552 TI - Interoceptive awareness in patients with functional neurological symptoms. AB - Historically, emotional factors, such as trauma or psychological conflict, have been suggested as causal factors of functional motor disorders (FMD). More recent approaches have instead stressed potential neural and cognitive abnormalities in the allocation and maintenance of attention. Yet these studies have mostly focused on how attention is allocated to exteroceptive signals about the state of the body. Given the proposed important role of interoception for emotion, the study of FMD patients' ability to monitor their interoceptive signals may serve as a useful, mechanistic link between studies that aim to identify key emotional factors in FMD, and those that examine specific sensorimotor or cognitive abnormalities. In the current study, we compared the interoceptive awareness of a group of individuals with FMD (N=16) with a group of healthy controls (N=17). We employed a commonly used heartbeat detection task which tracks the level of concordance between one's heart rate and its subjective perception, as a proxy for interoceptive awareness more generally. We found that FMD patients have lower interoceptive accuracy than healthy subjects, and such reduced interoceptive accuracy was predictive of their depressive symptoms, as well as their tendency to focus on the external features of their body (self-objectification). Contary to our predictions, interoceptive accuracy was not predictive of alexithymia. These results suggest a potental trade-off between the allocation of attention to internal versus external aspects of the body in FMD. More generally, they warrant further investigation of interoceptive awareness in this population, as a means to understand their emotional abnormalities at a more mechanistic level than studies concentrating on traumatic life events and related risk factors. PMID- 26528554 TI - Direct Comparison of a Natural Loss-Of-Function Single Nucleotide Polymorphism with a Targeted Deletion in the Ncf1 Gene Reveals Different Phenotypes. AB - The genetic targeting of mouse models has given insight into complex processes. However, phenotypes of genetically targeted mice are susceptible to artifacts due to gene manipulation, which may lead to misinterpretation of the observations. To directly address these issues, we have compared the immunological phenotypes of Ncf1 knockout mice with Ncf1m1J mice possessing a naturally occurring intronic loss-of-function SNP in their Ncf1 gene. Neutrophil cytosolic factor 1 (NCF1) is the key regulatory component of the phagocytic NADPH oxidase 2 (NOX2) complex. Defects in NCF1 lead to lower production of reactive oxygen species (ROS) associated with autoimmune diseases in humans. In mice, collagen induced arthritis (CIA) and psoriatic arthritis are autoimmune disorders known to be regulated by Ncf1, and they were utilized in the present study to compare the Ncf1 knockout with Ncf1m1J mice. Targeted Ncf1 knockout mice were generated on a pure C57BL/6N genetic background, and thereafter crossed with B10.Q.Ncf1m1J mice. The targeting silenced the Ncf1 gene as intended, and both the B6N;B10.Q.Ncf1m1J mice as well as the knockout littermates had reduced ROS production compared to wild type mice. Both also exhibited enhanced STAT1 (signal transducer and activator of transcription 1) protein expression as an indicator of pronounced interferon signature reported recently for Ncf1 deficient mice. Surprisingly, female Ncf1 knockout mice were protected from CIA whereas the Ncf1m1J females developed severe disease. Ovariectomization retrieved the susceptibility of Ncf1 knockout females pointing to a sex hormone regulated protection against CIA in these mice. The data partly explains the discrepancy of the phenotypes reported earlier utilizing the Ncf1m1J mice or Ncf1 knockout mice. These observations indicate that even a targeted knockout mutation may lead to a different biological outcome in comparison to the natural loss-of-function mutation of the same gene. PMID- 26528555 TI - Early Life Experiences and Exercise Associate with Canine Anxieties. AB - Personality and anxiety disorders across species are affected by genetic and environmental factors. Shyness-boldness personality continuum exists across species, including the domestic dog, with a large within- and across-breed variation. Domestic dogs are also diagnosed for several anxiety-related behavioral conditions, such as generalized anxiety disorders, phobias, and separation anxiety. Genetic and environmental factors contributing to personality and anxiety are largely unknown. We collected questionnaire data from a Finnish family dog population (N = 3264) in order to study the associating environmental factors for canine fearfulness, noise sensitivity, and separation anxiety. Early life experiences and exercise were found to associate with anxiety prevalence. We found that fearful dogs had less socialization experiences (p = 0.002) and lower quality of maternal care (p < 0.0001) during puppyhood. Surprisingly, the largest environmental factor associating with noise sensitivity (p < 0.0001) and separation anxiety (p = 0.007) was the amount of daily exercise; dogs with noise sensitivity and separation anxiety had less daily exercise. Our findings suggest that dogs share many of the same environmental factors that contribute to anxiety in other species as well, such as humans and rodents. Our study highlights the importance of early life experiences, especially the quality of maternal care and daily exercise for the welfare and management of the dogs, and reveals important confounding factors to be considered in the genetic characterization of canine anxiety. PMID- 26528553 TI - Genome-Wide Association Studies of the Human Gut Microbiota. AB - The bacterial composition of the human fecal microbiome is influenced by many lifestyle factors, notably diet. It is less clear, however, what role host genetics plays in dictating the composition of bacteria living in the gut. In this study, we examined the association of ~200K host genotypes with the relative abundance of fecal bacterial taxa in a founder population, the Hutterites, during two seasons (n = 91 summer, n = 93 winter, n = 57 individuals collected in both). These individuals live and eat communally, minimizing variation due to environmental exposures, including diet, which could potentially mask small genetic effects. Using a GWAS approach that takes into account the relatedness between subjects, we identified at least 8 bacterial taxa whose abundances were associated with single nucleotide polymorphisms in the host genome in each season (at genome-wide FDR of 20%). For example, we identified an association between a taxon known to affect obesity (genus Akkermansia) and a variant near PLD1, a gene previously associated with body mass index. Moreover, we replicate a previously reported association from a quantitative trait locus (QTL) mapping study of fecal microbiome abundance in mice (genus Lactococcus, rs3747113, P = 3.13 x 10-7). Finally, based on the significance distribution of the associated microbiome QTLs in our study with respect to chromatin accessibility profiles, we identified tissues in which host genetic variation may be acting to influence bacterial abundance in the gut. PMID- 26528556 TI - Specifications of Standards in Systems and Synthetic Biology. AB - Standards shape our everyday life. From nuts and bolts to electronic devices and technological processes, standardised products and processes are all around us. Standards have technological and economic benefits, such as making information exchange, production, and services more efficient. However, novel, innovative areas often either lack proper standards, or documents about standards in these areas are not available from a centralised platform or formal body (such as the International Standardisation Organisation). Systems and synthetic biology is a relatively novel area, and it is only in the last decade that the standardisation of data, information, and models related to systems and synthetic biology has become a community-wide effort. Several open standards have been established and are under continuous development as a community initiative. COMBINE, the ‘COmputational Modeling in BIology’ NEtwork has been established as an umbrella initiative to coordinate and promote the development of the various community standards and formats for computational models. There are yearly two meeting, HARMONY (Hackathons on Resources for Modeling in Biology), Hackathon type meetings with a focus on development of the support for standards, and COMBINE forums, workshop-style events with oral presentations, discussion, poster, and breakout sessions for further developing the standards. For more information see http://co.mbine.org/. So far the different standards were published and made accessible through the standards’ web- pages or preprint services. The aim of this special issue is to provide a single, easily accessible and citable platform for the publication of standards in systems and synthetic biology. This special issue is intended to serve as a central access point to standards and related initiatives in systems and synthetic biology, it will be published annually to provide an opportunity for standard development groups to communicate updated specifications. PMID- 26528557 TI - The CellML 1.1 Specification. AB - This document specifies CellML 1.1, an XML-based language for describing and exchanging models of cellular and subcellular processes. MathML embedded in CellML documents is used to define the underlying mathematics of models. Models consist of a network of reusable components, each with variables and equations manipulating those variables. Models may import other models to create systems of increasing complexity. Metadata may be embedded in CellML documents using RDF. PMID- 26528558 TI - The CellML Metadata Framework 2.0 Specification. AB - The CellML Metadata Framework 2.0 is a modular framework that describes how semantic annotations should be made about mathematical models encoded in the CellML (www.cellml.org) format, and their elements. In addition to the Core specification, there are several satellite specifications, each designed to cater for model annotation in a different context. Basic Model Information, Citation, License and Biological Annotation specifications are presented. PMID- 26528559 TI - COMBINE Archive Specification Version 1. AB - Several standard formats have been proposed that can be used to describe models, simulations, data or other essential information in a consistent fashion. These constitute various separate components required to reproduce a given published scientific result. The Open Modeling EXchange format (OMEX) supports the exchange of all the information necessary for a modeling and simulation experiment in biology. An OMEX file is a ZIP container that includes a manifest file, an optional metadata file, and the files describing the model. The manifest is an XML file listing all files included in the archive and their type. The metadata file provides additional information about the archive and its content. Although any format can be used, we recommend an XML serialization of the Resource Description Framework. Together with the other standard formats from the Computational Modeling in Biology Network (COMBINE), OMEX is the basis of the COMBINE Archive. The content of a COMBINE Archive consists of files encoded in COMBINE standards whenever possible, but may include additional files defined by an Internet Media Type. The COMBINE Archive facilitates the reproduction of modeling and simulation experiments in biology by embedding all the relevant information in one file. Having all the information stored and exchanged at once also helps in building activity logs and audit trails. PMID- 26528560 TI - Simulation Experiment Description Markup Language (SED-ML) Level 1 Version 2. AB - The number, size and complexity of computational models of biological systems are growing at an ever increasing pace. It is imperative to build on existing studies by reusing and adapting existing models and parts thereof. The description of the structure of models is not sufficient to enable the reproduction of simulation results. One also needs to describe the procedures the models are subjected to, as recommended by the Minimum Information About a Simulation Experiment (MIASE) guidelines. This document presents Level 1 Version 2 of the Simulation Experiment Description Markup Language (SED-ML), a computer-readable format for encoding simulation and analysis experiments to apply to computational models. SED-ML files are encoded in the Extensible Markup Language (XML) and can be used in conjunction with any XML-based model encoding format, such as CellML or SBML. A SED-ML file includes details of which models to use, how to modify them prior to executing a simulation, which simulation and analysis procedures to apply, which results to extract and how to present them. Level 1 Version 2 extends the format by allowing the encoding of repeated and chained procedures. PMID- 26528561 TI - Systems Biology Graphical Notation: Process Description language Level 1 Version 1.3. AB - The Systems Biological Graphical Notation (SBGN) is an international community effort for standardized graphical representations of biological pathways and networks. The goal of SBGN is to provide unambiguous pathway and network maps for readers with different scientific backgrounds as well as to support efficient and accurate exchange of biological knowledge between different research communities, industry, and other players in systems biology. Three SBGN languages, Process Description (PD), Entity Relationship (ER) and Activity Flow (AF), allow for the representation of different aspects of biological and biochemical systems at different levels of detail. The SBGN Process Description language represents biological entities and processes between these entities within a network. SBGN PD focuses on the mechanistic description and temporal dependencies of biological interactions and transformations. The nodes (elements) are split into entity nodes describing, e.g., metabolites, proteins, genes and complexes, and process nodes describing, e.g., reactions and associations. The edges (connections) provide descriptions of relationships (or influences) between the nodes, such as consumption, production, stimulation and inhibition. Among all three languages of SBGN, PD is the closest to metabolic and regulatory pathways in biological literature and textbooks, but its well-defined semantics offer a superior precision in expressing biological knowledge. PMID- 26528562 TI - Systems Biology Graphical Notation: Entity Relationship language Level 1 Version 2. AB - The Systems Biological Graphical Notation (SBGN) is an international community effort for standardized graphical representations of biological pathways and networks. The goal of SBGN is to provide unambiguous pathway and network maps for readers with different scientific backgrounds as well as to support efficient and accurate exchange of biological knowledge between different research communities, industry, and other players in systems biology. Three SBGN languages, Process Description (PD), Entity Relationship (ER) and Activity Flow (AF), allow for the representation of different aspects of biological and biochemical systems at different levels of detail. The SBGN Entity Relationship language (ER) represents biological entities and their interactions and relationships within a network. SBGN ER focuses on all potential relationships between entities without considering temporal aspects. The nodes (elements) describe biological entities, such as proteins and complexes. The edges (connections) provide descriptions of interactions and relationships (or influences), e.g., complex formation, stimulation and inhibition. Among all three languages of SBGN, ER is the closest to protein interaction networks in biological literature and textbooks, but its well-defined semantics offer a superior precision in expressing biological knowledge. PMID- 26528563 TI - Systems Biology Graphical Notation: Activity Flow language Level 1 Version 1.2. AB - The Systems Biological Graphical Notation (SBGN) is an international community effort for standardized graphical representations of biological pathways and networks. The goal of SBGN is to provide unambiguous pathway and network maps for readers with different scientific backgrounds as well as to support efficient and accurate exchange of biological knowledge between different research communities, industry, and other players in systems biology. Three SBGN languages, Process Description (PD), Entity Relationship (ER) and Activity Flow (AF), allow for the representation of different aspects of biological and biochemical systems at different levels of detail. The SBGN Activity Flow language represents the influences of activities among various entities within a network. Unlike SBGN PD and ER that focus on the entities and their relationships with others, SBGN AF puts the emphasis on the functions (or activities) performed by the entities, and their effects to the functions of the same or other entities. The nodes (elements) describe the biological activities of the entities, such as protein kinase activity, binding activity or receptor activity, which can be easily mapped to Gene Ontology molecular function terms. The edges (connections) provide descriptions of relationships (or influences) between the activities, e.g., positive influence and negative influence. Among all three languages of SBGN, AF is the closest to signaling pathways in biological literature and textbooks, but its well-defined semantics offer a superior precision in expressing biological knowledge. PMID- 26528564 TI - The Systems Biology Markup Language (SBML): Language Specification for Level 3 Version 1 Core. AB - Computational models can help researchers to interpret data, understand biological function, and make quantitative predictions. The Systems Biology Markup Language (SBML) is a file format for representing computational models in a declarative form that can be exchanged between different software systems. SBML is oriented towards describing biological processes of the sort common in research on a number of topics, including metabolic pathways, cell signaling pathways, and many others. By supporting SBML as an input/output format, different tools can all operate on an identical representation of a model, removing opportunities for translation errors and assuring a common starting point for analyses and simulations. This document provides the specification for Version 1 of SBML Level 3 Core. The specification defines the data structures prescribed by SBML as well as their encoding in XML, the eXtensible Markup Language. This specification also defines validation rules that determine the validity of an SBML document, and provides many examples of models in SBML form. Other materials and software are available from the SBML project web site, http://sbml.org/. PMID- 26528565 TI - The Systems Biology Markup Language (SBML) Level 3 Package: Layout, Version 1 Core. AB - Many software tools provide facilities for depicting reaction network diagrams in a visual form. Two aspects of such a visual diagram can be distinguished: the layout (i.e.: the positioning and connections) of the elements in the diagram, and the graphical form of the elements (for example, the glyphs used for symbols, the properties of the lines connecting them, and so on). For software tools that also read and write models in SBML (Systems Biology Markup Language) format, a common need is to store the network diagram together with the SBML representation of the model. This in turn raises the question of how to encode the layout and the rendering of these diagrams. The SBML Level 3 Version 1 Core specification does not provide a mechanism for explicitly encoding diagrams, but it does provide a mechanism for SBML packages to extend the Core specification and add additional syntactical constructs. The Layout package for SBML Level 3 adds the necessary features to SBML so that diagram layouts can be encoded in SBML files, and a companion package called SBML Rendering specifies how the graphical rendering of elements can be encoded. The SBML Layout package is based on the principle that reaction network diagrams should be described as representations of entities such as species and reactions (with direct links to the underlying SBML elements), and not as arbitrary drawings or graphs; for this reason, existing languages for the description of vector drawings (such as SVG) or general graphs (such as GraphML) cannot be used. PMID- 26528566 TI - SBML Level 3 package: Hierarchical Model Composition, Version 1 Release 3. AB - Constructing a model in a hierarchical fashion is a natural approach to managing model complexity, and offers additional opportunities such as the potential to re use model components. The SBML Level 3 Version 1 Core specification does not directly provide a mechanism for defining hierarchical models, but it does provide a mechanism for SBML packages to extend the Core specification and add additional syntactical constructs. The SBML Hierarchical Model Composition package for SBML Level 3 adds the necessary features to SBML to support hierarchical modeling. The package enables a modeler to include submodels within an enclosing SBML model, delete unneeded or redundant elements of that submodel, replace elements of that submodel with element of the containing model, and replace elements of the containing model with elements of the submodel. In addition, the package defines an optional "port" construct, allowing a model to be defined with suggested interfaces between hierarchical components; modelers can chose to use these interfaces, but they are not required to do so and can still interact directly with model elements if they so chose. Finally, the SBML Hierarchical Model Composition package is defined in such a way that a hierarchical model can be "flattened" to an equivalent, non-hierarchical version that uses only plain SBML constructs, thus enabling software tools that do not yet support hierarchy to nevertheless work with SBML hierarchical models. PMID- 26528567 TI - The Systems Biology Markup Language (SBML) Level 3 Package: Flux Balance Constraints. AB - Constraint-based modeling is a well established modelling methodology used to analyze and study biological networks on both a medium and genome scale. Due to their large size, genome scale models are typically analysed using constraint based optimization techniques. One widely used method is Flux Balance Analysis (FBA) which, for example, requires a modelling description to include: the definition of a stoichiometric matrix, an objective function and bounds on the values that fluxes can obtain at steady state. The Flux Balance Constraints (FBC) Package extends SBML Level 3 and provides a standardized format for the encoding, exchange and annotation of constraint-based models. It includes support for modelling concepts such as objective functions, flux bounds and model component annotation that facilitates reaction balancing. The FBC package establishes a base level for the unambiguous exchange of genome-scale, constraint-based models, that can be built upon by the community to meet future needs (e. g. by extending it to cover dynamic FBC models). PMID- 26528568 TI - The Systems Biology Markup Language (SBML) Level 3 Package: Qualitative Models, Version 1, Release 1. AB - Quantitative methods for modelling biological networks require an in-depth knowledge of the biochemical reactions and their stoichiometric and kinetic parameters. In many practical cases, this knowledge is missing. This has led to the development of several qualitative modelling methods using information such as, for example, gene expression data coming from functional genomic experiments. The SBML Level 3 Version 1 Core specification does not provide a mechanism for explicitly encoding qualitative models, but it does provide a mechanism for SBML packages to extend the Core specification and add additional syntactical constructs. The SBML Qualitative Models package for SBML Level 3 adds features so that qualitative models can be directly and explicitly encoded. The approach taken in this package is essentially based on the definition of regulatory or influence graphs. The SBML Qualitative Models package defines the structure and syntax necessary to describe qualitative models that associate discrete levels of activities with entity pools and the transitions between states that describe the processes involved. This is particularly suited to logical models (Boolean or multi-valued) and some classes of Petri net models can be encoded with the approach. PMID- 26528570 TI - Synthetic Biology Open Language (SBOL) Version 2.0.0. AB - Synthetic biology builds upon the techniques and successes of genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. The field still faces substantial challenges, including long development times, high rates of failure, and poor reproducibility. One method to ameliorate these problems would be to improve the exchange of information about designed systems between laboratories. The Synthetic Biology Open Language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, filling a need not satisfied by other pre-existing standards. This document details version 2.0 of SBOL, introducing a standardized format for the electronic exchange of information on the structural and functional aspects of biological designs. The standard has been designed to support the explicit and unambiguous description of biological designs by means of a well defined data model. The standard also includes rules and best practices on how to use this data model and populate it with relevant design details. The publication of this specification is intended to make these capabilities more widely accessible to potential developers and users in the synthetic biology community and beyond. PMID- 26528569 TI - Systems Biology Markup Language (SBML) Level 2 Version 5: Structures and Facilities for Model Definitions. AB - Computational models can help researchers to interpret data, understand biological function, and make quantitative predictions. The Systems Biology Markup Language (SBML) is a file format for representing computational models in a declarative form that can be exchanged between different software systems. SBML is oriented towards describing biological processes of the sort common in research on a number of topics, including metabolic pathways, cell signaling pathways, and many others. By supporting SBML as an input/output format, different tools can all operate on an identical representation of a model, removing opportunities for translation errors and assuring a common starting point for analyses and simulations. This document provides the specification for Version 5 of SBML Level 2. The specification defines the data structures prescribed by SBML as well as their encoding in XML, the eXtensible Markup Language. This specification also defines validation rules that determine the validity of an SBML document, and provides many examples of models in SBML form. Other materials and software are available from the SBML project web site, http://sbml.org. PMID- 26528571 TI - Serologic and Molecular Survey of Hepatitis E Virus in German Deer Populations. AB - Hepatitis E virus (HEV) is a human pathogen that is primarily transmitted by the fecal-oral route and causes a usually self-limiting acute viral hepatitis. The virus is endemic in developing countries of Africa, Asia, and Latin America and is responsible for sporadic cases in industrialized countries. In western Europe, an increasing number of autochthonous cases have been associated with zoonotic transmissions of HEV from domestic and wild animals. In Germany, animal reservoirs for HEV have been mainly assigned to domestic pigs and wild boars. To investigate the potential role of deer as a reservoir of HEV, we surveyed HEV specific antibodies and RNA in deer samples from geographic regions in Germany. We sampled red deer (Cervus elaphus) and roe deer (Capreolus capreolus) during active surveillance in three forest districts in northern Hesse and southern Lower Saxony during 2011-12 and 2012-13, respectively. Additionally, archived samples of red, roe, and fallow deer (Dama dama), collected in 2000-01 in German national parks, were included in the study. Antibody prevalence ranged from 2 3.3% in red deer to 5.4-6.8% in roe deer. Viral RNA was detected in red deer and fallow deer at prevalences of 2.0-6.6% and 4.3%, respectively. The investigation confirmed the presence of HEV infections in three deer species in Germany. Red, roe, and fallow deer should be further monitored to assess their role as hosts and potential reservoirs of HEV in Germany. PMID- 26528573 TI - PREVALENCE AND DIVERSITY OF BARTONELLA SPECIES IN WILD SMALL MAMMALS IN ASIA. AB - We collected 641 small mammals belonging to 17 species of Rodentia and four species of Soricomorpha in Japan, Korea, Russia, Taiwan, and Thailand and investigated the prevalence and genetic diversity of Bartonella species. Apodemus (field mice) and Rattus (rats) were the most-common genera captured, making up 56.0% and 23.1% of the total specimens, respectively. Bartonellae were isolated from 54.6% of the collected animals, and the prevalence varied depending on the host species and the country of origin. The isolates were identified to the species level based on gltA and rpoB sequences. Although most Bartonella species were shared by more than two host species, the distribution patterns of Bartonella species clearly differed among the four most-common host genera: Apodemus, Rattus, Myodes (voles), and Suncus (shrews). The predominant Bartonella species were Bartonella grahamii in Apodemus, Bartonella tribocorum in Rattus, B. grahamii and Bartonella taylorii in Myodes, and an unclassified Bartonella sp. in Suncus. PMID- 26528574 TI - Health Status of Galapagos Sea Lions (Zalophus wollebaeki) on San Cristobal Island Rookeries Determined by Hematology, Biochemistry, Blood Gases, and Physical Examination. AB - The Galapagos sea lion, Zalophus wollebaeki, is an endemic and endangered species subject to population decline associated with environmental variability, such as El Nino events, constant feeding stress, and exposure to diseases through contact with introduced species. Reference blood parameter intervals have been published for some pinniped species, but baseline biochemical and blood gas values are lacking from Z. wollebaeki. We analyzed blood samples from 30 juvenile Galapagos sea lions (19 females, 11 males) captured in two rookeries on San Cristobal Island. A portable blood analyzer (iSTAT) was used to obtain near-immediate field results for pH, partial pressure of O2, partial pressure of CO2, bicarbonate (HCO3(-)), hematocrit (Hct), hemoglobin, Na, K, ionized Ca, and glucose, and blood lactate was measured using a portable Lactate Plus(TM) analyzer. Average heart rate, biochemistry, and hematology parameters were comparable with healthy individuals of other pinniped species. Hemoglobin was significantly correlated with body condition of juvenile Galapagos sea lions. When compared with available blood values of clinically healthy California sea lions, Galapagos sea lions had higher total protein and Hct and lower Ca and K levels. Our results provide baseline data that may be useful in comparisons among populations and in detecting changes in health status among Galapagos sea lions. PMID- 26528575 TI - Conjoined Fetal Twins in a Harbor Seal (Phoca vitulina). AB - In July 2013, a stranded harbor seal (Phoca vitulina) died giving birth to conjoined fetuses. The twins were joined at the abdomen and thoracolumbar spine with the vertebral axis at 180 degrees . The cause of this unique anomaly--a first for this species--was not identified. PMID- 26528576 TI - PREVALENCE OF ANTIBODY TO ALEUTIAN MINK DISEASE VIRUS IN EUROPEAN MINK (MUSTELA LUTREOLA) AND AMERICAN MINK (NEOVISON VISON) IN SPAIN. AB - The European mink (Mustela lutreola) has undergone a dramatic decline and is one of the most endangered mammals in the world. The invasive American mink (Neovison vison) is considered the main factor for this decline. However, the American mink's introduction and the subsequent ecological concurrence of the two species cannot solely explain the decline or disappearance of the European mink. Aleutian mink disease virus (AMDV) is the main health problem in fur farming worldwide, causing varied clinical syndromes that depend on the viral strain and host factors. Infection with AMDV has been speculated to contribute to the decline of the European mink, but a detailed study has not been performed. To assess the potential effects of AMDV infection on the conservation of the European mink, we surveyed AMDV antibody in samples from 492 native European mink and 1,735 feral American mink collected over 16 yr. The antibody prevalence in European mink was 32%. There were no statistically significant differences in antibody prevalence between sexes, among years, or among weight classes. For recaptured European mink, incidence of seroconversion (negative to positive) was 0.46 cases per animal-year at risk. For positive animals, the incidence of conversion from positive to negative was 0.18 cases per animal-year at risk. In 1,735 feral American minks, the overall prevalence was 32.4% and varied among the six wild populations studied. Infection with AMDV appears to be endemic, distributed across the entire ranges of both species, and no effects on the population dynamics of either species were observed. PMID- 26528577 TI - The intercalatus nucleus of Staderini. AB - Rutilio Staderini was one of the leading Italian anatomists of the twentieth century, together with some scientists, such as Giulio Chiarugi, Giovanni Vitali, and others. He was also a member of a new generation of anatomists. They had continued the tradition of the most famous Italian scientists, which started from the Renaissance up until the nineteenth century. Although he carried out important studies of neuroanatomy and comparative anatomy, as well as embryology, his name is rarely remembered by most medical historians. His name is linked to the nucleus he discovered: the Staderini nucleus or intercalated nucleus, a collection of nerve cells in the medulla oblongata located lateral to the hypoglossal nucleus. This article focuses on the biography of the neuroanatomist as well as the nucleus that carries his name and his other research, especially on comparative anatomy and embryology. PMID- 26528578 TI - The Role of Narrative and Other-Referencing in Attenuating Psychological Reactance to Diabetes Self-Care Messages. AB - This study charts pathways through message resistance to enhance the persuasiveness of diabetes self-care messages. A 2 (narrative) * 2 (other referencing) * 2 (message) * 4 (order) experiment with adult diabetics (N = 58) tested whether packaging overt recommendations as a story rather than an informational argument (i.e., narrative structure) and highlighting the impact of health decisions on family and friends rather than the individual (i.e., other referencing) can effectively attenuate psychological reactance to messages encouraging healthy diet and physical activity. Narrative and other-referencing each led to lower perceived threat to choice, less state anger and counterarguing, less negative cognitive responses, more positive attitudes toward the ad and the behaviors promoted, and greater intended compliance with message recommendations. Findings illustrate two strategies that communicators may employ in order to benefit from clear, direct health messages while avoiding the reactance they may provoke. Moreover, findings inform message design for diabetes self-care education. PMID- 26528579 TI - Jararhagin disruption of endothelial cell anchorage is enhanced in collagen enriched matrices. AB - Hemorrhage is one of the most striking effects of bites by viper snakes resulting in fast bleeding and ischemia in affected tissues. Snake venom metalloproteinases (SVMPs) are responsible for hemorrhagic activity, but the mechanisms involved in SVMP-induced hemorrhage are not entirely understood and the study of such mechanisms greatly depends on in vivo experiments. In vivo, hemorrhagic SVMPs accumulate on basement membrane (BM) of venules and capillary vessels allowing the hydrolysis of collagen IV with consequent weakness and rupture of capillary walls. These effects are not reproducible in vitro with conventional endothelial cell cultures. In this study we used two-dimension (2D) or three-dimension (3D) cultures of HUVECs on matrigel and observed the same characteristics as in ex vivo experiments: only the hemorrhagic toxin was able to localize on surfaces or internalize endothelial cells in 2D cultures or in the surface of tubules formed on 3D cultures. The contribution of matrigel, fibronectin and collagen matrices in jararhagin-induced endothelial cell damage was then analyzed. Collagen and matrigel substrates enhanced the endothelial cell damage induced by jararhagin allowing toxin binding to focal adhesions, disruption of stress fibers, detachment and apoptosis. The higher affinity of jararhagin to collagen than to fibronectin explains the localization of the toxin within BM. Moreover, once located in BM, interactions of jararhagin with alpha2beta1 integrin would favor its localization on focal adhesions, as observed in our study. The accumulation of toxin in focal adhesions, observed only in cells grown in collagen matrices, would explain the enhancement of cell damage in these matrices and reflects the actual interaction among toxin, endothelial cells and BM components that occurs in vivo and results in the hemorrhagic lesions induced by viper venoms. PMID- 26528580 TI - Digital image analysis of AgNORs in cervical smears of women with premalignant and malignant lesions of the uterine cervix. AB - We performed a hospital-based, unmatched case-control study to investigate the association between progressive stages of cervical neoplasia and digital analysis of cell proliferation by silver stained nucleolus organizer region associated proteins (AgNORs). We measured cell proliferation levels in the cervical epithelial cells of 10 women with low grade squamous intraepithelial lesions (LG SIL), eight with high grade squamous intraepithelial lesions (HG-SIL), 11 with cervical cancer (CC) and eight with no cervical lesions (controls) using the AgNORs technique. Cell proliferation was measured by digital image analysis (DIA). DIA revealed increased total areas of AgNORs in HG-SIL and CC compared to LG-SIL and control patients. AgNORs with a kidney or cluster shape exhibited greater areas than those with a spherical or long shape. We propose a cut-off of 118 pixels to differentiate benign (control and LG-SIL) from malignant (HG-SIL and CC) lesions. DIA of AgNORs is a simple and inexpensive method for studying proliferation. The increased total area of AgNORs in malignant lesions provides information regarding cell behavior and may be related to cervical carcinogenesis; however, further validation studies are required to establish its usefulness in cytological analysis. PMID- 26528581 TI - A Novel Drug-Resistant HIV-1 Circulating Recombinant Form CRF76_01B Identified by Near Full-Length Genome Analysis. AB - HIV-1 CRF01_AE and subtype B (B) have dominated and their different circulating recombinant forms (CRFs) have emerged in East and Southeast Asian countries. Here, we report a novel drug-resistant HIV-1 CRF. Five independent recombinant specimens exhibiting discordant subtype results for the gag, pol, and env sequences were isolated. These recombinants had the CRF01_AE (gag p17)/B (pol PR RT and IN)/CRF01_AE (env C2-V3) pattern similar to CRF69_01B. Sequence analysis of four near full-length HIV-1 genomes revealed a unique phylogenetic cluster distinct from previously reported CRFs. Of the four recombinants, three shared an identical mosaic structure including seven breakpoints in the gag, pol, vif, and env regions, designated CRF76_01B. The one remaining recombinant had additional recombination breakpoints in the vpu region and exhibited another unique recombinant form composed of CRF76_01B and B. These findings provide important insight into the transmission dynamics of HIV-1 in Asia that may be important for its effective prevention. PMID- 26528582 TI - Which Is The Best Sandwich Compound? Hexaphenylbenzene Substituted By Sandwich Compounds Bearing Sc, Cr, and Fe. AB - The electronic properties of nine different hexaarylbenzene molecules substituted by sandwich compounds have been studied by applying density functional theory. Different structures and the particular electron donor power of these systems have been considered in order to analyze their oxidant capacity, using bis(ciclopentadienyl) scandium, ferrocene, and bis(benzene)chromium as sandwich compounds. Both monometallic and bimetallic combinations are investigated. According to the ionization energies and electron affinities, compounds with Cr are nucleophiles and represent the best electron donors, whereas compounds with Sc are electrophiles and represent the best electron acceptors. The worse electron donor or acceptor is hexakis(4-ferrocenyl phenyl) benzene. This is very significant, as it implies that the very well-known electronic properties of hexakis(4-ferrocenyl phenyl) benzene can be improved by substituting with other metals, such as Sc and Cr. This suggests several possible applications for these compounds. PMID- 26528583 TI - Identification of metabolites of oridonin in rats with a single run on UPLC Triple-TOF-MS/MS system based on multiple mass defect filter data acquisition and multiple data processing techniques. AB - Oridonin (ORI) is an active natural ent-kaurane diterpenoid ingredient originating from well-known traditional Chinese herb medicine and is expected to be pursued as a new anticancer agent. In the present study, a novel and efficient approach was developed for in vivo screening and identification of ORI metabolites using ultra high performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UPLC-Triple-TOF MS/MS). This analytical strategy was as follows: an effective on-line data acquisition method multiple mass defect filter (MMDF) combined with dynamic background subtraction (DBS), was developed to trace all of potential metabolites of ORI. The MMDF and DBS method could trigger an information dependent acquisition scan, which could give the information of low-level metabolites masked by background noise and endogenous components in complex matrix. Moreover, the sensitive and specific multiple data-mining techniques including extracted ion chromatography, mass defect filtering, product ion filtering and neutral loss filtering were employed to identify the metabolites of ORI. Then, structures for the metabolites were successfully assigned based on accurate masses, the mass fragmentation of ORI and metabolic knowledge. Finally, an important parameter Clog P was used to estimate the retention time of isomers. Based on the proposed strategy, 16 phase I and 2 phase II metabolites were detected in rats after oral administration of ORI. The main biotransformation route of ORI was identified as reduction, oxidation, dehydroxylation and glucuronic acid conjugation. This is the first study of ORI metabolism in vivo. This study not only proposed a practical strategy for rapidly screening and identifying metabolites, but also provided useful information for further study of the pharmacology and mechanism of ORI in vivo. At the same time this methodology can be widely applied for the structural characterization of the metabolites of other ent-kaurane diterpenoid. PMID- 26528584 TI - Detection of ethanolamine altering in fetuses of pregnancy-associated hypertensive mice treated with vasodepressors by using UPLC and MALDI-TOF/MS. AB - Since serotonin, homocysteine and oxytocin are known to fluctuate during mammalian gestation, we screened amines altered in pregnant-associated hypertensive (PAH) mice by tagging their amino groups with 6-aminoquinoline carbamoyl (AQC) group in concert with ultra high-performance liquid chromatography (UPLC). Interestingly, a candidate amine significantly increased in PAH mice was recovered to the basal level, when treated with antihypertensive drugs. Mass spectrometric analyses indicated that the molecular mass of this amine was 61.2, which was identified as ethanolamine. PMID- 26528585 TI - pH-Sensitive Biocompatible Nanoparticles of Paclitaxel-Conjugated Poly(styrene-co maleic acid) for Anticancer Drug Delivery in Solid Tumors of Syngeneic Mice. AB - In the present study, we have synthesized poly(styrene-co-maleic anhydride), a biocompatible copolymer that was further conjugated with paclitaxel (PTX) via ester linkage and self-assembled to form poly(styrene-co-maleic acid)-paclitaxel (PSMAC-PTX) nanoparticles (NPs). The in vitro release of PTX from PSMAC-PTX NPs showed a higher release at lower pH than at the physiological pH of 7.4, confirming its pH-dependent release. The cell viability of PSMAC-PTX nanoparticles was evaluated using MTT assay. IC50 values of 9.05-18.43 ng/mL of PTX equivalent were observed in various cancer cell lines after 72 h of incubation. Confocal microscopy, Western blotting, and Flow cytometry results further supported that the cellular uptake and apoptosis of cancer cells with PSMAC-PTX NPs. Pharmacokinetic studies revealed that the conjugation of PTX to the PSMAC co-polymer not only increased the plasma and tumor C(max) of PTX but also prolonged its plasma half-life and retention in tumor via enhanced permeability and retention (EPR) effect. Administration of PSMAC-PTX NPs showed significant tumor growth inhibition with improved apoptosis effects in vivo on Ehrlich Ascites Tumor (EAT)-bearing BALB/c syngeneic mice in comparison with Taxol, without showing any cytotoxicity. On the basis of preliminary results, no subacute toxicity was observed in major organs, tissues and hematological system up to a dosage of 60 mg/kg body weight in mice. Therefore, PSMAC-PTX NPs may be considered as an alternative nanodrug delivery system for the delivery of PTX in solid tumors. PMID- 26528586 TI - Intellectual property rights, benefit-sharing and development of "improved traditional medicines": A new approach. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Protection of intellectual property rights and benefit-sharing are key issues for all ethnopharmacological research. The International Society of Ethnobiology has produced helpful guidelines on access and benefit-sharing which are widely viewed as a "gold standard" but the question remains how best to apply these guidelines in practice. Difficult questions include ownership of traditional knowledge, making appropriate agreements, and how appropriately to share benefits. MATERIALS AND METHODS: We present the case study of the development of an "improved traditional medicine" for malaria in Mali and we report how benefit-sharing was applied in this case. RESULTS: The knowledge about the selected plant came independently from several families and traditional healers. The IPR approach was to recognise that this traditional knowledge belongs to the people of Mali and was used for their benefit in developing a new "improved traditional medicine" (ITM). The traditional healer whose method of preparation was used, and who collaborated in clinical trials, did not request any financial reward but asked for the ITM to be named after him. The most sustainable benefit for the community was sharing the results of which preparation of which medicinal plant seemed to be the most effective for treating malaria. Attempts at providing a health centre and training a health worker for the village did not prove to be sustainable. CONCLUSIONS: Respect for intellectual property rights and benefit-sharing are possible even in a context where the knowledge is not owned by a clearly identified person or group of people. The most sustainable benefits are intangible rather than material: namely recognition, improved knowledge about which traditional treatment is the best and how to prepare and take it. PMID- 26528587 TI - Safety and efficacy of Sclerocarya birrea (A.Rich.) Hochst (Marula) oil: A clinical perspective. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sclerocarya birrea (A.Rich.) Hochst (Marula) nut oil is a popular ingredient in cosmetics such as skin lotions, lipsticks and foundations. The demand for this African oil increased tremendously such that in 2008 almost US$ 20 million was spent on Marula oil for cosmetic product manufacturing. The ethnobotanical literature states that the Zulu people in South Africa amongst others applied the oil to maintain a healthy skin. Scientific studies to support the traditional use as well as the inclusion of Marula oil in cosmetic products is lacking. This study evaluated the irritancy potential (safety), the moisturising and hydrating effects as well occlusivity properties (efficacy) of Marula oil after topical application. In addition, the Marula oil used in this study was comprehensively characterised using two-dimensional gas chromatography coupled to mass spectrometry. METHODS AND MATERIALS: Quantification of the fatty acid methyl esters (FAMEs) was done using a LECO Pegasus 4D GC * GC-MS. To determine the safety and efficacy of Marula oil healthy caucasian adult female volunteers (n = 20) who complied with the inclusion and exclusion criteria for the irritancy patch, moisture efficacy, hydrating and occlusivity tests were recruited for each study. A 2 * magnifying lamp (visual observation), Chromameter(r), Aquaflux(r) and Corneometer(r) instruments were used to evaluate and monitor the irritancy level, skin barrier function, transepidermal water loss, hydrating and occlusive effects of topically applied Marula oil. RESULTS: The GC * GC-MS analysis identified several saturated as well as unsaturated fatty acids. Oleic acid was the major fatty acid constituting 69.0% of the oil followed by palmitic acid (15.3%), linoleic acid (9.2%), palmitoleic acid (4.1%) and stearic acid (1.5%). The clinical study revealed that Marula oil is non-irritant (p < 0.001), with moisturising and hydrating properties (p < 0.001) when applied to a lipid-dry (xerosis) skin. Additionally the oil exhibited occlusive effects (p < 0.001) when applied to normal skin. These findings may be linked to the absorption of the oil into the skin due to the high percentage of oleic acid and the presence of palmitic acid which are known to disturb the stratum corneum intercellular lipids. These fatty acids present in Marula oil are very similar to those present in the epidermis, and can be considered biomimetic. CONCLUSIONS: Marula oil rich in fatty acids exhibits moisturising, hydrating and occlusive properties. As the oil is non-irritating and provides a moisturising effect with moderate prevention of transepidermal water loss, average moisture retention properties and noteworthy occlusive effects, its inclusion in cosmetic products based on its traditional use may be justified depending on the application. PMID- 26528588 TI - Ficus religiosa L. bark extracts inhibit human rhinovirus and respiratory syncytial virus infection in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ficus religiosa L. is one of the most relevant members of the family of Moraceae. It is the most sacred tree of South Asia, and it is used in traditional Ayurvedic and Unani medicine to cure respiratory disorders like cough, wheezing and asthma. Some studies were performed to investigate the anti-asthmatic potential of F. religiosa bark, leaves and fruit extracts but none of them tested their antiviral activity against viruses responsible for the exacerbation of wheezing and asthma. AIM OF THE STUDY: The present study was undertaken to investigate the antiviral activity of F. religiosa L. extracts against respiratory viruses such as human respiratory syncytial virus (RSV) and human rhinovirus (HRV). MATERIALS AND METHODS: The antiviral activity of F. religiosa L. was tested in vitro by plaque reduction and virus yield assays and the major mechanism of action was investigated by virus inactivation and time-of-addition assays. RESULTS: F. religiosa L. methanol bark extract was the most active against HRV with an EC50 of 5.52 ug/mL. This extract likely inhibited late steps of replicative cycle. Water bark extract was the most active against RSV with an EC50 between 2.23 and 4.37 ug/mL. Partial virus inactivation and interference with virus attachment were both found to contribute to the anti-RSV activity. Replication of both viruses was inhibited in viral yield reduction assays. CONCLUSIONS: The results of the present study demonstrate that F. religiosa L. is endowed with antiviral activity against RSV and HRV in vitro. Further work remains to be done to identify the active components and to assess the therapeutic potential in vivo. PMID- 26528590 TI - Immobilization of Uranium in Contaminated Sediments by Hydroxyapatite Addition. AB - Batch equilibrations were performed to investigate the ability of hydroxyapatite (Ca5(PO4)3OH) to chemically immobilize U in two contaminated sediment samples having different organic carbon contents (123 and 49 g kg(-1), respectively). Apatite additions lowered aqueous U to near proposed drinking water standards in batch equilibrations of two distinct sediment strata having total U concentrations of 1703 and 2100 mg kg(-1), respectively. Apatite addition of 50 g kg(-1) reduced the solubility of U to values less than would be expected if autunite (Ca(UO2)2(PO4)2.10H2O) was the controlling solid phase. A comparison of the two sediment types suggests that aqueous phase U may be controlled by both the DOC content through complexation and the equilibrium pH for a given apatite application rate. Sequential chemical extractions demonstrated that apatite amendment transfers U from more chemically labile fractions, including water soluble, exchangeable, and acid-soluble (pH ~ 2.55) fractions, to the Mn-occluded fraction (pH ~ 1.26). This suggests that apatite amendment redirects solid-phase speciation with secondary U phosphates being solubilized due to the lower pH of the Mn-occluded extractant, despite the lack of significant quantities of Mn oxides within these sediments. Energy dispersive X-ray (EDX) analysis conducted in a transmission electron microscope (TEM) confirmed that apatite amendment sequesters some U in secondary Al/Fe phosphate phases. PMID- 26528589 TI - Functional ET(A)-ET(B) Receptor Cross-talk in Basilar Artery In Situ From ET(B) Receptor Deficient Rats. AB - The role of endothelin (ET)(A)-ET(B) receptor cross-talk in limiting the ET(A) receptor antagonist inhibition of ET-1 constriction is revealed by the partial or complete dependency of the ET(A) receptor antagonist inhibition on functional removal of the ET(B) receptor. Although functional removal of the ET(B) receptor is generally accomplished with ET(B) receptor antagonist, a novel approach using rats containing a naturally occurring deletion mutation in the ET(B) receptor [rescued "spotting lethal" (sl) rats; ET(B)(sl/sl)] demonstrated increased ET(A) receptor antagonist inhibition of ET-1 constriction in vena cava. We investigated whether this deletion mutation was also sufficient to remove the ET(B) receptor dependency of the ET(A) receptor antagonist inhibition of ET-1 constriction in the basilar artery. Consistent with previous reports, ET-1 plasma levels were elevated in ET(B)(sl/sl) as compared with ET(B)(+/+) rats. ET(B) receptor antagonist failed to relax the ET-1 constricted basilar artery from ET(B)(+/+) and ET(B)(sl/sl) rats. Relaxation to combined ET(A) and ET(B) receptor antagonist was greater than relaxation to ET(A) receptor antagonist in the basilar artery from ET(B)(+/+) and, unexpectedly, ET(B)(sl/sl) rats. These findings confirm the presence of ET(A)-ET(B) receptor cross-talk in the basilar artery. We speculate that mutant ET(B) receptor expression produced by alternative splicing may be sufficient to allow cross-talk. PMID- 26528591 TI - Nanoassemblies Based on Supramolecular Complexes of Nonionic Amphiphilic Cyclodextrin and Sorafenib as Effective Weapons to Kill Human HCC Cells. AB - Sorafenib (Sor), an effective chemiotherapeutic drug utilized against hepatocellular carcinoma (HCC), robustly interacts with nonionic amphiphilic cyclodextrin (aCD, SC6OH), forming, in aqueous solution, supramolecular complexes that behave as building blocks of highly water-dispersible colloidal nanoassemblies. SC6OH/Sor complex has been characterized by complementary spectroscopic techniques, such as UV-vis, steady-state fluorescence and anisotropy, resonance light scattering and (1)H NMR. The spectroscopic evidences and experiments carried out in the presence of an adamantane derivative, which competes with drug for CD cavity, agree with the entrapment of Sor in aCD, pointing out the role of the aCD cavity in the interaction between drug and amphiphile. Nanoassemblies based on SC6OH/Sor display size of ~200 nm, negative zeta-potential (zeta = -11 mV), and both maximum loading capacity (LC ~ 17%) and entrapment efficiency (EE ~ 100%). Kinetic release profiles show a slower release of Sor from nanoassemblies with respect to the free drug. SC6OH/Sor nanoassemblies have very low hemolytic activity and high efficiency in vitro in decreasing cell growth and viability of HCC cell lines, such as HepG2, Hep3B, and PLC/PRF/5, opening promising chances to their in vivo applications. PMID- 26528592 TI - Ride Quality Evaluation II: Modelling of Airline Passenger Comfort. AB - Quantitative environmental and subjective data obtained aboard commercial airlines are used to model passenger reaction. Several models for comfort are compared. The manner in which the overall response to the flight environment depends on the time history is examined and the variability about the mean response discussed. The relationship to passenger satisfaction is presented giving a quantitative means of relating the physical environment to passenger acceptance. The proposed models give aircraft designers and operators a method by which they may seek to maximize passenger comfort and therefore satisfaction. PMID- 26528593 TI - Experience of Mean Speed Related to Speeds over Parts of a Trip. AB - Subjects were asked to judge the mean speed of a model engine which travelled part of a fixed distance at one steady speed and the remainder at a different steady speed. Mean speed was consistently overestimated when compared with judgements of constant speed over the same distance, suggesting that the faster speed was given too much weight when an impression of mean speed was formed. This, and results reported earlier by the author, indicate that when a driver is allowed to speed up for short periods of time he may overestimate the effect of these spurts on his mean speed and travel time. PMID- 26528594 TI - The Effect of Two-Axis Vibration on the Legibility of Reading Material. AB - The legibility of reading material subjected to single-axis sinusoidal vibration is believed to be dependent on the form of the nodal images. It has been hypothesised that when motions in two axes combine to cause reading material to move with a circular motion the absence of nodal images will greatly reduce legibility. Nine subjects wore required to read arrays of one hundred digits of the form recommended in British Standard 3693A. The effect on reading errors and reading time of seven frequencies of vibration (from 3 to 10 Hz) and the three double amplitudes (4.7 to 8.7 mm) were investigated for vertical, horizontal and circular motion of the digits. It was found that errors and reading time were appreciably greater for the circular motion and increased with increasing vibration frequency and displacement. The legibility of some digits was less affected by the vibration than others and it was found that many reading errors were due to confusion between digits that appear similar when vibrating. It seems probable that a system of digits could be devised to reduce the effects of vibration on reading errors and reading time and it is concluded that the dual axis nature of many vibration environments may be of great practical importance. PMID- 26528595 TI - A Study of Dimension Layout for Engineering Drawings. AB - Three experiments are described which studied the ability of readers of engineering drawings to solve simple dimension problems as a function of the layout of dimensional information. Different dimensional layouts were compared for (i) different types of object drawn, (ii) different types of dimension problem requiring solution, and (iii) undergraduates and experienced draughtsmen. The results showed that (i) there is an interaction between the type of problem the reader tries to solve and the type of drawn object, (ii) drawing variables additional to the geometry of the object drawn influence a reader's ability to extract dimension information rapidly and correctly, (iii) there are individual differences in performance but all subjects studied in these experiments were affected in a very similar manner by changes in the layout of dimensional information and changes in the type of object drawn, and (iv) there is limited support for a hybrid form of ' abstracted " dimensioning. PMID- 26528596 TI - Validity and Reliability of Subjective Ratings of Perceived Exertion During Work. AB - The purpose of the present investigation was to determine the reliability of the Borg (RPE) Scale under a variety of experimental conditions. Fourteen sedentary female subjects performed six repeated work tasks (12 in all) distributed over four experimental testing sessions and presented in a randomized order. Work tasks involved treadmill walking and jogging, cycling, and stool stepping. Work loads were presented in progressive (step-wise), oscillating, or single load submaximal intensities. During work, heart rate (HR) was recorded at regular intervals and ratings of perceived exertion (RPE) were elicited either at regular intervals (interval) or only during the final minute of work (terminal). RPE responses were found to be highly reproducible whether interval or terminal. High correlations were also found between interval and terminal RPE responses. RPE demonstrated a strong relationship with HR and work intensity. It was concluded that category ratings of perceived exertion according to the Borg (RPE) Scale offer a sensitive and reliable measure of stress encountered during work. PMID- 26528597 TI - Monetary and Non-Monetary Incentives in Motor Performance. AB - Performance on a previously reported simple motor task of drawing between parallel straight lines was measured in three experiments. The experiments were identical except for the monetary value of the cumulative achievement feedback. Results for movement speed were identical for all three experiments, but errors were reduced by 45% when real rather than imaginary money was used as feedback. Overall performance was greatly improved from previous experiments where no knowledge of results were given. Neither the risk of losing money nor changes in the cost of errors altered performance significantly. The implications of these results for motor skills research and testing are discussed. PMID- 26528598 TI - The Effects of Spaced Character Formats on the Production and Legibility of Handwritten Names. AB - Three alternative formats for handwritten answers were compared in terms of their case of use. Two of these formats were typical of those employed in the preparation of information for computer analysis. These formats involved subdivisions for spacing individual characters. The third format was a simple unspaced blank. Using speed as a dependent variable, spaced character formats were found to impair both writing and reading and to increase the estimated time required for reading. This impairment in writing and reading was greater with a format in which the characters were spaced by small equidistant vertical marks than with a format in which the spaces for individual characters were defined by a sequence of boxes. PMID- 26528599 TI - Visual Feedback and Skilled Keying: Differential Effects of Masking the Printed Copy and the Keyboard. AB - The results of three experiments are reported. They were designed to substantiate the importance for skilled keying behaviour of information derived from the printed copy and the keyboard. Experiment 1 showed that consulting the copy and the keyboard during transcription constituted part of normal keying activity and that the frequency of consultation was a function of the specific demands of the task..Experiment 2, with no requirement to correct errors, and Experiment 3, with a requirement to correct errors, involved the independent masking of the copy and the keyboard as well as on unmasked control condition. Both experiments showed that an adverse effect on performance, as measured by speed and accuracy, occurred only in the keyboard masked condition. Experiment 3 revealed an additional adverse effect on performance, as measured by the reduced percentage of errors corrected, which occurred only in the copy masked condition. It was concluded that the keyboard provides ' guidance ' information, permitting the appropriate co-ordination of fingers and keys and the location of unfamiliar keys by sight, and the printed copy provides ' feedback ' information concerning the commission of errors. It is argued that the results resolve a contradiction reported in previous research and suggest that visual feedback has a continuing role even in highly practised skills, such as keying. PMID- 26528605 TI - Editorial Notes. PMID- 26528606 TI - Using conceptual work products of health care to design health IT. AB - This paper introduces a new, model-based design method for interactive health information technology (IT) systems. This method extends workflow models with models of conceptual work products. When the health care work being modeled is substantially cognitive, tacit, and complex in nature, graphical workflow models can become too complex to be useful to designers. Conceptual models complement and simplify workflows by providing an explicit specification for the information product they must produce. We illustrate how conceptual work products can be modeled using standard software modeling language, which allows them to provide fundamental requirements for what the workflow must accomplish and the information that a new system should provide. Developers can use these specifications to envision how health IT could enable an effective cognitive strategy as a workflow with precise information requirements. We illustrate the new method with a study conducted in an outpatient multiple sclerosis (MS) clinic. This study shows specifically how the different phases of the method can be carried out, how the method allows for iteration across phases, and how the method generated a health IT design for case management of MS that is efficient and easy to use. PMID- 26528607 TI - Real-space numerical grid methods in quantum chemistry. PMID- 26528608 TI - [Orbitozygomatic approaches to skull base tumors spreading into the orbit, paranasal sinuses, nasal cavity, and pterygopalatine and infratemporal fossae]. AB - The paper analyzes application of orbitozygomatic approaches at the Department of Skull Base and Craniofacial Surgery of the Burdenko Neurosurgical Institute for a 14-year period. During this time, 723 patients were operated on using the orbitozygomatic approach, which has become the workhorse of surgery for skull base tumors spreading into the orbit, paranasal sinuses, and pterygopalatine and infratemporal fossae. The authors describe seven major modifications of the orbitozygomatic approach that they have used in their practice. PMID- 26528609 TI - [Comparison of electrocorticographic patterns with focal cortical dysplasia types in children with epilepsy]. AB - OBJECTIVE: the objective of the study was to determine significant differences in electrocorticographic patterns for various types of focal cortical dysplasias. MATERIAL AND METHODS: 42 patients diagnosed with drug-resistant focal epilepsy were operated on at the Burdenko Neurosurgical Institute in the period from 2006 to 2013. Patients who were histologically diagnosed with focal cortical dysplasia (FCD) and underwent video-electroencephalography and electrocorticography were analyzed. RESULTS: The classification of epileptiform patterns proposed by Palmini in 1995 was used. The sporadic epileptiform activity pattern was predominant in electrocorticographic studies. The continued pattern was more frequent in the case of type II focal cortical dysplasias (FCDs), both combined and isolated; burst and sporadic activity patterns prevailed in combinations in the case of type III FCDs. A uniform distribution of all pattern types of the epileptiform activity was observed in type I FCDs. The data are statistically significant for groups with sporadic and continued patterns. CONCLUSION: The continued epileptiform activity pattern is predominant in type II focal cortical dysplasia that corresponds to the most pronounced epileptogenesis processes of brain tissue with the presence of pathological forms of neurons. A uniform pattern distribution is observed for type I FCD. Patterns of the epileptiform activity and sporadic spike bursts are predominant in the case of type III FCDs. The sporadic activity is likely to be non-specific and almost uniformly distributed in all types of cortical dysplasias. PMID- 26528610 TI - [Cerebrovascular resistance in patients with severe combined traumatic brain injury]. AB - Cerebrovascular resistance is an important parameter of the microcirculation. The main objective of cerebrovascular resistance is to maintain the constancy of cerebral blood flow and protect downstream vessels when changing perfusion pressure. The purpose of the study was to assess cerebrovascular resistance (CVR) in patients with severe combined traumatic brain injury (CTBI) with and without intracranial hematomas (IHs). MATERIAL AND METHODS: We analyzed treatment outcomes in 70 patients with severe CTBI (42 males and 28 females). The mean age was 35.5 +/- 14.8 years (min 15 years; max 73 years). All patients were divided into 2 groups, depending on the presence of intracranial hemorrhage. The first group included 34 patients without IH, and the second group included 36 patients with epidural (6), subdural (26), and multiple (4) hematomas. The GCS score was 10.4 +/- 2.6 in the first group and 10.6 +/- 2.8 in the second group. The ISS severity injury score was 32 +/- 8 in the first group and 31 +/- 11 in the second group. All patients were operated on within the first 3 days, with 30 (83.3%) patients being operated on during the first day. Perfusion computed tomography (PCT) of the brain was performed within 1-14 days after TBI in the first group and within 2-8 days after surgical evacuation of hematoma in the second group. After PCT, the mean arterial pressure was measured, and the blood flow rate in the middle cerebral artery was determined using transcranial dopplerography. Cerebrovascular resistance was calculated using the formula modificated by P. Scheinberg. Comparisons between the groups were performed using the Student t test and chi2 criterion. RESULTS: The mean CVR values in each group (both with and without hematomas) were statistically significantly higher than the mean normal value of this parameter. Intergroup comparison of CVR values demonstrated a statistically significant increase in the CVR level in group 2 on the side of removed hematoma compared to group 1 (p=0.037). CVR in the perifocal zone of removed hematoma remained significantly higher compared to the symmetrical zone of the contralateral hemisphere (p=0.0009). CONCLUSION: Cerebrovascular resistance in patients with combined traumatic brain injury is significantly increased compared to the normal value. Cerebrovascular resistance in the perifocal zone after evacuation of hematoma in patients with multiple injury remains significantly increased compared to the symmetrical zone in the contralateral hemisphere. PMID- 26528611 TI - [Experience in the use of high-frequency selective percutaneous rhizotomy in trigeminal neuralgia associated with multiple sclerosis]. AB - OBJECTIVE: the study was aimed at assessment of the efficacy of percutaneous high frequency selective rhizotomy (PHFSR) after failure of conservative treatment of trigeminal neuralgia (TN) in multiple sclerosis (MS). MATERIAL AND METHODS: A retrospective analysis of 28 patients with TN associated with MS who underwent percutaneous rhizotomy in the period from 2000 to 2014 was performed. All patients were definitely diagnosed with MS according to the McDonald criteria (version of 2001, 2005, and 2010). The patients were divided by age, gender, and the trigeminal nerve branches involved in the process. The patients' condition was evaluated at different times after surgery. RESULTS: Good outcomes in the form of pain syndrome regression were achieved in 100% of the patients. A disease recurrence was observed in 6 (21%) patients during a follow-up period of 3 months to 14 years. Dysesthesia complications occurred in 4 (14%) patients. There were no deaths and severe complications. The percentage of minor complications was low. CONCLUSION: These data confirm that PHFSR is a safe, repeatable, and effective method of symptomatic neurosurgical treatment of TN associated with MS and may be recommended in the case of failure/intolerance of medication. PMID- 26528612 TI - [Vertebrology 2.0: an automatic virtual consultation system]. AB - The use of computer information and Internet technologies to solve clinical problems becomes trivial but is still a topical and promising direction closely related to the "Healthcare 2.0" concept. The methodology for developing virtual patient consultation systems is associated with the capabilities to process obtained data and optimize the choice of optimal tactics for further treatment, taking opportunities of the Internet. The study objective was to develop an automatic virtual consultation system for patients with spine and spinal cord diseases on the basis of the online vertebrologi.ru portal. MATERIAL AND METHODS: 33 signs with different answer variants were selected for advising. On the basis of these signs, an expert advised more than 170 patients. RESULTS AND CONCLUSION: On the basis of consultation analysis, a set of rules was developed to automatically generate a consultation text, depending on selected sign values. Currently, the automatic virtual consultation system, which was developed jointly by the Institute for Systems Analysis, Burdenko Neurosurgical Institute, and Volynskaya Clinical Hospital No1, operates online on the vertebrologi.ru portal as one of its modules. PMID- 26528613 TI - [Principles and experience of surgical treatment of spina bifida in adults]. AB - AIM: The study objective was to summarize our own experience of surgical treatment of spina bifida in adults. MATERIAL AND METHODS: The mean age of patients was 33 years. The time elapsed since the onset of clinical presentations till surgery varied from 11 to 14 years. Among all elective, surgically significant pathologies of the spinal cord (tumors, syringomyelia, arachnoid cysts, spontaneous epidural hematoma, epidural abscess, abscess), spina bifida in adults amounted to 5.9%. RESULTS: The level of social adaptation of patients at the time of diagnosis was quite acceptable (patients had a normal index of intellectual development and the ability to move). The amount of surgery was large and included implementation of several important surgical manipulations. The operative time was 5.5 h, on average. As a result, the spinal cord and its roots were released from compression and retaining structures that, to some extent, allowed for avoiding dissection of the terminal ligament. CONCLUSION: Minimally invasive technologies can not still ensure implementation of all surgical manipulations for correction of the vertebral-medullary anomaly. Surgical treatment of congenital anomalies of the spinal cord in adults proved to be reasonable and effective. PMID- 26528614 TI - [Cerebral actinomycotic granuloma mimicking malignant brain tumor]. AB - We report a clinical case of cerebral actinomycotic granuloma that was preoperatively diagnosed as an intracerebral tumor. On the basis of a histological examination performed after lesion resection, the diagnosis of a cerebral actinomycotic granuloma was made. The article presents long-term outcomes of the surgery. The literature data on cases of various forms of cerebral actinomycosis are provided. PMID- 26528615 TI - [A case report of a high bifurcation of the median nerve]. AB - We present a clinical case of injury to the flexor tendons of the fingers and wrist and to the median and ulnar nerves at the forearm level. An atypical high bifurcation of the median nerve at the forearm level was revealed during surgery. PMID- 26528616 TI - [MRI diagnosis of spinal metastasis of medulloblastoma. A clinical case and literature review]. AB - OBJECTIVE: the study objective was to improve the quality of detection of medulloblastoma metastases. MATERIAL AND METHODS: Magnetic resonance imaging (MRI) of the spinal cord in a child with medulloblastoma of the posterior cranial fossa, which was performed on the first day after surgery, detected contrast positive thickenings of the meninges in the cervical, thoracic, and lumbar spinal cord that might be erroneously diagnosed as metastasis. These lesions spontaneously regressed within 3 weeks, which was verified by control MRI. CONCLUSION: In the case of misinterpretation of a MRI picture of contrast positive thickenings of the meninges, a patient is erroneously regarded as having tumor metastases and is subject to more intensive treatment. However, the lesions spontaneously disappear or greatly reduce after 2-3 weeks. The article presents a case of this phenomenon, describes the putative mechanisms of its development, and provides recommendations for its differential diagnosis from metastases. PMID- 26528617 TI - [Pseudomeningocele with spinal cord compression following removal of meningioma at the Th3-Th4 level: a case report]. AB - Pseudomeningocele is an abnormal extradural collection of the cerebrospinal fluid in soft tissues, communicating with the arachnoid space through a dural defect. Postoperative pseudomenigocele of the thoracic spine presenting with myelopathy is a rare phenomenon; we found only two such cases in the literature. A clinical case of a female patient operated on for meningioma at the Th3-Th4 level with postoperative pseudomenigocele and spinal cord compression is presented. PMID- 26528618 TI - [Endoscopic endonasal removal of the invaginated odontoid process of the C2 vertebra]. AB - Pathological processes in the craniovertebral region (clivus, C1 anterior arch, odontoid process and body of the C2 vertebra, i.e. C0-C1-C2 segments) are very difficult to diagnose and treat. The craniovertebral junction instability may develop in the case of a significant lesion of C1-C2 segments. Among diseases causing destruction of the clivus structures and C1-C2 vertebrae and compression of the spinal cord, the following ones are most common: chordoma, giant cell tumor, osteoblastoma, rheumatoid lesion, metastases, platybasia, and basilar impression. These diseases can cause the initial instability of the craniovertebral junction and be accompanied by gross neurological disorders, which complicates the diagnosis and surgical treatment of these patients. MATERIAL AND METHODS: We operated on two patients diagnosed with invagination of the odontoid process of the C2 vertebra. In both cases, one-stage operation was performed that included occipitospondylodesis and endoscopic endonasal removal of the C2 odontoid process. RESULTS: In the postoperative period, partial regression of the neurological symptoms was observed that included an increase in the strength and range of motions in the arms and distal legs, regressed spasticity in the arms and significantly reduced spasticity in the legs, and a significant improvement in all kinds of sensitivity in the arms, legs, and torso. Postoperative liquorrhea was observed in 1 case (patient 2); re-operation to close a CSF fistula was conducted. Later, no signs of liquorrhea were noted. In both cases, control MRI and spiral CT revealed a postoperative bone defect of the C2 odontoid process and clivus, complete decompression of the medulla oblongata and upper cervical spine segments, and no evidence of spinal canal stenosis; the stabilizing system was competent and properly placed. CONCLUSION: The endoscopic endonasal approach, compared to the standard transoral approach, has significant advantages in that the soft palate remains intact, the oropharynx area is less damaged, and the hospitalization and rehabilitation duration is reduced. Also, there are no problems and complications such as possible failure of sutures in the oral cavity and a large wound surface in the oropharynx area. The patient can eat on his own immediately after the operation without the use of a stomach tube (it does not cause any inflammatory complications of the oral cavity). However, the surgical technique of the endoscopic endonasal approach to the C1-C2 segment is more complex than that of transoral surgery and requires the surgeon to be skilled and experienced. PMID- 26528619 TI - [Clinical guidelines for the use of intraoperative fluorescence diagnosis in brain tumor surgery]. AB - In this paper, we present a review of current literature on the application of intraoperative fluorescence diagnosis and fluorescence spectroscopy using 5 aminolevulinic acid in surgery for various types of brain tumors, both alone and in combination with other neuroimaging methods. Authors' extensive experience with these methods allowed them to develop a set of clinical guidelines for the use of intraoperative fluorescence diagnosis and fluorescence spectroscopy in surgery of brain tumors. PMID- 26528620 TI - Nitrogen-doped hollow carbon spheres with large mesoporous shells engineered from diblock copolymer micelles. AB - Nitrogen-doped hollow carbon spheres with engineered large tunable mesoporous (~20 nm) shells were successfully synthesized for the first time by using the colloidal silica and the diblock copolymer PS-b-PEO as the dual-template and dopamine as the precursor. The unique structural properties enable them to be promising materials as adsorbents, catalyst supports, electrode materials, drug delivery carriers and hosts for active substances. PMID- 26528621 TI - Modeling and Prediction of Oyster Norovirus Outbreaks along Gulf of Mexico Coast. AB - BACKGROUND: Oyster norovirus outbreaks often pose high risks to human health. However, little is known about environmental factors controlling the outbreaks, and little can be done to prevent the outbreaks because they are generally considered to be unpredictable. OBJECTIVE: We sought to develop a mathematical model for predicting risks of oyster norovirus outbreaks using environmental predictors. METHODS: We developed a novel probability-based Artificial Neural Network model, called NORF model, using 21 years of environmental and norovirus outbreak data collected from Louisiana oyster harvesting areas along the Gulf of Mexico coast, USA. The NORF model involves six input variables that were selected through stepwise regression analysis and sensitivity analysis. RESULTS: We found that the model-based probability of norovirus outbreaks was most sensitive to gage height (the depth of water in an oyster bed) and water temperature, followed by wind, rainfall, and salinity, respectively. The NORF model predicted all historical oyster norovirus outbreaks from 1994 through 2014. Specifically, norovirus outbreaks occurred when the NORF model probability estimate was > 0.6, whereas no outbreaks occurred when the estimated probability was < 0.5. Outbreaks may also occur when the estimated probability is 0.5-0.6. CONCLUSIONS: Our findings require further confirmation, but they suggest that oyster norovirus outbreaks may be predictable using the NORF model. The ability to predict oyster norovirus outbreaks at their onset may make it possible to prevent or at least reduce the risk of norovirus outbreaks by closing potentially affected oyster beds. CITATION: Wang J, Deng Z. 2016. Modeling and prediction of oyster norovirus outbreaks along Gulf of Mexico coast. Environ Health Perspect 124:627-633; http://dx.doi.org/10.1289/ehp.1509764. PMID- 26528623 TI - Reversible Tuning of Interfacial and Intramolecular Charge Transfer in Individual MnPc Molecules. AB - The reversible selective hydrogenation and dehydrogenation of individual manganese phthalocyanine (MnPc) molecules has been investigated using photoelectron spectroscopy (PES), low-temperature scanning tunneling microscopy (LT-STM), synchrotron-based near edge X-ray absorption fine structure (NEXAFS) measurements, and supported by density functional theory (DFT) calculations. It is shown conclusively that interfacial and intramolecular charge transfer arises during the hydrogenation process. The electronic energetics upon hydrogenation is identified, enabling a greater understanding of interfacial and intramolecular charge transportation in the field of single-molecule electronics. PMID- 26528622 TI - Comparative genomic study of arachnid immune systems indicates loss of beta-1,3 glucanase-related proteins and the immune deficiency pathway. AB - Analyses of arthropod genomes have shown that the genes in the different innate humoral immune responses are conserved. These genes encode proteins that are involved in immune signalling pathways that recognize pathogens and activate immune responses. These immune responses include phagocytosis, encapsulation of the pathogen and production of effector molecules for pathogen elimination. So far, most studies have focused on insects leaving other major arthropod groups largely unexplored. Here, we annotate the immune-related genes of six arachnid genomes and present evidence for a conserved pattern of some immune genes, but also evolutionary changes in the arachnid immune system. Specifically, our results suggest that the family of recognition molecules of beta-1,3-glucanase related proteins (betaGRPs) and the genes from the immune deficiency (IMD) signalling pathway have been lost in a common ancestor of arachnids. These findings are consistent with previous work suggesting that the humoral immune effector proteins are constitutively produced in arachnids in contrast to insects, where these have to be induced. Further functional studies are needed to verify this. We further show that the full haemolymph clotting cascade found in the horseshoe crab is retrieved in most arachnid genomes. Tetranychus lacks at least one major component, although it is possible that this cascade could still function through recruitment of a different protein. The gel-forming protein in horseshoe crabs, coagulogen, was not recovered in any of the arachnid genomes; however, it is possible that the arachnid clot consists of a related protein, spatzle, that is present in all of the genomes. PMID- 26528624 TI - Whole-cell biocatalytic production of variously substituted beta-aryl- and beta heteroaryl-beta-amino acids. AB - Biologically-active beta-peptides and pharmaceuticals that contain key beta-amino acids are emerging as target therapeutics; thus, synthetic strategies to make substituted, enantiopure beta-amino acids are increasing. Here, we use whole-cell Escherichia coli (OD600 ~ 35) engineered to express a Pantoea agglomerans phenylalanine aminomutase (PaPAM) biocatalyst. In either 5 mL, 100mL, or 1L of M9 minimal medium containing alpha-phenylalanine (20mM), the cells produced ~ 1.4 mg mL(-1) of beta-phenylalanine in each volume. Representative pilot-scale 5-mL cultures, fermentation reactions converted 18 variously substituted alpha arylalanines to their (S)-beta-aryl-beta-amino acids in vivo and were not toxic to cells at mid- to late-stage growth. The beta-aryl-beta-amino acids made ranged from 0.043 mg (p-nitro-beta-phenylalanine, 4% converted yield) to 1.2mg (m-bromo beta-phenylalanine, 96% converted yield) over 6h in 5 mL. The substituted beta amino acids made herein can be used in redox and Stille-coupling reactions to make synthetic building blocks, or as bioisosteres in drug design. PMID- 26528625 TI - Corynebacterium glutamicum ggtB encodes a functional gamma-glutamyl transpeptidase with gamma-glutamyl dipeptide synthetic and hydrolytic activity. AB - In this work the role of gamma-glutamyl transpeptidase in the metabolism of gamma glutamyl dipeptides produced by Corynebacterium glutamicum ATCC 13032 was studied. The enzyme is encoded by the gene ggtB (cg1090) and synthesized as a 657 amino acids long preprotein. Gamma-glutamyl transpeptidase activity was found to be associated with intact cells of C. glutamicum and was abolished upon deletion of ggtB. Bioinformatic analysis indicated that the enzyme is a lipoprotein and is attached to the outer side of the cytoplasmic membrane. Biochemical parameters of recombinant GgtB were determined using the chromogenic substrate gamma-glutamyl-p nitroanilide. Highest activity of the enzyme was measured in sodium bicarbonate buffer at pH 9.6 and 45 degrees C. The KM value was 123MUM. GgtB catalyzed the concentration-dependent synthesis and hydrolysis of gamma-glutamyl dipeptides and showed strong glutaminase activity. The intracellular concentrations of five gamma-glutamyl dipeptides (gamma-Glu-Glu, gamma-Glu-Gln, gamma-Glu-Val, gamma-Glu Leu, gamma-Glu-Met) were determined by HPLC-MS and ranged from 0.15 to 0.4mg/g CDW after exponential growth in minimal media. Although deletion and overexpression of ggtB had significant effects on intracellular dipeptide concentrations, it was neither essential for biosynthesis nor catabolism of these dipeptides in vivo. PMID- 26528627 TI - Ischemic mitral regurgitation: can we identify who is at risk? PMID- 26528626 TI - Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). AB - The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, metformin is transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic cation transporter 1, OCT1, the major hepatic uptake transporter for metformin, was also the primary hepatic uptake transporter for thiamine, vitamin B1. In this study, we tested the reverse, i.e., that metformin is a substrate of thiamine transporters (THTR-1, SLC19A2, and THTR-2, SLC19A3). Our study demonstrated that human THTR-2 (hTHTR-2), SLC19A3, which is highly expressed in the small intestine, but not hTHTR-1, transports metformin (Km = 1.15 +/- 0.2 mM) and other cationic compounds (MPP(+) and famotidine). The uptake mechanism for hTHTR-2 was pH and electrochemical gradient sensitive. Furthermore, metformin as well as other drugs including phenformin, chloroquine, verapamil, famotidine, and amprolium inhibited hTHTR-2 mediated uptake of both thiamine and metformin. Species differences in the substrate specificity of THTR-2 between human and mouse orthologues were observed. Taken together, our data suggest that hTHTR-2 may play a role in the intestinal absorption and tissue distribution of metformin and other organic cations and that the transporter may be a target for drug-drug and drug-nutrient interactions. PMID- 26528628 TI - New oral nitric oxide-dependent medications for patients with coronary artery disease who have persistent angina pectoris. PMID- 26528629 TI - Tuning thermoelectric properties of graphene/boron nitride heterostructures. AB - Using density functional theory combined with a Green's function scattering approach, we examine the thermoelectric properties of hetero-nanoribbons formed from alternating lengths of graphene and boron nitride. In such structures, the boron nitride acts as a tunnel barrier, which weakly couples states in the graphene, to form mini-bands. In un-doped nanoribbons, the mini bands are symmetrically positioned relative to the Fermi energy and do not enhance thermoelectric performance significantly. In contrast, when the ribbons are doped by electron donating or electron accepting adsorbates, the thermopower S and electronic figure of merit are enhanced and either positive or negative thermopowers can be obtained. In the most favourable case, doping with the electron donor tetrathiafulvalene increases the room-temperature thermopower to 284 MUv K(-1) and doping by the electron acceptor tetracyanoethylene increases S to 210 MUv K(-1). After including both electron and phonon contributions to the thermal conductance, figures of merit ZT up to of order 0.9 are obtained. PMID- 26528630 TI - Phylogeographic surveys and apomictic genetic connectivity in the North Atlantic red seaweed Mastocarpus stellatus. AB - The North Atlantic red alga Mastocarpus stellatus is characterized by two life histories (sexual-type and direct-type), which correspond to two geographically isolated breeding groups. These features enable M. stellatus to be an interesting model to investigate how environmental shift and apomictic propagation have influenced its population genetic structure, historical demography and distribution dynamic. To test these ideas, we obtained 456 specimens from 15 locations on both sides of the North Atlantic and sequenced portion of the nuclear internal transcribed spacer (ITS), mitochondrial cox2-3 region (COX) and plastid RuBisCo spacer (RLS). Median-joining networks and ML trees inferred from COX and RLS consistently revealed two gene lineages (mtDNA: CN, CS; cpDNA: RN, RS). The concatenated COX and RLS markers yielded three cytotypes: a northern CN RN, a southern CS-RS and a mixed cytotype CS-RN, which enabled us to roughly separate samples into D (direct-type life-cycle) and S (sexual-type life-cycle) groups (northern CN-RN and mixed cytotype CS-RN=D; southern CS-RS=S). Pairwise FST analysis of the D group revealed a high level of genetic differentiation both along European coasts and across the Atlantic basin. Bayesian skyline plots (BSPs) and IMa analyses indicated that M. stellatus underwent slight demographic expansion at the late-Pleistocene, with the beginning of divergence between lineages dating to c. 0.189Ma (95%HPD: 0.083-0.385Ma). IMa analyses also revealed asymmetric genetic exchange among European populations and a predominant postglacial trans-Atlantic migration from Norway and Galway Bay to North America. Our study highlights the importance of phylogeographic approaches to discover the imprints of climate change, life histories and gene flow in driving population genetic connectivity and biogeographic distribution of intertidal seaweeds in the North Atlantic. PMID- 26528631 TI - A comprehensive meta-analysis on evidence of Mediterranean diet and cardiovascular disease: Are individual components equal? AB - Many studies have reported that higher adherence to Mediterranean diet may decrease cardiovascular disease (CVD) incidence and mortality. We performed a meta-analysis to explore the association in prospective studies and randomized control trials (RCTs) between Mediterranean diet adherence and CVD incidence and mortality. The PubMed database was searched up to June 2014. A total of 17 studies were extracted and 11 qualified for the quantitative analysis. Individuals in the highest quantile of adherence to the diet had lower incidence [relative risk (RR): 0.76, 95% confidence intervals (CI): 0.68, 0.83] and mortality (RR: 0.76, 95% CI: 0.68, 0.83) from CVD compared to those least adherent. A significant reduction of risk was found also for coronary heart disease (CHD) (RR: 0.72, 95% CI: 0.60, 0.86), myocardial infarction (MI) (RR: 0.67; 95% CI: 0.54, 0.83), and stroke (RR: 0.76; 95% CI: 0.60, 0.96) incidence. Pooled analyses of individual components of the diet revealed that the protective effects of the diet appear to be most attributable to olive oil, fruits, vegetables, and legumes. An average reduced risk of 40% for the aforementioned outcomes has been retrieved when pooling results of RCTs. A Mediterranean dietary pattern is associated with lower risks of CVD incidence and mortality, including CHD and MI. The relative effects of specific food groups should be further investigated. PMID- 26528632 TI - Correction: Ultrafast immunoassays by coupling dielectrophoretic biomarker enrichment in nanoslit channel with electrochemical detection on graphene. AB - Correction for 'Ultrafast immunoassays by coupling dielectrophoretic biomarker enrichment in nanoslit channel with electrochemical detection on graphene' by Bankim J. Sanghavi et al., Lab Chip, 2015, DOI: 10.1039/c5lc00840a. PMID- 26528633 TI - Isolation and Functional Analysis of Human Neutrophils. AB - This unit describes the isolation of human polymorphonuclear neutrophils (PMN) from blood using dextran sedimentation and Percoll or Ficoll-Paque density gradients. Assays of neutrophil functions including respiratory burst activation, phagocytosis, and microbial killing are also described. PMID- 26528634 TI - A novel percutaneous coronary intervention technique for chronic total occlusion: Contralateral angiography with a single guiding catheter. AB - We report two successful cases with a new percutaneous coronary intervention (PCI) technique to treat chronic total occlusion (CTO) by using contra-lateral coronary angiography with a single guiding catheter (GC) safely. Firstly, a GC was inserted into the coronary artery supplying collaterals and a microcatheter was inserted into the distal side of the coronary artery. Then, the GC was retroflexed and engaged in the targeted coronary artery with CTO. While the contra-lateral coronary artery was visualized by injection through a microcatheter, a guide wire was controlled and passed through the CTO lesion. Two sheaths insertion were necessary to perform contra-lateral angiography in CTO PCI. This new technique makes it possible to perform safe contra-lateral angiography with a single sheath and a single GC. It could reduce vascular access complication rates. (c) 2015 Wiley Periodicals, Inc. PMID- 26528635 TI - Special AT-rich sequence binding protein 1 expression correlates with response to preoperative radiotherapy and clinical outcome in rectal cancer. AB - Our recent study showed the important role of special AT-rich sequence binding protein 1 (SATB1) in the progression of human rectal cancer. However, the value of SATB1 in response to radiotherapy (RT) for rectal cancer hasn't been reported so far. Here, SATB1 was determined using immunohistochemistry in normal mucosa, biopsy, primary cancer, and lymph node metastasis from 132 rectal cancer patients: 66 with and 66 without preoperative RT before surgery. The effect of SATB1 knockdown on radiosensitivity was assessed by proliferation-based assay and clonogenic assay. The results showed that SATB1 increased from normal mucosa to primary cancer, whereas it decreased from primary cancer to metastasis in non-RT patients. SATB1 decreased in primary cancers after RT. In RT patients, positive SATB1 was independently associated with decreased response to preoperative RT, early time to metastasis, and worse survival. SATB1 negatively correlated with ataxia telangiectasia mutated (ATM) and pRb2/p130, and positively with Ki-67 and Survivin in RT patients, and their potential interaction through different canonical pathways was identified in network ideogram. Taken together, our findings disclose for the first time that radiation decreases SATB1 expression and sensitizes cancer cells to confer clinical benefit of patients, suggesting that SATB1 is predictive of response to preoperative RT and clinical outcome in rectal cancer. PMID- 26528636 TI - Galectin-3 and sST2 in prediction of left ventricular ejection fraction after myocardial infarction. AB - BACKGROUND: Fibrosis is a pivotal event in infarct repair and progressive remodeling after myocardial infarction (MI). Biomarkers may be used to monitor fibrosis, and therefore we evaluated the predictive value of galectin-3 and sST2 for cardiac remodeling after MI. METHODS: Plasma galectin-3 and sST2 were measured in patients admitted with primary percutaneous coronary intervention (PCI) for acute MI, at baseline and at 4months. Left ventricular ejection fraction (LVEF) and infarct size were measured after 4months with cardiac MRI (CMR). RESULTS: In total, 247 patients had blood samples and CMR data available (mean age 57.7+/-11.6years; 79.8% male). Increased baseline galectin-3 (>=17.8ng/mL) identified patients with lower LVEF (50.3% (+/-9.1) vs. non elevated galectin-3 55.0% (+/-8.0); P<0.001), and larger infarct size (13.8g. (+/ 12.9) vs. 8.6g. (+/-8.7); P=0.002) after 4months. Elevated sST2 (>=35.0ng/mL) did not predict decreased LVEF or larger infarct size. Furthermore we showed that at baseline, galectin-3 was an independent predictor for LVEF (beta=-0.18; P=0.005) and infarct size (beta=0.18; P=0.004). We repeated the analyses using median values of galectin-3 (13.4ng/mL) and sST2 (30.3ng/mL) as a cut point, and this validated our results. CONCLUSION: The fibrosis biomarker galectin-3, but not sST2, taken immediately after MI, predicts LVEF and infarct size after 4months. We hypothesize that galectin-3 may play a role in the pathophysiology of cardiac remodeling after acute MI. PMID- 26528637 TI - Pitfalls in the detection of gross gene rearrangements using MLPA in Fabry disease. AB - MLPA (Multiplex Ligation-dependent Probe Amplification) is a semiquantitative molecular technique developed to uncover gross gene rearrangements in several monogenic diseases, including the X-linked Fabry disease (FD) caused by mutations in the GLA gene. Heterozygosity of the X chromosome in females makes it important to combine routine sequencing analysis with at least one allelic dosage assay (i.e. MLPA). We identified two new gross GLA gene rearrangements, which were not properly detected by MLPA in male patients with FD. In Patient 1, routine sequencing did not amplify GLA exon 7. MLPA failed to confirm such deletion. An alternative allele dosage, based on the Quantitative Fluorescent Multiplex-PCR (QFM-PCR), confirmed the mutation in the proband and excluded it in the mother, revealing that the mutation was de novo in the proband. Patient 2 harboured a gross GLA gene deletion encompassing almost the entire exon 5, the entire intron 5 and part of exon 6. MLPA confirmed the deletion of exon 5 but missed the partial deletion of exon 6. We characterised the breakpoint (c.652_886del452) and carried out screening for possible heterozygosity among at risk female family members. MLPA can miss some gross GLA gene rearrangements making the combination with other allele dosage assays mandatory to confirm or exclude FD at the molecular level. PMID- 26528638 TI - Too Many Rationales, Not Enough Reason: A Call to Examine the Goals of Including Lay Members on Institutional Review Boards. AB - Every major U.S. commission appointed to review Institutional Review Boards (IRBs) as well as numerous reports and scholarly articles have recommended increasing the number of lay (nonscientist and unaffiliated) members on IRBs. Meanwhile, qualitative studies have shown that lay IRB members experience confusion about their roles, including ambiguity whether their roles are different from other members of the board. Without articulating the unique reasons why unaffiliated and nonscientist members are needed, IRBs have little guidance on how to recruit and train these members, and how many should be at the table. By looking back through the history of IRB regulations, policies, and commentaries we can articulate unique contributions these members can make. Only with these contributions in mind can we make arguments for how to best achieve them and make the case that increasing their numbers is necessary. PMID- 26528639 TI - Pharmacovigilance in Clinical Trials: Current Practice and Challenges. AB - In view of the MENA increasing participation in multinational trials and the increasing number of national/regional trials, this article explores potential areas of pharmacovigilance, requiring reform and provides recommendations for building a robust safety reporting system. Regulatory silence on expedited reporting requirements creates confusion for local sites that are part of multinational trials. Not allowing waiver for serious adverse events that are protocol specified or are study endpoints, along with lack of emphasis on causality as reporting criteria, adds substantial burden of uninformative cases for regulatory review. Despite global focus on Development Safety Update Report, local regulators are not yet insistent on real-time update of a drug's cumulative safety profile. Issues like reporting requirements for generic trials, pregnancy reporting and lenient timeline for death/life-threatening events need attention. Finally, the need to formulate an all-encompassing local pharmacovigilance guideline, in sync with global practice cannot be overemphasized. PMID- 26528640 TI - Left cheek bias for emotion perception, but not expression, is established in children aged 3-7 years. AB - As the left hemiface is controlled by the emotion-dominant right hemisphere, emotion is expressed asymmetrically. Portraits showing a model's left cheek consequently appear more emotive. Though the left cheek bias is well established in adults, it has not been investigated in children. To determine whether the left cheek biases for emotion perception and expression are present and/or develop between the ages of 3 and 7 years, 145 children (71 male, 74 female; M age = 65.49 months) completed two experimental tasks: one assessing biases in emotion perception, and the other assessing biases in emotion expression. Regression analysis confirmed that children aged 3-7 years find left cheek portraits happier than right cheek portraits, and age does not predict the magnitude of the bias. In contrast when asked to pose for a photo expressing happiness children did not show a left cheek bias, with logistic regression confirming that age did not predict posing orientations. These findings indicate that though the left cheek bias for emotion perception is established by age 3, a similar bias for emotion expression is not evident by age 7. This implies that tacit knowledge of the left cheek's greater expressivity is not innate but develops in later childhood/adolescence. PMID- 26528641 TI - Antipsychotic treatment of adults in the United States. AB - OBJECTIVE: Despite safety risks associated with antipsychotic medications, little is known about their use in older adults. This article describes patterns of antipsychotic treatment of older and younger adults in the United States. METHOD: The IMS LifeLink LRx Longitudinal Prescription database was analyzed retrospectively, focusing on adults who filled antipsychotic prescriptions. The database was searched for the years 2006 and 2008-2010. Denominators were adjusted to generalize annual antipsychotic use percentages by sex and single year of age to the US population. Among adults with any antipsychotic use, percentages with short-term (<= 30 days) and long-term (>= 120 days) use, prescriptions from psychiatrists, use of other psychotropic medication classes, and ICD-9 clinical diagnoses were also evaluated. RESULTS: The percentages of US adults by age group who used antipsychotics in 2010 were 0.93% (20-34 years), 1.46% (35-59 years), 1.54% (60-64 years), 1.36% (65-69 years), 1.36% (70-74 years), 1.58% (75-79 years), and 2.09% (80-84 years). Women were consistently more likely than men to use antipsychotics. The percentages of antipsychotic treated older adults with long-term use were 53.7% (70-74 years), 49.2% (75-79 years), and 46.2% (80-84 years). Among adults with any antipsychotic use, percentages with prescriptions from psychiatrists decreased with age from 66.2% (20-34 years) to 20.6% (80-84 years). Dementia was commonly diagnosed among antipsychotic-treated adults aged 75-79 years (37.2%) and 80-84 years (47.8%) who had any mental disorder or dementia diagnoses. CONCLUSIONS: Despite concerns over the safety of antipsychotic treatment of older adults, long-term use is common. Key challenges for clinical research and practice include development and implementation of management strategies for older adults that are safer than antipsychotic medications. PMID- 26528642 TI - Narrowing the gaps between what we know and what we do in psychiatry. AB - There are many important research-practice gaps. Evidence to inform clinical decision-making is remarkably scant. A greater research focus on more clinically informative patient samples, clinically relevant questions, the use of innovative trial designs and analyses, and reporting of results in clinically understandable and potentially actionable ways can help reduce these gaps. Efforts to reduce intellectual silos, lessen the burden of research, and revise some academic incentives and publication practices would also be of help in reducing these gaps and hopefully improving patient care and outcomes. PMID- 26528643 TI - Early career psychiatrists. Introduction. PMID- 26528644 TI - Response of depression to electroconvulsive therapy: a meta-analysis of clinical predictors. AB - OBJECTIVE: Roughly one-third of individuals with depression do not respond to electroconvulsive therapy (ECT). Reliable predictors of ECT response would be useful for patient selection, but have not been demonstrated definitively. We used meta-analysis to measure effect sizes for a series of clinical predictors of ECT response in depression. DATA SOURCES: PubMed was searched systematically to identify studies published after 1980 that tested at least 1 clinical predictor of response to ECT. STUDY SELECTION: Of 51 studies identified, 32 were compatible with meta-analysis. DATA EXTRACTION: The weighted mean odds ratio (OR) or standardized mean difference (SMD) was computed for each of 10 clinical predictors, based on dichotomous outcomes (responder vs nonresponder). Statistical analyses examined robustness, bias, and heterogeneity. RESULTS: Shorter depressive episode duration predicted higher ECT response rate (SMD = 0.37, 7 studies, 702 subjects, P = 4 * 10(-6)). History of medication failure in the current episode was also a robust predictor: response rates were 58% and 70%, respectively, for those with and without medication failure (OR = 0.56, 11 studies, 1,175 subjects, P = 1 * 10(-5)). Greater age and psychotic features were weakly associated with higher ECT response rates, but heterogeneity was notable. Bipolar diagnosis, sex, age at onset, and number of previous episodes were not significant predictors. Analyses of symptom severity and melancholic features were inconclusive due to study heterogeneity. CONCLUSIONS: Longer depressive episodes and medication failure at baseline are robust predictors of poor response to ECT, with effect sizes that are modest but clinically relevant. Patient characteristics used traditionally such as age, psychosis, and melancholic features are less likely to be clinically useful. More robust clinical and biological predictors are needed for management of depressed patients considering ECT. PMID- 26528645 TI - Perinatal depression in HIV-infected African women: a systematic review. AB - OBJECTIVE: To systematically review the literature on prevalence and incidence of perinatal depression in human immunodeficiency virus (HIV)-infected African women. DATA SOURCES: We searched 17 databases, including PubMed, PsycINFO, Cochrane, EMBASE, Web of Science, ClinicalTrials.gov, Google Scholar, and OpenGrey, from inception through August 2014 using the search strategy ((antenatal OR peripartum OR perinatal OR postnatal OR postpartum) AND (depression OR mental disorder) AND HIV AND Africa NOT (-) American). STUDY SELECTION: We included English-language articles on studies conducted in Africa with prevalence or incidence rates of diagnostically confirmed depression or suspected depression in HIV-infected women during pregnancy through 12 months postpartum. DATA EXTRACTION: We examined details of study design, location, means of measurement, incidence and prevalence rates of diagnostically confirmed depression or suspected depression and any associated risk factors for development of depression. Mean prevalence rates were calculated and weighted based on study size. RESULTS: Twenty-two articles met inclusion criteria. Two reported diagnostically confirmed antenatal depression, and 9 reported suspected antenatal depression prevalence. Two reported diagnostically confirmed postnatal depression, and 10 reported suspected postnatal depression prevalence. Weighted mean prevalence of antenatal depression was 23.4%, and suspected antenatal depression was 43.5%. Weighted mean prevalence of postnatal depression was 22.5%, and suspected postnatal depression was 31.1%. No studies reported incidence rates. CONCLUSIONS: Few studies have examined the rate of perinatal depression in HIV-infected African women. Existing studies show a high prevalence of perinatal depression, with even higher prevalence rates of suspected depression. No data on the incidence of perinatal depression in this population exist. PMID- 26528646 TI - Detection and classification of suicidal behavior and nonsuicidal self-injury behavior in emergency departments. AB - OBJECTIVE: The degree of concordance between clinical and standardized assessments in the detection and classification of suicidal behavior and nonsuicidal self-injury behavior in psychiatric emergency department settings was examined. METHOD: Two hundred fifty-four patients at 3 psychiatric emergency departments between 2007 and 2011 were evaluated by research staff using standardized assessments of suicidal behavior and nonsuicidal self-injury behavior. Of 254 patients, 128 (50%) made a recent suicide attempt, 30 (12%) engaged in recent nonsuicidal self-injury behavior, 20 (8%) made a recent suicide attempt interrupted by self or others, and 76 (30%) had other psychiatric symptoms in the absence of recent suicidal or nonsuicidal self-injury behavior. The classifications derived from the standardized assessments using the Centers for Disease Control and Prevention (CDC) nomenclature were compared to clinical assessments independently extracted from emergency department medical records. RESULTS: Agreement between clinical and standardized assessments was substantial for both suicide attempts (kappa = 0.76, P < .001) and nonsuicidal self-injury behavior (kappa = 0.72, P < .001). Importantly, 18% of patients determined to have made a suicide attempt in the past week by standardized assessment were not identified as such by clinical assessment. In addition, as measured by the Columbia Suicide Severity Rating Scale, the potential lethality of attempts for patients classified as making a recent suicide attempt by both clinician and standardized assessments was significantly greater (t120 = 2.1, P = .04) than that for patients who were classified as having made an attempt by the standardized but not clinical assessment. CONCLUSIONS: The use of standardized assessment measures may improve sensitivity and accuracy of identifying suicidal behavior and nonsuicidal self-injury behavior in psychiatric emergency departments. PMID- 26528647 TI - Posttraumatic stress disorder and risk of obesity: systematic review and meta analysis. AB - OBJECTIVE: To examine the association between posttraumatic stress disorder (PTSD) and obesity in the literature to date. DATA SOURCES: We systematically searched PubMed, Embase, Scopus, Web of Science, and ProQuest from database inception till September 2013. Search phrases combining the terms Obesity and Post-Traumatic Stress Disorder were used. STUDY SELECTION: We selected observational studies estimating obesity prevalence in samples of people with PTSD, as well as in comparison groups without PTSD. DATA EXTRACTION: Obesity rates as well as demographic, clinical, and methodological variables were extracted from each publication or obtained directly from its authors. RESULTS: A total of 113, 395, 59, 115, and 400 records were generated from PubMed, Embase, Scopus, Web of Science, and ProQuest, respectively. Thirteen studies were eligible according to inclusion criteria. The pooled crude odds ratio (OR) and 95% confidence interval (CI) for obesity among people with PTSD, based on 589,781 subjects, was 1.55 (1.32-1.82). A large heterogeneity was found (I(2) = 90%), and risk of publication bias was statistically significant (P = .002). However,subgroup and sensitivity analyses including only studies with most accurate methods to assess obesity (OR = 1.35; 95% CI,1.05-1.74; I(2) = 47%) and PTSD (OR = 1.82; 95% CI, 1.33-2.50; I(2) = 75%) also confirmed the association between PTSD and obesity. CONCLUSIONS: Despite some limitations, individuals suffering from PTSD seem more likely, relative to controls, to suffer from obesity. As such, individuals with this comorbidity should be targeted for intensive prevention and treatment focused on both disorders. Future research is needed to identify the role of unknown factors and mediators that might clarify the nature of this association. PMID- 26528648 TI - Impact of psychiatric comorbidity and cognitive deficit on function in 22q11.2 deletion syndrome. AB - OBJECTIVE: Presence of psychiatric comorbidity is associated with poor functioning and is an important consideration in treatment. Many individuals with 22q11.2 deletion syndrome (22q11DS) develop comorbid psychiatric disorders, yet its pattern and impact on functioning have not been formally investigated. In this cross-sectional study, we examined the relationship between comorbid psychopathology and neurocognitive deficits and their association with global functioning. We hypothesized that higher psychiatric burden and psychosis spectrum features would be associated with reduced functioning and increased neurocognitive deficits. METHOD: The cohort included 171 individuals with 22q11DS and mean (SD) age of 17.4 (8.1) years, recruited from a tertiary children's hospital and nationally through social media between September 2010 and December 2013. Psychiatric diagnoses and functioning were assessed using semistructured interviews and the Global Assessment of Functioning (GAF) scale, respectively. On the basis of psychopathology and number of comorbid diagnoses, participants were assigned to unaffected (n = 32), nonpsychosis spectrum (n = 24), nonpsychosis spectrum-plus (n = 15), psychosis spectrum (n = 29), and psychosis spectrum-plus (n = 71) groups. Executive function, episodic memory, complex cognition, social cognition, and praxis speed were assessed using a computerized neurocognitive battery (CNB). Cognitive profile and GAF scores were compared among the groups, and the association of GAF with cognitive performance and psychopathology was examined. RESULTS: We observed high rates of comorbid psychiatric disorders. Approximately 50% of the participants had >= 2 diagnoses. Psychosis spectrum disorders were most frequently comorbid with other disorders. GAF score was progressively worse with increased psychiatric burden. Mean (SD) GAF score for the unaffected group (81.1 [8.9]) was significantly different from those of nonpsychosis spectrum (68.6 [12.1]), nonpsychosis spectrum-plus (63.4 [8.8]), psychosis spectrum (58.7 [13.1]), or psychosis spectrum-plus (55.5 [13.3]) (P < .05) groups. All groups performed poorly and were comparable to each other on the CNB (P = .273). Notably, verbal memory (P = .003), spatial processing (P = .001), and parent education level (P < .001) were significantly associated with GAF. CONCLUSIONS: Individuals with 22q11DS have high rates of comorbid psychiatric disorders and diffuse cognitive deficits regardless of psychiatric burden. Those with psychotic spectrum disorders and comorbid psychiatric disorders are at an increased risk for poor overall functioning. PMID- 26528649 TI - Drug utilization trends in patients with posttraumatic stress disorder in a postconflict setting: consistency with clinical practice guidelines. AB - OBJECTIVE: The objective of this study was to compare observed patterns of drug utilization among patients with posttraumatic stress disorder (PTSD) in a postconflict setting with current guidelines and to present baseline period prevalence and change in period prevalence from 2 time periods, 2002 and 2012. METHOD: The study provides details of the annual number of patients with PTSD with at least 1 redeemed prescription containing the diagnostic code F43.1 according to International Classification of Diseases (ICD-10) for fiscal years 2002 through 2012 in Croatia. Using longitudinal data analysis, overall change in medication use frequency was calculated for each medication and therapeutic subgroup classified by the Anatomic Therapeutic Chemical classification system according to absolute frequency. RESULTS: Over the 11-year study period, the number of patients receiving pharmacotherapy associated with PTSD increased 7 fold. The annual frequency of drug use was highest for anxiolytics, with use of anxiolytics increasing from 73.32% in 2002 to 75.83% in 2012; antidepressants, from 44.56% to 61.36%; hypnotics, from 18.67% to 35.68%; and antipsychotics, from 21.81% to 30.21%. Overall change in drug utilization frequency was most prominent for hypnotics (17.01%), antidepressants (16.80%), and antipsychotics (8.40%) during the period 2002-2012. CONCLUSIONS: Drug utilization trends in our postconflict setting were predominantly inconsistent with current guidelines for treatment of PTSD due to excessive anxiolytic use, implying that psychopharmacotherapy was used mainly for tranquilizing properties to address non diagnosis-specific symptoms. Promising rising trends in utilization of antidepressants were not followed with compensatory reductions in anxiolytic use. These data revealed areas of inconsistent use of drugs, generating suggestions for interventions to improve drug use and also hypotheses for additional research. PMID- 26528650 TI - Physical activity and sedentary behavior measured objectively and subjectively in overweight and obese adults with schizophrenia or schizoaffective disorders. AB - OBJECTIVE: Describe objective and subjective physical activity levels and time spent being sedentary in adults with schizophrenia or schizoaffective disorders (SZO/SA). METHOD: Baseline physical activity and sedentary behaviors were assessed among 46 overweight and obese community-dwelling adults (aged 18-70 years; BMI > 27 kg/m(2)) diagnosed with SZO/SA by DSM-IV-TR, with mild symptom severity (Positive and Negative Syndrome Scale score < 90) who were interested in losing weight and participated in the Weight Assessment and Intervention in Schizophrenia Treatment (WAIST) study from 2004 to 2008. Objective physical activity levels, measured using actigraphs, in WAIST were compared to a nationally representative sample of users (n = 46) and nonusers (n = 46) of mental health service (MHS) from the National Health and Nutrition Examination Survey (NHANES 2003-2004) matched by sex, BMI, and age. RESULTS: On average, adults with SZO/SA wore actigraphs more than 15 h/d for 7 days averaging 151,000 counts/d. The majority of monitoring time (81%) was classified as sedentary (approximately 13 h/d). Moderate/vigorous and light physical activity accounted for only 2% (19 min/d) and 17% (157 min/d) of monitoring time/d, respectively. Primary source of activity was household activities (409 +/- 438 min/wk). Fifty three percent reported walking for transportation or leisure. Adults with SZO/SA were significantly less active (176 min/d) and more sedentary (756 min/d) than NHANES users of MHS (293 and 640 min/d, respectively) and nonusers of MHS (338 and 552 min/d, respectively) (P < .01). CONCLUSIONS: Overweight and obese adults with SZO/SA were extremely sedentary; engaged in unstructured, intermittent, low intensity physical activity; and significantly less active than NHANES users and nonusers of MHS. This sedentary lifestyle is significantly lower than those of other inactive US populations, is costly for the individual and community, and highlights the need for physical activity promotion and interventions in this high risk population. PMID- 26528651 TI - Cost-effectiveness of smoking cessation treatment initiated during psychiatric hospitalization: analysis from a randomized, controlled trial. AB - OBJECTIVE: We examined the cost-effectiveness of smoking cessation treatment for psychiatric inpatients. METHOD: Smokers, regardless of intention to quit, were recruited during psychiatric hospitalization and randomized to receive stage based smoking cessation services or usual aftercare. Smoking cessation services, quality of life, and biochemically verified abstinence from cigarettes were assessed during 18 months of follow-up. A Markov model of cost-effectiveness over a lifetime horizon was constructed using trial findings and parameters obtained in a review of the literature on quit and relapse rates and the effect of smoking on health care cost, quality of life, and mortality. RESULTS: Among 223 smokers randomized between 2006 and 2008, the mean cost of smoking cessation services was $189 in the experimental treatment group and $37 in the usual care condition (P < .001). At the end of follow-up, 18.75% of the experimental group was abstinent from cigarettes, compared to 6.80% abstinence in the usual care group (P < .05). The model projected that the intervention added $43 in lifetime cost and generated 0.101 additional quality-adjusted life-years (QALYs), an incremental cost-effectiveness ratio of $428 per QALY. Probabilistic sensitivity analysis found the experimental intervention was cost-effective against the acceptance criteria of $50,000/QALY in 99.0% of the replicates. CONCLUSIONS: A cessation intervention for smokers identified in psychiatric hospitalization did not result in higher mental health care costs in the short-run and was highly cost-effective over the long-term. The stage-based intervention was a feasible and cost effective way of addressing the high smoking prevalence in persons with serious mental illness. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00136812. PMID- 26528652 TI - Do advanced statistical techniques really help in the diagnosis of the metabolic syndrome in patients treated with second-generation antipsychotics? AB - OBJECTIVE: Metabolic and cardiovascular diseases in patients with schizophrenia have gained a lot of interest in recent years. Developing an algorithm to detect the metabolic syndrome based on readily available variables would eliminate the need for blood sampling, which is considered expensive and inconvenient in this population. METHOD: All patients fulfilled DSM-IV diagnosis of schizophrenia or schizoaffective disorder. We used the International Diabetes Federation criteria (European population) to diagnose the metabolic syndrome. We used logistic regression and optimized artificial neural networks and support vector machines to detect the metabolic syndrome in a cohort of schizophrenic patients of the University Psychiatric Center Kortenberg, KU Leuven, Belgium. Testing was done on one-third of the included cohort (202 patients); training was performed using a 10-fold stratified cross-validation scheme. The data were collected between 2000 and 2008. RESULTS: All 3 methods yielded similar results, with satisfying accuracies of about 80%. However, none of the advanced statistical methods could improve on the results obtained using a very simple and naive model including only central obesity and information on blood pressure. CONCLUSIONS: Although so called pattern recognition techniques bear high promise in improving clinical decision making, the results should be presented with caution and preferably in comparison with a less complicated technique. PMID- 26528653 TI - Depression, obesity, and metabolic syndrome: prevalence and risks of comorbidity in a population-based representative sample of Mexican Americans. AB - INTRODUCTION: We examined the prevalence of depression, obesity, and metabolic syndrome and associations between them in a population-based representative cohort of Mexican Americans living on the United States-Mexico border. METHOD: The sample in this cross-sectional analysis consisted of 1,768 Mexican American adults (>= 18 years of age) assessed between the years 2004 and 2010, with whom we tested our central hypothesis of a significant relationship between obesity and depression. Depression was measured using the Center for Epidemiologic Studies-Depression scale (CES-D) with a cutoff score of >= 16 for depression and a cutoff score of >= 27 for severe depression. We categorized body mass index (BMI) values as obese (>= 30kg/m(2)) and later subdivided the obese subjects into obese (30-39 kg/m(2)[inclusive]) and morbidly obese (>= 40 kg/m(2)). Metabolic syndrome was defined using the American Heart Association definition requiring at least 3 of the following: increased waist circumference, elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol, elevated blood pressure, and elevated fasting glucose. Weighted data were analyzed to establish prevalence of depression, obesity, and metabolic syndrome. Univariate and multivariable weighted regression models were used to test potential associations between these disorders. RESULTS: Using weighted prevalence, we observed high rates of depression (30%), obesity (52%), and metabolic syndrome (45%). Univariate models revealed female gender (P = .0004), low education (P = .003), low HDL level (P = .009), and increased waist circumference (P = .03) were associated with depression. Female gender (P = .01), low education (P = .003), and morbid obesity (P = .002) were risk factors for severe depression and remained significant in multivariable models. CONCLUSIONS: In this large cohort of Mexican Americans, obesity, female gender, and low education were identified risk factors for depression. These indicators may serve as targets for early detection, prevention, and intervention in this population. PMID- 26528654 TI - Cognitive reactivity versus dysfunctional cognitions and the prediction of relapse in recurrent major depressive disorder. AB - OBJECTIVE: Major depressive disorder (MDD) is a burdensome disease that has a high risk of relapse/recurrence. Cognitive reactivity appears to be a risk factor for relapse. It remains unclear, however, whether dysfunctional cognitions alone or the reactivity of such cognitions to mild states of sadness (ie, cognitive reactivity) is the crucial factor that increases relapse risk. We aimed to assess the long-term predictive value of cognitive reactivity versus dysfunctional cognitions and other risk factors for depressive relapse. METHOD: In a prospective cohort of outpatients (N = 116; studied between 2000-2005) who had experienced >= 2 previous major depressive episodes (MDEs) and were in remission (DSM-IV) at the start of follow-up, we measured cognitive reactivity, with the Leiden Index of Depression Sensitivity (LEIDS), and dysfunctional cognitions, with the Dysfunctional Attitudes Scale, simultaneously. Course of illness (with the primary outcome of MDE assessed by the Structured Clinical Interview for DSM IV Axis I Disorders Patient Edition) and time to relapse were monitored prospectively for 3.5 years. RESULTS: Cognitive reactivity scores were associated with time to relapse over the 3.5-year follow-up and also when corrected for the number of previous MDEs and concurrent depressive symptoms (hazard ratio for 1 standard deviation [(HR(SD)); 20 points of the LEIDS, measuring cognitive reactivity] = 1.47; 95% CI, 1.04-2.09; P = .031). Rumination appeared to be a particularly strong predictor of relapse (HR(SD) = 1.60; 95% CI, 1.13-2.26; P = .007). Dysfunctional cognitions did not predict relapse over 3.5 years (HR(SD) = 1.00; 95% CI, 0.74-1.37; P = .93). Every 20-point increase on the cognitive reactivity scale resulted in a 10% to 15% increase in risk of relapse (corrected for previous MDEs and concurrent depressive symptoms). CONCLUSIONS: Cognitive reactivity--and particularly rumination--is a long-term predictor of relapse. Future research should address whether psychological interventions can improve cognitive reactivity scores and thereby prevent depressive relapses. TRIAL REGISTRATION: ISRCTN Identifier: 68246470. PMID- 26528655 TI - Toward personalized treatment in psychiatry. PMID- 26528656 TI - Acquainted with the night again and again: key factors associated with relapse in major depressive disorder. PMID- 26528657 TI - Reactivity at different levels of cognitive analysis: products versus operations. PMID- 26528658 TI - The primary outcome measure and its importance in clinical trials. AB - The primary outcome measure is the outcome that an investigator considers to be the most important among the many outcomes that are to be examined in the study. The primary outcome needs to be defined at the time the study is designed. There are 2 reasons for this: it reduces the risk of false-positive errors resulting from the statistical testing of many outcomes, and it reduces the risk of a false negative error by providing the basis for the estimation of the sample size necessary for an adequately powered study. This article discusses the setting of the primary outcome measure, the need for it, the increased risk of false positive and false-negative errors in secondary outcome results, how to regard articles that do not state the primary outcome, how to interpret results when secondary outcomes are statistically significant but not the primary outcome, and limitations of the concept of a primary outcome measure in clinical trial research. PMID- 26528660 TI - Recommended treatment strategies for patients with excessive daytime sleepiness. AB - Excessive daytime sleepiness (EDS) is a common and bothersome phenomenon. It can be associated with insufficient sleep syndrome, narcolepsy, idiopathic hypersomnia, obstructive sleep apnea, shift work disorder, Kleine-Levin syndrome, or Parkinson's disease. Once the underlying cause of the excessive sleepiness is determined, clinicians must select the most appropriate behavioral and pharmacologic interventions to reduce daytime sleepiness, alleviate other symptoms, improve functioning, and ensure the safety of patients and those around them. Patient history, adverse effects, and efficacy in specific conditions should be considered in pharmacologic treatment options for patients with EDS. PMID- 26528661 TI - Using standardized methods to assess suicidal behavior: the need is even greater than it looks. PMID- 26528662 TI - Laying the groundwork for standardized assessment of suicidal behavior. PMID- 26528663 TI - What is the right pharmacotherapy for alcohol use disorder in patients with schizophrenia? PMID- 26528664 TI - How to best treat patients with schizophrenia and co-occurring alcohol use disorder. PMID- 26528665 TI - The epidemic of depression with obesity. PMID- 26528666 TI - Consequences of misdiagnosis: inaccurate treatment and poor patient outcomes in bipolar disorder. AB - Bipolar depression is difficult to diagnose and is often mistaken for unipolar depression. Unfortunately, this misdiagnosis creates a cascade of negative outcomes. Patients will probably receive inadequate or inappropriate treatment that will not alleviate the symptoms or impairment of the disorder and may even further destabilize their mood. These individuals are then at risk for experiencing numerous social and occupational impairments, alcohol or substance abuse, and suicidal behavior. An accurate diagnosis and appropriate treatment of bipolar disorder are necessary to prevent this chain of potentially disastrous events. PMID- 26528668 TI - The use of micro computed tomography to ascertain the morphology of bloodstains on fabric. AB - Very little is known about the interactions of blood and fabric and how bloodstains on fabric are formed. Whereas the blood stain size for non-absorbent surfaces depends on impact velocity, previous work has suggested that for fabrics the blood stain size is independent of impact velocity when the drop size is kept constant. Therefore, a greater understanding of the interaction of blood and fabric is required. This paper explores the possibility of using a micro computed tomography (CT) scanner to study bloodstain size and shape throughout fabrics. Two different fabrics were used: 100% cotton rib knit and 100% cotton bull drill. Bloodstains were created by dropping blood droplets from three heights; 500 mm, 1000 mm and 1500 mm. Results from the CT scanner clearly showed the bloodstain shape throughout the fabric. The blood was found to form a diamond shaped stain, with the maximum cross-sectional area 0.3-0.5mm below the surface. The bloodstain morphology depended on both the impact velocity and fabric structure. PMID- 26528669 TI - Evaluation of tools for environmental sampling of Bacillus anthracis spores. AB - This study describes the validation of sampling techniques used to detect biological warfare agents used in terror attacks. For this purpose, we tested the efficiencies of different sampling media and extraction solutions for the recovery of bacterial pathogens. We first used Bacillus cereus ATCC 4342 spores as a surrogate for highly pathogenic B. anthracis to compare recovery efficiencies of spores from four different surfaces. We used three different types of sampling swabs and four different solutions to extract spores from the swabs. The most effective sampling method employed rayon swabs moistened with water. The efficencies of the four extraction solutions did not differ significantly, although yields were highest using phosphate-buffered saline containing Tween 80 (PBS-T). Using rayon swabs and sterile water, we recovered B. cereus ATCC 4342 and B. anthracis spores with equivalent efficiencies. These findings indicate that because of its reduced pathogenicity and relative ease in handling (Biosafety Level 1), use of B. cereus ATCC 4342 will facilitate further optimization of techniques to detect B. anthracis. PMID- 26528670 TI - Symptoms of Depression are Common in Patients With Idiopathic Normal Pressure Hydrocephalus: The INPH-CRasH Study. AB - BACKGROUND: If patients with idiopathic normal pressure hydrocephalus (INPH) also have depression, this could have important clinical ramifications in assessment and management of their cognitive function and response to shunting. In many dementias, depression is overrepresented, but the prevalence of depression in shunted patients with INPH is unknown. OBJECTIVE: The objective of this case control study was to assess the prevalence of symptoms of depression in shunted INPH patients compared with population-based controls. METHODS: INPH patients consecutively shunted from 2008 to 2010 in Sweden were analyzed. Patients remaining after inclusion (within 60-85 years and not having dementia, ie, mini mental state examination >=23) had a standardized visit to their healthcare provider and answered an extensive questionnaire. Age- and sex-matched population based controls underwent the same procedure. Symptoms of depression were assessed using the Geriatric Depression Scale 15 (suspected depression defined as >=5 points, suspected severe depression as >=12 points). This study is part of the INPH-CRasH study. RESULTS: One hundred seventy-six INPH patients and 368 controls participated. After adjustment for age, sex, cerebrovascular disease, and systolic and diastolic blood pressure, patients had a higher mean depression score (patients: 4.9 +/- 3.7 SD, controls: 1.9 +/- 2.3 SD; OR 1.4, 95% CI 1.3 1.6, P < .001), more patients had suspected depression (46% vs 13%, OR 6.4, 95% CI 3.8-10.9, P < .001), and more patients had suspected severe depression (7.3% vs 0.6%, OR 14.4, 95% CI 3.0-68.6, P < .005). CONCLUSION: Symptoms of depression are overrepresented in INPH patients compared with the population, despite treatment with a shunt. Screening for depression should be done in the evaluation of INPH patients in order to find and treat a coexisting depression. PMID- 26528671 TI - The History of the Kernohan Notch Revisited. AB - The history of false localizing signs is intimately linked to the birth of modern neurology and the unraveling of the mysteries of localization through neurological examination at the end of the 19th century. This phenomenon has attracted much attention but has not been properly explained, even in the authoritative handbooks such as that by Oppenheim. A scholarly article written by Kernohan and Woltman in 1929 is considered to be a landmark in the history of neurology and neurosurgery in that it provided the definitive answer and an exhaustive explanation of the problem, leading some neurologists to conclude that the localization of a lesion is not an exact science. However, despite the professional manner in which Kernohan and Woltman presented their case, they did not offer an explanation. In another article published 2 years earlier in 1927, Groeneveld and Schaltenbrand provided a pathophysiological and anatomical explanation of the phenomenon, described in detail. Although Kernohan and Woltman themselves refer to that previous article, it was this article that provided the first logical, clear, indubitable explanation of the phenomenon that we today refer to as the Kernohan notch. PMID- 26528672 TI - Military Neurosurgery: A Range of Service Options. AB - The pathway to military neurosurgical practice can include a number of accession options. This article is an objective comparison of fiscal, tangible, and intangible benefits provided through different military neurosurgery career paths. Neurosurgeons may train through active duty, reserve, or civilian pathways. These modalities were evaluated on the basis of economic data during residency and the initial 3 years afterwards. When available, military base pay, basic allowance for housing and subsistence, variable special pay, board certified pay, incentive pay, multiyear special pay, reserve drill pay, civilian salary, income tax, and other tax incentives were analyzed using publically available data. Civilians had lower residency pay, higher starting salaries, increased taxes, malpractice insurance cost, and increased overhead. Active duty service saw higher residency pay, lower starting salary, tax incentives, increased benefits, and almost no associated overhead including malpractice coverage. Reserve service saw a combination of civilian benefits with supplementation of reserve drill pay in return for weekend drill and the possibility of deployment and activation. Being a neurosurgeon in the military is extremely rewarding. From a financial perspective, ignoring intangibles, this article shows most entry pathways with initially modest differences between the cumulative salaries of active duty and civilian career paths and with higher overall compensation available from the reserve service option. These pathways become increasingly discrepant over time as civilian pay greatly exceeds that of military neurosurgeons. We hope that those curious about or considering serving in the United States military benefit from our accounting and review of these comparative paths. ABBREVIATIONS: FAP, Financial Assistance ProgramNADDS, Navy Active Duty Delay for SpecialistsTMS, Training in Medical Specialties. PMID- 26528673 TI - Comparing Preoperative With Postoperative Stereotactic Radiosurgery for Resectable Brain Metastases: A Multi-institutional Analysis. AB - BACKGROUND: Stereotactic radiosurgery (SRS) is an increasingly common modality used with surgery for resectable brain metastases (BM). OBJECTIVE: To present a multi-institutional retrospective comparison of outcomes and toxicities of preoperative SRS (Pre-SRS) and postoperative SRS (Post-SRS). METHODS: We reviewed the records of patients who underwent resection of BM and either Pre-SRS or Post SRS alone between 2005 and 2013 at 2 institutions. Pre-SRS used a dose-reduction strategy based on tumor size, with planned resection within 48 hours. Cumulative incidence with competing risks was used to determine estimated rates. RESULTS: A total of 180 patients underwent surgical resection for 189 BM: 66 (36.7%) underwent Pre-SRS and 114 (63.3%) underwent Post-SRS. Baseline patient characteristics were balanced except for higher rates of performance status 0 (62.1% vs 28.9%, P < .001) and primary breast cancer (27.2% vs 10.5%, P = .010) for Pre-SRS. Pre-SRS had lower median planning target volume margin (0 mm vs 2 mm) and peripheral dose (14.5 Gy vs 18 Gy), but similar gross tumor volume (8.3 mL vs 9.2 mL, P = .85). The median imaging follow-up period was 24.6 months for alive patients. Multivariable analyses revealed no difference between groups for overall survival (P = .1), local recurrence (P = .24), and distant brain recurrence (P = .75). Post-SRS was associated with significantly higher rates of leptomeningeal disease (2 years: 16.6% vs 3.2%, P = .010) and symptomatic radiation necrosis (2 years: 16.4% vs 4.9%, P = .010). CONCLUSION: Pre-SRS and Post-SRS for resected BM provide similarly favorable rates of local recurrence, distant brain recurrence, and overall survival, but with significantly lower rates of symptomatic radiation necrosis and leptomeningeal disease in the Pre-SRS cohort. A prospective clinical trial comparing these treatment approaches is warranted. ABBREVIATIONS: BM, brain metastasesCI, confidence intervalCTV, clinical target volumeDBR, distant brain recurrenceGTV, gross tumor volumeLC, local controlLMD, leptomeningeal diseaseLR, local recurrenceMVA, multivariable analysisOS, overall survivalPost-SRS, postoperative stereotactic radiosurgeryPre SRS, preoperative stereotactic radiosurgeryPTV, planning target volumeRN, radiation necrosisSRN, symptomatic radiation necrosisSRS, stereotactic radiosurgeryWBRT, whole-brain radiation therapy. PMID- 26528674 TI - Recent assembly of the global herbaceous flora: evidence from the paper daisies (Asteraceae: Gnaphalieae). AB - The global flora is thought to contain a large proportion of herbs, and understanding the general spatiotemporal processes that shaped the global distribution of these communities is one of the most difficult issues in biogeography. We explored patterns of world-wide biogeography in a species-rich herbaceous group, the paper daisy tribe Gnaphalieae (Asteraceae), based on the hitherto largest taxon sampling, a total of 835 terminal accessions representing 80% of the genera, and encompassing the global geographic range of the tribe, with nuclear internal transcribed spacer (ITS) and external transcribed spacer (ETS) sequences. Biogeographic analyses indicate that Gnaphalieae originated in southern Africa during the Oligocene, followed by repeated migrations into the rest of Africa and the Mediterranean region, with subsequent entries into other continents during various periods starting in the Miocene. Expansions in the late Miocene to Pliocene appear to have been the driving force that shaped the global distribution of the tribe as forests were progressively broken up by the mid continent aridification and savannas and grasslands expanded into the interior of the major continents. This pattern of recent colonizations may explain the world wide distribution of many other organisms in open ecosystems and it is highlighted here as an emerging pattern in the evolution of the global flora. PMID- 26528675 TI - Tin(II) ketoacidoximates: synthesis, X-ray structures and processing to tin(II) oxide. AB - Tin(II) ketoacidoximates of the type [HON=CRCOO]2Sn (R = Me 1, CH2Ph 2) and (MeON=CMeCOO)3Sn](-) NH4(+).2H2O 3 were synthesized by reacting pyruvate- and hydroxyl- or methoxylamine RONH2 (R = H, Me) with tin(II) chloride dihydrate SnCl2.2H2O. The single crystal X-ray structure reveals that the geometry at the Sn atom is trigonal bipyramidal in 1, 2 and trigonal pyramidal in 3. Inter- or intramolecular hydrogen bonding is observed in 1-3. Thermogravimetric (TG) analysis shows that the decomposition of 1-3 to SnO occurs at ca. 160 degrees C. The evolved gas analysis during TG indicates complete loss of the oximato ligand in one step for 1 whereas a small organic residue is additionally removed at temperatures >400 degrees C for 2. Above 140 degrees C, [HON=C(Me)COO]2Sn (1) decomposes in air to spherical SnO particles of size 10-500 nm. Spin coating of 1 on Si or a glass substrate followed by heating at 200 degrees C results in a uniform film of SnO. The band gap of the produced SnO film and nanomaterial was determined by diffuse reflectance spectroscopy to be in the range of 3.0-3.3 eV. X-ray photoelectron spectroscopy indicates surface oxidation of the SnO film to SnO2 in ambient atmosphere. PMID- 26528676 TI - Hydrophilic Nitrogen and Sulfur Co-doped Molybdenum Carbide Nanosheets for Electrochemical Hydrogen Evolution. AB - Nitrogen and sulfur dual-doped Mo2 C nanosheets provide low operating potential ( 86 mV for driving 10 mA cm(-2) of current density). Co-doping of N and S heteroatoms can improve the wetting property of the Mo2C electrocatalyst in aqueous solution and induce synergistic effects via sigma-donation and pi-back donation with hydronium cation. PMID- 26528677 TI - The toxic effects of ammonia exposure on antioxidant and immune responses in Rockfish, Sebastes schlegelii during thermal stress. AB - Rockfish, Sebastes schlegelii (mean weight 14.53 +/- 1.14 cm, and mean weight 38.36 +/- 3.45 g) were exposed for 4 weeks (2 weeks and 4 weeks) with the different levels of ammonia in the concentrations of 0, 0.1, 0.5, 1.0mg/L at 19 and 24 degrees C. The ammonia exposure induced significant alterations in antioxidant responses. The activities of SOD, CAT, and GST were considerably increased by the ammonia exposure depending on water temperature, whereas the GSH level was notably decreased after 2 and 4 weeks. In the stress indicators, the cortisol and HSP 70 were significantly elevated by the exposure to ammonia depending on water temperature. In innate immune responses, the phagocytosis and lysozyme activity were notably decreased by ammonia exposure depending on water temperature after 2 and 4 weeks. The results suggest that ammonia exposure depending on water temperature can induce the considerable alterations in antioxidant responses, stress, and immune inhibition. PMID- 26528678 TI - ERCP-directed radiofrequency ablation of ampullary adenomas: a knife-sparing alternative in patients unfit for surgery. PMID- 26528679 TI - Clip and snare lifting technique to assist cannulation of a papilla hidden behind a mucosal fold. PMID- 26528680 TI - Electrohydraulic lithotripsy of large bile duct stones under direct cholangioscopy with a double-balloon endoscope. PMID- 26528681 TI - Subphrenic hematoma mimicking malpositioned gallbladder during endoscopic retrograde cholangiopancreatography. PMID- 26528682 TI - Endoscopic muscularis excavation of a rectal duplication cyst. PMID- 26528683 TI - A pseudopyloric channel created by repeated blind post-pyloric feeding tube placement. PMID- 26528684 TI - Primary small-bowel diffuse large B-cell lymphoma presenting as hematemesis. PMID- 26528685 TI - Extensive hyperplastic recurrence after complete R0 resection by endoscopic submucosal dissection of a gastric hyperplastic polyp with dysplasia. PMID- 26528686 TI - Combined percutaneous retrograde and peroral antegrade esophagoscopy for the treatment of complete upper esophageal obstruction. PMID- 26528687 TI - Rupture of a pseudoaneurysm caused by endoscopic papillary large-balloon dilation. PMID- 26528688 TI - Calcium oxalate stones in a colonic surgical suture: an uncommon endoscopic finding. PMID- 26528689 TI - Transaortic endoscopic ultrasound-guided fine-needle aspiration of a positron emission tomography-positive abdominal para-aortic lymph node. PMID- 26528690 TI - Endoscopic submucosal dissection for venous lake in the submucosa of the transverse colon. PMID- 26528691 TI - Jejunojejunal intussusception after polypectomy by spiral enteroscopy in Peutz Jeghers syndrome. PMID- 26528692 TI - Overtube and over-the-wire, through-the-scope balloon-assisted ERCP in a patient with complex hypopharyngeal stenosis after neck surgery. PMID- 26528693 TI - Digital cholangioscopy: assessing the impact of radiofrequency ablation. PMID- 26528694 TI - Light wavelength-dependent E. coli survival changes after simulated solar disinfection of secondary effluent. AB - In this study, the photoreactivation and the modification of dark repair of E. coli in a simulated secondary effluent were investigated after initial irradiation under different conditions. The simulated solar exposure of the secondary wastewater was followed by exposure to six different low-intensity fluorescent lamps (blacklight blue, actinic blacklight, blue, green, yellow and indoor light) for up to 8 h. When photoreactivation was monitored, blue and green colored fluorescent light led to increased bacterial regrowth. Blacklight lamps further inactivated the remaining bacteria, while yellow and indoor light led to accelerated growth of healthy cells. Exposure to fluorescent lamps was followed by long term storage in darkness, to monitor the bacterial repair in the dark. The response was correlated with the pre-exposure dose of applied solar irradiation, and to a lesser extent with the fluorescent light dose. Bacteria which had undergone extensive exposure showed no response under fluorescent light or during storage in the dark. Finally, the statistical treatment of the data allowed us to suggest a linear model, which is non-selective in terms of the fluorescent light applied. The estimation of the final bacterial population was predicted well (R-sq ~ 75%) and the photoreactivation risk was found to be more important for cultivable cells. PMID- 26528695 TI - Clinicopathologic, molecular, and prognostic implications of the loss of EPCAM expression in colorectal carcinoma. AB - We aimed to comprehensively investigate the clinicopathologic and molecular implications of altered epithelial cell adhesion molecule (EPCAM) expression in colorectal carcinoma (CRC). EPCAM immunohistochemical expression, EPCAM 3' end deletion, EPCAM promoter methylation, microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP) were analyzed in large cohorts of human CRCs. Among 218 MSI-high CRCs, complete loss (CL) of EPCAM expression was observed in two cases, both of which displayed MSH2 deficiency and EPCAM 3' deletion. Thirty-one of the 218 MSI-high CRCs demonstrated the partial loss (PL) of EPCAM expression without EPCAM deletion or methylation and were correlated with CIMP-high and poor disease-free survival. Histologically, foci exhibiting EPCAM loss in EPCAM-PL tumors were dominantly distributed in poorly differentiated tumor components and/or in the invasive tumor front. The implications of EPCAM-PL were further validated in a consecutive series of 726 CRCs. EPCAM-PL (n = 50; 6.9%) was also associated with CIMP-high and adverse pathologic factors and was confirmed to be an independent poor prognostic factor in CRC (HR, 1.57; 95% CI, 1.04 to 2.39). EPCAM-CL can be used to screen for EPCAM deletion-induced Lynch syndrome-associated CRC, whereas EPCAM-PL can be used as an indicator of tumor aggressiveness and poor prognosis in CRC. PMID- 26528696 TI - Neutropenia predicts better prognosis in patients with metastatic gastric cancer on a combined epirubicin, oxaliplatin and 5-fluorouracil regimen. AB - Chemotherapy-induced neutropenia (CIN) reportedly indicated better prognosis for some cancers. We retrospectively analyzed 150 evaluable metastatic gastric cancer (MGC) patients who had received first-line EOF5 (combination regimen of epirubicin, oxaliplatin and 5-day continuous infusion of 5-fluorouracil) treatment. We divided patients into three groups according to the worst grade of CIN: absent group (grade 0), moderate group (grade 1-2) and severe group (grade 3 4). Multivariate analyses of overall survival (OS) proved moderate and severe CIN were important prognostic factors whether regarding CIN as a time-varying covariate (TVC) or not. Compared with absent CIN, hazard ratio (HR) for moderate and severe CIN were 0.31 (95% confidential interval (CI): 0.17-0.55; P < 0.001) and 0.36 (95% CI: 0.20-0.64; P = 0.001) respectively with TVC; and were 0.31 (95% CI: 0.17-0.56; P < 0.001) and 0.34 (95% CI: 0.19-0.61; P < 0.001) respectively without TVC. In progression-free survival (PFS) analyses, moderate and severe CIN showed similar results. In the landmark group (n = 122 patients) analyses with TVC, moderate and severe CIN remained prognostic factors for PFS, while only moderate CIN was prognostic factor for OS. CIN predicted longer OS and PFS in MGC patients treated with first-line EOF5 chemotherapy. PMID- 26528697 TI - CMTM7 knockdown increases tumorigenicity of human non-small cell lung cancer cells and EGFR-AKT signaling by reducing Rab5 activation. AB - The dysregulation of epidermal growth factor receptor (EGFR) signaling has been well documented to contribute to the progression of non-small cell lung cancer (NSCLC), the leading cause of cancer death in the world. EGF-stimulated EGFR activation induces receptor internalization and degradation, which plays an important role in EGFR signaling. This process is frequently deregulated in cancer cells, leading to enhanced EGFR levels and signaling. Our previous study on CMTM7 is only limited to a brief description of the relationship of overexpressed CMTM7 with EGFR-AKT signaling. The biological functions of endogenous CMTM7 and its molecular mechanism remained unclear. In this study, we show that the stable knockdown of CMTM7 augments the malignant potential of NSCLC cells and enhances EGFR-AKT signaling by decreasing EGFR internalization and degradation. Mechanistically, CMTM7 knockdown reduces the activation of Rab5, a protein known to be required for early endosome fusion. In NSCLC, the loss of CMTM7 would therefore serve to sustain aberrant EGFR-mediated oncogenic signaling. Together, our findings highlight the role of CMTM7 in the regulation of EGFR signaling in tumor cells, revealing CMTM7 as a novel molecule related to Rab5 activation. PMID- 26528699 TI - The Complexity of Pain Management in Patients with Erythromelalgia. AB - A 15-year-old girl diagnosed with erythromelalgia was admitted to the hospital with severe pain in her feet associated with burning, pruritus, erythema, and swelling. She had not responded to conventional management and received some relief only from cold bath immersions, which resulted in chronic blistering and multiple episodes of superinfection. After a successful trial of spinal cord stimulation, she had a permanent implantation procedure. The spinal cord stimulator relieved her pain and improved function but not the sensation of burning pain. However, this pain resolved after she started daily mexiletine. This case demonstrates that erythromelalgia sometimes can be managed successfully with a combination of pharmacologic and interventional procedures. PMID- 26528698 TI - Interleukin 6 trigged ataxia-telangiectasia mutated activation facilitates lung cancer metastasis via MMP-3/MMP-13 up-regulation. AB - Our previous studies show that the phosphorylation of ataxia-telangiectasia mutated (ATM) induced by interleukin 6 (IL-6) treatment contributes to multidrug resistance formation in lung cancer cells, but the exact role of ATM activation in IL-6 increased metastasis is still elusive. In the present study, matrix metalloproteinase-3 (MMP-3) and MMP-13 were firstly demonstrated to be involved in IL-6 correlated cell migration. Secondly, IL-6 treatment not only increased MMP-3/MMP-13 expression but also augmented its activities. Thirdly, the inhibition of ATM phosphorylation efficiently abolished IL-6 up-regulating MMP 3/MMP-13 expression and increasing abilities of cell migration. Most importantly, the in vivo test showed that the inhibition of ATM abrogate the effect of IL-6 on lung cancer metastasis via MMP-3/MMP-13 down-regulation. Taken together, these findings demonstrate that IL-6 inducing ATM phosphorylation increases the expression of MMP-3/MMP-13, augments the abilities of cell migration, and promotes lung cancer metastasis, indicating that ATM is a potential target molecule to overcome IL-6 correlated lung cancer metastasis. PMID- 26528700 TI - Intravenous Lidocaine Infusion to Treat Chemotherapy-Induced Peripheral Neuropathy. AB - Chemotherapy-induced peripheral neuropathy is a debilitating side effect of chemotherapy, which manifests as paresthesias, dysesthesias, and numbness in the hands and feet. Numerous chemoprotective agents and treatments have been used with limited success to treat chemotherapy-induced peripheral neuropathy. We report a case in which a patient presenting with chemotherapy-induced peripheral neuropathy received an IV lidocaine infusion over the course of 60 minutes with complete symptomatic pain relief for a prolonged period of 2 weeks. PMID- 26528701 TI - Serotonin Syndrome: The Potential for a Severe Reaction Between Common Perioperative Medications and Selective Serotonin Reuptake Inhibitors. AB - Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to patients of all ages. Although generally considered safe, therapy with SSRIs can be complicated by serotonin syndrome (SS), a life-threatening condition. We present a case of SS that developed in a young man who was receiving a stable dose of fluoxetine and then received several commonly used medications during an emergent appendectomy. Because polypharmacy in the perioperative setting may trigger SS, it is important for anesthesiologists to be cognizant of the interactions between SSRIs and common perioperative medications to formulate anesthetic plans that optimize patient safety. PMID- 26528702 TI - Spinal Surgery and Abrupt Intrathecal Baclofen Withdrawal. AB - Abrupt cessation of intrathecal baclofen can lead to a serious withdrawal syndrome. The anesthesiologist must be prepared to avoid intraoperative interruption of baclofen delivery before starting spinal surgery and to recognize and treat the symptoms of baclofen withdrawal in the immediate postoperative period. PMID- 26528703 TI - Slipping Rib Syndrome as Persistent Abdominal and Chest Pain. AB - Slipping rib syndrome is an overlooked cause of persistent abdominal or chest pain. The etiology of this syndrome is not well understood, but the characteristic pain is from hypermobility of the false ribs. Although it is a diagnosis of exclusion, misdiagnosis may lead to an excessive workup. A simple clinical examination via the hooking maneuver is the most significant feature of its diagnosis. We describe the case of a 41-year-old woman with slipping rib syndrome. PMID- 26528704 TI - The Effect of Patient Position during Mid-Urethral Sling Operations on the Postoperative Outcomes of Sling Success: A Randomized Clinical Study. AB - AIMS: To determine and compare the effectiveness, peri- and postoperative outcomes of mid-urethral sling (MUS) operations for urinary incontinence, using 2 different patient positions during surgery. METHODS: In this study, 146 patients underwent MUS surgery in a urogynecology clinic. Of them, 72 patients underwent the intraoperative surgical procedure of reverse trendelenburg patient positioning for tape adjustment (group 1) and the remaining 74 patients had the routine surgical procedure of MUS surgery (group 2). The primary outcome was the evaluation of postoperative urine leaks, using the stress test, and secondary outcomes were quality of life, using the International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF, Turkish version) and complication rates. RESULTS: There were no significant differences in demographic variables between the 2 groups. The overall cure rates for incontinence in the lithotomy position was 97.22 and 85.13% for groups 1 and 2, respectively, in which group 1 had a statistically significant decrease in urine leak postoperatively (p < 0.05; OR 3.08, 95% CI 2.78-22.14). The postoperative ICQ-SF scores showed no significant difference between the 2 groups (p = 0.19). CONCLUSION: Applying a 45 degree reverse trendelenburg position for tape adjusting during MUS operation results in a greater objective cure rate compared with the typical dorsolithotomy position; however, there was no difference in the subjective outcome. PMID- 26528705 TI - A Phase I Trial of High-Dose Chemotherapy Combining Topotecan plus Cyclophosphamide with Hematopoietic Stem Cell Transplantation for Ovarian Cancer: The ITOV 01bis Study. AB - BACKGROUND: Dose-intensive chemotherapy with hematopoietic stem cell transplantation has been evaluated as a salvage treatment for recurrent ovarian cancer, but its benefit has not yet been demonstrated. In a previous phase I trial, we reported the feasibility of administering topotecan as a salvage regimen. METHODS: Twenty-one patients were treated with escalating doses of topotecan associated with a fixed dose of cyclophosphamide. RESULTS: The maximum tolerated dose was established at 9.0 mg/m2 on a 5-day regimen, analogously to what was reported for topotecan monotherapy. One toxic death from septic shock and multiorgan failure occurred. Although hematopoietic toxicities were overcome by peripheral blood stem cell transplantation, superior nonhematological toxicities were observed as compared to the initial trial. CONCLUSION: Response rates were generally short and survival rates were poor. Results of the ITOV 01bis study demonstrate that, in the setting of recurrent ovarian cancer, intensive chemotherapy based on topotecan-cyclophosphamide association is not currently clinically indicated. PMID- 26528708 TI - Neutral Nickel Catalysts for Olefin Homo- and Copolymerization: Relationships between Catalyst Structures and Catalytic Properties. PMID- 26528706 TI - Loss of Runx2 sensitises osteosarcoma to chemotherapy-induced apoptosis. AB - BACKGROUND: Osteosarcoma (OS) is the most common bone malignancy in the paediatric population, principally affecting adolescents and young adults. Minimal advancements in patient prognosis have been made over the past two decades because of the poor understanding of disease biology. Runx2, a critical transcription factor in bone development, is frequently amplified and overexpressed in OS. However, the molecular and biological consequences of Runx2 overexpression remain unclear. METHODS: si/shRNA and overexpression technology to alter Runx2 levels in OS cells. In vitro assessment of doxorubicin (doxo)-induced apoptosis and in vivo chemosensitivity studies. Small-molecule inhibitor of c-Myc transcriptional activity was used to assess its role. RESULTS: Loss of Runx2 sensitises cells to doxo-induced apoptosis both in vitro and in vivo. Furthermore, in conjunction with chemotherapy, decreasing Runx2 protein levels activates both the intrinsic and extrinsic apoptotic pathways. Transplanted tumour studies demonstrated that loss of endogenous Runx2 protein expression enhances caspase-3 cleavage and tumour necrosis in response to chemotherapy. Finally, upon doxo-treated Runx2 knockdown OS cells there was evidence of enhanced c-Myc expression and transcriptional activity. Inhibition of c-Myc under these conditions resulted in decreased activation of apoptosis, therefore insinuating a role for c-Myc in dox-induced activation of apoptotic pathways. CONCLUSIONS: Therefore, we have established a novel molecular mechanism by which Runx2 provides a chemoprotective role in OS, indicating that in conjunction to standard chemotherapy, targeting Runx2 may be a new therapeutic strategy for patients with OS. PMID- 26528709 TI - Cobalt- and Nickel-Catalyzed Carboxylation of Alkenyl and Sterically Hindered Aryl Triflates Utilizing CO2. AB - A highly efficient cobalt-catalyzed reductive carboxylation reaction of alkenyl trifluoromethanesulfonates (triflates) has been developed. By employing Mn powder as a reducing reagent under 1 atm pressure of CO2 at room temperature, diverse alkenyl triflates can be converted to the corresponding alpha,beta-unsaturated carboxylic acids. Moreover, the carboxylation of sterically hindered aryl triflates proceeds smoothly in the presence of a nickel or cobalt catalyst. PMID- 26528707 TI - RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR TKIs. AB - BACKGROUND: Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs. METHODS: Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT-PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan-Meier estimates and Cox regression. RESULTS: We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29-0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31-0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44-3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28-0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19 0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29-0.73); P=0.001). CONCLUSIONS: RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti VEGFR-TKIs. Prospective validation is warranted. PMID- 26528710 TI - Chloride Incorporation Process in CH3NH3PbI(3-x)Cl(x) Perovskites via Nanoscale Bandgap Maps. AB - CH3NH3PbI(3-x)Cl(x) perovskites enable fabrication of highly efficient solar cells. Chloride ions benefit the morphology, carrier diffusion length, and stability of perovskite films; however, whether those benefits stem from the presence of Cl(-) in the precursor solution or from their incorporation in annealed films is debated. In this work, the photothermal-induced resonance, an in situ technique with nanoscale resolution, is leveraged to measure the bandgap of CH3NH3PbI(3-x)Cl(x) films obtained by a multicycle coating process that produces high efficiency (~16%) solar cells. Because chloride ions modify the perovskite lattice, thereby widening the bandgap, measuring the bandgap locally yields the local chloride content. After a mild annealing (60 min, 60 degrees C) the films consist of Cl-rich (x < 0.3) and Cl-poor phases that upon further annealing (110 degrees C) evolve into a homogeneous Cl-poorer (x < 0.06) phase, suggesting that methylammonium-chrloride is progressively expelled from the film. Despite the small chloride content, CH3NH3PbI(3-x)Cl(x) films show better thermal stability up to 140 degrees C with respect CH3NH3PbI3 films fabricated with the same methodology. PMID- 26528711 TI - Donor/Acceptor Molecular Orientation-Dependent Photovoltaic Performance in All Polymer Solar Cells. AB - The correlated donor/acceptor (D/A) molecular orientation plays a crucial role in solution-processed all-polymer solar cells in term of photovoltaic performance. For the conjugated polymers PTB7-th and P(NDI2OD-T2), the preferential molecular orientation of neat PTB7-th films kept face-on regardless of the properties of processing solvents. However, an increasing content of face-on molecular orientation in the neat P(NDI2OD-T2) films could be found by changing processing solvents from chloronaphthalene (CN) and o-dichlorobenzene (oDCB) to chlorobenzene (CB). Besides, the neat P(NDI2OD-T2) films also exhibited a transformation of preferential molecular orientation from face-on to edge-on when extending film drying time by casting in the same solution. Consequently, a distribution diagram of molecular orientation for P(NDI2OD-T2) films was depicted and the same trend could be observed for the PTB7-th/P(NDI2OD-T2) blend films. By manufacture of photovoltaic devices with blend films, the relationship between the correlated D/A molecular orientation and device performance was established. The short-circuit current (Jsc) of devices processed by CN, oDCB, and CB enhanced gradually from 1.24 to 8.86 mA/cm(2) with the correlated D/A molecular orientation changing from face-on/edge-on to face-on/face-on, which could be attributed to facile exciton dissociation at D/A interface with the same molecular orientation. Therefore, the power conversion efficiency (PCE) of devices processed by CN, oDCB, and CB improved from 0.53% to 3.52% ultimately. PMID- 26528712 TI - Ambient PM2.5, O3, and NO2 Exposures and Associations with Mortality over 16 Years of Follow-Up in the Canadian Census Health and Environment Cohort (CanCHEC). AB - BACKGROUND: Few studies examining the associations between long-term exposure to ambient air pollution and mortality have considered multiple pollutants when assessing changes in exposure due to residential mobility during follow-up. OBJECTIVE: We investigated associations between cause-specific mortality and ambient concentrations of fine particulate matter (<= 2.5 MUm; PM2.5), ozone (O3), and nitrogen dioxide (NO2) in a national cohort of about 2.5 million Canadians. METHODS: We assigned estimates of annual concentrations of these pollutants to the residential postal codes of subjects for each year during 16 years of follow-up. Historical tax data allowed us to track subjects' residential postal code annually. We estimated hazard ratios (HRs) for each pollutant separately and adjusted for the other pollutants. We also estimated the product of the three HRs as a measure of the cumulative association with mortality for several causes of death for an increment of the mean minus the 5th percentile of each pollutant: 5.0 MUg/m3 for PM2.5, 9.5 ppb for O3, and 8.1 ppb for NO2. RESULTS: PM2.5, O3, and NO2 were associated with nonaccidental and cause-specific mortality in single-pollutant models. Exposure to PM2.5 alone was not sufficient to fully characterize the toxicity of the atmospheric mix or to fully explain the risk of mortality associated with exposure to ambient pollution. Assuming additive associations, the estimated HR for nonaccidental mortality corresponding to a change in exposure from the mean to the 5th percentile for all three pollutants together was 1.075 (95% CI: 1.067, 1.084). Accounting for residential mobility had only a limited impact on the association between mortality and PM2.5 and O3, but increased associations with NO2. CONCLUSIONS: In this large, national level cohort, we found positive associations between several common causes of death and exposure to PM2.5, O3, and NO2. CITATION: Crouse DL, Peters PA, Hystad P, Brook JR, van Donkelaar A, Martin RV, Villeneuve PJ, Jerrett M, Goldberg MS, Pope CA III, Brauer M, Brook RD, Robichaud A, Menard R, Burnett RT. 2015. Ambient PM2.5, O3, and NO2 exposures and associations with mortality over 16 years of follow-up in the Canadian Census Health and Environment Cohort (CanCHEC). Environ Health Perspect 123:1180-1186; http://dx.doi.org/10.1289/ehp.1409276. PMID- 26528713 TI - The Role of CHI3L1 (Chitinase-3-Like-1) in the Pathogenesis of Infections in Burns in a Mouse Model. AB - In severe burn injury the unique setting of a depleted, dysfunctional immune system along with a loss of barrier function commonly results in opportunistic infections that eventually proof fatal. Unfortunately, the dynamic sequence of bacterial contamination, colonization and eventually septic invasion with bacteria such as Pseudomonas species is still poorly understood although a limiting factor in clinical decision making. Increasing evidence supports the notion that inhibition of bacterial translocation into the wound site may be an effective alternative to prevent infection. In this context we investigated the role of the mammalian Chitinase-3-Like-1 (CHI3L1) non-enyzmatic protein predominately expressed on epithelial as well as innate immune cells as a potential bacterial-translocation-mediating factor. We show a strong trend that a modulation of chitinase expression is likely to be effective in reducing mortality rates in a mouse model of burn injury with superinfection with the opportunistic PA14 Pseudomonas strain, thus demonstrating possible clinical leverage. PMID- 26528714 TI - Differential Involvement of the Dentate Gyrus in Adaptive Forgetting in the Rat. AB - How does the brain discriminate essential information aimed to be stored permanently from information required only temporarily, and that needs to be cleared away for not saturating our precious memory space? Reference Memory (RM) refers to the long-term storage of invariable information whereas Working Memory (WM) depends on the short-term storage of trial-unique information. Previous work has revealed that WM tasks are very sensitive to proactive interference. In order to prevent such interference, irrelevant old memories must be forgotten to give new ones the opportunity to be stabilized. However, unlike memory, physiological processes underlying this adaptive form of forgetting are still poorly understood. Here, we precisely ask what specific brain structure(s) could be responsible for such process to occur. To answer this question, we trained rats in a radial maze using three paradigms, a RM task and two WM tasks involving or not the processing of interference but strictly identical in terms of locomotion or motivation. We showed that an inhibition of the expression of Zif268 and c Fos, two indirect markers of neuronal activity and synaptic plasticity, was observed in the dentate gyrus of the dorsal hippocampus when processing such interfering previously stored information. Conversely, we showed that inactivating the dentate gyrus impairs both RM and WM, but improves the processing of interference. Altogether, these results strongly suggest for the first time that the dentate gyrus could be a key structure involved in adaptive forgetting. PMID- 26528715 TI - MARCKS Signaling Differentially Regulates Vascular Smooth Muscle and Endothelial Cell Proliferation through a KIS-, p27kip1- Dependent Mechanism. AB - BACKGROUND: Overexpression of the myristolated alanine-rich C kinase substrate (MARCKS) occurs in vascular proliferative diseases such as restenosis after bypass surgery. MARCKS knockdown results in arrest of vascular smooth muscle cell (VSMC) proliferation with little effect on endothelial cell (EC) proliferation. We sought to identify the mechanism of differential regulation by MARCKS of VSMC and EC proliferation in vitro and in vivo. METHODS AND RESULTS: siRNA-mediated MARCKS knockdown in VSMCs inhibited proliferation and prevented progression from phase G0/G1 to S. Protein expression of the cyclin-dependent kinase inhibitor p27kip1, but not p21cip1 was increased by MARCKS knockdown. MARCKS knockdown did not affect proliferation in VSMCs derived from p27kip1-/- mice indicating that the effect of MARCKS is p27kip1-dependent. MARCKS knockdown resulted in decreased phosphorylation of p27kip1 at threonine 187 and serine 10 as well as, kinase interacting with stathmin (KIS), cyclin D1, and Skp2 expression. Phosphorylation of p27kip1 at serine 10 by KIS is required for nuclear export and degradation of p27kip1. MARCKS knockdown caused nuclear trapping of p27kip1. Both p27kip1 nuclear trapping and cell cycle arrest were released by overexpression of KIS, but not catalytically inactive KIS. In ECs, MARCKS knockdown paradoxically increased KIS expression and cell proliferation. MARCKS knockdown in a murine aortic injury model resulted in decreased VSMC proliferation determined by bromodeoxyuridine (BrdU) integration assay, and inhibition of vascular wall thickening. MARCKS knockdown increased the rate of re-endothelialization. CONCLUSIONS: MARCKS knockdown arrested VSMC cell cycle by decreasing KIS expression. Decreased KIS expression resulted in nuclear trapping of p27kip1 in VSMCs. MARCKS knockdown paradoxically increased KIS expression in ECs resulting in increased EC proliferation. MARCKS knockdown significantly attenuated the VSMC proliferative response to vascular injury, but accelerated reestablishment of an intact endothelium. MARCKS is a novel translational target with beneficial cell type-specific effects on both ECs and VSMCs. PMID- 26528716 TI - Directed Evolution and Resolution Mechanism of 1, 3-Propanediol Oxidoreductase from Klebsiella pneumoniae toward Higher Activity by Error-Prone PCR and Bioinformatics. AB - 1, 3-propanediol oxidoreductase (PDOR) is a key enzyme in glycerol bioconversion to 1,3-propanediol (1, 3-PD) which is a valuable chemical and one of the six new petrochemical products. We used error-prone PCR and activity screening to identify mutants of Klebsiella pneumoniae (K. pneumoniae) PDOR with improved activity. The activity of one of the identified mutants, PDOR'-24, which includes a single mutation, A199S, was 48 U/mg, 4.9 times that of the wild-type enzyme. Molecular docking was performed to analyze the identified mutants; and amino acids S103, H271, N366, D106, N262 and D364 were predicted to bond with NADH. The origins of the improved activity of PDOR'-24, as well as three other mutants were analyzed by simulating the interaction mechanism of the mutants with the substrate and coenzyme, respectively. This research provides useful information about the use of safranine O plate screening for the directed evolution of oxidoreductases, identifies interesting sites for improving PDOR activity, and demonstrates the utility of using molecular docking to analyze the interaction mechanism of the mutants with the substrate and coenzyme, respectively. PMID- 26528717 TI - Semiochemical Production and Laboratory Behavior Response of the Brown Marmorated Stink Bug, Halyomorpha Halys. AB - BACKGROUND: The brown marmorated stink bug (BMSB) is an exotic insect pest that was first recognized in the United States in 2001. As of today, it has been found in more than 42 states. BMSB has a very broad host plant range and damage to crops in mid-Atlantic States has reached a critical level. A reliable and accurate tool for infestation detection and population monitoring is urgently needed to provide better and more timely interventions. Pheromones produced by male BMSB have been previously identified and are currently used in BMSB infestation detection. However, the conditions affecting BMSB production of these pheromones were unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we collected headspace volatiles from male BMSB under laboratory conditions, measured the temporal patterns of release of these pheromones, and assayed the attractiveness to conspecifics. In addition to the pheromone components, tridecane (C13) and E-2-decenal (an alarm compound) were observed in headspace collections of males, as well as in females and nymphs. Exposure of pheromone emitting adult males to synthetic C13 greatly reduced pheromone emission. CONCLUSIONS/SIGNIFICANCE: This information should lead to a better understanding of the biology, physiology, and chemical ecology of BMSB, which will help scientists and growers develop more efficient strategies based on natural products to manage BMSB population, therefore, reducing pesticide usage and protecting the crops from BMSB damage. PMID- 26528719 TI - Correction: Distribution and Frequency of kdr Mutations within Anopheles gambiae s.l. Populations and First Report of the Ace.1G119S Mutation in Anopheles arabiensis from Burkina Faso (West Africa). PMID- 26528718 TI - Metabolic Coupling Determines the Activity: Comparison of 11beta-Hydroxysteroid Dehydrogenase 1 and Its Coupling between Liver Parenchymal Cells and Testicular Leydig Cells. AB - BACKGROUND: 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) interconverts active 11beta-hydroxyl glucocorticoids and inactive 11keto forms. However, its directionality is determined by availability of NADP+/NADPH. In liver cells, 11beta-HSD1 behaves as a primary reductase, while in Leydig cells it acts as a primary oxidase. However, the exact mechanism is not clear. The direction of 11beta-HSD1 has been proposed to be regulated by hexose-6-phosphate dehydrogenase (H6PDH), which catalyzes glucose-6-phosphate (G6P) to generate NADPH that drives 11beta-HSD1 towards reduction. METHODOLOGY: To examine the coupling between 11beta-HSD1 and H6PDH, we added G6P to rat and human liver and testis or Leydig cell microsomes, and 11beta-HSD1 activity was measured by radiometry. RESULTS AND CONCLUSIONS: G6P stimulated 11beta-HSD1 reductase activity in rat (3 fold) or human liver (1.5 fold), but not at all in testis. S3483, a G6P transporter inhibitor, reversed the G6P-mediated increases of 11beta-HSD1 reductase activity. We compared the extent to which 11beta-HSD1 in rat Leydig and liver cells might be coupled to H6PDH. In order to clarify the location of H6PDH within the testis, we used the Leydig cell toxicant ethane dimethanesulfonate (EDS) to selectively deplete Leydig cells. The depletion of Leydig cells eliminated Hsd11b1 (encoding 11beta-HSD1) expression but did not affect the expression of H6pd (encoding H6PDH) and Slc37a4 (encoding G6P transporter). H6pd mRNA level and H6PDH activity were barely detectable in purified rat Leydig cells. In conclusion, the availability of H6PDH determines the different direction of 11beta-HSD1 in liver and Leydig cells. PMID- 26528721 TI - Estimating Consumption to Biomass Ratio in Non-Stationary Harvested Fish Populations. AB - The food consumption to biomass ratio (C) is one of the most important population parameters in ecosystem modelling because its quantifies the interactions between predator and prey. Existing models for estimating C in fish populations are per recruit cohort models or empirical models, valid only for stationary populations. Moreover, empirical models lack theoretical support. Here we develop a theory and derive a general modelling framework to estimate C in fish populations, based on length frequency data and the generalised von Bertalanffy growth function, in which models for stationary populations with a stable-age distributions are special cases. Estimates using our method are compared with estimates from per recruit cohort models for C using simulated harvested fish populations of different lifespans. The models proposed here are also applied to three fish populations that are targets of commercial fisheries in southern Chile. Uncertainty in the estimation of C was evaluated using a resampling approach. Simulations showed that stationary and non-stationary population models produce different estimates for C and those differences depend on the lifespan, fishing mortality and recruitment variations. Estimates of C using the new model exhibited smoother inter-annual variation in comparison with a per-recruit model estimates and they were also smaller than C predicted by the empirical equations in all population assessed. PMID- 26528720 TI - Exocyst-Dependent Membrane Addition Is Required for Anaphase Cell Elongation and Cytokinesis in Drosophila. AB - Mitotic and cytokinetic processes harness cell machinery to drive chromosomal segregation and the physical separation of dividing cells. Here, we investigate the functional requirements for exocyst complex function during cell division in vivo, and demonstrate a common mechanism that directs anaphase cell elongation and cleavage furrow progression during cell division. We show that onion rings (onr) and funnel cakes (fun) encode the Drosophila homologs of the Exo84 and Sec8 exocyst subunits, respectively. In onr and fun mutant cells, contractile ring proteins are recruited to the equatorial region of dividing spermatocytes. However, cytokinesis is disrupted early in furrow ingression, leading to cytokinesis failure. We use high temporal and spatial resolution confocal imaging with automated computational analysis to quantitatively compare wild-type versus onr and fun mutant cells. These results demonstrate that anaphase cell elongation is grossly disrupted in cells that are compromised in exocyst complex function. Additionally, we observe that the increase in cell surface area in wild type peaks a few minutes into cytokinesis, and that onr and fun mutant cells have a greatly reduced rate of surface area growth specifically during cell division. Analysis by transmission electron microscopy reveals a massive build-up of cytoplasmic astral membrane and loss of normal Golgi architecture in onr and fun spermatocytes, suggesting that exocyst complex is required for proper vesicular trafficking through these compartments. Moreover, recruitment of the small GTPase Rab11 and the PITP Giotto to the cleavage site depends on wild-type function of the exocyst subunits Exo84 and Sec8. Finally, we show that the exocyst subunit Sec5 coimmunoprecipitates with Rab11. Our results are consistent with the exocyst complex mediating an essential, coordinated increase in cell surface area that potentiates anaphase cell elongation and cleavage furrow ingression. PMID- 26528722 TI - Liver Sinusoidal Endothelial Cells Escape Senescence by Loss of p19ARF. AB - Liver sinusoidal endothelial cells (LSECs) represent a highly differentiated cell type that lines hepatic sinusoids. LSECs form a discontinuous endothelium due to fenestrations under physiological conditions, which are reduced upon chronic liver injury. Cultivation of rodent LSECs associates with a rapid onset of stress induced senescence a few days post isolation, which limits genetic and biochemical studies ex vivo. Here we show the establishment of LSECs isolated from p19ARF-/- mice which undergo more than 50 cell doublings in the absence of senescence. Isolated p19ARF-/- LSECs display a cobblestone-like morphology and show the ability of tube formation. Analysis of DNA content revealed a stable diploid phenotype after long-term passaging without a gain of aneuploidy. Notably, p19ARF-/- LSECs express the endothelial markers CD31, vascular endothelial growth factor receptor (VEGFR)-2, VE-cadherin, von Willebrand factor, stabilin-2 and CD146 suggesting that these cells harbor and maintain an endothelial phenotype. In line, treatment with small molecule inhibitors against VEGFR-2 caused cell death, demonstrating the sustained ability of p19ARF-/- LSECs to respond to anti-angiogenic therapeutics. From these data we conclude that loss of p19ARF overcomes senescence of LSECs, allowing immortalization of cells without losing endothelial characteristics. Thus, p19ARF-/- LSECs provide a novel cellular model to study endothelial cell biology. PMID- 26528723 TI - Mixed Inhibition of cPEPCK by Genistein, Using an Extended Binding Site Located Adjacent to Its Catalytic Cleft. AB - Cytosolic phosphoenolpyruvate carboxykinase (cPEPCK) is a critical enzyme involved in gluconeogenesis, glyceroneogenesis and cataplerosis. cPEPCK converts oxaloacetic acid (OAA) into phosphoenol pyruvate (PEP) in the presence of GTP. cPEPCK is known to be associated with type 2 diabetes. Genistein is an isoflavone compound that shows anti-diabetic and anti-obesitic properties. Experimental studies have shown a decrease in the blood glucose level in the presence of genistein by lowering the functional activity of cPEPCK, an enzyme of gluconeogenesis. Using computational techniques such as molecular modeling, molecular docking, molecular dynamics simulation and binding free energy calculations, we identified cPEPCK as a direct target of genistein. We studied the molecular interactions of genistein with three possible conformations of cPEPCK-unbound cPEPCK (u_cPEPCK), GTP bound cPEPCK (GTP_cPEPCK) and GDP bound cPEPCK (GDP_cPEPCK). Binding of genistein was also compared with an already known cPEPCK inhibitor. We analyzed the interactions of genistein with cPEPCK enzyme and compared them with its natural substrate (OAA), product (PEP) and known inhibitor (3-MPA). Our results demonstrate that genistein uses the mechanism of mixed inhibition to block the functional activity of cPEPCK and thus can serve as a potential anti-diabetic and anti-obesity drug candidate. We also identified an extended binding site in the catalytic cleft of cPEPCK which is used by 3-MPA to inhibit cPEPCK non-competitively. We demonstrate that extended binding site of cPEPCK can further be exploited for designing new drugs against cPEPCK. PMID- 26528724 TI - Correction: Sex-Related Responses of Populus cathayana Shoots and Roots to AM Fungi and Drought Stress. PMID- 26528726 TI - Viscosity-Lowering Effect of Amino Acids and Salts on Highly Concentrated Solutions of Two IgG1 Monoclonal Antibodies. AB - Monoclonal antibodies display complicated solution properties in highly concentrated (>100 mg/mL) formulations, such as high viscosity, high aggregation propensity, and low stability, among others, originating from protein-protein interactions within the colloidal protein solution. These properties severely hinder the successful development of high-concentration mAb solution for subcutaneous injection. We hereby investigated the effects of several small molecule excipients with diverse biophysical-chemical properties on the viscosity, aggregation propensity, and stability on two model IgG1 (JM1 and JM2) mAb formulations. These excipients include nine amino acids or their salt forms (Ala, Pro, Val, Gly, Ser, HisHCl, LysHCl, ArgHCl, and NaGlu), four representative salts (NaCl, NaAc, Na2SO4, and NH4Cl), and two chaotropic reagents (urea and GdnHCl). With only salts or amino acids in their salt-forms, significant decrease in viscosity was observed for JM1 (by up to 30-40%) and JM2 (by up to 50-80%) formulations, suggesting charge-charge interaction between the mAbs dictates the high viscosity of these mAbs formulations. Most of these viscosity-lowering excipients did not induce substantial protein aggregation or changes in the secondary structure of the mAbs, as evidenced by HPLC-SEC, DSC, and FT-IR analysis, even in the absence of common protein stabilizers such as sugars and surfactants. Therefore, amino acids in their salt-forms and several common salts, such as ArgHCl, HisHCl, LysHCl, NaCl, Na2SO4, and NaAc, could potentially serve as viscosity-lowering excipients during high-concentration mAb formulation development. PMID- 26528725 TI - Salinomycin Promotes Anoikis and Decreases the CD44+/CD24- Stem-Like Population via Inhibition of STAT3 Activation in MDA-MB-231 Cells. AB - Triple-negative breast cancer (TNBC) is an aggressive tumor subtype with an enriched CD44+/CD24- stem-like population. Salinomycin is an antibiotic that has been shown to target cancer stem cells (CSC); however, the mechanisms of action involved have not been well characterized. The objective of the present study was to investigate the effect of salinomycin on cell death, migration, and invasion, as well as CSC-like properties in MDA-MB-231 breast cancer cells. Salinomycin significantly induced anoikis-sensitivity, accompanied by caspase-3 and caspase-8 activation and PARP cleavage, during anchorage-independent growth. Salinomycin treatment also caused a marked suppression of cell migration and invasion with concomitant downregulation of MMP-9 and MMP-2 mRNA levels. Notably, salinomycin inhibited the formation of mammospheres and effectively reduced the CD44+/CD24- stem-like population during anchorage-independent growth. These observations were associated with the inhibition of STAT3 phosphorylation (Tyr705). Furthermore, interleukin-6 (IL-6)-induced STAT3 activation was strongly suppressed by salinomycin challenge. These findings support the notion that salinomycin may be potentially efficacious for targeting breast cancer stem-like cells through the inhibition of STAT3 activation. PMID- 26528727 TI - Repurposing the Microsoft Kinect for Windows v2 for external head motion tracking for brain PET. AB - Medical imaging systems such as those used in positron emission tomography (PET) are capable of spatial resolutions that enable the imaging of small, functionally important brain structures. However, the quality of data from PET brain studies is often limited by subject motion during acquisition. This is particularly challenging for patients with neurological disorders or with dynamic research studies that can last 90 min or more. Restraining head movement during the scan does not eliminate motion entirely and can be unpleasant for the subject. Head motion can be detected and measured using a variety of techniques that either use the PET data itself or an external tracking system. Advances in computer vision arising from the video gaming industry could offer significant benefits when re purposed for medical applications. A method for measuring rigid body type head motion using the Microsoft Kinect v2 is described with results presenting ?0.5 mm spatial accuracy. Motion data is measured in real-time at 30 Hz using the KinectFusion algorithm. Non-rigid motion is detected using the residual alignment energy data of the KinectFusion algorithm allowing for unreliable motion to be discarded. Motion data is aligned to PET listmode data using injected pulse sequences into the PET/CT gantry allowing for correction of rigid body motion. Pilot data from a clinical dynamic PET/CT examination is shown. PMID- 26528728 TI - Method Effects on an Adaptation of the Rosenberg Self-Esteem Scale in Greek and the Role of Personality Traits. AB - Rosenberg's Self-Esteem Scale is a balanced, 10-item scale designed to be unidimensional; however, research has repeatedly shown that its factorial structure is contaminated by method effects due to item wording. Beyond the substantive self-esteem factor, 2 additional factors linked to the positive and negative wording of items have been theoretically specified and empirically supported. Initial evidence has revealed systematic relations of the 2 method factors with variables expressing approach and avoidance motivation. This study assessed the fit of competing confirmatory factor analytic models for the Rosenberg Self-Esteem Scale using data from 2 samples of adult participants in Cyprus. Models that accounted for both positive and negative wording effects via 2 latent method factors had better fit compared to alternative models. Measures of experiential avoidance, social anxiety, and private self-consciousness were associated with the method factors in structural equation models. The findings highlight the need to specify models with wording effects for a more accurate representation of the scale's structure and support the hypothesis of method factors as response styles, which are associated with individual characteristics related to avoidance motivation, behavioral inhibition, and anxiety. PMID- 26528730 TI - Ginger and alpha lipoic acid ameliorate age-related ultrastructural changes in rat liver. AB - Because of the important role that oxidative stress is thought to play in the aging process, antioxidants could be candidates for preventing its related pathologies. We investigated the ameliorative effects of two antioxidant supplements, ginger and alpha lipoic acid (ALA), on hepatic ultrastructural alterations in old rats. Livers of young (4 months) and old (24 months) Wistar rats were studied using transmission electron microscopy. Livers of old rats showed sinusoidal collapse and congestion, endothelial thickening and defenestration, and inconsistent perisinusoidal extracellular matrix deposition. Aged hepatocytes were characterized by hypertrophy, cytoplasmic vacuolization and a significant increase in the volume densities of the nuclei, mitochondria and dense bodies. Lipofuscin accumulation and decreased microvilli in bile canaliculi and space of Disse also were observed. The adverse alterations were ameliorated significantly by both ginger and ALA supplementation; ALA was more effective than ginger. Ginger and ALA appear to be promising anti-aging agents based on their amelioration of ultrastructural alterations in livers of old rats. PMID- 26528731 TI - Volatile N-nitrosamines in meat products: Potential precursors, influence of processing, and mitigation strategies. AB - Meat products can be contaminated with carcinogenic N-nitrosamines, which is ascribed to the reaction between a nitrosating agent, originating from nitrite or smoke, and a secondary amine, derived from protein and lipid degradation. Although in model systems it is demonstrated that many amine containing compounds can be converted to N-nitrosamines, the yield is dependent of reaction conditions (e.g., low pH and high temperature). In this article, the influence of the composition of the meat products (e.g., pH, aw, spices) and processing (e.g., ageing, ripening, fermentation, smoking, heat treatment and storage) on the presence and availability of the amine precursors and the N-nitrosamine formation mechanism is discussed. In addition, this article explores the current N nitrosamine mitigation strategies in order to obtain healthier and more natural meat products. PMID- 26528729 TI - Cortical depth and differential transport of vegetally localized dorsal and germ line determinants in the zebrafish embryo. AB - In zebrafish embryos, factors involved in both axis induction and primordial germ cell (PGC) development are localized to the vegetal pole of the egg. However, upon egg activation axis induction factors experience an asymmetric off-center shift whereas PGC factors undergo symmetric animally-directed movement. We examined the spatial relationship between the proposed dorsal genes wnt8a and grip2a and the PGC factor dazl at the vegetal cortex. We find that RNAs for these genes localize to different cortical depths, with the RNA for the PGC factor dazl at a deeper cortical level than those for axis-inducing factors. In addition, and in contrast to the role of microtubules in the long-range transport of dorsal determinants, we find that germ line determinant transport depends on the actin cytoskeleton. Our results support a model in which vegetal cortex differential RNA transport behavior is facilitated by RNA localization along cortical depth and differential coupling to cortical transport. PMID- 26528732 TI - Cranial base characteristics in anteroposterior malocclusions: A meta-analysis. AB - OBJECTIVE: To investigate cranial base characteristics in malocclusions with sagittal discrepancies. MATERIALS AND METHODS: An electronic search was performed in PubMed, Embase, Web of Science, and the Cochrane Library. A fixed- or random effect model was applied to calculate weighted mean difference with 95% confidence intervals (CIs) according to statistical heterogeneity. Outcome measures were anterior, posterior, and total cranial base length and cranial base angle. Sensitivity analysis and publication bias were conducted. RESULTS: Twenty studies that together included 1121 Class I, 1051 Class II, and 730 Class III cases qualified for the final analysis. Class III malocclusion demonstrated significantly reduced anterior (95% CI: -1.74, -0.53; P < .001 vs Class I; 95% CI: -3.30, -2.09; P < .001 vs Class II) and total cranial base length (95% CI: 3.33, -1.36; P < .001 vs Class I; 95% CI: -7.38, -4.05; P < .001 vs Class II). Further, Class II patients showed significantly greater anterior and total cranial base length than did Class I patients (95% CI: 0.51, 1.87; P < .001 for SN; 95% CI: 2.20, 3.30; P < .001 for NBa). Cranial base angle was significantly smaller in Class III than in Class I (95% CI: -3.14, -0.93; P < .001 for NSBa; 95% CI: -2.73, -0.68; P = .001 for NSAr) and Class II malocclusions (95% CI: 5.73, -1.06; P = .004 for NSBa; 95% CI: -6.11, -1.92; P < .001 for NSAr) and greater in Class II than in Class I malocclusions (95% CI: 1.38, 2.38; P < .001 for NSBa). CONCLUSIONS: This meta-analysis showed that anterior and total cranial base length and cranial base angle were significantly smaller in Class III malocclusion than in Class I and Class II malocclusions, and that they were greater in Class II subjects compared to controls. PMID- 26528733 TI - Key beliefs influencing young drivers' engagement with social interactive technology on their smartphones: A qualitative study. AB - OBJECTIVE: The main aim of this study was to identify young drivers' underlying beliefs (i.e., behavioral, normative, and control) regarding initiating, monitoring/reading, and responding to social interactive technology (i.e., functions on a Smartphone that allow the user to communicate with other people). METHOD: This qualitative study was a beliefs elicitation study in accordance with the theory of planned behavior and sought to elicit young drivers' behavioral (i.e., advantages, disadvantages), normative (i.e., who approves, who disapproves), and control beliefs (i.e., barriers, facilitators) that underpin social interactive technology use while driving. Young drivers (N = 26) aged 17 to 25 years took part in an interview or focus group discussion. RESULTS: Though differences emerged between the 3 behaviors of initiating, monitoring/reading, and responding for each of the behavioral, normative, and control belief categories, the strongest distinction was within the behavioral beliefs category (e.g., communicating with the person that they were on the way to meet was an advantage of initiating; being able to determine whether to respond was an advantage of monitoring/reading; and communicating with important people was an advantage of responding). Normative beliefs were similar for initiating and responding behaviors (e.g., friends and peers more likely to approve than other groups) and differences emerged for monitoring/reading (e.g., parents were more likely to approve of this behavior than initiating and responding). For control beliefs, there were differences between the beliefs regarding facilitators of these behaviors (e.g., familiar roads and conditions facilitated initiating; having audible notifications of an incoming communication facilitated monitoring/reading; and receiving a communication of immediate importance facilitated responding); however, the control beliefs that presented barriers were consistent across the 3 behaviors (e.g., difficult traffic/road conditions). CONCLUSION: The current study provides an important addition to the extant literature and supports emerging research that suggests that initiating, monitoring/reading, and responding may indeed be distinct behaviors with different underlying motivations. PMID- 26528734 TI - Is the External Branch of the Superior Laryngeal Nerve Dispensable in Thyroid Surgery? AB - BACKGROUND: There is growing evidence that the external branch of the superior laryngeal nerve (eSLN) participates in thyroarytenoid (TA) contraction, but little data quantify its role in vocal cord adduction. Injury to the eSLN, such as in thyroid surgery, is difficult to diagnose and likely underappreciated. It is the authors' belief that eSLN injury contributes to aspiration by depriving its contribution to the laryngeal plexus. The goal of this study was to measure the glottic closing force (GCF) from eSLN stimulation in a porcine model. METHODS: The recurrent laryngeal nerve (RLN) and eSLN were identified bilaterally in four porcine necks. Bilateral RLNs and eSLNs were stimulated simultaneously to obtain a control GCF using a pressure transducer placed in the glottis. Subsequently, bilateral eSLNs were stimulated and the GCF measured to quantify its percent contribution to the control value. RESULTS: Stimulation of the RLNs and the eSLNs each led to TA muscle contraction and a measureable GCF in all four porcine necks. The control GCF was 1000.1 mmHg, while the eSLN mediated CGF was 800 mmHg. The percentage GCF attributable to the eSLN was thus 800/1000 = 80%. CONCLUSIONS: Reflex glottic closure is one of the most important mechanisms for the prevention of aspiration during deglutition. The biomechanical quantification of glottic closure can be shown as the GCF. This study has shown that the eSLN contributes in a significant way to the GCF in a porcine model, a finding that has not been quantified to the best of the authors' knowledge. Therefore, greater focus should be placed on preserving this nerve in thyroid surgery. PMID- 26528735 TI - Characterization of recombinant human granulocyte colony-stimulating factor expression by FT-IR spectroscopy: Studies on thermal induction and media formulation on the stability of the protein secondary structure. AB - The Fourier-transform infrared (FT-IR) spectroscopic approach has been employed to understand the recombinant human G-CSF (rhG-CSF) protein accumulation, secondary structure, and thermal stability in Escherichia coli grown under a temperature shift strategy (37 and 28 degrees C) in various media formulations. The choline + sodium pyruvate (37 degrees C) and sodium pyruvate (28 degrees C) formulations have shown the highest inclusion body (IB) accumulation of 0.41 and 0.46 mg/mL, respectively. Furthermore, insights on the structure of the rhG-CSF within IBs and intact cells have been investigated through secondary structure analysis. Thermal stability experiments were also carried out to explain the pattern of the second derivative structure of rhG-CSF. The studies showed that choline + sodium pyruvate formulation has preserved the protein secondary structure even at 82 degrees C. Overall, the FT-IR spectroscopic technique can also be adopted to accelerate the characterization of other recombinant therapeutic proteins of E. coli origin. PMID- 26528736 TI - Engineering PQQ-glucose dehydrogenase into an allosteric electrochemical Ca(2+) sensor. AB - Electrochemical biosensors convert biological events to an electrical current. To date most electrochemical biosensors exploit activities of naturally occurring enzymes. Here we demonstrated that insertion of a calmodulin domain into the redox enzyme PQQ-glucose dehydrogenase resulted in a selective Ca(2+) biosensor that could be used to rapidly measure Ca(2+) concentrations in human biological fluids. We were able to convert a point-of-care glucometer into Ca(2+) monitor by refurbishing it with the developed biosensor. We propose that similar engineering strategies may be used to create highly specific electrochemical biosensors to other analytes. Compatibility with cheap and ubiquitous amperometric detectors is expected to accelerate progression of these biosensors into clinical applications. PMID- 26528738 TI - Predatory grasshopper mice. AB - A Quick Guide on grasshopper mice which, contrary to the great majority of mouse species, are obligate carnivores. PMID- 26528739 TI - Poison frogs. AB - Stynoski et al. introduce the dendrobatids, a charismatic group of frogs known for their colourful and often poisonous skin. PMID- 26528740 TI - Is there any evidence for vocal learning in chimpanzee food calls? AB - In their study "Vocal Learning in the Functionally Referential Food Grunts of Chimpanzees", Watson et al.[1] claimed that they "provide the first evidence for vocal learning in a referential call in non-humans". We challenge this conclusion, on two counts. For one, we are not convinced that the authors controlled for arousal (or at least they did not report such data); furthermore, the vocal characteristics of the two groups largely overlapped already at the beginning of the study. Accordingly, we also question the authors' claim that their finding "sheds new light on the evolutionary history of human referential words". PMID- 26528741 TI - Reply to Fischer et al. AB - We welcome the correspondence from Fischer and colleagues regarding our recent paper on vocal learning in chimpanzee food grunts [1]. Fischer et al. make two challenges to our paper's conclusions, which we address here. PMID- 26528742 TI - Planar polarity: forcing cells into line. AB - Polarisation of tissues in the plane of an epithelium is fundamental for both animal morphogenesis and organ function. A new paper describes a role for mechanical cues in determining how such polarity is aligned with the body axes. PMID- 26528743 TI - Neuroethology: unweaving the senses of direction. AB - Three recent studies have significantly advanced our understanding of the highly conserved central complex of the insect brain, showing how it provides an internal representation of body orientation, encodes behaviorally relevant sensory cues, and at the same time controls motor actions. PMID- 26528744 TI - Evolution: two (very long) legs to stand on. AB - How do the legs of jerboas get so long? A comprehensive study of the Dipodidae family of two-legged rodents reveals many evolutionary refinements in toe numbers, bone structures and proportions. Clearly, this adorable emerging developmental model system has legs. PMID- 26528745 TI - Learning and memory: do bees dream? AB - In mammals, evidence for memory reactivation during sleep highlighted the important role that sleep plays in memory consolidation. A new study reports that memory reactivation is evolutionarily conserved and can also be found in the honeybee. PMID- 26528746 TI - Early histocompatibility: color the mechanism green and red. AB - Allorecognition in Hydractinia, a cnidarian, is governed by two different, highly polymorphic genes encoding transmembrane proteins. Using a fluorescent cell read out system, a new study now shows that the basis for specificity involves homophilic interactions between extracellular domains. PMID- 26528747 TI - Sensory development: late integration of multiple cues. AB - Young children use multiple cues to appreciate the three-dimensional structure of the world. A new study reveals that these cues are properly integrated only years later, thus showing that sensory development is protracted well into teenage years. PMID- 26528748 TI - Animal communication: he's giving me good vibrations. AB - A unique bioassay allows a substrate-borne vibration signal to be isolated and manipulated to test its role in eliciting female mate choice, which may be driving a speciation event, by a live, unrestrained male. PMID- 26528749 TI - Palaeobiology: ecological revelations in Ediacaran reproduction. AB - The biology of Ediacaran organisms - the oldest fossils of large multicellular life - has been notoriously hard to decipher, as they show little obvious relation to extant life forms. Ecological analyses, rather than anatomy, yield new revelations about their reproduction. PMID- 26528750 TI - Organization of the locus coeruleus-norepinephrine system. AB - The release of the neurotransmitter norepinephrine throughout the mammalian brain is important for modulating attention, arousal, and cognition during many behaviors. Furthermore, disruption of norepinephrine-mediated signaling is strongly associated with several psychiatric and neurodegenerative disorders in humans, emphasizing the clinical importance of this system. Most of the norepinephrine released in the brain is supplied by a very small, bilateral nucleus in the brainstem called the locus coeruleus. The goal of this minireview is to emphasize the complexity of the locus coeruleus beyond its primary definition as a norepinephrine-producing nucleus. Several recent studies utilizing innovative technologies highlight how the locus coeruleus norepinephrine system can now be targeted with increased accuracy and resolution, in order to better understand its role in modulating diverse behaviors. PMID- 26528753 TI - When block copolymer self-assembly in hierarchically ordered honeycomb films depicts the breath figure process. AB - Nowadays, a challenge in the preparation of hierarchically ordered materials is the control of concomitant and interacting self-organization processes occurring in time at different length scales. In the present paper, the breath figure process is combined with block copolymer nano-phase segregation to elaborate hierarchically structured honeycomb porous films. Copolymer ordering, at the nanometer length scale, is observed and described in detail with respect to the array of pores of micrometer dimension, hence pointing out the structural interplays between both length-scales. The study is focused on two diblock copolymers made of polystyrene and poly(tert-butyl acrylate) (PS-b-PtBA) with compositions producing lamellae or hexagonal packing of cylinders at thermodynamical equilibrium. Transmission Electron Microscopy completed with Small and Ultra-Small Angle Scattering are performed to evidence the inner morphologies of the honeycomb. The structural data are discussed in the light of the honeycomb film formation process establishing the interest in using kinetically trapped block copolymer self-organization as an imprint to elucidate the complex breath figure process. PMID- 26528754 TI - Clinical outcomes following stent placement in refractory benign esophageal stricture: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: The management of refractory benign esophageal strictures (RBESs) is challenging. Stent placement has been proposed as a possible rescue strategy. We performed a systematic review and meta-analysis to examine the efficacy of this strategy in the long-term resolution of dysphagia. METHODS: PubMed, SCOPUS, and Google Scholar were searched (up to January 2015). Studies recruiting adults with RBES treated with stent placement were eligible. The success, adverse event, and migration rates were pooled by means of a random effect model to obtain odds with a 95 % confidence interval (CI). RESULTS: Eighteen studies (444 patients) were eligible for inclusion. The pooled clinical success rate was 40.5 % (95 %CI 31.5 % - 49.5 %), yielding odds of 0.68 (95 %CI 0.46 - 0.98) with high heterogeneity (I(2) = 65.0 %). The meta-regression analysis showed stricture etiology as the only influencing factor. Treatment with self-expanding plastic (SEPSs) and metal stents (SEMSs) did not result in significantly higher success rates than treatment with biodegradable stents (BDSs) (46.2 % vs. 40.1 % vs. 32.9 %, respectively). The migration rate was 28.6 % (95 %CI 21.9 % - 37.1 %), yielding odds of 0.40 (95 %CI 0.28 - 0.59), with migration rates for SEPSs and SEMSs reported as being not significantly higher than BDSs (33.3 % vs. 31.5 % vs. 15.3 %, respectively). The adverse event rate was 20.6 % (95 %CI 15.3 % - 28.1 %), yielding odds of 0.26 (95 %CI 0.18 - 0.39) with no significant difference between stent types (19.4 % vs. 21.9 % vs. 21.9 %, respectively). CONCLUSIONS: Stent placement in patients with RBES is effective in about 40 % of cases. Further studies should investigate whether the clinical success rate varies according to the stricture etiology.(PROSPERO registration number: CRD42015019017.). PMID- 26528755 TI - Propensity score matching analysis of cisplatin-based concurrent chemotherapy in low risk nasopharyngeal carcinoma in the intensity-modulated radiotherapy era. AB - BACKGROUND: Patients with stage II nasopharyngeal carcinoma were reported to benefit from adding cisplatin-based concurrent chemotherapy to two-dimensional conventional radiotherapy. But this benefit becomes uncertain in the intensity modulated radiotherapy (IMRT) era, owing to its significant advantage. METHODS: We enrolled 661 low risk (T1N1M0, T2N0-1M0 or T3N0M0, the 2010 UICC/AJCC staging system) patients who underwent IMRT with or without concurrent chemotherapy. Particularly, patients with IMRT alone or IMRT plus cisplatin-based concurrent chemotherapy were equally matched using propensity-score matching method. Overall survival (OS), distant metastasis-free survival (DMFS) and locoregional relapse free survival (LRFS) were assessed with Kaplan-Meier method, log-rank test and Cox regression. RESULTS: Among 661 patients, IMRT alone achieved parallel OS (P = 0.379), DMFS (P = 0.169) and LRFS (P = 0.849) to IMRT plus concurrent chemotherapy. In the propensity-matched cohort of 482 patients, similar survival were observed between both arms (4-years OS 97.4% vs 96.1%, P = 0.134; DMFS 96.5% vs 95.1%, P = 0.763; LRFS 93.8% vs 91.5%, P = 0.715). In multivariate analysis, cisplatin-based concurrent chemotherapy did not lower the risk of death, distant metastasis or locoregional relapse. And this association remained unchanged in subgroups by age, sex, histology and stage. CONCLUSIONS: In this study, low risk nasopharyngeal carcinoma patients who underwent IMRT could not benefit from cisplatin-based concurrent chemotherapy. PMID- 26528756 TI - Identification of a novel platelet antagonist that binds to CLEC-2 and suppresses podoplanin-induced platelet aggregation and cancer metastasis. AB - Podoplanin (PDPN) enhances tumor metastases by eliciting tumor cell-induced platelet aggregation (TCIPA) through activation of platelet C-type lectin-like receptor 2 (CLEC-2). A novel and non-cytotoxic 5-nitrobenzoate compound 2CP was synthesized that specifically inhibited the PDPN/CLEC-2 interaction and TCIPA with no effect on platelet aggregation stimulated by other platelet agonists. 2CP possessed anti-cancer metastatic activity in vivo and augmented the therapeutic efficacy of cisplatin in the experimental animal model without causing a bleeding risk. Analysis of the molecular action of 2CP further revealed that Akt1/PDK1 and PKCMU were two alternative CLEC-2 signaling pathways mediating PDPN-induced platelet activation. 2CP directly bound to CLEC-2 and, by competing with the same binding pocket of PDPN in CLEC-2, inhibited PDPN-mediated platelet activation. This study provides evidence that 2CP is the first defined platelet antagonist with CLEC-2 binding activity. The augmentation in the therapeutic efficacy of cisplatin by 2CP suggests that a combination of a chemotherapeutic agent and a drug with anti-TCIPA activity such as 2CP may prove clinically effective. PMID- 26528758 TI - Exosomes enriched in stemness/metastatic-related mRNAS promote oncogenic potential in breast cancer. AB - Cancer cells efficiently transfer exosome contents (essentially mRNAs and microRNAs) to other cell types, modifying immune responses, cell growth, angiogenesis and metastasis. Here we analyzed the exosomes release by breast tumor cells with different capacities of stemness/metastasis based on CXCR4 expression, and evaluated their capacity to generate oncogenic features in recipient cells. Breast cancer cells overexpressing CXCR4 showed an increase in stemness-related markers, and in proliferation, migration and invasion capacities. Furthermore, recipient cells treated with exosomes from CXCR4-cells showed increased in the same abilities. Moreover, inoculation of CXCR4-cell derived exosomes in immunocompromised mice stimulated primary tumor growth and metastatic potential. Comparison of nucleic acids contained into exosomes isolated from patients revealed a "stemness and metastatic" signature in exosomes of patients with worse prognosis. Finally, our data supported the view that cancer cells with stem-like properties show concomitant metastatic behavior, and their exosomes stimulate tumor progression and metastasis. Exosomes-derived nucleic acids from plasma of breast cancer patients are suitable markers in the prognosis of such patients. PMID- 26528760 TI - Static allometry of unicellular green algae: scaling of cellular surface area and volume in the genus Micrasterias (Desmidiales). AB - The surface area-to-volume ratio of cells is one of the key factors affecting fundamental biological processes and, thus, fitness of unicellular organisms. One of the general models for allometric increase in surface-to-volume scaling involves fractal-like elaboration of cellular surfaces. However, specific data illustrating this pattern in natural populations of the unicellular organisms have not previously been available. This study shows that unicellular green algae of the genus Micrasterias (Desmidiales) have positive allometric surface-to volume scaling caused by changes in morphology of individual species, especially in the degree of cell lobulation. This allometric pattern was also detected within most of the cultured and natural populations analysed. Values of the allometric S:V scaling within individual populations were closely correlated to the phylogenetic structure of the clade. In addition, they were related to species-specific cellular morphology. Individual populations differed in their allometric patterns, and their position in the allometric space was strongly correlated with the degree of allometric S:V scaling. This result illustrates that allometric shape patterns are an important correlate of the capacity of individual populations to compensate for increases in their cell volumes by increasing the surface area. However, variation in allometric patterns was not associated with phylogenetic structure. This indicates that the position of the populations in the allometric space was not evolutionarily conserved and might be influenced by environmental factors. PMID- 26528759 TI - Myc promotes glutaminolysis in human neuroblastoma through direct activation of glutaminase 2. AB - Deamidation of glutamine to glutamate by glutaminase 1 (GLS1, also called GLS) and GLS2 is an essential step in both glutaminolysis and glutathione (GSH) biosynthesis. However, mechanisms whereby cancer cells regulate glutamine catabolism remains largely unknown. We report here that N-Myc, an essential Myc family member, promotes conversion of glutamine to glutamate in MYCN-amplified neuroblastoma cells by directly activating GLS2, but not GLS1, transcription. Abrogation of GLS2 function profoundly inhibited glutaminolysis, which resulted in feedback inhibition of aerobic glycolysis likely due to thioredoxin interacting protein (TXNIP) activation, dramatically decreasing cell proliferation and survival in vitro and in vivo. Moreover, elevated GLS2 expression is significantly elevated in MYCN-amplified neuroblastomas in comparison with non-amplified ones, correlating with unfavorable patient survival. In aggregate, these results reveal a novel mechanism deciphering context-dependent regulation of metabolic heterogeneities, uncovering a previously unsuspected link between Myc, GLS2 and tumor metabolism. PMID- 26528757 TI - Identification of short-form RON as a novel intrinsic resistance mechanism for anti-MET therapy in MET-positive gastric cancer. AB - Despite the promising results from initial studies, there are significant limitations in the application of MET-targeted therapy in gastric cancer. Intrinsic resistance is one of the major obstacles. The aim of this study is to identify the responsible receptor tyrosine kinases (RTKs) that determine the unresponsiveness of MET inhibitor in MET-positive gastric cancer. through an RNA interference-based functional screen targeting most human RTKs, we identified that activation of the fibroblast growth factor receptor 2 (FGFR2) and recepteur d'origine nantais (RON) pathways attenuated MET inhibitor-induced suppression of cell proliferation and migration. Notably, in the two forms of RON pathway activation, only upregulation of short-form RON (sf-RON), but not stimulation of full length RON with macrophage stimulating protein, conferred MET inhibitor resistance in vitro and in vivo. Furthermore, the profile of the gastric cancer samples observed that sf-RON was frequently upregulated in MET-positive gastric cancer. Our findings indicate that activation of the sf-RON signaling pathway represents a novel mechanism underlying MET inhibitor unresponsiveness. A combination strategy with drugs targeting both RON and MET pathways is believed to improve the efficacy of MET-targeted therapy. PMID- 26528761 TI - Identification of Small Aliphatic Aldehydes in Pretreated Lignocellulosic Feedstocks and Evaluation of Their Inhibitory Effects on Yeast. AB - Six lignocellulosic hydrolysates produced through acid pretreatment were analyzed for the occurrence of formaldehyde, acetaldehyde, and glycolaldehyde. Acetaldehyde was found in all six (0.3-1.6 mM) and formaldehyde in four (<= 4.4 mM), whereas glycolaldehyde was not detected. To assess the relevance of these findings, fermentations with yeast and formaldehyde or acetaldehyde were performed in the concentration interval 0.5-10 mM. Formaldehyde already inhibited at 1.0 mM, whereas 5.0 mM acetaldehyde was needed to obtain a clear inhibitory effect. After 24 h of fermentation, 1.5 mM formaldehyde reduced the glucose consumption by 85%, the balanced ethanol yield by 92%, and the volumetric productivity by 91%. The results show that formaldehyde and acetaldehyde are prevalent in pretreated lignocellulose and that formaldehyde in some cases could explain a large part of the inhibitory effects on yeast by lignocellulosic hydrolysates, as three of six hydrolysates contained >= 1.9 mM formaldehyde, which was shown to be strongly inhibitory. PMID- 26528763 TI - Central Precocious Puberty: Adult Height in Girls Treated with Quarterly or Monthly Gonadotropin-Releasing Hormone Analog Triptorelin. AB - BACKGROUND/AIMS: Treatment with quarterly gonadotropin-releasing hormone (GnRH) analogs may improve compliance and optimize outcome in girls with central precocious puberty (CPP), but long-term comparative data between the new and the monthly formulations are very scarce. METHODS: A group of girls with idiopathic CPP (n = 13; age 7.9 +/- 0.6 years) were treated from the beginning with quarterly triptorelin (11.25 mg/90 days) and followed up to the achievement of adult height (AH). A group of girls with idiopathic CPP (n = 12; age 8.0 +/- 0.6 years) treated with monthly triptorelin (3.75 mg/28 days) served as controls. RESULTS: The AH (157.1 +/- 4.9 cm) of girls treated with quarterly triptorelin was not significantly different from their mid-parental height (159.7 +/- 3.8 cm) and significantly increased in comparison with predicted AH (average tables) at the beginning of GnRH analog therapy. The AH of girls treated with quarterly triptorelin was not significantly different in comparison with that of girls treated with the monthly formulation (158.1 +/- 6.6 cm; mid-parental height 158.4 +/- 5.0 cm). CONCLUSION: Treatment with quarterly triptorelin formulation permitted to achieve an AH adequate for mid-parental height in girls with CPP. Significant differences of AH between girls with CPP treated with quarterly or monthly formulations were not found. PMID- 26528764 TI - Prenatal diagnosis of Bartter syndrome: amniotic fluid aldosterone. AB - OBJECTIVE: Bartter syndrome is a severe inherited tubulopathy characterized by postnatal salt wasting, severe polyuria, dehydration, failure to thrive and secondary hyperaldosteronism. Prenatally, the disease is usually discovered following the onset of severe polyhydramnios in the second trimester. We studied amniotic fluid aldosterone concentration in Bartter syndrome and in controls. METHODS: Amniotic fluid aldosterone was assayed by radioimmunoassay. We undertook a retrospective case-control study based on 36 cases of prenatally suspected and postnatally confirmed Bartter syndrome (22 with identified mutations): and 72 gestational age matched controls presenting with polyhydramnios and 72 without polyhydramnios. Amniotic fluid aldosterone was compared between the three groups. RESULTS: The median amniotic fluid aldosterone concentration in the Bartter syndrome group (90 pg/mL) was not different from that in the controls with polyhydramnios (90 pg/mL, P = 0.33) or without polyhydramnios (87 pg/mL, P = 0.41). CONCLUSION: Amniotic fluid aldosterone assay cannot be used for prenatal diagnosis of Bartter syndrome. (c) 2015 John Wiley & Sons, Ltd. PMID- 26528762 TI - Association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with early-onset bipolar disorder. AB - OBJECTIVES: Brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early-onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association. METHODS: DNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early-onset bipolar disorder. Bipolar cases were classified as early onset if the first manic or depressive episode occurred at age <=19 years (versus adult-onset cases at age >19 years). After quality control, 69 TEAM early-onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early-onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log-additive allele effects. RESULTS: Comparison of TEAM cases with controls suggested association of early-onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early-onset adult bipolar disorder cases from the Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early-onset TEAM and Mayo Clinic early-onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04). CONCLUSIONS: These preliminary analyses of a relatively small sample with early-onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early-onset expression of the disorder. PMID- 26528765 TI - Redox-Triggered Gatekeeper-Enveloped Starlike Hollow Silica Nanoparticles for Intelligent Delivery Systems. AB - The design and development of multifunctional carriers for drug delivery based on hollow nanoparticles (HNPs) have attracted intense interests. Ordinary spherical HNPs are demonstrated to be promising candidates. However, the application of HNPs with special morphologies has rarely been reported. HNPs with sharp horns are expected to own higher endocytosis efficiencies than spherical counterparts. In this work, novel starlike hollow silica nanoparticles (SHNPs) with different sizes are proposed as platforms for the fabrication of redox-triggered multifunctional systems for synergy of gene therapy and chemotherapy. The CD-PGEA gene vectors (consisting of beta-CD cores and ethanolamine-functionalized poly(glycidyl methacrylate) (denoted BUCT-PGEA) arms) are introduced ingeniously onto the surfaces of SHNPs with plentiful disulfide bond-linked adamantine guests. The resulting supramolecular assemblies (SHNP-PGEAs) possess redox responsive gatekeepers for loaded drugs in the cavities of SHNPs. Meanwhile, they also demonstrate excellent performances to deliver genes. The gene transfection efficiencies, controlled drug release behaviors, and synergistic antitumor effect of hollow silica-based carriers with different morphologies are investigated in detail. Compared with ordinary spherical HNP-based counterparts, SHNP-PGEA carriers with six sharp horns are proven to be superior gene vectors and possess better efficacy for cellular uptake and antitumor effects. The present multifunctional carriers based on SHNPs will have promising applications in drug/gene codelivery and cancer treatment. PMID- 26528766 TI - ABO-immune complex formation and impact on platelet function, red cell structural integrity and haemostasis: an in vitro model of ABO non-identical transfusion. AB - BACKGROUND: Transfusion of ABO non-identical platelets has been associated with fatal haemolytic reactions, increased red cell transfusion needs and other adverse effects, but the practice of ABO matching in platelet transfusion is controversial. Immune complexes can be formed from the anti-A and/or anti-B antibodies and ABO soluble antigen(s) present in donor and recipient plasma after ABO non-identical transfusions. We hypothesized that these immune complexes affect recipient red cell structural integrity, platelet function and haemostasis. STUDY DESIGN AND METHODS: Haemolysis, platelet function and haemostatic function were assessed before and after incubation of recipient red cells, platelets and whole blood with normal saline controls, ABO-identical plasma controls or in vitro-generated ABO-immune complexes. RESULTS: ABO-immune complexes caused significantly increased haemolysis (P < 0.001), inhibition of platelet function (P = 0.001) and disruption of clot formation kinetics (P < 0.005) in both group A and O recipient samples. CONCLUSIONS: Substantial changes in platelet function, red cell integrity and haemostasis occur after in vitro exposure to immune complexes. These in vitro findings may explain, in part, previously observed associations of ABO non-identical platelet transfusions with adverse effects including increased red cell transfusion needs, organ failure and mortality. PMID- 26528767 TI - Fabrication of Alginate/Calcium Carbonate Hybrid Microparticles for Synergistic Drug Delivery. AB - A hybrid drug delivery system coloaded with different drugs for synergistic drug delivery was developed. Alginate/calcium carbonate (CaCO3) hybrid microparticles (MPs) were fabricated via a facile coprecipitation method under mild conditions without using any organic solvent and surfactant. Due to the incorporation of negatively charged alginate chains onto the surface, the obtained hybrid MPs with spherical morphology showed good colloidal stability in an aqueous solution. An antitumor drug (doxorubicin, DOX) and a drug resistance reversal agent (verapamil, VP) were coloaded in the hybrid MPs simultaneously to obtain dual drug-loaded MPs (DOX/VP/MP). Due to the presence of inorganic CaCO3 (~54 wt%), the drugs could be loaded in the hybrid MPs with high encapsulation efficiency and the drug release could be effectively sustained. The cell growth inhibition of the drug-loaded MPs was evaluated in HeLa cells. An in vitro study showed DOX/VP/MP exhibited higher cell growth inhibition as compared with DOX monodrug loaded MPs (DOX/MP). These results suggest the hybrid MPs can potentially be used as a synergistic drug delivery platform for cancer chemotherapy. PMID- 26528769 TI - Reducing Hospital Readmissions via Optimization of Emergency Department Care. AB - Over the past 5 years, early hospital readmissions have become a national focus. With several recent publications highlighting the high rates of early hospital readmissions among transplant recipients, more work is needed to identify risk factors and strategies for reducing unnecessary readmissions among this patient population. Although the American Society of Transplant Surgeons is advocating the exclusion of transplant recipients from the calculation of hospital readmission rates, the outcome of their advocacy efforts remains uncertain. One potential strategy for reducing early hospital readmissions is to critically examine care received by transplant recipients in the emergency department (ED), a critical pathway to readmission. As a starting point, research is needed to assess rates of ED presentation among transplant recipients, diagnostic algorithms, and communication among clinical teams. Mixed-methods studies that enhance understanding of system-level barriers to optimized evaluation and treatment of transplant recipients in the ED may lead to quality improvement interventions that reduce unnecessary readmissions, even if the rates of transplant recipients presenting to the ED remains high. PMID- 26528768 TI - Impact of Thymoglobulin by Stem Cell Source (Peripheral Blood Stem Cell or Bone Marrow) After Myeloablative Stem Cell Transplantation From HLA 10/10-Matched Unrelated Donors: A Report From the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. AB - BACKGROUND: The impact of antithymocyte globulin (ATG) in the setting of a myeloablative conditioning transplantation remains controversial, especially when using bone marrow (BM) as the stem cell source. METHODS: We therefore conducted a retrospective analysis to investigate the impact of ATG in patients with acute myeloid leukemia or myelodysplastic syndrome receiving myeloablative conditioning followed by a matched 10 of 10 unrelated donor transplant from BM or peripheral blood stem cells (PBSCs). Our study included 356 patients conditioned with cyclophosphamide associated with fractionated total body irradiation or busulfan. RESULTS: Median follow-up was 17.6 months (range, 0-156). The ATG and PBSCs were the only variables that independently decreased the cumulative incidence (CI) of chronic graft-versus-host disease (GvHD) (hazards ratio [HR], 0.4; 95% CI, 0.21 0.73; P < 0.01; and HR, 0.53; 95% CI, 0.30-0.90; P = 0.02, respectively). The ATG had no impact on overall survival, disease-free survival, relapse, and nonrelapse mortality. In the PBSC group (n = 139), ATG was associated with a lower CI of both grades III to IV acute GvHD (HR, 0.17; 95% CI, 0.03-0.91; P = 0.04), chronic GvHD (HR, 0.31; 95% CI, 0.11-0.87; P = 0.03), and GvHD-free/relapse-free survival (HR, 0.48; 95% CI, 0.29-0.80; P < 0.01), whereas these correlations were not significant in the group of patients (n = 217) receiving BM (HR, 0.36; 95% CI, 0.11-1.93; P = 0.06 for grade III-IV acute GvHD; HR, 0.49; 95% CI, 0.22-1.06; P = 0.08 for chronic GvHD; and HR, 0.69; 95% CI, 0.46-1.01; P = 0.06 for GvHD free/relapse-free survival). CONCLUSIONS: Although our results confirm the recommendation for ATG to be added after PBSC transplantation, no obvious benefit was identified using this approach in the setting of BM transplantation. Only prospective studies may yield definitive answers to this question. PMID- 26528770 TI - Long-term Outcome of Living Kidney Donation: Position Paper of the European Committee on Organ Transplantation, Council of Europe. PMID- 26528771 TI - Prevention of Transnational Transplant-Related Crimes-What More Can be Done? AB - BACKGROUND: Many nations are able to prosecute transplant-related crimes committed in their territory, but transplant recipients, organ sellers and brokers, and transplant professionals may escape prosecution by engaging in these practices in foreign locations where they judge the risk of criminal investigation and prosecution to be remote. METHODS: The Declaration of Istanbul Custodian Group convened an international working group to evaluate the possible role of extraterritorial jurisdiction in strengthening the enforcement of existing laws governing transplant-related crimes across national boundaries. Potential practical and ethical concerns about the use of extraterritorial jurisdiction were examined, and possible responses were explored. RESULTS: Extraterritorial jurisdiction is a legitimate tool to combat transplant-related crimes. Further, development of a global registry of transnational transplant activities in conjunction with a standardized international referral system for legitimate travel for transplantation is proposed as a mechanism to support enforcement of national and international legal tools. CONCLUSIONS: States are encouraged to include provisions on extraterritorial jurisdiction in their laws on transplant-related crimes and to collaborate with professionals and international authorities in the development of a global registry of transnational transplant activities. These actions would assist in the identification and evaluation of illicit activities and provide information that would help in developing strategies to deter and prevent them. PMID- 26528772 TI - Temporal and spatial requirements for Nodal-induced anterior mesendoderm and mesoderm in anterior neurulation. AB - Zebrafish with defective Nodal signaling have a phenotype analogous to the fatal human birth defect anencephaly, which is caused by an open anterior neural tube. Previous work in our laboratory found that anterior open neural tube phenotypes in Nodal signaling mutants were caused by lack of mesendodermal/mesodermal tissues. Defects in these mutants are already apparent at neural plate stage, before the neuroepithelium starts to fold into a tube. Consistent with this, we found that the requirement for Nodal signaling maps to mid-late blastula stages. This timing correlates with the timing of prechordal plate mesendoderm and anterior mesoderm induction, suggesting these tissues act to promote neurulation. To further identify tissues important for neurulation, we took advantage of the variable phenotypes in Nodal signaling-deficient sqt mutant and Lefty1 overexpressing embryos. Statistical analysis indicated a strong, positive correlation between a closed neural tube and presence of several mesendoderm/mesoderm-derived tissues (hatching glands, cephalic paraxial mesoderm, notochord, and head muscles). However, the neural tube was closed in a subset of embryos that lacked any one of these tissues. This suggests that several types of Nodal-induced mesendodermal/mesodermal precursors are competent to promote neurulation. PMID- 26528773 TI - Synthesis of a Conjugation-Ready, Phosphorylated, Tetrasaccharide Fragment of the O-PS of Vibrio cholerae O139. AB - A new pathway to the tetrasaccharide alpha-Colp-(1->2)-4,6-P-beta-d-Galp-(1->3) [alpha-Colp-(1->4)]-beta-d-GlcpNAc-1-(OCH2CH2)3NH2 has been developed. Glycosylation of 8-azido-3,6-dioxaoctyl 4,6-O-benzylidene-2-deoxy-2 trichloroacetamido-beta-d-glucopyranoside with 3,4,6-tri-O-acetyl-2-O-bromoacetyl alpha-d-galactopyranosyl bromide afforded the beta-linked disaccharide. Debromoacetylation followed by reductive opening of the benzylidene acetal afforded the disaccharide diol acceptor. Halide-assisted glycosylation with 2,4 di-O-benzyl-alpha-colitosyl bromide gave the 1,2-cis-coupling product. Deacetylation followed by regioselective phosphorylation gave isomeric (R,S)-(P) 4(II),6(II)-cyclic phosphates, which were globally deprotected by one-step catalytic (Pd/C) hydrogenation/hydrogenolysis. The target tetrasaccharide, obtained in high overall yield, is amenable for conjugation to proteins. PMID- 26528774 TI - New versus Conventional Helmet for Delivering Noninvasive Ventilation: A Physiologic, Crossover Randomized Study in Critically Ill Patients. AB - BACKGROUND: The helmet is a well-tolerated interface for noninvasive ventilation, although it is associated with poor patient-ventilator interaction. A new helmet (NH) has proven to attenuate this limitation of the standard helmet (SH) in both bench study and healthy volunteers. The authors compared a NH and a SH in intensive care unit patients receiving noninvasive ventilation for prevention of postextubation respiratory failure; both helmets were also compared with the endotracheal tube in place before extubation. METHODS: Fourteen patients underwent 30-min trials in pressure support during invasive ventilation and then with a SH and a NH in a random order. The authors measured comfort, triggering delays, rates of pressurization (airway pressure-time product [PTP] of the first 300 [PTP(300-index)] and 500 [PTP(500-index)] ms from the onset of effort, and the first 200 ms from the onset of insufflation [PTP200]), time of synchrony between effort and assistance (Time(synch)/Ti(neu)), respiratory drive and frequency, arterial blood gases (ABGs), and rate of asynchrony. RESULTS: Compared with SH, NH improved comfort (5.5 [5.0 to 6.0] vs. 8.0 [7.8 to 8.0]), respectively, P < 0.001), inspiratory trigger delay (0.31 [0.22 to 0.43] vs. 0.25 [0.18 to 0.31] s, P = 0.007), and pressurization (PTP(300-index): 0.8 [0.1 to 1.8] vs. 2.7 [7.1 to 10.0]%; PTP(500-index): 4.8 [2.5 to 9.9] vs. 27.3 [16.2 to 34.8]%; PTP200: 13.6 [10.1 to 19.6] vs. 30.4 [24.9 to 38.4] cm H2O/s, P < 0.01 for all comparisons) and Time(synch)/Ti(neu) (0.64 [0.48 to 0.72] vs. 0.71 [0.61 to 0.81], P = 0.007). Respiratory drive and frequency, ABGs, and rate of asynchrony were not different between helmets. Endotracheal tube outperformed both helmets with respect to all variables, except for respiratory rate, ABGs, and asynchronies. CONCLUSIONS: Compared with a SH, a NH improved comfort and patient-ventilator interaction. PMID- 26528775 TI - Pregabalin Has Analgesic, Ventilatory, and Cognitive Effects in Combination with Remifentanil. AB - BACKGROUND: Pregabalin is widely used perioperatively. The authors explored the effects of pregabalin, remifentanil, and their combination on experimental pain, ventilatory, and cognitive function. METHODS: In a randomized, double-blinded crossover study, 12 volunteers received (1) pregabalin + placebo, (2) placebo + remifentanil, (3) pregabalin + remifentanil, and (4) placebo + placebo. Pregabalin 150 mg/placebo was administered twice orally. After baseline, remifentanil/placebo was given as effect-site target-controlled infusion (TCI): 0.6, 1.2, and 2.4 ng/ml. Pain during cold pressor test was scored on visual analog scale (0 to 100 mm). Ventilation was measured by spirometry and cognition tested with Color-Word Interference and Rapid Information Processing tests. RESULTS: Pain intensity after placebo was (mean) 72 mm (95% CI, 62 to 83). Pregabalin reduced pain score by -10 mm (-14 to -7, P < 0.001). Remifentanil had dose-dependent analgesic effect, reducing pain score by -47 mm (-54 to -39, P < 0.001) on highest TCI level, whereas pregabalin + remifentanil exerted additive effect, reducing pain score by -57 mm (-64 to -50, P < 0.001). Respiratory depression was potentiated by adding pregabalin to remifentanil; end-tidal carbon dioxide was 39.3 mmHg (37.2 to 41.3) with placebo, increased 1.8 mmHg (-0.9 to 4.6, P = 0.4) with pregabalin, 10.1 mmHg (4.9 to 15.4, P < 0.001) with remifentanil, and 16.4 mmHg (11.3 to 21.5, P < 0.001) with pregabalin + remifentanil on highest TCI level. The combination pregabalin + remifentanil, but not either drug alone, adversely affected all cognitive tests. CONCLUSIONS: The combination of pregabalin and remifentanil had additive analgesic effects, pregabalin potentiated remifentanil ventilatory depression, and the combination adversely affected cognition. These results question the clinical benefit of the combination compared with higher doses of opioids. PMID- 26528776 TI - Cerebral Fat Embolism Syndrome. PMID- 26528777 TI - Wherefore Gabapentinoids?: Was There Rush Too Soon to Judgment? PMID- 26528778 TI - Images in Anesthesiology: Harlequin Phenomenon in a Newborn after Induction of General Anesthesia. PMID- 26528779 TI - Effect of MacroRAFT Copolymer Adsorption on the Colloidal Stability of Layered Double Hydroxide Nanoparticles. AB - The colloidal behavior of layered double hydroxide nanoparticles containing Mg(2+) and Al(3+) ions as intralayer cations and nitrates as counterions (MgAl NO3-LDH) was studied in the presence of a short statistical copolymer of acrylic acid (AA) and butyl acrylate (BA) terminated with 4-cyano-4 thiothiopropylsulfanyl pentanoic acid (CTPPA) (P(AA7.5-stat-BA7.5)-CTPPA) synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Surface charge properties and aggregation of the particles were investigated by electrophoresis and dynamic light scattering (DLS), respectively. The negatively charged P(AA7.5-stat-BA7.5)-CTPPA adsorbed strongly on the oppositely charged particles, leading to charge neutralization at the isoelectric point (IEP) and charge reversal at higher copolymer concentrations. The dispersions were unstable, i.e., fast aggregation of the MgAl-NO3-LDH occurred near the IEP while high stability was achieved at higher P(AA7.5-stat-BA7.5) CTPPA concentrations. Atomic force (AFM) and transmission electron (TEM) microscopy imaging revealed that the platelets preferentially adopted a face-to face orientation in the aggregates. While the stability of the bare particles was very sensitive to ionic strength, the P(AA7.5-stat-BA7.5)-CTPPA copolymer-coated particles were extremely stable even at high salt levels. Accordingly, the limited colloidal stability of bare MgAl-NO3-LDH dispersions was significantly improved by adding an appropriate amount of P(AA7.5-stat-BA7.5)-CTPPA to the suspension. PMID- 26528780 TI - Laboratory Maintenance of Nocardia Species. AB - Nocardia spp. are aerobic, Gram-positive, catalase-positive, non-motile actinomycetes. Various species of the genus Nocardia have attracted attention due to their detrimental effects on human health. Recent discoveries, however, have exposed their importance as producers of bioactive compounds and degraders of complex organic compounds, as well as their involvement in biotransformation into valuable products. This unit includes general protocols for the laboratory maintenance of Nocardia spp., including growth in liquid medium, growth on solid agar, and long-term storage. Nocardia sp. CS682 (KCTC11297BP), isolated from soil collected in Jeonnam, Korea, is used as a prototype for explaining the considerations for efficient laboratory maintenance of Nocardia spp. PMID- 26528781 TI - Preparation of Cell Cultures and Vaccinia Virus Stocks. AB - The culturing of cell lines used with vaccinia virus, both as monolayer and in suspension, is described. The preparation of chick embryo fibroblasts (CEF) is presented for use in the production of the highly attenuated and host range restricted modified vaccinia virus Ankara (MVA) strain of vaccinia virus. Protocols for the preparation, titration, and trypsinization of vaccinia virus stocks, as well as viral DNA preparation and virus purification methods are also included. PMID- 26528782 TI - Generation of Recombinant Vaccinia Viruses. AB - This unit describes how to infect cells with vaccinia virus and then transfect them with a plasmid-transfer vector or PCR fragment to generate a recombinant virus. Selection and screening methods used to isolate recombinant viruses and a method for the amplification of recombinant viruses are described. Finally, a method for live immunostaining that has been used primarily for detection of recombinant modified vaccinia virus Ankara (MVA) is presented. PMID- 26528783 TI - Biosafety Oversight and Compliance: What do you Mean, I have to Fill Out Another Form?! AB - This unit is an overview of biosafety compliance and oversight in the United States. Specific attention is given to the oversight of the Institutional Biosafety Committee (IBC) and how the purview of the IBC may overlap with other local committees, such as the Institutional Animal Care and Use Committee (IACUC) for animal research and the Institutional Review Board (IRB) for research on human subjects. Requirements for the Federal Select Agent Program and Dual Use Research of Concern (DURC) are also briefly reviewed for those working with materials and experiments covered under these regulations. This unit serves as a guide for new and established investigators who are navigating the regulatory world and how regulatory oversight applies to their research. PMID- 26528784 TI - Electrotransformation and Clonal Isolation of Rickettsia Species. AB - Genetic manipulation of obligate intracellular bacteria of the genus Rickettsia is currently undergoing a rapid period of change. The development of viable genetic tools, including replicative plasmids, transposons, homologous recombination, fluorescent protein-encoding genes, and antibiotic selectable markers has provided the impetus for future research development. This unit is designed to coalesce the basic methods pertaining to creation of genetically modified Rickettsia. The unit describes a series of methods, from inserting exogenous DNA into Rickettsia to the final isolation of genetically modified bacterial clones. Researchers working towards genetic manipulation of Rickettsia or similar obligate intracellular bacteria will find these protocols to be a valuable reference. PMID- 26528785 TI - Myxococcus xanthus Growth, Development, and Isolation. AB - Myxobacteria are a highly social group among the delta proteobacteria that display unique multicellular behaviors during their complex life cycle and provide a rare opportunity to study the boundary between single cells and multicellularity. These organisms are also unusual as their entire life cycle is surface associated and includes a number of social behaviors: social gliding and rippling motility, 'wolf-pack'-like predation, and self-organizing complex biostructures, termed fruiting bodies, which are filled with differentiated environmentally resistant spores. Here we present methods for the growth, maintenance, and storage of Myxococcus xanthus, the most commonly studied of the myxobacteria. We also include methods to examine various developmental and social behaviors (fruiting body and spore formation, predation, and rippling motility). As the myxobacteria, similar to the streptomycetes, are excellent sources of many characterized and uncharacterized antibiotics and other natural products, we have provided a protocol for obtaining natural isolates from a variety of environmental sources. PMID- 26528786 TI - Whole-body bone SPECT in breast cancer patients: the future bone scan protocol? AB - OBJECTIVE: The aim of the study was to compare the detectability rate of bone metastases in breast cancer patients using whole-body single-photon emission computed tomography (WB-SPECT) performed with a half-time acquisition algorithm with that of planar +/- selected field-of-view SPECT [standard bone scintigraphy (BS)]. MATERIALS AND METHODS: Ninety-two consecutive breast cancer patients (age range 35-74 years) underwent planar BS followed by WB-SPECT (acquisition time 28 min). Clinical and imaging follow-up data from BS, 18F-FDG-PET/CT and CT were used as composite reference standards. Institutional review board approval was obtained. For a review of standard BS results, data from a selected SPECT field of-view were extracted from the WB-SPECT when requested by the readers. Diagnostic confidence of interpretation criteria were defined using a five-point level-of-confidence grading scale of lesions. RESULTS: Bone metastases were diagnosed in 34 of 92 studies (37%). On patient-based analysis, the detectability rate of standard BS was 97% (33/34 patients) as compared with 100% for WB-SPECT (P=NS). On a lesion-based analysis, 268 foci were detected, including 124 metastases. Standard BS detected 195 lesions (73%; 99 metastases and 96 benign) and missed 73 lesions (25 metastases and 48 benign). WB-SPECT detected 266 lesions (99%; 124 metastases and 142 benign) and missed two benign foci because of SPECT reconstruction artefacts. The lesion-based detectability rate of metastases for standard BS was 80% compared with 100% for WB-SPECT (P<0.001). WB SPECT was associated with a higher level of confidence compared with standard BS for both benign (P<0.01) and malignant lesions (P<0.05). CONCLUSION: WB-SPECT is a useful tool for skeletal assessment, showing good performance in comparison with standard BS in breast cancer patients, and may eliminate the need for an initial planar scan. PMID- 26528787 TI - Design and evaluation of an adaptive multipinhole collimator for high-performance clinical and preclinical imaging. AB - OBJECTIVE: Pinhole single-photon emission computed tomography provides superior trade-off between resolution and detection efficiency as compared with conventional parallel-hole collimators for imaging small objects. This study aims to design and evaluate an optimized adaptive multipinhole (MPH) collimator for improved clinical myocardial perfusion single-photon emission computed tomography imaging (MPI) and preclinical small-animal imaging (SAI) of rats based on a clinical scanner. METHODS: The target resolution and field of view was set to be 1/20 cm for MPI and 0.15/5 cm for SAI, respectively. We determined the design parameters by maximizing the detection efficiency based on system constraints. Point source simulations using Geant4 Application for Emission Tomography were performed for different collimator-to-center of field of view distances to assess the detection efficiency and resolution trade-off. The XCAT phantom with Tc-99m sestamibi distribution and the four-dimensional mouse whole-body phantom with Tc 99m methylene diphosphonate distribution were used to generate noise-free and noisy projections using a three-dimensional analytical MPH projector. Projections were reconstructed using a three-dimensional MPH ordered-subset expectation maximization algorithm. Noise and bias were assessed on the reconstructed images for different collimators. RESULTS: The design parameters are (i) 14 pinholes with 3.42 mm aperture size, 14.5 cm collimator-to-detector distance for MPI; (ii) six pinholes with an aperture size of 0.94 mm, 21.2 cm collimator-to-detector distance for SAI. For MPI, the projected full width at half maximum values were 10.68 and 8.19 mm for low energy high resolution (LEHR) and MPH, respectively, whereas MPH had double detection efficiency. For SAI, the projected full width at half maximum values for LEHR and MPH were 4.93 and 1.20 mm, respectively, whereas the detection efficiency of MPH showed 17.5% improvement as compared with LEHR. The noise-bias trade-off improved for MPH as compared with LEHR for both MPI and SAI. The proposed collimator will have adjustable collimator-to-detector distances - that is, 14.5 cm for MPI and 21.2 cm for SAI. CONCLUSION: The new collimator yields substantial improvement in image quality as compared with current MPI using LEHR with extra capability for SAI, bridging the clinical and preclinical imaging based on the same platform. PMID- 26528788 TI - Bu4NI Catalyzed C-N Bond Formation via Cross-Dehydrogenative Coupling of Aryl Ethers (Csp3-H) and Tetrazoles (N-H). AB - Intermolecular C-N bond formations via cross-dehydrogenative coupling (CDC) of aryl ethers and tetrazoles have been developed under a metal-free condition. In the presence of catalytic amount of tetrabutylammonium iodide (TBAI) and aqueous TBHP, aryl ethers coupled efficiently with tetrazoles to afford hemiaminal ethers. This strategy showed high level of regioselectivity for substrates possessing multiple sp(3) C-H bonds adjacent to the ethereal oxygen. PMID- 26528789 TI - The Influence of Risk Perceptions and Efficacy Beliefs on Leisure-Time Physical Activity During Pregnancy. AB - BACKGROUND: Pregnancy risk perceptions and physical activity efficacy beliefs may facilitate or impede pregnancy leisure-time physical activity (LTPA). We examined the separate and joint influence of these variables on LTPA behavior among pregnant women. METHODS: Pregnant women (n = 302) completed a survey containing questions on LTPA efficacy beliefs and behavior, as well as pregnancy risk perceptions with respect to the health of the unborn baby. As stipulated by the Risk Perception Attitude (RPA) Framework, 4 attitudinal groups were created: Responsive (High Risk+High Efficacy), Proactive (Low+High), Avoidant (High+Low), and Indifferent (Low+Low). Moderate LTPA and vigorous LTPA were dichotomized for study analyses. RESULTS: A total of 82 women (27.2%) met the moderate physical activity guideline and 90 women (30.1%) performed any vigorous LTPA. Responsive and proactive pregnant women (those with high efficacy) were most likely to meet the moderate guideline and participate in vigorous LTPA. Hierarchical logistic regression did not reveal an interactive effect of pregnancy risk perceptions and LTPA efficacy beliefs for meeting the moderate guideline (OR = 0.94, 95% CI = 0.66-1.36) or any vigorous LTPA participation (OR = 1.41, 95% CI = 0.86-2.29). CONCLUSIONS: LTPA efficacy beliefs appear important in facilitating greater levels of pregnancy LTPA. Significant interactive effects between pregnancy risk perceptions and LTPA efficacy beliefs were not found. PMID- 26528790 TI - A close look at axonal transport: Cargos slow down when crossing stationary organelles. AB - The bidirectional transport of cargos along the thin axon is fundamental for the structure, function and survival of neurons. Defective axonal transport has been linked to the mechanism of neurodegenerative diseases. In this paper, we study the effect of the local axonal environment to cargo transport behavior in neurons. Using dual-color fluorescence imaging in microfluidic neuronal devices, we quantify the transport dynamics of cargos when crossing stationary organelles such as non-moving endosomes and stationary mitochondria in the axon. We show that the axonal cargos tend to slow down, or pause transiently within the vicinity of stationary organelles. The slow-down effect is observed in both retrograde and anterograde transport directions of three different cargos (TrkA, lysosomes and TrkB). Our results agree with the hypothesis that bulky axonal structures can pose as steric hindrance for axonal transport. However, the results do not rule out the possibility that cellular mechanisms causing stationary organelles are also responsible for the delay in moving cargos at the same locations. PMID- 26528791 TI - Genetic association of GWAS-supported MAD1L1 gene polymorphism rs12666575 with schizophrenia susceptibility in a Chinese population. AB - Schizophrenia (SCZ) is a severe neuropsychiatric disorder with high heritability. A recent European genome-wide association study has reported that mitotic arrest deficient-like 1 (MAD1L1) polymorphism rs12666575 is associated with SCZ susceptibility. This study aims to test the association of MAD1L1 variant rs12666575 with SCZ susceptibility in a Chinese population. A total of 1400 participants, which include 700 SCZ patients and 700 sex- and age-matched controls (Zhuang: 300, Han: 400, respectively), were genotyped using the Sequenom MassARRAY iPLEX platform. 591 SCZ patients underwent positive and negative syndrome scale (PANSS) assessment. Genetic association analysis was performed using the PLINK program. The results showed MAD1L1 rs12666575 polymorphism was significantly associated with SCZ susceptibility in the recessive model (p(adj)=0.013). Also, rs12666575 was significantly associated with general psychopathology sub-scale score (p(adj)=0.043) and thought disturbance factor score (p(adj)=0.045). Our data suggested that MAD1L1 rs12666575 polymorphism may play a protective role against SCZ in the Chinese population. Furthermore, rs12666575 may be associated with general psychopathology and thought disturbance in SCZ patients. PMID- 26528792 TI - Hydrogen peroxide centrally attenuates hyperosmolarity-induced thirst and natriuresis. AB - Intragastric hypertonic NaCl that simulates the ingestion of osmotically active substances by food intake induces thirst, vasopressin and oxytocin release, diuresis and natriuresis. Reactive oxygen species (ROS) produced endogenously in central areas may act modulating autonomic and behavioral responses. In the present study, we investigated the effects of H2O2 injected centrally on water intake and renal responses induced by increasing plasma osmolality with intragastric (ig) administration of 2M NaCl (2 ml/rat). Male Holtzman rats (280 320 g) with stainless steel cannula implanted in the lateral ventricle (LV) were used. Injections of H2O2 (2.5 MUmol/1 MUl) into the LV reduced ig 2M NaCl-induced water intake (3.1 +/- 0.7, vs. PBS: 8.6 +/- 1.0 ml/60 min, p<0.05), natriuresis (769 +/- 93, vs. PBS: 1158 +/- 168 MUEq/120 min, p<0.05) and diuresis (4.1 +/- 0.5, vs. PBS: 5.0 +/- 0.5 ml/120 min, p<0.05). Injections of H2O2 into the LV also decreased meal associated water intake (4.9 +/- 1.5, vs. PBS: 11.0 +/- 1.7 ml/120 min). However, H2O2 into the LV did not modify 2% sucrose intake (3.3 +/- 1.5, vs. PBS: 5.4 +/- 2.3 ml/120 min) or 24h food deprivation-induced food intake (8.2 +/- 2.0, vs. PBS: 11.0 +/- 1.6g/120 min), suggesting that this treatment does not produce nonspecific inhibition of ingestive behaviors. The data suggest an inhibitory role for H2O2 acting centrally on thirst and natriuresis induced by hyperosmolarity and on meal-associated thirst. PMID- 26528793 TI - Cine viability magnetic resonance imaging of the heart without increased scan time. AB - Cardiac magnetic resonance imaging (MRI) provides information about myocardial morphology, function, and viability from cine, tagged, and late gadolinium enhancement (LGE) images, respectively. While the cine and tagged images are acquired in a time-resolved fashion, the LGE images are acquired at a single timeframe. The purpose of this work is to develop a method for generating cine LGE images without additional scan time. The motion field is extracted from the tagged images, and is then used to guide the deformation of the infarcted region from the acquired LGE image at the acquired timeframe to any other timeframe. Major techniques for motion estimation, including harmonic phase (HARP) and optical flow analysis, are tested in this work for motion estimation. The proposed method is tested on numerical phantom and images from four human subjects. The generated cine LGE images showed both viability and wall motion information in the same set of images without additional scan time or image misregistration problems. The band-pass optical flow analysis resulted in the most accurate motion estimation compared to other methods, especially HARP, which fails to track points at the myocardial boundary. Infarct transmurality from the generated images showed good agreement with myocardial strain, and wall thickening showed good agreement with that measured from conventional cine images. In conclusion, the developed technique allows for generating cine LGE images that enable simultaneous display of wall motion and viability information. The generated images could be useful for estimating myocardial contractility reserve and for treatment prognosis. PMID- 26528794 TI - Development and validation of an in vitro, seven-in-one human cytochrome P450 assay for evaluation of both direct and time-dependent inhibition. AB - INTRODUCTION: Direct and time-dependent inhibition (TDI) of cytochrome P450 enzymes (CYP) raises drug safety concerns and has major implications in drug development. This study describes the development of a liquid chromatography tandem mass spectrometry (LC-MS/MS) based screening tool to simultaneously assess both the direct and the time-dependent inhibitory potential of xenobiotics on the seven major CYPs using a two-step approach. METHODS: The in vitro cocktail of FDA recognized model substrates was incubated with human liver microsomes (HLM) and consisted of caffeine (CYP1A2), bupropion (CYP2B6), rosiglitazone (CYP2C8), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6) and midazolam (CYP3A4). Direct and time-dependent inhibitory profiles of direct and time-dependent reference inhibitors for each CYP were studied. For validation, the results were compared to those obtained with the traditional single substrate approach. Statistical uncertainty was quantified using the bootstrap method. RESULTS: The direct inhibition assay showed an acceptable fold bias of 1.35 (geometric mean fold absolute deviation, range 1.01-2.61) in the IC50 values for the cocktail assay compared to the single substrate results with no trend for under- or overestimation. Using a single point inactivation assay to assess TDI, we were able to identify all seven tested time-dependent reference inhibitors, without any false negatives. DISCUSSION: The presented design enhances throughput by assessing the seven major CYPs simultaneously and allows for detection of and discrimination between direct and time-dependent CYP inhibition via IC50 and single point inactivation experiments. For the latter, a threshold of 10% TDI is proposed for carrying out more detailed inactivation kinetic experiments. PMID- 26528795 TI - Would calcium or potassium channels be responsible for cardiac arrest produced by adenosine and ATP in the right atria of Wistar rats? AB - Autonomic nerves release ATP, which is processed into adenosine in the synaptic cleft. Adenosine and ATP exert a negative chronotropic effect in the heart. This study aims to evaluate adenosine and P2 receptors and cellular signalling in cardiac arrest produced by purines in the heart. Right atria of adult Wistar rats were used to evaluate the effects of adenosine, ATP and CPA (an adenosine A1 receptor agonist), in the presence and absence of DPCPX, an adenosine A1 receptor antagonist. Effects of adenosine A2 and A3 receptors agonists and antagonists were also investigated. Finally, involvement of calcium and potassium channels in these responses was assessed using BayK 8644 and 4-Aminopyridine. Cumulative concentration-effect curves of adenosine and CPA resulted in a negative chronotropic effect culminating in cardiac arrest at 1000MUM (adenosine) and 1uM (CPA). Furthermore, ATP produced a negative chronotropic effect at 1-300uM and cardiac arrest at 1000MUM in the right atrium. ATPgammaS (a non-hydrolysable analogue of ATP) reduced chronotropism only. The effects of adenosine, CPA and ATP were inhibited by DPCPX, a selective adenosine A1 receptor antagonist. The selective adenosine A2 and A3 receptors antagonists did not alter the chronotropic response of adenosine. 4-Aminopyridine, a blocker of potassium channels at 10mM, prevented the cardiac arrest produced by adenosine and ATP, while BayK 8644, activator of calcium channels, did not prevent cardiac arrest. Adenosine A1 receptor activation by adenosine and ATP produces cardiac arrest in the right atrium of Wistar rats predominantly through activation of potassium channels. PMID- 26528796 TI - Myristoleic acid inhibits osteoclast formation and bone resorption by suppressing the RANKL activation of Src and Pyk2. AB - Cytoskeletal changes in osteoclasts such as formation of actin ring is required for bone-resorbing activity. The tyrosine kinase Src is a key player in massive cytoskeletal change of osteoclasts, thereby in bone destruction. In order for Src to be activated, trafficking to the inner plasma membrane via myristoylation is of importance. A previous study reported that myristoleic acid derived from myristic acid, inhibited N-myristoyl-transferase, an essential enzyme for myristoylation process. This prompted us to investigate whether myristoleic acid could affect osteoclastogenesis. Indeed, we observed that myristoleic acid inhibited RANKL-induced osteoclast formation in vitro, especially, at later stages of differentiation. Myristoleic acid attenuated the tyrosine phosphorylation of c-Src and Pyk2, which associates with Src, by RANKL. When myristoleic acid was co-administered with soluble RANKL into mice, RANKL-induced bone loss was substantially prevented. Bone dissection clearly revealed that the number of multinucleated osteoclasts was significantly diminished by myristoleic acid. On the other hand, myristoleic acid treatment had little or no influence on early osteoclast differentiation markers, such as c-Fos and NFATc1, and proteins related to cytoskeletal rearrangement, including DC-STAMP, integrin alphav and integrin beta3 in vitro. Taken together, our data suggest that myristoleic acid is capable of blocking the formation of large multinucleated osteoclasts and bone resorption likely through suppressing activation of Src and Pyk2. PMID- 26528797 TI - Levosimendan inhibits interleukin-1beta-induced apoptosis through activation of Akt and inhibition of inducible nitric oxide synthase in rat cardiac fibroblasts. AB - Levosimendan, a calcium sensitizer, known as an inotropic agent has a cytoprotective effect against apoptosis in cardiomyocytes. However, the cytoprotective effect of levosimendan on cardiac fibroblasts has not been clarified. The aim of this study was to examine whether levosimendan modulates interleukin (IL)-1beta-induced apoptosis in adult rat cardiac fibroblast. Cardiac fibroblasts were isolated from adult male Wistar rats. Apoptosis of cardiac fibroblasts was evaluated by 4',6-diamidino-2-phenylindole staining and TdT mediated d-UTP nick end labeling (TUNEL)-based staining. Expression of inducible nitric oxide (NO) synthase (iNOS) and phosphorylation of Akt (Ser473) were determined by Western blotting. Assessment of NO production in the culture medium was performed by using 4,5-diaminofluorescein as a fluorescent probe. Immunofluorescence staining was performed to examine cytochrome-c translocation. Levosimendan (3-100MUM) concentration-dependently inhibited IL-1beta (4ng/ml, 24h)-induced apoptotic changes in cardiac fibroblasts, such as cellular shrinkage, nuclear condensation and the increase of TUNEL-positive cells. Levosimendan inhibited IL-1beta-induced iNOS expression and subsequent NO production. 1400W, an iNOS inhibitor, suppressed the IL-1beta-induced apoptosis. Levosimendan alone-treatment concentration-dependently increased phosphorylation of Akt (Ser473). LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, reversed the protective effect of levosimendan on IL-1beta-induced apoptosis in TUNEL assay. In addition, levosimendan and 1400W inhibited the IL-1beta-induced cytosolic translocation of cytochrome-c. LY294002 reversed the suppressive effects of levosimendan. The present study for the first time demonstrated that levosimendan inhibits IL-1beta-induced apoptosis via the activation of PI3K/Akt pathway and the inhibition of iNOS expression in adult rat cardiac fibroblasts. PMID- 26528798 TI - Deoxyandrographolide promotes glucose uptake through glucose transporter-4 translocation to plasma membrane in L6 myotubes and exerts antihyperglycemic effect in vivo. AB - Skeletal muscle is the principal site for postprandial glucose utilization and augmenting the rate of glucose utilization in this tissue may help to control hyperglycemia associated with diabetes mellitus. Here, we explored the effect of Deoxyandrographolide (DeoAn) isolated from the Andrographis paniculata Nees on glucose utilization in skeletal muscle and investigated its antihyperglycemic effect in vivo in streptozotocin-induced diabetic rats and genetically diabetic db/db mice. In L6 myotubes, DeoAn dose-dependently stimulated glucose uptake by enhancing the translocation of glucose transporter 4 (GLUT4) to cell surface, without affecting the total cellular GLUT4 and GLUT1 content. These effects of DeoAn were additive to insulin. Further analysis revealed that DeoAn activated PI 3-K- and AMPK-dependent signaling pathways, account for the augmented glucose transport in L6 myotubes. Furthermore, DeoAn lowered postprandial blood glucose levels in streptozotocin-induced diabetic rats and also suppressed the rises in the fasting blood glucose, serum insulin, triglycerides and LDL-Cholesterol levels of db/db mice. These findings suggest the therapeutic efficacy of the DeoAn for type 2 diabetes mellitus and can be potential phytochemical for its management. PMID- 26528799 TI - Functional variants of gene encoding folate metabolizing enzyme and methotrexate related toxicity in children with acute lymphoblastic leukemia. AB - Methotrexate (MTX) is commonly used agent in therapy of malignancies, including acute lymphoblastic leukemia (ALL). Based on the literature data it is known that MTX elimination and toxicity can be affected by polymorphisms in genes encoding enzymes involved in MTX metabolism. The aim of our study was to investigate the influence of C677T and A1298C polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene on MTX-induced toxicity during treatment of children with ALL. We also tried to answer the question whether simultaneous occurrence of these two polymorphisms has a clinical significance. MTHFR polymorphisms were assessed in 47 pediatric ALL patients, treated according to intensive chemotherapy for childhood ALL, ALL IC BFM 2009. Prolonged MTX elimination and higher incidence of toxicity were observed for patients with 677T-1298A haplotype. On the other hand, occurrence of 677C-1298A haplotype had protective effect on MTX clearance and toxicity, that was not observed in carriers of 677C 1298C haplotype. In patients with coexistence of studied variants 677CT/1298AC heterozygotes as well as in 677TT/1298AA homozygotes more frequently toxicity incidents were noted. The obtained results suggest that occurrence of 677T allele and coexistence of 677T and 1298C alleles may be associated with lower MTX clearance and elevated risk of adverse effects during MTX-treatment of pediatric ALL patients. PMID- 26528800 TI - The Standardized Field Sobriety Tests (SFST) and measures of cognitive functioning. AB - OBJECTIVE: The Standardized Field Sobriety Tests (SFST) are utilised widely to assess fitness to drive when law enforcement suspects a driver's ability to drive is impaired, whether by drugs or alcohol. The SFST ostensibly achieve this through assessment of the level of drivers' cognitive and psychomotor impairment, although no studies have explicitly assessed the relatedness of cognitive ability and performance on the SFST. The current study aimed to assess the relationship between the three components of the SFST with a well validated computerised cognitive battery. METHOD: A sub-set of 61 placebo condition participants comprised the sample, with 33 females and 28 males (mean age 25.45 years). Correlations between the individual SFST subscales 'Horizontal Gaze Nystagmus' (HGN), the 'One Leg Stand' (OLS) and the 'Walk and Turn' test (WAT) and Cognitive Drug Research (CDR) sub-scales of 'Quality of Working Memory', 'Power of Attention' and 'Continuity of Attention' were analysed using point-biserial correlation. RESULTS: Sixty participants were included for analyses. A weak moderate positive (five subscales) and a moderate-strong negative (two subscales) association was noted between seven of the nine individual CDR subscales and the SFST subscale of the WAT test (all p<0.05). Individually, a moderate positive association was noted between the sub-scale 'Nystagmus lack of smooth pursuit' and 'digit vigilance reaction time' and 'choice reaction time; reaction time' (both p<0.05) and 'Nystagmus head move and/or jerk' and 'simple reaction time' (p<0.001). When assessed as a partially composite factor, a comparable association was also noted between the composite score of the SFST subscale 'Nystagmus head move and/or jerk' and both (a) simple and (b) digit vigilance reaction time (both p<0.05). No association was noted between any of the individual cognitive variables and the SFST subscale 'OLS', or between composite cognitive scores 'Quality of Working Memory', 'Power of Attention' and 'Continuity of Attention' and total SFST scores. DISCUSSION: Variation in some aspects of cognitive performance was found to be moderately and positively correlated with some individual aspects of the SFST; particularly among tasks which assess reaction time. Impairment of these cognitive processes can also contribute to the completion of complex tasks such as driving or the SFST. Complex behavioural tasks such as driving are often severely impaired due to intoxication, and thus in a practical sense, the SFST can still be considered a useful screening tool to identify drug or alcohol impaired drivers. PMID- 26528801 TI - A Breath of Fresh Air. PMID- 26528802 TI - Conversion of Percutaneous Cholecystostomy to Internal Transmural Gallbladder Drainage Using an Endoscopic Ultrasound-Guided, Lumen-Apposing Metal Stent. AB - Patients with acute cholecystitis sometimes require placement of percutaneous cholecystostomy catheters, either as a bridge to surgery or as primary therapy. In patients who cannot undergo surgery, subsequent removal of the catheter can lead to recurrence of cholecystitis, whereas leaving the drain in place can cause adverse events. We investigated internalization of percutaneous cholecystostomy drainage catheters, using endoscopic ultrasound (EUS)-guided placement of lumen apposing metal stents (LAMS) as an alternative treatment strategy. Seven patients (median age, 57 years; 6 men) underwent EUS-guided cholecystoenterostomy for internalization of gallbladder drainage with EUS-guided placement of a 10- or 15 mm LAMS. All had initially been treated with placement of a percutaneous cholecystostomy catheter for cholecystitis and were later deemed unfit for cholecystectomy. Technical success was achieved in all patients in 1 endoscopic session, with subsequent removal of all percutaneous drains. Two patients required placement of self-expandable metal stents within the LAMS to successfully bridge the gallbladder and gastrointestinal lumen. No adverse events occurred after a median follow-up of 2.5 months. EUS-guided cholecystoenterostomy using a LAMS is therefore a viable option for internal gallbladder drainage in patients who have a percutaneous cholecystostomy catheter and are poor candidates for cholecystectomy. PMID- 26528803 TI - Sex and Racial Disparity in Incidence of Esophageal Adenocarcinoma: Observations and Explanations. PMID- 26528804 TI - Age-dependent alterations of voltage-gated Na(+) channel isoforms in rat sinoatrial node. AB - Multiple isoforms of voltage-gated Na(+) channels (NaChs) have been identified in sinoatrial node (SAN) and contribute to a rapid intrinsic heart rate. However, their roles in aging remain unclear. Here, we sought to clarify whether the age related expression of NaChs contributes to the impaired SAN function during aging. Blockade of the tetrodotoxin (TTX)-sensitive Na(+) current with nanomolar concentrations of TTX prolonged the cycle length (CL) in both the rat intact heart and SAN. The effect of nanomolar concentrations of TTX on SAN pacemaking was lessened in adulthood compared with that in youth. Interestingly, the pacemaking became more sensitive to TTX and TTX-induced sinus arrhythmias occurred more frequently in the senescent group. The presences of NaCh alpha subunit isoforms Nav1.1, Nav1.6 as well as beta subunit isoforms Navbeta1 and Navbeta3 in SAN were confirmed by immunohistochemistry. Western blot revealed a declination of Nav1.1, Nav1.6, Navbeta1 and Navbeta3 proteins during aging. Furthermore, laser captured SAN cells were used for further real-time quantitative RT-PCR analysis, which also confirmed the presences of Nav1.1, Nav1.6, Navbeta1 and Navbeta3 mRNA and their reduced levels in rat SAN during aging. These results indicated an age-dependent alterations in expression and relative function of NaCh in rat SAN. PMID- 26528805 TI - Electrochemical sensor for glutathione detection based on mercury ion triggered hybridization chain reaction signal amplification. AB - In this work, we design a new simple and highly sensitive strategy for electrochemical detection of glutathione (GSH) via mercury ion (Hg(2+)) triggered hybridization chain reaction (HCR) signal amplification. It is observed that in the absence of GSH, a specific thymine-Hg(2+)-thymine (T-Hg(2+)-T) coordination can fold into hairpin structures. While in the presence of GSH, it thus can be chelated with Hg(2+), resulting in Hg(2+) released from the T-Hg(2+)-T hairpin complex which then forms into ssDNA structure to further hybridize with the surface-immobilized capture DNA probe on the gold electrode with a sticky tail left. The presence of two hairpin helper probes through HCR leads to the formation of extended dsDNA superstructure on the electrode surface, which therefore causes the intercalation of numerous electroactive species ([Ru(NH3)6](3+)) into the dsDNA grooves, followed by a significantly amplified signal output whose intensity is related to the concentration of the GSH. Taking advantage of merits of enzyme-free amplification power of the HCR, the inherent high sensitivity of the electrochemical technique, and label-free detection which utilizes an electroactive species as a signaling molecule that binds to the anionic phosphate backbone of DNA strands via electrostatic force, not only does the proposed strategy enable sensitive detection of GSH, but show high selectivity against other amino acid, making our method a simple and sensitive addition to the amplified GSH detection. PMID- 26528806 TI - A mitochondria-targeted ratiometric two-photon fluorescent probe for biological zinc ions detection. AB - A mitochondria-targeted ratiometric two-photon fluorescent probe (Mito-MPVQ) for biological zinc ions detection was developed based on quinolone platform. Mito MPVQ showed large red shifts (68 nm) and selective ratiometric signal upon Zn(2+) binding. The ratio of emission intensity (I488 nm/I420 nm) increases dramatically from 0.45 to 3.79 (ca. 8-fold). NMR titration and theoretical calculation confirmed the binding of Mito-MPVQ and Zn(2+). Mito-MPVQ also exhibited large two photon absorption cross sections (150 GM) at nearly 720 nm and insensitivity to pH within the biologically relevant pH range. Cell imaging indicated that Mito MPVQ could efficiently located in mitochondria and monitor mitochondrial Zn(2+) under two-photon excitation with low cytotoxicity. PMID- 26528807 TI - All-in-one bioprobe devised with hierarchical-ordered magnetic NiCo2O4 superstructure for ultrasensitive dual-readout immunosensor for logic diagnosis of tumor marker. AB - A new enzyme-free all-in-one bioprobe, consisted of hematin decorated magnetic NiCo2O4 superstructure (ATS-MNS-Hb), was designed for ultrasensitive photoelectrochemical and electrochemical dual-readout immunosensing of carcinoembryonic antigen (CEA) on carbon nanohorns (CNH) support. Herein, the MNS, possessed hierarchical-ordered structure, good porosity and magnetism, acted as nanocarrier to absorb abundant Hb molecular after functionalization, providing a convenient collection means by magnetic control as well as enhanced dual readout sensing performances. CNH superstructures were employed as support to immobilize abounding captured antibodies, and then as-designed dual mode bioprobe, covalent binding with secondary antibody of CEA, was introduced for ultrasensitive detection of CEA by sandwich immunosensing. Photoelectrochemical response originated from plentiful hematin molecular, a excellent photosensitizer with good visible light harvesting efficiency, absorbed by functionalized porous MNS. The resultant concentration dependant linear calibration range was from 10 fg/mL to 1 ng/mL with ultralow detection limit of 10 fg/mL. For electrochemical process, catalase-like property of MNS was validated, moreover, MNS-Hb hybrid exhibited much higher mimic enzyme catalytic activity and evidently amplified electrocatalytic signal, performing a wide dynamic linear range from 1 ng/mL to 40 ng/mL with low detection limit of 1 ng/mL. Additionally, due to the improved accuracy of dual signals detection, the exact diagnoses of serum samples were gotten by operating resulting dual signals with AND logic system. This work demonstrated the promising application of MNS in developing ultrasensitive, cost effective and environment friendly dual-readout immunosensor and accurate diagnoses strategy for tumor markers. PMID- 26528808 TI - A generalized in situ electrodeposition of Zn doped CdS-based photoelectrochemical strategy for the detection of two metal ions on the same sensing platform. AB - An efficient strategy for the sensitive detection of Cd(2+) and Cu(2+) on the same sensing platform was first developed based on the photocurrents generated from the electrodeposited Zn doped CdS (CdZnS) film. The enhancement of the photocurrents, which was directly obtained from the in situ electrodeposited CdZnS on ITO with the gradual addition of Cd(2+), was used an indicator for the content of Cd(2+) with theoretical and technical simplicity. Moreover, the electrodeposited CdZnS was further applied to sensing of Cu(2+) based on the interaction between Cu(2+) and S(2-) by immersing the hetero-structural film electrode into a Cu(2+)-containing sample for an appropriate time, leading to decrease the photocurrent of CdZnS. The decrease extent of photocurrent was depended on the concentration of Cu(2+) in the sample solution. Due to the sensitivity of the photoelectrochemical (PEC) sensor was enhanced obviously through the doping of Zn, the present electrodeposited PEC method demonstrated acceptable linear range of 10(-9)-10(-2)M and 10(-8)-10(-4)M, with low detection limit down to 0.35 nM and 3 nM for Cd(2+) and Cu(2+) respectively, which were lower than the Environmental Protection Agency (EPA) and World Health Organization (WHO) guidelines. The proposed CdZnS-based PEC strategy achieved two metal ions detection on the same sensing platform, which had positive and significant effect on solving the common problems, such as time-consuming, high cost, complex operation and high detection limit in the detection of metal ions. In addition, the proposed PEC device was further successfully applied to an assay of Cd(2+) and Cu(2+) in water sample. PMID- 26528809 TI - A new strategy for achieving vertically-erected and hierarchical TiO2 nanosheets array/carbon cloth as a binder-free electrode for protein impregnation, direct electrochemistry and mediator-free glucose sensing. AB - We present a new approach to directly grow uniform and highly-ordered TiO2 nanosheets array (NSA) on a low-cost flexible carbon cloth substrate while simultaneously fulfill precise TiO2 nanostructure tailoring and crystal phase control. The unique vertically-erected TiO2 NSA/carbon cloth with hierarchical structures was directly explored as electrode for enzyme immobilization and biosensing applications without suffering any influences of insulating binders usually used to fix nanomaterials on conductive substrates during sensor fabrications. Efficient direct electron transfer was successfully achieved for glucose oxidase (GOx) immobilized on the TiO2 NSA/carbon cloth, which produces a stable, mediator-free glucose sensor with good selectivity, high-sensitivity (52 MUA mM(-1)cm(-2)), low response time (<5s) and low detection limit (23.4 MUM, S/N=3). The mechanism of the superior direct electrochemical properties and sensing performance was investigated in detail, and discussed from the aspects of material nanostructure and crystalline form of TiO2 NSA, and an intimate contact between TiO2 and carbon cloth resulted from direct crystallization and growth of TiO2 nanosheets on the substrate. PMID- 26528810 TI - The pathogenesis of soluble PrP fragments containing Abeta binding sites. AB - Prion protein (PrP) has proven to bind amyloid beta (Abeta) oligomers with high affinity, changing our understanding of both prion diseases (PD) and Alzheimer's disease (AD) at the molecular and phenotypic levels, although the latter currently lacks sufficient attentions. Transgenic mice expressing anchorless PrP developed unusual diseases reminiscent of AD with tremendous amyloid plaque formation. In this review, we described two interesting observations at the phenotypic level. First, common pathogenic mutations of the PRNP gene in Gerstmann-Straussler-Scheinker (GSS) syndrome were clustered at PrP95-105. Meanwhile, all nonsense PRNP mutations that generated soluble PrP 95-105 exhibited phenotypes with abundant amyloid formations. We speculate that PrP Abeta oligomers binding might be the underlying mechanism of the predominant amyloid phenotypes. Second, soluble PrP-Abeta oligomer complexes might exist in the extracellular space at the beginning of both PD and AD and subserve an initial neuroprotective function. Thus, the diseases would only present after long-term accumulation. This might be the central common pathogenic event of both PD and AD. PMID- 26528811 TI - Object-Oriented Classification of Sugarcane Using Time-Series Middle-Resolution Remote Sensing Data Based on AdaBoost. AB - Most areas planted with sugarcane are located in southern China. However, remote sensing of sugarcane has been limited because useable remote sensing data are limited due to the cloudy climate of this region during the growing season and severe spectral mixing with other crops. In this study, we developed a methodology for automatically mapping sugarcane over large areas using time series middle-resolution remote sensing data. For this purpose, two major techniques were used, the object-oriented method (OOM) and data mining (DM). In addition, time-series Chinese HJ-1 CCD images were obtained during the sugarcane growing period. Image objects were generated using a multi-resolution segmentation algorithm, and DM was implemented using the AdaBoost algorithm, which generated the prediction model. The prediction model was applied to the HJ 1 CCD time-series image objects, and then a map of the sugarcane planting area was produced. The classification accuracy was evaluated using independent field survey sampling points. The confusion matrix analysis showed that the overall classification accuracy reached 93.6% and that the Kappa coefficient was 0.85. Thus, the results showed that this method is feasible, efficient, and applicable for extrapolating the classification of other crops in large areas where the application of high-resolution remote sensing data is impractical due to financial considerations or because qualified images are limited. PMID- 26528812 TI - An Investigation of the Shortcomings of the CONSORT 2010 Statement for the Reporting of Group Sequential Randomised Controlled Trials: A Methodological Systematic Review. AB - BACKGROUND: It can be argued that adaptive designs are underused in clinical research. We have explored concerns related to inadequate reporting of such trials, which may influence their uptake. Through a careful examination of the literature, we evaluated the standards of reporting of group sequential (GS) randomised controlled trials, one form of a confirmatory adaptive design. METHODS: We undertook a systematic review, by searching Ovid MEDLINE from the 1st January 2001 to 23rd September 2014, supplemented with trials from an audit study. We included parallel group, confirmatory, GS trials that were prospectively designed using a Frequentist approach. Eligible trials were examined for compliance in their reporting against the CONSORT 2010 checklist. In addition, as part of our evaluation, we developed a supplementary checklist to explicitly capture group sequential specific reporting aspects, and investigated how these are currently being reported. RESULTS: Of the 284 screened trials, 68(24%) were eligible. Most trials were published in "high impact" peer-reviewed journals. Examination of trials established that 46(68%) were stopped early, predominantly either for futility or efficacy. Suboptimal reporting compliance was found in general items relating to: access to full trials protocols; methods to generate randomisation list(s); details of randomisation concealment, and its implementation. Benchmarking against the supplementary checklist, GS aspects were largely inadequately reported. Only 3(7%) trials which stopped early reported use of statistical bias correction. Moreover, 52(76%) trials failed to disclose methods used to minimise the risk of operational bias, due to the knowledge or leakage of interim results. Occurrence of changes to trial methods and outcomes could not be determined in most trials, due to inaccessible protocols and amendments. DISCUSSION AND CONCLUSIONS: There are issues with the reporting of GS trials, particularly those specific to the conduct of interim analyses. Suboptimal reporting of bias correction methods could potentially imply most GS trials stopping early are giving biased results of treatment effects. As a result, research consumers may question credibility of findings to change practice when trials are stopped early. These issues could be alleviated through a CONSORT extension. Assurance of scientific rigour through transparent adequate reporting is paramount to the credibility of findings from adaptive trials. Our systematic literature search was restricted to one database due to resource constraints. PMID- 26528813 TI - A Stochastic Burst Follows the Periodic Morning Peak in Individual Drosophila Locomotion. AB - Coupling between cyclically varying external light and an endogenous biochemical oscillator known as the circadian clock, modulates a rhythmic pattern with two prominent peaks in the locomotion of Drosophila melanogaster. A morning peak appears around the time lights turn on and an evening peak appears just before lights turn off. The close association between the peaks and the external 12:12 hour light/dark photoperiod means that respective morning and evening peaks of individual flies are well-synchronized in time and, consequently, feature prominently in population-averaged data. Here, we report on a brief but strong stochastic burst in fly activity that, in contrast to morning and evening peaks, is detectable only in single fly recordings. This burst was observed across 3 wild-type strains of Drosophila melanogaster. In a single fly recording, the burst is likely to appear once randomly within 0.5-5 hours after lights turn on, last for only 2-3 minutes and yet show 5 times greater activity compared to the maximum of morning peak with data binned in 3 minutes. Owing to its variable timing and short duration, the burst is virtually undetectable in population averaged data. We use a locally-built illumination system to study the burst and find that its incidence in a population correlates with light intensity, with ~85% of control flies showing the behavior at 8000 lux (1942 MUW/cm2). Consistent with that finding, several mutant flies with impaired vision show substantially reduced frequency of the burst. Additionally, we find that genetic ablation of the clock has insignificant effect on burst frequency. Together, these data suggest that the pronounced burst is likely generated by a light-activated circuit that is independent of the circadian clock. PMID- 26528815 TI - Influence of Reynolds Number on Multi-Objective Aerodynamic Design of a Wind Turbine Blade. AB - At present, the radius of wind turbine rotors ranges from several meters to one hundred meters, or even more, which extends Reynolds number of the airfoil profile from the order of 105 to 107. Taking the blade for 3MW wind turbines as an example, the influence of Reynolds number on the aerodynamic design of a wind turbine blade is studied. To make the study more general, two kinds of multi objective optimization are involved: one is based on the maximum power coefficient (CPopt) and the ultimate load, and the other is based on the ultimate load and the annual energy production (AEP). It is found that under the same configuration, the optimal design has a larger CPopt or AEP (CPopt//AEP) for the same ultimate load, or a smaller load for the same CPopt//AEP at higher Reynolds number. At a certain tip-speed ratio or ultimate load, the blade operating at higher Reynolds number should have a larger chord length and twist angle for the maximum Cpopt//AEP. If a wind turbine blade is designed by using an airfoil database with a mismatched Reynolds number from the actual one, both the load and Cpopt//AEP will be incorrectly estimated to some extent. In some cases, the assessment error attributed to Reynolds number is quite significant, which may bring unexpected risks to the earnings and safety of a wind power project. PMID- 26528814 TI - Language and Memory Improvements following tDCS of Left Lateral Prefrontal Cortex. AB - Recent research demonstrates that performance on executive-control measures can be enhanced through brain stimulation of lateral prefrontal regions. Separate psycholinguistic work emphasizes the importance of left lateral prefrontal cortex executive-control resources during sentence processing, especially when readers must override early, incorrect interpretations when faced with temporary ambiguity. Using transcranial direct current stimulation, we tested whether stimulation of left lateral prefrontal cortex had discriminate effects on language and memory conditions that rely on executive-control (versus cases with minimal executive-control demands, even in the face of task difficulty). Participants were randomly assigned to receive Anodal, Cathodal, or Sham stimulation of left lateral prefrontal cortex while they (1) processed ambiguous and unambiguous sentences in a word-by-word self-paced reading task and (2) performed an n-back memory task that, on some trials, contained interference lure items reputed to require executive-control. Across both tasks, we parametrically manipulated executive-control demands and task difficulty. Our results revealed that the Anodal group outperformed the remaining groups on (1) the sentence processing conditions requiring executive-control, and (2) only the most complex n-back conditions, regardless of executive-control demands. Together, these findings add to the mounting evidence for the selective causal role of left lateral prefrontal cortex for executive-control tasks in the language domain. Moreover, we provide the first evidence suggesting that brain stimulation is a promising method to mitigate processing demands encountered during online sentence processing. PMID- 26528816 TI - Tissue-Specific Effects of Reduced beta-catenin Expression on Adenomatous Polyposis Coli Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium. AB - Adenomatous polyposis coli (APC) inactivating mutations are present in most human colorectal cancers and some other cancers. The APC protein regulates the beta catenin protein pool that functions as a co-activator of T cell factor (TCF) regulated transcription in Wnt pathway signaling. We studied effects of reduced dosage of the Ctnnb1 gene encoding beta-catenin in Apc-mutation-induced colon and ovarian mouse tumorigenesis and cell culture models. Concurrent somatic inactivation of one Ctnnb1 allele, dramatically inhibited Apc mutation-induced colon polyposis and greatly extended Apc-mutant mouse survival. Ctnnb1 hemizygous dose markedly inhibited increases in beta-catenin levels in the cytoplasm and nucleus following Apc inactivation in colon epithelium, with attenuated expression of key beta-catenin/TCF-regulated target genes, including those encoding the EphB2/B3 receptors, the stem cell marker Lgr5, and Myc, leading to maintenance of crypt compartmentalization and restriction of stem and proliferating cells to the crypt base. A critical threshold for beta-catenin levels in TCF-regulated transcription was uncovered for Apc mutation-induced effects in colon epithelium, along with evidence of a feed-forward role for beta catenin in Ctnnb1 gene expression and CTNNB1 transcription. The active beta catenin protein pool was highly sensitive to CTNNB1 transcript levels in colon cancer cells. In mouse ovarian endometrioid adenocarcinomas (OEAs) arising from Apc- and Pten-inactivation, while Ctnnb1 hemizygous dose affected beta-catenin levels and some beta-catenin/TCF target genes, Myc induction was retained and OEAs arose in a fashion akin to that seen with intact Ctnnb1 gene dose. Our findings indicate Ctnnb1 gene dose exerts tissue-specific differences in Apc mutation-instigated tumorigenesis. Differential expression of selected beta catenin/TCF-regulated genes, such as Myc, likely underlies context-dependent effects of Ctnnb1 gene dosage in tumorigenesis. PMID- 26528817 TI - The Impact of Vitamin D Levels on Inflammatory Status: A Systematic Review of Immune Cell Studies. AB - Chronic low-grade inflammation accompanies obesity and its related chronic conditions. Both peripheral blood mononuclear cells (PBMCs) and cell lines have been used to study whether vitamin D has immune modulating effects; however, to date a detailed systematic review describing the published evidence has not been completed. We therefore conducted a systematic review on the effect of vitamin D on the protein expression and secretion of inflammatory markers by human-derived immune cells. The review was registered at the International Prospective Register for Systematic Reviews (PROSPERO, Registration number CRD42015023222). A literature search was conducted using Pubmed, Science Direct, Scopus, Web of Science and Medline. The search strategy used the following search terms: Vitamin D or cholecalciferol or 1,25-dihydroxyvitamin or 25-hydroxy-Vitamin D and Inflam* or cytokine* and supplement* or cell*. These terms were searched in the abstract, title and keywords. Inclusion criteria for study selection consisted of human derived immune cell lines or cellular studies where PBMCs were obtained from humans, reported in the English language, and within the time period of 2000 to 2015. The selection protocol was mapped according to PRISMA guidelines. Twenty three studies (7 cell line and 16 PBMCs studies) met our criteria. All studies selected except one used the active metabolite 1,25(OH)2, with one study using cholecalciferol and two studies also using 25(OH)D. Four out of seven cell line studies showed an anti-inflammatory effect where suppression of key markers such as macrophage chemotactic protein 1, interleukin 6 and interleukin 8 were observed. Fourteen of sixteen PBMC studies also showed a similar anti inflammatory effect based on common inflammatory endpoints. Mechanisms for such effects included decreased protein expression of toll-like receptor-2 and toll like receptor-4; lower levels of phosphorylated p38 and p42/42; reduced expression of phosphorylated signal transducer and activator of transcription 5 and decreased reactive oxygen species. This review demonstrates that an anti inflammatory effect of vitamin D is a consistent observation in studies of cell lines and human derived PBMCs. PMID- 26528818 TI - Evaluation of Transient Elastography, Acoustic Radiation Force Impulse Imaging (ARFI), and Enhanced Liver Function (ELF) Score for Detection of Fibrosis in Morbidly Obese Patients. AB - BACKGROUND: Liver fibrosis induced by non-alcoholic fatty liver disease causes peri-interventional complications in morbidly obese patients. We determined the performance of transient elastography (TE), acoustic radiation force impulse (ARFI) imaging, and enhanced liver fibrosis (ELF) score for fibrosis detection in bariatric patients. PATIENTS AND METHODS: 41 patients (median BMI 47 kg/m2) underwent 14-day low-energy diets to improve conditions prior to bariatric surgery (day 0). TE (M and XL probe), ARFI, and ELF score were performed on days 15 and -1 and compared with intraoperative liver biopsies (NAS staging). RESULTS: Valid TE and ARFI results at day -15 and -1 were obtained in 49%/88% and 51%/90% of cases, respectively. High skin-to-liver-capsule distances correlated with invalid TE measurements. Fibrosis of liver biopsies was staged as F1 and F3 in n = 40 and n = 1 individuals. However, variations (median/range at d-15/-1) of TE (4.6/2.6-75 and 6.7/2.9-21.3 kPa) and ARFI (2.1/0.7-3.7 and 2.0/0.7-3.8 m/s) were high and associated with overestimation of fibrosis. The ELF score correctly classified 87.5% of patients. CONCLUSION: In bariatric patients, performance of TE and ARFI was poor and did not improve after weight loss. The ELF score correctly classified the majority of cases and should be further evaluated. PMID- 26528819 TI - Intracellular Networks of the PI3K/AKT and MAPK Pathways for Regulating Toxoplasma gondii-Induced IL-23 and IL-12 Production in Human THP-1 Cells. AB - Interleukin (IL)-23 and IL-12 are closely related in structure, and these cytokines regulate both innate and adaptive immunity. However, the precise signaling networks that regulate the production of each in Toxoplasma gondii infected THP-1 monocytic cells, particularly the PI3K/AKT and MAPK signaling pathways, remain unknown. In the present study, T. gondii infection upregulated the expression of IL-23 and IL-12 in THP-1 cells, and both cytokines increased with parasite dose. IL-23 secretion was strongly inhibited by TLR2 monoclonal antibody (mAb) treatment in a dose-dependent manner and by TLR2 siRNA transfection, whereas IL-12 secretion was strongly inhibited by TLR4 mAb treatment dose-dependently and by TLR4 siRNA transfection. IL-23 production was dose-dependently inhibited by the PI3K inhibitors LY294002 and wortmannin, whereas IL-12 production increased dose-dependently. THP-1 cells exposed to live T. gondii tachyzoites underwent rapid p38 MAPK, ERK1/2 and JNK activation. IL-23 production was significantly upregulated by the p38 MAPK inhibitor SB203580 dose dependently, whereas pretreatment with 10 MUM SB203580 significantly downregulated IL-12 production. ERK1/2 inhibition by PD98059 was significantly downregulated IL-23 production but upregulated IL-12 production. JNK inhibition by SP600125 upregulated IL-23 production, but IL-12 production was significantly downregulated dose-dependently. T. gondii infection resulted in AKT activation, and AKT phosphorylation was inhibited dose-dependently after pretreatment with PI3K inhibitors. In T. gondii-infected THP-1 cells, ERK1/2 activation was regulated by PI3K; however, the phosphorylation of p38 MAPK and JNK was negatively modulated by the PI3K signaling pathway. Collectively, these results indicate that IL-23 production in T. gondii-infected THP-1 cells was regulated mainly by TLR2 and then by PI3K and ERK1/2; however, IL-12 production was mainly regulated by TLR4 and then by p38 MAPK and JNK. Our findings provide new insight concerning the intracellular networks of the PI3K/AKT and MAPK signaling cascades for regulating T. gondii-induced IL-23 and IL-12 secretion in human monocytic cells. PMID- 26528821 TI - 3D nonrigid medical image registration using a new information theoretic measure. AB - This work presents a novel method for the nonrigid registration of medical images based on the Arimoto entropy, a generalization of the Shannon entropy. The proposed method employed the Jensen-Arimoto divergence measure as a similarity metric to measure the statistical dependence between medical images. Free-form deformations were adopted as the transformation model and the Parzen window estimation was applied to compute the probability distributions. A penalty term is incorporated into the objective function to smooth the nonrigid transformation. The goal of registration is to optimize an objective function consisting of a dissimilarity term and a penalty term, which would be minimal when two deformed images are perfectly aligned using the limited memory BFGS optimization method, and thus to get the optimal geometric transformation. To validate the performance of the proposed method, experiments on both simulated 3D brain MR images and real 3D thoracic CT data sets were designed and performed on the open source elastix package. For the simulated experiments, the registration errors of 3D brain MR images with various magnitudes of known deformations and different levels of noise were measured. For the real data tests, four data sets of 4D thoracic CT from four patients were selected to assess the registration performance of the method, including ten 3D CT images for each 4D CT data covering an entire respiration cycle. These results were compared with the normalized cross correlation and the mutual information methods and show a slight but true improvement in registration accuracy. PMID- 26528820 TI - Etiology of Childhood Infectious Diarrhea in a Developed Region of China: Compared to Childhood Diarrhea in a Developing Region and Adult Diarrhea in a Developed Region. AB - In China, great differences in economy, social characteristics and hygiene exist between developing and developed regions. A comparative study of infectious diarrhea between two regions was needed. Three groups of diarrheal patients were collected: children <=5 year-olds from Beijing (developed region) and Henan Province (developing region), and adults over 18 year-olds from Beijing. A questionnaire was used to survey and feces samples were examined for 16 enteropathogens. We enrolled 1422 children and 1047 adults from developed region and 755 children from developing region. Virus positive rates were 32.98% for children and 23.67% for adults in developed region. The most prevalent pathogen for children was rotavirus whereas for adults was norovirus. Bacterial isolation rates were 13.92% for children from developed region, while 29.14% for children from the developing regions. For the greatest difference, Shigella accounted for 50.79% and was the dominant pathogen in the developing region, whereas in the developed region it was only 1.45%. There was no significant relationship between the local levels of development with diarrheogenic Escherichia coli (DEC) categories. But it was seen the notable differences between the population with different age: enteropathogenic E.coli (EPEC) and enteroaggregative E.coli (EAggEC) were the primary classes of DEC in children from both regions, whereas it was enterotoxigenic E.coli (ETEC) in adults. The symptoms of Shigella and Salmonella infection, such as bloody stools, white blood cells (WBC) and red blood cells (RBC) positivity and fever were similar in children, which may lead to the misidentification. Yersinia enterocolitica and shiga toxin-producing E.coli (STEC) infections were firstly reported in Beijing. There was a large difference in etiology of bacterial diarrhea between children in developing and developed regions of China. PMID- 26528822 TI - Relationship of Pretreatment Rorschach Factors to Symptoms, Quality of Life, and Real-Life Functioning in a 3-Year Follow-Up of Traumatized Refugee Patients. AB - Response to mental health treatment varies highly among refugee patients. Research has not established which factors relate to differences in outcome. This study is a follow-up of Opaas and Hartmann's (2013) Rorschach Inkblot Method (RIM; Exner, 2003) pretreatment study of traumatized refugees, where 2 RIM principal components, Trauma Response and Reality Testing, were found descriptive of participants' trauma-related personality functioning. This study's aims were to examine relationships of the RIM components with measures of anxiety, depression, posttraumatic stress, quality of life (QOL), employment, and exile language skills throughout 3 years. We found that impaired Reality Testing was related to more mental health symptoms and poorer QOL; furthermore, individuals with adequate Reality Testing improved in posttraumatic stress symptoms the first year and retained their improvement. Individuals with impaired Reality Testing deteriorated the first year and improved only slightly the next 2 years. The results of this study imply that traumatized refugee patients with impaired Reality Testing might need specific treatment approaches. Research follow-up periods should be long enough to detect changes. The reality testing impairment revealed by the RIM, mainly perceptual in quality, might not be easily detected by diagnostic interviews and self-report. PMID- 26528823 TI - Mechanical Stretch on Human Skin Equivalents Increases the Epidermal Thickness and Develops the Basement Membrane. AB - All previous reports concerning the effect of stretch on cultured skin cells dealt with experiments on epidermal keratinocytes or dermal fibroblasts alone. The aim of the present study was to develop a system that allows application of stretch stimuli to human skin equivalents (HSEs), prepared by coculturing of these two types of cells. In addition, this study aimed to analyze the effect of a stretch on keratinization of the epidermis and on the basement membrane. HSEs were prepared in a gutter-like structure created with a porous silicone sheet in a silicone chamber. After 5-day stimulation with stretching, HSEs were analyzed histologically and immunohistologically. Stretch-stimulated HSEs had a thicker epidermal layer and expressed significantly greater levels of laminin 5 and collagen IV/VII in the basal layer compared with HSEs not subjected to stretch stimulation. Transmission electron microscopy revealed that the structure of the basement membrane was more developed in HSEs subjected to stretching. Our model may be relevant for extrapolating the effect of a stretch on the skin in a state similar to an in vivo system. This experimental system may be useful for analysis of the effects of stretch stimuli on skin properties and wound healing and is also expected to be applicable to an in vitro model of a hypertrophic scar in the future. PMID- 26528824 TI - Mycotoxins in spices and herbs-An update. AB - Spices and herbs have been used since ancient times as flavor and aroma enhancers, colorants, preservatives, and traditional medicines. There are more than 30 spices and herbs of global economic and culinary importance. Among the spices, black pepper, capsicums, cumin, cinnamon, nutmeg, ginger, turmeric, saffron, coriander, cloves, dill, mint, thyme, sesame seed, mustard seed, and curry powder are the most popular spices worldwide. In addition to their culinary uses, a number of functional properties of aromatic herbs and spices are also well described in the scientific literature. However, spices and herbs cultivated mainly in tropic and subtropic areas can be exposed to contamination with toxigenic fungi and subsequently mycotoxins. This review provides an overview on the mycotoxin risk in widely consumed spices and aromatic herbs. PMID- 26528825 TI - Correction: Correction: Physiological and Molecular Responses to Excess Boron in Citrus macrophylla W. PMID- 26528826 TI - A New, Discontinuous 2 Phases of Aging Model: Lessons from Drosophila melanogaster. AB - Aging is commonly described as being a continuous process affecting progressively organisms as time passes. This process results in a progressive decrease in individuals fitness through a wide range of both organismal-decreased motor activity, fertility, resistance to stress-and molecular phenotypes-decreased protein and energy homeostasis, impairment of insulin signaling. In the past 20 years, numerous genes have been identified as playing a major role in the aging process, yet little is known about the events leading to that loss of fitness. We recently described an event characterized by a dramatic increase of intestinal permeability to a blue food dye in aging flies committed to die within a few days. Importantly, flies showing this so called 'Smurf' phenotype are the only ones, among a population, to show various age-related changes and exhibit a high risk of impending death whatever their chronological age. Thus, these observations suggest that instead of being one continuous phenomenon, aging may be a discontinuous process well described by at least two distinguishable phases. In this paper we addressed this hypothesis by implementing a new 2 Phases of Aging mathematiCal model (2PAC model) to simulate longevity curves based on the simple hypothesis of two consecutive phases of lifetime presenting different properties. We first present a unique equation for each phase and discuss the biological significance of the 3 associated parameters. Then we evaluate the influence of each parameter on the shape of survival curves. Overall, this new mathematical model, based on simple biological observations, is able to reproduce many experimental longevity curves, supporting the existence of 2 phases of aging exhibiting specific properties and separated by a dramatic transition that remains to be characterized. Moreover, it indicates that Smurf survival can be approximated by one single constant parameter for a broad range of genotypes that we have tested under our environmental conditions. PMID- 26528828 TI - Role of Endothelial Progenitor Cells in Maintaining Stemness and Enhancing Differentiation of Mesenchymal Stem Cells by Indirect Cell-Cell Interaction. AB - A hot issue in current research regarding stem cells for regenerative medicine is the retainment of the stemness and multipotency of stem cell. Endothelial progenitor cells (EPCs) are characterized by an angiogenic switch that induces angiogenesis and further ameliorates the local microenvironment in ischemic organs. This study investigated whether EPCs could modulate the multipotent and differential abilities of mesenchymal stem cells (MSCs) in vitro and in vivo. We established an EPC/MSC indirect Transwell coculture system and then examined the effects of EPCs on the regulation of MSC biological properties in vitro and bone formation in vivo. The in vitro studies showed that cocultured MSCs (coMSCs) display no overt changes in cell morphology but an enhanced MSC phenotype compared with monocultured MSCs (monoMSCs). Our studies regarding the cellular, molecular, and protein characteristics of coMSCs and monoMSCs demonstrated that EPCs greatly promote the proliferation and differentiation potentials of coMSCs under indirect coculture condition. The expression of the pluripotency factors OCT4, SOX2, Nanog, and Klf4 was also upregulated in coMSCs. Furthermore, coMSCs combined with fibrin glue showed improved bone regeneration when used to repair rat alveolar bone defects compared with monoMSC grafts in vivo. This study is the first to demonstrate that EPCs have dynamic roles in maintaining MSC stemness and regulating MSC differentiation potential. PMID- 26528827 TI - Targeting Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer by Inducing Epidermal Growth Factor Receptor Degradation via Methionine 790 Oxidation. AB - AIMS: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat non-small cell lung cancer (NSCLC) patients with EGFR mutation, but TKI resistance is common. Almost half of the acquired resistance patients are due to additional T790M mutation on EGFR (EGFR(T790M)), thus overcoming TKI resistance is important. In this study, we aim to investigate the role of reactive oxygen species (ROS) in TKI resistance as well as the molecular and biological effects of EGFR(T790M) after redox manipulation. RESULTS: The basal ROS levels in EGFR(T790M)-containing TKI-resistant NSCLC cell lines were substantially high. Sixty-three human lung tumors showed higher NADPH oxidase isoform 2 (NOX2) expression than normal lung tissues, which may contribute to high basal ROS in cancer and poor survival. Interestingly, only NOX3 was upregulated by sanguinarine, a pharmacological agent to elevate ROS, and resulted in EGFR overoxidation, degradation, and apoptosis. By contrast, such responses were lacking in EGFR(WT) cells. Selective EGFR(T790M) degradation was manipulated by redox imbalance between NOX3 and methionine reductase A (MsrA). Furthermore, the in vivo tumor suppression effect of sanguinarine, NOX3 upregulation, and EGFR degradation were confirmed. INNOVATION: We have found a new treatment strategy to overcome TKI resistance by selectively inducing EGFR(T790M) degradation via specific stimulation of methionine 790 (M790) oxidation. It can be achieved via manipulating redox imbalance between NOX3 and MsrA. CONCLUSION: Targeting EGFR by elevating ROS and redox imbalance is a potential new strategy to develop a new EGFR inhibitor for TKI-resistant patients with a wide therapeutic window between EGFR(T790M) and EGFR(WT). PMID- 26528829 TI - A postmarket safety comparison of 2 vaccination strategies for measles, mumps, rubella and varicella in Italy. AB - It is strategically important to monitor the safety profile of vaccination schedules in order to achieve and maintain high levels of coverage. We analyzed the cohort of individuals actively invited for measles, mumps, rubella and varicella (MMRV) vaccination in the Veneto region (north-east Italy) from 8/1/2013 to 7/31/2014, assessing the onset of adverse events (AE) relating to 2 different vaccination strategies for MMRV (MMR+V vs MMRV). During the vaccination session at 14 months old, parents were given a form for recording local and systemic reactions to vaccinations for 4 weeks afterwards. Overall, 12,288 forms were returned, and 84.6% of them were included in this analysis (5,130 relating to MMR+V and 5,265 to MMRV); 37.3% of the sample reported no AEs, with no difference between the 2 groups. Local reactions were more common in the MMR+V group (9.6% vs 2.9%; RR 3.33; 95% CI 2.79-3.98), while there was no difference in general reactions between the 2 groups (50% MMR+V vs 52% MMRV). The events most often reported were "fever <39.5 degrees C," which was more frequently associated with the MMRV strategy (p<0.001), and "skin blotches and marks," which occurred more often in the MMR+V group (p<0.001). Reports of "fever >=39.5 degrees C" were equally distributed between the 2 groups. Sixteen cases of febrile seizures were reported (0.14% in the MMR+V group and 0.17% in the MMRV group). Similar safety profiles were identified for the 2 vaccination strategies. Although the method used to record reactions to vaccination demanded considerable resources, it enabled important information to be collected on parents' perception of the AEs occurring in response to their child's vaccination. PMID- 26528830 TI - Development and Validation of a New Low-Cost Enzyme-Linked Immunoassay for Serum and Dried Blood Spot Thyroglobulin. AB - BACKGROUND: Thyroglobulin (Tg), a biomarker of iodine nutrition, can be measured on dried blood spots (DBS), which simplifies collection and transport in surveys. The World Health Organization recommends DBS-Tg for monitoring iodine status in children. It could also be a useful iodine biomarker during pregnancy. However, the Tg antibody (Ab) used in earlier DBS-Tg assays is no longer commercially available. The aims of the present study were: (i) to develop a new low-cost serum and DBS-Tg sandwich enzyme-linked immunosorbent assay for assessment of Tg in population studies; (ii) to check the stability of DBS-Tg during long-term storage; and (iii) to assess within-subject variability in DBS-Tg. METHODS: Serum and DBS samples were measured from healthy pregnant women (n = 424) with the new assays, as well as the Immulite 2000 (Siemens), including TgAb positive (n = 150) and TgAb negative (n = 274) women. DBS-Tg stability was tested over 15 weeks of storage at -20 degrees C. Within-subject variability was evaluated over four weeks in four healthy adults. RESULTS: Intra-assay and interassay variability was 4.4-7.3% and 10.1-12.9% for the new serum Tg assay, and 7.6-12.3% and 7.6-16.5% for the DBS-Tg assay. Correlation between the two serum methods was high (r = 0.68, p < 0.01). Assay performance in all women and those TgAb negative was comparable. Correlation between the new serum Tg assay and the DBS-Tg assay was high (r = 0.78, p < 0.01), and agreement expressed as a function of the average Tg concentration for the two methods (X) was 0.59X -4.59 MUg/L. DBS-Tg was stable for 15 weeks stored at -20 degrees C. Within-subject variability in DBS-Tg was 21.1%. Reagents and antibodies costs for the new serum and DBS assays are ~ US$1. CONCLUSIONS: These new low-cost serum and DBS-Tg assays perform well over a wide range of Tg concentrations, and the field-friendly DBS assay may be particularly useful in population studies of iodine nutrition. PMID- 26528832 TI - A new type of biocompatible fluorescent probe AFN for fixed and live cell imaging of intracellular lipid droplets. AB - We discovered a new class of nontoxic, highly fluorogenic and biocompatible probe AFN for selective staining of intracellular Lipid Droplets (LDs) in both fixed and live human cervical cancer cells (HeLa) and 3T3-L1 pre-adipocytes without any background artifacts. The salient features of the probe are its visible excitation maximum, aqueous compatibility, selectivity and remarkable stability (for more than a week) in live cells, even better than commercially available Nile red. PMID- 26528833 TI - Correction: Silver-mediated direct phosphorylation of benzothiazoles and thiazoles with diarylphosphine oxides. AB - Correction for 'Silver-mediated direct phosphorylation of benzothiazoles and thiazoles with diarylphosphine oxides' by Hui-Jun Zhang et al., Chem. Commun., 2015, 51, 3450-3453. PMID- 26528831 TI - Activation of AMPK Stimulates Neurotensin Secretion in Neuroendocrine Cells. AB - AMP-activated protein kinase (AMPK), a critical fuel-sensing enzyme, regulates the metabolic effects of various hormones. Neurotensin (NT) is a 13-amino acid peptide predominantly localized in enteroendocrine cells of the small bowel and released by fat ingestion. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with an increased risk of diabetes, cardiovascular disease, and mortality; however, the mechanisms regulating NT release are not fully defined. We previously reported that inhibition of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) increases NT secretion and gene expression through activation of the MEK/ERK pathway. Here, we show that activation of AMPK increases NT secretion from endocrine cell lines (BON and QGP-1) and isolated mouse crypt cells enriched for NT-positive cells. In addition, plasma levels of NT increase in mice treated with 5-aminoimidazole-4-carboxamide riboside, a pharmacologic AMPK activator. Small interfering RNA-mediated knockdown of AMPKalpha decrease, whereas overexpression of the subunit significantly enhances, NT secretion from BON cells treated with AMPK activators or oleic acid. Similarly, small interfering RNA knockdown of the upstream AMPK kinases, liver kinase B1 and Ca(2+) calmodulin-dependent protein kinase kinase 2, also attenuate NT release and AMPK phosphorylation. Moreover, AMPK activation increases NT secretion through inhibition of mTORC1 signaling. Together, our findings show that AMPK activation enhances NT release through inhibition of mTORC1 signaling, thus demonstrating an important cross talk regulation for NT secretion. PMID- 26528836 TI - The Twelve Principles of CO2 CHEMISTRY. AB - This paper introduces a set of 12 Principles, based on the acronym CO2 CHEMISTRY, which are intended to form a set of criteria for assessing the viability of different processes or reactions for using CO2 as a feedstock for making organic chemicals. The principles aim to highlight the synergy of Carbon Dioxide Utilisation (CDU) with the components of green and sustainable chemistry as well as briefly pointing out the connection to the energy sector. PMID- 26528835 TI - Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles. AB - Nanoparticles (NPs) are considered a promising tool in both diagnosis and therapeutics. Theranostic NPs possess the combined properties of targeted imaging and drug delivery within a single entity. While the categorization of theranostic NPs is based on their structure and composition, the pharmacokinetics of NPs are significantly influenced by the physicochemical properties of theranostic NPs as well as the routes of administration. Consequently, altered pharmacokinetics modify the pharmacodynamic efficacy and toxicity of NPs. Although theranostic NPs hold great promise in nanomedicine and biomedical applications, a lack of understanding persists on the mechanisms of the biodistribution and adverse effects of NPs. To better understand the diagnostic and therapeutic functions of NPs, this review discusses the factors that influence the pharmacokinetics, pharmacodynamics and toxicology of theranostic NPs, along with several strategies for developing novel diagnostic and therapeutic modalities. PMID- 26528837 TI - Physiological and genomic characterization of two novel marine thaumarchaeal strains indicates niche differentiation. AB - Ammonia-oxidizing Archaea (AOA) are ubiquitous throughout the oceanic water column; however, our knowledge on their physiological and ecological diversity in different oceanic regions is rather limited. Here, we report the cultivation and characterization of two novel Nitrosopumilus strains, originating from coastal surface waters of the Northern Adriatic Sea. The combined physiological and genomic information revealed that each strain exhibits different metabolic and functional traits, potentially reflecting contrasting life modes. Strain NF5 contains many chemotaxis-related genes and is able to express archaella, suggesting that it can sense and actively seek favorable microenvironments such as nutrient-rich particles. In contrast, strain D3C is non-motile and shows higher versatility in substrate utilization, being able to use urea as an alternative substrate in addition to ammonia. Furthermore, it encodes a divergent, second copy of the AmoB subunit of the key enzyme ammonia monooxygenase, which might have an additional catalytic function and suggests further metabolic versatility. However, the role of this gene requires further investigation. Our results provide evidence for functional diversity and metabolic versatility among phylogenetically closely related thaumarchaeal strains, and point toward adaptations to free-living versus particle-associated life styles and possible niche differentiation among AOA in marine ecosystems. PMID- 26528838 TI - Legionella species diversity and dynamics from surface reservoir to tap water: from cold adaptation to thermophily. AB - Water samples of the Drinking Water Supply System (DWSS) of the city of Braunschweig were analysed for its Legionella species composition using genus specific PCR amplicons and single-strand conformation polymorphism (SSCP) fingerprint analyses based on 16S rRNA genes. These analyses comprised the whole supply chain including raw water, treatment process and large-scale storage, and a seasonal study of finished drinking water sampled monthly from cold and hot tap water. Treatment of raw water had a major impact on Legionella species by reducing their diversity and abundances. The Legionella species composition of the tap water was highly distinct from that of both source waters. In cold water, 8-14 different phylotypes of Legionella (PTLs) were observed per sample with relative abundances ranging from >1% to 53%. In hot water, L. pneumophila was present during all seasons at high relative abundances (8-40%) accompanied by 5 14 other PTLs of which 6 PTLs were in common with cold water. This thermophilic Legionella community, including L. pneumophila, was able to grow in the hot water above 50 degrees C. Such thermophilic Legionella populations are of general relevance for drinking water management and public health, but also for the ecology and evolution of the genus Legionella. PMID- 26528839 TI - The Learning Curve in Endoscopic Dacryocystorhinostomy: Outcomes in Surgery Performed by Trainee Oculoplastic Surgeons. AB - PURPOSE: To report outcomes of endoscopic DCR (En-DCR) performed by oculoplastic trainees and describe factors to improve success rates for trainees. METHODS: Retrospective, single-centre audit of En-DCR procedures performed by three consecutive trainee oculoplastic surgeons, over a 3-year period. Trainees also completed a reflective-learning questionnaire highlighting challenging and technically difficult aspects of En-DCR surgery, with relevant tips. RESULTS: Thirty-eight consecutive independently-performed en-DCR procedures on 38 patients (mean age 58.6 +/- 21.4 years) were studied. Mean time spent in the operating theatre was 95.7 +/- 27.3 minutes. Success rate for each year was 15/17(88%), 8/8(100%) and 7/13(54%), respectively, at mean follow-up 12.5 +/- 12 months. The lowest success rate year coincided with use of silicone stents in 31% cases compared to 94% and 100% in the previous 2 years. In cases that failed, video analysis highlighted inadequate superior bony rhinostomy (2 cases), incomplete retroplacement of posterior-nasal mucosal-flaps (3 cases), significant bleeding (1 case). Those who underwent revision surgery (n = 6), were found to have soft tissue ostium and sac closure requiring flap revision. Two-cases required further bone removal supero-posterior to the lacrimal sac. Trainees-tips that helped improve their surgery related to patient positioning, instrument handling, bone removal and posture. CONCLUSION: Good surgical outcomes are achievable training in en-DCR surgery. Adequate operating time needs to be planned. Failure was primarily due to closure of the soft-tissue ostium, either secondary to inadequate osteotomy and sac-marsupialisation or postoperative scarring. Intra operative mucosal trauma is higher amongst trainees and adjuvant silicone stenting during the training period may be of value where mucosal adhesions are anticipated. PMID- 26528840 TI - Lung function and functional capacity among foundry workers using effective risk control measures. AB - BACKGROUND: Inhaled dust in the environment can trigger specific reactions in the airways and cause various respiratory diseases. OBJECTIVE: Evaluate the lung function and functional capacity of foundry workers who are exposed to metals and use effective control measures. METHOD: A cross-sectional study was realized with 108 workers at a bronze foundry and machining plant and in maintenance at a private university, both in Brazil. The workers were divided into two groups: the study group exposed to metals but using risk control measues and a control group not exposed to metal work. The Medical Research Council Questionnaire on Respiratory Symptoms and the International Physical Activity Questionnaire were administered, and lung function and functional capacity were evaluated. Comparative statistics were used to identify differences in the outcome measures between the two groups. RESULTS: The groups had similar personal and anthropometric characteristics and time on the job. Spirometry and peak expiratory flow presented no significant differences between the groups. And there was also no statistically significant difference between groups in functional capacity as assessed by performance on the six-minute walk test. CONCLUSION: Foundry industry workers in Brazil who were exposed to metal but used risk control measures had similar lung function and functional capacity when compared to the control group who were not exposed to metal. This is a positive results and maybe related to age, time exposure and control of occupational hazards. However, these workers need to continue being monitored in longitudinal studies. PMID- 26528841 TI - Expanding vocational retraining options for injured workers: An experiment in worker choice. AB - BACKGROUND: An innovative self-directed vocational retraining alternative (Option 2) has been offered to eligible Washington State injured workers since 2008. OBJECTIVE: We aimed to describe: (1) how frequently Option 2 was selected and by whom, (2) the extent to which Option 2 workers used their reserved retraining funds, and (3) how worker satisfaction and employment outcomes for Option 2 workers compared with those of workers undergoing traditional vocational retraining. METHODS: Five-year cohort study involving workers' compensation data, state wage files, and two worker surveys. RESULTS: Fewer than 25% of Option 2 workers used their retraining funds. Retraining fund use was associated with better employment outcomes. Workers who were older, whose preferred language was not English, or who had lower pre-injury wages or less education, were least likely to use Option 2 retraining funds. Many workers chose Option 2 because they thought the approved traditional retraining plan was not a good fit for them. CONCLUSIONS: Self-directed retraining may benefit workers who have the ability, resources, and motivation to independently identify and complete retraining. Additional efforts may be needed to ensure that traditional retraining plans are well-suited to workers' circumstances, and to identify and remove barriers to use of reserved retraining funds. PMID- 26528842 TI - Comparison of static lifting capacity between experienced and novice Taiwanese female workers. AB - BACKGROUND: Previous studies have analyzed the lifting capacity of either experienced workers or novices, but a systematic comparison of the lifting capacity of experienced female workers and novices has not been conducted. OBJECTIVE: This study was conducted to identify differences in lifting strengths and postures between experienced and novice Taiwanese female workers. METHODS: Twenty-three experienced female workers and 23 novices volunteered for this study. Their static lifting strengths (n = 46) and lifting postures (n = 22) were analyzed using statistical analysis software. RESULTS: Experienced workers' vertical lifting strengths were approximately 5-7 kg lower than those of novices at lower heights (<=50 cm). However, at heights equal to or higher than 90 cm, the experienced workers generated approximately 2-3 kg higher toward-body lifting strengths than did novices. The experienced workers' strengths at all 15 lifting heights were relatively unchanged, compared with changes in the novices' strengths. Experienced workers tended to adopt a consistently deep squat at lower heights and a more flexed arm posture at higher heights. CONCLUSIONS: Through daily work experience, experienced workers may have subconsciously learned to shift their postures to avoid overexertion. These techniques for safe lifting should be taught to new Taiwanese female workers. PMID- 26528843 TI - Work readiness tools for young adults with chronic conditions. AB - BACKGROUND: Young adults with chronic health conditions can experience barriers to work performance, ability, and their present and future worker roles. OBJECTIVE: Work readiness resources can expand individuals' work skills, abilities, and interests. METHODS: Five work readiness tools are presented (1) building an occupational profile, (2) generating environmental strategies, (3) on the-job strategy use, and exploration of online tools (4) O*NET(r) and (5) O*NET(r) Interest Profiler, along with two theories (Knowles's Andragogy and Lawton's Ecological Model) to guide tool use. RESULTS: Use of these tools can assist young adults to better manage their health and expand their vocational identities for success at work. CONCLUSIONS: These approaches and tools support health professionals, community partners, and vocational organizations in their efforts to help young adults with chronic conditions. PMID- 26528844 TI - The Work of Faculty-in-Residence in North American Higher Education. PMID- 26528845 TI - Rhett Talks: The development, implementation, and assessment of a faculty-in residence program. AB - Student-faculty interactions outside the classroom have long been touted as beneficial to students' success at an institution of higher education. However, obstacles to realizing these interactions have also been well-documented. This case study profiles how student affairs administrators and faculty-in-residence overcame these obstacles to develop, implement, and assess an award-winning program for facilitating student-faculty interactions outside the classroom. Named after the Boston University (BU) mascot (Rhett the Boston terrier) and inspired by the popular online lecture series (TED Talks), Rhett Talks has met BU's unique campus needs, facilitated potent student-faculty interactions, and demonstrated effective partnering between student affairs and academic affairs. PMID- 26528846 TI - Whither goest the future of faculty-in-residence work? AB - Despite the evidence in support of the substantial benefits that come from FIR work, there still are real barriers to promoting such programs at colleges and universities. This Sounding Board reflects on the future of FIR work given those barriers. The author encourages senior administrators to reward FIR work in their faculty review processes and to encourage collaboration between faculty and student affairs professionals. Moreover, the author recommends additional, more rigorous studies of FIR work across a range of institution-types in higher education. PMID- 26528847 TI - Self-care project for faculty and staff of future health care professionals: Case report. AB - Self-care among health care providers is an important component of their ability to provide quality health care to patients. Health care institutions have programs in place for students that emphasize health and wellness, but few programs are available for faculty and staff. To address this gap and facilitate modeling health and wellness strategies for students, a New England institution that educates health care practitioners began a pilot self-care project for faculty and staff. Both quantitative and qualitative data were collected. The template used for this project could be used as a stepping-stone for future wellness self-care program in higher education for faculty, staff, and students. PMID- 26528848 TI - Lumbar spine and hip flexibility and trunk strength in helicopter pilots with and without low back pain history. AB - BACKGROUND: Low back pain (LBP) is one of the most common musculoskeletal issues facing military helicopter pilots. It is clinically important to identify differences in musculoskeletal characteristics between pilots with and without a LBP history for formulating effective interventions. OBJECTIVE: To compare lumbar spine and hip flexibility and trunk strength in pilots with and without a LBP history. METHODS: A total of 30 pilots with a LBP history were matched with pilots without a LBP history. An isokinetic dynamometer and a digital inclinometer were used to evaluate trunk and hip strength and a range-of-motion (ROM), respectively. All tests were performed bilaterally, if applicable, and agonist/antagonist ratios and side-to-side (low/high) symmetries were calculated. Paired t-tests or Wilcoxon tests were used to assess group differences (p < 0.050). RESULTS: The LBP group demonstrated significantly lower trunk extension strength and trunk extension/flexion strength ratio (p < 0.008). The LBP group demonstrated significantly less lateral flexion ROM as well as greater lateral flexion and rotation side-to-side asymmetry (p < 0.009). The LBP group demonstrated significantly greater total hip rotation side-to-side asymmetry (p = 0.037). CONCLUSIONS: Given the results, specific exercises that are targeted to improve trunk strength, ROM, and side-to-side symmetries could be developed to reduce LBP in helicopter pilots. PMID- 26528849 TI - The influences of faculty-in-residence programs on the role of the professoriate: A case study. AB - In a time when faculty face criticism for possible disengagement from undergraduate student learning, faculty-in-residence programs bring students and faculty together in a living-learning community. The benefits of such student faculty interaction are known, but lesser known is how to develop those interactions. This case study provides an account of how Baylor University - a private, research university in the Southwest - underwent a paradigm shift from a Sleep-and-Eat Model of residential education to a Learning Model. The change in culture not only benefited students, but also led to the reconceptualization of professorial work for faculty in higher education. PMID- 26528850 TI - Congenital Portosystemic Shunts: Clinic Heterogeneity Requires an Individual Management of the Patient. AB - INTRODUCTION: Congenital portosystemic shunt (CPSS) is a rare entity without insufficiency in treatment issues. The aim of this article is to show our experience in the heterogeneity of this condition. MATERIAL AND METHODS: A retrospective study of 25 CPSS in the period 1995 to 2014 was conducted. Description of the morphology, clinical impact, and treatment is given. RESULTS: According to the imaging techniques (IT), the shunt was apparently intrahepatic in 14 patients, extrahepatic in 10 patients, and mixed in 1 patient. In 14 children, IT showed hepatic portal circulation. In total shunts in which radiological examination was performed, invasive radiological techniques were able to demonstrate intrahepatic portal vein. In other patients, it was not investigated as they are asymptomatic. A child presented multiorgan failure with fulminant hepatic failure at birth. The shunt was radiologically closed and clinical impairment reversed rapidly. He is now asymptomatic with no longer images of CPSS in ultrasound scan controls. Also, seven children are asymptomatic at this time and are monitored periodically. Seven children had prenatal diagnosis, in five the shunt closed spontaneously. Nine children were symptomatic in their evolution (hyperammonemia, regenerative nodules, cholestasis, gastrointestinal bleeding). Of these, in five we performed balloon test occlusion, tolerated in all patients, followed by radiological closure. In our experience, the advancement of interventional radiology techniques avoided surgery to close the shunt. CONCLUSIONS: Morphologically, the CPSS is extremely heterogeneous, with multiple possible connections established. CPSS has multiple clinical presentations, from asymptomatic patients to acute liver failure. The therapeutic approach should be individualized and therefore held in overspecialized centers. PMID- 26528851 TI - Factors Conducive to Catch-Up Growth in Postoperative Jejunoileal Atresia Patients as Prognostic Markers of Outcome. AB - INTRODUCTION: Jejunoileal atresia (JIA) is a major congenital anomaly that requires surgical intervention in the neonatal period. During follow-up after surgery, there is usually a period of catch-up growth (CUG) that is sufficient for patients to regain normal weight for age. However, in some cases, CUG is inadequate. The aim of this study was to assess postoperative JIA patients to determine factors that may be associated with good CUG. MATERIAL AND METHODS: We retrospectively reviewed JIA patients treated at our institution by classifying them into three groups based on a comparison of postoperative weight with standard weight for healthy matched controls; that is, more than mean at 12 months after surgery (group M+), less than mean at 12 months after surgery but more than mean at 24 months after surgery because of CUG (group M-CUG+), less than mean at 24 months after surgery because there was no CUG (group M-CUG-). The following parameters were evaluated: gestational age, birth weight, sight of atresia: jejunum or ileum, length of residual small intestine, ratio of the length of residual small intestine to the predicted length of small intestine for matched gestational age (RP ratio), and duration of parenteral nutrition. RESULTS: A total of 42 patients were reviewed and classified into group M+ (n = 13), group M-CUG+ (n = 11), and group M-CUG- (n = 18). There were no significant differences in gestational age, birth weight, and duration of parenteral nutrition between the three groups. Incidence of JIA according to site was also similar. Length of residual small intestine was not significantly different between the three groups, but RP ratios were significantly higher in M+ (84.7 +/- 15.4%) and M-CUG+ (83.8 +/- 17.7%) compared with M-CUG- (69.2 +/- 18.1%) (p = 0.02, respectively). CONCLUSIONS: A higher RP ratio (approximately 84%) would appear to be conducive to CUG while a lower ratio (less than 70%) was not. Actual length of residual small intestine was not relevant to CUG. We recommend calculating the RP ratio in postoperative JIA patients and using 70% as a cutoff value to predict patients with poor potential for CUG who may benefit from more aggressive nutritional support to achieve normal growth. PMID- 26528852 TI - Can Image-Defined Risk Factors Predict Surgical Complications in Localized Neuroblastoma? AB - INTRODUCTION: Image-defined risk factors (IDRFs) have been propounded for predicting the surgical risks associated with localized neuroblastoma (NB) since 2009. In 2011, a new guideline (NG) for assessing IDRFs was published. According to the NG, the situation in which "the tumor is only in contact with renal vessels," should be considered to be "IDRF-present." Previously, this situation was diagnosed as "IDRF absent." In this study, we evaluated the IDRFs in localized NB patients to clarify the predictive capability of IDRFs for surgical complications, as well as the usefulness of the NG. Materials and METHODS: A total of 107 localized patients with NB were included in this study. The enhanced computed tomography and magnetic resonance images from the time of their diagnoses were evaluated by a single radiologist. We also analyzed the association of clinical factors, including the IDRFs (before and after applying the NG), with surgical complications. RESULTS: Of the 107 patients, 33 and 74 patients were diagnosed as IDRF-present (OP group), and IDRF-absent (ON group) before the NG, respectively. According to the NG, there were 76 and 31 patients who were classified as IDRF-present (NP group) and IDRF absent (NN group), respectively. Thus, 43 (40%) patients in the ON group were reassigned to the NP group after the NG. Surgical complications were observed in 17 of 82 patients who underwent surgical resection. Of the patients who underwent secondary operations, surgical complication rates were 55% in the OP group and 44% in the NP group. According to a univariate analysis, non-INSS 1, IDRFs before and after the NG and secondary operations were significantly associated with surgical complications. In a multivariate analysis, non-INSS 1 status and IDRFs after the NG were significantly associated with surgical complications. PMID- 26528853 TI - Two-Port Laparoscopic Descending Colostomy with Separated Stomas for Anorectal Malformations in Newborns. AB - Introduction We describe a two-port laparoscopic technique to create a colostomy in the descending colon with separated stomas for newborns with anorectal malformations. Material and Methods Six patients with an anorectal malformation underwent this procedure in the early-neonatal period. The surgical technique was performed with two ports, which allows for an accurate inspection of the abdominal contents. The first loop of the sigmoid colon is grasped through the first port and exteriorized while the attachments to the left retroperitoneum and direction of the loop are checked with the scope introduced in the second port. The division of the colon is performed extracorporally, the colon irrigated of meconium, and the distal colon moved to the second port incision. Both stomas are then fixed to the abdominal wall. Results The time of the procedure ranged from 50 to 90 minutes. A Mullerian duplication was noted in one case. Oral intake was started during the first 12 to 24 hours. No complications were seen during or after the procedure. Conclusions This technique allows for the precise localization of the colostomy with direct visualization, provides for the inspection of the internal genitalia, eliminates the incision between the two stomas and its complications, allows for painless stoma bag changes immediately after surgery, avoids twisting of the colostomy, and permits a cosmetically pleasing incision at the colostomy closure. PMID- 26528854 TI - Foxo3a-mediated overexpression of microRNA-622 suppresses tumor metastasis by repressing hypoxia-inducible factor-1alpha in ERK-responsive lung cancer. AB - Metastatic spread of cancer cells portends a poor prognosis and mortality for lung cancer patients. Hypoxia-inducible factor-1alpha (HIF-1alpha) enhances tumor cell motility by activating the epithelial-to-mesenchymal transition (EMT), which is considered a prerequisite for metastasis. Recent studies of microRNA involvement in cancer invasion and metastasis have highlighted the role of such RNAs in tumor development. However, little work has been done to identify tumor suppressor microRNAs that target HIF-1alpha to down-modulate the EMT and thereby counteract the aggressiveness and metastasis of lung cancer cells. Here, we identified the 3'-untranslated region of HIF-1alpha mRNA as a target of miR-622 and established that miR-622-mediated down-modulation of HIF-1alpha correlates with decreased levels of mesenchymal proteins, including Snail, beta-catenin, and vimentin. Functional analyses revealed that increased miR-622 expression inhibited lung cancer cell migration and invasion in vitro. miR-622 also inhibited the genesis of metastatic lung nodules as demonstrated in a lung cancer xenograft model in which nude mice were transplanted with A549 cells expressing miR-622. Mechanistic analyses showed that overexpression of EGF decreased the miR 622 level in A549 cells, and this reduction could be rescued by administrating U0126, an inhibitor of ERK. Moreover, miR-622 overexpression mediated by the transcription factor FOXO3a decreased the invasiveness of lung tumor cells by inhibiting HIF-1alpha via inactivation of ERK signaling in U0126-treated A549 cells. These findings highlight the pivotal role of the FOXO3a/miR-622 axis in inhibiting HIF-1alpha to interfere with tumor metastasis, and this information may contribute to development of novel therapeutic strategies for treating aggressive lung cancer. PMID- 26528855 TI - Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA. AB - Sarcomas are malignant tumors accounting for a high percentage of cancer morbidity and mortality in children and young adults. Surgery and radiation therapy are the accepted treatments for most sarcomas; however, patients with metastatic disease are treated with systemic chemotherapy. Many tumors display marginal levels of chemoresponsiveness and new treatment approaches are needed. Deregulation of the G1 checkpoint is crucial for various oncogenic transformation processes, suggesting that many cancer cell types depend on CDK4/6 activity. Thus, CDK4/6 activity appears to represent a promising therapeutic target for cancer treatment. In the present work, we explore the efficacy of CDK4 inhibition using palbociclib (PD0332991), a highly selective inhibitor of CDK4/6, in a panel of sarcoma cell lines and sarcoma tumor xenografts (PDXs). Palbociclib induces senescence in these cell lines and the responsiveness of these cell lines correlated with their levels of CDK4 mRNA. Palbociclib is also active in vivo against sarcomas displaying high levels of CDK4 but not against sarcomas displaying low levels of CDK4 and high levels of p16ink4a. The analysis of tumors growing after palbociclib showed a clear decrease in the CDK4 levels, indicating that clonal selection occurred in these treated tumors. In summary, our data support the efficacy of CDK4 inhibitors against sarcomas displaying increased CDK4 levels, particularly fibrosarcomas and MPNST. Our results also suggest that high levels of p16ink4a may indicate poor efficacy of CDK4 inhibitors. PMID- 26528856 TI - Collective cancer cell invasion induced by coordinated contractile stresses. AB - The physical underpinnings of fibrosarcoma cell dissemination from a tumor in a surrounding collagen-rich matrix are poorly understood. Here we show that a tumor spheroid embedded in a 3D collagen matrix exerts large contractile forces on the matrix before invasion. Cell invasion is accompanied by complex spatially and temporally dependent patterns of cell migration within and at the surface of the spheroids that are fundamentally different from migratory patterns of individual fibrosarcoma cells homogeneously distributed in the same type of matrix. Cells display a continuous transition from a round morphology at the spheroid core, to highly aligned elongated morphology at the spheroid periphery, which depends on both beta1-integrin-based cell-matrix adhesion and myosin II/ROCK-based cell contractility. This isotropic-to-anisotropic transition corresponds to a shift in migration, from a slow and unpolarized movement at the core, to a fast, polarized and persistent one at the periphery. Our results also show that the ensuing collective invasion of fibrosarcoma cells is induced by anisotropic contractile stresses exerted on the surrounding matrix. PMID- 26528857 TI - ILs-3, 6 and 11 increase, but ILs-10 and 24 decrease stemness of human prostate cancer cells in vitro. AB - Cancer stem cells (CSCs) are associated with cancer recurrence and metastasis. Prostate cancer cells often metastasize to the bone with a complex microenvironment of cytokines favoring cell survival. In this study, the cell stemness influence of a group of interleukins including IL-3, 6, 10, 11 and 24 on human prostate cancer cell lines LNCaP and PC-3 was explored in vitro. Sulforhodamine B(SRB) and 5-ethynyl-2'-deoxyuridine (EdU) assays were applied to examine the effect on cell proliferation, and wound healing and transwell assays were used for migration and invasion studies, in addition to colony formation, Western blotting and flowcytometry for the expression of stemness factors and chemotherapy sensitivity. We observed that ILs-3, 6 and 11 stimulated while ILs 10 and 24 inhibited the growth, invasion and migration of both cell lines. Interestingly, ILs-3, 6 and 11 significantly promoted colony formation and increased the expression of SOX2, CD44 and ABCG2 in both prostate cancer cell lines. However, ILs-10 and 24 showed the opposite effect on the expression of these factors. In line with the above findings, treatment with either IL-3 or IL 6 or IL-11 decreased the chemosensitivity to docetaxel while treatment with either IL-10 or IL-24 increased the sensitivity of docetaxel chemotherapy. In conclusion, our results suggest that ILs-3, 6 and 11 function as tumor promoters while ILs-10 and 24 function as tumor suppressors in the prostate cancer cell lines PC-3 and LNCaP in vitro, and such differences may attribute to their different effect on the stemness of PCa cells. PMID- 26528859 TI - Formation of oil-in-water emulsions from natural emulsifiers using spontaneous emulsification: sunflower phospholipids. AB - This study examined the possibility of producing oil-in-water emulsions using a natural surfactant (sunflower phospholipids) and a low-energy method (spontaneous emulsification). Spontaneous emulsification was carried out by titrating an organic phase (oil and phospholipid) into an aqueous phase with continuous stirring. The influence of phospholipid composition, surfactant-to-oil ratio (SOR), initial phospholipids location, storage time, phospholipid type, and preparation method was tested. The initial droplet size depended on the nature of the phospholipid used, which was attributed to differences in phospholipid composition. Droplet size decreased with increasing SOR and was smallest when the phospholipid was fully dissolved in the organic phase rather than the aqueous phase. The droplets formed using spontaneous emulsification were relatively large (d > 10 MUm), and so the emulsions were unstable to gravitational separation. At low SORs (0.1 and 0.5), emulsions produced with phospholipids had a smaller particle diameter than those produced with a synthetic surfactant (Tween 80), but at a higher SOR (1.0), this trend was reversed. High-energy methods (microfluidization and sonication) formed significantly smaller droplets (d < 10 MUm) than spontaneous emulsification. The results from this study show that low energy methods could be utilized with natural surfactants for applications for which fine droplets are not essential. PMID- 26528860 TI - Divergence in mating signals correlates with genetic distance and behavioural responses to playback. AB - Animals use acoustic signals to defend resources against rivals and attract breeding partners. As with many biological traits, acoustic signals may reflect ancestry; closely related species often produce more similar signals than do distantly related species. Whether this similarity in acoustic signals is biologically relevant to animals is poorly understood. We conducted a playback experiment to measure the physical and vocal responses of male songbirds to the songs of both conspecific and allopatric-congeneric animals that varied in their acoustic and genetic similarity. Our subjects were territorial males of four species of neotropical Troglodytes wrens: Brown-throated Wrens (Troglodytes brunneicollis), Cozumel Wrens (T. beani), Clarion Wrens (T. tanneri) and Socorro Wrens (T. sissonii). Our results indicate that birds respond to playback of both conspecific and allopatric-congeneric animals; that acoustic differences increase with genetic distance; and that genetic divergence predicts the strength of behavioural responses to playback, after removing the effects of acoustic similarity between subjects' songs and playback stimuli. Collectively, these results demonstrate that the most distantly related species have the most divergent songs; that male wrens perceive divergence in fine structural characteristics of songs; and that perceptual differences between species reflect evolutionary history. This study offers novel insight into the importance of acoustic divergence of learned signals and receiver responses in species recognition. PMID- 26528858 TI - Mutually exclusive mutations in NOTCH1 and PIK3CA associated with clinical prognosis and chemotherapy responses of esophageal squamous cell carcinoma in China. AB - BACKGROUND: Recurrent genetic abnormalities that correlate with clinical features could be used to determine patients' prognosis, select treatments and predict responses to therapy. Esophageal squamous cell carcinoma (ESCC) contains genomic alterations of undefined clinical significance. We aimed to identify mutually exclusive mutations that are frequently detected in ESCCs and characterized their associations with clinical variables. METHODS: We analyzed next-generation sequencing data from 104 ESCCs from Taihang Mountain region of China; 96 pairs were selected for deep target-capture-based validation and analysis of clinical and pathology data. We used model proposed by Szczurek to identify exclusive mutations and to associate these with pathology findings. Univariate and multivariate analyses with Cox proportional hazards model were used to examine the association between mutations and overall survival and response to chemotherapy. Findings were validated in an analysis of samples from 89 patients with ESCC from Taihang Mountain. RESULTS: We identified statistically significant mutual exclusivity between mutations in NOTCH1 and PIK3CA in ESCC samples. Mutations in NOTCH1 were associated with well-differentiated, early-stage malignancy and less metastasis to regional lymph nodes. Nonetheless, patients with NOTCH1 mutations had shorter survival times than patients without NOTCH1 mutations, and failed to respond to chemotherapy. In contrast, patients with mutations in PIK3CA had better responses to chemotherapy and longer survival times than patients without PIK3CA mutations. CONCLUSIONS: In a genetic analysis of ESCCs from patients in China, we identified mutually exclusive mutations in NOTCH1 and PIK3CA. These findings might increase our understanding of ESCC development and be used as prognostic factors. PMID- 26528862 TI - Cetuximab Plus Various Chemotherapy Regimens for Patients with KRAS Wild-Type Metastatic Colorectal Cancer. AB - BACKGROUND: The aim of this study was to compare the efficacy and hematologic toxicity of cetuximab combined with various types of chemotherapy regimens in patients with KRAS wild-type metastatic colorectal cancer (mCRC). METHODS: The response rate, progression-free survival (PFS) and overall survival of the patients were analyzed. RESULTS: In total, 45 patients were included in the study. The overall response rate for the combination of cetuximab and FOLFOX, FOLFIRI and CAPOX was 20, 46 and 30%, respectively, but the differences were not statistically significant. The median PFS for the three groups were 8, 6 and 3.5 months, respectively, but again these differences were not significant. All-grade leukopenia and anemia for the cetuximab plus FOLFOX group were significantly higher than for the other chemotherapy regimens. CONCLUSION: Our findings suggest that the combination of cetuximab and the three standard chemotherapy regimens resulted in the same outcomes in our patient population of mCRC, with higher hematologic toxicities among the FOLFOX subgroup. PMID- 26528861 TI - Prevalence and Clinical Relevance of IgE Sensitization to Profilin in Childhood: A Multicenter Study. AB - BACKGROUND: Little is known about the prevalence and clinical relevance of hypersensitivity to the plant panallergen profilin in children. OBJECTIVES: The present study aimed to investigate prevalence, risk factors and clinical relevance of profilin sensitization in a large cohort of Italian children of different ages living in different geographic areas. METHODS: Children with pollen allergy enrolled by 16 pediatric outpatient clinics sited in three main geographic areas of Italy were studied. SPT were carried out with commercial pollen extracts and a commercial purified date palm pollen profilin. IgE specific for allergenic pollen molecules, Phl p 12 (grass profilin) and Pru p 3 (peach lipid transfer protein) were tested by ImmunoCAP FEIA. RESULTS: IgE to Phl p 12 (>=0.35 kU/l) was observed in 296 of the 1,271 participants (23%), including 17 of the 108 (16%) preschool children. Profilin SPT was positive (>=3 mm) in 320/1,271 (25%) participants. The two diagnostic methods were concordant in 1,151 (91%, p < 0.0001) cases. Phl p 12 IgE prevalence declined from northern to southern Italy and was directly associated with IgE to Phl p 1 and/or Phl p 5 and Ole e 1. Among children with IgE to Phl p 12, OAS was provoked by kiwi, melon, watermelon, banana, apricot and cucumber. CONCLUSIONS: Profilin sensitization is very frequent among pollen-allergic children, occurs at a very young age and contributes to the development of childhood OAS with a typical pattern of offending foods. Pediatricians should always consider IgE sensitization to profilin while examining pollen-allergic children, even if they are at preschool age. PMID- 26528863 TI - Neurofilament levels as biomarkers in asymptomatic and symptomatic familial amyotrophic lateral sclerosis. AB - Neurofilaments are elevated in the cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients. However, timing of this increase is unknown. To characterize the premanifest disease phase, we performed a cross sectional study on asymptomatic (n = 12) and symptomatic (n = 64) ALS mutation carriers and family controls (n = 19). Neurofilaments NF-L (neurofilament-light chain) and pNF-H (phosphorylated neurofilament-heavy chain) are normal before symptom onset and increased by at least an order of magnitude at early symptom onset in CSF (pNF-H) or serum and CSF (NF-L). Thus, blood and CSF neurofilament levels are linked to the symptomatic phase of ALS and might serve as objective markers of structural damage to the nervous system. PMID- 26528864 TI - Antibiotic prophylaxis in cirrhosis: Good and bad. AB - Patients with cirrhosis, particularly those with decompensated cirrhosis, are at increased risk of bacterial infections that may further precipitate other liver decompensations including acute-on-chronic liver failure. Infections constitute the main cause of death in patients with advanced cirrhosis, and strategies to prevent them are essential. The main current strategy is the use of prophylactic antibiotics targeted at specific subpopulations at high risk of infection: prior episode of spontaneous bacterial peritonitis, upper gastrointestinal bleeding, and low-protein ascites with associated poor liver function. Antibiotic prophylaxis effectively prevents not only the development of bacterial infections in all these indications but also further decompensation (variceal bleeding, hepatorenal syndrome) and improves survival. However, antibiotic prophylaxis is also associated with a clinically relevant and increasing drawback, the development of infections due to multidrug-resistant organisms. Several strategies have been suggested to balance the risks and benefits of antibiotic prophylaxis. CONCLUSION: Antibiotic stewardship principles such as the restriction of antibiotic prophylaxis to subpopulations at a very high risk for infection, the avoidance of antibiotic overuse, and early deescalation policies are key to achieve this balance; nonantibiotic prophylactic measures such as probiotics, prokinetics, bile acids, statins, and hematopoietic growth factors could also contribute to ameliorate the development and spread of multidrug resistant bacteria in cirrhosis. (Hepatology 2016;63:2019-2031). PMID- 26528865 TI - Nanoscale probing of dynamics in local molecular environments. AB - Vibrational spectroscopy can provide information about structure, coupling, and dynamics underlying the properties of complex molecular systems. While measurements of spectral line broadening can probe local chemical environments, the spatial averaging in conventional spectroscopies limits insight into underlying heterogeneity, in particular in disordered molecular solids. Here, using femtosecond infrared scattering scanning near-field optical microscopy (IR s-SNOM), we resolve in vibrational free-induction decay (FID) measurements a high degree of spatial heterogeneity in polytetrafluoroethylene (PTFE) as a dense molecular model system. In nanoscopic probe volumes as small as 10(3) vibrational oscillators, we approach the homogeneous response limit, with extended vibrational dephasing times of several picoseconds, that is, up to 10 times the inhomogeneous lifetime, and spatial average converging to the bulk ensemble response. We simulate the dynamics of relaxation with a finite set of local vibrational transitions subject to random modulations in frequency. The combined results suggest that the observed heterogeneity arises due to static and dynamic variations in the local molecular environment. This approach thus provides real space and real-time visualization of the subensemble dynamics that define the properties of many functional materials. PMID- 26528866 TI - Comparison of Epidural or Regional Analgesia and Patient-controlled Analgesia: A Critical Analysis of Patient Data by the Acute Pain Service in a University Hospital. AB - OBJECTIVES: A large number of patients still experience pain after surgery. This study investigates if epidural or regional analgesia (continuous infusion peripheral nerve blocks [CPNB]) provide superior pain relief compared with patient-controlled analgesia (PCIA) and identifies the incidence of minor and major adverse effects or complications of these techniques. MATERIALS AND METHODS: Prospectively collected data of postoperative patients from an online data registration system of a special dedicated nurse-based acute pain service were analyzed. The acute pain service consultations were documented from January 2008 to August 2013 in a university hospital in The Netherlands. RESULTS: An analysis was applied on data of 12,399 consecutive patients. Results showed that patients who received epidural analgesia and CPNB reported lower pain scores than those who received PCIA, after undergoing the same procedures. In addition, pain scores at rest were significantly lower than movement-evoked pain scores, in abdominal surgery. Severe nausea was mostly observed in patients with PCIA and itching was most common in patients with epidural analgesia. Opioid-induced respiratory depression was found in 5 patients with PCIA. DISCUSSION: Epidural analgesia and CPNB provide better pain relief to patients than PCIA, especially in dynamic pain scores of patients. Evaluating real patient data on every patient visit is important for further improvement of the quality of postoperative pain management. Pain scores may vary widely between patients with similar surgical procedures. Therefore, we recommend that future research focuses on personalized pain measurement and pain management, to improve clinical practice more intensely. PMID- 26528867 TI - Subacute Pain and Persistent Postsurgical Pain After Orthopedic Surgery. PMID- 26528868 TI - Deciphering Physical versus Chemical Contributions to the Ionic Conductivity of Functionalized Poly(methacrylate)-Based Ionogel Electrolytes. AB - Polymer-supported ionic liquids (ionogels) are emergent, nonvolatile electrolytes for electrochemical energy storage applications. Here, chemical and physical interactions between the ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (EMI TFSI) and three different cross-linked polymer scaffolds with varying chemical functional groups have been investigated in ionogels fabricated via in situ UV-initiated radical polymerization of methyl methacrylate (MMA), 2,2,2-trifluoroethyl methacrylate (TFEMA), or 2 (dimethylamino)ethyl methacrylate (DMAEMA) and a small amount of the cross-linker pentaerythritol tetraacrylate. Experimental findings demonstrate that the chemical functionality of the polymer side groups can significantly affect the degree of ion dissociation within the ionic liquid component of the ionogel and that the fraction of dissociated ions is the dominant factor in determining relative ionic conductivity in these materials, rather than any large differences in ion diffusivity. The MMA-based polymer scaffold exhibits a stronger attractive interaction with EMI TFSI (as evidenced by a higher activation energy of ionic conductivity) compared to the TFEMA- and DMAEMA-based scaffolds, resulting in consistently lower ionic conductivity values for MMA-based ionogels. These results may offer guidance toward the rational selection of future polymer-ionic liquid pairings in order to maximize the fraction of dissociated ions, thereby yielding highly conductive ionogel electrolytes. PMID- 26528869 TI - Context for Practice: Medical Adhesive-Related Skin Injury, Unstageable Pressure Ulcers, Incontinence-Associated Dermatitis, Fluid Intake, and Overactive Bladder. PMID- 26528870 TI - Defining Unstageable Pressure Ulcers as Full-Thickness Wounds: Are These Wounds Being Misclassified? AB - PURPOSE: The purpose of this study was to describe the evolution of unstageable pressure ulcers (PUs) over time to determine if their healing trajectory is consistent with full- or partial-thickness wounds. DESIGN: Retrospective review of electronic medical record and a clinical PU database. SUBJECTS AND SETTINGS: Patients with hospital-acquired, unstageable PUs were evaluated. Subjects were cared for at a level 1 trauma/burn center and safety net hospital in the Pacific Northwest between November 2007 and March 2011. METHODS: Electronic medical records and a clinical PU database for 194 unstageable PUs were examined. The PU database is managed by certified wound care nurses; it includes data on all verified hospital-acquired PUs since 2007. The unit of analysis for this study was the individual PU site. RESULTS: Of the initial 194 unstageable PUs identified, 120 were excluded due to lack of data needed to address research questions. Out of the 74 unstageable PUs that remained in the study, approximately one-third (33.8%) were found to follow a healing trajectory consistent with partial-thickness wounds. CONCLUSION: Findings indicate that while approximately two-thirds of unstageable PUs demonstrate healing trajectories consistent with full-thickness wounds, slightly more than a third follow a trajectory consistent with partial-thickness wounds. Additional research is needed to clarify the healing trajectories of unstageable PUs and to determine whether the current definition for unstageable PUs is adequate. PMID- 26528871 TI - Medical Adhesive-Related Skin Injury Prevalence Among Adult Acute Care Patients: A Single-Center Observational Study. AB - PURPOSE: The purpose of this study was to measure the daily prevalence of adhesive product use and related skin injuries in adult patients in a non intensive care unit setting. DESIGN: Prospective, descriptive study. SUBJECTS AND SETTING: The study sample consisted of patients cared for on 2 inpatient care units in a university-based acute care facility in the Midwestern United States. One was a 30-bed medical/surgical unit and the second was a 35-bed cardiac/telemetry unit. Their median age was 58 years; the average daily proportion of males and females was 56% and 42%, respectively. METHODS: Medical adhesive-related skin injury (MARSI) prevalence was calculated using 3 methods: (1) the proportion of subjects who had any MARSI injury (subject prevalence), (2) the prevalence of MARSI by injury type and severity (severity prevalence), and (3) the proportion of medical adhesive products that had any associated MARSI (product prevalence). RESULTS: The daily subject prevalence of any MARSI injury ranged from 3.4% to 25.0% with a mean and median of 13.0% and 12.7%, respectively. The severity prevalence of MARSI injury ranged from 8 to 149 per 1000 product-days with a mean and median of 63 and 56 MARSIs per 1000 product days, respectively. The median (range) product prevalence among all adhesive products varied from a high of 70 injuries per 1000 product-days for surgical closure to a low of 0 injuries per 1000 product-days for peripheral intravenous line dressing. CONCLUSIONS: Medical adhesive-related skin injury is a prevalent event in the acute care setting. Preventing skin injury has the potential to reduce complications, increase patient satisfaction, and improve clinical outcomes. PMID- 26528872 TI - Severe Dermatonecrotic Toxin and Wound Complications Associated With Box Jellyfish Stings 2008-2013. AB - BACKGROUND: The Toxic Jellyfish Network and its surveillance system were set up in 2008 and in 2009, respectively. Case investigations detected 3 cases with severe cutaneous injuries described in this article. CASES: There were 57 probable cases of box jellyfish stings between 2008 and 2013. Three of these injuries resulted in dermal necrosis, and 2 were associated with severe wound complications. A Thai man aged 21 years sustained wounds on his left knee and thigh. He received oral antibiotics and daily wet dressings; he did not receive steroids. He subsequently developed blisters, swelling of the lower left leg, neuritis, and severe itching in the later stages. Nevertheless, his wounds did not become infected and there was no keloid scarring. An American woman aged 25 years sustained stings on her right hand and arm. She received antibiotic ointment and a tape that was placed directly on the wound without any gauze or padding underneath. She developed a wound infection 2 weeks postinjury. Surgical debridement was required twice to remove necrotic tissue; keloid scars persisted on evaluation at 4 months. An American woman aged 33 years received stings on her left upper thigh. Initial treatment was provided by local residents, who crushed morning glory leaves to extract the juice and then applied the juice (mixed with water) to her wounds. She received intravenous steroids, oral antihistamines, oral analgesics, and antibiotic cream at the hospital. Despite this aggressive treatment, the wounds became gangrenous and surgical debridement was required to remove necrotic tissue. CONCLUSION: Clinicians need to be knowledgeable regarding the potentially serious wounds that can develop following jellyfish stings. Additional research is needed to identify best management approaches. PMID- 26528873 TI - Does Increasing or Decreasing the Daily Intake of Water/Fluid by Adults Affect Overactive Bladder Symptoms? AB - BACKGROUND: Modifying fluid intake to decrease overactive bladder (OAB) symptoms, urgency, frequency, and urge urinary incontinence is advocated by health care professionals. OBJECTIVE: This Evidence Based Report Card reviews whether increasing or decreasing the daily intake of water and/or fluids by adults decreases their OAB symptoms. SEARCH STRATEGY: Three reviewers systematically reviewed the literature for studies that evaluated the association or effect of fluid intake on OAB urinary symptoms in adult men and women. A professional librarian performed the literature search, which yielded 260 articles. Following title and abstract reviews, 48 articles were identified for full-text review, and of these, 10 articles met the criteria for inclusion in this review. FINDINGS: Results of studies measuring the effect of fluid intake on the severity of OAB symptoms support that reducing fluid intake is beneficial in reducing OAB symptoms of urge UI, urgency, and frequency. There is evidence that increasing fluid by 25% to 50% could increase daytime frequency; however, studies did not show a significant effect on urgency. Increasing fluid intake is associated with worsening of OAB symptoms in observational studies and shows no difference in symptoms compared to controls in interventional studies. CONCLUSION: WOC nurses should recommend decreased fluid intake for managing OAB symptoms, while ensuring adequate hydration for other health needs (Strength of Recommendations for Treatment statement level 1). PMID- 26528874 TI - Clinical Evaluation of a Prototype Underwear Designed to Detect Urine Leakage From Continence Pads. AB - PURPOSE: We evaluated the performance of prototype underwear designed to detect urine leakage from continence pads, their acceptability to users, and their effect on health-related quality of life and psychosocial factors. DESIGN: Prototype product evaluation. SUBJECTS AND SETTING: Participants were 81 women with an average age of 67 years (range, 32-98 years) recruited between October 2010 and February 2012 from outpatient clinics, general practice surgeries, community continence services, and through charities and networks. METHODS: The TACT3 project developed and manufactured a prototype undergarment designed to alert the wearer to a pad leak before it reaches outer clothing or furniture. The study was conducted in 2 stages: a pilot/feasibility study to assess general performance and a larger study to measure performance, acceptability to users, health-related quality of life, and psychosocial impact. Participants were asked to wear the prototype underwear for a period of 2 weeks, keeping a daily diary of leakage events for the first 7 days. They also completed validated instruments measuring lower urinary tract symptoms, health-related quality of life, and psychosocial impact. RESULTS: On average, 86% of the time participants were alerted to pad leakage events. More than 90% thought the prototype underwear was "good" or "OK" and that it would or could give them more confidence. Mean scores for the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form indicated no change in the level of symptoms reported before or after the intervention, and no significant changes in health-related quality of life status occurred, except improvement in for travel restrictions. Evaluation via the Psychosocial Impact of Assistive Devices Scale also indicated a positive impact. CONCLUSION: The prototype underwear evaluated in this study was effective and acceptable for 5 out of every 10 wearers. Findings also suggest that the prototype underwear is suitable for women of all ages, dress sizes, and continence severity. PMID- 26528875 TI - Feasibility of 4% Topical Lidocaine for Pain Management During Negative Pressure Wound Therapy Dressing Changes in Pediatric Patients: A Case Study. AB - BACKGROUND: Opioid analgesics such as morphine are frequently used for pain management in pediatric patients undergoing dressing changes for negative pressure wound therapy (NPWT). While these medications reduce associated pain, they are also associated with adverse side effects ranging from constipation, headache, and dizziness to respiratory depression, chest wall rigidity, and death. Alternative analgesic approaches are needed for pediatric patients undergoing NPWT. METHODS: Four percent topical lidocaine was used for pain management during dressing changes for NPWT in a 15-year-old Hispanic male with necrotizing adenopathy. CONCLUSION: The 4% topical lidocaine reduced the pain associated with dressing changes during NPWT. No adverse side effects were observed. PMID- 26528878 TI - Identification of Newly Emerging Influenza Viruses by Surface-Enhanced Raman Spectroscopy. AB - In this work, we demonstrate in situ virus identification based on surface enhanced Raman scattering (SERS). We hypothesized that newly emerging influenza viruses possess surface proteins and lipids that can generate distinctive Raman signals. To test this hypothesis, SERS signals were measured from the surface of a noninfluenza virus, two different influenza viruses, and a genetically shuffled influenza virus. To ensure the safety for experimenters we constructed nonreplicating pseudotyped viruses that display main influenza virus surface components. Pseudotype with influenza virus components produced enhanced Raman peaks, on gold nanoparticles, that are easily distinguishable from those of pseudotype with a noninfluenza virus component, vesicular stomatitis virus G protein (VSVG). Furthermore, virus with the surface components of a newly emerging influenza strain, A/California/04/2009 (H1N1), generated Raman peaks different from those of viruses with components of the conventional laboratory adapted influenza strain, A/WSN/33 (H1N1). Interestingly, the virus simultaneously displaying surface components of both influenza strains, a model mutant with genome reassortment, also produced a Raman signal pattern that is clearly distinguishable from those of each strain. This work highlights that SERS can provide a powerful label-free strategy to quickly identify newly emerging and potentially fatal influenza viruses. PMID- 26528879 TI - Procalcitonin Reveals Early Dehiscence in Colorectal Surgery: The PREDICS Study. AB - OBJECTIVES: We designed a multicentric, observational study to test if Procalcitonin (PCT) might be an early and reliable marker of anastomotic leak (AL) after colorectal surgery (ClinicalTrials.govIdentifier:NCT01817647). BACKGROUND: Procalcitonin is a biomarker used to monitor bacterial infections and guide antibiotic therapy. Anastomotic leak after colorectal surgery is a severe complication associated with relevant short and long-term sequelae. METHODS: Between January 2013 and September 2014, 504 patients underwent colorectal surgery, for malignant colorectal diseases, in elective setting. White blood count (WBC), C-reactive protein (CRP) and PCT levels were measured in 3rd and 5th postoperative day (POD). AL and all postoperative complications were recorded. RESULTS: We registered 28 (5.6%) anastomotic leaks. Specificity and negative predictive value for AL with PCT less than 2.7 and 2.3 ng/mL were, respectively, 91.7% and 96.9% in 3rd POD and 93% and 98.3% in 5th POD. Receiver operating characteristic curve for biomarkers shows that in 3rd POD, PCT and CRP have similar area under the curve (AUC) (0.775 vs 0.772), both better than WBC (0.601); in 5th POD, PCT has a better AUC than CRP and WBC (0.862 vs 0.806 vs 0.611). Measuring together PCT and CRP significantly improves AL diagnosis in 5th POD (AUC: 0.901). CONCLUSIONS: PCT and CRP demonstrated to have a good negative predictive value for AL, both in 3rd and in 5th POD. Low levels of PCT, together with low CRP values, seem to be early and reliable markers of AL after colorectal surgery. These biomarkers might be safely added as additional criteria of discharge protocols after colorectal surgery. PMID- 26528880 TI - Genetic variations of CD36 and low platelet CD36 expression - a risk factor for lipemic plasma donation in Taiwanese apheresis donors. AB - BACKGROUND: New CD36 mutations are constantly being identified, although no study has specifically targeted a Taiwanese population. CD36 deficiency can result in dyslipid state and slow clearance of chylomicron. This could be linked to more frequent lipemic donations. STUDY DESIGN AND METHODS: We used flow cytometric methods to study the CD36 deficiency in 640 regular volunteer platelet apheresis donors from Taipei blood centre. The coding exons of CD36 gene were sequenced in CD36-deficient individuals, and the allele frequencies of CD36 variants were determined in the larger population by mutation-specific PCR and oligonucleotide hybridization. Visual inspection of lipemic plasma was routinely performed on samples taken before commencement of apheresis. Individuals found to have lipemic plasma are deferred until next donation. We investigated the link between positive lipemic deferral record and low platelet CD36 expression status. RESULTS: We found four donors (0.6%) with type I CD36 deficiency (both platelets and monocytes CD36(null) ) and six (1.0%) with type II CD36 deficiency (PLT: CD36(null) , monocyte: CD36(low) ). Six CD36 genetic variants were identified, two of them were novel, all but one are found exclusively in CD36(null) and CD36(low) expressors. Subjects with CD36 genetic variants also displayed deficient or reduced CD36 on monocytes. Donors with null or low PLT CD36 expression were more likely to have a lipemic deferral record than control subjects with normal PLT CD36 expression (X(2) = 27.36, odds ratio = 2.6, 95% conference interval: 1.8-3.8, P < 0.0001). CONCLUSION: Through this study, we established a donor registry to supply CD36-negative platelets for patients in need. PMID- 26528882 TI - Aspergillosis prophylaxis with voriconazole for 90 days in high-risk liver transplant recipients: Right drug and duration? PMID- 26528883 TI - Meeting abstracts: Abstracts presented at the American association of clinical anatomists (AACA) 32nd annual meeting June 9-12, 2015, Henderson, Nevada. PMID- 26528881 TI - Translating cancer genomes and transcriptomes for precision oncology. AB - Understanding the molecular landscape of cancer has facilitated the development of diagnostic, prognostic, and predictive biomarkers for clinical oncology. Developments in next-generation DNA sequencing technologies have increased the speed and reduced the cost of sequencing the nucleic acids of cancer cells. This has unlocked opportunities to characterize the genomic and transcriptomic landscapes of cancer for basic science research through projects like The Cancer Genome Atlas. The cancer genome includes DNA-based alterations, such as point mutations or gene duplications. The cancer transcriptome involves RNA-based alterations, including changes in messenger RNAs. Together, the genome and transcriptome can provide a comprehensive view of an individual patient's cancer that is beginning to impact real-time clinical decision-making. The authors discuss several opportunities for translating this basic science knowledge into clinical practice, including a molecular classification of cancer, heritable risk of cancer, eligibility for targeted therapies, and the development of innovative, genomic-based clinical trials. In this review, key applications and new directions are outlined for translating the cancer genome and transcriptome into patient care in the clinic. PMID- 26528884 TI - Potential Controls the Interaction of Liposomes with Octadecanol-Modified Au Electrodes: An in Situ AFM Study. AB - The formation of supported lipid bilayers using liposomes requires interaction with the solid surface, rupture of the liposome, and spreading to cover the surface with a lipid bilayer. This can result in a less-than-uniform coating of the solid surface. Presented is a method that uses the electrochemical poration of an adsorbed lipid-like layer on a Au electrode to control the interaction of 100 nm DOPC liposomes. An octadecanol-coated Au-on-mica surface was imaged using tapping-mode AFM during the application of potential in the presence or absence of liposomes. When the substrate potential was made negative enough, defects formed in the adsorbed layer and new taller features were observed. More features were observed and existing features increased in size with time spent at this negative poration potential. The new features were 1.8-2.0 nm higher than the octadecanol-coated gold surface, half the thickness of a DOPC bilayer. These features were not observed in the absence of liposomes when undergoing the same potential perturbation. In the presence of liposomes, the application of a poration potential was needed to initiate the formation of these taller features. Once the applied potential was removed, the features stopped growing and no new regions were observed. The size of these new regions was consistent with the footprint of a flattened 100 nm liposome. It is speculated that the DOPC liposomes were able to interact with the defects and became soluble in the octadecanol, creating a taller region that was limited in size to the liposome that adsorbed and became incorporated. This AFM study confirms previous in situ fluorescence measurements of the same system and illustrates the use of a potential perturbation to control the formation of these regions of increased DOPC content. PMID- 26528885 TI - Anterior cervical corpectomy for cervical spondylotic myelopathy: Reconstruction with expandable cylindrical cage versus iliac crest autograft. A retrospective study. AB - OBJECTIVES: To compare retrospectively the clinical and radiographic outcomes between cervical reconstruction with expandable cylindrical cage (ECC) and iliac crest autograft after one- or two-level anterior cervical corpectomy for spondylotic myelopathy. PATIENTS AND METHODS: Forty-two patients underwent cervical reconstruction with either iliac crest autograft and plating (20 patients) or ECC and plating (22 patients). The average clinical and radiological follow-up period was 77.54 +/- 44.28 months (range 14-155 months). The authors compared clinical parameters (Nurick Myelopathy Grade, modified Japanese Orthopedic Association (mJOA) scores), perioperative parameters (hospital stays, complications) and radiological parameters (Cobb's angles of the fused segments and C2-C7 segments, cervical subsidence, fusion rate). Fusion was assessed on flexion-extension X-ray films. RESULTS: No significant differences between the two groups were found in demographics, neurological presentation, preoperative sagittal alignment, clinical improvement and length of hospitalization. Patients of the autograft group experienced more postoperative complications, although the difference between the two treatment groups was not statistically significant (15 versus 4.5%, p=0.232). The fusion rate was 100% in both groups. The average lordotic increase of the segmental angle was significantly greater in the ECC group (p<0.05). Other radiological parameters were not significantly different in the two groups. CONCLUSION: Cervical reconstruction either with iliac crest autograft and plating or ECC and plating provides good clinical results and similar fusion rates after one- or two-level corpectomy for spondylotic myelopathy. However, the use of ECC obviates donor site complications and provides a more significant increase of lordosis in segmental angle. PMID- 26528886 TI - Gentamicin alters Akt-expression and its activation in the guinea pig cochlea. AB - Gentamicin treatment induces hair cell death or survival in the inner ear. Besides the well-known toxic effects, the phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway was found to be involved in cell protection. After gentamicin application, the spatiotemporal expression patterns of Akt and its activated form (p-Akt) were determined in male guinea pigs. A single dose of 0.1 mL gentamicin (4 mg/ear/animal) was intratympanically injected. The auditory brainstem responses (ABRs) were recorded prior to application and 1, 2 and 7 days afterward. At these three time points the cochleae (n=10 in each case) were removed, transferred to fixative and embedded in paraffin. Seven ears were used as untreated controls. Gentamicin, Akt and p-Akt were identified immunohistochemically in various regions of the cochlea and their staining intensities were quantified on sections using digital image analysis. The application of gentamicin resulted in hearing loss with a concomitant up regulation of Akt-expression in the organ of Corti and spiral ganglion cells and an additional activation in spiral ganglion cells. At the level of individual ears, clear intracellular correlations were found between Akt- and p-Akt expression in the stria vascularis and interdental cells and, to a minor extent, in the spiral ligament and the organ of Corti. Furthermore, statistical evidence for the connection between gentamicin up-take and hearing loss was detected. The increase in Akt- and p-Akt-expression in the organ of Corti and spiral ganglion cells indicates a selected response of the cochlea against gentamicin toxicity. PMID- 26528888 TI - Asymmetric Aldol-Tishchenko Reaction of Sulfinimines. AB - Methods for the preparation of 1,3-amino alcohols and their derivatives containing two stereogenic centers usually involve a two-step installation of the chiral centers. An aldol-Tishchenko reaction of chiral sulfinimines which involves the first reported reduction of a C?N in this type of reaction is described. Two and even three chiral centers can be installed in one synthetic step, affording anti-1,3-amino alcohols in good diastereo- and enantioselectivity. PMID- 26528887 TI - Interaction of ApoE3 and ApoE4 isoforms with an ITM2b/BRI2 mutation linked to the Alzheimer disease-like Danish dementia: Effects on learning and memory. AB - Mutations in Amyloid beta Precursor Protein (APP) and in genes that regulate APP processing--such as PSEN1/2 and ITM2b/BRI2--cause familial dementia, such Familial Alzheimer disease (FAD), Familial Danish (FDD) and British (FBD) dementias. The ApoE gene is the major genetic risk factor for sporadic AD. Three major variants of ApoE exist in humans (ApoE2, ApoE3, and ApoE4), with the ApoE4 allele being strongly associated with AD. ITM2b/BRI2 is also a candidate regulatory node genes predicted to mediate the common patterns of gene expression shared by healthy ApoE4 carriers and late-onset AD patients not carrying ApoE4. This evidence provides a direct link between ITM2b/BRI2 and ApoE4. To test whether ApoE4 and pathogenic ITM2b/BRI2 interact to modulate learning and memory, we crossed a mouse carrying the ITM2b/BRI2 mutations that causes FDD knocked-in the endogenous mouse Itm2b/Bri2 gene (FDDKI mice) with human ApoE3 and ApoE4 targeted replacement mice. The resultant ApoE3, FDDKI/ApoE3, ApoE4, FDDKI/ApoE4 male mice were assessed longitudinally for learning and memory at 4, 6, 12, and 16-17 months of age. The results showed that ApoE4-carrying mice displayed spatial working/short-term memory deficits relative to ApoE3-carrying mice starting in early middle age, while long-term spatial memory of ApoE4 mice was not adversely affected even at 16-17 months, and that the FDD mutation impaired working/short-term spatial memory in ApoE3-carrying mice and produced impaired long-term spatial memory in ApoE4-carrying mice in middle age. The present results suggest that the FDD mutation may differentially affect learning and memory in ApoE4 carriers and non-carriers. PMID- 26528889 TI - Effect of the SPARK Program on Physical Activity, Cardiorespiratory Endurance, and Motivation in Middle-School Students. AB - BACKGROUND: This study aimed to examine the effect of a 9-week SPARK program on physical activity (PA), cardiorespiratory endurance (Progressive Aerobic Cardiovascular Endurance Run; PACER), and motivation in middle-school students. METHODS: 174 students attended baseline and posttests and change scores computed for each outcome. A MANOVA was employed to examine change score differences using follow-up ANOVA and Bonferroni post hoc tests. RESULTS: MANOVA yielded a significant interaction for Grade * Gender * Group (Wilks's Lambda = 0.89, P < .001). ANOVA for PA revealed significant differences between SPARK grades 6 and 7 (Mean Delta = 8.11, P < .01) and Traditional grades 6 and 8 (Mean Delta = -6.96, P < .01). ANOVA also revealed greater PACER change for Traditional boys in grade 8 (P < .01) and SPARK girls in grade 8 (P < .01). There were significant interactions with perceived competence differences between SPARK grades 6 and 8 (Mean Delta = 0.38, P < .05), Enjoyment differences between SPARK grades 6 and 7 (Mean Delta = 0.67, P < .001), and SPARK grades 6 and 8 (Mean Delta = 0.81, P < .001). CONCLUSIONS: Following the intervention, SPARK displayed greater increases on PA and motivation measures in younger students compared with the Traditional program. PMID- 26528890 TI - Synthesis, Structural Characterization, and Host-Guest Studies of Aminoquinonato Bridged Re(I) Supramolecular Rectangles. AB - Aminoquinonato bridged Re(I)-based metallarectangles have been constructed via an orthogonal bonding approach. Self-assembly of Re2(CO)10 and aminoquinone ligands in the presence of ditopic linear pyridyl ligands has resulted in the formation of metallarectangles of the general formula [{(CO)3Re(MU-eta(4)-L)Re(CO)3}2(MU-N L'-N)2] (1-4), wherein 1, L = 2,5-bis(n-butylamino)-1,4-benzoquinonato (bbbq) and N-L'-N = 4,4'-bipyridine (bpy); 2, L = 2,5-bis(phenethylamino)-1,4-benzoquinonato (bpbq) and N-L'-N = 4,4'-bipyridine; 3, L = 2,5-bis(n-butylamino)-1,4 benzoquinonato (bbbq) and N-L'-N = trans-1,2-bis(4-pyridyl)ethylene (bpe) and 4, L = 2,5-bis(phenethylamino)-1,4-benzoquinonato (bpbq) and N-L'-N = trans-1,2 bis(4-pyridyl)ethylene (bpe). Metallarectangles 1-4 have been characterized by elemental analysis, IR, NMR, and UV-vis absorption spectroscopic techniques. The molecular structures of 1 and 4 were determined by single-crystal X-ray diffraction methods. The molecular recognition capability of 1 and 3 with pyrene and triphenylene has been investigated using UV-vis absorption and emission spectroscopic techniques. The formation of host-guest complex has been further corroborated by the single-crystal X-ray structural evidence of carceplex system (3?pyrene).(DMF). PMID- 26528891 TI - Toxicological evaluation of acyl glucuronides utilizing half-lives, peptide adducts, and immunostimulation assays. AB - Chemical reactivity of acyl glucuronides (AGs) is believed to be involved in the toxicity of carboxylic acid-containing drugs. Both direct and immune-mediated toxicity have been suggested as possible mechanisms of toxicity; however, it remains unclear. In the present study, we performed assays of half-lives, peptide adducts, and immunostimulation to evaluate the potential risk of AGs of 21 drugs and analyzed the relationship to the toxic category. AGs of all withdrawn drugs tested in this study showed short half-lives and peptide adducts formation, but so did those of several safe drugs. In contrast, only AGs of withdrawn and warning drugs induced interleukin-8 (IL-8) in human peripheral blood mononuclear cells (hPBMCs). Using a DNA microarray assay, we found that zomepirac AG induced the mRNAs of 5 genes, including IL-8 in hPBMCs. In addition, withdrawn and warning drugs were distinguished from safe drugs by an integrated score of relative mRNA expression levels of 5 genes. The immunostimulation assay showed higher sensitivity, specificity, and accuracy compared with other methods. In preclinical drug development, the evaluation of the reactivity of AGs using half lives and peptide adducts assays followed by the evaluation of immunostimulation by highly reactive AGs using hPBMCs can contribute to improved drug safety. PMID- 26528892 TI - Decarboxylation, CO2 and the reversion problem. AB - Decarboxylation reactions occur rapidly in enzymes but usually are many orders of magnitude slower in solution, if the reaction occurs at all. Where the reaction produces a carbanion and CO2, we would expect that the high energy of the carbanion causes the transition state for C-C bond cleavage also to be high in energy. Since the energy of the carbanion is a thermodynamic property, an enzyme obviously cannot change that property. Yet, enzymes overcome the barrier to forming the carbanion. In thinking about decarboxylation, we had assumed that CO2 is well behaved and forms without its own barriers. However, we analyzed reactions in solution of compounds that resemble intermediates in enzymic reaction and found some of them to be subject to unexpected forms of catalysis. Those results caused us to discard the usual assumptions about CO2 and carbanions. We learned that CO2 can be a very reactive electrophile. In decarboxylation reactions, where CO2 forms in the same step as a carbanion, separation of the products might be the main problem preventing the forward reaction because the carbanion can add readily to CO2 in competition with their separation and solvation. The basicity of the carbanion also might be overestimated because when we see that the decarboxylation is slow, we assume that it is because the carbanion is high in energy. We found reactions where the carbanion is protonated internally; CO2 appears to be able to depart without reversion more rapidly. We tested these ideas using kinetic analysis of catalytic reactions, carbon kinetic isotope effects, and synthesis of predecarboxylation intermediates. In another case, we observed that the decarboxylation is subject to general base catalysis while producing a significant carbon kinetic isotope effect. This requires both a proton transfer from an intermediate and C-C bond breaking in the rate-determining step. This would occur if the route involves the surprising initial addition of water to the carboxyl, with the cleavage step producing bicarbonate. Interestingly, some enzyme-catalyzed reactions also appear to produce intermediates formed by the initial addition of water or a nucleophile to the carboxyl or to nascent CO2. We conclude that decarboxylation is not necessarily a problem that results from the energy of the carbanionic products alone but from their formation in the presence of CO2. Catalysts that facilitate the separation of the species on either side of the C-C bond that cleaves could solve the problem using catalytic principles that we find in many enzymes that promote hydrolytic processes, suggesting linkages in catalysis through evolution of activity. PMID- 26528893 TI - Aggressive interactions are associated with reductions in RFamide-related peptide, but not kisspeptin, neuronal activation in mice. AB - Aggressive interactions lead to changes in both future behavior and circulating testosterone (T) concentrations in animals across taxa. The specific neural circuitry and neurochemical systems by which these encounters alter neuroendocrine functioning are not well understood. Neurons expressing the inhibitory and stimulatory neuropeptides, RFamide-related peptide (RFRP) and kisspeptin, respectively, project to neural loci regulating aggression in addition to neuroendocrine cells controlling sex steroid production. Given these connections to both the reproductive axis and aggression circuitry, RFRP and kisspeptin are in unique positions to mediate post-encounter changes in both T and behavior. The present study examined the activational state of RFRP and kisspeptin neurons of male C57BL/6 mice following an aggressive encounter. Both winners and losers exhibited reduced RFRP/FOS co-localization relative to handling stress controls. Social exposure controls did not display reduced RFRP neuronal activation, indicating that this effect is due to aggressive interaction specifically rather than social interaction generally. RFRP neuronal activation positively correlated with latencies to display several offensive behaviors within winners. These effects were not observed in the anteroventral periventricular (AVPV) nucleus kisspeptin cell population. Together, these findings point to potential neuromodulatory role for RFRP in aggressive behavior and in disinhibiting the reproductive axis to facilitate an increase in T in response to social challenge. PMID- 26528894 TI - Antidepressant-like effects of ginsenosides: A comparison of ginsenoside Rb3 and its four deglycosylated derivatives, Rg3, Rh2, compound K, and 20(S) protopanaxadiol in mice models of despair. AB - Ginsenoside Rb3 has been proved to have antidepressant-like effects, which possesses 1 xylose and 3 glucose moieties with 20(S)-protopanaxadiol (PPD) as the aglycone. However, it is commonly accepted that orally ingested ginsenosides can be deglycosylated or partially deglycosylated into active derivatives by the intestinal bacteria. To identify potential antidepressant drug candidates, we compared the antidepressant-like activities between ginsenoside Rb3 and its four deglycosylated derivatives, Rg3, Rh2, compound K (C-K), and PPD. Effects of acute (1-day), short chronic (7-days), and longer chronic treatments (14-days) with these ginsenosides (50 and 100mg/kg, p.o.) on the behavioral changes in the forced swim test (FST), tail suspension test (TST) and open field test were investigated. Serum corticosterone and adrenocorticotropic hormone (ACTH) levels and mouse brain monoamine neurotransmitters 5-HT, NA and DA levels were measured using commercially available competitive enzyme-linked immunosorbent assay (ELISA) kits. Interestingly, C-K showed antidepressant-like activities similar to that of Rb3, and Rg3 displayed antidepressant-like effects at lower dosage and faster time, indicating it has better effects than Rb3, whereas Rh2 and PPD failed to show any effect. Our results also showed, unlike the positive control fluoxetine, Rb3, Rg3 and C-K significantly increased the NA levels in the brain regions of mice exposed to FST but did not affect the 5-HT and DA levels. Moreover, treatment with Rg3 could reverse swim stress-induced increased levels of serum ACTH and corticosterone. These results suggest that C-K and Rg3 are the active deglycosylated derivatives, especially the latter compound, which is more potent than Rb3 and exerts antidepressant-like effects by regulating NA, ACTH and corticosterone levels. PMID- 26528895 TI - Effects of heart failure on cerebral blood flow in COPD: Rest and exercise. AB - Cerebral blood flow (CBF) and oxygenation (COx) are generally well-preserved in COPD. It is unknown whether prevalent cardiovascular co-morbidities, such as heart failure, may impair CBF and COx responses to exertion. Eighteen males with moderate-to-severe COPD (8 with and 10 without overlapping heart failure) underwent a progressive exercise test with pre-frontal CBF and COx measurements (indocyanine green and near-infrared spectroscopy). Mean arterial pressure and cardiac output were lower from rest to exercise in overlap. Only COPD patients demonstrated an increase in arterialized PCO2 towards the end of progressive exercise. CBF index was consistently higher and increased further by ~40% during exercise in COPD whereas a ~10% reduction was observed in overlap. COx was lower in overlap despite preserved arterial oxygenation. In conclusion, heart failure introduces pronounced negative effects on CBF and COx in COPD which may be associated with clinically relevant outcomes, including dyspnea, exercise intolerance, cerebrovascular disease and cognitive impairment. PMID- 26528896 TI - Morphological changes in the rat carotid body following acute sodium nitrite treatment. AB - The carotid body (CB) is a small neural crest-derived chemosensory organ that detects the chemical composition of the arterial blood and responds to its changes by regulating breathing. The effects of acute nitrite treatment on the CB morphology in rats were examined by morphometry. We found that 1h after administrating a single dose of sodium nitrite, the CB underwent structural changes characterized by a prominent increase in its size with a marked, several fold dilation of the blood vessels. The obvious CB enlargement mostly due to apparent vasodilation and glomus cell hypertrophy was at its highest one day later and persisted until the fifth day. 20 days after the treatment, the CB regained its size to the normoxic control state. Morphometric analysis revealed that the CB size increase in treated animals is statistically significant when compared to that of untreated controls. It can be inferred that the nitrite exposed CB displays remarkable structural plasticity and enlarges its size mostly through vascular expansion. PMID- 26528897 TI - Chronic intermittent hypoxia creates the perfect storm with calamitous consequences for respiratory control. AB - Obstructive sleep apnoea syndrome (OSAS) is a common respiratory disorder with devastating consequences for integrative body systems. A picture is emerging to illustrate wide-ranging deleterious consequences of disordered breathing during sleep for major homeostatic control systems, with considerable interest in cardiorespiratory and autonomic morbidity underpinning the development of hypertension. The vista is bleak when one also considers the link between OSAS and a host of other maladies. Exposure to chronic intermittent hypoxia (CIH), resulting from repeated obstructions of the pharyngeal airway, is a hallmark feature of OSAS that appears, in animal models, to drive the development and maintenance of several key morbidities. A growing body of evidence now points to aberrant respiratory plasticity at multiple levels following exposure to CIH. Herein, we review the experimental data revealing that CIH causes: respiratory muscle weakness and fatigue; impaired motor control of the upper airway; and, discordant respiratory rhythm and pattern generation. This multifaceted conspiracy creates the perfect storm with the potential to exacerbate OSAS serving to establish an inescapable cycle of respiratory morbidity. Several pharmacological interventions in animal models appear wholly effective in preventing the calamitous consequences of CIH and may have application as adjunctive therapies in the treatment of OSAS. PMID- 26528898 TI - Sex-specific response to hypoxia in a reduced brainstem preparation from Xenopus laevis. AB - Respiratory reflexes and tolerance to hypoxia show significant sexual dimorphism. However, the data supporting this notion originates exclusively from mammals. To determine whether this concept is limited to this group of vertebrates, we examined the sex-specific response to acute hypoxia in an adult reduced brainstem preparation from Xenopus laevis. Within the first 5min of exposure to hypoxic aCSF (98% N2/2% CO2), recordings of respiratory-related activity show a stronger increase in fictive breathing frequency in males than females. This initial response was followed by a decrease in respiratory-related activity; this depression occurred 6min sooner in males than females. These results represent new evidences of sexual dimorphism in respiratory control in amphibians and provide potential insight in understanding the homology with other groups of vertebrates, including mammals. PMID- 26528899 TI - Identification and proportion of the enantiomers of the antihypertensive drug chlortalidone in its Form II by high quality single-crystal X-ray diffraction data. AB - Chlortalidone (CTD) is a diuretic drug largely used as part of antihypertensive therapies. It is marketed as an equimolar mixture of its enantiomers in the racemic crystal phase named Form I, despite of the higher aqueous solubility of another crystal form. The latter, named Form II, was thought to contain both enantiomers as a racemic conglomerate, i.e., in the form of a mixture of crystals, half of which consists solely of the (R)-enantiomer, the other half the (S)-enantiomer. The occurrence of both enantiomers in individual crystals of CTD Form II was demonstrated in this study. Spontaneous resolution does really occur upon crystallization, as presumed previously even without physical evidence of the (S)-enantiomer. Both (R) and (S)-enantiomers were successfully identified as two domains of a twinned by inversion single crystal of CTD Form II. A reliable Flack parameter of 0.14(4) allowed to determine the proportion of the enantiomers in the crystal, which is formed with 86% of the (R)-enantiomer and 14% of the (S) enantiomer. PMID- 26528900 TI - Bridging small interfering RNA with giant therapeutic outcomes using nanometric liposomes. AB - The scope of RNAi based therapeutics is unquestionable. However, if we dissect the current trend of clinical trials for afore mentioned drug class, some stark trends appear: 1) naked siRNA only exerts influence in topical mode whilst systemic delivery requires a carrier and 2) even after two decades of extensive efforts, not even a single siRNA containing product is commercially available. It was therefore felt that a perspective simplifying the unique intricacies of working with a merger of siRNA and liposomes from a pharmaceutical viewpoint could draw the attention of a wider array of interested researchers. We begin from the beginning and attempt to conduit the gap between theoretical logic and experimental/actual constraints. This, in turn could stimulate the next generation of investigators, gearing them to tackle the conundrum, which is siRNA delivery. PMID- 26528901 TI - Determination of an optimal dosing schedule for combining Irinophore CTM and temozolomide in an orthotopic model of glioblastoma. AB - Our laboratory reported that Irinophore CTM (IrCTM; a lipid-based nanoparticulate formulation of irinotecan) is effective against an orthotopic model of glioblastoma (GBM) and that treatment with IrCTM was associated with vascular normalization within the tumor. Here, the therapeutic effects of IrCTM when used in combination with temozolomide (TMZ) in concurrent and sequential treatment schedules were tested. It was anticipated that IrCTM engendered vascular normalization would increase the delivery of TMZ to the tumor and that this would be reflected by improved treatment outcomes. The approach compared equally efficacious doses of irinotecan (IRN; 50 mg/kg) and IrCTM (25 mg/kg) in order to determine if there was a unique advantage achieved when combining TMZ with IrCTM. The TMZ sensitive U251MG(O) cell line (null expression of O-6-methylguanine-DNA methyltransferase (MGMT)) modified to express the fluorescent protein mKate2 was inoculated orthotopically into NOD.CB17-SCID mice and treatment was initiated 14 days later. Our results demonstrated that IrCTM and TMZ administered concurrently resulted in optimal treatment outcomes, with 50% long term survivors (>180 days) in comparison to 17% long term survivors in animals treated with IRN and TMZ or TMZ alone. Indeed, the different treatments resulted in a 353%, 222% and 280% increase in median survival time (MST) compared to untreated animals for, respectively, IrCTM combined with TMZ, IRN combined with TMZ, and TMZ alone. When TMZ was administered after completion of IRN or IrCTM dosing, an increase in median survival time of 167-174% was observed compared to untreated animals and of 67% and 74%, respectively, when IRN (50 mg/kg) and IrCTM (25mg/kg) were given as single agents. We confirmed in these studies that after completion of the Q7D*3 dosing of IrCTM, but not IRN, the tumor-associated vascular was normalized as compared to untreated tumors. Specifically, reductions in the fraction of collagen IV-free CD31 staining (p<0.05) and reductions in tumor vessel diameter were observed in tumors from IrCTM-treated animals when compared to tumors from untreated or IRN treated animals. Analysis by transmission electron microscopy of the ultra-structure of tumors from IrCTM-treated and untreated animals revealed that tumor-associated vessels from treated animals were smaller, more organized and exhibited a morphology comparable to normal blood vessels. In conclusion, optimal treatment outcomes were achieved when IrCTM and TMZ were administered concurrently, whereas IrCTM followed by TMZ treatment given sequentially did not confer any therapeutic advantage. PMID- 26528902 TI - Physical Health of Young, Australian Women: A Comparison of Two National Cohorts Surveyed 17 Years Apart. AB - INTRODUCTION: Very little is known about the extent of physical health issues among young women in early adulthood and whether this is changing over time. METHODS: We used data from two national samples of young women aged 18-23 years, surveyed 17 years apart, who participated in the Australian Longitudinal Study on Women's Health. We used multinomial logistic regression to compare the women's physical health (i.e., self-rated health, common symptoms and conditions) and identify whether sociodemographic factors, health behaviours and stress explained any physical health differences between the samples. RESULTS: Women aged 18-23 years in 2013 (N = 17,069) were more likely to report poor self-rated health and physical symptoms (particularly urogenital and bowel symptoms) than women aged 18 23 years in 1996 (N = 14,247). Stress accounted for a large proportion of the physical health differences between the cohorts, particularly for allergies, headaches, self-rated health, severe tiredness, skin problems, severe period pain and hypertension. CONCLUSIONS: Women's health appears to be changing, with young women born in more recent decades reporting greater physical symptom levels. Changing socio-cultural and economic conditions may place pressure on young adults, negatively affecting their health and wellbeing. Assessing the extent to which social structures and health care policies are offering adequate support to young women may offer avenues for promoting positive health and wellbeing. PMID- 26528903 TI - HCV viral load at baseline and at week 4 of telaprevir/boceprevir based triple therapies are associated with virological outcome in HIV/hepatitis C co-infected patients. AB - BACKGROUND: As first generation HCV-specific protease inhibitors, boceprevir (BOC) or telaprevir (TVR) can achieve 60% to 70% sustained virological response (SVR) for HCV infected patients with genotype 1 infections, they could remain temporary a therapeutic option in patients living in resources limited countries with limited access to the new anti-HCV direct acting antiviral (DAA) drugs, such as sofosbuvir. OBJECTIVES AND STUDY DESIGN: Here we evaluated in a routine practice setting, the treatment responses, tolerance and factors associated with SVR of a triple therapy with BOC or TVR, combined with pegylated interferon and ribavirin (PegIFN/RBV) in HIV/HCV co-infected patients, included in a large cohort of HIV/HCV coinfected patients (ANRS CO13-HEPAVIH). RESULTS: Among the 89 HIV/HCV coinfected patients treated, 65% of whom were previous non-responders to PegIFN/RBV therapy, 65%, 55% and 41% had at baseline genotype 1a, a high baseline HCV-RNA (>=800,000 IU/ml) and a cirrhosis, respectively. The SVR12 rate was 63% overall, 53% for BOC-based regimen and 66% for TVR-based regimen. In multivariate analysis, two factors were significantly associated with HCV SVR: HCV viral load <800,000 IU/mL at treatment initiation versus >=800,000 IU/mL (OR 4.403, 95% CI 1.29-15.04; p=0.018) and virological response at W4 (HCV-RNA undetectable after 4 weeks of triple therapy) (OR 3.35, 95% CI 1.07-10.48; p=0.038). CONCLUSIONS: Overall SVR12 was 63% and our results suggest that HIV/HCV coinfected patients with low HCV viral load (<800,000 IU/mL) and undetectable HCV-RNA after 4 weeks of triple therapy with TVR or BOC-based regimen have a higher probability of treatment success. PMID- 26528904 TI - Genomic DNA "finger-printing" in diagnostic virology to clarify discrepant HIV results. AB - BACKGROUND: We describe two case studies in the antenatal setting where human immunodeficiency virus (HIV) antibody results were discrepant in serial sera. Root cause analysis including genomic DNA fingerprinting was performed. OBJECTIVE: To analyze serial sera with HIV antibody discrepant results using genomic DNA "finger-printing" to determine whether the sera were from the same or different individuals. STUDY DESIGN: In case study 1, two serial sera with HIV antibody discrepant results, supposedly from a pregnant lady were subjected to root cause analysis. In case study 2, four serial sera 'from' a pregnant lady were subjected to root cause analysis. All sera were analyzed forensically using genomic DNA (gDNA) fingerprinting. In the case study 1, public health look-back exercise was done prior to forensic analysis unlike case study 2, when it was planned for later. RESULTS: Case study 1 gDNA results showed that both sera had identical genotypes and sex indicating that these were from the same individual and that the problem was within automated serum separator pipette syringe. Case study 2 gDNA analysis showed that the 3 of 4 sera were from three different unrelated females indicating an intentional sample mix-up. CONCLUSIONS: Forensic gDNA "finger-printing" in diagnostic virology changed the direction of the investigations; one pointing to a laboratory issue and the other to an intentional deception by the patient. We recommend considering gDNA fingerprinting in any sample discrepancy investigation prior to any public health investigation. This is the first reported use of gDNA analysis in diagnostic virology. PMID- 26528905 TI - The utilization of natural soda resource of Ordos in the cultivation of Nannochloropsis oceanica. AB - Nannochloropsis oceanica is famous for its strong environmental adaptability and oil-richness, especially high eicosapentaenoic acid (EPA) content. In this report, the possibility and cultivation parameters for N. oceanica using natural crude soda were testified and compared with seawater culture. To keep a suitable salinity range, different ratio of sea salt addition into soda lake water were used and the growth, lipid content, Fv/Fm and fatty acids profiling were inspected with nitrogen repletion or depletion. The results showed the best performance were achieved while 18g/L (salinity 250/00) sea salt was added into crude soda solution. The MUmax and EPA content in fatty acids were 0.72/0.42 and 36%/23% in 500mL/100L bioreactor cultivations respectively, which maintained a relative high productivity to other reports. By comparing the growth and operations with Spirulina production, the feasibility of N. Oceanica in Ordos was proved on both technical and economical point of view. PMID- 26528906 TI - Enhancing bio-butanol production from biomass of Chlorella vulgaris JSC-6 with sequential alkali pretreatment and acid hydrolysis. AB - This study presents a successful butanol production method using alkali and acid pretreated biomass of Chlorella vulgaris JSC-6. The butanol concentration, yield, and productivity were 13.1g/L, 0.58mol/mol sugar, 0.66g/L/h, respectively. Nearly 2.93L/L of biohydrogen was produced during the acidogenesis phase in ABE fermentation. The hydrogen yield and productivity were 0.39mol/mol sugar and 104.2g/L/h respectively. In addition, the high glucose consumption efficiency (97.5%) suggests that the hydrolysate pretreated with NaOH (1%) followed by H2SO4 (3%) did not contain inhibitors to the fermentation. It was also discovered that an excess amount of nitrogen sources arising from hydrolysis of highly concentrated microalgal biomass negatively affected the butanol production. This work demonstrates the technical feasibility of producing butanol from sustainable third-generation feedstock (i.e., microalgal biomass). PMID- 26528907 TI - Cooperative cathode electrode and in situ deposited copper for subsequent enhanced Cd(II) removal and hydrogen evolution in bioelectrochemical systems. AB - Bioelectrochemical systems (BESs) were first operated in microbial fuel cell mode for recovering Cu(II), and then shifted to microbial electrolysis cells for Cd(II) reduction on the same cathodes of titanium sheet (TS), nickel foam (NF) or carbon cloth (CC). Cu(II) reduction was similar to all materials (4.79-4.88mg/Lh) whereas CC exhibited the best Cd(II) reduction (5.86+/-0.25mg/Lh) and hydrogen evolution (0.35+/-0.07m(3)/m(3)d), followed by TS (5.27+/-0.43mg/Lh and 0.15+/ 0.02m(3)/m(3)d) and NF (4.96+/-0.48mg/Lh and 0.80+/-0.07m(3)/m(3)d). These values were higher than no copper controls by factors of 2.0 and 5.0 (TS), 4.2 and 2.0 (NF), and 1.8 and 7.0 (CC). These results demonstrated cooperative cathode electrode and in situ deposited copper for subsequent enhanced Cd(II) reduction and hydrogen production in BESs, providing an alternative approach for efficiently remediating Cu(II) and Cd(II) co-contamination with simultaneous hydrogen production. PMID- 26528908 TI - Parallel-hole collimator concept for stationary SPECT imaging. AB - Parallel-hole SPECT collimators have traditionally been manufactured by stacking sheets of lead foil or by casting. These techniques significantly restrict our options in terms of collimator geometry. However, recent developments in metal additive manufacturing are making novel collimator designs possible, giving rise to new opportunities in SPECT imaging. In this paper we propose an innovative type of collimator for stationary SPECT, using parallel-holes whose collimation direction depends on their axial position. Its main advantage compared to current stationary SPECT systems (which are based on pinholes) is that, using only axial bed translations, we can achieve complete angular sampling of an increased portion of the transaxial area of the collimator bore. This allows the system to be much more compact than current stationary SPECT systems that image objects of the same size. We describe three possible designs, for full-body, brain and small animal imaging, respectively, and test their feasibility using simulations. The system modeling method is validated against realistic Monte Carlo simulations, and then used in the evaluation of the systems' performances and reconstructions. The simulations show that the system is able to reconstruct objects occupying the predicted field of view ([Formula: see text] of the transaxial area of the bore) without sampling artifacts. In particular, we perform reconstructions from noisy projection data obtained for an activity and scanning time similar to standard protocols for the three applications, and the resulting images indicate the possibility of using the proposed systems in practice. PMID- 26528909 TI - The Effects of Media Reports on Disease Spread and Important Public Health Measurements. AB - Controlling the spread of influenza to reduce the effects of infection on a population is an important mandate of public health. Mass media reports on an epidemic or pandemic can provide important information to the public, and in turn, can induce positive healthy behaviour practices (i.e., handwashing, social distancing) in the individuals, that will reduce the probability of contracting the disease. Mass media fatigue, however, can dampen these effects. Mathematical models can be used to study the effects of mass media reports on epidemic/pandemic outcomes. In this study we employ a stochastic agent based model to provide a quantification of mass media reports on the variability in important public health measurements. We also include mass media report data compiled by the Global Public Health Intelligence Network, to study the effects of mass media reports in the 2009 H1N1 pandemic. We find that the report rate and the rate at which individuals relax their healthy behaviours (media fatigue) greatly affect the variability in important public health measurements. When the mass media reporting data is included in the model, two peaks of infection result. PMID- 26528910 TI - Aquatic ecotoxicity of lanthanum - A review and an attempt to derive water and sediment quality criteria. AB - Rare earth elements (REE) used to be taken as tracers of geological origin for fluvial transport. Nowadays their increased applications in innovative environmental-friendly technology (e.g. in catalysts, superconductors, lasers, batteries) and medical applications (e.g. MRI contrast agent) lead to man-made, elevated levels in the environment. So far, no regulatory thresholds for REE concentrations and emissions to the environment have been set because information on risks from REE is scarce. However, evidence gathers that REE have to be acknowledged as new, emerging contaminants with manifold ways of entry into the environment, e.g. through waste water from hospitals or through industrial effluents. This paper reviews existing information on bioaccumulation and ecotoxicity of lanthanum in the aquatic environment. Lanthanum is of specific interest as one of the major lanthanides in industrial effluents. This review focuses on the freshwater and the marine environment, and tackles the water column and sediments. From these data, methods to derive quality criteria for sediment and water are discussed and preliminary suggestions are made. PMID- 26528911 TI - Spatial Access to Emergency Services in Low- and Middle-Income Countries: A GIS Based Analysis. AB - Injury is a leading cause of the global disease burden, accounting for 10 percent of all deaths worldwide. Despite 90 percent of these deaths occurring in low and middle-income countries (LMICs), the majority of trauma research and infrastructure development has taken place in high-income settings. Furthermore, although accessible services are of central importance to a mature trauma system, there remains a paucity of literature describing the spatial accessibility of emergency services in LMICs. Using data from the Service Provision Assessment component of the Demographic and Health Surveys of Namibia and Haiti we defined the capabilities of healthcare facilities in each country in terms of their preparedness to provide emergency services. A Geographic Information System-based network analysis method was used to define 5- 10- and 50-kilometer catchment areas for all facilities capable of providing 24-hour care, higher-level resuscitative services or tertiary care. The proportion of a country's population with access to each level of service was obtained by amalgamating the catchment areas with a population layer. A significant proportion of the population of both countries had poor spatial access to lower level services with 25% of the population of Haiti and 51% of the population of Namibia living further than 50 kilometers from a facility capable of providing 24-hour care. Spatial access to tertiary care was considerably lower with 51% of Haitians and 72% of Namibians having no access to these higher-level services within 50 kilometers. These results demonstrate a significant disparity in potential spatial access to emergency services in two LMICs compared to analogous estimates from high-income settings, and suggest that strengthening the capabilities of existing facilities may improve the equity of emergency services in these countries. Routine collection of georeferenced patient and facility data in LMICs will be important to understanding how spatial access to services influences outcomes. PMID- 26528912 TI - Computational Characterization of Exogenous MicroRNAs that Can Be Transferred into Human Circulation. AB - MicroRNAs have been long considered synthesized endogenously until very recent discoveries showing that human can absorb dietary microRNAs from animal and plant origins while the mechanism remains unknown. Compelling evidences of microRNAs from rice, milk, and honeysuckle transported to human blood and tissues have created a high volume of interests in the fundamental questions that which and how exogenous microRNAs can be transferred into human circulation and possibly exert functions in humans. Here we present an integrated genomics and computational analysis to study the potential deciding features of transportable microRNAs. Specifically, we analyzed all publicly available microRNAs, a total of 34,612 from 194 species, with 1,102 features derived from the microRNA sequence and structure. Through in-depth bioinformatics analysis, 8 groups of discriminative features have been used to characterize human circulating microRNAs and infer the likelihood that a microRNA will get transferred into human circulation. For example, 345 dietary microRNAs have been predicted as highly transportable candidates where 117 of them have identical sequences with their homologs in human and 73 are known to be associated with exosomes. Through a milk feeding experiment, we have validated 9 cow-milk microRNAs in human plasma using microRNA-sequencing analysis, including the top ranked microRNAs such as bta-miR-487b, miR-181b, and miR-421. The implications in health-related processes have been illustrated in the functional analysis. This work demonstrates the data driven computational analysis is highly promising to study novel molecular characteristics of transportable microRNAs while bypassing the complex mechanistic details. PMID- 26528913 TI - Shortening Turnaround Times for Newborn HIV Testing in Rural Tanzania: A Report from the Field. PMID- 26528914 TI - Using wintergreen oil for mounting mosquito larvae: a safer alternative to xylene. AB - Permanent mounting of fourth instar mosquito larvae is essential for identifying Aedes spp. This procedure requires extensive exposure to xylene, a clearing agent in the mounting process. We investigated wintergreen oil as a substitute for xylene. Five hundred larvae were mounted on slides to evaluate shrinkage or expansion of specimens after clearing using xylene or wintergreen oil. We examined the ventral brush and siphonal hair tufts for species identification and for preservation of morphological characteristics after clearing specimens in xylene or wintergreen oil. Shrinkage of the length of whole larvae and width of the head, thorax and abdomen after mounting was significantly greater after clearing with xylene than with wintergreen oil. The length of the comb scale nearest the ventral brush was similar for both clearing agents. The clarity of the specimens after mounting was improved by clearing with wintergreen oil, but the integrity of the ventral brush and siphonal hair tufts were similar for both clearing agents. PMID- 26528915 TI - Ecological Risk Assessment of a Metal-Contaminated Area in the Tropics. Tier II: Detailed Assessment. AB - This study presents data on the detailed evaluation (tier 2) of a site-specific ecological risk assessment (ssERA) in a former smelter area contaminated with metals (Santo Amaro, Bahia, Brazil). Combining information from three lines of evidence (LoE), chemical (ChemLoE), ecotoxicological (EcotoxLoE) and ecological (EcoLoE), in the Triad approach, integrated risk values were calculated to rank sites and confirm the potential risk disclosed with tier 1. Risk values were calculated for the habitat and for the retention functions in each sampling point. Habitat function included the ChemLoE calculated from total metal concentrations. The EcotoxLoE was based on reproduction tests with terrestrial invertebrates (Folsomia candida, Enchytraeus crypticus, Eisenia andrei), shoot length and plant biomass (Avena sativa, Brassica rapa). For the EcoLoE, ecological parameters (microbial parameters, soil invertebrate community, litter breakdown) were used to derive risk values. Retention function included the ChemLoE, calculated from extractable metal concentrations, and the EcotoxLoE based on eluate tests with aquatic organisms (Daphnia magna reproduction and Pseudokirchneriella subcapitata growth). Results related to the habitat function indicated that the metal residues are sufficient to cause risk to biota, while the low metal levels in extracts and the general lack of toxicity in aquatic tests indicated a high soil retention capacity in most sampling points. Integrated risk of tier 2 showed the same trend of tier 1, suggesting the need to proceed with remediation actions. The high risk levels were related to direct toxicity to organisms and indirect effects, such as failure in the establishment of vegetation and the consequent loss of habitat quality for microorganisms and soil fauna. This study shed some light on the selection of tools for the tier 2 of an ssERA in tropical metal-contaminated sites, focusing on ecological receptors at risk and using available chemical methods, ecological surveys and ecotoxicity tests. PMID- 26528916 TI - 13C- and 15N-Labeling Strategies Combined with Mass Spectrometry Comprehensively Quantify Phospholipid Dynamics in C. elegans. AB - Membranes define cellular and organelle boundaries, a function that is critical to all living systems. Like other biomolecules, membrane lipids are dynamically maintained, but current methods are extremely limited for monitoring lipid dynamics in living animals. We developed novel strategies in C. elegans combining 13C and 15N stable isotopes with mass spectrometry to directly quantify the replenishment rates of the individual fatty acids and intact phospholipids of the membrane. Using multiple measurements of phospholipid dynamics, we found that the phospholipid pools are replaced rapidly and at rates nearly double the turnover measured for neutral lipid populations. In fact, our analysis shows that the majority of membrane lipids are replaced each day. Furthermore, we found that stearoyl-CoA desaturases (SCDs), critical enzymes in polyunsaturated fatty acid production, play an unexpected role in influencing the overall rates of membrane maintenance as SCD depletion affected the turnover of nearly all membrane lipids. Additionally, the compromised membrane maintenance as defined by LC-MS/MS with SCD RNAi resulted in active phospholipid remodeling that we predict is critical to alleviate the impact of reduced membrane maintenance in these animals. Not only have these combined methodologies identified new facets of the impact of SCDs on the membrane, but they also have great potential to reveal many undiscovered regulators of phospholipid metabolism. PMID- 26528917 TI - Analysis of Precipitation Characteristics during 1957-2012 in the Semi-Arid Loess Plateau, China. AB - Precipitation is the only water supply and most important factor affecting vegetation growth on the slopes of semi-arid Loess Plateau of China. Based on precipitation data from 7 synoptic stations in the study area over the period 1957-2012, the trends of precipitation and standardized precipitation index (SPI) were analyzed by using linear regression, Mann-Kendall, and Spearman's Rho tests at the 5% significance level. The results show that (1) the precipitation fluctuation of monthly precipitation was intense (coefficients of variation> 100%), and the drier years were recorded as 1965 and 1995 at all stations. (2) The significant change trend of different stations varied on different time scales: the Changwu station had a significant decreasing trend in April (-0.488 mm/year) and November (-0.249 mm/year), while Luochuan station was in April ( 0.457 mm/year); Changwu station displayed a significant increasing trends in winter (0.220 mm/year) and a significant decreasing trends in spring (-0.770 mm/year). The significant decreasing trends in annual precipitation were detected at the Suide (-2.034 mm/year) and Yan'an (-2.129 mm/year) stations. (3) The SPI 12 series analysis suggests that the drought degree of Yulin and Changwu was the lowest and that of Hengshan was the highest among the 7 synoptic stations. PMID- 26528918 TI - Interaction of anions with a newly characterized alpha carbonic anhydrase from Halomonas sp. AB - The inhibition and characterization of the alpha-class carbonic anhydrase (CA, EC 4.2.1.1) from the Halomonas sp. are reported for the first time. The enzyme was purified 91-fold with a yield of 39%, and a specific activity of 600 U/mg proteins was obtained. It has an optimum pH at 7.5, an optimum ionic strength at 20 mM and an optimum temperature at 20 degrees C. The following anions, SCN(-), Br(-), Cl(-), I(-), [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] showed inhibitory effects on the hydratase activity of the enzyme. Sulfate, sulfide, azide, nitrate, nitrite and iodide exhibited the strongest inhibitory activity, in the micromolar range (KI-s of 5.5-15.5 uM). SCN(-), Br(-), Cl(-), [Formula: see text] were moderate inhibitors, whereas other anions showed only weak activities. Our findings indicate that these anions inhibit the Halomonas sp. CA (HmCA) enzyme in a similar manner to other alpha-CAs from mammals investigated earlier, but the susceptibility to various anions differs significantly between the Halomonas sp. and other organism CAs. PMID- 26528919 TI - Improved Object Localization Using Accurate Distance Estimation in Wireless Multimedia Sensor Networks. AB - Object localization plays a key role in many popular applications of Wireless Multimedia Sensor Networks (WMSN) and as a result, it has acquired a significant status for the research community. A significant body of research performs this task without considering node orientation, object geometry and environmental variations. As a result, the localized object does not reflect the real world scenarios. In this paper, a novel object localization scheme for WMSN has been proposed that utilizes range free localization, computer vision, and principle component analysis based algorithms. The proposed approach provides the best possible approximation of distance between a wmsn sink and an object, and the orientation of the object using image based information. Simulation results report 99% efficiency and an error ratio of 0.01 (around 1 ft) when compared to other popular techniques. PMID- 26528920 TI - Subcellular Localization of Matrin 3 Containing Mutations Associated with ALS and Distal Myopathy. AB - BACKGROUND: Mutations in Matrin 3 [MATR3], an RNA- and DNA-binding protein normally localized to the nucleus, have been linked to amyotrophic lateral sclerosis (ALS) and distal myopathies. In the present study, we have used transient transfection of cultured cell lines to examine the impact of different disease-causing mutations on the localization of Matrin 3 within cells. RESULTS: Using CHO and human H4 neuroglioma cell models, we find that ALS/myopathy mutations do not produce profound changes in the localization of the protein. Although we did observe variable levels of Matrin 3 in the cytoplasm either by immunostaining or visualization of fluorescently-tagged protein, the majority of cells expressing either wild-type (WT) or mutant Matrin 3 showed nuclear localization of the protein. When cytoplasmic immunostaining, or fusion protein fluorescence, was seen in the cytoplasm, the stronger intensity of staining or fluorescence was usually evident in the nucleus. In ~80% of cells treated with sodium arsenite (Ars) to induce cytoplasmic stress granules, the nuclear localization of WT and F115C mutant Matrin 3 was not disturbed. Notably, over expression of mutant Matrin 3 did not induce the formation of obvious large inclusion-like structures in either the cytoplasm or nucleus. CONCLUSIONS: Our findings indicate that mutations in Matrin 3 that are associated with ALS and myopathy do not dramatically alter the normal localization of the protein or readily induce inclusion formation. PMID- 26528921 TI - Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. AB - Turmeric (Curcuma longa) is a type of herb belonging to ginger family, which is widely grown in southern and south western tropical Asia region. Turmeric, which has an importance place in the cuisines of Iran, Malesia, India, China, Polynesia, and Thailand, is often used as spice and has an effect on the nature, color, and taste of foods. Turmeric is also known to have been used for centuries in India and China for the medical treatments of illnesses such as dermatologic diseases, infection, stress, and depression. Turmeric's effects on health are generally centered upon an orange-yellow colored, lipophilic polyphenol substance called "curcumin," which is acquired from the rhizomes of the herb. Curcumin is known recently to have antioxidant, anti-inflammatory, anticancer effects and, thanks to these effects, to have an important role in prevention and treatment of various illnesses ranging notably from cancer to autoimmune, neurological, cardiovascular diseases, and diabetic. Furthermore, it is aimed to increase the biological activity and physiological effects of the curcumin on the body by synthesizing curcumin analogues. This article reviews the history, chemical and physical features, analogues, metabolites, mechanisms of its physiological activities, and effects on health of curcumin. PMID- 26528922 TI - Effective Killing of Cancer Cells Through ROS-Mediated Mechanisms by AMRI-59 Targeting Peroxiredoxin I. AB - AIMS: The intrinsic increase of reactive oxygen species (ROS) production in cancer cells after malignant transformation frequently induces redox adaptation, leading to enhanced antioxidant capacity. Peroxiredoxin I (PrxI), an enzyme responsible for eliminating hydrogen peroxide, has been found to be elevated in many types of cancer cells. Since overexpression of PrxI promoted cancer cells' survival and resistance to chemotherapy and radiotherapy, PrxI has been proposed as a therapeutic target for anticancer drugs. In this study, we aimed to investigate the anticancer efficacy of a small molecule inhibitor of PrxI. RESULTS: By a high-throughput screening approach, we identified AMRI-59 as a potent inhibitor of PrxI. AMRI-59 increased cellular ROS, leading to the activation of both mitochondria- and apoptosis signal-regulated kinase-1-mediated signaling pathways, resulting in apoptosis of A549 human lung adenocarcinoma. AMRI-59 caused no significant changes in ROS level, proliferation, and apoptosis of PrxI-knockdown A549 cells by RNA interference. PrxI overexpression or N acetylcysteine pretreatment abrogated AMRI-59-induced cytotoxicity in A549 cells. AMRI-59 rendered tumorigenic ovarian cells more susceptible to ROS-mediated death compared with nontumorigenic cells. Moreover, significant antitumor activity of AMRI-59 was observed in mouse tumor xenograft model implanted with A549 cells with no apparent acute toxicity. INNOVATION: This study offers preclinical proof of-concept for AMRI-59, a lead small molecule inhibitor of PrxI, as an anticancer agent. CONCLUSIONS: Our results highlight a promising strategy for cancer therapy that preferentially eradicates cancer cells by targeting the PrxI-mediated redox dependent survival pathways. PMID- 26528923 TI - Systemic Administration of the TRPV3 Ion Channel Agonist Carvacrol Induces Hypothermia in Conscious Rodents. AB - Therapeutic hypothermia is a promising new strategy for neuroprotection. However, the methods for safe and effective hypothermia induction in conscious patients are lacking. The current study explored the Transient Receptor Potential Vanilloid 3 (TRPV3) channel activation by the agonist carvacrol as a potential hypothermic strategy. It was found that carvacrol lowers core temperature after intraperitoneal and intravenous administration in mice and rats. However, the hypothermic effect at safe doses was modest, while higher intravenous doses of carvacrol induced a pronounced drop in blood pressure and substantial toxicity. Experiments on the mechanism of the hypothermic effect in mice revealed that it was associated with a decrease in whole-body heat generation, but not with a change in cold-seeking behaviors. In addition, the hypothermic effect was lost at cold ambient temperature. Our findings suggest that although TRPV3 agonism induces hypothermia in rodents, it may have a limited potential as a novel pharmacological method for induction of hypothermia in conscious patients due to suboptimal effectiveness and high toxicity. PMID- 26528924 TI - A systematic review on the efficacy and safety of Infliximab in patients with psoriasis. AB - OBJECTIVE: To assess the efficacy and safety of infliximab for the treatment of psoriasis in a meta-analysis framework. METHODS: Data were extracted by searching the EMBASE (1974-2014), PubMed(1966-2014) and the Cochrane library2013.4th databases. Only randomized and placebo-controlled studies were selected in this study. RESULTS: Statistically significant differences in efficacy were found for the infliximab (3 or 5 mg/kg) group compared with the control group which received placebo in the treatment of psoriasis vulgaris [OR 13.55, 95%CI (11.14,16.48)]or[OR85.45, 95%CI (39.13,186.58)]. There were also significant differences in efficacy between the infliximab (5 mg/kg) group and the placebo control group during treatment of psoriasis arthritis (PsA) [OR8.36, 95%CI (5.63, 12.40)]. A controlled trial used infliximab (5 mg/kg) in the treatment of palmoplantar psoriasis. This study showed that the effective rate of the infliximab group was 33.3% (4/12) when compared to the placebo control group, which was 8.3% (1/12). CONCLUSION: Infliximab is significantly associated with symptom relief, skin lesion improvement, and an increase in the quality of life of psoriasis patients. The most common drug-induced adverse events were pain, hepatic dysfunction, and infusion reaction. PMID- 26528925 TI - Hannelore Wass: Insights Into Creative Teaching and Other Ways of Knowing When Facing Aging and Mortality. AB - Art is about freeze framing life and making it available for contemplation. This article describes creative strategies for teaching meaning-making and critical thinking through the use of imagery and the visual arts and how they have been influenced by the wisdom and guidance of Dr. Hannelore Wass. Dr. Wass's passion for encouraging death educators to explore "other ways of knowing" is reflected in the connections between visual imagery and topics such as caregiving, aging, self-care, and professional boundaries. The group known as Women in Thanatology as a mechanism for professional mentoring and support is described, including Dr. Wass's role in its history and evolution. PMID- 26528926 TI - Correction: Deforestation and Forest Fragmentation in South Ecuador since the 1970s--Losing a Hotspot of Biodiversity. PMID- 26528927 TI - State Estimation of the Time-Varying and Spatially Localized Concentration of Signal Molecules from the Stochastic Adsorption Dynamics on the Carbon Nanotube Based Sensors and Its Application to Tumor Cell Detection. AB - This paper addresses a problem of estimating time-varying, local concentrations of signal molecules with a carbon-nanotube (CNT)-based sensor array system, which sends signals triggered by monomolecular adsorption/desorption events of proximate molecules on the surfaces of the sensors. Such sensors work on nano scale phenomena and show inherently stochastic non-Gaussian behavior, which is best represented by the chemical master equation (CME) describing the time evolution of the probabilities for all the possible number of adsorbed molecules. In the CME, the adsorption rate on each sensor is linearly proportional to the local concentration in the bulk phase. State estimators are proposed for these types of sensors that fully address their stochastic nature. For CNT-based sensors motivated by tumor cell detection, the particle filter, which is nonparametric and can handle non-Gaussian distributions, is compared to a Kalman filter that approximates the underlying distributions by Gaussians. In addition, the second-order generalized pseudo Bayesian estimation (GPB2) algorithm and the Markov chain Monte Carlo (MCMC) algorithm are incorporated into KF and PF respectively, for detecting latent drift in the concentration affected by different states of a cell. PMID- 26528929 TI - The first report of direct inhibitors that target the C-terminal MEEVD region on heat shock protein 90. AB - Sixteen linear and cyclic peptides were designed de novo to target the C-terminus of heat shock protein 90 (Hsp90). Protein binding data indicates that three compounds directly block co-chaperone access to Hsp90's C-terminus and luciferase renaturation assays confirm Hsp90-mediated protein folding is disrupted. This is the first report of an inhibitor that binds directly to the C-terminal MEEVD region of Hsp90. PMID- 26528928 TI - Effects of Controlled Cortical Impact on the Mouse Brain Vasculome. AB - Perturbations in blood vessels play a critical role in the pathophysiology of brain injury and neurodegeneration. Here, we use a systematic genome-wide transcriptome screening approach to investigate the vasculome after brain trauma in mice. Mice were subjected to controlled cortical impact and brains were extracted for analysis at 24 h post-injury. The core of the traumatic lesion was removed and then cortical microvesels were isolated from nondirectly damaged ipsilateral cortex. Compared to contralateral cortex and normal cortex from sham operated mice, we identified a wide spectrum of responses in the vasculome after trauma. Up-regulated pathways included those involved in regulation of inflammation and extracellular matrix processes. Decreased pathways included those involved in regulation of metabolism, mitochondrial function, and transport systems. These findings suggest that microvascular perturbations can be widespread and not necessarily localized to core areas of direct injury per se and may further provide a broader gene network context for existing knowledge regarding inflammation, metabolism, and blood-brain barrier alterations after brain trauma. Further efforts are warranted to map the vasculome with higher spatial and temporal resolution from acute to delayed phase post-trauma. Investigating the widespread network responses in the vasculome may reveal potential mechanisms, therapeutic targets, and biomarkers for traumatic brain injury. PMID- 26528930 TI - Enhancement of spin polarization induced by Coulomb on-site repulsion between localized pz electrons in graphene embedded with line defects. AB - It is well known that the effect of Coulomb on-site repulsion can significantly alter the physical properties of the systems that contain localized d and/or f electrons. However, little attention has been paid to the Coulomb on-site repulsion between localized p electrons. In this study, we demonstrated that Coulomb on-site repulsion between localized pz electrons also plays an important role in graphene embedded with line defects. It is shown that the magnetism of the system largely depends on the choice of the effective Coulomb on-site parameter Ueff. Ueff at the edges of the defect enhances the exchange splitting, which increases the magnetic moment and stabilizes a ferromagnetic state of the system. In contrast, Ueff at the center of the defect weakens the spin polarization of the system. The behavior of the magnetism is explained with the Stoner criterion and the charge accumulation at the edges of the defect. Based on the linear response approach, we estimate reasonable values of Ueff to be 2.55 eV (2.3 eV) at the center (edges) of the defects. More importantly, using a DFT+U+J method, we find that exchange interactions between localized p electrons also play an important role in the spin polarization of the system. These results imply that Coulomb on-site repulsion is necessary to describe the strong interaction between localized pz electrons of carbon related materials. PMID- 26528931 TI - Chemical sporulation and germination: cytoprotective nanocoating of individual mammalian cells with a degradable tannic acid-FeIII complex. AB - Individual mammalian cells were coated with cytoprotective and degradable films by cytocompatible processes maintaining the cell viability. Three types of mammalian cells (HeLa, NIH 3T3, and Jurkat cells) were coated with a metal organic complex of tannic acid (TA) and ferric ion, and the TA-Fe(III) nanocoat effectively protected the coated mammalian cells against UV-C irradiation and a toxic compound. More importantly, the cell proliferation was controlled by programmed formation and degradation of the TA-Fe(III) nanocoat, mimicking the sporulation and germination processes found in nature. PMID- 26528933 TI - Editorial: The French Orthopaedic Trauma Society (GETRAUM). Who are we? PMID- 26528934 TI - Total hip arthroplasty with minimal invasive surgery in elderly patients with neck of femur fractures: our institutional experience. AB - The purpose of this study was to investigate whether minimal invasive surgery (MIS) in elderly patients with neck of femur fractures would reduce the peri operative complications and improve the post-operative ambulation and length of hospital stay in his cohort of patients. Forty elderly patients were treated with either total hip arthroplasty (THA) or bipolar prosthesis using MIS transgluteal approach. A matched reference group treated with a conventional surgical approach formed the control group. All procedures were performed by the same surgeon. Selection of acetabular component included Novae(r) uncemented press fit dual mobility concept socket or Bipolar Hemi-Arthroplasty (BHA). The femoral implant was Corail(r) uncemented stem or Fjord(r) cemented stem when primary instability was encountered. The follow-up was done for all patients and its minimum length was more than thirty-six months. The average length of the skin incision was 7 (6 8) SD 0.7 cm. Eighteen THA, twenty-two BHA, thirty-seven uncemented femoral stems and three cemented stems were implemented. The length of the procedure was the same as those of the reference group. The operative and post-operative blood loss and analgesic use were significantly decreased in the MIS group. Radiographic implants positioning was similar amongst the two groups. No skin complication, no primary infection, no death within ninety days and no dislocations were observed. MIS approach for implanting THA after a femoral neck fracture in the elderly appears to be a reliable procedure. PMID- 26528935 TI - Proximal ulnar fractures in adults: a review of 163 cases. AB - The aim of this study was to report the epidemiological characteristics and the experience of 5 departments of trauma, in France, in the management of fractures of the proximal ulna. 163 patients with fractures of the proximal ulna with a mean age of 49.9 years (range 16-97) were managed. The most common mode of injury was a motor vehicle collision (48%). 18% sustained associated injuries to the ipsilateral limb. Open fractures were present in 42 patients (25%). A total of 109 patients had a fracture of the olecranon, with the Mayo 2A and B types most frequently seen (66%). The patients were invited for clinical examination at a mean duration of 16 months, retrospectively. Validated patient-oriented assessment scores involving the Mayo Elbow Performance Index (MEPI) and the Broberg and Morrey score were evaluated. All patients had follow-up radiographs. The mean arc of elbow motion was 130 degrees (70-150 degrees ). The mean MEPI was 91 (20-100) with good results in 23% and excellent results in 52% of the patients. The mean Broberg and Morrey score was 90 after isolated olecranon fracture, and decreased with the complexity of the lesion. 117 fractures (72%) healed with ulnohumeral congruity. 9 fracture non-unions occurred (6%). Although the fracture of the proximal ulna can be described in several classifications, none of them accommodate it satisfactorily, because of the complexity of the lesion. The coronoid process is the keystone for the stability of the elbow. It forms the anterior buttress with the radial head. Tension band wire fixation is by far the commonest technique of internal fixation used for the treatment of non comminuted olecranon fractures. Dorsal plate fixation is a useful option by providing improved fixation of complex comminuted fractures and fracture dislocations. The radiocapitellar joint has to be restored appropriately, preserving the radial head when possible and replacing it with a prosthesis otherwise. The lateral collateral ligament complex is commonly disrupted and usually can be reattached to its origin from the lateral epicondyle. In addition, a brief period of hinged external fixation should be considered. PMID- 26528936 TI - Open reduction and internal fixation of osteoporotic acetabular fractures through the ilio-inguinal approach: use of buttress plates to control medial displacement of the quadrilateral surface. AB - The number of acetabular fractures in the geriatric population requiring open reduction and internal fixation is increasing. Fractures with medial or anterior displacement are the most frequent types, and via the ilio-inguinal approach buttress plates have proved helpful to maintain the quadrilateral surface or medial acetabular wall. Seven to ten hole 3.5 mm reconstruction plates may be used as buttress plates, placed underneath the usual pelvic brim plate. This retrospective study presents our results with this technique in 13 patients at a minimum follow-up of 12 months (average, 31 months). 85% of the patients had a good result. The early onset of post-traumatic osteoarthritis necessitated total hip arthroplasty in two patients (15%) at 12 and 18 months follow-up, respectively. This treatment option should be considered in the surgeon's armamentarium when fixing these challenging cases. PMID- 26528937 TI - Management of upper cervical spine fractures in elderly patients: current trends and outcomes. AB - Upper cervical spine fractures in the elderly represent serious injuries. Their frequency is on the rise. Their early accurate diagnosis might be compromised by the existence of extensive degenerative changes and deformities. Adequate stabilisation allowing fracture healing is of paramount importance. However, the debate is ongoing as to the best protocol that can be applied taking into consideration the presence of comorbidities and the increase risk of mortality in this frail patient population. A literature review, based on PubMed, related to protocols reporting on fracture fixation of the upper cervical spine, fractures (C1-C2) was carried out. Papers including information about type of fracture, treatment carried out, complication rates, mortality and morbidities were eligible to be included in this study. Fourteen papers met the inclusion criteria. Six reported on all types of injuries of the upper cervical spine, and eight only odontoid fractures (C2). Overall mortality rate ranged between 0 to 31.4%. Overall morbidity rate was from 10.3 to 90.9%. No significant difference was identified between three types of treatment (rigid collar cuff without fracture reduction, halo cast with reduction of fracture displacement, and surgical treatment). Halo-cast got the highest rate of complications. Surgical treatment got a mortality rate from 0 to 40.0%, and a morbidity rate from 10.3 to 62.5%. Non-union rate ranged between 8.9 to 62.5%. Elderly patients with upper cervical spine fractures must be notified that these injuries are associated with high incidence of non-union, morbidity and mortality. PMID- 26528938 TI - Terrible triad of the elbow: treatment protocol and outcome in a series of eighteen cases. AB - The terrible triad is an uncommon injury, which includes an elbow posterior dislocation with fractures of the radial head and coronoid process of the ulna. In addition there is rupture of the lateral and medial collateral ligaments. The short-term and long term results are historically poor, with a high rate of complications. The main objective of this study is to report the results of a multicentre study of patients who sustained the terrible triad injury focusing on surgical treatment in order to offer a standardized surgical protocol. We retrospectively review the results of surgical treatment of eighteen terrible triads from a multicentre study of 226 elbow dislocations. At an average follow up of 31.5 months postoperatively, all eighteen patients returned for clinical examination, functional evaluation, and radiographs. The mean MEPS score value was 78 (25-100), which correspond to three excellent results, ten good results, three fair results, and two poor results. Five early and three late complications were reported. This particular case of elbow dislocation is very unstable and leads to many complications. The surgeon should attempt to restore stability by preserving the radial head whenever possible or replacing it with prosthesis otherwise, by repairing the lateral collateral ligament and performing fixation of the coronoid fracture. If after anatomical restoration of stability elements, the elbow remains unstable, options include repair of the medial collateral ligament or stabilization assumed by hinged external fixator. PMID- 26528939 TI - In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin. AB - Major physiological changes are governed by alternative splicing of RNA, and its misregulation may lead to specific diseases. With the use of a genome-wide approach, we show here that this splicing step can be modified by medication and demonstrate the effects of the biguanide metformin, on alternative splicing. The mechanism of action involves AMPK activation and downregulation of the RBM3 RNA binding protein. The effects of metformin treatment were tested on myotonic dystrophy type I (DM1), a multisystemic disease considered to be a spliceopathy. We show that this drug promotes a corrective effect on several splicing defects associated with DM1 in derivatives of human embryonic stem cells carrying the causal mutation of DM1 as well as in primary myoblasts derived from patients. The biological effects of metformin were shown to be compatible with typical therapeutic dosages in a clinical investigation involving diabetic patients. The drug appears to act as a modifier of alternative splicing of a subset of genes and may therefore have novel therapeutic potential for many more diseases besides those directly linked to defective alternative splicing. PMID- 26528940 TI - Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification. AB - The acute hepatic porphyrias are caused by inherited enzymatic deficiencies in the heme biosynthesis pathway. Induction of the first enzyme 5-aminolevulinic acid synthase 1 (ALAS1) by triggers such as fasting or drug exposure can lead to accumulation of neurotoxic heme intermediates that cause disease symptoms. We have demonstrated that hepatic ALAS1 silencing using siRNA in a lipid nanoparticle effectively prevents and treats induced attacks in a mouse model of acute intermittent porphyria. Herein, we report the development of ALN-AS1, an investigational GalNAc-conjugated RNAi therapeutic targeting ALAS1. One challenge in advancing ALN-AS1 to patients is the inability to detect liver ALAS1 mRNA in the absence of liver biopsies. We here describe a less invasive circulating extracellular RNA detection assay to monitor RNAi drug activity in serum and urine. A striking correlation in ALAS1 mRNA was observed across liver, serum, and urine in both rodents and nonhuman primates (NHPs) following treatment with ALN AS1. Moreover, in donor-matched human urine and serum, we demonstrate a notable correspondence in ALAS1 levels, minimal interday assay variability, low interpatient variability from serial sample collections, and the ability to distinguish between healthy volunteers and porphyria patients with induced ALAS1 levels. The collective data highlight the potential utility of this assay in the clinical development of ALN-AS1, and in broadening our understanding of acute hepatic porphyrias disease pathophysiology. PMID- 26528941 TI - Pilot Study Examining the Effects of Atropine on Performance during Uncompensable Heat Stress. AB - In many operational scenarios, hypohydration can be corrected with oral rehydration following the work interval. Although rare, there are potential situations that require extended intervals of uncompensable heat stress exposure while working in personal protective equipment (PPE). Under these conditions, retention of body water may be valuable to preserve work capacity and reduce cardiovascular strain. We conducted a pilot study comparing intramuscular atropine sulfate versus saline placebo to establish the safety profile of the protocol and to provide pilot data for future investigations. Five, healthy, heat acclimated subjects completed this crossover design laboratory study. Each subject performed up to one hour of exertion in a hot environment while wearing a chemical resistant coverall. Atropine sulfate (0.02 mg/kg) or an equivalent volume of sterile saline was administered by intramuscular injection. Core temperature, heart rate, perceptual measures, and changes in body mass were measured. All five subjects completed the acclimation period and both protocols. No adverse events occurred, and no pharmacologically induced delirium was identified. Change in body mass was less following exercise influenced by atropine sulfate (p = 0.002). Exertion time tended to be longer in the atropine sulfate arm (p = 0.08). Other measures appeared similar between groups. Intramuscular atropine sulfate reduced sweating and tended to increase the work interval under uncompensable heat stress when compared to saline placebo. Heart rate and temperature changes during exertion were similar in both conditions suggesting that the influence of an anticholinergic agent on thermoregulation may be minimal during uncompensable heat stress. KEY WORDS: thermoregulation; cholinolytic; anticholinergic; reaction time. PMID- 26528942 TI - Exercise Training Improves Whole Body Insulin Resistance via Adiponectin Receptor 1. AB - Little is known regarding whether adiponectin receptors mediate high-intensity interval training (HIT)-induced improvement of insulin resistance associated with obesity. This study investigated the effect of HIT on whole body insulin resistance in high-fat diet-induced obese mice. 5-week-old male mice (N=30) were randomly assigned to standard chow (SC) (n=10) or HFD (n=20) for 23 weeks. After 15 weeks of dietary treatment, the HFD mice were further assigned to HFD (n=10) or HFD plus HIT (HFD+HIT, n=10). The HFD+HIT mice were subjected to HIT during the last 8 weeks of the 23-week HFD course. HFD resulted in whole body insulin resistance, hypoadiponectinemia, suppressed expression of adiponectin receptor 1(AdipoR1) and 2 (AdipoR2), suppressed expression of phosphorylated AMP-activated protein kinase (p-AMPK) and NAD-dependent deacetylase sirtuin-1 (SIRT1), and decreased mRNAs of peroxisome proliferator-activated receptor-alpha (PPARalpha), carnitine palmitoyltransferase I (CPT1), and acyl CoA oxidase (ACO) in skeletal muscle. In contrast, HIT alleviated whole body insulin resistance and prevented decreased levels of total adiponectin in both serum and adipose tissue. HIT also prevented the down-regulation of AdipoR1 and AMPK/SIRT1 proteins and the down regulation of PPARalpha, CPT1, and ACO mRNAs. The current findings show that HIT alleviates whole body insulin resistance due to HFD-induced obesity via the AdipoR1 and AMPK/SIRT1 mediated-signaling pathway in skeletal muscle, implying the potential role of HIT to combat this metabolic condition. PMID- 26528943 TI - Protective Effect of Moderate Exercise for BALB/c Mice with Salmonella Typhimurium Infection. AB - Moderate exercise enhances resistance to pathogen-associated infections. However, its influence on intestinal IgA levels and resistance to Salmonella typhimurium in mice has not been reported. The aim of this study was to assess the impact of moderate exercise on bacterial resistance and the intestinal-IgA response in a murine typhoid model. Sedentary and exercised (under a protocol of moderate swimming) BALB/c mice were orally infected with Salmonella typhimurium and sacrificed on days 7 or 14 post-infection (n=5 per group). Compared with infected sedentary mice, infected exercised animals had i) lower intestinal and systemic bacterial loads; ii) higher total and specific intestinal-IgA levels, iii) a higher percentage of IgA plasma cells in lamina propria; iv) a higher level on day 7 and lower level on day 14 of intestinal alpha- and J-chain mRNA and plasma corticosterone, v) unchanged mRNA expression of intestinal pIgR, and vi) a higher mRNA expression of liver pIgR, alpha-chain and J-chain on day 7. Hence, it is likely that an increase in corticosterone levels (stress response) induced by moderate exercise increased intestinal IgA levels by enabling greater liver expression of pIgR mRNA, leading to a rise in IgA transcytosis from the liver to intestine. The overall effect of these changes is an enhanced resistance to infection. PMID- 26528944 TI - Using Thorax Expansion to Detect a Ventilatory Inflection Point in the Field. AB - Assessing an individual's physical fitness can usually be achieved through evaluating lactate or ventilatory thresholds. Unfortunately, the detection of ventilatory thresholds still requires uncomfortable mass flow sensors and a laboratory setting. Therefore, this study aimed to evaluate a ventilatory inflection point (VIP) derived from thorax expansion as a useful surrogate to assess an individual's physical fitness under field conditions. 348 and 107 ramp tests have been selected respectively to examine validity and retest variability of VIP. The individual anaerobic threshold (IAT) determined by means of blood lactate sampling was used as reliable rationale for evaluation. Calibrated respiratory inductance plethysmography (RIP) was utilized to derive ventilation from thorax expansion during the ramp test. An automated software routine was applied to detect the VIP. Speed, heart rate and ventilation at the VIP correlated significantly to corresponding values at IAT (r=0.840, 0.876, 0.933). Non-systematic differences between repeated testing ranged within +/-1.15 km.h( 1), +/-8.74 b.min(-1) and +/-12.69 l.min(-1) (+/-1.96 SD). The timing of VIP is not solely dependent on the aerobic capacity and might instead quantify an individual's physical fitness in terms of the efficiency of the compensative and supportive ventilatory response during increased exercise intensities. PMID- 26528945 TI - In vitro nematicidal activity of aryl hydrazones and comparative GC-MS metabolomics analysis. AB - A series of aryl hydrazones were synthesized and in vitro assayed for their activity on the root-knot nematode Meloidogyne incognita. The phenylhydrazones of thiophene-2-carboxyaldehyde 5, 3-methyl-2-thiophenecarboxyaldehyde, 6, and salicylaldehyde, 2, were the most potent with EC50/48h values of 16.6 +/- 2.2, 23.2 +/- 2.7, and 24.3 +/- 1.4 mg/L, respectively. A GC-MS metabolomics analysis, after in vitro nematode treatment with hydrazone 6 at 100 mg/L for 12 h, revealed elevated levels of fatty acids such as lauric acid, stearic acid, 2-octenoic acid, and palmitic acid. Whereas control samples showed the highest levels of monoacylglycerols such as monostearin and 2-monostearin, surprisingly, 2 h after treatment with hydrazone 6, nematodes excreted 3 times the levels of ammonia eliminated in the same conditions by controls. Thus, phenylhydrazones may represent a good scaffold in the discovery and synthesis of new nematicidal compounds, and a metabolomics approach may be helpful in understanding their mechanisms of toxicity and mode of action. PMID- 26528946 TI - The immunosuppressive signature of menstrual blood mesenchymal stem cells entails opposite effects on experimental arthritis and graft versus host diseases. AB - Recently, a noninvasive and highly proliferative stem cell population from menstrual blood called MenSCs has been identified. Despite their use in clinical studies, their immunomodulatory properties have not yet been investigated. In this context, we studied the immunosuppressive properties of MenSCs in comparison with the well-characterized bone marrow derived-MSCs (BM-MSCs). Using an in vitro proliferation assays, we showed that MenSCs displayed a lower suppressive effect on peripheral blood mononuclear cells and in particular on the proinflammatory CD4(+) IFN-gamma(+) and CD8(+) IFNgamma(+) cells than BM-MSCs. Moreover, compared to BM-MSCs, MenSCs activated with IFN-gamma and IL-1beta produced lower amounts of immunosuppressive factors such as IDO, PDL-1, PGE2, and Activin A and exhibited a substantial lower expression level of IFN-gamma receptor subunits. In the collagen induced arthritis model, while BM-MSCs administration resulted in a potent therapeutic effect associated with a significant decrease of proinflammatory T cell frequency in the lymph nodes, MenSCs injection did not. In contrast, in the xeno-GVHD model, only MenSCs administration significantly increased the survival of mice. This beneficial effect mediated by MenSCs was associated with a higher capacity to migrate into the intestine and liver and not to their anti-inflammatory capacities. All together our results demonstrate for the first time that the therapeutic potential of MSC in the experimental xeno GVHD model is independent of their immunosuppressive properties. These findings should be taken into consideration for the development of safe and effective cell therapies. PMID- 26528947 TI - Closing the Circle. PMID- 26528948 TI - Finding a Way to Cope: A Qualitative Study of the Experiences of Persons With Spinal Cord Injury. AB - PURPOSE: Spinal cord injury (SCI) is a catastrophe that causes disabilities and permanently changes people's lives. The people have to adapt to the loss of self care ability and may need long-term rehabilitation. The recovery can be problematic, affecting physiological, psychological, and financial aspects of life. The purpose of this study was to explore the lived experiences of persons with SCI living in Taiwan. METHODS: In 2009, we conducted a qualitative study on 10 participants with SCI recruited from the Association of Spinal Cord Injury Persons in Taiwan. Open-ended interviews were conducted using a guide and tape recorder for subsequent transcription. A phenomenological method was used to collect data by interviews. RESULTS: The core experience of persons with SCI was "finding a way to cope," which was a process from despair to self-acceptance and composed of four categories: (a) shock and unpreparedness for the injury: the catastrophe of the injury itself and the underrecognition of physiological disabilities; (b) panic and fear: denying the injury and yearning for a miracle; (c) abyss of despair: imprinting of life, bearing the agony alone, and chaos of life; and (d) reflection on the meaning of life: adaptation to physical disabilities, self-acceptance, and growth. CONCLUSIONS: Our research was descriptive and focused on the structure of the lived experiences of persons with SCI. Many issues of inequality also revealed physical disabilities, such as difficulty looking professional, resulting in burden of stress and frustration. These results highlight persons with SCI should be classified as case management and integration of social welfare resources to facilitate care for persons with SCI after discharge. PMID- 26528949 TI - Understanding Parkinson Disease: A Complex and Multifaceted Illness. AB - Parkinson disease is an incredibly complex and multifaceted illness affecting millions of people in the United States. Parkinson disease is characterized by progressive dopaminergic neuronal dysfunction and loss, leading to debilitating motor, cognitive, and behavioral symptoms. Parkinson disease is an enigmatic illness that is still extensively researched today to search for a better understanding of the disease, develop therapeutic interventions to halt or slow progression of the disease, and optimize patient outcomes. This article aims to examine in detail the normal function of the basal ganglia and dopaminergic neurons in the central nervous system, the etiology and pathophysiology of Parkinson disease, related signs and symptoms, current treatment, and finally, the profound impact of understanding the disease on nursing care. PMID- 26528950 TI - Time to Blood Pressure Control Before Thrombolytic Therapy in Patients With Acute Ischemic Stroke: Comparison of Labetalol, Nicardipine, and Hydralazine. AB - BACKGROUND: Elevated blood pressure is common in patients with acute ischemic stroke. Thrombolytic therapy is contraindicated in patients with a systolic blood pressure greater than 185 mmHg or diastolic blood pressure greater than 110 mmHg. Elevated blood pressure can lead to a delay in thrombolytic therapy, which is associated with increased morbidity. There is currently insufficient evidence to support the use of a specific antihypertensive agent in this setting. OBJECTIVE: This study aimed to compare the effects of labetalol, nicardipine, or hydralazine on time to target blood pressure before alteplase administration in patients with acute ischemic stroke. METHODS: A retrospective chart review was conducted to identify patients who received labetalol, nicardipine, or hydralazine to treat elevated blood pressure (systolic blood pressure > 185 or diastolic blood pressure > 110) before intravenous alteplase therapy for ischemic stroke. Data collection included time to blood pressure control, door-to-needle time, total dose administered, and use of additional antihypertensive agent(s). RESULTS: Most patients in this study received labetalol (25/29). Median time to blood pressure control was 10, 22, and 15 minutes in the labetalol, nicardipine, and hydralazine groups, respectively. Among patients who received labetalol, the average time to blood pressure control was 10 minutes longer in those who received 10 mg initially versus those who received 20 mg. Patients who required higher total doses of labetalol tended to achieve blood pressure control more slowly, had longer door-to-needle times, and required additional antihypertensive agents. CONCLUSIONS: Adequate initial dosing of antihypertensive treatment has the potential to reduce time to blood pressure control and possibly time to alteplase therapy. The optimal antihypertensive regimen for controlling blood pressure before alteplase therapy remains unclear. PMID- 26528951 TI - The Elderly Person With Multiple Sclerosis: Clinical Implications for the Increasing Life-Span. AB - Multiple sclerosis (MS) is a chronic, unpredictable, progressive, and disabling autoimmune disease with significant neurodegenerative and inflammatory components. To effectively treat and care for older persons with MS, it is essential to examine the factors associated with a decrease in their quality of life. Typically, MS is diagnosed between 20 and 50 years old. Although not a fatal disease, the natural history data of persons with MS reveal survival approximately 38 years after diagnosis. With the advent of disease-modifying therapies, life-span has increased substantially over the past 2 decades among people with MS. Approximately 90% of people with MS now in their 20s may live into their 70s. Their quality of life as an older adult will be impacted by what we learn today. Currently, approximately a quarter of people with MS are mature adults over 65 years old. Older adults with MS are more likely to have a decreased health-related quality of life (HRQOL). HRQOL is a multidimensional construct that refers to an individual's physical functioning, ability to perform activities of daily living, sense of well-being, satisfaction with life, perception of psychological status, and social functioning. This article focuses on the current literature in HRQOL in older persons with MS. A specific aim is to examine the factors associated with a decreased QOL in older persons with MS. Nursing screening and implementation of interventions that may reduce these factors and improve function of patients will be discussed. Although measures to improve HRQOL do not substitute for treatment of the disease, knowledge of factors that reduce HRQOL is essential to understand patient perceptions of their health and disease. PMID- 26528952 TI - Health-Related Quality of Life and Related Factors in Children and Adolescents With Epilepsy in Iran. AB - The effects of epilepsy may disturb the ability of the child and family to function and has detrimental effects on health-related quality of life (HRQOL). We determined HRQOL and related factors in children and adolescents with epilepsy in Iran. This cross-sectional study was performed in a private neurology pediatric clinic in Guilan Province (North of Iran). We evaluated 108 children and adolescents with epilepsy. Data were collected by interview with parents and review of medical records. Generic and specific HRQOL was evaluated by Child Health Questionnaire and QOL in Childhood Epilepsy Questionnaire, respectively. The mean of overall generic HRQOL score was 71.05 +/- 11.31. The lowest score was related to parental impact: emotional (52.59 +/- 15.49). The average total specific HRQOL score was 71.95 +/- 11.16. The lowest score dedicated to general health (51.21 +/- 18.25). In multivariate regression analysis, duration of epilepsy (p < .016) was independently associated with generic HRQOL scores. Variables were independently associated with specific HRQOL scores including gender (p < .003), duration of epilepsy (p < .011), and family history of epilepsy (p < .005). We found that epilepsy duration was the strongest predictor of both generic and specific HRQOL in children and adolescents with epilepsy. This will be useful for clinicians in epilepsy management, which will enhance HRQOL. PMID- 26528954 TI - DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease. AB - OBJECTIVE: DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair bound within ~10 years from onset). Here, for the first time, we report DNAJC6 mutations in early-onset Parkinson's disease (PD). METHODS: The DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies. RESULTS: We identified two families with different novel homozygous DNAJC6 mutations segregating with PD. In each family, the DNAJC6 mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady-state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding DNAJC6 variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early-onset PD, had symptoms onset in the third-to-fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early-onset PD. INTERPRETATION: Our findings delineate a novel form of hereditary early-onset PD. Screening of DNAJC6 is warranted in all patients with early-onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis. PMID- 26528955 TI - The profile of platelet alpha-granule released molecules affects postoperative liver regeneration. AB - Platelets promote liver regeneration through site-specific serotonin release from dense granules, triggering proliferative signaling in hepatocytes. However, the effects of factors derived from platelet alpha-granules on liver regeneration are unclear, because alpha-granules contain bioactive molecules with opposing functions. Because alpha-granule molecules are stored in separate compartments, it has been suggested that platelets selectively release their alpha-granule content dependent on the environmental stimulus. Therefore, we investigated the pattern of circulating alpha-granule molecules during liver regeneration in 157 patients undergoing partial hepatectomy. We measured plasma levels of alpha granule-derived factors in the liver vein at the end of liver resection, as well as on the first postoperative day. We observed a rapid accumulation of platelets within the liver after induction of liver regeneration. Platelet count and P selectin (a ubiquitous cargo of alpha-granules) were not associated with postoperative liver dysfunction. However, low plasma levels of vascular endothelial growth factor (VEGF), but high levels of thrombospondin 1 (TSP-1), predicted liver dysfunction after resection. Patients with an unfavorable postoperative alpha-granule release profile (high TSP-1/low VEGF) showed substantially worse postoperative clinical outcomes. The unfavorable postoperative alpha-granule release profile was associated with increased postoperative portal venous pressure and von Willebrand factor antigen levels as a marker for intrahepatic endothelial dysfunction. CONCLUSION: The postoperative profile of circulating platelet-derived factors correlates with the ability of the remnant liver to regenerate. Portal venous pressure and intrahepatic endothelial dysfunction might account for the selective granule release profile. Selective modulation of platelet alpha-granule release in patients may represent an attractive target for therapeutic interventions to improve liver regeneration and clinical outcomes after partial hepatectomy. PMID- 26528956 TI - Vibronic resonances facilitate excited-state coherence in light-harvesting proteins at room temperature. AB - Until recently it was believed that photosynthesis, a fundamental process for life on earth, could be fully understood with semiclassical models. However, puzzling quantum phenomena have been observed in several photosynthetic pigment protein complexes, prompting questions regarding the nature and role of these effects. Recent attention has focused on discrete vibrational modes that are resonant or quasi-resonant with excitonic energy splittings and strongly coupled to these excitonic states. Here we unambiguously identify excited state coherent superpositions in photosynthetic light-harvesting complexes using a new experimental approach. Decoherence on the time scale of the excited state lifetime allows low energy (56 cm(-1)) oscillations on the signal intensity to be observed. In conjunction with an appropriate model, these oscillations provide clear and direct experimental evidence that the persistent coherences observed originate from quantum superpositions among vibronic excited states. PMID- 26528957 TI - Low-Dose Docetaxel Combined with Dexamethasone Is Feasible for Patients with Castration-Resistant Prostate Cancer. AB - AIM: Docetaxel-based chemotherapy against castration-resistant prostate cancer (CRPC) has recently been shown to be effective and tolerable. The objective of this study was to retrospectively evaluate the efficacy and toxicity of low-dose docetaxel in combination with dexamethasone. METHODS: Thirty-seven CRPC patients were administered a treatment regimen consisting of 50 mg/m2 docetaxel once every 3-4 weeks and 1 mg dexamethasone daily at our institution, between November 2004 and April 2014. RESULTS: Twenty-four patients (65%) had a decrease in serum prostate-specific antigen (PSA) >50%. The median overall survival (OS) and PSA progression-free survival were 26.2 and 10.0 months, respectively. Ten of 12 patients (83%) taking analgesic agents reduced their intake because of decreased pain levels. Grade 3 febrile neutropenia occurred in 2 patients (5%). Nonhematological toxicities were less frequent but sometimes severe. Treatment related death occurred in 2 octogenarian patients, 1 due to gastric bleeding and the other due to infective endocarditis. CONCLUSION: Low-dose docetaxel in combination with dexamethasone is feasible in Japanese CRPC patients. Hematological toxicity is less than that seen with standard docetaxel therapy, but it is necessary to monitor patients for severe nonhematological toxicities, particularly very elderly patients. PMID- 26528958 TI - Understanding the Amide-II Vibrations in beta-Peptides. AB - In this work, the vibrational characteristics of the amide-II modes in beta peptides in five helical conformations, namely, 8-, 10-, 12-, 14-, and 10/12 helices, have been examined. Remarkable conformational dependence of the amide-II spectral profile is obtained by ab initio computations as well as modeling analysis. Intramolecular hydrogen-bonding interaction and its influence on backbone structure and on the amide-II local-mode transition frequencies and intensities are examined. Through-space and through-bond contributions of the amide-II vibrational couplings are analyzed, and it was found that hydrogen bonding interaction is not a determining factor for the coupling strength. The results reported here provide useful benchmarks for understanding experimental amide-II infrared spectra of beta-peptides and suggest the potential application of this mode on monitoring the structures and dynamics of beta-peptides. PMID- 26528960 TI - Unbiased Scanning Method and Data Banking Approach Using Ultra-High Performance Liquid Chromatography Coupled with High-Resolution Mass Spectrometry for Quantitative Comparison of Metabolite Exposure in Plasma across Species Analyzed at Different Dates. AB - An unbiased scanning methodology using ultra high-performance liquid chromatography coupled with high-resolution mass spectrometry was used to bank data and plasma samples for comparing the data generated at different dates. This method was applied to bank the data generated earlier in animal samples and then to compare the exposure to metabolites in animal versus human for safety assessment. With neither authentic standards nor prior knowledge of the identities and structures of metabolites, full scans for precursor ions and all ion fragments (AIF) were employed with a generic gradient LC method to analyze plasma samples at positive and negative polarity, respectively. In a total of 22 tested drugs and metabolites, 21 analytes were detected using this unbiased scanning method except that naproxen was not detected due to low sensitivity at negative polarity and interference at positive polarity; and 4'- or 5-hydroxy diclofenac was not separated by a generic UPLC method. Statistical analysis of the peak area ratios of the analytes versus the internal standard in five repetitive analyses over approximately 1 year demonstrated that the analysis variation was significantly different from sample instability. The confidence limits for comparing the exposure using peak area ratio of metabolites in animal plasma versus human plasma measured over approximately 1 year apart were comparable to the analysis undertaken side by side on the same days. These statistical analysis results showed it was feasible to compare data generated at different dates with neither authentic standards nor prior knowledge of the analytes. PMID- 26528961 TI - Optimization of Antifungal Extracts from Ficus hirta Fruits Using Response Surface Methodology and Antifungal Activity Tests. AB - The fruits of Ficus hirta (FH) display strong antifungal activity against Penicillium italicum and Penicillium digitatum. In order to optimize the extraction conditions of antifungal extracts from FH fruit, various extraction parameters, such as ethanol concentration, extraction time, solvent to solid ratio and temperature, were chosen to identify their effects on the diameters of inhibition zones (DIZs) against these two Penicillium molds. Response surface methodology (RSM) was applied to obtain the optimal combination of these parameters. Results showed that the optimal extraction parameters for maximum antifungal activity were: 90% (v/v) ethanol concentration, 65 min extraction time, 31 mL/g solvent to solid ratio and 51 degrees C temperature. Under the abovementioned extraction conditions, the experimental DIZs values obtained experimentally were 57.17 +/- 0.75 and 39.33 +/- 0.82 mm, which were very close to the values of 57.26 and 39.29 mm predicted by the model. Further, nine kinds of phytopathogens were tested in vitro to explore the antifungal activity of the FH extracts. It was found for the first time that the FH extracts showed significant inhibition on the growth of P. italicum, A. citri, P. vexans, P. cytosporella and P. digitatum. PMID- 26528962 TI - Comparative Anticonvulsant Study of Epoxycarvone Stereoisomers. AB - Stereoisomers of the monoterpene epoxycarvone (EC), namely (+)-cis-EC, (-)-cis EC, (+)-trans-EC, and (-)-trans-EC, were comparatively evaluated for anticonvulsant activity in specific methodologies. In the pentylenetetrazole (PTZ)-induced anticonvulsant test, all of the stereoisomers (at 300 mg/kg) increased the latency to seizure onset, and afforded 100% protection against the death of the animals. In the maximal electroshock-induced seizures (MES) test, prevention of tonic seizures was also verified for all of the isomers tested. However, the isomeric forms (+) and (-)-trans-EC showed 25% and 12.5% inhibition of convulsions, respectively. In the pilocarpine-induced seizures test, all stereoisomers demonstrated an anticonvulsant profile, yet the stereoisomers (+) and (-)-trans-EC (at 300 mg/kg) showed a more pronounced effect. A strychnine induced anticonvulsant test was performed, and none of the stereoisomers significantly increased the latency to onset of convulsions; the stereoisomers probably do not act in this pathway. However, the stereoisomers (+)-cis-EC and (+)-trans-EC greatly increased the latency to death of the animals, thus presenting some protection. The four EC stereoisomers show promise for anticonvulsant activity, an effect emphasized in the isomers (+)-cis-EC, (+) trans-EC, and (-)-trans-EC for certain parameters of the tested methodologies. These results serve as support for further research and development of antiepileptic drugs from monoterpenes. PMID- 26528963 TI - X-ray Crystallography, DFT Calculations and Molecular Docking of Indole Arylpiperazine Derivatives as alpha1A-Adrenoceptor Antagonists. AB - Indole-arylpiperazine derivatives have exhibited good selectivity for the alpha1A adrenoceptor, but the structure-activity-binding mechanism relationship remains unclear. In the current study, three compounds (1, 2 and 3) were investigated through single-crystal X-ray diffraction analysis, density functional theory (DFT) calculations and molecular docking using a homology model of the alpha1A receptor. Compounds 1 and 3 form H-bonds networks to stabilize their three dimensional structures, while C-H...pi interactions play a significant role in the packing of 2. Based on DFT-optimized conformations, the HOMO-LUMO energy gaps and molecular electrostatic potential (MEP) were theoretically calculated at the B3LYP/6-311G (d, p) level of theory. Chemical reactivity increases in the order of 3 < 2 < 1, and the maximum positive region of the MEP maps is mainly localized over the NH group. The binding mechanisms of ligand-alpha1A-adrenoceptor complexes were illustrated by molecular docking. Binding to Gln177 of the second extracellular loop region via hydrogen bonds is likely to be essential for alpha1A-selective antagonists. The present work sheds light on the studies of structure-activity-binding mechanism and aids in the design of alpha1A antagonists with high selectivity. PMID- 26528964 TI - Tetracycline-Containing MCM-41 Mesoporous Silica Nanoparticles for the Treatment of Escherichia coli. AB - Tetracycline (TC) is a well-known broad spectrum antibiotic, which is effective against many Gram positive and Gram negative bacteria. Controlled release nanoparticle formulations of TC have been reported, and could be beneficial for application in the treatment of periodontitis and dental bone infections. Furthermore, TC-controlled transcriptional regulation systems (Tet-on and Tet off) are useful for controlling transgene expression in vitro and in vivo for biomedical research purposes; controlled TC release systems could be useful here, as well. Mesoporous silica nanomaterials (MSNs) are widely studied for drug delivery applications; Mobile crystalline material 41 (MCM-41), a type of MSN, has a mesoporous structure with pores forming channels in a hexagonal fashion. We prepared 41 +/- 4 and 406 +/- 55 nm MCM-41 mesoporous silica nanoparticles and loaded TC for controlled dug release; TC content in the TC-MCM-41 nanoparticles was 18.7% and 17.7% w/w, respectively. Release of TC from TC-MCM-41 nanoparticles was then measured in phosphate-buffered saline (PBS), pH 7.2, at 37 degrees C over a period of 5 h. Most antibiotic was released from both over this observation period; however, the majority of TC was released over the first hour. Efficacy of the TC-MCM-41 nanoparticles was then shown to be superior to free TC against Escherichia coli (E. coli) in culture over a 24 h period, while blank nanoparticles had no effect. PMID- 26528965 TI - Anticancer and Antibacterial Activity Studies of Gold(I)-Alkynyl Chromones. AB - Three gold(I) complexes of alkynyl chromones were synthesized and characterized. The single-crystal X-ray structure analysis of a dinuclear compound and of a flavone derivative exhibit a typical d10 gold(I)-alkynyl linear arrangement. All complexes were evaluated as anticancer and antibacterial agents against four human cancer cell lines and four pathogenic bacterial strains. All compounds show antiproliferative activity at lower micromolar range concentrations. Complex 4 showed a broad activity profile, being more active than the reference drug auranofin against HepG2, MCF-7 and CCRF-CEM cancer cells. The cellular uptake into MCF-7 cells of the investigated complexes was measured by atomic absorption spectroscopy (AAS). These measurements showed a positive correlation between an increased cellular gold content and the incubation time of the complexes. Unexpectedly an opposite effect was observed for the most active compound. Biological assays revealed various molecular mechanisms for these compounds, comprising: (i) thioredoxin reductase (TrxR) inhibition, (ii) caspases-9 and -3 activation; (iii) DNA damaging activity and (iv) cell cycle disturbance. The gold(I) complexes were also bactericidal against Gram-positive methicillin sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) bacterial strains, while showing no activity against the Gram-negative Escherichia coli bacterial strain. PMID- 26528966 TI - The Functions of BMP3 in Rabbit Articular Cartilage Repair. AB - Bone morphogenetic proteins (BMPs) play important roles in skeletal development and repair. Previously, we found fibroblast growth factor 2 (FGF2) induced up regulation of BMP2, 3, 4 in the process of rabbit articular cartilage repair, which resulted in satisfactory repair effects. As BMP2/4 show a clearly positive effect for cartilage repair, we investigated the functions of BMP3 in rabbit articular cartilage repair. In this paper, we find that BMP3 inhibits the repair of partial-thickness defect of articular cartilage in rabbit by inducing the degradation of extracellular matrix, interfering with the survival of chondrocytes surrounding the defect, and directly inhibiting the expression of BMP2 and BMP4. Meanwhile BMP3 suppress the repair of full-thickness cartilage defect by destroying the subchondral bone through modulating the proliferation and differentiation of bone marrow stem cells (BMSCs), and directly increasing the expression of BMP4. Although BMP3 has different functions in the repair of partial and full-thickness defects of articular cartilage in rabbit, the regulation of BMP expression is involved in both of them. Together with our previous findings, we suggest the regulation of the BMP signaling pathway by BMP3 is essential in articular cartilage repair. PMID- 26528967 TI - A Co-Culture Model of Fibroblasts and Adipose Tissue-Derived Stem Cells Reveals New Insights into Impaired Wound Healing After Radiotherapy. AB - External radiation seems to be associated with increased amounts of cytokines and other cellular modulators. Impaired microcirculation and fibrosis are examples of typical long term damage caused by radiotherapy. Adipose tissue-derived stem cells (ASC) are discussed to enhance wound healing, but their role in wounds due to radiotherapy is poorly understood. Normal human fibroblasts (NHF) and ASCs were co-cultured and external radiation with doses from 2-12 Gray (Gy) was delivered. Cell proliferation and mRNA levels of matrix metalloproteinases (MMP1, MMP2 and MMP13) were determined 48 h after irradiation of the co-cultures by qPCR. Additionally, tissue inhibitors of matrix metalloproteinases (TIMP1, TIMP2) were determined by enzyme-linked immunosorbent assay (ELISA). There was a reduction of cell proliferation after external radiation in mono-cultures of NHFs and ASCs compared to controls without irradiation. The co-culture of ASCs and NHFs showed reduced impairment of cell proliferation after external radiation. Gene expression of MMP1 and MMP13 was reduced after external irradiation in NHF. MMP2 expression of irradiated NHFs was increased. In the co-culture setting, MMP1 and MMP2 gene expression levels were upregulated. TIMP1 and TIMP2 protein expression was increased after irradiation in NHFs and their co-cultures with ASCs. ASCs seem to stimulate cell proliferation of NHFs and modulate relevant soluble mediators as well as proteinases after external radiation. PMID- 26528968 TI - Energy Metabolism of the Brain, Including the Cooperation between Astrocytes and Neurons, Especially in the Context of Glycogen Metabolism. AB - Glycogen metabolism has important implications for the functioning of the brain, especially the cooperation between astrocytes and neurons. According to various research data, in a glycogen deficiency (for example during hypoglycemia) glycogen supplies are used to generate lactate, which is then transported to neighboring neurons. Likewise, during periods of intense activity of the nervous system, when the energy demand exceeds supply, astrocyte glycogen is immediately converted to lactate, some of which is transported to the neurons. Thus, glycogen from astrocytes functions as a kind of protection against hypoglycemia, ensuring preservation of neuronal function. The neuroprotective effect of lactate during hypoglycemia or cerebral ischemia has been reported in literature. This review goes on to emphasize that while neurons and astrocytes differ in metabolic profile, they interact to form a common metabolic cooperation. PMID- 26528969 TI - Proteomics Analysis of Cellular Proteins Co-Immunoprecipitated with Nucleoprotein of Influenza A Virus (H7N9). AB - Avian influenza A viruses are serious veterinary pathogens that normally circulate among avian populations, causing substantial economic impacts. Some strains of avian influenza A viruses, such as H5N1, H9N2, and recently reported H7N9, have been occasionally found to adapt to humans from other species. In order to replicate efficiently in the new host, influenza viruses have to interact with a variety of host factors. In the present study, H7N9 nucleoprotein was transfected into human HEK293T cells, followed by immunoprecipitated and analyzed by proteomics approaches. A series of host proteins co immunoprecipitated were identified with high confidence, some of which were found to be acetylated at their lysine residues. Bioinformatics analysis revealed that spliceosome might be the most relevant pathway involved in host response to nucleoprotein expression, increasing our emerging knowledge of host proteins that might be involved in influenza virus replication activities. PMID- 26528970 TI - Electrophysiological Monitoring of Brain Injury and Recovery after Cardiac Arrest. AB - Reliable prognostic methods for cerebral functional outcome of post cardiac arrest (CA) patients are necessary, especially since therapeutic hypothermia (TH) as a standard treatment. Traditional neurophysiological prognostic indicators, such as clinical examination and chemical biomarkers, may result in indecisive outcome predictions and do not directly reflect neuronal activity, though they have remained the mainstay of clinical prognosis. The most recent advances in electrophysiological methods--electroencephalography (EEG) pattern, evoked potential (EP) and cellular electrophysiological measurement--were developed to complement these deficiencies, and will be examined in this review article. EEG pattern (reactivity and continuity) provides real-time and accurate information for early-stage (particularly in the first 24 h) hypoxic-ischemic (HI) brain injury patients with high sensitivity. However, the signal is easily affected by external stimuli, thus the measurements of EP should be combined with EEG background to validate the predicted neurologic functional result. Cellular electrophysiology, such as multi-unit activity (MUA) and local field potentials (LFP), has strong potential for improving prognostication and therapy by offering additional neurophysiologic information to understand the underlying mechanisms of therapeutic methods. Electrophysiology provides reliable and precise prognostication on both global and cellular levels secondary to cerebral injury in cardiac arrest patients treated with TH. PMID- 26528971 TI - Changes in Ultrastructure and Cytoskeletal Aspects of Human Normal and Osteoarthritic Chondrocytes Exposed to Interleukin-1beta and Cyclical Hydrostatic Pressure. AB - The aim of this study was to examine the ultrastructure and cytoskeletal organization in human normal and Osteoarhritic (OA) chondrocytes, exposed to interleukin-1beta (IL-1beta) and cyclic hydrostatic pressure (HP). Morphological examination by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) revealed differences between normal and OA chondrocytes at the nuclear and cytoplasmic level. IL-1beta (5 ng/mL) induced a decrease of the number of mitochondria and Golgi bodies and a significant increase on the percentage of cells rich in vacuolization and in marginated chromatin. Cyclical HP (1-5 MPa, 0.25 Hz, for 3 h) did not change the morphology of normal chondrocytes, but had a beneficial effect on OA chondrocytes increasing the number of organelles. Normal and OA cells subjected to IL-1beta and HP recovered cytoplasmic ultrastructure. Immunofluorescence (IF) examination of normal chondrocytes showed an actin signal polarized on the apical sides of the cytoplasm, tubulin and vimentin uniformly distributed throughout cytoplasm and vinculin revealed a punctuated pattern under the plasma membrane. In OA chondrocytes, these proteins partially lost their organization. Stimulation with IL-1beta caused, in both type of cells, modification in the cytoskeletal organization; HP counteracted the negative effects of IL-1beta. Our results showed structural differences at nuclear, cytoplasmic and cytoskeletal level between normal and OA chondrocytes. IL-1beta induced ultrastructural and cytoskeletal modifications, counteracted by a cyclical low HP. PMID- 26528973 TI - Design and Fabrication of a Real-Time Measurement System for the Capsaicinoid Content of Korean Red Pepper (Capsicum annuum L.) Powder by Visible and Near Infrared Spectroscopy. AB - This research aims to design and fabricate a system to measure the capsaicinoid content of red pepper powder in a non-destructive and rapid method using visible and near infrared spectroscopy (VNIR). The developed system scans a well-leveled powder surface continuously to minimize the influence of the placenta distribution, thus acquiring stable and representative reflectance spectra. The system incorporates flat belts driven by a sample input hopper and stepping motor, a powder surface leveler, charge-coupled device (CCD) image sensor embedded VNIR spectrometer, fiber optic probe, and tungsten halogen lamp, and an automated reference measuring unit with a reference panel to measure the standard spectrum. The operation program includes device interface, standard reflectivity measurement, and a graphical user interface to measure the capsaicinoid content. A partial least square regression (PLSR) model was developed to predict the capsaicinoid content; 44 red pepper powder samples whose measured capsaicinoid content ranged 13.45-159.48 mg/100 g by per high-performance liquid chromatography (HPLC) and 1242 VNIR absorbance spectra acquired by the pungency measurement system were used. The determination coefficient of validation (RV2) and standard error of prediction (SEP) for the model with the first-order derivative pretreatment method for Korean red pepper powder were 0.8484 and +/ 13.6388 mg/100 g, respectively. PMID- 26528974 TI - SITRUS: Semantic Infrastructure for Wireless Sensor Networks. AB - Wireless sensor networks (WSNs) are made up of nodes with limited resources, such as processing, bandwidth, memory and, most importantly, energy. For this reason, it is essential that WSNs always work to reduce the power consumption as much as possible in order to maximize its lifetime. In this context, this paper presents SITRUS (semantic infrastructure for wireless sensor networks), which aims to reduce the power consumption of WSN nodes using ontologies. SITRUS consists of two major parts: a message-oriented middleware responsible for both an oriented message communication service and a reconfiguration service; and a semantic information processing module whose purpose is to generate a semantic database that provides the basis to decide whether a WSN node needs to be reconfigurated or not. In order to evaluate the proposed solution, we carried out an experimental evaluation to assess the power consumption and memory usage of WSN applications built atop SITRUS. PMID- 26528972 TI - Chondrocyte Apoptosis in the Pathogenesis of Osteoarthritis. AB - Apoptosis is a highly-regulated, active process of cell death involved in development, homeostasis and aging. Dysregulation of apoptosis leads to pathological states, such as cancer, developmental anomalies and degenerative diseases. Osteoarthritis (OA), the most common chronic joint disease in the elderly population, is characterized by progressive destruction of articular cartilage, resulting in significant disability. Because articular cartilage depends solely on its resident cells, the chondrocytes, for the maintenance of extracellular matrix, the compromising of chondrocyte function and survival would lead to the failure of the articular cartilage. The role of subchondral bone in the maintenance of proper cartilage matrix has been suggested as well, and it has been proposed that both articular cartilage and subchondral bone interact with each other in the maintenance of articular integrity and physiology. Some investigators include both articular cartilage and subchondral bone as targets for repairing joint degeneration. In late-stage OA, the cartilage becomes hypocellular, often accompanied by lacunar emptying, which has been considered as evidence that chondrocyte death is a central feature in OA progression. Apoptosis clearly occurs in osteoarthritic cartilage; however, the relative contribution of chondrocyte apoptosis in the pathogenesis of OA is difficult to evaluate, and contradictory reports exist on the rate of apoptotic chondrocytes in osteoarthritic cartilage. It is not clear whether chondrocyte apoptosis is the inducer of cartilage degeneration or a byproduct of cartilage destruction. Chondrocyte death and matrix loss may form a vicious cycle, with the progression of one aggravating the other, and the literature reveals that there is a definite correlation between the degree of cartilage damage and chondrocyte apoptosis. Because current treatments for OA act only on symptoms and do not prevent or cure OA, chondrocyte apoptosis would be a valid target to modulate cartilage degeneration. PMID- 26528975 TI - Advanced Interrogation of Fiber-Optic Bragg Grating and Fabry-Perot Sensors with KLT Analysis. AB - The Karhunen-Loeve Transform (KLT) is applied to accurate detection of optical fiber sensors in the spectral domain. By processing an optical spectrum, although coarsely sampled, through the KLT, and subsequently processing the obtained eigenvalues, it is possible to decode a plurality of optical sensor results. The KLT returns higher accuracy than other demodulation techniques, despite coarse sampling, and exhibits higher resilience to noise. Three case studies of KLT based processing are presented, representing most of the current challenges in optical fiber sensing: (1) demodulation of individual sensors, such as Fiber Bragg Gratings (FBGs) and Fabry-Perot Interferometers (FPIs); (2) demodulation of dual (FBG/FPI) sensors; (3) application of reverse KLT to isolate different sensors operating on the same spectrum. A simulative outline is provided to demonstrate the KLT operation and estimate performance; a brief experimental section is also provided to validate accurate FBG and FPI decoding. PMID- 26528976 TI - Development and Evaluation of a UAV-Photogrammetry System for Precise 3D Environmental Modeling. AB - The specific requirements of UAV-photogrammetry necessitate particular solutions for system development, which have mostly been ignored or not assessed adequately in recent studies. Accordingly, this paper presents the methodological and experimental aspects of correctly implementing a UAV-photogrammetry system. The hardware of the system consists of an electric-powered helicopter, a high resolution digital camera and an inertial navigation system. The software of the system includes the in-house programs specifically designed for camera calibration, platform calibration, system integration, on-board data acquisition, flight planning and on-the-job self-calibration. The detailed features of the system are discussed, and solutions are proposed in order to enhance the system and its photogrammetric outputs. The developed system is extensively tested for precise modeling of the challenging environment of an open-pit gravel mine. The accuracy of the results is evaluated under various mapping conditions, including direct georeferencing and indirect georeferencing with different numbers, distributions and types of ground control points. Additionally, the effects of imaging configuration and network stability on modeling accuracy are assessed. The experiments demonstrated that 1.55 m horizontal and 3.16 m vertical absolute modeling accuracy could be achieved via direct geo-referencing, which was improved to 0.4 cm and 1.7 cm after indirect geo-referencing. PMID- 26528977 TI - Improving Ambiguity Resolution for Medium Baselines Using Combined GPS and BDS Dual/Triple-Frequency Observations. AB - The regional constellation of the BeiDou navigation satellite system (BDS) has been providing continuous positioning, navigation and timing services since 27 December 2012, covering China and the surrounding area. Real-time kinematic (RTK) positioning with combined BDS and GPS observations is feasible. Besides, all satellites of BDS can transmit triple-frequency signals. Using the advantages of multi-pseudorange and carrier observations from multi-systems and multi frequencies is expected to be of much benefit for ambiguity resolution (AR). We propose an integrated AR strategy for medium baselines by using the combined GPS and BDS dual/triple-frequency observations. In the method, firstly the extra-wide lane (EWL) ambiguities of triple-frequency system, i.e., BDS, are determined first. Then the dual-frequency WL ambiguities of BDS and GPS were resolved with the geometry-based model by using the BDS ambiguity-fixed EWL observations. After that, basic (i.e., L1/L2 or B1/B2) ambiguities of BDS and GPS are estimated together with the so-called ionosphere-constrained model, where the ambiguity fixed WL observations are added to enhance the model strength. During both of the WL and basic AR, a partial ambiguity fixing (PAF) strategy is adopted to weaken the negative influence of new-rising or low-elevation satellites. Experiments were conducted and presented, in which the GPS/BDS dual/triple-frequency data were collected in Nanjing and Zhengzhou of China, with the baseline distance varying from about 28.6 to 51.9 km. The results indicate that, compared to the single triple-frequency BDS system, the combined system can significantly enhance the AR model strength, and thus improve AR performance for medium baselines with a 75.7% reduction of initialization time on average. Besides, more accurate and stable positioning results can also be derived by using the combined GPS/BDS system. PMID- 26528978 TI - Smart Building: Decision Making Architecture for Thermal Energy Management. AB - Smart applications of the Internet of Things are improving the performance of buildings, reducing energy demand. Local and smart networks, soft computing methodologies, machine intelligence algorithms and pervasive sensors are some of the basics of energy optimization strategies developed for the benefit of environmental sustainability and user comfort. This work presents a distributed sensor-processor-communication decision-making architecture to improve the acquisition, storage and transfer of thermal energy in buildings. The developed system is implemented in a near Zero-Energy Building (nZEB) prototype equipped with a built-in thermal solar collector, where optical properties are analysed; a low enthalpy geothermal accumulation system, segmented in different temperature zones; and an envelope that includes a dynamic thermal barrier. An intelligent control of this dynamic thermal barrier is applied to reduce the thermal energy demand (heating and cooling) caused by daily and seasonal weather variations. Simulations and experimental results are presented to highlight the nZEB thermal energy reduction. PMID- 26528979 TI - Calibration of Kinect for Xbox One and Comparison between the Two Generations of Microsoft Sensors. AB - In recent years, the videogame industry has been characterized by a great boost in gesture recognition and motion tracking, following the increasing request of creating immersive game experiences. The Microsoft Kinect sensor allows acquiring RGB, IR and depth images with a high frame rate. Because of the complementary nature of the information provided, it has proved an attractive resource for researchers with very different backgrounds. In summer 2014, Microsoft launched a new generation of Kinect on the market, based on time-of-flight technology. This paper proposes a calibration of Kinect for Xbox One imaging sensors, focusing on the depth camera. The mathematical model that describes the error committed by the sensor as a function of the distance between the sensor itself and the object has been estimated. All the analyses presented here have been conducted for both generations of Kinect, in order to quantify the improvements that characterize every single imaging sensor. Experimental results show that the quality of the delivered model improved applying the proposed calibration procedure, which is applicable to both point clouds and the mesh model created with the Microsoft Fusion Libraries. PMID- 26528980 TI - Dynamic Performance Comparison of Two Kalman Filters for Rate Signal Direct Modeling and Differencing Modeling for Combining a MEMS Gyroscope Array to Improve Accuracy. AB - In this paper, the performance of two Kalman filter (KF) schemes based on the direct estimated model and differencing estimated model for input rate signal was thoroughly analyzed and compared for combining measurements of a sensor array to improve the accuracy of microelectromechanical system (MEMS) gyroscopes. The principles for noise reduction were presented and KF algorithms were designed to obtain the optimal rate signal estimates. The input rate signal in the direct estimated KF model was modeled with a random walk process and treated as the estimated system state. In the differencing estimated KF model, a differencing operation was established between outputs of the gyroscope array, and then the optimal estimation of input rate signal was achieved by compensating for the estimations of bias drifts for the component gyroscopes. Finally, dynamic simulations and experiments with a six-gyroscope array were implemented to compare the dynamic performance of the two KF models. The 1sigma error of the gyroscopes was reduced from 1.4558 degrees /s to 0.1203 degrees /s by the direct estimated KF model in a constant rate test and to 0.5974 degrees /s by the differencing estimated KF model. The estimated rate signal filtered by both models could reflect the amplitude variation of the input signal in the swing rate test and displayed a reduction factor of about three for the 1sigma noise. Results illustrate that the performance of the direct estimated KF model is much higher than that of the differencing estimated KF model, with a constant input signal or lower dynamic variation. A similarity in the two KFs' performance is observed if the input signal has a high dynamic variation. PMID- 26528981 TI - Sparse Auto-Calibration for Radar Coincidence Imaging with Gain-Phase Errors. AB - Radar coincidence imaging (RCI) is a high-resolution staring imaging technique without the limitation of relative motion between target and radar. The sparsity driven approaches are commonly used in RCI, while the prior knowledge of imaging models needs to be known accurately. However, as one of the major model errors, the gain-phase error exists generally, and may cause inaccuracies of the model and defocus the image. In the present report, the sparse auto-calibration method is proposed to compensate the gain-phase error in RCI. The method can determine the gain-phase error as part of the imaging process. It uses an iterative algorithm, which cycles through steps of target reconstruction and gain-phase error estimation, where orthogonal matching pursuit (OMP) and Newton's method are used, respectively. Simulation results show that the proposed method can improve the imaging quality significantly and estimate the gain-phase error accurately. PMID- 26528982 TI - A Model-Based Approach to Support Validation of Medical Cyber-Physical Systems. AB - Medical Cyber-Physical Systems (MCPS) are context-aware, life-critical systems with patient safety as the main concern, demanding rigorous processes for validation to guarantee user requirement compliance and specification-oriented correctness. In this article, we propose a model-based approach for early validation of MCPS, focusing on promoting reusability and productivity. It enables system developers to build MCPS formal models based on a library of patient and medical device models, and simulate the MCPS to identify undesirable behaviors at design time. Our approach has been applied to three different clinical scenarios to evaluate its reusability potential for different contexts. We have also validated our approach through an empirical evaluation with developers to assess productivity and reusability. Finally, our models have been formally verified considering functional and safety requirements and model coverage. PMID- 26528983 TI - Time-Efficient High-Rate Data Flooding in One-Dimensional Acoustic Underwater Sensor Networks. AB - Because underwater communication environments have poor characteristics, such as severe attenuation, large propagation delays and narrow bandwidths, data is normally transmitted at low rates through acoustic waves. On the other hand, as high traffic has recently been required in diverse areas, high rate transmission has become necessary. In this paper, transmission/reception timing schemes that maximize the time axis use efficiency to improve the resource efficiency for high rate transmission are proposed. The excellence of the proposed scheme is identified by examining the power distributions by node, rate bounds, power levels depending on the rates and number of nodes, and network split gains through mathematical analysis and numerical results. In addition, the simulation results show that the proposed scheme outperforms the existing packet train method. PMID- 26528984 TI - A Mixed Approach to Similarity Metric Selection in Affinity Propagation-Based WiFi Fingerprinting Indoor Positioning. AB - The weighted k-nearest neighbors (WkNN) algorithm is by far the most popular choice in the design of fingerprinting indoor positioning systems based on WiFi received signal strength (RSS). WkNN estimates the position of a target device by selecting k reference points (RPs) based on the similarity of their fingerprints with the measured RSS values. The position of the target device is then obtained as a weighted sum of the positions of the k RPs. Two-step WkNN positioning algorithms were recently proposed, in which RPs are divided into clusters using the affinity propagation clustering algorithm, and one representative for each cluster is selected. Only cluster representatives are then considered during the position estimation, leading to a significant computational complexity reduction compared to traditional, flat WkNN. Flat and two-step WkNN share the issue of properly selecting the similarity metric so as to guarantee good positioning accuracy: in two-step WkNN, in particular, the metric impacts three different steps in the position estimation, that is cluster formation, cluster selection and RP selection and weighting. So far, however, the only similarity metric considered in the literature was the one proposed in the original formulation of the affinity propagation algorithm. This paper fills this gap by comparing different metrics and, based on this comparison, proposes a novel mixed approach in which different metrics are adopted in the different steps of the position estimation procedure. The analysis is supported by an extensive experimental campaign carried out in a multi-floor 3D indoor positioning testbed. The impact of similarity metrics and their combinations on the structure and size of the resulting clusters, 3D positioning accuracy and computational complexity are investigated. Results show that the adoption of metrics different from the one proposed in the original affinity propagation algorithm and, in particular, the combination of different metrics can significantly improve the positioning accuracy while preserving the efficiency in computational complexity typical of two-step algorithms. PMID- 26528985 TI - A Cutting Pattern Recognition Method for Shearers Based on Improved Ensemble Empirical Mode Decomposition and a Probabilistic Neural Network. AB - In order to guarantee the stable operation of shearers and promote construction of an automatic coal mining working face, an online cutting pattern recognition method with high accuracy and speed based on Improved Ensemble Empirical Mode Decomposition (IEEMD) and Probabilistic Neural Network (PNN) is proposed. An industrial microphone is installed on the shearer and the cutting sound is collected as the recognition criterion to overcome the disadvantages of giant size, contact measurement and low identification rate of traditional detectors. To avoid end-point effects and get rid of undesirable intrinsic mode function (IMF) components in the initial signal, IEEMD is conducted on the sound. The end point continuation based on the practical storage data is performed first to overcome the end-point effect. Next the average correlation coefficient, which is calculated by the correlation of the first IMF with others, is introduced to select essential IMFs. Then the energy and standard deviation of the reminder IMFs are extracted as features and PNN is applied to classify the cutting patterns. Finally, a simulation example, with an accuracy of 92.67%, and an industrial application prove the efficiency and correctness of the proposed method. PMID- 26528986 TI - A Neural Network-Based Gait Phase Classification Method Using Sensors Equipped on Lower Limb Exoskeleton Robots. AB - An exact classification of different gait phases is essential to enable the control of exoskeleton robots and detect the intentions of users. We propose a gait phase classification method based on neural networks using sensor signals from lower limb exoskeleton robots. In such robots, foot sensors with force sensing registers are commonly used to classify gait phases. We describe classifiers that use the orientation of each lower limb segment and the angular velocities of the joints to output the current gait phase. Experiments to obtain the input signals and desired outputs for the learning and validation process are conducted, and two neural network methods (a multilayer perceptron and nonlinear autoregressive with external inputs (NARX)) are used to develop an optimal classifier. Offline and online evaluations using four criteria are used to compare the performance of the classifiers. The proposed NARX-based method exhibits sufficiently good performance to replace foot sensors as a means of classifying gait phases. PMID- 26528987 TI - A Novel Wireless Power Transfer-Based Weighed Clustering Cooperative Spectrum Sensing Method for Cognitive Sensor Networks. AB - In a cognitive sensor network (CSN), the wastage of sensing time and energy is a challenge to cooperative spectrum sensing, when the number of cooperative cognitive nodes (CNs) becomes very large. In this paper, a novel wireless power transfer (WPT)-based weighed clustering cooperative spectrum sensing model is proposed, which divides all the CNs into several clusters, and then selects the most favorable CNs as the cluster heads and allows the common CNs to transfer the received radio frequency (RF) energy of the primary node (PN) to the cluster heads, in order to supply the electrical energy needed for sensing and cooperation. A joint resource optimization is formulated to maximize the spectrum access probability of the CSN, through jointly allocating sensing time and clustering number. According to the resource optimization results, a clustering algorithm is proposed. The simulation results have shown that compared to the traditional model, the cluster heads of the proposed model can achieve more transmission power and there exists optimal sensing time and clustering number to maximize the spectrum access probability. PMID- 26528988 TI - Nitric Oxide Synthase in the Central Nervous System and Peripheral Organs of Stramonita haemastoma: Protein Distribution and Gene Expression in Response to Thermal Stress. AB - Nitric oxide (NO) is generated via the oxidation of l-arginine by the enzyme NO synthase (NOS) both in vertebrates and invertebrates. Three NOS isoforms, nNOS, iNOS and eNOS, are known in vertebrates, whereas a single NOS isoform is usually expressed in invertebrates, sharing structural and functional characteristics with nNOS or iNOS depending on the species. The present paper is focused on the constitutive Ca(2+)/calmodulin-dependent nNOS recently sequenced by our group in the neogastropod Stramonita haemastoma (ShNOS). In this paper we provide new data on cellular distribution of ShNOS in the CNS (pedal ganglion) and peripheral organs (osphradium, tentacle, eye and foot) obtained by WB, IF, CM and NADPHd. Results demonstrated that NOS-like proteins are widely expressed in sensory receptor elements, neurons and epithelial cells. The detailed study of NOS distribution in peripheral and central neurons suggested that NOS is both intracellular and presynaptically located. Present findings confirm that NO may have a key role in the central neuronal circuits of gastropods and in sensory perception. The physiological relevance of NOS enzymes in the same organs was suggested by thermal stress experiments demonstrating that the constitutive expression of ShNOS is modulated in a time- and organ-dependent manner in response to environmental stressors. PMID- 26528989 TI - Fish Synucleins: An Update. AB - Synucleins (syns) are a family of proteins involved in several human neurodegenerative diseases and tumors. Since the first syn discovery in the brain of the electric ray Torpedo californica, members of the same family have been identified in all vertebrates and comparative studies have indicated that syn proteins are evolutionary conserved. No counterparts of syns were found in invertebrates suggesting that they are vertebrate-specific proteins. Molecular studies showed that the number of syn members varies among vertebrates. Three genes encode for alpha-, beta- and gamma-syn in mammals and birds. However, a variable number of syn genes and encoded proteins is expressed or predicted in fish depending on the species. Among biologically verified sequences, four syn genes were identified in fugu, encoding for alpha, beta and two gamma (gamma1 and gamma2) isoforms, whereas only three genes are expressed in zebrafish, which lacks alpha-syn gene. The list of "non verified" sequences is much longer and is often found in sequence databases. In this review we provide an overview of published papers and known syn sequences in agnathans and fish that are likely to impact future studies in this field. Indeed, fish models may play a key role in elucidating some of the molecular mechanisms involved in physiological and pathological functions of syn proteins. PMID- 26528990 TI - Structure Elucidation and in Vitro Toxicity of New Azaspiracids Isolated from the Marine Dinoflagellate Azadinium poporum. AB - Two strains of Azadinium poporum, one from the Korean West coast and the other from the North Sea, were mass cultured for isolation of new azaspiracids. Approximately 0.9 mg of pure AZA-36 (1) and 1.3 mg of pure AZA-37 (2) were isolated from the Korean (870 L) and North Sea (120 L) strains, respectively. The structures were determined to be 3-hydroxy-8-methyl-39-demethyl-azaspiracid-1 (1) and 3-hydroxy-7,8-dihydro-39-demethyl-azaspiracid-1 (2) by 1H- and (13)C-NMR. Using the Jurkat T lymphocyte cell toxicity assay, (1) and (2) were found to be 6 and 3-fold less toxic than AZA-1, respectively. PMID- 26528991 TI - Effects of Cylindrospermopsin Producing Cyanobacterium and Its Crude Extracts on a Benthic Green Alga-Competition or Allelopathy? AB - Cylindrospermopsin (CYN) is a toxic secondary metabolite produced by filamentous cyanobacteria which could work as an allelopathic substance, although its ecological role in cyanobacterial-algal assemblages is mostly unclear. The competition between the CYN-producing cyanobacterium Chrysosporum (Aphanizomenon) ovalisporum, and the benthic green alga Chlorococcum sp. was investigated in mixed cultures, and the effects of CYN-containing cyanobacterial crude extract on Chlorococcum sp. were tested by treatments with crude extracts containing total cell debris, and with cell debris free crude extracts, modelling the collapse of a cyanobacterial water bloom. The growth inhibition of Chlorococcum sp. increased with the increasing ratio of the cyanobacterium in mixed cultures (inhibition ranged from 26% to 87% compared to control). Interestingly, inhibition of the cyanobacterium growth also occurred in mixed cultures, and it was more pronounced than it was expected. The inhibitory effects of cyanobacterial crude extracts on Chlorococcum cultures were concentration-dependent. The presence of C. ovalisporum in mixed cultures did not cause significant differences in nutrient content compared to Chlorococcum control culture, so the growth inhibition of the green alga could be linked to the presence of CYN and/or other bioactive compounds. PMID- 26528992 TI - Structure of an Amino Acid-Decorated Exopolysaccharide Secreted by a Vibrio alginolyticus Strain. AB - Vibrio alginolyticus (CNCM I-4994) secretes an exopolysaccharide that can be used as an ingredient in cosmetic applications. The structure was resolved using chromatography and one- and two-dimensional NMR spectroscopy experiments. The results show that the carbohydrate backbone is made of two residues: d galacturonic acid and N-acetyl-d-glucosamine (GlcNac), which together constitute a tetrasaccharide repetition unit: [->3)-alpha-d-GalA-(1->4)-alpha-d-GalA-(1->3) alpha-d-GalA-(1->3)-beta-GlcNAc(1->]. Two amino acids, alanine and serine, are linked to GalA residues via amido linkages. The position and the distribution of the amino acids were characterized by two-dimensional NMR spectroscopy. To our knowledge, this is the first description of a structure for a marine exopolysaccharide decorated with an amino acid. PMID- 26528993 TI - Evaluation of Rural Primary Health Care in Western China: A Cross-Sectional Study. AB - PURPOSE: China's Ministry of Health has enacted Rural Primary Health Care Program (2001-2010) (HCP) guidelines to improve the quality of people's health. However, the program's success in Western China remains unevaluated. Thus, this study aims to begin to fill that gap by analyzing the provision and utilization of Rural Primary Health Care (RPHC) in Western China. METHODS: A cross-sectional study was conducted to collect secondary data on the socio-economic characteristics, system construction, services use and implementation of RPHC, and the residents' health status of the sampled areas. Four hundred counties from 31 provinces in China were selected via stratified random sampling, including 171 counties from 12 Western provinces. Twenty-seven analysis indicators, covering system construction, services use and implementation of RPHC were chosen to assess Western China's primary health quality. Analysis of Variance (ANOVA) and Least Significant Difference (LSD) methods were used to measure the RPHC disparities between Western and Eastern and Central China. Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) was used to rank Western, Eastern and Central internal provinces regarding quality of their RPHC. RESULTS: Of the 27 indicators, 13 (48.15%) were below the standard in Western China. These focused on rural health service system construction, Chinese medicine services, and public health. In the comparison between Western, Central and Eastern China, 12 indicators had statistical significance (p < 0.05), and using LSD to compare between Western and Eastern China, all indicators were statistically significant (p < 0.05), demonstrating regional disparities. Xinjiang Province's RPHC ranked highest overall, and Yunnan Province ranked the lowest, indicating the internal differences within the 12 Western provinces; and Western provinces' Ci value was lower than that of Eastern and Central China overall. CONCLUSION: Western China's RPHC has proceeded well, but remains weaker than that of Eastern and Central China. Differences within Western internal provinces threaten the successful implementation of RPHC. PMID- 26528994 TI - Regional Risk Evaluation of Flood Disasters for the Trunk-Highway in Shaanxi, China. AB - Due to the complicated environment there are various types of highway disasters in Shaanxi Province (China). The damages caused are severe, losses are heavy, and have rapidly increased over the years, especially those caused by flood disasters along the rivers in mountainous areas. Therefore, research on risk evaluations, which play important roles in the prevention and mitigation of highway disasters are very important. An evaluation model was established based on the superposition theory of regional influencing factors to highway flood disasters. Based on the formation mechanism and influencing factors of highway flood disasters, the main influencing factors were selected. These factors include rainstorms, terrain slopes, soil types, vegetation coverage and regional river density, which are based on evaluation indexes from climate conditions and underlying surface of the basin. A regional risk evaluation of highway flood disasters in Shaanxi was established using GIS. The risk index was divided into five levels using statistical methods, in accordance with the regional characteristics of highway flood disasters. Considering the difference in upfront investments, road grade, etc, between expressways and trunk-highways in China, a regional risk evaluation of trunk-highway flood disasters was completed. The evaluation results indicate that the risk evaluation is consistent with the actual situation. PMID- 26528995 TI - Lactic Acid Fermentation, Urea and Lime Addition: Promising Faecal Sludge Sanitizing Methods for Emergency Sanitation. AB - In this research, three faecal sludge sanitizing methods-lactic acid fermentation, urea treatment and lime treatment-were studied for application in emergency situations. These methods were investigated by undertaking small scale field trials with pit latrine sludge in Blantyre, Malawi. Hydrated lime was able to reduce the E. coli count in the sludge to below the detectable limit within 1 h applying a pH > 11 (using a dosage from 7% to 17% w/w, depending faecal sludge alkalinity), urea treatment required about 4 days using 2.5% wet weight urea addition, and lactic acid fermentation needed approximately 1 week after being dosed with 10% wet weight molasses (2 g (glucose/fructose)/kg) and 10% wet weight pre-culture (99.8% pasteurised whole milk and 0.02% fermented milk drink containing Lactobacillus casei Shirota). Based on Malawian prices, the cost of sanitizing 1 m3 of faecal sludge was estimated to be ?32 for lactic acid fermentation, ?20 for urea treatment and ?12 for hydrated lime treatment. PMID- 26528996 TI - Delayed Response of Lake Area Change to Climate Change in Siling Co Lake, Tibetan Plateau, from 2003 to 2013. AB - The Tibetan Plateau is a key area for research on global environmental changes. During the past 50 years, the climate in the Siling Co lake area has become continuously warmer and wetter, which may have further caused the increase in Siling Co lake area. Based on the Siling Co lake area (2003 to 2013) and climate data acquired from the Xainza and Baingoin meteorological stations (covering 1966 to 2013), we analyzed the delayed responses of lake area changes to climate changes through grey relational analysis. The following results were obtained: (1) The Siling Co lake area exhibited a rapid expansion trend from 2003 to 2013. The lake area increased to 2318 km2, with a growth ratio of 14.6% and an annual growth rate of 26.84 km2.year(-1); (2) The rate of air temperature increase was different in the different seasons. The rate in the cold season was about 0.41 degrees C per ten years and 0.32 degrees C in hot season. Precipitation evidently increased, with a change rate of 17.70 mm per ten years in the hot season and a slight increase with a change rate of 2.36 mm per ten years in the cold season. Pan evaporation exhibited evidently decreasing trends in both the hot and cold seasons, with rates of -33.35 and -14.84 mm per ten years, respectively; (3) An evident delayed response of lake area change to climate change is observed, with a delay time of approximately one to two years. PMID- 26528997 TI - Associations of MMP1, MMP2 and MMP3 Genes Polymorphism with Coal Workers' Pneumoconiosis in Chinese Han Population. AB - Coal workers' pneumoconiosis (CWP) has been associated with abnormalities in the extracellular matrix remodeling, as well as aberrant matrix metalloproteinases (MMPs) in lung tissues. We investigated the association of three functional polymorphisms in MMP gene promoters (MMP1 rs1799750, MMP2 rs2285053 and MMP3 rs522616) with the risk of CWP. A total of 693 CWP cases and 690 controls were included in a case-control study. Genotype analysis was performed by the TaqMan method. Statistically significant differences were found in distributions of MMP3 rs522616 under a recessive model (p = 0.047) between CWP cases and controls. In the stratification analysis, individuals with MMP3 rs522616 GG genotype decreased the risk of CWP (adjusted OR = 0.72, 95% CI = 0.52-0.99) compared to those with AA/AG genotype obviously, particularly among subgroups of no smokers (adjusted OR = 0.64, 95% CI = 0.41-1.00). Furthermore, serum MMP3 protein levels measured with enzyme-linked immune-sorbent assay in the control group was significantly lower than that in the CWP groups (p = 0.02). Extremely lower MMP3 among subjects with the rs522616 GG or AG genotype compared with the AA genotype carriers (p < 0.05, p < 0.01 respectively) in the normal serum. These findings indicate that the MMP3 rs522616 polymorphism may contribute to the etiology of CWP in the Chinese population and MMP3 might be a potential diagnostic biomarker for CWP, additional independent studies are warranted to validate our findings in different populations as well as in a larger series. PMID- 26528998 TI - Association between Vitamin D Receptor Gene Polymorphisms with Childhood Temporal Lobe Epilepsy. AB - Vitamin D (VD) is implicated in multiple aspects of human physiology and vitamin D receptor (VDR) polymorphisms are associated with a variety of neuropsychiatric disorders. Although VD deficiency is highly prevalent in epilepsy patients and converging evidence indicates a role for VD in the development of epilepsy, no data is available on the possible relationship between epilepsy and genetic variations of VDR. In this study, 150 controls and 82 patients with temporal lobe epilepsy (TLE) were genotyped for five common VDR polymorphisms (Cdx-2, FokI, BsmI, ApaI and TaqI) by the polymerase chain reaction-ligase detection reaction method. Our results revealed that the frequency of FokI AC genotype was significantly higher in the control group than in the patients (p = 0.003, OR = 0.39, 95% CI = 0.21-0.73), whereas the AA genotype of ApaI SNP was more frequent in patients than in controls (p = 0.018, OR = 2.92, 95% CI = 1.2-7.1). However, no statistically significant association was found between Cdx-2, BsmI and TaqI polymorphisms and epilepsy. Additionally, in haplotype analysis, we found the haplotype GAT (BsmI/ApaI/TaqI) conferred significantly increased risk for developing TLE (p = 0.039, OR = 1.62, 95% CI = 1.02-2.56). As far as we know, these results firstly underline the importance of VDR polymorphisms for the genetic susceptibility to epilepsy. PMID- 26528999 TI - Relationship between Objectively Measured Transportation Behaviors and Health Characteristics in Older Adults. AB - This study used objective Global Positioning Systems (GPS) to investigate the relationship between pedestrian and vehicle trips to physical, cognitive, and psychological functioning in older adults living in retirement communities. Older adults (N = 279; mean age = 83 +/- 6 years) wore a GPS and accelerometer for 6 days. Participants completed standard health measures. The Personal Activity and Location Measurement System (PALMS) was used to calculate the average daily number of trips, distance, and minutes traveled for pedestrian and vehicle trips from the combined GPS and accelerometer data. Linear mixed effects regression models explored relationships between these transportation variables and physical, psychological and cognitive functioning. Number, distance, and minutes of pedestrian trips were positively associated with physical and psychological functioning but not cognitive functioning. Number of vehicle trips was negatively associated with fear of falls; there were no other associations between the vehicle trip variables and functioning. Vehicle travel did not appear to be related to functioning in older adults in retirement communities except that fear of falling was related to number of vehicle trips. Pedestrian trips had moderate associations with multiple physical and psychological functioning measures, supporting a link between walking and many aspects of health in older adults. PMID- 26529000 TI - Bacteria that Travel: The Quality of Aircraft Water. AB - The travelling population is increasing globally year on year. International tourist arrival figures reached 1087 million in 2013 and 1133 million in 2014; of which 53% and 54% respectively accounted for air transport. The water on board aircraft is sourced from surface or ground water; piped to a central filling point and distributed to each aircraft by water service vehicles at the home base or at the destination airport. The purpose of this study was to ascertain the microbial, chemical (pH; Total and Free chlorine) and physical (temperature) quality of water from two aircraft, long- and short-haul, as well as from the original water source and the water service vehicle. A total of 154 water samples were collected and analysed. Long-haul flights were found to be significantly poorer in terms of microbial quality than short haul flights (p = 0.015). Furthermore, correlation and regression analysis showed that the water service vehicle was a significant source of increased microbial load in aircraft. Microbial diversity was also demonstrated, with 37 bacterial species identified belonging to eight classes: gamma-Proteobacteria; beta-Proteobacteria; alpha Proteobacteria; Bacilli; Actinobacteria; Flavobacteria; Sphingobacteria and Cytophaga; using phenotypic and 16S rDNA sequence-based analysis. We present a novel quantified study of aircraft-related potable water supplies. PMID- 26529001 TI - Human Health and Ecological Risk Assessment of 16 Polycyclic Aromatic Hydrocarbons in Drinking Source Water from a Large Mixed-Use Reservoir. AB - Reservoirs play an important role in living water supply and irrigation of farmlands, thus the water quality is closely related to public health. However, studies regarding human health and ecological risk assessment of polycyclic aromatic hydrocarbons (PAHs) in the waters of reservoirs are very few. In this study, Shitou Koumen Reservoir which supplies drinking water to 8 million people was investigated. Sixteen priority PAHs were analyzed in a total of 12 water samples. In terms of the individual PAHs, the average concentration of Fla, which was 5.66 * 10(-1) MUg/L, was the highest, while dibenz(a,h)anthracene which was undetected in any of the water samples was the lowest. Among three PAH compositional patterns, the concentration of low-molecular-weight and 4-ring PAHs was dominant, accounting for 94%, and the concentration of the total of 16 PAHs was elevated in constructed-wetland and fish-farming areas. According to the calculated risk quotients, little or no adverse effects were posed by individual and complex PAHs in the water on the aquatic ecosystem. In addition, the results of hazard quotients for non-carcinogenic risk also showed little or no negative impacts on the health of local residents. However, it could be concluded from the carcinogenic risk results that chrysene and complex PAHs in water might pose a potential carcinogenic risk to local residents. Moreover, the possible sources of PAHs were identified as oil spills and vehicular emissions, as well as the burning of biomass and coal. PMID- 26529002 TI - Prevalence and Associated Factors of Passive Smoking among Women in Jilin Province, China: A Cross-Sectional Study. AB - BACKGROUND: The present study aimed to investigate the prevalence and associated socio-demographic factors of passive smoking among women in Jilin Province, China. METHODS: A cross-sectional study was conducted in 2012, using a self reported questionnaire interview. A representative sample of 9788 non-smoking women aged 18-79 years was collected in Jilin Province of China by a multistage stratified random cluster sampling design. Descriptive data analysis and 95% confidence intervals (CI) of prevalence/frequency were conducted. Multivariable logistic regressions were used to examine the associated socio-demographic factors of passive smoking. RESULTS: The overall prevalence of passive smoking among non-smoking women in Jilin Province was 60.6% (95% CI: 59.3-61.8), 58.3% (95% CI: 56.7-59.9) from urban areas, and 63.4% (95% CI: 61.6-65.3) from rural areas. Twenty-six percent (95% CI: 24.9-27.1) of the non-smoking women reported daily passive smoking, of which 42.9% (95% CI: 41.6-44.1) reported passive smoking at home, and 5.1% (95% CI: 4.5-5.7) reported passive smoking in restaurants. Women in urban areas were less likely to be passive smokers than those in rural ones (OR-Odds Ratio: 0.825, 95% CI: 0.729-0.935), elderly women were less likely to be passive smokers than younger women (55-64 years OR: 0.481, 95% CI: 0.342-0.674; 65-79 years OR: 0.351, 95% CI: 0.241-0.511). Seperated/divorced women were less likely to be passive smokers (OR: 0.701, 95% CI: 0.500-0.982), and widowed women (OR: 0.564, 95%CI: 0.440-0.722), as the married were the reference group. Retired women second-hand smoked due to environmental causes significantly less than manual workers (OR: 0.810, 95% CI: 0.708-0.928). Women with a monthly family income of more than 5000 RMB were less likely to be passive smokers than those with an income less than 500 RMB (OR: 0.615, 95% CI: 0.432-0.876). CONCLUSIONS: The prevalence of passive smoking is lower than that reported in 2010 Global Adult Tobacco Survey (GATS) China, but passive smoking is still prevalent and has been an acute public health problem among non-smoking women in Jilin Province, China. Our findings suggest an urgent need for tobacco control and the efforts of public health should be both comprehensive and focus on high-risk populations in Jilin Province, China. PMID- 26529004 TI - Validation of the MINI (DSM IV) Tool for the Assessment of Alcohol Dependence among Young People in Northern Tanzania Using the Alcohol Biomarker Phosphatidylethanol (PEth). AB - The alcohol dependence section of the Mini International Neuropsychiatric Interview questionnaire (MINI) has not been evaluated in young Africans. We applied the MINI in a cross-sectional study of 202 alcohol users from northern Tanzania, aged 18-24 years (103 male casual workers and 99 students), and validated it against phophatidylethanol (PEth) at a cut-off suggesting heavy chronic alcohol use (>=0.30 umol/L). Blood was assayed for PEth (16:0/18:1 subform) by liquid chromatography-tandem mass spectrometry. The MINI dependence criteria (>=3 positive responses) were met by 39% participants although their PEth levels were low. Contrary, many young people with high PEth levels were not classified as dependent. The sensitivity of the MINI ranged from 0% to 69% (female students and male workers, respectively) and specificity from 52% to 85% (workers and female students, respectively). The highest AUROC (0.68) occurred with a cut-off of >=4 positive responses. A modified MINI with three affirmative responses to five questions increased specificity to 92%-97%; however, sensitivity remained low. The performance of the MINI in detecting dependence among young people from northern-Tanzania is unsatisfactory. Specificity was improved using a modified version but sensitivity remained low. An accurate tool for the diagnosis of alcohol dependence is needed for epidemiological and clinical purposes. PMID- 26529005 TI - Investigation of Plasma Treatment on Micro-Injection Moulded Microneedle for Drug Delivery. AB - Plasma technology has been widely used to increase the surface energy of the polymer surfaces for many industrial applications; in particular to increase in wettability. The present work was carried out to investigate how surface modification using plasma treatment modifies the surface energy of micro injection moulded microneedles and its influence on drug delivery. Microneedles of polyether ether ketone and polycarbonate and have been manufactured using micro-injection moulding and samples from each production batch have been subsequently subjected to a range of plasma treatment. These samples were coated with bovine serum albumin to study the protein adsorption on these treated polymer surfaces. Sample surfaces structures, before and after treatment, were studied using atomic force microscope and surface energies have been obtained using contact angle measurement and calculated using the Owens-Wendt theory. Adsorption performance of bovine serum albumin and release kinetics for each sample set was assessed using a Franz diffusion cell. Results indicate that plasma treatment significantly increases the surface energy and roughness of the microneedles resulting in better adsorption and release of BSA. PMID- 26529003 TI - MicroRNAs in Breastmilk and the Lactating Breast: Potential Immunoprotectors and Developmental Regulators for the Infant and the Mother. AB - Human milk (HM) is the optimal source of nutrition, protection and developmental programming for infants. It is species-specific and consists of various bioactive components, including microRNAs, small non-coding RNAs regulating gene expression at the post-transcriptional level. microRNAs are both intra- and extra-cellular and are present in body fluids of humans and animals. Of these body fluids, HM appears to be one of the richest sources of microRNA, which are highly conserved in its different fractions, with milk cells containing more microRNAs than milk lipids, followed by skim milk. Potential effects of exogenous food-derived microRNAs on gene expression have been demonstrated, together with the stability of milk-derived microRNAs in the gastrointestinal tract. Taken together, these strongly support the notion that milk microRNAs enter the systemic circulation of the HM fed infant and exert tissue-specific immunoprotective and developmental functions. This has initiated intensive research on the origin, fate and functional significance of milk microRNAs. Importantly, recent studies have provided evidence of endogenous synthesis of HM microRNA within the human lactating mammary epithelium. These findings will now form the basis for investigations of the role of microRNA in the epigenetic control of normal and aberrant mammary development, and particularly lactation performance. PMID- 26529006 TI - Effects of Fructans from Mexican Agave in Newborns Fed with Infant Formula: A Randomized Controlled Trial. AB - BACKGROUND: The importance of prebiotics consumption is increasing all over the world due to their beneficial effects on health. Production of better prebiotics from endemic plants raises possibilities to enhance nutritional effects in vulnerable population groups. Fructans derived from Agave Plant have demonstrated their safety and efficacy as prebiotics in animal models. Recently, the safety in humans of two fructans obtained from Agave tequilana (Metlin((r)) and Metlos((r))) was demonstrated. METHODS: This study aimed to demonstrate the efficacy as prebiotics of Metlin((r)) and Metlos((r)) in newborns of a randomized, double blind, controlled trial with a pilot study design. Biological samples were taken at 20 +/- 7 days, and three months of age from healthy babies. Outcomes of efficacy include impact on immune response, serum ferritin, C reactive protein, bone metabolism, and gut bacteria changes. RESULTS: There were differences statistically significant for the groups of infants fed only with infant formula and with formula enriched with Metlin((r)) and Metlos((r)). CONCLUSIONS: Our results support the efficacy of Metlin((r)) and Metlos((r)) as prebiotics in humans, and stand the bases to recommend their consumption. TRIAL REGISTRATION: ClinicalTrials.gov, NCT 01251783. PMID- 26529007 TI - Iron Absorption from Two Milk Formulas Fortified with Iron Sulfate Stabilized with Maltodextrin and Citric Acid. AB - BACKGROUND: Fortification of milk formulas with iron is a strategy widely used, but the absorption of non-heme iron is low. The purpose of this study was to measure the bioavailability of two iron fortified milk formulas designed to cover toddlers' nutritional needs. These milks were fortified with iron sulfate stabilized with maltodextrin and citric acid. METHODS: 15 women (33-47 years old) participated in study. They received on different days, after an overnight fast, 200 mL of Formula A; 200 mL of Formula B; 30 mL of a solution of iron and ascorbic acid as reference dose and 200 mL of full fat cow's milk fortified with iron as ferrous sulfate. Milk formulas and reference dose were labeled with radioisotopes (59)Fe or (55)Fe, and the absorption of iron measured by erythrocyte incorporation of radioactive Fe. RESULTS: The geometric mean iron absorption corrected to 40% of the reference dose was 20.6% for Formula A and 20.7% for Formula B, versus 7.5% of iron fortified cow's milk (p < 0.001). The post hoc Sheffe indeed differences between the milk formulas and the cow's milk (p < 0.001). CONCLUSION: Formulas A and B contain highly bioavailable iron, which contributes to covering toddlers' requirements of this micronutrient. PMID- 26529008 TI - Increased Intraepithelial Valpha24 Invariant NKT Cells in the Celiac Duodenum. AB - Celiac Disease (CD) is an interferon (IFN)gamma-mediated duodenal hypersensitivity to wheat gluten occurring in genetically predisposed individuals. Gluten-free diet (GFD) leads to a complete remission of the disease. Valpha24-restricted invariant NKT (iNKT) cells are important to maintain immune homeostasis in the gut mucosa because of their unique capacity to rapidly produce large quantities of both T-helper (Th)1 and Th2 cytokines upon stimulation. We studied the presence of these cells in the CD duodenum. Duodenal biopsies were obtained from 45 untreated-CD patients (uCD), 15 Gluten Free Diet-CD patients (GFD-CD), 44 non-inflamed non-CD controls (C-controls) and 15 inflamed non-CD controls (I-controls). Two populations from Spain and Argentina were recruited. Messenger RNA (mRNA) expression of Valpha24-Jalpha18 (invariant TCRalpha chain of human iNKT cells), IFNgamma and intracellular transcription factor Forkhead Box P3 (Foxp3), and flow cytometry intraepithelial lymphocyte (IEL) profile were determined. Both uCD and GFD-CD patients had higher Valpha24-Jalpha18 mRNA levels than non-CD controls (I and C-controls). The expression of Valpha24-Jalpha18 correlated with Marsh score for the severity of mucosal lesion and also with increased mRNA IFNgamma levels. uCD and GFD-CD patients had decreased mRNA expression of FoxP3 but increased expression of Valpha24-Jalpha18, which revealed a CD-like molecular profile. Increased numbers of iNKT cells were confirmed by flow cytometry within the intraepithelial lymphocyte compartment of uCD and GFD CD patients and correlated with Valpha24-Jalpha18 mRNA expression. In conclusion, we have found an increased number of iNKT cells in the duodenum from both uCD and GFD-CD patients, irrespective of the mucosal status. A CD-like molecular profile, defined by an increased mRNA expression of Valpha24-Jalpha18 together with a decreased expression of FoxP3, may represent a pro-inflammatory signature of the CD duodenum. PMID- 26529009 TI - The Effect of Plant Proteins Derived from Cereals and Legumes on Heme Iron Absorption. AB - The aim of this study is to determine the effect of proteins from cereals and legumes on heme iron (Fe) absorption. The absorption of heme Fe without its native globin was measured. Thirty adult females participated in two experimental studies (15 per study). Study I focused on the effects of cereal proteins (zein, gliadin and glutelin) and study II on the effects of legume proteins (soy, pea and lentil) on heme Fe absorption. When heme was given alone (as a control), study I and II yielded 6.2% and 11.0% heme absorption (p > 0.05). In study I, heme Fe absorption was 7.2%, 7.5% and 5.9% when zein, gliadin and glutelin were added, respectively. From this, it was concluded that cereal proteins did not affect heme Fe absorption. In study II, heme Fe absorption was 7.3%, 8.1% and 9.1% with the addition of soy, pea and lentil proteins, respectively. Only soy proteins decreased heme Fe absorption (p < 0.05). These results suggest that with the exception of soy proteins, which decreased absorption, proteins derived from cereals and legumes do not affect heme Fe absorption. PMID- 26529010 TI - Polyphenol Compound as a Transcription Factor Inhibitor. AB - A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor-DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein-protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and beta-catenin/T cell factor (Tcf)). PMID- 26529011 TI - Effects of Four-Week Supplementation with a Multi-Vitamin/Mineral Preparation on Mood and Blood Biomarkers in Young Adults: A Randomised, Double-Blind, Placebo Controlled Trial. AB - This study explored the effects of four-week multi-vitamin and mineral (MVM) supplementation on mood and neurocognitive function in healthy, young adults. Fifty-eight healthy adults, 18-40 years of age (M = 25.82 years, SD = 4.87) participated in this randomised, double-blind, placebo-controlled trial, in which mood and blood biomarkers were assessed at baseline and after four weeks of supplementation. Compared to placebo, MVM supplementation was associated with significantly lowered homocysteine and increased blood B-vitamin levels (p < 0.01). MVM treatment was also associated with significantly improved mood, as measured by reduced scores on the "depression-dejection" subscale of the Profile of Mood States (p = 0.018). These findings suggest that the four weeks of MVM supplementation may have beneficial effects on mood, underpinned by elevated B vitamins and lowered homocysteine in healthy young adults. PMID- 26529012 TI - Nodularia spumigena peptides--accumulation and effect on aquatic invertebrates. AB - Thus far, the negative effects of Nodularia spumigena blooms on aquatic organisms have been mainly attributed to the production of the hepatotoxic nodularin (NOD). In the current work, the accumulation of other N. spumigena metabolites in blue mussels and crustaceans, and their effect on Thamnocephalus platyurus and Artemia franciscana, were examined. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses provided evidence that both blue mussels collected after a cyanobacterial bloom in the Baltic Sea and the crustaceans exposed under laboratory conditions to N. spumigena extract accumulated the cyclic anabaenopeptins (APs). In the crustaceans, the linear peptides, spumigins (SPUs) and aeruginosins (AERs), were additionally detected. Exposure of T. platyurus and A. franciscana to N. spumigena extract confirmed the negative effect of nodularin on the organisms. However, high numbers of dead crustaceans were also recorded in the nodularin-free fraction, which contained protease inhibitors classified to spumigins and aeruginosins. These findings indicate that cyanobacterial toxicity to aquatic organisms is a complex phenomenon and the induced effects can be attributed to diverse metabolites, not only to the known hepatotoxins. PMID- 26529013 TI - Polyketides, toxins and pigments in Penicillium marneffei. AB - Penicillium marneffei (synonym: Talaromyces marneffei) is the most important pathogenic thermally dimorphic fungus in China and Southeastern Asia. The HIV/AIDS pandemic, particularly in China and other Southeast Asian countries, has led to the emergence of P. marneffei infection as an important AIDS-defining condition. Recently, we published the genome sequence of P. marneffei. In the P. marneffei genome, 23 polyketide synthase genes and two polyketide synthase-non ribosomal peptide synthase hybrid genes were identified. This number is much higher than those of Coccidioides immitis and Histoplasma capsulatum, important pathogenic thermally dimorphic fungi in the Western world. Phylogenetically, these polyketide synthase genes were distributed evenly with their counterparts found in Aspergillus species and other fungi, suggesting that polyketide synthases in P. marneffei did not diverge from lineage-specific gene duplication through a recent expansion. Gene knockdown experiments and ultra-high performance liquid chromatography-photodiode array detector/electrospray ionization-quadruple time of flight-mass spectrometry analysis confirmed that at least four of the polyketide synthase genes were involved in the biosynthesis of various pigments in P. marneffei, including melanin, mitorubrinic acid, mitorubrinol, monascorubrin, rubropunctatin, citrinin and ankaflavin, some of which were mycotoxins and virulence factors of the fungus. PMID- 26529014 TI - Acupoint injection of onabotulinumtoxin A for migraines. AB - Onabotulinumtoxin A (BoNTA) has been reported to be effective in the therapy for migraines. Acupuncture has been used worldwide for the treatment of migraine attacks. Injection of a small amount of drug at acupuncture points is an innovation as compared to traditional acupuncture. The purpose of this study was to evaluate and compare the effectiveness of fixed (muscle)-site and acupoint site injections of BoNTA for migraine therapy in a randomized, double-blinded, placebo-controlled clinical trial extending over four months. Subjects with both episodic and chronic migraines respectively received a placebo (n = 19) or BoNTA (2.5 U each site, 25 U per subject) injection at fixed-sites (n = 41) including occipitofrontalis, corrugator supercilii, temporalis and trapeziue, or at acupoint-sites (n = 42) including Yintang (EX-HN3), Taiyang (EX-HN5), Baihui (GV20), Shuaigu (GB8), Fengchi (GB20) and Tianzhu (BL10). The variations between baseline and BoNTA post-injection for four months were calculated monthly as outcome measures. BoNTA injections at fixed-sites and acupoint-sites significantly reduced the migraine attack frequency, intensity, duration and associated symptoms for four months compared with placebo (p < 0.01). The efficacy of BoNTA for migraines in the acupoint-site group (93% improvement) was more significant than that in the fixed-site group (85% improvement) (p < 0.01). BoNTA administration for migraines is effective, and at acupoint-sites shows more efficacy than at fixed-sites. Further blinded studies are necessary to establish the efficacy of a low dose toxin (25 U) introduced with this methodology in chronic and episodic migraines. PMID- 26529015 TI - The Saccharomyces boulardii CNCM I-745 strain shows protective effects against the B. anthracis LT toxin. AB - The probiotic yeast Saccharomyces boulardii (S. boulardii) has been prescribed for the prophylaxis and treatment of several infectious diarrheal diseases. Gastrointestinal anthrax causes fatal systemic disease. In the present study, we investigated the protective effects conferred by Saccharomyces boulardii CNCM I 745 strain on polarized T84 columnar epithelial cells intoxicated by the lethal toxin (LT) of Bacillus anthracis. Exposure of polarized T84 cells to LT affected cell monolayer integrity, modified the morphology of tight junctions and induced the formation of actin stress fibers. Overnight treatment of cells with S. boulardii before incubation with LT maintained the integrity of the monolayers, prevented morphological modification of tight junctions, restricted the effects of LT on actin remodeling and delayed LT-induced MEK-2 cleavage. Mechanistically, we demonstrated that in the presence of S. boulardii, the medium is depleted of both LF and PA sub-units of LT and the appearance of a cleaved form of PA. Our study highlights the potential of the S. boulardii CNCM I-745 strain as a prophylactic agent against the gastrointestinal form of anthrax. PMID- 26529016 TI - Honeybee venom proteome profile of queens and winter bees as determined by a mass spectrometric approach. AB - Venoms of invertebrates contain an enormous diversity of proteins, peptides, and other classes of substances. Insect venoms are characterized by a large interspecific variation resulting in extended lists of venom compounds. The venom composition of several hymenopterans also shows different intraspecific variation. For instance, venom from different honeybee castes, more specifically queens and workers, shows quantitative and qualitative variation, while the environment, like seasonal changes, also proves to be an important factor. The present study aimed at an in-depth analysis of the intraspecific variation in the honeybee venom proteome. In summer workers, the recent list of venom proteins resulted from merging combinatorial peptide ligand library sample pretreatment and targeted tandem mass spectrometry realized with a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS/MS). Now, the same technique was used to determine the venom proteome of queens and winter bees, enabling us to compare it with that of summer bees. In total, 34 putative venom toxins were found, of which two were never described in honeybee venoms before. Venom from winter workers did not contain toxins that were not present in queens or summer workers, while winter worker venom lacked the allergen Api m 12, also known as vitellogenin. Venom from queen bees, on the other hand, was lacking six of the 34 venom toxins compared to worker bees, while it contained two new venom toxins, in particularly serine proteinase stubble and antithrombin-III. Although people are hardly stung by honeybees during winter or by queen bees, these newly identified toxins should be taken into account in the characterization of a putative allergic response against Apis mellifera stings. PMID- 26529017 TI - Effects of Mycotoxins on mucosal microbial infection and related pathogenesis. AB - Mycotoxins are fungal secondary metabolites detected in many agricultural commodities and water-damaged indoor environments. Susceptibility to mucosal infectious diseases is closely associated with immune dysfunction caused by mycotoxin exposure in humans and other animals. Many mycotoxins suppress immune function by decreasing the proliferation of activated lymphocytes, impairing phagocytic function of macrophages, and suppressing cytokine production, but some induce hypersensitive responses in different dose regimes. The present review describes various mycotoxin responses to infectious pathogens that trigger mucosa associated diseases in the gastrointestinal and respiratory tracts of humans and other animals. In particular, it focuses on the effects of mycotoxin exposure on invasion, pathogen clearance, the production of cytokines and immunoglobulins, and the prognostic implications of interactions between infectious pathogens and mycotoxin exposure. PMID- 26529018 TI - Role of the Polycystins in Cell Migration, Polarity, and Tissue Morphogenesis. AB - Cystic kidney diseases (CKD) is a class of disorders characterized by ciliary dysfunction and, therefore, belonging to the ciliopathies. The prototype CKD is autosomal dominant polycystic kidney disease (ADPKD), whose mutated genes encode for two membrane-bound proteins, polycystin-1 (PC-1) and polycystin-2 (PC-2), of unknown function. Recent studies on CKD-associated genes identified new mechanisms of morphogenesis that are central for establishment and maintenance of proper renal tubular diameter. During embryonic development in the mouse and lower vertebrates a convergent-extension (CE)-like mechanism based on planar cell polarity (PCP) and cellular intercalation is involved in "sculpting" the tubules into a narrow and elongated shape. Once the appropriate diameter is established, further elongation occurs through oriented cell division (OCD). The polycystins (PCs) regulate some of these essential processes. In this review we summarize recent work on the role of PCs in regulating cell migration, the cytoskeleton, and front-rear polarity. These important properties are essential for proper morphogenesis of the renal tubules and the lymphatic vessels. We highlight here several open questions and controversies. Finally, we try to outline some of the next steps required to study these processes and their relevance in physiological and pathological conditions. PMID- 26529019 TI - "Cancer 2015": A Prospective, Population-Based Cancer Cohort-Phase 1: Feasibility of Genomics-Guided Precision Medicine in the Clinic. AB - "Cancer 2015" is a longitudinal and prospective cohort. It is a phased study whose aim was to pilot recruiting 1000 patients during phase 1 to establish the feasibility of providing a population-based genomics cohort. Newly diagnosed adult patients with solid cancers, with residual tumour material for molecular genomics testing, were recruited into the cohort for the collection of a dataset containing clinical, molecular pathology, health resource use and outcomes data. 1685 patients have been recruited over almost 3 years from five hospitals. Thirty two percent are aged between 61-70 years old, with a median age of 63 years. Diagnostic tumour samples were obtained for 90% of these patients for multiple parallel sequencing. Patients identified with somatic mutations of potentially "actionable" variants represented almost 10% of those tumours sequenced, while 42% of the cohort had no mutations identified. These genomic data were annotated with information such as cancer site, stage, morphology, treatment and patient outcomes and health resource use and cost. This cohort has delivered its main objective of establishing an upscalable genomics cohort within a clinical setting and in phase 2 aims to develop a protocol for how genomics testing can be used in real-time clinical decision-making, providing evidence on the value of precision medicine to clinical practice. PMID- 26529020 TI - Within-Colony Variation in the Immunocompetency of Managed and Feral Honey Bees (Apis mellifera L.) in Different Urban Landscapes. AB - Urbanization has the potential to dramatically affect insect populations worldwide, although its effects on pollinator populations are just beginning to be understood. We compared the immunocompetency of honey bees sampled from feral (wild-living) and managed (beekeeper-owned) honey bee colonies. We sampled foragers from feral and managed colonies in rural, suburban, and urban landscapes in and around Raleigh, NC, USA. We then analyzed adult workers using two standard bioassays for insect immune function (encapsulation response and phenoloxidase activity). We found that there was far more variation within colonies for encapsulation response or phenoloxidase activity than among rural to urban landscapes, and we did not observe any significant difference in immune response between feral and managed bees. These findings suggest that social pollinators, like honey bees, may be sufficiently robust or variable in their immune responses to obscure any subtle effects of urbanization. Additional studies of immune physiology and disease ecology of social and solitary bees in urban, suburban, and natural ecosystems will provide insights into the relative effects of changing urban environments on several important factors that influence pollinator productivity and health. PMID- 26529021 TI - Bacterial Infection Increases Reproductive Investment in Burying Beetles. AB - The Nicrophorus genus lives and breeds in a microbe rich environment. As such, it would be expected that strategies should be in place to counter potentially negative effects of the microbes common to this environment. In this study, we show the response of Nicrophorus vespilloides to the common soil bacterium, Bacillus subtilis. Phenoloxidase (PO) levels are not upregulated in response to the challenge and the bacteria are observed to multiply within the haemolymph of the host. Despite the growth of B. subtilis, survival is not affected, either in virgin or in breeding beetles. Some limit on bacterial growth in the haemolymph does seem to be occurring, suggesting mechanisms of resistance, in addition to tolerance mechanisms. Despite limited detrimental effects on the individual, the challenge by Bacillus subtilis appears to act as a cue to increase reproductive investment. The challenge may indicate a suite of negative environmental conditions that could compromise future breeding opportunities. This could act as a cue to increase parental investment in the current bout. PMID- 26529022 TI - Identification of Epstein-Barr Virus Replication Proteins in Burkitt's Lymphoma Cells. AB - The working model to describe the mechanisms used to replicate the cancer associated virus Epstein-Barr virus (EBV) is partly derived from comparisons with other members of the Herpes virus family. Many genes within the EBV genome are homologous across the herpes virus family. Published transcriptome data for the EBV genome during its lytic replication cycle show extensive transcription, but the identification of the proteins is limited. We have taken a global proteomics approach to identify viral proteins that are expressed during the EBV lytic replication cycle. We combined an enrichment method to isolate cells undergoing EBV lytic replication with SILAC-labeling coupled to mass-spectrometry and identified viral and host proteins expressed during the OPEN ACCESS Pathogens 2015, 4 740 EBV lytic replication cycle. Amongst the most frequently identified viral proteins are two components of the DNA replication machinery, the single strand DNA binding protein BALF2, DNA polymerase accessory protein BMRF1 and both subunits of the viral ribonucleoside-diphosphate reductase enzyme (BORF2 and BaRF1). An additional 42 EBV lytic cycle proteins were also detected. This provides proteomic identification for many EBV lytic replication cycle proteins and also identifies post-translational modifications. PMID- 26529023 TI - Candida albicans Shed Msb2 and Host Mucins Affect the Candidacidal Activity of Salivary Hst 5. AB - Salivary Histatin 5 (Hst 5) is an antimicrobial peptide that exhibits potent antifungal activity towards Candida albicans, the causative agent of oral candidiasis. However, it exhibits limited activity in vivo, largely due to inactivation by salivary components of both host and pathogen origin. Proteins secreted by C. albicans during infection such as secreted aspartyl proteases (Saps) and shed mucin Msb2 can reduce Hst 5 activity; and human salivary mucins, while suggested to protect Hst 5 from proteolytic degradation, can entrap peptides into mucin gels, thereby reducing bioavailability. We show here that Sap6 that is secreted during hyphal growth reduces Hst 5 activity, most likely a result of proteolytic degradation of Hst 5 since this effect is abrogated with heat inactivated Sap 6. We further show that just like C. albicans shedding Msb2, mammalian mucins, fetuin and porcine gut mucin (that is related to salivary mucins), also reduce Hst 5 activity. However, we identify mucin-like protein induced changes in C. albicans cell morphology and aggregation patterns, suggesting that the effect of such proteins on Hst 5 cannot be interpreted independently of their effect on yeast cells. PMID- 26529024 TI - Adolescent Alcoholism and Drug Addiction: The Experience of Parents. AB - Alcoholism and drug addiction have marked impacts on the ability of families to function. Much of the literature has been focused on adult members of a family who present with substance dependency. There is limited research into the effects of adolescent substance dependence on parenting and family functioning; little attention has been paid to the parents' experience. This qualitative study looks at the parental perspective as they attempted to adapt and cope with substance dependency in their teenage children. The research looks into family life and adds to family functioning knowledge when the identified client is a youth as opposed to an adult family member. Thirty-one adult caregivers of 21 teenagers were interviewed, resulting in eight significant themes: (1) finding out about the substance dependence problem; (2) experiences as the problems escalated; (3) looking for explanations other than substance dependence; (4) connecting to the parent's own history; (5) trying to cope; (6) challenges of getting help; (7) impact on siblings; and (8) choosing long-term rehabilitation. Implications of this research for clinical practice are discussed. PMID- 26529025 TI - The Key to Individualized Addiction Treatment is Comprehensive Assessment and Monitoring of Symptoms and Behavioral Change. AB - Modern health services now strive for individualized treatment. This approach has been enabled by the increase in knowledge derived from neuroscience and genomics. Substance use disorders are no exception to individualized treatment even though there are no gene-specific medications yet available. What is available is the ability to quickly and precisely assess and monitor biopsychosocial variables known to vary during addiction recovery and which place addicts at increased risk of relapse. Monitoring a broad spectrum of biopsychosocial health enables providers to address diverse genome-specific changes that might trigger withdrawal from treatment or recovery relapse in time to prevent that from occurring. This paper describes modern measurement tools contained in the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) and the NIH Toolbox and suggests how they might be applied to support recovery from alcohol and other substance use disorders in both pharmacological and abstinence-oriented modalities of care. PMID- 26529027 TI - A Nanoparticle Based Sp17 Peptide Vaccine Exposes New Immuno-Dominant and Species Cross-reactive B Cell Epitopes. AB - Sperm protein antigen 17 (Sp17), expressed in primary as well as in metastatic lesions in >83% of patients with ovarian cancer, is a promising ovarian cancer vaccine candidate. Herein we describe the formulation of nanoparticle based vaccines based on human Sp17 (hSp17) sequence derived peptides, and map the immuno-dominant T cell and antibody epitopes induced using such formulations. The primary T and B cell immuno-dominant region within Sp17 was found to be the same when using biocompatible nanoparticle carriers or the conventional "mix-in" pro inflammatory adjuvant CpG, both mapping to amino acids (aa) 111-142. However, delivery of hSp17111-142 as a nanoparticle conjugate promoted a number of new properties, changing the dominant antibody isotype induced from IgG2a to IgG1 and the fine specificity of the B cell epitopes within hSp17111-142, from an immuno dominant region 134-142 aa for CpG, to region 121-138 aa for nanoparticles. Associated with this change in specificity was a substantial increase in antibody cross-reactivity between mouse and human Sp17. These results indicate conjugation of antigen to nanoparticles can have major effects on fine antigen specificity, which surprisingly could be beneficially used to increase the cross-reactivity of antibody responses. PMID- 26529026 TI - Fetal Alcohol Spectrum Disorder: Potential Role of Endocannabinoids Signaling. AB - One of the unique features of prenatal alcohol exposure in humans is impaired cognitive and behavioral function resulting from damage to the central nervous system (CNS), which leads to a spectrum of impairments referred to as fetal alcohol spectrum disorder (FASD). Human FASD phenotypes can be reproduced in the rodent CNS following prenatal ethanol exposure. Several mechanisms are expected to contribute to the detrimental effects of prenatal alcohol exposure on the developing fetus, particularly in the developing CNS. These mechanisms may act simultaneously or consecutively and differ among a variety of cell types at specific developmental stages in particular brain regions. Studies have identified numerous potential mechanisms through which alcohol can act on the fetus. Among these mechanisms are increased oxidative stress, mitochondrial damage, interference with the activity of growth factors, glia cells, cell adhesion molecules, gene expression during CNS development and impaired function of signaling molecules involved in neuronal communication and circuit formation. These alcohol-induced deficits result in long-lasting abnormalities in neuronal plasticity and learning and memory and can explain many of the neurobehavioral abnormalities found in FASD. In this review, the author discusses the mechanisms that are associated with FASD and provides a current status on the endocannabinoid system in the development of FASD. PMID- 26529029 TI - Effect of Cholesterol on the Structure of a Five-Component Mitochondria-Like Phospholipid Membrane. AB - Cellular membranes have a complex phospholipid composition that varies greatly depending on the organism, cell type and function. In spite of this complexity, most structural data available for phospholipid bilayers concern model systems containing only one or two different phospholipids. Here, we examine the effect of cholesterol on the structure of a complex membrane reflecting the lipid composition of mitochondrial membranes, with five different types of headgroups (phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS) and cardiolipin (CL)) and a variety of hydrocarbon tails. This particular system was chosen because elevated cholesterol contents in mitochondrial membranes have been linked to a breaking down of Bax-mediated membrane permeabilization and resistance to cancer treatments. High resolution electron density profiles were determined by X-ray reflectivity, while the area per phospholipid chain, Apc, and the chain order parameter, SX-ray, were determined by wide-angle X-ray scattering (WAXS). We show that chain order increases upon the addition of cholesterol, resulting in both a thickening of the lipid bilayer and a reduction in the average surface area per phospholipid chain. This effect, well known as cholesterol's condensation effect, is similar, but not as pronounced as for single-component phospholipid membranes. We conclude by discussing the relevance of these findings for the insertion of the pro-apoptotic protein Bax in mitochondrial membranes with elevated cholesterol content. PMID- 26529028 TI - The Use of Synthetic Carriers in Malaria Vaccine Design. AB - Malaria vaccine research has been ongoing since the 1980s with limited success. However, recent improvements in our understanding of the immune responses required to combat each stage of infection will allow for intelligent design of both antigens and their associated delivery vaccine vehicles/vectors. Synthetic carriers (also known as vectors) are usually particulate and have multiple properties, which can be varied to control how an associated vaccine interacts with the host, and consequently how the immune response develops. This review comprehensively analyzes both historical and recent studies in which synthetic carriers are used to deliver malaria vaccines. Furthermore, the requirements for a synthetic carrier, such as size, charge, and surface chemistry are reviewed in order to understand the design of effective particle-based vaccines against malaria, as well as providing general insights. Synthetic carriers have the ability to alter and direct the immune response, and a better control of particle properties will facilitate improved vaccine design in the near future. PMID- 26529030 TI - Bees as Biosensors: Chemosensory Ability, Honey Bee Monitoring Systems, and Emergent Sensor Technologies Derived from the Pollinator Syndrome. AB - This review focuses on critical milestones in the development path for the use of bees, mainly honey bees and bumble bees, as sentinels and biosensors. These keystone species comprise the most abundant pollinators of agro-ecosystems. Pollinating 70%-80% of flowering terrestrial plants, bees and other insects propel the reproduction and survival of plants and themselves, as well as improve the quantity and quality of seeds, nuts, and fruits that feed birds, wildlife, and us. Flowers provide insects with energy, nutrients, and shelter, while pollinators are essential to global ecosystem productivity and stability. A rich and diverse milieu of chemical signals establishes and maintains this intimate partnership. Observations of bee odor search behavior extend back to Aristotle. In the past two decades great strides have been made in methods and instrumentation for the study and exploitation of bee search behavior and for examining intra-organismal chemical communication signals. In particular, bees can be trained to search for and localize sources for a variety of chemicals, which when coupled with emerging tracking and mapping technologies create novel potential for research, as well as bee and crop management. PMID- 26529032 TI - No evidence of asymptomatic variant CJD infection in immunodeficiency patients treated with UK-sourced immunoglobulin. AB - Surveillance of 75 immunodeficiency patients exposed to UK-sourced immunoglobulin, including batches derived from donors who went on to develop vCJD, has not detected any clinical cases of vCJD, or of asymptomatic infection in 15 patients with available tissue samples of sufficient quality for testing. PMID- 26529034 TI - "Nettermania" and the Matthew Effect: It is Time to Plead for Carlos A. G. Machado. PMID- 26529031 TI - The RNA Splicing Response to DNA Damage. AB - The number of factors known to participate in the DNA damage response (DDR) has expanded considerably in recent years to include splicing and alternative splicing factors. While the binding of splicing proteins and ribonucleoprotein complexes to nascent transcripts prevents genomic instability by deterring the formation of RNA/DNA duplexes, splicing factors are also recruited to, or removed from, sites of DNA damage. The first steps of the DDR promote the post translational modification of splicing factors to affect their localization and activity, while more downstream DDR events alter their expression. Although descriptions of molecular mechanisms remain limited, an emerging trend is that DNA damage disrupts the coupling of constitutive and alternative splicing with the transcription of genes involved in DNA repair, cell-cycle control and apoptosis. A better understanding of how changes in splice site selection are integrated into the DDR may provide new avenues to combat cancer and delay aging. PMID- 26529033 TI - Mucosal alpha-papillomaviruses are not associated with esophageal squamous cell carcinomas: Lack of mechanistic evidence from South Africa, China and Iran and from a world-wide meta-analysis. AB - Epidemiological and mechanistic evidence on the causative role of human papillomaviruses (HPV) in esophageal squamous cell carcinoma (ESCC) is unclear. We retrieved alcohol- and formalin-fixed paraffin-embedded ESCC tissues from 133 patients seropositive for antibodies against HPV early proteins, from high incidence ESCC regions: South Africa, China and Iran. With rigorous care to prevent nucleic acid contamination, we analyzed these tissues for the presence of 51 mucosotropic human alpha-papillomaviruses by two sensitive, broad-spectrum genotyping methods, and for the markers of HPV-transformed phenotype: (i) HPV16/18 viral loads by quantitative real-time PCR, (ii) type-specific viral mRNA by E6*I/E6 full-length RT-PCR assays and (iii) expression of cellular protein p16(INK4a). Of 118 analyzable ESCC tissues, 10 (8%) were positive for DNA of HPV types: 16 (4 tumors); 33, 35, 45 (1 tumor each); 11 (2 tumors) and 16, 70 double infection (1 tumor). Inconsistent HPV DNA+ findings by two genotyping methods and negativity in qPCR indicated very low viral loads. A single HPV16 DNA+ tumor additionally harbored HPV16 E6*I mRNA but was p16(INK4a) negative (HPV16 E1 seropositive patient). Another HPV16 DNA+ tumor from an HPV16 E6 seropositive patient showed p16(INK4a) upregulation but no HPV16 mRNA. In the tumor tissues of these serologically preselected ESCC patients, we did not find consistent presence of HPV DNA, HPV mRNA or p16(INK4a) upregulation. These results were supported by a meta-analysis of 14 other similar studies regarding HPV transformation of ESCC. Our study does not support the etiological role of the 51 analyzed mucosotropic HPV types in the ESCC carcinogenesis. PMID- 26529035 TI - Effect of Sensorineural Hearing Loss on Neurocognitive Functioning in Pediatric Brain Tumor Survivors. AB - BACKGROUND: Intensified therapy with platinum-based regimens for pediatric brain tumors has dramatically increased the number of pediatric brain tumor survivors (PBTS) but frequently causes permanent sensorineural hearing loss (SNHL). Although neurocognitive decline in PBTS is known to be associated with radiation therapy (RT), SNHL represents a potential additional contributor whose long-term impact has yet to be fully determined. METHODS: The neurocognitive impact of significant SNHL (Chang scale >= 2b) in PBTS was assessed through a retrospective cohort study of audiograms and neurocognitive testing. Scores for neurocognitive domains and subtest task performance were analyzed to identify specific strengths and weakness for PBTS with SNHL. RESULTS: In a cohort of PBTS (n = 58) treated with platinum therapy, significant SNHL was identified in more than half (55%, n = 32/58), of which the majority required hearing aids (72%, 23/32). RT exposure was approximately evenly divided between those with and without SNHL. PBTS were 6.7 +/- 0.6 and 11.3 +/- 0.7 years old at diagnosis and neurocognitive testing, respectively. In multivariate analyses adjusted for RT dose, SNHL was independently associated with deficits in intelligence, executive function, and verbal reasoning skills. Subtests revealed PBTS with SNHL to have poor learning efficiency but intact memory and information acquisition. CONCLUSIONS: SNHL in PBTS increases the risk for severe therapy-related intellectual and neurocognitive deficits. Additional prospective investigation in malignant brain tumors is necessary to validate these findings through integration of audiology and neurocognitive assessments and to identify appropriate strategies for neurocognitive screening and rehabilitation specific to PBTS with and without SNHL. PMID- 26529036 TI - Reversible On-Off Luminescence Switching in Self-Healable Hydrogels. AB - We present herein an easy way to prepare novel responsive hydrogels by simply doping lanthanide complexes into a polymer hydrogel, poly(2-acrylamido-2-methyl-1 propanesulfonicacid) (PAMPSA). The resulting hybrid hydrogels can be readily processed into a range of shapes. Both the on-off luminescence switching and the healable properties are simultaneously achieved in the resulting responsive hybrid hydrogels. They exhibit effectively self-healing performance without any external stimulus and reversible "on-off" luminescence switching triggered by exposure to acid-base vapor. The key to this on-off luminescence switching behavior is that the protonation of the organic ligands compete with full coordination to Ln(3+) and that incomplete coordination affects the luminescence yield. The high proton strength in the resulting hydrogels makes the doped lanthanide complexes unstable, and ammonia (or triethylamine) vapor can dramatically decrease the proton strength through neutralization, driving the full coordination of the ligand to Ln(3+). PMID- 26529037 TI - Proteomic Analysis of Embryonic and Young Human Vitreous. AB - PURPOSE: The proteomic profile of vitreous from second-trimester human embryos and young adults was characterized using mass spectrometry and analyzed for changes in protein levels that may relate to structural changes occurring during this time. This vitreous proteome was compared to previous reports to confirm proteins already identified and reveal novel ones. METHODS: Vitreous from 17 human embryos aged 14 to 20 weeks gestation (WG) and from a 12-, a 14-, a 15-, and a 28-year-old was individually analyzed using tandem mass spectrometry-based proteomics. Peptide spectral count associations with embryonic age were assessed using a general linear model of fold changes and Spearman's rank correlation. Differences between embryonic and young adult vitreous proteomes were also compared. Immunohistochemistry was used to evaluate three proteins in five additional fetal (10-18 WG) human eyes. RESULTS: There were 1217 proteins identified in fetal and young adult human vitreous, 206 after quantile normalization and variance filtering. In embryos, the peptide counts of 37 proteins changed significantly from 14 to 20 WG: 75.7% increased, 24.3% decreased. Immunohistochemistry confirmed the absence of clusterin and cadherin in 10 and 14 WG eyes and their presence at 18 WG. Comparing embryonic to young adult vitreous, 47 proteins were significantly higher or lower. A total of 768 proteins not previously identified in the literature are presented. CONCLUSIONS: Proteins previously unreported in the human vitreous were identified. The human vitreous proteome undergoes significant changes during embryogenesis and young adulthood. A number of protein levels change considerably during the second trimester, with the majority decreasing. PMID- 26529038 TI - Use of Clopidogrel and Poor Visual Outcome. PMID- 26529039 TI - Author Response: Use of Clopidogrel and Poor Visual Outcome. PMID- 26529040 TI - Inhibitory Effects of 2,2'-Dipyridyl and 1,2,3,4,6-Penta-O-Galloyl-b-D Glucopyranose on Biofilm Formation in Contact Lens Cases. AB - PURPOSE: This study observed biofilm formation by Pseudomonas aeruginosa and Staphylococcus aureus in contact lens cases and investigated the inhibitory effects of 2,2'-dipyridyl (2DP) and 1,2,3,4,6-penta-O-galloyl-b-D-glucopyranose (PGG). METHODS: Biofilm formation of P. aeruginosa ATCC 9027 and S. aureus ATCC 25923 and ATCC 6538 in contact lens cases was determined for a range of initial inocula and incubation times using crystal violet staining. The effects of 2DP and PGG on biofilm were evaluated alone and in combination by their incorporation into the media at commencement of incubation. RESULTS: At 24 hours, biofilm production was related to initial concentration. However, with extended incubation, higher initial concentrations affected formation in S. aureus. Presence of 312 MUM 2DP significantly inhibited P. aeruginosa biofilm formation, but had little effect on that of S. aureus. In contrast, PGG (50 MUM) inhibited S. aureus biofilm formation, but had much less effect on that of P. aeruginosa. Combination of the agents effectively inhibited biofilm formation of all three organisms throughout a week-long incubation period with OD levels barely exceeding cell-free controls. CONCLUSIONS: Biofilm formation of P. aeruginosa could be prevented by 2DP, while biofilm formation of S. aureus was inhibited by PGG. However, combining these agents showed better inhibition of biofilm production than use of either agent alone on both species. This combination may be useful in prevention of biofilm in contact lens cases, thereby reducing infection risk due to poor compliance with lens case cleaning and replacement. Further work is needed to confirm compatibility with multipurpose solutions and investigate cytotoxicity to ocular tissues. PMID- 26529041 TI - Evaluation of Oxidative Stress Markers in Human Conjunctival Epithelial Cells Exposed to Diesel Exhaust Particles (DEP). AB - PURPOSE: The aim of this study was to evaluate oxidative stress markers in human conjunctival epithelial cells (IOBA-NHC) exposed to diesel exhaust particles (DEP). METHODS: Reactive oxygen (ROS) and nitrogen (RNS) species production; hydrogen peroxide (H2O2) levels; protein oxidation; antioxidant enzymes activities (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx], glutathione S-transferase [GST], and glutathione reductase [GR]); total reactive antioxidant potential (TRAP); reduced (GSH) and oxidized glutathione (GSSG) were evaluated. Transmission electron microscopy was performed to evaluate DEP uptake. RESULTS: Diesel exhaust particles were entrapped by membrane protrusions developed by IOBA-NHC. Cells exposed to DEP 50 and 100 MUg/mL showed a significant increase in ROS, RNS, H2O2 levels, SOD, GPx, and GST compared with the control group. A significant decay in GR was observed in both groups, meanwhile CAT levels remained unchanged. The group exposed to DEP 100 MUg/mL displayed a significant increase in protein oxidation. In both groups, TRAP was significantly reduced as well as the GSH/GSSG ratio. CONCLUSIONS: The decrease in nonenzymatic antioxidants and the compensatory increase of SOD, GPX, and GST activities are consequence of the increase in ROS and RNS production due to DEP exposure and its accumulation inside the cells. The decay in GR activity leads to the decrease in GSH/GSSG recycling. These results suggest that oxidative stress could play an important role in the development of DEP effects on human conjunctival epithelial cells. PMID- 26529042 TI - Quantifying Ocular Surface Inflammation and Correlating It With Inflammatory Cell Infiltration In Vivo: A Novel Method. AB - PURPOSE: The purpose of this study was to develop a novel, objective, and semiautomated method to quantify conjunctival redness by correlating measured redness with standard clinical redness and symptom scales and inflammatory cell infiltration. METHODS: Eleven outpatients presenting with mild to severe conjunctival hyperemia were included in the study. Clinical examination included patient history; visual analogue score (VAS) for ocular symptoms; 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) for quality of life/vision; photographs of the anterior segment graded for conjunctival hyperemia, using Efron, relative redness of image (RRI), and edge feature (EF) scales; and conjunctival impression cytology analyzed by flow cytometry. Differences between affected and unaffected eyes were evaluated, and correlations among questionnaire scores, ocular hyperemia grading scores, and assessment of biological markers were performed. RESULTS: Visual analogue score (P < 0.0001), Efron scale (P = 0.0003), RRI scores (P = 0.0004), and EF scores (P < 0.0001) and the percentage of granulocytes (defined as cluster of differentiation [CD] 45dim; P = 0.0080) were significantly higher in affected eyes. Conversely, the percentage of CD45bright leukocytes was reduced in affected eyes (P = 0.0054). Both the RRIs and EFs were positively correlated with VAS, Efron scale, percentages of conjunctival granulocytes, and CD45brightCD3neg cells, whereas they were negatively correlated with the percentage of CD45brightCD3pos cells. Edge feature and RRI were correlated (Spearman r = 0.78, P < 0.0001). CONCLUSIONS: Ocular redness is a cardinal sign driving clinical judgment in highly prevalent ocular disorders; hence, we suggest that our semiautomated and reproducible method may represent a helpful tool in the follow-up of these patients. Italian Abstract. PMID- 26529043 TI - Erratum. Size of the Oblique Extraocular Muscles and Superior Oblique Muscle Contractility in Brown Syndrome. PMID- 26529044 TI - Profiling of Cytokines Secreted by Conventional Aqueous Outflow Pathway Endothelial Cells Activated In Vitro and Ex Vivo With Laser Irradiation. AB - PURPOSE: To profile which cytokine genes are differentially expressed (DE) as up- or downregulated by cultured human trabecular meshwork (TMEs) and Schlemm's canal endothelial cells (SCEs) after three experimental treatments consisting of selective laser trabeculoplasty (SLT) irradiation, exposure to media conditioned either by SLT-irradiated TMEs (TME-cm) or by SCEs (SCE-cm). Also, to profile which cytokines are upregulated ex vivo in SLT-irradiated human conventional aqueous outflow pathway (CAOP) tissues. METHODS: After each treatment, Affymetrix microarray assays were used to detect upregulated and downregulated genes for cytokines and their receptors in TMEs and SCEs. ELISA and protein antibody arrays were used to detect upregulated cytokines secreted in SLT-irradiated CAOP tissues ex vivo. RESULTS: The SLT irradiation upregulated numerous cytokine genes in TMEs, but only a few in SCEs. Exposure to TME- and SCE-cm induced SCEs to upregulate many more cytokine genes than TMEs. Selective laser trabeculoplasty irradiation and exposure to TME-cm downregulated several cytokine genes in TMEs but none in SCEs. Selective laser trabeculoplasty irradiation induced one upregulated and three downregulated cytokine-receptor genes in TMEs but none in SCEs. Exposure to TME-cm induced upregulation of one and downregulation of another receptor gene in TMEs, whereas two unique cytokine-receptor genes were upregulated in SCEs. Cytokine protein expression analysis showed that at least eight cytokines were upregulated in SLT-irradiated human CAOP tissues in situ/ex vivo. CONCLUSIONS: This study has helped us identify a cytokine signaling pathway and to consider newly identified mechanisms regulating aqueous outflow that may lay the foundation for the future development of cytokine-based glaucoma therapies. PMID- 26529045 TI - Early Onset Ultrastructural and Functional Defects in RPE and Photoreceptors of a Stargardt-Like Macular Dystrophy (STGD3) Transgenic Mouse Model. AB - PURPOSE: We investigated the interplay between photoreceptors expressing mutant ELOVL4 (responsible for Stargardt-like disease, STGD3) and RPE in the initial stages of retinal degeneration. METHODS: Using electron microscopy and electroretinogram (ERG), we assessed RPE and photoreceptor ultrastructure and function in transgenic ELOVL4 (TG1-2 line; TG) and wild-type (WT) littermates. Experiments were done at P30, 1 month before photoreceptor loss in TG and at P90, a time point with approximately 30% rod loss. To further elucidate the mechanism underlying our ultrastructural and functional results, we undertook Western blotting and immunohistochemistry of key proteins involved in phagocytosis of outer segments by RPE cells. RESULTS: Firstly, we showed that in TG mouse photoreceptors, endogenous ELOVL4 protein is not mislocalized in the presence of the mutated ELOVL4 protein. Secondly, we found evidence of RPE toxicity at P30, preceding any photoreceptor loss. Pathology in RPE cells was exacerbated at P90. Furthermore, higher proportions of phagosomes remained at the apical side of RPE cells. Subretinal lysosomal deposits were immunopositive for phagocytic proteins. Ultrastructural analysis of photoreceptor (rod) outer segments showed disrupted surface morphology consisting of disc spacing irregularities. Finally, rods and RPE exhibited signs of dysfunction as measured by the ERG a-wave leading edge (P30) and c-wave (P90), respectively. CONCLUSIONS: The presence of human mutant ELOVL4 in transgenic mouse photoreceptors leads to early outer segment disc pathology and RPE cytotoxicity. Defective processing of these abnormal discs by RPE cells ultimately may be responsible for outer segment truncation, photoreceptor death, and vision loss. PMID- 26529046 TI - Nucleoside Reverse Transcriptase Inhibitors Suppress Laser-Induced Choroidal Neovascularization in Mice. AB - PURPOSE: To evaluate the efficacy of nucleoside reverse transcriptase inhibitors (NRTIs) in the laser-induced mouse model of choroidal neovascularization (CNV). METHODS: We evaluated the NRTIs lamivudine (3TC), zidovudine (AZT), and abacavir (ABC) and the P2X7 antagonist A438079. Choroidal neovascularization was induced by laser injury in C57BL/6J wild-type, Nlrp3-/-, and P2rx7-/- mice, and CNV volume was measured after 7 days by confocal microscopy. Drugs were administered by intravitreous injection immediately after the laser injury. Vascular endothelial growth factor-A in RPE-choroid lysates was measured 3 days after laser injury by ELISA. HEK293 cells expressing human and mouse P2X7 were exposed to the selective P2X7 receptor agonist 2', 3'-(benzoyl-4-benzoyl)-ATP (Bz-ATP) with or without 3TC, and VEGF-A levels in media were measured by ELISA. RESULTS: Intravitreous injection of 3TC, AZT, and ABC significantly suppressed laser induced CNV in C57BL/6J wild-type and Nlrp3-/- mice (P < 0.05) but not in P2rx7-/ mice. Intravitreous injection of A438079 also suppressed the laser-induced CNV (P < 0.05). The NRTIs 3TC, AZT, and ABC blocked VEGF-A levels in the RPE/choroid after laser injury in wild-type (P < 0.05) but not P2rx7-/- mice. Moreover, there was no additive effect of 3TC on CNV inhibition when coadministered with a neutralizing VEGF-A antibody. Stimulation of human and mouse P2X7-expressing HEK293 cells with Bz-ATP increased VEGF secretion (P < 0.001), which was abrogated by 3TC (P < 0.001). Stimulation of primary human RPE cells with Bz-ATP increased VEGFA and IL6 mRNA levels, which were abrogated by 3TC. CONCLUSIONS: Multiple clinically relevant NRTIs suppressed laser-induced CNV and downregulated VEGF-A, via P2X7. PMID- 26529047 TI - Full-Field Pupillary Light Responses, Luminance Thresholds, and Light Discomfort Thresholds in CEP290 Leber Congenital Amaurosis Patients. AB - PURPOSE: To investigate visual function in patients with CEP290 Leber congenital amaurosis (LCA-CEP290), using three full-field tests that can be performed by patients with poor fixation. METHODS: Six patients (age range, 9-39 years) with LCA-CEP290 participated in the study. Stimuli for all three tests (full-field stimulus test [FST], pupillometry, and light discomfort threshold [LDT] testing) were generated by the Diagnosys ColorDome ganzfeld, by using achromatic stimuli as well as long- and short-wavelength stimuli to target rod and cone photoreceptors with all three tests and, in the latter two tests, melanopsin photoreceptors. RESULTS: Dark-adapted FST thresholds in LCA-CEP290 patients were cone mediated and elevated between 4.8 and 6.2 log units above the normal achromatic threshold. The FST threshold was not measurable in one patient. The rod-mediated transient pupillary light reflex (PLR) was absent in all but the youngest patient, where unreliable responses precluded PLR quantification. Cone mediated transient PLRs were subnormal in five patients, and absent in another. Sustained melanopsin-mediated PLRs were measurable in all patients. Full-field LDT thresholds were elevated compared to normal controls, and were lower for short-wavelengh than for long-wavelength stimuli. CONCLUSIONS: The FST thresholds and transient PLRs were cone mediated in our cohort LCA-CEP290 patients. Rod mediated PLRs were undetectable, whereas melanopsin-mediated sustained responses were detected in all patients, suggesting a relative preservation of inner-retina function. The LDT elevations for the patients are somewhat paradoxical, given their subjective perception of photoaversion. Relative aversion to short wavelength light suggests influence from melanopsin on LDTs in these patients. PMID- 26529049 TI - N-Methyl-N-Nitrosourea-Induced Acute Alteration of Retinal Function and Morphology in Monkeys. AB - PURPOSE: The purpose of this study was to investigate both functional and morphologic alteration of the retina acutely induced by N-methyl-N-nitrosourea (MNU) in monkeys. METHODS: The MNU was administered intravenously at a single dose of 40 mg/kg to six cynomolgus monkeys, and standard full-field electroretinograms (ERGs) were recorded 1, 3, and 7 days after dosing. In addition, the rod and cone a-waves in response to high-intensity flashes were analyzed by the a-wave fitting model (a-wave analysis). The photopic negative response (PhNR) was also recorded at the same time points. Furthermore, the retinas of two animals each were examined histopathologically 1, 3, or 7 days after dosing. RESULTS: The MNU attenuated all the standard full-field ERGs including the rod-driven and cone-driven responses; in the combined rod-cone response, the b-wave was more affected than the a-wave. In the a-wave analysis, the sensitivity parameters (S) of the rod and cone a-waves had decreased on the day after dosing and remained unchanged thereafter. The maximum response parameter (Rmax) of the rod a-wave gradually decreased. On the other hand, the Rmax in the cone a-wave transiently increased on the day after dosing and decreased thereafter; the PhNR amplitude showed a similar time course change. Histopathologically, the retinal lesion on the day after dosing mainly consisted of pyknosis and karyorrhexis in the photoreceptor nucleus. Depletion of some photoreceptor nuclei, and shortening and disorientation of the photoreceptor segments became prominent at 3 and 7 days after dosing. Localization of degenerated photoreceptors was consistent with that of rhodopsin-positive photoreceptors, resulting in a well-preserved central fovea. CONCLUSIONS: Our results indicated that MNU acutely induced rod-dominant photoreceptor degeneration in monkey retinas, but the photoreceptor function was impaired in both the rods and cones. Functional involvement of the postreceptoral components was also indicated. PMID- 26529048 TI - Phosphatidylserine (PS) Is Exposed in Choroidal Neovascular Endothelium: PS Targeting Antibodies Inhibit Choroidal Angiogenesis In Vivo and Ex Vivo. AB - PURPOSE: Choroidal neovascularization (CNV) accounts for 90% of cases of severe vision loss in patients with advanced age-related macular degeneration. Identifying new therapeutic targets for CNV may lead to novel combination therapies to improve outcomes and reduce treatment burden. Our goal was to test whether phosphatidylserine (PS) becomes exposed in the outer membrane of choroidal neovascular endothelium, and whether this could provide a new therapeutic target for CNV. METHODS: Choroidal neovascularization was induced in C57BL/6J mice using laser photocoagulation. Choroidal neovascularization lesions costained for exposed PS and for intercellular adhesion molecule 2 (or isolectin B4) were imaged in flat mounts and in cross sections. The laser CNV model and a choroidal sprouting assay were used to test the effect of PS-targeting antibodies on choroidal angiogenesis. Choroidal neovascularization lesion size was determined by intercellular adhesion molecule 2 (ICAM-2) staining of flat mounts. RESULTS: We found that PS was exposed in CNV lesions and colocalized with vascular endothelial staining. Treatment with PS-targeting antibodies led to a 40% to 80% reduction in CNV lesion area when compared to treatment with a control antibody. The effect was the same as that seen using an equal dose of an anti VEGF antibody. Results were confirmed using the choroid sprouting assay, an ex vivo model of choroidal angiogenesis. CONCLUSIONS: We demonstrated that PS is exposed in choroidal neovascular endothelium. Furthermore, targeting this exposed PS with antibodies may be of therapeutic value in CNV. PMID- 26529050 TI - Sexual dysfunction and neuroendocrine correlates of posttraumatic stress disorder in combat veterans: Preliminary findings. AB - Sexual dysfunction is not a symptom of PTSD but is a common clinical complaint in trauma survivors with this disorder. In that there are biological parallels in the neuroendocrine processes underlying both PTSD and sexual behavior, we conducted an exploratory investigation of the relationship of PTSD and related neuroendocrine indicators with sexual dysfunction in armed service veterans. Major Depressive Disorder, highly comorbid with PTSD and sexual dysfunction, was also assessed. In veterans with PTSD, sexual problems were associated with plasma DHEA and cortisol, urinary catecholamines, and glucocorticoid sensitivity, even when controlling for the effects of comorbid depression. In a subsample analysis, testosterone levels did not distinguish PTSD or sexual dysfunction, suggesting that sexual problems reported by veterans in this sample were not the result of organic disorder. PTSD did predict higher dihydrotestosterone (DHT) levels, which were associated with sexual problems. More detailed assessment of sexual dysfunction in biologically informed studies of PTSD is warranted to clarify the relationships of PTSD symptomatology and related neurobiology with sexual dysfunction. PMID- 26529051 TI - The lifetime experience of traumatic events is associated with hair cortisol concentrations in community-based children. AB - Adversity early in life can disrupt the functioning of the hypothalamic-pituitary adrenal axis (HPAA) and increase risk for negative health outcomes. Recent research suggests that cortisol in scalp hair represents a promising measure of HPAA function. However, little is known about the relationship between early exposure to traumatic events and hair cortisol concentrations (HCC) in childhood, a critical period of HPAA development. The current study measured HCC in scalp hair samples collected from 70 community-based children (14 males, mean age=9.50) participating in the Imaging Brain Development in the Childhood to Adolescence Transition Study (iCATS). Data were also collected on lifetime exposure to traumatic events and current depressive symptoms. Lifetime exposure to trauma was associated with elevated HCC; however, HCC was not associated with current depressive symptoms. Consistent with some prior work, males were found to have higher HCC than females, although results should be treated with caution due to the small number of males who took part. Our findings suggest that hair cortisol may represent a biomarker of exposure to trauma in this age group; however, further study is necessary with a particular focus on the characterization of trauma and other forms of adversity. PMID- 26529052 TI - Stress activates the nucleus incertus and modulates plasticity in the hippocampo medial prefrontal cortical pathway. AB - The nucleus incertus (NI) is a small cluster of brainstem neurons presumed to play a role in stress responses. We show that swim stress (normal water: 30 min and cold water: 20 min) and elevation stress robustly induced c-Fos expression in the NI and significantly suppressed long-term potentiation (LTP) in the hippocampo-medial prefrontal cortical (HP-mPFC) pathway. To examine whether activation of CRF1 receptors in the NI plays a role in the suppression of HP-mPFC LTP, antalarmin, a specific CRF1 receptor antagonist, was infused directly into the NI either before presentation of (1) elevation stress or (2) high frequency stimulation. As predicted, the intra-NI infusion of antalarmin reversed the elevation stress-induced suppression of LTP in the HP-mPFC pathway. This report suggests that the CRF1 receptor in the NI contributes to stress-related impairment in plasticity of the HP-mPFC pathway. The findings suggest that the NI HP-mPFC is a stress responsive circuit in the rodent brain. PMID- 26529053 TI - Virulence of Aggregatibacter actinomycetemcomitans serotypes and DGGE subtypes isolated from chronic adult periodontitis in Thailand. AB - A high proportion of non-serotypeable isolates of Aggregatibacter actinomycetemcomitans among Thai periodontitis cases has been previously reported. The aim of this study was to investigate the expression of leukotoxin and toxicity, cytolethal distending toxin (Cdts), and internalization and the killing effect on fibroblasts by A. actinomycetemcomitans subtypes from Thai chronic periodontitis cases. A total of 96 A. actinomycetemcomitans strains from 37 periodontitis cases, previously serotyped with PCR and subtyped with DGGE, were examined for the presence of the ltx gene and cdt genes (cdtBC), and tested for leukotoxin expression, leukotoxicity, internalization, and apoptosis of fibroblast cells. The ltx gene was present in all isolates, while 84.4% showed the cdtBC gene. Two strains with a JP2-like ltx gene with a deletion of 530 bp in the promoter region, serotyped as c, showed virulence of similar magnitude to the JP2 strain. Furthermore, a higher virulence was found in the two non-serotypeable DGGE subtypes, NS1 and NS2, compared with the serotypeable strains (serotype a-f, serotype b and d were absent). Generally, the virulence of strains obtained from deep periodontal pockets was higher than those isolated from shallow non-bleeding pockets. A. actinomycetemcomitans subtypes isolated from adult Thais with chronic periodontitis showed a highly variable virulence, leukotoxin expression, leukotoxicity, internalization and apoptosis of fibroblast, and are regulated both genetically and environmentally. PMID- 26529054 TI - Ruthenium(II) Catalyzed Regiospecific C-H/O-H Annulations of Directing Arenes via Weak Coordination. AB - Ruthenium(II) catalyzed oxidative C-H/O-H annulations have been demonstrated using two different directing arenes viz. 2-arylquinolinone and 2 arylbenzoxazinone with internal alkynes. Regiospecific annulations have been observed for both directing arenes via the assistance of weaker carbonyl oxygen in the presence of a stronger nitrogen-directing site. In this substrate controlled convergent protocol the weaker directing group dictates the annulation path. PMID- 26529055 TI - A Qualitative Investigation of Australian Youth Perceptions to Enhance School Physical Activity: The Environmental Perceptions Investigation of Children's Physical Activity (EPIC-PA) Study. AB - BACKGROUND: There is more demand than ever for schools to equip children with the necessary skills to be physically active. The purpose of the Environmental Perceptions Investigation of Children's Physical Activity (EPIC-PA) study was to investigate elementary and secondary school children's perceptions to enhance the school physical activity environment. METHODS: Four Australian government schools (2 elementary and 2 secondary) were recruited for the EPIC-PA study. During the study, 78 children were recruited aged 10 to 13 years. The focus group discussions consisted of 54 children (32 elementary and 22 secondary) and the map drawing sessions included 24 children (17 elementary and 7 secondary). RESULTS: The findings from the EPIC-PA study revealed insight into uniquely desired features to encourage physical activity such as adventure physical activity facilities (eg, rock climbing walls), recreational physical activity facilities (eg, jumping pillows), physical activity excursions, animal activity programs and teacher-directed activities. In addition to specific features, childrens revealed a host of policies for equipment borrowing, access to sports equipment/areas, music during physical activity time and external physical education lessons. CONCLUSIONS: Understanding the multiple suggestions from children of features to enhance physical activity can be used by schools and researchers to create environments conducive to physical activity participation. PMID- 26529056 TI - Quality of Life in Patients With Vestibular Schwannomas According to Management Strategy. AB - OBJECTIVE: This study aimed to evaluate the quality of life of patients treated for unilateral vestibular schwannoma via observation, microsurgery, or gamma knife radiosurgery. STUDY DESIGN: The study design was retrospective and cross sectional. METHODS: Patients treated for vestibular schwannoma at our institute in 2012-2013 completed a standardized questionnaire (Short Form-36) via telephone to evaluate their quality of life at least 6 months after treatment. Patients were categorized according to management (microsurgery, n = 47; gamma knife radiosurgery, n = 27; and observation, n = 34). Clinical characteristics and quality of life were compared among the groups. RESULTS: Tumor control rates were 94.0% in the microsurgery group and 96.2% in the radiosurgery group. The most annoying symptoms were hearing loss in the microsurgery group, dizziness in the radiosurgery group, and tinnitus in the observation group. Quality-of-life scores did not differ significantly among the three groups in four of the eight domains of the questionnaire. The microsurgery group had a significantly higher score in the general health perception domain than the other groups (p = 0.003). CONCLUSION: Quality of life is higher after microsurgery than after radiosurgery. One specific management strategy cannot always guarantee the better quality of life. The functional status and personality traits of the patient should be considered, as well as tumor size and location when choosing a management option. PMID- 26529057 TI - Responses to Drs. Kaski and Bronstein and Dr. Crane. PMID- 26529058 TI - Ir(III)-Based Phosphors with Bipyrazolate Ancillaries; Rational Design, Photophysics, and Applications in Organic Light-Emitting Diodes. AB - A series of three charge-neutral Ir(III) complexes bearing both neutral chelating ligands 4,4'-di-t-butyl-2,2'-bipyridine (dtbbpy) and monoanionic cyclometalated ligands derived from 2-phenylpyridine (ppyH), together with either two monoanionic ligands (i.e., chloride and monodentate pyrazolate) or a single dianionic chelate derived from 5,5'-di(trifluoromethyl)-3,3'-bipyrazole (bipzH2) or 5,5'-(1-methylethylidene)-bis-(3-trifluoromethyl-1H-pyrazole) (mepzH2), was successfully synthesized. These complexes are derived from a common, structurally characterized, Ir(III) intermediate complex [Ir(dtbbpy) (ppy)Cl2] (1), from treatment of IrCl3.3H2O with equal amount of the diimine (N^N) and precursor of the cyclometalated (C^N) ligands in a form of one-pot reaction. Treatment of 1 with various functional pyrazoles afforded [Ir(dtbbpy) (ppy) (pz)Cl] (2), [Ir(dtbbpy) (ppy) (bipz)] (3), and [Ir(dtbbpy) (ppy) (mepz)] (4), which display intense room-temperature emission with lambdamax spanning the region between 532 and 593 nm in both fluid and solid states. The Ir(III) complexes, 3 and 4, showcase rare examples of three distinctive chelates (i.e., neutral, anionic, and dianionic) assembled around the central Ir(III) cation. Hybrid density functional theory (DFT; B3LYP) electronic structure calculations on 1-4 reveal the lowest unoccupied molecular orbital to be pi*(bpy) in character for all complexes and highest occupied molecular orbital (HOMO) offering d(Ir)-pi(phenyl) character for 1, 2, and 4 and pi(bipz) character for 3. The different HOMO composition of 3 and 4 is also predicted by calculations using pure DFT (BLYP) and wave function (MP2) methods. On the basis of time-dependent DFT calculations, the emissive processes are dominated by the phenyl group-to-bipyridine, ligand(ppy)-to-ligand(bpy) charge transfer admixed with metal-to-ligand transition for all Ir(III) complexes. Organic light emitting diodes were successfully fabricated. A double emitting layer design was adopted in the device architecture using Ir(III) metal complexes 3 and 4, attaining peak external quantum efficiencies, luminance efficiencies, and power efficiencies of 18.1% (59.0 cd/A and 38.6 lm/W) and 16.6% (53.3 cd/A and 33.5 lm/W), respectively. PMID- 26529059 TI - Hybrid Aortic Repair of Dissecting Aortic Arch Aneurysm after Surgical Treatment of Acute Type A Dissection. AB - BACKGROUND: The aim of this study was to evaluate the short-term and midterm results of hybrid repair of dissecting aortic arch aneurysms subsequent to surgical treatment of acute type A dissections. METHODS: Between 2003 and 2014, 7 consecutive patients, previously operated for acute type A dissection, underwent hybrid repair of their aortic arch for a dissecting aortic arch aneurysm (6 men, mean age 62 +/- 11 years). Aneurysm formation requiring treatment in these aortic arches was observed from 2 to 20 years after the initial aortic dissection repair. A hybrid technique was used in all patients, with supra-aortic debranching through a redo sternotomy and either simultaneous (6 patients) or staged endovascular stent grafting (1 patient). Two patients were treated in an emergent setting (1 ruptured and 1 symptomatic aneurysm). Two patients required a more extensive aortic repair of either the thoracic aorta (n, 1) or of the thoracoabdominal aorta (n, 1). One patient underwent, saphenous vein bypass from the ascending aorta to the anterior descending coronary artery on full cardiopulmonary bypass. Follow-up computed tomography scans were performed at 1 week, 3, and 6 months, and annually thereafter. RESULTS: Technical success was achieved in all the cases. One transient ischemic attack, 1 stroke, and 1 episode of transient spinal cord ischemia were observed. Thirty-day mortality was not observed. A type I endoleak at 6 months was successfully treated with deployment of a second stent graft. After a mean follow-up of 3.5 +/- 3.1 years (range, 0.4 9.6 years), no aortic-related mortality was observed. No cases of stent-graft migration or secondary rupture were observed. CONCLUSIONS: Our experience demonstrates the promising potential of endovascular repair of dissecting aortic arch aneurysms after surgical treatment of acute type A dissection. The potential to diminish the magnitude of the surgical procedure and the consequences of aortic arch exposure, and above all avoiding the need for circulatory arrest are promising and mandate further investigation to determine the efficacy and durability of this technique. PMID- 26529060 TI - Modulating adsorption and stability properties in pillared metal-organic frameworks: a model system for understanding ligand effects. AB - Metal-organic frameworks (MOFs) are nanoporous materials with highly tunable properties that make them ideal for a wide array of adsorption applications. Through careful choice of metal and ligand precursors, one can target the specific functionality and pore characteristics desired for the application of interest. However, among the wide array of MOFs reported in the literature, there are varying trends in the effects that ligand identity has on the adsorption, chemical stability, and intrinsic framework dynamics of the material. This is largely due to ligand effects being strongly coupled with structural properties arising from the differing topologies among frameworks. Given the important role such properties play in dictating adsorbent performance, understanding these effects will be critical for the design of next generation functional materials. Pillared MOFs are ideal platforms for understanding how ligand properties can affect the adsorption, stability, and framework dynamics in MOFs. In this Account, we highlight our recent work demonstrating how experiment and simulation can be used to understand the important role ligand identity plays in governing the properties of isostructural MOFs containing interconnected layers pillared by bridging ligands. Changing the identity of the linear, ditopic ligand in either the 2-D layer or the pillaring third dimension allows targeted modulation of the chemical functionality, porosity, and interpenetration of the framework. We will discuss how these characteristics can have important consequences on the adsorption, chemical stability, and dynamic properties of pillared MOFs. The structures discussed in this Account comprise the greatest diversity of isostructural MOFs whose stability properties have been studied, allowing valuable insight into how ligand properties dictate the chemical stability of isostructural frameworks. We also discuss how functional groups can affect adsorbate energetics at their most favorable adsorption sites to elucidate how functional groups can affect the adsorptive performance of these materials in ways that are unexpected based on the isolated ligand's properties. We then highlight a variety of simulation tools that not only can be used to understand the differing molecular-level behavior of the adsorbate and framework dynamics within these isostructural MOFs, but also can shed light on possible mechanisms that govern the differing chemical stability properties among these materials. Lastly, we provide perspective on the challenges and opportunities for utilizing the structure-property relationships arising from the ligand effects described in this Account for the design of further MOFs with enhanced chemical stability and adsorption properties. PMID- 26529061 TI - Evelyn Witkin and the coordinated response to DNA damage. PMID- 26529062 TI - Discrimination of germline V genes at different sequencing lengths and mutational burdens: A new tool for identifying and evaluating the reliability of V gene assignment. AB - Immune repertoires are collections of lymphocytes that express diverse antigen receptor gene rearrangements consisting of Variable (V), (Diversity (D) in the case of heavy chains) and Joining (J) gene segments. Clonally related cells typically share the same germline gene segments and have highly similar junctional sequences within their third complementarity determining regions. Identifying clonal relatedness of sequences is a key step in the analysis of immune repertoires. The V gene is the most important for clone identification because it has the longest sequence and the greatest number of sequence variants. However, accurate identification of a clone's germline V gene source is challenging because there is a high degree of similarity between different germline V genes. This difficulty is compounded in antibodies, which can undergo somatic hypermutation. Furthermore, high-throughput sequencing experiments often generate partial sequences and have significant error rates. To address these issues, we describe a novel method to estimate which germline V genes (or alleles) cannot be discriminated under different conditions (read lengths, sequencing errors or somatic hypermutation frequencies). Starting with any set of germline V genes, this method measures their similarity using different sequencing lengths and calculates their likelihood of unambiguous assignment under different levels of mutation. Hence, one can identify, under different experimental and biological conditions, the germline V genes (or alleles) that cannot be uniquely identified and bundle them together into groups of specific V genes with highly similar sequences. PMID- 26529063 TI - Impact of the 5As brief counseling on smoking cessation among pregnant clients of Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) clinics in Ohio. AB - OBJECTIVES: We assessed whether smoking cessation improved among pregnant smokers who attended Women, Infants and Children (WIC) Supplemental Nutrition Program clinics trained to implement a brief smoking cessation counseling intervention, the 5As: ask, advise, assess, assist, arrange. METHODS: In Ohio, staff in 38 WIC clinics were trained to deliver the 5As from 2006 through 2010. Using 2005-2011 Pregnancy Nutrition Surveillance System data, we performed conditional logistic regression, stratified on clinic, to estimate the relationship between women's exposure to the 5As and the odds of self-reported quitting during pregnancy. Reporting bias for quitting was assessed by examining whether differences in infants' birth weight by quit status differed by clinic training status. RESULTS: Of 71,526 pregnant smokers at WIC enrollment, 23% quit. Odds of quitting were higher among women who attended a clinic after versus before clinic staff was trained (adjusted odds ratio, 1.16; 95% confidence interval, 1.04-1.29). The adjusted mean infant birth weight was, on average, 96 g higher among women who reported quitting (P<0.0001), regardless of clinic training status. CONCLUSIONS: Training all Ohio WIC clinics to deliver the 5As may promote quitting among pregnant smokers, and thus is an important strategy to improve maternal and child health outcomes. PMID- 26529064 TI - Methylsulfonyl Zn phthalocyanine: A polyvalent and powerful hydrophobic photosensitizer with a wide spectrum of photodynamic applications. AB - BACKGROUND: The biomedical photodynamic principle is based on the light-induced and photosensitizer-mediated killing of unwanted or harmful cells by overproduction of reactive oxygen species. Motivated by the success of photodynamic therapy (PDT) against several types of tumors, further applications of this approach are constantly identified which require the design and synthesis of novel photosensitizers with specifically tailored properties for a particular clinical application. METHODS: Hydrophobic photosensitizers are currently gaining attention and hence a tetramethylsulfonyl Zn(II) phthalocyanine (2) was designed with respect to the desired photoproperties. The photodynamic potential of 2 was assessed by the determination of its photophysical and photochemical properties, and by a large range of biological tests including its phototoxicity against cancer cells and Gram(+) bacteria. Unsubstituted ZnPc was used as a reference compound for comparison purposes. RESULTS: Phthalocyanine 2 has a better oxygen generation and is more photostable than ZnPc. 2 is a polyvalent and powerful hydrophobic photosensitizer with a wide spectrum of photodynamic applications against cancer (tested on A431 cells) and for Gram(+) PDI. Against Staphylococcus aureus, a maximum photokilling efficiency of more than 6 log10 steps was induced by a 5MUM concentration of 2, outperforming the 3 log10 criterion for an antimicrobial effect (according to the recommendation of the American Society for Microbiology) by more than three orders of magnitude. CONCLUSIONS: Phthalocyanine 2 has attractive photophysical and -chemical characteristics. Initial evaluation of its application in anti-tumor PDT and PDI suggest potential for further pre clinical and clinical development of this compound. PMID- 26529065 TI - The impact of visual impairment on the ability to perform activities of daily living for persons with severe/profound intellectual disability. AB - BACKGROUND: The ability to perform activities of daily living (ADL) as a component of participation is one of the factors that contribute to quality of life. The ability to perform ADL for persons experiencing severe/profound intellectual disability (ID) may be reduced due to their cognitive and physical capacities. However, until recently, the impact of the significantly prevalent visual impairments on the performance of activities of daily living has not yet been revealed within this group. AIM: The purpose of this prospective cross sectional study was to investigate the impact of visual impairment on the performance of activities of daily living for persons with a severe/profound intellectual disability. METHOD: The Barthel Index (BI) and Comfortable Walking Speed (CWS) were used to measure the ability of performing activities of daily living (ADL) in 240 persons with severe/profound ID and having Gross Motor Functioning Classification System (GMFCS) levels I, II or III; this included 120 persons with visual impairment. The impact of visual impairment on ADL was analyzed with linear regression. RESULTS: The results of the study demonstrated that visual impairment slightly affects the ability of performing activities of daily living (BI) for persons experiencing a severe/profound intellectual disability. GMFCS Levels II or III, profound ID level, and visual impairment each have the effect of lowering BI scores. GMFCS Levels II or III, and profound ID level each have the effect of increasing CWS scores, which indicates a lower walking speed. A main effect of visual impairment is present on CWS, but our results do show a substantive interaction effect between GMFCS level III and visual impairment on Comfortable Walking Speed in persons with a severe/profound intellectual disability. CONCLUSIONS: Visual impairment has a slight effect on ability to perform ADL in persons experiencing severe/profound ID. PMID- 26529066 TI - Influenza vaccine effectiveness against hospitalisation with influenza in adults in Australia in 2014. AB - We provide estimates of the influenza vaccine protection against hospitalisation with laboratory-confirmed influenza in the 2014 Australian season where the A/H1N1/pdm09 strain predominated. This was performed using a case-test negative study design as part of a national sentinel surveillance system in Australia. Vaccine effectiveness was estimated as (1-OR)*100% where the odds ratio of vaccination in cases vs test negative participants was estimated from a conditional logistic regression. Between April and November, 1692 adult patients were admitted with laboratory-confirmed influenza. Vaccine effectiveness was estimated from 1283 patients with influenza and 1116 test negative patients where vaccination status was ascertained. Vaccination was associated with a reduction in the risk of hospitalisation with influenza of 51.5% (95% CI: 41.6%, 59.7%) in all patients, and a reduction of 50.7% (95% CI: 40.1%, 59.3%) in the target population for vaccination. We estimate that the influenza vaccine was moderately protective against hospitalisation with laboratory-confirmed influenza during the 2014 influenza season in Australia. PMID- 26529067 TI - Assessment of the enhancement of PLGA nanoparticle uptake by dendritic cells through the addition of natural receptor ligands and monoclonal antibody. AB - Targeting of specific receptors on antigen-presenting cells is an appealing prospect in the production of novel nanoparticulate vaccines. In particular, the targeting of vaccines to dendritic cell (DC) subsets has been shown in models to significantly improve the induction of immune responses. This paper describes the evaluation of natural ligands, mannan and chitosan, and monoclonal antibodies as targeting motifs to enhance uptake of PLGA nanoparticle carriers by bovine DCs. To assess enhancement of uptake after the addition of natural ligands a bovine monocyte derived DC (MoDC) model was used. For the assessment of monoclonal antibody targeting, the model was expanded to include afferent lymph DCs (ALDCs) in a competitive uptake assay. Mannan, proved unsuccessful at enhancing uptake or targeting by MoDCs. Chitosan coated particle uptake could be impeded by the addition of mannan suggesting uptake may be mediated through sugar receptors. Inclusion of monoclonal antibodies specific for the DEC-205 (CD205) receptor increased the number of receptor expressing DCs associated with particles as well as the number of particles taken up by individual cells. These results support the further evaluation of active targeting of nanovaccines to DCs to enhance their immunogenicity in cattle and other large mammalian species including humans. PMID- 26529068 TI - Production of high titer attenuated poliovirus strains on the serum-free PER.C6((r)) cell culture platform for the generation of safe and affordable next generation IPV. AB - BACKGROUND: As poliovirus eradication draws closer, alternative Inactivated Poliovirus Vaccines (IPV) are needed to overcome the risks associated with continued use of the Oral Poliovirus Vaccine and of neurovirulent strains used during manufacture of conventional (c) IPV. We have previously demonstrated the susceptibility of the PER.C6((r)) cell line to cIPV strains; here we investigated the suspension cell culture platform for growth of attenuated poliovirus strains. METHODS: We examined attenuated Sabin strain productivity on the PER.C6((r)) cell platform compared to the conventional Vero cell platform. The suitability of the suspension cell platform for propagation of rationally-attenuated poliovirus strains (stabilized Sabin type 3 S19 derivatives and genetically attenuated and stabilized MonoCre(X) strains), was also assessed. Yields were quantified by infectious titer determination and D-antigen ELISA using either serotype-specific polyclonal rabbit sera for Sabin strains or monoclonal cIPV-strain-specific antibodies for cIPV, S19 and MonoCre(X) strains. RESULTS: PER.C6((r)) cells supported the replication of Sabin strains to yields of infectious titers that were in the range of cIPV strains at 32.5 degrees C. Sabin strains achieved 30 fold higher yields (p<0.0001) on the PER.C6((r)) cell platform as compared to the Vero cell platform in infectious titer and D-antigen content. Furthermore, Sabin strain productivity on the PER.C6((r)) cell platform was maintained at 10l scale. Yields of infectious titers of S19 and MonoCre(X) strains were 0.5-1 log10 lower than seen for cIPV strains, whereas D-antigen yield and productivities in doses/ml using rationally-attenuated strains were in line with yields reported for cIPV strains. CONCLUSIONS: Sabin and rationally-attenuated polioviruses can be grown to high infectious titers and D-antigen yields. Sabin strain infection shows increased productivity on the PER.C6((r)) cell platform as compared to the conventional Vero cell platform. Novel cell platforms with the potential for higher yields could contribute to increased affordability of a next generation of IPV vaccines needed for achieving and maintaining poliovirus eradication. PMID- 26529069 TI - Pros and cons of VP1-specific maternal IgG for the protection of Enterovirus 71 infection. AB - Enterovirus 71 (EV71) causes hand, foot, and mouth diseases and can result in severe neurological disorders when it infects the central nervous system. Thus, there is a need for the development of effective vaccines against EV71 infection. Here we report that viral capsid protein 1 (VP1), one of the main capsid proteins of EV71, efficiently elicited VP1-specific immunoglobulin G (IgG) in the serum of mice immunized with recombinant VP1. The VP1-specific IgG produced in female mice was efficiently transferred to their offspring, conferring protection against EV71 infection immediately after birth. VP1-specific antibody can neutralize EV71 infection and protect host cells. VP1-specific maternal IgG in offspring was maintained for over 6 months. However, the pre-existence of VP1-specific maternal IgG interfered with the production of VP1-specific IgG antibody secreting cells by active immunization in offspring. Therefore, although our results showed the potential for VP1-specific maternal IgG protection against EV71 in neonatal mice, other strategies must be developed to overcome the hindrance of maternal IgG in active immunization. In this study, we developed an effective and feasible animal model to evaluate the protective efficacy of humoral immunity against EV71 infection using a maternal immunity concept. PMID- 26529070 TI - Randomized comparison of the safety of Flublok((r)) versus licensed inactivated influenza vaccine in healthy, medically stable adults >= 50 years of age. AB - BACKGROUND: The safety and tolerability of Flublok((r)), a purified recombinant hemagglutinin seasonal influenza vaccine, was compared to AFLURIA((r)) in a randomized, blinded clinical trial in adults >= 50 years of age with attention to hypersensitivity reactions. METHODS: This blinded, randomized trial of healthy adults >= 50 years of age compared safety of Flublok vs. AFLURIA with respect to pre-specified possible hypersensitivity: "rash," "urticaria," "swelling" and "non dependent edema;" solicited reactogenicity and unsolicited adverse events. Subject-reported outcomes were collected for 30 days after vaccination. All adverse event terms were reviewed by physicians blinded to vaccine group, who added other terms possibly reflecting hypersensitivity. Case records of subjects with possible hypersensitivity were adjudicated by independent experts blinded to treatment assignment to identify likely hypersensitivity reactions. Non inferiority of the incidence of hypersensitivity in the two vaccine groups was pre-defined as an absolute difference with an upper bound of 2-sided 95% confidence limits <= 0.015. RESULTS: A total of 2640 subjects were enrolled, evenly split in age cohorts of 50-64 and >= 65 years. Fifty-two subjects reported at least one term possibly representing hypersensitivity, with a slight imbalance of 31 on Flublok and 21 on AFLURIA. The adjudicators determined that six and four subjects on Flublok and AFLURIA, respectively, likely met clinical criteria for hypersensitivity, yielding a difference in incidence between the two vaccine groups of 0.15% (upper bound of 2-sided 95% CI=0.9%). Reactogenicity and overall adverse event profiles were similar across both vaccines. CONCLUSIONS: Flublok was non-inferior to AFLURIA in adults >= 50 years of age with respect to expert adjudicated events of likely hypersensitivity during 30 days following vaccination (Sponsored by Protein Sciences Corporation; ClinicalTrials.gov number NCT01825200). PMID- 26529071 TI - Pediatric provider vaccine hesitancy: An under-recognized obstacle to immunizing children. AB - OBJECTIVE: To describe vaccine attitudes among pediatric healthcare providers attending immunization conferences. STUDY DESIGN: Attendees of 5 American Academy of Pediatrics (AAP)-sponsored vaccine conferences held between June and November 2013 anonymously completed a questionnaire assessing vaccine attitudes and practices prior to the opening of educational sessions. Pearson's chi-square tests and Fisher's exact tests were used to analyze associations between vaccine attitudes, vaccine practices and provider characteristics. RESULTS: 680 providers attending AAP-sponsored vaccine conferences were included. 661/666 (99%) enrolled providers state they routinely recommend standard pediatric vaccines, yet, 30 (5%) state that they do not routinely recommend influenza and/or human papillomavirus (HPV) vaccines. These providers expressed vaccine safety (87/680 (13%)) and efficacy (21/680 (31%)) concerns and stated belief in vaccine misperceptions: vaccine causes autism (34/668, 5%), multiple vaccines at a single visit reduces vaccine efficacy (43/680, 6%) or overwhelms the immune system (63/680, 9%), and administering HPV vaccine will increase the likelihood of unprotected adolescent sexual activity (29/680, 4%). Six percent of providers who do not routinely recommend all pediatric vaccines correctly identified themselves as vaccine hesitant. CONCLUSION: Vaccine hesitancy is under-recognized among pediatric providers attending AAP-sponsored immunization conferences. Educational interventions tailored to address provider vaccine concerns are needed to improve provider vaccine confidence. PMID- 26529072 TI - A new EV71 VP3 epitope in norovirus P particle vector displays neutralizing activity and protection in vivo in mice. AB - Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16), as the main agents causing hand, foot and mouth disease (HFMD), have become a serious public health concern in the Asia-Pacific region. Recently, various neutralizing B cell epitopes of EV71 were identified as targets for promising vaccine candidates. Structural studies of Picornaviridae indicated that potent immunodominant epitopes typically lie in the hypervariable loop of capsid surfaces. However, cross-neutralizing antibodies and cross-protection between EV71 and CVA16 have not been observed. Therefore, we speculated that divergent sequences of the two viruses are key epitopes for inducing protective neutralizing responses. In this study, we selected 10 divergent epitope candidates based on alignment of the EV71 and CVA16 P1 amino acid sequences using the Multalin interface page, and these epitopes are conserved among all subgenotypes of EV71. Simultaneously, by utilizing the norovirus P particle as a novel vaccine delivery carrier, we identified the 71-6 epitope (amino acid 176-190 of VP3) as a conformational neutralizing epitope against EV71 in an in vitro micro-neutralization assay as well as an in vivo protection assay in mice. Altogether, these results indicated that the incorporation of the 71-6 epitope into the norovirus P domain can provide a promising candidate for an effective synthetic peptide-based vaccine against EV71. PMID- 26529073 TI - Pertussis vaccination during pregnancy in Vietnam: Results of a randomized controlled trial Pertussis vaccination during pregnancy. AB - A pertussis vaccination during pregnancy has recently been adopted in several countries to indirectly protect young infants. This study assessed the effect of adding a pertussis component to the tetanus vaccination, in the pregnancy immunization program in Vietnam. A randomized controlled trial was performed. Pregnant women received either a Tdap (tetanus, diphtheria acellular pertussis) vaccine or a tetanus only vaccine between 19 and 35 weeks' gestational age. Immunoglobulin G (IgG) against tetanus (TT), diphtheria (DT), pertussis toxin (PT), filamentous hemaglutinin (FHA) and pertactin (Prn) were measured using commercial ELISA tests, at baseline, 1 month after maternal vaccination, at delivery, and in infants from cord blood and before and after the primary series (EPI: month 2-3-4) of a pertussis containing vaccine. Significantly higher geometric mean concentrations (GMC) were observed for all 3 measured pertussis antigens in the offspring of the Tdap group, up to 2 months of age. One month after completion of the primary infant vaccination schedule, anti-Prn GMC, but not anti-PT and anti-FHA GMCs, was significantly (p=0.006) higher in the control group. Maternal antibodies induced by vaccination during pregnancy close the susceptibility gap for pertussis in young infants. Limited interference with the infant vaccine responses was observed. Whether this interference effect disappears with the administration of a fourth vaccine dose is further studied. PMID- 26529074 TI - Differences in efficiency, satisfaction and adverse events between self administered intradermal and nurse-administered intramuscular influenza vaccines in hospital workers. AB - Vaccinating healthcare workers against influenza takes tens of thousands of hours of work annually. This study was undertaken to determine the acceptability, success rate, and time to vaccinate healthcare workers in nurse-led groups that self-vaccinated with intradermal influenza vaccine compared with nurse administered intramuscular vaccine. METHODS: Volunteer hospital workers were randomly assigned to groups that either self-administered intradermal influenza vaccine (Intanza((r))) in a nurse-led group or received nurse-administered intramuscular vaccine (Vaxigrip((r))). Research assistants timed vaccination procedures; pre- and post-injection questionnaires assessed acceptability and reactogenicity. RESULTS: 810 adults, 21-69 years of age, from two study sites were vaccinated: 401 self-administered the intradermal vaccine while 409 received their intramuscular vaccine from a nurse. Of those who self-administered for the first time, 98.5% were successful on their first attempt with an additional 1.5% on their second attempt. Acceptability was high: 96% were very or somewhat certain that they administered the vaccine correctly, 83% would choose intradermal influenza vaccine again and of those, 75% would choose self administration again, if given the choice. It took 51.3-72.6s per person for the nurses to guide the groups through the self-administration process, which was significantly less time than it took to individually administer the intramuscular vaccines (93.6s). CONCLUSION: Self-administration of intradermal influenza vaccine by people working in healthcare settings is a possible alternative to nurse administered vaccinations, with nurse-led group sessions a good way of teaching the technique while being available to respond to unanticipated problems (NCT01665807). PMID- 26529075 TI - Non-thermal plasma for inactivated-vaccine preparation. AB - Vaccines are of great importance in controlling the spread of infectious diseases in poultry farming. The safety and efficacy of vaccines are also essential. To explore the feasibility of a novel technology (non-thermal plasma) in inactivated vaccine preparation, an alternating current atmospheric pressure non-thermal plasma (NTP) jet with Ar/O2/N2 as the operating gas was used to inactivate a Newcastle disease virus (NDV, LaSota) strain and H9N2 avian influenza virus (AIV, A/Chicken/Hebei/WD/98) for vaccine preparation. The results showed that complete inactivation could be achieved with 2 min of NTP treatment for both NDV and AIV. Moreover, a proper NTP treatment time is needed for inactivation of a virus without destruction of the antigenic determinants. Compared to traditional formaldehyde-inactivated vaccine, the vaccine made from NDV treated by NTP for 2 min (NTP-2 min-NDV-vaccine) could induce a higher NDV-specific antibody titer in specific pathogen-free (SPF) chickens, and the results of a chicken challenge experiment showed that NTP-2 min-NDV-vaccine could protect SPF chickens from a lethal NDV challenge. Vaccines made from AIV treated by NTP for 2 min (NTP-2 min AIV-vaccine) also showed a similar AIV-specific antibody titer compared with traditional AIV vaccines prepared using formaldehyde inactivation. Studies of the morphological changes of the virus, chemical analysis of NDV allantoic fluid and optical emission spectrum analysis of NTP suggested that reactive oxygen species and reactive nitrogen species produced by NTP played an important role in the virus inactivation process. All of these results demonstrated that it could be feasible to use non-thermal NTP as an alternative strategy to prepare inactivated vaccines for Newcastle disease and avian influenza. PMID- 26529076 TI - PneuMum: Impact from a randomised controlled trial of maternal 23-valent pneumococcal polysaccharide vaccination on middle ear disease amongst Indigenous infants, Northern Territory, Australia. AB - BACKGROUND: We assessed maternal 23-valent pneumococcal polysaccharide (23vPPV) vaccine efficacy (VE) against middle ear disease and pneumococcal carriage amongst Australian Indigenous infants. METHODS: In an open label, allocation concealed, outcome-assessor blinded, community stratified, randomised controlled trial, healthy pregnant Indigenous women aged 17-39 years in the Northern Territory of Australia received the 23vPPV (1:1:1) at: 30-36 weeks gestation, birth, or were unvaccinated (ClinicalTrials.gov NCT00714064). Co-primary outcomes were the point prevalences of infant middle ear disease and 23vPPV-type carriage at age 7 months. RESULTS: The consent rate was 50% (313/632). Among 227 eligible participants randomised, retention rates were 86% (66/77) controls; 89% (67/75) pregnancy vaccinees; 88% (66/75) birth vaccinees. At infant age 7 months, ear disease prevalence was: 71% (47/66) controls, 63% (42/67) pregnancy vaccinees, 76% (50/66) birth vaccinees; and 23vPPV-type carriage was: 26% (17/66) controls, 18% (12/67) pregnancy vaccinees, 18% (12/66) birth vaccinees. For pregnancy vaccinees, VE was 12% (95% CI -12% to 31%) against infant ear disease and 30% (95% CI -34% to 64%) against 23vPPV-type carriage. In a post-hoc analysis, VE against infant ear disease concurrent with carriage of 23vPPV or related types was 51% (95% CI -2% to 76%). There were no serious adverse effects following receipt of the 23vPPV in pregnancy or at birth. CONCLUSIONS: In a high risk population, our study was unable to demonstrate efficacy of 23vPPV in pregnancy against the co-primary outcomes of either all-cause infant ear disease or 23vPPV type nasopharyngeal carriage at age 7 months. Efficacy against ear disease concurrent with carriage of vaccine-related serotypes (a more specific outcome) suggests 23vPPV in pregnancy may complement childhood pneumococcal vaccination programs. PMID- 26529077 TI - Intranasal immunisation with recombinant adenovirus vaccines protects against a lethal challenge with pneumonia virus of mice. AB - Pneumonia virus of mice (PVM) infection of BALB/c mice induces bronchiolitis leading to a fatal pneumonia in a dose-dependent manner, closely paralleling the development of severe disease during human respiratory syncytial virus infection in man, and is thus a recognised model in which to study the pathogenesis of pneumoviruses. This model system was used to investigate delivery of the internal structural proteins of PVM as a potential vaccination strategy to protect against pneumovirus disease. Replication-deficient recombinant human adenovirus serotype 5 (rAd5) vectors were constructed that expressed the M or N gene of PVM pathogenic strain J3666. Intranasal delivery of these rAd5 vectors gave protection against a lethal challenge dose of PVM in three different mouse strains, and protection lasted for at least 20 weeks post-immunisation. Whilst the PVM-specific antibody response in such animals was weak and inconsistent, rAd5N primed a strong PVM-specific CD8(+) T cell response and, to a lesser extent, a CD4(+) T cell response. These findings suggest that T-cell responses may be more important than serum IgG in the observed protection induced by rAd5N. PMID- 26529078 TI - Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis. AB - BACKGROUND AND AIMS: Approximately 95% of bile acids (BAs) excreted into bile are reabsorbed in the gut and circulate back to the liver for further biliary secretion. Therefore, pharmacological inhibition of the ileal apical sodium dependent BA transporter (ASBT/SLC10A2) may protect against BA-mediated cholestatic liver and bile duct injury. METHODS: Eight week old Mdr2(-/-) (Abcb4( /-)) mice (model of cholestatic liver injury and sclerosing cholangitis) received either a diet supplemented with A4250 (0.01% w/w) - a highly potent and selective ASBT inhibitor - or a chow diet. Liver injury was assessed biochemically and histologically after 4weeks of A4250 treatment. Expression profiles of genes involved in BA homeostasis, inflammation and fibrosis were assessed via RT-PCR from liver and ileum homogenates. Intestinal inflammation was assessed by RNA expression profiling and immunohistochemistry. Bile flow and composition, as well as biliary and fecal BA profiles were analyzed after 1week of ASBT inhibitor feeding. RESULTS: A4250 improved sclerosing cholangitis in Mdr2(-/-) mice and significantly reduced serum alanine aminotransferase, alkaline phosphatase and BAs levels, hepatic expression of pro-inflammatory (Tnf-alpha, Vcam1, Mcp-1) and pro-fibrogenic (Col1a1, Col1a2) genes and bile duct proliferation (mRNA and immunohistochemistry for cytokeratin 19 (CK19)). Furthermore, A4250 significantly reduced bile flow and biliary BA output, which correlated with reduced Bsep transcription, while Ntcp and Cyp7a1 were induced. Importantly A4250 significantly reduced biliary BA secretion but preserved HCO3(-) and biliary phospholipid secretion resulting in an increased HCO3(-)/BA and PL/BA ratio. In addition, A4250 profoundly increased fecal BA excretion without causing diarrhea and altered BA pool composition, resulting in diminished concentrations of primary BAs tauro-beta-muricholic acid and taurocholic acid. CONCLUSIONS: Pharmacological ASBT inhibition attenuates cholestatic liver and bile duct injury by reducing biliary BA concentrations in mice. PMID- 26529079 TI - Enhanced extracellular production of trans-resveratrol in Vitis vinifera suspension cultured cells by using cyclodextrins and coronatine. AB - In the present work the effect of cyclodextrin and coronatine on both trans resveratrol production and the expression of stilbene biosynthetic genes in Vitis vinifera L. cv Monastrell suspension cultured cells were evaluated. The results showed the maximum level of trans-resveratrol produced by cells and secreted to the culture medium with 50 mM cyclodextrins and 1 MUM coronatine. Since the levels of trans-resveratrol produced in the combined treatment were higher than the sum of the individual treatments, a synergistic effect between both elicitors was assumed. In addition, all the analysed genes were induced by cyclodextrins and/or coronatine. The expression of the phenylalanine ammonia lyase and stilbene synthase genes was greatly enhanced by coronatine although an increase in the amount of trans-resveratrol in the spent medium was not detected. Therefore, despite the fact that trans-resveratrol production is related with the expression of genes involved in the biosynthetic process, other factors may be involved, such as post-transcriptional and post-traductional regulation. The expression maximal levels of cinnamate 4-hydroxylase and 4-coumarate-CoA ligase genes were found with cyclodextrins alone or in combination with coronatine suggesting that the activity of these enzymes could be not only important for the formation of intermediates of trans-R biosynthesis but also for those intermediates involved in the biosynthesis of lignins and/or flavonoids. PMID- 26529080 TI - Improving mass detection using combined feature representations from projection views and reconstructed volume of DBT and boosting based classification with feature selection. AB - In digital breast tomosynthesis (DBT), image characteristics of projection views and reconstructed volume are different and both have the advantage of detecting breast masses, e.g. reconstructed volume mitigates a tissue overlap, while projection views have less reconstruction blur artifacts. In this paper, an improved mass detection is proposed by using combined feature representations from projection views and reconstructed volume in the DBT. To take advantage of complementary effects on different image characteristics of both data, combined feature representations are extracted from both projection views and reconstructed volume concurrently. An indirect region-of-interest segmentation in projection views, which projects volume-of-interest in reconstructed volume into the corresponding projection views, is proposed to extract combined feature representations. In addition, a boosting based classification with feature selection has been employed for selecting effective feature representations among a large number of combined feature representations, and for reducing false positives. Experiments have been conducted on a clinical data set that contains malignant masses. Experimental results demonstrate that the proposed mass detection can achieve high sensitivity with a small number of false positives. In addition, the experimental results demonstrate that the selected feature representations for classifying masses complementarily come from both projection views and reconstructed volume. PMID- 26529081 TI - Poecilia picta, a Close Relative to the Guppy, Exhibits Red Male Coloration Polymorphism: A System for Phylogenetic Comparisons. AB - Studies on the evolution of female preference and male color polymorphism frequently focus on single species since traits and preferences are thought to co evolve. The guppy, Poecilia reticulata, has long been a premier model for such studies because female preferences and orange coloration are well known to covary, especially in upstream/downstream pairs of populations. However, focused single species studies lack the explanatory power of the comparative method, which requires detailed knowledge of multiple species with known evolutionary relationships. Here we describe a red color polymorphism in Poecilia picta, a close relative to guppies. We show that this polymorphism is restricted to males and is maintained in natural populations of mainland South America. Using tests of female preference we show female P. picta are not more attracted to red males, despite preferences for red/orange in closely related species, such as P. reticulata and P. parae. Male color patterns in these closely related species are different from P. picta in that they occur in discrete patches and are frequently Y chromosome-linked. P. reticulata have an almost infinite number of male patterns, while P. parae males occur in discrete morphs. We show the red male polymorphism in P. picta extends continuously throughout the body and is not a Y linked trait despite the theoretical prediction that sexually-selected characters should often be linked to the heterogametic sex chromosome. The presence/absence of red male coloration of P. picta described here makes this an ideal system for phylogenetic comparisons that could reveal the evolutionary forces maintaining mate choice and color polymorphisms in this speciose group. PMID- 26529082 TI - Prognostic value of multi-detector computed tomography in asymptomatic aortic valve stenosis. AB - BACKGROUND: Multi-Detector Computed Tomography (MDCT) is a high-resolution imaging technique with potential additive value in the evaluation of patients with aortic valve stenosis (AS). We aimed to assess the prognostic value of MDCT in asymptomatic patients with AS compared to conventional transthoracic echocardiography (TTE). METHODS: 116 patients with asymptomatic AS (Vmax>2.5m/s assessed by clinical screening TTE, LVEF>50%) were examined with TTE (Vivid e9) and MDCT (Aquilion 320) on the same day. The treating physician was blinded for research protocol defined imaging results. Outcome was defined as indication for aortic valve replacement (AVR) determined by the treating physician or sudden cardiac death. RESULTS: The mean age was 72 (8) years, 27% were women, mean AVA by TTE was 1.01 (0.30) cm(2). Median follow up time was 27 (IQR 19-44) months. Forty seven patients (41%) developed indication for AVR. No patients suffered a sudden cardiac death. AVA and aortic valve calcification were significant univariable predictors of AVR when measured by both TTE and MDCT, whereas left ventricular mass was only significant measured by MDCT. Significant coronary artery disease by MDCT tended to predict future indication for AVR, but this did not reach statistical significance (HR: 1.79 (95% CI 0.96-3.44), p=0.08). CONCLUSION: MDCT derived AVA can be of use as an alternative to TTE derived AVA in patients with asymptomatic AS to predict future clinical indication for AVR. PMID- 26529083 TI - Paradoxical thromboembolism despite prophylactic antithrombotic therapy in atrial fibrillation: A case report. PMID- 26529084 TI - Risk of revisits to the emergency department in admitted versus discharged patients with chest pain but without myocardial infarction in relation to high sensitivity cardiac troponin T levels. AB - BACKGROUND: Recent studies have indicated that it may be safe to discharge chest pain patients with an initial high-sensitivity cardiac troponin T (hs-cTnT) level of <5 ng/L from the emergency department (ED) without further evaluation. We sought to assess the effects of discharge from the ED versus admission to hospital on downstream resource utilisation in low-risk chest pain patients. METHODS: We included all patients who sought medical attention for chest pain during 2 years at the Karolinska University Hospital and who had no myocardial infarction (MI). Adjusted hazard ratios (HRs) were calculated for revisits to the ED, revisits leading to hospitalisation, coronary angiography, or revascularisation during follow-up for admitted compared with discharged patients. RESULTS: 13,046 patients were included, of whom 7694 (59%) had at least one revisit to the ED during a mean of 516 days' follow-up. Admitted patients with hs-cTnT levels of <5 ng/L were 12% more likely to return to the ED during follow-up (HR 1.12, 95% confidence interval (CI) 1.04 to 1.20), and 24% more likely to return to the ED within 30 days (HR 1.24, CI 1.05 to 1.46) than patients who were discharged. The risk of revisit leading to hospitalisation was almost doubled, and the likelihood of undergoing coronary angiography or revascularisation was three-fold in admitted compared with discharged patients. CONCLUSIONS: Increased risks of revisit to the ED, hospitalisation, coronary angiography, and revascularisation were observed when patients with chest pain and hs-cTnT levels of <5 ng/L were admitted instead of discharged home. PMID- 26529085 TI - Stem cell therapy for heart disease-Meta-analysis may be misleading. PMID- 26529086 TI - Inheriting a high aerobic fitness predisposes to skeletal muscle and endothelial dysfunction in chronic heart failure. PMID- 26529087 TI - Fungal Endophyte Diversity and Bioactivity in the Indian Medicinal Plant Ocimum sanctum Linn. AB - Endophytic mycopopulation isolated from India's Queen of herbs Tulsi (Ocimum sanctum) were explored and investigated for their diversity and antiphytopathogenic activity against widespread plant pathogens Botrytis cinerea, Sclerotinia sclerotiorum, Rhizoctonia solani and Fusarium oxysporum. 90 fungal isolates, representing 17 genera were recovered from 313 disease-free and surface sterilised plant segments (leaf and stem tissues) from three different geographic locations (Delhi, Hyderabad and Mukteshwar) during distinct sampling times in consequent years 2010 and 2011 in India. Fungal endophytes were subjected to molecular identification based on rDNA ITS sequence analysis. Plant pathogens such as F. verticillioides, B. maydis, C. coarctatum, R. bataticola, Hypoxylon sp., Diaporthe phaseolorum, Alternaria tenuissima and A. alternata have occurred as endophyte only during second sampling (second sampling in 2011) in the present study. Bi-plot generated by principal component analysis suggested tissue specificity of certain fungal endophytes. Dendrogram revealed species abundance as a function of mean temperature of the location at the time of sampling. Shannon diversity in the first collection is highest in Hyderabad leaf tissues (H' = 1.907) whereas in second collection it was highest from leaf tissues of Delhi (H' = 1.846). Mukteshwar (altitude: 7500 feet) reported least isolation rate in second collection. Nearly 23% of the total fungal isolates were considered as potent biocontrol agent. Hexane extract of M. phaseolina recovered from Hyderabad in first collection demonstrated highest activity against S. sclerotiorum with IC50 value of 0.38 mg/ml. Additionally, its components 2H-pyran 2-one, 5,6-dihydro-6-pentyl and palmitic acid, methyl ester as reported by GC-MS Chromatogram upon evaluation for their antiphytopathogenic activity exhibited IC50 value of 1.002 and 0.662 against respectively S. sclerotiorum indicating their significant role in antiphytopathogenic activity of hexane extract. The production of 2H-pyran-2-one, 5,6-dihydro-6-pentyl from M. phaseolina, an endophytic fungus is being reported for the first time. PMID- 26529088 TI - Turning quickly on myself: Automatic interpretation biases in dysphoria are self referent. AB - Cognitive theories emphasise automatic interpretation biases (AIB) in the development and maintenance of depression. The current study examined AIB using the word sentence association paradigm for depression (WSAP-D) via endorsement rates and reaction time indices. We directly tested the importance of self relevance for AIB by modifying the WASP-D task to include self-referent ambiguous stimuli and contrasting them with other-referent ambiguous stimuli. We hypothesised that the dysphoric group, but not the non-dysphoric group, would demonstrate AIB only for self-referent ambiguous stimuli. Consistent with our main hypotheses, dysphoric individuals endorsed negative interpretations more often and faster than non-dysphoric individuals, only for self-referent ambiguous stimuli. Self-relevance may be a critical aspect of AIB in dysphoric populations. PMID- 26529089 TI - Investigation of the protective effect of ellagic acid for preventing kidney injury in rats exposed to nicotine during the fetal period. AB - We investigated the possible protective effects of ellagic acid on rat kidneys exposed to nicotine during the fetal period. Twenty pregnant female rats were divided randomly into four groups: control (C), nicotine (N), ellagic acid (EA) and nicotine + ellagic acid (N + EA). Nicotine and ellagic acid treatments were continued throughout the pregnancies and for 15 days after delivery. On day 15, all neonatal pups were sacrificed and their kidneys were removed for biochemical and histopathological examination. The nicotine treatment significantly decreased body weight, total glutathione (GSH), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities, and increased malondialdehyde (MDA) and nitric oxide (NO) levels in the N group compared to controls. EA treatment ameliorated decreased body weight, GSH, GSH-Px and SOD activities, and increased MDA and NO levels in group N + EA compared to group N (p < 0.05). Nicotine caused kidney damage as shown by incomplete development of glomeruli and Bowman's capsules. Nicotine also caused greater apoptosis in group N compared to group C. Ellagic acid treatment produced histological kidney structure that was closer to normal and it exerted an anti-apoptotic effect in the N + EA group compared to the N group. EA played a protective role against nicotine-induced nephrotoxicity and oxidative stress in rats owing to its antioxidant, radical scavenging and anti-apoptotic effects. PMID- 26529090 TI - Potential factors associated with fruit and vegetable intake after premature acute coronary syndrome: a prospective cohort study. AB - Studies on dietary changes and their associated factors are limited, particularly with respect to younger cardiovascular patients. Our objective was to evaluate the factors associated with fruit and vegetable intake among adults with premature acute coronary syndrome (ACS) 1 year after the event. We used data from GENESIS-PRAXY, a multicentre prospective study of adults aged 18-55 years, hospitalised for ACS. Participants were 704 adults from 24 centres in Canada, 1 in USA and 1 in Switzerland. Data were collected through questionnaires and chart reviews at baseline and 1 year post-ACS. Fruit and vegetable intake was low among adults with premature ACS, and remained suboptimal at 1 year post-ACS, with only 21% meeting the minimum recommendations of at least 5 daily servings. The findings suggest that patient lifestyle characteristics, such as the number of hours spent at work and baseline intake are factors that may be associated with the intake of fruits and vegetables. More research is needed to assess effective strategies to increase fruit and vegetable intake among patients with premature ACS so that they meet dietary recommendations. PMID- 26529091 TI - Correlation between Inter-Blink Interval and Episodic Encoding during Movie Watching. AB - Human eye blinking is cognitively suppressed to minimize loss of visual information for important real-world events. Despite the relationship between eye blinking and cognitive state, the effect of eye blinks on cognition in real-world environments has received limited research attention. In this study, we focused on the temporal pattern of inter-eye blink interval (IEBI) during movie watching and investigated its relationship with episodic memory. As a control condition, 24 healthy subjects watched a nature documentary that lacked a specific story line while electroencephalography was performed. Immediately after viewing the movie, the subjects were asked to report its most memorable scene. Four weeks later, subjects were asked to score 32 randomly selected scenes from the movie, based on how much they were able to remember and describe. The results showed that the average IEBI was significantly longer during the movie than in the control condition. In addition, the significant increase in IEBI when watching a movie coincided with the most memorable scenes of the movie. The results suggested that the interesting episodic narrative of the movie attracted the subjects' visual attention relative to the documentary clip that did not have a story line. In the episodic memory test executed four weeks later, memory performance was significantly positively correlated with IEBI (p<0.001). In summary, IEBI may be a reliable bio-marker of the degree of concentration on naturalistic content that requires visual attention, such as a movie. PMID- 26529092 TI - Determinants of the Sympatric Host-Pathogen Relationship in Tuberculosis. AB - Major contributions from pathogen genome analysis and host genetics have equated the possibility of Mycobacterium tuberculosis co-evolution with its human host leading to more stable sympatric host-pathogen relationships. However, the attribution to either sympatric or allopatric categories depends on the resolution or grain of genotypic characterization. We explored the influence on the sympatric host-pathogen relationship of clinical (HIV infection and multidrug resistant tuberculosis [MDRTB]) and demographic (gender and age) factors in regards to the genotypic grain by using spacer oligonucleotide typing (spoligotyping) for classification of M. tuberculosis strains within the Euro American lineage. We analyzed a total of 547 tuberculosis (TB) cases, from six year consecutive sampling in a setting with high TB-HIV coinfection (32.0%). Of these, 62.0% were caused by major circulating pathogen genotypes. The sympatric relationship was defined according to spoligotype in comparison to the international spoligotype database SpolDB4. While no significant association with Euro-American lineage was observed with any of the factors analyzed, increasing the resolution with spoligotyping evidenced a significant association of MDRTB with sympatric strains, regardless of the HIV status. Furthermore, distribution curves of the prevalence of sympatric and allopatric TB in relation to patients' age showed an accentuation of the relevance of the age of onset in the allopatric relationship, as reflected in the trimodal distribution. On the contrary, sympatric TB was characterized by the tendency towards a typical (standard) distribution curve. Our results suggest that within the Euro-American lineage a greater degree of genotyping fine-tuning is necessary in modeling the biological processes behind the host-pathogen interplay. Furthermore, prevalence distribution of sympatric TB to age was suggestive of host genetic determinisms driven by more common variants. PMID- 26529094 TI - High potential of symbiotic interactions between native mycorrhizal fungi and the exotic tree Eucalyptus camaldulensis for phytostabilization of metal-contaminated arid soils. AB - Waste dumps generated by mining activities contain heavy metals that are dispersed into areas leading to significant environmental contamination. The objectives of this study were (i) to survey native plants and their associated AM fungal communities from waste soils in a Moroccan mine site and (ii) to follow Eucalyptus growth in soil collected from the waste-mine. AM spores from native plant species were collected from the mining site and the surrounding uncontaminated areas were multiplied and inoculated onto Eucalyptus camaldulensis. The results showed that (i) the native plant species recorded in the waste did not show an active metal uptake, (ii) the selected native plant species are associated with AM mycorrhizal fungi and (iii) the use of AM fungi adapted to these drastic conditions can improve the growth of the fast-growing tree, E. camaldulensis and its tolerance to high soil Cu content. In conclusion, it is suggested that in order to define efficient low-cost phytostabilization processes, the use of native resources (i.e., mixtures of native mycorrhizal fungi) in combination with fast-growing tree species such as Eucalyptus, could be used to optimize the establishment of a permanent cover plant in contaminated areas. PMID- 26529095 TI - GC-Based Techniques for Breath Analysis: Current Status, Challenges, and Prospects. AB - Breath analysis is a noninvasive diagnostic method that profiles a person's physical state by volatile organic compounds in the breath. It has huge potential in the field of disease diagnosis. In order to offer opportunities for practical applications, various GC-based techniques have been investigated for on-line breath analysis since GC is the most preferred technique for mixed gas separation. This article reviews the development of breath analysis and GC-based techniques in basic breath research, involving sampling methods, preconcentration methods, conventional GC-based techniques, and newly developed GC techniques for breath analysis. The combination of GC and newly developed detection techniques takes advantages of the virtues of each. In addition, portable GC or micro GC are poised to become field GC-based techniques in breath analysis. Challenges faced in GC-based techniques for breath analysis are discussed candidly. Effective cooperation of experts from different fields is urgent to promote the development of breath analysis. PMID- 26529097 TI - The Growing Trend of Moderate Preterm Births: An Ecological Study in One Region of Brazil. AB - BACKGROUND: Preterm birth is a serious public health problem, as it is linked to high rates of neonatal and child morbidity and mortality, with Brazil listed among the countries with the ten highest numbers of premature births. Nonetheless, knowledge is scarce regarding prematurity and associated factors in mid-sized cities. The objective of this study was to analyze the trend of preterm births and associated factors in a municipality located in the state of Parana, Brazil. METHODS: This was an ecological time series study of births recorded into the Live Birth Information System for residents of Maringa, Parana, Brazil, between 2000 and 2013. The polynomial regression model was used for trend analysis of preterm birth, characteristics of the mother, gestation and delivery, and newborn. The association with preterm birth was analyzed using odds ratio (OR). RESULTS: A total of 61,634 live births were analyzed, of which 5,632 were preterm births. Prematurity increased from 7.9% in 2000 to 11.2% in 2013 -an average increase of 0.54% per year (r2 = 0.93)-with a growing share of moderate preterm births (32 to <37 weeks), which rose from 7.0% in 2000 to 9.7% in 2013. Between 2011 and 2013, multiple pregnancy (OR = 16.64; CI = 13.24-20.92), inadequate number of prenatal visits (OR = 2.81; CI = 2.51-3.15), Apgar score below 7 at 1 (OR = 4.07; CI = 3.55-4.67) and 5 minutes (OR = 10.88; CI = 7.71 15.36), low birth weight (OR = 38.75; CI = 33.72-44.55) and congenital malformations (OR = 3.18; CI = 2.14-4.74) were associated with preterm birth. A growing trend was observed for multiple pregnancies, with an average annual increase of 0.32% (r2 = 0.90), as well as for C-section birth (2.38% yearly increase). Of all newborn characteristics, Apgar score below 7 at 5 minutes ( 0.19% per year) and low birth weight (-1.43%) decreased, whereas congenital malformations rose (0.20% per year). CONCLUSIONS: Efforts are required to prevent premature delivery, particularly during the moderate period, as well as greater care during the prenatal period towards expectant mothers bearing multiple pregnancies, birth defects, in addition to reducing C-section birth as it may be linked to preterm birth. PMID- 26529096 TI - TNF Accelerates Death of Mandibular Condyle Chondrocytes in Rats with Biomechanical Stimulation-Induced Temporomandibular Joint Disease. AB - OBJECTIVE: To determine if temporomandibular joint chondrocyte apoptosis is induced in rats with dental biomechanical stimulation and what a role TNF takes. METHODS: Thirty-two rats were divided into 4 groups (n = 8/group) and exposed to incisor mal-occlusion induced by unilateral anterior crossbite biomechanical stimulation. Two groups were sampled at 2 or 4 weeks. The other two groups were treated with local injections of a TNF inhibitor or PBS into the temporomandibular joints area at 2 weeks and then sampled at 4 weeks. Twenty-four rats either served as unilateral anterior crossbite mock operation controls (n = 8/group) with sampling at 2 or 4 weeks or received a local injection of the TNF inhibitor at 2 weeks with sampling at 4 weeks. Chondrocytes were isolated from the temporomandibular joints of 6 additional rats and treated with TNF in vitro. Joint samples were assessed using Hematoxylin&eosin, Safranin O, TUNEL and immunohistochemistry staining, real-time PCR, fluorogenic activity assays and Western blot analyses. The isolated chondrocytes were also analyzed by flow cytometry. RESULTS: Unilateral anterior crossbite stimulation led to temporomandibular joint cartilage degradation, associated with an increase in TUNEL-positive chondrocytes number, caspase-9 expression levels, and the release of cytochrome c from mitochondria at 2 weeks without changes in TNF and caspase-8 levels until after 4 weeks. TNF stimulated apoptosis of the isolated chondrocytes and up-regulated caspase-8 expression, but did not change caspase-9 expression levels. Local injection of TNF inhibitor down-regulated caspase-8 expression and reduced TUNEL-positive cell number, but did not reverse cartilage thickness reduction, caspase-9 up-regulation or cytochrome c release. CONCLUSIONS: Unilateral anterior crossbite stimulation induces mitochondrion-mediated apoptosis of articular chondrocytes. TNF accelerated the unilateral anterior crossbite induced chondrocytes apoptosis via death-receptor pathway. However, anti-TNF therapy does not prevent cartilage loss in this model of temporomandibular joint. PMID- 26529098 TI - Influence of Spirituality and Modesty on Acceptance of Self-Sampling for Cervical Cancer Screening. AB - INTRODUCTION: Whereas systematic screening programs have reduced the incidence of cervical cancer in developed countries, the incidence remains high in developing countries. Among several barriers to uptake of cervical cancer screening, the roles of religious and cultural factors such as modesty have been poorly studied. Knowledge about these factors is important because of the potential to overcome them using strategies such as self-collection of cervico-vaginal samples. In this study we evaluate the influence of spirituality and modesty on the acceptance of self-sampling for cervical cancer screening. METHODOLOGY: We enrolled 600 participants in Nigeria between August and October 2014 and collected information on spirituality and modesty using two scales. We used principal component analysis to extract scores for spirituality and modesty and logistic regression models to evaluate the association between spirituality, modesty and preference for self-sampling. All analyses were performed using STATA 12 (Stata Corporation, College Station, Texas, USA). RESULTS: Some 581 (97%) women had complete data for analysis. Most (69%) were married, 50% were Christian and 44% were from the south western part of Nigeria. Overall, 19% (110/581) of the women preferred self sampling to being sampled by a health care provider. Adjusting for age and socioeconomic status, spirituality, religious affiliation and geographic location were significantly associated with preference for self-sampling, while modesty was not significantly associated. The multivariable OR (95% CI, p-value) for association with self-sampling were 0.88 (0.78-0.99, 0.03) for spirituality, 1.69 (1.09-2.64, 0.02) for religious affiliation and 0.96 (0.86-1.08, 0.51) for modesty. CONCLUSION: Our results show the importance of taking cultural and religious beliefs and practices into consideration in planning health interventions like cervical cancer screening. To succeed, public health interventions and the education to promote it must be related to the target population and its preferences. PMID- 26529099 TI - Women's experiences with medication for menstrual regulation in Bangladesh. AB - Menstrual regulation has been legal in Bangladesh since 1974, but the use of medication for menstrual regulation is new. In this study, we sought to understand women's experiences using medication for menstrual regulation in Bangladesh. We conducted 20 in-depth interviews with rural and urban women between December 2013 and February 2014. All interviews were audiotaped, transcribed, translated, computer recorded and coded for analysis. The majority of women in our study had had positive experiences with medication for menstrual regulation and successful outcomes, regardless of whether they obtained their medication from medicine sellers/pharmacies, doctors or clinics. Women were strongly influenced by health providers when deciding which method to use. There is a need to educate not only women of reproductive age, but also communities as a whole, about medication for menstrual regulation, with a particular emphasis on cost and branding the medication. Continued efforts to improve counselling by providers about the dose, medication and side-effects of medication for menstrual regulation, along with education of the community about medication as an option for menstrual regulation, will help to de-stigmatise the procedure and the women who seek it. PMID- 26529093 TI - Dispersion of the HIV-1 Epidemic in Men Who Have Sex with Men in the Netherlands: A Combined Mathematical Model and Phylogenetic Analysis. AB - BACKGROUND: The HIV-1 subtype B epidemic amongst men who have sex with men (MSM) is resurgent in many countries despite the widespread use of effective combination antiretroviral therapy (cART). In this combined mathematical and phylogenetic study of observational data, we aimed to find out the extent to which the resurgent epidemic is the result of newly introduced strains or of growth of already circulating strains. METHODS AND FINDINGS: As of November 2011, the ATHENA observational HIV cohort of all patients in care in the Netherlands since 1996 included HIV-1 subtype B polymerase sequences from 5,852 patients. Patients who were diagnosed between 1981 and 1995 were included in the cohort if they were still alive in 1996. The ten most similar sequences to each ATHENA sequence were selected from the Los Alamos HIV Sequence Database, and a phylogenetic tree was created of a total of 8,320 sequences. Large transmission clusters that included >=10 ATHENA sequences were selected, with a local support value >= 0.9 and median pairwise patristic distance below the fifth percentile of distances in the whole tree. Time-varying reproduction numbers of the large MSM majority clusters were estimated through mathematical modeling. We identified 106 large transmission clusters, including 3,061 (52%) ATHENA and 652 Los Alamos sequences. Half of the HIV sequences from MSM registered in the cohort in the Netherlands (2,128 of 4,288) were included in 91 large MSM-majority clusters. Strikingly, at least 54 (59%) of these 91 MSM-majority clusters were already circulating before 1996, when cART was introduced, and have persisted to the present. Overall, 1,226 (35%) of the 3,460 diagnoses among MSM since 1996 were found in these 54 long-standing clusters. The reproduction numbers of all large MSM-majority clusters were around the epidemic threshold value of one over the whole study period. A tendency towards higher numbers was visible in recent years, especially in the more recently introduced clusters. The mean age of MSM at diagnosis increased by 0.45 years/year within clusters, but new clusters appeared with lower mean age. Major strengths of this study are the high proportion of HIV-positive MSM with a sequence in this study and the combined application of phylogenetic and modeling approaches. Main limitations are the assumption that the sampled population is representative of the overall HIV positive population and the assumption that the diagnosis interval distribution is similar between clusters. CONCLUSIONS: The resurgent HIV epidemic amongst MSM in the Netherlands is driven by several large, persistent, self-sustaining, and, in many cases, growing sub-epidemics shifting towards new generations of MSM. Many of the sub-epidemics have been present since the early epidemic, to which new sub-epidemics are being added. PMID- 26529100 TI - Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3. AB - Cancer progression depends on stepwise accumulation of oncogenic mutations and a select group of growth factors essential for tumor growth, metastasis and angiogenesis. Agents blocking the epidermal growth factor receptor (EGFR, also called HER1 and ERBB1) and the co-receptor called HER2/ERBB2 have been approved over the last decade as anti-cancer drugs. Because the catalytically defective member of the family, HER3/ERBB3, plays critical roles in emergence of resistance of carcinomas to various drugs, current efforts focus on antibodies and other anti-HER3/ERBB3 agents, which we review herein with an emphasis on drug combinations and some unique biochemical features of HER3/ERBB3. PMID- 26529102 TI - Psychiatric Hospital Bed Numbers and Prison Population Sizes in 26 European Countries: A Critical Reconsideration of the Penrose Hypothesis. AB - BACKGROUND: Recently, there has been a revived interest in the validity of the Penrose hypothesis, which was originally postulated over 75 years ago. It suggests an inverse relationship between the numbers of psychiatric hospital beds and the sizes of prison population. This study aims to investigate the association between psychiatric hospital beds and prison populations in a large sample of 26 European countries between 1993 and 2011. METHODS: The association between prison population sizes and numbers of psychiatric hospital beds was assessed by means of Spearman correlations and modeled by a mixed random coefficient regression model. Socioeconomic variables were considered as covariates. Data were retrieved from Eurostat, the statistical office of the European Union. OUTCOMES: Mean Spearman correlation coefficients between psychiatric beds and prison population showed a significant negative association (-0.35; p = <0.01). However, in the mixed regression model including socioeconomic covariates there were no significant fixed parameter estimates. Meanwhile, the covariance estimates for the random coefficients psychiatric beds (sigma2 = 0.75, p = <0.01) and year (sigma2 = 0.0007, p = 0.03) yielded significant results. INTERPRETATION: These findings do not support the general validity of the Penrose hypothesis. Notably, the results of the mixed-model show a significant variation in the magnitude and direction of the association of psychiatric hospital bed numbers and the prison population sizes between countries. In this sense, our results challenge the prevalent opinion that a reduction of psychiatric beds subsequently leads to increasing incarcerations. These findings also work against the potential stigmatization of individuals suffering from mental disorders as criminals, which could be an unintentional byproduct of the Penrose hypothesis. PMID- 26529101 TI - Brain-Derived Neurotrophic Factor and Antidepressive Effect of Electroconvulsive Therapy: Systematic Review and Meta-Analyses of the Preclinical and Clinical Literature. AB - Emerging data suggest that Electro-Convulsive Treatment (ECT) may reduce depressive symptoms by increasing the expression of Brain-Derived Neurotrophic Factor (BDNF). Yet, conflicting findings have been reported. For this reason we performed a systematic review and meta-analysis of the preclinical and clinical literature on the association between ECT treatment (ECS in animals) and changes in BDNF concentrations and their effect on behavior. In addition, regional brain expression of BDNF in mouse and human brains were compared using Allen Brain Atlas. ECS, over sham, increased BDNF mRNA and protein in animal brain (effect size [Hedge's g]: 0.38-0.54; 258 effect-size estimates, N = 4,284) but not in serum (g = 0.06, 95% CI = -0.05-0.17). In humans, plasma but not serum BDNF increased following ECT (g = 0.72 vs. g = 0.14; 23 effect sizes, n = 281). The gradient of the BDNF increment in animal brains corresponded to the gradient of the BDNF gene expression according to the Allen brain atlas. Effect-size estimates were larger following more ECT sessions in animals (r = 0.37, P < .0001) and in humans (r = 0.55; P = 0.05). There were some indications that the increase in BDNF expression was associated with behavioral changes in rodents, but not in humans. We conclude that ECS in rodents and ECT in humans increase BDNF concentrations but this is not consistently associated with changes in behavior. PMID- 26529103 TI - Self-Care Behaviors of African Americans Living with Heart Failure. AB - African Americans have a higher risk of developing heart failure (HF) than persons from other ethnic groups. Once diagnosed, they have lower rates of HF self-care and poorer health outcomes. Promoting engagement in HF self-care is amenable to change and represents an important way to improve the health of African Americans with HF. This study used a community-based participatory action research methodology called photovoice to explore the practice of HF self-care among low-income, urban, community dwelling African Americans. Using the photovoice methodology, themes emerged regarding self-care management and self care maintenance. PMID- 26529104 TI - Annual Cognitive Assessment for Older Adults: Update for Nurses. AB - Alzheimer's disease is predicted to bankrupt Medicare by 2050 if current trends in disease prevalence do not change (Alzheimer's Association, 2012). Earlier diagnosis and access to health care for Alzheimer's disease result in decreased health care costs (Brosch & Matthews, 2014). Consequently, in January 2011 screening for cognitive impairment became a component of the annual wellness visit (AWV) outlined in the Patient Protection and Affordable Care Act. Many community health nurses are unaware of this benefit. This article includes a review of the updated 2011 definition of Alzheimer's disease, the components of the AWV, and tools for conducting cognitive assessment. PMID- 26529105 TI - Association of Self-Efficacy and Self-Regulation with Nutrition and Exercise Behaviors in a Community Sample of Adults. AB - This study examined the association of self-efficacy and self-regulation with nutrition and exercise behaviors. The study used a cross-sectional design and included 108 participants (54 men, 54 women). Nutrition behaviors (fruit/vegetable consumption, dinner cooking, and restaurant eating) and exercise were measured using total days in last week a behavior was reported. Instruments measuring self-efficacy and self-regulation demonstrated excellent Cronbach's alphas (.93-.95). Path analysis indicated only fruit/vegetable consumption and exercise were associated with self-efficacy and self-regulation. Self-regulation showed direct association with fruit/vegetable consumption and exercise, but self efficacy had direct association only with exercise. Self-efficacy and self regulation should be strategically used to promote health behaviors. PMID- 26529106 TI - An Environmental Clinical Experience in a RN-BS Program. PMID- 26529107 TI - Design of a Medical Triage Evidence-Based Clinical Management Protocol and Implementation of Medical Triage On-Line Training for Use by Mission of Mercy Volunteers. AB - Evidence-based protocols in safety net settings can help standardize care practices, increase organizational workflow, and enhance quality outcomes for those receiving services. The purpose of this quality improvement project is two fold: to design an evidence-based medical triage clinical management protocol, and, to influence adherence to that protocol by safety net medical triage volunteers through an on-line volunteer orientation. Leadership skills were required to help translate evidence-based practice recommendations into useful tools to assist in directing practice. Project outcomes included successful multidisciplinary practice change, significantly improved volunteer knowledge surrounding medical triage protocol parameters, increased organizational workflow, and enhanced quality client outcomes. PMID- 26529110 TI - Acute Myocardial Infarction Risk in Patients with Coronary Artery Disease Doubled after Upper Gastrointestinal Tract Bleeding: A Nationwide Nested Case-Control Study. AB - Prior studies of upper gastrointestinal bleeding (UGIB) and acute myocardial infarction (AMI) are small, and long-term effects of UGIB on AMI have not been delineated. We investigated whether UGIB in patients diagnosed with coronary artery disease (CAD) increased their risk of subsequent AMI. This was a population-based, nested case-control study using Taiwan's National Health Insurance Research Database. After propensity-score matching for age, gender, comorbidities, CAD date, and follow-up duration, we identified 1,677 new-onset CAD patients with AMI (AMI[+]) between 2001 and 2006 as the case group and 10,062 new-onset CAD patients without (AMI[-]) as the control group. Conditional logistic regression was used to examine the association between UGIB and AMI. Compared with UGIB[-] patients, UGIB[+] patients had twice the risk for subsequent AMI (adjusted odds ratio [AOR] = 2.08; 95% confidence interval [CI], 1.72-2.50). In the subgroup analysis for gender and age, UGIB[+] women (AOR = 2.70; 95% CI, 2.03-3.57) and patients < 65 years old (AOR = 2.23; 95% CI, 1.56 3.18) had higher odds of an AMI. UGIB[+] AMI[+] patients used nonsignificantly less aspirin than did UGIB[-] AMI[+] patients (27.69% vs. 35.61%, respectively). UGIB increased the risk of subsequent AMI in CAD patients, especially in women and patients < 65. This suggests that physicians need to use earlier and more aggressive intervention to detect UGIB and prevent AMI in CAD patients. PMID- 26529111 TI - A Soluble Activin Receptor IIB Fails to Prevent Muscle Atrophy in a Mouse Model of Spinal Cord Injury. AB - Myostatin (MST) is a potent regulator of muscle growth and size. Spinal cord injury (SCI) results in marked atrophy of muscle below the level of injury. Currently, there is no effective pharmaceutical treatment available to prevent sublesional muscle atrophy post-SCI. To determine whether inhibition of MST with a soluble activin IIB receptor (RAP-031) prevents sublesional SCI-induced muscle atrophy, mice were randomly assigned to the following groups: Sham-SCI; SCI+Vehicle group (SCI-VEH); and SCI+RAP-031 (SCI-RAP-031). SCI was induced by complete transection at thoracic level 10. Animals were euthanized at 56 days post-surgery. RAP-031 reduced, but did not prevent, body weight loss post-SCI. RAP-031 increased total lean tissue mass compared to SCI-VEH (14.8%). RAP-031 increased forelimb muscle mass post-SCI by 38% and 19% for biceps and triceps, respectively (p < 0.001). There were no differences in hindlimb muscle weights between the RAP-031 and SCI-VEH groups. In the gastrocnemius, messenger RNA (mRNA) expression was elevated for interleukin (IL)-6 (8-fold), IL-1beta (3 fold), and tumor necrosis factor alpha (8-fold) in the SCI-VEH, compared to the Sham group. Muscle RING finger protein 1 mRNA was 2-fold greater in the RAP-031 group, compared to Sham-SCI. RAP-031 did not influence cytokine expression. Bone mineral density of the distal femur and proximal tibia were decreased post-SCI ( 26% and -28%, respectively) and were not altered by RAP-031. In conclusion, MST inhibition increased supralesional muscle mass, but did not prevent sublesional muscle or bone loss, or the inflammation in paralyzed muscle. PMID- 26529112 TI - DOS and electron attachment effects in the electron-induced vibrational excitation of terphenylthiol SAMs. AB - Low energy electron scattering on terphenylthiol (TPT, HS-(C6H4)2-C6H5) self assembled monolayers (SAMs) deposited onto gold was investigated using high resolution electron energy loss spectroscopy (HREELS) by recording specular elastic and inelastic excitation functions. The electron elastic reflectivity could be directly compared to the sample density-of-states (DOS) above vacuum level. A high reflectivity region was observed in the range 7.2-8.6 eV. Inelastic excitation functions were studied to get insights into the mechanisms involved in the excitation of a selection of vibrational modes (dipolar and impact scattering). In particular, a resonant mechanism was observed in the excitation of the stretching mode nu(CC) at 196 meV. The purely resonant contribution to the electron-induced excitation of the stretching modes nu(CH) (379 meV) could be extracted from the overtone excitation. It is located at 7.2 eV above the vacuum level and is characterized by a width of 3.4 eV. PMID- 26529113 TI - Correction: Antioxidant Activity of Caffeic Acid against Iron-Induced Free Radical Generation--A Chemical Approach. PMID- 26529114 TI - The Temporal Profiles of Changes in Nerve Excitability Indices in Familial Amyloid Polyneuropathy. AB - Familial amyloid polyneuropathy (FAP) caused by a mutation in transthyretin (TTR) gene is an autosomal dominant inherited disorder. The aim of this study is to explore the pathophysiological mechanism of FAP. We prospectively recruited 12 pauci-symptomatic carriers, 18 patients who harbor a TTR mutation, p.A97S, and two-age matched control groups. Data of nerve excitability test (NET) from ulnar motor and sensory axons were collected.NET study of ulnar motor axons of patients shows increased threshold and rheobase, reduced threshold elevation during hyperpolarizing threshold electrotonus (TE), and increased refractoriness. In sensory nerve studies, there are increased threshold reduction in depolarizing TE, lower slope of recovery and delayed time to overshoot after hyperpolarizing TE, increased refractoriness and superexcitability in recovery cycle. NET profiles obtained from the ulnar nerve of carriers show the increase of threshold and rheobase, whereas no significant threshold changes in hyperpolarizing TE and superexcitability. The regression models demonstrate that the increase of refractoriness and prolonged relative refractory period are correlated to the disease progression from carriers to patients. The marked increase of refractoriness at short-width stimulus suggests a defect in sodium current which may represent an early, pre-symptomatic pathophysiological change in TTR-FAP. Focal disruption of basal lamina and myelin may further increase the internodal capacity, manifested by the lower slope of recovery and delayed time to overshoot after hyperpolarization TE as well as the increase of superexcitability. NET could therefore make a pragmatic tool for monitoring disease progress from the very early stage of TTR-FAP. PMID- 26529117 TI - Innovations in EMS Fellow Education. PMID- 26529116 TI - Experimental resource pulses influence social-network dynamics and the potential for information flow in tool-using crows. AB - Social-network dynamics have profound consequences for biological processes such as information flow, but are notoriously difficult to measure in the wild. We used novel transceiver technology to chart association patterns across 19 days in a wild population of the New Caledonian crow--a tool-using species that may socially learn, and culturally accumulate, tool-related information. To examine the causes and consequences of changing network topology, we manipulated the environmental availability of the crows' preferred tool-extracted prey, and simulated, in silico, the diffusion of information across field-recorded time ordered networks. Here we show that network structure responds quickly to environmental change and that novel information can potentially spread rapidly within multi-family communities, especially when tool-use opportunities are plentiful. At the same time, we report surprisingly limited social contact between neighbouring crow communities. Such scale dependence in information-flow dynamics is likely to influence the evolution and maintenance of material cultures. PMID- 26529118 TI - Relapse Prevention in Major Depressive Disorder After Successful Acute Electroconvulsive Treatment: a 6-month Double-blind Comparison of Three Fixed Dosages of Escitalopram and a Fixed Dose of Nortriptyline - Lessons from a Failed Randomised Trial of the Danish University Antidepressant Group (DUAG-7). AB - INTRODUCTION: Electroconvulsive treatment (ECT) is an effective treatment for severe depression but carries a risk of relapse in the following months. METHODS: Major depressive disorder patients in a current episode attaining remission from ECT (17-item Hamilton Depression Rating Scale (HAM-D17) score<=9) received randomly escitalopram 10 mg, 20 mg, 30 mg or nortriptyline 100 mg as monotherapies and were followed for 6 months in a multicentre double-blind set up. Primary endpoint was relapse (HAM-D17>=16). RESULTS: As inclusion rate was low the study was prematurely stopped with only 47 patients randomised (20% of the planned sample size). No statistically significant between-group differences could be detected. When all patients receiving escitalopram were compared with those receiving nortriptyline, a marginal superiority of nortriptyline was found (p=0.08). One third of patients relapsed during the study period, and one third completed. DISCUSSION: Due to small sample size, no valid efficacy inferences could be made. The outcome was poor, probably due to tapering off of non-study psychotropic drugs after randomisation; this has implications for future study designs. ClinicalTrials.gov Identifier: NCT00660062. PMID- 26529119 TI - Effects of training pre-movement sensorimotor rhythms on behavioral performance. AB - OBJECTIVE: Brain-computer interface (BCI) technology might contribute to rehabilitation of motor function. This speculation is based on the premise that modifying the electroencephalographic (EEG) activity will modify behavior, a proposition for which there is limited empirical data. The present study asked whether learned modulation of pre-movement sensorimotor rhythm (SMR) activity can affect motor performance in normal human subjects. APPROACH: Eight individuals first performed a joystick-based cursor-movement task with variable warning periods. Targets appeared randomly on a video monitor and subjects moved the cursor to the target and pressed a select button within 2 s. SMR features in the pre-movement EEG that correlated with performance speed and accuracy were identified. The subjects then learned to increase or decrease these features to control a two-target BCI task. Following successful BCI training, they were asked to increase or decrease SMR amplitude in order to initiate the joystick task. MAIN RESULTS: After BCI training, pre-movement SMR amplitude was correlated with performance in subjects with initial poor performance: lower amplitude was associated with faster and more accurate movement. The beneficial effect on performance of lower SMR amplitude was greater in subjects with lower initial performance levels. SIGNIFICANCE: These results indicate that BCI-based SMR training can affect a standard motor behavior. They provide a rationale for studies that integrate such training into rehabilitation protocols and examine its capacity to enhance restoration of useful motor function. PMID- 26529120 TI - Potent Human Telomerase Inhibitors: Molecular Dynamic Simulations, Multiple Pharmacophore-Based Virtual Screening, and Biochemical Assays. AB - Telomere maintenance is a universal cancer hallmark, and small molecules that disrupt telomere maintenance generally have anticancer properties. Since the vast majority of cancer cells utilize telomerase activity for telomere maintenance, the enzyme has been considered as an anticancer drug target. Recently, rational design of telomerase inhibitors was made possible by the determination of high resolution structures of the catalytic telomerase subunit from a beetle and subsequent molecular modeling of the human telomerase complex. A hybrid strategy including docking, pharmacophore-based virtual screening, and molecular dynamics simulations (MDS) were used to identify new human telomerase inhibitors. Docking methodology was applied to investigate the ssDNA telomeric sequence and two well known human telomerase inhibitors' (BIBR1532 and MST-312) modes of interactions with hTERT TEN domain. Subsequently molecular dynamic simulations were performed to monitor and compare hTERT TEN domain, TEN-ssDNA, TEN-BIBR1532, TEN-MST-312, and TEN-ssDNA-BIBR1532 behavior in a dynamic environment. Pharmacophore models were generated considering the inhibitors manner in the TEN domain anchor site. These exploratory studies identified several new potent inhibitors whose IC50 values were generated experimentally in a low micromolar range with the aid of biochemical assays, including both the direct telomerase and the telomeric repeat amplification protocol (TRAP) assays. The results suggest that the current models of human telomerase are useful templates for rational inhibitor design. PMID- 26529121 TI - Dysregulation of Wnt-Signaling and a Candidate Set of miRNAs Underlie the Effect of Metformin on Neural Crest Cell Development. AB - Neural crest cells (NCC) are a population of epithelial cells that arise from the dorsal tube and undergo epithelial-mesenchymal transition (EMT) eventually generating tissues from peripheral nervous system, melanocytes, craniofacial cartilage, and bone. The antidiabetic drug metformin reportedly inhibits EMT in physiological conditions like cancer and fibrosis. We hypothesize that perturbation of EMT may also contribute to developmental disabilities associated with neural crest (NC) development. To understand the molecular network underlying metformin action during NC formation, we first differentiated murine embryonic stem (ES) cells into NCC and characterized them by demonstrating spatiotemporal regulation of key markers. Metformin treatment prompted a delay in delamination of NCC by inhibiting key markers like Sox-1, Sox-9, HNK-1, and p-75. We then revealed that metformin impedes Wnt axis, a major signaling pathway active during NC formation via DVL-3 inhibition and impairment in nuclear translocation of beta-catenin. Concomitantly we identified and tested a candidate set of miRNAs that play a crucial role in NC cell fate determination. Further studies involving loss and gain of function confirmed that NCC specifiers like Sox-1 and Sox-9 are direct targets of miR-200 and miR-145, respectively and that they are essentially modulated by metformin. Our in vitro findings were strongly supported by in vivo studies in zebrafish. Given that metformin is a widely used drug, for the first time we demonstrate that it can induce a delayed onset of developmental EMT during NC formation by interfering with canonical Wnt signaling and mysregulation of miR-145 and miR-200. PMID- 26529122 TI - The Combination of Anti-CTLA-4 and PD1-/- Mice Unmasks the Potential of Isoniazid and Nevirapine To Cause Liver Injury. AB - Our laboratory recently reported what we believe is the first valid animal model of idiosyncratic drug-induced liver injury (IDILI) by treating PD1-/- mice with an anti-CTLA-4 antibody and amodiaquine (AQ). PD1 and CTLA-4 are important immune checkpoint receptors that are involved in inducing immune tolerance. This model was able to produce significant liver injury that looks very similar to the liver injury seen in humans. Although this model was shown to work with AQ, the question becomes whether blocking immune tolerance would unmask the potential of other drugs to cause IDILI. In this study, we tested isoniazid and nevirapine, both drugs with significant histories of causing IDILI in humans even though they do not cause significant injury in animals with doses that result in therapeutic blood levels. Both drugs in combination with these immune checkpoint inhibitors caused mild but significant delayed onset liver injury, which is similar to the mild injury that they can cause in humans. INH-induced liver injury in this model was associated with an increase in NK cells, while NVP-induced liver injury was associated with a greater increase in CD8 T cells. Although the liver injury caused by these drugs in this model was mild, these results suggest that impairing immune tolerance may be a general method for unmasking the potential of drugs to cause IDILI and therefore provide a screening tool for drug development. PMID- 26529123 TI - Parallel Plating of Simulated Distal Humerus Fractures Demonstrates Increased Stiffness Relative to Orthogonal Plating With a Distal Humerus Locking Plate System. AB - OBJECTIVES: This study compared the stiffness of precontoured parallel and orthogonal locking plate configurations in cyclic torsion and bending, and then extension to failure. METHODS: Tests were conducted on 9 matched pairs of cadaveric humeri. A 10 mm block of bone was excised from the distal humerus metaphysis to simulate comminution, and fractures were repaired in matched fashion using parallel or orthogonal Biomet ALPS distal humerus locking plates (Biomet, Inc, Warsaw, IN). Specimens were tested at 0.5 degree per second up to +/-2 N-m in internal and external rotation for 20 cycles, then in flexion and extension cantilevered bending at 1 mm/s to +/-50 N, followed by bending at 1 mm/s to failure in extension. RESULTS: Torsional stiffness of the parallel configuration group was greater than the orthogonal configuration in both internal and external rotation (P < 0.0001). Also, stiffness in bending was significantly greater in the parallel configuration group in both flexion and extension (P < 0.0001). In extension to failure testing, the parallel plate construct stiffness was significantly greater than the orthogonal configuration (P < 0.005). CONCLUSIONS: The parallel plate configuration demonstrated significantly greater stiffness than the orthogonal plate configuration in torsion and bending using locked distal humerus plates. This greater stiffness may prove desirable in the postoperative management of patients with comminuted distal humerus fractures, providing a stable anatomic reconstruction of the joint to allow early range of motion. PMID- 26529124 TI - Symptom severity, self-reported adherence, and electronic pill monitoring in poorly adherent patients with bipolar disorder. AB - OBJECTIVES: This analysis of screening and baseline data from an ongoing trial examined self-report versus automated adherence monitoring and assessed the relationship between bipolar disorder (BD) symptoms and adherence in 104 poorly adherent individuals. METHODS: Adherence was measured with the Tablets Routine Questionnaire (TRQ) and the Medication Event Monitoring System (MEMS). Symptoms were measured with the Montgomery-Asberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), and the Brief Psychiatric Rating Scale (BPRS). RESULTS: The mean age of the sample was 46.3 years [standard deviation (SD) = 9.41 years], with 72% (n = 75) women and 71% (n = 74) African American subjects. Adherence improved from screening to baseline, with a mean missed drug proportion measured by TRQ of 61.43% (SD = 26.48%) versus a baseline mean of 46.61% (SD = 30.55%). The mean proportion of missed medication using MEMS at baseline was 66.43% (SD = 30.40%). The correlation between TRQ and MEMS was 0.47. The correlation between a single index drug and all BD medications was 0.95. Symptoms were generally positively correlated with TRQ (worse adherence = more severe symptoms), but in most instances was only at a trend level (p > 0.05), with the exception of the correlations between baseline TRQ and MADRS and BPRS, which were positive (r = 0.20 and r = 0.21, respectively) and significant (p <= 0.05). CONCLUSIONS: In patients with BD, monitoring increased adherence by 15%. MEMS identified 20% more non-adherence than self-report. Using a standard procedure to identify a single index drug for adherence monitoring may be one way to assess global adherence in patients with BD receiving polypharmacy treatment. Greater BD symptom severity may be a clinical indicator to assess for adherence problems. PMID- 26529125 TI - ERK Plays a Role in Chromosome Alignment and Participates in M-Phase Progression. AB - Cell division, a prerequisite for cell proliferation, is a process in which each daughter cell inherits one complete set of chromosomes. The mitotic spindle is a dedicated apparatus for the alignment and segregation of chromosomes. Extracellular signal-regulated kinase (ERK) 1/2 plays crucial roles in cell cycle progression, particularly during M-phase. Although, association with the mitotic spindle has been reported, the precise roles played by ERK in the dynamics of the mitotic spindle and in M-phase progression remain to be elucidated. In this study, we used MEK inhibitors U0126 and GSK1120212 to dissect the roles of ERK in M-phase progression and chromosome alignment. Fluorescence microscopy revealed that ERK is localized to the spindle microtubules in a manner independent of Src kinase, which is one of the kinases upstream of ERK at mitotic entry. ERK inhibition induces an increase in the number of prophase cells and a decrease in the number of anaphase cells. Time-lapse imaging revealed that ERK inhibition perturbs chromosome alignment, thereby preventing cells from entering anaphase. These results suggest that ERK plays a role in M-phase progression by regulating chromosome alignment and demonstrate one of the mechanisms by which the aberration of ERK signaling may produce cancer cells. PMID- 26529127 TI - How Atomic Steps Modify Diffusion and Inter-adsorbate Forces: Empirical Evidence from Hopping Dynamics in Na/Cu(115). AB - We followed the collective atomic-scale motion of Na atoms on a vicinal Cu(115) surface within a time scale of pico- to nanoseconds using helium spin echo spectroscopy. The well-defined stepped structure of Cu(115) allows us to study the effect that atomic steps have on the adsorption properties, the rate for motion parallel and perpendicular to the step edge, and the interaction between the Na atoms. With the support of a molecular dynamics simulation we show that the Na atoms perform strongly anisotropic 1D hopping motion parallel to the step edges. Furthermore, we observe that the spatial and temporal correlations between the Na atoms that lead to collective motion are also anisotropic, suggesting the steps efficiently screen the lateral interaction between Na atoms residing on different terraces. PMID- 26529126 TI - An empirical broad spectrum antibiotic therapy in health-care-associated infections improves survival in patients with cirrhosis: A randomized trial. AB - Early diagnosis and appropriate treatment of infections in cirrhosis are crucial because of their high morbidity and mortality. Multidrug-resistant (MDR) infections are on the increase in health care settings. Health-care-associated (HCA) infections are still frequently treated as community-acquired with a detrimental effect on survival. We aimed to prospectively evaluate in a randomized trial the effectiveness of a broad spectrum antibiotic treatment in patients with cirrhosis with HCA infections. Consecutive patients with cirrhosis hospitalized with HCA infections were enrolled. After culture sampling, patients were promptly randomized to receive a standard or a broad spectrum antibiotic treatment (NCT01820026). The primary endpoint was in-hospital mortality. Efficacy, side effects, and the length of hospitalization were considered. Treatment failure was followed by a change in antibiotic therapy. Ninety-six patients were randomized and 94 were included. The two groups were similar for demographic, clinical, and microbiological characteristics. The prevalence of MDR pathogens was 40% in the standard versus 46% in the broad spectrum group. In hospital mortality showed a substantial reduction in the broad spectrum versus standard group (6% vs. 25%; P = 0.01). In a post-hoc analysis, reduction of mortality was more evident in patients with sepsis. The broad spectrum showed a lower rate of treatment failure than the standard therapy (18% vs. 51%; P = 0.001). Length of hospitalization was shorter in the broad spectrum (12.3 +/- 7 days) versus standard group (18 +/- 15 days; P = 0.03). Five patients in each group developed a second infection during hospitalization with a similar prevalence of MDR (50% broad spectrum vs. 60% standard). CONCLUSIONS: A broad spectrum antibiotic therapy as empirical treatment in HCA infections improves survival in cirrhosis. This treatment was significantly effective, safe, and cost saving. PMID- 26529131 TI - Inhibitory Effects of Zinc Ions on Enamel Demineralisation Kinetics in vitro. AB - Metal ions including zinc have the ability to influence enamel demineralisation. However, there is a paucity of data regarding reductions in demineralisation effected by zinc ions (Zn2+) in the literature. Therefore the aim was to measure the effects of zinc ion concentration ([Zn2+]) on the real-time in vitro demineralisation of enamel, during exposure to caries-simulating conditions, using scanning microradiography (SMR). Human enamel blocks were fixed in SMR environmental cells, through which acidic solutions (0.1 M acetic acid, pH 4.0) were circulated for periods of 50 h. SMR was used to quantitatively measure continuous mineral mass loss. Subsequently, the effects of sequentially increasing [Zn2+] (0.1-3,565 ppm) in the acidic solutions were measured on the rate of enamel demineralisation. This study demonstrated that Zn2+ even at low concentrations significantly reduces enamel demineralisation. There was a log linear relationship between the mean percentage reduction in demineralisation and increasing [Zn2+] up to 3,565 ppm, i.e. the change in the overall percentage reduction in demineralisation was greater at lower concentrations than at higher concentrations, with 60% reduction at 36 ppm increasing to 90% at 3,565 ppm. In conclusion, SMR demonstrated the ability of Zn2+ to reduce the rate of enamel demineralisation under real-time in vitro acid conditions simulating dental caries. The results suggest that Zn2+ in the oral fluids could protect against enamel demineralisation during an acidic challenge. The log-linear relationship between [Zn2+] and demineralisation suggests that the reduction in enamel dissolution is limited by the saturation of surface sites on the enamel surface. PMID- 26529132 TI - A sumatriptan patch (Zecuity) for migraine. PMID- 26529128 TI - Dynamics of Hydrophobic Core Phenylalanine Residues Probed by Solid-State Deuteron NMR. AB - We conducted a detailed investigation of the dynamics of two phenylalanine side chains in the hydrophobic core of the villin headpiece subdomain protein (HP36) in the hydrated powder state over the 298-80 K temperature range. Our main tools were static deuteron NMR measurements of longitudinal relaxation and line shapes supplemented with computational modeling. The temperature dependence of the relaxation times reveals the presence of two main mechanisms that can be attributed to the ring-flips, dominating at high temperatures, and small-angle fluctuations, dominating at low temperatures. The relaxation is nonexponential at all temperatures with the extent of nonexponentiality increasing from higher to lower temperatures. This behavior suggests a distribution of conformers with unique values of activation energies. The central values of the activation energies for the ring-flipping motions are among the smallest reported for aromatic residues in peptides and proteins and point to a very mobile hydrophobic core. The analysis of the widths of the distributions, in combination with the earlier results on the dynamics of flanking methyl groups (Vugmeyster et al. J. Phys. Chem. B 2013, 117, 6129-6137), suggests that the hydrophobic core undergoes slow concerted fluctuations. There is a pronounced effect of dehydration on the ring-flipping motions, which shifts the distribution toward more rigid conformers. The crossover temperature between the regions of dominance of the small-angle fluctuations and ring-flips shifts from 195 K in the hydrated protein to 278 K in the dry one. This result points to the role of solvent in softening the core and highlights aromatic residues as markers of the protein dynamical transitions. PMID- 26529133 TI - Two long-acting injectable antipsychotics for schizophrenia. PMID- 26529134 TI - Budesonide rectal foam (Uceris) for ulcerative colitis. PMID- 26529135 TI - Transdermal fentanyl (Ionsys) for postoperative pain. PMID- 26529136 TI - In brief: Hepatic injury with hepatitis C drugs. PMID- 26529137 TI - Addendum: Flibanserin (Addyi) for hypoactive sexual desire disorder. PMID- 26529138 TI - Perceived blood transfusion safety: a cross-European comparison. AB - BACKGROUND AND OBJECTIVES: During the past decades, blood transfusions have become an ever safer clinical procedure in developed countries. Extensive donor screening together with improved infectious disease testing has led to a minimization of risks for transfusion recipients. Still, the general public perceives the process of blood transfusion as risky. MATERIALS AND METHODS: This study tested variation in perceived transfusion safety across countries and explained it with individual and country factors. We examined whether individual demographic and macro-level factors (i.e. Human Development Index and Power Distance Index) explain variation within and across European countries. We applied multilevel models to 2009 Eurobarometer data collected in 26 countries (N = 20 874). RESULTS: Results were largely in line with expectations derived from risk perception and power and status difference theories. Generally, women, older adults, the lower educated and those earning lower incomes perceived heightened risk. Most of the variation across Europe was explained by the Human Development Index. Risk perception regarding blood transfusions was lower in countries with higher Human Development Indices, that is countries with higher average education, life expectancy and Gross Domestic Product. CONCLUSION: This study provides new insights of how risk perception regarding blood transfusions is shaped within and across Europe. Both individual demographic factors and country characteristics play a role. PMID- 26529139 TI - Phase-dependent climate-predator interactions explain three decades of variation in neonatal caribou survival. AB - Climate can have direct and indirect effects on population dynamics via changes in resource competition or predation risk, but this influence may be modulated by density- or phase-dependent processes. We hypothesized that for ungulates, climatic conditions close to parturition have a greater influence on the predation risk of neonates during population declines, when females are already under nutritional stress triggered by food limitation. We examined the presence of phase-dependent climate-predator (PDCP) interactions on neonatal ungulate survival by comparing spatial and temporal fluctuations in climatic conditions, cause-specific mortality and per capita resource limitation. We determined cause specific fates of 1384 caribou (Rangifer tarandus) from 10 herds in Newfoundland, spanning more than 30 years during periods of numerical increase and decline, while exposed to predation from black bears (Ursus americanus) and coyotes (Canis latrans). We conducted Cox proportional hazards analysis for competing risks, fit as a function of weather metrics, to assess pre- and post-partum climatic influences on survival on herds in population increase and decline phases. We used cumulative incidence functions to compare temporal changes in risk from predators. Our results support our main hypothesis; when caribou populations increased, weather conditions preceding calving were the main determinants of cause-specific mortality, but when populations declined, weather conditions during calving also influenced predator-driven mortality. Cause-specific analysis showed that weather conditions can differentially affect predation risk between black bears and coyotes with specific variables increasing the risk from one species and decreasing the risk from the other. For caribou, nutritional stress appears to increase predation risk on neonates, an interaction which is exacerbated by susceptibility to climatic events. These findings support the PDCP interactions framework, where maternal body condition influences susceptibility to climate-related events and, subsequently, risk from predation. PMID- 26529140 TI - Kidney transplantation in the Hispanic population. AB - Hispanic race and low socioeconomic status are established predictors of disparity in access to kidney transplantation. This single-center retrospective review was undertaken to determine whether Hispanic race predicted kidney transplant outcomes. A total of 720 patients underwent kidney transplantation from January 1, 2004 to December 31, 2013, including 398 Hispanic patients and 322 non-Hispanic patients. Hispanic patients were significantly younger (p < 0.0001), on hemodialysis for longer (p = 0.0018), had a greater percentage with public insurance (p < 0.0001), more commonly had diabetes as the cause of end stage renal disease (p = 0.0167), and had a lower percentage of living donors (p = 0.0013) compared to non-Hispanic patients. There was no difference in one-, five-, and 10-yr graft (97%, 81%, and 61% vs. 95%, 76%, and 42% p = 0.18) or patient survival (98%, 90%, and 84% vs. 97%, 87%, and 69% p = 0.11) between the Hispanic and non-Hispanic recipients. Multivariate analysis identified increased recipient age and kidney donor profile index to be predictive of lower graft survival and increasing recipient age to be predictive of lower patient survival. In the largest single-center study on kidney transplantation outcomes in Hispanic patients, there is no difference in graft and recipient survival between Hispanic and non-Hispanic kidney transplant patients, and in multivariate analysis, Hispanic race is not a risk factor for graft or patient survival. PMID- 26529141 TI - Evaluation and Outcome of Central Nervous System Involvement in Pediatric Acute Lymphoblastic Leukemia in Dar es Salaam, Tanzania. AB - BACKGROUND: Outcomes for acute lymphoblastic leukemia (ALL) in low-income countries lag far behind high-income countries (HIC). We explored the impact of central nervous system (CNS) involvement on outcome of pediatric patients with ALL in Tanzania. PROCEDURE: Comprehensive chart review was performed to characterize CNS involvement, treatment, and outcomes of pediatric patients with ALL at Muhimbili National Hospital in Dar es Salaam, Tanzania between January 1, 2011 and December 31, 2013. RESULTS: One hundred fifty-six patients with confirmed ALL had accessible data, and 128 initiated therapy. Sixteen percent of 156 patients had a documented cerebral spinal fluid analysis by cytospin. Seventy patients (45%) had a documented lumbar puncture with intrathecal (IT) therapy within 1 week of diagnosis. Thirteen patients presented with CNS involvement at diagnosis based on cytospin and/or unequivocal symptoms. Twenty-one patients (16%) experienced CNS relapse, three of whom had CNS disease at diagnosis. Median event-free survival (EFS) for all patients was 7.9 months and estimated EFS at 24 months was 31%. For the patients with CNS involvement at diagnosis, the estimated EFS at 24 months was 45%. Only three of 21 patients with CNS relapse were still alive with a median follow up of 3 months. CONCLUSIONS: The rate of CNS disease in patients with ALL in Dar es Salaam at diagnosis and relapse was higher than that reported in HIC, and overall survival was lower. Improving outcomes will require further advances including consistent CNS prophylaxis and may include targeting high-risk patients with additional IT treatments. PMID- 26529142 TI - Free-Standing Monolayer Two-Dimensional Supramolecular Organic Framework with Good Internal Order. AB - Utilizing dynamic self-assembly and self-sorting to obtain large-area, molecularly precise monolayered structures represents a promising approach toward two-dimensional supramolecular organic frameworks (2D SOF) or 2D supramolecular polymers. So far, related approaches suffer from small domain sizes, fragility and weak long-range internal order. Here we report on the self-assembly of a host guest enhanced donor-acceptor interaction, consisting of a tris(methoxynaphthyl) substituted truxene spacer, and a naphthalene diimide substituted with N-methyl viologenyl moieties as donor and acceptor monomers, respectively, in combination with cucurbit[8]uril as host monomer toward monolayers of an unprecedented 2D SOF. Featuring orthogonal solubility, the participating molecules self-assemble at a liquid-liquid interface, yielding exceptionally large-area, insoluble films, which were analyzed by transmission electron microscopy, atomic force microscopy and optical microscopy to be monolayers with a thickness of 1.8 nm, homogeneously covering areas up to 0.25 cm(2), and featuring the ability to be free-standing over holes of 10 MUm(2). Characterization with ultraviolet-visible absorption spectroscopy, solid-state nuclear magnetic resonance spectroscopy, infrared spectroscopy, and grazing incidence wide-angle X-ray scattering allowed for confirmation of a successful complexation of all three monomers toward an internal long-range order and gave indications to an expected hexagonal superstructure. Our results extend the existing variety of two-dimensional soft nanomaterials by a versatile supramolecular approach, whereas the possibility of varying the functional monomers is supposed to open adaptability to different applications like membranes, sensors, molecular sieves, and optoelectronics. PMID- 26529146 TI - Panic: Nikolay Viting. PMID- 26529143 TI - Highly Compliant Vascular Grafts with Gelatin-Sheathed Coaxially Structured Nanofibers. AB - We have developed three types of materials composed of polyurethane-gelatin, polycaprolactone-gelatin, or polylactic acid-gelatin nanofibers by coaxially electrospinning the hydrophobic core and gelatin sheath with a ratio of 1:5 at fixed concentrations. Results from attenuated total reflection-Fourier transformed infrared spectroscopy demonstrated the gelatin coating around nanofibers in all of the materials. Transmission electron microscopy images further displayed the core-sheath structures showing the core-to-sheath thickness ratio varied greatly with the highest ratio found in polyurethane-gelatin nanofibers. Scanning electron microscopy images revealed similar, uniform fibrous structures in all of the materials, which changed with genipin cross-linking due to interfiber interactions. Thermal analyses revealed varied interactions between the hydrophilic sheath and hydrophobic core among the three materials, which likely caused different core-sheath structures, and thus physicomechanical properties. The addition of gelatin around the hydrophobic polymer and their interactions led to the formation of graft scaffolds with tissue-like viscoelasticity, high compliance, excellent swelling capability, and absence of water permeability while maintaining competent tensile modulus, burst pressure, and suture retention. The hydrogel-like characteristics are advantageous for vascular grafting use, because of the capability of bypassing preclotting prior to implantation, retaining vascular fluid volume, and facilitating molecular transport across the graft wall, as shown by coculturing vascular cells sandwiched over a thick-wall scaffold. Varied core-sheath interactions within scaffolding nanofibers led to differences in graft functional properties such as water swelling ratio, compliance, and supporting growth of cocultured vascular cells. The PCL-gelatin scaffold with thick gelatin-sheathed nanofibers demonstrated a more compliant structure, elastic mechanics, and high water swelling property. Our results demonstrate a feasible approach to produce new hybrid, biodegradable nanofibrous scaffold biomaterials with interactive core sheath structure, good biocompatibility, and tissue-like viscoelasticity, which may reduce potential problems with the use of individual polymers for vascular grafts. PMID- 26529155 TI - New Opportunities for Integrating Drug Safety Risk Management Programs Into the Health Care System: Bridging the Divide. PMID- 26529156 TI - A PIECE OF MY MIND. When Minutes Matter. PMID- 26529157 TI - Antiretroviral Therapy for Nevirapine-Exposed Children With HIV Infection. PMID- 26529158 TI - Thrombectomy for Acute Ischemic Stroke. PMID- 26529159 TI - Efavirenz-Based Antiretroviral Therapy Among Nevirapine-Exposed HIV-Infected Children in South Africa: A Randomized Clinical Trial. AB - IMPORTANCE: Advantages of using efavirenz as part of treatment for children infected with human immunodeficiency virus (HIV) include once-daily dosing, simplification of co-treatment for tuberculosis, preservation of ritonavir boosted lopinavir for second-line treatment, and harmonization of adult and pediatric treatment regimens. However, there have been concerns about possible reduced viral efficacy of efavirenz in children exposed to nevirapine for prevention of mother-to-child transmission. OBJECTIVE: To evaluate whether nevirapine-exposed children achieving initial viral suppression with ritonavir boosted lopinavir-based therapy can transition to efavirenz-based therapy without risk of viral failure. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label noninferiority trial conducted at Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa, from June 2010 to December 2013, enrolling 300 HIV infected children exposed to nevirapine for prevention of mother-to-child transmission who were aged 3 years or older and had plasma HIV RNA of less than 50 copies/mL during ritonavir-boosted lopinavir-based therapy; 298 were randomized and 292 (98%) were followed up to 48 weeks after randomization. INTERVENTIONS: Participants were randomly assigned to switch to efavirenz-based therapy (n = 150) or continue ritonavir-boosted lopinavir-based therapy (n = 148). MAIN OUTCOMES AND MEASURES: Risk difference between groups in (1) viral rebound (ie, >=1 HIV RNA measurement of >50 copies/mL) and (2) viral failure (ie, confirmed HIV RNA >1000 copies/mL) with a noninferiority bound of -0.10. Immunologic and clinical responses were secondary end points. RESULTS: The Kaplan Meier probability of viral rebound by 48 weeks was 0.176 (n = 26) in the efavirenz group and 0.284 (n = 42) in the ritonavir-boosted lopinavir group. Probabilities of viral failure were 0.027 (n = 4) in the efavirenz group and 0.020 (n = 3) in the ritonavir-boosted lopinavir group. The risk difference for viral rebound was 0.107 (1-sided 95% CI, 0.028 to infinity) and for viral failure was -0.007 (1-sided 95% CI, -0.036 to infinity). We rejected the null hypothesis that efavirenz is inferior to ritonavir-boosted lopinavir (P < .001) for both end points. By 48 weeks, CD4 cell percentage was 2.88% (95% CI, 1.26%-4.49%) higher in the efavirenz group than in the ritonavir-boosted lopinavir group. CONCLUSIONS AND RELEVANCE: Among HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission and with initial viral suppression with ritonavir boosted lopinavir-based therapy, switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound or viral failure. This therapeutic approach may offer advantages in children such as these. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01146873. PMID- 26529160 TI - Trends in Prescription Drug Use Among Adults in the United States From 1999-2012. AB - IMPORTANCE: It is important to document patterns of prescription drug use to inform both clinical practice and research. OBJECTIVE: To evaluate trends in prescription drug use among adults living in the United States. DESIGN, SETTING, AND PARTICIPANTS: Temporal trends in prescription drug use were evaluated using nationally representative data from the National Health and Nutrition Examination Survey (NHANES). Participants included 37,959 noninstitutionalized US adults, aged 20 years and older. Seven NHANES cycles were included (1999-2000 to 2011 2012), and the sample size per cycle ranged from 4861 to 6212. EXPOSURES: Calendar year, as represented by continuous NHANES cycle. MAIN OUTCOMES AND MEASURES: Within each NHANES cycle, use of prescription drugs in the prior 30 days was assessed overall and by drug class. Temporal trends across cycles were evaluated. Analyses were weighted to represent the US adult population. RESULTS: Results indicate an increase in overall use of prescription drugs among US adults between 1999-2000 and 2011-2012 with an estimated 51% of US adults reporting use of any prescription drugs in 1999-2000 and an estimated 59% reporting use of any prescription drugs in 2011-2012 (difference, 8% [95% CI, 3.8%-12%]; P for trend <.001). The prevalence of polypharmacy (use of >=5 prescription drugs) increased from an estimated 8.2% in 1999-2000 to 15% in 2011-2012 (difference, 6.6% [95% CI, 4.4%-8.2%]; P for trend <.001). These trends remained statistically significant with age adjustment. Among the 18 drug classes used by more than 2.5% of the population at any point over the study period, the prevalence of use increased in 11 drug classes including antihyperlipidemic agents, antidepressants, prescription proton-pump inhibitors, and muscle relaxants. CONCLUSIONS AND RELEVANCE: In this nationally representative survey, significant increases in overall prescription drug use and polypharmacy were observed. These increases persisted after accounting for changes in the age distribution of the population. The prevalence of prescription drug use increased in the majority of, but not all, drug classes. PMID- 26529161 TI - Endovascular Thrombectomy for Acute Ischemic Stroke: A Meta-analysis. AB - IMPORTANCE: Endovascular intervention for acute ischemic stroke improves revascularization. But trials examining endovascular therapy yielded variable functional outcomes, and the effect of endovascular intervention among subgroups needs better definition. OBJECTIVE: To examine the association between endovascular mechanical thrombectomy and clinical outcomes among patients with acute ischemic stroke. DATA SOURCES: We systematically searched MEDLINE, EMBASE, CINAHL, Google Scholar, and the Cochrane Library without language restriction through August 2015. STUDY SELECTION: Eligible studies were randomized clinical trials of endovascular therapy with mechanical thrombectomy vs standard medical care, which includes the use of intravenous tissue plasminogen activator (tPA). DATA EXTRACTION AND SYNTHESIS: Independent reviewers evaluated the quality of studies and abstracted the data. We calculated odds ratios (ORs) and 95% CIs for all outcomes using random-effects meta-analyses and performed subgroup and sensitivity analyses to examine whether certain imaging, patient, treatment, or study characteristics were associated with improved functional outcome. The strength of the evidence was examined for all outcomes using the GRADE method. MAIN OUTCOMES AND MEASURES: Ordinal improvement across modified Rankin scale (mRS) scores at 90 days, functional independence (mRS score, 0-2), angiographic revascularization at 24 hours, symptomatic intracranial hemorrhage within 90 days, and all-cause mortality at 90 days. RESULTS: Data were included from 8 trials involving 2423 patients (mean [SD] age, 67.4 [14.4] years; 1131 [46.7%] women), including 1313 who underwent endovascular thrombectomy and 1110 who received standard medical care with tPA. In a meta-analysis of these trials, endovascular therapy was associated with a significant proportional treatment benefit across mRS scores (OR, 1.56; 95% CI, 1.14-2.13; P = .005). Functional independence at 90 days (mRS score, 0-2) occurred among 557 of 1293 patients (44.6%; 95% CI, 36.6%-52.8%) in the endovascular therapy group vs 351 of 1094 patients (31.8%; 95% CI, 24.6%-40.0%) in the standard medical care group (risk difference, 12%; 95% CI, 3.8%-20.3%; OR, 1.71; 95% CI, 1.18-2.49; P = .005). Compared with standard medical care, endovascular thrombectomy was associated with significantly higher rates of angiographic revascularization at 24 hours (75.8% vs 34.1%; OR, 6.49; 95% CI, 4.79-8.79; P < .001) but no significant difference in rates of symptomatic intracranial hemorrhage within 90 days (70 events [5.7%] vs 53 events [5.1%]; OR, 1.12; 95% CI, 0.77-1.63; P = .56) or all cause mortality at 90 days (218 deaths [15.8%] vs 201 deaths [17.8%]; OR, 0.87; 95% CI, 0.68-1.12; P = .27). CONCLUSIONS AND RELEVANCE: Among patients with acute ischemic stroke, endovascular therapy with mechanical thrombectomy vs standard medical care with tPA was associated with improved functional outcomes and higher rates of angiographic revascularization, but no significant difference in symptomatic intracranial hemorrhage or all-cause mortality at 90 days. PMID- 26529162 TI - Hospital-Diagnosed Pertussis Infection in Children and Long-term Risk of Epilepsy. AB - IMPORTANCE: Pertussis is associated with encephalopathy and seizures in infants. However, the risk of childhood epilepsy following pertussis is unknown. OBJECTIVE: To examine whether pertussis is associated with the long-term risk of epilepsy. DESIGN, SETTING, AND PARTICIPANTS: We used individually linked data from population-based medical registries covering all Danish hospitals to identify a cohort of all patients with pertussis born between 1978 and 2011, followed up through 2011. We used the Civil Registration System to identify 10 individuals from the general population for each patient with pertussis, matched on sex and year of birth. EXPOSURES: Inpatient or hospital-based outpatient diagnosis of pertussis. MAIN OUTCOMES AND MEASURES: Cumulative incidence and hazard ratio of time to hospital-based epilepsy diagnosis (pertussis cohort vs general population cohort), adjusted for birth year, sex, maternal history of epilepsy, presence of congenital malformations, and gestational age. Unique personal identifiers permitted unambiguous data linkage and complete follow-up for death, emigration, and hospital contacts. RESULTS: We identified 4700 patients with pertussis (48% male), of whom 90 developed epilepsy during the follow-up. The cumulative incidence of epilepsy at age 10 years was 1.7% (95% CI, 1.4%-2.1%) for patients with pertussis and 0.9% (95% CI, 0.8%-1.0%) for the matched comparison cohort. The corresponding adjusted overall hazard ratio was 1.7 (95% CI, 1.3-2.1). CONCLUSIONS AND RELEVANCE: In Denmark, risk of epilepsy was increased in children with hospital-diagnosed pertussis infections compared with the general population; however, the absolute risk was low. PMID- 26529163 TI - Diabetes Risk Assessment and Glycemic Control. PMID- 26529164 TI - Interventions for Hirsutism. AB - CLINICAL QUESTION: What medical therapies are associated with greatest efficacy and fewest adverse events for treating hirsutism? BOTTOM LINE: Oral contraceptive pills (OCPs) have been associated with improvement for mild hirsutism, as has flutamide (250 mg) twice daily and spironolactone for more severe cases. Finasteride and gonadotropin-releasing analogues are associated with inconsistent results and metformin is not associated with benefit. PMID- 26529165 TI - Evaluation of Patients With Asymptomatic Microhematuria. PMID- 26529166 TI - Trends in Neisseria gonorrhoeae Susceptibility to Cephalosporins in the United States, 2006-2014. PMID- 26529167 TI - Use of Implantable Cardioverter-Defibrillators Among Medicare Patients. PMID- 26529168 TI - Use of Implantable Cardioverter-Defibrillators Among Medicare Patients--Reply. PMID- 26529169 TI - Risk Prediction for Individuals. PMID- 26529170 TI - Risk Prediction for Individuals--Reply. PMID- 26529172 TI - Knowledge and Wisdom in Medicine. PMID- 26529173 TI - JAMA PATIENT PAGE. Bladder Cancer. PMID- 26529174 TI - Cellular and humoral coagulation profiles and occurrence of IVH in VLBW and ELWB infants. AB - BACKGROUND AND STUDY PURPOSE: Intraventricular hemorrhage (IVH) is a major complication in preterm neonates with significant long-term morbidity and an increased mortality rate. The role of the immature coagulation system in the pathogenesis of IVH in these infants is still under debate. The aim of this study was to provide reference values for coagulation studies within the first 24h of life, and to relate these findings to the incidence of IVH. PATIENTS AND METHODS: In this retrospective study, a total of 250 (male: 123/female: 127; VLBW: 150 and ELBW: 100) infants were included over a 4-year-period. Coagulation studies were performed within the first 24h of life in all infants. Multiple regression analysis was employed to demonstrate a potential association between IVH and a number of known risk and protective factors for IVH (antenatal steroids, birth weight, gender, IUGR, APGAR score at 10minutes, platelet count, INR, PTT, fibrinogen). RESULTS: Mean birth weight was 1047.9+/-305.6 (range: 320-1490g). Both cellular (platelets, nucleated red blood cells) and plasmatic coagulation parameters (INR, fibrinogen and antithrombin III) were dependent on birth weight. Moreover, INR levels (p<0.05) were significantly increased in neonates with IVH of any grade. Also, INR was positively correlated with the severity of IVH (Spearman's correlation coefficient: 0.193; p=0.003). While overall fibrinogen levels were not associated with IVH, a fibrinogen level<100mg/dL significantly increased the risk for IVH (p<0.01). CONCLUSIONS: Our data provide a robust set of reference values for both cellular and humoral coagulation studies in VLBW and ELBW infants for the first 24h of life. The results of our study indicate that abnormal INR levels and fibrinogen levels<100mg/dL are significantly associated with the occurrence of IVH in this susceptible cohort. PMID- 26529175 TI - Randomized controlled trial to compare sleep and wake in preterm infants less than 32weeks of gestation receiving two different modes of non-invasive respiratory support. AB - AIM: To determine whether respiratory support via heated humidified high flow nasal cannulae (HHHFNC) results in infants <32weeks gestation spending a greater proportion of time in sleep compared to those receiving nasal continuous positive airway pressure (NCPAP). METHODS: A subgroup of infants enrolled in a randomized controlled trial to compare HHHFNC or NCPAP post-extubation had sleep and wake activity measured by actigraphy for 72hours post-extubation. Activity diaries were completed contemporaneously to record episodes of infant handling. Actigraphy data were downloaded with known periods of handling excluded from the analysis. RESULTS: 28 infants with mean gestation of 28.3weeks (SD 2) and birth weight 1074g (SD 371) were studied. Infants receiving HHHFNC spent a lesser proportion of time in sleep 59.8% (SD 18.5) than those on NCPAP 82.2% (SD 23.8) p=0.004. Infants receiving HHHFNC had a lower sleep efficiency and higher mean activity score than those on NCPAP (p=0.003, p=0.002, respectively). CONCLUSION: Infants receiving HHHFNC had a higher mean activity score and spent less time in sleep than those allocated NCPAP. Further study of sleep wake activity in preterm infants receiving respiratory support is required as this may impact on neurodevelopmental outcomes. PMID- 26529176 TI - Skin to skin care and heart rate regulation. PMID- 26529177 TI - Coumarins with alpha-glucosidase and alpha-amylase inhibitory activities from the flower of Edgeworthia gardneri. AB - The flower of Edgeworthia gardneri is consumed in beverages in Tibet and has potential health benefits for diabetes. As a part of our continuous studies on dietary supplements for diabetes, two monomers, five dimers and one trimer of coumarins were isolated from the flowers of E. gardneri. One dimer was a new compound (1) and its structure was determined by spectroscopic methods, including multiple NMR techniques and mass spectrometry. The inhibitory activities of all coumarins against alpha-amylase and alpha-glucosidase were evaluated. Compound 4 displayed potent inhibitory effect on both alpha-amylase and alpha-glucosidase, with an IC50 of 90 and 86MUg/mL, respectively. The IC50 of compound 3 against alpha-glucosidase was 18.7MUg/mL, and its inhibition mode was noncompetitive. Based on the fluorescence analysis, the binding constant and the number of binding sites of compound 3 were calculated as 2.05*10(5) and 1.24, respectively. Furthermore, the interaction between compound 3 and alpha-glucosidase was a spontaneous process that was driven mainly by hydrophobic force. This study could facilitate the utilization of E gardneri as functional food ingredient. PMID- 26529179 TI - Stereoselective Construction of Bridged trans-aza-Bicyclo[7/6,3/2,1]alkenyl Imines through Ring Expansion aza-Cope Rearrangement. AB - A highly stereoselective method for efficient synthesis of unprecedented bridged bicyclo[7/6,3/2,1]alkenyl amidines is described using cyclic N-allyl-aminoalkyne as a substrate. A ketenimine formation/cyclization/aza-Cope rearrangement cascade proceeds either with or without the aid of external DIPEA depending on substrate basicity. Fused bicycloamidines are also obtained via the same protocol using different N-allyl cyclic aminoalkynes. PMID- 26529180 TI - Bone Mineral Density and Biochemical Markers of Bone Metabolism in Women Engaging in Recreational Horseback Riding. AB - BACKGROUND: An increased occurrence of lifestyle-related diseases such as osteoporosis indicates the necessity for taking preventive action, including regularly engaging in physical activity. The aim of the study was to assess the areal bone mineral density (aBMD) and bone turnover markers levels in young adult women engaging in recreational horseback riding and to determine the relationship between training characteristics and bone metabolism indices. METHODS: The study involved 43 women: 23 equestrians and 20 age- and body mass index-matched controls. The hip and spine aBMD and serum levels of the bone turnover markers: osteocalcin and collagen type I cross-linked C-telopeptide were measured. RESULTS: No significant differences were found in somatic features, concentrations of bone turnover markers, or bone mass variables. Correlation analysis of the equestrian participants showed significant relationship between body mass and BMDL1-L4 (P < .05) as well as between BMI and BMDL1-L4 (P <= .01) and z-score L1-L4 (P < .05). CONCLUSIONS: The study showed no differences in bone mass and levels of bone metabolic indices between groups of women practicing horseback riding at the recreational level and subjects who do not participate in frequent systematic physical activity. No relationship between training characteristics and bone turnover markers were found. PMID- 26529178 TI - Outcomes of Allogeneic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-analysis. AB - A large number of elderly patients with acute myeloid leukemia (AML) are not offered treatments with curative intent, such as allogeneic stem cell transplantation (SCT), because of fears of toxicity and perceived futility of intensive treatment. Therefore, the outcomes of SCT in elderly AML patients remain poorly defined. We performed a meta-analysis of all previous articles up until September 22, 2015 of SCT in AML patients >60 years. The primary endpoints were relapse-free survival (RFS) and overall survival (OS) at 6 months and at 1, 2, and 3 years. A total of 13 studies (749 patients) were included. The pooled estimates and 95% confidence intervals (CI) for RFS at 6 months, 1 year, 2 years, and 3 years were 62% (95% CI, 54% to 69%), 47% (95% CI, 42% to 53%), 44% (95% CI, 33% to 55%), and 35% (95% CI, 26% to 45%), respectively. The corresponding numbers for OS were 73% (95% CI, 66% to 79%), 58% (95% CI, 50% to 65%), 45% (95% CI, 35% to 54%), and 38% (95% CI, 29% to 48%), respectively. We found no evidence of publication bias in our primary endpoints, with the exception of relapse, where there appeared to be a relative lack of small studies with high relapse rates. Sensitivity analysis did not identify an overtly influential study for our primary endpoints, with 1 exception in 2-year RFS analysis. The present analysis argues against significant publication bias and demonstrates consistency among reports despite differences in patient-, disease-, center-, and transplantation related characteristics. Our results suggest that reduced-intensity SCT is a viable treatment option for elderly AML patients with a 3-year RFS of 35% for those over the age of 60. These results argue against using age per se as the sole criterion against SCT and would help remove some of the barriers that often preclude curative intent treatment. Correct identification of patients who would benefit from SCT can improve outcomes in this frequently undertreated population. PMID- 26529181 TI - Mild N-O Bond Cleavage Reactions of a Pyramidalized Nitrosyl Ligand Bridging a Dimolybdenum Center. AB - Complex [Mo2Cp2(MU-PCy2)(MU-NO)(NO)2] (1) was prepared by reacting [Mo2Cp2(MU H)(MU-PCy2)(CO)4] with 2 equiv of [NO]BF4 and then treating the resulting product [Mo2Cp2(MU-PCy2)(CO)2(NO)2](BF4) with NaNO2 at 323 K, and it was shown to display a bridging nitrosyl ligand with significant pyramidalization at the N atom, a circumstance related to an unusual behavior concerning degradation of the bridging nitrosyl. Indeed, complex 1 reacts with HBF4.OEt2 to give the nitroxyl bridged derivative [Mo2Cp2(MU-PCy2)(MU-kappa(1):eta(2)-HNO)(NO)2](BF4), is reduced by Zn(Hg) in the presence of trace H2O to give the amido complex [Mo2Cp2(MU-PCy2)(MU-NH2)(NO)2], and reacts with excess P(OPh)3 to give the phosphoraniminato-bridged derivative [Mo2Cp2(MU-PCy2){MU-NP(OPh)3}(NO)2]. PMID- 26529182 TI - Bisphenol-A promotes antiproliferative effects during neonatal prostate development in male and female gerbils. AB - The aim of this study was to evaluate the development of male and female neonatal gerbil prostate under normal conditions and exposed to bisphenol-A (BPA). Normal postnatal development of the female gerbil prostate occurs earlier than and is morphologically distinct from that occurring in males. In BPA-exposed PND8 gerbils, we have not observed evidence of alterations in the ductal branching in either gender. However, the exposure to BPA alters the immunolabeling pattern of AR, ERalpha, and PCNA. In males, the exposure to high dosages of BPA resulted in a decrease in the proliferative status of the developing ventral prostate. In females, both high and low dosages were sufficient to decrease the proliferation of paraurethral buds in the branching process by more than 50%. Therefore, the obtained data indicate that BPA promotes antiproliferative effects during the neonatal development of the gerbil prostate, with more sensitivity to this endocrine disruptor in females. PMID- 26529183 TI - Combinatorial effects of genistein and sex-steroids on the level of cystic fibrosis transmembrane regulator (CFTR), adenylate cyclase (AC) and cAMP in the cervix of ovariectomised rats. AB - The combinatorial effects of genistein and estrogen (E) or estrogen plus progesterone (E+P) on CFTR, AC and cAMP levels in cervix were investigated. Ovariectomised adult female rats received 50 or 100mg/kg/day genistein with E or E followed by E+P [E+(E+P)] for seven consecutive days. Cervixes were harvested and analyzed for CFTR mRNA levels by Real-time PCR. Distribution of AC and CFTR proteins in endocervix were observed by immunohistochemistry. Levels of cAMP were measured by enzyme-immunoassay. Molecular docking predicted interaction between genistein and AC. Our results indicate that levels of CFTR, AC and cAMP in cervix of rats receiving genistein plus E were higher than E-only treatment (p<0.05) while genistein plus [E+(E+P)] were higher than E+(E+P)-only treatment (p<0.05). In conclusions, increased levels of CFTR, AC and cAMP in cervix of E and E+(E+P) treated rats by genistein could affect the cervical secretory function which could influence the female reproductive processes. PMID- 26529184 TI - Curcumin Attenuates Amyloid-beta Aggregate Toxicity and Modulates Amyloid-beta Aggregation Pathway. AB - The abnormal misfolding and aggregation of amyloid-beta (Abeta) peptides into beta-sheet enriched insoluble deposits initiates a cascade of events leading to pathological processes and culminating in cognitive decline in Alzheimer's disease (AD). In particular, soluble oligomeric/prefibrillar Abeta have been shown to be potent neurotoxins. The naturally occurring polyphenol curcumin has been shown to exert a neuroprotective effect against age-related neurodegenerative diseases such as AD. However, its protective mechanism remains unclear. In this study, we investigated the effects of curcumin on the aggregation of Abeta40 as well as Abeta40 aggregate induced neurotoxicity. Our results show that the curcumin does not inhibit Abeta fibril formation, but rather enriches the population of "off-pathway" soluble oligomers and prefibrillar aggregates that were nontoxic. Curcumin also exerted a nonspecific neuroprotective effect, reducing toxicities induced by a range of Abeta conformers, including monomeric, oligomeric, prefibrillar, and fibrillar Abeta. The neuroprotective effect is possibly membrane-mediated, as curcumin reduced the extent of cell membrane permeabilization induced by Abeta aggregates. Taken together, our study shows that curcumin exerts its neuroprotective effect against Abeta induced toxicity through at least two concerted pathways, modifying the Abeta aggregation pathway toward the formation of nontoxic aggregates and ameliorating Abeta-induced toxicity possibly through a nonspecific pathway. PMID- 26529185 TI - Self-Targeted, Shape-Assisted, and Controlled-Release Self-Delivery Nanodrug for Synergistic Targeting/Anticancer Effect of Cytoplasm and Nucleus of Cancer Cells. AB - We constructed 10-hydroxycamptothecin (CPT) "nanodrugs" with functionalization of lipid-PEG-methotrexate (MTX) to prepare high-drug-loaded, and sustained/controlled-release MTX-PEG-CPT nanorods (NRs), in which MTX drug itself can serve as a specific "targeting ligand". The self-targeted nanodrug can codeliver both CPT and MTX drugs with distinct anticancer mechanisms. Furthermore, MTX-PEG-CPT NRs significantly reduced burst release, improved blood circulation and tumor accumulation, enhanced cellular uptake, and synergistically increased anticancer effect against tumor cells compared with MTX-PEG-CPT nanospheres (NSs) and either both free drugs or individual free drug. Therefore, the synergistic targeting/therapeuticy nano-multi-drug codelivery assisted by shape design may advantageously offer a promising new strategy for nanomedicine. PMID- 26529186 TI - Genetic analysis of 17 Y-STR loci from 1019 individuals of six Han populations in East China. AB - In this study, we analyzed 17 Y-STRs on 1019 male Han individuals collected from six provinces in East China, including Anhui, Jiangsu, Jiangxi, Shandong, Shanghai and Zhejiang. The haplotype diversities of six populations reach to 0.99991, 0.99998, 1, 0.99994, 1 and 0.99990, respectively. Six Han populations of the present study had no significant differences between each other except Shandong and Zhejiang. Han populations of Anhui, Jiangsu, Jiangxi, Shandong, Shanghai and Zhejiang showed significant differences between 2, 4, 3, 3, 2 and 5 Chinese Han populations from earlier reports, respectively. Han populations of the present study also showed significant differences between the other Chinese ethnic populations. The data provide a reference for Y-STR database in China and may be valuable for forensic and population genetic analysis. PMID- 26529187 TI - Increases of desmin and alpha-actinin in mouse cardiac myofibrils as a response to diastolic dysfunction. AB - Up-regulation of desmin has been reported in cardiac hypertrophy and failure but the pathophysiological cause and significance remain to be investigated. By examining genetically modified mouse models representative for diastolic or systolic heart failure, we found significantly increased levels of desmin and alpha-actinin in the myofibrils of hearts with impaired diastolic function but not hearts with weakened systolic function. The increased desmin and alpha actinin are mainly found in myofibrils at the Z-disks. Two weeks of transverse aortic constriction (TAC) induced increases of desmin and alpha-actinin in mouse hearts of occult diastolic failure but not in wild type or transgenic mouse hearts with mildly lowered systolic function or with increased diastolic function. The chronic or TAC-induced increase of desmin showed no proportional increase in phosphorylation, implicating an up-regulated expression rather than a decreased protein turnover. The data demonstrate a novel early response specifically to diastolic heart failure, indicating a function of the Z-disk in the challenging clinical condition of heart failure with preserved ejection fraction (HFpEF). PMID- 26529188 TI - The adjuvanticity of ophiopogon polysaccharide liposome against an inactivated porcine parvovirus vaccine in mice. AB - In this study, the adjuvant activity of ophiopogon polysaccharide liposome (OPL) was investigated. The effects of OPL on the splenic lymphocyte proliferation of mice were measured in vitro. The results showed that OPL could significantly promote lymphocyte proliferation singly or synergistically with PHA and LPS and that the effect was better than ophiopogon polysaccharide (OP) at most of concentrations. The adjuvant activities of OPL, OP and mineral oil were compared in BALB/c mice inoculated with inactivated PPV in vivo. The results showed that OPL could significantly enhance lymphocyte proliferation, increase the proportion of CD4(+) and CD8(+) T cells, improve the HI antibody titre and specific IgG response, and promote the production of cytokines, and the efficacy of OPL was significantly better than that of OP. In addition, OPL significantly improved the cellular immune response compared with oil adjuvant. These results suggested that OPL possess superior adjuvanticity and that a medium dose had the best efficacy. Therefore, OPL can be used as an effective immune adjuvant for an inactivated PPV vaccine. PMID- 26529189 TI - Classification, mode of action and production strategy of xylanase and its application for biofuel production from water hyacinth. AB - Xylanases are classified under glycoside hydrolase families which represent one of the largest groups of commercial enzymes. Depolymerizing xylan molecules into monomeric pentose units involves the synergistic action of mainly two key enzymes which are endo-beta-xylanase and beta-xylosidase. Xylanases are different with respect to their mode of action, substrate specificities, biochemical properties, 3D structure and are widely produced by a spectrum of bacteria and fungi. Currently, large scale production of xylanase can be produced through the application of genetic engineering tool which allow fast identification of novel xylanase genes and their genetic variations makes it an ideal enzymes. Due to depletion of fossil fuel, there is urgent need to find out environment friendly and sustainable energy sources. Therefore, utilisation of cheap lignocellulosic materials along with proper optimisation of process is most important for cost efficient ethanol production. Among, various types of lignocellulosic substances, water hyacinth, a noxious aquatic weed, has been found in many tropical. Therefore, the technological development for biofuel production from water hyacinth is becoming commercially worthwhile. In this review, the classification and mode of action of xylanase including genetic regulation and strategy for robust xylanase production have been critically discussed from recent reports. In addition various strategies for cost effective biofuel production from water hyacinth including chimeric proteins design has also been critically evaluated. PMID- 26529190 TI - Activation effect of Ganoderma lucidum polysaccharides liposomes on murine peritoneal macrophages. AB - The activation of murine peritoneal macrophages by Ganoderma lucidum polysaccharides liposomes (GLPL) was investigated in vitro. After treatment with GLPL, the changes of the nitric oxide (NO) secretion and iNOS (inducible nitric oxide synthase) activity were evaluated. The results showed that NO production and iNOS activity of macrophages were enhanced compared to GLP and BL group. In addition, both the phagocytic activity and levels of cytokines IL-1beta, TNF alpha and IFN-gamma were enhanced in the peritoneal macrophages of mice by stimulation of GLPL. The expression of the major histocompatibility complex class II molecule (MHC II) on the surface of peritoneal macrophages significantly increased. These indicated that GLPL could enhance the activation of peritoneal macrophages and their potential for use as a delivery system of GLP. PMID- 26529191 TI - A specific antimicrobial protein CAP-1 from Pseudomonas sp. isolated from the jellyfish Cyanea capillata. AB - A bacterium strain, designated as CMF-2, was isolated from the jellyfish Cyanea capillata and its culture supernatant exhibited a significant antimicrobial activity. The strain CMF-2 was identified as Pseudomonas sp. based on the morphological, biochemical and physiological characteristics as well as 16S rRNA sequence analysis. In this study, an antimicrobial protein, named as CAP-1, was isolated from the culture of CMF-2 through ammonium sulfate precipitation and gel filtration chromatography. According to the result of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), a major band indicated that the antimicrobial protein had a molecular mass of about 15 kDa, and it was identified as a hypothetical protein by MALDI-TOF-MS analysis and Mascot searching. CAP-1 displayed a broad antimicrobial spectrum against the indicator bacteria and fungus, including Staphylococcus aureus, Escherichia coli, Bacillus subtilis and Candida albicans, especially some marine-derived microorganisms such as Vibrio vulnificus, Vibrio alginolyticus, Vibrio parahaemolyticus, Vibrio cholera, and Vibrio anguillarum, but showed little impact on tumor cells and normal human cells. The protein CAP-1 remained a stable antimicrobial activity in a wide range of temperature (20-80 degrees C) and pH (2-10) conditions. These results suggested that CAP-1 might have a specific antimicrobial function not due to cytotoxicity. PMID- 26529192 TI - Composite wound dressings of pectin and gelatin with aloe vera and curcumin as bioactive agents. AB - Aloe vera and curcumin loaded oxidized pectin-gelatin (OP-Gel) matrices were used as antimicrobial finishes on nonwoven cotton fabrics to produce composite wound care devices. The drug release characteristics of the biocomposite dressings indicated that curcumin is released through a biphasic mechanism - erosion of the polymeric matrix, followed by diffusion, while aloe vera is released upon leaching of the polymeric matrix. A 50/50 composition of aloe vera/curcumin was used to fabricate OP-Gel-Aloe Curcumin dressings. However, contrary to our expectations, OP-Gel-Aloe Curcumin dressings exhibited lesser antimicrobial activity compared to OP-Gel-Aloe and OP-Gel-Curcumin dressings. The cytocompatibility of the fabricated dressings was evaluated using NIH3T3 mouse fibroblast cells. OP-Gel-Aloe treated fibroblasts had the highest viability, with the matrices providing a substrate for good cell attachment and proliferation. On the other hand, OP-Gel-Curcumin and OP-Gel-Aloe Curcumin seemed to have induced apoptosis in NIH3T3 cells. In vivo wound healing analysis was carried out using an excisional splint wound model on C57BL/6J mice. OP-Gel-Aloe treated wounds exhibited very rapid healing with 80% of the wound healing in just 8 days. Furthermore, aloe vera exerted a strong anti-inflammatory effect and prominent scar prevention. Histological examination revealed that an ordered collagen formation and neovascularization could be observed along with migration of nuclei. Therefore, OP-Gel-Aloe biocomposite dressings are proposed as viable materials for effective wound management. PMID- 26529194 TI - Position tracking and identity tracking are separate systems: Evidence from eye movements. AB - How do we track multiple moving objects in our visual environment? Some investigators argue that tracking is based on a parallel mechanism (e.g., Cavanagh & Alvarez, 2005; Pylyshyn, 1989), others argue that tracking contains a serial component (e.g. Holcombe & Chen, 2013; Oksama & Hyona, 2008). In the present study, we put previous theories into a direct test by registering observers' eye movements when they tracked identical moving targets (the MOT task) or when they tracked distinct object identities (the MIT task). The eye movement technique is a useful tool to study whether overt focal attention is exploited during tracking. We found a qualitative difference between these tasks in terms of eye movements. When the participants tracked only position information (MOT), the observers had a clear preference for keeping their eyes fixed for a rather long time on the same screen position. In contrast, active eye behavior was observed when the observers tracked the identities of moving objects (MIT). The participants updated over four target identities with overt attention shifts. These data suggest that there are two separate systems involved in multiple object tracking. The position tracking system keeps track of the positions of the moving targets in parallel without the need of overt attention shifts in the form of eye movements. On the other hand, the identity tracking system maintains identity-location bindings in a serial fashion by utilizing overt attention shifts. PMID- 26529193 TI - First Insights into the Viral Communities of the Deep-sea Anoxic Brines of the Red Sea. AB - The deep-sea brines of the Red Sea include some of the most extreme and unique environments on Earth. They combine high salinities with increases in temperature, heavy metals, hydrostatic pressure, and anoxic conditions, creating unique settings for thriving populations of novel extremophiles. Despite a recent increase of studies focusing on these unusual biotopes, their viral communities remain unexplored. The current survey explores four metagenomic datasets obtained from different brine-seawater interface samples, focusing specifically on the diversity of their viral communities. Data analysis confirmed that the particle attached viral communities present in the brine-seawater interfaces were diverse and generally dominated by Caudovirales, yet appearing distinct from sample to sample. With a level of caution, we report the unexpected finding of Phycodnaviridae, which infects algae and plants, and trace amounts of insect infecting Iridoviridae. Results from Kebrit Deep revealed stratification in the viral communities present in the interface: the upper-interface was enriched with viruses associated with typical marine bacteria, while the lower-interface was enriched with haloviruses and halophages. These results provide first insights into the unexplored viral communities present in deep-sea brines of the Red Sea, representing one of the first steps for ongoing and future sampling efforts and studies. PMID- 26529195 TI - Cultural effects on mindreading. AB - People from other cultural backgrounds sometimes seem inscrutable. We identified a potential cause of this phenomenon in two experiments demonstrating that adults' mental state inferences are influenced by the cultural identity of the target. We adapted White, Hill, Happe, and Frith's (2009) Strange Stories to create matched intra-cultural and cross-cultural mindreading and control conditions. Experiment 1 showed that Australian participants were faster to respond and received higher scores in the intra-cultural mindreading condition relative to the cross-cultural mindreading condition, but performance in the control conditions was equivalent. Experiment 2 replicated this pattern in independent samples of Australian and Chilean participants. These findings have important implications for cross-cultural communication and understanding. PMID- 26529196 TI - Titanium Mesh Shaping and Fixation for the Treatment of Comminuted Mandibular Fractures. AB - PURPOSE: Treating comminuted mandibular fractures remains a challenge. In this study, we used titanium mesh to treat comminuted mandibular fractures. MATERIALS AND METHODS: Nine patients with traumatically comminuted mandibular fractures who received open reduction and internal stable fixation with titanium mesh were retrospectively reviewed. Open reduction-internal stable fixation was performed 7 to 10 days after primary debridement of the facial trauma. After the fractured mandible and the displaced fragments were reduced, the titanium mesh was reshaped according to the morphology of the mandible, and the reduced bone fragments were fixed with the reshaped titanium mesh and screws. Then, the surgical effects were evaluated during routine follow-up. RESULTS: Most of the displaced fragments were preserved and exhibited a favorable shaping ability in restoring the morphology of the mandible during surgery. No intraoperative complications were encountered. In addition, all patients were infection free, with no obvious resorption in the fixed fragments after surgery. The mandible also exhibited favorable morphology and offered sufficient bone mass for dental implantation or a denture prosthesis. CONCLUSIONS: We conclude that titanium mesh shaping and fixation can effectively treat comminuted mandibular fractures with little bone fragment loss, little soft tissue exposure, a low infection rate, and favorable mandibular morphology. PMID- 26529197 TI - External Reference Nasal Pin for Orthognathic Maxillary Positioning: What Is the Proper Method of Placement? AB - PURPOSE: Intracranial perforation with an external reference nasal pin is a possible complication during maxillary orthognathic surgery. This study attempts to quantify the maximum allowable depth of pin penetration from the soft tissue nasion (STN) and hard tissue nasion (HTN) to the anterior cranial fossa (ACF) and to evaluate the depth and direction of the nasal pin track using postsurgical cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Two groups of patients were evaluated. A retrospective cross-sectional chart review evaluated the distance from the STN and HTN to the ACF from random patients on CBCT scans. In addition, a different group of postsurgical orthognathic cases treated between March 2013 and August 2015 were analyzed for the depth and direction of the nasal pin track toward the next anatomic cavity, which included the ACF, frontal sinus, or nasal cavity. RESULTS: We identified 103 random patients, aged 14 to 90 years. The mean distance from the STN to the ACF was 21.85 mm (range, 14.06 to 29.12 mm), and the mean distance from the HTN to the ACF was 14.16 mm (range, 7.35 to 20.53 mm). Forty postsurgical CBCT scans showed an overall nasal pin track depth of 12.91 mm (range, 8.53 to 22.60 mm), with the direction of the pin track toward the nasal cavity in most cases. CONCLUSIONS: The depth of penetration of an external reference nasal pin should be limited to a maximum of 10 to 12 mm from the STN. Initial skin penetration should begin immediately caudal to the STN, and the pin should be directed in a caudal direction to avoid inadvertent entrance into the ACF, as well as to facilitate a relatively safe penetration into the nasal cavity, if the maximum depth is excessive. PMID- 26529198 TI - Could 5-Fluorouracil or Triamcinolone Be an Effective Treatment Option for Keloid After Surgical Excision? A Meta-Analysis. AB - PURPOSE: There is no universally accepted treatment regimen to decrease the recurrence rate of keloid formation after its removal, although many treatment options have been suggested. The purpose of this study was to investigate treatment options to prevent keloid recurrence after surgical excision. MATERIALS AND METHODS: A systematic literature review and meta-analysis was performed using the Medline, Embase, and Cochrane databases. Predictor variables were 5 fluorouracil (5-FU) or triamcinolone adjuvant therapy, and the outcome variable was keloid recurrence rate. The Newcastle-Ottawa scale was used to assess the quality of the studies and the Cochrane risk-of-bias tool was used. Publication bias was evaluated using a funnel plot. RESULTS: There were 1,224 publications identified; after screening, 5 were selected for review (1 retrospective cohort, 3 prospective cohorts, and 1 randomized controlled trial). The mean level of keloid recurrence was statistically lower in patients who received 5-FU compared with those who did not (control group; risk ratio, 0.18; 95% confidence interval [CI], 0.04 to 0.75). Triamcinolone was ineffective in lowering the keloid recurrence (risk difference, 0.06; 95% CI, -0.16 to 0.28). CONCLUSION: 5-FU can be considered an effective treatment to decrease keloid recurrence after surgical excision, although further research, including a randomized controlled trial, is required. PMID- 26529199 TI - Co-delivery of drugs and plasmid DNA for cancer therapy. AB - Cancer is an extremely complex disease involving multiple signaling pathways that enable tumor cells to evade programmed cell death, thus making cancer treatment extremely challenging. The use of combination therapy involving both gene therapy and chemotherapy has resulted in enhanced anti-cancer effects and has become an increasingly important strategy in medicine. This review will cover important design parameters that are incorporated into delivery systems for the co administration of drug and plasmid-based nucleic acids (pDNA and shRNA), with particular emphasis on polymers as delivery materials. The unique challenges faced by co-delivery systems and the strategies to overcome such barriers will be discussed. In addition, the advantages and disadvantages of combination therapy using separate carrier systems versus the use of a single carrier will be evaluated. Finally, future perspectives in the design of novel platforms for the combined delivery of drugs and genes will be presented. PMID- 26529200 TI - Evaluation of 3D radio-frequency electromagnetic fields for any matching and coupling conditions by the use of basis functions. AB - A procedure for evaluating radio-frequency electromagnetic fields in anatomical human models for any matching and coupling conditions is introduced. The procedure resorts to the extraction of basis functions: such basis functions, which represent the fields produced by each individual port without any residual coupling, are derived through an algebraic procedure which uses the S parameter matrix and the fields calculated in one (only) full-wave simulation. The basis functions are then used as building-blocks for calculating the fields for any other S parameter matrix. The proposed approach can be used both for volume coil driven in quadrature and for parallel transmission configuration. PMID- 26529201 TI - A solid-state NMR method to determine domain sizes in multi-component polymer formulations. AB - Polymer domain sizes are related to many of the physical properties of polymers. Here we present a solid-state NMR experiment that is capable of measuring domain sizes in multi-component mixtures. The method combines selective excitation of carbon magnetization to isolate a specific component with proton spin diffusion to report on domain size. We demonstrate the method in the context of controlled release formulations, which represents one of today's challenges in pharmaceutical science. We show that we can measure domain sizes of interest in the different components of industrial pharmaceutical formulations at natural isotopic abundance containing various (modified) cellulose derivatives, such as microcrystalline cellulose matrixes that are film-coated with a mixture of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC). PMID- 26529202 TI - Evaluation of plasma-based transmit coils for magnetic resonance. AB - In this work a new concept for designing transmit coils for magnetic resonance using a plasma is introduced. Unlike conventional coils, a plasma can be turned on and off, eliminating electrical interactions between coils, and enabling radiofrequency-invisibility when desired. A surfatron has been designed to produce a surface-mode wave which propagates along the inner surface of a commercial fluorescent lighting tube. NMR spectra and images have been produced using the plasma as the transmit coil and a copper-based monopole to receive the signal. The transmit efficiency of the plasma tube was estimated, and is currently much lower than that of an equivalently-sized metal-based structure: however, there are many potential methods for increasing the efficiency using a custom-built plasma tube. PMID- 26529203 TI - Measurement of deformations by NMR. AB - Two NMR data acquisition protocols together with corresponding data processing algorithms for locating macroscopic objects, measuring distances between them or monitoring their displacements or deformations with microscopic precision are presented and discussed. The performance of the methods is demonstrated by applying them to the measurement of deformations of a freely supported beam under loading. We believe that our methods will find their applications in mechanics, civil engineering and medicine. PMID- 26529204 TI - Long-lived spin states as a source of contrast in magnetic resonance spectroscopy and imaging. AB - A method is proposed to create Long-Lived spin States (LLSs) from longitudinal spin magnetization, which is based on adiabatic switching of a Radio-Frequency (RF) field with proper frequency. The technique is simple to implement with standard Nuclear Magnetic Resonance (NMR) equipment, providing an excellent conversion of population from the triplet T+ (or T-) state to the singlet state of a pair of spins and back. The method has been tested for the amino acid tyrosine and its partially deuterated isotopomer; for the deuterated compound, we have achieved a LLS lifetime, which exceeds the longitudinal relaxation time by a factor of 21. Furthermore, by slightly modifying the method, an enhanced contrast with respect to LLSs in NMR spectra is achieved; contrast enhancements of more than 1200 are feasible. This enables efficient suppression of longitudinal spin magnetization in NMR allowing one to look selectively at LLSs. Using this method we have demonstrated that not only spectral but also spatial contrast can be achieved: we have obtained spatial NMR images with strongly improved contrast originating from the difference of LLS lifetimes at different positions in the sample. PMID- 26529205 TI - Spin polarization transfer mechanisms of SABRE: A magnetic field dependent study. AB - We have investigated the magnetic field dependence of Signal Amplification By Reversible Exchange (SABRE) arising from binding of para-hydrogen (p-H2) and a substrate to a suitable transition metal complex. The magnetic field dependence of the amplification of the (1)H Nuclear Magnetic Resonance (NMR) signals of the released substrates and dihydrogen, and the transient transition metal dihydride species shows characteristic patterns, which is explained using the theory presented here. The generation of SABRE is most efficient at low magnetic fields due to coherent spin mixing at nuclear spin Level Anti-Crossings (LACs) in the SABRE complexes. We studied two Ir-complexes and have shown that the presence of a (31)P atom in the SABRE complex doubles the number of LACs and, consequently, the number of peaks in the SABRE field dependence. Interestingly, the polarization of SABRE substrates is always accompanied by the para-to-ortho conversion in dihydride species that results in enhancement of the NMR signal of free (H2) and catalyst-bound H2 (Ir-HH). The field dependences of hyperpolarized H2 and Ir-HH by means of SABRE are studied here, for the first time, in detail. The field dependences depend on the chemical shifts and coupling constants of Ir HH, in which the polarization transfer takes place. A negative coupling constant of -7Hz between the two chemically equivalent but magnetically inequivalent hydride nuclei is determined, which indicates that Ir-HH is a dihydride with an HH distance larger than 2A. Finally, the field dependence of SABRE at high fields as found earlier has been investigated and attributed to polarization transfer to the substrate by cross-relaxation. The present study provides further evidence for the key role of LACs in the formation of SABRE-derived polarization. Understanding the spin dynamics behind the SABRE method opens the way to optimizing its performance and overcoming the main limitation of NMR, its notoriously low sensitivity. PMID- 26529206 TI - White Matter and Hippocampal Volume Predict the Risk of Dementia in Patients with Cerebral Small Vessel Disease: The RUN DMC Study. AB - BACKGROUND: The relationship between cerebral small vessel disease (SVD) and dementia has been studied without considering white matter (WM) volume, the microstructural integrity of the WM surrounding the SVD, and grey matter (GM). OBJECTIVE: We prospectively investigated the relationship between these structures and the risk of dementia, and formed a prediction model to investigate which characteristics (macro- or microstructural) explained most of the variance. METHODS: The RUN DMC study is a prospective cohort study among 503 non-demented participants with an age between 50 and 85 years at baseline, with baseline assessment in 2006 and follow-up assessment in 2012. Two were lost to follow-up (yielding a 99.6% response-rate). Cox regression analysis was used, to calculate hazard ratios for dementia, of baseline MRI characteristics. Tract-Based Spatial Statistics (TBSS) analysis was used to assess the added value of microstructural integrity of the WM. RESULTS: Mean age at baseline was 65.6 years (SD 8.8) and 56.8% was male. 43 participants developed dementia (8.6%), resulting in a 5.5 year cumulative risk of 11.1% (95% CI 7.7-14.6). Low WM and hippocampal volume are significant predictors for dementia. WM, WM hyperintensities, and hippocampal volume explained most of the variance. TBSS analyses showed no additional value of diffusion parameters. CONCLUSIONS: WM and hippocampal volume were the main predictors for the development of incident dementia at 5-year follow-up in elderly with SVD. There was no additional diagnostic value of the diffusion tensor imaging parameters on top of the macrostructural characteristics. PMID- 26529207 TI - Network-Based and Binless Frequency Analyses. AB - We introduce and develop a new network-based and binless methodology to perform frequency analyses and produce histograms. In contrast with traditional frequency analysis techniques that use fixed intervals to bin values, we place a range +/ zeta around each individual value in a data set and count the number of values within that range, which allows us to compare every single value of a data set with one another. In essence, the methodology is identical to the construction of a network, where two values are connected if they lie within a given a range (+/ zeta). The value with the highest degree (i.e., most connections) is therefore assimilated to the mode of the distribution. To select an optimal range, we look at the stability of the proportion of nodes in the largest cluster. The methodology is validated by sampling 12 typical distributions, and it is applied to a number of real-world data sets with both spatial and temporal components. The methodology can be applied to any data set and provides a robust means to uncover meaningful patterns and trends. A free python script and a tutorial are also made available to facilitate the application of the method. PMID- 26529208 TI - Editorial. PMID- 26529209 TI - Introduction. PMID- 26529210 TI - Reducing specificity of autobiographical memory in nonclinical participants: The role of rumination and schematic models. AB - Two experiments are reported in which nondysphoric participants, not prone to excessive levels of rumination in everyday life, were asked to retrieve autobiographical memories using the Williams and Broadbent ( 1986 ) procedure (AMT). In the first experiment, two variants of a self-related category fluency task were interleaved among sets of autobiographical memory cues. In one variant (blocked) a normal model of analytic rumination was induced by grouping prompts on a single superordinate theme together. In the other (intermixed) prompts from several different themes were grouped together. It was predicted that the blocked variant would reduce the number of specific memories recollected and increase the number of categoric memories relative to the intermixed variant. This prediction was confirmed and provides the first demonstration of a bidirectional causal influence of analytic rumination on the balance between specific and categoric retrievals. A second experiment showed no alteration in this balance when the same fluency manipulation involved animal-related categories rather than self related ones. The results support a two component model of autobiographical retrieval being driven in part by the extent to which an analytic mode of processing is adopted in the short term and in part by the level of differentiation in self-related schematic models. PMID- 26529211 TI - Retrieval of autobiographical memories: The mechanisms and consequences of truncated search. AB - Five studies examined the extent to which autobiographical memory retrieval is hierarchical, whether a hierarchical search depends on central executive resources, and whether retrieving memories that are "higher" in the hierarchy impairs problem-solving ability. The first study found that random generation (assessed using a button-pressing task) was sensitive to changes in memory load (digit span). The second study showed that when participants fail to retrieve a target event, they respond with a memory that is higher up the hierarchy. The third study showed that memory is more generic only when participants use low imageable cues under cognitive load. The final two experiments showed that experimental manipulation of memory specificity affects problem solving (MEPS performance). The data are consistent with Conway and Pleydell-Pearce's hierarchical retrieval model of autobiographical memory, and suggest that overgeneral memory in nonclinical participants is associated with reduced executive capacity only when retrieval is "top-down" (generative). PMID- 26529212 TI - Impact of depressive symptoms, self-esteem and neuroticism on trajectories of overgeneral autobiographical memory over repeated trials. AB - The present study examined trajectories of change in the frequency of overgeneral autobiographical memory (OGM) over the course of repeated trials, and tested whether particular dimensions of depressive symptomatology (somatic and cognitive affective distress), self-esteem, and neuroticism account for individual differences in these trajectories. Given that depression is associated with impairments in effortful processing, we predicted that over repeated trials depression would be associated with increasingly OGM. Generalised Linear Mixed Models with Penalised Quasi-Likelihood demonstrated significant linear and quadratic trends in OGM over repeated trials, and somatic distress and self esteem moderated these slopes. The form of these interactions suggested that somatic distress and low self-esteem primarily contribute to OGM during the second half of the trial sequence. The present findings demonstrate the value of a novel analytical approach to OGM that estimates individual trajectories of change over repeated trials. PMID- 26529213 TI - Reduced autobiographical memory specificity and affect regulation. AB - The effect of specificity of autobiographical memory (AM) retrieval on the affective impact of an emotional event was examined. In Study 1 (N = 90) the impact of a negative and positive experience was compared between student participants who habitually retrieve autobiographical memories (AMs) in a specific way and participants who generally retrieve less specific memories. In Study 2 (N = 48) the effect of an experimentally induced (specific vs. overgeneral) retrieval style on the impact of a negative experience was studied in student participants who habitually retrieve less specific memories. Study 1 replicated the finding of Raes, Hermans, de Decker, Eelen, & Williams ( 2003 ) that a negative event leads to less subjective distress in low-specific participants as compared with high-specific participants. However, both groups did not differ in their affective reaction to a positive event. Important, reduced memory specificity was associated with "repressive coping", providing further evidence for the idea that reduced memory specificity is used as an avoidant or repressive-defensive mechanism to regulate negative affect ( Williams, 1996 ). In Study 2, participants who were induced to retrieve memories in an overgeneral way experienced more distress following a negative event as compared with participants who were induced to retrieve memories in a specific way. Results are discussed in the context of recent findings concerning AM specificity and emotion regulation ( Philippot, Schaefer, & Herbette, 2003 ). Directions for further research are suggested. PMID- 26529214 TI - Retrieval-induced forgetting of autobiographical memory details. AB - Several studies suggest that intrusive and overgeneral autobiographical memory are correlated. Thus, paradoxically, in some patients a hyperaccessibility of memory for one (series of) event(s) goes hand-in-hand with a scarcity of memories for other personal experiences. This clinical observation is reminiscent of the laboratory phenomenon of retrieval-induced forgetting (RIF). This refers to the finding that repeatedly recalling some experimental stimuli impairs subsequent recall of related (i.e., tied to the same retrieval cue) stimuli. RIF of emotional autobiographical memories might provide an experimental model for the clinical memory phenomena in question. The present paper reports two experiments that explored the merits of applying the retrieval practice paradigm to relatively broad categories of autobiographical memories. Both studies found a significant RIF effect in that practised memories were recalled better than unrelated unpractised (baseline) memories. In addition, unpractised memories that were related to the practised memories were recalled more poorly than baseline memories. Implications of these findings for modelling the co-occurrence of intrusive and overgeneral memories are discussed. PMID- 26529215 TI - Autobiographical memory in depressed and nondepressed patients with borderline personality disorder after long-term psychotherapy. AB - The present study investigated whether scores on the Autobiographical Memory Test (AMT) in 55 patients with borderline personality disorder (BPD) were modified after long-term psychotherapy and whether the pretreatment AMT scores would predict improvement in depression severity or BPD symptom severity at the end of treatment. In addition, it was analysed whether changes in ratings of mood, thought suppression, dissociation, and BPD symptom severity following treatment were associated with changes in AMT scores. Only patients with BPD and a comorbid diagnosis of depression at time 1, generated significantly more specific memories and fewer categoric memories after 15 months of therapy. Moreover, these changes were unrelated to type of therapy and changes in depression severity, borderline symptom severity, dissociation, or thought suppression. The AMT scores at initial assessment did not predict depression severity at 15 months. The percentage of negative specific memories tended to predict BPD symptom severity. PMID- 26529216 TI - Facets of autobiographical memory in adolescents with major depressive disorder and never-depressed controls. AB - Adolescence is a crucial developmental window because it involves elaboration of the self-concept, the laying down of lifelong autobiographical memories, and the development of emotional resilience during a time of substantial risk for mood problems. Autobiographical memory retrieval plays an important role in depression both in adults ( van Vreeswijk & de Wilde, 2004 ) and adolescents (Kuyken, Howell, & Dalgleish, 2005; Park, Goodyer, & Teasdale, 2002 ). This study examined facets of autobiographical memory associated with memory retrieval in never depressed and currently depressed adolescents: personal importance, imagery, recency, source monitoring, and field-observer perspective. Compared with never depressed adolescents, adolescents with depression were significantly more likely to retrieve memories from an observer perspective and more recent time period, preferentially rehearsed negative memories and rated their memories as more personally important. Depressed adolescents who reported a history of trauma retrieved more vivid autobiographical memories than depressed adolescents not reporting such a history, had rehearsed them more frequently, and reported more confidence in their veracity. PMID- 26529217 TI - Effects of age, dysphoria, and emotion-focusing on autobiographical memory specificity in children. AB - Overgeneral autobiographical memory (OGM) is strongly associated with depression in adults and appears to reflect a stable cognitive bias. However, it is not known whether this bias exists in children or what factors contribute to its development. We examined the roles of age, dysphoria, and a new variable, emotion focusing (EF), on the production of specific autobiographical memory (AM) in children, using the standard Autobiographical Memory Test (AMT; Williams & Broadbent, 1986 ). Results show that older children are more specific than younger children, irrespective of cue valence. Dysphoria was linked to less specific retrieval of positive memories in children. A three-way interaction between age, valence, and dysphoria was also found, such that older dysphoric children demonstrated a difficulty in retrieving specific negative memories. In addition, emotion-focusing was associated with specific AM recall, especially to negative cues. Results are discussed with reference to the development of depressogenic biases. PMID- 26529218 TI - Autobiographical memory in dysphoric and non-dysphoric college students using a computerised version of the AMT. AB - On autobiographical memory tests (AMTs) using positive and negative cue words, research has consistently found that depressed individuals (relative to nondepressed controls) are more likely to recall overgeneral memories (OGMs) and are less likely to recall specific memories. A total of 56 undergraduates who scored high or low on a measure of depression were shown positive and negative word cues and event cues in a computerised AMT. Dysphoric college students made significantly fewer specific and more categoric (overgeneral) responses than controls, but did not differ from controls in terms of extended responses. Results suggest that the difference in memory specificity between low and high dysphoric students generalises across word and event cues and that a computerised version of the AMT can be used as an alternative to interviews as a form of administration. PMID- 26529219 TI - Suicide attempts: Patients with and without an affective disorder show impaired autobiographical memory specificity. AB - A number of studies have shown reduced recall of specific autobiographical memories (AMs) in patients after attempted suicide, but in all of them the study samples were confounded with diagnoses of affective disorders. The present study aims to demonstrate impaired specific autobiographical memory in patients after a suicide attempt without a diagnosis of an affective disorder. Four groups were compared: (1) patients with an actual major depression and a suicide attempt; (2) patients after a suicide attempt without a lifetime history of an affective diagnosis; (3) patients currently suffering from major depression without a suicide attempt; and (4) control persons not suffering from either of the two conditions during their entire life. Individuals with major depression and a suicide attempt showed reduced specificity of AM and, most importantly, patients with a suicide attempt-despite the absence of an affective disorder-were equally impaired with recall of specific AMs as were patients with major depression. The authors propose that reduced specific AM is a common vulnerability factor that can lead either to the development of an affective disorder and/or to a suicide attempt. PMID- 26529220 TI - Autobiographical memory specificity in adults reporting repressed, recovered, or continuous memories of childhood sexual abuse. AB - Some psychotherapists believe that adult survivors of childhood sexual abuse (CSA) are characterised by memory deficits for their childhood. Using the Autobiographical Memory Test (AMT), we asked nonabused control participants and participants who reported either continuous, recovered, or repressed memories of CSA to retrieve a specific personal memory in response to either positive or negative cue words from either childhood or adolescence/adulthood. The results indicated that participants who believed they harboured repressed memories of abuse tended to exhibit the greatest difficulty retrieving specific memories from their childhood. Neither posttraumatic stress disorder (PTSD) nor major depression was related to diminished memory specificity. PMID- 26529221 TI - Autobiographical memory deficits in schizophrenia. AB - This study investigated autobiographical memory processes in a group of individuals diagnosed with schizophrenia and matched controls. The schizophrenia group displayed an overgeneral style of autobiographical memory retrieval on two widely used measures, and displayed problems retrieving both autobiographical facts and events. They showed a specific impairment in the recall of autobiographical events and facts in early adulthood, around the time of onset of their illness. Retrieval deficits were independent of mood state and premorbid intellectual functioning. The magnitude of the deficits in autobiographical memory retrieval specificity were considerably greater than any general impairments in episodic and working memory. PMID- 26529222 TI - Capture and rumination, functional avoidance, and executive control (CaRFAX): Three processes that underlie overgeneral memory. AB - This article reviews the papers published in this Special Issue of Cognition and Emotion on Specificity in Autobiographical Memory. Together, the studies address some critical issues relating to the etiology of and mechanisms underlying the phenomenon of overgeneral memory. In terms of etiology, there is now substantial evidence of links between overgeneral memory and current or past depression, and between overgeneral memory and trauma history, and suicidal ideation and behaviour, independent of depression. In terms of mechanisms, three factors are emerging as the critical mechanisms underlying the phenomenon: Capture and rumination (CaR), functional avoidance (FA), and executive control dysfunction (X). Each of these has separately been found to produce overgenerality in memory; together they are almost certain to do so. PMID- 26529223 TI - Quirks of dye nomenclature. 5. Rhodamines. AB - Rhodamines were first produced in the late 19(th) century, when they constituted a new class of synthetic dyes. These compounds since have been used to color many things including cosmetics, inks, textiles, and in some countries, food products. Certain rhodamine dyes also have been used to stain biological specimens and currently are widely used as fluorescent probes for mitochondria in living cells. The early history and current biological applications are sketched briefly and an account of the ambiguities, complications and confusions concerning dye identification and nomenclature are discussed. PMID- 26529224 TI - The Association between Continuity of Care and All-Cause Mortality in Patients with Newly Diagnosed Obstructive Pulmonary Disease: A Population-Based Retrospective Cohort Study, 2005-2012. AB - BACKGROUND: The disease burden is increasing for chronic obstructive pulmonary disease (COPD) due to increasing of the growth rate of prevalence and mortality. But the empirical researches are a little for COPD that studied the association between continuity of care and death and about predictors effect on mortality. OBJECTIVE: To investigate the association between continuity of care (COC) and chronic obstructive pulmonary disease (COPD) mortality and to identify other mortality-related factors in COPD patients. METHODS: We conducted a longitudinal, population-based retrospective cohort study in adult patients with COPD from 2002 to 2012 using a nationwide health insurance claims database. The study sample included individuals aged 40 years and over who developed COPD in 2005 and survived until 2006. We performed a Cox proportional hazard regression analysis with COC analyzed as a time-dependent covariate. RESULTS: Of the 3,090 participants, 60.8% died before the end of study (N = 1,879). The median years of survival for individuals with high COC (COC index>=0.75) was 3.92, and that for patients with low COC (COC index<0.75) was 2.58 in a Kaplan Meier analysis. In a multivariate, time-dependent analysis, low COC was associated with a 22% increased risk of all-cause mortality (HR, 1.22; 95% CI, 1.09-1.36). Not receiving oxygen therapy at home was associated with a 23% increased risk of all cause mortality (HR, 1.23; 95% CI, 1.01-1.49). Moreover, the risk of all-cause mortality for individuals who admitted one time increased 38% (HR, 1.38; 95% CI, 1.21-1.59), two times was 63% (HR, 1.63; 95% CI, 1.34-1.99) and 3+ times was 96% (HR, 1.96; 95% CI, 1.63-2.36) relative to the reference group (no admission). CONCLUSIONS: High COC was associated with a decreased risk of all-cause mortality. In addition, home oxygen therapy and number of hospital admissions may predict mortality in patients with COPD. PMID- 26529225 TI - Theta Burst Stimulation of the Cerebellum Modifies the TMS-Evoked N100 Potential, a Marker of GABA Inhibition. AB - Theta burst stimulation (TBS) of the cerebellum, a potential therapy for neurological disease, can modulate corticospinal excitability via the dentato thalamo-cortical pathway, but it is uncertain whether its effects are mediated via inhibitory or facilitatory networks. The aim of this study was to investigate the effects of 30Hz cerebellar TBS on the N100 waveform of the TMS-evoked potential (TEP), a marker of intracortical GABAB-mediated inhibition. 16 healthy participants (aged 18-30 years; 13 right handed and 3 left handed) received 30Hz intermittent TBS (iTBS), continuous TBS (cTBS) or sham stimulation over the right cerebellum, in three separate sessions. The first 8 participants received TBS at a stimulus intensity of 80% of active motor threshold (AMT), while the remainder received 90% of AMT. Motor evoked potentials (MEP) and TEP were recorded before and after each treatment, by stimulating the first dorsal interosseus area of the left motor cortex. Analysis of the 13 right handed participants showed that iTBS at 90% of AMT increased the N100 amplitude compared to sham and cTBS, without significantly altering MEP amplitude. cTBS at 80% of active motor threshold decreased the N100 amplitude and cTBS overall reduced resting MEP amplitude. The study demonstrates effects of 30Hz cerebellar TBS on inhibitory cortical networks that may be useful for treatment of neurological conditions associated with dysfunctional intracortical inhibition. PMID- 26529226 TI - T1rho relaxation time in brain regions increases with ageing: an experimental MRI observation in rats. AB - OBJECTIVE: T1rho variation is associated with neurodegenerative diseases. This study aims to observe T1rho relaxation time changes in rat brains associated with normal ageing in Sprague-Dawley (SD) rats, Wistar Kyoto (WKY) rats and spontaneously hypertension rats (SHRs). METHODS: 18 male SD rats, 11 male WKY rats and 11 male SHRs were used. T1rho measurement was performed at 3-T MR with a spin-lock frequency of 500 Hz. SD rats were scanned at the ages of 5, 8, 10 and 15 months. SHRs and WKY rats were scanned at the ages of 6, 9 and 12 months. RESULTS: For SD rats, T1rho at the thalamus, hippocampus and frontal cortices increased significantly from 5 to 15 months (p < 0.05). For the WKY rats and SHRs, the T1rho values in the thalamus, hippocampus and frontal cortices also increased significantly from 6 to 12 months (p < 0.05). Furthermore, T1rho in the thalamus, hippocampus and frontal cortices of SHRs were consistently higher than those of WKY rats at the ages of 6, 9 and 12 months (p < 0.05). The percentage regional T1rho differences between WKY rats and SHRs did not change during ageing. CONCLUSION: An increase in T1rho was associated with age-related changes of the rat brain. ADVANCES IN KNOWLEDGE: An age-related and hypertension-related T1rho increase in rat brain regions was observed in the thalamus, hippocampus and frontal cortical regions of the rat brain. PMID- 26529227 TI - Follow-up for covered stent treatment of carotid blow-out syndrome in patients with head and neck cancer. AB - OBJECTIVE: Carotid blow-out syndrome (CBS) is a life-threatening complication of head and neck cancer (HNC). One of the various methods used for emergency management of CBS is covered stent placement (CSP). Our initial experience in CSP is evaluated and compared with reports in the literature. METHODS: This study analysed 17 patients with HNC who had received CSP for CBS at Kaohsiung Medical University Chung-Ho Memorial Hospital from May 2005 to December 2013. The medical records and images for these patients were retrospectively reviewed to evaluate the causes of CBS, treatment success rates and complications. RESULTS: The initial angiography success rate was 100%. Procedural or periprocedural complications were noted in two (12%) cases, both suffering from cerebral vascular accident (CVA). Short-term complications were noted in eight (47%) cases, including four rebleeding cases and four CVA cases. Medium- to long-term complications were noted in nine cases, which included two asymptomatic in-stent thrombosis cases, one symptomatic CVA case, two abscess formation cases and four rebleeding cases. Overall, eight (47%) cases of rebleeding occurred during follow up. Three of the eight cases were fatal, accounting for 27% of the all-cause mortality. CONCLUSION: Although CSP is considered effective for achieving haemostasis in patients with HNC with CBS, the medium- to long-term outcomes are unfavourable owing to high risks of rebleeding, CVA and other complications. Therefore, CSP should be considered a temporary life-saving technique rather than a definitive treatment. ADVANCES IN KNOWLEDGE: Analysis of the relatively large series of patients with HNC in this study suggests that CSP is a useful temporary treatment for CBS. PMID- 26529228 TI - Periprocedural complications in endovascular stroke treatment. AB - Endovascular stroke treatment is a neurointerventional emergency where the main goal is the early recanalization of the occlusion within the critical time window, as safely as possible. Although the time window and rate of complications for endovascular stroke treatment differ with anterior and posterior circulation strokes, awareness of potential periprocedural complications is important, as they affect patient morbidity and mortality. Periprocedural complications are classified as haemorrhagic complications, procedure-/device-related, puncture site complications, and late-onset events including vascular stenosis. We present the digital subtraction angiography and CT imaging findings related to these complications in a study of 56 stroke patients, as they relate to previous findings in the literature. PMID- 26529229 TI - Utility of double inversion recovery MRI in paediatric epilepsy. AB - Detecting focal abnormalities in MRI examinations of children with epilepsy can be a challenging task given the frequently subtle appearance of cortical dysplasia, mesial temporal sclerosis and similar lesions. In this report, we demonstrate the utility of double inversion recovery MRI in the detection of paediatric epileptogenic abnormalities, promoted primarily by increased lesion conspicuity due to complementary suppression of both cerebrospinal fluid and normal white matter signal. PMID- 26529230 TI - Pancreatic mucinous cystoadenomas and cystoadenocarcinomas: differential diagnosis by means of MRI. AB - OBJECTIVE: To determine the accuracy of MRI in differentiating mucinous cystoadenomas (MCAs) from mucinous cystoadenocarcinomas (MCACs) of the pancreas, with histopathological analysis as the reference standard, for better surgical planning. METHODS: A total of 65 patients with histopathologically proven mucinous cystic neoplasms (MCNs) underwent MRI and surgery. Quantitative image analysis included size, septa and wall thickness and number of loculations. Qualitative image analysis included nodules; hyperintensity of the cystic content on T1 weighted images; compression and/or infiltration of adjacent vessels or organs; and metastases. A comparison between MCAs and MCACs was performed with Student's t-test for quantitative variables and with Fisher test for qualitative variables. Receiver operating characteristic analysis was performed to determine the accuracy in the differential diagnosis between MCAs and MCACs on the basis of a score system obtained by giving 1 point for each quantitative and qualitative variable observed in each patient. RESULTS: At histopathology, 43 lesions were MCAs and 22 lesions were MCACs. A statistically significant difference was observed for size >7cm (<0.001), septa and wall thickness >3 mm (<0.0001), number of loculations >4 (<0.0001), nodules (<0.0001), hyperintensity of the cystic content on T1 weighted images (<0.0001), compression (<0.01) and/or infiltration (<0.01) of adjacent vessels or organs and metastases (<0.05). The best cut-off value to discriminate MCAs from MCACs was the presence of three features (p < 0.001), with an accuracy of 91%. CONCLUSION: MRI has an accuracy of 91% in the differential diagnosis between MCA and MCAC, helping in identifying forms that could undergo parenchyma-sparing surgery (MCAs), reducing post-surgical morbidity and mortality. ADVANCES IN KNOWLEDGE: In this study, the differentiation between MCAs and MCACs of the pancreas by means of MRI is addressed. The differential diagnosis allows selecting benign forms, susceptible of parenchyma-sparing surgery, with the advantage of reducing post-surgical morbidity and stratifying prognosis of MCNs. PMID- 26529231 TI - (18)F-FDG PET-CT: a powerful tool for the diagnosis and treatment of relapsing polychondritis. AB - OBJECTIVE: This study aimed to evaluate fluorine-18 fludeoxyglucose positron emission tomography-CT ((18)F-FDG PET-CT) for the diagnosis, targeted biopsy and therapy of relapsing polychondritis (RP). METHODS: The literature pertaining to the use of (18)F-FDG PET-CT in patients with RP was retrieved from the Cochrane Library, PubMed, Excerpta Medica Database (EMBASE), China National Knowledge Infrastructure (CNKI) and Wanfang databases until July 2015. Clinical characteristics, auxiliary examination results, chest CT findings, tracheoscopy and biopsy findings, high metabolic activity lesions, maximum standardized uptake values, (18)F-FDG PET-CT-guided biopsy site, pathologic results of biopsy samples and alteration in high (18)F-FDG-uptake lesions after treatment were retrospectively analysed. RESULTS: 18 publications with 26 cases were enrolled. The five most common symptoms of patients with RP diagnosed with (18)F-FDG PET-CT were cough, fever, chest tightness, sore throat and arthralgia. Of the 26 patients, 23 patients had multiple and symmetric cartilage lesions with high metabolic activity, revealed by (18)F-FDG PET-CT. The disease mainly affected organs such as the bronchus, trachea, throat, costicartilage and auricle. The maximum standardized uptake values ranged from 1.93 to 13.03 (mean, 4.94). (18)F FDG PET-CT revealed that patients with RP with tracheal and bronchial involvement had a close correlation with cough (chi(2) = 6.80, p = 0.006). (18)F-FDG PET-CT showed a significantly higher positive biopsy rate compared with bronchoscopy (chi(2) = 12.91, p < 0.001) for targeted lesions with high metabolic activity. Post-treatment re-examinations with (18)F-FDG PET-CT showed obvious subsidence or complete disappearance of high (18)F-FDG-uptake lesions in 13 cases, showing highly consistent symptom improvements. CONCLUSION: (18)F-FDG PET-CT is likely to become a valuable imaging tool in the diagnosis and treatment of RP. ADVANCES IN KNOWLEDGE: The presence of symmetrically distributed high FDG-uptake lesions may be a criterion for the diagnosis of RP. (18)F-FDG PET-CT is useful for targeting biopsy sites, which remarkably increase the positive biopsy rate. Therefore, (18)F-FDG PET-CT may be of great value in the diagnosis and treatment of RP. PMID- 26529232 TI - Depletion of UDP-Glucose and UDP-Galactose Using a Degron System Leads to Growth Cessation of Leishmania major. AB - Interconversion of UDP-glucose (UDP-Glc) and UDP-galactose (UDP-Gal) by the UDP Glc 4'-epimerase intimately connects the biosynthesis of these two nucleotide sugars. Their de novo biosynthesis involves transformation of glucose-6-phosphate into glucose-1-phosphate by the phosphoglucomutase and subsequent activation into UDP-Glc by the specific UDP-Glc pyrophosphorylase (UGP). Besides UGP, Leishmania parasites express an uncommon UDP-sugar pyrophosphorylase (USP) able to activate both galactose-1-phosphate and glucose-1-phosphate in vitro. Targeted gene deletion of UGP alone was previously shown to principally affect expression of lipophosphoglycan, resulting in a reduced virulence. Since our attempts to delete both UGP and USP failed, deletion of UGP was combined with conditional destabilisation of USP to control the biosynthesis of UDP-Glc and UDP-Gal. Stabilisation of the enzyme produced by a single USP allele was sufficient to maintain the steady-state pools of these two nucleotide sugars and preserve almost normal glycoinositolphospholipids galactosylation, but at the apparent expense of lipophosphoglycan biosynthesis. However, under destabilising conditions, the absence of both UGP and USP resulted in depletion of UDP-Glc and UDP-Gal and led to growth cessation and cell death, suggesting that either or both of these metabolites is/are essential. PMID- 26529233 TI - Sensitization of breast cancer cells to doxorubicin via stable cell line generation and overexpression of DFF40. AB - There are a number of reports demonstrating a relationship between the alterations in DFF40 expression and development of some cancers. Here, increased DFF40 expression in T-47D cells in the presence of doxorubicin was envisaged for therapeutic usage. The T-47D cells were transfected with an eukaryotic expression vector encoding the DFF40 cDNA. Following incubation with doxorubicin, propidium iodide (PI) staining was used for cell cycle distribution analysis. The rates of apoptosis were determined by annexin V/PI staining. Apoptosis was also evaluated using the DNA laddering analysis. The viability of DFF40-transfected cells incubated with doxorubicin was significantly decreased compared with control cells. However, there were no substantial changes in the cell cycle distribution of pIRES2-DFF40 cells incubated with doxorubicin compared to control cells. The expression of DFF40, without doxorubicin incubation, had also no significant effect on the cell cycle distribution. There was no DNA laddering in cells transfected with the empty pIRES2 vector when incubated with doxorubicin. In contrast, DNA laddering was observed in DFF40 transfected cells in the presence of doxorubicin after 48 h. Also, the expression of DFF40 and DFF45 was increased in DFF40 transfected cells in the presence of doxorubicin enhancing cell death. Collectively our results indicated that co-treatment of DFF40-transfected cells with doxorubicin can enhance the killing of these tumor cells via apoptosis. Thus, modulation of DFF40 level may be a beneficial strategy for treatment of chemo-resistant cancers. PMID- 26529234 TI - A Strontium-Modified Titanium Surface Produced by a New Method and Its Biocompatibility In Vitro. AB - OBJECTIVE: To present a new and effective method of producing titanium surfaces modified with strontium and to investigate the surface characteristics and in vitro biocompatibility of titanium (Ti) surfaces modified with strontium (Sr) for bone implant applications. MATERIALS AND METHODS: Sr-modified Ti surfaces were produced by sequential treatments with NaOH, strontium acetate, heat and water. The surface characteristics and the concentration of the Sr ions released from the samples were examined. Cell adhesion, morphology and growth were investigated using osteoblasts isolated from the calvaria of neonatal Sprague-Dawley rats. Expression of osteogenesis-related genes and proteins was examined to assess the effect of the Sr-modified Ti surfaces on osteoblasts. RESULTS: The modified titanium surface had a mesh structure with significantly greater porosity, and approximately5.37+/-0.35at.% of Sr was incorporated into the surface. The hydrophilicity was enhanced by the incorporation of Sr ions and water treatment. The average amounts of Sr released from the Sr-modified plates subjected to water treatment were slight higher than the plates without water treatment. Sr promoted cellular adhesion, spreading and growth compared with untreated Ti surfaces. The Sr-modified Ti plates also promoted expression of osteogenesis-related genes,and expression of OPN and COL-I by osteoblasts. Ti plates heat treated at 700 degrees C showed increased bioactivity in comparison with those treated at 600 degrees C. Water treatment upregulated the expression of osteogenesis-related genes. CONCLUSIONS: These results show that Sr-modification of Ti surfaces may improve bioactivity in vitro. Water treatment has enhanced the response of osteoblasts. The Sr-modified Ti heat-treated at 700 degrees C exhibited better bioactivity compared with that heated at 600 degrees C. PMID- 26529235 TI - Positive and negative perceived consequences of first intercourse among middle and high school students in Puebla, Mexico. AB - Relatively little is known about young people's interpretations of sexual behaviour in Latin America. In this study, we examine the most commonly perceived consequences of first sexual intercourse among Mexican middle and high school students, how perceived consequences differ by gender, and factors that may predict experiencing more positive or negative consequences. Sexually active Mexican students aged 12-19 years (n = 268) reported whether they had experienced each of 19 consequences following first intercourse. Both positive consequences, such as physical satisfaction and closeness to partner, and negative consequences, such as worry about STDs and pregnancy, were common. Sex with a non relationship partner was associated with fewer positive and more negative consequences, with the effect for positive consequences being stronger for young women. Pressure to have sex was associated with fewer positive consequences of first intercourse, and pressure to remain a virgin was associated with more positive and negative consequences. These findings suggest that young people often report mixed feelings about their first sexual intercourse and that relationship context and sexual socialisation influence their perceptions of the event. PMID- 26529236 TI - Mutant Huntingtin Does Not Affect the Intrinsic Phenotype of Human Huntington's Disease T Lymphocytes. AB - Huntington's disease is a fatal neurodegenerative condition caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system is dysregulated in Huntington's disease and may contribute to its pathogenesis. However, it is not clear whether or to what extent the adaptive immune system is also involved. Here, we carry out the first comprehensive investigation of human ex vivo T lymphocytes in Huntington's disease, focusing on the frequency of a range of T lymphocyte subsets, as well as analysis of proliferation, cytokine production and gene transcription. In contrast to the innate immune system, the intrinsic phenotype of T lymphocytes does not appear to be affected by the presence of mutant huntingtin, with Huntington's disease T lymphocytes exhibiting no significant functional differences compared to control cells. The transcriptional profile of T lymphocytes also does not appear to be significantly affected, suggesting that peripheral immune dysfunction in Huntington's disease is likely to be mediated primarily by the innate rather than the adaptive immune system. This study increases our understanding of the effects of Huntington's disease on peripheral tissues, while further demonstrating the differential effects of the mutant protein on different but related cell types. Finally, this study suggests that the potential use of novel therapeutics aimed at modulating the Huntington's disease innate immune system should not be extended to include the adaptive immune system. PMID- 26529237 TI - Comparative Genome of GK and Wistar Rats Reveals Genetic Basis of Type 2 Diabetes. AB - The Goto-Kakizaki (GK) rat, which has been developed by repeated inbreeding of glucose-intolerant Wistar rats, is the most widely studied rat model for Type 2 diabetes (T2D). However, the detailed genetic background of T2D phenotype in GK rats is still largely unknown. We report a survey of T2D susceptible variations based on high-quality whole genome sequencing of GK and Wistar rats, which have generated a list of GK-specific variations (228 structural variations, 2660 CNV amplification and 2834 CNV deletion, 1796 protein affecting SNVs or indels) by comparative genome analysis and identified 192 potential T2D-associated genes. The genes with variants are further refined with prior knowledge and public resource including variant polymorphism of rat strains, protein-protein interactions and differential gene expression. Finally we have identified 15 genetic mutant genes which include seven known T2D related genes (Tnfrsf1b, Scg5, Fgb, Sell, Dpp4, Icam1, and Pkd2l1) and eight high-confidence new candidate genes (Ldlr, Ccl2, Erbb3, Akr1b1, Pik3c2a, Cd5, Eef2k, and Cpd). Our result reveals that the T2D phenotype may be caused by the accumulation of multiple variations in GK rat, and that the mutated genes may affect biological functions including adipocytokine signaling, glycerolipid metabolism, PPAR signaling, T cell receptor signaling and insulin signaling pathways. We present the genomic difference between two closely related rat strains (GK and Wistar) and narrow down the scope of susceptible loci. It also requires further experimental study to understand and validate the relationship between our candidate variants and T2D phenotype. Our findings highlight the importance of sequenced-based comparative genomics for investigating disease susceptibility loci in inbreeding animal models. PMID- 26529239 TI - Effects of Suicide Awareness Material on Implicit Suicide Cognition: A Laboratory Experiment. AB - In spite of the increasing adoption of suicide awareness campaigns to prevent suicide, little is known about the effective construction of awareness messages used and on their impact on suicidal cognition. We hypothesized that media reporting on an individual overcoming a suicidal crisis increases the automatic association between "life" and self. University students (N = 112) were randomly allocated to one of three groups in a laboratory experiment. Participants allocated to treatment group 1 or group 2 read awareness material about a person coping with suicidal ideation by getting professional help. The only difference between the two groups was the amount of social similarity (low vs. high) between the protagonist and the participants. The control group read an article unrelated to suicide. Awareness material increased implicit cognition in terms of a strengthening of self-life associations. This effect was restricted to participants scoring low on wishful identification with the suicidal protagonist. This finding suggests that only individuals who do not wishfully identify with a protagonist going through difficult life circumstances benefit from the awareness material in terms of suicidal cognition. These findings provide a rich basis for further research and have potentially high relevance to the construction of suicide-awareness messages. PMID- 26529238 TI - A Phase I, Open-Label Trial, Evaluating the Safety and Immunogenicity of Candidate Tuberculosis Vaccines AERAS-402 and MVA85A, Administered by Prime-Boost Regime in BCG-Vaccinated Healthy Adults. AB - BACKGROUND: MVA85A and AERAS-402 are two clinically advanced viral vectored TB vaccine candidates expressing Mycobacterium tuberculosis antigens designed to boost BCG-induced immunity. Clinical trials with candidate malaria vaccines have demonstrated that adenoviral vector based priming immunisation, followed by MVA vector boost, induced high levels of immunity. We present the safety and immunogenicity results of the first clinical trial to evaluate this immunisation strategy in TB. METHODS: In this phase 1, open-label trial, 40 healthy previously BCG-vaccinated participants were enrolled into three treatment groups and vaccinated with 1 or 2 doses of AERAS-402 followed by MVA85A; or 3 doses of AERAS 402. RESULTS: Most related adverse events (AEs) were mild and there were no vaccine related serious AEs. Boosting AERAS-402 with MVA85A significantly increased Ag85A-specific T-cell responses from day of vaccination. Two priming doses of AERAS-402 followed by MVA85A boost, resulted in a significantly higher AUC post-peak Ag85A response compared to three doses of AERAS-402 and historical data with MVA85A vaccination alone. The frequency of CD8+ T-cells producing IFN gamma, TNF-alpha and IL-2 was highest in the group receiving two priming doses of AERAS-402 followed by MVA85A. CONCLUSIONS: Vaccination with AERAS-402 followed by MVA85A was safe and increased the durability of antigen specific T-cell responses and the frequency and polyfunctionality of CD8+ T-cells, which may be important in protection against TB. Further clinical trials with adenoviral prime-MVA85A boost regimens are merited to optimise vaccination intervals, dose and route of immunisation and to evaluate this strategy in the target population in TB high burden countries. TRIAL REGISTRATION: ClinicalTrials.gov NCT01683773. PMID- 26529240 TI - Increased Cortical Gamma-Aminobutyric Acid Precedes Incomplete Extinction of Conditioned Fear and Increased Hippocampal Excitatory Tone in a Mouse Model of Mild Traumatic Brain Injury. AB - Mild traumatic brain injury (mTBI) contributes to development of affective disorders, including post-traumatic stress disorder (PTSD). Psychiatric symptoms typically emerge in a tardive fashion post-TBI, with negative effects on recovery. Patients with PTSD, as well as rodent models of PTSD, demonstrate structural and functional changes in brain regions mediating fear learning, including prefrontal cortex (PFC), amygdala (AMYG), and hippocampus (HC). These changes may reflect loss of top-down control by which PFC normally exhibits inhibitory influence over AMYG reactivity to fearful stimuli, with HC contribution. Considering the susceptibility of these regions to injury, we examined fear conditioning (FC) in the delayed post-injury period, using a mouse model of mTBI. Mice with mTBI displayed enhanced acquisition and delayed extinction of FC. Using proton magnetic resonance spectroscopy ex vivo, we examined PFC, AMYG, and HC levels of gamma-aminobutyric acid (GABA) and glutamate as surrogate measures of inhibitory and excitatory neurotransmission, respectively. Eight days post-injury, GABA was increased in PFC, with no significant changes in AMYG. In animals receiving FC and mTBI, glutamate trended toward an increase and the GABA/glutamate ratio decreased in ventral HC at 25 days post-injury, whereas GABA decreased and GABA/glutamate decreased in dorsal HC. These neurochemical changes are consistent with early TBI-induced PFC hypoactivation facilitating the fear learning circuit and exacerbating behavioral fear responses. The latent emergence of overall increased excitatory tone in the HC, despite distinct plasticity in dorsal and ventral HC fields, may be associated with disordered memory function, manifested as incomplete extinction and enhanced FC recall. PMID- 26529242 TI - Unusually high thermal stability and peroxidase activity of cytochrome c in ionic liquid colloidal formulation. AB - Ionic liquid (IL) surfactant choline dioctylsulfosuccinate, [Cho][AOT], formed polydispersed vesicular structures in the IL, ethylmethylimidazolium ethylsulfate, [C2mim][C2OSO3]. Cytochrome c dissolved in such a colloidal medium has shown very high peroxidase activity (~2 times to that in neat IL and ~4 times to that in an aqueous buffer). Significantly, the enzyme retained both structural stability and functional activity in IL colloidal solutions up to 180 degrees C, demonstrating the suitability of the system as a high temperature bio-catalytic reactor. PMID- 26529241 TI - Carry-Over Effects of Nonbreeding Habitat on Start-to-Finish Spring Migration Performance of a Songbird. AB - For migratory animals, conditions during the nonbreeding period may carry-over to influence spring migration performance. Animals in low-quality habitats are predicted to be in poorer condition, show later migration timing, and travel at slower speeds. This can result in subsequent negative effects on fitness. We tested the hypothesis that nonbreeding season body condition and habitat quality carry-over to affect spring migration performance of a long-distance migratory songbird, the Wood Thrush (Hylocichla mustelina). We tracked individual birds between multiple breeding sites in North America and nonbreeding sites in Central America. First, we compared body condition of nonbreeding birds migrating to the same general region of the breeding range with spring migration performance (timing, speed, and duration) obtained from light-level geolocators. Second, we assessed the Normalized Difference Vegetation Index (NDVI) as a proxy for nonbreeding habitat quality, and predicted that birds from wetter habitat or in wetter years (higher NDVI) would show improved migration performance relative to birds from drier sites. We found no evidence of individual-level carry-over effects of nonbreeding season body condition on spring migration performance. Lower NDVI of nonbreeding habitat resulted in delayed spring migration departure, but this effect disappeared by arrival at breeding sites. Birds occupying drier nonbreeding sites migrated faster and for fewer days, compensating for their relatively late departure. We also documented a broader pattern in NDVI and migration timing and distance, in that birds that occupied the wettest areas in the southern part of the nonbreeding range departed significantly later and migrated farther. Our results suggest that individual carry-over effects of nonbreeding habitat quality may be compensated for by a faster and shorter migration strategy. At a broad scale, consistently later spring timing and longer migration distances were associated with the wettest areas (the highest quality habitats) of the Wood Thrush non-breeding range. This supports the theory that high-quality habitats offset the costs of farther migration, resulting in a leap frog migration pattern. PMID- 26529243 TI - Human Lipocalin-Type Prostaglandin D Synthase-Based Drug Delivery System for Poorly Water-Soluble Anti-Cancer Drug SN-38. AB - Lipocalin-type prostaglandin D synthase (L-PGDS) is a member of the lipocalin superfamily, which is composed of secretory transporter proteins, and binds a wide variety of small hydrophobic molecules. Using this function, we have reported the feasibility of using L-PGDS as a novel drug delivery vehicle for poorly water-soluble drugs. In this study, we show the development of a drug delivery system using L-PGDS, one that enables the direct clinical use of 7-ethyl 10-hydroxy-camptothecin (SN-38), a poorly water-soluble anti-cancer drug. In the presence of 2 mM L-PGDS, the concentration of SN-38 in PBS increased 1,130-fold as compared with that in PBS. Calorimetric experiments revealed that L-PGDS bound SN-38 at a molecular ratio of 1:3 with a dissociation constant value of 60 MUM. The results of an in vitro growth inhibition assay revealed that the SN-38/L-PGDS complexes showed high anti-tumor activity against 3 human cancer cell lines, i.e., Colo201, MDA-MB-231, and PC-3 with a potency similar to that of SN-38 used alone. The intravenous administration of SN-38/L-PGDS complexes to mice bearing Colo201 tumors showed a pronounced anti-tumor effect. Intestinal mucositis, which is one of the side effects of this drug, was not observed in mice administered SN 38/L-PGDS complexes. Taken together, L-PGDS enables the direct usage of SN-38 with reduced side effects. PMID- 26529244 TI - Programmable diode/resistor-like behavior of nanostructured vanadium pentoxide xerogel thin film. AB - Electrical properties of a Cr/V2O5/Cr structure are investigated and switching of the device due to electrochemical reactions is observed at low bias (<1 V). Depending on the polarity of the first applied bias, the switched device can behave like a diode (forward sweep first) or a resistor (reverse sweep first). The switching is irreversible and persistent, lasting for more than one month. By performing environmental tests, we prove that water molecules in the atmosphere and intercalated in the xerogel film are involved in the electrochemical reactions. It is proposed that an interfacial layer with reduced oxidation state forms at the Cr/V2O5 interface, and creates a higher Schottky barrier due to rise of electron affinity. Different interfacial layer thicknesses in forward and reverse first sweeps are responsible for different I-V characteristics in subsequent sweeps. The results suggest future applications of these V2O5 thin films in low-power read-only memory devices and diode-resistor networks. PMID- 26529245 TI - Genome-Wide Association Implicates Candidate Genes Conferring Resistance to Maize Rough Dwarf Disease in Maize. AB - Maize rough dwarf disease (MRDD) is a destructive viral disease in China, which results in 20-30% of the maize yield losses in affected areas and even as high as 100% in severely infected fields. Understanding the genetic basis of resistance will provide important insights for maize breeding program. In this study, a diverse maize population comprising of 527 inbred lines was evaluated in four environments and a genome-wide association study (GWAS) was undertaken with over 556000 SNP markers. Fifteen candidate genes associated with MRDD resistance were identified, including ten genes with annotated protein encoding functions. The homologous of nine candidate genes were predicted to relate to plant defense in different species based on published results. Significant correlation (R2 = 0.79) between the MRDD severity and the number of resistance alleles was observed. Consequently, we have broadened the resistant germplasm to MRDD and identified a number of resistance alleles by GWAS. The results in present study also imply the candidate genes in defense pathway play an important role in resistance to MRDD in maize. PMID- 26529247 TI - Enantioselective oxidative boron Heck reactions. AB - This review highlights the use of the oxidative boron Heck reaction in enantioselective Heck-type couplings. The enantioselective oxidative boron Heck reaction overcomes several limitations of the traditional Pd(0)-catalysed Heck coupling and has subsequently allowed for intermolecular couplings of challenging systems such as cyclic enones, acyclic alkenes, and even site selectively on remote alkenes. PMID- 26529248 TI - Correction: Interactions of L-3,5,3'-Triiodothyronine, Allopregnanolone, and Ivermectin with the GABAA Receptor: Evidence for Overlapping Intersubunit Binding Modes. PMID- 26529249 TI - Stereoscopic Integrated Imaging Goggles for Multimodal Intraoperative Image Guidance. AB - We have developed novel stereoscopic wearable multimodal intraoperative imaging and display systems entitled Integrated Imaging Goggles for guiding surgeries. The prototype systems offer real time stereoscopic fluorescence imaging and color reflectance imaging capacity, along with in vivo handheld microscopy and ultrasound imaging. With the Integrated Imaging Goggle, both wide-field fluorescence imaging and in vivo microscopy are provided. The real time ultrasound images can also be presented in the goggle display. Furthermore, real time goggle-to-goggle stereoscopic video sharing is demonstrated, which can greatly facilitate telemedicine. In this paper, the prototype systems are described, characterized and tested in surgeries in biological tissues ex vivo. We have found that the system can detect fluorescent targets with as low as 60 nM indocyanine green and can resolve structures down to 0.25 mm with large FOV stereoscopic imaging. The system has successfully guided simulated cancer surgeries in chicken. The Integrated Imaging Goggle is novel in 4 aspects: it is (a) the first wearable stereoscopic wide-field intraoperative fluorescence imaging and display system, (b) the first wearable system offering both large FOV and microscopic imaging simultaneously, PMID- 26529250 TI - Evidence against hypothalamic-pituitary-adrenal axis suppression in the antidiabetic action of leptin. AB - Leptin administration restores euglycemia in rodents with severe insulin deficient diabetes, and recent studies to explain this phenomenon have focused on the ability of leptin to normalize excessive hypothalamic-pituitary-adrenal (HPA) axis activity. Here, we employed a streptozotocin-induced rat model (STZ-DM) of uncontrolled insulin-deficient diabetes mellitus (uDM) to investigate the contribution of HPA axis suppression to leptin-mediated glucose lowering. Specifically, we asked if HPA axis activation is required for diabetic hyperglycemia, whether HPA axis normalization can be achieved using a dose of leptin below that needed to normalize glycemia, and if the ability of leptin to lower plasma glucocorticoid levels is required for its antidiabetic action. In STZ-DM rats, neither adrenalectomy-induced (ADX-induced) glucocorticoid deficiency nor pharmacological glucocorticoid receptor blockade lowered elevated blood glucose levels. Although elevated plasma levels of corticosterone were normalized by i.v. leptin infusion at a dose that raises low plasma levels into the physiological range, diabetic hyperglycemia was not altered. Lastly, the potent glucose-lowering effect of continuous intracerebroventricular leptin infusion was not impacted by systemic administration of corticosterone at a dose that maintained elevated plasma levels characteristic of STZ-DM. We conclude that, although restoring low plasma leptin levels into the physiological range effectively normalizes increased HPA axis activity in rats with uDM, this effect is neither necessary nor sufficient to explain leptin's antidiabetic action. PMID- 26529251 TI - Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma. AB - Rationally designed combinations of targeted therapies for refractory cancers, such as activated B cell-like diffuse large B cell lymphoma (ABC DLBCL), are likely required to achieve potent, durable responses. Here, we used a pharmacoproteomics approach to map the interactome of a tumor-enriched isoform of HSP90 (teHSP90). Specifically, we chemically precipitated teHSP90-client complexes from DLBCL cell lines with the small molecule PU-H71 and found that components of the proximal B cell receptor (BCR) signalosome were enriched within teHSP90 complexes. Functional assays revealed that teHSP90 facilitates BCR signaling dynamics by enabling phosphorylation of key BCR signalosome components, including the kinases SYK and BTK. Consequently, treatment of BCR-dependent ABC DLBCL cells with PU-H71 attenuated BCR signaling, calcium flux, and NF-kappaB signaling, ultimately leading to growth arrest. Combined exposure of ABC DLBCL cell lines to PU-H71 and ibrutinib, a BCR pathway inhibitor, more potently suppressed BCR signaling than either drug alone. Correspondingly, PU-H71 combined with ibrutinib induced synergistic killing of lymphoma cell lines, primary human lymphoma specimens ex vivo, and lymphoma xenografts in vivo, without notable toxicity. Together, our results demonstrate that a pharmacoproteome-driven rational combination therapy has potential to provide more potent BCR-directed therapy for ABC DLCBL patients. PMID- 26529252 TI - FGF21 and the late adaptive response to starvation in humans. AB - In mice, FGF21 is rapidly induced by fasting, mediates critical aspects of the adaptive starvation response, and displays a number of positive metabolic properties when administered pharmacologically. In humans, however, fasting does not consistently increase FGF21, suggesting a possible evolutionary divergence in FGF21 function. Moreover, many key aspects of FGF21 function in mice have been identified in the context of transgenic overexpression or administration of supraphysiologic doses, rather than in a physiologic setting. Here, we explored the dynamics and function of FGF21 in human volunteers during a 10-day fast. Unlike mice, which show an increase in circulating FGF21 after only 6 hours, human subjects did not have a notable surge in FGF21 until 7 to 10 days of fasting. Moreover, we determined that FGF21 induction was associated with decreased thermogenesis and adiponectin, an observation that directly contrasts with previous reports based on supraphysiologic dosing. Additionally, FGF21 levels increased after ketone induction, demonstrating that endogenous FGF21 does not drive starvation-mediated ketogenesis in humans. Instead, a longitudinal analysis of biologically relevant variables identified serum transaminases- markers of tissue breakdown--as predictors of FGF21. These data establish FGF21 as a fasting-induced hormone in humans and indicate that FGF21 contributes to the late stages of adaptive starvation, when it may regulate the utilization of fuel derived from tissue breakdown. PMID- 26529253 TI - The Canadian clinician-scientist training program must be reinstated. AB - Clinical investigators within the Canadian and international communities were shocked when the Canadian Institutes of Health Research (CIHR) announced that their funding for the MD/PhD program would be terminated after the 2015-2016 academic year. The program has trained Canadian clinician-scientists for more than two decades. The cancellation of the program is at odds with the CIHR's mandate, which stresses the translation of new knowledge into improved health for Canadians, as well as with a series of internal reports that have recommended expanding the program. Although substantial evidence supports the analogous Medical Scientist Training Program in the United States, no parallel analysis of the MD/PhD program has been performed in Canada. Here, we highlight the long-term consequences of the program's cancellation in the context of increased emphasis on translational research. We argue that alternative funding sources cannot ensure continuous support for students in clinician-scientist training programs and that platform funding of the MD/PhD program is necessary to ensure leadership in translational research. PMID- 26529254 TI - The C-terminal CGHC motif of protein disulfide isomerase supports thrombosis. AB - Protein disulfide isomerase (PDI) has two distinct CGHC redox-active sites; however, the contribution of these sites during different physiologic reactions, including thrombosis, is unknown. Here, we evaluated the role of PDI and redox active sites of PDI in thrombosis by generating mice with blood cells and vessel wall cells lacking PDI (Mx1-Cre Pdifl/fl mice) and transgenic mice harboring PDI that lacks a functional C-terminal CGHC motif [PDI(ss-oo) mice]. Both mouse models showed decreased fibrin deposition and platelet accumulation in laser induced cremaster arteriole injury, and PDI(ss-oo) mice had attenuated platelet accumulation in FeCl3-induced mesenteric arterial injury. These defects were rescued by infusion of recombinant PDI containing only a functional C-terminal CGHC motif [PDI(oo-ss)]. PDI infusion restored fibrin formation, but not platelet accumulation, in eptifibatide-treated wild-type mice, suggesting a direct role of PDI in coagulation. In vitro aggregation of platelets from PDI(ss-oo) mice and PDI-null platelets was reduced; however, this defect was rescued by recombinant PDI(oo-ss). In human platelets, recombinant PDI(ss-oo) inhibited aggregation, while recombinant PDI(oo-ss) potentiated aggregation. Platelet secretion assays demonstrated that the C-terminal CGHC motif of PDI is important for P-selectin expression and ATP secretion through a non-alphaIIbbeta3 substrate. In summary, our results indicate that the C-terminal CGHC motif of PDI is important for platelet function and coagulation. PMID- 26529255 TI - Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects. AB - BACKGROUND: Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation of NLRP3 inflammasome-linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate NLRP3 inflammasome activation, we investigated whether fasting blunts inflammasome activation via sirtuin-mediated augmentation of mitochondrial integrity. METHODS: We performed a clinical study of 19 healthy volunteers. Each subject underwent a 24-hour fast and then was fed a fixed-calorie meal. Blood was drawn during the fasted and fed states and analyzed for NRLP3 inflammasome activation. We enrolled an additional group of 8 healthy volunteers to assess the effects of the sirtuin activator, nicotinamide riboside, on NLRP3 inflammasome activation. RESULTS: In the fasting/refeeding study, individuals showed less NLRP3 inflammasome activation in the fasted state compared with that in refed conditions. In a human macrophage line, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation in association with excessive mitochondrial ROS production. Furthermore, genetic and pharmacologic SIRT3 activation blunted NLRP3 activity in parallel with enhanced mitochondrial function in cultured cells and in leukocytes extracted from healthy volunteers and from refed individuals but not in those collected during fasting. CONCLUSIONS: Together, our data indicate that nutrient levels regulate the NLRP3 inflammasome, in part through SIRT3-mediated mitochondrial homeostatic control. Moreover, these results suggest that deacetylase-dependent inflammasome attenuation may be amenable to targeting in human disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT02122575 and NCT00442195. FUNDING: Division of Intramural Research, NHLBI of the NIH. PMID- 26529256 TI - DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport. AB - The small intestine is a dynamic and complex organ that is characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota. Lymphatic capillaries of the small intestine, called lacteals, play key roles in dietary fat absorption and the gut immune response; however, little is known about the molecular regulation of lacteal function. Here, we performed a high-resolution analysis of the small intestinal stroma and determined that lacteals reside in a permanent regenerative, proliferative state that is distinct from embryonic lymphangiogenesis or quiescent lymphatic vessels observed in other tissues. We further demonstrated that this continuous regeneration process is mediated by Notch signaling and that the expression of the Notch ligand delta like 4 (DLL4) in lacteals requires activation of VEGFR3 and VEGFR2. Moreover, genetic inactivation of Dll4 in lymphatic endothelial cells led to lacteal regression and impaired dietary fat uptake. We propose that such a slow lymphatic regeneration mode is necessary to match a unique need of intestinal lymphatic vessels for both continuous maintenance, due to the constant exposure to dietary fat and mechanical strain, and efficient uptake of fat and immune cells. Our work reveals how lymphatic vessel responses are shaped by tissue specialization and uncover a role for continuous DLL4 signaling in the function of adult lymphatic vasculature. PMID- 26529258 TI - Cutaneous Collagenous Vasculopathy: A Rare Form of Microangiopathy Successfully Treated with a Combination of Multiplex Laser and Optimized Pulsed Light with a Review of the Literature. AB - Cutaneous collagenous vasculopathy (CCV) is a rare idiopathic microangiopathy of the cutaneous vasculature characterized histologically by the presence of dilated small blood vessels with flat endothelial cells and thickened walls containing hyaline material in the upper dermis. We report an elderly patient presenting with an extensive form of CCV involving the trunk, upper and lower limbs. She was treated with Multiplex PDL 595-nm/Nd:YAG 1,064-nm laser and optimized pulsed light. This approach, which has never been reported for CCV so far, resulted in a striking and almost complete clearance of the widespread lesions. We here review our knowledge about CCV and therapeutic options available with a survey of the literature. PMID- 26529257 TI - Myo9b is a key player in SLIT/ROBO-mediated lung tumor suppression. AB - Emerging evidence indicates that the neuronal guidance molecule SLIT plays a role in tumor suppression, as SLIT-encoding genes are inactivated in several types of cancer, including lung cancer; however, it is not clear how SLIT functions in lung cancer. Here, our data show that SLIT inhibits cancer cell migration by activating RhoA and that myosin 9b (Myo9b) is a ROBO-interacting protein that suppresses RhoA activity in lung cancer cells. Structural analyses revealed that the RhoGAP domain of Myo9b contains a unique patch that specifically recognizes RhoA. We also determined that the ROBO intracellular domain interacts with the Myo9b RhoGAP domain and inhibits its activity; therefore, SLIT-dependent activation of RhoA is mediated by ROBO inhibition of Myo9b. In a murine model, compared with control lung cancer cells, SLIT-expressing cells had a decreased capacity for tumor formation and lung metastasis. Evaluation of human lung cancer and adjacent nontumor tissues revealed that Myo9b is upregulated in the cancer tissue. Moreover, elevated Myo9b expression was associated with lung cancer progression and poor prognosis. Together, our data identify Myo9b as a key player in lung cancer and as a ROBO-interacting protein in what is, to the best of our knowledge, a newly defined SLIT/ROBO/Myo9b/RhoA signaling pathway that restricts lung cancer progression and metastasis. Additionally, our work suggests that targeting the SLIT/ROBO/Myo9b/RhoA pathway has potential as a diagnostic and therapeutic strategy for lung cancer. PMID- 26529259 TI - Diamond formation due to a pH drop during fluid-rock interactions. AB - Diamond formation has typically been attributed to redox reactions during precipitation from fluids or magmas. Either the oxidation of methane or the reduction of carbon dioxide has been suggested, based on simplistic models of deep fluids consisting of mixtures of dissolved neutral gas molecules without consideration of aqueous ions. The role of pH changes associated with water silicate rock interactions during diamond formation is unknown. Here we show that diamonds could form due to a drop in pH during water-rock interactions. We use a recent theoretical model of deep fluids that includes ions, to show that fluid can react irreversibly with eclogite at 900 degrees C and 5.0 GPa, generating diamond and secondary minerals due to a decrease in pH at almost constant oxygen fugacity. Overall, our results constitute a new quantitative theory of diamond formation as a consequence of the reaction of deep fluids with the rock types that they encounter during migration. Diamond can form in the deep Earth during water-rock interactions without changes in oxidation state. PMID- 26529260 TI - Emergent and Urgent Transfers to Neurosurgical Centers in Ontario. AB - Critically ill neurosurgical patients require expedient access to neurosurgical centers (NC) to improve outcome. In regionalized health systems patients are often initially evaluated at a non-neurosurgical center (NNC) and are subsequently transferred to a NC using air or ground vehicles. We sought to identify barriers to accessing a NC for critically ill patients by analyzing interfacility transfer times and referral patterns in the province of Ontario. A retrospective observational analysis was undertaken. The cohort included patients in Ontario with emergent and urgent neurologic pathologies who underwent transfer from a NNC to NC between January 1, 2011 and December 31, 2013. Timing, clinical, and geographic data were collected for each transfer. We identified 1103 emergent/urgent transfers. The median transfer time to a NC was 3.4 h (IQR -2.2, 3.8) and varied by the geographic region of origin. A total of 17% of the patients bypassed a closer NC during transfer to their destination NC. Transfers that bypassed a closer NC travelled further (101 miles vs. 296 miles, p < 0.001), took longer (3.1 h vs. 3.9 h, p < 0.001), and in some regions were associated with a higher risk of in-transit clinical decline (3.0% vs. 8.3%, p < 0.05) when compared with transfers that ended at the closest NC. Regionalization of neurosurgical services in Ontario has led to heavy reliance upon patient transfers to maintain continuity of care. Access to a NC varied across the province, which may represent regional differences in neurosurgical bed availability, resource limitations at smaller NCs, or environmental factors. Our descriptions of referral patterns and transport times can guide health system planning in Ontario and similar jurisdictions in the United States and Canada. PMID- 26529261 TI - Current role of anticholinergic drugs in the treatment of asthma: key messages for clinical practice. AB - Anticholinergic bronchodilators such as tiotropium, a potent long-acting drug, are central to the symptomatic treatment of chronic obstructive pulmonary disease. Its role in asthma treatment has been recently investigated. This review critically evaluates documented evidence of clinical trials and assesses the therapeutic implications of anticholinergic drugs in asthma management. So far, the results of 10 Phases II and III randomized controlled trials evaluating the effect of adding tiotropium to the treatment of mild-to-moderate or severe asthma have been published. These trials had a duration of 4 to 52 weeks and involved 3368 subjects with mild-to-moderate asthma and 1019 subjects with severe asthma [corrected]. Also, 1 systematic review and 6 meta-analyses have appraised the results of published and unpublished trials investigating the role of tiotropium in asthma. The results of the trials in mild to moderate asthma showed that adding tiotropium to inhaled corticosteroids (ICSs) was not inferior to adding long-acting beta2-agonists (LABAs). In addition, the safety and efficacy of tiotropium were similar to those of salmeterol. The results of studies on severe asthma showed that adding tiotropium to a treatment with high doses of an ICS plus LABA results in further improvement in lung function, increases the time to the first severe exacerbation of asthma and to worsening of asthma, and improves asthma control. Except for dry mouth, the safety profile of tiotropium was similar to placebo both in moderate and in severe asthma. Adding tiotropium to an ICS or ICS plus LABA improves lung function, symptoms, and asthma control, and in severe asthma, it increases the time to exacerbations, with good safety profile. The effect seems independent of baseline characteristics such as age, level of bronchial obstruction, smoking status, allergic status, and bronchial reversibility. PMID- 26529262 TI - Structure, Anharmonic Vibrational Frequencies, and Intensities of NNHNN(+). AB - A semiglobal potential energy surface (PES) and quartic force field (QFF) based on fitting high-level electronic structure energies are presented to describe the structures and spectroscopic properties of NNHNN(+). The equilibrium structure of NNHNN(+) is linear with the proton equidistant between the two nitrogen groups and thus of D(infinityh) symmetry. Vibrational second-order perturbation theory (VPT2) calculations based on the QFF fails to describe the proton "rattle" motion, i.e., the antisymmetric proton stretch, due to the very flat nature of PES around the global minimum but performs properly for other modes with sharper potential wells. Vibrational self-consistent field/virtual state configuration interaction (VSCF/VCI) calculations using a version of MULTIMODE without angular momentum terms successfully describe this motion and predict the fundamental to be at 759 cm(-1). This is in good agreement with the value of 746 cm(-1) from a fixed-node diffusion Monte Carlo calculation and the experimental Ar-tagged result of 743 cm(-1). Other VSCF/VCI energies are in good agreement with other experimentally reported ones. Both double-harmonic intensity and rigorous MULTIMODE intensity calculations show the proton-transfer fundamental has strong intensity. PMID- 26529263 TI - Diagnostic Accuracy of Full-Body Linear X-Ray Scanning in Multiple Trauma Patients in Comparison to Computed Tomography. AB - PURPOSE: The purpose of this study was to evaluate the diagnostic accuracy of full-body linear X-ray scanning (LS) in multiple trauma patients in comparison to 128-multislice computed tomography (MSCT). MATERIALS AND METHODS: 106 multiple trauma patients (female: 33; male: 73) were retrospectively included in this study. All patients underwent LS of the whole body, including extremities, and MSCT covering the neck, thorax, abdomen, and pelvis. The diagnostic accuracy of LS for the detection of fractures of the truncal skeleton and pneumothoraces was evaluated in comparison to MSCT by two observers in consensus. Extremity fractures detected by LS were documented. RESULTS: The overall sensitivity of LS was 49.2 %, the specificity was 93.3 %, the positive predictive value was 91 %, and the negative predictive value was 57.5 %. The overall sensitivity for vertebral fractures was 16.7 %, and the specificity was 100 %. The sensitivity was 48.7 % and the specificity 98.2 % for all other fractures. Pneumothoraces were detected in 12 patients by CT, but not by LS. 40 extremity fractures were detected by LS, of which 4 fractures were dislocated, and 2 were fully covered by MSCT. CONCLUSION: The diagnostic accuracy of LS is limited in the evaluation of acute trauma of the truncal skeleton. LS allows fast whole-body X-ray imaging, and may be valuable for detecting extremity fractures in trauma patients in addition to MSCT. KEY POINTS: The overall sensitivity of LS for truncal skeleton injuries in multiple-trauma patients was < 50 %. The diagnostic reference standard MSCT is the preferred and reliable imaging modality. LS may be valuable for quick detection of extremity fractures. PMID- 26529264 TI - Reducing Radiation Dose in Adult Head CT using Iterative Reconstruction - A Clinical Study in 177 Patients. AB - PURPOSE: To assess how ASIR (adaptive statistical iterative reconstruction) contributes to dose reduction and affects image quality of non-contrast cranial computed tomography (cCT). MATERIALS AND METHODS: Non-contrast emergency CT scans of the head acquired in 177 patients were evaluated. The scans were acquired and processed using four different protocols: Group A (control): 120 kV, FBP (filtered back projection) n = 71; group B1: 120 kV, scan and reconstruction performed with 20 % ASIR (blending of 20 % ASIR and 80 % FBP), n = 86; group B2: raw data from group B1 reconstructed using a blending of 40 % ASIR and 60 % FBP, n = 74; group C1: 120 kV, scan and reconstruction performed with 30 % ASIR, n = 20; group C2: raw data from group C1 reconstructed using a blending of 50 % ASIR and 50 % FBP, n = 20. The effective dose was calculated. Image quality was assessed quantitatively and qualitatively. RESULTS: Compared to group A, groups B1/2 and C1/2 showed a significantly reduced effective dose of 40.4 % and 73.3 % (p < 0.0001), respectively. Group B1 and group C1/2 also showed significantly reduced quantitative and qualitative image quality parameters. In group B2, quantitative measures were comparable to group A, and qualitative scores were lower compared to group A but higher compared to group B1. Diagnostic confidence grading showed groups B1/2 to be adequate for everyday clinical practice. Group C2 was considered acceptable for follow-up imaging of severe acute events such as bleeding or subacute stroke. CONCLUSION: Use of ASIR makes it possible to reduce radiation significantly while maintaining adequate image quality in non-contrast head CT, which may be particularly useful for younger patients in an emergency setting and in follow-up. KEY POINTS: ASIR may reduce radiation significantly while maintaining adequate image quality. cCT protocol with 20 % ASIR and 40 %ASIR/60 %FBP blending is adequate for everyday clinical use. cCT protocol with 30 % ASIR and 50 %ASIR/50 %FBP blending is adequate for follow-up imaging PMID- 26529265 TI - Strain Elastography of Breast and Prostata Cancer: Similarities and Differences. AB - Typically both breast and prostate cancer present as tissue with decreased elasticity. Palpation is the oldest technique of tumor detection in both organs and is based on this principle. Thus an operator can grade a palpable mass as suspicious for cancer. Strain elastography as modern ultrasound technique allows the visualization of tissue elasticity in a color coded elastogram and can be understood as technical finger. The following article shows similarities and differences of ultrasound strain elastography in the diagnosis of breast and prostate cancer. KEY POINTS: * In prostata cancer elastography, in breast cancer B-mode is the primary sonographic search modality. * The diagnostic value of the search modalities change with increasing age.* A cut-off value for a strain ratio is hard to obtain in the elastography of the prostata, because there is no stabile reference tissue in the prostata. PMID- 26529266 TI - Interventional Ischemic Stroke Treatment--A (R)evolution. AB - In recent years ischemic stroke caused by an intracranial vessel occlusion has become a treatable disease. Over decades intravenous thrombolysis by recombinant tissue plasminogen activator was the only accepted causal treatment of ischemic stroke supported by the results of randomized, controlled trials. However, there has been continuous development of endovascular treatment strategies over recent years. Today there are 5 prospective, randomized multicenter studies showing the highly significant superiority of endovascular, mechanical recanalization over intravenous thrombolysis in cases of acute occlusion of an intracranial vessel of the anterior circulation. In all those studies endovascular treatment resulted in a tremendous increase in functional independence together with a reduction of mortality without a significant increase in complications. This article reviews the developments resulting in the current data and gives an overview of the present studies focusing on endovascular stroke treatment. KEY POINTS: * In the last 20 years ischemic stroke due to an main stem occlusion has become a potentially treatable disease. * Several in 2015 published randomized Multicenter trials could prove the superiority of endovascular, mechanical recanalization over i.v. thrombolysis alone. * Acute ischemic stroke due to a main stem occlusion should be treated with swift endovascular stent-retriever based recanalization in specialized neurovascular centers. PMID- 26529267 TI - [Not Available]. PMID- 26529268 TI - [Not Available]. PMID- 26529269 TI - Development of hand phenotypes and changes in hand pain and problems over time in older people. AB - Hand disabilities are frequent causes of pain and disability in older people, yet knowledge regarding the characteristics and patterns of hand pain and problems over time is lacking. The main aim of this study was to identify subgroups of older individuals with distinct presentations (phenotypes) of hand pain and function, investigate how these might change over a 6-year period, and explore what characteristics and factors are associated with long-term status. The study population stemmed from the North Staffordshire Osteoarthritis Project, a large, general population-based, prospective, cohort study of adults aged 50 years and older. Information on hand pain and problems was collected using questionnaires at baseline, 3 years, and 6 years. Overall, 5617 participants responded at all time points and were included in the analysis. Five phenotypes were identified using latent transition analysis ("least affected," "high pain," "poor gross function," "high pain and poor gross function," and "severely affected") based on 8 hand pain and functional items. The most common transition between phenotypes was from "high pain" at baseline to "least-affected" group. There was a high level of stability in individuals in the "least-affected" or "severely affected" group at baseline. Individuals with widespread body pain, nodes, sleep problems, and pain in both hands at baseline were more likely to be in a severe hand phenotype at 6 years. The results provide clinically relevant information regarding the pattern of hand pain and problems over time and factors that predict transition to more severe hand phenotypes. PMID- 26529270 TI - A comprehensive categorical and bibliometric analysis of published research articles on pediatric pain from 1975 to 2010. AB - The field of pediatric pain research began in the mid-1970s and has undergone significant growth and development in recent years as evidenced by the variety of books, conferences, and journals on the topic and also the number of disciplines engaged in work in this area. Using categorical and bibliometric meta-trend analysis, this study offers a synthesis of research on pediatric pain published between 1975 and 2010 in peer-reviewed journals. Abstracts from 4256 articles, retrieved from Web of Science, were coded across 4 categories: article type, article topic, type and age of participants, and pain stimulus. The affiliation of the first author and number of citations were also gathered. The results suggest a significant increase in the number of publications over the time period investigated, with 96% of the included articles published since 1990 and most research being multiauthored publications in pain-focused journals. First authors were most often from the United States and affiliated with a medical department. Most studies were original research articles; the most frequent topics were pain characterization (39.86%), pain intervention (37.49%), and pain assessment (25.00%). Clinical samples were most frequent, with participants most often characterized as children (6-12 years) or adolescents (13-18 years) experiencing chronic or acute pain. The findings provide a comprehensive overview of contributions in the field of pediatric pain research over 35 years and offers recommendations for future research in the area. PMID- 26529271 TI - Chemotherapy-induced pain and neuropathy: a prospective study in patients treated with adjuvant oxaliplatin or docetaxel. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer therapy. This study evaluates symptoms of CIPN and CIPN-related pain and its influence on psychological functioning and potential predictors of chronic CIPN and pain. In this large prospective questionnaire study, 174 patients receiving adjuvant oxaliplatin or docetaxel were consecutively included. Patients were asked to complete a questionnaire with validated questions on peripheral neuropathy, pain, anxiety and depression, and quality of life at baseline, after the first cycle, halfway through therapy, and 1 year after baseline. Chronic CIPN symptoms (tingling and/or numbness) in the feet at 1-year follow-up were present in 63.6% of patients without preexisting neuropathy in the oxaliplatin group and in 44.8% in the docetaxel group, whereas pain in hands and feet was found in 31.3% and 35.1%, respectively. Both groups had significantly different pain profiles, and persistent pain in the docetaxel group was found to have effect on psychological function. Cumulative dose predicted oxaliplatin-induced neuropathy (P = 0.004), whereas endocrine therapy predicted peripheral pain in the docetaxel group (P = 0.04). There are important differences in acute neuropathic symptoms and chronic pain profiles in patients after oxaliplatin and docetaxel treatment. It is, however, important to recognize that chronic peripheral pain may be unrelated to neuropathy and can be caused by concomitant treatments. Future studies should focus on characterizing and distinguishing CIPN-related pain from other types of pain to determine the best outcome measures for trials on prevention or relief. PMID- 26529273 TI - Recombinant Mitochondrial Manganese Containing Superoxide Dismutase Protects Against Ochratoxin A-Induced Nephrotoxicity. AB - Ochratoxin A (OTA) is a natural mycotoxin, involved in the development of important human and animal diseases. In this work we have studied the role of oxidative stress in the development of OTA nephrotoxicity and the effect of a new recombinant mitochondrial manganese containing superoxide dismutase (rMnSOD) to prevent kidney damage induced by OTA. Blood pressure, glomerular filtration rate and renal histology were analyzed in control rats and in OTA treated rats. In addition, lipid peroxidation, catalase and superoxide dismutase productions were measured. Our data showed that animals treated with OTA presented hypertension and reduction of glomerular filtration rate (GFR). These effects are most probably related to an increase in the reactive oxygen species (ROS) productions. In fact, we have shown that treatment with rMnSOD restored the levels of blood pressure and GFR simultaneously. Moreover, we have noted that OTA induced alteration on glomerular and tubular degeneration and interstitial infiltrates and that use of rMnSOD combined with OTA prevent this renal histological damage confirming the potential therapeutic role in the treatment of rMnSOD OTA nephrotoxicity. PMID- 26529274 TI - Sensor fusion and computer vision for context-aware control of a multi degree-of freedom prosthesis. AB - OBJECTIVE: Myoelectric activity volitionally generated by the user is often used for controlling hand prostheses in order to replicate the synergistic actions of muscles in healthy humans during grasping. Muscle synergies in healthy humans are based on the integration of visual perception, heuristics and proprioception. Here, we demonstrate how sensor fusion that combines artificial vision and proprioceptive information with the high-level processing characteristics of biological systems can be effectively used in transradial prosthesis control. APPROACH: We developed a novel context- and user-aware prosthesis (CASP) controller integrating computer vision and inertial sensing with myoelectric activity in order to achieve semi-autonomous and reactive control of a prosthetic hand. The presented method semi-automatically provides simultaneous and proportional control of multiple degrees-of-freedom (DOFs), thus decreasing overall physical effort while retaining full user control. The system was compared against the major commercial state-of-the art myoelectric control system in ten able-bodied and one amputee subject. All subjects used transradial prosthesis with an active wrist to grasp objects typically associated with activities of daily living. MAIN RESULTS: The CASP significantly outperformed the myoelectric interface when controlling all of the prosthesis DOF. However, when tested with less complex prosthetic system (smaller number of DOF), the CASP was slower but resulted with reaching motions that contained less compensatory movements. Another important finding is that the CASP system required minimal user adaptation and training. SIGNIFICANCE: The CASP constitutes a substantial improvement for the control of multi-DOF prostheses. The application of the CASP will have a significant impact when translated to real-life scenarious, particularly with respect to improving the usability and acceptance of highly complex systems (e.g., full prosthetic arms) by amputees. PMID- 26529275 TI - Inhibition of Polyamine Uptake Potentiates the Anti-Proliferative Effect of Polyamine Synthesis Inhibition and Preserves the Contractile Phenotype of Vascular Smooth Muscle Cells. AB - Increased vascular smooth muscle cell (VSMC) proliferation is a factor in atherosclerosis and injury-induced arterial (re) stenosis. Inhibition of polyamine synthesis by alpha-difluoro-methylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, attenuates VSMC proliferation with high sensitivity and specificity. However, cells can escape polyamine synthesis blockade by importing polyamines from the environment. To address this issue, polyamine transport inhibitors (PTIs) have been developed. We investigated the effects of the novel trimer44NMe (PTI-1) alone and in combination with DFMO on VSMC polyamine uptake, proliferation and phenotype regulation. PTI-1 efficiently inhibited polyamine uptake in primary mouse aortic and human coronary VSMCs in the absence as well as in the presence of DFMO. Interestingly, culture with DFMO for 2 days substantially (>95%) reduced putrescine (Put) and spermidine (Spd) contents without any effect on proliferation. Culture with PTI-1 alone had no effect on either polyamine levels or proliferation rate, but the combination of both treatments reduced Put and Spd levels below the detection limit and inhibited proliferation. Treatment with DFMO for a longer time period (4 days) reduced Put and Spd below their detection limits and reduced proliferation, showing that only a small pool of polyamines is needed to sustain VSMC proliferation. Inhibited proliferation by polyamine depletion was associated with maintained expression of contractile smooth marker genes. In cultured intact mouse aorta, PTI-1 potentiated the DFMO-induced inhibition of cell proliferation. The combination of endogenous polyamine synthesis inhibition with uptake blockade is thus a viable approach for targeting unwanted vascular cell proliferation in vivo, including vascular restenosis. PMID- 26529276 TI - Presence of nucleotide substitutions in the ABO promoter in individuals with phenotypes A3 and B3. AB - Recently, the involvement of mutation and deletion of transcription regulatory elements in the Bm , Am , A3 and B3 phenotypes has been reported. In the present study, we carried out genetic analysis of individuals with A3 and B3 using peptide nucleic acid-clamping PCR to exclude amplification of O alleles. Two single-point mutations, -76G>C and -68G>T, were found in the ABO promoter on the A-allele in three A3 individuals and on the B allele in a B3 individual, respectively. Transient transfection of luciferase reporter plasmids carrying the same mutations into K562 cells revealed decreased luciferase activity in comparison with that carrying the wild-type promoter. These observations suggest that the mutations downregulate the promoter activity, leading to reduction in A- or B-antigen expression on red blood cells in individuals with the A3 and B3 phenotypes. PMID- 26529278 TI - Plant cytokinesis-No ring, no constriction but centrifugal construction of the partitioning membrane. AB - Plants have evolved a unique way of partitioning the cytoplasm of dividing cells: Instead of forming a contractile ring that constricts the plasma membrane, plant cells target membrane vesicles to the plane of division where the vesicles fuse with one another to form the partitioning membrane. Plant cytokinesis starts in the centre and progresses towards the periphery, culminating in the fusion of the partitioning membrane with the parental plasma membrane. This membrane dynamics is orchestrated by a specific cytoskeletal array named phragmoplast that originates from interzone spindle remnants. Here we review the properties of the process as well as molecules that play specific roles in that process. PMID- 26529279 TI - Lipolytic and thermogenic depletion of adipose tissue in cancer cachexia. AB - Although muscle wasting is the obvious manifestation of cancer cachexia that impacts on patient quality of life, the loss of lipid reserves and metabolic imbalance in adipose tissue also contribute to the devastating impact of cachexia. Depletion of fat depots in cancer patients is more pronounced than loss of muscle and often precedes, or even occurs in the absence of, reduced lean body mass. Rapid mobilisation of triglycerides stored within adipocytes to supply the body with fatty acids in periods of high-energy demand is normally mediated through a well-defined process of lipolysis involving the lipases ATGL, HSL and MGL. Studies into how these lipases contribute to fat loss in cancer cachexia have revealed the prominent role for ATGL in initiating lipolysis during adipose tissue atrophy, together with links between tumour-derived factors and the signalling pathways that control lipid flux within fat cells. The recent findings of increased thermogenesis in brown fat during cancer cachexia indicate that metabolically active adipose tissue contributes to the imbalance in energy homeostasis involved in catabolic wasting. Such energetically futile use of fatty acids liberated from adipose tissue to generate heat represents a maladaptive response in conjunction with anorexia experienced by cancer patients. As IL-6 release by tumours provokes lipolysis and activates the thermogenic programme in brown fat, this review explores the overlap in dysregulated metabolic processes due to inflammatory mediators in cancer cachexia and other disease states characterised by elevated cytokines such as obesity and diabetes. PMID- 26529280 TI - Association between microRNA-196A2 and microRNA-146A polymorphisms and progression to cirrhosis and hepatocellular carcinoma in patients with viral hepatitis B. AB - BACKGROUND/AIM: MicroRNAs (miRNAs) are small noncoding RNAs that have been implicated in mechanisms underlying various types of cancers including hepatocellular carcinoma (HCC). Reports have indicated that single nucleotide polymorphisms in miRNA-196A2 and miRNA-146A genes may contribute to the risk of progression of hepatitis B virus (HBV) infection to cirrhosis and HCC. This study aimed to examine the effect of miRNA-196A2 and miRNA-146A polymorphisms on the progression of HBV infection to cirrhosis and/or HCC in HBV patients in the Malaysian population. PATIENTS AND METHODS: This study consists of 423 chronic HBV patients without either cirrhosis or HCC and 103 chronic HBV patients diagnosed with liver cirrhosis or with cirrhosis and HCC. The single nucleotide polymorphisms of miRNA-196A2 (rs12304647 and rs11614913) and miRNA-146A (rs2910164) were genotyped using the Sequenom MassARRAY platform. RESULTS: The genotype distribution in chronic HBV without either cirrhosis or HCC, relative to chronic HBV patients diagnosed with liver cirrhosis or with cirrhosis and HCC revealed that rs12304647 has a protective effect from the development of HCC (odds ratio=0.37, 95% confidence interval=0.15-0.89, P=0.027). However, rs11614913 and rs2910164 were not significantly associated with progression of the HBV infection. CONCLUSION: In summary, rs12304647 is associated with a reduced risk of progression to HCC in patients with chronic HBV infection. PMID- 26529281 TI - Differences in body mass index according to fat mass- and obesity-associated (FTO) genotype in Mexican patients with bipolar disorder. AB - OBJECTIVES: The prevalence of obesity has dramatically increased in many countries and it is particularly high in patients with bipolar disorder (BD). A region in the first intron of the fat mass- and obesity-associated (FTO) gene, encompassing markers rs9939973, rs8050136, and rs9939609, has been consistently associated with obesity and body mass index (BMI) in different populations. We sought to determine whether FTO is associated with BMI and/or obesity in patients with BD. METHODS: The sample included 129 Mexican Mestizo patients with bipolar I or bipolar II disorder. After obtaining informed consent, participants were evaluated with the Structured Clinical Interview for DSM-IV Axis I Disorders and weight, height, and body measurements were recorded. DNA was extracted from a 5 mL blood sample and real-time polymerase chain reaction was performed. The results were analyzed with Haploview v4.2 and SPSS v21. RESULTS: Differences in mean BMI were explained by rs8050136 and rs9939609 genotypes, especially by comparing non-carriers and carriers of two copies of the risk allele (Tukey's p <= 0.019), with a mean difference in BMI as high as 7.81 kg/m(2) . Differences in BMI were also explained by the interaction of the genotype (rs8050136 and/or rs9939609), the use of second-generation antipsychotics, and the use of mood stabilizers (p <= 0.41). Obesity was also associated with these two markers when patients with and without obesity were compared. CONCLUSIONS: In patients with BD, differences in BMI may be affected by the presence of FTO risk alleles, especially in homozygous individuals for these variants. Besides evaluating the possible metabolic effects of certain antipsychotics or mood stabilizers, it is important to evaluate the role of other factors such as FTO risk alleles. PMID- 26529282 TI - HIV-1 Genetic Diversity and Transmitted Drug Resistance in Antiretroviral Treatment-Naive Individuals from Amapa State, Northern Brazil. AB - The pattern of HIV-1 subtype distribution and prevalence of transmitted drug resistance mutations (TDRM) is heterogeneous across different Brazilian regions. Little information is available about the molecular epidemiologic profile in Northern Brazil. HIV-1 protease (PR) and reverse transcriptase (RT) sequences were obtained from 97 drug-naive HIV-1-infected individuals from Amapa, one of the most isolated Northern Brazilian states, for subtype determination and analysis of drug resistance mutations. The most prevalent HIV-1 clade observed in Amapa was subtype B (74%), followed by subtype F1 (14%), BF1 recombinants (8%), subtype C (1%), CRF31_BC (1%), and CRF02_AG (1%). Only one TDRM (K103N) was detected in a single patient from our study population. This study reveals that the HIV-1 epidemic in Amapa is characterized by a high level of genetic diversity comparable to that observed in major Brazilian cities, but a much lower rate of TDRM (1%). PMID- 26529283 TI - Nanoscale Trapping and Squeeze-Out of Confined Alkane Monolayers. AB - We present combined force curve and conduction atomic force microscopy (AFM) data for the linear alkanes CnH2n+2 (n = 10, 12, 14, 16) confined between a gold coated AFM tip and a graphite surface. Solvation layering is observed in the force curves for all liquids, and conduction AFM is used to study in detail the removal of the confined (mono)layer closest to the graphite surface. The squeeze out behavior of the monolayer can be very different depending upon the temperature. Below the monolayer melting transition temperatures the molecules are in an ordered state on the graphite surface, and fast and complete removal of the confined molecules is observed. However, above the melting transition temperature the molecules are in a disordered state, and even at large applied pressure a few liquid molecules are trapped within the tip-sample contact zone. These findings are similar to a previous study for branched alkanes [ Gosvami Phys. Rev. Lett. 2008, 100, 076101 ], but the observation for the linear alkane homologue series demonstrates clearly the dependence of the squeeze-out and trapping on the state of the confined material. PMID- 26529284 TI - Exploring the Role of Substitution on the Formation of Se...O/N Noncovalent Bonds. AB - In this article, we have examined the effect of substitution on the formation of neutral XHSe...O/N (X = -H, -F, -CH3, -CF3, -Cl, -OH, -OCH3, -NH2, -NHCH3, -CN) noncovalent bonds with the oxygen atom from H2O molecule and the nitrogen atom from NH3 being the electron donor atoms, respectively. In addition to this, analysis has also been performed on XMeSe...O/N complexes to study the effect of the role of hydrogen bonding with the hydrogen atoms of the methyl group on Se...O/N interactions. Binding energy calculations were performed to determine the strength of these contacts. The obtained results establish the fact that the presence of a methyl group influences the strength of the observed Se...O/N interactions. Also in some cases, the O-H...Se interaction was observed to be more preferable over the Se...O interaction. The major contribution for stabilization of such Se...O/N interactions is from an interplay among the electrostatics and the exchange energy. To obtain deeper insights and understanding of such Se...O/N contacts, a topological analysis, using the QTAIM approach were also performed. This analysis showed that although the presence of a Me group modifies the Se...O/N interaction, it does not necessitate the formation of hydrogen bonds. To obtain insights into the orbital contributions, a natural bond orbital (NBO) analysis were performed which depicts that the strength of such interactions were derived via charge transfer from the oxygen/nitrogen lone pair to the sigma* orbital of the Se-X bond. PMID- 26529285 TI - Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis. AB - INTRODUCTION: Liver fibrosis develops when hepatic stellate cells (HSC) are activated into collagen-producing myofibroblasts. In non-alcoholic steatohepatitis (NASH), the adipokine leptin is upregulated, and promotes liver fibrosis by directly activating HSC via the hedgehog pathway. We reported that hedgehog-regulated osteopontin (OPN) plays a key role in promoting liver fibrosis. Herein, we evaluated if OPN mediates leptin-profibrogenic effects in NASH. METHODS: Leptin-deficient (ob/ob) and wild-type (WT) mice were fed control or methionine-choline deficient (MCD) diet. Liver tissues were assessed by Sirius red, OPN and alphaSMA IHC, and qRT-PCR for fibrogenic genes. In vitro, HSC with stable OPN (or control) knockdown were treated with recombinant (r)leptin and OPN neutralizing or sham-aptamers. HSC response to OPN loss was assessed by wound healing assay. OPN-aptamers were also added to precision-cut liver slices (PCLS), and administered to MCD-fed WT (leptin-intact) mice to determine if OPN neutralization abrogated fibrogenesis. RESULTS: MCD-fed WT mice developed NASH fibrosis, upregulated OPN, and accumulated alphaSMA+ cells. Conversely, MCD-fed ob/ob mice developed less fibrosis and accumulated fewer alphaSMA+ and OPN+ cells. In vitro, leptin-treated HSC upregulated OPN, alphaSMA, collagen 1alpha1 and TGFbeta mRNA by nearly 3-fold, but this effect was blunted by OPN loss. Inhibition of PI3K and transduction of dominant negative-Akt abrogated leptin mediated OPN induction, while constitutive active-Akt upregulated OPN. Finally, OPN neutralization reduced leptin-mediated fibrogenesis in both PCLS and MCD-fed mice. CONCLUSION: OPN overexpression in NASH enhances leptin-mediated fibrogenesis via PI3K/Akt. OPN neutralization significantly reduces NASH fibrosis, reinforcing the potential utility of targeting OPN in the treatment of patients with advanced NASH. PMID- 26529286 TI - Highly Selective and Sensitive Detection of Cu(2+) Ions Using Ce(III)/Tb(III) Doped SrF2 Nanocrystals as Fluorescent Probe. AB - We report a green synthetic approach to the synthesis of water dispersible Ce(3+)/Tb(3+)-doped SrF2 nanocrystals, carried out using environment friendly microwave irradiation with water as solvent. The nanocrystals display strong green emission due to energy transfer from Ce(3+) to Tb(3+) ions. This strong green emission from Tb(3+) ions is selectively quenched upon addition of Cu(2+) ions, thus making the nanocrystals a potential Cu(2+) ions sensing material. There is barely any interference by other metal ions on the detection of Cu(2+) ions and the detection limit is as low as 2 nM. This sensing ability is highly reversible by the addition of ethylenediaminetetraacetic acid (EDTA) with the recovery of almost 90% of the original luminescence. The luminescence quenching and recovery cycle was repeated multiple times without much effect on the sensitivity. The study was extended to real world water samples and obtained similar results. In addition to the sensing, we strongly predict the small size and high luminescence of the Ce(3+)/Tb(3+)-doped SrF2 nanocrystals can be used for bioimaging applications. PMID- 26529287 TI - Discovery and Preclinical Validation of [(11)C]AZ13153556, a Novel Probe for the Histamine Type 3 Receptor. AB - The histamine type 3 receptor (H3) is a G protein-coupled receptor implicated in several disorders of the central nervous system. Herein, we describe the radiolabeling and preclinical evaluation of a candidate radioligand for the H3 receptor, 4-(1S,2S)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl]-N-methyl benzamide (5), and its comparison with one of the frontrunner radioligands for H3 imaging, namely, GSK189254 (1). Compounds 1 and 5 were radiolabeled with tritium and carbon-11 for in vitro and in vivo imaging experiments. The in vitro binding of [(3)H]1 and [(3)H]5 was examined by (i) saturation binding to rat and nonhuman primate brain tissue homogenate and (ii) in vitro autoradiography on tissue sections from rat, guinea pig, and human brain. The in vivo binding of [(11)C]1 and [(11)C]5 was examined by PET imaging in mice and nonhuman primates. Bmax values obtained from Scatchard analysis of [(3)H]1 and [(3)H]5 binding were in good agreement. Autoradiography with [(3)H]5 on rat, guinea pig, and human brain slices showed specific binding in regions known to be enhanced in H3 receptors, a high degree of colocalization with [(3)H]1, and virtually negligible nonspecific binding in tissue. PET measurements in mice and nonhuman primates demonstrated that [(11)C]5 binds specifically and reversibly to H3 receptors in vivo with low nonspecific binding in brain tissue. Whereas [(11)C]1 showed similar binding characteristics in vivo, the binding kinetics appeared faster for [(11)C]5 than for [(11)C]1. CONCLUSIONS: [(11)C]5 has suitable properties for quantification of H3 receptors in nonhuman primate brain and has the potential to offer improved binding kinetics in man compared to [(11)C]1. PMID- 26529288 TI - Genetic polymorphisms in GSTM1, GSTT1 and GSTP1 genes and risk of lung cancer in a North Indian population. AB - BACKGROUND: A number of studies done so far in different populations have shown that polymorphisms within the GST genes play an important role in determining individual susceptibility to lung cancer; however, data obtained so far have been contradictory within the same or different populations. Few studies have focused on the combinatorial effect of the GST genes on susceptibility to lung cancer and also for different histological subtypes. Our aim is to investigate the roles of GSTM1, GSTT1, and GSTP1 polymorphisms as genetic modifiers of risk for lung cancer and histological subtypes using a larger sample size in a North Indian population. METHODS: In total 540 subjects (270 lung cancer cases and 270 controls) were evaluated for the GST polymorphism. Genotyping for the GSTM1, GSTT1 and GSTP1 gene was done by using a multiplex PCR and PCR-RFLP method. RESULTS: GSTM1 null genotype was found to be associated with lung cancer (OR=1.65, 95%CI: 116-2.3, P=0.005) and this risk was higher in cases of adenocarcinoma (ADCC). GSTT1 and GSTP1 did not show any significant association with lung cancer; however, when stratified for histological subtypes a significant association was observed for ADCC and small-cell lung cancer (SCLC) for both GSTT1 null and variant GSTP1 genotypes. The combined 'at risk' genotypes of null GSTM1 and GSTT1 genes were found to be associated with lung cancer risk, and this risk was higher in cases of ADCC (OR=4.09, 95%CI: 110-10.2, P=0.002). There is a twofold increased risk for lung cancer with the null GSTM1 and wild type GSTP1 genotypes (P=0.0004); similarly, a fourfold increased risk was observed with the null GSTT1 and wild-type GSTP1 genotypes (P=0.0001). CONCLUSIONS: The deficient GST genotypes seem thus to be important risk modifiers for lung cancer and related histological subtypes, especially in combination. PMID- 26529289 TI - Sensitization trends after renal allograft failure: the role of DQ eplet mismatches in becoming highly sensitized. AB - Sensitization following renal allograft failure (AF) is highly variable. Some patients remain non-sensitized (NS), while others become highly sensitized (HS). We studied 66 NS patients who experienced AF after initial kidney transplantation. Post-failure, two main groups of NS panel reactive antibody (PRA) class I and II <10% and HS patients (PRA class I or II >=80%) were identified. The impact of acute rejection (AR), immunosuppression withdrawal (ISW) at AF, allograft nephrectomy, graft intolerance syndrome (GIS), and both standard serologic and eplet-based mismatches (MM) in inducing HS status after failure was examined. Late PRA testing post-failure revealed 18 patients remained NS and 34 patients became HS. African American recipients, ISW at AF, DQB1 eplet MM, and presence of GIS were associated with becoming HS. Presence of total zero eplet MM, zero DQA1/B1 eplet MM, continuation of immunosuppression after failure, and a hyporesponsive immune status characterized by recurrent infections were features of NS patients. DQ eplet MM represents a significant risk for becoming HS after AF. Studies comparing ISW vs. continuation in re-transplant candidates with high baseline DQ eplet MM burden should be performed. This may provide insights if sensitization post-AF can be lessened. PMID- 26529290 TI - Sertraline reduces glutamate uptake in human platelets. AB - Mitochondrial damage and declines in ATP levels have been recently attributed to sertraline. The effects of sertraline on different parameters were investigated in washed platelets from 18 healthy male volunteers, after 24h of drug exposure. Sertraline toxicity was observed only at the highest concentrations, 30 and 100 MUM, which significantly reduced platelet viability to 76 +/- 3% and 20 +/- 2%, respectively. The same concentrations significantly decreased total ATP to 73 +/- 3% and 13 +/- 2%, respectively. Basal values of glycogen were not significantly affected by sertraline treatment. Glutamate uptake was significantly reduced after treatment with 3, 30 and 100 MUM, by 28 +/- 6%, 32 +/- 5% and 54 +/- 4%, respectively. Our data showed that sertraline at therapeutic concentrations does not compromise platelet viability and ATP levels, but they suggest that in a situation where extracellular glutamate levels are potentially increased, sertraline might aggravate an excitotoxic condition. PMID- 26529291 TI - It is not all pheromones: No evidence that pheromones affect digging face choice during ant nest excavation. AB - Ants create nests of a size that is tailored to the number of individuals in a nest via a self-organized process. It is not yet clear how they accomplish this. Deposition and evaporation of pheromones at the digging face has been hypothesised by Deneubourg and Franks (1995) and Buhl et al. (2005) to be part of the nest construction process, with models being presented to support this contention. This hypothesis was tested by allowing groups of 5 Acromyrmex lundi workers to choose between two excavation sites, one that was freshly exposed to digging and one where digging had ceased an hour previously. It was expected that if pheromones played a role in stimulating digging, then ants would show a preference for digging in the "fresh" sites rather than the "aged" sites where the putative digging pheromone had decayed. No significant difference in digging activity between "fresh" and "aged" sites was detected. It is therefore likely that, while digging pheromones may play other roles in other parts of the digging system, they do not play an important role in regulation of soil excavation at the digging face. PMID- 26529292 TI - Neighborhood Walkability and Walking for Transport Among South Asians in the MASALA Study. AB - BACKGROUND: The neighborhood built environment can have a strong influence on physical activity levels, particularly walking for transport. In examining racial/ethnic differences in physical activity, one important and understudied group is South Asians. This study aims to describe the association between neighborhood walkability and walking for transport among South Asian men and women in the United States in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study. METHODS: A cross-sectional study was conducted in 2014 using the baseline dataset of the MASALA study (N = 906). Mean age was 55 years old and 54% of the sample was male. Weekly minutes spent walking for transport was assessed using a questionnaire adapted from the Cross-Cultural Activity Participation Study. Neighborhood walkability was measured using Walk Score, a composite index of walkability. RESULTS: After adjusting for covariates, with each 10-point increase in Walk Score, South Asian American men engaged in 13 additional minutes per week of walking for transport (P = .008). No association was observed between walkability and walking for transport in South Asian American women. CONCLUSIONS: Results provide new evidence for how the effects of environmental influences on walking for transport may vary between South Asian men and women. PMID- 26529294 TI - Use of Diffusion Weighted Imaging in Differentiating Between Maligant and Benign Meningiomas. A Multicenter Analysis. AB - BACKGROUND: Meningioma is the most frequent intracranial tumor and is often an incidental finding on imaging. Some imaging-based scores were suggested for differentiating low- and high-grade meningiomas. The purpose of this work was to compare diffusion-weighted imaging findings of different meningiomas in a large multicenter study by using apparent diffusion coefficient (ADC) values for predicting tumor grade and proliferation potential. METHODS: Data from 7 radiologic departments were acquired retrospectively. Overall, 389 patients were collected. All meningiomas were investigated by magnetic resonance imaging (1.5-T scanner) by using diffusion-weighted imaging (b values of 0 and 1000 s/mm(2)). The comparison of ADC values was performed by Mann-Whitney U test. RESULTS: World Health Organization grade I was diagnosed in 271 cases (69.7%), grade II in 103 (26.5%), and grade III in 15 patients (3.9%). Grade I meningiomas showed statistically significant higher ADC values (1.05 +/- 0.39 * 10(-3) mm(2)s(-1)) in comparison with grade II (0.77 +/- 0.15 * 10(-3) mm(2)s(-1); P = 0.001) and grade III tumors (0.79 +/- 0.21 * 10(-3) mm(2)s(-1); P = 0.01). An ADC value of <0.85 * 10(-3) mm(2)s(-1) was determined as the threshold in differentiating between grade I and grade II/III meningiomas (sensitivity, 72.9%; specificity, 73.1%; accuracy, 73.0%). Ki67 was associated with ADC (r = -0.63, P < 0.001). The optimal threshold for the ADC was (less than) 0.85 * 10(-3) mm(2)s(-1) for detecting tumors with high proliferation potential (Ki67 >=5%). CONCLUSIONS: The estimated threshold ADC value of 0.85 can differentiate grade I meningioma from grade II and III tumors. The same ADC value is helpful for detecting tumors with high proliferation potential. PMID- 26529295 TI - Perspective on Ionizing Radiation Exposure to Neurosurgery Residents in the Modern Era. PMID- 26529296 TI - Flap the Cyst. PMID- 26529297 TI - Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by deposition of amyloid plaques and neurofibrillary tangles, as well as microglial and astroglial activation, and, finally, leading to neuronal dysfunction and death. Current treatments for AD primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for the treatment of AD patients. This review will provide an overview of the antioxidant, anti-inflammatory, anti amyloidogenic, neuroprotective, and cognition-enhancing effects of a variety of nutraceuticals including curcumin, apigenin, docosahexaenoic acid, epigallocatechin gallate, alpha-lipoic acid and resveratrol and their potential for AD prevention and treatment. We suggest that therapeutic use of these compounds might lead to a safe strategy to delay the onset of AD or slow down its progression. The continuing investigation of the potential of these substances is necessary as they are promising compounds to yield a possible remedy for this pervasive disease. PMID- 26529298 TI - The Diagnostic Performance of Multiparametric Magnetic Resonance Imaging to Detect Significant Prostate Cancer. AB - PURPOSE: We assess the accuracy of multiparametric magnetic resonance imaging for significant prostate cancer detection before diagnostic biopsy in men with an abnormal prostate specific antigen/digital rectal examination. MATERIALS AND METHODS: A total of 388 men underwent multiparametric magnetic resonance imaging, including T2-weighted, diffusion weighted and dynamic contrast enhanced imaging before biopsy. Two radiologists used PI-RADS to allocate a score of 1 to 5 for suspicion of significant prostate cancer (Gleason 7 with more than 5% grade 4). PI-RADS 3 to 5 was considered positive. Transperineal template guided mapping biopsy of 18 regions (median 30 cores) was performed with additional manually directed cores from magnetic resonance imaging positive regions. The anatomical location, size and grade of individual cancer areas in the biopsy regions (18) as the primary outcome and in prostatectomy specimens (117) as the secondary outcome were correlated to the magnetic resonance imaging positive regions. RESULTS: Of the 388 men who were enrolled in the study 344 were analyzed. Multiparametric magnetic resonance imaging was positive in 77.0% of patients, 62.5% had prostate cancer and 41.6% had significant prostate cancer. The detection of significant prostate cancer by multiparametric magnetic resonance imaging had a sensitivity of 96%, specificity of 36%, negative predictive value of 92% and positive predictive value of 52%. Adding PI-RADS to the multivariate model, including prostate specific antigen, digital rectal examination, prostate volume and age, improved the AUC from 0.776 to 0.879 (p <0.001). Anatomical concordance analysis showed a low mismatch between the magnetic resonance imaging positive regions and biopsy positive regions (4 [2.9%]), and the significant prostate cancer area in the radical prostatectomy specimen (3 [3.3%]). CONCLUSIONS: In men with an abnormal prostate specific antigen/digital rectal examination, multiparametric magnetic resonance imaging detected significant prostate cancer with an excellent negative predictive value and moderate positive predictive value. The use of multiparametric magnetic resonance imaging to diagnose significant prostate cancer may result in a substantial number of unnecessary biopsies while missing a minimum of significant prostate cancers. PMID- 26529300 TI - Non-invasive flow path characterization in a mining-impacted wetland. AB - Time-lapse electrical resistivity (ER) was used to capture the dilution of a seasonal pulse of acid mine drainage (AMD) contamination in the subsurface of a wetland downgradient of the abandoned Pennsylvania mine workings in central Colorado. Data were collected monthly from mid-July to late October of 2013, with an additional dataset collected in June of 2014. Inversion of the ER data shows the development through time of multiple resistive anomalies in the subsurface, which corroborating data suggest are driven by changes in total dissolved solids (TDS) localized in preferential flow pathways. Sensitivity analyses on a synthetic model of the site suggest that the anomalies would need to be at least several meters in diameter to be adequately resolved by the inversions. The existence of preferential flow paths would have a critical impact on the extent of attenuation mechanisms at the site, and their further characterization could be used to parameterize reactive transport models in developing quantitative predictions of remediation strategies. PMID- 26529299 TI - Preparation of quadri-subtype influenza virus-like particles using bovine immunodeficiency virus gag protein. AB - Influenza VLPs comprised of hemagglutinin (HA), neuraminidase (NA), and matrix (M1) proteins have been previously used for immunological and virological studies. Here we demonstrated that influenza VLPs can be made in Sf9 cells by using the bovine immunodeficiency virus gag (Bgag) protein in place of M1. We showed that Bgag can be used to prepare VLPs for several influenza subtypes including H1N1 and H10N8. Furthermore, by using Bgag, we prepared quadri-subtype VLPs, which co-expressed within the VLP the four HA subtypes derived from avian origin H5N1, H7N9, H9N2 and H10N8 viruses. VLPs showed hemagglutination and neuraminidase activities and reacted with specific antisera. The content and co localization of each HA subtype within the quadri-subtype VLP were evaluated. Electron microscopy showed that Bgag-based VLPs resembled influenza virions with the diameter of 150-200nm. This is the first report of quadri-subtype design for influenza VLP and the use of Bgag for influenza VLP preparation. PMID- 26529301 TI - Biodegradation of phenol, salicylic acid, benzenesulfonic acid, and iomeprol by Pseudomonas fluorescens in the capillary fringe. AB - Mass transfer and biological transformation phenomena in the capillary fringe were studied using phenol, salicylic acid, benzenesulfonic acid, and the iodinated X-ray contrast agent iomeprol as model organic compounds and the microorganism strain Pseudomonas fluorescens. Three experimental approaches were used: Batch experiments (uniform water saturation and transport by diffusion), in static columns (with a gradient of water saturation and advective transport in the capillaries) and in a flow-through cell (with a gradient of water saturation and transport by horizontal and vertical flow: 2-dimension flow-through microcosm). The reactors employed for the experiments were filled with quartz sand of defined particle size distribution (dp=200...600 MUm, porosity epsilon=0.42). Batch experiments showed that phenol and salicylic acid have a high, whereas benzenesulfonic acid and iomeprol have a quite low potential for biodegradation under aerobic conditions and in a matrix nearly close to water saturation. Batch experiments under anoxic conditions with nitrate as electron acceptor revealed that the biodegradation of the model compounds was lower than under aerobic conditions. Nevertheless, the experiments showed that the moisture content was also responsible for an optimized transport in the liquid phase of a porous medium. Biodegradation in the capillary fringe was found to be influenced by both the moisture content and availability of the dissolved substrate, as seen in static column experiments. The gas-liquid mass transfer of oxygen also played an important role for the biological activity. In static column experiments under aerobic conditions, the highest biodegradation was found in the capillary fringe (e.g. betat/beta0 (phenol)=0 after t=6 d) relative to the zone below the water table and unsaturated zone. The highest biodegradation occurred in the flow through cell experiment where the height of the capillary fringe was largest. PMID- 26529302 TI - Reconstruction of in-situ porosity and porewater compositions of low-permeability crystalline rocks: Magnitude of artefacts induced by drilling and sample recovery. AB - Geological site characterisation programmes typically rely on drill cores for direct information on subsurface rocks. However, porosity, transport properties and porewater composition measured on drill cores can deviate from in-situ values due to two main artefacts caused by drilling and sample recovery: (1) mechanical disruption that increases porosity and (2) contamination of the porewater by drilling fluid. We investigated the effect and magnitude of these perturbations on large drill core samples (12-20 cm long, 5 cm diameter) of high-grade, granitic gneisses obtained from 350 to 600 m depth in a borehole on Olkiluoto Island (SW Finland). The drilling fluid was traced with sodium-iodide. By combining out-diffusion experiments, gravimetry, UV-microscopy and iodide mass balance calculations, we successfully quantified the magnitudes of the artefacts: 2-6% increase in porosity relative to the bulk connected porosity and 0.9 to 8.9 vol.% contamination by drilling fluid. The spatial distribution of the drilling induced perturbations was revealed by numerical simulations of 2D diffusion matched to the experimental data. This showed that the rims of the samples have a mechanically disrupted zone 0.04 to 0.22 cm wide, characterised by faster transport properties compared to the undisturbed centre (1.8 to 7.7 times higher pore diffusion coefficient). Chemical contamination was shown to affect an even wider zone in all samples, ranging from 0.15 to 0.60 cm, in which iodide enrichment was up to 180 mg/kg water, compared to 0.5 mg/kg water in the uncontaminated centre. For all samples in the present case study, it turned out that the magnitude of the artefacts caused by drilling and sample recovery is so small that no correction is required for their effects. Therefore, the standard laboratory measurements of porosity, transport properties and porewater composition can be taken as valid in-situ estimates. However, it is clear that the magnitudes strongly depend on site- and drilling-specific factors and therefore our results cannot be transferred simply to other locations. We recommend the approach presented in this study as a route to obtain reliable values in future drilling campaigns aimed at characterising in-situ bedrock properties. PMID- 26529303 TI - Nitrogen, carbon, and sulfur isotopic change during heterotrophic (Pseudomonas aureofaciens) and autotrophic (Thiobacillus denitrificans) denitrification reactions. AB - In batch culture experiments, we examined the isotopic change of nitrogen in nitrate (delta(15)NNO3), carbon in dissolved inorganic carbon (delta(13)CDIC), and sulfur in sulfate (delta(34)SSO4) during heterotrophic and autotrophic denitrification of two bacterial strains (Pseudomonas aureofaciens and Thiobacillus denitrificans). Heterotrophic denitrification (HD) experiments were conducted with trisodium citrate as electron donor, and autotrophic denitrification (AD) experiments were carried out with iron disulfide (FeS2) as electron donor. For heterotrophic denitrification experiments, a complete nitrate reduction was accomplished, however bacterial denitrification with T. denitrificans is a slow process in which, after seventy days nitrate was reduced to 40% of the initial concentration by denitrification. In the HD experiment, systematic change of delta(13)CDIC (from -7.70/00 to -12.20/00) with increase of DIC was observed during denitrification (enrichment factor epsilonN was 4.70/00), suggesting the contribution of C of trisodium citrate (delta(13)C= 12.40/00). No SO4(2-) and delta(34)SSO4 changes were observed. In the AD experiment, clear fractionation of delta(13)CDIC during DIC consumption (epsilonC=-7.80/00) and delta(34)SSO4 during sulfur use of FeS2-S (around 20/00), were confirmed through denitrification (epsilonN=-12.50/00). Different pattern in isotopic change between HD and AD obtained on laboratory-scale are useful to recognize the type of denitrification occurring in the field. PMID- 26529304 TI - Working Towards a Reproducible Method for Quantifying Placental Syncytial Knots. AB - Prominent syncytial knots (SK) in placentas signal advanced gestation or placental malperfusion, reflecting exposures that adversely affect placental development and pregnancy outcomes. Molecular-level interrogations of syncytiotrophoblast have altered perceptions of and raised questions about the function and disposition of SK. Quantifying SK and achieving acceptable levels of interrater reliability have been challenging. Our objective was to develop a simple, reproducible protocol for counting SK and demonstrate interrater reliability overall and within 3 parameters, ie, preterm vs term delivery, presence vs absence of diffuse prominent SK (DPSK), and SK relationship with a lesion, all of which could influence measurement reproducibility and interpretation. Criteria for defining SK and a grid system drawn on glass slides were developed for counting percentage of villi with SK. One disc section each from 151 placentas, sampled from 8 groups defined by the 3 parameters, was assessed by 2 pretrained pathologists. The resulting weighted kappa statistic for overall interrater agreement was 0.60 (very good) and Spearman correlation coefficient for ranking quartiles was >0.70. Agreement was best for preterm placentas, kappa = 0.61, and those only showing DPSK associated with a lesion, kappa = 0.67. Agreement was low in the absence of DPSK, kappa = 0.22, or when DPSK was present in a placenta not associated with a lesion, kappa = 0.32. The proposed method offers a potentially reliable approach for categorizing SK counts as normal vs abnormal or providing continuous measure counts. More extensive pretraining, focused on placentas with few SK and those without an associated lesion, is recommended to improve agreement. PMID- 26529305 TI - Effects of curcumin on methyl methanesulfonate damage to mouse kidney. AB - Methylmethane sulfonate (MMS) is an alkylating agent that may react with DNA and damage it. We investigated histological changes and apoptosis caused by MMS and the effects of curcumin on MMS treated mouse kidneys. Twenty-four mice were divided into four equal groups: controls injected with saline, a group injected with 40 mg/kg MMS, a group injected with 40 mg/kg MMS and given 100 mg/kg curcumin by gavage, and a group given 100 mg/kg curcumin by gavage. MMS caused congestion and vacuole formation, and elevated the apoptotic index significantly, but had no other effect on kidney tissue. Curcumin improved the congestion and vacuole formation caused by MMS and decreased the apoptotic index. Curcumin administered with MMS appears to decrease the deleterious effects of MMS on the kidney. PMID- 26529306 TI - Effects of Climate Change on Habitat Availability and Configuration for an Endemic Coastal Alpine Bird. AB - North America's coastal mountains are particularly vulnerable to climate change, yet harbour a number of endemic species. With little room "at the top" to track shifting climate envelopes, alpine species may be especially negatively affected by climate-induced habitat fragmentation. We ask how climate change will affect the total amount, mean patch size, and number of patches of suitable habitat for Vancouver Island White-tailed Ptarmigan (Lagopus leucura saxatilis; VIWTP), a threatened, endemic alpine bird. Using a Random Forest model and a unique dataset consisting of citizen science observations combined with field surveys, we predict the distribution and configuration of potential suitable summer habitat for VIWTP under baseline and future (2020s, 2050s, and 2080s) climates using three general circulation models and two greenhouse gas scenarios. VIWTP summer habitat is predicted to decline by an average of 25%, 44%, and 56% by the 2020s, 2050s, and 2080s, respectively, under the low greenhouse gas scenario and 27%, 59%, and 74% under the high scenario. Habitat patches are predicted to become fragmented, with a 52-79% reduction in mean patch size. The average elevation of suitable habitat patches is expected to increase, reflecting a loss of patches at lower elevations. Thus ptarmigan are in danger of being "squeezed off the mountain", as their remaining suitable habitat will be increasingly confined to mountaintops in the center of the island. The extent to which ptarmigan will be able to persist in increasingly fragmented habitat is unclear. Much will depend on their ability to move throughout a more heterogeneous landscape, utilize smaller breeding areas, and survive increasingly variable climate extremes. Our results emphasize the importance of continued monitoring and protection for high elevation specialist species, and suggest that White-tailed Ptarmigan should be considered an indicator species for alpine ecosystems in the face of climate change. PMID- 26529307 TI - Performance of the disease risk score in a cohort study with policy-induced selection bias. AB - AIM: To examine the performance of the disease risk score (DRS) in a cohort study with evidence of policy-induced selection bias. METHODS: We examined two cohorts of new users of bisphosphonates. Estimates for 1-year hip fracture rates between agents using DRS, exposure propensity scores and traditional multivariable analysis were compared. RESULTS: The results for the cohort with no evidence of policy-induced selection bias showed little variation across analyses (-4.1 2.0%). Analysis of the cohort with evidence of policy-induced selection bias showed greater variation (-13.5-8.1%), with the greatest difference seen with DRS analyses. CONCLUSION: Our findings suggest that caution may be warranted when using DRS methods in cohort studies with policy-induced selection bias, further research is needed. PMID- 26529308 TI - Conformational change in individual enzyme molecules. AB - Single beta-galactosidase molecule assays were performed using a capillary electrophoresis based protocol, employing post-column laser-induced fluorescence detection. In a first set of experiments, the distribution of single beta galactosidase molecule catalytic rates and electrophoretic mobilities were determined from lysates of Escherichia coli strains containing deletions for different heat shock proteins and grown under normal and heat shock conditions. There was no clear observed pattern of effect of heat shock protein expression on these distributions. In a second set of experiments, individual enzyme molecule catalytic rates were determined at 21 degrees C before and after 2 sequential brief periods of incubation at 50, 28, and 10 degrees C. The brief incubations at 50 degrees C caused a change in the enzyme molecules resulting in a different catalytic rate. Any given molecule was just as likely to show an increase in rate as a decrease, resulting in no significant difference in the average rate of the population. The average change in individual molecule rate was dependent upon the temperature of the brief incubation period, with a lesser average change occurring at 28 degrees C and negligible change at 10 degrees C. A third set of experiments was similar to that of the second with the exception that it was electrophoretic mobility that was considered. This provided a similar result. Incubation at higher temperature resulted in a change in electrophoretic mobility. The probability of an individual molecules switching to a higher mobility was approximately equal to that of switching to a lower mobility, resulting in no net average change in the population. The magnitude of the changes in electrophoretic mobilities suggest that the associated conformational changes are subtle. PMID- 26529309 TI - Protein misfolding in Dictyostelium: Using a freak of nature to gain insight into a universal problem. AB - Prion-like proteins can undergo conformational rearrangements from an intrinsically disordered to a highly ordered amyloid state. This ability to change conformation is encoded in distinctive domains, termed prion domains (PrDs). Previous work suggests that PrDs change conformation to affect protein function and create phenotypic diversity. More recent work shows that PrDs can also undergo many weak interactions when disordered, allowing them to organize the intracellular space into dynamic compartments. However, mutations within PrDs and altered aggregation properties have also been linked to age-related diseases in humans. Thus, the physiological role of prion-like proteins, the mechanisms regulating their conformational promiscuity and the links to disease are still unclear. Here, we summarize recent work with prion-like proteins in Dictyostelium discoideum. This work was motivated by the finding that D. discoideum has the highest content of prion-like proteins of all organisms investigated to date. Surprisingly, we find that endogenous and exogenous prion-like proteins remain soluble in D. discoideum and do not misfold and aggregate. We provide evidence that this is due to specific adaptations in the protein quality control machinery, which may allow D. discoideum to tolerate its highly aggregation-prone proteome. We predict that D. discoideum will be an important model to study the function of prion-like proteins and their mechanistic links to disease. PMID- 26529310 TI - Premarket Regulation of Tissue Engineered Medical Products in China. AB - Tissue engineered medical products (TEMPs) use state-of-the-art technologies and offer the patients with alternative clinical options for diseases that conventional treatments may fail or be incompetent. However promising, this technology is comparatively new with very limited hands-on experiences with both manufacturing and clinical therapy. Of great significance to products with such complexity and novelty is the establishment of a complete jurisdiction framework and a standardization database so that the safety of the technique in clinical treatment can be ensured. Although different regulatory routes are adopted in different countries, risks are generally considered to be derived from the cellular components within the product, the material scaffolds, and potentially from the final products. This article is to provide an insight of the regulatory considerations and the role of China Food and Drug Administration (CFDA) in the supervision of TEMPs. PMID- 26529311 TI - Quality Control Measures over 30 Years in a Multicenter Clinical Study: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study. AB - Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented. PMID- 26529312 TI - Long-Range Correlations and Memory in the Dynamics of Internet Interdomain Routing. AB - Data transfer is one of the main functions of the Internet. The Internet consists of a large number of interconnected subnetworks or domains, known as Autonomous Systems (ASes). Due to privacy and other reasons the information about what route to use to reach devices within other ASes is not readily available to any given AS. The Border Gateway Protocol (BGP) is responsible for discovering and distributing this reachability information to all ASes. Since the topology of the Internet is highly dynamic, all ASes constantly exchange and update this reachability information in small chunks, known as routing control packets or BGP updates. In the view of the quick growth of the Internet there are significant concerns with the scalability of the BGP updates and the efficiency of the BGP routing in general. Motivated by these issues we conduct a systematic time series analysis of BGP update rates. We find that BGP update time series are extremely volatile, exhibit long-term correlations and memory effects, similar to seismic time series, or temperature and stock market price fluctuations. The presented statistical characterization of BGP update dynamics could serve as a basis for validation of existing and developing better models of Internet interdomain routing. PMID- 26529313 TI - 18F-FDG PET-CT after Neoadjuvant Chemoradiotherapy in Esophageal Cancer Patients to Optimize Surgical Decision Making. AB - BACKGROUND: Prognosis of esophageal cancer patients can be significantly improved by neoadjuvant chemoradiotherapy (nCRT). Given the aggressive nature of esophageal tumors, it is conceivable that in a significant portion of patients treated with nCRT, dissemination already becomes manifest during the period of nCRT. The aim of this retrospective study was to determine the value and diagnostic accuracy of PET-CT after neoadjuvant chemoradiotherapy to identify patients with metastases preoperatively in order to prevent non-curative surgery. METHODS: From January 2011 until February 2013 esophageal cancer patients deemed eligible for a curative approach with nCRT and surgical resection underwent a PET CT after completion of nCRT. If abnormalities on PET-CT were suspected metastases, histological proof was acquired. A clinical decision model was designed to assess the cost-effectiveness of this diagnostic strategy. RESULTS: 156 patients underwent a PET-CT after nCRT. In 31 patients (19.9%) PET-CT showed abnormalities suspicious for dissemination, resulting in 17 cases of proven metastases (10.9%). Of the patients without proven metastases 133 patients were operated. In 6 of these 133 cases distant metastases were detected intraoperatively, corresponding to 4.5% false-negative results. The standard introduction of a post-neoadjuvant therapy PET-CT led to a reduction of overall health care costs per patient compared to a scenario without restaging with PET CT ($34,088 vs. $36,490). CONCLUSION: In 10.9% of esophageal cancer patients distant metastases were detected by standard PET-CT after neoadjuvant chemoradiotherapy. To avoid non-curative resections we advocate post-neoadjuvant therapy PET-CT as a cost-effective step in the standard work-up of candidates for surgery. PMID- 26529314 TI - fMRI Activity in Posterior Parietal Cortex Relates to the Perceptual Use of Binocular Disparity for Both Signal-In-Noise and Feature Difference Tasks. AB - Visually guided action and interaction depends on the brain's ability to (a) extract and (b) discriminate meaningful targets from complex retinal inputs. Binocular disparity is known to facilitate this process, and it is an open question how activity in different parts of the visual cortex relates to these fundamental visual abilities. Here we examined fMRI responses related to performance on two different tasks (signal-in-noise "coarse" and feature difference "fine" tasks) that have been widely used in previous work, and are believed to differentially target the visual processes of signal extraction and feature discrimination. We used multi-voxel pattern analysis to decode depth positions (near vs. far) from the fMRI activity evoked while participants were engaged in these tasks. To look for similarities between perceptual judgments and brain activity, we constructed 'fMR-metric' functions that described decoding performance as a function of signal magnitude. Thereafter we compared fMR-metric and psychometric functions, and report an association between judged depth and fMRI responses in the posterior parietal cortex during performance on both tasks. This highlights common stages of processing during perceptual performance on these tasks. PMID- 26529315 TI - The Influence of LepR Tyrosine Site Mutations on Mouse Ovary Development and Related Gene Expression Changes. AB - Leptin exerts many biological functions, such as in metabolism and reproduction, through binding to and activating the leptin receptor, LepRb, which is expressed in many regions of the brain. To better understand the roles of LepR downstream signaling pathways, Y123F mice, which expressed mutant leptin receptors with phenylalanine (F) substituted for three tyrosines (Y) (Tyr985, Tyr1077 and Tyr1138), were generated. The body weight and abdominal fat deposits of Y123F homozygous mice (HOM) were higher than those of wild-type mice (WT). HOM ovaries were atrophic and the follicles developed abnormally; however, the HOM ovaries did not exhibit polycystic phenotypes. Moreover, Y123F HOM adults had no estrous cycle and the blood estrogen concentration remained stable at a low level below detection limit of 5 pg/ml. LepR expression in HOM ovaries was higher than in WT ovaries. Using cDNA Microarrays, the mRNA expressions of 41 genes were increased, and 100 were decreased in HOM vs. WT ovaries, and many signaling pathways were evaluated to be involved significantly. The expressions of 19 genes were validated by real-time quantitative PCR, most of which were consistent with the microarray results. Thus, Y123F HOM mice were suggested as a new animal model of PCOS for research that mainly emphasizes metabolic disorders and anovulation, but not the polycystic phenotype. Meanwhile, using the model, we found that JAK-STAT and hormone biosynthesis pathways were involved in the follicular development and ovulation disorders caused by LepR deficiency in ovaries, although we could not exclude indirect actions from the brain. PMID- 26529316 TI - Anemia and Red Blood Cell Abnormalities in HIV-Infected and HIV-Exposed Breastfed Infants: A Secondary Analysis of the Kisumu Breastfeeding Study. AB - BACKGROUND: Anemia results in increased morbidity and mortality, underscoring the need to better understand its pathophysiology amongst HIV-exposed and infected children in sub-Saharan Africa, the region where most infant HIV exposure and infections occur. METHODS: This analysis used samples obtained from children in the Kisumu Breastfeeding Study (KiBS). KiBS was a longitudinal phase IIB, open label, one-arm clinical trial, designed to investigate the safety, tolerability and effectiveness of a maternal triple-antiretroviral (ARV) regimen for prevention of mother-to-child transmission (PMTCT) of HIV, during late pregnancy and early infancy while breastfeeding. Blood samples from 482 children were obtained at birth, 2, 6, 10 and 14 weeks and 6, 9, 12, 18 and 24 months. Severity of anemia was graded using the NIH Division of AIDS (DAIDS) toxicity tables. We describe the proportion of children with anemia and anomalies in red blood cell parameters at various time points over 24 months and compare rates of anemia between HIV-infected and HIV-uninfected children and by mothers' ARV regimen and infant malaria infection. RESULTS: The proportion of children with anemia significantly increased after the breastfeeding period in both HIV-infected and HIV-uninfected children with higher proportion among HIV-infected children compared to HIV-uninfected children (RR: 1.72; CI: 1.22-2.44, p = 0.002). Maternal triple-antiretroviral regimen was not associated with infant anemia (p = 0.11). There was no significant difference in mean hemoglobin between HIV uninfected children with and without malaria at each time point except at 24 months. CONCLUSION: A relatively lower proportion of children with severe anemia during the breastfeeding period suggest that exposure to mother's triple antiretroviral combinations through breast milk, posed minimal risk of hematologic toxicity. PMID- 26529317 TI - Integrating Protein Engineering and Bioorthogonal Click Conjugation for Extracellular Vesicle Modulation and Intracellular Delivery. AB - Exosomes are small, cell-secreted vesicles that transfer proteins and genetic information between cells. This intercellular transmission regulates many physiological and pathological processes. Therefore, exosomes have emerged as novel biomarkers for disease diagnosis and as nanocarriers for drug delivery. Here, we report an easy-to-adapt and highly versatile methodology to modulate exosome composition and conjugate exosomes for intracellular delivery. Our strategy combines the metabolic labeling of newly synthesized proteins or glycan/glycoproteins of exosome-secreting cells with active azides and bioorthogonal click conjugation to modify and functionalize the exosomes. The azide-integrated can be conjugated to a variety of small molecules and proteins and can efficiently deliver conjugates into cells. The metabolic engineering of exosomes diversifies the chemistry of exosomes and expands the functions that can be introduced into exosomes, providing novel, powerful tools to study the roles of exosomes in biology and expand the biomedical potential of exosomes. PMID- 26529318 TI - Identification and Characterization of the Interaction Site between cFLIPL and Calmodulin. AB - Overexpression of the cellular FLICE-like inhibitory protein (cFLIP) has been reported in a number of tumor types. As an inactive procaspase-8 homologue, cFLIP is recruited to the intracellular assembly known as the Death Inducing Signaling Complex (DISC) where it inhibits apoptosis, leading to cancer cell proliferation. Here we characterize the molecular details of the interaction between cFLIPL and calmodulin, a ubiquitous calcium sensing protein. By expressing the individual domains of cFLIPL, we demonstrate that the interaction with calmodulin is mediated by the N-terminal death effector domain (DED1) of cFLIPL. Additionally, we mapped the interaction to a specific region of the C-terminus of DED1, referred to as DED1 R4. By designing DED1/DED2 chimeric constructs in which the homologous R4 regions of the two domains were swapped, calmodulin binding properties were transferred to DED2 and removed from DED1. Furthermore, we show that the isolated DED1 R4 peptide binds to calmodulin and solve the structure of the peptide-protein complex using NMR and computational refinement. Finally, we demonstrate an interaction between cFLIPL and calmodulin in cancer cell lysates. In summary, our data implicate calmodulin as a potential player in DISC-mediated apoptosis and provide evidence for a specific interaction with the DED1 of cFLIPL. PMID- 26529319 TI - Production and Functional Characterization of Murine Osteoclasts Differentiated from ER-Hoxb8-Immortalized Myeloid Progenitor Cells. AB - In vitro differentiation into functional osteoclasts is routinely achieved by incubation of embryonic stem cells, induced pluripotent stem cells, or primary as well as cryopreserved spleen and bone marrow-derived cells with soluble receptor activator of nuclear factor kappa-B ligand and macrophage colony-stimulating factor. Additionally, osteoclasts can be derived from co-cultures with osteoblasts or by direct administration of soluble receptor activator of nuclear factor kappa-B ligand to RAW 264.7 macrophage lineage cells. However, despite their benefits for osteoclast-associated research, these different methods have several drawbacks with respect to differentiation yields, time and animal consumption, storage life of progenitor cells or the limited potential for genetic manipulation of osteoclast precursors. In the present study, we therefore established a novel protocol for the differentiation of osteoclasts from murine ER-Hoxb8-immortalized myeloid stem cells. We isolated and immortalized bone marrow cells from wild type and genetically manipulated mouse lines, optimized protocols for osteoclast differentiation and compared these cells to osteoclasts derived from conventional sources. In vitro generated ER-Hoxb8 osteoclasts displayed typical osteoclast characteristics such as multi-nucleation, tartrate resistant acid phosphatase staining of supernatants and cells, F-actin ring formation and bone resorption activity. Furthermore, the osteoclast differentiation time course was traced on a gene expression level. Increased expression of osteoclast-specific genes and decreased expression of stem cell marker genes during differentiation of osteoclasts from ER-Hoxb8-immortalized myeloid progenitor cells were detected by gene array and confirmed by semi quantitative and quantitative RT-PCR approaches. In summary, we established a novel method for the quantitative production of murine bona fide osteoclasts from ER-Hoxb8 stem cells generated from wild type or genetically manipulated mouse lines. These cells represent a standardized and theoretically unlimited source for osteoclast-associated research projects. PMID- 26529320 TI - Methylprednisolone for the Treatment of Patients with Acute Spinal Cord Injuries: A Systematic Review and Meta-Analysis. AB - Previous meta-analyses of methylprednisolone (MPS) for patients with acute traumatic spinal cord injuries (TSCIs) have not addressed confidence in the quality of evidence used for pooled effect estimates, and new primary studies have been recently published. We aimed to determine whether MPS improves motor recovery and is associated with increased risks for adverse events. We searched MEDLINE, EMBASE, and The Cochrane Library, and two reviewers independently screened articles, extracted data, and evaluated risk of bias. We pooled outcomes from randomized, controlled trials (RCTs) and controlled observational studies separately and used the Grades of Recommendation, Assessment, Development, and Evaluation approach to evaluate confidence. We included four RCTs and 17 observational studies. MPS was not associated with an increase in long-term motor score recovery (two RCTs: 335 participants; mean difference [MD], -1.11; 95% confidence interval [CI], -4.75 to 2.53; p = 0.55, low confidence; two observational studies: 528 participants; MD, 1.37; 95% CI, -3.08 to 5.83; p = 0.55, very low confidence) or improvement by at least one motor grade (three observational studies: 383 participants; risk ratio [RR], 0.84; 95% CI, 0.53 1.33; p = 0.46, very low confidence). Evidence from two RCTs demonstrated superior short-term motor score improvement if MPS was administered within 8 h of injury (two RCTs: 250 participants; MD, 4.46; 95% CI, 0.97-7.94; p = 0.01, low confidence), but risk of bias and imprecision limit confidence in these findings. Observational studies demonstrated a significantly increased risk for gastrointestinal bleeding (nine studies: 2857 participants; RR, 2.18; 95% CI, 1.13-4.19; p = 0.02, very low confidence), but RCTs did not. Pooled evidence does not demonstrate a significant long-term benefit for MPS in patients with acute TSCIs and suggests it may be associated with increased gastrointestinal bleeding. These findings support current guidelines against routine use, but strong recommendations are not warranted because confidence in the effect estimates is limited. PMID- 26529321 TI - De Novo Assembly and Characterization of the Invasive Northern Pacific Seastar Transcriptome. AB - Invasive species are a major threat to global biodiversity but can also serve as valuable model systems to examine important evolutionary processes. While the ecological aspects of invasions have been well documented, the genetic basis of adaptive change during the invasion process has been hampered by a lack of genomic resources for the majority of invasive species. Here we report the first larval transcriptomic resource for the Northern Pacific Seastar, Asterias amurensis, an invasive marine predator in Australia. Approximately 117.5 million 100 base-pair (bp) paired-end reads were sequenced from a single RNA-Seq library from a pooled set of full-sibling A. amurensis bipinnaria larvae. We evaluated the efficacy of a pre-assembly error correction pipeline on subsequent de novo assembly. Error correction resulted in small but important improvements to the final assembly in terms of mapping statistics and core eukaryotic genes representation. The error-corrected de novo assembly resulted in 115,654 contigs after redundancy clustering. 41,667 assembled contigs were homologous to sequences from NCBI's non-redundant protein and UniProt databases. We assigned Gene Ontology, KEGG Orthology, Pfam protein domain terms and predicted protein coding sequences to > 36,000 contigs. The final transcriptome dataset generated here provides functional information for 18,319 unique proteins, comprising at least 11,355 expressed genes. Furthermore, we identified 9,739 orthologs to P. miniata proteins, evaluated our annotation pipeline and generated a list of 150 candidate genes for responses to several environmental stressors that may be important for adaptation of A. amurensis in the invasive range. Our study has produced a large set of A. amurensis RNA contigs with functional annotations that can serve as a resource for future comparisons to other echinoderm transcriptomes and gene expression studies. Our data can be used to study the genetic basis of adaptive change and other important evolutionary processes during a successful invasion. PMID- 26529323 TI - Mesoporous carbon derived from vitamin B12: a high-performance bifunctional catalyst for imine formation. AB - Mesoporous carbon derived from natural vitamin B12 is applied for the first time in organic synthesis and exhibits exceptionally high dual activity for imine formation via the cross-coupling of alcohols with amines and the self-coupling of primary amines using molecular oxygen or air as the terminal oxidant. PMID- 26529322 TI - Transcription Factor SomA Is Required for Adhesion, Development and Virulence of the Human Pathogen Aspergillus fumigatus. AB - The transcription factor Flo8/Som1 controls filamentous growth in Saccharomyces cerevisiae and virulence in the plant pathogen Magnaporthe oryzae. Flo8/Som1 includes a characteristic N-terminal LUG/LUH-Flo8-single-stranded DNA binding (LUFS) domain and is activated by the cAMP dependent protein kinase A signaling pathway. Heterologous SomA from Aspergillus fumigatus rescued in yeast flo8 mutant strains several phenotypes including adhesion or flocculation in haploids and pseudohyphal growth in diploids, respectively. A. fumigatus SomA acts similarly to yeast Flo8 on the promoter of FLO11 fused with reporter gene (LacZ) in S. cerevisiae. FLO11 expression in yeast requires an activator complex including Flo8 and Mfg1. Furthermore, SomA physically interacts with PtaB, which is related to yeast Mfg1. Loss of the somA gene in A. fumigatus resulted in a slow growth phenotype and a block in asexual development. Only aerial hyphae without further differentiation could be formed. The deletion phenotype was verified by a conditional expression of somA using the inducible Tet-on system. A adherence assay with the conditional somA expression strain indicated that SomA is required for biofilm formation. A ptaB deletion strain showed a similar phenotype supporting that the SomA/PtaB complex controls A. fumigatus biofilm formation. Transcriptional analysis showed that SomA regulates expression of genes for several transcription factors which control conidiation or adhesion of A. fumigatus. Infection assays with fertilized chicken eggs as well as with mice revealed that SomA is required for pathogenicity. These data corroborate a complex control function of SomA acting as a central factor of the transcriptional network, which connects adhesion, spore formation and virulence in the opportunistic human pathogen A. fumigatus. PMID- 26529324 TI - Potential Response to Selection of HSP70 as a Component of Innate Immunity in the Abalone Haliotis rufescens. AB - Assessing components of the immune system may reflect disease resistance. In some invertebrates, heat shock proteins (HSPs) are immune effectors and have been described as potent activators of the innate immune response. Several diseases have become a threat to abalone farming worldwide; therefore, increasing disease resistance is considered to be a long-term goal for breeding programs. A trait will respond to selection only if it is determined partially by additive genetic variation. The aim of this study was to estimate the heritability (h2) and the additive genetic coefficient of variation (CVA) of HSP70 as a component of innate immunity of the abalone Haliotis rufescens, in order to assess its potential response to selection. These genetic components were estimated for the variations in the intracellular (in haemocytes) and extracellular (serum) protein levels of HSP70 in response to an immunostimulant agent in 60 full-sib families of H. rufescens. Levels of HSP70 were measured twice in the same individuals, first when they were young and again when they were pre-harvest adults, to estimate the repeatability (R), the h2 and the potential response to selection of these traits at these life stages. High HSP70 levels were observed in abalones subjected to immunostimulation in both the intracellular and extracellular haemolymph fractions. This is the first time that changes in serum levels of HSP70 have been reported in response to an immune challenge in molluscs. HSP70 levels in both fractions and at both ages showed low h2 and R, with values that were not significantly different from zero. However, HSP70 induced levels had a CVA of 13.3-16.2% in young adults and of 2.7-8.1% in pre-harvest adults. Thus, despite its low h2, HSP70 synthesis in response to an immune challenge in red abalone has the potential to evolve through selection because of its large phenotypic variation and the presence of additive genetic variance, especially in young animals. PMID- 26529325 TI - Characteristics of Patients Who Report Confusion After Reading Their Primary Care Clinic Notes Online. AB - Patient access to online electronic medical records (EMRs) is increasing and may offer benefits to patients. However, the inherent complexity of medicine may cause confusion. We elucidate characteristics and health behaviors of patients who report confusion after reading their doctors' notes online. We analyzed data from 4,528 patients in Boston, MA, central Pennsylvania, and Seattle, WA, who were granted online access to their primary care doctors' clinic notes and who viewed at least one note during the 1-year intervention. Three percent of patients reported confusion after reading their visit notes. These patients were more likely to be at least 70 years of age (p < .0001), have fewer years of education (p < .0017), be unemployed (p < .0001), have lower levels of self reported health (p < .0043), and worry more after reading visit notes (relative risk [RR] 4.83; confidence interval [CI] 3.17, 7.36) compared to patients who were not confused. In adjusted analyses, they were less likely to report feeling more in control of their health (RR 0.42; CI 0.25, 0.71), remembering their care plan (RR 0.26; CI 0.17, 0.42), and understanding their medical conditions (RR 0.32; CI 0.19, 0.54) as a result of reading their doctors' notes compared to patients who were not confused. Patients who were confused by reading their doctors' notes were less likely to report benefits in health behaviors. Understanding this small subset of patients is a critical step in reducing gaps in provider-patient communication and in efforts to tailor educational approaches for patients. PMID- 26529326 TI - Catalytic addition of amines to carbodiimides by bis(beta diketiminate)lanthanide(II) complexes and mechanistic studies. AB - Reduction reactions of bis(beta-diketiminate)lanthanide(III) chlorides formed in situ by reactions of anhydrous LnCl3 with 2 equiv. of sodium salt of the beta diketiminate ligand in THF with a Na/K alloy afforded a series of bis(beta diketiminate)lanthanide(II) complexes LnL2(THF)n (L = L(2,6-Me2) = [N(2,6 Me2C6H3)C(Me)]2CH(-), n = 1, Ln = Eu (1); L = L(2,4,6-Me3) = [N(2,4,6 Me3C6H2)C(Me)]2CH(-), n = 1, Ln = Eu (2); L = L(2,6-iPr2) = [N(2,6 (i)Pr2C6H3)C(Me)]2CH(-), n = 0, Ln = Eu (3), Sm (4); L = L(2,6-ipr2)(Ph) = [(2,6 (i)Pr2C6H3)NC(Me)CHC(Me)N(C6H5)](-), n = 0, Ln = Eu (5), Yb (6); L = L(2-Me) = [N(2-MeC6H4)C(Me)]2CH(-), n = 1, Ln = Yb (7)) in high yields. All the complexes, especially the complexes of Sm(II) (4) and Eu(II) (5), were found to be excellent pre-catalysts for catalytic addition of amines to carbodiimides to multi substituted guanidines with a wide scope of substrates. The activity depends both on the central metals and the ligands with the active sequence of Yb(II) < Eu(II) and Eu(II) < Sm(II) and L(2,6-Me2) < L(2,4,6-Me3) ~ L(2,6-iPr2) < L(2,6-ipr2)(Ph) for the ligands. The mechanistic study by the isolation of guanidinate species and their reactivity revealed that Eu(II) monoguanidinate complexes Eu(L(2,6 Me2))[(C6H5N)C(NHCy)(NCy)](DME) (8) and Eu(L(2,6 ipr2)Ph)[(C6H5N)C(NHCy)(NCy)](THF)2 (9) should be the key active intermediates for the systems with Eu(II) complexes and a Yb(III) bis(guanidinate) complex Yb(L(2-Me))[(C6H5N)C(NHCy)(NCy)]2 (11) for the system using a Yb(II) complex. PMID- 26529327 TI - Accelerated nanoparticles synthesis in alcohol-water-mixture-based solution plasma. AB - An extraordinary high-speed synthesis of gold nanoparticles (AuNPs) was discovered by synthesizing the AuNPs in ethanol-water mixtures using a solution plasma process (SPP). The influence of the ethanol mole fraction (chiethanol) in the ethanol-water mixtures on the reduction rate of gold chloride ions to AuNPs under the SPP system was studied. The results indicated that the reaction rate of the AuNPs synthesis exhibited a maximum value (i.e. 35.2 times faster than in a pure water system) at the significant point where the partial molar volumes of ethanol and water changed drastically. PMID- 26529329 TI - Significance of Subcategory Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance Showing Both Cytologic and Architectural Atypia in Thyroid Aspiration Cytology. AB - OBJECTIVE: The Bethesda System for Reporting Thyroid Cytopathology is now widely used as the standard reporting system for fine-needle aspiration cytology (FNAC). Recently, several studies have attempted to subcategorize the atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) category. We aimed to analyze the significance of a subcategory of AUS/FLUS showing both cytologic and architectural atypia (AUS/FLUS-C&A). STUDY DESIGN: From April 2011 to May 2014, 18,091 patients underwent FNAC at Samsung Medical Center. For those patients we analyzed the clinical significance of the subcategory AUS/FLUS-C&A. RESULTS: One hundred and sixty-three patients were diagnosed as AUS/FLUS-C&A. Of 71 cases with subsequent histologic confirmation, 47 (66.2%) were diagnosed with papillary thyroid carcinoma (PTC). Of the 47 PTC cases, 32 (68.1%) were follicular variant-PTC. A significant difference in the PTC rate (58.3 vs. 82.6%) and PTC size (average: 1.8 and 0.9 cm) was noted between circumscribed lesions and infiltrative lesions on ultrasonography. CONCLUSION: We demonstrated that the subcategory of AUS/FLUS-C&A has considerable clinical implications and one should be aware of the cytological and ultrasonographic features. PMID- 26529331 TI - Hydrogen Sulfide Alleviates Peritoneal Fibrosis via Attenuating Inflammation and TGF-beta1 Synthesis. AB - BACKGROUND/AIMS: Peritoneal fibrosis is one of the long-term complications in peritoneal dialysis (PD) patients. Recent evidences have suggested that hydrogen sulfide (H2S) is beneficial in treating various fibrotic diseases, including pulmonary fibrosis, cirrhosis, kidney fibrosis and cardiac hypertrophy. However, no information is known about the effect of H2S on peritoneal fibrosis. In the present study, we investigated the effect of H2S on peritoneal fibrosis and explored its potential mechanisms. METHODS: We developed a model of peritoneal fibrosis by intraperitoneally injecting 4.25%-glucose PD fluids and lipopolysaccharide to Sprague-Dawley rats. The rats received daily intraperitoneal injections of NaHS (56 MUg/kg), an H2S donor. After 28 days, the peritoneal equilibration test (PET) was used to assess peritoneal function. At the end of dialysis, the rats were killed and parietal peritoneum was harvested for microscopic examination and immunohistochemistry. RESULTS: On the 28th day, the parietal peritoneum of the PD rats markedly thickened as a result of increased depositions of type III collagen and fibronectin. Moreover, the number of ED-1-positive cells and the expressions of monocyte chemoattractant protein-1, transforming growth factor-beta1 (TGF-beta1), alpha-smooth muscle actin and CD31 were significantly increased in the fibrotic peritoneum. Administration of NaHS markedly decreased the biomarkers of inflammation, fibrosis and angiogenesis in the peritoneum. NaHS also improved peritoneal function assessed by PET. CONCLUSION: Exogenous H2S ameliorates the pathologic process of peritonitis via attenuating inflammatory events and TGF-beta1 synthesis. These results suggest that H2S may be a potential therapy against peritoneal fibrosis during chronic PD. In the future, compounds releasing H2S at controlled rate will be assessed as potential candidates to treat peritoneal fibrosis. PMID- 26529333 TI - Disturbances in insulin secretion and subclinical inflammation in normoglycemic women with a history of pregnancy complicated by gestational diabetes mellitus. PMID- 26529334 TI - Asthma control uncontrolled. PMID- 26529335 TI - Diffuse large B-cell lymphoma: R-CHOP forever? PMID- 26529336 TI - Infection and autoimmunity: antibodies against Legionella pneumophila in the serum of patients with autoimmune rheumatic disorders. PMID- 26529337 TI - Asthma and obesity: are they interrelated? PMID- 26529338 TI - Clinical outcomes in patients after surgical and transcatheter aortic valve replacement. PMID- 26529339 TI - Hijacked journals are emerging as a challenge for scholarly publishing. PMID- 26529340 TI - Diagnosis and therapy of antiphospholipid syndrome. PMID- 26529341 TI - Diagnosis and therapy of antiphospholipid syndrome. Author's reply. PMID- 26529342 TI - Suction-based propulsion as a basis for efficient animal swimming. AB - A central and long-standing tenet in the conceptualization of animal swimming is the idea that propulsive thrust is generated by pushing the surrounding water rearward. Inherent in this perspective is the assumption that locomotion involves the generation of locally elevated pressures in the fluid to achieve the expected downstream push of the surrounding water mass. Here we show that rather than pushing against the surrounding fluid, efficient swimming animals primarily pull themselves through the water via suction. This distinction is manifested in dominant low-pressure regions generated in the fluid surrounding the animal body, which are observed by using particle image velocimetry and a pressure calculation algorithm applied to freely swimming lampreys and jellyfish. These results suggest a rethinking of the evolutionary adaptations observed in swimming animals as well as the mechanistic basis for bio-inspired and biomimetic engineered vehicles. PMID- 26529343 TI - Emergency Incident Rehabilitation. PMID- 26529345 TI - Revisiting Pathological Criteria for Earlier Diagnosis of Coeliac Disease. AB - OBJECTIVES: The diagnosis of coeliac disease (CD) remains sometimes difficult because the histological criteria are not fully met. The aim of this study was to refine histological diagnostic criteria of CD. METHODS: One hundred seventy-five duodenal bulb D1 (n = 79) and duodenal D2 (n = 96) biopsies of 96 patients with CD (58 girls, mean age 7 years), 135 normal D2 biopsies (69 girls, mean age 12 years), and 64 D2 biopsies of other digestive disorders (DDs) (39 girls, mean age 13 years) obtained from children during a period of 4 years were reviewed. RESULTS: Interobserver agreement was greater for the classification of Corazza Villanacci than for Marsh-Oberhuber (kappa = 0.812 vs kappa = 0.409, respectively). Between 40 and 70 intraepithelial lymphocytes (IELs) per 100 epithelial cells (ECs), 32% of patients were CD, whereas 50% had other DD. Above 70 IELs per 100 EC, 53% were CD, and only 6% had other DD. In CD, IELs were significantly located above EC nuclei compared with other DD, (12 IELs/100 EC vs 2 IELs/100 EC, respectively). In 21% of CD cases, D2 were normal and the diagnosis could only be made on D1. Finally, 6% of CD cases showed isolated increase of IELs in D1 without architectural modification. CONCLUSIONS: D1 allowed diagnosis of CD in 21% of cases and IEL >70 per 100 EC correlated strongly with CD. Between 40 and 70 IELs per 100 EC, CD is very likely but other DD must be considered. Finally, the preferential localisation of IELs above EC nuclei favours CD, and increased IEL in D1 may be the sole abnormality. PMID- 26529344 TI - Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s). AB - Undesirable side effects associated with orthosteric agonists/antagonists of cannabinoid 1 receptor (CB1R), a tractable target for treating several pathologies affecting humans, have greatly limited their translational potential. Recent discovery of CB1R negative allosteric modulators (NAMs) has renewed interest in CB1R by offering a potentially safer therapeutic avenue. To elucidate the CB1R allosteric binding motif and thereby facilitate rational drug discovery, we report the synthesis and biochemical characterization of first covalent ligands designed to bind irreversibly to the CB1R allosteric site. Either an electrophilic or a photoactivatable group was introduced at key positions of two classical CB1R NAMs: Org27569 (1) and PSNCBAM-1 (2). Among these, 20 (GAT100) emerged as the most potent NAM in functional assays, did not exhibit inverse agonism, and behaved as a robust positive allosteric modulator of binding of orthosteric agonist CP55,940. This novel covalent probe can serve as a useful tool for characterizing CB1R allosteric ligand-binding motifs. PMID- 26529346 TI - Intraperitoneal Fetus in Fetu: A Rare Cause of Abdominal Mass. PMID- 26529348 TI - Pruning the Hamiltonian Matrix in MULTIMODE: Test for C2H4 and Application to CH3NO2 Using a New Ab Initio Potential Energy Surface. AB - We report vibrational self-consistent field/virtual state configuration interaction energies of nitromethane using the code MULTIMODE and a new full dimensional potential energy surface (PES). The PES is a precise, permutationally invariant linear least-squares fit to 17,049 electronic energies, using the CCSD(T)-F12b method with HaDZ basis (cc-pVDZ basis for H atoms, and aug-cc-pVDZ basis for C, O, N atoms). Nitromethane has 15 vibrational degrees of freedom, including one that is a nearly free internal methyl torsion, which is accurately described by the PES. This torsional mode makes vibrational calculations very challenging and here we present the results of calculations without it. Nevertheless, 14-mode calculations are still challenging and can lead to very large Hamiltonian matrices. To address this issue, we apply a pruning scheme, suggested previously by Handy and Carter, that reduces the size of matrix without sacrificing accuracy in the eigenvalues. The method is briefly described here in the context of partitioning theory. A new and more efficient implementation of it, coded in the latest version of MULTIMODE program, is described. The accuracy and efficiency are demonstrated for 12-mode C2H4 and then applied to CH3NO2. Agreement with available experimental values of the CH3NO2 14 fundamentals is very good. Diffusion Monte Carlo calculations in full dimensionality are done for the zero-point energy and wavefuction. These indicate that the torisonal motion is nearly a free-rotor in this state. PMID- 26529347 TI - Morbidity and Risk Factors of Laparoscopic-Assisted Ileostomies in Children With Ulcerative Colitis. AB - INTRODUCTION: Laparoscopic-assisted ileostomy (LAI) represents a cornerstone for the staged approach to ulcerative colitis (UC). The aim is to determine stoma morbidity in a series of pediatric patients and possibly identify specific risk factors. METHODS: All of the patients who underwent LAI for UC between January 2008 and December 2014 were included. The following data were collected: patient demographics, preoperative medical treatment, body mass index (BMI) at surgery, Pediatric UC Index (PUCAI), and stoma-related complications. In this series of patients, a staged approach has been adopted (subtotal colectomy + ileostomy; restorative proctocolectomy with J-pouch ileo-rectal anastomosis + ileostomy; ileostomy closure). RESULTS: Seventy-two LAIs were fashioned in 37 pediatric patients with UC. Median age at surgery was 12 years (range 5-14.8 years). Boy to girl ratio was 0.85:1. Mortality was zero. Complications occurred after 8 procedures after a median of 31 days postoperatively (range 8-60 days). Those were significantly more frequent in the case of BMI-z score >-0.51 (deleted in revised manuscript, ie, relatively overweight patients) and in the case of preoperative azathioprine administration. Pediatric UC Index score, sex, number of preoperative medications, and other preoperative parameters did not correlate with the incidence of complications. CONCLUSIONS: Our study suggests to keep a prudent behavior in the case of patients with a BMI-z score >-0.51 and received preoperative azathioprine administration. Parents should be adequately acknowledged on this regard. PMID- 26529350 TI - 3D Ultrasound Evaluation of the Fetal Ear - Comparison of an xMatrix Probe with a Conventional Mechanical Probe. AB - Purpose New 3 D technologies like xMatrix probes promise superiority over conventional mechanical probes and may allow a more detailed and time-saving prenatal diagnosis. In a comparison study we evaluate fetal ears. The aim of our study was to compare the following aspects of both techniques: (1) ultrasound detail resolution, (2) raw data acquisition time (AT) and (3) influence of covariates. Materials and Methods 3 D raw data volumes of the fetal ear were collected with the V6 - 2 (V6) and with the xMatrix (X6) probe and were stored after offline customization to a single picture. Two observers scored these images independently. Furthermore, the 3 D raw data acquisition time (AT) was recorded. Concordance between observers, maternal age, body mass index (BMI), weeks of gestation and location of the placenta were evaluated. Results Data volumes of 103 patients were analyzed. The X6 detected anatomic structures like the scapha (p = 0.0146), fossa triangularis (p = 0.0075) and cymba conchae (p = 0.0025) more often. The mean AT of the X6 was shorter compared to the V6 (p < 0.0001). A placenta location in the scanning field increased the AT only for the V6 (p < 0.01). Concordance between observers was higher for the X6 in most cases. Detailed structures were less visible at the end of pregnancy for both devices. Conclusion The comparison study demonstrated clear advantages of the new xMatrix technology concerning an advanced and fast examination of detailed structures like the fetal ear. The importance of 3 D assessment in cases of fetal ear anomaly should be proven in further studies. PMID- 26529351 TI - Adrenal Incidentaloma and Subclinical Cushing's Syndrome: A Longitudinal Follow Up Study by Endoscopic Ultrasound. AB - Purpose Adrenal incidentaloma (AI) and adrenal masses in cases of subclinical Cushing's syndrome (SCS) initially require follow-up imaging. In this study we used endoscopic ultrasound (EUS) as a method for high-resolution imaging. The aim was to evaluate the growth rate of AI and SCS by EUS. Materials and Methods This retrospective analysis included 93 out of 229 patients with AI or SCS who were investigated longitudinally by EUS in our university hospital between 1997 and 2013. The longitudinal follow-up required at least two investigations by EUS and evaluation of endocrine function. Plasma renin, serum aldosterone, 24 h urinary catecholamines and 2 mg dexamethasone suppression test were performed. EUS was performed at baseline and during follow-up. Each time, the maximum diameter was measured. Three groups were defined: non-functioning adenomas (NFA), non functioning nodular hyperplasias (NFH) and SCS. Results 86 patients had non functioning masses [NFM] (59 NFA, 48 NFH) and 7 patients had SCS (10 masses). At baseline the mean diameter was 19.4 (+/- 9.3) mm (NFM) and 19.6 (+/- 9.2) mm (SCS). The mean follow-up period was 31.6 +/- 28.7 months. The estimated mean growth rates per year were low: They were 0.35 mm/yr [NFA], 0.02 mm/yr [NFH] and 0.53 mm/yr [SCS]. Furthermore, there was no malignant progression of any mass. Conclusion The growth rate as determined by EUS was low for all tumor entities observed in this study. There was no difference in tumor growth between the groups. PMID- 26529352 TI - Chorionic Villus Sampling in Assisted Versus Spontaneous Conception Twins. AB - Purpose To compare the outcome of chorionic villus sampling (CVS) in twin pregnancies following assisted reproduction technology (ART) versus twins that have been conceived spontaneously. Materials and Methods Retrospective analysis of dichorionic twin pregnancies that underwent CVS between 1986 and 2013 at our department which is a tertiary center for fetal medicine. 32 twin pregnancies after ART and 130 spontaneously conceived twin pregnancies, which underwent CVS, were analyzed. Results No difference was observed in the pregnancy loss rate between the two groups (0 % in the ART group vs. 3 % in the spontaneous twins group). The rate of preterm delivery before 28 weeks was higher in the ART group (18.8 %) compared to the control group (1.6 %). The perinatal mortality rate was similar in the two groups. Conclusion The pregnancy loss rate following CVS is similar in ART twins and in spontaneous twins. However, the risk of prematurity before 28 weeks is significantly higher in the ART group. PMID- 26529353 TI - Detection of Fetal Corpus Callosum Abnormalities by Means of 3D Ultrasound. AB - PURPOSE: The objective of this study was to prenatally detect corpus callosum pathologies such as agenesis, partial agenesis, hypo- and hyperplasia and enhanced echogenicity. MATERIALS AND METHODS: Between 2009 and 2013 detailed 3D ultrasound examinations of the fetal corpus callosum were carried out as part of a level III examination for fetal anomalies. All scans were performed using Voluson E8 equipment (GE, Zipf, Austria) with a 5 - 8 MHz 3D transabdominal and 5 - 9 MHz 3D transvaginal transducer. All cases were evaluated for the following variables: inner, outer and curved length of the corpus callosum, height of the different segments of the corpus callosum and the corpus callosum area. All parameters were compared with normal growth charts. In all cases of suspected corpus callosum anomaly direct and indirect signs for corpus callosum agenesis and associated malformations were observed. RESULTS: 31 fetuses with pathological corpus callosum were diagnosed with 3D ultrasound. Gestational age at the time of diagnosis ranged from 20 to 38 weeks. 12 cases showed agenesis, 11 cases partial agenesis, 5 cases hypoplasia, 2 cases a combination of partial hyper- and hypoplasia and one case a lipoma of the corpus callosum. In corpus callosum underdevelopment, the more affected parts were the body and splenium. Associated anomalies were present in 25 of the 31 cases (80.6%) of corpus callosum pathologies. CONCLUSION: 3D neurosonography serves as an excellent tool to precisely demonstrate the pathological development of the fetal corpus callosum. By correlating the measures with the function of each affected corpus callosum segment, we can try to get a vague prediction of the neurological prognosis. PMID- 26529354 TI - Prospective Evaluation of Acoustic Radiation Force Impulse (ARFI) Elastography and High-Frequency B-Mode Ultrasound in Compensated Patients for the Diagnosis of Liver Fibrosis/Cirrhosis in Comparison to Mini-Laparoscopic Biopsy. AB - PURPOSE: Ultrasound is a well-established noninvasive test for assessing patients with liver disease. This study aims to prospectively compare ultrasound to the new technique elastography (ARFI) for the assessment of liver fibrosis/cirrhosis. MATERIALS AND METHODS: High-frequency B-mode ultrasound (liver surface/vein irregularity, liver homogeneity, spleen size), ARFI quantification, mini laparoscopic liver evaluation including biopsy were prospectively obtained in compensated patients scheduled for liver biopsy. For the diagnosis of cirrhosis, a combined gold standard (cirrhosis at histology and/or at macroscopic liver evaluation) was used. RESULTS: Out of 157 patients, 35 patients were diagnosed cirrhotic. Ultrasound (combination of liver vein and/or surface irregularity) showed no significant difference compared to ARFI quantification for the diagnosis of significant liver fibrosis (Ishak> = 3) and cirrhosis. Diagnosis of cirrhosis had a sensitivity/specificity/PPV/NPV of 83 %(+/- 12) / 82 %(+/- 7) / 57 %(+/- 14) / 94 %(+/- 4), respectively, with ultrasound and 86 %(+/- 12) / 81 %(+/- 7) / 57 %(+/- 13) / 95 %(+/- 4), respectively, with ARFI quantification. The sensitivity/specificity/PPV/NPV for the detection of significant fibrosis were 68 %(+/- 13) / 86 %(+/- 7) / 71 %(+/- 13) / 84 %(+/- 7), respectively, for ultrasound and 70 %(+/- 12) / 84 %(+/- 7) / 69 %(+/- 12) / 84 %(+/- 7), respectively, for ARFI quantification. CONCLUSION: ARFI elastography and high frequency B-mode ultrasound show similar and good results for the diagnosis of compensated liver cirrhosis and high-grade fibrosis. A key benefit of both methods is the high NPV suggesting them as noninvasive exclusion tests. PMID- 26529355 TI - Registration of Supine MR Mammography with Breast Ultrasound for Surgical Planning of Breast Conserving Surgery: A Feasibility Study. AB - Purpose To report the feasibility, accuracy and initial clinical experience of the use of real-time magnetic resonance navigated ultrasound (rtMRnUS) in the surgical planning of breast-conserving surgery (BCS) via guide wire insertion. Materials and Methods 29 participants were recruited into this prospective ethics committee approved study. The first 4 cases were utilized as a training set. Participants underwent a supine contrast-enhanced breast MR examination with external fiducials and corresponding ink marks placed on the skin of the affected breast to act as co-registration pairs. MR examinations included both functional and morphological images. A LOGIQ E9 ultrasound system (GE Healthcare, Milwaukee, WI, USA) equipped with a 6 - 15 MHz transducer was utilized for rtMRnUS. To facilitate point co-registration of the previously acquired MR dataset with the real-time ultrasound, co-registration pairs were identified on both imaging modalities. The following co-registration quality metrics were recorded: root mean square deviation (RMSD), lesion and global accuracies. Post co-registration guide wire insertion was performed. Results Co-registration was successfully undertaken in all participants. Results from 25 participants are presented. The median (min, max) RMSD was 3.3 mm (0.6 mm, 8.8 mm). The global accuracy was assessed as very good (8), good (12), moderate (3) and poor (2) while the median (min, max) lesion accuracy was recorded at 8.9 mm (2.1 mm, 33.2 mm). Conclusion The use of rtMRnUS to facilitate guide wire insertion is a feasible technique. Generally, very good or good global registration can be expected. Lesion accuracy results indicate that a median difference, in 3 D space, of 9 mm can be expected between imaging modalities. PMID- 26529356 TI - Ventricular Diastolic Function in Normal Fetuses and Fetuses with Hb Bart's Disease Assessed by Color M-Mode Propagation Velocity using Cardio-STIC-M (Spatio Temporal Image Correlation M-Mode). AB - Purpose: To determine whether ventricular diastolic dysfunction contributes to the pathogenesis of fetal cardiac failure due to fetal anemia using fetal Hb Bart's disease as a live model and cardio-STIC-M as a diagnostic tool. Materials and Methods: Color cardio-STIC volume datasets were acquired from fetuses at risk for Hb Bart's disease during 18 - 22 weeks of gestation and normal pregnancies and pregnancies with hydrops fetalis caused by Hb Bart's disease at 28 - 32 weeks. The volumes were analyzed off-line for velocity propagation (Vp) of the right and left ventricles to assess ventricular diastolic function using color cardio-STIC-M. Results: The Vp for the right and left ventricles was studied in fetuses at 18 - 22 weeks, including 64 normal fetuses (group 1) and 22 fetuses with Hb Bart's disease (group 2), and in fetuses at 28 - 32 weeks, including 22 normal fetuses (group 3) and 16 fetuses with Hb Bart's hydrops fetalis (group 4). The Vp of the fetuses in group 1 and group 2 was not significantly different. However, the Vp for the right and left ventricles in group 4 was significantly lower than in group 3 (19.02 vs. 9.78, p < 0.001; and 20.24 vs. 13.40, p < 0.001, respectively). The inter-observer variability had fair agreement with the intra class correlation coefficient of 0.531 (95 % CI 0.393 - 0.646, p < 0.001). Conclusion: Hydrops fetalis secondary to fetal anemia is initially caused by hypervolemia rather than ventricular diastolic dysfunction while ventricular diastolic compromise is a late occurring consequence of persistent hypervolemia, different from the mechanism of hydropic changes caused by cardiac causes. PMID- 26529357 TI - Saving in medical costs by achieving guideline-based asthma symptom control: a population-based study. AB - BACKGROUND: Asthma control is increasingly used as an outcome measure in asthma trials. Economic evaluations of asthma interventions require converting the impact of interventions on control to impact on resource use. The purpose of this study was to estimate the savings in direct costs by achieving asthma symptom control as defined in the Global Initiative for Asthma (GINA) 2014 management strategy. METHODS: Adolescents and adults with asthma were recruited through random digit dialing. Asthma control per GINA and the use of healthcare resources were assessed at baseline and three-monthly visits up to 1 year. We used regression models to associate costs, measured in 2012 Canadian dollars ($), with symptom control, adjusting for potential confounding variables. RESULTS: The final sample included 517 individuals (average age 48.9, 65.8% female) with mostly mild-moderate asthma contributing 2033 follow-up visits. In 598 (29.4%), 809 (39.8%), and 626 (30.8%) of visits, asthma was symptomatically controlled, partially controlled, or uncontrolled, respectively. The average 3-month costs of asthma were $134.5. Of these, 20.5% were attributable to inpatient care, 47.8% to outpatient care, and 31.5% to medication. Compared to controlled asthma, partially controlled asthma was associated with a nonsignificant increase of $9.5 (95% CI -$13.6 - $32.6) in adjusted 3-month costs and uncontrolled asthma with a statistically significant increase of $81.7 (95% CI $48.5 - $114.9). CONCLUSION: A substantial fraction of this population-based sample of largely mild-moderate asthmatics was symptomatically uncontrolled. Achieving symptom control was associated with a reduction in direct costs. The adjusted values from this study can be used to inform cost-effectiveness analyses of asthma treatments. PMID- 26529358 TI - Identification of a homozygous missense mutation in LRP2 and a hemizygous missense mutation in TSPYL2 in a family with mild intellectual disability. AB - Non-syndromic autosomal recessive intellectual disability (ID) is a genetically heterogeneous disorder with more than 50 mutated genes to date. ID is characterized by deficits in memory skills and language development with difficulty in learning, problem solving, and adaptive behaviors, and affects ~ 1% of the population. For detection of disease-causing mutations in such a heterogeneous disorder, homozygosity mapping together with exome sequencing is a powerful approach, as almost all known genes can be assessed simultaneously in a high-throughput manner. In this study, a hemizygous c.786C>G:p.Ile262Met in the testis specific protein Y-encoded-like 2 (TSPYL2) gene and a homozygous c.11335G>A:p.Asp3779Asn in the low-density lipoprotein receptor-related protein 2 (LRP2) gene were detected after genome-wide genotyping and exome sequencing in a consanguineous Pakistani family with two boys with mild ID. Mutations in the LRP2 gene have previously been reported in patients with Donnai-Barrow and Stickler syndromes. LRP2 has also been associated with a 2q locus for autism (AUTS5). The TSPYL2 variant is not listed in any single-nucleotide polymorphism databases, and the LRP2 variant was absent in 400 ethnically matched healthy control chromosomes, and is not listed in single-nucleotide polymorphism databases as a common polymorphism. The LRP2 mutation identified here is located in one of the low-density lipoprotein-receptor class A domains, which is a cysteine-rich repeat that plays a central role in mammalian cholesterol metabolism, suggesting that alteration of cholesterol processing pathway can contribute to ID. PMID- 26529359 TI - Signal transfer within a cultured asymmetric cortical neuron circuit. AB - OBJECTIVE: Simplified neuronal circuits are required for investigating information representation in nervous systems and for validating theoretical neural network models. Here, we developed patterned neuronal circuits using micro fabricated devices, comprising a micro-well array bonded to a microelectrode array substrate. APPROACH: The micro-well array consisted of micrometre-scale wells connected by tunnels, all contained within a silicone slab called a micro chamber. The design of the micro-chamber confined somata to the wells and allowed axons to grow through the tunnels bidirectionally but with a designed, unidirectional bias. We guided axons into the point of the arrow structure where one of the two tunnel entrances is located, making that the preferred direction. MAIN RESULTS: When rat cortical neurons were cultured in the wells, their axons grew through the tunnels and connected to neurons in adjoining wells. Unidirectional burst transfers and other asymmetric signal-propagation phenomena were observed via the substrate-embedded electrodes. Seventy-nine percent of burst transfers were in the forward direction. We also observed rapid propagation of activity from sites of local electrical stimulation, and significant effects of inhibitory synapse blockade on bursting activity. SIGNIFICANCE: These results suggest that this simple, substrate-controlled neuronal circuit can be applied to develop in vitro models of the function of cortical microcircuits or deep neural networks, better to elucidate the laws governing the dynamics of neuronal networks. PMID- 26529360 TI - Noninvasive assessment of liver stiffness by transient elastography (FibroScan) in liver fluke disease. AB - AIM: Transient elastography is a noninvasive and reliable method for the assessment of liver stiffness. This study aimed to assess liver stiffness of asymptomatic liver fluke disease patients by FibroScan and evaluate the factors influencing liver stiffness. METHODS: Overall, 65 patients were prospectively recruited from The First People's Hospital of Foshan, Guangdong, China. All patients were diagnosed with liver fluke disease; their durations of ingested freshwater raw fish or shrimp were more than 10 years, and none of them had abnormal liver function and hepatitis B virus or hepatitis C virus infection, or clinical symptoms. All patients underwent FibroScan, blood biochemical examination, and BMI measurement on the same day. Liver stiffness measurement (LSM) values, sex, age, durations of ingested freshwater raw fish or shrimp, and BMI were recorded. LSM value greater than 7.4 kPa was defined as abnormal. RESULTS: A total of 27 patients (41.5%) had abnormal LSM values. On partial correlation analysis, duration of ingested freshwater raw fish or shrimp was the independent factor that showed a positive correlation with abnormal LSM values (r=0.502, P=0.012). An independent-samples t-test showed that the durations of patients with abnormal LSM values were significantly longer than the durations of patients with normal LSM values (P<0.001). Sex, age, and BMI were not significantly correlated with LSM values (P>0.05). CONCLUSION: A high proportion of asymptomatic liver fluke disease patients had abnormal LSM values. The durations of patients with abnormal LSM values were significantly longer than the durations of patients with normal LSM values and the durations of patients with abnormal LSM values were an independent factor that showed a positive correlation with abnormal LSM values. PMID- 26529361 TI - Combined surgery for primary colorectal cancer and synchronous pulmonary metastasis: a pilot experience in two patients. AB - BACKGROUND: Pulmonary metastasectomy in patients with pulmonary metastases from primary colorectal cancer seems to improve survival in properly selected patients. Therefore, pulmonary metastasectomy has been incorporated widely into the management of colorectal pulmonary metastases. Generally, in patients presenting with primary colorectal cancer and synchronous pulmonary metastases, the primary colorectal cancer is resected first, followed by pulmonary metastasectomy during a second-stage procedure. In the current paper we describe our pilot experience with laparoscopic resection of primary colorectal cancer and thoracoscopic pulmonary metastasectomy during the same operative session. PATIENTS AND METHODS: The results of two patients who underwent laparoscopic resection of primary colorectal cancer and thoracoscopic pulmonary metastasectomy during the same operative session are described. RESULTS: Both patients were healthy women, 60 and 81 years old, respectively, and without severe comorbidities. In both patients, the colorectal resection was performed first by a laparoscopic approach. Subsequently, thoracoscopic resection of a single pulmonary metastasis followed in both patients. The operative procedure and postoperative course were uneventful and the patients could be discharged within 1 week after surgery. Both the primary colorectal cancer and the pulmonary metastasis were radically removed in both patients. Current follow-up, 14 and 8 months after surgery, respectively, showed no signs of disease recurrence on computed tomographic scan of the abdomen and chest in both patients. CONCLUSION: The outcome in these two patients suggests that simultaneous resection of primary colorectal cancer and pulmonary metastasectomy using minimal invasive surgery is safe and might lead to both a decrease in costs and benefit to patients. This simultaneous approach could therefore be considered as an alternative for a two stage approach in properly selected patients. However, these results should be validated in a larger series. PMID- 26529362 TI - Solid-phase extraction using bis(indolyl)methane-modified silica reinforced with multiwalled carbon nanotubes for the simultaneous determination of flavonoids and aromatic organic acid preservatives. AB - A novel bis(indolyl)methane-modified silica reinforced with multiwalled carbon nanotubes sorbent for solid-phase extraction was designed and synthesized by chemical immobilization of nitro-substituted 3,3'-bis(indolyl)methane on silica modified with multiwalled carbon nanotubes. Coupled with high-performance liquid chromatography analysis, the extraction properties of the sorbent were evaluated for flavonoids and aromatic organic acid compounds. Under optimum conditions, the sorbent can simultaneously extract five flavonoids and two aromatic organic acid preservatives in aqueous solutions in a single-step solid-phase extraction procedure. Wide linear ranges were obtained with correlation coefficients (R(2) ) ranging from 0.9843 to 0.9976, and the limits of detection were in the range of 0.5-5 MUg/L for the compounds tested. Compared with the silica modified with multiwalled carbon nanotubes sorbent and the nitro-substituted 3,3' bis(indolyl)methane-modified silica sorbent, the developed sorbent exhibited higher extraction efficiency toward the selected analytes. The synergistic effect of nitro-substituted 3,3'-bis(indolyl)methane and multiwalled carbon nanotubes not only improved the surface-to-volume ratio but also enhanced multiple intermolecular interactions, such as hydrogen bonds, pi-pi, and hydrophobic interactions, between the new sorbent and the selected analytes. The as established solid-phase extraction with high-performance liquid chromatography and diode array detection method was successfully applied to the simultaneous determination of flavonoids and aromatic organic acid preservatives in grape juices with recoveries ranging from 83.9 to 112% for all the selected analytes. PMID- 26529363 TI - Suppression of RAD21 Induces Senescence of MDA-MB-231 Human Breast Cancer Cells Through RB1 Pathway Activation Via c-Myc Downregulation. AB - Cellular senescence impedes cancer progression by limiting uncontrolled cell proliferation. To identify new genetic events controlling senescence, we performed a small interfering RNA screening human cancer cells and identified a number of targets potentially involved in senescence of MDA-MB-231 human breast cancer cells. Importantly, we showed that knockdown of RAD21 resulted in the appearance of several senescent markers, including enhanced senescence-associated beta-galactosidase activity and heterochromatin focus formation, as well as elevated p21 protein levels and RB1 pathway activation. Further biochemical analyses revealed that RAD21 knockdown led to the downregulation of c-Myc and its targets, including CDK4, a negative regulator of RB1, and blockedRB1 phosphorylation (pRB1), and the RB1-mediated transcriptional repression of E2F. Moreover, c-Myc downregulation was partially mediated by proteasome-dependent degradation within promyelocytic leukemia (PML) nuclear bodies, which were found to be highly abundant during RAD21 knockdown-induced senescence. Exogenous c-Myc reconstitution rescued cells from RAD21 silencing-induced senescence. Altogether, data arising from this study implicate a novel function of RAD21 in cellular senescence in MDA-MB-231 cells that is mainly dependent onRB1 pathway activation via c-Myc downregulation. PMID- 26529364 TI - Regulation and Functional Implications of Opioid Receptor Splicing in Opioid Pharmacology and HIV Pathogenesis. AB - Despite the identification and characterization of four opioid receptor subtypes and the genes from which they are encoded, pharmacological data does not conform to the predications of a four opioid receptor model. Instead, current studies of opioid pharmacology suggest the existence of additional receptor subtypes; however, no additional opioid receptor subtype has been identified to date. It is now understood that this discrepancy is due to the generation of multiple isoforms of opioid receptor subtypes. While several mechanisms are utilized to generate these isoforms, the primary mechanism involves alternative splicing of the pre-mRNA transcript. Extensive alternative splicing patterns for opioid receptors have since been identified and discrepancies in opioid pharmacology are now partially attributed to variable expression of these isoforms. Recent studies have been successful in characterizing the localization of these isoforms as well as their specificity in ligand binding; however, the regulation of opioid receptor splicing specificity is poorly characterized. Furthermore, the functional significance of individual receptor isoforms and the extent to which opioid- and/or HIV-mediated changes in the opioid receptor isoform profile contributes to altered opioid pharmacology or the well-known physiological role of opioids in the exacerbation of HIV neurocognitive dysfunction is unknown. As such, the current review details constitutive splicing mechanisms as well as the specific architecture of opioid receptor genes, transcripts, and receptors in order to highlight the current understanding of opioid receptor isoforms, potential mechanisms of their regulation and signaling, and their functional significance in both opioid pharmacology and HIV-associated neuropathology. PMID- 26529365 TI - Predominance of CRF06_cpx and Transmitted HIV Resistance in Algeria: Update 2013 2014. AB - Since 2008, no data on HIV diversity or the transmission rate of HIV resistance mutations in naive patients have been presented for Algeria, a country of MENA region. Between 2013 and 2014, we studied 152 samples including 89 naive patients. The current study describes the change in HIV diversity in Algeria with the predominance of CRF06_cpx and the huge increase of transmitted HIV resistance, which now reaches 15%. PMID- 26529366 TI - Discovery, Development, and Commercialization of Gold Catalysts for Acetylene Hydrochlorination. AB - Vinyl chloride monomer (VCM) is a major chemical intermediate for the manufacture of polyvinyl chloride (PVC), which is the third most important polymer in use today. Hydrochlorination of acetylene is a major route for the production of vinyl chloride, since production of the monomer is based in regions of the world where coal is abundant. Until now, mercuric chloride supported on carbon is used as the catalyst in the commercial process, and this exhibits severe problems associated with catalyst lifetime and mercury loss. It has been known for over 30 years that gold is a superior catalyst, but it is only now that it is being commercialized. In this Perspective we discuss the use and disadvantages of the mercury catalyst and the advent of the gold catalysts for this important reaction. The nature of the active site and the possible reaction mechanism are discussed. Recent advances in the design and preparation of active gold catalysts containing ultralow levels of gold are described. In the final part, a view to the future of this chemistry will be discussed as well as the possible avenues for the commercial potential of gold catalysis. PMID- 26529367 TI - Extracting spatial-temporal coherent patterns in large-scale neural recordings using dynamic mode decomposition. AB - BACKGROUND: There is a broad need in neuroscience to understand and visualize large-scale recordings of neural activity, big data acquired by tens or hundreds of electrodes recording dynamic brain activity over minutes to hours. Such datasets are characterized by coherent patterns across both space and time, yet existing computational methods are typically restricted to analysis either in space or in time separately. NEW METHOD: Here we report the adaptation of dynamic mode decomposition (DMD), an algorithm originally developed for studying fluid physics, to large-scale neural recordings. DMD is a modal decomposition algorithm that describes high-dimensional dynamic data using coupled spatial-temporal modes. The algorithm is robust to variations in noise and subsampling rate; it scales easily to very large numbers of simultaneously acquired measurements. RESULTS: We first validate the DMD approach on sub-dural electrode array recordings from human subjects performing a known motor task. Next, we combine DMD with unsupervised clustering, developing a novel method to extract spindle networks during sleep. We uncovered several distinct sleep spindle networks identifiable by their stereotypical cortical distribution patterns, frequency, and duration. COMPARISON WITH EXISTING METHODS: DMD is closely related to principal components analysis (PCA) and discrete Fourier transform (DFT). We may think of DMD as a rotation of the low-dimensional PCA space such that each basis vector has coherent dynamics. CONCLUSIONS: The resulting analysis combines key features of performing PCA in space and power spectral analysis in time, making it particularly suitable for analyzing large-scale neural recordings. PMID- 26529368 TI - Impact of non-anastomotic biliary strictures after liver transplantation on healthcare consumption, use of ionizing radiation and infectious events. AB - BACKGROUND: Non-anastomotic biliary strictures (NAS) after orthotopic liver transplantation (OLT) have a negative influence on graft survival. Expert opinion suggests a negative effect of NAS on other important aspects of post-transplant care, although its impact is largely unknown as data are scarce. METHODS: This retrospective single center study analyzed data on healthcare consumption, use of ionizing radiation, infectious complications and development of highly resistant microorganisms (HRMO) in adult patients with NAS. A comparison with a matched control group was made. RESULTS: Forty-three liver recipients with NAS and 43 controls were included. Hospital admissions were higher in patients with NAS. Most common reason for admission was bacterial cholangitis (BC), with 70% of the patients having at least one episode compared to 9% in the control group. In patients with NAS, 67% received at least one ERCP compared to 21% in the control group (p = 0.001). This resulted in a larger yearly received radiation dose for patients with NAS (p = 0.001). Frequency of intravenous antibiotic therapy was higher (p = 0.001) for patients with NAS, consistently resulting in a higher number of cultures found with HRMO (p = 0.012). CONCLUSION: NAS after OLT have a negative effect on post-transplant care, increasing readmission rates, interventional procedures, exposure to ionizing radiation, use of antibiotics, and development of HRMO. PMID- 26529369 TI - Why is it appropriate to recommend human papillomavirus vaccination as cervical cancer prevention? PMID- 26529370 TI - Minimally invasive interval debulking surgery in ovarian neoplasm (MISSION trial NCT02324595): a feasibility study. AB - BACKGROUND: Laparoscopy has acquired an increasing role in the management of ovarian cancer. Laparoscopic cytoreduction could represent a new frontier for selected patients after neoadjuvant chemotherapy (NACT). OBJECTIVE: We sought to assess feasibility and early complication rate of minimally invasive (MI) interval debulking surgery (IDS) in stage III-IV epithelial ovarian cancer (EOC) patients after NACT. STUDY DESIGN: This is a phase II multicentric study in advanced EOC cases with clinical complete response after NACT, according to Gynecologic Cancer Intergroup and Response Evaluation Criteria In Solid Tumors criteria. Institutional review board approval was obtained and all patients signed written informed consent to be included in the protocol. The study was registered in clinicaltrials.gov (NCT02324595) and was named "MISSION" trial. For patients meeting inclusion criteria, surgical procedures started with diagnostic laparoscopy to confirm preoperative findings and assess surgical complexity. MI IDS included hysterectomy, bilateral salpingo-oophorectomy, appendectomy, omentectomy, peritonectomy, and bowel resection. Pelvic and/or aortic lymphadenectomy was not considered as standard procedure in these cases. Intraoperative and postoperative outcomes, time to restart chemotherapy, survival rate, and quality of life data were registered. RESULTS: From December 2013 through February 2015, of 184 advanced EOC patients considered eligible for IDS, 52 (28.2%) met inclusion criteria and were enrolled in the study. For 22 (12%) of them, standard laparotomic approach was preferred because of intraoperative surgeon evaluation. Thirty (16.3%) patients received the planned treatment of MI IDS. Median age was 61 (range 39-81) years and median body mass index was 24 (range 20-31) kg/m(2). Median numbers of NACT cycles was 4 (range 3-7). Median operative time was 285 (range 124-418) minutes and median estimated blood loss was 100 (range 50-200) mL. Surgical procedures included 28 (93.3%) hysterectomy and bilateral salpingo-oophorectomy, 29 (96.6%) omentectomy, 2 (6.6%) appendectomy, 11 (36.6%) regional peritonectomy, and 1 (3.4%) bowel resection. A residual tumor of 0 cm was reached in 29 (96.6%) patients and 0.5 cm in only 1 (3.4%) case. The vast majority of patients were discharged on postoperative day 2 (range 2-3). No early postoperative complications were registered. Median time to restart chemotherapy was 20 (10-30) days and all patients successfully completed the cycles. Histological findings showed 3 (10%) complete response, 9 (30%) microscopic residual disease, and 18 (60%) evidence of macroscopic residual disease. With a median follow-up of 10.5 month, 5 peritoneal and 2 lymph nodal recurrences were observed. Psychometric test revealed moderate discomfort in the vast majority of patients (66.7%). All patients are still alive. CONCLUSION: Invasive-IDS in patients with clinically complete response to NACT seems to be feasible and safe in terms of perioperative outcomes, psycho-oncological impact, and survival rate. The equivalence between MI surgery and laparotomy needs to be confirmed with a longer follow-up and a larger number of patients. PMID- 26529371 TI - Perioperative adverse events associated with colpocleisis for uterovaginal and posthysterectomy vaginal vault prolapse. AB - BACKGROUND: Colpocleisis, a vaginal obliterative procedure, offers women with symptomatic pelvic organ prolapse an effective, durable anatomic repair and is associated with high patient satisfaction rates. Historically, colpocleisis was reserved for the medically frail or elderly with the goal of limiting anesthetic exposure, decreasing operative time, and minimizing adverse events. Several colpocleisis and colpectomy procedures exist and limited evaluation has been performed comparing these differences in regards to perioperative adverse events. OBJECTIVE: The primary objective was to describe the overall rate of perioperative adverse events in patients undergoing colpocleisis. The secondary objective was to compare rates of adverse events between different colpocleisis procedures. STUDY DESIGN: This is a retrospective chart review of patients who underwent colpocleisis at a tertiary care center from January 2003 through December 2013. Subjects were identified by their Current Procedural Terminology (CPT) codes and categorized into 3 groups: (1) partial or complete vaginectomy/colpectomy (CPT 57106, 57110); (2) vaginal hysterectomy with total or partial colpectomy (CPT 58275, 58280); and (3) Le Fort colpocleisis (CPT 57120). Baseline demographics, perioperative data, and postoperative data were collected. Analysis of variance was used to describe perioperative and postoperative adverse events in all subjects and to compare outcomes among the 3 groups. RESULTS: In all, 245 subjects underwent colpocleisis during the study period. Mean age and body mass index were 78 (+/-7) years and 27.7 (+/-5.8) kg/m(2), respectively; 59.1% (140/245) of subjects had stage-4 prolapse. The most common adverse event was urinary tract infection occurring in 34.7% of subjects. Major adverse events were uncommon. There were no differences in event rates among the groups except for the following: patients undergoing concurrent vaginal hysterectomy had longer mean operative time (144 vs 108 vs 111 minutes, P = .0001), had higher estimated blood loss (253 vs 135 vs 146 mL, P = .0001), and were more likely to experience postoperative venous thromboembolism (4.6% vs 0% vs 0%, P = .01). After controlling for age, body mass index, medical comorbidities, estimated blood loss, and operative time, the risk of venous thromboembolism was no longer significant. CONCLUSION: The overall rate of major perioperative and postoperative adverse events in women undergoing colpocleisis is low; however, concomitant hysterectomy is associated with longer operative times and higher blood loss. PMID- 26529372 TI - Length of second stage of labor and preterm birth in a subsequent pregnancy. AB - BACKGROUND: During the second stage of labor, it is plausible that the pressure of the fetal head against a completely dilated cervix may lead to changes in the cervical integrity and cervical strength lending it susceptible to premature dilation in a subsequent pregnancy. Therefore, a prolonged second stage of labor has been hypothesized to be a risk factor for cervical insufficiency and spontaneous preterm birth (sPTB). OBJECTIVE: We sought to evaluate the effect that the length of second stage of labor in one pregnancy has on the risk of sPTB in a subsequent pregnancy. STUDY DESIGN: This was a planned secondary analysis of a large retrospective cohort study of women with 2 consecutive deliveries at our institution from 2005 through 2010. Women with a term pregnancy that reached the second stage were included; women with a prior sPTB were excluded. The primary outcome was sPTB <37 weeks. A prolonged second stage was defined as >=3 hours. Fisher exact tests were used to compare categorical data. Linear and logistic regression was used to calculate odds. RESULTS: In all, 757 women were included. The overall length of the second stage ranged from 0-7.3 hours. The sPTB rate in a subsequent pregnancy was 8.7%. There was no association between length of second stage (hours) as a continuous variable and sPTB after adjusting for confounders (adjusted odds ratio, 0.83; [95% CI 0.58-1.20]). A prolonged second stage >=3 hours occurred in 48 (6.3%) women. Women with a second stage >=3 hours were older, less likely to be African American, and were less likely to be overweight or obese as compared to women with a second stage <3 hours. The women with second stage >=3 hours were more likely to be nulliparous and have a larger neonate. The sPTB risk was not different between a second stage >=3 hours (10.4%) and <3 hours (7.9%), P = .5. The sPTB risk was, however, modified by mode of delivery in the second stage. There was no difference in sPTB rate among women with a vaginal delivery when comparing those with and without a prolonged second stage (7.4 vs 7.8%, P = .9). There also was no difference among women with a cesarean when comparing those with and without a prolonged second stage (11.8 vs 14.3%, P = .8). While not statistically significant, the absolute risk of a subsequent sPTB after a cesarean delivery with a second stage >=3 hours is twice as high as the risk of a sPTB after a vaginal delivery with a second stage >=3 hours (adjusted odds ratio, 2.08; [0.32-13.78]). CONCLUSION: A prolonged second stage of labor alone does not increase the risk of sPTB in a subsequent pregnancy. Cesarean delivery after a prolonged second stage of labor may confer a possible increased risk. It is important to continue to evaluate potential risk factors for sPTB. If these risk factors are confirmed in future studies, it will aid in the counseling of women and may open the door for therapeutic strategies to be studied among these newly identified at-risk women. PMID- 26529374 TI - Automatic Mode Transition Enabled Robust Triboelectric Nanogenerators. AB - Although the triboelectric nanogenerator (TENG) has been proven to be a renewable and effective route for ambient energy harvesting, its robustness remains a great challenge due to the requirement of surface friction for a decent output, especially for the in-plane sliding mode TENG. Here, we present a rationally designed TENG for achieving a high output performance without compromising the device robustness by, first, converting the in-plane sliding electrification into a contact separation working mode and, second, creating an automatic transition between a contact working state and a noncontact working state. The magnet assisted automatic transition triboelectric nanogenerator (AT-TENG) was demonstrated to effectively harness various ambient rotational motions to generate electricity with greatly improved device robustness. At a wind speed of 6.5 m/s or a water flow rate of 5.5 L/min, the harvested energy was capable of lighting up 24 spot lights (0.6 W each) simultaneously and charging a capacitor to greater than 120 V in 60 s. Furthermore, due to the rational structural design and unique output characteristics, the AT-TENG was not only capable of harvesting energy from natural bicycling and car motion but also acting as a self-powered speedometer with ultrahigh accuracy. Given such features as structural simplicity, easy fabrication, low cost, wide applicability even in a harsh environment, and high output performance with superior device robustness, the AT TENG renders an effective and practical approach for ambient mechanical energy harvesting as well as self-powered active sensing. PMID- 26529373 TI - Sex differences in the risk of rapid cycling and other indicators of adverse illness course in patients with bipolar I and II disorder. AB - OBJECTIVES: To examine the independent effects of sex on the risk of rapid cycling and other indicators of adverse illness course in patients with bipolar I disorder (BP-I) or bipolar II disorder (BP-II). METHODS: We analyzed data from the first 1,225 patients enrolled in the Mayo Clinic Individualized Medicine Biobank for Bipolar Disorder. Demographic and clinical variables were ascertained using standardized questionnaires; height and weight were assessed to determine body mass index (BMI). Rates of rapid cycling, cycle acceleration, and increased severity of mood episodes over time were compared between women and men overall and within subgroups defined by bipolar disorder subtype (BP-I or BP-II). Multiple logistic regression analysis was used to assess the independent effect of sex on the risk of these indicators of adverse illness course. RESULTS: Women had significantly higher rates of rapid cycling than men. Overall rates of rapid cycling were higher in patients with BP-II than BP-I; and sex differences in the rate of rapid cycling were more pronounced in patients with BP-II than BP-I, although the power to detect statistically significant differences was reduced due to the lower sample size of subjects with BP-II. Female sex was a significant predictor of rapid cycling, cycle acceleration, and increased severity of mood episodes over time after adjusting for age, bipolar disorder subtype, BMI, having any comorbid psychiatric disorder, and current antidepressant use. CONCLUSIONS: Female sex was associated with significantly higher risk of rapid cycling, cycle acceleration, and increased severity of mood episodes over time in a sample of 1,225 patients with bipolar disorders. PMID- 26529375 TI - [Age determination by English model is not manageable]. PMID- 26529376 TI - [Not Available]. PMID- 26529377 TI - [The care of children with cancer is far from optimal. New dissertation raises the question: "Why does no one complain?"]. PMID- 26529378 TI - [Not Available]. PMID- 26529379 TI - Mechanism Behind the Apparent Large Stokes Shift in LSSmOrange Investigated by Time-Resolved Spectroscopy. AB - LSSmOrange is a fluorescent protein with a large energy gap between the absorption and emission bands (5275 cm(-1)). The electronic structure of the LSSmOrange chromophore, 2-[(5-)-2-hydroxy-dihydrooxazole]-4-(p hydroxybenzylidene)-5-imidazolinone, is affected by deprotonation of the p hydroxybenzylidene group. We investigated LSSmOrange by time-resolved spectroscopy in the femtosecond and nanosecond range. The ground state chromophore was almost exclusively in the neutral form, which had a main absorption band at 437 nm with a small shoulder at 475 nm. The absorption at a wavelength within the former band promoted the protein to the excited state where excited state proton transfer (ESPT) could lead to deprotonation in 0.8 ps. Following ESPT, the chromophore emitted fluorescence with a maximum at 573 nm and a decay time of 3500 ps. Although deprotonation by ESPT occurs, we unexpectedly found a slow accumulation of the anionic form in the ground state upon repeated high intensity excitation. This accumulation of the anionic form was accompanied by a shift of the absorption band to 553 nm without changing the emission band. MALDI-MS revealed that this shift is accompanied by decarboxylation of E222, which is interacting with the imidazolinone ring of the chromophore. We concluded that the photoinduced decarboxylation induced a conformational change that affected local environment around the hydroxyl group, resulting in a stable deprotonated form of the chromophore. PMID- 26529380 TI - Molecular and cellular analysis of the pH response transcription factor PacC in the fungal symbiont Epichloe festucae. AB - In order to survive and adapt to the environment, it is imperative for fungi to be able to sense and respond to changes in extracellular pH conditions. In ascomycetes, sensing of extracellular pH is mediated by the Pal pathway resulting in activation of the PacC transcription factor at alkaline pH. The role of PacC in regulating fungal virulence and pathogenicity has been described in several pathogenic fungi but to date not in a symbiotic fungus. Epichloe festucae is a biotrophic fungal endophyte that forms a stable mutualistic interaction with Lolium perenne. In this study, pacC deletion (DeltapacC) and dominant active (pacC(C)) mutants were generated in order to study the cellular roles of PacC in E. festucae. Deletion of pacC resulted in increased sensitivity of the mutant to salt-stress but surprisingly did not affect the ability of the mutant to grow under alkaline pH conditions. Alkaline pH was observed to induce conidiation in wild-type E. festucae but not in the DeltapacC mutant. On the other hand the pacC(C) mutant had increased conidiation at neutral pH alone. Null pacC mutants had no effect on the symbiotic interaction with ryegrass plants whereas the pacC(C) mutant increased the tiller number. Examination of the growth of the pacC(C) mutant in the plant revealed the formation of aberrant convoluted hyphal structures and an increase in hyphal breakage, which are possible reasons for the altered host interaction phenotype. PMID- 26529382 TI - Efficient Organic Light-Emitting Diode through Triplet Exciton Reharvesting by Employing Blended Electron Donor and Acceptor as the Emissive Layer. AB - A blended bimolecular exciplex formation was demonstrated between two individual donor and acceptor molecules, which are tris(4-carbazoyl-9-ylphenyl)amine (TCTA) and 2,4,6-tris(3'-(pyridin-3-yl)biphenyl-3-yl)-1,3,5-triazine (Tm3PyBPZ). The photoluminescence spectrum of the exciplex in the solid state showed an emission with a peak around 514 nm (~2.49 eV). By applying this exciplex as an emitting layer, a highly efficient all-fluorescent organic lighting emitting diode with maximum efficiencies of 13.1% and 53.4 lm/W can be realized under an extremely low turn-on voltage of only 2.4 V. The thermally activated delayed fluorescence (TADF) process is believed to be responsible for the excellent device performance. PMID- 26529381 TI - Homozygous deletion of ATC1 and NTC1 genes in Candida parapsilosis abolishes trehalase activity and affects cell growth, sugar metabolism, stress resistance, infectivity and biofilm formation. AB - A double homozygous atc1Delta/atc1Delta/ntc1Delta/ntc1Delta mutant (atc1Delta/ntc1Delta KO) was constructed in the pathogen opportunistic yeast Candida parapsilosis by disruption of the two chromosomal alleles coding for NTC1 gene (encoding a neutral trehalase) in a Cpatc1Delta/atc1Delta background (atc1Delta KO strain, deficient in acid trehalase). The Cpatc1Delta/ntc1Delta KO mutant failed to counteract the inability of Cpatc1Delta cells to metabolize exogenous trehalose and showed a similar growth pattern on several monosaccharides and disaccharides. However, upon prolonged incubation in either rich medium (YPD) or nutrient-starved medium the viability of Cpatc1Delta cells exhibited a sensitive phenotype, which was augmented by further CpNTC1/NTC1 disruption. Furthermore, Cpatc1Delta/ntc1Delta KO cells had difficulty in resuming active growth in fresh YPD. This homozygous mutant also lacked any in vitro measurable trehalase activity, whether acid or neutral, suggesting that a single gene codes for each enzyme. By contrast, in Cpatc1Delta/ntc1Delta KO strain the resistance to oxidative and heat stress displayed by atc1Delta mutant was suppressed. Cpatc1Delta/ntc1Delta KO cells showed a significant decrease in virulence as well as in the capacity to form biofilms. These results point to a major role for acid trehalase (Atc1p) in the pathobiology of C. parapsilosis, whereas the activity of neutral trehalase can only partially counteract Atc1p deficiency. They also support the use of ATC1 and NTC1 genes as interesting antifungal targets. PMID- 26529383 TI - Dose-response-time modelling: Second-generation turnover model with integral feedback control. AB - This study presents a dose-response-time (DRT) analysis based on a large preclinical biomarker dataset on the interaction between nicotinic acid (NiAc) and free fatty acids (FFA). Data were collected from studies that examined different rates, routes, and modes of NiAc provocations on the FFA time course. All information regarding the exposure to NiAc was excluded in order to demonstrate the utility of a DRT model. Special emphasis was placed on the selection process of the biophase model. An inhibitory Imax-model, driven by the biophase amount, acted on the turnover rate of FFA. A second generation NiAc/FFA model, which encompasses integral (slow buildup of tolerance - an extension of the previously used NiAc/FFA turnover models) and moderator (rapid and oscillatory) feedback control, was simultaneously fitted to all time courses in normal rats. The integral feedback control managed to capture an observed 90% adaptation (i.e., almost a full return to baseline) when 10 days constant-rate infusion protocols of NiAc were used. The half-life of the adaptation process had a 90% prediction interval between 3.5-12 in the present population. The pharmacodynamic parameter estimates were highly consistent when compared to an exposure-driven analysis, partly validating the DRT modelling approach and suggesting the potential of DRT analysis in areas where exposure data are not attainable. Finally, new numerical algorithms, which rely on sensitivity equations to robustly and efficiently compute the gradients in the parameter optimization, were successfully used for the mixed-effects approach in the parameter estimation. PMID- 26529384 TI - Physical Activity and Exercise: Perspectives of Adults With Ankylosing Spondylitis. AB - BACKGROUND: Exercise is a key component of the management of ankylosing spondylitis (AS). Despite numerous benefits, compliance with exercise programs is low. Little attention has been accorded to the experiences of individuals with AS toward physical activity (PA). This study aimed to explore the attitudes toward PA and exercise of adults with AS. METHODS: A qualitative descriptive design using thematic analysis was used. Seventeen adults with AS participated in individual, semistructured interviews. Interviews were recorded, transcribed, coded and analyzed for themes and subthemes. RESULTS: Four themes emerged from the analysis: (1) benefits, (2) barriers, (3) motivation, and (4) strategies and enablers. Benefits included amelioration of symptoms, improvements in general health, and enhancement of quality of life. Subthemes of barriers to PA included lack of resources, negative attitudes to exercise, misinformation, and condition related factors. Motivation to exercise was influenced by intrinsic and extrinsic factors. Participants proposed strategies to enhance PA participation and exercise engagement. CONCLUSIONS: Awareness of the benefits of PA appears insufficient to motivate individuals with AS to exercise; a number of factors influence individual motivation to exercise. Many perceived barriers to PA may be considered modifiable. Individually-tailored interventions, collaboratively developed by the individual and the healthcare professionals, were proposed as strategies for effective PA and exercise prescription. PMID- 26529385 TI - Single nucleotide polymorphisms in 5'-UTR of the SLC2A4 gene regulate solute carrier family 2 member 4 gene expression in visceral adipose tissue. AB - BACKGROUND: The glucose uptake by numerous cells like adipocytes or skeletal muscle cells requires activation of specific proteins called glucose transporters. GLUT4 content and its activation as well as SLC2A4 gene expression level are decreased in patients with type 2 diabetes. The SLC2A4 gene expression rate might be modulated by genetic variances in UTRs. The relationship between two SNPs in 5'UTR and one SNP in 3'UTR and SLC2A4 gene expression rate in adipose tissue and lymphocytes has been evaluated. METHODS: The study was performed on lymphocytes collected from 34 type 2 diabetic patients and equal number of controls. Visceral adipose tissue biopsies were collected from 15 patients with T2DM and from 24 controls. RESULTS: SLC2A4 gene expression level was slightly lower within type 2 diabetic patients in both type of tissues. Furthermore, the negative correlation between SLC2A4 gene expression level in visceral adipose tissue and BMI has been noticed. The genotypes of two SNPs in 5'UTRs (rs5417 and rs5418) were correlated with lower mRNA amount of GLUT4 within recessive homozygotes belonging to control group. CONCLUSIONS: Present results suggest the relationship between genetic variances within UTRs of SLC2A4 gene and gene expression rate. However, the relationship is tissue specific and is noticeable in adipose tissue of lean and healthy subjects. PMID- 26529386 TI - Imaging-based analysis of liposome internalization to macrophage cells: Effects of liposome size and surface modification with PEG moiety. AB - Liposome is one of the frequently used carriers for active targeting systems in vivo. Such parameters as its size, surface charge, and surface modifiers are known to influence the liposome uptake by macrophage cells. In this study, we investigated the effects of liposome size and polyethylene glycol (PEG) surface modifier on the liposomal internalization to murine macrophage (RAW-264.7), by using an imaging analysis technique. Three different sized liposomes (100, 200, and 400 nm in nominal diameter) labeled with rhodamine fluorescence were used. Liposome internalization appeared to reach a pseudo-steady plateau in about 5h incubation, and most of the internalized liposomes were seen to accumulate in the cytosol including cellular extensions. The maximum fluorescent density from the internalized liposomes was similar between 100 nm and 200 nm liposomes. However, that of the larger 400 nm liposome was approximately 1.7 times higher than the others, confirming the previous report that the larger the liposomes are the higher the degree of internalization is. When the outside of the 200 nm liposomes was modified with biocompatible anchor molecule (BAM) consisting of PEG (ca. 2kD molecular weight) moiety, the endocytosis was indeed reduced by about 2.1-fold, despite the increase of the hydrodynamic size due to BAM conjugation. This fluorescence-based cellular imaging analysis can be used to quantitatively monitor and optimize cellular internalization systems. PMID- 26529387 TI - Cytotoxicity assessment of graphene-based nanomaterials on human dental follicle stem cells. AB - Graphene-oxide (GO) and its most encountered derivatives, thermally reduced graphene oxide (TRGO) and nitrogen-doped graphene (N-Gr), were synthesized and structurally characterized by spectroscopic techniques, like Raman and (13)C MAS solid state NMR. Several biological effects (cytotoxicity, oxidative stress induction, and cellular and mithocondrial membrane alterations) induced by such graphene-based materials on human dental follicle stem cells were investigated. Graphene oxide shows the lowest cytotoxic effect, followed by the nitrogen-doped graphene, while thermally reduced graphene oxide exhibits high cytotoxic effects. Graphene oxide induces oxidative stress without causing cell membrane damage. Nitrogen-doped graphene shows a slight antioxidant activity; however, at high doses (20 and 40 MUg/ml) it causes membrane damage. Both graphene oxide and nitrogen-doped graphene seem to be valuable candidates for usage in dental nanocomposites. PMID- 26529388 TI - Whey protein mucoadhesive properties for oral drug delivery: Mucin-whey protein interaction and mucoadhesive bond strength. AB - Whey protein is a natural polymer recently used as an excipient in buccoadhesive tablets but its mucoadhesive properties were barely studied. In this work, we characterize mucoadhesion of whey protein in order to determine the mechanisms and optimal conditions for use as excipient in oral drug delivery. Thus, native and denatured whey protein (NWP and DWP) were investigated and the effect of concentration and pH were also studied. Many methods of characterization were selected to allow the study of chemical and physical interactions with mucin and then the results were bound with an ex vivo experiments. Turbidity of WP-mucin mixture increased at acidic pH 1.2 till 4.5 indicating interaction with mucin but not at pH 6.8. No interaction with mucin was also found by ITC method at pH 6.8 for native and denatured whey protein used at 1% (w/w). Forces of bioadhesion evaluated by viscosity measurements were the best for high concentrated (10.8%) DWP solutions at pH 6.8 and were low at pH 1.2 for NWP and DWP solutions. Addition of chemical blockers indicated that hydrogen bondings and disulfide bridges were the main mechanisms of interactions with mucin. Reticulation of DWP with calcium ions to obtain microparticles (MP) did not influence the ability of interaction with mucin as shown by FTIR analysis. These results correlated with ex vivo study on rat tissue demonstrating important adhesion (75%) of WP MP on the intestine and null on the stomach after 2h of deposit. PMID- 26529389 TI - Macrophages in bone fracture healing: Their essential role in endochondral ossification. AB - In fracture healing, skeletal and immune system are closely interacting through common cell precursors and molecular mediators. It is thought that the initial inflammatory reaction, which involves migration of macrophages into the fracture area, has a major impact on the long term outcome of bone repair. Interestingly, macrophages reside during all stages of fracture healing. Thus, we hypothesized a critical role for macrophages in the subsequent phases of bone regeneration. This study examined the impact of in vivo induced macrophage reduction, using clodronate liposomes, on the different healing phases of bone repair in a murine model of a standard closed femoral fracture. A reduction in macrophages had no obvious effect on the early fracture healing phase, but resulted in a delayed hard callus formation, thus severely altering endochondral ossification. Clodronate treated animals clearly showed delayed bony consolidation of cartilage and enhanced periosteal bone formation. Therefore, we decided to backtrack macrophage distribution during fracture healing in non-treated mice, focusing on the identification of the M1 and M2 subsets. We observed that M2 macrophages were clearly prevalent during the ossification phase. Therefore enhancement of M2 phenotype in macrophages was investigated as a way to further bone healing. Induction of M2 macrophages through interleukin 4 and 13 significantly enhanced bone formation during the 3week investigation period. These cumulative data illustrate their so far unreported highly important role in endochondral ossification and the necessity of a fine balance in M1/M2 macrophage function, which appears mandatory to fracture healing and successful regeneration. PMID- 26529390 TI - Mechanical-chemical analyses and sub-chronic systemic toxicity of chemical treated organic bovine bone. AB - Sequentially chemical-treated bovine bone was not only evaluated by mechanical and chemical analyses but also implanted into the gluteal muscles of rats for 12 weeks to investigate potential local pathological effects and systemic toxicities. The test (chemical treated bone) and control (heat treated bone) materials were compared using scanning electron microscope (SEM), x-ray diffraction pattern, inductively coupled plasma analysis, and bending strength test. In the SEM images, the micro-porous structure of heat-treated bone was changed to sintered ceramic-like structure. The structure of bone mineral from test and control materials was analyzed as100% hydroxyapatite. The ratio of calcium (Ca) to potassium (P), the main inorganic elements, was same even though the Ca and P percentages of the control material was relatively higher than the test material. No death or critical symptoms arose from implantation of the test (chemical treated bone) and control (physiological saline) materials during 12 weeks. The implanted sites were macroscopically examined, with all the groups showing non-irritant results. Our results indicate that chemical processed bovine bone has a better mechanical property than the heat treated bone and the implantation of this material does not produce systemic or pathological toxicity. PMID- 26529391 TI - Pattern formation--A missing link in the study of ecosystem response to environmental changes. AB - Environmental changes can affect the functioning of an ecosystem directly, through the response of individual life forms, or indirectly, through interspecific interactions and community dynamics. The feasibility of a community level response has motivated numerous studies aimed at understanding the mutual relationships between three elements of ecosystem dynamics: the abiotic environment, biodiversity and ecosystem function. Since ecosystems are inherently nonlinear and spatially extended, environmental changes can also induce pattern forming instabilities that result in spatial self-organization of life forms and resources. This, in turn, can affect the relationships between these three elements, and make the response of ecosystems to environmental changes far more complex. Responses of this kind can be expected in dryland ecosystems, which show a variety of self-organizing vegetation patterns along the rainfall gradient. This paper describes the progress that has been made in understanding vegetation patterning in dryland ecosystems, and the roles it plays in ecosystem response to environmental variability. The progress has been achieved by modeling pattern forming feedbacks at small spatial scales and up-scaling their effects to large scales through model studies. This approach sets the basis for integrating pattern formation theory into the study of ecosystem dynamics and addressing ecologically significant questions such as the dynamics of desertification, restoration of degraded landscapes, biodiversity changes along environmental gradients, and shrubland-grassland transitions. PMID- 26529392 TI - An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo. AB - Systemic delivery of mRNA-based therapeutics remains a challenging issue for preclinical and clinical studies. Here, we describe new lipid-like nanoparticles (TT-LLNs) developed through an orthogonal array design, which demonstrates improved delivery efficiency of mRNA encoding luciferase in vitro by over 350 fold with significantly reduced experimental workload. One optimized TT3 LLN, termed O-TT3 LLNs, was able to restore the human factor IX (hFIX) level to normal physiological values in FIX-knockout mice. Consequently, these mRNA based nanomaterials merit further development for therapeutic applications. PMID- 26529393 TI - N-truncated Abeta2-X starting with position two in sporadic Alzheimer's disease cases and two Alzheimer mouse models. AB - According to the modified amyloid hypothesis, the key event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid beta-peptides (Abetas) in plaques and cerebral blood vessels. Additionally to full-length peptides, a great diversity of N-truncated Abeta variants is derived from the larger amyloid-beta protein precursor (AbetaPP). Vast evidence suggests that Abetax-42 isoforms play an important role in triggering neurodegeneration due to their high abundance, amyloidogenic propensity and toxicity. Although N-truncated Abeta peptides and Abetax-42 species appear to be the crucial players in AD etiology, the Abeta2-X isoforms did not receive much attention yet. The present study is the first to show immunohistochemical evidence of Abeta2-X in cases of AD and its distribution in AbetaPP/PS1KI and 5XFAD transgenic mouse models using a novel antibody pAB77 that has been developed using Abeta2-14 as antigen. Positive plaques and congophilic amyloid angiopathy (CAA) were observed in AD cases and in both mouse models. While in AD cases, abundant CAA and less pronounced plaque pathology was evident, the two mouse models showed predominantly extracellular Abeta deposits and minor CAA staining. Western blotting and a capillary isoelectric focusing immunoassay demonstrated the high specificity of the antibody pAb77 against Abeta-variants starting with the N terminal Alanine-2. PMID- 26529394 TI - Peripherally applied synthetic tetrapeptides HAEE and RADD slow down the development of cerebral beta-amyloidosis in AbetaPP/PS1 transgenic mice. PMID- 26529396 TI - Anaplastic lymphoma kinase: Role in cancer and therapy perspective. AB - Anaplastic lymphoma kinase (ALK) is correlated with oncogenesis in different types of cancers, such as anaplastic large cell lymphoma, lung cancer, neuroblastoma, and even breast cancer, by abnormal fusion of ALK or non-fusion ALK activation. ALK is a receptor tyrosine kinase, with a single transmembrane domain, that plays an important role in development. Upon ligand binding to the extracellular domain, the receptor undergoes dimerization and subsequent autophosphorylation of the intracellular kinase domain. In recent years, ALK inhibitors have been developed for cancer treatment. These inhibitors target ALK activity and show effectiveness in ALK-positive non-small cell lung cancer. However, acquired treatment resistance makes the future of this therapy unclear; new strategies are underway to overcome the limitations of current ALK inhibitors. PMID- 26529397 TI - Case Report: Congenital Erythroleukemia in a Premature Infant with Dysmorphic Features. AB - We present a case of pure erythroleukemia, diagnosed at autopsy, in a dysmorphic premature infant who died of multiorgan failure within 24 hours of birth. Dysmorphic features included facial and limb abnormalities with long philtrum, microagnathia, downturned mouth, short neck as well as abnormal and missing nails, missing distal phalanx from the second toe, and overlapping toes. Internal findings included gross hepatomegaly and patchy hemorrhages in the liver, splenomegaly, and cardiomegaly; and subdural, intracerebral, and intraventricular hemorrhages. Histology revealed infiltration of bone marrow, kidney, heart, liver, adrenal, lung, spleen, pancreas, thyroid, testis, thymus, and placenta by pure erythroleukemia. Only 6 cases of congenital erythroleukemia have been previously reported with autopsy findings similar to those of this case. The dysmorphic features, although not fitting any specific syndrome, make this case unique. Congenital erythroleukemia and possible syndromes suggested by the dysmorphic features are discussed. PMID- 26529398 TI - Quercetin protection against ciprofloxacin induced liver damage in rats. AB - Ciprofloxacin is a common, broad spectrum antibacterial agent; however, evidence is accumulating that ciprofloxacin may cause liver damage. Quercetin is a free radical scavenger and antioxidant. We investigated histological changes in hepatic tissue of rats caused by ciprofloxacin and the effects of quercetin on these changes using histochemical and biochemical methods. We divided 28 adult female Wistar albino rats into four equal groups: control, quercetin treated, ciprofloxacin treated, and ciprofloxacin + quercetin treated. At the end of the experiment, liver samples were processed for light microscopic examination and biochemical measurements. Sections were prepared and stained with hematoxylin and eosin, and a histopathologic damage score was calculated. The sections from the control group appeared normal. Hemorrhage, inflammatory cell infiltration and intracellular vacuolization were observed in the ciprofloxacin group. The histopathological findings were reduced in the group treated with quercetin. Significant differences were found between the control and ciprofloxacin groups, and between the ciprofloxacin and ciprofloxacin + quercetin groups. Quercetin administration reduced liver injury caused by ciprofloxacin in rats. We suggest that quercetin may be useful for preventing ciprofloxacin induced liver damage. PMID- 26529399 TI - Anthocyanin extraction from plant tissues: A review. AB - Anthocyanins have gathered the attention of the scientific community mostly due to their vast range of possible applications. They have been the center point of the research in many different fields, among which is food development, where their innate coloring, antioxidant capacity, and biological potential open interesting venues to the development of new food additives and functional foodstuffs. As the range of application grows, so does the necessity to obtain these compounds, and since they are naturally occurring, the most common way to obtain anthocyanins is to extract them from different plant sources, such as fruits and flowers. Several efforts have been made to develop methods that allow for better extraction yields and higher purification rates therefore this review aims to compile the information regarding extraction and purification procedures in a comprehensive manner. PMID- 26529400 TI - Caffeine fostering of mycoparasitic fungi against phytopathogens. AB - Caffeine (1,3,7-trimethixanthine) is a typical purine alkaloid produced in more than 80 plant species. Its biological role is considered to strengthen plant's defense capabilities, directly as a toxicant to biotic attackers (allelopathy) and indirectly as an activator of defense system (priming). Caffeine is actively secreted into rhizosphere through primary root, and possibly affects the structure of microbe community nearby. The fungal community in coffee plant rhizosphere is enriched with particular species, including Trichoderma family, a mycoparasite that attacks and kills phytopathogens by coiling and destroying their hyphae. In the present study, the caffeine response of 8 filamentous fungi, 4 mycoparasitic Trichoderma, and 4 prey phytopathogens, was examined. Results showed that allelopathic effect of caffeine on fungal growth and development was differential, being stronger on pathogens than on Trichoderma species. Upon confronting, the prey immediately ceased the growth, whereas the predator continued to grow, indicating active mycoparasitism to have occurred. Caffeine enhanced mycoparasitism up to 1.7-fold. Caffeine thus functions in a double-track manner against fungal pathogens: first by direct suppression of growth and development, and second by assisting their natural enemy. These observations suggest that caffeine is a powerful weapon in the arms race between plants and pathogens by fostering enemy's enemy, and we propose the idea of "caffeine fostering" as the third role of caffeine. PMID- 26529401 TI - Ear-Shaped Stable Auricular Cartilage Engineered from Extensively Expanded Chondrocytes in an Immunocompetent Experimental Animal Model. AB - Advancement of engineered ear in clinical practice is limited by several challenges. The complex, largely unsupported, three-dimensional auricular neocartilage structure is difficult to maintain. Neocartilage formation is challenging in an immunocompetent host due to active inflammatory and immunological responses. The large number of autologous chondrogenic cells required for engineering an adult human-sized ear presents an additional challenge because primary chondrocytes rapidly dedifferentiate during in vitro culture. The objective of this study was to engineer a stable, human ear-shaped cartilage in an immunocompetent animal model using expanded chondrocytes. The impact of basic fibroblast growth factor (bFGF) supplementation on achieving clinically relevant expansion of primary sheep chondrocytes by in vitro culture was determined. Chondrocytes expanded in standard medium were either combined with cryopreserved, primary passage 0 chondrocytes at the time of scaffold seeding or used alone as control. Disk and human ear-shaped scaffolds were made from porous collagen; ear scaffolds had an embedded, supporting titanium wire framework. Autologous chondrocyte-seeded scaffolds were implanted subcutaneously in sheep after 2 weeks of in vitro incubation. The quality of the resulting neocartilage and its stability and retention of the original ear size and shape were evaluated at 6, 12, and 20 weeks postimplantation. Neocartilage produced from chondrocytes that were expanded in the presence of bFGF was superior, and its quality improved with increased implantation time. In addition to characteristic morphological cartilage features, its glycosaminoglycan content was high and marked elastin fiber formation was present. The overall shape of engineered ears was preserved at 20 weeks postimplantation, and the dimensional changes did not exceed 10%. The wire frame within the engineered ear was able to withstand mechanical forces during wound healing and neocartilage maturation and prevented shrinkage and distortion. This is the first demonstration of a stable, ear-shaped elastic cartilage engineered from auricular chondrocytes that underwent clinical-scale expansion in an immunocompetent animal over an extended period of time. PMID- 26529402 TI - Temporal Effects of a Begomovirus Infection and Host Plant Resistance on the Preference and Development of an Insect Vector, Bemisia tabaci, and Implications for Epidemics. AB - Persistent plant viruses, by altering phenotypic and physiological traits of their hosts, could modulate the host preference and fitness of hemipteran vectors. A majority of such modulations increase vector preference for virus infected plants and improve vector fitness, ultimately favouring virus spread. Nevertheless, it remains unclear how these virus-induced modulations on vectors vary temporally, and whether host resistance to the pathogen influences such effects. This study addressed the two questions using a Begomovirus-whitefly tomato model pathosystem. Tomato yellow leaf curl virus (TYLCV) -susceptible and TYLCV-resistant tomato genotypes were evaluated by whitefly-mediated transmission assays. Quantitative PCR revealed that virus accumulation decreased after an initial spike in all genotypes. TYLCV accumulation was less in resistant than in susceptible genotypes at 3, 6, and 12 weeks post inoculation (WPI). TYLCV acquisition by whiteflies over time from resistant and susceptible genotypes was also consistent with virus accumulation in the host plant. Furthermore, preference assays indicated that non-viruliferous whiteflies preferred virus infected plants, whereas viruliferous whiteflies preferred non-infected plants. However, this effect was prominent only with the susceptible genotype at 6 WPI. The development of whiteflies on non-infected susceptible and resistant genotypes was not significantly different. However, developmental time was reduced when a susceptible genotype was infected with TYLCV. Together, these results suggest that vector preference and development could be affected by the timing of infection and by host resistance. These effects could play a crucial role in TYLCV epidemics. PMID- 26529403 TI - Attention-Deficit/Hyperactivity Disorder (ADHD) in Adulthood: Concordance and Differences between Self- and Informant Perspectives on Symptoms and Functional Impairment. AB - Attention-deficit/hyperactivity disorder (ADHD) is a severe mental illness, associated with major impairment and a high comorbidity rate. Particularly undiagnosed ADHD in adulthood has serious consequences. Thus, a valid diagnosis is important. In adulthood, the diagnostic process for ADHD is complicated: symptoms may overlap with comorbid disorders, and the onset and progression of the disorder must be reconstructed retrospectively. Guidelines for the diagnostic process recommend the inclusion of additional informant ratings. Research into the relation between self- and informant ratings shows extremely heterogeneous results. The levels of agreement range from low to high. The focus of this study is the concordance and differences between self- and informant ratings on ADHD symptoms and impairments. In this regard, two possible influencing factors (gender and relationship type) are also examined. 114 people participated in this study, 77 with an ADHD diagnosis and 37 without a diagnosis. For all participants, either parents or partners also rated ADHD symptoms and impairments. Small to moderate concordance was found between self- and informant ratings, with females being slightly more concordant than males, particularly for ratings of problems with self-concept. Examination of the consistency within a particular perspective showed that people with ADHD seemed to be unaware of the causal relation between ADHD symptoms and their impairments. A close investigation found almost no influence of gender and relationship type on differences within perspectives. Based on these results, the implications for the diagnostic process are that additional informant information is clearly necessary and helpful. PMID- 26529404 TI - The Role of Nerve Growth Factor in Ginsenoside Rg1-Induced Regeneration of Injured Rat Sciatic Nerve. AB - Sciatic nerve injury is commonly seen in clinical practice predominantly associated with trauma or sports injuries. Recent studies indicated that ginsenoside Rg1 (Gs Rg1), extracted from Chinese herbs, was found to promote regeneration of injured rat sciatic nerve and that nerve growth factor (NGF) may be involved in this process. The aim of this study was to examine the role that NGF may play in ginsenoside Rg1-induced regeneration of rat sciatic nerve following injury. Animals following surgical right sciatic nerve injury were subsequently administered intraperitoneally either saline (sham control) or different doses of 2, 4, 8, or 12 mg/kg daily GsRg1 for 2 to 8 wk. In addition, 100 MUg/kg mecobalamin, a drug utilized to treat nerve injuries, was employed as a positive control. After 2, 4, or 8 wk, sciatic functional index (SFI) and mean nerve conduction velocity (MNCV), markers of sciatic nerve function, were assessed to determine whether recovery of injured sciatic nerve occurred. In addition, immunohistochemistry and Western blot methods were used to examine NGF protein expression changes. Results showed that all doses of GsRg1 significantly increased SFI and MNCV in injured sciatic-nerve-damaged rats in a manner similar to that noted with mecobalamin. It is of interest that the intermediate 4- and 8 mg/kg doses were more effective in restoring nerve functions. Immunohistochemistry and Western blot results also demonstrated a similar pattern with enhanced NGF protein expression at all doses, but greater effects were noted at 4 and 8 mg/kg GsRg1. Data suggest that GsRg1 promotes recovery of injured sciatic nerve functions within a specific dose range and that NGF may be involved in this physiological process. PMID- 26529405 TI - Sex, Diet, and the Social Environment: Factors Influencing Hair Cortisol Concentration in Free-Ranging Black Bears (Ursus americanus). AB - Increasingly, measures of glucocorticoid levels (e.g., cortisol), key components of the neuroendocrine stress axis, are being used to measure past hypothalamic pituitary-adrenal (HPA) activity to index psychological and physiological stress exhibited by wildlife for assessing individual and population-level well-being. However, many intrinsic and extrinsic factors affect HPA activity in animals. Using American black bears (Ursus americanus; n = 116) as an ecological model and hair cortisol concentration (HCC) as an integrative measure of past HPA activity, we evaluated the influence of diet, sex and the social environment on black bear HCC in a free-ranging population that spanned adjoining ecoregions with differing densities of potential conspecific and heterospecific competitors. HCC varied by sex, with female HCC ranging from 0.6 to 10.7 pg/mg (median = 4.5 +/- 1.2 mean absolute deviation [MAD]) and male HCC ranging from 0.5 to 35.1 pg/mg (median = 6.2 +/- 2.6 MAD). We also observed a three-way interaction among sex, delta14C and ecoregion, which may indicate that some differences in HCC between female and male black bears results from variability in the nutritional needs of larger bodied males relative to smaller-bodied females, slight differences in food resources use between ecoregions as well as sex-based differences regarding the social environment. Once we understand what drives sex-specific differences in HCC, HCC may aid our understanding of the physiological responses by bears and other wildlife to diverse environmental challenges. PMID- 26529406 TI - Habitat Selectivity and Reliance on Live Corals for Indo-Pacific Hawkfishes (Family: Cirrhitidae). AB - Hawkfishes (family: Cirrhitidae) are small conspicuous reef predators that commonly perch on, or shelter within, the branches of coral colonies. This study examined habitat associations of hawkfishes, and explicitly tested whether hawkfishes associate with specific types of live coral. Live coral use and habitat selectivity of hawkfishes was explored at six locations from Chagos in the central Indian Ocean extending east to Fiji in the Pacific Ocean. A total of 529 hawkfishes from seven species were recorded across all locations with 63% of individuals observed perching on, or sheltering within, live coral colonies. Five species (all except Cirrhitus pinnulatus and Cirrhitichthys oxycephalus) associated with live coral habitats. Cirrhitichthys falco selected for species of Pocillopora while Paracirrhites arcatus and P. forsteri selected for both Pocillopora and Acropora, revealing that these habitats are used disproportionately more than expected based on the local cover of these coral genera. Habitat selection was consistent across geographic locations, and species of Pocillopora were the most frequently used and most consistently selected even though this coral genus never comprised more than 6% of the total coral cover at any of the locations. Across locations, Paracirrhites arcatus and P. forsteri were the most abundant species and variation in their abundance corresponded with local patterns of live coral cover and abundance of Pocilloporid corals, respectively. These findings demonstrate the link between small predatory fishes and live coral habitats adding to the growing body of literature highlighting that live corals (especially erect branching corals) are critically important for sustaining high abundance and diversity of fishes on coral reefs. PMID- 26529407 TI - The Role of Anterior Nuclei of the Thalamus: A Subcortical Gate in Memory Processing: An Intracerebral Recording Study. AB - OBJECTIVE: To study the involvement of the anterior nuclei of the thalamus (ANT) as compared to the involvement of the hippocampus in the processes of encoding and recognition during visual and verbal memory tasks. METHODS: We studied intracerebral recordings in patients with pharmacoresistent epilepsy who underwent deep brain stimulation (DBS) of the ANT with depth electrodes implanted bilaterally in the ANT and compared the results with epilepsy surgery candidates with depth electrodes implanted bilaterally in the hippocampus. We recorded the event-related potentials (ERPs) elicited by the visual and verbal memory encoding and recognition tasks. RESULTS: P300-like potentials were recorded in the hippocampus by visual and verbal memory encoding and recognition tasks and in the ANT by the visual encoding and visual and verbal recognition tasks. No significant ERPs were recorded during the verbal encoding task in the ANT. In the visual and verbal recognition tasks, the P300-like potentials in the ANT preceded the P300-like potentials in the hippocampus. CONCLUSIONS: The ANT is a structure in the memory pathway that processes memory information before the hippocampus. We suggest that the ANT has a specific role in memory processes, especially memory recognition, and that memory disturbance should be considered in patients with ANT-DBS and in patients with ANT lesions. ANT is well positioned to serve as a subcortical gate for memory processing in cortical structures. PMID- 26529408 TI - Molecular Cloning of a cDNA Encoding for Taenia solium TATA-Box Binding Protein 1 (TsTBP1) and Study of Its Interactions with the TATA-Box of Actin 5 and Typical 2 Cys Peroxiredoxin Genes. AB - TATA-box binding protein (TBP) is an essential regulatory transcription factor for the TATA-box and TATA-box-less gene promoters. We report the cloning and characterization of a full-length cDNA that encodes a Taenia solium TATA-box binding protein 1 (TsTBP1). Deduced amino acid composition from its nucleotide sequence revealed that encodes a protein of 238 residues with a predicted molecular weight of 26.7 kDa, and a theoretical pI of 10.6. The NH2-terminal domain shows no conservation when compared with to pig and human TBP1s. However, it shows high conservation in size and amino acid identity with taeniids TBP1s. In contrast, the TsTBP1 COOH-terminal domain is highly conserved among organisms, and contains the amino acids involved in interactions with the TATA-box, as well as with TFIIA and TFIIB. In silico TsTBP1 modeling reveals that the COOH-terminal domain forms the classical saddle structure of the TBP family, with one alpha helix at the end, not present in pig and human. Native TsTBP1 was detected in T. solium cysticerci's nuclear extract by western blot using rabbit antibodies generated against two synthetic peptides located in the NH2 and COOH-terminal domains of TsTBP1. These antibodies, through immunofluorescence technique, identified the TBP1 in the nucleus of cells that form the bladder wall of cysticerci of Taenia crassiceps, an organism close related to T. solium. Electrophoretic mobility shift assays using nuclear extracts from T. solium cysticerci and antibodies against the NH2-terminal domain of TsTBP1 showed the interaction of native TsTBP1 with the TATA-box present in T. solium actin 5 (pAT5) and 2-Cys peroxiredoxin (Ts2-CysPrx) gene promoters; in contrast, when antibodies against the anti-COOH-terminal domain of TsTBP1 were used, they inhibited the binding of TsTBP1 to the TATA-box of the pAT5 promoter gene. PMID- 26529410 TI - Insulin Resistance Is Associated with Prevalence of Physician-Diagnosed Urinary Incontinence in Postmenopausal Non-Diabetic Adult Women: Data from the Fourth Korea National Health and Nutrition Examination Survey. AB - OBJECTIVE: To investigate the association between insulin resistance (IR) and urinary incontinence in Korean adult women by analyzing the data from the Korea National Health and Nutrition Examination Survey IV (KNHANES) 2007-2009. METHODS: A nationally representative sample of 5318 non-diabetic Korean women >=19-years of-age (3043 premenopausal and 2275 postmenopausal women) was included from KNHANES 2008-2010. IR was measured using the homeostasis model assessment of IR (HOMA-IR). Participants in the highest and lowest quartile of HOMA-IR were defined as insulin-resistant and insulin-sensitive respectively. Women who have current physician-diagnosed urinary incontinence were classified as having urinary incontinence. RESULTS: Incontinence was found in 9.18% of the total population, 8.51% of the premenopausal population, and 10.86% of the postmenopausal population. The prevalence of incontinence increased with age, reaching a peak at 60-69-years-of-age. The prevalence of urinary incontinence increased significantly with higher HOMA-IR quartiles in pre- and post-menopausal women (p for linear association = 0.0458 and 0.0009 respectively). Among post menopausal women, those in the highest quartile of HOMA-IR were significantly more likely to have urinary incontinence compared to those in the lowest quartile [adjusted odds ratio, 1.72; 95% confidence interval, 1.07-2.77]. However premenopausal population exhibited no association between incontinence and HOMA IR quartiles. CONCLUSION: Our results suggest that the prevalence of incontinence increased across HOMA-IR in non-diabetic adult women, and especially, IR might be a risk factor for incontinence in postmenopausal non-diabetic women. PMID- 26529409 TI - An Investigation of Emotion Recognition and Theory of Mind in People with Chronic Heart Failure. AB - OBJECTIVES: Cognitive deficits are common in patients with chronic heart failure (CHF), but no study has investigated whether these deficits extend to social cognition. The present study provided the first empirical assessment of emotion recognition and theory of mind (ToM) in patients with CHF. In addition, it assessed whether each of these social cognitive constructs was associated with more general cognitive impairment. METHODS: A group comparison design was used, with 31 CHF patients compared to 38 demographically matched controls. The Ekman Faces test was used to assess emotion recognition, and the Mind in the Eyes test to measure ToM. Measures assessing global cognition, executive functions, and verbal memory were also administered. RESULTS: There were no differences between groups on emotion recognition or ToM. The CHF group's performance was poorer on some executive measures, but memory was relatively preserved. In the CHF group, both emotion recognition performance and ToM ability correlated moderately with global cognition (r = .38, p = .034; r = .49, p = .005, respectively), but not with executive function or verbal memory. CONCLUSION: CHF patients with lower cognitive ability were more likely to have difficulty recognizing emotions and inferring the mental states of others. Clinical implications of these findings are discussed. PMID- 26529411 TI - Adipose Mesenchymal Stem Cell Secretome Modulated in Hypoxia for Remodeling of Radiation-Induced Salivary Gland Damage. AB - BACKGROUND AND PURPOSE: This study was conducted to determine whether a secretome from mesenchymal stem cells (MSC) modulated by hypoxic conditions to contain therapeutic factors contributes to salivary gland (SG) tissue remodeling and has the potential to improve irradiation (IR)-induced salivary hypofunction in a mouse model. MATERIALS AND METHODS: Human adipose mesenchymal stem cells (hAdMSC) were isolated, expanded, and exposed to hypoxic conditions (O2 < 5%). The hypoxia conditioned medium was then filtered to a high molecular weight fraction and prepared as a hAdMSC secretome. The hAdMSC secretome was subsequently infused into the tail vein of C3H mice immediately after local IR once a day for seven consecutive days. The control group received equal volume (500 MUL) of vehicle (PBS) only. SG function and structural tissue remodeling by the hAdMSC secretome were investigated. Human parotid epithelial cells (HPEC) were obtained, expanded in vitro, and then irradiated and treated with either the hypoxia-conditioned medium or a normoxic control medium. Cell proliferation and IR-induced cell death were examined to determine the mechanism by which the hAdMSC secretome exerted its effects. RESULTS: The conditioned hAdMSC secretome contained high levels of GM-CSF, VEGF, IL-6, and IGF-1. Repeated systemic infusion with the hAdMSC secretome resulted in improved salivation capacity and increased levels of salivary proteins, including amylase and EGF, relative to the PBS group. The microscopic structural integrity of SG was maintained and salivary epithelial (AQP-5), endothelial (CD31), myoepithelial (alpha-SMA) and SG progenitor cells (c Kit) were successfully protected from radiation damage and remodeled. The hAdMSC secretome strongly induced proliferation of HPEC and led to a significant decrease in cell death in vivo and in vitro. Moreover, the anti-apoptotic effects of the hAdMSC secretome were found to be promoted after hypoxia-preconditioning relative to normoxia-cultured hAdMSC secretome. CONCLUSION: These results show that the hAdMSC secretome from hypoxic-conditioned medium may provide radioprotection and tissue remodeling via release of paracrine mediators. PMID- 26529412 TI - Mild Traumatic Brain Injury Decreases Broadband Power in Area CA1. AB - Cognitive impairment caused by traumatic brain injury (TBI) can lead to devastating consequences for both patients and their families. The underlying neurological basis for TBI-induced cognitive dysfunction remains unknown. However, many lines of research have implicated the hippocampus in the pathophysiology of TBI. In particular, past research has found that theta oscillations, long thought to be the electrophysiological basis of learning and memory, are decreased in the hippocampus post-TBI. Here, we recorded in vivo electrophysiological activity in the hippocampi of 16 mice, 8 of which had previously undergone a TBI. Consistent with previous data, we found that theta power in the hippocampus was decreased in TBI animals compared to sham controls; however, this effect was driven by changes in broadband power and not theta oscillations. This result suggests that broadband fluctuations in the hippocampal local field potential can be used as an electrophysiological surrogate of abnormal neurological activity post-TBI. PMID- 26529413 TI - Correction: Low Serum High Density Lipoprotein Cholesterol Concentration is an Independent Predictor for Enhanced Inflammation and Endothelial Activation. PMID- 26529414 TI - Mechanical Predictors of Discomfort during Load Carriage. AB - Discomfort during load carriage is a major issue for activities using backpacks (e.g. infantry maneuvers, children carrying school supplies, or outdoor sports). It is currently unclear which mechanical parameters are responsible for subjectively perceived discomfort. The aim of this study was to identify objectively measured mechanical predictors of discomfort during load carriage. We compared twelve different configurations of a typical load carriage system, a commercially available backpack with a hip belt. The pressure distribution under the hip belt and the shoulder strap, as well as the tensile force in the strap and the relative motion of the backpack were measured. Multiple linear regression analyses were conducted to investigate possible predictors of discomfort. The results demonstrate that static peak pressure, or alternatively, static strap force is a significant (p<0.001) predictor of discomfort during load carriage in the shoulder and hip region, accounting for 85% or more of the variation in discomfort. As an additional finding, we discovered that the regression coefficients of these predictors are significantly smaller for the hip than for the shoulder region. As static peak pressure is measured directly on the body, it is less dependent on the type of load carriage system than static strap force. Therefore, static peak pressure is well suited as a generally applicable, objective mechanical parameter for the optimization of load carriage system design. Alternatively, when limited to load carriage systems of the type backpack with hip belt, static strap force is the most valuable predictor of discomfort. The regionally differing regression coefficients of both predictors imply that the hip region is significantly more tolerant than the shoulder region. In order to minimize discomfort, users should be encouraged to shift load from the shoulders to the hip region wherever possible, at the same time likely decreasing the risk of low back pain or injury. PMID- 26529417 TI - Surface-enhanced Raman spectroscopy of novel psychoactive substances using polymer-stabilized Ag nanoparticle aggregates. AB - A set of seized "legal high" samples and pure novel psychoactive substances have been examined by surface-enhanced Raman spectroscopy using polymer-stabilized Ag nanoparticle (Poly-SERS) films. The films both quenched fluorescence in bulk samples and allowed identification of MUg quantities of drugs collected with wet swabs from contaminated surfaces. PMID- 26529415 TI - Differential microRNA Expression in Fast- and Slow-Twitch Skeletal Muscle of Piaractus mesopotamicus during Growth. AB - Pacu (Piaractus mesopotamicus) is a Brazilian fish with a high economic value in pisciculture due to its rusticity and fast growth. Postnatal growth of skeletal muscle in fish occurs by hyperplasia and/or hypertrophy, processes that are dependent on the proliferation and differentiation of myoblasts. A class of small noncoding RNAs, known as microRNAs (miRNAs), represses the expression of target mRNAs, and many studies have demonstrated that miR-1, miR-133, miR-206 and miR 499 regulate different processes in skeletal muscle through the mRNA silencing of hdac4 (histone deacetylase 4), srf (serum response factor), pax7 (paired box 7) and sox6 ((sex determining region Y)-box 6), respectively. The aim of our work was to evaluate the expression of these miRNAs and their putative target mRNAs in fast- and slow-twitch skeletal muscle of pacu during growth. We used pacus in three different development stages: larval (aged 30 days), juvenile (aged 90 days and 150 days) and adult (aged 2 years). To complement our study, we also performed a pacu myoblast cell culture, which allowed us to investigate miRNA expression in the progression from myoblast proliferation to differentiation. Our results revealed an inverse correlation between the expression of the miRNAs and their target mRNAs, and there was evidence that miR-1 and miR-206 may regulate the differentiation of myoblasts, whereas miR-133 may regulate the proliferation of these cells. miR-499 was highly expressed in slow-twitch muscle, which suggests its involvement in the specification of the slow phenotype in muscle fibers. The expression of these miRNAs exhibited variations between different development stages and between distinct muscle twitch phenotypes. This work provides the first identification of miRNA expression profiles in pacu skeletal muscle and suggests an important role of these molecules in muscle growth and in the maintenance of the muscle phenotype. PMID- 26529416 TI - Interferon-alpha Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms. AB - HIV-1 is transmitted primarily across mucosal surfaces and rapidly spreads within the intestinal mucosa during acute infection. The type I interferons (IFNs) likely serve as a first line of defense, but the relative expression and antiviral properties of the 12 IFNalpha subtypes against HIV-1 infection of mucosal tissues remain unknown. Here, we evaluated the expression of all IFNalpha subtypes in HIV-1-exposed plasmacytoid dendritic cells by next-generation sequencing. We then determined the relative antiviral potency of each IFNalpha subtype ex vivo using the human intestinal Lamina Propria Aggregate Culture model. IFNalpha subtype transcripts from the centromeric half of the IFNA gene complex were highly expressed in pDCs following HIV-1 exposure. There was an inverse relationship between IFNA subtype expression and potency. IFNalpha8, IFNalpha6 and IFNalpha14 were the most potent in restricting HIV-1 infection. IFNalpha2, the clinically-approved subtype, and IFNalpha1 were both highly expressed but exhibited relatively weak antiviral activity. The relative potencies correlated with binding affinity to the type I IFN receptor and the induction levels of HIV-1 restriction factors Mx2 and Tetherin/BST-2 but not APOBEC3G, F and D. However, despite the lack of APOBEC3 transcriptional induction, the higher relative potency of IFNalpha8 and IFNalpha14 correlated with stronger inhibition of virion infectivity, which is linked to deaminase independent APOBEC3 restriction activity. By contrast, both potent (IFNalpha8) and weak (IFNalpha1) subtypes significantly induced HIV-1 GG-to-AG hypermutation. The results unravel non-redundant functions of the IFNalpha subtypes against HIV 1 infection, with strong implications for HIV-1 mucosal immunity, viral evolution and IFNalpha-based functional cure strategies. PMID- 26529418 TI - Clinical Outcomes in Patients with Severe Renal Dysfunction Including Dialysis Following Defibrillator Implantation. AB - BACKGROUND: Renal dysfunction is associated with increased mortality in heart failure (HF) patients. However, there are limited data regarding clinical and arrhythmic outcomes associated with implantable cardioverter defibrillator (ICD) therapy in this population. METHODS: We evaluated outcomes associated with the severity of renal dysfunction with or without dialysis among 2,289 patients who were enrolled and prospectively followed up in the Israeli ICD Registry. The primary endpoint of the study was all-cause mortality. Secondary endpoints included cardiac mortality, HF hospitalization, non-cardiac hospitalization, and appropriate and inappropriate ICD therapy. RESULTS: Severe renal dysfunction patients (estimated glomerular filtration rate<30 ml/min/1.73 m2; n=144 patients; 6%) were older, with higher comorbidities prevalence, and more likely to suffer from advanced HF. Among severe renal dysfunction patients, those on dialysis had a lower prevalence of wide QRS and complete left bundle branch morphology, resulting in lower cardiac resynchronization therapy defibrillator (CRTD) implantation rates. Dialysis was associated with an overall increased risk for all-cause mortality (hazard ratio (HR) 3.22; 95% CI 1.69-6.13; p<0.01) and for noncardiac hospitalizations (HR 2.80; p<0.001) compared to all other study patients. However, within the subgroup of patients with severe renal dysfunction, the presence of dialysis was not an independent risk factor for all-cause mortality (HR 0.99; p=0.97) as compared to non-dialysis. The rate of appropriate ICD therapy for ventricular tachyarrhythmias increased with declining renal function, with the highest rate observed among those undergoing dialysis. CONCLUSIONS: The present findings suggest that dialysis does not significantly modify the adverse outcomes associated with severe renal dysfunction following ICD/CRTD implantation. PMID- 26529419 TI - Measuring Alcohol-Specific Communication with Friends: Conceptualizing and Operationalizing Communication as Multidimensional. AB - According to primary socialization theory, adolescents develop beliefs about alcohol by interacting with peers, as well as other socialization agents. Although communication is essential to this belief-formation process, few studies have identified the specific alcohol-related messages that adolescents exchange with their peers, and more specifically friends, that lead to certain anti- and/or pro-alcohol-related beliefs. Consequently, the goal of this study was to develop a multidimensional measure of alcohol-specific communication with friends. Based on survey data from 259 high school students, the results indicated that communication with friends involving warnings against drinking alcohol, disapproval of alcohol consumption, and making fun of others for drinking alcohol was negatively related to pro-alcohol beliefs and intentions. Communication with friends involving rumors, teasing each other about drinking alcohol, intentions to drink alcohol, different types of alcohol, experiences with alcohol, and talking about how many peers drink alcohol was positively related to pro-alcohol beliefs and intentions. PMID- 26529420 TI - Decision-Making Process Related to Participation in Phase I Clinical Trials: A Nonsystematic Review of the Existing Evidence. AB - Due to the lack of other treatment options, patient candidates for participation in phase I clinical trials are considered the most vulnerable, and many ethical concerns have emerged regarding the informed consent process used in the experimental design of such trials. Starting with these considerations, this nonsystematic review is aimed at analyzing the decision-making processes underlying patients' decision about whether to participate (or not) in phase I trials in order to clarify the cognitive and emotional aspects most strongly implicated in this decision. Considering that there is no uniform decision calculus and that many different variables other than the patient-physician relationship (including demographic, clinical, and personal characteristics) may influence patients' preferences for and processing of information, we conclude that patients' informed decision-making can be facilitated by creating a rigorously developed, calibrated, and validated computer tool modeled on each single patient's knowledge, values, and emotional and cognitive decisional skills. Such a tool will also help oncologists to provide tailored medical information that is useful to improve the shared decision-making process, thereby possibly increasing patient participation in clinical trials. PMID- 26529422 TI - Neural mediator of the schizotypy-antisocial behavior relationship. AB - Prior studies have established that schizotypal personality traits (schizotypy) were associated with antisocial behavior (crime), but it is unclear what neural factors mediate this relationship. This study assessed the mediating effect that sub-regional prefrontal gray, specifically the orbitofrontal gray matter volume, has on the schizotypy-antisocial behavior relationship. Five prefrontal sub regional (superior, middle, inferior, orbitofrontal and rectal gyral) gray matter volumes were assessed using structural magnetic resonance imaging in 90 adults from the community, together with schizotypy and antisocial behavior. Among all five prefrontal sub-regions, the orbitofrontal cortex (OFC) was the major region of-interest in the present study. Mediation analyses showed that orbitofrontal gray fully mediated the association between schizotypy and antisocial behavior. After having controlled the sex, age, socio-economic statuses, whole brain volumes and substance abuse/dependence of test subjects, the orbitofrontal gray still significantly mediated the effect of schizotypy on antisocial behavior by 53.5%. These findings are the first that document a neural mediator of the schizotypy-antisocial behavior relationship. Findings also suggest that functions subserved by the OFC, including impulse control and inhibition, emotion processing and decision-making, may contribute to the above comorbidity. PMID- 26529423 TI - Motivation and value influences in the relative balance of goal-directed and habitual behaviours in obsessive-compulsive disorder. AB - Our decisions are based on parallel and competing systems of goal-directed and habitual learning, systems which can be impaired in pathological behaviours. Here we focus on the influence of motivation and compare reward and loss outcomes in subjects with obsessive-compulsive disorder (OCD) on model-based goal-directed and model-free habitual behaviours using the two-step task. We further investigate the relationship with acquisition learning using a one-step probabilistic learning task. Forty-eight OCD subjects and 96 healthy volunteers were tested on a reward and 30 OCD subjects and 53 healthy volunteers on the loss version of the two-step task. Thirty-six OCD subjects and 72 healthy volunteers were also tested on a one-step reversal task. OCD subjects compared with healthy volunteers were less goal oriented (model-based) and more habitual (model-free) to reward outcomes with a shift towards greater model-based and lower habitual choices to loss outcomes. OCD subjects also had enhanced acquisition learning to loss outcomes on the one-step task, which correlated with goal-directed learning in the two-step task. OCD subjects had greater stay behaviours or perseveration in the one-step task irrespective of outcome. Compulsion severity was correlated with habitual learning in the reward condition. Obsession severity was correlated with greater switching after loss outcomes. In healthy volunteers, we further show that greater reward magnitudes are associated with a shift towards greater goal-directed learning further emphasizing the role of outcome salience. Our results highlight an important influence of motivation on learning processes in OCD and suggest that distinct clinical strategies based on valence may be warranted. PMID- 26529424 TI - A requirement of serotonergic p38alpha mitogen-activated protein kinase for peripheral immune system activation of CNS serotonin uptake and serotonin-linked behaviors. AB - Alterations in central serotonin (5-hydroxytryptamine, 5-HT) neurotransmission and peripheral immune activation have been linked to multiple neuropsychiatric disorders, including depression, schizophrenia and autism. The antidepressant sensitive 5-HT transporter (SERT, SLC6A4), a critical determinant of synaptic 5 HT inactivation, can be regulated by pro-inflammatory cytokine signaling. Systemic innate immune system activation via intraperitoneal lipopolysaccharide (LPS) injection rapidly elevates brain SERT activity and 5-HT clearance. Moreover, the pro-inflammatory cytokine interleukin (IL)-1beta rapidly stimulates SERT activity in raphe nerve terminal preparations ex vivo, effects that are attenuated by pharmacological p38 MAPK inhibition. To establish a role of serotonergic p38alpha MAPK signaling in LPS/IL-1beta-induced SERT regulation and attendant behavioral responses, we pursued studies in mice that afford conditional elimination of p38alpha MAPK in 5-HT neurons (p38alpha(5HT-)). We found p38alpha(5HT-) and control (p38alpha(5HT+)) littermates to be indistinguishable in viability and growth and to express equivalent levels of SERT protein and synaptosomal 5-HT transport activity. Consistent with pharmacological studies, however, IL-1beta fails to increase SERT activity in midbrain synaptosomes prepared from p38alpha(5HT-) animals. Moreover, although LPS elevated plasma corticosterone and central/peripheral pro-inflammatory cytokines in p38alpha(5HT-) animals, elevations in midbrain SERT activity were absent nor were changes in depressive and anxiety-like behaviors observed. Our studies support an obligate role of p38alpha MAPK signaling in 5-HT neurons for the translation of immune activation to SERT regulation and 5-HT-modulated behaviors. PMID- 26529425 TI - A genome-wide association study of antidepressant response in Koreans. PMID- 26529426 TI - Effective emotion regulation strategies improve fMRI and ECG markers of psychopathology in panic disorder: implications for psychological treatment action. AB - Impairments in emotion regulation are thought to have a key role in the pathogenesis of anxiety disorders, but the neurobiological underpinnings contributing to vulnerability remain poorly understood. It has been a long-held view that exaggerated fear is linked to hyperresponsivity of limbic brain areas and impaired recruitment of prefrontal control. However, increasing evidence suggests that prefrontal-cortical networks are hyperactive during threat processing in anxiety disorders. This study directly explored limbic-prefrontal neural response, connectivity and heart-rate variability (HRV) in patients with a severe anxiety disorder during incidental versus intentional emotion regulation. During 3 Tesla functional magnetic resonance imaging, 18 participants with panic disorder and 18 healthy controls performed an emotion regulation task. They either viewed negative images naturally (Maintain), or they were instructed to intentionally downregulate negative affect using previously taught strategies of cognitive reappraisal (Reappraisal). Electrocardiograms were recorded throughout to provide a functional measure of regulation and emotional processing. Compared with controls, patients showed increased neural activation in limbic-prefrontal areas and reduced HRV during incidental emotion regulation (Maintain). During intentional regulation (Reappraisal), group differences were significantly attenuated. These findings emphasize patients' ability to regulate negative affect if provided with adaptive strategies. They also bring prefrontal hyperactivation forward as a potential mechanism of psychopathology in anxiety disorders. Although these results challenge models proposing impaired allocation of prefrontal resources as a key characteristic of anxiety disorders, they are in line with more recent neurobiological frameworks suggesting that prefrontal hyperactivation might reflect increased utilisation of maladaptive regulation strategies quintessential for anxiety disorders. PMID- 26529429 TI - Contents Vol. 231, 2015. PMID- 26529427 TI - Neuroplasticity-dependent and -independent mechanisms of chronic deep brain stimulation in stressed rats. AB - Chronic ventromedial prefrontal cortex (vmPFC) deep brain stimulation (DBS) improves depressive-like behaviour in rats via serotonergic and neurotrophic related mechanisms. We hypothesise that, in addition to these substrates, DBS induced increases in hippocampal neurogenesis may also be involved. Our results show that stress-induced behavioural deficits in the sucrose preference test, forced swim test, novelty-suppressed feeding test (NSFT) and elevated plus maze were countered by chronic vmPFC DBS. In addition, stressed rats receiving stimulation had significant increases in hippocampal neurogenesis, PFC and hippocampal brain-derived neurotrophic factor levels. To block neurogenesis, stressed animals given DBS were injected with temozolomide. Such treatment reversed the anxiolytic-like effect of stimulation in the NSFT without significantly affecting performance in other behavioural tests. Taken together, our findings suggest that neuroplastic changes, including neurogenesis, may be involved in specific anxiolytic effects of DBS without affecting its general antidepressant-like response. PMID- 26529430 TI - Biomechanics of Hybrid Anterior Cervical Fusion and Artificial Disc Replacement in 3-Level Constructs: An In Vitro Investigation. AB - BACKGROUND: The ideal surgical approach for cervical disk disease remains controversial, especially for multilevel cervical disease. The purpose of this study was to investigate the biomechanics of the cervical spine after 3-level hybrid surgery compared with 3-level anterior cervical discectomy and fusion (ACDF). MATERIAL AND METHODS: Eighteen human cadaveric spines (C2-T1) were evaluated under displacement-input protocol. After intact testing, a simulated hybrid construct or fusion construct was created between C3 to C6 and tested in the following 3 conditions: 3-level disc plate disc (3DPD), 3-level plate disc plate (3PDP), and 3-level plate (3P). RESULTS: Compared to intact, almost 65~80% of motion was successfully restricted at C3-C6 fusion levels (p<0.05). 3DPD construct resulted in slight increase at the 3 instrumented levels (p>0.05). 3PDP construct resulted in significant decrease of ROM at C3-C6 levels less than 3P (p<0.05). Both 3DPD and 3PDP caused significant reduction of ROM at the arthrodesis level and produced motion increase at the arthroplasty level. For adjacent levels, 3P resulted in markedly increased contribution of both upper and lower adjacent levels (p<0.05). Significant motion increases lower than 3P were only noted at partly adjacent levels in some conditions for 3DPD and 3PDP (p<0.05). CONCLUSIONS: ACDF eliminated motion within the construct and greatly increased adjacent motion. Artificial cervical disc replacement normalized motion of its segment and adjacent segments. While hybrid conditions failed to restore normal motion within the construct, they significantly normalized motion in adjacent segments compared with the 3-level ACDF condition. The artificial disc in 3-level constructs has biomechanical advantages compared to fusion in normalizing motion. PMID- 26529431 TI - Flavones Inhibit the Activity of AKR1B10, a Promising Therapeutic Target for Cancer Treatment. AB - AKR1B10 is an NADPH-dependent reductase that plays an important function in several physiological reactions such as the conversion of retinal to retinol, reduction of isoprenyl aldehydes, and biotransformation of procarcinogens and drugs. A growing body of evidence points to the important role of the enzyme in the development of several types of cancer (e.g., breast, hepatocellular), in which it is highly overexpressed. AKR1B10 is regarded as a therapeutic target for the treatment of these diseases, and potent and specific inhibitors may be promising therapeutic agents. Several inhibitors of AKR1B10 have been described, but the area of natural plant products has been investigated sparingly. In the present study almost 40 diverse phenolic compounds and alkaloids were examined for their ability to inhibit the recombinant AKR1B10 enzyme. The most potent inhibitors-apigenin, luteolin, and 7-hydroxyflavone-were further characterized in terms of IC50, selectivity, and mode of action. Molecular docking studies were also conducted, which identified putative binding residues important for the interaction. In addition, cellular studies demonstrated a significant inhibition of the AKR1B10-mediated reduction of daunorubicin in intact cells by these inhibitors without a considerable cytotoxic effect. Although these compounds are moderately potent and selective inhibitors of AKR1B10, they constitute a new structural type of AKR1B10 inhibitor and may serve as a template for the development of better inhibitors. PMID- 26529432 TI - Blinded Evaluation of Combination Drug Therapy for Prolonged Ventricular Fibrillation Using a Swine Model of Sudden Cardiac Arrest. AB - Despite experimental evidence supporting the use of resuscitation drugs in the treatment of sudden cardiac arrest (CA), there are no good human clinical data to support the decades-old practice of giving these medications during out-of hospital CA resuscitation. We hypothesized that the lack of efficacy in clinical practice in ventricular fibrillation (VF) is the failure-based manner in which resuscitation drugs have historically been administered (one at a time interspersed with chest compressions and a defibrillation attempt, giving the next only if the previous one was ineffective). The aim of this study was to determine if giving and circulating a combination of commonly available, historically used resuscitation drugs together, prior to the first defibrillation attempt after prolonged VF, might improve short-term outcomes compared with the failure-based serial drug approach used in the past. We used a well-established swine model of sudden prolonged untreated VF. Animals were randomized to receive epinephrine (0.01 mg/kg), vasopressin (0.5 U/kg), amiodarone (4 mg/kg), and sodium bicarbonate (1.0 mEq/kg) in series (SERIES group [n = 53]) or a combination of epinephrine (0.01 mg/kg), vasopressin (0.5 U/kg), amiodarone (4 mg/kg), sodium bicarbonate (1.0 mEq/kg), and metoprolol (0.2 mg/kg) (COCKTAIL group) delivered in rapid succession at the beginning of the attempted resuscitation (n = 27). Data were analyzed descriptively. Baseline characteristics and chemistries between the two groups were the same. Termination of VF was statistically similar in the two groups: 88.7% (47/53) versus 85.2% (23/27) p = 0.66, with an adjusted relative risk ratio (RRR) of 0.94 (0.37, 1.15). However, ROSC was higher in the SERIES group (56.6% [30/53] versus 22.2% [6/27], adjusted RRR = 2.83; [1.16, 3.84] p = 0.029) as was 20-minute survival (52.8% [28/53] versus 18.5% [5/27], adjusted RRR = 3.15 [1.14, 4.54] p = 0.032). The combination of drugs studied, at these dosages, inexplicably worsened short term outcomes after prolonged untreated VF. PMID- 26529433 TI - Stepwise surgical approach to equinocavovarus in patients with cerebral palsy. AB - This study investigated the radiologic results of a stepwise surgical approach to equinocavovarus in 24 patients with cerebral palsy and determined the extent to which each procedure affected radiographic parameters using a linear mixed model. The anteroposterior talus-first metatarsal and anteroposterior talonavicular coverage angles were improved. The calcaneal pitch angle, tibiocalcaneal angle, lateral talus-first metatarsal angle, and naviculocuboid overlap were also improved. The Dwyer sliding osteotomy affected the tibiocalcaneal angle, whereas first metatarsal dorsal wedge osteotomy improved the calcaneal pitch angle and lateral first metatarsal angle. The stepwise surgical approach is effective for correction of equinocavovarus in cerebral palsy patients. PMID- 26529434 TI - Isomerism of Cyanomethanimine: Accurate Structural, Energetic, and Spectroscopic Characterization. AB - The structures, relative stabilities, and rotational and vibrational parameters of the Z-C-, E-C-, and N-cyanomethanimine isomers have been evaluated using state of-the-art quantum-chemical approaches. Equilibrium geometries have been calculated by means of a composite scheme based on coupled-cluster calculations that accounts for the extrapolation to the complete basis set limit and core correlation effects. The latter approach is proved to provide molecular structures with an accuracy of 0.001-0.002 A and 0.05-0.1 degrees for bond lengths and angles, respectively. Systematically extrapolated ab initio energies, accounting for electron correlation through coupled-cluster theory, including up to single, double, triple, and quadruple excitations, and corrected for core electron correlation and anharmonic zero-point vibrational energy, have been used to accurately determine relative energies and the Z-E isomerization barrier with an accuracy of about 1 kJ/mol. Vibrational and rotational spectroscopic parameters have been investigated by means of hybrid schemes that allow us to obtain rotational constants accurate to about a few megahertz and vibrational frequencies with a mean absolute error of ~1%. Where available, for all properties considered, a very good agreement with experimental data has been observed. PMID- 26529436 TI - The great fluid debate: methodology, physiology and appendicitis. PMID- 26529437 TI - Accuracy of the Spacelabs 90217 ambulatory blood pressure monitor in a pediatric population. AB - BACKGROUND: Ambulatory blood pressure monitoring techniques provide unique advantages for diagnosing hypertension, although few devices have been independently validated in the pediatric population. METHODS: We sought to validate the accuracy of ambulatory blood pressure monitoring with the Spacelabs 90217 monitor in children using a modified British Hypertension Society protocol. RESULTS: A total of 112 children, aged between 6 and 17 years, completed the study at one of the three participating centers. Overall, the monitor earned an 'A' for systolic blood pressure and 'B' for diastolic blood pressure. It performed slightly better among 6-12 year olds (A/A) compared with 13-17 year olds (A/B). CONCLUSIONS: We conclude that the Spacelabs 90217 monitor is an appropriate monitor for use in children who are 6 years of age or older. PMID- 26529438 TI - ATTENUATION OF THE GANGLION CELL LAYER IN A PREMATURE INFANT REVEALED WITH HANDHELD SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To report on subclinical retinal abnormalities shown through handheld spectral domain optical coherence tomography on a premature infant. METHODS: Case report. RESULTS: The initial and follow-up exams on a premature infant revealed severely attenuated ganglion cell and nerve fiber layers. There was cystoid macular edema in both eyes at the initial visits, which resolved by the 1-year follow-up. DISCUSSION: Optical coherence tomography can reveal significant retinal abnormalities in premature infants which are not detectable through funduscopic exam. Documenting such findings may be useful for the comprehensive management of vision problems in children with a history of premature birth. PMID- 26529439 TI - Efficient resting-state EEG network facilitates motor imagery performance. AB - OBJECTIVE: Motor imagery-based brain-computer interface (MI-BCI) systems hold promise in motor function rehabilitation and assistance for motor function impaired people. But the ability to operate an MI-BCI varies across subjects, which becomes a substantial problem for practical BCI applications beyond the laboratory. APPROACH: Several previous studies have demonstrated that individual MI-BCI performance is related to the resting state of brain. In this study, we further investigate offline MI-BCI performance variations through the perspective of resting-state electroencephalography (EEG) network. MAIN RESULTS: Spatial topologies and statistical measures of the network have close relationships with MI classification accuracy. Specifically, mean functional connectivity, node degrees, edge strengths, clustering coefficient, local efficiency and global efficiency are positively correlated with MI classification accuracy, whereas the characteristic path length is negatively correlated with MI classification accuracy. The above results indicate that an efficient background EEG network may facilitate MI-BCI performance. Finally, a multiple linear regression model was adopted to predict subjects' MI classification accuracy based on the efficiency measures of the resting-state EEG network, resulting in a reliable prediction. SIGNIFICANCE: This study reveals the network mechanisms of the MI-BCI and may help to find new strategies for improving MI-BCI performance. PMID- 26529440 TI - Power and Greed. PMID- 26529442 TI - Polypharmacy in Older Adults. AB - Polypharmacy, by definition, is the concurrent use of several different medications consumed by a person. Often these multiple medications are in the same class and are used to treat more than one chronic condition. Older individuals are often faced with issues of polypharmacy due to multiple chronic conditions and multiple providers. The risks associated with polypharmacy can lead to increased adverse effects, falls, and decreased risk of medication compliance. This paper will discuss the issues surrounding polypharmacy and provide a case example to illustrate the significance of this problem. PMID- 26529444 TI - Impact of APN Home Visits in Reducing Healthcare Costs and Improving Function in Homebound Heart Failure. AB - By providing quality primary care in the home setting, nurse practitioners can treat homebound patients effectively and decrease the number of hospitalizations, 30-day readmissions, and emergency department visits. Forty patients with a diagnosis of Class III or IV heart failure who were homebound were chosen for this project. The project manager, an Adult-Gerontological nurse practitioner, made home visits to these patients on a monthly and as-needed basis throughout the 3-month project. The rate of hospital admissions, emergency department visits, and 30-day readmissions was reduced by 64%, 85%, and 95%, respectively. Patients were assessed using the Kansas City Cardiomyopathy Questionnaire (Green et al., 2000) at the initial visit and at 3 months. The scoring for physical functionality, symptom frequency, and quality of life were improved by 44%, 40%, and 54%, respectively. PMID- 26529445 TI - Overview of Glucagon-like Peptide-1 Receptor Agonists. AB - Type 2 diabetes mellitus is an increasingly prevalent disease in the United States and globally. Multiple pharmacologic therapies are typically required over time to achieve and maintain target blood glucose levels. When first-line oral medications such as metformin (Glucophage) are not effective in achieving desired glycosylated hemoglobin (HbA1C) levels, glucagon-like peptide-1 receptor agonists may be used. This article provides an overview of this class of agents and provides implications for home healthcare clinicians. PMID- 26529446 TI - Rethinking Care Coordination: Paradigm Shifting From Volume to Value. AB - Although care coordination is not a new concept, it has been fraught with a myriad of definitions. Among these, core themes can be gleaned to help the home healthcare clinician understand their role and responsibilities as part of a high functioning team. For a shift from volume to value to occur, in a way that is meaningful to the patient, a holistic paradigm needs to be fully embraced by all members of the interdisciplinary team. As healthcare continues to shift to a fair market demand for services system, transparency becomes a driver for patient information and choice. Care coordination, clinical outcomes, and consumerism in this new era become integrally linked. Home care clinicians have a higher level of accountability to deliver patient-centered care that necessitates shifting from a "disease state" mentality to a view that encompasses mind, body, and spirit in totality. Home healthcare agencies will need to view their own organization as occurring within a maturation cycle of interdisciplinary team development and continually strive for exceptional care delivery, transparency in outcomes, and full team collaboration with a holistic mindset, in order to make the shift from volume to value that will be necessary to thrive. PMID- 26529447 TI - Diabetes and Nephropathy. PMID- 26529448 TI - Check That Ambien Dose. PMID- 26529449 TI - Monitoring and Managing Ill Home Care and Hospice Staff. PMID- 26529450 TI - A Day in the Life of a Nurse Practitioner Who Performs In-Home Physical Exams. PMID- 26529451 TI - 7 Myths About Physical Therapy. PMID- 26529452 TI - An Interview With Deputy Chief, Health Care Fraud Unit at the U.S. Attorney's Office. PMID- 26529453 TI - Certification for Home Care Nurses: It Needs to Happen. PMID- 26529454 TI - Sequence Variation in the Response Element Determines Binding by the Transcription Factor p73. AB - How the sequence of a response element affects the binding of a transcription factor and, ultimately, the differential rate of transcription of genes under its control is not well-understood. In the case of the p73 transcription factor, it binds to >200 response elements to trigger developmental, cell arrest, and apoptotic pathways. The p73 response elements match the 20 bp consensus sequence of the p53 response elements that are formed by two 10 bp half-sites, where each half-site is an inverted repeat of two 5 bp quarter-sites. Using sedimentation velocity and fluorescence anisotropy experiments, we studied how systematic variations in the sequence of a half-site response element modify the DNA binding affinity of the p73 DNA-binding domain. We observed that each nucleotide position in the response element has a different influence in determining the binding of the p73 DNA-binding domain. The cytosine in the fourth position of each quarter site is the largest determinant of DNA binding, followed by the nucleotide in the fifth position, and last, the first three positions show a slight regulatory preference for purines. Together with previous structural and functional results, our data suggest a hierarchical model of binding in which some nucleotide positions in the response element are more important than others in determining the binding of the transcription factor. PMID- 26529455 TI - Normal limits for serum thyrotropin vary greatly depending on method. AB - CONTEXT: Thyroid-stimulating hormone (TSH) levels within populations do not follow Gaussian distribution, and normal limits are derived after mathematical normalization. The clinical relevance of these limits is unknown. The objective of this study was to compare upper and lower TSH limits by four data normalization methods with non-normalized data and assess their clinical relevance. DESIGN, PATIENTS AND MEASUREMENTS: Results of blood samples taken by community physicians and stored in a computerized database were analysed after removing samples from patients with evidence of thyroid illness. TSH values were normalized by the Hoffmann and Tukey methods and each method with natural log transformation. Non-normalized data for TSH in the uppermost and lowermost percentile were also calculated. Clinical relevance was determined by alterations in thyroid hormone levels at, below and above the limits for each method. RESULTS: The maximal reduction from non-normalized data for the upper normal limit (UNL) was by the Hoffman method 43% = 3.1 mIU/l). The maximal increase for the lower normal limit (LNL) was also by the Hoffman method (708% = 0.81 mIU/l). There was very limited difference in average FT3 and FT4 between patients with TSH within, below or above the normal range for all methods. CONCLUSIONS: Different normalization methods alter the normal limits greatly. However, in individuals without thyroid illness, thyroid hormone values are stable over a wide range of TSH levels including beyond the UNL for all methods. Indeed, there may be no true universal upper TSH cut-off level and clinical decision-making cannot rely on these calculated limits. PMID- 26529456 TI - Breast reconstruction with the deep inferior epigastric perforator flap is a reliable alternative in slim patients. AB - INTRODUCTION: For slim patients eligible to breast reconstruction, clinical concerns exist on availability of adequate amount of donor tissue to restore breast volume and challenges in donor-site closure, when using the deep inferior epigastric perforator (DIEP) flap. The purpose of the current study is to analyze whether the DIEP flap can provide adequate volume for breast reconstruction in slim patients, without increased complication rates or prolonged hospital stay. PATIENTS AND METHODS: All patients receiving a unilateral DIEP breast reconstruction at the center 2007-2010 were included (n = 171). The patients were analyzed in subgroups of delayed and immediate reconstruction and of BMI. Complications were analyzed according to Clavien-Dindo. Flap weight was compared to mastectomy specimen weight among immediate reconstructions (n = 91). RESULTS: There was no difference in specimen to flap weight ratio between the different BMI-groups (BMI <25, 25-29.9 and >30: 0.81, 0.87 and 0.96 respectively, P = 0.360. Overall complication rate was 43.1% (BMI <25); 43.0% (BMI 25-29.9): and 70.0% (BMI >30) (P = 0.018). The results were similar for both the immediate and the delayed reconstructions. Length of hospital stay was similar in the different BMI groups. Delayed donor-site healing was higher in patients with BMI <25; 17.2%, compared to patients with BMI 25-29.9; 11.8%, but lower than for patients with BMI >30; 29.7% (P = 0.033). CONCLUSION: The DIEP flap provides adequate volume for unilateral breast reconstruction in slim patients, both in immediate and delayed settings. However, in delayed reconstructions slim patients need to be informed about the increased risk of donor-site complications. (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:552-558, 2016. PMID- 26529457 TI - SmartColor: Real-Time Color and Contrast Correction for Optical See-Through Head Mounted Displays. AB - Users of optical see-through head-mounted displays (OHMD) perceive color as a blend of the display color and the background. Color-blending is a major usability challenge as it leads to loss of color encodings and poor text legibility. Color correction aims at mitigating color blending by producing an alternative color which, when blended with the background, more closely approximates the color originally intended. In this paper we present an end-to end approach to the color blending problem addressing the distortions introduced by the transparent material of the display efficiently and in real time. We also present a user evaluation of correction efficiency. Finally, we present a graphics library called SmartColor showcasing the use of color correction for different types of display content. SmartColor uses color correction to provide three management strategies: correction, contrast, and show-up-on-contrast. Correction determines the alternate color which best preserves the original color. Contrast determines the color which best supports text legibility while preserving as much of the original hue. Show-up-on-contrast makes a component visible when a related component does not have enough contrast to be legible. We describe SmartColor's architecture and illustrate the color strategies for various types of display content. PMID- 26529458 TI - Interactive Near-Field Illumination for Photorealistic Augmented Reality with Varying Materials on Mobile Devices. AB - At present, photorealistic augmentation is not yet possible since the computational power of mobile devices is insufficient. Even streaming solutions from stationary PCs cause a latency that affects user interactions considerably. Therefore, we introduce a differential rendering method that allows for a consistent illumination of the inserted virtual objects on mobile devices, avoiding delays. The computation effort is shared between a stationary PC and the mobile devices to make use of the capacities available on both sides. The method is designed such that only a minimum amount of data has to be transferred asynchronously between the participants. This allows for an interactive illumination of virtual objects with a consistent appearance under both temporally and spatially varying real illumination conditions. To describe the complex near-field illumination in an indoor scenario, HDR video cameras are used to capture the illumination from multiple directions. In this way, sources of illumination can be considered that are not directly visible to the mobile device because of occlusions and the limited field of view. While our method focuses on Lambertian materials, we also provide some initial approaches to approximate non diffuse virtual objects and thereby allow for a wider field of application at nearly the same cost. PMID- 26529459 TI - Monocular 3D Reconstruction and Augmentation of Elastic Surfaces with Self Occlusion Handling. AB - This paper focuses on the 3D shape recovery and augmented reality on elastic objects with self-occlusions handling, using only single view images. Shape recovery from a monocular video sequence is an underconstrained problem and many approaches have been proposed to enforce constraints and resolve the ambiguities. State-of-the art solutions enforce smoothness or geometric constraints, consider specific deformation properties such as inextensibility or resort to shading constraints. However, few of them can handle properly large elastic deformations. We propose in this paper a real-time method that uses a mechanical model and able to handle highly elastic objects. The problem is formulated as an energy minimization problem accounting for a non-linear elastic model constrained by external image points acquired from a monocular camera. This method prevents us from formulating restrictive assumptions and specific constraint terms in the minimization. In addition, we propose to handle self-occluded regions thanks to the ability of mechanical models to provide appropriate predictions of the shape. Our method is compared to existing techniques with experiments conducted on computer-generated and real data that show the effectiveness of recovering and augmenting 3D elastic objects. Additionally, experiments in the context of minimally invasive liver surgery are also provided and results on deformations with the presence of self-occlusions are exposed. PMID- 26529460 TI - Active Exploration of Large 3D Model Repositories. AB - With broader availability of large-scale 3D model repositories, the need for efficient and effective exploration becomes more and more urgent. Existing model retrieval techniques do not scale well with the size of the database since often a large number of very similar objects are returned for a query, and the possibilities to refine the search are quite limited. We propose an interactive approach where the user feeds an active learning procedure by labeling either entire models or parts of them as "like" or "dislike" such that the system can automatically update an active set of recommended models. To provide an intuitive user interface, candidate models are presented based on their estimated relevance for the current query. From the methodological point of view, our main contribution is to exploit not only the similarity between a query and the database models but also the similarities among the database models themselves. We achieve this by an offline pre-processing stage, where global and local shape descriptors are computed for each model and a sparse distance metric is derived that can be evaluated efficiently even for very large databases. We demonstrate the effectiveness of our method by interactively exploring a repository containing over 100 K models. PMID- 26529461 TI - An Automated Approach for Slicing Plane Placement in Visual Data Analysis. AB - Effective display and visual analysis of complex 3D data is a challenging task. Occlusions, overlaps, and projective distortions-as frequently caused by typical 3D rendering techniques-can be major obstacles to unambiguous and robust data analysis. Slicing planes are a ubiquitous tool to resolve several of these issues. They act as simple clipping geometry to provide clear cut-away views of the data. We propose to enhance the visualization and analysis process by providing methods for automatic placement of such slicing planes based on local optimization of gradient vector flow. The final obtained slicing planes maximize the total amount of information displayed with respect to a pre-specified importance function. We demonstrate how such automated slicing plane placement is able to support and enrich 3D data visualization and analysis in multiple scenarios, such as volume or surface rendering, and evaluate its performance in several benchmark data sets. PMID- 26529462 TI - Morphable Word Clouds for Time-Varying Text Data Visualization. AB - A word cloud is a visual representation of a collection of text documents that uses various font sizes, colors, and spaces to arrange and depict significant words. The majority of previous studies on time-varying word clouds focuses on layout optimization and temporal trend visualization. However, they do not fully consider the spatial shapes and temporal motions of word clouds, which are important factors for attracting people's attention and are also important cues for human visual systems in capturing information from time-varying text data. This paper presents a novel method that uses rigid body dynamics to arrange multi temporal word-tags in a specific shape sequence under various constraints. Each word-tag is regarded as a rigid body in dynamics. With the aid of geometric, aesthetic, and temporal coherence constraints, the proposed method can generate a temporally morphable word cloud that not only arranges word-tags in their corresponding shapes but also smoothly transforms the shapes of word clouds over time, thus yielding a pleasing time-varying visualization. Using the proposed frame-by-frame and morphable word clouds, people can observe the overall story of a time-varying text data from the shape transition, and people can also observe the details from the word clouds in frames. Experimental results on various data demonstrate the feasibility and flexibility of the proposed method in morphable word cloud generation. In addition, an application that uses the proposed word clouds in a simulated exhibition demonstrates the usefulness of the proposed method. PMID- 26529463 TI - Latency in Distributed Acquisition and Rendering for Telepresence Systems. AB - Telepresence systems use 3D techniques to create a more natural human-centered communication over long distances. This work concentrates on the analysis of latency in telepresence systems where acquisition and rendering are distributed. Keeping latency low is important to immerse users in the virtual environment. To better understand latency problems and to identify the source of such latency, we focus on the decomposition of system latency into sub-latencies. We contribute a model of latency and show how it can be used to estimate latencies in a complex telepresence dataflow network. To compare the estimates with real latencies in our prototype, we modify two common latency measurement methods. This presented methodology enables the developer to optimize the design, find implementation issues and gain deeper knowledge about specific sources of latency. PMID- 26529464 TI - Ingestion of Plastic Microfibers by the Crab Carcinus maenas and Its Effect on Food Consumption and Energy Balance. AB - Microscopic plastic fragments (<5 mm) are a worldwide conservation issue, polluting both coastal and marine environments. Fibers are the most prominent plastic type reported in the guts of marine organisms, but their effects once ingested are unknown. This study investigated the fate of polypropylene rope microfibers (1-5 mm in length) ingested by the crab Carcinus maenas and the consequences for the crab's energy budget. In chronic 4 week feeding studies, crabs that ingested food containing microfibers (0.3-1.0% plastic by weight) showed reduced food consumption (from 0.33 to 0.03 g d(-1)) and a significant reduction in energy available for growth (scope for growth) from 0.59 to -0.31 kJ crab d(-1) in crabs fed with 1% plastic. The polypropylene microfibers were physically altered by their passage through the foregut and were excreted with a smaller overall size and length and amalgamated into distinctive balls. These results support of the emerging paradigm that a key biological impact of microplastic ingestion is a reduction in energy budgets for the affected marine biota. We also provide novel evidence of the biotransformations that can affect the plastics themselves following ingestion and excretion. PMID- 26529465 TI - Interaction Between Human Polyomavirus BK and Hypoxia Inducible Factor-1 alpha. AB - BK polyomavirus (BKV) has a worldwide seroprevalence of approximately 90%. After primary infection, BKV establishes a life-long latency within the urogenital tract. The severe immunological impairment occurring in renal transplant recipients leads to BKV reactivation, which may result in polyomavirus associated nephropathy (PVAN). While the transplanted kidney is transiently unperfused, Hypoxia Inducible Factors (HIFs) mediate the cellular response to hypoxia. The alpha-subunit of HIF isoform 1 (HIF-1alpha) may interact with several viruses, but until now, there has been no information regarding the interaction between BKV and HIF-1alpha. The aim of this study is to investigate the possible interaction between HIF-1alpha and BKV and its potential effect on the pathogenesis of PVAN. Screening of 17 kidney tissue samples revealed that HIF 1alpha expression was 13.6-fold higher in PVAN tissues compared to control tissues. A luminometric assay in co-transfected African green monkey kidney cells (VERO) demonstrated BKV promoter activation ranging from two to sixfold (P < 0.05) when HIF-1alpha was over-expressed. A Chromatin ImmunoPrecipitation (ChIP) assay showed structural binding between the BKV promoter and HIF-1alpha. The amount of BKV DNA increased by threefold in VERO infected cells that were exposed to simulated hypoxia, compared to the cells not subjected to hypoxia. Both ex vivo and in vitro interactions between HIF-1alpha and BKV were observed, suggesting that HIF-1alpha, stabilized during transplantation, may be able to bind the BKV promoter and enhance BKV replication. Thus, hypoxia should be considered a risk factor for the development of PVAN in kidney transplant recipients. PMID- 26529466 TI - Molecular Characterization of Mexican HIV-1 Vif Sequences. AB - The viral infectivity factor (Vif) is an HIV accessory protein that counteracts host antiviral proteins of the APOBEC3 family. Accumulating evidence highlights the pivotal role that accessory HIV proteins have on disease pathogenesis, a fact that has made them targets of interest for novel therapeutic and preventive strategies. Little is known about Vif sequence diversity outside of African or white populations. Mexico is home to Americas' third largest HIV-affected population and Mexican Hispanics represent an ever-increasing U.S. minority. This study provides a detailed analysis of the diversity seen in 77 Mexican Vif protein sequences. Phylogenetic analysis shows that most sequences cluster with HIV-1 subtype B, while less than 10% exhibit greater similarity to subtype D and A subtypes. Although most functional motifs are conserved among the Mexican sequences, substantial diversity was seen in some APOBEC binding sites, the nuclear localization inhibitory signal, and the CBFbeta interaction sites. PMID- 26529467 TI - Asymmetric Catalysis with Ethylene. Synthesis of Functionalized Chiral Enolates. AB - Trialkylsilyl enol ethers are versatile intermediates often used as enolate surrogates for the synthesis of carbonyl compounds. Yet there are no reports of broadly applicable, catalytic methods for the synthesis of chiral silyl enol ethers carrying latent functionalities useful for synthetic operations beyond the many possible reactions of the silyl enol ether moiety itself. Here we report a general procedure for highly catalytic (substrate:catalyst ratio up to 1000:1) and enantioselective (92% to 98% major enantiomer) synthesis of such compounds bearing a vinyl group at a chiral carbon at the beta-position. The reactions, run under ambient conditions, use trialkylsiloxy-1,3-dienes and ethylene (1 atm) as precursors and readily available (bis-phosphine)-cobalt(II) complexes as catalysts. The silyl enolates can be readily converted into novel enantiopure vinyl triflates, a class of highly versatile cross-coupling reagents, enabling the syntheses of other enantiomerically pure, stereodefined trisubstituted alkene intermediates not easily accessible by current methods. Examples of Kumada, Stille, and Suzuki coupling reactions are illustrated. PMID- 26529468 TI - Synthesis and Characterization of a Novel Mycophenolic Acid-Quinic Acid Conjugate Serving as Immunosuppressant with Decreased Toxicity. AB - Mycophenolic acid (MPA) is one of the most commonly used immunosuppressive drugs for improving the outcome of cell and organ transplantations. However, an undesired adverse effect of MPA impedes its application in the clinics for post transplant patients. By conjugating MPA to quinic acid (QA) via amide bonds, we synthesized a novel immunosuppressant, N-[2-[[(4E)-6-(1,3-dihydro-4-hydroxy-6 methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-1-oxo-4-hexen-1 yl]amino]ethyl]-(1alpha,3R,4alpha,5R)-1,3,4,5 tetrakis(acetyloxy)cyclohexanecarboxamide (abbreviated as MQ4), which exhibits improved stability demonstrated by its incubation in vitro with human plasma, suggesting its better resistance to hydrolytic degradation induced by plasma enzyme. While the immunosuppressive effect of MQ4 on human lymphocyte proliferation was partially compromised as shown by flow cytometry, significant decrease in cytotoxicity of MQ4 to insulin producing beta cells could compensate this drawback to some degree. There was a decreased level of apoptotic mediator caspase-3, which may contribute to the decreased toxicity of MQ4 to INS-1E cells. MQ4 could further improve insulin stimulation index and downregulate NFkappaB expression compared to physical mixing of QA to MPA. Taken together, MQ4 is a promising immunosuppressive agent for preventing and minimizing post-transplanted immune rejection. PMID- 26529469 TI - Sleep architecture and homeostasis in mice with partial ablation of melanin concentrating hormone neurons. AB - Recent reports support a key role of tuberal hypothalamic neurons secreting melanin concentrating-hormone (MCH) in the promotion of Paradoxical Sleep (PS). Controversies remain concerning their concomitant involvement in Slow-Wave Sleep (SWS). We studied the effects of their selective loss achieved by an Ataxin 3 mediated ablation strategy to decipher the contribution of MCH neurons to SWS and/or PS. Polysomnographic recordings were performed on male adult transgenic mice expressing Ataxin-3 transgene within MCH neurons (MCH(Atax)) and their wild type littermates (MCH(WT)) bred on two genetic backgrounds (FVB/N and C57BL/6). Compared to MCH(WT) mice, MCH(Atax) mice were characterized by a significant drop in MCH mRNAs (-70%), a partial loss of MCH-immunoreactive neurons (-30%) and a marked reduction in brain density of MCH-immunoreactive fibers. Under basal condition, such MCH(Atax) mice exhibited higher PS amounts during the light period and a pronounced SWS fragmentation without any modification of SWS quantities. Moreover, SWS and PS rebounds following 4-h total sleep deprivation were quantitatively similar in MCH(Atax)vs. MCH(WT) mice. Additionally, MCH(Atax) mice were unable to consolidate SWS and increase slow-wave activity (SWA) in response to this homeostatic challenge as observed in MCH(WT) littermates. Here, we show that the partial loss of MCH neurons is sufficient to disturb the fine tuning of sleep. Our data provided new insights into their contribution to subtle process managing SWS quality and its efficiency rather than SWS quantities, as evidenced by the deleterious impact on two powerful markers of sleep depth, i.e., SWS consolidation/fragmentation and SWA intensity under basal condition and under high sleep pressure. PMID- 26529470 TI - Cross-Sectional Examination of the Associations Between Symptoms, Community Integration, and Mental Health in Multiple Sclerosis. AB - OBJECTIVE: To determine the frequency and severity of 8 symptoms in persons with multiple sclerosis (MS) and to examine the association between these symptoms and community integration and mental health. DESIGN: Cross-sectional survey that assessed 8 symptoms (pain, fatigue, imbalance, numbness, weakness, shortness of breath, vision loss, and memory loss), disease progression (self-report version of the Expanded Disability Status Scale), community integration, and mental health. SETTING: Community. PARTICIPANTS: Adults with self-reported MS who responded to a mailed survey (N=180). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The presence and intensity of symptoms were measured with a symptoms checklist. Community integration was assessed with the Community Integration Questionnaire, and mental health was measured by the Mental Health Index of the Medical Outcomes Study 36-Item Short-Form Health Survey. RESULTS: The average number of symptoms reported was 5.07+/-2.18. The most common symptoms (fatigue, weakness, and imbalance) were also rated as the most severe. Not all symptoms were associated with level of disease progression or with MS subtype. Symptoms related to mobility were more likely to be associated with these variables. The 8 symptoms as a whole accounted for significant amounts of variance (range, 13% 21%) in measures of community integration and mental health, with specific symptoms making differential independent contributions to these measures. CONCLUSIONS: This study demonstrates that most individuals with MS report a number of bothersome symptoms. Type of MS or level of progression does not tell the whole story regarding the impact of symptoms. PMID- 26529471 TI - Reducing Sitting Time After Stroke: A Phase II Safety and Feasibility Randomized Controlled Trial. AB - OBJECTIVE: To test the safety, feasibility, and effectiveness of reducing sitting time in stroke survivors. DESIGN: Randomized controlled trial with attention matched controls and blinded assessments. SETTING: Community. PARTICIPANTS: Stroke survivors (N=35; 22 men; mean age, 66.9+/-12.7y). INTERVENTIONS: Four counseling sessions over 7 weeks with a message of sit less and move more (intervention group) or calcium for bone health (attention-matched control group). MAIN OUTCOME MEASURES: Measures included safety (adverse events, increases in pain, spasticity, or fatigue) and feasibility (adherence to trial protocol). Secondary measures included time spent sitting (including in prolonged bouts >=30min), standing, and stepping as measured by the thigh-worn inclinometer (7d, 24h/d protocol) and time spent in physical activity of at least moderate intensity as measured by a triaxial accelerometer. The Multimedia Activity Recall for Children and Adults was used to describe changes in use of time. RESULTS: Thirty-three participants completed the full protocol. Four participants reported falls during the intervention period with no other adverse events. From a baseline average of 640.7+/-99.6min/d, daily sitting time reduced on average by 30+/-50.6min/d (95% confidence interval [CI], 5.8-54.6) in the intervention group and 40.4+/-92.5min/d in the control group (95% CI, 13.0-93.8). Participants in both groups also reduced their time spent in prolonged sitting bouts (>=30min) and increased time spent standing and stepping. CONCLUSIONS: Our protocol was both safe and feasible. Participants in both groups spent less time sitting and more time standing and stepping postintervention, but outcomes were not superior for intervention participants. Attention matching is desirable in clinical trials and may have contributed to the positive outcomes for control participants. PMID- 26529472 TI - Multifunctional Electroactive Nanocomposites Based on Piezoelectric Boron Nitride Nanotubes. AB - Space exploration missions require sensors and devices capable of stable operation in harsh environments such as those that include high thermal fluctuation, atomic oxygen, and high-energy ionizing radiation. However, conventional or state-of-the-art electroactive materials like lead zirconate titanate, poly(vinylidene fluoride), and carbon nanotube (CNT)-doped polyimides have limitations on use in those extreme applications. Theoretical studies have shown that boron nitride nanotubes (BNNTs) have strength-to-weight ratios comparable to those of CNTs, excellent high-temperature stability (to 800 degrees C in air), large electroactive characteristics, and excellent neutron radiation shielding capability. In this study, we demonstrated the experimental electroactive characteristics of BNNTs in novel multifunctional electroactive nanocomposites. Upon application of an external electric field, the 2 wt % BNNT/polyimide composite was found to exhibit electroactive strain composed of a superposition of linear piezoelectric and nonlinear electrostrictive components. When the BNNTs were aligned by stretching the 2 wt % BNNT/polyimide composite, electroactive characteristics increased by about 460% compared to the nonstretched sample. An all-nanotube actuator consisting of a BNNT buckypaper layer between two single-walled carbon nanotube buckypaper electrode layers was found to have much larger electroactive properties. The additional neutron radiation shielding properties and ultraviolet/visible/near-infrared optical properties of the BNNT composites make them excellent candidates for use in the extreme environments of space missions. PMID- 26529473 TI - Pregnancy Outcomes in Women with 1-Hour Glucose Challenge Test >= 200 mg/dL. AB - OBJECTIVE: Many protocols diagnose gestational diabetes mellitus (GDM) solely on a 1-hour glucose challenge test (GCT) >= 200 mg/dL. However, pregnancy outcomes in these women compared with women diagnosed with a 3-hour glucose tolerance test (GTT) has not been adequately evaluated. We hypothesize that a 1-hour GCT >= 200 mg/dL is associated with worse pregnancy outcomes as compared with a GCT 135 to 199 mg/dL with positive GTT. STUDY DESIGN: A retrospective cohort of singleton pregnancies complicated by GDM. Maternal outcomes included A2DM, preeclampsia, primary cesarean, and failed trial of labor after cesarean. Perinatal outcomes were large/small for gestational age, shoulder dystocia, and birth injury. Groups were compared with t-test and chi-square test, and logistic regression to adjust for confounders. RESULTS: A total of 602 women diagnosed with GDM by 1-hour GCT 135 to 199 mg/dL and confirmatory 3-hour GTT (< 200 group) and 225 women diagnosed with 1-hour GCT >= 200 alone (>= 200) were included. The >= 200 group had a higher incidence of preeclampsia (16.4 vs. 10.6%) and shoulder dystocia (3.1 vs. 1.0%). Adjusted odds ratio and 95% confidence interval were 1.80 (1.10 2.94) and 5.10 (1.25-20.76), respectively. CONCLUSION: Preeclampsia and shoulder dystocia are more frequent in women with GCT >= 200 mg/dL than those with a positive GTT following a GCT of 135 to 199 mg/dL. PMID- 26529474 TI - Effect of Tocolytics on Surfactant Secretion When Administered with Betamethasone: An in Vitro Study. AB - OBJECTIVE: To analyze the amount of surfactant protein (SP)-B and lecithin/sphingomyelin (L/S) ratio in response to betamethasone (BMS) alone as compared with magnesium sulfate (Mg(2+)), indomethacin (Indo), and nifedipine (Nif) with or without BMS. STUDY DESIGN: NCI-H441 human lung cells were grown and distributed into eight plates. BMS and tocolytics were added and the final plates were: control, BMS only, and each tocolytic +/- BMS. Cells were stained with SP-B antibodies and relative fluorescence was measured. Lipids were also extracted, identified, and examined for relative densities. The L/S ratio was calculated. RESULTS: Nine independent measurements were obtained for each plate. The protein analysis revealed that among all eight plates, SP-B levels were highest among BMS only. There was a nonsignificant decrease in SP-B in each of the combinations of tocolytics + BMS as compared with BMS only. Compared with BMS only, L/S ratio was decreased in Mg(2+) + BMS (p = 0.041), Indo + BMS (p = 0.042), and Nif + BMS (p = 0.025). CONCLUSION: In our in vitro human lung cell model, SP-B and L/S ratio increased in response to BMS administration alone. The addition of tocolytics to BMS resulted in no increase in L/S ratio and no changes seen in SP-B production compared with BMS alone. PMID- 26529475 TI - Comparative Analysis of Two- Versus Three-Dimensional Sonography for Nuchal Translucency Measurement. AB - OBJECTIVE: The aim of this article is to test the hypothesis that three dimensional (3D) sonography is correlated to the two-dimensional (2D) sonography for nuchal translucency (NT) measurement during first trimester screening (FTS). METHODS: We performed a prospective observational study on patients presenting for FTS. Three NT measurements were performed using the current standardized 2D method at the midsagittal planes, and NT sonography was then repeated for each case using 3D sagittal and axial plane. The Kruskal-Wallis test and the Spearman rank correlation were used to evaluate the relationship between 2D and 3D NT methods of measurement. A p-value <0.05 was considered significant. RESULTS: The study included 366 patients with singleton pregnancies. Mean maternal age was 31.2 years, and mean gestational age was 12(3/7) weeks. The mean maximal NT measurement for 2D and 3D sagittal and axial planes were 1.65, 1.70, and 1.66 mm, respectively (p = 0.42). The Spearman rank correlation of 2D sagittal plane sonography with 3D sagittal and axial planar sonography was 0.73 and 0.68, respectively (p < 0.001). CONCLUSION: 3D NT measurement appears to be a tool highly correlated to the conventional 2D sonographic approach. This may be useful in selected cases in which there is difficulty in obtaining optimal 2D measurements of the NT space. PMID- 26529476 TI - Vascular Endothelial Growth Factor/Placental Growth Factor Heterodimer Levels in Preterm Infants with Bronchopulmonary Dysplasia. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is associated with changes in pulmonary angiogenesis. However, the role of the vascular endothelial growth factor/placental growth factor (VEGF/PlGF) heterodimer, an antiangiogenic factor, remains unknown in this disease. OBJECTIVE: To compare VEGF/PlGF levels in preterm infants with and without BPD. METHODS: This study was approved by the Institutional Review Board. Preterm neonates with birth weight <2,000 g and gestational age <= 34 weeks were included. Exclusion criteria were: neonates transferred from other institutions after 72 hours of life; death before blood collection; presence of major congenital malformations, inborn errors of metabolism, and early sepsis; and mothers with multiple pregnancies, TORCH infections, HIV infection, or autoimmune diseases. BPD was defined as the need for oxygen therapy for a period equal to or greater than 28 days, accompanied by radiographic changes compatible with the disease. Blood was collected from neonates in the first 72 hours of life. VEGF/PlGF levels were measured using the enzyme-linked immunosorbent assay method. The chi-square test, t-test, Mann Whitney test, analysis of variance, and Kruskal-Wallis test were used for statistical analysis. Variables found to be significant in the univariate analysis were included in the multivariate analysis. RESULTS: Seventy-three patients were included (19 with BPD, 43 without BPD, and 11 neonates who died in the first 28 days of life), with a mean (SD) gestational age of 30.32 (2.88) weeks and birth weight of 1,288 (462) g. Median VEGF/PlGF levels were higher in the groups with BPD and death in the first 28 days of life than in the group without BPD (16.46 [IQR, 12.19-44.57] and 20.64 [IQR, 13.39-50.22], respectively, vs. 9.14 [IQR, 0.02-20.64] pg/mL], p < 0.001). Higher VEGF/P1GF levels remained associated with BPD and death in the first 28 days of life in the multivariate analysis. CONCLUSION: Higher plasma VEGF/PlGF levels were found in preterm neonates with BPD and in those who died in the first 28 days of life, suggesting an important role of this substance in pulmonary vascular development. PMID- 26529477 TI - Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. AB - Because dysregulation and mutations of protein kinases play causal roles in human disease, this family of enzymes has become one of the most important drug targets over the past two decades. The X-ray crystal structures of 21 of the 27 FDA approved small molecule inhibitors bound to their target protein kinases are depicted in this paper. The structure of the enzyme-bound antagonist complex is used in the classification of these inhibitors. Type I inhibitors bind to the active protein kinase conformation (DFG-Asp in, alphaC-helix in). Type I1/2 inhibitors bind to a DFG-Asp in inactive conformation while Type II inhibitors bind to a DFG-Asp out inactive conformation. Type I, I1/2, and type II inhibitors occupy part of the adenine binding pocket and form hydrogen bonds with the hinge region connecting the small and large lobes of the enzyme. Type III inhibitors bind next to the ATP-binding pocket and type IV inhibitors do not bind to the ATP or peptide substrate binding sites. Type III and IV inhibitors are allosteric in nature. Type V inhibitors bind to two different regions of the protein kinase domain and are therefore bivalent inhibitors. The type I-V inhibitors are reversible. In contrast, type VI inhibitors bind covalently to their target enzyme. Type I, I1/2, and II inhibitors are divided into A and B subtypes. The type A inhibitors bind in the front cleft, the back cleft, and near the gatekeeper residue, all of which occur within the region separating the small and large lobes of the protein kinase. The type B inhibitors bind in the front cleft and gate area but do not extend into the back cleft. An analysis of the limited available data indicates that type A inhibitors have a long residence time (minutes to hours) while the type B inhibitors have a short residence time (seconds to minutes). The catalytic spine includes residues from the small and large lobes and interacts with the adenine ring of ATP. Nearly all of the approved protein kinase inhibitors occupy the adenine-binding pocket; thus it is not surprising that these inhibitors interact with nearby catalytic spine (CS) residues. Moreover, a significant number of approved drugs also interact with regulatory spine (RS) residues. PMID- 26529478 TI - Mathematical model for shear stress dependent NO and adenine nucleotide production from endothelial cells. AB - We developed a mass transport model for a parallel-plate flow chamber apparatus to predict the concentrations of nitric oxide (NO) and adenine nucleotides (ATP, ADP) produced by cultured endothelial cells (ECs) and investigated how the net rates of production, degradation, and mass transport for these three chemical species vary with changes in wall shear stress (tauw). These simulations provide an improved understanding of experimental results obtained with parallel-plate flow chambers and allows quantitative analysis of the relationship between tauw, adenine nucleotide concentrations, and NO produced by ECs. Experimental data obtained after altering ATP and ADP concentrations with apyrase were analyzed to quantify changes in the rate of NO production (RNO). The effects of different isoforms of apyrase on ATP and ADP concentrations and nucleotide-dependent changes in RNO could be predicted with the model. A decrease in ATP was predicted with apyrase, but an increase in ADP was simulated due to degradation of ATP. We found that a simple proportional relationship relating a component of RNO to the sum of ATP and ADP provided a close match to the fitted curve for experimentally measured changes in RNO with apyrase. Estimates for the proportionality constant ranged from 0.0067 to 0.0321 MUM/s increase in RNO per nM nucleotide concentration, depending on which isoform of apyrase was modeled, with the largest effect of nucleotides on RNO at low tauw (<6 dyn/cm(2)). PMID- 26529479 TI - A bridged di-iron porphyrin hyponitrite complex as a model for biological N2O production from hyponitrite. AB - Heme-hyponitrites are intermediates that form at the bimetallic active sites of bacterial nitric oxide reductases. To probe a possible effect of the Fe-Fe distance on hyponitrite stability, we prepared a bridged bis-porphyrin Fe hyponitrite compound, namely [(OEP-CH2)Fe]2(MU2,eta(1),eta(1)-ONNO). Its upsilonNO of 992 cm(-1) (upsilon15NO of 976 cm(-1)) is close to the upsilonNO of 983 cm(-1) reported previously by us for the crystallographically characterized [(OEP)Fe]2(MU2,eta(1),eta(1)-ONNO) compound. The bridged bis-porphyrin Fe hyponitrite complex is unstable with respect to N2O production, supporting the role of the bis-Fe porphyrin system in hyponitrite conversion to N2O. The preparation and crystallographic determination of the bridging sulfato derivative is also reported. PMID- 26529480 TI - Process Evaluation Results From an Intergenerational Physical Activity Intervention for Grandparents Raising Grandchildren. AB - BACKGROUND: Grandparents and the grandchildren they raise may experience stress related to their caregiving relationship that negatively impacts their health. Thus, there is a need to develop intergenerational health promotion interventions for these kinship families. METHODS: An 8-week intergenerational physical activity intervention for kinship families was developed and implemented. The specific goal was to understand the process of implementing the intervention. Content analysis of observational data provided an in-depth account of the intervention's process (ie, recruitment, dose delivered, dose received, fidelity, and context). RESULTS: Community and support service organizations referred more participants to the study than individual stakeholders. Most participants attended approximately 10 classes, and the grandparents were more engaged than the grandchildren during the classes. Intervention fidelity was confirmed with the fidelity checklist and observational notes. Health emerged as a barrier to participation, while the intergenerational nature of the intervention was a facilitator. Lastly, the context domain described how the grandparents' complex lives affected their ability to participate, while the dedication of the recreation staff helped the intervention to proceed efficiently. CONCLUSION: The distinct details gleaned from this study can provide guidance on how to develop and implement future intergenerational interventions. PMID- 26529481 TI - PVP-Assisted Synthesis of Uniform Carbon Coated Li2S/CB for High-Performance Lithium-Sulfur Batteries. AB - The lithium-sulfur (Li-S) battery is a great alternative to the state-of-the-art lithium ion batteries due to its high energy density. However, low utilization of active materials, the insulating nature of sulfur or lithium sulfide (Li2S), and polysulfide dissolution in organic liquid electrolyte lead to low initial capacity and fast performance degradation. Herein, we propose a facile and viable approach to address these issues. This new approach entails synthesis of Li2S/carbon black (Li2S/CB) cores encapsulated by a nitrogen-doped carbon shell with polyvinylpyrrolidone (PVP) assistance. Combining energy-filtered transmission electron microscopy (EFTEM) elemental mappings, XPS and FTIR measurements, it is confirmed that the as-synthesized material has a structure of a Li2S/CB core with a nitrogen-doped carbon shell (denoted as Li2S/CB@NC). The Li2S/CB@NC cathode yields an exceptionally high initial capacity of 1020 mAh/g based on Li2S mass at 0.1 C with stable Coulombic efficiency of 99.7% over 200 cycles. Also, cycling performance shows the capacity decay per cycle as small as 0.17%. Most importantly, to further understand the materials for battery applications, field emission transmission electron microscopy (FETEM) and elemental mapping tests without exposure to air for Li2S samples in cycled cells are reported. Along with the first ever FETEM and field emission scanning electron microscopy (FESEM) investigations of cycled batteries, Li2S/CB@NC cathode demonstrates the capability of robust core-shell nanostructures for different rates and improved capacity retention, revealing Li2S/CB@NC designed here as an outstanding system for high-performance lithium-sulfur batteries. PMID- 26529482 TI - Non-synergistic cytotoxic effects of Fusarium and Alternaria toxin combinations in Caco-2 cells. AB - Exposure of humans and animals to mycotoxins via food and feed generally involves a conglomeration of compounds contaminating the consumed products. Investigations on combinatory effects of mycotoxins are therefore of great importance. In this study, cytotoxic effects of binary mixtures of the Fusarium toxins enniatin B, aurofusarin, deoxynivalenol, nivalenol and zearalenone, and tenuazonic acid produced by Alternaria spp., were evaluated by the WST-1 assay in the colorectal carcinoma cell-line Caco-2 after 24h of incubation. The selection of these mycotoxins was based on typically occurring natural contamination patterns in grains. Aurofusarin, which can be found abundantly in contaminated foodstuff and has not been toxicologically characterized properly so far, showed pronounced cytotoxicity, decreasing the mitochondrial activity at 10MUM to 51% compared to a solvent control. Combinations of other mycotoxins with aurofusarin showed additive effects. In contrast, binary mixtures of enniatin B, deoxynivalenol, nivalenol and zearalenone at cytotoxic concentrations, predominantly resulted in antagonistic effects. Binary combinations of these four Fusarium toxins with tenuazonic acid also revealed interacting effects leading to a decrease in cytotoxicity, compared to expected combinatory effects. Especially in combination with deoxynivalenol, tenuazonic acid was found to significantly reduce the cytotoxicity of this mycotoxin in Caco-2 cells. Synergistic effects were not observed for any toxin combination under the chosen conditions. PMID- 26529483 TI - Perfluorooctane sulfonate (PFOS) exposure could modify the dopaminergic system in several limbic brain regions. AB - Perfluorooctane sulfonate (PFOS) is the most representative of a rising class of persistent organic pollutants perfluorochemicals. In the present study, its neurotoxicity was examined using adult male rats orally treated with 0.5; 1.0; 3.0 and 6.0 mg of PFOS/kg/day for 28 days. At the end of the treatment, the dopamine concentration and its metabolism expressed like the ratio 3,4 dihydroxyphenylacetic acid (DOPAC)/dopamine and homovanillic acid (HVA)/dopamine were measured in the amygdala, prefrontal cortex and hippocampus. Gene and protein expression of the dopamine receptors D1 and D2 were also determined in these limbic areas. The obtained results suggest that: (1) PFOS can alter the dopamine system by modifying its neuronal activity and/or its D1 and D2 receptors in the studied brain regions; (2) the dopamine concentration and metabolism seem to be more sensitive against PFOS toxicity in the hippocampus than in the other analyzed brain areas; (3) the inhibited gene and protein expression of the D1 receptors induced by PFOS in the amygdala could be related to several changes in the HPA axis activity, and lastly; (4) the observed alterations on the dopamine system induced by PFOS could be a possible neurotoxicity mechanism of PFOS, leading to many neurological diseases. PMID- 26529484 TI - Does the passability of apertures change when walking through human versus pole obstacles? AB - The current study set out to evaluate how individuals walk through apertures created by different stationary obstacles. Specifically, we examined whether the passability of apertures differed between human and pole obstacles by quantifying aperture crossing behaviors such as the critical point. Participants walked an 8m path toward a visible goal located at the end. Two obstacles were positioned 5m from the starting location and participants were instructed to pass between the obstacles without hitting them. The distance between the obstacles ranged between 1.0 and 1.8* the participant's shoulder width. Results revealed that, when the obstacles were humans, individuals rotated their shoulders more frequently at larger apertures, as evidenced by a larger critical point (1.7 vs 1.3 for poles), initiated shoulder rotations earlier, rotated to a larger degree, left a wider clearance between their shoulders and the obstacles at the time of crossing, and walked slower when approaching and passing through the obstacles compared to when the obstacles were poles. Furthermore, correlational analyses revealed that the amount of change between an individual's critical point for the poles and the critical point for the human obstacles was related to social risk-taking and changes in walking speed. Therefore, it appears that the passability of apertures changes when walking between two people versus two objects such that more space and greater caution are needed for human obstacles. It is possible that the greater caution observed for human obstacles is to account for the personal space needs of others that do not exist in the same extent for poles and that the degree of caution is related to social factors. PMID- 26529485 TI - Dioxinodehydroeckol protects human keratinocyte cells from UVB-induced apoptosis modulated by related genes Bax/Bcl-2 and caspase pathway. AB - Although ultraviolet B (UVB) has a low level of skin penetration, it readily results in epidermal sunburn of keratinocytes that are destined to apoptosis after sun expose, and leads to DNA damage. Dioxinodehydroeckol (DHE), a phlorotannin from Ecklonia cava has been explored for its preventive activity against UVB-induced apoptosis in human keratinocyte (HaCaT) cells; however, the protective effects of treatment with low doses of DHE on UVB-damaged cells post UVB exposure and their underlying mechanisms still remain unclear. The HaCaT cells were exposed to 20 mJcm(-2) of UVB irradiation which is the minimal erythema dose (MED) for individuals to be able to tan, and the expression levels of Bax/Bcl-2 and caspase-3,-8, -9 which are associated genes with apoptosis were investigated when we either treated cells with DHE doses after UVB irradiation or exposed them to UVB only. Our results suggest insight into proposed mechanistic pathway of protective activity of DHE on the HaCaT cells from UVB-induced apoptosis, indicating the benefit of DHE as a repair agent for skin damage against UVB. PMID- 26529486 TI - Endocannabinoid CB1 receptor activation upon global ischemia adversely impact recovery of reward and stress signaling molecules, neuronal survival and behavioral impulsivity. AB - Global cerebral ischemia in rodents, which mimics cardiac arrest in humans, is associated with a surge in endocannabinoids and increased transmission of dopamine and glutamate leading to excitotoxic cell death. The current study assessed the role of CB1 receptor activation at the moment of an ischemic insult on ensuing regulation of stress and reward signaling molecules, neuronal injury and anxiety-like behavior. Male Wistar rats were separated into 4 groups (n=10/group); sham and ischemic rats administered the CB1 endocannabinoid receptor antagonist AM251 (2mg/kg, i.p.) 30min prior to global cerebral ischemia, and vehicle-treated counterparts. The effects of CB1 receptor blockade on corticotropin-releasing hormone (CRH), vesicular glutamate transporter 2 (vGluT2), tyrosine hydroxylase (TH) and dopamine receptor 1 (DRD1) signaling expression, together with CA1 neuronal damage and anxiety-like behaviors were assessed. Our findings show attenuated CA1 injury and behavioral deficits in AM251-treated ischemic rats. AM251-pretreatment also partially or completely reversed ischemia-induced alterations in TH-ir expression at the hippocampus, ventral tegmental area (VTA), nucleus accumbens (NAc) and basolateral amygdala (BLA), normalized DRD1-ir at the medial forebrain bundle, and diminished BLA and PVN-CRH expression. All groups showed comparable vGluT2 expression at the BLA and PVN-parvocellular subdivision. These findings support a determinant role of CB1 receptor activation at time of ischemia on functional recovery. They also support "state-dependent" effects of endocannabinoids, raising considerations in the development of effective molecules to regulate HPA axis function and mood disorders following cardiac arrest and stroke. PMID- 26529487 TI - Binding site identification and role of permanent water molecule of PIM-3 kinase: A molecular dynamics study. AB - The kinome is a protein kinase complement of the human genome, categorized as serine/threonine and tyrosine kinases. These kinases catalyze phosphorylation reaction by using ATP as phosphoryl donor. Proviral Integration Site for Moloney Murine Leukemia Virus (PIM) kinase encodes serine/threonine protein kinases that recognized as proto-oncogene, responsible for rapid growth of cancerous cells. It is implicated in cell survival and function via cell cycle progression and its metabolism. PIM-3, sub-member of PIM kinases is a proto-oncogene, its overexpression inhibits apoptosis, and results in progression of hepatocellular carcinoma. PIM-3 is considered as a promising drug target but attempts to develop its specific inhibitors is slowed down due to the lack of 3D structure by any experimental technique. In silico techniques generally facilitate scientist to explore hidden structural features in order to improve drug discovery. In the present study, homology modeling, molecular docking and MD simulation techniques were utilized to explore the structure and dynamics of PIM-3 kinase. Induction of water molecules during molecular docking simulation explored differences in the hinge region between PIM-1 and PIM-3 kinases that may be responsible for specificity. Furthermore, role of water molecules in the active site was also explored via radial distribution function (RDF) after a 10 ns molecular dynamics (MD) simulations. Generated RDF plots exhibited the importance of water for inhibitor binding through their bridging capability that links the ligand with binding site residues. PMID- 26529488 TI - Visuomotor control in patients with Parkinson's disease. AB - Previous studies have suggested that the deteriorated visuomotor control in patients with PD (Parkinson's disease) is due to deficits in various aspects of the sensory-motor processing rather than motor control itself. In the current study, by taking a control-theoretic approach, we systematically examined how PD and antiparkinsonian medication affect visuomotor control and the underlying sensory-motor system. We tested 20 PD patients in both ON and OFF medication states and 20 demographically matched healthy controls with a commonly used manual control task. Specifically, in each 95-s trial, participants were instructed to use a joystick to control a randomly moving target to keep it centered on a computer display. We found that although antiparkinsonian medication improved visuomotor control in PD patients, they still showed significantly decreased control precision (measured by RMS error) and response amplitude (gain) as well as increased response delay (phase lag) compared with healthy controls. Our model-driven analysis revealed that PD impairs the responsiveness and the predicting ability of the sensory-motor system as well as the stability of the neuromuscular system. Taking antiparkinsonian medication improves the responsiveness of the sensory-motor system. More importantly, it improves the ability of the sensory-motor system to make sensory predictions of the current control actions (see Wolpert et al., 1995) to anticipate the input error signals and generate control responses ahead of time up to the level of healthy controls. However, taking antiparkinsonian medication does not improve the stability of the neuromuscular system. These results support the claim that the effect of antiparkinsonian medication on visuomotor control is mainly through improving visual-stimulus-dependent sensory-motor processing. The present study provides the first quantitative examination of the effects of PD and antiparkinsonian medication on the visual-stimulus-dependent sensory-motor and visual-stimulus-independent neuromuscular systems underlying visuomotor control. The findings have practical implications for developing sensitive assessment tools to evaluate the efficacy of different therapies for PD and preliminary screening and training tools for fitness-to-drive in PD patients. PMID- 26529489 TI - A cortical network that marks the moment when conscious representations are updated. AB - In order to survive in a complex, noisy and constantly changing environment we need to categorize the world (e.g., Is this food edible or poisonous?) and we need to update our interpretations when things change. How does our brain update when object categories change from one to the next? We investigated the neural correlates associated with this updating process. We used event-related fMRI while people viewed a sequence of images that morphed from one object (e.g., a plane) to another (e.g., a shark). All participants were naive as to the identity of the second object. The point at which participants 'saw' the second object was unpredictable and uncontaminated by any dramatic or salient change to the images themselves. The moment when subjective perceptual representations changed activated a circumscribed network including the anterior insula, medial and inferior frontal regions and inferior parietal cortex. In a setting where neither the timing nor nature of the visual transition was predictable, this restricted cortical network signals the time of updating a perceptual representation. The anterior insula and mid-frontal regions (including the ACC) were activated not only at the actual time when change was reported, but also immediately before, suggesting that these areas are also involved in processing alternative options after a mismatch has been detected. PMID- 26529491 TI - Simultaneous Thermoelectric and Optoelectronic Characterization of Individual Nanowires. AB - Semiconducting nanowires have been explored for a number of applications in optoelectronics such as photodetectors and solar cells. Currently, there is ample interest in identifying the mechanisms that lead to photoresponse in nanowires in order to improve and optimize performance. However, distinguishing among the different mechanisms, including photovoltaic, photothermoelectric, photoemission, bolometric, and photoconductive, is often difficult using purely optoelectronic measurements. In this work, we present an approach for performing combined and simultaneous thermoelectric and optoelectronic measurements on the same individual nanowire. We apply the approach to GaN/AlGaN core/shell and GaN/AlGaN/GaN core/shell/shell nanowires and demonstrate the photothermoelectric nature of the photocurrent observed at the electrical contacts at zero bias, for above- and below-bandgap illumination. Furthermore, the approach allows for the experimental determination of the temperature rise due to laser illumination, which is often obtained indirectly through modeling. We also show that under bias, both above- and below-bandgap illumination leads to a photoresponse in the channel with signatures of persistent photoconductivity due to photogating. Finally, we reveal the concomitant presence of photothermoelectric and photogating phenomena at the contacts in scanning photocurrent microscopy under bias by using their different temporal response. Our approach is applicable to a broad range of nanomaterials to elucidate their fundamental optoelectronic and thermoelectric properties. PMID- 26529490 TI - Mechanisms employed by cellulase systems to gain access through the complex architecture of lignocellulosic substrates. AB - To improve the deconstruction of biomass, the most abundant terrestrial source of carbon polymers, en route to renewable fuels, chemicals, and materials more knowledge is needed into the mechanistic interplay between thermochemical pretreatment and enzymatic hydrolysis. In this review we highlight recent progress in advanced imaging techniques that have been used to elucidate the effects of thermochemical pretreatment on plant cell walls across a range of spatial scales and the relationship between the substrate structure and the function of various glycoside hydrolase components. The details of substrate and enzyme interactions are not yet fully understood and the challenges of characterizing plant cell wall architecture, how it dictates recalcitrance, and how it relates to enzyme-substrate interactions is the focus for many research groups in the field. Better understanding of how to match pretreatments with improved enzyme mixtures will lead to lower costs for industrial biorefining. PMID- 26529492 TI - Origin of artificial radionuclides in soil and sediment from North Wales. AB - During the operations at the Sellafield nuclear fuel reprocessing complex, artificial radionuclides are discharged to the Irish Sea under authorisation, where they are dispersed. In this study, the southern distribution and transport of Sellafield derived radionuclides have been investigated. Both natural and artificial radionuclides have been studied in a soil core from the riverbank of the Afon Goch in Anglesey, North Wales. Particulate input is dominant for all artificial radionuclides (including the more soluble (137)Cs and (236)U) with an estimated lag time of about a decade. The preferential northward seawater movement in the NE Irish Sea limits solution input of (137)Cs and (236)U to the areas south of Sellafield. The relatively long lag time reflects both the water circulation pattern and distance between the study site in north Wales and the source point in Cumbria. Two redox active zones are observed in the top and the bottom of this core, although there is no evidence for any redistribution of Pu and natural uranium by these redox processes. However, (236)U, derived from irradiated uranium, showed variable distribution in the core. This could be a potential response to the geochemical conditions, showing that (236)U may be a promising tracer for the environmental processes and a signature of the Sellafield historical discharges of irradiated uranium. PMID- 26529493 TI - Authors respond to the commentary on Chong et al. "How many infants are temperamentally difficult?" (40 (2015) 20-28). PMID- 26529494 TI - Commentary on paper by Chong et al. "How many infants are temperamentally difficult?" 40 (2015) 20-28. PMID- 26529496 TI - Nasopharyngeal Capillary Arteriovenous Malformation with Ancient/Symplastic Change: A Simulator of Malignancy. AB - There are only 8 published cases of symplastic hemangioma (SH), a relatively recently described, distinct benign entity characterized by pleomorphic vascular smooth muscle and interstitial cells in a pre-existing, long-standing vascular lesion. Seven of these cases were of SH in cutaneous locations, and 1 case was described in the mediastinum. We report the case of the 12-year-old girl with a nasopharyngeal tumor mass with prominent symplastic changes arising in the background of a combined capillary arteriovenous malformation. After critical analysis of all published cases of SH, it is clear that these lesions commonly represent capillary arteriovenous malformations (CAVM) with ancient/symplastic changes according to current terminology proposed in the classification required by the International Society for the Study of Vascular Anomalies (ISSVA). This is the first such lesion reported in a mucosal location and presenting in the pediatric age group. CAVM with ancient/symplastic change follows a benign clinical course, but it can simulate a malignant vascular tumor. PMID- 26529495 TI - Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo. AB - MK-1775 is the first-in-class selective Wee1 inhibitor which has been demonstrated to synergize with CHK1 inhibitors in various malignancies. In this study, we report that the pan-histone deacetylase inhibitor (HDACI) panobinostat synergizes with MK-1775 in acute myeloid leukemia (AML), a malignancy which remains a clinical challenge and requires more effective therapies. Using both AML cell line models and primary patient samples, we demonstrated that panobinostat and MK-1775 synergistically induced proliferation arrest and cell death. We also demonstrated that panobinostat had equal anti-leukemic activities against primary AML blasts derived from patients either at initial diagnosis or at relapse. Interestingly, treatment with panobinostat alone or in combination with MK-1775 resulted in decreased Wee1 protein levels as well as downregulation of the CHK1 pathway. shRNA knockdown of CHK1 significantly sensitized AML cells to MK-1775 treatment, while knockdown of Wee1 significantly enhanced both MK-1775 and panobinostat-induced cell death. Our results demonstrate that panobinostat synergizes with MK-1775 in AML cells, at least in part through downregulation of CHK1 and/or Wee1, providing compelling evidence for the clinical development of the combination treatment in AML. PMID- 26529497 TI - Impact of esophagogastroduodenoscopy and ileocolonoscopy on diagnosis and therapy in patients with rheumatic diseases-a retrospective cohort study. AB - OBJECTIVES: Many rheumatic diseases as well as their medications may cause gastrointestinal (GI) pathologies; in addition, some primary GI diseases may contribute or lead to rheumatic disease manifestations. The aim of this study is to analyze the clinical relevance of esophagogastroduodenoscopy (EGD) and ileocolonoscopy (IC) in patients suffering from inflammatory rheumatic diseases. METHODS: A retrospective chart review was performed for all rheumatological inpatients who underwent EGD and/or IC within 2 years. RESULTS: Within 2 years, 456 patients (261 female, 195 male) underwent 752 endoscopic investigations of the GI tract (419 EGDs and 333 ICs). Of all patients, 152 (33.3%) did not report any GI complaints. However, 28 of these asymptomatic patients (18.4%) suffered from esophagitis, a gastric ulcer could be identified in 20 patients (13%), whereas unspecific colitis was diagnosed in 19 patients (12.5%). In addition, 14 patients (9.2%) suffered from clinically unapparent Crohn's disease and two patients from Whipple's disease. In one patient with polymyalgia rheumatica, colon cancer was diagnosed. Altogether 304 patients reported GI complaints. Of these, 292 (39%) endoscopic investigations had impact on the final diagnosis or therapeutic strategy. The antirheumatic medication or the concomitant medication was changed in 18% of the patients due to the endoscopic findings; in 29 patients (6.5%) the initially clinically presumed diagnosis had to be corrected. In 70 patients (15%) with an undefined rheumatic diagnosis prior to endoscopy, endoscopic findings were decisive to establish the final diagnosis. CONCLUSION: EGD and IC have a high diagnostic impact on patients with rheumatic diseases presenting with or without concomitant GI symptoms. PMID- 26529498 TI - Altered serum and salivary C-reactive protein levels in patients with oral premalignant lesions and oral squamous cell carcinoma. AB - Chronic inflammation is associated with cancer development. C-reactive protein (CRP), an acute phase protein synthesized primarily in the liver, is a marker for inflammation and for the progression of many cancers. We compared serum and salivary CRP levels in 20 normal individuals, 20 patients with oral premalignant lesions and 20 patients with oral squamous cell carcinoma (OSCC) to assess its efficacy as a prognostic indicator for OSCC. Saliva and blood samples were obtained and evaluated for CRP levels. Mean CRP levels were higher in patients with oral premalignant lesions compared to controls. CRP levels in OSCC patients were elevated and were associated with advanced tumor stages. PMID- 26529499 TI - The importance of test accuracy in economic evaluations of companion diagnostics. AB - BACKGROUND: Economic evaluations of companion diagnostics often fail to include the impact that tests have on the overall economic value of test-drug combinations. METHODS: To illustrate the importance of test accuracy on the cost effectiveness of companion diagnostics by means of examples. Data were extracted from the literature. RESULTS: The accuracy of a test and in particularly its specificity, is often more influential on the overall cost-effectiveness results than the price of the test. Specificity becomes more crucial when prevalence of the biomarker is low. Multiple, simultaneous testing faces specific challenges regarding its overall specificity. CONCLUSION: This article opens a discussion on some fundamental points linked to economic evaluations of test-therapy combinations. PMID- 26529500 TI - Thermal pasteurization of ready-to-eat foods and vegetables: Critical factors for process design and effects on quality. AB - Increasing consumer desire for high quality ready-to-eat foods makes thermal pasteurization important to both food producers and researchers. To be in compliance with the Food Safety Modernization Act (FSMA), food companies seek regulatory and scientific guidelines to ensure that their products are safe. Clearly understanding the regulations for chilled or frozen foods is of fundamental importance to the design of thermal pasteurization processes for vegetables that meet food safety requirements. This article provides an overview of the current regulations and guidelines for pasteurization in the U.S. and in Europe for control of bacterial pathogens. Poorly understood viral pathogens, in terms of their survival in thermal treatments, are an increasing concern for both food safety regulators and scientists. New data on heat resistance of viruses in different foods are summarized. Food quality attributes are sensitive to thermal degradation. A review of thermal kinetics of inactivation of quality-related enzymes in vegetables and the effects of thermal pasteurization on vegetable quality is presented. The review also discusses shelf-life of thermally pasteurized vegetables. PMID- 26529501 TI - Osteogenic Differentiation Gene Expression Profiling of hMSCs on Hydroxyapatite and Mineralized Collagen. AB - In this study, human mesenchymal stem cells (hMSCs) were cultured on the hydroxyapatite (HA) and mineralized collagen (MC), and their proliferation, adhesion, and differentiation, especially the molecular mechanisms on gene level, were investigated. Proliferation and morphological responses of hMSCs and their osteogenic differentiation were detected by quantitative detection of alkaline phosphatase. Gene expression profilings were examined by microarrays, and the gene expression data were studied through gene ontology terms and pathway analyses. The results showed that MC promoted cell proliferation and osteogenic differentiation of hMSCs. Microarray analysis showed that MC was conducive to express osteogenesis-related genes, such as BMP-2, COL1A1, and CTSK, and stimulate osteogenic differentiation, such as osteoblast differentiation pathway and skeletal system development pathway. PMID- 26529502 TI - Effects of Testosterone Treatment on Synaptic Plasticity and Behavior in Senescence Accelerated Mice. AB - Learning and memory are known to be influenced by circulating sex steroidal hormones and these behavioral processes are diminished in aging. Thus, the aim of this study was to examine the mechanism underlying testosterone-induced effects on cognitive performance in the senescence accelerated mouse P8 (SAMP8) model. Treatment with testosterone (T) as evidenced by the Morris water maze test produced a significantly shorter escape latency and reduced path length to reach the platform compared to the control (C). No significant differences were noted in mean swim speed among all groups. During the probe trials, the T group spent a significantly greater percent of time in the target quadrant and improved the number of platform crossings. Flutamide (F), an antiandrogen, significantly inhibited the effects of T on behavioral and memory performances indicators. Following Nissl staining, the number of intact pyramidal cells was markedly elevated in the treated mice, and this effect was blocked by F. Immunohistochemistry and Western blot analysis showed that the expression levels of NMDAR1, SYN, and p-CREC/CREB protein levels were significantly increased in the T group, while F inhibited the T-mediated effects. Western blot analysis showed that there were no significant differences in the expression levels of SYN, p-CREC/CREB, and NMDAR1 between C, F, and F + T groups. Reverse transcription polymerase chain reaction (RT-PCR) analysis showed that the mRNA expression levels of NMDAR1 and SYN were significantly increased in T administered mice, while F inhibited the T-mediated effects. Data suggest that the T-mediated increase in SYN expression levels resulted in improvement in behavioral performances and learning, which may involve stimulation of central nervous system androgen receptors (AR). PMID- 26529503 TI - Relative Prevalence of Grapevine Leafroll-Associated Virus Species in Wine Grape Growing Regions of California. AB - Some diseases manifest as one characteristic set of symptoms to the host, but can be caused by multiple pathogens. Control treatments based on plant symptoms can make it difficult to effectively manage such diseases, as the biology of the underlying pathogens can vary. Grapevine leafroll disease affects grapes worldwide, and is associated with several viral species in the family Closteroviridae. Whereas some of the viruses associated with this disease are transmitted by insect vectors, others are only graft-transmissible. In three regions of California, we surveyed vineyards containing diseased vines and screened symptomatic plants for all known viral species associated with grapevine leafroll disease. Relative incidence of each virus species differed among the three regions regions, particularly in relation to species with known vectors compared with those only known to be graft-transmitted. In one region, the pathogen population was dominated by species not known to have an insect vector. In contrast, populations in the other surveyed regions were dominated by virus species that are vector-transmissible. Our survey did not detect viruses associated with grapevine leafroll disease at some sites with characteristic disease symptoms. This could be explained either by undescribed genetic diversity among these viruses that prevented detection with available molecular tools at the time the survey was performed, or a misidentification of visual symptoms that may have had other underlying causes. Based on the differences in relative prevalence of each virus species among regions and among vineyards within regions, we expect that region and site-specific management strategies are needed for effective disease control. PMID- 26529504 TI - Multicenter Evaluation of the Bruker MALDI Biotyper CA System for the Identification of Clinical Aerobic Gram-Negative Bacterial Isolates. AB - The prompt and accurate identification of bacterial pathogens is fundamental to patient health and outcome. Recent advances in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) have revolutionized bacterial identification in the clinical laboratory, but uniform incorporation of this technology in the U.S. market has been delayed by a lack of FDA-cleared systems. In this study, we conducted a multicenter evaluation of the MALDI Biotyper CA (MBT-CA) System (Bruker Daltonics Inc, Billerica, MA) for the identification of aerobic gram-negative bacteria as part of a 510(k) submission to the FDA. A total of 2,263 aerobic gram negative bacterial isolates were tested representing 23 genera and 61 species. Isolates were collected from various clinical sources and results obtained from the MBT-CA System were compared to DNA sequencing and/or biochemical testing. Isolates that failed to report as a "high confidence species ID" [log(score) >=2.00] were re-tested using an extraction method. The MBT-CA System identified 96.8% and 3.1% of isolates with either a "high confidence" or a "low confidence" [log(score) value between 1.70 and <2.00] species ID, respectively. Two isolates did not produce acceptable confidence scores after extraction. The MBT-CA System correctly identified 99.8% (2,258/2,263) to genus and 98.2% (2,222/2,263) to species level. These data demonstrate that the MBT-CA System provides accurate results for the identification of aerobic gram-negative bacteria. PMID- 26529505 TI - Inosine Improves Neurogenic Detrusor Overactivity following Spinal Cord Injury. AB - Neurogenic detrusor overactivity and the associated loss of bladder control are among the most challenging complications of spinal cord injury (SCI). Anticholinergic agents are the mainstay for medical treatment of detrusor overactivity. However, their use is limited by significant side effects such that a search for new treatments is warranted. Inosine is a naturally occurring purine nucleoside with neuroprotective, neurotrophic and antioxidant effects that is known to improve motor function in preclinical models of SCI. However, its effect on lower urinary tract function has not been determined. The objectives of this study were to determine the effect of systemic administration of inosine on voiding function following SCI and to delineate potential mechanisms of action. Sprague-Dawley rats underwent complete spinal cord transection, or cord compression by application of an aneurysm clip at T8 for 30 sec. Inosine (225 mg/kg) or vehicle was administered daily via intraperitoneal injection either immediately after injury or after a delay of 8 wk. At the end of treatment, voiding behavior was assessed by cystometry. Levels of synaptophysin (SYP), neurofilament 200 (NF200) and TRPV1 in bladder tissues were measured by immunofluorescence imaging. Inosine administration decreased overactivity in both SCI models, with a significant decrease in the frequency of spontaneous non voiding contractions during filling, compared to vehicle-treated SCI rats (p<0.05), including under conditions of delayed treatment. Immunofluorescence staining demonstrated increased levels of the pan-neuronal marker SYP and the Adelta fiber marker NF200, but decreased staining for the C-fiber marker, TRPV1 in bladder tissues from inosine-treated rats compared to those from vehicle treated animals, including after delayed treatment. These findings demonstrate that inosine prevents the development of detrusor overactivity and attenuates existing overactivity following SCI, and may achieve its effects through modulation of sensory neurotransmission. PMID- 26529506 TI - Adolescent Intermittent Alcohol Exposure: Deficits in Object Recognition Memory and Forebrain Cholinergic Markers. AB - The long-term effects of intermittent ethanol exposure during adolescence (AIE) are of intensive interest and investigation. The effects of AIE on learning and memory and the neural functions that drive them are of particular interest as clinical findings suggest enduring deficits in those cognitive domains in humans after ethanol abuse during adolescence. Although studies of such deficits after AIE hold much promise for identifying mechanisms and therapeutic interventions, the findings are sparse and inconclusive. The present results identify a specific deficit in memory function after AIE and establish a possible neural mechanism of that deficit that may be of translational significance. Male rats (starting at PND-30) received exposure to AIE (5g/kg, i.g.) or vehicle and were allowed to mature into adulthood. At PND-71, one group of animals was assessed using the spatial-temporal object recognition (stOR) test to evaluate memory function. A separate group of animals was used to assess the density of cholinergic neurons in forebrain areas Ch1-4 using immunohistochemistry. AIE exposed animals manifested deficits in the temporal component of the stOR task relative to controls, and a significant decrease in the number of ChAT labeled neurons in forebrain areas Ch1-4. These findings add to the growing literature indicating long-lasting neural and behavioral effects of AIE that persist into adulthood and indicate that memory-related deficits after AIE depend upon the tasks employed, and possibly their degree of complexity. Finally, the parallel finding of diminished cholinergic neuron density suggests a possible mechanism underlying the effects of AIE on memory and hippocampal function as well as possible therapeutic or preventive strategies for AIE. PMID- 26529507 TI - High Risk versus Proportional Benefit: Modelling Equitable Strategies in Cardiovascular Prevention. AB - OBJECTIVE: To examine the performances of an alternative strategy to decide initiating BP-lowering drugs called Proportional Benefit (PB). It selects candidates addressing the inequity induced by the high-risk approach since it distributes the gains proportionally to the burden of disease by genders and ages. STUDY DESIGN AND SETTING: Mild hypertensives from a Realistic Virtual Population by genders and 10-year age classes (range 35-64 years) received simulated treatment over 10 years according to the PB strategy or the 2007 ESH/ESC guidelines (ESH/ESC). Primary outcomes were the relative life-year gain (life-years gained-to-years of potential life lost ratio) and the number needed to treat to gain a life-year. A sensitivity analysis was performed to assess the impact of changes introduced by the ESH/ESC guidelines appeared in 2013 on these outcomes. RESULTS: The 2007 ESH/ESC relative life-year gains by ages were 2%; 10%; 14% in men, and 0%; 2%; 11% in women, this gradient being abolished by the PB (relative gain in all categories = 10%), while preserving the same overall gain in life-years. The redistribution of benefits improved the profile of residual events in younger individuals compared to the 2007 ESH/ESC guidelines. The PB strategy was more efficient (NNT = 131) than the 2013 ESH/ESC guidelines, whatever the level of evidence of the scenario adopted (NNT = 139 and NNT = 179 with the evidence-based scenario and the opinion-based scenario, respectively), although the 2007 ESH/ESC guidelines remained the most efficient strategy (NNT = 114). CONCLUSION: The Proportional Benefit strategy provides the first response ever proposed against the inequity of resource use when treating highest risk people. It occupies an intermediate position with regards to the efficiency expected from the application of historical and current ESH/ESC hypertension guidelines. Our approach allows adapting recommendations to the risk and resources of a particular country. PMID- 26529508 TI - The dissertation on pain by Jan Krtitel Bohac published in 1746. AB - It is reported that continuous attention to the topic of pain in the Czech lands started only in the sixties of the twentieth century. Newly discovered archival documents show, however, that the subject of pain was studied at the Prague Medical Faculty more than 200 years before. In 1746 one of the medical students, Jan Krtitel Bohac (John Baptist Bohadsch) defended his dissertation on pain, titled "De Doloribus in Genere." Unlike other dissertations of the time, Bohac's treatise was not a mere transcription of the teaching texts. A detailed examination of his dissertation shows that it contained a thesis for a disputation, an act that took place regularly at that time during university study. Only 22 years old, Bohac showed in his dissertation a perfect knowledge of the contemporary literature, providing a more accurate classification of the causes and effects of pain. He also disagreed with statements and conclusions of authorities at the beginning of the eighteenth century and even offered his own opinion. The present work summarizes the concept of the nervous system and pain in the middle of the eighteenth century and compares them with the translation of selected parts of Bohac's formerly unknown dissertation. PMID- 26529509 TI - High Prevalence of Severe Food Insecurity and Malnutrition among HIV-Infected Adults in Senegal, West Africa. AB - BACKGROUND: Malnutrition and food insecurity are associated with increased mortality and poor clinical outcomes among people living with HIV/AIDS; however, the prevalence of malnutrition and food insecurity among people living with HIV/AIDS in Senegal, West Africa is unknown. The objective of this study was to determine the prevalence and severity of food insecurity and malnutrition among HIV-infected adults in Senegal, and to identify associations between food insecurity, malnutrition, and HIV outcomes. METHODS: We conducted a cross sectional study at outpatient clinics in Dakar and Ziguinchor, Senegal. Data were collected using participant interviews, anthropometry, the Household Food Insecurity Access Scale, the Individual Dietary Diversity Scale, and chart review. RESULTS: One hundred and nine HIV-1 and/or HIV-2 participants were enrolled. The prevalence of food insecurity was 84.6% in Dakar and 89.5% in Ziguinchor. The prevalence of severe food insecurity was 59.6% in Dakar and 75.4% in Ziguinchor. The prevalence of malnutrition (BMI <18.5) was 19.2% in Dakar and 26.3% in Ziguinchor. Severe food insecurity was associated with missing clinic appointments (p = 0.01) and not taking antiretroviral therapy due to hunger (p = 0.02). Malnutrition was associated with lower CD4 cell counts (p = 0.01). CONCLUSIONS: Severe food insecurity and malnutrition are highly prevalent among HIV-infected adults in both Dakar and Ziguinchor, and are associated with poor HIV outcomes. Our findings warrant further studies to determine the root causes of malnutrition and food insecurity in Senegal, and the short- and long-term impacts of malnutrition and food insecurity on HIV care. Urgent interventions are needed to address the unacceptably high rates of malnutrition and food insecurity in this population. PMID- 26529510 TI - Highly Invasive Listeria monocytogenes Strains Have Growth and Invasion Advantages in Strain Competition. AB - Multiple Listeria monocytogenes strains can be present in the same food sample; moreover, infection with more than one L. monocytogenes strain can also occur. In this study we investigated the impact of strain competition on the growth and in vitro virulence potential of L. monocytogenes. We identified two strong competitor strains, whose growth was not (or only slightly) influenced by the presence of other strains and two weak competitor strains, which were outcompeted by other strains. Cell contact was essential for growth inhibition. In vitro virulence assays using human intestinal epithelial Caco2 cells showed a correlation between the invasion efficiency and growth inhibition: the strong growth competitor strains showed high invasiveness. Moreover, invasion efficiency of the highly invasive strain was further increased in certain combinations by the presence of a low invasive strain. In all tested combinations, the less invasive strain was outcompeted by the higher invasive strain. Studying the effect of cell contact on in vitro virulence competition revealed a complex pattern in which the observed effects depended only partially on cell-contact suggesting that competition occurs at two different levels: i) during co cultivation prior to infection, which might influence the expression of virulence factors, and ii) during infection, when bacterial cells compete for the host cell. In conclusion, we show that growth of L. monocytogenes can be inhibited by strains of the same species leading potentially to biased recovery during enrichment procedures. Furthermore, the presence of more than one L. monocytogenes strain in food can lead to increased infection rates due to synergistic effects on the virulence potential. PMID- 26529511 TI - Plant Uptake and Distribution of Endosulfan and Its Sulfate Metabolite Persisted in Soil. AB - The distributions of endosulfan (ED) residues (alpha-, beta-isomers, and sulfate metabolite) in cucumbers grown in soils treated with ED at concentrations of 20 and 40 mg kg-1 were assessed using indoor and outdoor experiments. In all treatments, degradation rates of the alpha-isomer in soils were higher than that of the beta-isomer. In the indoor tests, uptake amounts of total ED by cucumbers, after 15 d of growth, were 7.8 and 14.5 mg kg-1 in 20 and 40 mg kg-1-treated pots, respectively. For growth time from 15 to 30 d, uptake amounts in 20 and 40 mg kg-1-treated pots were 3.8 and 7.9 mg kg-1, respectively. Outdoor tests resulted in smaller ED residues in cucumbers than those in indoor tests. In both indoor and outdoor tests, ED residues absorbed were highest in roots, and the alpha-isomer was the more frequently absorbed isomer. These results will be useful for determining management criteria for soil persistent pesticides. PMID- 26529512 TI - Functional Modulation of Regulatory T Cells by IL-2. AB - The suppressive function of regulatory T cells (Tregs) is critical to the maintenance of immune homeostasis in vivo and yet, the specific identification of Tregs by phenotypic markers is not perfect. Tregs were originally identified in the CD4+CD25+ fraction of T cells, but FoxP3 expression was later included as an additional marker of Tregs as FoxP3 expression was identified as being critical to the development and function of these cells. Intracellular expression of FoxP3 makes it difficult in using to isolate live and not permeabilized cells for functional assays. As such CD4+CD25+ fraction is still frequently used for functional assays of Tregs. Although, the CD4+CD25+ fraction substantially overlaps with the FoxP3+ fraction, the minor mismatch between CD4+CD25+ and FoxP3+ fractions may confound the functional characteristics of Tregs. In this study, we isolated CD4+FoxP3+ as well as CD4+CD25+ fractions from Foxp3 knock-in mice, and compared their proliferative and suppressive activity in the presence or absence of various concentrations of IL-2. Our results showed comparable patterns of proliferative and suppressive responses for both fractions, except that contrary to the CD4+CD25+ fraction the FoxP3+ fraction did not proliferate in an autocrine fashion even in response to a strong stimulation. In presence of exogenous IL-2, both CD4+CD25+ and CD4+FoxP3+ fractions were more sensitive than the CD4+CD25- responder cells in proliferative responsiveness. In addition, a low dose IL-2 enhanced whereas a high dose abrogated the suppressive activities of the CD4+CD25+ and CD4+FoxP3+ fractions. These results may provide an additional understanding of the characteristics of the various fractions of isolated Tregs based on phenotype and function and the role of varying levels of exogenous IL-2 on the suppressive activity of these cells. PMID- 26529513 TI - Informed Choice in the German Mammography Screening Program by Education and Migrant Status: Survey among First-Time Invitees. AB - Breast cancer is the most prevalent cancer among women and mammography screening programs are seen as a key strategy to reduce breast cancer mortality. In Germany, women are invited to the population-based mammography screening program between ages 50 to 69. It is still discussed whether the benefits of mammography screening outweigh its harms. Therefore, the concept of informed choice comprising knowledge, attitude and intention has gained importance. The objective of this observational study was to assess the proportion of informed choices among women invited to the German mammography screening program for the first time. A representative sample of 17,349 women aged 50 years from a sub-region of North Rhine Westphalia was invited to participate in a postal survey. Turkish immigrant women were oversampled. The effects of education level and migration status on informed choice and its components were assessed. 5,847 (33.7%) women responded to the postal questionnaire of which 4,113 were used for analyses. 31.5% of the women had sufficient knowledge. The proportion of sufficient knowledge was lower among immigrants and among women with low education levels. The proportion of women making informed choices was low (27.1%), with similar associations with education level and migration status. Women of low (OR 2.75; 95% CI 2.18-3.46) and medium education level (OR 1.49; 95% CI 1.27-1.75) were more likely to make an uninformed choice than women of high education level. Turkish immigrant women had the greatest odds for making an uninformed choice (OR 5.30, 95% CI 1.92-14.66) compared to non-immigrant women. Other immigrant women only had slightly greater odds for making an uninformed choice than non-immigrant women. As immigrant populations and women with low education level have been shown to have poor knowledge, they need special attention in measures to increase knowledge and thus informed choices. PMID- 26529514 TI - Evaluating adult cystic fibrosis care in British Columbia: Disparities in access to a multidisciplinary treatment centre. PMID- 26529516 TI - Metal-free tandem oxidative C(sp(3))-H bond functionalization of alkanes and dearomatization of N-phenyl-cinnamamides: access to alkylated 1 azaspiro[4.5]decanes. AB - The TBPB promoted tandem oxidative C(sp(3))-H bond functionalization of simple alkanes/alkylation-initiated dearomatization of N-phenyl-cinnamamides is reported, providing a direct method for the synthesis of alkylated 1 azaspiro[4.5]decanes with excellent regioselectivity and diastereoselectivity. The formation of two C(sp(3))-C(sp(3)) bonds and construction of a spirodienone motif are involved in one step. PMID- 26529515 TI - Associations of White Matter Microstructure with Clinical and Demographic Characteristics in Heavy Drinkers. AB - Damage to the brain's white matter is a signature injury of alcohol use disorders (AUDs), yet understanding of risks associated with clinical and demographic characteristics is incomplete. This study investigated alcohol problem severity, recent drinking behavior, and demographic factors in relation to white matter microstructure in heavy drinkers. Magnetic resonance imaging (MRI) scans, including diffusion tensor imaging (DTI), were collected from 324 participants (mean age = 30.9 +/- 9.1 years; 30% female) who reported five or more heavy drinking episodes in the past 30 days. Drinking history and alcohol problem severity were assessed. A common white matter factor was created from fractional anisotropy (FA) values of five white matter tracts: body of corpus callosum, fornix, external capsule, superior longitudinal fasciculus, and cingulate gyrus. Previous research has implicated these tracts in heavy drinking. Structural equation modeling (SEM) analyses tested the hypothesis that, after controlling for duration of alcohol exposure, clinical and behavioral measures of alcohol use severity would be associated with lower white matter factor scores. Potential interactions with smoking status, gender, age, treatment-seeking status, and depression or anxiety symptoms also were tested. Controlling for number of years drinking, greater alcohol problem severity and recent drinking frequency were significantly associated with lower white matter factor scores. The effect of drinking frequency differed significantly for men and women, such that higher drinking frequency was linked to lower white matter factor scores in women but not in men. In conclusion, alcohol problem severity was a significant predictor of lower white matter FA in heavy drinkers, after controlling for duration of alcohol exposure. In addition, more frequent drinking contributed to lower FA in women but not men, suggesting gender-specific vulnerability to alcohol neurotoxicity. PMID- 26529518 TI - Doctors' Attachment Orientations, Emotion Regulation Strategies, and Patient Satisfaction: A Multilevel Analysis. AB - Extending recent research on emotion regulation in doctor-patient interaction, the present study examined relationships between doctors' attachment orientations, their emotion regulation strategies, and patients' satisfaction with the encounter. Forty doctors completed scales of attachment orientations and emotion regulation strategies, and 160 of their patients reported on a standard measure of satisfaction with their doctor. Results from multilevel analyses showed that doctors' avoidant and anxious attachment orientations were independently associated with lower satisfaction for patients higher on serious illness perceptions. Doctors' emotion regulation strategies did not mediate insecure attachment orientation relationships with patients' satisfaction as anticipated, but these regulatory strategies were an independent factor associated with satisfaction levels of patients with higher illness severity perceptions. The study confirms predictions based on attachment theory that doctors' insecure attachment can have adverse effects for doctor-patient interaction. PMID- 26529517 TI - High Cardiorespiratory Fitness Is Negatively Associated with Daily Cortisol Output in Healthy Aging Men. AB - Physical fitness has salutary psychological and physical effects in older adults by promoting neuroplasticity and adaptation to stress. In aging, however, the effects of fitness on the hypothalamic-pituitary-adrenal (HPA) axis are mixed. We investigated the association between cardiorespiratory fitness and HPA activity in healthy elderly men (n = 22, mean age 68 y; smokers, obese subjects, those taking drugs or reporting recent stressful events were excluded), by measuring in saliva: i) daily pattern of cortisol secretion (6 samples: 30' post-awakening, and at 12.00, 15.00, 18.00, 21.00, 24.00 h); and ii) the cortisol response to a mental challenge. Cardiorespiratory fitness (VO2max) was estimated using the Rockport Walking Test and the participants were assigned to high-fit (HF, >=60 degrees , n = 10) and low-fit (LF, <=35 degrees , n = 12) groups according to age specific percentiles of VO2max distribution in the general population. At all daytimes, basal cortisol levels were lower in the HF than the LF group, most notably in the evening and midnight samples, with a significant main effect of physical fitness for cortisol levels overall; the area-under-the-curve for total daily cortisol output was significantly smaller in the HF group. Among the subjects who responded to mental stress (baseline-to-peak increment >1.5 nmol/L; n = 13, 5 LF, 8 HF), the amplitude of cortisol response and the steepness of recovery decline displayed an increasing trend in the HF subjects, although between-group differences failed to reach the threshold for significance. In conclusion, cardiorespiratory fitness in healthy aging men is negatively correlated with daily cortisol output and contributes to buffering the HPA dysregulation that occurs with advancing age, thus possibly playing a beneficial role in contrasting age-related cognitive and physical decline. PMID- 26529519 TI - A theoretical study of O2 activation by the Au7-cluster on Mg(OH)2: roles of surface hydroxyls and hydroxyl defects. AB - Using density functional theory (DFT) calculations, we investigated O2 activation by the Au7-cluster supported on the perfect and hydroxyl defective Mg(OH)2(0001) surface. It is revealed that hydroxyl groups on the perfect Mg(OH)2(0001) surface can not only enhance the stability of the Au7-cluster, but also help the adsorption of the O2 molecule through hydrogen-bonding interactions with the 2nd layered interfacial Au sites. Density of states (DOS) analysis shows that the d band centers of the 2nd-layered interfacial Au atoms are very close to the Fermi level, which thereby reduce the Pauli repulsion and promote the O2 adsorption. These two responses make the 2nd-layered interfacial Au atoms favor O2 activation. Interestingly, the surface hydrogen atoms activated by the 1st layered Au atoms can facilitate the O2 dissociation process as well. Such a process is dynamically favorable and more inclined to occur at low temperatures compared to the direct dissociation process. Meanwhile, the hydroxyl defects of Mg(OH)2(0001) located right under the Au7-cluster can also up-shift the d-band centers of the surrounding Au atoms toward the Fermi level, enhancing its catalytic activity for O2 dissociation. In contrast, the d-band center of Au atoms surrounding the hydroxyl defect near the Au7-cluster exhibits an effective down-shift to lower energies, and therefore holds low activity. These results unveiled the roles of surface hydroxyls and hydroxyl defects on the Au/Mg(OH)2 catalyst in O2 activation and could provide a theoretical guidance for chemists to efficiently synthesize Au/hydroxide catalysts. PMID- 26529520 TI - Energy Balance in Huntington's Disease. AB - INTRODUCTION: Little is known about the energy needs in Huntington's disease (HD). The aims of this study are to analyze and compare the total energy expenditure (TEE) and energy balance (EB) in a representative sample of HD patients with healthy controls. METHODS: This is an observational, case-control single-center study. Food caloric energy intake (EI) and TEE were considered for estimating EB. A dietary recall questionnaire was used to assess the EI. TEE was computed as the sum of resting energy expenditure (REE), measured by indirect calorimetry and physical activity (PA) monitored by an actigraph. RESULTS: A total of 22 patients were included (36% men, mean age 50.3 +/- 15.6 years, motor Unified Huntington's Disease Scale 27.9 +/- 23.7, total functional capacity 11.0 (7.0-13.0), EI 38.6 +/- 10.0 kcal/kg, PA 5.3 (3.0-7.4) kcal/kg, REE 30.9 +/- 6.4 kcal/kg, TEE 2,023.4 (1,592.0-2,226.5) kcal/day) and 18 controls (50% men, mean age 47.4 +/- 13.8 years, EI 38.6 +/- 10.3 kcal/kg, PA 8.4 (5.0-13.8) kcal/kg, REE 30.8 +/- 6.6 kcal/kg, TEE 2,281.0 (2,057.3-2,855.3) kcal/day). TEE was significantly lower in patients compared to controls (p = 0.03). PA was lower in patients compared to controls (p = 0.02). CONCLUSIONS: Although patients with HD appeared to have lower energy expenditure, mainly due to decreased voluntary PA, they were still able to maintain their energy needs with an adequate food intake. (c) 2015 S. Karger AG, Basel. PMID- 26529521 TI - Growth in Boys with 45,X/46,XY Mosaicism: Effect of Growth Hormone Treatment on Statural Growth. AB - 45,X/46,XY mosaicism is a rare sex chromosome disorder of sex development. Short stature is a main feature of boys with this condition. Different causes likely contribute to growth impairment. Growth hormone (GH) has been administered to treat short stature in boys with 45,X/46,XY mosaicism, but conflicting data are available. Here, spontaneous growth patterns as well as short- and long-term follow-up studies during GH therapy in these patients are reviewed. Short- and mid-term data showed an improvement of the growth pattern in GH-treated boys, mainly when hormonal therapy was started early, while long-term follow-up demonstrated similar adult heights in GH-treated and untreated patients. Individual biological factors (e.g. different chromosome constitution, different mosaicism among various tissues, impaired pubertal growth spurt), non-homogeneous GH doses and different ages at start of therapy may contribute to the variable results. Thus, early GH therapy at pharmacological doses may improve the growth pattern of short boys with 45,X/46,XY mosaicism, but data on adult height are disappointing. Evaluation of larger patient samples treated by homogeneous doses and long-term follow-up studies assessing adult height and safety are needed to reach definitive conclusions on GH therapy in boys with 45,X/46,XY mosaicism. PMID- 26529522 TI - Parallel Representation of Value-Based and Finite State-Based Strategies in the Ventral and Dorsal Striatum. AB - Previous theoretical studies of animal and human behavioral learning have focused on the dichotomy of the value-based strategy using action value functions to predict rewards and the model-based strategy using internal models to predict environmental states. However, animals and humans often take simple procedural behaviors, such as the "win-stay, lose-switch" strategy without explicit prediction of rewards or states. Here we consider another strategy, the finite state-based strategy, in which a subject selects an action depending on its discrete internal state and updates the state depending on the action chosen and the reward outcome. By analyzing choice behavior of rats in a free-choice task, we found that the finite state-based strategy fitted their behavioral choices more accurately than value-based and model-based strategies did. When fitted models were run autonomously with the same task, only the finite state-based strategy could reproduce the key feature of choice sequences. Analyses of neural activity recorded from the dorsolateral striatum (DLS), the dorsomedial striatum (DMS), and the ventral striatum (VS) identified significant fractions of neurons in all three subareas for which activities were correlated with individual states of the finite state-based strategy. The signal of internal states at the time of choice was found in DMS, and for clusters of states was found in VS. In addition, action values and state values of the value-based strategy were encoded in DMS and VS, respectively. These results suggest that both the value-based strategy and the finite state-based strategy are implemented in the striatum. PMID- 26529523 TI - Implications of BMI for the Prognosis of Gastric Cancer among the Japanese Population. AB - BACKGROUND: The clinical significance of body mass index (BMI) on the surgical outcomes in gastric cancer patients still remains controversial. METHODS: The subjects included 427 patients who underwent gastrectomy between January 2001 and December 2005. The patients were principally divided into 3 groups on the basis of BMI: low (<18.5 kg/m2), normal (>=18.5-<25.0 kg/m2) and high (>=25.0 kg/m2). RESULTS: The low-BMI patients had more advanced disease than the other patients. There were no statistically significant differences in the characteristics of the normal- and high-BMI patients. The operation time was longer in the high-BMI group, but there were no differences in terms of lymph node dissection and postoperative complications among these 3 groups. The overall survival and disease-specific survival of the low-BMI group were worse than the other 2 groups. These survival rates of high-BMI group tended to be better than those of the normal BMI group; however, it was not statistically different. A multivariate analysis of these survival rate showed that a low BMI was an independent predictor of a poor prognosis. CONCLUSIONS: A low-BMI was an independent factor of poor prognosis for overall and disease-specific survivals after surgery in Japanese patients with gastric cancer. A high-BMI was not a risk factor. PMID- 26529524 TI - How do People Make Sense of Unfamiliar Visualizations?: A Grounded Model of Novice's Information Visualization Sensemaking. AB - In this paper, we would like to investigate how people make sense of unfamiliar information visualizations. In order to achieve the research goal, we conducted a qualitative study by observing 13 participants when they endeavored to make sense of three unfamiliar visualizations (i.e., a parallel-coordinates plot, a chord diagram, and a treemap) that they encountered for the first time. We collected data including audio/video record of think-aloud sessions and semi-structured interview; and analyzed the data using the grounded theory method. The primary result of this study is a grounded model of NOvice's information Vlsualization Sensemaking (NOVIS model), which consists of the five major cognitive activities: 1 encountering visualization, 2 constructing a frame, 3 exploring visualization, 4 questioning the frame, and 5 floundering on visualization. We introduce the NOVIS model by explaining the five activities with representative quotes from our participants. We also explore the dynamics in the model. Lastly, we compare with other existing models and share further research directions that arose from our observations. PMID- 26529525 TI - Off the Radar: Comparative Evaluation of Radial Visualization Solutions for Composite Indicators. AB - A composite indicator (CI) is a measuring and benchmark tool used to capture multi-dimensional concepts, such as Information and Communication Technology (ICT) usage. Individual indicators are selected and combined to reflect a phenomena being measured. Visualization of a composite indicator is recommended as a tool to enable interested stakeholders, as well as the public audience, to better understand the indicator components and evolution over time. However, existing CI visualizations introduce a variety of solutions and there is a lack in CI's visualization guidelines. Radial visualizations are popular among these solutions because of CI's inherent multi-dimensionality. Although in dispute, Radar-charts are often used for CI presentation. However, no empirical evidence on Radar's effectiveness and efficiency for common CI tasks is available. In this paper, we aim to fill this gap by reporting on a controlled experiment that compares the Radar chart technique with two other radial visualization methods: Flower-charts as used in the well-known OECD Betterlife index, and Circle-charts which could be adopted for this purpose. Examples of these charts in the current context are shown in Figure 1. We evaluated these charts, showing the same data with each of the mentioned techniques applying small multiple views for different dimensions of the data. We compared users' performance and preference empirically under a formal task-taxonomy. Results indicate that the Radar chart was the least effective and least liked, while performance of the two other options were mixed and dependent on the task. Results also showed strong preference of participants toward the Flower chart. Summarizing our results, we provide specific design guidelines for composite indicator visualization. Fig. 1: Three radial solutions for composite indicator visualizations compared empirically for users' performance and preferences. PMID- 26529527 TI - Misuse of "Power" and Other Mechanical Terms in Sport and Exercise Science Research. AB - Despite the Systeme International d'Unites (SI) that was published in 1960, there continues to be widespread misuse of the terms and nomenclature of mechanics in descriptions of exercise performance. Misuse applies principally to failure to distinguish between mass and weight, velocity and speed, and especially the terms "work" and "power." These terms are incorrectly applied across the spectrum from high-intensity short-duration to long-duration endurance exercise. This review identifies these misapplications and proposes solutions. Solutions include adoption of the term "intensity" in descriptions and categorizations of challenge imposed on an individual as they perform exercise, followed by correct use of SI terms and units appropriate to the specific kind of exercise performed. Such adoption must occur by authors and reviewers of sport and exercise research reports to satisfy the principles and practices of science and for the field to advance. PMID- 26529529 TI - [3D-TOF MR-angiography with high spatial resolution for surgical planning in insular lobe gliomas]. AB - Despite the obvious progress in modern neurosurgery, surgery for glial tumors of the insular lobe is often associated with a high risk of postoperative neurological deficit, which is primarily caused by damage to perforating arteries of the M1 segment of the middle cerebral artery. OBJECTIVE: The work is aimed at evaluating the effectiveness of high resolution time-of-flight (3D-TOF) MR angiography in imaging of medial and lateral lenticulostriate arteries and determining their relationship to tumor edge in patients with gliomas of the insula. MATERIAL AND METHODS: 3D-TOF MR angiography data were analyzed in 20 patients with primarily diagnosed cerebral gliomas involving the insula. All patients underwent non-contrast enhanced 3D-TOF MR angiography. In 6 cases, 3D TOF MRA was performed before and after contrast enhancement. RESULTS: 3D-TOF angiography before intravenous contrast injection was capable of visualizing the medial lenticulostriate arteries in 19 patients (95% of all cases) and lateral lenticulostriate arteries in 18 patients (90% of all cases). Contrast-enhanced 3D TOF angiography allows for better visualization of both the proximal and distal segments of lenticulostriate arteries. Three variants of relationship between the tumor and lenticulostriate arteries were identified. Variant I: the tumor grew over the arteries without their displacement in 2 cases (10% of the total number of observations); variant II: the tumor caused medial displacement of arteries without growing over them in 11 cases (55% of the total number of observations); variant III: the tumor partially grew over and displaced arteries in 2 cases (10%). In 25% of cases (5 patients), tumor was poorly visualized on 3D-TOF MR angiograms because their signal characteristics did not differ from those of the medulla (tumor tissue was T1 isointense). As a result, it was impossible to determine the relationship between the tumor and lenticulostriate arteries. CONCLUSION: High spatial resolution time-of-flight MR angiography can be recommended for preoperative imaging of lenticulostriate arteries to plan the extent of neurosurgical resection in patients with glial tumors of the insular lobe. PMID- 26529530 TI - [Blood-brain barrier permeability in healthy rats and rats with experimental C6 glioma after fractionated radiotherapy of the brain]. AB - OBJECTIVE: To evaluate the effect of fractionated radiotherapy on permeability of the blood-brain barrier in healthy rats and rats with C6 glioma in vivo. MATERIAL AND METHODS: An increase in BBB permeability in C6 glioma was assessed by dynamic MRI monitoring (glioma size before and after radiation therapy in combination with immunotherapy, n=30) and confocal microscopy (fluorescence imaging of tumor invasion boundaries in a dose-dependent experiment for the amount of injected antibodies). In healthy rats, BBB permeability to macromolecular substances (MMS) was assessed by ELISA (n=23, 192 plasma samples) and confocal microscopy (n=7). RESULTS: It was shown that BBB permeability to biological macromolecules in blood brain and brain-blood directions was increased after fractionated radiotherapy. CONCLUSION: Drug delivery to the brain can be improved using therapeutic doses of radiation treatment that affects the BBB and minimizes the risk of serious side effects that are often associated with the drug dose. PMID- 26529531 TI - [Preliminary results of chronic intrathecal therapy in treatment of spastic syndromes of various etiologies]. AB - OBJECTIVE: To estimate the effectiveness of the chronic intrathecal baclofen infusion (ITB) for the treatment of botuloresistant spastic disorders. MATERIAL AND METHODS: ITB have been performed in 15 cases of spastic disorders. In 8 cases spasticity was the result of cerebral palsy, 5 - spinal cord injure, 1 - cerebral injure, 1 - pyogenic spinal epiduritis. The results of surgical treatment were estimated with the Ashworth, GMFM-88 and Arens scales. These data have been exposed statistically analysis. RESULTS: Significantly decrease of spasticity have been revealed in most cases: from 4.26+/-0.7 points before the operation to 1.8+/-0.67 points after the operation (p<0.004). In 8 cases we have observed improvement in motor functions. CONCLUSION: ITB is an effective procedure which leads to decreasing of spasticity, incree of movement volume and improvement in motor functions in patients with spastic disorders. PMID- 26529532 TI - [Comprehensive assessment of the outcomes of surgical treatment of patients with metastatic spinal cord injuries]. AB - INTRODUCTION: Every year the number of cancer patients increases due to increased life expectancy. According to various sources, metastases in the spine are found during autopsy in 30-90% of patients with a history of cancer. So far, there have been no full-scale studies of the quality of life of patients with various metastatic tumors of the spine who underwent surgical treatment in Russian literature. The main objective of this study was to demonstrate the need for implementing the comprehensive treatment of patients with metastases in the spine and target setting as the main tool to identify the factors that adversely affect the patients' quality of life. MATERIAL AND METHODS: The quality of life of 56 patients aged 16 to 81 years was assessed, including 26 males and 30 females. Twenty-six patients underwent surgical treatment between 2002 and 2009, and thirty patients underwent surgical treatment between 2009 and 2014. Kidney cancer was a primary disease in 30.3% of patients, multiple myeloma was a primary disease in 23.1% of cases, and the primary source of a tumor was not identified in cancer screening in 10.5% of cases. There were also isolated cases of melanoma, thymoma, metastases of tumors of the gastrointestinal tract, uterus, ovary, lung, prostate, pancreas, and the thyroid gland, which on the average amounted to 3.5% (1.8 to 7.14%). The quality of life of patients was studied using the EORTC QLQ C30 scale. The patients were surveyed prior to the surgery and then 1, 3, 6 and 12 months after surgical treatment during 1 year or until death. Preoperative and postoperative contrast-enhanced SCT and MRI examinations were used to control the extent of decompression of neural structures. RESULTS: On the basis of these findings, the authors identified the main factors affecting the quality of life of patients and formulated a range of treatment goals for patients with metastases in the spine. CONCLUSION: Surgical treatment has a positive effect on the quality of life of patients with metastases in the spine. However, it is not a key factor in the context of survival rate of these patients. Therefore, a decision on the possibility and necessity of surgical treatment should be taken in cooperation with the patient and oncologists of different specialties. PMID- 26529533 TI - [Optimization of segmental lumbar spine instability treatment using minimally invasive spinal fusion technique]. AB - Open transforaminal lumbar interbody fusion (TLIF) using transpedicular rods and interbody cage, which is used to treat segmental instability, is associated with a significant paravertebral muscle and ligament injury. A new rigid fusion method was introduced to improve the outcome of patients' treatment. OBJECTIVE: To conduct a comparative analysis of the effectiveness of minimally invasive fusion technique and TLIF to improve the treatment results in patients with symptomatic lumbar spine degeneration concomitant with moderate segmental instability of the lumbar spine. MATERIAL AND METHODS: The study involved 90 patients, which were divided into 2 groups. Transforaminal interbody fusion with Pezo-T PEEK cage was performed after spinal canal reconstruction in both groups. In the first group (n=45), interbody fusion was augmented by 4-point transpedicular rod fixation (Konmet, Russia); in the second group (n=45), by Coflex-F rigid interspinous spacer. Patients were followed up and the results were assessed within 24 months after surgery. RESULTS: The intergroup comparison of pain level using the visual analogue scale, the need for analgesics, and quality of life according to Oswestry Disability Index score during the early postoperative period demonstrated significantly better outcomes in the second group of patients due to lesser operative trauma of the paravertebral soft tissue. Interbody fusion was observed within 20-36 months in 95% of group I patients and 94% of group II patients (p>0.05). Postoperative complications were observed in 17.8% of patients in group I and in 2.2% of cases in group II (p<0.001). CONCLUSION: Stabilization by rigid interspinous spacer and transforaminal interbody cage provides better clinical outcomes and fewer postoperative complications as compared to the conventional TLIF technique with similar X-ray rate of bone block formation in patients with moderate segmental instability of the lumbar spine, thus optimizing the treatment of such patients. PMID- 26529534 TI - [Features of the course of nosocomial meningitis in patients of neurosurgical intensive care unit]. AB - OBJECTIVE: To determine the incidence rate and risk factors of nosocomial meningitis in patients with complicated postoperative period. MATERIAL AND METHODS: We report the results of prospective observation of the course of bacterial meningitis in patients with complicated postoperative period at neurosurgical intensive care unit in 2010-2014. RESULTS: Nosocomial meningitis (NM) developed in 146 patients, which accounted for 12.6+/-1.0% (CI, 10.74 14.66). Patients with meningitis were characterized by longer stay at ICU, prolonged mechanical ventilation, need for central venous access and invasive hemodynamic monitoring, as well as longer course of antibacterial therapy. Frequency of invasive monitoring of intracranial pressure was similar in these two groups of patients. Bloodstream infections (14.8% vs. 4.9%; p<0.000), respiratory tract infections (55% vs. 35.6%; p<0.000), and urinary tract infections (56.4% vs. 30.9%; p<0.000) were more frequently observed in patients with NM. The following significant differences were observed between the group of NM patients and the control group: more frequent use of external ventricular drain (72.5% vs. 26.1%; p<0.000), number of reoperations (64.7% vs. 36.3%; p<0.000), and the total operating room time (417.3 min vs. 337.5 min; p<0.000). Etiology was ascertained in 61.0+/-4.0% of cases of nosocomial meningitis. CoNS (33.0%) and Acinetobacter baumannii (21.3%) were the main pathogens isolated from cerebrospinal fluid. The mortality in patients with meningitis was 31.5+/-3.8%. CONCLUSION: External ventricular drain, repeated surgery, long-term stay in the operating room, as well as other types of infections may be considered as risk factors for developing nosocomial meningitis in neurosurgical patients at ICU. PMID- 26529535 TI - [The structure of activation of the language zone in patients with intracerebral tumors according to fMRI with respect to tumor location and the functional asymmetry profile]. AB - MATERIAL AND METHODS: A total of 50 patients were examined prior to surgical resection of intracranial tumors of the temporal and frontal lobes. Left-sided tumors were observed in 33 patients and right-sided tumors were observed in 17 patients. The functional asymmetry profile was determined using self-assessment, the Annet questionnaire, and the dichotic listening task. Twelve patients were left-handers or retrained left-handers and the remaining 38 patients were right handers. FMRI examination was carried out on a 3.0 T SignaHDxt magnetic resonance tomograph (GE). The standard language block design paradigm was used in the study. We used the following tests: 1) recitation of months in reverse order; 2) generation of nouns according to the initial letters shown on the screen (K, M, L, N, P, C); 3) generation of verbs according to simple actions shown on the screen; 4) producing sentences using nouns shown on the screen; 5) listening to text through headphones. Data were processed using the standard BrainWave PA software (General Electric). Z-test was used in the range from 6 to 9. In all the studies, p<0.001. Statistical data processing included the nonparametric Spearman's test to determine the correlation between lateralization of the detected activation zone under speech load and tumor location (tumor is adjacent to the language zone, invades the language zone, or is located far from the language zone), as well as left- or right-handedness. RESULTS: Among 16 patients (right-handers and 2 left-handers) the activation of language zones was observed only on the left side; in one left-handed patient, Broca's area was detected only on the right side. In other patients (including right-handers with right-sided tumors), lateralization of language zones was different, including bilateral. Statistical processing revealed that bilateral activation of both Broca's and Wernicke's areas was more frequently observed in left-handers. Broca's area was more frequently detected on the left side in the presence of a distant tumor, while this trend did not apply for Wernicke's area. CONCLUSION: Localization of activation of Broca's area is more dependent on tumor location, while it depends on personal characteristics of an individual in the case of Wernicke's area. PMID- 26529536 TI - [Growing teratoma syndrome in a patient with intracranial germ cell tumor]. AB - A six-year-old patient with non-germinomatous germ cell tumor of the chiasmatic sellar area developed polyuria and polydipsia as the first symptoms of the disease. Then there were signs of precocious puberty and vision impairment. MRI examination revealed a shiasmatic sellar tumor and occlusive hydrocephalus. Tumor marker levels in blood serum were elevated. The alpha-fetoprotein level was increased 5-fold; human chorionic gonadotropin 20-fold. These levels increased over time. The patient received 2 cycles of PEI multiagent chemotherapy (Ifosfamide 1.5 g/m(2), Cisplatin 20 mg/m(2), Etoposide 100 mg/m(2)) during 5 days and 1 cycle of second-line multiagent chemotherapy (Cisplatin 100 mg/m(2) for 1 day and Endoxan 1500 mg/m(2) for 2 days). Despite the decrease in tumor marker levels to normal values, the patient's vision still deteriorated. MRI examination revealed that tumor size increased and its structure changed. Total tumor resection led to vision improvement and regression of intracranial hypertension. Histological analysis of tumor tissue only revealed a mature teratoma. This phenomenon, known as growing teratoma syndrome, is very rare among patients with intracranial non-germinomatous germ cell tumors. PMID- 26529537 TI - [Cardiac arrest after induction of anesthesia in neurosurgical patients]. AB - The paper reports two clinical cases observed with a time lag of four years. In both cases, there were severe clinical symptoms of intracranial hypertension before the surgery. Prompt full-scale resuscitation was required in both cases due to asystole that developed immediately after induction of anesthesia and tracheal intubation. In one case, cardiac activity was successfully recovered by complex resuscitation with the emergency drainage of the cerebral ventricles. The possible causes of complications and preventive measures were discussed. PMID- 26529538 TI - [Transarterial and transvenous embolization of deep binodal arteriovenous malformation of the brain]. AB - INTRODUCTION: The multimodal approach to treatment of arteriovenous malformations yields good results. However, small and deep malformations still pose a big problem for surgeons. Transvenous embolization was designed as an alternative for the cases when endovascular treatment is required and conventional transarterial embolization is not available. CASE STUDY: A 41-year-old patient with binodal malformation in the subcortical nuclei of the left hemisphere of the brain, which had previously become a source of massive parenchymal ventricular hemorrhage, was operated on using the transarterial and, for the first time in our clinic, transvenous approaches. Transarterial embolization of the thalamic node of malformation was performed as the first step. After 6 months, transvenous embolization of the hypothalamic node of malformations was performed as the second step. Successful operation was ensured by using a stable coaxial guiding catheter system with the maximum distal approach and intranidal positioning of a microcatheter with detachable distal portion upon temporary occlusion of afferent vessels of the malformations using a balloon catheter. The operation resulted in total thrombosis of the malformation. No perioperative complications were observed. Control examination in 6 months did not reveal recanalization of the malformation. CONCLUSION: The transvenous approach can be successfully used in endovascular treatment of small and deep arteriovenous malformations with a single drainage vein, which are inaccessible to direct surgery. It can also be used when radiosurgery is associated with a high risk in cases where transarterial embolization is infeasible. PMID- 26529539 TI - [New surgical treatment for vertebral artery pseudoaneurysm at the boundary between the V2 and V3 segments]. AB - The clinical case of a patient with a pseudoaneurysm of the left vertebral artery at the boundary between V(2) and V(3) segments after a stab wound to the neck is reported. The patient underwent a rare variant of surgical reconstruction of the vertebral artery, including resection of the vertebral artery pseudoaneurysm at the boundary between the V(2) and V(3) segments, the vertebrovertebral autovenous shunting (from the C(IV) vertebra to the C(I)-C(II) vertebrae with resection of the anterior wall of the vertebral artery canal). Postoperatively, SCT angiography revealed satisfactory blood flow in the shunt and improvement of the neurological status. The article provides a literature review on surgical procedures at the distal portion of the vertebral artery. The surgical technique was illustrated (intraoperative photos), demonstrating that the vertebral artery can be easily mobilized at any part of the V(2) segment with minimum damage to the adjacent tissues. PMID- 26529540 TI - Protein Arginine Methyltransferase 8: Tetrameric Structure and Protein Substrate Specificity. AB - Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of various proteins, and their dysregulations often correlate with tumorigenesis or developmental deficiency. Recent studies have focused on the in vivo substrate identification and the enzyme mechanism with peptide substrates. However, how PRMTs recognize substrates at the protein level remains unknown. PRMT8 is one of the least characterized type I PRMTs, and its crystal structure has not been reported. Here, we report the crystal structure of the PRMT8:SAH complex, identify a new non-histone protein substrate NIFK, and uncover a previously unknown regulatory region specifically required for recognizing NIFK. Instead of the canonical dimeric structure for other type I PRMTs, PRMT8 exists as a tetramer in solution. Using X-ray crystallography in combination with small angle X-ray scattering experiments, the dimer of dimers architecture in which two PRMT8 dimers are held together mainly by beta strand interactions was proposed. Mutation of PRMT8-beta15 impedes the methylation of NIFK but still allows methylation of the histone H2A/H2B dimer or a peptide substrate, suggesting a possible structural basis for recognition of protein substrates. Lastly, we observed two PRMT8 dimer orientations resulting in open (without SAH) and closed (with SAH bound) conformations. The comparison between open and closed conformations may provide useful information for PRMT1/8 inhibitor design. PMID- 26529541 TI - On the Origin of AMS "Cooking Organic Aerosol" at a Rural Site. AB - A number of field observations employing aerosol mass spectrometers (AMS) have demonstrated that organic matter rich in monocarboxylic acids and aliphatic carbonyls originating from cooking activities (the COA factor) contributes significantly to ambient organic matter (OM) in urban environments. Little is known about the contribution and nature of COA in rural localities. We studied the correlation of COA with chemical tracers at a rural site in the Po Valley, Italy. Our statistical approach, based on positive matrix factorization (PMF) shows that the COA factor was clearly linked to local emissions of chloride and methanesulfonic acid (MSA), chemical tracers not associated with cooking emissions, or with combustion sources. While the association with Cl is not understood at this stage, the emission of reduced sulfur compounds, aliphatic carbonyls and monocarboxylic acids is consistent with several agricultural practices (e.g., manure storage) and waste disposal systems (e.g., landfills) which characterize the suburban and rural areas of the Po Valley and of other many populated environments. It is concluded that the nature and origins of the AMS COA factor measured at a rural site are complex and include far more than the emissions from food cooking. PMID- 26529542 TI - Interaction between methylphenidate, methadone and different antidepressant drugs on antinociception in mice, and possible clinical implications. AB - OBJECTIVES: Methylphenidate (MPH), a psychostimulant used for treatment of attention deficit hyperactivity disorder (ADHD), is widely used by patients on antidepressants and methadone maintenance treatment (MMT). Preclinical studies showed MPH to exert analgesic effects when given alone or with morphine. METHODS: Using the hotplate assay on mice, we studied the interaction of acute doses of MPH with sub-threshold doses of methadone and different antidepressant medications and the interaction of increasing doses of MPH with chronic methadone. RESULTS: Adding a sub-threshold dose of venlafaxine, desipramine or clomipramine to MPH produced significant augmentation of MPH antinociception with each medication (P < 0.05). No such interactions were found between escitalopram and acute methadone. However, addition of increasing doses of MPH to chronic methadone given for 2 weeks using ALZET osmotic mini pumps induced augmentation of the antinociceptive effect of chronic methadone exclusively at high dose of MPH (7.5 mg/kg). CONCLUSIONS: These findings may implicate the need of an excessive attention to the administration of MPH to MMT patients. The no interaction found between MPH and escitalopram may hint to the possibly safe co administration of MPH and selective serotonin reuptake inhibitors (SSRIs) to depressed ADHD patients. Further studies are needed in order to validate these possible clinical implications. PMID- 26529543 TI - A Continuous Visible Light Spectrophotometric Approach To Accurately Determine the Reactivity of Radical-Trapping Antioxidants. AB - Inhibited autoxidations-monitored either by O2 consumption or hydroperoxide formation-are the most reliable way to obtain kinetic and stoichiometric information on the activity of radical-trapping antioxidants (RTAs). While many comparatively simple "antioxidant assays" (e.g., the DPPH assay) have supplanted these in popularity, they are generally very poor substitutes since they often do not employ peroxyl radicals as the oxidant and do not account for both the kinetics and stoichiometry of the radical-trapping reaction(s). In an effort to make inhibited autoxidations as simple as the most popular "antioxidant assays", we have developed a spectrophotometric approach for monitoring reaction progress in inhibited autoxidations. The approach employs easily prepared 1 phenylbutadiene-conjugated or styrene-conjugated BODIPY chromophores (PBD-BODIPY or STY-BODIPY, respectively) as signal carriers that co-autoxidize along with a hydrocarbon substrate. We show that inhibition rate constants (kinh) are accurately determined for a range of phenolic and diarylamine RTAs using this approach and that mechanistic experiments, such as kinetic isotope effects and kinetic solvent effects, are equally easily carried out. Moreover, synergistic interactions between RTAs, as well as the unconventional activity of diarylamine RTAs, are captured using this methodology. Lastly, we show that the approach can be employed for monitoring reactions in aqueous solution. PMID- 26529544 TI - Sevoflurane prevents lipopolysaccharide-induced barrier dysfunction in human lung microvascular endothelial cells: Rho-mediated alterations of VE-cadherin. AB - Acute lung injury (ALI) mainly occurs as increased permeability of lung tissue and pleural effusion. Inhaled anesthetic sevoflurane has been demonstrated to alleviate lung permeability by upregulating junction proteins after ischemia reperfusion. However, the exact mechanisms of its protective effect on reperfusion injury remain elusive. The aim of this study was to assess possible preconditioning with sevoflurane in an in vitro model of lipopolysaccharide (LPS) induced barrier dysfunction in human lung microvascular endothelial cells (HMVEC Ls). In this study, HMVEC-Ls were exposed to minimum alveolar concentration of sevoflurane for 2 h. LPS significantly increased the permeability of HMVEC-L. Moreover, the distribution of junction protein, vascular endothelial (VE) cadherin, in cell-cell junction area and the total expression in HMVEC-Ls were significantly decreased by LPS treatment. However, the abnormal distribution and decreased expression of VE-cadherin and hyperpermeability of HMVEC-Ls were significantly reversed by pretreatment with sevoflurane. Furthermore, LPS-induced activation of the RhoA/ROCK signaling pathway was significantly inhibited with sevoflurane. Such activation, abnormal distribution and decreased expression of VE-cadherin and hyperpermeability of HMVEC-Ls were significantly inhibited with sevoflurane pretreatment or knockdown of RhoA or ROCK-2. In conclusion, sevoflurane prevented LPS-induced rupture of HMVEC-L monolayers by suppressing the RhoA/ROCK-mediated VE-cadherin signaling pathway. Our results may explain, at least in part, some beneficial effects of sevoflurane on pulmonary dysfunction such as ischemia-reperfusion injury. PMID- 26529545 TI - Differential expression of estrogen receptor alpha and beta isoforms in multiple and solitary leiomyomas. AB - Uterine leiomyomas are benign myometrial neoplasms that function as one of the common indications for hysterectomy. Clinical and biological evidences indicate that uterine leiomyomas are estrogen-dependent. Estrogen stimulates cell proliferation through binding to the estrogen receptor (ER), of which both subtypes alpha and beta are present in leiomyomas. Clinically, leiomyomas may be singular or multiple, where the first one is rarely recurring if removed and the latter associated to a relatively young age or genetic predisposition. These markedly different clinical phenotypes indicate that there may different mechanism causing a similar smooth muscle response. To investigate the relative expression of ERalpha and ERbeta in multiple and solitary uterine leiomyomas, we collected samples from 35 Chinese women (multiple leiomyomas n = 20, solitary leiomyoma n = 15) undergoing surgery to remove uterine leiomyomas. ELISA assay was performed to detect estrogen(E2) concentration. Quantitative real-time PCR analysis was performed to detect ERalpha and ERbeta mRNA expression. Western blot and immunohistochemical analysis were performed to detect ERalpha and ERbeta protein expression. We found that ERalpha mRNA and protein levels of in multiple leiomyomas were significantly lower than those of solitary leiomyomas, whereas ERbeta mRNA and protein levels in multiple leiomyomas were significantly higher than those in solitary leiomyomas, irrespectively of the menstrual cycle stage. In both multiple and solitary leiomyomas, ERalpha expression was higher than that of ERbeta. E2 concentration in multiple and solitary leiomyomas correlated with that of ERalpha expression. ERalpha was present in nuclus and cytoplasma while estrogen receptor beta localized only in nuclei in both multiple and solitary leiomyomas. Our findings suggest that the difference of ERalpha and ERbeta expression between multiple and solitary leiomyomas may be responsible for the course of the disease subtypes. PMID- 26529546 TI - Death-associated protein kinase 2 mediates nocodazole-induced apoptosis through interaction with tubulin. AB - Death-associated protein kinase 2 (DAPK2) is a positive regulator of apoptosis. Although we recently reported that 14-3-3 proteins inhibit DAPK2 activity and its subsequent apoptotic effects via binding to DAPK2, the molecular mechanisms underlying the DAPK2-mediated apoptotic pathway remain unclear. Therefore, we attempted to further identify DAPK2-interacting proteins using pull-down assays and mass spectrometry. The microtubule beta-tubulin was identified as a novel DAPK2-binding protein in HeLa cells. Pull-down assays revealed that DAPK2 interacted with the alpha/beta-tubulin heterodimer, and that the C-terminal region of DAPK2, which differs from that of other DAPK family members, was sufficient for the association with beta-tubulin. Although the microtubule depolymerizing agent nocodazole induced apoptosis in HeLa cells, the level of apoptosis was significantly decreased in the DAPK2 knockdown cells. Furthermore, we found that treatment with nocodazole resulted in an increased binding of DAPK2 to beta-tubulin. These findings indicate that DAPK2 mediates nocodazole-induced apoptosis via binding to tubulin. PMID- 26529548 TI - Computational Study of Hydrogen Shifts and Ring-Opening Mechanisms in alpha Pinene Ozonolysis Products. AB - Autoxidation by sequential peroxy radical hydrogen shifts (H-shifts) and O2 additions has recently emerged as a promising mechanism for the rapid formation of highly oxidized, low-volatility organic compounds in the atmosphere. A key prerequisite for autoxidation is that the H-shifts of the initial peroxy radicals formed by, e.g., OH or O3 oxidation are fast enough to compete with bimolecular sink reactions. In most atmospheric conditions, these restrict the lifetime of peroxy radicals to be on the order of seconds. We have systematically investigated all potentially important (nonmethyl, sterically unhindered) H shifts of all four peroxy radicals formed in the ozonolysis of alpha-pinene using density functional (omegaB97XD) and coupled cluster [CCSD(T)-F12] theory. In contrast to the related but chemically simpler cyclohexene ozonolysis system, none of the calculated H-shifts have rate constants above 1 s(-1) at 298 K, and most are below 0.01 s(-1). The low rate constants are connected to the presence of the strained cyclobutyl ring in the alpha-pinene-derived peroxy radicals, which hinders H-shifts both from and across the ring. For autoxidation to yield the experimentally observed highly oxidized products in the alpha-pinene ozonolysis system, additional ring-opening reaction mechanisms breaking the cyclobutyl ring are therefore needed. We further investigate possible uni- and bimolecular pathways for opening the cyclobutyl ring in the alpha-pinene ozonolysis system. PMID- 26529547 TI - Effects of ion interactions with a cholesterol-rich bilayer. AB - Previous molecular dynamics (MD) simulations of ion-lipid interactions have focused on pure phospholipid bilayers. Many functional microdomains in membranes have a complex composition of cholesterol and phospholipids. Here, we reveal the distinctiveness of the interactions and the effects of the ions on a cholesterol rich bilayer by performing MD simulations of a cholesterol-rich bilayer with a Na(+)/K(+) mixture or a Na(+)/K(+)/Ca(2+)/Mg(2+) mixture. The simulations reveal that Ca(2+) maintains its dominant role in the interaction with the cholesterol rich bilayer, but the binding affinity of Mg(2+) to the cholesterol-rich bilayer is even weaker than the affinities of Na(+) and K(+), whereas its interaction with pure phospholipid bilayers is strong and is only slightly weaker than that of Ca(2+). Additionally, it was found that the presence of additional divalent cations induces the headgroups of phospholipids to be more perpendicular to the membrane surface, reducing the lateral movement of lipids and slightly altering the ordering and packing of the cholesterol-rich bilayer, different from divalent cations, which strongly influence that ordering and packing of pure phospholipid bilayers. Therefore, this study indicates that cholesterol in the membrane could affect the interactions between membrane and cations. The findings could be helpful in understanding the biological processes relevant to regulation of cations in cholesterol-rich regions. PMID- 26529549 TI - Evaluation of Automatic Analysis of Ultradeep Pyrosequencing Raw Data to Determine Percentages of HIV Resistance Mutations in Patients Followed-Up in Hospital. AB - A major obstacle to using next generation sequencing (NGS) technology in clinical routine practice is reliable data analysis. Thousands of sequences need to be aligned and validated, to exclude sequencing artifacts and generate accurate results. We compared two analysis pipelines for Roche 454 ultradeep pyrosequencing (UDPS) raw data generated from HIV-1 clinical samples: a commercial and fully automated Web-based software NGS HIV-1 Module (SmartGene, Zug, Switzerland) vs. the Amplicon Variant Analyzer software (AVA, 454 Life Sciences; Roche). Results were also compared to those obtained with Sanger sequencing. HIV-1 reverse transcriptase and protease genes from 34 plasma samples were submitted to Sanger sequencing and GS Junior UDPS. Raw UDPS data (sff files) from all samples were analyzed with AVA 2.7 software plus manual review of the alignments and the fully automated SmartGene NGS HIV-1 Module prototype (SMG). Results obtained with both analysis pipelines showed good correlation (85.0%). Divergent results were mainly observed at homopolymer positions, such as K101, where the frame-aware alignment and error corrections of the automated approach were more efficient and more accurate, both in terms of detecting and quantifying drug resistance mutations. Our study shows that NGS data can easily be analyzed via a fully automated analysis pipeline, here the SmartGene NGS HIV-1 Module, thus minimizing the need for manual review of alignments by the user, otherwise essential to ensure accurate results. Such automated analysis pipelines may facilitate the adoption of NGS platforms in the routine clinical laboratory. PMID- 26529550 TI - Characterization of the cell-free DNA released by cultured cancer cells. AB - The most prominent factor that delays the translation of cell-free DNA (cfDNA) analyses to clinical practice is the lack of knowledge regarding its origin and composition. The elucidation of the former is complicated by the seemingly random fluctuation of quantitative and qualitative characteristics of cfDNA in the blood of healthy and diseased individuals. Besides methodological discrepancies, this could be ascribed to a web of cellular responses to various environmental cues and stressors. Since all cells release cfDNA, it follows that the cfDNA in the blood of cancer patients is not only representative of tumor derived DNA, but also of DNA released by healthy cells under different conditions. Additionally, cfDNA released by malignant cells is not necessarily just aberrant, but likely includes non-mutated chromosomal DNA fragments. This may cause false positive/negative results. Although many have acknowledged that this is a major problem, few have addressed it. We propose that many of the current stumbling blocks encountered in in vivo cfDNA studies can be partially circumvented by in vitro models. Accordingly, the purpose of this work was to evaluate the release of cfDNA from cultured cells and to gauge its potential use for elucidating the nature of cfDNA. Results suggest that the occurrence of cfDNA is not a consequence of apoptosis or necrosis, but primarily a result of actively secreted DNA, perhaps in association with a protein complex. This study demonstrates the potential of in vitro cell culture models to obtain useful information about the phenomenon of cfDNA. PMID- 26529551 TI - [Insufficient use of anticoagulants in geriatric in-patients with atrial fibrillation and flutter]. PMID- 26529552 TI - Peripapillary Focal Choroidal Excavation in Association With Central Serous Chorioretinopathy. PMID- 26529553 TI - VITRECTOMY WITHOUT INNER LIMITING MEMBRANE PEELING FOR MACULAR RETINOSCHISIS IN HIGHLY MYOPIC EYES. AB - PURPOSE: To determine if it is necessary to peel inner limiting membrane during vitrectomy for macular retinoschisis in highly myopic eyes. METHODS: This retrospective noncomparative interventional case series included 112 eyes of 84 patients with myopic foveoschisis who were treated by 23-gauge 3-port pars plana vitrectomy. During vitrectomy, triamcinolone acetonide was injected into the vitreous cavity to visualize the vitreous. The inner limiting membrane was not peeled, but the posterior hyaloid membrane was removed from the macular surface with active suction or a flute needle. A fluid-gas exchange was carried out using 16% perfluoropropane gas. RESULTS: A total of 106 eyes (95%) exhibited collapse of the foveoschismatic intermediary zone after surgery. Best-corrected visual acuity at baseline and at the end of the follow-up did not differ significantly (1.06 +/- 0.74 logarithm of the minimum angle of resolution versus 0.92 +/- 0.56 logarithm of the minimum angle of resolution, P = 0.18). An improvement in best corrected visual acuity of greater than 2 lines was achieved in 84 eyes (75%). A macular hole with retinal detachment was found in 6 eyes (5%) 1 to 8 months after surgery. Intraoperatively, all 112 eyes exhibited vitreous liquefaction. The posterior hyaloid membranes were tightly adherent to the posterior retinal surface and vessels except for 1 eye that had a complete posterior vitreous detachment. There were no or only a very small amount of triamcinolone acetonide particles attached to the surface of posterior retina in 38 eyes, which seemed that a completely posterior vitreous detachment had happened. But these membranes on the surface of the posterior retina can be removed easily, which indicated these membranes were posterior hyaloid membranes instead of internal limiting membranes. CONCLUSION: In the treatment of macular retinoschisis in highly myopic eyes, vitrectomy associated with posterior hyaloid membranes peeling may achieve successful anatomical results. Internal limiting membrane peeling seems unnecessary. PMID- 26529554 TI - Intraoperative Infusion-related Jet Stream Enlargement of Macular Hole. PMID- 26529555 TI - INTRAVITREAL BEVACIZUMAB FOR CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION: 5-Year Results of The Pan-American Collaborative Retina Study Group. AB - PURPOSE: To report the long-term anatomical and functional outcomes of patients with choroidal neovascularization secondary to age-related macular degeneration treated with intravitreal bevacizumab (IVB). METHODS: Retrospective case series. Patients diagnosed with subfoveal choroidal neovascularization secondary to age related macular degeneration that were treated with at least 1 intravitreal injection of 1.25 mg of IVB and had a minimum follow-up of 60 months. Patients underwent best-corrected Snellen visual acuity testing, optical coherence tomography, and ophthalmoscopic examination at baseline and follow-up visits. RESULTS: Two hundred and forty-seven consecutive patients (292 eyes) were included. The mean number of IVB injections per eye was 10.9 +/- 6.4. At 5 years, the BCVA decreased from 20/150 (logMAR 0.9 +/- 0.6) at baseline to 20/250 (logMAR 1.1 +/- 0.7) (P = <0.0001). The mean CMT decreased from 343.1+ 122.3 MUm at baseline to 314.7 +/- 128.8 MUm at 60 months of follow-up (P = 0.009). Geographic atrophy (GA) was observed at baseline in 47 (16%) of 292 eyes. By 5 years, GA developed or progressed in 124 (42.5%) of 292 eyes (P < 0.0001). CONCLUSION: The early visual gains obtained from IVB were not maintained at 5 years of follow-up. In addition, IVB may play a role in the development or progression of GA. PMID- 26529556 TI - High feather mercury concentrations in the wandering albatross are related to sex, breeding status and trophic ecology with no demographic consequences. AB - Hg can affect physiology of seabirds and ultimately their demography, particularly if they are top consumers. In the present study, body feathers of >200 wandering albatrosses from Possession Island in the Crozet archipelago were used to explore the potential demographic effects of the long-term exposure to Hg on an apex predator. Variations of Hg with sex, age class, foraging habitat (inferred from delta(13)C values), and feeding habits (inferred from delta(15)N values) were examined as well as the influence of Hg on current breeding output, long-term fecundity and survival. Wandering albatrosses displayed among the highest Hg feather concentrations reported for seabirds, ranging from 5.9 to 95 ug g(-1), as a consequence of their high trophic position (delta(15)N values). These concentrations fall within the same range of those of other wandering albatross populations from subantarctic sites, suggesting that this species has similar exposure to Hg all around the Southern Ocean. In both immature and adult albatrosses, females had higher Hg concentrations than males (28 vs. 20 ug g(-1) dw on average, respectively), probably as a consequence of females foraging at lower latitudes than males (delta(13)C values). Hg concentrations were higher in immature than in adult birds, and they remained fairly constant across a wide range of ages in adults. Such high levels in immature individuals question (i) the frequency of moult in young birds, (ii) the efficiency of Hg detoxification processes in immatures compared to adults, and (iii) importantly the potential detrimental effects of Hg in early life. Despite very high Hg concentrations in their feathers, neither effects on adults' breeding probability, hatching failure and fledgling failure, nor on adults' survival rate were detected, suggesting that long-term bioaccumulated Hg was not under a chemical form leading to deleterious effects on reproductive parameters in adult individuals. PMID- 26529557 TI - Thickness of skin and subcutaneous tissue of the free flap donor sites: A histologic study. AB - PURPOSE: The aim of this study is to compare the thickness of skin and hypodermis of the free flap donor sites. METHODS: In 12 cadavers, specimens were harvested from donor sites of radial forearm flap (RF), anterolateral thigh flap (ALT), thoracodorsal perforator flap (TD), and deep inferior epigastric perforator flap (DIEP). Tissues were stained with Masson-trichrome. RESULTS: The thickness of the epidermis ranged 32-42 MUm according to the donor sites. The thickness of the dermis ranged 949-1,350 MUm. The dermis of the TD (2,152 +/- 575 MUm) was the thickest. The thickness of the hypodermis ranged 1,913-7,105 MUm. The hypodermis of the DIEP (7,105 +/- 4,543 MUm) was the thickest followed by the ALT (6,012 +/- 4,092 MUm) and TD (4,688 +/- 1,905 MUm). The dermis (949 +/- 311 MUm) and the hypodermis (1,913 +/- 1,066 MUm) of the RF were the thinnest. As the thickness of the dermis increased, the thickness of the hypodermis also increased. CONCLUSION: Thin hypodermis was found in radial forearm flap and thoracodorsal perforator flap donor sites, which may be used for reconstruction of thin defects. PMID- 26529558 TI - Nanoparticle-Based ARV Drug Combinations for Synergistic Inhibition of Cell-Free and Cell-Cell HIV Transmission. AB - Nanocarrier-based drug delivery systems are playing an emerging role in human immunodeficiency virus (HIV) chemoprophylaxis and treatment due to their ability to alter the pharmacokinetics and improve the therapeutic index of various antiretroviral (ARV) drug compounds used alone and in combination. Although several nanocarriers have been described for combination delivery of ARV drugs, measurement of drug-drug activities facilitated by the use of these nanotechnology platforms has not been fully investigated for topical prevention. Here, we show that physicochemically diverse ARV drugs can be encapsulated within polymeric nanoparticles to deliver multidrug combinations that provide potent HIV chemoprophylaxis in relevant models of cell-free, cell-cell, and mucosal tissue infection. In contrast to existing approaches that coformulate ARV drug combinations together in a single nanocarrier, we prepared single-drug-loaded nanoparticles that were subsequently combined upon administration. ARV drug nanoparticles were prepared using emulsion-solvent evaporation techniques to incorporate maraviroc (MVC), etravirine (ETR), and raltegravir (RAL) into poly(lactic-co-glycolic acid) (PLGA) nanoparticles. We compared the antiviral potency of the free and formulated drug combinations for all pairwise and triple drug combinations against both cell-free and cell-associated HIV-1 infection in vitro. The efficacy of ARV-drug nanoparticle combinations was also assessed in a macaque cervicovaginal explant model using a chimeric simian-human immunodeficiency virus (SHIV) containing the reverse transcriptase (RT) of HIV-1. We observed that our ARV-NPs maintained potent HIV inhibition and were more effective when used in combinations. In particular, ARV-NP combinations involving ETR-NP exhibited significantly higher antiviral potency and dose-reduction against both cell-free and cell-associated HIV-1 BaL infection in vitro. Furthermore, ARV-NP combinations that showed large dose-reduction were identified to be synergistic, whereas the equivalent free-drug combinations were observed to be strictly additive. Higher intracellular drug concentration was measured for cells dosed with the triple ARV-NP combination compared to the equivalent unformulated drugs. Finally, as a first step toward evaluating challenge studies in animal models, we also show that our ARV-NP combinations inhibit RT-SHIV virus propagation in macaque cervicovaginal tissue and block virus transmission by migratory cells emigrating from the tissue. Our results demonstrate that ARV-NP combinations control HIV-1 transmission more efficiently than free-drug combinations. These studies provide a rationale to better understand the role of nanocarrier systems in facilitating multidrug effects in relevant cells and tissues associated with HIV infection. PMID- 26529559 TI - CD151 Regulates T-Cell Migration in Health and Inflammatory Bowel Disease. AB - The continuous recirculation of mature lymphocytes and their entry into the peripheral lymph nodes are crucial for the development of an immune response to foreign antigens. Occasionally, the entry and the subsequent response of T lymphocytes in these sites lead to severe inflammation and pathological conditions. Here, we characterized the tetraspanin molecule, CD151, as a regulator of T cell motility in health and in models of inflammatory bowel disease. CD151 formed a cell surface complex with VLA-4 and LFA-1 integrins, and its activation led to enhanced migration of T cells. Picomolar levels of CCL2 that were previously shown to inhibit T-cell migration to lymph nodes suppressed CD151 expression and dissociated CD151-integrin complexes in T lymphocytes, resulting in attenuated migration toward T-cell attractant chemokines. To directly inhibit CD151 function, a truncated CD151 peptide fragment mimicking of the CD151 extracellular loop was designed. CD151 extracellular loop inhibited T cell migration in vitro and in vivo and attenuated the development of dextrane sulfate sodium-induced colitis. Thus, CD151 is a key orchestrator of T cell motility; interference with its proper function results in attenuated progression of inflammatory bowel disease. PMID- 26529560 TI - A Controlled Study of a Group Mindfulness Intervention for Individuals Living With Inflammatory Bowel Disease. AB - BACKGROUND: This study aimed to evaluate the feasibility, acceptability, and effectiveness of a mindfulness-based intervention for patients with inflammatory bowel disease (MI-IBD). DESIGN: Treatment-as-usual control versus mindfulness based stress reduction intervention. METHODS: Sixty patients participated in either the MI-IBD (n = 33) or treatment-as-usual group (n = 27) conditions. The MI-IBD consisted of an 8-week mindfulness-based stress reduction training group. Outcome measures were administered at baseline (before intervention), immediately after intervention, and 6 months after intervention. Primary outcomes included measures of quality of life, psychological distress (depression and anxiety), and mindfulness. Data for MI-IBD group participants also included weekly attendance, daily minutes meditated, and satisfaction with the program. RESULTS: There were no baseline differences between intervention and control groups on demographic variables or inflammatory bowel disease severity. Compared with the control group, the MI-IBD group reported significantly greater improvements in anxiety, quality of life, and mindfulness at after intervention, with reduction in depression and improvements in quality of life and mindfulness maintained at 6 months after intervention. CONCLUSIONS: Results demonstrate the feasibility, acceptability, and efficacy of a mindfulness intervention for patients with inflammatory bowel disease, with medium-to-large effects on psychological distress, quality of life, and mindfulness. PMID- 26529561 TI - Physician Perspectives on Unresolved Issues in the Management of Ulcerative Colitis: The UC Horizons Project. AB - BACKGROUND: There is still uncertainty about what constitutes the best therapeutic practice in ulcerative colitis (UC). OBJECTIVE: The purpose of the "UC Horizons Project" was to raise a series of questions regarding the management of UC to provide responses based on the best scientific evidence available. METHODS: The 11 members of the scientific committee prepared draft answers to the 10 questions from available evidence after a literature search. A total of 48 Spanish gastroenterology specialists nationwide participated in the project. The national meeting discussed the 10 issues in working groups and reached consensus regarding the recommendations by anonymous, interactive vote following the Delphi methodology. Final answers were developed, based on evidence and clinical experience of the participants. RESULTS: All the recommendations achieved a high level of agreement in the plenary vote, although the quality of the evidence was markedly heterogeneous. The lowest percentage of agreement corresponded to the questions with the weakest level of evidence, highlighting the necessity of conducting further studies in these areas. The recommendations focused on (1) aminosalicylates therapy (regarding dose and appropriateness of coadministration with thiopurines), (2) corticosteroid therapy (regarding dose and route of administration), (3) thiopurine treatment (regarding indications and possibility of withdrawal), (4) anti-tumor necrosis factor therapy (regarding appropriateness of combination with thiopurines, intensification, or discontinuation of treatment), and (5) colorectal cancer (regarding risk and time trends). CONCLUSIONS: The UC Horizons Project raised a series of eminently practical questions about the management of UC and provided responses based on the best scientific evidence available. PMID- 26529562 TI - Microscopic Colitis: What Do We Know About Pathogenesis? AB - Microscopic colitis (MC) is a common cause of chronic diarrhea. The 2 most frequent forms of MC are collagenous colitis and lymphocytic colitis. Over the past years, the incidence and prevalence of microscopic colitis are rising and this is largely attributed to a greater awareness, and concomitantly an increasing number of diagnoses. Patients with microscopic colitis report watery, nonbloody diarrhea of chronic course, abdominal pain, weight loss, and fatigue that may impair patient's health-related quality of life. The underlying mechanisms involved in the pathogenesis of microscopic colitis remain unspecified but is probably multifactorial. Collagenous colitis and lymphocytic colitis may represent specific mucosal responses to different luminal agents in predisposed individuals, resulting in an uncontrolled immune response. Genetic predisposition, altered modulation of cytokines and miRNAs, and aberrant response to drugs seem to be involved in the development of MC. Despite the progress of knowledge, still many questions remain unsolved regarding the etiology, pathophysiology, and optimal management of MC. This review gives an update on the immunological aspects of collagenous colitis and lymphocytic colitis. PMID- 26529563 TI - Olfactory Impact of Higher Alcohols on Red Wine Fruity Ester Aroma Expression in Model Solution. AB - This study focused on the impact of five higher alcohols on the perception of fruity aroma in red wines. Various aromatic reconstitutions were prepared, consisting of 13 ethyl esters and acetates and 5 higher alcohols, all at the average concentrations found in red wine. These aromatic reconstitutions were prepared in several matrices. Sensory analysis revealed the interesting behavior of certain compounds among the five higher alcohols following their individual addition or omission. The "olfactory threshold" of the fruity pool was evaluated in several matrices: dilute alcohol solution, dilute alcohol solution containing 3-methylbutan-1-ol or butan-1-ol individually, and dilute alcohol solution containing the mixture of five higher alcohols, blended together at various concentrations. The presence of 3-methylbutan-1-ol or butan-1-ol alone led to a significant decrease in the "olfactory threshold" of the fruity reconstitution, whereas the mixture of alcohols raised the olfactory threshold. Sensory profiles highlighted changes in the perception of fruity nuances in the presence of the mixture of higher alcohols, with specific perceptive interactions, including a relevant masking effect on fresh- and jammy-fruit notes of the fruity mixture in both dilute alcohol solution and dearomatized red wine matrices. When either 3 methylbutan-1-ol or butan-1-ol was added to the fruity reconstitution in dilute alcohol solution, an enhancement of butyric notes was reported with 3-methylbutan 1-ol and fresh- and jammy-fruit with butan-1-ol. This study, the first to focus on the impact of higher alcohols on fruity aromatic expression, revealed that these compounds participate, both quantitatively and qualitatively, in masking fruity aroma perception in a model fruity wine mixture. PMID- 26529564 TI - Identification of a Hematopoietic Cell Dedifferentiation-Inducing Factor. AB - It has long been realized that hematopoietic cells may have the capacity to trans differentiate into non-lymphohematopoietic cells under specific conditions. However, the mechanisms and the factors for hematopoietic cell trans differentiation remain unknown. In an in vitro culture system, we found that using a conditioned medium from proliferating fibroblasts can induce a subset of hematopoietic cells to become adherent fibroblast-like cells (FLCs). FLCs are not fibroblasts nor other mesenchymal stromal cells, based on their expression of type-1 collagen, and other stromal cell marker genes. To identify the active factors in the conditioned medium, we cultured fibroblasts in a serum-free medium and collected it for further purification. Using the fractions from filter devices of different molecular weight cut-offs, and ammonium sulfate precipitation collected from the medium, we found the active fraction is a protein. We then purified this fraction by using fast protein liquid chromatography (FPLC) and identified it by mass spectrometer as macrophage colony stimulating factor (M-CSF). The mechanisms of M-CSF-inducing trans differentiation of hematopoietic cells seem to involve a tyrosine kinase signalling pathway and its known receptor. The FLCs express a number of stem cell markers including SSEA-1 and -3, OCT3/4, NANOG, and SOX2. Spontaneous and induced differentiation experiments confirmed that FLCs can be further differentiated into cell types of three germ layers. These data indicate that hematopoietic cells can be induced by M-CSF to dedifferentiate to multipotent stem cells. This study also provides a simple method to generate multipotent stem cells for clinical applications. PMID- 26529565 TI - Crystal structure of cleaved vaspin (serpinA12). AB - The adipokine vaspin (serpinA12) is mainly expressed in white adipose tissue and exhibits various beneficial effects on obesity-related processes. Kallikrein 7 is the only known target protease of vaspin and is inhibited by the classical serpin inhibitory mechanism involving a cleavage of the reactive center loop between P1 (M378) and P1' (E379). Here, we present the X-ray structure of vaspin, cleaved between M378 and E379. We provide a comprehensive analysis of differences between the uncleaved and cleaved forms in the shutter, breach, and hinge regions with relation to common molecular features underlying the serpin inhibitory mode. Furthermore, we point out differences towards other serpins and provide novel data underlining the remarkable stability of vaspin. We speculate that the previously reported FKGx1Wx2x3 motif in the breach region may play a decisive role in determining the reactive center loop configuration in the native vaspin state and might contribute to the high thermostability of vaspin. Thus, this structure may provide a basis for future mutational studies. PMID- 26529566 TI - Functional and Parametric Estimation in a Semi- and Nonparametric Model with Application to Mass-Spectrometry Data. AB - Motivated by modeling and analysis of mass-spectrometry data, a semi- and nonparametric model is proposed that consists of linear parametric components for individual location and scale and a nonparametric regression function for the common shape. A multi-step approach is developed that simultaneously estimates the parametric components and the nonparametric function. Under certain regularity conditions, it is shown that the resulting estimators is consistent and asymptotic normal for the parametric part and achieve the optimal rate of convergence for the nonparametric part when the bandwidth is suitably chosen. Simulation results are presented to demonstrate the effectiveness and finite sample performance of the method. The method is also applied to a SELDI-TOF mass spectrometry data set from a study of liver cancer patients. PMID- 26529567 TI - Testing the Relative Performance of Data Adaptive Prediction Algorithms: A Generalized Test of Conditional Risk Differences. AB - Comparing the relative fit of competing models can be used to address many different scientific questions. In classical statistics one can, if appropriate, use likelihood ratio tests and information based criterion, whereas clinical medicine has tended to rely on comparisons of fit metrics like C-statistics. However, for many data adaptive modelling procedures such approaches are not suitable. In these cases, statisticians have used cross-validation, which can make inference challenging. In this paper we propose a general approach that focuses on the "conditional" risk difference (conditional on the model fits being fixed) for the improvement in prediction risk. Specifically, we derive a Wald type test statistic and associated confidence intervals for cross-validated test sets utilizing the independent validation within cross-validation in conjunction with a test for multiple comparisons. We show that this test maintains proper Type I Error under the null fit, and can be used as a general test of relative fit for any semi-parametric model alternative. We apply the test to a candidate gene study to test for the association of a set of genes in a genetic pathway. PMID- 26529568 TI - What Protects Certain Nerves from Stretch Injury? AB - The human tibial nerves is less prone to injury following joint arthroplasty compared with the peroneal nerves. Besides the anatomical distribution, other features may confer protection from stretch injury. We therefore examined the size, shape and connective tissue distribution for the two nerves. The tibial and peroneal nerves from each side of nine fresh human cadavers we reharvested mid thigh. Proximal segments manually stretched 20%-25% were fixed in aldehyde, while the adjacent distal segments were fixed in their natural length. Paraffin sections stained by Masson's trichrome method for connective tissue were examined by light microscopy. Tibial nerves had 2X more fascicles compared with the peroneal, but the axonal content appeared similar. Analysis showed that neither nerve had a significant reduction in cross sectional area of the fascicles following stretch. However, fascicles from stretched tibial nerves become significantly more oval compared with those from unstretched controls and peroneal nerves. Tibial nerves had a greater proportion that was extrafascicular tissue (50-55%) compared with peroneal nerves (38%-42%). This epineurium was typically adipose tissue. Perineurial thickness in both nerves was directly related to fascicular size. Tibial nerves have several unique histological features associated with size, shape and tissue composition compared with the peroneal nerve. We suggest that more fascicles with their tightly bound perineurium and more robust epineurium afford protection against stretch injury. Mechanical studies should clarify how size and shape contribute to nerve protection and/or neurapraxia. PMID- 26529569 TI - Bypass Grafting Versus Percutaneous Intervention-Which Is Better in Multivessel Coronary Disease: Lessons From SYNTAX and Beyond. AB - The landmark Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) Trial has aided in reducing the area of uncertainty in decision-making between percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery in patients with complex coronary artery disease. As part of the SYNTAX Trial, quantification of the coronary artery disease burden was prospectively undertaken by the Heart Team - consisting of at least an interventional cardiologist and cardiac surgeon - utilising the anatomical SYNTAX Score (www.syntaxscore.com) as a clinical tool in order to agree that equivalent anatomical revascularisation could be achieved. The anatomical SYNTAX Score is now advocated in both European and US revascularisation guidelines to guide decision-making between CABG and PCI as part of the SYNTAX pioneered Heart Team approach. In addition, the SYNTAX Trial has lead to the development and validation of the SYNTAX Score II, in which the anatomical SYNTAX Score was augmented with clinical variables, to allow for more objective and tailored decision making for the individual patient. Prospective validation of the SYNTAX Score II tool is currently ongoing in the SYNTAX II (ClinicalTrials.gov Identifier: NCT02015832) and EXCEL (ClinicalTrials.gov identifier: NCT01205776) trials. The present paper presents lessons learned from SYNTAX, including the development and/or validation of several SYNTAX based clinical tools, and the potential implications for current and future clinical practice. PMID- 26529570 TI - Continuous Carbon Nanotube-Ultrathin Graphite Hybrid Foams for Increased Thermal Conductivity and Suppressed Subcooling in Composite Phase Change Materials. AB - Continuous ultrathin graphite foams (UGFs) have been actively researched recently to obtain composite materials with increased thermal conductivities. However, the large pore size of these graphitic foams has resulted in large thermal resistance values for heat conduction from inside the pore to the high thermal conductivity graphitic struts. Here, we demonstrate that the effective thermal conductivity of these UGF composites can be increased further by growing long CNT networks directly from the graphite struts of UGFs into the pore space. When erythritol, a phase change material for thermal energy storage, is used to fill the pores of UGF-CNT hybrids, the thermal conductivity of the UGF-CNT/erythritol composite was found to increase by as much as a factor of 1.8 compared to that of a UGF/erythritol composite, whereas breaking the UGF-CNT bonding in the hybrid composite resulted in a drop in the effective room-temperature thermal conductivity from about 4.1 +/- 0.3 W m(-1) K(-1) to about 2.9 +/- 0.2 W m(-1) K( 1) for the same UGF and CNT loadings of about 1.8 and 0.8 wt %, respectively. Moreover, we discovered that the hybrid structure strongly suppresses subcooling of erythritol due to the heterogeneous nucleation of erythritol at interfaces with the graphitic structures. PMID- 26529571 TI - Vibrio diabolicus challenge in Bathymodiolus azoricus populations from Menez Gwen and Lucky Strike hydrothermal vent sites. AB - Menez Gwen (MG) and Lucky Strike (LS) deep-sea hydrothermal vents are located at 850 m and 1730 m depths respectively and support chemosynthesis-based ecosystems partially differing in heavy metal concentration, temperature range, and faunistic composition. The successfully adapted deep-sea vent mussel Bathymodiolus azoricus is found at both vent locations. In such inhospitable environments survival strategies rely on the establishment of bacteria-vent animal symbiosis In spite of the toxic nature of deep-sea vents, the problem of microbial threat and the need for immunity exist in B. azoricus. This study aims at investigating the immune system of B. azoricus from MG and LS populations by comparing immune gene expressions profiles using the deep-sea vent-related Vibrio diabolicus. Expression of nineteen immune genes was analyzed from gill, digestive gland and mantle tissues upon 3 h, 12 h and 24 h V. diabolicus challenges. Based on quantitative-Polymerase Chain Reaction (qPCR) significant gene expression differences were found among MG and LS populations and challenge times MG mussels revealed that gill and digestive gland gene expression levels were remarkably higher than those from LS mussels. Expression of Carcinolectin, Serpin-2, SRCR, IRGs, RTK, TLR2, NF-kappaB, HSP70 and Ferritin genes was greater in MG than LS mussels. In contrast, mantle tissue from LS mussels revealed the highest peak of expression at 24 h for most genes analyzed. The activation of immune signaling pathways demonstrated that gene expression profiles are distinct between the two mussel populations. These differences may possibly ensue from intrinsic immune transcriptional activities upon which host responses are modulated in presence of V. diabolicus. mRNA transcript variations were assessed during 24 h acclimatization taking into account the partial depuration to which mussels were subjected to. Additionally, gene expression differences may reflect still accountable effects from the presence of vent remaining microfluidic environments within the tissues analyzed. PMID- 26529572 TI - Efficient Luminescence from Perovskite Quantum Dot Solids. AB - Nanocrystals of CsPbX3 perovskites are promising materials for light-emitting optoelectronics because of their colloidal stability, optically tunable bandgap, bright photoluminescence, and excellent photoluminescence quantum yield. Despite their promise, nanocrystal-only films of CsPbX3 perovskites have not yet been fabricated; instead, highly insulating polymers have been relied upon to compensate for nanocrystals' unstable surfaces. We develop solution chemistry that enables single-step casting of perovskite nanocrystal films and overcomes problems in both perovskite quantum dot purification and film fabrication. Centrifugally cast films retain bright photoluminescence and achieve dense and homogeneous morphologies. The new materials offer a platform for optoelectronic applications of perovskite quantum dot solids. PMID- 26529574 TI - The Type IVB secretion system: an enigmatic chimera. AB - Type IV secretion systems (T4SSs) are transporters that span the bacterial inner and outer membranes and deliver substrate biomolecules, including proteins and DNAs, into cells. Recent progress in structural analyses of conjugative plasmid encoded type IVA secretion systems (T4ASSs) has revealed a unique molecular architecture. The essential virulence system, the Dot/Icm Type IVB secretion system (T4BSS) encoded by the intracellular bacterial pathogen Legionella pneumophila is distantly related to T4ASSs. Molecular and structural analyses of the Dot/Icm T4BSS have provided insights into the mechanisms of assembly and function. Here we highlight the chimeric quality of T4BSSs that possess components with similarity to many bacterial secretion systems. PMID- 26529575 TI - A linear free energy analysis of PAMPA models for biological systems. AB - Equation coefficients in the Abraham linear free energy relationship have been obtained for a number of parallel artificial membrane permeability assays, PAMPA, and have been compared to equation coefficients for several biological processes and a large number of water-solvent partitions. From a principal component analysis of the equation coefficients we show that one particular PAMPA (Wohnsland and Faller, 2001) is a good model for human intestinal absorption, but we could find no PAMPA that was a good model for rat brain permeation, mouse brain permeation, blood-brain distribution, skin permeation or water-skin partition, although models that include PAMPA and other descriptors may be useful. The water-octanol system is a poor model for all the biological process we have studied, but water-nonpolar solvent partitions are good models for permeation through egg lecithin membranes. PMID- 26529576 TI - pH sensitive polymeric complex of cisplatin with hyaluronic acid exhibits tumor targeted delivery and improved in vivo antitumor effect. AB - Cisplatin (CDDP) is widely used anticancer drug for various solid tumors including lung cancer. However, its indiscriminate distribution causes serious adverse effects and limits its therapeutic effect. In this study, by using hyaluronic acid (HA) we synthesized a complex of CDDP (HA-CDDP), by utilizing ionic interaction between Pt(2+) of CDDP with carboxyl group of HA. The mean HA CDDP particle size was 208.5nm in PBS according to dynamic light scattering which was also confirmed by TEM, which could exert tumor-targeting property by enhanced permeability and retention (EPR) effect. The CDDP loading in this preparation was 13% (w/w), and release rate of free CDDP from the HA-CDDP complex at physiological pH (7.4) was ~20%/day. However, in acidic pH the release was much faster, i.e., ~95% of CDDP was released in 72h at pH 5.5. Moreover, HA-CDDP showed a 2.5-fold higher tumor accumulation than free CDDP whereas no increase of distribution was found in most normal tissues. In addition, because HA receptor CD44 is overexpressed in many tumor cells, we also observed CD44-based endocytosis of HA-CDDP in mouse lung carcinoma LCC cells. These findings together suggest that HA-CDDP may show tumor-selective cytotoxicity by taking advantage of EPR effect, weak acidic environment of tumor tissues (e.g., pH 6~7), as well as CD44-based intracellular uptake. As expected, HA-CDDP exhibited much improved therapeutic effect than free CDDP in mouse LCC tumor model, whereas no apparent side effect was found. These findings may shed some light on the potential utility of HA for development of tumor-targeted polymeric CDDP drugs, which need further investigations. PMID- 26529577 TI - Development and preclinical pharmacokinetics of a novel subcutaneous thermoresponsive system for prolonged delivery of heparin. AB - Heparin is still widely used for treatment and prevention of thromboembolic diseases. Due to specific physicochemical properties, it requires frequent parenteral injections. In this study we present the development and in vitro evaluation of an advanced delivery system for prolonged subcutaneous release of heparin. The delivery system consisted of an in situ forming thermoresponsive poloxamer-based platform combined with pH-responsive polyelectrolyte heparin/chitosan nanocomplexes. Thermoresponsive hydrogels were tested for gelation temperature, gel dissolution and in vitro heparin release, whereas polyelectrolyte nanocomplexes were physico-chemically characterized, as well as tested for in vitro cytotoxicity and in vitro heparin release. Hydrogel combined of two poloxamers demonstrated the highest gelation temperature (28.6 degrees C), while the addition of hydroxypropyl methylcellulose prolonged gel dissolution. On the other hand, nanocomplexes' dispersions, prepared at 1:1 heparin/chitosan mass ratio and in the concentration range 0.375-1.875mg/mL, demonstrated mean diameter <400nm and zeta potential >34mV. Pharmacokinetics of selected formulations (thermoresponsive hydrogel, nanocomplexes and a dual system consisting of nanocomplexes incorporated into thermoresponsive hydrogel) were studied in rats. Heparin plasma concentration-time profiles revealed a double-peak phenomenon, probably due to heparin diffusion inside the polymer matrix and gel dissolution. Pharmacokinetic parameters were determined by a non-linear mixed effects modeling approach. It was demonstrated that thermoresponsive hydrogel with heparin/chitosan nanocomplexes enabled the lowest absorption rate of heparin into systemic circulation and provided heparin concentration above the prophylaxis threshold for 5 days. In situ gelling thermoresponsive matrix combined with chitosan nanocomplexes present a promising delivery system for heparin, requiring less frequent administration during long-term treatment. PMID- 26529578 TI - Ease of opening of blistered solid dosage forms in a senior citizens target group. AB - Blisters differing in design and handling are established as packaging material for solid dosage forms. The ease of opening of blisters influences application and patient's compliance. In this study the influence of visibility and movability of solid dosage forms in blister packaging on both, easy opening and patient's satisfaction, were investigated by target group testing according to ONR CEN/TS 15945. For each testing 20 participants in the age of 65-80 years were recruited randomly. They opened the blisters on realistic terms without any auxiliary devices. Video documentation of the hands' movements was recorded to analyze the opening procedure. To show the influence of visibility of the dosage form in the blister, capsules size 1 were packed in transparent and opaque blisters. A moderate influence of the visibility on both, the ease of opening and patient satisfaction, was observed. A second study dealt with the movability of solid dosage forms in blisters. Therefore, three different sizes of tablets with similar shapes were packed in identical cavities. Limited movability was found as major criterion on effectiveness and effectivity of opening as well as on satisfaction with the opening procedure. PMID- 26529579 TI - The influence of distractors and numerical direction on mental number line bisection. AB - Spatial relationships are used to mentally represent numerical information. We visualize small numbers on the left and large numbers on the right, forming a mental number line. When determining the midpoint between two numbers, healthy participants show a bias to the left, similar to the bias on line bisection. Upper space distractors increase leftward line bisection biases and the current study examined the influence of distractors on mental number line bisection. Participants viewed sequential number triplets, presented concurrently with distractors. In Experiment 1, participants performed more accurately when numbers were presented in ascending order and showed stronger left biases for descending trials. Further, a responding bias was observed, where participants pressed the response key on the same side as the distractors. In Experiment 2, an orthogonal response mapping was used, which confirmed the occurrence of a responding bias. Interestingly, distractors weakened pseudoneglect, demonstrating a dissociation between line bisection and mental number line bisection in terms of distractibility. Numerical direction influenced asymmetries, such that leftward biases were stronger on descending trials. It is suggested that a right-to-left orientation of attention on descending trials might lead participants to overestimate how far along the number line they have moved, which increases leftward biases. PMID- 26529580 TI - Improved fidelity of brain microstructure mapping from single-shell diffusion MRI. AB - Diffusion weighted imaging (DWI) is sensitive to alterations in the diffusion of water molecules caused by microstructural barriers. Different microstructural compartments are characterized by differences in DWI signal. Diffusion tensor imaging conflates the signal from these compartments into a single tensor, which poorly represents multiple white matter fascicles and extra-axonal space. Diffusion compartment imaging (DCI) models overcome this limitation by providing parametric representations for the signal contribution of each compartment, thereby improving the fidelity of brain microstructure mapping. However, current approaches fail to identify DCI model parameters from conventional single-shell DWI with the desired accuracy. It has been demonstrated that part of this inaccuracy is due to the ill-posedness of the estimation of DCI model parameters from conventional single-shell acquisitions. In this paper, we propose to regularize the estimation problem for single-shell DWI by learning a prior distribution of DCI model parameters from DWI acquired at multiple b-values in an external population of subjects. We demonstrate that this population-informed prior enables, for the first time, accurate estimation of DCI models from single shell DWI typically acquired in clinical practice. We validated our approach on synthetic and in vivo data of healthy subjects and patients with autism spectrum disorder. We applied the approach to population studies of brain microstructure in autism and found that introducing a population-informed prior leads to reliable detection of group differences. Our algorithm enables novel investigation from large existing DWI datasets in normal development and in disease and injury. PMID- 26529581 TI - To divide or not to divide: An alternative behavior for teratocytes in Encarsia pergandiella (Hymenoptera: Aphelinidae). AB - Encarsia pergandiella (Hymenoptera: Aphelinidae) is an endoparasitoid with an unusual embryonic development compared to most of congeneric species and all other members of the superfamily Chalcidoidea. The developmental background of this wasp is based on an alecithal hydropic egg, with the embryo developing inside an extra-embryonic membrane which dissociates at hatching into special larva-assisting cells, the teratocytes. In E. pergandiella many teratocytes at hatching were multinucleated syncytial cells with no evidence of a cellular membrane separating the nuclei. These teratocytes during larval development produced smaller uninucleated teratocytes, through successive divisions obtained by progressive ingrowth of the plasmatic membrane, accompanied by appearance of degeneration symptoms, such as protrusions and blebs. As a consequence of this divisional process teratocytes showed a size reduction and an increase in number of about four times during the second day of larval development. Only on the third day of larval life teratocytes started to decrease in number, until total disappearance at larval maturation. This behaviour is in striking contrast with all other studied systems in which teratocytes do not divide and progressively decrease in number as the parasitoid larva develops. PMID- 26529582 TI - Micromorphology of the elytral cuticle of beetles, with an emphasis on weevils (Coleoptera: Curculionoidea). AB - The elytral cuticle of 40 beetle species, comprising 14 weevils (Curculionoidea) and 26 representatives of other taxa, is examined. All weevils and 18 other species have an endocuticle with prominent macrofibers, which corresponds to a modified pseudo-orthogonal cuticle. Angles between successive layers of macrofibers range between 30 degrees and 90 degrees , but are constantly less than 60 degrees in weevils. In all Curculionoidea, as well as in one buprestid and one erotylid species exo- and endocuticle are densely interlocked. In the weevil Sitophilus granarius, transmission electron microscopy revealed vertical microfibrils extending from the exocuticle between the macrofibers of the underlaying endocuticle. Vertical microfibrils connecting successive macrofiber layers of the endocuticle were observed in S. granarius and Trigonopterus nasutus. Distinct cuticular characters are traced on a beetle phylogeny: the angles between unidirectional endocuticle layers; the presence and the shape of endocuticular macrofibers; and the interlocking of exo- and endocuticle. While character traits seem to be more or less randomly distributed among Coleoptera, the Curculionoidea have a uniform groundplan: The "weevil-specific" combination of characters includes 1) interlocking of exo- and endocuticle, 2) an endocuticle with distinct ovoid macrofibers embedded in a matrix and 3) comparatively small angles between successive endocuticular layers. Thus, phylogenetic constraints appear equally important to functional factors in the construction of the weevil elytron. PMID- 26529583 TI - The effectiveness of powered, active lower limb exoskeletons in neurorehabilitation: A systematic review. AB - OBJECTIVE: This review examines the utility of current active, powered, wearable lower limb exoskeletons as aids to rehabilitation in paraplegic patients with gait disorders resulting from central nervous system lesions. METHODS: The PRISMA guidelines were used to review literature on the use of powered and active lower limb exoskeletons for neurorehabilitative training in paraplegic subjects retrieved in a search of the electronic databases PubMed, EBSCO, Web of Science, Scopus, ProQuest, and Google Scholar. RESULTS: We reviewed 27 studies published between 2001 and 2014, involving a total of 144 participants from the USA, Japan, Germany, Sweden, Israel, Italy, and Spain. Seventy percent of the studies were experimental tests of safety or efficacy and 29% evaluated rehabilitative effectiveness through uncontrolled (22%) or controlled (7%) clinical trials. CONCLUSIONS: Exoskeletons provide a safe and practical method of neurorehabilitation which is not physically exhausting and makes minimal demands on working memory. It is easy to learn to use an exoskeleton and they increase mobility, improve functioning and reduce the risk of secondary injury by reinstating a more normal gait pattern. A limitation of the field is the lack of experimental methods for demonstrating the relative effectiveness of the exoskeleton in comparison with other rehabilitative techniques and technologies. PMID- 26529584 TI - Flexible and Semitransparent Organolead Triiodide Perovskite Network Photodetector Arrays with High Stability. AB - Organolead triiodide perovskite (CH3NH3PbI3) as a light-sensitive material has attracted extensive attention in optoelectronics. The reported perovskite photodetectors (PDs) mainly focus on the individual, which limits their spatial imaging applications. Uniform perovskite networks combining transparency and device performance were synthesized on poly(ethylene terephthalate) (PET) by controlling perovskite crystallization. Photodetector arrays based on above network were fabricated to demonstrate the potential for image mapping. The trade off between the PD performance and transparency was systematically investigated and the optimal device was obtained from 30 wt % precursor concentration. The switching ratio, normalized detectivity, and equivalent dark current derived shot noise as the critical parameters of PD arrays reached 300, 1.02 * 10(12) Jones, and 4.73 * 10(-15)A Hz(-1/2), respectively. Furthermore, the PD arrays could clearly detect spatial light intensity distribution, thus demonstrating its preliminary imaging function. The perovskite network PD arrays fabricated on PET substrates could also conduct superior flexibility under wide angle and large number of bending. For the common problem of perovskite optoelectronics in stability, the perovskite networks sheathed with hydrophobic polymers greatly enhanced the device stability due to the improved interface contacts, surface passivation, and moisture isolation. Taking into consideration transparency, flexibility, imaging and stability, the present PD arrays were expected to be widely applied in visualized portable optoelectronic system. PMID- 26529585 TI - Reversal effects of Raloxifene on paclitaxel resistance in 2 MDR breast cancer cells. AB - Raloxifene hydrochloride (RAL), one of second generation of selective estrogen receptor modulators (SERMs), is usually used in preventing osteoporosis and breast cancer. The present study evaluated whether Raloxifene might sensitize multidrug resistant (MDR) breast cancers to chemotherapies, especially in estrogen receptor negative (ER-) breast cancer. The results showed that RAL could significantly sensitize ER- MDR breast tumors to paclitaxel both in vitro and in vivo. Combination of Raloxifene could significantly enhance paclitaxel-induced cell apoptosis, G2-M arrest as well as inhibition of cell proliferation in MDR tumors. Further studies showed that the combined treatment did not alter P glycoprotein expression but increased P-gp ATPase activity. These results suggested that raloxifene might be a valuable chemosensitizer agent for breast cancer therapy. PMID- 26529586 TI - The Danish PEP Registry: Experience with the use of post-exposure prophylaxis following blood exposure to HIV from 1999-2012. AB - BACKGROUND: The risk of occupational exposures to blood cannot be eliminated completely and access to post-exposure prophylaxis (PEP) to prevent HIV transmission is important. However, PEP administration has been associated with frequent adverse effects, low compliance and difficulties to ensure a proper risk assessment. This nationwide study describes 14 years of experience with the use of PEP following blood exposure in Denmark. METHODS: A descriptive study of all PEP cases following non-sexual exposure to HIV in Denmark from 1999-2012. RESULTS: A total of 411 cases of PEP were described. There was a mean of 29.4 cases/year, increasing from 23 cases in 1999 to 49 cases in 2005 and then decreasing to 16 cases in 2012. Overall 67.2% of source patients were known to be HIV-positive at the time of PEP initiation, with no significant change over time. The median time to initiation of PEP was 2.5 h (0.15-28.5) following occupational exposure. Adverse effects were reported by 50.9% with no significant difference according to PEP regimen. In 85.1% of cases with available data, either a full course of PEP was completed or PEP was stopped because the source was tested HIV negative. Only 6.6% stopped PEP early due to adverse effects. CONCLUSIONS: PEP in Denmark is generally prescribed according to the guidelines and the annual number of cases has declined since 2005. Adverse effects were common regardless of PEP regimens used and new drug regimens should be considered. PMID- 26529587 TI - Physical and chemical modification of starches: A review. AB - The development of green material in the last decade has been increased, which tends to reduce the impact of humans on the environment. Starch as an agro sourced polymer has become very popular recently due to its characteristics, such as wide availability, low cost, and total compostability without toxic residues. Starch is the most abundant organic compound found in nature after cellulose. Starches are inherently unsuitable for most applications and, therefore, must be modified physically and/or chemically to enhance their positive attributes and/or to minimize their defects. Modification of starches is generally carried out by using physical methods that are simple and inexpensive due to the absence of chemical agents. However, chemical modification involves the exploitation of hydroxyl group present in the starches that brings about the desired results for the utilization of starches for specific applications. All these techniques have the tendency to produce starches with altered physicochemical properties and modified structural attributes for various food and nonfood applications. This paper reviews the recent knowledge and developments using physical modification methods, some chemical modification methods, and a combination of both to produce a novel molecule with substantial applications, in food industry along with future perspectives. PMID- 26529589 TI - Statistical optimization of medium components and physicochemical parameters to simultaneously enhance bacterial growth and esterase production by Bacillus thuringiensis. AB - Bacillus thuringiensis is a genus extensively studied because of its high potential for biotechnological application, principally in biocontrol techniques. However, the optimization of esterase production by this strain has been scarcely studied. The aim of this work was to select and optimize the physicochemical and nutritional parameters that significantly influence the growth and esterase production of B. thuringiensis. To this purpose, 6 nutritional factors and 2 physicochemical parameters were evaluated using a Plackett-Burman design. Significant variables were optimized using a Box-Behnken design and through the desirability function to select the levels of the variables that simultaneously maximize microbial growth and esterase production. The optimum conditions resulting from simultaneous optimization of the responses under study were found to be 1 g/L glucose, 15 g/L peptone, and 3.25 g/L NaCl. Under these optimal conditions, it was possible to achieve a 2.5 log CFU/mL increase in bacterial growth and a 113-fold increase in esterase productivity, compared with minimal medium without agitation. PMID- 26529590 TI - Effects of environmental intervention on sedentary time, musculoskeletal comfort and work ability in office workers. AB - Sit-stand workstations offer a potential strategy to reduce prolonged occupational sitting. This controlled intervention study examined the effects of an environmental intervention on occupational sedentary time, musculoskeletal comfort and work ability, and the usability of sit-stand workstations in office work via a self-reported questionnaire. The intervention group (n = 24) used sit stand workstations during the 6-month intervention period, and the control group (n = 21) used traditional sitting workstations. The results showed that working at sit-stand workstations can reduce sitting time significantly compared to control workstations (-6.7% vs. 5.0%, p = .019), which is reallocated mostly to standing (r = -0.719, p < .001). Sit-stand workstations improved perceived musculoskeletal comfort in the neck and shoulders (p = .028), as well as work ability (p = .022). The majority of intervention subjects rated sit-stand workstation adjustability as good (83.3%), and 75.0% were satisfied with the workstation. About 41.7% of the intervention participants, who were exclusively female, used the sit-stand function on a daily basis. While the environmental change alone was effective, it is likely that promoting the daily use of sit stand workstations with counselling would lead to even more substantial positive effects. PMID- 26529591 TI - Singultus foetalis and Dr. Alfons Mermann. AB - During intrauterine life, hiccups are universally present, their incidence peaking in the third trimester. Alfons Mermann (1852-1908), a gynecologist from Mannheim, Germany, best known for having established the Luisenheim Woechnerinnenasyl [lying-in asylum] there in 1887, is viewed as the first physician to name and describe singultus foetalis [fetal hiccups] in a modern peer-reviewed scientific publication. This short report attempts to shed some light on the work of Dr. Mermann and to explore whether or not he was indeed the first to recognize this phenomenon. PMID- 26529592 TI - Unreliable Tracking Ability of the Third-Generation FloTrac/VigileoTM System for Changes in Stroke Volume after Fluid Administration in Patients with High Systemic Vascular Resistance during Laparoscopic Surgery. AB - BACKGROUND: The FloTrac/VigileoTM system does not thoroughly reflect variable arterial tones, due to a lack of external calibration. The ability of this system to measure stroke volume and track its changes after fluid administration has not been fully evaluated in patients with the high systemic vascular resistance that can develop during laparoscopic surgery. METHODS: In 42 patients undergoing laparoscopic prostatectomy, the stroke volume derived by the third-generation FloTrac/VigileoTM system (SV-Vigileo), the stroke volume measured using transesophageal echocardiography (SV-TEE) as a reference method, and total systemic vascular resistance were evaluated before and after 500 ml fluid administration during pneumoperitoneum combined with the Trendelenburg position. RESULTS: Total systemic vascular resistance was 2159.4 +/- 523.5 dyn.s/cm5 before fluid administration. The SV-Vigileo was significantly higher than the SV-TEE both before (68.8 +/- 15.9 vs. 57.0 +/- 11.0 ml, P < 0.001) and after (73.0 +/- 14.8 vs. 64.9 +/- 12.2 ml, P = 0.003) fluid administration. During pneumoperitoneum combined with the Trendelenburg position, Bland-Altman analysis for repeated measures showed a 53.8% of percentage error between the SV-Vigileo and the SV-TEE. Four-quadrant plot (69.2% of a concordance rate) and polar plot analysis (20.6 degrees of a mean polar angle, 16.4 degrees of the SD of a polar angle, and +/-51.5 degrees of a radial sector containing 95% of the data points) did not indicate a good trending ability of the FloTrac/VigileoTM system. CONCLUSIONS: The third-generation FloTrac/VigileoTM system may not be useful in patients undergoing laparoscopic surgery, based on unreliable performance in measuring the stroke volume and in tracking changes in the stroke volume after fluid administration during pneumoperitoneum combined with the Trendelenburg position. PMID- 26529593 TI - Adolescents with Type 1 Diabetes--The Impact of Gender, Age, and Health-Related Functioning on Eating Disorder Psychopathology. AB - OBJECTIVE: To investigate correlates of eating disorder psychopathology in adolescent males and females with type 1 diabetes. METHOD: A total of 105 adolescents with type 1 diabetes (42% males), aged 12-20 years, were recruited from the Norwegian Childhood Diabetes Registry in this population-based study. All participants were interviewed with the Child Eating Disorder Examination. Additionally, the Brief Illness Perception Questionnaire, the Adolescent Coping Orientation for Problem Experiences and the Beliefs about Medicines Questionnaire were administered to assess health-related functioning. Clinical data were obtained from the Norwegian Childhood Diabetes Registry. RESULTS: Significant gender differences were demonstrated in the pattern of correlates of eating disorder pathology. Among females, eating disorder psychopathology was significantly associated with body mass index adjusted for age and gender, age, insulin restriction, coping, illness perceptions, and perceptions of insulin concern. In a regression model, age, illness perceptions, and insulin restriction remained significantly associated with eating disorder psychopathology, explaining 48% of the variance. None of the variables were associated with eating disorder psychopathology among males. DISCUSSION: Greater clinical awareness of illness perceptions, attitudes toward insulin, and insulin restriction may potentially decrease the risk of developing eating disorders among female adolescents with type 1 diabetes, and the subsequent increased morbidity and mortality associated with comorbid type 1 diabetes and eating disorders. PMID- 26529594 TI - Novel Anthropometry-Based Calculation of the Body Heat Capacity in the Korean Population. AB - Heat capacity (HC) has an important role in the temperature regulation process, particularly in dealing with the heat load. The actual measurement of the body HC is complicated and is generally estimated by body-composition-specific data. This study compared the previously known HC estimating equations and sought how to define HC using simple anthropometric indices such as weight and body surface area (BSA) in the Korean population. Six hundred participants were randomly selected from a pool of 902 healthy volunteers aged 20 to 70 years for the training set. The remaining 302 participants were used for the test set. Body composition analysis using multi-frequency bioelectrical impedance analysis was used to access body components including body fat, water, protein, and mineral mass. Four different HCs were calculated and compared using a weight-based HC (HC_Eq1), two HCs estimated from fat and fat-free mass (HC_Eq2 and HC_Eq3), and an HC calculated from fat, protein, water, and mineral mass (HC_Eq4). HC_Eq1 generally produced a larger HC than the other HC equations and had a poorer correlation with the other HC equations. HC equations using body composition data were well-correlated to each other. If HC estimated with HC_Eq4 was regarded as a standard, interestingly, the BSA and weight independently contributed to the variation of HC. The model composed of weight, BSA, and gender was able to predict more than a 99% variation of HC_Eq4. Validation analysis on the test set showed a very high satisfactory level of the predictive model. In conclusion, our results suggest that gender, BSA, and weight are the independent factors for calculating HC. For the first time, a predictive equation based on anthropometry data was developed and this equation could be useful for estimating HC in the general Korean population without body-composition measurement. PMID- 26529595 TI - Conservation Planning for Offsetting the Impacts of Development: A Case Study of Biodiversity and Renewable Energy in the Mojave Desert. AB - Balancing society's competing needs of development and conservation requires careful consideration of tradeoffs. Renewable energy development and biodiversity conservation are often considered beneficial environmental goals. The direct footprint and disturbance of renewable energy, however, can displace species' habitat and negatively impact populations and natural communities if sited without ecological consideration. Offsets have emerged as a potentially useful tool to mitigate residual impacts after trying to avoid, minimize, or restore affected sites. Yet the problem of efficiently designing a set of offset sites becomes increasingly complex where many species or many sites are involved. Spatial conservation prioritization tools are designed to handle this problem, but have seen little application to offset siting and analysis. To address this need we designed an offset siting support tool for the Desert Renewable Energy Conservation Plan (DRECP) of California, and present a case study of hypothetical impacts from solar development in the Western Mojave subsection. We compare two offset scenarios designed to mitigate a hypothetical 15,331 ha derived from proposed utility-scale solar energy development (USSED) projects. The first scenario prioritizes offsets based precisely on impacted features, while the second scenario offsets impacts to maximize biodiversity conservation gains in the region. The two methods only agree on 28% of their prioritized sites and differ in meeting species-specific offset goals. Differences between the two scenarios highlight the importance of clearly specifying choices and priorities for offset siting and mitigation in general. Similarly, the effects of background climate and land use change may lessen the durability or effectiveness of offsets if not considered. Our offset siting support tool was designed specifically for the DRECP area, but with minor code modification could work well in other offset analyses, and could provide continuing support for a potentially innovative mitigation solution to environmental impacts. PMID- 26529596 TI - A Reevaluation of the Voluntary Medical Male Circumcision Scale-Up Plan in Zimbabwe. AB - BACKGROUND: The voluntary medical male circumcision (VMMC) program in Zimbabwe aims to circumcise 80% of males aged 13-29 by 2017. We assessed the impact of actual VMMC scale-up to date and evaluated the impact of potential alterations to the program to enhance program efficiency, through prioritization of subpopulations. METHODS AND FINDINGS: We implemented a recently developed analytical approach: the age-structured mathematical (ASM) model and accompanying three-level conceptual framework to assess the impact of VMMC as an intervention. By September 2014, 364,185 males were circumcised, an initiative that is estimated to avert 40,301 HIV infections by 2025. Through age-group prioritization, the number of VMMCs needed to avert one infection (effectiveness) ranged between ten (20-24 age-group) and 53 (45-49 age-group). The cost per infection averted ranged between $811 (20-24 age-group) and $5,518 (45-49 age group). By 2025, the largest reductions in HIV incidence rate (up to 27%) were achieved by prioritizing 10-14, 15-19, or 20-24 year old. The greatest program efficiency was achieved by prioritizing 15-24, 15-29, or 15-34 year old. Prioritizing males 13-29 year old was programmatically efficient, but slightly inferior to the 15-24, 15-29, or 15-34 age groups. Through geographic prioritization, effectiveness varied from 9-12 VMMCs per infection averted across provinces. Through risk-group prioritization, effectiveness ranged from one (highest sexual risk-group) to 60 (lowest sexual risk-group) VMMCs per infection averted. CONCLUSION: The current VMMC program plan in Zimbabwe is targeting an efficient and impactful age bracket (13-29 year old), but program efficiency can be improved by prioritizing a subset of males for demand creation and service availability. The greatest program efficiency can be attained by prioritizing young sexually active males and males whose sexual behavior puts them at higher risk for acquiring HIV. PMID- 26529597 TI - Iron-catalyzed aerobic oxidative cleavage of the C-C sigma-bond using air as the oxidant: chemoselective synthesis of carbon chain-shortened aldehydes, ketones and 1,2-dicarbonyl compounds. AB - A simple iron-catalyzed aerobic oxidative C-C sigma-bond cleavage of ketones has been developed. Readily available and environmentally benign air is used as the oxidant. This reaction avoids the use of noble metal catalysts or specialized oxidants, chemoselectively yielding carbon chain-shortened aldehydes, ketones and 1,2-dicarbonyl compounds without overoxidation. PMID- 26529598 TI - Ancestral State Reconstruction Reveals Rampant Homoplasy of Diagnostic Morphological Characters in Urticaceae, Conflicting with Current Classification Schemes. AB - Urticaceae is a family with more than 2000 species, which contains remarkable morphological diversity. It has undergone many taxonomic reorganizations, and is currently the subject of further systematic studies. To gain more resolution in systematic studies and to better understand the general patterns of character evolution in Urticaceae, based on our previous phylogeny including 169 accessions comprising 122 species across 47 Urticaceae genera, we examined 19 diagnostic characters, and analysed these employing both maximum-parsimony and maximum likelihood approaches. Our results revealed that 16 characters exhibited multiple state changes within the family, with ten exhibiting >eight changes and three exhibiting between 28 and 40. Morphological synapomorphies were identified for many clades, but the diagnostic value of these was often limited due to reversals within the clade and/or homoplasies elsewhere. Recognition of the four clades comprising the family at subfamily level can be supported by a small number carefully chosen defining traits for each. Several non-monophyletic genera appear to be defined only by characters that are plesiomorphic within their clades, and more detailed work would be valuable to find defining traits for monophyletic clades within these. Some character evolution may be attributed to adaptive evolution in Urticaceae due to shifts in habitat or vegetation type. This study demonstrated the value of using phylogeny to trace character evolution, and determine the relative importance of morphological traits for classification. PMID- 26529599 TI - The Culture-Transmission Motive in Immigrants: A World-Wide Internet Survey. AB - A world-wide internet survey was conducted to test central assumptions of a recent theory of cultural transmission in minorities proposed by the authors. 844 1st to 2nd generation immigrants from a wide variety of countries recruited on a microjob platform completed a questionnaire designed to test eight hypotheses derived from the theory. Support was obtained for all hypotheses. In particular, evidence was obtained for the continued presence, in the immigrants, of the culture-transmission motive postulated by the theory: the desire to maintain the culture of origin and transmit it to the next generation. Support was also obtained for the hypothesized anchoring of the culture-transmission motive in more basic motives fulfilled by cultural groups, the relative intra- and intergenerational stability of the culture-transmission motive, and its motivating effects for action tendencies and desires that support cultural transmission under the difficult conditions of migration. Furthermore, the findings suggest that the assumption that people have a culture-transmission motive belongs to the folk psychology of sociocultural groups, and that immigrants regard the fulfillment of this desire as a moral right. PMID- 26529600 TI - Emotional Experiences of Obese Women with Adequate Gestational Weight Variation: A Qualitative Study. AB - BACKGROUND: As a result of the growth of the obese population, the number of obese women of fertile age has increased in the last few years. Obesity in pregnancy is related to greater levels of anxiety, depression and physical harm. However, pregnancy is an opportune moment for the intervention of health care professionals to address obesity. The objective of this study was to describe how obese pregnant women emotionally experience success in adequate weight control. METHODS AND FINDINGS: Using a qualitative design that seeks to understand content in the field of health, the sample of subjects was deliberated, with thirteen obese pregnant women selected to participate in an individual interview. Data was analysed by inductive content analysis and includes complete transcription of the interviews, re-readings using suspended attention, categorization in discussion topics and the qualitative and inductive analysis of the content. The analysis revealed four categories, three of which show the trajectory of body care that obese women experience during pregnancy: 1) The obese pregnant woman starts to think about her body;2) The challenge of the diet for the obese pregnant woman; 3) The relation of the obese pregnant woman with the team of antenatal professionals. The fourth category reveals the origin of the motivation for the change: 4) The potentializing factors for change: the motivation of the obese woman while pregnant. CONCLUSIONS: During pregnancy, obese women are more in touch with themselves and with their emotional conflicts. Through the transformations of their bodies, women can start a more refined self-care process and experience of the body-mind unit. The fear for their own and their baby's life, due to the risks posed by obesity, appears to be a great potentializing factor for change. The relationship with the professionals of the health care team plays an important role in the motivational support of the obese pregnant woman. PMID- 26529601 TI - Effect of Oral Beta-Hydroxy-Beta-Methylbutyrate (HMB) Supplementation on Physical Performance in Healthy Old Women Over 65 Years: An Open Label Randomized Controlled Trial. AB - Although older people are particularly liable to sarcopenia, limited research is available on beta-hydroxy-beta-methylbutyrate (HMB) supplementation in this population, particularly in healthy subjects. In this parallel-group, randomized, controlled, open-label trial, we aimed to evaluate whether an oral supplement containing 1.5 g of calcium HMB for 8 weeks could improve physical performance and muscle strength parameters in a group of community-dwelling healthy older women. Eighty healthy women attending a twice-weekly mild fitness program were divided into two equal groups of 40, and 32 of the treated women and 33 control completed the study. We considered a change in the Short Physical Performance Battery (SPPB) score as the primary outcome and changes in the peak torque (PT) isometric and isokinetic strength of the lower limbs, 6-minute walking test (6MWT), handgrip strength and endurance as secondary outcomes. Body composition was assessed with dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computerized tomography (pQCT). The mean difference between the two groups on pre-post change were finally calculated (delta) for each outcome. After 8 weeks, there were no significant differences between the groups' SPPB, handgrip strength or DXA parameters. The group treated with HMB scored significantly better than the control group for PT isokinetic flexion (delta = 1.56+/-1.56 Nm; p = 0.03) and extension (delta = 3.32+/-2.61 Nm; p = 0.03), PT isometric strength (delta = 9.74+/-3.90 Nm; p = 0.02), 6MWT (delta = 7.67+/-8.29 m; p = 0.04), handgrip endurance (delta = 21.41+/-16.28 s; p = 0.02), and muscle density assessed with pQCT. No serious adverse effects were reported in either group. In conclusion, a nutritional supplement containing 1.5 g of calcium HMB for 8 weeks in healthy elderly women had no significant effects on SPPB, but did significantly improve several muscle strength and physical performance parameters. TRIAL REGISTRATION: ClinicalTrials.gov NCT02118181. PMID- 26529602 TI - Deciphering RNA Regulatory Elements Involved in the Developmental and Environmental Gene Regulation of Trypanosoma brucei. AB - Trypanosoma brucei is a vector-borne parasite with intricate life cycle that can cause serious diseases in humans and animals. This pathogen relies on fine regulation of gene expression to respond and adapt to variable environments, with implications in transmission and infectivity. However, the involved regulatory elements and their mechanisms of actions are largely unknown. Here, benefiting from a new graph-based approach for finding functional regulatory elements in RNA (GRAFFER), we have predicted 88 new RNA regulatory elements that are potentially involved in the gene regulatory network of T. brucei. We show that many of these newly predicted elements are responsive to both transcriptomic and proteomic changes during the life cycle of the parasite. Moreover, we found that 11 of predicted elements strikingly resemble previously identified regulatory elements for the parasite. Additionally, comparison with previously predicted motifs on T. brucei suggested the superior performance of our approach based on the current limited knowledge of regulatory elements in T. brucei. PMID- 26529604 TI - Task-Dependent Intermuscular Motor Unit Synchronization between Medial and Lateral Vastii Muscles during Dynamic and Isometric Squats. AB - PURPOSE: Motor unit activity is coordinated between many synergistic muscle pairs but the functional role of this coordination for the motor output is unclear. The purpose of this study was to investigate the short-term modality of coordinated motor unit activity-the synchronized discharge of individual motor units across muscles within time intervals of 5ms-for the Vastus Medialis (VM) and Lateralis (VL). Furthermore, we studied the task-dependency of intermuscular motor unit synchronization between VM and VL during static and dynamic squatting tasks to provide insight into its functional role. METHODS: Sixteen healthy male and female participants completed four tasks: Bipedal squats, single-leg squats, an isometric squat, and single-leg balance. Monopolar surface electromyography (EMG) was used to record motor unit activity of VM and VL. For each task, intermuscular motor unit synchronization was determined using a coherence analysis between the raw EMG signals of VM and VL and compared to a reference coherence calculated from two desynchronized EMG signals. The time shift between VM and VL EMG signals was estimated according to the slope of the coherence phase angle spectrum. RESULTS: For all tasks, except for singe-leg balance, coherence between 15-80Hz significantly exceeded the reference. The corresponding time shift between VM and VL was estimated as 4ms. Coherence between 30-60Hz was highest for the bipedal squat, followed by the single-leg squat and the isometric squat. CONCLUSION: There is substantial short-term motor unit synchronization between VM and VL. Intermuscular motor unit synchronization is enhanced for contractions during dynamic activities, possibly to facilitate a more accurate control of the joint torque, and reduced during single-leg tasks that require balance control and thus, a more independent muscle function. It is proposed that the central nervous system scales the degree of intermuscular motor unit synchronization according to the requirements of the movement task at hand. PMID- 26529605 TI - Integrating Client and Clinician Perspectives on Psychotropic Medication Decisions: Developing a Communication-Centered Epistemic Model of Shared Decision Making for Mental Health Contexts. AB - Shared decision making (SDM) interventions aim to improve client autonomy, information sharing, and collaborative decision making, yet implementation of these interventions has been variably perceived. Using interviews and focus groups with clients and clinicians from mental health clinics, we explored experiences with and perceptions about decision support strategies aimed to promote SDM around psychotropic medication treatment. Using thematic analysis, we identified themes regarding beliefs about participant involvement, information management, and participants' broader understanding of their epistemic expertise. Clients and clinicians highly valued client-centered priorities such as autonomy and empowerment when making decisions. However, two frequently discussed themes revealed complex beliefs about what that involvement should look like in practice: (a) the role of communication and information exchange and (b) the value and stability of clinician and client epistemic expertise. Complex beliefs regarding these two themes suggested a dynamic and reflexive approach to information management. Situating these findings within the Theory of Motivated Information Management, we discuss implications for conceptualizing SDM in mental health services and adapt Siminoff and Step's Communication Model of Shared Decision Making (CMSDM) to propose a Communication-centered Epistemic Model of Shared Decision Making (CEM-SDM). PMID- 26529606 TI - A Systematic Review and Meta-Analysis of Ilizarov Methods in the Treatment of Infected Nonunion of Tibia and Femur. AB - BACKGROUND: Infected nonunion of tibia and femur are common in clinical practice, however, the treatment of these diseases has still been a challenge for orthopaedic surgeons. Ilizarov methods can eradicate infection, compensate bone defects and promote the bone union through progressive bone histogenesis. The objective of this systematic review was to review current available studies reporting on Ilizarov methods in the treatment of infected nonunion of tibia and femur, and to perform meta-analysis of bone and functional results and complications to evaluate the efficacy of Ilizarov methods. METHODS: A comprehensive literature search was performed from the SCI, PubMed, Cochrane Library; and Embase between January 1995 and August 2015. Some major data were statistically analyzed using weighted means based on the sample size in each study by SPSS 13.0, including number of patients, mean age, mean previous surgical procedures, mean bone defects, mean length of follow-up, bone union, complications per patient, external fixation time, and external fixation index(EFI). Bone results (excellent, good, fair and poor rate), functional results (excellent, good, fair and poor rate) and complications were analyzed by Stata 9.0. FINDINGS: A total of 590 patients from 24 studies were included in this systematic review. The average of bone union rate was 97.26% in all included studies. The poor rate in bone results and functional results was 8% (95%CI, 0.04 0.12; I2 = 44.1%, P = 0.065) and 10% (95%CI, 0.05-0.14; I2 = 34.7%, P = 0.121) in patients with infected nonunion of tibia and femur treated by Ilizarov methods. The rate of refracture, malunion, infectious recurrence, knee stiffness, amputation, limb edema and peroneal nerve palsy was respectively 4%, 7%, 5%, 12%, 4%, 13% and 13%. CONCLUSIONS: Our systematic review showed that the patients with infected nonunion of tibia and femur treated by Ilizarov methods had a low rate of poor bone and functional results. Therefore, Ilizarov methods may be a good choice for the treatment of infected nonunion of tibia and femur. PMID- 26529607 TI - Can HN[double bond, length as m-dash]NH, FN[double bond, length as m-dash]NH, or HN[double bond, length as m-dash]CHOH bridge the sigma-hole and the lone pair at P in binary complexes with H2XP, for X = F, Cl, NC, OH, CN, CCH, CH3, and H? AB - Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to investigate the properties of complexes formed between H2XP, for X = F, Cl, NC, OH, CN, CCH, CH3, and H, and the possible bridging molecules HN[double bond, length as m-dash]NH, FN[double bond, length as m-dash]NH, and HN[double bond, length as m-dash]CHOH. H2XP:HNNH and H2XP:FNNH complexes are stabilized by PN pnicogen bonds, except for H2(CH3)P:FNNH and H3P:FNNH which are stabilized by N-HP hydrogen bonds. H2XP:HNCHOH complexes are stabilized by PN pnicogen bonds and nonlinear O-HP hydrogen bonds. For a fixed H2XP molecule, binding energies decrease in the order HNCHOH > HNNH > FNNH, except for the binding energies of H2(CH3)P and H3P with HNNH and FNNH. Binding energies of complexes with HNCHOH and HNNH increase as the P-N1 distance decreases, but binding energies of complexes with FNNH show little dependence on this distance. The large binding energies of H2XP:HNCHOH complexes arise from a cooperative effect involving electron-pair acceptance by P to form a pnicogen bond, and electron-pair donation by P to form a hydrogen bond. The dominant charge-transfer interaction in these complexes involves electron-pair donation by N across the pnicogen bond, except for complexes in which X is one of the more electropositive substituents, CCH, CH3, and H. For these, lone-pair donation by P across the hydrogen bond dominates. AIM and NBO data for these complexes are consistent with their bonding characteristics, showing molecular graphs with bond critical points and charge-transfer interactions associated with hydrogen and pnicogen bonds. EOM-CCSD spin-spin coupling constants (1p)J(P-N) across the pnicogen bond for each series of complexes correlate with the P-N distance. In contrast, (2h)J(O-P) values for complexes H2XP:HNCHOH do not correlate with the O-P distance, a consequence of the nonlinearity of these hydrogen bonds. PMID- 26529608 TI - Correction: Acoustic actuated fluorescence activated sorting of microparticles. AB - Correction for 'Acoustic actuated fluorescence activated sorting of microparticles' by Ola Jakobsson et al., Lab Chip, 2014, 14, 1943-1950. PMID- 26529610 TI - Electrophysiological Detection of Scalar-Changing Perimodiolar Cochlear Electrode Arrays: A Six-Month Follow-Up Study. AB - The position of the cochlear electrode array within the scala tympani is essential for optimal hearing benefit. An intraoperative neural response telemetry ratio (NRT ratio; a threshold ratio of pairs of apical and basal electrodes) has been established, which can provide information about the intracochlear electrode array position. Out of a previous collective of 85 patients, the 6-month follow-up electrophysiological NRT data of 37 patients have been included in this study. Comparing the intraoperatively estimated NRT ratio with the 6-month follow-up NRT ratio, it remained unchanged intraindividually in 92% of cases. Within this group the NRT ratio and the intracochlear position of the electrode array matched in all cases. There were two newly occurring mismatches and one new match was observed. After a period of 6 months the NRT ratio remained unchanged in most cases and showed a good correlation with the intracochlear position of the electrode array. PMID- 26529611 TI - Single Chirality (6,4) Single-Walled Carbon Nanotubes for Fluorescence Imaging with Silicon Detectors. AB - Postsynthetic single-walled carbon nanotube (SWCNT) sorting methods such as density gradient ultracentrifugation, gel chromatography, and electrophoresis have all been inspired by established biochemistry separation techniques designed to separate subcellular components. Biochemistry separation techniques have been refined to the degree that parameters such as pH, salt concentration, and temperature are necessary for a successful separation, yet these conditions are only now being applied to SWCNT separation methodologies. Slight changes in pH produce radically different behaviors of SWCNTs inside a density gradient, allowing for the facile separation of ultrahigh purity (6,4) SWCNTs from as synthesized carbon nanotubes. The (6,4) SWCNTs are novel fluorophores emitting below ~900 nm and can be easily detected with conventional silicon-based charge coupled device detectors without the need for specialized InGaAs cameras. The (6,4) SWCNTs are used to demonstrate their potential as a clinically relevant NIR I fluorescence stain for the immunohistochemical staining of cells and cancer tissue sections displaying high endothelial growth factor receptor levels. PMID- 26529612 TI - FireProt: Energy- and Evolution-Based Computational Design of Thermostable Multiple-Point Mutants. AB - There is great interest in increasing proteins' stability to enhance their utility as biocatalysts, therapeutics, diagnostics and nanomaterials. Directed evolution is a powerful, but experimentally strenuous approach. Computational methods offer attractive alternatives. However, due to the limited reliability of predictions and potentially antagonistic effects of substitutions, only single point mutations are usually predicted in silico, experimentally verified and then recombined in multiple-point mutants. Thus, substantial screening is still required. Here we present FireProt, a robust computational strategy for predicting highly stable multiple-point mutants that combines energy- and evolution-based approaches with smart filtering to identify additive stabilizing mutations. FireProt's reliability and applicability was demonstrated by validating its predictions against 656 mutations from the ProTherm database. We demonstrate that thermostability of the model enzymes haloalkane dehalogenase DhaA and gamma-hexachlorocyclohexane dehydrochlorinase LinA can be substantially increased (DeltaTm = 24 degrees C and 21 degrees C) by constructing and characterizing only a handful of multiple-point mutants. FireProt can be applied to any protein for which a tertiary structure and homologous sequences are available, and will facilitate the rapid development of robust proteins for biomedical and biotechnological applications. PMID- 26529613 TI - Effect of hormone therapy on the risk of bone fractures: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: The aim of this study was to investigate the association between hormone therapy (HT) use and the development of bone fractures. METHODS: Using terms related to HT and fractures, we searched PubMed, Embase, and the Cochrane library for randomized controlled trials on HT and the associated risk of fractures published before August 2014. Two evaluators independently selected studies on the basis of predetermined selection criteria, and 28 studies were included in the meta-analysis. Summary estimates were obtained using fixed- or random-effects models as appropriate. RESULTS: A total of 28 studies included 33,426 participants and 2,516 fractures cases. The overall relative risk of HT was 0.74 (95% confidence interval [CI] 0.69-0.80) for total fractures, 0.72 (95% CI 0.53-0.98) for hip fractures, and 0.63 (95% CI 0.44-0.91) for vertebral fractures. In subgroup analyses, women of an age less than 60 years had lower risk of total fractures compared with women of an age more than 60 years (P = 0.003). Estradiol led to greater decrease in the risk of total fractures compared with conjugated equine estrogens (P = .01). There is greater reduction in total fracture risk in trials of follow-up less than 36 months than that of follow-up more than 36 months (P = 0.003). No increase in the incidence of total cancer events but an increase in the incidence of thrombus was found to be associated with HT. CONCLUSIONS: HT is associated with a reduced risk of total, hip, and vertebral fractures, with a possible attenuation of this protection effect after it is stopped or when it is begun after 60 years. However, there may be an increase in the incidence of thrombus formation associated with HT. PMID- 26529614 TI - Dry eye in postmenopausal women: a hormonal disorder. AB - OBJECTIVE: This review examines the etiology and pathophysiology of dry eye disease in postmenopausal women, and describes the steroid reproductive hormone influences that may contribute to its development. METHODS: We have reviewed the relevant studies on dry eye disease related to hormonal status and hormone therapy (HT) in both animal models and humans. RESULTS: Although both low and high estrogen levels have been associated with symptoms of dry eye disease, low androgen levels are a more consistent factor in its etiology. Postmenopausal HT with estrogen or estrogen plus progestogen has shown a limited benefit for dry eye symptoms and may even result in progression of meibomian gland dysfunction, decreased tear film break up time, and tear flow reduction. However, systemic or local androgen treatment has shown promising results in improving dry eye symptoms. CONCLUSIONS: Because of the high incidence of dry eye among postmenopausal women that may be related to the hormonal treatment, we propose that a multidisciplinary approach should be considered between gynecologists and ophthalmologists in management of this disorder. PMID- 26529615 TI - Peter F. Schnatz, DO, FACOG, FACP, NCMP 2015-2016 NAMS President. PMID- 26529616 TI - Estradiol variability, stressful life events, and the emergence of depressive symptomatology during the menopausal transition. AB - OBJECTIVE: The aim of the study was to examine the role of estradiol fluctuation in triggering depressive symptoms in the menopausal transition and assess the role of recent very stressful life events (VSLEs) as a moderating factor in this relationship. METHODS: A total of 52 euthymic women in the menopausal transition or early postmenopause (age 45-60) who were assigned to the placebo arm of a randomized controlled trial of hormone therapy provided the data for this report. At enrollment, women's experience of recent VSLEs, depressive symptoms, serum estradiol, and progesterone were assessed. At months 1, 8, and 14, depressive symptoms and hormones were reassessed, and participants underwent a stressor battery involving a speech and a mental arithmetic task. Participants rated their feelings of anxiety, fear, anger, and rejection. The standard deviation of estradiol provided an index of hormone variability over the entire 14 months. RESULTS: Greater estradiol variability across the 14 months predicted greater depressive symptoms at month 14, though only in women reporting a higher number of VSLEs at baseline (39% of women reported <=1 recent event). Greater estradiol variability also predicted greater feelings of rejection to the laboratory stressor at months 8 and 14. Furthermore, among women reporting higher VSLEs at baseline, feelings of rejection in response to the laboratory stressor at month 8 predicted depressive symptoms at month 14. CONCLUSIONS: These data suggest that estradiol variability may enhance emotional sensitivity to psychosocial stress, particularly sensitivity to social rejection. Combined with VSLEs proximate to the menopausal transition, this increased sensitivity may contribute to the development of depressed mood. PMID- 26529618 TI - [Combined treatment of cerebral arteriovenous malformations. Experience of the Burdenko Neurosurgical Institute]. AB - OBJECTIVE: Despite the achievements of recent years, cerebral AVMs continue to pose a challenge to treatment. The objective of this work was the development of recommendations for combined treatment of AVMs based on analysis of the available material and published data. MATERIAL AND METHODS: The study included 93 patients hospitalized at the Neurosurgical Institute for combined treatment of cerebral AVMs in 2010-2014. A group of combined surgery (removal of an AVM with preoperative embolization) consisted of 40 patients, and a group of combined radiotherapy (radiation after partial embolization or partial removal of an AVM) included 53 patients. 36 patients underwent radiosurgery, and 17 patients received stereotactic radiation therapy. Both groups were analyzed in terms of outcomes, complications, and follow-up results. RESULTS: In the group of combined surgery, according to the Glasgow outcome scale, good results (grade 4-5) were achieved in 35 (87.5%) patients at discharge and in 27 (90%) patients during follow-up. Treatment outcomes, surgery duration, and the amount of blood loss were not significantly different from those in the control group. Complete AVM obliteration was achieved in 29 (80.6%) patients 3 years after radiosurgery and in 8 (47%) patients after stereotactic radiotherapy. In discussion, these findings are compared to the published data, and recommendations for AVM treatment are suggested. CONCLUSION: The combined treatment of AVMs is effective management for patients with complex AVMs (Spetzler-Martin grade III-IV AVMs). Successful treatment of AVMs requires careful planning and teamwork of vascular and endovascular neurosurgeons, radiologists, and neurologists. PMID- 26529619 TI - [Endovascular treatment of large and giant intracranial aneurysms using flow diverting stents]. AB - OBJECTIVE: The objective was to evaluate the efficacy of treatment of patients with large and giant cerebral arterial aneurysms using flow-diverting stents (FDSs). MATERIAL AND METHODS: The treatment outcomes of 210 patients with large and giant intracranial aneurysms were analyzed. The study included patients with both asymptomatic and symptomatic aneurysms (manifested by SAH or pseudotumorous course). The rate of giant aneurysms was 62.3%. RESULTS: The technical success rate was 96%. In the perioperative period, the rate of clinically significant complications was 2.8%; the postoperative mortality was 3.3%. In the long-term period, total thrombosis of the aneurysm was observed in the majority of cases (80%) in the period from 4 to 12 months. Complete regression of clinical symptoms was observed in 26% of the cases, partial regression in 35%, and deterioration in 6% (of them, 4.9% of the cases were clinically significant). The long-term mortality was 2.5%. CONCLUSION: FDS is a highly efficient device for remodeling of the arterial lumen at the level of large, giant and fusiform intracranial aneurysms that significantly reduces the number of deconstructive operations and decreases the risk of ischemic complications of endovascular treatment for this complex vascular pathology. PMID- 26529620 TI - [Endovascular treatment of large and giant intracranial aneurysms using stent assistance]. AB - OBJECTIVE: The study objective was to evaluate the efficacy of occlusions of large and giant intracranial aneurysms with microcoils using stent assistance (SA). MATERIAL AND METHODS: The study is based on analysis of treatment outcomes in 37 patients with large (15-25mm) and giant (more than 25mm) intracranial aneurysms, aged 18 to 72 years, who were hospitalized at the Burdenko Neurosurgical Institute in the period between 2004 and 2014. Selection of patients for endovascular treatment using SA was based on the anatomical parameters of the aneurysm and carrier vessel. The main determining factor was the index of the aneurysm body to neck size ratio. Occlusion of aneurysms was performed with microcoils of different configurations, including those with a biologically active coating. Self-expanding stents with both an open-cell and closed-cell design were used for SA. The results of intervention for large and giant aneurysms were evaluated using control angiography immediately after occlusion of the aneurysm. The condition of patients with unruptured aneurysms as well as with ruptured aneurysms in the "cold" period was evaluated using the modified Rankin scale. The condition of patients in the acute period of SAH was evaluated on the Hunt and Hess scale. RESULTS: The technical success (successful implantation of stents and coils with total or subtotal aneurysm occlusion) was 94.5%. The postoperative disability was 2.7%; mortality was 2.7%. 28 patients were followed up for the period of 5 to 84 months (the mean was 20 months.). In the long-term period, the total and subtotal occlusion rate, including the results of re-operations, amounted to 90%. Delayed disability was 10.7%, and mortality was 3.5%. CONCLUSION: Stent assistance enables achieving total or subtotal occlusion of large and giant aneurysms in 90% of cases. In certain clinical situations, it is an alternative to other existing methods. PMID- 26529621 TI - [Supracerebellar transtentorial approach to tumors of the posterior portions of the medial temporal region]. AB - OBJECTIVE: Despite the advances in microsurgery, the choice of the most adequate approach to the posterior part of the medial temporal region (MTR) remains a very controversial issue. The supracerebellar transtentorial approach (STA) is considered as the most preferable one, since it provides the optimal balance between retraction, incision, and resection of the brain tissue. Here, we present our consecutive series of 20 patients who underwent STA surgery. MATERIAL AND METHODS: Twenty patients with glial tumors affecting the posterior MTR underwent STA surgery between 2006 and 2014. The mean age of the patients was 20 years. Benign tumors were predominant (18 out of 20 cases). RESULTS: Resection of the posterior and middle MTRs was conducted in 16 cases. The anterior MTR was accessed through STA in 1 patient only; in 2 patients, STA was combined with the infraoccipital approach. Cerebellar edema occurred in 4 patients, with hemiparesis persisting in one of the cases for 1 year after surgery. Of 8 patients with drug resistant epilepsy, the Engel class 1 or 2 outcome was achieved in 6 cases within 1 year after surgery. CONCLUSION: STA provides an excellent surgical route to the posterior and middle MTR portions; however, the anterior MTR portions cannot be reached safely. The operative risks of STA increase as the surgeon proceeds with resection of the anterior MTR portions. Anterior MTR structures can be removed using a combination of the supracerebellar and infraoccipital transtentorial approaches or two-stage resection. PMID- 26529622 TI - [Surgical anatomy of the insular cortex]. AB - OBJECTIVE: The objective of the study was to investigate the surgical anatomy of the insular cortex, morphology and vascularization of the insula and adjacent opercula in terms of transsylvian and transcortical approaches, and identification of the permissible anatomical boundaries for resection of glial tumors of the insula. MATERIAL AND METHODS: The study was conducted on 18 anatomical specimens fixed in an alcohol-glycerol solution. Perfusion of the internal carotid artery with red latex was used to study the arterial system. Dissection of the arteries and Sylvian fissure, investigation of the morphological features of the opercula as well as simulation of the transsylvian and transcortical approaches to the insula were performed using a surgical microscope, in a certain sequence. RESULTS: In the trassylvian approach, the anteroinferior part of the insula (including the limen insulae) is the most technically easy-to-reach area, whereas the superior parts of the insula are the most difficult-to-reach areas. With the tumor localized in the superior insula, the transcortical approach may be recommended that, unlike the transsylvian approach, does not require a significant retraction of the brain matter and provides a larger surgical corridor. The transcortical approach, regardless the insular region, provides a better surgical view and workspace compared to the transsylvian approach. However, the previous approach is characterized by less access to the important anatomical landmarks such as the peri-insular sulci, limen insulae, and lateral lenticulostriate arteries. Furthermore, the approach requires dissection of the brain matter of the frontal and temporal lobes. CONCLUSION: Detailed knowledge of the surgical anatomy of the insular region provides correct intraoperative identification of a number of the major anatomical landmarks (limen insulae, peri-insular sulci, most distal lenticulostriate artery) and facilitates choosing the proper surgical approach. PMID- 26529623 TI - [The use of frameless navigation during endoscopic interventions in children with multilocular hydrocephalus]. AB - INTRODUCTION: The use of the endoscopic technique largely improves treatment outcomes in patients with multilocular hydrocephalus. However, impaired anatomy and the lack of usual landmarks often cause problems in planning and intraoperative identification of changed structures. The use of frameless navigation during endoscopic interventions can significantly facilitate surgeon tasks and increases the efficacy of surgery. During surgery, the neuronavigation system visualizes a rigid endoscope that interconnects separated ventricles and cysts. Surgery can be completed with guiding a stent through an operating channel of the endoscope and implanting a shunt system. MATERIAL AND METHODS: Ten children underwent 11 endoscopic interventions using frameless intraoperative navigation at our clinic in 2013-2014. The number of surgically interconnected compartments ranged from 3 to 5. Simultaneous placement of a shunt system was performed in 8 of 11 interventions. RESULTS: Clinical improvement as a result of the operation was achieved in all children. 2 patients underwent re-operations 5 months and 1 year after endoscopic intervention. CONCLUSION: Thus, the use of frameless navigation during endoscopic interventions makes their implementation most efficient and safe for the patient. PMID- 26529624 TI - [SCT perfusion in the diagnosis of sellar and parasellar tumors]. AB - The study is devoted to the use of a minimally invasive method of SCT perfusion for the differential diagnosis of sellar and parasellar tumors. Given a wide differential diagnostic range of tumors occurring in this area, the tumor perfusion indicators were used as an auxiliary diagnostic criterion. MATERIAL AND METHODS: The study analyzed outcomes in 115 patients with various tumors of the sellar area who underwent surgery or biopsy for histological verification of the diagnosis. RESULTS: The statistically significant differences were obtained for certain groups of tumors based on the values of hemodynamic parameters (p<0.05) that enable, with a high confidence, making a conclusion on the histologic type of most tumors. CONCLUSION: These findings demonstrated that SCT perfusion is a highly informative method of the preoperative differential diagnosis of these tumors. The sensitivity and specificity of SCT perfusion in the study were 100% and 81.2%, respectively. PMID- 26529625 TI - [The successful treatment of a patient with Lhermitte--Duclos disease (A case report and literature rewiew)]. AB - INTRODUCTION: Lhermitte--Duclos disease is a rare autosomal dominant inherited disorder characterized by the loss of the normal cerebellar cortex architecture and hamartoma formation in the cerebellar hemispheres. Most commonly, this disease manifests in the third and fourth decades of life. Approximately 220 cases of Lhermitte--Duclos disease have been reported in medical literature to date. MATERIAL AND METHODS: The authors describe successful two-stage surgical treatment of a young female patient with Lhermitte--Ducos disease. CONCLUSION: This case report familiarizes practitioners with the clinical manifestations and neuroimaging features of Lhermitte--Duclos disease that facilitates timely diagnosis and proper treatment of the condition. PMID- 26529626 TI - [Granulomatous inflammation in the bed of resected cerebral cavernoma in a child, caused by a hemostatic agent]. AB - OBJECTIVE: The study presents a clinical observation of foreign body granuloma, which is rare productive inflammation, developed on treatment with a hemostatic material upon removal of cerebral cavernoma. MATERIAL AND METHODS: A 4-year-old boy operated on for left parietal lobe cavernoma was diagnosed with a mass lesion during a follow-up MRI examination 4 months after surgery. The patient was re operated in connection with suspected abscess formation. The pathological tissue was subjected to the histological and immunohistochemical examination. RESULTS: Inflammation was accompanied by the formation of foreign body granulomas, and, in some areas, had immune nature with signs of focal destructive vasculitis, delayed maturation of the granulation tissue, and disturbance of the current organization and encapsulation processes. It is worth noting that granulomatous inflammation around a hemostatic material in the brain has no specific features during introscopy and mimics an abscess or tumor recurrence. CONCLUSION: The use of hemostatic materials upon resection of cerebral cavernous malformations may cause formation of granuloma mimicking disease relapse or abscess in the long term period. To prevent granulomatous inflammation, removal of a hemostatic material, if possible, from the surgical field is recommended when reliable hemostasis is achieved. PMID- 26529627 TI - [Orbitozygomatic approaches to the skull base]. AB - The paper is written in the lecture format and dedicated to one of the main basal approaches, the orbitozygomatic approach, that has been widely used by neurosurgeons for several decades. The authors describe the historical background of the approach development and the surgical technique features and also analyze the published data about application of the orbitozygomatic approach in surgery for skull base tumors and cerebral aneurysms. PMID- 26529629 TI - Low Level of Osteocalcin Is Related With Arterial Stiffness in Korean Adults: An Inverse J-Shaped Relationship. AB - CONTEXT: The relationship between bone turnover markers and atherosclerosis is controversial. OBJECTIVE: The purpose of this study was to determine the association of arterial stiffness with the levels of osteocalcin and C-terminal telopeptide of type I collagen (CTx). DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included 1691 men and 1913 women who participated in the medical examination programs of a hospital from March 2008 to December 2011. MAIN OUTCOME MEASURES: Arterial stiffness was estimated by brachial-ankle pulse wave velocity (baPWV). Osteocalcin and CTx were assayed by chemiluminescence immunoassay. Bone mineral density was measured by dual-energy X-ray absorptiometry. RESULTS: The mean baPWV was elevated at both ends of the osteocalcin quintiles in both men and women. However, the adjusted mean was higher in the lowest quintile of osteocalcin than in the other quintiles in men and women. Before adjustment, negative and positive relationships of baPWV with the levels of osteocalcin and CTx were observed in men (beta = -0.123 and -0.078 for osteocalcin and CTx, respectively) and women (beta = 0.151 and 0.193), respectively. After adjustment for age and metabolic parameters, osteocalcin was negatively related with baPWV at lower osteocalcin levels (Q1-Q2) in both sexes (in the fully adjusted model, beta = -0.090 for men and -0.053 for women). No significant relationship was observed at higher values. The osteocalcin level was fit for a quadratic model for baPWV showing an inverse J-shape. CONCLUSIONS: The level of serum osteocalcin showed an inverse J-shaped relationship with arterial stiffness in both men and women. However, the association between the CTx level and arterial stiffness was not significant. PMID- 26529628 TI - Relating Phthalate and BPA Exposure to Metabolism in Peripubescence: The Role of Exposure Timing, Sex, and Puberty. AB - CONTEXT: Exposure to endocrine-disrupting chemicals during development may play a role in the increasing prevalence of metabolic syndrome and type 2 diabetes among children and adolescents by interfering with metabolic homeostasis. OBJECTIVE: To explore associations between in utero and peripubertal urinary phthalate metabolite and bisphenol A (BPA) concentrations and markers of peripubertal metabolic homeostasis. DESIGN: Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT): a longitudinal cohort study of pregnant women in Mexico City and their offspring. SETTING: Public maternity hospitals in Mexico City. PATIENTS OR OTHER PARTICIPANTS: Women recruited during pregnancy; offspring recruited for follow-up at age 8-14 years (n = 250). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Fasting serum c-peptide, IGF-1, leptin, and glucose concentrations among children at follow-up; calculated measures of insulin secretion and insulin resistance. RESULTS: Phthalate metabolites and BPA were associated with metabolism biomarkers at age 8-14 years in patterns that varied by sex, pubertal status, and exposure timing. For example, in utero monoethyl phthalate was associated with lower insulin secretion among pubertal boys (P = .02) and higher leptin among girls (P = .04). In utero di-2-ethylhexyl phthlate was associated with higher IGF-1 among pubertal girls; peripubertal di-2-ethylhexyl phthlate was associated with higher IGF-1, insulin secretion, and resistance among prepubertal girls. In contrast, peripubertal dibutyl phthalate, monobenzyl phthalate, and mono-3-carboxypropyl phthalate were associated with lower IGF-1 among pubertal boys. Peripubertal BPA was associated with higher leptin in boys (P = .01). CONCLUSIONS: Considering the long-term health effects related to metabolic syndrome, additional research on exposure and metabolic outcomes across developmental periods and early adulthood is needed. PMID- 26529631 TI - A Nonsense Mutation in the Hedgehog Receptor CDON Associated With Pituitary Stalk Interruption Syndrome. AB - BACKGROUND: Pituitary stalk interruption syndrome (PSIS) and holoprosencephaly (HPE) are congenital midline defects. Rare mutations in the sonic hedgehog (SHH) signaling gene CDON have recently been reported in patients with HPE. OBJECTIVE: To report a unique case of PSIS with a maternally inherited nonsense mutation in the SHH signaling protein CDON. METHOD: We performed exome sequencing on a case of PSIS. Control databases (1000 Genomes, dbSNP, Exome Variant Server, ExAC Browser) and an ancestry-matched control panel were screened upon identification of CDON mutation. RESULTS: We identified a novel heterozygous nonsense mutation (c.2764T>C, Glu922Ter) in a case of PSIS without HPE who presented with neonatal hypoglycemia and cholestasis associated with GH, TSH, and ACTH deficiencies. This mutation was absent in all control databases and from 400 healthy ancestry matched control subjects. The mutation was inherited from the patient's mother, who was operated on in childhood for strabismus. The absence of this variant in control samples suggests that it is likely to be responsible for the phenotype. CONCLUSION: We report for the first time a mutation in the CDON gene associated with PSIS. PMID- 26529630 TI - Differential Clinicopathological Risk and Prognosis of Major Papillary Thyroid Cancer Variants. AB - CONTEXT: Individualized management, incorporating papillary thyroid cancer (PTC) variant-specific risk, is conceivably a useful treatment strategy for PTC, which awaits comprehensive data demonstrating differential risks of PTC variants to support. OBJECTIVE: This study sought to establish the differential clinicopathological risk of major PTC variants: conventional PTC (CPTC), follicular-variant PTC (FVPTC), and tall-cell PTC (TCPTC). METHODS: This was a retrospective study of clinicopathological outcomes of 6282 PTC patients (4799 females and 1483 males) from 26 centers and The Cancer Genome Atlas in 14 countries with a median age of 44 years (interquartile range, 33-56 y) and median follow-up time of 37 months (interquartile range, 15-82 mo). RESULTS: The cohort consisted of 4702 (74.8%) patients with CPTC, 1126 (17.9%) with FVPTC, and 239 (3.8%) with TCPTC. The prevalence of high-risk parameters was significantly different among the three variants, including extrathyroidal invasion, lymph node metastasis, stages III/IV, disease recurrence, mortality, and the use (need) of radioiodine treatment (all P < .001), being highest in TCPTC, lowest in FVPTC, and intermediate in CPTC, following an order of TCPTC > CPTC ? FVPTC. Recurrence and mortality in TCPTC, CPTC, and FVPTC were 27.3 and 6.7%, 16.1 and 2.5%, and 9.1 and 0.6%, corresponding to events per 1000 person-years (95% confidence interval [CI]) of 92.47 (64.66-132.26) and 24.61 (12.31-49.21), 34.46 (30.71 38.66), and 5.87 (4.37-7.88), and 24.73 (18.34-33.35) and 1.68 (0.54-5.21), respectively. Mortality hazard ratios of CPTC and TCPTC over FVPTC were 3.44 (95% CI, 1.07-11.11) and 14.96 (95% CI, 3.93-56.89), respectively. Kaplan-Meier survival analyses showed the best prognosis in FVPTC, worst in TCPTC, and intermediate in CPTC in disease recurrence-free probability and disease-specific patient survival. This was particularly the case in patients at least 45 years old. CONCLUSION: This large multicenter study demonstrates differential prognostic risks of the three major PTC variants and establishes a unique risk order of TCPTC > CPTC ? FVPTC, providing important clinical implications for specific variant-based management of PTC. PMID- 26529632 TI - Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. AB - CONTEXT: Hypophosphatasia (HPP) is an inborn error of metabolism that, in its most severe perinatal and infantile forms, results in 50-100% mortality, typically from respiratory complications. OBJECTIVES: Our objective was to better understand the effect of treatment with asfotase alfa, a first-in-class enzyme replacement therapy, on mortality in neonates and infants with severe HPP. DESIGN/SETTING: Data from patients with the perinatal and infantile forms of HPP in two ongoing, multicenter, multinational, open-label, phase 2 interventional studies of asfotase alfa treatment were compared with data from similar patients from a retrospective natural history study. PATIENTS: Thirty-seven treated patients (median treatment duration, 2.7 years) and 48 historical controls of similar chronological age and HPP characteristics. INTERVENTIONS: Treated patients received asfotase alfa as sc injections either 1 mg/kg six times per week or 2 mg/kg thrice weekly. MAIN OUTCOME MEASURES: Survival, skeletal health quantified radiographically on treatment, and ventilatory status were the main outcome measures for this study. RESULTS: Asfotase alfa was associated with improved survival in treated patients vs historical controls: 95% vs 42% at age 1 year and 84% vs 27% at age 5 years, respectively (P < .0001, Kaplan-Meier log rank test). Whereas 5% (1/20) of the historical controls who required ventilatory assistance survived, 76% (16/21) of the ventilated and treated patients survived, among whom 75% (12/16) were weaned from ventilatory support. This better respiratory outcome accompanied radiographic improvements in skeletal mineralization and health. CONCLUSIONS: Asfotase alfa mineralizes the HPP skeleton, including the ribs, and improves respiratory function and survival in life-threatening perinatal and infantile HPP. PMID- 26529633 TI - De novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long lasting chronic CMV-lymphadenitis and microcephaly. AB - PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1) gain-of-function has recently been described in patients with recurrent sinopulmonary infections, chronic CMV-/EBV-infections, lymphoproliferation, and hypogammaglobulinemia. Here we report a 15-year-old boy with treatment refractory CMV lymphadenitis, severe combined immunodeficiency, microcephaly and a severe developmental defect of Th17 cells. To avoid poor outcome, hematopoietic stem cell transplantation (HSCT) was performed. Subsequently, whole exome sequencing revealed a de novo heterozygous G to-C mutation (chr5: 5:67,589,663: G>C) at the splice donor site of the PIK3R1 gene. Our data suggest that PIK3R1 gain-of-function leads to developmental defects in helper and regulatory T-cell subsets, the latter expanding the immunological features of PIK3R1 gain-of-function. T-cell subsets play a critical role in the regulation of immune response against infectious agents and of autoimmunity and thus may be particularly accountable for the clinical phenotype of affected patients. PMID- 26529634 TI - Volumetric changes in transplanted vascularized fat flaps after ischemic or congestive stresses and their relationship to capillary density in a zucker fatty rat model. AB - BACKGROUND: The aim of this study was to examine volumetric changes in fat flaps after stresses as well as their relationship with capillary density (CD) in a Zucker fatty rat model. METHODS: A total of 12 male Zucker-fa/fa rats were randomly divided into two stress groups. Superficial epigastric fat flaps were evaluated on the right side as control and on the left side as the stress (ischemic or congestive) condition in the same rat in order to avoid biases. Stress conditions were made by obstructing the pedicle vessels with a vascular clip for 3 hours. The volumes of these flaps were measured weekly. After 12 weeks of measurements, the CD of harvested flaps was examined in histologically immunostained sections. Percent changes in the body-weight-corrected flap volume [cFV(%)], the stress/control ratio [FV-ratio(%)], and the stress/control ratio of CD (CD-ratio) were defined. RESULTS: cFV(%) 12 weeks after surgery was 34.7 +/- 26.7 in the control flaps and 13.2 +/- 10.5 in the stress flaps. The FV-ratio(%) after 12 weeks was 7.4-202.5 (70.2 +/- 77.9) in the ischemic group and 14.6-66.3 (37.7 +/- 22.2) in the congestive group. The difference in variance between two groups was significant (P = 0.030). cFV(%) correlated with total CD (P = 0.011). The FV-ratio(%) correlated with the CD-ratio (P = 0.002). CONCLUSIONS: Weekly measurements of flap volumes in the Zucker fatty rat model were new and useful methods. The FV-ratio(%) in the congestive group decreased at a constant rate, while that in the ischemic group decreased or increased slightly. The rate of decreases in the flap volume correlated with CD. PMID- 26529635 TI - Estimation of ground and excited state dipole moment of laser dyes C504T and C521T using solvatochromic shifts of absorption and fluorescence spectra. AB - The absorption and fluorescence spectra of laser dyes: coumarin 504T (C504T) and coumarin 521T (C521T) have been recorded at room temperature in a series of non polar and polar solvents. The spectra of these dyes showed bathochromic shift with increasing in solvent polarity indicating the involvement of pi->pi* transition. Kamlet-Taft and Catalan solvent parameters were used to analyze the effect of solvents on C504T and C521T molecules. The study reveals that both general solute-solvent interactions and specific interactions are operative in these two systems. The ground state dipole moment was estimated using Guggenheim's method and also by quantum mechanical calculations. The solvatochromic data were used to determine the excited state dipole moment (MU(e)). It is observed that dipole moment value of excited state (MU(e)) is higher than that of the ground state in both the laser dyes indicating that these dyes are more polar in nature in the excited state than in the ground state. PMID- 26529636 TI - Spectroscopic and structural study of the newly synthesized heteroligand complex of copper with creatinine and urea. AB - Study of copper complex of creatinine and urea is very important in life science and medicine. In this paper, spectroscopic and structural study of a newly synthesized heteroligand complex of copper with creatinine and urea has been discussed. Structural studies have been carried out using DFT calculations and spectroscopic analyses were carried out by FT-IR, Raman, UV-vis absorption and fluorescence techniques. The copper complex of creatinine and the heteroligand complex were found to have much increased water solubility as compared to pure creatinine. The analysis of FT-IR and Raman spectra helps to understand the coordination properties of the two ligands and to determine the probable structure of the heteroligand complex. The LIBS spectra of the heteroligand complex reveal that the complex is free from other metal impurities. UV-visible absorption spectra and the fluorescence emission spectra of the aqueous solution of Cu-Crn-urea heteroligand complex at different solute concentrations have been analyzed and the complex is found to be rigid and stable in its monomeric form at very low concentrations. PMID- 26529637 TI - A novel Ag+ cation sensor based on polyamidoamine dendrimer modified with 1,8 naphthalimide derivatives. AB - In this study, 4-amino-1,8-naphthalimide-conjugated polyamidoamine dendrimer was synthesized and characterized and its potentiality as a cation sensor was investigated. 4-Amino-1,8-naphthalic anhydride reacted with polyamidoamine dendrimer and the product was characterized using FTIR, (1)H NMR, (13)C NMR and melting point analysis method. The synthesized compound was applied to detect various cations in water media and N,N-dimethylformamide (DMF) via monitoring the quenching of the fluorescence intensity. Furthermore, various metal cations including Cu(2+), Ni(2+), Zn(2+), Pb(2+),Ca(2+), Ba(2+), Cd(2+), Hg(2+), Fe(2+), Fe(3+) and Ag(+) were tested. The complexes formed between the synthesized compound and metal cations in solution and their effects on Photoinduced Electron Transfer (PET) process were investigated regarding the potential application of the newly-synthesized dendrimer as a colorimetric and fluorescent sensor for such cations. The results clearly confirmed that the 1,8-naphthalimide groups surrounding the central dendrimer core showed strong green fluorescence emission at 553 nm. This effect considerably decreased with the introduction of all cations, except Ag(+) where the fluorescence quenching effect was remarkable and more dominant. Therefore, it can be concluded that the synthesized dye has the potentiality of being a highly sensitive and selective fluorescence sensor for Ag(+) cation. PMID- 26529638 TI - A triazole Schiff base-based selective and sensitive fluorescent probe for Zn2+: A combined experimental and theoretical study. AB - A triazole-Schiff base, 4-(5-Chloro-2-hydroxybenzylideneamino)-1H-1,2,4-triazole 5(4H)-thione (HL), exhibits the high selectivity and sensitivity for Zn(2+) in the fluorescence spectrometry over other common metal ions, especially Cd(2+) in DMSO:H2O (1:9, v/v) solution. A 1:1 binding ratio of Zn(2+)/L for the complex has been obtained by Uv-Vis titration experiments and Job's plot with the detection limit of 51 nmol/L. The coordination mode of the complex in solution was further confirmed by density functional theory (DFT) calculations. Time-dependent density functional theory (TD-DFT) calculations indicate that a chelation-enhanced fluorescence (CHEF) effect occurs in the process of detecting Zn ion. PMID- 26529639 TI - Synthesis characterization and luminescence studies of gamma irradiated nanocrystalline yttrium oxide. AB - Nanocrystalline Y2O3 is synthesized by solution combustion technique using urea and glycine as fuels. X-ray diffraction (XRD) pattern of as prepared sample shows amorphous nature while annealed samples show cubic nature. The average crystallite size is calculated using Scherrer's formula and is found to be in the range 14-30 nm for samples synthesized using urea and 15-20 nm for samples synthesized using glycine respectively. Field emission scanning electron microscopy (FE-SEM) image of 1173 K annealed Y2O3 samples show well separated spherical shape particles and the average particle size is found to be in the range 28-35 nm. Fourier transformed infrared (FTIR) and Raman spectroscopy reveals a stretching of Y-O bond. Electron spin resonance (ESR) shows V(-) center, O2(-) and Y(2+) defects. A broad photoluminescence (PL) emission with peak at ~386nm is observed when the sample is excited with 252 nm. Thermoluminescence (TL) properties of gamma-irradiated Y2O3 nanopowder are studied at a heating rate of 5 K s(-1). The samples prepared by using urea show a prominent and well resolved peak at ~383 K and a weak one at ~570 K. It is also found that TL glow peak intensity (I(m1)) at ~383 K increases with increase in gamma-dose up to ~6.0 kGy and then decreases with increase in dose. However, glycine used Y2O3 shows a prominent TL glow with peaks at 396 K and 590 K. Among the fuels, urea used Y2O3 shows simple and well resolved TL glows. This might be due to fuel and hence particle size effect. The kinetic parameters are calculated by Chen's glow curve peak shape method and results are discussed in detail. PMID- 26529640 TI - Use of an integrated modelling and simulation approach to develop a simplified peginterferon alfa-2a dosing regimen for children with hepatitis C. AB - AIM: The aim of the study was to simplify the dosing regimen of peginterferon alfa-2a in paediatric patients with chronic hepatitis C. METHODS: A population pharmacokinetic (PK) model was developed using PK data from 14 children aged 2-8 years and 402 adults. Simulations were produced to identify a simplified dosing regimen that would provide exposures similar to those observed in the paediatric clinical trials and in the range known to be safe/efficacious in adults. Model predictions were evaluated against observed adult and paediatric data to reinforce confidence of the proposed dosing regimen. RESULTS: The final model was a two compartment model with a zero order resorption process. Covariates included a linear influence of body surface area (BSA) on apparent oral clearance (CL/F) and a linear influence of body weight on apparent volume of distribution of the central compartment (V1 /F). A simplified dosing regimen was developed which is expected to provide exposures in children aged >=5 years similar to the dosing formula used in the paediatric clinical trial and within the range that is safe/efficacious in adults. This simplified regimen is approved in the EU and in other countries for the treatment of chronic hepatitis C in treatment-naive children/adolescents aged >=5 years in combination with ribavirin. CONCLUSION: Pre-existing adult PK data were combined with relatively limited paediatric PK data to develop a PK model able to predict exposure in both populations adequately. This provided increased confidence in characterizing PK in children and helped in the development of a simplified dosing regimen of peginterferon alfa-2a in paediatric patients. PMID- 26529641 TI - Active skin perfusion and thermoregulatory response in the hand following nerve injury and repair in human upper extremities. AB - Cutaneous vasoconstriction/vasodilatation occurs in response to whole body and local cooling/heating, and the vasomotor activities play a pivotal role in thermal control of the human body. The mechanisms underlying regulation of skin blood flow involve both neurogenic and humeral/local chemical influence, contributing to the initial response to thermal stimuli and the prolonged phase of response, respectively. Previous studies have suggested the impairment of cutaneous thermal regulation after nerve injury. However, the evidence regarding how the skin perfusion and thermoregulatory response evolve after nerve injury and repair remains limited. Here we observed, by utilizing laser-Doppler perfusion imaging, baseline skin perfusion and perfusion change in response to thermal stimuli after median and ulnar nerve injury, and the results showed that baseline perfusion in autonomous skin area profoundly decreased and active rewarming after clod stress dramatically diminished before sensory recovery of the skin became detectable. In addition, baseline cutaneous perfusion was recovered as the skin regained touch sensation, and exhibited positive correlation to touch sensibility of the skin. These data indicate that both active perfusion and thermoregulatory response of the skin are markedly compromised during skin denervation and can be recovered by re-innervation. This suggests the importance of timely repair of injured nerve, especially in the practice of replantation. PMID- 26529642 TI - Use of engineered Schwann cells in peripheral neuropathy: Hopes and hazards. AB - Many diseases of the peripheral nervous system affect the function of Schwann cells. Recent developments in stem cell technology offer the opportunity to engineer stem cell derived glial cell populations that reveal essential phenotypic characteristics of Schwann cells including growth support and myelination of peripheral axons. Potential applications of these cells include its use as platform for human cell-based disease models as well as potential source for cell transplantation strategies. In this review we provide an update on the latest developments in engineering Schwann cells as diagnostic tools or for cell replacement therapies in peripheral neuropathic conditions. This article is part of a Special Issue entitled PSC and the brain. PMID- 26529643 TI - Circadian rhythms of clock gene expression in the cerebellum of serotonin deficient Pet-1 knockout mice. AB - Serotonin plays an important role in the central regulation of circadian clock function. Serotonin levels are generally higher in the brain during periods of high activity, and these periods are in turn heavily regulated by the circadian clock located in the suprachiasmatic nucleus. However, the role of serotonin as a regulator of circadian rhythms elsewhere in the brain has not been extensively examined. In this study, we examined circadian rhythms of clock gene expression in the cerebellum in mice lacking the Pet-1 transcription factor, which results in a developed brain that is deficient in serotonin neurons. If serotonin helps to synchronize rhythms in brain regions other than the suprachiasmatic nucleus, we would expect to see differences in clock gene expression in these serotonin deficient mice. We found minor differences in the expression of Per1 and Per2 in the knockout mice as compared to wild type, but these differences were small and of questionable functional importance. We also measured the response of cerebellar clocks to injections of the serotonin agonist 8-OH-DPAT during the early part of the night. No effect on clock genes was observed, though the immediate-early gene Fos showed increased expression in wild type mice but not the knockouts. These results suggest that serotonin is not an important mediator of circadian rhythms in the cerebellum in a way that parallels its regulation of the circadian clock in the suprachiasmatic nucleus. PMID- 26529644 TI - Effects of hindlimb unloading on neurotrophins in the rat spinal cord and soleus muscle. AB - The aim of the present study was to investigate the effects of hindlimb unloading (HU) on the expression of neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF), together with the expression of their high-affinity receptors tropomyosin receptor kinase C (TrkC) and tropomyosin receptor kinase B (TrkB), in lumbar (L4-6) segment of the spinal cord and in the soleus muscle. The mRNA and protein levels of the genes of interest were compared using quantitative PCR and western blot assays. Immunohistochemistry for NT-3 and BDNF was used to detect the levels of protein in the motoneurons in the lateral motor column. In this study, NT-3 and BDNF mRNA and protein expression were significantly increased in the spinal cord and soleus muscle after HU. NT-3 immunoreactivity, but not BDNF immunoreactivity, was significantly increased in the large motoneurons located in lateral motor column after 14 days of HU. The level of TrkC protein in the spinal cord and soleus muscle were significantly elevated after both 7 days and 14 days of HU. However, TrkC mRNA, TrkB mRNA and TrkB protein levels did not change significantly. Elevated BDNF, NT-3 and TrkC levels in the neuromuscular system indicate that neurotrophins are involved in HU-induced neuromuscular plasticity. NT-3 is a candidate to mediate the synaptic efficacy between alpha motoneurons and group Ia afferents. PMID- 26529645 TI - Neuroanatomical distribution of oxytocin receptor binding in the female rabbit forebrain: Variations across the reproductive cycle. AB - Oxytocin receptors (OTR) have been characterized in the brains of several mammals, including rodents, carnivores, and primates. Their species-specific distribution in the brain has been associated with species differences in social organization, including mating strategy and parenting behavior. In several species, the density of OTR binding in specific brain regions varies according to reproductive condition, including ovarian cycle, pregnancy and lactation. Rabbits are induced ovulators, polygamous, and monoparental but their distribution and regulation of brain OTR has not been described. Here we used receptor autoradiography to quantitatively characterize OTR binding in the brains of estrous, ovariectomized, late pregnant, and lactating does. Intense binding occurred in the prefrontal cortex (PFC), preoptic area (POA), lateral septum (LS; dorsal and ventral), hippocampus, and medial amygdala. Variations among the experimental groups were seen only in PFC, POA, LS. Ovariectomy increased OTR density in PFC but had the opposite effect in POA. Lactating does had significantly reduced OTR density, relative to late pregnancy, in PFC and POA. Our results are consistent with a possible role of OT in modulating social and maternal behavior in rabbits since the brain regions sensitive to OT have been implicated in social interaction, learning and memory, olfactory processing and maternal behavior. PMID- 26529646 TI - Brain region and activity-dependent properties of M for calibrated fMRI. AB - Calibrated fMRI extracts changes in oxidative energy demanded by neural activity based on hemodynamic and metabolic dependencies of the blood oxygenation level dependent (BOLD) response. This procedure requires the parameter M, which is determined from the dynamic range of the BOLD signal between deoxyhemoglobin (paramagnetic) and oxyhemoglobin (diamagnetic). Since it is unclear if the range of M-values in human calibrated fMRI is due to regional/state differences, we conducted a 9.4T study to measure M-values across brain regions in deep (alpha chloralose) and light (medetomidine) anesthetized rats, as verified by electrophysiology. Because BOLD signal is captured differentially by gradient echo (R2*) and spin-echo (R2) relaxation rates, we measured M-values by the product of the fMRI echo time and R2' (i.e., the reversible magnetic susceptibility component), which is given by the absolute difference between R2* and R2. While R2' mapping was shown to be dependent on the k-space sampling method used, at nominal spatial resolutions achieved at high magnetic field of 9.4T the M-values were quite homogenous across cortical gray matter. However cortical M-values varied in relation to neural activity between brain states. The findings from this study could improve precision of future calibrated fMRI studies by focusing on the global uniformity of M-values in gray matter across different resting activity levels. PMID- 26529647 TI - Development of a system for multicopy gene integration in Saccharomyces cerevisiae. AB - In this study we describe construction and evaluation of a vector for multicopy integration in yeast Saccharomyces cerevisiae. In this vector a modified selective marker and a reporter gene PHO8 (encoding alkaline phosphatase) were flanked with delta sequences of the Ty1 transposon. Modified by error-prone PCR version of selection marker kanMX4 was obtained from Escherichia coli clone with impaired geneticin (G418) resistance. The attenuation of kanMX4 gene provides an opportunity to select for explicitly multicopy integration of the module in S. cerevisiae using moderate (200 mg L(-1)) antibiotic concentrations. The developed system provided integration of 3-10 copies of the module in the genome of S. cerevisiae. High copy integration events were confirmed by qRT-PCR, Southern hybridization and reporter enzyme activity measurements. PMID- 26529648 TI - A new method for monitoring the extracellular proteolytic activity of wine yeasts during alcoholic fermentation of grape must. AB - The existing methods for testing proteolytic activity are time consuming, quite difficult to perform, and do not allow real-time monitoring. Proteases have attracted considerable interest in winemaking and some yeast species naturally present in grape must, such as Metschnikowia pulcherrima, are capable of expressing this activity. In this study, a new test is proposed for measuring proteolytic activity directly in fermenting grape must, using azocasein, a chromogenic substrate. Several yeast strains were tested and differences in proteolytic activity were observed. Moreover, analysis of grape must proteins in wines revealed that protease secreted by Metschnikowia strains may be active against wine proteins. PMID- 26529649 TI - RETRACTED: Bone morphogenetic protein 4 (BMP4) induces buffalo (Bubalus bubalis) embryonic stem cell differentiation into germ cells. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Editor-in-Chief.Problems related to images published in this paper in Figure 12 were brought to the authors' attention. Unfortunately this figure contains duplicate images for ESC controls for VASA, GDF9, and ZP4, which display identical patterns superimposed on varying intensities of background.Therefore, the authors retract the paper with the agreement of the editors and deeply regret this situation and apologize for any inconvenience to the editors and readers of Biochimie. PMID- 26529650 TI - Impact of Time on Fluid Resuscitation with Hypertonic Saline (NaCl 7.5%) in Rats with LPS-Induced Acute Lung Injury. AB - Acute lung injury (ALI) is a common complication associated with septic shock that directly influences the prognosis of sepsis patients. Currently, one of the main supportive treatment modalities for septic shock is fluid resuscitation. The use of hypertonic saline (HS: 7.5% NaCl) for fluid resuscitation has been described as a promising therapy in experimental models of sepsis-induced ALI, but it has failed to produce similar results in clinical practice. Thus, we compared experimental timing versus clinical timing effectiveness (i.e., early vs. late fluid resuscitation) after the inflammatory scenario was established in a rat model of bacterial lipopolysaccharide-induced ALI. We found that late fluid resuscitation with hypertonic saline (NaCl 7.5%) did not reduce the mortality rates of animals compared with the mortality late associated with early treatment. Late fluid resuscitation with both hypertonic and normal saline increased pulmonary inflammation, decreased pulmonary function, and induced pulmonary injury by elevating metalloproteinase-2 and metalloproteinase-9 activity and collagen deposition in the animals, unlike early treatment. The animals with lipopolysaccharide-induced ALI that received late resuscitation with any kind of fluids demonstrated aggravated pulmonary injury and respiratory function. Moreover, we showed that the therapeutic window for a beneficial effect of fluid resuscitation with hypertonic saline is very narrow. PMID- 26529651 TI - Impact of Platelets and Platelet-Derived Microparticles on Hypercoagulability Following Burn Injury. AB - An acute burn induced coagulopathy develops after scald injury, which evolves into a subacute, hypercoagulable state. Microparticles, specifically platelet derived MPs (PMPs), have been suggested as possible contributors. We first developed a model of burn-induced coagulopathy and then sought to investigate the role of platelets and PMPs in coagulation after burn. We hypothesized that changes in circulating platelet and PMP populations after injury would contribute to the post-burn, hypercoagulable state. A murine scald model with 28% TBSA full thickness burn injury was utilized and blood samples were collected at intervals after injury. Circulating MP populations, platelet counts, overall coagulation, and platelet function were determined. Burn injury led to hypercoagulability on post-burn day one (PBD1), which persisted 6 days after injury (PBD6). On PBD1, there was a significant decrease in platelet numbers and a decline in platelet contribution to clot formation with a concomitant increase in circulating procoagulant PMPs. On PBD6, there was a significant increase in platelet numbers and in platelet activation with no change in PMPs compared with sham. Further, on PBD1 decreased ADP-induced platelet activation was observed with a contrasting increase in ADP-induced platelet activation on PBD6. We therefore concluded that there was a temporal change in the mechanisms leading to a hypercoagulable state after scald injury, that PMPs are responsible for changes seen on PBD1, and finally that ADP-induced platelet activation was key to the augmented clotting mechanisms 6 days after burn. PMID- 26529652 TI - Effects of the 34C>T Variant of the AMPD1 Gene on Immune Function, Multi-Organ Dysfunction, and Mortality in Sepsis Patients. AB - INTRODUCTION: Adenosine exerts anti-inflammatory and tissue-protective effects during systemic inflammation. While the tissue-protective effects might limit organ damage, its anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance. The common 34C>T loss-of-function variant of AMPD1 (rs17602729) is associated with increased adenosine formation, but effects on immune function and outcome in sepsis patients are unknown. METHODS: The effects of the presence of the 34C>T variant on sepsis susceptibility, immune function, multi-organ dysfunction, and mortality in septic patients were studied. Patients suffering from community acquired pneumonia (CAP, initial cohort n = 285; replication cohort n = 212) and ventilator-associated pneumonia (VAP, n = 117; n = 33) and control patients without infection (n = 101) were enrolled. Genetic distributions of the AMPD1 SNP were CC 76%, CT 22%, and TT 2% in the initial cohort and CC 80%, CT 18%, and TT 2% in the replication cohort. RESULTS: The occurrence of septic CAP, but not septic VAP, was increased for the CT versus CC genotype (OR (95% CI) 2.0 (1.1-3.7); P = 0.02) in the initial cohort. The increased risk for the CT versus CC genotype was also observed in the replication cohort but did not reach statistical significance there (P = 0.38), resulting in an OR of the total group of 1.7 (95% CI 1.0-3.1), P = 0.07. In septic patients carrying the CT genotype, the ex vivo production of TNF-alpha by LPS-stimulated monocytes was attenuated (P = 0.005), indicative of a more pronounced immunoparalytic state in these patients. CONCLUSIONS: Presence of the AMPD1 34C>T variant is associated with higher infection susceptibility to CAP, but not to VAP. More pronounced immunoparalysis in these patients mediated by the anti inflammatory effects of adenosine may account for this observation. PMID- 26529653 TI - Refrigerated Platelets for the Treatment of Acute Bleeding: A Review of the Literature and Reexamination of Current Standards. PMID- 26529654 TI - Soluble Heparan Sulfate in Serum of Septic Shock Patients Induces Mitochondrial Dysfunction in Murine Cardiomyocytes. AB - The heart is one of the most frequently affected organs in sepsis. Recent studies focused on lipopolysaccharide-induced mitochondrial dysfunction; however myocardial dysfunction is not restricted to gram-negative bacterial sepsis. The purpose of this study was to investigate circulating heparan sulfate (HS) as an endogenous danger associated molecule causing cardiac mitochondrial dysfunction in sepsis. We used an in vitro model with native sera (SsP) and sera eliminated from HS (HS-free), both of septic shock patients, to stimulate murine cardiomyocytes. As determined by extracellular flux analyzing, SsP increased basal mitochondrial respiration, but reduced maximum mitochondrial respiration, compared with unstimulated cells (P < 0.0001 and P < 0.0001, respectively). Cells stimulated with HS-free serum revealed unaltered basal and maximum mitochondrial respiration, compared with unstimulated cells (P = 0.1174 and P = 0.8992, respectively). Cellular ATP-level were decreased in SsP-stimulated cells but unaltered in cells stimulated with HS-free serum compared with unstimulated cells (P < 0.0001 and P = 0.1593, respectively). Live-cell imaging revealed an increased production of mitochondrial reactive oxygen species in cells stimulated with SsP compared with cells stimulated with HS-free serum (P < 0.0001). Expression of peroxisome proliferator-activated receptors (PPARalpha and PPARgamma) and their co-activators PGC-1alpha, which regulate mitochondrial function, were studied using PCR. Cells stimulated with SsP showed downregulated PPARs and PGC-1alpha mRNA-levels compared with HS-free serum (P = 0.0082, P = 0.0128, and P = 0.0185, respectively). Blocking Toll-like receptor 4 revealed an inhibition of HS-dependent downregulation of PPARs and PGC-1alpha (all P < 0.0001). In conclusion, circulating HS in serum of septic shock patients cause cardiac mitochondrial dysfunction, suggesting that HS may be targets of therapeutics in septic cardiomyopathy. PMID- 26529655 TI - Predictors of the Onset of Hemodynamic Decompensation During Progressive Central Hypovolemia: Comparison of the Peripheral Perfusion Index, Pulse Pressure Variability, and Compensatory Reserve Index. AB - INTRODUCTION: As technological advances allow for the development of more sophisticated measurement of the mechanisms that contribute to compensation for loss of circulating blood volume such as hemorrhage, it is important to compare the discriminative ability of these new measures to standard vital signs and other new physiologic metrics of interest. The purpose of this study was to compare the discriminative ability of the following three measures to predict the onset of hemodynamic decompensation: peripheral perfusion index (PPI), pulse pressure variability (PPV), and the compensatory reserve index (CRI). MATERIALS AND METHODS: There were 51 healthy participants who underwent a progressive simulated hemorrhage to induce central hypovolemia by lower body negative pressure (LBNP). The least-squares means and 95% confidence intervals for each measure were reported by LBNP level and stratified by tolerance status (high tolerance vs. low tolerance). Generalized estimating equations were used to perform repeated measures logistic regression analysis by regressing the onset of hemodynamic decompensation on each of the vital signs of interest. These probabilities were used to calculate sensitivity, specificity, and receiver operating characteristic area under the curve (ROCAUC) for PPI, PPV, and CRI. RESULTS: Compared with both PPV (ROCAUC = 0.79) and PPI (0.56), the CRI (0.90) had superior discriminative ability (P <= 0.0001) to predict the onset of hemodynamic decompensation. This included higher sensitivity (0.86 vs. 0.78 and 0.71) and specificity (0.78 vs. 0.69 and 0.29) for the CRI compared with PPV and PPI, respectively. Further, CRI was the only measure with mean predicted probabilities of the onset of hemodynamic decompensation that progressively increased as the level of simulated hemorrhage increased. DISCUSSION: There are two potential rationales for why the CRI had superior discriminative ability to predict hemodynamic decompensation. First, the CRI more accurately predicted the onset of hemodynamic decompensation at all levels of simulated hemorrhage, but especially at lower levels of hemorrhage. Second, the CRI was better able to differentiate high versus low tolerant participants. CONCLUSION: Consistent with previous research, the CRI had superior discriminative ability to predict the onset of hemodynamic decompensation. For those patients at greatest risk for developing impending circulatory shock, identifying the most sensitive and specific measures of the onset of hemodynamic decompensation is critical for both the early recognition and implementation of life-saving interventions. PMID- 26529656 TI - Lipopolysaccharide Disrupts Mitochondrial Physiology in Skeletal Muscle via Disparate Effects on Sphingolipid Metabolism. AB - Lipopolysaccharides (LPS) are prevalent pathogenic molecules that are found within tissues and blood. Elevated circulating LPS is a feature of obesity and sepsis, both of which are associated with mitochondrial abnormalities that are key pathological features of LPS excess. However, the mechanism of LPS-induced mitochondrial alterations remains poorly understood. Herein we demonstrate the necessity of sphingolipid accrual in mediating altered mitochondrial physiology in skeletal muscle following LPS exposure. In particular, we found LPS elicited disparate effects on the sphingolipids dihydroceramides (DhCer) and ceramides (Cer) in both cultured myotubes and in muscle of LPS-injected mice. Although LPS treated myotubes had reduced DhCer and increased Cer as well as increased mitochondrial respiration, muscle from LPS-injected mice manifested a reverse trend, namely elevated DhCer, but reduced Cer as well as reduced mitochondrial respiration. In addition, we found that LPS treatment caused mitochondrial fission, likely via dynamin-related protein 1, and increased oxidative stress. However, inhibition of de novo sphingolipid biosynthesis via myriocin protected normal mitochondrial function in spite of LPS, but inhibition of DhCer desaturase 1, which increases DhCer, but not Cer, exacerbated mitochondrial respiration with LPS. In an attempt to reconcile the incongruent effects of LPS in isolated muscle cells and whole muscle tissue, we incubated myotubes with conditioned medium from treated macrophages. In contrast to direct myotube LPS treatment, conditioned medium from LPS-treated macrophages reduced myotube respiration, but this was again mitigated with sphingolipid inhibition. Thus, macrophage sphingolipid production appears to be necessary for LPS-induced mitochondrial alterations in skeletal muscle tissue. PMID- 26529657 TI - Evaluation of Perfusion Index as a Predictor of Vasopressor Requirement in Patients with Severe Sepsis. AB - We evaluated the ability of perfusion index (PI) to predict vasopressor requirement during early resuscitation in patients with severe sepsis. All consecutive patients with clinically suspected severe sepsis as defined by the criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference were included. Perfusion variables included PI, arterial lactate level, central venous oxygen saturation, and the difference between central venous carbon dioxide and arterial carbon dioxide pressures, and were recorded before resuscitation and 6 h thereafter. We enrolled 36 patients with severe sepsis. Twenty-one patients required vasopressors, whereas 15 did not. The cut-off of the PI value for predicting vasopressor requirement was <=0.3. This cut-off value had a sensitivity of 100% and a specificity of 93%; the area under the curve was 0.96 (95% confidence interval 0.8-0.99, P < 0.0001). The cut-off of the arterial lactate level for predicting vasopressor requirement was >=1.8 mg dL. This cut-off value had a sensitivity of 82% and a specificity of 80%; the area under the curve was 0.84 (95% confidence interval 0.68-0.94, P < 0.0001). Other perfusion variables failed to predict vasopressor requirement in patients with severe sepsis. We concluded that PI and arterial lactate level are good predictors of vasopressor requirement during early resuscitation in patients with severe sepsis. Further studies are warranted to investigate whether monitoring PI during resuscitation improves the outcome of patients with septic shock. PMID- 26529659 TI - The in Vitro Immune-Modulating Properties of a Sweat Gland-Derived Antimicrobial Peptide Dermcidin. AB - The epidermal barriers of the skin serve as the first layer of defense by limiting the access of many pathogens to the blood circulation. In addition, human skin also contains sweat glands that can secrete a wide array of antimicrobial peptides to restrain the growth of various microbes. In the case of microbial infection, macrophages and monocytes constitute the first line of defense by producing a wide array of proinflammatory cytokines and chemokines. This process is triggered either by pathogen-associated molecular pattern molecules (such as bacterial endotoxin) or damage-associated molecular pattern molecules (such as HMGB1). In light of our findings that a sweat gland-derived antimicrobial peptide, dermcidin, affected both pathogen-associated molecular pattern and damage-associated molecular pattern-induced cytokines/chemokines by macrophages/monocytes, we propose that dermcidin may play an important role in the regulation of the innate immune responses to infection and injury. Future investigations are warranted to further test this understudied hypothesis in both preclinical and clinical settings. PMID- 26529660 TI - BLOCKADE OF ENDOTHELIAL GROWTH FACTOR, ANGIOPOIETIN-2, REDUCES INDICES OF ARDS AND MORTALITY IN MICE RESULTING FROM THE DUAL-INSULTS OF HEMORRHAGIC SHOCK AND SEPSIS. AB - We have demonstrated hemorrhagic shock "priming" for the development of indirect acute respiratory distress syndrome (iARDS) in mice following subsequent septic challenge, and show pathology characteristic of patients with iARDS, including increased lung microvascular permeability and arterial PO2/FI02 reduced to levels comparable to mild/moderate ARDS during the 48 h following hemorrhage. Loss of endothelial cell (EC) barrier function is a major component in the development of iARDS. EC growth factors, Angiopoietin (Ang)-1 and 2, maintain vascular homeostasis via tightly regulated competitive interaction with tyrosine kinase receptor, Tie2, expressed on ECs. Ang-2/Tie2 binding, in contrast to Ang-1, is believed to produce vessel destabilization, pulmonary leakage, and inflammation. Recent clinical findings from our trauma/surgical intensive care units and others have reported elevated Ang-2 in the plasma from patients that develop ARDS. We have previously described similarly elevated Ang-2 in plasma and lung tissue in our shock/sepsis model for the development of iARDS, and demonstrated effective reduction in indices of inflammation and lung tissue injury following siRNA inhibition of Ang-2 protein synthesis. In this study we show that Ang-2 in lung tissue and plasma spikes following hemorrhage (priming) and remain elevated at sepsis induction. In addition, that transient inhibition of Ang-2 function immediately following hemorrhage, suppressing priming, but not following sepsis, impacts the development of iARDS in our model. Our data demonstrate that selective temporal blockade of Ang-2 function following hemorrhagic shock priming significantly improved PO2/FIO2, decreased lung protein leak and indices of inflammation, and improved 10-day survival in our murine model for the development iARDS. PMID- 26529662 TI - Metabolomic Analyses of Brain Tissue in Sepsis Induced by Cecal Ligation Reveal Specific Redox Alterations--Protective Effects of the Oxygen Radical Scavenger Edaravone. AB - The pathophysiology of sepsis-associated encephalopathy (SAE) is complex and remains incompletely elucidated. Dysregulated reactive oxygen species (ROS) production and mitochondrial-mediated necrotic-apoptotic pathway have been proposed as part of the pathogenesis. The present study aimed at analyzing the preventive effect of the free radical scavenger edaravone on sepsis-induced brain alterations. Sepsis was induced by cecal ligation and puncture (CLP) and the mice were divided into three groups-CLP vehicle (CLPV), CLP and edaravone (MCI-186, 3 methyl-1-phenyl-2-pyrazolin-5-one) (CLPE), and sham-operated (Sham). Mice in CLPV and CLPE were injected with saline or edaravone intraperitoneally at a dose of 10 mg/kg twice daily. The treatments were initiated 4 days prior to the surgical procedure. Mortality, histological changes, electron microscopy (EM), and expression of Bcl-2 family genes (Bcl-2 and Bax) were analyzed in selected brain regions. CLPE showed significant improvement in survival compared with CLPV 18 h postinduction of sepsis (P < 0.05). At the same time point, pathohistological analysis also showed marked reduction of neuronal cell death in both parietal cortex and hippocampus in the CLPE (P < 0.05). RT-PCR and immunoblotting directed at the Bcl-2 family revealed increased Bax mRNA levels in hippocampus at 12 h in CLPV as well as an increased Bax/Bcl-2 protein ratio, changes that were significantly suppressed in CLPE. In conclusion, our study suggests that sepsis induced by cecal ligation alters cerebral redox status and supports a proapoptotic phenotype. The free radical scavenger edavarone reduces mortality of septic mice and protects against sepsis-induced neuronal cell death. PMID- 26529661 TI - IMMUNE CELL PHENOTYPE AND FUNCTION IN SEPSIS. AB - Cells of the innate and adaptive immune systems play a critical role in the host response to sepsis. Moreover, their accessibility for sampling and their capacity to respond dynamically to an acute threat increases the possibility that leukocytes might serve as a measure of a systemic state of altered responsiveness in sepsis.The working group of the 14th Acute Dialysis Quality Initiative (ADQI) conference sought to obtain consensus on the characteristic functional and phenotypic changes in cells of the innate and adaptive immune system in the setting of sepsis. Techniques for the study of circulating leukocytes were also reviewed and the impact on cellular phenotypes and leukocyte function of nonextracorporeal treatments and extracorporeal blood purification therapies proposed for sepsis was analyzed.A large number of alterations in the expression of distinct neutrophil and monocyte surface markers have been reported in septic patients. The most consistent alteration seen in septic neutrophils is their activation of a survival program that resists apoptotic death. Reduced expression of HLA-DR is a characteristic finding on septic monocytes, but monocyte antimicrobial function does not appear to be significantly altered in sepsis. Regarding adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and it involves all types of T cells (CD4, CD8, and Natural Killer) except T regulatory cells, thus favoring immunosuppression. Finally, numerous promising therapies targeting the host immune response to sepsis are under investigation. These potential treatments can have an effect on the number of immune cells, the proportion of cell subtypes, and the cell function. PMID- 26529663 TI - SHOCK VOLUME: A PATIENT-SPECIFIC INDEX THAT PREDICTS TRANSFUSION REQUIREMENTS AND ORGAN DYSFUNCTION IN MULTIPLY INJURED PATIENTS. AB - Multiply injured patients (MIPs) in hemorrhagic shock develop oxygen debt which causes organ dysfunction and can lead to death. We developed a noninvasive patient-specific index, Shock Volume (SV), to quantify the magnitude of hypoperfusion. SV integrates the magnitude and duration that incremental shock index values are elevated above known thresholds of hypoperfusion using serial individual vital sign data. SV can be monitored in real time to assess ongoing hypoperfusion. The goal of this study was to determine how SV corresponded to transfusion requirements and organ dysfunction in a retrospective cohort of 74 MIPs. We measured SV in 6-h increments for 48 h after injury in multiply injured adults (18-65; Injury Severity Score >=18). Patients who had accumulated 40 units of SV within 6 h of injury and 100 units of SV within 12 h of injury were at high risk for requiring massive transfusion or multiple critical administration transfusions. SV measurements were equally sensitive and specific as compared with base deficit values in predicting transfusions. SV measurements at 6 h after injury stratified patients at risk for multiple organ failure determined by Denver scores. In addition, SV values corresponded to the magnitude of organ failure determined by Sequential Organ Failure Assessment scores. SV is a patient specific index that can be quantified in real time in critically injured patients. It is a surrogate for cumulative hypoperfusion and it predicts high volume transfusions and organ dysfunction. PMID- 26529664 TI - PLASMA RESUSCITATION PROMOTES COAGULATION HOMEOSTASIS FOLLOWING SHOCK-INDUCED HYPERCOAGULABILITY. AB - BACKGROUND: Increased thrombin generation in injured patients possibly contributes to early consumption of coagulation factors, exacerbating hemorrhage. Identifying optimal resuscitation products for restoring plasma homeostasis following injury is important for improving management of these patients. OBJECTIVES: To determine the effects of crystalloid versus plasma resuscitation on thrombin generation in a rat model of trauma and hemorrhagic shock (HS). PATIENTS/METHODS: Rats were subjected to trauma and HS followed by resuscitation with Lactated Ringer's solution (LR) or fresh frozen plasma (FFP). Blood was collected at baseline, decompensation, and 3-h post-resuscitation. Thrombin generation was measured by calibrated automated thrombogram and antithrombin III (AT) by ELISA. In a prospective observational study, admission blood samples were collected on highest-level activation trauma patients and diluted with LR or FFP for thrombin generation analysis. RESULTS: Resuscitation with LR resulted in persistent hypercoagulability; however, FFP resuscitation reversed this hypercoagulability to baseline thrombin generation or below. Plasma AT levels decreased following HS and remained low in rats receiving LR, but were corrected in rats receiving FFP. Similarly, in trauma patient plasma LR increased thrombin generation while FFP reduced it. However, results with AT-deficient plasma dilution were similar to LR. In patients with admission hypocoagulability, FFP slightly increased thrombin generation. CONCLUSIONS: HS in rats is associated with increased thrombin generation and resuscitation with FFP, not LR, reverses hypercoagulability. Dilution of trauma patient plasma with LR or FFP yielded similar results; however, the modulatory effects of FFP were attenuated when AT was absent. Importantly, FFP reduced thrombin generation in hypercoagulable patient plasma, but slightly increased thrombin generation in hypocoagulable patient plasma. Thus, FFP restores hemostatic balance following trauma and HS which is, in part, by delivering AT. PMID- 26529665 TI - HYDROGEN-RICH MEDIUM AMELIORATES LIPOPOLYSACCHARIDE-INDUCED BARRIER DYSFUNCTION VIA RHOA-MDIA1 SIGNALING IN CACO-2 CELLS. AB - Gastrointestinal barrier dysfunction is associated with the severity and prognosis of sepsis. Hydrogen gas (H2) can ameliorate multiple organ damage in septic animals. Ras homolog gene family member A (RhoA) and mammalian diaphanous related formin 1 (mDia1) are important to regulate tight junction (TJ) and adherens junction (AJ), both of which determine the integrity of the intestinal barrier. This study was aimed to investigate whether H2 could modulate lipopolysaccharide (LPS)-stimulated dysfunction of the intestinal barrier and whether RhoA-mDia1 signaling is involved. Caco-2 cells were exposed to different concentrations of LPS (1 MUg/mL-1 mg/mL). The permeability of the intestinal barrier was evaluated by transepithelial resistance (TER) and fluorescein isothiocyanate-dextran flux. Expression and distribution of occludin and E cadherin were analyzed by Western blot and immunofluorescence. RhoA activity was measured by G-Lisa assay, and mDia1 expression was assessed by Western blot. LPS (100 MUg/mL) decreased TER and increased fluorescein-isothiocyanate-dextran flux, which were alleviated by H2-rich medium. Also, H2 down-regulated LPS-induced oxidative stress. Moreover, H2 improved the down-regulated expression and redistribution of occludin and E-cadherin caused by LPS. Additionally, H2 alleviated LPS-caused RhoA activation, and the beneficial effects of H2 on barrier were counteracted by RhoA agonist CN03. Rho inhibitor C3 exoenzyme mitigated LPS-induced barrier breakdown. Furthermore, H2-rich medium increased mDia1 expression, and mDia1 knockdown abolished protections of H2 on barrier permeability. mDia1 knockdown eliminated H2-induced benefits for occludin and E cadherin. These findings suggest that H2 improves LPS-induced hyperpermeability of the intestinal barrier and disruptions of TJ and AJ by moderating RhoA-mDia1 signaling. PMID- 26529666 TI - Trypan Blue Exclusion Test of Cell Viability. AB - The protocol described in this appendix allows for light microscopic quantitation of cell viability. Cells are suspended in PBS containing trypan blue and then examined to determine the percentage of cells that have clear cytoplasm (viable cells) versus cells that have blue cytoplasm (nonviable cells). PMID- 26529667 TI - Ghrelin protects against depleted uranium-induced apoptosis of MC3T3-E1 cells through oxidative stress-mediated p38-mitogen-activated protein kinase pathway. AB - Depleted uranium (DU) mainly accumulates in the bone over the long term. Osteoblast cells are responsible for the formation of bone, and they are sensitive to DU damage. However, studies investigating methods of reducing DU damage in osteoblasts are rarely reported. Ghrelin is a stomach hormone that stimulates growth hormones released from the hypothalamic-pituitary axis, and it is believed to play an important physiological role in bone metabolism. This study evaluates the impact of ghrelin on DU-induced apoptosis of the osteoblast MC3T3-E1 and investigates its underlying mechanisms. The results show that ghrelin relieved the intracellular oxidative stress induced by DU, eliminated reactive oxygen species (ROS) and reduced lipid peroxidation by increasing intracellular GSH levels; in addition, ghrelin effectively suppressed apoptosis, enhanced mitochondrial membrane potential, and inhibited cytochrome c release and caspase-3 activation after DU exposure. Moreover, ghrelin significantly reduced the expression of DU-induced phosphorylated p38-mitogen-activated protein kinase (MAPK). A specific inhibitor (SB203580) or specific siRNA of p38-MAPK could significantly suppress DU-induced apoptosis and related signals, whereas ROS production was not affected. In addition, ghrelin receptor inhibition could reduce the anti-apoptosis effect of ghrelin on DU and reverse the effect of ghrelin on intracellular ROS and p38-MAPK after DU exposure. These results suggest that ghrelin can suppress DU-induced apoptosis of MC3T3-E1 cells, reduce DU-induced oxidative stress by interacting with its receptor, and inhibit downstream p38-MAPK activation, thereby suppressing the mitochondrial-dependent apoptosis pathway. PMID- 26529668 TI - Arsenic induces structural and compositional colonic microbiome change and promotes host nitrogen and amino acid metabolism. AB - Chronic exposure to arsenic in drinking water causes cancer and non-cancer diseases. However, mechanisms for chronic arsenic-induced pathogenesis, especially in response to lower exposure levels, are unclear. In addition, the importance of health impacts from xeniobiotic-promoted microbiome changes is just being realized and effects of arsenic on the microbiome with relation to disease promotion are unknown. To investigate impact of arsenic exposure on both microbiome and host metabolism, the stucture and composition of colonic microbiota, their metabolic phenotype, and host tissue and plasma metabolite levels were compared in mice exposed for 2, 5, or 10weeks to 0, 10 (low) or 250 (high) ppb arsenite (As(III)). Genotyping of colonic bacteria revealed time and arsenic concentration dependent shifts in community composition, particularly the Bacteroidetes and Firmicutes, relative to those seen in the time-matched controls. Arsenic-induced erosion of bacterial biofilms adjacent to the mucosal lining and changes in the diversity and abundance of morphologically distinct species indicated changes in microbial community structure. Bacterical spores increased in abundance and intracellular inclusions decreased with high dose arsenic. Interestingly, expression of arsenate reductase (arsA) and the As(III) exporter arsB, remained unchanged, while the dissimilatory nitrite reductase (nrfA) gene expression increased. In keeping with the change in nitrogen metabolism, colonic and liver nitrite and nitrate levels and ratios changed with time. In addition, there was a concomitant increase in pathogenic arginine metabolites in the mouse circulation. These data suggest that arsenic exposure impacts the microbiome and microbiome/host nitrogen metabolism to support disease enhancing pathogenic phenotypes. PMID- 26529670 TI - Comparison of bupivacaine and dexmedetomidine femoral and sciatic nerve blocks with bupivacaine and buprenorphine epidural injection for stifle arthroplasty in dogs. AB - OBJECTIVE: To compare the quality of anesthesia and analgesia from femoral and sciatic nerve blocks (FS) with bupivacaine and dexmedetomidine with that from an epidural injection (EPI) with bupivacaine and buprenorphine in dogs undergoing unilateral stifle arthroplasty. STUDY DESIGN: Prospective, blinded, randomized, clinical comparison. ANIMALS: Twenty-six dogs weighing 36 +/- 10 kg and aged 5 (1 11) years. METHODS: Dogs were randomly assigned to either FS [n = 13; bupivacaine 0.5% (0.5 mg kg(-1) ) plus dexmedetomidine (0.1 MUg kg(-1) ) for each nerve] or EPI [n = 13; bupivacaine 0.5% (1 mg kg(-1) ) plus buprenorphine (4 MUg kg(-1) )]. Data collected included intraoperative cardiopulmonary variables and postoperative pain scores (Glasgow Composite Pain Scale), sedation scores, opioid consumption, time to urination and time to return of various behaviors. Rescue analgesia (hydromorphone 0.05 mg kg(-1) ) was administered intravenously whenever pain scores were >= 6/24. Subsequent data from rescued dogs were excluded from further analysis. RESULTS: No differences were found for any of the variables evaluated during and after anesthesia. Over 60% (nine dogs in FS, eight dogs in EPI) of patients from either group did not need additional analgesia within the 24 hour observational period. Three and four patients in FS and EPI, respectively, that required rescue analgesia did so within the first 30 minutes after extubation; only one patient in EPI required supplemental analgesia more than 4 hours after extubation. One patient in each group did not urinate spontaneously for 24 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Both techniques have the potential to provide sufficient analgesia for up to 24 hours in approximately two-thirds of dogs. Careful observation for signs of pain and preparedness to intervene is still recommended. The incidence of urinary retention was low in both groups. These techniques show promise for providing high-quality analgesia for stifle arthroplasty. PMID- 26529669 TI - Genetic variation in metallothionein and metal-regulatory transcription factor 1 in relation to urinary cadmium, copper, and zinc. AB - BACKGROUND: Metallothionein (MT) proteins play critical roles in the physiological handling of both essential (Cu and Zn) and toxic (Cd) metals. MT expression is regulated by metal-regulatory transcription factor 1 (MTF1). Hence, genetic variation in the MT gene family and MTF1 might influence excretion of these metals. METHODS: 321 women were recruited in Seattle, WA and Las Cruces, NM and provided demographic information, urine samples for measurement of metal concentrations by mass spectrometry and creatinine, and blood or saliva for extraction of DNA. Forty-one single nucleotide polymorphisms (SNPs) within the MTF1 gene region and the region of chromosome 16 encoding the MT gene family were selected for genotyping in addition to an ancestry informative marker panel. Linear regression was used to estimate the association of SNPs with urinary Cd, Cu, and Zn, adjusted for age, urinary creatinine, smoking history, study site, and ancestry. RESULTS: Minor alleles of rs28366003 and rs10636 near the MT2A gene were associated with lower urinary Cd, Cu, and Zn. Minor alleles of rs8044719 and rs1599823, near MT1A and MT1B, were associated with lower urinary Cd and Zn, respectively. Minor alleles of rs4653329 in MTF1 were associated with lower urinary Cd. CONCLUSIONS: These results suggest that genetic variation in the MT gene region and MTF1 influences urinary Cd, Cu, and Zn excretion. PMID- 26529671 TI - [Pneumococcal Vaccination for Adults - starting before 60? Con]. PMID- 26529672 TI - [Pneumococcal Vaccination for Adults - starting before 60? Pro]. PMID- 26529673 TI - Cell membrane causes the lipid bilayers to behave as variable capacitors: A resonance with self-induction of helical proteins. AB - Cell membrane has a unique feature of storing biological energies in a physiologically relevant environment. This study illustrates a capacitor model of biological cell membrane including DPPC structures. The electron density profile models, electron localization function (ELF) and local information entropy have been applied to study the interaction of proteins with lipid bilayers in the cell membrane. The quantum and coulomb blockade effects of different thicknesses in the membrane have also been specifically investigated. It has been exhibited the quantum effects can appear in a small region of the free space within the membrane thickness due to the number and type of phospholipid layers. In addition, from the viewpoint of quantum effects by Heisenberg rule, it is shown the quantum tunneling is allowed in some micro positions while it is forbidden in other forms of membrane capacitor systems. Due to the dynamical behavior of the cell membrane, its capacitance is not fixed which results a variable capacitor. In presence of the external fields through protein trance membrane or ions, charges exert forces that can influence the state of the cell membrane. This causes to appear the charge capacitive susceptibility that can resonate with self induction of helical coils; the resonance of which is the main reason for various biological pulses. PMID- 26529674 TI - Adsorption of the antimicrobial peptide tritrpticin onto solid and liquid surfaces: Ion-specific effects. AB - Developing functional biointerfaces is important for technological applications. We investigated the interaction and adsorption of the antimicrobial peptide tritrpticin (VRRFPWWWPFLRR, TRP3) onto solid and liquid surfaces and the influence of ions on these processes by several techniques. Surface tension measurements showed that salt addition to TRP3 solution causes a high decrease of surface tension due to the adsorption of TRP3 at air-liquid surface. Ellipsometry studies show the TRP3 adsorption on silicon surfaces forming nanometric films that are able to further interact with liposomes. Contact angle measurements gave insight on the nature of thin film and its roughness. AFM shows the topology of the film on the solid substrates. In addition, those techniques also showed that anions can act as modulators on adsorption phenomena and are correlated with the Hofmeister series. The findings of the current work are relevant for the development of functional interfaces such as biocidal surfaces. PMID- 26529675 TI - Aggressive Angiomyxoma: Imaging Findings in 3 Cases With Clinicopathological Correlation and Review of the Literature. AB - Aggressive angiomyxoma is a rare mesenchymal tumor with a typical presentation as a slowly growing perineal soft tissue mass in paravulvar and pararectal region in young adult women. We present 3 cases of aggressive angiomyxoma with clinicopathological correlation and describe their main imaging features with emphasis on magnetic resonance imaging, adding useful information about their behavior on dynamic contrast-enhanced sequences and diffusion-weighted imaging and including a comprehensive review of the existing literature. PMID- 26529676 TI - High-Resolution 3-T Magnetic Resonance Imaging of the Shoulder in Nonsymptomatic Professional Baseball Pitcher Draft Picks. AB - OBJECTIVES: To retrospectively assess the qualitative and quantitative high resolution 3-T magnetic resonance imaging (MRI) findings in nonsymptomatic baseball pitcher draft picks. METHODS: Institutional review board-approved and HIPAA compliant study. Three-Tesla MRI of the dominant shoulder of 19 asymptomatic baseball pitcher draft picks and detailed clinical examination was performed before contract signing. Two radiologists performed independently qualitative and quantitative evaluation of shoulder structures. Descriptive statistics were performed. RESULTS: Sixty-eight percent (13/19), 32% (6/19), and 21% (4/19) of the baseball pitcher draft picks showed tendinopathy, partial thickness tendon tear of the supraspinatus, and acromioclavicular joint osteoarthritis, respectively. Glenohumeral subluxation, glenoid remodeling, and Bennett lesion were present in 53% (10/19), 79% (15/19), and 21% (4/19) of the subjects, respectively. Interclass coefficient was 0.633 to 0.863 and kappa was 0.27 to 1. CONCLUSIONS: In asymptomatic baseball pitcher draft picks, 3-T MRI frequently shows abnormalities involving rotator cuff tendons, the coracohumeral, inferior glenohumeral, labrum, and osseous structures. PMID- 26529677 TI - Routine Coronary Calcium Scan Can Precisely Measure Vertebral Bone Density Without a Quantitative Calibration Phantom. AB - OBJECTIVE: We aimed to assess accuracy and precision of quantitative computed tomography (QCT) and phantomless in thoracic bone mineral density (BMD) assessment using coronary artery calcium scan (CACS). METHODS: A total of 513 subjects underwent CACS with a calibration phantom. The thoracic spine BMD and concentration of calcium hydroxyapatite in phantom rods, as well CT Hounsfield unit of both, were measured. The thoracic BMD and phantom-rods calcium concentration were obtained using phantomless. The accuracy and precision error of QCT and phantomless were compared. RESULTS: The mean biases from true calcium concentration of phantom rods were 2.9% and 3.8% for the QCT and phantomless, respectively (P < 0.001). The biases of thoracic BMD from QCT by phantomless were 3.8% with a similar precision error in both methods. CONCLUSIONS: The thoracic BMD can be assessed accurately and precisely using QCT and phantomless with a routine CACS. PMID- 26529678 TI - The nature of the CO2 -concentrating mechanisms in a marine diatom, Thalassiosira pseudonana. AB - Diatoms are widespread in aquatic ecosystems where they may be limited by the supply of inorganic carbon. Their carbon dioxide-concentrating mechanisms (CCMs) involving transporters and carbonic anhydrases (CAs) are well known, but the contribution of a biochemical CCM involving C4 metabolism is contentious. The CCM(s) present in the marine-centric diatom, Thalassiosira pseudonana, were studied in cells exposed to high or low concentrations of CO2 , using a range of approaches. At low CO2 , cells possessed a CCM based on active uptake of CO2 (70% contribution) and bicarbonate, while at high CO2 , cells were restricted to CO2 . CA was highly and rapidly activated on transfer to low CO2 and played a key role because inhibition of external CA produced uptake kinetics similar to cells grown at high CO2 . The activities of phosphoenolpyruvate (PEP) carboxylase (PEPC) and the PEP-regenerating enzyme, pyruvate phosphate dikinase (PPDK), were lower in cells grown at low than at high CO2 . The ratios of PEPC and PPDK to ribulose bisphosphate carboxylase were substantially lower than 1, even at low CO2 . Our data suggest that the kinetic properties of this species results from a biophysical CCM and not from C4 type metabolism. PMID- 26529679 TI - Physiophenomenology in retrospect: Memory reliably reflects physiological arousal during a prior threatening experience. AB - Psychologists have long studied links between physiology and subjective feelings, but little is known about how those links are preserved in memory. Here we examine this question via arousal, a subjective feeling with strong physiological correlates. Using virtual reality, we immersed participants in a threatening scene (Room 101) where they confronted a variety of disturbing events. Later, participants watched the scene on a desktop computer while continuously rating how aroused they remembered feeling. Analyses of those time series revealed that retrospective reports were coherent with participants' unique patterns in physiological arousal (skin conductance and heart rate) during the original events. Analyses further revealed that coherence did not depend on simulating physiological arousal and that it was particularly strong among individuals high in interoceptive accuracy. These data demonstrate that memory encodes physiological information during emotional episodes such that individuals' recall of arousal reliably reflects physiological signals as they unfolded over time. PMID- 26529680 TI - Timing matters! The neural signature of intuitive judgments differs according to the way information is presented. AB - One can conceive of intuition as the preliminary perception of coherence. Since this requires holistic perception, it is hypothesized that underlying processing strategies are dependent on the possibility to obtain all relevant information at once. The present study used magnetoencephalography (MEG) to investigate neural mechanisms underlying intuitive coherence perception when semantic concepts are presented all together (simultaneously) or one after the other (sequentially). With simultaneous presentation, absolute activation increases in the left OFC when participants recognize coherence. With sequential presentation activation increases in the right OFC when participants conclude that there is no common associate between the words presented. Behavioral performance was similar in the two experiments. These results demonstrate that the way information is revealed over time changes the processing of intuitive coherence perception. We propose that such changes must be taken into account to disentangle the neural and behavioral mechanisms underlying different accounts of intuition and related phenomena. PMID- 26529681 TI - Duration sensitivity of neurons in the primary auditory cortex of albino mouse. AB - Many neurons in the central auditory system of a number of species have been found to be sensitive to the duration of sound stimuli. While previous studies have shown that gamma-aminobutyric acid (GABA)-ergic inhibitory input is important for duration sensitivity in the inferior colliculus (IC), it is still unknown whether (GABA)-ergic inhibitory input plays an important role in generating duration sensitivity in the cortex. Using free-field sound stimulation and in vivo extracellular recording, we investigated duration sensitivity in primary auditory cortical (AI) neurons of the Nembutal anesthetized albino mouse (Mus musculus, Km) and examined the effect of the GABAA receptor antagonist bicuculline on AI neuron duration sensitivity. A total of 63 duration tuning curves were measured in AI neurons. Of these, 44% (28/63) exhibited duration sensitive responses, while 43% (27/63) lacked duration sensitivity. The remaining 13% (8/63) exhibited long-pass properties likely reflecting both duration sensitive and insensitive features. We found that duration sensitive neurons had shorter first spike latency (FSL) and longer firing duration (FD) when stimulated with best duration (p < 0.05), while duration insensitive neurons had invariable FSL and FD at different sound durations (p>0.05). Furthermore, 60% (6/10) of duration sensitive neurons and 75% (3/4) long-pass neurons lost duration sensitivity following bicuculline application. Taken together, our results show that cortical neurons in the albino mouse are sensitive to sound duration, and that GABAergic inhibition may play an important role in the formation of de novo duration sensitivity in AI. The possible mechanism and behavioral significance of duration sensitivity in AI neurons is discussed. PMID- 26529682 TI - Ultrafine Iron Pyrite (FeS2) Nanocrystals Improve Sodium-Sulfur and Lithium Sulfur Conversion Reactions for Efficient Batteries. AB - Nanocrystals with quantum-confined length scales are often considered impractical for metal-ion battery electrodes due to the dominance of solid-electrolyte interphase (SEI) layer effects on the measured storage properties. Here we demonstrate that ultrafine sizes (~4.5 nm, average) of iron pyrite, or FeS2, nanoparticles are advantageous to sustain reversible conversion reactions in sodium ion and lithium ion batteries. This is attributed to a nanoparticle size comparable to or smaller than the diffusion length of Fe during cation exchange, yielding thermodynamically reversible nanodomains of converted Fe metal and NaxS or LixS conversion products. This is compared to bulk-like electrode materials, where kinetic and thermodynamic limitations of surface-nucleated conversion products inhibit successive conversion cycles. Reversible capacities over 500 and 600 mAh/g for sodium and lithium storage are observed for ultrafine nanoparticles, with improved cycling and rate capability. Unlike alloying or intercalation processes, where SEI effects limit the performance of ultrafine nanoparticles, our work highlights the benefit of quantum dot length-scale nanocrystal electrodes for nanoscale metal sulfide compounds that store energy through chemical conversion reactions. PMID- 26529683 TI - Reducing Snapshots to Points: A Visual Analytics Approach to Dynamic Network Exploration. AB - We propose a visual analytics approach for the exploration and analysis of dynamic networks. We consider snapshots of the network as points in high dimensional space and project these to two dimensions for visualization and interaction using two juxtaposed views: one for showing a snapshot and one for showing the evolution of the network. With this approach users are enabled to detect stable states, recurring states, outlier topologies, and gain knowledge about the transitions between states and the network evolution in general. The components of our approach are discretization, vectorization and normalization, dimensionality reduction, and visualization and interaction, which are discussed in detail. The effectiveness of the approach is shown by applying it to artificial and real-world dynamic networks. PMID- 26529684 TI - MobilityGraphs: Visual Analysis of Mass Mobility Dynamics via Spatio-Temporal Graphs and Clustering. AB - Learning more about people mobility is an important task for official decision makers and urban planners. Mobility data sets characterize the variation of the presence of people in different places over time as well as movements (or flows) of people between the places. The analysis of mobility data is challenging due to the need to analyze and compare spatial situations (i.e., presence and flows of people at certain time moments) and to gain an understanding of the spatio temporal changes (variations of situations over time). Traditional flow visualizations usually fail due to massive clutter. Modern approaches offer limited support for investigating the complex variation of the movements over longer time periods. PMID- 26529685 TI - MotionFlow: Visual Abstraction and Aggregation of Sequential Patterns in Human Motion Tracking Data. AB - Pattern analysis of human motions, which is useful in many research areas, requires understanding and comparison of different styles of motion patterns. However, working with human motion tracking data to support such analysis poses great challenges. In this paper, we propose MotionFlow, a visual analytics system that provides an effective overview of various motion patterns based on an interactive flow visualization. This visualization formulates a motion sequence as transitions between static poses, and aggregates these sequences into a tree diagram to construct a set of motion patterns. The system also allows the users to directly reflect the context of data and their perception of pose similarities in generating representative pose states. We provide local and global controls over the partition-based clustering process. To support the users in organizing unstructured motion data into pattern groups, we designed a set of interactions that enables searching for similar motion sequences from the data, detailed exploration of data subsets, and creating and modifying the group of motion patterns. To evaluate the usability of MotionFlow, we conducted a user study with six researchers with expertise in gesture-based interaction design. They used MotionFlow to explore and organize unstructured motion tracking data. Results show that the researchers were able to easily learn how to use MotionFlow, and the system effectively supported their pattern analysis activities, including leveraging their perception and domain knowledge. PMID- 26529686 TI - A Case Study Using Visualization Interaction Logs and Insight Metrics to Understand How Analysts Arrive at Insights. AB - We present results from an experiment aimed at using logs of interactions with a visual analytics application to better understand how interactions lead to insight generation. We performed an insight-based user study of a visual analytics application and ran post hoc quantitative analyses of participants' measured insight metrics and interaction logs. The quantitative analyses identified features of interaction that were correlated with insight characteristics, and we confirmed these findings using a qualitative analysis of video captured during the user study. Results of the experiment include design guidelines for the visual analytics application aimed at supporting insight generation. Furthermore, we demonstrated an analysis method using interaction logs that identified which interaction patterns led to insights, going beyond insight-based evaluations that only quantify insight characteristics. We also discuss choices and pitfalls encountered when applying this analysis method, such as the benefits and costs of applying an abstraction framework to application specific actions before further analysis. Our method can be applied to evaluations of other visualization tools to inform the design of insight promoting interactions and to better understand analyst behaviors. PMID- 26529687 TI - VA2: A Visual Analytics Approach for // Evaluating Visual Analytics Applications. AB - Evaluation has become a fundamental part of visualization research and researchers have employed many approaches from the field of human-computer interaction like measures of task performance, thinking aloud protocols, and analysis of interaction logs. Recently, eye tracking has also become popular to analyze visual strategies of users in this context. This has added another modality and more data, which requires special visualization techniques to analyze this data. However, only few approaches exist that aim at an integrated analysis of multiple concurrent evaluation procedures. The variety, complexity, and sheer amount of such coupled multi-source data streams require a visual analytics approach. Our approach provides a highly interactive visualization environment to display and analyze thinking aloud, interaction, and eye movement data in close relation. Automatic pattern finding algorithms allow an efficient exploratory search and support the reasoning process to derive common eye interaction-thinking patterns between participants. In addition, our tool equips researchers with mechanisms for searching and verifying expected usage patterns. We apply our approach to a user study involving a visual analytics application and we discuss insights gained from this joint analysis. We anticipate our approach to be applicable to other combinations of evaluation techniques and a broad class of visualization applications. PMID- 26529688 TI - VisOHC: Designing Visual Analytics for Online Health Communities. AB - Through online health communities (OHCs), patients and caregivers exchange their illness experiences and strategies for overcoming the illness, and provide emotional support. To facilitate healthy and lively conversations in these communities, their members should be continuously monitored and nurtured by OHC administrators. The main challenge of OHC administrators' tasks lies in understanding the diverse dimensions of conversation threads that lead to productive discussions in their communities. In this paper, we present a design study in which three domain expert groups participated, an OHC researcher and two OHC administrators of online health communities, which was conducted to find with a visual analytic solution. Through our design study, we characterized the domain goals of OHC administrators and derived tasks to achieve these goals. As a result of this study, we propose a system called VisOHC, which visualizes individual OHC conversation threads as collapsed boxes-a visual metaphor of conversation threads. In addition, we augmented the posters' reply authorship network with marks and/or beams to show conversation dynamics within threads. We also developed unique measures tailored to the characteristics of OHCs, which can be encoded for thread visualizations at the users' requests. Our observation of the two administrators while using VisOHC showed that it supports their tasks and reveals interesting insights into online health communities. Finally, we share our methodological lessons on probing visual designs together with domain experts by allowing them to freely encode measurements into visual variables. PMID- 26529689 TI - 3D Regression Heat Map Analysis of Population Study Data. AB - Epidemiological studies comprise heterogeneous data about a subject group to define disease-specific risk factors. These data contain information (features) about a subject's lifestyle, medical status as well as medical image data. Statistical regression analysis is used to evaluate these features and to identify feature combinations indicating a disease (the target feature). We propose an analysis approach of epidemiological data sets by incorporating all features in an exhaustive regression-based analysis. This approach combines all independent features w.r.t. a target feature. It provides a visualization that reveals insights into the data by highlighting relationships. The 3D Regression Heat Map, a novel 3D visual encoding, acts as an overview of the whole data set. It shows all combinations of two to three independent features with a specific target disease. Slicing through the 3D Regression Heat Map allows for the detailed analysis of the underlying relationships. Expert knowledge about disease specific hypotheses can be included into the analysis by adjusting the regression model formulas. Furthermore, the influences of features can be assessed using a difference view comparing different calculation results. We applied our 3D Regression Heat Map method to a hepatic steatosis data set to reproduce results from a data mining-driven analysis. A qualitative analysis was conducted on a breast density data set. We were able to derive new hypotheses about relations between breast density and breast lesions with breast cancer. With the 3D Regression Heat Map, we present a visual overview of epidemiological data that allows for the first time an interactive regression-based analysis of large feature sets with respect to a disease. PMID- 26529690 TI - Supporting Iterative Cohort Construction with Visual Temporal Queries. AB - Many researchers across diverse disciplines aim to analyze the behavior of cohorts whose behaviors are recorded in large event databases. However, extracting cohorts from databases is a difficult yet important step, often overlooked in many analytical solutions. This is especially true when researchers wish to restrict their cohorts to exhibit a particular temporal pattern of interest. In order to fill this gap, we designed COQUITO, a visual interface that assists users defining cohorts with temporal constraints. COQUITO was designed to be comprehensible to domain experts with no preknowledge of database queries and also to encourage exploration. We then demonstrate the utility of COQUITO via two case studies, involving medical and social media researchers. PMID- 26529691 TI - PhenoBlocks: Phenotype Comparison Visualizations. AB - The differential diagnosis of hereditary disorders is a challenging task for clinicians due to the heterogeneity of phenotypes that can be observed in patients. Existing clinical tools are often text-based and do not emphasize consistency, completeness, or granularity of phenotype reporting. This can impede clinical diagnosis and limit their utility to genetics researchers. Herein, we present PhenoBlocks, a novel visual analytics tool that supports the comparison of phenotypes between patients, or between a patient and the hallmark features of a disorder. An informal evaluation of PhenoBlocks with expert clinicians suggested that the visualization effectively guides the process of differential diagnosis and could reinforce the importance of complete, granular phenotypic reporting. PMID- 26529692 TI - VEEVVIE: Visual Explorer for Empirical Visualization, VR and Interaction Experiments. AB - Empirical, hypothesis-driven, experimentation is at the heart of the scientific discovery process and has become commonplace in human-factors related fields. To enable the integration of visual analytics in such experiments, we introduce VEEVVIE, the Visual Explorer for Empirical Visualization, VR and Interaction Experiments. VEEVVIE is comprised of a back-end ontology which can model several experimental designs encountered in these fields. This formalization allows VEEVVIE to capture experimental data in a query-able form and makes it accessible through a front-end interface. This front-end offers several multi-dimensional visualization widgets with built-in filtering and highlighting functionality. VEEVVIE is also expandable to support custom experimental measurements and data types through a plug-in visualization widget architecture. We demonstrate VEEVVIE through several case studies of visual analysis, performed on the design and data collected during an experiment on the scalability of high-resolution, immersive, tiled-display walls. PMID- 26529693 TI - The Data Context Map: Fusing Data and Attributes into a Unified Display. AB - Numerous methods have been described that allow the visualization of the data matrix. But all suffer from a common problem - observing the data points in the context of the attributes is either impossible or inaccurate. We describe a method that allows these types of comprehensive layouts. We achieve it by combining two similarity matrices typically used in isolation - the matrix encoding the similarity of the attributes and the matrix encoding the similarity of the data points. This combined matrix yields two of the four submatrices needed for a full multi-dimensional scaling type layout. The remaining two submatrices are obtained by creating a fused similarity matrix - one that measures the similarity of the data points with respect to the attributes, and vice versa. The resulting layout places the data objects in direct context of the attributes and hence we call it the data context map. It allows users to simultaneously appreciate (1) the similarity of data objects, (2) the similarity of attributes in the specific scope of the collection of data objects, and (3) the relationships of data objects with attributes and vice versa. The contextual layout also allows data regions to be segmented and labeled based on the locations of the attributes. This enables, for example, the map's application in selection tasks where users seek to identify one or more data objects that best fit a certain configuration of factors, using the map to visually balance the tradeoffs. PMID- 26529694 TI - Temporal MDS Plots for Analysis of Multivariate Data. AB - Multivariate time series data can be found in many application domains. Examples include data from computer networks, healthcare, social networks, or financial markets. Often, patterns in such data evolve over time among multiple dimensions and are hard to detect. Dimensionality reduction methods such as PCA and MDS allow analysis and visualization of multivariate data, but per se do not provide means to explore multivariate patterns over time. We propose Temporal Multidimensional Scaling (TMDS), a novel visualization technique that computes temporal one-dimensional MDS plots for multivariate data which evolve over time. Using a sliding window approach, MDS is computed for each data window separately, and the results are plotted sequentially along the time axis, taking care of plot alignment. Our TMDS plots enable visual identification of patterns based on multidimensional similarity of the data evolving over time. We demonstrate the usefulness of our approach in the field of network security and show in two case studies how users can iteratively explore the data to identify previously unknown, temporally evolving patterns. PMID- 26529695 TI - Visual Analytics for Development and Evaluation of Order Selection Criteria for Autoregressive Processes. AB - Order selection of autoregressive processes is an active research topic in time series analysis, and the development and evaluation of automatic order selection criteria remains a challenging task for domain experts. We propose a visual analytics approach, to guide the analysis and development of such criteria. A flexible synthetic model generator-combined with specialized responsive visualizations-allows comprehensive interactive evaluation. Our fast framework allows feedback-driven development and fine-tuning of new order selection criteria in real-time. We demonstrate the applicability of our approach in three use-cases for two general as well as a real-world example. PMID- 26529696 TI - TrajGraph: A Graph-Based Visual Analytics Approach to Studying Urban Network Centralities Using Taxi Trajectory Data. AB - We propose TrajGraph, a new visual analytics method, for studying urban mobility patterns by integrating graph modeling and visual analysis with taxi trajectory data. A special graph is created to store and manifest real traffic information recorded by taxi trajectories over city streets. It conveys urban transportation dynamics which can be discovered by applying graph analysis algorithms. To support interactive, multiscale visual analytics, a graph partitioning algorithm is applied to create region-level graphs which have smaller size than the original street-level graph. Graph centralities, including Pagerank and betweenness, are computed to characterize the time-varying importance of different urban regions. The centralities are visualized by three coordinated views including a node-link graph view, a map view and a temporal information view. Users can interactively examine the importance of streets to discover and assess city traffic patterns. We have implemented a fully working prototype of this approach and evaluated it using massive taxi trajectories of Shenzhen, China. TrajGraph's capability in revealing the importance of city streets was evaluated by comparing the calculated centralities with the subjective evaluations from a group of drivers in Shenzhen. Feedback from a domain expert was collected. The effectiveness of the visual interface was evaluated through a formal user study. We also present several examples and a case study to demonstrate the usefulness of TrajGraph in urban transportation analysis. PMID- 26529697 TI - Visually Exploring Transportation Schedules. AB - Public transportation schedules are designed by agencies to optimize service quality under multiple constraints. However, real service usually deviates from the plan. Therefore, transportation analysts need to identify, compare and explain both eventual and systemic performance issues that must be addressed so that better timetables can be created. The purely statistical tools commonly used by analysts pose many difficulties due to the large number of attributes at trip- and station-level for planned and real service. Also challenging is the need for models at multiple scales to search for patterns at different times and stations, since analysts do not know exactly where or when relevant patterns might emerge and need to compute statistical summaries for multiple attributes at different granularities. To aid in this analysis, we worked in close collaboration with a transportation expert to design TR-EX, a visual exploration tool developed to identify, inspect and compare spatio-temporal patterns for planned and real transportation service. TR-EX combines two new visual encodings inspired by Marey's Train Schedule: Trips Explorer for trip-level analysis of frequency, deviation and speed; and Stops Explorer for station-level study of delay, wait time, reliability and performance deficiencies such as bunching. To tackle overplotting and to provide a robust representation for a large numbers of trips and stops at multiple scales, the system supports variable kernel bandwidths to achieve the level of detail required by users for different tasks. We justify our design decisions based on specific analysis needs of transportation analysts. We provide anecdotal evidence of the efficacy of TR-EX through a series of case studies that explore NYC subway service, which illustrate how TR-EX can be used to confirm hypotheses and derive new insights through visual exploration. PMID- 26529698 TI - Visual Analysis and Dissemination of Scientific Literature Collections with SurVis. AB - Bibliographic data such as collections of scientific articles and citation networks have been studied extensively in information visualization and visual analytics research. Powerful systems have been built to support various types of bibliographic analysis, but they require some training and cannot be used to disseminate the insights gained. In contrast, we focused on developing a more accessible visual analytics system, called SurVis, that is ready to disseminate a carefully surveyed literature collection. The authors of a survey may use our Web based system to structure and analyze their literature database. Later, readers of the survey can obtain an overview, quickly retrieve specific publications, and reproduce or extend the original bibliographic analysis. Our system employs a set of selectors that enable users to filter and browse the literature collection as well as to control interactive visualizations. The versatile selector concept includes selectors for textual search, filtering by keywords and meta information, selection and clustering of similar publications, and following citation links. Agreement to the selector is represented by word-sized sparkline visualizations seamlessly integrated into the user interface. Based on an analysis of the analytical reasoning process, we derived requirements for the system. We developed the system in a formative way involving other researchers writing literature surveys. A questionnaire study with 14 visual analytics experts confirms that SurVis meets the initially formulated requirements. PMID- 26529699 TI - CiteRivers: Visual Analytics of Citation Patterns. AB - The exploration and analysis of scientific literature collections is an important task for effective knowledge management. Past interest in such document sets has spurred the development of numerous visualization approaches for their interactive analysis. They either focus on the textual content of publications, or on document metadata including authors and citations. Previously presented approaches for citation analysis aim primarily at the visualization of the structure of citation networks and their exploration. We extend the state-of-the art by presenting an approach for the interactive visual analysis of the contents of scientific documents, and combine it with a new and flexible technique to analyze their citations. This technique facilitates user-steered aggregation of citations which are linked to the content of the citing publications using a highly interactive visualization approach. Through enriching the approach with additional interactive views of other important aspects of the data, we support the exploration of the dataset over time and enable users to analyze citation patterns, spot trends, and track long-term developments. We demonstrate the strengths of our approach through a use case and discuss it based on expert user feedback. PMID- 26529700 TI - Interactive Visual Profiling of Musicians. AB - Determining similar objects based upon the features of an object of interest is a common task for visual analytics systems. This process is called profiling, if the object of interest is a person with individual attributes. The profiling of musicians similar to a musician of interest with the aid of visual means became an interesting research question for musicologists working with the Bavarian Musicians Encyclopedia Online. This paper illustrates the development of a visual analytics profiling system that is used to address such research questions. Taking musicological knowledge into account, we outline various steps of our collaborative digital humanities project, priority (1) the definition of various measures to determine the similarity of musicians' attributes, and (2) the design of an interactive profiling system that supports musicologists in iteratively determining similar musicians. The utility of the profiling system is emphasized by various usage scenarios illustrating current research questions in musicology. PMID- 26529701 TI - VAiRoma: A Visual Analytics System for Making Sense of Places, Times, and Events in Roman History. AB - Learning and gaining knowledge of Roman history is an area of interest for students and citizens at large. This is an example of a subject with great sweep (with many interrelated sub-topics over, in this case, a 3,000 year history) that is hard to grasp by any individual and, in its full detail, is not available as a coherent story. In this paper, we propose a visual analytics approach to construct a data driven view of Roman history based on a large collection of Wikipedia articles. Extracting and enabling the discovery of useful knowledge on events, places, times, and their connections from large amounts of textual data has always been a challenging task. To this aim, we introduce VAiRoma, a visual analytics system that couples state-of-the-art text analysis methods with an intuitive visual interface to help users make sense of events, places, times, and more importantly, the relationships between them. VAiRoma goes beyond textual content exploration, as it permits users to compare, make connections, and externalize the findings all within the visual interface. As a result, VAiRoma allows users to learn and create new knowledge regarding Roman history in an informed way. We evaluated VAiRoma with 16 participants through a user study, with the task being to learn about roman piazzas through finding relevant articles and new relationships. Our study results showed that the VAiRoma system enables the participants to find more relevant articles and connections compared to Web searches and literature search conducted in a roman library. Subjective feedback on VAiRoma was also very positive. In addition, we ran two case studies that demonstrate how VAiRoma can be used for deeper analysis, permitting the rapid discovery and analysis of a small number of key documents even when the original collection contains hundreds of thousands of documents. PMID- 26529702 TI - Exploring Evolving Media Discourse Through Event Cueing. AB - Online news, microblogs and other media documents all contain valuable insight regarding events and responses to events. Underlying these documents is the concept of framing, a process in which communicators act (consciously or unconsciously) to construct a point of view that encourages facts to be interpreted by others in a particular manner. As media discourse evolves, how topics and documents are framed can undergo change, shifting the discussion to different viewpoints or rhetoric. What causes these shifts can be difficult to determine directly; however, by linking secondary datasets and enabling visual exploration, we can enhance the hypothesis generation process. In this paper, we present a visual analytics framework for event cueing using media data. As discourse develops over time, our framework applies a time series intervention model which tests to see if the level of framing is different before or after a given date. If the model indicates that the times before and after are statistically significantly different, this cues an analyst to explore related datasets to help enhance their understanding of what (if any) events may have triggered these changes in discourse. Our framework consists of entity extraction and sentiment analysis as lenses for data exploration and uses two different models for intervention analysis. To demonstrate the usage of our framework, we present a case study on exploring potential relationships between climate change framing and conflicts in Africa. PMID- 26529703 TI - The Visual Causality Analyst: An Interactive Interface for Causal Reasoning. AB - Uncovering the causal relations that exist among variables in multivariate datasets is one of the ultimate goals in data analytics. Causation is related to correlation but correlation does not imply causation. While a number of casual discovery algorithms have been devised that eliminate spurious correlations from a network, there are no guarantees that all of the inferred causations are indeed true. Hence, bringing a domain expert into the casual reasoning loop can be of great benefit in identifying erroneous casual relationships suggested by the discovery algorithm. To address this need we present the Visual Causal Analyst-a novel visual causal reasoning framework that allows users to apply their expertise, verify and edit causal links, and collaborate with the causal discovery algorithm to identify a valid causal network. Its interface consists of both an interactive 2D graph view and a numerical presentation of salient statistical parameters, such as regression coefficients, p-values, and others. Both help users in gaining a good understanding of the landscape of causal structures particularly when the number of variables is large. Our framework is also novel in that it can handle both numerical and categorical variables within one unified model and return plausible results. We demonstrate its use via a set of case studies using multiple practical datasets. PMID- 26529704 TI - The Role of Uncertainty, Awareness, and Trust in Visual Analytics. AB - Visual analytics supports humans in generating knowledge from large and often complex datasets. Evidence is collected, collated and cross-linked with our existing knowledge. In the process, a myriad of analytical and visualisation techniques are employed to generate a visual representation of the data. These often introduce their own uncertainties, in addition to the ones inherent in the data, and these propagated and compounded uncertainties can result in impaired decision making. The user's confidence or trust in the results depends on the extent of user's awareness of the underlying uncertainties generated on the system side. This paper unpacks the uncertainties that propagate through visual analytics systems, illustrates how human's perceptual and cognitive biases influence the user's awareness of such uncertainties, and how this affects the user's trust building. The knowledge generation model for visual analytics is used to provide a terminology and framework to discuss the consequences of these aspects in knowledge construction and though examples, machine uncertainty is compared to human trust measures with provenance. Furthermore, guidelines for the design of uncertainty-aware systems are presented that can aid the user in better decision making. PMID- 26529705 TI - An Uncertainty-Aware Approach for Exploratory Microblog Retrieval. AB - Although there has been a great deal of interest in analyzing customer opinions and breaking news in microblogs, progress has been hampered by the lack of an effective mechanism to discover and retrieve data of interest from microblogs. To address this problem, we have developed an uncertainty-aware visual analytics approach to retrieve salient posts, users, and hashtags. We extend an existing ranking technique to compute a multifaceted retrieval result: the mutual reinforcement rank of a graph node, the uncertainty of each rank, and the propagation of uncertainty among different graph nodes. To illustrate the three facets, we have also designed a composite visualization with three visual components: a graph visualization, an uncertainty glyph, and a flow map. The graph visualization with glyphs, the flow map, and the uncertainty analysis together enable analysts to effectively find the most uncertain results and interactively refine them. We have applied our approach to several Twitter datasets. Qualitative evaluation and two real-world case studies demonstrate the promise of our approach for retrieving high-quality microblog data. PMID- 26529706 TI - egoSlider: Visual Analysis of Egocentric Network Evolution. AB - Ego-network, which represents relationships between a specific individual, i.e., the ego, and people connected to it, i.e., alters, is a critical target to study in social network analysis. Evolutionary patterns of ego-networks along time provide huge insights to many domains such as sociology, anthropology, and psychology. However, the analysis of dynamic ego-networks remains challenging due to its complicated time-varying graph structures, for example: alters come and leave, ties grow stronger and fade away, and alter communities merge and split. Most of the existing dynamic graph visualization techniques mainly focus on topological changes of the entire network, which is not adequate for egocentric analytical tasks. In this paper, we present egoSlider, a visual analysis system for exploring and comparing dynamic ego-networks. egoSlider provides a holistic picture of the data through multiple interactively coordinated views, revealing ego-network evolutionary patterns at three different layers: a macroscopic level for summarizing the entire ego-network data, a mesoscopic level for overviewing specific individuals' ego-network evolutions, and a microscopic level for displaying detailed temporal information of egos and their alters. We demonstrate the effectiveness of egoSlider with a usage scenario with the DBLP publication records. Also, a controlled user study indicates that in general egoSlider outperforms a baseline visualization of dynamic networks for completing egocentric analytical tasks. PMID- 26529707 TI - TargetVue: Visual Analysis of Anomalous User Behaviors in Online Communication Systems. AB - Users with anomalous behaviors in online communication systems (e.g. email and social medial platforms) are potential threats to society. Automated anomaly detection based on advanced machine learning techniques has been developed to combat this issue; challenges remain, though, due to the difficulty of obtaining proper ground truth for model training and evaluation. Therefore, substantial human judgment on the automated analysis results is often required to better adjust the performance of anomaly detection. Unfortunately, techniques that allow users to understand the analysis results more efficiently, to make a confident judgment about anomalies, and to explore data in their context, are still lacking. In this paper, we propose a novel visual analysis system, TargetVue, which detects anomalous users via an unsupervised learning model and visualizes the behaviors of suspicious users in behavior-rich context through novel visualization designs and multiple coordinated contextual views. Particularly, TargetVue incorporates three new ego-centric glyphs to visually summarize a user's behaviors which effectively present the user's communication activities, features, and social interactions. An efficient layout method is proposed to place these glyphs on a triangle grid, which captures similarities among users and facilitates comparisons of behaviors of different users. We demonstrate the power of TargetVue through its application in a social bot detection challenge using Twitter data, a case study based on email records, and an interview with expert users. Our evaluation shows that TargetVue is beneficial to the detection of users with anomalous communication behaviors. PMID- 26529708 TI - LiteVis: Integrated Visualization for Simulation-Based Decision Support in Lighting Design. AB - State-of-the-art lighting design is based on physically accurate lighting simulations of scenes such as offices. The simulation results support lighting designers in the creation of lighting configurations, which must meet contradicting customer objectives regarding quality and price while conforming to industry standards. However, current tools for lighting design impede rapid feedback cycles. On the one side, they decouple analysis and simulation specification. On the other side, they lack capabilities for a detailed comparison of multiple configurations. The primary contribution of this paper is a design study of LiteVis, a system for efficient decision support in lighting design. LiteVis tightly integrates global illumination-based lighting simulation, a spatial representation of the scene, and non-spatial visualizations of parameters and result indicators. This enables an efficient iterative cycle of simulation parametrization and analysis. Specifically, a novel visualization supports decision making by ranking simulated lighting configurations with regard to a weight-based prioritization of objectives that considers both spatial and non-spatial characteristics. In the spatial domain, novel concepts support a detailed comparison of illumination scenarios. We demonstrate LiteVis using a real-world use case and report qualitative feedback of lighting designers. This feedback indicates that LiteVis successfully supports lighting designers to achieve key tasks more efficiently and with greater certainty. PMID- 26529709 TI - TimeLineCurator: Interactive Authoring of Visual Timelines from Unstructured Text. AB - We present TimeLineCurator, a browser-based authoring tool that automatically extracts event data from temporal references in unstructured text documents using natural language processing and encodes them along a visual timeline. Our goal is to facilitate the timeline creation process for journalists and others who tell temporal stories online. Current solutions involve manually extracting and formatting event data from source documents, a process that tends to be tedious and error prone. With TimeLineCurator, a prospective timeline author can quickly identify the extent of time encompassed by a document, as well as the distribution of events occurring along this timeline. Authors can speculatively browse possible documents to quickly determine whether they are appropriate sources of timeline material. TimeLineCurator provides controls for curating and editing events on a timeline, the ability to combine timelines from multiple source documents, and export curated timelines for online deployment. We evaluate TimeLineCurator through a benchmark comparison of entity extraction error against a manual timeline curation process, a preliminary evaluation of the user experience of timeline authoring, a brief qualitative analysis of its visual output, and a discussion of prospective use cases suggested by members of the target author communities following its deployment. PMID- 26529710 TI - BiSet: Semantic Edge Bundling with Biclusters for Sensemaking. AB - Identifying coordinated relationships is an important task in data analytics. For example, an intelligence analyst might want to discover three suspicious people who all visited the same four cities. Existing techniques that display individual relationships, such as between lists of entities, require repetitious manual selection and significant mental aggregation in cluttered visualizations to find coordinated relationships. In this paper, we present BiSet, a visual analytics technique to support interactive exploration of coordinated relationships. In BiSet, we model coordinated relationships as biclusters and algorithmically mine them from a dataset. Then, we visualize the biclusters in context as bundled edges between sets of related entities. Thus, bundles enable analysts to infer task-oriented semantic insights about potentially coordinated activities. We make bundles as first class objects and add a new layer, "in-between", to contain these bundle objects. Based on this, bundles serve to organize entities represented in lists and visually reveal their membership. Users can interact with edge bundles to organize related entities, and vice versa, for sensemaking purposes. With a usage scenario, we demonstrate how BiSet supports the exploration of coordinated relationships in text analytics. PMID- 26529711 TI - Visual Mementos: Reflecting Memories with Personal Data. AB - In this paper we discuss the creation of visual mementos as a new application area for visualization. We define visual mementos as visualizations of personally relevant data for the purpose of reminiscing, and sharing of life experiences. Today more people collect digital information about their life than ever before. The shift from physical to digital archives poses new challenges and opportunities for self-reflection and self-representation. Drawing on research on autobiographical memory and on the role of artifacts in reminiscing, we identified design challenges for visual mementos: mapping data to evoke familiarity, expressing subjectivity, and obscuring sensitive details for sharing. Visual mementos can make use of the known strengths of visualization in revealing patterns to show the familiar instead of the unexpected, and extend representational mappings beyond the objective to include the more subjective. To understand whether people's subjective views on their past can be reflected in a visual representation, we developed, deployed and studied a technology probe that exemplifies our concept of visual mementos. Our results show how reminiscing has been supported and reveal promising new directions for self-reflection and sharing through visual mementos of personal experiences. PMID- 26529712 TI - Vials: Visualizing Alternative Splicing of Genes. AB - Alternative splicing is a process by which the same DNA sequence is used to assemble different proteins, called protein isoforms. Alternative splicing works by selectively omitting some of the coding regions (exons) typically associated with a gene. Detection of alternative splicing is difficult and uses a combination of advanced data acquisition methods and statistical inference. Knowledge about the abundance of isoforms is important for understanding both normal processes and diseases and to eventually improve treatment through targeted therapies. The data, however, is complex and current visualizations for isoforms are neither perceptually efficient nor scalable. To remedy this, we developed Vials, a novel visual analysis tool that enables analysts to explore the various datasets that scientists use to make judgments about isoforms: the abundance of reads associated with the coding regions of the gene, evidence for junctions, i.e., edges connecting the coding regions, and predictions of isoform frequencies. Vials is scalable as it allows for the simultaneous analysis of many samples in multiple groups. Our tool thus enables experts to (a) identify patterns of isoform abundance in groups of samples and (b) evaluate the quality of the data. We demonstrate the value of our tool in case studies using publicly available datasets. PMID- 26529713 TI - Speculative Practices: Utilizing InfoVis to Explore Untapped Literary Collections. AB - In this paper we exemplify how information visualization supports speculative thinking, hypotheses testing, and preliminary interpretation processes as part of literary research. While InfoVis has become a buzz topic in the digital humanities, skepticism remains about how effectively it integrates into and expands on traditional humanities research approaches. From an InfoVis perspective, we lack case studies that show the specific design challenges that make literary studies and humanities research at large a unique application area for information visualization. We examine these questions through our case study of the Speculative W@nderverse, a visualization tool that was designed to enable the analysis and exploration of an untapped literary collection consisting of thousands of science fiction short stories. We present the results of two empirical studies that involved general-interest readers and literary scholars who used the evolving visualization prototype as part of their research for over a year. Our findings suggest a design space for visualizing literary collections that is defined by (1) their academic and public relevance, (2) the tension between qualitative vs. quantitative methods of interpretation, (3) result- vs. process-driven approaches to InfoVis, and (4) the unique material and visual qualities of cultural collections. Through the Speculative W@nderverse we demonstrate how visualization can bridge these sometimes contradictory perspectives by cultivating curiosity and providing entry points into literary collections while, at the same time, supporting multiple aspects of humanities research processes. PMID- 26529714 TI - Poemage: Visualizing the Sonic Topology of a Poem. AB - The digital humanities have experienced tremendous growth within the last decade, mostly in the context of developing computational tools that support what is called distant reading - collecting and analyzing huge amounts of textual data for synoptic evaluation. On the other end of the spectrum is a practice at the heart of the traditional humanities, close reading - the careful, in-depth analysis of a single text in order to extract, engage, and even generate as much productive meaning as possible. The true value of computation to close reading is still very much an open question. During a two-year design study, we explored this question with several poetry scholars, focusing on an investigation of sound and linguistic devices in poetry. The contributions of our design study include a problem characterization and data abstraction of the use of sound in poetry as well as Poemage, a visualization tool for interactively exploring the sonic topology of a poem. The design of Poemage is grounded in the evaluation of a series of technology probes we deployed to our poetry collaborators, and we validate the final design with several case studies that illustrate the disruptive impact technology can have on poetry scholarship. Finally, we also contribute a reflection on the challenges we faced conducting visualization research in literary studies. PMID- 26529715 TI - Guidelines for Effective Usage of Text Highlighting Techniques. AB - Semi-automatic text analysis involves manual inspection of text. Often, different text annotations (like part-of-speech or named entities) are indicated by using distinctive text highlighting techniques. In typesetting there exist well-known formatting conventions, such as bold typeface, italics, or background coloring, that are useful for highlighting certain parts of a given text. Also, many advanced techniques for visualization and highlighting of text exist; yet, standard typesetting is common, and the effects of standard typesetting on the perception of text are not fully understood. As such, we surveyed and tested the effectiveness of common text highlighting techniques, both individually and in combination, to discover how to maximize pop-out effects while minimizing visual interference between techniques. To validate our findings, we conducted a series of crowdsourced experiments to determine: i) a ranking of nine commonly-used text highlighting techniques; ii) the degree of visual interference between pairs of text highlighting techniques; iii) the effectiveness of techniques for visual conjunctive search. Our results show that increasing font size works best as a single highlighting technique, and that there are significant visual interferences between some pairs of highlighting techniques. We discuss the pros and cons of different combinations as a design guideline to choose text highlighting techniques for text viewers. PMID- 26529716 TI - Acquired Codes of Meaning in Data Visualization and Infographics: Beyond Perceptual Primitives. AB - While information visualization frameworks and heuristics have traditionally been reluctant to include acquired codes of meaning, designers are making use of them in a wide variety of ways. Acquired codes leverage a user's experience to understand the meaning of a visualization. They range from figurative visualizations which rely on the reader's recognition of shapes, to conventional arrangements of graphic elements which represent particular subjects. In this study, we used content analysis to codify acquired meaning in visualization. We applied the content analysis to a set of infographics and data visualizations which are exemplars of innovative and effective design. 88% of the infographics and 71% of data visualizations in the sample contain at least one use of figurative visualization. Conventions on the arrangement of graphics are also widespread in the sample. In particular, a comparison of representations of time and other quantitative data showed that conventions can be specific to a subject. These results suggest that there is a need for information visualization research to expand its scope beyond perceptual channels, to include social and culturally constructed meaning. Our paper demonstrates a viable method for identifying figurative techniques and graphic conventions and integrating them into heuristics for visualization design. PMID- 26529717 TI - Visual Encodings of Temporal Uncertainty: A Comparative User Study. AB - A number of studies have investigated different ways of visualizing uncertainty. However, in the temporal dimension, it is still an open question how to best represent uncertainty, since the special characteristics of time require special visual encodings and may provoke different interpretations. Thus, we have conducted a comprehensive study comparing alternative visual encodings of intervals with uncertain start and end times: gradient plots, violin plots, accumulated probability plots, error bars, centered error bars, and ambiguation. Our results reveal significant differences in error rates and completion time for these different visualization types and different tasks. We recommend using ambiguation - using a lighter color value to represent uncertain regions - or error bars for judging durations and temporal bounds, and gradient plots - using fading color or transparency - for judging probability values. PMID- 26529718 TI - Time Curves: Folding Time to Visualize Patterns of Temporal Evolution in Data. AB - We introduce time curves as a general approach for visualizing patterns of evolution in temporal data. Examples of such patterns include slow and regular progressions, large sudden changes, and reversals to previous states. These patterns can be of interest in a range of domains, such as collaborative document editing, dynamic network analysis, and video analysis. Time curves employ the metaphor of folding a timeline visualization into itself so as to bring similar time points close to each other. This metaphor can be applied to any dataset where a similarity metric between temporal snapshots can be defined, thus it is largely datatype-agnostic. We illustrate how time curves can visually reveal informative patterns in a range of different datasets. PMID- 26529719 TI - Evaluation of Parallel Coordinates: Overview, Categorization and Guidelines for Future Research. AB - The parallel coordinates technique is widely used for the analysis of multivariate data. During recent decades significant research efforts have been devoted to exploring the applicability of the technique and to expand upon it, resulting in a variety of extensions. Of these many research activities, a surprisingly small number concerns user-centred evaluations investigating actual use and usability issues for different tasks, data and domains. The result is a clear lack of convincing evidence to support and guide uptake by users as well as future research directions. To address these issues this paper contributes a thorough literature survey of what has been done in the area of user-centred evaluation of parallel coordinates. These evaluations are divided into four categories based on characterization of use, derived from the survey. Based on the data from the survey and the categorization combined with the authors' experience of working with parallel coordinates, a set of guidelines for future research directions is proposed. PMID- 26529720 TI - Orientation-Enhanced Parallel Coordinate Plots. AB - Parallel Coordinate Plots (PCPs) is one of the most powerful techniques for the visualization of multivariate data. However, for large datasets, the representation suffers from clutter due to overplotting. In this case, discerning the underlying data information and selecting specific interesting patterns can become difficult. We propose a new and simple technique to improve the display of PCPs by emphasizing the underlying data structure. Our Orientation-enhanced Parallel Coordinate Plots (OPCPs) improve pattern and outlier discernibility by visually enhancing parts of each PCP polyline with respect to its slope. This enhancement also allows us to introduce a novel and efficient selection method, the Orientation-enhanced Brushing (O-Brushing). Our solution is particularly useful when multiple patterns are present or when the view on certain patterns is obstructed by noise. We present the results of our approach with several synthetic and real-world datasets. Finally, we conducted a user evaluation, which verifies the advantages of the OPCPs in terms of discernibility of information in complex data. It also confirms that O-Brushing eases the selection of data patterns in PCPs and reduces the amount of necessary user interactions compared to state-of-the-art brushing techniques. PMID- 26529721 TI - A comparative study between RadViz and Star Coordinates. AB - RadViz and star coordinates are two of the most popular projection-based multivariate visualization techniques that arrange variables in radial layouts. Formally, the main difference between them consists of a nonlinear normalization step inherent in RadViz. In this paper we show that, although RadViz can be useful when analyzing sparse data, in general this design choice limits its applicability and introduces several drawbacks for exploratory data analysis. In particular, we observe that the normalization step introduces nonlinear distortions, can encumber outlier detection, prevents associating the plots with useful linear mappings, and impedes estimating original data attributes accurately. In addition, users have greater flexibility when choosing different layouts and views of the data in star coordinates. Therefore, we suggest that analysts and researchers should carefully consider whether RadViz's normalization step is beneficial regarding the data sets' characteristics and analysis tasks. PMID- 26529722 TI - Automatic Selection of Partitioning Variables for Small Multiple Displays. AB - Effective small multiple displays are created by partitioning a visualization on variables that reveal interesting conditional structure in the data. We propose a method that automatically ranks partitioning variables, allowing analysts to focus on the most promising small multiple displays. Our approach is based on a randomized, non-parametric permutation test, which allows us to handle a wide range of quality measures for visual patterns defined on many different visualization types, while discounting spurious patterns. We demonstrate the effectiveness of our approach on scatterplots of real-world, multidimensional datasets. PMID- 26529723 TI - A Simple Approach for Boundary Improvement of Euler Diagrams. AB - General methods for drawing Euler diagrams tend to generate irregular polygons. Yet, empirical evidence indicates that smoother contours make these diagrams easier to read. In this paper, we present a simple method to smooth the boundaries of any Euler diagram drawing. When refining the diagram, the method must ensure that set elements remain inside their appropriate boundaries and that no region is removed or created in the diagram. Our approach uses a force system that improves the diagram while at the same time ensuring its topological structure does not change. We demonstrate the effectiveness of the approach through case studies and quantitative evaluations. PMID- 26529724 TI - Occlusion-free Blood Flow Animation with Wall Thickness Visualization. AB - We present the first visualization tool that combines pathlines from blood flow and wall thickness information. Our method uses illustrative techniques to provide occlusion-free visualization of the flow. We thus offer medical researchers an effective visual analysis tool for aneurysm treatment risk assessment. Such aneurysms bear a high risk of rupture and significant treatment related risks. Therefore, to get a fully informed decision it is essential to both investigate the vessel morphology and the hemodynamic data. Ongoing research emphasizes the importance of analyzing the wall thickness in risk assessment. Our combination of blood flow visualization and wall thickness representation is a significant improvement for the exploration and analysis of aneurysms. As all presented information is spatially intertwined, occlusion problems occur. We solve these occlusion problems by dynamic cutaway surfaces. We combine this approach with a glyph-based blood flow representation and a visual mapping of wall thickness onto the vessel surface. We developed a GPU-based implementation of our visualizations which facilitates wall thickness analysis through real-time rendering and flexible interactive data exploration mechanisms. We designed our techniques in collaboration with domain experts, and we provide details about the evaluation of the technique and tool. PMID- 26529725 TI - NeuroBlocks--Visual Tracking of Segmentation and Proofreading for Large Connectomics Projects. AB - In the field of connectomics, neuroscientists acquire electron microscopy volumes at nanometer resolution in order to reconstruct a detailed wiring diagram of the neurons in the brain. The resulting image volumes, which often are hundreds of terabytes in size, need to be segmented to identify cell boundaries, synapses, and important cell organelles. However, the segmentation process of a single volume is very complex, time-intensive, and usually performed using a diverse set of tools and many users. To tackle the associated challenges, this paper presents NeuroBlocks, which is a novel visualization system for tracking the state, progress, and evolution of very large volumetric segmentation data in neuroscience. NeuroBlocks is a multi-user web-based application that seamlessly integrates the diverse set of tools that neuroscientists currently use for manual and semi-automatic segmentation, proofreading, visualization, and analysis. NeuroBlocks is the first system that integrates this heterogeneous tool set, providing crucial support for the management, provenance, accountability, and auditing of large-scale segmentations. We describe the design of NeuroBlocks, starting with an analysis of the domain-specific tasks, their inherent challenges, and our subsequent task abstraction and visual representation. We demonstrate the utility of our design based on two case studies that focus on different user roles and their respective requirements for performing and tracking the progress of segmentation and proofreading in a large real-world connectomics project. PMID- 26529726 TI - AnimoAminoMiner: Exploration of Protein Tunnels and their Properties in Molecular Dynamics. AB - In this paper we propose a novel method for the interactive exploration of protein tunnels. The basic principle of our approach is that we entirely abstract from the 3D/4D space the simulated phenomenon is embedded in. A complex 3D structure and its curvature information is represented only by a straightened tunnel centerline and its width profile. This representation focuses on a key aspect of the studied geometry and frees up graphical estate to key chemical and physical properties represented by surrounding amino acids. The method shows the detailed tunnel profile and its temporal aggregation. The profile is interactively linked with a visual overview of all amino acids which are lining the tunnel over time. In this overview, each amino acid is represented by a set of colored lines depicting the spatial and temporal impact of the amino acid on the corresponding tunnel. This representation clearly shows the importance of amino acids with respect to selected criteria. It helps the biochemists to select the candidate amino acids for mutation which changes the protein function in a desired way. The AnimoAminoMiner was designed in close cooperation with domain experts. Its usefulness is documented by their feedback and a case study, which are included. PMID- 26529727 TI - Isosurface Visualization of Data with Nonparametric Models for Uncertainty. AB - The problem of isosurface extraction in uncertain data is an important research problem and may be approached in two ways. One can extract statistics (e.g., mean) from uncertain data points and visualize the extracted field. Alternatively, data uncertainty, characterized by probability distributions, can be propagated through the isosurface extraction process. We analyze the impact of data uncertainty on topology and geometry extraction algorithms. A novel, edge crossing probability based approach is proposed to predict underlying isosurface topology for uncertain data. We derive a probabilistic version of the midpoint decider that resolves ambiguities that arise in identifying topological configurations. Moreover, the probability density function characterizing positional uncertainty in isosurfaces is derived analytically for a broad class of nonparametric distributions. This analytic characterization can be used for efficient closed-form computation of the expected value and variation in geometry. Our experiments show the computational advantages of our analytic approach over Monte-Carlo sampling for characterizing positional uncertainty. We also show the advantage of modeling underlying error densities in a nonparametric statistical framework as opposed to a parametric statistical framework through our experiments on ensemble datasets and uncertain scalar fields. PMID- 26529728 TI - Effective Visualization of Temporal Ensembles. AB - An ensemble is a collection of related datasets, called members, built from a series of runs of a simulation or an experiment. Ensembles are large, temporal, multidimensional, and multivariate, making them difficult to analyze. Another important challenge is visualizing ensembles that vary both in space and time. Initial visualization techniques displayed ensembles with a small number of members, or presented an overview of an entire ensemble, but without potentially important details. Recently, researchers have suggested combining these two directions, allowing users to choose subsets of members to visualization. This manual selection process places the burden on the user to identify which members to explore. We first introduce a static ensemble visualization system that automatically helps users locate interesting subsets of members to visualize. We next extend the system to support analysis and visualization of temporal ensembles. We employ 3D shape comparison, cluster tree visualization, and glyph based visualization to represent different levels of detail within an ensemble. This strategy is used to provide two approaches for temporal ensemble analysis: (1) segment based ensemble analysis, to capture important shape transition time steps, clusters groups of similar members, and identify common shape changes over time across multiple members; and (2) time-step based ensemble analysis, which assumes ensemble members are aligned in time by combining similar shapes at common time-steps. Both approaches enable users to interactively visualize and analyze a temporal ensemble from different perspectives at different levels of detail. We demonstrate our techniques on an ensemble studying matter transition from hadronic gas to quark-gluon plasma during gold-on-gold particle collisions. PMID- 26529729 TI - Glyph-Based Comparative Visualization for Diffusion Tensor Fields. AB - Diffusion Tensor Imaging (DTI) is a magnetic resonance imaging modality that enables the in-vivo reconstruction and visualization of fibrous structures. To inspect the local and individual diffusion tensors, glyph-based visualizations are commonly used since they are able to effectively convey full aspects of the diffusion tensor. For several applications it is necessary to compare tensor fields, e.g., to study the effects of acquisition parameters, or to investigate the influence of pathologies on white matter structures. This comparison is commonly done by extracting scalar information out of the tensor fields and then comparing these scalar fields, which leads to a loss of information. If the glyph representation is kept, simple juxtaposition or superposition can be used. However, neither facilitates the identification and interpretation of the differences between the tensor fields. Inspired by the checkerboard style visualization and the superquadric tensor glyph, we design a new glyph to locally visualize differences between two diffusion tensors by combining juxtaposition and explicit encoding. Because tensor scale, anisotropy type, and orientation are related to anatomical information relevant for DTI applications, we focus on visualizing tensor differences in these three aspects. As demonstrated in a user study, our new glyph design allows users to efficiently and effectively identify the tensor differences. We also apply our new glyphs to investigate the differences between DTI datasets of the human brain in two different contexts using different b-values, and to compare datasets from a healthy and HIV-infected subject. PMID- 26529730 TI - Extracting, Tracking, and Visualizing Magnetic Flux Vortices in 3D Complex-Valued Superconductor Simulation Data. AB - We propose a method for the vortex extraction and tracking of superconducting magnetic flux vortices for both structured and unstructured mesh data. In the Ginzburg-Landau theory, magnetic flux vortices are well-defined features in a complex-valued order parameter field, and their dynamics determine electromagnetic properties in type-II superconductors. Our method represents each vortex line (a 1D curve embedded in 3D space) as a connected graph extracted from the discretized field in both space and time. For a time-varying discrete dataset, our vortex extraction and tracking method is as accurate as the data discretization. We then apply 3D visualization and 2D event diagrams to the extraction and tracking results to help scientists understand vortex dynamics and macroscale superconductor behavior in greater detail than previously possible. PMID- 26529731 TI - Distribution Driven Extraction and Tracking of Features for Time-varying Data Analysis. AB - Effective analysis of features in time-varying data is essential in numerous scientific applications. Feature extraction and tracking are two important tasks scientists rely upon to get insights about the dynamic nature of the large scale time-varying data. However, often the complexity of the scientific phenomena only allows scientists to vaguely define their feature of interest. Furthermore, such features can have varying motion patterns and dynamic evolution over time. As a result, automatic extraction and tracking of features becomes a non-trivial task. In this work, we investigate these issues and propose a distribution driven approach which allows us to construct novel algorithms for reliable feature extraction and tracking with high confidence in the absence of accurate feature definition. We exploit two key properties of an object, motion and similarity to the target feature, and fuse the information gained from them to generate a robust feature-aware classification field at every time step. Tracking of features is done using such classified fields which enhances the accuracy and robustness of the proposed algorithm. The efficacy of our method is demonstrated by successfully applying it on several scientific data sets containing a wide range of dynamic time-varying features. PMID- 26529732 TI - Visualization and Analysis of Rotating Stall for Transonic Jet Engine Simulation. AB - Identification of early signs of rotating stall is essential for the study of turbine engine stability. With recent advancements of high performance computing, high-resolution unsteady flow fields allow in depth exploration of rotating stall and its possible causes. Performing stall analysis, however, involves Significant effort to process large amounts of simulation data, especially when investigating abnormalities across many time steps. In order to assist scientists during the exploration process, we present a visual analytics framework to identify suspected spatiotemporal regions through a comparative visualization so that scientists are able to focus on relevant data in more detail. To achieve this, we propose efficient stall analysis algorithms derived from domain knowledge and convey the analysis results through juxtaposed interactive plots. Using our integrated visualization system, scientists can visually investigate the detected regions for potential stall initiation and further explore these regions to enhance the understanding of this phenomenon. Positive feedback from scientists demonstrate the efficacy of our system in analyzing rotating stall. PMID- 26529733 TI - Diderot: a Domain-Specific Language for Portable Parallel Scientific Visualization and Image Analysis. AB - Many algorithms for scientific visualization and image analysis are rooted in the world of continuous scalar, vector, and tensor fields, but are programmed in low level languages and libraries that obscure their mathematical foundations. Diderot is a parallel domain-specific language that is designed to bridge this semantic gap by providing the programmer with a high-level, mathematical programming notation that allows direct expression of mathematical concepts in code. Furthermore, Diderot provides parallel performance that takes advantage of modern multicore processors and GPUs. The high-level notation allows a concise and natural expression of the algorithms and the parallelism allows efficient execution on real-world datasets. PMID- 26529734 TI - Visualization-by-Sketching: An Artist's Interface for Creating Multivariate Time Varying Data Visualizations. AB - We present Visualization-by-Sketching, a direct-manipulation user interface for designing new data visualizations. The goals are twofold: First, make the process of creating real, animated, data-driven visualizations of complex information more accessible to artists, graphic designers, and other visual experts with traditional, non-technical training. Second, support and enhance the role of human creativity in visualization design, enabling visual experimentation and workflows similar to what is possible with traditional artistic media. The approach is to conceive of visualization design as a combination of processes that are already closely linked with visual creativity: sketching, digital painting, image editing, and reacting to exemplars. Rather than studying and tweaking low-level algorithms and their parameters, designers create new visualizations by painting directly on top of a digital data canvas, sketching data glyphs, and arranging and blending together multiple layers of animated 2D graphics. This requires new algorithms and techniques to interpret painterly user input relative to data "under" the canvas, balance artistic freedom with the need to produce accurate data visualizations, and interactively explore large (e.g., terabyte-sized) multivariate datasets. Results demonstrate a variety of multivariate data visualization techniques can be rapidly recreated using the interface. More importantly, results and feedback from artists support the potential for interfaces in this style to attract new, creative users to the challenging task of designing more effective data visualizations and to help these users stay "in the creative zone" as they work. PMID- 26529735 TI - Planar Visualization of Treelike Structures. AB - We present a novel method to create planar visualizations of treelike structures (e.g., blood vessels and airway trees) where the shape of the object is well preserved, allowing for easy recognition by users familiar with the structures. Based on the extracted skeleton within the treelike object, a radial planar embedding is first obtained such that there are no self-intersections of the skeleton which would have resulted in occlusions in the final view. An optimization procedure which adjusts the angular positions of the skeleton nodes is then used to reconstruct the shape as closely as possible to the original, according to a specified view plane, which thus preserves the global geometric context of the object. Using this shape recovered embedded skeleton, the object surface is then flattened to the plane without occlusions using harmonic mapping. The boundary of the mesh is adjusted during the flattening step to account for regions where the mesh is stretched over concavities. This parameterized surface can then be used either as a map for guidance during endoluminal navigation or directly for interrogation and decision making. Depth cues are provided with a grayscale border to aid in shape understanding. Examples are presented using bronchial trees, cranial and lower limb blood vessels, and upper aorta datasets, and the results are evaluated quantitatively and with a user study. PMID- 26529736 TI - Interstitial and Interlayer Ion Diffusion Geometry Extraction in Graphitic Nanosphere Battery Materials. AB - Large-scale molecular dynamics (MD) simulations are commonly used for simulating the synthesis and ion diffusion of battery materials. A good battery anode material is determined by its capacity to store ion or other diffusers. However, modeling of ion diffusion dynamics and transport properties at large length and long time scales would be impossible with current MD codes. To analyze the fundamental properties of these materials, therefore, we turn to geometric and topological analysis of their structure. In this paper, we apply a novel technique inspired by discrete Morse theory to the Delaunay triangulation of the simulated geometry of a thermally annealed carbon nanosphere. We utilize our computed structures to drive further geometric analysis to extract the interstitial diffusion structure as a single mesh. Our results provide a new approach to analyze the geometry of the simulated carbon nanosphere, and new insights into the role of carbon defect size and distribution in determining the charge capacity and charge dynamics of these carbon based battery materials. PMID- 26529737 TI - Effectiveness of Structured Textures on Dynamically Changing Terrain-like Surfaces. AB - Previous perceptual research and human factors studies have identified several effective methods for texturing 3D surfaces to ensure that their curvature is accurately perceived by viewers. However, most of these studies examined the application of these techniques to static surfaces. This paper explores the effectiveness of applying these techniques to dynamically changing surfaces. When these surfaces change shape, common texturing methods, such as grids and contours, induce a range of different motion cues, which can draw attention and provide information about the size, shape, and rate of change. A human factors study was conducted to evaluate the relative effectiveness of these methods when applied to dynamically changing pseudo-terrain surfaces. The results indicate that, while no technique is most effective for all cases, contour lines generally perform best, and that the pseudocontour lines induced by banded color scales convey the same benefits. PMID- 26529738 TI - Interactive Visualization for Singular Fibers of Functions f : R3 -> R2. AB - Scalar topology in the form of Morse theory has provided computational tools that analyze and visualize data from scientific and engineering tasks. Contracting isocontours to single points encapsulates variations in isocontour connectivity in the Reeb graph. For multivariate data, isocontours generalize to fibers inverse images of points in the range, and this area is therefore known as fiber topology. However, fiber topology is less fully developed than Morse theory, and current efforts rely on manual visualizations. This paper presents how to accelerate and semi-automate this task through an interface for visualizing fiber singularities of multivariate functions R3 -> R2. This interface exploits existing conventions of fiber topology, but also introduces a 3D view based on the extension of Reeb graphs to Reeb spaces. Using the Joint Contour Net, a quantized approximation of the Reeb space, this accelerates topological visualization and permits online perturbation to reduce or remove degeneracies in functions under study. Validation of the interface is performed by assessing whether the interface supports the mathematical workflow both of experts and of less experienced mathematicians. PMID- 26529739 TI - Association Analysis for Visual Exploration of Multivariate Scientific Data Sets. AB - The heterogeneity and complexity of multivariate characteristics poses a unique challenge to visual exploration of multivariate scientific data sets, as it requires investigating the usually hidden associations between different variables and specific scalar values to understand the data's multi-faceted properties. In this paper, we present a novel association analysis method that guides visual exploration of scalar-level associations in the multivariate context. We model the directional interactions between scalars of different variables as information flows based on association rules. We introduce the concepts of informativeness and uniqueness to describe how information flows between scalars of different variables and how they are associated with each other in the multivariate domain. Based on scalar-level associations represented by a probabilistic association graph, we propose the Multi-Scalar Informativeness Uniqueness (MSIU) algorithm to evaluate the informativeness and uniqueness of scalars. We present an exploration framework with multiple interactive views to explore the scalars of interest with confident associations in the multivariate spatial domain, and provide guidelines for visual exploration using our framework. We demonstrate the effectiveness and usefulness of our approach through case studies using three representative multivariate scientific data sets. PMID- 26529740 TI - Mining Graphs for Understanding Time-Varying Volumetric Data. AB - A notable recent trend in time-varying volumetric data analysis and visualization is to extract data relationships and represent them in a low-dimensional abstract graph view for visual understanding and making connections to the underlying data. Nevertheless, the ever-growing size and complexity of data demands novel techniques that go beyond standard brushing and linking to allow significant reduction of cognition overhead and interaction cost. In this paper, we present a mining approach that automatically extracts meaningful features from a graph based representation for exploring time-varying volumetric data. This is achieved through the utilization of a series of graph analysis techniques including graph simplification, community detection, and visual recommendation. We investigate the most important transition relationships for time-varying data and evaluate our solution with several time-varying data sets of different sizes and characteristics. For gaining insights from the data, we show that our solution is more efficient and effective than simply asking users to extract relationships via standard interaction techniques, especially when the data set is large and the relationships are complex. We also collect expert feedback to confirm the usefulness of our approach. PMID- 26529741 TI - Visualizing Tensor Normal Distributions at Multiple Levels of Detail. AB - Despite the widely recognized importance of symmetric second order tensor fields in medicine and engineering, the visualization of data uncertainty in tensor fields is still in its infancy. A recently proposed tensorial normal distribution, involving a fourth order covariance tensor, provides a mathematical description of how different aspects of the tensor field, such as trace, anisotropy, or orientation, vary and covary at each point. However, this wealth of information is far too rich for a human analyst to take in at a single glance, and no suitable visualization tools are available. We propose a novel approach that facilitates visual analysis of tensor covariance at multiple levels of detail. We start with a visual abstraction that uses slice views and direct volume rendering to indicate large-scale changes in the covariance structure, and locations with high overall variance. We then provide tools for interactive exploration, making it possible to drill down into different types of variability, such as in shape or orientation. Finally, we allow the analyst to focus on specific locations of the field, and provide tensor glyph animations and overlays that intuitively depict confidence intervals at those points. Our system is demonstrated by investigating the effects of measurement noise on diffusion tensor MRI, and by analyzing two ensembles of stress tensor fields from solid mechanics. PMID- 26529742 TI - Adaptive Multilinear Tensor Product Wavelets. AB - Many foundational visualization techniques including isosurfacing, direct volume rendering and texture mapping rely on piecewise multilinear interpolation over the cells of a mesh. However, there has not been much focus within the visualization community on techniques that efficiently generate and encode globally continuous functions defined by the union of multilinear cells. Wavelets provide a rich context for analyzing and processing complicated datasets. In this paper, we exploit adaptive regular refinement as a means of representing and evaluating functions described by a subset of their nonzero wavelet coefficients. We analyze the dependencies involved in the wavelet transform and describe how to generate and represent the coarsest adaptive mesh with nodal function values such that the inverse wavelet transform is exactly reproduced via simple interpolation (subdivision) over the mesh elements. This allows for an adaptive, sparse representation of the function with on-demand evaluation at any point in the domain. We focus on the popular wavelets formed by tensor products of linear B splines, resulting in an adaptive, nonconforming but crack-free quadtree (2D) or octree (3D) mesh that allows reproducing globally continuous functions via multilinear interpolation over its cells. PMID- 26529743 TI - Reconstruction and Visualization of Coordinated 3D Cell Migration Based on Optical Flow. AB - Animal development is marked by the repeated reorganization of cells and cell populations, which ultimately determine form and shape of the growing organism. One of the central questions in developmental biology is to understand precisely how cells reorganize, as well as how and to what extent this reorganization is coordinated. While modern microscopes can record video data for every cell during animal development in 3D+t, analyzing these videos remains a major challenge: reconstruction of comprehensive cell tracks turned out to be very demanding especially with decreasing data quality and increasing cell densities. In this paper, we present an analysis pipeline for coordinated cellular motions in developing embryos based on the optical flow of a series of 3D images. We use numerical integration to reconstruct cellular long-term motions in the optical flow of the video, we take care of data validation, and we derive a LIC-based, dense flow visualization for the resulting pathlines. This approach allows us to handle low video quality such as noisy data or poorly separated cells, and it allows the biologists to get a comprehensive understanding of their data by capturing dynamic growth processes in stills. We validate our methods using three videos of growing fruit fly embryos. PMID- 26529744 TI - Gaze Stripes: Image-Based Visualization of Eye Tracking Data. AB - We present a new visualization approach for displaying eye tracking data from multiple participants. We aim to show the spatio-temporal data of the gaze points in the context of the underlying image or video stimulus without occlusion. Our technique, denoted as gaze stripes, does not require the explicit definition of areas of interest but directly uses the image data around the gaze points, similar to thumbnails for images. A gaze stripe consists of a sequence of such gaze point images, oriented along a horizontal timeline. By displaying multiple aligned gaze stripes, it is possible to analyze and compare the viewing behavior of the participants over time. Since the analysis is carried out directly on the image data, expensive post-processing or manual annotation are not required. Therefore, not only patterns and outliers in the participants' scanpaths can be detected, but the context of the stimulus is available as well. Furthermore, our approach is especially well suited for dynamic stimuli due to the non-aggregated temporal mapping. Complementary views, i.e., markers, notes, screenshots, histograms, and results from automatic clustering, can be added to the visualization to display analysis results. We illustrate the usefulness of our technique on static and dynamic stimuli. Furthermore, we discuss the limitations and scalability of our approach in comparison to established visualization techniques. PMID- 26529745 TI - Anisotropic Ambient Volume Shading. AB - We present a novel method to compute anisotropic shading for direct volume rendering to improve the perception of the orientation and shape of surface-like structures. We determine the scale-aware anisotropy of a shading point by analyzing its ambient region. We sample adjacent points with similar scalar values to perform a principal component analysis by computing the eigenvectors and eigenvalues of the covariance matrix. In particular, we estimate the tangent directions, which serve as the tangent frame for anisotropic bidirectional reflectance distribution functions. Moreover, we exploit the ratio of the eigenvalues to measure the magnitude of the anisotropy at each shading point. Altogether, this allows us to model a data-driven, smooth transition from isotropic to strongly anisotropic volume shading. In this way, the shape of volumetric features can be enhanced significantly by aligning specular highlights along the principal direction of anisotropy. Our algorithm is independent of the transfer function, which allows us to compute all shading parameters once and store them with the data set. We integrated our method in a GPU-based volume renderer, which offers interactive control of the transfer function, light source positions, and viewpoint. Our results demonstrate the benefit of anisotropic shading for visualization to achieve data-driven local illumination for improved perception compared to isotropic shading. PMID- 26529746 TI - JiTTree: A Just-in-Time Compiled Sparse GPU Volume Data Structure. AB - Sparse volume data structures enable the efficient representation of large but sparse volumes in GPU memory for computation and visualization. However, the choice of a specific data structure for a given data set depends on several factors, such as the memory budget, the sparsity of the data, and data access patterns. In general, there is no single optimal sparse data structure, but a set of several candidates with individual strengths and drawbacks. One solution to this problem are hybrid data structures which locally adapt themselves to the sparsity. However, they typically suffer from increased traversal overhead which limits their utility in many applications. This paper presents JiTTree, a novel sparse hybrid volume data structure that uses just-in-time compilation to overcome these problems. By combining multiple sparse data structures and reducing traversal overhead we leverage their individual advantages. We demonstrate that hybrid data structures adapt well to a large range of data sets. They are especially superior to other sparse data structures for data sets that locally vary in sparsity. Possible optimization criteria are memory, performance and a combination thereof. Through just-in-time (JIT) compilation, JiTTree reduces the traversal overhead of the resulting optimal data structure. As a result, our hybrid volume data structure enables efficient computations on the GPU, while being superior in terms of memory usage when compared to non-hybrid data structures. PMID- 26529747 TI - A Novel Lead Design for Modulation and Sensing of Deep Brain Structures. AB - GOAL: Develop and characterize the functionality of a novel thin-film probe technology with a higher density of electrode contacts than are currently available with commercial deep brain stimulation (DBS) lead technology. Such technology has potential to enhance the spatial precision of DBS and enable a more robust approach to sensing local field potential activity in the context of adaptive DBS strategies. METHODS: Thin-film planar arrays were microfabricated and then assembled on a cylindrical carrier to achieve a lead with 3-D conformation. Using an integrated and removable stylet, the arrays were chronically implanted in the subthalamic nucleus and globus pallidus in two parkinsonian nonhuman primates. RESULTS: This study provides the first in vivo data from chronically implanted DBS arrays for translational nonhuman primate studies. Stimulation through the arrays induced a decrease in parkinsonian rigidity, and directing current around the lead showed an orientation dependence for eliciting motor capsule side effects. The array recordings also showed that oscillatory activity in the basal ganglia is heterogeneous at a smaller scale than detected by the current DBS lead technology. CONCLUSION: These 3-D DBS arrays provide an enabling tool for future studies that seek to monitor and modulate deep brain activity through chronically implanted leads. SIGNIFICANCE: DBS lead technology with a higher density of electrode contacts has potential to enable sculpting DBS current flow and sensing biomarkers of disease and therapy. PMID- 26529748 TI - Methods for 2-D and 3-D Endobronchial Ultrasound Image Segmentation. AB - Endobronchial ultrasound (EBUS) is now commonly used for cancer-staging bronchoscopy. Unfortunately, EBUS is challenging to use and interpreting EBUS video sequences is difficult. Other ultrasound imaging domains, hampered by related difficulties, have benefited from computer-based image-segmentation methods. Yet, so far, no such methods have been proposed for EBUS. We propose image-segmentation methods for 2-D EBUS frames and 3-D EBUS sequences. Our 2-D method adapts the fast-marching level-set process, anisotropic diffusion, and region growing to the problem of segmenting 2-D EBUS frames. Our 3-D method builds upon the 2-D method while also incorporating the geodesic level-set process for segmenting EBUS sequences. Tests with lung-cancer patient data showed that the methods ran fully automatically for nearly 80% of test cases. For the remaining cases, the only user-interaction required was the selection of a seed point. When compared to ground-truth segmentations, the 2-D method achieved an overall Dice index = 90.0% +/-4.9%, while the 3-D method achieved an overall Dice index = 83.9 +/- 6.0%. In addition, the computation time (2-D, 0.070 s/frame; 3 D, 0.088 s/frame) was two orders of magnitude faster than interactive contour definition. Finally, we demonstrate the potential of the methods for EBUS localization in a multimodal image-guided bronchoscopy system. PMID- 26529749 TI - Interactive Cell Segmentation Based on Active and Semi-Supervised Learning. AB - Automatic cell segmentation can hardly be flawless due to the complexity of image data particularly when time-lapse experiments last for a long time without biomarkers. To address this issue, we propose an interactive cell segmentation method by classifying feature-homogeneous superpixels into specific classes, which is guided by human interventions. Specifically, we propose to actively select the most informative superpixels by minimizing the expected prediction error which is upper bounded by the transductive Rademacher complexity, and then query for human annotations. After propagating the user-specified labels to the remaining unlabeled superpixels via an affinity graph, the error-prone superpixels are selected automatically and request for human verification on them; once erroneous segmentation is detected and subsequently corrected, the information is propagated efficiently over a gradually-augmented graph to un labeled superpixels such that the analogous errors are fixed meanwhile. The correction propagation step is efficiently conducted by introducing a verification propagation matrix rather than rebuilding the affinity graph and re performing the label propagation from the beginning. We repeat this procedure until most superpixels are classified into a specific category with high confidence. Experimental results performed on three types of cell populations validate that our interactive cell segmentation algorithm quickly reaches high quality results with minimal human interventions and is significantly more efficient than alternative methods, since the most informative samples are selected for human annotation/verification early. PMID- 26529750 TI - Computer Aided Theragnosis Using Quantitative Ultrasound Spectroscopy and Maximum Mean Discrepancy in Locally Advanced Breast Cancer. AB - A noninvasive computer-aided-theragnosis (CAT) system was developed for the early therapeutic cancer response assessment in patients with locally advanced breast cancer (LABC) treated with neoadjuvant chemotherapy. The proposed CAT system was based on multi-parametric quantitative ultrasound (QUS) spectroscopic methods in conjunction with advanced machine learning techniques. Specifically, a kernel based metric named maximum mean discrepancy (MMD), a technique for learning from imbalanced data based on random undersampling, and supervised learning were investigated with response-monitoring data from LABC patients. The CAT system was tested on 56 patients using statistical significance tests and leave-one-subject out classification techniques. Textural features using state-of-the-art local binary patterns (LBP), and gray-scale intensity features were extracted from the spectral parametric maps in the proposed CAT system. The system indicated significant differences in changes between the responding and non-responding patient populations as well as high accuracy, sensitivity, and specificity in discriminating between the two patient groups early after the start of treatment, i.e., on weeks 1 and 4 of several months of treatment. The proposed CAT system achieved an accuracy of 85%, 87%, and 90% on weeks 1, 4 and 8, respectively. The sensitivity and specificity of developed CAT system for the same times was 85%, 95%, 90% and 85%, 85%, 91%, respectively. The proposed CAT system thus establishes a noninvasive framework for monitoring cancer treatment response in tumors using clinical ultrasound imaging in conjunction with machine learning techniques. Such a framework can potentially facilitate the detection of refractory responses in patients to treatment early on during a course of therapy to enable possibly switching to more efficacious treatments. PMID- 26529751 TI - Chip Scale Atomic Resonator Frequency Stabilization System With Ultra-Low Power Consumption for Optoelectronic Oscillators. AB - We present a long-term chip scale stabilization scheme for optoelectronic oscillators (OEOs) based on a rubidium coherent population trapping (CPT) atomic resonator. By locking a single mode of an OEO to the (85)Rb 3.035-GHz CPT resonance utilizing an improved phase-locked loop (PLL) with a PID regulator, we achieved a chip scale frequency stabilization system for the OEO. The fractional frequency stability of the stabilized OEO by overlapping Allan deviation reaches 6.2 *10(-11) (1 s) and ~ 1.45 *10 (-11) (1000 s). This scheme avoids a decrease in the extra phase noise performance induced by the electronic connection between the OEO and the microwave reference in common injection locking schemes. The total physical package of the stabilization system is [Formula: see text] and the total power consumption is 400 mW, which provides a chip scale and portable frequency stabilization approach with ultra-low power consumption for OEOs. PMID- 26529752 TI - Temporal Super Resolution Enhancement of Echocardiographic Images Based on Sparse Representation. AB - A challenging issue for echocardiographic image interpretation is the accurate analysis of small transient motions of myocardium and valves during real-time visualization. A higher frame rate video may reduce this difficulty, and temporal super resolution (TSR) is useful for illustrating the fast-moving structures. In this paper, we introduce a novel framework that optimizes TSR enhancement of echocardiographic images by utilizing temporal information and sparse representation. The goal of this method is to increase the frame rate of echocardiographic videos, and therefore enable more accurate analyses of moving structures. For the proposed method, we first derived temporal information by extracting intensity variation time curves (IVTCs) assessed for each pixel. We then designed both low-resolution and high-resolution overcomplete dictionaries based on prior knowledge of the temporal signals and a set of prespecified known functions. The IVTCs can then be described as linear combinations of a few prototype atoms in the low-resolution dictionary. We used the Bayesian compressive sensing (BCS) sparse recovery algorithm to find the sparse coefficients of the signals. We extracted the sparse coefficients and the corresponding active atoms in the low-resolution dictionary to construct new sparse coefficients corresponding to the high-resolution dictionary. Using the estimated atoms and the high-resolution dictionary, a new IVTC with more samples was constructed. Finally, by placing the new IVTC signals in the original IVTC positions, we were able to reconstruct the original echocardiography video with more frames. The proposed method does not require training of low-resolution and high-resolution dictionaries, nor does it require motion estimation; it does not blur fast-moving objects, and does not have blocking artifacts. PMID- 26529753 TI - Acoustic Interaction Forces and Torques Acting on Suspended Spheres in an Ideal Fluid. AB - In this paper, the acoustic interaction forces and torques exerted by an arbitrary time-harmonic wave on a set of N objects suspended in an inviscid fluid are theoretically analyzed. We utilize the partial-wave expansion method with translational addition theorem and re-expansion of multipole series to solve the related multiple scattering problem. We show that the acoustic interaction force and torque can be obtained using the farfield radiation force and torque formulas. To exemplify the method, we calculate the interaction forces exerted by an external traveling and standing plane wave on an arrangement of two and three olive-oil droplets in water. The droplets' radii are comparable to the wavelength (i.e., Mie scattering regime). The results show that the acoustic interaction forces present an oscillatory spatial distribution which follows the pattern formed by interference between the external and rescattered waves. In addition, acoustic interaction torques arise on the absorbing droplets whenever a nonsymmetric wavefront is formed by the external and rescattered waves' interference. PMID- 26529754 TI - Twenty-Five Years of Applications of the Modified Allan Variance in Telecommunications. AB - The Modified Allan Variance (MAVAR) was originally defined in 1981 for measuring frequency stability in precision oscillators. Due to its outstanding accuracy in discriminating power-law noise, it attracted significant interest among telecommunications engineers since the early 1990s, when it was approved as a standard measure in international standards, redressed as Time Variance (TVAR), for specifying the time stability of network synchronization signals and of equipment clocks. A dozen years later, the usage of MAVAR was also introduced for Internet traffic analysis to estimate self-similarity and long-range dependence. Further, in this field, it demonstrated superior accuracy and sensitivity, better than most popular tools already in use. This paper surveys the last 25 years of progress in extending the field of application of the MAVAR in telecommunications. First, the rationale and principles of the MAVAR are briefly summarized. Its adaptation as TVAR for specification of timing stability is presented. The usage of MAVAR/TVAR in telecommunications standards is reviewed. Examples of measurements on real telecommunications equipment clocks are presented, providing an overview on their actual performance in terms of MAVAR. Moreover, applications of MAVAR to network traffic analysis are surveyed. The superior accuracy of MAVAR in estimating long-range dependence is emphasized by highlighting some remarkable practical examples of real network traffic analysis. PMID- 26529755 TI - Measuring Buffer-Gas Pressure in Sealed Glass Cells: An Assessment of the KSK Technique. AB - In alkali rf-discharge lamps used for optical pumping in atomic clocks and magnetometers, a buffer-gas (Kr or Xe) allows electrons to extract energy from an rf-field, and these energized electrons eventually produce alkali resonant light. Contrary to naive intuition, rf-discharge lamps can lose their noble-gas buffer over time. Recently, we began a long-term experimental program to better understand the mechanism of noble-gas loss in rf-discharge lamps, and needed a nondestructive means of measuring buffer-gas pressure changes in sealed glass cells. For this purpose, we settled on the Kazantsev, Smirnova, and Khutorshchikov (KSK) technique, which is based on inferring buffer-gas pressure from the collision shift of an alkali ground-state hyperfine transition frequency nuhfs. Here, we discuss the basic KSK technique and two modifications that we have implemented for its improvement: use of a diode laser for optical pumping, and extrapolation of nuhfs to zero magnetic field. Testing our system's long-term performance with a very low pressure reference cell (i.e., 3.3 torr Xe), we find a reproducibility of 0.2% and an absolute accuracy of 5%. Further, our systematic drift is less than 1 mtorr/month. PMID- 26529756 TI - The Time Deviation in Packet-Based Synchronization. AB - The telecommunications industry has used the time deviation (TDEV) very effectively for specifying network equipment clock performance as well as the performance of timing signals generated by Central Office equipment such as primary reference clocks and building integrated timing supplies (BITS) and synchronization supply units (SSUs). We discuss here the development of TDEV, and the variations of TDEV motivated by the advent of packet-switching and the steady transformation of the telecom network from circuit-switched-based to packet switched-based. We illustrate these with simulation of the performance of the precise time protocol (PTP) across a packet-switched network. We then apply published methods to automatically determine noise types, and use these to predict time dispersion from a master clock for a slave clock using these PTP packets to stay synchronized. The result shows how TDEV and the other deviations provide an extensive array of tools for telecom networks, as well as for general time and frequency applications. PMID- 26529757 TI - A Wavelet Perspective on the Allan Variance. AB - The origins of the Allan variance trace back 50 years ago to two seminal papers, one by Allan (1966) and the other by Barnes (1966). Since then, the Allan variance has played a leading role in the characterization of high-performance time and frequency standards. Wavelets first arose in the early 1980s in the geophysical literature, and the discrete wavelet transform (DWT) became prominent in the late 1980s in the signal processing literature. Flandrin (1992) briefly documented a connection between the Allan variance and a wavelet transform based upon the Haar wavelet. Percival and Guttorp (1994) noted that one popular estimator of the Allan variance-the maximal overlap estimator-can be interpreted in terms of a version of the DWT now widely referred to as the maximal overlap DWT (MODWT). In particular, when the MODWT is based on the Haar wavelet, the variance of the resulting wavelet coefficients-the wavelet variance-is identical to the Allan variance when the latter is multiplied by one-half. The theory behind the wavelet variance can thus deepen our understanding of the Allan variance. In this paper, we review basic wavelet variance theory with an emphasis on the Haar-based wavelet variance and its connection to the Allan variance. We then note that estimation theory for the wavelet variance offers a means of constructing asymptotically correct confidence intervals (CIs) for the Allan variance without reverting to the common practice of specifying a power-law noise type a priori. We also review recent work on specialized estimators of the wavelet variance that are of interest when some observations are missing (gappy data) or in the presence of contamination (rogue observations or outliers). It is a simple matter to adapt these estimators to become estimators of the Allan variance. Finally we note that wavelet variances based upon wavelets other than the Haar offer interesting generalizations of the Allan variance. PMID- 26529758 TI - Allan Deviation Plot as a Tool for Quartz-Enhanced Photoacoustic Sensors Noise Analysis. AB - We report here on the use of the Allan deviation plot to analyze the long-term stability of a quartz-enhanced photoacoustic (QEPAS) gas sensor. The Allan plot provides information about the optimum averaging time for the QEPAS signal and allows the prediction of its ultimate detection limit. The Allan deviation can also be used to determine the main sources of noise coming from the individual components of the sensor. Quartz tuning fork thermal noise dominates for integration times up to 275 s, whereas at longer averaging times, the main contribution to the sensor noise originates from laser power instabilities. PMID- 26529759 TI - An Algorithm for Synchronizing a Clock When the Data Are Received Over a Network With an Unstable Delay. AB - A method is presented for synchronizing the time of a clock to a remote time standard when the channel connecting the two has significant delay variation that can be described only statistically. The method compares the Allan deviation of the channel fluctuations to the free-running stability of the local clock, and computes the optimum interval between requests based on one of the three selectable requirements: 1) choosing the highest possible accuracy; 2) choosing the best tradeoff of cost versus accuracy; or 3) minimizing the number of requests to realize a specific accuracy. Once the interval between requests is chosen, the final step is to steer the local clock based on the received data. A typical adjustment algorithm, which supports both the statistical considerations based on the Allan deviation comparison and the timely detection of errors, is included as an example. PMID- 26529760 TI - Degrees of Freedom for Allan Deviation Estimates of Multiple Clocks. AB - The three-cornered-hat (TCH) technique is used frequently in the timing community to estimate the stability of single frequency standards (clocks) when the only measurement data available are paired differences. In previous work, we presented an analytic method to estimate the reduced degrees of freedom produced when using the TCH estimation technique. In this paper, we extend that method to estimate the reduced degrees of freedom related to the more general case of the M-cornered hat. PMID- 26529762 TI - GMM Estimation of 2D-RCA Models With Applications to Texture Image Classification. AB - The 2D indexed random coefficients autoregressive (2D-RCA) models are obtained by introducing appropriate random field coefficients to an AR model on Z(2). The study of such models is motivated by their capability to capture the space varying behavior of the volatility. A generalized method of moment approach is considered to estimate the 2D-RCA models. Consistency and asymptotic normality of the estimates are derived. Estimated parameters are used, at a later stage, as pixel features in texture image classification. PMID- 26529761 TI - Robust Tracking of Small Displacements With a Bayesian Estimator. AB - Radiation-force-based elasticity imaging describes a group of techniques that use acoustic radiation force (ARF) to displace tissue to obtain qualitative or quantitative measurements of tissue properties. Because ARF-induced displacements are on the order of micrometers, tracking these displacements in vivo can be challenging. Previously, it has been shown that Bayesian-based estimation can overcome some of the limitations of a traditional displacement estimator such as normalized cross-correlation (NCC). In this work, we describe a Bayesian framework that combines a generalized Gaussian-Markov random field (GGMRF) prior with an automated method for selecting the prior's width. We then evaluate its performance in the context of tracking the micrometer-order displacements encountered in an ARF-based method such as ARF impulse (ARFI) imaging. The results show that bias, variance, and mean-square error (MSE) performance vary with prior shape and width, and that an almost one order-of-magnitude reduction in MSE can be achieved by the estimator at the automatically selected prior width. Lesion simulations show that the proposed estimator has a higher contrast to-noise ratio but lower contrast than NCC, median-filtered NCC, and the previous Bayesian estimator, with a non-Gaussian prior shape having better lesion-edge resolution than a Gaussian prior. In vivo results from a cardiac, radio-frequency ablation ARFI imaging dataset show quantitative improvements in lesion contrast to-noise ratio over NCC as well as the previous Bayesian estimator. PMID- 26529763 TI - Large Margin Multi-Modal Multi-Task Feature Extraction for Image Classification. AB - The features used in many image analysis-based applications are frequently of very high dimension. Feature extraction offers several advantages in high dimensional cases, and many recent studies have used multi-task feature extraction approaches, which often outperform single-task feature extraction approaches. However, most of these methods are limited in that they only consider data represented by a single type of feature, even though features usually represent images from multiple modalities. We, therefore, propose a novel large margin multi-modal multi-task feature extraction (LM3FE) framework for handling multi-modal features for image classification. In particular, LM3FE simultaneously learns the feature extraction matrix for each modality and the modality combination coefficients. In this way, LM3FE not only handles correlated and noisy features, but also utilizes the complementarity of different modalities to further help reduce feature redundancy in each modality. The large margin principle employed also helps to extract strongly predictive features, so that they are more suitable for prediction (e.g., classification). An alternating algorithm is developed for problem optimization, and each subproblem can be efficiently solved. Experiments on two challenging real-world image data sets demonstrate the effectiveness and superiority of the proposed method. PMID- 26529764 TI - Salient Region Detection via High-Dimensional Color Transform and Local Spatial Support. AB - In this paper, we introduce a novel approach to automatically detect salient regions in an image. Our approach consists of global and local features, which complement each other to compute a saliency map. The first key idea of our work is to create a saliency map of an image by using a linear combination of colors in a high-dimensional color space. This is based on an observation that salient regions often have distinctive colors compared with backgrounds in human perception, however, human perception is complicated and highly nonlinear. By mapping the low-dimensional red, green, and blue color to a feature vector in a high-dimensional color space, we show that we can composite an accurate saliency map by finding the optimal linear combination of color coefficients in the high dimensional color space. To further improve the performance of our saliency estimation, our second key idea is to utilize relative location and color contrast between superpixels as features and to resolve the saliency estimation from a trimap via a learning-based algorithm. The additional local features and learning-based algorithm complement the global estimation from the high dimensional color transform-based algorithm. The experimental results on three benchmark datasets show that our approach is effective in comparison with the previous state-of-the-art saliency estimation methods. PMID- 26529765 TI - Efficient Algorithms for Convolutional Sparse Representations. AB - When applying sparse representation techniques to images, the standard approach is to independently compute the representations for a set of overlapping image patches. This method performs very well in a variety of applications, but results in a representation that is multi-valued and not optimized with respect to the entire image. An alternative representation structure is provided by a convolutional sparse representation, in which a sparse representation of an entire image is computed by replacing the linear combination of a set of dictionary vectors by the sum of a set of convolutions with dictionary filters. The resulting representation is both single-valued and jointly optimized over the entire image. While this form of a sparse representation has been applied to a variety of problems in signal and image processing and computer vision, the computational expense of the corresponding optimization problems has restricted application to relatively small signals and images. This paper presents new, efficient algorithms that substantially improve on the performance of other recent methods, contributing to the development of this type of representation as a practical tool for a wider range of problems. PMID- 26529766 TI - Depth Analogy: Data-Driven Approach for Single Image Depth Estimation Using Gradient Samples. AB - Inferring scene depth from a single monocular image is a highly ill-posed problem in computer vision. This paper presents a new gradient-domain approach, called depth analogy, that makes use of analogy as a means for synthesizing a target depth field, when a collection of RGB-D image pairs is given as training data. Specifically, the proposed method employs a non-parametric learning process that creates an analogous depth field by sampling reliable depth gradients using visual correspondence established on training image pairs. Unlike existing data driven approaches that directly select depth values from training data, our framework transfers depth gradients as reconstruction cues, which are then integrated by the Poisson reconstruction. The performance of most conventional approaches relies heavily on the training RGB-D data used in the process, and such a dependency severely degenerates the quality of reconstructed depth maps when the desired depth distribution of an input image is quite different from that of the training data, e.g., outdoor versus indoor scenes. Our key observation is that using depth gradients in the reconstruction is less sensitive to scene characteristics, providing better cues for depth recovery. Thus, our gradient-domain approach can support a great variety of training range datasets that involve substantial appearance and geometric variations. The experimental results demonstrate that our (depth) gradient-domain approach outperforms existing data-driven approaches directly working on depth domain, even when only uncorrelated training datasets are available. PMID- 26529768 TI - Optimal Multitrial Prediction Combination and Subject-Specific Adaptation for Minimal Training Brain Switch Designs. AB - Brain-Computer Interface (BCI) systems are traditionally designed by taking into account user-specific data to enable practical use. More recently, subject independent (SI) classification algorithms have been developed which bypass the subject specific adaptation and enable rapid use of the system. A brain switch is a particular BCI system where the system is required to distinguish from two separate mental tasks corresponding to the on-off commands of a switch. Such applications require a low false positive rate (FPR) while having an acceptable response time (RT) until the switch is activated. In this work, we develop a methodology that produces optimal brain switch behavior through subject specific (SS) adaptation of: a) a multitrial prediction combination model and b) an SI classification model. We propose a statistical model of combining classifier predictions that enables optimal FPR calibration through a short calibration session. We trained an SI classifier on a training synchronous dataset and tested our method on separate holdout synchronous and asynchronous brain switch experiments. Although our SI model obtained similar performance between training and holdout datasets, 86% and 85% for the synchronous and 69% and 66% for the asynchronous the between subject FPR and TPR variability was high (up to 62%). The short calibration session was then employed to alleviate that problem and provide decision thresholds that achieve when possible a target FPR=1% with good accuracy for both datasets. PMID- 26529769 TI - Fertilization of Mouse Gametes in Vitro Using a Digital Microfluidic System. AB - We demonstrated in vitro fertilization (IVF) using a digital microfluidic (DMF) system, so-called electrowetting on dielectric (EWOD). The DMF device was proved to be biocompatible and the DMF manipulation of a droplet was harmless to the embryos. This DMF platform was then used for the fertilization of mouse gametes in vitro and for embryo dynamic culture based on a dispersed droplet form. Development of the embryos was instantaneously recorded by a time-lapse microscope in an incubator. Our results indicated that increasing the number of sperms for IVF would raise the rate of fertilization. However, the excess of sperms in the 10 MUL culture medium would more easily make the embryo dead during cell culture. Dynamic culture powered with EWOD can manipulate a single droplet containing mouse embryos and culture to the eight-cell stage. The fertilization rate of IVF demonstrated by DMF system was 34.8%, and about 25% inseminated embryos dynamically cultured on a DMF chip developed into an eight-cell stage. The results indicate that the DMF system has the potential for application in assisted reproductive technology. PMID- 26529770 TI - A Molecular Communications Model for Drug Delivery. AB - This paper considers the scenario of a targeted drug delivery system, which consists of deploying a number of biological nanomachines close to a biological target (e.g., a tumor), able to deliver drug molecules in the diseased area. Suitably located transmitters are designed to release a continuous flow of drug molecules in the surrounding environment, where they diffuse and reach the target. These molecules are received when they chemically react with compliant receptors deployed on the receiver surface. In these conditions, if the release rate is relatively high and the drug absorption time is significant, congestion may happen, essentially at the receiver site. This phenomenon limits the drug absorption rate and makes the signal transmission ineffective, with an undesired diffusion of drug molecules elsewhere in the body. The original contribution of this paper consists of a theoretical analysis of the causes of congestion in diffusion-based molecular communications. For this purpose, it is proposed a reception model consisting of a set of pure loss queuing systems. The proposed model exhibits an excellent agreement with the results of a simulation campaign made by using the Biological and Nano-Scale communication simulator version 2 (BiNS2), a well-known simulator for molecular communications, whose reliability has been assessed through in vitro experiments. The obtained results can be used in rate control algorithms to optimally determine the optimal release rate of molecules in drug delivery applications. PMID- 26529771 TI - Bioinspired Nanonetworks for Targeted Cancer Drug Delivery. AB - A biomimicry approach to nanonetworks is proposed here for targeted cancer drug delivery (TDD). The swarm of bioinspired nanomachines utilizes the blood distribution network and chemotaxis to carry drug through the vascular system to the cancer site, recognized by a high concentration of vascular endothelial growth factor (VEGF). Our approach is multi-scale and includes processes that occur both within cells and with their neighbors. The proposed bionanonetwork takes advantage of several organic processes, some of which already occur within the human body, such as a plate-like structure similar to those of red blood cells for more environmental contact; a berry fruit architecture for its internal multi-foams architecture; the penetrable structure of cancer cells, tissue, as well as the porous structure of the capillaries for drug penetration; state of glycocalyx for ligand-receptor adhesion; as well as changes in pH state of blood and O 2 release for nanomachine communication. For a more appropriate evaluation, we compare our work with a conventional chemotherapy approach using a mathematical model of cancer under actual experimental parameter settings. Simulation results show the merits of the proposed method in targeted cancer therapy by improving the densities of the relevant cancer cell types and VEGF concentration, while following more organic and natural processes. PMID- 26529772 TI - PETs: A Stable and Accurate Predictor of Protein-Protein Interacting Sites Based on Extremely-Randomized Trees. AB - Protein-protein interaction (PPI) plays crucial roles in the performance of various biological processes. A variety of methods are dedicated to identify whether proteins have interaction residues, but it is often more crucial to recognize each amino acid. In practical applications, the stability of a prediction model is as important as its accuracy. However, random sampling, which is widely used in previous prediction models, often brings large difference between each training model. In this paper, a Predictor of protein-protein interaction sites based on Extremely-randomized Trees (PETs) is proposed to improve the prediction accuracy while maintaining the prediction stability. In PETs, a cluster-based sampling strategy is proposed to ensure the model stability: first, the training dataset is divided into subsets using specific features; second, the subsets are clustered using K-means; and finally the samples are selected from each cluster. Using the proposed sampling strategy, samples which have different types of significant features could be selected independently from different clusters. The evaluation shows that PETs is able to achieve better accuracy while maintaining a good stability. The source code and toolkit are available at https://github.com/BinXia/PETs. PMID- 26529773 TI - An Analytical Model for Molecular Propagation in Nanocommunication via Filaments Using Relay-Enabled Nodes. AB - Molecular communication is a nanoscale communication method in which information is encoded in molecules. Molecular communication using microtubules in free space is one of the realistic scenarios proposed for this type of nanocommunication. Based on this technique, molecular communication via filaments using nano-relays is proposed in this paper to improve the performance of the system in terms of delay and bit error probability. An analytical model using jump diffusion processes is proposed for molecular propagation in this scenario. It is shown that the proposed mathematical model is capable of tracking molecular propagation in molecular communication via filaments using nano-relays. Also, the model is used to investigate effects of different parameters on delay and bit error probability. PMID- 26529774 TI - Mining Contiguous Sequential Generators in Biological Sequences. AB - The discovery of conserved sequential patterns in biological sequences is essential to unveiling common shared functions. Mining sequential generators as well as mining closed sequential patterns can contribute to a more concise result set than mining all sequential patterns, especially in the analysis of big data in bioinformatics. Previous studies have also presented convincing arguments that the generator is preferable to the closed pattern in inductive inference and classification. However, classic sequential generator mining algorithms, due to the lack of consideration on the contiguous constraint along with the lower closed one, still pose a great challenge at spawning a large number of inefficient and redundant patterns, which is too huge for effective usage. Driven by some extensive applications of patterns with contiguous feature, we propose ConSgen, an efficient algorithm for discovering contiguous sequential generators. It adopts the n-gram model, called shingles, to generate potential frequent subsequences and leverages several pruning techniques to prune the unpromising parts of search space. And then, the contiguous sequential generators are identified by using the equivalence class-based lower-closure checking scheme. Our experiments on both DNA and protein data sets demonstrate the compactness, efficiency, and scalability of ConSgen. PMID- 26529775 TI - BowMapCL: Burrows-Wheeler Mapping on Multiple Heterogeneous Accelerators. AB - The computational demand of exact-search procedures has pressed the exploitation of parallel processing accelerators to reduce the execution time of many applications. However, this often imposes strict restrictions in terms of the problem size and implementation efforts, mainly due to their possibly distinct architectures. To circumvent this limitation, a new exact-search alignment tool (BowMapCL) based on the Burrows-Wheeler Transform and FM-Index is presented. Contrasting to other alternatives, BowMapCL is based on a unified implementation using OpenCL, allowing the exploitation of multiple and possibly different devices (e.g., NVIDIA, AMD/ATI, and Intel GPUs/APUs). Furthermore, to efficiently exploit such heterogeneous architectures, BowMapCL incorporates several techniques to promote its performance and scalability, including multiple buffering, work-queue task-distribution, and dynamic load-balancing, together with index partitioning, bit-encoding, and sampling. When compared with state-of the-art tools, the attained results showed that BowMapCL (using a single GPU) is 2 * to 7.5 * faster than mainstream multi-threaded CPU BWT-based aligners, like Bowtie, BWA, and SOAP2; and up to 4 * faster than the best performing state-of the-art GPU implementations (namely, SOAP3 and HPG-BWT). When multiple and completely distinct devices are considered, BowMapCL efficiently scales the offered throughput, ensuring a convenient load-balance of the involved processing in the several distinct devices. PMID- 26529776 TI - Improving Identification of Key Players in Aging via Network De-Noising and Core Inference. AB - Current "ground truth" knowledge about human aging has been obtained by transferring aging-related knowledge from well-studied model species via sequence homology or by studying human gene expression data. Since proteins function by interacting with each other, analyzing protein-protein interaction (PPI) networks in the context of aging is promising. Unlike existing static network research of aging, since cellular functioning is dynamic, we recently integrated the static human PPI network with aging-related gene expression data to form dynamic, age specific networks. Then, we predicted as key players in aging those proteins whose network topologies significantly changed with age. Since current networks are noisy , here, we use link prediction to de-noise the human network and predict improved key players in aging from the de-noised data. Indeed, de-noising gives more significant overlap between the predicted data and the "ground truth" aging-related data. Yet, we obtain novel predictions, which we validate in the literature. Also, we improve the predictions by an alternative strategy: removing "redundant" edges from the age-specific networks and using the resulting age specific network "cores" to study aging. We produce new knowledge from dynamic networks encompassing multiple data types, via network de-noising or core inference, complementing the existing knowledge obtained from sequence or expression data. PMID- 26529777 TI - Ontology-Based Search of Genomic Metadata. AB - The Encyclopedia of DNA Elements (ENCODE) is a huge and still expanding public repository of more than 4,000 experiments and 25,000 data files, assembled by a large international consortium since 2007; unknown biological knowledge can be extracted from these huge and largely unexplored data, leading to data-driven genomic, transcriptomic, and epigenomic discoveries. Yet, search of relevant datasets for knowledge discovery is limitedly supported: metadata describing ENCODE datasets are quite simple and incomplete, and not described by a coherent underlying ontology. Here, we show how to overcome this limitation, by adopting an ENCODE metadata searching approach which uses high-quality ontological knowledge and state-of-the-art indexing technologies. Specifically, we developed S.O.S. GeM (http://www.bioinformatics.deib.polimi.it/SOSGeM/), a system supporting effective semantic search and retrieval of ENCODE datasets. First, we constructed a Semantic Knowledge Base by starting with concepts extracted from ENCODE metadata, matched to and expanded on biomedical ontologies integrated in the well-established Unified Medical Language System. We prove that this inference method is sound and complete. Then, we leveraged the Semantic Knowledge Base to semantically search ENCODE data from arbitrary biologists' queries. This allows correctly finding more datasets than those extracted by a purely syntactic search, as supported by the other available systems. We empirically show the relevance of found datasets to the biologists' queries. PMID- 26529778 TI - A Guaranteed Similarity Metric Learning Framework for Biological Sequence Comparison. AB - Similarity of sequences is a key mathematical notion for Classification and Phylogenetic studies in Biology. The distance and similarity between two sequence are very important and widely studied. During the last decades, Similarity(distance) metric learning is one of the hottest topics of machine learning/data mining as well as their applications in the bioinformatics field. It is feasible to introduce machine learning technology to learn similarity metric from biological data. In this paper, we propose a novel framework of guaranteed similarity metric learning (GMSL) to perform alignment of biology sequences in any feature vector space. It introduces the (epsilon, gamma, tau) goodness similarity theory to Mahalanobis metric learning. As a theoretical guaranteed similarity metric learning approach, GMSL guarantees that the learned similarity function performs well in classification and clustering. Our experiments on the most used datasets demonstrate that our approach outperforms the state-of-the-art biological sequences alignment methods and other similarity metric learning algorithms in both accuracy and stability. PMID- 26529780 TI - SparseNCA: Sparse Network Component Analysis for Recovering Transcription Factor Activities with Incomplete Prior Information. AB - Network component analysis (NCA) is an important method for inferring transcriptional regulatory networks (TRNs) and recovering transcription factor activities (TFAs) using gene expression data, and the prior information about the connectivity matrix. The algorithms currently available crucially depend on the completeness of this prior information. However, inaccuracies in the measurement process may render incompleteness in the available knowledge about the connectivity matrix. Hence, computationally efficient algorithms are needed to overcome the possible incompleteness in the available data. We present a sparse network component analysis algorithm (sparseNCA), which incorporates the effect of incompleteness in the estimation of TRNs by imposing an additional sparsity constraint using the norm, which results in a greater estimation accuracy. In order to improve the computational efficiency, an iterative re-weighted method is proposed for the NCA problem which not only promotes sparsity but is hundreds of times faster than the norm based solution. The performance of sparseNCA is rigorously compared to that of FastNCA and NINCA using synthetic data as well as real data. It is shown that sparseNCA outperforms the existing state-of-the-art algorithms both in terms of estimation accuracy and consistency with the added advantage of low computational complexity. The performance of sparseNCA compared to its predecessors is particularly pronounced in case of incomplete prior information about the sparsity of the network. Subnetwork analysis is performed on the E.coli data which reiterates the superior consistency of the proposed algorithm. PMID- 26529779 TI - MrBayes tgMC3++: A High Performance and Resource-Efficient GPU-Oriented Phylogenetic Analysis Method. AB - MrBayes is a widespread phylogenetic inference tool harnessing empirical evolutionary models and Bayesian statistics. However, the computational cost on the likelihood estimation is very expensive, resulting in undesirably long execution time. Although a number of multi-threaded optimizations have been proposed to speed up MrBayes, there are bottlenecks that severely limit the GPU thread-level parallelism of likelihood estimations. This study proposes a high performance and resource-efficient method for GPU-oriented parallelization of likelihood estimations. Instead of having to rely on empirical programming, the proposed novel decomposition storage model implements high performance data transfers implicitly. In terms of performance improvement, a speedup factor of up to 178 can be achieved on the analysis of simulated datasets by four Tesla K40 cards. In comparison to the other publicly available GPU-oriented MrBayes, the tgMC3++ method (proposed herein) outperforms the tgMC3 (v1.0), nMC3 (v2.1.1) and oMC3 (v1.00) methods by speedup factors of up to 1.6, 1.9 and 2.9, respectively. Moreover, tgMC3++ supports more evolutionary models and gamma categories, which previous GPU-oriented methods fail to take into analysis. PMID- 26529781 TI - Dynamical Robustness against Multiple Mutations in Signaling Networks. AB - It has been known that the robust behavior of a cellular signaling network is strongly related to the structural characteristics of the network, such as connectivity, the number of feedback loops, and the number of feed-forward loops. Previous studies proved such relationships through dynamical simulations of various random network models. Most of them, however, focused on robustness against a single node mutation. Considering that complex diseases such as cancer are mostly caused by simultaneous dysfunction of multiple genes, it is needed to investigate the robustness of a network against multiple node mutations. In this paper, we investigated the robustness of a network against multiple node mutations through extensive simulations on the basis of Boolean network models. We found that the robustness against multiple mutations is, in most cases, weaker than the robustness against a single node mutation on average. Moreover, we found that the robustness against multiple mutations is strongly positively correlated with the robustness against single mutation. The difference between the multiple- and single-mutation robustness became larger as the number of mutated nodes increased or the number of nodes that are robust to single-mutation decreased. We further found that a node of relatively large connectivity or being involved with many feedback loops tends to be non-robust against multiple mutations. This finding is supported by the observation that poly-genic disease genes have high connectivity and are involved with a large number of feedback loops than mono genic disease genes in a human signaling network. Together, our study shows that previous studies for a single node mutation can be extended to understand the network dynamics for multiple node mutations. PMID- 26529782 TI - A 200-Channel Area-Power-Efficient Chemical and Electrical Dual-Mode Acquisition IC for the Study of Neurodegenerative Diseases. AB - Microelectrode array (MEA) can be used in the study of neurodegenerative diseases by monitoring the chemical neurotransmitter release and the electrical potential simultaneously at the cellular level. Currently, the MEA technology is migrating to more electrodes and higher electrode density, which raises power and area constraints on the design of acquisition IC. In this paper, we report the design of a 200-channel dual-mode acquisition IC with highly efficient usage of power and area. Under the constraints of target noise and fast settling, the current channel design saves power by including a novel current buffer biased in discrete time (DT) before the TIA (transimpedance amplifier). The 200 channels are sampled at 20 kS/s and quantized by column-wise SAR ADCs. The prototype IC was fabricated in a 0.18 MUm CMOS process. Silicon measurements show the current channel has 21.6 pArms noise with cyclic voltammetry (CV) and 0.48 pArms noise with constant amperometry (CA) while consuming 12.1 MUW . The voltage channel has 4.07 MUVrms noise in the bandwidth of 100 kHz and 0.2% nonlinearity while consuming 9.1 MUW. Each channel occupies 0.03 mm(2) area, which is among the smallest. PMID- 26529783 TI - Low-Complexity Seizure Prediction From iEEG/sEEG Using Spectral Power and Ratios of Spectral Power. AB - Prediction of seizures is a difficult problem as the EEG patterns are not wide sense stationary and change from seizure to seizure, electrode to electrode, and from patient to patient. This paper presents a novel patient-specific algorithm for prediction of seizures in epileptic patients from either one or two single channel or bipolar channel intra-cranial or scalp electroencephalogram (EEG) recordings with low hardware complexity. Spectral power features are extracted and their ratios are computed. For each channel, a total of 44 features including 8 absolute spectral powers, 8 relative spectral powers and 28 spectral power ratios are extracted every two seconds using a 4-second window with a 50% overlap. These features are then ranked and selected in a patient-specific manner using a two-step feature selection. Selected features are further processed by a second-order Kalman filter and then input to a linear support vector machine (SVM) classifier. The algorithm is tested on the intra-cranial EEG (iEEG) from the Freiburg database and scalp EEG (sEEG) from the MIT Physionet database. The Freiburg database contains 80 seizures among 18 patients in 427 hours of recordings. The MIT EEG database contains 78 seizures from 17 children in 647 hours of recordings. It is shown that the proposed algorithm can achieve a sensitivity of 100% and an average false positive rate (FPR) of 0.0324 per hour for the iEEG (Freiburg) database and a sensitivity of 98.68% and an average FPR of 0.0465 per hour for the sEEG (MIT) database. These results are obtained with leave-one-out cross-validation where the seizure being tested is always left out from the training set. The proposed algorithm also has a low complexity as the spectral powers can be computed using FFT. The area and power consumption of the proposed linear SVM are 2 to 3 orders of magnitude less than a radial basis function kernel SVM (RBF-SVM) classifier. Furthermore, the total energy consumption of a system using linear SVM is reduced by 8% to 23% compared to system using RBF-SVM. PMID- 26529784 TI - Multiple Ordinal Regression by Maximizing the Sum of Margins. AB - Human preferences are usually measured using ordinal variables. A system whose goal is to estimate the preferences of humans and their underlying decision mechanisms requires to learn the ordering of any given sample set. We consider the solution of this ordinal regression problem using a support vector machine algorithm. Specifically, the goal is to learn a set of classifiers with common direction vectors and different biases correctly separating the ordered classes. Current algorithms are either required to solve a quadratic optimization problem, which is computationally expensive, or based on maximizing the minimum margin (i.e., a fixed-margin strategy) between a set of hyperplanes, which biases the solution to the closest margin. Another drawback of these strategies is that they are limited to order the classes using a single ranking variable (e.g., perceived length). In this paper, we define a multiple ordinal regression algorithm based on maximizing the sum of the margins between every consecutive class with respect to one or more rankings (e.g., perceived length and weight). We provide derivations of an efficient, easy-to-implement iterative solution using a sequential minimal optimization procedure. We demonstrate the accuracy of our solutions in several data sets. In addition, we provide a key application of our algorithms in estimating human subjects' ordinal classification of attribute associations to object categories. We show that these ordinal associations perform better than the binary one typically employed in the literature. PMID- 26529785 TI - Echo State Networks With Orthogonal Pigeon-Inspired Optimization for Image Restoration. AB - In this paper, a neurodynamic approach for image restoration is proposed. Image restoration is a process of estimating original images from blurred and/or noisy images. It can be considered as a mapping problem that can be solved by neural networks. Echo state network (ESN) is a recurrent neural network with a simplified training process, which is adopted to estimate the original images in this paper. The parameter selection is important to the performance of the ESN. Thus, the pigeon-inspired optimization (PIO) approach is employed in the training process of the ESN to obtain desired parameters. Moreover, the orthogonal design strategy is utilized in the initialization of PIO to improve the diversity of individuals. The proposed method is tested on several deteriorated images with different sorts and levels of blur and/or noise. Results obtained by the improved ESN are compared with those obtained by several state-of-the-art methods. It is verified experimentally that better image restorations can be obtained for different blurred and/or noisy instances with the proposed neurodynamic method. In addition, the performance of the orthogonal PIO algorithm is compared with that of several existing bioinspired optimization algorithms to confirm its superiority. PMID- 26529786 TI - Deep Learning of Part-Based Representation of Data Using Sparse Autoencoders With Nonnegativity Constraints. AB - We demonstrate a new deep learning autoencoder network, trained by a nonnegativity constraint algorithm (nonnegativity-constrained autoencoder), that learns features that show part-based representation of data. The learning algorithm is based on constraining negative weights. The performance of the algorithm is assessed based on decomposing data into parts and its prediction performance is tested on three standard image data sets and one text data set. The results indicate that the nonnegativity constraint forces the autoencoder to learn features that amount to a part-based representation of data, while improving sparsity and reconstruction quality in comparison with the traditional sparse autoencoder and nonnegative matrix factorization. It is also shown that this newly acquired representation improves the prediction performance of a deep neural network. PMID- 26529787 TI - Group Component Analysis for Multiblock Data: Common and Individual Feature Extraction. AB - Real-world data are often acquired as a collection of matrices rather than as a single matrix. Such multiblock data are naturally linked and typically share some common features while at the same time exhibiting their own individual features, reflecting the underlying data generation mechanisms. To exploit the linked nature of data, we propose a new framework for common and individual feature extraction (CIFE) which identifies and separates the common and individual features from the multiblock data. Two efficient algorithms termed common orthogonal basis extraction (COBE) are proposed to extract common basis is shared by all data, independent on whether the number of common components is known beforehand. Feature extraction is then performed on the common and individual subspaces separately, by incorporating dimensionality reduction and blind source separation techniques. Comprehensive experimental results on both the synthetic and real-world data demonstrate significant advantages of the proposed CIFE method in comparison with the state-of-the-art. PMID- 26529788 TI - Saliency-Aware Nonparametric Foreground Annotation Based on Weakly Labeled Data. AB - In this paper, we focus on annotating the foreground of an image. More precisely, we predict both image-level labels (category labels) and object-level labels (locations) for objects within a target image in a unified framework. Traditional learning-based image annotation approaches are cumbersome, because they need to establish complex mathematical models and be frequently updated as the scale of training data varies considerably. Thus, we advocate the nonparametric method, which has shown potential in numerous applications and turned out to be attractive thanks to its advantages, i.e., lightweight training load and scalability. In particular, we exploit the salient object windows to describe images, which is beneficial to image retrieval and, thus, the subsequent image level annotation and localization tasks. Our method, namely, saliency-aware nonparametric foreground annotation, is practical to alleviate the full label requirement of training data, and effectively addresses the problem of foreground annotation. The proposed method only relies on retrieval results from the image database, while pretrained object detectors are no longer necessary. Experimental results on the challenging PASCAL VOC 2007 and PASCAL VOC 2008 demonstrate the advance of our method. PMID- 26529789 TI - Stability of Analytic Neural Networks With Event-Triggered Synaptic Feedbacks. AB - In this paper, we investigate stability of a class of analytic neural networks with the synaptic feedback via event-triggered rules. This model is general and include Hopfield neural network as a special case. These event-trigger rules can efficiently reduces loads of computation and information transmission at synapses of the neurons. The synaptic feedback of each neuron keeps a constant value based on the outputs of the other neurons at its latest triggering time but changes at its next triggering time, which is determined by a certain criterion. It is proved that every trajectory of the analytic neural network converges to certain equilibrium under this event-triggered rule for all the initial values except a set of zero measure. The main technique of the proof is the Lojasiewicz inequality to prove the finiteness of trajectory length. The realization of this event-triggered rule is verified by the exclusion of Zeno behaviors. Numerical examples are provided to illustrate the efficiency of the theoretical results. PMID- 26529790 TI - A Consistent Model for Lazzaro Winner-Take-All Circuit With Invariant Subthreshold Behavior. AB - This paper considers the basic Lazzaro winner-take-all analog computing circuit with N current inputs, N voltage outputs, and a bias current. Motivated by low power applications, we find a mathematical accurate model of the network when all MOS devices remain inside the subthreshold region all along the transient. This involves analytical inequalities relating the range of admissible input currents to transistor parameters, to supply voltage, and to bias current. The restrictions are sufficiently weak to allow extra demands of functionality or performance. The technical novelty here is that by a slight cut of the maximal subthreshold domain and by choosing proper coordinates, we get a ordinary differential equation invariance problem on a rectangle of RN+1 space which is analytically tractable. A more precise localization of the asymptotically stable steady state inside the region of interest is also inferred. Although the work is mainly theoretical, an effort to infer simple, interpretable formulas useful for synthesis has been made. The results are numerically verified and their feasibility is discussed in detail. The subject matter is new and it is worth extending it to larger classes of circuits with regional behavior. PMID- 26529791 TI - Methodological Comparisons of Heart Rate Variability Analysis in Patients With Type 2 Diabetes and Angiotensin Converting Enzyme Polymorphism. AB - Angiotensin converting enzyme (ACE) polymorphism has been shown to be important in hypertension progression and also in diabetes complications, especially associated with heart disease. Heart rate variability (HRV) is an established measure for classification of autonomic function regulating heart rate, based on the interbeat interval time series derived from a raw ECG recording. Results of this paper show that the length (number of interbeat intervals) and preprocessing of the tachogram affect the HRV analysis outcome. The comparison was based on tachogram lengths of 250, 300, 350, and 400 RR-intervals and five preprocessing approaches. An automated adaptive preprocessing method for the heart rate biosignal and tachogram length of 400 interbeat intervals provided the best classification. HRV results differed for the Type 2 Diabetes Mellitus (T2DM) group between the I/I genotype and the I/D and D/D genotypes, whereas for controls there was no significant difference in HRV between genotypes. Selecting an appropriate length of recording and automated preprocessing has confirmed that there is an effect of ACE polymorphism including the I/I genotype and that I/I should not be combined with I/D genotype in determining the extent of autonomic modulation of the heart rate. PMID- 26529792 TI - Nuclei-Based Features for Uterine Cervical Cancer Histology Image Analysis With Fusion-Based Classification. AB - Cervical cancer, which has been affecting women worldwide as the second most common cancer, can be cured if detected early and treated well. Routinely, expert pathologists visually examine histology slides for cervix tissue abnormality assessment. In previous research, we investigated an automated, localized, fusion based approach for classifying squamous epithelium into Normal, CIN1, CIN2, and CIN3 grades of cervical intraepithelial neoplasia (CIN) based on image analysis of 61 digitized histology images. This paper introduces novel acellular and atypical cell concentration features computed from vertical segment partitions of the epithelium region within digitized histology images to quantize the relative increase in nuclei numbers as the CIN grade increases. Based on the CIN grade assessments from two expert pathologists, image-based epithelium classification is investigated with voting fusion of vertical segments using support vector machine and linear discriminant analysis approaches. Leave-one-out is used for the training and testing for CIN classification, achieving an exact grade labeling accuracy as high as 88.5%. PMID- 26529793 TI - A Fast Adaptive Tunable RBF Network For Nonstationary Systems. AB - This paper describes a novel on-line learning approach for radial basis function (RBF) neural network. Based on an RBF network with individually tunable nodes and a fixed small model size, the weight vector is adjusted using the multi innovation recursive least square algorithm on-line. When the residual error of the RBF network becomes large despite of the weight adaptation, an insignificant node with little contribution to the overall system is replaced by a new node. Structural parameters of the new node are optimized by proposed fast algorithms in order to significantly improve the modeling performance. The proposed scheme describes a novel, flexible, and fast way for on-line system identification problems. Simulation results show that the proposed approach can significantly outperform existing ones for nonstationary systems in particular. PMID- 26529794 TI - Experience Replay for Optimal Control of Nonzero-Sum Game Systems With Unknown Dynamics. AB - In this paper, an approximate online equilibrium solution is developed for an N player nonzero-sum (NZS) game systems with completely unknown dynamics. First, a model identifier based on a three-layer neural network (NN) is established to reconstruct the unknown NZS games systems. Moreover, the identifier weight vector is updated based on experience replay technique which can relax the traditional persistence of excitation condition to a simplified condition on recorded data. Then, the single-network adaptive dynamic programming (ADP) with experience replay algorithm is proposed for each player to solve the coupled nonlinear Hamilton- (HJ) equations, where only the critic NN weight vectors are required to tune for each player. The feedback Nash equilibrium is provided by the solution of the coupled HJ equations. Based on the experience replay technique, a novel critic NN weights tuning law is proposed to guarantee the stability of the closed loop system and the convergence of the value functions. Furthermore, a Lyapunov based stability analysis shows that the uniform ultimate boundedness of the closed-loop system is achieved. Finally, two simulation examples are given to verify the effectiveness of the proposed control scheme. PMID- 26529795 TI - New Results on Stability and Stabilization of Networked Control Systems With Short Time-Varying Delay. AB - New stability criteria and stabilization methods on networked control systems (NCSs) with short time-varying delay (STVD) are proposed in this paper. An NCS with STVD is transformed into a time-varying discrete time system. And then, this discrete time system is converted into a equivalent time-invariant system with norm-bounded uncertainties by using robust control techniques. Using this method, the conservatism of the stability condition caused by STVD can be reduced. Based on that, a single norm-bounded uncertainty is replaced by N norm-bounded uncertainties to further reduce conservatism. Theoretical analysis shows that when N is increased, the stability condition becomes less conservative. For a fixed sampling period, the obtained stability conditions explicitly depend on the upper and lower bounds of the time delay. The existence condition and design method for the controllers are also presented. Finally, three numerical examples are provided to demonstrate the effectiveness of the proposed scheme. PMID- 26529798 TI - [Money Until In The First Place]. PMID- 26529797 TI - An unusual Cause of Periorbital Swelling in a Young Female. PMID- 26529796 TI - Human Health Effects of Biphenyl: Key Findings and Scientific Issues. AB - BACKGROUND: In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA) has evaluated the human health hazards of biphenyl exposure. OBJECTIVES: We review key findings and scientific issues regarding expected human health effects of biphenyl. METHODS: Scientific literature from 1926 through September 2012 was critically evaluated to identify potential human health hazards associated with biphenyl exposure. Key issues related to the carcinogenicity and noncancer health hazards of biphenyl were examined based on evidence from experimental animal bioassays and mechanistic studies. DISCUSSION: Systematic consideration of experimental animal studies of oral biphenyl exposure took into account the variety of study designs (e.g., study sizes, exposure levels, and exposure durations) to reconcile differing reported results. The available mechanistic and toxicokinetic evidence supports the hypothesis that male rat urinary bladder tumors arise through urinary bladder calculi formation but is insufficient to hypothesize a mode of action for liver tumors in female mice. Biphenyl and its metabolites may induce genetic damage, but a role for genotoxicity in biphenyl-induced carcinogenicity has not been established. CONCLUSIONS: The available health effects data for biphenyl provides suggestive evidence for carcinogenicity in humans, based on increased incidences of male rat urinary bladder tumors at high exposure levels and on female mouse liver tumors. Kidney toxicity is also a potential human health hazard of biphenyl exposure. CITATION: Li Z, Hogan KA, Cai C, Rieth S. 2016. Human health effects of biphenyl: key findings and scientific issues. Environ Health Perspect 124:703 712; http://dx.doi.org/10.1289/ehp.1509730. PMID- 26529799 TI - [Upper G.I. Cancer]. PMID- 26529800 TI - [Upper G.I. Cancer. I. Diagnosis of Magnifying Endoscopy for Evaluating the Invasion Depth of Superficial Esophageal Cancer]. PMID- 26529801 TI - [Upper G.I. Cancer. II. Endoscopic Surgery for Esophageal Cancer]. PMID- 26529802 TI - [Upper G.I. Cancer. III. Gastric Cancer Prevention of Gastric Cancer by Eradication of Helicobacter pylori]. PMID- 26529803 TI - [Upper G.I. Cancer. IV. Is Conversion Therapy Possible for Stage IV Gastric Cancer?]. PMID- 26529804 TI - Bone Forum Thailand. Foreword. PMID- 26529805 TI - Efficacy of Bisphosphonates Evaluated by Biological Bone Markers. AB - This research aimed to study the benefits of bone markers on bisphosphonate, alendronate plus (vitamin D3 2800IU) administered once a week as a model especially regarding BetacrossLap, CTx. The enrolled cases were 306 (female = 282, male = 24) with high CTx (>= 0.300 ng/ml). The exclusion criteria were diabetes, abnormal renal or liver profiles, recent fractures and medication 1 month before the study. The duration of observation was 3 months for making decision on treatment. The bloodfor bone markers were checked at thefirst and third months. It was found that 10 percent of alendronate intake showed no response, i.e. neither decrease nor increase in CTx and 16.1 percent of cases showed strong bone suppression, i.e. high anti-resorption which the value of CTx below 0.100 ng/ ml after 3 months of the treatment. This bad condition may induce bone crack or stress fracture in the long run. It was also found 83.9 percent of cases presented good responses with the value ofCTx at 0.100-0.299 ng/ml after 3 months. These cases can be continuing bisphosphonate until good satisfaction takes place. The benefits of bone markers help the physicians' decision either to stop or continue the treatment. For the no response group, the bone markers (CTx) will save the cost oftreatment. When the anti-resorption is marked (CTx < 0.100 ng/ ml), the physicians can stop the treatment before unwanted effects occur. The bone markers shorten the timefor producing the treatment results and indicting whether the bisphosphonates have been properly used. The bone markers, formative marker, PINP showed a decrease in bone formation after 3 months; PINP = 38.51%. This is a good lesson to be learned, that boneformation hardly ever occurs especially primary boneformation in cases where bisphosphonates is being taking. This study manifested the benefits of biological markers with quick response that can help the physicians treat the patients properly, save time and the cost of medication. PMID- 26529806 TI - Estimation of Osteoblastic Functions by Biological Bone Markers. AB - The purpose of this study is to identify the lowest value ofNMID osteocalcin and PINP when CTx is below or equal to 0.10 ng/ml at which neither bone formation nor bone resorption occurs. This may be harmful to bone texture. The 223 cases of CTx equal or below 0.100 ng/ml of CTx were enrolled. They consisted of 42 cases or 18.83% of menopausal women, 110 cases or 49.32% ofpost anti-resorptive therapy, 22 cases or 9.8% elderly and 49 cases or 21.97% unknown causes. The results show PINP = 15.88 ng/ml and NMID osteocalcin = 10.81 ng/ml. We used them as a cut value for diagnosis of bone condition. The benefits of this study: helping the physician in the treatment of bone diseases, osteoporosis in cases of over treatment, when the value of CTx is below or above 0.1 ng/ml or 0.01-0.099 ng/ml; when there is no bone resorption and osteoblastic function is poor if the values of NMID osteocalcin or PINP are still equal to 10.81, 15.88 ng/ml at any level of BetacrossLap, respectively. PMID- 26529807 TI - BMD Changes Following 2-Year Treatment of Osteoporosis by using BMK to Monitor the Dose of Bisphosphonates. AB - Reasons for using BMK to adjust dose for Osteoporosis patients: 1) To keep balance between bone formation and bone resorption, 2) To set balance ofboneformation to be higher than bone resorption (+10%), 3) To slightly lengthen bone life cycle. Only 127 out of 197 patients who joined the program ofusingBMKto monitor Bisphosphonate dose could complete the 2-year follow-up. The measurement ofBMK used before the treatment was compared with that ofthe 2-year follow-up by using both T-score and PR. As a result, the adjustment of the Bishosphonates given period by using BMK can better reinforce both spine and hip T-scores and PR summaries, more increasing and steadier than decreasing. It can be said that usingBMK to monitor the dose of bisphosphonates can offer balance between bone formation and bone resorption (balanced with plus and steadiness than minus). Moreover it can lengthen the bone cell life cycle more than usual (CTx = 80-100% of normal value, 0.31, in women or CTx 0.25-0.31). Besides, it helps the patients to reduce the cost oftreatment of bisphosphonate by lengthening the time of administration by up to 3-6 times. PMID- 26529808 TI - Study of the Safe Dosage of Ergocalciferol. AB - Vitamin D2 or ergocalciferol can replace vitamin D3, but its dosage must be a higher international unit: one unit of vitamin D3 is equal to 4 units ofvitamin D2. A proper interval of administration should take 200,000 IUper day. The 123 cases enrolled for study, every case had blood levels of 25 (OH) D and blood calcium checked before intake of vitamin D2 followed by a second check after 2 months. The means of before-intake group was 31.92 ng/ml and after-intake group was 48.62 ng/ml; the pair sample mean was 0.001. We found the level of 25 (OH) D was greater than 70 ng/ml (max = 90), 3.2 percent. Twelve cases showed no response, 9.6 percent. No cases of hypercalcemia or allergic phenomenon were noted. Before the study, we tried a random dosage of 200,000 IU per week and found the pair mean showed nothing significant (p = 0.052). In practice, the dosage of 200,000 IU of vitamin D2 is suitable for treatment of vitamin D deficiency, but for long-term treatment, dosage should be adjusted by monitoring the levels of 25 (OH) D from time to time. PMID- 26529809 TI - The Intriguing Correlation between Undercarboxylated Osteocalcin and Vitamin D. AB - Osteocalcin (OC) or bone Gla protein (BGP), a bone specific protein, is one of circulating biomarkers that can be used to determine the quality of bone tissues. It is synthesized by the osteoblast and the odontocyte. The process of OC production requires two types ofvitamin: vitamin D and vitamin K. Vitamin D is requiredfor the production of immature OC or undercarboxylated OC (UcOC) whereas vitamin K is requiredfor the transformation of UcOC to mature OC. In the past, several researchers believed that UcOC was the sensitive marker to determine vitamin K status. In fact, the level of UcOC also depends on vitamin D. This study aims to know the correlation between the levels ofvitamin D and UcOC. The collected data of UcOC and vitamin D levels from 95 healthy volunteers were analyzed. The finding was that there was a weak correlation between UcOC and vitamin D (r = 0.238; p = 0.020) together with UcOC and reciprocal ofvitamin D (r = 0.267; p = 0.009). From this correlation, the serum level of UcOC may be not the real marker for vitamin K. PMID- 26529810 TI - Prevalence of Vitamin D Insufficiency among Elderly Males Living in Rural Khon Kaen Province, Northeast Thailand. AB - BACKGROUND: Vitamin D is essential for bone strength. In our previous study of urban, elderly, males, the prevalence of vitamin D insufficiency was 48%, and they had a lower level of bone turnover marker than normal, young adult, Thai males. OBJECTIVE: To A) ascertain the prevalence of vitamin D insufficiency, B) to determine the bone turnover marker level in rural elderly males, and C) to compare urban and rural males with these parameters. RESULTS: The prevalence of vitamin D insufficiency among rural elderly males was 13.6%, while the level of bone turnover markers (P-CTx, and PINP) were in the normal Thai reference range. It was also found that rural elderly males had a significantly higher level of the calcidiol, iPTH, beta-CTx, and PINP than their urban counterparts. CONCLUSION: The prevalence of vitamin D insufficiency among rural elderly males was significantly lower than among urban males and rural males had a higher level of calcidiol, iPTH and bone turnover marker. The hypothesis was that differences in rural vs. urban lifestyle accounted for the discrepancy, possibly because elderly rural males performed strenuous outdoor labor while most urbanites stayed at home and/or had sedentary jobs. PMID- 26529811 TI - Effects of Short-Term Vitamin D Supplementation on Musculoskeletal and Body Balance for Prevention of Falling in Postmenopausal Women. AB - OBJECTIVE: The objective of this research was to examine the effects of the short duration (4 weeks) vitamin D supplementation on biochemical bone markers, muscle strength and balance of the postmenopausal females. MATERIAL AND METHOD: The participants consisted of 52 female participants from Chulalongkorn University, aged between 45-55 years old. They were divided into two groups: 26 females in the vitamin D supplementation (VID) and 26 females in the control group (CON) by the simple random sampling method. The experimental group received 20,000 IU of vitamin D2 per week, for a period of 4 weeks. The control group did not receive vitamin D2. The collected data before and after the experiment were the results of the physiology test, the biochemical bone markers, the muscle strength and the balance ability. The collected data were compared and analyzed by the mean and standard deviation. The differences of the tests are statistically significant at the 0.05 level. RESULTS: After the 4-week experiment, the vitamin D2 supplementation group had significantly improved balance ability on normal stability surfaces when being compared with the pretest and the control group (p < 0.05). CONCLUSION: A short-term vitamin D2 supplementation had positive effect on balance. This is, therefore, a good alternative for postmenopausal people and may reduce the risks of falling in women in particular. PMID- 26529812 TI - The Factor Causing Poor Results in Late Developmental Dysplasia of the Hip (DDH). AB - BACKGROUND: Treatment of DDH in walking-age children often resulting in persistent or recurrent hip dysplasia, AVN and/ or loss of reduction. The incidence of secondary procedures in this age group after closed or open reduction of the hip in DDH varies from 38% to 80% in longterm studies. The goal of this study was to determine the factors that will predict poor results in walking-age children with DDH. MATERIAL AND METHOD: The study was a retrospectively study of 25 walking children with late DDH (22 female and 3 male) treated with closed or open reduction of the hips. The data were collected from medical records and radiographs. Tonnis and Severin classifications were used to evaluate the condition of the hips. Fisher exact test and student t-test were used to evaluate the factors related to the poor result. RESULTS: Age > 28 months and > 30 months at the reduction is a factor resulting in poor results evaluated by Tonnis and Severin classification (p = 0.007), and (p = 0.008). Acetabular index (AI) and Center-edge angle (CE) at the time of index surgery are not statistical significant causing the poor results. Bilateral or unilateral of DDH are not statistical significant to cause poor results. CONCLUSION: From our study, age at presentation is the most important factor predicting poor results in walking DDH, age > 28 months at presenting leading to secondary procedure and poor Tonnis and Severin Grades. National Health Policy for Hip Screening is the most important for early detectoing of children with DDH to improve the outcome and prevent the children from multiple operations. PMID- 26529813 TI - Results of Primary Talectomy for Clubfoot in Infants and Toddlers with Arthrogryposis Multiplex Congenita. AB - BACKGROUND: Equinovarus deformity in arthrogryposis multiplex congenita patients is rigid and difficult to treat. Radical soft tissue operations yielded good results though recurrence of deformity was high. Talectomy is a bony procedure recommended as either a salvage procedure or a primary operation. OBJECTIVE: To evaluate the results ofprimary talectomy in infant and toddler patients retrospectively. MATERIAL AND METHOD: Arthrogryposis multiplex congenita patients with rigid equinovarus deformity treated with talectomy initially were retrospectively reviewed. Pain score, residual foot deformity, shoe modification, and ambulatory status were assessed. RESULTS: Talectomy were performed in 19 arthrogrypotic feet in 10 infants and toddlers. There were 6 males and 4 females. The mean age at surgery was 1.3 years old and the mean age of the follow-up time was 4.9 years. All patients had plantigrade foot without pain. One arthrogrypotic foot required posteromedial release 2 years after index surgery due to recurrent deformity. CONCLUSION: Talectomy as theprimaryprocedure in arthrogrypotic infants and toddlers demonstrated good results withfew residual deformities and recurrence. Patients could achieve plantigrade position. PMID- 26529814 TI - Effects of Aerobic Step Combined with Resistance Training on Biochemical Bone Markers, Health-Related Physical Fitness and Balance in Working Women. AB - The objectives of this research were to develop an aerobic step combined with resistance training exercise program, and to compare the effects of A) aerobic step exercise training (STE), B) resistance aerobic exercise training (RES), C) a combined aerobic step with resistance exercise training (COM) on the health related fitness, balance, and biochemical bone markers. Sixty participants were working female volunteers at the age of 35-45. They were divided into 4 groups by simple random sampling method. Fifteen of the participants were in the STE group, 14 in the RES group, 15 in the COM group, and 16 in the control group (CON). The STE, RES and COM exercise training programs were designed to yield the same intensity and achieve the same range of heart rate during each stage of the program. During the training, music was used to set the tempo of the workouts. At the 8th week, it was found that resting heart rate and systolic blood pressure significantly-increased only in the STE and COM groups. After 16 weeks, the experiment results showed the significant improvement in the COM and STE groups of exercise training for beta-CrossLaps, P1NP NMID Osteocalcin and bone formation (PINP/beta-CrossLaps x0.31) but not in the RES group. For balance ability, the COM group showed significantly greater change than the RES group after the training intervention (p < 0.05). It can thus be concluded that the STE and COM training were effective in improving bone formation (PINP/beta-CrossLaps x 0.31) but not in the RES group. For balance ability, the COM group showed more significant change than the RES group. Therefore, this is not only a good exercise choice for the working-age people but also it can help reduce the risks of osteoporosis and falling in women in particular. PMID- 26529815 TI - Effects of Low Impact Aerobic Dance and Fitball Training on Bone Resorption and Health-Related Physical Fitness in Thai Working Women. AB - OBJECTIVE: To investigate the effects of low impact aerobic dance and fitball training on bone resorption in Thai working women. MATERIAL AND METHOD: The samples of this study consisted of 47 females at the age from 35-45. The subjects were divided into two groups: A) 23 females in a low impact aerobic dance (20 min) and fitball (15 min) training group, and B) 24 females in a low impact aerobic dance training group (35 min). Both groups wore a heart rate monitor during the exercise training. The sessions in the training program over 12 weeks were performed a 3-day a week, 35-minute for work out per session at an intensity of 60-80% of maximum heart rate. Before and after the 12-week training program, bone resorption (Telopeptidecrosslinked: beta-CrossLaps) and bone formation (N terminal propeptine of procollagen type 1: P1NP) including physiological and fitness data were assessed. The data of pre and post trainings within and between the groups as well as the data of changes in dependent variables were compared and analyzed by using paired t-test and independent-test. The statistically significant difference was set at the 0.05 level. RESULTS: Both the low impact aerobic dance and fitball training group and the low impact aerobic dance training group revealed their lower level of bone resorption (beta-CrossLaps) while the first group showed statistically significant change (p < 0.05). In addition, there were no significant changes of bone resorption (beta-CrossLaps) and bone formation (P1NP) between these two groups. However; both groups had not only a significant decrease in resting heart rate, systolic and diastolic pressure, but also an increase in muscular strength and endurance and maximum oxygen uptake when the training was completed. Flexibility ofthe group withfitball was increased significantly (p < 0.05). CONCLUSION: Low impact aerobic dance and fitball training has the positive effect of slowing down bone resorption and is beneficial to healthy bones. They concurrently increase lower back flexibility. PMID- 26529816 TI - A Comparison between the Effects of Aerobic Dance Training on Mini-Trampoline and Hard Wooden Surface on Bone Resorption, Health-Related Physical Fitness, Balance, and Foot Plantar Pressure in Thai Working Women. AB - OBJECTIVE: To compare the effects of aerobic dance training on mini-trampoline and hard wooden surface on bone resorption, health-related physical fitness, balance, and foot plantar pressure in Thai working women. MATERIAL AND METHOD: Sixty-three volunteered females aged 35-45 years old participated in the study and were divided into 3 groups: A) aerobic dance on mini-trampoline (21 females), B) aerobic dance on hard wooden surface (21 females), and C) control group (21 females). All subjects in the aerobic dance groups wore heart rate monitors during exercise. Aerobic dance worked out 3 times a week, 40 minutes a day for 12 weeks. The intensity was set at 60-80% of the maximum heart rate. The control group engaged in routine physical activity. The collected data were bone formation (N-terminal propeptine of procollagen type I: P1NP) bone resorption (Telopeptide cross linked: beta-CrossLaps) health-related physical fitness, balance, and foot plantar pressure. The obtained data from pre- and post trainings were compared and analyzed by paired samples t-test and one way analysis of covariance. The significant difference was at 0.05 level. RESULTS: After the 12-week training, the biochemical bone markers of both mini-trampoline and hard wooden surface aerobic dance training subjects decreased in bone resorption (beta-CrossLaps) but increased in boneformation (P1NP). Health-related physical fitness, balance, and foot plantar pressure were not only better when comparing to the pre-test result but also significantly different when comparing to the control group (p < 0.05). The aerobic dance on mini-trampoline showed that leg muscular strength, balance and foot plantar pressure were significantly better than the aerobic dance on hard wooden surface (p < 0.05). CONCLUSION: The aerobic dance on mini-trampoline and hard wooden surface had positive effects on biochemical bone markers. However, the aerobic dance on mini-trampoline had more leg muscular strength and balance including less foot plantar pressure. It is considered to be an appropriate exercise programs in working women. PMID- 26529817 TI - Cost-Utility Analysis of Osteoporotic Hip Fractures in Thais. AB - A prospective study was conducted among osteoporotic hip fracture in 2008. It was aimed to assess cost per quality adjusted life year (QALY) of hip fracture in the context of a developing country. The patients who were diagnosed as hip fracture and admitted to the orthopedic wards were included. Any pathological fractures or missing data were discarded from the analysis. Median cost was evaluated from a societal perspective. EQ-5D was used to assess health utility state and then converted into a time trade off Cost per QALYwas estimated at one year of follow up. Forty-two patients completed a quality of life assessment. The average age was 75.6 years old and 71% were female. Most of them were undergone either hemiarthroplasty or internal fixation. The median total cost per year was US$ 4,210.60. The median QALY was 0.636 and cost per QALY was US$ 6,620.52. Cost utility of a hip fracture in Thai setting was lower than other developed countries due to strong family support and insufficient rehabilitation. However it has high impact on 78.8% of the Thai Gross National Product. Prevention of hip fracture is needed in underdeveloped countries as much as others, worldwide. PMID- 26529818 TI - Effect of a Short-Term Treatment with Once-A-Week Medication of Alendronate 70 Mg on Bone Turnover Markers in Postmenopausal Women with Osteoporosis. AB - OBJECTIVE: The study was carried out to evaluate safety and efficacy of once-a week medication of Kasparalendronate for inhibiting high bone turnover rate. MATERIAL AND METHOD: Forty-nine postmenopausal osteoporotic participants were included in the study. This investigation was carried out as an open study. The participants received the drug every weekfor 12 weeks. Pain, drugside effects and bone turnover markers were evaluated at the 6"' week and 12' week after the first visit. RESULTS: None had significant complication and all could complete the trial. Thirteen participants, (26.3%), had minimal side ffects, which the trial drug could be administered until the end ofstudy. At the 12th week follow-up, 42/49 participants (85.7%) had normal serum Beta-crosslab and 45/49 participants (91.8%) had normal serum N-MID osteocalcin. None showed any decrease in serum P1NP All participants had slight reduction in serum alkaline phosphatase. CONCLUSION: The trial drug could inhibit high bone turnover in about 85% of post menopausalparticipants within 12 weeks of drug administration and no severe side effect took place. PMID- 26529819 TI - The Impacts of Early Hip Surgery in High-Risk Elderly Taking Antithrombotic Agents and Afflicted with Intertrochanteric Fracture. AB - OBJECTIVE: To compare the outcome of early hip surgery in intertrochanteric fracture between high surgical risk patients receiving antiplatelet and anticoagulant drugs and those who did not. DESIGN: Retrospective study. MATERIAL AND METHOD: One hundred and four elderly patients with intertrochanteric fracture and having American Society of Anesthesiologist grade III-IV who underwent early hip surgery (within 72 hours after admission) with proximalfemoral nail anti rotation (PFNA), were recruited and allocated into two group: antiplatelet and anticoagulant (AA-AC) group (n = 65), and no drug group (n = 39). Perioperative and postoperative outcomes were recorded and analyzed. RESULTS: The mean age was 81?8 years. The overall 1-year mortality was 6.7% (7 patients: 5 AA-AC group, and 2 no drug group, p = 0.7). Intra-operative blood loss in AA-AC group and No drug group were 87 +/- 70 and 91 +/- 65 ml, respectively (p = 0.74). There was no significant difference in blood transfusion, postoperative complications, and 1 year ambulatory status between both groups (p > 0.05 all). However, AA-AC group showed significant longer in duration of hospital stay compared with no drug group (p = 0.02). CONCLUSION: Early hip fracture surgery with PFNA in patients who received antiplatelet and anticoagulant medications is safe and does not significantly increase perioperative blood loss, blood transfusion, and postoperative mortality and morbidity. PMID- 26529820 TI - The Association of Bone Mineral Density and G2014A Polymorphism in the Estrogen Receptor Alpha Gene in Osteoporotic Hip Fracture in Thai Population. AB - OBJECTIVE: This study aimed to determine the association of a recent identified G2014A single nucleotide polymorphism (SNP) genotype distribution in exon 8 of the estrogen receptor in postmenopausal Thai women. MATERIAL AND METHOD: A prospective study was conducted at Ramathibodi Hospital between July 2005 and July 2006. Postmenopausal Thai women, aged more than 55 years and had sustained osteoporotic hipfracture, were included. Exclusion criteria were renal and metabolic bone diseases. Age, body mass index (BMI), blood tests for metabolic bone disease, and G2014A SNP genotype, bone mineral density (BMD) were collected. The relationship between the degree of osteoporosis (normal, osteopenia, and osteoporosis) and SNP genotype was analyzed by Fisher's exact test. RESULTS: Sixty-five postmenopausal women with osteoporosis were included. The average age was 76.2 +/- 10.9 years old, and the average BMI was 21.3 +/- 3.5 kg/m2. The data expressing the genotype distribution of gene G2014A SNP were G/G 23.1%, G/A 29.2% and A/A 47.7%. There was no statistical difference between age and BMI in each genotype. Gene G2014A was associated with osteoporosis of lumbar spine, femoral neck, ward triangle, and femoral neck. CONCLUSION: It could be concluded that a G2014A SNP genotype in exon 8 of the estrogen receptor was associated with postmenopausal women who had osteoporotic hip fracture. PMID- 26529821 TI - Effects of Circuit Aerobic Step Exercise Program on Musculoskeletal for Prevention of Falling and Enhancement of Postural Balance in Postmenopausal Women. AB - OBJECTIVE: The objective of this research was to develop a circuit aerobic step exercise program and to examine the effects of the circuit aerobic step exercise program on bone formation, bone resorption, muscle strength and body balance of the postmenopausal females. MATERIAL AND METHOD: The samples consisted of 52 female participants from Chulalongkorn University, aged between 45-55 years old. The subjects were divided into two groups: 26 females in the circuit aerobic step exercise group (CASE) and 26 females in the control group (CON) by the simple random sampling method. The experimental group participated in the aerobic step exercise program while wearing heart rate monitors. The exercise speed was determined by the rhythm of the music. The experimental group completed two circuits of aerobic step exercise at 6 stations, 3 times per week, for a period of 4 weeks. The intensity is 55-75% of a maximum heart rate. The control group did not participate in the circuit aerobic step exercise program. The collected data of the before and after experiment were the results of physiology test, biochemical bone markers, muscle strength and balance ability. The collected data were compared and analyzed by the mean and standard deviation. The differences of the tests were statistically significant at the 0.05 level. RESULTS: After the 4 week experiment training, the circuit aerobic step exercise group had significantly decreased in resting heart rate and bone resorption (p < 0.05). Muscle strength and balance on normal stability surfaces improved significantly only in the circuit aerobic step exercise group when being compared with the pretest and the control group (p < 0.05). CONCLUSION: The circuit aerobic step exercise had positive effect on bon eformation, muscle strength and body balance. This, therefore, is a good exercise choice for postmenopausal people and can help reduce the risks of falling especially in postmenopausal women. PMID- 26529822 TI - Traumatic Injury in a Child with Scurvy: A Case Report. AB - This case report aimed to describe the clinical presentation, treatments and prognosis of a child who had scurvy and traumatic injury of the left thigh. A 30 month-old boy had presented with left hip pain two weeks after falling down on the floor while walking. He developed pain, warmness of the left hip and thigh, and finally was unable to bear weight. He also had a high fever gingival hemorrhage, dental caries, petechiae, positive rolling test and limited range of motion of the left hip. The radiographs revealed Wimberger's ring and Frenkel line as scurvy. Vitamin C supplement had been prescribed for one week. However, there was no clinical response and magnetic resonance imaging (MR) suggested subperiosteal abscess as well as osteomyelitis of bilateral femurs and tibias. Debridement and biopsy of the left femur were performed and found only subperiosteal blood. A clinical improvement was noted on the second day after surgery. Vitamin C level was reported at 0.03 mg/dl which was very low. Bacterial culture was negative and the pathological findings were callus formation with hemorrhage. The patient continued the treatment for two months and all conditions were healed eventually. In severe scurvy with trauma, prolonged subperiosteal hematoma was susceptible to infection, and may need debridement simultaneously with vitamin C supplement to shorten the clinical course. PMID- 26529823 TI - The Poor Osteoblastic Functions Can Correct by Teriparatide. AB - A study of stimulation of poor osteoblastic function by teriparatide and monitored by bone markers. Eighty-one cases were enrolled with poor osteoblastic functions, which were classified with the values of both markers: NMID Osteocalcin was less than 10.81 ng/ml and the PINP was less than 15.88 ng/ml. Most CTx were below 0.1 ng/ml or at any level. Every case took oral bisphosphanates for at least 2 years. Average age was 68 years old; 79 cases are female the others male. The base line of bone markers: NMID osteocalcin, PINP and CTx are 9.3, 14.3 and 0.08 ng/ml, respectively. The duration of Teriparatide injections was 6 months, dose 20 microgram subcutaneous per day. The blood calcium, uric acid and renal profile were monitored too. The results of98 percent of cases showed that dramatic increase of osteoblastic products and at the second month; all markers increased above the normal values that are indicators of osteoblastic resumes and their activities. The hypercalcemia can occur during treatment (22.2%) and hyperuricemia 12.34%; therefore, blood chemistry and bone markers should be monitored every month as a precaution. PMID- 26529824 TI - Smoking-related deaths linked to a wider range of diseases. PMID- 26529825 TI - Careful assessment key in managing prostatitis. AB - Prostatitis is a common condition estimated to affect up to 30% of men in their lifetime, it is most prevalent in men aged between 35 and 50. Prostatitis is subclassified into: acute bacterial prostatitis, chronic bacterial prostatitis, chronic pelvic pain and asymptomatic inflammatory prostatitis. Acute bacterial prostatitis presents with acute onset pelvic pain which may or may not be related to voiding, lower urinary tract symptoms, sometimes haematuria or haematospermia and systemic symptoms such as fever and rigors. A documented history of recurrent urinary tract infections is the key feature of chronic bacterial prostatitis. Duration of symptoms > 3 months defines chronicity. The key symptom of chronic pelvic pain syndrome is pain. Patients may describe pain during or after ejaculation as their predominant symptom. Clinical assessment includes a thorough history and examination. A digital rectal examination should be performed after a midstream urine (MSU) sample has been collected for urine dipstick, microscopy and culture. The prostate should be checked for nodules. In acute bacterial prostatitis the MSU is the only laboratory investigation required. Chronic pelvic pain syndrome may be multifactorial and part of a more generalised pain disorder. Pelvic floor muscle abnormalities, altered neuroendocrine pathways, chemically induced inflammation, bacterial infection, autoimmune processes, dysfunctional voiding as well intraprostatic ductal reflux mechanisms have all been identified in men with chronic pelvic pain syndrome. PMID- 26529826 TI - New developments in metastatic prostate cancer therapy. AB - Metastatic prostate cancer is still commonly a lethal condition. The concept that 'men with prostate cancer die with rather than of their cancer' has been shown to be false. It is estimated that 10-20% of men in the UK present with locally advanced disease. Median overall survival remains only 3.5 years for men presenting with metastatic disease. The use of LHRH analogues to achieve medical castration has become the gold standard for both locally advanced prostate cancer, combined with radiotherapy, and metastatic disease. Androgen deprivation therapy (ADT) is the standard first-line treatment for advanced disease resulting in improvements in symptoms, radiological findings and PSA levels. Ultimately the majority of men with advanced prostate cancer will develop resistance to ADT Docetaxel is the standard first-line therapy recommended by international guidelines for patients with symptomatic metastatic castrate refractory prostate cancer who are suitable candidates for chemotherapy. More than 90% of patients with castrate refractory prostate cancer have bone metastases. Radium-223 dichloride is a novel alpha-emitting radiopharmaceutical agent, which mimics calcium and therefore targets bone metastases. It is indicated in patients with metastatic castrate refractory prostate cancer who have symptomatic bone metastases without visceral metastases. PMID- 26529827 TI - Improving the diagnosis and management of GORD in adults. AB - Gastro-oesophageal reflux disease (GORD) is defined as a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications. Many patients with GORD complications such as oesophagitis, and up to a third of patients with Barrett's oesophagus have no reflux or heartburn symptoms. Conversely, patients can be symptomatic even when normal reflux levels are found and there is an absence of mucosal damage. Significant GORD symptoms occur at least once a week in 8.8-26% of Europeans, with equal prevalence of symptoms in men and women. The frequency and severity of symptoms do not accurately predict the degree of oesophageal damage. If patients with GORD also describe symptoms of dyspepsia this should be considered first with H. py/oritesting or direct referral for gastroscopy if the patient is over 55 given the risk of gastric cancer in these patients. Oesophageal disease can account for up to 20% of cases of chronic cough. Symptoms of GORD occur in more than 45% of patients with asthma, and erosive oesophagitis on endoscopy has a 50% higher likelihood of a diagnosis of asthma. GORD is a risk factor for Barrett's oesophagus and oesophageal adenocarcinoma. The risk increases with duration, severity and frequency. Endoscopy should not be routinely offered at initial presentation unless the patient has dysphagia or other symptoms suggestive of upper GI cancer. Smoking cessation and weight loss are beneficial in reducing GORD symptoms. Abdominal obesity causes GORD by elevating intra-abdominal pressure, which promotes reflux and the development of hiatus hernia. GORD symptoms are increased by 70% among daily smokers who have been smoking for more than 20 years. PMID- 26529828 TI - UNDERUSE OF SUBLINGUAL MEDICATION. 1915. PMID- 26529829 TI - Acne. PMID- 26529830 TI - How my dog influenced the way I practise. PMID- 26529832 TI - Oral health of individuals aged 3-80 years in Jonkoping, Sweden, during 40 years (1973-2013). I. Review of findings on oral care habits and knowledge of oral health. AB - The aim of the this study was to present data on oral care habits and knowledge of oral health in 2013, and to compare these data with results from a series of four previous cross-sectional epidemiological studies. All these studies were carried out in the city of Jonkoping, Sweden, in 1973, 1983, 1993, 2003, and 2013. The 1973 study constituted a random sample of 1,ooo individuals evenly distributed in the age groups 3, 5, 10, 15, 20, 30, 40, 50, 60, and 70 years. The same age groups with addition of a group of 80-year-olds were included in the 1983, 1993, 2003, and 2013 studies, which comprised 1,104; 1,078; 987; and 1,010 individuals, respectively. A questionnaire about dental care habits and knowledge of oral health was used. The questionnaire contained the same questions in all the five studies, although some had to be slightly modernised during the 40-year period. During the period 1973-2013, a continous increase of individuals in the age group 20-60 years were treated by the Public Dental Service amounting to about 50%. Almost 70% of the 70- and 80-year-olds were treated by private practitioners. In 2013, 10-20% of the individuals in the age groups 30-40 years did not regularly visit neither Public Dental Service nor a private practitioner. The corresponding figures for the individuals 50-80 years old were 4-7%. Similar number of avoidance was reported in the previous studies. In the survey 2013, about 20-30% of the individuals in the age groups 20-50 felt frightened, sick, or ill at ease at the prospect of an appointment with the dentist. These findings were in agreement with the results from the surveys 1973-2003. Among the younger age groups, 0-15 years, a reduction in self-reported "ill at ease" was found in the surveys 2003 and 2013 compared to the previous surveys in this series. In 2013, the knowledge of the etiology of caries was known by about 60% of the individuals which was similar to that reported 1973-2003. Twenty per cent of the individuals stated that they did not know which etiological factors that causes caries. This percentage was equivalent during the period 1973-2013.About 85% of the individuals in all age groups brushed their teeth with fluoride tooth paste at least two times a day. These frequencies have gradually increased during the 40-year period. Around 40% in the age groups 50-80 years used toothpicks regularly in 2013. This is a about 1/3-1/2 less compared to 2003. In the age groups 20-40 years 3-14% used toothpicks for proximal cleaning in 2013. In 2013, about 35% of the individuals never consumed soft drinks, in comparison with 20% in 2003. In the age groups 3-20 years about 20% were consuming soft drinks every day or several times a week,which is a reduction by half compared to 2013. PMID- 26529833 TI - Oral health of individuals aged 3-80 years in Jonkoping, Sweden during 40 years (1973-2013). II. Review of clinical and radiographic findings. AB - The aim of this epidemiological study performed in 2013 was to analyze various clinical and radiographic data on oral health and compare the results to those of four cross-sectional studies carried out 1973-2003. In 1973, 1983, 1993, 2003, and 2013 random samples of 1,000; 1,104; 1,078; 987; and 1,010 individuals, respectively, were studied. The individuals were evenly distributed in the age groups 3, 5, 10, 15, 20, 30, 40, 50, 60, 70, and 80o years. Eighty-year-olds were not included in 1973. All subjects were inhabitants of the city of Jonkoping, Sweden. The clinical and radiographic examination assessed edentulousness, removable dentures, implants, number of teeth, caries, restorations, oral hygiene, calculus, periodontal status, and endodontic treatment. The frequency of edentulous individuals aged 40-70 years was 16, 12, 8, 1, and 0.3% in 1973, 1983, 1993, 2003, and 2013, respectively. No complete denture weareryounger than 80 years old was found in 2013. During the 40-year period, the mean number of teeth in the age groups 30-80 years increased. In 2013, the 60-year-olds had nearly complete dentitions. Implants were found in all age groups from 30 years of age. The total number of individuals with implants was 36 in 2013. This was higher than earlier surveys, 4 in 1993, and 18 in 2003. The percentage of children and adults without caries and restorations increased during the 40-year period. It was found that the percentage of caries-free 3- and 5-year-olds were 79% and 69%, respectively, of the individuals in 2013. In the age groups 10-20 years, the percentage of caries-free individuals increased between 2003 and 2013. In 2013, 43% of the 15-year-olds were completely free from caries and restorations compared to 20% in 2003. In all age groups 5-60 years, DFS was lower in 2013 compared to the earlier examinations.There was no major change in DFS between 2003 and 2013 in the age groups 70 and 80 years. The most obvious change was the decrease in number of FS over the 40-year period of time. Regarding crowned teeth the most clear changes between 1973 to 2013 were the decrease in percentage of crowned teeth in the age groups 40 and 50-year-olds. The percentage of endodontically treated teeth decreased between 1973 and 2013 in all age groups. In age groups 10-30-year-olds a major reduction from about 30% to 15% in mean plaque score was seen between 1973-2003. Only a minor change in plaque score was seen during the last decade. For the age groups 40 years and older, a decrease in the percentage of surfaces with plaque was observed between 2003-2013. The percentage of tooth sites with gingivitis was for 20 years and older about 40% in 1973. In 2013, the percentage was about 15%. The frequency of sites with gingivitis was generally lower in 2013 compared with the otheryears,1973-1993. The percentage of individuals with probing pocket depths > 4mm increased with age. Between 2003-2013 a clear reduction was seen in all age groups in frequency of individuals with probing pocket depth > 4mm. Over the 40-year period an increase in the number of individuals with no marginal bone loss and a decrease in the number of subjects with moderate alveolar bone loss were seen. The continuous improvement in oral health and the reduced need of restorative treatment will seriously affect the provision of dental helath care and dental delivery system in the near future. PMID- 26529834 TI - Diagnoses and treatment proposals in periodontal treatment. A comparison between dentists, dental hygienists and undergraduate students. AB - The aim of this study is to find out how professionals in Swedish dental care perform diagnostic procedures in general. Is there a common ground between dentists and dental hygienists concerning sharing different job assignments in an effective way? Are the methods of treatment used in accordance with degree of severity of the disease and to what extent is proposed treatment in accordance with the National Guidelines? A questionnaire consisting of three different patient cases with periodontal disease was sent to 804 private practitioners, 809 dentists in Dental Public Service, 802 dental hygienists and 40 dental students on their final semester at the Dental School in Malmo. The questionnaire was completed by 1,103 respondents (47%). A majority of all practitioner groups (94%) found that a relatively healthy patient had disease, the risk for developing further disease was deemed none too low by 97%, but 91% wanted to give preventive care. A vast majority suggested more dental care to healthy patients as compared to patients with severe periodontal disease. In Conclusion the two groups, i.e. dentists and dental hygienists, did not to a sufficiently high degree share views on diagnosis and treatment, in order to optimize the resources in dentistry. The delivery of dental care was not in line with the severity of disease and too much attention was paid to the needs of relatively healthy persons. To change this pattern, the incentives in and structure of the national assurance system could be adapted. Furthermore, the knowledge basis for periodontal diagnosis and treatment needs, with special reference to the National Guidelines, should to a higher degree be shared by all caregivers. PMID- 26529835 TI - What factors can be protective for both self-rated oral health and general health? AB - The aim of this study was to analyze if the same protective factors are significant for both self-rated health and oral health. It was hypothesized that these factors should be the same. The material is based on a population sample of 17 113 women and men aged 18-84 years in one county in central Sweden.The response rate was 61%. The data were collected through a postal questionnaire "Life and Health" in 2008. The questionnaire comprised of 149 questions and was divided into a number of areas, e.g. socioeconomic conditions, quality of life, social relations, lifestyle, and health. To analyze the strength of the protective factors whilst taking into account the relationships between the various independent variables, multivariate analyses were conducted using binary multiple logistic regression. The outcome measures with the strongest association to general health is belonging to the age group 18-34 years, positive faith in the future, good sleeping pattern and to be employed/self-employed/retired. The outcomes with the strongest association to oral health are good finances, belonging to the age group 18-34 years, to be born in Sweden and positive faith in the future. Conclusions. This study shows that, in general, the same protective factors are significant for both self-rated health and self-rated oral health, making it possible to use the same approach to strengthen both general health and oral health. One important outcome, not often considered, is having positive faith in the future. It is a task for the health care system to strengthen people's faith in the future, partly through a very high quality care when needed, but also through active health promotion that increases the chances of a healthy life, both from a public health perspective as from an oral health perspective. PMID- 26529836 TI - Dental fear among children and adolescents in a multicultural population--a cross sectional study. AB - The aim of this study was to explore dental fear in a multicultural population of child and adolescent dental patients, with background, gender, age, and socioeconomic status taken into account. A specific aim was to investigate whether the level of DF differed between patients with a non- Swedish background and patients with a Swedish background. In conjunction with a routine visit to the dental clinic, 301 patients (8-19 years old) assessed their dental fear on the Children's Fear Survey Schedule - Dental Subscale, using self-ratings. Following an interview protocol, patients' and their parents' country of birth, and parents' education and occupation/employment were registered. An interpreter was present when needed. Self-rated dental fear was almost equal among patients coming from a non-Swedish background and patients with a Swedish background. Girls scored higher than boys and younger children scored slightly higher compared to older children, but the pattern of dental fear variation was inconsistent. Socioeconomic status differed between the groups with a non-Swedish vs. a Swedish background, but no impact on dental fear was revealed. When children and adolescents with a non-Swedish vs. a Swedish background were modelled separately, female gender and younger age had an impact on dental fear only in the group with a Swedish background. No differences in dental fear were found between children and adolescents from non-Swedish vs. Swedish backgrounds. Dental fear variations according to gender and age were more pronounced in the group with a Swedish background compared to the group with a non-Swedish background. No impact of socioeconomic status could be revealed. PMID- 26529837 TI - Using clinical cases to stimulate active learning in a short periodontal continuing professional development course. AB - A case-based approach was used in a two-day periodontal continuing professional development course as a strategy to stimulate active learning. The present study investigates the outcome of this course format in terms of feasibility, perceived efficiency as a learning approach and reported individual learning goals. The study was performed in five identical courses entitled'risk analysis and treatment in periodontal patients'at Malmo University between 2011-2014. Before the course, clinical cases were used to activate participants' prior knowledge and to attune their focus on the course content. During the course, cases were discussed to synchronise theory with practical application. A pre- and end-course questionnaire were developed to evaluate participants' characteristics (age, clinical expertise, experience and expectations), perceptions on feasibility and instructiveness and emerged individual learning goals. The participants (39 dentists and 78 dental hygienists) reported an average preparation time of 62 minutes (range 2-190) and had positive perceptions on the accessibility, instructiveness and difficulty of cases. Expectations ranged between refreshing, acquiring new knowledge and mastering the course subject. Most reported learning goals were related to daily clinical practice including the development of a treatment plan, when to continue non-surgical treatment or to extract teeth/perform surgery, the approach to periodontitis, how to motivate non compliant patients and when to refer. Conclusion: The use of clinical cases to stimulate active learning in a short-term continuing professional development periodontal course was positively perceived by the dentists and dental hygienists in terms of feasibility and learning potential. PMID- 26529838 TI - Protein and bacteria binding to exposed root surfaces and the adjacent enamel surfaces in vivo. AB - Exposure of root surfaces due to inflammatory tissue breakdown is a clinical characteristic of periodontitis. The gingival margin may further recede during treatment. Pellicles and early dental plaque on enamel surfaces of periodontitis patients have previously been described. The binding properties of exposed root surfaces, which may affect the incorporation of proteins from especially the GCF into the enamel pellicle and thereby early dental plaque formation are largely unknown. The aim of this study was to examine if exposed root surfaces could affect pellicle and initial dental plaque formation on the enamel surface by the analysis of proteins and early adhering bacteria binding to the exposed root surfaces and to the adjacent, gingival enamel surface. Supragingival pellicle and plaque samples were taken from exposed root surfaces and the adjacent enamel surfaces in eleven surgically treated periodontitis patients. For comparison, samples were taken from enamel surfaces of teeth not in need of treatment. Additionally, subgingival bacterial samples were taken. Pellicle proteins were analysed by SDS-PAGE, immunoblotting and image analysis, and bacterial samples by culturing. Significantly more plasma proteins and bacteria were found on the exposed root surfaces than on the enamel. The depth of the gingival recessions was negatively correlated to the amount of plasma proteins in the enamel pellicle. Actinomyces spp. were most frequently found on the exposed root surfaces. The total viable counts and streptococci (%TVC) were positively correlated between subgingival samples and samples from the root surface and enamel of surgically treated teeth. A positive correlation was also found for the findings of Gram-negative anaerobes in subgingival samples and samples from the enamel surface. Our findings suggest that an exposed root surface has binding properties different from an enamel surface and could affect early biofilm formation on the adjacent enamel surface. PMID- 26529839 TI - Oral health and oromotor function in rare diseases--a database study. AB - The aim was to study oral health and oromotor function in individuals with rare diseases. A disease is defined as rare when it affects no more than 100 individuals per million population and leads to a marked degree of disability. An affected nervous or musculoskeletal system, cognitive impairment, neuropsychiatric disorders and craniofacial malformations are common in rare diseases and may all be risk factors for oral health and oromotor function. In 1996-2008, 1,703 individuals with 169 rare diseases, aged 3-67 years, answered a questionnaire about general health, oral health and orofacial function and 1,614 participated in a clinical examination. A control group of 135 healthy children, aged 3-14 years, was also included in the study. Oral health was examined by a dentist and oromotor function by a speech-language pathologist. The participants with rare diseases were recruited via family programmes, referrals to the clinic and research projects, while the controls were randomly selected from a Swedish municipality. In the diagnosis group, 40% had moderate or severe problems coping with dental treatment, 43% were receiving specialised dental care. Difficulties related to tooth brushing were common compared with the controls. Approximately two thirds of the study group and the control group were caries free. Frontal open bite, long face and high palate were common in individuals with rare diseases compared with controls. Oromotor impairment was a frequent finding (43%) and was absent among the controls. There was a significant correlation between oromotor impairment and certain structural deviations and oral-health issues. Compared with healthy controls, individuals with rare diseases often have difficulty coping with dental treatment and managing tooth brushing. Dysmorphology and oromotor dysfunction are frequent findings in this population and they often require extra prophylactic dental care and access to specialised dental care in order to prevent oral disease. PMID- 26529840 TI - The influence of immigrant background on the choice of sedation method in paediatric dentistry. AB - The effects of immigration on the demographics of the Swedish population have changed the situation for many dental care providers, placing increased demand on cultural competence. The aim of this investigation was to study the choice of sedation method among children with immigrant background, referred to paediatric dentistry specialists, because of behaviour management problems or dental fear in combination with treatment needs. The material consisted of dental records from children referred to two clinics for paediatric dentistry: 117 records from children with an immigrant background and 106 from children with a non-immigrant background. Information about choice of sedation method (conventional treatment, conscious sedation with midazolam, nitrous oxide, or general anaesthesia) and dental status was collected from the records. The number of missed appointments (defaults) was also registered. Binary logistic regression analyses were used to calculate the influence of potential predictors on choice of sedation method. The mean age of the patients in the immigrant group was 4.9 yrs, making them significantly younger than the patients in the non-immigrant group (mean 5.7 yrs). In the immigrant group, 26% of the patients defaulted from treatments, while the corresponding frequency was significantly lower for the reference group (7%). The numbers of primary teeth with caries and permanent teeth with caries were positively and significantly correlated with the choice of treatment under general anaesthesia. Conscious sedation was used significantly more often in younger children and in the non-immigrant group, while nitrous oxide was preferred in the older children. In conclusion, conscious sedation was more frequently used in the non-immigrant group. The choice of sedation was influenced by caries frequency and the age of the child. PMID- 26529842 TI - The key interrelationships that influence behavior over time. PMID- 26529841 TI - Dental caries and associated factors in a group of Swedish snus users. AB - The aim of this study was to investigate the effects of the Swedish moist powder tobacco product known as "snus" on dental caries and to measure the pH fall in dental plaque. The subjects comprised male and female adults between 26 and 62 years of age (n = 102), all habitual snus users for >= 10 years. The control group (n = 101) consisted of similar individuals in terms of gender, age and educational level but with no tobacco use for >= 10 years. A clinical and radiographic examination and a questionnaire were completed. The pH fall after a sucrose rinse was estimated in situ in 10 randomly selected subjects per group. The salivary secretion rate was higher in snus users than non-users (2.5 vs 2.2 ml/min, p = 0.005).There was no statistically significant difference regarding salivary buffer capacity. No differences were found between the two groups in terms of the plaque index, primary or secondary enamel and dentine caries, DFS and salivary counts of mutans streptococci or lactobacilli. The pH fall was somewhat more pronounced among non-users compared with snus users (NS). Snus users had a lower intake of snacks between meals and a less frequent intake of cookies (p = 0.000). Furthermore, snus users had a mean gingival index (+/- SD) for the whole dentition of 20.4 +/- 18.2, while the index for non-users was 14.4 +/- 13.9 (p = 0.09); the corresponding values for teeth 13-23 were 14.9 +/- 20.6 and 7.7 +/- 11.9 respectively (p = 0.003). To conclude, this clinical study revealed no statistically significant differences in caries prevalence between snus users and non-users and only minor differences regarding different caries associated factors. PMID- 26529843 TI - Interview With Joel T Allison, FACHE, CEO of Baylor Scott & White Health. PMID- 26529844 TI - The Scale Imperative for Academic Medical Centers: Part 2--Case Study. PMID- 26529845 TI - The Mayo Model of Community Care: Integrating Population Health and Patient Experience Initiatives for Efficient Reform. PMID- 26529846 TI - Organizational Characteristics Associated With Fundraising Performance of Nonprofit Hospitals. AB - Fundraising has become increasingly important to nonprofit hospitals as access to capital has grown more difficult and reimbursement for services more complex. This study analyzes the variation in organizational characteristics and fundraising performance among nonprofit acute care hospitals in the United States to identify and measure critical factors related to one key fundraising performance indicator: public support. Results indicate that the presence of an endowment, along with its value, investments in fundraising, and the geographic location of the organization, account for approximately 46% of variance in public support among nonprofit hospitals. The use of a separate foundation for the fundraising operation is not necessarily associated with measures of fundraising success; however, a majority of hospitals do use a foundation, signaling a strategic choice that may be made for numerous reasons. The study results and limitations are discussed and recommendations are made for maximizing the effectiveness of the fundraising enterprise within nonprofit hospitals. Increasing awareness of challenges associated with fundraising success will enhance the strategic management of fundraising operations by hospital executives and board members. PMID- 26529847 TI - Practitioner application. PMID- 26529848 TI - Physical Work Environment as a Managerial Tool for Decreasing Job-Related Anxiety and Improving Employee-Employer Relations. AB - The expected increase in healthcare needs resulting from the Affordable Care Act and the growing population of older citizens in the United States is challenging owners and operators of hospitals to improve quality of care and reduce operational costs. Meanwhile, studies have indicated a serious shortage in the healthcare workforce and have highlighted the critical role of employees' job related attitudes and feelings. The main objective of this study was to test whether employees' evaluations of important environments within hospitals were significantly associated with their job-related attitudes and feelings, and whether this relationship varied across different demographic groups. About 700 healthcare professionals from 10 acute-care hospitals run by three healthcare organizations participated in this cross-sectional study. Structural equation modeling found that employees' evaluations of their physical work environment were significantly associated with lower rates of job-related anxiety, higher levels of job satisfaction, and increased rates of organizational commitment. Perceived organizational support was responsible for mediating part of these relationships, indicating that employees can perceive a healthy work environment as a sign of their organization valuing them and caring about their well-being. When distinguishing between different spaces, analysis found that satisfaction with rest areas and work spaces had the largest effect size, while the influence of patient areas was small. Employees newer to the facility and to the organization were more influenced by the physical work environment. This study provides preliminary evidence that facility design can be used as a managerial tool for improving employees' job-related attitudes and feelings and earning their commitment. PMID- 26529849 TI - Practitioner application. PMID- 26529850 TI - Burnout Among Primary Care Physicians: A Test of the Areas of Worklife Model. AB - Examinations of the current state of the physician workforce, in the United States and globally, indicate a declining overall well-being, and specifically increasing levels of burnout. The consequences of these effects include early retirements or exits from the medical profession, difficulties improving the patient experience, and low levels of provider engagement with clinic-level and system-level initiatives. Such consequences affect physicians, healthcare organizations, and patients. While most research has focused on identifying burnout, cataloging its effects, and creating a case for attending to its impact, relatively few studies have focused on exploring the antecedents of burnout for physicians. The goal of this study was to test an etiological model, the Areas of Worklife Scale (AWS), for practicing primary care physicians. Using the AWS and the Maslach Burnout Inventory, the study used a longitudinal survey research design method to query primary care physicians employed at a large integrated delivery system in the United States. Data collected successfully fit the AWS model for burnout among primary care physicians, supporting our theory that workplace drivers are responsible for burnout. Workload, control, and values congruence are the largest drivers of burnout for practicing primary care physicians. The AWS model provides key insights into the domains of work that cause stress and ultimately burnout for physicians, and these domains can guide physicians and managers to develop interventions to fight the rising incidence of burnout. PMID- 26529851 TI - Practitioner application. PMID- 26529852 TI - Pathophysiology of Pain. PMID- 26529853 TI - How to Assess Pain? PMID- 26529854 TI - Management of Acute Pain. PMID- 26529855 TI - Back Pain: A Simplified Guide. PMID- 26529856 TI - Role of Interventional Pain Management in Pain Practice. PMID- 26529857 TI - Role of Physiotherapy in Pain Management. PMID- 26529858 TI - Psychogenic Pain Disorder--Differential Diagnosis and Treatment. PMID- 26529859 TI - Aplastic Anaemia. PMID- 26529860 TI - Epidemiology, Pathogenesis and Diagnosis of Aplastic Anaemia. PMID- 26529861 TI - Aplastic Anaemia in Children. PMID- 26529862 TI - Immunosuppressive Therapy for Aplastic Anaemia. AB - Immunosuppressive therapy is the standard of care in aplastic anaemia in younger patients who do not have a matched sibling donor, and also in adults and older patients. Hence, a large population of patients with aplastic anaemia undergo this treatment. In patients who have responded to the first course of ATG, and have had a relapse, a second course of ATG can be administered with reasonable response rates. Response rates to first course of ATG vary from 50-85% in both children and adult. Indian data also suggests similar response rates. PMID- 26529863 TI - Stem Cell Transplantation in Aplastic Anaemia. PMID- 26529864 TI - Supportive Care and Newer Therapies in Aplastic Anaemia. PMID- 26529865 TI - Epidemiology, Clinico-Haematological Profile and Management of Aplastic Anaemia: AIIMS Experience. AB - BACKGROUND: The incidence of aplastic anaemia (AA) is higher in Asia than in the West. The precise incidence of AA in India is not known due to lack of epidemiological study. 20-40% of pancytopenic patients in referral centres are of aplastic anaemia. PATIENTS AND METHODS: This was an analysis of 1501 patients diagnosed with aplastic anaemia over a period of seven and half years (January 2007- June 2014) attending the Aplastic clinic of department of haematology of All India Institute of Medical Sciences, New Delhi. The details regarding medical history, physical examination, complete blood count, bone marrow aspirate and biopsy, treatment received, were retrieved. Inherited bone marrow failure was screened in patients below 35 years. Treatment response was analysed for various treatment modalities. RESULTS: 1501 patients of AA from 20 different states of India were analysed. The bulk of patients were from Uttar Pradesh (28.7%), Bihar (23.6%), Delhi/NCR (20%) and Haryana (7%).The average number of new aplastic anaemia patients enrolled per year 214 (range: 101 -263). The median age at presentation was 25 years (range 2-83),with M;F - 2.3:1. Severity of AA revealed: severe (SAA): 75%, very severe (VSAA): 15%, non-severe (NSAA): 10%. Inherited bone marrow failure syndromes constituted 5% (75 patients) of all aplastic anaemia patients. The most common clinical presentations were pallor (97%), bleeding manifestations (69.6%) and fever (54%). The haematological parameters showed: median level of haemoglobin level: 5.9 gm/dL, WBC: 2700/mm3, ANC: 380/mm3, platelet: 1 0000/mm3. PNH clone was present in 13.5% of patients. 107 patients (7%) were lost to follow up or expired before any treatment was initiated. Only 69 patients (4.5%) received treatment with HLA-matched sibling stem cell transplantation and another 232 (15.5%) patients received ATG plus cyclosporine as immunosuppressive therapy. Seven hundred thirteenpatients (47.5%) received cyclosporine. The overall response to various treatment modalities was: HLA matched sibling haematopoietic stem cell transplant: 75.3%, Anti-thymocyte globulin plus cyclosporine: 58.7%, cyclosporine plus androgen: 45.6%, cyclosporine alone: 32.2%. CONCLUSION: Management of AA is a real challenge in developing countries.This is one of the largest case series from a single centre from India. It is our endeavour to reduce the detrimental outcome by increasing awareness among patients and referring physicians to reduce the delay between diagnosis and treatment. PMID- 26529866 TI - Immunosuppressive Therapy and Bone Marrow Transplantation for Aplastic Anaemia- The CMC Experience. AB - This is a single centre experience on the use of immunosuppressive therapy (IST) and stem cell transplantation (SCT) in patients with aplastic anaemia. Between 1985 and December 2013, 530 patients underwent IST while 214 underwent allogeneic SCT. Overall response rate with the use of IST was 58% with higher responses seen in adults (65.1%) compared to children (35.8%) [p = 0.001]. At a median follow up of 34 months (range: 1 - 264), 5 year KM estimates for OS for the entire group is 68.2 +/- 2.2%. Loss of response or relapse was seen in 27 responders while clonal evolution to PNH was seen in 8 patients and transformation to MDS or AML was seen in 3. The 5 yr OS for children (45.7 +/- 4.7%) was significantly lower than the OS of age groups 16-30 (75.6 +/- 3.6%), 31-50 years (76.2 +/- 4.2%) and > 50 years (73.0 +/-4.2%) (p = 0.0001). SCT was performed in 214 patients with engraftment seen in 91%. The incidence of grade II-IV acute graft versus host disease (GVHD) was 38.4% with grade III-IV GVHD in 11.7%. Chronic GVHD was seen in 47.5% of evaluable patients with majority (73%) being limited chronic GVHD. At a median follow up of 32 months (range: 1 - 244), the 5 year KM estimates of OS for the entire cohort is 64.8 +/- 3.3%); The 5 yr OS was significantly higher with the use of Flu/Cy (5 yr OS of 73.8 +/- 3.6%) compared to Cy/ATG (5 yr OS of 44.4 +/- 9.6%) or Flu/Bu conditioning (5 yr OS of 52.4 +/- 8.9%) [p = 0.001]. Imp: SCT and IST offer good response rates and survival in Indian patients with AA except in children receiving IST. PMID- 26529867 TI - REDEFINING A VALUE EQUATION. PMID- 26529868 TI - IMPROVING INDIVIDUAL PROVIDER PATIENT SATISFACTION SCORES IN CARDIOLOGY. PMID- 26529869 TI - IMPLEMENTING THE CHRONIC CARE MODEL: A GRASSROOTS APPROACH. PMID- 26529870 TI - THE RISE OF THE CHIEF EXPERIENCE OFFICER. PMID- 26529871 TI - IS IT TIME TO RE-EVALUATE THE C-SUITE? PMID- 26529873 TI - TOP 10 SURVIVAL TIPS FOR PHYSICIANS MOVING FROM VOLUME TO VALUE. PMID- 26529872 TI - THE SNOWFLAKE THEORY: A PRACTICAL GUIDE TO BUILDING AN ACO. PMID- 26529874 TI - LEARNING BY DOING: DEVELOPING PHYSICIAN LEADERS THROUGH ACTION. PMID- 26529875 TI - THE PHYSICIAN LEADER'S ROLE IN PROMOTING ORGANIZATIONAL JUSTICE. PMID- 26529876 TI - FROM CRITICAL DECLINE TO UNPRECEDENTED SUCCESS: AN L'TACH TURNAROUND STORY. PMID- 26529877 TI - THE HIGH COST OF CURE: DOCTORS WADE INTO THE DRUG-PRICING BATTLES. PMID- 26529878 TI - PAY ATTENTION! PMID- 26529880 TI - THE FIVE FUNDAMENTAL TASKS OF A TRANSFORMATIONAL LEADER. PMID- 26529879 TI - FROM MEDICAL DECISION-MAKING TO MEDICAL-COST-COMPARATIVE DECISION-MAKING. PMID- 26529881 TI - GENERATING STAFF BUY-IN FOR THE PATIENT-CENTERED MEDICAL HOME. PMID- 26529882 TI - YOU CAN LEAVE YOUR HAT ON. PMID- 26529883 TI - A FEW MINUTES WITH ASSOCIATION BOARD CHAIR HODA ASMAR. PMID- 26529884 TI - PRESIDENT'S MESSAGE. PMID- 26529885 TI - UNDERSTANDING OR NURSES' REACTIONS TO ERRORS AND USING THIS UNDERSTANDING TO IMPROVE PATIENT SAFETY. AB - The operating room can be home to many different types of nursing errors due to the invasiveness of OR procedures. The nurses' reactions towards errors can be a key factor in patient safety. This article is based on a study, with the aim of investigating nurses' reactions toward nursing errors and the various contributing and resulting factors, conducted at Kurdistan University of Medical Sciences in Sanandaj, Iran in 2014. The goal of the study was to determine how OR nurses' reacted to nursing errors with the goal of having this information used to improve patient safety. Research was conducted as a cross-sectional descriptive study. The participants were all nurses employed in the operating rooms of the teaching hospitals of Kurdistan University of Medical Sciences, which was selected by a consensus method (170 persons). The information was gathered through questionnaires that focused on demographic information, error definition, reasons for error occurrence, and emotional reactions for error occurrence, and emotional reactions toward the errors. 153 questionnaires were completed and analyzed by SPSS software version 16.0. "Not following sterile technique" (82.4 percent) was the most reported nursing error, "tiredness" (92.8 percent) was the most reported reason for the error occurrence, "being upset at having harmed the patient" (85.6 percent) was the most reported emotional reaction after error occurrence", with "decision making for a better approach to tasks the next time" (97.7 percent) as the most common goal and "paying more attention to details" (98 percent) was the most reported planned strategy for future improved outcomes. While healthcare facilities are focused on planning for the prevention and elimination of errors it was shown that nurses can also benefit from support after error occurrence. Their reactions, and coping strategies, need guidance and, with both individual and organizational support, can be a factor in improving patient safety. PMID- 26529886 TI - PERIOPERATIVE CERTIFIED NURSES CELEBRATE 20 YEARS OF SPECIALTY CERTIFICATION. PMID- 26529887 TI - [How to become a pharmacist via the medical juries, during the Consulate and the Empire]. AB - The law of Germinal an XI organized the education of pharmacists. It offered two different pathways to become a pharmacist. The first one needed three years in a pharmacy followed by three years of courses in a School of Pharmacy (located in Paris, Montpellier or Strasbourg) and the examination had to be passed in the School. The second one needed eight years in a pharmacy followed by an examination in front of a Medical jury. Medical juries were organized in every department and were composed by three physicians and four pharmacists. An interesting document, a book gathering together all the preparations realized during years 1811, 1812, 1813, collected by Claude Dumeril in many departments, will allow to study what had been asked to the candidates in Rouen, in 1813, and what were reference pharmacopoeias used. PMID- 26529888 TI - [Rise and fall of Lactarium Linas]. AB - The pharmacist Gabriel Linas (1863-1951) founded in Versailles (France), in 1904, a model establishment: the "milk-bank Linas". This article discusses the history of this establishment and the judicial problems of its owner during the First World War. PMID- 26529889 TI - [Portable pharmacies during the 19th century, starting from the example of Reichard' pharmacy in his guided for travelers in Europe (1805)]. AB - The portable pharmacy of Reichard, in his 1805 Guide for travelers in Europe is an example among others of a growing determination to answer the needs of the people to have access to drugs even in absence of health care professionals. One can observe the ultimate result by looking at portable pharmacies offered for sale by companies such as Menier and Pharmacie Centrale de France, but also by individual pharmacists. In spite of favorable changes of health care in all countries during the XXe century, portable pharmacy and kits are still widely proposed for sale, on Internet for example, for frequent diseases, including for pets! PMID- 26529890 TI - [The "catgut's" laboratory of Auguste Fandre in Nancy]. AB - Auguste Fandre, owner of a pharmacy in Nancy since 1906, specializes his enterprise in biological analyses and in the production of sterilized serums and blisters. In 1907, he imagines the "Catgut Fandre". During the First World War, his production becomes enormous and he must reorganize his laboratory. At the beginning of the 1920s, he undertakes the construction of moderns installations behind the pharmacy. These buildings are used up to the 1980s and then the laboratory is transfered to Ludres in the vicinity of Nancy. In the middle of these years, the old buildings are destroyed; they have been replaced by a fallow ground. PMID- 26529891 TI - [Edouard Filhol (1814-1883), a Toulousian scientist under the Second Empire]. AB - After having been internal in pharmacy in Paris in 1835, Edouard Filhol regains his birthplace Toulouse. Professor of chemistry and pharmacy at the pharmacy and Medical school of Toulouse, he becomes director of this school in 1858, he also occupied the pulpit of chemistry to the Faculty of Science of Toulouse. He belonged to many local learned societies like with the Academy of medicine like national associate. It is thanks to him that the museum of natural history was born. He was also a mayor under the Second Empire what will be worth solids enmities then to him. All its activities did not prevent it from making many and varied research having generally a local interest. He has, in particular, studied mineral water, milk, the ryegrass enivrante thus that anthropology and toxicology. PMID- 26529892 TI - [The apothecaries of the quartier de la Harpe in Paris in the 16th and 17th centuries]. AB - Large families of apothecaries, some of them very famous, lived in the Quartier de la Harpe in Paris, on the left bank of Seine, from the 16th to the 17th century. The study confirms a well-established fact that apothecaries practised endogamy, in others words marriage within the same social class. The biographical research includes ten apothecaries, most of whom lived in the rue Saint-Andre-des Arts. PMID- 26529893 TI - [Of the pharmacy of Marine to the industrial pharmacy: a precursor of nanomedicines, Andre Lancien (1885-1938)]. AB - After a biographic reminder on Andre Lancien, pharmacist of Marine, we describe her activities of research. The first ones concern the radium and the uranic by products, but the main part concerns the development of a process of obtaining by electric way of stable colloidal solutions to very fine metallic or metalloidic particles. These colloids were applied to the therapeutics in diverse domains, prefiguring before the term existed what we call now nanomedicine. PMID- 26529894 TI - [The Arabic influence in the "Coloquios dos simples e drogas da India" of Garcia da Orta]. AB - The "Coloquios dos simples e drogas he cousas medicinais de India" (Conversations on the simples, drugs and medicinal substances of India) (1563) of Garcia da Orta is a botanical and pharmacognosy book. The author is a Portuguese physician who studied in the Spanish universities and practiced medicine mainly in India. He studies in short chapters presented in the form of dialogues about sixty simples. Sources to which he refers are indicative of a "classical" training, but also the mark of a curious and open mind to different cultures. The Arabic sources are numerous and mainly concern the identification of substances by abundant synonyms of their names in foreign languages and different medicinal uses that may have been done by the ancient physicians. However, Da Orta is critical with respect to these sources, seeking contradictions and differences of opinion among authors. He confronts them with the oral information collected thanks to a wide network of contacts. PMID- 26529895 TI - [Pharmaceutical heritage]. PMID- 26529896 TI - [Twenty-eighth pharmaceutical brand: S. Letellier and "ophthalmic Eau de Loche"]. PMID- 26529897 TI - [Response to Schmilblick No. 385: an herbal box]. PMID- 26529898 TI - Mechanism of Disyllabic Tonal Reduction in Taiwan Mandarin. AB - This study was designed to test the hypothesis that time pressure is a direct cause of tonal reduction in Taiwan Mandarin. Tonal reduction refers to the phenomenon of the tones of a disyllabic unit being contracted into a monosyllabic unit. An experiment was carried out in which six native Taiwan Mandarin male speakers produced sentences containing disyllabic compound words /ma/+/ma/ with varying tonal combinations at different speech rates. Analyses indicated that increasing time pressure led to severe tonal reductions. Articulatory effort, measured by the slope of F0 peak velocity of unidirectional movement over F0 movement amplitude, is insufficient to compensate for duration-dependent undershoot (in particular, when time pressure exceeds certain thresholds). Mechanisms of tonal reduction were further examined by comparing F0 velocity profiles against the Edge-in model, a rule-based phonological model. Results showed that the residual tonal variants in contracted syllables are gradient rather than categorical--as duration is shortened, the movement towards the desired targets is gradually curtailed. PMID- 26529899 TI - Perceptions of Gender and Femininity Based on Language: Implications for Transgender Communication Therapy. AB - Recent research presents a picture of diminishing gender differences in language. Two experiments examined whether language use can predict perceptions of gender and femininity; one included male and female speakers telling a personal narrative, the other also included male-to-female transgender speakers and analyzed an oral picture description. In each experiment, raters read transcribed samples before judging the gender and rating the femininity of the speaker. Only number of T-units, words per T-unit, dependent clauses per T-unit, and personal pronouns per T-unit emerged as different between gender groups. As none of the variables were strongly correlated with perceptual judgments, regression analysis was used to determine how combinations of linguistic variables predict female/feminine ratings. Results from these two studies demonstrate that gender related differences in language use for these two contexts are limited, and that any relationship of language to perceptions of gender and femininity is complex and multivariate. This information calls into question the utility of training key language features in transgender communication therapy. PMID- 26529900 TI - Early Speech Segmentation in French-learning Infants: Monosyllabic Words versus Embedded Syllables. AB - Lexical acquisition relies on many mechanisms, one of which corresponds to segmentation abilities, that is, the ability to extract word forms from fluent speech. This ability is important since words are rarely produced in isolation even when talking to infants. The present study explored whether young French learning infants segment from fluent speech the rhythmic unit of their native language, the syllable. Using the Headturn Preference Procedure and the passage word order, we explored whether these infants can segment monosyllabic words (at 6 and 8 months), syllables embedded in bisyllabic words (at 6 months) and bisyllabic words (at 6 months). Our results bring direct evidence in support of the early rhythmic segmentation hypothesis, by establishing syllabic segmentation both for monosyllabic words and embedded syllables at 6 months, while failing to find segmentation of bisyllabic words at the same age. They also indirectly extend to French previously reported effects of coarticulation, acoustic variation and infant-directed speech on segmentation found in English. Therefore, our study contributes to a better understanding of the similarities and differences in early segmentation across languages, and thus to a better understanding of the mechanisms underlying segmentation. PMID- 26529901 TI - Biomechanically Conditioned Variation at the Origin of Diachronic Intervocalic Voicing. AB - This paper addresses the question of how synchronic variation in intervocalic voicing of voiceless obstruents, as observed in several languages (e.g., Rome Italian /lato/ [lato] - [lado]), may initiate and give rise to a regular sound change (e.g., /t/ > /d/ between vowels). We hypothesize that a biomechanically motivated linkage between male gender, speech rate, and voicing may provide a way to accelerate the spread of the phenomenon and lead to an eventual generalized recategorization. In order to explore this hypothesis, first we reanalyze the results of a previous study on intervocalic voicing in Spanish, focusing on individual differences and, in particular, the possible role of gender. Then we report on a study of the same phenomenon in Basque, focusing also on interspeaker variation. Finally, we report on a controlled experiment where speech rate was manipulated. PMID- 26529902 TI - Talker Versus Dialect Effects on Speech Intelligibility: A Symmetrical Study. AB - This study investigates the relative effects of talker-specific variation and dialect-based variation on speech intelligibility. Listeners from two dialects of American English performed speech-in-noise tasks with sentences spoken by talkers of each dialect. An initial statistical model showed no significant effects for either talker or listener dialect group, and no interaction. However, a mixed effects regression model including several acoustic measures of the talker's speech revealed a subtle effect of talker dialect once the various acoustic dimensions were accounted for. Results are discussed in relation to other recent studies of cross-dialect intelligibility. PMID- 26529903 TI - Categorical phonotactic knowledge filters second language input, but probabilistic phonotactic knowledge can still be acquired. AB - Probabilistic phonotactic knowledge facilitates perception, but categorical phonotactic illegality can cause misperceptions, especially of non-native phoneme combinations. If misperceptions induced by first language (L1) knowledge filter second language input, access to second language (L2) probabilistic phonotactics is potentially blocked for L2 acquisition. The facilitatory effects of L2 probabilistic phonotactics and categorical filtering effects of L1 phonotactics were compared and contrasted in a series of cross-modal priming experiments. Dutch native listeners and L1 Spanish and Japanese learners of Dutch had to perform a lexical decision task on Dutch words that started with /sC/ clusters that were of different degrees of probabilistic wellformedness in Dutch but illegal in Spanish and Japanese. Versions of target words with Spanish illegality resolving epenthesis in the clusters primed the Spanish group, showing an L1 filter; a similar effect was not found for the Japanese group. In addition, words with wellformed /sC/ clusters were recognised faster, showing a positive effect on processing of probabilistic wellformedness. However, Spanish learners with higher proficiency were facilitated to a greater extent by wellformed but epenthesised clusters, showing that although probabilistic learning occurs in spite of the L1 filter, the acquired probabilistic knowledge is still affected by L1 categorical knowledge. Categorical phonotactic and probabilistic knowledge are of a different nature and interact in acquisition. PMID- 26529904 TI - DNA sequence and structure properties analysis reveals similarities and differences to promoters of stress responsive genes in Arabidopsis thaliana. AB - Understanding regulatory mechanisms of stress response in plants has important biological and agricultural significances. In this study, we firstly compiled a set of genes responsive to different stresses in Arabidopsis thaliana and then comparatively analysed their promoters at both the DNA sequence and three dimensional structure levels. Amazingly, the comparison revealed that the profiles of several sequence and structure properties vary distinctly in different regions of promoters. Moreover, the content of nucleotide T and the profile of B-DNA twist are distinct in promoters from different stress groups, suggesting Arabidopsis genes might exploit different regulatory mechanisms in response to various stresses. Finally, we evaluated the performance of two representative promoter predictors including EP3 and PromPred. The evaluation results revealed their strengths and weakness for identifying stress-related promoters, providing valuable guidelines to accelerate the discovery of novel stress-related promoters and genes in plants. PMID- 26529905 TI - TrieAMD: a scalable and efficient apriori motif discovery approach. AB - Motif discovery is the problem of finding recurring patterns in biological sequences. It is one of the hardest and long-standing problems in bioinformatics. Apriori is a well-known data-mining algorithm for the discovery of frequent patterns in large datasets. In this paper, we apply the Apriori algorithm and use the Trie data structure to discover motifs. We propose several modifications so that we can adapt the classic Apriori to our problem. Experiments are conducted on Tompa's benchmark to investigate the performance of our proposed algorithm, the Trie-based Apriori Motif Discovery (TrieAMD). Results show that our algorithm outperforms all of the tested tools on real datasets for the average sensitivity measure, which means that our approach is able to discover more motifs. In terms of specificity, the performance of our algorithm is comparable to the other tools. The results also confirm both linear time and linear space scalability of the algorithm. PMID- 26529906 TI - Mitigating bias in planning two-colour microarray experiments. AB - Two-colour microarrays are used to study differential gene expression on a large scale. Experimental planning can help reduce the chances of wrong inferences about whether genes are differentially expressed. Previous research on this problem has focused on minimising estimation errors (according to variance-based criteria such as A-optimality) on the basis of optimistic assumptions about the system studied. In this paper, we propose a novel planning criterion to evaluate existing plans for microarray experiments. The proposed criterion is 'Generalised A Optimality' that is based on realistic assumptions that include bias errors. Using Generalised-A Optimality, the reference-design approach is likely to yield greater estimation accuracy in specific situations in which loop designs had previously seemed superior. However, hybrid designs are likely to offer higher estimation accuracy than reference, loop and interwoven designs having the same number of samples and slides. These findings are supported by data from both simulated and real microarray experiments. PMID- 26529907 TI - Gene function prediction with knowledge from gene ontology. AB - Gene function prediction is an important problem in bioinformatics. Due to the inherent noise existing in the gene expression data, the attempt to improve the prediction accuracy resorting to new classification techniques is limited. With the emergence of Gene Ontology (GO), extra knowledge about the gene products can be extracted from GO and facilitates solving the gene function prediction problem. In this paper, we propose a new method which utilises GO information to improve the classifiers' performance in gene function prediction. Specifically, our method learns a distance metric under the supervision of the GO knowledge using the distance learning technique. Compared with the traditional distance metrics, the learned one produces a better performance and consequently classification accuracy can be improved. The effectiveness of our proposed method has been corroborated by the extensive experimental results. PMID- 26529908 TI - An integrated strategy for functional analysis of microbial communities based on gene ontology and 16S rRNA gene. AB - In order to analyse the similarity among microbial communities on functional state after assigning 16S rRNA sequences from all microbial communities to species. It's an important addition to the species-level relationship between two compared communities and can quantify their differences in function. We downloaded all functional annotation data of several microbiotas. It's developed to identify the functional distribution and the significantly enriched functional categories of microbial communities. We analysed the similarity between two microbial communities on functional state. In the experimental results, it shows that the semantic similarity can quantify the difference between two compared species on function level. It can analyse the function of microbial communities by gene ontology based on 16S rRNA gene. Exploration of the function relationship between two sets of species assemblages will be a key result of microbiome studies and may provide new insights into assembly of a wide range of ecosystems. PMID- 26529909 TI - Assessing protein-protein interactions based on the semantic similarity of interacting proteins. AB - The Gene Ontology (GO) has been used in estimating the semantic similarity of proteins since it has the largest and reliable vocabulary of gene products and characteristics. We developed a new method which can assess Protein-Protein Interactions (PPI) using the branching factor and information content of the common ancestor of interacting proteins in the GO hierarchy. We performed a comparative evaluation of the measure with other GO-based similarity measures and evaluation results showed that our method outperformed others in most GO domains. PMID- 26529910 TI - A novel random forests-based feature selection method for microarray expression data analysis. AB - High-dimensional data and a large number of redundancy features in bioinformatics research have created an urgent need for feature selection. In this paper, a novel random forests-based feature selection method is proposed that adopts the idea of stratifying feature space and combines generalised sequence backward searching and generalised sequence forward searching strategies. A random forest variable importance score is used to rank features, and different classifiers are used as a feature subset evaluating function. The proposed method is examined on five microarray expression datasets, including leukaemia, prostate, breast, nervous and DLBCL, and the average accuracies of the SVM classifier in these datasets are 100%, 95.24%, 85%, 91.67%, and 91.67%, respectively. The results show that the proposed method could not only improve the classification accuracy but also greatly reduce the computation time of the feature selection process. PMID- 26529911 TI - Develop a system to collect patient credit card information. PMID- 26529912 TI - 5 last-minute ICD-10 steps for physician practices. PMID- 26529913 TI - New accreditation program assists practices with key compliance issues. PMID- 26529914 TI - Informed consent: When do you need it? PMID- 26529915 TI - Last call for ICD-10 prep. PMID- 26529916 TI - Becoming risk-capable: A group's transformation story. PMID- 26529917 TI - Don't be held hostage by your coder. Preview of MGMA 2015 Annual Conference session. PMID- 26529919 TI - Establishing work hours for exempt office managers. PMID- 26529918 TI - Why Stark-compliant compensation matters more than ever. PMID- 26529920 TI - Member recalls path to certification, details benefits of volunteering. PMID- 26529921 TI - [Status and issues of medical treatment for osteoporosis]. AB - Although various osteoporosis medications have become available with proven effects for protecting against bone fracture, such osteoporosis treatment is only given to 20 to 25% of those eligible in Japan. The most urgent task at present is to increase the treatment rate. The guidelines for prevention and treatment of osteoporosis were revised in 2015 and now include criteria for commencing medical treatment. However, guidelines for management of osteoporosis, including the duration of medical treatment for osteoporosis, are still under discussion. PMID- 26529922 TI - [Frontier in bone biology]. AB - Bone is an active organ in which bone mass is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption, i.e., coupling of bone formation and bone resorption. Recent advances in molecular bone biology uncovered the molecular mechanism of the coupling. A fundamental role of osteocyte in the maintenance of bone mass and whole body metabolism has also been revealed recently. Moreover, neurons and neuropeptides have been shown to be intimately involved in bone homeostasis though inter-organ network, in addition to "traditional" regulators of bone metabolism such as soluble factors and cytokines PMID- 26529923 TI - [Pharmacology of bone resorption inhibitor]. AB - Currently, bone resorption inhibitor is mainly used for osteoporosis. A number of these agents have been developed. These pharmacological action are various. Bisphosphonate inhibit functions of the osteoclasts by inducing apoptosis. On the one hand, RANK-ligand inhibitor and selective estrogen receptor modulator inhibit formation of osteoclasts. It is important to understand these pharmacological action for the selection of the appropriate medicine. PMID- 26529924 TI - [Pharmacology of bone anabolic agents]. AB - Bone is constantly remodeled to maintain its volume, structural integrity and strength Currently available bone anabolic agent is teriparatide. Teriparatide increases bone mass and strength via both remodeling-dependent and -independent mechanisms, although remodeling-dependent mechanism overweighs the other. Canonical Wnt signal plays an important role in enhancing osteoblast differentiation and bone formation, and its osteocyte-derived inhibitor, sclerostin, regulates bone formation via the regulation of Wnt signaling. Anti sclerostin antibody stimulates Wnt signaling and enhances bone formation. Phase II clinical trials with anti-sclerostin antibodies, romosozumab and blosozumab, demonstrated a marked increase in bone mineral density after one year of treatment. The new modality of anabolic agents via remodeling-independent stimulation of bone formation may open up a new avenue for the treatment of osteoporosis. PMID- 26529925 TI - [The new concept for the diagnosis of osteoporosis]. AB - For the diagnosis of osteoporosis, a medical interview, physical examination, diagnostic imaging, and blood and urine examinations should be conducted first. Then, bone assessment must be conducted with bone mass measurement and spinal radiography. Based on this information, diseases causing low bone mass or secondary osteoporosis should be excluded, and then an accurate diagnosis of primary osteoporosis should be made based on the diagnostic criteria. Based on new knowledge about risk factors and the consideration about using FRAX, the criteria for initiating pharmacological treatment to prevent fragility fracture was established by Japanese 2011 Guidelines for Prevention and Treatment of Osteoporosis. PMID- 26529926 TI - [Bone turnover marker]. AB - Recently the clinical application of bone turnover markers (BTMs) have been achieved significant progress and the measurements of these indices give us better understanding of pathogenesis of osteoporosis. BTMs are known the bone formation marker, the bone resorption marker and the bone matrix-related marker, respectively. In the Guidelines for the Use of Bone Metabolic Markers in the Diagnosis and Treatment of Osteoporosis (2012 Edition) from publishing Japan Osteoporosis Society Committee, the newly and commonly BTMs were considered to give the normal reference value in Japanese people, the influence of renal function on BTMs. The flow chart of the measurement of bone resorption markers and bone formation markers when selecting drug treatment for osteoporosis, the evaluation of therapeutic effects of bone antiresorption drugs and/or bone formation promoting drug using bone resorption markers and/or bone formation marker were corrected newly in the guideline 2012 edition. Moreover, BTMs were suggested to contribute to adhere with osteoporosis treatment. BTMs are adapted to selection of the drug for osteoporosis and to evaluate the drug efficacy. Therefore, it is very important to guide the proper application and assessment of BTMs in clinical practice. PMID- 26529927 TI - [Bone mineral density measurement]. AB - Bone mineral density (BMD) is measured using X-ray or gamma-ray, and dual energy X-ray absorptiometry (DXA) using X-ray beam is a standard method for the osteoporosis diagnosis and monitoring. Quantitative computed tomography (QCT) provides volumetric BMD as well as geometric information based on the three dimensional CT image data, which contributes to evaluate the pathophysiology and efficacy of anti-osteoporotic agents. High resolution peripheral QCT becomes widespread, which provides volumetric BMD as well as microstructural parameters in the radius and tibia. This is the only modality to assess microstructure in the spongiosa and cortices with high resolution in vivo. PMID- 26529928 TI - [Bone quality]. AB - Bone quality is thought to encompass the structural and material properties of bone. Bone collagen crosslinking plays important roles in bone strength. The quantitative and qualitative deterioration of lysyl oxidase control and non enzymatic cross-links (advanced glycation end products, AGEs, pentosidine) of collagen in patients with osteoporotic femoral neck fracture and diabetes, and chronic kidney disease might be affected by increased oxidative stress and glycation. A higher urinary or plasma pentosidine and homocysteine levels were an independent risk factor for osteoporotic fracture. If confirmed in large, prospective trials, measurements of serum homocysteine and serum or urine levels of pentosidine might be characterized as markers reflecting bone collagen deterioration. PMID- 26529929 TI - [Selective estrogen receptor modulators (SERMs)]. AB - Selective estrogen receptor modulators (SERMs) have the potential to provide the skeletal benefits of estrogen without the increased risk of uterine and breast cancer. Raloxifene, second generation SERM has been approved for the prevention and treatment of post-menopausal osteoporosis. Bazedoxifene, third generation SERM acts as a tissue selective estrogen antagonist or agonist. These SERMs inhibited bone turnover and prevented bone loss caused estrogen deficiency. Furthermore, these SERMs did not affect the uterine endometrial thickness and reduced serum cholesterol. These data suggest that SERMs are potential drug for the prevention of osteoporosis in postmenopausal women. PMID- 26529930 TI - [Bisphosphonate]. AB - Bisphosphonates (BPs) are first-line drugs in the management of osteoporosis. BPs' significant efficacy in the prevention of vertebral, non-vertebral, and hip fractures has been proven. BPs are now available as an injection as well as as oral administration in Japan. This review gives an overview of the efficacy as well as the clinical issues of the bisphosphonates. PMID- 26529931 TI - [Anti-RANKL antibody]. AB - RANKL (receptor activator of nuclear factor-kappaB ligand) critically regulates the differentiation, activation, and survival of the osteoclast, and the hyperactivation of the RANKL-RANK signaling pathway leads to osteoporosis. Denosumab is a complete human monoclonal antibody against human RANKL, and suppresses bone resorption by inhibiting the interaction between RANKL and RANK. Accumulating evidence has demonstrated the clinical usefulness of denosumab on postmenopausal osteoporosis. Although the effectiveness of denosumab on disease activity of rheumatoid arthritis has not been clarified yet, previous studies reported that denosumab significantly increased the bone density of lumbar spine and proximal femur of rheumatoid arthritis patients. PMID- 26529932 TI - [PTH preparations]. AB - Parathyroid hormone(PTH) is essential for maintaining serum calcium level. PTH increases serum calcium partly by enhancing bone resorption. Therefore, persistent excessive actions of PTH result in cortical bone loss by increased bone resorption. In contrast, intermittent injections of PTH preparations increase trabecular bone mainly by enhancing bone formation. Teriparatide is a peptide with 34 amino acids corresponding to the N-terminal portion of PTH. Both once daily and once weekly subcutaneous injections of teriparatide are available in Japan. Teriparatide was shown to prevent vertebral fractures. In addition, once daily injections of teriparatide also reduce non-vertebral fractures. However, there still remain several unanswered questions about the precise mechanisms of actions of teriparatide preparations. PMID- 26529933 TI - [Active vitamin D3 analog]. AB - Vitamin D is a fat-soluble vitamin and exerts effects on skeletal and extraskeletal health in children and adults of all ages. Vitamin D insufficiency is related to low muscle strength, increasing body sway, falls in the elderly. Supplementation with vitamin D reduces risk of osteoporotic fracture, and improves muscle strength and postural balance to prevent the elderly from fall. The preferred vitamin D analog for daily supplementation is cholecalciferol (vitamin D3). The active form of vitamin D3 is 1,25-dihydroxy-vitamin D3. Alfacalcidol, calcitriol and eldecalcitol are used to treat osteoporosis in Japan. Randomized placebo-controlled, double-blinded clinical trial for osteoporotic subjects showed that eldecalcitol is more efficacious to increase bone mineral density and prevent vertebral and wrist fractures in osteoporotic patients with vitamin D sufficiency than alfacalcidol. PMID- 26529934 TI - [Therapeutic agents for osteoporotic pain]. AB - Low back pain (LBP) is one of the major symptoms of elderly patients with osteoporosis. Pain control is important because pain hinders quality of life. The pathogenesis of the osteoporosis-related LBP is divided as follows, (1) vertebral fracture with bone fragility, (2) imbalance of sagittal alignment, (3) osteoporotic bone pain, (4) reduction of the descending pain inhibition system of serotonine, (5) psychological condition, (6) neural pain. For the treatment of osteoporosis-related LBP, there are two types of medicine. One is a medicine for osteoporosis with an analgetic action, another is an analgetic agent. In this chapter, we explained various analgetic agents for osteoporosis-related LBP. PMID- 26529935 TI - [New anti-osteoporotic drugs under development]. AB - Cathepsin K is a cysteine protease indispensable for collagen degradation and bone resorption by osteoclasts. Cathepsin K inhibitors suppress bone resorption while keeping osteoclasts alive, which is believed to maintain osteoblast stimulating activity of osteoclasts. Sclerostin is an osteocyte-derived soluble factor that inhibits the Wnt canonical pathway. Neutralizing antibody against sclerostin strongly but transiently stimulates bone formation. This review will discuss unique actions on bone metabolism and clinical efficacy of these two anti osteoporotic drugs under development. PMID- 26529936 TI - [Diabetes-related osteoporosis]. AB - Accumulating evidence has shown that the risk of osteoporotic fracture is increased in patients with type 1 and 2 diabetes mellitus. Measurement of bone mineral density is not a good evaluation tool for diabetes-related osteoporosis because the underlying mechanism is based on the deterioration of bone quality with accumulation of collagen cross-links of advanced glycation end products, decreased bone formation, and cortical porosity. Thus, we should choose the anti osteoporosis drug while taking the mechanism into consideration. However, the evidence of treatments for diabetes-related osteoporosis is not sufficient so far. Therefore, further studies are necessary to solve this issue in future. PMID- 26529937 TI - [Osteoporosis treatment for patients with chronic kidney disease]. AB - Osteoporosis is defined as a condition of impairment in bone strength and predisposes individuals to an increased risk of fractures. The risk of fragility fracture is shown to be high in patients with chronic kidney disease (CKD). Osteoporosis treatment for patients with CKD G1-3 should not differ from treatment for patients without CKD, as long as there are no accompanying hyperparathyroidism and hyperphosphatemia that indicate the co-existence of CKD mineral and bone disorder. However, there are few published data on osteoporosis treatment for patients with CKD G4, 5. So, considerations for current pharmacologic therapy (such as bisphosphonate, denosumab, teriparatide, and raloxifene) should be a thoughtful and open discussion with these patients. PMID- 26529938 TI - [Endocrine disorders and osteoporosis]. AB - Secondary osteoporosis is a bone disease characterized by decreased bone mass that predisposes fractures due to underlying disorders or medication. Disorders of the endocrine system, such as primary hyperparathyroidism, hyperthyroidism, hypogonadism, growth hormone deficiency, Cushing's syndrome, and anorexia nervosa frequently cause secondary osteoporosis. In those diseases, hormone excess or deficiency affects functions of osteoblasts, osteocyte, and osteoclasts, leading to aberrant bone remodeling. Bisphosphonates are the first-choice pharmacological agents for fracture prevention in most patients with secondary osteoporosis along with treatment of the underlying disease. PMID- 26529939 TI - [Glucocorticoid-induced osteoporosis]. AB - Osteoporosis is the most common and important adverse effect of glucocorticoid (GC) therapy. Since GC-induced bone loss is most rapid during the initial 3-6 months and primary prevention of bone loss is especially important, guidelines for management of GC-induced osteoporosis have been published overseas and in Japan. The Japanese Society for Bone and Mineral Research (JSBMR) has updated the Guidelines on the Management and Treatment of Glucocorticoid-induced Osteoporosis(GIO) and has incorporated a new scoring method. By analyzing five Japanese GIO cohorts from primary and secondary prevention studies, age, GC dose, lumbar BMD, and prior fragility fractures were identified as factors predicting future fracture and the fracture risk for an individual can be calculated as the sum of the scores for each risk factor. The guidelines were updated on the basis of a score of 3 as the optimal cut-off score for pharmacological intervention. Among these agents approved for the treatment of osteoporosis in Japan, the committee comprehensively reviewed validity for both primary and secondary prevention and assessed the benefit for both BMD and fracture prevention based on the results of clinical studies. Both alendronate and risedronate are recommended as first-line treatment. Ibandronate, teriparatide, and active vitamin D3 derivatives are recommended as alternative option. PMID- 26529940 TI - [Pharmacological treatment of other types of secondary osteoporosis]. AB - This article reviews the treatment strategy for the secondary osteoporosis excluding those caused by diabetes, CKD, endocrine disorders, or glucocorticoid, which proceeding articles deal with. Among numerous possible causes for such secondary osteoporosis, the author has selected osteogenesis imperfecta (OI), osteoporosis associated with gastrectomy or bariatric surgery, inflammatory bowel diseases (IBD), and chronic obstructive pulmonary disease (COPD). For OI, current standard treatment is bisphosphonates (BPs), of which efficacy for fracture inhibition has recently been of issue. Other treatment modalities, e.g. PTH, have just been explored. Osteoporosis associated with gastrectomy, bariatric surgery or IBD, have been treated with vitamin D, calcium, and BPs. Despite high fracture rates, there are almost no treatment data for osteoporosis associated with COPD. PMID- 26529941 TI - [The concept of locomotive syndrome and its relationship with frailty and sarcopenia]. AB - Frailty and sarcopenia both contribute to a functional decline among the elderly, and are reportedly reversible with physical exercise. Locomotive syndrome represents the decline in locomotor function as a result of impairments of the locomotor organs. A healthy locomotor organ is essential for locomotor function, as well as daily living and social activities. Hence, elucidating the mechanism underlying locomotive syndrome may help provide physical fitness professionals with insight into the locomotor function in the elderly. Importantly, locomotor organs primarily undergo degenerative changes after middle age. Moreover, overloading may be a risk factor for degenerated cartilages and intervertebral disks, whereas underloading may also predispose bones and muscles to certain risks. PMID- 26529942 TI - [Cost-effectiveness considerations in the treatment of osteoporosis]. AB - Osteoporotic fractures are associated with increased morbidity and mortality, and impose a huge financial burden on healthcare systems. Preventing osteoporotic fractures in the elderly therefore represents an important issue in terms of health economics. To date, the efficacy and cost-effectiveness of osteoporosis treatments have been studied extensively. In this article, the basic idea of health economic evaluation was introduced and articles of cost-effectiveness analysis for osteoporosis treatment were reviewed. PMID- 26529943 TI - [Current status and issues of regional clinic network for hip fractures in the elderly]. AB - I investigated presence of taking medicine and a taking medicine continuation rate to evaluate how to use the regional post-referral treatment plan about the osteoporosis treatment for the secondary hip fractures prevention. I evaluated the present conditions of the regional post-referral treatment plan that I considered from acute care hospital points of view. The osteoporosis treatment that continued and expanse of the osteoporosis liaison service are necessary to quit the chain of the osteoporotic fracture. It is necessary to improve a taking medicine continuation rate. PMID- 26529944 TI - [Osteoporosis liaison service]. AB - Osteoporosis is nowadays big burden for aging societies. However, low treatment rate even after first hip fracture results in the increase of second hip fracture in both developed and developing countries. Fracture liaison services, commonly known as FLS, are coordinator-based, secondary fracture prevention services implemented by health care systems for the treatment of osteoporotic patients. Osteoporosis liaison service (OLS) in Japan includes not only FLS but also educational program, medical check-up for bone fragility and risk assessment for primary fracture in osteoporotic subjects. Japan Osteoporosis Society gives coordinators and medical doctors the certificates as a specialist for OLS since 2015. OLS in Japan should facilitate better performance of the treatment of osteoporosis and should contribute the reduction of clinical fractures. PMID- 26529945 TI - [Lymphangiomatosis and Gorham-Stout disease]. AB - Lymphangiomatosis (recently renamed "generalized lymphatic anomaly") is a rare disease of unknown etiology that features an increase in the number of lymphatic vessels in many different tissues. Gorham-Stout disease(GSD) is a related disease characterized by lymphatic vessels involving the bones and resulting in progressive bone destruction. Respective definitions remain unclear because these conditions largely overlap in the clinical setting and are both associated with pleural effusion and other visceral lesions. These two conditions have recently been differentiated based on imaging findings. GSD is characterized by progressive osteolysis with loss of cortical bone. These diseases present considerable diagnostic and therapeutic challenges. Implementation of basic and clinical research is mandatory to improve understanding of these conditions and optimize management. PMID- 26529946 TI - Editorial. PMID- 26529947 TI - Open Dialogue method of mental health care launched in the UK. PMID- 26529948 TI - Letter to the editor. PMID- 26529950 TI - Growing pains. PMID- 26529951 TI - Talk it out. PMID- 26529952 TI - The ART of the matter. PMID- 26529953 TI - Welfare writes. PMID- 26529954 TI - Outside the box. PMID- 26529955 TI - The bigger picture. PMID- 26529956 TI - Under-reported suicides hiding or compounding the tragedy? PMID- 26529957 TI - Legal eye. PMID- 26529958 TI - Doctor's orders. PMID- 26529959 TI - Viewpoint. PMID- 26529960 TI - Network. PMID- 26529962 TI - Online support. PMID- 26529961 TI - Food for thought. PMID- 26529963 TI - Debs Taylor. PMID- 26529965 TI - Ship Shape. PMID- 26529964 TI - BLUE SKIES AHEAD: THREE TRENDS FAVOR NEW CANDIDATES. PMID- 26529966 TI - Using EHR Technology To Improve Dementia Care. PMID- 26529967 TI - [Accuracy of Gender Distinction Based on Basic Laboratory Test Results: Comparison between Conventional Logistic Regression Analysis and a Weighted Log Likelihood Estimation]. AB - Feasibility of gender distinction based on laboratory tests was explored by employing test results for 21 basic analytes which were obtained from 1,944 healthy Japanese (males = 856; females = 1,088: age = 20-64) in a multicenter reference interval (RI) study conducted in 2009. Two methods for the distinction were examined. One was logistic regression analysis with stepwise selection of analytes representing gender differences. The estimated probability (EP) of the sample's being from a female was calculated from the regression model. The other was the weighted-average log-likelihood (WALL) method, which is based on matching of an arbitrary set of lab test results with those of a given diagnostic category. In this study, WALLs belonging to distributions of male test results were computed with SDR (SD representing gender-difference divided by SD comprising RI) set as the weight for each analyte. WALL was computed by inclusion of either all analytes(WALL1), those with SDR >= 0.3(WALL2), or SDR >= 0.5(WALL3). The performance of EP and WALLs was evaluated as accuracy (% correct distinction) and area under the ROC curve (AUC). Because SDR decreased with age 46, EP and WALLs were computed for all-ages, age <= 45 and age >= 46. Analytes chosen in the logistic model were not necessarily those with high SDR. In all-age analysis, accuracy and AUC for EP vs. WALL1 were 94.2% and 0.986 vs. 91.1% and 0.973; respectively; in age <= 45 analysis, 95.1% and 0.990 vs. 93.2% and 0.981; in age 46 analysis, 92.6%, and 0.980 vs. 90.5% and 0.973. WALL2 showed slightly better performance in any age group. WALL analysis showed a little less performance than the conventional logistic regression analysis, but it has superior properties for the binary categorization with its nonparametric nature and flexibility in the selection of test items. PMID- 26529969 TI - [Rapid and Easy Measurement of Serum Fatty Acid Composition of Neonates, Infants and Young People Using the Gas Chromatography Mass Spectrometry]. AB - A variation of the fatty acid composition is closely associated with the clinical state of inflammatory disorder and metabolic syndrome. The analysis of serum fatty acid composition of neonates and infants has been measured hardly at the laboratory, because a large quantity of serum was required for an analysis and the measurement procedure was cumbersome. We examined the rapid and easy analysis in a small amount of serum using the combination methods of the gas chromatography mass spectrometry (GC MS) and the quick transmethylation. The serum fatty acid composition of neonates and infants were compared with the young people. The serum fatty acids with the internal standard material were performed transmethylation using the microwave, and then the lipids were extracted. The fatty acid esters were analyzed by GC MS with capillary column, and the statistical procedure used nonparametric method. The repeatability of each fatty acid concentration was CV = 5-11.3% (n = 5) with serum 50 MUl. The lowest quantity of sample was possible to measure with 13 MUl of serum. The total serum fatty acid, saturated fatty acid and monounsaturated fatty acid levels did not show a significant difference at all age, but the polyunsaturated fatty acid (PUFA) level of neonates and infants was significantly lower than young people, p = 0.007. The four main PUFA exclusive of alpha-linolenic acid showed a significant difference. The fatty acid composition with small quantities serum was measured by the rapid and accurate method using the GC MS and the microwave. The serum PUFA concentrations have fluctuated according to growth, therefore it was necessary to evaluate serum fatty acid composition in each age category. PMID- 26529968 TI - [A Study to Determine the Optimum Antigens for the Serodiagnosis of Helicobacter Pylori Infection in Japanese Patients and the Association with IgG Subclass and Gastric Cancer]. AB - Atrophic gastritis is caused by Helicobacter pylori infection, and is involved in gastric cancer. In this study, we investigated the association with total IgG and IgG subclass antibodies using several strains isolated from Japanese in H. pylori positive and negative individuals, and gastric atrophy using measuring pepsinogen I and II levels. We found that total IgG antibody measurement using typical Japanese genotype as an antigen was available for diagnosis of H. pylori infection, whereas IgG1 and IgG2 antibodies were not for diagnosis. Furthermore, the IgG1/G2 ratio was elevated in a patient with gastric cancer. The accuracy of serodiagnosis of H. pylori infection may increase when the optimal antigens are used, and measurement IgG subclass may provide additional prediction of gastric cancer. PMID- 26529970 TI - [Changes in PT and APTT When Administrating Rivaroxaban, a Direct Inhibitor of Activated Factor X]. AB - The effects of oral rivaroxaban (RX), a direct inhibitor of activated factor X (Xa), on prothrombin time (PT) and activated partial thromboplastin time (APTT) were examined. PT and APTT before and after administration of 15 mg RX in 10 healthy subjects were measured by using various reagents. In addition, the blood Xa inhibitor concentration was measured and its correlation with PT and APTT, as measured by each reagent, was examined. Furthermore, the relationship (sensitivity) between the prolongation ratio and FX activity was evaluated. Prolongation of both PT and APTT was observed after RX administration, and maximal prolongation was observed four hours after administration for each reagent. The prolongation ratio was different among the reagents used for examination, and the reagent with the highest sensitivity to FX and factor VII showed the largest prolongation ratio. PT and APTT were positively correlated with RX concentration when measured by any reagent. In this study, neither PT, APTT, nor RX concentration returned to the values measured prior to dosing even at 24 hours after administration of RX. Our results suggest that approximate concentration of remaining RX may be estimated by PT (second) when using a reagent showing a larger prolongation ratio. PMID- 26529971 TI - [What Has Been Done in Surugadai Nihon University Hospital as a Laboratory Physician--Encounter with FAB Classification and Establishing the Additional Laboratory Management Fee]. AB - I was requested by Nihon University to contribute to the official journal of the Japanese Society of Laboratory Medicine (Rinsho Byori). A special review of the final lecture at Surugadai Nihon University Hospital was requested by the editorial board of the Japanese Society of Laboratory Medicine. I submitted a review under the heading of "I have carried out upon retirement, ..." based on the final lecture at Surugadai Nihon University Hospital. The contents of the lecture were how to widely disseminate the FAB classification of acute leukemia and how to establish an additional laboratory management fee. Finally, I showed how to charge an additional management fee correctly based on a laboratory physician's activities in Surugadai Nihon University Hospital. I summarize the lecture in this article. PMID- 26529972 TI - [Quality Management of Pre-Testing Step of POCT]. AB - To maintain a trusting relationship between clinical and hospital laboratory staff, highly reliable reporting based on precise quality control of the test results is required. Testing work is divided into 3 steps: pre-testing, testing, and post-testing. Quality control (QC) of laboratory testing has been performed to improve the precision and accuracy of measurements after sample collection, mainly in the testing step. However, various factors influencing the measurement results are present in the process from requests for testing to the reporting of the test results, and it is necessary to make efforts to minimize these factors. The characteristics of POCT devices and reagents are their simple operation method, compact size, and use at sites other than laboratories, and most users are physicians and nurses. Sample measurement rooms have opened at sites other than medical institutions, and testing using POCT-compatible devices and reagents has been rapidly spreading. It is very important to clarify factors leading to false high and low values in the pre-testing step. The results of investigating reasons for predicted events were presented, and the necessity of quality management in the pre-testing step was clarified. If the pre-testing step is not properly performed, accuracy cannot be assured even though quality management of the testing and post-testing steps is optimal. PMID- 26529973 TI - [Management of POCT Devices and Reagents]. AB - In order to ensure the accuracy of POCT devices and reagents, it is necessary to appropriately manage and store them. There are various points to be considered for these items, such as management before and environments when using them; it is more complex than when using conventional analysis apparatuses in clinical laboratories. In addition, staff using such devices should be provided with opportunities to obtain sufficient knowledge and skills. These approaches are indispensable to ensure POCT accuracy and provide reliable data, and, in this respect, support for staff with expertise in clinical examination is crucial. PMID- 26529974 TI - [Internal Quality Control and External Quality Assessment on POCT]. AB - The quality management (QM) of POCT summarizes its internal quality control (IQC) and external quality assessment (EQA). For QM requirements in POCT, ISO 22870 Point-of-care testing (POCT) -Requirements for quality and competence and ISO 15189-Medical laboratories-Requirements for quality and competence, it is performed under the guidance of the QM committee. The role of the POC coordinator and/or medical technologist of the clinical laboratory is important. On measurement performance of POCT devices, it is necessary to confirm data on measurement performance from the manufacturer other than those in the inserted document. In the IQC program, the checking and control of measurement performance are the targets. On measurements of QC samples by the manufacturer, it is essential to check the function of devices. In addition, regarding the EQA program, in 2 neighboring facilities, there is an effect to confirm the current status of measurement and commutability assessment in these laboratories using whole blood along with residual blood samples from daily examinations in the clinical laboratory. PMID- 26529975 TI - [Effective IT-Based Quality Management of Clinical Laboratories--Using POCT Apparatus]. AB - Clinical laboratories are beneficial for users with difficulty in participating in a regular health examination to conveniently undergo it and directly and promptly receive the results. As some users possibly make their own judgments on such results, and submit them to clinics or hospitals, it is necessary for clinical laboratories analyzing patients' samples to provide accurate results based on quality management. For rapid result-reporting, POCT apparatus and kits may be more appropriate examination devices, rather than those for analysis, which are large and used in general examination rooms. Effective IT-based data management systems combined with such devices may enable users to obtain reliable examination results. PMID- 26529976 TI - [Role of the POC Coordinator in Japan]. AB - Point-of-care testing (POCT) is able to shorten the therapeutic turn around time (TTAT) because of its portability, proximity to the patient, and the use of rapid testing methodologies. These advantages are dependent on the quality of POCT procedures. It is recommended that all POCT instrumentation and operators conform to the hospital's POCT policy. There are two basic requirements necessary for high-quality POCT in a hospital setting. First is the proper management of all POCT instrumentation including reagents, and the second is training/competency assessment for all operators. This training should include the correct use of equipment, reagent requirements, and trouble-shooting any errors that might occur during testing. In many cases, POCT operators are not familiar with the importance of analytical quality management because of their lack of experience with laboratory techniques. However, users can improve their POCT ability and knowledge via the training/education program managed by the POCT department. The POC coordinator's role is to oversee that the proper procedure, based on the hospital's policy, is being followed. It is advised that the hospital form a POCT committee. The members should consist of at least: the Director of Laboratory Medicine, POC coordinator, a financial advisor, and several representative users from physicians and nursing staff. The POC coordinator will act as a representative of the POCT committee and work to maintain a quality program within the hospita/institution. In this article, we have summarized the role of the POC coordinator and the function of a POCT committee in a Japanese hospital. PMID- 26529977 TI - [Management of Ethical Problems in the Japanese Society of Laboratory Medicine]. AB - The Ethics Committee of the Japanese Society of Laboratory Medicine published "Opinions of Japanese Society of Laboratory Medicine about utilization of specimens after laboratory examinations for laboratory work, education and clinical studies" in 2002, and amended it in 2008. The Ethics Committee, Committee for Conflict of Interest, Compliance Committee, and Editorial Committee for Rinsho Byori, the official journal of the Japanese Society of Laboratory Medicine, cooperate to solve ethical problems in laboratory medicine. The management of ethical problems in the Japanese Society of Laboratory Medicine is discussed. PMID- 26529978 TI - [Kidney Disease and Laboratory Examinations--Opening Remarks: For Better Understanding of CKD]. AB - Chronic kidney diseases (CKD) have been cited as major risk factors not only for endstage renal failure, but also for the development of cardiovascular diseases and death. In the former criteria for CKD diagnosis (NKF K/DOQI, 2002), estimation of the severity of CKD was simply based on GFR, in order for it to be widely and easily understood by general physicians and patients. Therefore, the use of the CKD guideline without information on the causes and grades of albuminuria was limited for estimation of the prognosis. The revised guideline for CKD diagnosis (KDIGO CKD guideline 2012), with the disease category specified for diabetes mellitus and the different scoring system of microalbuminuria, is presently being effectively utilized by nephrologists as well as general physicians. In this symposium, to advice understanding of the causes and evaluation methods of CKD, speakers were invited to discuss topics in kidney pathology, urine sample examination, urinary biomarkers, and GFR. PMID- 26529979 TI - [Recent Advances in Urinalysis as a Diagnostic Indicator of Renal Diseases]. AB - Urinary sediments may be associated with the pathogenesis of renal diseases. It is important to examine the presence of dysmorphic red blood cells, macrophages, tubular epithelial cells, fibrin casts, glomerular epithelial cells, and ammonium acid urate crystals in urine for evaluating the clinical status of glomerulonephritis. Collecting evidence regarding the relationship between urinary sediments and renal disease activity may provide cost-effective and prompt clinical information to improve clinical practice. PMID- 26529980 TI - [Clinical Importance of GFR-Estimating Equations (eGFRcreat and eGFRcys)]. AB - Evaluation of the renal function is fundamental for the diagnosis and treatment of kidney diseases. It is also important for adjustment of the doses of drugs that are excreted by the kidney. The incidence of contrast-induced nephropathy is high in subjects with a low GFR. Assessment of the renal function is required prior to contrast medium injections. Renal inulin clearance with continuous venous injection is the gold standard for measuring GFR. However, the method is time-consuming. The recent Japanese CKD guide and KDIGO guidelines for CKD management recommended the use of the estimated GFR based on serum creatinine (eGFRcreat) or serum cystatin C (eGFRcys). Because the serum creatinine level is affected by the muscle mass, eGFRcreat is under- or overestimated in subjects with a high or low muscle mass, respectively. The serum cystatin C concentration is less influenced by the muscle mass. Assessment of the renal function by eGFRcys may be useful in subjects with a low or high muscle mass. Recently, it was reported that the association between eGFRcys and the risk of all-cause mortality was much closer compared with eGFRcreat. eGFRcys may be useful for detecting a high risk of complications in a general population and in subjects with CKD. PMID- 26529981 TI - [Towards the Clinical Application of iPS Cell Technology for the Treatment of Kidney Diseases]. AB - In Japan, around 13 million adults have been estimated to suffer from chronic kidney disease (CKD), and more than 300 thousand patients with end-stage renal failure are receiving dialysis therapy, causing both medical and medicoeconomic problems. Regenerative medicine strategies using induced pluripotent stem (iPS) cells are among the candidate approaches to solve the problems. The mechanisms of kidney development and cell fate in the development of renal lineage cells have been elucidated using experimental animal models. Based on the knowledge of kidney development, intensive research has already been conducted to generate renal lineage cells from mouse embryonic stem (ES) cells, while few reports have been on studies using human iPS/ES cells. Recently, several research groups, including ours, have established methods to differentiate human iPS/ES cells into the intermediate mesoderm, an embryonic germ layer that gives rise to the kidney, and embryonic renal progenitors. Some reports also described the formation of three-dimensional renal tissues, such as renal tubules and glomeruli. Continued efforts are required to elucidate the mechanisms of kidney development and generate renal cells or tissues from human iPS cells, which could open up the new research avenues towards clinical application and practical use to overcome problems associated with kidney disease, such as human embryology, cell therapy, toxicology, drug discovery, and disease modeling. PMID- 26529982 TI - Linezolid-resistant Staphylococcus aureus isolated from 2006 through 2008 at six hospitals in Japan. AB - Limited use of linezolid for treating methicillin-resistant Staphylococcus aureus (MRSA) infection was approved in Japan in 2006. We report here the status of linezolid-resistant MRSAs in Japan. Eleven linezolid-resistant clinical isolates from 11 patients at six hospitals were collected from 2006 through 2008. The minimal inhibitory concentration (MIC) of linezolid in these strains varied from 8 to 64 MUg/ml. All strains had at least one G2576T mutation in the chromosomal gene(s) encoding domain V of the 23S ribosomal RNA (rRNA). Chromosomal DNA encoding five copies of the domain V region was analyzed by polymerase chain reaction (PCR). Strains with the linezolid MICs of 64, 32, 16, and 8 MUg/ml had the G2576T mutation(s) in four, three (or four), two, and one copy of the 23S rRNA genes, respectively. These results suggest that the level of linezolid resistance seems to be roughly correlated with the number of mutations in the genes encoding 23S rRNA. DNA samples from all 11 strains were subjected to pulsed field gel electrophoresis and were classified into seven independent clones having >92% identity. Among the 11 patients, five had been treated with linezolid and the remainder, in two hospitals, had no history of prior linezolid use. The results suggested possible nosocomial infections by linezolid-resistant MRSA. PMID- 26529983 TI - The emerging ST8 methicillin-resistant Staphylococcus aureus clone in the community in Japan: associated infections, genetic diversity, and comparative genomics. AB - Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has become a major concern worldwide. In the United States, ST8 CA-MRSA with SCCmecIVa (USA300) has been predominant, affecting the entire United States. In this study, we investigated Japanese ST8 CA-MRSA with new SCCmecIV1 (designated ST8 CA-MRSA/J), which has emerged in Japan since 2003. Regarding community spread and infections, ST8 CA-MRSA/J spread in 16.2-34.4% as a major genotype in the community in Japan, and was associated with skin and soft tissue infections (SSTIs), colitis, and invasive infections (sepsis, epidural abscesses, and necrotizing pneumonia), including influenza prodrome cases and athlete infections, similar to USA300. It spread to even public transport and Hong Kong through a Japanese family. Regarding genetic diversity, ST8 CA-MRSA/J included ST and spa variants and was classified into at least three pulsed-field gel electrophoresis types, ST8 Jalpha to gamma. Of those, ST8 Jbeta was associated with severe invasive infections. As for genomics, ST8 CA-MRSA/J showed high similarities to USA300, but with marked diversity in accessory genes; e.g., ST8 CA-MRSA/J possessed enhanced cytolytic peptide genes of CA-MRSA, but lacked the Panton-Valentine leukocidin phage and arginine catabolic mobile element, unlike USA300. The unique features of ST8 CA-MRSA/J included a novel mosaic SaPI (designated SaPIj50) carrying the toxic shock syndrome toxin-1 gene with high expression; the evolution included salvage (through recombination) of hospital acquired MRSA virulence. The data suggest that ST8 CA-MRSA/J has become a successful native clone in Japan, in association with not only SSTIs but also severe invasive infections (posing a threat), requiring attention. PMID- 26529984 TI - Comparison of clinical characteristics and laboratory findings of malaria, dengue, and enteric fever in returning travelers: 8-year experience at a referral center in Tokyo, Japan. AB - BACKGROUND: Without specific symptoms, diagnosis of febrile illness in returning travelers is challenging. Dengue, malaria, and enteric fever are common causes of fever in returning travelers and timely and appropriate treatment is important. However, differentiation is difficult without specific diagnostic tests. METHODS: A retrospective study was conducted at the National Centre for Global Health and Medicine (NCGM) from April 2005 to March 2013. Febrile travelers returning from overseas who were diagnosed with dengue, malaria, or enteric fever were included in this study. Clinical characteristics and laboratory findings were compared for each diagnosis. RESULTS: During the study period, 86 malaria, 85 dengue, and 31 enteric fever cases were identified. The mean age of the study cohort was 33.1 +/ 12 years and 134 (66.3%) study participants were male. Asia was the most common area visited by returning travelers with fevers (89% of dengue, 18.6% of malaria, and 100% of enteric fever cases), followed by Africa (1.2% of dengue and 70.9% of malaria cases). Clinical characteristics and laboratory findings were significantly different among each group with each diagnosis. Decision tree models revealed that returning from Africa and CRP levels < 10 mg/L were factors specific for diagnosis of malaria and dengue fever, respectively. CONCLUSION: Clinical manifestations, simple laboratory test results, and regions of travel are helpful to distinguish between dengue, malaria, and enteric fever in febrile returning travelers with non-specific symptoms. PMID- 26529985 TI - Healthcare management research. PMID- 26529986 TI - Interview With Beaufort B. Longest Jr., PhD, FACHE, Professor of Health Policy and Management at University of Pittsburgh. PMID- 26529987 TI - The Scale Imperative for Academic Medical Centers: Part 1--Approach. PMID- 26529988 TI - The Per Capita Payment Model. PMID- 26529989 TI - Journal Rankings by Health Management Faculty Members: Are There Differences by Rank, Leadership Status, or Area of Expertise? AB - Health administration (HA) faculty members publish in a variety of journals, including journals focused on management, economics, policy, and information technology. HA faculty members are evaluated on the basis of the quality and quantity of their journal publications. However, it is unclear how perceptions of these journals vary by subdiscipline, department leadership role, or faculty rank. It is also not clear how perceptions of journals may have changed over the past decade since the last evaluation of journal rankings in the field was published. The purpose of the current study is to examine how respondents rank journals in the field of HA, as well as the variation in perception by academic rank, department leadership status, and area of expertise. Data were drawn from a survey of HA faculty members at U.S. universities, which was completed in 2012. Different journal ranking patterns were noted for faculty members of different subdisciplines. The health management-oriented journals (Health Care Management Review and Journal of Healthcare Management) were ranked higher than in previous research, suggesting that journal ranking perceptions may have changed over the intervening decade. Few differences in perceptions were noted by academic rank, but we found that department chairs were more likely than others to select Health Affairs in their top three most prestigious journals (beta = 0.768; p < .01). Perceived journal prestige varied between a department chair and untenured faculty in different disciplines, and this perceived difference could have implications for promotion and tenure decisions. PMID- 26529990 TI - Practitioner Application. PMID- 26529991 TI - Characterizing Primary Care Visit Activities at Veterans Health Administration Clinics. AB - Medical home models seek to increase efficiency and maximize the use of resources by ensuring that all care team members work at the top of their licenses. We sought to break down primary care office visits into measurable activities to better under stand how primary care providers (PCPs) currently spend visit time and to provide insight into potential opportunities for revision or redistribution of healthcare tasks. We videotaped 27 PCPs during office visits with 121 patients at four Veterans Health Administration medical centers. Based on patterns emerging from the data, we identified a taxonomy of 12 provider activity categories that enabled us to quantify the frequency and duration of activities occurring during routine primary care visits. We conducted descriptive and multivariate analyses to examine associations between visit characteristics and provider and clinic characteristics. We found that PCPs spent the greatest percentage of their visit time discussing existing conditions (20%), discussing new conditions (18%), record keeping (13%), and examining patients (13%). Providers spent the smallest percentage of time on preventive care and coordination of care. Mean visit length was 22.9 minutes (range 7.9-58.0 minutes). Site-level ratings of medical home implementation were not associated with differences in how visit time was spent. These data provide a window into how PCPs are spending face-to-face time with patients. The methodology and taxonomy presented here may prove useful for future quality improvement and research endeavors, particularly those focused on opportunities to increase nonappointment care and to ensure that team members work at the top of their skill level. PMID- 26529992 TI - Practitioner application. PMID- 26529993 TI - Understanding High-Reliability Organizations: Are Baldrige Recipients Models? AB - Chassin and Loeb argue persuasively that healthcare organizations (HCOs) can and should be "high-reliability organizations" (HROs) seeking zero defects in outcomes quality. They suggest that the Baldrige model is a sound platform for achieving high reliability. This article analyzes the similarity of the HRO concept to the Baldrige model using a recent Malcolm Baldrige National Quality Award recipient's application. The analysis suggests that neither high reliability nor Baldrige criteria are easily achieved, but the two have strong similarities. The principal difference is in Baldrige's emphasis on strategic independence versus the HRO commitment to "zero patient harm" and quality as "the organization's highest-priority strategic goal." Based on this analysis, the article reviews data on the actual performance of Baldrige recipients as recorded at WhyNotTheBest.org. The data show that the Baldrige approach is an effective method of generating above-average performance. Award recipients have made substantial strides in safety, reductions of infections, immunizations, and patient satisfaction, but receipt of the award has not translated as effectively to reduced readmissions, mortality, and costs. The pattern of results suggests that Baldrige recipients have exploited the right to establish their own strategic goals and are likely to respond to strengthened financial rewards for quality. The Baldrige model has documented successes in quality improvement and should be the standard of excellence in managing all HCOs. PMID- 26529994 TI - Practitioner application. PMID- 26529995 TI - Improving Capacity Management in the Emergency Department: A Review of the Literature, 2000-2012. AB - Capacity management (CM) is a critical component of maintaining and improving healthcare quality and patient safety. One particular area for concern has been the emergency department and the growing issues of patient overcrowding, boarding, and ambulance diversion, which can result in poor patient care and less efficient operations. This study provides a review of the current and most relevant academic literature on capacity management directly related to hospital emergency departments, identifies strengths and weaknesses of the approaches discussed in the literature, and provides practical recommendations for health services administrators implementing CM in their organizations. An extensive literature search was conducted using several search engines and scholarly databases. Articles were identified based on a combination of keywords and then were reviewed and selected for inclusion in the study in adherence to specified criteria. The CM literature includes a great divergence of themes, topics, and definitions. Twenty-two articles were selected for their relevance to emergency department CM with a focus on operations management concepts. A categorization scheme was used, resulting in four thematic groups of articles: problems, solutions, outcomes, and metrics. Healthcare managers wishing to implement solutions to CM problems have a wide variety of operations literature to draw on that can address scheduling and patient throughput, but there are also a number of studies that consider electronic and technological solutions to CM problems. All of these solutions have the potential to positively influence the quality of patient care, including satisfaction. PMID- 26529996 TI - Practitioner application. PMID- 26529997 TI - [Tadini: From a utopia of the 18th century to an overwhelming reality of the 21st century]. PMID- 26529998 TI - Brainstem reflexes in familial dysautonomia. Reply to "Evidence of brainstem dysfunction in patients with familial dysautonomia and carriers of the IKBKAP mutation". PMID- 26529999 TI - Does sensory gating have a protective effect against hallucinatory behavior in schizophrenia? PMID- 26530000 TI - Whole Blood Electrochemiluminescent Detection of Dopamine. AB - Direct detection of medically relevant biomarkers in whole blood without the need for pretreatment or extraction is a great challenge for biomedical analysis and diagnosis. Electrochemical techniques, such as electrochemiluminescence (ECL), are promising tools for this area of analysis. ECL offers high sensitivities together with the ability to obtain time and spacial control over the process. This work exploits these features together with the low background signals obtained from ECL detection to clearly identify and quantify dopamine in whole blood with relative standard deviations lower than 5% (n = 5). This near-infrared quantum dot based ECL sensor displayed a linear response over the range 3.7 <= [dopamine] <= 450 MUM, allowing the rapid detection of dopamine and providing a platform for future development. Significantly, the near-infrared quantum dots exhibited excellent penetrability through biological samples such as whole blood, and show the ECL detection of dopamine in whole blood for the first time. This will likely be at the forefront of development in biosensing and imaging fields in the foreseeable future. PMID- 26530001 TI - [Author's reply]. PMID- 26530002 TI - [Family and community medicine and chronic obstructive pulmonary disease]. PMID- 26530003 TI - Evaluation of an Ultrafiltration-Based Procedure for Simultaneous Recovery of Diverse Microbes in Source Waters. AB - In this study, hollow-fiber ultrafiltration (UF) was assessed for recovery of Escherichia coli, Clostridium perfringens spores, Cryptosporidium parvum oocysts, echovirus 1, and bacteriophages MS2 and PhiX174 from ground and surface waters. Microbes were seeded into twenty-two 50-L water samples that were collected from the Southeastern United States and concentrated to ~500 mL by UF. Secondary concentration was performed for C. parvum by centrifugation followed by immunomagnetic separation. Secondary concentration for viruses was performed using centrifugal ultrafilters or polyethylene glycol precipitation. Nine water quality parameters were measured in each water sample to determine whether water quality data correlated with UF and secondary concentration recovery efficiencies. Average UF recovery efficiencies were 66%-95% for the six enteric microbes. Average recovery efficiencies for the secondary concentration methods were 35%-95% for C. parvum and the viruses. Overall, measured water quality parameters were not significantly associated with UF recovery efficiencies. However, recovery of PhiX174 was negatively correlated with turbidity. The recovery data demonstrate that UF can be an effective method for concentrating diverse microbes from ground and surface waters. This study highlights the utility of tangential-flow hollow fiber ultrafiltration for recovery of bacteria, viruses, and parasites from large volume environmental water samples. PMID- 26530004 TI - Compartmentalized microchannel array for high-throughput analysis of single cell polarized growth and dynamics. AB - Interrogating polarized growth is technologically challenging due to extensive cellular branching and uncontrollable environmental conditions in conventional assays. Here we present a robust and high-performance microfluidic system that enables observations of polarized growth with enhanced temporal and spatial control over prolonged periods. The system has built-in tunability and versatility to accommodate a variety of scientific applications requiring precisely controlled environments. Using the model filamentous fungus, Neurospora crassa, our microfluidic system enabled direct visualization and analysis of cellular heterogeneity in a clonal fungal cell population, nuclear distribution and dynamics at the subhyphal level, and quantitative dynamics of gene expression with single hyphal compartment resolution in response to carbon source starvation and exchange. Although the microfluidic device is demonstrated on filamentous fungi, the technology is immediately extensible to a wide array of other biosystems that exhibit similar polarized cell growth, with applications ranging from bioenergy production to human health. PMID- 26530006 TI - Pediatric Readiness in Indian Health Service and Tribal Emergency Departments: Results from the National Pediatric Readiness Project. AB - INTRODUCTION: In 2014, 45 Indian Health Service (IHS)/Tribal emergency departments serving American Indian and Alaskan Native communities treated approximately 650,000 patients of which, 185,000 (28%) were children and youth younger than 19 years. This study presents the results of the National Pediatric Readiness Project (NPRP) assessment of the 45 IHS/Tribal emergency departments. METHODS: Data were obtained from the 2013 NPRP national assessment, which is a 55 question Web-based questionnaire based on previously published 2009 national consensus guidelines. The main measure of readiness is the weighted pediatric readiness score (WPRS), with the highest score being 100. RESULTS: The overall mean WPRS for all emergency departments is 60.9. Of the IHS/Tribal emergency departments that had pediatric emergency care coordinators, scores across all domains were higher than those of emergency departments without pediatric emergency care coordinators. All 45 emergency departments have readily available a pediatric medication dosing chart, length-based tape, medical software, or other system to ensure proper sizing of resuscitation equipment and proper dosing of medication. Of the 45 IHS/Tribal 37% report having 100% of the equipment items, and 78% report having at least 80% of these items. DISCUSSION: This article reports the results of the NPRP assessment in IHS/Tribal emergency departments that, despite serving a historically vulnerable population, scored favorably when compared with national data. The survey identified areas for improvement, including implementation of QI processes, stocking of pediatric specific equipment, implementation of policies and procedures on interfacility transport, and maintaining staff pediatric competencies. PMID- 26530007 TI - One-dimensional sawtooth and zigzag lattices for ultracold atoms. AB - We describe tunable optical sawtooth and zigzag lattices for ultracold atoms. Making use of the superlattice generated by commensurate wavelengths of light beams, tunable geometries including zigzag and sawtooth configurations can be realised. We provide an experimentally feasible method to fully control inter- (t) and intra- (t') unit-cell tunnelling in zigzag and sawtooth lattices. We analyse the conversion of the lattice geometry from zigzag to sawtooth, and show that a nearly flat band is attainable in the sawtooth configuration by means of tuning the lattice parameters. The bandwidth of the first excited band can be reduced up to 2% of the ground bandwidth for a wide range of lattice setting. A nearly flat band available in a tunable sawtooth lattice would offer a versatile platform for the study of interaction-driven quantum many-body states with ultracold atoms. PMID- 26530005 TI - High specific selectivity and Membrane-Active Mechanism of the synthetic centrosymmetric alpha-helical peptides with Gly-Gly pairs. AB - We used a template-assisted approach to develop synthetic antimicrobial peptides, which differ from naturally occurring antimicrobial peptides that can compromise host natural defenses. Previous researches have demonstrated that symmetrical distribution patterns of amino acids contribute to the antimicrobial activity of natural peptides. However, there is little research describing such design ideas for synthetic alpha-helical peptides. Therefore, here, we established a centrosymmetric alpha-helical sequence template (y + hhh + y)n (h, hydrophobic amino acid; +, cationic amino acid; y, Gly or hydrophobic amino acid), which contributed to amphipathicity, and a series of centrosymmetric peptides was designed with pairs of small amino acids (Ala and Gly), which were utilized to modulate the biological activity. The centrosymmetric peptides with 3 repeat units exhibited strong antimicrobial activity; in particular, the Gly-rich centrosymmetric peptide GG3 showed stronger selectivity for gram-negative bacteria without hemolysis. Furthermore, beyond our expectation, fluorescence spectroscopy and electron microscopy analyses indicated that the GG3, which possessed poor alpha-helix conformation, dramatically exhibited marked membrane destruction via inducing bacterial membrane permeabilization, pore formation and disruption, even bound DNA to further exert antimicrobial activity. Collectively, the Gly-rich centrosymmetric peptide GG3 was an ideal candidate for commercialization as a clinical therapeutic to treat gram-negative bacterial infections. PMID- 26530009 TI - Supramolecular photochemistry: recent progress and key challenges. AB - Supramolecular photochemistry has progressed enormously since it was first introduced thirty years ago. This article summarises the Closing Remarks from the Faraday Discussions on this topic, emphasising the recent progress made in the field as well as the key challenges that remain to be addressed. Specific examples in topical areas involving solar energy conversion, luminescent sensors, molecular logic and machines, and supramolecular photocatalysis are presented. PMID- 26530008 TI - Neuromuscular regulation in zebrafish by a large AAA+ ATPase/ubiquitin ligase, mysterin/RNF213. AB - Mysterin (also known as RNF213) is a huge intracellular protein with two AAA+ ATPase modules and a RING finger ubiquitin ligase domain. Mysterin was originally isolated as a significant risk factor for the cryptogenic cerebrovascular disorder moyamoya disease, and was found to be involved in physiological angiogenesis in zebrafish. However, the function and the physiological significance of mysterin in other than blood vessels remain largely unknown, although mysterin is ubiquitously expressed in animal tissues. In this study, we performed antisense-mediated suppression of a mysterin orthologue in zebrafish larvae and revealed that mysterin-deficient larvae showed significant reduction in fast myofibrils and immature projection of primary motoneurons, leading to severe motor deficits. Fast muscle-specific restoration of mysterin expression cancelled these phenotypes, and interestingly both AAA+ ATPase and ubiquitin ligase activities of mysterin were indispensable for proper fast muscle formation, demonstrating an essential role of mysterin and its enzymatic activities in the neuromuscular regulation in zebrafish. PMID- 26530010 TI - Spontaneous Tl(I)-to-Tl(III) oxidation in dynamic heterobimetallic Hg(II)/Tl(I) porphyrin complexes. AB - Strapped heterobimetallic Hg(II)/Tl(I) porphyrin complexes, with both metal ions bridged by the N-core in a dynamic way, undergo spontaneous Tl(I)-to-Tl(III) oxidation leading to a mono-Tl(III) complex and a mixed valence Tl(I)/Tl(III) bimetallic complex. It provides a new opportunity to tune metal ion translocations in bimetallic porphyrin systems. PMID- 26530012 TI - Targeted water soluble copper-tetrazolate complexes: interactions with biomolecules and catecholase like activities. AB - Two new mononuclear water soluble copper(II) complexes, [Cu{(5 pyrazinyl)tetrazolate}2(1,10-phenanthroline)] 1 and [Cu{(5 pyrazinyl)tetrazolate}(1,10-phenanthroline)2](NO3)0.5(N3)0.5 2, have been synthesized using the metal mediated [2 + 3] cycloaddition reaction between copper bound azide and pyrazinecarbonitrile. The interactions of these copper tetrazolate complexes 1 and 2 with biomolecules like DNA and bovine serum albumin (BSA) are studied and the catecholase like catalytic activity of compound 2 is also explored. Structural determination reveals that both compounds 1 and 2 are octahedral in nature. Screening tests were conducted to quantify the binding ability of complexes (1 and 2) towards DNA and it was revealed that complex 2 has a stronger affinity to bind to CT-DNA. DFT studies indicated that a lower HOMO LUMO energy gap between the DNA fragment and metal complexes might be the reason for this type of stronger interaction. DNA cleavage activity was explored by gel electrophoresis and moderate to strong DNA cleavage properties were observed in the presence and absence of co-reagents. Inhibition of cleavage in the presence of sodium azide indicates the propagation of the activity through the production of singlet molecular oxygen. Furthermore enzyme kinetic studies reflect that complex 2 is also effective in mimicking catecholase like activities. An ESI-MS spectral study indicates the probable involvement of dimeric species [(phen)2Cu (OH)2-Cu(phen)2](2+) in the catalytic cycle. PMID- 26530011 TI - EBV-miR-BHRF1-2 targets PRDM1/Blimp1: potential role in EBV lymphomagenesis. AB - PRDM1/Blimp1, a master regulator of B-cell terminal differentiation, has been identified as a tumor suppressor gene in aggressive lymphomas, including diffuse large B-cell lymphoma (DLBCL). It has been shown in DLBCL and Hodgkin lymphoma that PRDM1 is downregulated by cellular microRNAs. In this study, we identify the Epstein-Barr virus (EBV) microRNA (miRNA), EBV-miR-BHRF1-2, as a viral miRNA regulator of PRDM1. EBV-miR-BHRF1-2 repressed luciferase reporter activity by specific interaction with the seed region within the PRDM1 3' untranslated region. EBV-miR-BHRF1-2 inhibition upregulated PRDM1 protein expression in lymphoblastoid cell lines (LCL), supporting a role of miR-BHRF1-2 in PRDM1 downregulation in vivo. Discordance of PRDM1 messenger RNA and protein expressions is associated with high EBV-miR-BHRF1-2 levels in LCLs and primary post-transplant EBV-positive DLBCL. Enforced expression of PRDM1-induced apoptosis and cell cycle arrest in LCL cells. Inhibition of EBV-miR-BHRF1-2 negatively regulates cell cycle and decreases expression of SCARNA20, a small nucleolar RNA that is also downregulated by PRDM1 overexpression. The interaction between EBV-miR-BHRF1-2 and PRDM1 may be one of the mechanisms by which EBV-miR BHRF1-2 promotes EBV lymphomagenesis. Our results support the potential of EBV miR-BHRF1-2 as a therapeutic target in EBV-associated lymphoma. PMID- 26530013 TI - At last! A Working Model of a Data Ecosystem for Continuous Learning in the Evolving Health Noosphere. PMID- 26530014 TI - Stimulation of immune systems by conjugated polymers and their potential as an alternative vaccine adjuvant. AB - Recently, conjugated polymers have been widely explored in the field of nanomedicine. Careful evaluations of their biological effects are thus urgently needed. Hereby, we systematically evaluated the biological effects of different types of conjugated polymers on macrophages and dendritic cells (DCs), which play critical roles in the innate and adaptive immune systems, respectively. While naked poly-(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate) ( PEDOT: PSS) exhibits a high level of cytotoxicity, polyethylene glycol (PEG) modified PEDOT: PSS (PEDOT:PSS-PEG) shows greatly reduced toxicity to various types of cells. To our surprise, PEGylation of PEDOT: PSS could obviously enhance the cellular uptake of these nanoparticles, leading to subsequent immune stimulations of both macrophages and DCs. In contrast, another type of conjugated polymer, polypyrrole (PPy), is found to be an inert material with neither significant cytotoxicity nor noticeable immune-stimulation activity. Interestingly, utilizing ovalbumin (OVA) as a model antigen, it is further uncovered in our ex vivo experiment that PEDOT: PSS-PEG may serve as an adjuvant to greatly enhance the immunogenicity of OVA upon simple mixing. Our study on the one hand suggests the promise of developing novel nano-adjuvants based on conjugated polymers, and on the other hand highlights the importance of careful evaluations of the impacts of any new nanomaterials developed for nanomedicine on the immune systems. PMID- 26530015 TI - Reconstructing temporal variation in great ape and other primate diets: A methodological framework for isotope analyses in hair. AB - Stable isotope analysis of carbon and nitrogen in hair provides a versatile tool for reconstructing feeding behavior in elusive primate species. Particularly in great apes, researchers can sample long hair completely non-invasively from nests, allowing the investigation of inter- and intra-individual dietary variation. Given its incremental growth pattern, hair records temporal shifts in diet over long periods and allows one to reconstruct seasonal dietary patterns in species that cannot be directly observed. However, as for other sample materials, there are potential drawbacks related to the properties of hair keratin. Here I review some important facts on the nature of primate hair and also introduce new isotopic data from infant bonobo hair to provide methodological recommendations for future sample collection in the field and sample preparation in the laboratory. While these methodological guidelines focus on great apes which can be sampled strictly non-invasively, I also consider applications to other free ranging primates. The biochemical composition, growth cycle, isotope turnover rate and isotopic fractionation in hair keratin are particularly relevant for data analysis and interpretation. Also, one can microscopically identify infant hairs and analyze them separately to study nursing and weaning behavior in primates. The goal of this article is to encourage primatologists to analyze the stable isotope ratios of hair to assess primate feeding ecology. Am. J. Primatol. 78:1004-1016, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26530016 TI - Reporting standards. PMID- 26530017 TI - Driven by theory. PMID- 26530018 TI - Drug therapy smartens up. PMID- 26530020 TI - Magnetic atoms: The makings of a Hund's metal. PMID- 26530021 TI - Dissipative adaptation in driven self-assembly. AB - In a collection of assembling particles that is allowed to reach thermal equilibrium, the energy of a given microscopic arrangement and the probability of observing the system in that arrangement obey a simple exponential relationship known as the Boltzmann distribution. Once the same thermally fluctuating particles are driven away from equilibrium by forces that do work on the system over time, however, it becomes significantly more challenging to relate the likelihood of a given outcome to familiar thermodynamic quantities. Nonetheless, it has long been appreciated that developing a sound and general understanding of the thermodynamics of such non-equilibrium scenarios could ultimately enable us to control and imitate the marvellous successes that living things achieve in driven self-assembly. Here, I suggest that such a theoretical understanding may at last be emerging, and trace its development from historic first steps to more recent discoveries. Focusing on these newer results, I propose that they imply a general thermodynamic mechanism for self-organization via dissipation of absorbed work that may be applicable in a broad class of driven many-body systems. PMID- 26530023 TI - Broadening students' minds. PMID- 26530022 TI - Controlling upconversion nanocrystals for emerging applications. AB - Lanthanide-doped upconversion nanocrystals enable anti-Stokes emission with pump intensities several orders of magnitude lower than required by conventional nonlinear optical techniques. Their exceptional properties, namely large anti Stokes shifts, sharp emission spectra and long excited-state lifetimes, have led to a diversity of applications. Here, we review upconversion nanocrystals from the perspective of fundamental concepts and examine the technical challenges in relation to emission colour tuning and luminescence enhancement. In particular, we highlight the advances in functionalization strategies that enable the broad utility of upconversion nanocrystals for multimodal imaging, cancer therapy, volumetric displays and photonics. PMID- 26530024 TI - Dielectrophoretic behavior of PEGylated RNase A inside a microchannel with diamond-shaped insulating posts. AB - Ribonuclease A (RNase A) has proven potential as a therapeutic agent, especially in its PEGylated form. Grafting of PEG molecules to this protein yields mono PEGylated (mono-PEG) and di-PEGylated (di-PEG) RNase A conjugates, and the unreacted protein. Mono-PEG RNase A is of great interest. The use of electrokinetic forces in microdevices represents a novel alternative to chromatographic methods to separate this specie. This work describes the dielectrophoretic behavior of the main protein products of the RNase A PEGylation inside a microchannel with insulators under direct current electric fields. This approach represents the first step in route to design micro-bioprocesses to separate PEGylated RNase A from unreacted native protein. The three proteins exhibited different dielectrophoretic behaviors. All of them experienced a marked streaming pattern at 3000 V consistent with positive dielectrophoresis. Native protein was not captured at any of the conditions tested, while mono-PEG RNase A and di-PEG RNase A were captured presumably due to positive dielectrophoresis at 4000 and 2500 V, respectively. Concentration of mono-PEG RNase A with a maximal enrichment efficiency of ~9.6 times the feed concentration was achieved in few seconds. These findings open the possibility of designing novel devices for rapid separation, concentration, and recovery of PEGylated RNase A in a one-step operation. PMID- 26530025 TI - Pien Tze Huang inhibits the proliferation, and induces the apoptosis and differentiation of colorectal cancer stem cells via suppression of the Notch1 pathway. AB - Cancer stem cells (CSCs) possess properties of continuous self-renewal, multi directional differentiation and natural chemoresistance, leading to the initiation, progression and relapse of cancer. The characteristics of CSCs are strongly associated with multiple cellular pathways such as Notch1 signaling. Therefore, targeting CSCs via suppressing the Notch1 pathway might represent a promising strategy for cancer treatment. The well-known traditional Chinese medicine (TCM) formula Pien Tze Huang (PZH) has long been used as an alternative remedy for various cancers including colorectal cancer (CRC). We previously reported that PZH contains a broad range of anticancer activities including an inhibitory effect on CSCs. To further elucidate the mode of action of PZH, in this study we isolated the stem-like side population (SP) from the human CRC SW480 cell line to investigate its effect on CSCs as well as the possible molecular mechanisms. As compared with non-SP cells, the isolated SW480 SP cells displayed stronger capacities of spheroid formation in vitro and tumorigenicity in vivo, demonstrating the stem cell-like features of SP cells. However, PZH treatment significantly decreased the percentage of SP cells in a dose-dependent manner. In addition, PZH significantly and does-dependently inhibited the viability and promoted the apoptosis and differentiation of the isolated SW480 SP cells. Moreover, PZH treatment profoundly reduced the mRNA and protein expression of Notch1 and Hes1 in the SP cells. Our findings suggest that PZH negatively modulates the characteristics of CSCs through suppression of the Notch1 signaling pathway. PMID- 26530026 TI - A Reversible DNA Logic Gate Platform Operated by One- and Two-Photon Excitations. AB - We demonstrate the use of two different wavelength ranges of excitation light as inputs to remotely trigger the responses of the self-assembled DNA devices (D OR). As an important feature of this device, the dependence of the readout fluorescent signals on the two external inputs, UV excitation for 1 min and/or near infrared irradiation (NIR) at 800 nm fs laser pulses, can mimic function of signal communication in OR logic gates. Their operations could be reset easily to its initial state. Furthermore, these DNA devices exhibit efficient cellular uptake, low cytotoxicity, and high bio-stability in different cell lines. They are considered as the first example of a photo-responsive DNA logic gate system, as well as a biocompatible, multi-wavelength excited system in response to UV and NIR. This is an important step to explore the concept of photo-responsive DNA based systems as versatile tools in DNA computing, display devices, optical communication, and biology. PMID- 26530027 TI - Congenital and childhood-onset myotonic dystrophy: importance of long-term data in natural history. PMID- 26530028 TI - Grade Inflation in Nursing Education: Proposed Solutions for an Ongoing Problem. AB - PROBLEM: The purpose of assigning grades at the conclusion of a course is to convey the level of achievement of learners. However, with the presence of grade inflation in nursing education, it poses a great threat to the evaluation process. PURPOSE: The purpose of this article is to highlight the factors that influence grade inflation and to explore possible solutions to minimize the incidence of grade inflation in nursing education. FINDINGS: A review of the literature revealed that a variety of factors influenced grade inflation and educators were indeed lenient with their grading practices, which hence attenuates the purpose of grading and evaluation. CONCLUSION: While it may be an arduous task for nursing faculty to evaluate nursing students, nursing faculty have the obligation to preserve academic integrity and must devise appropriate solutions to address the incidence of grade inflation in nursing education. PMID- 26530029 TI - "Every method seems to have its problems"- Perspectives on side effects of hormonal contraceptives in Morogoro Region, Tanzania. AB - BACKGROUND: Family planning has been shown to be an effective intervention for promoting maternal, newborn and child health. Despite family planning's multiple benefits, women's experiences of - or concerns related to - side effects present a formidable barrier to the sustained use of contraceptives, particularly in the postpartum period. This paper presents perspectives of postpartum, rural, Tanzanian women, their partners, public opinion leaders and community and health facility providers related to side effects associated with contraceptive use. METHODS: Qualitative interviews were conducted with postpartum women (n = 34), their partners (n = 23), community leaders (n = 12) and health providers based in both facilities (n = 12) and communities (n = 19) across Morogoro Region, Tanzania. Following data collection, digitally recorded data were transcribed, translated and coded using thematic analysis. RESULTS: Respondents described family planning positively due to the health and economic benefits associated with limiting and spacing births. However, side effects were consistently cited as a reason that women and their partners choose to forgo family planning altogether, discontinue methods, switch methods or use methods in an intermittent (and ineffective) manner. Respondents detailed side effects including excessive menstrual bleeding, missed menses, weight gain and fatigue. Women, their partners and community leaders also described concerns that contraceptives could induce sterility in women, or harm breastfeeding children via contamination of breast milk. Use of family planning during the postpartum period was viewed as particularly detrimental to a newborn's health in the first months of life. CONCLUSIONS: To meet Tanzania's national target of increasing contraceptive use from 34 to 60 % by 2015, appropriate counseling and dialogue on contraceptive side effects that speaks to pressing concerns outlined by women, their partners, communities and service providers are needed. PMID- 26530030 TI - Monitoring the oleuropein content of olive leaves and fruits using ultrasound- and salt-assisted liquid-liquid extraction optimized by response surface methodology and high-performance liquid chromatography. AB - A novel and rapid ultrasound- and salt-assisted liquid-liquid extraction coupled with high-performance liquid chromatography has been optimized by response surface methodology for the determination of oleuropein from olive leaves. Box Behnken design was used for optimizing the main parameters including ultrasound time (A), pH (B), salt concentration (C), and volume of miscible organic solvent (D). In this technique, a mixture of plant sample and extraction solvent was subjected to ultrasound waves. After ultrasound-assisted extraction, phase separation was performed by the addition of salt to the liquid phase. The optimal conditions for the highest extraction yield of oleuropein were ultrasound time, 30 min; volume of organic solvent, 2.5 mL; salt concentration, 25% w/v; and sample pH, 4. Experimental data were fitted with a quadratic model. Analysis of variance results show that BC interaction, A(2) , B(2) , C(2) , and D(2) are significant model terms. Unlike the conventional extraction methods for plant extracts, no evaporation and reconstitution operations were needed in the proposed technique. PMID- 26530031 TI - Cognitive-behavioural therapy for heroin and cocaine use: Ecological momentary assessment of homework simplification and compliance. AB - OBJECTIVES: The purpose of this study was to evaluate the effects of homework task difficulty and electronic-diary reminders on written homework completion during cognitive-behavioural therapy (CBT) for addiction. Completion of homework is an important element in CBT that may affect outcome. DESIGN: All participants received all combinations of our two interventions in a factorial 2 * 2 counterbalanced Latin-square design. METHODS: Methadone-maintained cocaine and heroin users were given homework between each of 12 weekly CBT sessions and carried electronic diaries that collected ecological momentary assessment (EMA) data on craving and exposure to drug-use triggers in four 3-week blocks assessing two levels of homework difficulty and prompted and unprompted homework. RESULTS: Neither simplified (picture-based) homework nor electronic reminders increased homework completion. In EMA reports, standard but not simplified homework seemed to buffer the craving that followed environmental exposure to drug cues. EMA recordings before and after the CBT intervention confirmed a decrease over time in craving for cocaine and heroin. CONCLUSIONS: These findings demonstrate the utility of EMA to assess treatment effects. However, the hypothesis that simplified homework would increase compliance was not supported. PRACTITIONER POINTS: Our simplifications of homework assignments for cognitive-behavioural therapy were mostly ineffective, or even counterproductive, perhaps because they did not engage sufficient depth of processing or because they were perceived as too simplistic. Our reminder beeps for homework were mostly ineffective, or even counterproductive, suggesting that mobile electronic interventions for substance use disorders may need to be more interactive. PMID- 26530032 TI - Characterization of the ecological role of genes mediating acid resistance in Lactobacillus reuteri during colonization of the gastrointestinal tract. AB - Rodent-derived strains of Lactobacillus reuteri densely colonize the forestomach of mice and possess several genes whose predicted functions constitute adaptations towards an acidic environment. The objective of this study was to systematically determine which genes of L. reuteri 100-23 contribute to tolerance towards host gastric acid secretion. Genes predicted to be involved in acid resistance were inactivated, and their contribution to survival under acidic conditions was confirmed in model gastric juice. Fitness of five mutants that showed impaired in vitro acid resistance were then compared through competition experiments in ex-germ-free mice that were either treated with omeprazole, a proton-pump inhibitor that suppresses acid secretion in the stomach, or left untreated. This analysis revealed that the urease cluster was the predominant factor in mediating resistance to gastric acid production. Population levels of the mutant, which were substantially decreased in untreated mice, were almost completely restored through omeprazole, demonstrating that urease production in L. reuteri is mainly devoted to overcome gastric acid. The findings provide novel information on the mechanisms by which L. reuteri colonizes its gastric niche and demonstrate that in silico gene predictions and in vitro tests have limitations for predicting the ecological functions of colonization factors in bacterial symbionts. PMID- 26530033 TI - Pemetrexed clinical studies in performance status 2 patients with non-small cell lung cancer (Review). AB - Because poor performance status (PS) is an independent prognostic factor in non small cell lung cancer (NSCLC), PS scores are widely used by oncologists to make treatment decisions. Advanced NSCLC patients with an Eastern Cooperative Oncology Group PS of 2 have poor prognoses and are frequently excluded from clinical trials. This article reviews the efficacy and safety of pemetrexed in this patient group. We identified English-language literature (through March 2015) involving completed and ongoing studies through searches of PubMed, meeting abstracts, ClinicalTrials.gov and the European Clinical Trials Register; search terms included 'pemetrexed,' 'NSCLC' and 'PS2'. Only studies reporting >=1 subset analysis of PS2 patients receiving pemetrexed were chosen. Our search identified a total of ten pemetrexed studies in PS2 patients. Eight studies included only chemonaive patients, one study included both chemonaive patients and patients with one prior chemotherapy regimen and one study included only patients with one prior regimen. In subset analyses in these studies, PS2 patients had worse outcomes than PS0-1 patients regardless of treatment. In a phase 3 study, chemonaive advanced NSCLC patients with PS2 receiving pemetrexed-carboplatin versus pemetrexed experienced improved overall survival [hazard ratio (HR)=0.62; P=0.001], progression-free survival (HR=0.46; P<0.001) and response (P=0.032). This review confirms the poorer outcomes in PS2 vs. PS0-1 patients. Although it is not an approved combination therapy, in clinical studies, PS2 patients treated with pemetrexed plus carboplatin as first-line therapy had improved response rates and survival. Additional research on PS2 patients is needed. PMID- 26530034 TI - The influence of motivation and attentional style on affective, cognitive, and behavioral outcomes of an exercise class. AB - Exercise classes are a popular form of physical activity. A greater understanding of the individual difference factors that might influence the outcomes of such classes could help to minimize the high dropout rates associated with exercise. The study explored the effects of dominant attentional style and degree of self determination on affective, cognitive, and behavioral outcomes following structured exercise classes. Data from 417 female participants revealed that those with a dominant attentional style for association (Associators) reported significantly (P < 0.05) more positive affective, cognitive, and behavioral outcomes than did Dissociators, and were more self-determined. Highly self determined individuals reported the most positive outcomes. Almost 29% of the variance in participants' affective valence could be explained by Dissociators' behavioral regulations. Results lend support to the notion that attentional style is associated with motivation. The combination of attentional style and degree of self-determination appear to be noteworthy individual difference factors that influence responses to exercise classes and could thus have a bearing on long term exercise adherence. PMID- 26530035 TI - Measures of Maternal Socioeconomic Status in Yemen and Association with Maternal and Child Health Outcomes. AB - BACKGROUND: Reliable measurement of socioeconomic status (SES) in health research requires extensive resources and can be challenging in low-income countries. We aimed to develop a set of maternal SES indices and investigate their associations with maternal and child health outcomes in rural Yemen. METHODS: We applied factor analysis based on principal component analysis extraction to construct the SES indices by capturing household attributes for 7295 women of reproductive age. Data were collected from a sub-national household survey conducted in six rural districts in four Yemeni provinces in 2008-2009. Logistic regression models were fitted to estimate the associations between the SES indices and maternal mortality, spontaneous abortion, stillbirth, neonatal and infant mortality. RESULTS: Three SES indices (wealth, educational and housing quality) were extracted, which together explained 54 % of the total variation in SES. Factor scores were derived and categorized into tertiles. After adjusting for potential confounding factors, higher tertiles of all the indices were inversely associated with spontaneous abortion. Higher tertiles of wealth and educational indices were inversely associated with stillbirth, neonatal and infant mortality. None of the SES indices was strongly associated with maternal mortality. CONCLUSION: By subjecting a number of household attributes to factor analysis, we derived three SES indices (wealth, educational, and housing quality) that are useful for maternal and child health research in rural Yemen. The indices were worthwhile in predicting a number of maternal and child health outcomes. In low-income settings, failure to account for the multidimensionality of SES may underestimate the influence of SES on maternal and child health. PMID- 26530036 TI - Evaluating Latino WIC Mothers' Perceptions of Infant's Healthy Growth: A Formative Assessment. AB - OBJECTIVES: This article reports on a formative assessment with Latino mothers in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) evaluating knowledge, attitudes and behaviors regarding healthy growth for infants and their understanding of infant growth monitoring. Further, we explored the acceptability and feasibility of mothers' monitoring their infants' growth. This assessment includes healthy growth perceptions from mothers, caregivers and from WIC staff. METHODS: Utilizing a mixed method approach, this assessment included qualitative focus groups with WIC mothers that included a growth chart plotting exercise and a quantitative survey. In-depth interviews with clinic staff discussing protocols used in assessing children's growth were also conducted in one WIC clinic. RESULTS: Focus group participants included 34 mothers and 19 caregivers with a mean age of 32 years; 90 % identified as Latino. Themes included concern for underweight status, and reports of limited conversations between mothers and healthcare providers regarding overweight status, and infant feeding practices/beliefs that may contribute to feeding behaviors associated with risk for excess weight gain during infancy. Growth charts were well received, mothers were able to plot with modest accuracy; but effectiveness of growth plotting might be limited without refinement for health literacy and the provision of culturally-sensitive education in relation to feeding behaviors to support healthy infant growth. CONCLUSIONS: This represents a first effort in evaluating Latino mothers' perceptions of infants' healthy growth and use growth charts as a potential tool that can help prevent excess weight gain in early infancy. PMID- 26530037 TI - Resveratrol attenuates the progress of liver fibrosis via the Akt/nuclear factor kappaB pathways. AB - Liver fibrosis is a wound-healing response to chronic liver injury that results in the accumulation of extracellular matrix proteins. It eventually leads to cirrhosis of the liver and liver failure, and it is a critical threat to the health and lives of patients with chronic liver diseases. No effective treatment is currently available. Resveratrol is a polyphenol with antioxidant, anti-cancer and anti-inflammatory properties. It has been reported that resveratrol prevents liver fibrosis, possibly by inhibiting NF-kappaB activation. The present study investigated the mechanisms by which resveratrol prevented liver fibrosis, focusing on the possible involvement of the NF-kappaB pathway. Mice with carbon tetrachloride (CCl4)-induced liver fibrosis were treated with various concentrations of resveratrol. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and tumor necrosis factor (TNF)-alpha were detected by ELISAs. Expression of alpha-smooth muscle actin (alpha-SMA), collagen I, inhibitor of NF-kappaB (IkappaB) and NF-kappaB were detected by western blot analysis. In addition, the present study examined the effects of resveratrol on the expression of fibrosis markers in LX-2 cells. Western blot analysis was further used to detect the levels of Akt and phosphorylated Akt, as well as the nuclear levels of IkappaB, phosphorylated IkappaB and NF-kappaB p65. The expression of alpha-SMA in resveratrol-treated LX-2 cells was detected by immunofluorescence and flow cytometry, which demonstrated that resveratrol decreased the expression of alpha-SMA in LX-2 cells. Resveratrol also decreased CCl4-induced upregulation of serum AST, ALT, TNF-alpha, alpha-SMA and collagen I. Finally, resveratrol prevented the activation of NF-kappaB and Akt. The results of the present study therefore indicated that resveratrol attenuates liver fibrosis via the Akt/NF-kappaB pathways. PMID- 26530038 TI - Identification of QTL for resistance to Mediterranean corn borer in a maize tropical line to improve temperate germplasm. AB - BACKGROUND: A QTL mapping study for maize resistance to the Mediterranean corn borer (MCB) was performed with a RIL population derived from the cross B73 * CML103. To develop commercial inbreds of maize resistant to the MCB for use in Europe, it would be useful to transfer resistance from tropical germplasm like the subtropical inbred CML103 to temperate lines. The inbred B73 was chosen as representative of the Stiff Stock heterotic group, a major heterotic group used in hybrid grown in both North American and Europe. The objectives were to study the architecture of genetic factors for resistance to MCB and to check the feasibility of using marker-assisted selection (MAS) for transferring those genetic factors. RESULTS: Eight quantitative trait loci (QTL) were declared significant for resistance traits and eight QTL were located for agronomic traits. Alleles from CML103 at QTL significant for tunnel length could reduce tunnel length made for MCB in inbred B73 in more than 8 cm; favorable alleles for yield were also found in CML103 and no genetic correlation coefficient between tunnel length and yield was detected. CONCLUSIONS: MAS for transferring resistance genes to corn borer attack from CML103 to B73 could be successful based on cross validation results and a negative effect on yield would not be expected. PMID- 26530039 TI - Effects of tofacitinib monotherapy on patient-reported outcomes in a randomized phase 3 study of patients with active rheumatoid arthritis and inadequate responses to DMARDs. AB - INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. METHOD: In this 6-month, phase 3, randomized, placebo controlled trial, 611 patients with inadequate response to disease-modifying anti rheumatic drugs (DMARD-IR) were randomized 4:4:1:1 to receive: tofacitinib 5 mg BID or tofacitinib 10 mg BID for the duration of the study, or placebo for 3 months followed by tofacitinib 5 mg BID or tofacitinib 10 mg BID. Patient reported outcomes (PROs) included: Patient Global Assessment of Disease Activity (PtGA); Patient Assessment of Pain (Pain); Health Assessment Questionnaire Disability Index (HAQ-DI); Medical Outcomes Survey (MOS) Short Form-36 (SF-36); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); and MOS Sleep Scale. Time-to-event data (PtGA and Pain) were collected using an interactive voice response system daily diary (baseline through day 14). RESULTS: At month 3, tofacitinib 5 and 10 mg BID demonstrated statistically significant improvements versus placebo in PtGA (both p < 0.0001), Pain (both p < 0.0001), HAQ-DI (both p < 0.0001), SF-36 Physical (p < 0.0001) and Mental (p < 0.05 [5 mg BID] and p < 0.0001 [10 mg BID]), Component Summary scores and all domain scores (p < 0.05-p < 0.0001) and FACIT-F (both p < 0.0001). Statistically significant changes from baseline in MOS Sleep Scale were reported for 10 mg BID (p < 0.05). Benefits of tofacitinib treatment were rapid in onset and significant improvements were reported at week 2 for PtGA, Pain and HAQ-DI, and differentiation from baseline was seen as early as 3 days after treatment initiation for interactive voice response system (IVRS) PtGA and IVRS Pain. The numbers needed to treat for patients to report changes greater than or equal to the minimum clinically important difference in PtGA, Pain, HAQ-DI, SF-36 Physical Component Summary score and FACIT-F ranged between 4.0-6.1 (5 mg BID) and 3.2-5.0 (10 mg BID). CONCLUSION: Tofacitinib monotherapy in DMARD-IR patients resulted in statistically significant and clinically meaningful improvements in multiple PROs versus placebo at month 3, with sustained improvements over 6 months. TRIAL REGISTRATION: Clinicaltrials.gov registration NCT00814307 , registered 22 December 2008. PMID- 26530040 TI - Development of coronary artery lesions in indolent Kawasaki disease following initial spontaneous defervescence: a retrospective cohort study. AB - BACKGROUND: No standard treatment protocol exists for Kawasaki disease (KD) after spontaneous defervescence that does not use intravenous immunoglobulin (IVIG). Moreover, some cases present an indolent course and later develop coronary artery lesions (CALs). We aimed herein to assess the short-term prognosis of KD after defervescence and to clarify the characteristics of indolent KD. STUDY DESIGN: The present report is the culmination of a 10-year retrospective cohort study of KD at two Japanese tertiary pediatric centers. Cases of spontaneously defervesced KD <= 7 days of illness without IVIG which were afebrile for >= 3 days were classified as 'defervesced KD' (dKD). Of these, cases which developed CALs, or received IVIG for ongoing systemic inflammation were sub-classified into the indolent KD group (iKD). The primary outcome was the prevalence of CALs. RESULTS: Among 968 KD patients, 7.3 % (71/968) fell into the dKD, and 11.2 % (8/71) into the iKD, groups. No difference in CAL prevalence was observed between the dKD group and the KD group treated with IVIG (9.9 % vs. 7.6 %, p value = 0.49). Six of the 8 iKD cases developed CALs between Days 11 and 23 (median 16) of illness. All iKD cases presented recurrent fever or re-elevated CRP; however, there were generally fewer persistent KD symptoms than at diagnosis. CONCLUSIONS: The prognosis of spontaneously defervesced KD was relatively benign. However, indolent cases with ongoing, systemic inflammation developed CALs. In some cases, immediate IVIG use can be withheld as long as recurrent fever and re-elevation of CRP are monitored and supplementary echocardiogram are conducted. PMID- 26530041 TI - Intramuscular Nodular Fasciitis of the Pectoralis Major. PMID- 26530042 TI - Using mesenchymal stem cells as a therapy for bone regeneration and repairing. AB - Bone is a unique tissue which could regenerate completely after injury rather than heal itself with a scar. Compared with other tissues the difference is that, during bone repairing and regeneration, after the inflammatory phase the mesenchymal stem cells (MSCs) are recruited to the injury site and differentiate into either chondroblasts or osteoblasts precursors, leading to bone repairing and regeneration. Besides these two precursors, the MSCs can also differentiate into adipocyte precursors, skeletal muscle precursors and some other mesodermal cells. With this multilineage potentiality, the MSCs are probably used to cure bone injury and other woundings in the near future. Here we will introduce the recent developments in understanding the mechanism of MSCs action in bone regeneration and repairing. PMID- 26530043 TI - Complex-I Alteration and Enhanced Mitochondrial Fusion Are Associated With Prostate Cancer Progression. AB - Mitochondria (mt) encoded respiratory complex-I (RCI) mutations and their pathogenicity remain largely unknown in prostate cancer (PCa). Little is known about the role of mtDNA loss on mt integrity in PCa. We determined mtDNA mutation in human and mice PCa and assessed the impact of mtDNA depletion on mt integrity. We also examined whether the circulating exosomes from PCa patients are transported to mt and carry mtDNA or mt proteins. We have employed next generation sequencing of the whole mt genome in human and Hi-myc PCa. The impact of mtDNA depletion on mt integrity, presence of mtDNA, and protein in sera exosomes was determined. A co-culture of human PCa cells and the circulating exosomes followed by confocal imaging determined co-localization of exosomes and mt. We observed frequent RCI mutations in human and Hi-myc PCa which disrupted corresponding complex protein expression. Depletion of mtDNA in PCa cells influenced mt integrity, increased expression of MFN1, MFN2, PINK1, and decreased expression of MT-TFA. Increased mt fusion and expression of PINK1 and DNM1L were also evident in the Hi-myc tumors. RCI-mtDNA, MFN2, and IMMT proteins were detected in the circulating exosomes of men with benign prostate hyperplasia (BPH) and progressive PCa. Circulating exosomes and mt co-localized in PCa cells. Our study identified new pathogenic RCI mutations in PCa and defined the impact of mtDNA loss on mt integrity. Presence of mtDNA and mt proteins in the circulating exosomes implicated their usefulness for biomarker development. PMID- 26530044 TI - Developmental Changes in Cross-Situational Word Learning: The Inverse Effect of Initial Accuracy. AB - Intuitively, the accuracy of initial word-referent mappings should be positively correlated with the outcome of learning. Yet recent evidence suggests an inverse effect of initial accuracy in adults, whereby greater accuracy of initial mappings is associated with poorer outcomes in a cross-situational learning task. Here, we examine the impact of initial accuracy on 4-year-olds, 10-year-olds, and adults. For half of the participants most word-referent mappings were initially correct and for the other half most mappings were initially incorrect. Initial accuracy was positively related to learning outcomes in 4-year-olds, had no effect on 10-year-olds' learning, and was inversely related to learning outcomes in adults. Examination of item learning patterns revealed item interdependence for adults and 4-year-olds but not 10-year-olds. These findings point to a qualitative change in language learning processes over development. PMID- 26530046 TI - Characterization of the Saccharomyces cerevisiae ATP-Interactome using the iTRAQ SPROX Technique. AB - The stability of proteins from rates of oxidation (SPROX) technique was used in combination with an isobaric mass tagging strategy to identify adenosine triphosphate (ATP) interacting proteins in the Saccharomyces cerevisiae proteome. The SPROX methodology utilized in this work enabled 373 proteins in a yeast cell lysate to be assayed for ATP interactions (both direct and indirect) using the non-hydrolyzable ATP analog, adenylyl imidodiphosphate (AMP-PNP). A total of 28 proteins were identified with AMP-PNP-induced thermodynamic stability changes. These protein hits included 14 proteins that were previously annotated as ATP binding proteins in the Saccharomyces Genome Database (SGD). The 14 non-annotated ATP-binding proteins included nine proteins that were previously found to be ATP sensitive in an earlier SPROX study using a stable isotope labeling with amino acids in cell culture (SILAC)-based approach. A bioinformatics analysis of the protein hits identified here and in the earlier SILAC-SPROX experiments revealed that many of the previously annotated ATP-binding protein hits were kinases, ligases, and chaperones. In contrast, many of the newly discovered ATP-sensitive proteins were not from these protein classes, but rather were hydrolases, oxidoreductases, and nucleic acid-binding proteins. Graphical Abstract ?. PMID- 26530047 TI - Combining split-and-merge and multi-seed region growing algorithms for uterine fibroid segmentation in MRgFUS treatments. AB - Uterine fibroids are benign tumors that can affect female patients during reproductive years. Magnetic resonance-guided focused ultrasound (MRgFUS) represents a noninvasive approach that uses thermal ablation principles to treat symptomatic fibroids. During traditional treatment planning, uterus, fibroids, and surrounding organs at risk must be manually marked on MR images by an operator. After treatment, an operator must segment, again manually, treated areas to evaluate the non-perfused volume (NPV) inside the fibroids. Both pre- and post-treatment procedures are time-consuming and operator-dependent. This paper presents a novel method, based on an advanced direct region detection model, for fibroid segmentation in MR images to address MRgFUS post-treatment segmentation issues. An incremental procedure is proposed: split-and-merge algorithm results are employed as multiple seed-region selections by an adaptive region growing procedure. The proposed approach segments multiple fibroids with different pixel intensity, even in the same MR image. The method was evaluated using area-based and distance-based metrics and was compared with other similar works in the literature. Segmentation results, performed on 14 patients, demonstrated the effectiveness of the proposed approach showing a sensitivity of 84.05 %, a specificity of 92.84 %, and a speedup factor of 1.56* with respect to classic region growing implementations (average values). PMID- 26530045 TI - Acute Atherosis of the Uterine Spiral Arteries: Clinicopathologic Implications. AB - Acute atherosis is unique vascular changes of the placenta associated with poor placentation. It is characterized by subendothelial lipid-filled foam cells, fibrinoid necrosis of the arterial wall, perivascular lymphocytic infiltration, and it is histologically similar to early-stage atherosclerosis. Acute atherosis is rare in normal pregnancies, but is frequently observed in non- transformed spiral arteries in abnormal pregnancies, such as preeclampsia, small for gestational age (SGA), fetal death, spontaneous preterm labor and preterm premature rupture of membranes. In preeclampsia, spiral arteries fail to develop physiologic transformation and retain thick walls and a narrow lumen. Failure of physiologic transformation of spiral arteries is believed to be the main cause of uteroplacental ischemia, which can lead to the production of anti-angiogenic factors and induce endothelial dysfunction and eventually predispose the pregnancy to preeclampsia. Acute atherosis is more frequently observed in the spiral arteries of the decidua of the placenta (parietalis or basalis) than in the decidual or myometrial segments of the placental bed. The presence and deeper location of acute atherosis is associated with poorer pregnancy outcomes, more severe disease, earlier onset of preeclampsia, and a greater frequency of SGA neonates in patients with preeclampsia. Moreover, the idea that the presence of acute atherosis in the placenta may increase the risk of future cardiovascular disease in women with a history of preeclampsia is of growing concern. Therefore, placental examination is crucial for retrospective investigation of pregnancy complications and outcomes, and accurate placental pathology based on universal diagnostic criteria in patients with abnormal pregnancies is essential for clinicopathologic correlation. PMID- 26530048 TI - Unsupervised segmentation of lung fields in chest radiographs using multiresolution fractal feature vector and deformable models. AB - Segmenting lung fields in a chest radiograph is essential for automatically analyzing an image. We present an unsupervised method based on multiresolution fractal feature vector. The feature vector characterizes the lung field region effectively. A fuzzy c-means clustering algorithm is then applied to obtain a satisfactory initial contour. The final contour is obtained by deformable models. The results show the feasibility and high performance of the proposed method. Furthermore, based on the segmentation of lung fields, the cardiothoracic ratio (CTR) can be measured. The CTR is a simple index for evaluating cardiac hypertrophy. After identifying a suspicious symptom based on the estimated CTR, a physician can suggest that the patient undergoes additional extensive tests before a treatment plan is finalized. PMID- 26530049 TI - Optical Coherence Tomography of the Labial Salivary Glands Reveals Age-Related Differences in Women. AB - The labial minor salivary glands (LSGs) play a role in medical research and practice due to their superficial location and involvement in both systemic and localized diseases. Swept-source optical coherence tomography (OCT) is a noninvasive modality that enables in vivo, micrometer resolution, wide-field three-dimensional imaging in seconds. A purpose-built swept-source OCT instrument was employed to acquire three-dimensional datasets covering the area of 2.43 cm(2) of the mucosa of the lower lip to the depth of 3.4 mm in young (n = 14; mean age +/- SD: 27 +/- 3 years; body mass index [BMI] 20.4 +/- 2.3 kg/m(2) ) and middle-aged women (n = 11; 54 +/- 6 years; 25.5 +/- 3.2 kg/m(2) ). Glandular tissue reflectivity mode (range 0-255; 86 +/- 17 vs. 68 +/- 12, p = 0.005), average single LSG area in tissue sample (5.26 +/- 2.62 mm(2) vs. 2.87 +/- 1.26 mm(2) , p = 0.011), and LSG surface filling factor (0.23 +/- 0.13 vs. 0.11 +/- 0.10, p = 0.027) had higher values in younger than in middle-aged women. A correlation between BMI and glandular tissue reflectivity mode (Spearman's rho = 0.60) was found (p = 0.002). The results highlight the potential value of LSGs' OCT morphometry in research regarding ageing. PMID- 26530050 TI - Analysis of the expression of Kv10.1 potassium channel in patients with brain metastases and glioblastoma multiforme: impact on survival. AB - BACKGROUND: Kv10.1, a voltage-gated potassium channel only detected in the healthy brain, was found to be aberrantly expressed in extracerebral cancers. Investigations of Kv10.1 in brain metastasis and glioblastoma multiforme (GBM) are lacking. METHODS: We analyzed the expression of Kv10.1 by immunohistochemistry in these brain tumors (75 metastasis from different primary tumors, 71 GBM patients) and the influence of a therapy with tricyclic antidepressants (which are Kv10.1 blockers) on survival. We also investigated Kv10.1 expression in the corresponding primary carcinomas of metastases patients. RESULTS: We observed positive Kv10.1 expression in 85.3 % of the brain metastases and in 77.5 % of GBMs. Patients with brain metastases, showing low Kv10.1 expression, had a significantly longer overall survival compared to those patients with high Kv10.1 expression. Metastases patients displaying low Kv10.1 expression and also receiving tricyclic antidepressants showed a significantly longer median overall survival as compared to untreated patients. CONCLUSIONS: Our data show that Kv10.1 is not only highly expressed in malignant tumors outside CNS, but also in the most frequent cerebral cancer entities, metastasis and GBM, which remain incurable in spite of aggressive multimodal therapies. Our results extend the correlation between dismal prognosis and Kv10.1 expression to patients with brain metastases or GBMs and, moreover, they strongly suggest a role of tricyclic antidepressants for personalized therapy of brain malignancies. PMID- 26530051 TI - A Platform-Independent Plugin for Navigating Online Radiology Cases. AB - Software methods that enable navigation of radiology cases on various digital platforms differ between handheld devices and desktop computers. This has resulted in poor compatibility of online radiology teaching files across mobile smartphones, tablets, and desktop computers. A standardized, platform independent, or "agnostic" approach for presenting online radiology content was produced in this work by leveraging modern hypertext markup language (HTML) and JavaScript web software technology. We describe the design and evaluation of this software, demonstrate its use across multiple viewing platforms, and make it publicly available as a model for future development efforts. PMID- 26530052 TI - Liver receptor homologue-1 and steroidogenic factor-1 expression in cultured granulosa cells from patients with endometriosis: A preliminary study. AB - AIM: The expression of aromatase (via CYP19 and the CYP19 PII promoter) and the orphan nuclear receptor family members, liver receptor homologue-1 (LRH-1) and steroidogenic factor-1 (SF-1) in cultured luteinized granulosa cells from women with endometriosis were investigated. METHODS: Luteinized granulosa cells from patients undergoing in vitro fertilization (16 patients with endometriosis and 28 controls) were examined for messenger ribonucleic acid (mRNA) expression of CYP19, CYP19 PII, LRH-1 and SF-1, determined by quantitative reverse transcription-polymerase chain reaction. Student's t-test, the Mann-Whitney U test and Spearman's rank correlation were used for statistical analysis. RESULTS: The number of high quality embryos in the endometriosis group was significantly lower than in the control group. The mRNA expression levels of CYP19, CYP19 PII, LRH-1 and SF-1 in granulosa-lutein cells were decreased in women with endometriosis compared to the control group. The simultaneous down-regulation expression of LRH-1, SF-1 and CYP19 PII in endometriotic granulosa cells indicated their positive correlation. CONCLUSION: Our results demonstrate aberrant expressions of SF-1 and LRH-1 in endometriotic granulosa-lutein cells. This finding may be helpful in understanding infertility associated with endometriosis and reduced P450 aromatase activity in endometriotic granulosa cells. PMID- 26530053 TI - Soybean yield in relation to distance from the Itaipu reservoir. AB - Crops close to small water bodies may exhibit changes in yield if the water mass causes significant changes in the microclimate of areas near the reservoir shoreline. The scientific literature describes this effect as occurring gradually, with higher intensity in the sites near the shoreline and decreasing intensity with distance from the reservoir. Experiments with two soybean cultivars were conducted during four crop seasons to evaluate soybean yield in relation to distance from the Itaipu reservoir and determine the effect of air temperature and water availability on soybean crop yield. Fifteen experimental sites were distributed in three transects perpendicular to the Itaipu reservoir, covering an area at approximately 10 km from the shoreline. The yield gradient between the site closest to the reservoir and the sites farther away in each transect did not show a consistent trend, but varied as a function of distance, crop season, and cultivar. This finding indicates that the Itaipu reservoir does not affect the yield of soybean plants grown within approximately 10 km from the shoreline. In addition, the variation in yield among the experimental sites was not attributed to thermal conditions because the temperature was similar within transects. However, the crop water availability was responsible for higher differences in yield among the neighboring experimental sites related to water stress caused by spatial variability in rainfall, especially during the soybean reproductive period in January and February. PMID- 26530054 TI - Nicotine enhances invasion and metastasis of human colorectal cancer cells through the nicotinic acetylcholine receptor downstream p38 MAPK signaling pathway. AB - Nicotine as a cigarette component is an established risk factor for colorectal cancer tumorigenesis. The downstream signaling pathways of nicotinic acetylcholine receptors (nAchRs) are believed to be responsible for the cellular effects. In the present study, we evaluated the effects and novel mechanisms for nicotine on the capacity for colorectal cancer cell invasion and metastasis. LOVO and SW620 colorectal cancer cells were stimulated with nicotine in vitro. A Transwell chamber model was applied to detect the capacity for tumor cell invasion. Assays for gelatin zymography and western blotting were applied to detect the activity and expression of metastasis-related matrix metalloproteinases (MMPs), respectively. Signal transduction was assessed by immunoblotting for the phosphorylation of relevant signal molecules and the application of pharmaceutical inhibitors. We showed that nicotine increased LOVO and SW620 colorectal cancer cell invasion along with enhanced activity and expression of MMP-1, -2 and -9. Nicotine increased phosphorylation of p38, ERK, Akt and PI3K p85 but had no effect on phosphorylation of JNK, or NF-kappaB. Of the pharmaceutical inhibitors of U0126 (ERK1/2 inhibitor), LY294002 (Akt activation inhibitor), SB239063 (p38 MAPK activation inhibitor) and hexamethonium (Hex) (nAchRs inhibitor), the cellular and molecular effects were reduced by the applications of SB239063 and Hex. We concluded that nicotine stimulates the invasion and metastasis of colon cancer cells in vitro via activation of the nAchRs and the p38 MAPK downstream signaling pathway. Therefore, p38 MAPK may have potential as a therapeutic target for smoking-related human colorectal cancer metastasis. PMID- 26530055 TI - Recurrent nightly ketosis after prolonged exercise in type 1 diabetes - the need for glycogen replacement strategies. Case report and review of literature. AB - Exercise in diabetes patients has many benefits but also several risks, of which hypoglycemia is most often discussed. We present a case with recurrent keto acidosis post-exercise, in which we hypothesize that glycogen replacement strategies were insufficient. Our experience in this case and review of the literature emphasize the importance of discussing glycogen replacement strategies with your diabetic athletes. PMID- 26530056 TI - Targeting Dopaminergic System for Treating Nicotine Dependence. AB - BACKGROUND: Smoking is the world's leading cause of preventable death among populations. Cigarette smoking increases the risk of numerous health problems, including heart diseases, stroke, atherosclerosis and many types of cancer, including lung, stomach and bladder cancers. OUTCOMES: Many individuals find it difficult to stop smoking because of the addictive effects of nicotine and the presence of several monoamine oxidase (MAO) inhibitors in the tobacco smoke extract. OBJECTIVE: The development of novel, safe and effective medications for smoking cessation is a high public health priority. RESULTS: The role of mesocorticolimbic dopaminergic pathways in withdrawal symptoms and general reinforcement processes clearly recommends dopaminergic system as a potential target for the treatment of nicotine addiction. CONCLUSION: This review article discusses the new pharmacological treatments of nicotine dependence, which are targeting dopaminergic neurotransmission. This includes blockade of dopamine transporter and inhibition of MAO as pharmacotherapy for the treatment of nicotine dependence. PMID- 26530057 TI - Basing approval of drugs for type 2 diabetes on real world outcomes. PMID- 26530059 TI - Breastfeeding-Associated Hypernatremia: A Systematic Review of the Literature. AB - There are increasing reports on hypernatremia, a potentially devastating condition, in exclusively breastfed newborn infants. Our purposes were to describe the clinical features of the condition and identify the risk factors for it. We performed a review of the existing literature in the National Library of Medicine database and in the search engine Google Scholar. A total of 115 reports were included in the final analysis. Breastfeeding-associated neonatal hypernatremia was recognized in infants who were <= 21 days of age and had >= 10% weight loss of birth weight. Cesarean delivery, primiparity, breast anomalies or breastfeeding problems, excessive prepregnancy maternal weight, delayed first breastfeeding, lack of previous breastfeeding experience, and low maternal education level were significantly associated with breastfeeding-associated hypernatremia. In addition to excessive weight loss (>= 10%), the following clinical findings were observed: poor feeding, poor hydration state, jaundice, excessive body temperature, irritability or lethargy, decreased urine output, and epileptic seizures. In conclusion, the present survey of the literature identifies the following risk factors for breastfeeding-associated neonatal hypernatremia: cesarean delivery, primiparity, breastfeeding problems, excessive maternal body weight, delayed breastfeeding, lack of previous breastfeeding experience, and low maternal education level. PMID- 26530058 TI - Emerging Treatments for Neuropathic Pain. AB - Neuropathic pain is a series of well-known conditions caused by diseases or lesions to the somatosensory system. Due to the better understanding of the pathophysiology of neuropathic pain, previously unexplored therapies have been used with encouraging results. As such, Acetyl-L-carnitine (ALC), Alpha-lipoic acid (ALA), cannabinoids, Clonidine, EMA401, Botulinum Toxin type A, and new voltage-gated sodium channel blockers, can be cited. Furthermore, new modalities in neuromodulation such as high-frequency spinal cord stimulation, burst stimulation, dorsal root ganglion stimulation, transcranial direct current stimulation, and many others have been showing exciting results. Besides, changing paradigms may occur with the advent of optogenetics and a better understanding of epigenetic regulation. This article reviews the published literature on the treatment of NP. Despite the interesting results, randomized controlled trials are demanded for the majority of the therapies previously mentioned. PMID- 26530060 TI - Errata to NLP study of infusion notes to identify outpatient infusions in the VA. PMID- 26530062 TI - Multi-walled carbon nanotubes increase anxiety levels in rats and reduce exploratory activity in the open field test. AB - The results of the first study on the effects of multi-walled carbon nanotubes (MWNTs) on the exploratory activity and the emotional state in laboratory rats assessed by the open field test are reported. During three or ten days, rats received 8-10 nm MWNTs added to their food at a dose of 500 mg/kg. It was demonstrated that, in the group of rats which were fed with MWNTs, the integrated anxiety level index began to increase as early as the third day of the experiment; on the tenth day, it appeared to be twice increased. It was also demonstrated that MWNTs decreased the integrated exploratory activity index nearly twofold on the third day and nearly fourfold on the tenth day. PMID- 26530063 TI - Structure of "species flocks" in fishes: Channels of the splanchnocranium divergence in endemic lacustrine benthivorous charrs (Salvelinus, Salmonidae, Teleostei) in Lake Kronotskoye, Kamchatka. AB - The structure of splanchnocranium bones has been studied in four endemic benthivorous charrs (the genus Salvelinus) from Lake Kronotskoe (Kamchatka). It has been found that, according to the whole set of characters of the splanchnocranium structure, the most expressed differences are observed between specialized forms, nosed and largemouth charrs, inhabiting different biotopes of the lake. Differences between small-mouth and white charrs are less pronounced, and the species are characterized by generalized features of the structure of jaws. It can be suggested that, in addition to diverse feeding preferences within a feeding niche, an extremely high diversity of charrs in Lake Kronotskoe is due to a complex geomorphological structure of the water system. Thus, the "species flock" comprising a complex set of diverse benthivorous morphotypes has been formed and exists in Lake Kronotskoe. Charrs from Lake Kronotskoe are a representative example of sympatric speciation by way of formation of new forms differing from each other in morphological, ecological, and trophic features. PMID- 26530064 TI - Phylogenetic position of the Gansu mole Scapanulus oweni Thomas, 1912 and the relationships between strictly fossorial tribes of the family talpidae. AB - The results of the first molecular study focused on the phylogenetic position of the Gansu mole, Scapanulus oweni are presented. The analysis based on sequences of the mitochondrial cytb gene and five nuclear genes supports the monophyly of the Scalopini tribe including S. oweni and shows that two highly fossorial talpid tribes, Talpini and Scalopini, are not immediate sister taxa. These results highlight the role of morphological parallelism as a potential source of conflict between molecular and morphology-based phylogenies in Talpidae. PMID- 26530065 TI - Fluxes of energy, H2O, and CO2 between the atmosphere and the monsoon tropical forest in Southern Vietnam. AB - The 2.5-year dynamics of heat, water and carbon dioxide fluxes in the tropical monsoon semi-evergreen forest in Southern Vietnam obtained by means of continuous eddy covariance observations using standard procedures of FLUXNET global network are analyzed. The features of wet seasons during the measurement period were close to long-term average ones, but dry seasons had a great heterogeneity. The maximal duration of the period with little precipitation was 4 months. The annual radiation balance in the south of Vietnam exceeded the balance at all stations of FLUXNET in tropical forests, except one. Annual evapotranspiration in monsoon forest of south of Vietnam is approximately equal to the evaporation of the rain forests of Central Amazonia. During the wet season evapotranspiration spent 80% of the radiation balance, and in the driest months this value decreased to 50%. In the dry season reduction of evapotranspiration and gross primary production was relatively small due to photosynthesizing trees of 2-4 canopy sub-layers. For the first time a large net sink of carbon dioxide from the atmosphere in the monsoon forest ecosystem was identified. PMID- 26530066 TI - Scanning electron microscopy of the iridescent feather architectonics of the white throated needletail (Hirundapus caudacutus, Apodidae, Aves). AB - By means of SEM, it has been demonstrated that structural coloration of the needletail Hirundapus caudacutus depends on architectonics of iridescent feathers of the bird. PMID- 26530067 TI - The lophophore innervation pattern of the inarticulate brachiopod Lingula anatina (Brachiopoda) supports monophyly of Lophophorata. AB - Lophophore innervation in the brachiopod Lingula anatina has been investigated using immunocytochemistry and laser confocal microscopy. Three prominent nerves, namely, the main brachial nerve, the accessory brachial nerve, and the lower brachial nerve, have been found to extend along each brachium of the lophophore. Tentacle innervation is also described in detail. Comparative analysis revealed homologous nerves in lophophores of brachiopods, phoronids, and bryozoans. Similarities in tentacle innervation in these phyla of invertebrates have been detected. The results obtained confirm lophophore homology in different groups of lophophorates and provide evidence for monophyly of Lophophorata. PMID- 26530068 TI - The late Neopleistocene dhole (Carnivora, Canidae, Cuon alpinus Pallas, 1811) from the Urals. AB - Morphotypic and morphometric analyses of the M2 tooth found in the Late Pleistocene deposits of the Ignatievskaya Cave (southern Urals) demonstrate that this tooth belongs to the dhole (Cuon alpinus Pallas, 1811). This is the first reliable evidence for the presence of the dhole in the Urals. Radiocarbon dating and associated theriofauna allow the tooth to be dated to the first half of the late Neopleistocene or, more precisely, to marine isotope stages (MISs) 3 and 4. PMID- 26530069 TI - A new map of the vegetation of central European Russia based on high-resolution satellite data. AB - The scientific basis of and approaches to regional thematic mapping of vegetation based on high-resolution satellite data have been elaborated. A vegetation map of central European Russia has been compiled. The map includes 12 thematic classes, six of which pertain to forest ecosystems. The map has been compared to the data of the GFC project (University of Maryland, United States) and the official data of the Rosstat Federal Service of State Statistics (Russia). The new vegetation map is currently used in the information system of the remote monitoring of forest fires in Russia. PMID- 26530070 TI - Impact of industrial contamination on the populations of small forest rodents. AB - Investigations performed for monitoring the impact of industrial contamination from the Kostomuksha ore mining and processing enterprise (northern Karelia) on the populations of forest mouse-like rodents revealed increased embryonic mortality (three to four times higher compared to the control) in breeding females from the areas contaminated by nitrogen and sulfur oxides within the territory studied. The toxicants also influence other parameters of the population: abundance dynamics, ecological and spatial structure of the population, and reproduction rates. The results demonstrate that the population reactions of species may turn out to be more accurate and demonstrative when estimating the consequences of industrial contamination than the direct concentrations of a particular toxicant in the animal body. PMID- 26530071 TI - The first record of Deinotherium (Proboscidea, Mammalia) in the Miocene of Adygea. AB - The data on an isolated upper tooth (P4) of Deinotherium sp. from the Late Miocene beds of the Maikop 1 locality (Maikop, Republic of Adygea) are reported. This is the first record of Deinotherium from the Upper Miocene of Russia. The tooth crown of P4 is similar in size to D. proavum Eichwald, 1831 (= D. gigantissimum Stefanescu, 1892). PMID- 26530072 TI - The role of CK2 protein kinase in stress response of RAW 264.7 macrophages. AB - The role of casein kinase 2 (CK2) in the activation of the key NF-kappaB signaling cascade and other signaling and stress proteins during stress induced by exposure to nonthermal low-intensity electromagnetic radiation has been investigated. The ability of CK2 to regulate the activation of the NF-kappaB signaling cascade and upregulate the proinflammatory cytokine production and TLR4 receptor expression has been demonstrated. The existence of an alternative signaling pathway for NF-kappaB cascade activation directly involving protein kinase CK2 has been demonstrated using inhibition analysis in cells stressed by microwave irradiation. PMID- 26530073 TI - Role of B cells in presentation of autoantigens to CD4(+) T cells in patients with autoimmune thyroiditis. AB - The antigen-presenting activity of B cells and expression of molecules involved in antigen presentation by B cells have been studied in patients with autoimmune thyroiditis (AIT). The disease is characterized by enhanced expression of the costimulatory molecule CD80 in naive B cells (CD19(+)CD27(-) cells) both ex vivo and under the conditions of polyclonal cell activation in a culture. Under in vitro conditions, antigen-loaded B cells have been shown to be capable of inducing proliferation of autologous CD4(+) cells, in particular, proliferation of autospecific T cells in patients with AIT. Given that an intense infiltration of thyroid tissue by B cells is a typical sign of AIT, the antigen-presenting activity of B cells appears to contribute to this pathology. PMID- 26530074 TI - The effect of kisspeptin on the functional characteristics of isolated NK cells. AB - The effect of kisspeptin at concentrations typical of pregnancy on the functional activity of isolated cytokine-primed NK cells has been investigated. The hormone has been shown to promote an increase in the proportion of CD56(bright) NK cells, as well as an increase in the L-selectin expression on the cell surface. Assessment of cytokine levels has shown that kisspeptin suppresses the production of IL-4, IL-10, and IFN-gamma while stimulating the production of TGF-beta by isolated NK cells. The overall effect of the hormone investigated consisted in the formation of a phenotype and a cytokine spectrum characteristic of the regulatory NK3 subpopulation of NK cells in pregnancy. PMID- 26530075 TI - Analysis of In Vitro Aptamer Selection Parameters. AB - Nucleic acid aptamers are novel molecular recognition tools that offer many advantages compared to their antibody and peptide-based counterparts. However, challenges associated with in vitro selection, characterization, and validation have limited their wide-spread use in the fields of diagnostics and therapeutics. Here, we extracted detailed information about aptamer selection experiments housed in the Aptamer Base, spanning over two decades, to perform the first parameter analysis of conditions used to identify and isolate aptamers de novo. We used information from 492 published SELEX experiments and studied the relationships between the nucleic acid library, target choice, selection methods, experimental conditions, and the affinity of the resulting aptamer candidates. Our findings highlight that the choice of target and selection template made the largest and most significant impact on the success of a de novo aptamer selection. Our results further emphasize the need for improved documentation and more thorough experimentation of SELEX criteria to determine their correlation with SELEX success. PMID- 26530076 TI - Sequence Mutation and Structural Alteration Transform a Noncatalytic DNA Sequence into an Efficient RNA-Cleaving DNAzyme. AB - We have previously shown that through test-tube molecular evolution, an arbitrarily chosen noncatalytic DNA sequence can be evolved into a catalytic DNA (DNAzyme) with significant RNA-cleaving activity. In this study, we aim to address the question of whether the catalytic activity of such a DNAzyme can be further optimized using in vitro selection. Several cycles of selective enrichment starting with a partially randomized DNA library have resulted in the isolation of many sequence variations that show notably improved catalytic activity. Bioinformatic analysis and activity examination of several DNAzyme substrate constructs have led to two interesting findings about sequence mutations and the secondary structure of this DNAzyme: (1) three crucial mutations have transformed the DNAzyme into 8-17, a DNAzyme that has been discovered in multiple previous in vitro selection experiments, and (2) other mutations have allowed this special 8-17 variant to make structural fine-tuning in order to cleave an arbitrarily chosen RNA-containing substrate with a defined sequence. Our study not only showcases the combined power of directed molecular evolution and in vitro selection techniques in turning a noncatalytic nucleic acid sequence into an efficient enzyme, but it also raises the question of whether mother nature has used a similar approach to evolve natural enzymes. PMID- 26530078 TI - Does the Swiss School of Public Health exist? PMID- 26530079 TI - Age Deficits in Facial Affect Recognition: The Influence of Dynamic Cues. AB - Objectives: Older adults have difficulties in identifying most facial expressions of emotion. However, most aging studies have presented static photographs of intense expressions, whereas in everyday experience people see emotions that develop and change. The present study was designed to assess whether age-related difficulties with emotion recognition are reduced when more ecologically valid (i.e., dynamic) stimuli are used. Method: We examined the effect of stimuli format (i.e., static vs. dynamic) on facial affect recognition in two separate studies that included independent samples and distinct stimuli sets. In addition to younger and older participants, a middle-aged group was included in Study 1 and eye gaze patterns were assessed in Study 2. Results: Across both studies, older adults performed worse than younger adults on measures of facial affect recognition. In Study 1, older and-middle aged adults benefited from dynamic stimuli, but only when the emotional displays were subtle. Younger adults gazed more at the eye region of the face relative to older adults (Study 2), but dynamic presentation increased attention towards the eye region for younger adults only. Discussion: Together, these studies provide important and novel insights into the specific circumstances in which older adults may be expected to experience difficulties in perceiving facial emotions. PMID- 26530077 TI - Animal and human mucosal tissue models to study HIV biomedical interventions: can we predict success? AB - INTRODUCTION: Preclinical testing plays an integral role in the development of HIV prevention modalities. Several models are used including humanized mice, non human primates and human mucosal tissue cultures. DISCUSSION: Pharmaceutical development traditionally uses preclinical models to evaluate product safety. The HIV prevention field has extended this paradigm to include models of efficacy, encompassing humanized mice, non-human primates (typically Asian macaques) and human mucosal tissue (such as cervical and colorectal). As our understanding of the biology of HIV transmission improves and includes the influence of human behaviour/biology and co-pathogens, these models have evolved as well to address more complex questions. These three models have demonstrated the effectiveness of systemic (oral) and topical use of antiretroviral drugs. Importantly, pharmacokinetic/pharmacodynamic relationships are being developed and linked to information gathered from human clinical trials. The models are incorporating co pathogens (bacterial and viral) and the effects of coitus (mucosal fluids) on drug distribution and efficacy. Humanized mice are being tailored in their immune reconstitution to better represent humans. Importantly, human mucosal tissue cultures are now being used in early clinical trials to provide information on product efficacy to more accurately characterize efficacious products to advance to larger clinical trials. While all of these models have made advancements in product development, each has limitations and the data need to be interpreted by keeping these limitations in mind. CONCLUSIONS: Development and refinement of each of these models has been an iterative process and linkages to data generated among each of them and from human clinical trials are needed to determine their reliability. Preclinical testing has evolved from simply identifying products that demonstrate efficacy prior to clinical trials to defining essential pharmacokinetic/pharmacodynamic relationships under a variety of conditions and has the potential to improve product selection prior to the initiation of large scale human clinical trials. The goal is to provide researchers with ample information to make conversant decisions that guide optimized and efficient product development. PMID- 26530080 TI - Benzothiazole-Pyimidine-Based BF2 Complex for Selective Detection of Cysteine. AB - Due to the similar structure and reactivity of cysteine (Cys), homocysteine (Hcy) and glutathione (GSH), the simultaneous discrimination of Cys over Hcy and GSH by a single fluorescent sensor is still a great challenge. In this work, a benzothiazole-pyimidine-based boron difluoride complex (BPB) was developed as a new fluorescent sensor for Cys. The sensor exhibits a highly selective "turn-on" response to cysteine over Hcy, GSH and other amino acids in aqueous solution at physiological pH. The observed pseudo-first-order rate constant for the reaction of BPB with Cys was calculated to be about 0.062 min(-1) . The detection limit of this sensor for Cys was determined to be 332 nm, and bioimaging of exogenous Cys by this sensor was successfully applied in living cells, thus indicating that this sensor holds great potential for biological applications. PMID- 26530081 TI - Exploring the phosphoproteome profiles during Xenopus egg activation by calcium stimulation using a fully automated phosphopeptide purification system. AB - To explore the phosphoproteome profiles duringXenopusegg activation by Ca(2+) stimulation, an automated phosphopeptide purification system involving a titania column was improved by introducing 4-step elution with phosphate buffers. The number of detected phosphopeptides in the tryptic digest of aXenopusegg cytosol fraction on mass spectrometry (MS) was increased 1.5-fold and the percentage of multiply phosphorylated peptides increased from 17 to 24% with introduction of the 4-step elution method. Phosphopeptides were purified by the improved method from tryptic digests of cytosol fractions ofXenopuseggs without and with a Ca(2+) stimulus, and then, analysed by MS. One thousand three hundred and seventy-five and 994 phosphopeptides were reproducibly detected on duplicate MS, respectively. They included 818 and 437 phosphopeptides specific to each digest, respectively. A method involving isobaric tags for relative and absolute quantitation (iTRAQ) was also applied to compare the phosphorylation levels inXenopuseggs without and with a Ca(2+)-stimulus, the ratios for 112 phosphopeptides in tryptic digests of these egg cytosol fractions being obtained. It was suggested from all the results that the phosphorylation sites and levels change duringXenopusegg activation for many known and unknown sites on structural proteins, signalling related proteins, cell cycle-related proteins and others. PMID- 26530082 TI - Advancing the Science of Pediatric Antimicrobial Stewardship Beyond Utilization and Direct Costs. PMID- 26530084 TI - Sphingosine-1-phosphate metabolism: can its enigmatic lyase promote the autophagy of fibrosis? PMID- 26530085 TI - Diagnostic procedures for non-small-cell lung cancer (NSCLC): recommendations of the European Expert Group. AB - BACKGROUND: There is currently no Europe-wide consensus on the appropriate preanalytical measures and workflow to optimise procedures for tissue-based molecular testing of non-small-cell lung cancer (NSCLC). To address this, a group of lung cancer experts (see list of authors) convened to discuss and propose standard operating procedures (SOPs) for NSCLC. METHODS: Based on earlier meetings and scientific expertise on lung cancer, a multidisciplinary group meeting was aligned. The aim was to include all relevant aspects concerning NSCLC diagnosis. After careful consideration, the following topics were selected and each was reviewed by the experts: surgical resection and sampling; biopsy procedures for analysis; preanalytical and other variables affecting quality of tissue; tissue conservation; testing procedures for epidermal growth factor receptor, anaplastic lymphoma kinase and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) in lung tissue and cytological specimens; as well as standardised reporting and quality control (QC). Finally, an optimal workflow was described. RESULTS: Suggested optimal procedures and workflows are discussed in detail. The broad consensus was that the complex workflow presented can only be executed effectively by an interdisciplinary approach using a well-trained team. CONCLUSIONS: To optimise diagnosis and treatment of patients with NSCLC, it is essential to establish SOPs that are adaptable to the local situation. In addition, a continuous QC system and a local multidisciplinary tumour-type oriented board are essential. PMID- 26530086 TI - Plants Release Precursors of Histone Deacetylase Inhibitors to Suppress Growth of Competitors. AB - To secure their access to water, light, and nutrients, many plant species have developed allelopathic strategies to suppress competitors. To this end, they release into the rhizosphere phytotoxic substances that inhibit the germination and growth of neighbors. Despite the importance of allelopathy in shaping natural plant communities and for agricultural production, the underlying molecular mechanisms are largely unknown. Here, we report that allelochemicals derived from the common class of cyclic hydroxamic acid root exudates directly affect the chromatin-modifying machinery in Arabidopsis thaliana. These allelochemicals inhibit histone deacetylases both in vitro and in vivo and exert their activity through locus-specific alterations of histone acetylation and associated gene expression. Our multilevel analysis collectively shows how plant-plant interactions interfere with a fundamental cellular process, histone acetylation, by targeting an evolutionarily highly conserved class of enzymes. PMID- 26530089 TI - Epigenetic Battles Underfoot: Allelopathy among Plants Can Target Chromatin Modification. PMID- 26530087 TI - The EF-Hand Ca2+ Binding Protein MICU Choreographs Mitochondrial Ca2+ Dynamics in Arabidopsis. AB - Plant organelle function must constantly adjust to environmental conditions, which requires dynamic coordination. Ca(2+) signaling may play a central role in this process. Free Ca(2+) dynamics are tightly regulated and differ markedly between the cytosol, plastid stroma, and mitochondrial matrix. The mechanistic basis of compartment-specific Ca(2+) dynamics is poorly understood. Here, we studied the function of At-MICU, an EF-hand protein of Arabidopsis thaliana with homology to constituents of the mitochondrial Ca(2+) uniporter machinery in mammals. MICU binds Ca(2+) and localizes to the mitochondria in Arabidopsis. In vivo imaging of roots expressing a genetically encoded Ca(2+) sensor in the mitochondrial matrix revealed that lack of MICU increased resting concentrations of free Ca(2+) in the matrix. Furthermore, Ca(2+) elevations triggered by auxin and extracellular ATP occurred more rapidly and reached higher maximal concentrations in the mitochondria of micu mutants, whereas cytosolic Ca(2+) signatures remained unchanged. These findings support the idea that a conserved uniporter system, with composition and regulation distinct from the mammalian machinery, mediates mitochondrial Ca(2+) uptake in plants under in vivo conditions. They further suggest that MICU acts as a throttle that controls Ca(2+) uptake by moderating influx, thereby shaping Ca(2+) signatures in the matrix and preserving mitochondrial homeostasis. Our results open the door to genetic dissection of mitochondrial Ca(2+) signaling in plants. PMID- 26530088 TI - FILAMENTOUS FLOWER Is a Direct Target of JAZ3 and Modulates Responses to Jasmonate. AB - The plant hormone jasmonate (JA) plays an important role in regulating growth, development, and immunity. Activation of the JA-signaling pathway is based on the hormone-triggered ubiquitination and removal of transcriptional repressors (JASMONATE-ZIM DOMAIN [JAZ] proteins) by an SCF receptor complex (SCF(COI1)/JAZ). This removal allows the rapid activation of transcription factors (TFs) triggering a multitude of downstream responses. Identification of TFs bound by the JAZ proteins is essential to better understand how the JA-signaling pathway modulates and integrates different responses. In this study, we found that the JAZ3 repressor physically interacts with the YABBY (YAB) family transcription factor FILAMENTOUS FLOWER (FIL)/YAB1. In Arabidopsis thaliana, FIL regulates developmental processes such as axial patterning and growth of lateral organs, shoot apical meristem activity, and inflorescence phyllotaxy. Phenotypic analysis of JA-regulated responses in loss- and gain-of-function FIL lines suggested that YABs function as transcriptional activators of JA-triggered responses. Moreover, we show that MYB75, a component of the WD-repeat/bHLH/MYB complex regulating anthocyanin production, is a direct transcriptional target of FIL. We propose that JAZ3 interacts with YABs to attenuate their transcriptional function. Upon perception of JA signal, degradation of JAZ3 by the SCF(COI1) complex releases YABs to activate a subset of JA-regulated genes in leaves leading to anthocyanin accumulation, chlorophyll loss, and reduced bacterial defense. PMID- 26530091 TI - Microarray Analysis Gene Expression Profiles in Laryngeal Muscle After Recurrent Laryngeal Nerve Injury. AB - OBJECTIVES: The pathophysiology of recurrent laryngeal nerve (RLN) transection injury is rare in that it is characteristically followed by a high degree of spontaneous reinnervation, with reinnervation of the laryngeal adductor complex (AC) preceding that of the abducting posterior cricoarytenoid (PCA) muscle. Here, we aim to elucidate the differentially expressed myogenic factors following RLN injury that may be at least partially responsible for the spontaneous reinnervation. METHODS: F344 male rats underwent RLN injury (n = 12) or sham surgery (n = 12). One week after RLN injury, larynges were harvested following euthanasia. The mRNA was extracted from PCA and AC muscles bilaterally, and microarray analysis was performed using a full rat genome array. RESULTS: Microarray analysis of denervated AC and PCA muscles demonstrated dramatic differences in gene expression profiles, with 205 individual probes that were differentially expressed between the denervated AC and PCA muscles and only 14 genes with similar expression patterns. CONCLUSIONS: The differential expression patterns of the AC and PCA suggest different mechanisms of reinnervation. The PCA showed the gene patterns of Wallerian degeneration, while the AC expressed the gene patterns of reinnervation by adjacent axonal sprouting. This finding may reveal important therapeutic targets applicable to RLN and other peripheral nerve injuries. PMID- 26530090 TI - Activity guided isolation and modification of juglone from Juglans regia as potent cytotoxic agent against lung cancer cell lines. AB - BACKGROUND: Juglans regia has been found to exhibit significant anticancer activity against various human cancer cell lines. This study was undertaken to isolate the active chemical constituent (Juglone) and to investigate its cytotoxic activity along with its various analogs against different human cancer cell lines. METHODS: Isolation of juglone, a napthoquinone, from the chloroform extract of the root part of Juglans regia was executed by flash chromatography using silica gel as stationary phase. The isolated Juglone was used as starting material for the further synthesis of a novel series of triazolyl analogs using click chemistry approach to investigate their cytotoxic potential against different human cancer cell lines using 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) assay. RESULTS: The different extracts of Juglans regia and the isolated compound (juglone) exhibited satisfactory cytotoxic activity against a panel of eight different human cancer cell lines namely, prostate colon (Colo-205 and HCT-116), breast (T47D), prostate (PC-3 and DU-145), skin (A-431) and lung (NCI-H322 and A549). Interestingly, all the synthesised analogs displayed enhanced and selective cytotoxic activity against lung cancer cell lines only. Of the synthesized derivatives, 15a and 16a displayed the best activity with IC50 of 4.72 and 4.67 MUM against A549 cells. Both these derivatives exhibited superior potency to BEZ-235 against both the lung cancer cell lines. So far as the structural aspects are concerned, electron withdrawing substituents at the ortho position of R moiety of the triazolyl analogs seem to be essential for attaining better activity. CONCLUSION: The present study demonstrates the selective and enhanced cytotoxic activity of the triazolyl analogs of juglone against NCI-H322 and A549 human lung cancer cell lines. Some derivatives exhibited superior potency to BEZ-235, a commercially available anticancer agent. PMID- 26530092 TI - External Branch of the Superior Laryngeal Nerve Mediated Glottic Closing Force in the Porcine Model. AB - OBJECTIVES: Based on our laboratory's newly confirmed motor pathway for glottic closure, we measured the glottic closing force (GCF) during isolated stimulation of the external branch of the superior laryngeal nerve (eSLN) in the porcine model. Glottic closure is 1 of the primary mechanisms for prevention of aspiration during deglutition. METHODS: The recurrent laryngeal nerve (RLN) and eSLN were identified bilaterally in 4 porcine necks. Subsequently, GCF was measured with a pressure transducer as the distal ends of individual nerves were stimulated in 4 animals. The RLN mediated GCF was measured first, followed by isolated eSLN mediated GCF, followed by transection of the RLN and repeat measurement of the eSLN GCF. Ultimately, the cricothyroid (CT) muscle attachment was released and the GCF measured. RESULTS: The GCF during isolated eSLN stimulation before and after RLN transection is approximately 89% of the RLN mediated GCF in each animal. The GCF after CT release is approximately 84% of the RLN perceived GCF. Transection of the RLN did not alter the eSLN observed GCF. CONCLUSIONS: The GCF obtained during isolated eSLN stimulation is adequate for delivery of an appropriate laryngeal protective response and may be considered a target motor nerve for augmenting GCF in selected rehab settings. PMID- 26530093 TI - Nasal and Tracheal Microbial Colonization in Laryngectomized Patients. AB - OBJECTIVE: Complete separation of upper and lower respiratory tract after total laryngectomy results in loss of physiological nasal functions and presence of "unconditioned" inspired air in lower airways. Aim of this study is evaluating the presence of a microbial colonization of nasal cavities and trachea in laryngectomized long-term survivors. METHODS: Twenty-five laryngectomized patients underwent symptoms' anamnestic evaluation, endoscopic fiber optic nasal and tracheal examination, specimen collection for microbiological exam, and culture. Enrolled patients had at least a 2-year follow-up period in order to evaluate long-term microflora. RESULTS: Gram positive polimicrobic flora represented the main finding in nasal cavities and trachea (92% and 48% of patients, respectively). Other bacteria were non-fermenters Gram negative bacteria, Enterobacteriaceae and Staphylococcus aureus. The same microflora was demonstrated in nasal cavity and trachea in 5 patients (20%), while sterile nasal cavity and trachea were seen in 3 (12%) and 4 (16%) cases, respectively. No fungi were observed in nasal cavity and trachea. CONCLUSION: Nasal cavities and trachea of laryngectomized patients are colonized by nonpathogenic and/or potentially pathogenic bacteria, in absence of signs and symptoms of infection. Colonizer microflora should be kept in mind when a culture from nasal or tracheal swabs is needed in daily practice. PMID- 26530094 TI - Audioprofile Surfaces: The 21st Century Audiogram. AB - OBJECTIVE: To present audiometric data in 3 dimensions by considering age as an addition dimension. METHODS: Audioprofile surfaces (APSs) were fitted to a set of audiograms by plotting each measurement of an audiogram as an independent point in 3 dimensions with the x, y, and z axes representing frequency, hearing loss in dB, and age, respectively. RESULTS: Using the Java-based APS viewer as a standalone application, APSs were pre-computed for 34 loci. By selecting APSs for the appropriate genetic locus, a clinician can compare this APS-generated average surface to a specific patient's audiogram. CONCLUSION: Audioprofile surfaces provide an easily interpreted visual representation of a person's hearing acuity relative to others with the same genetic cause of hearing loss. Audioprofile surfaces will support the generation and testing of sophisticated hypotheses to further refine our understanding of the biology of hearing. PMID- 26530095 TI - Prognostic Relevance of Mucosal Waves in Patients With Unilateral Vocal Fold Paralysis. AB - OBJECTIVES: To analyze the prognostic relevance of mucosal waves (MWs) for recovery of unilateral vocal fold paralysis (UVP). METHODS: The charts and stroboscopic examinations of 100 consecutive patients with a complete UVP were reviewed retrospectively. All had a minimal (estimated <3 mm) mucosal gap on stroboscopy. A positive or negative MW on the paralyzed vocal fold was associated with complete recovery to full adduction and abduction. All patients were followed for at least 12 months. RESULTS: Causes of the paralysis were iatrogenic/traumatic (n = 82), malignancy associated (n = 10), and idiopathic (n = 8). In patients with positive MW at diagnosis (n = 80), the chance of recovery of unilateral vocal fold paralysis was 91.25%, whereas the chance of recovery with a negative mucosal wave (n = 20) was only 10%. CONCLUSION: Positive MWs in stroboscopy are a predictor for recovery of (iatrogenic/traumatic) unilateral vocal fold paralysis and should be used in routine diagnostic assessment. PMID- 26530096 TI - 68Ga-DOTA-Siglec-9--a new imaging tool to detect synovitis. AB - INTRODUCTION: Vascular adhesion protein-1 (VAP-1) is an adhesion molecule, which upon inflammation is rapidly translocated from intracellular sources to the endothelial cell surface. We have recently discovered that sialic acid- binding immunoglobulin-like lectin 9 (Siglec-9) is a leukocyte ligand of VAP-1 and that 68Ga-labeled Siglec-9 motif peptide facilitates in vivo imaging of inflammation. This study evaluated the feasibility of 68Ga-DOTA-Siglec-9 positron emission tomography (PET) for the assessment of synovitis. METHODS: Rabbits with synovial inflammation were injected with 18F-FDG or 68Ga-DOTA-Siglec-9 and studied by gamma counting and autoradiography. Certain rabbits were also examined with magnetic resonance imaging (MRI). After PET imaging, rabbits were intravenously administered with anti-VAP-1 antibody to evaluate luminal expression of VAP-1 by immunohistochemistry. Finally, binding of Siglec-9 peptide and VAP-1 positive vessels were evaluated by double staining of rheumatoid arthritis synovium. RESULTS: Intra-articular injection of hemagglutinin induced mild synovial inflammation in rabbit knee with luminal expression of VAP-1. Synovitis was clearly visualized by 68Ga-DOTA-Siglec-9 PET in addition to 18F-FDG-PET and MRI. Compared with the 18F-FDG, the ex vivo inflamed-to-control synovium ratio of 68Ga DOTA-Siglec-9 was similar (1.7 +/- 0.4 vs. 1.5 +/- 0.2, P = 0.32). Double staining revealed that Siglec-9 peptide binds to VAP-1 positive vessels in human rheumatoid synovium. CONCLUSION: Ga-DOTA-Siglec-9 PET tracer detected VAP-1 positive vasculature in the mild synovitis of rabbits comparable with 18F-FDG, suggesting its potential for in vivo imaging of synovial inflammation in patients with rheumatic diseases. PMID- 26530097 TI - Identification of miRNAs associated with dark-induced senescence in Arabidopsis. AB - BACKGROUND: microRNAs (miRNAs) are endogenous small (~21 nucleotide) single stranded non-coding RNAs that typically function by guiding cleavage of target genes. To find the miRNAs that may be involved in dark-induced leaf senescence, we identified miRNAs by microarray platform using Arabidopsis thaliana leaves from both whole darkened plants (DPs) and individually darkened leaves (IDLs). RESULTS: We found that the expressions of 137 miRNAs (P < 0.01, signal intensity >0) were significantly changed both in DP and IDL leaves. Among them, the expression levels of 44 miRNAs were relative higher than others (P < 0.01, signal intensity > 500). Of these differentially expressed miRNAs, 6 miRNAs (miR319a, 319c, miR159, miR164a, miR164c and miR390a) have been previously reported to be involved in dark-induced leaf senescence, and the remaining 38 miRNAs have not been implicated in leaf senescence before. Target genes of all 44 miRNAs were predicted, and some of them, such as NAC1, At3g28690, At2g17640 and At2g45160, were found in the Leaf Senescence Database (LSD). GO and KEGG analysis of 137 miRNAs showed that the predicted target genes were significantly enriched in transcription regulation, development-related biological processes and metabolic pathways. Expression levels of some of the corresponding miRNA targets (At1g73440, At2g03220 and At5g54810) were analysed and found to be significantly different in DP/IDL than that in WT. CONCLUSIONS: A microarray analysis about dark-induced miRNAs involved in leaf senescence are present here. Further expression analysis revealed that some new founding miRNAs maybe regulate leaf senescence in Arabidopsis, and the findings highlight the important role of miRNAs in dark-induced leaf senescence. PMID- 26530099 TI - Editor's note: new biomaterials for dental and craniomaxillofacial applications section. PMID- 26530098 TI - Advantages of a next generation sequencing targeted approach for the molecular diagnosis of retinoblastoma. AB - BACKGROUND: Retinoblastoma (RB) is the most common malignant childhood tumor of the eye and results from inactivation of both alleles of the RB1 gene. Nowadays RB genetic diagnosis requires classical chromosome investigations, Multiplex Ligation-dependent Probe Amplification analysis (MLPA) and Sanger sequencing. Nevertheless, these techniques show some limitations. We report our experience on a cohort of RB patients using a combined approach of Next-Generation Sequencing (NGS) and RB1 custom array-Comparative Genomic Hybridization (aCGH). METHODS: A total of 65 patients with retinoblastoma were studied: 29 cases of bilateral RB and 36 cases of unilateral RB. All patients were previously tested with conventional cytogenetics and MLPA techniques. Fifty-three samples were then analysed using NGS. Eleven cases were analysed by RB1 custom aCGH. One last case was studied only by classic cytogenetics. Finally, it has been tested, in a lab sensitivity assay, the capability of NGS to detect artificial mosaicism series in previously recognized samples prepared at 3 different mosaicism frequencies: 10, 5, 1 %. RESULTS: Of the 29 cases of bilateral RB, 28 resulted positive (96.5 %) to the genetic investigation: 22 point mutations and 6 genomic rearrangements (four intragenic and two macrodeletion). A novel germline intragenic duplication, from exon18 to exon 23, was identified in a proband with bilateral RB. Of the 36 available cases of unilateral RB, 8 patients resulted positive (22 %) to the genetic investigation: 3 patients showed point mutations while 5 carried large deletion. Finally, we successfully validated, in a lab sensitivity assay, the capability of NGS to accurately measure level of artificial mosaicism down to 1 %. CONCLUSIONS: NGS and RB1-custom aCGH have demonstrated to be an effective combined approach in order to optimize the overall diagnostic procedures of RB. Custom aCGH is able to accurately detect genomic rearrangements allowing the characterization of their extension. NGS is extremely accurate in detecting single nucleotide variants, relatively simple to perform, cost savings and efficient and has confirmed a high sensitivity and accuracy in identifying low levels of artificial mosaicisms. PMID- 26530100 TI - Esophageal squamous cell carcinoma cell proliferation induced by exposure to low concentration of cigarette smoke extract is mediated via targeting miR-101-3p/COX 2 pathway. AB - Cigarette smoke has been implicated as a major risk factor for esophageal squamous cell carcinoma (ESCC). Several lines of evidence have suggested that the promoting effect of cigarette smoking extract (CSE) on ESCC is mediated by upregulation of cyclooxygenase-2 (COX-2) expression. Yet, the underlying molecular and cellular mechanisms of how CSE stimulates COX-2 expression and facilitates ESCC development are largely unknown. In the present study, we revealed microRNA (miR)-101-3p expression was downregulated upon exposure to low concentration of CSE in Eca109 cancer cells, and suppression of miR-101-3p was required for low CSE-induced cell proliferation, presenting as overexpression of miR-101-3p reversing CSE stimulated cancer cell growth. Luciferase assay revealed that COX-2 was a direct target for miR-101-3p and overexpression of miR-101-3p decreased cellular COX-2 protein expression. Furthermore, we found that COX-2 inhibitor and knockdown of COX-2 by siRNA interference could abolish CSE-induced cell proliferation, indicating that promotion of cancer cell proliferation by low concentration of CSE was dependent on COX-2 activity. Finally, downregulation of miR-101-3p expression and upregulation of COX-2 was found in ESCC specimens from patients with smoking history. Taken together, our findings revealed a new post transcriptional mechanism by which CSE regulated COX-2 expression to favor cancer cell proliferation, suggesting miR-101-3p as a potential biomarker and therapeutic target for smoke-related ESCC. PMID- 26530101 TI - Electroacupuncture Upregulates SIRT1-Dependent PGC-1alpha Expression in SAMP8 Mice. AB - BACKGROUND: Abnormalities of brain energy metabolism are involved in Alzheimer disease (AD). Sirtuin 1 (SIRT1) is a class III histone deacetylase and activates peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC 1alpha), which enhances mitochondrial biogenesis and energy homeostasis. Electroacupuncture (EA) has been reported to improve brain energy metabolism in AD. However, the effect of EA on SIRT1 and PGC-1alpha in AD remains unclear. MATERIAL AND METHODS: ATP levels were measured using assay kits in the hippocampus and frontal cortex of senescence-accelerated mouse prone 8 (SAMP8) mice. Western blotting analysis and quantitative real-time RT-PCR were performed to measure the expression of SIRT1 and PGC-1a in the hippocampus of SAMP8 mice. PGC-1alpha acetylation was analyzed using immunoprecipitation. RESULTS: Compared with senescence-accelerated resistant mice 1 (SAMR1) mice, SAMP8 mice had a decline in ATP levels and the expression of SIRT1 and PGC-1alpha. EA treatment improved ATP levels, upregulated the expression of SIRT1 and PGC-1alpha, and decreased PGC-1alpha acetylation. CONCLUSIONS: These data suggest that EA improved brain energy metabolism, potentially associated with the upregulation of SIRT1-dependent PGC-1alpha expression. PMID- 26530102 TI - Erythropoietin and Its Derivates Modulate Mitochondrial Dysfunction after Diffuse Traumatic Brain Injury. AB - Inhibiting the opening of mitochondrial permeability transition pore (mPTP), thereby maintaining the mitochondrial membrane potential and calcium homeostasis, could reduce the induction of cell death. Although recombinant human erythropoietin (rhEpo) and carbamylated erythropoietin (Cepo) were shown to prevent apoptosis after traumatic brain injury (TBI), their impact on mPTP is yet unknown. Thirty minutes after diffuse TBI (impact-acceleration model), rats were intravenously administered a saline solution (TBI-saline), 5000 UI/kg rhEpo (TBI rhEpo) or 50 MUg/kg Cepo (TBI-Cepo). A fourth group received no TBI insult (sham operated) (n = 11 rats per group). Post-traumatic brain edema was measured using magnetic resonance imaging. A first series of experiments was conducted 2 h after TBI (or equivalent) to investigate the mitochondrial function with the determination of thresholds for mPTP opening and ultrastructural mitochondrial changes. In addition, the intramitochondrial calcium content [Caim] was measured. In a second series of experiments, brain cell apoptosis was assessed at 24 h post injury. TBI-rhEpo and TBI-Cepo groups had a reduced brain edema compared with TBI saline. They had higher threshold for mPTP opening with succinate as substrate: 120 (120-150) (median, interquartiles) and 100 (100-120) versus 80 (60-90) nmol calcium/mg protein in TBI-saline, respectively (p < 0.05). Similar findings were shown with glutamate-malate as substrate. TBI-rhEpo and Cepo groups had less morphological mitochondrial disruption in astrocytes. The elevation in [Caim] after TBI was not changed by rhEpo and Cepo treatment. Finally, rhEpo and Cepo reduced caspase-3 expression at 24 h post-injury. These results indicate that rhEpo and Cepo could modulate mitochondrial dysfunction after TBI. The mechanisms involved are discussed. PMID- 26530103 TI - Regional cardiac dysfunction and outcome in patients with left ventricular dysfunction, heart failure, or both after myocardial infarction. AB - AIMS: Global measures of left ventricular (LV) function, in particular LV ejection fraction (LVEF) and global myocardial strain measures, are powerful predictors of outcomes in patients with LV dysfunction, heart failure, or both. However, less is known about the relationship between regional myocardial function, especially that assessed by strain echocardiography and clinical prognosis. METHODS AND RESULTS: We studied 248 patients with LV dysfunction, heart failure, or both 5 days after first myocardial infarction (MI) from the VALIANT study. We assessed peak longitudinal strain (LS) via B-mode speckle tracking in 12 segments from the apical 4- and 2-chamber views and visually assessed LV wall motion score (WMS). We related these measures of regional myocardial function to each other and to clinical outcomes over 20-month follow up. Normal reference values for segmental LS were derived from 50 healthy controls. Regional LS (-7.7%, Q1: -11.2%, Q3: -4.9%) was worse in segments with abnormal WMS, although was significantly impaired even in segments scored as normokinetic compared with normal controls (-10.4 +/- 5.2% vs. -20.0 +/- 7.6%, P < 0.001). In multivariable Cox proportional hazards models, each additional abnormal LS segment was associated with an increased risk of all-cause mortality (hazard ratio: 1.42, 95% confidence interval: 1.06-1.90, P = 0.02) even after adjustment for clinical covariates, including LVEF, LV end-systolic volume, and number of abnormal segments by WMS. CONCLUSION: In patients with LV dysfunction, heart failure, or both after MI, regional LS is significantly depressed even in segments with normal WMS, and this measure was related to adverse outcome. PMID- 26530104 TI - Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes. PMID- 26530105 TI - Huge aneurysm of aortic right coronary sinus in an adult. PMID- 26530106 TI - Subcutaneous implantable cardioverter-defibrillator and drug-induced Brugada syndrome: the importance of repeat morphology analysis during ajmaline challenge. PMID- 26530107 TI - Defining HFpEF: where do we draw the line? PMID- 26530108 TI - Vascular access and antiplatelet therapies: does one influence the other? PMID- 26530109 TI - Deciding about prolonged ticagrelor therapy in coronary clot formers: an ongoing dilemma. PMID- 26530110 TI - [Central pattern generators in the spinal cord of the cat and their relevance in rehabilitation after spinal lesion]. AB - The ability of the spinal cord to recover after partial or complete transection, and even reinitiate motor function, was investigated in several studies in cats. It has been shown that even after a complete spinalisation at the level of T12/T13, the possibility of restoration of hind-limb function is good. Central pattern generators (CPGs), located in the spinal cord, play an important role in this situation. Although CPGs alone are unable to restore function, the combination of CPGs with targeted and consistent mobility training and, in some cases, hind-limb sensory stimulation is essential to improve function. These result in a reorganisation of the CPGs and neuronal networks in the spinal cord. The age of the animal at the time of injury and the extent and localisation of lesions, play a crucial role in recovery. A new focus of research is the influence of neurotransmitters/neuromodulators on spinal-cord regeneration. How and to what extent these factors support locomotor training remains for further clinical investigation. PMID- 26530111 TI - A novel method to detect articular chondrocyte death during early stages of osteoarthritis using a non-invasive ApoPep-1 probe. AB - INTRODUCTION: Current methods for early diagnosis of osteoarthritis (OA) are limited. We assessed whether in vivo detection of chondrocyte death by ApoPep-1 (CQRPPR), a peptide that binds to histone H1 of apoptotic and necrotic cells, could be used to detect the initiation of OA. METHODS: Apoptosis-induced ATDC5 cells were labeled with Annexin V and ApoPep-1. Surgical destabilization of the medial meniscus (DMM) was performed on both knees of 12-week-old male mice and severity of OA was determined by histological analysis according to the Osteoarthritis Research Society International (OARSI) guidelines. At 1, 2, 4, and 8 weeks post-surgery, mice were intravenously injected with fluorescence-labeled ApoPep-1 or control peptide and in vivo imaging was performed within 30 minutes of injection by near-infrared fluorescence (NIRF). Binding of ApoPep-1 to OA joints was demonstrated by ex vivo imaging and immunofluorescent staining using TUNEL and histone H1 and type II collagen antibodies. RESULTS: Strong signals of ApoPep-1 were observed on the apoptotic ATDC5 cells. Knees corresponded to grade II, III, and V OA at 2, 4, and 8 weeks after DMM, respectively. Between 2 and 8 weeks after surgery, the in vivo NIRF signal at OA-ApoPep1-injected joints was consistently stronger than sham-operated or OA-control peptide-injected joints. ApoPep-1, TUNEL, and histone H1 signals were stronger in grade II OA cartilage than sham-operated cartilage when detected by immunofluorescent staining. Type II collagen expression was similar between grade II OA and sham group. CONCLUSION: ApoPep-1 can be used to detect OA in vivo by binding to apoptotic chondrocytes. This is a novel, sensitive, and rapid method which can detect apoptotic cells in OA rodent models soon after its onset. PMID- 26530112 TI - In vitro culture of hFOB1.19 osteoblast cells on TGF-beta1-SF-CS three dimensional scaffolds. AB - The aim of the present study was to examine the biocompatibility of transforming growth factor-beta1-silk fibroin-chitosan (TGF-beta1-SF-CS) scaffolds. In order to provide an ideal scaffold for use in bone tissue engineering, TGF-beta1 was introduced into the SF-CS scaffold in order to reconstruct a three dimensional scaffold, following which hFOB1.19 osteoblast cells were seeded onto TGF-beta1-SF CS and SF-CS scaffolds. On the TGF-beta1-SF-CS and SF-CS scaffolds, the cell adhesion rate increased in a time-dependent manner. Scanning electron microscopy revealed that the cells grew actively and exhibited normal morphological features with multiple fissions, and granular and filamentous substrates were observed surrounding the cells. In addition, the cell microfilaments were closely connected with the scaffolds. The cells exhibited attached growth on the surfaces of the scaffolds, however, the growth also extended into the scaffolds. Cell Counting Kit-8 and ALP analyses revealed that TGF-beta1 significantly promoted the growth and proliferation of the hFOB1.19 osteoblast cells in the SF-CS scaffolds, and the enhancement of osteoblast cell proliferation and activity by TGF-beta1 occurred in a time-dependent manner. The TGF-beta1-SF-CS composite material may offer potential as an ideal scaffold material for bone tissue engineering. PMID- 26530113 TI - Optimal pain management for radical prostatectomy surgery: what is the evidence? AB - BACKGROUND: Increase in the diagnosis of prostate cancer has increased the incidence of radical prostatectomy. However, the literature assessing pain therapy for this procedure has not been systematically evaluated. Thus, optimal pain therapy for patients undergoing radical prostatectomy remains controversial. METHODS: Medline, Embase, and Cochrane Central Register of Controlled Trials were searched for studies assessing the effects of analgesic and anesthetic interventions on pain after radical prostatectomy. All searches were conducted in October 2012 and updated in June 2015. RESULTS: Most treatments studied improved pain relief and/or reduced opioid requirements. However, there were significant differences in the study designs and the variables evaluated, precluding quantitative analysis and consensus recommendations. CONCLUSIONS: This systematic review reveals that there is a lack of evidence to develop an optimal pain management protocol in patients undergoing radical prostatectomy. Most studies assessed unimodal analgesic approaches rather than a multimodal technique. There is a need for more procedure-specific studies comparing pain and analgesic requirements for open and minimally invasive surgical procedures. Finally, while we wait for appropriate procedure specific evidence from publication of adequate studies assessing optimal pain management after radical prostatectomy, we propose a basic analgesic guideline. PMID- 26530114 TI - Community physicians' knowledge of secondary prevention after ischemic stroke: a questionnaire survey in Shanxi Province, China. AB - BACKGROUND: This cross-sectional, questionnaire-based survey, conducted in Shanxi Province, China, evaluated the knowledge of community physicians of secondary prevention of ischemic stroke and transient ischemic attacks (TIAs). METHODS: A total of 1910 physicians practicing at 832 community-based clinics, hospitals and other care centers in 11 prefectures of Shanxi Province completed the questionnaires between 1 July and 30 September 2013. RESULTS: Over 90 % of participants were aware of the most common risk factors for stroke, but lifestyle related factors were seen as of low or medium importance for secondary prevention. Only about 50 % of physicians were aware of the existence of commonly used stroke scales, and fewer said that they would use those scales in their clinical practice. There were slight differences in the responses to some of the questions on risk factors and stroke scales were associated with the physicians' gender, academic qualifications, practice duration and location. Less than half of the participants were aware of the secondary prevention recommendations included in the most recent guidelines. CONCLUSION: The survey revealed a huge gap in knowledge of current guidelines for secondary prevention of ischemic stroke and TIA among the physicians surveyed. Continuing education and training of community physicians, administered as a public health program, is needed to improve the healthcare of ischemic stroke and TIA patients. PMID- 26530115 TI - FH535 suppresses the proliferation and motility of hepatocellular carcinoma cells. AB - The Wnt signaling pathway is activated in hepatocellular carcinoma (HCC). This study investigated the effects of FH535, an inhibitor of the Wnt signaling pathway, on the proliferation and motility of HCC cells. HLF cells and PLC/PRF/5 cells, HCC cells, were subjected to 3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay with the addition of FH535. RNA was isolated from the cells and subjected to real time quantitative PCR. Hematoxylin and eosin (H&E) staining was performed to analyze apoptosis. A scratch assay was performed to analyze cell motility. Cell proliferation significantly decreased (P<0.05). The expression levels of cyclin D1 significantly decreased in both cell lines (P<0.05). Pyknotic nuclei were observed in the cells cultured with FH535 (50 uM). In the scratch assay, the distance between the growing edges of cells and the scratched line significantly decreased with the addition of FH535 at 50 uM (P<0.05). The expression levels of matrix metalloproteinase 9 significantly decreased at 50 uM (P<0.05). FH535 suppressed the proliferation of HCC cells by downregulating the expression of cyclin D1 and by inducing apoptosis. Further, it suppressed cell motility by downregulating the expression of matrix metalloproteinase. PMID- 26530116 TI - [Sinus pericranii; a congenital swelling on the scalp]. AB - BACKGROUND: Sinus pericranii is a rare congenital disorder of the skull. It involves a venous connection between the intracranial and extracranial venous systems caused by a defect at the level of a cranial sinus. CASE DESCRIPTION: We present the case of a 20-year-old woman with a soft compressible swelling on the back of her head from birth. MRI examination revealed sinus pericranii. The treatment consisted of coagulating the venous connection and closing the cranial malformation. CONCLUSION: In a patient with soft-tissue swelling on the back of the head that has been present since birth, differential diagnostics should extend beyond epidermoid cysts alone and also include consideration of sinus pericranii. This is particularly important if the swelling is in the midline. PMID- 26530117 TI - [Ocular deviation as the cause of "psychiatric" problems]. AB - We describe two cases with complaints of atypical headache who were initially diagnosed as having psychiatric problems, but who, after careful evaluation, were found to have an underlying eye disorder. Both patients were known to have an ophthalmic history. Patient A, a 21-year-old female, presented with severe headache, which was so disabling that she was declared unfit for work. A diagnosis of tension headache was made and she received psychological treatment with neurofeedback, homeopathy and acupuncture, which had no effect. Patient B, a 26-year-old male, complained of extreme photophobia, nausea and dizziness. The patient was diagnosed as having a conversion disorder and was admitted to a psychiatric clinic and given psychotropic treatment. Careful ophthalmological examination revealed that an ocular deviation was causing the symptoms in both patients and could be treated appropriately with strabismus surgery. These cases emphasise the importance of a thorough general medical and ophthalmic history and proper examination at all times without putting a psychiatric stigma on the patient. PMID- 26530118 TI - [Chronic recurrent appendicitis: a contradiction in terms?]. AB - For two years, every 6 weeks a 23-year-old man presented with episodes of severe abdominal pain and fever. After an extensive diagnostic workup, showing only slightly increased infectious parameters during the pain attacks and infiltration around the terminal ileum, a diagnostic laparoscopy diagnosed 'chronic recurrent appendicitis'. A 40-year-old female had severe attacks of abdominal pain and fever every 4-6 weeks for 1.5 years. Some inflammation around the appendix was seen on colonoscopy, and a diagnostic laparoscopy finally confirmed the same diagnosis 'chronic recurrent appendicitis'. Patients with recurrent abdominal pain often are a diagnostic challenge for the clinician. The appendix is rarely recognized as the causative factor and the diagnosis 'chronic recurrent appendicitis' is not widely accepted. This disease entity often has an atypical presentation and well-defined criteria are lacking. In this article we plea for a broader acceptance of this diagnosis, which, in our opinion, deserves to be included in the differential diagnosis of longstanding or recurrent abdominal pain attacks. PMID- 26530119 TI - [Non-invasive prenatal testing: challenges for future implementation]. AB - The non-invasive prenatal test (NIPT) is an accurate and safe test in which blood from the pregnant woman is used to investigate if the unborn child possibly has trisomy 21 (Down's syndrome), trisomy 18 (Edwards' syndrome) or trisomy 13 (Patau syndrome). Since April 2014 the NIPT has been available in the Netherlands as part of the TRIDENT implementation project for those in whom the first trimester combined test showed an elevated risk (> 1:200) of trisomy, or on medical indication, as an alternative to chorionic villous sampling or amniocentesis. Since the introduction of the NIPT the use of these invasive tests, which are associated with a risk of miscarriage, has fallen steeply. The NIPT may replace the combined test. Also the number of conditions that is tested for can be increased. Modification of current prenatal screening will require extensive discussion, but whatever the modification, careful counseling remains essential to facilitate pregnant women's autonomous reproductive decision making. PMID- 26530120 TI - [Integral financing stifles innovation: consequences of the new form of financing for specialists]. AB - Of the 22,800 Dutch medical specialists, 43% are self-employed, which involves various tax benefits. In 2015 an important change took place. In the past, specialists declared their services independently from the hospital, which impeded process adjustments. Although this gives the impression of improvement, it is not, mainly because specialists are organized separately from the hospital organization. In addition, specialists are not entrepreneurs, which means that they avoid risks and uncertainty. The complex situation that has arisen is further complicated by fuzzy implementation that lacks an overall plan. For the individual specialist, the situation is unclear. The specialists consider necessary renewals and innovations to be irresponsible risks. This creates a cautious attitude and inertia. To achieve improvement, government and policy makers should set clear rules and health insurers should value good governance. This protection would allow specialists and hospital boards to balance medical content and finance. PMID- 26530121 TI - [Healing with art?]. AB - Music and other forms of art are increasingly being integrated into hospitals. As well as the aesthetic value of art, more and more attention is being paid to its contribution to the healing of the patient. Scientific research indicates the possible benefits of specific art in healthcare facilities. Using this knowledge of the role and employability of surroundings and art in the healing of patients may be complementary to the high quality of care in the Netherlands. By means of proper, methodologically correct research, it is possible to investigate the use of different aspects of the patient's environment as simple, safe and low-cost measures in improving health and well-being of patients. PMID- 26530122 TI - [Changing views: consequences of guideline revisions for the individual patient]. AB - Guidelines contain evidence-based recommendations for clinical practice. Physicians and other healthcare providers are expected to follow these guidelines to provide proper care to their patients. Deviation from guidelines is possible, but should be undertaken for a reason. New evidence and insights involve guidelines having to be revised periodically. What are the implications of such revisions for doctors and patients? And what can be done about patients who have been lost to care but who are eligible for treatment according to the new guideline? Difficult dilemmas lie in waiting. It is a joint responsibility of both drafters and users of guidelines to implement changes in guidelines appropriately for the individual patient. PMID- 26530124 TI - Automated fastener versus manually tied knots in minimally invasive mitral valve repair: impact on operation time and short- term results. AB - BACKGROUND: This study compares the influence of two different annuloplasty attachment suture applications, namely the use of an automated fastener versus manually tied knots using a traditional knot pusher, on total operation time, on cardiopulmonary-bypass time and on cross-clamp time, and on short-term outcome. METHODS: Sixty patients underwent isolated minimally invasive mitral valve repair in Carpentier Type-II mitral disease with implantation of an annuloplasty ring in combination with correction of the prolapsing leaflet using artificial chords. The first 30 patients after implementation of a novel automated fastener were compared with the last 30 patients corrected with a traditional knot pusher. No significant differences with regard to demographic data (age, gender, NYHA class, ejection fraction, BMI, cardiovascular risk factors) between the two groups were found. All patients received isolated mitral valve repair in the first run. Bretschneider HTK was used for cardioplegic cardiac arrest in all patients. RESULTS: Transesophageal and transthoracic echocardiography at the end of operation and at discharge revealed no (n = 25), trace (n = 28) or mild (n = 7) residual regurgitation with no evidence of ring dehiscence and without any significant clinical differences between the groups. Cross-clamp, cardiopulmonary bypass and total- operation time were significantly reduced in the automated fastener group compared to the group using a traditional knot pusher (87.1 +/- 17.9 vs. 101.3 +/- 17.8; p < 0.01, 138.1 +/- 25.6 vs. 152.7 +/- 24.9; p < 0.05, and 203.9 +/- 31.02 vs. 223.8 +/- 29.01; p < 0.01, respectively). CONCLUSION: Our short-term results indicate a safe, reliable and fast application of the novel automated fastener device in combination with significant time savings in cardioplegic arrest and cardiopulmonary bypass. PMID- 26530123 TI - Macrophage migration inhibitory factor - a therapeutic target in gallbladder cancer. AB - BACKGROUND: Poor prognosis in gallbladder cancer is due to late presentation of the disease, lack of reliable biomarkers for early diagnosis and limited targeted therapies. Early diagnostic markers and novel therapeutic targets can significantly improve clinical management of gallbladder cancer. METHODS: Proteomic analysis of four gallbladder cancer cell lines based on the invasive property (non-invasive to highly invasive) was carried out using the isobaric tags for relative and absolute quantitation labeling-based quantitative proteomic approach. The expression of macrophage migration inhibitory factor was analysed in gallbladder adenocarcinoma tissues using immunohistochemistry. In vitro cellular assays were carried out in a panel of gallbladder cancer cell lines using MIF inhibitors, ISO-1 and 4-IPP or its specific siRNA. RESULTS: The quantitative proteomic experiment led to the identification of 3,653 proteins, among which 654 were found to be overexpressed and 387 were downregulated in the invasive cell lines (OCUG-1, NOZ and GB-d1) compared to the non-invasive cell line, TGBC24TKB. Among these, macrophage migration inhibitory factor (MIF) was observed to be highly overexpressed in two of the invasive cell lines. MIF is a pleiotropic proinflammatory cytokine that plays a causative role in multiple diseases, including cancer. MIF has been reported to play a central role in tumor cell proliferation and invasion in several cancers. Immunohistochemical labeling of tumor tissue microarrays for MIF expression revealed that it was overexpressed in 21 of 29 gallbladder adenocarcinoma cases. Silencing/inhibition of MIF using siRNA and/or MIF antagonists resulted in a significant decrease in cell viability, colony forming ability and invasive property of the gallbladder cancer cells. CONCLUSIONS: Our findings support the role of MIF in tumor aggressiveness and suggest its potential application as a therapeutic target for gallbladder cancer. PMID- 26530125 TI - Analysis of licensed over-the-counter (OTC) antibiotics in the European Union and Norway, 2012. AB - Antimicrobial resistance is recognised as a growing problem that seriously threatens public health and requires prompt action. Concerns have therefore been raised about the potential harmful effects of making antibiotics available without prescription. Because of the very serious concerns regarding further spread of resistance, the over-the-counter (OTC) availability of antibiotics was analysed here. Topical and systemic OTC antibiotics and their indications were determined across 26 European Union (EU) countries and Norway by means of a European survey. We identified a total of 48 OTC products containing 20 different single antibiotics and three antibiotic combinations as active substances, used mainly as topical preparations in short treatment courses. Given the relevance of these medicines and the increasing risk of antimicrobial resistance, it is important to limit the availability of OTC antibiotics and to monitor their use. PMID- 26530126 TI - Evaluating the impact of a community developed collaborative project for the prevention of early childhood caries: the Healthy Smile Happy Child project. AB - INTRODUCTION: To determine the effectiveness of the Healthy Smile Happy Child (HSHC) project, a community-developed initiative promoting early childhood oral health in Manitoba, Canada. Specific aims were to assess improvements in caregiver knowledge, attitudes, and behaviours relating to early childhood oral health, and the burden of early childhood caries (ECC) and severe ECC (S-ECC). METHODS: A serial cross-sectional study design was selected to contrast findings following the Healthy Smile Happy Child (HSHC) campaign in four communities with the previous baseline data. One community was a remote First Nation in northern Manitoba and another was a rural First Nation in southern Manitoba. The other two communities were urban centres, one of which was located in northern Manitoba. A community-development approach was adopted for the project to foster community solutions to address ECC. Goals of the HSHC program were to promote the project in each community, use existing community-based programs and services to deliver the oral health promotion and ECC prevention activities, and recruit and train natural leaders to assist in program development and to deliver the ECC prevention program. The HSHC coordinator worked with communities to develop a comprehensive list of potential strategies to address ECC. Numerous activities occurred in each community to engage members and increase their knowledge of early childhood oral health and ultimately lead them to adopt preventive oral health practices for their young children. Children under 71 months of age and their primary caregivers participated in this follow-up study. A -value <=0.05 was statistically significant. RESULTS: 319 children (mean age 38.2+/-18.6 months) and their primary caregivers participated. Significant improvements in caregiver knowledge and attitudes were observed following the HSHC campaign, including that baby teeth are important (98.8%), that decay involving primary teeth can impact on health (94.3%), and the importance of a dental visit by the first birthday (82.4%). Significantly more respondents indicated that their child had visited the dentist (50.2%) and had started brushing their child's teeth (86.7%) when compared to baseline. Overall, 52.0% had ECC, 38.6% had S-ECC. The mean deft score was 3.85+/-4.97 (range 0-20). There was no significant change is ECC prevalence between the follow-up and baseline investigations. However, age adjusted logistic regression for S-ECC in this follow-up study revealed a significant reduction in prevalence compared with the baseline study (=0.021). Similarly, age-adjusted Poisson regression revealed that there were significant reductions in both the decayed teeth and decayed, extracted and filled teeth scores between follow-up and baseline study periods (0.016 and .0001, respectively). CONCLUSIONS: Follow-up study results suggest that the HSHC initiative may have contributed to improvements in caregiver knowledge, attitudes, and behaviours towards early childhood oral health and subsequently modest yet statistically significant reductions in caries scores and the prevalence of S-ECC. PMID- 26530127 TI - Development, optimization and in vivo characterization of domperidone-controlled release hot-melt-extruded films for buccal delivery. AB - OBJECTIVE: The aim of the present investigation was the development and in vivo characterization of domperidone (DOM) hot-melt extruded (HME) controlled release films by central composite design (CCD) for buccal delivery. METHODS: Concentration of PEO N750 (X1) and HPMC E5 LV (X2) as independent variables and tensile strength (Y1), percent drug release at 6 h (Q6, Y2) and percent drug permeated at 6 h (Y3, P6) as responses. In total, 13 formulations were prepared and studied. HME films were evaluated for drug excipient compatibility, physico mechanical properties, drug content, in vitro drug release, bioadhesion, swelling and erosion, ex vivo permeation. Furthermore, statistically optimized formulation was subjected for bioavailability studies in healthy human volunteers. RESULTS: Statistically optimized formulation exhibited a tensile strength (3.86 kg/mm(2)), 93.62 +/- 2.84% of drug release and 63.36 +/- 2.12% of drug permeated in 6 h. HME films demonstrated no drug excipient interaction and excellent content uniformity. Furthermore, optimized formulation exhibited elongation at break (38.6% mm(2)), peak detachment force (1.75 N), work of adhesion (3.21 mJ), swelling index (240.4%) and erosion (8.5%). Bioavailability from the statistically optimized buccal films was 3.2 times higher than the oral dosage form (p < 0.05). The ex vivo-in vivo correlation was found to have biphasic pattern and followed type A correlation. The stability of the optimized formulation was studied and no significant changes were detected in 6 months. CONCLUSION: The results indicate that hot-melt extrusion is a viable technique for the preparation of DOM buccal-adhesive controlled release films with improved bioavailability by CCD. PMID- 26530128 TI - Strong Optomechanical Coupling in Nanobeam Cavities based on Hetero Optomechanical Crystals. AB - Nanobeam cavities based on hetero optomechanical crystals are proposed. With optical and mechanical modes separately confined by two types of periodic structures, the mechanical frequency is designed as high as 5.88 GHz. Due to the optical field and the strain field concentrated in the optomechanical cavity and resembling each other with an enhanced overlap, a high optomechanical coupling rate of 1.31 MHz is predicted. PMID- 26530129 TI - Identification and functional analysis of novel FZD4 mutations in Han Chinese with familial exudative vitreoretinopathy. AB - Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disease characterized by defects in the development of retinal vessels. However, known genetic mutations can only explain approximately 50% of FEVR patients. To assess the mutation frequency of Frizzled 4 (FZD4) in Chinese patients, we analysed patients with FEVR from 61 families from China to identify mutations in FZD4 and to study the effects of identified mutations on FZD4 function. All coding exons and adjacent intronic regions of FZD4 were amplified by polymerase chain reaction and subjected to Sanger sequencing analysis. Three mutations in the FZD4 gene were identified in these families. Of these, two were novel mutations: p.E134* and p.T503fs. Both mutations involve highly conserved residues and were not present in 800 normal individuals. Each of these two novel FZD4 mutations was introduced into wild-type FZD4 cDNA by site-directed mutagenesis. Wild-type and mutant FZD4 DNAs were introduced into HEK293 cells to analyse the function of FZD4 in Norrin-dependent activation of the Norrin/beta-catenin pathway using luciferase reporter assays. Both the p.E134* and p.T503fs mutants failed to induce luciferase reporter activity in response to Norrin. Our study identified two novel FZD4 mutations in Chinese patients with FEVR. PMID- 26530130 TI - Upregulation of long non-coding RNA PRNCR1 in colorectal cancer promotes cell proliferation and cell cycle progression. AB - Colorectal cancer (CRC) is one of the most common cancers worldwide. Long non coding RNAs (lncRNAs) have been confirmed to play a critical regulatory role in various biological processes including carcinogenesis, which indicates that lncRNAs are valuable biomarkers and therapeutic targets. The novel lncRNA prostate cancer non-coding RNA 1 (PRNCR1) is located in the susceptible genomic area of CRC, however the functional role of PRNCR1 remains unknown. Thus, we aimed to investigate the clinical significance and biological function of PRNCR1 in CRC. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess the expression profile of PRNCR1 in CRC tissues and cell lines. An antisense oligonucleotide (ASO) was designed to knock down PRNCR1. In a cohort of 63 patients, PRNCR1 was significantly overexpressed in CRC tissues compared with the expression in adjacent tissues, with an average fold increase of 10.55 (P=0.006). Additionally, a high level of PRNCR1 was associated with large tumor volume (P<0.05). Based on receiver operating characteristic curve (ROC), we found that the area under the curve (AUC) of PRNCR1 was 0.799 while the AUC of conventional biomarker CEA-CA199 was 0.651, indicating that PRNCR1 could be a sensitive diagnostic biomarker of CRC. Compared with the normal human colorectal epithelial cell line (FHC), PRNCR1 was upregulated in most CRC cell lines (HCT116, SW480, LoVo and HT-29). After knockdown of PRNCR1 by ASO, CRC cell proliferation ability was significantly inhibited. We further found that PRNCR1 knockdown induced cell cycle arrest in the G0/G1 phase and a significant decrease in the proportion of cells in the S phases. In contrast, PRNCR1 knockdown did not affect cell apoptosis or invasive ability. Hence, these data indicate that PRNCR1 promotes the proliferation of CRC cells and is a potential oncogene of CRC. PMID- 26530131 TI - Prevalence and associated factors of active trachoma among childeren aged 1-9 years in rural communities of Gonji Kolella district, West Gojjam zone, North West Ethiopia. AB - BACKGROUND: Trachoma is the leading infectious cause of blindness worldwide. Though trachoma can be treated with antibiotic it is still endemic in most part of Ethiopia. METHODS: A community based cross-sectional study was conducted among 618 children 1-9 years of age from December 2013 to June 2014. A multistage systematic sampling technique was applied. Data were collected using pretested and structured questionnaire and also observation by using binocular loupe to differentiate active trachoma cases. The World Health Organization's simplified classification scheme for assessing trachoma in community based surveys was used for the purpose. Bivariate and multivariate logistic regression model was fitted to identify factors associated with trachoma among children aged 1-9 years. An adjusted odds ratio with 95 % confidence interval was computed to determine the level of significance. RESULTS: The overall prevalence of active trachoma among children aged 1-9 years were 23.1 % (Trachomatous inflammation-Follicular, in 22.5 % (95 % CI: 22.3-22.69 %); Trachomatous inflammation-Intense, in 0.6 % (95 % CI: 0.4-0.79 %). Family size (>5) (AOR = 14.32, 95 % CI = 6.108-33.601), number of children under 10 years of age within household (AOR = 25.53, 95 % CI = 9.774 66.686), latrine utilizations (AOR = 10.274, 95 % CI = 4.274-24.968), route of waste disposal (AOR = 3.717, 95 % CI = 1.538 to -8.981), household literacy (AOR = 2.892, 95 % CI = 1.447-5.780), cattle housing practice (AOR = 4.75, 95 % CI = 1.815-12.431), time to collect water (AOR = 25.530, 95 % CI = 8.995-72.461), frequency of face washing practice (AOR = 6.384, 95 % CI = 2.860-14.251) and source of water (AOR = 2.353, 95 % CI = 1.134-4.882) were found to be associated with the presence of active trachoma in this study population. CONCLUSION: The prevalence of active trachoma among rural communities of children aged 1-9 years was found to be high in reference to WHO recommended thresholds to initiate trachoma control recommendation (>10 % prevalence), which indicates that active trachoma is still a major public health concern in the study area. Therefore, it is recommended that coordinated work on implementing the WHO endorsed SAFE strategy in particular and enhancing the overall living conditions of the community is crucial. PMID- 26530132 TI - Strain assisted electrocaloric effect in PbZr0.95Ti0.05O3 films on 0.7Pb(Mg1/3Nb2/3)O3-0.3PbTiO3 substrate. AB - Solid state cooling technologies based on electrocaloric, magnetocaloric and mechanocaloric effects have received much attention during the past decade. To further improve the cooling efficiency and reduce the driving field, it is desirable to combine multiple effects in a single system. Here, we report on the caloric effects induced by both electric field and strain in PbZr0.95Ti0.05O3 films deposited on 0.7Pb(Mg1/3Nb2/3)O3-0.3PbTiO3 substrate. The isothermal entropy change (DeltaS) induced by the antiferroelectric-ferroelectric phase transition of PbZr0.95Ti0.05O3 films is calculated to be 6.78 J K(-1) kg(-1). Furthermore, the strain from 0.7Pb(Mg1/3Nb2/3)O3-0.3PbTiO3 substrate can reduce the electric field where DeltaS reaches the maximum by as much as 50 kV/cm. The electrocaloric efficiency is also increased from 0.366 to 0.378 by the strain effect. The electrocaloric effect in an antiferroelectric material assisted by strain may lead to more efficient solid state cooling technology. PMID- 26530133 TI - Oral tolerance is inefficient in neonatal mice due to a physiological vitamin A deficiency. AB - Increased risk of allergy during early life indicates deficient immune regulation in this period of life. To date, the cause for inefficient neonatal immune regulation has never been elucidated. We aimed to define the ontogeny of oral tolerance and to identify necessary conditions specific for this stage of life. Ovalbumin (OVA) was administered orally to mice through breast milk and efficiency of systemic tolerance to OVA was assessed in adulthood using a model of allergic airway inflammation. Oral tolerance induction was fully efficient starting third week of life. Inefficiency in neonates was a consequence of abnormal antigen transfer across the gut barrier and retinaldehyde dehydrogenase expression by mesenteric lymph node CD103(+) neonatal dendritic cells, resulting in inefficient T-cell activation. Neonates' serum retinol levels were three times lower than in adult mice, and vitamin A supplementation was sufficient to rescue neonatal defects and allow tolerance induction from birth. The establishment of oral tolerance required the differentiation of Th1 lymphocytes in both vitamin A supplemented neonates and 3-week-old unsupplemented mice. This knowledge should guide the design of interventions for allergy prevention that are adapted to the neonatal stage of life such as vitamin A supplementation. PMID- 26530134 TI - Epithelial IL-1R2 acts as a homeostatic regulator during remission of ulcerative colitis. AB - Ulcerative colitis (UC) is a chronic intestinal inflammatory disease that may undergo periods of activity followed by remission. We aimed to identify the endogenous regulatory mechanisms that may promote disease remission. Transcriptional and protein analysis of the intestinal mucosa revealed that the IL-1 decoy receptor, interleukin-1 receptor type 2 (IL1R2), was upregulated in remission compared with active UC and controls. We identified epithelial cells as being responsible for increased IL-1R2 production during remission. Expression of IL1R2 was negatively regulated by Wnt/beta-catenin signals in colonic crypts or epithelial stem cell cultures; accordingly, epithelial stem cells upregulated IL 1R2 upon differentiation. Blocking IL-1R2 in isolated colonic crypt cultures of UC patients in remission and T-cell cultures stimulated with biopsy supernatant from UC patients in remission boosted IL-1beta-dependent production of inflammation-related cytokines. Finally, IL1R2 transcription was significantly lower in patients that relapsed during a 1-year follow-up period compared with those in endoscopic remission. Collectively, our results reveal that the IL-1/IL 1R2 axis is differentially regulated in the remitting intestinal mucosa of UC patients. We hypothesize that IL-1R2 in the presence of low concentrations of IL 1beta may act locally as a regulator of intestinal homeostasis. PMID- 26530135 TI - miR-511-3p, embedded in the macrophage mannose receptor gene, contributes to intestinal inflammation. AB - MiR-511-3p is embedded in intron 5 of the CD206/MRC1 gene Mrc1, expressed by macrophage and dendritic cell populations. CD206 and miR-511-3p expression are co regulated, and their contribution to intestinal inflammation is unclear. We investigated their roles in intestinal inflammation in both mouse and human systems. Colons of CD206-deficient mice displayed normal numbers of monocytes, macrophage, and dendritic cells. In experimental colitis, CD206-deficient mice had attenuated inflammation compared with wild-type (WT) mice. However, neither a CD206 antagonist nor a blocking antibody reproduced this phenotype, suggesting that CD206 was not involved in this response. Macrophages isolated from CD206 deficient mice had reduced levels of miR-511-3p and Tlr4 compared with WT, which was associated with reduced pro-inflammatory cytokine production upon lipopolysaccharides (LPS) and fecal supernatant stimulation. Macrophages overexpressing miR-511-3p showed 50% increase of Tlr4 mRNA, whereas knockdown of miR-511-3p reduced Tlr4 mRNA levels by 60%, compared with scrambled microRNA (miRNA)-transduced cells. Response to anti-tumor necrosis factor (TNF) treatment has been associated with elevated macrophage CD206 expression in the mucosa. However, in colon biopsies no statistically significant change in miR-511-3p was detected. Taken together, our data show that miR-511-3p controls macrophage mediated microbial responses and is involved in the regulation of intestinal inflammation. PMID- 26530136 TI - The respiratory DC/macrophage network at steady-state and upon influenza infection in the swine biomedical model. AB - Human and mouse respiratory tracts show anatomical and physiological differences, which will benefit from alternative experimental models for studying many respiratory diseases. Pig has been recognized as a valuable biomedical model, in particular for lung transplantation or pathologies such as cystic fibrosis and influenza infection. However, there is a lack of knowledge about the porcine respiratory immune system. Here we segregated and studied six populations of pig lung dendritic cells (DCs)/macrophages (Mthetas) as follows: conventional DCs (cDC) 1 and cDC2, inflammatory monocyte-derived DCs (moDCs), monocyte-derived Mthetas, and interstitial and alveolar Mthetas. The three DC subsets present migratory and naive T-cell stimulation capacities. As observed in human and mice, porcine cDC1 and cDC2 were able to induce T-helper (Th)1 and Th2 responses, respectively. Interestingly, porcine moDCs increased in the lung upon influenza infection, as observed in the mouse model. Pig cDC2 shared some characteristics observed in human but not in mice, such as the expression of FCERIalpha and Langerin, and an intra-epithelial localization. This work, by unraveling the extended similarities of the porcine and human lung DC/Mtheta networks, highlights the relevance of pig, both as an exploratory model of DC/Mtheta functions and as a model for human inflammatory lung pathologies. PMID- 26530137 TI - Transforming growth factor-beta1 sustains the survival of Foxp3(+) regulatory cells during late phase of oropharyngeal candidiasis infection. AB - As CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play crucial immunomodulatory roles during infections, one key question is how these cells are controlled during antimicrobial immune responses. Mechanisms controlling their homeostasis are central to ensure efficient protection against pathogens, as well as to control infection-associated immunopathology. Here we studied how their viability is regulated in the context of mouse oropharyngeal candidiasis (OPC) infection, and found that these cells show increased protection from apoptosis during late phase of infection and reinfection. Tregs underwent reduced cell death because they are refractory to T cell receptor restimulation-induced cell death (RICD). We confirmed their resistance to RICD, using mouse and human Tregs in vitro, and by inducing alpha-CD3 antibody-mediated apoptosis in vivo. The enhanced viability is dependent on increased transforming growth factor-beta1 (TGF-beta1) signaling that results in upregulation of cFLIP (cellular FLICE (FADD-like IL-1beta converting enzyme)-inhibitory protein) in Tregs. Protection from cell death is abrogated in the absence of TGF-beta1 signaling in Tregs during OPC infection. Taken together, our data unravel the previously unrecognized role of TGF-beta1 in promoting Treg viability, coinciding with the pronounced immunomodulatory role of these cells during later phase of OPC infection, and possibly other mucosal infections. PMID- 26530139 TI - Light-matter decoupling and A(2) term detection in superconducting circuits. AB - The spontaneous and stimulated emission of a superconducting qubit in the presence of propagating microwaves originates from an effective light-matter interaction that, similarly to the case of the atomic case, can contain a diamagnetic term proportional to the square vector potential A(2). In the present work we prove that an increase in the strength of the diamagnetic term leads to an effective decoupling of the qubit from the electromagnetic field, and that this effect is observable at any range of qubit-photon coupling. To measure this effect we propose to use a transmon suspended over a transmission line, where the relative strength of the A(2) term is controlled by the qubit-line separation. We show that the spontaneous emission rate of the suspended transmon onto the line can, at short distances, increase with such a separation, instead of decreasing. PMID- 26530138 TI - Antithrombotic treatment in elderly patients with atrial fibrillation: a practical approach. AB - BACKGROUND: Atrial fibrillation (AF) in the elderly is a complex condition. It has a direct impact on the underuse of antithrombotic therapy reported in this population. DISCUSSION: All patients aged >=75 years with AF have an individual yearly risk of stroke >4 %. However, the risk of hemorrhage is also increased. Moreover, in this population it is common the presence of other comorbidities, cognitive disorders, risk of falls and polymedication. This may lead to an underuse of anticoagulant therapy. Direct oral anticoagulants (DOACs) are at least as effective as conventional therapy, but with lesser risk of intracranial hemorrhage. The simplification of treatment with these drugs may be an advantage in patients with cognitive impairment. The great majority of elderly patients with AF should receive anticoagulant therapy, unless an unequivocal contraindication. DOACs may be the drugs of choice in many elderly patients with AF. In this manuscript, the available evidence about the management of anticoagulation in elderly patients with AF is reviewed. In addition, specific practical recommendations about different controversial issues (i.e. patients with anemia, thrombocytopenia, risk of gastrointestinal bleeding, renal dysfunction, cognitive impairment, risk of falls, polymedication, frailty, etc.) are provided. PMID- 26530140 TI - High infiltration of mast cells positive to tryptase predicts worse outcome following resection of colorectal liver metastases. AB - BACKGROUND: Accumulation of tumor-infiltrating mast cells (MCs) predicts poor survival in several cancers after resection. However, its effect on the prognosis of patients with colorectal liver metastases (CRLM) is not known. METHODS: Our retrospective study included 135 patients who underwent potentially curative resection for CRLM between 2001 and 2010. Expression of tryptase, MAC387, CD83, and CD31, which are markers for MCs, macrophages, mature dendritic cells, and vascular endothelial cells, respectively, was determined via immunohistochemistry of resected tumor specimens. The relationship between immune cell infiltration and long-term outcome was investigated. RESULTS: The median follow-up time was 48.4 months for all patients and 57.5 months for survivors. Overall survival (OS) rates at 1, 3, and 5 years were 91.0, 62.4, and 37.4 %, respectively. Five-year disease-free survival (DFS) and OS rates were 21.6 and 38.1 %, respectively, in patients with high MC infiltration, and 42.6 and 55.6 %, respectively, in patients with low MC infiltration (p < 0.01 for both DFS and OS). Infiltration of other types of immune cells did not correlate with survival. Multivariate analyses indicated that hypoalbuminemia and high peritumoral MC infiltration were significant predictors of unfavorable OS. CONCLUSION: High peritumoral MC infiltration predicts poor prognosis in patients who underwent hepatectomy for CRLM. The number of MCs in metastatic lesions is important for predicting the prognosis of CRLM patients and as an indication of therapy. PMID- 26530141 TI - Serological diagnostic potential of recombinant outer membrane proteins (rOMPs) from Brucella melitensis in mouse model using indirect enzyme-linked immunosorbent assay. AB - BACKGROUND: Brucella melitensis is the most important pathogenic species of Brucella spp. which affects goats and sheep and causes caprine and ovine brucellosis, respectively. Serological tests for diagnosis of brucellosis such as Rose Bengal plate test (RBPT) and enzyme-linked immunosorbent assay (ELISA) usually utilize smooth lipopolysaccharides (S-LPS) as a diagnostic antigen which could give false positive serological reactions. Outer membrane proteins (OMP) of B. melitensis have been used as alternative diagnostic antigens rather than S-LPS for differential serological diagnosis of brucellosis, mainly in ELISA with single recombinant OMP (rOMP) as a diagnostic antigen. Nevertheless, the use of single format mainly showed lack of sensitivity against the desired rOMP. Therefore, this study aimed to determine whether a newly developed rOMPs indirect ELISA (rOMPs I-ELISA), based on combination of rOMP25, rOMP28 and rOMP31of B. melitensis, has a potential benefit for use in the serodiagnosis of brucellosis. METHODS: In this study, omp25, omp28 and omp31 of B. melitensis were cloned and expressed using prokaryotic pET-32 Ek/LIC system and their respective rOMPs were combined as one coating antigen to develop rOMPs I-ELISA. Three groups of BALB/c mice were used to elicit antibody response. Group 1, infected with B. melitensis strain 0331 field strain; group 2, injected with B. melitensis Rev.1 vaccine strain and group 3, infected with Yersinia enterocolitica O:9. Antibody responses in three groups of mice were investigated using Rose Bengal plate test (RBPT) and rOMPs I-ELISA. RESULTS: The production of rOMP25, rOMP28 and rOMP31 of B. melitensis were achieved and Western immunoblotting analysis demonstrated their reactivity. The RBPT was unable to differentiate the vaccinated mice (group 2) and mice infected with Y. enterocolitica O:9 (group 3) and categorized them wrongly as positive for brucellosis. In contrast, the rOMPs I-ELISA was able to differentiate the mice infected with B. melitensis strain 0331 (group 1) from both of group 2 and group 3, and recorded 100% sensitivity and 100% specificity. CONCLUSIONS: The results of this study suggested that rOMPs of B. melitensis has potential diagnostic ability to differentiate the FPSR in serological diagnosis of brucellosis. PMID- 26530142 TI - Mid-term results of 150 TAVI comparing apical versus femoral approaches. AB - BACKGROUND: Transcatheter aortic-valve implantation (TAVI) is a new therapeutic choice for treating aortic stenosis in patients considered high risk for surgery. This blooming therapeutic technique still requires evaluation of medium and long term outcome. METHOD: We hereby report our results of the first 150 consecutive patients to receive TAVI implants in our population recruited from July 2009 to March 2013 in a retrospective and monocentric study. We analyzed long term morbidity and mortality criteria. We compared the apical and femoral approach results and researched predictors of cardiac mortality. RESULTS: The mean monitoring period was 387.62 days, mean Euroscore was 21.8, and mean Society of Thoracic Surgeons (STS) risk score was 9.2. The success rate for the procedure was 94.6 %. A total of 39 patients died. The mortality rates at the immediate perioperative point, 30 days, 1 year, and 2 years, were 4 %, 11.3 %, 22.7 %, and 26 %, respectively. As regards complications, there were 10 hemodynamic complications (6.6 %) and 20 vascular (13.3 %), 11 cardiac tamponades (7.4 %), eight mechanical (5.3 %), ten major hemorrhagic (6.7 %), 14 pulmonary (9.3 %), and 18 infectious complications (12 %). When comparing the rates of reported complications in terms of different approaches, we observed significantly more hemodynamic complications in the apical group (p = 0.049). Pulmonary complications were also significantly more common in cases of apical approach (p = 0.029). The majority of the patients reported clear functional improvement throughout their follow-up. CONCLUSION: The results of the first 150 patients to receive the implant at the Nancy University Teaching Hospital (CHU Nancy) were consistent with findings in the literature. TAVI proved a credible and effective alternative to surgical valve replacement for patients at high risk during surgery. PMID- 26530143 TI - Electro membrane extraction using sorbent filled porous membrane bag. AB - Electro membrane extraction-solid-liquid phase microextraction (EME-SLPME) was developed for the first time to determine phenolic contaminants in water. The extraction system consisted of a solid/liquid interface that permitted a three phase microextraction approach involving an aqueous sample (donor phase): an organic solvent-sorbent within a membrane bag, and an organic solvent (extractant phase), operated in a direct immersion sampling system. The sorbent, reduced graphene oxide/polyvinyl alcohol, synthesized using graphene oxide and polyvinyl alcohol by dispersing the graphene oxide in polyvinyl alcohol and chemically reducing it in aqueous solution. The prepared sorbent was dispersed in 1-octanol and the solution was immobilized by sonication in the membrane bag wall pores which was in contact with the aqueous donor solution and organic extractant solvent (1-octanol) in the main bag itself. The analytes were transported by application of an electrical potential difference of 100V across the sorbent/solvent phase from the aqueous sample into the organic extractant phase in the membrane bag. After extraction and derivatization, gas chromatography-mass spectrometry was used to determine the derivatized analytes. This proposed EME LSPME procedure provided high extraction efficiency with relative recoveries up to 99.6%. A linearity range of between 0.05 and 100MUgL(-1) with corresponding coefficients of determination (r(2)) of between 0.987 and 0.996 were obtained. The limits of detection were in the range of between 0.003 and 0.053MUgL(-1). This proposed method was successfully applied to the extraction of phenolic contaminants from water sample. PMID- 26530144 TI - Toward a microfabricated preconcentrator-focuser for a wearable micro-scale gas chromatograph. AB - This article describes work leading to a microfabricated preconcentrator-focuser (MUPCF) designed for integration into a wearable microfabricated gas chromatograph (MUGC) for monitoring workplace exposures to volatile organic compounds (VOCs) ranging in vapor pressure from ~0.03 to 13kPa at concentrations near their respective Threshold Limit Values. Testing was performed on both single- and dual-cavity, etched-Si MUPCF devices with Pyrex caps and integrated resistive heaters, packed with the graphitized carbons Carbopack X (C-X) and/or Carbopack B (C-B). Performance was assessed by measuring the 10% breakthrough volumes and injection bandwidths of a series of VOCs, individually and in mixtures, as a function of the VOC air concentrations, mixture complexity, sampling and desorption flow rates, adsorbent masses, temperature, and the injection split ratio. A dual-cavity device containing 1.4mg of C-X and 2.0mg of C-B was capable of selectively and quantitatively capturing a mixture of 14 VOCs at low-ppm concentrations in a few minutes from sample volumes sufficiently large to permit detection at relevant concentrations for workplace applications with the MUGC detector that we ultimately plan to use. Thermal desorption at 225 degrees C for 40s yielded >=99% desorption of all analytes, and injected bandwidths as narrow as 0.6s facilitated efficient separation on a downstream 6-m GC column in <3min. A preconcentration factor of 620 was achieved for benzene from a sample of just 31mL. Increasing the mass of C-X to 2.3mg would be required for exhaustive capture of the more volatile target VOCs at high-ppm concentrations. PMID- 26530145 TI - Qualitative and quantitative analysis of branches in dextran using high performance anion exchange chromatography coupled to quadrupole time-of-flight mass spectrometry. AB - Dextran, a family of natural polysaccharides, consists of an alpha (1->6) linked glucose main (backbone) chain having a number of branches. The determination of the types and the quantities of branches in dextran is important in understanding its various biological roles. In this study, a hyphenated method using high performance anion exchange chromatography (HPAEC) in parallel with pulsed amperometric detection (PAD) and mass spectrometry (MS) was applied to qualitative and quantitative analysis of dextran branches. A rotary cation exchange cartridge array desalter was used for removal of salt from the HPAEC eluent making it MS compatible. MS and MS/MS were used to provide structural information on the enzymatically prepared dextran oligosaccharides. PAD provides quantitative data on the ratio of enzyme-resistant, branched dextran oligosaccharides. Both the types and degree of branching found in a variety of dextrans could be simultaneously determined online using this method. PMID- 26530146 TI - Formulation studies for mirtazapine orally disintegrating tablets. AB - OBJECTIVE: Orally disintegrating tablets (ODTs) recently have gained much attention to fulfill the needs for pediatric, geriatric, and psychiatric patients with dysphagia. Aim of this study was to develop new ODT formulations containing mirtazapine, an antidepressant drug molecule having bitter taste, by using simple and inexpensive preparation methods such as coacervation, direct compression and to compare their characteristics with those of reference product (Remereon SolTab). MATERIALS AND METHODS: Coacervation method was chosen for taste masking of mirtazapine. In vitro characterization studies such as diameter and thickness, weight variation, tablet hardness, tablet friability and disintegration time were performed on tablet formulations. Wetting time and in vitro dissolution tests of developed ODTs also studied using 900 mL 0.1 N HCl medium, 900 mL pH 6.8 phosphate buffer or 900 mL pH 4.5 acetate buffer at 37 +/- 0.2 degrees C as dissolution medium. RESULTS: Ratio of Eudragit(r) E-100 was chosen as 6% (w/w) since the dissolution profile of A1 (6% Eudragit(r) E-100) was found closer to the reference product than A2 (4% Eudragit(r) E-100) and A3 (8% Eudragit(r) E 100). Group D, E and F formulations were presented better results in terms of disintegration time. Dissolution results indicated that Group E and F formulations showed optimum properties in all three dissolution media. DISCUSSION: Formulations D1, D4, D5, E3, E4, F1 and F5 found suitable as ODT formulations due to their favorable disintegration times and dissolution profiles. CONCLUSION: Developed mirtazapine ODTs were found promising in terms of showing the similar characteristics to the original formulation. PMID- 26530147 TI - IGF-loaded silicon and zinc doped brushite cement: physico-mechanical characterization and in vivo osteogenesis evaluation. AB - Dopants play critical roles in controlling the physical, mechanical, degradation kinetics, and in vivo properties of calcium phosphates. The aim of the present study was to evaluate the effects of silicon (Si) and zinc (Zn) dopants on the physico-mechanical and in vivo osteogenesis properties of brushite cements (BrCs) alone and in combination with insulin like growth factor 1 (IGF-1). Addition of 0.5 wt% Si did not alter the setting time, beta-TCP content, and compressive strength of BrCs significantly; however, 0.25 wt% Zn incorporation was accompanied by a significant decrease in mechanical strength from 4.78 +/- 0.21 MPa for pure BrC to 3.78 +/- 0.59 MPa and 3.28 +/- 0.22 MPa for Zn-BrC and Si/Zn BrC, respectively. The in vivo bone regeneration properties of doped BrCs alone and in combination with IGF-1 were assessed and compared using chronological radiography, histology, scanning electron microscopy and fluorochrome labeling at 2 and 4 months post implantation in a rabbit femoral defect model. Based on in vivo characterization focusing on osteogenesis and vasculogenesis, Si-BrC and Si/Zn-BrC showed the best performance followed by Zn-BrC and pure BrCs. Addition of IGF-1 further improved bone regeneration. Our findings confirm that addition of Si and/or Zn alters the physico-mechanical properties of BrCs and promotes the early stage in vivo osseointegration and bone remodeling properties. PMID- 26530148 TI - Six-coordinate ferric porphyrins containing bidentate N-t-butyl-N nitrosohydroxylaminato ligands: structure, magnetism, IR spectroelectrochemisty, and reactivity. AB - NONOates (diazeniumdiolates) containing the [X{N2O2}](-) functional group are frequently employed as nitric oxide (NO) donors in biology, and some NONOates have been shown to bind to metalloenzymes. We report the preparation, crystal structures, detailed magnetic behavior, redox properties, and reactivities of the first isolable alkyl C-NONOate complexes of heme models, namely (OEP)Fe(eta(2) ON(t-Bu)NO) (1) and (TPP)Fe(eta(2)-ON(t-Bu)NO) (2) (OEP = octaethylporphyrinato dianion, TPP = tetraphenylporphyrinato dianion). The compounds display the unusual NONOate O,O-bidentate binding mode for porphyrins, resulting in significant apical Fe displacements (+0.60 A for 1, and +0.69 A for 2) towards the axial ligands. Magnetic susceptibility and magnetization measurements made from 1.8-300 K at magnetic fields from 0.02 to 5 T, yielded magnetic moments of 5.976 and 5.974 Bohr magnetons for 1 and 2, respectively, clearly identifying them as high-spin (S = 5/2) ferric compounds. Variable-frequency (9.4 GHz and 34.5 GHz) EPR measurements, coupled with computer simulations, confirmed the magnetization results and yielded more precise values for the spin Hamiltonian parameters: g(avg) = 2.00 +/- 0.03, |D| = 3.89 +/- 0.09 cm(-1), and E/D = 0.07 +/ 0.01 for both compounds, where D and E are the axial and rhombic zero-field splittings. IR spectroelectrochemistry studies reveal that the first oxidations of these compounds occur at the porphyrin macrocycles and not at the Fe-NONOate moieties. Reactions of 1 and 2 with a histidine mimic (1-methylimidazole) generate RNO and NO, both of which may bind to the metal center if sterics allow, as shown by a comparative study with the Cupferron complex (T(p-OMe)PP)Fe(eta(2) ON(Ph)NO). Protonation of 1 and 2 yields N2O as a gaseous product, presumably from the initial generation of HNO that dimerizes to the observed N2O product. PMID- 26530149 TI - Diacylglycerol kinase-delta regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics. AB - Decrease of AMPK-related signal transduction and insufficient lipid oxidation contributes to the pathogenesis of obesity and type 2 diabetes. Previously, we identified that diacylglycerol kinase-delta (DGKdelta), an enzyme involved in triglyceride biosynthesis, is reduced in skeletal muscle from type 2 diabetic patients. Here, we tested the hypothesis that DGKdelta plays a role in maintaining appropriate AMPK action in skeletal muscle and energetic aspects of contraction. Voluntary running activity was reduced in DGKdelta(+/-) mice, but glycogen content and mitochondrial markers were unaltered, suggesting that DGKdelta deficiency affects skeletal muscle energetics but not mitochondrial protein abundance. We next determined the role of DGKdelta in AMPK-related signal transduction and lipid metabolism in isolated skeletal muscle. AMPK activation and signaling were reduced in DGKdelta(+/-) mice, concomitant with impaired lipid oxidation and elevated incorporation of free fatty acids into triglycerides. Strikingly, DGKdelta deficiency impaired work performance, as evident by altered force production and relaxation dynamics in response to repeated contractions. In conclusion, DGKdelta deficiency impairs AMPK signaling and lipid metabolism, thereby highlighting the deleterious role of excessive lipid metabolites in the development of peripheral insulin resistance and type 2 diabetes pathogenesis. DGKdelta deficiency also influences skeletal muscle energetics, which may lead to low physical activity levels in type 2 diabetes. PMID- 26530150 TI - Stromal cell-derived factor-1 mediates changes of bone marrow stem cells during the bone repair process. AB - Osteoblasts, osteoclasts, chondrocytes, and macrophages that participate in the bone repair process are derived from hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). However, the roles of these stem cells during the repair of injured bone tissue are still unclear. In the present study, we examined the effects of bone defect on HSCs and MSCs in bone marrow and spleen in 75 mice and its mechanism. We analyzed the HSC and MSC populations in these tissues of a mouse with femoral bone damage by using flow cytometry. The number of HSCs in the bone marrow of mice with damaged femurs was significantly lower than the number of these cells in the bone marrow of the contralateral intact femurs on day 2 after injury. Meanwhile, the number of MSCs in the bone marrow of mice with damaged femurs was significantly higher than that of the contralateral femurs. Both intraperitoneal administration of AMD3100, a C-X-C chemokine receptor 4 (CXCR4) antagonist, and local treatment with an anti-stromal cell derived factor-1 (SDF-1) antibody blunted the observed decrease in HSC and increase in MSC populations within the bone marrow of injured femurs. In conclusion, the present study revealed that there is a concurrent decrease and increase in the numbers of HSCs and MSCs, respectively, in the bone marrow during repair of mouse femoral bone damage. Furthermore, the SDF-1/CXCR4 system was implicated as contributing to the changes in these stem cell populations upon bone injury. PMID- 26530151 TI - Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice. AB - Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis. PMID- 26530152 TI - Enhanced insulin sensitivity mediated by adipose tissue browning perturbs islet morphology and hormone secretion in response to autonomic nervous activation in female mice. AB - Insulin resistance results in a compensatory increase in insulin secretion to maintain normoglycemia. Conversely, high insulin sensitivity results in reduced insulin secretion to prevent hypoglycemia. The mechanisms for this inverse adaptation are not well understood. We utilized highly insulin-sensitive mice, due to adipocyte-specific overexpression of the FOXC2 transcription factor, to study mechanisms of the reversed islet adaptation to increased insulin sensitivity. We found that Foxc2TG mice responded to mild hyperglycemia with insulin secretion significantly lower than that of wild-type mice; however, when severe hyperglycemia was induced, Foxc2TG mice demonstrated insulin secretion equal to or greater than that of wild-type mice. In response to autonomic nervous activation by 2-deoxyglucose, the acute suppression of insulin seen in wild-type mice was absent in Foxc2TG mice, suggesting impaired sympathetic signaling to the islet. Basal glucagon was increased in Foxc2TG mice, but they displayed severely impaired glucagon responses to cholinergic and autonomic nervous stimuli. These data suggest that the autonomic nerves contribute to the islet adaptation to high insulin sensitivity, which is compatible with a neuro-adipo regulation of islet function being instrumental for maintaining glucose regulation. PMID- 26530153 TI - Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers. AB - The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways. PMID- 26530154 TI - Equine hyperinsulinemia: investigation of the enteroinsular axis during insulin dysregulation. AB - Compared with some other species, insulin dysregulation in equids is poorly understood. However, hyperinsulinemia causes laminitis, a significant and often lethal disease affecting the pedal bone/hoof wall attachment site. Until recently, hyperinsulinemia has been considered a counterregulatory response to insulin resistance (IR), but there is growing evidence to support a gastrointestinal etiology. Incretin hormones released from the proximal intestine, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, augment insulin secretion in several species but require investigation in horses. This study investigated peripheral and gut-derived factors impacting insulin secretion by comparing the response to intravenous (iv) and oral d glucose. Oral and iv tests were performed in 22 ponies previously shown to be insulin dysregulated, of which only 15 were classified as IR (iv test). In a more detailed study, nine different ponies received four treatments: d-glucose orally, d-glucose iv, oats, and commercial grain mix. Insulin, glucose, and incretin concentrations were measured before and after each treatment. All nine ponies showed similar iv responses, but five were markedly hyperresponsive to oral d glucose and four were not. Insulin responsiveness to oral d-glucose was strongly associated with blood glucose concentrations and oral glucose bioavailability, presumably driven by glucose absorption/distribution, as there was no difference in glucose clearance rates. Insulin was also positively associated with the active amide of GLP-1 following d-glucose and grain. This study has confirmed a functional enteroinsular axis in ponies that likely contributes to insulin dysregulation that may predispose them to laminitis. Moreover, iv tests for IR are not reliable predictors of the oral response to dietary nonstructural carbohydrate. PMID- 26530155 TI - The anabolic response to a meal containing different amounts of protein is not limited by the maximal stimulation of protein synthesis in healthy young adults. AB - We have determined whole body protein kinetics, i.e., protein synthesis (PS), breakdown (PB), and net balance (NB) in human subjects in the fasted state and following ingestion of ~40 g [moderate protein (MP)], which has been reported to maximize the protein synthetic response or ~70 g [higher protein (HP)] protein, more representative of the amount of protein in the dinner of an average American diet. Twenty-three healthy young adults who had performed prior resistance exercise (X-MP or X-HP) or time-matched resting (R-MP or R-HP) were studied during a primed continuous infusion of l-[(2)H5]phenylalanine and l [(2)H2]tyrosine. Subjects were randomly assigned into an exercise (X, n = 12) or resting (R, n = 11) group, and each group was studied at the two levels of dietary protein intake in random order. PS, PB, and NB were expressed as increases above the basal, fasting values (mg.kg lean body mass(-1).min(-1)). Exercise did not significantly affect protein kinetics and blood chemistry. Feeding resulted in positive NB at both levels of protein intake: NB was greater in response to the meal containing HP vs. MP (P < 0.00001). The greater NB with HP was achieved primarily through a greater reduction in PB and to a lesser extent stimulation of protein synthesis (for all, P < 0.0001). HP resulted in greater plasma essential amino acid responses (P < 0.01) vs. MP, with no differences in insulin and glucose responses. In conclusion, whole body net protein balance improves with greater protein intake above that previously suggested to maximally stimulating muscle protein synthesis because of a simultaneous reduction in protein breakdown. PMID- 26530156 TI - The impact of a human IGF-II analog ([Leu27]IGF-II) on fetal growth in a mouse model of fetal growth restriction. AB - Enhancing placental insulin-like growth factor (IGF) availability appears to be an attractive strategy for improving outcomes in fetal growth restriction (FGR). Our approach was the novel use of [Leu(27)]IGF-II, a human IGF-II analog that binds the IGF-II clearance receptor IGF-IIR in fetal growth-restricted (FGR) mice. We hypothesized that the impact of [Leu(27)]IGF-II infusion in C57BL/6J (wild-type) and endothelial nitric oxide synthase knockout (eNOS(-/-); FGR) mice would be to enhance fetal growth and investigated this from mid- to late gestation; 1 mg.kg(-1).day(-1) [Leu(27)]IGF-II was delivered via a subcutaneous miniosmotic pump from E12.5 to E18.5. Fetal and placental weights recorded at E18.5 were used to generate frequency distribution curves; fetuses <5th centile were deemed growth restricted. Placentas were harvested for immunohistochemical analysis of the IGF system, and maternal serum was collected for measurement of exogenously administered IGF-II. In WT pregnancies, [Leu(27)]IGF-II treatment halved the number of FGR fetuses, reduced fetal(P = 0.028) and placental weight variations (P = 0.0032), and increased the numbers of pups close to the mean fetal weight (131 vs. 112 pups within 1 SD). Mixed-model analysis confirmed litter size to be negatively correlated with fetal and placental weight and showed that [Leu(27)]IGF-II preferentially improved fetal weight in the largest litters, as defined by number. Unidirectional (14C)MeAIB transfer per gram placenta (System A amino acid transporter activity) was inversely correlated with fetal weight in [Leu(27)]IGF-II-treated WT animals (P < 0.01). In eNOS(-/-) mice, [Leu(27)]IGF-II reduced the number of FGR fetuses(1 vs. 5 in the untreated group). The observed reduction in FGR pup numbers in both C57 and eNOS(-/-) litters suggests the use of this analog as a means of standardizing and rescuing fetal growth, preferentially in the smallest offspring. PMID- 26530157 TI - Advances in high-density lipoprotein physiology: surprises, overturns, and promises. AB - Emerging evidence strongly supports that changes in the HDL metabolic pathway, which result in changes in HDL proteome and function, appear to have a causative impact on a number of metabolic disorders. Here, we provide a critical review of the most recent and novel findings correlating HDL properties and functionality with various pathophysiological processes and disease states, such as obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, inflammation and sepsis, bone and obstructive pulmonary diseases, and brain disorders. PMID- 26530159 TI - [Uterine neoplasia in two geriatric miniature pet pigs - diagnostics and therapy. Two case reports]. AB - Miniature pet pigs are becoming ever more common among the patients of small animal practices. Due to an advanced age attained in these animals in comparison with conventional pigs in pork production, miniature pet pigs develop age-related diseases that are infrequently observed in farm pigs, including neoplastic alterations of the uterus. We describe two cases of a uterine adenocarcinoma and a leiomyoma, respectively, in two miniature pet pig sows. Options and limits of diagnostic measures (unspecific clinical symptoms, x-ray, sonography and computed tomography) and therapy within the legal limits as well as the risk of an incorrect diagnosis based upon the more common differential diagnoses in swine medicine, including obstipation, cystitis and endometritis, are discussed. PMID- 26530158 TI - Chloroquine inhibits hepatocellular carcinoma cell growth in vitro and in vivo. AB - Recently, chloroquine (CQ) has been widely used to improve the efficacy of different chemotherapy drugs to treat tumors. However, the effects of single treatment of CQ on liver cancer have not been investigated. In the present study, we examined the effects of CQ on the growth and viability of liver cancer cells in vitro and in vivo, and revealed that CQ treatment triggered G0/G1 cell cycle arrest, induced DNA damage and apoptosis in a dose- and time-dependent manner in liver cancer cells. Moreover, administration of CQ to tumor-bearing mice suppressed the tumor growth in an orthotopic xenograft model of liver cancer. These findings extend our understanding and suggest that CQ could be repositioned as a treatment option for liver cancer as a single treatment or in combination. PMID- 26530160 TI - Phase transfer of 1- and 2-dimensional Cd-based nanocrystals. AB - In this work, luminescent CdSe@CdS dot-in-rod nanocrystals, CdSe@CdS/ZnS nanorods as well as CdSe-CdS core-crown nanoplatelets were transferred into aqueous phase via ligand exchange reactions. For this purpose, bifunctional thiol-based ligands were employed, namely mercaptoacetic acid (MAA), 3-mercaptopropionic acid (MPA), 11-mercaptoundecanoic acid (MUA) as well as 2-(dimethylamino)ethanthiol (DMAET). Systematic investigations by means of photoluminescence quantum yield measurements as well as photoluminescence decay measurements have shown that the luminescence properties of the transferred nanostructures are affected by hole traps (induced by the thiol ligands themselves) as well as by spatial insulation and passivation against the environment. The influence of the tips of the nanorods on the luminescence is, however, insignificant. Accordingly, different ligands yield optimum results for different nanoparticle samples, mainly depending on the inorganic passivation of the respective samples. In case of CdSe@CdS nanorods, the highest emission intensities have been obtained by using short-chain ligands for the transfer preserving more than 50% of the pristine quantum yield of the hydrophobic nanorods. As opposed to this, the best possible quantum efficiency for the CdSe@CdS/ZnS nanorods has been achieved via MUA. The gained knowledge could be applied to transfer for the first time 2-dimensional CdSe-CdS core-crown nanoplatelets into water while preserving significant photoluminescence (up to 12% quantum efficiency). PMID- 26530161 TI - 'Morals can not be drawn from facts but guidance may be': the early life of W.D. Hamilton's theory of inclusive fitness. AB - W.D. Hamilton's theory of inclusive fitness saw the evolution of altruism from the point of view of the gene. It was at heart a theory of limits, redefining altruistic behaviours as ultimately selfish. This theory inspired two controversial texts published almost in tandem, E.O. Wilson's Sociobiology: The New Synthesis (1975) and Richard Dawkins's The Selfish Gene (1976). When Wilson and Dawkins were attacked for their evolutionary interpretations of human societies, they claimed a distinction between reporting what is and declaring what ought to be. Can the history of sociobiological theories be so easily separated from its sociopolitical context? This paper draws upon unpublished materials from the 1960s and early 1970s and documents some of the ways in which Hamilton saw his research as contributing to contemporary concerns. It pays special attention to the 1969 Man and Beast Smithsonian Institution symposium in order to explore the extent to which Hamilton intended his theory to be merely descriptive versus prescriptive. From this, we may see that Hamilton was deeply concerned about the political chaos he perceived in the world around him, and hoped to arrive at a level of self-understanding through science that could inform a new social order. PMID- 26530162 TI - The triple whammy anxiety depression and osteoarthritis in long-term conditions. AB - Improving the management of people with long-term conditions is a key priority of the UK National Health Service. Whilst the coexistence of two or more long-term conditions in one person is increasingly the norm in primary care, guidelines and delivery of care remain focused on single disease management.Anxiety, depression and osteoarthritis are frequently comorbid with other long-term conditions and with each other, with up to 70 % of people with anxiety and depression also suffering from chronic pain. The relationships between anxiety, depression and pain are reciprocal, with each predicting and worsening the outcome of the others. Where these conditions occur in the context of other long-term conditions, further reduction in health-related quality of life and poorer clinical outcomes for all comorbid conditions is observed. It therefore follows that optimising the management of one comorbid condition should confer benefit to the other/s. Yet despite this, anxiety, depression and chronic pain are seldom prioritised by either patient or clinician, therefore remaining under-recognised and under-treated.Case-finding aims to identify and offer timely treatment to individuals with a given disease in a population at risk, therefore offering one possible solution. Yet case-finding is not without its problems, with well recognised barriers including lack of time, cultural difficulties and inadequate resources and practitioner skills. So whilst the merits of why to actively seek these conditions is clear, how this may be best achieved is not. We explore the potential role of case-finding for anxiety, depression and osteoarthritis-related joint pain in individuals with comorbid long-term conditions, assessing whether adopting an integrated approach to care may allow opportunistic case-finding therefore promoting identification and timely management of these deleterious conditions. PMID- 26530163 TI - Lower urinary tract dysfunction in patients with dysautonomia. AB - OBJECTIVE: With the goal of better defining the types of bladder dysfunction observed in this population, we present the chief urologic complaints, results of urodynamic studies, and treatments of patients with dysautonomia-related urinary symptoms. METHODS: All patients with dysautonomia referred to our neurourology clinic between 2005 and 2015 for management of lower urinary tract dysfunction were retrospectively reviewed. Each patient's chief urologic complaint was recorded and used to initially characterize the bladder storage or voiding symptoms. Patient evaluation included history and physical examination, urinalysis, post void bladder ultrasound, and urodynamic studies. Successful treatment modalities that subjectively or objectively improved symptoms were recorded. RESULTS: Of 815 patients with the diagnosis of dysautonomia, 82 (10 %) were referred for evaluation of lower urinary tract dysfunction. Mean age was 47 years (range 12-83) and 84 % were female. The chief complaint was urinary urgency +/- incontinence in 61 % and hesitancy in 23 % of patients. Urodynamic findings demonstrated detrusor overactivity +/- incontinence in 50 % of patients, although chief complaint did not reliably predict objective findings. Successful objective and subjective treatments were multimodal and typically non-operative. INTERPRETATION: Lower urinary tract dysfunction may develop in at least 10 % of patients with dysautonomia, predominantly females. Bladder storage or voiding complaints do not reliably predict urodynamic findings. Urodynamically, most patients exhibited detrusor overactivity. The majority of patients were successfully managed with medical or physical therapy. PMID- 26530164 TI - Hepatitis B virus X protein activates Notch signaling by its effects on Notch1 and Notch4 in human hepatocellular carcinoma. AB - Deregulated expression of Notch receptors and abnormal activity of Notch signaling have been observed in a growing number of malignant tumors, however, the expression and activity of Notch in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and their relationship with HBV X protein (HBx) are still not fully elucidated. To address this, we examined the overall expression of Notch receptors in HBV-associated HCC tissues, analyzed their relationship with HBx, and further investigated the role of Notch signaling in HBx stable transfected HepG2 cells (HepG2X). The results showed that Notch signaling could be activated by HBx in HepG2 cells. The expression of cytoplasmic Notch1 or nuclear Notch4 was correlated with the expression of HBx in HBV associated HCC tissues. The expression of cytoplasmic Notch1 or nuclear Notch4 could also be upregulated by HBx in HepG2X cells. The upregulation of Notch1 by HBx was through p38 MAPK pathway. Moreover, HBx was found to directly interact with Notch1, whereas, not with Notch4 in HepG2X cells. Suppression of Notch signaling by gamma-secretase inhibitor (GSI) decreased cell growth, blocked cell cycle progression and induced cell apoptosis in HepG2X cells. The present study indicates that HBx activates Notch signaling by its effects on Notch1 and Notch4, and therefore, recruits Notch signaling as a downstream pathway contributing to its carcinogenic role in HBV-associated HCC. PMID- 26530165 TI - Oral supplementations with L-glutamine or L-alanyl-L-glutamine do not change metabolic alterations induced by long-term high-fat diet in the B6.129F2/J mouse model of insulin resistance. AB - In this work, we aimed to investigate the effects of long-term supplementations with L-glutamine or L-alanyl-L-glutamine in the high-fat diet (HFD)-fed B6.129SF2/J mouse model over insulin sensitivity response and signaling, oxidative stress markers, metabolism and HSP70 expression. Mice were fed in a standard low-fat diet (STA) or a HFD for 20 weeks. In the 21th week, mice from the HFD group were allocated in five groups and supplemented for additional 8 weeks with different amino acids: HFD control group (HFD-Con), HFD + dipeptide L alanyl-L-glutamine group (HFD-Dip), HFD + L-alanine group (HFD-Ala), HFD + L glutamine group (HFD-Gln), or the HFD + L-alanine + L-glutamine (in their free forms) group (HFD-Ala + Gln). HFD induced higher body weight, fat pad, fasted glucose, and total cholesterol in comparison with STA group. Amino acid supplementations did not induce any modifications in these parameters. Although insulin tolerance tests indicated insulin resistance in all HFD groups, amino acid supplementations did not improve insulin sensitivity in the present model. There were also no significant differences in the immunocontents of insulin receptor, Akt, and Toll-like receptor-4. Notably, total 70 kDa heat shock protein (HSP72 + HSP73) contents in the liver was markedly increased in HFD-Con group as compared to STA group, which might suggest that insulin resistance is only in the beginning. Apparently, B6.129SF2/J mice are more resistant to the harmful effects of HFD through a mechanism that may include gut adaptation, reducing the absorption of nutrients, including amino acids, which may explain the lack of improvements in our intervention. PMID- 26530166 TI - Extracellular heat shock proteins protect U937 cells from H2O2-induced apoptotic cell death. AB - The cytoprotective role of heat shock proteins (HSPs) has been demonstrated in various cell types however, only few studies have investigated the role of extracellular exposure to HSPs in the survival of human lymphoma cell line U937. In the present study, we investigated the effect of extracellular exposure to four HSPs (HSP90, HSP70, HSP60, and HSP47) on apoptotic cell death induced by either oxidative stress (hydrogen peroxide) or endoplasmic reticulum stress mediated intracellular calcium overload. It was found that extracellular exposure to HSPs reduced the cytotoxicity induced by hydrogen peroxide, but not that evoked by thapsigargin (a specific inhibitor of cytosolic calcium reuptake which is able to induce endoplasmic reticulum stress with subsequent intracellular calcium overload). Similarly, it was observed that exogenous HSPs were able to suppress the caspase-3 activation induced by hydrogen peroxide. These findings indicate that extracellular HSPs increase the resistance of human lymphoma cell line U937 to apoptotic cell death induced by hydrogen peroxide and diminish oxidative stress-mediated injures. PMID- 26530167 TI - Metabolism of benzo(a)pyrene by aortic subcellular fractions in the setting of abdominal aortic aneurysms. AB - As exposure to polycyclic aromatic hydrocarbons (PAHs; a family of environmental toxicants) have been implicated in cardiovascular diseases, the ability of the aortic tissue to process these toxicants is important from the standpoint of abdominal aortic aneurysms and atherosclerosis. Benzo(a)pyrene (B(a)P), a representative PAH compound is released into the environment from automobile exhausts, industrial emissions, and considerable intake of B(a)P is also expected in people who are smokers and barbecued red meat eaters. Therefore, knowledge of B(a)P metabolism in the cardiovascular system will be of importance in the management of vascular disorders. Toward this end, subcellular fractions (nuclear, cytosolic, mitochondrial, and microsomal) were isolated from the aortic tissues of Apo E mice that received a 5 mg/kg/week of B(a)P for 42 days and 0.71 mg/kg/day for 60 days. The fractions were incubated with 1 and 3 MUM B(a)P. Post incubation, samples were extracted with ethyl acetate and analyzed by reverse phase HPLC. Microsomal B(a)P metabolism was greater than the rest of the fractions. The B(a)P metabolite levels generated by all the subcellular fractions showed a B(a)P exposure concentration-dependent increase for both the weekly and daily B(a)P treatment categories. The preponderance of B(a)P metabolites such as 7,8-dihydrodiol, 3,6-, and 6,12-dione metabolites are interesting due to their reported involvement in B(a)P-induced toxicity through oxidative stress. PMID- 26530168 TI - [Aneurysm in the main pulmonary artery in patient with pulmonary hypertension: Successful surgical treatment]. PMID- 26530169 TI - [Inferior myocardial infarction with extension to right ventricle secondary to giant right coronary artery aneurysm]. PMID- 26530170 TI - The biphasic bioresorbable scaffold (Trufit((r))) in the osteochondral knee lesions: long-term clinical and MRI assessment in 30 patients. AB - BACKGROUND: Chondral or osteochondral defects have been reported in 60-67 % of patients in studies reporting knee arthroscopies. The surgical management of chondral and osteochondral defects (OCD's) of the articular surface of the knee joint remains a controversial topic. Osteochondral injuries can be treated with transfer cartilage procedure and with implantation of biodegradable scaffolds. For patients over 50 years old with largest osteochondral lesions, we prefer to use the biodegradable scaffold, like Trufit((r)) plug (Smith & Nephew, Andover, MA). The purpose of this study is to evaluate the outcome of this series of surgical procedure with Trufit. METHODS: In our institute, the Trufit was used for the treatment of one or more focal osteochondral lesions of the femoral condyles positive MRI with or without concomitant ligamentous or meniscal pathology. We reviewed 30 patients with mean age of 60.57 years (range 32-79 years) with a clinical and imaging control at 6, 12, 24 and 48 months of follow up. RESULTS: The clinical evaluation has shown the good outcome. The MRI conducted has shown the progressive partial integration of the scaffolds. CONCLUSIONS: The results obtained indicate a clear improvement of the clinical symptoms and slowing joint degeneration. The clinical and imaging results confirm that the Trufit constitutes a valid surgical alternative in case of focal osteochondral. PMID- 26530171 TI - [Methods of induction of labor in termination of pregnancy after 22weeks: About 3procedures]. AB - OBJECTIVES: To propose a protocol for induction of labor to terminate pregnancy after 22weeks of amenorrhea allowing to decrease the duration of labor and of hospitalization but also, allowing to reduce the number of emergency pretreatment induced fetal death, to improve the experience of the patients and to limit the cost. METHODS: We realized a retrospective single-center study including 269patients and comparing three protocols, with and without laminaria and with various intervals mifepristone-misoprostol (14 and 38hours). The outcome measures were the misoprostol-delivery interval, the delivery time and the number of emergency pretreatment-induced fetal death. RESULTS: We showed that the misoprostol-delivery interval and the delivery time were comparable for the three periods of our study, even after decrease of 24hours of the mifepristone misoprostol interval and in the absence of laminaria. The misoprostol-delivery interval was between 7h30 and 8h35 between protocols (P=0.055). The delivery time was between 5:18pm and 6:48pm between protocols (P=0.252). The early administration of misoprostol allowed the patients to give birth earlier (P=0.001). Finally, we showed that the increase of the size and the number of laminarias were risk factors of emergency pretreatment-induced fetal death (respectively P=0.013 and P=0.002). CONCLUSION: The absence of laminaria and the reduction of the interval mifepristone-misoprostol of 24hours do not change the time to delivery and allow to reduce the duration of hospitalization, the number of emergency pretreatment-induced fetal death and the cost of the TOP. PMID- 26530172 TI - [Postpartum pelvic floor muscle training and abdominal rehabilitation: Guidelines]. AB - OBJECTIVE: Provide guidelines for clinical practice concerning postpartum rehabilitation. METHODS: Systematically review of the literature concerning postpartum pelvic floor muscle training and abdominal rehabilitation. RESULTS: Pelvic-floor rehabilitation using pelvic floor muscle contraction exercises is recommended to treat persistent urinary incontinence at 3 months postpartum (grade A), regardless of the type of incontinence. At least 3 guided sessions with a therapist is recommended, associated with pelvic floor muscle exercises at home. This postpartum rehabilitation improves short-term urinary incontinence (1 year) but not long-term (6-12 years). Early pelvic-floor rehabilitation (within 2 months following childbirth) is not recommended (grade C). Postpartum pelvic floor rehabilitation in women presenting with anal incontinence, is associated with a lower prevalence of anal incontinence symptoms in short-term (1 year) (EL3) but not long-term (6 and 12) (EL3). Postpartum pelvic-floor rehabilitation is recommended to treat anal incontinence (grade C) but results are not maintained in medium or long term. No randomized trials have evaluated the pelvic floor rehabilitation in asymptomatic women in order to prevent urinary or anal incontinence in medium or long term. It is therefore not recommended (expert consensus). Rehabilitation supervised by a therapist (physiotherapist or midwife) is not associated with better results than simple advice for voluntary contraction of the pelvic floor muscles to prevent/correct, in short term (6 months), a persistent prolapse 6 weeks postpartum (EL2), whether or not with a levator ani avulsion (EL3). Postpartum pelvic-floor rehabilitation is not associated with a decrease in the prevalence of dyspareunia at 1-year follow-up (EL3). Postpartum pelvic-floor rehabilitation guided by a therapist is therefore not recommended to treat or prevent prolapse (grade C) or dyspareunia (grade C). No randomized trials have evaluated the effect of pelvic floor muscle training after an episode of postpartum urinary retention or bladder outlet obstruction symptoms, or for the primary prevention of anal incontinence following third degree anal sphincter tear or in patients presenting with anal incontinence after third-degree anal sphincter tear. The electrostimulation devices used alone were not assessed in this postpartum context (regardless of symptoms); therefore, isolated pelvic floor electrostimulation is not recommended (expert consensus). CONCLUSION: Pelvic floor muscle therapy is recommended for persistent postpartum urinary (grade A) or anal (grade C) incontinence (3 months after delivery). PMID- 26530173 TI - [Maternal care after vaginal delivery and management of complications in immediate post-partum--Guidelines for clinical practice]. AB - OBJECTIVE: To provide recommendations on maternal care after vaginal delivery, and management of complications in immediate post-partum period. METHODS: Bibliographic research from the Pubmed database and recommendations issued by the main scientific societies, and assignment of a level of evidence and a recommendation grade. RESULTS: After a vaginal delivery, monitoring of blood pressure, heart rate, bleeding, uterine involution, genital pain, urination, temperature, transit and signs of phlebitis is recommended (professional consensus). Post-partum Anemia is defined by a hemoglobin<11 g/dL at 48 hours (grade C). Anemia must be searched only in women who have bled during delivery or who present symptoms of anemia (professional consensus). Oral iron supplementation is only proposed in cases of biologically proven anemia (professional consensus). In case of post-partum hypertension or de novo preeclampsia, the prescription rules for antihypertensive treatments and magnesium sulfate are the same as in prenatal period (professional consensus). Oral NSAIDs are effective for perineal pain and uterine involution (EL2). In case of broken down perineal wounds following childbirth, there is no argument in favor of suturing or not suturing, however the suturing is to be preferred for large dehisced perineal wounds (professional consensus). Infection of perineal scar justifies an oral broad-spectrum antibiotics, in addition to local nursing (professional consensus). In case of obstetric anal sphincter injuries, an antibiotic prophylaxis is recommended (grade B). Hygiene advice should be given to all women who had an episiotomy or a perineal tear (professional consensus). The only etiological treatment of post-dural puncture headache is the blood patch (EL2). It must not be carried out before 48 hours (professional consensus). Thromboembolic risk after a vaginal birth is about 10/00 (EL2). The prescription of thromboprophylaxis with LMWH and graduated compression stockings should be based on risk factors (professional consensus). CONCLUSION: During the immediate post-partum period, complications may be unrecognized or confused with the natural post-partum evolution, which implies a strong vigilance from practitioners. This vigilance is all the more necessary that the maternal residence durations are shortened. PMID- 26530174 TI - [Hysterectomy for benign pathology: Guidelines for clinical practice]. AB - OBJECTIVE: The objective of the study was to provide guidelines for clinical practice from the French college of obstetrics and gynecology (CNGOF), based on the best evidence available, concerning hysterectomy for benign pathology. METHODS: Each recommendation for practice was allocated a grade which depends on the level of evidence (guidelines for clinical practice method). RESULTS: Hysterectomy should be performed by a high volume surgeon (>10 procedures of hysterectomy per year) (grade C). Rectal enema stimulant laxatives are not recommended prior to hysterectomy (grade C). It is recommended to carry out vaginal disinfection using povidone iodine solution prior to an hysterectomy (grade B). Antibioprophylaxis is recommended during a hysterectomy, regardless of the surgical route (grade B). The vaginal or the laparoscopic routes are recommended for hysterectomy for benign pathology (grade B), even if the uterus is large and/or the patient is obese (grade C). The choice between these two surgical approaches depends on others parameters, such as the surgeon's experience, the mode of anesthesia and organizational constraints (operative duration and medico economic factors). Hysterectomy by vaginal route is not contraindicated in nulliparous women (grade C) or in women with previous c section (grade C). No specific technique to achieve hemostasis is recommended with a view to avoid urinary tract injuries (grade C). In the absence of ovarian pathology and personal or family history of breast/ovarian carcinoma, it is recommended to conserve ovaries in pre-menopausal women (grade B). Subtotal hysterectomy is not recommended in order to diminish the risk of per- or postoperative complications (grade B). CONCLUSION: The application of these recommendations should minimize risks associated with hysterectomy. PMID- 26530175 TI - [Breastfeeding (part III): Breastfeeding complications--Guidelines for clinical practice]. AB - OBJECTIVE: Provide guidelines for management of breastfeeding complications. MATERIALS AND METHODS: Systematically review of the literature between 1972 and May 2015 from the database Medline, Google Scholar, Cochrane Library, and the international recommendations about inhibition of lactation with establishment of levels of evidence (EL) and grades of recommendation. RESULTS: Nipple stimulation preparation techniques or antenatal correction an anatomical variation of the nipple are not recommended to decrease nipple complications or improve the success of breastfeeding (grade B). The use of lanolin and application of breast milk may have an interest in diseases of the nipple (EL4). The current published data are insufficient to conclude on the effectiveness of nipple shield, (professional consensus). Manual breast expression or using a breast pump may have an interest in preventing breast engorgement (professional agreement). A bacteriological sample of milk for mastitis is necessary to decide an antibiotic and interrupt breastfeeding with breast infected while continuing its drainage with a breast pump (professional consensus). Incision and drainage of breast abscess are recommended (professional consensus) and iterative puncture is an alternative to surgical drainage in the moderate forms (professional consensus). Breastfeeding is not contraindicated for women with a past history of esthetic breast surgery or breast cancer (professional consensus). There is no scientific justification to recommend the use of breast pumps to improve breastfeeding (grade B). Because of the potential side effects, the use of domperidone and metoclopramide are not recommended in the stimulation of lactation (grade C). CONCLUSION: Breastfeeding exposes women to specific complications, which may impede the continuation of breastfeeding. Prevention of mastitis is essential. PMID- 26530176 TI - [Guidelines for clinical practice: Shoulder dystocia--Introduction]. PMID- 26530177 TI - [Rare benign breast tumors including Abrikossoff tumor (granular cell tumor), erosive adenomatosis of the nipple, cytosteatonecrosis, fibromatosis (desmoid tumor), galactocele, hamartoma, hemangioma, lipoma, juvenile papillomatosis, pseudoangiomatous hyperplasia, and syringomatous adenoma: Guidelines for clinical practice]. AB - OBJECTIVES: To provide guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF), based on the best evidence available, concerning rare benign breast tumors: Abrikossoff (granular cell tumor), erosive adenomatosis of the nipple, cytosteatonecrosis, fibromatosis (desmoid tumor), galactocele, hamartoma, hemangioma, lipoma, juvenile papillomatosis, pseudoangiomatous hyperplasia, and syringomatous adenoma. METHODS: Bibliographical search in French and English languages by consultation of Pubmed, Cochrane and international databases. RESULTS: For erosive adenomatosis of the nipple, surgical excision is recommended to exclude Paget's disease or cancer (grade C). When surgery is performed for breast desmoid tumor or syringomatous adenoma, free margins are recommended (grade C). Without clinico radio-histologic discordance, surgical abstention may be proposed for Abrikossoff tumor (granular cell tumor), cytosteatonecrosis, galactocele, hamartoma, hemangioma, lipoma, juvenile papillomatosis, pseudoangiomatous hyperplasia, and syringomatous adenoma (grade C). PMID- 26530178 TI - [Management of shoulder dystocia]. AB - OBJECTIVE: The objective of this review is to propose recommendations on the management of shoulder dystocia. MATERIALS AND METHODS: The PubMed database, the Cochrane Library and the recommendations from the foreign obstetrical societies or colleges have been consulted. RESULTS: In case of shoulder dystocia, if the obstetrician is not present at delivery, he should be systematically informed as quickly as possible (professional consensus). A third person should also be called for help in order to realize McRoberts maneuver (professional consensus). The patient has to be properly installed in gynecological position (professional consensus). It is recommended not to pull excessively on the fetal head (grade C), do not perform uterine expression (grade C) and do not realize inverse rotation of the fetal head (professional consensus). McRoberts maneuver, with or without a suprapubic pressure, is simple to perform, effective and associated with low morbidity, thus, it is recommended in the first line (grade C). Regarding the maneuvers of the second line, the available data do not suggest the superiority of one maneuver in relation to another (grade C). We proposed an algorithm; however, management should be adapted to the experience of the operator. If the posterior shoulder is engaged, Wood's maneuver should be performed preferentially; if the posterior shoulder is not engaged, delivery of the posterior arm should be performed preferentially (professional consensus). Routine episiotomy is not recommended in shoulder dystocia (professional consensus). Other second intention maneuvers are described. It seems necessary to know at least two maneuvers to perform in case of shoulder dystocia unresolved by the maneuver McRoberts (professional consensus). CONCLUSION: All physicians and midwives should know and perform obstetric maneuvers if needed quickly but without precipitation. PMID- 26530179 TI - [Breast-feeding (part IV): Therapeutic uses, dietetic and addictions--guidelines for clinical practice]. AB - OBJECTIVE: To describe the practical aspects of the use of the most commonly prescribed drugs during the postpartum period, the dietetic measures and the management of breast-feeding in case of addictive behaviors. METHODS: Review of the literature between 1972 and May 2015 from the databases Medline, Google Scholar, Cochrane Library, and international recommendations of learned societies. RESULTS: The precaution to stop breast-feeding when drugs are necessary is not justified in many situations (professional consensus). Aspirin at antiaggregant dose is allowed during breast-feeding while high doses are not recommended; NSAIDs with short half-life can be used (professional consensus). Precautions are needed in cases of use of morphonics (professional consensus). There is no justification to delay the initiation of breast-feeding in case of locoregional or general analgesia or for caesarean section. Antibiotic treatment does not justify discontinuing breast-feeding (professional consensus). Anxiolytics of the class of antihistaminic sedating H1 such as hydroxyzine (Atarax(r)) should not be prescribed in case of breast-feeding (professional consensus). Imaging does not justify to stop breast-feeding (professional consensus). Tobacco consumption is discouraged but is not a contraindication to breast-feed (professional consensus). It is recommended to avoid the consumption of alcohol (professional consensus). In case of occasional and moderate consumption of alcohol, delaying breast-feeding for a minimum of two hours is recommended (professional consensus). Cocaine consumption is a contraindication of breast-feeding (professional agreement), and breast-feeding is not recommended in case of cannabis use (professional consensus). CONCLUSION: Few drug treatments are not compatible with breast-feeding that can be continued in most of the cases. PMID- 26530180 TI - [Delivery management for the prevention of shoulder dystocia in case of identified risk factors]. AB - OBJECTIVE: To determine the impact of (i) computed tomographic (CT) pelvimetry for the choice of the mode of delivery, (ii) cesarean, (iii) induction of labor, and of (iv) various delivery managements on the risk of shoulder dystocia in case of fetal macrosomia, with or without maternal diabetes, and in women with previous history of shoulder dystocia. METHODS: The PubMed database, the Cochrane Library and the recommendations from the French and foreign obstetrical societies or colleges have been consulted. RESULTS: In case of clinically suspected macrosomia, a sonography should be performed to increase diagnostic performances and to assist in decision-making (Professional consensus). Because CT pelvimetry is associated with high false positive rates and increases cesarean deliveries, its use is not recommended to prevent shoulder dystocia in case of fetal macrosomia (Professional consensus). To avoid the neonatal complications of shoulder dystocia, mainly permanent brachial plexus palsy, cesarean delivery is recommended in case of estimated fetal weight (EFW) greater than 4500 g if associated with maternal diabetes (grade C), and greater than 5000 g in the absence of maternal diabetes (grade C). The published data do not provide definitive evidences to recommend systematic labor induction in case of impending fetal macrosomia (Professional consensus). In case of favourable cervix and gestational age greater than 39 weeks of gestation, labor induction should be promoted (Professional consensus). Prophylactic McRoberts maneuver is not recommended to prevent shoulder dystocia in case of fetal macrosomia (grade C). Because data are lacking, no recommendation is possible regarding the use of episiotomy. In case of fetal macrosomia and failure to progress in the second stage of labor, midpelvic and higher instrumental deliveries are not recommended and a cesarean delivery should be preferred (grade C), if the fetal head is at or lower than a +2 station, cesarean delivery is not recommended and an instrumental delivery should be preferred (grade C). Finally, cesarean delivery should be discussed when history of shoulder dystocia has been associated with severe neonatal or maternal complications (Professional consensus). CONCLUSION: To avoid shoulder dystocia and its complications, only two measures are proposed. Induction of labor is recommended in case of impending macrosomia if the cervix is favourable and gestational age greater than 39 weeks of gestation (Professional consensus). Cesarean delivery is recommended before labor in case of (i) EFW greater than 4500 g if associated with maternal diabetes (grade C), (ii) EFW greater than 5000 g in the absence of maternal diabetes (grade C), and finally (iii) during labor, in case of fetal macrosomia and failure to progress in the second stage, when the fetal head is above a +2 station (grade C). Finally, cesarean delivery should be discussed when history of shoulder dystocia has been associated with severe neonatal or maternal complications (Professional consensus). PMID- 26530181 TI - [Not Available]. PMID- 26530183 TI - [In Process Citation]. PMID- 26530182 TI - Multimodality imaging with CT, MR and FDG-PET for radiotherapy target volume delineation in oropharyngeal squamous cell carcinoma. AB - BACKGROUND: This study aimed to quantify the variation in oropharyngeal squamous cell carcinoma gross tumour volume (GTV) delineation between CT, MR and FDG PET CT imaging. METHODS: A prospective, single centre, pilot study was undertaken where 11 patients with locally advanced oropharyngeal cancers (2 tonsil, 9 base of tongue primaries) underwent pre-treatment, contrast enhanced, FDG PET-CT and MR imaging, all performed in a radiotherapy treatment mask. CT, MR and CT-MR GTVs were contoured by 5 clinicians (2 radiologists and 3 radiation oncologists). A semi-automated segmentation algorithm was used to contour PET GTVs. Volume and positional analyses were undertaken, accounting for inter-observer variation, using linear mixed effects models and contour comparison metrics respectively. RESULTS: Significant differences in mean GTV volume were found between CT (11.9 cm(3)) and CT-MR (14.1 cm(3)), p < 0.006, CT-MR and PET (9.5 cm(3)), p < 0.0009, and MR (12.7 cm(3)) and PET, p < 0.016. Substantial differences in GTV position were found between all modalities with the exception of CT-MR and MR GTVs. A mean of 64 %, 74 % and 77 % of the PET GTVs were included within the CT, MR and CT-MR GTVs respectively. A mean of 57 % of the MR GTVs were included within the CT GTV; conversely a mean of 63 % of the CT GTVs were included within the MR GTV. CT inter-observer variability was found to be significantly higher in terms of position and/or volume than both MR and CT-MR (p < 0.05). Significant differences in GTV volume were found between GTV volumes delineated by radiologists (9.7 cm(3)) and oncologists (14.6 cm(3)) for all modalities (p = 0.001). CONCLUSIONS: The use of different imaging modalities produced significantly different GTVs, with no single imaging technique encompassing all potential GTV regions. The use of MR reduced inter-observer variability. These data suggest delineation based on multimodality imaging has the potential to improve accuracy of GTV definition. TRIAL REGISTRATION: ISRCTN Registry: ISRCTN34165059 . Registered 2nd February 2015. PMID- 26530185 TI - Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS. AB - In neuromyelitis optica (NMO), astrocytes become targets for pathogenic aquaporin 4 (AQP4)-specific antibodies which gain access to the central nervous system (CNS) in the course of inflammatory processes. Since these antibodies belong to a T cell-dependent subgroup of immunoglobulins, and since NMO lesions contain activated CD4(+) T cells, the question arose whether AQP4-specific T cells might not only provide T cell help for antibody production, but also play an important role in the induction of NMO lesions. We show here that highly pathogenic, AQP4 peptide-specific T cells exist in Lewis rats, which recognize AQP4268-285 as their specific antigen and cause severe panencephalitis. These T cells are re activated behind the blood-brain barrier and deeply infiltrate the CNS parenchyma of the optic nerves, the brain, and the spinal cord, while T cells with other AQP4-peptide specificities are essentially confined to the meninges. Although AQP4268-285-specific T cells are found throughout the entire neuraxis, they have NMO-typical "hotspots" for infiltration, i.e. periventricular and periaqueductal regions, hypothalamus, medulla, the dorsal horns of spinal cord, and the optic nerves. Most remarkably, together with NMO-IgG, they initiate large astrocyte destructive lesions which are located predominantly in spinal cord gray matter. We conclude that the processing of AQP4 by antigen presenting cells in Lewis rats produces a highly encephalitogenic AQP4 epitope (AQP4268-285), that T cells specific for this epitope are found in the immune repertoire of normal Lewis rats and can be readily expanded, and that AQP4268-285-specific T cells produce NMO like lesions in the presence of NMO-IgG. PMID- 26530186 TI - Evaluation and assessment of the efficacy of an abatement strategy in a former lead smelter community, Boolaroo, Australia. AB - This study examines the recent soil Lead Abatement Strategy (LAS) in Boolaroo, New South Wales, Australia, that was designed to "achieve a reduction in human exposure to lead dust contamination in surface soils". The abatement programme addressed legacy contamination of residential areas following closure of lead smelting operations in 2003 at the Pasminco Cockle Creek Smelter (PCCS). The principal objective of the LAS was to "cap and cover" lead-contaminated soils within the urban environment surrounding the PCCS. Soil lead concentrations of 2500-5000 mg/kg were scheduled for removal and replacement, while concentrations between 1500 and 2500 mg/kg were replaced only under limited circumstances. To date, there has been no industry, government or independent assessment of the clean-up programme that involved >2000 homes in the township of Boolaroo. Thus, by measuring post-abatement soil lead concentrations in Boolaroo, this study addresses this knowledge gap and evaluates the effectiveness of the LAS for reducing the potential for lead exposure. Soil lead concentrations above the Australian residential soil health investigation level value for residential soils (300 mg/kg) were identified at all but one of the residential properties examined (n = 19). Vacuum dust samples (n = 17) from the same homes had a mean lead concentration of 495 mg/kg (median 380 mg/kg). Bio-accessibility testing revealed that lead in household vacuum dust was readily accessible (% bio accessible) (mean = 92 %, median = 90 %), demonstrating that the risk of exposure via this pathway remains. Assessment of a limited number of properties (n = 8) where pre-abatement soil lead levels were available for comparison showed they were not statistically different to post-abatement. Although the LAS did not include treatment of non-residential properties, sampling of community areas including public sports fields, playgrounds and schools (n = 32) was undertaken to determine the contamination legacy in these areas. Elevated mean soil lead concentrations were found across public lands: sports fields = 5130 mg/kg (median = 1275 mg/kg), playgrounds and schools = 812 mg/kg (median = 920 mg/kg) and open space = 778 mg/kg (median = 620 mg/kg). Overall, the study results show that the LAS programme that was dominated by a "cap and cover" approach to address widespread lead contamination was inadequate for mitigating current and future risk of lead exposures. PMID- 26530187 TI - Differential expression analysis of human endogenous retroviruses based on ENCODE RNA-seq data. AB - BACKGROUND: Human endogenous retroviruses (HERVs) are flanked by long terminal repeats (LTRs), which possess promoter activity and can therefore influence the expression of neighboring genes. HERV involvement in different types of cancer has already been thoroughly documented. However, so far there has been no systematic study of HERV expression patterns in a multitude of cell types in health and disease. In particular, the publication of the comprehensive ENCODE dataset has already facilitated many gene expression studies, but none so far focusing exclusively on HERVs. RESULTS: We present a comprehensive differential analysis of HERV expression based on ENCODE Tier 1 and Tier 2 RNA-seq data produced by Cold Spring Harbor Laboratories and the California Institute of Technology. This analysis was conducted for individual HERV loci and for entire HERV families in twelve different cell lines, of which six correspond to the normal condition and the other six represent cancer cell types. Although the principal component analysis revealed that the two groups of cells show distinguishable expression patterns, we were not able to link these differences to one or multiple particular HERV families. Two samples exhibit expression patterns, which are not similar to the corresponding cell lines of the other producing lab. Instead they show signs of cancer formation and expression of the pluripotency marker HERVH, despite being classified as a normal cell line and a differentiated cell, respectively. CONCLUSIONS: Our study demonstrates that ENCODE data are generally comparable between the different contributing labs and that the analysis of HERV elements can provide novel insights into differentiation and disease state of a cell that are easily overlooked when focusing on protein-coding genes. Our findings hint at a change in HERV expression during cancerogenesis. PMID- 26530189 TI - Erratum to: technology consumption and cognitive control: Contrasting action video game experience with media multitasking. PMID- 26530188 TI - Factors affecting serum albumin in the perioperative period of colorectal surgery: a retrospective study. AB - BACKGROUND: Albumin is considered a negative acute-phase protein because its concentration decreases during injury and sepsis. Hypoalbuminemia is a risk factor for mortality, postoperative complications, and prolonged hospital stay. The magnitude of the systemic inflammatory response during the perioperative period, as indicated by the acute-phase proteins-C-reactive protein (CRP) in particular-, may help identify the risk of postoperative infectious complication. The correlation between serum albumin and CRP with gastrointestinal cancer has been reported. However, it is unclear whether antecedent CRP could be utilized to predict future hypoalbuminemia in the perioperative period in colorectal surgery. The primary endpoint of this study was to reveal that antecedent CRP could be utilized to predict future hypoalbuminemia in the perioperative period of colorectal surgery. METHODS: Thirty-seven patients who underwent elective open colorectal surgery were included in this study. Correlations between preoperative CRP and serum albumin on postoperative day (POD) 3, between preoperative CRP and serum albumin on POD 7 and between CRP on POD 3 and serum albumin on POD 7 were examined. Relationships between preoperative CRP and hypoalbuminemia on POD 3, between preoperative CRP and hypoalbuminemia on POD 7 and between CRP on POD 3 and hypoalbuminemia on POD 7 were examined by receiver operating characteristic analysis. RESULTS: Three-quarters of patients were older than 65 years of age. Significant correlations were observed between preoperative CRP and serum albumin on POD 3 (p = 0.023), between preoperative CRP and serum albumin on POD 7 (p = 0.023) and between CRP on POD 3 and serum albumin on POD 7 (p < 0.001). The area under the receiver operating characteristic curve of CRP on POD 3 to development of hypoalbuminemia on POD 7 was 0.833 (95 % CI 0.679-0.987) with an optimal threshold of 12.43 mg/dL, sensitivity 75 % and specificity 80 %. CONCLUSIONS: The present study revealed that antecedent CRP was associated with future serum albumin. Additionally, CRP on POD 3 could be useful in predicting the development of hypoalbuminemia on POD 7. This result suggests that CRP on POD 3 may be a valuable indicator for early nutritional intervention. PMID- 26530190 TI - Management of patients with flail chest by surgical fixation using claw-type titanium plate. AB - BACKGROUND: The goal of the study was to compare surgical rib fixation using claw type titanium plate with conservative treatment in the management of patients with flail chest. METHODS: The study retrospectively studied 23 patients suffering from flail chest injury, who admitted to our hospital from October, 2010 to February, 2014. The patients received surgical fixation by using claw type titanium plate (surgical fixation group). A age and sex-matched cohort of 29 patients received conservative treatment and defined as conservative treatment group. Outcome variables included number of cases undergoing mechanical ventilation, ventilation time, time of hospital stay, incidence of respiratory complications, incidence of thoracic deformity and postoperative forced expiratory volume in the first second (FEV1). RESULTS: Compared with conservative treatment group, surgical fixation group had fewer cases undergoing mechanical ventilation, shorter ventilation time, shorter hospital stay, lower incidence of respiratory complications and thoracic deformity and improved pulmonary function. Patients undergoing surgery earlier had shorter time of mechanical ventilation. CONCLUSIONS: Surgical rib fixation with claw-type titanium plate is a reliable and efficient method in the management of patients with flail chest. PMID- 26530191 TI - [Nicotinic acid increases cellular transport of high density lipoprotein cholesterol in patients with hypoalphalipoproteinemia]. AB - BACKGROUND: Plasma high density lipoproteins (HDL) are involved in reverse cholesterol transport mediated by the scavenger receptor class B type I (SR-BI). Nicotinic acid increases HDL cholesterol levels, even though its specific impact on SR-BI dependent-cellular cholesterol transport remains unknown. AIM: To determine the effect of nicotinic acid on HDL particle functionality in cholesterol efflux and uptake mediated by SR-BI in cultured cells in hypoalphalipoproteinemic patients. MATERIAL AND METHODS: In a pilot study, eight patients with low HDL (<= 40 mg/dL) were treated with extended release nicotinic acid. HDL cholesterol and phospholipid levels, HDL2 and HDL3 fractions and HDL particle sizes were measured at baseline and post-therapy. Before and after nicotinic acid treatment, HDL particles were used for cholesterol transport studies in cells transfected with SR-BI. RESULTS: Nicotinic acid treatment raised total HDL cholesterol and phospholipids, HDL2 levels as well as HDL particle size. Nicotinic acid significantly increased HDL cholesterol efflux and uptake capacity mediated by SR-BI in cultured cells. CONCLUSIONS: Nicotinic acid therapy increases SR-BI-dependent HDL cholesterol transport in cultured cells, establishing a new cellular mechanism by which this lipid-lowering drug appears to modulate HDL metabolism in patients with hypoalphalipoproteinemia. PMID- 26530192 TI - [Frequency of kidney failure in cardiologic patients: the need to search]. AB - BACKGROUND: Chronic kidney disease is a major health problem since it is associated with a high cardiovascular risk, total morbidity and mortality, increasing prevalence and high cost treatment. AIM: To assess the frequency of chronic kidney disease among patients consulting in a cardiology clinic. MATERIAL AND METHODS: Cross-sectional assessment of 649 patients attended at a cardiology clinic. Demographic, clinical, electrocardiographic, echocardiographic and laboratory variables were registered. Patients were considered to have a kidney failure when their estimated glomerular filtration rate was < 60 ml/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) formula. Kidney failure was considered chronic if this alteration lasted >= 3 months and hidden when serum creatinine levels were normal. RESULTS: The frequency of kidney failure was 20.8% (28.4% in patients >= 65 years old). The mean age of patients with the disease was 71.5 +/- 9.1 years and 52% were women. Eighty seven percent were in stage 3, 10% in stage 4 and 3% in stage 5. Among patients with kidney failure, in 114 (84%) it was chronic and in 28%, hidden. The latter was observed almost exclusively in women with creatinine levels of approximately 1 mg/dl. Hypertension (Odds ratio (OR) 4.2), age (OR 1.1), ventricular ejection fraction (OR 0.97) and low hemoglobin (OR 0.735) were the risk factors for kidney failure detected in the multivariate analysis. CONCLUSIONS: The frequency of kidney failure (chronic or hidden) was high in this group of cardiologic patients. Most patients had a mild to moderate failure and the risk factors were hypertension, age, low ventricular ejection fraction and low hemoglobin levels. PMID- 26530193 TI - [Incidence and consequences of acute kidney injury among patients admitted to critical care units]. AB - BACKGROUND: Acute Kidney Injury (AKI) increases morbidity, mortality and hospital stay in critical patients units (CPU). AIM: To determine the incidence and mortality of AKI in CPU. MATERIAL AND METHODS: Review of electronic medical records of 1,769 patients aged 61 +/- 20 years (47% males) discharged from a CPU during one year. Acute Kidney Injury diagnosis and severity was established using the Acute Kidney Injury Network (AKIN) criteria. RESULTS: A history of hypertension and Diabetes Mellitus was present in 44 and 22% of patients, respectively. APACHE II and SOFA scores were 14.6 +/- 6.8 and 3.6 +/- 2.1 respectively. AKI incidence was 28.9% (stage I, 16.7%, stage II, 5.3% and stage III, 6.9%). Mortality during the first 30 days and during the first year was 8.1 and 20.0% respectively. Patients with stage III AKI had the highest mortality (23.8 and 40.2% at 30 days and one year respectively). Compared with patients without AKI, the Odds ratio for mortality at 30 days and one year of patients with AKI stage III was 3.7 and 2.5, respectively. CONCLUSIONS: Thirty percent of patients admitted to UPC develop an AKI, which influences 30 days and one year mortality. PMID- 26530194 TI - [Endoscopic treatment in chronic pancreatitis: long-term results in 18 patients]. AB - BACKGROUND: Intraductal stones, ductal abnormalities and pancreatic pseudocysts are part of chronic pancreatitis (CP). The goal of treatment is pain relief, resolution of local complications and relapse prevention. Endoscopic therapy (ET) can be considered in those who do not respond to medical treatment. AIM: To evaluate the indication, immediate and long-term results of ET in CP patients. PATIENTS AND METHODS: Review of a database of patients with CP analyzing results of ET in 18 patients aged 16 to 60 years (13 males). Demographics, etiology, endoscopic technique, indication for treatment, pain relief, relapses and complications were recorded. RESULTS: The etiology of CP was alcohol consumption in 5, idiopathic in 11, hereditary in one and autoimmune in one case. The follow up period was 6 months to 14 years. Seven patients had diabetes mellitus type 3c and eight had moderate to severe exocrine pancreatic insufficiency. Pancreatic papillotomy was performed in all patients, with removal of some stones, without attempting a complete clearance of the pancreatic duct. In addition, a 7-10 French stent was placed in the main pancreatic duct in 15 patients with varying permanence (months to years). The stent was changed guided by recurrence of clinical symptoms. During the follow-up period, 10 patients remained asymptomatic and in three, pain or relapse were significantly reduced. Stenting failed in one patient for technical reasons. Two patients were operated. There were neither immediate nor late complications from ET. CONCLUSIONS: Long-lasting improvement of CP was observed in 13 of 18 patients treated with ET, without complications associated with the procedure. PMID- 26530195 TI - [Heart rate variability and insulin resistance among obese males]. AB - BACKGROUND: Heart rate variability analysis provides quantitative information about vagal and sympathetic modulation of cardiac function. AIM: To analyze the relationship between heart rate variability and insulin resistance in obese patients. MATERIAL AND METHODS: Male participants were studied, divided in 10 obese subjects aged 27 +/- 2 years with a body mass index (BMI) of 31.2 +/- 1.3 kg/m2, 15 overweight subjects aged 24 +/- 3 years with a BMI of 26.7 +/- 1.5 kg/m2 and 14 normal weight subjects aged 21 +/- 2 years with a BMI of 22.5 +/- 1.3 kg/m2. Resting heart rate variability was measured in a period of 5 minutes. A spectral analysis was done measuring the low frequency/high frequency ratio (LF/HF). A non- linear analysis was carried out measuring the standard deviation of the instantaneous variation of RR intervals (SD1) and alpha-1 or a fractal analysis of RR interval complexity. A fasting blood sample was obtained to measure blood glucose and insulin and calculate the homeostasis model assessment for insulin resistance (HOMA-IR). RESULTS: Among obese subjects HOMA-IR, LF/HF, alpha-1 and SD1 values were 2.6 +/- 2.1, 2.4 +/- 1.8, 1.2 +/- 0.06 and 22.5 +/- 10 respectively. The figures for normal weight subjects were 0.5 +/- 0.1, 1.3 +/- 0.2, 0.9 +/- 0.3 and 26 +/- 7.8 respectively. CONCLUSIONS: There is an association between spectral and fractal values of heart rate variability and HOMA-IR. These results may indicate a predominance of sympathetic control of heart rate among obese subjects. PMID- 26530196 TI - [Effects of the Bright Bodies Program in Chilean obese children]. AB - BACKGROUND: Yale University's Bright Bodies Program consists on a lifestyle intervention, in areas such as nutrition and exercise, while focusing on behavior modification and family support. AIM: To evaluate the impact of the Program in Chilean children and adolescents with obesity who participated in the Program during 8 months. MATERIAL AND METHODS: The weight management Program was carried out during 8 months and consisted in weekly sessions directed by dietitians or psychologists and exercise sessions twice per week in charge of physical education teachers. The family component was based on sessions for parents or caregivers to achieve the same goals of children activities. RESULTS: Twenty eight obese children aged 9.5 +/- 2 years completed the eight months of intervention. There was a significant 5% reduction of body mass index (BMI), a 15% reduction of BMI z score and a 2.9% reduction of waist circumference. Bioelectrical impedance showed a 9% reduction of percentage body fat and a 7% increase in lean body mass. Blood pressure, blood glucose, total and LDL cholesterol and triglycerides decreased significantly, without changes in HOMA IR. The frequency of metabolic syndrome decreased from 36% at baseline to 18% at the end of the intervention. A 43% reduction in caloric intake and an improvement in physical condition was also observed. CONCLUSIONS: The Bright Bodies Program produced significant and positive changes on anthropometric and metabolic parameters in this group of children. PMID- 26530197 TI - [Validation of the Personal Wellbeing Index (PWI) in vulnerable users of health care services in Santiago, Chile]. AB - BACKGROUND: Personal well-being calculates quality of life in terms of the necessary conditions required to live well. AIM: To validate the Personal Wellbeing Index (PWI) in a representative sample of vulnerable users of the public health system in Santiago, Chile. MATERIAL AND METHODS: A probabilistic and multistage sample consisting of 400 individuals aged 44 +/- 18 years (61% females) belonging to the lower income group of the National Health Fund (FONASA), residents of Gran Santiago was surveyed. Internal consistency and correlation between items and scale were examined. Structure was analyzed through confirmatory factor analysis. RESULTS: The seven-item PWI is a good indicator of subjective well-being in the population under study, considering internal consistency, factor loadings, relation with overall life satisfaction and goodness of fit. The indicators mostly associated with personal well-being are the socioeconomic level followed by relationships with the community, health conditions and achievements. CONCLUSIONS: The 7-item version of the PWI is suitable for application in vulnerable health service users. PMID- 26530198 TI - [Evaluation of a teaching training program implemented in a faculty of medicine]. AB - BACKGROUND: Since 2010, the Faculty of Medicine at Finis Terrae University implemented a training program aiming to train health professionals in effective educational practices. AIM: To evaluate the effect of training in teachers who are in charge of planning courses, conducting classes and learning assessment. MATERIAL AND METHODS: Quality of planning, lecture performance and academic performance of students were evaluated in 55 teachers prior and after attending the training course on teaching methodologies and in 47 teachers not attending the course. RESULTS: The percentage of trained teachers complying with the aforementioned indicators was significantly higher than those without training (p < 0.01). There were significant differences in favor of the group of teachers who attended and passed the Diploma. Trained teachers had significantly higher students' approval rate. (Odds ratio 4.5, p < 0.01). CONCLUSIONS: The teaching Diploma in Health Sciences improved the planning, teaching and academic performance of teachers. PMID- 26530199 TI - [Cellular effectors of the inflammatory response in chronic obstructive pulmonary disease (COPD)]. AB - Approximately 3 million people in the world die every year as a consequence of COPD, which is associated with an abnormal inflammatory response of the lung to noxious particles and gases. This inflammatory pattern causes pathological changes leading to a narrowing of small airways and destruction of lung parenchyma, also known as emphysema. Classically, these changes were associated to macrophages and neutrophils, although T CD8+ lymphocytes were latter added to the equation to explain the origin of emphysematous lesions. However, in recent years, multiple evidences have arisen indicating that inflammatory response in COPD is much more complex. These findings point to a key role for mast cells, dendritic cells, T CD4+ and B cells. The aim of this article is to review such evidence and report what is known so far about those cells involved in the inflammatory response in COPD. PMID- 26530200 TI - [Acquired hemophagocytic syndrome treated with HLH 94-04 chemotherapy protocol: Report of four cases]. AB - Hemophagocytic syndrome is a severe condition of excessive immune activation that has a high mortality in the absence of treatment. The syndrome is classified as primary if associated with congenital or hereditary problems, or secondary/acquired if associated with infectious, autoimmune or oncology diseases. We report four adult cases of the syndrome, one with viral, two with autoimmune and one with idiopathic causes who were successfully treated with HLH 94-04 chemotherapy protocol. Our experience shows that a high index of suspicion, early diagnosis and an opportune therapy are essential in the treatment of this disease. PMID- 26530201 TI - [Mental health financing in Chile: a pending debt]. AB - In spite of the high prevalence of mental health disorders in Chile, there is a significant financing deficit in this area when compared to the world's average. The financing for mental health has not increased in accordance with the objectives proposed in the 2000 Chilean National Mental Health and Psychiatry Plan, and only three of the six mental health priorities proposed by this plan have secure financial coverage. The National Health Strategy for the Fulfilment of Health Objectives for the decade 2011-2020 acknowledges that mental disorders worsen the quality of life, increase the risk of physical illness, and have a substantial economic cost for the country. Thus, this article focuses on the importance of investing in mental health, the cost of not doing so, and the need for local mental health research. The article discusses how the United States is trying to eliminate the financial discrimination suffered by patients with mental health disorders, and concludes with public policy recommendations for Chile. PMID- 26530202 TI - [In Memory of a Master: Professor Ernesto L. Medina, M.D. (1925-2013)]. AB - Seldom, in the history of Chilean medicine, there has been such a unique parallelism between the professional development of a person and that of a discipline as it has been the case of Professor Ernesto L. Medina and Public Health in Chile. Dr. Medina's undergraduate (University of Chile) and postgraduate (Harvard School of Public Health) studies coincided with the foundation of the University of Chile School of Public Health by an agreement among the University and two governmental health care providers, and also with the foundation of the Chilean National Health Service. His research covered the epidemiology of non- infectious diseases in the adult, such as cancer, their socio economic impact, the importance of early detection, treatment and surveillance, as well as the epidemiology of other chronic diseases, accidents and new epidemics. As Director of the School of Public Health for 25 years, he promoted the development of disciplines and courses addressed to health and other care-providers in order to improve their knowledge and expertise as statisticians, epidemiologists, administrators, budget officers. An example of his innovative look at medical education was the creation of post graduate training in the basic clinical specialties combined with public health, in order to have specialists able to undertake both the clinical and administrative duties at the primary care clinics. These programs ran in parallel with the rural internships financed by the Kellogg Foundation at the School of Medicine. Enumerating the distinctions and prizes awarded to Professor Medina would be too long for the purpose of this tribute, and selecting just a few would run the risk of being unfair. Still, there is one: the "Orden de la Cruz del Sur" that deserves the exception given its long existence and the fact that it was awarded to a physician "for distinguished achievements in Public Health". PMID- 26530203 TI - [How do students who feel "not free to participate" perceived their tutorial sessions in problem based learning?]. AB - BACKGROUND: Verbal interactions are paramount to develop cognitive and social skills of students taught using problem based learning in small group tutorials. Responses to a questionnaire showed that 27% of second year medical students did not feel free to participate in their groups AIM: To explore if these students may have different perceptions respect to their peers, regarding the functioning of their tutorials. MATERIAL AND METHODS: The answer to the item "feel free to participate" was the criterion to allocate students in two groups, study (n = 25) and control (n = 66). The means of the perceptions were compared between groups in the 15 items' questionnaire. RESULTS: Students in the study group had different perceptions in eight of the items. These students enjoyed and considered interesting the topics addressed in the tutorials less frequently. Also they did not study all learning issues, did not always understand the case and foresaw less opportunities to participate in their groups. CONCLUSIONS: Quiet students perceived tutorials different than their more active peers. Those differences concerned motivation and a mixture of cognitive (individual) and social (rest of the group) strategies that were not conducive to build a suitable learning environment for those students in their respective tutorial groups. PMID- 26530205 TI - [Large vessel involvement in ANCA-associated vasculitis: Report of one case]. AB - Pauci-immune glomerulonephritis in systemic vasculitides usually have anti neuthrophil cytoplasmic antibodies (ANCA). However, vasculitides of large vessels such as Takayasu's and giant cell (temporal) arteritis do not. Exceptionally ANCA(+) small vessel vasculitides are associated with large vessel vasculitis. It may be a coincidence or both vasculitides have a common pathogenesis. We report a 30 years old woman on hemodialysis due to a chronic glomerulonephritis ANCA(+) diagnosed nine years ago. Eight years later, she presented with an aortitis with severe stenosis of distal aorta and vasculitis of left subclavian artery. She was treated with adrenal steroids and cyclophosphamide. During the ensuing five years she has been stable and without signs of reactivation of the disease. PMID- 26530204 TI - [Coverage of diagnostic upper gastrointestinal endoscopy for the prevention of gastric cancer in Chile: results from the 2009-2010 National Health Survey]. AB - BACKGROUND: In Chile, gastric cancer (GC) is a major cause of cancer related deaths. The current screening strategy consists of an upper gastrointestinal endoscopy (UGE) for people aged 40 years or more with epigastric pain. AIM: To evaluate the diagnostic coverage of the use of UGE for early detection of GC in Chile. MATERIAL AND METHODS: As part of the digestive module of the 2009-10 National Health Survey, 5293 adults over 15 years were asked about the presence of epigastric pain, possible upper gastrointestinal bleeding (PUGB), use of proton pump inhibitors (PPIs) or histamine H2-receptor antagonists (H2RAs), family history of GC and having performed an UGE. RESULTS: Persistent epigastric pain was observed in 3.4% of the population. PUGB signs were observed in 3.3% of the population. The prevalence of PPIs and H2RAs use was 4.3% and 2.2% respectively, reaching 21.6% in people aged 70 years and older. Life span prevalence of UGE was 18.3%, with differences by region, health insurance and educational level. UGE coverage in people aged 40 years or older with and without persistent epigastric pain was 14.4% and 3.2% respectively (Odds ratio 4.8, p < 0.01). The prevalence of UGE was similar among people with or without PUGB or family history of CG. CONCLUSIONS: The estimated coverage of the current GC prevention strategy in Chile is 14.4%, evaluated at a population level. Further studies are required to determine the impact of this strategy on early GC diagnosis and mortality. PMID- 26530206 TI - Multiorgan disorder syndrome (MODS) in an octagenarian suggests mitochondrial disorder. AB - Non-syndromic, multi-organ mitochondrial disorders (MIDs) are frequently missed if treating physicians are not aware of them. We report a 85 years old Caucasian male, referred for tonic-clonic seizures, presenting with a plethora of abnormalities, including neurodermitis, atopic dermatitis, diabetes, hypertension, renal insufficiency, non-specific colitis, urine bladder lithiasis, bilateral cataracts, atrial fibrillation, diverticulosis, polyneuropathy, vitamin D-deficiency, renal cysts, left anterior hemi-block, right bundle branch block, pulmonary artery hypertension, and heart failure. Neurological investigations revealed ptosis, quadriparesis, fasciculations, dysarthria, dysdiadochokinesia, tremor, hyperkinesia, ataxia, leukoencephalopathy, and basal ganglia calcification. Based upon this combination of abnormalities a non-syndromic mitochondrial multi-organ disorder syndrome (MIMODS, encephalo-myo cardiomyopathy) was diagnosed. PMID- 26530207 TI - [Ketosis prone type 2 diabetes (KPD)]. AB - Ketosis prone type 2 diabetes (KPD) is presently a well-defined clinical entity, characterized by a debut with severe hyperglycemia and ketoacidosis similar to the presenting form of Type 1 diabetes mellitus (DM1). However, it appears in subjects with Type 2 diabetes mellitus (DM2) phenotype. This situation is caused by an acute, reversible dysfunction of the beta cell in individuals with insulin resistance. Once the acute stage subsides, patients behave as having a DM2 and do not require insulin treatment. They should be kept on a diet and oral hypoglycemic drugs due to their susceptibility to have recurrent acute ketotic decompensations. PMID- 26530208 TI - [Reliability for cut-off scores: re-analysis of Alvarado et al]. PMID- 26530209 TI - [Spinocerebellar ataxia type 3 (Machado-Joseph disease) and varenicline]. PMID- 26530210 TI - [New pathway to obtain a specialty in Internal Medicine, in Poland]. PMID- 26530211 TI - Peak oxygen uptake during the incremental shuttle walk test in a predominantly female population with Chagas heart disease. AB - BACKGROUND: Chagas heart disease (CHD) patients may have a reduced functional capacity (FC). Field tests, as the Incremental Shuttle Walk Test (ISWT), can estimate peak oxygen uptake (VO2 peak). However, the relationship between the ISWT and the Cardiopulmonary Exercise Testing (CPET), the gold standard in the assessment of FC, is not well established in CHD patients. AIM: This study aimed to evaluate the FC of CHD patients by ISWT with direct measurement of VO2 peak and to compare these findings with data obtained from CPET. A secondary goal was to derive a regression equation to calculate the VO2 peak by ISWT. DESIGN: Cross sectional and correlative study. SETTING: Research laboratory setting. POPULATION: Thirty-two CHD patients (58.8+/-9.0 years, 81.3% women) participated in this study. METHODS: Eligible patients underwent clinical evaluation, echocardiography, CPET by ramp protocol and ISWT according to current guidelines. RESULTS: The distance walked in ISWT showed a positive correlation with VO2 peak from CPET and ISWT (r=0.456, P=0.009 and r=0.869, P<0.001, respectively). In the agreement analysis, the values of the differences between VO2 peak from CPET and ISWT showed absence of bias (mean bias +/-95% CI and mean -1.29+/-5.09 mL.kg.min). Based in real values of VO2 obtained from ISWT, one equation including sex, functional class and distance walked was provided to predict the VO2 values in this test. CONCLUSION: This study showed the good correlation between distance walked in ISWT and VO2 peak directly measured in both tests, and additionally, provided an equation to calculate a predictive VO2 peak by ISWT, suggesting a good alternative to evaluate the FC of CHD patients, especially in locations where sophisticated testing is not available. CLINICAL REHABILITATION IMPACT: The results confirm the possibility of using the ISWT for the evaluation of the FC in patients with CHD, especially in locations where sophisticated testing is not available. PMID- 26530212 TI - Reverse left ventricular remodeling: effect of cardiac rehabilitation exercise training in myocardial infarction patients with preserved ejection fraction. AB - BACKGROUND: In the increasingly prevalent population of postmyocardial infarction (MI) patients with preserved left ventricular (LV) ejection fraction (>45%), the effect of cardiac rehabilitation (CR) exercise training on LV structure and function is unknown. AIM: To examine the reverse LV remodeling effect of CR exercise training in post-MI patients with preserved LV ejection fraction (>45%). DESIGN: Prospective, longitudinal, controlled trial. SETTING: Outpatient CR programme. POPULATION: Fifty six asymptomatic, post-MI patients without residual myocardial ischemia and LV ejection fraction >45%. METHODS: Within 3-6 weeks of MI, and 10 weeks later, echocardiography and cardiopulmonary exercise testing were performed. An exercise training group (N.=36) completed twice weekly gym based cardiovascular exercise (60-80% VO2 peak) and a resistance training programme, whilst a non-exercise group (N.=20) did not. RESULTS: In comparison to the non-exercise group, in which there was no change, 10 weeks of CR exercise training resulted in increased VO2peak and reduced LV end diastolic and systolic volumes (all P<0.05 vs. non-exercise group). CONCLUSIONS: In post-MI patients with preserved LV ejection fraction (>45%), CR exercise training is effective in improving functional capacity and reducing LV volumes. CLINICAL REHABILITATION IMPACT: In this previously unstudied population, the measurement of reverse LV volumetric remodeling may prove useful as an indicator of CR exercise programme efficacy. To maximize the potential clinical benefit from reverse LV remodeling, this patient group, should be actively encouraged to engage in CR exercise training. PMID- 26530213 TI - Early rehabilitation for severe acquired brain injury in intensive care unit: multicenter observational study. AB - BACKGROUND: The increased survival after a severe acquired brain injury (sABI) raise the problem of making most effective the treatments in Intensive Care Unit (ICU)/Neurointensive Care Unit (NICU), also integrating rehabilitation care. Despite previous studies reported that early mobilization in ICU was effective in preventing complications and reducing hospital stay, few studies addressed the rehabilitative management of sABI patients in ICU/NICU. AIM: To collect clinical and functional data about the early rehabilitative management of sABI patients during ICU/NICU stay. DESIGN: Prospective, observational, multicenter study. SETTING: Fourteen facilities supplied by intensive neurorehabilitation units and ICU/NICUs. POPULATION: Consecutive sABI patients admitted to ICU/NICU. METHODS: Patients were evaluated at admission and then every 3-5 days. Clinical, functional and rehabilitative data, including Glasgow Coma Scale (GCS), Disability Rating Scale (DRS), The Rancho Los Amigos Levels of Cognitive Functioning Scale (LCF), Early Rehabilitation Barthel Index (ERBI), Glasgow Outcome scale (GOS) and Functional Independence Measure (FIM) were collected. RESULTS: One hundred and two patients (F/M 44/58) were enrolled. The mean duration of ICU stay was 24.7+/-13.9 days and the first rehabilitative evaluation occurred after 8.7+/-8.8 days. Regular postural changes and multijoint mobilization were prescribed in 63.7% and 64.7% cases, respectively. The mean session duration was 38+/-11.5 minutes. Swallowing evaluation was performed in 14.7% patients, psychological support was provided to 12.7% of patients' caregivers, while 17.6% received a psycho-educational intervention, and 28.4% were involved in interdisciplinary team meetings. The main discharge destinations were Severe Acquired Brain Injury rehabilitation units for 43.7%, intensive neurorehabilitation units for 20.7%. CONCLUSIONS: Data showed that early rehabilitation was not diffusely performed in sABI subjects in ICU/NICU and rehabilitative interventions were variable; one-third of subjects were not referred to dedicated rehabilitation unit at discharge. CLINICAL REHABILITATION IMPACT: The study stresses the need to spread and implement a rehabilitative culture also for critical ill patients due to neurological diseases. PMID- 26530214 TI - Review on initial drug treatment in Parkinson's disease did not mention entacapone. PMID- 26530215 TI - Leaf mechanical resistance in plant trait databases: comparing the results of two common measurement methods. AB - BACKGROUND AND AIMS: The influence of leaf mechanical properties on local ecosystem processes, such as trophic transfer, decomposition and nutrient cycling, has resulted in a growing interest in including leaf mechanical resistance in large-scale databases of plant functional traits. 'Specific work to shear' and 'force to tear' are two properties commonly used to describe mechanical resistance (toughness or strength) of leaves. Two methodologies have been widely used to measure them across large datasets. This study aimed to assess correlations and standardization between the two methods, as measured by two widely used apparatuses, in order to inter-convert existing data in those global datasets. METHODS: Specific work to shear (W(SS)) and force to tear (FT) were measured in leaves of 72 species from south-eastern Australia. The measurements were made including and excluding midribs. Relationships between the variables were tested by Spearman correlations and ordinary least square regressions. KEY RESULTS: A positive and significant correlation was found between the methods, but coefficients varied according to the inclusion or exclusion of the midrib in the measurements. Equations for prediction varied according to leaf venation pattern. A positive and significant (r = 0.90, P < 0.0001) correlation was also found between W(SS) values for fresh and rehydrated leaves, which is considered to be of practical relevance. CONCLUSIONS: In the context of broad-scale ecological hypotheses and used within the constraints recommended here, leaf mechanical resistance data obtained with both methodologies could be pooled together into a single coarser variable, using the equations provided in this paper. However, more detailed datasets of FT cannot be safely filled in with estimations based on W(SS), or vice versa. In addition, W(SS) values of green leaves can be predicted with good accuracy from W(SS) of rehydrated leaves of the same species. PMID- 26530216 TI - Obstetric complications on deployed operations: a guide for the military surgeon. AB - Modern military general surgeons tend to train and then practice in 'conventional' surgical specialties in their home nation; however, the reality of deployed surgical practice, either in a combat zone or on a humanitarian mission, is that they are likely to have to manage patients with a broad range of ages, conditions and pathologies. Obstetric complications of war injury include injury to the uterus and fetus as well as the mother and both placental abruption and uterine rupture are complications that military surgeons may have little experience of recognising and managing. On humanitarian deployments, fetomaternal complications are a common reason for surgical intervention. We report a recent patient's story to highlight the obstetric training needs of military surgeons. PMID- 26530217 TI - Sphere-formation culture of testicular germ cells in the common marmoset, a small New World monkey. AB - Spermatogonia are specialized cells responsible for continuous spermatogenesis and the production of offspring. Because of this biological property, in vitro culture of spermatogonia provides a powerful methodology to advance reproductive biology and engineering. However, methods for culturing primate spermatogonia are poorly established. We have designed a novel method for culturing spermatogonia in the common marmoset (Callithrix jacchus), a small primate. By using our method with a suite of growth factors, adult marmoset testis-derived germ cells could be cultured in the form of a floating sphere for several weeks. Notably, this method could be applied not only to freshly isolated cells but also to cryopreserved cell stocks. The spheres enriched spermatogonia and early spermatocytes, and could be assembled from a C-KIT(+) spermatogonial population. Techniques for culturing spermatogonia could facilitate increased understanding of primate reproduction as well as the preservation of valuable biomaterials from nonhuman primates. PMID- 26530218 TI - Forest seasonality shapes diet of limestone-living rhesus macaques at Nonggang, China. AB - Limestone forests are an unusual habitat for primates, but little information is available for the genus Macaca in such habitats, making a comparative understanding of extant limestone primates' behavioral adaptation incomplete. We collected data on the diet of rhesus macaques (Macaca mulatta) in a limestone habitat at Nonggang Nature Reserve, southwestern Guangxi, China, and examined the effects of forest seasonality on their diet. Our results indicated that a total of 114 species of plants are consumed by macaques. Young leaves are a preferred food, accounting for 48.9 and 56.9% of the overall diets. One group significantly increased young leaf consumption in response to availability. Fruits contributed to only 27.3 and 28.7% of overall diet. The macaque diet varied according to season. They fed on more fruits in the rainy season. Consumption of mature leaves increased when the availability of young leaves and fruits declined in the dry season, indicating that mature leaves are a fallback food for macaques in a limestone habitat. Similar to sympatric Assamese macaques, Bonia saxatilis, a shrubby, karst-endemic bamboo was consumed by rhesus macaques throughout the year, and was the top food species through most of the year, suggesting that bamboo consumption represents a key factor in the macaque's dietary adaptation to limestone habitat. PMID- 26530219 TI - Rapid increase in e-cigarette advertising spending as Altria's MarkTen enters the marketplace. PMID- 26530220 TI - New Isolated-Pentagon-Rule Isomer of C92 Isolated as Trifluoromethyl and Chlorido Derivatives: C92(38)(CF3)14/16 and C92(38)Cl20/22. AB - High-temperature trifluoromethylation and chlorination of the C92 fraction followed by single-crystal X-ray diffraction with the use of synchrotron radiation resulted in the structure determination of C92(38)(CF3)14, five isomers of C92(38)(CF3)16, and C92(38)Cl20/22. Their addition patterns are stabilized by the formation of isolated C?C bonds and aromatic substructures. According to quantum-chemical calculations, the newly detected C1-C92(38) belongs to the most stable isomers of C92. PMID- 26530221 TI - Reduced cerebral cortical thickness in Non-cirrhotic patients with hepatitis C. AB - Hepatitis C virus (HCV) infection is associated with fatigue, depression, and cognitive impairment even in the absence of severe liver fibrosis or cirrhosis. HCV has been hypothesised to cause neurodegenerative changes through low-grade neuroinflammation. Our aim was to examine whether cortical thickness (CTh) differs between chronic HCV patients and healthy controls, suggestive of cortical atrophy. In this case-control study 43 HCV patients without severe liver fibrosis, substance abuse, or comorbid HIV or hepatitis B virus infection, and 43 age and sex matched controls underwent MRI. Cortical thickness was measured using a surface based approach. Participants underwent semi-structured psychiatric interview and fatigue was assessed using the fatigue severity scale. HCV was associated with higher fatigue scores, and 58 % of HCV patients suffered from significant fatigue (p < 0.0001). Depression was observed in 16 % of patients. Areas of significantly reduced CTh were found in both left and right occipital cortex and in the left frontal lobe after correction for multiple comparisons (p < 0.05). No association between fatigue, former substance abuse, or psychotropic medication and CTh was found. No overall difference in cerebral white and grey matter volume was found. The findings support the hypothesis that HCV is associated with neurodegenerative changes. PMID- 26530222 TI - Relationship between glycated hemoglobin A1c and cognitive function in nondemented elderly patients with type 2 diabetes. AB - Elderly patients with type 2 diabetes are at a greater risk for cognitive decline. The purpose of this study was to assess the relationship between the degree of hyperglycemia and cognitive status in nondemented, elderly diabetics. Between Jan 2013 and Dec 2014, 1174 geriatric patients with type 2 diabetes were enrolled in the study (579 males; age >= 60 years; from Fuzhou, Fujian, China). Cognitive function was measured with the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). A statistically significant, age-adjusted association was observed between the A1C levels and the scores on two cognitive tests (MMSE and MoCA). Specifically, a 1% higher A1C value was associated with a 0.21-point lower MMSE score (95% CI; compare -0.11 to -0.28; P < 0.0001), as well as a 0.11-point lower MoCA score (95% CI; compare -0.10 to -0.38; P < 0.0001). Higher A1C levels were not significantly associated with lower MMSE and MoCA test scores after adjusting for all variables. No significant correlation was found between the two variables in patients older than 80 years of age (n = 215; OR = 1.019; 95% CI = 0.968 - 1.099; p = 0.251). Evidence strongly suggests that chronic hyperglycemia is associated with a decline in cognitive function in nondemented elderly patients with type 2 diabetes. When cognitive assessments are made, comprehensive factors such as advanced age, education level, duration of diabetes, hypertension and other vascular risks should be taken into account. For older geriatric patients (age >= 80 years), there is no significant correlation between A1c levels and cognitive function. PMID- 26530223 TI - Linking Essential Tremor to the Cerebellum: Physiological Evidence. AB - Essential tremor (ET), clinically characterized by postural and kinetic tremors, predominantly in the upper extremities, originates from pathological activity in the dynamic oscillatory network comprising the majority of nodes in the central motor network. Evidence indicates dysfunction in the thalamus, the olivocerebellar loops, and intermittent cortical engagement. Pathology of the cerebellum, a structure with architecture intrinsically predisposed to oscillatory activity, has also been implicated in ET as shown by clinical, neuroimaging, and pathological studies. Despite electrophysiological studies assessing cerebellar impairment in ET being scarce, their impact is tangible, as summarized in this review. The electromyography-magnetoencephalography combination provided the first direct evidence of pathological alteration in cortico-subcortical communication, with a significant emphasis on the cerebellum. Furthermore, complex electromyography studies showed disruptions in the timing of agonist and antagonist muscle activation, a process generally attributed to the cerebellum. Evidence pointing to cerebellar engagement in ET has also been found in electrooculography measurements, cerebellar repetitive transcranial magnetic stimulation studies, and, indirectly, in complex analyses of the activity of the ventral intermediate thalamic nucleus (an area primarily receiving inputs from the cerebellum), which is also used in the advanced treatment of ET. In summary, further progress in therapy will require comprehensive electrophysiological and physiological analyses to elucidate the precise mechanisms leading to disease symptoms. The cerebellum, as a major node of this dynamic oscillatory network, requires further study to aid this endeavor. PMID- 26530224 TI - [Validation and adhesion to GESIDA quality indicators in patients with HIV infection]. AB - INTRODUCTION: The objective of the study is to validate the relevant GESIDA quality indicators for HIV infection, assessing the reliability, feasibility and adherence to them. METHODS: The reliability was evaluated using the reproducibility of 6 indicators in peer review, with the second observer being an outsider. The feasibility and measurement of the level of adherence to the 22 indicators was conducted with annual fragmented retrospective collection of information from specific databases or the clinical charts of the nine participating hospitals. RESULTS: Reliability was very high, with interobserver agreement levels higher than 95% in 5 of the 6 indicators. The median time to achieve the indicators ranged between 5 and 600minutes, but could be achieved progressively from specific databases, enabling obtaining them automatically. As regards adherence to the indicators related with the initial evaluation of the patients, instructions and suitability of the guidelines for ART, adherence to ART, follow-up in clinics, and achieve an undetectable HIV by PCR at week 48 of the ART. Indicators of quality related to the prevention of opportunistic infections and control of comorbidities, the standards set were not achieved, and significant heterogeneity was observed between hospitals. CONCLUSION: The GESIDA quality indicators of HIV infection enabled the relevant indicators to be feasibly and reliably measured, and should be collected in all the units that care for patients with HIV infection. PMID- 26530225 TI - [Acute eosinophilic pneumonia secondary to daptomycin]. PMID- 26530226 TI - Thyroid cancer survivors' perceptions of survivorship care follow-up options: a cross-sectional, mixed-methods survey. AB - PURPOSE: This study investigated thyroid cancer (TC) survivors' perceived satisfaction with and perceptions of survivorship care follow-up options. METHODS: Well-differentiated TC (WDTC) patients receiving follow-up care at an academic cancer centre completed a questionnaire assessing perceived satisfaction with follow-up care involving different clinicians and mediated by the Internet (email or videoconference) and their perceptions of these follow-up options. We examined associations between patient characteristics and perceived satisfaction with follow-up care options. Qualitative responses were analysed using conventional content analysis. RESULTS: Two hundred and two respondents completed the questionnaire (80 % response rate). The majority strongly agreed or agreed that they would be satisfied with specialist (surgeon, oncologist, or endocrinologist) follow-up (90.6 %) or a shared-care model that integrates specialists with primary care (67.5 %). One third (32 %) would be satisfied with video-based and 26 % with email-based specialist follow-up, 15 % with primary care alone. Longer time since diagnosis and health-related Internet use were associated with higher perceived satisfaction with Internet-based follow-up. Younger age was associated with higher perceived satisfaction with primary care follow-up. Qualitative responses (n = 145) revealed that survivors need reassurance they are receiving adequate care, regardless of the model or medium. Enablers to primary care and Internet-based follow-up are discussed. CONCLUSIONS: WDTC survivors want specialists involved in their follow-up. A specialist/primary care shared-care approach appears to be a suitable alternative to specialist-led follow-up for TC survivors. Internet-based visits could address some aspects of follow-up care for some WDTC survivors. Future work should examine patient and provider requirements for shared, multi-modal survivorship care. PMID- 26530227 TI - Family caregiving challenges in advanced colorectal cancer: patient and caregiver perspectives. AB - PURPOSE: Family caregivers of advanced colorectal cancer patients may be at increased risk for psychological distress. Yet their key challenges in coping with the patient's illness are not well understood. Soliciting both patient and caregiver perspectives on these challenges would broaden our understanding of the caregiving experience. Thus, the purpose of this research was to identify caregivers' key challenges in coping with their family member's advanced colorectal cancer from the perspective of patients and caregivers. METHODS: Individual, semi-structured qualitative interviews were conducted with 23 advanced colorectal cancer patients and 23 primary family caregivers. Interview data were analyzed via thematic analysis. RESULTS: In nearly all cases, patient and caregiver reports of the caregiver's key challenge were discrepant. Across patient and caregiver reports, caregivers' key challenges included processing emotions surrounding the patient's initial diagnosis or recurrence and addressing the patient's practical and emotional needs. Other challenges included coping with continual uncertainty regarding the patient's potential functional decline and prognosis and observing the patient suffer from various physical symptoms. CONCLUSIONS: Findings suggest that eliciting the perspectives of both patients and caregivers regarding caregivers' challenges provides a more comprehensive understanding of their experience. Results also point to the need to assist caregivers with the emotional and practical aspects of caregiving. PMID- 26530228 TI - Efficacy and safety of olanzapine for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) as reported in phase I and II studies: a systematic review. AB - INTRODUCTION: Olanzapine is an atypical antipsychotic drug that inhibits serotonergic, dopaminergic, alpha-1 adrenergic, histaminic, and muscarinic receptors. Several phase I and II trials have been published documenting the use of olanzapine in controlling chemotherapy-induced nausea and vomiting (CINV). This review aims to summarize all phase I and II trials that reported on olanzapine for the prophylaxis of CINV. METHODS: A literature search was conducted in Ovid MEDLINE from 1946 to July week 1 2015, Embase Classic and Embase from 1947 to 2015 week 28, and the Cochrane Central Register of Controlled Trials up until June 2015. Phase I and II trials reporting on olanzapine for the prophylaxis for CINV were included if they reported on at least one of four primary endpoints: complete response (CR), complete control (CC), no nausea, and no emesis. Other endpoints of interest included the safety of olanzapine as measured by the M.D. Anderson Symptom Inventory. RESULTS: Across the seven included studies, there were a total of 201 patients. The CR across four studies was 97.2, 83.1, and 82.8 % for the acute, delayed, and overall phases, respectively. The CC for acute, delayed, and overall phases was 92.5, 87.5, and 82.5 %, respectively. The overall no nausea rate was 92.7, 71.8, and 70.6 % for the acute, delayed, and overall phases, respectively. The overall no emesis rates for the acute, delayed, and overall phases were 100, 94.5, and 90.4 %, respectively. Fatigue, drowsiness, and disturbed sleep were common side effects. CONCLUSION: Olanzapine is efficacious and safe when used as a prophylaxis for CINV. PMID- 26530229 TI - Unmet needs mediate the relationship between symptoms and quality of life in breast cancer survivors. AB - PURPOSE: This study aimed to compare the symptoms, unmet needs, and QoL reported by women at 6 months to <2 years and 2 to 5 years following surgery and adjuvant treatment for breast cancer. It also evaluated the relationships among symptoms, unmet needs, and QoL using structural equation modeling. METHODS: In this study, 113 and 137 survivors following breast cancer treatment 6 months to <2 years and 2 to 5 years, respectively, completed the Memorial Symptom Assessment Scale, the Supportive Care Needs Survey-34, and the Medical Outcomes Study 12-item Short Form Health Survey version 2.0 during their medical follow-up. RESULTS: The mean numbers of symptoms and unmet needs were 5.43 and 3.0, respectively, for survivors at <2 years, and 5.24 and 2.42, respectively, for survivors at 2 to 5 years following treatment. The most common reported symptoms were related primarily to physical domains. No significant differences were found between the two survivor groups on the MSAS scores. Survivors at <2 years reported significantly higher scores in Psychological and Health Care System/Information needs (p < 0.01), and lower composite scores in physical and mental QoL (p < 0.05) than those at 2 to 5 years post-treatment. Significant direct and indirect effects were found of symptom burden through unmet needs on survivors' physical and mental QoL after adjustment for survival time, and the models showed a good fit. CONCLUSIONS: Results suggest that breast cancer survivors continue to endure many symptoms independent of the survivorship period. The unmet needs mediate the relationship between symptom burden and survivors' QoL. PMID- 26530230 TI - Flexible ureterorenoscopy (F-URS) with holmium laser versus extracorporeal shock wave lithotripsy (ESWL) for treatment of renal stone <2 cm: a meta-analysis. AB - The objective of the study was to systematically review the efficacy and safety of flexible ureterorenoscopy (F-URS) with holmium laser versus extracorporeal shock wave lithotripsy (ESWL) for the treatment of renal stone <2 cm. A systematic literature review was performed in April 2015 using the PubMed, Embase, Web of Science and the Chinese Biomedical Literature (CNKI and Wanfang) databases to identify relevant studies. All clinical trials were retrieved and their included references investigated. Two reviewers independently assessed the quality of all included studies, and the eligible studies were included and analyzed using the RevMan 5.3 software. Six prospective randomized comparison trials and eight retrospective comparison trials were included, involving a total of 2348 patients. For renal stone 1-2 cm, F-URS technique provided a significantly higher stone-free rate (SFR) [weighted mean difference (WMD) = 2.35, 95 % confidence interval (CI) 1.65-3.34, P < 0.00001], lower auxiliary procedure rate (APR) [odds ratio (OR) 0.33, 95 % CI 0.22-0.50, P < 0.00001] and lower retreatment rate (RR) (OR 0.07, 95 % CI 0.01-0.37, P = 0.002). Similar results were found in the lower pole stone for 1-2 cm subgroup. For renal stone <1 cm, F-URS technique also showed a significantly higher SFR than ESWL (WMD = 2.13, 95 % CI 1.13-4.00, P = 0.02). F-URS is associated with higher SFR, lower APR and RR than ESWL. F-URS is a safe and effective procedure. It can successfully treat patients with stones for 1-2 cm, especially for lower pole stone, without increasing complications, operative time and hospital stay. F-URS can be used as an alternative treatment to ESWL in selected cases with larger renal stones. However, further randomized trials are needed to confirm these findings. PMID- 26530232 TI - Distinguishing of tumor cell-targeting peptide ligands through a color-encoding microarray. AB - A silicon-based microarray system was constructed to discover the affinity peptides and to distinguish the specific peptides from a high throughput library. Using a color-encoding strategy, in situ peptide distinguishing between HER1 ligands and HER2 ligands was achieved. Novel affinity peptide sequences H1P (HER1 ligand) and H2P (HER2 ligand) were determined with nmol affinity. PMID- 26530231 TI - A direct role of collagen glycation in bone fracture. AB - Non-enzymatic glycation (NEG) is an age-related process accelerated by diseases like diabetes, and causes the accumulation of advanced glycation end-products (AGEs). NEG-mediated modification of bone's organic matrix, principally collagen type-I, has been implicated in impairing skeletal physiology and mechanics. Here, we present evidence, from in vitro and in vivo models, and establish a causal relationship between collagen glycation and alterations in bone fracture at multiple length scales. Through atomic force spectroscopy, we established that NEG impairs collagen's ability to dissipate energy. Mechanical testing of in vitro glycated human bone specimen revealed that AGE accumulation due to NEG dramatically reduces the capacity of organic and mineralized matrix to creep and caused bone to fracture under impact at low levels of strain (3000-5000 MUstrain) typically associated with fall. Fracture mechanics tests of NEG modified human cortical bone of varying ages, and their age-matched controls revealed that NEG disrupted microcracking based toughening mechanisms and reduced bone propagation and initiation fracture toughness across all age groups. A comprehensive mechanistic model, based on experimental and modeling data, was developed to explain how NEG and AGEs are causal to, and predictive of bone fragility. Furthermore, fracture mechanics and indentation testing on diabetic mice bones revealed that diabetes mediated NEG severely disrupts bone matrix quality in vivo. Finally, we show that AGEs are predictive of bone quality in aging humans and have diagnostic applications in fracture risk. PMID- 26530234 TI - Evaluation of preventive effect of shilajit on radiation-induced apoptosis on ovaries. AB - PURPOSE: Canc er is the second leading cause of death in children in developed countries and most of childhood malignancies can be treated with chemo radiotherapy. Although radiation therapy is a successful treatment modality in cancer patients, it has various adverse effects. Especially the gonads are very sensitive and prone to radiation-related damage. Radiation impairs the ovaries by triggering apoptosis of follicular cells and chromosomal damage and oxidative stress. Shilajit, a traditional medicinal agent in India, Russia, and other parts of the world, contains various antioxidant agents and has ovogenic effects. To evaluate the ability of shilajit to prevent radiation-induced ovarian damage. METHODS: Forty Wistar albino female rats were divided into four groups as: Control group, shilajit group, radiation only group, and radiation + shilajit group. Four days after radiation exposure, the rats were sacrificed and the ovaries were removed and evaluated immuno-histopathologically. RESULTS: There was a statistically significant difference in follicle counts (primordial, primary, preantral, antral, and atretic follicles) between the groups (p < 0.001). Almost all follicles at all stages were atretic in the radiation only group whereas normal-looking primordial follicles were detected in the radiation + shilajit group. In radiation + shilajit group, p53, Bax and caspase 3 expression was less intense than that in the radiation only group follicles. CONCLUSION: This is the first reported study evaluating the effects of shilajit on radiation-related ovarian damage prevention. Shilajit decreased the expression of p53, Bax, and caspase 3, thereby blocking the apoptotic pathways. Shilajit was found to be especially protective of primordial follicles. PMID- 26530235 TI - Association between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss: a comprehensive evaluation. AB - PURPOSE: Numerous studies have investigated the associations between methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss (RPL); however, the results remain controversial. The aim of this study is to drive a more precise estimation of association between MTHFR gene polymorphisms and risk of RPL. METHODS: We searched PubMed, EMBASE, Cochrane library, Web of Science and China Knowledge Resource Integrated Database for papers on MTHFR gene C677T and A1298C polymorphisms and RPL risk. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of association in the homozygous model, heterozygous model, dominant model, recessive model and an additive model. The software STATA (Version 13.0) was used for statistical analysis. RESULTS: Overall, 57 articles were included in the final meta-analysis. In maternal group the MTHFR C677T polymorphism showed pooled odds ratios for the homozygous comparison [OR = 2.285, 95 % CI (1.702, 3.067)] and the MTHFR A1298C polymorphism showed pooled odds ratios for recessive model [OR = 1.594, 95 % CI (1.136, 2.238)]. In fetal group the MTHFR C677T polymorphism showed pooled odds ratios for dominant model [OR = 1.037, 95 % CI (0.567, 1.894)] and the MTHFR A1298C polymorphism showed pooled odds ratios for dominant model [OR = 1.495, 95 % CI (1.102, 2.026)]. CONCLUSIONS: In summary, the results of our meta-analysis indicate that maternal and paternal MTHFR gene C677T and A1298C polymorphisms are associated with RPL. We also observed a significant association between fetal MTHFR A1298C polymorphism and RPL but not C677T. PMID- 26530236 TI - A dynamin-like protein involved in bacterial cell membrane surveillance under environmental stress. AB - In ever-changing natural environments, bacteria are continuously challenged with numerous biotic and abiotic stresses. Accordingly, they have evolved both specific and more general mechanisms to counteract stress-induced damage and ensure survival. In the soil habitat of Bacillus subtilis, peptide antibiotics and bacteriophages are among the primary stressors that affect the integrity of the cytoplasmic membrane. Dynamin-like proteins (DLPs) play a major role in eukaryotic membrane re-modelling processes, including antiviral activities, but the function of the corresponding bacterial homologues was so far poorly understood. Here, we report on the protective function of a bacterial DLP, DynA from B. subtilis. We provide evidence that DynA plays an important role in a membrane surveillance system that counteracts membrane pore formation provoked by antibiotics and phages. In unstressed cells, DynA is a highly dynamic membrane associated protein. Upon membrane damage, DynA localizes into large and static assemblies, where DynA acts locally to counteract stress-induced pores, presumably by inducing lipid bilayer fusion and sealing membrane gaps. Thus, lack of DynA increases the sensitivity to antibiotic exposure and phage infection. Taken together, our work suggests that DynA, and potentially other bacterial DLPs, contribute to the innate immunity of bacteria against membrane stress. PMID- 26530237 TI - Feasibility of an innovative electronic mobile system to assist health workers to collect accurate, complete and timely data in a malaria control programme in a remote setting in Kenya. AB - BACKGROUND: The cornerstone of decision making aimed at improving health services is accurate and timely health information. The Ministry of Public Health and Sanitation in Kenya decided to pilot feasibility of Fionet, an innovation that integrates diagnostics, data capture and cloud services, in its malaria control programme to demonstrate usability and feasibility by primary level workers in a remote setting in Kenya. METHODS: Eleven sites comprising one sub-district hospital, ten health centres and dispensaries were selected in three districts of Kisumu County to participate. Two health workers per site were selected, trained over a two-day period in the use of the Deki ReaderTM to undertake rapid diagnostic testing (RDT) for malaria and data capture of patients' records. Health managers in the three districts were trained in the use of FionetTM portal (web portal to cloud based information) to access the data uploaded by the Deki Readers. Field Support was provided by the Fio Corporation representative in Kenya. RESULTS: A total of 5812 malaria RDTs were run and uploaded to the cloud database during this implementation research study. Uploaded data were automatically aggregated into predetermined reports for use by service managers and supervisors. The Deki Reader enhanced the performance of the health workers by not only guiding them through processing of a malaria RDT test, but also by doing the automated analysis of the RDT, capturing the image, determining whether the RDT was processed according to guidelines, and capturing full patient data for each patient encounter. Supervisors were able to perform remote Quality assurance/Quality control (QA/QC) activities almost in real time. CONCLUSION: Quality, complete and timely data collection by health workers in a remote setting in Kenya is feasible. This paperless innovation brought unprecedented quality control and quality assurance in diagnosis, care and data capture, all in the hands of the health worker at point of care in an integrated way. PMID- 26530238 TI - Roles of catalase (CAT) and ascorbate peroxidase (APX) genes in stress response of eggplant (Solanum melongena L.) against Cu(+2) and Zn(+2) heavy metal stresses. AB - Eggplant (Solanum melongena L.) is a good source of minerals and vitamins and this feature makes its value comparable with tomato which is economically the most important vegetable worldwide. Due to its common usage as food and in medicines, eggplant cultivation has a growing reputation worldwide. But genetic yield potential of an eggplant variety is not always attained, and it is limited by some factors such as heavy metal contaminated soils in today's world. Today, one of the main objectives of plant stress biology and agricultural biotechnology areas is to find the genes involved in antioxidant stress response and engineering the key genes to improve the plant resistance mechanisms. In this regard, the current study was conducted to gain an idea on the roles of catalase (CAT) and ascorbate peroxidase (APX) genes in defense mechanism of eggplant (S. melongena L., Pala-49 (Turkish cultivar)) treated with different concentrations of Cu(+2) and Zn(+2). For this aim, the steady-state messenger RNA (mRNA) levels of CAT and APX genes were determined by quantitative real-time PCR (qRT-PCR) in stressed eggplants. The results of the current study showed that different concentrations of Cu(+2) and Zn(+2) stresses altered the mRNA levels of CAT and APX genes in eggplants compared to the untreated control samples. When the mRNA levels of both genes were compared, it was observed that CAT gene was more active than APX gene in eggplant samples subjected to Cu(+2) contamination. The current study highlights the importance of CAT and APX genes in response to Cu(+2) and Zn(+2) heavy metal stresses in eggplant and gives an important knowledge about this complex interaction. PMID- 26530240 TI - Exploring Self-Reported Benefits of Auricular Acupuncture Among Veterans With Posttraumatic Stress Disorder. AB - PURPOSE: Auricular acupuncture treatments are becoming increasingly available within military treatment facilities, resulting in an expansion of nonpharmacologic treatment options available to veterans with posttraumatic stress disorder (PTSD). This study aimed to explore the self-reported benefits of auricular acupuncture treatments for veterans living with PTSD. DESIGN: A qualitative research methodology, thematic content analysis, was used to analyze data. METHOD: Seventeen active duty veterans with PTSD provided written comments to describe their experiences and perceptions after receiving a standardized auricular acupuncture regimen for a 3-week period as part of a pilot feasibility study. FINDINGS: A variety of symptoms experienced by veterans with PTSD were improved after receiving auricular acupuncture treatments. Additionally, veterans with PTSD were extremely receptive to auricular acupuncture treatments. Four themes emerged from the data: (1) improved sleep quality, (2) increased relaxation, (3) decreased pain, and (4) veterans liked/loved the auricular acupuncture treatments. CONCLUSIONS: Veterans with PTSD reported numerous benefits following auricular acupuncture treatments. These treatments may facilitate healing and recovery for veterans with combat-related PTSD, although further investigations are warranted into the mechanisms of action for auricular acupuncture in this population. PMID- 26530239 TI - Proteins and peptides in parotid saliva of irradiated patients compared to that of healthy controls using SELDI-TOF-MS. AB - BACKGROUND: Radiotherapy to the head and neck area damages the salivary glands. As a consequence hyposalivation may occur, but also the protein composition of saliva may be affected possibly compromising oral health. The aim of our study was to compare the relative abundance of proteins and peptides in parotid saliva of irradiated patients to that of healthy controls. METHODS: Using Lashley cups and citric acid, saliva from the parotid glands was collected from nine irradiated patients and ten healthy controls. The samples were analyzed with SELDI-TOF-MS using a NP20 and IMAC-30 chip in the molecular weight range of 1-30 kDa. RESULTS: On the NP20 chip 61 (out of 217) and on the IMAC-30 chip 32 (out of 218) peaks differed significantly in intensity between the saliva of the irradiated patients and healthy controls. 55 % of the significant peaks showed higher intensity and 45 % showed lower intensity in the saliva of irradiated patients. The peaks may represent, amongst others, the salivary proteins lysozyme, histatins, cystatin, protein S100 and PRP's. CONCLUSIONS: Large differences were found in the relative abundance of a wide range of proteins and peptides in the parotid saliva of irradiated patients compared to healthy controls. PMID- 26530241 TI - The Use of Talking Circles to Describe a Native American Transcultural Caring Immersion Experience. AB - BACKGROUND: The Christine E. Lynn College of Nursing at the Florida Atlantic University is grounded in the Nursing as Caring theory. A transcultural caring immersion experience for nursing students is provided within the tribal community of the United Keetoowah Band of Cherokees. AIMS: The purpose of this study was to ascertain descriptions of nursing students' transcultural immersion experience. DESIGN: A qualitative descriptive approach was used via the Talking Circle method. The consensual qualitative research analytical approach was used to categorize participant responses. FINDINGS: Six themes emerged that are consistent with the Nursing as Caring theoretical key concepts: (1) persons are caring as diverse human beings, (2) persons care from a unique cultural perspective moment to moment, (3) persons are whole and complete in the moment when engaging with diverse others, (4) personhood is a process of living with meaningful purpose by diverse persons, (5) personhood evolves while caring for diverse others in nurturing relationships, and (6) connecting nursing as both a profession and a discipline occurs among unique and diverse persons. CONCLUSIONS: The findings from this study reveal the value of providing a transcultural caring immersion experience to students from a Nursing as Caring theoretical perspective. PMID- 26530242 TI - Imaging in childhood urinary tract infection. AB - INTRODUCTION: Urinary tract infection (UTI) is a common query in pediatric radiology. Imaging for and after UTI is still a heavily debated topic with different approaches, as thorough evidence to decide upon a definite algorithm is scarce. CONTENT AND OBJECTIVE: This review article tries to address the clinical rational of the various approaches (general imaging, top-down or bottom-up, selected and individualized imaging concepts...), describes the available imaging modalities and the respective findings in imaging children with UTI, and proposes an imaging algorithm for the work-up of children during and after UTI discussing the "pros and cons" of the different attitudes. CONCLUSION: In summary, imaging by US is generally considered for all infants and children with a febrile or complicated (upper) UTI, particularly without previously known urinary tract anatomy. The further work-up (searching for renal scarring and assessment of vesico-ureteric reflux) is then decided according to these initial findings as well as the clinical presentation, course, and scenario. PMID- 26530243 TI - Follow-up after the Ross procedure, how significant it is, case reports of three patients. AB - BACKGROUND: Dilatation of the pulmonary autograft is a major drawback of the Ross procedure and it is the leading cause for reoperation in these patients. CASE PRESENTATION: In this report we describe 3 cases reports, each one with a different outcome, of patients that underwent the Ross procedure. CONCLUSIONS: In order to prevent any lethal or non-lethal complications of the pulmonary autograft these patients need a close and life- long systematic follow-up. PMID- 26530245 TI - The interplay between feedback-related negativity and individual differences in altruistic punishment: An EEG study. AB - To date, the interplay betwexen neurophysiological and individual difference factors in altruistic punishment has been little understood. To examine this issue, 45 individuals participated in a Dictator Game with punishment option while the feedback-related negativity (FRN) was derived from the electroencephalogram (EEG). Unlike previous EEG studies on the Dictator Game, we introduced a third party condition to study the effect of fairness norm violations in addition to employing a first person perspective. For the first time, we also examined the role of individual differences, specifically fairness concerns, positive/negative affectivity, and altruism/empathy as well as recipients' financial situation during altruistic punishment. The main results show that FRN amplitudes were more pronounced for unfair than for fair assignments in both the first person and third party perspectives. These findings suggest that FRN amplitudes are sensitive to fairness norm violations and play a crucial role in the recipients' evaluation of dictator assignments. With respect to individual difference factors, recipients' current financial situation affected the FRN fairness effect in the first person perspective, indicating that when being directly affected by the assignments, more affluent participants experienced stronger violations of expectations in altruistic punishment decisions. Regarding individual differences in trait empathy, in the third party condition FRN amplitudes were more pronounced for those who scored lower in empathy. This may suggest empathy as another motive in third party punishment. Independent of the perspective taken, higher positive affect was associated with more punishment behavior, suggesting that positive emotions may play an important role in restoring violated fairness norms. PMID- 26530244 TI - Binding neutral information to emotional contexts: Brain dynamics of long-term recognition memory. AB - There is abundant evidence in memory research that emotional stimuli are better remembered than neutral stimuli. However, effects of an emotionally charged context on memory for associated neutral elements is also important, particularly in trauma and stress-related disorders, where strong memories are often activated by neutral cues due to their emotional associations. In the present study, we used event-related potentials (ERPs) to investigate long-term recognition memory (1-week delay) for neutral objects that had been paired with emotionally arousing or neutral scenes during encoding. Context effects were clearly evident in the ERPs: An early frontal ERP old/new difference (300-500 ms) was enhanced for objects encoded in unpleasant compared to pleasant and neutral contexts; and a late central-parietal old/new difference (400-700 ms) was observed for objects paired with both pleasant and unpleasant contexts but not for items paired with neutral backgrounds. Interestingly, objects encoded in emotional contexts (and novel objects) also prompted an enhanced frontal early (180-220 ms) positivity compared to objects paired with neutral scenes indicating early perceptual significance. The present data suggest that emotional--particularly unpleasant- backgrounds strengthen memory for items encountered within these contexts and engage automatic and explicit recognition processes. These results could help in understanding binding mechanisms involved in the activation of trauma-related memories by neutral cues. PMID- 26530246 TI - Inhibitory effects of fermented extract of Ophiopogon japonicas on thrombin induced vascular smooth muscle cells. AB - Ophiopogon japonicus is known to have various pharmacological effects. The present study investigated the effects of an extract of fermented Ophiopogon japonicas (FEOJ) on thrombin-treated vascular smooth muscle cells (VSMCs). FEOJ treatment inhibited the proliferation of VSMCs treated with thrombin as indicated by an MTT assay. These inhibitory effects were associated with decreased phosphorylation of AKT, reduced expression of cyclin D1 and increased expression of p27KIP1 in thrombin-induced VSMCs. In addition, FEOJ treatment suppressed the thrombin-stimulated migration of VSMCs as demonstrated by a wound-healing migration assay. Furthermore, zymographic analyses demonstrated that treatment of FEOJ with VSMCs suppressed the thrombin-induced expression of matrix metalloproteinase (MMP)-2, which was attributed to the reduction of nuclear factor (NF)-kappaB binding activity. Collectively, these results demonstrated that FEOJ induced p27KIP1 expression, reduced cyclin D1 expression and AKT phosphorylation, and inhibited MMP-2 expression mediated by downregulation of NF kappaB binding activity in thrombin-treated VSMCs, which led to growth inhibition and repression of migration. These results supported the use of FEOJ for the prevention of vascular diseases and provided novel insight into the underlying mechanism of action. PMID- 26530247 TI - Therapeutic Approaches in Mitochondrial Dysfunction, Proteolysis, and Structural Alterations of Diaphragm and Gastrocnemius in Rats With Chronic Heart Failure. AB - Patients with chronic heart failure (CHF) experience exercise intolerance, fatigue and muscle wasting, which negatively influence their survival. We hypothesized that treatment with either the antioxidant N-acetyl cysteine (NAC) or the proteasome inhibitor bortezomib of rats with monocrotaline-induced CHF may restore inspiratory and limb muscle mass, function, and structure through several molecular mechanisms involved in protein breakdown and metabolism in the diaphragm and gastrocnemius. In these muscles of CHF-cachectic rats with and without treatment with NAC or bortezomib (N = 10/group) and non-cachectic controls, proteolysis (tyrosine release, proteasome activities, ubiquitin proteasome markers), oxidative stress, inflammation, mitochondrial function, myosin, NF-kappaB transcriptional activity, muscle structural abnormalities, and fiber morphometry were analyzed together with muscle and cardiac functions. In diaphragm and gastrocnemius of CHF-cachectic rats, tyrosine release, proteasome activity, protein ubiquitination, atrogin-1, MURF-1, NF-kappaB activity, oxidative stress, inflammation, and structural abnormalities were increased, while muscle and cardiac functions, myosin content, slow- and fast-twitch fiber sizes, and mitochondrial activity were decreased. Concomitant treatment of CHF cachectic rats with NAC or bortezomib improved protein catabolism, oxidative stress, inflammation, muscle fiber sizes, function and damage, superoxide dismutase and myosin levels, mitochondrial function (complex I, gastrocnemius), cardiac function and decreased NF-kappaB transcriptional activity in both muscles. Treatment of CHF-cachectic animals with NAC or bortezomib attenuated the functional (heart, muscles), biological, and structural alterations in muscles. Nonetheless, future studies conducted in actual clinical settings are warranted in order to assess the potential beneficial effects and safety concerns of these pharmacological agents on muscle mass loss and wasting in CHF-cachectic patients. PMID- 26530249 TI - [Frequency of prescriptions of off-label drugs and drugs not approved for pediatric use in primary health care in a southern municipality of Brazil]. AB - OBJECTIVE: To determine the frequency of prescriptions of off-label drugs and drugs not approved for pediatric use in primary health care in medium-sized municipality of Rio Grande do Sul, Brazil. METHODS: Cross-sectional study with retrospective data collection, which analyzed prescriptions issued to 326 patients from August to December/2012 in two basic health units in the city of Viamao, state of Rio Grande do Sul. It included all prescriptions of patients whose medical records or service records were available and complete in relation to the date of presence, weight and date of birth. Off-label prescriptions were those which, in relation to the drug leaflet, showed dose different the recommended range, frequency of prescription and/or different form of administration and younger age than the indicated range. Descriptive statistics with absolute frequencies, means and standard deviations were used. RESULTS: During the study period, a total of 731 drug prescriptions were issued and the frequency of off-label medications prescribed was 31.7%, especially antihistamines and antiasthmatics (32.3% and 31.5%, respectively). The main type of off-label prescription was dose (38.8%), followed by age range (31.5%) and frequency of administration (29.3%). Regarding the dose off-label prescription, overdose was more frequent (93.3%) than the underdose (6.7%). Prescriptions of unapproved drugs were not identified. CONCLUSIONS: The study showed that off label prescription is common in both assessed units. The observed percentage of off label prescription was higher than that reported by European studies carried out in primary care. On the other hand, the prescription of drugs not approved for children was not observed. PMID- 26530250 TI - Autophagy Modulation by Lanthionine Ketimine Ethyl Ester Improves Long-Term Outcome after Central Fluid Percussion Injury in the Mouse. AB - Diffuse axonal injury is recognized as a progressive and long-term consequence of traumatic brain injury. Axonal injury can have sustained negative consequences on neuronal functions such as anterograde and retrograde transport and cellular processes such as autophagy that depend on cytoarchitecture and axon integrity. These changes can lead to somatic atrophy and an inability to repair and promote plasticity. Obstruction of the autophagic process has been noted after brain injury, and rapamycin, a drug used to stimulate autophagy, has demonstrated positive effects in brain injury models. The optimization of drugs to promote beneficial autophagy without negative side effects could be used to attenuate traumatic brain injury and promote improved outcome. Lanthionine ketimine ethyl ester, a bioavailable derivative of a natural sulfur amino acid metabolite, has demonstrated effects on autophagy both in vitro and in vivo. Thirty minutes after a moderate central fluid percussion injury and throughout the survival period, lanthionine ketimine ethyl ester was administered, and mice were subsequently evaluated for learning and memory impairments and biochemical and histological changes over a 5-week period. Lanthionine ketimine ethyl ester, which we have shown previously to modulate autophagy markers and alleviate pathology and slow cognitive decline in the 3 * TgAD mouse model, spared cognition and pathology after central fluid percussion injury through a mechanism involving autophagy modulation. PMID- 26530251 TI - The role of interleukin 35 in atherosclerosis. AB - Atherosclerosis has been widely recognized as a slow progressing inflammatory disease of the arterial walls involving both inflammation and autoimmune processes with a complex etiology in which the immune system plays a key role. A hallmark of atherosclerosis is that the macrophages pick up the lipids to form the foam cells which build up the plaque in the arterial wall. Consequently, the arteries become narrowed. Plaque rupture can trigger thrombosis which is superimposed on atherosclerotic lesion. The activation of macrophages and T cells plays key roles in these lesions. Cells involved in the atherosclerotic process secrete soluble factors, known as cytokines. These cytokines can be further divided into two classes namely proinflammatory and anti-inflammatory cytokines based on their roles in inflammation. Among the cytokines, interleukin (IL)-35 is the one most recently discovered that suppresses inflammatory responses of immune cells. Accumulating evidence suggests that IL-35 represents an attractive target for antiatherosclerotic therapy based on its several atheroprotective features. In this review, we will provide a brief overview of IL-35 biology and the role of IL-35 in the development, or the progression of atherosclerosis. PMID- 26530252 TI - Isolation of Rhp-PSP, a member of YER057c/YjgF/UK114 protein family with antiviral properties, from the photosynthetic bacterium Rhodopseudomonas palustris strain JSC-3b. AB - Rhodopseudomonas palustris strain JSC-3b isolated from a water canal adjacent to a vegetable field produces a protein that was purified by bioactivity-guided fractionation based on ammonium sulfate precipitation, ion-exchange absorption and size exclusion. The protein was further identified as an endoribonuclease L PSP (Liver-Perchloric acid-soluble protein) by shotgun mass spectrometry analysis and gene identification, and it is member of YER057c/YjgF/UK114 protein family. Herein, this protein is designated Rhp-PSP. Rhp-PSP exhibited significant inhibitory activities against tobacco mosaic virus (TMV) in vivo and in vitro. To our knowledge, this represents the first report on the antiviral activity of a protein of the YER057c/YjgF/UK114 family and also the first antiviral protein isolated from R. palustris. Our research provides insight into the potential of photosynthetic bacterial resources in biological control of plant virus diseases and sustainable agriculture. PMID- 26530253 TI - That's my teacher! Children's ability to recognize personally familiar and unfamiliar faces improves with age. AB - Most previous research on the development of face recognition has focused on recognition of highly controlled images. One of the biggest challenges of face recognition is to identify an individual across images that capture natural variability in appearance. We created a child-friendly version of Jenkins, White, Van Montford, and Burton's sorting task (Cognition, 2011, Vol. 121, pp. 313-323) to investigate children's recognition of personally familiar and unfamiliar faces. Children between 4 and 12years of age were presented with a familiar/unfamiliar teacher's house and a pile of face photographs (nine pictures each of the teacher and another identity). Each child was asked to put all the pictures of the teacher inside the house while keeping the other identity out. Children over 6years of age showed adult-like familiar face recognition. Unfamiliar face recognition improved across the entire age range, with considerable variability in children's performance. These findings suggest that children's ability to tolerate within-person variability improves with age and support a face-space framework in which faces are represented as regions, the size of which increases with age. PMID- 26530254 TI - A novel aspirin prodrug inhibits NFkappaB activity and breast cancer stem cell properties. AB - INTRODUCTION: Activation of cyclooxygenase (COX)/prostaglandin and nuclear factor kappaB (NFkappaB) pathways can promote breast tumor initiation, growth, and progression to drug resistance and metastasis. Thus, anti-inflammatory drugs have been widely explored as chemopreventive and antineoplastic agents. Aspirin (ASA), in particular, is associated with reduced breast cancer incidence but gastrointestinal toxicity has limited its usefulness. To improve potency and minimize toxicity, ASA ester prodrugs have been developed, in which the carboxylic acid of ASA is masked and ancillary pharmacophores can be incorporated. To date, the effects of ASA and ASA prodrugs have been largely attributed to COX inhibition and reduced prostaglandin production. However, ASA has also been reported to inhibit the NFkappaB pathway at very high doses. Whether ASA prodrugs can inhibit NFkappaB signaling remains relatively unexplored. METHODS: A library of ASA prodrugs was synthesized and screened for inhibition of NFkappaB activity and cancer stem-like cell (CSC) properties, an important PGE2-and NFkappaB-dependent phenotype of aggressive breast cancers. Inhibition of NFkappaB activity was determined by dual luciferase assay, RT-QPCR, p65 DNA binding activity and Western blots. Inhibition of CSC properties was determined by mammosphere growth, CD44(+)CD24(-)immunophenotype and tumorigenicity at limiting dilution. RESULTS: While we identified multiple ASA prodrugs that are capable of inhibiting the NFkappaB pathway, several were associated with cytotoxicity. Of particular interest was GTCpFE, an ASA prodrug with fumarate as the ancillary pharmacophore. This prodrug potently inhibits NFkappaB activity without innate cytotoxicity. In addition, GTCpFE exhibited selective anti-CSC activity by reducing mammosphere growth and the CD44(+)CD24( )immunophenotype. Moreover, GTCpFE pre-treated cells were less tumorigenic and, when tumors did form, latency was increased and growth rate was reduced. Structure-activity relationships for GTCpFE indicate that fumarate, within the context of an ASA prodrug, is essential for anti-NFkappaB activity, whereas both the ASA and fumarate moieties contributed to attenuated mammosphere growth. CONCLUSIONS: These results establish GTCpFE as a prototype for novel ASA-and fumarate-based anti-inflammatory drugs that: (i) are capable of targeting CSCs, and (ii) may be developed as chemopreventive or therapeutic agents in breast cancer. PMID- 26530255 TI - Exploring narratives of psychological input in the acute inpatient setting. AB - OBJECTIVES: This research explored what happens when psychological input is offered in the inpatient setting and examined service users' and staff members' understanding and portrayal of these experiences. DESIGN: Narrative analysis, an interview design, was used to examine experiences of inpatient psychological interventions in National Health Service inpatient mental health settings. METHODS: Ten participants (four service users and six staff members; five males and five females; seven White British, one White Irish, one Black African, and one Black Caribbean) were recruited via clinical psychologists from an inpatient psychology department and participated in 18- to 90-min interviews. RESULTS: Evidence suggested that direct, indirect, and strategic psychological interventions were used in the inpatient setting, with formulation and the therapeutic relationship conceptualized as common features. Connections between inpatient psychology and change, evidenced in the stories, suggested that interventions can help people make sense of a crisis, improve relationships, and contribute to meaningful recovery. Evidence of barriers suggests that psychological input in this setting might not always be compatible with everyone's needs. CONCLUSIONS: This paper explored service users' and staff members' experiences of psychological input in the inpatient setting. The analysis revealed that psychological provision in the inpatient mental health setting is varied and encompasses direct and indirect input, valued by service users and clinicians. It also identified that psychological input in the acute inpatient mental health setting is perceived as meaningful and can lead to changes at an interpersonal and intrapersonal level. There is a sense that providing psychological thinking in the inpatient setting can be challenging due to environmental constraints and individual factors. This highlights the need for further research focused on the costs and clinical effectiveness of providing psychological thinking within the acute inpatient mental health setting. PRACTITIONER POINTS: Staff members and service users made connections between psychological input and change, suggesting that interventions can improve relationships, help people make sense of a crisis, and contribute to meaningful recovery. There are significant barriers to and challenges of providing psychological input in this setting: Some participants suggested that this approach might not suit everyone. PMID- 26530256 TI - Chemical fingerprint and quantitative analysis for the quality evaluation of Vitex negundo seeds by reversed-phase high-performance liquid chromatography coupled with hierarchical clustering analysis. AB - A simple and efficient method was developed for the chemical fingerprint analysis and simultaneous determination of four phenylnaphthalene-type lignans in Vitex negundo seeds using high-performance liquid chromatography with diode array detection. For fingerprint analysis, 13 V. negundo seed samples were collected from different regions in China, and the fingerprint chromatograms were matched by the computer-aided Similarity Evaluation System for Chromatographic Fingerprint of TCM (Version 2004A). A total of 21 common peaks found in all the chromatograms were used for evaluating the similarity between these samples. Additionally, simultaneous quantification of four major bioactive ingredients was conducted to assess the quality of V. negundo seeds. Our results indicated that the contents of four lignans in V. negundo seeds varied remarkably in herbal samples collected from different regions. Moreover, the hierarchical clustering analysis grouped these 13 samples into three categories, which was consistent with the chemotypes of those chromatograms. The method developed in this study provides a substantial foundation for the establishment of reasonable quality control standards for V. negundo seeds. PMID- 26530257 TI - Catalytic asymmetric chemoselective 1,3-dipolar cycloadditions of an azomethine ylide with isatin-derived imines: diastereo- and enantioselective construction of a spiro[imidazolidine-2,3'-oxindole] framework. AB - A catalytic asymmetric chemoselective 1,3-dipolar cycloaddition (1,3-DC) of an azomethine ylide with imines has been established via a three-component reaction of isatin-derived imines, aldehydes and an amino-ester in the presence of chiral phosphoric acid, which efficiently constructed biologically important spiro[imidazolidine-2,3'-oxindole] frameworks in good yields, and with high diastereo- and enantioselectivities (up to 76% yield, 97 : 3 er, all >95 : 5 dr). This reaction not only realized a catalytic asymmetric chemoselective 1,3-DC of an azomethine ylide, but also represented the first enantioselective construction of a spiro[imidazolidine-2,3'-oxindole] skeleton. PMID- 26530258 TI - Flavobacterium paronense sp. nov., isolated from freshwater of an artificial vegetated island. AB - A Gram-stain-negative, motile by gliding, yellow-pigmented bacterial strain, designated KNUS1T, was isolated from Lake Paro in Korea. The phylogenetic tree based on 16S rRNA gene sequences showed that strain KNUS1T formed a distinct lineage within the genus Flavobacterium. Strain KNUS1T was closely related to Flavobacterium cheonhonense ARSA-15T (96.8 %16S rRNA gene sequence similarity), Flavobacterium pectinovorum DSM 6368T (96.3 %) and Flavobacterium dankookense ARSA-19T (96.1 %). The major fatty acids of strain KNUS1T were iso-C15 : 0 and iso-C15 : 1 G. The major polyamine was sym-homospermidine. The major polar lipids of strain KNUS1T were phosphatidylethanolamine, five unidentified aminolipids and three unidentified polar lipids. The major respiratory'quinone was menaquinone 6 (MK-6). The DNA G+C content of strain KNUS1T was 34.2 mol%. On the basis of the evidence presented in this study, strain KNUS1T represents a novel species of the genus Flavobacterium, for which the name Flavobacterium paronense sp. nov. is proposed. The type strain is KNUS1T ( = KACC 17692T = CECT 8460T). PMID- 26530259 TI - The role of biopsy in the management of patients with presumed diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline. AB - QUESTION: What is the optimal role of biopsy in the initial management of presumptive low-grade glioma in adults? TARGET POPULATION: Adult patients with imaging suggestive of a low-grade glioma. RECOMMENDATIONS: LEVEL III: Stereotactic biopsy is recommended when definitive surgical resection is limited by lesions that are deep-seated, not resectable, and/or located within eloquent cortex, or in patients unable to undergo craniotomy due to medical co-morbidities to obtain the critical tissue diagnosis needed for targeted treatment planning for patients with low-grade gliomas. QUESTION: What is the best technique for brain biopsy? TARGET POPULATION: Adult patients with imaging suggestive of a low grade glioma. RECOMMENDATIONS: LEVEL III: Frameless and frame-based stereotactic brain biopsy for low-grade gliomas are recommended based on clinical circumstances as they provide similar diagnostic yield, diagnostic accuracy, morbidity, and mortality. It is recommended the surgeon consider advanced imaging techniques (e.g., perfusion, spectroscopy, metabolic studies) to target specific regions of interest to potentially improve diagnostic accuracy. PMID- 26530260 TI - The role of emerging therapy in the management of patients with diffuse low grade glioma. AB - QUESTION: What is the role of immunotherapy/tumor vaccines in the treatment of low grade gliomas? TARGET POPULATION: Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma. RECOMMENDATIONS: There is no evidence to support a recommendation in regards to the efficacy of immunotherapy or tumor vaccines for the treatment of low grade gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess immunotherapies and tumor vaccines for low grade gliomas. QUESTION: What is the role of nutrition in the treatment of low grade gliomas? TARGET POPULATION: Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo astroctyoma, or oligodendroglioma. RECOMMENDATIONS: There was no evidence to support a recommendation in regard to the efficacy of nutritional therapy for the treatment of low grade gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess the efficacy of nutrition for this target population. QUESTION: Is there a role for alternative or targeted therapies in the treatment of low grade gliomas? TARGET POPULATION: Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma. RECOMMENDATION: There was no evidence to support a recommendation in regard to the efficacy of targeted or alternative agents for the treatment of low grade gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess alternative and targeted therapies for this target population. PMID- 26530261 TI - The role of initial chemotherapy for the treatment of adults with diffuse low grade glioma : A systematic review and evidence-based clinical practice guideline. AB - TARGET POPULATION: Adult patients (older than 18 years of age) with newly diagnosed World Health Organization (WHO) Grade II gliomas (Oligodendroglioma, astrocytoma, mixed oligoastrocytoma). QUESTION: Is there a role for chemotherapy as adjuvant therapy of choice in treatment of patients with newly diagnosed low grade gliomas? RECOMMENDATIONS: LEVEL III: Chemotherapy is recommended as a treatment option to postpone the use of radiotherapy, to slow tumor growth and to improve progression free survival (PFS), overall survival (OS) and clinical symptoms in adult patients with newly diagnosed LGG. QUESTION: Who are the patients with newly diagnosed LGG that would benefit the most from chemotherapy? RECOMMENDATION: LEVEL III: Chemotherapy is recommended as an optional component alone or in combination with radiation as the initial adjuvant therapy for all patients who cannot undergo gross total resection (GTR) of a newly diagnosed LGG. Patient with residual tumor >1 cm on post-operative MRI, presenting diameter of >4 cm or older than 40 years of age should be considered for adjuvant therapy as well. QUESTION: Are there tumor markers that can predict which patients can benefit the most from initial treatment with chemotherapy? RECOMMENDATION: LEVEL III: The addition of chemotherapy to standard RT is recommended in LGG patients that carry IDH mutation. In addition, temozolomide (TMZ) is recommended as a treatment option to slow tumor growth in patients who harbor the 1p/19q co deletion. QUESTION: How soon should the chemotherapy be started once the diagnosis of LGG is confirmed? RECOMMENDATION: There is insufficient evidence to make a definitive recommendation on the timing of starting chemotherapy after surgical/pathological diagnosis of LGG has been made. However, using the 12 weeks mark as the latest timeframe to start adjuvant chemotherapy is suggested. It is recommended that patients be enrolled in properly designed clinical trials to assess the timing of chemotherapy initiation once diagnosis is confirmed for this target population. QUESTION: What chemotherapeutic agents should be used for treatment of newly diagnosed LGG? RECOMMENDATION: There is insufficient evidence to make a recommendation of one particular regimen. Enrollment of subjects in properly designed trials comparing the efficacy of these or other agents is recommended so as to determine which of these regimens is superior. QUESTION: What is the optimal duration and dosing of chemotherapy as initial treatment for LGG? RECOMMENDATION: Insufficient evidence exists regarding the duration of any specific cytotoxic drug regimen for treatment of newly diagnosed LGG. Enrollment of subjects in properly designed clinical investigations assessing the optimal duration of this therapy is recommended. QUESTION: Should chemotherapy be given alone or in conjunction with RT as initial therapy for LGG? RECOMMENDATION: Insufficient evidence exists to make recommendations in this regard. Hence, enrollment of patients in properly designed clinical trials assessing the difference between chemotherapy alone, RT alone or a combination of them is recommended. QUESTION: Should chemotherapy be given in addition to other type of adjuvant therapy to patients with newly diagnosed LGG? RECOMMENDATION: Level II: It is recommended that chemotherapy be added to the RT in patients with unfavorable LGG to improve their progression free survival. PMID- 26530262 TI - The role of imaging in the management of adults with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline. AB - QUESTION: What is the optimal imaging technique to be used in the diagnosis of a suspected low grade glioma, specifically: which anatomic imaging sequences are critical for most accurately identifying or diagnosing a low grade glioma (LGG) and do non-anatomic imaging methods and/or sequences add to the diagnostic specificity of suspected low grade gliomas? TARGET POPULATION: These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven LGG. RECOMMENDATION: LEVEL II: In patients with a suspected brain tumor, the minimum magnetic resonance imaging (MRI) exam should be an anatomic exam with both T2 weighted and pre- and post-gadolinium contrast enhanced T1 weighted imaging. CRITICAL IMAGING FOR THE IDENTIFICATION AND DIAGNOSIS OF LOW GRADE GLIOMA: LEVEL II: In patients with a suspected brain tumor, anatomic imaging sequences should include T1 and T2 weighted and Fluid Attenuation Inversion Recovery (FLAIR) MR sequences and will include T1 weighted imaging after the administration of gadolinium based contrast. Computed tomography (CT) can provide additional information regarding calcification or hemorrhage, which may narrow the differential diagnosis. At a minimum, these anatomic sequences can help identify a lesion as well as its location, and potential for surgical intervention. IMPROVEMENT OF DIAGNOSTIC SPECIFICITY WITH THE ADDITION OF NON-ANATOMIC (PHYSIOLOGIC AND ADVANCED IMAGING) TO ANATOMIC IMAGING: LEVEL II: Class II evidence from multiple studies and a significant number of Class III series support the addition of diffusion and perfusion weighted MR imaging in the assessment of suspected LGGs, for the purposes of discriminating the potential for tumor subtypes and identification of suspicion of higher grade diagnoses. LEVEL III: Multiple series offer Class III evidence to support the potential for magnetic resonance spectroscopy (MRS) and nuclear medicine methods including positron emission tomography and single-photon emission computed tomography imaging to offer additional diagnostic specificity although these are less well defined and their roles in clinical practice are still being defined. QUESTION: Which imaging sequences or parameters best predict the biological behavior or prognosis for patients with LGG? TARGET POPULATION: These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven LGG. RECOMMENDATION: Anatomic and advanced imaging methods and prognostic stratification LEVEL III: Multiple series suggest a role for anatomic and advanced sequences to suggest prognostic stratification among low grade gliomas. Perfusion weighted imaging, particularly when obtained as a part of diagnostic evaluation (as recommended above) can play a role in consideration of prognosis. Other imaging sequences remain investigational in terms of their role in consideration of tumor prognosis as there is insufficient evidence to support more formal recommendations as to their use at this time. QUESTION: What is the optimal imaging technique to be used in the follow-up of a suspected (or biopsy proven) LGG? TARGET POPULATION: This recommendation applies to adults with a newly diagnosed low grade glioma. RECOMMENDATIONS: LEVEL II: In patients with a diagnosis of LGG, anatomic imaging sequences should include T2/FLAIR MR sequences and T1 weighted imaging before and after the administration of gadolinium based contrast. Serial imaging should be performed to identify new areas of contrast enhancement or significant change in tumor size, which may signify transformation to a higher grade. LEVEL III: Advanced imaging utility may depend on tumor subtype. Multicenter clinical trials with larger cohorts are needed. For astrocytic tumors, baseline and longitudinal elevations in tumor perfusion as assessed by dynamic susceptibility contrast perfusion MRI are associated with shorter time to tumor progression, but can be difficult to standardize in clinical practice. For oligodendrogliomas and mixed gliomas, MRS may be helpful for identification of progression. PMID- 26530263 TI - The role of neuropathology in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline. AB - TARGET POPULATION: Adult patients (age >=18 years) who have suspected low-grade diffuse glioma. QUESTION: What are the optimal neuropathological techniques to diagnose low-grade diffuse glioma in the adult? RECOMMENDATION: LEVEL I: Histopathological analysis of a representative surgical sample of the lesion should be used to provide the diagnosis of low-grade diffuse glioma. LEVEL III: Both frozen section and cytopathologic/smear evaluation should be used to aid the intra-operative assessment of low-grade diffuse glioma diagnosis. A resection specimen is preferred over a biopsy specimen, to minimize the potential for sampling error issues. TARGET POPULATION: Patients with histologically-proven WHO grade II diffuse glioma. QUESTION: In adult patients (age >=18 years) with histologically-proven WHO grade II diffuse glioma, is testing for IDH1 mutation (R132H and/or others) warranted? If so, is there a preferred method? RECOMMENDATION: LEVEL II: IDH gene mutation assessment, via IDH1 R132H antibody and/or IDH1/2 mutation hotspot sequencing, is highly-specific for low-grade diffuse glioma, and is recommended as an additional test for classification and prognosis. TARGET POPULATION: Patients with histologically-proven WHO grade II diffuse glioma. QUESTION: In adult patients (age >=18 years) with histologically proven WHO grade II diffuse glioma, is testing for 1p/19q loss warranted? If so, is there a preferred method? RECOMMENDATION: LEVEL III: 1p/19q loss-of heterozygosity testing, by FISH, array-CGH or PCR, is recommended as an additional test in oligodendroglial cases for prognosis and potential treatment planning. TARGET POPULATION: Patients with histologically-proven WHO grade II diffuse glioma. QUESTION: In adult patients (age >=18 years) with histologically proven WHO grade II diffuse glioma, is MGMT promoter methylation testing warranted? If so, is there a preferred method? RECOMMENDATION: There is insufficient evidence to recommend methyl-guanine methyl-transferase (MGMT) promoter methylation testing as a routine for low-grade diffuse gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess the value of this and related markers for this target population. TARGET POPULATION: Patients with histologically-proven WHO grade II diffuse glioma. QUESTION: In adult patients (age >=18 years) with histologically-proven WHO grade II diffuse glioma, is Ki-67/MIB1 immunohistochemistry warranted? If so, is there a preferred method to quantitate results? RECOMMENDATION: LEVEL III: Ki67/MIB1 immunohistochemistry is recommended as an option for prognostic assessment. PMID- 26530264 TI - Management of patients with recurrence of diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline. AB - TARGET POPULATION: These recommendations apply to adult patients with recurrent low-grade glioma (LGG) with initial pathologic diagnosis of a WHO grade II infiltrative glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). PATHOLOGY AT RECURRENCE: QUESTION: Do pathologic and molecular characteristics predict outcome/malignant transformation at recurrence? RECOMMENDATIONS: IDH STATUS AND RECURRENCE: (Level III) IDH mutation status should be determined as LGGs with IDH mutations have a shortened time to recurrence. It is unclear whether knowledge of IDH mutation status provides benefit in predicting time to progression or overall survival. TP53 STATUS AND RECURRENCE: (Level III) TP53 mutations occur early in LGG pathogenesis, remain stable, and are not recommended as a marker of predisposition to malignant transformation at recurrence or other measures of prognosis. MGMT STATUS AND RECURRENCE: (Level III) Assessment of MGMT status is recommended as an adjunct to assessing prognosis as LGGs with MGMT promoter methylation are associated with shorter PFS (in the absence of TMZ) and longer post-recurrence survival (in the presence of TMZ), ultimately producing similar overall survival to LGGs without MGMT methylation. The available retrospective reports are conflicting and comparisons between reports are limited CDK2NA STATUS AND RECURRENCE: (Level III) Assessment of CDK2NA status is recommended when possible as the loss of expression of the CDK2NA via either methylation or loss of chromosome 9p is associated with malignant progression of LGGs. PROLIFERATIVE INDEX AND RECURRENCE: (Level III) It is recommended that proliferative indices (MIB-1 or BUdR) be measured in LGGs as higher proliferation indices are associated with increased likelihood of recurrence and shorter progression free and overall survival. 1P/19Q STATUS AND RECURRENCE: There is insufficient evidence to make any recommendations. CHEMOTHERAPY AT RECURRENCE: QUESTION: What role does chemotherapy have in LGG recurrence? RECOMMENDATIONS: TEMOZOLOMIDE AND RECURRENCE: (Level III) Temozolomide is recommended in the therapy of recurrent LGG as it may improve clinical symptoms. Oligodendrogliomas and tumors with 1p/19q co-deletion may derive the most benefit. PCV AND RECURRENCE: (Level III) PCV is recommended in the therapy of LGG at recurrence as it may improve clinical symptoms with the strongest evidence being for oligodendrogliomas. CARBOPLATIN AND RECURRENCE : (Level III) Carboplatin is not recommended as there is no significant benefit from carboplatin as single agent therapy for recurrent LGGs. OTHER TREATMENTS (NITROSUREAS, HYDROXYUREA/IMANITIB, IRINOTECAN, PACLITAXEL) AND RECURRENCE: There is insufficient evidence to make any recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess these chemotherapeutic agents. RADIATION AT RECURRENCE: QUESTION: What role does radiation have in LGG recurrence? RECOMMENDATIONS: RADIATION AT RECURRENCE WITH NO PREVIOUS IRRADIATION: (Level III) Radiation is recommended at recurrence if there was no previous radiation treatment. RE-IRRADIATION AT RECURRENCE: (Level III) It is recommended that re-irradiation be considered in the setting of LGG recurrence as it may provide benefit in disease control. SURGERY AT RECURRENCE: There is insufficient evidence to make any specific recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess the role of surgery at recurrence. PMID- 26530266 TI - The role of radiotherapy in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline. AB - QUESTIONS: (1) What is the optimal role of external beam radiotherapy in the management of adult patients with newly diagnosed low-grade glioma (LGG) in terms of improving outcome (i.e., survival, complications, seizure control or other reported outcomes of interest)? (2) Which radiation strategies (dose, timing, fractionation, stereotactic radiation, brachytherapy, chemotherapy) improve outcomes compared to standard external beam radiation therapy in the initial management of low grade gliomas in adults? (3) Do specific factors (e.g., age, volume, extent of resection, genetic subtype) identify subgroups with better outcomes following radiation therapy than the general population of adults with newly diagnosed low-grade gliomas? TARGET POPULATION: These recommendations apply to adults with newly diagnosed diffuse LGG. RECOMMENDATIONS: OUTCOMES IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA TREATED WITH RADIOTHERAPY: Level I Radiotherapy is recommended in the management of newly diagnosed low-grade glioma in adults to prolong progression free survival, irrespective of extent of resection. Level II Radiotherapy is recommended in the management of newly diagnosed low grade glioma in adults as an equivalent alternative to observation in preserving cognitive function, irrespective of extent of resection. Level III Radiotherapy is recommended in the management of newly diagnosed low grade glioma in adults to improve seizure control in patients with epilepsy and subtotal resection. Level III Radiotherapy is recommended in the management of newly diagnosed low-grade glioma in adults to prolong overall survival in patients with subtotal resection. Level III Consideration of the risk of radiation induced morbidity, including cognitive decline, imaging abnormalities, metabolic dysfunction and malignant transformation, is recommended when the delivery of radiotherapy is selected in the management of newly diagnosed low-grade glioma in adults. STRATEGIES OF RADIOTHERAPY IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA: Level I Lower dose radiotherapy is recommended as an equivalent alternative to higher dose immediate postoperative radiotherapy (45-50.4 vs. 59.4 64.8 Gy) in the management of newly diagnosed low-grade glioma in adults with reduced toxicity. Level III Delaying radiotherapy until recurrence or progression is recommended as an equivalent alternative to immediate postoperative radiotherapy in the management of newly diagnosed low-grade glioma in adults but may result in shorter time to progression. Level III The addition of chemotherapy to radiotherapy is not recommended over whole brain radiotherapy alone in the management of low-grade glioma, as it provides no additional survival benefit. Level III Limited-field radiotherapy is recommended over whole brain radiotherapy in the management of low-grade glioma. Level III Either stereotactic radiosurgery or brachytherapy are recommended as acceptable alternatives to external radiotherapy in selected patients. PROGNOSTIC FACTORS IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA TREATED WITH RADIOTHERAPY: Level II It is recommended that age greater than 40 years, astrocytic pathology, diameter greater than 6 cm, tumor crossing the midline and preoperative neurological deficit be considered as negative prognostic indicators when predicting overall survival in adult low grade glioma patients treated with radiotherapy. Level II It is recommended that smaller tumor size, extent of surgical resection and higher mini-mental status exam be considered as positive prognostic indicators when predicting overall survival and progression free survival in patients in adult low grade glioma patients treated with radiotherapy. Level III It is recommended that seizures at presentation, presence of oligodendroglial histological component and 1p19q deletion (along with additional relevant factors see Table 1) be considered as positive prognostic indicators when predicting response to radiotherapy in adults with low grade gliomas. Level III It is recommended that increasing age, decreasing performance status, decreasing cognition, presence of astrocytic histological component (along with additional relevant factors (see Tables 1, 2) be considered as negative prognostic indicators when predicting response to radiotherapy. PMID- 26530265 TI - The role of surgery in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline. AB - QUESTION: Should patients with imaging suggestive of low grade glioma (LGG) undergo observation versus treatment involving a surgical procedure? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: Surgical resection is recommended over observation to improve overall survival for patients with diffuse low-grade glioma (Level III) although observation has no negative impact on cognitive performance and quality of life (Level II). QUESTION: What is the impact of extent of resection on progression free survival (PFS) or overall survival (OS) in LGG patients? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: IMPACT OF EXTENT OF RESECTION ON PFS: LEVEL II: It is recommended that GTR or STR be accomplished instead of biopsy alone when safe and feasible so as to decrease the frequency of tumor progression recognizing that the rate of progression after GTR is fairly high. IMPACT OF EXTENT OF RESECTION ON OS: LEVEL III: Greater extent of resection can improve OS in LGG patients. QUESTION: What tools are available to increase extent of resection in LGG patients? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: INTRAOPERATIVE MRI DURING SURGERY: LEVEL III: The use of intraoperative MRI should be considered as a method of increasing the extent of resection of LGGs. QUESTION: What is the impact of surgical resection on seizure control and accuracy of pathology in low grade glioma patients? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: SURGICAL RESECTION AND SEIZURE CONTROL: LEVEL III: After taking into account the patient's clinical status and tumor location, gross total resection is recommended for patients with diffuse LGG as a way to achieve more favorable seizure control. ACCURACY OF DIAGNOSIS: LEVEL III: Taking into account the patient's clinical status and tumor location, surgical resection should be carried out to maximize the chance of accurate diagnosis. QUESTION: What tools can improve the safety of surgery for LGGs in eloquent locations? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: PREOPERATIVE IMAGING: LEVEL III: It is recommended that preoperative functional MRI and diffusion tensor imaging be utilized in the appropriate clinical setting to improve functional outcome after surgery for LGG. INTRAOPERATIVE MAPPING OF TUMORS IN ELOQUENT AREAS: LEVEL III: Intraoperative mapping is recommended for patients with diffuse LGGs in eloquent locations compared to patients with non eloquently located diffuse LGGs as a way of preserving function. PMID- 26530267 TI - Temozolomide reverses doxorubicin resistance by inhibiting P-glycoprotein in malignant glioma cells. AB - Temozolomide is a standard chemotherapy agent for malignant gliomas, but the efficacy is still not satisfactory. Therefore, combination chemotherapy using temozolomide with other anti-tumor compounds is now under investigation. Here we studied the mechanism of the synergistic anti-tumor effect achieved by temozolomide and doxorubicin, and elucidated the inhibitory effect of temozolomide on P-glycoprotein (P-gp). Temozolomide significantly enhanced sensitivity to P-gp substrate in glioma cells, particularly in P-gp-overexpressed cells. Synergetic effects, as determined by isobologram analysis, were observed by combining temozolomide and doxorubicin. Subsequently, flow cytometry was utilized to assess the intracellular retention of doxorubicin in cells treated with doxorubicin with or without temozolomide. Temozolomide significantly increased the accumulation of doxorubicin in these cells. The P-gp adenosine triphosphatase (ATPase) assay showed that temozolomide inhibited the ATPase activity of P-gp. In addition, temozolomide combined with doxorubicin significantly prolonged the survival of 9L intracranial allografted glioma bearing rats compared to single agent treatment. Collectively, our findings suggest that temozolomide can reverse doxorubicin resistance by directly affecting P-gp transport activity. Combination chemotherapy using temozolomide with other agents may be effective against gliomas in clinical applications. PMID- 26530268 TI - Effects of Baseline Blood Pressure and Low-Density Lipoprotein Cholesterol on Safety and Efficacy of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus. AB - INTRODUCTION: Sodium glucose co-transporter 2 inhibitors decrease hemoglobin A1c (HbA1c) and blood pressure (BP) and slightly increase low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes mellitus (T2DM). The effects of baseline BP and LDL-C on the safety and efficacy of canagliflozin in patients were analyzed post hoc in a phase III study. METHODS: Japanese patients with T2DM were classified by baseline systolic BP (SBP) of <130 or >=130 mmHg, diastolic BP (DBP) of <80 or >=80 mmHg, and LDL-C of <120 or >=120 mg/dL. Canagliflozin was administered daily to patients for 52 weeks at doses of either 100 mg (n = 584) or 200 mg (n = 715). The effects of canagliflozin on the incidence of adverse events (AEs), BP, and LDL-C were evaluated. RESULTS: No clear differences were observed in overall safety among the subgroups classified by baseline SBP, DBP, or LDL-C, except for a slight imbalance in AEs associated with volume depletion with 200 mg of canagliflozin. The decrease in mean SBP and DBP was evident in subgroups with baseline SBP >=130 mmHg and DBP >=80 mmHg. Mean LDL-C was decreased in subgroups with baseline LDL-C >=120 mg/dL at both canagliflozin doses, and they were slightly increased, but did not exceed 120 mg/dL in subgroups with baseline LDL-C <120 mg/dL. The changes in HbA1c and body weight from those observed at baseline were not different between subgroups classified by SBP, DBP, and LDL-C at either dose. CONCLUSION: The present post hoc analysis indicates that canagliflozin is well tolerated irrespective of baseline BP and LDL-C in patients with T2DM. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01387737. FUNDING: Mitsubishi Tanabe Pharma Corporation. PMID- 26530269 TI - Very long-term outcomes of the Carpentier-Edwards Perimount aortic valve in patients aged 50-65 years. AB - OBJECTIVES: Aortic valve replacement (AVR) using a bioprosthesis remains controversial for patients aged 50-65 years. This cohort study reports the very long-term outcomes of AVR using Carpentier-Edwards Perimount pericardial bioprosthesis in this age group. METHODS: From 1984 to 2008, 522 Carpentier Edwards Perimount pericardial aortic bioprostheses were implanted in 516 patients aged 50-65 years (mean age, 60 +/- 4 years; 19% female). Multiple valve replacements were excluded fro m our cohort. Baseline demographic, perioperative and follow-up data were recorded prospectively. Mean follow-up was 9 +/- 6 years, for a total of 4428 valve-years. Follow-up was complete for 97% of patients included. RESULTS: Operative mortality rate was 2%. One hundred and forty-six late deaths occurred for a linearized rate of 3%/valve-year. Actuarial survival rates averaged 73 +/- 2, 59 +/- 3 and 35 +/- 5% after 10, 15 and 20 years of follow-up, respectively. Mortality rate associated with reoperation was 2%. Actuarial freedom from reoperation rates due to structural valve deterioration (SVD) at 10, 15 and 20 years was respectively of 91 +/- 2, 76 +/- 3 and 50 +/- 6%. Competing risk analysis demonstrated an actual risk of explantation secondary to SVD at 20 years of 30 +/- 3%. Expected valve durability was 19 years for this age group. Age was not a significant risk factor for SVD in this middle-aged population. CONCLUSIONS: In patients aged 50-65 years undergoing AVR with the Carpentier-Edwards Perimount bioprosthesis, the expected valve durability was 19 years. Age was not a significant risk factor for SVD within this age group. Patient selection and attention to timing of reintervention may be determinants of long-term outcomes. PMID- 26530270 TI - Lung transplantation for cystic fibrosis: differential characteristics and outcomes between children and adults. AB - OBJECTIVES: The survival benefit of lung transplantation (LTx) for cystic fibrosis (CF) patients is well demonstrated. We aim to compare children and adult CF recipients to assess whether there are differences in survival and clinical outcomes, and to identify risk factors for mortality. METHODS: A retrospective analysis of 442 consecutive LTx performed at our institution in a 20-year period was conducted. CF patients were distributed into two groups: children (age <18 years) and adults (age >=18 years). Donor and recipient general demographic data, perioperative and postoperative factors including 30-day mortality, survival, primary graft dysfunction (PGD), complications, acute rejection (AR) and chronic lung allograft dysfunction (CLAD) were analysed and compared between groups. Univariable, Kaplan-Meier and Cox regression analyses were performed. RESULTS: The study group included 120 consecutive CF patients: 50 children (13 +/- 3 years) and 70 adults (25 +/- 6 years) undergoing 111 bilateral, 4 lobar, 4 combined and 1 unilateral LTx. Comparative analysis (children versus adults): survival (overall; 5, 10 and 15 years) 57, 45, 35% vs 67, 55, 43% (P = 0.32); survival (1-year survivors; 5, 10 and 15 years): 75, 64, 46% vs 90, 75, 59% (P = 0.09); 30-day mortality: 14 vs 16% (P = 0.27); urgent LTx: 32 vs 17% (P = 0.04); use of cardiopulmonary bypass (CPB): 56 vs 28% (P = 0.002); intensive care unit stay: 20 +/- 19 vs 10 +/- 9 days (P = 0.006); AR episodes (n): 1.4 +/- 0.7 vs 1.2 +/- 0.8 (P = 0.004). Incidence of PGD and freedom from CLAD did not differ between groups. Predictors of mortality were: use of CPB (HR 3.12; 95% CI 1.33 7.35; P < 0.01), post-transplant diabetes mellitus (HR 2.49; 95% CI 1.13-5.43; P = 0.02) and pneumonia episodes within the first month post-transplant (HR 2.82; 95% CI 1.27-6.29; P = 0.01). CONCLUSION: Paediatric CF patients usually present with poorer pre-transplant status, require CPB more frequently and have a higher incidence of post-LTx diabetes and infections. This might explain the trend towards a better long-term survival observed in adult CF patients. PMID- 26530271 TI - Translating Research to Practice for Children With Autism Spectrum Disorder: Part I: Definition, Associated Behaviors, Prevalence, Diagnostic Process, and Interventions. AB - INTRODUCTION: The number of children with autism spectrum disorder (ASD) is rising, along with the potential for challenging behaviors during health care encounters. METHOD: We present an overview of the emerging science related to ASD diagnosis and interventions for children with ASD. RESULTS: Emerging science on ASD reveals common associated challenging behaviors, increasing prevalence, emphasis on early diagnosis at 18 to 24 months of age, changes in the diagnostic process with criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, and interventions with medication, education, and behavior management. DISCUSSION: Family and health care provider preparation strategies facilitate care of children with ASD and their families. Early diagnosis at 18 to 24 months of age and evidence-based interventions contribute to best outcomes for children and families. Health care providers must be aware of the state of the science for diagnosis and best practices to provide family centered care for this growing population. PMID- 26530272 TI - Implementing an anti-smoking program in rural-remote communities: challenges and strategies. AB - INTRODUCTION: Rural-remote communities report higher smoking rates and poorer health outcomes than that of metropolitan areas. While anti-smoking programs are an important measure for addressing smoking and improving health, little is known of the challenges faced by primary healthcare staff implementing those programs in the rural-remote setting. The aim of this study was to explore the challenges and strategies of implementing an anti-smoking program by primary healthcare staff in rural-remote Australia. METHODS: Guided by a phenomenological approach, semi-structured interviews and focus groups were conducted with health service managers, case managers and general practitioners involved in program implementation in Australian rural-remote communities between 2008 and 2010. RESULTS: Program implementation was reported to be challenged by limited primary and mental healthcare resources and client access to services; limited collaboration between health services; the difficulty of accessing staff training; high levels of community distress and disadvantage; the normalisation of smoking and its deleterious impact on smoking abstinence among program clients; and low morale among health staff. Strategies identified to overcome challenges included appointing tobacco-dedicated staff; improving health service collaboration, access and flexibility; providing subsidised pharmacotherapies and boosting staff morale. CONCLUSIONS: Findings may assist health services to better tailor anti-smoking programs for the rural-remote setting, where smoking rates are particularly high. Catering for the unique challenges of the rural-remote setting is necessary if anti-smoking programs are to be efficacious, cost effective and capable of improving rural-remote health outcomes. PMID- 26530273 TI - Self-regulated oscillation of transport and topology of magnetic islands in toroidal plasmas. AB - The coupling between the transport and magnetic topology is an important issue because the structure of magnetic islands, embedded in a toroidal equilibrium field, depends on the nature of the transport at the edge of the islands. Measurements of modulated heat pulse propagation in the DIII-D tokamak have revealed the existence of self-regulated oscillations in the radial energy transport into magnetic islands that are indicative of bifurcations in the island structure and transport near the q = 2 surface. Large amplitude heat pulses are seen in one state followed by small amplitude pulses later in the discharge resulting in a repeating cycle of island states. These two states are interpreted as a bifurcation of magnetic island with high and low heat pulse accessibility. This report describes the discovery of a bifurcation in the coupled dynamics between the transport and topology of magnetic islands in tokamak plasmas. PMID- 26530274 TI - Significance of DEK overexpression for the prognostic evaluation of non-small cell lung carcinoma. AB - In the present study, we explored the role of DEK expression for the prognostic evaluation of non-small cell lung carcinoma (NSCLC). DEK protein and mRNA expression levels were detected in NSCLC cells and fresh tissue samples of NSCLC paired with adjacent non-tumor tissues, respectively. NSCLC cases (n=196) meeting strict follow-up criteria were selected for immunohistochemical staining of DEK protein. Correlations between DEK expression and clinicopathological features of the NSCLC cases were evaluated using Chi-square tests. Survival rates were calculated using the Kaplan-Meier method, and the relationship between prognostic factors and patient overall survival was analyzed using Cox proportional hazard analysis. Based on the results, the levels of DEK protein and mRNA were significantly upregulated in 6 fresh tissue samples of NSCLC. Immunohistochemical analysis showed that the DEK expression rate was significantly higher in the NSCLC samples compared with either the adjacent non-tumor tissues or normal lung tissues. DEK expression was correlated with poor differentiation and late pathological stage of NSCLC. DEK expression was also correlated with low disease free survival and overall survival rates. In the early-stage group, disease-free and overall survival rates of patients with DEK expression were significantly lower than those of patients without DEK expression. Further analysis using a Cox proportional hazard regression model revealed that DEK expression emerged as a significant independent hazard factor for the overall survival rate of patients with NSCLC. Consequently, DEK plays an important role in the progression of NSCLC. DEK may potentially be used as an independent biomarker for the prognostic evaluation of NSCLC. PMID- 26530275 TI - Sirtuin inhibitors, EX527 and AGK2, suppress cell migration by inhibiting HSF1 protein stability. AB - The histone deacetylases (HDACs), Sirtuin 1 (Sirt1) and Sirt2, play crucial roles in many biological processes, including cell proliferation, differentiation and apoptosis. HDAC inhibitors have been considered as a potential therapeutic approach for various types of cancers. Here, we demonstrated that the Sirt1 and Sirt2 inhibitors EX527 and AGK2 suppressed cell growth and caused G1 phase arrest by inhibiting the expression of Cdk6 and/or Cdk4. An agar colony formation assay revealed that EX527 and AGK2 decreased colony formation in soft agar. Furthermore, EX527 and AGK2 pretreatment inhibited the expression of HSF1 and HSP27 and induced HSF1 ubiquitination. Sirt1 overexpression increased HSF1 expression and/or stabilization and induced cell migration in a scratch assay. Overall, these results indicate that EX527 and AGK2 suppress cell growth and migration by inhibiting HSF1 protein stability. PMID- 26530277 TI - Phosphidoboratabenzene-rhodium(i) complexes as precatalysts for the hydrogenation of alkenes at room temperature and atmospheric pressure. AB - The di-tert-butylphosphido-boratabenzene ligand (DTBB) reacts with [(C2H4)2RhCl]2 yielding the dimeric species [(C2H4)Rh(DTBB)]2 (1). This species was fully characterized by multinuclear NMR and X-ray crystallography. Complex 1 readily dissociates ethylene in solution and upon exposure to 1 atm of H2 is capable of carrying out the hydrogenation of ethylene. The characterization of two Rh-H species by multinuclear NMR spectroscopy is provided. The reactivity of 1 towards the catalytic hydrogenation of alkenes and alkynes at room temperature and 1 atm of H2 is reported and compared to the activity of Wilkinson's catalyst under the same reaction conditions. PMID- 26530276 TI - Capillary zone electrophoresis tandem mass spectrometry detects low concentration host cell impurities in monoclonal antibodies. AB - We have evaluated CZE-ESI-MS/MS for detection of trace amounts of host cell protein impurities in recombinant therapeutics. Compared to previously published procedures, we have optimized the buffer pH used in the formation of a pH junction to increase injection volume. We also prepared a 5-point calibration curve by spiking 12 standard proteins into a solution of a human mAb. A custom CZE-MS/MS system was used to analyze the tryptic digest of this mixture without depletion of the antibody. CZE generated a ~70-min separation window (~90-min total analysis duration) and ~300-peak capacity. We also analyzed the sample using ultra-performance LC-MS/MS. CZE-MS/MS generated approximately five times higher base peak intensity and more peptide identifications for low-level spiked proteins. Both methods detected all proteins spiked at ~100 ppm level with respect to the antibody. PMID- 26530278 TI - Enabling occupational participation and social inclusion for people recovering from mental ill-health through community gardening. AB - INTRODUCTION: There is a need for mental health practitioners to understand how inclusive environments that enable participation can be developed. This paper presents the findings from an ethnographic exploration of Mind 'Sprout', a supported community garden situated in inner-city Melbourne. The study explored how this community development project created a socially inclusive environment, and enabled occupational participation among people recovering from mental ill health. METHODS: Consistent with the ethos of ethnography, data were collected through participant observation and asking questions of people as they participated at 'Sprout'. Six individual interviews and review of organisational documents were also conducted. Qualitative analysis was used to identify the understandings of how the Sprout community was created and experienced by its members. RESULTS: Three interrelated themes were revealed: Sprout community garden enabled social inclusion and occupational participation by creating community, creating a flexible environment that supports participation and creating a learning environment. The way Sprout operated enabled its members to participate together in occupation and to interact socially within the garden community and beyond as part of the local community. CONCLUSION: Sprout has developed a philosophy of active participation. The findings point to the opportunities that community development projects offer for creating environments that enable participation and social inclusion. They also suggest that an opportunity exists for occupational therapists to broaden their practise by leading or collaborating in these projects. PMID- 26530279 TI - Characteristics and external validity of the German Health Risk Institute (HRI) Database. AB - PURPOSE: The aim of this study was to describe characteristics and external validity of the German Health Risk Institute (HRI) Database. METHODS: The HRI Database is an anonymized healthcare database with longitudinal data from approximately six Mio Germans. In addition to demographic information (gender, age, region of residence), data on persistence of insurants over time, hospitalization rates, mortality rates and drug prescription rates were extracted from the HRI database for 2013. Corresponding national reference data were obtained from official sources. RESULTS: The proportion of men and women was similar in the HRI Database and Germany, but the database population was slightly younger (mean 40.4 vs 43.7 years). The proportion of insurants living in the eastern part of Germany was lower in the HRI Database (10.1% vs 19.7%). There was good accordance to German reference data with respect to hospitalization rates, overall mortality rate and prescription rates for the 20 most often reimbursed drug classes, with the overall burden of morbidity being slightly lower in the HRI database. From insurants insured on 1 January 2009 (N = 6.2 Mio), a total of 70.6% survived and remained continuously insured with the same statutory health insurance until 31 December 2013. This proportion increased to 77.5% if only insurants >=40 years were considered. CONCLUSIONS: There was good overall accordance of the HRI database and the German population in terms of measures of morbidity, mortality and drug usage. Persistence of insurants with the database over time was high, indicating suitability of the data source for longitudinal epidemiological analyses. PMID- 26530281 TI - Article on what went wrong at Addenbrooke's was ill informed and misleading. PMID- 26530280 TI - Patterns of Multi-Antibiotic-Resistant Escherichia Coli from Streams with No History of Antimicrobial Inputs. AB - A growing body of evidence suggests that contaminated environments may harbor a greater proportion of antibiotic-resistant microorganisms than unpolluted reference sites. Here, we report the screening of 427 Escherichia coli strains isolated from 11 locations on nine streams draining the US Department of Energy's Savannah River Site against a panel of five antibiotics. Streams were chosen to capture a wide range of watersheds from minimally disturbed to highly impacted. Overall, higher levels of resistance were found in waterborne E. coli that also generally exhibited low spatial variability. However, 3 of 11 locations also demonstrated elevated resistance levels in sediments. Two of these occurred in highly disturbed tributaries with no obvious sources of antimicrobials. To further investigate these patterns, we screened a subset of isolates obtained from three streams against 23 antibiotics or antibiotic combinations. A large proportion of these isolates (>40 %) demonstrated resistance to 10 or more antimicrobials, suggesting that environmental multi-antibiotic resistance may be prevalent in this bacterial commensal. Only 4 of 87 viable isolates were tested susceptible to all 23 antibiotics and combinations. Among these multi-antibiotic resistant isolates, several demonstrated resistance to all structural classes of antimicrobial agents tested, including frontline antibiotics such as gatifloxacin and ciprofloxacin. PMID- 26530282 TI - Primed Mesenchymal Stem Cells Alter and Improve Rat Medial Collateral Ligament Healing. AB - Cell therapy with mesenchymal stem cells (MSCs) can improve tissue healing. It is possible, however, that priming MSCs prior to implantation can further enhance their therapeutic benefit. This study was then performed to test whether priming MSCs to be more anti-inflammatory would enhance healing in a rat ligament model, i.e. a medial collateral ligament (MCL). MSCs were primed for 48 h using polyinosinic acid and polycytidylic acid (Poly (I:C)) at a concentration of 1 MUg/ml. Rat MCLs were surgically transected and administered 1 * 10(6) cells in a carrier solution at the time of injury. A series of healing metrics were analyzed at days 4 and 14 post-injury in the ligaments that received primed MSCs, unprimed MSCs, or no cells (controls). Applying primed MSCs beneficially altered healing by affecting endothelialization, type 2 macrophage presence, apoptosis, procollagen 1alpha, and IL-1Ra levels. When analyzing MSC localization, both primed and unprimed MSCs co-localized with endothelial cells and pericytes suggesting a supportive role in angiogenesis. Priming MSCs prior to implantation altered key ligament healing events, resulted in a more anti-inflammatory environment, and improved healing. PMID- 26530283 TI - [Rise of the machines? Left ventricular assist devices for treatment of severe heart failure]. AB - The use of left ventricular assist devices (LVAD) as a treatment for severe heart failure has gained momentum in recent years. Even at this stage the number of worldwide LVAD implantations far exceeds the volume of heart transplantations in view of the chronic shortage of donor organs. Third generation continuous flow assist devices have helped to improve survival, quality of life and symptom burden of heart failure patients in comparison to a regimen of optimal medication management. Alongside bridging to transplantation, destination therapy has become an established strategy of LVAD implantation. A careful patient selection process is crucial for a good clinical outcome after device implantation and risk assessment for postoperative right ventricular failure is of particular importance in this context. The rate of hospitalization during LVAD support is still high, despite the step-wise attempts to widen the indications to less severely ill heart failure patients. An effective perioperative and postoperative management will help to lower the incidence of complications (e.g. bleeding, infections, thromboembolic events and right ventricular failure) and to improve the encouraging results of mechanical circulatory support. PMID- 26530285 TI - Rapid and inexpensive blood typing on thermoplastic chips. AB - A portable and cost-effective colorimetric diagnostic device was fabricated for rapid ABO and Rh blood typing. Using microfluidic construction on a thermoplastic chip, blood antibodies were preloaded into a reaction channel and exposed to blood samples to initiate a haemagglutination reaction. Downstream high-aspect ratio filters, composed of 2 MUm high microslits, block agglutinated red blood cells (RBCs) to turn the reaction channel red, indicating the presence of the corresponding blood antigen. Users manually actuate the blood sample using a simple screw pump that drives the solution through serpentine reaction channels and chaotic micromixers for maximum interaction of the preloaded antibodies with the blood sample antigens. Mismatched RBCs and antibodies elute from the channel into an outlet reservoir based on the rheological properties of RBCs with no colorimetric change. As a result, unambiguous blood typing tests can be distinguished by the naked eye in as little as 1 min. Blood disorders, such as thalassemia, can also be distinguished using the device. The required blood volume for the test is just 1 MUL, which can be obtained by the less invasive finger pricking method. The low reagent consumption, manual driving force, low cost of parts, high yield, and robust fabrication process make this device sensitive, accurate, and simple enough to use without specialized training in resource constrained settings. PMID- 26530284 TI - Enzymatic Depletion of the Polysialic Acid Moiety Associated with the Neural Cell Adhesion Molecule Inhibits Antidepressant Efficacy. AB - Antidepressant drugs are too often ineffective, the exact mechanism of efficacy is still ambiguous, and there has been a paucity of novel targets for pharmacotherapy. In an attempt to understand the pathogenesis of depression and subsequently develop more efficacious antidepressant drugs, multiple theories have been proposed, including the modulation of neurotransmission, the upregulation of neurogenesis and neurotrophic factors, normalizing hypothalamic pituitary-adrenal reactivity, and the reduction of neuroinflammation; all of which have supporting lines of evidence. Therefore, an ideal molecular target for novel pharmaceutical intervention would function at the confluence of these theories. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) functions broadly, serving to mediate synaptic plasticity, neurogenesis, neurotrophic factor signaling, and inflammatory signaling throughout the brain; all of which are associated with the pathophysiology and treatment of depression. Moreover, the expression of PSA-NCAM is reduced by depression, and conversely enhanced by antidepressant treatment, particularly within the hippocampus. Here we demonstrate that selectively cleaving the polysialic acid moiety, using the bacteriophage-derived enzyme endoneuraminidase N, completely inhibits the antidepressant efficacy of the selective-serotonin reuptake inhibitor fluoxetine (FLX) in a chronic unpredictable stress model of depression. We also observe a corresponding attenuation of FLX-induced hippocampal neuroplasticity, including decreased hippocampal neurogenesis, synaptic density, and neural activation. These data indicate that PSA-NCAM-mediated neuroplasticity is necessary for antidepressant action; therefore PSA-NCAM represents an interesting, and novel, target for pharmacotherapy. PMID- 26530286 TI - Factors associated with access to HIV care services in eastern Uganda: the Kumi home based HIV counseling and testing program experience. AB - BACKGROUND: The HIV/AIDS health challenge continues to ravage many resource constrained countries of the world. Approximately 75 % of all the global HIV/AIDS related deaths totaling 1.6 (1.4-1.9) million in 2012 occurred in sub-Saharan Africa, Uganda contributed 63,000 (52,000-81,000) to these deaths. Most of the morbidity and mortality associated with HIV/AIDS can be averted if individuals with HIV/AIDS have improved access to HIV care and treatment. The aim of this study therefore, was to explore the factors associated with access to HIV care services among HIV seropositive clients identified by a home based HIV counseling and testing program in Kumi district, eastern Uganda. METHODS: In a cross sectional study conducted in February 2009, we explored predictor variables: socio-demographics, health facility and community factors related to access to HIV care and treatment. The main outcome measure was reported receipt of cotrimoxazole for prophylaxis. RESULTS: The majority [81.1 % (284/350)] of respondents received cotrimoxazole prophylaxis (indicating access to HIV care). The main factors associated with access to HIV care include; age 25-34 years (AOR = 5.1, 95 % CI: 1.5-17.1), male sex (AOR = 2.3, 95 % CI: 1.2-4.4), urban residence (AOR = 2.5, CI: 1.1-5.9) and lack of family support (AOR = 0.5, CI: 0.2 0.9). CONCLUSIONS: There was relatively high access to HIV care and treatment services at health facilities for HIV positive clients referred from the Kumi home based HIV counseling and testing program. The factors associated with access to HIV care services include; age group, sex, residence and having a supportive family. Stakeholders involved in providing HIV care and treatment services in similar settings should therefore consider these socio-demographic variables as they formulate interventions to improve access to HIV care services. PMID- 26530287 TI - Optogenetic stimulation of cholinergic brainstem neurons during focal limbic seizures: Effects on cortical physiology. AB - Focal temporal lobe seizures often cause impaired cortical function and loss of consciousness. Recent work suggests that the mechanism for depressed cortical function during focal seizures may depend on decreased subcortical cholinergic arousal, which leads to a sleep-like state of cortical slow-wave activity. To test this hypothesis, we sought to directly activate subcortical cholinergic neurons during focal limbic seizures to determine the effects on cortical function. Here we used an optogenetic approach to selectively stimulate cholinergic brainstem neurons in the pedunculopontine tegmental nucleus during focal limbic seizures induced in a lightly anesthetized rat model. We found an increase in cortical gamma activity and a decrease in delta activity in response to cholinergic stimulation. These findings support the mechanistic role of reduced subcortical cholinergic arousal in causing cortical dysfunction during seizures. Through further work, electrical or optogenetic stimulation of subcortical arousal networks may ultimately lead to new treatments aimed at preventing cortical dysfunction during seizures. PMID- 26530288 TI - Current practice of diabetes education in children and adolescents with type 1 diabetes in Germany and Austria: analysis based on the German/Austrian DPV database. AB - BACKGROUND: Diabetes education of patients and/or parents is an essential part of diabetes care with effects on diabetes outcome. The objective of our study was to describe the current practice of diabetes education in Germany and Austria with regard to training frequency, patient age, migration background and diabetes therapy in a large cohort of pediatric patients with diabetes mellitus type 1 (T1DM). METHODS: We analyzed data from pediatric T1DM patients with diabetes training in 2013 and complete data available for treatment year in the multicenter Diabetes Patienten Verlaufsdokumentation (DPV) registry using sas 9.4. RESULTS: In 2013 21 871 pediatric patients with T1DM were documented [52.4% male, age: 12.70 (9.35-15.30) yr (median (interquartile range)], diabetes duration: 3.80 (1.45-7.00) yr, migration background: 21.4%, twice daily injections: 5.5%, multiple daily injections: 52.5%, insulin-pump therapy: 42%. Of these 32.31% were trained in 2013. Younger patients and their parents were trained more intensely and more frequently as inpatients compared with older patients (0-6 vs. 6-12 and 12-18 yr: teaching units: 13.07 vs. 12.05 and 9.79; inpatient: 79% vs. 72% and 70%). There was also a difference in training frequency with regard to migration background. Severe hypoglycemia or ketoacidosis resulted in intensification of training (4.0 vs. 2.0%; 7.8 vs. 3.1%). Centre-specific education tools were used frequently alone or in combination with published, standardized education programs. CONCLUSION: Training frequency was highest in younger patients and during the first year of diabetes. Acute complications resulted in more frequent diabetes training, indicating that currently many education sessions take place in consequence to these complications. PMID- 26530289 TI - Improving Memory Performances by Adjusting the Symmetry and Polarity of O Fluoroazobenzene-Based Molecules. AB - Three O-fluoroazobenzene-based molecules were chosen as memory-active molecules: FAZO-1 with a D-A2-D symmetric structure, FAZO-2 with an A1-A2-A1 symmetric structure, and FAZO-3 with a D-A2-A1 asymmetric structure. Both FAZO-1 and FAZO-2 had a lower molecular polarity, whereas FAZO-3 had a higher polarity. The fabricated indium-tin oxide (ITO)/FAZO-1/Al (Au) and ITO/FAZO-2/Al (Au) memory devices both exhibited volatile static random access memory (SRAM) behavior, whereas the ITO/FAZO-3/Al (Au) device showed nonvolatile ternary write-once-read many-times (WORM) behavior. It should be noted that the reproducibility of these devices was considerably high, which is significant for practical application in memory devices. In addition, the different memory performances of the three active materials were determined to be attributable to the stability of electric field-induced charge-transfer complexes. Therefore, the switching memory behavior could be tuned by adjusting the molecular polarity. PMID- 26530291 TI - Minimally invasive pancreatic surgery. AB - Minimally invasive pancreatic surgery is feasible and safe. Laparoscopic distal pancreatectomy should be widely adopted for benign lesions of the pancreas. Laparoscopic pancreaticoduodenectomy, although technically demanding, in the setting of pancreatic ductal adenocarcinoma has a number of advantages including shorter hospital stay, faster recovery, allowing patients to recover in a timelier manner and pursue adjuvant treatment options. Furthermore, it seems that progression-free survival is longer in patients undergoing laparoscopic pancreaticoduodenectomy in comparison with those undergoing open pancreaticoduodenectomy. Minimally invasive middle pancreatectomy seems appropriate for benign or borderline tumors of the neck of the pancreas. Technological advances including intraoperative ultrasound and intraoperative fluorescence imaging systems are expected to facilitate the wide adoption of minimally invasive pancreatic surgery. Although, the oncological outcome seems similar with that of open surgery, there are still concerns, as the majority of relevant evidence comes from retrospective studies. Large multicenter randomized studies comparing laparoscopic with open pancreatectomy as well as robotic assisted with both open and laparoscopic approaches are needed. Robotic approach could be possibly shown to be less invasive than conventional laparoscopic approach through the less traumatic intra-abdominal handling of tissues. In addition, robotic approach could enable the wide adoption of the technique by surgeon who is not that trained in advanced laparoscopic surgery. A putative clinical benefit of minimally invasive pancreatic surgery could be the attenuated surgical stress response leading to reduced morbidity and mortality as well as lack of the detrimental immunosuppressive effect especially for the oncological patients. PMID- 26530290 TI - Solid-state characterization of Felodipine-Soluplus amorphous solid dispersions. AB - The aim of the current study is to develop amorphous solid dispersion (SD) via hot melt extrusion technology to improve the solubility of a water-insoluble compound, felodipine (FEL). The solubility was dramatically increased by preparation of amorphous SDs via hot-melt extrusion with an amphiphilic polymer, Soluplus(r) (SOL). FEL was found to be miscible with SOL by calculating the solubility parameters. The solubility of FEL within SOL was determined to be in the range of 6.2-9.9% (w/w). Various techniques were applied to characterize the solid-state properties of the amorphous SDs. These included Fourier Transform Infrared Spectrometry spectroscopy and Raman spectroscopy to detect the formation of hydrogen bonding between the drug and the polymer. Scanning electron microscopy was performed to study the morphology of the SDs. Among all the hot melt extrudates, FEL was found to be molecularly dispersed within the polymer matrix for the extrudates containing 10% drug, while few small crystals were detected in the 30 and 50% extrudates. In conclusion, solubility of FEL was enhanced while a homogeneous SD was achieved for 10% drug loading. PMID- 26530292 TI - Minimally invasive treatment of pectus excavatum. AB - Pectus excavatum (PE) is the most common congenital chest wall deformity. It consists of a concavity of the sternum, and the costal cartilages derived from an unbalanced growth of the costochondral regions of the anterior chest wall. The standard operative treatment for PE has been the Ravitch procedure. This technique requires a long incision in the anterior chest wall and bilateral resection of the affected costal cartilages, needing in most cases a posterior metal bar support. The belief that the treatment of PE is basically esthetic led Donald Nuss to develop in 1998 a minimally invasive surgical treatment based on the skeletal frame plasticity and reshape capacity applied to the thorax. Thereby he deviced a technique involving a retrosternal steel bar modifying the sternum's concavity and supporting the shape of the amended thorax, all performed through two small incisions at each side of the thorax with the help of a thoracoscope. The bar is maintained from 2 to 3 years, and removed after this period. This procedure obtains >90% of positive results with significant esthetic improvement and patient satisfaction. This minimally surgical approach for PE is to be discussed in this review. PMID- 26530293 TI - Should patients with laryngeal small cell neuroendocrine carcinoma receive prophylactic cranial irradiation? AB - While small cell neuroendocrine carcinomas (SCNCs) most often arise in the lung, extrapulmonary SCNCs arise in a variety of locations-including the head and neck region. In particular, laryngeal SCNCs-while rare tumors-are nevertheless recognized as distinct lesions. The rarity of laryngeal SCNC gives rise to two distinct difficulties: first (particularly with small biopsy specimens), laryngeal SCNC can be difficult to diagnose by routine light microscopy; second, limited experience with these tumors can make the crafting of a treatment plan for individual patients difficult. As regards the first problem, pathologic diagnosis is greatly enhanced by the application of immunohistochemistry. The second problem-crafting a successful treatment strategy-presents a much larger difficulty. It is tempting to extrapolate from experience with the (more common) pulmonary SCNC in search of a strategy applicable to laryngeal SCNC; such an extrapolation, however, may not be uniformly successful. In particular, while a combination of radiation therapy and chemotherapy appears to be as valuable in the treatment of extrapulmonary as it is in the treatment of pulmonary SCNC, prophylactic cranial irradiation (PCI)-which has enjoyed some success in the treatment of some patients with pulmonary SCNC-does not appear to have similar utility in patients with laryngeal SCNC. Accordingly, the use of PCI does not appear to have a role to play at this point in time in the treatment of patients with laryngeal SCNC. PMID- 26530295 TI - Hypoactive Sexual Desire Disorder: Separating Fact from Fiction. PMID- 26530294 TI - Endoscopic ultrasonic dacryocystorhinostomy: clinical profile and outcomes. AB - Ultrasonic endoscopic dacryocystorhinostomy (UEnDCR) is emerging alternative modality of managing nasolacrimal duct obstructions. The aim of this study was to report the clinical profile and outcomes with a UEnDCR with mitomycin C and silicone intubation. Prospective interventional case series performed on all consecutive patients undergoing an ultrasonic endoscopic dacryocystorhinostomy over a 1-year period from September 2013 to October 2014. All surgeries were performed by a single surgeon (MJA). Data collected include demographics, presentation, indications for surgery, past interventions, intraoperative and post-operative complications and outcomes. The main outcome measures were anatomical and functional success of the surgery. 44 procedures were performed in 41 patients. The mean age was 31.6 years. Children with complex congenital nasolacrimal duct obstructions refractory to probing and intubation accounted for 17 % (7/41) of the cohort. Past history of acute dacryocystitis was noted in 35.6 % (15/41). Two patients (4.9 %, 2/41) had failed external DCR. A minimal follow up of 6 months following surgery was taken for final analysis. Complications included intraoperative focal epithelial burn in one patient that healed spontaneously and post-operative ostium granulomas in 15.9 % (7/44) of the ostia. At the 6-month follow-up, anatomical and functional successes were noted in 93.1 % (41/44) and 88.6 % (39/44), respectively. Ultrasonic dacryocystorhinostomy is a safe and effective alternative modality in the management of nasolacrimal duct obstructions in pediatric and adult age groups. Setup was easy and no additional technical difficulties were observed. PMID- 26530297 TI - Transcriptome sequencing of human breast cancer reveals aberrant intronic transcription in amplicons and dysregulation of alternative splicing with major therapeutic implications. AB - Advances in genomic and transcriptome sequencing are revealing the massive scale of previously unrecognised alterations occurring during neoplastic transformation. Breast cancers are genetically and phenotypically heterogeneous. Each of the three major subtypes [ERBB2 amplified, estrogen receptor (ESR) positive and triple-negative] poses diagnostic and therapeutic challenges. Here we show, using high-resolution next-generation transcriptome sequencing, that in all three breast cancer subtypes, but not matched controls, there was significant overexpression of transcripts from intronic and untranslated regions in addition to exons from specific genes, particularly amplified oncogenes and hormone receptors. For key genes ERBB2 and ESR1, we demonstrate that overexpression is linked to the production of highly modified and truncated splice variants in tumours, but not controls, correlated with tumour subtype. Translation of these tumour-specific splice variants generates truncated proteins with altered subcellular locations and functions, modifying the phenotype, affecting tumour biology, and targeted antitumour therapies. In contrast, tumour suppressors TP53, BRCA1/2 and NF1 did not show intronic overexpression or truncated splice variants in cancers. These findings emphasize the detection of intronic as well as exonic changes in the transcriptional landscapes of cancers have profound therapeutic implications. PMID- 26530296 TI - Coffee consumption and NAFLD: a community based study on 1223 subjects. AB - BACKGROUND: Objective of the present cross-sectional study was to investigate the impact of caffeine consumption on fatty liver and serum alanine aminotransferase (ALT) concentrations in a random population sample. METHODS: All subjects (n = 1452; 789 women, 663 men; average age 42.3 +/- 12.8 years) underwent ultrasonographic examination of the liver and completed a standardized questionnaire regarding personal and lifestyle data, in particular relating to coffee consumption and past medical history. In addition, anthropometric data were documented and laboratory examinations performed. Statistical interpretation of the data was performed descriptively and by means of bivariate and multivariate analysis. RESULTS: Data of the present study demonstrated a significant association between hepatic steatosis male gender (p < 0.0001), advanced age (p < 0.0001) and elevated body-mass index (BMI; p < 0.0001). No association between caffeine consumption and fatty liver was identified. An association between caffeine consumption and elevated serum ALT concentrations was not identified. CONCLUSIONS: The findings of the present study provide no evidence for an association between caffeine consumption and either the prevalence of hepatic steatosis or serum ALT concentrations. PMID- 26530298 TI - Biomechanical comparison of transfacet screws to lateral mass screw-rod constructs in the lower cervical spine. AB - PURPOSE: Transfacet screws have been used as an alternative posterior fixation in the cervical spine. There is lack of spinal stability of the transfacet screws either as stand-along constructs or combined with anterior plate. This study was designed to evaluate spinal stability of transfacet screws following posterior ligamentous injury and combined with anterior plate, respectively, and compare transfacet screws to lateral mass screw-rod constructs. METHODS: Flexibility tests were conducted on eight cadaveric specimens in an intact and injury, and instrumented with the transfacet screw fixation and lateral mass screw-rod construct at C5-C7 levels either after section of the posterior ligamentous complex or combined with an anterior plate and a mesh cage for C6 corpectomy reconstruction. A pure moment of +/-2.0 Nm was applied to the specimen in flexion extension, lateral bending, and axial rotation. Ranges of motion (ROM) were calculated for the C5-C7 segment. RESULTS: ROM with the transfacet screws was 22 % of intact in flexion-extension, 9 % in lateral bending and 11 % in axial rotation, while ROM with the lateral mass screw-rod construct was 9 % in flexion extension, 8 % in lateral bending and 22 % in axial rotation. The only significant difference between two constructs was seen in flexion-extension (5.8 +/- 4.2 degrees vs. 2.4 +/- 1.2 degrees , P = 0.002). When combined with an anterior plate and mesh cage, the transfacet screw fixation reduced ROM to 3.0 degrees in flexion-extension, 1.2 degrees in lateral bending, and 1.1 degrees in axial rotation, which was similar to the lateral mass screw-rod construct. CONCLUSIONS: This study identified the transfacet screw fixation, as stand-alone posterior fixation, was equivalent to the lateral mass screw-rod constructs in axial rotation and lateral bending except in flexion-extension. When combined with an anterior plate, the transfacet screw fixation was similar to the lateral mass screw-rod construct in motion constraint. The results suggested the transfacet screw fixation a biomechanically effective way as supplementation of anterior fixation. PMID- 26530299 TI - Cervical spondylotic myelopathy: the relevance of the spinal cord back shift after posterior multilevel decompression. A systematic review. AB - PURPOSE: Spinal cord back shift has been considered the desired end point of posterior decompression procedures for cervical spondylotic myelopathy (CSM). However, the association with postoperative outcomes has not been definitively demonstrated. The aim of this review is to obtain an overview of the current knowledge on the spinal back shift after posterior decompression to clarify the main controversial aspects and provide recommendations for further studies on the subject. METHODS: A comprehensive quantitative review of the literature was performed. Bibliographic databases were searched using the following keywords: spinal cord drift, spinal cord shift, CSM, ossification of posterior longitudinal ligament, posterior decompression, laminoplasty, laminectomy and fusion. RESULTS: Twelve eligible studies were included. The authors measured the spinal cord back shift in different ways, using the posterior edge, the center or the anterior margin of the spinal cord as reference points. Six studies analyzed the correlation between the spinal cord back shift and the recovery rate, but their results were discordant. The correlation between the posterior cord migration and cervical alignment was not confirmed in all studies. CONCLUSIONS: There is a need for a consensus on the best way to measure the spinal cord back shift. The action of multiple factors on spinal cord back shift can explain the difference in the results collected from the studies. We recommend further studies to clarify the behavior of the spinal cord after posterior decompression and its clinical meaning. PMID- 26530300 TI - Within-brain classification for brain tumor segmentation. AB - PURPOSE: In this paper, we investigate a framework for interactive brain tumor segmentation which, at its core, treats the problem of interactive brain tumor segmentation as a machine learning problem. METHODS: This method has an advantage over typical machine learning methods for this task where generalization is made across brains. The problem with these methods is that they need to deal with intensity bias correction and other MRI-specific noise. In this paper, we avoid these issues by approaching the problem as one of within brain generalization. Specifically, we propose a semi-automatic method that segments a brain tumor by training and generalizing within that brain only, based on some minimum user interaction. CONCLUSION: We investigate how adding spatial feature coordinates (i.e., i, j, k) to the intensity features can significantly improve the performance of different classification methods such as SVM, kNN and random forests. This would only be possible within an interactive framework. We also investigate the use of a more appropriate kernel and the adaptation of hyper parameters specifically for each brain. RESULTS: As a result of these experiments, we obtain an interactive method whose results reported on the MICCAI BRATS 2013 dataset are the second most accurate compared to published methods, while using significantly less memory and processing power than most state-of-the art methods. PMID- 26530301 TI - Effects of biofloc on growth performance, digestive enzyme activities and liver histology of common carp (Cyprinus carpio L.) fingerlings in zero-water exchange system. AB - Biofloc technology is considered as a method that degrades organic waste by microorganisms and produces microbial flocs. A 30-day experiment was performed to investigate the effects of partial replacement of daily feeding intake with biofloc on the growth performances, digestive enzymes activity and liver histology of the common carp Cyprinus carpio L. fingerlings. Two hundred and eight healthy fingerlings (58.6 +/- 0.2 g) were randomly distributed in 12 tanks (30 L) at a density of 25.4 kg m(-3) and fed experimental treatments (100 % daily feeding rate as a control, biofloc + 75% daily feeding rate, biofloc + 50% daily feeding rate, biofloc + 25% daily feeding rate). At the end of experiment, the results indicated that the highest weight gain was observed in the fish fed BFT 75% and control which differed significantly from those fed BFT 25 % (P < 0.05). Diet BFT 75% improved total protease and pepsin activity compared with BFT 25 and 50% (P > 0.05). No significant difference was observed in case of lipase, amylase and alkaline phosphatase activity between the treatments. In the liver, histological alterations were found in the treatments, and feeding the fish with BFT 75% significantly improved hepatocellular quantification and qualification than the other groups. The results obtained in this experiment suggest that the biofloc improves growth performances, digestive enzyme activity and liver condition of the common carp fingerlings when 25% of daily feeding rate (BFT 75%) was replaced with one carbohydrate such as molasses in zero-water exchange system. PMID- 26530302 TI - To notify or not to notify: decision aid for policy makers on whether to make an infectious disease mandatorily notifiable. AB - Mandatory notification can be a useful tool to support infectious disease prevention and control. Guidelines are needed to help policymakers decide whether mandatory notification of an infectious disease is appropriate. We developed a decision aid, based on a range of criteria previously used in the Netherlands or in other regions to help decide whether to make a disease notifiable. Criteria were categorised as being effective, feasible and necessary with regard to the relevance of mandatory notification. Expert panels piloted the decision aid. Here we illustrate its use for three diseases (Vibrio vulnificus infection, chronic Q fever and dengue fever) for which mandatory notification was requested. For dengue fever, the expert panel advised mandatory notification; for V. vulnificus infection and chronic Q fever, the expert panel concluded that mandatory notification was not (yet) justified. Use of the decision aid led to a structured, transparent decision making process and a thorough assessment of the advantages and disadvantages of mandatory notification of these diseases. It also helped identify knowledge gaps that required further research before a decision could be made. We therefore recommend use of this aid for public health policy making. PMID- 26530303 TI - Association of CagPAI integrity with severeness of Helicobacter pylori infection in patients with gastritis. AB - BACKGROUND AND AIM: The Helicobacter pylori cag pathogenicity island (cagPAI) is involved in delivery of CagA effector protein and peptidoglycan into host cells and also in IL-8 induction in the human gastric tissue. Diversity of cagPAI may affect disease status and clinical outcome of the infected patients. Our study was aimed to investigate diversity of this island and its intactness in Iranian patients to investigate possible associations between cagPAI integrity and pathological changes of the infected tissue. MATERIAL/PATIENTS AND METHODS: Out of the 75 patients, H. pylori strains were obtained from 30 patients with severe active gastritis (SAG) (n=11), moderate chronic gastritis (CG) (n=14) and intestinal metaplasia/dysplasia (IM) (n=5). Intactness of the cagPAI was determined using 12 sets of primer pairs specific for functionally important loci of cagPAI by polymerase chain reaction (PCR). RESULTS: The cagPAI positive strains were significantly observed in patients with SAG (52.4%) in comparison to those presenting CG (33.3%) and IM (14.3%). In addition, the presence of intact cagPAI was 87.5% in H. pylori strains isolated from patients with SAG, which was higher than those obtained from patients with CG (12.5%) or IM (0%). A significant increase in the frequency of cagalpha-cagY and cagW-cagT segments, as exterior proteins of the CagPAI, was illustrated in strains from SAG patients compared with those from patients with CG. CONCLUSIONS: Overall, these results strongly proposed an association between the severity of histopathological changes and intactness of cagPAI in the gastric tissue of patients infected with H. pylori. PMID- 26530304 TI - Editorial. PMID- 26530306 TI - Scratching under positive and negative arousal in common marmosets (Callithrix jacchus). AB - Scratching has been widely used as an indicator of anxiety in many primate species. However, a handful of studies have shown no change in scratching under anxiety-provoking circumstances. In addition, the existing literature has investigated scratching only in relation to negative arousal (i.e., anxiety), even though anxiety and excitement (positive arousal) share important physiological and behavioral correlates, including increased heart rate, blood pressure, and locomotion. In the current study, we scored all instances of scratching in 11 outdoor-housed captive common marmosets (Callithrix jacchus) during three contexts that were intended to be negatively arousing and three contexts that were intended to be positively arousing during a baseline, manipulation, and post-induction period. Summed across the three negative arousal contexts, the results showed that subjects exhibited significantly lower scratching rates during the manipulation than during either the baseline or post induction periods, and the pattern of means was the same for all three of those contexts. Under the three contexts of positive arousal, subjects exhibited different patterns of scratching rates during the manipulation periods (play = increases, foraging = decreases, food anticipation = no change). Data from the current study, and a close examination of data from studies showing no change in scratching under anxiety-provoking circumstances, suggest that the anxiety scratching relationship may be more complex than has been reported previously. Our results raise a potential concern about the unchallenged use of scratching as a behavioral indicator of anxiety in captive non-human primates, with important implications for welfare and management of these species. PMID- 26530305 TI - Different neural circuitry is involved in physiological and psychological stress induced PTSD-like "nightmares" in rats. AB - Posttraumatic nightmares are a core component of posttraumatic stress disorder (PTSD) and mechanistically linked to the development and maintenance of this disorder, but little is known about their mechanism. We utilized a communication box to establish an animal model of physiological stress (foot-shock [FS]) and psychological stress (PS) to mimic the direct suffering and witnessing of traumatic events. Twenty-one days after traumatic stress, some of the experimental animals presented startled awakening (i.e., were startled awake by a supposed "nightmare") with different electroencephalographic spectra features. Our neuroanatomical results showed that the secondary somatosensory cortex and primary auditory cortex may play an important role in remote traumatic memory retrieval in FS "nightmare" (FSN) rats, whereas the temporal association cortex may play an important role in PS "nightmare" (PSN) rats. The FSN and PSN groups possessed common emotion evocation circuits, including activation of the amygdala and inactivation of the infralimbic prefrontal cortex and ventral anterior cingulate cortex. The decreased activity of the granular and dysgranular insular cortex was only observed in PSN rats. The present results imply that different types of stress may cause PTSD-like "nightmares" in rodents and identified the possible neurocircuitry of memory retrieval and emotion evocation. PMID- 26530308 TI - Erratum. AB - Lopez de Lapuente A, Pinto-Medel MJ, Astobiza I, et al. Cell-specific effects in different immune subsets associated with SOCS1 genotypes in multiple sclerosis. Mult Scler 2015; 21: 1498-1512. DOI: 10.1177/1352458514566418. PMID- 26530307 TI - Why and when citizens call for emergency help: an observational study of 211,193 medical emergency calls. AB - BACKGROUND: A medical emergency call is citizens' access to pre-hospital emergency care and ambulance services. Emergency medical dispatchers are gatekeepers to provision of pre-hospital resources and possibly hospital admissions. We explored causes for access, emergency priority levels, and temporal variation within seasons, weekdays, and time of day for emergency calls to the emergency medical dispatch center in Copenhagen in a two-year study period (December 1(st), 2011 to November 30(th), 2013). METHODS: Descriptive analysis was performed for causes for access and emergency priority levels. A Poisson regression model was used to calculate adjusted ratio estimates for the association between seasons, weekdays, and time of day overall and stratified by emergency priority levels. RESULTS: We analyzed 211,193 emergency calls for temporal variation. Of those, 167,635 calls were eligible for analysis of causes and emergency priority level. "Unclear problem" was the most frequent category (19%). The five most common causes with known origin were categorized as "Wounds, fractures, minor injuries" (13%), "Chest pain/heart disease" (11%), "Accidents" (9%), "Intoxication, poisoning, drug overdose" (8%), and "Breathing difficulties" (7%). The highest emergency priority levels (Emergency priority level A and B) were assigned in 81% of calls. In the analysis of temporal variation, the total number of calls peaked at wintertime (26%), Saturdays (16%), and during daytime (39%). CONCLUSION: The pattern of citizens' contact causes fell into four overall categories: unclear problems, medical problems, intoxication and accidents. The majority of calls were urgent. The magnitude of unclear problems represents a modifiable factor and highlights the potential for further improvement of supportive dispatch priority tools or educational interventions at dispatch centers. Temporal variation was identified within seasons, weekdays and time of day and reflects both system load and disease occurrence. Data on contact patterns could be utilized in a public health perspective, benchmarking of EMS systems, and ultimately development of best practice in the area of emergency medicine. PMID- 26530309 TI - Tailorable chiroptical activity of metallic nanospiral arrays. AB - The engineering of the chiroptical activity of the emerging chiral metamaterial, metallic nanospirals, is in its infancy. We utilize glancing angle deposition (GLAD) to facilely sculpture the helical structure of silver nanospirals (AgNSs), so that the scope of chiroptical engineering factors is broadened to include the spiral growth of homochiral AgNSs, the combination of left- and right-handed helical chirality to create heterochiral AgNSs, and the coil-axis alignment of the heterochiral AgNSs. It leads to flexible control over the chiroptical activity of AgNS arrays with respect to the sign, resonance wavelength and amplitude of circular dichroism (CD) in the UV and visible regime. The UV chiroptical mode has a distinct response from the visible mode. Finite element simulation together with LC circuit theory illustrates that the UV irradiation is mainly adsorbed in the metal and the visible is preferentially scattered by the AgNSs, accounting for the wavelength-related chiroptical distinction. This work contributes to broadening the horizons in understanding and engineering chiroptical responses, primarily desired for developing a wide range of potential chiroplasmonic applications. PMID- 26530310 TI - Masked priming by misspellings: Word frequency moderates the effects of SOA and prime-target similarity. AB - University students made lexical decisions to eight- or nine-letter words preceded by masked primes that were the target, an unrelated word, or a typical misspelling of the target. At a stimulus onset asynchrony (SOA) of 47 ms, primes that were misspellings of the target produced a priming benefit for low-, medium , and high-frequency words, even when the misspelled primes were changed to differ phonologically from their targets. At a longer SOA of 80 ms, misspelled primes facilitated lexical decisions only to medium- and low-frequency targets, and a phonological change attenuated the benefit for medium-frequency targets. The results indicate that orthographic similarity can be preserved over changes in letter position and word length, and that the priming effect of misspelled words at the shorter SOA is orthographically based. Orthographic-priming effects depend on the quality of the orthographic learning of the target word. PMID- 26530311 TI - Geometric stability of topological lattice phases. AB - The fractional quantum Hall (FQH) effect illustrates the range of novel phenomena which can arise in a topologically ordered state in the presence of strong interactions. The possibility of realizing FQH-like phases in models with strong lattice effects has attracted intense interest as a more experimentally accessible venue for FQH phenomena which calls for more theoretical attention. Here we investigate the physical relevance of previously derived geometric conditions which quantify deviations from the Landau level physics of the FQHE. We conduct extensive numerical many-body simulations on several lattice models, obtaining new theoretical results in the process, and find remarkable correlation between these conditions and the many-body gap. These results indicate which physical factors are most relevant for the stability of FQH-like phases, a paradigm we refer to as the geometric stability hypothesis, and provide easily implementable guidelines for obtaining robust FQH-like phases in numerical or real-world experiments. PMID- 26530312 TI - Low-FODMAP formula improves diarrhea and nutritional status in hospitalized patients receiving enteral nutrition: a randomized, multicenter, double-blind clinical trial. AB - BACKGROUND: Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are poorly absorbed, short-chain carbohydrates that play an important role in inducing functional gut symptoms. A low-FODMAP diet improves abdominal symptoms in patients with inflammatory bowel disease and irritable bowel syndrome. However, there were no study for the effect of FODMAP content on gastrointestinal intolerance and nutritional status in patients receiving enteral nutrition (EN). METHODS: In this randomized, multicenter, double-blind, 14-day clinical trial, eligible hospitalized patients receiving EN (n = 100) were randomly assigned to three groups; 84 patients completed the trial (low-FODMAP EN, n = 30; moderate-FODMAP EN, n = 28; high-FODMAP EN, n = 26). Anthropometric and biochemical parameters were measured; stool assessment was performed using the King's Stool Chart and clinical definition. RESULTS: Baseline values were not significantly different among the three groups. After the 14-day intervention, diarrhea significantly improved in the low-FODMAP group than in the moderate- and high-FODMAP groups (P < 0.05). King's Stool scores in diarrhea subjects were significantly and steadily reduced in the low-FODMAP group compared with the other two groups (P for time and EN type interaction <0.05). BMI increased significantly in the low- and high-FODMAP groups during the intervention (P < 0.05 for both), and showed a trend toward increasing in the moderate-FODMAP group (P < 0.10). Serum prealbumin increased significantly in all groups by 14-day; by 3-day, it had increased to the levels at 14-day in the low-FODMAP group. At 14 day, serum transferrin had increased significantly in the moderate-FODMAP group. In addition, subjects were classified by final condition (unimproved, normal maintenance, diarrhea only improved, constipation only improved, and recurrent diarrhea/constipation improved). Seventy-five percent of the diarrhea improved group consumed the low-FODMAP EN formula. 38.5 and 46.2% of recurrent diarrhea/constipation improved group consumed the low- and moderate-FODMAP EN respectively. BMI significantly increased in all groups except the unimproved. Prealbumin levels significantly increased in the diarrhea-improved and recurrent diarrhea/constipation groups at 3-day and continued by 14-day, and in the constipation-improved group at 14-day. Transferrin levels significantly increased in the diarrhea-improved and recurrent diarrhea/constipation groups at 14-day. CONCLUSION: Low-FODMAP EN may improve diarrhea, leading to improved nutritional status and facilitating prompt recovery from illness. PMID- 26530313 TI - Molluscum Contagiosum Diagnosis on Nipple Scraping Sample. PMID- 26530314 TI - The Synthetic Elicitor 2-(5-Bromo-2-Hydroxy-Phenyl)-Thiazolidine-4-Carboxylic Acid Links Plant Immunity to Hormesis. AB - Synthetic elicitors are drug-like compounds that induce plant immune responses but are structurally distinct from natural defense elicitors. Using high throughput screening, we previously identified 114 synthetic elicitors that activate the expression of a pathogen-responsive reporter gene in Arabidopsis (Arabidopsis thaliana). Here, we report on the characterization of one of these compounds, 2-(5-bromo-2-hydroxy-phenyl)-thiazolidine-4-carboxylic acid (BHTC). BHTC induces disease resistance of plants against bacterial, oomycete, and fungal pathogens and has a unique mode of action and structure. Surprisingly, we found that low doses of BHTC enhanced root growth in Arabidopsis, while high doses of this compound inhibited root growth, besides inducing defense. These effects are reminiscent of the hormetic response, which is characterized by low-dose stimulatory effects of a wide range of agents that are toxic or inhibitory at higher doses. Like its effects on defense, BHTC-induced hormesis in Arabidopsis roots is partially dependent on the WRKY70 transcription factor. Interestingly, BHTC-induced root hormesis is also affected in the auxin-response mutants axr1-3 and slr-1. By messenger RNA sequencing, we uncovered a dramatic difference between transcriptional profiles triggered by low and high doses of BHTC. Only high levels of BHTC induce typical defense-related transcriptional changes. Instead, low BHTC levels trigger a coordinated intercompartmental transcriptional response manifested in the suppression of photosynthesis- and respiration-related genes in the nucleus, chloroplasts, and mitochondria as well as the induction of development-related nuclear genes. Taken together, our functional characterization of BHTC links defense regulation to hormesis and provides a hypothetical transcriptional scenario for the induction of hormetic root growth. PMID- 26530315 TI - Constitutive and Companion Cell-Specific Overexpression of AVP1, Encoding a Proton-Pumping Pyrophosphatase, Enhances Biomass Accumulation, Phloem Loading, and Long-Distance Transport. AB - Plant productivity is determined in large part by the partitioning of assimilates between the sites of production and the sites of utilization. Proton-pumping pyrophosphatases (H(+)-PPases) are shown to participate in many energetic plant processes, including general growth and biomass accumulation, CO2 fixation, nutrient acquisition, and stress responses. H(+)-PPases have a well-documented role in hydrolyzing pyrophosphate (PPi) and capturing the released energy to pump H(+) across the tonoplast and endomembranes to create proton motive force (pmf). Recently, an additional role for H(+)-PPases in phloem loading and biomass partitioning was proposed. In companion cells (CCs) of the phloem, H(+)-PPases localize to the plasma membrane rather than endomembranes, and rather than hydrolyzing PPi to create pmf, pmf is utilized to synthesize PPi. Additional PPi in the CCs promotes sucrose oxidation and ATP synthesis, which the plasma membrane P-type ATPase in turn uses to create more pmf for phloem loading of sucrose via sucrose-H(+) symporters. To test this model, transgenic Arabidopsis (Arabidopsis thaliana) plants were generated with constitutive and CC-specific overexpression of AVP1, encoding type 1 ARABIDOPSIS VACUOLAR PYROPHOSPHATASE1. Plants with both constitutive and CC-specific overexpression accumulated more biomass in shoot and root systems. (14)C-labeling experiments showed enhanced photosynthesis, phloem loading, phloem transport, and delivery to sink organs. The results obtained with constitutive and CC-specific promoters were very similar, such that the growth enhancement mediated by AVP1 overexpression can be attributed to its role in phloem CCs. This supports the model for H(+)-PPases functioning as PPi synthases in the phloem by arguing that the increases in biomass observed with AVP1 overexpression stem from improved phloem loading and transport. PMID- 26530316 TI - Reversible Burst of Transcriptional Changes during Induction of Crassulacean Acid Metabolism in Talinum triangulare. AB - Drought tolerance is a key factor for agriculture in the 21st century as it is a major determinant of plant survival in natural ecosystems as well as crop productivity. Plants have evolved a range of mechanisms to cope with drought, including a specialized type of photosynthesis termed Crassulacean acid metabolism (CAM). CAM is associated with stomatal closure during the day as atmospheric CO2 is assimilated primarily during the night, thus reducing transpirational water loss. The tropical herbaceous perennial species Talinum triangulare is capable of transitioning, in a facultative, reversible manner, from C3 photosynthesis to weakly expressed CAM in response to drought stress. The transcriptional regulation of this transition has been studied. Combining mRNA Seq with targeted metabolite measurements, we found highly elevated levels of CAM cycle enzyme transcripts and their metabolic products in T. triangulare leaves upon water deprivation. The carbohydrate metabolism is rewired to reduce the use of reserves for growth to support the CAM-cycle and the synthesis of compatible solutes. This large-scale expression dataset of drought-induced CAM demonstrates transcriptional regulation of the C3-CAM transition. We identified candidate transcription factors to mediate this photosynthetic plasticity, which may contribute in the future to the design of more drought-tolerant crops via engineered CAM. PMID- 26530317 TI - Interpersonal continuity of care and type two diabetes. AB - INTRODUCTION: Continuity of care is one of the core principles of primary care. The importance of interpersonal continuity in treating diabetic patients is unclear. AIM: To examine the association of interpersonal continuity of care, by the primary care physician, on the process of diabetic care and on health end points including diabetes control, hospital admissions and mortality. METHODS: We conducted a population based cohort study, 23,294 eligible participants were identified in Clalit Health Services Central Region at January 1, 2011 and followed through to December 31, 2012. Multivariate logistic regression models were applied to the data to study simultaneously the independent relationship between low interpersonal continuity, adjusted for background characteristics, and outcomes of care, including hospitalization and mortality. RESULTS: Achieving clinical targets was more likely in the high interpersonal continuity group HBA1 C OR 1.11 (CI 1.04-1.19), blood pressure OR 1.12 (1.04-1.20), LDL OR 1.14 (1.06 1.22). Patients with high interpersonal continuity had lower odds for mortality OR 0.59 (0.50-0.70). Admissions to hospital were lower in the high interpersonal continuity group, OR 0.82 (0.75-0.90), however when adjusting for background characteristics the difference in OR for hospital admissions became non significant 0.92 (0.84-1.01). CONCLUSION: High interpersonal continuity was associated with improved outcomes of process, and both primary and secondary clinical targets amongst adult patients with diabetes. This study is the first to find an association between interpersonal continuity and mortality amongst adults with diabetes. PMID- 26530318 TI - Response to 'Infrapatellar fat pad maximal area and changes in knee symptoms: gender-related difference or gender difference in reporting?' by Bai et al. PMID- 26530319 TI - Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis. AB - OBJECTIVES: Events in the lungs might contribute to generation of anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA). We investigated if signs of immune activation are present in bronchial biopsies and bronchoalveolar lavage (BAL) of patients with early-untreated RA without clinical signs of lung involvement. METHODS: Twenty-four patients with RA with symptom duration <1 year and naive to disease-modifying antirheumatic drugs were subjected to bronchoscopy where BAL and mucosal bronchial biopsies were retrieved. For comparison, 15 bronchial biopsies and 79 BAL samples from healthy volunteers were available. Histological examination was performed to evaluate lymphocyte infiltration, presence of immune cells (T and B cells, plasma cells, dendritic cells and macrophages) and immune activation markers. Cell composition of BAL samples was analysed by differential counting and T cell subsets by flow cytometry. RESULTS: Lymphocyte infiltration was more frequently found in ACPA positive patients (50%) as compared with ACPA-negative patients (17%) and controls (13%). Germinal centres, B cells and plasma cells were only found in ACPA-positive patients. The frequency of T cells in bronchial biopsies of patients with ACPA-positive RA was positively associated with expression of immune activation markers. BAL samples of patients with ACPA-positive, but not ACPA-negative, RA had significantly higher relative numbers of lymphocytes and expressed higher levels of activation markers compared with controls. CONCLUSIONS: Signs of immune cell accumulation and activation are present both in the bronchial tissue and in BAL of untreated patients with early RA without concomitant lung disease, strengthening the role of the lung compartment as an important player in ACPA-positive RA. PMID- 26530320 TI - Further thoughts about the ILLUMINATE studies of tabalumab in SLE. PMID- 26530321 TI - Impact of preoperative urodynamic testing for urinary incontinence and pelvic organ prolapse on clinical management in Chinese women. AB - AIM: To assess the impact of preoperative urodynamic testing on the clinical management of urinary incontinence and pelvic organ prolapse. METHODS: Urodynamic testing was performed prior to surgery in 307 patients with pelvic organ prolapse or urinary incontinence. The resulting changes to planned treatment were recorded and retrospectively assessed. RESULTS: Results of urodynamic testing prompted changes to the treatment plan in 136 cases (44.2%), including 86 cases of no or slight-stress urinary incontinence, 28 cases of bladder outlet obstruction, 12 cases of occult stress urinary incontinence and 10 cases of detrusor overactivity and urge urinary incontinence. Urodynamic testing excluded disadvantageous factors in 69 cases (22.4%), including 46 cases of overactive bladder and 23 cases of voiding dysfunction. The information provided to patients when seeking informed consent was augmented by the results of urodynamic testing in 63 cases (20.5%). Urodynamic testing was of no value in 39 cases (12.7%). CONCLUSIONS: Preoperative urodynamic testing for urinary incontinence and pelvic organ prolapse can result in changes to treatment plans, exclusion of disadvantageous factors, and augmentation of information provided to patients when seeking informed consent. PMID- 26530322 TI - Photoinduced Bioorthogonal 1,3-Dipolar Poly-cycloaddition Promoted by Oxyanionic Substrates for Spatiotemporal Operation of Molecular Glues. AB - PGlue(PZ), a pyrazoline (PZ)-based fluorescent adhesive which can be generated spatiotemporally in living systems, was developed. Since PGlue(PZ) carries many guanidinium ion (Gu(+)) pendants, it strongly adheres to various oxyanionic substrates through a multivalent salt-bridge interaction. PGlue(PZ) is given by bioorthogonal photopolymerization of a Gu(+)-appended monomer (Glue(TZ)), bearing tetrazole (TZ) and olefinic termini. Upon exposure to UV light, Glue(TZ) transforms into a nitrileimine (NI) intermediate (Glue(NI)), which is eligible for 1,3-dipolar polycycloaddition. However, Glue(NI) in aqueous media can concomitantly be deactivated into Glue(WA) by the addition of water, and the polymerization hardly occurs unless Glue(NI) is concentrated. We found that, even under high dilution, Glue(NI) is concentrated on oxyanionic substrates to a sufficient level for the polymerization, so that their surfaces can be point specifically functionalized with PGlue(PZ) by the use of a focused beam of UV light. PMID- 26530323 TI - Contrast-optimized composite image derived from multigradient echo cardiac magnetic resonance imaging improves reproducibility of myocardial contours and T2* measurement. AB - OBJECTIVES: Reproducibility of myocardial contour determination in cardiac magnetic resonance imaging is important, especially when determining T2* values per myocardial segment as a prognostic factor of heart failure or thalassemia. A method creating a composite image with contrasts optimized for drawing myocardial contours is introduced and compared with the standard method on a single image. MATERIALS AND METHODS: A total of 36 short-axis slices from bright-blood multigradient echo (MGE) T2* scans of 21 patients were acquired at eight echo times. Four observers drew free-hand myocardial contours on one manually selected T2* image (method 1) and on one image composed by blending three images acquired at TEs providing optimum contrast-to-noise ratio between the myocardium and its surrounding regions (method 2). RESULTS: Myocardial contouring by method 2 met higher interobserver reproducibility than method 1 (P < 0.001) with smaller Coefficient of variance (CoV) of T2* values in the presence of myocardial iron accumulation (9.79 vs. 15.91%) and in both global myocardial and mid-ventricular septum regions (12.29 vs. 16.88 and 5.76 vs. 8.16%, respectively). CONCLUSION: The use of contrast-optimized composite images in MGE data analysis improves reproducibility of myocardial contour determination, leading to increased consistency in the calculated T2* values enhancing the diagnostic impact of this measure of iron overload. PMID- 26530324 TI - Development and Psychometric Evaluation of the HPV Clinical Trial Survey for Parents (CTSP-HPV) Using Traditional Survey Development Methods and Community Engagement Principles. AB - OBJECTIVE: This study describes the development and psychometric evaluation of HPV Clinical Trial Survey for Parents with Children Aged 9 to 15 (CTSP-HPV) using traditional instrument development methods and community engagement principles. METHODS: An expert panel and parental input informed survey content and parents recommended study design changes (e.g., flyer wording). A convenience sample of 256 parents completed the final survey measuring parental willingness to consent to HPV clinical trial (CT) participation and other factors hypothesized to influence willingness (e.g., HPV vaccine benefits). Cronbach's a, Spearman correlations, and multiple linear regression were used to estimate internal consistency, convergent and discriminant validity, and predictively validity, respectively. RESULTS: Internal reliability was confirmed for all scales (a >= 0.70.). Parental willingness was positively associated (p < 0.05) with trust in medical researchers, adolescent CT knowledge, HPV vaccine benefits, advantages of adolescent CTs (r range 0.33-0.42), supporting convergent validity. Moderate discriminant construct validity was also demonstrated. Regression results indicate reasonable predictive validity with the six scales accounting for 31% of the variance in parents' willingness. CONCLUSIONS: This instrument can inform interventions based on factors that influence parental willingness, which may lead to the eventual increase in trial participation. Further psychometric testing is warranted. PMID- 26530325 TI - MicroRNA-148b targets Rho-associated protein kinase 1 to inhibit cell proliferation, migration and invasion in hepatocellular carcinoma. AB - microRNA(miR)-148b has been found to be downregulated in various human malignancies, including hepatocellular carcinoma (HCC) as well as gastric, pancreatic, colon and oral cancer. However, the function of miR-148b in HCC has remained elusive. The present study examined the effects of miR-148b on the proliferation, migration and invasion of HCC cells in vitro. After transfection of the HepG2 and SMMC-7721 HCC cell lines with miR-148b, an MTT assay, a Transwell migration and invasion assay as well as western blot analysis were performed. miR-148b was shown to inhibit cell proliferation, migration and invasion in the two cell lines. Using a luciferase reporter assay, the present study also provided the first evidence that miR-148b directly targets Rho associated protein kinase 1 in HCC. These results suggested that miR-148 may represent a novel molecular marker and a potential molecular therapeutic for inhibiting metastasis of HCC. PMID- 26530326 TI - Emotion regulation and mania risk: Differential responses to implicit and explicit cues to regulate. AB - BACKGROUND AND OBJECTIVES: People prone to mania use emotion regulation (ER) strategies well when explicitly coached to do so in laboratory settings, but they find these strategies ineffective in daily life. We hypothesized that, compared with control participants, mania-prone people would show ER deficits when they received implicit, but not explicit, cues to use ER. METHODS: Undergraduates (N = 66) completed the Hypomanic Personality Scale (HPS) and were randomly assigned to one of three experimental conditions: automatic ER (scrambled sentence primes), deliberate ER (verbal instructions), or control (no priming or instructions to use ER). Then, participants played a videogame designed to evoke anger. Emotion responses were measured with a multi-modal assessment of self-reported affect, psychophysiology, and facial expressions. Respiratory sinus arrhythmia (RSA) was used to index ER. RESULTS: The videogame effectively elicited subjective anger, angry facial expressions, and heart rate increases when keys malfunctioned. As hypothesized, persons who were more mania prone showed greater RSA increases in the deliberate ER condition than in the automatic or control conditions. LIMITATIONS: One potential limitation is the use of an analog sample. CONCLUSIONS: Findings suggest that those at risk for mania require more explicit instruction to engage ER effectively. PMID- 26530327 TI - Mood repair in healthy individuals: Both processing mode and imagery content matter. AB - BACKGROUND: The recall of positive autobiographical memories (mood repair) is an effective strategy for improving sad mood. In depressed individuals mood repair has shown to be most effective, if the memory was processed in a concrete (imaginable), as opposed to an abstract (verbal) processing mode. However, it is not yet clear whether this also applies to healthy subjects. Moreover we do not know whether intensity and content of an imagery stimulus influences its effectiveness. We report on two experimental studies in healthy participants. METHODS: Negative emotion induction was followed by mood repair via recall of positive autobiographical memories. In study I, abstract processing was compared to two concrete processing strategies (high concrete/low concrete). In study II, the content of the memories was systematically varied (social/achievement). RESULTS: In study I, a concrete processing resulted in better mood repair, however no differences were found between high and low concrete processing. In study II, both types of memories had comparable effects on mood repair but promoted different emotions. LIMITATIONS: Only a young, healthy, predominantly female population was investigated. CONCLUSIONS: Adopting a concrete processing mode when recalling positive memories leads to better mood repair in healthy participants. Moreover, the content of the memory determines the corresponding emotions. PMID- 26530328 TI - Mitofilin and CHCHD6 physically interact with Sam50 to sustain cristae structure. AB - The inner mitochondrial membrane (IMM) invaginates to form cristae and the maintenance of cristae depends on the mitochondrial contact site (MICOS) complex. Mitofilin and CHCHD6, which physically interact, are two components of the MICOS. In this study, we performed immunoprecipitation experiments with Mitofilin and CHCHD6 antibodies and identified a complex containing Mitofilin, Sam50, and CHCHD 3 and 6. Using transcription activator-like effector nucleases (TALENs), we generated knockdown/knockout clones of Mitofilin and CHCHD6. Transmission electron microscopy (TEM) revealed that vesicle-like cristae morphology appeared in cell lines lacking Mitofilin, and mitochondria exhibited lower cristae density in CHCHD6-knockout cells. Immunoblot analysis showed that knockdown of Mitofilin, but not knockout of CHCHD6, affected their binding partners that control cristae morphology. We also demonstrated that Mitofilin and CHCHD6 directly interacted with Sam50. Additionally, we observed that Mitofilin-knockdown cells showed decreased mitochondrial membrane potential (DeltaPsim) and intracellular ATP content, which were minimally affected in CHCHD6-knockout cells. Taken together, we conclude that the integrity of MICOS and its efficient interaction with Sam50 are indispensable for cristae organization, which is relevant to mitochondrial function. PMID- 26530329 TI - Changes in mental health in compliers and non-compliers with physical activity recommendations in patients with stress-related exhaustion. AB - BACKGROUND: There is a lack of research regarding the long-lasting effects of a more physically active lifestyle in patients with mental disorders. In the present study, clinical data were analysed to examine if initially physically inactive patients, clinically diagnosed with stress-related exhaustion, taking part in 12-month multimodal treatment (MMT), differ at the 18-month follow-up regarding mental health, depending on whether they did or did not comply with the physical activity (PA) recommendations resembling those of the American College of Sports Medicine. METHODS: The study population consisted of 69 patients (65% women) who were referred to a stress clinic due to stress-related exhaustion. All patients received MMT. A major goal was to increase patients' PA levels. The patients received general comprehensive instructions including personal advice regarding the positive effects of PA on mental health and could self-select for an 18-week coached exercise program. Changes in mental health symptoms over an 18 month period were compared between non-compliers (n = 26), mild compliers (n = 22) and strong compliers (n = 21) with the PA recommendations included in the MMT. RESULTS: Non-compliers, mild and strong compliers did not differ regarding burnout, depression and anxiety at baseline. Although substantial improvements occurred in all groups, mild and strong compliers reported significantly lower burnout and depression levels at the 18-month follow-up than the non-complying group (p < .05). The general pattern of findings was corroborated, if standard cut-off criteria for clinical burnout were used. CONCLUSIONS: Compliance with PA recommendations is associated with decreased levels of burnout and depression in patients with stress-related exhaustion. Thus, the promotion of a more active lifestyle among patients with stress-related exhaustion should be implemented as a part of MMT, to achieve a more sustainable decrease of symptoms of burnout and depression. TRIAL REGISTRATION: This is not a clinical trial. PMID- 26530330 TI - [No reflow: What are the predictors?]. AB - INTRODUCTION: During the past 20 years, significant progress has been made in the recanalization of ACS with ST elevation. It is now accepted that the reopening of the large coronary vessels in the acute phase of infarction by thrombolysis or angioplasty is necessary but not sufficient, because in 20-50% of cases, the coronary recanalization is an illusion of reperfusion. This phenomenon is called "no reflow". OBJECTIVE: The main objective of our study was to identify predictors of poor perfusion or "no reflow" in the acute phase of myocardial infarction. METHODS: Observational prospective study, in the department of cardiology and internal medicine, university hospital of Blida, over a period of 28 months from 1st September 2010 to 31st January 2013. We identified all patients hospitalized for myocardial infarction in acute phase, who underwent primary angioplasty or thrombolysis with angiographic control during a good TIMI flow. The endpoint was regression of ST segment (regression<50% ST-segment defined no reflow). RESULTS: Three hundred and seventy-nine patients were included. The mean age was 56.3+/-2.1, 87.8% of patients were male. In total, 35.9% hypertensive, 27.1% diabetic type 2, 50.1% and 10.8% dyslipidemia, smoking. One hundred and forty-seven (38.8%) developed a no reflow. Mortality was 3.9%, strongly correlated with no reflow (P=0.001). Predictors of no reflow after multivariate analysis were: age (OR 98, 0.961-0.996 95%, P=0.02), heart rate (1.01, 95% CI 0.998-1.02, P=0.035), the type 2 diabetes (odds ratio 1.87, CI 1.2 3.0, P=0.08), reaching the core (OR 7, 95% CI 1.2-18.4, P=0.027), direct stenting (OR 0.48, 95% CI 0.31-0.78, P=0.003). An interesting subgroup of patients was identified namely the subgroup strategy deferred primary angioplasty with stenting best reperfusion (OR 3.7, 95% CI 1.5-8.8, P=0.04), a lower rate of reocclusion of culprit artery and a lower rate of stenting with 23/51 (45.1%) versus 136/136 (100%) of immediate stenting group with a P<0.001. CONCLUSION: No reflow is a common phenomenon, strongly correlated with mortality predictors are age, heart rate, diabetes, achieving the core and direct stenting. The distal embolization in primary angioplasty is an important phenomenon, a delayed stenting strategy appears to limit this phenomenon. PMID- 26530331 TI - Global detection and semi-quantification of Fritillaria alkaloids in Fritillariae Ussuriensis Bulbus by a non-targeted multiple reaction monitoring approach. AB - Methods based on triple quadrupole tandem mass spectrometry have been widely used and reported as highly selective and sensitive methods for quantifying substances of herbal medicines. However, most of them were limited to targeted components, due to the difficulties to optimize the multiple reaction monitoring transitions without authentic standards. This study proposed a novel strategy for non targeted optimization of multiple reaction monitoring method based on the diagnostic ion guided family classifications, tandem mass spectrometry database establishment, and transitions and collision energy screening. Applying this strategy, 59 Fritillaria alkaloids in Fritillariae Ussuriensis Bulbus have been classified, and 51 of these Fritillaria alkaloids were successfully detected by the optimal multiple reaction monitoring method. For semi-quantification, the easy-to-obtain Fritillaria alkaloids of each type, such as verticinone for cevanine type and peimisine for jervine type, were used as the reference standards to calibrate the other Fritillaria alkaloids in the same type. The method was demonstrated a good linearity (R(2) > 0.998) with satisfactory accuracy and precision, and the lower limits of quantification of verticinone and peimisine were estimated to be 0.076 and 0.216 pg, respectively. In addition, the results suggested that the proposed strategy might obtained high quality metabolomics data in discrimination of Fritillaria unibracteata and Fritillaria ussuriensis. PMID- 26530332 TI - A qualitative study of adolescents with medically unexplained symptoms and their parents. Part 1: Experiences and impact on daily life. AB - Medically unexplained symptoms (MUS) are common among adolescents and are frequently encountered in primary care. Our aim was to explore how these adolescents and their parents experience the condition and its impact on their daily lives and to provide recommendations for health professionals. Using a qualitative approach, six focus groups and two individual interviews were conducted. These involved a total of ten adolescents with different types of MUS and sixteen parents. The respondents were recruited in a university hospital in Switzerland. A thematic analysis was conducted according to the Grounded Theory. The analysis of the data highlighted four core themes: disbelief, being different, concealing symptoms, and priority to adolescent's health. Transcending these themes was a core issue regarding the discrepancy between the strategies that adolescents and their parents use to cope with the symptoms. Health professionals should be made aware of the emotional needs of these patients and their families. PMID- 26530333 TI - Chlamydial seasonal dynamics and isolation of 'Candidatus Neptunochlamydia vexilliferae' from a Tyrrhenian coastal lake. AB - The Chlamydiae are a phylum of obligate intracellular bacteria comprising important human and animal pathogens, yet their occurrence in the environment, their phylogenetic diversity and their host range has been largely underestimated. We investigated the seasonality of environmental chlamydiae in a Tyrrhenian coastal lake. By catalysed reporter deposition fluorescence in situ hybridization, we quantified the small planktonic cells and detected a peak in the abundance of environmental chlamydiae in early autumn with up to 5.9 * 10(4) cells ml(-1) . Super-resolution microscopy improved the visualization and quantification of these bacteria and enabled the detection of pleomorphic chlamydial cells in their protist host directly in an environmental sample. To isolate environmental chlamydiae together with their host, we applied a high throughput limited dilution approach and successfully recovered a Vexillifera sp., strain harbouring chlamydiae (93% 16S rRNA sequence identity to Simkania negevensis), tentatively named 'Candidatus Neptunochlamydia vexilliferae'. Transmission electron microscopy in combination with fluorescence in situ hybridization was used to prove the intracellular location of these bacteria representing the first strain of marine chlamydiae stably maintained alongside with their host in a laboratory culture. Taken together, this study contributes to a better understanding of the distribution and diversity of environmental chlamydiae in previously neglected marine environments. PMID- 26530334 TI - Morning Blood Pressure Surge as a Predictor of Development of Chronic Kidney Disease. AB - Blood pressure (BP) usually increases upon awakening--a physiological mechanism called morning BP surge (MBPS). BP values above the MBPS threshold are associated with target organ damage, including left ventricular hypertrophy and proteinuria. Despite these data, there have been no studies that have investigated the association between elevated MBPS and the development of incident chronic kidney disease (CKD). In this study, patients with essential hypertension were included and underwent ambulatory BP measurements and MBPS. Patients were followed for a median of 3.33 years. In total, 622 patients were enrolled. The mean age of patients was 57.6+/-12.4 years, 54.0% were men, 16.7% had diabetes, and 10.6% had prevalent cardiovascular disease. During follow-up, 32 patients developed CKD. Higher MBPS, analyzed both as continuous and categorical variables, was associated with incident CKD in all models. Elevated MBPS is associated with kidney function deterioration and the development of CKD. Studies are needed to further examine underlying mechanisms regarding MBPS and these renal outcomes. PMID- 26530335 TI - Patterns of Alcohol Use after Traumatic Brain Injury. AB - Alcohol misuse and traumatic brain injury (TBI) frequently co-occur. The negative consequences of this interaction are well documented, but the patterns of long term post-injury alcohol consumption are less clear. This study examined patterns of alcohol use among 170 adults with a history of complicated mild to severe TBI. Participants were recruited from a Level 1 Trauma Center at the time of their injury and completed evaluations at 1 month, 6 months, 12 months, and 3-5 years post-injury. Pre-injury alcohol use was also assessed at the time of the 1-month assessment. A modified Quantity-Frequency Index of alcohol consumption was then calculated for each time point. The results revealed high levels of pre-injury alcohol consumption, followed by a reduction in consumption at 1-month post injury. A significant increase in consumption was noted by 6 months post-injury, followed by more gradual increases in alcohol consumption at 1 year. Post-injury alcohol consumption was comparable to the general public at 6 months, 12 months, and 3-5 years post-injury. These results suggest that the first 6 months post injury may be the critical window of opportunity for alcohol intervention. PMID- 26530336 TI - Upper critical solution temperature (UCST) phase transition of halide salts of branched polyethylenimine and methylated branched polyethylenimine in aqueous solutions. AB - The upper critical solution temperature (UCST) phase transition of halide salts of branched polyethylenimine (PEI) and methylated branched polyethylenimine (MPEI) is first reported in aqueous solutions. In particular, iodide counter-ions can introduce UCST properties in MPEI. The importance of the counter-ion composition of MPEI for UCST transition is discussed in detail. PMID- 26530337 TI - CD44 deficiency inhibits unloading-induced cortical bone loss through downregulation of osteoclast activity. AB - The CD44 is cellular surface adhesion molecule that is involved in physiological processes such as hematopoiesis, lymphocyte homing and limb development. It plays an important role in a variety of cellular functions including adhesion, migration, invasion and survival. In bone tissue, CD44 is widely expressed in osteoblasts, osteoclasts and osteocytes. However, the mechanisms underlying its role in bone metabolism remain unclear. We found that CD44 expression was upregulated during osteoclastogenesis. CD44 deficiency in vitro significantly inhibited osteoclast activity and function by regulating the NF-kappaB/NFATc1 mediated pathway. In vivo, CD44 mRNA levels were significantly upregulated in osteoclasts isolated from the hindlimb of tail-suspended mice. CD44 deficiency can reduce osteoclast activity and counteract cortical bone loss in the hindlimb of unloaded mice. These results suggest that therapeutic inhibition of CD44 may protect from unloading induced bone loss by inhibiting osteoclast activity. PMID- 26530338 TI - Zoledronic Acid Use and Risk of Cognitive Decline among Elderly Women and Men with Osteoporosis. AB - OBJECTIVES: Bisphosphonates are the first line treatment options in the prevention and treatment of osteoporosis among elderly women or men. Age associated cognitive decline may increase due to adverse effects of medications. The aim of the present study was to observe the course of cognitive skills in elderly subjects treated with a bisphosphonate. MATERIALS AND METHODS: This prospective study enrolled 120 community-dwelling, non-demented women and men with osteoporosis aged 65 and older who were treated with first-ever zoledronic acid. Mini mental state examination (MMSE) was measured along with geriatric depression scale (GDS) measurement, clock drawing test (CDT), and other clinical and laboratory evaluations that could affect cognition at baseline and 12 months. The primary outcome was at least one point decrease in the final MMSE score at one year. RESULTS: Scores of MMSE (28.29+/-2.17 and 28.23+/-2.37, p=0.681), GDS (3.24+/-2.88 and 2.96+/-2.88, p=0.062) and CDT (3.69+/-0.68 and 3.75+/-0.60, p=0.268) did not change after zoledronic acid infusion at one year. Education in years and presence of newly started medicines with anticholinergic properties was independently associated with at least one point reduction in MMSE score [odds ratio: 3.07 (%95 confidence interval: 1.00-9.44)]. CONCLUSION: Among elderly woman and men with osteoporosis, cognitive functions remained stable 12 months after the administration of first-ever zoledronic acid. PMID- 26530339 TI - Roseomonas eburnea sp. nov., isolated from activated sludge. AB - A Gram-stain-negative, aerobic, short rod-shaped, non-endospore-forming, ivory pigmented and non-motile bacterium, designated strain BUT-5T, was isolated from activated sludge of an herbicides-manufacturing wastewater treatment facility in Jiangsu Province, China. The major fatty acids (>5 % of total fatty acids) were C16 : 0, C18 : 1 2-OH and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). The predominant respiratory quinone was ubiquinone Q-10. The polar lipids profile of strain BUT-5T included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and two unknown aminolipids. The DNA G+C content was 67.6 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain BUT-5T showed the highest sequence similarities to Roseomonas soli 5N26T (97.5 % 16S rRNA gene sequence similarity), followed by Roseomonas lacus TH-G33T (97.3 %) and Roseomonas terrae DS-48T (97.1 %). Strain BUT-5T showed low DNA-DNA relatedness with Roseomonas soli KACC 16376T (41 %), Roseomonas lacus KACC 11678T (46 %) and Roseomonas terrae KACC 12677T (42 %), respectively. On the basis of phenotypic and genotypic properties, as well as chemotaxonomic data, strain BUT-5T represents a novel species of the genus Roseomonas, for which the name Roseomonas eburnea sp. nov. is proposed. The type strain is BUT-5T ( = CCTCC AB2013276T = KACC 17166T). PMID- 26530341 TI - Preservation of Biomarkers from Cyanobacteria Mixed with Mars-Like Regolith Under Simulated Martian Atmosphere and UV Flux. AB - The space mission EXPOSE-R2 launched on the 24th of July 2014 to the International Space Station is carrying the BIOMEX (BIOlogy and Mars EXperiment) experiment aimed at investigating the endurance of extremophiles and stability of biomolecules under space and Mars-like conditions. In order to prepare the analyses of the returned samples, ground-based simulations were carried out in Planetary and Space Simulation facilities. During the ground-based simulations, Chroococcidiopsis cells mixed with two Martian mineral analogues (phyllosilicatic and sulfatic Mars regolith simulants) were exposed to a Martian simulated atmosphere combined or not with UV irradiation corresponding to the dose received during a 1-year-exposure in low Earth orbit (or half a Martian year on Mars). Cell survival and preservation of potential biomarkers such as photosynthetic and photoprotective pigments or DNA were assessed by colony forming ability assays, confocal laser scanning microscopy, Raman spectroscopy and PCR-based assays. DNA and photoprotective pigments (carotenoids) were detectable after simulations of the space mission (570 MJ/m(2) of UV 200-400 nm irradiation and Martian simulated atmosphere), even though signals were attenuated by the treatment. The fluorescence signal from photosynthetic pigments was differently preserved after UV irradiation, depending on the thickness of the samples. UV irradiation caused a high background fluorescence of the Martian mineral analogues, as revealed by Raman spectroscopy. Further investigation will be needed to ensure unambiguous identification and operations of future Mars missions. However, a 3-month exposure to a Martian simulated atmosphere showed no significant damaging effect on the tested cyanobacterial biosignatures, pointing out the relevance of the latter for future investigations after the EXPOSE-R2 mission. Data gathered during the ground-based simulations will contribute to interpret results from space experiments and guide our search for life on Mars. PMID- 26530342 TI - Variation of choroidal thickness and vessel diameter in patients with posterior non-infectious uveitis. AB - BACKGROUND: Choroidal thickness (CTh) and choroidal vessel diameter (VD) in the Haler's layer were evaluated as markers of inflammatory insult in non-infectious uveitis (NIU). Spectral-domain optical coherence tomography (Spectralis(r), Heidelberg Engineering Inc.) scans were acquired from 23 normal subjects (39 eyes - group 1), 7 subjects with high myopia (14 eyes - group 2), and 19 patients with NIU (23 eyes - group 3). In groups 1 and 2, CTh and VD were measured at 3 different points of the same horizontal OCT scan passing through the fovea and a mean calculated. Mean CTh and VD were calculated in 2 other locations, 2 mm superior and inferior from the chosen foveal horizontal scan. In group 3, three measurements of CTh and VD were obtained within 1 mm of a horizontal scan passing through a retinal lesion; mean CTh and VD were then computed. A ratio (R) between the VD and the corresponding CTh was calculated. RESULTS: Group 1, 2 and 3 mean age was 29.6, 29.1 and 45.9 years, respectively. Sixteen normal subjects, three myopic subjects and six NIU patients were male.. Group 1 mean CTh did not differ from group 2 (261.6+/-45.6 vs. 260.2+/-50.6 um um; p>0.05); mean VD was marginally higher in Group 2 (159.8+/-32.2 vs. 163.2+/-33.2 um; p>0.05). Group 3 demonstrated thinner CTh (193.6+/-54.6 um) than Groups 1 and 2 (p = 0.02 and <0.001). Group 3 mean VD (123.6+/-37.4 um) was also less than that in Groups 1 and 2; the difference was statistically significant only when compared to group 2, p = 0.01. R did not differ across groups (p-values >0.05), indicating that variations in CTh and VD followed the same trend. CONCLUSIONS: The study reports potential quantitative OCT-derived parameters that may be explored in future trials of non-infectious uveitis. Thinning of choroid and decrease of vessel diameter are observed in patients with chronic NIU compared to controls. PMID- 26530343 TI - Combined depth imaging of choroid in uveitis. AB - BACKGROUND: Understanding the changes that occur in the choroid is of paramount importance in various uveitis entities. B-scan ultrasonography and indocyanine green angiography can be used to study choroid. Currently, spectral-domain optical coherence tomography is used as the standard noninvasive technique to study the choroid by enhanced depth imaging. Our aim was to study the structural visibility of the choroid using spectral-domain optical coherence tomography in the same area of interest in patients with uveitis with posterior segment manifestations using conventional, enhanced depth imaging (EDI), and combined depth imaging (CDI) techniques. RESULTS: Fifty-eight (58) eyes of 48 patients between age group 9 and 82 years were confirmed cases of uveitis. Out of the 48 patients, 21 (43.75%) were males while 27 (56.25%) were females. Sixteen eyes (27.59%) had intermediate uveitis, 33 (56.9%) had posterior uveitis, and 9 eyes (15.51%) had panuveitis. For posterior vitreous, there was substantial agreement for all the three groups (kappa value of 0.77, 0.73, and 0.72 in groups 1, 2, and 3, respectively). For vitreo retinal interface and inner choroid, there was perfect interobserver agreement, and for outer choroid, there was substantial to almost perfect interobserver agreement (kappa value of 0.71, 0.81, and 0.86 in groups 1, 2, and 3, respectively). Chi-squared test was done to compare the three groups. The method of scanning had a significant effect on the visualization of posterior vitreous and the outer choroid (p < 0.01) and did not have an effect on the visualization of vitreoretinal interface, inner retina, outer retina, and inner choroidal layers (p > 0.05). CONCLUSION: The CDI technique alone might provide a good structural visibility compared to normal and EDI scanning done separately in patients with uveitis with posterior segment pathology. CDI OCT technique is thus able to visualize all posterior structures in a single image in patients with uveitis with posterior segment manifestations. PMID- 26530344 TI - A case of panuveitis with hypopyon due to presumed ocular leishmaniasis in a HIV patient. AB - BACKGROUND: Post-kala-azar dermal leishmaniasis is a well-known immunologic cutaneous reaction. There are few case reports of ocular leishmaniasis. It is a sight-threatening condition that needs to be rapidly recognized and treated to avoid permanent visual loss. Ocular leishmaniasis panuveitis can present with severe inflammation in patients with highly active anti-retroviral therapy (HAART)-induced immune reconstitution syndrome. FINDINGS: A case of a 40-year-old man, human immunodeficiency virus (HIV) positive on HAART, with a presumed diagnosis of ocular leishmaniasis, is presented. He had a past history of visceral leishmaniasis and was referred to the uveitis service with rapidly worsening panuveitis and counting fingers vision in both eyes. On empirical anti leishmania therapy and systemic steroids, the visual acuity of the left eye improved to 6/9 but remained poor in the right eye. Based on the medical history, improvement with therapy and the exclusion of other common infections, a presumed diagnosis of ocular leishmaniasis-related panuveitis was made. CONCLUSIONS: A major immune reaction against lingering parasites may play a key role in the pathogenesis of this sight-threatening and rapidly progressive condition. Both the infection and the immune reaction should be treated. PMID- 26530345 TI - Double trouble: a patient with both HLA-B27 anterior uveitis and HLA-A29 birdshot chorioretinitis. AB - BACKGROUND: Birdshot chorioretinitis (BSCR) is a rare ocular inflammatory disorder associated with HLA-A29 and characterized by bilateral choroidal lesions, vitritis, macular edema, and retinal vasculitis. Ocular inflammation associated with HLA-B27 is typically a recurrent, unilateral, acute anterior uveitis (AAU) that is frequently associated with ankylosing spondylitis (AS). To date, there are no reports of patients with both HLA-A29-positive BSCR and HLA B27 AAU/AS in the English literature. FINDINGS: A 50-year-old man with a history of bilateral anterior uveitis, vitritis, retinal vasculitis, and cream-colored depigmented oval choroidal lesions was found to be HLA-A29 and HLA-B27 positive. His lumbar spine and sacroiliac joint films revealed fusion of the spine, known as 'bamboo spine' compatible with the diagnosis of ankylosing spondyloarthropathy. He had chronic ocular inflammation that was difficult to control with systemic steroids and immunomodulatory agents. CONCLUSIONS: This is the only report of a patient with both HLA-A29-positive BSCR and HLA-B27-positive AS and associated anterior uveitis. The severity of his disease suggests that patients who test positive for both HLA-A29 and HLA-B27 carry a poor visual prognosis. Prompt diagnosis and treatment with local or systemic corticosteroids or steroid-sparing agents may control the disease. PMID- 26530340 TI - Longitudinal Trends in Western Australian HIV-1 Sequence Diversity and Viral Transmission Networks and Their Influence on Clinical Parameters: 2000-2014. AB - We examined baseline HIV-1 protease and reverse transcriptase sequences and HIV clinical parameters from 1,021 consecutive patients (814 male, 207 female) through the Royal Perth Hospital HIV service to investigate HIV-1 subtype diversity and local phylogenetic networks from 2000 to 2014. HIV-1 subtype B virus sequences were demonstrated in 619 (61%) of cases, with increasing non-B HIV-1 subtypes from 23.2% (2000-2003) to 48% (2008-2011) and 43% (2012-2014) (p < 0.001), including the CRF01_AE subtype [6.6% (2000-2003) to 21.5% (2008-2011)] and HIV-1 C subtype [9.5% (2000-2003) to 20.2% (2008-2011)]. More HIV-1 B subtypes were assigned to phylogenetic clusters compared to non-B subtypes (34% vs. 18%; p < 0.001), with larger clusters identified (cluster size >2: 135/211; 64% vs. 13/69; 19%; p = 0.001), including one cluster of 53 HIV-1 B subtype sequences that evolved from 2008 to 2014. Non-B subtype HIV-1 was associated with lower baseline CD4 T cell count (p = 0.005) but not plasma HIV-1 RNA levels (p = 0.31), suggesting relatively delayed diagnosis. Baseline viral load was strongly associated with calendar time [mean 18,620 copies/ml in 2000-2003; 75,858 copies/ml in 2012-2014 (p < 0.001)], and was also associated with larger phylogenetic clusters (size >2) in adjusted analyses (p = 0.03). This study identifies a number of temporal trends over the past 15 years, including an increasing prevalence of non-B subtype HIV-1 that highlights the growing influence of migration and travel on the Australian HIV-1 epidemic and the associated increased role of heterosexual HIV-1 transmission in this context. At the same time, these data indicate that local transmission within predominantly male networks remains a challenging issue for HIV-1 prevention. PMID- 26530346 TI - Real-time and nested polymerase chain reaction in the diagnosis of multifocal serpiginoid choroiditis caused by Mycobacterium tuberculosis - a case report. AB - BACKGROUND: The term multifocal serpiginoid choroiditis (MSC) has been proposed for the infective variant of serpiginous choroiditis (SC) to distinguish it from typical SC believed to be autoimmune related. The role of Mycobacterium tuberculosis (MTb) in MSC has been studied by conventional polymerase chain reaction (PCR). However, the use of real-time PCR (RT-PCR) and nested PCR (N-PCR) in MSC has not been reported. This paper aims to highlight the usefulness of PCR in identifying MTb as a causative agent for MSC leading to its correct treatment with anti-tubercular therapy (ATT). FINDINGS: A young male with a family history of tuberculosis (TB) presented with a history of diminution of vision (DOV) since 3 months in his right eye (RE). He gave similar history in his left eye (LE) since 3 years. His fundus findings were suggestive of MSC. His high-resolution computed tomography (HRCT) chest and Quanti-FERON TB gold results were positive for MTb. These suggested TB to be the likely cause for MSC. This was confirmed by a positive N-PCR report of his aqueous specimen. Further RT-PCR was done to quantify the bacillary load before starting therapy. He was advised 9 months of ATT with 6 weeks of oral steroids. At last follow-up, the RE showed better healing than the LE with fewer chorioretinal scars and a better visual acuity. CONCLUSIONS: RT and N-PCR for MTb are useful in establishing a tuberculous etiology in MSC. Coupled with a good response to ATT, these tests justify the use of ATT in MSC with a PCR-confirmed MTb report. PMID- 26530347 TI - The non-medical out-of-pocket costs to attend a free anxiety disorders treatment clinic in Australia. AB - OBJECTIVE: Australia has high out-of-pocket costs for medical and non-medical treatments. The 'cost to attend' is seldom added to these estimates. METHOD: A sequence of 92 participants attending a free Anxiety Disorders Clinic at an inner city public hospital were surveyed about the costs to attend one appointment, including costs such as private /public transport costs and lost income. RESULTS: We found that these out-of-pocket costs were on average AUD$57 per person to attend an appointment at a free point-of-service clinic. Of the 45% who experienced financial burden from attending, the majority reported only slight burden. CONCLUSION: This level of 'cost to attend' a free outpatient treatment clinic is non-trivial given people with anxiety and depressive disorders, like many others with chronic disorders, will need at least 6-10 visits to complete a course of treatment. PMID- 26530348 TI - Argentine psychiatry: report on the 30th Congress. AB - OBJECTIVES: To give a contextualised personal account of the 30th Annual Congress of the Argentine Association of Psychiatrists. METHODS: Conference attendance and analysis of talks. RESULTS: The congress demonstrated that Argentine psychiatry is held back by oppressive political regimes and by government underfunding. The drug companies and third-party payers are entering the vacuum. CONCLUSIONS: Argentine trainees and consultants feel ill-prepared to meet the demands of the biomedical psychiatry. PMID- 26530349 TI - Making defensible decisions in the era of recovery and rights. AB - OBJECTIVES: Our aim was to develop a framework for clinical decision-making that can be used to take into account risk in an era of recovery and rights. CONCLUSION: We developed a framework influenced by civil liability law to develop a guide for clinical decision-making which emphasises collaboration, clarification of the available information and communication of decisions as essential components of recovery-oriented risk management. PMID- 26530350 TI - "You didn't just consult community, you involved us": transformation of a 'top down' Aboriginal mental health project into a 'bottom-up' community-driven process. AB - OBJECTIVE: Recently, there has been a consistent call for Indigenous health research to be community-driven. However, for a variety of reasons, many projects, such as the one featured here, start as 'top-down'. Using ten accepted principles for Aboriginal health research, the present article illustrates how a top-down project can be transformed into a 'bottom-up' community-driven project. METHOD: A table of examples is provided to show how the ten principles were translated into practice to create a bottom-up process. RESULTS: We suggest that key elements for creating a bottom-up process are iterative conversations and community involvement that goes beyond notional engagement. A feature of community involvement is generating and sustaining ongoing conversations with multiple levels of community (organisations, health professionals, Elders, community members, project-specific groups) in a variety of different forums across the entire duration of a project. Local research teams, a commitment to building capacity in the local Indigenous workforce, and adequate timelines and funding are other factors that we hypothesise may contribute to successful outcomes. CONCLUSION: The article contributes to a much-needed evidence base demonstrating how appropriate structures and strategies may create bottom-up processes leading to successful outcomes. PMID- 26530351 TI - Adaptation of the autotrophic acetogen Sporomusa ovata to methanol accelerates the conversion of CO2 to organic products. AB - Acetogens are efficient microbial catalysts for bioprocesses converting C1 compounds into organic products. Here, an adaptive laboratory evolution approach was implemented to adapt Sporomusa ovata for faster autotrophic metabolism and CO2 conversion to organic chemicals. S. ovata was first adapted to grow quicker autotrophically with methanol, a toxic C1 compound, as the sole substrate. Better growth on different concentrations of methanol and with H2-CO2 indicated the adapted strain had a more efficient autotrophic metabolism and a higher tolerance to solvent. The growth rate on methanol was increased 5-fold. Furthermore, acetate production rate from CO2 with an electrode serving as the electron donor was increased 6.5-fold confirming that the acceleration of the autotrophic metabolism of the adapted strain is independent of the electron donor provided. Whole-genome sequencing, transcriptomic, and biochemical studies revealed that the molecular mechanisms responsible for the novel characteristics of the adapted strain were associated with the methanol oxidation pathway and the Wood-Ljungdahl pathway of acetogens along with biosynthetic pathways, cell wall components, and protein chaperones. The results demonstrate that an efficient strategy to increase rates of CO2 conversion in bioprocesses like microbial electrosynthesis is to evolve the microbial catalyst by adaptive laboratory evolution to optimize its autotrophic metabolism. PMID- 26530352 TI - Schwann cells promote EMT and the Schwann-like differentiation of salivary adenoid cystic carcinoma cells via the BDNF/TrkB axis. AB - Perineural invasion (PNI) is a striking biological behavior observed in salivary adenoid cystic carcinoma (SACC). The present study was designed to establish a co culture model of SACC cells with Schwann cells (SCs), and then study epithelial mesenchymal transition (EMT) and the Schwann-like differentiation of SACC cells to investigate the likely molecular mechanism of PNI. The co-culture models of SCs with tumor cells (SACC-83, SACC-LM and MEC-1) were established using a Transwell system. An elevated concentration of brain-derived neurotrophic factor (BDNF) was detected by ELISA assay in the co-cultured medium of the SACC-83 group and SACC-LM group rather than the MEC-1 group. The EMT process and Schwann-like differentiation in SACC-83 cells were analyzed by RT-PCR, western blotting, immunofluorescence, photography, and migration and perineural invasion assays. The SACC-83 cells under the co-culture condition with SCs changed to a mesenchymal morphology and had higher migration and invasion capabilities compared with the solely cultured SACC-83 cells, accompanied by the downregulation of E-cadherin and upregulation of N-cadherin and vimentin. The co cultured SACC-83 cells also developed Schwann-like differentiation with increased expression of SC markers, S100A4 and GFAP. However, inhibition of tropomyosin related kinase B (TrkB) by K252a markedly blocked these effects. Additionally, the expression and correlation of TrkB, E-cadherin and S100A4 were analyzed by immunohistochemistry in 187 primary SACC cases. The levels of TrkB and S100A4 expression were both positively associated with PNI in the SACC cases, while E cadherin expression was negatively associated with PNI. Elevated expression of TrkB was significantly correlated with the downregulated expression of E-cadherin and the upregulated expression of S100A4 in the SACC cases. Our results suggest that SCs play a pivotal role in the PNI process by inducing the EMT process and the Schwann-like differentiation of SACC cells via the BDNF/TrkB axis. Interruption of the interreaction between SACC cells and SCs by targeting the BDNF/TrkB axis may be a potential strategy for anti-PNI therapy in SACC. PMID- 26530353 TI - Auranofin induces mesothelioma cell death through oxidative stress and GSH depletion. AB - Mesothelioma is an aggressive tumor associated with asbestos exposure. Auranofin as an inhibitor of thioredoxin reductase (TrxR) affects many biological processes such as inflammation and proliferation. In the present study, we investigated the cellular effects of auranofin on patient-derived mesothelioma cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. Basal TrxR1 levels have no difference between mesothelial cells and certain mesothelioma cells. In particular, ADA, CON and Hmeso mesothelioma cells showed lower levels of TrxR1 expression. Auranofin inhibited the proliferation of mesothelioma cells in a dose dependent manner. Among mesothelioma cells were ADA and CON cells sensitive to auranofin. This agent also induced caspase-independent apoptosis and necrosis in ADA cells. In addition, auranofin increased ROS levels including O2(*-) and induced GSH depletion in mesothelioma cells. While N-acetyl cysteine (NAC) prevented cell death and decreased ROS levels in auranofin-treated mesothelioma cells, L-buthionine sulfoximine (BSO) intensified apoptosis and GSH depletion in these cells. In conclusion, auranofin induced mesothelioma cell death through oxidative stress and the death was regulated by the status of GSH content. PMID- 26530354 TI - Discriminating dengue-infected hepatic cells (WRL-68) using dielectrophoresis. AB - Dielectrophoresis (DEP), the induced movement of dielectric particles placed in a nonuniform electric field, has been used as a potential technique for manipulation and separation of many biological samples without destructive consequences to the cell. Cells of the same genotype in different physiological and pathological states have unique morphological and structural features, therefore, it is possible to differentiate between them using their DEP responses. This paper reports the experimental discrimination of normal and dengue-infected human hepatic fetal epithelial cells (WRL-68 cells) based on their DEP crossover frequency, at which no resultant movement occurs in the cells in response to the DEP force. A microarray dot electrode was used to conduct the DEP experiments. The DEP forces applied to the cells were quantified by analyzing the light intensity shift within the electrode's dot region based on the Cumulative Modal Intensity Shift image analysis technique. The differences in dielectric properties between infected and uninfected cells were exploited by plotting a unique DEP spectrum for each set of cells. We observed that the crossover frequency decreased from 220 kHz for the normal WRL-68 cells to 140 kHz after infection with the dengue virus in a medium conductivity of 100 MUS/cm. We conclude that the change in the DEP crossover frequency between dengue-infected cells and their healthy counterparts should allow direct characterization of these cell types by exploiting their electrophysiological properties. PMID- 26530355 TI - Reduction of trabecular and cortical volumetric bone mineral density at the proximal femur in patients with acromegaly. AB - OBJECTIVE: Data on dual energy absorptiometry (DXA)-measured bone mineral density (BMD) at the level of the total hip (TH) and femoral neck (FN) in patients with acromegaly (ACRO) are conflicting. Increase in bone size associated with ACRO may limit the reliability of DXA. Our objective is to evaluate trabecular and cortical volumetric BMD (vBMD) across the proximal femur in ACRO patients. DESIGN: Cross sectional study in a clinical research center. PATIENTS: Thirty five ACRO patients (19 males; mean age, 48+/-7 years; BMI, 27.5+/-4.4 kg/m(2); 17 with active disease) and 35 age, gender, and BMI-matched controls. RESULTS: vBMD was assessed by quantitative computed tomography at the level of the TH, FN, trochanter (TR), and intertrochanteric (IT). Trabecular vBMD was lower in both total and active ACRO as compared with controls (P<0.01). Cortical vBMD was lower in ACRO patients (active and controlled) vs controls at both TH and TR sites (P<0.05). These findings were confirmed when only eugonadal patients were analyzed. Both total cross sectional area (CSA) and average cortical thickness (ACT) were greater in ACRO patients vs controls (P<0.05). An inverse association between disease duration and trabecular vBMD at TH (r=-0.42, P=0.023) and IT (r= 0.41, P=0.026) was also found. CONCLUSION: Both cortical and trabecular vBMD are reduced at the proximal femur in ACRO patients, regardless of gender, gonadal status, and disease activity. Disease duration is negatively associated with trabecular vBMD at the TH and IT. PMID- 26530356 TI - Cancer Biomarkers: A Status Quo. AB - At present, there are a growing number of biomolecules under investigation to understand their potential role as cancer biomarker for diagnostic, prognostic and therapeutic purposes. Intriguingly, the state of art on cancer biomarkers research shows interesting and promising results together to clamorous failures. Also from a clinical point of view, there are contradictory results on routine clinical use of the present cancer biomarkers. Some patients may be simply monitored in their course by a periodic blood sample, but sometimes this monitoring show dramatic limits. A lot of patients show serious and extensive relapses without significant change in serum concentrations of biomarkers tested. Often the physician who should utilize these biomarkers does not entirely know their limits and the total potential applications as well and sometimes this knowledge is influenced by economical and marketing strategies. This limited and "polluted" knowledge may have dramatic consequences for patient. A critical approach towards old and new cancer biomarkers should foster a deepened and useful understanding of the diagnostic and prognostic index of these fundamental parameters of laboratory medicine and in the same time can facilitate the research of new and more sensitive-specific signals of the cancer cell proliferation. PMID- 26530357 TI - Cancer Biomarkers Discovery and Validation: State of the Art, Problems and Future Perspectives. AB - Cancer is one of the major public health problems worldwide representing the leading cause of morbidity and mortality in industrialized countries. To reduce cancer morbidity and mortality as well as to facilitate the evolution from the traditional "one size fits all" strategy to a new "personalized" cancer therapy (i.e., the right drug to the right patient at the right time, using the right dose and schedule), there is an urgent need of reliable, robust, accurate and validated cancer biomarker tests.Unfortunately, despite the impressive advances in tumor biology research as well as in high-powerful "omics" technologies, the translation of candidate cancer biomarkers from bench to bedside is lengthy and challenging and only a few tumor marker tests have been adopted successfully into routine clinical care of oncologic patients.This chapter provides an updated background on biomarkers research in oncology, including biomarkers clinical uses, and discusses the problems of discovery pipeline, biomarkers failures and future perspectives. PMID- 26530358 TI - Use of Biomarkers in Screening for Cancer. AB - Screening for premalignant lesions or early invasive disease has the potential to reduce mortality from cancer. Because of their ease of measurement, several biomarkers have been evaluated or are currently undergoing evaluation as screening tests for early malignancy. These include the use of AFP in screening for hepatocellular cancer in high-risk subjects, CA 125 in combination with transvaginal ultrasound (TVU) in screening for epithelial ovarian cancer, PSA in screening for prostate cancer, faecal occult blood testing (FOBT) in screening for colorectal cancer (CRC) and vanillymandelic acid and homovanillic acid in screening for neuroblastoma in newborn infants, Of these biomarkers, only the use of FOBT in screening for CRC has unequivocally been shown to reduce mortality from cancer. Although 2 large randomized prospective trials have evaluated PSA as a screening test for prostate cancer, it is still unclear whether the benefits outweigh the harms in this setting. Although biomarkers have many attractive features as cancer screening tests, lack of sensitivity and specificity, when combined with the low prevalence of specific cancer types in asymptomatic subjects, limit their application for the early detection of malignancy. PMID- 26530359 TI - The Role of Metabolomics in the Study of Cancer Biomarkers and in the Development of Diagnostic Tools. AB - This chapter introduces the emerging field of metabolomics and its application in the context of cancer biomarker research. Taking advantage of modern high throughput technologies, and enhanced computational power, metabolomics has a high potential for cancer biomarker identification and the development of diagnostic tools. This chapter describes current metabolomics technologies used in cancer research, starting with metabolomics sample preparation, elaborating on current analytical methodologies for metabolomics measurement and introducing existing software for data analysis. The last part of this chapter deals with the statistical analysis of very large metabolomics datasets and their relevance for cancer biomarker identification. PMID- 26530360 TI - The Role of Epigenomics in the Study of Cancer Biomarkers and in the Development of Diagnostic Tools. AB - Epigenetics plays a key role in cancer development. Genetics alone cannot explain sporadic cancer and cancer development in individuals with no family history or a weak family history of cancer. Epigenetics provides a mechanism to explain the development of cancer in such situations. Alterations in epigenetic profiling may provide important insights into the etiology and natural history of cancer. Because several epigenetic changes occur before histopathological changes, they can serve as biomarkers for cancer diagnosis and risk assessment. Many cancers may remain asymptomatic until relatively late stages; in managing the disease, efforts should be focused on early detection, accurate prediction of disease progression, and frequent monitoring. This chapter describes epigenetic biomarkers as they are expressed during cancer development and their potential use in cancer diagnosis and prognosis. Based on epigenomic information, biomarkers have been identified that may serve as diagnostic tools; some such biomarkers also may be useful in identifying individuals who will respond to therapy and survive longer. The importance of analytical and clinical validation of biomarkers is discussed, along with challenges and opportunities in this field. PMID- 26530361 TI - Efficient, Adaptive Clinical Validation of Predictive Biomarkers in Cancer Therapeutic Development. AB - Predictive biomarkers, defined as biomarkers that can be used to identify patient populations who will optimally benefit from therapy, are an important part of the future of oncology. They have the potential to reduce the size and cost of clinical development programs for oncology therapy, while increasing their probability of success and the ultimate value of cancer medicines. But predictive biomarkers do not always work, and under these circumstances they add cost, complexity, and time to drug development. This chapter describes Phase 2 and 3 development methods which efficiently and adaptively evaluate the ability of the biomarker to predict clinical outcomes. In the end, the biomarker is emphasized to the extent that it is actually predictive. This allows clinical cancer drug developers to manage uncertainty in the validity of biomarkers, leading to maximal value for predictive biomarkers and their associated oncology therapies. PMID- 26530362 TI - Prostate Specific Antigen as a Tumor Marker in Prostate Cancer: Biochemical and Clinical Aspects. AB - In this chapter the use of prostate specific antigen (PSA) as a tumor marker for prostate cancer is discussed. The chapter provides an overview of biological and clinical aspects of PSA. The main drawback of total PSA (tPSA) is its lack of specificity for prostate cancer which leads to unnecessary biopsies. Moreover, PSA-testing poses a risk of overdiagnosis and subsequent overtreatment. Many PSA based markers have been developed to improve the performance characteristics of tPSA. As well as different molecular subforms of tPSA, such as proPSA (pPSA) and free PSA (fPSA), and PSA derived kinetics as PSA-velocity (PSAV) and PSA-doubling time (PSADT). The prostate health index (phi), PSA-density (PSAD) and the contribution of non PSA-based markers such as the urinary transcripts of PCA3 and TMPRSS-ERG fusion are also discussed. To enable further risk stratification tumor markers are often combined with clinical data (e.g. outcome of DRE) in so-called nomograms. Currently the role of magnetic resonance imaging (MRI) in the detection and staging of prostate cancer is being explored. PMID- 26530363 TI - The Actual Role of LDH as Tumor Marker, Biochemical and Clinical Aspects. AB - Lactate dehydrogenase (LDH) among many biochemical parameters represents a very valuable enzyme in patients with cancer with possibility for easy routine measurement in many clinical laboratories. Previous studies where mostly based on investigated LDH in serum of patients with cancer with aims to estimate their clinical significance. The new directions in investigation of LDH where based on the principle that tumor cells release intracellular enzymes trough damaged cell membrane, that is mostly consequence in intracellular mitochondrial machinery alteration, and apoptosis deregulation. This consideration can be used not only in-vitro assays, but also in respect to clinical characteristics of tumor patients. Based on new techniques of molecular biology it is shown that intracellular characteristics of LDH enzyme are very sensitive indicators of the cellular metabolic state, aerobic or anaerobic direction of glycolysis, activation status and malignant transformation. Using different molecular analyses it is very useful to analyzed intracellular LDH activity in different cell line and tumor tissues obtained from patients, not only to understanding complexity in cancer biochemistry but also in early clinical diagnosis. Based on understandings of the LDH altered metabolism, new therapy option is created with aims to blocking certain metabolic pathways and stop tumors growth. PMID- 26530364 TI - Neuron-Specific Enolase as a Biomarker: Biochemical and Clinical Aspects. AB - Neuron-specific enolase (NSE) is known to be a cell specific isoenzyme of the glycolytic enzyme enolase. In vertebrate organisms three isozymes of enolase, expressed by different genes, are present: enolase alpha is ubiquitous; enolase beta is muscle-specific and enolase gamma is neuron-specific. The expression of NSE, which occurs as gammagamma- and alphagamma-dimer, is a late event in neural differentiation, thus making it a useful index of neural maturation.NSE is a highly specific marker for neurons and peripheral neuroendocrine cells. As a result of the findings of NSE in specific tissues under normal conditions, increased body fluids levels of NSE may occur with malignant proliferation and thus can be of value in diagnosis, staging and treatment of related neuroendocrine tumours (NETs).NSE is currently the most reliable tumour marker in diagnosis, prognosis and follow-up of small cell lung cancer (SCLC), even though increased levels of NSE have been reported also in non-small cell lung cancer (NSCLC). The level of NSE correlates with tumour burden, number of metastatic sites and response to treatment.NSE can be also useful at diagnosis of NETs and gastroenteropancreatic (GEP)-NETs.Raised serum levels of NSE have been found in all stages of neuroblastoma, although the incidence of increased concentration is greater in widespread and metastatic disease. Moreover, NSE determination in cord blood offers an early postnatal possibility of confirming the diagnosis of neuroblastoma in newborns.NSE has been demonstrated to provide quantitative measures of brain damage and/or to improve the diagnosis and the outcome evaluation in ischaemic stroke, intracerebral hemorrhage, seizures, comatose patients after cardiopulmonary resuscitation for cardiac arrest and traumatic brain injury.Increased NSE serum levels have also been found associated with melanoma, seminoma, renal cell carcinoma, Merkel cell tumour, carcinoid tumours, dysgerminomas and immature teratomas, malignant phaechromocytoma, Guillain-Barre syndrome and Creutzfeldt-Jakob disease. PMID- 26530365 TI - Components of the Plasminogen-Plasmin System as Biologic Markers for Cancer. AB - Members of the plasminogen-plasmin (PP) system participate in many physiologic functions. In particular, uPA, its receptor (uPAR) and its inhibitor PAI-1 play an important role in cell migration, cell proliferation and tissue remodeling. Through a number of interactions, these components of the PP system are also involved in the pathogenesis of many diseases. In cancer, they modulate the essential processes of tumor development, growth, invasion and metastasis as well as angiogenesis and fibrosis. Thus, quantification of uPA, uPAR and PAI-1 in tumors and, in some cases in the circulating blood, became of potential value in the prognostication of many types of cancer. These include cancer of the breast, stomach, colon and rectum, esophagus, pancreas, glioma, lung, kidney, prostate, uterine cervix, ovary, liver and bone. Published data are reviewed in this chapter. Clinical validation of the prognostic value has also been made, particularly in cancer of the breast. Inclusion of these biomarkers in the risk assessment of cancer patients is now considered in the risk-adapted management in carcinoma of the breast. Factors limiting its broader use are discussed with suggestions how these can be overcome. Hopefully the use of these biomarkers will be applied to other types of cancer in the near future. PMID- 26530366 TI - The Role of Human Chorionic Gonadotropin as Tumor Marker: Biochemical and Clinical Aspects. AB - Tumor markers are biological substances that are produced/released mainly by malignant tumor cells, enter the circulation in detectable amounts and are potential indicators of the presence of a tumor. The most useful biochemical markers are the tumor-specific molecules, i.e., receptors, enzymes, hormones, growth factors or biological response modifiers that are specifically produced by tumor cells and not, or minimally, by the normal counterpart (Richard et al. Principles and practice of gynecologic oncology. Wolters Kluwer Health, Philadelphia, 2009). Based on their specificity and sensitivity in each malignancy, biomarkers are used for screening, diagnosis, disease monitoring and therapeutic response assessment in clinical management of cancer patients.This chapter is focused on human chorionic gonadotropin (hCG), a hormone with a variety of functions and widely used as a tumor biomarker in selected tumors. Indeed, hCG is expressed by both trophoblastic and non-trophoblastic human malignancies and plays a role in cell transformation, angiogenesis, metastatization, and immune escape, all process central to cancer progression. Of note, hCG testing is crucial for the clinical management of placental trophoblastic malignancies and germ cell tumors of the testis and the ovary. Furthermore, the production of hCG by tumor cells is accompanied by varying degrees of release of the free subunits into the circulation, and this is relevant for the management of cancer patients (Triozzi PL, Stevens VC, Oncol Rep 6(1):7-17, 1999).The name chorionic gonadotropin was conceived: chorion derives from the latin chordate meaning afterbirth, gonadotropin indicates that the hormone is a gonadotropic molecule, acting on the ovaries and promoting steroid production (Cole LA, Int J Endocrinol Metab 9(2):335-352, 2011). The function, the mechanism of action and the interaction between hCG and its receptor continue to be the subject of intensive investigation, even though many issues about hCG have been well documented (Tegoni M et al., J Mol Biol 289(5):1375-1385, 1999). PMID- 26530367 TI - Biomarkers for Hepatocellular Carcinoma (HCC): An Update. AB - The past decades have witnessed increased use of biomarkers in disease management. A biomarker is any characteristic that can be objectively measured and evaluated as an indicator of normal biological process, pathogenic process, or pharmacological response to a therapeutic intervention. The clinical measurements of biomarkers can be carried out in vivo using imaging modalities like ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI), as well as in vitro utilizing serum or plasma or other body fluids as specimens. In contrast to the imaging modalities, a prominent value of serum biomarkers is that they could be biologically relevant and disease-specific to pathophysiologic or pathologic process of disease development. This article provides an update of serum biomarkers for hepatocellular carcinoma (HCC) in risk assessment for early detection through surveillance. PMID- 26530368 TI - Mucins and Cytokeratins as Serum Tumor Markers in Breast Cancer. AB - Structural and functional characteristics of mucins and cytokeratins are shortly described. Thereafter, those commonly used in breast cancer as serum tumor markers are considered. First CA15.3, MCA, CA549, CA27.29 mucins and CYFRA21.1, TPA, TPS cytokeratins alone or in association have been examined in different stages and conditions. Then their usefulness in monitoring disease-free breast cancer patients is evaluated. The central role of the established cut-off and critical change, the "early" treatment of recurrent disease and the potential benefit in survival are other issues that have been highlighted and discussed. The successive sections and subsections deal with the monitoring of advanced disease. In them, the current recommendations and the principal findings on using the above mentioned mucins and cytokeratins have been reported. A computer program for interpreting consecutive measurements of serum tumor markers also has been illustrated. The final part of the chapter is devoted to mucins and cytokeratins as markers of circulating and disseminated tumor cells and their usefulness for prognosis. PMID- 26530369 TI - The Role of CA 125 as Tumor Marker: Biochemical and Clinical Aspects. AB - CA 125 also known as mucin 16 or MUC16 is a large membrane glycoprotein belonging to the wide mucin family, encoded by the homonymous MUC16 gene. Following its discovery in the blood of some patients with specific types of cancers or other benign conditions, CA125 has found application as a tumor marker of ovarian cancer. Thirty years after its discovery, use of CA 125 is still FDA-recommended to monitor response to therapy in patients with epithelial ovarian cancer and to detect residual or recurrent disease in patients who have undergone first-line therapy and would be considered for second-look procedures. However, due to its limited specificity and sensitivity, CA 125 alone cannot still be an ideal biomarker. Increased clinical performance, in terms of better sensitivity and specificity in identifying epithelial ovarian cancer relapse, has been obtained by combined use of CA 125 with HE4, another ovarian cancer marker recently introduced in clinical use. Significant advancements have been achieved more recently, due to the introduction of FDA-approved ROMA and OVA1 algorithms to evaluate the risk of ovarian cancer for patients with a pelvic mass. PMID- 26530370 TI - CA 19-9: Biochemical and Clinical Aspects. AB - CA19-9 (carbohydrate antigen 19-9, also called cancer antigen 19-9 or sialylated Lewis a antigen) is the most commonly used and best validated serum tumor marker for pancreatic cancer diagnosis in symptomatic patients and for monitoring therapy in patients with pancreatic adenocarcinoma. Normally synthesized by normal human pancreatic and biliary ductal cells and by gastric, colon, endometrial and salivary epithelia, CA 19-9 is present in small amounts in serum, and can be over expressed in several benign gastrointestinal disorders. Importantly, it exhibits a dramatic increase in its plasmatic levels during neoplastic disease. However, several critical aspects for its clinical use, such as false negative results in subjects with Lewis (a-b-) genotype and false positive elevation, occasional and transient, in patients with benign diseases, together with its poor positive predictive value (72.3 %), do not make it a good cancer-specific marker and renders it impotent as a screening tool. In the last years a large number of putative biomarkers for pancreatic cancer have been proposed, most of which is lacking of large scale validation. In addition, none of these has showed to possess the requisite sensitivity/specificity to be introduced in clinical use. Therefore, although with important limitations we well-know, CA 19-9 continues being the only pancreatic cancer marker actually in clinical use. PMID- 26530371 TI - Non Coding RNA Molecules as Potential Biomarkers in Breast Cancer. AB - The pursuit of minimally invasive biomarkers is a challenging but exciting area of research. Clearly, such markers would need to be sensitive and specific enough to aid in the detection of breast cancer at an early stage, would monitor progression of the disease, and could predict the individual patient's response to treatment. Unfortunately, to date, markers with such characteristics have not made it to the clinic for breast cancer. Past years, many studies indicated that the non-coding part of our genome (the so called 'junk' DNA), may be an ideal source for these biomarkers. In this chapter, the potential use of microRNAs and long non-coding RNAs as biomarkers will be discussed. PMID- 26530372 TI - Urinary Prostate Cancer Antigen 3 as a Tumour Marker: Biochemical and Clinical Aspects. AB - Due to low specificity of Prostate-Specific Antigen (PSA) we face a certain risk of overdiagnosis and overtreatment of Prostate Cancer (PCa). The benefits and harms of PSA-screening are controversially discussed. To overcome this weakness of PSA novel PCa biomarkers and detection tools are required.The urine-based biomarker Prostate Cancer Antigen 3 (PCA3) has been shown to be highly PCa specific. Application of PCA3 was tested in the diagnostic setting and staging. Several studies pointed out the additional value of PCA3 for further stratification of men selected for biopsy (BX) based on an elevated PSA and/or an abnormal digital rectal examination (DRE). Its combined use with established clinical risk factors for positive prostate BX, particularly within nomograms or risk calculators, may represent a valid and helpful aid for clinicians in patient counselling and BX indication confirmation.When it comes to prediction of favourable or unfavourable histopathological features, respectively, such as tumour volume or PCa significance, PCA3's value remains controversial. Based on relatively small patient numbers, PCA3 has been identified to independently predict small-volume and insignificant PCa. However, in other studies PCA3 was not associated with advanced disease and its ability of predicting PCa aggressiveness in men undergoing radical prostatectomy is limited.PCA3's value may be best given for BX outcome prediction. Finally, the implementation of the PCA3 promoter in developing new highly PCa-specific gene therapies represents a promising perspective in the near future. PMID- 26530373 TI - Biomarker in Cisplatin-Based Chemotherapy for Urinary Bladder Cancer. AB - The treatment of metastasized bladder cancer has been evolving during recent years. Cisplatin based chemotherapy combinations are still gold standard in the treatment of advanced and metastasized bladder cancer. But new therapies are approaching. Based to this fact biological markers will become more important for decisions in bladder cancer treatment. A systematic MEDLINE search of the key words "cisplatin", "bladder cancer", "DNA marker", "protein marker", "methylation biomarker", "predictive marker", "prognostic marker" has been made. This review aims to highlight the most relevant clinical and experimental studies investigating markers for metastasized transitional carcinoma of the urothelium treated by cisplatin based regimens. PMID- 26530374 TI - A Critical Approach to Clinical Biochemistry of Chromogranin A. AB - Chromogranin A (CGA) is a member of the granin family of proteins which are widespread in endocrine, neuroendocrine, peripheral, and central nervous tissues, where they are typically found in secretory granules. It is well accepted that CGA cooperates to regulate synthesis and secretion of these various granule signaling molecules.Because of its ubiquitous distribution within neuroendocrine tissues, CGA can be a useful diagnostic marker for neuroendocrine neoplasms, including carcinoids, pheochromocytomas, neuroblastomas, medullary thyroid carcinomas (MTC), some pituitary tumors, functioning and nonfunctioning islet cell tumors and other amine precursor uptake and decarboxylation (APUD) tumors. It is also useful as a prognostic marker for detection of recurrence and monitoring of response to different treatments. As other tumor markers, it is imperative to know its physiology and pathophysiology, its sensitivity and specificity in different neuroendocrine tumors (NETs), and carefully integrate these data with the clinical data of the single patient, to maximize its diagnostic/prognostic index. PMID- 26530375 TI - The Actual Role of Receptors as Cancer Markers, Biochemical and Clinical Aspects: Receptors in Breast Cancer. AB - A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. The discovery and development of proper biomarkers is a critical part of modern oncology. Among the many different types of biomarkers, cell receptors have demonstrated important roles as diagnostic, prognostic, and predictive biomarkers in cancer research and therapy, leading to their integration into drug development trials. In breast cancer, Estrogen/Progesterone receptors and HER2/neu receptors are two good examples of biomarkers that are prognostic of outcomes, as well as predictive of response to certain therapies. Limitations exist, however, such as the invasive procedures required obtaining tissue, and the difficulty measuring the actual distribution of the receptors. Thus, continued efforts to develop receptors as comprehensive cancer biomarkers with novel approaches is mandated to further advance the modern oncology. PMID- 26530377 TI - Insertion and isomerisation of internal olefins at alkylaluminium hydride: catalysis with zirconocene dichloride. AB - The insertion of internal olefins (hydroalumination) and chain walking isomerisation at di-n-octylaluminium hydride [Al(Oct)2H], promoted by zirconocene dichloride [Cp2ZrCl2] has been studied. The reaction between [Cp2ZrCl2] and [Al(Oct)2H] in non-polar solvents leads to clusters containing bridging hydride ligands between Zr and Al. This system promotes hydroalumination of 1-octene but is largely ineffective for internal octenes (2-, 3-, 4-octene). In tetrahydrofuran the Zr-Al hydride clusters formed are more reactive and catalyse insertion and isomerisation of internal olefins to primary metal-alkyls, although this is accompanied by catalyst deactivation. Elimination and removal of 1-octene from the system post insertion/isomerisation was attempted, but it was found that the presence of the Zr catalyst leads to back-isomerisation to internal octenes, along with further decomposition with n-octane formation. Some possible pathways of catalyst decomposition, involving reduction of Zr and alkane elimination, have been studied theoretically. PMID- 26530376 TI - The Role of CTCs as Tumor Biomarkers. AB - Detection of Circulating Tumor Cells (CTCs) in peripheral blood can serve as a "liquid biopsy" approach and as a source of valuable tumor markers. CTCs are rare, and thus their detection, enumeration and molecular characterization are very challenging. CTCs have the unique characteristic to be non-invasively isolated from blood and used to follow patients over time, since these cells can provide significant information for better understanding tumour biology and tumour cell dissemination. CTCs molecular characterization offers the unique potential to understand better the biology of metastasis and resistance to established therapies and their analysis presents nowadays a promising field for both advanced and early stage patients. In this chapter we focus on the latest findings concerning the clinical relevance of CTC detection and enumeration, and discuss their potential as tumor biomarkers in various types of solid cancers. We also highlight the importance of performing comparison studies between these different methodologies and external quality control systems for establishing CTCs as tumor biomarkers in the routine clinical setting. PMID- 26530378 TI - Electrodeposition in Ionic Liquids. AB - Due to their attractive physico-chemical properties, ionic liquids (ILs) are increasingly used as deposition electrolytes. This review summarizes recent advances in electrodeposition in ILs and focuses on its similarities and differences with that in aqueous solutions. The electrodeposition in ILs is divided into direct and template-assisted deposition. We detail the direct deposition of metals, alloys and semiconductors in five types of ILs, including halometallate ILs, air- and water-stable ILs, deep eutectic solvents (DESs), ILs with metal-containing cations, and protic ILs. Template-assisted deposition of nanostructures and macroporous structures in ILs is also presented. The effects of modulating factors such as deposition conditions (current density, current density mode, deposition time, temperature) and electrolyte components (cation, anion, metal salts, additives, water content) on the morphology, compositions, microstructures and properties of the prepared materials are highlighted. PMID- 26530379 TI - Facilitators and barriers to social and community participation following spinal cord injury. AB - BACKGROUND/AIM: One of the factors known to contribute to a 'good life' following an acquired disability is making connections with others, often achieved through participation in activities outside the home. The majority of outcomes research following SCI has focussed on impairments and activity limitations with less emphasis on participation. This paper reports part of a larger study that explored the experience and meaning of social and community participation following SCI. The research question guiding the part of the study reported in this paper was: What are the facilitators and barriers to social and community participation following acquired SCI? METHODS: Semi-structured interviews were conducted with 17 adults with traumatically acquired spinal cord injury living in the community. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis. RESULTS: Three main themes and 11 subthemes were identified. The main themes were: Resources and environmental accessibility impact social participation; other people influence community engagement; health issues affect social participation. Adequate financial resources and social support (from friends and family, and from peer mentors) were found to assist social participation, while the physical environment, unsupportive social attitudes and mental health issues were identified as barriers to community participation. CONCLUSIONS: This study contributes to the evidence base regarding outcomes following SCI. Enabling engagement in meaningful activities in the community must be at the forefront of occupational therapy intervention, both at an individual client level and through advocacy and policy involvement, to improve the quality of life of people with SCI living in the community. PMID- 26530380 TI - Trends in rates of acetaminophen-related adverse events in the United States. AB - PURPOSE: The goal of this study is to summarize trends in rates of adverse events attributable to acetaminophen use, including hepatotoxicity and mortality. METHODS: A comprehensive analysis of data from three national surveillance systems estimated rates of acetaminophen-related events identified in different settings, including calls to poison centers (2008-2012), emergency department visits (2004-2012), and inpatient hospitalizations (1998-2011). Rates of acetaminophen-related events were calculated per setting, census population, and distributed drug units. RESULTS: Rates of poison center calls with acetaminophen related exposures decreased from 49.5/1000 calls in 2009 to 43.5/1000 calls in 2012. Rates of emergency department visits for unintentional acetaminophen related adverse events decreased from 58.0/1000 emergency department visits for adverse drug events in 2009 to 50.2/1000 emergency department visits in 2012. Rates of hospital inpatient discharges with acetaminophen-related poisoning decreased from 119.8/100 000 hospitalizations in 2009 to 108.6/100 000 hospitalizations in 2011. After 2009, population rates of acetaminophen-related events per 1 million census population decreased for poison center calls and hospitalizations, while emergency department visit rates remained stable. However, when accounting for drug sales, the rate of acetaminophen-related events (per 1 million distributed drug units) increased after 2009. Prior to 2009, the rates of acetaminophen-related hospitalizations had been slowly increasing (p trend = 0.001). CONCLUSIONS: Acetaminophen-related adverse events continue to be a public health burden. Future studies with additional time points are necessary to confirm trends and determine whether recent risk mitigation efforts had a beneficial impact on acetaminophen-related adverse events. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26530381 TI - The Consequences of Replicating in the Wrong Orientation: Bacterial Chromosome Duplication without an Active Replication Origin. AB - Chromosome replication is regulated in all organisms at the assembly stage of the replication machinery at specific origins. In Escherichia coli, the DnaA initiator protein regulates the assembly of replication forks at oriC. This regulation can be undermined by defects in nucleic acid metabolism. In cells lacking RNase HI, replication initiates independently of DnaA and oriC, presumably at persisting R-loops. A similar mechanism was assumed for origin independent synthesis in cells lacking RecG. However, recently we suggested that this synthesis initiates at intermediates resulting from replication fork fusions. Here we present data suggesting that in cells lacking RecG or RNase HI, origin-independent synthesis arises by different mechanisms, indicative of these two proteins having different roles in vivo. Our data support the idea that RNase HI processes R-loops, while RecG is required to process replication fork fusion intermediates. However, regardless of how origin-independent synthesis is initiated, a fraction of forks will proceed in an orientation opposite to normal. We show that the resulting head-on encounters with transcription threaten cell viability, especially if taking place in highly transcribed areas. Thus, despite their different functions, RecG and RNase HI are both important factors for maintaining replication control and orientation. Their absence causes severe replication problems, highlighting the advantages of the normal chromosome arrangement, which exploits a single origin to control the number of forks and their orientation relative to transcription, and a defined termination area to contain fork fusions. Any changes to this arrangement endanger cell cycle control, chromosome dynamics, and, ultimately, cell viability. IMPORTANCE: Cell division requires unwinding of millions of DNA base pairs to generate the template for RNA transcripts as well as chromosome replication. As both processes use the same template, frequent clashes are unavoidable. To minimize the impact of these clashes, transcription and replication in bacteria follow the same directionality, thereby avoiding head-on collisions. This codirectionality is maintained by a strict regulation of where replication is started. We have used Escherichia coli as a model to investigate cells in which the defined location of replication initiation is compromised. In cells lacking either RNase HI or RecG, replication initiates away from the defined replication origin, and we discuss the different mechanisms by which this synthesis arises. In addition, the resulting forks proceed in a direction opposite to normal, thereby inducing head on collisions between transcription and replication, and we show that the resulting consequences are severe enough to threaten the viability of cells. PMID- 26530382 TI - Rhesus Macaque B-Cell Responses to an HIV-1 Trimer Vaccine Revealed by Unbiased Longitudinal Repertoire Analysis. AB - Next-generation sequencing (NGS) has been used to investigate the diversity and maturation of broadly neutralizing antibodies (bNAbs) in HIV-1-infected individuals. However, the application of NGS to the preclinical assessment of human vaccines, particularly the monitoring of vaccine-induced B-cell responses in a nonhuman primate (NHP) model, has not been reported. Here, we present a longitudinal NGS analysis of memory B-cell responses to an HIV-1 trimer vaccine in a macaque that has been extensively studied by single B-cell sorting and antibody characterization. We first established an NHP antibodyomics pipeline using the available 454 pyrosequencing data from this macaque and developed a protocol to sequence the NHP antibody repertoire in an unbiased manner. Using these methods, we then analyzed memory B-cell repertoires at four time points of NHP immunization and traced the lineages of seven CD4-binding site (CD4bs) directed monoclonal antibodies previously isolated from this macaque. Longitudinal analysis revealed distinct patterns of B-cell lineage development in response to an HIV-1 trimer vaccine. While the temporal B-cell repertoire profiles and lineage patterns provide a baseline for comparison with forthcoming HIV-1 trimer vaccines, the newly developed NHP antibody NGS technologies and antibodyomics tools will facilitate future evaluation of human vaccine candidates. IMPORTANCE: The nonhuman primate model has been widely used in the preclinical assessment of human vaccines. Next-generation sequencing of B-cell repertoires provides a quantitative tool to analyze B-cell responses to a vaccine. In this study, the longitudinal B-cell repertoire analysis of a rhesus macaque immunized with an HIV-1 trimer vaccine revealed complex B-cell lineage patterns and showed the potential to facilitate the evaluation of future HIV-1 vaccines. The repertoire sequencing technologies and antibodyomics methods reported here can be extended to vaccine development for other human pathogens utilizing the nonhuman primate model. PMID- 26530383 TI - Silica Gel for Enhanced Activity and Hypochlorite Protection of Cyanuric Acid Hydrolase in Recombinant Escherichia coli. AB - Chlorinated isocyanuric acids are widely used water disinfectants that generate hypochlorite, but with repeated application, they build up cyanuric acid (CYA) that must be removed to maintain disinfection. 3-Aminopropyltriethoxysilane (APTES)-treated Escherichia coli cells expressing cyanuric acid hydrolase (CAH) from Moorella thermoacetica exhibited significantly high CYA degradation rates and provided protection against enzyme inactivation by hypochlorite (chlorine). APTES coating or encapsulation of cells had two benefits: (i) overcoming diffusion limitations imposed by the cell wall and (ii) protecting against hypochlorite inactivation of CAH activity. Cells encapsulated in APTES gels degraded CYA three times faster than nonfunctionalized tetraethoxysilane (TEOS) gels, and cells coated with APTES degraded CYA at a rate of 29 umol/min per mg of CAH protein, similar to the rate with purified enzyme. UV spectroscopy, fluorescence spectroscopy, and scanning electron microscopy showed that the higher rates were due to APTES increasing membrane permeability and enhancing cyanuric acid diffusion into the cytoplasm to reach the CAH enzyme. Purified CAH enzyme was shown to be rapidly inactivated by hypochlorite. APTES aggregates surrounding cells protected via the amine groups reacting with hypochlorite as shown by pH changes, zeta potential measurements, and infrared spectroscopy. APTES-encapsulated E. coli cells expressing CAH degraded cyanuric acid at high rates in the presence of 1 to 10 ppm hypochlorite, showing effectiveness under swimming pool conditions. In contrast, CAH activity in TEOS gels or free cells was completely inactivated by hypochlorite. These studies show that commercially available silica materials can selectively enhance, protect, and immobilize whole cell biocatalysts for specialized applications. IMPORTANCE: Hypochlorite is used in vast quantities for water disinfection, killing bacteria on surfaces, and washing and whitening. In pools, spas, and other waters, hypochlorite is frequently delivered as chlorinated isocyanuric acids that release hypochlorite and cyanuric acid. Over time, cyanuric acid accumulates and impairs disinfection and must be removed. The microbial enzyme cyanuric acid hydrolase can potentially remove cyanuric acid to restore disinfection and protect swimmers. Whole bacterial cells expressing cyanuric acid hydrolase were encapsulated in an inert silica matrix containing an amine group. The amine group serves to permeabilize the cell membrane and accelerate cyanuric acid degradation, and it also reacts with hypochlorite to protect against inactivation of cyanuric acid hydrolase. Methods for promoting whole-cell biocatalysis are important in biotechnology, and the present work illustrates approaches to enhance rates and protect against an inhibitory substance. PMID- 26530384 TI - EtpE Binding to DNase X Induces Ehrlichial Entry via CD147 and hnRNP-K Recruitment, Followed by Mobilization of N-WASP and Actin. AB - Obligate intracellular bacteria, such as Ehrlichia chaffeensis, perish unless they can enter eukaryotic cells. E. chaffeensis is the etiological agent of human monocytic ehrlichiosis, an emerging infectious disease. To infect cells, Ehrlichia uses the C terminus of the outer membrane invasin entry-triggering protein (EtpE) of Ehrlichia (EtpE-C), which directly binds the mammalian cell surface glycosylphosphatidyl inositol-anchored protein, DNase X. How this binding drives Ehrlichia entry is unknown. Here, using affinity pulldown of host cell lysates with recombinant EtpE-C (rEtpE-C), we identified two new human proteins that interact with EtpE-C: CD147 and heterogeneous nuclear ribonucleoprotein K (hnRNP-K). The interaction of CD147 with rEtpE-C was validated by far-Western blotting and coimmunoprecipitation of native EtpE with endogenous CD147. CD147 was ubiquitous on the cell surface and also present around foci of rEtpE-C-coated bead entry. Functional neutralization of surface-exposed CD147 with a specific antibody inhibited Ehrlichia internalization and infection but not binding. Downregulation of CD147 by short hairpin RNA (shRNA) impaired E. chaffeensis infection. Functional ablation of cytoplasmic hnRNP-K by a nanoscale intracellular antibody markedly attenuated bacterial entry and infection but not binding. EtpE-C also interacted with neuronal Wiskott-Aldrich syndrome protein (N WASP), which is activated by hnRNP-K. Wiskostatin, which inhibits N-WASP activation, and cytochalasin D, which inhibits actin polymerization, inhibited Ehrlichia entry. Upon incubation with host cell lysate, EtpE-C but not an EtpE N terminal fragment stimulated in vitro actin polymerization in an N-WASP- and DNase X-dependent manner. Time-lapse video images revealed N-WASP recruitment at EtpE-C-coated bead entry foci. Thus, EtpE-C binding to DNase X drives Ehrlichia entry by engaging CD147 and hnRNP-K and activating N-WASP-dependent actin polymerization. IMPORTANCE: Ehrlichia chaffeensis, an obligate intracellular bacterium, causes a blood-borne disease called human monocytic ehrlichiosis, one of the most prevalent life-threatening emerging tick-transmitted infectious diseases in the United States. The survival of Ehrlichia bacteria, and hence, their ability to cause disease, depends on their specific mode of entry into eukaryotic host cells. Understanding the mechanism by which E. chaffeensis enters cells will create new opportunities for developing effective therapies to prevent bacterial entry and disease in humans. Our findings reveal a novel cellular signaling pathway triggered by an ehrlichial surface protein called EtpE to induce its infectious entry. The results are also important from the viewpoint of human cell physiology because three EtpE-interacting human proteins, DNase X, CD147, and hnRNP-K, are hitherto unknown partners that drive the uptake of small particles, including bacteria, into human cells. PMID- 26530385 TI - Genotypic Differences in Dengue Virus Neutralization Are Explained by a Single Amino Acid Mutation That Modulates Virus Breathing. AB - Flaviviruses sample an ensemble of virion conformations resulting from the conformational flexibility of their structural proteins. To investigate how sequence variation among strains impacts virus breathing, we performed studies with the monoclonal antibody (MAb) E111, which binds an inaccessible domain III envelope (E) protein epitope of dengue virus serotype 1 (DENV1). Prior studies indicated that an observed ~200-fold difference in neutralization between the DENV1 strains Western Pacific-74 (West Pac-74) and 16007 could not be explained by differences in the affinity of MAb E111 for each strain. Through neutralization studies with wild-type and variant viruses carrying genes encoding reciprocal mutations at all 13 amino acid differences between the E proteins of West Pac-74 and 16007, we found that E111 neutralization susceptibility mapped solely to the presence of a lysine or arginine at E domain II residue 204, located distally from the E111 epitope. This same residue correlated with neutralization differences observed for MAbs specific for epitopes distinct from E111, suggesting that this amino acid dictates changes in the conformational ensembles sampled by the virus. Furthermore, an observed twofold difference in the stability of infectious West Pac-74 versus 16007 in solution also mapped to E residue 204. Our results demonstrate that neutralization susceptibility can be altered in an epitope-independent manner by natural strain variation that influences the structures sampled by DENV. That different conformational ensembles of flaviviruses may affect the landscape available for antibody binding, as well as virus stability, has important implications for functional studies of antibody potency, a critical aspect of vaccine development. IMPORTANCE: The global burden of dengue virus (DENV) is growing, with recent estimates of ~390 million human infections each year. Antibodies play a crucial role in protection from DENV infection, and vaccines that elicit a robust antibody response are being actively pursued. We report here the identification of a single amino acid residue in the envelope protein of DENV serotype 1 that results in global changes to virus structure and stability when it is changed. Our results indicate that naturally occurring variation at this particular site among virus strains impacts the ensemble of structures sampled by the virus, a process referred to as virus breathing. The finding that such limited and conservative sequence changes can modulate the landscape available for antibody binding has important implications for both vaccine development and the study of DENV-reactive antibodies. PMID- 26530387 TI - Proteomics: Strength in numbers. PMID- 26530386 TI - Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy. AB - Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regimens were simulated in the in vitro hollow-fiber infection model (HFIM) system to identify the linezolid therapies that minimize toxicity, maximize antibacterial activity, and prevent drug resistance. Linezolid inhibited mitochondrial proteins in an exposure-dependent manner, with toxicity being driven by trough concentrations. Once-daily linezolid killed M. tuberculosis in an exposure-dependent manner. Further, 300 mg linezolid given every 12 hours generated more bacterial kill but more toxicity than 600 mg linezolid given once daily. None of the regimens prevented linezolid resistance. These findings show that with linezolid monotherapy, a clear tradeoff exists between antibacterial activity and toxicity. By identifying the pharmacokinetic parameters linked with toxicity and antibacterial activity, these data can provide guidance for clinical trials evaluating linezolid in multidrug antituberculosis regimens. IMPORTANCE: The emergence and spread of multidrug-resistant M. tuberculosis are a major threat to global public health. Linezolid is an oxazolidinone that is licensed for human use and has demonstrated potent activity against multidrug-resistant M. tuberculosis. However, long-term use of linezolid has shown to be toxic in patients, often resulting in thrombocytopenia. We examined therapeutic linezolid regimens in an in vitro model to characterize the exposure-toxicity relationship. The antibacterial activity against M. tuberculosis was also assessed for these regimens, including the amplification or suppression of resistant mutant subpopulations by the chosen regimen. Higher exposures of linezolid resulted in greater antibacterial activity, but with more toxicity and, for some regimens, increased resistant mutant subpopulation amplification, illustrating the trade off between activity and toxicity. These findings can provide valuable insight for designing optimal dosage regimens for linezolid that are part of the long combination courses used to treat multidrug-resistant M. tuberculosis. PMID- 26530388 TI - Cell signalling: How mTORC1 senses leucine. PMID- 26530389 TI - Autophagy: Nuclear autophagy in tumour suppression. PMID- 26530391 TI - Cell division: Hippo regulates cell division. PMID- 26530392 TI - DNA damage response: H1--a linker of ubiquitylation and repair. PMID- 26530390 TI - The expanding world of small RNAs in plants. AB - Plant genomes encode various small RNAs that function in distinct, yet overlapping, genetic and epigenetic silencing pathways. However, the abundance and diversity of small-RNA classes varies among plant species, suggesting coevolution between environmental adaptations and gene-silencing mechanisms. Biogenesis of small RNAs in plants is well understood, but we are just beginning to uncover their intricate regulation and activity. Here, we discuss the biogenesis of plant small RNAs, such as microRNAs, secondary siRNAs and heterochromatic siRNAs, and their diverse cellular and developmental functions, including in reproductive transitions, genomic imprinting and paramutation. We also discuss the diversification of small-RNA-directed silencing pathways through the expansion of RNA-dependent RNA polymerases, DICER proteins and ARGONAUTE proteins. PMID- 26530394 TI - Posttraumatic intra-articular heterotopic ossification of the shoulder joint in a 15-month-old boy. AB - Heterotopic ossification (HO) can result from a single severe injury, repeated microtrauma, central nervous system injury, extensive burns, or muscular bleeding due to hemophilia. Although relatively rare in childhood and extremely rare within a joint, HO should be included in the differential diagnosis of an intra articular mass when indicated by clinical, radiographic, and histologic findings. Here, we report a posttraumatic intra-articular HO of the shoulder joint in a 15 month-old boy without underlying hematologic disease. Intra-articular HO in a healthy infant has not been reported previously in the published literature. Because of the unusual presentation and location in a patient of such young age, tumorigenic conditions were considered in the differential diagnosis. PMID- 26530393 TI - Benign and malignant tumors of the foot and ankle. AB - Pain and focal masses in the foot and ankle are frequently encountered and often initiate a workup including imaging. It is important to differentiate benign lesions from aggressive benign or malignant lesions. In this review, multiple examples of osseous and soft tissue tumors of the foot and ankle will be presented. Additionally, the compartmental anatomy of the foot and ankle will be discussed in terms of its relevance for percutaneous biopsy planning and eventual surgery. Finally, a general overview of the surgical management of benign, benign aggressive and malignant tumors of the foot and ankle will be discussed. PMID- 26530395 TI - Aberrant topological patterns of brain structural network in temporal lobe epilepsy. AB - OBJECTIVE: Although altered large-scale brain network organization in patients with temporal lobe epilepsy (TLE) has been shown using morphologic measurements such as cortical thickness, these studies, have not included critical subcortical structures (such as hippocampus and amygdala) and have had relatively small sample sizes. Here, we investigated differences in topological organization of the brain volumetric networks between patients with right TLE (RTLE) and left TLE (LTLE) with unilateral hippocampal atrophy. METHODS: We performed a cross sectional analysis of 86 LTLE patients, 70 RTLE patients, and 116 controls. RTLE and LTLE groups were balanced for gender (p = 0.64), seizure frequency (Mann Whitney U test, p = 0.94), age (p = 0.39), age of seizure onset (p = 0.21), and duration of disease (p = 0.69). Brain networks were constructed by thresholding correlation matrices of volumes from 80 cortical/subcortical regions (parcellated with Freesurfer v5.3 https://surfer.nmr.mgh.harvard.edu/) that were then analyzed using graph theoretical approaches. RESULTS: We identified reduced cortical/subcortical connectivity including bilateral hippocampus in both TLE groups, with the most significant interregional correlation increases occurring within the limbic system in LTLE and contralateral hemisphere in RTLE. Both TLE groups demonstrated less optimal topological organization, with decreased global efficiency and increased local efficiency and clustering coefficient. LTLE also displayed a more pronounced network disruption. Contrary to controls, hub nodes in both TLE groups were not distributed across whole brain, but rather found primarily in the paralimbic/limbic and temporal association cortices. Regions with increased centrality were concentrated in occipital lobes for LTLE and contralateral limbic/temporal areas for RTLE. SIGNIFICANCE: These findings provide first evidence of altered topological organization of the whole brain volumetric network in TLE, with disruption of the coordinated patterns of cortical/subcortical morphology. PMID- 26530397 TI - Carrie MacEwen: Champions vision and visibility. PMID- 26530396 TI - Astrocyte-Dependent Vulnerability to Excitotoxicity in Spermine Oxidase Overexpressing Mouse. AB - Transgenic mice overexpressing spermine oxidase (SMO) in the cerebral cortex (Dach-SMO mice) showed increased vulnerability to excitotoxic brain injury and kainate-induced epileptic seizures. To investigate the mechanisms by which SMO overexpression leads to increased susceptibility to kainate excitotoxicity and seizure, in the cerebral cortex of Dach-SMO and control mice we assessed markers for astrocyte proliferation and neuron loss, and the ability of kainate to evoke glutamate release from nerve terminals and astrocyte processes. Moreover, we assessed a possible role of astrocytes in an in vitro model of epileptic-like activity in combined cortico-hippocampal slices recorded with a multi-electrode array device. In parallel, as the brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant mechanisms, we analyzed the oxidative status of the cerebral cortex of both SMO-overexpressing and control mice by evaluating enzymatic and non-enzymatic scavengers such as metallothioneins. The main findings in the cerebral cortex of Dach-SMO mice as compared to controls are the following: astrocyte activation and neuron loss; increased oxidative stress and activation of defense mechanisms involving both neurons and astrocytes; increased susceptibility to kainate-evoked cortical epileptogenic activity, dependent on astrocyte function; appearance of a glutamate-releasing response to kainate from astrocyte processes due to activation of Ca(2+)-permeable AMPA receptors in Dach-SMO mice. We conclude that reactive astrocytosis and activation of glutamate release from astrocyte processes might contribute, together with increased reactive oxygen species production, to the vulnerability to kainate excitotoxicity in Dach-SMO mice. This mouse model with a deregulated polyamine metabolism would shed light on roles for astrocytes in increasing vulnerability to excitotoxic neuron injury. PMID- 26530398 TI - Bilateral cataracts in a 6-yr-old with new onset diabetes: a novel presentation of a known INS gene mutation. AB - The prevalence of diabetes-related cataracts during childhood is less than 1%. When cataracts occur, it is often in adolescent females with prolonged symptoms and significant hyperglycemia. Cataracts are not a classic feature of monogenic diabetes. We report a case of a 6-yr-old, previously healthy Caucasian male, who presented with bilateral acquired cataracts and was subsequently diagnosed with new onset diabetes. Additional symptoms at presentation included a several year history of polyuria and polydipsia, mild hepatomegaly, and short stature. Pertinent negatives include acanthosis nigricans, lipoatrophy, deafness, muscle weakness, or neuropathy. HbA1c was significantly elevated at diagnosis (>14%, 129.5 mmol/mol) without evidence of ketosis. Autoantibody testing was negative. Features of Mauriac syndrome (short stature, hepatomegaly) as well as acquired cataracts indicated long-standing hyperglycemia with sufficient insulin production to prevent ketone production and development of diabetic ketoacidosis. Whole exome sequencing was conducted and a de novo heterozygous mutation in the INS gene (c.94G>A; p.Gly32Ser) was identified. INS gene mutations are common causes of permanent neonatal diabetes but rare causes of antibody-negative diabetes in children. Importantly, INS gene mutations have not been previously associated with acquired cataracts. Knowledge of a monogenic cause of diabetes allows clinicians to tailor counseling and screening of diabetes-related comorbidities. In summary, this case highlights the need to consider testing for monogenic diabetes, specifically INS gene mutations, in pediatric patients with antibody-negative diabetes, especially if complications of prolonged hyperglycemia are present at diagnosis. PMID- 26530400 TI - CTAB enhancement of FRET in DNA structures. AB - The effect of cetyl-trimethylammonium bromide (CTAB) on enhancing the fluorescence resonance energy transfer (FRET) between two dye-conjugated DNA strands was studied using fluorescence emission spectroscopy and dynamic light scattering (DLS). For hybridized DNA where one strand is conjugated with a TAMRA donor and the other with a TexasRed acceptor, increasing the concentration of CTAB changes the fluorescence emission properties and improves the FRET transfer efficiency through changes in the polarity of the solvent, neutralization of the DNA backbone and micelle formation. For the DNA FRET system without CTAB, the DNA hybridization leads to contact quenching between TAMRA donor and TexasRed acceptor producing reduced donor emission and only a small increase in acceptor emission. At 50 uM CTAB, however, the sheathing and neutralization of the dye conjugated dsDNA structure significantly reduces quenching by DNA bases and dye interactions, producing a large increase in FRET efficiency, which is almost four fold higher than without CTAB. PMID- 26530399 TI - [Perioperative risk and mortality after major surgery]. AB - Although anesthesia-associated mortality has been significantly reduced down to 0.00068-0.00082% over the last decades, recent studies have revealed a high perioperative mortality of 0.8- 4%. Apart from anesthesia and surgery-induced major complications, perioperative mortality is primarily negatively influenced by individual patient comorbidities. These risk factors predispose for acute critical incidents (e.g., myocardial infarction); however, the majority of fatal complications are a result of slowly progressing conditions, particularly infections or the sequelae of systemic inflammation. This implicates a broad window of opportunity for the detection and treatment of slow-onset complications to improve the perioperative outcome. The term "failure to rescue" (FTR), i.e., the proportion of patients who die from major complications compared to the number of all patients with complications, has been introduced as a valid indicator for the quality of perioperative care. Growing evidence has already shown that FTR is an underestimated factor in perioperative medicine accounting for or at least being involved in the development of postoperative mortality. While the incidence of severe postoperative complications amazingly does not show much variation between hospitals, FTR shows significant differences implying a major potential for improvement. With 14 million surgical procedures per year in Germany, a postoperative mortality of approximately 1% and an avoidable FTR rate of 40% mean that there are an estimated 60,000 preventable deaths per year. Hence, in the future it will be imperative to (1) identify patients at risk, (2) to prevent the development of postoperative complications with the use of adequate adjunctive therapeutic strategies, (3) to establish surveillance and monitoring systems for the early detection of postoperative complications and (4) to treat postoperative complications efficiently and in time when they arise. PMID- 26530401 TI - Pharmacokinetic interaction study between flavanones (hesperetin, naringenin) and rasagiline mesylate in wistar rats. AB - Cytochrome P-450 (CYP) enzymes and P-glycoprotein (P-gp) play an important role in the oral bioavailability and first-pass-metabolism (FPM) of many drugs. Rasagiline is a selective, monoamine oxidase-B inhibitor and it undergoes significant FPM in the liver prior to excretion by CYP1A2. Hesperetin and naringenin are naturally occurring flavanones and are reported as modulators of CYP enzymes and P-gp. The objective of the present investigation was to evaluate the effect of hesperetin and naringenin on the pharmacokinetics (PK) of rasagiline in rats. Rats were treated orally with rasagiline (2 mg/kg) alone and co-administered with hesperetin and naringenin (12.5 and 25 mg/kg) for 15 consecutive days. Blood samples were collected from tail vein on the 1st day in a single dose PK study (SDS) and on 15th day in the multiple dose PK study (MDS). Hesperetin and naringenin co-administration significantly enhanced the area under the curve (AUC), maximum plasma concentration (Cmax) and elimination half life (t1/2) of rasagiline with a concomitant reduction in clearance (CL/F) in both SDS and MDS. Rasagiline concentrations were significantly increased when co administered with hesperetin and naringenin in the brain. No significant difference was found in rasagiline transport from mucosal to serosal side in the presence of hesperetin and naringenin ex vivo (rat everted gut sacs used). Our findings suggested that hesperetin and naringenin enhanced the systemic exposure of rasagiline might be through the inhibition of CYP1A2 but not P-gp. Further studies are needed on CYP1A2 and P-gp over expressed cells to confirm this interaction at cellular level. PMID- 26530402 TI - Unusual localization of Mongolian spot in a Caucasian infant. PMID- 26530403 TI - Association between HER2 status in gastric cancer and clinicopathological features: a retrospective study using whole-tissue sections. AB - BACKGROUND: Gastric cancer is usually diagnosed in an advanced stage of disease and treatment options are sparse. Trastuzumab was recently approved for metastatic or locally advanced carcinomas arising in the stomach or in the gastroesophageal junction in patients with HER2-positive tumors. However, data on the frequency of HER2-positive cases among Brazilian patients are limited. Our aim was to characterize HER2 protein and gene status in a series of Brazilian patients with gastric cancer and to evaluate its association with clinicopathological data. METHODS: Histological slides from 124 primary gastrectomies were reviewed and their pathological reports were retrieved from the files at a Brazilian university hospital. Automated immunohistochemistry for HER2 was performed on whole-tissue sections from each tumor. HER2-equivocal cases by immunohistochemistry were submitted to automated dual in situ hybridization for gene amplification evaluation. HER2 status was confronted with clinicopathological parameters in order to assess statistically significant associations. RESULTS: Immunohistochemistry analysis revealed that 13/124 cases (10.5 %) were HER2 positive (3+), 10/124 cases (8.1 %) were equivocal (2+) and 101/124 cases (81.4 %) were negative, being 7 cases 1+. None of the equivocal cases showed gene amplification. The overall HER2 positivity rate was 10.5 %. There was an association between HER2 expression and Lauren's intestinal histological subtype (P = 0.048), well to moderately differentiated tumors (P = 0.004) and presence of lymphovascular invasion (P = 0.031). No association was found between HER2 status and tumor topography. CONCLUSIONS: Confronted with data published by other authors, the lower percentage of HER2-positive cases found in our series might be partially explained by the lower frequency of tumors arising at the gastroesophageal junction in comparison with distal gastric carcinomas in Brazilian patients. This could also account for the lack of statistically significant association between HER2 status and tumor topography in our study. PMID- 26530404 TI - Neurobiological features of binge eating disorder. AB - Biobehavioral features associated with binge-eating disorder (BED) have been investigated; however, few systematic reviews to date have described neuroimaging findings from studies of BED. Emerging functional and structural studies support BED as having unique and overlapping neural features as compared with other disorders. Neuroimaging studies provide evidence linking heightened responses to palatable food cues with prefrontal areas, particularly the orbitofrontal cortex (OFC), with specific relationships to hunger and reward-sensitivity measures. While few studies to date have investigated non-food-cue responses; these suggest a generalized hypofunctioning in frontostriatal areas during reward and inhibitory control processes. Early studies applying neuroimaging to treatment efforts suggest that targeting neural function underlying motivational processes may prove important in the treatment of BED. PMID- 26530405 TI - Detection of neuroendocrine tumors using promoter-specific secreted Gaussia luciferase. AB - Accurate detection of neuroendocrine (NE) tumors is critically important for better prognosis and treatment outcomes in patients. To demonstrate the efficacy of using an adenoviral vector for the detection of NE tumors, we have constructed a pair of adenoviral vectors which, in combination, can conditionally replicate and release Gaussia luciferase into the circulation after infecting the NE tumors. The expression of these two vectors is regulated upstream by an INSM1 promoter (insulinoma-associated-1) that is specifically active in NE tumors and developing NE tissues, but silenced in normal adult tissues. In order to retain the tumor-specificity of the INSM1 promoter, we have modified the promoter using the core insulator sequence from the chicken beta-globin HS4 insulator and the neuronal restrictive silencing element (NRSE). This modified INSM1-promoter can retain NE tumor specificity in an adenoviral construct while driving a mutated adenovirus E1A gene (?24E1A), the Metridia, or Gaussia luciferase gene. The in vitro cell line and mouse xenograft human tumor studies revealed the NE specificity of the INSM1-promoter in NE lung cancer, neuroblastoma, medulloblastoma, retinoblastoma, and insulinoma. When we combined the INSM1 promoter driven Gaussia luciferase with ?24E1A, the co-infected NE tumor secreted higher levels of Gaussia luciferase as compared to the INSM1p-Gaussia virus alone. In a mouse subcutaneous xenograft tumor model, the combination viruses secreted detectable level of Gaussia luciferase after infecting an INSM1-positive NE lung tumor for >=12 days. Therefore, the INSM1-promoter specific conditional replicating adenovirus represents a sensitive diagnostic tool to aid clinicians in the detection of NE tumors. PMID- 26530406 TI - Direct-to-PCR tissue preservation for DNA profiling. AB - Disaster victim identification (DVI) often occurs in remote locations with extremes of temperatures and humidities. Access to mortuary facilities and refrigeration are not always available. An effective and robust DNA sampling and preservation procedure would increase the probability of successful DNA profiling and allow faster repatriation of bodies and body parts. If the act of tissue preservation also released DNA into solution, ready for polymerase chain reaction (PCR), the DVI process could be further streamlined. In this study, we explored the possibility of obtaining DNA profiles without DNA extraction, by adding aliquots of preservative solutions surrounding fresh human muscle and decomposing human muscle and skin tissue samples directly to PCR. The preservatives consisted of two custom preparations and two proprietary solutions. The custom preparations were a salt-saturated solution of dimethyl sulfoxide (DMSO) with ethylenediaminetetraacetic (EDTA) and TENT buffer (Tris, EDTA, NaCl, Tween 20). The proprietary preservatives were DNAgard (Biomatrica((r))) and Tissue Stabilising Kit (DNA Genotek). We obtained full PowerPlex((r)) 21 (Promega) and GlobalFiler((r)) (Life Technologies) DNA profiles from fresh and decomposed tissue preserved at 35 degrees C for up to 28 days for all four preservatives. The preservative aliquots removed from the fresh muscle tissue samples had been stored at -80 degrees C for 4 years, indicating that long-term archival does not diminish the probability of successful DNA typing. Rather, storage at -80 degrees C seems to reduce PCR inhibition. PMID- 26530407 TI - Transmission patterns of human enterovirus 71 to, from and among European countries, 2003 to 2013. AB - Enterovirus 71 (EV-71) is involved in epidemics of hand, foot, and mouth disease (HFMD) and has been reported to occur with severe neurological complications in eastern and south-east Asia. In other geographical areas, the transmission of this virus is poorly understood. We used large sequence datasets (of the gene encoding the viral protein 1, VP1) and a Bayesian phylogenetic approach to compare the molecular epidemiology and geographical spread patterns of EV-71 subgenogroups B4, B5, C1, C2, and C4 in Europe relative to other parts of the world. For the study, European countries considered were European Union (EU) Member States and Iceland, Norway and Switzerland. Viruses of the B4, B5, and C4 subgenogroups circulate mainly in eastern and south-east Asia. In Europe sporadic introductions of these subgenogroups are observed, however C1 and C2 viruses predominate. The phylogenies showed evidence of multiple events of spread involving C1 and C2 viruses within Europe since the mid-1990s. Two waves of sporadic C2 infections also occurred in 2010 and 2013. The 2007 Dutch outbreak caused by C2 and the occurrence of B5 and C4 infections in the EU between 2004 and 2013 arose while the circulation of C1 viruses was low. A transmission chain involving a C4 virus was traced from Japan to the EU and then further to Canada between 2001 and 2006. Recent events whereby spread of viruses have occurred from, to, and within Europe appear to be involved in the long term survival of EV 71, highlighting the need for enhanced surveillance of this virus. PMID- 26530408 TI - [Metabolic control in children and adolescents with type 1 diabetes]. AB - INTRODUCTION: Type 1 diabetes mellitus (T1D) is an important disease in children and adolescent being a major risk factor for early morbidity and mortality. OBJECTIVE: To know the degree of metabolic control and prevalence of cardiovascular risk factors in T1D patients. PATIENTS AND METHOD: Retrospective study including patients under 19 years of age with T1D controlled at a Chilean hospital in 2011. RESULTS: 94 patients were evaluated (average age at diagnosis: 7.3 years; current age: 11,9 years; evolution time: 4.5 years). Seventy-nine percent (79.8%) of patients presented glycated hemoglobin (HbA1c) over the recommended level with an average of 8.9%. The group between 13 and 19 years of age exhibited the worst metabolic control (86% with HbA1c abnormal levels). Overweight or obesity occurred in 26.6% of patients, 20.3% had LDL >100mg/dl and 4.2% had hypertension. CONCLUSIONS: Only about twenty percent of patients had adequate metabolic control as measured by HbA1c, although cardiovascular risk profile was acceptable. Therapeutic and educational efforts must be reinforced mainly in adolescents, emphasizing the importance of adequate nutritional management as a primary method to treat this entity. PMID- 26530409 TI - Forest soil carbon is threatened by intensive biomass harvesting. AB - Forests play a key role in the carbon cycle as they store huge quantities of organic carbon, most of which is stored in soils, with a smaller part being held in vegetation. While the carbon storage capacity of forests is influenced by forestry, the long-term impacts of forest managers' decisions on soil organic carbon (SOC) remain unclear. Using a meta-analysis approach, we showed that conventional biomass harvests preserved the SOC of forests, unlike intensive harvests where logging residues were harvested to produce fuelwood. Conventional harvests caused a decrease in carbon storage in the forest floor, but when the whole soil profile was taken into account, we found that this loss in the forest floor was compensated by an accumulation of SOC in deeper soil layers. Conversely, we found that intensive harvests led to SOC losses in all layers of forest soils. We assessed the potential impact of intensive harvests on the carbon budget, focusing on managed European forests. Estimated carbon losses from forest soils suggested that intensive biomass harvests could constitute an important source of carbon transfer from forests to the atmosphere (142-497 Tg C), partly neutralizing the role of a carbon sink played by forest soils. PMID- 26530410 TI - The variability in the external rotation axis of the distal femur: an MRI-based anatomical study. AB - Commonly used total knee arthroplasty (TKA) systems utilising measured resection techniques default to 5 degrees -7 degrees valgus for the distal cut relative to the anatomical axis and 3 degrees external rotation of the femoral component relative to posterior condylar axis (PCA). Rotational errors of the femoral component are associated with pain, patella maltracking and a poorer outcome. We analysed MRI scans from patients undergoing TKA using patient-specific instrumentation to assess coronal and rotational alignment from landmarks identified on the scans. One hundred and eight scans in 59 males and 49 females were studied with age range 35-93 years (mean 67.9 years). We found 91 % of patients had a femoral valgus angle between 5 degrees and 7 degrees (mean angles 5.9 degrees ), while only 24 % had an external rotation angle between 2.5 degrees and 3.5 degrees relative to PCA. There was no statistical significance in rotation between males and females although outliers tended to be female. Mean Whiteside's angle was 92.9 degrees (87.8-98). This study highlights the variations in external rotation between patients undergoing TKA using the PCA as a reference for rotation. This may be a contributing factor in implant malalignment and patient dissatisfaction. PMID- 26530411 TI - Editor note - congratulations to Prof Claire Rickard. PMID- 26530412 TI - The impact of sedation on pulse pressure variation. AB - OBJECTIVE: Pulse pressure variations (PPV) are mainly influenced by ventilation. The impact of sedation on PPV is not known. The aim of the study was to test the influence of sedation on pulse pressure variation in mechanically ventilated critically ill patients and to compare PPV in critically ill and brain dead patients. Beside the absolute value of PPV, the adjusted values of pulse pressure were used to eliminate influence of ventilation. DESIGN AND INTERVENTION: Mechanically ventilated patients received four different breath frequencies. At each frequency airway pressure was adjusted to keep the end-tidal CO2 stable. In critically ill patients the frequencies were applied at basal (bispectral index - BIS median 38) and deeper sedation (BIS 29). MAIN OUTCOME MEASURES: Simultaneous haemodynamic and respiratory data including oesophageal pressure were recorded, adjusted PPV were calculated as PPV/VT, PPV/dPair, PPV/dPes where VT is tidal volume, dPair and dPes are airway and oesophageal driving pressures. SETTING: University Hospital, ICU. PARTICIPANTS: 30 critically ill and 23 patients with a diagnosis of brain death. RESULTS: The pulse pressure variation did not change significantly during deep sedation compared to basal sedation (median 10.3 vs 10.9%) whereas PPV/dPair increased from 0.7 to 0.8%/cmH2O and PPV/dPes from 1.9%/cmH2O to 2.4%/cmH2O (p=0.04). Patients with a diagnosis of brain death had higher PPV and adjusted PPV than critically ill patients. CONCLUSION: Deeper sedation increases values of adjusted pulse pressure variation. PMID- 26530413 TI - Diffusion-weighted MR imaging of mediastinal lymphadenopathy. PMID- 26530414 TI - P elements and the determinants of hybrid dysgenesis have different dynamics of propagation in Drosophila melanogaster populations. AB - Intraspecific hybrid dysgenesis (HD) appears after some strains of D. melanogaster are crossed. The predominant idea is that the movement of transposable P elements causes HD. It is believed that P elements appeared in the D. melanogaster genome in the middle of the last century by horizontal transfer, simultaneously with the appearance of HD determinants. A subsequent simultaneous expansion of HD determinants and P elements occurred. We analyzed the current distribution of HD determinants in natural populations of D. melanogaster and found no evidence of their further spread. However, full-sized P elements were identified in the genomes of all analyzed natural D. melanogaster strains independent of their cytotypes. Thus, the expansion of P elements does not correlate with the expansion of HD determinants. We found that the ovaries of dysgenic females did not contain germ cells despite the equal number of primordial germ cells in early stages in dysgenic and non-dysgenic embryos. We propose that HD does not result from DNA damage caused by P element transposition, but it would be the disruption in the regulation of dysgenic ovarian formation that causes the dysgenic phenotypes. PMID- 26530415 TI - Accelerated failure time model for case-cohort design with longitudinal covariates subject to measurement error and detection limits. AB - Biomarkers are often measured over time in epidemiological studies and clinical trials for better understanding of the mechanism of diseases. In large cohort studies, case-cohort sampling provides a cost effective method to collect expensive biomarker data for revealing the relationship between biomarker trajectories and time to event. However, biomarker measurements are often limited by the sensitivity and precision of a given assay, resulting in data that are censored at detection limits and prone to measurement errors. Additionally, the occurrence of an event of interest may preclude biomarkers from being further evaluated. Inappropriate handling of these types of data can lead to biased conclusions. Under a classical case cohort design, we propose a modified likelihood-based approach to accommodate these special features of longitudinal biomarker measurements in the accelerated failure time models. The maximum likelihood estimators based on the full likelihood function are obtained by Gaussian quadrature method. We evaluate the performance of our case-cohort estimator and compare its relative efficiency to the full cohort estimator through simulation studies. The proposed method is further illustrated using the data from a biomarker study of sepsis among patients with community acquired pneumonia. PMID- 26530416 TI - Metabolomic and Gene Expression Profiles Exhibit Modular Genetic and Dietary Structure Linking Metabolic Syndrome Phenotypes in Drosophila. AB - Genetic and environmental factors influence complex disease in humans, such as metabolic syndrome, and Drosophila melanogaster serves as an excellent model in which to test these factors experimentally. Here we explore the modularity of endophenotypes with an in-depth reanalysis of a previous study by Reed et al. (2014), where we raised 20 wild-type genetic lines of Drosophila larvae on four diets and measured gross phenotypes of body weight, total sugar, and total triglycerides, as well as the endophenotypes of metabolomic and whole-genome expression profiles. We then perform new gene expression experiments to test for conservation of phenotype-expression correlations across different diets and populations. We find that transcript levels correlated with gross phenotypes were enriched for puparial adhesion, metamorphosis, and central energy metabolism functions. The specific metabolites L-DOPA and N-arachidonoyl dopamine make physiological links between the gross phenotypes across diets, whereas leucine and isoleucine thus exhibit genotype-by-diet interactions. Between diets, we find low conservation of the endophenotypes that correlate with the gross phenotypes. Through the follow-up expression study, we found that transcript-trait correlations are well conserved across populations raised on a familiar diet, but on a novel diet, the transcript-trait correlations are no longer conserved. Thus, physiological canalization of metabolic phenotypes breaks down in a novel environment exposing cryptic variation. We cannot predict the physiological basis of disease in a perturbing environment from profiles observed in the ancestral environment. This study demonstrates that variation for disease traits within a population is acquired through a multitude of physiological mechanisms, some of which transcend genetic and environmental influences, and others that are specific to an individual's genetic and environmental context. PMID- 26530417 TI - Application of Population Sequencing (POPSEQ) for Ordering and Imputing Genotyping-by-Sequencing Markers in Hexaploid Wheat. AB - The advancement of next-generation sequencing technologies in conjunction with new bioinformatics tools enabled fine-tuning of sequence-based, high-resolution mapping strategies for complex genomes. Although genotyping-by-sequencing (GBS) provides a large number of markers, its application for association mapping and genomics-assisted breeding is limited by a large proportion of missing data per marker. For species with a reference genomic sequence, markers can be ordered on the physical map. However, in the absence of reference marker order, the use and imputation of GBS markers is challenging. Here, we demonstrate how the population sequencing (POPSEQ) approach can be used to provide marker context for GBS in wheat. The utility of a POPSEQ-based genetic map as a reference map to create genetically ordered markers on a chromosome for hexaploid wheat was validated by constructing an independent de novo linkage map of GBS markers from a Synthetic W7984 * Opata M85 recombinant inbred line (SynOpRIL) population. The results indicated that there is strong agreement between the independent de novo linkage map and the POPSEQ mapping approach in mapping and ordering GBS markers for hexaploid wheat. After ordering, a large number of GBS markers were imputed, thus providing a high-quality reference map that can be used for QTL mapping for different traits. The POPSEQ-based reference map and whole-genome sequence assemblies are valuable resources that can be used to order GBS markers and enable the application of highly accurate imputation methods to leverage the application GBS markers in wheat. PMID- 26530418 TI - Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing. AB - Moyamoya disease (MMD) is a rare disorder characterized by cerebrovascular occlusion and development of hemorrhage-prone collateral vessels. Approximately 10-12% of cases are familial, with a presumed low penetrance autosomal dominant pattern of inheritance. Diagnosis commonly occurs only after clinical presentation. The recent identification of the RNF213 founder mutation (p.R4810K) in the Asian population has made a significant contribution, but the etiology of this disease remains unclear. To further develop the variant landscape of MMD, we performed high-depth whole exome sequencing of 125 unrelated, predominantly nonfamilial, ethnically diverse MMD patients in parallel with 125 internally sequenced, matched controls using the same exome and analysis platform. Three subpopulations were established: Asian, Caucasian, and non-RNF213 founder mutation cases. We provided additional support for the previously observed RNF213 founder mutation (p.R4810K) in Asian cases (P = 6.01*10(-5)) that was enriched among East Asians compared to Southeast Asian and Pacific Islander cases (P = 9.52*10(-4)) and was absent in all Caucasian cases. The most enriched variant in Caucasian (P = 7.93*10(-4)) and non-RNF213 founder mutation (P = 1.51*10(-3)) cases was ZXDC (p.P562L), a gene involved in MHC Class II activation. Collapsing variant methodology ranked OBSCN, a gene involved in myofibrillogenesis, as most enriched in Caucasian (P = 1.07*10(-4)) and non-RNF213 founder mutation cases (P = 5.31*10(-5)). These findings further support the East Asian origins of the RNF213 (p.R4810K) variant and more fully describe the genetic landscape of multiethnic MMD, revealing novel, alternative candidate variants and genes that may be important in MMD etiology and diagnosis. PMID- 26530419 TI - Comparative Genomics of an Emerging Amphibian Virus. AB - Ranaviruses, a genus of the Iridoviridae, are large double-stranded DNA viruses that infect cold-blooded vertebrates worldwide. Ranaviruses have caused severe epizootics in commercial frog and fish populations, and are currently classified as notifiable pathogens in international trade. Previous work shows that a ranavirus that infects tiger salamanders throughout Western North America (Ambystoma tigrinum virus, or ATV) is in high prevalence among salamanders in the fishing bait trade. Bait ATV strains have elevated virulence and are transported long distances by humans, providing widespread opportunities for pathogen pollution. We sequenced the genomes of 15 strains of ATV collected from tiger salamanders across western North America and performed phylogenetic and population genomic analyses and tests for recombination. We find that ATV forms a monophyletic clade within the rest of the Ranaviruses and that it likely emerged within the last several thousand years, before human activities influenced its spread. We also identify several genes under strong positive selection, some of which appear to be involved in viral virulence and/or host immune evasion. In addition, we provide support for the pathogen pollution hypothesis with evidence of recombination among ATV strains, and potential bait-endemic strain recombination. PMID- 26530420 TI - A Novel Saccharomyces cerevisiae FG Nucleoporin Mutant Collection for Use in Nuclear Pore Complex Functional Experiments. AB - FG nucleoporins (Nups) are the class of proteins that both generate the permeability barrier and mediate selective transport through the nuclear pore complex (NPC). The FG Nup family has 11 members in Saccharomyces cerevisiae, and the study of mutants lacking different FG domains has been instrumental in testing transport models. To continue analyzing the distinct functional roles of FG Nups in vivo, additional robust genetic tools are required. Here, we describe a novel collection of S. cerevisiae mutant strains in which the FG domains of different groups of Nups are absent (Delta) in the greatest number documented to date. Using this plasmid-based DeltaFG strategy, we find that a GLFG domain-only pore is sufficient for viability. The resulting extensive plasmid and strain resources are available to the scientific community for future in-depth in vivo studies of NPC transport. PMID- 26530421 TI - Mapping Quantitative Trait Loci Underlying Function-Valued Traits Using Functional Principal Component Analysis and Multi-Trait Mapping. AB - We previously proposed a simple regression-based method to map quantitative trait loci underlying function-valued phenotypes. In order to better handle the case of noisy phenotype measurements and accommodate the correlation structure among time points, we propose an alternative approach that maintains much of the simplicity and speed of the regression-based method. We overcome noisy measurements by replacing the observed data with a smooth approximation. We then apply functional principal component analysis, replacing the smoothed phenotype data with a small number of principal components. Quantitative trait locus mapping is applied to these dimension-reduced data, either with a multi-trait method or by considering the traits individually and then taking the average or maximum LOD score across traits. We apply these approaches to root gravitropism data on Arabidopsis recombinant inbred lines and further investigate their performance in computer simulations. Our methods have been implemented in the R package, funqtl. PMID- 26530422 TI - Target Enrichment Improves Mapping of Complex Traits by Deep Sequencing. AB - Complex traits such as crop performance and human diseases are controlled by multiple genetic loci, many of which have small effects and often go undetected by traditional quantitative trait locus (QTL) mapping. Recently, bulked segregant analysis with large F2 pools and genome-level markers (named extreme-QTL or X-QTL mapping) has been used to identify many QTL. To estimate parameters impacting QTL detection for X-QTL mapping, we simulated the effects of population size, marker density, and sequencing depth of markers on QTL detectability for traits with differing heritabilities. These simulations indicate that a high (>90%) chance of detecting QTL with at least 5% effect requires 5000* sequencing depth for a trait with heritability of 0.4-0.7. For most eukaryotic organisms, whole-genome sequencing at this depth is not economically feasible. Therefore, we tested and confirmed the feasibility of applying deep sequencing of target-enriched markers for X-QTL mapping. We used two traits in Arabidopsis thaliana with different heritabilities: seed size (H(2) = 0.61) and seedling greening in response to salt (H(2) = 0.94). We used a modified G test to identify QTL regions and developed a model-based statistical framework to resolve individual peaks by incorporating recombination rates. Multiple QTL were identified for both traits, including previously undiscovered QTL. We call our method target-enriched X-QTL (TEX-QTL) mapping; this mapping approach is not limited by the genome size or the availability of recombinant inbred populations and should be applicable to many organisms and traits. PMID- 26530423 TI - Chemically Induced Oncogenesis in the Peripheral Nervous System Is Suppressed in Congenic BDIX.BDIV-Mss1 and -Mss7 Rats. AB - Human malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft-tissue sarcomas with a poor prognosis that arise either in the context of neurofibromatosis 1 or sporadically. Inbred BDIX and BDIV rat strains highly susceptible and resistant, respectively, to the development of ethylnitrosourea induced MPNST enable us to identify, by using methods not applicable in humans, variant alleles involved in the pathways underlying individual MPNST risk. On the basis of a genome-wide association analysis using reciprocal intercrosses of BDIX and BDIV, BDIV alleles of two loci on chromosome 10, Mss1 and Mss7, were predicted to lower the risk of MPNST, the latter locus with a female bias. In this study we confirm the two nonoverlapping loci by exposing two congenic strains, BDIX.BDIV-Mss1 (Mss1) and BDIX.BDIV-Mss7 (Mss7), each carrying a BDIV genomic segment spanning the respective locus, to ethylnitrosourea. Compared with BDIX rats, the rate of MPNST is reduced 6.2-fold and 2.0-fold for Mss1 and Mss7 rats of both sexes, respectively. Although a moderate gain of survival time (30 50 days) is seen in Mss1 rats of both sexes and Mss7 males, Mss7 females survive 134 days longer than BDIX females. BDIV alleles at Mss7 obviously cause a markedly increased intrastrain sex difference regarding survival time in Mss7 compared with BDIX rats. Fine mapping will lead to the identification of allelic variants modulating rat MPNST risk and subsequently to their human counterparts. This is of particular relevance, because so far neither gene nor anonymous sequence variants have been identified that influence the risk of human sporadic Schwann cell malignancy. PMID- 26530425 TI - A self-cleaning polybenzoxazine/TiO2 surface with superhydrophobicity and superoleophilicity for oil/water separation. AB - Two important properties-the low surface free energy of polybenzoxazine (PBZ) and the photocatalysis-induced self-cleaning property of titanium dioxide (TiO2) nanoparticles-are combined to develop a promising approach for oil/water separation. They are integrated into a multifunctional superhydrophobic and superoleophilic material, PBZ/TiO2 modified polyester non-woven fabrics (PBZT), through a simple dip coating and subsequent thermal curing method. The resulting PBZT reveals excellent mechanical durability and strong resistance to ultraviolet (UV) irradiation as well as acid and alkali. This durable superhydrophobic and superoleophilic fabric is efficient for separating oil/water mixtures by gravity with high separation efficiency, and it can also purify wastewater that contains soluble dyes, which makes it more effective and promising in treating water pollution. Importantly, PBZT demonstrates an integrated self-cleaning performance on the removal of both oil and particle contamination. It is expected that this simple process can be readily adopted for the design of multifunctional PBZ/TiO2 based materials for oil/water separation. PMID- 26530424 TI - Haplotype Detection from Next-Generation Sequencing in High-Ploidy-Level Species: 45S rDNA Gene Copies in the Hexaploid Spartina maritima. AB - Gene and whole-genome duplications are widespread in plant nuclear genomes, resulting in sequence heterogeneity. Identification of duplicated genes may be particularly challenging in highly redundant genomes, especially when there are no diploid parents as a reference. Here, we developed a pipeline to detect the different copies in the ribosomal RNA gene family in the hexaploid grass Spartina maritima from next-generation sequencing (Roche-454) reads. The heterogeneity of the different domains of the highly repeated 45S unit was explored by identifying single nucleotide polymorphisms (SNPs) and assembling reads based on shared polymorphisms. SNPs were validated using comparisons with Illumina sequence data sets and by cloning and Sanger (re)sequencing. Using this approach, 29 validated polymorphisms and 11 validated haplotypes were reported (out of 34 and 20, respectively, that were initially predicted by our program). The rDNA domains of S. maritima have similar lengths as those found in other Poaceae, apart from the 5'-ETS, which is approximately two-times longer in S. maritima. Sequence homogeneity was encountered in coding regions and both internal transcribed spacers (ITS), whereas high intragenomic variability was detected in the intergenic spacer (IGS) and the external transcribed spacer (ETS). Molecular cytogenetic analysis by fluorescent in situ hybridization (FISH) revealed the presence of one pair of 45S rDNA signals on the chromosomes of S. maritima instead of three expected pairs for a hexaploid genome, indicating loss of duplicated homeologous loci through the diploidization process. The procedure developed here may be used at any ploidy level and using different sequencing technologies. PMID- 26530426 TI - Topologically protected elastic waves in phononic metamaterials. AB - Surface waves in topological states of quantum matter exhibit unique protection from backscattering induced by disorders, making them ideal carriers for both classical and quantum information. Topological matters for electrons and photons are largely limited by the range of bulk properties, and the associated performance trade-offs. In contrast, phononic metamaterials provide access to a much wider range of material properties. Here we demonstrate numerically a phononic topological metamaterial in an elastic-wave analogue of the quantum spin Hall effect. A dual-scale phononic crystal slab is used to support two effective spins for phonons over a broad bandwidth, and strong spin-orbit coupling is realized by breaking spatial mirror symmetry. By preserving the spin polarization with an external load or spatial symmetry, phononic edge states are shown to be robust against scattering from discrete defects as well as disorders in the continuum, demonstrating topological protection for phonons in both static and time-dependent regimes. PMID- 26530427 TI - Comparison of community-acquired, hospital-acquired, and intensive care unit acquired acute respiratory distress syndrome: a prospective observational cohort study. AB - INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a syndrome characterized by diffuse pulmonary edema and severe hypoxemia that usually occurs after an injury such as sepsis, aspiration and pneumonia. Little is known about the relation between the setting where the syndrome developed and outcomes in ARDS patients. METHODS: This is a 1-year prospective observational study conducted at a tertiary referred hospital. ARDS was defined by the Berlin criteria. Community-acquired ARDS, hospital-acquired ARDS and intensive care unit (ICU)-acquired ARDS were defined as ARDS occurring within 48 hours of hospital or ICU admission, more than 48 hours after hospital admission and ICU admission. The primary and secondary outcomes were short- and long- term mortality rates and ventilator-free and ICU-free days. RESULTS: Of the 3002 patients screened, 296 patients had a diagnosis of ARDS, including 70 (23.7 %) with community-acquired ARDS, 83 (28 %) with hospital-acquired ARDS, and 143 (48.3 %) with ICU-acquired ARDS. The overall ICU mortality rate was not significantly different in mild, moderate and severe ARDS (50 %, 50 % and 56 %, p = 0.25). The baseline characteristics were similar other than lower rate of liver disease and metastatic malignancy in community-acquired ARDS than in hospital-acquired and ICU-acquired ARDS. A multiple logistic regression analysis indicated that age, sequential organ function assessment score and community-acquired ARDS were independently associated with hospital mortality. For community-acquired, hospital-acquired and ICU-acquired ARDS, ICU mortality rates were 37 % 61 % and 52 %; hospital mortality rates were 49 %, 74 % and 68 %. The ICU and hospital mortality rates of community-acquired ARDS were significantly lower than hospital acquired and ICU-acquired ARDS (p = 0.001 and p = 0.001). The number of ventilator-free days was significantly lower in ICU-acquired ARDS than in community-acquired and hospital-acquired ARDS (11 +/- 9, 16 +/- 9, and 14 +/- 10 days, p = 0.001). The number of ICU-free days was significantly higher in community-acquired ARDS than in hospital-acquired and ICU-acquired ARDS (8 +/- 10, 4 +/- 8, and 3 +/- 6 days, p = 0.001). CONCLUSIONS: Community-acquired ARDS have lower short- and long-term mortality rates than hospital-acquired or ICU acquired ARDS. PMID- 26530428 TI - Exploring Decision-Making about Neo-adjuvant Chemotherapy for Breast Cancer. PMID- 26530429 TI - A Novel Topical 2% Povidone-Iodine Solution for the Treatment of Common Warts: A Randomized, Double-Blind, Vehicle-Controlled Trial. AB - INTRODUCTION: Verruca vulgaris, also known as common warts, are benign skin growths caused by infection of the skin by human papillomavirus. Warts are common in both childhood and adulthood and are spread by direct contact or autoinoculation. Treatment options vary from locally destructive methods to immuno-modulatory therapy. Common warts are often resistant to treatment. Though many remedies exist, there is no consensus therapy backed by randomized controlled clinical trials that are FDA approved for the treatment of verruca vulgaris. We describe here the results of a small, randomized, double-blind, vehicle-controlled Phase II clinical trial with a novel topical agent for the treatment of common warts. METHODS: Twenty-one patients aged 8 years and older were enrolled in this single-center, randomized, double-blind, vehicle-controlled Phase II clinical trial to assess the efficacy, safety and tolerability of twice daily application of a novel 2% topical povidone-iodine solution in a dimethyl sulfoxide vehicle for 12 weeks duration. Patients were block randomized into two groups consisting of 14 patients in the active arm and 7 patients in the vehicle only arm. All patients were evaluated at baseline, week 4, 8 and 12 and the results compared for overall Global Aesthetic Improvement Scale (GAIS) improvement. RESULTS: There were a total of 21 patients included in the study. Sustained improvement in the GAIS scale was observed at the final week 12 exam visit in 77% of subjects in the treatment arm and 33% of patients in the control arm. There were no serious safety or tolerability issues reported. CONCLUSION: Twice-daily topical povidone-iodine solution in the novel vehicle employed for this study is an effective, safe and easy-to-use treatment for common warts. Further study of this agent in expanded Phase II and Phase III clinical trials is warranted. FUNDING: ALC Therapeutics LLC. PMID- 26530430 TI - Temporal fluctuations of tremor signals from inertial sensor: a preliminary study in differentiating Parkinson's disease from essential tremor. AB - BACKGROUND: Parkinson's disease (PD) and essential tremor (ET) are the two most common movement disorders but the rate of misdiagnosis rate in these disorders is high due to similar characteristics of tremor. The purpose of the study is to present: (a) a solution to identify PD and ET patients by using the novel measurement of tremor signal variations while performing the resting task, (b) the improvement of the differentiation of PD from ET patients can be obtained by using the ratio of the novel measurement while performing two specific tasks. METHODS: 35 PD and 22 ET patients were asked to participate in the study. They were asked to wear a 6-axis inertial sensor on his/her index finger of the tremor dominant hand and perform three tasks including kinetic, postural and resting tasks. Each task required 10 s to complete. The angular rate signal measured during the performance of these tasks was band-pass filtered and transformed into a two-dimensional representation. The ratio of the ellipse area covering 95 % of this two-dimensional representation of different tasks was investigated and the two best tasks were selected for the purpose of differentiation. RESULTS: The ellipse area of two-dimensional representation of the resting task of PD and ET subjects are statistically significantly different (p < 0.05). Furthermore, the fluctuation ratio, defined as a ratio of the ellipse area of two-dimensional representation of resting to kinetic tremor, of PD subjects were statistically significantly higher than ET subjects in all axes (p = 0.0014, 0.0011 and 0.0001 for x, y and z-axis, respectively). The validation shows that the proposed method provides 100 % sensitivity, specificity and accuracy of the discrimination in the 5 subjects in the validation group. While the method would have to be validated with a larger number of subjects, these preliminary results show the feasibility of the approach. CONCLUSIONS: This study provides the novel measurement of tremor variation in time domain termed 'temporal fluctuation'. The temporal fluctuation of the resting task can be used to discriminate PD from ET subjects. The ratio of the temporal fluctuation of the resting task to the kinetic task improves the reliability of the discrimination. While the method is powerful, it is also simple so it could be applied on low resource platforms such as smart phones and watches which are commonly equipped with inertial sensors. PMID- 26530431 TI - Binding thermodynamics of paromomycin, neomycin, neomycin-dinucleotide and -diPNA conjugates to bacterial and human rRNA. AB - Isothermal titration calorimetry (ITC) is a powerful technique able to evaluate the energetics of target-drug binding within the context of drug discovery. In this work, the interactions of RNAs reproducing bacterial and human ribosomal A site, with two well-known antibiotic aminoglycosides, Paromomycin and Neomycin, as well as several Neomycin-dinucleotide and -diPNA conjugates, have been evaluated by ITC and the corresponding thermodynamic quantities determined. The comparison of the thermodynamic data of aminoglycosides and their chemical analogues allowed to select Neomycin-diPNA conjugates as the best candidates for antimicrobial activity. PMID- 26530432 TI - Clear cell adenocarcinoma arising from adenomyotic cyst: A case report and literature review. AB - Ovaries are the primary sites of cancerous disease that is derived from endometriosis. Uterine cancer originating from endometriosis is very rare. The most frequent histological subtype of cancer derived from endometriosis is endometrioid adenocarcinoma, a subtype of clear cell carcinoma which is exceedingly rare. We report a case of a 40-year-old Japanese woman with a six year history of uterine leiomyoma. The patient was clinically and radiologically suspected to have degenerative uterine myoma with a possible malignant association and underwent a transabdominal total hysterectomy. Histopathological examination of the specimens revealed clear cell adenocarcinoma arising from the adenomyotic cyst. A literature review of clear cell adenocarcinomas arising from uterine adenomyotic cysts (cystic adenomyosis), emphasizes the clinically and radiologically important features of this very rare entity. Clear cell carcinoma association should be suspected in patients who are under follow-up for uterine myomas and present with cystic uterine changes with solid component on magnetic resonance imaging or computed tomography scans. PMID- 26530433 TI - Synthesis of Cyclic Alkenyl Triflates by a Cationic Cyclization Reaction and its Application in Biomimetic Polycyclizations and Synthesis of Terpenes. AB - Cyclic alkenyl triflates are useful intermediates in organic synthesis usually synthesized from ketones through a reaction involving enolization and trapping with a triflating agent. This sequence suffers from some stereochemical drawbacks owing to the basic conditions required. Herein, we describe a new acid-mediated cationic cyclization reaction of enyne derivatives (or alkynols) to access cyclic alkenyl triflates. This new atom-economical process is high yielding, scalable, technically very simple, proceeds without the need of any metallic reagent or catalyst, and more importantly, it complements and challenges conventional methodologies. We have also developed new biomimetic cationic cyclization reactions to yield interesting polycyclic compounds. As a demonstration of the potential of this method in the context of total synthesis, we have synthesized two terpenes: austrodoral and pallescensin A. Using the cationic cyclization in the key step of the synthetic routes allowed the synthesis of these natural products in a very simple, concise, scalable, and efficient way. PMID- 26530434 TI - Farmers' perception of the role of veterinary surgeons in vaccination strategies on British dairy farms. AB - There is limited research investigating the motivators and barriers to vaccinating dairy cattle. Veterinary surgeons have been identified as important sources of information for farmers making vaccination and disease control decisions, as well as being farmers' preferred vaccine suppliers. Vets' perception of their own role and communication style can be at odds with farmers' reported preferences. The objective of this study was to investigate how dairy farmers perceived the role of vets in implementing vaccination strategies on their farm. Semi-structured interviews were conducted with 24 dairy farmers from across Britain. The data were analysed using thematic analysis. Analysis revealed that farmers perceive vets to have an important role in facilitating decision making in all aspects of vaccination, including the aspects of vaccine distribution and advice on implementation. This important role is acknowledged by farmers who have regular veterinary contact, but also farmers with solely emergency veterinary contact. Given this finding, future work should investigate the attitudes of vets towards vaccination and how they perceive their role. Combining this knowledge will enable optimisation of vaccination strategies on British dairy farms. PMID- 26530435 TI - Retrospective Study of First-Generation Drug-Eluting Stents, Second-Generation Drug-Eluting Stents and Non-Drug Eluting Stent Methods in the Treatment of Native Vessel In-Stent Restenosis in Real-World Clinical Practice. AB - BACKGROUND: The efficacy of second-generation drug-eluting stents (DES) in treating in-stent restenosis (ISR) compared to first-generation DES and non-DES treatment methods in real-world cohorts has not yet been adequately addressed. This research intends to examine optimum treatment of in-stent restenosis, considering first-generation DES, second-generation DES and non-DES treatment methods in a real-world cohort. METHODS: Retrospective analysis was performed on 114 patients treated for native-vessel BMS or DES ISR. Thirty-two were treated with a first-generation DES (81% sirolimus, 19% paclitaxel), 32 with a second generation DES (72% everolimus, 28% zotarolimus) and 28 with non-DES methods (32% bare-metal stent, 39% balloon angioplasty, 29% cutting balloon). The composite primary endpoint was total adverse cardiac events, recurrent stable angina, unstable angina, myocardial infarction (MI), target vessel revascularisation (TVR) and cardiac death at minimum clinical follow-up of six months. RESULTS: Primary endpoint rates were significantly higher in the non-DES and second generation DES treatment groups than in first-generation DES (42.9%, 25.9%, 6.2%; p=0.004). Rates of MI and TVR were significantly higher in the non-DES treatment group, compared to first and second-generation DES (MI: 17.9%, 0%, 5.6%; p=0.018; TLR: 21.4%, 3.1%, 7.4%; p=0.041). CONCLUSIONS: First-generation DES may be superior to second-generation DES and non-DES in treating BMS or DES ISR with regard to overall adverse cardiac events. PMID- 26530436 TI - A Body Shape Index and Body Roundness Index: Two New Body Indices to Identify left Ventricular Hypertrophy among Rural Populations in Northeast China. AB - BACKGROUND: Recently, two new anthropometric indices, the A Body Shape Index (ABSI) and Body Roundness Index (BRI) have been developed as possible improved alternatives to body mass index (BMI) and waist circumference (WC). The main research aim is to assess the capacity of the ABSI and BRI to identify subjects with left ventricular hypertrophy (LVH) and the secondary aim is to determine whether ABSI and / or BRI is superior to BMI, WC, and waist-to-height ratio (WHtR). METHODS AND RESULTS: This cross-sectional study was conducted among the rural population in northeast China and finally included 10,907 participants. Pearson rank test showed that BRI showed the highest correlation coefficient for LVH. Body Roundness Index had the highest AUCs for eccentric and concentric LVH (AUC: 0.74, 95% CI: 0.72-0.75; AUC: 0.67, 95% CI: 0.64-0.70, respectively). A multivariate logistic regression analysis also showed that BRI was the best predictor of eccentric and concentric LVH (OR: 5.11, 95% CI: 3.62-7.22; OR: 2.48, 95% CI: 1.40-4.40, respectively). In the five anthropometric indices, only BRI had predictive ability for concentric LVH. CONCLUSIONS: We have shown that BRI, not ABSI was superior measure compared to BMI, WC and WHtR for determining the presence of LVH, especially for eccentric LVH. PMID- 26530437 TI - Early Mortality and Long-term Survival after Repair of Post-infarction Ventricular Septal Rupture: An Institutional Report of Experience. AB - BACKGROUND: To determine predictors of mortality after surgical management of post-infarction ventricular septal rupture repair. METHODS: A total of 63 patients (73.2%, mean age 67.22+/-7.71 years, male:female ratio; 35:28) underwent open heart surgery for post-infarction ventricular septal rupture repair. Patient demographics, operative data and postoperative parameters were analysed to reveal predictors of early mortality and long-term survival. RESULTS: In-hospital mortality was 54.0% (34/63). Time from myocardial infarction to operation <= 14 days (OR: 4.10, 95% CI 1.16-14.46, p=0.02), systolic pulmonary artery pressure > 45 mmHg (OR: 4.14, 95% CI 1.110-15.496, p=0.03) and age (years) (OR: 1.09, 95% CI 1.002-1.194, p=0.04) were found to be independent predictors of in-hospital mortality. In multivariate Cox regression analysis, presence of pulmonary oedema on admission (HR: 4.95, 95% CI 1.58-15.54, p=0.006), age (years) (HR: 1.09, 95% CI 1.009-1.180, p= 0.02) and cross-clamp time <60 min (HR: 3.93, 95% CI 1.13 13.64, p=0.03) were found to be independent predictors of long-term survival. Within a follow-up of a median of 60.0 months, five-year survival rate was 67+/ 9.0%. CONCLUSION: In line with the previous studies, our study demonstrated the benefits of delaying the repair for post-infarction ventricular septal rupture to allow adequate myocardial healing if haemodynamic status of the patient allows. PMID- 26530438 TI - Association of Serum Cholesterol Levels with Short-term Mortality in Patients with Acute Pulmonary Embolism. AB - BACKGROUND: Serum cholesterols play an important role in pathophysiology and prognosis of acute thrombotic diseases. The aim of the present study was to investigate the prognostic value of serum lipid parameters in acute pulmonary embolism (APE). METHODS: From January 2008 to January 2014 a total of 275 patients who were hospitalised with a diagnosis of APE were retrospectively screened. Clinical data, laboratory parameters, serum cholesterol levels were recorded and pulmonary embolism severity index (PESI) scores were calculated. Mortality rate at 30 days was investigated as the clinical outcome. RESULTS: In our study population, 24 patients (8.7%) died within 30 days. Serum total cholesterol, LDL-C, HDL-C and triglyceride levels were significantly lower in deceased patients when compared to the survived patients (3.1 +/- 0.6 vs. 4.7 +/- 1.2 mmol/L, p < 0.01; 1.8 +/- 0.9 vs. 2.9 +/- 0.9 mmol/L, p < 0.01; 0.9 +/- 0.3 vs. 1.2 +/- 0.3 mmol/L, p < 0.01; 1.4 +/- 0.7 vs. 1.7 +/- 0.6 mmol/L, p = 0.04, respectively). In multivariate regression analysis; PESI scores (OR: 1.06 95% CI: 1.01-1.11, p < 0.01), right ventricular diameter (OR: 11.31 95% CI: 3.25-52.64, p < 0.01), total cholesterol (OR: 1.09 95% CI: 1.02-1.17, p < 0.01), LDL-C (OR: 1.06 95% CI: 1.01-1.12, p = 0.02), HDL-C (OR: 1.21 95% CI: 1.04-1.41, p < 0.01) and triglyceride (OR: 1.03 95% CI: 1.01-1.05, p < 0.01) levels were independently correlated with mortality. CONCLUSIONS: Serum total cholesterol, LDL-C, HDL-C and triglyceride levels, obtained within the first 24hours of hospital admission, may have prognostic value in patients with APE. PMID- 26530439 TI - Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells. AB - Paxillin (PXN) encodes a 68-kDa focal adhesion-associated protein and plays an important role in signal transduction, regulation of cell morphology, migration, proliferation and apoptosis. The aim of the present study was to evaluate the relationship between PXN and clinicopathological factors in colorectal cancer, the role of PXN in cetuximab resistance, and whether knockdown of PXN expression could improve the sensitivity to cetuximab in colorectal cancer cells. In the present study, immunohistochemical staining in 148 colorectal carcinoma and 126 normal adjacent tissues was performed, which showed that the positive rate of PXN was significantly higher in the colorectal adenocarcinoma samples than that in the normal colorectal mucosa samples (P<0.001). Moreover, PXN presence was also positively correlated with TNM stage (P=0.023), distant metastasis (P=0.014), recurrence (P=0.032) and reduced survival (P=0.004). In vitro, PXN expression was positively correlated with the proliferation rate in colorectal cells insensitive to cetuximab. Inhibition of PXN expression by PXN-siRNA clearly increased apoptosis by downregulating the phosphorylation of extracellular signal regulated kinase (p-Erk) level, and overexpression of PXN by PXN-cDNA decreased apoptosis by upregulating the p-Erk level. This suggests that overexpression of PXN could be one of the reasons for cetuximab resistance, and downregulation of PXN plays an important role in improving sensitivity to cetuximab by suppressing the activitation of p-Erk in colorectal cancer cells. Above all, knockdown of PXN could represent a rational therapeutic strategy for increasing the sensitivity or overcoming cetuximab-resistance in patients with colorectal cancer. PMID- 26530441 TI - Stroma-associated master regulators of molecular subtypes predict patient prognosis in ovarian cancer. AB - High-grade serous ovarian carcinoma (HGS-OvCa) has the lowest survival rate among all gynecologic cancers and is hallmarked by a high degree of heterogeneity. The Cancer Genome Atlas network has described a gene expression-based molecular classification of HGS-OvCa into Differentiated, Mesenchymal, Immunoreactive and Proliferative subtypes. However, the biological underpinnings and regulatory mechanisms underlying the distinct molecular subtypes are largely unknown. Here we showed that tumor-infiltrating stromal cells significantly contributed to the assignments of Mesenchymal and Immunoreactive clusters. Using reverse engineering and an unbiased interrogation of subtype regulatory networks, we identified the transcriptional modules containing master regulators that drive gene expression of Mesenchymal and Immunoreactive HGS-OvCa. Mesenchymal master regulators were associated with poor prognosis, while Immunoreactive master regulators positively correlated with overall survival. Meta-analysis of 749 HGS-OvCa expression profiles confirmed that master regulators as a prognostic signature were able to predict patient outcome. Our data unraveled master regulatory programs of HGS OvCa subtypes with prognostic and potentially therapeutic relevance, and suggested that the unique transcriptional and clinical characteristics of ovarian Mesenchymal and Immunoreactive subtypes could be, at least partially, ascribed to tumor microenvironment. PMID- 26530442 TI - Factors influencing the development of end-of-life communication skills: A focus group study of nursing and medical students. AB - BACKGROUND: Poor communication between health care professionals and dying patients and their families results in complaints about end-of-life care. End-of life communication skills should be a core part of nursing and medical education but research suggests that qualified doctors and nurses find this a challenging area of practice. AIMS: The aim of this study was to explore factors influencing the development of end-of-life communication skills by nursing and medical students. DESIGN: A qualitative study comprising five focus groups. PARTICIPANTS: Second year undergraduate nursing (n=9 across 2 focus groups) and fourth year undergraduate medical students (n=10 across 3 focus groups) from a London University. FINDINGS: Barriers and facilitators influenced nursing and medical students' experience of communication with dying patients and their families in clinical practice. Extrinsic barriers included gatekeeping by qualified staff and lack of opportunity to make sense of experiences through discussion. Intrinsic barriers included not knowing what to say, dealing with emotional responses, wasting patients' time, and concerns about their own ability to cope with distressing experiences. Facilitating factors included good role models, previous experience, and classroom input. CONCLUSION: In addition to clinical placements, formal opportunities for reflective discussion are necessary to facilitate the development of students' confidence and skills in end-of-life communication. For students and mentors to view end-of-life communication as a legitimate part of their learning it needs to be specified written practice-learning outcome. Mentors and supervisors may require training to enable them to facilitate students to develop end-of-life communication skills. PMID- 26530443 TI - Adipocyte and leptin accumulation in tumor-induced thymic involution. AB - Cell-mediated immunity is an important defense mechanism against pathogens and developing tumor cells. The thymus is the main lymphoid organ involved in the formation of the cell-mediated immune response by the maturation and differentiation of lymphocytes that travel from the bone marrow, through the lymphatic ducts, to become T lymphocytes. Thymic involution has been associated with aging; however, other factors such as obesity, viral infection and tumor development have been shown to increase the rate of shrinkage of this organ. The heavy infiltration of adipocyte fat cells has been reported in the involuted thymuses of aged mice. In the present study, the possible accumulation of such cells in the thymus during tumorigenesis was examined by immunohistochemistry. A significant number of adipocytes around and infiltrating the thymuses of tumor bearing mice was observed. Leptin is a pro-inflammatory adipocytokine that enhances thymopoiesis and modulates T cell immune responses. The levels of leptin and adiponectin, another adipocytokine that has anti-inflammatory properties, were examined by western blot analysis. While no changes were observed in the amounts of adiponectin present in the thymuses of the normal and tumor-bearing mice, significantly higher levels of leptin were detected in the thymocytes of the tumor-bearing mice. This correlated with an increase in the expression of certain cytokines, such as interleukin (IL)-2, interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF). The co-culture of thymocytes isolated from normal mice with ex vivo isolated adipocytes from tumor bearing mice yielded similar results. Our findings suggest that the infiltration and accumulation of adipocytes in the thymuses of tumor-bearing mice play an important role in their altered morphology and functions. PMID- 26530444 TI - Strong Prognostic Value of Microsatellite Instability in Intestinal Type Non cardia Gastric Cancer. AB - BACKGROUND: The clinical role of microsatellite instability (MSI) in gastric cancer (GC) is controversial. A large series of patients submitted to respective surgery for primary GC with a long follow-up time was evaluated. METHODS: 472 patients with prospectively collected frozen samples of normal mucosa and tumor tissue stored in a biological tissue bank were included. Microsatellite analysis was evaluated using 5 quasi monomorphic mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21, and NR-27). The presence of MSI in 2 or more loci was classified as MSI-H, whereas all other cases were included in the microsatellite-stable (MSS) group. RESULTS: MSI-H phenotype was found in 111 of 472 patients (23.5%). MSI-H status was related significantly with older age, female gender, non-cardia location, WHO histotype, non-cardia Lauren intestinal type, and less advanced stages. Cancer-related 5-year survival was significantly higher in MSI-H versus MSS group (67.6% vs. 35%, p < 0.001). Stratified analysis revealed a significant impact of MSI on prognosis in non-cardia tumors of intestinal type or tubular/poorly differentiated histology, particularly in stages II and III; multivariate Cox regression analysis confirmed MSS status as a strong predictor of poor prognosis (hazard ratio 2.65, 95% CI 1.56-4.51, p < 0.001) in non-cardia intestinal type. No prognostic value of MSI in the diffuse-mixed type and signet ring cell/mucinous histotypes was observed. CONCLUSIONS: MSI was confirmed as a significant predictor of long term outcome in a large series of GC with a long follow-up time, but the prognostic value is limited to selected histotypes of non cardia tumors. PMID- 26530445 TI - Clinical Significance of the C-Reactive Protein to Albumin Ratio for Survival After Surgery for Colorectal Cancer. AB - OBJECTIVE: This study was designed to estimate the clinical significance of the C reactive protein (CRP)/albumin ratio (CAR) for prediction of postoperative survival in patients with colorectal cancer (CRC). BACKGROUND: The Glasgow Prognostic Score (GPS), calculated from the serum levels of CRP and albumin, is well known to be a valuable inflammation-based prognostic system for several types of cancer. A recent study has demonstrated that the CAR is also useful for prediction of treatment outcome in patients with hepatocellular carcinoma. METHODS: Uni- and multivariate analyses using the Cox proportional hazards model were performed to detect the clinical characteristics that were most closely associated with overall survival (OS). All recommended cutoff values were defined using receiver operating characteristic curve analyses. Kaplan-Meier analysis was used to compare OS curves between the two groups. RESULTS: A total of 627 patients who had undergone elective CRC surgery were enrolled. Multivariate analysis using the results of univariate analyses demonstrated that CAR (>0.038/<=0.038) was associated with OS (hazard ratio 2.596; 95% confidence interval 1.603-4.204; P < 0.001) along with pathological differentiation (others/well or moderately), carcinoembryonic antigen level (>8.7/<=8.7, ng/ml), stage (III, IV/0, I, II), neutrophil to lymphocyte ratio (NLR) (>2.9/<=2.9), and GPS (2/0, 1). Kaplan-Meier analysis and log rank test demonstrated a significant difference in OS curves between patients with low CAR (<=0.038) and those with high CAR (>0.038; P < 0.001). CONCLUSIONS: CAR is as useful for predicting the postoperative survival of patients with CRC as previously reported inflammation based prognostic systems, such as GPS and NLR. PMID- 26530446 TI - Left-Sided Breast Irradiation does not Result in Increased Long-Term Cardiac Related Mortality Among Women Treated with Breast-Conserving Surgery. AB - BACKGROUND: Standard therapy following lumpectomy for breast cancer has included adjuvant whole-breast radiotherapy. Recent, long-term studies have suggested a possible association between left-sided whole breast radiotherapy and long-term cardiac-related mortality. We sought to determine whether left-sided breast cancers treated with breast-conserving treatment have worse cardiac-related outcomes. METHODS: The surveillance, epidemiology, and end results database was queried for female breast cancer cases diagnosed from 1990 to 1999. Subjects who underwent lumpectomy and adjuvant radiotherapy were included for study and grouped according to laterality. The primary outcome measure was the rate of cardiac-related mortality. Secondary outcome measures were overall and cancer specific survival. A Cox proportional hazards model was constructed to analyze the primary outcome measure and included age, race, grade, stage, hormone receptor status, and histologic subtype. RESULTS: A total of 66,687 subjects were identified. These were divided equally by laterality groups: 33,866 left (50.8 %) and 32,801 right (49.2 %). Median follow-up was 15.5 years, and the groups were otherwise well-matched. Left-sided cancer was not associated with poorer survival for any of the metrics. Fifteen-year overall survival and disease-specific survival were 62.8 and 87.0 % for left-sided and 63.0 and 87.1 % for right-sided breast cancers, respectively (p = 0.260, p = 0.702). Rate of cardiac-related mortality at 5-, 10-, and 15-year follow-up were 1.5, 4.3, and 7.7 % for left sided cancers and 1.6, 4.4, and 8.0 % for right-sided cancers, respectively (p = 0.435). CONCLUSIONS: In this large population-based study, women receiving left sided external beam radiation for breast cancer did not have an increase in cardiac-related mortality. PMID- 26530447 TI - Is Linitis Plastica a Contraindication for Surgical Resection: A Multi Institution Study of the U.S. Gastric Cancer Collaborative. AB - BACKGROUND: Current staging and treatment guidelines for gastric adenocarcinoma do not differentiate between linitis plastic (LP) and non-LP cancers. Significant controversy exists regarding the surgical management of LP patients. METHODS: Using the multi-institutional U.S. Gastric Cancer Collaborative database, 869 gastric cancer patients who underwent resection between 2000 and 2012 were identified. Clinicopathologic and outcomes data of 58 LP patients were compared to 811 non-LP patients. RESULTS: Stage III/IV disease was more common at presentation in LP patients compared with non-LP patients (90 vs. 44 %, p < 0.01). Despite the fact that most LP patients underwent total gastrectomy (88 vs. 39 %, p < 0.01), final positive margins were more common in LP patients (33 vs. 7 %, p < 0.01). The use of frozen section allowed 15 intraoperative positive margins in 38 patients to be converted to negative final margins. Median overall survival (OS) was significantly worse in patients with LP (11.6 vs. 37.8 months, p < 0.01). There was no difference in median OS of LP patients based on stage (I/II, 17.3 mo; III, 10.6 mo; IV, 12.0 mo; p = 0.46). LP and non-LP patients who underwent optimal resection (negative margin and D2/3 lymphadenectomy) had better survival compared with those with nonoptimal resections. The median OS for optimally resected stage III LP (n = 22) and stage III non-LP (n = 185) patients was nearly identical (26.7 vs. 25.3 mo; p = 0.69). CONCLUSIONS: Future staging systems and treatment guidelines should differentiate between LP and non-LP gastric cancers. Long-term survival in select LP patients who undergo optimal resections is comparable to optimally resected non-LP patients. PMID- 26530448 TI - Comparative plasma disposition kinetics of albendazole and its new benzimidazol prodrug in dog. AB - The comparative pharmacokinetic behavior of albendazole (ABZ) and its new benzimidazol prodrug [1-tert-butyloxycarbonyl-5-propylthio-1-H-benzimidazol 2ylcarbamate of methyl] (ABZBoc), following their oral administration (10mg/kg) to healthy dogs was explored. Blood samples were obtained serially over a 24h period after treatment, then the plasma was analyzed by high-performance liquid chromatography (HPLC) to search the albendazole metabolites (ABZSO and ABZSO2). However, the albendazole parent drug was not detectable at any time after both treatments (ABZ and ABZBoc). By albendazole metabolites (ABZSO and ABZSO2) were the analytes recovered in the plasma after oral administration of ABZ and ABZBoc. Furthermore, some amounts of ABZBoc were also available in the plasma samples treated with this new produg. The plasma profile of each analyte followed a similar pattern after both treatments, the active metabolite (ABZSO) was the major analyte recovered in plasma (between 1 and 24h post-treatment). The pharmacokinetic parameters of both groups were calculated (Cmax, Tmax, t1/2, AUC0 >infinity), and analyzed using the Student's t-test, P<0.05. Thus,the pharmacokinetic analysis indicated four statistically significant changes in the pharmacokinetic parameters defined above of the albendazole metabolites (ABZSO, ABZSO2) between the group treated with albendazole (group A) and that treated with ABZBoc prodrug (group B). Hence, the levels of the various pharmacokinetics parameters were low in the group treated with prodrug, as well they did not reach equivalent concentrations to that of albendazole. These differences between albendazole and its new prodrug may be explained by the fact that ABZBoc prodrug was not effectively reduced in the intestine of dogs. PMID- 26530449 TI - Separation of intact proteins on gamma-ray-induced polymethacrylate monolithic columns: A highly permeable stationary phase with high peak capacity for capillary high-performance liquid chromatography with high-resolution mass spectrometry. AB - Polymethacrylate-based monolithic capillary columns, prepared by gamma-radiation induced polymerization, were used to optimize the experimental conditions (nature of the organic modifiers, the content of trifluoroacetic acid and the column temperature) in the separation of nine standard proteins with different hydrophobicities and a wide range of molecular weights. Because of the excellent permeability of the monolithic columns, an ion-pair reversed-phase capillary liquid chromatography with high-resolution mass spectrometry method has been developed by coupling the column directly to the mass spectrometer without a flow split and using a standard electrospray interface. Additionally, the high working flow and concomitant high efficiency of these columns allowed us to employ a longer column (up to 50 cm) and achieve a peak capacity value superior to 1000. This work is motivated by the need to develop new materials for high-resolution chromatographic separation that combine chemical stability at elevated temperatures (up to 75 degrees C) and a broad pH range, with a high peak capacity value. The advantage of the gamma-ray-induced monolithic column lies in the batch to-batch reproducibility and long-term high-temperature stability. Their proven high loading capacity, recovery, good selectivity and high permeability, moreover, compared well with that of a commercially available poly(styrene divinylbenzene) monolithic column, which confirms that such monolithic supports might facilitate analysis in proteomics. PMID- 26530450 TI - The local environment determines the assembly of root endophytic fungi at a continental scale. AB - Root endophytic fungi are found in a great variety of plants and ecosystems, but the ecological drivers of their biogeographic distribution are poorly understood. Here, we investigate the occurrence of root endophytes in the non-mycorrhizal plant genus Microthlaspi, and the effect of environmental factors and geographic distance in structuring their communities at a continental scale. We sampled 52 plant populations across the northern Mediterranean and central Europe and used a cultivation approach to study their endophytic communities. Cultivation of roots yielded 2601 isolates, which were grouped into 296 operational taxonomic units (OTUs) by internal transcribed spacer sequencing of 1998 representative colonies. Climatic and spatial factors were the best descriptors of the structure of endophytic communities, outweighing soil characteristics, host genotype and geographical distance. OTU richness was negatively affected by precipitation, and the composition of communities followed latitudinal gradients of precipitation and temperature. Only six widespread OTUs belonging to the orders Pleosporales, Hypocreales and Helotiales represented about 50% of all isolates. Assessments of their individual distribution revealed particular ecological preferences or a cosmopolitan occurrence. Our findings support a strong influence of the local environment in determining root endophytic communities, and show a different niche occupancy by individual endophytes. PMID- 26530451 TI - Fever and infections in pregnancy and risk of attention deficit/hyperactivity disorder in the offspring. AB - BACKGROUND: Fever and infections are common events during pregnancy, and have been shown to be associated with neurodevelopmental impairment in the offspring. The evidence in relation to attention deficit/hyperactivity disorder (ADHD) is, however, nonexistent for fever and limited for infections. The aim of this study was therefore to investigate the impact of these exposures on the occurrence of ADHD in the offspring, considering gestational timing as well as intensity of exposure. METHODS: The study was conducted within the Danish National Birth Cohort, using data on 89,146 pregnancies enrolled during 1996-2002. Exposure to fever and infections were assessed prospectively in two computer-assisted telephone interviews during pregnancy and ADHD status in the child was determined using registry information from three nation-wide patient and prescription registers. Stratified Cox regressions were used to calculate adjusted hazard ratios of ADHD occurrence. RESULTS: The analyses revealed no overall association between maternal exposure to fever or infections and ADHD in the offspring [adjusted hazard ratio (aHR): 1.03, 95% confidence interval (CI): 0.93-1.13 and aHR: 1.01, 95% CI: 0.92-1.11]. When the exposures were considered during specific gestational periods, increased rates of ADHD were observed following fever in gestational weeks 9-12 (aHR: 1.33, 95% CI: 1.12-1.58), and genitourinary infections in weeks 33-36 (aHR: 1.60, 95% CI: 1.13-2.26). CONCLUSIONS: Although no overall adverse association between fever and infections in pregnancy and ADHD in the offspring was found, the analyses indicated that exposures during specific time windows of the pregnancy could be associated with increased ADHD occurrence. PMID- 26530452 TI - Association Between Adiposity and Left Ventricular Mass in Children With Hypertension. AB - Left ventricular hypertrophy (LVH) is prevalent among hypertensive children; however, blood pressure (BP) does not predict its presence. The authors conducted a 1-year prospective cohort study to examine the hypothesis that obesity-related risk factors are associated with left ventricular mass index (LVMI) in hypertensive children, and the association between adiposity and LVMI is mediated by BP-dependent and -independent pathways. A total of 49 hypertensive children were enrolled: 51% were overweight/obese and 41% had LVH at baseline. Children overweight/obese at baseline and follow-up had a greater LVMI increase than those of healthy weight at each visit: mean change of 6.4 g/m(2.7) vs 0.95 g/m(2.7) . Baseline body mass index z score was independently associated with LVMI change (beta=4.08, 1.54-6.61; P=.002). Only pulse pressure and serum aldosterone partially mediated this relationship. Hypertensive youth manifest multiple cardiovascular disease risk factors that worsen over time despite treatment. Of these, adiposity is most associated with LVH and increasing LVMI. PMID- 26530453 TI - A pillar[6]arene-based [2]pseudorotaxane in solution and in the solid state and its photo-responsive self-assembly behavior in solution. AB - A pillar[6]arene-based [2]pseudorotaxane was constructed in solution and studied in the solid state, and its photo-responsive self-assembly behavior in solution was investigated. PMID- 26530454 TI - Dual subcellular compartment delivery of doxorubicin to overcome drug resistant and enhance antitumor activity. AB - In order to overcome drug resistant and enhance antitumor activity of DOX, a new pH-sensitive micelle (DOX/DQA-DOX@DSPE-hyd-PEG-AA) was prepared to simultaneously deliver DOX to nucleus and mitochondria. Drug released from DOX/DQA-DOX@DSPE-hyd PEG-AA showed a pH-dependent manner. DOX/DQA-DOX@DSPE-hyd-PEG-AA induced the depolarization of mitochondria and apoptosis in MDA-MB-231/ADR cells and A549 cells, which resulted in the high cytotoxicity of DOX/DQA-DOX@DSPE-hyd-PEG-AA against MDA-MB-231/ADR cells and A549 cells. Confocal microscopy confirmed that DOX/DQA-DOX@DSPE-hyd-PEG-AA simultaneously delivered DQA-DOX and DOX to the mitochondria and nucleus of tumor cell. After DOX/DQA-DOX@DSPE-hyd-PEG-AA was injected to the tumor-bearing nude mice by the tail vein, DOX was mainly found in tumor tissue. But DOX was widely distributed in the whole body after the administration of free DOX. Compared with free DOX, the same dose of DOX/DQA DOX@DSPE-hyd-PEG-AA significantly inhibited the growth of DOX-resistant tumor in tumor-bearing mice without obvious systemic toxicity. Therefore, dual subcellular compartment delivery of DOX greatly enhanced the antitumor activity of DOX on DOX resistant tumor. DOX/DQA-DOX@DSPE-hyd-PEG-AA has the potential in target therapy for DOX-resistant tumor. PMID- 26530455 TI - Joint association of fruit, vegetable, and heterocyclic amine intake with DNA damage levels in a general population. AB - OBJECTIVE: To assess joint effects of heterocyclic amine (HCA), fruit, and vegetable intake on DNA damage in a general population. METHODS: A cross sectional survey (ISA-Capital) was performed among adults and older adults in Brazil. We selected 73 participants with high HCA intake and 73 sex- and age matched participants with non-HCA intake (n = 146) for the present study. Diet was assessed by a 24-h dietary recall and a structured questionnaire with cooking methods and levels of meat doneness. DNA damage was measured by 8-oxo-2' deoxyguanosine (8-OHdG). The association between DNA damage and dietary intake was analyzed by linear regression models. RESULTS: Fruit intake showed significantly inverse association with 8-OHdG (beta, -0.787; P = 0.035), whereas HCA intake was significantly associated with increased DNA damage (beta, 1.621; P = 0.036) after adjusting for covariates, including sex, age, body mass index, energy intake, smoking, physical activity, and C-reactive protein. Vegetable intake was not significantly associated with 8-OHdG. We also found a significant association between joint fruit and HCA intake and DNA damage, and the difference in 8-OHdG levels was significantly higher between participants with the lowest fruit intake and highest HCA intake and those with the highest fruit intake and non-HCA intake (P = 0.049). CONCLUSIONS: Lower intake of fruits and higher intake of HCAs were associated with higher DNA damage levels and showed an additive effect pattern. PMID- 26530456 TI - Bacillus gobiensis sp. nov., isolated from a soil sample. AB - A Gram-stain-positive, rod-shaped, endospore-forming, aerobic bacterium designated FJAT-4402T, was isolated from the weed rhizosphere soil of the Gobi desert in the Xinjiang Autonomous Region in the north-west of China. Isolate FJAT 4402T grew at 15-40 degrees C (optimum 30 degrees C), pH 5-10 (optimum pH 7) and in 0-3 % (w/v) NaCl (optimum 0 %). Phylogenetic analyses, based on 16S rRNA gene sequences, showed that isolate FJAT-4402T was a member of the genus Bacillus and was most closely related to Bacillus licheniformis DSM 13T (96.2 %). The isolate showed 33.3 % DNA-DNA relatedness to the closest reference isolate, B. licheniformis DSM 13T. The diagnostic diamino acid of the peptidoglycan of isolate FJAT-4402T was meso-diaminopimelic acid and the predominant isoprenoid quinone was MK-7. The major cellular fatty acids were anteiso-C15 : 0 (28.5 %), iso-C15 : 0 (20.1 %), anteiso-C17 : 0 (14.3 %), iso-C16 : 0 (9.6 %), C16 : 0 (8.4 %), iso-C17 : 0 (6.2 %) and iso-C14 : 0 (4.7 %) and the DNA G+C content was 42.0 mol%. The phenotypic, chemotaxonomic and genotypic properties indicated that strain FJAT-4402T represents a novel species within the genus Bacillus, for which the name Bacillus gobiensis sp. nov. is proposed. The type strain is FJAT-4402T ( = DSM 29500T = CGMCC 1.12902T). PMID- 26530457 TI - Cardiovascular Implantable Electronic Device Infections: Risk Scoring and Role of Antibiotic Envelope in Prevention. AB - Cardiac implantable electronic device (CIED) has been increasingly used with expanding indications in patients with cardiac diseases. There is substantial evidence to suggest of their role in improving outcomes in patients with and without heart failure. Complications of the device implantation including infections are associated with increased morbidity and mortality and also substantial financial burden to the society. Several clinical characteristics have been recognized as risk factors for the occurrence of the infections. Considering that infections occur in the presence of multiple risk factors acting together, scoring systems have been developed in identifying patients at risk. Despite preventive measures, the rates of infections associated with CIEDs have increased over the last decade. Recent studies have documented the role of implantable antibiotic eluting pouches in reducing infections in patients undergoing CIED implantation. The present review will address the risk scoring systems studied and also address the role of antibiotic pouch and the recent patents in developing this technology. PMID- 26530458 TI - Basic and Clinical Research Against Advanced Glycation End Products (AGEs): New Compounds to Tackle Cardiovascular Disease and Diabetic Complications. AB - Diabetes is a major risk factor for cardiovascular disease, and recent advances in research indicate that a detailed understanding of the pathophysiology of its effects is mandatory to reduce diabetes-related mortality and morbidity. Advanced Glycation End Products (AGEs) play a central role in the genesis and progression of complications of both type 1 and type 2 diabetes mellitus, and have been found to be important even in non-diabetic patients as a marker of cardiovascular disease. AGEs have a profound impact on patient's prognosis regardless of the glycemic control, and therefore pharmacologic approaches against AGEs accumulation have been proposed over the years to treat cardiovascular diseases, parallel to a more detailed understanding of AGEs pathophysiology. Compounds with anti-AGEs effects are currently under investigation in both pre-clinical and clinical scenarios, and many of the drugs previously used to treat specific diseases have been found to have AGE-inhibitory effects. Some products are still in "bench evaluation", whereas others have been already investigated in clinical trials with conflicting evidences. This review aims at summarizing the mechanisms of AGEs formation and accumulation, and the most relevant issues in pre-clinical and clinical experiences in anti-AGEs treatment in cardiovascular research. PMID- 26530459 TI - MouseMove: an open source program for semi-automated analysis of movement and cognitive testing in rodents. AB - The Open Field (OF) test is one of the most commonly used assays for assessing exploratory behaviour and generalised locomotor activity in rodents. Nevertheless, the vast majority of researchers still rely upon costly commercial systems for recording and analysing OF test results. Consequently, our aim was to design a freely available program for analysing the OF test and to provide an accompanying protocol that was minimally invasive, rapid, unbiased, without the need for specialised equipment or training. Similar to commercial systems, we show that our software-called MouseMove-accurately quantifies numerous parameters of movement including travel distance, speed, turning and curvature. To assess its utility, we used MouseMove to quantify unilateral locomotor deficits in mice following the filament-induced middle cerebral artery occlusion model of acute ischemic stroke. MouseMove can also monitor movement within defined regions-of interest and is therefore suitable for analysing the Novel Object Recognition test and other field-related cognitive tests. To the best of our knowledge, MouseMove is the first open source software capable of providing qualitative and quantitative information on mouse locomotion in a semi-automated and high throughput fashion, and hence MouseMove represents a sound alternative to commercial movement analysis systems. PMID- 26530460 TI - In Vivo Toxicity and Immunological Characterization of Detoxified Recombinant Botulinum Neurotoxin Type A. AB - PURPOSE: A double-mutant E224A/E262A full-length botulinum neurotoxin (BoNT) Type A with structural similarity to native BoNT/A but lacking the endopeptidase activity provides an ideal surrogate for testing pharmacokinetics and immunochemical characteristics of BoNT. METHODS: We determined lethality (LD50) of deactivated recombinant botulinum neurotoxin (drBoNT/A) to be 24.0 MUg by intraperitoneal route (i.p). The polypeptide drBoNT/A labeled with near infra-red dye 800 (NIR 800) was used to examine its distribution to different organs using whole body imaging when administered to mice via intravenous (i.v) or i.p route. Also, drBoNT/A was used to evaluate its immunogenicity in Balb/C mice model. RESULTS: drBoNT/A was found to be highly immunogenic when tested under various in vivo conditions in Balb/C mice model. For the first time we have demonstrated that a full length 150 kDa drBoNT/A, by administering via inhalation route in mice model, has evoked both circulating immunoglobulin levels of IgG and secretory IgA at the mucosal surface. The immunoglobulin levels were sufficient enough to protect against the challenge dose of native BoNT toxin in mice model. Tissue distribution of drBoNT/A seems to be similar to that of native toxin. CONCLUSIONS: Based on the characteristics described in this report this nontoxic holotoxin protein will assist us to explore the window of opportunity available for therapeutic treatment in case of unnatural poisoning, and also it can be an effective vaccine candidate. PMID- 26530461 TI - Clinical significance of Gremlin 1 in cervical cancer and its effects on cancer stem cell maintenance. AB - Gremlin 1 is one of the bone morphogenetic protein (BMP) antagonists and is also related to differentiation in combination with BMPs and is associated with various types of diseases. Gremlin 1 is overexpressed in various types of human cancers and has been reported to play a role in cervical cancer oncogenesis. However, there is no report concerning the relationship between Gremlin 1 and cervical cancer stem cells (CSCs). The objective of the present study was to identify the clinical significance of Gremlin 1 in cervical cancer and its effects on CSC-like properties in vitro. Clinical samples were obtained. Gremlin 1 mRNA expression levels in the cervical cancer tissues were measured by RT-qPCR and assessed for correlation with their clinical prognosis [overall survival (OS), progression-free survival (PFS)] and with other prognostic factors. In vitro, cervical cancer, CaSki cells, exposed to Gremlin 1 (1,000 ng/ml) for 24 h were evaluated for expression of undifferentiated-cell markers (Nanog, Oct3/4, Sox2) by RT-qPCR, the population of ALDH-positive cells by flow cytometry and sphere-forming ability on a ultra-low attachment culture dish. Cervical cancer tissues from 104 patients were collected. A high mRNA expression level of Gremlin 1 was an independent poor prognostic factor of PFS but not of OS. A high mRNA expression level of Gremlin 1 was correlated with bulky (>4 cm) tumors. The Nanog mRNA expression level was significantly increased in the CaSki cells exposed to Gremlin 1 (P=0.0008) but not Oct3/4 and Sox2 mRNA expression levels. The population of ALDH-positive cells in the Gremlin 1-exposed cells was 1.41-fold higher compared with the control (P=0.0184). Sphere-forming ability was increased when 1,000 Gremlin 1-exposed cells were seeded (P=0.0379). In cervical cancer, it is suggested that Gremlin 1 may have a role in clinical recurrence and maintaining CSC-like properties. PMID- 26530462 TI - Lifestyle for a lifetime. PMID- 26530463 TI - The differentiation of hMSCs counteracts their migration capability and pro angiogenic effects in vitro. AB - Human mesenchymal stem cells (hMSCs) have been applied therapeutically in numerous clinical trials. The pro-angiogenic effects of hMSCs, as well as their strong tumor tropism, have been shown both in vitro and in vivo. Some studies suggest using hMSCs as potential drug-carriers for tumor therapy. In previous investigations by our group, the pro-tumorigenic effects of hMSCs on head and neck squamous cell carcinoma (HNSCC) were shown. However, the influence of hMSCs on tumor vascularization as well as the possibility of its inhibition are yet to be elucidated. The cytokine patterns of the HNSCC cell line FaDu, native hMSCs (hMSCs-nat), hMSCs differentiated into adipocytes (hMSCs-adip) and osteocytes (hMSCs-ost) were evaluated. Human umbilical vein endothelial cells (HUVECs) were co-cultured with FaDu cells, hMSCs-nat, hMSCs-adip and hMSCs-ost. The capillary tube formation assay was applied. Furthermore, the migration capability of hMSCs nat, hMSCs-adip and hMSCs-ost towards FaDu cells was measured in a Transwell system. Spheroids were cultured from hMSCs-nat, FaDu cells and DiI-labeled HUVECs. FaDu cells, hMSCs-nat, hMSCs-adip and hMSCs-ost released a wide range of cytokines and growth factors, e.g., IL-6, IL-8, IL-10, GRO and MCP. In the capillary tube formation assay, HUVECs generated significantly longer tubes after co-cultivation with hMSCs-nat as compared to HUVECs alone and FaDu. Differentiation into adipocytes and osteocytes counteracted the tube formation. The adipogenic differentiation did not alter hMSC motility, whereas osteogenic differentiation significantly inhibited hMSC migration. Generation of multi cellular spheroids from hMSCs-nat, FaDu cells and DiI-labeled HUVECs was possible. Florescence microscopy revealed that all HUVECs were present in the spheroid core. Taken together, hMSCs-nat have a pro-angiogenic effect. The effects are counteracted by the differentiation of hMSCs towards osteogenic and adipogenic lineages. The differentiation of stem cells into different lineages may be a promising solution to generating carriers for cancer therapy without pro tumorigenic properties. PMID- 26530464 TI - Long Non-Coding RNA Central of Glucose Homeostasis. AB - Glucose metabolism is one of the fundamental biochemical processes in mammals. Metabolism of glucose is subjected to tissue and cell specific regulation involving many transporters, enzymes, and transcriptional factors. Dysregulation of glucose metabolism has been linked to many human diseases such as diabetes and cancer. Long non-coding RNAs (lncRNAs) are a novel class of functional RNAs that regulate multiple biological functions through diverse mechanisms including recruitment of epigenetic modifier proteins, control of mRNA decay and translation, and DNA sequestration of transcription factors. Recent studies have demonstrated that lncRNAs play an important role in regulating differentiation and homeostasis of metabolic tissues. This review will discuss lncRNA biology with a focus on their role in regulating glucose metabolism in cancer cells and metabolic tissues. PMID- 26530465 TI - Effect of thermodiffusion on pH-regulated surface charge properties of nanoparticle. AB - Surface properties of nanoparticle are of high importance in the field of biotechnology, drug delivery and micro/nanofabrication. In this article, we developed a comprehensive theoretical model and subsequently solved that numerically to study the effect of thermodiffusion of ions on surface charge properties of nanoparticle. The theoretical study has been done considering silica nanoparticle for two aqueous solutions NaCl and KCl. The effect of solution pH in conjunction with nanoparticle temperature on surface charge density has been obtained for different salt concentrations (1, 10 and 100 mM) and nanoparticle size (diameter of 2 and 100 nm). It is observed from the results that with increasing temperature of the nanoparticle, the negative surface charge density gets higher due to increasing thermodiffusion effect. It is also found out that the magnitude of surface charge density is higher for KCl solution than NaCl solution under same condition which is attributed mostly due to less thermodiffusion of counterions for KCl than NaCl. Present study also shows that magnitude of surface charge density decreases with increasing nanoparticle size until it reaches a limiting value (called critical size) above which the effect of nanoparticle size on surface charge density is insignificant. PMID- 26530466 TI - Charge-displacement analysis as a tool to study chalcogen bonded adducts and predict their association constants in solution. AB - The secondary interaction between a polarized chalcogen atom and different Lewis bases, either anionic or neutral, has been studied by charge displacement analysis. Using charge displacement analysis, the charge rearrangement in the adduct upon the formation of the interaction has been quantified and described in great detail. By comparing the theoretical results with the experimental association constants, two linear correlations can be found for anionic and neutral bases. Such correlations can be used to reliably predict the association constants of adducts for which experimental data are not available yet. PMID- 26530472 TI - Electronic and geometric structures of Au30 clusters: a network of 2e-superatom Au cores protected by tridentate protecting motifs with u3-S. AB - Density functional theory calculations have been performed to study the experimentally synthesized Au30S(SR)18 and two related Au30(SR)18 and Au30S2(SR)18 clusters. The patterns of thiolate ligands on the gold cores for the three thiolate-protected Au30 nanoclusters are on the basis of the "divide and protect" concept. A novel extended protecting motif with u3-S, S(Au2(SR)2)2AuSR, is discovered, which is termed the tridentate protecting motif. The Au cores of Au30S(SR)18, Au30(SR)18 and Au30S2(SR)18 clusters are Au17, Au20 and Au14, respectively. The superatom-network (SAN) model and the superatom complex (SAC) model are used to explain the chemical bonding patterns, which are verified by chemical bonding analysis based on the adaptive natural density partitioning (AdNDP) method and aromatic analysis on the basis of the nucleus-independent chemical shift (NICS) method. The Au17 core of the Au30S(SR)18 cluster can be viewed as a SAN of one Au6 superatom and four Au4 superatoms. The shape of the Au6 core is identical to that revealed in the recently synthesized Au18(SR)14 cluster. The Au20 core of the Au30(SR)18 cluster can be viewed as a SAN of two Au6 superatoms and four Au4 superatoms. The Au14 core of Au30S2(SR)18 can be regarded as a SAN of two pairs of two vertex-sharing Au4 superatoms. Meanwhile, the Au14 core is an 8e-superatom with 1S(2)1P(6) configuration. Our work may aid understanding and give new insights into the chemical synthesis of thiolate protected Au clusters. PMID- 26530471 TI - Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. AB - Although platinum-based drugs are widely used chemotherapeutics for cancer treatment, the determinants of tumor cell responsiveness remain poorly understood. We show that the loss of subunits LRRC8A and LRRC8D of the heteromeric LRRC8 volume-regulated anion channels (VRACs) increased resistance to clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% of cisplatin uptake depended on LRRC8A and LRRC8D, but neither on LRRC8C nor on LRRC8E. Cell swelling strongly enhanced LRRC8-dependent cisplatin uptake, bolstering the notion that cisplatin enters cells through VRAC. LRRC8A disruption also suppressed drug-induced apoptosis independently from drug uptake, possibly by impairing VRAC-dependent apoptotic cell volume decrease. Hence, by mediating cisplatin uptake and facilitating apoptosis, VRAC plays a dual role in the cellular drug response. Incorporation of the LRRC8D subunit into VRAC substantially increased its permeability for cisplatin and the cellular osmolyte taurine, indicating that LRRC8 proteins form the channel pore. Our work suggests that LRRC8D-containing VRACs are crucial for cell volume regulation by an important organic osmolyte and may influence cisplatin/carboplatin responsiveness of tumors. PMID- 26530468 TI - A fronto-striato-subthalamic-pallidal network for goal-directed and habitual inhibition. AB - Classically, the basal ganglia have been considered to have a role in producing habitual and goal-directed behaviours. In this article, we review recent evidence that expands this role, indicating that the basal ganglia are also involved in neural and behavioural inhibition in the motor and non-motor domains. We then distinguish between goal-directed and habitual (also known as automatic) inhibition mediated by fronto-striato-subthalamic-pallido-thalamo-cortical networks. We also suggest that imbalance between goal-directed and habitual action and inhibition contributes to some manifestations of Parkinson's disease, Tourette syndrome and obsessive-compulsive disorder. Finally, we propose that basal ganglia surgery improves these disorders by restoring a functional balance between facilitation and inhibition. PMID- 26530473 TI - Identifying clinical correlates for suicide among epilepsy patients in South Korea: A case-control study. AB - OBJECTIVE: Suicide is a major cause of premature mortality in patients with epilepsy. We aimed to identify the clinical correlates of suicide in these patients. METHODS: We conducted a matched, case-control study based on a clinical case registry of epilepsy patients (n = 35,638) treated between January 1994 and December 2011 at an academic tertiary medical center in Seoul, Korea. Each epilepsy patient in the suicide group (n = 74) was matched with three epilepsy patients in the nonsuicide group (n = 222) by age, gender, and approximate time at first treatment. The clinical characteristics of the patients in both groups were then compared. RESULTS: In a univariate analysis, seizure frequency during the year before suicide, use of antiepileptic drug polytherapy, lack of aura before seizure, diagnosis of temporal lobe epilepsy, use of levetiracetam, psychiatric comorbidity, and use of antidepressants were all significantly higher in the suicide group than in the nonsuicide group. Multivariate analysis revealed that a high seizure frequency (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.04-10.2), a lack of aura before seizure (OR 4.0, 95% CI 1.7-9.3), temporal lobe epilepsy (OR 3.7, 95% CI 1.6-8.6), and use of levetiracetam (OR 7.6, 95% CI 1.1 53.7) and antidepressants (OR 7.2, 95% CI 1.5-34.1) were all associated with a higher probability of suicide. SIGNIFICANCE: Patients with temporal lobe epilepsy who experience seizures weekly or more frequently, experience a lack of aura, use levetiracetam, or take antidepressants are all at a higher risk of suicide and should be monitored closely. PMID- 26530474 TI - The Potential Explanatory Role of Perceived Stress in Associations Between Subjective Social Status and Health-Related Quality of Life Among Homeless Smokers. AB - Homeless individuals smoke at high rates relative to the general population and are at heightened risk of tobacco-related illnesses and poor health-related quality of life (HRQoL). Homeless smokers also report low subjective social status (SSS) or perceived social standing relative to others. SSS may contribute to poor HRQoL, potentially through perceived stress. The current study examined the role of perceived stress in the association of SSS and HRQoL among 227 (70.9% male, Mage = 43.2) homeless smokers. Participants completed self-report measures of SSS, perceived stress, and HRQoL. Perceived stress partially explained the relation between SSS (United States and Community) and HRQoL in covariate adjusted analyses. Results suggested that perceived stress is a pathway through which SSS contributes to HRQoL among homeless smokers. Findings broaden current understanding of the impact of social disadvantage and perceived stress on HRQoL among homeless smokers. PMID- 26530475 TI - Distress Tolerance as a Predictor of Adherence to a Yoga Intervention: Moderating Roles of BMI and Body Image. AB - This study tested whether distress tolerance, body image, and body mass index (BMI) predicted adherence to a yoga intervention. Participants were 27 women who participated in a yoga intervention as part of a randomized controlled trial. Attendance and distress tolerance were assessed weekly, and body image and BMI were measured at baseline. Multilevel modeling revealed a three-way interaction of distress tolerance, BMI, and body image (p < .001). For participants with few body image concerns, distress tolerance was positively associated with adherence regardless of BMI (p = .009). However, for those with poor body image, increases in distress tolerance were associated with increases in adherence among overweight participants (p < .001) but lower adherence among obese participants (p = .007). Distress tolerance may be implicated in adherence to a yoga intervention, although its effects may be dependent on body image concerns, BMI, and their interaction. Research and clinical implications are discussed. PMID- 26530476 TI - Low Mass Blood Peptides Discriminative of Inflammatory Bowel Disease (IBD) Severity: A Quantitative Proteomic Perspective. AB - Breakdown of the protective gut barrier releases effector molecules and degradation products into the blood stream making serum and plasma ideal as a diagnostic medium. The enriched low mass proteome is unexplored as a source of differentiators for diagnosing and monitoring inflammatory bowel disease (IBD) activity, that is less invasive than colonoscopy. Differences in the enriched low mass plasma proteome (<25 kDa) were assessed by label-free quantitative mass spectrometry. A panel of marker candidates were progressed to validation phase and "Tier-2" FDA-level validated quantitative assay. Proteins important in maintaining gut barrier function and homeostasis at the epithelial interface have been quantitated by multiple reaction monitoring in plasma and serum including both inflammatory; rheumatoid arthritis controls, and non-inflammatory healthy controls; ulcerative colitis (UC), and Crohn's disease (CD) patients. Detection by immunoblot confirmed presence at the protein level in plasma. Correlation analysis and receiver operator characteristics were used to report the sensitivity and specificity. Peptides differentiating controls from IBD originate from secreted phosphoprotein 24 (SPP24, p = 0.000086, 0.009); whereas those in remission and healthy can be differentiated in UC by SPP24 (p = 0.00023, 0.001), alpha-1-microglobulin (AMBP, p = 0.006) and CD by SPP24 (p = 0.019, 0.05). UC and CD can be differentiated by Guanylin (GUC2A, p = 0.001), and Secretogranin-1 (CHGB p = 0.035). Active and quiescent disease can also be differentiated in UC and CD by CHGB (p <= 0.023) SPP24 (p <= 0.023) and AMBP (UC p = 0.046). Five peptides discriminating IBD activity and severity had very little-to-no correlation to erythrocyte sedimentation rate, C-reactive protein, white cell or platelet counts. Three of these peptides were found to be binding partners to SPP24 protein alongside other known matrix proteins. These proteins have the potential to improve diagnosis and evaluate IBD activity, reducing the need for more invasive techniques. Data are available via ProteomeXchange with identifier PXD002821. PMID- 26530477 TI - Liposuction Preserves the Morphological Integrity of the Microvascular Network: Flow Cytometry and Confocal Microscopy Evidence in a Controlled Study. AB - BACKGROUND: Liposuction is a very popular technique in plastic surgery that allows for the taking adipose tissue (AT) on large surfaces with little risk of morbidity. Although liposuction was previously shown to preserve large perforator vessels, little is known about the effects of liposuction on the microvasculature network. OBJECTIVES: The aim of this study was to analyze the effect of liposuction on the preservation of microvessels at tissue and cellular levels by flow cytometry and confocal microscopy following abdominoplasty procedure. METHODS: Percentage of endothelial cells in AT from liposuction and en bloc AT was determined by multicolor flow cytometry. Moreover, vessel density and adipocyte content were analyzed in situ in 3 different types of AT (en bloc, from liposuction, and residual AT after liposuction) by confocal microscopy. RESULTS: Flow cytometric analysis showed that en bloc AT contained 30.6% +/- 12.9% and AT from liposuction 21.6% +/- 9.9% of endothelial cells (CD31(pos)/CD45(neg)/CD235a(neg)/CD11b(neg)) (P = .009). Moreover, analysis of paired AT from the same patients (n = 5) confirmed a lower percentage of endothelial cells in AT from liposuction compared to en bloc AT (17.7% +/- 4.5% vs 21.9% +/- 3.3%, P = .031). Likewise, confocal microscopy showed that en bloc AT contained 8.2% +/- 6.3%, AT from liposuction only 1.6% +/- 1.0% (P < .0001), and AT after liposuction 8.9% +/- 4.1% (P = .111) of CD31(pos) vessels. Conversely, adipocyte content was 39.5% +/- 14.5% in the en bloc AT, 45% +/- 18.4% in AT from liposuction (P = .390), and 18.8 +/- 14.8% in AT after liposuction (P = .011). CONCLUSIONS: For the first time, we demonstrate that liposuction preserves the microvascular network. Indeed, a low percentage of endothelial cells was found in AT from liposuction and we confirm the persistence of microvessels in the tissue after liposuction. PMID- 26530478 TI - Placement of Absorbable Dermal Staples in Mammaplasty and Abdominoplasty: A 12 Month Prospective Study of 60 Patients. AB - BACKGROUND: The duration to close an incision is an important consideration in plastic surgery. The placement of Insorb absorbable subcuticular staples (Insorb, Incisive Surgical, Plymouth, MN) may allow for a decreased closure time compared with other modalities. OBJECTIVES: The authors evaluated the utility of Insorb staples for the closure of mammaplasty and abdominoplasty incisions. METHODS: Sixty patients who underwent anterior abdominal dermatolipectomy, total circular abdominal dermatolipectomy, bilateral breast reduction, or bilateral mastopexy were evaluated in a prospective study. Dermal closure was achieved on 1 side of each patient with Insorb absorbable staples and on the other with absorbable monofilament sutures. Scar quality, pruritus, and pain were scored according to a modified Vancouver Scar Scale (mVSS) at 1, 6, and 12 months postoperatively. RESULTS: Closure with absorbable staples was approximately 7-fold faster than closure with absorbable sutures for all surgical procedures. No significant differences in mVSS scores were noted between incisions closed with staples vs sutures. CONCLUSIONS: Absorbable staples enable faster closure of a surgical incision without compromising scar quality or patient comfort. LEVEL OF EVIDENCE: 3 Therapeutic. PMID- 26530479 TI - Nasopharyngeal Placement of a Nelaton Suction Catheter in Respiratory Monitoring of Sedated Patients. PMID- 26530480 TI - Commentary on: Interaction Between Breast Cancer Cells and Adipose Tissue Cells Derived from Fat Grafting. PMID- 26530481 TI - A Comparison of Research Productivity Across Plastic Surgery Fellowship Directors. AB - BACKGROUND: Objective measures of research productivity depend on how frequently a publication is cited. Metrics such as the Hirsch index (h-index; total number of publications h that have at least h citations) allow for an objective measurement of the scientific impact of an author's publications. OBJECTIVES: The purpose of this study was to assess and compare the h-index among aesthetic plastic surgery fellowship directors to that of fellowship directors in craniofacial surgery and microsurgery. METHODS: We conducted a cross-sectional study of all fellowship directors in aesthetic surgery, craniofacial surgery, and microsurgery in the United States and Canada. The gathered data were categorized as bibliometric (h-index, i10-index, total number of publications, total number of citations, maximum citations for a single work, and number of self-citations) and demographic (gender, training background). Descriptive statistics were computed. RESULTS: The sample was composed of 30 aesthetic surgeons (93% male), 33 craniofacial surgeons (97% male), and 32 microsurgeons (94% male). The mean h index was 13.7 for aesthetics, 16.9 for craniofacial, and 12.4 for microsurgery. There were no significant differences for any of the bibliometric measures between the three subspecialties, despite the fact that academic rank and years in practice were significantly different. CONCLUSIONS: As measured by the h index, there is a high level of academic productivity among fellowship directors, regardless of subspecialty area. Unlike other plastic surgery subspecialties however, the h-index of aesthetic plastic surgeons is not correlated to academic rank, revealing a discrepancy between perceptions of aesthetic plastic surgery and its actual academic impact. PMID- 26530482 TI - Breast Implant Registries: The Problem with Ambition. PMID- 26530483 TI - Reliability of Nasofacial Analysis Using Rhinobase(r) Software. AB - OBJECTIVE: Rhinoplasty is a constant challenge for the surgeon, where the correct evaluation of facial aesthetic parameters allows harmonic changes appropriate for each patient. The aim of this study was to compare the preoperative and postoperative results of nasofacial analysis, performed by Rhinobase(r) software (indirect anthropometry) compared with direct anthropometry (caliper), in patients undergoing aesthetic rhinoplasty. METHODS: The authors assessed the reliability of using Rhinobase(r) software for measuring nasofacial characteristics in 20 individuals (18 F, 2 M). In each patient, the nasofacial analysis was performed before and after surgery. Two raters performed indirect anthropometry on each image on two separate occasions. RESULTS: Intrarater and interrater reliability for most indirect anthropometric measurements had intraclass correlation coefficients greater than 0.8. Regarding intermethod reliability, Pearson correlation coefficients ranged from 0.6 to 0.9 for most measurements. The highest correlation was found in interalar width, chin vertical, and lower facial height. The Cronbach's alpha coefficient calculated for all measurements was 0.8. CONCLUSIONS: The Rhinobase(r) software is an easy and safe method for facial analysis. This study provides evidence of high reliability for several nasofacial measurements. The nasofacial analysis allows an accurate preoperative evaluation, surgical planning, and analysis of outcomes in rhinoplasty and may be a useful tool for both novice and experienced surgeons. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26530484 TI - Risk Factors for Complications in Immediate Expander-Implant Breast Reconstruction for Non-obese Patients: Impact of Breast Size on Complications. AB - BACKGROUND: Although obesity is a well-known risk factor for complications in immediate expander-implant breast reconstruction, no studies have identified risk factors for non-obese patients. The purpose of this study was to identify risk factors for complications in non-obese patients. METHODS: A retrospective analysis of prospectively collected data from 397 consecutive immediate expander implant breast reconstructions in 367 non-obese patients at a single institution over a 5-year period was conducted. Univariable and multivariable analysis were performed to determine the influence of six patient-related and eight procedure related characteristics on complications. RESULTS: Mean BMI was 21.7 +/- 2 kg/m(2) and median mastectomy weight was 298.0 g (range: 40-1164 g). Multivariable analysis showed that neither BMI nor the use of acellular dermal matrix was a predictor for complications. Adjuvant radiation (odds = 3.12, p < 0.001) and mastectomy weight (p < 0.001) were independent risk factors for complications. A 100 g increase in the mastectomy weight was significantly associated with a 23 % increase in the odds of overall complications (p = 0.003), major complications (p = 0.004), and skin flap complications (p = 0.007), as well as a 28 % increase in the odds of seroma (p = 0.044), but was not associated with reconstruction failure. Adjuvant radiation (p < 0.001) and hypertension (p < 0.001) were risk factors for reconstruction failure. CONCLUSIONS: Breast size was an independent risk factor for complications in non-obese patients while BMI was not. In the reconstruction of large breasts, greater attention and additional adjunctive procedures would be needed to prevent complications. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26530485 TI - Quinone-Catalyzed Selective Oxidation of Organic Molecules. AB - Quinones are common stoichiometric reagents in organic chemistry. Para-quinones with high reduction potentials, such as DDQ and chloranil, are widely used and typically promote hydride abstraction. In recent years, many catalytic applications of these methods have been achieved by using transition metals, electrochemistry, or O2 to regenerate the oxidized quinone in situ. Complementary studies have led to the development of a different class of quinones that resemble the ortho-quinone cofactors in copper amine oxidases and mediate the efficient and selective aerobic and/or electrochemical dehydrogenation of amines. The latter reactions typically proceed by electrophilic transamination and/or addition-elimination reaction mechanisms, rather than hydride abstraction pathways. The collective observations show that the quinone structure has a significant influence on the reaction mechanism and has important implications for the development of new quinone reagents and quinone-catalyzed transformations. PMID- 26530486 TI - PTEN and TP53 Mutations in Oncocytic Follicular Carcinoma. AB - Oncocytic follicular carcinoma (OFC)/Hurthle cell carcinoma represents 3-4 % thyroid carcinomas and can be associated with more aggressive behavior and compromised survival compared to non-oncocytic thyroid carcinoma. In this study, we utilized targeted next-generation sequencing to investigate the molecular alterations in a heterogeneous group of clinically aggressive OFC. A total of 12 cases of OFC were included in this study. Targeted next-generation sequencing was performed using panels of 47 or 20 genes, which are frequently mutated in solid tumors. The case cohort comprised eight cases of angioinvasive OFC, two cases of poorly differentiated OFC, one case of OFC with anaplastic change, and one case of OFC with capsular invasion only. Five out of 12 cases (42 %) harbored TP53 mutation. PTEN mutations were also seen in three cases with TP53 mutation (25 %). Based on this study, TP53 and PTEN are possibly involved in the pathogenesis of OFC. Further studies on a larger case cohort are needed to further elucidate this mechanism and its effect on clinical behavior of these intriguing tumors. PMID- 26530487 TI - Optical reprogramming of human cells in an ultrashort femtosecond laser microfluidic transfection platform. AB - Induced pluripotent stem cell (iPS cell) technology can be used to produce unlimited numbers of functional cells for both research and therapeutic purposes without ethical controversy. Typically, viruses are applied for efficient intracellular delivery of genes/transcription factors to generate iPS cells. However, the viral genomic integration may cause a risk of mutation as well as tumor formation therefore limits its clinical application. Here we demonstrate that spatially shaped extreme ultrashort laser pulses of sub-20 femtoseconds induce transient membrane permeabilisation which enables contamination-free transfection of cells in a microfluidic tube with multiple genes at the individual cell level in order to achieve optical reprogramming of large cell populations. We found that the ultrashort femtosecond laser-microfluidic cell transfection platform enhanced the efficacy of iPS-like colony-forming following merely a single transfection. Illustration of the spatially shaped femtosecond laser-assisted microfluidic cell transfection platform for production of iPS cell colonies. PMID- 26530488 TI - [Differential diagnostics of hypomelanoses]. AB - Hypomelanoses of the skin encompass a wide spectrum of congenital and acquired alterations in melanin pigmentation. These diseases can be localized or universal. The pathobiology of cutaneous hypomelanoses is heterogeneous and includes defects in melanoblast migration from the neural crest to the epidermis, alterations in melanogenesis and melanin transfer to keratinocytes, and destruction of pigment cells by autoimmune and inflammatory processes. Importantly, some congenital forms of universal hypomelanoses are associated with involvement of internal organs (e.g., Hermansky-Pudlack or Chediak-Higashi syndrome) and require interdisciplinary patient management. In recent years, significant progress has been made in our current understanding of the pathophysiology especially of vitiligo, thus, resulting in promising new treatment strategies. This disease being one of the most common forms of acquired hypomelanoses of the skin can now be treated in a guideline-oriented and evidence based manner. PMID- 26530489 TI - [Modern allergy diagnostic procedures and their clinical application]. AB - Due to the increasing incidence of allergies, the importance of allergy diagnostic procedures is growing. In addition to a patient's history and prick, intracutaneous and patch testing, serological testing is an important diagnostic procedure. In recent years, tremendous advances have been made in the area of in vitro allergy tests. In particular, it is possible to predict severity and risk management of food allergies with component-based IgE diagnostic procedures. Even new allergy syndromes have been elucidated at the molecular level. PMID- 26530490 TI - California doctor convicted of murder over deaths of three patients by overdose. PMID- 26530491 TI - Comparison of amoxicillin + clavulanate with or without intranasal fluticasone for the treatment of uncomplicated acute rhinosinusitis in children. AB - AIM: Intranasal corticosteroids (INS) have been proven effective in controlling postnasal drip, decreasing inflammatory response, reducing nasal swelling, and increasing aeration of the sinuses such that INS are recommended as treatment of sinusitis. METHODS: Fifty children with acute rhinosinusitis, 50 children with acute rhiniosinusitis and allergic rhinitis (AR), and 20 rhiniosinusitis children as control were selected for investigation. Each group had a single-blind treatment of three types: with coamoxiclav only, with coamoxiclav plus INS, and with matched placebo (without antibiotics and INS) for two weeks. Nasal symptoms were then evaluated. The outcome was measured by using major symptom score (MSS) after treatment for 14 days. RESULTS: Therapeutic effectiveness was 92% in rhinosinusitis patients treated with co-amoxiclav and 84% in those treated with co-amoxiclav plus INS. Among patients with sinusitis combined with AR, therapeutic efficacy was 88% for those treated with co-amoxiclav and 96% for those treated with co-amoxiclav plus INS. Only 30% of the symptoms were reduced in the placebo group. CONCLUSION: There are no statistical differences in the acute sinusitis group treated with co-amoxiclav with or without INS. In the sinusitis with AR group, the efficacy of co-amoxiclav with INS is higher than in children treated with co-amoxiclav alone. PMID- 26530492 TI - [Neurological and neuropsychological comparison between subjects with learning disorder and those suffering from learning difficulties when eeg abnormalities are detected at pediatric age]. AB - AIM: The objective of the study is to compare data and investigate the points of overlap between the two clinical conditions. The hypothesis is to observe a similar cognitive and neuropsychological profile in LD children and subjects with electroencephalogram (EEG) abnormalities. METHODS: The present study consists of a descriptive analysis of 35 children who have been tested for suspected learning disorder (LD). The diagnostic protocol includes a detailed cognitive and neuropsychological evaluation, as well as logopedic and neuropsychomotor assessment. Children carried neurological visit, EEG in waking and encephalic nuclear magnetic resonance (NMR). In this study, anamnestic data and the results of some of the neuropsychological tests were administrated to children and subsequently were analyzed. Depending on EEG report (positive or negative), subjects were split in two subsample: subjects with "pure" LD and subjects who showed significant paroxysmal abnormalities at the EEG. RESULTS: This comparison shows that the profile of the two subsamples matches for many aspects. The only statistically significant differences are the increased impairment of meta phonological skills and reading speed in children with EEG abnormalities. On the other hand, children with "pure" LD are inclined to manifest more frequently difficulties in highly-modularized processes, such as counting. CONCLUSION: In conclusion, the substantial overlap of the two profiles causes a reflection about the difficulty in making differential diagnosis in children who show a suspected LD, in absence of an accurate neurophysiological and neuroradiological investigation. The study did not find out useful markers to select subjects who should carry EEG and encephalic NMR. Our team established to keep EEG in waking in the diagnostic protocol, for all children with LD diagnosis. Only in case of abnormalities at the track, we prescribed EEG in sleeping and encephalic NMR. PMID- 26530493 TI - [Diagnosis and treatment of Helicobacter pylori infection in pediatrics: recommendation for 2014 clinical practice]. AB - Helicobacter pylori (H. pylori) infection is a large worldwide infection usually acquired during childhood, whose prevalence in pediatric population varies, with lower incidence rates in developed countries compared to developing countries (up to 10-15% and 70%, respectively). Diagnosis can be performed both with endoscopic based methods and noninvasive diagnostic tests, such as urea breath test and fecal antigen. Current guidelines recommend endoscopic evaluation of the young patients, in order to determine the underlying cause of abdominal pain. Even in case of suspected functional pain, patient should not be investigated for infection, unless upper endoscopy is performed to rule out organic causes. Nowadays, in pediatric population, applications of noninvasive tests are limited to verifying eradication after therapy and to investigating the presence of infection in asymptomatic patients with first-degree relatives affected by gastric cancer. Since correlation between abdominal pain and H. pylori gastritis, in absence of peptic ulcer disease is still debated, "test and treat" strategy is not recommended in children. As for adults, treatment regimens are based on the combination of proton-pump inhibitor and two or more antibiotics, for 7-14 days, depending on resistance rates of geographic areas. PMID- 26530494 TI - Laparoscopy or retroperitoneoscopy for pediatric patients with adrenal masses? AB - Minimally invasive approach to the adrenal gland was first reported in 1992. Since then, the experience with the laparoscopic technique for adrenal disease in children has been limited. We report our experience with minimally invasive adrenal surgery in children. Two young girls (2 and 4 years old) with a left adrenal mass were operated using minimally invasive surgery (MIS) in our Unit. Ultrasonography and MRI showed in the oldest a 2 x 3 cm adrenal mass, while in the youngest a 5.5 x 5 cm adrenal tumor was found. According to the pre-existing literature, we approached the smallest lesion via retroperitoneoscopy, and the largest one laparoscopically. The operating time was 110 minutes for retroperitoneoscopy and 75 minutes for laparoscopy. No major intra or postoperative complications occurred. There were no conversions to open surgery. Postoperative hospital stay was 5 days for both patients. In both cases, the anatomo-pathological result was an adenoma. Minimally invasive adrenalectomy is a safe and feasible procedure in children with good results. For lesions smaller than 3-4 cm retroperitonescopy is feasible, while for tumors larger than 5 cm, due to malignancy risk, the laparoscopic approach is indicated. To keep oncologic criteria it is important to avoid tumor rupture and to extract the specimen in an endobag. PMID- 26530495 TI - Poststreptococcal acute glomerulonephritis presenting as posterior reversible encephalopathy syndrome in an eleven-year-old boy. PMID- 26530496 TI - Conditional Beliefs of Primary-Care Patients with Treatment-Resistant Depression. AB - BACKGROUND: Cognitive behaviour therapy (CBT) for patients with treatment resistant depression (TRD) aims to reframe underlying conditional beliefs that are thought to maintain depression. AIM: To systematically explore conditional beliefs expressed by primary-care based patients with TRD, defined as non response to at least 6 weeks of antidepressants. METHOD: Conditional beliefs (stated in an "If. . .then. . ." format) were extracted from a random sample of 50 sets of therapist notes from the CoBalT trial, a large randomized controlled trial of CBT for TRD in primary care. The beliefs were separated into their two constituent parts; the demands (Ifs) and consequences (thens). An approach based on framework analysis provided a systematic way of organizing the data, and identifying key themes. RESULTS: Four main themes emerged from the demand part of the conditional beliefs (Ifs): 1. High standards; 2. Putting others first/needing approval; 3. Coping; and 4. Hiding "true" self. Three main themes emerged from the consequence part of the conditional beliefs (thens): 1. Defectiveness; 2. Responses of others; 3. Control of emotions. CONCLUSIONS: Identifying common themes in the conditional beliefs of patients with TRD adds to our clinical understanding of this client group, providing useful information to facilitate the complex process of collaborative case conceptualization and working with conditional beliefs within CBT interventions. PMID- 26530497 TI - A review of potential pharmacogenetic effects on catecholamine responses. AB - Considerably, variability in the clinical response to inotropic agents is observed and could be explained partially by the genetic variants, such as single nucleotide polymorphism (SNP) in genes encoding for enzymes implicated in catecholamines synthesis, metabolism, storage and release or in the signaling pathway. This review highlights the potential effect of pharmacogenetics studies in hemodynamic response and identified 11 SNPs that could be relevant to explain the high variability drug response for a same dose. Cardiovascular instability, such as hypotension, is one of the premature birth complications. The pharmacogenetics studies evaluating these SNP may be useful to better understand the clinical outcome, particularly in this population. PMID- 26530498 TI - TIPE2 functions as a metastasis suppressor via negatively regulating beta-catenin through activating GSK3beta in gastric cancer. AB - Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TNFAIP8L2, TIPE2) is a novel anti-inflammatory factor involved in maintaining immune homeostasis. Accumulating evidence has also shown that TIPE2 displays tumor-suppressive effects in several tumor types. Previous studies revealed that TIPE2 inhibits hepatocellular carcinoma metastasis by repressing Ral and Rac1 GTPases. However, its antimetastatic activity and underlying mechanism in other human cancers is largely unknown. We investigated TIPE2 in AGS, HGC-27 and SGC-7901 human gastric cancer cells compared with GES-1 normal human gastric mucous epithelial cells. We demonstrated that TIPE2 was expressed in GES-1 gastric mucous epithelial cells but lost in all three types of gastric cancer cells. We then performed a gain-of function study by adenovirus-mediated TIPE2 overexpression (AdVTIPE2) and investigated the effects of TIPE2 on migration and invasion of AGS human gastric cancer cells. Wound healing and Transwell invasion assays showed that forced expression of TIPE2 markedly suppressed the gastric cancer cell migration and invasion in vitro. Mechanistically, TIPE2 remarkably reduced the total levels of pAKT, pGSK3beta and beta-catenin as well as the nuclear level of beta-catenin in gastric cancer cells. The TIPE2-elicited antimetastatic effect in gastric cancer was closely associated with the inhibition of AKT signaling and enhancement of GSK3beta activity followed by the degradation and decreased translocation to nucleus of beta-catenin. These results provide the first compelling evidence that TIPE2 suppresses gastric cancer metastasis via downregulating beta-catenin signaling through inhibiting AKT and activating GSK3beta, indicating that TIPE2 is a promising therapeutic target for human gastric cancer metastasis. PMID- 26530499 TI - Hepatitis B virus, hepatitis C virus and human immunodeficiency virus infection in undocumented migrants and refugees in southern Italy, January 2012 to June 2013. AB - Screening of undocumented migrants or refugees for hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections has been offered free of charge and free from bureaucratic procedures since 2012 at four primary-level clinical centres in Naples and Caserta, Italy. Of 926 undocumented migrants and refugees visiting one of the primary-level clinical centres from January 2012 to June 2013, 882 (95%) were screened for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (anti-HBc) and antibodies against HCV and HIV. Of the 882 individuals enrolled, 78 (9%) were HBsAg positive, 35 (4%) anti-HCV positive and 11 (1%) anti-HIV positive (single infections); seven (1%) had more than one infection (three were HBsAg positive). Of the 801 HBsAg-negative patients, 373 (47%) were anti-HBc positive. The HBsAg positivity rate was high (14%; 62/444) in individuals from sub-Saharan Africa and intermediate in those from eastern Europe (6%; 12/198), northern Africa (2%; 2/80) and Bangladesh, India, Pakistan and Sri Lanka (the 'India-Pakistan area') (3%; 4/126). Anti-HCV was detected in 9/126 (7%) individuals originating from the India-Pakistan area, in 12/198 (6%) from eastern Europe, in 17/444 (4%) from sub Saharan and in 2/80 (2%) from northern Africa. The HBV, HCV and HIV infections in the undocumented migrants and refugees screened serve as a reminder to the Italian healthcare authorities to carry out extensive screening and educational programmes for these populations. PMID- 26530500 TI - Good continuum of HIV care in Belgium despite weaknesses in retention and linkage to care among migrants. AB - BACKGROUND: The Belgian HIV epidemic is largely concentrated among men who have sex with men and Sub-Saharan Africans. We studied the continuum of HIV care of those diagnosed with HIV living in Belgium and its associated factors. METHODS: Data on new HIV diagnoses 2007-2010 and HIV-infected patients in care in 2010 2011 were analysed. Proportions were estimated for each sequential stage of the continuum of HIV care and factors associated with attrition at each stage were studied. RESULTS: Of all HIV diagnosed patients living in Belgium in 2011, an estimated 98.2% were linked to HIV care, 90.8% were retained in care, 83.3% received antiretroviral therapy and 69.5% had an undetectable viral load (<50 copies/ml). After adjustment for sex, age at diagnosis, nationality and mode of transmission, we found lower entry into care in non-Belgians and after preoperative HIV diagnoses; lower retention in non-Belgians and injecting drug users; higher retention in men who have sex with men and among those on ART. Younger patients had lower antiretroviral therapy uptake and less viral suppression; those with longer time from diagnosis had higher ART uptake and more viral suppression; Sub-Saharan Africans on ART had slightly less viral suppression. CONCLUSIONS: The continuum of HIV care in Belgium presents low attrition rates over all stages. The undiagnosed HIV-infected population, although not precisely estimated, but probably close to 20% based on available survey and surveillance results, could be the weakest stage of the continuum of HIV care. Its identification is a priority along with improving the HIV care continuum of migrants. PMID- 26530501 TI - Pharmacokinetics, pharmacodynamics and toxicology of new psychoactive substances (NPS): 2C-B, 4-fluoroamphetamine and benzofurans. AB - BACKGROUND: Recently, the number of new psychoactive substances (NPS) appearing on the illicit drug market has shown a marked increase. Although many users perceive the risk of using NPS as medium or low, these substances can pose a serious health risk and several NPS have been implicated in drug-related deaths. In Europe, frequently detected NPS are 4-bromo-2,5-dimethoxyphenethylamine (2C B), 4-fluoroamphetamine (4-FA) and benzofurans (5-(2-aminopropyl)benzofuran (5 APB) or 6-(2-aminopropyl)benzofuran (6-APB)). However, little is known about the health risks of these specific NPS. METHODS: In this paper, existing literature on the pharmacokinetics and pharmacodynamics of 2C-B, 4-FA and benzofurans (5 APB/6-APB) was reviewed. RESULTS: Our review showed that the clinical effects of 2C-B, 4-FA and benzofurans (5-APB/6-APB) are comparable with common illicit drugs like amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Therefore, NPS toxicity can be handled by existing treatment guidelines that are based on clinical effects instead of the specific drug involved. Even so, information on the health risks of these substances is limited to a number of case reports that are complicated by confounders such as analytical difficulties, mislabelling of drugs, concomitant exposures and interindividual differences. CONCLUSION: To aid in early legislation, data on clinical effects from poisons centres and user fora should be combined with (in vitro) screening methods and collaboration on an (inter)national level is essential. As a result, potentially hazardous NPS could be detected more quickly, thereby protecting public health. PMID- 26530502 TI - Pain acceptance and opiate use disorders in addiction treatment patients with comorbid pain. AB - OBJECTIVES: Studies from pain treatment settings indicate that poor acceptance of pain may be an important and modifiable risk factor for higher severity of opioid use. However, the degree to which pain acceptance relates to opioid use severity in the addiction treatment population is unknown. In this study of addiction treatment patients with co-morbid pain, we examined correlates of severity of opiate (heroin and prescription opioid) use, with a particular focus on the role of pain acceptance. METHODS: Patients in residential addiction treatment with comorbid pain (N=501) were stratified into low, moderate and high severity of opiate use. Demographic and clinical characteristics were compared across opiate severity categories. RESULTS: 72% (N=360) of the participants had symptoms that were consistent with an opiate use disorder. Younger age, Caucasian race, female gender, cocaine use and lower pain acceptance were associated with higher severity of opiate use, whereas pain intensity was not. Controlling for demographic and other risk factors, such as substance use and pain intensity, higher pain acceptance was associated with lower odds of severe prescription opioid (AOR 0.50, 95% CI 0.38-0.68 for a one SD increase in pain acceptance) and heroin use (AOR 0.57, 95% CI 0.44-0.75 for a one SD increase in pain acceptance). CONCLUSIONS: Problematic opiate use is common in addictions treatment patients with chronic pain. Lower pain acceptance is related to greater opiate use severity, and may be an important modifiable target for interventions to successfully treat both pain and opiate use disorders. PMID- 26530503 TI - Referring Parkinson's disease patients for deep brain stimulation: a RAND/UCLA appropriateness study. AB - In 2005, a European expert panel developed and validated an electronic tool to support the appropriate referral of patients with Parkinson's disease (PD) for the consideration of deep brain stimulation (DBS). Since new evidence has become available over the last decade an update of the tool is necessary. A world-wide expert panel (71 neurologists and 11 neurosurgeons) used the RAND/UCLA Appropriateness Method to assess the appropriateness of referral for 1296 scenarios (9-point scale). Scenarios were permutations of 8 clinical variables relevant to the decision of referral. Appropriateness of referral was calculated on the basis of the median score and the extent of agreement. Compared to 2005, the impact of clinical variables on the appropriateness of referral was similar for severity of on-off fluctuations, dyskinesias and refractory tremor (positive association, p < 0.001), and cognitive impairment (negative association, p < 0.001). A relatively stronger negative impact was seen for levodopa-unresponsive gait and balance disturbances as well as older age, the latter most likely due to a higher cut-off value (75 versus 70 years in the previous study). The impact of PD duration on the appropriateness of referral was less pronounced than in 2005. The contribution of the newly included variable 'non-motor side effects of anti PD medication' was very modest. Based on these results the panel produced new recommendations on the appropriateness of referral for the evaluation of DBS in PD patients. Differences from the previous study reflect the new clinical evidence, particularly related to the use of DBS in an earlier stage of PD. The validation of the updated recommendations is in progress. PMID- 26530504 TI - Orthostatic hypotension in acute cerebellar infarction. AB - To investigate the frequency and pattern of orthostatic hypotension (OH) associated with acute isolated cerebellar infarction, and to identify the cerebellar structure(s) potentially responsible for OH, 29 patients (mean age 60.0) with acute isolated cerebellar infarction performed a standard battery of autonomic function tests including the head up tilt test using Finapres for recording of the beat-to-beat BP response during the acute period. Cerebellar infarction related OH was defined as fall in BP (>20 mmHg systolic BP) on tilting in patients without any disease(s) that could potentially cause autonomic dysfunction, or in patients who had a potential cause of autonomic dysfunction, but showed the absence of OH during a follow-up test. The severity and distribution of autonomic dysfunction were measured by the composite autonomic severity score (CASS). Nine patients (31 %) had OH (range 24-53 mmHg) on tilting during the acute period. Most patients (7/9) had a remarkable decrement in systolic BP immediately upon tilting, but OH rapidly normalized. Mean of maximal decrease in systolic BP during head up tilt test was 37.0 mmHg. The OH group showed mild autonomic dysfunctions (CASS, 3.7) with adrenergic sympathetic dysfunction appearing as the most common abnormality. Lesion subtraction analyses revealed that damage to the medial part of the superior semilunar lobule (Crus I) and tonsil was more frequent in OH group compared to non-OH group. Cerebellar infarction may cause a brief episode of OH. The medial part of the superior semilunar lobule and tonsil may participate in regulating the early BP response during orthostasis. PMID- 26530506 TI - Parkinsonism-hyperpyrexia syndrome and deep brain stimulation. PMID- 26530505 TI - Autonomic dysfunction in subjects at high risk for Parkinson's disease. AB - Aim of this project was to evaluate autonomic dysfunction in subjects proposed to be at high risk to develop Parkinson's disease (PD) compared to control subjects and PD patients at different disease stages. Combinations of substantia nigra hyperechogenicity (SN+) assessed by transcranial ultrasound (TCS), hyposmia, lifetime prevalence of depression and mild PD-specific motor signs were used to identify subjects at high risk for motor Parkinson's disease (HR-PD). Supine and standing blood pressure (BP), hearth rate (HR), orthostatic, urinary, sexual and bowel symptoms were evaluated in HR-PD, healthy control subjects and PD patients, divided into mild and advanced stages. The study group consisted of 113 PD patients (mild PD n = 71, advanced PD, n = 42), 40 HR-PD individuals and 50 controls. Compared to controls, HR-PD subjects complained more often about urinary (p = 0.002) and bowel dysfunction (p = 0.001) and had a higher diastolic BP drop after standing (p = 0.01). The cumulative number of autonomic symptoms differentiated PD as well as HR-PD significantly from controls (p < 0.001). Advanced PD patients presented often and severe orthostatic symptoms, not significantly different from mild PD after concomitant medication correction. Our results support the presence of urinary and bowel dysfunction in subjects at high risk for motor PD. Presence and severity of orthostatic symptoms was higher during stages and increase in advanced stages, at least partly due to increase in dopaminergic and conflicting medication. Understanding the progression of non motor aspects in PD might offer the possibility to use them as targets for disease-modifying therapies. PMID- 26530507 TI - High-resolution MRI: detection of a culprit plaque after recurrent thrombolysis. PMID- 26530508 TI - Mitochondrial DNA mutation 14487T>C manifesting as Leber's hereditary optic neuropathy. PMID- 26530509 TI - Powerhouse failure and oxidative damage in autosomal recessive spastic ataxia of Charlevoix-Saguenay. AB - Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease due to mutations in SACS, which encodes sacsin, a protein localized on the mitochondrial surface and possibly involved in mitochondrial dynamics. In view of the possible mitochondrial involvement of sacsin, we investigated mitochondrial activity at functional and molecular level in skin fibroblasts obtained from ARSACS patients. We observed remarkable bioenergetic damage in ARSACS cells, as indicated by reduced basal, adenosine triphosphate (ATP)-linked and maximal mitochondrial respiration rate, and by reduced respiratory chain activities and mitochondrial ATP synthesis. These phenomena were associated with increased reactive oxygen species production and oxidative nuclear DNA damage. Our results suggest that loss of sacsin is associated with oxidative stress and mitochondrial dysfunction, and thus highlight a novel mechanism in the pathogenesis of ARSACS. The involvement of mitochondria and oxidative stress in disease pathogenesis has been described in a number of other neurodegenerative diseases. Therefore, on the basis of our findings, which suggest a potential therapeutic role for antioxidant agents, ARSACS seems to fall within a larger group of disorders. PMID- 26530510 TI - Relationship between cortex and pulvinar abnormalities on diffusion-weighted imaging in status epilepticus. AB - The aim of this study was to analyze the pattern of magnetic resonance diffusion weighted imaging (DWI) findings in status epilepticus in terms of clinical characteristics. Participants comprised 106 patients with status epilepticus who were admitted to our hospital and underwent DWI. Forty-five patients (42.5 %) showed abnormal findings on DWI and were divided into two groups, comprising 26 patients (24.5 %) with cortex lesions alone and 19 patients (17.9 %) with cortex and pulvinar lesions in the same hemisphere. A long duration of status epilepticus (>120 min) tended to be more prevalent among patients with cortex and pulvinar lesions (57.9 %) than among patients with cortex lesions alone (30.8 %) by univariate and multivariate analyses. Todd's palsy tended to be more frequent in patients with abnormalities on DWI (24/45, 53.3 %) than in patients with normal DWI (21/61, 34.4 %). Six of the 26 patients with cortex lesions alone (23.1 %) had taken anti-epileptic drugs before the attack compared to none of the 19 patients with both cortex and pulvinar lesions. The trend toward a longer duration of status epilepticus in patients with both cortex and pulvinar lesions favors a spreading pattern of seizure discharge from cortex to pulvinar via cortico-pulvinar pathways, and anti-epileptic drugs might, to some extent, prevent spreading of seizure discharge from cortex to pulvinar. In addition, existence of high-intensity areas on DWI at the onset of epilepsy may be a predictive factor for the occurrence of Todd's palsy. PMID- 26530511 TI - Can postural instability tests improve the prediction of future falls in people with Parkinson's disease beyond knowing existing fall history? AB - This study sought to determine whether the backward-stepping Push and Release (P&R) Test and the Pull Test, or comprehensive batteries of postural instability (the Mini-BESTest and Brief-BESTest), significantly improve the prediction of future falls beyond knowing a person's baseline fall history. Complete data were available for 43 of 80 participants with PD. At baseline, participants completed the BESTest (which was scored for all versions and includes the P&R Test), the Unified PD Rating Scale (UPDRS) motor section (which includes the Pull Test), and the participants' reported falls experienced in the previous 6 months. Participants were classified as recurrent fallers if they reported more than one fall in the 12 months subsequent to baseline. Stepwise logistic regressions determined whether the P&R Test, Pull Test, Brief-BESTest, Mini-BESTest, or UPDRS motor score improved predictions of recurrent fallers independent of baseline fall-group status. Independently, all assessments significantly predicted future recurrent fallers, but only the Mini-BESTest and Brief-BESTest significantly improved predictions of future recurrent fallers independent of baseline fall group status. The results suggest that, although single tests of reactive postural control do not offer significant predictive benefit, predictions of future recurrent fallers with PD do benefit from a balance examination in addition to knowing whether an individual has a recent history of falls. PMID- 26530513 TI - Poor short-term outcome in patients with ischaemic stroke and active cancer. AB - Stroke risk is increased in cancer patients and cancer activity has been claimed to play a role in the development of ischaemic stroke (IS). We wanted to further test these assumptions and to explore the impact of such relation on short-term prognosis. We identified all IS patients that were admitted to the neurological department of our primary and tertiary care university hospital between 2008 and 2014 (n = 4918) and reviewed their medical records for an additional diagnosis of cancer. Cancer patients were categorized into those with "active cancer" (AC: recurrent malignant tumour, metastases, ongoing chemo-/radiotherapy) and "non active cancer" (NAC). We compared demographic, clinical and neuroimaging features of both patient groups and assessed their association with in-hospital mortality. 300 IS patients with known cancer were identified (AC: n = 73; NAC: n = 227). IS patients with AC were significantly younger (70.3 +/- 10.6 vs. 74.9 +/- 9.9 years), had more severe strokes at admission (NIHSS: median 5 vs. 3), more frequently cryptogenic strokes (50.7 vs. 32.5 %) and more often infarcts in multiple vascular territories of the brain (26 vs. 5.2 %) compared to IS patients with NAC. In-hospital mortality was significantly higher in AC patients (21.9 vs. 6.2 %). Multivariate analysis identified AC (odds ratio [OR] 3.70, 95 % confidence interval [CI] 1.50-9.30), NIHSS at admission (OR 1.10, CI 1.10-1.20) and C-reactive protein level (OR 1.01, CI 1.00-1.02) as factors significantly and independently associated with in-hospital death. Our findings support a direct role of AC in the pathogenesis and prognosis of acute IS. This needs to be considered in the management and counselling of such patients. PMID- 26530514 TI - Biometamaterials: Black Ultrathin Gold Film Fabricated on Lotus Leaf. AB - We report on a black metamaterial of gold fabricated on a lotus leaf that was used as a template. In spite of the extremely thin gold coating (10-nm thick) on the lotus leaf, the surface shows reflectivity below 0.01 over the entire visible spectral range. Finite-difference time-domain (FDTD) calculations suggest that the low reflectivity stems from the secondary structures on the lotus leaf, where randomly oriented nanorods are distributed. PMID- 26530512 TI - Status of diagnostic approaches to AQP4-IgG seronegative NMO and NMO/MS overlap syndromes. AB - Distinguishing aquaporin-4 IgG(AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD) from opticospinal predominant multiple sclerosis (MS) is a clinical challenge with important treatment implications. The objective of the study was to examine whether expert clinicians diagnose and treat NMO/MS overlapping patients in a similar way. 12 AQP4-IgG-negative patients were selected to cover the range of clinical scenarios encountered in an NMO clinic. 27 NMO and MS experts reviewed their clinical vignettes, including relevant imaging and laboratory tests. Diagnoses were categorized into four groups (NMO, MS, indeterminate, other) and management into three groups (MS drugs, immunosuppression, no treatment). The mean proportion of agreement for the diagnosis was low (p o = 0.51) and ranged from 0.25 to 0.73 for individual patients. The majority opinion was divided between NMOSD versus: MS (nine cases), monophasic longitudinally extensive transverse myelitis (LETM) (1), acute disseminated encephalomyelitis (ADEM) (1) and recurrent isolated optic neuritis (RION) (1). Typical NMO features (e.g., LETM) influenced the diagnosis more than features more consistent with MS (e.g., short TM). Agreement on the treatment of patients was higher (p o = 0.64) than that on the diagnosis with immunosuppression being the most common choice not only in patients with the diagnosis of NMO (98 %) but also in those indeterminate between NMO and MS (74 %). The diagnosis in AQP4-IgG-negative NMO/MS overlap syndromes is challenging and diverse. The classification of such patients currently requires new diagnostic categories, which incorporate lesser degrees of diagnostic confidence. Long-term follow-up may identify early features or biomarkers, which can more accurately distinguish the underlying disorder. PMID- 26530515 TI - Adult bone marrow mesenchymal and neural crest stem cells are chemoattractive and accelerate motor recovery in a mouse model of spinal cord injury. AB - INTRODUCTION: Stem cells from adult tissues were considered for a long time as promising tools for regenerative therapy of neurological diseases, including spinal cord injuries (SCI). Indeed, mesenchymal (MSCs) and neural crest stem cells (NCSCs) together constitute the bone marrow stromal stem cells (BMSCs) that were used as therapeutic options in various models of experimental SCI. However, as clinical approaches remained disappointing, we thought that reducing BMSC heterogeneity should be a potential way to improve treatment efficiency and reproducibility. METHODS: We investigated the impact of pure populations of MSCs and NCSCs isolated from adult bone marrow in a mouse model of spinal cord injury. We then analyzed the secretome of both MSCs and NCSCs, and its effect on macrophage migration in vitro. RESULTS: We first observed that both cell types induced motor recovery in mice, and modified the inflammatory reaction in the lesion site. We also demonstrated that NCSCs but especially MSCs were able to secrete chemokines and attract macrophages in vitro. Finally, it appears that MSC injection in the spinal cord enhance early inflammatory events in the blood and spinal cord of SCI mice. CONCLUSIONS: Altogether, our results suggest that both cell types have beneficial effects in experimental SCI, and that further investigation should be dedicated to the regulation of the inflammatory reaction following SCI, in the context of stem cell-based therapy but also in the early phase clinical management of SCI patients. PMID- 26530516 TI - Meta-analysis of laparoscopic surgery for recurrent Crohn's disease. AB - PURPOSES: It remains unclear whether laparoscopic surgery is suitable for recurrent Crohn's disease (CD). The objective of this meta-analysis was to evaluate the safety and feasibility of laparoscopic resection for recurrent vs. primary CD by comparing intraoperative and postoperative outcomes. METHODS: We searched the PubMed and Cochrane Library databases for studies that compared complications associated with laparoscopic resection for primary and recurrent CD. The primary study endpoints were conversion rates and postoperative complication rates. RESULTS: Seven trials with a collective total of 627 participants (413 with primary CD and 214 with recurrent CD) met our inclusion criteria. Laparoscopic resection was associated with a significantly higher conversion rate when performed for recurrent CD than for primary CD (OR = 2.53; 95 % CI 1.22-5.25; p = 0.01). However, there was no significant difference in the total complication rate between laparoscopic resection for primary vs. that for recurrent CD (OR = 1.41; 95 % CI 0.86-2.34; p = 0.18). CONCLUSIONS: Although a higher conversion rate suggests technical complexity, laparoscopic resection for recurrent CD is considered a safe and feasible procedure, without an increased risk of postoperative complications. PMID- 26530517 TI - Fibrinogen and base excess levels as predictive markers of the need for massive blood transfusion after blunt trauma. AB - BACKGROUND: Assessment blood consumption and trauma-associated severe hemorrhage scores are useful for predicting the need for massive transfusion (MT) in severe trauma patients. However, fibrinogen (Fbg) and base excess (BE) levels might also be useful indicators for the need for MT. We evaluated the accuracy of prediction for MT of the scoring system vs. Fbg and BE. METHODS: The subjects of this retrospective single center observational study were patients with injury severity score >=16 trauma, divided into a non-MT group and an MT group. We compared variables, including the scoring system (comprising vital signs and focused assessment with sonography for trauma; FAST) and Fbg between the groups. We then performed a multiple logistic regression modeling and a receiver operating characteristic analysis to clarify which value was the most useful predictive indicator for MT. RESULTS: There were 114 patients in the non-MT group and 39 in the MT group. The level of Fbg and BE were independent predictors of MT. The area under the curve values for Fbg and BE were 0.765 and 0.845, respectively, and the optimal cutoff values of Fbg and BE were 211 mg/dL and 1.4, respectively. CONCLUSIONS: Fbg and BE levels can be used as an independent predictor for MT. PMID- 26530518 TI - Bayesian meta-analytical methods to incorporate multiple surrogate endpoints in drug development process. AB - A number of meta-analytical methods have been proposed that aim to evaluate surrogate endpoints. Bivariate meta-analytical methods can be used to predict the treatment effect for the final outcome from the treatment effect estimate measured on the surrogate endpoint while taking into account the uncertainty around the effect estimate for the surrogate endpoint. In this paper, extensions to multivariate models are developed aiming to include multiple surrogate endpoints with the potential benefit of reducing the uncertainty when making predictions. In this Bayesian multivariate meta-analytic framework, the between study variability is modelled in a formulation of a product of normal univariate distributions. This formulation is particularly convenient for including multiple surrogate endpoints and flexible for modelling the outcomes which can be surrogate endpoints to the final outcome and potentially to one another. Two models are proposed, first, using an unstructured between-study covariance matrix by assuming the treatment effects on all outcomes are correlated and second, using a structured between-study covariance matrix by assuming treatment effects on some of the outcomes are conditionally independent. While the two models are developed for the summary data on a study level, the individual-level association is taken into account by the use of the Prentice's criteria (obtained from individual patient data) to inform the within study correlations in the models. The modelling techniques are investigated using an example in relapsing remitting multiple sclerosis where the disability worsening is the final outcome, while relapse rate and MRI lesions are potential surrogates to the disability progression. PMID- 26530519 TI - Angiogenesis and Vascular Endothelial Growth Factor-A Expression Associated with Inflammation in Pediatric Crohn's Disease. AB - BACKGROUND AND AIMS: Angiogenesis is a component of chronic inflammatory diseases including inflammatory bowel disease. Some studies describe increased angiogenesis associated with acute disease in adult Crohn's disease and ulcerative colitis, while animal models aid investigations of mechanism and pathophysiology of angiogenesis. We aim to explore the role of angiogenesis and its pathways in pediatric Crohn's disease. METHODS: Surgical specimens were obtained from pediatric Crohn's disease (both inflamed and non-inflamed regions of ileum) and control patients. Samples were examined for inflammation, microvessel density, and molecular expression of vascular endothelial growth factor-A, platelet-derived growth factor-beta, angiopoietin-1, and angiopoietin 2. RESULTS: Angiogenesis and inflammation were increased in parallel in Crohn's disease compared to controls. We also discovered increased angiogenesis in Crohn's disease tissue that was relatively free of inflammatory disease. Vascular endothelial growth factor-A gene expression (P = 0.034) was elevated in Crohn's disease over controls, while gene expression of platelet-derived growth factor beta (P = 0.069), angiopoietin-1 (P = 0.206), and angiopoietin-2 (P = 0.082) was not significantly elevated. CONCLUSIONS: We confirm that inflammation-associated angiogenesis is upregulated in pediatric Crohn's disease. This population also exhibits elevated mucosal angiogenesis at the surgical margin with limited inflammation. This suggests that angiogenesis is an additional pathologic characteristic to potentially identify normal mucosa and margins of surgical resection that are uninvolved with disease and, furthermore, may have implications for monitoring complete disease remission. We further identify the vascular endothelial growth factor-A pathway involvement in the disease process, which may serve as a future molecular target for anti-angiogenic therapy in inflammatory bowel disease. PMID- 26530520 TI - Nanoscale direct mapping of localized and induced noise sources on conducting polymer films. AB - The localized noise-sources and those induced by external-stimuli were directly mapped by using a conducting-AFM integrated with a custom-designed noise measurement set-up. In this method, current and noise images of a poly(9,9 dioctylfluorene)-polymer-film on a conducting-substrate were recorded simultaneously, enabling the mapping of the resistivity and noise source density (NT). The polymer-films exhibited separate regions with high or low resistivities, which were attributed to the ordered or disordered phases, respectively. A larger number of noise-sources were observed in the disordered phase-regions than in the ordered-phase regions, due to structural disordering. Increased bias-voltages on the disordered-phase-regions resulted in increased NT, which is explained by the structural deformation at high bias-voltages. On photo illumination, the ordered-phase-regions exhibited a rather large increase in the conductivity and NT. Presumably, the illumination released carriers from deep traps which should work as additional noise-sources. These results show that our methods provide valuable insights into noise-sources and, thus, can be powerful tools for basic research and practical applications of conducting polymer films. PMID- 26530521 TI - A dual-isotope approach to allow conclusive partitioning between three sources. AB - Stable isotopes have proved to be a transformative tool; their application to distinguish between two sources in a mixture has been a cornerstone of biogeochemical research. However, quantitatively partitioning systems using two stable isotopes (for example, (13)C and (12)C) has been largely limited to only two sources, and systems of interest often have more than two components, with interactive effects. Here we introduce a dual-isotope approach to allow conclusive partitioning between three sources, using only two stable isotopes. We demonstrate this approach by partitioning soil CO2 emissions derived from microbial mineralization of soil organic carbon (SOC), added pyrogenic organic matter (PyOM) and root respiration. We find that SOC mineralization in the presence of roots is 23% higher (P<0.05) when PyOM is also present. Being able to discern three sources with two isotopes will be of great value not only in biogeochemical research, but may also expand hitherto untapped methodologies in diverse fields. PMID- 26530522 TI - Childhood Language Disorder and Social Anxiety in Early Adulthood. AB - Language disorder is associated with anxiety and with social problems in childhood and adolescence. However, the relation between language disorder and adult social anxiety is not well known. This study examines social anxiety in early adulthood in a 26-year prospective longitudinal study following individuals identified with a communication disorder at age 5 and a control group. Social anxiety diagnoses and subthreshold symptoms were examined at ages 19, 25, and 31 using a structured diagnostic interview; social anxiety symptoms related to social interaction and social performance were also assessed dimensionally at age 31. Multiple imputation was used to address attrition. Compared to controls, participants with childhood language disorder had higher rates of subthreshold social phobia at ages 19 and 25 and endorsed higher levels of social interaction anxiety symptoms at age 31, with particular difficulty talking to others and asserting their perspectives. Childhood language disorder is a specific risk factor for a circumscribed set of social anxiety symptoms in adulthood, which are likely associated with communication challenges. PMID- 26530523 TI - A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies: important issues and lessons relevant to the design of future clinical research. AB - Preclinical evidence suggests that anesthetic agents harm the developing brain thereby causing long-term neurocognitive impairments. It is not clear if these findings apply to humans, and retrospective epidemiological studies thus far have failed to show definitive evidence that anesthetic agents are harmful to the developing human brain. AIM: The aim of this systematic review was to summarize the preclinical studies published over the past decade, with a focus on methodological issues, to facilitate the comparison between different preclinical studies and inform better design of future trials. METHOD: The literature search identified 941 articles related to the topic of neurotoxicity. As the primary aim of this systematic review was to compare methodologies applied in animal studies to inform future trials, we excluded a priori all articles focused on putative mechanism of neurotoxicity and the neuroprotective agents. Forty-seven preclinical studies were finally included in this review. RESULTS: Methods used in these studies were highly heterogeneous-animals were exposed to anesthetic agents at different developmental stages, in various doses and in various combinations with other drugs, and overall showed diverse toxicity profiles. Physiological monitoring and maintenance of physiological homeostasis was variable and the use of cognitive tests was generally limited to assessment of specific brain areas, with restricted translational relevance to humans. CONCLUSION: Comparison between studies is thus complicated by this heterogeneous methodology and the relevance of the combined body of literature to humans remains uncertain. Future preclinical studies should use better standardized methodologies to facilitate transferability of findings from preclinical into clinical science. PMID- 26530524 TI - Prevalence of POMC R236G mutation in Pakistan. AB - Obesity has become a great health issue and socioeconomic burden globally in the past few decades and has afflicted Pakistan in the same way. However, there is limited research on obesity genetics in Pakistan. Proopiomelanocortin (POMC) neurons bear leptin receptor and act as anorectic targets of leptin in the brain. Leptin binding induces a series of processing events producing melanocortins which then bind to their respective signals. R236G is a mutation which disrupts such a normal processing event resulting in an overall weight gain and early onset obesity. A total of 475 subjects were genotyped to search for this mutation, and their serum traits were measured. We detected one obese subject heterozygous for R236G (0.4%) and no control subject with the mutation. We then systematically searched for previous reports of R236 substitution and combined the results of our study with the previous frequencies and found that the mutation has an overall prevalence of 0.704% in obese cases and 0.18% in non obese controls. In conclusion, such mutations involving a prohormone processing site are very rare in nature and may not contribute a significant proportion of common forms of obesity observed currently. Such mutations may exert their effect by affecting other pathways and are more prominent in the early stages of life only. PMID- 26530525 TI - Mammoth 2.0: will genome engineering resurrect extinct species? AB - It is impossible to 'clone' species for which no living cells exist. Genome editing may therefore provide the only means to bring extinct species--or, more accurately, extinct traits--back to life. PMID- 26530526 TI - Elucidation of the effect of aptamer immobilization strategies on the interaction between cell and its aptamer using atomic force spectroscopy. AB - The immobilization strategy of cell-specific aptamers is of great importance for studying the interaction between a cell and its aptamer. However, because of the difficulty of studying living cell, there have not been any systematic reports about the effect of immobilization strategies on the binding ability of an immobilized aptamer to its target cell. Because atomic force spectroscopy (AFM) could not only be suitable for the investigation of living cell under physiological conditions but also obtains information reflecting the intrinsic properties of individuals, the effect of immobilization strategies on the interaction of aptamer/human hepatocarcinoma cell Bel-7404 was successively evaluated using AFM here. Two different immobilization methods, including polyethylene glycol immobilization method and glutaraldehyde immobilization method were used, and the factors, such as aptamer orientation, oligodeoxythymidine spacers and dodecyl spacers, were investigated. Binding events measured by AFM showed that a similar unbinding force was obtained regardless of the change of the aptamer orientation, the immobilization method, and spacers, implying that the biophysical characteristics of the aptamer at the molecular level remain undisturbed. However, it showed that the immobilization orientation, immobilization method, and spacers could alter the binding probability of aptamer/Bel-7404 cell. Presumably, these factors may affect the accessibility of the aptamer toward its target cell. These results may provide valuable information for aptamer sensor platforms including ultrasensitive biosensor design. PMID- 26530527 TI - Isolation and Structure Determination of a Missing Endohedral Fullerene La@C70 through In Situ Trifluoromethylation. AB - D5h-symmetric fullerene C70 (D5h-C70) is one of the most abundant members of the fullerene family. One longstanding mystery in the field of fullerene chemistry is whether D5h-C70 is capable of accommodating a rare-earth metal atom to form an endohedral metallofullerene M@D5h-C70, which would be expected to show novel electronic properties. The molecular structure of La@C70 remains unresolved since its discovery three decades ago because of its extremely high instability under ambient conditions and insolubility in organic solvents. Herein, we report the single-crystal X-ray structure of La@C70(CF3)3, which was obtained through in situ exohedral functionalization by means of trifluoromethylation. The X-ray crystallographic study reveals that La@C70(CF3)3 is the first example of an endohedral rare-earth fullerene based on D5h-C70. The dramatically enhanced stability of La@C70(CF3)3 compared to La@C70 can be ascribed to trifluoromethylation-induced bandgap enlargement. PMID- 26530528 TI - The old age health security in rural China: where to go? AB - INTRODUCTION: The huge number of rural elders and the deepening health problems (e.g. growing threats of infectious diseases and chronic diseases etc.) place enormous pressure on old age health security in rural China. This study aims to provide information for policy-makers to develop effective measures for promoting rural elders' health care service access by examining the current developments and challenges confronted by the old age health security in rural China. METHODS: Search resources are electronic databases, web pages of the National Bureau of Statistics of China and the National Health and Family Planning Commission of China on the internet, China Population and Employment Statistics Yearbook, China Civil Affairs' Statistical Yearbook and China Health Statistics Yearbooks etc. Articles were identified from Elsevier, Wiley, EBSCO, EMBASE, PubMed, SCI Expanded, ProQuest, and National Knowledge Infrastructure of China (CNKI) which is the most informative database in Chinese. Search terms were "rural", "China", "health security", "cooperative medical scheme", "social medical assistance", "medical insurance" or "community based medical insurance", "old", or "elder", "elderly", or "aged", "aging". Google scholar was searched with the same combination of keywords. RESULTS: The results showed that old age health security in rural China had expanded to all rural elders and substantially improved health care service utilization among rural elders. Increasing chronic disease prevalence rates, pressing public health issues, inefficient rural health care service provision system and lack of sufficient financing challenged the old age health security in rural China. CONCLUSIONS: Increasing funds from the central and regional governments for old age health security in rural China will contribute to reducing urban-rural disparities in provision of old age health security and increasing health equity among rural elders between different regions. Meanwhile, initiating provider payment reform may contribute to improving the efficiency of rural health care service provision system and promoting health care service access among rural elders. PMID- 26530529 TI - Molecular pathological epidemiology of colorectal cancer in Chinese patients with KRAS and BRAF mutations. AB - An investigation of interactive effects of exogenous and endogenous factors and tumor molecular changes can lead to a better understanding of tumor molecular signatures in colorectal cancer. We here report a molecular pathological epidemiology study in a large cohort of 945 colorectal cancer patients. Mutations of KRAS (36.6%) and BRAF (3.46%) were nearly mutually exclusive. KRAS-mutated tumors were more common in female patients (odds ratio [OR] = 1.68; P = 0.0001) and never smokers (OR = 1.60; P = 0.001). Whereas BRAF-mutated tumors demonstrated no discrepancy in aspects of gender and smoking status compared with wild-type tumors. In addition, tumors with BRAF or KRAS mutations were in correlation with elevated serum level of carbohydrate antigen (CA19-9) and carcinoma embryonic antigen (CEA) and the combination of serum biomarkers and molecular mutation status may enhance the more precise risk stratification of CRC patients. Further studies are needed to define the mechanism brought about by the aforementioned epidemiologic and clinicopathologic characteristics that may help optimize cancer prevention and precision therapy. PMID- 26530531 TI - Reactions of Hexa-aquo Transition Metal Ions with the Hydrated Electron up to 300 degrees C. AB - Reactions of the hydrated electron with divalent aqueous transition-metal ions, Cd(2+), Zn(2+), Ni(2+), Cu(2+), Co(2+), Fe(2+), and Mn(2+), were studied using a pulse radiolysis technique. The kinetics study was carried out at a constant pressure of 120 bar with temperatures up to 300 degrees C. The rate constants at room temperature agree with those reported in the literature. The reaction of Cd(2+) is approximately diffusion-limited, but none of the first-row transition metal ion reactions are diffusion-controlled at any temperature studied. The activation energies obtained from the Arrhenius plots are in the range 14.5-40.6 kJ/mol. Pre-exponential factors are quite large, between 1 * 10(13) and 7 * 10(15) M(-1) s(-1). There appears to be a large degree of entropy-enthalpy compensation in the activation of Zn(2+), Ni(2+), Co(2+), and Cu(2+), as the larger pre-exponential factors strongly correlate with higher activation energy. Saturation of the ionic strength effect suggests that these reactions could be long-range nonadiabatic electron "jumps", but Marcus theory is incompatible with direct formation of ground state (M(+))aq ions. A self-consistent explanation is that electron transfer occurs to excited states derived from the metal 4s orbitals. The ionic strength effect in the Mn(2+) and Fe(2+) reactions suggests that these proceed by short-range adiabatic electron attachment involving breakdown of the water coordination shell. PMID- 26530530 TI - Latexin exhibits tumor-suppressor potential in pancreatic ductal adenocarcinoma. AB - Recent studies suggest that latexin (Lxn) expression is involved in stem cell regulation and that it plays significant roles in tumor cell migration and invasion. The clinicopathological significance of Lxn expression and its possible correlation with CD133 expression in pancreatic ductal adenocarcinoma (PDAC) is currently unknown. In the present study, immunohistochemical analysis was performed to determine Lxn and CD133 expression in 43 PDAC patient samples and in 32 corresponding adjacent non-cancerous samples. The results were analyzed and compared with patient age, gender, tumor site and size, histological grade, clinical stage and overall mean survival time. Lxn expression was clearly decreased in the PDAC tissues compared with that in the adjacent non-cancerous tissues, while CD133 expression was increased. Low Lxn expression in the PDAC tissues was significantly correlated with tumor size (P=0.002), histological grade (P=0.000), metastasis (P=0.007) and clinical stage (P=0.018), but not with age (P=0.451), gender (P=0.395) or tumor site (P=0.697). Kaplan-Meier survival analysis revealed that low Lxn expression was significantly correlated with reduced overall survival time (P=0.000). Furthermore, Lxn expression was found to be inversely correlated with CD133 expression (r=-0.485, P=0.001). Furthermore, CD133-positive MIA PaCa-2 pancreatic tumor cells were sorted by magnetic activated cell sorting (MACS), and those that overexpressed Lxn exhibited a significantly higher rate of apoptosis and lower proliferative activity. Our findings suggest that Lxn may function as a tumor suppressor that targets CD133 positive pancreatic cancer cells. PMID- 26530533 TI - The ethics of migration and what moves us to care. PMID- 26530532 TI - Elevated GRP78 expression is associated with poor prognosis in patients with pancreatic cancer. AB - Glucose-regulated protein 78 (GRP78) is a member of the heat-shock protein 70 family. We evaluated the expression of GRP78 using tissue microarray-based immunohistochemistry in tumor tissues and adjacent nontumor tissues from 180 pancreatic ductal adenocarcinoma (PDAC) patients. The associations between the expression levels of GRP78, clinicopathological factors, and overall survival were evaluated. The results showed that the expression of GRP78 was significantly higher in PDAC cells than in normal pancreatic duct cells within adjacent nontumor tissues (p < 0.05). The increased expression of GRP78 in the tumor tissues was significantly correlated with a higher T-stage (p < 0.05) and a shorter overall survival (OS, p < 0.05). In an in vitro study, the regulation of GRP78 in the PDAC cell lines affected the proliferation, migration, and invasion of PDAC cells through the regulation of CyclinD1, cyclin-dependent kinase (CDK) 4, CDK6, phospho-signal transducer, activator of transcription 3 (p-STAT3), janus kinase 2 (JAK2), ras homolog gene family member A (RhoA), Rho-associated kinase 1 (ROCK1), and sterile alpha motif domain containing protein 4 (Smad4). The present data suggest that GRP78 plays a crucial role in the proliferation, migration, and invasion of pancreatic cancer cells and may be a suitable prognostic marker in PDAC. PMID- 26530534 TI - Reflections on 16th nursing ethics and 1st International Care Ethics Observatory conference, University of Surrey, Guildford, 17th and 18th July 2015. PMID- 26530537 TI - IOX1, a JMJD2A inhibitor, suppresses the proliferation and migration of vascular smooth muscle cells induced by angiotensin II by regulating the expression of cell cycle-related proteins. AB - The epigenetic modification of vascular smooth muscle cell (VSMC) phenotypic switching, proliferation, migration, apoptosis and extracellular matrix synthesis is known to occur in atherosclerosis. The aim of the present study was to investigate the effects of IOX1, a Jumonji domain-containing 2A (JMJD2A) inhibitor, on regulation of the cell cycle in angiotensin II (Ang II)-stimulated VSMCs and to elucidate the possible mechanisms involved. The proliferation and migration of the Ang II-stimulated VSMCs in the presence or absence of IOX1 were evaluated in vitro. Flow cytometric analysis was used to determine the effects of IOX1 on cell cycle progression. RT-qPCR and western blot analysis were carried out to measure the expression levels of cell cycle-related genes. The trimethylation of histone H3 lysine 9 (H3K9me3) at the promoters of these genes was detected by chromatin immunoprecipitation (ChIP) assay. We confirmed that the JMJD2A levels were increased, whereas the H3K9me3 levels were decreased in the Ang II-stimulated VSMCs. The inhibition of JMJD2A by IOX1 suppressed the Ang II induced cell proliferation, migration and cell cycle progression by inhibiting cyclin D1 expression and increasing p21 expression. The underlying mechanisms were related to the restoration of the H3K9me3 levels at the promoters of these genes. In conclusion, the findings of our study indicate that IOX1 exerts its anti-proliferative and anti-migratory effects by regulating the expression of the cell cycle-related proteins, cyclin D1 and p21. PMID- 26530538 TI - Experimental evidence for heritable reproductive time in 2 allochronic populations of pine processionary moth. AB - Phenology allows organisms to overcome seasonally variable conditions through life-cycle adjustment. Changes in phenology can drastically modify the evolutionary trajectory of a population, while a shift in the reproductive time may cause allochronic differentiation. The hypothesis of heritable reproductive time was experimentally tested, by studying a unique population of the pine processionary moth Thaumetopoea pityocampa (Den. & Schiff.) which has a shifted phenology, and however co-occurs with the typical population following the classical life cycle. When populations of both types were reared under controlled conditions, the reproductive time was maintained asynchronous, as observed in the field. The shifted population was manipulated in the laboratory to reproduce later than usual, yet the offspring emerged in the next year at the expected dates thus "coming back" to the usual cycle. Hybrids from crosses performed between the 2 populations showed an intermediate phenology. From the emergence times of parents and offspring, a high heritability of the reproductive time (h = 0.76) was observed. The offspring obtained from each type of cross was genetically characterized using microsatellite markers. Bayesian clustering analysis confirmed that hybrids can be successfully identified and separated from the parental genetic classes by genotyping. Findings support the hypothesis that, for this particular population, incipient allochronic speciation is due to a heritable shift in the reproductive time that further causes assortative mating and might eventually cause ecological adaptation/maladaptation in response to environmental changes. PMID- 26530539 TI - Outcome of myeloablative allogeneic peripheral blood hematopoietic stem cell transplantation for refractory/relapsed AML patients in NR status. AB - To further find effective method to improve the long term survival of refractory or relapsed acute myeloid leukemia (AML) patients, we retrospectively analyzed the outcomes of myeloablative hematopoietic stem cell transplantation (HSCT) for 133 consecutive patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) therapy related AML(t-AML) in not remission status. The overall 3 year OS and DFS were 40.9% and 35.6% respectively. The variables associated with improved long term DFS were a bone marrow blast cell count less than 20% and an intensified conditioning regimen. In addition, the t-AML group had higher rates of relapse and III-IV acute GVHD than the primary AML group. The unrelated donor group had similar OS and DFS with sibling groups. Our study suggested that decreasing bone marrow blast cell counts before HSCT and strengthening the conditioning regimen may improve long-term DFS for refractory/relapsed AML patients, and unrelated donor group can get similar effect when compared to the sibling group. PMID- 26530540 TI - Systematic Review of Therapies for Stable Coronary Artery Disease in Diabetic Patients. AB - Diabetes mellitus is a significant risk modifier for stable coronary artery disease, causing patients to have more extensive and diffuse lesions. Opposing treatment strategies remain a matter of debate. A multiple database search was conducted and outcomes, lesion, and patient characteristics were compared. Overall mortality, cardiac death, major adverse cardiovascular and cerebrovascular events, and need for revascularization were higher with percutaneous coronary intervention than with coronary artery bypass graft surgery. Multivessel disease and high Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) scores were associated with better outcomes for coronary artery bypass graft surgery. PMID- 26530541 TI - Patterns of Regional Lymph Node Recurrence After Radical Surgery for Thoracic Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: This study aimed to investigate the patterns of regional lymph node recurrence after radical surgery for thoracic esophageal squamous cell carcinoma (ESCC). METHODS: We retrospectively reviewed clinical characteristics of ESCC patients admitted to two institutions from 1990 to 2011, and analyzed the patterns of regional lymph node recurrence. RESULTS: The records of 315 eligible patients with ESCC were reviewed. Of the 378 regional lymph node recurrence sites, 177 (46.8%) were in the supraclavicular areas, 120 (31.7%) in the mediastinum, and 81 (21.4%) in the upper abdominal areas. The most common sites of recurrence were the supraclavicular and mediastinum areas in patients with upper and middle thoracic ESCC. Approximately equal percentages of patients with lower thoracic tumors had supraclavicular, mediastinal, and upper abdominal (celiac) lymph node recurrence. Patients with tumor located in the lower thoracic esophagus had a lower probability of supraclavicular lymph node recurrence (p = 0.013). None of the assessed factors was associated with mediastinal lymph node recurrence. Celiac lymph node recurrence was more frequent among patients with lower thoracic ESCC (p = 0.004) and advanced pathologic nodal (pN) stage (pN2, p = 0.034; pN3, p = 0.009). CONCLUSIONS: After radical surgery for thoracic ESCC, the patterns of regional lymph node recurrence are related to the tumor location and pN stage. PMID- 26530542 TI - Telemedical Wearable Sensing Platform for Management of Chronic Venous Disorder. AB - Enabled by emerging wearable sensors, telemedicine can potentially offer personalized medical services to long-term home care or remote clinics in the future, which can be particularly helpful in the management of chronic diseases. The wireless wearable pressure sensing system reported in this article provides an excellent example of such an innovation, whereby periodic or continuous monitoring of interface pressure can be obtained to guide routine compression therapy, the cornerstone of chronic venous disorder management. By applying a novel capacitive, iontronic sensing technology, a flexible, ultrathin, and highly sensitive pressure sensing array is seamlessly incorporated into compression garments for the monitoring of interface pressure. The linear pressure sensing array assesses pressure distribution along the limb in a real-time manner (up to a scanning rate of 5 kHz), and the measurement data can be processed and displayed on a mobile device locally, as well as transmitted through a Bluetooth communication module to a remote clinical service. The proposed interface pressure measuring system provides real-time interface pressure distribution data and can be utilized for both clinical and self-management of compression therapy, where both treatment efficacy and quality assurance can be ascertained. PMID- 26530543 TI - The effects of a physical activity counseling program after an exacerbation in patients with Chronic Obstructive Pulmonary Disease: a randomized controlled pilot study. AB - BACKGROUND: In some patients with COPD, the disease is characterized by exacerbations. Severe exacerbations warrant a hospitalization, with prolonged detrimental effects on physical activity. Interventions after an exacerbation may improve physical activity, with longstanding health benefits. Physical activity counseling and real-time feedback were effective in stable COPD. No evidence is available on the use of this therapeutic modality in patients after a COPD exacerbation. METHODS: Thirty patients were randomly assigned to usual care or physical activity counseling, by telephone contacts at a frequency of 3 times a week and real-time feedback. Lung function, peripheral muscle strength, functional exercise capacity, symptom experience and COPD-related health status were assessed during hospital stay and 1 month later. RESULTS: Both groups significantly recovered in physical activity (PAsteps: control group: 1013 +/- 1275 steps vs intervention group: 984 +/- 1208 steps (p = 0.0005); PAwalk: control group: 13 +/- 14 min vs intervention group: 13 +/- 16 min (p = 0.0002)), functional exercise capacity (control group: 64 +/- 59 m (p = 0.002) vs intervention group: 67 +/- 84 m (p = 0.02)) and COPD-related health status (CAT: control group: -5 [-7 to 1] (p = 0.02) vs intervention group: -3 [-10 to 1] points (p = 0.03)). No differences between groups were observed. CONCLUSION: From our pilot study, we concluded that telephone based physical activity counseling with pedometer feedback after an exacerbation did not result in better improvements in physical activity and clinical outcomes compared to usual care. Because of the difficult recruitment and the negative intermediate analyses, this study was not continued. TRIAL REGISTRATION: Clinicaltrials.gov NCT02223962. Registered 4 September 2013. PMID- 26530544 TI - The Porphyromonas gingivalis O antigen is required for inhibition of apoptosis in gingival epithelial cells following bacterial infection. AB - BACKGROUND AND OBJECTIVE: Porphyromonas gingivalis infection induces apoptosis inhibition in gingival epithelial cells; however, it is not fully understood which bacterial effectors are involved in this process. The aim of this study is to evaluate whether the P. gingivalis lipopolysaccharide (LPS), specifically the O-antigen region, affects adherence, invasion, viability and apoptosis of gingival epithelial cells. MATERIAL AND METHODS: Gingival epithelial cells (OKF6/TERT2 line) were infected by different freshly prepared P. gingivalis clinical isolates, obtained from subjects with chronic periodontitis (CP3 and CP4) and healthy individuals (H1 and H3). Periodontitis and healthy isolates show differences in O-antigen production, as healthy isolates lack the O-antigen region. In addition, cells were infected by a site-specific mutant lacking the O antigen portion. After 24 h postinfection, cell proliferation, viability and apoptosis were evaluated by Trypan blue, MTS and annexin V assays, respectively. Bacterial invasion, adhesion and proliferation were measured by gentamicin/metronidazole protection assays. Finally, toll-like receptor (TLR)2 and TLR4 mRNA expression was evaluated by quantitative reverse transcription polymerase chain reaction. Statistical analysis was performed using ANOVA, Tukey's or Dunnett's tests (p < 0.05). RESULTS: At 24 h postinfection, strains lacking the O-antigen region (healthy isolates and O-antigen ligase-deficient strain) were unable to increase proliferation and viability, or decrease apoptosis as compared with strains producing intact LPS (periodontitis isolates and reference strain). However, the presence of the O-antigen neither contributed to changes in the ability of the bacteria to adhere to or invade cells, nor to intracellular survival. The presence of O-antigen also increased the expression of TLR4 (nearly sixfold), which correlated with inhibition of apoptosis. CONCLUSION: The O-antigen region of P. gingivalis LPS is required to increase gingival epithelial cell viability upon infection by bacteria and this increase is attributable to a reduction in apoptosis. Moreover, although bacterial internalization is required, the effects observed are not due to alterations in P. gingivalis adherence, invasion or intracellular survival. Interestingly, inhibition of apoptosis correlates with increased TLR4 expression, suggesting a role for TLR4 in this process. PMID- 26530547 TI - Over-reliance on unregistered staff is a false economy, says professor. PMID- 26530545 TI - Estimation of Daily Sodium and Potassium Excretion Using Spot Urine and 24-Hour Urine Samples in a Black Population (Benin). AB - The 24-hour urine collection method is considered the gold standard for the estimation of ingested potassium and sodium. Because of the impracticalities of collecting all urine over a 24-hour period, spot urine is often used for epidemiological investigations. This study aims to assess the agreement between spot urine and 24-hour urine measurements to determine sodium and potassium intake. A total of 402 participants aged 25 to 64 years were randomly selected in South Benin. Spot urine was taken during the second urination of the day. Twenty four-hour urine was also collected. Samples (2-mL) were taken and then stored at 20 degrees C. The analysis was carried out using potentiometric dosage. The agreement between spot urine and 24-hour urine measurements was established using Bland-Altman plots. A total of 354 results were analyzed. Daily sodium chloride and potassium chloride urinary excretion means were 10.2+/-4.9 g/24 h and 2.9+/ 1.4 g/24 h, respectively. Estimated daily sodium chloride and potassium chloride means from the spot urine were 10.7+/-7.0 g/24 h and 3.9+/-2.1 g/24 h, respectively. Concordance coefficients were 0.61 at d=-0.5 g, (d+/-2SD=-11 g and 10.1 g) for sodium chloride and 0.61 at d=-1 g, (d+/-2SD=-3.8 g and 1.8 g) for potassium chloride. Spot urine method is acceptable for estimating 24-hour urinary sodium and potassium excretion to assess sodium and potassium intake in a black population. However, the confidence interval for the mean difference, which is too large, makes the sodium chloride results inadmissible at a clinical level. PMID- 26530546 TI - No more excuses on institutional care. PMID- 26530548 TI - Adequate work breaks would help reduce nurses' obesity--RCN. PMID- 26530549 TI - NMC addresses concerns for students in Wales. PMID- 26530550 TI - Local public will see 'Ofsted' health service ratings. PMID- 26530551 TI - Distinguish designated and named nurse roles for children in care, says RCN. PMID- 26530553 TI - A chance to meet Miss Nightingale. PMID- 26530552 TI - Partnerships set to move learning disability patients to community. PMID- 26530554 TI - England ready for revalidation. PMID- 26530555 TI - College warns of midwifery 'retirement time bomb'. PMID- 26530557 TI - Real scenarios help patients picture their care. PMID- 26530558 TI - Trusts fall short on sepsis training despite toll of avoidable deaths. PMID- 26530559 TI - Primary care and the workforce time bomb that must be defused. PMID- 26530565 TI - Liver disease. PMID- 26530566 TI - Seven-day services open new doors. PMID- 26530568 TI - Revalidation support for agency workers. PMID- 26530579 TI - Vitamin Deficiency Finder. PMID- 26530581 TI - People living with post-polio syndrome must not be forgotten. PMID- 26530582 TI - Nurses are duty-bound to keep our first aid skills up to scratch. PMID- 26530583 TI - Practice nurses should take the initiative to attract recruits. PMID- 26530585 TI - Notes and queries column could help provide the answers. PMID- 26530587 TI - E-Portfolio makes document storage straightforward. PMID- 26530588 TI - Princess Campbell 1939-2015. PMID- 26530589 TI - Rosemary Maguire 1939-2015. PMID- 26530590 TI - How to check the arterial pulse. PMID- 26530591 TI - Understanding and managing the health needs of veterans. AB - Military service has many possible consequences for an individual's health. However, the health needs of veterans are not well understood by healthcare professionals. A veteran may present with overlapping symptoms of mental and physical ill health. Problems such as hazardous levels of alcohol consumption and aggressive behaviour may be evident alongside anxiety, depression, post-traumatic stress disorder, chronic pain and disfigurement. Female veterans may present with other complex health issues, such as military sexual trauma. The author suggests that pre-registration curricula for all healthcare professionals should include learning on veterans as a vulnerable patient group. Primary care settings often have first contact with veterans and their families, and every new patient should be asked about their employment history. Collaboration between healthcare professions is vital in assessing and managing the health needs of veterans. PMID- 26530592 TI - Opportunities for suicide prevention in the general medical setting. AB - People who complete suicide are in contact with general medical services frequently in the year before their death. The high rate of medical contacts in the year before suicide and evidence that psychiatric conditions are under diagnosed suggests that a significant opportunity for suicide prevention exists in the general medical setting. This article makes several recommendations to seize this opportunity with the aim of reaching as many patients as possible, ensuring early diagnosis and treatment of mental health problems and providing compassionate care to those who most need it. PMID- 26530593 TI - Preventing catheter-associated urinary tract infection. AB - Urinary tract infections (UTIs) are common in hospital and community settings. The major risk factor for developing a UTI is having a urethral catheter in situ. The longer the catheter remains in place, the higher the risk of infection. The consensus in guidelines is that indwelling urethral catheters should not be used unless necessary and should be removed within 24 hours if possible. The care of patients and nursing home residents who are catheterised for long periods could be improved if guidelines were implemented fully. PMID- 26530594 TI - Fatigue in MS patients. PMID- 26530595 TI - Failure is an option. PMID- 26530597 TI - Spotlight on winning causes. PMID- 26530598 TI - Make the media work for you. PMID- 26530599 TI - Make the most of your time on placement. PMID- 26530600 TI - Correction: Hydrophobic pillared square grids for selective removal of CO2 from simulated flue gas. AB - Correction for 'Hydrophobic pillared square grids for selective removal of CO2 from simulated flue gas' by Sameh K. Elsaidi et al., Chem. Commun., 2015, 51, 15530-15533. PMID- 26530601 TI - Ageing and health--an agenda half completed. PMID- 26530602 TI - Neuraminidase inhibitors for influenza: a call for better research. PMID- 26530603 TI - What are the Geneva Conventions for? PMID- 26530606 TI - And then there were two...polio-endemic countries. PMID- 26530604 TI - Maternal, newborn, and child health and the Sustainable Development Goals--a call for sustained and improved measurement. PMID- 26530607 TI - Japan will be model for future super-ageing societies. PMID- 26530608 TI - Profile: Southern Africa Consortium for Research Excellence. PMID- 26530609 TI - Egyptian cowrie necklace. PMID- 26530611 TI - Moffat Nyirenda: investigating diabetes and other NCDs in Malawi. PMID- 26530612 TI - Ending mass atrocity and ending famine. PMID- 26530613 TI - Emmanuel Gasakure. PMID- 26530614 TI - Mental health in the Syrian crisis: beyond immediate relief. PMID- 26530615 TI - Medical leadership--from inspiration to education. PMID- 26530616 TI - Medical leadership--we need more good followers. PMID- 26530617 TI - Cuba: defeating mother-to-child transmission of syphilis. PMID- 26530618 TI - Mortality risk with dual antiplatelet therapy? PMID- 26530619 TI - Mortality risk with dual antiplatelet therapy? PMID- 26530620 TI - Mortality risk with dual antiplatelet therapy? - Authors' reply. PMID- 26530621 TI - How systematic reviews cause research waste. PMID- 26530622 TI - Department of Error. PMID- 26530623 TI - The double challenge of resistant hypertension and chronic kidney disease. AB - Resistant hypertension is defined as blood pressure above goal despite adherence to a combination of at least three optimally dosed antihypertensive medications, one of which is a diuretic. Chronic kidney disease is the most frequent of several patient factors or comorbidities associated with resistant hypertension. The prevalence of resistant hypertension is increased in patients with chronic kidney disease, while chronic kidney disease is associated with an impaired prognosis in patients with resistant hypertension. Recommended low-salt diet and triple antihypertensive drug regimens that include a diuretic, should be complemented by the sequential addition of other antihypertensive drugs. New therapeutic innovations for resistant hypertension, such as renal denervation and carotid barostimulation, are under investigation especially in patients with advanced chronic kidney disease. We discuss resistant hypertension in chronic kidney disease stages 3-5 (ie, patients with an estimated glomerular filtration rate below 60 mL/min per 1.73 m(2) and not on dialysis), in terms of worldwide epidemiology, outcomes, causes and pathophysiology, evidence-based treatment, and a call for action. PMID- 26530624 TI - The surgeon and the child. AB - For many reasons pediatric surgeons have been asked to do all general and thoracic procedures in children. The profession has responded by training more, but the core of special cases requiring pediatric surgical expertise has not changed, and there is concern that the many surgeons now in training will not each do enough cases to attain and maintain operative expertise. This presentation examines the psychological, educational, and surgical literature on the development of expertise, especially operative expertise. From this I conclude that individual surgeon volume when gained in deliberate practice with a coach and with effort is essential, and that several technologies hold promise for allowing deliberate practice in simulation environments. I propose that in order to avoid a decline in pediatric surgical operative expertise we must reorganize pediatric surgical training and practice to align with Optimal Resources for Children's Surgery and the evolution of training in general surgery. PMID- 26530625 TI - No effect on pharmacokinetics of tamoxifen and 4-hydroxytamoxifen by multiple doses of red clover capsule in rats. AB - Tamoxifen is used in clinical practice for breast cancer patients and to prevent osteoporosis. Red clover (Trifolium pratense) preparations are consumed worldwide as dietary supplements for relieving postmenopausal symptoms. In the present study we investigated the possible herb-drug interaction between red clover and tamoxifen in rats. 15 days pre-treatment with red clover did not alter the tamoxifen and its active metabolite 4-hydroxytamoxifen pharmacokinetics significantly (p > 0.05). Therefore the therapeutic efficacy of the tamoxifen may not be compromised by the co-administration with red clover. Tamoxifen metabolism is primarily mediated by CYP2D6, CYP3A4 with minor contribution from CYP2C9, CYP2E1 and CYP1A2 isoforms. Although, red clover pre-treatment significantly (p < 0.05) decreased the mRNA expression and activity of CYP3a2, no effect on CYP2d4 and increased expression and activity of CYP2c11 could be the plausible reasons for lack of effect on tamoxifen and its metabolite pharmacokinetics in rats. CYP1a1 and CYP2b2 mRNA expression and activity were also significantly reduced by red clover. To extend the clinical utility of the present study, effect of red clover extract on major CYPs using human liver microsomes and HepG2 cell lines were also determined. Similar finding were observed in the human liver preparations as in rats. PMID- 26530626 TI - The CYP1A2 -163C > A polymorphism is associated with super-refractory schizophrenia. PMID- 26530627 TI - Bridging psychophysiological and phenomenological characteristics of psychosis- Preliminary evidence for the relevance of emotion regulation. AB - In psychosis, the alleged increased subjective stress-sensitivity is reflected in abnormal physiological arousal such as higher heart rate, elevated skin conductance levels, decreased vagal activity, and unusual cortisol levels. Despite ongoing research, possible mechanisms that explain the interplay between the phenomenological (i.e., subjective stress and symptoms) and psychophysiological processes are not thoroughly understood. Building on the model of neurovisceral integration by Thayer and Lane (2000) that focuses on regulative mechanisms, we postulate that emotion regulation will be associated with vagal activity, and with both subjective and physiological stress. In the present analysis, we used data from a baseline relaxation period including a 5 minute assessment of heart rate variability (HRV), salivary cortisol, and momentary subjective stress ratings from a sample of 19 participants with psychosis (mean age=40.9, SD=11.1; 36.8% female). Emotion regulation modification skills were assessed for specific emotions (i.e., stress and arousal, anxiety, anger, sadness, shame) if these were present during the previous week. Vagal HRV was significantly and moderately associated with emotion regulation. Both stress parameters (i.e., cortisol, subjective stress) were significantly associated with emotion regulation, but not with HRV. We provide preliminary support for the notion that emotion regulatory processes represent a crucial link between phenomenological and psychophysiological phenomena in psychosis. A potential model that ascribes emotion regulation a central role in the restoration of homeostasis is discussed. Future studies are needed to verify its generalizability and predictive value. PMID- 26530628 TI - Modeling the role of negative symptoms in determining social functioning in individuals at clinical high risk of psychosis. AB - A priority for improving outcome in individuals at clinical high risk (CHR) is enhancing our understanding of predictors of psychosis as well as psychosocial functioning. Social functioning, in particular, is a unique indicator of risk as well as an important outcome in itself. Negative symptoms are a significant determinant of social functioning in CHR individuals; yet, it is unclear which specific negative symptoms drive functional outcome and how these symptoms function relative to other predictors, such as neurocognition and mood/anxiety symptoms. In a sample of 85 CHR individuals, we examined whether a two-factor negative symptom structure that is found in schizophrenia (experiential vs expressive symptoms) would be replicated in a CHR sample; and tested the degree to which specific negative symptoms predict social functioning, relative to neurocognition and mood/anxiety symptoms, which are known to predict functioning. The two-factor negative symptom solution was replicated in this CHR sample. Negative symptom severity was found to be uniquely predictive of social functioning, above and beyond depression/anxiety and neurocognition. Experiential symptoms were more strongly associated with social functioning, relative to expression symptoms. In addition, experiential symptoms mediated the relationship between expressive negative symptoms and social functioning. These results suggest that experiences of motivational impairment are more important in determining social functioning, relative to affective flattening and alogia, in CHR individuals, thereby informing the development of more precise therapeutic targets. Developing novel interventions that stimulate goal-directed behavior and reinforce rewarding experiences in social contexts are recommended. PMID- 26530630 TI - Lats1 suppresses centrosome overduplication by modulating the stability of Cdc25B. AB - Numerical aberration of the centrosome results in chromosome missegregation, eventually leading to chromosomal instability, a hallmark of human tumor malignancy. Large tumor suppressors 1 and 2 (Lats1 and Lats2) are central kinases in the Hippo pathway and regulate development and tumorigenesis by coordinating the balance between cell proliferation and apoptosis. Importantly, Lats1 and Lats2 also play pivotal roles in cell cycle checkpoint and mitosis. The Lats proteins localize at centrosomes, but their centrosomal functions remain elusive. Here, we generated Lats1-null knockout (Lats1(-/-)) mice and established Lats1 null mouse embryonic fibroblasts (MEFs). In Lats1(-/-) MEFs, centrosomes were markedly overduplicated, leading to severe mitotic defects such as chromosome missegregation and cytokinesis failure. We also found that Lats1 physically interacts with Cdc25B phosphatase that localizes both at the centrosome and in the nucleus and regulates the linkage between the centrosome cycle and mitotic progression. Although Lats1 did not phosphorylate Cdc25B, loss of Lats1 in MEFs caused abnormal accumulation of Cdc25B protein and hyperactivation of Cdk2 toward nucleophosmin (NPM/B23), one of the licensing factors involved in centriole duplication. Taken together, these data suggest that Lats1 regulates Cdc25B protein level and subsequent Cdk2 activity, thereby suppressing centrosome overduplication during interphase. PMID- 26530629 TI - The Structural Connectome of the Human Central Homeostatic Network. AB - Homeostatic adaptations to stress are regulated by interactions between the brainstem and regions of the forebrain, including limbic sites related to respiratory, autonomic, affective, and cognitive processing. Neuroanatomic connections between these homeostatic regions, however, have not been thoroughly identified in the human brain. In this study, we perform diffusion spectrum imaging tractography using the MGH-USC Connectome MRI scanner to visualize structural connections in the human brain linking autonomic and cardiorespiratory nuclei in the midbrain, pons, and medulla oblongata with forebrain sites critical to homeostatic control. Probabilistic tractography analyses in six healthy adults revealed connections between six brainstem nuclei and seven forebrain regions, several over long distances between the caudal medulla and cerebral cortex. The strongest evidence for brainstem-homeostatic forebrain connectivity in this study was between the brainstem midline raphe and the medial temporal lobe. The subiculum and amygdala were the sampled forebrain nodes with the most extensive brainstem connections. Within the human brainstem-homeostatic forebrain connectome, we observed that a lateral forebrain bundle, whose connectivity is distinct from that of rodents and nonhuman primates, is the primary conduit for connections between the brainstem and medial temporal lobe. This study supports the concept that interconnected brainstem and forebrain nodes form an integrated central homeostatic network (CHN) in the human brain. Our findings provide an initial foundation for elucidating the neuroanatomic basis of homeostasis in the normal human brain, as well as for mapping CHN disconnections in patients with disorders of homeostasis, including sudden and unexpected death, and epilepsy. PMID- 26530631 TI - beta-Elemonic acid inhibits the cell proliferation of human lung adenocarcinoma A549 cells: The role of MAPK, ROS activation and glutathione depletion. AB - beta-elemonic acid, a known triterpene, exhibits anti-inflammatory effects, yet research on the pharmacological effects of beta-elemonic acid is rare. We investigated the anticancer effects and the related molecular mechanisms of beta elemonic acid on human non-small cell lung cancer (NSCLC) A549 cells. The effects of beta-elemonic acid on the growth of A549 cells were studied using a 3-(4,5) 2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected using Annexin V staining. The effect of beta-elemonic acid on the cell cycle of A549 cells was assessed using the propidium iodide method. The change in reactive oxygen species (ROS) was detected using a dichlorodihydrofluorescein diacetate (DCFH-DA) assay with microscopic examination. The expression levels of Bcl-2 family proteins, mitogen-activated protein kinase (MAPK) family proteins and cyclooxygenase 2 (COX 2) were detected using western blot analysis. Our data revealed that beta elemonic acid strongly induced human A549 lung cancer cell death in a dose- and time-dependent manner as determined by the MTT assay. beta-elemonic acid-induced cell death was considered to be apoptotic when the phosphatidylserine exposure was observed using Annexin V staining. The death of human A549 lung cancer cells was caused by apoptosis induced by activation of ROS activity, increase in the sub-G1 proportion, downregulation of Bcl-2 expression, upregulation of Bax expression and inhibition of the MAPK signaling pathways. These results clearly demonstrated that beta-elemonic acid inhibits proliferation by inducing hypoploid cells and cell apoptosis. Moreover, the anticancer effects of beta-elemonic acid were related to the MAPK signaling pathway, ROS activation and glutathione depletion in human A549 lung cancer cells. PMID- 26530632 TI - Resveratrol induces cell cycle arrest in human gastric cancer MGC803 cells via the PTEN-regulated PI3K/Akt signaling pathway. AB - Resveratrol is a polyphenolic compound that is extracted from Polygonum cuspidatum and is used in traditional Chinese medicine. Previous data have shown that resveratrol inhibits the growth of human gastric cancer. MTT [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and trypan blue assays showed that resveratrol significantly decreased the survival rate of MGC803 cells in a concentration- and time-dependent manner. Our flow cytometric analysis showed that resveratrol treatment arrested the cells at the G0/G1 phase of the cell cycle. Furthermore, western blotting demonstrated that resveratrol decreased the protein expression of phospho-glycogen synthase kinase 3beta (p-GSK3beta), cyclin D1, phospho-phosphatase and tensin homologue (p-PTEN), phospho phosphatidylinositol 3'-OH kinase (p-PI3K), and phospho-protein kinase B (p PKB/Akt). We also found that resveratrol inhibited the progression of the cell cycle in MGC803 cells by repressing p-PI3K and p-Akt expression. Meanwhile, resveratrol did not decrease the phosphorylation level of Akt when the PTEN gene expression was knocked down by an siRNA in the MGC803 cells. Taken together, these results suggest that resveratrol induced cell cycle arrest in human gastric cancer MGC803 cells by regulating the PTEN/PI3K/Akt signaling pathway. PMID- 26530633 TI - Recovery of terrestrial plants in vegetative vigor and seedling emergence tests from exposure to atrazine. AB - Ten species of terrestrial plants, including 6 dicotyledonous and 4 monocotyledonous species, were exposed to a direct overspray of atrazine according to US Environmental Protection Agency seedling emergence and vegetative vigor study guidelines and subsequently evaluated for potential recovery. For each species, no-observed-effect rate (NOER), 10% effect rate, 25% effect rate, and 50% effect rate values were calculated (where possible) for a variety of guideline-required endpoints (but focusing on growth rate) for both the standard experimental phase and a recovery phase; and the rates subsequently were compared. For the seedling emergence study, the standard experimental (designated test 1) and recovery (designated test 2) phases encompassed days 0 to 14 and days 14 to 28, respectively. Similarly, for the vegetative vigor study, test 1 and test 2 encompassed days 0 to 21 and days 21 to 42, respectively. Plants were exposed to atrazine at nominal application rates ranging from 1.1 g active ingredient (a.i.)/ha (0.0010 lb a.i./A) to 28,000 g a.i./ha (25 lb a.i./A), depending on the species; the 28,000 g a.i./ha rate is greater than 12 times the maximum application rate of 2250 g a.i./ha (2 lb a.i./A) registered on corn. For seedling emergence, only 2 of 10 species tested, cabbage and tomato, provided clear rate responses in the initial 14 d of exposure (test 1). Based on a comparison of x% effect rate (ERx) and NOER values for growth rates of shoot length and shoot dry weight for days 0 to 14 relative to days 14 to 28, recovery was apparent for cabbage shoot length growth rate and tomato shoot length and shoot dry weight growth rates. Test application rates selected for the remaining 8 species showed either a weak response that did not allow a clear assessment of recovery or no response at all. For the vegetative vigor study, 9 of the 10 species tested provided clear rate responses in test 1 (days 0-21); corn did not demonstrate any herbicidal response up to the highest rate tested, 28,000 g a.i./ha. Based on comparison of day 0 to 21 (test 1) relative to day 21 to 42 (test 2) ERx and NOER values for shoot length, average growth rates indicated that 8 of 9 species clearly demonstrated an increase in 2 or more metrics (cabbage did not demonstrate a response based on shoot length). Clear recovery was also indicated by an increase in ERx and/or NOER values from test 1 to test 2 for shoot dry weight average growth rates for 7 of the 9 species (corn did not show a response, and oat and soybean showed variable responses). Thus, in most species, where initial herbicidal effects were observed, the effects are largely ameliorated over time. PMID- 26530634 TI - In-capillary detection of fast antibody-peptide binding using fluorescence coupled capillary electrophoresis. AB - Herein, we report a technique for detecting the fast binding of antibody-peptide inside a capillary. Anti-HA was mixed and interacted with FAM-labeled HA tag (FAM E4 ) inside the capillary. Fluorescence coupled capillary electrophoresis (CE-FL) was employed to measure and record the binding process. The efficiency of the antibody-peptide binding on in-capillary assays was found to be affected by the molar ratio. Furthermore, the stability of anti-HA-FAM-E4 complex was investigated as well. The results indicated that E4 YPYDVPDYA (E4) or TAMRA-E4 YPYDVPDYA (TAMRA-E4) had the same binding priorities with anti-HA. The addition of excess E4 or TAMRA-E4 could lead to partial dissociation of the complex and take a two-step mechanism including dissociation and association. This method can be applied to detect a wide range of biomolecular interactions. PMID- 26530635 TI - A Lattice-Boltzmann scheme for the simulation of diffusion in intracellular crowded systems. AB - BACKGROUND: The intracellular environment is a complex and crowded medium where the diffusion of proteins, metabolites and other molecules can be decreased. One of the most popular methodologies for the simulation of diffusion in crowding systems is the Monte Carlo algorithm (MC) which tracks the movement of each particle. This can, however, be computationally expensive for a system comprising a large number of molecules. On the other hand, the Lattice Boltzmann Method (LBM) tracks the movement of collections of molecules, which represents significant savings in computational time. Nevertheless in the classical manifestation of such scheme the crowding conditions are neglected. METHODS: In this paper we use Scaled Particle Theory (SPT) to approximate the probability to find free space for the displacement of hard-disk molecules and in this way to incorporate the crowding effect to the LBM. This new methodology which couples SPT and LBM is validated using a kinetic Monte Carlo (kMC) algorithm, which is used here as our "computational experiment". RESULTS: The results indicate that LBM over-predicts the diffusion in 2D crowded systems, while the proposed coupled SPT-LBM predicts the same behaviour as the kinetic Monte Carlo (kMC) algorithm but with a significantly reduced computational effort. Despite the fact that small deviations between the two methods were observed, in part due to the mesoscopic and microscopic nature of each method, respectively, the agreement was satisfactory both from a qualitative and a quantitative point of view. CONCLUSIONS: A crowding-adaptation to LBM has been developed using SPT, allowing fast simulations of diffusion-systems of different size hard-disk molecules in two-dimensional space. This methodology takes into account crowding conditions; not only the space fraction occupied by the crowder molecules but also the influence of the size of the crowder which can affect the displacement of molecules across the lattice system. PMID- 26530636 TI - Nocardioides albidus sp. nov., an actinobacterium isolated from garden soil. AB - A novel bacterial strain, designated THG-S11.7T, was isolated from garden soil in Incheon, South Korea. Cells of the strain were Gram-stain-positive, aerobic, non motile cocci, and were catalase- and oxidase-positive. Colonies of the strain were white. Strain THG-S11.7T grew optimally at 28 degrees C, at pH 7.0 and in the presence of 2.0 % NaCl. 16S rRNA gene sequence analysis indicated that the strain was a member of the genus Nocardioides. Strain THG-S11.7T showed a 16S rRNA gene sequence similarity of 98.2 % to Nocardioides kongjuensis KCTC 19054T, 98.0 % to Nocardioides caeni KCTC 19600T, 97.9 % to Nocardioides daeguensis KCTC 19799T, 97.8 % to Nocardioides nitrophenolicus KCTC 047BPT, 97.6 % to Nocardioides aromaticivorans KACC 20613T, 97.5 % to Nocardioides simplex KACC 20620T and 97.0 % to Nocardioides ginsengisoli KCTC 19135T. DNA-DNA relatedness values between strain THG-S11.7T and the closest phylogenetic neighbours were below 45.0 % and the DNA G+C content of strain THG-S11.7T was 72.2 mol%. Strain THG-S11.7T was characterized chemotaxonomically as having ll-diaminopimelic acid in the cell-wall peptidoglycan and menaquinone MK-8(H4) as the predominant isoprenoid quinone. The major phospholipid was determined to be diphosphatidylglycerol. The major cellular fatty acids of strain THG-S11.7T were iso-C15 : 0, C16 : 0 and iso-C16 : 0. Based on the phenotypic, genotypic and phylogenetic analyses, it is proposed that the isolate represents a novel species of the genus Nocardioides, for which the name Nocardioides albidus sp. nov. is proposed. The type strain is THG-S11.7T ( = KCTC 39607T = CCTCC AB 2015297T). PMID- 26530638 TI - Dynamic Diglyme-Mediated Self-Assembly of Gold Nanoclusters. AB - We report the assembly of gold nanoclusters by the nonthiolate ligand diglyme into discrete and dynamic assemblies. To understand this surprising phenomenon, the assembly of Au20(SC2H4Ph)15-diglyme into Au20(SC2H4Ph)15-diglyme Au20(SC2H4Ph)15 is explored in detail. The assembly is examined by high-angle annular dark field scanning transmission electron microscopy, size exclusion chromatography, mass spectrometry, IR spectroscopy, and calorimetry. We establish a dissociation constant for dimer to monomer conversion of 20.4 MUM. Theoretical models validated by transient absorption spectroscopy predict a low-spin monomer and a high-spin dimer, with assembly enabled through weak diglyme oxygen-gold interactions. Close spatial coupling allows electron delocalization between the nanoparticle cores. The resulting assemblies thus possess optical and electronic properties that emerge as a result of assembly. PMID- 26530637 TI - Cloning of novel rice blast resistance genes from two rapidly evolving NBS-LRR gene families in rice. AB - Most rice blast resistance genes (R-genes) encode proteins with nucleotide binding site (NBS) and leucine-rich repeat (LRR) domains. Our previous study has shown that more rice blast R-genes can be cloned in rapidly evolving NBS-LRR gene families. In the present study, two rapidly evolving R-gene families in rice were selected for cloning a subset of genes from their paralogs in three resistant rice lines. A total of eight functional blast R-genes were identified among nine NBS-LRR genes, and some of these showed resistance to three or more blast strains. Evolutionary analysis indicated that high nucleotide diversity of coding regions served as important parameters in the determination of gene resistance. We also observed that amino-acid variants (nonsynonymous mutations, insertions, or deletions) in essential motifs of the NBS domain contribute to the blast resistance capacity of NBS-LRR genes. These results suggested that the NBS regions might also play an important role in resistance specificity determination. On the other hand, different splicing patterns of introns were commonly observed in R-genes. The results of the present study contribute to improving the effectiveness of R-gene identification by using evolutionary analysis method and acquisition of novel blast resistance genes. PMID- 26530639 TI - Synthesis, and crystal and electronic structure of sodium metal phosphate for use as a hybrid capacitor in non-aqueous electrolyte. AB - Energy storage devices based on sodium have been considered as an alternative to traditional lithium based systems because of the natural abundance, cost effectiveness and low environmental impact of sodium. Their synthesis, and crystal and electronic properties have been discussed, because of the importance of electronic conductivity in supercapacitors for high rate applications. The density of states of a mixed sodium transition metal phosphate (maricite, NaMn(1/3)Co(1/3)Ni(1/3)PO4) has been determined with the ab initio generalized gradient approximation (GGA)+Hubbard term (U) method. The computed results for the mixed maricite are compared with the band gap of the parent NaFePO4 and the electrochemical experimental results are in good agreement. A mixed sodium transition metal phosphate served as an active electrode material for a hybrid supercapacitor. The hybrid device (maricite versus carbon) in a non-aqueous electrolyte shows redox peaks in the cyclic voltammograms and asymmetric profiles in the charge-discharge curves while exhibiting a specific capacitance of 40 F g( 1) and these processes are found to be quasi-reversible. After long term cycling, the device exhibits excellent capacity retention (95%) and coulombic efficiency (92%). The presence of carbon and the nanocomposite morphology, identified through X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM) studies, ensures the high rate capability while offering possibilities to develop new cathode materials for sodium hybrid devices. PMID- 26530640 TI - Brain ventricle development in H. huso (Beluga sturgeon) larvae. AB - The development of ventricles in the brain of H. huso (Beluga sturgeon) from 1 to 54 days old is presented in this study. The components observed in the 1-day-old ventricular system were the telencephalic, tectal, and cerebellar ventricles. These ventricles were not observed to have any recess or sulcus. They were surrounded by copious ependymal and embryonic cells. Two different parts were detected in the 6-day-old telencephalic ventricle: the olfactory and lateral ventricle. The olfactory ventricle was observed as a cranial extension of the telencephalic ventricle from 6 days old, as was the inner cell layer of the olfactory bulb (ic) adjacent to this extension. In the preoptic region, the lateral ventricle was connected to the preoptic recess from 15 days old, and this recess was connected by the interventricular foramen to the third ventricle in the diencephalon. At 6 days old, the third ventricle in the diencephalon was visible at the caudal part of the lateral ventricle, and the third ventricle had a recess near to the inferior lobe of the hypothalamus. At 6 days old, the tectal ventricle was observed to have bilateral extensions which proceeded to grow with age. The cerebellar ventricle, situated between the two lobes of the cerebellum, was observed from 1 day old. The cerebellar ventricle grew with age, extending laterally from 6 days old. The connection of the cerebellar ventricle to the fourth ventricle in the medulla oblongata was visible from 6 days old. Upon dividing the ventricular system into three regions (forebrain, midbrain, and hindbrain), stereological studies performed utiizing Cavalieri's principle indicated that the forebrain ventricular region had the smallest volume while the hindbrain ventricular region had the largest. PMID- 26530641 TI - Molecular imaging analysis of Rab GTPases in the regulation of phagocytosis and macropinocytosis. AB - Phagocytosis and macropinocytosis, actin-dependent endocytic pathways that mediate the uptake of particles and fluid, respectively, are fundamental routes that enable cells to sample their environment, eliminate pathogens and endogenous cell debris, and contribute to immunoprotection and the maintenance of tissue homeostasis. These processes require a well-organized network of actin cytoskeletal remodeling and membrane transport, which are spatiotemporally regulated by small GTPases. The Rab family of small GTPases, which functions as molecular switches, plays central roles in intracellular membrane trafficking. Although multiple Rab proteins are localized to phagosomes and regulate phagosome maturation, the precise role of each Rab family member in Fcgamma receptor (FcgammaR)-mediated phagocytosis is not fully characterized. Recently, we revealed that Rab35 and Rab20 are important regulators of phagosome formation and maturation, respectively. This review summarizes the functional implication of these Rab GTPases during FcgammaR-mediated phagocytosis in macrophages. Currently, compared with our knowledge of the regulatory mechanisms of receptor mediated endocytosis including phagocytosis, the molecular components and signaling cascades of macropinocytosis remain poorly elucidated. Our time-lapse imaging showed that several Rab GTPases are sequentially recruited to the membrane of macropinosomes. Based on our observations, these findings regarding the spatiotemporal localization of Rab GTPases during macropinocytosis are introduced. PMID- 26530642 TI - All levels of evidence contribute to our evolving knowledge. PMID- 26530643 TI - Iatrogenic vascular injuries during arthroplasty of the hip. AB - Vascular injuries during total hip arthroplasty (THA) are rare but when they occur, have serious consequences. These have traditionally been managed with open exploration and repair, but more recently there has been a trend towards percutaneous endovascular management. We performed a systematic review of the literature to assess if this change in trend has led to an improvement in the overall reported rates of morbidity and mortality during the last 22 years in comparison with the reviews of the literature published previously. We found a total of 61 articles describing 138 vascular injuries in 124 patients. Injuries because of a laceration were the most prevalent (n = 51, 44%) and the most common presenting feature, when recorded, was bleeding (n = 41, 53.3%). Delay in diagnosis was associated with the type of vascular lesion (p < 0.001) and the clinical presentation (p = 0.002). Open exploration and repair was the most common form of management, however percutaneous endovascular intervention was used in one third of the injuries and more constantly during the last 13 years. The main overall reported complications included death (n = 9, 7.3%), amputation (n = 2, 1.6%), and persistent ischaemia (n = 9, 7.3%). When compared with previous reviews there was a similar rate of mortality but lower rates of amputation and permanent disability, especially in patients managed by endovascular strategies. PMID- 26530644 TI - Putting the baby back in the bathwater: the interpretation of randomised trials in surgery. AB - Recently, several high impact randomised controlled trials have been published suggesting no greater benefit from orthopaedic surgery over conservative treatment, or limited surgical intervention. These studies can have profound effects on clinical practice, leading to the abandonment of previously widely used operations. How do surgeons who believe these operations are beneficial over conservative treatment rationalise these findings, and justify their use with hospital administrators and health care funders who require evidence for the value and efficacy of surgical treatment? PMID- 26530645 TI - A randomised controlled trial comparing highly cross-linked and contemporary annealed polyethylene after a minimal eight-year follow-up in total hip arthroplasty using cemented acetabular components. AB - Most published randomised controlled trials which compare the rates of wear of conventional and cross-linked (XL) polyethylene (PE) in total hip arthroplasty (THA) have described their use with a cementless acetabular component. We conducted a prospective randomised study to assess the rates of penetration of two distinct types of PE in otherwise identical cemented all-PE acetabular components. A total of 100 consecutive patients for THA were randomised to receive an acetabular component which had been either highly XL then remelted or moderately XL then annealed. After a minimum of eight years follow-up, 38 hips in the XL group and 30 hips in the annealed group had complete data (mean follow-up of 9.1 years (7.6 to 10.7) and 8.7 years (7.2 to 10.2), respectively). In the XL group, the steady state rate of penetration from one year onwards was -0.0002 mm/year (sd 0.108): in the annealed group it was 0.1382 mm/year (sd 0.129) (Mann Whitney U test, p < 0.001). No complication specific to either material was recorded. These results show that the yearly linear rate of femoral head penetration can be significantly reduced by using a highly XLPE cemented acetabular component. PMID- 26530646 TI - Oxinium modular femoral heads do not reduce polyethylene wear in cemented total hip arthroplasty at five years: a randomised trial of 120 hips using radiostereometric analysis. AB - We report the five-year outcome of a randomised controlled trial which used radiostereometric analysis (RSA) to assess the influence of surface oxidised zirconium (OxZr, Oxinium) on polyethylene wear in vivo. A total of 120 patients, 85 women and 35 men with a mean age of 70 years (59 to 80) who were scheduled for primary cemented total hip arthroplasty were randomly allocated to four study groups. Patients were blinded to their group assignment and received either a conventional polyethylene (CPE) or a highly cross-linked (HXL) acetabular component of identical design. On the femoral side patients received a 28 mm head made of either cobalt-chromium (CoCr) or OxZr. The proximal head penetration (wear) was measured with repeated RSA examinations over five years. Clinical outcome was measured using the Harris hip score. There was no difference in polyethylene wear between the two head materials when used with either of the two types of acetabular component (p = 0.3 to 0.6). When comparing the two types of polyethylene there was a significant difference in favour of HXLPE, regardless of the head material used (p < 0.001). In conclusion, we found no advantage of OxZr over CoCr in terms of polyethylene wear after five years of follow-up. Our findings do not support laboratory results which have shown a reduced rate of wear with OxZr. They do however add to the evidence on the better resistance to wear of HXLPE over CPE. PMID- 26530647 TI - The rates of wear of X3 highly cross-linked polyethylene at five years when coupled with a 36 mm diameter ceramic femoral head in young patients. AB - Polyethylene wear debris can cause osteolysis and the failure of total hip arthroplasty. We present the five-year wear rates of a highly cross-linked polyethylene (X3) bearing surface when used in conjunction with a 36 mm ceramic femoral head. This was a prospective study of a cohort of 100 THAs in 93 patients. Pain and activity scores were measured pre- and post-operatively. Femoral head penetration was measured at two months, one year, two years and at five years using validated edge-detecting software (PolyWare Auto). At a mean of 5.08 years (3.93 to 6.01), 85 hips in 78 patients were available for study. The mean age of these patients was 59.08 years (42 to 73, the mean age of males (n = 34) was 59.15 years, and females (n = 44) was 59.02 years). All patients had significant improvement in their functional scores (p < 0.001). The steady state two-dimensional linear wear rate was 0.109 mm/year. The steady state volumetric wear rate was 29.61 mm(3)/year. No significant correlation was found between rate of wear and age (p = 0.34), acetabular component size (p = 0.12) or clinical score (p = 0.74). Our study shows low steady state wear rates at five years in X3 highly cross-linked polyethylene in conjunction with a 36 mm ceramic femoral head. The linear wear rate was almost identical to the osteolysis threshold of 0.1 mm/year recommended in the literature. PMID- 26530648 TI - Cemented versus uncemented arthroplasty in patients with a displaced fracture of the femoral neck: a randomised controlled trial. AB - The aim of this randomised controlled study was to compare functional and radiological outcomes between modern cemented and uncemented hydroxyapatite coated stems after one year in patients treated surgically for a fracture of the femoral neck. A total of 141 patients aged > 65 years were included. Patients were randomised to be treated with a cemented Exeter stem or an uncemented Bimetric stem. The patients were reviewed at four and 12 months. The cemented group performed better than the uncemented group for the Harris hip score (78 vs 70.7, p = 0.004) at four months and for the Short Musculoskeletal Function Assesment Questionnaire dysfunction score at four (29.8 vs 39.2, p = 0.007) and 12 months (22.3 vs 34.9, p = 0.001). The mean EQ-5D index score was better in the cemented group at four (0.68 vs 0.53, p = 0.001) and 12 months (0.75 vs 0.58, p = < 0.001) follow-up. There were nine intra-operative fractures in the uncemented group and none in the cemented group. In conclusion, our data do not support the use of an uncemented hydroxyapatite coated stem for the treatment of displaced fractures of the femoral neck in the elderly. PMID- 26530649 TI - Pseudotumour incidence, cobalt levels and clinical outcome after large head metal on-metal and conventional metal-on-polyethylene total hip arthroplasty: mid-term results of a randomised controlled trial. AB - We compared the incidence of pseudotumours after large head metal-on-metal (MoM) total hip arthroplasty (THA) with that after conventional metal-on-polyethylene (MoP) THA and assessed the predisposing factors to pseudotumour formation. From a previous randomised controlled trial which compared large head (38 mm to 60 mm) cementless MoM THA with conventional head (28 mm) cementless MoP THA, 93 patients (96 THAs: 41 MoM (21 males, 20 females, mean age of 64 years, standard deviation (sd) 4) and 55 MoP (25 males, 30 females, mean age of 65 years, sd 5) were recruited after a mean follow-up of 50 months (36 to 64). The incidence of pseudotumours, measured using a standardised CT protocol was 22 (53.7%) after MoM THA and 12 (21.8%) after MoP THA. Women with a MoM THA were more likely to develop a pseudotumour than those with a MoP THA (15 vs 7, odds ratio (OR) = 13.4, p < 0.001). There was a similar incidence of pseudotumours in men with MoM THAs and those with MoP THAs (7 vs 5, OR = 2.1, p = 0.30). Elevated cobalt levels (>= 5 microgram/L) were only associated with pseudotumours in women with a MoM THA. There was no difference in mean Oxford and Harris hip scores between patients with a pseudotumour and those without. Contrary to popular belief, pseudotumours occur frequently around MoP THAs. Women with a MoM THA and an elevated cobalt level are at greatest risk. In this study, pseudotumours had no effect on the functional outcome after either large head MoM or conventional MoP THA. PMID- 26530650 TI - Successful return to high-level sports following early surgical repair of combined adductor complex and rectus abdominis avulsion. AB - Hip and groin injuries are common in athletes who take part in high level sports. Adductor muscle tendon injuries represent a small but important number of these injuries. Avulsion of the tendons attached to the symphysis pubis has previously been described: these can be managed both operatively and non-operatively. We describe an uncommon variant of this injury, namely complete avulsion of the adductor sleeve complex: this includes adductor longus, pectineus and rectus abdominis. We go on to describe a surgical technique which promotes a full return to the pre-injury level of sporting activity. Over a period of ten years, 15 high level athletes with an MRI-confirmed acute adductor complex avulsion injury (six to 34 days old) underwent surgical repair. The operative procedure consisted of anatomical re-attachment of the avulsed tissues in each case and mesh reinforcement of the posterior inguinal wall in seven patients. All underwent a standardised rehabilitation programme, which was then individualised to be sport specific. One patient developed a superficial wound infection, which was successfully treated with antibiotics. Of the 15 patients, four complained of transient local numbness which resolved in all cases. All patients (including seven elite athletes) returned to their previous level of participation in sport. PMID- 26530651 TI - The clinical outcome of minimally invasive Phase 3 Oxford unicompartmental knee arthroplasty: a 15-year follow-up of 1000 UKAs. AB - There have been concerns about the long-term survival of unicompartmental knee arthroplasty (UKA). This prospective study reports the 15-year survival and ten year functional outcome of a consecutive series of 1000 minimally invasive Phase 3 Oxford medial UKAs (818 patients, 393 men, 48%, 425 women, 52%, mean age 66 years; 32 to 88). These were implanted by two surgeons involved with the design of the prosthesis to treat anteromedial osteoarthritis and spontaneous osteonecrosis of the knee, which are recommended indications. Patients were prospectively identified and followed up independently for a mean of 10.3 years (5.3 to 16.6). At ten years, the mean Oxford Knee Score was 40 (standard deviation (sd) 9; 2 to 48): 79% of knees (349) had an excellent or good outcome. There were 52 implant-related re-operations at a mean of 5.5 years (0.2 to 14.7). The most common reasons for re-operation were arthritis in the lateral compartment (2.5%, 25 knees), bearing dislocation (0.7%, seven knees) and unexplained pain (0.7%, seven knees). When all implant-related re-operations were considered as failures, the ten-year rate of survival was 94% (95% confidence interval (CI) 92 to 96) and the 15-year survival rate 91% (CI 83 to 98). When failure of the implant was the endpoint the 15-year survival was 99% (CI 96 to 100). This is the only large series of minimally invasive UKAs with 15-year survival data. The results support the continued use of minimally invasive UKA for the recommended indications. PMID- 26530652 TI - Bariatric surgery does not improve outcomes in patients undergoing primary total knee arthroplasty. AB - Bariatric surgery has been advocated as a means of reducing body mass index (BMI) and the risks associated with total knee arthroplasty (TKA). However, this has not been proved clinically. In order to determine the impact of bariatric surgery on the outcome of TKA, we identified a cohort of 91 TKAs that were performed in patients who had undergone bariatric surgery (bariatric cohort). These were matched with two separate cohorts of patients who had not undergone bariatric surgery. One was matched 1:1 with those with a higher pre-bariatric BMI (high BMI group), and the other was matched 1:2 based on those with a lower pre-TKA BMI (low BMI group). In the bariatric group, the mean BMI before bariatric surgery was 51.1 kg/m(2) (37 to 72), which improved to 37.3 kg/m(2) (24 to 59) at the time of TKA. Patients in the bariatric group had a higher risk of, and worse survival free of, re-operation (hazard ratio (HR) 2.6; 95% confidence interval (CI) 1.2 to 6.2; p = 0.02) compared with the high BMI group. Furthermore, the bariatric group had a higher risk of, and worse survival free of re-operation (HR 2.4; 95% CI 1.2 to 3.3; p = 0.2) and revision (HR 2.2; 95% CI 1.1 to 6.5; p = 0.04) compared with the low BMI group. While bariatric surgery reduced the BMI in our patients, more analysis is needed before recommending bariatric surgery before TKA in obese patients. PMID- 26530653 TI - Optimal usage of unicompartmental knee arthroplasty: a study of 41,986 cases from the National Joint Registry for England and Wales. AB - Unicompartmental knee arthroplasty (UKA) has advantages over total knee arthroplasty but national joint registries report a significantly higher revision rate for UKA. As a result, most surgeons are highly selective, offering UKA only to a small proportion (up to 5%) of patients requiring arthroplasty of the knee, and consequently performing few each year. However, surgeons with large UKA practices have the lowest rates of revision. The overall size of the practice is often beyond the surgeon's control, therefore case volume may only be increased by broadening the indications for surgery, and offering UKA to a greater proportion of patients requiring arthroplasty of the knee. The aim of this study was to determine the optimal UKA usage (defined as the percentage of knee arthroplasty practice comprised by UKA) to minimise the rate of revision in a sample of 41 986 records from the for National Joint Registry for England and Wales (NJR). UKA usage has a complex, non-linear relationship with the rate of revision. Acceptable results are achieved with the use of 20% or more. Optimal results are achieved with usage between 40% and 60%. Surgeons with the lowest usage (up to 5%) have the highest rates of revision. With optimal usage, using the most commonly used implant, five-year survival is 96% (95% confidence interval (CI) 94.9 to 96.0), compared with 90% (95% CI 88.4 to 91.6) with low usage (5%) previously considered ideal. The rate of revision of UKA is highest with low usage, implying the use of narrow, and perhaps inappropriate, indications. The widespread use of broad indications, using appropriate implants, would give patients the advantages of UKA, without the high rate of revision. PMID- 26530654 TI - Which patients need critical care intervention after total joint arthroplasty? : a prospective study of factors associated with the need for intensive care following surgery. AB - Older patients with multiple medical co-morbidities are increasingly being offered and undergoing total joint arthroplasty (TJA). These patients are more likely to require intensive care support, following surgery. We prospectively evaluated the need for intensive care admission and intervention in a consecutive series of 738 patients undergoing elective hip and knee arthroplasty procedures. The mean age was 60.6 years (18 to 91; 440 women, 298 men. Risk factors, correlating with the need for critical care intervention, according to published guidelines, were analysed to identify high-risk patients who would benefit from post-operative critical care monitoring. A total of 50 patients (6.7%) in our series required critical care level interventions during their hospital stay. Six independent multivariate clinical predictors were identified (p < 0.001) including a history of congestive heart failure (odds ratio (OR) 24.26, 95% confidence interval (CI) 9.51 to 61.91), estimated blood loss > 1000 mL (OR 17.36, 95% CI 5.36 to 56.19), chronic obstructive pulmonary disease (13.90, 95% CI 4.78 to 40.36), intra-operative use of vasopressors (OR 8.10, 95% CI 3.23 to 20.27), revision hip arthroplasty (OR 2.71, 95% CI 1.04 to 7.04) and body mass index > 35 kg/m(2) (OR 2.70, 95% CI 123 to 5.94). The model was then validated against an independent, previously published data set of 1594 consecutive patients. The use of this risk stratification model can be helpful in predicting which high-risk patients would benefit from a higher level of monitoring and care after elective TJA and aid hospitals in allocating precious critical care resources. PMID- 26530655 TI - The cement spacer with multiple indentations: increasing antibiotic elution using a cement spacer 'teabag'. AB - We investigated whether the indentation of bone cement spacers used in revision of infected joint arthroplasty with a MacDonald dissector increased the elution of antibiotic in vitro. A total of 24 cement discs containing either 0.17 g (0.88% w/w), 0.25 g (1.41% w/w), or 0.33 g (1.75% w/w) gentamicin of constant size were made. Of these, 12 were indented with the dissector. Each disc was immersed in ammonium acetate buffer in a sealed container, and fluid from each container was sampled at zero, one, three, six, 24, 48 and 72 hours and at one, and two weeks. The concentration of gentamicin in the fluid was analysed using high performance liquid chromatography mass spectrometry. The fluid sampled at 72 hours from the indented discs containing 0.17 g gentamicin (0.88% w/w) contained a mean of 113 mcg/ml (90.12 to 143.5) compared with 44.5 mcg/ml (44.02 to 44.90) in the fluid sampled from the plain discs (p = 0.012). In discs containing 0.33 g gentamicin (1.75% w/w), the concentration eluted from the indented discs at 72 hours was a mean of 316 mcg/ml (223 to 421) compared with a mean of 118 mcg/ml (100 to 140) from the plain discs (p < 0.001). At two weeks, these significant differences persisted. At nine weeks the indented discs eluted a greater concentration for all gentamicin doses, but the difference was only significant for the discs containing 0.17 g (0.88% w/w, p = 0.006). However if the area under the curve is taken as a measure of the total antibiotic eluted, the indented discs eluted more gentamicin than the plain discs for the 0.17 g (0.88% w/w, p = 0.031), the 0.25 g (1.41% w/w, p < 0.001) and the 0.33 g (1.75% w/w, p < 0.001) discs. When preparing antibiotic spacers for use in staged revision arthroplasty surgery we recommend indenting the spacer with a MacDonald dissector to increase the elution of antibiotic. PMID- 26530656 TI - Failure to restore sagittal tibiotalar alignment in total ankle arthroplasty: Its relationship to the axis of the tibia and the positioning of the talar component. AB - The purpose of this study was to evaluate the change in sagittal tibiotalar alignment after total ankle arthroplasty (TAA) for osteoarthritis and to investigate factors affecting the restoration of alignment. This retrospective study included 119 patients (120 ankles) who underwent three component TAA using the Hintegra prosthesis. A total of 63 ankles had anterior displacement of the talus before surgery (group A), 49 had alignment in the normal range (group B), and eight had posterior displacement of the talus (group C). Ankles in group A were further sub-divided into those in whom normal alignment was restored following TAA (41 ankles) and those with persistent displacement (22 ankles). Radiographic and clinical results were assessed. Pre-operatively, the alignment in group A was significantly more varus than that in group B, and the posterior slope of the tibial plafond was greater (p < 0.01 in both cases). The posterior slope of the tibial component was strongly associated with restoration of alignment: ankles in which the alignment was restored had significantly less posterior slope (p < 0.001). An anteriorly translated talus was restored to a normal position after TAA in most patients. We suggest that surgeons performing TAA using the Hintegra prosthesis should aim to insert the tibial component at close to 90 degrees relative to the axis of the tibia, hence reducing posterior soft-tissue tension and allowing restoration of normal tibiotalar alignment following surgery. PMID- 26530657 TI - An alternative technique for stabilisation of the carpometacarpal joint of the thumb after dislocation or subluxation. AB - We report a new surgical technique for the treatment of traumatic dislocation of the carpometacarpal (CMC) joint of the thumb. This is a tenodesis which uses part of the flexor carpi radialis. Between January 2010 and August 2013, 13 patients with traumatic instability of the CMC joint of the thumb were treated using this technique. The mean time interval between injury and ligament reconstruction was 13 days (0 to 42). The mean age of the patients at surgery was 38 years: all were male. At a mean final follow-up of 26 months (24 to 29), no patient experienced any residual instability. The mean total palmar abduction of the CMC joint of the thumb was 61 degrees and the mean radial abduction 65 degrees The mean measurements for the uninjured hand were 66 degrees (60 degrees to 73 degrees ) and 68 degrees (60 degrees to 75 degrees ), respectively. The mean Kapandji thumb opposition score was 8.5 degrees (8 degrees to 9 degrees ). The mean pinch and grip strengths of the hand were 6.7 kg (3.4 to 8.2) and 40 kg (25 to 49), respectively. The mean Disabilities of the Arm, Shoulder, and Hand questionnaire score was 3 (1 to 6). Based on the Smith and Cooney score, we obtained a mean score of 85 (75 to 95), which included four excellent, seven good, and two fair results. Our technique offers an alternative method of treating traumatic dislocation of the CMC joint of the thumb: it produces a stable joint and acceptable hand function. PMID- 26530658 TI - The effect of the anatomy of the distal humerus and proximal ulna on the positioning of the components in total elbow arthroplasty. AB - Determining and accurately restoring the flexion-extension axis of the elbow is essential for functional recovery after total elbow arthroplasty (TEA). We evaluated the effect of morphological features of the elbow on variations of alignment of the components at TEA. Morphological and positioning variables were compared by systematic CT scans of 22 elbows in 21 patients after TEA. There were five men and 16 women, and the mean age was 63 years (38 to 80). The mean follow up was 22 months (11 to 44). The anterior offset and version of the humeral components were significantly affected by the anterior angulation of the humerus (p = 0.052 and p = 0.004, respectively). The anterior offset and version of the ulnar components were strongly significantly affected by the anterior angulation of the ulna (p < 0.001 and p < 0.001). The closer the anterior angulation of the ulna was to the joint, the lower the ulnar anterior offset (p = 0.030) and version of the ulnar component (p = 0.010). The distance from the joint to the varus angulation also affected the lateral offset of the ulnar component (p = 0.046). Anatomical variations at the distal humerus and proximal ulna affect the alignment of the components at TEA. This is explained by abutment of the stems of the components and is particularly severe when there are substantial deformities or the deformities are close to the joint. PMID- 26530659 TI - The influence of catastrophising on treatment outcomes after surgery for lumbar spinal stenosis. AB - Pain catastrophising is an adverse coping mechanism, involving an exaggerated response to anticipated or actual pain. The purpose of this study was to investigate the influence of pain 'catastrophising', as measured using the pain catastrophising scale (PCS), on treatment outcomes after surgery for lumbar spinal stenosis (LSS). A total of 138 patients (47 men and 91 women, mean age 65.9; 45 to 78) were assigned to low (PCS score < 25, n = 68) and high (PCS score >= 25, n = 70) PCS groups. The primary outcome measure was the Oswestry Disability Index (ODI) 12 months after surgery. Secondary outcome measures included the ODI and visual analogue scale (VAS) for back and leg pain, which were recorded at each assessment conducted during the 12-month follow-up period The overall changes in the ODI and VAS for back and leg pain over a 12-month period were significantly different between the groups (ODI, p < 0.001; VAS for back pain, p < 0.001; VAS for leg pain, p = 0.040). The ODI and VAS for back and leg pain significantly decreased over time after surgery in both groups (p < 0.001 for all three variables). The patterns of change in the ODI and VAS for back pain during the follow-up period significantly differed between the two groups, suggesting that the PCS group is a potential treatment moderator. However, there was no difference in the ODI and VAS for back and leg pain between the low and high PCS groups 12 months after surgery. In terms of minimum clinically important differences in ODI scores (12.8), 22 patients (40.7%) had an unsatisfactory surgical outcome in the low PCS group and 16 (32.6%) in the high PCS group. There was no statistically significant difference between the two groups (p = 0.539). Pre-operative catastrophising did not always result in a poor outcome 12 months after surgery, which indicates that this could moderate the efficacy of surgery for LSS. PMID- 26530660 TI - Comparison between percutaneous fluoroscopic-guided and conventional open pedicle screw placement techniques for the thoracic spine: a safety evaluation in human cadavers. AB - Percutaneous placement of pedicle screws is a well-established technique, however, no studies have compared percutaneous and open placement of screws in the thoracic spine. The aim of this cadaveric study was to compare the accuracy and safety of these techniques at the thoracic spinal level. A total of 288 screws were inserted in 16 (eight cadavers, 144 screws in percutaneous and eight cadavers, 144 screws in open). Pedicle perforations and fractures were documented subsequent to wide laminectomy followed by skeletalisation of the vertebrae. The perforations were classified as grade 0: no perforation, grade 1: < 2 mm perforation, grade 2: 2 mm to 4 mm perforation and grade 3: > 4 mm perforation. In the percutaneous group, the perforation rate was 11.1% with 15 (10.4%) grade 1 and one (0.7%) grade 2 perforations. In the open group, the perforation rate was 8.3% (12 screws) and all were grade 1. This difference was not significant (p = 0.45). There were 19 (13.2%) pedicle fractures in the percutaneous group and 21 (14.6%) in the open group (p = 0.73). In summary, the safety of percutaneous fluoroscopy-guided pedicle screw placement in the thoracic spine between T4 and T12 is similar to that of the conventional open technique. PMID- 26530661 TI - Comparison of simple arm sling and figure of eight clavicular bandage for midshaft clavicular fractures: a randomised controlled study. AB - Only a few randomised, controlled studies have compared different non-operative methods of treatment of mid-shaft fractures of the clavicle. In this prospective, randomised controlled study of 60 participants (mean age 31.6 years; 15 to 75) we compared the broad arm sling with the figure of eight bandage for the treatment of mid-shaft clavicle fractures. Our outcome measures were pain, Constant and American Shoulder and Elbow Surgeons scores and radiological union. The mean visual analogue scale (VAS) pain score on the first day after treatment was significantly higher (VAS 1 6.8; 4 to 9) in the figure of eight bandage group than the broad arm sling group (VAS 1 5.6; 3 to 8, p = 0.034). A mean shortening of 9 mm (3 to 17) was measured in the figure of eight bandage group, versus 7.5 mm (0 to 24) in the broad arm sling group (p = 0.30). The application of the figure of eight bandage is more difficult than of the broad arm sling, and patients experience more pain during the first day when treated with this option. We suggest the broad arm sling is preferable because of the reduction of early pain and ease of application. PMID- 26530662 TI - Does pathological fracture affect the rate of local recurrence in patients with a giant cell tumour of bone?: a meta-analysis. AB - We investigated whether the presence of a pathological fracture increased the risk of local recurrence in patients with a giant cell tumour (GCT) of bone. We also assessed if curettage is still an appropriate form of treatment in the presence of a pathological fracture. We conducted a comprehensive review and meta analysis of papers which reported outcomes in patients with a GCT with and without a pathological fracture at presentation. We computed the odds ratio (OR) of local recurrence in those with and without a pathological fracture. We selected 19 eligible papers for final analysis. This included 3215 patients, of whom 580 (18.0%) had a pathological fracture. The pooled OR for local recurrence between patients with and without a pathological fracture was 1.05 (95% confidence interval (CI) 0.66 to 1.67, p = 0.854). Amongst the subgroup of patients who were treated with curettage, the pooled OR for local recurrence was 1.23 (95% CI 0.75 to 2.01, p = 0.417). A post hoc sample size calculation showed adequate power for both comparisons. There is no difference in local recurrence rates between patients who have a GCT of bone with and without a pathological fracture at the time of presentation. The presence of a pathological fracture should not preclude the decision to perform curettage as carefully selected patients who undergo curettage can have similar outcomes in terms of local recurrence to those without such a fracture. PMID- 26530663 TI - Delayed diagnosis of developmental dysplasia of the hip in Northern Ireland: can we do better? AB - Developmental dysplasia of the hip (DDH) should be diagnosed as early as possible to optimise treatment. The current United Kingdom recommendations for the selective screening of DDH include a clinical examination at birth and at six weeks. In Northern Ireland babies continue to have an assessment by a health visitor at four months of age. As we continue to see late presentations of DDH, beyond one year of age, we hypothesised that a proportion had missed an opportunity for earlier diagnosis. We expect those who presented to our service with Tonnis grade III or IV hips and decreased abduction would have had clinical signs at their earlier assessments. We performed a retrospective review of all patients born in Northern Ireland between 2008 and 2010 who were diagnosed with DDH after their first birthday. There were 75 856 live births during the study period of whom 645 children were treated for DDH (8.5 per 1000). The minimum follow-up of our cohort from birth, to detect late presentation, was four years and six months. Of these, 32 children (33 hips) were diagnosed after their first birthday (0.42 per 1000). With optimum application of our selective screening programme 21 (65.6%) of these children had the potential for an earlier diagnosis, which would have reduced the incidence of late diagnosis to 0.14 per 1000. As we saw a peak in diagnosis between three and five months our findings support the continuation of the four month health visitor check. Our study adds further information to the debate regarding selective versus universal screening. PMID- 26530664 TI - Bilateral humeral lengthening in achondroplasia with unilateral external fixators: is it safe and does it improve daily life? AB - A retrospective study was performed in 18 patients with achondroplasia, who underwent bilateral humeral lengthening between 2001 and 2013, using monorail external fixators. The mean age was ten years (six to 15) and the mean follow-up was 40 months (12 to 104). The mean disabilities of the arm, shoulder and hand (DASH) score fell from 32.3 (20 to 40) pre-operatively to 9.4 (6 to 14) post operatively (p = 0.037). A mean lengthening of 60% (40% to 95%) was required to reach the goal of independent perineal hygiene. One patient developed early consolidation, and fractures occurred in the regenerate bone of four humeri in three patients. There were three transient radial nerve palsies. Humeral lengthening increases the independence of people with achondroplasia and is not just a cosmetic procedure. PMID- 26530665 TI - Re-dislocation after corrective osteotomy for chronic dislocation of the radial head in children. AB - This retrospective study was designed to evaluate the outcomes of re-dislocation of the radial head after corrective osteotomy for chronic dislocation. A total of 12 children with a mean age of 11 years (5 to 16), with further dislocation of the radial head after corrective osteotomy of the forearm, were followed for a mean of five years (2 to 10). Re-operations were performed for radial head re dislocation in six children, while the other six did not undergo re-operation ('non-re-operation group'). The active range of movement (ROM) of their elbows was evaluated before and after the first operation, and at the most recent follow up. In the re-operation group, there were significant decreases in extension, pronation, and supination when comparing the ROM following the corrective osteotomy and following re-operation (p < 0.05). The children who had not undergone re-operation achieved a better ROM than those who had undergone re operation. There was a significant difference in mean pronation (76 degrees vs 0 degrees ) between the non- re-operation and the re-operation group (p = 0.002), and a trend towards increases in mean flexion (133 degrees vs 111 degrees ), extension (0 degrees vs 23 degrees ), and supination (62 degrees vs 29 degrees ). We did not find a clear benefit for re-operation in children with a re dislocation following corrective osteotomy for chronic dislocation of the radial head. PMID- 26530666 TI - Professor Leslie Klenerman (1929 to 2015). PMID- 26530667 TI - Synthetic Strategies for Semiconductor Nanocrystals Expressing Localized Surface Plasmon Resonance. AB - The field of semiconductor plasmonics has grown rapidly since its outset, only roughly six years ago, and now includes many crystalline substances ranging from GeTe to wide-bandgap transition-metal oxides. One byproduct of this proliferation is the sea of differing synthetic methods to realize localized surface plasmon resonances (LSPRs) based on the studied material. Strategies vary widely from material to material, but all have the common goal of introducing extremely high carrier densities to the semiconductor system. This doping results in tunable, size-quantized, and on/off-switchable LSPR modes, which are a complete departure from traditional metal-nanoparticle-based plasmon resonances. This Minireview will provide an overview of the current state of nanocrystal and quantum-dot plasmonics and the physical basis thereof, however its main purpose is to summarize the methods for realizing LSPRs in the various syntheses and systems that have been reported to date. PMID- 26530668 TI - Nature Reviews Neurology: the early years. PMID- 26530669 TI - Solution-based synthesis and purification of zinc tin phosphide nanowires. AB - The solution-based synthesis of nanoscale earth-abundant semiconductors has the potential to unlock simple, scalable, and tunable material processes which currently constrain development of novel compounds for alternative energy devices. One such promising semiconductor is zinc tin phosphide (ZnSnP2). We report the synthesis of ZnSnP2 nanowires via a solution-liquid-solid mechanism utilizing metallic zinc and tin in decomposing trioctylphosphine (TOP). Dried films of the reaction product are purified of binary phosphide phases by annealing at 345 degrees C. Tin is removed using a 0.1 M nitric acid treatment leaving pure ZnSnP2 nanowires. Diffuse reflectance spectroscopy indicates ZnSnP2 has a direct bandgap energy of 1.24 eV which is optimal for solar cell applications. Using a photoelectrochemical cell, we demonstrate cathodic photocurrent generation at open circuit conditions from the ZnSnP2 nanowires upon solar simulated illumination confirming p-type conductivity. PMID- 26530670 TI - Comprehensive Mitochondrial Genome Analysis by Massively Parallel Sequencing. AB - Next-generation sequencing (NGS) based on massively parallel sequencing (MPS) of the entire 16,569 bp mitochondrial genome generates thousands of reads for each nucleotide position. The high-throughput sequence data generated allow the detection of mitochondrial DNA (mtDNA) point mutations and deletions with the ability to accurately quantify the mtDNA point mutation heteroplasmy and to determine the deletion breakpoints. In addition, this method is particularly sensitive for the detection of low-level mtDNA large deletions and multiple deletions. It is by far the most powerful tool for molecular diagnosis of mtDNA disorders. PMID- 26530671 TI - Analysis of Translesion DNA Synthesis by the Mitochondrial DNA Polymerase gamma. AB - Mitochondrial DNA is replicated by the nuclear-encoded DNA polymerase gamma (pol gamma) which is composed of a single 140 kDa catalytic subunit and a dimeric 55 kDa accessory subunit. Mitochondrial DNA is vulnerable to various forms of damage, including several types of oxidative lesions, UV-induced photoproducts, chemical adducts from environmental sources, as well as alkylation and inter strand cross-links from chemotherapy agents. Although many of these lesions block DNA replication, pol gamma can bypass some lesions by nucleotide incorporation opposite a template lesion and further extension of the DNA primer past the lesion. This process of translesion synthesis (TLS) by pol gamma can occur in either an error-free or an error-prone manner. Assessment of TLS requires extensive analysis of oligonucleotide substrates and replication products by denaturing polyacrylamide sequencing gels. This chapter presents protocols for the analysis of translesion DNA synthesis. PMID- 26530672 TI - Quantification of DNA Damage by Real-Time qPCR. AB - This chapter describes the use of real-time qPCR to quantify damages in genomic DNA. The method is based on the ability of a lesion in one strand to inhibit restriction enzyme digestion of double-stranded DNA. Subsequent amplification of the complementary strand after restriction cleavage gives a quantitative measure of the damage content in that site (Real-time qPCR Analysis of Damage Frequency; RADF). We compare the RADF assay with the commonly used technique to assess damages by their ability to inhibit amplification of a large PCR fragment relative to a short PCR fragment. The RADF method described here is quick, accurate and allows the detection of nuclear and mitochondrial DNA damage in detailed regions. PMID- 26530673 TI - Quantitation of Mitochondrial DNA Deletions Via Restriction Digestion/Long-Range Single-Molecule PCR. AB - Quantification of deletions in mtDNA is a long-standing problem in mutational analysis. We describe here an approach that combines the power of single-molecule PCR of the entire mitochondrial genome with the enrichment of the deletions by restriction digestion. This approach is indispensable if information about wide range of deletion types in a sample is critical, such as in studies concerning distribution of deletion breakpoints (as opposed to approaches where fraction of a single deletion or a limited set of deletions is used as a proxy for total deletion load). Because deletions in a sample are quantified almost exhaustively, the other important application of this approach involves studies where only small amounts of tissue, such as biopsies, are available. PMID- 26530674 TI - A Single-Cell Resolution Imaging Protocol of Mitochondrial DNA Dynamics in Physiopathology, mTRIP, Which Also Evaluates Sublethal Cytotoxicity. AB - Mitochondria autonomously replicate and transcribe their own genome, which is present in multiple copies in the organelle. Transcription and replication of the mitochondrial DNA (mtDNA), which are defined here as mtDNA processing, are essential for mitochondrial function. The extent, efficiency, and coordination of mtDNA processing are key parameters of the mitochondrial state in living cells. Recently, single-cell analysis of mtDNA processing revealed a large and dynamic heterogeneity of mitochondrial populations in single cells, which is linked to mitochondrial function and is altered during disease. This was achieved using mitochondrial Transcription and Replication Imaging Protocol (mTRIP), a modified fluorescence in situ hybridization (FISH) approach that simultaneously reveals the mitochondrial RNA content and mtDNA engaged in initiation of replication at the single-cell level. mTRIP can also be coupled to immunofluorescence or MitoTracker, resulting in the additional labeling of proteins or active mitochondria, respectively. Therefore, mTRIP detects quantitative and qualitative alterations of the dynamics of mtDNA processing in human cells that respond to physiological changes or result from diseases. In addition, we show here that mTRIP is a rather sensitive tool for detecting mitochondrial alterations that may lead to loss of cell viability, and is thereby a useful tool for monitoring sublethal cytotoxicity for instance during chronic drug treatment. PMID- 26530675 TI - Scalable Isolation of Mammalian Mitochondria for Nucleic Acid and Nucleoid Analysis. AB - Isolation of mitochondria from cultured cells and animal tissues for analysis of nucleic acids and bona fide mitochondrial nucleic acid binding proteins and enzymes is complicated by contamination with cellular nucleic acids and their adherent proteins. Protocols presented here allow for quick isolation of mitochondria from a small number of cells and for preparation of highly purified mitochondria from a larger number of cells using nuclease treatment and high salt washing of mitochondria to reduce contamination. We further describe a method for the isolation of mitochondrial DNA-protein complexes known as nucleoids from these highly purified mitochondria using a combination of glycerol gradient sedimentation followed by isopycnic centrifugation in a non-ionic iodixanol gradient. PMID- 26530676 TI - Tracking Mitochondrial DNA In Situ. AB - The methods of the detection of (1) non-labeled and (2) BrdU-labeled mitochondrial DNA (mtDNA) are described. They are based on the production of singlet oxygen by monovalent copper ions and the subsequent induction of DNA gaps. The ends of interrupted DNA serve as origins for the labeling of mtDNA by DNA polymerase I or they are utilized by exonuclease that degrades DNA strands, unmasking BrdU in BrdU-labeled DNA. Both methods are sensitive approaches without the need of additional enhancement of the signal or the use of highly sensitive optical systems. PMID- 26530677 TI - Analysis of Replicating Mitochondrial DNA by In Organello Labeling and Two Dimensional Agarose Gel Electrophoresis. AB - Our understanding of the mechanisms of DNA replication in a broad range of organisms and viruses has benefited from the application of two-dimensional agarose gel electrophoresis (2D-AGE). The method resolves DNA molecules on the basis of size and shape and is technically straightforward. 2D-AGE sparked controversy in the field of mitochondria when it revealed replicating molecules with lengthy tracts of RNA, a phenomenon never before reported in nature. More recently, radioisotope labeling of the DNA in the mitochondria has been coupled with 2D-AGE. In its first application, this procedure helped to delineate the "bootlace mechanism of mitochondrial DNA replication," in which processed mitochondrial transcripts are hybridized to the lagging strand template at the replication fork as the leading DNA strand is synthesized. This chapter provides details of the method, how it has been applied to date and concludes with some potential future applications of the technique. PMID- 26530678 TI - Translation and Assembly of Radiolabeled Mitochondrial DNA-Encoded Protein Subunits from Cultured Cells and Isolated Mitochondria. AB - In higher eukaryotes, the mitochondrial electron transport chain consists of five multi-subunit membrane complexes responsible for the generation of cellular ATP. Of these, four complexes are under dual genetic control as they contain subunits encoded by both the mitochondrial and nuclear genomes, thereby adding another layer of complexity to the puzzle of respiratory complex biogenesis. These subunits must be synthesized and assembled in a coordinated manner in order to ensure correct biogenesis of different respiratory complexes. Here, we describe techniques to (1) specifically radiolabel proteins encoded by mtDNA to monitor the rate of synthesis using pulse labeling methods, and (2) analyze the stability, assembly, and turnover of subunits using pulse-chase methods in cultured cells and isolated mitochondria. PMID- 26530679 TI - Analysis of Mitochondrial DNA Copy Number and Its Regulation Through DNA Methylation of POLGA. AB - Replication of mitochondrial DNA (mtDNA) is important for ensuring that cells have sufficient mtDNA copy number to meet their specific requirements for the generation of cellular energy through oxidative phosphorylation. A number of transcription and replication factors are required for this process, with a key factor being the nuclear-encoded mtDNA-specific DNA polymerase gamma. DNA polymerase gamma has a catalytic subunit (POLGA), whose gene has been shown to be DNA methylated at exon 2. This methylation is considered to be one of the key mechanisms that regulate mtDNA copy number. These findings have made it of great importance to establish optimal methods for investigating the effects of DNA methylation on mtDNA replication. Here, we provide methods to determine the extent of DNA methylation at exon 2 of POLGA as well as other gene targets of interest. We also show how mtDNA copy number is assessed and, from these two outputs, define the efficiency of mtDNA replication by calculating the mtDNA replicative efficiency index. PMID- 26530680 TI - Engineered mtZFNs for Manipulation of Human Mitochondrial DNA Heteroplasmy. AB - Enrichment of desired mitochondrial DNA (mtDNA) haplotypes, in both experimental systems and the clinic, is an end sought by many. Through use of a designer nuclease platform optimized for delivery to mitochondria-the mitochondrially targeted zinc finger-nuclease (mtZFN)-it is possible to discriminate between mtDNA haplotypes with specificity to the order of a single nucleotide substitution. Site-specific cleavage of DNA produces a shift in the heteroplasmic ratio in favor of the untargeted haplotype. Here, we describe protocols for assembly of paired, conventional tail-tail mtZFN constructs and experimental approaches to assess mtZFN activity in mammalian cell cultures. PMID- 26530681 TI - Generation of Xenomitochondrial Embryonic Stem Cells for the Production of Live Xenomitochondrial Mice. AB - The unique features of the mitochondrial genome, such as its high copy number and lack of defined mechanisms of recombination, have hampered efforts to manipulate its sequence to create specific mutations in mouse mtDNA. As such, the generation of in vivo mouse models of mtDNA disease has proved technically challenging. This chapter describes a unique approach to create mitochondrial oxidative phosphorylation (OXPHOS) defects in mouse ES cells by transferring mtDNA from different murid species into Mus musculus domesticus ES cells using cytoplasmic hybrid ("cybrid") fusion. The resulting "xenocybrid" ES cells carry OXPHOS defects of varying severity, and can be utilized to generate live mouse models of mtDNA disease. PMID- 26530682 TI - Import of Fluorescent RNA into Mitochondria of Living Cells. AB - Methods of in vivo visualization and manipulation of mitochondrial genetic machinery are limited due to the need to surpass not only the cytoplasmic membrane but also two mitochondrial membranes. Here, we employ the matrix addressing sequence of mitochondrial ribosomal 5S-rRNA (termed MAM), which is naturally imported into mammalian mitochondria, to construct an import system for in vivo targeting of mitochondrial (mt) DNA or mtRNA, in order to provide fluorescence hybridization of the desired sequences. PMID- 26530683 TI - Purification and Comparative Assay of the Human Mitochondrial Replicative DNA Helicase. AB - The replicative mitochondrial DNA (mtDNA) helicase is essential for mtDNA replication and maintenance of the mitochondrial genome. Despite substantial advances that have been made in its characterization, there is still much to be understood about the functional roles of its domains and its interactions with the other components of the minimal mitochondrial DNA replisome. Critical to achieving this is the ability to isolate the enzyme in a stable, active form. In this chapter we describe a modified, streamlined purification strategy for recombinant forms of the enzyme. We also present assays to assess its helix unwinding activity and the stimulatory effects of the mitochondrial single stranded DNA-binding protein (mtSSB). Finally, we describe a concentration/buffer exchange method that we have employed to achieve greater enzyme stability and appropriate conditions for biochemical and biophysical studies. PMID- 26530684 TI - Expression and Purification of Mitochondrial RNA Polymerase and Transcription Factor A from Drosophila melanogaster. AB - Mitochondrial gene expression is essential in all organisms. Our understanding of mitochondrial transcription on a biochemical level has been limited by the inability to purify the individual protein components involved in mitochondrial gene expression. Recently, new systems have been identified that permit purification of these proteins from bacteria. However, the generalizability of these systems is not clear. Here, we have applied the technology from the Cameron lab to express and purify mitochondrial RNA polymerase and transcription factor A from Drosophila melanogaster. We show that the use of SUMO system to produce SUMO fusion proteins in bacteria is effective not only for the human and mouse proteins, but also for the fly proteins. The application of this system to produce the mitochondrial proteins from other organisms should permit detailed understanding of mitochondrial transcription from any organism. PMID- 26530685 TI - Purification and Comparative Assay of Human Mitochondrial Single-Stranded DNA Binding Protein. AB - The mitochondrial single-stranded DNA-binding protein (mtSSB) coordinates the function of replisome components at the mitochondrial replication fork. In recent years, it has been demonstrated that mtSSB stimulates the activities of DNA polymerase gamma (Pol gamma) and mitochondrial DNA (mtDNA) helicase in a concentration-dependent manner. Here we present a new approach to purify the human mtSSB and our standard assays to evaluate its biochemical properties, including a Gel Mobility Shift Assay (GMSA) to assess single-stranded DNA (ssDNA) binding activity, and an assay to assess SSB stimulation of Pol gamma activity. PMID- 26530686 TI - Biolayer Interferometry: A Novel Method to Elucidate Protein-Protein and Protein DNA Interactions in the Mitochondrial DNA Replisome. AB - A lack of effective treatment for mitochondrial diseases prompts scientists to investigate the molecular processes that underlie their development. The major cause of mitochondrial diseases is dysfunction of the sole mitochondrial DNA polymerase, DNA polymerase gamma (Pol gamma). The development of treatment strategies will require a detailed characterization of the molecular properties of Pol gamma. A novel technique, biolayer interferometry, allows one to monitor molecular interactions in real time, thus providing an insight into the kinetics of the process. Here, we present an application of the biolayer interferometry technique to characterize the fundamental reactions that Pol gamma undergoes during the initiation phase of mitochondrial DNA replication: holoenzyme formation and binding to the primer-template. PMID- 26530687 TI - Selective Alkenylation and Hydroalkenylation of Enol Phosphates through Direct C H Functionalization. AB - An efficient and selective Rh-catalyzed direct C?H functionalization reaction of enol phosphates was developed. The method is applicable to a variety of coupling partners, including activated alkenes, alkynes, and allenes, and leads to the formation of various valuable alkenylated and hydroalkenylated enol phosphates through the action of the phosphate directing group. The versatility and utility of the coupling products were demonstrated through further transformations into synthetically useful building blocks. PMID- 26530688 TI - Three-dimensional multispectral optoacoustic mesoscopy reveals melanin and blood oxygenation in human skin in vivo. AB - Optical imaging plays a major role in disease detection in dermatology. However, current optical methods are limited by lack of three-dimensional detection of pathophysiological parameters within skin. It was recently shown that single wavelength optoacoustic (photoacoustic) mesoscopy resolves skin morphology, i.e. melanin and blood vessels within epidermis and dermis. In this work we employed illumination at multiple wavelengths for enabling three-dimensional multispectral optoacoustic mesoscopy (MSOM) of natural chromophores in human skin in vivo operating at 15-125 MHz. We employ a per-pulse tunable laser to inherently co register spectral datasets, and reveal previously undisclosed insights of melanin, and blood oxygenation in human skin. We further reveal broadband absorption spectra of specific skin compartments. We discuss the potential of MSOM for label-free visualization of physiological biomarkers in skin in vivo. PMID- 26530689 TI - Visual Hallucinations in Older People: Appraisals but not Content or Phenomenology Influence Distress. AB - BACKGROUND: A previous study (Gauntlett-Gilbert and Kuipers, 2005) has suggested that distress associated with complex visual hallucinations (CVHs) in younger adults with psychosis may more strongly relate to appraisals of meaning than to the content of the hallucination. However, visual hallucinations are most commonly seen in the disorders of later life, where this relationship has not been investigated. AIM: To establish if there is a relationship between appraisals of CVHs and distress in older, non-psychotic people with CVHs. METHOD: All variables were measured using a semi-structured interview and were compared between a high distress group (n = 16) and a low distress group (n = 19). RESULTS: The high distress group rated their hallucinations as more malevolent and omnipotent, with greater negative implications for physical and mental health. There was no significant difference between groups on ratings of hallucination content (independently rated), frequency, awareness or control. CONCLUSION: Appraisals of CVHs are linked to distress. PMID- 26530690 TI - Utilization of Percutaneous Needle Biopsy for Breast Diagnosis in a Comprehensive Breast Center: Implications for Development of Quality Indicators. AB - INTRODUCTION: Percutaneous needle biopsy (PNB) is the standard of care for diagnosis of breast lesions. Rates of excisional biopsy for breast diagnosis in North America have been reported at approximately 35 %, although significant regional variation exists. A target rate of PNB for diagnosis of breast abnormalities is needed to facilitate quality improvement. We sought to describe the use of PNB in a referral practice, the clinical scenarios prompting PNB or surgical biopsy (SB), and the accuracy and rate of PNB to inform the ultimate development of a benchmark rate of PNB in breast diagnosis. MATERIALS AND METHODS: Female patients age 18-90 years, referred to Sunnybrook Health Sciences Centre, a large teaching hospital affiliated with the University of Toronto, with a breast lesion prompting tissue diagnosis with SB and/or PNB between 2002 and 2009 were studied. Each biopsied lesion was characterized by method of biopsy: PNB, SB, or PNB followed by SB. For each lesion, we collected data on patient demographics and breast cancer risk, reason for referral, imaging characteristics (breast imaging-reporting and data system classification, full description, final impression before biopsy), and pathology from each biopsy method. We report concordance between the final impression pre-biopsy and the PNB diagnosis with final surgical diagnosis where applicable. RESULTS: One thousand and twenty-six lesions were biopsied, 987 (96 %) with PNB. The benign:malignant ratio for the entire cohort was 1.2:1. Final impression was concordant with final pathology in 674/862 (78 %) and PNB diagnosis was concordant with SB pathology in 487/556 (88 %). The reasons for SB without PNB were required pathologic evaluation of the entire lesion (n = 19), patient choice (n = 5), other biopsy technique used (n = 6), technical (n = 4), planned mastectomy (n = 3), and enlarging mass (n = 2). 155/559 (28 %) of lesions without evidence of malignancy on PNB ultimately underwent SB. Papillary lesions and radial scars were more likely to undergo SB with or without prior PNB. Lesions deemed to be suspicious or malignant on final impression were more likely to be excised after a benign diagnosis at PNB. CONCLUSION: The vast majority of lesions requiring tissue diagnosis can be accurately diagnosed with PNB. Benchmarks for rates of PNB of 90 % or greater may be considered for performance measurement in appropriate populations. PMID- 26530691 TI - Bile Duct Injuries Associated With 55,134 Cholecystectomies: Treatment and Outcome from a National Perspective. AB - BACKGROUND: Bile duct injury (BDI) is a rare complication associated with cholecystectomy, and recommendations for treatment are based on publications from referral centers with a selection of major injuries and failures after primary repair. The aim was to analyze the frequency, treatment, and outcome of BDIs in an unselected population-based cohort. METHODS: This was a retrospective cohort study including all BDIs registered in GallRiks (Swedish quality register for gallstone surgery and ERCP) during 2007-2011. Data for this study were based on a national follow-up survey where medical records were scrutinized and BDIs classified according to the Hannover classification. RESULTS: A total of 174 BDIs arising from 55,134 cholecystectomies (0.3%) identified at 60 hospitals were included with a median follow-up of 37 months (9-69). 155 BDIs (89%) were detected during cholecystectomy, and immediate repair was attempted in 140 (90%). A total of 27 patients (18%) were referred to a HPB referral center. Hannover Grade C1 (i.e., small lesion <5 mm) dominated (n = 102; 59%). The most common repair was "suture over T-tube" (n = 78; 45%) and reconstruction with hepaticojejunostomy was performed in 30 patients (17%). A total of 31 patients (18 %) were diagnosed with stricture, 19 of which were primarily repaired with "suture over T-tube." The median in-hospital-stay was 14 days (1-149). CONCLUSIONS: The majority of BDIs were detected during the cholecystectomy and repaired by the operating surgeon. Although this is against most current recommendations, short-term outcome was surprisingly good. PMID- 26530692 TI - Safety of Continuous Intraoperative Neuromonitoring (C-IONM) in Thyroid Surgery. PMID- 26530693 TI - Ovarian cancer targeted hyaluronic acid-based nanoparticle system for paclitaxel delivery to overcome drug resistance. AB - OBJECTIVE: Most primary human ovarian tumors and peritoneal implants, as well as tumor vascular endothelial cells, express the CD44 family of cell surface proteoglycans, the natural ligand for which is hyaluronic acid (HA). Paclitaxel (PTX) is an effective chemotherapeutic agent that is widely used for the treatment of several cancers, including ovarian cancer. This study aimed to develop a HA-based PTX-loaded nanoparticle system to improve the ovarian cancer therapeutic effects. METHODS: PTX-loaded cationic nanostructured lipid nanoparticles (PTX-NLCs) were prepared. HA-PE was then coated onto the PTX-NLCs by electrostatic adsorption to form HA-PTX-NLCs. In vitro tumor cell inhibition efficiency was analyzed on SKOV3 human ovarian cancer cells (SKOV3 cells) and PTX resistant SKOV3 cells (SKOV3/PTX cells). In vivo anticancer ability was evaluated with mice bearing SKOV3 ovarian cancer cells xenografts. RESULTS: HA-PTX-NLCs had an average diameter of 163 nm, and PTX was incorporated with an efficiency of over 80%. The in vitro viability of SKOV3 cells and SKOV3/PTX cells was obviously inhibited by HA-PTX-NLCs. In the ovarian cancer cells model, significant reduction in tumor growth was observed, whereas the conventional PTX injection group did not achieve significance. CONCLUSION: This study demonstrated that significantly improved results were obtained by the newly constructed HA-PTX NLCs, in terms of in vitro and in vivo therapeutic efficacy. These findings strongly support the superiority of HA based nano-system for the PTX delivery, thus enhance the efficacy of ovarian cancer chemotherapy. PMID- 26530694 TI - Preconditioning with VEGF Enhances Angiogenic and Neuroprotective Effects of Bone Marrow Mononuclear Cell Transplantation in a Rat Model of Chronic Cerebral Hypoperfusion. AB - Bone marrow mononuclear cell (BMMNC) transplantation is a promising therapy for brain ischemia. However, BMMNCs are few in number, and a limited time window is available during which they can penetrate the blood-brain barrier (BBB) and migrate to the brain. We investigated whether vascular endothelial growth factor (VEGF) can facilitate BMMNC migration into the ischemic brain and enhance their therapeutic effect in a rat model of chronic cerebral hypoperfusion. First, we assessed the impact of VEGF on the BBB of rats that had undergone permanent bilateral occlusion of the common carotid arteries (2VO). Then, we transplanted BMMNCs into 2VO rats pretreated with intracerebroventricular VEGF or vehicle. We examined cognitive function with the Morris water maze test, BMMNC migration by immunofluorescence analysis, and cytokine levels in the peripheral blood by enzyme-linked immunosorbent assay (ELISA). Angiogenesis and neural degeneration were evaluated by staining tissue with Ki67/lectin or Fluoro-Jade B. We found that at a dose of 0.2 MUg/rat, VEGF significantly increased BBB permeability without causing brain edema in 2VO rats. VEGF + BMMNC-treated rats had more BMMNC migration in the ischemic brain, better learning and memory, greater proliferation of vessels, and fewer degenerating neurons than did BMMNC-treated rats. Pretreatment with VEGF receptor inhibitor SU5416 significantly decreased BMMNC migration and abolished the therapeutic effect of BMMNC transplantation. We conclude that preconditioning with an appropriate dose of VEGF can enhance the therapeutic efficacy of BMMNC transplantation in 2VO rats, possibly by facilitating BMMNC migration into the ischemic brain. PMID- 26530695 TI - [Subcutaneous cervical and left thoracic emphysema in a 49-year-old woman on ventilation]. AB - We report the case of a 49-year-old woman who was admitted with community acquired pneumonia. The medical state worsened despite administration of antibiotics. She was intubated and ventilated because of respiratory distress. Several hours after intubation, she developed massive subcutaneous emphysema. The bronchoscopy showed tracheal transmural rupture 3 cm long on the posterior wall of the trachea. The high-risk surgery and massive doses of catecholamine favoured conservative treatment with bilateral endobronchial intubation and veno-venous extracorporeal membrane oxygenation. The patient made a full recovery. PMID- 26530696 TI - [Diagnosis and treatment of nephrolithiasis. What is established?]. AB - BACKGROUND: Kidney stones are a common and increasing problem worldwide. Nephrolithiasis is frequently a chronic disease given the risk of recurrence following passage of a first stone. OBJECTIVES: In the present article, an update on the diagnosis and treatment of kidney stones relevant for internal medicine physicians is provided. METHODS: This review is based on a selective literature search and our own work. RESULTS AND CONCLUSION: The diagnosis of kidney stones is based on the clinical history and physical examination. Confirmatory radiologic tests include noncontrast computerized tomography or ultrasonography with both techniques having recently been shown to have equivalent overall outcomes. The therapy of kidney stones is based on the clinical presentation and diagnostic findings (e.g., fever, response to pain management, and demonstration of relevant obstruction) as well as location, size, and composition of the stone. If invasive treatment is being considered, the urology department should be consulted. Given the high risk of recurrence, stone analysis must be performed as well as the concentration of lithogenic and litholytic substances measured in a 24-h urine collection. The newly established recurrence of kidney stone nomogram (ROKS nomogram) identifies kidney stone formers at greatest risk for a second symptomatic episode who may benefit from medical intervention. PMID- 26530697 TI - Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer. AB - Chronic inflammation is a well-known etiological factor for colorectal cancer (CRC) and cancer cells are known to preferentially metabolize glucose through aerobic glycolysis. However, the connection between chronic inflammation and aerobic glycolysis in the development of CRC is largely unexplored. The present study investigated whether interleukin-6 (IL-6), a pro-inflammatory cytokine, promotes the development of CRC by regulating the aerobic glycolysis and the underlying molecular mechanisms. In colitis-associated CRC mouse, anti-IL-6 receptor antibody treatment reduced the incidence of CRC and decreased the expression of key genes in aerobic glycolysis, whereas the plasma concentrations of glucose and lactate were not affected. Consistently, IL-6 treatment stimulated aerobic glycolysis, upregulated key genes in aerobic glycolysis and promoted cell proliferation and migration in SW480 and SW1116 CRC cells. 6-phoshofructo-2 kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) was the most downregulated gene by anti-IL-6 receptor antibody in colorectal adenoma tissues. Further analysis in human samples revealed overexpression of PFKFB3 in colorectal adenoma and adenocarcinoma tissues, which was also associated with lymph node metastasis, intravascular cancer embolus and TNM stage. In addition, the effect of IL-6 on CRC cells can be abolished by knocking down PRKFB3 through siRNA transfection. Our data suggest that chronic inflammation promotes the development of CRC by stimulating aerobic glycolysis and IL-6 is functioning, at least partly, through regulating PFKFB3 at early stage of CRC. PMID- 26530698 TI - Identification of the novel Kawasaki 2014 GII.17 human norovirus strain in Italy, 2015. AB - Surveillance of noroviruses in Italy identified the novel GII.17 human norovirus strain, Kawasaki 2014, in February 2015. This novel strain emerged as a major cause of gastroenteritis in Asia during 2014/15, replacing the pandemic GII.4 norovirus strain Sydney 2012, but being reported only sporadically elsewhere. This novel strain is undergoing fast diversification and continuous monitoring is important to understand the evolution of noroviruses and to implement the future strategies on norovirus vaccines. PMID- 26530699 TI - Canine parvovirus in Australia: A comparative study of reported rural and urban cases. AB - Canine parvovirus (CPV) is a highly contagious and often fatal disease reported worldwide. Outbreaks occur throughout Australia, and it has been suggested that disproportionally more CPV cases occur in rural locations. However, evidence to support this suggestion-and possible reasons for such a predisposition-has not existed until now. In this study a total of 4870 CPV cases reported from an Australian disease surveillance system between September 2009 and July 2014 were analysed. Australian postcodes were classified as rural or urban (based on human population density) and reported CPV cases were then categorised as rural or urban based on their reported home postcode. Parvovirus cases were predominately young (<12 months), entire, unvaccinated, mixed-breed dogs. More than twice as many of the reported cases were from a rural area (3321 cases) compared to an urban area (1549 cases). The overall case fatality rate was 47.2%; it was higher for those CPV cases reported from urban areas (50.6%) than rural areas (45.5%). A greater proportion of rural cases were younger, entire dogs compared to urban cases. The final multivariable model of CPV cases being reported from a rural area included age (<12 months) and vaccination status (never vaccinated) as significant predictors. Poor socioeconomic status might be a reason for the decision of rural owners not to vaccinate their dogs as readily as urban owners. The excess reporting of rural CPV cases compared to urban cases and the predictive risk factors identified in this study can be used by veterinarians to reduce the incidence of CPV by educating owners about the disease and promoting better vaccination programs in rural areas. This study also supports that the increased risk of CPV in rural areas may necessitate a need for increased vigilance around preventing CPV disease spread, additional care with puppies which are the most susceptible to this disease and tighter vaccination protocols, compared to urban areas. PMID- 26530700 TI - Choosing who to treat. PMID- 26530701 TI - Assessing Connectivity Between an Overlying Aquifer and a Coal Seam Gas Resource Using Methane Isotopes, Dissolved Organic Carbon and Tritium. AB - Coal seam gas (CSG) production can have an impact on groundwater quality and quantity in adjacent or overlying aquifers. To assess this impact we need to determine the background groundwater chemistry and to map geological pathways of hydraulic connectivity between aquifers. In south-east Queensland (Qld), Australia, a globally important CSG exploration and production province, we mapped hydraulic connectivity between the Walloon Coal Measures (WCM, the target formation for gas production) and the overlying Condamine River Alluvial Aquifer (CRAA), using groundwater methane (CH4) concentration and isotopic composition (delta(13)C-CH4), groundwater tritium ((3)H) and dissolved organic carbon (DOC) concentration. A continuous mobile CH4 survey adjacent to CSG developments was used to determine the source signature of CH4 derived from the WCM. Trends in groundwater delta(13)C-CH4 versus CH4 concentration, in association with DOC concentration and (3)H analysis, identify locations where CH4 in the groundwater of the CRAA most likely originates from the WCM. The methodology is widely applicable in unconventional gas development regions worldwide for providing an early indicator of geological pathways of hydraulic connectivity. PMID- 26530702 TI - Time series analysis of reported cases of hand, foot, and mouth disease from 2010 to 2013 in Wuhan, China. AB - BACKGROUND: Hand, foot, and mouth disease (HFMD) is an infectious disease caused by a group of enteroviruses, including Coxsackievirus A16 (CVA16) and Enterovirus A71 (EV-A71). In recent decades, Asian countries have experienced frequent and widespread HFMD outbreaks, with deaths predominantly among children. In several Asian countries, epidemics usually peak in the late spring/early summer, with a second small peak in late autumn/early winter. We investigated the possible underlying association between the seasonality of HFMD epidemics and meteorological variables, which could improve our ability to predict HFMD epidemics. METHODS: We used a time series analysis composed of a spectral analysis based on the maximum entropy method (MEM) in the frequency domain and the nonlinear least squares method in the time domain. The time series analysis was applied to three kinds of monthly time series data collected in Wuhan, China, where high-quality surveillance data for HFMD have been collected: (i) reported cases of HFMD, (ii) reported cases of EV-A71 and CVA16 detected in HFMD patients, and (iii) meteorological variables. RESULTS: In the power spectral densities for HFMD and EV-A71, the dominant spectral lines were observed at frequency positions corresponding to 1-year and 6-month cycles. The optimum least squares fitting (LSF) curves calculated for the 1-year and 6-month cycles reproduced the bimodal cycles that were clearly observed in the HFMD and EV-A71 data. The peak months on the LSF curves for the HFMD data were consistent with those for the EV-A71 data. The risk of infection was relatively high at 10 degrees C <= t < 15 degrees C (t, temperature [ degrees C]) and 15 degrees C <= t < 20 degrees C, and peaked at 20 degrees C <= t < 25 degrees C. CONCLUSION: In this study, the HFMD infections occurring in Wuhan showed two seasonal peaks, in summer (June) and winter (November or December). The results obtained with a time series analysis suggest that the bimodal seasonal peaks in HFMD epidemics are attributable to EV A71 epidemics. Our results suggest that controlling the spread of EV-A71 infections when the temperature is approximately 20-25 degrees C should be considered to prevent HFMD infections in Wuhan, China. PMID- 26530703 TI - The limited impact of indeterminacy for healthcare rationing: how indeterminacy problems show the need for a hybrid theory, but nothing more. AB - A notorious debate in the ethics of healthcare rationing concerns whether to address rationing decisions with substantial principles or with a procedural approach. One major argument in favour of procedural approaches is that substantial principles are indeterminate so that we can reasonably disagree about how to apply them. To deal with indeterminacy, we need a just decision process. In this paper I argue that it is a mistake to abandon substantial principles just because they are indeterminate. It is true that reasonable substantial principles designed to deal with healthcare rationing can be expected to be indeterminate. Yet, the indeterminacy is only partial. In some situations we can fully determine what to do in light of the principles, in some situations we cannot. The conclusion to draw from this fact is not that we need to develop procedural approaches to healthcare rationing, but rather that we need a more complex theory in which both substantial principles and procedural approaches are needed. PMID- 26530704 TI - Smiling through clenched teeth: why compassion cannot be written into the rules. AB - The discourse on the failings of the National Health System often cites lack of compassion as an important factor. This has resulted in proposals to enact rules which aimed at enforcing compassion in healthcare workers so as to improve the quality of healthcare and avoid future scandals. This paper argues that compassion cannot be enforced by any rule. Moreover, the contractual nature of the current doctor-patient relationship does not foster it. Experience from other service industries shows that attempts to enforce compassion in workers are futile. Rather than improving service, these attempts result in a culture of perfunctoriness and cynicism. PMID- 26530705 TI - Bayesian penalized spline models for the analysis of spatio-temporal count data. AB - In recent years, the availability of infectious disease counts in time and space has increased, and consequently, there has been renewed interest in model formulation for such data. In this paper, we describe a model that was motivated by the need to analyze hand, foot, and mouth disease surveillance data in China. The data are aggregated by geographical areas and by week, with the aims of the analysis being to gain insight into the space-time dynamics and to make short term predictions, which will aid in the implementation of public health campaigns in those areas with a large predicted disease burden. The model we develop decomposes disease-risk into marginal spatial and temporal components and a space time interaction piece. The latter is the crucial element, and we use a tensor product spline model with a Markov random field prior on the coefficients of the basis functions. The model can be formulated as a Gaussian Markov random field and so fast computation can be carried out using the integrated nested Laplace approximation approach. A simulation study shows that the model can pick up complex space-time structure and our analysis of hand, foot, and mouth disease data in the central north region of China provides new insights into the dynamics of the disease. PMID- 26530706 TI - Involving people with diabetes and the wider community in diabetes research: a realist review protocol. AB - BACKGROUND: Patient and public involvement in diabetes research is now actively encouraged in different countries because it is believed that involving people with experience of the condition will improve the quality and relevance of the research. However, reviews of patient involvement have noted that inadequate resources, patients' and communities' lack of research knowledge, and researchers' lack of skills to involve patients and communities in research may present significant contextual barriers. Little is known about the extent of patient/community involvement in designing or delivering interventions for people with diabetes. A realist review of involvement will contribute to assessing when, how and why involvement works, or does not work, to produce better diabetes interventions. METHODS/DESIGN: This protocol outlines the process for conducting a realist review to map how patients and the public have been involved in diabetes research to date. The review questions ask the following: How have people with diabetes and the wider community been involved in diabetes research? What are the characteristics of the process that appear to explain the relative success or failure of involvement? How has involvement (or lack of involvement) in diabetes research influenced the development and conduct of diabetes research? The degree of support in the surrounding context will be assessed alongside the ways in which people interact in different settings to identify patterns of interaction between context, mechanisms and outcomes in different research projects. The level and extent of the involvement will be described for each stage of the research project. The descriptions will be critically reviewed by the people with diabetes on our review team. In addition, researchers and patients in diabetes research will be asked to comment. Information from researcher-patient experiences and documents will be compared to theories of involvement across a range of disciplines to create a mid-range theory describing how involvement (or lack of involvement) in diabetes research influences the development and conduct of diabetes research. PMID- 26530707 TI - Total synthesis of palau'amine. AB - Palau'amine has received a great deal of attention in the past two decades as an attractive synthetic target by virtue of its intriguing molecular architecture and significant immunosuppressive activity. Here we report the total synthesis of palau'amine characterized by the construction of an ABDE tetracyclic ring core including a trans-bicylo[3.3.0]octane skeleton at a middle stage of total synthesis. The ABDE tetracyclic ring core is constructed by a cascade reaction of a cleavage of the N-N bond, including simultaneous formation of imine, the addition of amide anion to the resulting imine (D-ring formation) and the condensation of pyrrole with methyl ester (B-ring formation) in a single step. The synthetic palau'amine is confirmed to exhibit excellent immunosuppressive activity. The present synthetic route has the potential to help elucidate a pharmacophore as well as the mechanistic details of immunosuppressive activity. PMID- 26530708 TI - Long-term outcomes after supratotal resection of diffuse low-grade gliomas: a consecutive series with 11-year follow-up. AB - BACKGROUND: Total or subtotal surgical resection of WHO grade II glioma (diffuse low-grade glioma, DLGG) can significantly increase survival. Moreover, a supratotal resection, i.e., an extended resection with a margin beyond MR imaging abnormalities, could decrease the risk of malignant transformation. Here, the goal is to analyze the long-term functional and oncological outcomes following supratotal resection for DLGG. METHODS: Sixteen consecutive patients who underwent supratotal resection for a DLGG with a minimum follow-up of 8 years after surgery were included. The resection was continued up to functional cortical and subcortical structures defined by intrasurgical electrical mapping. The extent of resection was evaluated on postoperative FLAIR-weighted MR imaging. Data regarding clinicoradiological features, therapeutic management, and outcomes were analyzed. RESULTS: Seven men and nine women (mean age, 41.3 years, range, 26 63 years) were included (seizure in 15 cases, one incidental discovery). All patients resumed a normal life after surgery (no neurological deficits, no epilepsy). The volume of postoperative cavity was larger than the preoperative tumor volume in the 16 patients. Neuropathological examination confirmed the diagnosis of WHO grade II glioma in all cases. No adjuvant treatment was administrated after resection. The mean duration of postoperative follow-up was 132 months (range, 97-198 months). There was no relapse in eight cases. Eight patients experienced tumor recurrence, with an average time to relapse of 70.3 months (range, 32-105 months), but without malignant transformation. Five of them have been re-treated, with a reoperation (two cases), chemotherapy (three cases) and radiotherapy (two cases). All patients continue to enjoy a normal life. CONCLUSIONS: This is the first series demonstrating the prolonged impact of supratotal resection on malignant transformation of DLGG. These original data may suggest to remove a margin around the FLAIR-weighted MR imaging abnormalities in a more systematic manner for DLGG not involving eloquent structures. PMID- 26530709 TI - Parametric study of ventricular catheters for hydrocephalus. AB - BACKGROUND: To drain the excess of cerebrospinal fluid in a hydrocephalus patient, a catheter is inserted into one of the brain ventricles and then connected to a valve. This so-called ventricular catheter is a standard-size, flexible tubing with a number of holes placed symmetrically around several transversal sections or "drainage segments". Three-dimensional computational dynamics shows that most of the fluid volume flows through the drainage segment closest to the valve. This fact raises the likelihood that those holes and then the lumen get clogged by the cells and macromolecules present in the cerebrospinal fluid, provoking malfunction of the whole system. In order to better understand the flow pattern, we have carried out a parametric study via numerical models of ventricular catheters. METHODS: The parameters chosen are the number of drainage segments, the distances between them, the number and diameter of the holes on each segment, as well as their relative angular position. RESULTS: These parameters were found to have a direct consequence on the flow distribution and shear stress of the catheter. As a consequence, we formulate general principles for ventricular catheter design. CONCLUSIONS: These principles can help develop new catheters with homogeneous flow patterns, thus possibly extending their lifetime. PMID- 26530710 TI - Postoperative transient neurological symptoms and chronic subdural hematoma after extracranial-intracranial bypass for internal carotid/middle cerebral atherosclerotic steno-occlusive diseases: negative effect on cognitive performance. AB - BACKGROUND: The mechanisms underlying post-extracranial to intracranial (EC-IC) bypass neurocognitive changes are poorly understood. METHODS: Data from 55 patients who underwent a unilateral EC-IC bypass for atherosclerotic internal carotid artery (ICA)/middle cerebral artery (MCA) steno-occlusive disease were retrospectively evaluated. These patients underwent neuropsychological examinations (NPEs), including assessment by the Wechsler Adult Intelligence Scale-Third Edition and Wechsler Memory Scale-Revised (WMS-R) before and 6 months after EC-IC bypass. Results of NPEs were converted into Z-scores from which preoperative cognitive composite scores (CSpre) and postoperative cognitive composite scores (CSpost) were obtained. The association between the change of composite score between pre- and postoperative NPEs (CSpost-pre = CS post - CS pre) and various variables were assessed. These latter variables included occluded artery (ICA or MCA), preexisting ischemic lesion as verified in preoperative T2WI, robust bypass patency as verified by MRA performed approximately 6 months postoperatively, and postoperative transient neurological symptoms and/or postoperative chronic subdural hematoma (CSDH), both of which were dichotomized as postoperative events. RESULTS: Postoperative MRI follow-up (median, 6 months; interquartile range, 5-8 months) confirmed successful bypasses in all patients, with no additional ischemic lesions on T2WI when compared with preoperative imaging. Further, MRA showed patent bypasses in all patients. A nearly statistically significant CS post-pre decrease was observed in patients with postoperative events when compared with those without postoperative events ( 0.158 vs. 0.039; p = 0.069). A multiple regression model predicting CSpost-pre was performed. After controlling for occluded arteries, postoperative events were identified as an independent predictor of a decline in CSpost-pre (p = 0.044). In the group rate analysis, three of four postoperative NPE scores (Performance IQ, WMS-memory, WMS-attention) were significantly improved relative to preoperative NPE scores. CONCLUSIONS: Postoperative transient neurological symptoms and/or CSDH might play a significant role in the subtle decline in cognition following an EC-IC bypass. However, this detrimental effect was small, and based on the group rate analysis, we concluded that a successful unilateral EC-IC bypass does not adversely affect postoperative cognitive function. PMID- 26530711 TI - Airway management in laryngotracheal injuries from blunt neck trauma in children. AB - Pediatric laryngotracheal injuries from blunt neck trauma are extremely rare, but can be potentially catastrophic. Early diagnosis and skillful airway management is critical in avoiding significant morbidity and mortality associated with these cases. We present a case of a patient who suffered a complete tracheal transection and cervical spine fracture following a clothesline injury to the anterior neck. A review of the mechanisms of injury, clinical presentation, initial airway management, and anesthetic considerations in laryngotracheal injuries from blunt neck trauma in children are presented. PMID- 26530713 TI - Improving Bariatric Patient Aftercare Outcome by Improved Detection of a Functional Vitamin B12 Deficiency. AB - BACKGROUND: Vitamin B12 deficiency is common after bariatric surgery. Vitamin B12 is a poor predictor of functional vitamin B12 status, since deficiencies might even occur within the reference limits. Therefore, vitamin B12 deficiencies with serum vitamin B12 levels are between 140 and 200 pmol/L remain undetected. Methylmalonic acid (MMA), however, will detect these deficiencies as accumulates due to functional intracellular vitamin B12 deficiencies. MMA is a relative expensive analysis and is therefore not generally available. To lower the costs, we only request MMA when vitamin B12 levels are between these levels. As a result, more biochemical deficiencies are found. However, it was not known whether bariatric patients with vitamin B12 levels between 140 and 200 pmol/L would benefit from supplementation. METHOD: Bariatric patients with vitamin B12 levels between 140 and 200 pmol/L with (n = 45) and without (n = 45) intramuscular hydroxocobalamin injections were compared. RESULTS: Treated patients showed a significant increase of vitamin B12 levels (P < 0.001) and a significant decrease in MMA levels (P < 0.001). Biochemical improvement occurs in both patients with and without clinical symptoms. The control group showed a significant increase of MMA levels (P < 0.001). To examine whether biochemical benefits of vitamin B12 supplementation are correlated with clinical improvement, patient records were checked for complaints. Complaints were disappeared after treatment, while no improvement was seen in untreated patients. CONCLUSION: This study shows that all bariatric patients with vitamin B12 levels between 140 and 200 pmol/L benefit clinical and biochemical from vitamin B12 supplementation, regardless the MMA levels. PMID- 26530714 TI - Facilitators of prenatal care in an exemplar urban clinic. AB - BACKGROUND: Perinatal outcomes have complex causes that include biologic, maternal, structural, and societal components. We studied one urban nurse-led clinic serving women at risk for poor perinatal outcomes with superior pre-term birth rates (4%) when compared with the surrounding county (11.2%). AIM: To explore women's perspectives of their interface with the clinic, staff, and providers to understand this exemplary model. METHODS: A qualitative descriptive approach with semi-structured interviews as the primary data source. Participants (n=50) were recruited from an urban clinic in the Southeast United States designed to serve women of low socio-economic status or who are recent immigrants. FINDINGS: Women greatly valued a personal connection with the nurse midwives and staff, and felt this resulted in high-quality care. Convenient appointment times and the lack of wait for initial or subsequent appointments made care accessible. Participants reported the relaxed and helpful approach and attitudes of the office staff were essential components of their positive experience. Women valued unrushed visits to ask questions and receive information. In addition, participants felt that clinic staff were easy to reach. CONCLUSION: While qualitative data cannot demonstrate causation, this study provides support that a compassionate and personalized approach to care motivates women to access needed services in pregnancy. Clinic staff are an essential component of the access process. Women overcame barriers to obtain personalized, culturally appropriate care provided by kind, competent practitioners. Clinic staff and practitioners should develop a connection with each woman by providing care that meets her physical, cultural, and personal needs. PMID- 26530712 TI - Mechanism Underlying the Weight Loss and Complications of Roux-en-Y Gastric Bypass. Review. AB - Various bariatric surgical procedures are effective at improving health in patients with obesity associated co-morbidities, but the aim of this review is to specifically describe the mechanisms through which Roux-en-Y gastric bypass (RYGB) surgery enables weight loss for obese patients using observations from both human and animal studies. Perhaps most but not all clinicians would agree that the beneficial effects outweigh the harm of RYGB; however, the mechanisms for both the beneficial and deleterious (for example postprandial hypoglycaemia, vitamin deficiency and bone loss) effects are ill understood. The exaggerated release of the satiety gut hormones, such as GLP-1 and PYY, with their central and peripheral effects on food intake has given new insight into the physiological changes that happen after surgery. The initial enthusiasm after the discovery of the role of the gut hormones following RYGB may need to be tempered as the magnitude of the effects of these hormonal responses on weight loss may have been overestimated. The physiological changes after RYGB are unlikely to be due to a single hormone, or single mechanism, but most likely involve complex gut brain signalling. Understanding the mechanisms involved with the beneficial and deleterious effects of RYGB will speed up the development of effective, cheaper and safer surgical and non-surgical treatments for obesity. PMID- 26530715 TI - Introduction to Technologies in the Daily Lives of Individuals with Autism. AB - In this introduction to the Special Issue on Technology we explore the continued evolution of technologies designed to help individuals with autism. Through review articles, empirical reports, and perspectives, we examine how far the field has come and how much further we still can go. Notably, even as we highlight the continuing need for larger empirical studies of autism-focused technology, we note how improvements in the portability, sophistication, ubiquity, and reach of daily technologies are providing new opportunities for research, education, enhancement, knowledge, and inspiration. We conclude by discussing how the next generation of technologies may leverage the increasing promise of big-data approaches to move us towards a future where technology is more personal, more relevant, and pervasively transformative. PMID- 26530716 TI - Association between green tea/coffee consumption and biliary tract cancer: A population-based cohort study in Japan. AB - Green tea and coffee consumption may decrease the risk of some types of cancers. However, their effects on biliary tract cancer (BTC) have been poorly understood. In this population-based prospective cohort study in Japan, we investigated the association of green tea (total green tea, Sencha, and Bancha/Genmaicha) and coffee consumption with the risk for BTC and its subtypes, gallbladder cancer, and extrahepatic bile duct cancer. The hazard ratios and 95% confidence intervals were calculated using the Cox proportional hazard model. A total of 89 555 people aged 45-74 years were enrolled between 1995 and 1999 and followed up for 1 138 623 person-years until 2010, during which 284 cases of BTC were identified. Consumption of >720 mL/day green tea was significantly associated with decreased risk compared with consumption of <=120 mL/day (hazard ratio = 0.67 [95% confidence interval, 0.46-0.97]), and a non-significant trend of decreased risk associated with increased consumption was observed (P-trend = 0.095). In the analysis according to the location of the primary tumor, consuming >120 mL green tea tended to be associated with decreased risk of gallbladder cancer and extrahepatic bile duct cancer. When Sencha and Bancha/Genmaicha were analyzed separately, we observed a non-significant trend of decreased risk of BTC associated with Sencha but no association with Bancha/Genmaicha. For coffee, there was no clear association with biliary tract, gallbladder, or extrahepatic bile duct cancer. Our findings suggest that high green tea consumption may lower the risk of BTC, and the effect may be attributable to Sencha consumption. PMID- 26530717 TI - Pricing of alcohol in Canada: A comparison of provincial policies and harm reduction opportunities. AB - INTRODUCTION AND AIMS: Alcohol pricing is an effective prevention policy. This paper compares the 10 Canadian provinces on three research-based alcohol pricing policies-minimum pricing, pricing by alcohol content and maintaining prices relative to inflation. DESIGN AND METHODS: The selection of these three policies was based on systematic reviews and seminal research papers. Provincial data for 2012 were obtained from Statistics Canada and relevant provincial ministries, subsequently sent to provincial authorities for verification, and then scored by team members. RESULTS: All provinces, except for Alberta, have minimum prices for at least one beverage type sold in off-premise outlets. All provinces, except for British Columbia and Quebec, have separate (and higher) minimum pricing for on premise establishments. Regarding pricing on alcohol content, western and central provinces typically scored higher than provinces in Eastern Canada. Generally, minimum prices were lower than the recommended $1.50 per standard drink for off premise outlets and $3.00 per standard drink in on-premise venues. Seven of 10 provinces scored 60% or higher compared to the ideal on indexing prices to inflation. Prices for a representative basket of alcohol products in Ontario and Quebec have lagged significantly behind inflation since 2006. DISCUSSION AND CONCLUSIONS: While examples of evidence-based alcohol pricing policies can be found in every jurisdiction in Canada, significant inter-provincial variation leaves substantial unrealised potential for further reducing alcohol-related harm and costs. This comparative assessment of alcohol price policies provides clear indications of how individual provinces could adjust their pricing policies and practices to improve public health and safety. [Giesbrecht N, Wettlaufer A, Thomas G, Stockwell T, Thompson K, April N, Asbridge M, Cukier S, Mann R, McAllister J, Murie A, Pauley C, Plamondon L, Vallance K. Pricing of alcohol in Canada: A comparison of provincial policies and harm-reduction opportunities. Drug Alcohol Rev 2016;35:289-297]. PMID- 26530718 TI - The cost-effectiveness analysis of JinQi Jiangtang tablets for the treatment on prediabetes: a randomized, double-blind, placebo-controlled, multicenter design. AB - BACKGROUND: At present, diabetes is a chronic disease of great cost and heavy burdens. The International Diabetes Federation has repeatedly warned that by 2025, the global number of diabetics would rise to 333 million from 194 million in 2003. Although the occurrence of diabetes in developing countries is lower, China has a large population, so that the number of cases is increased. At the same time, more people have prediabetes, a growing health concern where a large percentage of the patients develop full type 2 diabetes. In addition, the patients of diabetes easily incur complications such as blindness, kidney failure, and cardiovascular diseases that can seriously affect the patients' quality of life and cause great economic burdens to family and society. Therefore, effective interventions for prediabetes are needed to prevent or delay the occurrence and development of diabetes. METHODS: A randomized controlled trial that was assessed with pharmacoeconomic methods was undertaken in this study. The study term was 24 months (12 months for the intervention and 12 months for follow up). Four hundred participants, recruited from four cities in China: Beijing, Tianjin, Xian, and Naning, were randomized to the treatment group (JQJT tablets) and the control group (placebo). Participants included in this study had been diagnosed with prediabetes according to the criteria for western medicine and Traditional Chinese Medicine (TCM). The end-point effectiveness indexes included the incidence of diabetes and the reversion rate. The drug costs and lifestyle intervention costs were included in the total costs. The study used the cost-effectiveness analysis to discuss the economic advantage of the JQJT tablets. RESULTS: The outcomes of the study contained 2 sections,namely clinical outcomes and cost-effectiveness analysis outcomes. The clinical outcomes: the treatment group and control group had no significant statistical difference P> 0.05) on the baseline of situation; Jinqi Jiangtang tablet effectively reduced the incidence of diabetes mellitus and enhanced reversion rate. compared with the control group (p< 0.05); the scores of SF-36 of two groups had no significant difference P> 0.05); finally the compliance of participants between the two groups had no significant difference. The cost-effectiveness analysis outcomes:in the intervention period of 12 months,on the aspect of reversion rate, the treatment group had better economic advantage by using cost-effectiveness ratio and the incremental cost-effectiveness ratio;on the aspect of the incidence of diabetes, the control group had better economic advantage by using cost effectiveness ratio and the incremental cost-effectiveness ratio; in the follow up period of 24 months, on the aspect of reversion rate, the treatment group had better economic advantage by using cost-effectiveness ratio and the incremental cost-effectiveness ratio, on the aspect of the incidence of diabetes, the control group had better economic advantage by using cost-effectivenes ratio and the incremental cost-effectiveness ratio.At the same time, these outcomes remained the same by sensitivity analysis. Assuming that prices and resident incomes rose 5%, the sensitiveness analysis shows that the two group affected by the paremeters changed little. CONCLUSION: The importance and effectiveness of lifestyle education and JinQi Jiangtang tablets was proven. In both the intervention period and follow-up, JinQi Jiangtang tablets combined with lifestyle education had a greater cost advantage effect than the lifestyle education alone on the reversion rate; the lifestyle education had a greater cost advantage effect than the JinQi Jiangtang tablets combined with lifestyle education on the incidence of diabetes. TRIAL REGISTRATION: Chinese Clinical Trials ChiCTR-TRC-09000401 ) , registered on 25 May 2009. PMID- 26530720 TI - The Transition Period in Soccer: A Window of Opportunity. AB - The aim of this paper is to describe the physiological changes that occur during the transition period in soccer players. A secondary aim is to address the issue of utilizing the transition period to lay the foundation for the succeeding season. We reviewed published peer-reviewed studies if they met the following three selection criteria: (1) the studied population comprised adult soccer players (aged >18 years), (2) time points of physiological and performance assessments were provided, and (3) appropriate statistics for the calculation of effect sizes were reported. Following two selection phases, 12 scientific publications were considered, involving a total sample of 252 players. The transition period elicits small to moderate negative changes in body composition, a moderate decline in sprint performance with and without changes of direction, and small to moderate decrements in muscle power. Detraining effects are also evident for endurance-related physiological and performance outcomes: large decrements in maximal oxygen consumption VO2max) and time to exhaustion, and moderate to very large impairments have been observed in intermittent-running performance. Off-season programs should be characterized by clear training objectives, a low frequency of training sessions, and simple training tools in order to facilitate compliance. The program suggested here may constitute the 'minimum effective dose' to maintain or at least attenuate the decay of endurance and neuromuscular-related performance parameters, as well as restore an adequate strength profile (reduce muscle strength imbalances). This periodization strategy may improve the ability of players to cope with the elevated training demands of pre-season training and therefore reduce the risk of injury. Moreover, this strategy will favor a more efficient development of other relevant facets of performance during the pre-competition phase (e.g., tactical organization). We contend that the transition period needs to be perceived as a 'window of opportunity' for players to both recover and 'rebuild' for the following season. PMID- 26530721 TI - How substandard dwellings and housing affordability problems are associated with poor health in a vulnerable population during the economic recession of the late 2000s. AB - INTRODUCTION: Given the increasing number of people in Spain struggling to pay housing-related costs during the economic recession, it is important to assess the health status of these communities as compared to the general population and to better understand the different housing dimensions that are related with poor mental health. This study aims to describe the housing conditions and health status of a sample of people assisted by Caritas Barcelona (Spain) and living in inadequate housing and/or struggling to pay their rent or mortgage, to compare the health outcomes of this population with those of the overall population of Barcelona, and to analyze the association between housing dimensions and mental health. METHODS: We used a cross-sectional design. The participating adults (n = 320) and children (n = 177) were those living in the dioceses of Barcelona, Sant Feliu and Terrassa (Spain) in 2012 and assisted by Caritas. They were asked to answer to three questionnaires on housing and health conditions. Eight health related variables were used to compare participants with Barcelona's residents and associations between housing conditions and poor mental health were examined with multivariate logistic regression models. RESULTS: In Barcelona, people seeking Caritas's help and facing serious housing problems had a much poorer health status than the general population, even when compared to those belonging to the most deprived social classes. For example, 69.4 % of adult participants had poor mental health compared to 11.5 % male and 15.2 % female Barcelona residents. Moreover, housing conditions were associated with poor mental health. CONCLUSIONS: This study has shown how, in a country hit by the financial recession, those people facing housing problems have much worse health compared to the general population. PMID- 26530722 TI - Specific small-RNA signatures in the amygdala at premotor and motor stages of Parkinson's disease revealed by deep sequencing analysis. AB - MOTIVATION: Most computational tools for small non-coding RNAs (sRNA) sequencing data analysis focus in microRNAs (miRNAs), overlooking other types of sRNAs that show multi-mapping hits. Here, we have developed a pipeline to non-redundantly quantify all types of sRNAs, and extract patterns of expression in biologically defined groups. We have used our tool to characterize and profile sRNAs in post mortem brain samples of control individuals and Parkinson's disease (PD) cases at early-premotor and late-symptomatic stages. RESULTS: Clusters of co-expressed sRNAs mapping onto tRNAs significantly separated premotor and motor cases from controls. A similar result was obtained using a matrix of miRNAs slightly varying in sequence (isomiRs). The present framework revealed sRNA alterations at premotor stages of PD, which might reflect initial pathogenic perturbations. This tool may be useful to discover sRNA expression patterns linked to different biological conditions. AVAILABILITY AND IMPLEMENTATION: The full code is available at http://github.com/lpantano/seqbuster CONTACT: lpantano@hsph.harvard.edu or eulalia.marti@crg.eu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26530724 TI - PHYLUCE is a software package for the analysis of conserved genomic loci. AB - Targeted enrichment of conserved and ultraconserved genomic elements allows universal collection of phylogenomic data from hundreds of species at multiple time scales (<5 Ma to > 300 Ma). Prior to downstream inference, data from these types of targeted enrichment studies must undergo preprocessing to assemble contigs from sequence data; identify targeted, enriched loci from the off-target background data; align enriched contigs representing conserved loci to one another; and prepare and manipulate these alignments for subsequent phylogenomic inference. PHYLUCE is an efficient and easy-to-install software package that accomplishes these tasks across hundreds of taxa and thousands of enriched loci. AVAILABILITY AND IMPLEMENTATION: PHYLUCE is written for Python 2.7. PHYLUCE is supported on OSX and Linux (RedHat/CentOS) operating systems. PHYLUCE source code is distributed under a BSD-style license from https://www.github.com/faircloth lab/phyluce/ PHYLUCE is also available as a package (https://binstar.org/faircloth-lab/phyluce) for the Anaconda Python distribution that installs all dependencies, and users can request a PHYLUCE instance on iPlant Atmosphere (tag: phyluce). The software manual and a tutorial are available from http://phyluce.readthedocs.org/en/latest/ and test data are available from doi: 10.6084/m9.figshare.1284521. CONTACT: brant@faircloth-lab.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26530723 TI - No Promoter Left Behind (NPLB): learn de novo promoter architectures from genome wide transcription start sites. AB - Promoters have diverse regulatory architectures and thus activate genes differently. For example, some have a TATA-box, many others do not. Even the ones with it can differ in its position relative to the transcription start site (TSS). No Promoter Left Behind (NPLB) is an efficient, organism-independent method for characterizing such diverse architectures directly from experimentally identified genome-wide TSSs, without relying on known promoter elements. As a test case, we show its application in identifying novel architectures in the fly genome. AVAILABILITY AND IMPLEMENTATION: Web-server at http://nplb.ncl.res.in Standalone also at https://github.com/computationalBiology/NPLB/ (Mac OSX/Linux). CONTACT: l.narlikar@ncl.res.in SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26530726 TI - The pectoralis minor muscle and shoulder movement-related impairments and pain: Rationale, assessment and management. AB - The adaptive shortening or tightness of the pectoralis minor muscle (PMm) is one of the potential biomechanical mechanisms associated with altered scapular alignment at rest and scapular motion during arm elevation (scapular dyskinesis) in patients with shoulder complaints. This masterclass briefly reviews the role of the PMm in shoulder movement-related impairments and provides a critical overview of the assessment of PMm tightness and the conventional approaches to increase its resting length and extensibility. A rehabilitation approach focused on PMm stretching and simultaneous optimization of the kinematic chain of arm elevation is also discussed, hoping to improve the management of shoulder movement-related impairments and pain. PMID- 26530725 TI - Gallic acid, a phenolic compound, exerts anti-angiogenic effects via the PTEN/AKT/HIF-1alpha/VEGF signaling pathway in ovarian cancer cells. AB - Gallic acid (GA), a polyphenol, is widely found in numerous fruits and vegetables, particularly in hickory nuts. In the present study, we found that gallic acid, a natural phenolic compound isolated from fruits and vegetables, had a more potent growth inhibitory effect on two ovarian cancer cell lines, OVCAR-3 and A2780/CP70, than the effect on a normal ovarian cell line, IOSE-364. These results demonstrated that GA selectively inhibits the growth of cancer cells. Gene expression was examined by ELISA and western blot analysis, and gene pathways were examined by luciferase assay. It was found that GA inhibited VEGF secretion and suppressed in vitro angiogenesis in a concentration-dependent manner. GA downregulated AKT phosphorylation as well as HIF-1alpha expression but promoted PTEN expression. The luciferase assay results suggest that the PTEN/AKT/HIF-1alpha pathway accounts for the inhibitory effect of GA on VEGF expression and in vitro angiogenesis. These findings provide strong support for the high potential of GA in the prevention and therapy of ovarian cancer. PMID- 26530727 TI - Invasive lobular carcinoma of the male breast: A rare histology of an uncommon disease. AB - Male breast carcinoma is a rare malignancy comprising less than 1% of all breast cancers. It is a serious disease with most patients presenting in advanced stages. Infiltrating ductal carcinoma is the most common histology while lobular carcinoma represents less than 1% of all these tumors. We report a case of locally advanced lobular carcinoma of breast in a 60 year old male. PMID- 26530728 TI - On-chip optical mode exchange using tapered directional coupler. AB - We present an on-chip optical mode exchange between two multiplexed modes by using tapered directional couplers on silicon-on-insulator platform. The device consisting of mode multiplexing and mode exchange is compact with relatively large fabrication error tolerance. The simulation results show efficient higher order mode excitation and mode exchange. A low excess loss less than 0.5 dB and high extinction ratio larger than 15 dB over 10 nm wavelength range from 1535 to 1545 nm are achieved. PMID- 26530729 TI - The activation of p38 MAPK limits the abnormal proliferation of vascular smooth muscle cells induced by high sodium concentrations. AB - The aim of the present study was to ascertain whether high sodium levels can directly promote the proliferation of vascular smooth muscle cells (VSMCs) and to elucidate the underlying mechanisms. Additional sodium chloride (NaCl) was added to the routine culture medium. Cell proliferation was evaluated by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 5-ethynyl 2'-deoxyuridine (EdU) incorporation assay. The mRNA expression level of proliferating cell nuclear antigen (PCNA) was measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The protein expression levels of PCNA and phosphorylated c-Jun amino N-terminal kinase (p-JNK), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) were measured by western blot analysis. Cell proliferation assay revealed that Na+ rather than Cl- or osmotic pressure promoted the proliferation of the VSMCs. The high sodium level upregulated the expression of PCNA and the phosphorylation levels of JNK, ERK1/2 and p38 MAPK. The inhibition of JNK and ERK1/2 decreased PCNA expression. Of note, the inhibition of p38 MAPK using the inhibitor, SB203580, increased PCNA expression. However, when p38 MAPK was activated by anisomycin, PCNA expression was decreased. On the whole, our findings demonstrate that a relatively high sodium level per se directly promotes the proliferation of VSMCs through the JNK/ERK1/2/PCNA pathway. At the same time, this induction of the proliferation of VSMCs due to high sodium levels can be maintained at a low level via the activation of p38 MAPK. PMID- 26530730 TI - Diagnostic potential of endoscopic ultrasonography-elastography for gastric submucosal tumors: A pilot study. AB - BACKGROUND AND AIM: Qualitative diagnosis for gastric submucosal tumors (SMT) is not easy. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in combination with EUS-elastography (EUS-EG) is reported useful for qualitatively diagnosing pancreatic tissues. We prospectively studied whether EUS-EG could be useful in qualitative diagnosis of gastric SMT. METHODS: We prospectively registered 25 consecutive patients with gastric SMT diagnosed by esophagogastroduodenoscopy and carried out qualitative evaluations using EUS-EG (May 2013 to March 2015) followed by histopathological diagnosis using EUS-FNA or endoscopic mucosal cutting biopsy. Elastic scores of gastric SMT were compared to the cytological diagnosis. RESULTS: Of 25 patients, 22 had a confirmed cytological diagnosis. Regarding the Giovannini elastic score, of three patients with aberrant pancreas, one was score 1 and two were score 2; of eight patients with leiomyoma, seven were score 2 and one was score 3. Both of two patients with schwannoma were score 4. Of nine patients with gastrointestinal stromal tumor, six were score 4 and three were score 5. Gastrointestinal stromal tumor (GIST) is harder than other types of gastric SMT, and our study's findings suggested the usefulness of EUS-EG, which can also assess tumor hardness of gastric SMT. CONCLUSION: EUS-EG might be helpful for the differential diagnosis of gastric SMT, especially to differentiate GIST from other SMT. PMID- 26530731 TI - Computed tomography as an aid to planning intubation in the difficult airway. AB - Patients having oral and maxillofacial operations often require nasal intubation, but limited mouth opening and unfavourable nasal anatomy can make it difficult. We aimed to find out whether there is an association between the prediction of difficult nasal intubation on computed tomography (CT) and actual problems. We retrospectively reviewed the imaging and anaesthetic records of 77 patients who had replacement of the temporomandibular joint (TMJ) as these patients often have limited mouth opening and have had a preoperative CT. There was a positive correlation between a radiographically-assessed difficult nostril and difficulty of intubation (p<0.001). The positive predictive value was 71.4%. As a consequence, our radiologists now routinely report on the nasal cavity in these patients, and their report and the scan are then reviewed by the anaesthetist before intubation. Our results suggest that review of the CT before planned nasal intubation should be part of routine practice. PMID- 26530732 TI - Role of intravenous dosage regimens of bisphosphonates in relation to other aetiological factors in the development of osteonecrosis of the jaws in patients with myeloma. AB - The aim of this case-control study was to identify possible explanatory risk factors for the development of bisphosphonate-related osteonecrosis of the jaws (BRONJ) by estimating the effects of intravenous dosage regimens of bisphosphonates, coexisting diseases, and other drugs on 201 patients with multiple myeloma, with or without BRONJ. We compared sex, treatment with bisphosphonates, incidence of diabetes, and the taking of drugs such as corticosteroids and chemotherapy in patients who had BRONJ (n=44) and patients who did not (n=157). Among the bisphosphonates given intravenously zoledronic acid showed a stronger correlation with BRONJ than pamidronic acid. The risk of developing BRONJ increased dramatically at cumulative intravenous doses of more than 78 mg of zoledronic acid or 600 mg of pamidronic acid, which corresponds to treatment for 18 months or longer. Diabetes mellitus correlated significantly with the development of BRONJ (p=0.01) while there was no correlation with sex, simultaneous treatment with corticosteroids, or chemotherapy. In conclusion, treatment with zoledronic acid, high doses of pamidronic acid, and the coexistence of diabetes mellitus seem to be associated with the development of BRONJ. PMID- 26530733 TI - Unusual form of sialolithiasis: case report with 3-dimensional imaging. PMID- 26530734 TI - Where do patients treated for oral cancer die? A 20-year cohort study 1992-2011. AB - Of 1290 consecutive patients treated between 1992 and 2011 for primary squamous cell carcinoma of the oral cavity at a regional centre, 750 had died by August 2013. About half of them (n=373) died in hospital, 113 (15%) in a hospice, 180 (24%) at home, 57 (8%) in a care home, and 22 (3%) elsewhere. Cancer was the underlying cause of death in 64%, and of them, 56% were oral cancers. The place of death was strongly associated with the age at death and cancer being the underlying cause. The percentage of people who died from cancer at home or in a hospice rose over time across all age groups and, from 2010, accounted for two thirds. In contrast, less than 1 in 5 who did not die from cancer, died at home or in a hospice, and in this there has been no discernible change over the last 20 years. The percentage of deaths from cancer in hospital and hospice ranged from 32%-38% and 20%-29%, respectively, across age groups. An increase in the number of deaths from cancer in care homes in those aged 75 years and over was mirrored by fewer at home. Most of those who did not die from cancer, died in hospital, two-thirds were under 65 years, 85% were aged 65-84, and 56% were older. This was mirrored by fewer deaths at home in those under 85 and more in care homes in those over 75. In conclusion, our findings suggest that patients' preferences not to die in hospital are being realised. However, at the end of their lives, patients and their carers need more support at home, and more research is required. PMID- 26530735 TI - RIG-I-like receptors and autoimmune diseases. AB - Type I interferon (IFN) plays an essential role in antiviral innate immune responses and also in adaptive immune responses. Defects in the production of IFN markedly increase susceptibility to viral invasion and attenuate the acquired immunity. Recently an increased expression of type I IFN, also termed IFN signature, has been reported in patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and Aicardi-Goutieres syndrome (AGS). The evidence clearly shows that the initiation and termination of IFN production should be tightly controlled. RIG-I-like receptors (RLRs) are viral RNA sensors and are essential for type I IFN induction. We herein summarize recent reports on RLR mutations in patients and MDA5 mutant mice, and discuss possible mechanisms by which aberrant activation of RLRs can cause autoimmunity. PMID- 26530736 TI - Hemispheric activation differences in novice and expert clinicians during clinical decision making. AB - Clinical decision making requires knowledge, experience and analytical/non analytical types of decision processes. As clinicians progress from novice to expert, research indicates decision-making becomes less reliant on foundational biomedical knowledge and more on previous experience. In this study, we investigated how knowledge and experience were reflected in terms of differences in neural areas of activation. Novice and expert clinicians diagnosed simple or complex (easy, hard) cases while functional magnetic resonance imaging (fMRI) data were collected. Our results highlight key differences in the neural areas activated in novices and experts during the clinical decision-making process. fMRI data were collected from ten second year medical students (novices) and ten practicing gastroenterologists (experts) while they diagnosed sixteen (eight easy and eight hard) clinical cases via multiple-choice questions. Behavioral data were collected for diagnostic accuracy (correct/incorrect diagnosis) and time taken to assign a clinical diagnosis. Two analyses were performed with the fMRI data. First, data from easy and hard cases were compared within respective groups (easy > hard, hard > easy). Second, neural differences between novices and experts (novice > expert, expert > novice) were assessed. Experts correctly diagnosed more cases than novices and made their diagnoses faster than novices on both easy and hard cases (all p's < 0.05). Time taken to diagnose hard cases took significantly longer for both novices and experts. While similar neural areas were activated in both novices and experts during the decision making process, we identified significant hemispheric activation differences between novice and expert clinicians when diagnosing hard clinical cases. Specifically, novice clinicians had greater activations in the left anterior temporal cortex and left ventral lateral prefrontal cortex whereas expert clinicians had greater activations in the right dorsal lateral, right ventral lateral, and right parietal cortex. Hemispheric differences in activation were not observed between novices and experts while diagnosing easy clinical cases. While clinical decision making engaged the prefrontal cortex (PFC) in both novices and experts, interestingly we observed expertise related differences in the regions and hemispheres of PFC activation between these groups for hard clinical cases. Specifically, in novices we observed activations in left hemisphere neural regions associated with factual rule-based knowledge, whereas in experts we observed right hemisphere activation in neural regions associated with experiential knowledge. Importantly, at the neural level, our data highlight differences in so called type 2 clinical decision-making processes related to prior knowledge and experience. PMID- 26530737 TI - Health behaviour procrastination: a novel reasoned route towards self-regulatory failure. AB - In this paper, we highlight a novel perspective on health behaviour failure by considering reasoned procrastination as a contributing factor. We argue that the failure to enact intentions does not necessarily occur because people are victims of their strong impulses, but that people may also knowingly and wilfully postpone their intended actions. While procrastination is acknowledged as a factor associated with intention-behaviour gaps in other domains, it has surprisingly received only very little attention in the domain of health behaviour. We argue that it is particularly important to recognise the waxing and waning of intentions: rather than being truly abandoned, intentions may sometimes be temporarily put aside. This paper describes how the procrastination account relates to the intention-behaviour gap as we know it, what is known about procrastination and health behaviour, and what theoretical and practical implications can be derived from the addition of this novel perspective to our understanding of health behaviour change. PMID- 26530739 TI - Stormy "Fourcast" for Brachytherapy. PMID- 26530738 TI - Evaluation of a rapid quantitative determination method of PSA concentration with gold immunochromatographic strips. AB - BACKGROUND: Prostate cancer remains the most common cancer in men. Qualitative or semi-quantitative immunochromatographic measurements of prostate specific antigen (PSA) have been shown to be simple, noninvasive and feasible. The aim of this study was to evaluate an optimized gold immunochromatographic strip device for the detection of PSA, in which the results can be analysed using a Chromogenic Rapid Test Reader to quantitatively assess the test results. METHODS: This reader measures the reflectance of the signal line via a charge-coupled device camera. For quantitative analysis, PSA concentration was computed via a calibration equation. Capillary blood samples from 305 men were evaluated, and two independent observers interpreted the test results after 12 min. Blood samples were also collected and tested with a conventional quantitative assay. RESULTS: Sensitivity, specificity, positive and negative predictive values, and accuracy of the PSA rapid quantitative test system were 100, 96.6, 89.5, 100, and 97.4 %, respectively. Reproducibility of the test was 99.2, and interobserver variation was 8 % with a false positive rate of 3.4 %. The correlation coefficient between the ordinary quantitative assay and the rapid quantitative test was 0.960. CONCLUSIONS: The PSA rapid quantitative test system provided results quickly and was easy to use, so that tests using this system can be easily performed at outpatient clinics or elsewhere. This system may also be useful for initial cancer screening and for point-of-care testing, because results can be obtained within 12 min and at a cost lower than that of conventional quantitative assays. PMID- 26530740 TI - Radiation Therapy Intensification for Solid Tumors: A Systematic Review of Randomized Trials. AB - PURPOSE: To systematically review the outcomes of randomized trials testing radiation therapy (RT) intensification, including both dose escalation and/or the use of altered fractionation, as a strategy to improve disease control for a number of malignancies. METHODS AND MATERIALS: We performed a literature search to identify randomized trials testing RT intensification for cancers of the central nervous system, head and neck, breast, lung, esophagus, rectum, and prostate. Findings were described qualitatively. Where adequate data were available, pooled estimates for the effect of RT intensification on local control (LC) or overall survival (OS) were obtained using the inverse variance method. RESULTS: In primary central nervous system tumors, esophageal cancer, and rectal cancer, randomized trials have not demonstrated that RT intensification improves clinical outcomes. In breast cancer and prostate cancer, dose escalation has been shown to improve LC or biochemical disease control but not OS. Radiation therapy intensification may improve LC and OS in head and neck and lung cancers, but these benefits have generally been limited to studies that did not incorporate concurrent chemotherapy. CONCLUSIONS: In randomized trials, the benefits of RT intensification have largely been restricted to trials in which concurrent chemotherapy was not used. Novel strategies to optimize the incorporation of RT in the multimodality treatment of solid tumors should be explored. PMID- 26530741 TI - Stress and Burnout Among Residency Program Directors in United States Radiation Oncology Programs. AB - PURPOSE: To evaluate stressors among radiation oncology residency program directors (PDs) and determine the prevalence and indicators of burnout. METHODS AND MATERIALS: An anonymous, online, cross-sectional survey was offered to PDs of US radiation oncology programs in the fall of 2014. Survey content examined individual and program demographics, perceptions surrounding the role of PD, and commonly encountered stressors. Burnout was assessed using the validated Maslach Burnout Inventory-Human Services Survey. RESULTS: In total, 47 of 88 PDs (53%) responded to the survey. Although 78% of respondents reported feeling "satisfied" or "highly satisfied" with their current role, 85% planned to remain as PD for <5 years. The most commonly cited stressors were satisfying Accreditation Council for Graduate Medical Education/Residency Review Committee requirements (47%), administrative duties (30%) and resident morale (28%). Three-quarters of respondents were satisfied that they became PDs. Overall, 11% of respondents met criteria for low burnout, 83% for moderate burnout, and 6% for high burnout. Not having served as a PD at a prior institution correlated with high depersonalization (OR 6.75, P=.04) and overall burnout (odds ratio [OR], 15.6; P=.04). Having more years on faculty prior to becoming PD correlated with less emotional exhaustion (OR, 0.44, P=.05) and depersonalization (OR, 0.20, P=.04). Finally, having dedicated time for PD duties correlated with less emotional exhaustion (OR, 0.27, P=.04). CONCLUSIONS: Moderate levels of burnout are common in U.S. radiation oncology PDs with regulatory stressors being common. Despite this, many PDs are fulfilled with their role. Longitudinal studies assessing dynamic external factors and their influence on PD burnout would be beneficial. PMID- 26530742 TI - Authorship in Radiation Oncology: Proliferation Trends Over 30 Years. AB - PURPOSE: To investigate authorship trends in the radiation oncology literature. METHODS AND MATERIALS: We examined the authorship credits of "original research articles" within 2 popular radiation oncology journals-International Journal of Radiation Oncology, Biology, Physics and Radiotherapy and Oncology-in 1984, 1994, 2004, and 2014. We compared the number of authors per publication during these 4 time periods using simple linear regression as a test for trend. We investigated additional author characteristics in a subset of articles. RESULTS: A total of 2005 articles were eligible. The mean number of authors per publication rose from 4.3 in 1984 to 9.1 in 2014 (P<.001). On subset analysis of 400 articles, there was an increase in the percentage of multidisciplinary bylines (from 52% to 72%), multi-institutional bylines (from 20% to 53%), and publications with a trainee first author (from 16% to 56%) during the study period. CONCLUSIONS: The mean number of authors per publication has more than doubled over the last 30 years in the radiation oncology literature. Possible explanations include increasingly complex and collaborative research as well as honorary authorship. Explicit documentation of author contributions could help ensure that scientific work is credited according to accepted standards. PMID- 26530744 TI - Dose and Fractionation in Stereotactic Body Radiation Therapy for Stage I Non Small Cell Lung Cancer: Lessons Learned and Where Do We Go Next? PMID- 26530743 TI - A Randomized Phase 2 Study Comparing 2 Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer: NRG Oncology RTOG 0915 (NCCTG N0927). AB - PURPOSE: To compare 2 stereotactic body radiation therapy (SBRT) schedules for medically inoperable early-stage lung cancer to determine which produces the lowest rate of grade >=3 protocol-specified adverse events (psAEs) at 1 year. METHODS AND MATERIALS: Patients with biopsy-proven peripheral (>=2 cm from the central bronchial tree) T1 or T2, N0 (clinically node negative by positron emission tomography), M0 tumors were eligible. Patients were randomized to receive either 34 Gy in 1 fraction (arm 1) or 48 Gy in 4 consecutive daily fractions (arm 2). Rigorous central accreditation and quality assurance confirmed treatment per protocol guidelines. This study was designed to detect a psAEs rate >17% at a 10% significance level (1-sided) and 90% power. Secondary endpoints included rates of primary tumor control (PC), overall survival (OS), and disease free survival (DFS) at 1 year. Designating the better of the 2 regimens was based on prespecified rules of psAEs and PC for each arm. RESULTS: Ninety-four patients were accrued between September 2009 and March 2011. The median follow-up time was 30.2 months. Of 84 analyzable patients, 39 were in arm 1 and 45 in arm 2. Patient and tumor characteristics were balanced between arms. Four (10.3%) patients on arm 1 (95% confidence interval [CI] 2.9%-24.2%) and 6 (13.3%) patients on arm 2 (95% CI 5.1%-26.8%) experienced psAEs. The 2-year OS rate was 61.3% (95% CI 44.2% 74.6%) for arm 1 patients and 77.7% (95% CI 62.5%-87.3%) for arm 2. The 2-year DFS was 56.4% (95% CI 39.6%-70.2%) for arm 1 and 71.1% (95% CI 55.5%-82.1%) for arm 2. The 1-year PC rate was 97.0% (95% CI 84.2%-99.9%) for arm 1 and 92.7% (95% CI 80.1%-98.5%) for arm 2. CONCLUSIONS: 34 Gy in 1 fraction met the prespecified criteria and, of the 2 schedules, warrants further clinical research. PMID- 26530745 TI - Three-Dimensional Radiation Therapy to the Primary Tumor With Concurrent Chemotherapy in Patients With Stage IV Non-Small Cell Lung Cancer: Results of a Multicenter Phase 2 Study From PPRA-RTOG, China. AB - PURPOSE: The aim of this prospective multi-institutional phase 2 study was to investigate disease control, survival outcomes, and toxicity after thoracic three dimensional radiation therapy (3D-RT) with concurrent chemotherapy for newly diagnosed stage IV non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Eligible patients were 18 to 80 years of age, had a Karnofsky performance status (KPS) score >=70%, and newly diagnosed stage IV NSCLC with limited metastatic disease (defined as involving <=3 organs). Patients received platinum-doublet chemotherapy with concurrent irradiation to the primary tumor. Primary endpoints were overall survival (OS) and acute toxicity. RESULTS: From May 2008 to May 2012, 198 eligible patients were enrolled from 7 cancer centers. Most patients died with distant metastasis; only 10% died with isolated primary recurrence. Median OS time was 13.0 months (95% confidence interval [CI]: 11.7-14.3); OS rates were 53.5% at 1 year, 15.8% at 2 years, and 9.2% at 3 years. Median progression-free survival (PFS) time was 9.0 months (95% CI: 7.7-10.3); corresponding PFS rates were 30.8%, 8.2%, and 6.1%. The 1-year, 2-year, and 3 year local (primary tumor) control rates were 78.8%, 57.7%, and 55.4%. Multivariate analysis showed that delivery of >=63 Gy to the primary tumor (P=.014), having a primary tumor volume <134 cm(3) (P=.008), and having a stable or higher KPS score after treatment (P=.01) were independent predictors of better OS. The most common severe (grades 3-4) acute toxicities were hematologic: leukopenia (37.9%), thrombocytopenia (10.1%), and anemia (6.9%). No patients experienced grade 4 or 5 radiation-related toxicity; 2.5% had acute grade 3 pneumonitis, and 6.6% had acute grade 3 radiation esophagitis. CONCLUSIONS: Thoracic 3D-RT to the primary tumor with concurrent chemotherapy led to satisfactory survival outcomes with acceptable toxicity. Radiation dose, primary tumor volume, and PFS after treatment all predicted survival in these patients with limited-metastasis NSCLC. PMID- 26530746 TI - Combined Ventilation and Perfusion Imaging Correlates With the Dosimetric Parameters of Radiation Pneumonitis in Radiation Therapy Planning for Lung Cancer. AB - PURPOSE: The purpose of this study was to prospectively investigate clinical correlations between dosimetric parameters associated with radiation pneumonitis (RP) and functional lung imaging. METHODS AND MATERIALS: Functional lung imaging was performed using four-dimensional computed tomography (4D-CT) for ventilation imaging, single-photon emission computed tomography (SPECT) for perfusion imaging, or both (V/Q-matched region). Using 4D-CT, ventilation imaging was derived from a low attenuation area according to CT numbers below different thresholds (vent-860 and -910). Perfusion imaging at the 10th, 30th, 50th, and 70th percentile perfusion levels (F10-F70) were defined as the top 10%, 30%, 50%, and 70% hyperperfused normal lung, respectively. All imaging data were incorporated into a 3D planning system to evaluate correlations between RP dosimetric parameters (where fV20 is the percentage of functional lung volume irradiated with >20 Gy, or fMLD, the mean dose administered to functional lung) and the percentage of functional lung volume. Radiation pneumonitis was evaluated using Common Terminology Criteria for Adverse Events version 4.0. Statistical significance was defined as a P value of <.05. RESULTS: Sixty patients who underwent curative radiation therapy were enrolled (48 patients for non-small cell lung cancer, and 12 patients for small cell lung cancer). Grades 1, 2, and >=3 RP were observed in 16, 44, and 6 patients, respectively. Significant correlations were observed between the percentage of functional lung volume and fV20 (r=0.4475 in vent-860 and 0.3508 in F30) or fMLD (r=0.4701 in vent-860 and 0.3128 in F30) in patients with grade >=2 RP. F30?vent-860 results exhibited stronger correlations with fV20 and fMLD in patients with grade >=2 (r=0.5509 in fV20 and 0.5320 in fMLD) and grade >=3 RP (r=0.8770 in fV20 and 0.8518 in fMLD). CONCLUSIONS: RP dosimetric parameters correlated significantly with functional lung imaging. PMID- 26530747 TI - Assessment of Parametrial Response by Growth Pattern in Patients With International Federation of Gynecology and Obstetrics Stage IIB and IIIB Cervical Cancer: Analysis of Patients From a Prospective, Multicenter Trial (EMBRACE). AB - PURPOSE: To assess disease response along the parametrial space according to tumor morphology in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIB and IIIB cervical cancer at the time of image-guided adaptive brachytherapy. METHODS AND MATERIALS: Patients with FIGO stage IIB and IIIB cervical cancer registered as of November 2013 in the EMBRACE study were evaluated. Tumors were stratified according to morphologic subtype on magnetic resonance imaging (expansive and infiltrative), and the characteristics of those subtypes were analyzed. Parametrial involvement at diagnosis and at brachytherapy was evaluated, and the response to chemo-radiotherapy was classified as good, moderate, or poor. The response grade was compared between the 2 groups and analyzed with regard to tumor volumes, and dosimetric parameters. RESULTS: A total of 452 patients were evaluated, of whom 186 had expansive growth type and 266 had infiltrative morphology. Patients with infiltrative tumors had more extensive disease, as indicated by a higher rate of FIGO stage IIIB disease, as well as radiologic evidence of extension into the distal parametrial space and to the pelvic side wall on magnetic resonance imaging. Cervical necrosis was more common in the infiltrative group. Good response was more common in the expansive group (34% vs 24%; P=.02), and poor response was more common in the infiltrative group (11% and 19%; P=.02). Mean gross tumor volume at diagnosis was equal in both groups (51.7 cm(3)). The high-risk clinical target volume was larger in infiltrative tumors (37.9 cm(3) vs 33.3 cm(3), P=.005). The mean high-risk clinical target volume D90 was slightly higher in expansive tumors (92.7 Gy and 89.4 Gy, P<.001). CONCLUSION: Infiltrative tumors are more advanced at presentation and respond less favorably to chemo-radiotherapy when compared with expansive tumors that are more or less equivalent in size. The use of image guided adaptive brachytherapy allows achieving reasonably high doses in both groups. PMID- 26530748 TI - Long-Term Impact of Endometrial Cancer Diagnosis and Treatment on Health-Related Quality of Life and Cancer Survivorship: Results From the Randomized PORTEC-2 Trial. AB - PURPOSE: To evaluate the long-term health-related quality of life (HRQL) after external beam radiation therapy (EBRT) or vaginal brachytherapy (VBT) among PORTEC-2 trial patients, evaluate long-term bowel and bladder symptoms, and assess the impact of cancer on these endometrial cancer (EC) survivors. PATIENTS AND METHODS: In the PORTEC-2 trial, 427 patients with stage I high-intermediate risk EC were randomly allocated to EBRT or VBT. The 7- and 10-year HRQL questionnaires consisted of EORTC QLQ-C30; subscales for bowel and bladder symptoms; the Impact of Cancer Questionnaire; and 14 questions on comorbidities, walking aids, and incontinence pads. Analysis was done using linear mixed models for subscales and (ordinal) logistic regression with random effects for single items. A two-sided P value <.01 was considered statistically significant. RESULTS: Longitudinal HRQL analysis showed persisting higher rates of bowel symptoms with EBRT, without significant differences in global health or any of the functioning scales. At 7 years, clinically relevant fecal leakage was reported by 10.6% in the EBRT group, versus 1.8% for VBT (P=.03), diarrhea by 8.4% versus 0.9% (P=.04), limitations due to bowel symptoms by 10.5% versus 1.8% (P=.001), and bowel urgency by 23.3% versus 6.6% (P<.001). Urinary urgency was reported by 39.3% of EBRT patients, 25.5% for VBT, P=.05. No difference in sexual activity was seen between treatment arms. Long-term impact of cancer scores was higher among the patients who had an EC recurrence or second cancer. CONCLUSIONS: More than 7 years after treatment, EBRT patients reported more bowel symptoms with impact on daily activities, and a trend for more urinary symptoms, without impact on overall quality of life or difference in cancer survivorship issues. PMID- 26530749 TI - Health-Related Quality of Life in SCALOP, a Randomized Phase 2 Trial Comparing Chemoradiation Therapy Regimens in Locally Advanced Pancreatic Cancer. AB - PURPOSE: Chemoradiation therapy (CRT) for patients with locally advanced pancreatic cancer (LAPC) provides survival benefits but may result in considerable toxicity. Health-related quality of life (HRQL) measurements during CRT have not been widely reported. This paper reports HRQL data from the Selective Chemoradiation in Advanced Localised Pancreatic Cancer (SCALOP) trial, including validation of the QLQ-PAN26 tool in CRT. METHODS AND MATERIALS: Patients with locally advanced, inoperable, nonmetastatic carcinoma of the pancreas were eligible. Following 12 weeks of induction gemcitabine plus capecitabine (GEMCAP) chemotherapy, patients with stable and responding disease were randomized to a further cycle of GEMCAP followed by capecitabine- or gemcitabine-based CRT. HRQL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EORTC Pancreatic Cancer module (PAN26). RESULTS: A total of 114 patients from 28 UK centers were registered and 74 patients randomized. There was improvement in the majority of HRQL scales during induction chemotherapy. Patients with significant deterioration in fatigue, appetite loss, and gastrointestinal symptoms during CRT recovered within 3 weeks following CRT. Differences in changes in HRQL scores between trial arms rarely reached statistical significance; however, where they did, they favored capecitabine therapy. PAN26 scales had good internal consistency and were able to distinguish between subgroups of patients experiencing toxicity. CONCLUSIONS: Although there is deterioration in HRQL following CRT, this resolves within 3 weeks. HRQL data support the use of capecitabine- over gemcitabine-based chemoradiation. The QLQ PAN26 is a reliable and valid tool for use in patients receiving CRT. PMID- 26530750 TI - Prognostic Relevance of HPV Infection and p16 Overexpression in Squamous Cell Anal Cancer. AB - PURPOSE: Human papillomavirus (HPV) DNA and p16 status have both been reported as prognostic factors in anal cancer, but the prognostic relevance of combined detection and particularly HPV-/p16+ and HPV+/p16- signatures is unknown. We evaluated combined HPV DNA and p16 status as a prognostic factor of treatment response in anal cancer. METHODS: 106 patients treated with radiochemotherapy (RCT+5-FU/MMC) with available paraffin-embedded tumor tissue specimens were evaluated regarding local control (LC) and overall survival (OS) at 5 years. In addition to HPV DNA/p16 status, the influence of age, gender, previous surgery, initial recurrence, T stage, N status, and tumor localization was analyzed. RESULTS: 63 patients were HPV+/p16+, 9 were HPV+/p16-, 11 were HPV-/p16+, and 23 were HPV-/p16-. In univariate analysis, LC was significantly better in patients with T1/2 stage, female gender, and HPV/p16 status. HPV+/p16+ was associated with significantly better LC (88.1%; 95% confidence interval [CI]: 78.89-97.31) compared with HPV-/p16+ (63.6%; 95% CI: 35.18-92.02; P=.021) and especially HPV /p16- (55.8%; 95% CI: 33.46-78.14; P=.002) but not with HPV+/p16- (77.8%; 95% CI: 50.56-105.04; P=.270). OS was influenced by T stage and LC. HPV+/p16+ patients showed a trend toward better OS compared with HPV-/p16- patients (HPV+/p16+: 81.1%; 95% CI: 70.12-92.08 vs HPV-/p16-: 68.8%; 95%CI: 47.44-90.16; P=.138). On multivariate analysis, T3/4 stage and HPV/p16 status (HPV-/p16+, HPV-/p16- vs HPV+/p16+) predicted poorer LC (T3/4: 50.3% vs T1/2: 86.6%, hazard ratio [HR] 0.22; 95% CI: 0.09-0.53; P<.001; HPV+/p16+ vs HPV-/p16+: HR 4.73; 95% CI: 1.33 16.82; P=.016, and HPV+/p16+ vs HPV-/p16-: HR 6.40; 95% CI: 2.23-18.35; P<.001), whereas local relapse dramatically influenced OS. CONCLUSION: Our data suggest that HPV/p16 signature determines prognosis. HPV+/p16+ patients had the best prognosis, and HPV-/p16+ and HPV-/p16- patients showed the worst outcome and therefore require therapy optimization, particularly given that LC is the most important factor for OS. PMID- 26530751 TI - Definition and Validation of "Favorable High-Risk Prostate Cancer": Implications for Personalizing Treatment of Radiation-Managed Patients. AB - PURPOSE: To define and validate a classification of favorable high-risk prostate cancer that could be used to personalize therapy, given that consensus guidelines recommend similar treatments for all radiation-managed patients with high-risk disease. METHODS AND MATERIALS: We studied 3618 patients with cT1-T3aN0M0 high risk or unfavorable intermediate-risk prostate adenocarcinoma treated with radiation at a single institution between 1997 and 2013. Favorable high-risk was defined as T1c disease with either Gleason 4 + 4 = 8 and prostate-specific antigen <10 ng/mL or Gleason 6 and prostate-specific antigen >20 ng/mL. Competing risks regression was used to determine differences in the risk of prostate cancer specific mortality (PCSM) after controlling for baseline factors and treatment. Our results were validated in a cohort of 13,275 patients using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. RESULTS: Patients with favorable high-risk disease had significantly better PCSM than other men with high-risk disease (adjusted hazard ratio [AHR] 0.42, 95% confidence interval [CI] 0.18-0.996, P=.049) and similar PCSM as men with unfavorable intermediate risk disease (AHR 1.17, 95% CI 0.50-2.75, P=.710). We observed very similar results within the SEER-Medicare cohort (favorable high-risk vs other high-risk: AHR 0.21, 95% CI 0.11-0.41, P<.001; favorable high-risk vs unfavorable intermediate-risk: AHR 0.67, 95% CI 0.33-1.36, P=.268). CONCLUSIONS: Patients with favorable high-risk prostate cancer have significantly better PCSM than other patients with high-risk disease and similar PCSM as those with unfavorable intermediate-risk disease, who are typically treated with shorter-course androgen deprivation therapy. This new classification system may allow for personalization of treatment within high-risk disease, such as consideration of shorter-course androgen deprivation therapy for favorable high-risk disease. PMID- 26530752 TI - Cardiac Function After Multimodal Breast Cancer Therapy Assessed With Functional Magnetic Resonance Imaging and Echocardiography Imaging. AB - PURPOSE: Breast intensity modulated radiation therapy (IMRT) reduces high-dose heart volumes but increases low-dose volumes. We prospectively assessed heart changes after 3D conformal RT (3DCRT) and IMRT for left-sided breast cancer. Heart dose was analyzed individually, 3DCRT patients were moderately exposed, and IMRT was performed only in patients with unacceptably high heart doses upon 3DCRT planning. METHODS AND MATERIALS: In 49 patients (38 patients received 3DCRT; 11 patients received IMRT; and 20 patients received neoadjuvant or adjuvant chemotherapy) magnetic resonance imaging (MRI) and echocardiography were performed before and at 6, 12, and 24 months after treatment. RESULTS: Mean heart dose for IMRT was 12.9 +/- 3.9 Gy versus 4.5 +/- 2.4 Gy for 3DCRT. Heart volumes receiving >40 Gy were 2.6% (3DCRT) versus 1.3% (IMRT); doses were >50 Gy only with 3DCRT. Temporary ejection fraction (EF) decrease was observed on MRI after 6 months (63%-59%, P=.005) resolving at 24 months. Only 3 patients had pronounced largely transient changes of EF and left ventricular enddiastolic diameter (LVEDD). Mitral (M) and tricuspid (T) annular plane systolic excursion (MAPSE and TAPSE) were reduced over the whole cohort (still within normal range). After 24 months left ventricular remodeling index decreased in patients receiving chemotherapy (0.80 vs 0.70, P=.028). Neither wall motion abnormalities nor late enhancements were found. On echocardiography, in addition to EF findings that were similar to those on MRI, global strain was unchanged over the whole cohort at 24 months after a transient decrease at 6 and 12 months. Longitudinal strain decreased in the whole cohort after 24 months in some segments, whereas it increased in others. CONCLUSIONS: Until 24 months after risk-adapted modern multimodal adjuvant therapy, only subclinical cardiac changes were observed in both 3DCRT patients with inclusion of small to moderate amounts of heart volume in RT tangents and in the patients treated with IMRT and reduced high-dose heart exposure. PMID- 26530753 TI - Exposure of the Heart in Breast Cancer Radiation Therapy: A Systematic Review of Heart Doses Published During 2003 to 2013. AB - PURPOSE: Breast cancer radiation therapy cures many women, but where the heart is exposed, it can cause heart disease. We report a systematic review of heart doses from breast cancer radiation therapy that were published during 2003 to 2013. METHODS AND MATERIALS: Eligible studies were those reporting whole-heart dose (ie, dose averaged over the whole heart). Analyses considered the arithmetic mean of the whole-heart doses for the CT plans for each regimen in each study. We termed this "mean heart dose." RESULTS: In left-sided breast cancer, mean heart dose averaged over all 398 regimens reported in 149 studies from 28 countries was 5.4 Gy (range, <0.1-28.6 Gy). In regimens that did not include the internal mammary chain (IMC), average mean heart dose was 4.2 Gy and varied with the target tissues irradiated. The lowest average mean heart doses were from tangential radiation therapy with either breathing control (1.3 Gy; range, 0.4 2.5 Gy) or treatment in the lateral decubitus position (1.2 Gy; range, 0.8-1.7 Gy), or from proton radiation therapy (0.5 Gy; range, 0.1-0.8 Gy). For intensity modulated radiation therapy mean heart dose was 5.6 Gy (range, <0.1-23.0 Gy). Where the IMC was irradiated, average mean heart dose was around 8 Gy and varied little according to which other targets were irradiated. Proton radiation therapy delivered the lowest average mean heart dose (2.6 Gy, range, 1.0-6.0 Gy), and tangential radiation therapy with a separate IMC field the highest (9.2 Gy, range, 1.9-21.0 Gy). In right-sided breast cancer, the average mean heart dose was 3.3 Gy based on 45 regimens in 23 studies. CONCLUSIONS: Recent estimates of typical heart doses from left breast cancer radiation therapy vary widely between studies, even for apparently similar regimens. Maneuvers to reduce heart dose in left tangential radiation therapy were successful. Proton radiation therapy delivered the lowest doses. Inclusion of the IMC doubled typical heart dose. PMID- 26530754 TI - Clinical Pathways: A Catalyst for the Adoption of Hypofractionation for Early Stage Breast Cancer. AB - PURPOSE: Hypofractionated whole-breast irradiation (HF-WBI) remains underutilized in the United States despite support by multiple clinical trials. We evaluated the success of iterative modifications of our breast cancer clinical pathway on the adoption of HF-WBI in a large, integrated radiation oncology network. METHODS AND MATERIALS: The breast clinical pathway was modified in January 2011 (Amendment 1) to recommend HF-WBI as the first option for women >=70 of age with stages 0 to IIA, while maintaining conventional fractionation (CF) as a pathway concordant secondary option. In January 2013 (Amendment 2), the pathway's HF-WBI recommendation was extended to women >=50 years of age. In January 2014 (Amendment 3), the pathway mandated HF-WBI as the only pathway-concordant option in women >=50 years of age, and all pathway-discordant plans were subject to peer review and justification. Women >=50 years of age with ductal carcinoma in situ or invasive breast cancer who underwent breast conserving surgery and adjuvant WBI were included in this analysis. RESULTS: We identified 5112 patients from 2009 to 2014 who met inclusion criteria. From 2009 to 2012, the overall HF-WBI use rate was 8.3%. Following Amendments 2 and 3 (2013 and 2014, respectively), HF WBI use significantly increased to 21.8% (17.3% in the community, 39.7% at academic sites) and 76.7% (75.5% in the community, 81.4% at academic sites), respectively (P<.001). Compared to 2009 to 2012, the relative risk of using HF WBI was 7.9 (95% confidence interval: 7.1-8.6, P<.001) and 10.7 (95% CI: 10.3 11.0, P<.001), respectively, after Amendments 2 and 3, respectively. Age >=70 and treatment at an academic site increased the likelihood of receiving HF-WBI in 2009 to 2012 and following Amendment 2 (P<.001). CONCLUSIONS: This study demonstrates the transformative effect of a clinical pathway on patterns of care for breast radiation therapy. Although our initial HF-WBI use rate was low (8% 22%) and consistent with national rates, the clinical pathway approach dramatically increased adoption rate to >75%. In contrast to passive guidelines, clinical pathways serve as active tools to promote current best practices. PMID- 26530755 TI - The Prognostic Value of Plasma Epstein-Barr Viral DNA and Tumor Response to Neoadjuvant Chemotherapy in Advanced-Stage Nasopharyngeal Carcinoma. AB - PURPOSE: To explore the prognostic value of the plasma load of Epstein-Barr viral (EBV) DNA and the tumor response to neoadjuvant chemotherapy (NACT) in advanced stage nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: In all, 185 consecutive patients with stage III to IVb NPC treated with NACT followed by concurrent chemoradiation therapy (CCRT) were prospectively enrolled. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS). RESULTS: EBV DNA was detected in 165 (89%) patients before treatment but was undetectable in 127 (69%) patients after NACT. Detectable EBV DNA levels after NACT were correlated with poor prognosis (3-year PFS 71.8% vs 85.2%, P=.008 and 3-year DMFS 82.5% vs 92.3%, P=.013). An unsatisfactory tumor response (stable disease or disease progression) after NACT was also correlated with poor clinical outcome (3-year PFS 71.1% vs 85.9%, P=.005 and 3-year LRFS 82.7% vs 93.5%, P=.012). Multivariate analysis showed that the EBV DNA level after NACT (hazard ratio [HR] 2.31, 95% CI 1.18-4.54, P=.015) and the tumor response to NACT (HR 2.84, 95% CI 1.42-5.67, P=.003) were both significant prognostic factors for PFS. Multivariate analysis also showed that EBV DNA after NACT was the only significant predictor of DMFS (HR 2.99, 95% CI 1.25-7.15, P=.014) and that tumor response to NACT was the only significant predictor of LRFS (HR 3.31, 95% CI 1.21-9.07, P=.020). CONCLUSION: Detectable EBV DNA levels and an unsatisfactory tumor response (stable disease or disease progression) after NACT serve as predictors of poor prognosis for patients with advanced-stage NPC. These findings will facilitate further risk stratification, early treatment modification, or both before CCRT. PMID- 26530756 TI - Leukoencephalopathy After Stereotactic Radiosurgery for Brain Metastases. AB - PURPOSE: Although the use of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases has increased dramatically during the past decade to avoid the neurocognitive dysfunction induced by whole brain radiation therapy (WBRT), the cumulative neurocognitive effect of numerous SRS sessions remains unknown. Because leukoencephalopathy is a sensitive marker for radiation-induced central nervous system damage, we studied the clinical and dosimetric predictors of SRS-induced leukoencephalopathy. METHODS AND MATERIALS: Patients treated at our institution with at least 2 sessions of SRS for brain metastases from 2007 to 2013 were reviewed. The pre- and post-SRS magnetic resonance imaging sequences were reviewed and graded for white matter changes associated with radiation leukoencephalopathy using a previously validated scale. Patient characteristics and SRS dosimetric parameters were reviewed for factors that contributed to leukoencephalopathy using Cox proportional hazards modeling. RESULTS: A total of 103 patients meeting the inclusion criteria were identified. The overall incidence of leukoencephalopathy was 29% at year 1, 38% at year 2, and 53% at year 3. Three factors were associated with radiation-induced leukoencephalopathy: (1) the use of WBRT (P=.019); (2) a higher SRS integral dose to the cranium (P=.036); and (3) the total number of intracranial metastases (P=.003). CONCLUSIONS: Our results have established that WBRT plus SRS produces leukoencephalopathy at a much higher rate than SRS alone. In addition, for patients who did not undergo WBRT before SRS, the integral dose was associated with the development of leukoencephalopathy. As the survival of patients with central nervous system metastases increases and as the neurotoxicity of chemotherapeutic and targeted agents becomes established, these 3 potential risk factors will be important to consider. PMID- 26530757 TI - Tumor Response After Stereotactic Body Radiation Therapy to Nonspine Bone Metastases: An Evaluation of Response Criteria. AB - PURPOSE: To evaluate the applicability of the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and University of Texas MD Anderson (MDA) Cancer Center criteria in the setting of stereotactic body radiation therapy (SBRT) to nonspine bone metastases. METHODS: Patients who were treated with SBRT to nonspine bone metastases were identified by retrospective chart review. An independent musculoskeletal radiologist evaluated response to treatment using computed tomography (CT) scans. RESULTS: Thirty-three patients were treated to 42 nonspine bone metastases. The most common primary cancer cites were renal cell carcinoma (RCC) (33.3%), lung (24.2%), and prostate (18.2%). Bone metastases were either mainly lytic (57.1%), mainly sclerotic (28.6%), or mixed (14.3%). When lytic and sclerotic lesions were evaluated according to RECIST 1.1, local control (LC) was 83%, 85%, 88%, and 80% for those with CT imaging between months 1 to 3, 4 to 6, 7 to 9, and 10 to 12, respectively. When evaluated by the MDA criteria by density, LC within each time period was slightly greater. Overall LC decreased considerably when evaluated by MDA in terms of size. CONCLUSIONS: Consensus definitions of response are required as they have implications on clinical trials and disease management. Without consistent response criteria, outcomes from clinical trials cannot be compared and treatment efficacy remains undetermined. PMID- 26530758 TI - White and Gray Matter Abnormalities After Cranial Radiation in Children and Mice. AB - PURPOSE: Pediatric patients treated with cranial radiation are at high risk of developing lasting cognitive impairments. We sought to identify anatomical changes in both gray matter (GM) and white matter (WM) in radiation-treated patients and in mice, in which the effect of radiation can be isolated from other factors, the time course of anatomical change can be established, and the effect of treatment age can be more fully characterized. Anatomical results were compared between species. METHODS AND MATERIALS: Patients were imaged with T1 weighted magnetic resonance imaging (MRI) after radiation treatment. Nineteen radiation-treated patients were divided into groups of 7 years of age and younger (7-) and 8 years and older (8+) and were compared to 41 controls. C57BL6 mice were treated with radiation (n=52) or sham treated (n=52) between postnatal days 16 and 36 and then assessed with in vivo and/or ex vivo MRI. In both cases, measurements of WM and GM volume, cortical thickness, area and volume, and hippocampal volume were compared between groups. RESULTS: WM volume was significantly decreased following treatment in 7- and 8+ treatment groups. GM volume was unchanged overall, but cortical thickness was slightly increased in the 7- group. Results in mice mostly mirrored these changes and provided a time course of change, showing early volume loss and normal growth. Hippocampal volume showed a decreasing trend with age in patients, an effect not observed in the mouse hippocampus but present in the olfactory bulb. CONCLUSIONS: Changes in mice treated with cranial radiation are similar to those in humans, including significant WM and GM alterations. Because mice did not receive any other treatment, the similarity across species supports the expectation that radiation is causative and suggests mice provide a representative model for studying impaired brain development after cranial radiation and testing novel treatments. PMID- 26530760 TI - How Important Is a Reproducible Breath Hold for Deep Inspiration Breath Hold Breast Radiation Therapy? AB - PURPOSE: Deep inspiration breath hold (DIBH) for left-sided breast cancer has been shown to reduce heart dose. Surface imaging helps to ensure accurate breast positioning, but it does not guarantee a reproducible breath hold (BH) at DIBH treatments. We examine the effects of variable BH positions for DIBH treatments. METHODS AND MATERIALS: Twenty-five patients who underwent free breathing (FB) and DIBH scans were reviewed. Four plans were created for each patient: FB, DIBH, FB_DIBH (the DIBH plans were copied to the FB images and recalculated, and image registration was based on breast tissue), and P_DIBH (a partial BH with the heart shifted midway between the FB and DIBH positions). The FB_DIBH plans give a "worst-case" scenario for surface imaging DIBH, where the breast is aligned by surface imaging but the patient is not holding their breath. Kolmogorov-Smirnov tests were used to compare the dose metrics. RESULTS: The DIBH plans gave lower heart dose and comparable breast coverage versus FB in all cases. The FB_DIBH plans showed no significant difference versus FB plans for breast coverage, mean heart dose, or maximum heart dose (P>=.10). The mean heart dose differed between FB_DIBH and FB by <2 Gy for all cases, and the maximum heart dose differed by <2 Gy for 21 cases. The P_DIBH plans showed significantly lower mean heart dose than FB (P<.01). The mean heart doses for the P_DIBH plans were 40 miRNAs with roles in cancer regulation were identified. We also identified 17 miRNAs associated with progression, 12 involved with clinical outcome and 7 that improved CC treatment response. The present review is expected to broaden understanding of the functional role and potential clinical uses of miRNAs in CC. PMID- 26530779 TI - Double-twist cylinders in liquid crystalline cholesteric blue phases observed by transmission electron microscopy. AB - Cholesteric blue phases are liquid crystalline phases in which the constituent rod-like molecules spontaneously form three-dimensional, helical structures. Despite theoretical predictions that they are composed of cylindrical substructures within which the liquid crystal molecules are doubly twisted, real space observation of the arrangement of such structures had not been performed. Through transmission electron microscopy of photopolymerized blue phases with controlled lattice plane orientations, we report real space observation and comparison of the lattice structures of blue phases I and II. The two systems show distinctly different contrasts, reflecting the theoretically predicted, body centred and simple cubic arrangement of the double-twist cylinders. Transmission electron microscopy also reveals different tendencies of the two blue phases to align on unidirectionally rubbed surfaces. We thus show that TEM observation of alignment-controlled, photopolymerized liquid crystals can be a powerful tool to investigate complex liquid crystalline order. PMID- 26530780 TI - Adenovirus-mediated p53 and ING4 gene co-transfer elicits synergistic antitumor effects through enhancement of p53 acetylation in breast cancer. AB - Multigene-based combination therapy may be an effective practice in cancer gene therapy. Substantial studies have demonstrated that tumor suppressor p53 acetylation is indispensable for p53 activation. Inhibitor of growth 4 (ING4), as a novel tumor suppressor, is capable of remarkably enhancing p53 acetylation and its transcriptional activity. Hence, we assumed that combined treatment of p53 and ING4 double tumor suppressors would exhibit enhanced antitumor effects. The combined therapeutic efficacy of p53 and ING4 for human cancers has not been previously reported. We thus generated multiple promoter expression cassette based recombinant adenovirus-co-expressing ING4 and p53 double tumor suppressor genes (AdVING4/p53), evaluated the combined effects of AdVING4/p53 on breast cancer using the MDA-MB-231 (mutant p53) human breast cancer cell line, and also elucidated its underlying molecular mechanisms. We demonstrated that AdVING4/p53 mediated p53 and ING4 co-expression induced synergistic growth inhibition and apoptosis as well as enhanced effects on upregulation of acetylated p53, P21, Bax, PUMA, Noxa, cleaved caspase-9, cleaved caspase-3 and cleaved PARP, and downregulation of Bcl-2, CD31 and microvessel density (MVD) in MDA-MB-231 breast cancer in vitro and/or in vivo subcutaneous (s.c.) xenografted tumors. The synergistic antitumor activity elicited by AdVING4/p53 was closely associated with the enhanced activation of the intrinsic apoptotic pathway and synergistic inhibition of tumor angiogenesis, very possibly via ING4-mediated enhancement of p53 acetylation and activity. Thus, our results indicate that cancer gene therapy combining two or more tumor suppressors such as p53 and ING4 may constitute a novel and effective therapeutic modality for human breast cancer and other cancers. PMID- 26530781 TI - Experiences of African-American Women with Smartphone-Based Ecological Momentary Assessment. AB - OBJECTIVE: Smartphone-based ecological momentary assessment (EMA), or real-time, repeated sampling of participants' states, behaviors, or experiences over time, is a promising approach to understanding obesity-related behaviors in African American women-a population with the highest obesity prevalence. In this study, we explored participants' experiences with this methodology. DESIGN AND SAMPLE: In this secondary analysis of data, 100 African-American women participated in seven consecutive days of EMA data collection. MEASURES: Measures related to acceptability (technical challenges, daily burden, emotional responses, willingness to participate in future studies) and data quality (reporting accuracy, behavior reactivity, adherence), as well as demographics, were collected. RESULTS: While there were few demographic differences, women who were unemployed, had the lowest educational levels, or had the lowest per capita income reported the greatest enjoyment with mobile technology-based EMA, while at the same time reporting the highest levels of challenge with use of the equipment. Participants consistently indicated willingness to participate in future EMA studies and indicated that the study method was acceptable. EMA methodology produced data of sufficient quality. CONCLUSION: Findings suggest future studies using smartphone-based EMA with African-American women are feasible. PMID- 26530782 TI - Single-drop microextraction combined in-line with capillary electrophoresis for the determination of nonsteroidal anti-inflammatory drugs in urine samples. AB - This study describes a method to determine nonsteroidal anti-inflammatory drugs (NSAIDs) in urine samples based on the use of single-drop microextraction (SDME) in a three-phase design as a preconcentration technique coupled in-line to capillary electrophoresis. Different parameters affecting the extraction efficiency of the SDME process were evaluated (e.g. type of extractant, volume of the microdroplet, and extraction time). The developed method was successfully applied to the analysis of human urine samples with LODs ranging between 1.0 and 2.5 MUg/mL for all of the NSAIDs under study. This method shows RSD values ranging from 8.5 to 15.3% in interday analysis. The enrichment factors were calculated, resulting 27-fold for ketoprofen, 14-fold for diclofenac, 12-fold for ibuprofen, and 44-fold naproxen. Samples were analyzed applying the SDME-CE method and the obtained results presented satisfactory recovery values (82-115%). The overall method can be considered a promising approach for the analysis of NSAIDs in urine samples after minimal sample pretreatment. PMID- 26530783 TI - Mechanical preparation of nanocrystalline biocompatible single-phase Mn-doped A type carbonated hydroxyapatite (A-cHAp): effect of Mn doping on microstructure. AB - Nanocrystalline biocompatible single-phase Mn-doped A-type carbonated hydroxyapatite (A-cHAp) powder has been synthesized by mechanical alloying of a stoichiometric mixture of CaCO3, CaHPO4.2H2O and MnO powder for 10 h at room temperature under open air. The A-type carbonation in HAp (substitution of CO3(2 ) for OH(-)) is confirmed by FTIR analysis. Microstructure characterization in terms of lattice imperfections and phase quantification of ball milled samples are made by analyzing XRD patterns employing the Rietveld structure refinement method. Rietveld analysis of XRD patterns recorded from Mn-doped HAp samples has been used to locate Mn(2+) cations in HAp. The Ca2 vacancy site is found to be more favorable for Mn substitution. Microstructure characterization by HRTEM corroborates the findings of the X-ray analysis where the presence of a significant amount of amorphous phase of HAp analogous to indigenous bone mineral is clearly found. MTT assay shows sufficiently high percentage cell viability confirming the cytocompatibility of the sample. PMID- 26530784 TI - Rhizobium acidisoli sp. nov., isolated from root nodules of Phaseolus vulgaris in acid soils. AB - Two Gram-negative, aerobic, non-motile, rod-shaped bacterial strains, FH13T and FH23, representing a novel group of Rhizobium isolated from root nodules of Phaseolus vulgaris in Mexico, were studied by a polyphasic analysis. Phylogeny of 16S rRNA gene sequences revealed them to be members of the genus Rhizobium related most closely to 'Rhizobium anhuiense' CCBAU 23252 (99.7 % similarity), Rhizobium leguminosarum USDA 2370T (98.6 %), and Rhizobium sophorae CCBAU 03386T and others ( <= 98.3 %). In sequence analyses of the housekeeping genes recA, glnII and atpD, both strains formed a subclade distinct from all defined species of the genus Rhizobium at sequence similarities of 82.3-94.0 %, demonstrating that they represented a novel genomic species in the genus Rhizobium. Mean levels of DNA-DNA relatedness between the reference strain FH13T and the type strains of related species varied between 13.0 +/- 2.0 and 52.1 +/- 1.2 %. The DNA G+C content of strain FH13T was 63.5 mol% (Tm). The major cellular fatty acids were 16 : 0, 17 : 0 anteiso, 18 : 0, summed feature 2 (12 : 0 aldehyde/unknown 10.928) and summed feature 8 (18 : 1omega7c). The fatty acid 17 : 1omega5c was unique for this strain. Some phenotypic features, such as failure to utilize adonitol, l arabinose, d-fructose and d-fucose, and ability to utilize d-galacturonic acid and itaconic acid as carbon source, could also be used to distinguish strain FH13T from the type strains of related species. Based upon these results, a novel species, Rhizobium acidisoli sp. nov., is proposed, with FH13T ( = CCBAU 101094T = HAMBI 3626T = LMG 28672T) as the type strain. PMID- 26530785 TI - tDRmapper: challenges and solutions to mapping, naming, and quantifying tRNA derived RNAs from human small RNA-sequencing data. AB - BACKGROUND: Small RNA-sequencing has revealed the diversity and high abundance of small RNAs derived from tRNAs, referred to as tRNA-derived RNAs. However, at present, there is no standardized nomenclature and there are no methods for accurate annotation and quantification of these small RNAs. tRNA-derived RNAs have unique features that limit the utility of conventional alignment tools and quantification methods. RESULTS: We describe here the challenges of mapping, naming, and quantifying tRNA-derived RNAs and present a novel method that addresses them, called tDRmapper. We then use tDRmapper to perform a comparative analysis of tRNA-derived RNA profiles across different human cell types and diseases. We found that (1) tRNA-derived RNA profiles can differ dramatically across different cell types and disease states, (2) that positions and types of chemical modifications of tRNA-derived RNAs vary by cell type and disease, and (3) that entirely different tRNA-derived RNA species can be produced from the same parental tRNA depending on the cell type. CONCLUSION: tDRmappernot only provides a standardized nomenclature and quantification scheme, but also includes graphical visualization that facilitates the discovery of novel tRNA and tRNA derived RNA biology. PMID- 26530786 TI - A Study of Overheating of Thermostatically Controlled TiO2 Thin Films by Using Raman Spectroscopy. AB - In this study a classic Raman spectroscopy method is applied and the intensity ratio of Stokes and anti-Stokes peaks is used to measure the temperature of thermostatically controlled TiO2 thin films. In addition, three mathematical formulae are used and analyzed to estimate the temperature of the TiO2 thin films. Overheating of the samples above the thermostatically controlled temperature was observed while recording the Raman spectra, with a temperature increase of up to 30 K being detected. DFT-periodic calculations showed that the anatase (101) surface had a smaller band gap than bulk anatase. Thus, it can absorb the laser radiation with a wavelength of 532 nm that is used in the experimental setup. Part of the absorbed photon energy transfers into phonon energy, heating up the anatase phase, thus leading to the heating of the samples. Moreover, overheating of the samples indicates that the experimental method used in this study can lead to deviations in their real absolute temperature values. PMID- 26530787 TI - Graphene wrinkling induced by monodisperse nanoparticles: facile control and quantification. AB - Controlled wrinkling of single-layer graphene (1-LG) at nanometer scale was achieved by introducing monodisperse nanoparticles (NPs), with size comparable to the strain coherence length, underneath the 1-LG. Typical fingerprint of the delaminated fraction is identified as substantial contribution to the principal Raman modes of the 1-LG (G and G'). Correlation analysis of the Raman shift of the G and G' modes clearly resolved the 1-LG in contact and delaminated from the substrate, respectively. Intensity of Raman features of the delaminated 1-LG increases linearly with the amount of the wrinkles, as determined by advanced processing of atomic force microscopy data. Our study thus offers universal approach for both fine tuning and facile quantification of the graphene topography up to ~60% of wrinkling. PMID- 26530788 TI - Broadly tunable graphene plasmons using an ion-gel top gate with low control voltage. AB - The electrostatic tunability of graphene is vital in the field of active plasmons and would be beneficial in tunable infrared and terahertz optical element applications. The key to realizing broad tunability is achieving high carrier densities in graphene. Here we use an ion-gel, currently one of the most efficient dielectrics with ultra-high capacitance, to realize broadly tunable graphene plasmons (~1270 cm(-1)) with low voltage modulation (~4 V shifted from the Dirac point). We further explore the coupling between graphene plasmons and the molecular vibration modes of the ion-gel, since strong plasmon-phonon coupling can split the plasmon resonance peak into multi-peaks and reduce their tunability. Our experiments demonstrate weak plasmon-phonon coupling in the graphene/ion-gel system, which has limited effects on plasmon properties. These properties make ion-gels an effective dielectric for broadly tunable graphene plasmonic devices, such as new optical modulators, filters and wavelength multiplexers. PMID- 26530789 TI - Special announcement: Guidelines to the Practice of Anesthesia - Revised Edition 2016. PMID- 26530790 TI - Superchiral Pd3 L6 Coordination Complex and Its Reversible Structural Conversion into Pd3 L3 Cl6 Metallocycles. AB - Large, non-symmetrical, inherently chiral bispyridyl ligand L derived from natural ursodeoxycholic bile acid was used for square-planar coordination of tetravalent Pd(II) , yielding the cationic single enantiomer of superchiral coordination complex 1 Pd3 L6 containing 60 well-defined chiral centers in its flower-like structure. Complex 1 can readily be transformed by addition of chloride into a smaller enantiomerically pure cyclic trimer 2 Pd3 L3 Cl6 containing 30 chiral centers. This transformation is reversible and can be restored by the addition of silver cations. Furthermore, a mixture of two constitutional isomers of trimer, 2 and 2', and dimer, 3 and 3', can be obtained directly from L by its coordination to trans- or cis-N-pyridyl-coordinating Pd(II) . These intriguing, water-resistant, stable supramolecular assemblies have been thoroughly described by (1) H DOSY NMR, mass spectrometry, circular dichroism, molecular modelling, and drift tube ion-mobility mass spectrometry. PMID- 26530791 TI - HLA-G as an Inhibitor of Immune Responses. AB - HLA-G is a nonclassical human leukocyte antigen (HLA) class I molecule which plays important tolerogenic functions in various physiological and pathological situations such as fetus and transplant acceptance, and immune escaping of virus infected and malignant cells. Here we describe a method, which allows for studying cell surface expression of HLA-G using specific antibodies with flow cytometry analysis. PMID- 26530792 TI - New Molecular and Cellular Mechanisms of Tolerance: Tolerogenic Actions of IL-2. AB - Interleukin-2 (IL-2) is an old molecule with brand new functions. Indeed, IL-2 has been first described as a T-cell growth factor but recent data pointed out that its main function in vivo is the maintenance of immune tolerance. Mechanistically, IL-2 is essential for the development and function of CD4(+) Foxp3(+) regulatory T cells (Treg cells) that are essential players in the control of immune responded to self, tumors, microbes and grafts. Treg cells are exquisitely sensitive to IL-2 due to their constitutive expression of the high affinity IL-2 receptor (IL-2R) and the new paradigm suggests that low-doses of IL 2 could selectively boost Treg cells in vivo. Consequently, a growing body of clinical research is aiming at using IL-2 at low doses as a tolerogenic drug to boost endogenous Treg cells in patients suffering from autoimmune or inflammatory conditions. In this manuscript, we briefly review IL-2/IL-2R biology and the role of IL-2 in the development, maintenance, and function of Treg cells; and also its effects on other immune cell populations such as CD4(+) T helper cells and CD8(+) memory T cells. Then, focusing on type 1 diabetes, we review the preclinical studies and clinical trials supporting the use of low-doses IL-2 as a tolerogenic immunotherapy. Finally, we discuss the limitations and future directions for IL-2 based immunotherapy. PMID- 26530793 TI - Expansion of Regulatory T Cells In Vitro and In Vivo by IL-33. AB - Thymic-derived, regulatory T cells (Treg) represent a subset of CD4(+) T cells that are required for normal immune homeostasis and suppression of unwanted responses against self-antigens (Ags) that prevent autoimmunity. Their role as immune regulators and potent ability to suppress T cell responses has been the focus of intense investigations aimed at utilizing these cells therapeutically, particularly in the settings of autoimmunity and transplantation. Many methods for expanding Treg have been described; however, efforts to generate large numbers of Treg for use in vivo often compromise their suppressor function or rely on the induction of Treg rather than their expansion. Our recent studies have focused on the barrier tissue-derived cytokine IL-33, a recently described IL-1 family member. IL-33 has emerged as a multifunctional protein, with reported roles in driving potent Type 1 and Type 2 immunity, as well as facilitating profound Treg expansion in vitro and in vivo. IL-33-expanded Treg express the IL 33 receptor (R) ST2, and express classical markers associated with Treg phenotype and suppressor function. They suppress both CD4(+) and CD8(+) T cell proliferation and effector functions in vitro, and Treg expressing ST2 have been identified as important regulators of detrimental immune responses in vivo. In the present chapter, we detail methods for expanding significant numbers of Treg using IL-33 both in vitro and in vivo that may potentially be used to promote/maintain organ transplant tolerance or suppress autoimmunity. PMID- 26530795 TI - Characterization and Immunoregulatory Properties of Innate Pro-B-Cell Progenitors. AB - Control of T-cell responses can be achieved by several subsets of B cells with immunoregulatory functions, mostly acting by provision of the anti-inflammatory cytokine IL-10 or exhibiting killing properties through Fas ligand (Fas-L) or granzyme B-induced cell death. We herein describe the characterization as well as the cellular and molecular mechanisms mediating the suppressive properties of bone marrow immature innate pro-B cell progenitors that emerge upon transient activation of Toll-like receptor 9. They are licensed by activated T-cell-derived IFN-gamma to become suppressive by up-regulating their Fas-L expression and inducing effector CD4(+) T-cell apoptosis. They also up-regulate their own IFN gamma production which dramatically reduces T-cell production of a major pathogenic cytokine, IL-21. A single adoptive transfer of as little as 60,000 of them efficiently prevents the onset of spontaneous type 1 diabetes in recipient nonobese diabetes (NOD) mice, highlighting the remarkable regulatory potency of these so-called CpG-proB cell progenitors compared to regulatory cells of diverse lineages so far described. The CpG-proB cell activity is prolonged in vivo by their differentiation after migration in the pancreas and the spleen into B-cell progeny with high Fas-L expression that can keep up inducing apoptosis of effector T cells in the long term. PMID- 26530796 TI - Generation and Characterization of Mouse Regulatory Macrophages. AB - In the last years, cell therapy has become a promising approach to therapeutically manipulate immune responses in autoimmunity, cancer, and transplantation. Several types of lymphoid and myeloid cells origin have been generated in vitro and tested in animal models. Their efficacy to decrease pharmacological treatment has successfully been established. Macrophages play an important role in physiological and pathological processes. They represent an interesting cell population due to their high plasticity in vivo and in vitro. Here, we describe a protocol to differentiate murine regulatory macrophages in vitro from bone marrow precursors. We also describe several methods to assess macrophage classical functions, as their bacterial killing capacity and antigen endocytosis and degradation. Importantly, regulatory macrophages also display suppressive characteristics, which are addressed by the study of their hypostimulatory T lymphocyte capacity and polyclonal T lymphocyte activation suppression. PMID- 26530794 TI - Standardization, Evaluation, and Area-Under-Curve Analysis of Human and Murine Treg Suppressive Function. AB - FOXP3+ T-regulatory (Treg) cells have important roles in immune homeostasis, and alterations in their number and function can predispose to diseases ranging from autoimmunity to allograft rejection and tumor growth. Reliable identification of human Tregs remains a persistent problem due to a lack of specific markers. The most definitive Treg characterization currently involves combined assessment of phenotypic, epigenetic and functional parameters, with the latter typically involving in vitro Treg suppression assays. Unfortunately, suppression assays are frequently performed using differing methods and readouts, limiting comparisons between studies. We provide a perspective on our experience with human and murine Treg suppression assay conditions, including Treg data obtained in clinical transplant studies, Tregs isolated from healthy donors and treated with epigenetically active compounds, and Tregs from standard murine strains (C57BL/6 and BALB/c). We provide detailed descriptions and illustrations of typical problems, shortcomings and troubleshooting; describe new modifications and approaches; and present a new method for calculation of suppressive assay data using a modified area-under-curve (AUC) method. This method allows us to directly compare Treg suppressive function between multiple patients (such as in clinical transplant studies), to reliably track changes in Treg function from the same person over time, or compare effects of Treg-modulating compounds tested with different healthy donors Tregs in separate or combined experimental settings. PMID- 26530797 TI - Generation and Expansion of T Helper 17 Lymphocytes Ex Vivo. AB - CD4(+) T helper (Th) lymphocytes are essential elements of the complex cellular networks regulating the initiation, development, and termination of adaptive immune responses. Different independent and specialized subsets of Th cells can be distinguished based on their dedicated transcription factor and cytokine expression profiles. Th17 lymphocytes have been described about a decade ago as CD4(+) Th cells producing high quantity of IL-17A as a signature cytokine. Since their initial discovery, Th17 have drawn intense scrutiny for their dominant role in the pathogenesis of multiple autoimmune, infectious diseases and allergy. The influence of Th17 lymphocytes in cancer remains however ambiguous. The plethoric functions of Th17 may rely on the remarkable plasticity of these cells, endowed with the ability to trans-differentiate into other Th subpopulations depending on the environmental cytokine context. The possibility to generate Th17 ex vivo has facilitated the elucidation of the signals and transcription factors required for their differentiation and functions and has allowed for the evaluation of their functions following adoptive transfer in vivo. Several protocols have been developed to produce Th17 in vitro. The intent of this chapter is to provide examples of procedures for generating and expanding Th17 ex vivo. PMID- 26530798 TI - Autoimmune Diabetes: An Overview of Experimental Models and Novel Therapeutics. AB - Type 1 diabetes (T1D) results from a chronic and selective destruction of insulin secreting beta-cells within the islets of Langerhans of the pancreas by autoreactive CD4(+) and CD8(+) T lymphocytes. The use of animal models of T1D was instrumental for deciphering the steps of the autoimmune process leading to T1D. The non-obese diabetic (NOD) mouse and the bio-breeding (BB) rat spontaneously develop the disease similar to the human pathology in terms of the immune responses triggering autoimmune diabetes and of the genetic and environmental factors influencing disease susceptibility. The generation of genetically modified models allowed refining our understanding of the etiology and the pathogenesis of the disease. In the present review, we provide an overview of the experimental models generated and used to gain knowledge on the molecular and cellular mechanisms underlying the breakdown of self-tolerance in T1D and the progression of the autoimmune response. Immunotherapeutic interventions designed in these animal models and translated into the clinical arena in T1D patients will also be discussed. PMID- 26530799 TI - Recent Advances in the Treatment of Immune-Mediated Inflammatory Diseases. AB - The treatment of immune-mediated inflammatory diseases (IMIDs) has dramatically improved over the last two decades by the development of a series of targeted biological therapies. This paper focuses on new developments in the treatment of IMIDs. In particular, we discuss how different ways of targeting the same mediators can lead to different efficacy and safety profiles, using B cell targeting as example. In addition, we discuss the emerging field of 'small molecules' that target specifically intracellular processes related to cytokine signaling, cell activation, cell migration, and other processes relevant to tissue inflammation. PMID- 26530800 TI - Application of Humanized Mice in Immunological Research. AB - During the past decade, the development of humanized mouse models and their general applications in biomedical research greatly accelerated the translation of outcomes obtained from basic research into potential diagnostic and therapeutic strategies in clinic. In this chapter, we firstly present an overview on the history and current progress of diverse humanized mouse models and then focus on those equipped with reconstituted human immune system. The update advancement in the establishment of humanized immune system mice and their applications in the studies of the development of human immune system and the pathogenesis of multiple human immune-related diseases are intensively reviewed here, while the shortcoming and perspective of these potent tools are discussed as well. As a valuable bridge across the gap between bench work and clinical trial, progressive humanized mouse models will undoubtedly continue to play an indispensable role in the wide area of biomedical research. PMID- 26530801 TI - Humanized Mice as Preclinical Models in Transplantation. AB - Animal models have been instrumental in our understanding of the mechanisms of rejection and the testing of novel treatment options in the context of transplantation. We have now entered an exciting era with research on humanized mice driving advances in translational studies and in our understanding of the function of human cells in response to pathogens and cancer as well as the recognition of human allogeneic tissues in vivo. In this chapter we provide a historical overview of humanized mouse models of transplantation to date, outlining the distinct strains and share our experiences in the study of human transplantation immunology. PMID- 26530802 TI - Dextran Sulfate Sodium (DSS)-Induced Acute Colitis in the Rat. AB - Inflammatory bowel diseases (IBDs) are complex multifactorial disease thought to result from inappropriate immune responses to the gut microbiota, in genetically susceptible individuals, under the influence of environmental factors. Among the different animal models developed to help in understanding IBDs pathophysiological mechanisms as well as to achieve pharmacological preclinical studies, the dextran sulfate sodium (DSS)-induced colitis model is the most widely used because of its simplicity, cost-effectiveness, and similarity with human IBDs. This section provides with a detailed protocol that we validated in our laboratory to perform DSS-induced acute colitis in the Sprague-Dawley (SPD) rat. PMID- 26530803 TI - Corneal Immunosuppressive Mechanisms, Anterior Chamber-Associated Immune Deviation (ACAID) and Their Role in Allograft Rejection. AB - Corneal transplantation is the most frequently performed transplant procedure in humans. Human leukocyte antigen matching, while imperative for other types of organ transplants, is usually not performed before cornea transplantation. With the use of topical steroid immunosuppressants, which are subsequently tailed off to almost zero, most corneal transplants will not be rejected in recipients with low risk of graft rejection. This phenomenon has been described as immune privilege by Medawar many years ago. However, this immune privilege is relative and can be easily eroded, e.g. by postoperative nonspecific inflammation or other causes of corneal or ocular inflammation. Interestingly, corneas that are at high risk of rejection have a higher failure rate than other organs. Considerable progress has been made in recent years to provide a better understanding of corneal immune privilege. This chapter will review current knowledge on ocular immunosuppressive mechanisms including anterior chamber-associated immune deviation and discuss their role(s) in corneal allograft rejection. Ultimately, this evolving information will be of benefit in developing therapeutic strategies to prevent corneal transplant rejection. PMID- 26530804 TI - Food Allergies: Novel Mechanisms and Therapeutic Perspectives. AB - Childhood food allergy (FA) rates have rapidly increased with significant direct medical costs for the health care system and even larger costs for the families with a food-allergic child. The possible causes of food allergy become the target of intense scrutiny in recent years. Increasing evidence underline the importance in early life of gut microbiome in the development of allergic diseases. There are a range of factors in the modern environment that may be associated with changes to both the gut microbiome and risk of FA, such as mode of delivery, antibiotic exposure, infant feeding practices, farming environment, and country of origin. Knowledge of the relationship between early life gut microbiome and allergic diseases may facilitate development of novel preventive and treatment strategies. Based on our current knowledge, there are no currently available approved therapies for food allergy. More studies are needed to evaluate the safety and efficacy of allergen-specific and allergen-nonspecific approaches, as well as combination approaches. PMID- 26530805 TI - Standardized Multi-Color Flow Cytometry and Computational Biomarker Discovery. AB - Multi-color flow cytometry has become a valuable and highly informative tool for diagnosis and therapeutic monitoring of patients with immune deficiencies or inflammatory disorders. However, the method complexity and error-prone conventional manual data analysis often result in a high variability between different analysts and research laboratories. Here, we provide strategies and guidelines aiming at a more standardized multi-color flow cytometric staining and unsupervised data analysis for whole blood patient samples. PMID- 26530806 TI - The Aryl Hydrocarbon Receptor in Immunity: Tools and Potential. AB - The signaling pathway of the evolutionary old transcription factor AhR is inducible by a number of small molecular weight chemicals, including toxicants such as polycyclic aromatic hydrocarbons, bacterial toxic pigments, and physiological compounds such as tryptophan derivatives or dietary indoles. AhR activation is of immunological importance, but at the same time mediates toxicity of environmental pollutants, such as immunosuppression by dioxins. Measuring AhR activity and identification of ligands is thus of great interest for a variety of research fields. In this chapter, I briefly introduce the AhR signaling pathway, its role in immunology, and the tools and assays needed to analyze AhR signaling. Both are also needed when therapeutic applications are envisioned. PMID- 26530807 TI - In vitro cytotoxicity and in vivo efficacy of 5-fluorouracil-loaded enteric coated PEG-cross-linked chitosan microspheres in colorectal cancer therapy in rats. AB - PURPOSE: Microspheres of chitosan (CS) cross-linked with polyethylene glycol (PEG) were prepared by emulsion-cross-linking followed by the solvent evaporation technique. The formulations were characterized and subjected to in vitro and in vivo tests to assess cell growth, changes in cell morphology, and activities by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on human HT-29 colon cancer cell-lines. METHODS: In vivo activity was evaluated for dimethyl hydrazine-induced colorectal cancer in albino male Wistar rats. Biochemical and histological parameters were evaluated to understand their effectiveness for colon cancer therapy. RESULTS: The 5-FU immediate release (IR) formulations suspended in SCMC produced an immediate cytotoxic effect, whereas microspheres inhibited proliferation of tumor cells to induce apoptosis over an extended time. Minimum inhibitory concentration (IC50) values for both standard plain 5-FU and 5-FU-loaded microspheres were respectively 5.00 +/- 0.004 ug/mL and 165 +/- 1.9 ug/mL which showed the improved safety profile of the microsphere formulation. Tissue distribution showed high concentration of 5-FU in colon that was higher than IC50 value required to stop the growth or death of colon cancer cells from the colonic dysplasia in Duke's stage A. Significant reduction in tumor volume and multiplicity was observed with increased levels of liver enzymes in animals when treated with standard 5-FU formulation compared with 5-FU loaded microspheres. Elevated levels of serum albumin, creatinine, leukocytopenia, and thrombocytopenia were observed in animals for the standard 5-FU formulation. CONCLUSION: The PEG cross-linked CS microspheres of this study slowly released 5 FU up to 24 h to colonic region and enhanced the antitumor activity. PMID- 26530808 TI - Engineered T cell therapies. AB - Alongside advancements in gene therapy for inherited immune disorders, the need for effective alternative therapeutic options for other conditions has resulted in an expansion in the field of research for T cell gene therapy. T cells are easily obtained and can be induced to divide robustly ex vivo, a characteristic that allows them to be highly permissible to viral vector-mediated introduction of transgenes. Pioneering clinical trials targeting cancers and infectious diseases have provided safety and feasibility data and important information about persistence of engineered cells in vivo. Here, we review clinical experiences with gamma-retroviral and lentiviral vectors and consider the potential of integrating transposon-based vectors as well as specific genome editing with designer nucleases in engineered T cell therapies. PMID- 26530809 TI - Alkaline Ammonia Electrolysis on Electrodeposited Platinum for Controllable Hydrogen Production. AB - Ammonia is beginning to attract a great deal of attention as an alternative energy source carrier, because clean hydrogen can be produced through electrolytic processes without the emission of COx . In this study, we deposited various shapes of Pt catalysts under potentiostatic mode; the electrocatalytic oxidation behavior of ammonia using these catalysts was studied in alkaline media. The electrodeposited Pt was characterized by both qualitative and quantitative analysis. To discover the optimal structure and the effect of ammonia concentration, the bulk pH value, reaction temperature, and applied current of ammonia oxidation were investigated using potential sweep and galvanostatic methods. Finally, ammonia electrolysis was conducted using a zero gap cell, producing highly pure hydrogen with an energy efficiency over 80 %. PMID- 26530810 TI - Adverse psychosocial work factors, blood pressure and hypertension incidence: repeated exposure in a 5-year prospective cohort study. AB - BACKGROUND: Two main theoretical models have been used to assess the impact of psychosocial work factors on blood pressure (BP): the demand-control (DC) model and the effort-reward imbalance (ERI) model. Previous studies have mostly used a single time point exposure to examine this association. OBJECTIVE: To examine the effect of repeated job strain and ERI exposure on (1) ambulatory BP (ABP) evolution over 5 years and (2) hypertension incidence over 5 years. METHOD: The design is a prospective cohort study. The study population was composed of 1394 white-collar workers (568 men and 826 women). They were assessed three times during a 5-year period (years 1, 3 and 5). At each time, psychosocial work factors were measured using validated scales and ABP was measured every 15 min during a working day. RESULTS: Men who were chronically exposed over 5 years to an active job had a higher cumulative incidence of hypertension (RR=2.05, 95% CI 1.36 to 3.09), compared with never-exposed men. In women, ERI exposure onset was associated with higher increases in systolic ABP (+2.5 mm Hg). No association was found between chronic high-strain exposure and ABP. CONCLUSIONS: Chronic exposure to active jobs in men led to a higher risk of hypertension and ERI exposure onset in women led to increases in systolic ABP. Results from the present study highlight the need to consider chronic exposure in order to fully capture the deleterious effect of adverse psychosocial work stressors on cardiovascular health. PMID- 26530811 TI - Sleep duration and health among older adults: associations vary by how sleep is measured. AB - BACKGROUND: Cohort studies have found that short and long sleep are both associated with worse outcomes, compared with intermediate sleep times. While demonstrated biological mechanisms could explain health effects for short sleep, long-sleep risk is puzzling. Most studies reporting the U shape use a single question about sleep duration, a measurement method that does not correlate highly with objectively measured sleep. We hypothesised that the U shape, especially the poor outcomes for long sleepers, may be an artefact of how sleep is measured. METHODS: We examined the cross-sectional prevalence of fair/poor health by sleep hour categories (<= 6, <= 7, <= 8, <= 9, > 9 h) in a national US sample of adults aged 62-90 that included several types of sleep measures (n = 727). Survey measures were: a single question; usual bedtimes and waking times; and a 3-day sleep log. Actigraphy measures were the sleep interval and total sleep time. Fair/poor health was regressed on sleep hour categories adjusted for demographics, with tests for both linear trend and U shape. RESULTS: Adjusted OR of fair/poor health across sleep hour categories from the single question were 4.6, 2.2, referent (8 h), 1.8 and 6.9. There was high prevalence of fair/poor health for <= 6 h for all sleep measures, but the long-sleep effect was absent for sleep logs and actigraphy measures. CONCLUSIONS: Associations between long sleep and poor health may be specific to studies measuring sleep with survey questions. As cohorts with actigraphy mature, our understanding of how sleep affects health may change. PMID- 26530812 TI - IL-8 suppresses E-cadherin expression in nasopharyngeal carcinoma cells by enhancing E-cadherin promoter DNA methylation. AB - Nasopharyngeal carcinoma (NPC) has the highest metastasis potential among head and neck cancers. Distant metastasis is the major cause of treatment failure. Recent studies from our laboratory have revealed that IL-8 promotes NPC metastasis via activation of AKT signaling and induction of epithelial mesenchymal transition (EMT) in the cells. In the present study, we found that IL 8 treatment for NPC cells resulted in an accumulation of DNMT1 protein through activating AKT1 pathway and consequent DNMT1 protein stabilization. Then DNMT1 suppressed E-cadherin expression by increasing the methylation of its promoter region. LY-294002 blocked IL-8-induced p-AKT1 activation resulting in reduction of DNMT1 and increase of E-cadherin expression, whereas forced demethylation using 5-aza-2'-deoxycytidine restored E-cadherin expression. In conclusion, our study, for the first time, shows that the IL-8/AKT1 signaling pathway stabilizes DNMT1 protein, consequently enhancing hypermethylation of E-cadherin promoter regions and downregulating E-cadherin protein level in NPC cells. Upon blockage of the IL-8/AKT pathway and inhibition of DNMT1, E-cadherin expression can be reversed. These data suggest that targeting the IL-8/AKT1 signaling pathway and DNMT1 may provide a potential therapeutic approach for blocking NPC metastasis. PMID- 26530813 TI - The arterial tumor enhancement pattern on contrast-enhanced computed tomography is associated with primary cancer death after radiofrequency ablation for small hepatocellular carcinoma. AB - BACKGROUND/PURPOSE: Critical recurrences after radiofrequency ablation for hepatocellular carcinoma (HCC), such as intrahepatic metastases or dissemination, and extrahepatic metastases or seeding, which are difficult to treat radically, almost certainly lead to primary cancer death. The present study aimed to clarify whether the arterial tumor enhancement pattern on contrast-enhanced computed tomography (CECT) is associated with critical recurrence and cancer death after RFA for small HCC. METHODS: Between April 2001 and September 2011, 226 patients with initial small hypervascular HCC (<=3 cm in diameter and <=3 tumors) were treated by RFA. Arterial tumor enhancement patterns on CECT before RFA were categorized by whether non-enhanced areas were included inside the tumor stain. RESULTS: The heterogeneous enhancement group included 44 patients, and the homogeneous enhancement group included 182 patients. The cumulative 5-year critical recurrence rates of the heterogeneous and homogeneous enhancement groups were 42 and 22% (p = 0.005), respectively. Univariate analysis for factors related to critical recurrence showed significant differences in sex, arterial enhancement pattern, and response to antiviral therapy. These factors were independent on multivariate analysis. The cumulative 5-year primary cancer death rates of the heterogeneous and homogeneous enhancement groups were 29 and 13% (p = 0.002), respectively. Univariate analysis for factors related to primary cancer death showed significant differences in arterial enhancement pattern and response to antiviral therapy. These factors were independent on multivariate analysis. CONCLUSIONS: Arterial heterogeneous tumor enhancement on CECT is associated with critical recurrence and cancer death after RFA for small HCC. PMID- 26530814 TI - Re-examining the role of Drosophila Sas-4 in centrosome assembly using two-colour 3D-SIM FRAP. AB - Centrosomes have many important functions and comprise a 'mother' and 'daughter' centriole surrounded by pericentriolar material (PCM). The mother centriole recruits and organises the PCM and templates the formation of the daughter centriole. It has been reported that several important Drosophila PCM-organising proteins are recruited to centrioles from the cytosol as part of large cytoplasmic 'S-CAP' complexes that contain the centriole protein Sas-4. In a previous paper (Conduit et al., 2014b) we showed that one of these proteins, Cnn, and another key PCM-organising protein, Spd-2, are recruited around the mother centriole before spreading outwards to form a scaffold that supports mitotic PCM assembly; the recruitment of Cnn and Spd-2 is dependent on another S-CAP protein, Asl. We show here, however, that Cnn, Spd-2 and Asl are not recruited to the mother centriole as part of a complex with Sas-4. Thus, PCM recruitment in fly embryos does not appear to require cytosolic S-CAP complexes. PMID- 26530816 TI - Privation, stress, and human sex ratio at birth. AB - This article reviews the growing interdisciplinary literature on the effect of privation and stress on human sex ratio at birth. Borrowing strength from the potential outcomes causal analysis framework, the discussion focuses on the issues of study design and identification strategy and how they have influenced the current state of the field. The review suggests that much of the inconsistency in the literature regarding the effect of privation and stress on human sex ratio at birth is due to the weak designs and over-simplistic identification strategies used in previous studies. Studies based on natural experimental designs and well-thought-out identification strategies, on the other hand, have produced rather compelling and consistent evidence suggesting that maternal privation and stress during pregnancy reduce male births. PMID- 26530815 TI - Restoration of Opa1-long isoform inhibits retinal injury-induced neurodegeneration. AB - Optic atrophy 1 (Opa1) is a critical factor that regulates fusion and other important functions of mitochondria. In mitochondrion, the N-terminal mitochondrial targeting sequence of Opa1 precursors is removed to generate Opa1 long isoforms (L-Opa1), which are further cleaved into short isoforms (S-Opa1). In the present study, we found that retinal ischemia-reperfusion (I/R) injury and intravitreal injection of carbonylcyanide m-chlorophenyl hydrazone (CCCP) both dramatically induced Opa1 cleavage and caused loss of L-Opa1. In cultured neuronal cells under hypoxia-reoxygenation (H/R) injury, similar changes for Opa1 were also observed. In contrast, restoration of L-Opa1 level by overexpression of S1 cleavage site deletion Opa1 splice 1 (Opa1-DeltaS1) not only normalized the H/R-induced mitochondrial morphology changes, but also inhibited the H/R-induced apoptosis, necrosis, and the intracellular ATP loss. Furthermore, recovering L Opa1 level in the I/R-injured retina by intravitreal injection of genipin or overexpression of Opa1-DeltaS1 inhibited apoptosis, necrosis, cell loss in the ganglion cell layer and retinal thickness reduction. Together, our data demonstrated the loss of L-Opa1 is involved in the development of retinal I/R injury, indicating restoring L-Opa1 level may be considered as a therapeutic target for I/R injury-related diseases, at least for the retina. Key messages: Retinal ischemia-reperfusion (I/R) or hypoxia-reoxygenation (H/R) injury induces L-Opa1 loss. Opa1-DeltaS1 overexpression inhibits H/R-induced L-Opa1 loss. Opa1 DeltaS1 overexpression inhibits H/R-induced mitochondria morphology change. Opa1 DeltaS1 and genipin inhibit retinal I/R injury-induced necroptosis. Opa1-DeltaS1 and genipin inhibit retinal I/R injury-induced neurodegeneration. PMID- 26530817 TI - Electrical Double Layer Capacitance in a Graphene-embedded Al2O3 Gate Dielectric. AB - Graphene heterostructures are of considerable interest as a new class of electronic devices with exceptional performance in a broad range of applications has been realized. Here, we propose a graphene-embedded Al2O3 gate dielectric with a relatively high dielectric constant of 15.5, which is about 2 times that of Al2O3, having a low leakage current with insertion of tri-layer graphene. In this system, the enhanced capacitance of the hybrid structure can be understood by the formation of a space charge layer at the graphene/Al2O3 interface. The electrical properties of the interface can be further explained by the electrical double layer (EDL) model dominated by the diffuse layer. PMID- 26530818 TI - Does primary biliary cirrhosis cluster in time? AB - The aetiology of primary biliary cirrhosis (PBC) is not well established. Previously we found evidence of space-time clustering and seasonal variation in the date of diagnosis, suggesting a possible role for a transient or seasonally varying environmental factor. We examined whether a temporally varying environmental agent may be involved by analysing population-based PBC data from northeast England over 1987-2003. Using an adaptation of a method proposed by Potthoff and Whittinghill, we found significant temporal variation by date of diagnosis at the level of aggregation of one year. However, there was no evidence for general irregular (non-seasonal) temporal clustering within periods less than a year. These results provide little support for the involvement of agents occurring in geographically widespread mini-epidemics, but--taken together with studies of spatial and spatio-temporal clustering--do not preclude the role of more localised sporadic mini-epidemics. Future research should seek to elicit putative environmental agents. PMID- 26530819 TI - Accounting for spatial effects in land use regression for urban air pollution modeling. AB - In order to accurately assess air pollution risks, health studies require spatially resolved pollution concentrations. Land-use regression (LUR) models estimate ambient concentrations at a fine spatial scale. However, spatial effects such as spatial non-stationarity and spatial autocorrelation can reduce the accuracy of LUR estimates by increasing regression errors and uncertainty; and statistical methods for resolving these effects--e.g., spatially autoregressive (SAR) and geographically weighted regression (GWR) models--may be difficult to apply simultaneously. We used an alternate approach to address spatial non stationarity and spatial autocorrelation in LUR models for nitrogen dioxide. Traditional models were re-specified to include a variable capturing wind speed and direction, and re-fit as GWR models. Mean R(2) values for the resulting GWR wind models (summer: 0.86, winter: 0.73) showed a 10-20% improvement over traditional LUR models. GWR-wind models effectively addressed both spatial effects and produced meaningful predictive models. These results suggest a useful method for improving spatially explicit models. PMID- 26530820 TI - Using lung cancer mortality to indirectly approximate smoking patterns in space. AB - Smoking is the leading cause of lung cancer. Non-smoking factors have been associated with the disease. Existing Swiss survey data only capture the country partially and temporal coverage does not allow for a time lag between exposure to tobacco and lung cancer outbreak. Knowledge about the distribution of tobacco-use is essential to estimate its contribution to disease burden. Bayesian regression models were applied to estimate spatial smoking patterns. Data were provided from the Swiss Health Survey (14521 participants). Regression models with spatial random effects (SREs) were employed to obtain smoking proxies based on mortality rates and SREs adjusted for environmental exposures. Population attributable fractions were estimated to assess the burden of tobacco-use on lung cancer mortality. Correlation between observed smoking prevalence with smoking proxies was moderate and stronger in females. In the absence of sufficient survey data, smooth unadjusted mortality rates can be used to assess smoking patterns in Switzerland. PMID- 26530821 TI - Space-time airborne disease mapping applied to detect specific behaviour of varicella in Valencia, Spain. AB - Airborne diseases are one of humanity's most feared sicknesses and have regularly caused concern among specialists. Varicella is an airborne disease which usually affects children before the age of 10. Because of its nature, varicella gives rise to interesting spatial, temporal and spatio-temporal patterns. This paper studies spatio-temporal exploratory analysis tools to detect specific behaviour of varicella in the city of Valencia, Spain, from 2008 to 2013. These methods have shown a significant association between the spatial and the temporal component, confirmed by the space-time models applied to the data. High relative risk of varicella is observed in economically disadvantaged regions, areas less involved in vaccination programmes. PMID- 26530822 TI - Comparing INLA and OpenBUGS for hierarchical Poisson modeling in disease mapping. AB - The recently developed R package INLA (Integrated Nested Laplace Approximation) is becoming a more widely used package for Bayesian inference. The INLA software has been promoted as a fast alternative to MCMC for disease mapping applications. Here, we compare the INLA package to the MCMC approach by way of the BRugs package in R, which calls OpenBUGS. We focus on the Poisson data model commonly used for disease mapping. Ultimately, INLA is a computationally efficient way of implementing Bayesian methods and returns nearly identical estimates for fixed parameters in comparison to OpenBUGS, but falls short in recovering the true estimates for the random effects, their precisions, and model goodness of fit measures under the default settings. We assumed default settings for ground truth parameters, and through altering these default settings in our simulation study, we were able to recover estimates comparable to those produced in OpenBUGS under the same assumptions. PMID- 26530823 TI - Comparing children's GPS tracks with geospatial proxies for exposure to junk food. AB - Various geospatial techniques have been employed to estimate children's exposure to environmental cardiometabolic risk factors, including junk food. But many studies uncritically rely on exposure proxies which differ greatly from actual exposure. Misrepresentation of exposure by researchers could lead to poor decisions and ineffective policymaking. This study conducts a GIS-based analysis of GPS tracks--'activity spaces'--and 21 proxies for activity spaces (e.g. buffers, container approaches) for a sample of 526 children (ages 9-14) in London, Ontario, Canada. These measures are combined with a validated food environment database (including fast food and convenience stores) to create a series of junk food exposure estimates and quantify the errors resulting from use of different proxy methods. Results indicate that exposure proxies consistently underestimate exposure to junk foods by as much as 68%. This underestimation is important to policy development because children are exposed to more junk food than estimated using typical methods. PMID- 26530824 TI - An integrated Bayesian model for estimating the long-term health effects of air pollution by fusing modelled and measured pollution data: A case study of nitrogen dioxide concentrations in Scotland. AB - The long-term health effects of air pollution can be estimated using a spatio temporal ecological study, where the disease data are counts of hospital admissions from populations in small areal units at yearly intervals. Spatially representative pollution concentrations for each areal unit are typically estimated by applying Kriging to data from a sparse monitoring network, or by computing averages over grid level concentrations from an atmospheric dispersion model. We propose a novel fusion model for estimating spatially aggregated pollution concentrations using both the modelled and monitored data, and relate these concentrations to respiratory disease in a new study in Scotland between 2007 and 2011. PMID- 26530825 TI - Improved R2* liver iron concentration assessment using a novel fuzzy c-mean clustering scheme. AB - BACKGROUND: In thalassemia patients, R2* liver iron concentration (LIC) measurement is a common clinical tool for assessing iron overload and for determining necessary chelator dose and evaluating its efficacy. Despite the importance of accurate LIC measurement, existing methods suffer from LIC variability, especially at the severe iron overload range due to inclusion of vessel parts in LIC calculation. In this study, we build upon previous Fuzzy C Mean (FCM) clustering work to formulate a scheme with superior performance in segmenting vessel pixels from the parenchyma. Our method (MIX-FCM) combines our novel 2D-FCM with the existing 1D-FCM algorithm. This study further assessed possible optimal clustering parameters (OP scheme) and proposed a semi-automatic (SA) scheme for routine clinical application. METHODS: Segmentation of liver parenchyma and vessels was performed on T2* images and their LIC maps in 196 studies from 147 thalassemia major patients. We used manual segmentation as the reference. 1D-FCM clustering was performed on the acquired image alone and 2D-FCM used both the acquired image and its LIC data. To execute the MIX-FCM method, the best outcome (OP-MIX-FCM) was selected from the aforementioned methods and was compared to the SA-MIX-FCM scheme. We used the percent value of the normalized interquartile range (nIQR) to its median to evaluate the variability of all methods. RESULTS: 2D-FCM clustering is more effective than 1D-FCM clustering at the severe overload range only, but inferior for other ranges (where 1D-FCM provides suitable results). This complementary performance between the two methods allows MIX-FCM to improve results for all ranges. OP-MIX-FCM clustering error was 2.1 +/- 2.3%, compared with 10.3 +/- 9.9% and 7.0 +/- 11.9% from 1D- and 2D-FCM clustering, respectively. SA-MIX-FCM result was comparable to OP-MIX FCM result, with both schemes showing ability to decrease overall nIQR by approximately 30%. CONCLUSION: Our proposed 2D-FCM algorithm is not as superior to 1D-FCM as hypothesized. In contrast, our MIX-FCM method benefits from the best of both methods to obtain the highest segmentation accuracy at all ranges. Moreover, segmentation accuracy of the practical scheme (SA-MIX-FCM) is comparable to segmentation accuracy of the reference scheme (OP-MIX-FCM). Finally, we confirmed that segmentation is crucial to improving LIC assessments, especially at the severe iron overload range. PMID- 26530826 TI - Sixty seconds on . . . malaria vaccination. PMID- 26530827 TI - Language, terminology and the readability of online cancer information. AB - Medical terms are a recognised problem in doctor-patient consultations. By contrast, the language difficulties of online healthcare documents are underestimated, even though patients are often encouraged to go to the internet for information. Literacy levels in the community vary, and for patients, carers and health workers with limited reading skills (including first- and second language users of English), the language of web-based health documents may be challenging or impenetrable. Online delivery of health information is inherently problematic because it cannot provide two-way discussion; and amid the range of health documents on the web, the intended readership (whether general or specialist) is rarely indicated up front. In this research study, we focus on the language and readability of web-based cancer documents, using lexicostatistical methods to profile the vocabularies in two large test databases of breast cancer information, one consisting of material designed for health professionals, the other for the general public. They yielded significantly different word frequency rankings and keyness values, broadly correlating with their different readerships, that is, scientifically literate readers for the professional dataset, and non-specialist readers for the public dataset. The higher type/token ratio in the professional dataset confirms its greater lexical demands, with no concessions to the variable language and literacy skills among second-language health workers. Their language needs can, however, be addressed by a new online multilingual termbank of breast cancer vocabulary, HealthTermFinder, designed to sit alongside health documents on the internet, and provide postconsultation help for patients and carers at their point of need. PMID- 26530828 TI - Expression of calcium-activated chloride channels Ano1 and Ano2 in mouse taste cells. AB - Specialized Ca(2+)-dependent ion channels ubiquitously couple intracellular Ca(2+) signals to a change in cell polarization. The existing physiological evidence suggests that Ca(2+)-activated Cl(-) channels (CaCCs) are functional in taste cells. Because Ano1 and Ano2 encode channel proteins that form CaCCs in a variety of cells, we analyzed their expression in mouse taste cells. Transcripts for Ano1 and Ano2 were detected in circumvallate (CV) papillae, and their expression in taste cells was confirmed using immunohistochemistry. When dialyzed with CsCl, taste cells of the type III exhibited no ion currents dependent on cytosolic Ca(2+). Large Ca(2+)-gated currents mediated by TRPM5 were elicited in type II cells by Ca(2+) uncaging. When TRPM5 was inhibited by triphenylphosphine oxide (TPPO), ionomycin stimulated a small but resolvable inward current that was eliminated by anion channel blockers, including T16Ainh-A01 (T16), a specific Ano1 antagonist. This suggests that CaCCs, including Ano1-like channels, are functional in type II cells. In type I cells, CaCCs were prominently active, blockable with the CaCC antagonist CaCCinh-A01 but insensitive to T16. By profiling Ano1 and Ano2 expressions in individual taste cells, we revealed Ano1 transcripts in type II cells only, while Ano2 transcripts were detected in both type I and type II cells. P2Y agonists stimulated Ca(2+)-gated Cl(-) currents in type I cells. Thus, CaCCs, possibly formed by Ano2, serve as effectors downstream of P2Y receptors in type I cells. While the role for TRPM5 in taste transduction is well established, the physiological significance of expression of CaCCs in type II cells remains to be elucidated. PMID- 26530830 TI - Context and the human microbiome. AB - Human microbiome reference datasets provide epidemiological context for researchers, enabling them to uncover new insights into their own data through meta-analyses. In addition, large and comprehensive reference sets offer a means to develop or test hypotheses and can pave the way for addressing practical study design considerations such as sample size decisions. We discuss the importance of reference sets in human microbiome research, limitations of existing resources, technical challenges to employing reference sets, examples of their usage, and contributions of the American Gut Project to the development of a comprehensive reference set. Through engaging the general public, the American Gut Project aims to address many of the issues present in existing reference resources, characterizing health and disease, lifestyle, and dietary choices of the participants while extending its efforts globally through international collaborations. PMID- 26530829 TI - Mechanisms underlying spontaneous constrictions of postcapillary venules in the rat stomach. AB - Postcapillary venules (PCVs) play a critical role in regulating capillary hydrostatic pressure, but their contractile mechanisms are not well understood. We examined the properties of spontaneous vasomotion and corresponding Ca(2+) transients in gastric PCV. In the rat gastric submucosa, changes in PCV diameter and intracellular Ca(2+) dynamics were visualised by video tracking system and fluorescent Ca(2+) imaging, respectively, while PCV morphology was examined by immunohistochemistry. Stellate-shaped PCV mural cells expressing alpha-smooth muscle actin exhibited synchronised spontaneous Ca(2+) transients to develop vasomotion which was abolished by nifedipine (1 MUM), cyclopiazonic acid (10 MUM), or Ca(2+)-activated Cl(-) channel inhibitors (100 MUM niflumic acid, 1 MUM T16Ainh-A01). A gap junction blocker (3 MUM carbenoxolone) disrupted the synchrony of spontaneous Ca(2+) transients amongst PCV mural cells and attenuated spontaneous vasomotion. Low chloride solution ([Cl(-)]0 = 12.4 mM) also disrupted the synchrony of spontaneous Ca(2+) transients and abolished vasomotion. Na(+) K(+)-Cl(-) co-transporter inhibitors (10 MUM bumetanide, 30 MUM furosemide) suppressed spontaneous Ca(2+) transients and vasoconstrictions. A phosphodiesterase type 5 (PDE5) inhibitor (1 MUM tadalafil) disrupted the spontaneous Ca(2+) transient synchrony and abolished vasomotion in a nitric oxide (NO)-dependent manner. Thus, gastric PCVs exhibit spontaneous vasomotion, resulting from synchronised spontaneous Ca(2+) transients within a network of stellate-shaped PCV mural cells. An active Cl(-) accumulation partly via Na(+) K(+)-Cl(-) co-transport appears to be fundamental in maintaining depolarisation upon the opening of Ca(2+)-activated Cl(-) channels that triggers Ca(2+) influx via voltage-dependent L-type Ca(2+) channels. Basal PDE5 activity may continuously counteract vaso-relaxing effects of endothelial NO to maintain spontaneous vasomotion. PMID- 26530831 TI - One pot oxidative N-S bond formation to access 2-sulfenylimine chromenes. AB - The synthesis of 2-sulfenylimine chromene compounds (8) is accomplished by reacting benzaldehyde (1), malanonitrile (2) and dimedone (3) followed by sequential addition of N-chlorosuccinimide and thiophenols to the in situ formed 2-amino-4(H) chromenes (4) in a one pot, catalyst free, five component reaction in toluene medium. When aniline was employed as the nucleophile in place of thiophenol, the formation of hexahydrobenzofuran-2-N-phenyl carboxamide derivatives (5) was observed. Excellent yields, simple reaction conditions and high compatibility are the advantages of this protocol. PMID- 26530833 TI - Occurrence and characterization of plum pox virus strain D isolates from European Russia and Crimea. AB - Numerous plum pox virus (PPV) strain D isolates have been found in geographically distant regions of European Russia and the Crimean peninsula on different stone fruit hosts. Phylogenetic analysis of their partial and complete genomes suggests multiple introductions of PPV-D into Russia. Distinct natural isolates from Prunus tomentosa were found to bear unique amino acid substitutions in the N terminus of the coat protein (CP) that may contribute to the adaptation of PPV-D to this host. Serological analysis using the PPV-D-specific monoclonal antibody 4DG5 provided further evidence that mutations at positions 58 and 59 of the CP are crucial for antibody binding. PMID- 26530834 TI - New poleroviruses associated with yellowing symptoms in different vegetable crops in Greece. AB - Four poleroviral isolates from Greece, two from lettuce, one from spinach and one from watermelon showing yellowing symptoms, were molecularly characterized by analyzing the sequence of a large part of the genome spanning from the 3' terminal part of the RdRp to the end of the CP gene. The sequences were analyzed for their similarity and phylogenetic relationships to other members of the genus Polerovirus as well as for evidence of recombination events. The results revealed the existence of two putatively new viruses: one from lettuce and one from spinach, provisionally named "lettuce yellows virus" and "spinach yellows virus", respectively. Also, a new recombinant virus infecting lettuce, herein named "lettuce mild yellows virus", and a watermelon isolate of pepo aphid-borne yellows virus (PABYV) were identified. Our study highlights the existence of high genetic diversity within the genus Polerovirus, which could be associated with the emergence of new viral diseases in various crops worldwide. PMID- 26530832 TI - MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro inflammatory cytokine responsiveness and myeloid cell recruitment. AB - Inflammation promotes phenotypic plasticity in melanoma, a source of non-genetic heterogeneity, but the molecular framework is poorly understood. Here we use functional genomic approaches and identify a reciprocal antagonism between the melanocyte lineage transcription factor MITF and c-Jun, which interconnects inflammation-induced dedifferentiation with pro-inflammatory cytokine responsiveness of melanoma cells favouring myeloid cell recruitment. We show that pro-inflammatory cytokines such as TNF-alpha instigate gradual suppression of MITF expression through c-Jun. MITF itself binds to the c-Jun regulatory genomic region and its reduction increases c-Jun expression that in turn amplifies TNF stimulated cytokine expression with further MITF suppression. This feed-forward mechanism turns poor peak-like transcriptional responses to TNF-alpha into progressive and persistent cytokine and chemokine induction. Consistently, inflammatory MITF(low)/c-Jun(high) syngeneic mouse melanomas recruit myeloid immune cells into the tumour microenvironment as recapitulated by their human counterparts. Our study suggests myeloid cell-directed therapies may be useful for MITF(low)/c-Jun(high) melanomas to counteract their growth-promoting and immunosuppressive functions. PMID- 26530835 TI - Continuous chloroprocaine infusion for thoracic and caudal epidurals as a postoperative analgesia modality in neonates, infants, and children. AB - BACKGROUND: Neonates and infants have decreased metabolic capacity for amide local anesthetics and increased risk of local anesthetic toxicity compared to the general population. Chloroprocaine is an ester local anesthetic that has an extremely short plasma half-life in infants as well as adults. Existing reports support the safety and efficacy of continuous chloroprocaine epidural infusions in neonates and young infants during the intraoperative period. Despite this, continuous chloroprocaine epidural infusion may be an under-utilized method of postoperative analgesia for this patient population. In particular, it may improve pain control in neonates and infants with incisions stretching many dermatomes or those with hepatic impairment. METHODS: We retrospectively reviewed our experience over 4 years with continuous chloroprocaine epidural infusions in neonates, infants, and children with a focus on the postoperative management of pain. RESULTS: Twenty-one pediatric patients received continuous 2-chloroprocaine epidural infusions for postoperative pain management from January 2010 to April 2014 for thoracic, abdominal, and limb procedures. The epidural infusion consisted of 1.5% chloroprocaine or 1.5% chloroprocaine with fentanyl. Tabulating the morphine and hydromorphone used for rescue analgesia, the median (interquartile range) opioid consumption (mg.kg(-1) .day(-1) of intravenous morphine equivalents) for the first, second, and third 24-h postoperative periods were 0.02 (0-0.48), 0.30 (0-0.44), and 0.14 (0-0.29), respectively. Examining the total fentanyl usage, the median (interquartile range) fentanyl consumption (MUg.kg(-1) .day(-1)) for first, second, and third 24-h postoperative periods were 3.89 (0.41-7.24), 0 (0.00-4.06), and 0 (0.00-0.51), respectively. The median N-PASS score assessed every 6 h from 0 to 72 h postoperatively was 0, 1, 2, 0, 0, 1, 0, 0, 0, 0, 1, 0, and 0, respectively. The median FLACC score assessed every 6 h from 0 to 72 h postoperatively was 0, 0, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, and 0, respectively. CONCLUSION: The results suggest that chloroprocaine offers an efficacious alternative to the amide local anesthetics for postoperative epidural analgesia in the pediatric population. PMID- 26530836 TI - Unravelling Swedish informal caregivers' Generalised Resistance Resources. AB - BACKGROUND: Interlinked aspects, as demographic changes, accentuation on home based community care, increase the amount of informal caregivers to older adults. To preserve and enhance their health are subsequently essential and a reoccurring topic on political agendas. How this may be achieved is vividly debated and mainly focused on elimination of risks and stresses associated with caregiving. Within health promotion, the salutogenic approach focusing on resources to health is recognised and this approach was used to acquire necessary knowledge to enhance caregivers' health 'the salutogenic way'. AIM: To present Generalised and Specific Resistance Resources (GRRs/SRRs) described by caregivers as stemming from themselves and their carerecipients. METHODOLOGY: To unravel caregivers' GRRs/SRRs, a theory-driven, explorative design guided by definitions of GRRs/SRRs was utilised. Data were collected through salutogenically guided interviews with 32 Swedish caregivers in one municipality. Inductively, data were analysed using content analysis to identify each caregiver's SRRs and thereafter deduction to identify the population's GRRs. FINDINGS: The synthesis of findings, caregivinghood, encompasses several domains of GRRs seemingly involved in caregivers' movements towards health. In the caregiver domain, 'Being someone significant in my own eyes' unites the essence of having access to GRRs stemming from oneself and 'Being "blessed" with a co-operative co-worker' that of having access to GRRs stemming from the carerecipient. This may be the core in an orientation to life which creates positive life experiences, since it enables caregivers to find a 'fit' between the possible and desired when resolving challenges. CONCLUSION AND IMPLICATIONS: Health-promoting initiatives should be conducted as partnerships between formal and informal sources due to the versatility of GRRs. It also seems essential to empower both parties so that they may make sense of their situation and use their available GRRs/SRRs in this 'joint venture' of managing. Thereby, their motivation to continue the journey through Caregivinghood may be enhanced. PMID- 26530837 TI - Cost comparison of robotic-assisted laparoscopic hysterectomy versus standard laparoscopic hysterectomy. AB - The aim of the study was to assess if the cost of robotic-assisted total laparoscopic hysterectomy is similar to the cost of standard laparoscopic hysterectomy when performed by surgeons past their initial learning curve. A retrospective chart review of all hysterectomies was performed for benign indications without concomitant major procedures at Orange Coast Memorial Medical Center (OCMMC) and Saddleback Memorial Medical Center between January 1, 2013 and September 30, 2013. Robotic-assisted total laparoscopic hysterectomies (RTLH) and standard laparoscopic hysterectomies (LAVH and TLH) were compared. Data analyzed included only those hysterectomies performed by surgeons past their initial learning curve (minimum of 30 previous robotic cases). The primary outcome was the direct total cost of patient's hospitalization related to hysterectomy. The secondary outcomes were estimated blood loss, surgery time, and days in hospital post-surgery. A multiple linear regression model was applied to evaluate the difference between RTLH and LAVH/TLH in hospital cost, blood loss, and surgery time, while adjusting for hospital, patient's age, body mass index (BMI), whether or not the patient had previous abdominal/pelvic surgery, and uterine weight. The chi (2) test was applied to examine the association between hospital stay and surgery type. There were 93 hysterectomies (5 LAVH, 88 RTLH) performed at OCMMC and 90 hysterectomies (6 LAVH, 17 TLH, 67 RTLH) performed at Saddleback Memorial Medical Center. The hospitalization total cost result showed that, after adjusting for hospital, age, BMI, previous abdominal/pelvic surgery, and uterine weight, RTLH was not significantly more expensive than LAVH/TLH (mean diff. = $283.1, 95 % CI = [-569.6, 1135.9]; p = 0.51) at the 2 study hospitals. However, the cost at OCMMC was significantly higher than Saddleback Memorial Medical Center (mean diff. = $2008.7, 95 % CI = [1380.6, 2636.7]; p < 0.0001); and the cost increased significantly with uterine weight (beta = 3.8, 95 % CI = [2.3, 5.3]; p < 0.0001). Further analysis showed significantly less blood loss (mean diff. = -78.5 ml, 95 % CI = [-116.8, -40.3]; p < 0.0001) and shorter surgery time (mean diff. = -21.9 min., 95 % CI = [-39.6, -4.2]; p = 0.016) for RTLH versus LAVH/TLH. There was no significant association between hospital stay and surgery type (p = 0.43). After adjusting for patient-level covariates, there was no statistically significant cost difference of performing robotically assisted laparoscopic hysterectomy versus standard laparoscopic hysterectomy when performed by surgeons past their initial learning curve at two community hospitals. PMID- 26530838 TI - Simultaneous bilateral robotic-assisted laparoscopic procedures in children. AB - Our main objective is to report the feasibility of performing simultaneous robotic-assisted laparoscopic (RAL) heminephrectomy with contralateral ureteroureterostomy in children with bilateral duplicated systems. Three female children with bilateral congenital renal/ureteral anomalies underwent concurrent RAL simultaneous unilateral partial nephrectomy with ureterectomy and contralateral ureteroureterostomy with redundant ureterectomy using a four/five port approach. Mean age at repair was 32.9 months (range 7-46 months) and mean weight was 13.7 kg (range 10.4-13.6 kg). The RAL heminephroureterectomy and contralateral ureteroureterostomy were performed via a four-port approach (five ports in one patient), and the patients were repositioned and draped when moving to the other side. Mean operative time was 446 min (range 356-503 min). Mean estimated blood loss was 23.3 cc (range 10-50 cc). Postoperative length of stay for two patients was 2 days and 1 day for one patient (mean = 1.7 days). Mean length of follow-up was 18.3 months (range 7-36 months). No significant intraoperative or postoperative complications occurred for any of the three patients. Two children had no hydronephrosis on postoperative imaging in follow up, and one child had a small stable, residual pararenal fluid collection on the side of heminephrectomy. Two patients underwent postoperative ureteral stent removal under general anesthesia. In children with bilateral duplicated urinary tract with ureterocele, ectopic ureter, and/or vesicoureteral reflux, laparoscopic repair with robotic assistance can be accomplished safely in a single operative procedure with a short hospital stay. PMID- 26530839 TI - Robotically assisted laparoscopy benefits surgical performance under stress. AB - While the benefits of robotic surgery for the patient have been relatively well established, little is known about the benefits for the surgeon. This study examined whether the advantages of robotically assisted laparoscopy (improved dexterity, a 3-dimensional view, reduction in tremors, etc.) enable the surgeon to better deal with stressful tasks. Subjective and objective (i.e. cardiovascular) responses to stress were assessed while surgeons performed on either a robotic or conventional laparoscopic system. Thirty-two surgeons were assigned to perform a surgical task on either a robotic system or a laparoscopic system, under three stress conditions. The surgeons completed self-report measures of stress before each condition. Furthermore, the surgeons' cardiovascular responses to stress were recorded prior to each condition. Finally, task performance was recorded throughout each condition. While both groups reported experiencing similar levels of stress, compared to the laparoscopic group, the robotic group displayed a more adaptive cardiovascular response to the stress conditions, reflecting a challenge state (i.e. higher blood flow and lower vascular resistance). Furthermore, despite no differences in completion time, the robotic group performed the tasks more accurately than the laparoscopic group across the stress conditions. These results highlight the benefits of using robotic technology during stressful situations. Specifically, the results show that stressful tasks can be performed more accurately with a robotic platform, and that surgeons' cardiovascular responses to stress are more favourable. Importantly, the 'challenge' cardiovascular response to stress displayed when using the robotic system has been associated with more positive long-term health outcomes in domains where stress is commonly experienced (e.g. lower cardiovascular disease risk). PMID- 26530840 TI - Does previous transurethral prostate surgery affect oncologic and continence outcomes after RARP? AB - We examined the effect of previous transurethral resection of the prostate (TURP) on multiple oncologic and continence outcomes after robotic-assisted radical prostatectomy (RARP). We performed a retrospective cohort study of a total of 2693 patients from 2007 to 2014 who underwent RARP. Patients were stratified into 49 patients who had previous TURP prior to RARP (group 1) and 2644 patients who had no TURP prior to RARP (group 2). We collected operative variables including estimated blood loss, operative time, and positive surgical margin (PSM) rates. Urinary continence, defined as 0 pads per day (PPD), and social continence, defined as 1-PPD, were also assessed. American Urological Association Symptoms Score (AUASS), overall ability to function sexually, and Expanded Prostate Cancer Index Composite (EPIC) questionnaire were evaluated at 3 and 12 months after RARP. Weakness of urinary stream (EPIC #4d) at 12 months imposed a greater problem for group 1 patients with prior TURP compared to group 2 patients without prior TURP (p = 0.012). PSM was not statistically significant between the two groups (p = 0.110). Group 1 patients had a greater PSM rate (30.61 %) as compared to group 2 (20.95 %). PSM locations in group 1 patients showed the most common locations at the posterior and apex. The difference between the two groups for AUASS, overall sexual function, estimated blood loss, operative time, urinary continence, and social continence was not statistically significant. We examined the effect of previous TURP on postoperative RARP continence and oncologic outcomes. This data can be used to counsel those with prior TURP before RARP. PMID- 26530841 TI - Transabdominal robotic repair of a congenital right diaphragmatic hernia containing an intrathoracic kidney: a case report. AB - Bochdalek diaphragmatic hernia is a rare condition and is typically diagnosed prior to adulthood. Furthermore, right-sided defects are also uncommon due to the location of the liver, but can contain colon, omentum, small bowel, or rarely the kidney. Minimally invasive laparoscopic and thoracoscopic diaphragmatic hernia repairs are associated with improved outcomes when compared to open approaches recently, robotic-assisted repairs have been performed in children with no morbidity and minimal complications. We report a case of an 80-year-old female who presented with an enlarging right-sided Bochdalek hernia containing an acquired intrathoracic kidney that was repaired using a robotic-assisted laparoscopic transabdominal approach with mesh placement. In this case, the robotic platform's advantages included excellent visualization of the posterolateral defect and efficient suturing during mesh placement. This approach is a viable option for skilled minimally invasive surgeons; however, further studies are warranted to investigate its utility in the management of diaphragmatic hernia repair. PMID- 26530842 TI - Toward high-speed 3D nonlinear soft tissue deformation simulations using Abaqus software. AB - We aim to achieve a fast and accurate three-dimensional (3D) simulation of a porcine liver deformation under a surgical tool pressure using the commercial finite element software Abaqus. The liver geometry is obtained using magnetic resonance imaging, and a nonlinear constitutive law is employed to capture large deformations of the tissue. Effects of implicit versus explicit analysis schemes, element type, and mesh density on computation time are studied. We find that Abaqus explicit and implicit solvers are capable of simulating nonlinear soft tissue deformations accurately using first-order tetrahedral elements in a relatively short time by optimizing the element size. This study provides new insights and guidance on accurate and relatively fast nonlinear soft tissue simulations. Such simulations can provide force feedback during robotic surgery and allow visualization of tissue deformations for surgery planning and training of surgical residents. PMID- 26530843 TI - Real-time navigation in transoral robotic nasopharyngectomy utilizing on table fluoroscopy and image overlay software: a cadaveric feasibility study. AB - Inability to integrate surgical navigation systems into current surgical robot is one of the reasons for the lack of development of robotic endoscopic skull base surgery. We describe an experiment to adapt current technologies for real-time navigation during transoral robotic nasopharyngectomy. A cone-beam CT was performed with a robotic C-arm after the injecting contrast into common carotid artery. 3D reconstruction of the skull images with the internal carotid artery (ICA) highlighted red was projected on the console. Robotic nasopharyngectomy was then performed. Fluoroscopy was performed with the C-arm. Fluoroscopic image was then overlaid on the reconstructed skull image. The relationship of the robotic instruments with the bony landmarks and ICA could then been viewed in real-time, acting as a surgical navigation system. Navigation during robotic skull base surgery is feasible with available technologies and can increase the safety of robotic skull base surgery. PMID- 26530844 TI - The effect of increased experience on complications in robotic hysterectomy for malignant and benign gynecological disease. AB - The study objective was to assess the effect of increased experience on complications in robotic hysterectomy for malignant and benign gynecological disease. This is a retrospective cohort study. It is a Canadian Task Force classification II-2 study conducted at the University Hospital, Sweden. The patients were 949 women planned for robotic hysterectomy for malignant (75 %) and benign (25 %) gynecological disease between October 2005 and December 2013. They were continuously evaluated for the rate of intraoperative and postoperative complications up to 1-year post-surgery, the latter according to Clavien-Dindo classification following the introduction of robotic surgery with special awareness of complications possibly related to robot-specific risk factors, the description of refinement of practice and assessment of the effect of these measures. The rate of intraoperative complications, the overall rate of complications and the rate of >=grade 3 complications decreased from the first to the last time period (4.8 vs 2.6 %, p = 0.037, 34 vs 19 %, p = 0.003 and 13.5 vs 3.2 %, p = 0.0003, respectively). The rate of intraoperative complications and the rate of postoperative complications possibly related to robot-specific risk factors was reduced from the first to the last time period (3.8 vs 0.6 %, p = 0.028 and 7.7 vs 1.5 %, p = 0.003, respectively). In patients undergoing robotic hysterectomy for malignant and benign gynecological disease intraoperative and postoperative complications and complications possibly related to the robotic approach diminish with training, experience and refinement of practice. PMID- 26530845 TI - Load evaluation of the da Vinci surgical system for transoral robotic surgery. AB - Transoral robotic surgery, performed with the da Vinci surgical system (da Vinci), is a surgical approach for benign and malignant lesions of the oral cavity and laryngopharynx. It provides several unique advantages, which include a 3-dimensional magnified view and ability to see and work around curves or angles. However, the current da Vinci surgical system does not provide haptic feedback. This is problematic because the potential risks specific to the transoral use of the da Vinci include tooth injury, mucosal laceration, ocular injury and mandibular fracture. To assess the potential for intraoperative injuries, we measured the load of the endoscope and the instrument of the da Vinci Si surgical system. We pressed the endoscope and instrument of the da Vinci Si against Load cell six times each and measured the dynamic load and the time-to-maximum load. We also struck the da Vinci Si endoscope and instrument against the Load cell six times each and measured the impact load. The maximum dynamic load was 7.27 +/- 1.31 kg for the endoscope and 1.90 +/- 0.72 for the instrument. The corresponding time-to-maximum loads were 1.72 +/- 0.22 and 1.29 +/- 0.34 s, but the impact loads were significantly lower than the dynamic load. It remains possible that a major load is exerted on adjacent structures by continuous contact with the endoscope and instrument of da Vinci Si. However, there is a minor delay in reaching the maximum load. Careful monitoring by an on-site assistant may, therefore, help prevent contiguous injury. PMID- 26530846 TI - Accuracy of thoracolumbar transpedicular and vertebral body percutaneous screw placement: coupling the Rosa(r) Spine robot with intraoperative flat-panel CT guidance--a cadaver study. AB - The primary objective of the present study was to evaluate the accuracy of a new robotic device when coupled with intraoperative flat-panel CT guidance. Screws (D8-S1) were implanted during two separate cadaver sessions by coupling the Rosa((r)) Spine robot with the flat-panel CT device. Of 38 implanted screws, 37 (97.4 %) were fully contained within the pedicle. One screw breached the lateral cortical of one pedicle by <1 mm. The mean +/- SD accuracy (relative to pre operative planning) was 2.05 +/- 1.2 mm for the screw head, 1.65 +/- 1.11 for the middle of the pedicle and 1.57 +/- 1.01 for the screw tip. When coupled with intraoperative flat-panel CT guidance, the Rosa((r)) Spine robot appears to be accurate in placing pedicle screws within both pedicles and the vertebral body. Large clinical studies are mandatory to confirm this preliminary cadaveric report. PMID- 26530847 TI - Robotic radical prostatectomy, day-case surgery and cardiac health: an opposing paradigm? PMID- 26530848 TI - Body mass index, conversion rate and complications among patients undergoing robotic surgery for endometrial carcinoma. AB - A retrospective cohort study was performed to evaluate the relationship of BMI to conversion rate in patients undergoing robotic surgery for endometrial cancer. Secondary outcomes were operative times, number of lymph nodes retrieved, and complications. Women with endometrial cancer scheduled for robotic surgery from September 2008 to September 2012 were included. Women were divided into three groups based on BMI, and conversion rates to laparotomy were compared. Descriptive and comparative analyses were performed among non-obese, obese, and morbidly obese women who completed robotic surgery. 298 women were scheduled for robotic surgery for endometrial carcinoma: 87 non-obese (BMI 19-29, MU 25.23), 110 obese (BMI 30-39, MU 34.21), and 101 morbidly obese (BMI 40-71, MU 47.38). Conversion to laparotomy occurred in 18 patients (6%), with no difference in conversion rate between BMI categories. Direct comparison between converted and completed robotic patients showed no significant differences in preoperative characteristics, except that patients who required conversion had a higher number of previous abdominal surgeries. Patients completing robotic surgery underwent node dissections at similar rates in all three BMI categories. Operating room time, but not surgical time, was increased in morbidly obese patients. There were no significant differences in complications, performance of lymphadenectomy, or lymph node yields between BMI categories. Increase in BMI was not associated with an increase in rate of conversion to laparotomy or complication rate in patients undergoing robotic surgery for endometrial carcinoma. Node dissections were pathologically equivalent between BMI categories. PMID- 26530849 TI - Mechanical evaluation of newly developed mouthpiece using polyethylene terephthalate glycol for transoral robotic surgery. AB - Transoral robotic surgery (TORS), performed with the da Vinci surgical system (da Vinci), has been classified as a surgical approach for benign and malignant lesions of the oral cavity and laryngopharynx. It provides several unique advantages, which include a three-dimensional magnified view, ability to see and work around curves or angles, and the availability of two or three robotic arms. At present, however, the da Vinci surgical system does not provide haptic feedback. The potential risks specific to the transoral use of the da Vinci include tooth injury, mucosal laceration, ocular injury, and mandibular fracture. To prevent such intra-operative tooth injuries, we created a mouthpiece made of polyethylene terephthalate glycol (PETG) individually shaped for the patient's teeth. We compared the safety and efficacy of the PETG mouthpiece with those of a conventional mouthpiece made of ethylene-vinyl acetate (EVA). To determine the difference in tooth injury resulting from the two types of mouthpiece, we constructed an experimental system to measure load and strain. We measured the dynamic load and the strain from the rod to the tooth using the PETG and EVA mouthpiece. The rod was pressed against the tooth model outfitted with two types of mouthpiece and the dynamic load was measured with a load cell and the strain with a strain gage. The maximum dynamic load was 1.29 +/- 0.03 kgf for the PETG mouthpiece and 2.24 +/- 0.05 kgf for the EVA mouthpiece. The load against the tooth was thus less for the EVA mouthpiece. The strain was -166.84 +/- 3.94 and 48.24 +/- 7.77 MUepsilon, respectively, while the load direction was parallel to that of the tooth axis for the PETG mouthpiece and perpendicular to the tooth axis for the EVA mouthpiece. The PETG mouthpiece reduced the tooth load compared with the EVA mouthpiece and the load direction was in parallel to the tooth axis. The PETG mouthpiece thus enhances tooth safety for TORS. PMID- 26530850 TI - Do Pediatricians Ask About Adverse Childhood Experiences in Pediatric Primary Care? AB - OBJECTIVE: The stress associated with adverse childhood experiences (ACEs) has immediate and long-lasting effects. The objectives of this study were to examine 1) how often pediatricians ask patients' families about ACEs, 2) how familiar pediatricians are with the original ACE study, and 3) physician/practice characteristics, physicians' mental health training, and physicians' attitudes/beliefs that are associated with asking about ACEs. METHODS: Data were collected from 302 nontrainee pediatricians exclusively practicing general pediatrics who completed the 2013 American Academy of Pediatrics Periodic Survey. Pediatricians indicated whether they usually, sometimes, or never inquired about or screened for 7 ACEs. Sample weights were used to reduce nonresponse bias. Weighted descriptive and logistic regression analyses were conducted. RESULTS: Only 4% of pediatricians usually asked about all 7 ACEs; 32% did not usually ask about any. Less than 11% of pediatricians reported being very or somewhat familiar with the ACE study. Pediatricians who screened/inquired about ACEs usually asked about maternal depression (46%) and parental separation/divorce (42%). Multivariable analyses showed that pediatricians had more than twice the odds of usually asking about ACEs if they disagreed that they have little effect on influencing positive parenting skills, disagreed that screening for social emotional risk factors within the family is beyond the scope of pediatricians, or were very interested in receiving further education on managing/treating mental health problems in children and adolescents. CONCLUSIONS: Few pediatricians ask about all ACEs. Pediatric training that emphasizes the importance of social/emotional risk factors may increase the identification of ACEs in pediatric primary care. PMID- 26530851 TI - Household Food Insecurity and Mental Health Problems Among Adolescents: What Do Parents Report? AB - OBJECTIVE: To investigate whether adolescents living in households with food insecurity have poorer parent-reported mental health (MH) than peers. METHODS: We analyzed cross-sectional data from ~8600 adolescents who participated in the 2007 (8th grade) wave of the Early Childhood Longitudinal Study-Kindergarten. Household food insecurity (HFI) was assessed by parental report on the 18-item US Household Food Security Scale. Total Difficulties score >13 on the parent reported Strengths and Difficulties Questionnaire (SDQ) indicated problems with adolescent MH. SDQ subscale scores (Emotional, Conduct, Hyperactivity, Peer Problems) were also calculated. Associations between HFI and MH were explored in bivariate and multivariable analyses. Interactions of HFI and gender and HFI and receipt of free/reduced-price school lunch were analyzed with regard to problems with MH. RESULTS: A total of 10.2% of adolescents lived with HFI; 11.2% had SDQ >13. Adolescents with HFI had higher rates of overall MH problems (28.7% vs 9.2%), emotional problems (21.6% vs 6.6%), conduct problems (26.5% vs 11.6%), hyperactivity (22.4% vs 11.3%), and peer problems (19.8% vs 8.6%) (all P < .01). After adjustment for confounders, the association between HFI and overall MH problems (odds ratio 2.3; 95% confidence interval 1.6-3.3) remained. Interactions of HFI and gender and HFI and free/reduced-price school lunch were not significant. CONCLUSIONS: HFI was associated with increased risk of parent reported MH problems among both male and female adolescents. Free/reduced-price school lunch did not significantly alter this relationship. Effective interventions to promote MH and reduce HFI among adolescents are necessary. PMID- 26530852 TI - Localization and expression of TRPV1 and TRPA1 in the human oropharynx and larynx. AB - BACKGROUND: Previous studies have found that TRPV1 and TRPA1 receptor agonists improve swallow response in patients with oropharyngeal dysphagia (OD), but little is known about the expression of these receptors in the human oropharynx. The aim of this study was to assess the expression and localization of TRPV1 and TRPA1 in human samples from the oropharynx of healthy patients, to provide the basis for new pharmacological treatments for OD. METHODS: Samples from oropharyngeal regions innervated by cranial nerves V, IX, and X (tongue, pharynx, and epiglottis) were obtained during ENT surgery and processed either for mRNA (21 patients) or for immunohistochemical assays (seven patients). The expression analysis was performed with RT-qPCR using ACTBh as reference gene. Hemotoxylin and eosin staining was used to study the histology; the immunohistochemical assay used (i) neuron-specific enolase to detect nerve fibers or (ii) fluorescent probes to locate TRPV1 and TRPA1. RESULTS: TRPV1 was expressed in the three studied regions, with higher levels in CN V region (tongue) than in CN X region (epiglottis; p < 0.05), and was localized at epithelial cells and nociceptive fibers in all studied regions. TRPA1 was also expressed in all studied regions, but was always localized below the basal lamina. No immunoreactivity for TRPA1 was found on epithelial cells. CONCLUSIONS & INFERENCES: TRPV1 and TRPA1 are widely expressed in the human oropharynx with two distinct patterns. Our study further confirms that TRPV1/A1 receptors are promising therapeutic targets to develop active treatments for OD patients. PMID- 26530854 TI - The Triboracyclopropenyl Dianion: The Lightest Possible Main-Group-Element Huckel pi Aromatic. AB - Huckel pi aromaticity is typically a domain of carbon-rich compounds. Only very few analogues with non-carbon frameworks are currently known, all involving the heavier elements. The isolation of the triboracyclopropenyl dianion is presented, a boron-based analogue of the cyclopropenyl cation, which belongs to the prototypical class of Huckel pi aromatics. Reduction of Cl2 BNCy2 by sodium metal produced [B3 (NCy2 )3 ](2-) , which was isolated as its dimeric Na(+) salt (Na4 [B3 (NCy2 )3 ]2 ?2 DME; 1) in 45 % yield and characterized by single-crystal X ray diffraction. Cyclic voltammetry measurements established an extremely high oxidation potential for 1 (Epc =-2.42 V), which was further confirmed by reactivity studies. The Huckel-type pi aromatic character of the [B3 (NCy2 )3 ](2 ) dianion was verified by various theoretical methods, which clearly indicated pi aromaticity for the B3 core of a similar magnitude to that in [C3 H3 ](+) and benzene. PMID- 26530853 TI - Health knowledge and smokeless tobacco quit attempts and intentions among married women in rural Bangladesh: Cross-sectional survey. AB - INTRODUCTION AND AIMS: The aim of this study was to investigate health knowledge, attitudes and smokeless tobacco quit attempts and intentions among married women in rural Bangladesh. DESIGN AND METHODS: A cross-sectional survey was conducted using an interviewer administered, pretested, semistructured questionnaire. All 8082 women living in the Jhaudi and Ghotmajhee local government areas, aged >=18 years with at least one pregnancy in their lifetime, were invited to participate. Questions covered smokeless tobacco consumption (STC), knowledge regarding its health effects, users' quit attempts and intentions and sociodemographic characteristics. RESULTS: Eight thousand seventy-four women completed the survey (response rate 99.9%). Almost half (45%) of current consumers thought STC was good for their health and many ascribed medicinal values to it, for example 25% thought STC reduced stomach aches. A quarter had previously tried to quit and 10% intended to quit. After adjusting for potential confounders, inaccurate knowledge of STC health consequences was associated with being older [adjusted odds ratio (aOR) = 2.71, 95% confidence interval (CI) 1.99-3.50], less educated (aOR = 2.18, 95% CI 1.66-2.85), Muslim (aOR = 17.0, 95% CI 12.0-23.9) and unemployed (aOR = 29.7, 95% CI: 25.2-35.1). Having less education (aOR = 2.52, 95% CI 0.98-6.45) and being unemployed (aOR = 1.52, 95% CI 1.03-2.23) were associated with the intention to quit. DISCUSSION AND CONCLUSIONS: Large gaps exist in rural Bangladeshi women's understanding of the adverse health effects of STC. Health awareness campaigns should highlight the consequences of STC. Routine screening and cessation advice should be provided in primary healthcare and smokeless tobacco control strategies should be implemented. [Hossain MS, Kypri K, Rahman B, Akter S, Milton AH. Health knowledge and smokeless tobacco quit attempts and intentions among married women in rural Bangladesh: Cross-sectional survey. Drug Alcohol Rev 2016;35:514-522]. PMID- 26530855 TI - Activity prediction of substrates in NADH-dependent carbonyl reductase by docking requires catalytic constraints and charge parameterization of catalytic zinc environment. AB - Molecular docking of substrates is more challenging compared to inhibitors as the reaction mechanism has to be considered. This becomes more pronounced for zinc dependent enzymes since the coordination state of the catalytic zinc ion is of greater importance. In order to develop a predictive substrate docking protocol, we have performed molecular docking studies of diketone substrates using the catalytic state of carbonyl reductase 2 from Candida parapsilosis (CPCR2). Different docking protocols using two docking methods (AutoDock Vina and AutoDock4.2) with two different sets of atomic charges (AM1-BCC and HF-RESP) for catalytic zinc environment and substrates as well as two sets of vdW parameters for zinc ion were examined. We have selected the catalytic binding pose of each substrate by applying mechanism based distance criteria. To compare the performance of the docking protocols, the correlation plots for the binding energies of these catalytic poses were obtained against experimental Vmax values of the 11 diketone substrates for CPCR2. The best correlation of 0.73 was achieved with AutoDock4.2 while treating catalytic zinc ion in optimized non bonded (NBopt) state with +1.01 charge on the zinc ion, compared to 0.36 in non bonded (+2.00 charge on the zinc ion) state. These results indicate the importance of catalytic constraints and charge parameterization of catalytic zinc environment for the prediction of substrate activity in zinc-dependent enzymes by molecular docking. The developed predictive docking protocol described here is in principle generally applicable for the efficient in silico substrate spectra characterization of zinc-dependent ADH. PMID- 26530856 TI - Treatment of Brain AVMs (TOBAS): study protocol for a pragmatic randomized controlled trial. AB - BACKGROUND: The management of unruptured brain arteriovenous malformation (AVM) patients remains controversial. Furthermore, curative attempts to treat ruptured AVM patients have not been questioned so far, and there is a lack of prospective data on clinical results according to treatment modality. Endovascular treatment is often used aiming to improve the safety or efficacy of surgery or radiation therapy, but benefits have never been documented in a trial. A care trial context is needed to evaluate interventions at the same time they are practised. METHODS/TRIAL DESIGN: TOBAS is a pragmatic, prospective, multicenter, randomized, controlled trial and registry which offers a care trial context for brain AVM patients, including surgical resection, radiosurgery or endovascular embolization, alone or combined. The study includes two RCTs and a multimodality prospective registry. The objectives of the proposed study are to assess whether preventive interventions (surgery, embolization, radiation therapy, alone or combined), selected by the local treatment team and performed as locally practiced, randomly allocated and compared with conservative management, in unruptured brain AVM patients eligible for active or conservative management, can improve the proportion of patients having an independent outcome (modified Rankin Scale (mRS) < 3, as assessed by a standardized questionnaire administered by non masked care personnel) at 10 years. All patients judged ineligible for randomized allocation are to be entered in a multimodal registry. The objective of a nested trial in patients with ruptured or unruptured AVMs to be treated by surgery or radiation therapy, is to assess whether pre-surgical or pre-radiation embolization, randomly allocated and compared with no embolization, can improve the proportion of patients with complete eradication of the AVM, as locally adjudicated, combined with a good clinical outcome (mRS < 3). The study will require up to 2000 patients in approximately 30 centers or more, followed for 10 years. TOBAS is registered at clinicaltrials.gov: NCT02098252 as of 25 March 2014. PMID- 26530858 TI - Measurement error models with interactions. AB - An important use of measurement error models is to correct regression models for bias due to covariate measurement error. Most measurement error models assume that the observed error-prone covariate (WW ) is a linear function of the unobserved true covariate (X) plus other covariates (Z) in the regression model. In this paper, we consider models for W that include interactions between X and Z. We derive the conditional distribution of X given W and Z and use it to extend the method of regression calibration to this class of measurement error models. We apply the model to dietary data and test whether self-reported dietary intake includes an interaction between true intake and body mass index. We also perform simulations to compare the model to simpler approximate calibration models. PMID- 26530857 TI - Comparative chemical profiling, cholinesterase inhibitions and anti-radicals properties of essential oils from Polygonum hydropiper L: a preliminary anti- Alzheimer's study. AB - BACKGROUND: Cholinesterase inhibition is a vital target for the development of novel and mechanism based inhibitors, owing to their role in the breakdown of acetylcholine (ACh) neurotransmitter to treat various neurological disorders including Alzheimer's disease (AD). Similarly, free radicals are implicated in the progression of various diseases like neurodegenerative disorders. Due to lipid solubility and potential to easily cross blood brain barrier, this study was designed to investigate the anticholinesterase and antioxidant potentials of the standardized essential oils from the leaves and flowers of Polygonum hydropiper. METHODS: Essential oils from the leaves (Ph.LO) and flowers (Ph.FO) of P. hdropiper were isolated using Clevenger apparatus. Oil samples were analyzed by GC-MS to identify major components and to attribute the antioxidant and anticholinesterase activity to specific components. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potentials of the samples were determined following Ellman's assay. Antioxidant assays were performed using 1,1 diphenyl,2-picrylhydrazyl (DPPH), 2,2-azinobis[3-ethylbenzthiazoline]-6-sulfonic acid (ABTS) and hydrogen peroxide (H2O2) free radical scavenging assays. RESULTS: In the GC-MS analysis 141 and 122 compounds were indentified in Ph.LO and Ph.FO respectively. Caryophylene oxide (41.42 %) was the major component in Ph.FO while decahydronaphthalene (38.29 %) was prominent in Ph.LO. In AChE inhibition, Ph.LO and Ph.FO exhibited 87.00** and 79.66***% inhibitions at 1000 MUg/ml with IC50 of 120 and 220 MUg/ml respectively. The IC50 value for galanthamine was 15 MUg/ml. In BChE inhibitory assay, Ph.LO and Ph.FO caused 82.66*** (IC50 130 MUg/ml) and 77.50***% (IC50 225 MUg/ml) inhibitions respectively at 1000 MUg/ml concentration. In DPPH free radical scavenging assay, Ph.LO and Ph.FO exhibited IC50 of 20 and 200 MUg/ml respectively. The calculated IC50s were 180 & 60 MUg/ml for Ph.LO, and 45 & 50 MUg/ml for Ph.FO in scavenging of ABTS and H2O2 free radicals respectively. CONCLUSIONS: In the current study, essential oils from leaves and flowers of P. hydropiper exhibited dose dependent anticholinesterase and antioxidant activities. Leaves essential oil were more effective and can be subjected to further in-vitro and in-vivo anti-Alzheimer's studies. PMID- 26530859 TI - miR-124 suppresses the migration and invasion of glioma cells in vitro via Capn4. AB - miR-124 and Capn4 are aberrantly expressed in glioblastoma multiforme (GBM) tissues. In the present study, we investigated miR-124 and Capn4 expression in GBM tissue specimens. The role of miR-124 and Capn4 in the migration and invasion of glioma cells in vitro was also examined. miR-124 and Capn4 expression in 20 GBM and 6 control brain specimens was examined using RT-qPCR and immuno-blotting. Data from The Cancer Genome Atlas were retrieved. Candidate mRNA target sites of miR-124 were predicted using TargetScan/microRNA and binding was examined using dual luciferase reporter assays. The U87 and U251 cells were transfected with scrambled microRNA, miR-124 mimics and/or pLenti-Capn4 prior to wound-healing and Transwell invasion assays. Proteins involved in the epithelial-mesenchymal transition were examined using immunoblotting. The results showed that miR-124 was significantly downregulated in GBM tissues. Immunoblotting showed a marked upregulation of Capn4 expression in GBM tissues. The Spearman's correlation analysis revealed a negative association between miR-124 expression and Capn4 protein levels. TargetScan/microRNA predicted the miR-124 binding site in the nucleotide 440-446 region within the Capn4 3'-UTR, which was confirmed by luciferase assays. Wound-healing and Transwell invasion assays demonstrated that Capn4 downregulation or miR-124 mimics suppressed the migration and invasion of glioma cells. Capn4 downregulation or miR-124 mimics reduced the level of phospho FAK and MMP2, vimentin and N-cadherin in U87 cells. In conclusion, miR-124 was found to suppress the migration and invasion of glioma cells in vitro via Capn4. PMID- 26530860 TI - Enhanced expression of polysialic acid correlates with malignant phenotype in breast cancer cell lines and clinical tissue samples. AB - Polysialic acid (PSA) is highly expressed during embryonic development, but barely expressed during postnatal development, and may be 're-expressed' in cancer tissues. In this study, motility and migration assays were performed to compare the changes in cell behavior between non-malignant and maligant cells. Next, the expression levels of PSA were evaluated in 4 human and mouse normal breast or breast cancer (BC) cell lines using 1,2-diamino-4,5 methylenedioxybenzene-labeling HPLC technology, as well as in human clinical BC tissue samples. PSA expression was significantly higher in malignant cells (where it appeared to facilitate cell migration and motility) than in non-malignant cells. Enhanced PSA expression levels were also observed during epithelial mesenchymal transition (EMT), a leading cause of cancer cell metastasis, which was induced in the NMuMG and MCF10A cells by treatment with transforming growth factor-beta1 (TGF-beta1). An increased PSA expression also correlated with the disease stage in the patients with BC (P<0.0001). Using RT-qPCR, we found that polysialyltransferase ST8SiaIV (PST) and polysialyltransferase ST8SiaII (STX), which are responsible for PSA synthesis, were differently expressed in the tested BC samples. However, PST, but not STX, was re-expressed in 14 out of 20 clinical BC samples. The findings of the present study indicate that the pathophysiology of BC involves the aberrant regulation of PSA expression and PST gene expression. PMID- 26530861 TI - Malaria Parasite Metabolic Pathways (MPMP) Upgraded with Targeted Chemical Compounds. AB - Malaria Parasite Metabolic Pathways (MPMP) is the website for the functional genomics of intraerythrocytic Plasmodium falciparum. All the published information about targeted chemical compounds has now been added. Users can find the drug target and publication details linked to a drug database for further information about the medicinal properties of each compound. PMID- 26530862 TI - [Primary care problems addressing breast pain in nursing mothers]. PMID- 26530863 TI - Early Adopters: Correlates of HIV Chemoprophylaxis Use in Recent Online Samples of US Men Who Have Sex with Men. AB - To date, little data on pre-exposure prophylaxis (PrEP) users outside of the clinical trial setting are available. A repeated cross-sectional survey of one of the largest social and sexual networking websites for men who have sex with men (MSM) in the United States was conducted in August 2013 (Wave 1) and January 2014 (Wave 2). Multivariable logistic regression models were used to assess factors associated with having heard of and having taken post-exposure prophylaxis (PEP) and PrEP in Wave 1 (N = 4043) and Wave 2 (N = 2737) separately. In Wave 1, 147 (3.6 %) and 61 (1.5 %) reported using PEP and PrEP, respectively, compared to 119 (4.4 %) and 62 (2.3 %) in Wave 2. Higher-risk sexual behaviors were associated with having taken PEP and PrEP, and previous PEP use was associated with having taken PrEP. Understanding factors that are associated with early use of PrEP may help inform wider utilization of PrEP by at risk MSM. PMID- 26530864 TI - Physiological Function of Rac Prophage During Biofilm Formation and Regulation of Rac Excision in Escherichia coli K-12. AB - Rac or rac-like prophage harbors many genes with important physiological functions, while it remains excision-proficient in several bacterial strains including Escherichia coli, Salmonella spp. and Shigella spp. Here, we found that rac excision is induced during biofilm formation, and the isogenic stain without rac is more motile and forms more biofilms in nutrient-rich medium at early stages in E. coli K-12. Additionally, the presence of rac genes increases cell lysis during biofilm development. In most E. coli strains, rac is integrated into the ttcA gene which encodes a tRNA-thioltransferase. Rac excision in E. coli K-12 leads to a functional change of TtcA, which results in reduced fitness in the presence of carbenicillin. Additionally, we demonstrate that YdaQ (renamed as XisR) is the excisionase of rac in E. coli K-12, and that rac excision is induced by the stationary sigma factor RpoS through inducing xisR expression. Taken together, our results reveal that upon rac integration, not only are new genes introduced into the host, but also there is a functional change in a host enzyme. Hence, rac excision is tightly regulated by host factors to control its stability in the host genome under different stress conditions. PMID- 26530865 TI - Coexistence of Graves' disease and unilateral functioning Struma ovarii: a case report. AB - BACKGROUND: Coexisting of Graves' disease and functioning struma ovarii is a rare condition. Although the histology of struma ovarii predominantly composed of thyrocytes, the majority of the patients did not have thyrotoxicosis. The mechanism underlying the functioning status of the tumor is still unclear but the presence of thyroid stimulating hormone receptor (TSHR) is thought to play a role. Here we describe the patient presentation and report the TSHR expression of the tumor. CASE PRESENTATION: A 56-year old Asian woman presented with long standing thyrotoxicosis for 23 years. She was diagnosed with Graves' disease and thyroid nodules. She had bilateral exophthalmos and had high titer of plasma TSHR antibody. Total thyroidectomy was performed and the histologic findings confirmed the clinical diagnosis. The patient had persistent thyrotoxicosis postoperatively. Thyroid uptake demonstrated the adequacy of the thyroid surgery and the whole body scan confirmed the presence of functioning thyroid tissue at pelvic area. The surgery was scheduled and the patient had hypothyroidism after the surgery. The pathological diagnosis was struma ovarii at right ovary. We performed TSHR staining in both the patient's struma ovarii and in 3 cases of non functioning struma ovarii. The staining results were all positive and the intensity of the TSHR staining of functioning struma ovarii was the same as that in other cases of non-functioning tumors, suggesting that the determinant of functioning struma ovarii might be the presence of TSHR stimuli rather than the intensity of the TSHR in the ovarian tissue. CONCLUSION: In patients with Graves' disease with persistent or recurrent thyrotoxicosis after adequate ablative treatment, the possibility of ectopic thyroid hormone production should be considered. TSHR expression is found in patients with functioning and non functioning struma ovarii and cannot solely be used to determine the functioning status of the tumor. PMID- 26530866 TI - [Assessment and prevalence of urinary incontinence after radical prostatectomy: Analysis of a historical series]. AB - OBJECTIVES: Prostate cancer can be treated by radical prostatectomy and provoke urinary incontinence as secondary effect. Our aim is to calculate the prevalence of urinary incontinence, characteristics of leakage and influential factors, through a historical series. METHODS: We perform a descriptive, observational and retrospective study of 1310 patients who received treatment for PCa between 1989 and 2011. Prevalence was obtained after 12 months of recovery and using ICS definition. To complete ICIQ-SF and number of pads/day used we perform a cross sectional study. The series is studied globally and divided in two groups according to oncologic characteristics. We perform a descriptive, comparative and predictive analysis. RESULTS: Prevalence of the series was 23.5%, 296 patients. 279 incontinent patients completed ICIQ-SF with a mean score of 11.1+/-4.03. 16.4% of the patients use 1 pad/day or none, 69% (11.4% of the total) use compress and 22% diapers. 8% of the total use more than 1 pad/day. Clinico pathological factors divide series in two groups: 1989-1999 with a prevalence of 24.6% and 2000-2011 with 22.8%. Multivariate analysis shows influential factors: age (65 years) (OR:1.65, p=0.013) and prostate volume (50cc) (OR:1.49, p=0.029). CONCLUSIONS: Urinary incontinence is a disease with some prevalence that varies depending on definition. The most common situation was to leak several times a day (42.2%), a small amount (59.1%), using compress (69%) most of incontinents with a mild (0-7: 88.2%) impact on quality of life. Predictive factors were age (65 years) and prostate volume (50cc). The historical changes does not influence over prevalence. PMID- 26530867 TI - [Effects of preventive double-J stent placement in ureteral obstruction treatment with metal stents on animal model]. AB - OBJECTIVES: The purpose of this experimental study is to assess the additive effects of temporary JJ stent placement together with metal stents (MS) in the treatment obstructive uropathy, in order to reduce urothelial hyperplasia formation. METHODS: Twenty-four pigs were included, and an experimental model of obstructive uropathy was created. Six weeks after obstructive uropathy model induction, ureteral obstruction was confirmed using ultrasonography, ureteropyelography and endoluminal ultrasound. Afterwards, animals were randomly distributed into 2 groups. Group I underwent covered MS placement and JJ ureteral stenting for 3 weeks. Animals in Group II received the same MS without simultaneous JJ stenting. The follow-up was at 3 weeks and at 6 months. RESULTS: Incidence of urothelial hyperplasia was higher in Group I than Group II, but without statically significant differences. On the other hand, Group II showed a significantly higher degree of obstruction severity due to hyperplasia. The migration rate in both groups was 33.3% at the end of the study. Significant differences were shown on animals showing urinary tract infection (UTI) and hyperplasia against those with hyperplasia but no infection. There was a high rate of correlation between UTI and obstructive urothelial hyperplasia. CONCLUSIONS: Placement of JJ ureteral catheter does not inhibit urothelial hyperplasia associated with placement of metal mesh stents, although it significantly reduces its obstructive severity in long-term follow-up. Urinary tract infection is directly related to the development and magnitude of the urothelial hyperplasia. PMID- 26530868 TI - A standardized scoring system in the prediction of success and complications of percutaneous nephrolithotomy: Guy's stone scoring system. AB - OBJECTIVES: In this study, our aim was to determine the role of Guy's stone scoring system (GSS) in the prediction of percutaneous nephrolithotomy (PNL) success and its ability to foresee potential complications in consideration of Clavien grading system (CGS). MATERIAL AND METHODS: The data of 244 patients who underwent PNL between January 2009 and May 2014 were retrospectively examined. Renal stones were evaluated using GSS with the aid of the patients' preoperative radiological evaluations and their postoperative complications were assessed with CGS. RESULTS: Mean age of the patients (men, n=166; 68% and women, n=78; 32%) was 46.50+/-13.12 years (range, 16-80 yrs). Clinically significant residual stones were not detected in 195 (79.9%) patients, while they were found in 49 (20.1%) patients. Guy's stone scores of 1, 2, 3 and 4 points were estimated in 21.3, 37.7, 29.9, and 11.1% of the cases, respectively. Based on modified Clavien complication grading system, complications were categorized as Clavien grade 1, 2 and 3 in 81.9, 17.2, and 0.8% of the cases, respectively. Clavien Grade 4 and 5 complications were not encountered. A statistically significant correlation was found between Guy's Stone scores and Clavien grades (p<0.02). A statistically and highly significant difference was detected between Guy's stone scores of the cases with respect to residual stones (p=0.001; p<0.01). CONCLUSION: Our study findings have revealed that GSS is a successful and easily applicable method for the prediction of success and likelihood of complications of PNL. PMID- 26530869 TI - Bilateral sporadic synchronous renal clear-cell carcinoma treated by bilateral partial laparoscopic nephrectomy: Report of two cases. AB - Bilateral sporadic renal cell carcinoma (RCC) is very rare and ultrasonography, computed tomography and magnetic resonance imaging are the major imaging methods in its diagnosis and further investigation. We report of two cases of bilateral synchronous sporadic RCC, which were successfully treated by laparoscopic partial nephrectomy. The diagnostic roles of imaging methods were discussed. In conclusion, the evaluation of both kidneys with regard to potential synchronous RCC has an utmost importance in the treatment strategy. PMID- 26530870 TI - [The use of S.T.O.N.E. scale in patients undergoing percutaneous nephrolithotomy]. AB - OBJECTIVES: The aim of this study was to apply the S.T.O.N.E. scale on our patients undergoing PCNL to predict stone free rate and complications using the modified Clavien scale. METHODS: A historical cohort of patients undergoing PCNL was analyzed. All patients with computed tomography to assess stone-free rate with the S.T.O.N.E. scale and complications were evaluated by the modified Clavien scale. RESULTS: In 102 patients 104 procedures were performed; the mean age was 48.4 years and 71% were women. The distribution of cases were classified as mild: 6.7%, moderate: 63.5% and severe: 29.8%. The stone free rate after the first procedure globally reached 58% and by grade was: mild 85.7%, moderate 71.2% and severe 25%. The RR for residual stones after the first procedure was 2.4 for moderate grade (CI 0.3 to 15, p=0.03) and 4.9 for severe grade (CI 0.7 - 30.9, p=0.08). The overall complication rate was 33%, separately Clavien 1: 14.4%, 2: 9.6%, 3a: 2.9%, 3b: 2.9% 4:1.9%, 5:1%. CONCLUSIONS: The S.T.O.N.E. scale applied in our population can predict accurately and easily stone free rate in patients undergoing PCNL. We found no predictive association for this scale on complications. PMID- 26530871 TI - Bacterial responses to environmental change on the Tibetan Plateau over the past half century. AB - Climate change and anthropogenic factors can alter biodiversity and can lead to changes in community structure and function. Despite the potential impacts, no long-term records of climatic influences on microbial communities exist. The Tibetan Plateau is a highly sensitive region that is currently undergoing significant alteration resulting from both climate change and increased human activity. Ice cores from glaciers in this region serve as unique natural archives of bacterial abundance and community composition, and contain concomitant records of climate and environmental change. We report high-resolution profiles of bacterial density and community composition over the past half century in ice cores from three glaciers on the Tibetan Plateau. Statistical analysis showed that the bacterial community composition in the three ice cores converged starting in the 1990s. Changes in bacterial community composition were related to changing precipitation, increasing air temperature and anthropogenic activities in the vicinity of the plateau. Collectively, our ice core data on bacteria in concert with environmental and anthropogenic proxies indicate that the convergence of bacterial communities deposited on glaciers across a wide geographical area and situated in diverse habitat types was likely induced by climatic and anthropogenic drivers. PMID- 26530872 TI - Are we any further forward with wound care as a clinical specialty? PMID- 26530874 TI - Creatinine Versus Cystatin C for Estimating GFR in Patients With Liver Cirrhosis. PMID- 26530875 TI - Hemodialysis Facility Variation in Hospitalization and Transfusions Using Medicare Claims: The DOPPS Practice Monitor for US Dialysis Care. PMID- 26530876 TI - Autosomal Dominant Polycystic Kidney Disease: Core Curriculum 2016. PMID- 26530877 TI - Creatine and creatinine contents in different diet types for dogs - effects of source and processing. AB - The concentrations of creatine and its degradation product creatinine were determined in a variety of unprocessed as well as processed feedstuffs suitable for dogs. Unprocessed feedstuffs were categorised as single feedstuffs, bone and raw food diets (BARF), and small vertebrates, for example prey animals. Processed feedstuffs were categorised as meat/meat and bone meals, complete wet diets and complete dry diets. The feedstuffs were chosen to cover a broad range of each of the three defined processed and unprocessed feed categories available on the market without further subclustering. The creatine content of the samples was compared on a dry matter, protein and energy basis. The relation of creatine to crude protein permitted a rating of the meat quality in terms of muscle tissue. RESULTS: We found no difference in creatine concentrations between the three categories of unprocessed feedstuffs (raw single feedstuffs, prey and BARF diets), neither on a dry matter basis nor when expressed relative to crude protein and metabolisable energy respectively. Significantly lower levels were determined in meat/meat and bone meal and commercial dry diets (e.g. 303 mg creatine/MJ ME in unprocessed vs. 6 mg/MJ ME in processed feedstuffs; p < 0.001). We conclude that in relation to ME, the exclusive use of conventionally processed diets for dogs, especially dry diets, leads to considerably lower intake of creatine which is a natural compound of the diet of this carnivorous and omnivorous species. PMID- 26530878 TI - Predicting stabilizing mutations in proteins using Poisson-Boltzmann based models: study of unfolded state ensemble models and development of a successful binary classifier based on residue interaction energies. AB - In many cases the stability of a protein has to be increased to permit its biotechnological use. Rational methods of protein stabilization based on optimizing electrostatic interactions have provided some fine successful predictions. However, the precise calculation of stabilization energies remains challenging, one reason being that the electrostatic effects on the unfolded state are often neglected. We have explored here the feasibility of incorporating Poisson-Boltzmann model electrostatic calculations performed on representations of the unfolded state as large ensembles of geometrically optimized conformations calculated using the ProtSA server. Using a data set of 80 electrostatic mutations experimentally tested in two-state proteins, the predictive performance of several such models has been compared to that of a simple one that considers an unfolded structure of non-interacting residues. The unfolded ensemble models, while showing correlation between the predicted stabilization values and the experimental ones, are worse than the simple model, suggesting that the ensembles do not capture well the energetics of the unfolded state. A more attainable goal is classifying potential mutations as either stabilizing or non-stabilizing, rather than accurately calculating their stabilization energies. To implement a fast classification method that can assist in selecting stabilizing mutations, we have used a much simpler electrostatic model based only on the native structure and have determined its precision using different stabilizing energy thresholds. The binary classifier developed finds 7 true stabilizing mutants out of every 10 proposed candidates and can be used as a robust tool to propose stabilizing mutations. PMID- 26530879 TI - Can tintinnids be used for discriminating water quality status in marine ecosystems? AB - Ciliated protozoa have many advantages in bioassessment of water quality. The ability of tintinnids for assessing water quality status was studied during a 7 yearcycle in Jiaozhou Bay of the Yellow Sea, northern China. The samples were collected monthly at four sites with a spatial gradient of environmental pollution. Environmental variables, e.g., temperature, salinity, chlorophyll a (Chl a), dissolved inorganic nitrogen, soluble reactive phosphate (SRP), and soluble active silicate (SRSi), were measured synchronously for comparison with biotic parameters. Results showed that: (1) tintinnid community structures represented significant differences among the four sampling sites; (2) spatial patterns of the tintinnid communities were significantly correlated with environmental variables, especially SRSi and nutrients; and (3) the community structural parameters and the five dominant species were significantly correlated with SRSi and nutrients. We suggested that tintinnids may be used as a potential bioindicator for discriminating water quality status in marine ecosystems. PMID- 26530880 TI - Isahaya Bay, freshwater lake to an estuary again. AB - The inner 1/3 of Isahaya Bay which is a tributary of Ariake Sea in Japan was shut off from the sea by a dike for the reclamation and disaster prevention in 1997. On the other hand, several environmental and fisheries problems occurred in Ariake Sea after 1990s. Some fishermen insisted that the major reason for the decrease of fishing must be the influence of the dike construction and filed lawsuits. Now the court decision is fixed and Japanese government must open the gates to reintroduce sea water into the reservoir. We made numerical simulations of currents, hydrography and sediment transport to assess the influences of the gate opening. To choose the environmentally wise procedure of gate opening, it is needed to reduce the erosion and deposition of bottom sediments caused by the enhanced tidal current and to minimize the occurrence of hypoxia in the reservoir. PMID- 26530881 TI - Anthropogenic influence on sediment transport in the Whittard Canyon, NE Atlantic. AB - Unusual peaks in turbidity were detected in two branches of the Whittard Canyon in June 2013. Enhanced nepheloid layers (ENLs) were defined as layers with concentrations of suspended particulate matter exceeding those of nepheloid layers typically observed in a given region. Here, ENLs had peaks in turbidity and elevated suspended particulate matter concentrations exceeding ~1 mg L(-1) with the largest ENLs measuring between ~2-8 mg L(-1). The ENLs measured ~100-260 m in vertical height and were detected in water depths of between 640 and 2880 m. Vessel Monitoring System data showed that high spatial and temporal activity of potential bottom trawling vessels coincided with the occurrence of the ENLs. Molar C/N ratios of the suspended organic material from the ENLs showed a high degree of degradation. Regular occurrences of such events are likely to have implications for increased sediment fluxes, burial of organic carbon and alteration of benthic and canyon ecosystems. PMID- 26530883 TI - Erratum. PMID- 26530882 TI - Targeted DNA Sequencing Detects Mutations Related to Susceptibility among Familial Non-medullary Thyroid Cancer. AB - Some studies have demonstrated that familial non-medullary thyroid cancer (FNMTC) has a more aggressive clinical behavior compared to sporadic NMTC (SNMTC). However, FNMTC is difficult to differentiate from SNMTC by the morphology and immunohistochemistry. Although genes responsible for FNMTC were unclear, screening for rare germline mutations on known important tumor suppressor genes might offer more insights on predicting susceptibility to FNMTC. Here, a customized panel was designed to capture all exons of 31 cancer susceptive genes possibly related to FNMTC. Using next-generation sequencing we performed deep sequencing to achieve 500* coverage of the targeted regions. At the end 45 variants were identified in 29 of 47 familial patients and 6 of 16 sporadic patients. Notably, several germline mutations were found matching between paired FNMTC patients from the same family, including APC L292F and A2778S, BRAF D22N, MSH6 G355S and A36V, MSH2 L719F, MEN1 G508D, BRCA1 SS955S, BRCA2 G2508S, and a GNAS inframe insertion. We demonstrated a novel approach to help diagnose and elucidate the genetic cause of the FNMTC patients, and assess whether their family members are exposed to a higher genetic risk. The findings would also provide insights on monitoring the potential second cancers for thyroid cancer patients. PMID- 26530884 TI - The micro-social risk environment for injection drug use: An event specific analysis of dyadic, situational, and network predictors of injection risk behavior. AB - BACKGROUND: This study explores the risk environment for drug use by examining injection risk behavior during specific injection episodes. By leveraging multiple observations of injection episodes of participants, the study attempts to move beyond global assessment of environmental variables to simultaneously model within (i.e., event level) as well as between (i.e., individual level) predictors of injection risk. Furthermore, gender is also explored as a potential moderator of the relationship between the association of specific partner characteristics (e.g., having an injection partner who is also a sexual partner) and injection risk behavior. METHODS: Data is used from the Sexual Acquisition of Transmission of HIV Cooperative Agreement Study (SATHCAP). Multilevel structural equation modeling is utilized to predict within and between variations in underlying injection risk behavior as measured using four indicators of injection risk. RESULTS: Results indicated that a number of partner level characteristics (i.e., being emotionally close with the partner, sexual partnership, being a first time partner) and one social situational (i.e., the number of non-injectors present at the injection episode) characteristic predicted event level injection risk behavior. However, the impact of partner characteristics also appears to be moderated by gender of the participants. More specifically, sharing a sexual partnership with an injection partner was more strongly associated with injection risk among females as compared to males and females indicated higher levels of risk when injecting with other females while the partner's gender showed no significant association with risk for male injectors. CONCLUSION: These results suggest that people who inject drug do report varying levels of risk during different injection episodes and this variation can be explained by partner and situational characteristics. Improved understanding of the social processes surrounding injection episodes is required to further refine harm reduction approaches. PMID- 26530885 TI - Nonlinear restoration of pulse and high noisy images via stochastic resonance. AB - We propose a novel scheme for restoring pulse and high noisy images using stochastic resonance, which is based on the modulation instability and provides a cross-correlation gain higher than 8. As opposed to previously reported designs, this unique approach employs a continuous noise and pulse signal for the generation of modulation instability. The visibility and quality of output images can be improved by appropriately adjusting the system parameters. This provides a simple and feasible method for detecting low-level or hidden pulse images in various imaging applications. PMID- 26530886 TI - Human chorionic gonadotropin beta subunit affects the expression of apoptosis regulating factors in ovarian cancer. AB - Expression of human chorionic gonadotropin, especially its free beta subunit (hCGbeta) were shown to play an important role in cancer growth, invasion and metastasis. It is postulated that hCGbeta is one of the factors determining cancer cell survival. To test this hypothesis, we applied two models: an in vitro model of ovarian cancer using OVCAR-3 and SKOV-3 cell lines transfected with the CGB5 gene and an in vivo model of ovarian cancer tissues. The material was tested against changes in expression level of genes encoding factors involved in apoptosis: BCL2, BAX and BIRC5. Overexpression of hCGbeta was found to cause a decrease in expression of the analyzed genes in the transfected cells compared with the control cells. In ovarian cancer tissues, high expression of CGB was related to significantly lower BCL2 but higher BAX and BIRC5 transcript levels. Moreover, a low BCL2/BAX ratio, characteristic of advanced stages of ovarian cancer, was revealed. Since tumors were discriminated by a significantly lower LHCGR level than the level noted in healthy fallopian tubes and ovaries, it may be stated that the effect of hCGbeta on changes in the expression of apoptosis regulating agents observed in ovarian cancer is LHCGR-independent. The results of the study suggest that the biological effects evoked by hCGbeta are related to apoptosis suppression. PMID- 26530887 TI - Suppressive effects of 3-bromopyruvate on the proliferation and the motility of hepatocellular carcinoma cells. AB - The compound 3-bromopyruvate (3BP) is an analogue of pyruvate, which is the final product of glycolysis that enters the citric acid cycle. The present study aimed to investigate the suppressive effects of 3BP on the proliferation and motility of hepatocellular carcinoma (HCC) cells. HLF and PLC/PRF/5 cells were cultured with 3BP and subjected to an MTS assay. Apoptosis was analyzed by hematoxylin and eosin staining. Cell motility was analyzed using a scratch assay. Real-time quantitative polymerase chain reaction (PCR) was performed to determine the expression levels of cyclin D1 and matrix metalloproteinase (MMP)9. Proliferation of both cell lines was significantly suppressed by 3BP at 100 uM (P<0.05). The expression level of cyclin D1 was decreased after 3BP treatment at 100 uM in both cell lines (P<0.05). Pyknotic nuclei were observed in the cells cultured with 3BP at 100 uM. These results revealed that 3BP suppressed cell proliferation, decreased the expression of cyclin D1, and induced apoptosis in HCC cells. 3BP significantly suppressed motility in both cell lines (P<0.05). The expression level of MMP9 was significantly decreased (P<0.05). 3BP suppressed the proliferation and motility of HCC cells by decreasing the expression of cyclin D1 and MMP9. PMID- 26530888 TI - Performance of novel hydroxyapatite nanowires in treatment of fluoride contaminated water. AB - Novel ultralong hydroxyapatite (HAP) nanowires were successfully prepared for fluoride removal for the first time. The fluoride adsorption on the HAP nanowires was studied on a batch mode. The results revealed that the adsorption data could be well described by the Freundlich model, and the adsorption kinetic followed the pseudo-second-order model. The maximum of adsorption capacity was 40.65 mg/g at pH 7.0 when the fluoride concentration is 200mg/L. The thermodynamic parameters suggested that the adsorption of fluoride was a spontaneous endothermic process. The FT-IR, XPS and Zeta potential analysis revealed that both anion exchange and electrostatic interactions were involved in the adsorption of fluoride. Furthermore, the HAP nanowires were made into HAP membrane through a simple process of suction filtration. Membrane filtration experiments revealed that the fluoride removal capabilities depended on the membrane thickness, flow rate and initial concentration of fluoride. The as prepared membrane could remove fluoride efficiently through continues filtration. The filtered water amount could reach 350, 192, and 64 L/m(2) when the fluoride concentrations were 4, 5 and 8 ppm, respectively, using the HAP membrane with only 150 MUm thickness. The as-synthesized ultralong HAP nanowires were thus demonstrated to be very effective and biocompatible adsorbents for fluoride removal from contaminated water. PMID- 26530889 TI - Inhibition of lipopolysaccharide induced acute inflammation in lung by chlorination. AB - Lipopolysaccharide (LPS, also called endotoxin) is a pro-inflammatory constituent of gram negative bacteria and cyanobacteria, which causes a potential health risk in the process of routine urban application of reclaimed water, such as car wash, irrigation, scenic water refilling, etc. Previous studies indicated that the common disinfection treatment, chlorination, has little effect on endotoxin activity removal measured by Limulus amebocyte lysate (LAL) assay. However, in this study, significant decrease of acute inflammatory effects was observed in mouse lung, while LAL assay still presented a moderate increase of endotoxin activity. To explore the possible mechanisms, the nuclear magnetic resonance (NMR) results showed the chlorination happened in alkyl chain of LPS molecules, which could affect the interaction between LPS and LPS-binding protein. Also the size of LPS aggregates was found to drop significantly after treatment, which could be another results of chlorination caused polarity change. In conclusion, our observation demonstrated that chlorination is effective to reduce the LPS induced inflammation in lung, and it is recommended to use health effect-based methods to assess risk removal of water treatment technologies. PMID- 26530890 TI - Filling environmental data gaps with QSPR for ionic liquids: Modeling n octanol/water coefficient. AB - Ionic liquids (ILs) form a wide group of compounds characterized by specific properties that allow using ILs in different fields of science and industry. Regarding that the growing production and use of ionic liquids increase probability of their emission to the environment, it is important to estimate the ability of these compounds to spread in the environment. One of the most important parameters that allow evaluating environmental mobility of compound is n-octanol/water partition coefficient (KOW). Experimental measuring of the KOW values for a large number of compounds could be time consuming and costly. Instead, computational predictions are nowadays being used more often. The paper presents new Quantitative Structure-Property Relationship (QSPR) model that allows predicting the logarithmic values of KOW for 335 ILs, for which the experimentally measured values had been unavailable. We also estimated bioaccumulation potential and point out which group of ILs could have negative impact on environment. PMID- 26530891 TI - One-step green synthesis of bimetallic Fe/Pd nanoparticles used to degrade Orange II. AB - To reduce cost and enhance reactivity, bimetallic Fe/Pd nanoparticles (NPs) were firstly synthesized using grape leaf aqueous extract to remove Orange II. Green synthesized bimetallic Fe/Pd NPs (98.0%) demonstrated a far higher ability to remove Orange II in 12h compared to Fe NPs (16.0%). Meanwhile, all precursors, e.g., grape leaf extract, Fe(2+) and Pd(2+), had no obvious effect on removing Orange II since less than 2.0% was removed. Kinetics study revealed that the removal rate fitted well to the pseudo-first-order reduction and pseudo-second order adsorption model, meaning that removing Orange II via Fe/Pd NPs involved both adsorption and catalytic reduction. The remarkable stability of Fe/Pd NPs showed the potential application for removing azo dyes. Furthermore, Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FTIR) confirmed the changes in Fe/Pd NPs before and after reaction with Orange II. High Performance Liquid Chromatography-Mass Spectrum (HPLC-MS) identified the degraded products in the removal of Orange II, and finally a removal mechanism was proposed. This one-step strategy using grape leaf aqueous extract to synthesize Fe/Pd NPs is simple, cost-effective and environmentally benign, making possible the large-scale production of Fe/Pd NPs for field remediation. PMID- 26530892 TI - Long-term performance and stability of a continuous granular airlift reactor treating a high-strength wastewater containing a mixture of aromatic compounds. AB - Continuous feeding operation of an airlift reactor and its inoculation with mature aerobic granules allowed the successful treatment of a mixture of aromatic compounds (p-nitrophenol, o-cresol and phenol). Complete biodegradation of p nitrophenol, o-cresol, phenol and their metabolic intermediates was achieved at an organic loading rate of 0.61 g COD L(-1)d(-1). Stable granulation was obtained throughout the long-term operation (400 days) achieving an average granule size of 2.0 +/- 1 mm and a sludge volumetric index of 26 +/- 1 mL g(-1) TSS. The identified genera in the aerobic granular biomass were heterotrophic bacteria able to consume aromatic compounds. Therefore, the continuous feeding regimen and the exposure of aerobic granules to a mixture of aromatic compounds make possible to obtain good granulation and high removal efficiency. PMID- 26530893 TI - Aqueous arsenite removal by simultaneous ultraviolet photocatalytic oxidation coagulation of titanium sulfate. AB - This study explored the efficacy and efficiency of a simultaneous UV-catalyzed oxidation-coagulation process of titanium sulfate (UV/Ti(SO4)2) for efficient removal of As(III) from water. It revealed that, As(III) could be oxidized to As(V) during the UV catalyzed coagulation of Ti(SO4)2 with highly efficient As(III) removal in the pH range 4-6. The UV catalyzed oxidation-coagulation showed surprisingly effective oxidation of As(III) to As(V) within a short time. XPS indicated that 84.7% of arsenic on the coagulated precipitate was in the oxidized form of As(V) after the UV/Ti(SO4)2 treatment of As(III) aqueous solutions at pH 5. Arsenic remaining in solution at high pH was in the oxidized form As(V). Removal efficiencies of As(III) were investigated as a function of pH, Ti(SO4)2 dosage, initial As(III) concentration and irradiation energy. As(III) could almost completely be removed (>99%) by the photocatalytic oxidation coagulation process with a moderate dose of Ti(SO4)2 in the pH range 4-6 at an initial arsenic concentration of 200 MUg/L. The mechanisms of the photocatalytic coagulation oxidation of Ti(SO4)2 are similar to those of UV/crystalline TiO2 particles, involving the formation and reactions of the hydroxyl radical OH and superoxide HO2/O2(-). PMID- 26530894 TI - Zirconium-catalyzed intermolecular hydrophosphination using a chiral, air-stable primary phosphine. AB - Catalytic hydrophosphination of alkenes using a chiral, air-stable primary phosphine, (R)-[2'-methoxy(1,1'-binapthalen)-2-yl]phosphine, (R)-MeO-MOPH2, proceeds under mild conditions with a zirconium catalyst, [kappa(5)-N,N,N,N,C (Me3SiNCH2CH2)2NCH2CH2NSiMe2CH]Zr (1), to selectively furnish anti-Markovnikov, air-stable secondary phosphines or tertiary phosphines with slight modification of the protocol. An intermediate in the catalysis, [(N3N)Zr(R)-MeO-MOPH] (4), was structurally characterized. PMID- 26530895 TI - Negative-Ion Electrospray Tandem Mass Spectrometry and Microarray Analyses of Developmentally Regulated Antigens Based on Type 1 and Type 2 Backbone Sequences. AB - Type 1 (Galbeta1-3GlcNAc) and type 2 (Galbeta1-4GlcNAc) sequences are constituents of the backbones of a large family of glycans of glycoproteins and glycolipids whose branching and peripheral substitutions are developmentally regulated. It is highly desirable to have microsequencing methods that can be used to precisely identify and monitor these oligosaccharide sequences with high sensitivity. Negative-ion electrospray tandem mass spectrometry with collision induced dissociation has been used for characterization of branching points, peripheral substitutions, and partial assignment of linkages in reducing oligosaccharides. We now extend this method to characterizing entire sequences of linear type 1 and type 2 chain-based glycans, focusing on the type 1 and type 2 units in the internal regions including the linkages connecting type 1 and type 2 disaccharide units. We apply the principles to sequence analysis of closely related isomeric oligosaccharides and demonstrate by microarray analyses distinct binding activities of antibodies and a lectin toward various combinations of type 1 and 2 units joined by 1,3- and 1,6-linkages. These sequence-specific carbohydrate-binding proteins are in turn valuable tools for detecting and distinguishing the type 1 and type 2-based developmentally regulated glycan sequences. PMID- 26530896 TI - This issue contains the variety of topics and locations for which our IJHPM is known. Introduction. PMID- 26530898 TI - Initial Assessment of Stewards of Children Program Effects on Child Sexual Abuse Reporting Rates in Selected South Carolina Counties. AB - Child sexual abuse (CSA) prevention programs often include a focus on increased reporting of suspected abuse, in addition to other prevention components such as helping trainees recognize suspected abusive situations. This study aimed to determine whether the Stewards of Children prevention program is associated with increased CSA reporting. Analyses examined whether rates of CSA allegations increased over time in three counties in South Carolina (SC) targeted with program dissemination efforts and whether CSA reporting trends differed between the three targeted counties and three comparison counties that did not experience substantial program dissemination. CSA allegation data were obtained by county and year for predissemination and postdissemination periods from the SC Department of Social Services. Results indicated that, for the targeted counties but not the nontargeted counties, estimated allegation rates increased significantly over time, corresponding with the onset of significant program dissemination efforts. Results also indicated significant between-groups differences in allegation trends for targeted versus nontargeted counties. These findings suggest that the Stewards prevention intervention may be associated with increased CSA allegations. However, results require replication with randomization of counties. Moreover, whether increased reporting is associated with decreased CSA incidence remains unknown. PMID- 26530899 TI - Boron-chelating fluorescent probe (BOPB) in the red region combined with CE-LIF for the detection of NO in mice liver. AB - Precise measurement of nitric oxide (NO) is of great importance to understand the function of NO in liver and the mechanism of liver injury. 8-(3',4'-Diamino phenyl)-3,5-(2-hydroxyphenyl)-dimethylene pyrrole (BOPB), a fluorescent probe in the red region (>600 nm) newly developed in our group, has good photostability and excitation/emission wavelength of 622/643 nm matching well with commercial 635 nm semiconductor laser of CE-LIF detection. Therefore, BOPB was used in CE LIF for the determination of NO in mice liver. Both derivatization and separation conditions were optimized. Derivatization reaction of BOPB and NO was carried out in pH 7.4 PBS buffer at 35 degrees C for 12 min and the separation of NO derivative of BOPB (BOPB-T) was achieved within 7.0 min in pH 9.0 running buffer containing 15 mM H3 BO3 -NaOH and 15 mM SDS. Good linearity was found in the range of 1.0 * 10(-9) -5.0 * 10(-7) M with the LOD of 0.02 nM. The proposed method was applied to the analysis of NO in real samples, and NO concentration was obviously increased in acute liver injury of mice. Compared to existing derivatization-based CE-LIF methods for NO, this method has lower LOD and less background interference owing to detection wavelength of BOPB in the red region. PMID- 26530900 TI - Tsukamurella hongkongensis sp. nov. and Tsukamurella sinensis sp. nov., isolated from patients with keratitis, catheter-related bacteraemia and conjunctivitis. AB - Three bacterial strains, HKU51T, HKU52T and HKU53, were isolated from a conjunctival swab, corneal scraping and blood culture of three patients in Hong Kong with conjunctivitis, keratitis and catheter-related bacteraemia, respectively. Cells were Gram-stain-positive, aerobic, catalase-positive, non sporulating and non-motile bacilli. The three strains had unique biochemical profiles that were distinguishable from those of closely related species of the genus Tsukamurella. Fatty acids, mycolic acids, cell-wall sugars and peptidoglycan analyses showed that they were typical of members of Tsukamurella. 16S rRNA gene sequence analysis revealed 100 % sequence identity between HKU52T and HKU53, and the two strains shared 99.5 % sequence identity with Tsukamurella sunchonensis JCM 15929T and Tsukamurella pseudospumae JCM 13375T; HKU51T shared 99.6 % sequence identity with Tsukamurella pulmonis CCUG 35732T. The DNA G+C contents of strains HKU51T, HKU52T and HKU53 were 70.9 +/- 2.2, 71.3 +/- 2.1 and 71.2 +/- 2.3 mol% (mean +/- sd; n = 3), respectively. DNA-DNA hybridization confirmed that the novel strains were distinct from other known species of the genus Tsukamurella ( <= 50.1 +/- 3.7 % DNA-DNA relatedness); two of the isolates, HKU52T and HKU53, represented the same species ( >= 94.6 +/- 5.6 % DNA-DNA relatedness), while the third isolate, HKU51T, represented another species. The novel species Tsukamurella hongkongensis sp. nov. is proposed to accommodate strains HKU52T and HKU53, with HKU52T ( = JCM 30715T = DSM 100208T) as the type strain; whilst another novel species, Tsukamurella sinensis sp. nov., is proposed to accommodate the third isolate, HKU51T ( = JCM 30714T = DSM 100207T), which is designated the type strain. PMID- 26530901 TI - Copper Keplerates: High-Symmetry Magnetic Molecules. AB - Keplerates are molecules that contain metal polyhedra that describe both Platonic and Archimedean solids; new copper keplerates are reported, with physical studies indicating that even where very high molecular symmetry is found, the low temperature physics does not necessarily reflect this symmetry. PMID- 26530902 TI - Identification of Bone-Derived Factors Conferring De Novo Therapeutic Resistance in Metastatic Prostate Cancer. AB - Resistance to currently available targeted therapies significantly hampers the survival of patients with prostate cancer with bone metastasis. Here we demonstrate an important resistance mechanism initiated from tumor-induced bone. Studies using an osteogenic patient-derived xenograft, MDA-PCa-118b, revealed that tumor cells resistant to cabozantinib, a Met and VEGFR-2 inhibitor, reside in a "resistance niche" adjacent to prostate cancer-induced bone. We performed secretome analysis of the conditioned medium from tumor-induced bone to identify proteins (termed "osteocrines") found within this resistance niche. In accordance with previous reports demonstrating that activation of integrin signaling pathways confers therapeutic resistance, 27 of the 90 osteocrines identified were integrin ligands. We found that following cabozantinib treatment, only tumor cells positioned adjacent to the newly formed woven bone remained viable and expressed high levels of pFAK-Y397 and pTalin-S425, mediators of integrin signaling. Accordingly, treatment of C4-2B4 cells with integrin ligands resulted in increased pFAK-Y397 expression and cell survival, whereas targeting integrins with FAK inhibitors PF-562271 or defactinib inhibited FAK phosphorylation and reduced the survival of PC3-mm2 cells. Moreover, treatment of MDA-PCa-118b tumors with PF-562271 led to decreased tumor growth, irrespective of initial tumor size. Finally, we show that upon treatment cessation, the combination of PF-562271 and cabozantinib delayed tumor recurrence in contrast to cabozantinib treatment alone. Our studies suggest that identifying paracrine de novo resistance mechanisms may significantly contribute to the generation of a broader set of potent therapeutic tools that act combinatorially to inhibit metastatic prostate cancer. PMID- 26530903 TI - Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations. AB - Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical relevance of our findings, we confirm that NRF2 and protumorigenic NRF2 target genes were activated in some actinic keratoses, the major precancerous lesion in human skin. Overall, our results reveal an unexpected tumor-promoting activity of activated NRF2 during early phases of skin tumorigenesis. PMID- 26530904 TI - Flexible CNT-array double helices Strain Sensor with high stretchability for Motion Capture. AB - Motion capture is attracting more and more attention due to its potential wide applications in various fields. However, traditional methods for motion capture still have weakness such as high cost and space consuming. Based on these considerations, a flexible, highly stretchable strain sensor with high gauge factor for motion capture is fabricated with carbon nanotube (CNT) array double helices as the main building block. Ascribed to the unique flexible double helical CNT-array matrix, the strain sensor is able to measure strain up to 410%, with low hysteresis. Moreover, a demonstration of using this strain sensor for capture hand motion and to control a mechanical hand in real time is also achieved. A model based on finite difference method is also made to help understand the mechanism of the strain sensors. Our work demonstrates that strain sensors can measure very large strain while maintaining high sensitivity, and the motion capture based on this strain sensor is expected to be less expensive, more convenient and accessible. PMID- 26530905 TI - Computer simulation of human leukocyte antigen genes supports two main routes of colonization by human populations in East Asia. AB - BACKGROUND: Recent genetic studies have suggested that the colonization of East Asia by modern humans was more complex than a single origin from the South, and that a genetic contribution via a Northern route was probably quite substantial. RESULTS: Here we use a spatially-explicit computer simulation approach to investigate the human migration hypotheses of this region based on one-route or two-route models. We test the likelihood of each scenario by using Human Leukocyte Antigen (HLA) - A, -B, and - DRB1 genetic data of East Asian populations, with both selective and demographic parameters considered. The posterior distribution of each parameter is estimated by an Approximate Bayesian Computation (ABC) approach. CONCLUSIONS: Our results strongly support a model with two main routes of colonization of East Asia on both sides of the Himalayas, with distinct demographic histories in Northern and Southern populations, characterized by more isolation in the South. In East Asia, gene flow between populations originating from the two routes probably existed until a remote prehistoric period, explaining the continuous pattern of genetic variation currently observed along the latitude. A significant although dissimilar level of balancing selection acting on the three HLA loci is detected, but its effect on the local genetic patterns appears to be minor compared to those of past demographic events. PMID- 26530906 TI - Potential for the development of a marketing option for the specialty local Ban pork of a Thai ethnic smallholder cooperative group in Northwest Vietnam. AB - Based on 12 years of research (SFB 564 "The Uplands Program"), a community-based breeding and marketing cooperative group was transferred to an ethnic farmer group. This study analyses the potential for developing a marketing channel for specialty local Ban pork as an alternative to supplying the local markets to ensure long-term sustainability of the communal local pig breeding and production system. Data on pig-keeping were investigated from 378 farmers who wanted to enroll in the cooperative group in 10 villages (near town, intermediate, and remote zones) in Son La province. The data on Ban pig marketing activities of the cooperative group were investigated for all of its 180 members. Information on the market demand for Ban pigs were collected by interviewing 57 traders in Hanoi city and Son La province. The results show a dominance of local Ban in remote areas, and a preference for crossbreds with exotics in closer-to-town areas. Before farmers joined the cooperative group, the commercialization of pigs in remote villages accounted for only 3.0 pigs/farm/year compared to 9.3 pigs/farm/year in the intermediate zone and 11.2 pigs/farm/year near town. Potential markets have been identified for each product category of the cooperative group. Pure Ban pigs with a weight of 10-15 kg were preferred most by customers in Hanoi city. The regular feedback of information on niche markets for different products has increased the awareness of farmers about the competitiveness of the local pig products, and the power of collective action in the market. Selected pure Ban pigs were increasingly sold to food stores in Hanoi with high prices. Farmers received an average of 9000 VND more compared to the local market price for each kg of live weight. The respective added value for the cooperative group amounted to 11,300 VND/kg live weight. The added value from selling specialty Ban pigs regularly to markets, encouraged farmers toward a market in local pig production and participation in the cooperative group. For the long-term development of the cooperative group, trademark registration is envisaged, along with strict quality control to help protect the brand of the product. PMID- 26530908 TI - The design of underwater superoleophobic Ni/NiO microstructures with tunable oil adhesion. AB - Controlling oil adhesion in water is a fundamental issue in many practical applications for surfaces. Currently, almost all studies on underwater oil adhesion control are concentrated on regulating surface chemistry on polymer surfaces, and structure-dependent underwater oil adhesion is still rare, especially on inorganic materials. Herein, we report a series of underwater superoleophobic Ni/NiO surfaces with controlled oil adhesions by combining electro-deposition and heating techniques. The adhesive forces between an oil droplet and the surfaces can be adjusted from an extremely low (less than 1 MUN) to a very high value (about 60 MUN), and the tunable effect can be attributed to different wetting states that result from different microstructures on the surfaces. Moreover, the oil-adhesion controllability for different types of oils was also analyzed and the applications of the surface including oil droplet transportation and self-cleaning were discussed. The results reported herein provide a new feasible method for fabrication of underwater superoleophobic surfaces with controlled adhesion, and improve the understanding of the relationship between surface microstructures, adhesion, and the fabrication principle of tunable oil adhesive surfaces. PMID- 26530907 TI - Crude glycerin combined with sugar cane silage in lamb diets. AB - This study aimed to evaluate the effect of the level of crude glycerin (CG) on in vitro fermentation kinetics (0, 20, 40, 60, and 80 g/kg DM of sugar cane silage), on in vitro neutral detergent fiber (NDF) degradation (0, 30, 60, and 90 g/kg DM of sugar cane silage), and intake and digestibility of nutrients and nitrogen balance (0, 20, 55, 82, and 108 g/kg DM of sugar cane silage) in lambs. The in vitro trials were conducted in a completely randomized design with three repetitions. The in vivo trial was conducted in a Latin square design with five repetitions (5 * 5). For variables in which the F test was considered significant, the statistical interpretation of the effect of CG substitution levels was carried out through regression analyses. Kinetic parameters were not affected by CG inclusion. On in vitro NDF degradation, a significant effect of CG levels was observed on the potentially degradable fraction of NDF, the insoluble potentially degradable fraction of NDF, and the undegradable NDF fraction. The intake and digestibility of nutrients and nitrogen balance were not affected by CG inclusion. The CG levels change in vitro NDF degradability parameters; however, there were no changes in animal intake, digestibility, and nitrogen balance with the inclusion levels used. PMID- 26530909 TI - The proteasome inhibitor lactacystin enhances GSH synthesis capacity by increased expression of antioxidant components in an Nrf2-independent, but p38 MAPK dependent manner in rat colorectal carcinoma cells. AB - Proteasome inhibitors may induce ER stress and oxidative stress, disrupt signaling pathways, and trigger apoptosis in several cancer cells. However, they are also reported to increase glutathione (GSH) synthesis and protect cells from oxidative stress. In the present study, we showed that the proteasome inhibitor lactacystin increased reactive oxygen species (ROS) and GSH levels after the treatment of HT-29 colorectal cancer cells. The increased GSH depended upon the activity of glutamate cysteine ligase (GCL), uptake of cystine/cysteine via the cystine/glutamate transporter [Formula: see text], and the activity of gamma glutamyltransferase (GGT). Increased transcription levels of the catalytic subunit of glutamate cysteine ligase (GCLC), the catalytic subunit xCT of [Formula: see text], and GGT were induced by lactacystin, although with different kinetics and stoichiometry. Lactacystin treatment also augmented protein levels of GCLC, xCT, and GGT, but significant levels were not detected until 48 h after initiation of lactacystin treatment. These increases in protein levels were dependent on the p38 MAPK pathway. Studies in cells transfected with siRNA against the transcription factor Nrf2 demonstrated that the promoter activities of xCT and GCLC, but not of GGT, depended on Nrf2. However, depletion of Nrf2 had no effect on lactacystin-induced upregulation of the GGT, GCLC, and xCT mRNA levels. Taken together, our results suggest that oxidative stress provoked by proteasomal inhibition results in the elevation of cellular GSH levels due to increased synthesis of GSH and uptake of cystine/cysteine. Following treatment with lactacystin, enhanced expression of antioxidant components involved in GSH homeostasis is p38 MAPK-dependent, but Nrf2-independent, resulting in increased GSH synthesis capacity. PMID- 26530910 TI - Melamine Alters Glutamatergic Synaptic Transmission of CA3-CA1 Synapses Presynaptically Through Autophagy Activation in the Rat Hippocampus. AB - Melamine is an industrial chemical that can cause central nervous system disorders including excitotoxicity and cognitive impairment. Its illegal use in powdered baby formula was the focus of a milk scandal in China in 2008. One of our previous studies showed that melamine impaired glutamatergic transmission in rat hippocampal CA1 pyramidal cells. However, the underlying mechanism of action of melamine is unclear, and it is unknown if the CA3-CA1 pathway is directly involved. In the present study, a whole-cell patch-clamp technique was employed to investigate the effect of melamine on the hippocampal CA3-CA1 pathway in vitro. Both the evoked excitatory postsynaptic current (eEPSC) and the paired pulse ratio (PPR) were recorded. Furthermore, we examined whether autophagy was involved in glutamatergic transmission alterations induced by melamine. Our data showed that melamine significantly increased the amplitude of eEPSCs in a dose dependent manner. Inhibition of the N-methyl-D-aspartic acid receptor did not prevent the increase in eEPSC amplitude. In addition, the PPR was remarkably decreased by a melamine concentration of 5 * 10(-5) g/mL. It was found that autophagy could be activated by melamine and an autophagy inhibitor, 3-MA, prevented the melamine-induced increase in eEPSC amplitude. Overall, our results show that melamine presynaptically alters glutamatergic synaptic transmission of hippocampal CA3-CA1 synapses in vitro and this is likely associated with autophagy alteration. PMID- 26530911 TI - Imaging Functional Nucleic Acid Delivery to Skin. AB - Monogenic skin diseases arise from well-defined single gene mutations, and in some cases a single point mutation. As the target cells are superficial, these diseases are ideally suited for treatment by nucleic acid-based therapies as well as monitoring through a variety of noninvasive imaging technologies. Despite the accessibility of the skin, there remain formidable barriers for functional delivery of nucleic acids to the target cells within the dermis and epidermis. These barriers include the stratum corneum and the layered structure of the skin, as well as more locally, the cellular, endosomal and nuclear membranes. A wide range of technologies for traversing these barriers has been described and moderate success has been reported for several approaches. The lessons learned from these studies include the need for combinations of approaches to facilitate nucleic acid delivery across these skin barriers and then functional delivery across the cellular and nuclear membranes for expression (e.g., reporter genes, DNA oligonucleotides or shRNA) or into the cytoplasm for regulation (e.g., siRNA, miRNA, antisense oligos). The tools for topical delivery that have been evaluated include chemical, physical and electrical methods, and the development and testing of each of these approaches has been greatly enabled by imaging tools. These techniques allow delivery and real time monitoring of reporter genes, therapeutic nucleic acids and also triplex nucleic acids for gene editing. Optical imaging is comprised of a number of modalities based on properties of light-tissue interaction (e.g., scattering, autofluorescence, and reflectance), the interaction of light with specific molecules (e.g., absorbtion, fluorescence), or enzymatic reactions that produce light (bioluminescence). Optical imaging technologies operate over a range of scales from macroscopic to microscopic and if necessary, nanoscopic, and thus can be used to assess nucleic acid delivery to organs, regions, cells and even subcellular structures. Here we describe the animal models, reporter genes, imaging approaches and general strategies for delivery of nucleic acids to cells in the skin for local expression (e.g., plasmid DNA) or gene silencing (e.g., siRNA) with the intent of developing nucleic acid-based therapies to treat diseases of the skin. PMID- 26530912 TI - In Vivo Magnetic Resonance Imaging of Small Interfering RNA Nanodelivery to Pancreatic Islets. AB - Pancreatic islet transplantation is a promising therapeutic approach for type 1 diabetes.However, recent advances in islet transplantation are limited by significant graft loss after transplantation. Multiple immunological and nonimmunological factors contribute to this loss. Novel therapies that could target the core reasons for the islet graft loss are desperately needed. Small interfering RNA can be used to inhibit the expression of virtually any gene with single-nucleotide specificity including genes responsible for islet damage. Applying adequate delivery of siRNA molecules to pancreatic islets prior to transplantation holds a great potential for improving the survival of islet grafts. Noninvasive imaging provides means for monitoring the survival of transplanted islets in real time. Here, we summarize the approach that has been developed to deliver siRNA to pancreatic islets in conjunction with tracking of the graft outcome by in vivo magnetic resonance imaging (MRI). We synthesize a nano-sized theranostic agent consisting of magnetic nanoparticles (MN), a reporter for MRI, labeled with Cy5.5 dye for near-infrared fluorescence (NIRF) imaging, and conjugated to siRNA molecule targeting genes that are harmful to islet grafts. Pre-labeling of islets by MN-Cy5.5-siRNA allowed us to monitor the survival of transplanted islet grafts by MRI and NIRF imaging and resulted in efficient silencing of the target genes in vivo. This novel approach combines a therapeutic effect provided by RNA interference technology with in vivo MR imaging and is expected to significantly improve the outcome of islet transplantation in patients with type 1 diabetes. PMID- 26530913 TI - Magnetic Resonance Spectroscopy of siRNA-Based Cancer Therapy. AB - Small interfering RNA (siRNA) is routinely used as a biological tool to silence specific genes, and is under active investigation in cancer treatment strategies. Noninvasive magnetic resonance spectroscopy (MRS) provides the ability to assess the functional effects of siRNA-mediated gene silencing in cultured cancer cells, and following nanoparticle-based delivery in tumors in vivo. Here we describe the use of siRNA to downregulate choline kinase, a critical enzyme in choline phospholipid metabolism of cancer cells and tumors, and the use of (1)H MRS of cells and (1)H magnetic resonance spectroscopic imaging (MRSI) of tumors to assess the efficacy of the downregulation. PMID- 26530914 TI - Targeted Delivery with Imaging Assessment of siRNA Expressing Nanocassettes into Cancer. AB - Molecular therapy using small interfering RNA (siRNA) shows great promise in the development of novel therapeutics for cancer. Although various approaches have been developed for in vivo delivery of siRNAs into tumors, stability of siRNA in blood circulation, and low efficiency of siRNA delivery into tumor cells are the major obstacles for further translation into cancer therapeutics. In this protocol, we describe methods of the production of shRNA expressing DNA nanocassettes by PCR amplification of double-stranded DNA fragments containing a U6 promoter and a shRNA gene. Those DNA nanocassettes can be conjugated to the polymer coating of nanoparticles that are targeted to cellular receptors highly expressed in tumor cells, such as urokinase plasminogen activator receptor (uPAR), for targeted delivery and receptor mediated internalization of shRNA expressing DNA nanocassettes. Methods for in vitro and in vivo evaluation of target specificity and gene-knockdown effect are also provided. PMID- 26530915 TI - Analyses of Tumor Burden In Vivo and Metastasis Ex Vivo Using Luciferase Expressing Cancer Cells in an Orthotopic Mouse Model of Neuroblastoma. AB - Cancer xenograft mouse models are useful for examining and understanding tumor growth and cancer progression in vivo. With the development of bioluminescent imaging, these parameters can now be monitored noninvasively with relative ease. Herein we describe imaging of luciferase-expressing cancer cells to quantitatively measure tumor burden in vivo and metastases ex vivo. Specifically, we detail the methodology to examine the effect of shRNA-mediated knockdown of a target gene on the growth and spread of neuroblastoma tumors in immune-deficient mice. PMID- 26530916 TI - Indium-Labeling of siRNA for Small Animal SPECT Imaging. AB - Ever since the discovery of RNA interference (RNAi), therapeutic delivery of siRNA has attracted a lot of interest. However, due to the nature and structure of siRNA, a carrier is needed for any mode of systemic treatment. Furthermore, specific imaging techniques are required to trace where the deposition of the siRNA occurs throughout the body after treatment. Tracking in vivo siRNA biodistribution allows understanding and interpreting therapeutics effects and side effects. A great advantage of noninvasive imaging techniques such as SPECT imaging is that several time points can be assessed in the same subject. Thus, the time course of biodistribution or metabolic processes can be followed. Therefore, we have described an approach to modify siRNA with a DTPA (Diethylene Triamine Pentaacetic Acid) chelator in order to utilize an indium labeled siRNA for SPECT imaging. Here, we explain the details of the labeling and purification procedures. PMID- 26530917 TI - Imaging of Electrotransferred siRNA. AB - SiRNA delivery to the cytoplasm can be obtained through the application of calibrated electric field pulses to a mixture of cells and oligonucleotides. To investigate the uptake pathway, time lapse confocal fluorescence microscopy provides a direct visualization of the transfer. SiRNA is electrophoretically drifted directly to the cytoplasm during the pulse. No post pulse transfer is observed. The uploaded siRNA then freely diffuse in the cytoplasm with no access to the nuclei. PMID- 26530918 TI - Whole-Body Scanning PCR, a Tool for the Visualization of the In Vivo Biodistribution Pattern of Endogenous and Exogenous Oligonucleotides in Rodents. AB - Characterizing the in vivo biodistribution pattern and relative expression levels of oligonucleotide-based molecules such as mRNA, miRNA, siRNA, and anti-miRNAs in animal models, could be a helpful first-step in the successful development of therapeutic oligonucleotides. Here we describe a simple procedure called "Whole Body Scanning PCR" (WBS-PCR), which combines the power of PCR with that of imaging. WBS-PCR relies on 384 well-defined extractions across a mouse whole-body section followed by a single dilution step which renders the lysates compatible with various qPCR-based assays. The in vivo biodistribution maps are generated by deconvoluting the qPCR data and converting it into a TissueView compatible image file which can be overlaid with an image of the whole-body section used for extractions. WBS-PCR is a flexible platform that can be adapted to other detection systems and thereby further expand the use of this technology. PMID- 26530920 TI - Sensing miRNA: Signal Amplification by Cognate RISC for Intracellular Detection of miRNA in Live Cells. AB - The ability to detect miRNA expression in live cells would leave these cells available for further manipulation or culture. Here, we describe the design of a miRNA sensor oligonucleotide whose sequence mimics the target mRNA. The sensor has a fluorescent label on one end of the oligo and a quencher on the other. When inside the cell, the sensor is recognized by its cognate miRNA-RISC and gets cleaved, setting the fluorophore free from its quencher. This results in fluorescence "turn on." Since cleavage by the RISC complex is an enzymatic process, the described approach has a very high level of sensitivity (nM). The rate of nonspecific cleavage of the sensor is very slow permitting the collection of meaningful signal over a long period of time. PMID- 26530919 TI - siRNA Nanoparticles for Ultra-Long Gene Silencing In Vivo. AB - Small interfering RNA (siRNA)-mediated gene silencing has shown prominent therapeutic effects in treating various diseases. However, adequate delivery and persistent gene silencing remain challenging. A nanoparticle-based delivery system which assembled by layering siRNAs between protease degradable polypeptides to show ultra-long gene silencing effect in vivo is developed. Gold nanoparticle is used as a scaffold for its unique properties including uniform size, biocompatibility, ready synthesis, and easy functionalization. A simple layer-by-layer fabrication approach, based on the electrostatic interaction between positively and negatively charged polymers, is applied to package the therapeutic siRNAs. PMID- 26530921 TI - Molecular Beacon-Based MicroRNA Imaging During Neurogenesis. AB - The fluorescence monitoring system for examining endogenous microRNA (miRNA) activity in cellular level provides crucial information on not only understanding a critical role of miRNA involving a variety of biological processes, but also evaluating miRNA expression patterns in a noninvasive manner. In this protocol, we report the details of a new procedure for a molecular beacon-based miRNA monitoring system, which includes the illustration scheme for miRNA detection strategy, exogenous miRNA detection, and measurement of endogenous miRNA expression level during neurogenesis. The fluorescence signal of miR-124a beacon quenched by BHQ2 was gradually recovered as increasing concentration of the miR 124a in tube. The functional work of miR-124a beacon was examined in intracellular environment, allowing for the internalization of the miR-124a beacon by lipofectamine, which resulted in activated fluorescent signals of the miR-124a beacon in the HeLa cells after the addition of synthetic miR-124a. The endogenous miR-124a expression level was detected by miR-124a beacon system during neurogenesis, showing brighter fluorescence intensity in cytoplasmic area of P19 cells after induction of neuronal differentiation by retinoic acid. The molecular beacon based-miRNA detection technique could be applicable to the simultaneous visualization of a variety of miRNA expression patterns using different fluorescence dyes. For the study of examining endogenous miRNA expression level using miRNA-beacon system, if cellular differentiation step is already prepared, transfection step of miR-124a beacon into P19 cells, and acquisition of activated fluorescence signal measured by confocal microscope can be conducted approximately within 6 h. PMID- 26530922 TI - Hypoxia-Responsive Copolymer for siRNA Delivery. AB - A wide variety of nanomedicine has been designed for cancer therapy. Herein, we describe the synthesis and evaluation of a hypoxia-responsive copolymer for siRNA delivery (Perche et al., Angew Chem Int Ed Engl 53:3362-3366, 2014). The synthesis is achieved using established coupling chemistry and accessible purification procedures. A polyelectrolyte-lipid conjugate (polyethyleneimine 1.8 kDa-dioleyl-phosphatidylinositol, PEI-PE) and polyethylene glycol 2000 (PEG) were assembled via the hypoxia-sensitive azobenzene (Azo) unit to obtain the PEG-Azo PEI-DOPE copolymer. This copolymer can condense siRNA and shows hypoxia-induced cellular internalization and reporter gene downregulation in vitro and tumor accumulation in vivo after parenteral administration (Perche et al., Angew Chem Int Ed Engl 53:3362-3366, 2014). We also detail procedures to evaluate hypoxia targeted polymers both in monolayer cultures, cancer cell spheroids and in tumor xenografts murine models. PMID- 26530923 TI - Controlling RNA Expression in Cancer Using Iron Oxide Nanoparticles Detectable by MRI and In Vivo Optical Imaging. AB - Herein, we describe a protocol for the preparation of iron oxide nanoparticle based contrast agents and drug delivery vehicles for noninvasive cancer imaging and therapy. In the first part of the chapter we describe the details of the contrast agent synthesis, functionalization, and characterization. In the second part we describe the methods for tumor imaging using the synthesized particles with noninvasive T2-weighted magnetic resonance imaging (MRI) and in vivo near infrared optical imaging. PMID- 26530924 TI - Microvesicles: Isolation, Characterization for In Vitro and In Vivo Procedures. AB - Microvesicles and exosomes are released to the extracellular milieu and are detectable in body fluids. They act as unique vehicles for cargo transfer to other cells/tissues. They contain a set of membrane receptors, intracellular proteins and nucleic acids. Here, we describe basic techniques for their isolation and characterization from cell culture media or body fluids. We also describe critical techniques for characterizing their cargo (miRNAs) and their protein content. Finally, we present labeling methods for their use in in vitro procedures and for their in vivo delivery and subsequent analysis of their cargo transfer to multiple cell types. PMID- 26530925 TI - Positive Bioluminescence Imaging of MicroRNA Expression in Small Animal Models Using an Engineered Genetic-Switch Expression System, RILES. AB - MicroRNAs (miRNAs) are a class of small, noncoding RNAs which regulate gene expression by directing their target mRNA for degradation or translational repression. Since their discovery in the early 1990s, miRNAs have emerged as key components in the posttranscriptional regulation of gene networks, shaping many biological processes from development, morphogenesis, differentiation, proliferation and apoptosis. Although understanding of the molecular basis of miRNA biology is improving, methods to monitor the dynamic and the spatiotemporal aspects of miRNA expression under physiopathological conditions are required. However, monitoring of miRNAs is difficult due to their small size, low abundance, high degree of sequence similarity, and their dynamic expression pattern which is subjected to tight transcriptional and post-transcriptional controls. Recently, we developed a miRNA monitoring system called RILES, standing for RNAi-inducible expression system, which relies on an engineered regulatable expression system, to switch on the expression of the luciferase gene when the targeted miRNA is expressed in cells. We demonstrated that RILES is a specific, sensitive, and robust method to determine the fine-tuning of miRNA expression during the development of an experimental pathological process in mice. Because RILES offers the possibility for longitudinal studies on individual subjects, sharper insights into miRNA regulation can be generated, with applications in physiology, pathophysiology and development of RNAi-based therapies. This chapter describes methods and protocols to monitor the expression of myomiR-206, -1, and 133 in the tibialis anterior muscle of mice. These protocols can be used and adapted to monitor the expression of other miRNAs in other biological processes. PMID- 26530926 TI - MicroRNA Imaging in Combination with Diagnostic Ultrasound and Bubble Liposomes for MicroRNA Delivery. AB - MicroRNA (miRNA) is expected to play an important role in the diagnosis and therapy of various diseases. In miRNA therapy, the development of delivery tools to the target site is considered to be essential. By using a delivery tool possessing imaging ability, miRNA colocalized with the carrier could be visualized after administration. We prepared polyethylene glycol (PEG)-modified liposomes containing echo-contrast gas, "Bubble liposomes" (BLs), and confirmed that BLs containing cationic lipid were capable of loading miRNA. Furthermore, we also achieved the imaging and delivery of systemically injected miRNA to target site in combination with ultrasound exposure. MiRNA-loaded BLs could be a useful tool for imaging and therapy. PMID- 26530927 TI - Vitamin D status, body composition and glycemic control in an ambulatory population with diabetes and chronic kidney disease. AB - BACKGROUND/OBJECTIVES: To determine the interrelationships between body composition, glycemic control and vitamin D status in an ambulatory population with diabetes (DM) and chronic kidney disease (CKD). SUBJECTS/METHODS: Adult (18 80 years) patients (n=60) with DM and stage 1-4 CKD were recruited from the Northern Alberta Renal Program. Outcome variables included body composition (absolute/regional fat (FM)/lean soft tissue/total mass, percent fat/lean/fat free (FFM) mass), glycemic control (glycated hemoglobin (HbA1c)), vitamin D intake (dietary/supplemental) and vitamin D status (25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D)) measured by validated methodologies. Sarcopenia was determined as an appendicular skeletal mass/height(2) less than 7.26 kg/m(2) (males) and 5.45 kg/m(2) (females). RESULTS: Suboptimal HbA1c (>7%), 25(OH)D (<50 nmol/l) and 1,25(OH)2D (<43 pmol/l) concentrations were present in 57, 8 and 11% of participants. Ten percent of subjects had sarcopenia. Gender/age/DM type, not CKD, significantly influenced regional/whole body composition. Females, older participants and those with type 2 DM had higher %FM. No significant interrelationships between vitamin D status and glycemic control were observed (P>0.05). Serum 25(OH)D concentrations were inversely associated with arm lean soft tissue/FFM/total mass, weight, appendicular skeletal mass, lean soft tissue/height(2), FFM/height(2), appendicular skeletal mass/height(2) and body mass index (P<0.05). Sarcopenia occurred more frequently in patients with 25(OH)D concentrations ?100 nmol/l. Regional/whole body %FM was inversely related to 1,25(OH)2D, not 25(OH)D. CONCLUSIONS: Body composition, not glycemic control, is associated with vitamin D status in an ambulatory population of adults with DM and CKD. PMID- 26530928 TI - Flavonoid and lignan intake in a Mediterranean population: proposal for a holistic approach in polyphenol dietary analysis, the Moli-sani Study. AB - BACKGROUND/OBJECTIVES: The objective of this study is to extract and assess data on the dietary intake of flavonoids and lignans in a healthy free-living Mediterranean population, using newly updated harmonized European Union food composition data. This work also aimed at analyzing in a holistic way the total content of the diet in major classes of polyphenols. SUBJECTS/METHODS: Six thousand nine hundred and eighty-one men and 7048 women (aged ? 35 years) of the Moli-sani cohort, randomly recruited from the general population, were analyzed. The European Prospective Investigation into Cancer (EPIC) and Nutrition-Food Frequency Questionnaire was used for dietary assessment. The polyphenol content of each food group was evaluated using Eurofir BioActive Substances in Food Information System and the United States Department of Agriculture food composition tables (FCTs), when data were missing. Flavonol, flavone, flavanone, flavanol, anthocyanin, isoflavone and lignan intakes were calculated and polyphenol antioxidant content (PAC) score (-28, 28) constructed, to assess the total content of the diet in these nutrients. RESULTS: Seasonal and citrus fruits, leafy, grain, pod and root vegetables, and onions and garlic accounted for different proportions (11-70%) of the total intake of different polyphenols. Within the Moli-sani population, men or older, or no/former smokers, or physically active or obese/overweight individuals presented higher consumption of flavonoids, lignans and PAC score (P for all <0.01). Multiple regression analysis showed that PAC score and its seven components were positively associated with Mediterranean diet (MeD) adherence in both genders (beta-coefficient >0, P<0.001). In addition, 1 unit increase in PAC score was associated with 7.1-7.8% increase in the likelihood of high MeD adherence (P<0.001). CONCLUSIONS: The intake of flavonoids and lignans in an European Union population was calculated using harmonized European Union FCT data. In addition, a holistic approach in dietary analysis of polyphenol intake was proposed. PMID- 26530929 TI - Cell phone intervention for you (CITY): A randomized, controlled trial of behavioral weight loss intervention for young adults using mobile technology. AB - OBJECTIVE: To determine the effect on weight of two mobile technology-based (mHealth) behavioral weight loss interventions in young adults. METHODS: Randomized, controlled comparative effectiveness trial in 18- to 35-year-olds with BMI >= 25 kg/m(2) (overweight/obese), with participants randomized to 24 months of mHealth intervention delivered by interactive smartphone application on a cell phone (CP); personal coaching enhanced by smartphone self-monitoring (PC); or Control. RESULTS: The 365 randomized participants had mean baseline BMI of 35 kg/m(2) . Final weight was measured in 86% of participants. CP was not superior to Control at any measurement point. PC participants lost significantly more weight than Controls at 6 months (net effect -1.92 kg [CI -3.17, -0.67], P = 0.003), but not at 12 and 24 months. CONCLUSIONS: Despite high intervention engagement and study retention, the inclusion of behavioral principles and tools in both interventions, and weight loss in all treatment groups, CP did not lead to weight loss, and PC did not lead to sustained weight loss relative to Control. Although mHealth solutions offer broad dissemination and scalability, the CITY results sound a cautionary note concerning intervention delivery by mobile applications. Effective intervention may require the efficiency of mobile technology, the social support and human interaction of personal coaching, and an adaptive approach to intervention design. PMID- 26530930 TI - Radiologic evidence that hypothalamic gliosis is associated with obesity and insulin resistance in humans. AB - OBJECTIVE: To use quantitative magnetic resonance imaging (MRI) to test whether mediobasal hypothalamic (MBH) gliosis is associated with obesity and insulin resistance in humans. METHODS: Sixty-seven participants underwent a fasting blood draw and MRI. Cases with radiologic evidence of MBH gliosis (N = 22) were identified as the upper tertile of left MBH T2 relaxation time and were compared to controls (N = 23) from the lowest tertile. In a separate postmortem study, brain slices (N = 10) through the MBH were imaged by MRI and stained for glial fibrillary acidic protein (GFAP). RESULTS: In all participants, longer T2 relaxation time in the left MBH was associated with higher BMI (P = 0.01). Compared with controls, cases had longer T2 relaxation times in the right MBH (P < 0.05), as well as higher BMI (P < 0.05), fasting insulin concentrations (P < 0.01), and HOMA-IR values (P < 0.01), adjusted for sex and age. Elevations in insulin and HOMA-IR were also independent of BMI. In the postmortem study, GFAP staining intensity was positively associated with MBH T2 relaxation time (P < 0.05), validating an MRI-based method for the detection of MBH gliosis in humans. CONCLUSIONS: These findings link hypothalamic gliosis to insulin resistance in humans and suggest that the link is independent of the level of adiposity. PMID- 26530931 TI - Neuromodulation targeted to the prefrontal cortex induces changes in energy intake and weight loss in obesity. AB - OBJECTIVE: Obesity is associated with decreased activity in the prefrontal cortex. Transcranial direct current stimulation (tDCS) modifies cortical excitability and may facilitate improved control of eating. The energy intake (EI) and body weight in subjects who received cathodal versus sham (study 1) and subsequent anodal versus sham (study 2) tDCS aimed at the left dorsolateral prefrontal cortex (LDLPFC) were measured. METHODS: Nine (3m, 6f) healthy volunteers with obesity (94 +/- 15 kg [M +/- SD]; 42 +/- 8 y) were admitted as inpatients for 9 days to participate in a double-blind, randomized, placebo controlled crossover experiment. Study 1: following 5 days of a weight maintaining diet, participants received cathodal or sham tDCS (2 mA, 40 min) on three consecutive mornings and then ate ad libitum from a computerized vending machine, which recorded EI. Weight was measured daily. Study 2: participants repeated the study, maintaining original assignment to active (this time anodal) and sham. RESULTS: Participants tended to consume fewer kilocalories per day (P = 0.07), significantly fewer kilocalories from soda (P = 0.02) and fat (P = 0.03), and had a greater % weight loss (P = 0.009) during anodal versus cathodal tDCS. CONCLUSIONS: The results indicated a role for the LDLPFC in obesity and food intake. This proof of concept study suggested, for the first time, the potential application of anodal tDCS to facilitate weight loss. PMID- 26530932 TI - Maternal high-fat diet and obesity impact palatable food intake and dopamine signaling in nonhuman primate offspring. AB - OBJECTIVE: To utilize a nonhuman primate model to examine the impact of maternal high-fat diet (HFD) consumption and pre-pregnancy obesity on offspring intake of palatable food and to examine whether maternal HFD consumption impaired development of the dopamine system, critical for the regulation of hedonic feeding. METHODS: The impact of exposure to maternal HFD and obesity on offspring consumption of diets of varying composition was assessed after weaning. The influence of maternal HFD consumption on the development of the prefrontal cortex dopaminergic system at 13 months of age was also examined. RESULTS: During a preference test, offspring exposed to maternal HFD consumption and obesity displayed increased intake of food high in fat and sugar content relative to offspring from lean control mothers. Maternal HFD consumption suppressed offspring dopamine signaling (as assessed by immunohistochemistry) relative to control offspring. Specifically, there was decreased abundance of dopamine fibers and of dopamine receptor 1 and 2 proteins. CONCLUSIONS: This study reveals that offspring exposed to both maternal HFD consumption and maternal obesity during early development are at increased risk for obesity due to overconsumption of palatable energy-dense food, a behavior that may be related to reduced central dopamine signaling. PMID- 26530933 TI - Effects of carbohydrate quantity and glycemic index on resting metabolic rate and body composition during weight loss. AB - OBJECTIVE: To examine the effects of diets varying in carbohydrate and glycemic index (GI) on changes in body composition, resting metabolic rate (RMR), and metabolic adaptation during and after weight loss. METHODS: Adults with obesity (n = 91) were randomized to one of four provided-food diets for 17 weeks. Diets differed in percentage energy from carbohydrate (55% or 70%) and GI (low or high) but were matched for protein, fiber, and energy. Body weight, body composition, RMR, and metabolic adaptation (measured RMR-predicted RMR) were measured during weight loss and subsequent weight stability. RESULTS: No effect of dietary carbohydrate content or GI on body weight loss or percentage of weight lost as fat mass (FM) was observed. Measured RMR was significantly lower (-226 kJ/day [95% CI: -314 to -138 kJ/day], P < 0.001) than predicted RMR following weight loss, but this difference was attenuated after 5 weeks of weight stability. Metabolic adaptation did not differ by dietary carbohydrate content or GI and was not associated with weight regain 12 months later. CONCLUSIONS: Moderate carbohydrate and low-GI diets did not preferentially reduce FM, preserve lean mass, or attenuate metabolic adaptation during weight loss compared to high carbohydrate and high-GI diets. PMID- 26530934 TI - Effects of high-fat feeding on ectopic fat storage and postprandial lipid metabolism in mouse offspring. AB - OBJECTIVE: Parental high-fat feeding was proposed to negatively impact metabolic health in offspring. Here, the ectopic fat storage in heart and liver in offspring was investigated, and the effects on mitochondrial function, de novo lipogenesis, and postprandial lipid metabolism were explored in detail. METHODS: Male and female mice received either a high-fat (HF) or standard chow (LF) diet during mating, gestation and lactation. All offspring animals received the HF diet. RESULTS: Abdominal visceral adipose tissue tended to be higher in HF/HF mice. Cardiac lipid content was also higher in the HF/HF mice (LF/HF vs. HF/HF: 1.03% +/- 0.08% vs. 1.33% +/- 0.07% of water signal, P = 0.01). In contrast, hepatic lipid content tended to be lower in HF/HF mice compared to LF/HF mice. A severely disturbed postprandial lipid clearance was revealed in HF/HF mice by the results from the triglyceride (TG) tolerance tests (LF/HF vs. HF/HF: 6,753 +/- 2,213 vs. 14,367 +/- 1,978 mmol l(-1) min(-1) , P = 0.01) and (13) C-fatty acid retention test (LF/HF vs. HF/HF: 2.73% +/- 0.85% vs. 0.89% +/- 0.26% retention from bolus, P = 0.04), which may underlie the lower hepatic lipid content. CONCLUSIONS: Here it is shown that HF diet negatively impacts postprandial TG clearance in offspring and results in an overall metabolic unfavorable phenotype and ectopic lipid deposition in the heart and in visceral storage sites. PMID- 26530935 TI - Impaired GLP-1 signaling contributes to reduced sensitivity to duodenal nutrients in obesity-prone rats during high-fat feeding. AB - OBJECTIVE: Increased consumption of a high-fat (HF) diet is a salient contributor to obesity; however, how diminished satiation signaling contributes to overconsumption and obesity development remains poorly understood. METHODS: Using obese-prone (OP) and obese-resistant (OR) rats, we tested feeding responses to intragastric liquid meal replacement, prior and after HF feeding. Next, chow- and HF-fed OP and OR rats were tested for sensitivity to intraduodenal glucose, intralipid, and meal replacement loads. To examine the role of glucagon-like peptide-1 (GLP-1) and vagal signaling, animals were treated with exendin-9, GLP-1 receptor antagonist, prior to meal replacement infusion, and Fos-like immunoreactivity (Fos-Li) in the dorsal hindbrain was examined after infusion. RESULTS: OP and OR rats reduced chow intake equally following gastric liquid meal; however, after 2 weeks of HF feeding, intragastric meal replacement reduced food intake less in OP than OR. Similarly, HF feeding, but not chow, diminished the suppressive effects of intraduodenal meal replacement, glucose, and intralipid in OP compared to OR. This effect was associated with lower Fos-Li expression in the dorsal hindbrain of OP rats. Finally, exendin-9 failed to attenuate reduction of food intake by meal replacement in OP rats during HF feeding. CONCLUSIONS: Susceptibility to obesity coupled with HF feeding results in rapid impairments in nutrient-induced satiation through blunted responses in endogenous GLP-1 and hindbrain vagal afferent signaling. PMID- 26530936 TI - Apoptosis and antitumor effects induced by the combination of an mTOR inhibitor and an autophagy inhibitor in human osteosarcoma MG63 cells. AB - The inhibition of the mammalian target of rapamycin (mTOR) signaling pathway promotes the initiation of autophagy. Although it remains under debate whether chemotherapy-induced autophagy in tumor cells is a protective response or is invoked to promote cell death, recent studies indicate that autophagy is a self defense mechanism of cancer cells that are subjected to antitumor agents and that blocking autophagy can trigger apoptosis. The aim of this study was to examine the effects of rapamycin, an mTOR inhibitor, on MG63 osteosarcoma cells. We further examined whether the combination of rapamycin and the small molecule inhibitor of autophagy Spautin-1 (specific and potent autophagy inhibitor-1) enhanced the rapamycin-induced apoptosis in MG63 cells. We examined the effects of rapamycin treatment on cell proliferation, phosphorylation of mTOR pathway components, and autophagy by western blot analysis. Furthermore, we examined the effects of rapamycin with or without Spautin-1 on the induction of apoptosis by western blot analysis and immunohistochemical staining. We found that rapamycin inhibited cell proliferation and decreased the phosphorylation of mTOR pathway components in MG63 cells. Rapamycin induced the apoptosis of MG63 cells, and this apoptosis was enhanced by Spautin-1. It was considered that Spautin-1 suppressed the protective mechanism induced by rapamycin in tumor cells and induced apoptosis. Therefore, the combination of an mTOR inhibitor and an autophagy inhibitor may be effective in the treatment of osteosarcoma because it effectively induces the apoptotic pathway. PMID- 26530937 TI - Left ventricular mass in HIV-infected patients. AB - BACKGROUND: The HIV infection has been associated with an increased incidence of vascular events. Left ventricular mass (LVM) is independently associated with greater overall mortality. Various studies have shown that patients with HIV infection have higher LVM than the uninfected population. We aim to describe the distribution of LVM in an extensive series of patients with HIV infection, and the factors associated with its increase. PATIENTS AND METHODS: A cross-sectional study was performed in HIV-infected patients followed in our center from 1 December 2009 to 28 February 2011. A transthoracic echocardiography (TTE) was performed in all patients who gave their consent. Demographic variables, viroimmunological status, cardiovascular risk factors, vascular risk at 10 years (VR10) and history of exposure to antiretroviral drugs were collected. LVM was considered to be the quantitative dependent variable. A univariate analysis was performed, including in the multivariate analysis those variables with P<,05. RESULTS: A TTE was performed in 400 patients, and the LVM was calculated in 388. Mean age was 45 years, 75.5 males. Mean LVM was 39.54g/m(2.7)(95% CI: 38.35 40.73). Age, height, body mass index, VR10, hypertension, dyslipidemia, different medications within the cardiovascular area and having taken nevirapine have been used in the history of the patient were associated to greater LVM. In the multivariate analysis, use of nevirapine in the history of the patient and VR10 remained in the model. CONCLUSIONS: VR10 may be associated with greater LVM. The relationship with nevirapine may respond to an indication bias. PMID- 26530938 TI - Community-based incidence rate of cardiovascular disease and mortality in 50-75 year old adults. AB - BACKGROUNDS AND OBJECTIVES: Updated information on the incidence of the principal cardiovascular diseases (CVD) and cardiovascular mortality is not available in Spain. We have studied the incidence rate of new cases of myocardial infarction, heart failure, stroke and cardiovascular mortality in the adult population in Sanlucar de Barrameda (Spain). MATERIAL AND METHODS: A community-based prospective follow-up study was conducted. The study enrolled 858 participants aged 50-75 years who were randomly selected from the population and followed-up for 5 years. Age and gender-adjusted incidence rates of cardiovascular disease and cardiovascular mortality were calculated, obtaining complete information for 855 participants. Prognostic risk factors of new cases of cardiovascular disease were obtained using Cox proportional hazard modeling. RESULTS: The community based incidence rate of heart failure was 455/100.000 persons-year. The incidence of myocardial infarction, stroke and cardiovascular mortality (506, 216 and 225/100.000 persons-year, respectively) was also very elevated. Male gender, family history of early cardiovascular disease, diabetes, hypertension and sedentary life style were independent risk factors of cardiovascular disease. CONCLUSIONS: The community-based incidence rate of heart failure in Sanlucar de Barrameda (Spain) is very high, and it is the first to be reported in Spain. The incidence of myocardial infarction is among the highest in Spain. PMID- 26530939 TI - HIV/HBV coinfection: Serological control and therapeutic strategies. AB - OBJECTIVES: The evolution and prognosis of patients co-infected by human immunodeficiency virus (HIV) and hepatitis B (HBV) is not well know. This study describes the treatment and serological, virological and biochemical and elastographic responses of HIV and HBV-coinfected patients. PATIENTS AND METHODS: A descriptive, retrospective study of all the HIV/HBV-coinfected patients seen in a specialized HIV department between 1 January 2007 and 30 November 2008 was performed. Virological and serological determinations of HIV and HBV infections as well as CD4 lymphocytes and transaminases prior to antiretroviral treatment and at the time of analysis were obtained. RESULTS: A total of 54 (5.4%) cases of HIV/HBV coinfection were identified. The median nadir and current CD4 were 179 and 437 cells/L, respectively. There was undetectable RNA-HIV in 70%. There were 52 patients (96.3%) who followed active drugs treatment against HBV. After treatment, 68.8% had HBeAg negative result, with 81.6% virologic response. The HBsAg became negative in 10.4%. ALT was normal in 75.5%. FibroScan((r)) was performed in 30 (55.6%) patients, yielding a median of 7.0kPa. CONCLUSIONS: The results obtained suggest a good serological, virological and biochemical control of HIV/HBV-coinfected patients with treatments recommended by clinical guidelines. PMID- 26530940 TI - Left ventricular mass, cardiovascular risk and human immunodeficiency virus infection. PMID- 26530941 TI - Diabetes and osteoporosis: Action of gastrointestinal hormones on the bone. AB - A 62-year-old woman consulted for evaluation of treatment for her type 2 diabetes diagnosed four years ago. He had been received treatment with metformin 850mg twice, with no chronic associated complications. She had hypertension and dyslipidemia. She was being treated with candesartan/hydrochlorothiazide 32/12.5mg and atorvastatin 40mg. Her weight was 92kg and height 162cm (BMI, 35.1kg/m(2)). The last analysis showed fasting glucose 168mg/dl and glycated hemoglobin 7.5%, Microalbuminuria was negative. Blood pressure and lipid profile were within the therapeutic range. Two years ago she suffered a nontraumatic Colle's fracture in her left arm for which she was taking a daily calcium and vitamin D supplement and weekly alendronate. In summary, this is an obese female patient with type 2 diabetes mellitus and inadequate metabolic control, She also has a history of fragility fracture. How should this patient be evaluated and treated? PMID- 26530942 TI - The management of pneumonia in internal medicine. AB - Pneumonia generates a high workload for internal medicine departments. Management of this disease is challenging, because patients are usually elderly and have multiple comorbid conditions. Furthermore, the interpretation and adherence to guidelines are far from clear in this setting. We report the opinion of 43 internists especially interested in infectious diseases that were questioned at the 2011 XXXII National Conference of Spanish Society of Internal Medicine about the main issues involved in the management of pneumonia in the internal medicine departments, namely, classification, admission criteria, microbiological workup, therapeutic management, discharge policy, and prevention of future episodes. Participants were asked to choose between 2 options for each statement by 4 investigators. Consensus could not be reached in many cases. The most controversial issues concerned recognition and management of healthcare associated pneumonia (HCAP). Most participants were aware of the differences in terms of underlying diseases, etiological distribution, and outcome of HCAP compared with community-acquired pneumonia, but only a minority agreed to manage HCAP as hospital-acquired pneumonia, as suggested by some guidelines. A clinical patient-to-patient approach proved to be the option preferred by internists in the management of HCAP. PMID- 26530943 TI - Mycotic abdominal aortic aneurysm following intravesical Bacillus Calmette-Guerin therapy. PMID- 26530944 TI - Infectious diseases in hospitalized patient over 89 years of age. PMID- 26530945 TI - Autoinflammatory diseases, more frequent than it seems? PMID- 26530946 TI - Methemoglobinemia as a result of accidental taladrina poisoning. PMID- 26530947 TI - Subacute cutaneous lupus induced by anti-tnf (adalimumab). PMID- 26530948 TI - Cardiac granulocytic sarcoma (chloroma). A rare cause of pericardial effusion. PMID- 26530949 TI - Cerebral aneurysmal arteriopathy and human immunodeficiency virus infection. PMID- 26530950 TI - Mirizzi syndrome. PMID- 26530951 TI - Case of a 64-year old woman with hyponatremia and hydrocephalus. PMID- 26530952 TI - Effect of dietary n-3 polyunsaturated fatty acids on antioxidant defense and sperm quality in rainbow trout (Oncorhynchus mykiss) under regular stripping conditions. AB - This study examined the effect of dietary n-3 polyunsaturated fatty acids (PUFA) on malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and reduced glutathione (GSH) levels; semen and liver fatty acid compositions; and spermatological values (semen volume and pH, sperm density, percentage and duration of sperm motility) in rainbow trout (Oncorhynchus mykiss) under regular stripping conditions. For this purpose, one control and two experimental diets were prepared as isonitrogenous and isocaloric. The control diet did not contain n-3 PUFA. However, the D1 and D2 diets were supplemented with n-3 PUFA concentrated anchovy oil at a 1% and 2% level, respectively. The n-3 PUFA content in the semen and liver, semen volume, initial sperm motility, duration of 50% sperm motility, total duration of sperm motility and sperm density values of the control fish fed the n-3 PUFA-deficient diet were decreased and were accompanied by a reduction of the antioxidant defense (SOD, CAT, GSH-Px and GSH) and an elevation of MDA in the blood, gonad, liver and kidney at all of the sampling periods (P<0.01 for each case). However, the effects of the sampling period on the MDA and antioxidant defense values in the blood, gonad, liver and kidney of the control diet fish (with the exception of the GSH and GSH-Px activities) and the D1 and D2 diet fish were not significant (P>0.01). However, supplementation with n-3 PUFA protected the fish from these adverse effects. The modulations were clearly observed in the fish fed the D2 diet because they were under lower oxidative stress, as indicated by MDA. The increased enzyme activity corresponds with the physiological mechanisms combating the elevation of free radicals under oxidative stress. The highest n-3 PUFA levels in the semen and liver and spermatological values were obtained from the fish fed the D2 diet at all of the sampling periods. On the other hand, the effects of the sampling stage on the spermatological values of the fish fed the D1 and D2 diets were not significant (P>0.01). However, the effects of the sampling stage in the fish fed the control diet on these values (with the exception of semen pH) were significant (P<0.01). In conclusion, the addition and balance of n-3 PUFA in the diet of broodstock fish can improve sperm quality and ultimately cause successful reproduction. PMID- 26530953 TI - Designing overall stoichiometric conversions and intervening metabolic reactions. AB - Existing computational tools for de novo metabolic pathway assembly, either based on mixed integer linear programming techniques or graph-search applications, generally only find linear pathways connecting the source to the target metabolite. The overall stoichiometry of conversion along with alternate co reactant (or co-product) combinations is not part of the pathway design. Therefore, global carbon and energy efficiency is in essence fixed with no opportunities to identify more efficient routes for recycling carbon flux closer to the thermodynamic limit. Here, we introduce a two-stage computational procedure that both identifies the optimum overall stoichiometry (i.e., optStoic) and selects for (non-)native reactions (i.e., minRxn/minFlux) that maximize carbon, energy or price efficiency while satisfying thermodynamic feasibility requirements. Implementation for recent pathway design studies identified non intuitive designs with improved efficiencies. Specifically, multiple alternatives for non-oxidative glycolysis are generated and non-intuitive ways of co-utilizing carbon dioxide with methanol are revealed for the production of C2+ metabolites with higher carbon efficiency. PMID- 26530954 TI - Efficacy of Several Pesticide Products on Brown Widow Spider (Araneae: Theridiidae) Egg Sacs and Their Penetration Through the Egg Sac Silk. AB - Information on pesticide effects on spiders is less common than for insects; similar information for spider egg sacs is scarcer in the open literature. Spider egg sacs are typically covered with a protective silk layer. When pesticides are directly applied to egg sacs, the silk might prevent active ingredients from reaching the eggs, blocking their insecticidal effect. We investigated the impact of six water-based pesticide sprays and four oil-based aerosol products against egg sacs of brown widow spiders, Latrodectus geometricus C. L. Koch. All water based spray products except one failed to provide significant mortality to egg sacs, resulting in successful spiderling emergence from treated egg sacs at a similar rate to untreated egg sacs. In contrast to water-based sprays, oil-based aerosols provided almost complete control, with 94-100% prevention of spiderling emergence. Penetration studies using colored pesticide products indicated that oil-based aerosols were significantly more effective in penetrating egg sac silk than were the water-based sprays, delivering the active ingredients on most (>99%) of the eggs inside the sac. The ability of pesticides to penetrate spider egg sac silk and deliver lethal doses of active ingredients to the eggs is discussed in relation to the chemical nature of egg sac silk proteins. Our study suggests that pest management procedures primarily relying on perimeter application of water-based sprays might not provide satisfactory control of brown widow spider eggs. Determination of the most effective active ingredients and carrier characteristics warrant further research to provide more effective control options for spider egg sacs. PMID- 26530955 TI - A phase 1 study of lenvatinib, multiple receptor tyrosine kinase inhibitor, in Japanese patients with advanced solid tumors. AB - PURPOSE: This phase 1 study aimed to assess the tolerability, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of lenvatinib capsules in Japanese patients with solid tumors when administered orally up to 24 mg on a once-daily (QD) continuous schedule. METHODS: Patients were enrolled in one of the two sequential cohorts (20 or 24 mg) of lenvatinib on a 28-day cycle based on the conventional 3 + 3 dose escalation design. Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, version 4.0. Tolerability was judged based on dose-limiting toxicities (DLTs) during Cycle 1. The drug was defined as tolerable when the incidence of DLTs was less than 33 %. RESULTS: Nine patients received lenvatinib [20 mg (n = 3); 24 mg (n = 6)]. No DLTs were observed. The most common AEs were thrombocytopenia, blood thyroid stimulating hormone increased, and hypertension (89 %), followed by leukopenia, headache, and proteinuria (78 %). The area under the concentration-time curve and maximum observed concentration increased dose proportionally. The PK profiles were similar to those in non-Japanese phase 1 studies. One patient with leiomyosarcoma showed a partial response, and three patients have maintained stable disease for more than 6 months. CONCLUSIONS: The 24-mg QD continuous dose of lenvatinib was determined to be tolerable with encouraging anti-tumor activity in Japanese patients with solid tumors. PMID- 26530956 TI - Lung cancer and other second neoplasms after treatment of Hodgkin lymphoma. AB - PURPOSE: To evaluate the risk factors associated with lung cancer (LC) and other second neoplasms (SN) in Hodgkin lymphoma (HL) survivors. METHODS: We retrospectively analyzed the clinical characteristics and outcomes of 604 patients treated in our institution between 1968 and 2012. RESULTS: 90 out of 604 patients developed SN: 27 LC and 63 other SN. The median time elapsed until LC and other SN was 16.5 and 11.8 years, respectively (p = 0.003). In the LC group, 85.5 % of patients were male and 84.6 % smokers (HR 7, 95 % CI 2.4-20.7, p < 0.001). Radiotherapy (RT) doses applied were higher in the SN group with an increased risk of LC (HR: 4.0 95 % CI 1.1-11.6, p = 0.010) and other SN (HR: 3.3 95 % CI 1.6-6.7 p = 0.001) with doses higher than 42 Gy. No association was found between alkylating agents and development of SN. In LC, the most frequent histology was adenocarcinoma with an elapsed time after HL of 13.2 years in early stages and 21.3 in advanced (p = 0.02). Median OS after a diagnosis of LC was 12.6 months ranging from 5.9 (in cases presenting due to symptoms) to 49.1 (incidentally diagnosed cases) (p = 0.005). CONCLUSIONS: RT treatment, especially with doses higher than 42 Gy, and smoking increase the risk of SN after HL. In this series, LC patients with early stages had a shorter elapsed time from HL diagnosis and longer OS, therefore the role of LC screening in HL survivors should be prospectively evaluated and smoking cessation counseling ought to be a key aspect during follow-up. PMID- 26530957 TI - [History of internal fixators. The subsequent importance for spinal surgery]. AB - BACKGROUND: This article presents a retrospective look at spinal implants of the 1970s and 1980s. OBJECTIVE: The historical development of internal fixators as the successor to external fixators. MECHANICAL PRINCIPLE: Pedicled screws are stably anchored in vertebral bodies of the thoracic or lumbar spine or the sacrum using a dorsal approach. They are joined by a rod as a longitudinal support, separated by freely selectable distances and in any desirable and initially modifiable angle. After locking this results in an angular and rotationally stable completely sunken bilateral construction for fixing two or more vertebrae together and the position can be manually adjusted using long lever arms on the pedicled screws. RESULTS: The first in vivo application in humans was on 22 December 1982 in Basel. The initial indications were unstable spinal fractures. The expectations placed on the new working principle of internal fixation and its realization were confirmed and short stretch fixation exclusively of the neighboring vertebra and immediate mobilization of patients could be routinely achieved. The indications were extended to include instability of the spine for conditions outside the field of traumatology. Further developments of implants and other technical solutions in the coupling system using the same basic principle in the direction of multisegmental applications, ease of operation and titanium-based materials became internationally established and were developed into universal spinal stabilization systems for spinal degeneration, deformities, tumors and olisthesis. CONCLUSION: The basic principle of spinal fixators (internal and external) is contained in the complete product range of dorsal stabilizing implants from practically all manufacturers worldwide and has become taken for granted. PMID- 26530958 TI - Laboratory and dialysis characteristics in hemodialysis patients suffering from chronic itch--results from a representative cross-sectional study. AB - BACKGROUND: A representative cross-sectional study showed that chronic itch (lasting for a minimum of 6 weeks) affects 25.2 % (point prevalence) of hemodialysis (HD) patients. Pathophysiology and etiology of chronic itch (CI) in HD are still unclear. METHODS: We investigated 860 HD patients from a representative randomly selected cluster-sample considering the regional distributions of dialysis units in Germany. The current analyses report comorbidities, laboratory values and dialysis characteristics of HD patients in relation to CI. RESULTS: Diabetes was the only comorbidity that was associated with the occurrence of itch but interestingly with less CI. Except for creatinine, phosphorus, and parathormone, there were no significant associations between the occurrence and characteristics of CI and any laboratory value. Kt/V was not associated with the presence of CI. Patients dialyzed with polyarylethersulfone-membrane showed significantly more CI in all prevalence estimates and those dialyzed with polysulfone-membrane were significantly less affected by CI. CONCLUSIONS: Long-term follow-up studies will show if the type of dialysis membrane influences the development of CI in HD patients. It is most likely that several factors e.g. elevated parathormone, origin of end stage renal disease (ESRD), type of dialysis membrane, and a neuropathic component all contribute to the occurrence of CI in HD patients. Future research should consider a multifactorial origin of itch in HD. PMID- 26530960 TI - Global health experts warn of a "looming co-epidemic" of tuberculosis and diabetes. PMID- 26530959 TI - Tissue-specific production of limonene in Camelina sativa with the Arabidopsis promoters of genes BANYULS and FRUITFULL. AB - MAIN CONCLUSION: Arabidopsis promoters of genes BANYULS and FRUITFULL are transcribed in Camelina. They triggered the transcription of limonene synthase and induced higher limonene production in seeds and fruits than CaMV 35S promoter. Camelina sativa (Camelina) is an oilseed crop of relevance for the production of biofuels and the plant has been target of a recent and intense program of genetic manipulation aimed to increase performance, seed yield and to modify the fatty acid composition of the oil. Here, we have explored the performance of two Arabidopsis thaliana (Arabidopsis) promoters in triggering transgene expression in Camelina. The promoters of two genes BANYULS (AtBAN pro ) and FRUITFULL (AtFUL pro ), which are expressed in seed coat and valves of Arabidopsis, respectively, have been chosen to induce the expression of limonene synthase (LS) from Citrus limon. In addition, the constitutive CaMV 35S promoter was utilized to overexpress LS in Camelina . The results of experiments revealed that AtBAN pro and AtFUL pro are actively transcribed in Camelina where they also retain specificity of expression in seeds and valves as previously observed in Arabidopsis. LS induced by AtBAN pro and AtFUL pro leads to higher limonene production in seeds and fruits than when the CaMV 35S was used to trigger the expression. In conclusion, the results of experiments indicate that AtBAN pro and AtFUL pro can be successfully utilized to induce the expression of the transgenes of interest in seeds and fruits of Camelina. PMID- 26530961 TI - Upper ministernotomy. AB - During the past 50 years, median sternotomy has been the gold standard approach in cardiac surgery with excellent long-term outcomes. However, since the 1990 s, minimally invasive cardiac surgery (MICS) has gained wide acceptance due to patient and economic demand. The advantages include less surgical trauma, less bleeding, less wound infections, less pain and faster recovery of the patients. One of these MICS approaches is the J-shaped upper ministernotomy which results in favourable long-term outcomes even in elderly and redo patients when compared with conventional sternotomy. Owing to its similarity to a full midline sternotomy, it has become the most popular MICS approach besides a mini thoracotomy. It is a safe and feasible access, but certain recognized principles are mandatory to minimize complications. After identification of the landmarks, the 5-cm skin incision is performed in the midline between the second and fourth rib. The third or fourth right intercostal space is located and dissected laterally off the sternum. After osteotomy, the pericardium is pulled up with stay sutures which allow excellent exposure. The surgical procedures are performed in a standard fashion with central cannulation. Continuous CO2 insufflation is used to minimize the risk of air embolism. Epicardial pacing wires are placed before the removal of the aortic cross-clamp and one chest tube is used. Sternal closure is achieved with three to five stainless steel wires. The pectoral muscle, subcutaneous tissue and skin are adapted with resorbable running sutures. When performed properly, complications are rare (conversion, bleeding and wound infection) and well manageable. PMID- 26530962 TI - AIBN/NaBr-promoted aerobic oxidation of benzylic alcohols via a radical process. AB - An economic and practical AIBN-initiated aerobic oxidation system of benzylic alcohols, hetero aryl alcohols and allyl alcohols was developed for the first time. Moderate to excellent yields were obtained with a broad substrate scope. Moreover, a proposed mechanism of a radical process was assumed and confirmed by the key intermediate detected. PMID- 26530963 TI - Direct suppression of a rice bacterial blight (Xanthomonas oryzae pv. oryzae) by monoterpene (S)-limonene. AB - Rice bacterial blight, caused by Xanthomonas oryzae pv. oryzae (Xoo), is a severe disease of rice plants. Upon pathogen infection, rice biosynthesizes phytoalexins, including diterpenoids such as momilactones, phytocassanes, and oryzalexins. However, information on headspace volatiles in response to Xoo infection is limited. We have examined headspace volatile terpenes, induced by the infection of Xoo, and investigated their biological roles in the rice plant. Monoterpenes alpha-thujene, alpha-pinene, sabinene, myrcene, alpha-terpene, and (S)-limonene and sesquiterpenes cyclosativene, alpha-copaene, and beta-elemene were detected from 1-week-old Xoo-infected rice seedlings, by solid-phase microextraction-gas chromatography-mass spectrometry. All monoterpenes were constitutively released from rice seedlings before Xoo infection. However, (S) limonene emission was further elicited after exposure of the seedlings to Xoo in coincidence with upregulation of limonene synthase gene (OsTPS20) transcripts. Only the stereospecific (S)-limonene [and not (R)-limonene or other monoterpenes] severely inhibited Xoo growth, as confirmed by disc diffusion and liquid culture assays. Rice seedlings showed suppressed pathogenic symptoms suggestive of resistance to Xoo infection after foliar treatment with (S)-limonene. Collectively, our findings suggest that (S)-limonene is a volatile phytoanticipin, which plays a significant role in suppressing Xoo growth in rice seedlings. PMID- 26530964 TI - Intestinal parasitic infections among children under five years of age presenting with diarrhoeal diseases to two public health facilities in Hawassa, South Ethiopia. AB - BACKGROUND: Diarrhoea is the leading cause of morbidity and mortality in children under 5 years of age in developing countries, including Ethiopia. It is caused by a wide range of pathogens, including parasites, bacteria and viruses. The aim of this study was to determine the prevalence of infection with intestinal parasites (IPs) (and types) among children under 5 years of age with diarrhoeal diseases. METHODS: A cross-sectional study was conducted at Adare Hospital and Millennium Health Centre, both located in Hawassa, South Ethiopia, from June 6 to October 28, 2011. Children under 5 years of age with diarrhoea who visited these health facilities during the study period were included in the study. Data relating to demography and risk factors associated with intestinal parasitic infections (IPIs) were gathered using a structured questionnaire. Single, fresh stool specimens were examined for IPs using the direct wet mount examination, followed by Ziehl-Neelsen staining of formol-ether concentrated samples, as per standard procedures. Data were analysed using SPSS Statistics 20 software. RESULTS: A total of 158 children (51.3 % male and 48.7 % female) participated in the study. Overall, the prevalence of IPs was 26.6 % (42/158). Two species of IPs were detected in six children (3.8 %). Entamoeba histolytica/dispar/moshkovskii was the predominant parasite identified (11.4 %), followed by Giardia duodenalis (7.0 %). The multivariable analysis revealed that the age group >=24 months was significantly associated (AOR = 0.221, 95 %CI: 0.085-0.576) with prevalence of IPIs. CONCLUSION: This study found that intestinal parasites are common among children with diarrheal diseases. The most frequently detected species was E. histolytica/dispar/moshkovskii. Health information about how to prevent diarrheal diseases in general and IPIs in particular should be provided to parents of young children. PMID- 26530965 TI - Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer. AB - Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution. PMID- 26530966 TI - Development and implementation results of an interactive computerized surgical checklist for robotic-assisted gynecologic surgery. AB - To address surgical complications, the World Health Organization (WHO) developed the Safe Surgery Saves Lives Checklist. With the foundation of the WHO's checklist, a robotic-specific checklist (RORCC) was developed using standardized content and face validity methods. The RORCC was implemented in a high volume gynecological (GYN) specialty group using minimally invasive robotic-assisted surgery. Data were abstracted from patients undergoing GYN procedures from four GYN surgeons at an urban, community hospital during November 16, 2010 to May 15, 2011 (pre-RORCC) n = 89 and from the period May 16, 2011 to November 16 2011 (post-RORCC) n = 121. Thirty-day readmissions pre-checklist and post-checklist were 12 and 5, respectively, which is a significant (p = 0.02) reduction. The duration of surgery was not significantly affected (p = 0.40) with pre-RORCC surgery time at 110.1 (35.7) min versus post-RORCC surgery time at 112.9 (37.4) min. This study demonstrated the feasibility of integrating an electronic, interactive, and robotic-specific checklist for gynecologic robotic-assisted surgery which resulted in a significant reduction in readmissions at the 30-day without significantly impacting operating room times. PMID- 26530967 TI - Cerebral tissue O2 saturation during prolonged robotic surgery in the steep Trendelenburg position: an observational case series in a diverse surgical population. AB - Demands associated with the Trendelenburg position (TP) are well known yet there is little attention given to regional cerebral tissue O2 saturation (SctO2) in those undergoing robotic surgery in the TP with CO2 insufflation (C-INSF). This is the first study to report on SctO2 in a wide range of patients undergoing lengthy TP and robotic surgery. We measured SctO2 during robotic surgery in patients in the TP with C-INSF, as well as a control robotic thyroid surgery group who were supine with no C-INSF. We recorded relevant variables and periods of cerebral desaturation (CD). We studied 42 patients in 25 degrees -45 degrees of TP for >=125 min. Management was at the providers' discretion. The INVOS((r)) 5100C Cerebral Oximeter (Covidien, Boulder, CO) recorded SctO2. CD was defined as a >20 % decrease from baseline SctO2 or a value <=55 % for >=10 min. Patients were assessed for adverse outcome. The sample consisted of 13 males and 29 females aged 22-73, BMI 22-36 had general (N = 3), urological (N = 14) and gynecological (N = 25) surgery; two patients had CD lasting 150 and 190 min and two had episodic CD lasting 10-35 min. The four were female aged 22-60 in 38 degrees -45 degrees of TP. Eleven cases had multiple episodic CD for <=15 min, 27 TP cases had no CD. Other observations included a consistent fall in SctO2 with phenylephrine; an increased SctO2 with ephedrine; and FiO2 and EtCO2 being generally strong, direct modifiers of SctO2. High MAP was inconsistently associated with high SctO2. BMI had no observed effect on SctO2. Pulse oximetry was >=97 % in all cases. We observed no adverse cerebral events on follow-up. Additional clinical studies are warranted. PMID- 26530968 TI - Development and testing of a robotic surgical training curriculum for novice surgeons. AB - A robotics practice curriculum was developed utilizing dry lab skills and testing parameters based upon the objective structured assessment of surgical tasks (OSATS) to determine its effectiveness in training novice surgeons. We recruited 20 medical students who were oriented to the DaVinci S console and instrumentation. They were pre-tested with four dry lab skills including manipulation, transection, suturing and knot tying. A control group was instructed to practice once weekly to attain proficiency and the intervention group was provided specific instructions regarding practice goals. Each subject was post-tested after a 6-week time. There were 17 students who completed the post-testing. All participants showed significant improvement in pre-test and post-test scores for manipulation (6.6-11.2, p < 0.0005), transection (3.5-6.9, p < 0.0005), knot tying (0.4-1.7, p = 0.003), and suturing (2.0-3.5, p = 0.001). There was no significant difference in pre-test and post-test scores between the control and intervention groups in manipulation, transection, knot tying, and suturing (p = 0.700, 0.782, 0.682, 0.605, respectively). Our study shows that novice surgeons such as medical students can improve dry lab robotics skills with instruction and practice. PMID- 26530969 TI - Modifications of transaxillary approach in endoscopic da Vinci-assisted thyroid and parathyroid gland surgery. AB - Endoscopic surgery for treatment of thyroid and parathyroid pathologies is increasingly gaining attention. The da Vinci system has already been widely used in different fields of medicine and quite recently in thyroid and parathyroid surgery. Herein, we report about modifications of the transaxillary approach in endoscopic surgery of thyroid and parathyroid gland pathologies using the da Vinci system. 16 patients suffering from struma nodosa in 14 cases and parathyroid adenomas in two cases were treated using the da Vinci system at the ENT Department of Homburg/Saar University and in cooperation with the Department of General Surgery in New Sant'Agostino Hospital, Modena/Italy. Two different retractors, endoscopic preparation of the access and three different incision modalities were used. The endoscopic preparation of the access allowed us to have a better view during preparation and reduced surgical time compared to the use of a headlamp. To introduce the da Vinci instruments at the end of the access preparation, the skin incisions were over the axilla with one incision in eight patients, two incisions in four patients and three incisions in a further four patients. The two and three skin incisions modality allowed introduction of the da Vinci instruments without arm conflicts. The use of a new retractor (Modena retractor) compared to a self-developed retractor made it easier during the endoscopic preparation of the access and the reposition of the retractor. The scar was hidden in the axilla and independent of the incisions selected, the cosmetic findings were judged by the patients to be excellent. The neurovascular structures such as inferior laryngeal nerve, superior laryngeal nerve and vessels, as well as the different pathologies, were clearly 3D visualized in all 16 cases. No paralysis of the vocal cord was observed. All patients had a benign pathology in their histological examination. The endoscopic surgery of the thyroid and parathyroid gland can be performed using the da Vinci system and offers an excellent, intra-operative, 3D visualization of the neurovascular structures. The new incision modalities, use of a new retractor, and endoscopic preparation of the access made the surgery easier and safer using the transaxillary access to the thyroid and parathyroid glands. The modified skin incisions allowed an improved movement of the da Vinci arms during operation. PMID- 26530970 TI - Self-assessment of surgical technique leads to reduction of positive surgical margins in partial nephrectomy. AB - The background of the study was to examine potential causes for a positive surgical margin (PSM) and develop strategies to improve surgical outcomes. A retrospective review of consecutive partial nephrectomy cases for renal cell carcinoma was performed. We divided the patients into 2 groups. The first group consisted of the first 67 renal tumors in 65 patients that underwent our early surgical technique. The second group consisted of the next 45 renal tumors in 39 patients that underwent the revised surgical technique which included wider resections and robotically controlled ultrasound. Our primary outcome was margin status and secondary outcome was disease recurrence. Univariate and multivariate analyses were performed to determine factors that resulted in a PSM. Positive margins were detected in 19 out of 67 (28 %) renal tumors in the early technique group compared to 1 out of 45 (2 %) positive margins in the revised technique group (p < 0.001). On multivariate analysis, only technique modification (OR 0.04, p = 0.003) and larger tumor size (OR 0.41, p = 0.01) were significant predictors of a lower rate of PSM. Smaller tumors were more common in robotic assisted partial nephrectomies which had a higher rate of PSM on univariate analysis (OR 3.51, p = 0.04). Only one patient with a PSM experienced a systemic disease recurrence. In our experience, self-assessment and technique modification resulted in a dramatic PSM improvement. Smaller tumors were associated with PSM. It is important for all surgeons to periodically look at their own surgical outcomes and modify their surgical technique accordingly. PMID- 26530971 TI - The effect of robotic telerounding in the surgical intensive care units impact on medical education. AB - Robotic telerounding is effective from the standpoint of patients' satisfaction and patients' care in teaching and community hospitals. However, the impact of robotic telerounding by the intensivist rounding remotely in the surgical intensive care unit (SICU), on patients' outcome and on the education of medical students physician assistants and surgical residents, as well as on nurses' satisfaction has not been studied. Prospective evaluation of robotic telerounding (RT) using a Likert Scale measuring tool to assess whether it can replace conventional rounding (CR) from the standpoint of patients' care and outcome, nursing satisfaction, and educational effectiveness. RT did not have a negative impact on patients' outcome during the study interval: mortality 5/42 (12 %) versus 6/37 (16 %), RT versus CR, respectively, p = 0.747. The intensivists rounding in the SICU were satisfied with their ability to deliver the same patients' care remotely (Likert score 4.4 +/- 0.2). The educational experience of medical students, physicia assistants, and surgical residents was not affected by RT (average Likert score 4.5 +/- 0.2, 3.9 +/- 0.4, and 4.4 +/- 0.4 for surgical residents, medical students and PAs, respectively, p > 0.05). However, as shown by a Likert score of 3.5 +/- 1.0, RT did not meet nurses' expectations from several standpoints. Intensivists regard robotic telerounding as an effective alternative to conventional rounding from the standpoint of patients' care and teaching. Medical students, physician assistants (PA's), and surgical residents do not believe that RT compromises their education. Despite similar patients' outcome, nurses have a less favorable opinion of RT; they believe that the physical presence of the intensivist is favorable at all times. PMID- 26530972 TI - Education and training in pediatric robotic surgery: lessons learned from an inaugural multinational workshop. AB - The introduction of robotic surgery into clinical practice brings new and specific needs for education and training. Application to the pediatric setting comes with unique considerations, warranting dedicated training resources that are accessible. A pediatric robotic surgery workshop was convened to address initial education and training requirements. The event was designed to offer an exposure rich environment for delegates to familiarize and learn basic principles in a maximally efficient manner. Pre- and post-workshop survey responses were evaluated to reflect on the quality of the educational experience and scope for improvement. Feasibility and sustainability of such events was further evaluated by reviewing various challenges encountered. A total of 29 surgeons participated in the workshop, with 7 countries represented. The majority of delegates (94 %) indicated they were "very satisfied" with the overall program. Delegates almost unanimously expressed preference and satisfaction for hands-on content. Qualitative feedback favored a stepwise and modular workshop structure, transitioning from didactic teaching to progressively more advanced training. At the basic and intermediate level, this style of event is able to satisfy initial training and educational needs. Feasibility and sustainability of such events is highly dependent on infrastructure resources that have numerous barriers to accessibility. PMID- 26530973 TI - Comment on "education and training in pediatric robotic surgery: lessons learned from an inaugural multinational workshop". PMID- 26530974 TI - Robotic technology results in faster and more robust surgical skill acquisition than traditional laparoscopy. AB - Technical surgical skills are said to be acquired quicker on a robotic rather than laparoscopic platform. However, research examining this proposition is scarce. Thus, this study aimed to compare the performance and learning curves of novices acquiring skills using a robotic or laparoscopic system, and to examine if any learning advantages were maintained over time and transferred to more difficult and stressful tasks. Forty novice participants were randomly assigned to either a robotic- or laparoscopic-trained group. Following one baseline trial on a ball pick-and-drop task, participants performed 50 learning trials. Participants then completed an immediate retention trial and a transfer trial on a two-instrument rope-threading task. One month later, participants performed a delayed retention trial and a stressful multi-tasking trial. The results revealed that the robotic-trained group completed the ball pick-and-drop task more quickly and accurately than the laparoscopic-trained group across baseline, immediate retention, and delayed retention trials. Furthermore, the robotic-trained group displayed a shorter learning curve for accuracy. The robotic-trained group also performed the more complex rope-threading and stressful multi-tasking transfer trials better. Finally, in the multi-tasking trial, the robotic-trained group made fewer tone counting errors. The results highlight the benefits of using robotic technology for the acquisition of technical surgical skills. PMID- 26530975 TI - Zenker diverticulectomy: first report of robot-assisted transaxillary approach. AB - Standard surgical treatment of Zenker's diverticulum consists of open cricopharyngeal myotomy with diverticulectomy. A rigid or flexible endoscopic approach allowing a cricopharyngeal myotomy without diverticulectomy is currently considered as a less invasive alternative to open surgery with reportedly comparable symptom relief at short term follow-up. In recent years, high safety and efficacy of a transaxillary gasless robotic access to the thyroid gland has been shown. The present study describes the feasibility and preliminary results of robot-assisted transaxillary approach for cricopharyngeal myotomy and excision of Zenker's diverticulum. Patients with troublesome dysphagia and radiological evidence of Zenker's diverticulum underwent a robot-assisted cricopharyngeal myotomy and diverticulum excision using left transaxillary access with the support of endoscopic assistance. One month after intervention, symptoms were reevaluated and a barium swallow study was performed. Four patients with symptomatic Zenker's diverticulum were successfully operated. No adverse event was recorded. One month after intervention, total dysphagia remission was declared by all four patients and there was no evidence of diverticulum recurrence at radiology. According to our preliminary data, left transaxillary robot-assisted approach for the surgical management of Zenker's diverticulum is feasible, safe and effective. Whether our encouraging results will be confirmed in larger patient cohorts with prolonged follow-up, the robot-assisted transaxillary Zenker's diverticulectomy may represent an alternative to traditional open diverticulectomy when endoscopic interventions cannot be performed or have failed. PMID- 26530976 TI - Head docking for single stage robotic cortical sparing adrenalectomy for bilateral pheochromocytoma. AB - The optimal operative approach in a patient with bilateral pheochromocytoma is controversial. Subtotal minimal invasive cortical sparing adrenalectomy is gaining interest in many centers. We describe a novel technique for single stage approach for cortical sparing adrenalectomy for bilateral pheochromocytoma using head docking in order to offer good exposure of bilateral upper peritoneum without requiring patient or robot repositioning. PMID- 26530977 TI - Low incidence of port-site metastasis after robotic assisted surgery for endometrial cancer staging: descriptive analysis. AB - The purpose of this study was to evaluate the incidence and characteristics of patients with port-site metastasis following robotic assisted surgery for gynecological malignancies. Patients who underwent robotic assisted total laparoscopic hysterectomy and surgical staging at a single institution from November 2006 through November 2011 were retrospectively identified. Medical records were reviewed and the following information was extracted: diagnosis, histology, tumor extension, procedure, complications and post-surgical intervention. Port-site metastases were differentiated between isolated and not isolated. All metastases were confirmed with biopsy and treated with chemotherapy and radiotherapy as indicated. Four hundred forty-six patients with endometrial carcinoma were identified who had undergone robotic assisted hysterectomy and staging. Eight patients were converted to laparotomy and excluded from the study. Of 438 patients, 384 patients were diagnosed with early stages (stages 1 and 2), and 54 were diagnosed with advanced stages (stages 3 and 4). A total of 332 patients underwent pelvic lymphadenectomy regardless of the endometrial cancer stage; of those, 283 with early stage disease underwent pelvic lymphadenectomy, while 49 with advanced stage disease underwent pelvic lymphadenectomy. One hundred seventy-six patients received adjuvant treatment after surgical staging. Four patients were identified with port-site metastases (0.9 %), two patients were reported as isolated metastases. The mean patient age was 63 and mean BMI was 37 kg/m(2). The incidence of port-site metastasis is low after robotic assisted surgery for treatment of endometrial cancer (0.9 %). There is no clear risk factor for development of port-site metastasis or easily identifiable prevention. PMID- 26530978 TI - Robotic surgical and anesthesia communication tool. AB - An original tool to promote intraoperative communication and patient safety for robot assit procedures. PMID- 26530980 TI - Subungual leiomyoma in the left thumb of a 16-year-old female. AB - Cutaneous leiomyomata, which are benign smooth muscle neoplasms, commonly present as dermal-based nodules or papules with smooth borders and firm consistency. Digital, particularly subungual leiomyomata are quite rare. A 16-year-old female presented to nail clinic complaining of discoloration of the lunula of the left thumbnail for 2.5 months. On initial examination, a pink longitudinal band was present in the center of the nail plate, with yellow discoloration and distal onycholysis. The patient had only mild tenderness with firm palpation, and did not recall trauma of the area. A nail matrix biopsy was performed to determine the etiology of the lesion. Microscopic examination demonstrated a well demarcated dermal-based spindle-cell fascicular proliferation. Bland cells exhibited eosinophilic cytoplasm and elongate nuclei with blunt ends and minimal cytologic atypia. Prominent nucleoli, mitoses or necrosis were not appreciated. Immunohistochemical stains for smooth muscle actin and caldesmon highlighted the cells. Contrarily, S-100, epithelial membrane antigen, p63, factor XIIIa, CD34, CD68 and p75 were all negative. Ki-67 showed a low proliferative index. The immunoprofile combined with the morphologic features were interpreted as subungual leiomyoma. Subungual leiomyoma is a very rare diagnosis. We seek to bring awareness and expedite the diagnosis in patients with this lesion. PMID- 26530981 TI - Defining lymphocyte-predominant breast cancer by the proportion of lymphocyte rich stroma and its significance in routine histopathological diagnosis. AB - Lymphocyte-predominant breast cancer (LPBC) defined by the density of stromal lymphocytes shows favorable behavior. However, considerable distribution heterogeneity of lymphocytes is a major problem. The present study defined LPBC by the proportion of lymphocyte-rich stroma with the cut-off values of 30, 50, and 75%, and clinicopathologically analyzed mainly LPBC (area > 30%) defined by the cut-off value of 30%. LPBCs (area > 30%), 39 cases in total, were composed mainly of triple-negative and HER2(+) /ER(-) subtypes, without any luminal A-like subtype. LPBCs were composed predominantly of histological grade 3 tumors, without any grade 1 lesions. Multivariate analyses on 477 consecutive tumors revealed that ER-negativity and grade 3 status associated significantly with LPBC. LPBC (area > 30%) showed better disease-free survival than grade-matched controls, and it was a good indicator of complete pathological remission after pre-operative chemotherapy. Patients with LPBC with the cut-off value of 50% and that of 75% showed 100% disease-free survival. These results demonstrated the validity of our definition of LPBC. Our data also suggest that de-differentiated cancers without TILs could be regarded as high-grade cancer without lymphocyte mediated responses. In conclusion, the definition of LPBC by the proportion of lymphoid stroma is useful for prognostication of high grade breast cancer in routine diagnosis. PMID- 26530982 TI - Fine-scale genetic structure of woodrat populations (Genus: Neotoma) and the spatial distribution of their tick-borne pathogens. AB - Dusky-footed woodrats are territorial cricetid rodents that individually occupy large stick houses from which they foray to gather food, find mates, and engage in other activities. These rodents are often bitten by Ixodes spp. ticks and are reservoirs of some strains of tick-borne bacterial pathogens such as Anaplasma phagocytophilum and Borrelia burgdorferi. Limited dispersal by hosts and vectors could create fine-scale population structure where related hosts and pathogen exposure are co-distributed in space. To quantify population genetic structure and infection status, we genotyped 167 woodrats using a panel of 15 microsatellite loci from three northern California study sites: Soquel (SD), Cold Canyon (CC), and Quail Ridge (QR). We used quantitative PCR and serology to test for infection with A. phagocytophilum and B. burgdorferi. All three populations maintained similar, moderately high levels of genetic variation. For A. phagocytophilum, the PCR-prevalence was higher at SD (30.0%) than CC (13%) and QR (7%) whereas the seroprevalence was similar at all three sites (13-18%). The B. burgdorferi PCR-prevalence at CC was 11%, no woodrats were PCR-positive at QR, and none were tested at SD. We found a negative correlation between pairwise genetic relatedness and spatial distance with the majority of highest order relatives occurring within 200m of one another. Related dyads were more likely to be adult females than males, suggesting that adult female residents are the primary source of spatially proximate, high-order relatives in woodrat populations. Despite spatial genetic clustering of hosts, our spatial window test found no significant clustering of pathogens. Woodrats that were seropositive for A. phagocytophilum had higher heterozygosity than seronegative woodrats, which could be consistent with genetically diverse individuals having greater capacity to mount an immune response. Overall, our analyses show that limited dispersal of individual woodrats leads to fine-scale genetic structure within populations. Genetic structure, coupled with the limited dispersal of I. pacificus ticks could result in disease dynamics that are uniquely restricted to small spatial scales. By combining host genetic and disease studies we are able to infer limited dispersal and structured populations among hosts which affect infectious disease clustering and dynamics. PMID- 26530983 TI - Molecular survey of Babesia infections in cattle from different areas of Myanmar. AB - Cattle babesiosis is one of the most important tick-borne diseases worldwide. The present study reports a molecular survey of Babesia infections in cattle in Myanmar. Nested PCR assays based on the Babesia bigemina apical membrane antigen 1 gene (AMA-1) and B. bovis rhoptry associated protein-1 gene (RAP-1) revealed that the overall percentage of B. bigemina and B. bovis infection were 9.8% (70/713) and 17.1% (122/713), respectively. A mixed infection was detected in 4.6% (33/713) of animals. Animals <1 year (OR=13.66, CI=5.15-36.26) and 1-5 years of age (OR=3.91, CI=1.50-10.17) were identified as potential risk factors for B. bigemina infection. For B. bovis infection, age <1 year (OR=3.06, CI=1.63-5.75) and 1-5 years (OR=2.08, CI=1.21-3.57), Friesian-Zebu crossbreeds (OR=2.04, CI=1.26-3.30) and grazing (OR=1.59, CI=1.06-2.38) were identified as potential risk factors. This is the first report on a nationwide survey of bovine Babesia infections in Myanmar, providing useful information for the management and control of the disease. PMID- 26530984 TI - Effective inhibition of thrombin by Rhipicephalus microplus serpin-15 (RmS-15) obtained in the yeast Pichia pastoris. AB - The cattle tick (Rhipicephalus microplus) affects cattle industries in tropical and subtropical countries because it is the vector of babesiosis and anaplasmosis which constitutes a threat to the health of cattle. During blooding feeding, ticks secrete saliva containing a complex of bioactive molecules into the injured site to evade host's defensive responses. Serine protease inhibitors (serpins) are important anti-haemostatic molecules present in tick saliva that are necessary for a successful blood feeding. Several serpin sequences have been reported in R. microplus but there is a gap of information about their functions during host-parasite interactions. In this study, the RmS-15 expressed in the yeast Pichia pastoris was characterised using kinetic assays and in vitro analysis. The inhibitory enzymatic assays conducted showed that RmS-15 is a physiological inhibitor of thrombin with a stoichiometric inhibition (SI) of 1.5 and high inhibition affinity with ka=9.3+/-0.5*104M(-1)s(-1). RmS-15 delayed the clotting of plasma in a dose-dependent manner as determined in a recalcification time assay. Significant elevated ELISA titres were observed in tick resistant and susceptible cattle on day 28 after the tick infestation (p<0.001). This data suggests direct contact of RmS-15 with the immune system of the host at the tick feeding site. The present study contributed to the understanding of the biological functions of R. microplus serpins during host-parasite interactions which contributes to the design of future innovative methods for tick control. PMID- 26530985 TI - A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. AB - Randomized controlled trials (RCTs) are conducted under idealized and rigorously controlled conditions that may compromise their external validity. A literature review was conducted of published English language articles that reported the findings of studies assessing external validity by a comparison of the patient sample included in RCTs reporting on pharmaceutical interventions with patients from everyday clinical practice. The review focused on publications in the fields of cardiology, mental health, and oncology. A range of databases were interrogated (MEDLINE; EMBASE; Science Citation Index; Cochrane Methodology Register). Double-abstract review and data extraction were performed as per protocol specifications. Out of 5,456 de-duplicated abstracts, 52 studies met the inclusion criteria (cardiology, n = 20; mental health, n = 17; oncology, n = 15). Studies either performed an analysis of the baseline characteristics (demographic, socioeconomic, and clinical parameters) of RCT-enrolled patients compared with a real-world population, or assessed the proportion of real-world patients who would have been eligible for RCT inclusion following the application of RCT inclusion/exclusion criteria. Many of the included studies concluded that RCT samples are highly selected and have a lower risk profile than real-world populations, with the frequent exclusion of elderly patients and patients with co morbidities. Calculation of ineligibility rates in individual studies showed that a high proportion of the general disease population was often excluded from trials. The majority of studies (n = 37 [71.2 %]) explicitly concluded that RCT samples were not broadly representative of real-world patients and that this may limit the external validity of the RCT. Authors made a number of recommendations to improve external validity. Findings from this review indicate that there is a need to improve the external validity of RCTs such that physicians treating patients in real-world settings have the appropriate evidence on which to base their clinical decisions. This goal could be achieved by trial design modification to include a more representative patient sample and by supplementing RCT evidence with data generated from observational studies. In general, a thoughtful approach to clinical evidence generation is required in which the trade-offs between internal and external validity are considered in a holistic and balanced manner. PMID- 26530986 TI - The responsiveness of the EQ-5D and time trade-off scores in schizophrenia, affective disorders, and alcohol addiction. AB - OBJECTIVE: To compare the responsiveness of the EQ-5D index (German and British tariff), the EQ-5D visual analogue scale (EQ VAS), and time trade-off (TTO) scores in schizophrenia, affective disorders, and alcohol addiction. METHODS: We used a sample of 502 patients and examined the measures at baseline and after 14 months. We used the generic "WHO Quality of Life BREF" (WHOQOL) and the disorder specific "Global Severity Index" (GSI) as anchors for a relevant improvement in a patient's health status. In a complete case analysis, we assessed the responsiveness, which is the ability to detect a change given a relevant change on the anchor. We computed the effect sizes (ESs) and standardised response means (SRMs). RESULTS: In patients with schizophrenia, the ESs and SRMs were large (ES/SRM > 0.8) for the British EQ-5D index (ESGSI: 0.93; SRMGSI: 0.89; SRMWHOQOL: 0.82). In patients with affective disorders, we found large ESs and SRMs for the EQ VAS (ESGSI: 1.79; ESWHOQOL: 0.90; SRMGSI: 1.52; SRMWHOQOL: 0.93) and a large ES for the British EQ-5D index (ESGSI: 0.88). In patients with alcohol addiction, the ESs and SRMs were large for the EQ VAS (ESGSI: 1.40; ESWHOQOL: 0.94; SRMGSI: 1.04; SRMWHOQOL: 0.83). The ESs and SRMs of the German EQ-5D index were consistently lower than those of the British EQ-5D index. Regarding TTO score, ESs and SRMs were generally less than 0.5. CONCLUSIONS: No preference-based instrument was consistently more responsive than others across all mental disorders. While the EQ VAS was the most responsive instrument in patients with affective disorders or alcohol addiction, the British EQ-5D index was reasonably responsive in patients with schizophrenia. PMID- 26530987 TI - 3-Bromopyruvate induces rapid human prostate cancer cell death by affecting cell energy metabolism, GSH pool and the glyoxalase system. AB - 3-bromopyruvate (3-BP) is an anti-tumour drug effective on hepatocellular carcinoma and other tumour cell types, which affects both glycolytic and mitochondrial targets, depleting cellular ATP pool. Here we tested 3-BP on human prostate cancer cells showing, differently from other tumour types, efficient ATP production and functional mitochondrial metabolism. We found that 3-BP rapidly induced cultured androgen-insensitive (PC-3) and androgen-responsive (LNCaP) prostate cancer cell death at low concentrations (IC(50) values of 50 and 70 MUM, respectively) with a multimodal mechanism of action. In particular, 3-BP-treated PC-3 cells showed a selective, strong reduction of glyceraldeide 3-phosphate dehydrogenase activity, due to the direct interaction of the drug with the enzyme. Moreover, 3-BP strongly impaired both glutamate/malate- and succinate dependent mitochondrial respiration, membrane potential generation and ATP synthesis, concomitant with the inhibition of respiratory chain complex I, II and ATP synthase activities. The drastic reduction of cellular ATP levels and depletion of GSH pool, associated with significant increase in cell oxidative stress, were found after 3-BP treatment of PC-3 cells. Interestingly, the activity of both glyoxalase I and II, devoted to the elimination of the cytotoxic methylglyoxal, was strongly inhibited by 3-BP. Both N-acetylcysteine and aminoguanidine, GSH precursor and methylglyoxal scavenger, respectively, prevented 3-BP-induced PC-3 cell death, showing that impaired cell antioxidant and detoxifying capacities are crucial events leading to cell death. The provided information on the multi-target cytotoxic action of 3-BP, finally leading to PC-3 cell necrosis, might be useful for future development of 3-BP as a therapeutic option for prostate cancer treatment. PMID- 26530988 TI - The Saccharomyces cerevisiae mitochondrial unselective channel behaves as a physiological uncoupling system regulated by Ca2+, Mg2+, phosphate and ATP. AB - It is proposed that the Saccharomyces cerevisiae the Mitochondrial Unselective Channel ((Sc)MUC) is tightly regulated constituting a physiological uncoupling system that prevents overproduction of reactive oxygen species (ROS). Mg(2+), Ca(2+) or phosphate (Pi) close (Sc)MUC, while ATP or a high rate of oxygen consumption open it. We assessed (Sc)MUC activity by measuring in isolated mitochondria the respiratory control, transmembrane potential (DeltaPsi), swelling and production of ROS. At increasing [Pi], less [Ca(2+)] and/or [Mg(2+)] were needed to close (Sc)MUC or increase ATP synthesis. The Ca(2+)-mediated closure of (Sc)MUC was prevented by high [ATP] while the Mg(2+) or Pi effect was not. When Ca(2+) and Mg(2+) were alternatively added or chelated, (Sc)MUC opened and closed reversibly. Different effects of Ca(2+) vs Mg(2+) effects were probably due to mitochondrial Mg(2+) uptake. Our results suggest that (Sc)MUC activity is dynamically controlled by both the ATP/Pi ratio and divalent cation fluctuations. It is proposed that the reversible opening/closing of (Sc)MUC leads to physiological uncoupling and a consequent decrease in ROS production. PMID- 26530989 TI - Pyrethroid resistance in Phytoseiulus macropilis (Acari: Phytoseiidae): cross resistance, stability and effect of synergists. AB - Phytoseiulus macropilis Banks (Acari: Phytoseiidae) is an effective predator of Tetranychus urticae Koch (Acari: Tetranychidae). The objectives of this research were to study the stability of fenpropathrin resistance and the cross-resistance relationships with different pyrethroids, and also to evaluate the effect of synergists [piperonyl butoxide (PBO), diethyl maleate (DEM) and S,S,S-tributyl phosphorotrithioate (DEF)] on fenpropathrin resistant and susceptible strains of this predaceous mite. The stability of fenpropathrin resistance was studied under laboratory conditions, using P. macropilis populations with initial frequencies of 75 and 50% of resistant mites. The percentages of fenpropathrin resistant mites were evaluated monthly for a period of up to 12 months. A trend toward decreased resistance frequencies was observed only during the first 3-4 months. After this initial decrease, the fenpropathrin resistance was shown to be stable, maintaining constant resistance frequencies (around 30%) until the end of the evaluation period. Toxicity tests carried out using fenpropathrin resistant and susceptible strains of P. macropilis indicated strong positive cross-resistance between fenpropathrin and the pyrethroids bifenthrin and deltamethrin. Bioassays with the synergists DEM, DEF and PBO were also performed. The maximum synergism ratio (SR = LC50 without synergist/LC50 with synergist) detected for the three evaluated synergists (PBO, DEM, DEF) was 5.86 (for DEF), indicating low influence of enzyme detoxification processes in fenpropathrin resistance. PMID- 26530990 TI - Precopulatory mate guarding influences the development of quiescent deutonymph females in the two-spotted spider mite (Acari: Tetranychidae). AB - Individuals of some organisms have a specific stage sensitive to environmental cues that initiate developmental plasticity which subsequently influences their entire development. Females may use male behaviour such as precopulatory mate guarding as an environmental cue to change their developmental rate. In the two spotted spider mite Tetranychus urticae (Acari: Tetranychidae), only the first insemination results in fertilization and males guard quiescent deutonymph females. As quiescent individuals take on a silvery appearance before moulting, the period of the quiescent stage can be divided into two parts: from entering the quiescent stage to becoming silvery (1st period) and from becoming silvery to moulting (2nd period). Females may be sensitive to precopulatory mate guarding immediately before moulting (i.e. 2nd period). Thus, I examined whether precopulatory mate guarding during either period affects the total developmental duration of quiescent deutonymph females. When guarded by a male, the whole developmental duration of the quiescent deutonymph females became significantly shorter (by 3-5%) than that of solitary ones, regardless whether the guarding occurred during the 1st period, the 2nd period or both periods. In conclusion, quiescent deutonymph T. urticae females use precopulatory mate guarding by conspecific males as an environmental cue for their developmental rate, although they are sensitive to the mate guarding not only immediately before moulting. PMID- 26530991 TI - Typhlodromus pyri and Euseius finlandicus (Acari: Phytoseiidae) as potential biocontrol agents against spider mites (Acari: Tetranychidae) inhabiting willows: laboratory studies on predator development and reproduction on four diets. AB - Typhlodromus pyri Scheuten and Euseius finlandicus (Oudemans) are important predators of phytophagous mites. The present laboratory study aimed to determine whether both species can develop and reach maturity feeding on spider mites occurring on willows, i.e., Schizotetranychus schizopus (Zacher), Schizotetranychus garmani Pritchard & Baker, and Tetranychus urticae Koch, and on Brassica napus L. pollen. The predators' development, reproduction and demographic parameters were significantly affected by diet. The data suggest that rape pollen can be useful in mass rearing of E. finlandicus but is completely unsuitable as alternative food for T. pyri. Short development time and high values of population parameters achieved by T. pyri feeding on larvae and protonymphs of S. schizopus and by E. finlandicus feeding on juvenile stages of S. garmani indicate great suitability of these preys as food for the phytoseiids, and make both predatory species promising biocontrol agents in spider mite control on willows. PMID- 26530992 TI - Cryptic speciation within Phytoptus avellanae s.l. (Eriophyoidea: Phytoptidae) revealed by molecular data and observations on molting Tegonotus-like nymphs. AB - Hazelnut big bud mite, Phytoptus avellanae Nalepa, is one of the most harmful pests of Corylus spp. (Corylaceae) worldwide. Herein, we show that this species represents a complex of two cryptic species: one that lives and reproduces in buds causing their enlargement ('big buds') and drying, whereas the other is a vagrant living on leaves, under bud scales and in catkins, based on phylogenetic analyzes of mitochondrial cytochrome c oxidase subunit I (COI) DNA and the nuclear D2 region of 28S rDNA sequences. A molecular assessment based on mtCOI DNA and nuclear D2 28S rDNA revealed consistent differences of 16.8 and 3.5% between the two species, respectively. Molecular analysis also revealed that atypical flattened nymphs (Tegonotus-like nymphs sensu Keifer in Mites Injurious to Economic Plants, University of California Press, Berkeley, pp 327-562, 1975) with differently annulated opisthosoma, which appear in the life cycle of P. avellanae s.l., belong to the 'vagrant' lineage, i.e. vagrant cryptic species. Light microscopy images of Tegonotus-like nymphs molting into males and females are presented for the first time. Our results suggest that the name P. avellanae comprise two species. Big bud mite should keep the name P. avellanae, and the vagrant cryptic species should be re-named after a proper morphological description is made. PMID- 26530993 TI - A study of embryonic development in eriophyoid mites (Acariformes, Eriophyoidea) with the use of the fluorochrome DAPI and confocal microscopy. AB - The embryonic development of four eriophyoid mite species, Cecidophyopsis ribis, Phytoptus avellanae, Oziella liroi and Loboquintus subsquamatus, has been studied with the use of fluorochrome DAPI and confocal microscopy. The first three nuclear divisions occur on the egg periphery (the groups of 2, 4, and 6 nuclei have been recorded), while the biggest part of yolk remains undivided. After four or five nuclear divisions all nuclei are situated only in one sector of the embryo, while other sectors contain only yolk suggesting possible meroblastic cleavage. Later, the formation of superficial blastoderm takes place. A few large yolk cells are situated inside the embryo. Germ band formation initiates as funnel-like cell invagination and leads to formation of a typical stage with four paired prosomal buds (chelicerae, palps, legs I and II). Each palp contains two lobes (anterior and posterior), the adult subcapitulum is presumably a fusion product of the anterior pair of the lobes. Neither rudiments of legs III and IV, traces of opisthosomal segments nor remnants of the prelarval exuvium under the egg shell were detected. Overall, the pattern of embryonic development in eriophyoids re-emphasizes the peculiarity of this ancient group of miniaturized phytoparasitic animals, and invites researches to pursue a deeper investigation of various fundamental aspects of this aberrant group of Acari. Further studies using various fluorescent dyes and transmission electron microscopy are needed to visualize plasma membranes and clarify the pattern of early cleavage of eriophyoids. PMID- 26530994 TI - Why do males choose heterospecific females in the red spider mite? AB - In some species, males readily show courtship behaviour towards heterospecific females and even prefer them to females of their own species. This behaviour is generally explained by indiscriminate mating to acquire more mates, but may partly be explained by male mate preference mechanisms that have developed to choose among conspecific females, as male preference for larger females causes mating with larger heterospecific females. Recently, we found that males of the red spider mite, Tetranychus evansi collected from Spain (invasive population), prefer to mate with females of the two-spotted spider mite, T. urticae rather than with conspecific females. In spider mites, mate preference for non-kin individuals has been observed. Here, we investigated if T. evansi males collected from the area of its origin (Brazil) also show preference for heterospecific females. Secondly, we investigated if mate preference of T. evansi males for heterospecific females is affected by their relatedness to conspecific females which are offered together with heterospecific females. We found that mate preference for heterospecific females exists in Brazilian T. evansi, suggesting that the preference for heterospecific females is not a lack of evolved premating isolation with an allopatric species. We found that T. evansi males showed lower propensity to mate with heterospecific females when alternative females were non kin in the two iso-female lines collected from Brazil. However, the effect of relatedness on male mate preference was not significant. We discuss alternative hypotheses explaining why T. evansi males prefer to mate with T. urticae females. PMID- 26530997 TI - Prevalence and clinical significance of cellular and acellular mucin in patients with locally advanced mucinous rectal cancer who underwent preoperative chemoradiotherapy followed by radical surgery. AB - AIM: The frequent presence of acellular mucin in specimens showing pathological complete response to preoperative chemoradiotherapy (CRT) and the poor response to preoperative CRT in mucinous rectal cancer have been reported. However, the prevalence and prognostic significance of cellular and acellular mucin have not been evaluated in resected specimens from patients with mucinous rectal cancer who undergo preoperative CRT. METHOD: We retrospectively evaluated the clinicopathological features and prognostic significance of mucin in resected specimens from 59 consecutive patients with mucinous rectal cancer who underwent long-course CRT followed by resection between January 2000 and December 2009. Patients were categorized according to the presence of mucin, as identified by pathological analysis. The clinicopathological findings and oncological results were compared. RESULTS: Mucin was identified in 25 of 59 patients with mucinous rectal cancer (42.4%). Mucin was more frequent in men (hazard ratio = 23.94, 95% confidence interval = 1.875-305.504, P = 0.015) and in specimens showing a good tumour response grade (hazard ratio = 64.26, 95% confidence interval = 6.940 595.045, P < 0.001). With a median follow-up of 67.7 (range 8.6-133.2) months, the 5-year overall survival (60.7% without mucin vs 51.4% with mucin, P = 0.898) and disease-free survival (59.9% without mucin vs 56.9% with mucin, P = 0.813) did not differ between the groups. CONCLUSION: The presence of mucin in rectal cancer with mucinous differentiation after preoperative CRT and resection is associated with male gender and a good tumour response grade, without significant impact on oncological outcome. PMID- 26530998 TI - Vacuum-assisted biopsy is a viable alternative to surgical biopsy in the investigation of breast lesions of uncertain malignant potential. AB - AIMS: In patients presenting with a breast lesion, when initial core biopsy histology falls into the category of "uncertain malignant potential" (i.e. a B3 lesion), the next line of investigation has traditionally been a surgical biopsy (SBx). Vacuum-assisted biopsy (VAB) may be a viable minimally invasive alternative to SBx for B3 lesions. The primary aims of this study were to establish whether VAB reduces the need for surgical biopsy and determine VAB sensitivity for carcinoma following initial B3 histology. MATERIALS AND METHODS: B3 lesion data was collected from 2004 to 2013 retrospectively, from a single institution that utilises both VAB and SBx. RESULTS: A total of 413 lesions were categorised B3 on initial biopsy. Mean age was 61 years (range: 24-91 years). Mean follow up was 52 months (range: 19-60 months). 156 patients (38%) underwent VAB. Only 20% of patients underwent VAB in 2004, with an increase to 95% by 2013. VAB histology revealed twelve carcinomas, all of which progressed to surgical excision. In six cases, a SBx was required following VAB in order to provide further diagnostic information. In one case, carcinoma was missed on VAB. CONCLUSION: The increase in VAB use over time suggests that the procedure is well tolerated. The results demonstrate a VAB sensitivity of 92% for carcinoma diagnosis. In 96% of cases (150 of 156), VAB results were conclusive enough to avoid a subsequent SBx. This data suggests that VAB may be a preferable alternative to surgical biopsy for many B3 lesions. PMID- 26530999 TI - A [4+1] Cyclative Capture Approach to 3H-Indole-N-oxides at Room Temperature by Rhodium(III)-Catalyzed C?H Activation. AB - The rhodium(III)-catalyzed [3+2] C?H cyclization of aniline derivatives and internal alkynes represents a useful contribution to straightforward synthesis of indoles. However, there is no report on the more challenging synthesis of pharmaceutically important N-hydroxyindoles and 3H-indole-N-oxides. Reported herein is the first rhodium(III)-catalyzed [4+1] C?H oxidative cyclization of nitrones with diazo compounds to access 3H-indole-N-oxides. More significantly, this reaction proceeds at room temperature and has been extended to the synthesis of N-hydroxyindoles and N-hydroxyindolines. PMID- 26531000 TI - Role of enteral nutrition in nonthyroidal illness syndrome: a retrospective observational study. AB - BACKGROUND: The nonthyroidal illness syndrome (NTIS) is prevalent among patients with enterocutaneous fistula and is associated with poor outcomes. The present study aimed to explore the role of enteral nutrition (EN) therapy on thyroid function among patients with enterocutaneous fistula and NTIS. METHODS: We conducted a retrospective observational study among patients with enterocutaneous fistula between January 2013 and April 2014. All enrolled patients received EN therapy. Thyroid function and other parameters were measured. RESULTS: After administration of 4 weeks of EN therapy, NTIS was resolved in 66 patients (Group A), while it persisted in 14 patients (Group B). The overall treatment success rate was 82.50 %. There were no significant differences between groups A and B at baseline for all parameters, except for the time from admission to start of EN therapy. The logistic analysis revealed that the time from admission to start of EN therapy was a significant independent indicator for achieving resolution of NTIS in our cohort. CONCLUSIONS: This retrospective observational cohort study demonstrated that EN therapy can aid in the resolution of NTIS among patients with enterocutaneous fistula. These findings confirm the benefit of EN in the treatment of enterocutaneous fistula. PMID- 26531001 TI - [Erythema ab igne, a peculiar side effect of laptops]. PMID- 26531002 TI - Sulforaphane exerts anti-inflammatory effects against lipopolysaccharide-induced acute lung injury in mice through the Nrf2/ARE pathway. AB - Sulforaphane (1-isothiocyanate-4-methyl sulfonyl butane) is a plant extract (obtained from cruciferous vegetables, such as broccoli and cabbage) and is known to exert anticancer, antioxidant and anti-inflammatory effects. It stimulates the generation of human or animal cells, which is beneficial to the body. The aim of the current study was to determine whether sulforaphane protects against lipopolysaccharide (LPS)-induced acute lung injury (ALI) through its anti inflammatory effects, and to investigate the signaling pathways involved. For this purpose, male BALB/c mice were treated with sulforaphane (50 mg/kg) and 3 days later, ALI was induced by the administration of LPS (5 mg/kg) and we thus established the model of ALI. Our results revealed that sulforaphane significantly decreased lactate dehydrogenase (LDH) activity (as shown by LDH assay), the wet-to-dry ratio of the lungs and the serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) (measured by ELISA), as well as nuclear factor-kappaB protein expression in mice with LPS-induced ALI. Moreover, treatment with sulforaphane significantly inhibited prostaglandin E2 (PGE2) production, and cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP 9) protein expression (as shown by western blot analysis), as well as inducible nitric oxide synthase (iNOS) activity in mice with LPS-induced ALI. Lastly, we noted that pre-treatment with sulforaphane activated the nuclear factor-E2 related factor 2 (Nrf2)/antioxidant response element (ARE) pathway in the mice with LPS-induced ALI. These findings demonstrate that sulforaphane exerts protective effects against LPS-induced ALI through the Nrf2/ARE pathway. Thus, sulforaphane may be a potential a candidate for use in the treatment of ALI. PMID- 26531003 TI - Skeletal muscle tuberculosis in an immunocompetent patient. PMID- 26531004 TI - TMPRSS3 modulates ovarian cancer cell proliferation, invasion and metastasis. AB - Overexpression of transmembrane protease, serine 3 (TMPRSS3) has been detected in ovarian cancer. However, the molecular mechanisms of TMPRSS3 in ovarian cancer remain unclear. In the present study, we found that TMPRSS3 was significantly expressed in ovarian cancer cells. Overexpression of TMPRSS3 promoted the proliferation, invasion and migration of A2780 cells. Conversely, knockdown of TMPRSS3 in HO8910 cells inhibited the proliferation, invasion and migration. Furthermore, TMPRSS3 affected the expression levels of E-cadherin, vimentin and Twist. In addition, TMPRSS3 induced activation of ERK1/2 in ovarian cancer cells, and the ERK1/2 pathway was required for the TMPRSS3-mediated proliferation, invasion and migration of ovarian cancer cells. Finally, knockdown of TMPRSS3 inhibited ovarian cancer HO8910 cell growth and metastasis in vivo. Collectively, the present study suggests that TMPRSS3 plays a crucial role in the development and progression of ovarian cancer. Therefore, TMPRSS3 represents a potential therapeutic target of ovarian cancer. PMID- 26531005 TI - Stress velopharyngeal incompetence: Two case reports and options for diagnosis and management. AB - Stress velopharyngeal incompetence (SVPI) commonly affects brass and wind musicians. We present a series of two patients who presented with nasal air emission following prolonged woodwind instrument practice. Neither patient demonstrated audible nasal air emission during speech, but endoscopy revealed localized air escape/bubbling from different sites for each patient with instrument playing only. Both underwent tailored surgical treatment with resolution of symptoms during performance. Diagnosis of SVPI requires examination during the action that induces VPI to allow for directed management. Treatment should be targeted based on nasopharyngoscopy findings. PMID- 26531006 TI - TRPC1 is required for survival and proliferation of cochlear spiral ganglion stem/progenitor cells. AB - OBJECTIVE: The present studies were designed to test the hypothesis that canonical transient receptor potential channel 1 (TRPC1) is required for the proliferation of cochlear spiral ganglion stem/progenitor cells (SPCs). METHODS AND MATERIALS: TRPC1 were detected and evaluated in postnatal day 1 CBA/CaJ mice pups derived-cochlear spiral ganglion SPCs by reverse transcription-polymerase chain reaction, Western blot, immunocytochemistry, and calcium imaging. The cell viability and proliferation of the spiral ganglion SPCs following si-RNA mediated knockdown of TRPC1 or addition of TRPC channel blocker SKF9635 were compared to controls. RESULTS: In spiral ganglion SPCs, TRPC1 was found to be the most abundantly expressed TRPC subunit and shown to contribute to store-operated calcium entry. Silencing of TRPC1 or addition of TRPC channel blockers significantly decreased the rate of cell proliferation. CONCLUSION: The results suggest that TRPC1 might serve as an essential molecule in regulating the proliferation of spiral ganglion SPCs. PMID- 26531007 TI - Comparative genomics and experimental evolution of Escherichia coli BL21(DE3) strains reveal the landscape of toxicity escape from membrane protein overproduction. AB - Achieving sufficient yields of proteins in their functional form represents the first bottleneck in contemporary bioscience and biotechnology. To accomplish successful overexpression of membrane proteins in a workhorse organism such as E. coli, defined and rational optimization strategies based on an understanding of the genetic background of the toxicity-escape mechanism are desirable. To this end, we sequenced the genomes of E. coli C41(DE3) and its derivative C43(DE3), which were developed for membrane protein production. Comparative analysis of their genomes with those of their ancestral strain E. coli BL21(DE3) revealed various genetic changes in both strains. A series of E. coli variants that are able to tolerate transformation with or overexpression of membrane proteins were generated by in vitro evolution. Targeted sequencing of the evolved strains revealed the mutational hotspots among the acquired genetic changes. By these combinatorial approaches, we found non-synonymous changes in the lac repressor gene of the lac operon as well as nucleotide substitutions in the lacUV5 promoter of the DE3 region, by which the toxic effect to the host caused by overexpression of membrane proteins could be relieved. A mutation in lacI was demonstrated to be crucial for conferring tolerance to membrane protein overexpression. PMID- 26531008 TI - Three-dimensional bioprinting of embryonic stem cells directs highly uniform embryoid body formation. AB - With the ability to manipulate cells temporarily and spatially into three dimensional (3D) tissue-like construct, 3D bioprinting technology was used in many studies to facilitate the recreation of complex cell niche and/or to better understand the regulation of stem cell proliferation and differentiation by cellular microenvironment factors. Embryonic stem cells (ESCs) have the capacity to differentiate into any specialized cell type of the animal body, generally via the formation of embryoid body (EB), which mimics the early stages of embryogenesis. In this study, extrusion-based 3D bioprinting technology was utilized for biofabricating ESCs into 3D cell-laden construct. The influence of 3D printing parameters on ESC viability, proliferation, maintenance of pluripotency and the rule of EB formation was systematically studied in this work. Results demonstrated that ESCs were successfully printed with hydrogel into 3D macroporous construct. Upon process optimization, about 90% ESCs remained alive after the process of bioprinting and cell-laden construct formation. ESCs continued proliferating into spheroid EBs in the hydrogel construct, while retaining the protein expression and gene expression of pluripotent markers, like octamer binding transcription factor 4, stage specific embryonic antigen 1 and Nanog. In this novel technology, EBs were formed through cell proliferation instead of aggregation, and the quantity of EBs was tuned by the initial cell density in the 3D bioprinting process. This study introduces the 3D bioprinting of ESCs into a 3D cell-laden hydrogel construct for the first time and showed the production of uniform, pluripotent, high-throughput and size-controllable EBs, which indicated strong potential in ESC large scale expansion, stem cell regulation and fabrication of tissue-like structure and drug screening studies. PMID- 26531009 TI - Photoelectron spectroscopy and density functional calculations of C(n)S(m)(-) (n = 2-7; m = 1, 2) clusters. AB - CnSm(-) (n = 2-7; m = 1, 2) clusters were investigated by using photoelectron spectroscopy combined with density functional theory calculations. We found that the vertical detachment energies of both CnS(-) and CnS2(-) (n = 2-7) clusters exhibit a strong odd-even alternation with an increasing number of carbon atoms: the VDEs of even-n clusters are higher than those of adjacent odd-n clusters. The most stable structures of the anionic and neutral CnS (n = 2-7) clusters are linear with the S atom locating at one end of the carbon chain except that the structure of C3S(-) is slightly bent. The ground state isomers of the anionic and neutral CnS2 (n = 2-7) clusters are all linear structures with two S atoms locating at two ends of the carbon chain. The electron affinities of the neutral CnS (n = 2, 4-7) and CnS2 (n = 2-7) clusters are determined based on the experimental adiabatic detachment energies of the corresponding anion species, because the most stable structures of the neutral clusters are similar to those of the corresponding anions. PMID- 26531010 TI - A Urologist's Guide to Ingredients Found in Top-Selling Nutraceuticals for Men's Sexual Health. AB - INTRODUCTION: Use of supplements is common among men seeking urologic evaluation for sexual health matters. With a dizzying array of formulations available and little regulation on the dosage, purity, or ingredients found in these products, the health effects of nutraceuticals are often confusing to patients and medical practitioners alike. AIM: In this review, we set out to concisely summarize the data on ingredients found within the top-selling nutraceutical agents marketed for men's sexual health in order to provide a clinical guide for urologists. METHODS: We used sales data from the most popular retail provider of men's health supplements to identify the top-selling products marketed toward improvement of men's sexual health. We summarized the available information related to the ingredients, dosage, cost, and mechanism of action for these substances and performed an extensive literature search to identify and review the current evidence available for each of the most common ingredients found in these nutraceuticals. RESULTS: The top-selling nutraceuticals marked for men's sexual health contain a blend of multiple supplements (up to 33 in one formulation identified), the most common being ginseng, tribulus, zinc, horny goat weed, B complex vitamins/trace minerals, fenugreek, L-arginine, maca, DHEA, ginkgo, and yohimbine. The currently available medical literature evaluating the efficacy of these substances is generally of low quality. CONCLUSIONS: Despite the dearth of evidence supporting nutraceutical agents in the men's health arena, these substances are still commonly used by patients. As these products can affect the health and well-being of men presenting to a urology clinic, a familiarity with commonly used agents can help the urologist appropriately counsel their patients. PMID- 26531011 TI - Different effects of identical symmetry-related mutations near the bacteriochlorophyll dimer in the photosynthetic reaction center of Rhodobacter sphaeroides. AB - In the bacterial photosynthetic reaction center (RC), asymmetric protein environment of the bacteriochlorophyll (BChl) dimer largely determines the photophysical and photochemical properties of the primary electron donor. Previously, we noticed significant differences in properties of Rhodobacter sphaeroides RCs with identical mutations in symmetry-related positions - I(M206)H and I(L177)H. The substitution I(L177)H resulted in covalent binding of BChl PA with the L-subunit, as well as in 6-coordination of BChl BB, whereas in RC I(M206)H no such changes of pigment-protein interactions were found. In addition, the yield of RC I(M206)H after its isolation from membranes was significantly lower than the yield of RC I(L177)H. This study shows that replacement of amino acid residues in the M203-M206 positions near BChls PB and BA by symmetry-related residues from the L-subunit near BChls PA and BB leads to further decrease in RC amount in the membranes associated obviously with poor assembly of the complex. Introduction of a new hydrogen bond between BChl PB and its protein environment by means of the F(M197)H mutation stabilized the mutant RC but did not affect its low yield. We suggest that the mutation I(M206)H and substitution of amino acid residues in M203-M205 positions could disturb glycolipid binding on the RC surface near BChl BA that is important for stable assembly of the complex in the membrane. PMID- 26531012 TI - Electron transfer in photosystem I containing native and modified quinone acceptors. AB - The pigment-protein complex of photosystem I (PS I) catalyzes light-driven oxidation of plastocyanin or cytochrome c6 and reduction of ferredoxin or flavodoxin in oxygenic photosynthetic organisms. In this review, we describe the current state of knowledge of the processes of excitation energy transfer and formation of the primary and secondary ion-radical pairs within PS I. The electron transfer reaction involving quinone cofactor in the A1 site and its role in providing asymmetry of electron transport as well as interaction with oxygen and ascorbate in PS I are discussed. PMID- 26531013 TI - The green alga Chlamydomonas reinhardtii as a tool for in vivo study of site directed mutations in PsbO protein of photosystem II. AB - The photosynthetic water oxidation in photosystem II (PS II) takes place in a special water-oxidizing complex (WOC) that consists of a catalytic center, Mn4CaO5 cluster, and also includes a group of extrinsic proteins needed for its stability. The most important of these is PsbO, which binds to the donor side of PS II near the Mn cluster and is directly involved in the regulation of its stability and activity. However, the molecular mechanism of PsbO involvement in photosynthetic water oxidation remains unclear. One of the main approaches to solving this problem is site-directed mutagenesis. Until recently, the effect of mutations in PsbO in vivo has been studied only in cyanobacteria (prokaryotes). In eukaryotic organisms, such studies (site-directed mutagenesis of PsbO) have not been carried out, though it is known that the role of PsbO protein in plants and cyanobacteria may be different. In this review, we consider the possibility of using for this purpose the unicellular green alga Chlamydomonas reinhardtii, a eukaryotic organism with a set of extrinsic proteins of the WOC similar to that of the higher plants. However, in contrast to higher plants, the DeltapsbO mutant of C. reinhardtii is viable. Another reason to use this alga is that the DeltapsbO strain of C. reinhardtii grown in the dark (heterotrophically) is able to build the minimal photochemically active complex of PS II, allowing investigation of the role of individual amino acid substitutions in PsbO in vivo without damaging PS II due to photoinactivation. PMID- 26531014 TI - Carbonic anhydrases in photosynthetic cells of higher plants. AB - This review presents information about carbonic anhydrases, enzymes catalyzing the reversible hydration of carbon dioxide in aqueous solutions. The families of carbonic anhydrases are described, and data concerning the presence of their representatives in organisms of different classes, and especially in the higher plants, are considered. Proven and hypothetical functions of carbonic anhydrases in living organisms are listed. Particular attention is given to those functions of the enzyme that are relevant to photosynthetic reactions. These functions in algae are briefly described. Data about probable functions of carbonic anhydrases in plasma membrane, mitochondria, and chloroplast stroma of higher plants are discussed. Update concerning carbonic anhydrases in chloroplast thylakoids of higher plants, i.e. their quantity and possible participation in photosynthetic reactions, is given in detail. PMID- 26531015 TI - ESR - a retinal protein with unusual properties from Exiguobacterium sibiricum. AB - This review covers the properties of a retinal protein (ESR) from the psychrotrophic bacterium Exiguobacterium sibiricum that functions as a light driven proton pump. The presence of a lysine residue at the position corresponding to intramolecular proton donor for the Schiff base represents a unique structural feature of ESR. We have shown that Lys96 successfully facilitates delivery of protons from the cytoplasmic surface to the Schiff base, thus acting as a proton donor in ESR. Since proton uptake during the photocycle precedes Schiff base reprotonation, we conclude that this residue is initially in the uncharged state and acquires a proton for a short time after Schiff base deprotonation and M intermediate formation. Involvement of Lys as a proton donor distinguishes ESR from the related retinal proteins - bacteriorhodopsin (BR), proteorhodopsin (PR), and xanthorhodopsin (XR), in which the donor function is performed by residues with a carboxyl side chain. Like other eubacterial proton pumps (PR and XR), ESR contains a histidine residue interacting with the proton acceptor Asp85. In contrast to PR, this interaction leads to shift of the acceptor's pKa to more acidic pH, thus providing its ability to function over a wide pH range. The presence of a strong H-bond between Asp85 and His57, the structure of the proton-conducting pathways from cytoplasmic surface to the Schiff base and to extracellular surface, and other properties of ESR were demonstrated by solving its three-dimensional structure, which revealed several differences from known structures of BR and XR. The structure of ESR, its photocycle, and proton transfer reactions are discussed in comparison with homologous retinal proteins. PMID- 26531016 TI - Bioluminescence assay for cell viability. AB - Theoretical aspects of the adenosine triphosphate bioluminescence assay based on the use of the firefly luciferin-luciferase system are considered, as well as its application for assessing cell viability in microbiology, sanitation, medicine, and ecology. Various approaches for the analysis of individual or mixed cultures of microorganisms are presented, and capabilities of the method for investigation of biological processes in live cells including necrosis, apoptosis, as well as for investigation of the dynamics of metabolism are described. PMID- 26531017 TI - Coelenterazine-dependent luciferases. AB - Bioluminescence is a widespread natural phenomenon. Luminous organisms are found among bacteria, fungi, protozoa, coelenterates, worms, molluscs, insects, and fish. Studies on bioluminescent systems of various organisms have revealed an interesting feature - the mechanisms underlying visible light emission are considerably different in representatives of different taxa despite the same final result of this biochemical process. Among the several substrates of bioluminescent reactions identified in marine luminous organisms, the most commonly used are imidazopyrazinone derivatives such as coelenterazine and Cypridina luciferin. Although the substrate used is the same, bioluminescent proteins that catalyze light emitting reactions in taxonomically remote luminous organisms do not show similarity either in amino acid sequences or in spatial structures. In this review, we consider luciferases of various luminous organisms that use coelenterazine or Cypridina luciferin as a substrate, as well as modifications of these proteins that improve their physicochemical and bioluminescent properties and therefore their applicability in bioluminescence imaging in vivo. PMID- 26531018 TI - Photobiosensors containing luminescent bacteria. AB - The scientific basis for producing luminescent biosensors containing free and immobilized luminescent bacteria is discussed. Modern technologies for engineering target objects, procedures used to immobilize bacteria in different carriers, as well as procedures for integral and specific biodetection of toxins are presented. Data regarding generation and application of biomonitoring for ecotoxicants derived from natural and genetically engineered photobacterial strains are analyzed. Special attention is given to immobilization of photobacteria in polyvinyl alcohol-containing cryogel. The main physicochemical, biochemical, and technological parameters for stabilizing luminescence in immobilized bacteria are described. Results of the application of immobilized photobacterial preparations both during discrete and continuous biomonitoring for different classes of ecotoxicants are presented. PMID- 26531019 TI - Photodynamic inactivation of gramicidin channels in bilayer lipid membranes: protective efficacy of singlet oxygen quenchers depends on photosensitizer location. AB - The impact of double bonds in fatty acyl tails of unsaturated lipids on the photodynamic inactivation of ion channels formed by the pentadecapeptide gramicidin A in a planar bilayer lipid membrane was studied. The presence of unsaturated acyl tails protected gramicidin A against photodynamic inactivation, with efficacy depending on the depth of a photosensitizer in the membrane. The protective effect of double bonds was maximal with membrane-embedded chlorin e6 monoethylenediamine monoamide dimethyl ester, and minimal - in the case of water soluble tri-sulfonated aluminum phthalocyanine (AlPcS3) known to reside at the membrane surface. By contrast, the protective effect of the hydrophilic singlet oxygen scavenger ascorbate was maximal for AlPcS3 and minimal for amide of chlorin e6 dimethyl ester. The depth of photosensitizer position in the lipid bilayer was estimated from the quenching of photosensitizer fluorescence by iodide. Thus, the protective effect of a singlet oxygen scavenger against photodynamic inactivation of the membrane-inserted peptide is enhanced upon location of the photosensitizer and scavenger molecules in close vicinity to each other. PMID- 26531020 TI - Development of bacteriochlorophyll a-based near-infrared photosensitizers conjugated to gold nanoparticles for photodynamic therapy of cancer. AB - We report the synthesis and characterization of a new sulfur-containing derivative of bacteriochlorophyll a. The latter was isolated from biomass of the nonsulfur purple bacterium Rhodobacter capsulatus strain B10. The developed photosensitizer is N-aminobacteriopurpurinimide with an exocyclic amino group acylated with a lipoic acid moiety, which is a biogenic substance that acts as a cofactor of the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes in the body. The disulfide moiety of lipoic acid confers the compound aurophilicity, thus allowing its conjugation with gold nanoparticles (NP-Au) via S-Au bonds. The shape and the size of the resulting nanoconjugate with immobilized photosensitizer (PS-Au) were assessed by dynamic light scattering and transmission electron microscopy. The conjugated nanoparticles are spherical with hydrodynamic diameter of 100-110 nm. The PS-Au conjugate absorbs light at 824 nm and emits strong fluorescence at 830 nm, which allowed in vivo study of its dynamic biodistribution in rats bearing sarcoma M-1. Compared to the free photosensitizer, PS loaded on the gold nanoparticles (PS-Au) showed extended circulation time in the blood and enhanced tumor uptake due to nonspecific passive targeting when the drug accumulates in tumor sites through the leaky tumor neovasculature and does not return to the circulation. PMID- 26531021 TI - On the mechanism of erythrocyte hemolysis induced by photooxidized psoralen. AB - Contemporary concepts on a possible mechanism of erythrocyte hemolysis induced by photooxidized psoralen - the medicinal photosensitizing furocoumarin - are reviewed. The hypothesis on the mechanochemical mechanism of hemolysis is considered in view of recent data on photoinduced aggregation in photooxidized psoralen solutions. Appropriate chemical structures of photoproduct hemolysins and aggregating photoproducts are discussed. PMID- 26531022 TI - Effect of laser optoperforation of the zona pellucida on mouse embryo development in vitro. AB - The effect of laser optical perforation of the zona pellucida on the viability and development of mouse embryos has been studied. Operations of zona pellucida thinning and single or double perforation were carried out on 2-cell embryo, morula, and blastocyst stages with a laser pulse (wavelength 1.48 um, pulse duration 2 ms). Embryo development up to the blastocyst stage and hatching efficiency were statistically analyzed. It was found that 2-cell or morula stage embryo zona pellucida thinning or single perforation did not affect development to the blastocyst stage and number of hatched embryos, but it accelerated embryo hatching compared to control groups one day earlier in vitro. Double optoperforation on 2-cell embryo or morula stage did not significantly affect development to the blastocyst stage, but it strongly decreased the number of hatched embryos. Also, zona pellucida perforation at the blastocyst stage had a negative effect: hatching did not occur after this manipulation. Blastocyst cell number calculation after single zona pellucida perforation at 2-cell and morula stages showed that cell number of hatching or hatched blastocysts did not differ from the same control groups. This fact points out that the laser single optoperforation method is a useful and safe experimental tool that allows further manipulations within the zona pellucida. PMID- 26531023 TI - Participation of intracellular and extracellular pH changes in photosynthetic response development induced by variation potential in pumpkin seedlings. AB - Electrical signals presented in plants by action potential and by variation potential (VP) can induce a reversible inactivation of photosynthesis. Changes in the intracellular and extracellular pH during VP generation are a potential mechanism of photosynthetic response induction; however, this hypothesis requires additional experimental investigation. The purpose of the present work was to analyze the influence of pH changes on induction of the photosynthetic response in pumpkin. It was shown that a burning of the cotyledon induced VP propagation into true leaves of pumpkin seedlings inducing a decrease in the photosynthetic CO2 assimilation and an increase in non-photochemical quenching of fluorescence, whereas respiration was activated insignificantly. The photosynthetic response magnitude depended linearly on the VP amplitude. The intracellular and extracellular concentrations of protons were analyzed using pH-sensitive fluorescent probes, and the VP generation was shown to be accompanied by apoplast alkalization (0.4 pH unit) and cytoplasm acidification (0.3 pH unit). The influence of changes in the incubation medium pH on the non-photochemical quenching of fluorescence of isolated chloroplasts was also investigated. It was found that acidification of the medium stimulated the non-photochemical quenching, and the magnitude of this increase depended on the decrease in pH. Our results confirm the contribution of changes in intracellular and extracellular pH to induction of the photosynthetic response caused by VP. Possible mechanisms of the influence of pH changes on photosynthesis are discussed. PMID- 26531024 TI - Photoinduced changes in subcellular structures of the retinal pigment epithelium from the Japanese quail Coturnix japonica. AB - Fifteen-week-old sexually mature female Japanese quails (Coturnix japonica) grown under various lighting conditions were used in the study. It was found that the number of mitochondria and phagosomes was increased by 1.5-fold in the retinal pigment epithelium from birds reared for 95 days under blue light (440-470 nm) vs. reduced blue light component conditions. Also, it was found that egg production was increased by 15% in birds reared under blue light compared to other lightning conditions. Thus, we concluded that blue light conditions resulted in elevating metabolic activity and accelerating pace of life in Japanese quails. It is assumed that the blue light-induced effects are probably due to inhibition of melatonin synthesis. PMID- 26531025 TI - Expression of neuronal and signaling proteins in penumbra around a photothrombotic infarction core in rat cerebral cortex. AB - Photodynamic impact on animal cerebral cortex using water-soluble Bengal Rose as a photosensitizer, which does not cross the blood-brain barrier and remains in blood vessels, induces platelet aggregation, vessel occlusion, and brain tissue infarction. This reproduces ischemic stroke. Irreversible cell damage within the infarction core propagates to adjacent tissue and forms a transition zone - the penumbra. Tissue necrosis in the infarction core is too fast (minutes) to be prevented, but much slower penumbral injury (hours) can be limited. We studied the changes in morphology and protein expression profile in penumbra 1 h after local photothrombotic infarction induced by laser irradiation of the cerebral cortex after Bengal Rose administration. Morphological study using standard hematoxylin/eosin staining showed a 3-mm infarct core surrounded by 1.5-2.0 mm penumbra. Morphological changes in the penumbra were lesser and decreased towards its periphery. Antibody microarrays against 224 neuronal and signaling proteins were used for proteomic study. The observed upregulation of penumbra proteins involved in maintaining neurite integrity and guidance (NAV3, MAP1, CRMP2, PMP22); intercellular interactions (N-cadherin); synaptic transmission (glutamate decarboxylase, tryptophan hydroxylase, Munc-18-1, Munc-18-3, and synphilin-1); mitochondria quality control and mitophagy (PINK1 and Parkin); ubiquitin-mediated proteolysis and tissue clearance (UCHL1, PINK1, Parkin, synphilin-1); and signaling proteins (PKBalpha and ERK5) could be associated with tissue recovery. Downregulation of PKC, PKCbeta1/2, and TDP-43 could also reduce tissue injury. These changes in expression of some neuronal proteins were directed mainly to protection and tissue recovery in the penumbra. Some upregulated proteins might serve as markers of protection processes in a penumbra. PMID- 26531026 TI - Chronic kidney disease after heart transplantation: a single-centre retrospective study at Skane University Hospital in Lund 1988-2010. AB - We aimed to study the incidence, predictors and outcome of chronic kidney disease (CKD) after heart transplantation (HT). All our HT patients 1988-2010 were considered for inclusion. Of these, 134 came for annual follow-ups including evaluation of glomerular filtration rate (GFR) using iohexol clearance measurements, and the CKD-EPI (adults) or Schwartz (children) formulae. Median GFR (Q1-Q3) (ml/min/1.73 m(2) ) declined from 67.0 (50.0-82.0) during transplant assessment (TA) to 56.0 (45.0-69.0) at year 1, 53.0 (41.0-68.0) at year 5 and 44.5 (25.0-57.3) at year 10. The cumulative incidence of CKD >= stage 4 was 25% at 5 years and 41% at 10 years after transplantation. Proteinuria the first year post-HT was the only predictor related (P < 0.05) to a higher rate of GFR decline (HR 5.15, 95% CI 1.23-21.55). GFR >=60 as compared to <60 before HT, or a first year GFR decline <30% as compared to >30%, was moreover associated (P < 0.05) with a lower risk of death (HR 0.30, 95% CI 0.12-0.76 and HR 0.35, 95% CI 0.13 0.90, respectively). Notably, the CKD-EPI and Schwartz formulae overestimated GFR by 28 +/- 29% and 26 +/- 33%, respectively. In conclusion, CKD in HT patients is common and associated with worse outcome. To avoid diagnostic delay, GFR estimating equations' validity in HT patients needs further study. PMID- 26531027 TI - Toward a Valid Animal Model of Bipolar Disorder: How the Research Domain Criteria Help Bridge the Clinical-Basic Science Divide. AB - Bipolar disorder is a diagnostically heterogeneous disorder, although mania emerges as a distinct phenotype characterized by elevated mood and increased activity or energy. While bipolar disorder's cyclicity is difficult to represent in animals, models of mania have begun to decode its fundamental underlying neurobiology. When psychostimulants such as amphetamine or cocaine are administered to rodents, a resulting upsurge of motor activity is thought to share face and predictive validity with mania in humans. Studying black Swiss mice, which inherently exhibit proclivity for reward seeking and risk taking, also has yielded some insight. Further, translating the biology of bipolar disorder in humans into animal models has led to greater understanding of roles for candidate biological systems such as the GRIK2 and CLOCK genes, as well as the extracellular signal-related kinase pathway involved in the pathophysiology of the illness. The National Institute of Mental Health Research Domain Criteria initiative seeks to identify building blocks of complex illnesses like bipolar disorder in hopes of uncovering the neurobiology of each, as well as how each fits together to produce syndromes like bipolar disorder or why so many mental illnesses co-occur together. Research Domain Criteria-driven preclinical models of isolated behaviors and domains involved in mania and bipolar disorder will ultimately inform movement toward nosology supported by neurobiology. PMID- 26531028 TI - Antimicrobial resistance: the Hydra among us. PMID- 26531029 TI - Ebola: Europe-Africa research collaborations. PMID- 26531030 TI - Drug assessment in the Ebola virus disease epidemic in west Africa. PMID- 26531031 TI - Preventing sepsis. PMID- 26531032 TI - Preventing sepsis. PMID- 26531033 TI - Behavioural research to inform understanding of hepatitis C resistance. PMID- 26531034 TI - Hepatitis C prevalence among people who inject drugs in Hungary. PMID- 26531035 TI - Soil-transmitted helminths in China. PMID- 26531036 TI - Challenges in mapping research investments for treatments against pneumonia. PMID- 26531037 TI - Anaplasma species in China. PMID- 26531038 TI - Malaria and MDGs: mission accomplished? PMID- 26531040 TI - ICAAC/ICC 2015. PMID- 26531041 TI - Inadequate vaccine coverage fuels polio outbreak in Ukraine. PMID- 26531044 TI - Measuring laboratory-based influenza surveillance capacity: development of the 'International Influenza Laboratory Capacity Review' Tool. AB - OBJECTIVES: The 2005 International Health Regulations (IHR 2005) emphasized the importance of laboratory capacity to detect emerging diseases including novel influenza viruses. To support IHR 2005 requirements and the need to enhance influenza laboratory surveillance capacity, the Association of Public Health Laboratories (APHL) and the Centers for Disease Control and Prevention (CDC) Influenza Division developed the International Influenza Laboratory Capacity Review (Tool). STUDY DESIGN: Data from 37 assessments were reviewed and analyzed to verify that the quantitative analysis results accurately depicted a laboratory's capacity and capabilities. METHODS: Subject matter experts in influenza and laboratory practice used an iterative approach to develop the Tool incorporating feedback and lessons learnt through piloting and implementation. To systematically analyze assessment data, a quantitative framework for analysis was added to the Tool. RESULTS: The review indicated that changes in scores consistently reflected enhanced or decreased capacity. The review process also validated the utility of adding a quantitative analysis component to the assessments and the benefit of establishing a baseline from which to compare future assessments in a standardized way. CONCLUSIONS: Use of the Tool has provided APHL, CDC and each assessed laboratory with a standardized analysis of the laboratory's capacity. The information generated is used to improve laboratory systems for laboratory testing and enhance influenza surveillance globally. We describe the development of the Tool and lessons learnt. PMID- 26531045 TI - The Mycobacterium tuberculosis H37Ra gene MRA_1916 causes growth defects upon down-regulation. AB - D-amino acid oxidases play an important role in converting D-amino acids to their corresponding alpha-keto acids. MRA_1916 of Mycobacterium tuberculosis H37Ra (Mtb Ra) is annotated to be a D-amino acid oxidase (DAO). However, not much information is available about its physiological role during Mtb-Ra growth and survival. The present study was taken-up to understand the role of DAO during different stages of growth and effect of its down-regulation on growth. Recombinant Mtb-Ra strains with DAO and GlcB (malate synthase: MRA_1848) gene knockdown were developed and their growth was studied using Microtiter Alamar Blue Assay (MABA) with glycerol, acetate and glycine as a carbon source. Ethyl bromopyruvate (BrP) was used as an inhibitor of GlcB. MABA study showed inhibition of wild-type (WT) and knockdowns in the presence of BrP (2.5mM). However, growth inhibition of WT was less noticeable at lower concentrations of BrP. Mtb-Ra with DAO knockdown showed poor utilization of glycine in the presence of BrP. The DAO localization study showed its prominent distribution in cytosolic fraction and to some extent in cell wall and membrane fractions. Growth profile of WT under oxygen and nutritional stress showed changes in expression of DAO, GlcB, PckA (phosphoenolpyruvate carboxykinase: MRA_0219) and GlyA1 (serine hydroxymethyltransferase: MRA_1104). PMID- 26531046 TI - Comparison on batch anaerobic digestion of five different livestock manures and prediction of biochemical methane potential (BMP) using different statistical models. AB - There is a lack of literature reporting the methane potential of several livestock manures under the same anaerobic digestion conditions (same inoculum, temperature, time, and size of the digester). To the best of our knowledge, no previous study has reported biochemical methane potential (BMP) predicting models developed and evaluated by solely using at least five different livestock manure tests results. The goal of this study was to evaluate the BMP of five different livestock manures (dairy manure (DM), horse manure (HM), goat manure (GM), chicken manure (CM) and swine manure (SM)) and to predict the BMP using different statistical models. Nutrients of the digested different manures were also monitored. The BMP tests were conducted under mesophilic temperatures with a manure loading factor of 3.5g volatile solids (VS)/L and a feed to inoculum ratio (F/I) of 0.5. Single variable and multiple variable regression models were developed using manure total carbohydrate (TC), crude protein (CP), total fat (TF), lignin (LIG) and acid detergent fiber (ADF), and measured BMP data. Three different kinetic models (first order kinetic model, modified Gompertz model and Chen and Hashimoto model) were evaluated for BMP predictions. The BMPs of DM, HM, GM, CM and SM were measured to be 204, 155, 159, 259, and 323mL/g VS, respectively and the VS removals were calculated to be 58.6%, 52.9%, 46.4%, 81.4%, 81.4%, respectively. The technical digestion time (T80-90, time required to produce 80-90% of total biogas production) for DM, HM, GM, CM and SM was calculated to be in the ranges of 19-28, 27-37, 31-44, 13-18, 12-17days, respectively. The effluents from the HM showed the lowest nitrogen, phosphorus and potassium concentrations. The effluents from the CM digesters showed highest nitrogen and phosphorus concentrations and digested SM showed highest potassium concentration. Based on the results of the regression analysis, the model using the variable of LIG showed the best (R(2)=0.851, p=0.026) for BMP prediction among the single variable models, and the model including variables of TC and TF showed the best prediction for BMPs (R(2)=0.913, p=0.068-0.075) comparing with other two-variable models, while the model including variables of CP, LIG and ADF performed the best in BMP prediction (R(2)=0.999, p=0.009-0.017) if three variable models were compared. Among the three kinetic models used, the first order kinetic model fitted the measured BMPs data best (R(2)=0.996-0.998, rRMSE=0.171-0.381) and deviations between measured and the first order kinetic model predicted BMPs were less than 3.0%. PMID- 26531047 TI - Biogas production enhancement using semi-aerobic pre-aeration in a hybrid bioreactor landfill. AB - Landfilling continues to be one of the main methods used in managing Municipal Solid Waste (MSW) worldwide, particularly in developing countries. Although in many countries national legislation aims to reduce this practice as much as possible, landfill is a necessary and unavoidable step in closing the material cycle. The need for innovative waste management techniques to improve landfill management and minimize the adverse environmental impact produced has resulted in an increasing interest in innovative systems capable of accelerating waste stabilization. Landfill bioreactors allow decomposition kinetics to be increased and post-operational phase to be shortened; in particular, hybrid bioreactors combine the benefits afforded by both aerobic and anaerobic processes. Six bioreactor simulators were used in the present study: four managed as hybrid, with an initial semi-aerobic phase and a second anaerobic phase, and two as anaerobic control bioreactors. The main goal of the first aerated phase is to reduce Volatile Fatty Acids (VFA) in order to increase pH and enhance methane production during the anaerobic phase; for this reason, air injection was stopped only when these parameters reached the optimum range for methanogenic bacteria. Biogas and leachate were constantly monitored throughout the entire methanogenic phase with the aim of calibrating a Gompertz Model and evaluating the effects of pre-aeration on subsequent methane production. The results showed that moderate and intermittent pre-aeration produces a positive effect both on methane potential and in the kinetics of reaction. PMID- 26531048 TI - Human corneal stromal stem cells support limbal epithelial cells cultured on RAFT tissue equivalents. AB - Human limbal epithelial cells (HLE) and corneal stromal stem cells (CSSC) reside in close proximity in vivo in the corneal limbal stem cell niche. However, HLE are typically cultured in vitro without supporting niche cells. Here, we re create the cell-cell juxtaposition of the native environment in vitro, to provide a tool for investigation of epithelial-stromal cell interactions and to optimize HLE culture conditions for potential therapeutic application. RAFT (Real Architecture For 3D Tissue) tissue equivalents (TEs) were used as a 3-dimensional substrate for co-culturing HLE and CSSC. Our results demonstrate that a monolayer of HLE that maintained expression of p63alpha, ABCB5, CK8 and CK15 (HLE markers), formed on the surface of RAFT TEs within 13 days of culture. CSSC remained in close proximity to HLE and maintained expression of mesenchymal stem cell markers. This simple technique has a short preparation time of only 15 days with the onset of HLE layering and differentiation observed. Furthermore, co cultivation of HLE with another niche cell type (CSSC) directly on RAFT TEs, eliminates the requirement for animal-derived feeder cells. RAFT TEs may be useful for future therapeutic delivery of multiple cell types to restore the limbal niche following ocular surface injury or disease. PMID- 26531049 TI - Platelet-activating factor promotes motility in breast cancer cells and disrupts non-transformed breast acinar structures. AB - A plethora of studies have demonstrated that chronic inflammatory microenvironment influences the genesis and progression of tumors. Such microenvironments are enriched with various lipid mediators. Platelet activating factor (PAF, 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is one such lipid mediator that is secreted by different immune cell types during inflammation and by breast cancer cells upon stimulation with growth factors. Overexpression of PAF-receptor has also been observed in many other cancers. Here we report the possible roles of PAF in tumor initiation and progression. MCF10A, a non transformed and non-malignant mammary epithelial cell line, when grown as 3D 'on top' cultures form spheroids that have a distinct hollow lumen surrounded by a monolayer of epithelial cells. Exposure of these spheroids to PAF resulted in the formation of large deformed acinar structures with disrupted lumen, implying transformation. We then examined the response of transformed cells such as MDA-MB 231 to stimulation with PAF. We observed collective cell migration as well as motility at the single cell level on PAF induction, suggesting its role during metastasis. This increase in collective cell migration is mediated via PI3-kinase and/or JNK pathway and is independent of the MAP-kinase pathway. Taken together this study signifies a novel role of PAF in inducing transformation of non tumorigenic cells and the vital role in promotion of breast cancer cell migration. PMID- 26531050 TI - Metabolic syndrome and retinal microvascular calibre in a high cardiovascular disease risk cohort. AB - AIMS: To investigate the independent associations between metabolic syndrome and retinal vessel calibre in a high cardiovascular risk cohort, and to determine whether these associations also exist in patients without diabetes, hypertension or coronary artery disease (CAD). METHODS: The Australian Heart Eye Study is an observational study that surveyed 1680 participants who presented to a tertiary referral hospital for the evaluation of potential CAD by coronary angiography. Metabolic syndrome was defined according to the Third Report of the National Cholesterol Education Program. Retinal arteriolar calibre narrowing and retinal venular calibre widening were measured from retinal photographs. CAD was quantified using severity (Gensini) and extent scores. Diabetes and hypertension were defined from clinical investigation (fasting plasma glucose >7.0 mmol/L and blood pressure >130/85 mm Hg) or from self-reported clinical diagnosis, including the use of medications. RESULTS: A total of 979 participants had complete information on metabolic syndrome components and were included in cross-sectional analyses. After adjusting for age, sex, smoking status and fellow vessel calibre, persons with metabolic syndrome (compared with persons without metabolic syndrome) had narrower retinal arteriolar calibre (mean difference 4.3 um, p<0.0001). No significant difference in venular calibre was observed (p=0.05). This association persisted in persons without diabetes (mean arteriolar calibre difference 4.4 um, p=0.0006) but not in participants without CAD and those without hypertension. CONCLUSIONS: Metabolic syndrome is independently associated with narrower retinal arterioles but not wider retinal venules among those at high risk of CAD. The association between metabolic syndrome and narrower retinal arterioles is likely due to the presence of CAD or hypertension in individuals with this syndrome, as the association is not significant in individuals without hypertension or without CAD. PMID- 26531051 TI - Risk factors for low vision related functioning in the Mycotic Ulcer Treatment Trial: a randomised trial comparing natamycin with voriconazole. AB - BACKGROUND/AIMS: The Mycotic Ulcer Treatment Trial I (MUTT I) was a double masked, multicentre, randomised controlled trial, which found that topical natamycin is superior to voriconazole for the treatment of filamentous fungal corneal ulcers. In this study, we determine risk factors for low vision-related quality of life in patients with fungal keratitis. METHODS: The Indian visual function questionnaire (IND-VFQ) was administered to MUTT I study participants at 3 months. Associations between patient and ulcer characteristics and IND-VFQ subscale score were assessed using generalised estimating equations. RESULTS: 323 patients were enrolled in the trial, and 292 (90.4%) completed the IND-VFQ at 3 months. Out of a total possible score of 100, the average VFQ score for all participants was 81.3 (range 0-100, SD 23.6). After correcting for treatment arm, each logMAR line of worse baseline visual acuity in the affected eye resulted in an average 1.2 points decrease on VFQ at 3 months (95% CI -1.8 to 0.6, p<0.001). Those who required therapeutic penetrating keratoplasty had an average of 25.2 points decrease on VFQ after correcting for treatment arm (95% CI -31.8 to -18.5, p<0.001). Study participants who were unemployed had on average 28.5 points decrease on VFQ (95% CI -46.9 to -10.2, p=0.002) after correcting for treatment arm. CONCLUSIONS: Monocular vision loss from corneal opacity due to fungal keratitis reduced vision-related quality of life. Given the relatively high worldwide burden of corneal opacity, improving treatment outcomes of corneal infections should be a public health priority. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov Identifier: NCT00996736. PMID- 26531052 TI - Evaluation of the efficacy and safety of a standardised intracameral combination of mydriatics and anaesthetics for cataract surgery. AB - BACKGROUND/AIMS: To compare the efficacy and safety of intracameral (IC) administration at the beginning of cataract surgery, of Mydrane, a standardised ophthalmic combination of tropicamide 0.02%, phenylephrine 0.31% and lidocaine 1%, to a standard topical regimen. METHODS: In this international phase III, prospective, randomised study, the selected eye of 555 patients undergoing phacoemulsification with intraocular lens (IOL) implantation received 200 MUL of Mydrane (Mydrane group) just after the first incision or a topical regimen of one drop each of tropicamide 0.5% and phenylephrine 10% repeated three times (reference group). The primary efficacy variable was achievement of capsulorhexis without additional mydriatics. The non-inferiority of Mydrane to the topical regimen was tested. The main outcome measures were pupil size, patient perception of ocular discomfort and safety. RESULTS: Capsulorhexis without additional mydriatics was performed in 98.9% of patients and 94.7% in the Mydrane and reference groups, respectively. Both groups achieved adequate mydriasis (>7 mm) during capsulorhexis, phacoemulsification and IOL insertion. IOL insertion was classified as 'routine' in a statistically greater number of eyes in the Mydrane group compared with the reference group (p=0.047). Patients in the Mydrane group reported statistically greater comfort than the reference group before IOL insertion (p=0.034). Safety data were similar between groups. CONCLUSIONS: Mydrane is an effective and safe alternative to standard eye drops for initiating and maintaining intraoperative mydriasis and analgesia. Patients who received IC Mydrane were significantly more comfortable before IOL insertion than the reference group. Surgeons found IOL insertion less technically challenging with IC Mydrane. TRIAL REGISTRATION NUMBER: NCT02101359; Results. PMID- 26531053 TI - Curcumin improves the efficacy of cisplatin by targeting cancer stem-like cells through p21 and cyclin D1-mediated tumour cell inhibition in non-small cell lung cancer cell lines. AB - Natural compounds such as curcumin have the ability to enhance the therapeutic effectiveness of common chemotherapy agents through cancer stem-like cell (CSC) sensitisation. In the present study, we showed that curcumin enhanced the sensitivity of the double-positive (CD166+/EpCAM+) CSC subpopulation in non-small cell lung cancer (NSCLC) cell lines (A549 and H2170) to cisplatin-induced apoptosis and inhibition of metastasis. Our results revealed that initial exposure of NSCLC cell lines to curcumin (10-40 uM) markedly reduced the percentage of viability to an average of ~51 and ~54% compared to treatment with low dose cisplatin (3 uM) with only 94 and 86% in both the A549 and H2170 cells. Moreover, sensitisation of NSCLC cell lines to curcumin through combined treatment enhanced the single effect induced by low dose cisplatin on the apoptosis of the double-positive CSC subpopulation by 18 and 20% in the A549 and H2170 cells, respectively. Furthermore, we found that curcumin enhanced the inhibitory effects of cisplatin on the highly migratory CD166+/EpCAM+ subpopulation, marked by a reduction in cell migration to 9 and 21% in the A549 and H2170 cells, respectively, indicating that curcumin may increase the sensitivity of CSCs to cisplatin-induced migratory inhibition. We also observed that the mRNA expression of cyclin D1 was downregulated, while a substantial increased in p21 expression was noted, followed by Apaf1 and caspase-9 activation in the double-positive (CD166+/EpCAM+) CSC subpopulation of A549 cells, suggested that the combined treatments induced cell cycle arrest, therefore triggering CSC growth inhibition via the intrinsic apoptotic pathway. In conclusion, we provided novel evidence of the previously unknown therapeutic effects of curcumin, either alone or in combination with cisplatin on the inhibition of the CD166+/EpCAM+ subpopulation of NSCLC cell lines. This finding demonstrated the potential therapeutic approach of using curcumin that may enhance the effects of cisplatin by targeting the CSC subpopulation in NSCLC. PMID- 26531054 TI - Poor self-rated health predicts mortality in patients with stable chronic heart failure. AB - AIMS: In heart failure, a holistic approach incorporating the patient's perspective is vital for prognosis and treatment. Self-rated health has strong associations with adverse events and short-term mortality risk, but long-term data are limited. We investigated the predictive value of two consecutive self rated health assessments with regard to long-term mortality in a large, well characterised sample of elderly patients with stable chronic heart failure. METHODS AND RESULTS: We measured self-rated health by asking 'In general, would you say your health is: 1, excellent; 2, very good; 3, good; 4, fair; 5, poor?' twice: at baseline and the end of a 12-week beta-blocker up-titration period in the CIBIS-ELD trial. Mortality was assessed in an observational follow-up after 2 4 years. A total of 720 patients (mean left ventricular ejection fraction 45+/ 12%, mean age 73+/-5 years, 36% women) rated their health at both time points. During long-term follow-up, 144 patients died (all-cause mortality 20%). Fair/poor self-rated health in at least one of the two reports was associated with increased mortality (hazard ratio 1.42 per level; 95% confidence interval 1.16-1.75; P<0.001). It remained independently significant in multiple Cox regression analysis, adjusted for N-terminal pro B-type natriuretic peptide (NTproBNP), heart rate and other risk prediction covariates. Self-rated health by one level worse was as predictive for mortality as a 1.9-fold increase in NTproBNP. CONCLUSION: Poor self-rated health predicts mortality in our long-term follow-up of patients with stable chronic heart failure, even after adjustment for established risk predictors. We encourage clinicians to capture patient reported self-rated health routinely as an easy to assess, clinically meaningful measure and pay extra attention when self-rated health is poor. PMID- 26531055 TI - Macrophages: Their Emerging Roles in Bone. AB - Macrophages are present in nearly all tissues and are critical for development, homeostasis, and regeneration. Resident tissue macrophages of bone, termed osteal macrophages, are recently classified myeloid cells that are distinct from osteoclasts. Osteal macrophages are located immediately adjacent to osteoblasts, regulate bone formation, and play diverse roles in skeletal homeostasis. Genetic or pharmacological modulation of macrophages in vivo results in significant bone phenotypes, and these phenotypes depend on which macrophage subsets are altered. Macrophages are also key mediators of osseous wound healing and fracture repair, with distinct roles at various stages of the repair process. A central function of macrophages is their phagocytic ability. Each day, billions of cells die in the body and efferocytosis (phagocytosis of apoptotic cells) is a critical process in both clearing dead cells and recruitment of replacement progenitor cells to maintain homeostasis. Recent data suggest a role for efferocytosis in bone biology and these new mechanisms are outlined. Finally, although macrophages have an established role in primary tumors, emerging evidence suggests that macrophages in bone support cancers which preferentially metastasize to the skeleton. Collectively, this developing area of osteoimmunology raises new questions and promises to provide novel insights into pathophysiologic conditions as well as therapeutic and regenerative approaches vital for skeletal health. PMID- 26531056 TI - A 2-(2'-hydroxyphenyl)benzothiazole (HBT)-quinoline conjugate: a highly specific fluorescent probe for Hg(2+) based on ESIPT and its application in bioimaging. AB - A benzothiazole derived chemosensor L has been designed based on the excited state intramolecular proton transfer (ESIPT) mechanism to afford a fluorescence turn-on response specifically in the presence of Hg(2+) ions over a host of biologically relevant metal ions as well as toxic heavy metal ions. The chemosensor exhibits high sensitivity with the detection limit down to 0.11 MUM. The metal binding is supported by (1)H NMR titrations, ESI-MS spectral analysis and substantiated by theoretical calculations using the density functional theory. The probe shows cell membrane permeability and efficiency for the detection of Hg(2+) in HeLa cells. PMID- 26531057 TI - A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding. AB - Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26531058 TI - Long-term care planning and preferences among Japanese American baby boomers: Comparison with non-Japanese Americans. AB - AIMS: Nikkei (Japanese American) communities are known to be forerunners for building culturally sensitive long-term care (LTC) services and programs. Existing literature highlights evolving cultural shifts among Nikkei communities as well as the baby boomers from the previous aging cohort. The present study's primary purpose was to examine Japanese American (JA) boomers' perceptions about their LTC planning compared with their non-JA counterparts. JA's residential and care preferences were also examined. METHODS: The study applied survey methodology with a total of 499 "boomers" (age 51-71 years) in the state of Washington. Data obtained from JA (n = 264) were compared with the data from non JA Washingtonians (non-JA, n = 235). Data from an additional subset of questions asking JA's preferences for retirement/LTC facilities were also analyzed. RESULTS: The findings showed similarities and differences between the two groups. No group differences were found with regard to caregiving experiences, exposure to LTC, expectation of requiring future LTC or physical proximity to their adult children. JA boomers, however, showed more knowledge about LTC-related facts, stronger preference to avoid becoming dependent on their families and a higher rate of LTC insurance purchases. JA boomers ranked higher preferences on culturally universal elements (e.g. transportation services, Internet access) for their retirement and LTC facilities over Japanese cultural-specific elements. JA boomers also preferred to reside with a mixture of racial/ethnic residents. CONCLUSIONS: The present study suggests that the LTC industry including JA communities should accommodate boomers' retirement plans and preferences with a multicultural selection of services and settings. Geriatr Gerontol Int 2016; 16: 1074-1084. PMID- 26531059 TI - Comparative genomic and transcriptional analyses of the carbohydrate-active enzymes and secretomes of phytopathogenic fungi reveal their significant roles during infection and development. AB - Our comparative genomic analysis showed that the numbers of plant cell wall (PCW) and fungal cell wall (FCW)-degradation-associated carbohydrate-active enzymes (CAZymes) in necrotrophic and hemibiotrophic fungi are significantly larger than that in most biotrophic fungi. However, our transcriptional analyses of CAZyme encoding genes in Melampsora larici-populina, Puccinia graminis and Sclerotinia sclerotiorum showed that many genes encoding PCW- and FCW-degradation-associated CAZymes were significantly up-regulated during the infection of both necrotrophic fungi and biotrophic fungi, indicating an existence of a universal mechanism underlying PCW degradation and FCW reorganization or modification, which are both intimately involved in necrotrophic and biotrophic fungal infection. Furthermore, our results showed that the FCW reorganization or modification was also related to the fungal development. Additionally, our transcriptional analysis of the secretome of S. sclerotiorum showed that many secreted protein-encoding genes were dramatically induced during infection. Among them, a small, cysteine-rich protein SsCVNH was experimentally confirmed to be essential for the virulence and sclerotial development, indicating that the small secreted proteins might also play crucial roles as potential effectors in host-non-specific necrotrophic fungi. PMID- 26531060 TI - Whole exome sequencing (WES) on formalin-fixed, paraffin-embedded (FFPE) tumor tissue in gastrointestinal stromal tumors (GIST). AB - BACKGROUND: Next generation sequencing (NGS) technology has been rapidly introduced into basic and translational research in oncology, but the reduced availability of fresh frozen (FF) tumor tissues and the poor quality of DNA extracted from formalin-fixed, paraffin-embedded (FFPE) has significantly impaired this process in the field of solid tumors. To evaluate if data generated from FFPE material can be reliably produced and potentially used in routine clinical settings, we performed whole exome sequencing (WES) from tumor samples of Gastrointestinal stromal tumors (GIST), either extracted FF or FFPE, and from matched normal DNA. METHODS: We performed whole exome enrichment and sequencing at 100bp in paired end on four GIST samples, either from FFPE or fresh-frozen tissue, and from matched normal DNA. RESULTS: The integrity of DNA extracted from FFPE was evaluated by a modified RAPD PCR method, thus identifying high quality (HQ) and low quality (LQ) FFPE. DNA library production and exome capture was feasible for both classes of FFPE, despite the smaller yield and insert size of LQ-FFPE. WES produced data of equal quality from FF and FFPE, while only HQ-FFPE yielded an amount of data comparable to FF samples. Bioinformatic analysis showed that the percentage of variants called both in FF and FFPE samples was very high in HQ-FFPE, reaching 94-96 % of the total number of called variants. Classification of somatic variants by nucleotide substitution type showed that HQ FFPE and FF had similar mutational profiles, while LQ-FFPE samples carried a much higher number of mutations than the FF counterpart, with a significant enrichment of C > T/G > A substitutions. Focusing on potential disease-related variants allowed the discovery of additional somatic variants in GIST samples, apart from the known oncogenic driver mutation, both from sequencing of FF and FFPE material. False positive and false negative calls were present almost exclusively in the analysis of FFPE of low quality. On the whole this study showed that WES is feasible also on FFPE specimens and that it is possible to easily select FFPE samples of high quality that yield sequencing results comparable to the FF counterpart. CONCLUSIONS: WES on FFPE material may represent an important and innovative source for GIST research and for other solid tumors, amenable of possible application in clinical practice. PMID- 26531061 TI - High-Efficiency Recognition and Identification of Disulfide Bonded Peptides in Rat Neuropeptidome Using Targeted Electron Transfer Dissociation Tandem Mass Spectrometry. AB - The main goal of the present study is to develop a method to recognize and identify endogenous intrachain disulfide bonded peptide, which are rarely sequenced in current peptidomics studies. In order to achieve highly efficient detection of these peptides in a neuropeptidome analysis, we alkylated the peptides, mined the raw mass spectrometry data, and then recognized the candidates of untreated disulfide bonded peptides from unalkylated peptide extracts. After removing more than 90% features, targeted electron transfer dissociation fragmentation was performed for detecting and fragmenting disulfide bonded peptides, and even most of them were present in low abundance in the original sample. Diverse endogenous disulfide bonded peptides were then detected and sequenced, opening up new perspectives for comprehensively understanding the response of a neuropeptidome. PMID- 26531062 TI - Membrane versus centrifuge-based therapeutic plasma exchange: a randomized prospective crossover study. AB - BACKGROUND: Therapeutic plasma exchange (TPE) is either performed using a highly permeable filter with standard multifunctional renal replacement equipment (mTPE) or a centrifugation device (cTPE). Although both techniques are well established in clinical practice, performance of these two modes of TPE was never compared in a prospective randomized fashion. Thus we aimed to compare two commercially available therapeutic apheresis systems: mTPE (Octonova with Plasmaflo filter) and cTPE (Spectra Optia apheresis system). METHODS: Twenty-one patients (age 51.6 +/- 13.5 years; 10 F/11 M; BMI 25.1 +/- 5.0 kg/m(2)) were enrolled in this randomized, prospective, paired, crossover study performed in the Hannover Medical School, Germany. First treatment (either mTPE or cTPE) was chosen by an online randomization list. The primary endpoints were plasma removal efficiency with 1.2* of the total plasma volume exchanged. Secondary endpoints were total amount of plasma substances removed, such as IgG and fibrinogen. Further, the treatment effect on platelet count and complications were evaluated. RESULTS: Despite a comparable volume of the processed plasma, mTPE treatment time was 10.5 % longer than cTPE treatment time (p < 0.05), resulting in a 10 % lower plasma removal rate of the mTPE treatment. Both treatments were comparable in terms of decrease in median (IQR) IgG [pre-mTPE 5.34 (3.48-8.37), post-mTPE 1.96 (1.43 2.84) g/L; pre-cTPE 5.88 (3.42-8.84), post-cTPE 1.89 (1.21-3.52) g/L]. Also the median (IQR) amount of IgG removed in mTPE [13.14 (7.42-16.10) g] was not different from the cTPE treatment [9.30 (6.26-15.69) g]. This was also true for IgM removal. Platelet loss during mTPE was nearly twice as much as with cTPE (15 +/- 9 versus 7 +/- 9 %, p < 0.05). CONCLUSION: Although the centrifugal procedures were conducted using flow rates that could easily be obtained using peripheral access, plasma removal efficiency was significantly higher and treatment time was significantly lower in cTPE as compared to mTPE. Despite this lower treatment time, the decline in markers of procedure efficacy was comparable. Especially in centers performing many procedures per year, cTPE in contrast to mTPE can reduce treatment time without compromising treatment efficacy. PMID- 26531063 TI - Focal cryoablation for unilateral low-intermediate-risk prostate cancer: 63-month mean follow-up results of 41 patients. AB - OBJECTIVE: To report (1) intermediate-term oncologic and functional outcomes of primary focal cryoablation (FC) in selected patients with clinically unilateral, low-intermediate-risk prostate cancer, and investigate (2) the impact of patient selection criteria at predicting outcomes after FC. MATERIALS AND METHODS: Forty one patients with unilateral prostate cancer were treated with FC. Patients were stratified using the 2007 Task Force Focal Prostate Cancer Patient selection criteria (Task Force criteria). Posttherapy follow-up included questionnaires, PSA measurement, and TRUS-guided biopsies. RESULTS: Complete follow-up was available in 40 patients (median follow-up 63 months; range 12-92 months). Compared to precryotherapy PSA level (mean 7.1 ng/ml), postcryotherapy PSA level (mean 1.8 ng/ml) dropped by 75 % at 3 months (P < 0.0001) and this decline persisted throughout the follow-up period, with no significant difference seen across patient selection criteria (P = 0.859). The treatment failure rate was 10 % (4/40) with no significant difference seen across patient selection criteria (P = 0.832). Of 32 patients undergoing postcryotherapy biopsy, 7 (22 %) had positive biopsies (2 ipsilateral lobes, 5 contralateral lobes). Patients of Task Force criteria group were less likely to have positive biopsy in contralateral lobe than focal control group (P = 0.032). Complete continence (no pads) and potency sufficient for intercourse were documented in 97.6 and 76.9 % of patients, respectively. CONCLUSIONS: The intermediate-term oncologic efficacy of primary FC in selected patients with clinically unilateral, low-intermediate-risk prostate cancer appears favorable, and the side-effect profile is low. The 2007 Task Force criteria appear to reduce the positive biopsy rate in contralateral lobe after FC. PMID- 26531064 TI - PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1 RIPK3-MLKL signaling. AB - Neutrophil extracellular trap (NET) formation contributes to gout, autoimmune vasculitis, thrombosis, and atherosclerosis. The outside-in signaling pathway triggering NET formation is unknown. Here, we show that the receptor-interacting protein kinase (RIPK)-1-stabilizers necrostatin-1 or necrostatin-1s and the mixed lineage kinase domain-like (MLKL)-inhibitor necrosulfonamide prevent monosodium urate (MSU) crystal- or PMA-induced NET formation in human and mouse neutrophils. These compounds do not affect PMA- or urate crystal-induced production of ROS. Moreover, neutrophils of chronic granulomatous disease patients are shown to lack PMA-induced MLKL phosphorylation. Genetic deficiency of RIPK3 in mice prevents MSU crystal-induced NET formation in vitro and in vivo. Thus, neutrophil death and NET formation may involve the signaling pathway defining necroptosis downstream of ROS production. These data imply that RIPK1, RIPK3, and MLKL could represent molecular targets in gout or other crystallopathies. PMID- 26531065 TI - Tissue XpertTM MTB/Rif assay is of limited use in diagnosing peritoneal tuberculosis in patients with exudative ascites. AB - BACKGROUND: XpertTM MTB/Rif is a multiplex hemi-nested real-time PCR-based assay to detect presence of M. tuberculosis within 2 hours of sample collection. The present study aimed at assessing efficacy of XpertTM MTB/Rif assay for diagnosing peritoneal tuberculosis. METHODS: Patients with exudative ascites, fluid negative for acid-fast bacilli on auramine O fluorescence staining and unyielding fluid cytology for malignant cells, were included. Ultrasound-guided omental biopsy samples were obtained in all. XpertTM MTB/Rif assay on tissue samples was assessed against a composite "reference" standard for diagnosis of peritoneal tuberculosis, defined as presence of any of the three-culture showing M tuberculosis, granulomatous inflammation on histology or resolution of ascites with 2 months of antitubercular therapy. RESULTS: During January 2012-July 2013, 28 patients (age:43 +/- 15 years; mean +/- SD; male:20) were recruited. Serum ascitic albumin gradient was <1.1 in all except in four patients with underlying cirrhosis. Twenty-one of the 28 patients had peritoneal TB as diagnosed by composite reference standard (histology:18; culture:4; treatment response:3). Seven patients (25%) had an alternative diagnosis (metastatic carcinoma 2, adenocarcinoma 2, mesothelioma 2, and systemic lupus erythematous 1). XpertTM MTB/Rif assay was positive in 4/21 patients with peritoneal tuberculosis and in none of the 7 patients with alternative diagnosis. Thus, sensitivity, specificity, positive, and negative predictive values for tissue XpertTM MTB/Rif assay in diagnosing peritoneal tuberculosis were 19% (95% C.I: 6% to 42%), 100% (95% C.I: 59% to 100%), 100% (40% to 100%), and 29% (95% C.I: 13% to 51%), respectively. INTERPRETATION AND CONCLUSION: Tissue XpertTM MTB/Rif assay was of limited use in diagnosing peritoneal tuberculosis. PMID- 26531067 TI - The use of ovarian reserve markers in IVF clinical practice: a national consensus. AB - Ovarian reserve markers have been documented to perform very well in the clinical practice. While this is widely recognized, still now there is no consensus on how to use new biomarkers in the clinical practice. This study was conducted among Italian IVF centres using the Delphi technique, a validated consensus-building process. Briefly three consecutive questionnaires were developed for clinicians in charge of IVF centres. In the first rounds, participants were asked to rate the importance of a list of statements regarding the categorization of ovarian response and the diagnostic role of biomarkers. In round 3, participants were asked to rate their agreement and consensus on the list of statements derived from the first two rounds. There were 120 respondents. Consensus was achieved for many points: (a) poor ovarian response is predicted on the basis of the following: AMH < 1 ng/ml or AFC < 7, FSH >= 10 IU/l, age >= 40 yrs; (b) hyper response is predicted on the basis of the following: AMH > 3 ng/ml or AFC > 14; (c) day 3 FSH measurement should always be associated to estradiol; (d) AMH can be measured on a random basis; (e) the measurement of the AFC with the 2D technology may be considered adequate and (f) the AFC should be measured in the early follicular phase and consists in the total number of 2-9 mm follicles in both the ovaries. The present study suggests that extensive consensus on the importance and use of new ovarian reserve markers to improve IVF safety and performance is already present among clinicians. PMID- 26531066 TI - The efficacy of accelerated, multiple, double-dose hepatitis B vaccine against hepatitis B virus infection in cancer patients receiving chemotherapy. AB - BACKGROUND: Hepatitis B virus (HBV) infection in cancer patients receiving chemotherapy carries high morbidity and mortality. Conventional hepatitis B vaccination with three doses at 0, 1, and 6 months apart is ineffective in prevention of HBV infection. OBJECTIVES: To compare the efficacy of accelerated, multiple, double-dose HB vaccine with conventional HB vaccine in cancer patients receiving chemotherapy (CT). METHODS: Patients of cancer who were planned for CT were screened for HBV markers (HBsAg, total anti-HB core, anti-HBs antibody and HBV DNA). Patients with negative HBV serum markers received HB vaccine in two groups. Group A received three double doses (40 MUg) of recombinant HB vaccine at 0, 1, and 3 weeks before CT and additional three double doses post CT. Group B received HB vaccine (20 MUg) at 0, 1, and 6 months. Efficacy of vaccine in the two groups was compared by anti-HBs titers achieved at 3, 6, and 9 months and by HBsAg positivity following CT at 1 year follow up. RESULTS: Protective anti-HBs titers (>10 mIU/mL) at 3, 6, and 9 months in group A and B was 41.1 %, 66.2 %, and 76% and 26 %, 37.7 %, and 49% respectively (p = 0.001). Seven of 454 (1.5%) patients in group A became HBsAg positive after vaccination compared to 19/472 (4.0%) in group B (p = 0.022). CONCLUSION: Accelerated, multiple, double-dose HB vaccine increases seroprotection and is more effective than conventional HB vaccine in preventing HBV infection. PMID- 26531068 TI - Skewed by Cues? The Motivational Role of Audiovisual Stimuli in Modelling Substance Use and Gambling Disorders. AB - The similarity between gambling disorder (GD) and drug addiction has recently been recognized at the diagnostic level. Understanding the core cognitive processes involved in these addiction disorders, and in turn their neurobiological mechanisms, remains a research priority due to the enormous benefits such knowledge would have in enabling effective treatment design. Animal models can be highly informative in this regard. Although numerous rodent behavioural paradigms that capture different facets of gambling-like behaviour have recently been developed, the motivational power of cues in biasing individuals towards risky choice has so far received little attention despite the central role played by drug-paired cues in successful laboratory models of chemical dependency. Here, we review some of the comparatively simple paradigms in which reward-paired cues are known to modulate behaviour in rodents, such as sign-tracking, Pavlovian-to-instrumental transfer and conditioned reinforcement. Such processes are thought to play an important role in mediating responding for drug reward, and the need for future studies to address whether similar processes contribute to cue-driven risky choice is highlighted. PMID- 26531069 TI - Superabsorption of light by nanoparticles. AB - Nanoparticles have a fundamental limit as to how much light they can absorb. This limit is based on the finite number of modes excited in the nanoparticle at a given wavelength and maximum absorption capacity per mode. The enhanced absorption can be achieved when each mode supported by the nanoparticle absorbs light up to the maximum capacity. Using a stochastic optimization algorithm, we design multilayer nanoparticles, in which we can make several resonant modes overlap at the same frequency resulting in superabsorption. We further introduce the efficiency of the absorption for a nanoparticle, which is the absorption normalized by the physical size of the particle, and show that efficient absorbers do not always operate in the superabsorption regime. PMID- 26531070 TI - Unique dose-dependent effects of the human pregnancy hormone estriol on the ratio of blood IgM to IgG in female mice. AB - The present study aimed to investigate the dose-dependent modulating effect of estriol (E3), an estrogen predominantly produced during human pregnancy, on antigen-induced production of specific antibodies in female BALB/c mice. The animals were immunized either with bovine serum albumin (BSA) or the pneumococcal polysaccharide serotype-14 (PPS-14), and the levels of specific serum antibodies were determined using ELISA kits. E3 was found to have very different effects on antigen-induced production of specific antibodies in animals immunized with these two antigens. While E3 stimulated the production of PPS-14-specific antibodies, it suppressed the production of BSA-specific antibodies. The results also demonstrated that the modulating effect of E3 on the production of antigen specific antibodies depends on the dose of E3 used. For BSA-induced antibody production, E3 had a dose-dependent inhibitory effect, whereas for PPS-14 specific antibody (Ab) production, E3 exerted the strongest stimulation at a lower dose, and produced less stimulation at higher doses. E3 caused thymus atrophy in animals immunized with either PPS-14 or BSA, but only induced spleen atrophy in BSA-injected mice. These observations suggest that E3 increases the ability of a pregnant female to avoid bacterial infections while decreasing the incidence of autoimmune responses against circulating components from either the fetus or pregnant female. PMID- 26531071 TI - Anticholinergic burden is associated with recurrent and injurious falls in older individuals. AB - OBJECTIVE: While the anticholinergic activity of medications has been linked to cognitive decline, few studies have linked anticholinergic burden with falls in older people. We evaluated the relationship between anticholinergic burden and recurrent and injurious falls among community-dwelling older adults. STUDY DESIGN: This case-control study was performed on 428 participants aged >=65 years, 263 cases with two or more falls or one injurious fall in the preceding 12 months, and 165 controls with no falls in the preceding 12 months. Anticholinergic burden was determined using the anticholinergic cognitive burden (ACB) scale. Upper and lower limb functional abilities were assessed with timed up and go (TUG), functional reach (FR) and grip strength (GS). Logistic regression analysis was employed to calculate the mediation effect of TUG, FR and GS on ACB associated falls. RESULTS: Univariate analysis revealed a significant association between an ACB score of >=1 with falls (OR, 1.8; 95% CI; 1.1-3.0; p=0.01) and significantly poorer TUG and FR. The association between ACB>=1 and falls was no longer significant after adjustment for either TUG (OR for ACB associated falls, 1.4; 95% CI, 0.88-2.4; p=0.14) or FR (OR for ACB associated falls, 1.4; 95% CI, 0.89-2.4, p=0.12) but remained significant with GS. CONCLUSION: The association between recurrent and injurious falls and the use of any medications listed in the ACB scale was mediated through gait and balance impairment but not by muscular weakness, providing a novel insight into the potential mechanistic link between ACB and falls. Future studies should determine whether TUG and FR measurements could help inform risk to benefit decisions where ACB medications are being considered. PMID- 26531072 TI - VO2/TiO2 Nanosponges as Binder-Free Electrodes for High-Performance Supercapacitors. AB - VO2/TiO2 nanosponges with easily tailored nanoarchitectures and composition were synthesized by electrostatic spray deposition as binder-free electrodes for supercapacitors. Benefiting from the unique interconnected pore network of the VO2/TiO2 electrodes and the synergistic effect of high-capacity VO2 and stable TiO2, the as-formed binder-free VO2/TiO2 electrode exhibits a high capacity of 86.2 mF cm(-2) (~548 F g(-1)) and satisfactory cyclability with 84.3% retention after 1000 cycles. This work offers an effective and facile strategy for fabricating additive-free composites as high-performance electrodes for supercapacitors. PMID- 26531073 TI - Altered Esthetics in Primary Central Incisors: The Child's Perception. AB - PURPOSE: This study's purpose was to determine preschool-age children's social perceptions and self-perceptions regarding altered dental esthetics. METHODS: A cross-sectional study was carried out involving 431 four- to five-year-olds. The participants were shown four photographs of children with incisors exhibiting discoloration, crown fracture, missing tooth, or normal teeth. The children were asked four questions for analysis of social perceptions and two additional questions for analysis of self-perceptions. Binary logistic regression was used for the statistical analysis. RESULTS: Children had negative social perceptions, as a significant association was found between their negative feelings and the altered dental esthetics in children pictured in the photographs. The affected anterior incisor was indicated as the main reason for this feeling (odds ratio equals 4.68, 95 percent confidence interval [CI] equals 2.39 to 9.15). When analyzing self-perceptions, a significant association was found between negative feelings and the child's own altered dental esthetics. Children with altered esthetics felt 1.92-fold sadder than those without altered esthetics (95 percent CI equals 1.22 to 3.02). Again, the affected teeth were indicated as the main reason for this feeling (prevalence ratio equals 1.22) in comparison to reasons cited. CONCLUSIONS: Four- to five-year-olds have negative social perceptions and self-perceptions regarding altered dental esthetics. PMID- 26531074 TI - Influence of Periodontal Therapy on Systemic Lipopolysaccharides in Children with Localized Aggressive Periodontitis. AB - PURPOSE: A previous study has shown that children with localized aggressive periodontitis (LAP) demonstrate a lipopolysaccharide (LPS) hyper-responsiveness in addition to elevated levels of systemic LPS when compared to periodontally healthy children. The purpose of this study was to evaluate whether periodontal therapy modulates systemic lipopolysaccharide levels and whether these levels may influence clinical outcomes. METHODS: Peripheral blood samples and clinical parameters (probing depth [PD], clinical attachment levels [CAL], percent sites greater than four mm, bleeding on probing [BoP], and visible plaque [P]) were collected from 29 LAP patients prior to and at three, six, and 12 months following scaling and root planning and systemic antibiotics. Serum LPS levels were quantified using a chromogenic assay. RESULTS: Twenty-five patients were compliant with the prescribed antibiotic treatment and demonstrated a significant reduction in LPS as well as overall PD, CAL, and plaque at all time points post therapy. Additionally LPS reductions correlated with reductions in PD, CAL, and plaque. CONCLUSIONS: Localized aggressive periodontitis therapy with antibiotics plays an important role in reducing systemic lipopolysaccharide levels. Since LPS is a key mediator of the LAP hyperinflammatory response, its systemic reduction is especially important for the successful management of these children. PMID- 26531075 TI - Three Incomplete Caries Removal Techniques Compared Over Two Years in Primary Molars with Asymptomatic Deep Caries or Reversible Pulpitis. AB - PURPOSE: To directly compare the survival rates of three incomplete caries removal techniques that differed in the amount of caries removal and the base material used. METHODS: Ninety-six primary molars with asymptomatic deep caries or reversible pulpitis were randomly assigned to three groups: (1) indirect pulp treatment (IPT); (2) minimal caries removal with both resin-modified glass ionomer base material and luting cement (MCRB/L); and (3) minimal caries removal with only resin-modified glass ionomer luting cement (MCRL). The treatments were followed clinically and radiographically for two years. RESULTS: The two-year survival probabilities in the IPT, MCRB/L, and MCRL groups were 0.90 (95 percent confidence interval [CI] equals 0.73 to 0.97), 0.93 (95 percent CI equals 0.76 to 0.98), and 0.77 (95 percent CI equals 0.58 to 0.89), respectively. There was no significant difference in the two-year survival probabilities of the three studied groups (generalized Wilcoxon P=.07). CONCLUSIONS: Following two years, neither the amount of caries removal nor the base material affected the success of incomplete caries removal treatment. However, minimal caries removal with MCRB/L presented the highest survival rate among the tested groups and resulted in no incidence of pulp exposure. PMID- 26531076 TI - Guideline on Adolescent Oral Health Care. PMID- 26531077 TI - Guideline on Behavior Guidance for the Pediatric Dental Patient. PMID- 26531078 TI - Guideline on Use of Local Anesthesia for Pediatric Dental Patients. PMID- 26531079 TI - Guideline on Acquired Temporomandibular Disorders in Infants, Children, and Adolescents. PMID- 26531080 TI - Guideline on Management Considerations for Pediatric Oral Surgery and Oral Pathology. PMID- 26531081 TI - Guideline on Informed Consent. PMID- 26531082 TI - The Influence of Early Life Events on Adult Oral Health: The Role of Pediatric Dentistry. PMID- 26531083 TI - Protocol for a Systematic Review and Meta-analysis of Vital Pulp Therapy for Children with Deep Caries in the Primary Dentition. AB - PURPOSE: The purpose of this protocol for a systematic review of randomized controlled trials of primary tooth vital pulp therapy is to describe the reasoning and need for the review, the objectives of the review, and the methodology that will be used to analyse data from the included studies. Publication of a systematic review protocol also helps establish and maintain transparency of the process and accountability for the stated methods and outcomes sought. METHODS: This protocol adheres to PRISMA-P standards for protocol reporting. A variety of relevant databases and resources will be searched. Trials selection, data extraction, and risk of bias assessment will be performed by two independent investigators. Primary outcome measures include clinical and radiographic success. Evidence tables will be generated for included study characteristics. The Cochrane risk of bias assessment tool will be applied to the selected studies. For meta-analysis, results will be pooled to provide estimates of appropriate effect size and heterogeneity of trials. The quality of evidence for outcomes will be determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: The proposed systematic review will provide findings useful for pediatric and general dentists, researchers, guideline developers, policymakers, and public and private insurers and can be the basis for an evidence-based guideline on pulp treatment of vital primary teeth with deep caries approximating the pulp. PMID- 26531084 TI - Impact of Pharmacological Interventions in Expectant Mothers Resulting in Altered Mutans Streptococci Levels in their Children. AB - PURPOSE: The purpose of this systematic review was to assess whether prenatal use of fluoride, chlorhexidine mouthrinses, and xylitol could alter the mutans streptococci levels in children. METHODS: A systematic search of clinical trials was implemented for the Cochrane Oral Health Group's Trials Register, PubMed, PMC, NCBI, ClinicalKey, Google Scholar, LILACS, and Science Direct. A search for ongoing trials was also undertaken in the clinicaltrial.gov database to identify eligible studies. Data regarding methodology, participants, types of interventions, and outcomes were extracted, and the risk of bias was also assessed independently by two review authors. RESULTS: Only two clinical trials fulfilled the inclusion criteria. Although one study showed significant results, the overall result of this systematic review showed no statistical significance. A risk ratio and 95 percent confidence interval of 0.1 (0.01 to 1.89) were obtained. CONCLUSIONS: Statistically significant results were reported in both the included studies; however, systematic analysis revealed a dearth of current evidence to support the general recommendation of pharmacological interventions for expectant mothers resulting in altered mutans streptococci levels in their children. PMID- 26531085 TI - Assessing Temperament as a Predictor of Oral Sedation Success Using the Children's Behavior Questionnaire Short Form. AB - PURPOSE: The purpose of this study was to investigate whether temperament, as measured by the Children's Behavior Questionnaire Short Form (CBQ-SF), was associated with success in oral sedation. METHODS: Child-caregiver dyads were enrolled from patients presenting for midazolam, meperidine, and hydroxyzine oral sedation. Children between 36 and 95 months of age, American Society of Anesthesiology (ASA) classification I or II, with diagnostic radiographs, whose parents believed he/she would swallow oral medications, were enrolled. To assess child temperament, caregivers completed the CBQ-SF. Behavior during sedation and overall sedation results were recorded using the Houpt Behavior Rating Scale. Failure was defined by Houpt overall ratings of fair or worse. The presence of disruptive behavior was also quantified. RESULTS: The sample population consisted of 61 patient-caregiver dyads. The overall sedation success rate was 87 percent (N equals 53). Disruptive behavior was present during 28 percent (N equals 17) of total cases. There was not a significant difference in failure rate or presence of disruptive behavior by age, sex, ASA status, insurance status, reason for sedation, or type of treatment provided. High impulsivity scores were significantly associated with disruptive behavior (P=.04). CONCLUSIONS: Impulsivity may be a determinant of a child's behavior during sedation. PMID- 26531086 TI - Parents' Ability to Assess Dental Fear in their Six- to 10-year-old Children. AB - PURPOSE: To investigate parents' ability to assess dental anxiety of their six- to 10-year-old children and to determine how parents' and children's fear assessments correlate with patient behavior during dental treatment. METHODS: From a continuous convenience sample, 184 child/parent dyads were recruited to complete the Children's Fear Survey Schedule-Dental Subscale (CFSS-DS) questionnaire prior to dental treatment. One provider treated all children, assessed their behavior, and assigned a Frankl score rating to them. Parent/child anxiety scores were compared to each other and to the behavior children presented during dental treatment. RESULTS: The mean dental anxiety score reported by the children was 30.30; the score reported by their parents was 2.94 points higher (P=.0016). There was poor consistency within parent/child pairs when precisely assessing dental anxiety. Parental assessments of their children's dental anxiety were a poor to fair predictor for observed behavior, whereas the children's self assessments were fair to good. Child age was not associated with ability to assess anxiety. Parents of children with low anxiety overestimated their children's anxiety, whereas parents of children with high anxiety underestimated their children's anxiety. CONCLUSIONS: Parents and children showed moderate agreement assessing dental anxiety measured by the CFSS-DS. The child's score is preferable for predicting behavior. PMID- 26531087 TI - Transitioning from Pediatric to Adult Dental Care for Adolescents with Special Health Care Needs: Adolescent and Parent Perspectives--Part One. AB - PURPOSE: The purpose of this study was to understand transitions from pediatric dental care to adult dental care for adolescents with special health care needs (ASHCNs) from parental and adolescent perspectives. METHODS: Focus groups and interviews were conducted with 59 parents and 13 adolescent-parent dyads to identify factors associated with transitions to adult-centered dental care for ASHCNs. RESULTS: Most parents believed ASHCNs were at risk for caries, but ASHCNs were not concerned about tooth decay. Parents of adolescents with complex SHCN believed it would be acceptable to continue seeing a pediatric dentist. Parents of Medicaid-enrolled ASHCNs reported lower efficacy in transitioning. ASHCNs desired personalized, adolescent-centered care and were motivated to transition when they felt out of place at the pediatric dentist office. Parents believed pediatric dentists play an important role in initiating and facilitating transitions. CONCLUSIONS: Pediatric dentists are well positioned to implement family and adolescent-centered policies to ensure dental transitions for adolescents with special health care needs and their families. PMID- 26531088 TI - Transitioning from Pediatric to Adult Dental Care for Adolescents with Special Health Care Needs: Dentist Perspectives--Part Two. AB - PURPOSE: The purpose of this study was to understand dental care transitions for adolescents with special health care needs (ASHCNs) from the dentist perspective. METHODS: We conducted semi-structured interviews with 13 dentists (seven pediatric dentists and six general dentists) to learn about the dental transition process for ASHCNs. RESULTS: Most dentists believed transitions from child centered to adult-centered dental care were important for ASHCNs. Dentists reported two main barriers to transitions: (1) low dental reimbursements by Medicaid; and (2) a shortage of general dentists qualified or willing to treat ASHCNs. Pediatric and general dentists reported playing complimentary roles in facilitating transitions for ASHCNs and their families. CONCLUSIONS: Dentists acknowledged the challenges that adolescents with special health care needs and their families face in transitioning to adult-centered care and believed in the importance of ASHCNs maintaining a dental home. Pediatric dentists and general dentists play a key role in working together to implement dental transition plans for ASHCNs and to ensure successful dental transitions. PMID- 26531089 TI - Incidental Finding of a Foreign Object on a Panoramic Radiograph. AB - This study's purpose was to describe a case involving the discovery of a foreign body in the ear canal of an eight-year-old boy, revealed during a recall evaluation to a dental clinic. A panoramic radiograph revealed a radiopaque object in the area of the external auditory meatus. The patient's mother reported one incidence of reported ear pain that resolved spontaneously, but the patient denied placing any object into his ear both in our clinic and at the time he reported ear pain to his mother. The patient was referred to an otolaryngologist, and the object was removed. PMID- 26531090 TI - Molar Incisor Hypomineralization of Eight- and 14-year-old Children: Prevalence, Severity, and Defect Characteristics. AB - PURPOSE: To report on the prevalence, severity, defect location, and other characteristics of molar incisor hypomineralization (MIH). METHODS: Representative samples of eight- and 14-year-old children (1,179 and 1,156, respectively) in three Greek cities were examined for MIH in the classroom using European Academy of Pediatric Dentistry criteria. MIH either mild or severe included the recording of defect color and location. RESULTS: MIH prevalence was 21 percent (498 of 2,335 children), with a statistically significant difference in one city (16 percent) from the other two (23 percent, P=.007; and 23 percent, P=.002). In 46 percent of MIH cases, only permanent first molars (PFMs) were affected. MIH severity was associated with age (severe MIH eight-year-olds comprised 13 percent; 14-year-olds comprised 35 percent, P<.001) and with number of affected teeth per child (mild equals 2.44, severe equals 4.22, P<.001). The lingual surfaces of mandibular PFMs and palatal/lingual surfaces of all incisors were significantly less frequently affected (all less than 10 percent) than their buccal/labial counterparts (P<.0001). CONCLUSIONS: Predominantly mild MIH was common in children's permanent teeth, with some intracountry variation. A surface predilection of MIH opacities was clearly revealed. The severity in 14-year-olds was threefold that of eight-year-olds. PMID- 26531091 TI - Association of Healthy Eating, Juice Consumption, and Bacterial Counts with Early Childhood Caries. AB - PURPOSE: To investigate the association of healthy diet, snacking, and bacterial count with early childhood caries in a group of preschool children in Alexandria, Egypt. METHODS: Sixty preschoolers were divided into three groups: (1) caries free children; (2) children with early childhood caries (ECC); and (3) children with severe early childhood caries (S-ECC). Saliva was cultured to determine bacterial counts. A questionnaire collected information about background, oral health practices, and snacking habits. A 24-hour food recall form assessed dietary intake and was analyzed using the Health Eating Index 2005. RESULTS: Compared to caries-free children, children with ECC and S-ECC had significantly lower odds of drinking juices (odds ratio equals 0.10 and 0.02). Caries-free children had significantly higher Healthy Eating Index values than children with ECC and S-ECC (P=0.003 and P<0.0001). Total streptococci and Streptococcus mutans counts were significantly higher in children with ECC and S-ECC (P<0.0001 for all), whereas Streptococcus sanguis counts were lower (P=0.04 and P=0.01). CONCLUSIONS: Drinking juices was associated with less early childhood caries and severe early childhood caries among preschoolers. Snacking on sweets was associated with more S-ECC. Healthy eating, brushing, and bacterial counts were not significantly associated with ECC or S-ECC in multivariate regression. PMID- 26531092 TI - Evaluation of Different Fissure Sealant Materials and Flowable Composites Used as Pit-and-fissure Sealants: A 24-Month Clinical Trial. AB - PURPOSE: The effectiveness of resin-based pit-and-fissure sealants mainly depends on their retention and integrity over time. The purpose of this study was to evaluate retention rates of two different pit-and-fissure sealants compared with a flowable composite and a self-adhesive flowable composite over a 24 month period. METHODS: A split-mouth study design was used for all four permanent first molars of each patient. They were subjected to different kinds of sealants- either flowable composites or with fissure sealants. The flowable composites used were: flowable composite with an adhesive system (Tetric EvoFlow); and a self adhesive flowable composite (Vertise Flow). The fissure sealants used were: a highly filled pit-and-fissure sealant (Fissurit FX); and a highly filled nano hybrid pit-and-fissure sealant (Grandio Seal). Evaluation of the sealants was carried out at three-, six-, 12-, 18-, and 24-month follow-up visits. RESULTS: The complete retention rates were 95.7 percent for Tetric EvoFlow, 80.6 percent for Fissurit FX, 73.1 percent for Grandio Seal, and 62.9 percent for Vertise Flow. The retention rate of Tetric EvoFlow was significantly higher among all materials tested (P<0.05). CONCLUSION: The flowable composite used with an adhesive system was found to be superior to other sealing materials. PMID- 26531093 TI - Usefulness of radiographic imaging of percutaneously inserted central venous catheters in critically ill infants and children. PMID- 26531094 TI - Phone triage in paediatric intensive care: one-year report from a French tertiary care center. PMID- 26531095 TI - Coenzyme Q10 dose-escalation study in hemodialysis patients: safety, tolerability, and effect on oxidative stress. AB - BACKGROUND: Coenzyme Q10 (CoQ10) supplementation improves mitochondrial coupling of respiration to oxidative phosphorylation, decreases superoxide production in endothelial cells, and may improve functional cardiac capacity in patients with congestive heart failure. There are no studies evaluating the safety, tolerability and efficacy of varying doses of CoQ10 in chronic hemodialysis patients, a population subject to increased oxidative stress. METHODS: We performed a dose escalation study to test the hypothesis that CoQ10 therapy is safe, well-tolerated, and improves biomarkers of oxidative stress in patients receiving hemodialysis therapy. Plasma concentrations of F2-isoprostanes and isofurans were measured to assess systemic oxidative stress and plasma CoQ10 concentrations were measured to determine dose, concentration and response relationships. RESULTS: Fifteen of the 20 subjects completed the entire dose escalation sequence. Mean CoQ10 levels increased in a linear fashion from 704 +/- 286 ng/mL at baseline to 4033 +/- 1637 ng/mL, and plasma isofuran concentrations decreased from 141 +/- 67.5 pg/mL at baseline to 72.2 +/- 37.5 pg/mL at the completion of the study (P = 0.003 vs. baseline and P < 0.001 for the effect of dose escalation on isofurans). Plasma F2-isoprostane concentrations did not change during the study. CONCLUSIONS: CoQ10 supplementation at doses as high as 1800 mg per day was safe in all subjects and well-tolerated in most. Short-term daily CoQ10 supplementation decreased plasma isofuran concentrations in a dose dependent manner. CoQ10 supplementation may improve mitochondrial function and decrease oxidative stress in patients receiving hemodialysis. TRIAL REGISTRATION: This clinical trial was registered on clinicaltrials.gov [NCT00908297] on May 21, 2009. PMID- 26531096 TI - Expression of adipophilin in gastric epithelial neoplasia is associated with intestinal differentiation and discriminates between adenoma and adenocarcinoma. AB - Adipophilin, a lipid droplet-associated protein that regulates lipid droplet structure and formation, is expressed in a wide variety of tumors. The aims of this study were to evaluate the frequency and distribution pattern of adipophilin expression in gastric epithelial neoplasia and to correlate these variables with clinicopathological features and the mucin phenotype. We retrospectively examined 159 cases of gastric epithelial neoplasia, which were classified according to the Vienna classification system as 52 noninvasive low-grade adenoma (category 3), 65 noninvasive high-grade neoplasia (category 4), and 42 invasive neoplasia (category 5). Immunohistochemistry for adipophilin was performed, and phenotypic marker expression was determined by immunohistostaining with MUC2, MUC5AC, CD10, MUC6, and villin. Adipophilin was expressed in 41 of the 52 (79 %) category 3 cases, in 42 of the 65 (65 %) category 4 cases, and in 23 of the 42 (55 %) category 5 cases. Expression of adipophilin was only present in lesions with complete or incomplete intestinal phenotypes. Adipophilin was expressed more frequently in the surface epithelium in category 3, whereas there was a stepwise increase in cryptal staining of adipophilin from category 3 to category 5. In conclusion, adipophilin expression is closely related to the intestinal differentiation of the tumor. The pattern of immunostaining for adipophilin might be a useful new marker for discriminating adenomas from adenocarcinomas. PMID- 26531097 TI - Iodine-catalyzed expeditious synthesis of sulfonamides from sulfonyl hydrazides and amines. AB - A new synthesis of sulfonamides has been developed via an iodine-catalyzed sulfonylation of amines with arylsulfonyl hydrazides. This metal-free strategy employs readily accessible and easy to handle starting materials, catalysts and oxidants, and can be easily conducted under mild conditions, providing a convenient access to a wide range of sulfonamides in moderate to excellent yields within a short reaction time. PMID- 26531098 TI - Access to anonymised patient data: corners cannot be cut if patient confidence is to be maintained. PMID- 26531100 TI - The risk factors for developing of chronic pulmonary aspergillosis in nontuberculous mycobacteria patients and clinical characteristics and outcomes in chronic pulmonary aspergillosis patients coinfected with nontuberculous mycobacteria. AB - Patients with chronic pulmonary aspergillosis (CPA) have a poor prognosis and CPA occurs in patients with various underlying diseases. Recently, the number of patients with CPA complicated by nontuberculous mycobacteria (NTM) has increased. Additionally, complications of both diseases have several problems like drug interactions. Since the impact of NTM on the outcome of CPA is not well understood, we investigated the risk factors for developing CPA and the clinical characteristics of CPA patients with or without NTM. We retrospectively investigated the medical records of NTM and CPA patients who were admitted to Nagasaki University Hospital between April 2008 and September 2013. Comorbid diseases, causative microorganisms, radiological findings, and outcomes were evaluated. During the study period, 82 and 41 patients were diagnosed as having NTM and CPA, respectively. Nine patients were coinfected with NTM and CPA, and cavitary type NTM and steroid usage were independent risk factors of development of CPA. Mortality rates in the coinfection group were significantly higher than those of the NTM without CPA group (P = .003, log-rank test). The rate of treatment initiation in the co-infection group (33.3%) was significantly lower than in the CPA without NTM group (84.4%) (P = .006). However, there were no significant differences in cumulative survival rate between both groups (P = .760, log-rank test). Cavity formation and steroid usage were the independent risk factors for NTM patients to develop CPA within long observation period, and development of CPA made outcomes poor. It is important to diagnose the development of CPA early and initiate treatment for CPA. PMID- 26531099 TI - ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation. AB - Although major genetic networks controlling early liver specification and morphogenesis are known, the mechanisms responsible for postnatal hepatic maturation are poorly understood. Here we employ global analyses of the mouse liver transcriptome to demonstrate that postnatal remodelling of the liver is accompanied by large-scale transcriptional and post-transcriptional transitions that are cell-type-specific and temporally coordinated. Combining detailed expression analyses with gain- and loss-of-function studies, we identify epithelial splicing regulatory protein 2 (ESRP2) as a conserved regulatory factor that controls the neonatal-to-adult switch of ~20% of splice isoforms in mouse and human hepatocytes. The normal shift in splicing coincides tightly with dramatic postnatal induction of ESRP2 in hepatocytes. We further demonstrate that forced expression of ESRP2 in immature mouse and human hepatocytes is sufficient to drive a reciprocal shift in splicing and causes various physiological abnormalities. These findings define a direct role for ESRP2 in the generation of conserved repertoires of adult splice isoforms that facilitate terminal differentiation and maturation of hepatocytes. PMID- 26531101 TI - Modelling the dynamics of polar auxin transport in inflorescence stems of Arabidopsis thaliana. AB - The polar transport of the plant hormone auxin has been the subject of many studies, several involving mathematical modelling. Unfortunately, most of these models have not been experimentally verified. Here we present experimental measurements of long-distance polar auxin transport (PAT) in segments of inflorescence stems of Arabidopsis thaliana together with a descriptive mathematical model that was developed from these data. It is based on a general advection-diffusion equation for auxin density, as suggested by the chemiosmotic theory, but is extended to incorporate both immobilization of auxin and exchange with the surrounding tissue of cells involved in PAT, in order to account for crucial observations. We found that development of the present model assisted effectively in the analysis of experimental observations. As an example, we discuss the analysis of a quadruple mutant for all four AUX1/LAX1-LAX3 influx carriers genes. We found a drastic change in the parameters governing the exchange of PAT channels with the surrounding tissue, whereas the velocity was still of the order of magnitude of the wild type. In addition, the steady-state flux of auxin through the PAT system of the mutant did not exhibit a saturable component, as we found for the wild type, suggesting that the import carriers are responsible for the saturable component in the wild type. In the accompanying Supplementary data available at JXB online, we describe in more detail the data driven development of the model, review and derive predictions from a mathematical model of the chemiosmotic theory, and explore relationships between parameters in our model and processes and parameters at the cellular level. PMID- 26531102 TI - Doctor, builder, soldier, lawyer, teacher, dancer, shopkeeper, vet: exploratory study of which eleven-year olds would like to become a doctor. AB - BACKGROUND: Very little is known about the extent to which eleven-year olds might consider a career in medicine. This exploratory study therefore asked children and their parents about medicine as a possible career, looking also at the relationship to a range of background measures. METHODS: A longitudinal, three wave, questionnaire study of students transferring from primary to secondary school (STARS), with data collection at primary school (wave 1; mean age 11.3 yrs), in the first months of secondary school (wave 2; mean age 11.7 yrs) and at the end of the first year of secondary school (wave 3; mean age 12.3 yrs). Parents/carers also completed questionnaires. Children were entering ten large comprehensive secondary schools in the south-east of England; 46.3 % were female, 15.6 % receiving free-school meals, 39.8 % were Black or Minority Ethnic and 28.8 % had a first language which was not English. Of 2287 children in the study, 1936 children (84.5 %) completed at least one questionnaire of the three waves (waves 1, 2 and 3). The main outcome measures were an open-ended question in each wave, "What job would you like to do when you grow up?", and a more detailed questionnaire in wave 3 asking about 33 different jobs. RESULTS: 9.9 % of children spontaneously mentioned medicine as a career on at least one occasion. For the specific jobs, would-be doctors particularly preferred Hospital Medicine, followed by Surgery, General Practice and then Psychiatry. Would-be doctors were also more interested in careers such as Nurse, Archaeologist, Lawyer and Teacher, and less interested in careers such as Shopkeeper, Sportsperson, or Actor/dancer/singer/musician. Would-be doctors were less Neurotic, more Open to Experience, more Conscientious, and preferred higher prestige occupations. Those interested in medicine did not score more highly on Key Stage 2 attainment tests or Cognitive Abilities Test, did not have a higher family income or greater parental/carer education, and did not have more experience of illness or deaths among family and friends. CONCLUSIONS: An interest in a medical career, unlike high prestige jobs in general, is not associated with higher educational attainment or cognitive ability, and it is likely that only one in ten of the children interested in medical careers will have sufficient educational attainment at GCSE or A-level to be able to enter medical school. PMID- 26531103 TI - Histidine residues are important for preserving the structure and heme binding to the C. elegans HRG-3 heme-trafficking protein. AB - C. elegans is a heme auxotroph that requires environmental heme for sustenance. As such, worms utilize HRG-3, a small heme-trafficking protein, to traffic heme from the intestine to extra-intestinal tissues and embryos. However, how HRG-3 binds and delivers heme remains unknown. In this study, we utilized electron paramagnetic resonance spectroscopy together with site-directed spin labeling, absorption spectroscopy, circular dichroism, and mutagenesis to gain structural and molecular insights into HRG-3. We showed that HRG-3 is a dimer, whereas H9 and H10 are significant residues that preserve a specific conformational state in the HRG-3 dimer. In the absence of H9 and H10, HRG-3 can still bind heme, although with a different affinity. Furthermore, the heme-binding site is closer to the N-termini than to the C-termini. Taken together, our results lay the groundwork for future mechanistic and structural studies of HRG-3 and inter tissue heme trafficking in metazoans. PMID- 26531104 TI - Synthesis and biological evaluation of novel platinum complexes of imidazolyl containing bisphosphonates as potential anticancer agents. AB - Four novel platinum complexes, [Pt(en)]2ZL (1), [Pt(en)]2IPrBP (2), [Pt(en)]2MIBP (3) and [Pt(en)]2EIBP (4) [en = ethylenediamine; ZL = 1-hydroxy-3-(1H-imidazol-1 yl)ethane-1,1-diylbisphosphonic acid, commonly known as zoledronic acid; IPrBP = 1-hydroxy-3-(1H-imidazol-1-yl)propane-1,1-diylbisphosphonic acid; MIBP = 1 hydroxy-2-(2-methyl-1H-imidazol-1-yl)ethane-1,1-diylbisphosphonic acid; EIBP = 1 hydroxy-2-(2-ethyl-1H-imidazol-1-yl)ethane-1,1-diylbisphosphonic acid], were prepared and evaluated against five human cancer cell lines, including U2OS, A549, HCT116, MDA-MB-231 and HepG2. While exhibiting lower efficacy on the inhibition of cancer cell lines than cisplatin (CDDP), four complexes showed higher cytotoxicity than the corresponding ligands and relatively stronger cytotoxic effect on the hepatoma cell lines HepG2, and the complex 1 showed higher cytotoxicity than others on the whole. These complexes have better selectivity than the corresponding ligands in inhibiting hepatocarcinoma cells rather than normal liver cells, and the selective inhibitory effect of the complex 1 at the high concentration (100 MUM) is better than that at the low concentration. Morphology studies exhibited typical characteristics of cell apoptosis and the cell cycle distribution analysis indicated that the complexes can inhibit cancer cells by inducing the cell cycle arrest at the G2/M phase, exhibiting a similar mechanism of action to CDDP. The binding interaction of complex with DNA has been explored by circular dichroism (CD) and UV-Vis absorption spectra, demonstrating these new complexes have moderate binding affinity for DNA. PMID- 26531105 TI - Knockdown of 15-kDa selenoprotein (Sep15) increases hLE cells' susceptibility to tunicamycin-induced apoptosis. AB - In this work, we investigated the effect of Sep15 gene knockdown on apoptosis in human lens epithelial (hLE) cells, trying to understand the relevance of Sep15 to cataract formation in the Sep15 knockout (KO) mice. The results showed that sole knockdown of Sep15 by RNA interference did not result in apoptosis; however, reduction of Sep15 expression aggravated tunicamycin (Tm)-induced cell apoptosis and caspases activation. Furthermore, Tm-induced mitochondrial dysfunction was also exacerbated under the Sep15 knockdown condition by measurement of mitochondrial membrane potential decrease and human cytochrome c release into cytosol. Interestingly, the knockdown of Sep15 exacerbated Tm-induced oxidative stress while endoplasmic reticulum (ER) stress was not correspondingly elevated. These results suggest that the protective role of Sep15 against Tm-induced apoptosis in hLE cells is operated via inhibiting oxidative stress rather than regulating Tm-induced ER stress, and the protective role becomes dependent on Sep15 only in acute stress condition. PMID- 26531106 TI - Lymphomatoid papulosis with pseudocarcinomatous hyperplasia in a 7-year-old girl: a case report. AB - Lymphomatoid papulosis (LyP) belongs to the group of cutaneous CD30+ lymphoproliferative disorders. Pseudocarcinomatous hyperplasia has rarely been reported in patients with LyP. In this report, we describe a case of LyP presenting as pseudocarcinomatous hyperplasia. The patient was a 7-year-old girl who presented with a recurrent papulonodular eruption on her face and trunk for 2 months. Histopathologic examination revealed an irregular growth of hyperkeratotic epidermis into the whole dermal layer with marked nests of squamous cells in the background of diffuse atypical lymphoid cells, eosinophils and neutrophils. The large atypical cells were positive for CD30 and CD3, but negative for CD4, CD5, CD8, CD20 and CD56. A TCR-gamma clone was identified by polymerase chain reaction (PCR). The correct diagnosis in cases of LyP with overlying pseudocarcinomatous epithelial hyperplasia can be very difficult both clinically and histopathologically. Clinical and histopathologic characteristics should be integrated to avoid an erroneous diagnosis of squamous cell carcinoma or keratoacanthoma. PMID- 26531107 TI - Is ALK-gene rearrangement overlooked in primary gastrointestinal T-cell lymphomas? About two cases. AB - A 41-year-old male patient with a history of ankylosing spondylitis and Crohn disease, treated with immunomodulators and disease-modifying drugs, was diagnosed with a primary intestinal T-cell lymphoma that followed a 7.5-year-course. This transmural proliferation lacked cytological characteristics of anaplastic large cell lymphoma (ALCL), and was CD8-positive, and CD30- and anaplastic lymphoma kinase (ALK)-negative by immunohistochemistry (IHC). However, ALK-gene rearrangement (ALK-gr) was detected by fluorescence in situ hybridization (FISH) in both initial and persistent disease. The possibility of indolent T-cell lymphoproliferative disease of the gastrointestinal tract with atypical features (transmural involvement) related to ALK-gr was suggested. A previous case of aggressive 'enteropathy-associated ALCL' in the context of celiac disease was recently reported, which also lacked anaplastic morphology, and where CD30 and ALK expression was incidentally demonstrated by IHC, and ALK-gr subsequently confirmed by FISH. These two recent cases represent two distinct rare entities pertaining to the group of primary intestinal T-cell lymphomas, and they both show unexpected ALK-gr. This suggests that ALK-gr has been overlooked in the group of primary intestinal T-cell lymphomas. Performing IHC and FISH tests for ALK-gr in primary gastrointestinal T-cell lymphomas might be of importance, particularly with the advancement of targeted therapy that could impact treatment and prognosis. PMID- 26531108 TI - Early maternal separation impacts cognitive flexibility at the age of first independence in mice. AB - Early life adversity is associated with increased risk for mental and physical health problems, including substance abuse. Changes in neural development caused by early life insults could cause or complicate these conditions. Maternal separation (MS) is a model of early adversity for rodents. Clear effects of MS have been shown on behavioral flexibility in rats, but studies of effects of MS on cognition in mice have been mixed. We hypothesized that previous studies focused on adult mice may have overlooked a developmental transition point when juvenile mice exhibit greater flexibility in reversal learning. Here, using a 4 choice reversal learning task we find that early MS leads to decreased flexibility in post-weaning juvenile mice, but no significant effects in adults. In a further study of voluntary ethanol consumption, we found that adult mice that had experienced MS showed greater cumulative 20% ethanol consumption in an intermittent access paradigm compared to controls. Our data confirm that the MS paradigm can reduce cognitive flexibility in mice and may enhance risk for substance abuse. We discuss possible interpretations of these data as stress related impairment or adaptive earlier maturation in response to an adverse environment. PMID- 26531109 TI - Robotic-assisted Heller myotomy: a modern technique and review of outcomes. AB - Achalasia is a debilitating esophageal motility disorder characterized by incomplete relaxation of the lower esophageal sphincter and lack of peristalsis. Manometry is the gold standard for diagnosis and laparoscopic Heller myotomy has been the gold standard for definitive therapy. However, current advances in surgical technology have introduced the robotic platform as a viable approach for this procedure. The safety and efficacy has been clearly established with comparable operative times to laparoscopy in experienced hands. Importantly, the rate of resolution of dysphagia postoperatively is over 80% which is comparable to laparoscopic outcomes. Moreover, some literature suggests lower esophageal perforation rates utilizing the robotic platform. Nevertheless, costs remain one of the largest barriers to widespread use of the robotic platform and future studies should aim to identify strategies in cost reduction. PMID- 26531110 TI - The roles and limitations of robotic surgery for obese endometrial cancer patients: a common challenge in gynecologic oncology. AB - In the United States, the epidemic of obesity is readily apparent in women diagnosed with endometrial cancer, the most common gynecologic malignancy. Overall, the benefits of minimally invasive surgery and its oncologic outcomes are similar among laparoscopy and robotic approaches. However, in stratifying obese patients by BMI, more data is needed on morbidly obese patients and their candidacy for robotic surgery along with the technical challenges of staging procedures. Cost analysis studies targeted specifically to the obese and morbidly obese patient is needed to further justify efforts at promoting robotic surgery in this patient population. PMID- 26531111 TI - Independent predictors of prolonged operative time during robotic-assisted radical prostatectomy. AB - The objective of this study is to investigate the determinants of prolonged operative time during robotic radical prostatectomy (RARP) after the learning curve period. Data were prospectively collected from consecutive patients with low- or intermediate-risk prostate cancer who underwent RARP at an academic institution from 2006 to 2012. The early learning curve period of 40 patients was excluded. Primary outcome was prolonged operative time, defined as greater than one standard deviation above the mean. Multivariable logistic regression was performed to identify predictors of prolonged operative time, and multivariable linear regression further quantified their impact. The mean age of the 440 men included in this cohort was 60 +/- 7 years, with a PSA of 7 +/- 3 and BMI and IIEF scores of 27 +/- 3 and 17 +/- 8, respectively. Seventy-one percent of patients had Stage 1 disease, the majority of which underwent bilateral (62%) or unilateral (21%) nerve-sparing prostatectomy with pelvic lymph node dissection (49%). The mean complete operative time was 187 +/- 32 min. Multivariable logistic regression revealed four independent predictors of prolonged operative time: blood loss, pre-operative PSA, robot malfunction, and gland volume. Operative time was most strongly affected by procedure-specific variables, including robotic malfunction (32 min/malfunction) and blood loss (6.5 min/100 ml). Operative time was also affected to a lesser degree by patient-specific variables of PSA (10 min/10 ng/ml) and gland volume (3 min/10 cc). Robotic malfunction was the strongest predictor of prolonged operative time. Blood loss, PSA, and gland volume were also associated with prolonged operative time. Knowledge of these predictors may assist in surgical planning and improve resource utilization. PMID- 26531112 TI - Impact of fellowship training on robotic-assisted laparoscopic partial nephrectomy: benchmarking perioperative safety and outcomes. AB - To provide perioperative benchmark data for surgeons entering practice from formal robotic training and performing robotic-assisted laparoscopic partial nephrectomy (RAPN). Perioperative outcomes of the first 100 RAPN from a surgeon entering into practice directly from robotic fellowship training were analyzed. Postoperative complications were categorized by Clavien-Dindo grade. Surgical "trifecta scores" and Margin, Ischemia, and Complication (MIC) scoring were utilized to assess surgical outcomes. Statistical analyses were performed using SAS (version 9.2; SAS Institute, Inc., Cary, North Carolina). Median age of the cohort was 63 years (22-81 years), and 34 (34.3%) patients were over age 65. Forty-one (41.4%) patients had a BMI > 30. Thirteen (13.1%) had RENAL 10-12 tumors, 22 of which (22.2%) were >4 cm in size. Median warm ischemia time was 17 min, and 13 patients had resection without warm ischemia. Five patients were converted to open partial nephrectomy, and 1 patient was converted to laparoscopic nephrectomy. Twenty-one patients (21.2%) experienced a complication, 6 of whom had a major (Clavien grade 3 or higher) complication with one grade 5 complication. Operating room time decreased with experience, but surgical complications and hospital stay did not change with experience. MIC score of renal cell carcinoma (RCC) patients was 74.7%, while the surgical trifecta was reached in 71.3 % of RCC patients. Surgeons may enter practice directly from formal robotic training and perform RAPN with perioperative outcomes, surgical complications, surgical trifecta scores, and MIC scoring in line with those the most experienced robotic partial nephrectomists. PMID- 26531113 TI - Robotic transverse colectomy for mid-transverse colon cancer: surgical techniques and oncologic outcomes. AB - Robot-assisted surgery for colon cancer has been reported in many studies, most of which worked on right and/or sigmoid colectomy. The aim of this study was to report our experience of robotic transverse colectomy with an intracorporeal anastomosis, provide details of the surgical technique, and present the theoretical benefits of the procedure. This is a retrospective review of prospectively collected data of robotic surgery for colorectal cancer performed by a single surgeon between May 2007 and February 2011. Out of 162 consecutive cases, we identified three robotic transverse colectomies, using a hand-sewn intracorporeal anastomosis. Two males and one female underwent transverse colectomies for malignant or premalignant disease. The mean docking time, time spent using the robot, and total operative time were 5, 268, and 307 min, respectively. There were no conversions to open or conventional laparoscopic technique. The mean length of specimen and number of lymph nodes retrieved were 14.1 cm and 6.7, respectively. One patient suffered from a wound seroma and recovered with conservative management. The mean hospital stay was 8.7 days. After a median follow-up of 72 months, there were no local or systemic recurrences. Robotic transverse colectomy seems to be a safe and feasible technique. It may minimize the necessity of mobilizing both colonic flexures, with facilitated intracorporeal hand-sewn anastomosis. However, further prospective studies with a larger number of patients are required to draw firm conclusions. PMID- 26531114 TI - Robotic versus laparoscopic resection for sigmoid diverticulitis with fistula. AB - Robotic abdominal surgery is growing despite a paucity of clinical reports to evaluate its impact on patient outcomes. In this retrospective case series, we aim to analyze our early experience with robotic resection in 11 consecutive patients with chronic colonic diverticulitis complicated by fistula to bladder, vagina, or skin and to compare the results of the robotic approach to 20 patients undergoing laparoscopic resection for the same indication. Our main outcome measures include operative time, blood loss, conversion rate, transfusion rate, hospital length of stay, complications, readmission, and fistula healing rate. In our study, we found robotic resection for colonic diverticulitis with fistula was technically feasible and yielded 100% fistula healing rate. The operative time, complication and readmission rates were similar to laparoscopy. A higher conversion rate, diverting stoma need, and longer hospital length of stay were noted in the robotic group; however, these findings could have been attributed to a higher number of cases involving rectal excision in the robotic group. Larger studies are needed to further examine the impact of robotic surgery on the outcome of patients with complicated chronic sigmoid diverticulitis. PMID- 26531115 TI - Early experience of robotic surgery for type I congenital dilatation of the bile duct. AB - Laparoscopic surgery for this disease is not widely spread due to difficulties in its procedure. We started a laparoscopic procedure for this disease since 2011, and the robotic surgery since 2012. The aim of this study is to assess early results of these procedures. We have operated seven cases from September 2011 through December 2013. First two cases were performed by laparoscopic procedure, and following cases were done by robotically assisted surgery. Of these cases, the perioperative outcome and short-term postoperative morbidity were evaluated. Their average age was 43.6 years old (20-64 years old), and male-female ratio was 2:5. Todani classification was type 1 in all cases. The operation time was 321 min in laparoscopic cases, while 489 min in robotic surgery cases. One case of robotic surgery developed postoperative intestinal obstruction of the biliary limb, requiring laparoscopic adhesiolysis. Pancreatic fistula and anastomotic leakage have not been observed. The robotic surgery for the congenital dilatation of the bile duct is feasible and is a theoretically useful option, especially for hepatico-jejunostomy. On the other hand, the limitation of energy devices, high running cost, and time consumption remain questionable. PMID- 26531116 TI - Postoperative (pressure) alopecia following sacrocolpopexy. AB - Postoperative alopecia is a rare occurrence seen after a variety of surgical procedures performed under general anesthesia. The speculated cause is pressure induced ischemia due to prolonged head immobilization. This case describes a patient who developed this complication after undergoing sacrocolpopexy. A 57 year-old postmenopausal Caucasian female was consented to undergo a robotic assisted sacrocolpopexy, perineoplasty, and midurethral sling with possible conversion to an open procedure. The indication was symptomatic proximal and distal rectocele with foreshortened vagina. It was converted to laparotomy due to difficult presacral dissection. Her total operative time was 540 with 240 min in the Trendelenburg position. No intraoperative hypotension or excessive blood loss was noted. She started complaining of scalp pain in the postoperative recovery area. She developed soreness, crusting, and later alopecia in the same area. It was noted at her 3-week office visit. Referral was made for dermatology and anesthesiology evaluation. There was spontaneous full recovery by the 5th month. Postoperative alopecia is a rare condition mimicking alopecia areata but it is preceded by inciting events. There is some evidence to suggest that it is a preventable condition by frequent head repositioning during surgery. This case report is intended to increase the surgeon's awareness about this rare complication as its occurrence can be distressing for the patient. PMID- 26531117 TI - Totally robotic combined right hemicolectomy and nephrectomy. PMID- 26531118 TI - R-LESS right colectomy with the single-site(r) robotic platform. AB - BACKGROUND: Use of robotics has exemplified single-site procedures by restoring the correct hand-instrument alignment and providing stable, stereoscopic visual field. Technique was initially introduced by the manufacturers for cholecystectomy, but experienced teams quickly extended the indications to more complex procedures. We hereby present a case of a patient that underwent robotic right colectomy and omentectomy through the single-site((r)) platform. METHODS: A single-site procedure was offered to our 58-year-old male patient with carcinoma of the ascending colon and he gave written consent for it. The VESPA((r)) single site platform was used according to the standards of the manufacturing company. The single-site port((r)) was placed at the umbilicus. Rest of setup and procedure steps were based on the multiport technique. An extended omentectomy accompanying the right colectomy has not previously reported to our knowledge. After sufficient mobilization specimen was exteriorized through the umbilicus, excised and the anastomosis was performed using linear staplers. RESULTS: Console time was 164 min and total operation time was 221 min. Intraoperatively, there was no need for conversion, additional ports or blood transfusions. Total console time was 164 min. Lacking of wristed instruments and bipolar energy were regarded as serious limitations. No drains were used. Patient did not require ICU stay and had no postoperative complaints. He was given liquid diet on PO day #2 and he was discharged on PO day #4. CONCLUSIONS: Robotic single-site right colectomy is safe and feasible in selected cases. Experience from single-site robotic cholecystectomy is a useful basis to expand the indications to more complex procedures. Further development of the instruments and large number of cases may justify the indications for using this technique in the future. PMID- 26531119 TI - Gastropleural fistula after bariatric surgery: a report of two cases. AB - INTRODUCTION: Gastropleural fistulas (GPF) were first described by Markowitz and Herter in 1960. These are uncommon entities and can occur as a consequence of pulmonary surgery, trauma, malignancy, hiatal hernia, infections, Nissen fundoplication and most recently, bariatric surgery. Many treatments have been used for GPF, such as conservative management with antibiotics, parenteral nutrition, percutaneous drainage of collections and endoscopic therapies, but these usually fail and may lead to complex surgical procedures. CASE DESCRIPTION/OPERATIVE TECHNIQUE: Two patients diagnosed with GPF after bariatric surgeries were treated in our program. After failure of conservative management, both were subjected to laparoscopic-robotic assisted gastropleural fistula resection. Case 1 was a patient who had a sleeve gastrectomy 1 year prior, required partial esophagogastrectomy and esophagojejunal anastomosis. Case 2 had an open gastric bypass 13 years prior, and when medical resolution of fistula was not possible, he underwent a partial remnant gastrectomy and hiatal hernia repair. DISCUSSION: Appearance of gastroplueral fistula after bariatric surgery is a rare occurrence. When surgical management is needed, we have noticed that the use of the robotic platform in these complex surgical cases is safe and feasible. PMID- 26531120 TI - Bladder sparing robot-assisted laparoscopic en bloc resection of urachus and umbilicus for urachal adenocarcinoma. AB - Urachal adenocarcinoma is a rare and aggressive form of bladder cancer that arises from the urachus. An en bloc resection of the urachus and umbilicus is recommended with either a total or partial cystectomy. However, there is no standard laparoscopic or robotic surgical technique for the operative management of these tumors. In the present report, we describe our robotic-assisted laparoscopic technique for the treatment of a primary malignant urachal tumor. PMID- 26531121 TI - Getting smarter with patient positioning. PMID- 26531122 TI - Neurocognitive functions and health-related quality of life in glioblastoma patients: a concise review of the literature. AB - The maintenance of quality of life in patients with high-grade glioma is an important endpoint during treatment, particularly in those with glioblastoma multiforme, given its dismal prognosis; thus, the primary aims of treatments are to reduce morbidity, restore or preserve neurological functions, and the capacity to perform daily activities. This review aims to summarise what is currently known about neurocognitive outcome and quality of life in patients with high grade glioma, particularly in glioblastoma patients. We considered all the variables that can influence neurocognitive functions, the perception of quality of life and their role as predictors for treatment outcomes. PMID- 26531123 TI - Health Impact Assessments, Regulation, and the Unconventional Gas Industry in the UK: Exploiting Resources, Ideology, and Expertise? AB - Health impact assessments (HIAs) across the globe may be used by governments and industries to secure approval for unconventional gas extraction developments. HIA is an umbrella term that covers an array of health review and assessment practices, ranging from the very general to quite specific and technical health studies. Our concern in this paper is principally with the specialist end of the HIA continuum and particularly its application to unconventional gas extraction in the UK. We outline the context within which HIAs in unconventional gas extraction may be conducted. We then explain what HIAs may do. HIAs are often commissioned from consultancy companies to assess unconventional gas extraction project risks and benefits and propose mitigation measures. Communities can rarely afford HIAs in the planning process and may consider them biased when commissioned by vested interests. The oil and gas industry uses these techniques for its own ends. Hiring experts, be they specialist consultants, researchers, lobbyists, ex-government officials, or regulators, to influence planning and regulation is a well-tried tactic and structural advantage exploited by industry in seeking license to operate. Equitable and ethical HIA principles are urgently needed in the UK in relation to unconventional gas to secure the integrity and probity of the emerging regulatory system and address concerns regarding unregulated practitioners. PMID- 26531124 TI - Memory Flexibility training (MemFlex) to reduce depressive symptomatology in individuals with major depressive disorder: study protocol for a randomised controlled trial. AB - BACKGROUND: Major depressive disorder (MDD) is associated with chronic biases in the allocation of attention and recollection of personal memories. Impaired flexibility in attention and autobiographical memory retrieval is seen to both maintain current symptoms and predict future depression. Development of innovative interventions to reduce maladaptive cognitive patterns and improve cognitive flexibility in the domain of memory may therefore advance current treatment approaches for depression. Memory specificity training and cognitive bias modification techniques have both shown some promise in improving cognitive flexibility. Here we outline plans for a trial of an innovative memory flexibility training programme, MemFlex, which advances current training techniques with the aim of improving flexibility of autobiographical memory retrieval. This trial seeks to estimate the efficacy of MemFlex, provide data on feasibility, and begin to explore mechanisms of change. METHODS/DESIGN: We plan a single-blind, randomised, controlled, patient-level trial in which 50 individuals with MDD will complete either psychoeducation (n = 25) or MemFlex (n = 25). After completing pre-treatment measures and an orientation session, participants complete eight workbook-based sessions at home. Participants will then be assessed at post-treatment and at 3 month follow-up. The co-primary outcomes are depressive symptoms and diagnostic status at 3 month follow-up. The secondary outcomes are memory flexibility at post-treatment and number of depression free days at 3 month follow-up. Other process outcomes and mediators of any treatment effects will also be explored. DISCUSSION: This trial will establish the efficacy of MemFlex in improving memory flexibility, and reducing depressive symptoms. Any effects on process measures related to relapse may also indicate whether MemFlex may be helpful in reducing vulnerability to future depressive episodes. The low intensity and workbook-based format of the programme may improve access to psychological therapies, and, if encouraging, the results of this study will provide a platform for later-phase trials. TRIAL REGISTRATION: NCT02371291 (ClinicalTrials.gov), registered 9 February 2015. PMID- 26531125 TI - Detection of anal dysplasia is enhanced by narrow band imaging and acetic acid. AB - AIM: Anal intraepithelial neoplasia precedes the development of anal squamous cell carcinoma. Detection of the lesion is essential to management. This paper describes a prospective study to detect and ablate anal squamous intraepithelial lesions (SILs) using white light narrow band imaging (NBI) and NBI with acetic acid (NBIA). METHOD: Sixty patients with abnormal anal cytology and risk factors for anal dysplasia underwent examination of the anoderm with a high definition gastroscope and NBIA. Targeted biopsies were taken and the lesions were ablated and characterized histopathologically. Visualization of the anal transitional zone was facilitated by retroflexion and examination through a disposable anoscope. RESULTS: Targeted biopsies were taken from lesions in 58 patients. No lesion was seen in two patients. Histopathology showed SIL in 48 (80.0%) of 60 biopsies. One biopsy showed lymphoid aggregates. Biopsies in nine (15%) of the 60 patients showed normal mucosa. Lesions were seen in white light in 27 (45%) of the 60 cases, NBI in 39 (65%) and NBIA in 57 (95%). There was no major morbidity. Sensitivity analysis showed that all methods were significantly different from each other. CONCLUSION: Anal SIL in the anal transitional zone and anal canal can be identified by NBIA. Patient selection influences findings. Limitations include small sample size and non-randomization. PMID- 26531126 TI - Information maximizing component analysis of left ventricular remodeling due to myocardial infarction. AB - BACKGROUND: Although adverse left ventricular shape changes (remodeling) after myocardial infarction (MI) are predictive of morbidity and mortality, current clinical assessment is limited to simple mass and volume measures, or dimension ratios such as length to width ratio. We hypothesized that information maximizing component analysis (IMCA), a supervised feature extraction method, can provide more efficient and sensitive indices of overall remodeling. METHODS: IMCA was compared to linear discriminant analysis (LDA), both supervised methods, to extract the most discriminatory global shape changes associated with remodeling after MI. Finite element shape models from 300 patients with myocardial infarction from the DETERMINE study (age 31-86, mean age 63, 20 % women) were compared with 1991 asymptomatic cases from the MESA study (age 44-84, mean age 62, 52 % women) available from the Cardiac Atlas Project. IMCA and LDA were each used to identify a single mode of global remodeling best discriminating the two groups. Logistic regression was employed to determine the association between the remodeling index and MI. Goodness-of-fit results were compared against a baseline logistic model comprising standard clinical indices. RESULTS: A single IMCA mode simultaneously describing end-diastolic and end-systolic shapes achieved best results (lowest Deviance, Akaike information criterion and Bayesian information criterion, and the largest area under the receiver-operating-characteristic curve). This mode provided a continuous scale where remodeling can be quantified and visualized, showing that MI patients tend to present larger size and more spherical shape, more bulging of the apex, and thinner wall thickness. CONCLUSIONS: IMCA enables better characterization of global remodeling than LDA, and can be used to quantify progression of disease and the effect of treatment. These data and results are available from the Cardiac Atlas Project ( http://www.cardiacatlas.org ). PMID- 26531127 TI - Age-dependent blood pressure elevation is due to increased vascular smooth muscle tone mediated by G-protein signalling. AB - AIMS: Arterial hypertension is a major risk factor for cardiovascular diseases. The kidney and its natriuretic function are in the centre of the prevailing models to explain the pathogenesis of hypertension; however, the mechanisms underlying blood pressure elevation remain unclear in most patients. Development of hypertension is strongly correlated with age, and this blood pressure increase typically accelerates in the fourth decade of life. The cause of age-dependent blood pressure elevation is poorly understood. This study aims to understand the role of procontractile G-protein-mediated signalling pathways in vascular smooth muscle in age-dependent hypertension. METHODS AND RESULTS: Similar to humans at mid-life, we observed in 1-year-old mice elevated blood pressure levels without any evidence for increased vessel stiffness, impaired renal function, or endocrine abnormalities. Hypertensive aged mice showed signs of endothelial dysfunction and had an increased vascular formation of reactive oxygen species (ROS) and elevated endothelial ET-1 expression. Age-dependent hypertension could be normalized by ETA receptor blockade, smooth muscle-specific inactivation of the gene encoding the ETA receptor, as well as by acute disruption of downstream signalling via induction of smooth muscle-specific Galpha12/Galpha13, Galphaq/Galpha11, or LARG deficiency using tamoxifen-inducible smooth muscle specific conditional mouse knock-out models. Induction of smooth muscle-specific ETA receptor deficiency normalized the blood pressure in aged mice despite the continuous presence of signs of endothelial dysfunction. CONCLUSION: Age dependent blood pressure elevation is due to a highly reversible activation of procontractile signalling in vascular smooth muscle cells indicating that increased vascular tone can be a primary factor in the development of hypertension. PMID- 26531128 TI - Ranolazine antagonizes catecholamine-induced dysfunction in isolated cardiomyocytes, but lacks long-term therapeutic effects in vivo in a mouse model of hypertrophic cardiomyopathy. AB - AIMS: Hypertrophic cardiomyopathy (HCM) is often accompanied by increased myofilament Ca(2+) sensitivity and diastolic dysfunction. Recent findings indicate increased late Na(+) current density in human HCM cardiomyocytes. Since ranolazine has the potential to decrease myofilament Ca(2+) sensitivity and late Na(+) current, we investigated its effects in an Mybpc3-targeted knock-in (KI) mouse model of HCM. METHODS AND RESULTS: Unloaded sarcomere shortening and Ca(2+) transients were measured in KI and wild-type (WT) cardiomyocytes. Measurements were performed at baseline (1 Hz) and under increased workload (30 nM isoprenaline (ISO), 5 Hz) in the absence or presence of 10 uM ranolazine. KI myocytes showed shorter diastolic sarcomere length at baseline, stronger inotropic response to ISO, and drastic drop of diastolic sarcomere length under increased workload. Ranolazine attenuated ISO responses in WT and KI cells and prevented workload-induced diastolic failure in KI. Late Na(+) current density was diminished and insensitive to ranolazine in KI cardiomyocytes. Ca(2+) sensitivity of skinned KI trabeculae was slightly decreased by ranolazine. Phosphorylation analysis of cAMP-dependent protein kinase A-target proteins and ISO concentration-response measurements on muscle strips indicated antagonism at beta-adrenoceptors with 10 uM ranolazine shifting the ISO response by 0.6 log units. Six-month treatment with ranolazine (plasma level >20 uM) demonstrated a beta-blocking effect, but did not reverse cardiac hypertrophy or dysfunction in KI mice. CONCLUSION: Ranolazine improved tolerance to high workload in mouse HCM cardiomyocytes, not by blocking late Na(+) current, but by antagonizing beta adrenergic stimulation and slightly desensitizing myofilaments to Ca(2+). This effect did not translate in therapeutic efficacy in vivo. PMID- 26531129 TI - The renin-angiotensin system promotes arrhythmogenic substrates and lethal arrhythmias in mice with non-ischaemic cardiomyopathy. AB - AIMS: The progression of pathological left ventricular remodelling leads to cardiac dysfunction and contributes to the occurrence of malignant arrhythmias and sudden cardiac death. The underlying molecular mechanisms remain unclear, however. Our aim was to examine the role of the renin-angiotensin system (RAS) in the mechanism underlying arrhythmogenic cardiac remodelling using a transgenic mouse expressing a cardiac-specific dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). This mouse model exhibits progressive cardiac dysfunction leading to lethal arrhythmias. METHODS AND RESULTS: Subcutaneous administration of aliskiren, a direct renin inhibitor, significantly suppressed the progression of pathological cardiac remodelling and improved survival among dnNRSF-Tg mice while reducing arrhythmogenicity. Genetic deletion of the angiotensin type 1a receptor (AT1aR) similarly suppressed cardiac remodelling and sudden death. In optical mapping analyses, spontaneous ventricular tachycardia (VT) and fibrillation (VF) initiated by breakthrough-type excitations originating from focal activation sites and maintained by functional re-entry were observed in dnNRSF-Tg hearts. Under constant pacing, dnNRSF-Tg hearts exhibited markedly slowed conduction velocity, which likely contributes to the arrhythmogenic substrate. Aliskiren treatment increased conduction velocity and reduced the incidence of sustained VT. These effects were associated with suppression of cardiac fibrosis and restoration of connexin 43 expression in dnNRSF-Tg ventricles. CONCLUSION: Renin inhibition or genetic deletion of AT1aR suppresses pathological cardiac remodelling that leads to the generation of substrates maintaining VT/VF and reduces the occurrence of sudden death in dnNRSF-Tg mice. These findings demonstrate the significant contribution of RAS activation to the progression of arrhythmogenic substrates. PMID- 26531130 TI - Toxicity and Pharmacokinetic Studies of Aerosolized Clinical Grade Azacitidine. AB - BACKGROUND: Azacitidine as an effective epigenetic therapeutic agent has not been used as an aerosol form to treat lung cancer patients. We aerosolized clinical grade azacitidine (Aza), optimized the formulation, and studied its pharmacokinetics and toxicity in mice. METHODS: Extrusion-precipitation method and DNA methyltransferase inhibition rate were used to measure the aerodynamic size and aerosolized Aza activity. In the single dose pharmacokinetic study, Aza concentrations in peripheral blood and lungs were measured by LC-MS method. In the multiple-dose toxicity studies, histo-pathological evaluation was used to determine the organ and bone marrow toxicities. RESULTS: In pharmacokinetic study, aerosolized Aza was found to deposit mainly into the lung with very little drug detected in the circulation. In contrast, intravenously injected (IV) Aza resulted in a high Aza concentration in the peripheral blood, with trace amounts of drug in the lung, and it was associated with significant myelosuppression. No significant myelosuppression, pulmonary toxicity, hepatotoxicity, or nephrotoxicity were observed at a daily dose of 2.5 mg/m(2) for 7 days. Reversible lung inflammation was found in mice treated with 7.5 mg/m(2) aerosolized Aza at 3 but not 6 weeks after treatment. CONCLUSIONS: Aerosol Aza aerodynamic size favors deposition of the drug to the human lower airways. The aerosol process do not compromise the drug activity. Aerosolized Aza has higher lung deposition and much less systemic toxicity than IV drug. The safe starting dose for clinical phase I trials should be 2.5 mg/m(2) for 5 to 7 days. PMID- 26531131 TI - Chemotherapeutic agent CPT-11 eliminates peritoneal resident macrophages by inducing apoptosis. AB - CPT-11 (Irinotecan) is a first-line chemotherapeutic agent in clinic, but it may induce side effects including diarrhea and enteritis in patients. The underlying mechanism of CPT-11's intestinal toxicity is unclear. Peritoneal resident macrophages have been reported to be important for the maintenance of intestinal homeostasis. In this study, we evaluated the cytotoxic effects of CPT-11 on mouse peritoneal resident macrophages. CPT-11 was administered intraperitoneally to mice and their peritoneal exudate cells were isolated for evaluation. CPT-11 treatment strikingly decreased the ratio of F4/80(hi)MHCII(low) large peritoneal macrophages (LPMs), which are regarded as prenatally-originated peritoneal resident macrophages. Consistent with this, the transcription factor GATA6 specifically expressed in LPMs was barely detectable in the macrophages from CPT 11-treated mice, indicative of elimination of LPMs. Such elimination of LPMs was at least partly due to CPT-induced apoptosis in macrophages, because inhibition of apoptosis by caspase-3 inhibitor z-DEVD-fmk significantly diminished the loss of GATA6(+) LPMs. As GATA6 is a transcription factor that controls expression of multiple genes regulating peritoneal B-1 cell development and translocation, elimination of GATA6(+) LPMs led to a great reduction in B-1 cells in the peritoneal cavity after CPT-11 treatment. These results indicated that CPT-11 induced apoptosis contributed to the elimination of peritoneal resident macrophages, which might in turn impair the function of peritoneal B-1 cells in maintaining intestinal homeostasis. Our findings may at least partly explain why CPT-11 treatment in cancer patients induces diarrhea and enteritis, which may provide a novel avenue to prevent such side effects. PMID- 26531132 TI - Training Pediatric Psychologists for Perinatal Behavioral Health Services in a Pediatric Hospital. AB - Although pediatric hospitals specialize in providing care to children and adolescents, at The Children's Hospital of Philadelphia (CHOP), our team has been providing behavioral health services for two unique parent populations-parents with a child in the Newborn Infant Intensive Care Unit and pregnant women carrying fetuses with specific birth defects and receiving prenatal care in the Center for Fetal Diagnosis and Treatment. A new training program was developed to expand the scope of pediatric psychologists' practice to include perinatal behavioral health services, specifically for these two unique parent populations served at CHOP. The program includes direct service provision for adult mental health concerns, as well as education and support to help families cope with the existing medical conditions. This article describes the training program and its implementation as a model of training for other pediatric hospitals. The roles of psychologists embedded in these units and hospital privileges are discussed. PMID- 26531133 TI - Tunable Cascade Reactions of Alkynols with Alkynes under Combined Sc(OTf)3 and Rhodium Catalysis. AB - Two tunable cascade reactions of alkynols and alkynes have been developed by combining Sc(OTf)3 and rhodium catalysis. In the absence of H2O, an endo cycloisomerization/C-H activation cascade reaction provided 2,3 dihydronaphtho[1,2-b]furans in good to high yields. In the presence of H2O, the product of alkynol hydration underwent an addition/C-H activation cascade reaction with an alkyne, which led to the formation of 4,5-dihydro-3H-spiro[furan 2,1'-isochromene] derivatives in good yields under mild reaction conditions. Mechanistic studies of the cascade reactions indicated that the rate-determining step involves C-H bond cleavage and that the hydration of the alkynol plays a key role in switching between the two reaction pathways. PMID- 26531134 TI - [Composition of 359 kidney stones from the East region of Algeria]. AB - PURPOSE: Determine stones composition of the upper urinary tract in the eastern region of Algeria. METHODS: Our study focuses on a set of 359 stones of the upper urinary tract collected between January 2007 and December 2012 at hospitals in the eastern region of Algeria and analyzed by Fourier transform infrared spectroscopy. RESULTS: The male/female ratio was only 1.32. Calcium oxalate prevailed in 68.5% of stones and 49.3% of nuclei, mainly as whewellite (51.8% of stones and 37.9% of nuclei vs 16.7% and 11.4% respectively for weddellite). Carbapatite prevailed in 15% of stones and 29.8% of nuclei. The struvite, identified in 11.1% of calculi, prevailed in 3.9% of stones and 3.1% of nuclei. Among purines, uric acid prevailed with frequencies quite close to 8.9% and 7% respectively in the stone and in the nucleus while the ammonium urate prevailed in only 0.3% of stones and 3.3% of nuclei. The cystine frequency was 3.6% in both stone and nucleus. The frequency of stone with umbilication was 26.2%. Whewellite was the main component of umbilicated stones with Randall's plaque. CONCLUSION: Our results suggest that stones of the urinary tract in the Algerian east region resemble those observed in industrialized countries. Some features such as stones location, the whewellite prevalence, the frequencies of main components in both the stone and the nucleus as well as the formation of stones on renal papilla confirm this trend. LEVEL OF EVIDENCE: 4. PMID- 26531135 TI - Novel water-soluble fisetin/cyclodextrins inclusion complexes: Preparation, characterization, molecular docking and bioavailability. AB - Novel water-soluble inclusion complexes for fisetin (FIT) were developed by introducing beta-cyclodextrin (beta-CD) and gamma-CD. Properties of the obtained complexes, as well as the interactions between each component, were systematically investigated in both solution and solid states by means of ESI-MS, NMR, FT-IR, XRD, DSC, SEM etc. All characterization information demonstrated that FIT/CDs inclusion complexes were formed, and exhibited different spectroscopic features and properties from FIT. A complex with 1:1 stoichiometry of FIT and CDs was confirmed with Job's method. Meanwhile, as supported by molecular modeling calculations, we suggested that phenyl group (C ring) of FIT molecule was included in the CDs cavity from the wide side. Moreover, the water solubility of FIT/CDs was successfully improved from 2.8 mg/mL (in ethanol aqueous solution) to 4.5 mg/mL (FIT/beta-CD complex) and 7.8 mg/mL (FIT/gamma-CD complex), and higher thermal stability results were shown by thermal analysis for those complexes. Notably, the inclusion complexes displayed almost two times higher cytotoxicity compared to free FIT against Hela and MCF-7 cells. These results suggested that FIT/CDs complexes could be potentially useful in food industry and healthcare area. PMID- 26531136 TI - Surface polysaccharides from Acinetobacter baumannii: Structures and syntheses. AB - The emergence of multidrug-resistance Acinetobacter baumannii requires novel approaches for prevention, treatment and diagnosis. The structures of surface polysaccharides from A. baumannii are valuable tools to understand pathogenesis, virulence and immunogenicity. The synthesis of bacterial mono- or polysaccharides may result in novel probes to become important therapeutic options in the fight against A. baumannii. This report exemplifies the relevance of glycochemistry for the development of new antibiotics. PMID- 26531137 TI - Characteristics of alpha-Gal epitope, anti-Gal antibody, alpha1,3 galactosyltransferase and its clinical exploitation (Review). AB - The alpha-Gal epitope (Galalpha1,3Galalpha1,4GlcNAc-R) is ubiquitously presented in non-primate mammals, marsupials and New World Monkeys, but it is absent in humans, apes and Old World monkeys. However, the anti-Gal antibody (~1% of immunoglobulins) is naturally generated in human, and is found as the immunoglobulin G (IgG), IgM and IgA isotypes. Owing to the specific binding of the anti-Gal antibody with the alpha-Gal epitope, humans have a distinct anti alpha-gal reactivity, which is responsible for hyperacute rejection of organs transplanted from alpha-gal donors. In addition, the alpha1,3 galactosyltransferases (alpha1,3GT) can catalyze the synthesis of the alpha-Gal epitope. Therefore, the alpha1,3GT gene, which encodes the alpha1,3GT, is developed profoundly. The distributions of the alpha-Gal epitope and anti-Gal antibody, and the activation of alpha1,3GT, reveal that the enzyme of alpha1,3GT in ancestral primates is ineffective. Comparison of the nucleotide sequence of the human alpha1,3-GT pseudogene to the corresponding different species sequence, and according to the evolutionary tree of different species, the results of evolutionary inactivation of the alpha1,3GT gene in ancestral primates attribute to the mutations under a stronger selective pressure. However, on the basis of the structure, the mechanism and the specificity of the alpha-Gal epitope and anti-Gal antibody, they can be applied to clinical exploitation. Knocking out the alpha1,3GT gene will eliminate the xenoantigen, Gal(alpha1,3)Gal, so that the transplantation of alpha1,3GT gene knockout pig organ into human becomes a potential clinically acceptable treatment for solving the problem of organ shortage. By contrast, the alpha-Gal epitope expressed through the application of chemical, biochemical and genetic engineering can be exploited for the clinical use. Targeting anti-Gal-mediated autologous tumor vaccines, which express alpha Gal epitope to antigen-presenting cells, would increase their immunogenicity and elicit an immune response, which will be potent enough to eradicate the residual tumor cells. For tumor vaccines, the way of increasing immunogenicity of certain viral vaccines, including flu vaccines and human immunodeficiency virus vaccines, can also be used in the elderly. Recently, alpha-Gal epitope nanoparticles have been applied to accelerate wound healing and further directions on regeneration of internally injured tissues. PMID- 26531138 TI - The pancreatic cancer secreted REG4 promotes macrophage polarization to M2 through EGFR/AKT/CREB pathway. AB - In the periphery of pancreatic ductal adenocarcinoma (PDAC), high accumulation of tumor-associated macrophages (TAMs), which exhibit M2 phenotype, has been shown to be correlated with extra-pancreatic invasion, lymph vessel invasion, lymph node involvement and shortened survival time. However, mechanisms by which tumor cells educate and reprogram TAMs remain largely unclear. The phenotype of TAMs in PDAC tissues was confirmed by immunofluoresence and confocal microscopy. Human CD14+ monocytes were incubated with recombinant human REG4 (rREG4) before being stimulated with LPS and IL-10 and IL-6 were measured with ELISA. A panel of M1 and M2 genes were measured by quantitative real-time PCR. Panc1, AsPC1 and BxPC3 cells were cultured in the conditioned medium (CM) and treated with REG4. The macrophages were infected with CREB shRNA or cultured by the CM of Panc1 cells infected with REG4 shRNA. The expression of CD163, CD206 and REG4 and the phosphorylation levels of epidermal growth factor receptor (EGFR), AKT and cAMP response element-binding protein (CREB) in cells were assessed with western blotting. Cell proliferation and invasiveness were also assessed. The rREG4 or the conditioned medium of Panc1 cells which secreted REG4 induced the polarization macrophages to M2 phenotype. Treatment of human macrophages with REG4 resulted in phosphorylation of EGFR, AKT and CREB. The latter was responsible for REG4-mediated macrophage polarization to M2. The conditioned medium of macrophages treated with rREG4 promoted the proliferation and invasion of pancreatic cancer cell lines. REG4, overexpressed in PDAC and secreted by cancer cells, promoted macrophage polarization to M2, through at least in part, activation of ERK1/2 and CREB and changed the microenvironment to facilitate cancer growth and metastasis. PMID- 26531139 TI - Retrospective evaluation of tooth injuries and associated factors at a hospital emergency ward. AB - BACKGROUND: The aim of study was to determine the occurrence of tooth injuries and associated factors among patients treated at a hospital emergency ward. METHODS: A cross-sectional study was conducted involving the analysis of 790 patient charts. The independent variables were gender, place of residence and type of accident. The dependent variable was tooth injury (fractures, concussion, luxation and avulsion). Statistical analysis involved the chi-square test, Poisson analysis and logistic regression. Explanatory variables with a p-value < 0.20 in the bivariate analysis were incorporated into the multivariate model. RESULTS: A total of 681 (86.2 %) patients had tooth injury, among whom 159 (20.1 %) had tooth fractures. Tooth concussion was associated with residence in urban areas (PR = 1.635; 95 % CI: 1.199-2.230), the male gender (PR = 1.673; 95 % CI: 1.225-2.285), violence (PR = 1.940; 95 % CI: 1.263-2.982) and sports (PR = 1.863; 95 % CI: 1.287-2.696). The prevalence rate of tooth fracture was higher among individuals having suffered a motorcycle (PR = 1.597; 95 % CI: 1.295-1.968) or bicycle accident (PR = 1.484; 95 % CI: 1.245-1.769). Victims of bicycle accidents had a 42.6-fold greater chance of suffering luxation (95 % CI: 20.917-86.808) and a threefold greater chance of suffering avulsion (95 % CI: 1.620-5.848). Victims of motorcycle accidents had a 2.96-fold greater chance of suffering avulsion (95 % CI: 1.471-5.937). CONCLUSIONS: In the study, concussion was the most frequent type of tooth injury. Motorcycle and bicycle accidents were associated with tooth fractures, luxation and avulsion, whereas sports and violence were associated with dental concussion. The findings on tooth injuries can contribute to public health policies regarding the prevention and health promotion measures. PMID- 26531140 TI - Myopia and diabetic retinopathy: A systematic review and meta-analysis. AB - AIMS: Myopia may have protective effects against diabetic retinopathy (DR). However, the data from epidemiologic studies are inconsistent. We aimed to examine the association between myopia and DR by conducting a meta-analysis. METHODS: We identified studies by searching the PubMed and EMBASE databases. Study-specific odds ratios (ORs) were pooled using a fixed or random effects model. Myopic eyes were defined as having a spherical equivalent (SE)<-0.5 diopters (D). Myopic SE, each diopter decrease in SE toward myopia, and each millimeter increase in axial length (AL) were used as independent surrogate variables for myopia. RESULTS: Data from 6 population-based and 3 clinic-based studies were included in the analyses. Myopic SE (compared with emmetropic eyes) and each millimeter increase in AL were associated with a decreased risk for DR (pooled odds ratio [OR], 0.80 and 0.79, respectively; 95% confidence interval [CI], 0.67-0.95 and 0.73-0.86, respectively; P=0.011 and 0.000, respectively). Each millimeter increase in AL was also associated with a decreased risk for vision-threatening diabetic retinopathy (VTDR) (pooled OR, 0.70; 95% CI, 0.60 0.82; P=0.000). No significant association between each diopter decrease in SE and DR was observed. CONCLUSIONS: Our meta-analysis suggests that individuals with myopia exhibit a decreased risk of developing DR or VTDR. An increased AL plays a critical role in this protective effect. PMID- 26531142 TI - A study of amplitude information-frequency characteristics for underwater active electrolocation system. AB - Weakly electric fish sense their surroundings in complete darkness by their active electrolocation system. For biologists, the active electrolocation system has been investigated for near 60 years. And for engineers, bio-inspired active electrolocation sensor has been investigated for about 20 years. But how the amplitude information response will be affected by frequencies of detecting electric fields in the active electrolocation system was rarely investigated. In this paper, an electrolocation experiment system has been built. The amplitude information-frequency characteristics (AIFC) of the electrolocation system for sinusoidal electric fields of varying frequencies have been investigated. We find that AIFC of the electrolocation system have relevance to the material properties and geometric features of the probed object and conductivity of surrounding water. Detect frequency dead zone (DFDZ) and frequency inflection point (FIP) of AIFC for the electrolocation system were found. The analysis model of the electrolocation system has been investigated for many years, but DFDZ and FIP of AIFC can be difficult to explain by those models. In order to explain those AIFC phenomena for the electrolocation system, a simple relaxation model based on Cole Cole model which is not only a mathematical explanation but it is a physical one for the electrolocation system was advanced. We also advance a hypothesis for physical mechanism of weakly electrical fish electrolocation system. It may have reference value for physical mechanism of weakly electrical fish active electrolocation system. PMID- 26531141 TI - CUG-BP1 regulates RyR1 ASI alternative splicing in skeletal muscle atrophy. AB - RNA binding protein is identified as an important mediator of aberrant alternative splicing in muscle atrophy. The altered splicing of calcium channels, such as ryanodine receptors (RyRs), plays an important role in impaired excitation-contraction (E-C) coupling in muscle atrophy; however, the regulatory mechanisms of ryanodine receptor 1 (RyR1) alternative splicing leading to skeletal muscle atrophy remains to be investigated. In this study we demonstrated that CUG binding protein 1 (CUG-BP1) was up-regulated and the alternative splicing of RyR1 ASI (exon70) was aberrant during the process of neurogenic muscle atrophy both in human patients and mouse models. The gain and loss of function experiments in vivo demonstrated that altered splicing pattern of RyR1 ASI was directly mediated by an up-regulated CUG-BP1 function. Furthermore, we found that CUG-BP1 affected the calcium release activity in single myofibers and the extent of atrophy was significantly reduced upon gene silencing of CUG-BP1 in atrophic muscle. These findings improve our understanding of calcium signaling related biological function of CUG-BP1 in muscle atrophy. Thus, we provide an intriguing perspective of involvement of mis-regulated RyR1 splicing in muscular disease. PMID- 26531143 TI - Assessment of the Biological Effects of a Multifunctional Nano-Drug-Carrier and Its Encapsulated Drugs. AB - Polymer-nanoparticle-encapsulated doxorubicin (DOX) and paclitaxel (TAX) have the potential for novel therapeutic use against cancer in the clinic. However, the systemic biological effect of the nanoparticle material, namely, methoxypoly(ethylene glycol)-poly(lactide-co-glycolide) (mPEG-PLGA), and its encapsulated drugs have not been fully studied. We have applied NMR-based metabonomics methodology to characterize and analyze the systemic metabolic changes in mice after being exposed to mPEG-PLGA, mPEG-PLGA-encapsulated DOX and TAX (NP-D/T), and their free forms. The study revealed that mPEG-PLGA exposure only induces temporary and slight metabolic alternations and that there are detoxification effects of nanoparticle packed with D/T drugs on the heart when comparing with free-form D/T drugs. Both NP-D/T and their free forms induce a shift in energy metabolism, stimulate antioxidation pathways, and disturb the gut microbial activity of the host. However, mPEG-PLGA packaging can relieve the energy metabolism inhibition and decrease the activation of antioxidation pathways caused by D/T exposure. These findings provide a holistic insight into the biological effect of polymer nanoparticle and nanoparticle-encapsulated drugs. This study also furthers our understanding of the molecular mechanisms involved in the amelioration effects of mPEG-PLGA packaging on the toxicity of the incorporated drugs. PMID- 26531144 TI - Accuracy Is Important-Re: Sensitivity and Specificity of the Phallometric Test for Hebephilia. PMID- 26531145 TI - [(18) F]-Fluorodeoxyglucose positron emission tomography combined with computed tomography imaging with remission of type 2 diabetes after gastric bypass surgery. PMID- 26531146 TI - Gas-Phase Unimolecular Dissociation Reveals Dominant Base Property of Protonated Homocysteine Sulfinyl Radical Ions. AB - Homocysteine sulfinyl radical ((SO?) Hcy) is a reactive intermediate involved during oxidative damage of DNA in the presence of high concentrations of homocysteine (Hcy). The short lifetime of (SO?) Hcy makes its preparation, isolation, and characterization challenging using traditional chemical measurement tools. Herein, we demonstrate the first study on mass-selected protonated (SO?) Hcy ions in the gas phase by investigating its unimolecular dissociation pathways from low energy collision-induced dissociation (CID). Tandem mass spectrometry (MS/MS), stable-isotope labeling, and theoretical calculations were employed to rationalize the observed fragmentation pathways. The dominant dissociation channel of protonated (SO?) Hcy was a charge-directed H2 O loss from the protonated sulfinyl radical (-SO?) moiety, forming a thiyl radical (-S?), which further triggered sequential radical-directed ?SH loss through multiple pathways. Compared to cysteine sulfinyl radical ((SO?) Cys), the small structural change induced by one additional methylene group in the side chain of (SO?) Hcy significantly promotes its base property while reducing the radical reactivity of sulfinyl radical. This observation provides new insight into studying reactions of (SO?) Hcy with biomolecules, which are critical in understanding toxicity induced by high levels of Hcy in biological conditions. PMID- 26531147 TI - Brain calcifications and primary hyperparathyroidism. PMID- 26531148 TI - Integrated analysis of microRNA and mRNA expression profiles in abdominal adipose tissues in chickens. AB - Excessive fat accretion is a crucial problem during broiler production. Abdominal fat weight (AbFW) and abdominal fat percentage (AbFP) are major phenotypic indices of fat traits. The present study used F2 females derived from a cross between Beijing-You and Cobb-Vantress chickens. Cohorts with extreme AbFP and AbFW phenotypes were chosen to construct high- and low-abdominal fat libraries (HAbF and LAbF, respectively) to investigate the expression profiles by RNA sequencing and microRNA (miRNA)-sequencing. Compared with the LAbF library, 62 differentially expressed miRNAs (DEMs) and 303 differentially expressed genes (DEGs) were identified in the HAbF birds. Integrated analysis of DEMs and DEGs showed that a total of 106 DEGs were identified as target genes for the 62 DEMs. These genes were designated as intersection genes, and 11 of these genes are involved in lipid metabolism pathways. The miRNA gga-miR-19b-3p accelerated the proliferation of preadipocytes, as well as adipocyte differentiation, by down- regulating ACSL1. These findings suggest that some strong candidate miRNAs and genes, important in relation to abdominal adipose deposition, were identified by the integrated analysis of DEMs and DEGs. These findings add to our current understanding of the molecular genetic controls underlying abdominal adipose accumulation in chickens. PMID- 26531149 TI - Development of surface immobilized 3-azidocoumarin-based fluorogenic probe via strain promoted click chemistry. AB - A new class of imaging probe, a fluorogenic version of 1, 3-dipolar cycloaddition of azides and alkynes has been developed. 3-azidocoumarin scaffolds were selectively immobilized on the DBCO modified bead surface via SPAAC and provide direct and strong fluorescence in fluorescence microscopy. This developed click on beads could be applied to label various biomolecules, such as nucleic acids, proteins and other molecules. To this end, 5'(7-hydroxy 3-azido coumarin) labelled DNA primer also displayed strong fluorescence upon successful immobilization on the bead surface. PMID- 26531150 TI - Benzo[7]annulene-based GluN2B selective NMDA receptor antagonists: Surprising effect of a nitro group in 2-position. AB - Benzo[7]annulen-7-amines 7 without further polar substituents have been reported as conformationally restricted Ro 25-6981 analogs and show unexpectedly high GluN2B affinity. Herein the corresponding 2-NO2 derivatives 8 were synthesized and pharmacologically evaluated. NO2 derivatives 8 show 5- to 10-fold higher GluN2B affinity than the unsubstituted ligands 7. Docking studies of ligands 7c and 8c reveal an important contribution of the 2-NO2-substituent in determining the binding pose and modulating the GluN2B affinity. PMID- 26531151 TI - Core chemotype diversification in the HIV-1 entry inhibitor class using field based bioisosteric replacement. AB - Demand remains for new inhibitors of HIV-1 replication and the inhibition of HIV 1 entry is an extremely attractive therapeutic approach. Using field-based bioisosteric replacements, we have further extended the chemotypes available for development in the HIV-1 entry inhibitor class. Moreover, using field-based disparity analysis of the compounds, 3D structure-activity relationships were derived that will be useful in the further development of these inhibitors towards clinical utility. PMID- 26531152 TI - Identification and optimisation of a series of tetrahydrobenzotriazoles as metabotropic glutamate receptor 5-selective positive allosteric modulators that improve performance in a preclinical model of cognition. AB - Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation. PMID- 26531153 TI - TCEB2 confers resistance to VEGF-targeted therapy in ovarian cancer. AB - Targeted therapy has revolutionized the therapeutic landscape in oncology in recent years and anti-VEGF agent has been approved for ovarian cancer (OC). Unfortunately, the efficacy of this treatment is limited due to the development of resistance, while the molecular mechanisms underlying OC resistance to anti VEGF therapy are less clear. In this study, we observed a differential response of OC cells to anti-VEGF agent bevacizumab (BV) by using xenograft models. Gene expression analysis showed that TCEB2 gene was significantly upregulated in the OC tumors with acquired resistance compared with the sensitive tumors. Further mechanism dissections demonstrated that TCEB2 played a critical role in the development of acquired resistance to BV in OC cells via promoting HIF-1alpha degradation and suppressing VEGF-A expression. In TCEB2 overexpressing cells, interleukin-8 (IL-8) was elevated and functioned as a compensatory angiogenesis signaling which was sensitive to IL-8 monoclonal antibody (IL-8 Ab). The combination of BV and IL-8 Ab exhibited synergistic effect of growth inhibition on both OC and endothelial cells. Thus, this study provides an alternative strategy of simultaneously targeting VEGF-A and IL-8 for combating OC. PMID- 26531154 TI - Tilt engineering of exchange coupling at G-type SrMnO3/(La,Sr)MnO3 interfaces. AB - With the recent realization of hybrid improper ferroelectricity and room temperature multiferroic by tilt engineering, "functional" octahedral tilting has become a novel concept in multifunctional perovskite oxides, showing great potential for property manipulation and device design. However, the control of magnetism by octahedral tilting has remained a challenging issue. Here a qualitative and quantitative tilt engineering of exchange coupling, one of the magnetic properties, is demonstrated at compensated G-type antiferromagnetic/ferromagnetic (SrMnO3/La2/3Sr1/3MnO3) interfaces. According to interfacial Hamiltonian, exchange bias (EB) in this system originates from an in plane antiphase rotation (a(-)) in G-type antiferromagnetic layer. Based on first principles calculation, tilt patterns in SrMnO3 are artificially designed in experiment with different epitaxial strain and a much stronger EB is attained in the tensile heterostructure than the compressive counterpart. By controlling the magnitude of octahedral tilting, the manipulation of exchange coupling is even performed in a quantitative manner, as expected in the theoretical estimation. This work realized the combination of tilt engineering and exchange coupling, which might be significant for the development of multifunctional materials and antiferromagnetic spintronics. PMID- 26531155 TI - Refining the treatment of membrane proteins by coarse-grained models. AB - Obtaining a quantitative description of the membrane proteins stability is crucial for understanding many biological processes. However the advance in this direction has remained a major challenge for both experimental studies and molecular modeling. One of the possible directions is the use of coarse-grained models but such models must be carefully calibrated and validated. Here we use a recent progress in benchmark studies on the energetics of amino acid residue and peptide membrane insertion and membrane protein stability in refining our previously developed coarse-grained model (Vicatos et al., Proteins 2014;82:1168). Our refined model parameters were fitted and/or tested to reproduce water/membrane partitioning energetics of amino acid side chains and a couple of model peptides. This new model provides a reasonable agreement with experiment for absolute folding free energies of several beta-barrel membrane proteins as well as effects of point mutations on a relative stability for one of those proteins, OmpLA. The consideration and ranking of different rotameric states for a mutated residue was found to be essential to achieve satisfactory agreement with the reference data. PMID- 26531156 TI - Depletion of Cks1 and Cks2 expression compromises cell proliferation and enhance chemotherapy-induced apoptosis in HepG2 cells. AB - The present study explored the oncogenic roles of overexpressed Cks1 and Cks2 in human hepatocellular carcinoma cells. Gene expression of Cks1 and Cks2 in HepG2 cells was disrupted by siRNA or increased by cDNA transfection. Cell proliferation was assayed by CCK-8 analysis and cell counting. Cisplatin-induced apoptosis after transfection was measured by flow cytometry using Annexin V/propidium iodide (PI) double staining. Cell cycle changes after transfection were determined by flow cytometry with PI staining. Protein levels of Akt and GSK 3beta were measured after transfection. The results revealed that HepG2 proliferation was decreased by depletion of endogenous Cks1 or Cks2, and increased by overexpression of Cks1 or Cks2. HepG2 apoptosis increased concordantly with the decline of Cks1 or Cks2 expression. Overexpression of Cks1 or Cks2 prevented cell apoptosis. Protein levels of p-Akt and p-GSK-3beta were downregulated after RNA interference of Cks1 or Cks2. In conclusion, Cks1 and Cks2 promoted proliferation and prevented apoptosis of HepG2 cells. The Akt/GSK 3beta-related PI3K/Akt signaling pathway may be a key signaling pathway that is involved in the regulation of cell growth and cell death. PMID- 26531157 TI - Genotyping of Campylobacter coli strains isolated in Brazil suggests possible contamination amongst environmental, human, animal and food sources. AB - Campylobacter coli and Campylobacter jejuni are two of the most common causative agents of food-borne gastroenteritis in numerous countries worldwide. In Brazil, campylobacteriosis is under diagnosed and under-reported, and few studies have molecularly characterized Campylobacter spp. in this country. The current study genotyped 63 C. coli strains isolated from humans (n512), animals (n521), food (n510) and the environment (n520) between 1995 and 2011 in Brazil. The strains were genotyped using pulsed-field gel electrophoresis (PFGE), sequencing the short variable region (SVR) of the flaA gene ( flaA-SVR) and high-resolution melting analysis (HRMA) of the clustered regularly interspaced short palindromic repeat (CRISPR) locus to better understand C. coli genotypic diversity and compare the suitability of these three methods for genotyping this species. Additionally, the discrimination index (DI) of each of these methods was assessed. Some C. coli strains isolated from clinical and non-clinical origins presented >=80 % genotypic similarity by PFGE and flaA-SVR sequencing. HRMA of the CRISPR locus revealed only four different melting profiles. In total, 22 different flaA-SVR alleles were detected. Of these, seven alleles, comprising gt1647-gt1653, were classified as novel. The most frequent genotypes were gt30 and gt1647. This distribution reveals the diversity of selected Brazilian isolates in comparison with the alleles described in the PubMLST database. The DIs for PFGE, flaA-SVR sequencing and CRISPR-HRMA were 0.986, 0.916 and 0.550, respectively. PFGE and flaA-SVR sequencing were suitable for subtyping C. coli strains, in contrast to CRISPR-HRMA. The high genomic similarity amongst some C. coli strains confirms the hypothesis that environmental and food sources potentially lead to human and animal contamination in Brazil. PMID- 26531158 TI - Group 9 bimetallic carbonyl permethylpentalene complexes. AB - We describe the synthesis, structure and bonding of the first iridium and rhodium permethylpentalene complexes, syn-[M(CO)2]2(MU:eta(5):eta(5)-Pn*) (M = Rh, Ir). In fact, [Ir(CO)2]2(MU:eta(5):eta(5)-Pn*) is the first iridium pentalene complex. An interesting preference for the isolation of the sterically more demanding syn isomer is observed and substantiated by DFT analysis. Upon photolysis, the rhodium analogue yields an unusual tetrameric species Rh4(CO)6(MU:eta(3):eta(5) Pn*)2 with bridging carbonyls and Rh-Rh bonds, which has been characterised by single crystal X-ray diffraction and by solution NMR spectroscopy. PMID- 26531159 TI - Kinship moderates the association between a demented individual's behavioral disturbance and a caregiver's burden: Findings from a national survey in Taiwan. AB - AIM: The present study aimed to assess the moderating role of kinship between the behavioral disturbance of care recipients (CRs) with dementia and the caregivers' (CGs') burden in Taiwan. METHODS: The data of 965 CG-CR dyads on the behavioral disturbance of CR with dementia, CG burden, CG kinship to CR and other relevant variables were obtained from the Assessment of the National Long-Term Care Need in Taiwan (ANLTCNT). To test the moderating effect of CG-CR kinship on the association between behavioral disturbance of CR and CG burden, a series of hierarchical multiple linear regression models were used after controlling for potential factors associated with CG burden. RESULTS: Different kinships had significant differences in terms of burden, except for relational burden. The interaction terms (of CRs' behavioral disturbance by kinship) were not significant on burden of time and emotional burden. On relational burden, the impact of CRs' behavioral disturbance on CG burden was significantly higher for a wife than for a daughter-in-law or a son. The impact of CRs' behavioral disturbance on financial burden was lower for a wife than for a daughter-in-law. In terms of the total burden, the impact of CRs' behavioral disturbance was higher for a daughter than for a son. CONCLUSION: These findings highlight the importance of CG kinship to CR moderating the association between the CRs' level of behavioral disturbance and the CGs' relational, financial, and total burden, when refining kinship-oriented interventions for community services to CRs with dementia and their CGs. Geriatr Gerontol Int 2016; 16: 1272-1280. PMID- 26531160 TI - Miniature Flow-Through Low-Temperature Plasma Ionization Source for Ambient Ionization of Gases and Aerosols. AB - The design and operation of an inexpensive, miniature low-temperature plasma ion source is detailed. The miniature low-temperature plasma ion source is operated in a "flow-through" configuration, wherein the gaseous or aerosolized analyte, caffeine or pyrolyzed ethyl cellulose, in a carrier gas is used as the plasma gas. In this flow-through configuration, the sensitivity for the caffeine standard and the pyrolysis products of ethyl cellulose is maintained or increased and the reproducibility of the ion source is increased. Changes in the relative intensity of ions from the aerosol produced by pyrolysis of ethyl cellulose are observed in the mass spectrum when the low-temperature plasma ion source is used in the flow-through configuration. Experiments suggest this change in relative intensity is likely due to differences in ionization efficiency rather than increased fragmentation of ethyl cellulose pyrolysis products during ionization. Flow-through low-temperature plasma ionization with the miniature ion source is shown to be a promising technique for the ionization of compounds in gases or aerosol particles. PMID- 26531161 TI - Glaucumolides A and B, Biscembranoids with New Structural Type from a Cultured Soft Coral Sarcophyton glaucum. AB - Glaucumolides A (1) and B (2), novel biscembranes composed of an unprecedented alpha,beta-unsaturated epsilon-lactone, along with the known metabolites ximaolide A (3) and isosarcophytonolide D (4), were isolated from the cultured soft coral Sarcophyton glaucum. The structures of the new metabolites were determined by extensive spectroscopic analyses. Compounds 1 and 2 were shown to exhibit cytotoxicity against a limited panel of cancer cell lines. In anti inflammation assay, compounds 1 and 2 displayed strong inhibition of superoxide anion generation and elastase release in human neutrophils stimulated by fMLP/CB. Furthermore, both 1 and 2 were shown to significantly inhibit the accumulation of the pro-inflammatory inducible nitric oxide synthase protein, and compounds 1-3 were found to effectively reduce the expression of cyclooxygenase-2 protein, in lipopolysaccharide-stimulated RAW264.7 macrophage cells. PMID- 26531162 TI - Genetic diversity in the plasticity zone and the presence of the chlamydial plasmid differentiates Chlamydia pecorum strains from pigs, sheep, cattle, and koalas. AB - BACKGROUND: Chlamydia pecorum is a globally recognised pathogen of livestock and koalas. To date, comparative genomics of C. pecorum strains from sheep, cattle and koalas has revealed that only single nucleotide polymorphisms (SNPs) and a limited number of pseudogenes appear to contribute to the genetic diversity of this pathogen. No chlamydial plasmid has been detected in these strains despite its ubiquitous presence in almost all other chlamydial species. Genomic analyses have not previously included C. pecorum from porcine hosts. We sequenced the genome of three C. pecorum isolates from pigs with differing pathologies in order to re-evaluate the genetic differences and to update the phylogenetic relationships between C. pecorum from each of the hosts. METHODS: Whole genome sequences for the three porcine C. pecorum isolates (L1, L17 and L71) were acquired using C. pecorum-specific sequence capture probes with culture independent methods, and assembled in CLC Genomics Workbench. The pairwise comparative genomic analyses of 16 pig, sheep, cattle and koala C. pecorum genomes were performed using several bioinformatics platforms, while the phylogenetic analyses of the core C. pecorum genomes were performed with predicted recombination regions removed. Following the detection of a C. pecorum plasmid, a newly developed C. pecorum-specific plasmid PCR screening assay was used to evaluate the plasmid distribution in 227 C. pecorum samples from pig, sheep, cattle and koala hosts. RESULTS: Three porcine C. pecorum genomes were sequenced using C. pecorum-specific sequence capture probes with culture independent methods. Comparative genomics of the newly sequenced porcine C. pecorum genomes revealed an increased average number of SNP differences (~11 500) between porcine and sheep, cattle, and koala C. pecorum strains, compared to previous C. pecorum genome analyses. We also identified a third copy of the chlamydial cytotoxin gene, found only in porcine C. pecorum isolates. Phylogenetic analyses clustered porcine isolates into a distinct clade, highlighting the polyphyletic origin of C. pecorum in livestock. Most surprising, we also discovered a plasmid in the porcine C. pecorum genome. Using this novel C. pecorum plasmid (pCpec) sequence, a) we developed a pCpec screening assay to evaluate the plasmid distribution in C. pecorum from different hosts; and b) to characterise the pCpec sequences from available previously sequenced C. pecorum genome data. pCpec screening showed that the pCpec is common in all hosts of C. pecorum, however not all C. pecorum strains carry pCpec. CONCLUSIONS: This study provides further insight into the complexity of C. pecorum epidemiology and novel genomic regions that may be linked to host specificity. C. pecorum plasmid characterisation may aid in improving our understanding of C. pecorum pathogenesis across the variety of host species this animal pathogen infects. PMID- 26531163 TI - Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma. AB - Kaposi sarcoma-associated herpesvirus (KSHV) is a principal causative agent of primary effusion lymphoma (PEL) with a poor prognosis in immunocompromised patients. However, it still lacks effective treatment which urgently requires the identification of novel therapeutic targets for PEL. Here, we report that the hepatocyte growth factor (HGF)/c-MET pathway is highly activated by KSHV in vitro and in vivo. The selective c-MET inhibitor, PF-2341066, can induce PEL apoptosis through cell cycle arrest and DNA damage, and suppress tumor progression in a xenograft murine model. By using microarray analysis, we identify many novel genes that are potentially controlled by HGF/c-MET within PEL cells. One of the downstream candidates, ribonucleoside-diphosphate reductase subunit M2 (RRM2), also displays the promising therapeutic value for PEL treatment. Our findings provide the framework for development of HGF/c-MET-focused therapy and implementation of clinical trials for PEL patients. PMID- 26531164 TI - Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform. AB - T-cell-directed killing of tumor cells using bispecific antibodies is a promising approach for the treatment of hematologic malignancies. Here we describe our preclinical work with a dual-affinity retargeting (DART) molecule generated from antibodies to CD3 and CD123, designed to redirect T cells against acute myeloid leukemia blasts. The CD3*CD123 DART (also referred to as MGD006/S80880) consists of 2 independent polypeptides, each composed of the VH of 1 antibody in tandem with the VL of the other antibody. The target antigen CD123 (interleukin 3RA) is highly and differentially expressed in acute myeloid leukemia (AML) blasts compared with normal hematopoietic stem and progenitor cells. In this study we demonstrate that the CD3*CD123 DART binds to both human CD3 and CD123 to mediate target-effector cell association, T-cell activation, proliferation, and receptor diversification. The CD3*CD123 DART also induces a dose-dependent killing of AML cell lines and primary AML blasts in vitro and in vivo. These results provide the basis for testing the CD3*CD123 DART in the treatment of patients with CD123(+) AML. PMID- 26531165 TI - Variability in thermal and phototactic preferences in Drosophila may reflect an adaptive bet-hedging strategy. AB - Organisms use various strategies to cope with fluctuating environmental conditions. In diversified bet-hedging, a single genotype exhibits phenotypic heterogeneity with the expectation that some individuals will survive transient selective pressures. To date, empirical evidence for bet-hedging is scarce. Here, we observe that individual Drosophila melanogaster flies exhibit striking variation in light- and temperature-preference behaviors. With a modeling approach that combines real world weather and climate data to simulate temperature preference-dependent survival and reproduction, we find that a bet hedging strategy may underlie the observed interindividual behavioral diversity. Specifically, bet-hedging outcompetes strategies in which individual thermal preferences are heritable. Animals employing bet-hedging refrain from adapting to the coolness of spring with increased warm-seeking that inevitably becomes counterproductive in the hot summer. This strategy is particularly valuable when mean seasonal temperatures are typical, or when there is considerable fluctuation in temperature within the season. The model predicts, and we experimentally verify, that the behaviors of individual flies are not heritable. Finally, we model the effects of historical weather data, climate change, and geographic seasonal variation on the optimal strategies underlying behavioral variation between individuals, characterizing the regimes in which bet-hedging is advantageous. PMID- 26531166 TI - Porcine epidemic diarrhea virus ORF3 gene prolongs S-phase, facilitates formation of vesicles and promotes the proliferation of attenuated PEDV. AB - Porcine epidemic diarrhea virus (PEDV) is a porcine enteropathogenic coronavirus that has received increasing attention since the emergence of a PEDV variant worldwide. Previous studies have shown that PEDV ORF3 encodes an ion channel protein. However, its influence on cell cycle and subcellular structure still require more research. In this study, we developed a Vero cell line that stably expresses PEDV ORF3 gene. Subcellular localization and influences of PEDV ORF3 on host cells were investigated. We further verified whether or not this gene enhances virus production. The results showed that PEDV ORF3 protein localizes in the cytoplasm and affects cell cycle progression by prolonging the S phase. In addition, the ORF3-expressing Vero cells had more vesicles than the host Vero cells. Furthermore, the attenuated PEDV rather than virulent PEDV could grow better in ORF3-expressing Vero cells. The expression level of the PEDV nucleocapsid protein also increased. These results provided information on the function of PEDV ORF3 and were helpful in understanding the mechanisms of PEDV replication. PMID- 26531167 TI - Potential advantages of the GuideLiner(r) catheter: insights from optical coherence tomography. AB - Optical coherence tomography (OCT) has been reported as promising not only for the evaluation of lesion morphology, but also for better clinical outcomes; however, in some cases with severe vessel tortuosity or angulated bifurcation, it is difficult to advance an intravascular imaging catheter. We report a case in which a GuideLiner(r) catheter facilitated obtaining better angiographic and OCT images with the sub-selective injection of minimal contrast medium, even in a case with a tortuous vessel or angulated bifurcation. Furthermore, OCT assessment of a vessel through the catheter may be other potential advantage of this device. PMID- 26531168 TI - Identification of Mutations Causing Aberrant Termination and Deficient Splice Donor Site on the HBA1 Gene. AB - alpha-Thalassemia (alpha-thal) is a common genetic disorder in Iran and many parts of the world. Genetic defects on the alpha-globin gene cluster can result in alpha-thal that may develop a clinical phenotype varying from almost asymptomatic to a lethal hemolytic anemia. In the present study, four Iranian individuals with hypochromic microcytic anemia, who revealed none of the known mutations responsible for alpha-thal, were subjected for further investigations. The thalassemic phenotype of these patients resulted from abnormal RNA splicing sites owing to a missense at the splice donor site, a truncated protein or hemoglobin (Hb) variants as a result of two different substitutions on the alpha1 globin gene. The clinical presentation of mild anemia in these individuals showed the contribution of these novel mutations in alpha-thal in spite of the dominantly expressed alpha2-globin gene. This study describes hematological manifestations of subjects carrying some novel mutations comparable to the reported phenotype of alpha(+)-thal trait. PMID- 26531169 TI - Development of a registration system for genetic counsellors and nurses in health care services in Europe. PMID- 26531170 TI - In vivo cancer targeting and fluorescence-CT dual-mode imaging with nanoprobes based on silver sulfide quantum dots and iodinated oil. AB - In this article, a fluorescence-CT dual-mode nanoprobe is successfully synthesized by making use of distearoylphosphatidylethanolamine-poly(ethylene glycol)-folate (DSPE-PEG2000-FA) and other amphiphilic molecules to coat silver sulfide (Ag2S) quantum dots (QDs) and iodinated oil simultaneously. In vitro experiments show that the fluorescence wavelength of the nanoprobe is 1170 nm in the near infrared-II region. Its size is 139.6 nm, it has good dispersibility, and it has low cellular toxicity at concentrations up to 25 MUg mL(-1) Ag. In vivo experiments revealed that the probe has a rather long circulation time (blood half-life of 5.7 hours), and the tissue histopathological tests show that it is not obviously harmful to major organs' normal function. Biochemical analysis (glutamic pyruvic transaminase and glutamic oxaloacetic transaminase levels) and blood analysis (white blood cell, red blood cell, hemoglobin and blood platelet counts) reveal that it has little influence on blood within 15 days of administration. When injected into HeLa xenograft nude mice by the tail vein, the probe elicited intensely enhanced fluorescence and X-ray computed tomography (CT) signals in the tumors after 24 hours, and the structure, size and position of tumor tissue were shown clearly. In a word, the probe has good tumor targeting capabilities, and it has significant value in fluorescence-CT dual-mode imaging in vivo. PMID- 26531171 TI - Effect of GnT-V knockdown on the proliferation, migration and invasion of the SMMC7721/R human hepatocellular carcinoma drug-resistant cell line. AB - Hepatocellular carcinoma (HCC) is a commonly occurring malignant tumor, with a high incidence rate. The present study aimed to investigate the effect of knocking down the N-glycosyltransferase-V (GnT-V) protein on the proliferation, migration and invasion of the human HCC drug-resistant cell line, SMMC7721/R. SMMC7721/R cells with GnT-V-knockdown (SMMC-7721/R-GnT-V) were constructed using the method of lentiviral transfection. The expression of GnT-V was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Cell proliferation was determined using an MTT assay, and the extent of cellular apoptosis was assessed using flow cytometric analysis. Additionally, the metastatic ability of the cells in vitro was analyzed using cell adhesion and invasion assays. Western blotting was used to investigate the protein expression levels of caspase-3, caspase-9, Bcl-2, Bax, matrix metalloproteinase (MMP)-2 and MMP-9, and RT-qPCR was used to determine the mRNA expression levels of the genes for the breast cancer resistance protein and P glycoprotein in the SMMC-7721/R cells. Taken together, the results of the present study revealed that the knockdown of GnT-V significantly suppressed the proliferation, migration and invasion (P<0.05) of the SMMC-7721/R cells. Furthermore, the possible mechanism underlying these phenomena may be associated with the induction of mitochondria-mediated apoptosis, inhibition of the degradation of the extracellular matrix and an enhancement of the drug sensitivity. GnT-V-knockdown may therefore be used to treat drug-resistant HCC in the future. PMID- 26531172 TI - Extraordinary high ductility/strength of the interface designed bulk W-ZrC alloy plate at relatively low temperature. AB - The refractory tungsten alloys with high ductility/strength/plasticity are highly desirable for a wide range of critical applications. Here we report an interface design strategy that achieves 8.5 mm thick W-0.5 wt. %ZrC alloy plates with a flexural strength of 2.5 GPa and a strain of 3% at room temperature (RT) and ductile-to-brittle transition temperature of about 100 degrees C. The tensile strength is about 991 MPa at RT and 582 MPa at 500 degrees C, as well as total elongation is about 1.1% at RT and as large as 41% at 500 degrees C, respectively. In addition, the W-ZrC alloy plate can sustain 3.3 MJ/m(2) thermal load without any cracks. This processing route offers the special coherent interfaces of grain/phase boundaries (GB/PBs) and the diminishing O impurity at GBs, which significantly strengthens GB/PBs and thereby enhances the ductility/strength/plasticity of W alloy. The design thought can be used in the future to prepare new alloys with higher ductility/strength. PMID- 26531173 TI - Cancer-related fatigue and physical activity among premenopausal cervical and endometrial cancer survivors in Japan. AB - PURPOSE: To examine the relationship between cancer-related fatigue (CRF) and physical activity in daily living in premenopausal disease-free cervical and endometrial cancer survivors. METHODS: A physical activity monitor was used to collect objective data on daily physical activity. CRF and related variables were measured using self-report scales in a cross-sectional manner. RESULTS: The average age was 44.9 years among 64 women. The higher CRF group comprised 22 women (34%), 10% of whom had severe fatigue. The participants had higher physical activity levels compared with the findings in previous studies, and reported an average of 40 min/day of moderate to vigorous activity. Moderate to vigorous levels of physical activity were derived from essential social activities rather than leisure time exercise. There were no significant differences in physical activity levels between the lower and higher CRF groups. CONCLUSION: Our study results suggested that the higher level of physical activity in daily living itself had no relationship with decreasing CRF among premenopausal cervical and endometrial cancer survivors. It would be better to focus on cognitive and psychological factors before introducing physical activity programs and be careful of the characteristics of the participants' physical activity among this population in daily basis. PMID- 26531174 TI - Physicians' perception of the "Guidelines for Obstetrical Practice in Japan" and the reasons for different compliances. AB - The "Guidelines for Obstetrical Practice in Japan" are the first consensus-based guidelines in the field of obstetrics and were published in 2008 owing to an obstetric medical care crisis in Japan. The Guidelines describe appropriate methods for obstetric care and were based on consensus among obstetricians in Japan. Originally, the Guidelines were not intended to be a rulebook to limit physician discretion; however, from a medical care litigation standpoint, medical practices that conform to the Guidelines are following the "medical standard". The present study aimed to investigate obstetricians' perceptions of the Guidelines, to assess the degree of compliance, and to consider the implication of physician discretion in medical litigation. A questionnaire exploring the perception of the Guidelines was completed by 341 obstetricians was conducted from February 2009 until May 2009; questionnaires were evaluated using simple aggregation, correlation analysis, and principal component analysis. Although more than 80% of physicians responded that content of the Guidelines was appropriate, only 34.7% complied with recommendation level A. Our findings suggest that the rate of compliance to the Guidelines should be improved, reasons for noncompliance should be clarified, and Guidelines that are easier for patients to understand should be drafted. PMID- 26531175 TI - The Orphan Receptor Tyrosine Kinase ROR2 Facilitates MSCs to Repair Lung Injury in ARDS Animal Model. AB - There are some limitations to the therapeutic effects of mesenchymal stem cells (MSCs) on acute respiratory distress syndrome (ARDS) due to their low engraftment and differentiation rates in lungs. We found previously that noncanonical Wnt5a signaling promoted the differentiation of mouse MSCs (mMSCs) into type II alveolar epithelial cells (AT II cells), conferred resistance to oxidative stress, and promoted migration of MSCs in vitro. As receptor tyrosine kinase-like orphan receptor 2 (ROR2) is an essential receptor for Wnt5a, it was reasonable to deduce that ROR2 might be one of the key molecules for the therapeutic effect of MSCs in ARDS. The mMSCs that stably overexpressed ROR2 or the green fluorescent protein (GFP) control were transplanted intratracheally into the ARDS mice [induced by intratracheal injection of lipopolysaccharide (LPS)]. The results showed that ROR2-overexpressing mMSCs led to more significant effects than the GFP controls, including the retention of the mMSCs in the lung, differentiation into AT II cells, improvement of alveolar epithelial permeability, improvement of acute LPS-induced pulmonary inflammation, and, finally, reduction of the pathological impairment of the lung tissue. In conclusion, MSCs that overexpress ROR2 could further improve MSC-mediated protection against epithelial impairment in ARDS. PMID- 26531176 TI - Investigation of benzoyloximes as benzoylating reagents: benzoyl-Oxyma as a selective benzoylating reagent. AB - Hydroxybenzotriazole (HOBt) and HOBt-derived reagents have been classified as Class I explosives, with restrictions on their transportation and storage. We explored a range of benzoylated oxime-based reagents as alternatives to benzoyloxybenzotriazole (BBTZ) for the selective benzoylation of carbohydrate polyols. Benzoylated oximes derived from 2-hydroximino-malononitrile, ethyl 2 hydroximino-2-cyanoacetate (Oxyma), and tert-butyl 2-hydroximino-2-cyanoacetate were most effective for benzoylation of a simple primary alcohol, with yields approaching that obtained for BBTZ. When applied to carbohydrate diols, the most effective reagent was identified as benzoyl-Oxyma. Benzoyl-Oxyma is a highly crystalline, readily prepared alternative to BBTZ, useful in the selective benzoylation of carbohydrate polyols. PMID- 26531177 TI - Fever in a Returning Traveler. PMID- 26531178 TI - Two-Year-Old Boy With Leukocoria and Strabismus. PMID- 26531179 TI - Hypertension in an Adolescent Athlete. PMID- 26531180 TI - Risk Factors for Failed Newborn Otoacoustic Emissions Hearing Screen. AB - Objective To identify any socioeconomic, demographic, neonatal, and perinatal factors that may be associated with failing the otoacoustic emissions (OAE) newborn hearing screen. Study Design A retrospective chart review was performed looking at hearing screens performed on 1272 newborn infants by OAE testing. Socioeconomic, demographic, neonatal, and perinatal factors were reviewed to determine association with failing the OAE newborn hearing screen. Results Our results demonstrate that Hispanic race was significantly associated with failing the newborn OAE hearing screen with an odds ratio of 2.54 (CI = 1.56-4.14, P = .0002). Family history of hearing loss was also significantly associated with failing the newborn hearing screen. Newborns with a family history of hearing loss were 13 times more likely to fail the newborn screen (odds ratio = 13.63, CI = 4.09-45.43, P < .0001). Conclusions Hispanic race and family history of hearing loss are statistically significant risk factors for failing the newborn OAE hearing screen. PMID- 26531181 TI - The edge artifact in the point-spread function-based PET reconstruction at different sphere-to-background ratios of radioactivity. AB - OBJECTIVE: The aim of this study was to quantitatively evaluate the edge artifacts in PET images reconstructed using the point-spread function (PSF) algorithm at different sphere-to-background ratios of radioactivity (SBRs). METHODS: We used a NEMA IEC body phantom consisting of six spheres with 37, 28, 22, 17, 13 and 10 mm in inner diameter. The background was filled with (18)F solution with a radioactivity concentration of 2.65 kBq/mL. We prepared three sets of phantoms with SBRs of 16, 8, 4 and 2. The PET data were acquired for 20 min using a Biograph mCT scanner. The images were reconstructed with the baseline ordered subsets expectation maximization (OSEM) algorithm, and with the OSEM + PSF correction model (PSF). For the image reconstruction, the number of iterations ranged from one to 10. The phantom PET image analyses were performed by a visual assessment of the PET images and profiles, a contrast recovery coefficient (CRC), which is the ratio of SBR in the images to the true SBR, and the percent change in the maximum count between the OSEM and PSF images (Delta % counts). RESULTS: In the PSF images, the spheres with a diameter of 17 mm or larger were surrounded by a dense edge in comparison with the OSEM images. In the spheres with a diameter of 22 mm or smaller, an overshoot appeared in the center of the spheres as a sharp peak in the PSF images in low SBR. These edge artifacts were clearly observed in relation to the increase of the SBR. The overestimation of the CRC was observed in 13 mm spheres in the PSF images. In the spheres with a diameter of 17 mm or smaller, the Delta % counts increased with an increasing SBR. The Delta % counts increased to 91 % in the 10-mm sphere at the SBR of 16. CONCLUSIONS: The edge artifacts in the PET images reconstructed using the PSF algorithm increased with an increasing SBR. In the small spheres, the edge artifact was observed as a sharp peak at the center of spheres and could result in overestimation. PMID- 26531182 TI - Asparagine requirement in Plasmodium berghei as a target to prevent malaria transmission and liver infections. AB - The proteins of Plasmodium, the malaria parasite, are strikingly rich in asparagine. Plasmodium depends primarily on host haemoglobin degradation for amino acids and has a rudimentary pathway for amino acid biosynthesis, but retains a gene encoding asparagine synthetase (AS). Here we show that deletion of AS in Plasmodium berghei (Pb) delays the asexual- and liver-stage development with substantial reduction in the formation of ookinetes, oocysts and sporozoites in mosquitoes. In the absence of asparagine synthesis, extracellular asparagine supports suboptimal survival of PbAS knockout (KO) parasites. Depletion of blood asparagine levels by treating PbASKO-infected mice with asparaginase completely prevents the development of liver stages, exflagellation of male gametocytes and the subsequent formation of sexual stages. In vivo supplementation of asparagine in mice restores the exflagellation of PbASKO parasites. Thus, the parasite life cycle has an absolute requirement for asparagine, which we propose could be targeted to prevent malaria transmission and liver infections. PMID- 26531183 TI - Patient-reported allergies cause inferior outcomes after total knee arthroplasty. AB - PURPOSE: The main objective of this study was to analyse the outcomes after total knee arthroplasty (TKA) of a group of patients with at least one self-reported allergy and a group of patients without reported allergies. We hypothesized there is a significant negative influence on clinical outcome scores after TKA in patients with self-reported allergies. METHODS: Four-hundred and seventy-five patients who had undergone TKA were analysed preoperatively and 1 year after surgery. The WOMAC, KSS and SF-36 scores were obtained. The patients' Yesavage depression questionnaire score was also recorded. The scores of the 330 (69.5 %) patients without self-reported allergies were compared to the scores of the 145 (30.5 %) patients with at least one self-reported allergy in the medical record. RESULTS: Preoperative scores were similar in both groups. The WOMAC post operative scores (23.6 vs 20.4; p = 0.037) and the KSS-Knee score (91.1 vs 87.6; p = 0.027) were worse in the group of patients with self-reported allergies than in the group without allergies. The scores from the Yesavage depression questionnaire and in the SF-36 were similar in both groups. CONCLUSION: Patients with at least one self-reported allergy have worse post-operative outcomes in terms of the WOMAC and KSS-Knee scores after TKA than patients without allergies. These poor outcomes do not seem to be related to depression. Therefore, more research is needed to explain them. Reported allergies could be considered a prognostic factor and used when counselling TKA patients. LEVEL OF EVIDENCE: I. PMID- 26531184 TI - Age does not affect the clinical and radiological outcomes after open-wedge high tibial osteotomy. AB - PURPOSE: Open-wedge high tibial osteotomy (OWHTO) is a well-established procedure in the management of medial compartment osteoarthritis and osteonecrosis of the medial femoral condyle. Several studies have evaluated factors that negatively influence outcomes. However, few reports have investigated the effect of age on HTO outcome. We evaluated the influence of the age on the outcome after HTO. METHODS: The TomoFix(r) plate was used to perform 60 consecutive OWHTOs. Twenty six knees in 23 patients >65 years old (mean age at surgery 68.7 +/- 2.9 years; range 65-75 years, group A) were compared with 34 knees in 27 patients <65 years old (mean age at surgery 56.2 +/- 7.5 years; range 38-64 years, group B) with respect to the clinical and radiological outcomes after HTO. The clinical evaluation included the Japanese Orthopedic Association Knee Score (JOA score), Oxford Knee Score (OKS) and complications after surgery. RESULTS: There were no statistical differences in the background factors between the two groups. Postoperatively, the mean JOA score showed a significant improvement in both groups. The mean OKS after surgery was 41.6 +/- 5.9 in group A and 41.4 +/- 5.9 in group B. There were no statistical differences in the postoperative knee alignment and clinical outcomes between the two groups. CONCLUSION: OWHTO using the rigid long plate was an effective procedure independent of patient's age. The results showed that age did not influence the clinical and radiological outcomes after OWHTO. PMID- 26531185 TI - Influence of mediolateral tibial baseplate position in TKA on knee kinematics and retropatellar pressure. AB - PURPOSE: Anterior knee pain is a major reason for unsatisfied patients after total knee arthroplasty (TKA). Since malposition and increased retropatellar peak pressure are supposed to contribute to pain, we conducted this in vitro study to analyse the influence of mediolateral tibial component position on tibiofemoral and patella kinematics as well as retropatellar pressure. METHODS: Eight fresh frozen cadaver specimens were tested after a fixed-bearing TKA. To evaluate the influence of mediolateral tibial component position, special inlays with 3 mm of medialization and lateralization were constructed. For the analysis, a weight bearing knee rig under a loaded squat from 20 degrees to 120 degrees of flexion was used. Tibiofemoral and patella kinematics were measured with an ultrasonic based three-dimensional motion analysis system. Additionally, retropatellar pressure distribution was registered with a pressure-sensitive film. RESULTS: Alteration of mediolateral tibial component position by 3 mm did not reveal a significant influence on retropatellar peak pressure (7.5 +/- 2.5 vs. 7.2 +/- 2.6 MPa). Regarding tibiofemoral kinematics, 3-mm medialization of the tibial baseplate significantly increased lateral femoral rollback and femorotibial external rotation. Medialization of 3 mm also significantly increased the relative medial patella shift and decreased lateral patella tilt. DISCUSSION: Medialization of the tibial baseplate came along with more lateral rollback and external femorotibial rotation. For the positioning of the tibial baseplate, rotational alignment seems to be more important than mediolateral orientation. Since retropatellar peak pressure remained rather unchanged, the tibial baseplate should be placed by the surgeon looking for a maximal tibial coverage without overhang. PMID- 26531186 TI - Protocol for a randomised controlled trial of fetal scalp blood lactate measurement to reduce caesarean sections during labour: the Flamingo trial [ACTRN12611000172909]. AB - BACKGROUND: The rate of caesarean sections around the world is rising each year, reaching epidemic proportions. Although many caesarean sections are performed for concerns about fetal welfare on the basis of abnormal cardiotocography, the majority of babies are shown to be well at birth, meaning that the operation, with its inherent short and long term risks, could have been avoided without compromising the baby's health. Previously, fetal scalp blood sampling for pH estimation was performed in the context of an abnormal cardiotocograph, to improve the identification of babies in need of expedited delivery. This test has largely been replaced by lactate measurement, although its validity is yet to be established through a randomised controlled trial. This study aims to test the hypothesis that the performance of fetal scalp blood lactate measurement for women in labour with an abnormal cardiotocograph will reduce the rate of birth by caesarean section from 38 % to 25 % (a 35 % relative reduction). METHODS/DESIGN: Prospective unblinded randomised controlled trial conducted at a single tertiary perinatal centre. Women labouring with a singleton fetus in cephalic presentation at 37 or more weeks' gestation with ruptured membranes and with an abnormal cardiotocograph will be eligible. Participants will be randomised to one of two groups: fetal monitoring by cardiotocography alone, or cardiotocography augmented by fetal scalp blood lactate analysis. Decisions regarding the timing and mode of delivery will be made by the treating team, in accordance with hospital protocols. The primary study endpoint is caesarean section with secondary outcomes collected from maternal, fetal and neonatal clinical course and morbidities. A cost effectiveness analysis will also be performed. A sample size of 600 will provide 90 % power to detect the hypothesised difference in the proportion of women who give birth by caesarean section. DISCUSSION: This world first trial is adequately powered to determine the impact of fetal scalp blood lactate measurement on rates of caesarean section. Preventing unnecessary caesarean sections will reduce the health and financial burdens associated with this operation, both in the index and any future pregnancies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611000172909. PMID- 26531187 TI - Demographic, tumor and clinical features of clinical trials versus clinical practice patients with HER2-positive early breast cancer: results of a prospective study. AB - BACKGROUND: Several randomized clinical trials (RCTs) have demonstrated the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancer (BC). However, RCT patients may not invariably be representative of patients routinely seen in clinical practice (CP). To address this issue, we compared the clinical and tumor features of RCT and CP patients with HER2-positive BC. PATIENTS AND METHODS: From January to December 2012, 650 consecutive patients with HER2-positive early BC, treated in 36 different types of Italian healthcare facilities, were enrolled in this study. Age, treatment, tumor size (T), nodes (N), grade (G), estrogen receptor (ER) and progesterone receptor (PgR) status were prospectively collected in these CP patients. The same data were extracted from the main adjuvant trastuzumab RCTs and pooled using the random-effects model of DerSimonian and Laird. RCT and CP patients were compared by using the Cochran Q statistics. RESULTS: Versus RCT patients, CP patients were more likely to be older than 50 years (65 vs. 49 %; p < 0.0001) and to have HR (ER and/or PgR) positive (72 vs. 54 %; p < 0.0001) BC and less likely to have tumor >2 cm (T >= 2 cm 39 vs. 59 %; p < 0.0001), positive N (47 vs. 89 %; p < 0.0001) and a high G (61 vs. 67 %; p = 0.0241). CP patients more frequently received adjuvant endocrine therapy (70 vs. 57 %; p < 0.0003) and less frequently adjuvant chemotherapy (97 vs. 99.7 %; p < 0.0001). CONCLUSIONS: Most tumor and clinical features differed significantly between CP and RCT patients. These data raise concerns about the applicability of RCT results to CP patients. PMID- 26531188 TI - Disseminated cutaneous Curvularia infection in an immunocompromised host; diagnostic challenges and experience with voriconazole. AB - An increasing spectrum and number of opportunistic fungal pathogens have been reported to cause disease in humans over the past decade. Disseminated phaeohyphomycoses caused by rare dematiaceous molds in immunocompromised patients have a high mortality rate and are increasingly reported in the literature. Early diagnosis of disseminated phaehyphomycosis is critical especially in neutropenic patients but can be hindered by the low sensitivity of fungal blood cultures and low clinical suspicion. Cutaneous manifestations are often the earliest sign of disease and conducting a thorough skin exam in febrile neutropenic patients can lead to more rapid diagnosis and initiation of treatment. PCR amplification and sequencing of mold RNA extracted from paraffin-embedded tissue can be useful for diagnosing rare fungal infections when negative fungal cultures preclude morphologic diagnosis. Effective treatment for disseminated phaehyphomycosis is lacking and there is a need to report experiences with the use of newer antifungals. PMID- 26531189 TI - An equality impact assessment of the new junior doctor contract? PMID- 26531190 TI - Actor-Network Theory as a sociotechnical lens to explore the relationship of nurses and technology in practice: methodological considerations for nursing research. AB - Actor-Network Theory is a research lens that has gained popularity in the nursing and health sciences domains. The perspective allows a researcher to describe the interaction of actors (both human and non-human) within networked sociomaterial contexts, including complex practice environments where nurses and health technology operate. This study will describe Actor-Network Theory and provide methodological considerations for researchers who are interested in using this sociotechnical lens within nursing and informatics-related research. Considerations related to technology conceptualization, levels of analysis, and sampling procedures in Actor-Network Theory based research are addressed. Finally, implications for future nursing research within complex environments are highlighted. PMID- 26531191 TI - Nonmelanoma subungual malignancies: A case-based review of radiation therapy. PMID- 26531192 TI - Comparison of two electronic apex locators on human cadavers. AB - OBJECTIVE: The aim of this study on human cadavers was to compare the accuracy of two electronic apex locators (EALs) Dentaport ZX (J. Morita Corporation, Tokyo, Japan) and Raypex 6 (VDW, Munich, Germany). MATERIALS AND METHODS: Twenty-two single rooted teeth of four human cadaver heads were scheduled for this study. Before the extraction, an access cavity was opened and the crown was cut to establish a stable reference point for all measurements. The working length determination was performed with Dentaport ZX and Raypex 6 in the presence or not of 5.25 % sodium hypochlorite (SH) using a k-file 10. The teeth were then extracted and the real working length (RWL) was measured under a stereomicroscope at *30 magnification. The difference between the two working lengths was calculated: positive values indicate measurements exceeding the foramen, while negative values indicated measurements short of the foramen. The data were analyzed with a t test analysis. RESULTS: The mean of distances was 0.33 +/- 0.20 mm and 0.32 +/- 0.2 mm for Dentaport ZX respectively in the presence or not of SH and 0.38 +/- 0.20 mm and 0.39 +/- 0.19 mm for Raypex 6. No statistical differences were found between the two devices (p > 0.05). CONCLUSIONS: Both apex locators showed a high accuracy in the presence or not of SH. CLINICAL RELEVANCE: Both electronic apex locators can be recommended for clinical use and their accuracy is not affected by SH. PMID- 26531193 TI - Intermittent or continuous ultrasonically activated irrigation: micro-computed tomographic evaluation of root canal system cleaning. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy of two passive ultrasonic irrigation (PUI) methods and conventional manual irrigation (CMI) in root canal system (RCS) cleaning. MATERIALS AND METHODS: Artificial single-rooted teeth were used. Four lateral canals were made 2 and 7 mm short from the apex. Root canals were filled with a contrast solution. The specimens were divided into four groups (n = 8): PUI1-intermittent flushing; PUI2-continuous flushing; CMI1 at 1 mm; and CMI2-at 3 mm. Micro-computed tomographic images were obtained. New images were taken after the irrigation protocols enabling the evaluation of the contrast solution volume (in mm(3)) within RCS (main and lateral root canals) in comparison to the initial analysis. The comparison among groups was performed using ANOVA and Tukey's tests with 5 % significance level. RESULTS: There was no difference among PUI1, PUI2, and CMI1 regarding the contrast solution removal from RCS (p > 0.05). These methods demonstrated greater cleaning than CMI2. At the apical third, CMI2 showed lower cleaning capacity when compared to the other methods (p < 0.05). CONCLUSIONS: PUI with intermittent or continuous flushing and CMI with the needle placed 1 mm from the working length were efficient in cleaning the main and lateral root canals. CLINICAL RELEVANCE: Root canal irrigation plays an important role in cleaning and disinfection of the RCS. Effective apical irrigation is an important procedure during root canal treatment. PUI and CMI (at 1 mm short) were effective in cleaning of the main and simulated lateral root canals. PMID- 26531194 TI - Muscarinic M1 receptors modulate endotoxemia-induced loss of synaptic plasticity. AB - Septic encephalopathy is associated with rapid deterioration of cortical functions. Using magnetic resonance imaging (MRI) we detected functional abnormalities in the hippocampal formation of patients with septic delirium. Hippocampal dysfunction was further investigated in an animal model for sepsis using lipopolysaccharide (LPS) injections to induce endotoxemia in rats, followed by electrophysiological recordings in brain slices. Endotoxemia induced a deficit in long term potentiation which was completely reversed by apamin, a blocker of small conductance calcium-activated potassium (SK) channels, and partly restored by treatment with physostigmine (eserine), an acetylcholinesterase inhibitor, or TBPB, a selective M1 muscarinic acetylcholine receptor agonist. These results suggest a novel role for SK channels in the etiology of endotoxemia and explain why boosting cholinergic function restores deficits in synaptic plasticity. Drugs which enhance cholinergic or M1 activity in the brain may prove beneficial in treatment of septic delirium in the intensive care unit. PMID- 26531195 TI - SHV-129: A Gateway to Global Suppressors in the SHV beta-Lactamase Family? AB - Enzymes are continually evolving in response to environmental pressures. In order to increase enzyme fitness, amino acid substitutions can occur leading to a changing function or an increased stability. These evolutionary drivers determine the activity of an enzyme and its success in future generations in response to changing conditions such as environmental stressors or to improve physiological function allowing continual persistence of the enzyme. With recent warning reports on antibiotic resistance and multidrug resistant bacterial infections, understanding the evolution of beta-lactamase enzymes, which are a large contributor to antibiotic resistance, is increasingly important. Here, we investigated a variant of the SHV beta-lactamase identified from a clinical isolate of Escherichia coli in 2011 (SHV-129, G238S-E240K-R275L-N276D) to identify the first instance of a global suppressor substitution in the SHV beta lactamase family. We have used this enzyme to show that several evolutionary principles are conserved in different class A beta-lactamases, such as active site mutations reducing stability and requiring compensating suppressor substitutions in order to ensure evolutionary persistence of a given beta lactamase. However, the pathway taken by a given beta-lactamase in order to reach its evolutionary peak under a given set of conditions is likely different. We also provide further evidence for a conserved stabilizing substitution among class A beta-lactamases, the back to consensus M182T substitution. In addition to expanding the spectrum of beta-lactamase activity to include the hydrolysis of cefepime, the amino acid substitutions found in SHV-129 provide the enzyme with an excess of stability, which expands the evolutionary landscape of this enzyme and may result in further evolution to potentially include resistance to carbapenems or beta-lactamase inhibitors. PMID- 26531196 TI - Feasibility of joystick guided colonoscopy. AB - The flexible endoscope is increasingly used to perform minimal invasive interventions. A novel add-on platform allows single-person control of both endoscope and instrument at the site of intervention. The setup changes the current routine of handling the endoscope. This study aims to determine if the platform allows effective and efficient manipulation to position the endoscope at potential intervention sites throughout the bowel. Five experts in flexible endoscopy first performed three colonoscopies on a computer simulator using the conventional angulation wheels. Next they trained with the joystick interface to achieve their personal level of intubation time with low pain score. 14 PhD students (novices) without hands-on experience performed the same colonoscopy case using either the conventional angulation wheels or joystick interface. Both novice groups trained to gain the average expert level. The cecal intubation time, pain score and visualization performance (% of bowel wall) were recorded. All experts reached their personal intubation time in 6 +/- 6 sessions. Three experts completed their learning curve with low pain score in 8 +/- 6 sessions. The novices required 11 +/- 6 sessions using conventional angulation wheels, and 12 +/- 6 sessions using the joystick interface. There was no difference in the visualization performance between the novice and between the expert groups. This study shows that the add-on platform enables endoscope manipulation required to perform colonoscopy. Experts need only a relatively short training period. Novices are as effective and as efficient in endoscope manipulation when comparing the add-on platform with conventional endoscope control. PMID- 26531197 TI - Virtual reality robotic surgery simulation curriculum to teach robotic suturing: a randomized controlled trial. AB - The objective of this randomized, controlled trial was to assess whether voluntary participation in a proctored, proficiency-based, virtual reality robotic suturing curriculum using the da Vinci((r)) Skills SimulatorTM improves robotic suturing performance. Residents and attending surgeons were randomized to participation or non-participation during a 5 week training curriculum. Robotic suturing skills were evaluated before and after training using an inanimate vaginal cuff model, which participants sutured for 10 min using the da Vinci((r)) Surgical System. Performances were videotaped, anonymized, and subsequently graded independently by three robotic surgeons. 27 participants were randomized. 23 of the 27 completed both the pre- and post-test, 13 in the training group and 10 in the control group. Mean training time in the intervention group was 238 +/- 136 min (SD) over the 5 weeks. The primary outcome (improvement in GOALS+ score) and the secondary outcomes (improvement in GEARS, total knots, satisfactory knots, and the virtual reality suture sponge 1 task) were significantly greater in the training group than the control group in unadjusted analysis. After adjusting for lower baseline scores in the training group, improvement in the suture sponge 1 task remained significantly greater in the training group and a trend was demonstrated to greater improvement in the training group for the GOALS+ score, GEARS score, total knots, and satisfactory knots. PMID- 26531198 TI - Robotic versus laparoscopic surgery for mid or low rectal cancer in male patients after neoadjuvant chemoradiation therapy: comparison of short-term outcomes. AB - The aim of our study was to compare short-term outcomes of robotic and laparoscopic sphincter-saving total mesorectal excision (TME) in male patients with mid-low rectal cancer (RC) after neadjuvant chemoradiotherapy (NCRT). The study was conducted as a retrospective review of a prospectively maintained database, and we analyzed 14 robotic and 65 laparoscopic sphincter saving TME (R TME and L-TME, respectively) performed by one surgeon between 2005 and 2013. Patient characteristics, perioperative recovery, postoperative complications and and pathology results were compared between the two groups. The patient characteristics did not differ significantly between the two groups. Median operating time was longer in the R-TME than in the L-TME group (182 min versus 140 min). Only two conversions occurred in the L-TME group. No difference was found between groups regarding perioperative recovery and postoperative complication rates. The median number of harvested lymph nodes was higher in the RTME than in the L-TME group (32 versus 23, p = 0.008). The median circumferential margin (CRM) was 10 mm in the R-TME group, 6.5 mm in the L-TME group (p = 0.047. The median distal resection margin (DRM) was 27.5 mm in the R TME, 15 mm in the L-TME group (p = 0.014). Macroscopic grading of the specimen in the R-TME group was complete in all patients. In the L-TME group, grading was complete in 52 (80%) and incomplete in 13 (20%) cases (p = 0.109). R-TME is a safe and feasible procedure that facilitates performing of TME in male patients with mid-low RC after NCRT. PMID- 26531199 TI - Postoperative rhabdomyolysis following robotic renal and adrenal surgery: a cautionary tale of compounding risk factors. AB - This study aimed at reviewing a contemporary series of patients who underwent robotic renal and adrenal surgery by a single surgeon at a tertiary referral academic medical center over a 6-year period, specifically focusing on the unique and serious complication of post-operative rhabdomyolysis of the dependent lower extremity. The cases of 315 consecutive patients who underwent robotic upper tract surgery over a 6-year period from August 2008 to June 2014 using a standardized patient positioning were reviewed and analyzed for patient characteristics and surgical variables that may be associated with the development of post-operative rhabdomyolysis. The incidence of post-operative rhabdomyolysis in our series was 3/315 (0.95%). All three affected patients had undergone robotic nephroureterectomy. Those patients who developed rhabdomyolysis had significantly higher mean Body Mass Index, Charlson Comorbidity Index, and median length of stay than those who did not. The mean OR time in the rhabdomyolysis group was noted to be 52 min longer than the non-rhabdomyolysis group, though this value did not reach statistical significance. Given the trends of increasing obesity in the United States and abroad as well as the continued rise in robotic upper tract urologic surgeries, urologists need to be increasingly vigilant for recognizing the risk factors and early treatment of the unique complication of post-operative rhabdomyolysis. PMID- 26531200 TI - Oncological outcomes following robotic-assisted radical prostatectomy in a multiracial Asian population. AB - This study evaluates the oncological outcomes of RARP in a multiracial Asian population from a single institution. All suitable patients from 1st January 2003 30th June 2013 were identified from a prospectively maintained cancer registry. Peri-operative and oncological outcomes were analysed. Significance was defined as p < 0.05. There were n = 725 patients identified with a mean follow-up duration 28 months. The mean operative time, EBL and LOS were 186 min, 215 ml and 3 days, respectively. The pathological stage was pT2 in 68.6% (n = 497/725), pT3 in 31.3% (n = 227/725) and n = 1 patient with pT4 disease. The pathological Gleason scores (GS) were 6 in 27.9% (n = 202/725), GS 7 in 63.6% (n = 461/725) and GS >= 8 in 8.0 % (n = 58/725). The node positivity rate was 5.8% (n = 21/360). The positive margin rates were 31.0% (n = 154/497) and 70.9% (n = 161/227) for pT2 and pT3, respectively, and decreasing PSM rates are observed with surgical maturity. The biochemical recurrence rates were 9.7% (n = 48/497) and 34.2% (n = 78/228) for pT2 and pT3/T4, respectively. On multivariate analysis, independent predictors of BCR were pathological T stage and pathological Gleason score. Post-operatively, 78.5% (n = 569/725) of patients had no complications and 17.7% (n = 128/725) had minor (Clavien grade I-II) complications. This series, representing the largest from Southeast Asia, suggests that RARP can be a safe and oncologically feasible treatment for localised prostate cancer in an institution with moderate workload. PMID- 26531201 TI - Concurrent use of a robotic uterine manipulator and a robotic laparoscope holder to achieve assistant-less solo laparoscopy: the double ViKY. AB - Three patients requiring gynecological surgery had uterine manipulation using a VCare((r)) controlled by a ViKY((r)) at the same time as having a ViKY((r)) robotic arm controlling the laparoscope. The setup time for each varied from 6-9 min for the uterine manipulator and 3-5 min for the laparoscope holder. In all cases (one endometriosis and two dermoid cysts) the operative field was good. Two patients were discharged within 24 h of surgery. One patient required an extra day in hospital after she went into acute urinary retention once the catheter was removed. This work demonstrated that assistant-less solo gynecological surgery is feasible using two ViKY robotic arms for both uterine manipulation and laparoscope holding. PMID- 26531202 TI - Robotic surgery and hemostatic agents in partial nephrectomy: a high rate of success without vascular clamping. AB - Robot-assisted partial nephrectomy has been proposed as a technique to overcome technical challenges of laparoscopic partial nephrectomy. We prospectively collected and analyzed data from 31 patients who underwent robotic partial nephrectomy with systematic use of hemostatic agents, between February 2009 and October 2014. Thirty-three renal tumors were treated in 31 patients. There were no conversions to open surgery, intraoperative complications, or blood transfusions. The mean size of the resected tumors was 27 mm (median 20 mm, range 5-40 mm). Twenty-seven of 33 lesions (82%) did not require vascular clamping and therefore were treated in the absence of ischemia. All margins were negative. The high partial nephrectomy success rate without vascular clamping suggests that robotic nephron-sparing surgery with systematic use of hemostatic agents may be a safe, effective method to completely avoid ischemia in the treatment of selected renal masses. PMID- 26531203 TI - Augmented reality and cone beam CT guidance for transoral robotic surgery. AB - In transoral robotic surgery preoperative image data do not reflect large deformations of the operative workspace from perioperative setup. To address this challenge, in this study we explore image guidance with cone beam computed tomographic angiography to guide the dissection of critical vascular landmarks and resection of base-of-tongue neoplasms with adequate margins for transoral robotic surgery. We identify critical vascular landmarks from perioperative c-arm imaging to augment the stereoscopic view of a da Vinci si robot in addition to incorporating visual feedback from relative tool positions. Experiments resecting base-of-tongue mock tumors were conducted on a series of ex vivo and in vivo animal models comparing the proposed workflow for video augmentation to standard non-augmented practice and alternative, fluoroscopy-based image guidance. Accurate identification of registered augmented critical anatomy during controlled arterial dissection and en bloc mock tumor resection was possible with the augmented reality system. The proposed image-guided robotic system also achieved improved resection ratios of mock tumor margins (1.00) when compared to control scenarios (0.0) and alternative methods of image guidance (0.58). The experimental results show the feasibility of the proposed workflow and advantages of cone beam computed tomography image guidance through video augmentation of the primary stereo endoscopy as compared to control and alternative navigation methods. PMID- 26531204 TI - Quality of life after robotically assisted atrial myxoma excision. AB - The aim of this study was to evaluate the clinical outcome after robotically assisted myxoma surgery performed at our institution. Altogether nine patients underwent robotically assisted atrial myxoma excision. A control group was selected from 18 consecutive patients who underwent an isolated atrial myxoma excision via conventional sternotomy. Preoperative patient characteristics were similar between the two study groups. Postoperative health-related quality of life (HRQoL) was also evaluated. All robotic operations were completed successfully using the da VinciTM telesurgical system. There was no mortality in either of the two study groups. Procedure, cardiopulmonary bypass, aortic occlusion, and ventilation times were shorter in the sternotomy group when compared to the robotic group. Length of stay was statistically significantly shorter in the robotically assisted group. Postoperative quality of life did not differ between the two study groups. We conclude that robotically assisted surgery is a feasible method for treating atrial myxomas. PMID- 26531205 TI - Side docking of the da Vinci robotic system for radical prostatectomy: advantages over traditional docking. AB - The standard low lithotomic position, used during robot-assisted radical prostatectomy (RARP), with prolonged positioning in stirrups together with steep Trendelenburg may expose the patient to neurapraxia phenomena of the lower limbs and can rarely be used in patients with problems of hip abduction. To overcome these hurdles, we evaluated the clinical benefits of "side docking" (SD) of the da Vinci((r)) robotic system in comparison to "traditional docking" (TD). A cohort of 120 patients submitted to RARP were prospectively randomized into two groups by docking approach: SD with the patient supine with lower limbs slightly abducted on the operating table, and TD docking time, intraoperative number of collisions between the robotic arms and postoperative neurological problems in the lower limbs were noted. Descriptive statistics was used to analyze outcomes. Docking time was shorter for the SD group [SD: median 13 min (range 10-18); TD: median 21 min (range 15-34)]. None in the SD group and six of 60 patients (10%) in the TD group suffered from temporary (<30 days) unilateral neurological deficits of the lower limbs. In both groups no collisions between the robotic arms occurred. The SD approach is technically feasible. It does not cause collisions between the robotic arms, and is a reliable method for reducing the setup time of RARP. The supine position of the patient may prevent neurological complications of the lower limbs. Based on these results, SD has become the standard docking technique used by our department. PMID- 26531206 TI - Robotic-assisted radical prostatectomy is less stressful than the open approach: results of a contemporary prospective study evaluating pathophysiology of cortisol stress-related kinetics in prostate cancer surgery. AB - The objective of this study was to investigate the effects of prostate cancer (PCA) surgery on the stress system and to identify potential independent factors associating with stress recovery. The design of the study was prospective and PCA surgery included robot-assisted radical prostatectomy (RARP) or retro pubic radical prostatectomy. Between February and December 2013, 151 consecutive patients were evaluated. The effects of PCA surgery on the stress system were measured by cortisol serum levels before and after surgery on post-operative day (POD) 0, 1, 3, 5 and 45. Statistical methods were applied. RARP was performed in 71% of cases. PCA surgery triggered the stress system which immediately (POD 0) responded by cortisol overproduction which induced the negative feedback mechanism that started on POD 1, continued on POD. PMID- 26531207 TI - Robot-assisted laparoscopic gastrectomy for Menetrier's disease. AB - Menetrier's disease, also known as hypoproteinemic hypertrophic gastropathy, is a rare condition characterized by the presence of gastric hypertrophy with foveolar infiltration that replaces the normal glandular architecture. We present a case of a 65-year-old female patient who had epigastric pain after meals which progressed to oral intolerance and weight loss. Upper endoscopy was performed showing prominent folds in the gastric mucosa and stenosis at the antrum-pylorus. Biopsy was taken and showed foveolar reactive hyperplasia and reactive glandular epithelium changes suggestive of Menetrier's disease. An abdominopelvic CT was performed showing a dilated stomach and gastric wall thickening. The patient was taken into the operation room for a robot-assisted total gastrectomy with esophagus-jejunum anastomosis. The patient's progress was satisfactory and he was discharged on the eighth postoperative day. Robot-assisted laparoscopic gastrectomy is a feasible and safe option that facilitates the performance of complex procedures. PMID- 26531208 TI - Bilateral simultaneous robot-assisted pyelolithotomy for large (>6 cm) kidney stones: technique and review of literature. AB - With wide availability and demonstrable efficacy of endourological techniques, open surgery for renal stone disease has largely been replaced in contemporary urological practice. However, with increasing experience of laparoscopy and robotic surgery in urology, the principle of open renal surgery is being revisited. In certain situations, laparoscopic or robotic pyelolithomy may be an excellent minimally invasive alternative to percutaneous nephrolithomy with its unique advantages. We present a case of bilateral large kidney stones managed with bilateral simultaneous robot-assisted laparoscopic pyelolithotomy with excellent results. PMID- 26531209 TI - Laparoscopic radical prostatectomy: continence and oncological outcomes in 268 cases. PMID- 26531210 TI - Seasonal variation in Azumiobodo hoyamushi infection among benthic organisms in the southern coast of Korea. AB - BACKGROUND: Recent studies have reported that soft tunic syndrome (STS) in the edible ascidian Halocynthia roretzi is caused by the kinetoplastid parasite Azumiobodo hoyamushi. In this study, we attempted to detect and quantify the pathogen in benthic animals. METHODS: Four species of ascidians, three species of echinoderms, two species of bivalves, one species each of sponge and algae, as well as seawater, were collected in 2014 and 2015 from an ascidian farm on the southern coast of Korea by SCUBA diving. Samples were collected from ascidian hanging culture ropes or the sea bottom. Inhalent siphons were excised for the analysis of ascidians, and soft body tissues were excised from the other species. Membrane filters were used to filter collected seawater. Tissues and membrane filters were analysed using culture testing, PCR testing, and qPCR diagnoses. RESULTS: Only organisms belonging to Ascidiacea are susceptible to A. hoyamushi infection. The infection rate (% infected of the total number collected) and infection intensity (number of cells infected/g tissue wet weight) varied depending on the seasonal variation in seawater temperatures. Most ascidians examined were infected with A. hoyamushi and showed higher infection intensity in cold water seasons (April 2014 and February 2015), followed by a dramatic drop during warm water seasons (August and November, 2014). In addition, infection intensity of A. hoyamushi during the warm water period was higher in ascidians from the sea bottom than those from the hanging culture rope. CONCLUSIONS: Among benthic organisms that inhabit the southern coast of Korea, most ascidians are susceptible to A. hoyamushi infection. Seasonal cycle of infection rates and intensities of the pathogen correspond well with the STS disappearance and onset cycle observed in ascidian farms. The high intensity of A. hoyamushi infection in the ascidians on the sea bottom of ascidian farms during summer suggest further studies on the role of the pathogen in resumption of STS occurrence in late fall or early winter in the southern coast of Korea. PMID- 26531211 TI - Erythropoiesis-stimulating agents in heart failure: leave it or re-take it? PMID- 26531212 TI - You'll be a clinician-scientist, my son. AB - Opinion-based commentary about the complex reality of being a clinician-scientist in today's modern biomedical environment. The essay uses the beautiful, but old, poem "If" from Rudyard Kipling to draw a parallel with the ambitions, dreams and limits of being a clinical-scientist today. PMID- 26531213 TI - Single Chemosensor for Double Analytes: Spectrophotometric Sensing of Cu(2+) and Fluorogenic Sensing of Al(3+) Under Aqueous Conditions. AB - (E)-N-((8-Hydroxy-1,2,3,5,6,7-hexahydropyrido-[3,2,1-ij]-quinolin-9-yl)methylene) 4-tert-butyl -benzhydrazide has been developed as a single, dual-functional chemosensor. The chemosensor showed a good selectivity and sensitivity toward to Al(3+) and Cu(2+) at a low detection limit, respectively. Theoretical calculations have also been carried out to understand the configuration of the complexes. PMID- 26531214 TI - Experimental Study of Kinematic Activity of Left Ventricular Myocardium. AB - A method of invasive and non-invasive examination of epicardial motion was tested on domestic pigs (n=15). The invasive study employed a contact kinematic sensor of the epicardial wall motion, which determined the amplitude, velocity, and angular parameters of examined epicardial region. A non-invasive assessment of the epicardial kinematics based on echocardiographic 2D Velocity Vector Imaging and ECG recoding used to determine the heart electrical axis. The 4-chamber views were uses to analyze the longitudinal displacements of lateral wall of the left ventricle at the basal, mid, and apical segments. In addition, the radial displacements were determined in short axis projections at basal and apical segments as well as at the level of papillary muscles. The animals with normal or horizontal heart's electrical axis demonstrated similar displacement of the epicardium along X-axis and in longitudinal direction, while displacement along Y axis corresponded to that in radial direction. The combined invasive and non invasive approach in measurement of epicardium motion makes it possible to quantify the kinematic epicardial activity. PMID- 26531215 TI - Nursing assessment of continuous vital sign surveillance to improve patient safety on the medical/surgical unit. AB - AIMS AND OBJECTIVES: Evaluate continuous vital sign surveillance as a tool to improve patient safety in the medical/surgical unit. BACKGROUND: Failure-to rescue is an important measure of hospital quality. Patient deterioration is often preceded by changes in vital signs. However, continuous multi-parameter vital sign monitoring may decrease patient safety with an abundance of unnecessary alarms. DESIGN: Prospective observational study at two geographically disperse hospitals in a single hospital system. METHODS: A multi-parameter vital sign monitoring system was installed in a medical/surgical unit in Utah and one in Alabama providing continuous display of SpO2, heart rate, blood pressure and respiration rate on a central station. Alarm thresholds and time to alert annunciations were set based on prior analysis of the distribution of each vital sign. At the end of 4 weeks, nurses completed a survey on their experience. An average alert per patient, per day was determined retrospectively from the saved vital signs data and knowledge of the alarm settings. RESULTS: Ninety-two per cent of the nurses agreed that the number of alarms and alerts were appropriate; 54% strongly agreed. On average, both units experienced 10.8 alarms per patient, per day. One hundred per cent agreed the monitor provided valuable patient data that increased patient safety; 79% strongly agreed. CONCLUSIONS: Continuous, multi-parameter patient monitoring could be performed on medical/surgical units with a small and appropriate level of alarms. Continuous vital sign assessment may have initiated nursing interventions that prevented failure-to-rescue events. Nurses surveyed unanimously agreed that continuous vital sign surveillance will help enhance patient safety. RELEVANCE TO CLINICAL PRACTICE: Nursing response to abnormal vital signs is one of the most important levers in patient safety, by providing timely recognition of early clinical deterioration. This occurs through diligent nursing surveillance, involving assessment, interpretation of data, recognition of a problem and meaningful response. PMID- 26531216 TI - Asthma control in children: Is it important and can we measure it? AB - The goal of asthma management is to achieve disease control. Poorly controlled asthma is associated with an increased number of days lost from school, exacerbations and days in hospital. Furthermore, children with uncontrolled asthma have more frequent contacts with the health-care system. Recent studies have added new information about the effects of poorly controlled asthma on a range of important, but less studied outcomes, including risk of obesity, daily physical activity, cardiovascular fitness, stress, concentration and focused attention, learning disabilities and risk of depression. From these studies it seems that poor asthma control may have a greater impact on the child than previously thought. This may have important long-term consequences for the child such as an increased risk of life-style associated diseases and poorer school performance. The level of control seems to be the most important determinant of these adverse effects and improvement in asthma control is associated with improvements in many of the outcomes. However, the improvement has to be maintained for a very long time (> 1 year). Accurate assessment of the level of asthma control is difficult. Various tools and scores have been developed. They are all based on various questionnaires, but their validation has been difficult because we have no golden standard to compare with. It seems as if the tests are most valuable when they suggest that the disease is poorly controlled because a large proportion of children in whom the tests suggest good asthma control may still have poorly controlled asthma when various objective outcomes are included in the assessment. A main reason for that seems to be that none of the tests accurately detects the child's adaptation in lifestyle. If you do not exercise you have fewer symptoms. PMID- 26531217 TI - Pulmonary Complications of Childhood Cancer Treatment. AB - Pulmonary complications of childhood cancer treatment are frequently seen. These can lead to adverse sequelae many years after treatment, with important impact on morbidity, quality of life and mortality in childhood cancer survivors. This review addresses the effects of chemotherapy, radiotherapy, surgery and alloimmunity (in haematopoietic cell transplantation) on the lung in children. It highlights the complexity of lung damage and lung disease in relation to growth and development, infections and other external factors. Screening high risk childhood cancer survivors for treatment related late effects, with therapy based screening protocols, using full medical assessment and pulmonary function tests is important. This will lead to recognition of pulmonary sequelae of cancer treatment, early detection of lung damage in survivors and better treatment and prevention. PMID- 26531218 TI - An exploration of the antioxidant effects of garlic saponins in mouse-derived C2C12 myoblasts. AB - In this study, we aimed to confirm the protective effects of garlic saponins against oxidative stress-induced cellular damage and to further elucidate the underlying mechanisms in mouse-derived C2C12 myoblasts. Relative cell viability was determined by 3-(4.5-dimethylthiazol-2-yl)-2.5 diphenyltetrazolium bromide assay. Comet assay was used to measure DNA damage and oxidative stress was determined using 2',7'-dichlorofluorescein diacetate to measure intracellular reactive oxygen species (ROS) generation. Western blot analysis and small interfering RNA (siRNA)-based knockdown were used in order to investigate the possible molecular mechanisms. Our results revealed that garlic saponins prevented hydrogen peroxide (H2O2)-induced growth inhibition and exhibited scavenging activity against intracellular ROS. We also observed that garlic saponins prevented H2O2-induced comet tail formation and decreased the phosphorylation levels of gammaH2AX expression, suggesting that they can prevent H2O2-induced DNA damage. In addition, garlic saponins increased the levels of heme oxygenase-1 (HO-1), a potent antioxidant enzyme associated with the induction and phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the translocation of Nrf2 from the cytosol into the nucleus. However, the protective effects of garlic saponins on H2O2-induced ROS generation and growth inhibition were significantly reduced by zinc protoporphyrin IX, an HO-1 competitive inhibitor. In addition, the potential of garlic saponins to mediate HO-1 induction and protect against H2O2-mediated growth inhibition was adversely affected by transient transfection with Nrf2-specific siRNA. Garlic saponins activated extracellular signal-regulated kinase (ERK) signaling, whereas a specific ERK inhibitor was able to inhibit HO-1 upregulation, as well as Nrf2 induction and phosphorylation. Taken together, the findings of our study suggest that garlic saponins activate the Nrf2/HO-1 pathway by enabling ERK to contribute to the induction of phase II antioxidant and detoxifying enzymes, including HO-1 in C2C12 cells. PMID- 26531219 TI - Klotho inhibits human follicular thyroid cancer cell growth and promotes apoptosis through regulation of the expression of stanniocalcin-1. AB - The new anti-aging gene Klotho has been identified as a multi-functional humoral factor which influences multiple biological processes, including tumor progression. Although ample evidence indicates that Klotho plays important roles in cervical, lung and breast cancer, the role and mechanism of Klotho in thyroid cancer are still unclear. The present study aimed to investigate the effects and mechanisms of Klotho in human thyroid cancer cell lines FTC133 and FTC238. Klotho overexpression markedly reduced thyroid cancer FTC133 and FTC238 cell proliferation and enhanced apoptosis, whereas, Klotho silencing in the FTC133 and FTC238 cells increased cell growth. Moreover, soluble human KL1 (sKL) and Klotho overexpression had a similar effect on FTC133 and FTC238 cell growth. A high level of Klotho was also found to be associated with a low level of stanniocalcin 1 (STC1) in both the FTC133 and FTC238 cell lines. STC1 silencing significantly inhibited thyroid cancer cell proliferation, whereas recombinant human STC1 (hSTC1) markedly enhanced cell proliferation. In addition, our study demonstrated that hSTC1 treatment attenuated Klotho-induced inhibition of cell proliferation and promotion of apoptosis. Our data revealed the existence of a moderating effect between Klotho and STC1, where Klotho may inhibit thyroid tumor progression by inhibiting the tumor marker level of STC1. PMID- 26531220 TI - Health workforce planning in Europe: Creating learning country clusters. AB - In this article, the different dimensions and determinants of health workforce planning (HWF) are investigated to improve context-sensitivity and mutual learning among groups of countries with similar HWF characteristics. A novel approach to scoring countries according to their HFW characteristics and type of planning is introduced using data collected in 2012 by a large European Union project involving 35 European countries (the 'Matrix Study' [8]). HWF planning is measured in terms of three major dimensions: (1) data infrastructure to monitor the capacities and dynamics of health workforces, (2) the institutions involved in defining and implementing labour market regulations, and (3) the availability of models to estimate supply-demand gaps and to forecast imbalances. The result shows that the three dimensions of HWF planning are weakly interrelated, indicating that countries invest in HWF in different ways. Determinant analysis shows that countries with larger health labour markets, National Healthcare Service (NHS), mobility, and strong primary health care score higher on HWF planning dimensions than others. Consequently, the results suggest that clustering countries with similar conditions in terms of HWF planning is a way forward towards mutual and contextual learning. PMID- 26531221 TI - H2S, a novel gasotransmitter, involves in gastric accommodation. AB - H2S is produced mainly by two enzymes:cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE), using L-cysteine (L-Cys) as the substrate. In this study, we investigated the role of H2S in gastric accommodation using CBS(+/ ) mice, immunohistochemistry, immunoblot, methylene blue assay, intragastric pressure (IGP) recording and electrical field stimulation (EFS). Mouse gastric fundus expressed H2S-generating enzymes (CBS and CSE) and generated detectable amounts of H2S. The H2S donor, NaHS or L-Cys, caused a relaxation in either gastric fundus or body. The gastric compliance was significantly increased in the presence of L-Cys (1 mM). On the contrary, AOAA, an inhibitor for CBS, largely inhibited gastric compliance. Consistently, CBS(+/-) mice shows a lower gastric compliance. However, PAG, a CSE inhibitor, had no effect on gastric compliances. L-Cys enhances the non-adrenergic, non-cholinergic (NANC) relaxation of fundus strips, but AOAA reduces the magnitude of relaxations to EFS. Notably, the expression level of CBS but not CSE protein was elevated after feeding. Consistently, the production of H2S was also increased after feeding in mice gastric fundus. In addition, AOAA largely reduced food intake and body weight in mice. Furthermore, a metabolic aberration of H2S was found in patients with functional dyspepsia (FD). In conclusion, endogenous H2S, a novel gasotransmitter, involves in gastric accommodation. PMID- 26531222 TI - Optimized bio-inspired stiffening design for an engine nacelle. AB - Structural efficiency is a common engineering goal in which an ideal solution provides a structure with optimized performance at minimized weight, with consideration of material mechanical properties, structural geometry, and manufacturability. This study aims to address this goal in developing high performance lightweight, stiff mechanical components by creating an optimized design from a biologically-inspired template. The approach is implemented on the optimization of rib stiffeners along an aircraft engine nacelle. The helical and angled arrangements of cellulose fibres in plants were chosen as the bio-inspired template. Optimization of total displacement and weight was carried out using a genetic algorithm (GA) coupled with finite element analysis. Iterations showed a gradual convergence in normalized fitness. Displacement was given higher emphasis in optimization, thus the GA optimization tended towards individual designs with weights near the mass constraint. Dominant features of the resulting designs were helical ribs with rectangular cross-sections having large height-to-width ratio. Displacement reduction was at 73% as compared to an unreinforced nacelle, and is attributed to the geometric features and layout of the stiffeners, while mass is maintained within the constraint. PMID- 26531223 TI - Canine retraction and anchorage loss self-ligating versus conventional brackets: a systematic review and meta-analysis. AB - BACKGROUND: The purpose of this systematic review is to identify and review the orthodontic literature with regards to assessing possible differences in canine retraction rate and the amount of antero-posterior anchorage (AP) loss during maxillary canine retraction, using conventional brackets (CBs) and self-ligating brackets (SLBs). METHODS: An electronic search without time or language restrictions was undertake in September 2014 in the following electronic databases: The Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE via OVID, EMBASE via OVID, Web of science. We also searched the reference lists of relevant articles. Quality assessment of the included articles was performed. Two of the authors were responsible for study selection, validity assessment and data extraction. RESULTS: Six studies met the inclusion criteria, including 2 randomized controlled trials and 4 control clinical studies. One was assessed as being at low risk of bias. Five trials were assessed as being at moderate risk of bias. The meta-analysis from 6 eligible studies showed that no statistically significant difference was observed between the 2 groups in the rate of canine retraction and loss of antero-posterior anchorage of the molars. CONCLUSION: There is some evidence from this review that both brackets showed the same rate of canine retraction and loss of antero-posterior anchorage of the molars. The results of the present systematic review should be viewed with caution due to the presence of uncontrolled interpreted factors in the included studies. Further well-designed and conducted randomized controlled trials are required, to facilitate comparisons of the results. PMID- 26531224 TI - Preparation and Characterization of Reconstituted Lipid-Synthetic Polymer Discoidal Particles. AB - Discoidal high-density lipoproteins generated by the apolipoprotein-mediated solubilization of membrane lipids in vivo can be reconstituted with phospholipids and apolipoproteins in vitro. Recently, it has been reported that such particles can be prepared using the hydrolyzed acid form of styrene-maleic anhydride copolymer (SMAaf) instead of apolipoproteins, but characterization of its physicochemical properties has remained less elucidated. In the present study, with the aim of applying SMAaf-based lipid nanoparticles as novel delivery vehicles of drugs and/or imaging agents, we investigated the preparation conditions and evaluated the physicochemical properties of lipid-SMAaf complexes. SMAaf induced spontaneous turbidity clearance of dimyristoylphosphatidylcholine (DMPC) vesicles accompanied by the formation of smaller particles not only at the phase transition temperature of DMPC but also above it. Such reductions in the turbidity were not observed with some other amphiphilic synthetic polymers tested under the same experimental conditions. Size exclusion chromatography analyses showed that homogeneously sized particles were prepared at lipid to SMAaf weight ratios of less than 1/1.5. Dynamic light scattering and transmission electron microscopy revealed that gel-filtered DMPC-SMAaf complexes were approximately 8 10 nm in diameter and discoidal in shape. The DMPC-SMAaf complexes were relatively stable even after lyophilization but were sensitive to pH changes. Fluorescence techniques demonstrated that the gel to liquid-crystalline phase transition temperature of DMPC in the discoidal complexes broadened significantly relative to that of liposomes, despite their common bilayer structure, which is a typical feature of discoidal lipid nanoparticles. These results provide fundamental insights into discoidal SMAaf-based lipid nanoparticles for the development of novel delivery vehicles. PMID- 26531225 TI - Evaluation of low-dose thalidomide as induction and maintenance therapy in patients with multiple myeloma not eligible for stem cell transplantation. AB - BACKGROUND: The role of thalidomide in induction and long-term maintenance therapy in patients with multiple myeloma not eligible for stem cell transplantation remains unclear. The aim of the present study was to evaluate the effect of low-dose thalidomide as induction therapy and as maintenance therapy for 24 months in patients with a complete remission after the induction chemotherapy and to monitor the survival and relapse rates. METHODS: Between October 2005 and September 2013, 50 patients with multiple myeloma received six courses of Cyclophosphamide-Vincristine Adriamycin and Dexamethazone (c-VAD) and pamidronate, and thalidomide 100 mg daily during induction, then thalidomide 100 mg daily for 24 months as maintenance. The effects of thalidomide were assessed objectively and subjectively. Whenever necessary, electromyography and nerve capacity volume were performed monthly for 6 months, then once every 3 months until the end of treatment. RESULTS: Primary response was 96% (CR or very good PR in 48/50 patients). Fifteen out of the remaining 48 patients relapsed during the follow-up period. Nine out of the 15 patients who relapsed showed very good partial response to treatment and four patients showed partial response. Survival rate was 81% in these patients. The primary outcome measures showed a mean and median progression-free survival of 33 and 27 months, respectively, and a mean and median overall survival of 43 and 39 months, respectively. CONCLUSION: Low dose thalidomide during induction therapy combined with conventional chemotherapy and a 2-year maintenance may be effective in preventing the relapse and improving the overall survival. PMID- 26531226 TI - Nutrition recommendations and science: next parallel steps. AB - This article examines nutrition recommendations in relation to developments in nutrition science. Combining data on the genome, metabolome and microbiota is likely to open possibilities for personalized nutrition planning, but we are still far from practical applications. However, even these new steps are unlikely to challenge the role and importance of population-based nutrition recommendations as a tool to promote dietary patterns, policies and public health. Developments in science could help in deriving more benefits from nutrition recommendations. For instance, improved accuracy of dietary intake assessment is needed both for surveillance and for understanding the quantitative interplay between diet and health. Applying metabolomics together with food diaries or questionnaires, and also modern technologies such as digital photography, are potentially interesting methods in this respect. Research on consumer behaviour, attitudes and policy interventions, such as taxation of unhealthy foods and nutrition labelling, are needed to gain more insight into how to change eating behaviour for better health at the population level. PMID- 26531227 TI - Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring. AB - Migrastatin and isomigrastatin analogues have been synthesised in order to contribute to structure-activity studies on tumour cell migration inhibitors. These include macrocycles varying in ring size, functionality and alkene stereochemistry, as well as glucuronides. The synthesis work included application of the Saegusa-Ito reaction for regio- and stereoselective unsaturated macroketone formation, diastereoselective Brown allylation to generate 9 methylmigrastatin analogues and chelation-induced anomerisation to vary glucuronide configuration. Compounds were tested in vitro against both breast and pancreatic cancer cell lines and inhibition of tumour cell migration was observed in both wound-healing (scratch) and Boyden chamber assays. One unsaturated macroketone showed low affinity for a range of secondary drug targets, indicating it is at low risk of displaying adverse side effects. PMID- 26531229 TI - Influence of family history of dementia in the development and progression of late-onset Alzheimer's disease. AB - Family history of dementia (FH) is a recognized risk factor for developing late onset Alzheimer's disease (AD). We asked whether having FH increases AD risk and influences disease severity (age at onset and cognitive impairment) in 420 AD patients and 109 controls with (FH+) or without (FH-). The relationships of APOE and other AD risk genes with FH were analyzed as well. The proportion of APOE e4 allele carriers was higher among the FH+ than the FH- AD patients (49.6% vs. 38.9%; P = 0.04). The distribution of the risk genotypes of nine AD susceptibility genes previously examined (CHAT, CYP17, CYP19, ESR1, FSHR, P53, P73, P21, PPARG) did not differ between the FH+ and the FH- AD patients, indicating that none contributed significantly to familial clustering of disease. FH was associated with an increased AD risk (odds ratio [OR] 2.71, 95% confidence interval [CI] 1.44-5.09; P = 0.002) independent of carrying the APOE e4 allele (OR 2.61, 95%CI 1.53-4.44; P = 0.0004). Having a first-degree relative or a parent with dementia was significantly associated with AD risk (OR 2.9, 95%CI 1.3 6.4; P = 0.009 and OR 2.7, 95%CI 1.1-6.2; P = 0.02) but having a sibling with dementia was not (OR 1.7, 95%CI 0.2 to 14.7; P = 0.6). Among the FH+ AD patients, having one or both parents affected seemed to raise the risk of earlier onset age (P = 0.02) and greater cognitive impairment (P = 0.02) than having only an affected sibling, whereas having two or more affected relatives did not. PMID- 26531230 TI - Resolvin D1 and E1 alleviate the progress of hepatitis toward liver cancer in long-term concanavalin A-induced mice through inhibition of NF-kappaB activity. AB - Resolvins, an endogenous lipid mediator derived from eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) of fish oil, has been reported to have anti inflammatory and antitumor effect in various pathogenic processes. However, there are no studies about the effects of resolvin D1 and E1 on concanavalin A-induced hepatitis. Hence, the present study is to illustrate whether resolvin D1 and E1 inhibit concanavalin A-induced liver injury, liver cancer and underlying mechanisms by which they may recover. C57BL/6 mice were pretreated with resolvin D1 and E1 for 4 h, and then injected with concanavalin A for 12 h. Subsequently, blood and liver tissue were collected at 0, 2, 4, 8 and 12 h for different analysis. Analysis of inflammatory cytokines indicated that the inhibition of necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-2, IL-1beta and IL-6 could be performed by resolvin D1 and E1. Moreover, Toll-like receptor (TLR) 4 expression, NF-kappaB and AP-1 activity also have been confirmed to have key roles in the development of liver injury. They were significantly suppressed in the treatment group, compared to model. In addition, resolvin D1 and E1 markedly downregulated CD4+ and CD8+ cell infiltration in the liver. A long-term concanavalin A treatment for 32 weeks was performed to analyze the changes of hepatitis to liver cancer and the antitumor effect of resolving D1 and E1. These results indicated that resolvin D1 and E1 prevent concanavalin A-induced liver injury and the changes of hepatitis to liver cancer in mice through inhibition of inflammatory cytokine secretion and NF-kappaB/AP-1 activity. Thus, they could be novel target to be considered in the process of finding sufficient drug to protect against various forms of hepatitis and liver cancer. PMID- 26531228 TI - Protein O-linked glycosylation in the plant pathogen Ralstonia solanacearum. AB - Ralstonia solanacearum is one of the most lethal phytopathogens in the world. Due to its broad host range, it can cause wilting disease in many plant species of economic interest. In this work, we identified the O-oligosaccharyltransferase (O OTase) responsible for protein O-glycosylation in R. solanacearum. An analysis of the glycoproteome revealed that 20 proteins, including type IV pilins are substrates of this general glycosylation system. Although multiple glycan forms were identified, the majority of the glycopeptides were modified with a pentasaccharide composed of HexNAc-(Pen)-dHex(3), similar to the O antigen subunit present in the lipopolysaccharide of multiple R. solanacearum strains. Disruption of the O-OTase led to the total loss of protein glycosylation, together with a defect in biofilm formation and reduced pathogenicity towards tomato plants. Comparative proteomic analysis revealed that the loss of glycosylation is not associated with widespread proteome changes. Only the levels of a single glycoprotein, the type IV pilin, were diminished in the absence of glycosylation. In parallel, disruption of glycosylation triggered an increase in the levels of a surface lectin homologous to Pseudomonas PA-IIL. These results reveal the important role of glycosylation in the pathogenesis of R. solanacearum. PMID- 26531231 TI - Oesophageal bezoar as a complication of enteral nutrition in critically ill patients. Two case studies. AB - Enteral nutrition has a relatively low incidence of major complications. The most common complications are mechanical problems, bronchoaspiration and diarrhoea. A rare complication associated with the use of enteral nutrition is oesophageal bezoar. A bezoar is a body of undigested and partially digested matter in the gastrointestinal tract. The main risks factors are gastric motility dysfunction and the use of opiates or sucralfate. The aim of this paper was to present two cases of oesophageal obstruction resulting from the formation of bezoars due to enteral nutrition. Both patients experienced prolonged stays in the intensive care unit and were receiving enteral nutrition, and both cases involved an obstruction of the nasogastric tube and the regurgitation of solid chunks of enteral nutrition through the mouth and the nose. Impactions of solidified enteral nutrition in the distal parts of the oesophagus were confirmed with gastroscopies. Enzymatic complexes containing papain, cellulose, pancreatin, pepsin and diastase were used to successfully dissolve the bezoars in both cases. PMID- 26531232 TI - Current controversies in prenatal diagnosis 3: is there still a value in a nuchal translucency screening ultrasound in conjunction with maternal plasma non invasive cell-free DNA testing? PMID- 26531233 TI - A novel 2,5-diaminopyrimidine-based affinity probe for Bruton's tyrosine kinase. AB - As a critical regulator of the B-cell receptor signaling pathway, Bruton's tyrosine kinase (Btk) has attracted intensive drug discovery efforts for treating B-cell lineage cancers and autoimmune disorders. In particular, covalent inhibitors targeting Cys481 in Btk have demonstrated impressive clinical benefits, and their companion affinity probes have been crucial in the drug development process. Recently, we have discovered a novel series of 2,5 diaminopyrimidine-based covalent irreversible inhibitors of Btk. Here, we present the discovery of a novel affinity Btk probe based on the aforementioned scaffold and demonstrate its usage in evaluating the target engagement of Btk inhibitors in live cells. PMID- 26531234 TI - Editorial: Pancreatic neuroendocrine tumors: Primum non nocere. PMID- 26531235 TI - Randomized prospective comparison of midline and off-midline closure techniques in pilonidal sinus surgery. AB - BACKGROUND: Pilonidal sinus is a chronic inflammatory disorder of the intergluteal sulcus. The disorder often negatively affects patients' quality of life, and there are numerous possible methods of operative treatment for pilonidal sinus. The aim of our study was to compare the results of 3 different operative procedures (tension-free primary closure, Limberg flap, and Karydakis technique) used in the treatment of pilonidal disease. METHODS: The study was conducted via a prospective randomized design. The patients were randomized into 3 groups via a closed envelope method. Patients were included in the study after admission to our clinic with pilonidal sinus disease and operative treatment already were planned. The 2 main outcomes of the study were early complications from the methods used and later recurrences of the disease. RESULTS: A total of 150 patients were included in the study, and the groups were similar in terms of age, sex, and American Society of Anesthesiologists scores. The median follow-up time of the study was 24.2 months (range, 18.5-34.27) postsurgery. The recurrence rates were 6% for both the Limberg and Karydakis groups and 4% for the tension free primary closure group. Therefore, there was no substantial difference in the recurrence rates. CONCLUSION: The search for an ideal treatment modality for pilonidal sinus disease is still ongoing. The main conclusion of our study is that a tension-free healing side is much more important than a midline suture line. Also, tension-free primary closure is as effective as a flap procedure, and it is also easier to perform. PMID- 26531236 TI - Text paging of surgery residents: Efficacy, work intensity, and quality improvement. AB - BACKGROUND: Text pages can communicate important information but also disrupt workflow, which can affect the safety of patient care. The purpose of this study was to analyze the content, volume, and distribution of text pages received by general surgery residents and physician's assistants (PAs) using natural language processing (NLP). METHODS: We studied text pages received by residents and PAs at a tertiary care teaching hospital from March to May 2012 using NLP. The number and content of pages were stratified by recipient seniority, surgical service, patient census, and patient location. Chi-square tests, t test, and analysis of variance were used to detect statistical significance. RESULTS: We captured 48,202 pages. The average number (mean +/- standard deviation) of pages per hour was 3.1 +/- 2.2 for postgraduate year (PGY)-1s and 2.8 +/- 1.9 for PAs (P < .0001). The greatest number of pages per day by Service was 86.1 +/- 37.5 on the acute care surgery service. The most common paging topic was medications (18,444 [38.3%]) and the most common symptom was pain (6,240 pages [12.9%]). On services where patients were located near each other (regionalized), the number of pages per day per recipient per patient on census was almost half that compared with nonregionalized services (1.40 vs 2.43; P < .0001). CONCLUSION: Residents receive a high volume of pages at this tertiary care center, particularly regarding medications and pain. Services with regionalized patients exhibit less paging need per patient. Initiatives to improve pain management and regionalize patients may streamline communication, decrease the number of pages, and increase patient safety. PMID- 26531237 TI - Expanding the net: The re-evaluation of the multidimensional nomogram calculating the upper limit of normal PTH (maxPTH) in the setting of secondary hyperparathyroidism and the development of the MultIdimensional Predictive hyperparaTHyroid model (Mi-PTH). AB - BACKGROUND: The multidimensional nomogram calculating the upper limit of normal PTH (maxPTH) model identifies a personalized upper limit of normal parathyroid hormone (PTH) and successfully predicts classical primary hyperparathyroidism (PHP). We aimed to assess whether maxPTH can distinguish normocalcemic PHP (NCPHP) from secondary hyperparathyroidism (SHP), including subjects who underwent bariatric surgery (BrS). METHODS: A total of 172 subjects with 359 complete datasets of serum calcium (Ca), 25-OH vitamin D, and intact PTH from Oregon were analyzed: 123 subjects (212 datasets) with PHP and 47 (143) with SHP, including 28 (100) with previous BrS. An improved prediction model, MultIdimensional evaluation for Primary hyperparaTHyroidism (Mi-PTH), was created with the same variables as maxPTH by the use of a combined cohort (995 subjects) including participants from previous studies. RESULTS: In the Oregon cohort, maxPTH's sensitivity was 100% for classical PHP and 89% for NCPHP, but only 50% for normohormonal PHP (NHPHP) and 40% specific for SHP. In comparison, although sensitivity for NCPHP was similar (89%), Mi-PTH vastly improved SHP specificity (85%). In the combined cohort, Mi-PTH had better sensitivity of 98.5% (vs 95%) and specificity 97% (vs 85%). CONCLUSION: MaxPTH was sensitive in detecting PHP; however, there was low specificity for SHP, especially in patients who underwent BrS. The creation of Mi-PTH provided improved performance measures but requires further prospective evaluation. PMID- 26531239 TI - Possibilities and limitations in separating Pt(IV) from Pd(II) combining imidazolium and phosphonium ionic liquids. AB - An investigation on a process designed for separating Pt(IV) and Pd(II) dissolved in acidic aqueous solution containing HCl using two ionic liquids, 1-octyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide ([OMIM][NTf2]) and trihexyltetradecylphosphonium bromide (Cyphos 102), is presented. To this end, the single extraction of platinum in [OMIM][NTf2] has been investigated as a function of the initial concentration of Pt(IV) ions dissolved in 1 M HCl. The distribution coefficient for Pt(IV), present in water as a PtCl6(2-) anion, decreases with the concentration of Pt(IV). The extraction of Pd(II) towards [OMIM][NTf2] or Cyphos 102 as a function of the concentration of HCl in the aqueous phase is also reported. Pd(II), present as PdCl4(2-) in water, is not extracted using [OMIM][NTf2]. On the other hand, the distribution coefficients of Pd(II) using Cyphos 102 are above 2000. In this ionic liquid, Pd(II) is extracted as a PdBr4(2-) anion. Separation of Pt(IV) from Pd(II) was then carried out starting from aqueous phases containing 1 M HCl and various initial concentrations of Pt(IV). The influence of the number of extraction steps using [OMIM][NTf2] on the extraction of Pt(IV) was also studied. Unlike the results obtained from single extraction experiments of Pt(IV), consecutive extraction of Pt(IV) in water using [OMIM][NTf2] does not improve significantly the extraction of this metal ion. The second step of the extraction process carried out using Cyphos 102 leads to the quantitative extraction of Pd(II) and Pt(IV) remaining in the aqueous phase. PMID- 26531238 TI - Dnmts and Tet target memory-associated genes after appetitive olfactory training in honey bees. AB - DNA methylation and demethylation are epigenetic mechanisms involved in memory formation. In honey bees DNA methyltransferase (Dnmt) function is necessary for long-term memory to be stimulus specific (i.e. to reduce generalization). So far, however, it remains elusive which genes are targeted and what the time-course of DNA methylation is during memory formation. Here, we analyse how DNA methylation affects memory retention, gene expression, and differential methylation in stimulus-specific olfactory long-term memory formation. Out of 30 memory associated genes investigated here, 9 were upregulated following Dnmt inhibition in trained bees. These included Dnmt3 suggesting a negative feedback loop for DNA methylation. Within these genes also the DNA methylation pattern changed during the first 24 hours after training. Interestingly, this was accompanied by sequential activation of the DNA methylation machinery (i.e. Dnmts and Tet). In sum, memory formation involves a temporally complex epigenetic regulation of memory-associated genes that facilitates stimulus specific long-term memory in the honey bee. PMID- 26531240 TI - Predominant role of msr(D) over mef(A) in macrolide resistance in Streptococcus pyogenes. AB - In Japan, the number of patients with streptococcal toxic shock syndrome is reported to be increasing. mef(A) gene-positive macrolide-resistant emm1 strains are thought to possibly contribute to the rise in the frequency of STSS. Although analyses of macrolide-resistant mechanisms, including mef(A) resistance, have been performed mainly in Streptococcus pneumoniae, the role of this gene in Streptococcus pyogenes has not been completely investigated. Therefore, to the best of our knowledge, we established the first mef(A)-knockout strain using an emm1-type S. pyogenes strain, and tested its susceptibility to erythromycin, clarithromycin and azithromycin. We found that the antimicrobial susceptibilities were almost identical to those of the parental strain. Hence, we established a knockout strain for another gene, msr(D), that is located immediately downstream of mef(A). The macrolide resistances of the resulting strain significantly decreased, and were further altered when both mef(A) and msr(D) were knocked out. The introduction of the msr(D) gene into a macrolide-sensitive strain conferred more resistance than the introduction of the mef(A) gene. The erythromycin susceptibilities of knockout strains were further dissected using two additional emm4- and emm75-type S. pyogenes strains. We found almost identical results for both strains except for the mef(A) knockout emm4 type, whose susceptibility was altered, although the change was less than that for the msr(D) knockout. These results suggest that both mef(A) and msr(D) are involved in macrolide resistance in S. pyogenes, and that the msr(D) gene plays a more predominant role in macrolide resistance than mef(A). PMID- 26531241 TI - The clinical significance of transforming acidic coiled-coil protein 3 expression in non-small cell lung cancer. AB - The relationship between TACC3, a member of the transforming acidic coiled-coil proteins (TACCs) family, and lung carcinoma remains unclear. The present study was designed to explore the prognostic and clinical significance of TACC3 in non small cell lung cancer (NSCLC). An immunohistochemistry (IHC) assay was performed to analyze the expression of TACC3 in 195 lung cancer cases. The mRNA and protein levels of TACC3 were examined by quantitative reverse transcription-PCR or western blotting. The correlation between TACC3 expression and clinicopathological factors was analyzed by chi2 analysis and Fisher's exact test. Kaplan-Meier analysis and the Cox proportional hazards model were used to examine the correlation of prognostic outcomes with TACC3. The results showed that the levels of TACC3 mRNA and total protein were higher in lung cancer lesions than paired non-cancerous tissues. IHC analysis revealed that TACC3 was highly expressed in 94 (48.2%) cases. The expression of TACC3 was strongly correlated with smoking status, histological classification, differentiation, cytokeratin 19 fragment levels, T stage and the clinical stage of NSCLC patients. Univariate and multivariate analyses demonstrated that TACC3 is a useful biomarker for NSCLC prognosis. The low TACC3 expression group exhibited better progression-free survival (PFS) among patients who received anti-microtubule chemotherapy. In conclusion, the results showed that a high level of TACC3 expression was correlated with advanced clinicopathological classifications, poor overall survival (OS) and poor recurrence-free survival (RFS) in NSCLC patients. Our findings indicate that TACC3 is a potential prognostic marker and therapeutic target for NSCLC. PMID- 26531242 TI - High titers of anti-HBs prevent rituximab-related viral reactivation in resolved hepatitis B patient with non-Hodgkin's lymphoma. AB - Rituximab, an anti-CD20 monoclonal antibody, is associated with an increased risk of hepatitis B virus (HBV) reactivation. This study aimed to determine the predictive factors for rituximab-related HBV reactivation in resolved hepatitis B patients, defined as HBsAg-negative, anti-HBc-positive, and undetectable HBV DNA. Among 840 consecutive patients with CD20-positive B-cell lymphoma who received rituximab-based chemotherapy from 2003 through 2014 at Seoul National University Hospital, 732 patients were excluded because either anti-HBc was not assessed or they were HBsAg-seropositive. This retrospective study included 108 resolved hepatitis B patients. During a median 33.5-month follow-up period, eight cases of HBV reactivation occurred only among the patients with low anti-HBs titers (<100 mIU/ml) at baseline and those who did not receive antiviral prophylaxis. Using multivariate analyses, antiviral prophylaxis and baseline anti-HBs titers were the protective factors for HBV reactivation (hazard ratio [HR], 0.90 and 0.95, respectively). Among those who did not receive antiviral prophylaxis, patients with high baseline anti-HBs (>=100 mIU/ml) experienced significantly lower risk of HBV reactivation (HR, 0.49; P = 0.006) than the patients with low baseline anti-HBs (<100 mIU/ml) whose cumulative HBV reactivation rates at 6 and 24 months after chemotherapy were 8.3% and 17.3%, respectively. High anti-HBs titer at baseline and antiviral prophylaxis prevented HBV reactivation, suggesting antiviral prophylaxis should be considered according to baseline anti-HBs titer. Meticulous follow-up for ALT and HBV DNA without antiviral prophylaxis might be possible for the patients with high baseline anti-HBs (>=100 mIU/ml). PMID- 26531243 TI - Instructions influence response to the Chinese version of the Movement-Specific Reinvestment Scale in community-dwelling older adults. AB - AIM: To examine whether differences emerged when the Chinese version of the Movement-Specific Reinvestment Scale (MSRS-C) was administered to community dwelling older adults with instructions to respond in the context of "general" movements, walking, using chopsticks or dressing. Furthermore, the difference between the six-point Likert scale and four-point Likert scale response formats of the MSRS-C was investigated. METHODS: The study was implemented in the community of Hong Kong with 52 older adults (mean age 77.4 years). Telephone interviews were carried out on two occasions for each participant. Participants provided a verbal response to each of 10 questions from the MSRS-C with different response formats (i.e., six-point or four-point Likert Scales) and different instructions in the response context (i.e. general, walking, using chopsticks, dressing). The sequence of response format and context was randomized for each participant. RESULTS: Older fallers scored significantly higher on the MSRS-C (general) with six-point or four-point response formats than non-fallers. The MSRS-C (general) and MSRS-C (walking) were not statistically different, and showed good discriminative power for previous older fall status (older fallers or older non-fallers). However, MSRS-C (chopsticks) and MSRS-C (dressing) failed to differentiate older fallers from older non-fallers. CONCLUSION: Both the MSRS-C (general) and MSRS-C (walking) with a six-point or a four-point response format showed good discrimination of older fallers from non-fallers. Older adults might respond to the MSRS-C with respect to the most challenging movements (e.g. fall related movements) in their daily living. Geriatr Gerontol Int 2016; 16: 1305 1311. PMID- 26531244 TI - Protein Structure-Function Correlation in Living Human Red Blood Cells Probed by Isotope Exchange-based Mass Spectrometry. AB - To gain insight into the underlying mechanisms of various biological events, it is important to study the structure-function correlation of proteins within cells. Structural probes used in spectroscopic tools to investigate protein conformation are similar across all proteins. Therefore, structural studies are restricted to purified proteins in vitro and these findings are extrapolated in cells to correlate their functions in vivo. However, due to cellular complexity, in vivo and in vitro environments are radically different. Here, we show a novel way to monitor the structural transition of human hemoglobin upon oxygen binding in living red blood cells (RBCs), using hydrogen/deuterium exchange-based mass spectrometry (H/DX-MS). Exploiting permeability of D2O across cell membrane, the isotope exchange of polypeptide backbone amide hydrogens of hemoglobin was carried out inside RBCs and monitored using matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). To explore the conformational transition associated with oxygenation of hemoglobin in vivo, the isotope exchange kinetics was simplified using the method of initial rates. RBC might be considered as an in vivo system of pure hemoglobin. Thus, as a proof-of-concept, the observed results were correlated with structural transition of hemoglobin associated with its function established in vitro. This is the first report on structural changes of a protein upon ligand binding in its endogenous environment. The proposed method might be applicable to proteins in their native state, irrespective of location, concentration, and size. The present in-cell approach opens a new avenue to unravel a plethora of biological processes like ligand binding, folding, and post-translational modification of proteins in living cells. PMID- 26531245 TI - Identification of Reliable Components in Multivariate Curve Resolution Alternating Least Squares (MCR-ALS): a Data-Driven Approach across Metabolic Processes. AB - There is an increasing need to use multivariate statistical methods for understanding biological functions, identifying the mechanisms of diseases, and exploring biomarkers. In addition to classical analyses such as hierarchical cluster analysis, principal component analysis, and partial least squares discriminant analysis, various multivariate strategies, including independent component analysis, non-negative matrix factorization, and multivariate curve resolution, have recently been proposed. However, determining the number of components is problematic. Despite the proposal of several different methods, no satisfactory approach has yet been reported. To resolve this problem, we implemented a new idea: classifying a component as "reliable" or "unreliable" based on the reproducibility of its appearance, regardless of the number of components in the calculation. Using the clustering method for classification, we applied this idea to multivariate curve resolution-alternating least squares (MCR ALS). Comparisons between conventional and modified methods applied to proton nuclear magnetic resonance ((1)H-NMR) spectral datasets derived from known standard mixtures and biological mixtures (urine and feces of mice) revealed that more plausible results are obtained by the modified method. In particular, clusters containing little information were detected with reliability. This strategy, named "cluster-aided MCR-ALS," will facilitate the attainment of more reliable results in the metabolomics datasets. PMID- 26531246 TI - Impact of Plasmodium falciparum Coinfection on Longitudinal Epstein-Barr Virus Kinetics in Kenyan Children. AB - Endemic Burkitt lymphoma is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum coinfection, although how P. falciparum exposure affects the dynamics of EBV infection is unclear. We have used a modeling approach to study EBV infection kinetics in a longitudinal cohort of children living in regions of high and low malaria transmission in Kenya. Residence in an area of high malaria transmission was associated with a higher rate of EBV expansion during primary EBV infection in infants and during subsequent episodes of EBV DNA detection, as well as with longer episodes of EBV DNA detection and shorter intervals between subsequent episodes of EBV DNA detection. In addition, we found that concurrent P. falciparum parasitemia also increases the likelihood of the first and subsequent peaks of EBV in peripheral blood. This suggests that P. falciparum infection is associated with increased EBV growth and contributes to endemic Burkitt lymphoma pathogenesis. PMID- 26531247 TI - Efficacy of Favipiravir Alone and in Combination With Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever. AB - We studied the therapeutic potential of favipiravir (T-705) for Lassa fever, both alone and in combination with ribavirin. Favipiravir suppressed Lassa virus replication in cell culture by 5 log10 units. In a novel lethal mouse model, it lowered the viremia level and the virus load in organs and normalized levels of cell-damage markers. Treatment with 300 mg/kg per day, commenced 4 days after infection, when the viremia level had reached 4 log10 virus particles/mL, rescued 100% of Lassa virus-infected mice. We found a synergistic interaction between favipiravir and ribavirin in vitro and an increased survival rate and extended survival time when combining suboptimal doses in vivo. PMID- 26531248 TI - Finer Distinctions: Variability in Satisfied Older Couples' Problem-Solving Behaviors. AB - This study utilized observational and self-report data from 64 maritally satisfied and stable older couples to explore if there were meaningful differences in how couples approached marital disagreements. Using a typology approach to classify couples based on their behaviors in a 15-minute problem solving interaction, findings revealed four types of couples: (1) problem solvers (characterized by both spouses' higher problem-solving skills and warmth), (2) supporters (characterized by both spouses' notable warmth), (3) even couples (characterized by both spouses' moderate problem-solving skills and warmth), and (4) cool couples (characterized by both spouses' greater negativity and lower problem-solving skills and warmth). Despite the differences in these behaviors, all couples had relatively high marital satisfaction and functioning. However, across nearly all indices, spouses in the cool couple cluster reported poorer marital functioning, particularly when compared to the problem solvers and supporters. These findings suggest that even modest doses of negativity (e.g., eye roll) may be problematic for some satisfied couples later in life. The implications of these typologies are discussed as they pertain to practitioners' efforts to tailor their approaches to a wider swath of the population. PMID- 26531249 TI - Years of life lost due to metastatic melanoma in 12 countries. AB - BACKGROUND: Regionally or distantly metastatic melanoma (stages IIIB/C and IV) place a high burden on society. To quantify this burden, this study estimated years of life lost (YLL) per patient for adults with metastatic melanoma in 12 countries in 2014. METHODS: General population growth and life expectancy were estimated from the Organization for Economic Co-operation and Development data and life tables for each country. Incidence of melanoma and mortality rates for the disease were based on GLOBOCAN and US registry data. The prevalence of metastatic melanoma was calculated using mortality rates and survival data from patients with melanoma. YLL per patient was estimated by the difference between the disease-free life expectancy and the life expectancy with metastatic melanoma. RESULTS: YLL per patient were as follows: Australia, men = 19.9 years, women = 22.7 years; Brazil, 16.3, 19.8; Canada, 19.4, 22.3; France, 18.8, 23.1; Germany, 18.3, 20.8; Italy, 19.3, 22.7; Mexico, 17.2, 19.0; the Netherlands, 18.5, 21.5; Spain, 19.2, 23.1; Sweden 19.4, 22.0; the UK, 18.7, 21.2; and the US, 17.9, 20.6. CONCLUSIONS: The burden of metastatic melanoma as measured by YLL is substantial in all 12 countries; although there is variation across countries and between men and women. PMID- 26531250 TI - Importance of demographic history for phylogeographic inference on the arctic alpine plant Phyllodoce caerulea in East Asia. AB - Arctic-alpine plants have enormous ranges in the Northern Hemisphere. Phylogeographic studies have provided insights into their glacial survival as well as their postglacial colonization history. However, our understanding of the population dynamics of disjunct alpine populations in temperate regions remains limited. During Pleistocene cold periods, alpine populations of arctic-alpine species in East Asia were either connected to an ice-free Beringia refugium or they persisted with prolonged isolation after their establishment. To estimate which of these scenarios is more likely, we elucidated the genetic structure of Phyllodoce caerulea (Ericaceae) in Beringia and northern Japan, East Asia. Sequence variation in multiple nuclear loci revealed that P. caerulea can be distinguished into northern and southern groups. A demographic analysis demonstrated that the north-south divergence did not predate the last glacial period and detected introgression from Phyllodoce aleutica, relative widely distributed in East Asia, exclusively into the southern group. Therefore, although there has been genetic divergence between northern Japan and Beringia in P. caerulea, the divergence is unlikely to have resulted from their prolonged geographic separation throughout several cycles of glacial and interglacial periods. Instead, our study suggests that the introgression contributed to the genetic divergence of P. caerulea and that the range of P. caerulea was plausibly connected between northern Japan and Beringia during the last glacial period. Overall, our study not only provides a biogeographic insight into alpine populations of arctic-alpine plants in East Asia but also emphasizes the importance of careful interpretation of genetic structure for inferring phylogeographic history. PMID- 26531251 TI - Mitochondrial DNA variants help monitor the dynamics of Wolbachia invasion into host populations. AB - Wolbachia is the most widespread endosymbiotic bacterium of insects and other arthropods that can rapidly invade host populations. Deliberate releases of Wolbachia into natural populations of the dengue fever mosquito, Aedes aegypti, are used as a novel biocontrol strategy for dengue suppression. Invasion of Wolbachia through the host population relies on factors such as high fidelity of the endosymbiont transmission and limited immigration of uninfected individuals, but these factors can be difficult to measure. One way of acquiring relevant information is to consider mitochondrial DNA (mtDNA) variation alongside Wolbachia in field-caught mosquitoes. Here we used diagnostic mtDNA markers to differentiate infection-associated mtDNA haplotypes from those of the uninfected mosquitoes at release sites. Unique haplotypes associated with Wolbachia were found at locations outside Australia. We also performed mathematical and qualitative analyses including modelling the expected dynamics of the Wolbachia and mtDNA variants during and after a release. Our analyses identified key features in haplotype frequency patterns to infer the presence of imperfect maternal transmission of Wolbachia, presence of immigration and possibly incomplete cytoplasmic incompatibility. We demonstrate that ongoing screening of the mtDNA variants should provide information on maternal leakage and immigration, particularly in releases outside Australia. As we demonstrate in a case study, our models to track the Wolbachia dynamics can be successfully applied to temporal studies in natural populations or Wolbachia release programs, as long as there is co-occurring mtDNA variation that differentiates infected and uninfected populations. PMID- 26531252 TI - Genomic population structure and prevalence of copy number variations in South African Nguni cattle. AB - BACKGROUND: Copy number variations (CNVs) are modifications in DNA structure comprising of deletions, duplications, insertions and complex multi-site variants. Although CNVs are proven to be involved in a variety of phenotypic discrepancies, the full extent and consequence of CNVs is yet to be understood. To date, no such genomic characterization has been performed in indigenous South African Nguni cattle. Nguni cattle are recognized for their ability to sustain harsh environmental conditions while exhibiting enhanced resistance to disease and parasites and are thought to comprise of up to nine different ecotypes. METHODS: Illumina BovineSNP50 Beadchip data was utilized to investigate genomic population structure and the prevalence of CNVs in 492 South African Nguni cattle. PLINK, ADMIXTURE, R, gPLINK and Haploview software was utilized for quality control, population structure and haplotype block determination. PennCNV hidden Markov model identified CNVs and genes contained within and 10 Mb downstream from reported CNVs. PANTHER and Ensembl databases were subsequently utilized for gene annotation analyses. RESULTS: Population structure analyses on Nguni cattle revealed 5 sub-populations with a possible sub-structure evident at K equal to 8. Four hundred and thirty three CNVs that formed 334 CNVRs ranging from 30 kb to 1 Mb in size are reported. Only 231 of the 492 animals demonstrated CNVRs. Two hundred and eighty nine genes were observed within CNVRs identified. Of these 149, 28, 44, 2 and 14 genes were unique to sub-populations A, B, C, D and E respectively. Gene ontology analyses demonstrated a number of pathways to be represented by respective genes, including immune response, response to abiotic stress and biological regulation processess. CONCLUSIONS: CNVs may explain part of the phenotypic diversity and the enhanced adaptation evident in Nguni cattle. Genes involved in a number of cellular components, biological processes and molecular functions are reported within CNVRs identified. The significance of such CNVRs and the possible effect thereof needs to be ascertained and may hold interesting insight into the functional and adaptive consequence of CNVs in cattle. PMID- 26531253 TI - A highly reactive chalcogenide precursor for the synthesis of metal chalcogenide quantum dots. AB - Metal chalcogenide semiconductor nanocrystals (NCs) are ideal inorganic materials for solar cells and biomedical labeling. In consideration of the hazard and instability of alkylphosphines, the phosphine-free synthetic route has become one of the most important trends in synthesizing selenide QDs. Here we report a novel phase transfer strategy to prepare phosphine-free chalcogenide precursors. The anions in aqueous solution were transferred to toluene via electrostatic interactions between the anions and didodecyldimethylammonium bromide (DDAB). The obtained chalcogenide precursors show high reactivity with metal ions in the organic phase and could be applied to the low-temperature synthesis of various metal chalcogenide NCs based on a simple reaction between metal ions (e.g. Ag(+), Pb(2+), Cd(2+)) and chalcogenide anions (e.g. S(2-)) in toluene. In addition to chalcogenide anions, other anions such as BH4(-) ions and AuCl4(-) ions can also be transferred to the organic phase for synthesizing noble metal NCs (such as Ag and Au NCs). PMID- 26531254 TI - Differential expression of ATP-gated P2X receptors in DRG between chronic neuropathic pain and visceralgia rat models. AB - There are divergences between neuropathic pain and visceralgia in terms of the duration, location, and character of hyperalgesia. It is generally recognized that nociceptive receptors, including P2X receptors, may play different roles in nociceptive mechanisms. The different roles of P2X1-7 receptors have not been fully understood both in neuropathic pain and visceral hyperalgesia. In order to explore the different expressions of P2X1-7 receptors in these two hyperalgesia models, the lumbosacral dorsal root ganglion (DRG) neurons from rat sciatic nerve chronic constriction injury (CCI) model and neonatal colorectal distention (NCRD) model were studied (both the primary nociceptive neuron afferents of those two models projected to the same segment of spinal cord). Both immunohistochemistry (IHC) technique and real-time fluorescence quantitative polymerase chain reaction (RT-PCR) technology were applied to analyze the protein expression levels and nucleic acid of P2X1-7 receptors. We found that except P2X2 and P2X3, the expression levels of P2X1 and P2X5 receptors increased in neuropathic pain while those expression levels of P2X4, P2X6, and P2X7 receptors increased in visceral pain. Our results also suggested that in addition to P2X2/3 heteromeric, other P2X subunits may also involved in generation heteromeric such as P2X1/5 and/or P2X2/5 in neuropathic pain and P2X4/6 and/or P2X4/7 in visceral pain. PMID- 26531255 TI - The Potential Utility of Acceptance and Commitment Therapy (ACT) for Reducing Stress and Improving Wellbeing in Cancer Patients in Kolkata. AB - As soon as a patient comes to know that he/she has cancer, the stress starts and psychological intervention is required. The authors assessed how well a cancer patient can manage stress over the course of the psychological intervention. Data was collected among 107 patients during pre and post intervention and at 2 months follow-up. Intervention was required to measures include acceptance of the disease, managing stress, well -being, and meaning of life. Finally, effects of acceptance and commitment therapy (ACT) were defined in acceptance measured in terms of a significant difference between pre and post intervention scores in the meaning of life and the acceptance level. This acceptance and commitment therapy can be an effective intervention approach for cancer patients that increases acceptance regarding disease and simultaneously leads to improvement in the meaning of life. PMID- 26531256 TI - GPs face sevenfold rise in fees to healthcare regulator. PMID- 26531257 TI - The high rate of long-term recurrences and sequelae after epistaxis treatment. AB - OBJECTIVE: Epistaxis is the most frequent rhinologic emergency with a high treatment morbidity. This study assessed the long-term outcome after epistaxis treatment with regard to patient comfort during the treatment, long-term complications and rate of recurrences. METHODS: A questionnaire cohort study was performed at the ENT department of the University Hospital Zurich. In April 2014, 363 patients were contacted, who were treated between March 2007 and April 2008 for the reason of epistaxis using a written questionnaire to elucidate the patients' condition after the treatment. The type of treatment, subjective discomfort as well as degree of pain, complications, permanent sequelae and recurrences were assessed. RESULTS: 109 questionnaires were analyzed (response rate of 36%). The overall same-sided recurrence rate after successful treatment during the 6.4-year follow-up was 22%. Discomfort was reported in 48% after cautery, 86% after packing and in 11% after surgery. Strong or very strong pain was perceived in 8% after cautery, 26% after packing and in 0% after surgery alone. Complications consisted of nasal crusting in 15% after cautery and nasal breathing impairment in 24% after packing. Permanent harm was reported in 4% after cautery versus 20% after packing plus surgery. CONCLUSIONS: The data confirm the high rate of recurrences despite adequate treatment in the long-term analysis. The rate of post-treatment complications is considerably high with nasal crusting being the main inconvenience. It further shows that patients keep a vivid memory of the treatment even many years later and that packing is extremely uncomfortable to patients. PMID- 26531258 TI - Triptolide reverses the Taxol resistance of lung adenocarcinoma by inhibiting the NF-kappaB signaling pathway and the expression of NF-kappaB-regulated drug resistant genes. AB - Paclitaxel (or Taxol(r)) is a first-line chemotherapeutic drug for the treatment of non-small cell lung cancer; however, resistance to the drug is an important factor, which influences the outcome of chemotherapy. The present study aimed to investigate the role of triptolide (TPL) in reversing Taxol-resistant human lung adenocarcinoma and to elucidate the underlying molecular mechanism of resistance reversal mediated by TPL. It was hypothesized that this experimental approach would assist in solving the problem of chemotherapeutic resistance in non-small cell lung cancer, thereby improving the clinical outcomes. The human Taxol resistant lung adenocarcinoma cell line, A549/Taxol, was established. The resistance index of the cell line was calculated, according to the half maximal inhibitory concentration (IC50) of A549/Taxol IC50 of A549, to be 51.87. The levels of apoptosis and the cell cycle in the A549/Taxol cell line were assessed to confirm the effects of TPL at three different concentrations (0.03, 0.3 and 3 umol/l) and treatment durations (2, 4, 6 and 12 h) by flow cytometric analysis, and the inhibition of the NF-kappaB signaling pathway and the expression of NF kappaB-regulated drug-resistant proteins were determined by immunofluorescence and western blotting, respectively. The administration of TPL promoted cell apoptosis in the A549/Taxol lung adenocarcinoma Taxol-resistant cell line and also promoted cell cycle regulation. The drug was also able to elicit a reversal of the drug resistance. TPL inhibited the nuclear factor-kappaB (NF-kappaB) signaling pathway and the expression of NF-kappaB-regulated drug-resistant genes, including those for FLICE-like inhibitory protein, X-linked inhibitor of apoptosis protein, Bcl-2, Bcl-xL and cyclo-oxygenase-2. TPL exerted a marked drug resistance-reversal effect on human lung adenocarcinoma Taxol resistance, and the effect was revealed to be dose- and time-dependent. In conclusion, TPL exerted its role in the process of resistance reversal by inhibiting the NF-kappaB signaling pathway, and the transcription and expression of NF-kappaB-regulated drug-resistant genes. PMID- 26531259 TI - Smart protein biogate as a mediator to regulate competitive host-guest interaction for sensitive ratiometric electrochemical assay of prion. AB - A novel competitive host-guest strategy regulated by protein biogate was developed for sensitive and selective analysis of prion protein. The methylene blue (MB)-tagged prion aptamer (MB-Apt) was introduced to the multiwalled carbon nanotubes-beta-cyclodextrins (MWCNTs-beta-CD) composites-modified glassy carbon (GC) electrode through the host-guest interaction between beta-CD and MB. In the absence of prion, MB-Apt could be displaced by ferrocenecarboxylic acid (FCA) due to its stronger binding affinity to beta-CD, resulting in a large oxidation peak of FCA. However, in the presence of prion, the specific prion-aptamer interaction drove the formation of protein biogate to seal the cavity of beta-CD, which hindered the guest displacement of MB by FCA and resulted in the oxidation peak current of MB (IMB) increased and that of FCA (IFCA) decreased. The developed aptasensor showed good response towards the target (prion protein) with a low detection limit of 160 fM. By changing the specific aptamers, this strategy could be easily extended to detect other proteins, showing promising potential for extensive applications in bioanalysis. PMID- 26531260 TI - Novel heart rate turbulence parameters. PMID- 26531261 TI - The influence of high volume hemofiltration on extra vascular lung water and alveolar-arterial oxygen pressure difference in patients with severe sepsis. AB - OBJECTIVE: To explore the effects of high-volume hemofiltration (HVHF) on the plasma interleukin-6 (IL-6), pro-calcitonin (PCT), extra vascular lung water index (EVLWI) and alveolar-arterial oxygen exchange in patients with septic shock. PATIENTS AND METHODS: 97 cases intensive patients with septic shock were enrolled from Department of Intensive Care Unit (ICU) of the Provincial Hospital affiliated to Shandong University between January 2011 and December 2014. According to the puting into practice of high-volume hemofiltration (HVHF) or not, all the patients were divided in two groups (NHVHF group, group A, n = 46 cases) and (HVHF group, group B, n = 51 cases). The plasma IL-6, PCT intrathoracic blood volume index (ITBVI), extra-vascular lung water index (EVLWI) and pulmonary vascular permeability index(PVPI) was detected before treatment and after treatment 24h, 72h The Alveolar- arterial oxygen pressure difference P(A a)DO2 was checked by arterial blood gas analysis (ABGA) at first and after treatment 24 hour, 72 hour, 7 day in two groups. The mortality at 28 day was compared between two groups. RESULTS: After 72h treatment, the plasma IL-6, PCT in group B has a significant decrease. After 72h treatment, the level ITBVI, EVLWI and PVPI in group B had a significant improvement. The levels of P(A-a)DO2 in HVHF group were reduced more significantly than N-HVHF group after 7 day. The EVLWI and P(A-a)DO2 had a significant positive correlation (correlation ratio = 0.712, 95% confident interval [0.617, 0.773], p = 0.001). The mortality at 28 day had a significant decrease between groups (15.22% vs. 34.15% chi2 = 4.242, p = 0.038). CONCLUSIONS: HVHF could decrease plasma inflammatory factors and EVLWI so that it could improve the levels of alveolar-arterial-oxygen exchange in patients with septic shock, so it could improve the survival rate of patients. PMID- 26531262 TI - Clinical study of 23 pediatric patients with cryptococcosis. AB - OBJECTIVE: Cryptococcus neoformans is a common opportunistic infection in adults with acquired immunodeficiency syndrome. However, limited data exist for pediatric patients. The aim of this study was to describe the clinical characteristics of cryptococcosis in pediatric patients. PATIENTS AND METHODS: A retrospective study was conducted at West China Second University Hospital, Sichuan University. Data on risk factors, clinical manifestations, diagnosis methods, treatment, and prognosis were evaluated. Clinical characteristics associated with cryptococcal meningitis and disseminated cryptococcosis were compared. RESULTS: Twelve cases of cryptococcal meningitis and 11 cases of disseminated cryptococcosis were identified. Seventeen cases had no underlying disease, but 6 cases had malnutrition. Only 6 cases had a history of exposure to pigeon droppings. No cases had pulmonary cryptococcosis alone. Coughing, pulmonary moist rales, swollen lymph nodes, liver and spleen, and skin rashes were seen only in disseminated cryptococcosis. The prevalence of headache and positive meningeal irritation sign was higher in cryptococcal meningitis than disseminated cryptococcosis. The proportion of increase in eosinophils was higher in disseminated cryptococcosis than cryptococcal meningitis. The primary methods used for diagnosis included cerebrospinal fluid ink staining, cerebrospinal fluid culture, blood culture, and lymph node biopsy. Two patients stopped treatment, and 21 patients received antifungal therapy. The mortality rate was 39.13%. CONCLUSIONS: Cryptococcosis occurs in non-HIV infected and immunocompetent children. Cryptococcosis lacks specific clinical manifestations. Disseminated cryptococcosis commonly occurs in children. Clinicians should consider a diagnosis of disseminated cryptococcosis for children who present with unexplained long-term fever, mild cough, chest imaging inconsistent with clinical symptoms, lymphadenectasis, hepatosplenomegaly, and eosinophilia. PMID- 26531263 TI - Predictors of Crimean-Congo hemorrhagic fever in the Emergency Department. AB - OBJECTIVE: Crimean-Congo hemorrhagic fever (CCHF) is an acute illness affecting multiple organ systems characterized by thrombocytopenia, and/or leukopenia, elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatine kinase (CK) and it has a case fatality of 8% to 80%. In this article, we aimed to determine the clinical and laboratory findings that predicts the disease on admission. PATIENTS AND METHODS: We retrospectively analyzed the medical data of the patients admitted to our emergency department (ED) due to tick bite. These patients were divided into two groups according to their transcriptase-polymerase chain reaction (RT-PCR) test results. Findings of PCR (+) (Group 1) and PCR (-) (Group 2) patients were compared. RESULTS: Epistaxis was found to be statistically significant clinical finding in Group 1. Also, while aspartate transaminase (AST) levels and potassium (K) level were significantly higher, platelet count and white blood count (WBC) were significantly lower in Group 1 when compared to Group 2. CONCLUSIONS: Predictors of CCHF in the ED are epistaxis, leukopenia, thrombocytopenia and elevated K and AST levels. In our study, the fatality rate of CCHF was found to be 21.6%. PMID- 26531264 TI - The relationship between the internal oxidation-reduction system and fetal distress on pregnant patients with intrahepatic cholestasis. AB - OBJECTIVE: To discuss the relationship between the internal oxidation-reduction system and fetal distress in pregnant patients with intrahepatic cholestasis in order to provide a new basis for clinical treatment and research. PATIENTS AND METHODS: From March 2012 to March 2015, eighty patients with intrahepatic cholestasis of pregnancy (ICP) were selected and divided into two groups: the distressed group (n = 31) and non-distressed group (n = 49). We compared the two groups for differences in MDA, SOD, NO level, GSH level, venous blood and total bile acid level. The relevance of the oxidation-reduction system indicators and the venous blood and total bile acid levels, as well as the differences in the delivery outcome and fetal distress, were compared between the two groups. RESULTS: The serum MDA level of the distressed group was higher than the non distressed group while the SOD, NO, and GSH levels were lower than the non distressed group. All differences were statistically significant (p < 0.05). Both the venous blood and total bile acid levels in the distressed group were higher than the non-distressed group and were statistically significant (p < 0.05). Based on Pearson's analysis, MDA was positively associated with the venous blood and total bile acid levels while SOD, NO and GSH levels were negatively associated with it. All differences were statistically significant (p < 0.05). The death rate of cesarean section and perinatal infant in the distressed group were higher than that of the non-distressed group. The proportion of mild and severe asphyxia was higher than the non-distressed group. However, the neonatal weight of the distressed group was lower. All differences were statistically significant (p < 0.05). CONCLUSIONS: The internal oxidation-reduction system indicators of pregnant patients with intrahepatic cholestasis, which are MDA, SOD, NO and GSH levels, may contribute to the occurrence of fetal distress. PMID- 26531265 TI - High-pressure physiological saline isotonic solution administration enhances brain NGF and NGF-receptors expression. AB - OBJECTIVE: Nerve growth factor (NGF) is a neurotrophin which promotes and regulates the survival of neurons in the peripheral nervous system. The aim of this study was to investigate the effect of high-pressure administration of sterile physiological saline isotonic solution (HpPSIS) into nasal cavity of laboratory animals on NGF levels and NGF-receptor expression in the olfactory bulbs and brain. MATERIALS AND METHODS: For this study we used three weeks old female Sprague Dawley SD rats (n=48). Rats were divided into two groups, the first one treated delivering physiological saline solution with a normal syringe modified at the extremity to fit the rats' nostril (5 ml) (n=24) and the second one treated spray with HpPSIS (n=24 rats). Rats were treated three times a day either for 5 consecutive days (shorth term treatment) or 10 consecutive days (longer treatment) in both nostrils of HpPSIS delivered at high pressure (pression emission level: PEL: 7 g/sec for emission time ET: 0.5 sec) with a specific forced spray erogator. Untreated rats received a similar manipulation three times a day through a syringe in the nostrils, but no HpPSIS administration. RESULTS: The results of these studies highlight the possibility that endogenous enhancement of NGF by stimulation of NGF-producing cells within the nasal cavities and also in the CNS represent a novel experimental approach to enhance the brain NGF levels with a new therapy. HpPSIS treatment further enhances the presence of NGF in the four brains examined. Indeed, a significant increase of NGF was first observed after 5 days of HpPSIS treatment, compared to HpPSIS untreated rats. The increase was over 25% in the OB, ST, HI and in CX, while 10 days after HpPSIS treatments the levels of NGF were even higher. These differences were statistically significant, p < 0.05. CONCLUSIONS: It was found that forced administration of HpPSIS enhances the presence of these neurotrophic signals, not only in the olfactory bulbs, but also in forebrain cholinergic neurons, which are known to degenerate as result of memory loss and brain aging, including Alzheimer Disease. These findings for the first time in the literature demonstrate the possibility of enhancing the endogenous NGF to protect NGF damaged neurons. Since the enhanced expression of NGF was first observed after 5 days of treatment and higher after 10 days of treatment, a reasonable hypothesis is that longer HpPSIS treatment might further enhance the level of NGF in brain and olfactory bulbs. PMID- 26531266 TI - A study of autologous stem cells therapy assisted regeneration of cartilage in avascular bone necrosis. AB - Application of 'regenerative medicine' has given a new hope to surgeons for the treatment of several chronic diseases and disorders including severe orthopedic conditions. There are a myriad of orthopedic conditions and injuries that presently have limited therapeutic treatments and could benefit from new developing therapies in regenerative medicine with the help of stem cell therapy[1]. Regenerative medicine therapies are mainly based on the applications of stem cells. Stem cells play a vital role in orthopedic treatments and the studies have shown to have promising results in repair of bone, tendon, cartilage including avascular necrosis (AVN), spondylitis etc. Bone and cartilage regeneration ability of stem cells has been demonstrated clinically. However, success rate may not be same in every case and it depends on the patient profile. Several factors can be responsible for the same which include patient's immune response, the type and grade of the disease, which along with other confounding factors decide the outcome of the treatment. In this paper we have presented some of the orthopedic case studies performed through autologous transplantation of the stem cells. PMID- 26531267 TI - microRNA-126 expression and its mechanism of action in patients with systemic lupus erythematosus. AB - OBJECTIVE: The aim of the present study is to investigate the expression level of microRNA-126 (miRNA-126) in the plasma of patients with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: Thirty SLE patients admitted at our institution were recruited in study group and 30 normal subjects seeking health check-up at our institution during the same period were included in control group. Plasma levels of miRNA-126 were determined using fluorescent quantitative RT-PCR. Plasma levels of IFN-alpha were determined and compared between two groups using ELISA. RT-PCR was performed to measure the levels of ISG56 mRNA, an IFN-inducible gene (IFNG), in the peripheral blood mononuclear cells (PBMC) of both groups. miRNA-126 expression was interfered in PBMC of SLE patients by introducing the mimic and inhibitor of miRNA-126. Levels of ISG56 mRNA in transfected PBMCs were determined using RT-PCR. RESULTS: Levels of miRNA-126 were significantly lower in the plasma of SLE patients than normal controls (p < 0.05). Plasma levels of IFN-alpha were significantly higher in SLE patients than normal population (p < 0.05). ISG56 mRNA in PBMC was significantly higher in SLE patients than controls (p < 0.05). As for SLE patients, levels of IFN-alpha and ISG56 mRNA were significantly decreased in PBMCs with high expression of miRNA 126 but were significantly increased in PBMCs with low expression of miRNA-126 (p < 0.05). CONCLUSIONS: miRNA-126 expression is reduced in SLE patients. miRNA-126 may be involved in the initiation and development of SLE by inhibiting the production of IFN. PMID- 26531268 TI - Recent advances in massage therapy--a review. AB - Massage therapy is one of the most widely accepted alternative form of medicine helping patients suffering from varied pathological states including arthritis, anxiety, sleep problems, pain management and injury repair. Besides this, it is one of the safest forms of alternative medicine and has become favorite among various health care professionals. However, there is still a lot of debate is going in medical world pertaining to its certain use in modern medicine. So, the present review shall enlighten all the latest aspects of massage therapy in current medicine. PMID- 26531269 TI - Extra-anatomical VATS lung resection: the outpatient experience with the aid of a digital chest drain device. AB - OBJECTIVE: The aim of the present study was to evaluate of the feasibility of video-assisted thoracic surgery (VATS) wedge resections in an outpatient setting using a digital air leak detection device. PATIENTS AND METHODS: Data from all patients who underwent outpatient VATS wedge resections from November 2010 to November 2013 was analyzed. The thoracoscopic approach was done in all cases under general anesthesia, with double lumen intubation, three port sites and one or two wedge resections without the reinforcement of the suture line. The chest drain with continuous suction (-20 cm/H2O) placed after surgery was removed when no air leak (0-10 ml/min) was detected digitally within two hours after surgery. Patients were discharged after exclusion of pneumothorax by chest x-ray. Patient distribution according to gender, smoking habit, indication for resection, number of wedge resections, and histological findings was compared. RESULTS: In the study period, 66 VATS patients (44.3%) of al VATS procedures were eligible for the outpatient procedure. Fifty-five of them (83.3%) were discharged on the same day, while 11 were admitted due to patients preference, presence of an air leak or for other medical reasons. In the outpatient group (OG) the indications for surgery were lung nodules in 90.9% (50 cases) and interstitial disease in the remaining 9.1%. In the OG, 18 patients (32.7%) received two wedge resections. All patients had no leak detected by digital device prior to drainage removal. The overall re-admission rate was 7.3% (4/55). Statistical analysis did not show any difference regarding sex, smoking habits, indications for surgery, number of parenchymal resection, disease localization, and malignant histology. All patients who had an outpatient procedure confirmed that they would repeat the procedure. CONCLUSIONS: Outpatient thoracoscopic non-anatomic resections managed with a digital chest drain device have both low complication rates as well as lead to fewer re-admissions. Because of the growing number of VATS Wedge Resections due to pre-identified lung nodules, this could have important implications. Further research should identify the most suitable subgroup of patients for this approach. PMID- 26531270 TI - Predictors of outcome for patients with severe respiratory failure requiring non invasive mechanical ventilation. AB - OBJECTIVE: Failure to identify patients in whom non-invasive ventilation (NIV) would be unsuccessful may cause inappropriate delay in intubation. Aim of this study was to determine predictors of NIV failure. PATIENTS AND METHODS: We retrospectively evaluated COPD patients, undergoing NIV for at least 12h because of hypercapnic acute respiratory failure. Univariable and multivariable analyses were performed on: age, gender, APACHE II and GCS, gas exchange at admission, during NIV and at discharge/death, length of stay. ROC analysis for pH START and APACHE II were performed. RESULTS: Among 201 individuals enrolled, NIV failed in 50. In the logistic regression model only APACHE II was found to have an independent effect on the outcome (p < 0.0001, OR 1.179, 95% CI 1.101-1.263 as quantitative variable; p < 0.0001, OR 3.753, 95% CI 1.798-7.835, as qualitative variable, > 20.5). CONCLUSIONS: APACHE II may be a crucial parameter in predicting NIV failure; further multicentric studies are needed to better define NIV indications. PMID- 26531271 TI - Is there a correlation between the pineal gland calcification and migraine? AB - OBJECTIVE: The pineal gland calcifications have been associated with some diseases such as cerebral infarction, Alzheimer's disease and intracerebral hemorrhage while most cases are considered idiopathic and physiologic. However, there are limited data in the current literature about the association of pineal calcification and migraine. Our aim was to evaluate this association between migraine and pineal calcification by computed tomography of the brain. PATIENTS AND METHODS: In our study, we assessed the computed tomography images of patients, who referred to the neurology outpatient clinic with the complaint of headache and were diagnosed with migraine without aura based according to 2004 criteria of the International Headache Society. 503 migraine patients and 500 control subjects without migraine diagnosis were included in this study. RESULTS: When migraine and control groups were compared by pineal calcification, the rates were determined as 80, 6% and 55% in migraine and control group, respectively. The difference was statistically significant (p < 0.001). In addition, it was seen that pineal calcifications, detected in migraine patients, did not show age related increase. CONCLUSIONS: According to our data, we can point that pineal calcification may be associated with migraine. PMID- 26531272 TI - Comparison of the after discharges induced by electrical stimulation of the prefrontal cortex in urethane- and ketamine-anesthetized mice. AB - OBJECTIVE: The study aims to compare the effects of urethane and ketamine anesthesia on kindling-induced after discharges (AD). MATERIALS AND METHODS: We divided forty 4-6 week old female C57BL/6J mice into two groups: one group was anesthetized with urethane (n = 20) and the other with ketamine (n = 20). Kindling was with an electrical stimulation (ES) consisting of a 1-s pulse train of 60 1-ms biphasic pulses at an initial intensity of 700 uA, delivered to the pre-frontal cortex every minute. Ten to fifteen minutes after the first AD was induced, identical electrical stimuli were delivered every 10 minutes for 200 minutes. EEG was continuously recorded from 15 minutes before the first ES until 10 minutes after the last ES. The EEG wave spectrum was analyzed by Fast Fourier Transform and the power spectrum densities (PSDs) of the delta, theta, alpha, beta and gamma bands were calculated. EEG wave amplitude was assessed using the root mean square value (RMS). RESULTS: In the urethane group, an initial AD was induced in 70% of mice following 39 ES. In the ketamine group, an initial AD was induced in 60% of mice following 74 ES. The changes in EEG spectra were similar in both groups. Pre-AD, EEG waves predominantly consisted of delta and theta components. During AD, gamma and beta components increased significantly (p < 0.05). Post-AD, beta and gamma components decreased and the delta: theta ratio increased to pre-AD levels. CONCLUSIONS: Our data suggest that AD can be induced by kindling stimulation of the pre-frontal cortex in mice under either urethane or ketamine anesthesia. PMID- 26531273 TI - The correlation of Helicobacter Pylori with the development of cholelithiasis and cholecystitis: the results of a prospective clinical study in Saudi Arabia. AB - OBJECTIVE: Gallstone disease is a common surgical ailment. Helicobacter pylori has a role in upper gastrointestinal disorders, including gallstones. This study aimed to determine the association of H. pylori with gallstones, so developing a preventative strategy for gallstone formations. PATIENTS AND METHODS: A prospective study was conducted on 95 patients referred to the surgical clinic of Al-Meeqat General Hospital, Al-Madinah Al-Munawarah, with gallstone disease. Detection of H. pylori antibodies (IgG) in serum was done in all the patients who underwent cholecystectomy. H. pylori stool antigen (HPSA) using stool samples was done for IgG sero-positive patients prior to the cholecystectomy. The bile collected from the gall bladder during operation was examined for the presence of H. pylori by Gram stain, culture and HPSA assay. Gallbladder mucosa was examined for urease A gene by polymerase chain reaction (PCR) in patients proven to be positive for stool or bile serology. RESULTS: Of the 95 patients, 75 (79%) were positive for H. pylori antibodies. Twenty-six (34.7%) patients were positive with H. pylori antigens in bile and 21 (28%) with H. pylori antigens in the stool samples. Among these 47 patients, PCR was positive in 29 (62%) subjects. H. pylori couldn't be detected among the studied patients by using either Gram stain or culture. CONCLUSIONS: The presence of H. pylori in bile may indicate a significant risk for cholelithiasis. PCR is a rapid reliable method for the detection of H. pylori DNA in bile. This rapid molecular approach together with culture and immunological methods could help clinicians to effectively manage patients at high risk of developing gallstones at an earlier stage. PMID- 26531274 TI - Effect of exposure to silica in inducing autoimmune hepatitis: an experimental animal-controlled study. AB - OBJECTIVE: The aim of this experimental study is to investigate the effect of subcutaneous and oral sodium silicate in inducing the autoimmune hepatitis. MATERIALS AND METHODS: Twelve Brown Norway rats were studied, six rats were challenged with Sodium Silicate and the rest were challenged with normal saline as a control group. At 14th week post-sodium silicate or normal saline exposure, the rats were sacrificed. Histopathological studies were conducted in six positive autoantibodies responding silicate group rats and then compared with an equal number of negative autoantibodies responding control rats. RESULTS: The liver findings from sodium silicate group of animals showed a histopathological reaction in 3/6 (50%) compared with 0/6 of the corresponding control saline group (p = 0.09). However, the absolute differences in the percentage between the two groups was 50%, the subcutaneous sodium silicate sub-group showed hepatic tissue response close to being statistically significant level (p = 0.05). CONCLUSIONS: After correlating the results with autoantibodies including serum antinuclear antibodies and anti ribo-nucleoprotein response of the same rats, it is concluded that sodium silicate play a role in inducing the autoimmune hepatitis in a genetically susceptible rat model. PMID- 26531275 TI - Effect of different anesthesia techniques on the serum brain-derived neurotrophic factor (BDNF) levels. AB - OBJECTIVE: Serum Brain-Derived Neurotrophic Factor (BDNF) levels are associated with neurotransmission and cognitive functions. The goal of this study was to examine the effect of general anesthesia on BDNF levels. It was also to reveal whether this effect had a relationship with the surgical stress response or not. PATIENTS AND METHODS: The study included 50 male patients, age 20-40, who were scheduled to have inguinoscrotal surgery, and who were in the ASA I-II risk group. The patients were divided into two groups according to the anesthesia techniques used: general (GA) and spinal (SA). In order to measure serum BDNF, cortisol, insulin and glucose levels, blood samples were taken at four different times: before and after anesthesia, end of the surgery, and before transferal from the recovery room. RESULTS: Serum BDNF levels were significantly low (p < 0.01), cortisol and glucose levels were higher (p < 0.05 and p < 0.01) in Group GA compared with Group SA. No significant difference was detected between the groups in terms of serum insulin levels. There was no correlation between serum BDNF and the stress hormones. CONCLUSIONS: Our findings suggested that general anesthetics had an effect on serum BDNF levels independent of the stress response. In future, BDNF could be used as biochemical parameters of anesthesia levels, but studies with a greater scope should be carried out to present the relationship between anesthesia and neurotrophins. PMID- 26531276 TI - Atorvastatin might inhibit insulin resistance induced by insulin through the triglyceride-lowering role of Apolipoprotein AV. AB - OBJECTIVE: We aimed to evaluate the effect of atorvastatin on apolipoprotein AV (ApoAV) in HepG2 cells of insulin resistance (IR), and further explore its mechanism. MATERIALS AND METHODS: Firstly, a model of IR in HepG2 cells was established by insulin, and then treated with various concentrations of atorvastatin (0, 10, 100 and 500 nM) for 12 h and 24 h, respectively. Detection of glucose concentration was performed by Glucose Oxidase kit. Subsequently, Enzyme-linked immunosorbent assay (ELISA) kits were used to measure the concentrations of triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and very low density lipoprotein (VLDL). The mRNA levels of ApoAV and ApoAV-related genes, including glucose transporter 1 (Glut1), Glut2, peroxisome proliferator activated receptor alpha (PPARalpha), and liver X receptor alpha (LXRalpha) were detected by qRT-PCR. RESULTS: We successfully established IR model in HepG2 cells by 10-6 nM insulin. Subsequently, we found that the glucose extraction rate and mRNA level of ApoAV significantly reduced in HepG2 cells of IR (p < 0.05); however, atorvastatin increased the glucose extraction rate and ApoAV mRNA level. Furthermore, atorvastatin inhibited the concentration of TG in HepG2 cells of IR (p < 0.05); however, atorvastatin had no effect on HDL, LDL and VLDL. Also, atorvastatin could increase the mRNA levels of Glut2 but not Glut1, PPARalpha, and LXRalpha. CONCLUSIONS: Our study indicated that atorvastatin might inhibit IR induced by insulin through the TG-lowering role of ApoAV. Furthermore, Glut2 might be involved in the effect of atorvastatin on ApoAV in HepG2 cells of IR. PMID- 26531277 TI - Short-term efficacy of surgical treatment of secondary hyperparathyroidism. AB - OBJECTIVE: We wished to explore short-term efficacy of surgical treatment of secondary hyperparathyroidism in patients with the end-stage renal disease. The treatment methods were subtotal or total parathyroidectomy, or total parathyroidectomy and autotransplantation. PATIENTS AND METHODS: 63 patients with secondary hyperparathyroidism were randomly divided into three groups which were respectively treated with subtotal parathyroidectomy (SPTX group), total parathyroidectomy (TPTX group), or total parathyroidectomy and autotransplantation (TPTX+AT group). The surgical outcomes included operating time, transoperative bleeding volume, length of stay, and cost of hospitalization. In addition, complication (e.g., postoperative wound infection, hematoma, hypocalcemia in perioperative period) rates were compared among groups. Blood levels of calcium and parathyroid hormone were assessed before the surgery, and 1 day, 1 months, 3 months and 6 months after the surgery. The follow-up period comprised 6 months. RESULTS: Surgical outcomes were the lowest in SPTX group and the highest in in TPTX+AT group. There were no significant differences among groups in treatment efficacy. Complication rates were also comparable among the three groups. The occurrence of hypocalcemia was the lowest in SPTX group (p < 0.05 vs. other groups). However, postoperative relapse rate was the highest in this group (p < 0.05 vs. other groups). There were no correlations between the levels of blood calcium and PTH preoperatively and postoperatively. CONCLUSIONS: Appropriate surgical treatment is selected in accordance with the patient's condition and willingness, with the attention paid to the prevention of hypocalcemia. PMID- 26531278 TI - Hypokalemic rhabdomyolysis: a rare manifestation of primary aldosteronism. AB - Rhabdomyolysis is a rare presentation of hypokalemia, although muscle weakness is a well-known manifestation of hypokalemia. Primary aldosteronism is characterized by hypertension, suppressed plasma renin activity, increased aldosterone excretion and hypokalemia with metabolic alkalosis. Rhabdomyolysis is not common in primary aldosteronism. We present here a 40-year-old woman presenting with rhabdomyolysis accompanied by severe hypokalemia as heralding symptom of primary aldosteronism. PMID- 26531279 TI - New probing and warm-wash-out technique improves early patency rates in arteriovenous fistula surgery. AB - OBJECTIVE: Arteriovenous fistulas (AVFs) are commonly used during hemodialysis. Early failure of AVFs is quite common with incidence of 43% to 63%. In this study we aimed to describe a novel approach to AVF surgery for improving early patency rates. PATIENTS AND METHODS: Patients were divided into two groups according to use of probing and warm-wash-out technique. Group I consisted of 31 patients with additional probing technique. Group II consisted of 32 patients without additional maneuver. End-to-side anastomosis were used to all patients. Technical success was defined as having palpation of a thrill on fistula. Flow rates of draining vein was measured at 1st hour, 24th hour, 1st week and 3rd week of surgery. SURGICAL TECHNIQUE: Classical maneuvers were performed until end of the anastomosis. At this time, vein lumen was washed by low-dosed heparinized warm fluid, with assistance of a simple catheter. RESULTS: Technical success was similar in both groups at 1st hour and 24th hour, while there were significantly differences between groups at 1st week (p = 0.042) and 3rd week (p = 0.05) assessments. Flow rates were also measured significantly higher in Group I at 1st hour (p = 0.011) and 24th hour (p = 0.016). Flow rates were almost similar in two groups at 1st and 3rd weeks but overall success rate was higher in Group I comparing with Group II (96.8% vs. 81.3%, respectively, p = 0.05). CONCLUSIONS: Probing and warm-wash out technique will simply increase the surgical success and flow rate of draining vein. PMID- 26531280 TI - Autonomic impairment in patients with migraine. AB - OBJECTIVE: Heart rate variability analysis of electrocardiogram is becoming an increasingly common method to non-invasively evaluate autonomic nervous function. The aim of the study was to investigate cardiac autonomic function in subjects with and without migraine by using 24-hour ambulatory electrocardiographic recordings. PATIENTS AND METHODS: We investigated 27 subjects with migraine (10 with migraine with aura and 17 without aura) during headache free periods and 10 age-matched healthy control subjects. The migraine was diagnosed using the International Classification of Headache Disorders 2nd Edition criteria. Beck Depression and Beck Anxiety Inventory forms were completed by all subjects. Time and frequency-domain of HRV was analyzed for two periods: diurnal and nocturnal. RESULTS: We found an increased frequency of anxiety and depressive symptoms in migraine patients, especially in migraine with aura group. The heart rate variability parameters SDNN, RMSSD, high frequency were decreased and low frequency was increased in migraine patients during night period compared with normal subjects, most affected were migraine with aura patients. During day period we found modification for SDNN, RMSSD and high frequency parameters only in migraine with aura group. CONCLUSIONS: Reduced parasympathetic activity with sympathetic predominance was found in migraine patients during the night period, most affected being migraine with aura patients. PMID- 26531281 TI - Assessment of the left ventricular systolic function in multi-vessel coronary artery disease with normal wall motion by two-dimensional speckle tracking echocardiography. AB - OBJECTIVE: To evaluate the clinical value of two-dimensional speckle tracking echocardiography for analyzing the left ventricular systolic function in patients with multi-vessel coronary artery disease with normal wall motion (NWM-MVD). PATIENTS AND METHODS: Forty-five NWM-MVD patients and thirty-six subjects with low risk of coronary artery disease (control group) were enrolled in this study. Echocardiogram images of the short axis of the left ventricle and apical long axis were obtained. The Q-analysis software was used to analyze the peak systolic strain of the left ventricular segments and the global longitudinal strain (GLS). We calculated the left ventricular global circumferential strain (GCS) and the radial strain (GRS), as well as the longitudinal, radial and circumferential strain of the basal (Bas-GLS, Bas-GCS, Bas-GRS), middle (Mid-GLS, Mid-GCS, Mid GRS) and apical segments (Ap-GLS, Ap-GCS, Ap-GRS). RESULTS: (1) The coronary occlusion or subtotal occlusion were visible in 85.71% of the NWM-MVD patients. (2) The heart rate of the NWM-MVD patients was lower than that of the control group [(61.78 +/- 6.76) beats/min vs. (66.13 +/- 6.24) beats/min, p < 0.05]. The conventional ultrasonic measurement indices are similar between the NWM-MVD group and the control group (p > 0.05). (3) Compared with the control group, the GLS, Bas-GLS, Mid-GLS, Bas-GCS, Mid-GCS, GRS and Bas-GRS were lower in the NWM-MVD group (p < 0.05). CONCLUSIONS: The longitudinal, circumferential and radial systolic functions of the NWM-MVD patients were impaired at different degrees. PMID- 26531282 TI - In vitro effect of sodium nitrite on platelet aggregation in human platelet rich plasma--preliminary report. AB - OBJECTIVE: The role of nitrates and nitric oxide on platelet functions has obtained an increasing attention with respect to their potential effects on cardiovascular disorders. In this study we aimed to analyze the effect of sodium nitrite on platelet functions in human platelets. PATIENTS AND METHODS: This in vitro study was designed to show the effect of sodium nitrite on platelet functions in seven healthy volunteers. Blood samples were centrifuged to prepare platelet rich plasma and platelet poor plasma. Platelet rich plasma was diluted with the platelet poor plasma to have a final count of 300,000 +/- 25,000 platelets. Platelet rich plasma was incubated with six different increasing doses (from 10 MUM to 5 mM) of sodium nitrite for 1 hour at 37 degrees C. Then stimulating agents including collagen (3 MUg ml-1), adenosine diphosphate (10 MUM), and epinephrine (10 MUM) were added to the cuvette. Changes in light transmission were observed for 10 minutes. In addition spontaneous aggregation were performed in control group with all aggregating agents separately. RESULTS: Effect of sodium nitrite on agonist-induced platelet aggregation depends on the concentration of sodium nitrite. Compared with control group, agonist-induced platelet aggregations were significantly suppressed by sodium nitrite at the concentration of 5, 1.0 and 0.5 mM. CONCLUSIONS: Our results suggested that sodium nitrite has inhibitory effects in vitro on platelet aggregation in a dose dependent manner. PMID- 26531283 TI - Atorvastatin improves cardiac function of rats with chronic cardiac failure via inhibiting Rac1/P47phox/P67phox-mediated ROS release. AB - OBJECTIVE: To discuss the protective mechanisms of atorvastatin treatment for isoproterenol (ISO)-induced chronic heart failure. MATERIALS AND METHODS: The rats were randomly divided into three groups: normal group (n = 15, age-matched normal adult rats), ISO group (n = 11, ISO induced heart failure) and atorvastatin group (n = 14, ISO induced lesion but received atorvastatin treatment). The cardiac function was evaluated by echocardiography and hemodynamics analysis. In addition, the Rac1 activity in the myocardium and the expression levels of Rac1, p47phox and p67phox were measured by RT-PCR and western blot. RESULTS: Rats in ISO group developed into heart failure with decreased cardiac function. The Rac1, p47phox and p67phox mRNA expressions and ROS release were increased in ISO group. Atorvastatin treatment improved cardiac function of rats with isoproterenol-induced chronic heart failure and decreased the Rac1, p47phox and p67phox mRNA expressions. Also, membrane protein expression of Rac1 and ROS release decreased significantly. CONCLUSIONS: Atorvastatin may improve cardiac function of rats with heart failure via inhibiting Rac1/P47phox/P67phox-mediated ROS release. PMID- 26531284 TI - The study of possible application of sodium selenite as an adjuvant in lithium treatment: an effect on oxidative processes in heart of rats. AB - OBJECTIVE: Despite numerous side effects, including heart disturbances, lithium is still used in medicine. Selenium treatment can protect against toxicity of harmful substances and side effects of other drugs. In this study possibility of sodium selenite application as an adjuvant in lithium treatment was studied. MATERIALS AND METHODS: Male Wistar rats were treated with: control - saline; Li group - Li2CO3 (2.7 mg Li/kg b.w.); Se group - Na2SeO3 (0.5 mg Se/kg b.w.); Li+Se group simultaneously with Li2CO3 and Na2SeO3 (2.7 mg Li/kg b.w. and 0.5 mg Se/kg b.w., respectively) by stomach tube for a period of six weeks, once a day. In heart homogenates total antioxidant status (TAS), activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) as well as concentrations of ascorbic acid (AA), reduced glutathione (GSH) and malonyldialdehyde (MDA) were determined. SOD/GPx, CAT/GPx and SOD/CAT ratios were evaluated. RESULTS: TAS was insignificantly increased, particularly in groups receiving selenium. GPx was slightly decreased in Li group and partially restored by Li+Se treatment. Selenium markedly enhanced AA concentration vs. CONTROL: MDA was increased significantly in Li and Se groups and restored in Li+Se treated. SOD/GPx and CAT/GPx. Ratios were slightly increased in Li group and restored by selenium co-administration. CONCLUSIONS: As Li+Se treatment resulted in no significant differences vs. control and restored MDA, SOD/GPx and CAT/GPx ratios. Research on selenium application during lithium therapy seems to be worth continuation. PMID- 26531285 TI - Influence of one-year neurologic outcome of treatment on newborns with moderate and severe hypoxic-ischemic encephalopathy by rhuEP0 combined with ganglioside (GM1). AB - OBJECTIVE: To observe the one-year neurologic prognostic outcome of newborns with moderate and severe hypoxic-ischemic encephalopathy (HIE) who received recombinant human erythropoietin (rhuEPO) combined with exogenous monosialotetrahexosylganglioside (GM1) treatment to provide new guidelines for clinical treatment. PATIENTS AND METHODS: Seventy-six newborns with moderate and severe HIE were selected from February 2011 to February 2014 in our hospital. This study received the informed consent of our hospital's Ethics Committee and the newborns' guardians. The newborns were divided to an observation group (n = 34 cases) and a control group (n = 42 cases). All newborns underwent hypothermia and conventional treatment for their conditions. The control group received GMl treatment and observation group received rhuEPO combined with GMl treatment. The curative differences and neural behavior from these two groups were compared. RESULTS: The excellent, efficient proportion and total effective rate of the newborns from the observation group were higher than the control group. The death rate, cerebral palsy and the invalid ratio of the newborns from the observation group were lower than that of the control group. Awareness, muscle tension, primitive reflex and increased intracranial pressure recovery time of the newborns in the observation group were less than those of the control group. The Neonatal Behavior Neurological Assessment (NBNA) score of both groups after the treatment of 7, 14 and 28 days were significantly higher and increased with time (p < 0.05). The MDI, PDI and DQ score of newborns from the two groups all increased after treatment of 3, 6 and 12 months than those of before, which increased with time (p < 0.05). CONCLUSIONS: The rhuEPO + GMl treatment in newborns with HIE improves short-term clinical effects and long-term neurological symptoms. PMID- 26531286 TI - Efficacy and safety of dabigatran in a "real-life" population at high thromboembolic and hemorrhagic risk: data from MonaldiCare registry. AB - OBJECTIVE: Dabigatran is a novel target specific oral anticoagulant for stroke prevention in non valvular atrial fibrillation. Little is still known about its real-world effectiveness and safety in the italian population. Aim of our study was to evaluate the efficacy and safety of dabigatran in a large single-center cohort of "real-life" italian population with non-valvular AF and to compare the results with those obtained from the RE-LY trial and the Medicare study. PATIENTS AND METHODS: We studied a prospective cohort of 2108 patients (1119 male; mean age 69.4 +/- 9.4 years) who started the oral anticoagulant treatment with dabigatran 110 mg twice-daily (DAB 110; N = 1075; 51%) or 150 mg twice-daily (DAB 150; N = 1033; 49%). Follow-up data were obtained trough outpatients visits each 3-6 months for assessing the clinical status, adherence to treatment, occurrence of side effects and major cardiovascular complications. RESULTS: In DAB 150 group the mean age was 64.9 +/- 8.8 years, 56.8% of patients was male. CHA2DS2Vasc Score was >= 3 in 94.3% and HAS-BLED was >= 3 in 59.7%. In DAB 110 group (N = 1075) the mean age was 73.9 +/- 7.5 years; 49.5% of patients was male. CHA2DS2Vasc Score was >= 3 in 73.4% and HAS-BLED was >= 3 in 87.4% of DAB 110 patients. One patient taking Dabigatran 110 mg bid had ischemic stroke without significantly neurological sequelae. In both groups, no patient experienced hemorrhagic stroke during the follow-up period. 147 patients (6.9%) of MonaldiCare population reported adverse effects from treatment with dabigatran, of whom 121 patients (5.7%) discontinued therapy. We reported one case of subarachnoid hemorrhage (0.05%) in a patient with high thrombo-embolic and high hemorrhagic risk score who was taking dabigatran 150 mg bid and one case (0.05%) of bladder bleeding in a patient who was taking dabigatran 110 mg bid. No major gastrointestinal bleeding was observed in the MonaldiCare population. CONCLUSIONS: MonaldiCare registry showed a safety profile of both dosages of dabigatran regarding major of fatal bleeding in a "real life" single center italian population at high thromboembolic and hemorrhagic risk. The majority of MonaldiCare patients tolerated dabigatran treatment without significant side effects. The efficacy of dabigatran was demonstrated by very low prevalence of ictus/TIA, also when patients underwent electrical AF cardioversion independently of the transesophageal examination. PMID- 26531287 TI - Property and current clinical applications of mammal hyaluronidase. AB - Hyaluronidase (Hyal), which is related to mammalian diseases, is greatly significant for mammal. It is the major enzyme for degrading hyaluronan (HA), which is a linear high molecular polymer that is ubiquitous in mammalian extracellular matrix. Previous studies suggested that the levels of Hyals play significant roles in predicting, determining and curing many diseases. This review summarizes previous studies on the classification and biophysical and therapeutic applications of mammalian Hyals and focuses on the current medicinal and clinical applications of Hyals. PMID- 26531288 TI - Formulation and in vitro evaluation of niacin-loaded nanoparticles to reduce prostaglandin mediated vasodilatory flushing. AB - OBJECTIVE: Niacin, activating G-protein coupled receptor (GPR) 109A, stimulates release of vasodilatory prostaglandins (PGs) such as PGE2 which can elicit niacin associated flushing side effects. Poly-lactic-co-glycolic acid (PLGA) and poly lactic acid (PLA) are used in nanoparticle (NP) drug delivery to reduce adverse effects and modulate drug release. Our study evaluated the in vitro effects of niacin-loaded PLGA or PLA-NPs on PGE2 expression in whole human blood as a model for niacin-induced flushing. MATERIALS AND METHODS: NPs were formulated using a solvent evaporation process and characterized by size, polydispersity, zeta potential, drug entrapment, morphology, and drug release. NP in vitro effects on PGE2 release were measured via ELISA analysis. RESULTS: PLGA-NPs demonstrated the lowest NP size (66.7 +/- 0.21 nm) with the highest zeta potential and percent drug entrapment (42.00 +/- 1.62 mV and 69.09 +/- 0.29%, respectively) when compared to PLA-NPs (130.4 +/- 0.66 nm, 27.96 +/- 0.18 mV, 69.63 +/- 0.03 %, respectively). In vitro release studies showed that PLGA-NPs underwent significant reductions in cumulative drug release when compared to PLA-NPs (p < 0.05). Furthermore, when compared to plain niacin, PLGA-NPs significantly reduced in vitro PGE2 release (p < 0.05). CONCLUSIONS: These results support the use of PLGA-NPs as a novel method of delivery for reducing niacin-associated flushing. PMID- 26531290 TI - Cardiosphere conditioned media influence the plasticity of human mediastinal adipose tissue-derived mesenchymal stem cells. AB - Nowadays, cardiac regenerative medicine is facing many limitations because of the complexity to find the most suitable stem cell source and to understand the regenerative mechanisms involved. Mesenchymal stem cells (MSCs) have shown great regenerative potential due to their intrinsic properties and ability to restore cardiac functionality, directly by transdifferentiation and indirectly by paracrine effects. Yet, how MSCs could respond to definite cardiac-committing microenvironments, such as that created by resident cardiac progenitor cells in the form of cardiospheres (CSs), has never been addressed. Recently, a putative MSC pool has been described in the mediastinal fat (hmADMSCs), but both its biology and function remain hitherto unexplored. Accordingly, we investigated the potential of hmADMSCs to be committed toward a cardiovascular lineage after preconditioning with CS-conditioned media (CCM). Results indicated that CCM affects cell proliferation. Gene expression levels of multiple cardiovascular and stemness markers (MHC, KDR, Nkx2.5, Thy-1, c-kit, SMA) are significantly modulated, and the percentage of hmADMSCs preconditioned with CCM and positive for Nkx2.5, MHC, and KDR is significantly higher relative to FBS and explant derived cell conditioned media (EDCM, the unselected stage before CS formation). Growth factor-specific and survival signaling pathways (i.e., Erk1/2, Akt, p38, mTOR, p53) present in CCM are all equally regulated. Nonetheless, earlier BAD phosphorylation (Ser112) occurs associated with the CS microenvironment (and to a lesser extent to EDCM), whereas faster phosphorylation of PRAS40 in FBS, and of Akt (Ser473) in EDCM and 5-azacytidine occurs compared to CCM. For the first time, we demonstrated that the MSC pool held in the mediastinal fat is adequately plastic to partially differentiate in vitro toward a cardiac-like lineage. Besides, we have provided novel evidence of the potent inductive niche-like microenvironment that the CS structure can reproduce in vitro. hmADMSCs can represent an interesting tool in order to exploit their possible role in cardiovascular diseases and treatment. PMID- 26531291 TI - Top consumer abundance influences lake methane efflux. AB - Lakes are important habitats for biogeochemical cycling of carbon. The organization and structure of aquatic communities influences the biogeochemical interactions between lakes and the atmosphere. Understanding how trophic structure regulates ecosystem functions and influences greenhouse gas efflux from lakes is critical to understanding global carbon cycling and climate change. With a whole-lake experiment in which a previously fishless lake was divided into two treatment basins where fish abundance was manipulated, we show how a trophic cascade from fish to microbes affects methane efflux to the atmosphere. Here, fish exert high grazing pressure and remove nearly all zooplankton. This reduction in zooplankton density increases the abundance of methanotrophic bacteria, which in turn reduce CH4 efflux rates by roughly 10 times. Given that globally there are millions of lakes emitting methane, an important greenhouse gas, our findings that aquatic trophic interactions significantly influence the biogeochemical cycle of methane has important implications. PMID- 26531292 TI - [Pathology and prognostic factors of conjunctival melanoma]. AB - BACKGROUND: Conjunctival melanoma is a rare but potentially fatal disease. The 10 year melanoma mortality can be up to 30 %, recurrence rates after treatment up to 50 % and the overall incidence of metastasis is 26 %. Improved treatment options are needed to increase the tumor-free survival of affected patients. OBJECTIVES: The aim of the study was to perform clinical and pathological staging using the TNM classification and to correlate the results with treatment modalities and recurrence rates. MATERIAL AND METHODS: The study included a case series of 80 eyes from 80 patients (42 females and 38 males, age 28-90 years) with histopathologically proven conjunctival melanoma studied by reviewing medical records, pathology reports and color photographs. The main evaluated characteristics were demographic information, tumor size, thickness, pathological diagnosis, BRAF mutation testing, clinical and pathological staging, recurrence, metastasis and duration of follow-up (mean 48 months). RESULTS: The lesions predominantly involved the bulbar conjunctiva (60 %) and other sites that were less often involved were the palpebral conjunctiva (23 %), conjunctival fornix (22 %) and lacrimal caruncle (15 %). Of the tumors 36 % were TNM classified as pTis, 34 % as pT1, 20 % as pT2 (palpebral, fornix and caruncle) and 10 % as pT3. Local recurrences were noted in 36 % of the patients (18 % Tis, 26 % T1, 32 % T2 and 70 % T3) and regional and distant metastasis in 20 % of the patients (0 % Tis, 10 % T1, 15 % T2 and 60 % T3). DISCUSSION: In this study increasing T stages were more often associated with recurrences and metastasis. Future studies correlating the TNM staging with histopathological and genetic predictors may help to improve the management of patients with conjunctival melanoma. PMID- 26531293 TI - [Low grade endophthalmitis caused by P. acnes : Case report]. AB - Low grade endophthalmitis is usually a chronic indolent inflammation that may be misdiagnosed as noninfectious uveitis. Therefore, this form of endophthalmitis is often unsuccessfully treated with corticosteroids. We describe the case of a patient with low grade endophthalmitis caused by Propionibacterium acnes after cataract surgery. This case report presents the difficulties in establishing the diagnosis of this form of endophthalmitis as well as the benefits of a combined operative therapy with pars plana vitrectomy, intravitreal antibiotics and posterior capsulectomy for successful treatment in such cases. PMID- 26531294 TI - [Erratum to: Unilateral visual impairment and conspicuous optical coherence tomography in a 23-year-old woman]. PMID- 26531295 TI - Benefits and barriers to participating in longitudinal research of youth-onset type 2 diabetes: Results from the TODAY retention survey. AB - BACKGROUND/AIMS: Conducting longitudinal research related to chronic illness in adolescents is inherently challenging due to developmental changes and psychosocial stressors. Participants in the Treatment Options for type 2 Diabetes in Adolescents and Youth clinical trial were socioeconomically disadvantaged as well. This study assessed attitudes and beliefs about retention in Treatment Options for type 2 Diabetes in Adolescents and Youth to shed light on the factors that potentially promote and detract from the likelihood of sustained participation. METHODS: After an average 7.3 years of follow-up (range 4.9-9.5), Treatment Options for type 2 Diabetes in Adolescents and Youth participants completed a survey examining their perceptions of the benefits and barriers to sustained involvement in the protocol. RESULTS: The most common reasons for staying in Treatment Options for type 2 Diabetes in Adolescents and Youth included having a strong relationship with the medical team, getting study provided diabetes care, access to free diabetes medicine and supplies, and being part of a large study to learn more about how to care for youth-onset type 2 diabetes. The most commonly endorsed challenges included scheduling conflicts, possibly disappointing others, difficulties getting to study visits, and the occurrence of other medical issues. CONCLUSIONS: Similar to other published reports, a supportive relationship with study staff was commonly endorsed as a benefit of engagement in the longitudinal study, suggesting that rapport, staff consistency, and relationship quality are important components of optimal retention. Moreover, our findings suggest the value of trying to remove logistical barriers, such as transportation and scheduling challenges, in order to promote long-term participation in research. Further research is recommended to evaluate factors that contribute to attrition versus retention in an a priori manner within longitudinal studies, especially protocols involving cohorts that are more vulnerable to attrition due to developmental transitions and/or socioeconomic challenges. Additional efforts to optimize quantitative and qualitative measurement of barriers would also help to expand our understanding of how to optimally retain participants in longitudinal protocols. PMID- 26531296 TI - Do you use social media? A study into new nursing and midwifery graduates' uptake of social media. AB - Social media use is expanding rapidly, so too is its use within hospitals and amongst healthcare professionals. This study describes the use of social media by Australian and New Zealand nursing and midwifery graduates of the Graduate e Cohort study; there were 112 (93%) respondents from a 2014 sample of 121 nurses and midwives. Findings suggest that the professional peak body goal of using social media as a vehicle for professional education requires consideration of the social media platforms that are actually being used by new graduates. We recommend that work by the respective professions at both an undergraduate and graduate level needs to focus on the implications of social media use or policy and practice to ensure that everyone is aware of when and how to engage in social media platforms and what to do and how to behave when using social media. PMID- 26531297 TI - Introducing a true minimally invasive meshless and dissectionless anchoring system for pelvic organ prolapse repair. AB - INTRODUCTION AND HYPOTHESIS: The objective was to demonstrate the biomechanical properties, feasibility, and potential advantages over conventional techniques of this new anchoring device, NeuGuideTM. METHODS: We evaluated the pull-out forces required to pull the NeuGuideTM anchor elements from a uniform porcine ligament and a cadaver ligament. We also evaluated the function of the NeuGuideTM and the characteristics of the device for the establishment of verification evidence ensuring the reliability and feasibility of the device. We also evaluated the safety and performance of the NeuGuideTM procedure in female cadavers by palpating the sacro-spinous ligament in real time. We assessed the ability to deploy and fixate the anchor to the sacro-spinous ligament and to stitch the sutures from both sides of the vaginal apex to the cervix, without damaging the surrounding structures. RESULTS: All 12 anchors were inserted into the porcine ligament and the cadaver sacro-spinous ligaments successfully (mean pull-out force 34.13 +/- 4.32 and 35.68 +/- 9.28 respectively). None of the measured forces were below 20 N. No statistically significant difference was noted in the pull-out forces between the porcine and the cadavers (p = 0.60), between the two cadavers (p = 0.19) and between the right and left sacro-spinous ligaments. No abnormalities or malfunctions were noted in the functional performance of the device. Upon laparotomy, dissection of the cadavers revealed that the sacro spinous ligaments were reached safely with no damage to the surrounding organs and tissues. CONCLUSIONS: This novel anchoring device (NeuGuideTM) is aimed at facilitating a durable, easy, and short procedure for sacro-spinous ligament fixation with hypothetically fewer operative complications. PMID- 26531298 TI - [Chronic potassium depletion in patient with biliopancreatic diversion]. PMID- 26531299 TI - Predictors of breastfeeding initiation in Hong Kong and Mainland China born mothers. AB - BACKGROUND: In recent years there has been a steady influx of immigrants into Hong Kong from Mainland China, where breastfeeding patterns differ. Studies in other regions have found substantial differences in breastfeeding rates between native-born and immigrant mothers. The purpose of this study was to examine factors associated with breastfeeding initiation in Hong Kong born and Mainland China born mothers living in Hong Kong. METHODS: We used a multi-center cross sectional study design and recruited 2761 new mothers from the postnatal wards of all eight public hospitals in Hong Kong that offer obstetric services. We assessed breastfeeding status as well as various socio-demographic, maternal and birth characteristics. Chi-square tests and multivariable logistic regression were used to identify the predictors of breastfeeding initiation in Hong Kong born and Mainland China born participants. RESULTS: 80.3 % of Hong Kong and 81.1 % of Mainland Chinese born women initiated breastfeeding. In the fully adjusted models, multiparity (Odds Ratio [OR] 0.53, 95 % CI 0.43-0.66) and maternal smoking (OR 0.29, 95 % CI 0.18-0.45) were strongly associated with failure to initiate breastfeeding in both Hong Kong and Mainland China born participants. In Hong Kong born mothers, participants with lower maternal education and those who had a cesarean section were significantly less likely to breastfeed. For Mainland China born mothers, paternal smoking (OR 0.70, 95 % CI 0.49-0.99) and having a pregnancy-related health problem (OR 0.60, 95 % CI 0.38-0.94) were both additional risk factors for not breastfeeding. CONCLUSION: This study has identified predictors of breastfeeding initiation in Hong Kong and Mainland China born mothers. Given the current high breastfeeding initiation rates among both groups, antenatal breastfeeding education and promotion programmes need to specifically intervene with sub-groups of pregnant women at risk for not breastfeeding so that their efforts are more strategic and cost-effective. PMID- 26531300 TI - Intraspecific and interspecific genetic variation of Gongylonema pulchrum and two rodent Gongylonema spp. (G. aegypti and G. neoplasticum), with the proposal of G. nepalensis n. sp. for the isolate in water buffaloes from Nepal. AB - The gullet worm (Gongylonema pulchrum) has been recorded from a variety of mammals worldwide. In an earlier study, we demonstrated two separate transmission cycles in cattle (Bos taurus) and wild mammals in Japan based on nucleotide sequences of the ribosomal RNA gene (rDNA) and cytochrome c oxidase subunit I (cox-1) region of mitochondrial DNA of multiple isolates of different origins. Our earlier study additionally demonstrated two major cox-1 haplotypes of G. pulchrum prevalent in cattle in Japan. In the present study, we collected G. pulchrum from cattle and goats (Capra hircus) in Alashan League, Inner Mongolia, China; Gongylonema aegypti from spiny mice (Acomys dimidiatus) in the Sinai Peninsula, Egypt; and Gongylonema neoplasticum from a black rat (Rattus rattus) in Okinawa Island, Japan, to analyze their genetic relationships with G. pulchrum in Japan. The gullet worms from Alashan League had almost identical rDNA nucleotide sequences and two cox-1 haplotypes as seen in G. pulchrum from the cattle in Japan. The two rodent Gongylonema spp. had distinct rDNA nucleotide sequences compared with those of G. pulchrum; only the 18S and 5.8S rDNA sequences showed high identities at 97.2-98.7%, while the remaining sequences were less than 75% identical. The 18S, 5.8S, and 28S rDNA sequences of the two rodent Gongylonema spp. showed nucleotide identities of 99.8% (1811/1814), 100% (158/158), and 98.9% (3550/3590), respectively. The cox-1 regions showed 91.6% (338/369)-92.1% (340/369) identities, with completely identical amino acid sequences. The genetic diversities of three distinct Gongylonema spp. and their possible intraspecific genetic variation may allow us to resolve the taxonomic position of Gongylonema spp. which display few obvious morphological differences from their congeners. Consequently, the Gongylonema isolate from water buffaloes (Bubalus bubalis) in Nepal reported in our previous study is concluded to be a new species, and Gongylonema nepalensis n. sp. is erected for it. PMID- 26531301 TI - Malaria and blood transfusion: major issues of blood safety in malaria-endemic countries and strategies for mitigating the risk of Plasmodium parasites. AB - Malaria inflicts humankind over centuries, and it remains as a major threat to both clinical medicine and public health worldwide. Though hemotherapy is a life sustaining modality, it continues to be a possible source of disease transmission. Hence, hemovigilance is a matter of grave concern in the malaria prone third-world countries. In order to pursue an effective research on hemovigilance, a comprehensive search has been conducted by using the premier academic-scientific databases, WHO documents, and English-language search engines. One hundred two appropriate articles were chosen for data extraction, with a particular reference to emerging pathogens transmitted through blood transfusion, specifically malaria. Blood donation screening is done through microscopic examination and immunological assays to improve the safety of blood products by detection major blood-borne pathogens, viz., HIV, HBV, HCV, syphilis, and malarial parasites. Transfusion therapy significantly dwindles the preventable morbidity and mortality attributed to various illnesses and diseases, particularly AIDS, tuberculosis, and malaria. Examination of thick and thin blood smears are performed to detect positivity and to identify the Plasmodium species, respectively. However, all of these existing diagnostic tools have their own limitations in terms of sensitivity, specificity, cost-effectiveness, and lack of resources and skilled personnel. Globally, despite the mandate need of screening blood and its components according to the blood-establishment protocols, it is seldom practiced in the low-income/poverty-stricken settings. In addition, each and every single phase of transfusion chain carries sizable inherent risks from donors to recipients. Interestingly, opportunities also lie ahead to enhance the safety of blood-supply chain and patients. It can be achieved through sustainable blood-management strategies like (1) appropriate usage of precise diagnostic tools/techniques, (2) promoting hemovigilance system, and (3) adopting novel processes of inactivation technology. Furthermore, selection of the zero-risk donors could pave the way to build a transmissible malaria-free world in the near future. PMID- 26531302 TI - Tuning of chalcogen bonds by cation-pi interactions: cooperative and diminutive effects. AB - The tunability of Y...N chalcogen bond via formation of a cation-pi interaction in ternary complexes M(+)-PhYH-NH3, M(+)-PhYH-NCH, and M(+)-PhCCCN-YHF (M = Li, Na; Y = Se, Te) is investigated at MP2/aug-cc-pVDZ computational level. Our results indicate that the strength of Y...N and cation-pi interactions in the ternary complexes depends on the role of the aromatic molecule. That is, a cooperative effect is evident if aromatic molecule acts as the Lewis acid and Lewis base, simultaneously, while a diminutive effect is observed when the aromatic molecule acts only as the Lewis base in both Y...N and cation-pi interactions. For a given aromatic system, the shortening or lengthening of Y...N distances is more important for Li(+) complexes than Na(+) counterparts. The mechanism of cooperative/diminutive effects in the ternary complexes is studied by molecular electrostatic potential (MEP) and topological analysis of the electron density. PMID- 26531303 TI - Theoretical study of the oxidation mechanisms of thiophene initiated by hydroxyl radicals. AB - The mechanisms for the oxidation of thiophene by OH radicals under inert conditions (Ar) have been studied using density functional theory in conjunction with various exchange-correlation functionals. These results were compared with benchmark CBS-QB3 theoretical results. Kinetic rate constants were estimated by means of variational transition state theory (VTST) and the statistical Rice Ramsperger-Kassel-Marcus (RRKM) theory. Effective rate constants were calculated via a steady-state analysis based upon a two-step model reaction mechanism. In line with experimental results, the computed branching ratios indicate that the most kinetically efficient process involves OH addition to a carbon atom adjacent to the sulfur atom. Due to the presence of negative activation energies, pressures larger than 10(4) bar are required to reach the high-pressure limit. Nucleus-independent chemical shift indices and natural bond orbital analysis show that the computed activation energies are dictated by changes in aromaticity and charge-transfer effects due to the delocalization of lone pairs from sulfur to empty pi(*) orbitals. Graphical Abstract CBS-QB3 energy profiles for the reaction pathways 1-3 characterizing the oxidation of thiophene by hydroxyl radicals into the related products. PMID- 26531304 TI - A theoretical investigation into the strength of N-NO2 bonds, ring strain and electrostatic potential upon formation of intermolecular H-bonds between HF and the nitro group in nitrogen heterocyclic rings C n H2n N-NO2 (n = 2-5), RDX and HMX. AB - Changes in N-NO2 bond strength, ring strain energy and electrostatic potential upon formation of intermolecular H-bonds between HF and the nitro group in nitrogen heterocyclic rings C n H2n N-NO2 (n = 2-5), RDX and HMX were investigated using DFT-B3LYP and MP2(full) methods with the 6-311++G(2df,2p) and aug-cc-pVTZ basis sets. Analysis of electron density shifts was also carried out. The results indicate that H-bonding energy correlates well with the increment of ring strain energy. Upon complex formation, the strength of the N-NO2 trigger bond is enhanced, suggesting reduced sensitivity, while judged by the increased ring strain energy, sensitivity is increased. However, some features of the molecular surface electrostatic potential, such as a local maximum above the N NO2 bond and ring, sigma + (2) and electrostatic balance parameter nu, remain essentially unchanged upon complex formation, and only a small change in the impact sensitivity h 50 is suggested. It is not sufficient to determine sensitivity solely on the basis of trigger bond or ring strain; as a global feature of a molecule, the molecular surface electrostatic potential is available to help judge the change of sensitivity in H-bonded complexes. Graphical Abstract The strengthened N-NO2 bond suggests reduced sensitivity, while it is reverse by theincreased ring strain energy upon the complex formation. However, the molecular surfaceelectrostatic potential (V S) shows the little change of h 50. The V S should be taken into accountin the analysis of explosive sensitivity in the H-bonded complex. PMID- 26531305 TI - The A673T mutation in the amyloid precursor protein reduces the production of beta-amyloid protein from its beta-carboxyl terminal fragment in cells. AB - INTRODUCTION: The A673T mutation in the amyloid precursor protein (APP) protects against Alzheimer's disease by reducing beta-amyloid protein (Abeta) production. This mutation reduced the release of the soluble APP fragment (sAPPbeta), which is processed by beta-secretase, suggesting a concomitant decrease in the beta carboxyl fragment of APP (C99), which is a direct substrate of gamma-secretase for Abeta production. However, it remains controversial whether the level of C99 is significantly reduced in cells expressing APP that carry A673T as the cause of reduced Abeta production. Here, we investigated the effect of the A673T mutation in C99 on gamma-cleavage in cells. RESULTS: We found that the level of C99 in cells expressing APP A673T was indistinctive of that observed in cells expressing wild-type APP, although the release of sAPPbeta was significantly reduced in the APP A673T cells. In addition, our reconstituted beta-secretase assay demonstrated no significant difference in beta-cleavage on an APP fragment carrying the A673T mutation compared with the wild-type fragment. Importantly, cells expressing C99 containing the A673T mutation (C99 A2T; in accordance with the Abeta numbering) produced roughly half the level of Abeta compared with the wild-type C99, suggesting that the C99 A2T is an insufficient substrate of gamma-secretase in cells. A cell-free gamma-secretase assay revealed that Abeta production from the microsomal fraction of cells expressing C99 A2T was diminished. A sucrose gradient centrifugation analysis indicated that the levels of the C99 A2T that was codistributed with gamma-secretase components in the raft fractions were reduced significantly. CONCLUSIONS: Our data indicate that the A673T mutation in APP alters the release of sAPPbeta, but not the C99 level, and that the C99 A2T is an inefficient substrate for gamma-secretase in cell-based assay. PMID- 26531306 TI - Response of Health and Social Care Information Centre to article on access to anonymised patient data. PMID- 26531307 TI - Poor outcomes of empiric ceftriaxone +/- azithromycin for community-acquired pneumonia caused by methicillin-susceptible Staphylococcus aureus. AB - While ceftriaxone 1 g q24h is commonly used for hospitalized patients with community-acquired pneumonia (CAP), the prescribing information recommends 2-4 g a day to treat methicillin-susceptible Staphylococcus aureus (MSSA). Similarly, recent pharmacodynamic analyses suggest shortcomings of 1 g q24h against the bulk of the MSSA. We evaluated the outcomes of empiric ceftriaxone 1 g q24h +/- azithromycin in patients with MSSA pneumonia, as compared with Streptococcus pneumoniae. Adult patients admitted to Hartford Hospital from 1/2005 to 12/2014 with respiratory culture for MSSA or S. pneumoniae were considered for inclusion. Non-ICU, CAP patients were included. Early clinical failure (ECF) was defined as persistent signs/symptoms or change of antibiotic due to poor response at 72-96 h. A multivariate analysis was performed to evaluate predictors of ECF. Over the study period, 403 MSSA and 227 S. pneumoniae positive respiratory cultures were identified. The majority of patients were excluded due to the following: no signs/symptoms of pneumonia, hospital-acquired pneumonia, alternative antibiotics, and polymicrobial infection. Thirty-nine patients met inclusion/exclusion criteria. All but three patients in the S. pneumoniae group received ceftriaxone + azithromycin. ECF was greater in the MSSA group (53 vs. 4 %, P = 0.003), as was length of stay (7.5 +/- 5.4 vs. 4.6 +/- 3.3 days, P = 0.006). When controlling for disease severity and macrolide non-susceptibility in a multivariate analysis, MSSA was significantly correlated with ECF (OR 12.3, 95 % CI 0.8-188.8). Poor clinical outcomes were observed in patients empirically treated with ceftriaxone +/- azithromycin for MSSA CAP. Despite the popularity of ceftriaxone 1 g q24h, these data suggest this dose or compound may be inadequate for CAP caused by MSSA. PMID- 26531308 TI - Osteopetrosis in siblings. PMID- 26531309 TI - Investigation of the cytokine response to NF-kappaB decoy oligonucleotide coated polysaccharide based nanoparticles in rheumatoid arthritis in vitro models. AB - INTRODUCTION: The transcription factor nuclear factor-kappa B (NF-kappaB) is highly involved in regulation of a number of cellular processes, including production of inflammatory mediators. Thus, this transcription factor plays a role in pathology of many diseases, including rheumatoid arthritis, an autoimmune disease hallmarked by an imbalance of pro and anti-inflammatory cytokines. Small nucleic acids with sequences that mimic the native binding site of NF-kappaB have been proposed as treatment options for RA; however due to low cellular penetration and a high degree of instability, clinical applications of these therapeutics have been limited. METHODS: Here, we describe the use of N-trimethyl chitosan-polysialic acid (PSA-TMC) nanoparticles coated with decoy oligodeoxynucleotides (ODNs) specific to transcription factor NF-kappaB (PSA-TMC ODN) as a method to enhance the stability of the nucleic acids and facilitate increased cellular penetration. In addition to decoy ODN, PSA-TMC nanoparticles were loaded with RA therapeutic methotrexate (MTX), to assess the anti inflammatory efficacy of a combination therapy approach. Two different in vitro models, a cell line based model as well as a primary RA cell model were used to investigate anti-inflammatory activity. One way ANOVA followed by Holm-Sidak stepdown comparisons was used to determine statistical significance. RESULTS: In general, free ODN did not significantly affect secretion of pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-8, (IL-8) while free MTX had variable efficacy. However, PSA-TMC-ODN and PSA-TMC-ODN-MTX resulted in significant decreases in the inflammatory mediators IL-6 and IL-8 in both cell models. In addition, PSA-TMC exhibited sufficient cellular uptake, as observed through fluorescence microscopy. CONCLUSIONS: These results support our previous findings that PSA-TMC nanoparticles are an effective delivery vehicle for small nucleic acids, and effectively alter the pro-inflammatory state characteristic of RA. PMID- 26531310 TI - Early detection of sensorineural hearing loss in Muckle-Wells-syndrome. AB - BACKGROUND: Muckle-Wells-syndrome (MWS) is an autoinflammatory disease characterized by systemic and organ-specific inflammation due to excessive interleukin (IL)-1 release. Inner ear inflammation results in irreversible sensorineural hearing loss, if untreated. Early recognition and therapy may prevent deafness. The aims of the study were to characterize the spectrum of hearing loss, optimize the otologic assessment for early disease and determine responsiveness to anti-IL-1-therapy regarding hearing. METHODS: A single center prospective cohort study of children and adults with MWS was performed. Standardized clinical, laboratory and otologic assessments including standard pure tone audiometry, additional high tone thresholds, vestibular organ testing, tinnitus evaluation and functional disability classes were determined serially. Pure-tone-average models were developed and evaluated. Risk factors for hearing loss and the impact of anti-IL-1 treatment were determined. RESULTS: A total of 23 patients with genetically confirmed MWS were included, of whom 63 % were females; 52 % were children. At baseline all patients had active MWS; 91 % reported clinically impaired hearing with 74 % having an abnormal standard assessment (0.5-4 kHz). In contrast, high frequency pure tone averages (HF-PTA) were abnormal in all symptomatic patients including those with early hearing loss (sensitivity 100 %). Females were at highest risk for hearing loss even after adjustment for age (p = 0.008). Treatment with IL-1 blockade resulted in improved or stable hearing in 91 % of patients. CONCLUSIONS: Early inner ear inflammation in MWS primarily affects the high frequencies, beyond the range of standard otologic assessment tools. The HF-PTA is a sensitive tool to detect imminent hearing loss and monitor treatment response. PMID- 26531311 TI - Erratum to: The Long and Short of Genetic Counseling Letters: A Case-control Study. PMID- 26531312 TI - High Satisfaction and Low Distress in Breast Cancer Patients One Year after BRCA Mutation Testing without Prior Face-to-Face Genetic Counseling. AB - According to standard practice following referral to clinical genetics, most high risk breast cancer (BC) patients in many countries receive face-to-face genetic counseling prior to BRCA-mutation testing (DNA-intake). We evaluated a novel format by prospective study: replacing the intake consultation with telephone, written and digital information sent home. Face-to-face counseling then followed BRCA-mutation testing (DNA-direct). One year after BRCA-result disclosure, 108 participants returned long-term follow-up questionnaires, of whom 59 (55 %) had previously chosen DNA-direct (intervention) versus DNA-intake (standard practice i.e., control: 45 %). Questionnaires assessed satisfaction and psychological distress. All participants were satisfied and 85 % of DNA-direct participants would choose this procedure again; 10 % would prefer DNA-intake and 5 % were undecided. In repeated measurements ANOVA, general distress (GHQ-12, p = 0.01) and BC-specific distress (IES-bc, p = 0.03) were lower in DNA-direct than DNA intake at all time measurements. Heredity-specific distress (IES-her) did not differ significantly between groups. Multivariate regression analyses showed that choice of procedure did not significantly contribute to either general or heredity-specific distress. BC-specific distress (after BC diagnosis) did contribute to both general and heredity-specific distress. This suggests that higher distress scores reflected BC experience, rather than the type of genetic diagnostic procedure. In conclusion, the large majority of BC patients that used DNA-direct reported high satisfaction without increased distress both in the short term, and 1 year after conclusion of genetic testing. PMID- 26531313 TI - Quality of life and participation in daily life of adults with Pompe disease receiving enzyme replacement therapy: 10 years of international follow-up. AB - BACKGROUND: Pompe disease is an inheritable metabolic disorder for which enzyme replacement therapy (ERT) has been available since 2006. Effects of ERT have been shown on distance walked, pulmonary function and survival. We investigated whether it also improves quality of life and participation in daily life in adult patients with the disease. METHODS: In an international survey, we assessed quality of life (Short Form 36, SF-36) and participation (Rotterdam Handicap Scale, RHS) annually between 2002 and 2012. Repeated measurements mixed effects models were used to describe the data over time. RESULTS: Responses were available for 174 adult patients. In the periods before and after start of ERT, the median follow-up times were 4 years each (range 0.5-8). The SF-36 Physical Component Summary measure (PCS) deteriorated before ERT (-0.73 score points per year (sp/y); CI 95 % -1.07 to -0.39), while it improved in the first 2 years of ERT (1.49 sp/y; CI 0.76 to 2.21), and remained stable thereafter. The Mental Component Summary measure (MCS) remained stable before and during ERT. After declining beforehand (-0.49 sp/year; CI -0.64 to-0.34), the RHS stabilized under ERT. CONCLUSION: In adult patients with Pompe disease, ERT positively affects quality of life and participation in daily life. Our results reinforce previous findings regarding the effect of ERT on muscle strength, pulmonary function and survival. PMID- 26531314 TI - Perspectives on Neuroscience and Behavior. PMID- 26531316 TI - Angiokeratoma of Fordyce response to long pulsed Nd:YAG laser treatment. AB - Angiokeratoma of Fordyce can be easily diagnosed by their typical erythra and cured by varied therapeutic methods including surgery, electrocoagulation, cryotherapy, or various laser systems. Which are the optimal therapeutic methods? There are no consentaneous opinions in the reported articles. We present our characteristic treatment with the application of long pulsed neodymium dopedyttrium-aluminum-garne (lpNd:YAG) laser in the treatment of angiokeratoma of Fordyce. A 1064 nm lpNd:YAG laser (spot size: 5 mm/7 mm, energy:90-130 J/cm(2) , and pulse duration: 10-20 ms.) was used to treat the patient's lesions. The desirable clinical endpoint of the treatment was lesions shrunk and turned pallor immediately after the irradiation. The treatment interval was at least 8 weeks. Of the 11 patients, 9 of them were cured and 2 of them were improved. The mean treatment sessions were 2.2 times. None of them had a scar formation and any other side effects. All of them were satisfied with the treatment results. We conclude that angiokeratoma of Fordyce responded well to lpNd:YAG laser treatment. It provided a simple, rapid, and no bleeding treatment in treating Angiokeratoma of Fordyce. PMID- 26531317 TI - Evaluating the systematic implementation of the 'Let Me Decide' advance care planning programme in long term care through focus groups: staff perspectives. AB - BACKGROUND: The 'Let Me Decide' Advance Care Planning (LMD-ACP) programme offers a structured approach to End-of-Life (EoL) care planning in long-term care for residents with and without capacity to complete an advance care directive/plan. The programme was implemented in three homes in the South of Ireland, with a view to improving quality of care at end of life. This paper will present an evaluation of the systematic implementation of the LMD-ACP programme in the homes. METHODS: Focus groups were conducted with 15 Clinical Nurse Managers and two Directors of Nursing where the programme had been implemented. A semi structured topic guide was used to direct questions that addressed implementation process, challenges implementing advance care planning, advantages/disadvantages and recommendations for the future. Data was analysed using manifest content analysis. RESULTS: Five key categories emerged, with 16 corresponding subcategories. These subcategories emerged as a result of 37 codes. Key benefits of the programme included enhancing communication, changing the care culture, promoting preference-based care and avoiding crisis decision making. Establishing capacity among residents and indecision were among the main challenges reported by staff. DISCUSSION: A number of recommendations were proposed by participants and included multi-disciplinary team involvement, and a blended approach to education on the topic. According to participants relationships with residents deepened, there was a more open and honest environment with family, end of life care focused more on symptom management, comfort and addressing spiritual care needs as opposed to crisis decision making and family conflict. CONCLUSION: The introduction of the LMD-ACP programme enhanced the delivery of care in the long term care sites and led to a more open and positive care environment. PMID- 26531318 TI - MicroRNA-375 overexpression influences P19 cell proliferation, apoptosis and differentiation through the Notch signaling pathway. AB - Our previous study reported that microRNA-375 (miR-375) is significantly upregulated in ventricular septal myocardial tissues from 22-week-old fetuses with ventricular septal defect as compared with normal controls. In the present study, the specific effects of miR-375 on P19 cell differentiation into cardiomyocyte-like cells were investigated. Stable P19 cell lines overexpressing miR-375 or containing empty vector were established, which could be efficiently induced into cardiomyocyte-like cells in the presence of dimethyl sulfoxide in vitro. miR-375 overexpression was verified using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Cell proliferation was determined according to total cell counts; cell cycle distribution and apoptosis levels were examined using flow cytometry. Apoptosis-related morphological changes were observed using Hoechst staining and fluorescence microscopy. During P19 cell differentiation, the cardiomyogenesis-related mRNAs (cardiac troponin T, GATA binding protein 4, myocyte-specific enhancer factor 2C) and mRNAs involved in the Notch signaling pathway (Notch2, Delta-like 1 and hes family bHLH transcription factor 1) were detected at days 0, 4, 6 and 10. Their differential expression was examined using RT-qPCR; the apoptosis-related genes BAX and Bcl-2 were also detected using this method. The corresponding proteins were evaluated by western blotting. Compared with the control group, miR-375 overexpression inhibited proliferation but promoted apoptosis in P19 cells, and the associated mRNAs and proteins were decreased during differentiation. miR-375 has an important role in cardiomyocyte differentiation, and can disrupt this process via the Notch signaling pathway. The present findings contribute to the understanding of the mechanisms of congenital heart disease and facilitate the development of new gene therapies. PMID- 26531319 TI - n-3 polyunsaturated fatty acids reverse the development of polyps in Apc(Min/+) transgenic mice. AB - Dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) have been demonstrated to reduce tumor load in Apc(Min/+) mice, supporting a role for n-3 PUFAs in the inhibition of colon carcinogenesis and progression. The aim of the present study was to investigate whether a diet enriched with n-3 PUFAs, known already to have anti-neoplastic efficacy in Apc(Min/+) mice, would reverse the development of intestinal polyps. For this purpose, Apc(Min/+) mice were randomly divided into 3 groups of 5 animal each and fed as follows: control ST1 and ST2 groups, received a purified AIN-93M standard diet for 5 and 10 weeks, respectively; the OM-3R group received a purified AIN-93M standard diet for 5 weeks and a diet supplemented with salmon oil, rich in n-3 PUFAs, for another 5 weeks. After dietary treatment, in intestinal tissue, we evaluated the polyp number and volume, expression levels of cell proliferation- and apoptosis-related proteins, as well as the protein expression of LDL receptor and the levels of fatty acid synthase (FAS) activity. The results showed the ability of a diet enriched with n 3 PUFAs to suppress intestinal polyps in Apc(Min/+) mice, and to significantly reverse polyp development associated with the downregulation of cell proliferation markers and with the induction of estrogen receptor beta and LDL receptor, which are negative modulators of cellular proliferation. This noteworthy finding is important for a translational study evaluating the therapeutic role of n-3 PUFAs in the prevention and treatment of subjects with gastrointestinal diseases. PMID- 26531320 TI - In vitro chromatin templates to study nucleotide excision repair. AB - In eukaryotic cells, DNA associates with histones and exists in the form of a chromatin hierarchy. Thus, it is generally believed that many eukaryotic cellular DNA processing events such as replication, transcription, recombination and DNA repair are influenced by the packaging of DNA into chromatin. This mini-review covers the current knowledge of DNA damage and repair in chromatin based on in vitro studies. Specifically, nucleosome assembly affects DNA damage formation in both random sequences and sequences with strong nucleosome-positioning signals such as 5S rDNA. At least three systems have been used to analyze the effect of nucleosome folding on nucleotide excision repair (NER) in vitro: (a) human cell extracts that have to rely on labeling of repair synthesis to monitor DNA repair, due to very low repair efficacy; (b) Xenopus oocyte nuclear extracts, that have very robust DNA repair efficacy, have been utilized to follow direct removal of DNA damage; (c) six purified human DNA repair factors (RPA, XPA, XPC, TFIIH, XPG, and XPF-ERCC1) that have been used to reconstitute excision repair in vitro. In general, the results have shown that nucleosome folding inhibits NER and, therefore, its activity must be enhanced by chromatin remodeling factors like SWI/SNF. In addition, binding of transcription factors such as TFIIIA to the 5S rDNA promoter also modulates NER efficacy. PMID- 26531321 TI - Fasting hyperinsulinaemia and 2-h glycaemia predict coronary heart disease in patients with type 2 diabetes. AB - AIM: Patients with diabetes are at greater risk of cardiovascular events. Insulin resistance (IR) and hyperinsulinaemia are both related to an increased cardiovascular risk, but whether IR predicts coronary heart disease (CHD) independently of other risk factors in patients with type 2 diabetes (T2D) is a topic of considerable controversy. The aim of the present study was to evaluate the prospective relationship of fasting insulin, HOMA-IR, fasting plasma glucose (FPG) and 2-h post-load glucose (2hPG) load with CHD incidence among such patients. METHODS: A total of 2607 patients with T2D were enrolled in a community dwelling cohort and followed for an average of 7.2 years. Conventional CHD risk factors, FPG, 2hPG, fasting insulin levels and HOMA-IR index were measured at baseline. Cox regression hazard ratios (HRs) were used to assess CHD risk. RESULTS: A total of 299 'hard' CHD events were registered (in 114 women and 185 men). Increasing levels of fasting insulinaemia were positively associated with CHD incidence. This correlation persisted after controlling for gender, body mass index, blood pressure, lipid profile, medication use and HbA1c [HR for each increase in quartile (fully adjusted model): 1.18 (95% CI: 1.06-1.32); P<0.01]. 2hPG showed a non-linear association with incident CHD [HR of highest vs lowest quartile: 1.64 (95% CI: 1.03-2.61)]. Fasting glycaemia was not associated with CHD risk, whereas HOMA-IR had a direct and independent correlation with CHD risk [HR for each one-quartile increase: 1.19 (95% CI: 1.07-1.34); P<0.01]. CONCLUSION: Fasting insulin levels are positively associated with incidence of CHD in T2D. Furthermore, 2hPG appears to be a significant predictor of incident CHD independently of other risk factors, including HbA1c. These findings suggest that strategies targeting the reduction of insulinaemia and post-load glycaemia may be useful for preventing cardiovascular complications. PMID- 26531322 TI - Solid-Phase Combinatorial Synthesis and Biological Evaluation of Destruxin E Analogues. AB - The solid-phase combinatorial synthesis of cyclodepsipeptide destruxin E has been demonstrated. The combinatorial synthesis of cyclization precursors 8 was achieved by using a split and pool method on SynPhase Lanterns. The products were successfully macrolactonized in parallel in the solution phase by using 2-methyl 6-nitrobenzoic anhydride and 4-(dimethylamino)pyridine N-oxide to afford macrolactones 9, and the subsequent formation of an epoxide in the side chain gave 18 member destruxin E analogues 6. Biological evaluation of analogues 6 indicated that the N-MeAla residue was crucial to the induction of morphological changes in osteoclast-like multinuclear cells (OCLs). Based on structure-activity relationships, azido-containing analogues 15 were then designed for use as a molecular probe. The synthesis and biological evaluation of analogues 15 revealed that 15 b, in which the Ile residue was replaced with a Lys(N3 ) residue, induced morphological changes in OCLs at a sufficient concentration, and modification around the Ile residue would be tolerated for attachment of a chemical tag toward the target identification of destruxin E (1). PMID- 26531323 TI - Dual electron transfer pathways from the excited C60 radical anion: enhanced reactivities due to the photoexcitation of reaction intermediates. AB - In the present study, electron transfer (ET) processes from excited radical anions have been investigated using dyad molecules including C60. The deactivation process of excited C60(-), including the internal conversion from the D1 to the D0 state and the cooling process of the vibrationally hot ground state (D), was observed spectroscopically for the first time. These processes could be unambiguously distinguished by the observation of the stimulated emission from the D1 state. The intramolecular ET processes from the excited C60( ) were confirmed by the transient absorption spectra. Clearly, both D1 and D states acted as precursors for the ET, i.e., dual ET pathways were confirmed. The driving force dependence of the ET rates was well characterized by the Marcus theory, which revealed that the forward ET processes are located at the top region of the Marcus parabola. In addition, the ET from the excited imide radical anion to C60 and that from the ground state C60(-) to imide were examined. The ET rate from the excited imide radical anion and that from ground state C60(-) did not follow the Marcus parabola estimated for the ET from the excited C60(-). The observed difference can be attributed to the difference in the energy required to form the reduced spacer (Delta) in the superexchange mechanism. Because the Delta value tends to become smaller for ET processes from excited radical ions, fast and efficient ET processes are expected from these states as demonstrated in the present study. PMID- 26531324 TI - Sensitivity of tumor motion simulation accuracy to lung biomechanical modeling approaches and parameters. AB - Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the neo Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right, anterior posterior, and superior-inferior directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation. PMID- 26531325 TI - Metabolic roles of endocrine fibroblast growth factors. AB - Considerable effort is currently being devoted to understanding the physiological and pharmacological action of the endocrine fibroblast growth factors (FGFs). These three proteins (FGF15/19, FGF21 and FGF23) act in a tissue-specific manner through a membrane-complex consisting of an FGF-receptor and alpha/betaKlotho. FGF15/19 is produced in the intestine and regulates postprandial liver metabolism and gallbladder filling. FGF21 is largely liver-derived and co-ordinates adaptive changes in response to nutritional and physiological stresses. FGF23 signals from the bone to the kidney to maintain phosphate homeostasis. In pharmacological settings, FGF15/19, FGF21, and the prototypical FGF1, potentially represent novel treatments for obesity and diabetes. This review summarises the recent advances in our understanding of the biology of these important metabolic regulators. PMID- 26531326 TI - The microbiome and its pharmacological targets: therapeutic avenues in cardiometabolic diseases. AB - Consisting of trillions of non-pathogenic bacteria living in a symbiotic relationship with their mammalian host, the gut microbiota has emerged in the past decades as one of the key drivers for cardiometabolic diseases (CMD). By degrading dietary substrates, the gut microbiota produces several metabolites that bind human pharmacological targets, impact subsequent signalling networks and in fine modulate host's metabolism. In this review, we revisit the pharmacological relevance of four classes of gut microbial metabolites in CMD: short-chain fatty acids (SCFA), bile acids, methylamines and indoles. Unravelling the signalling mechanisms of the microbial-mammalian metabolic axis adds one more layer of complexity to the physiopathology of CMD and opens new avenues for the development of microbiota-based pharmacological therapies. PMID- 26531327 TI - Administration of defined microbiota is protective in a murine Salmonella infection model. AB - Salmonella typhimurium is a major cause of diarrhea and causes significant morbidity and mortality worldwide, and perturbations of the gut microbiota are known to increase susceptibility to enteric infections. The purpose of this study was to investigate whether a Microbial Ecosystem Therapeutic (MET-1) consisting of 33 bacterial strains, isolated from human stool and previously used to cure patients with recurrent Clostridium difficile infection, could also protect against S. typhimurium disease. C57BL/6 mice were pretreated with streptomycin prior to receiving MET-1 or control, then gavaged with S. typhimurium. Weight loss, serum cytokine levels, and S. typhimurium splenic translocation were measured. NF-kappaB nuclear staining, neutrophil accumulation, and localization of tight junction proteins (claudin-1, ZO-1) were visualized by immunofluorescence. Infected mice receiving MET-1 lost less weight, had reduced serum cytokines, reduced NF-kappaB nuclear staining, and decreased neutrophil infiltration in the cecum. MET-1 also preserved cecum tight junction protein expression, and reduced S. typhimurium translocation to the spleen. Notably, MET 1 did not decrease CFUs of Salmonella in the intestine. MET-1 may attenuate systemic infection by preserving tight junctions, thereby inhibiting S. typhimurium from gaining access to the systemic circulation. We conclude that MET 1 may be protective against enteric infections besides C. difficile infection. PMID- 26531328 TI - EpViX: A cloud-based tool for epitope reactivity analysis and epitope virtual crossmatching to identify low immunologic risk donors for sensitized recipients. AB - One of the challenges facing solid organ transplantation programs globally is the identification of low immunological risk donors for sensitized recipients by HLA allele genotype. Because recognition of donor HLA alleles by host antibodies is at the core of organ rejection, the objective of this work was to develop a new version of the EpHLA software, named EpViX, which uses an HLAMatchmaker algorithm and performs automated epitope virtual crossmatching at the initiation of the organ donation process. EpViX is a free, web-based application developed for use over the internet on a tablet, smartphone or computer. This program was developed using the Ruby programming language and the Ruby-on-Rails framework. To improve the user experience, the EpViX software interface was developed based on the best human-computer interface practices. To simplify epitope analysis and virtual crossmatching, the program was integrated with important available web-based resources, such as OPTN, IMGT/HLA and the International HLA Epitope Registry. We successfully developed a program that allows people to work collaboratively and effectively during the donation process by accurately predicting negative crossmatches, saving time and other resources. PMID- 26531329 TI - Analyzing the impact of climate and management factors on the productivity and soil carbon sequestration of poplar plantations. AB - It is crucial to investigate how climate and management factors impact poplar plantation production and soil carbon sequestration interactively. We extracted above-ground net primary production (ANPP), climate and management factors from peer-reviewed journal articles and analyzed impact of management factor and climate on the mean annual increment (MAI) of poplar ANPP statistically. Previously validated mechanistic model (ED) is used to perform case simulations for managed poplar plantations under different harvesting rotations. The meta analysis indicate that the dry matter MAI was 6.3 Mg ha(-1) yr(-1) (n=641, sd=4.9) globally, and 5.1 (n=292, sd=4.0), 8.1 (n=224, sd=4.7) and 4.4 Mg ha(-1) yr(-1) (n=125, sd=3.2) in Europe, the US and China, respectively. Poplar MAI showed a significant response to GDD, precipitation and planting density and formed a quadratic relationship with stand age. The low annual production for poplar globally was probably caused by suboptimal water availability, rotation length and planting density. SEM attributes the variance of poplar growth rate more to climate than to management effects. Case simulations indicated that longer rotation cycle significantly increased soil carbon storage. Findings of this work suggests that management factor of rotation cycle alone could have dramatic impact on the above ground growth, as well as on the soil carbon sequestration of poplar plantations and will be helpful to quantify the long-term carbon sequestration through short rotation plantation. The findings of this study are useful in guiding further research, policy and management decisions towards sustainable poplar plantations. PMID- 26531330 TI - Type III TGF-beta receptor inhibits cell proliferation and migration in salivary glands adenoid cystic carcinoma by suppressing NF-kappaB signaling. AB - It is known that the TGF-beta superfamily receptors act as master regulators of cancer progression. However, alteration and role of type III TGF-beta receptor (TbetaRIII, or betaglycan) as the most abundant of the TGF-beta receptor has not been explored in salivary gland adenoid cystic carcinoma (ACC). Here, we reported that tumor biopsies and matched normal human salivary glands from patients with ACC were examined for the expression of TbetaRIII. The expression of TbetaRIII protein is significantly decreased in ACC patients based on immunohistochemistry and western blot analysis. In vitro, a transient overexpression of TbetaRIII markedly induced apoptosis and cell cycle arrest in the G2/M phase, thereby inhibited cell viability and migration of ACC-M cells. Co-immunoprecipitation revealed that TbetaRIII, scaffolding protein-arrestin2 (beta-arrestin2) and IkappaBalpha formed a complex. Transient overexpression of TbetaRIII decreased p p65 expression and increased IkappaBalpha expression, which was abolished by knockdown of beta-arrestin2. The present study defines TbetaRIII as a biomarker exerting antitumor action on ACC progression.Gene therapy of TbetaRIII may be a powerful new approach for ACC disease. PMID- 26531331 TI - Corrigendum: Structural Evolution of Chemically-Driven RuO2 Nanowires and 3 Dimensional Design for Photo-Catalytic Applications. PMID- 26531332 TI - Genome-wide association study with the risk of schizophrenia in a Korean population. AB - Schizophrenia is regarded as a multifactorial and polygenic brain disorder that is attributed to different combinations of genetic and environmental risk factors. Recently, several genome-wide association studies (GWASs) of schizophrenia have identified numerous risk factors, but the replication results remain controversial and ambiguous. To identify schizophrenia susceptibility loci in the Korean population, we performed a GWAS using the Illumina HumanOmni1-Quad V1.0 Microarray. We genotyped 1,140,419 single nucleotide polymorphisms (SNPs) in 350 Korea schizophrenia patients and 700 control subjects, and approximately 620,001 autosomal SNPs were passed our quality control. In the case-control analysis, the rs9607195 A>G on intergenic area 250 kb away from the ISX gene and the rs12738007 A>G on the intron of the MECR gene were the most strongly associated SNPs with the risk of schizophrenia (P = 6.2 * 10(-8) , OR = 0.50 and P = 3.7 * 10(-7) , OR = 2.39, respectively). In subsequent fine-mapping analysis, 6 SNPs of MECR were genotyped with 310 schizophrenia patients and 604 control subjects. The association of the MECR rs12738007, a top ranked-SNP in GWAS, was replicated (P = 1.5 * 10(-2) , OR = 1.53 in fine mapping analysis, P = 1.5 * 10( 6) , OR = 1.90 in combined analysis). The identification of putative schizophrenia susceptibility loci could provide new insights into genetic factors related with schizophrenia and clues for the development of diagnosis strategies. PMID- 26531333 TI - Combined Extraperitoneal and Transperitoneal Laparoscopic Extended Partial Cystectomy for the Treatment of Urachal Carcinoma. AB - PURPOSE: To evaluate the application of laparoscopic extended partial cystectomy (PC) and bilateral extended pelvic lymph node dissection (PLND) for the treatment of urachal carcinomas (UrCs). METHODS: Combined laparoscopic extended PC and bilateral extended PLND was performed in 16 cases with UrCs in our hospital between April 2009 and December 2012. The surgical procedure included the dilation of the extraperitoneal space, circumscription of the umbilicus, dissection from the umbilicus caudad to the dome of the bladder, excision of the tumor, and the suture of the bladder. The average age of the patients was 52.8 years (35-73 years). The average tumor size was 3.2 cm (1.5-5.6 cm). A median follow-up period of 36 months was obtained to evaluate patient survival and recrudescence. RESULTS: All 16 procedures were completed laparoscopically without open conversion. The median operation time was 85 minutes (65-125 minutes), with a median estimated blood loss of 50 mL (30-110 mL). The median hospital stay was 5 days (4-7 days). The bladder margins were negative in all cases. However, five cases were confirmed postoperatively with positive lymph nodes. No intraoperative or postoperative complications occurred. Histopathology confirmed mucous urachal adenocarcinoma in 11 cases, mixed carcinoma in 1 case, and papillary adenocarcinoma in 4 cases. After a median follow-up period of 36 months, the 2- and 3-year survival rates were 62.5% (10/16) and 50% (8/16), respectively. CONCLUSION: Combined laparoscopic extended PC and bilateral extended PLND is a safe and feasible method for treating patients with urachal malignancy. PMID- 26531671 TI - Maternal-fetal medicine specialists' experiences of conducting feticide as part of termination of pregnancy: a qualitative study. AB - OBJECTIVES: This study aimed to explore maternal-fetal medicine specialists' experiences of conducting feticide in late termination of pregnancy. METHODS: Participants were recruited via email. Purposeful sampling resulted in ten maternal-fetal specialists. Semistructured interviews were used to examine their experiences of conducting feticide. Interviews occurred across four English National Health Service hospitals. Interpretative phenomenological analysis was used. RESULTS: An ongoing doctor-patient relationship when conducting feticide facilitated participants' self-image as clinicians rather than technicians. Coping involved rationalisation, with feticide viewed as 'part of the job'. Supportive team relationships helped keep emotional expression within control. Participants were not distressed if they felt, through relationship-based decision-making, that the feticide aligned with their values and legal interpretation. To avoid negative judgements, they disclosed selectively, only telling trusted individuals that they conducted feticides. CONCLUSIONS: Participants experienced conducting feticides as difficult but necessary, eliciting pride from the skills involved. Some noted management of personal distress. Optimal conditions were involvement in the process from the initial decision-making and team support. Providing feticides was deemed as potentially stigmatising, with selective disclosure employed. Training in managing feticides and guidance on providing optimal service conditions may decrease selectivity of disclosures and enhance staff well-being and the quality of feticide provisions. (c) 2015 John Wiley & Sons, Ltd. PMID- 26531673 TI - Synthesis of 2-(lutidinyl)organoboranes and their reactivities against dihydrogen and pinacol borane. AB - Two 2,4,6-tris(trifluoromethyl)phenyl-substituted 2-(lutidinyl)organoboranes (5a and 5b) were prepared. These complexes can function as intramolecular vicinal B/N frustrated Lewis pairs to heterolytically activate dihydrogen. When these complexes were treated with HBpin, two different reaction pathways took place. Whereas the reaction between 5a and HBpin affords a formal ligand-redistribution product, the reaction of 5b with HBpin leads to a dearomative dehydroborylation product. PMID- 26531672 TI - Injecting vascular endothelial growth factor into the temporomandibular joint induces osteoarthritis in mice. AB - It is unclear whether vascular endothelial growth factor (VEGF) can initiate osteoarthritis (OA) in the temporomandibular joint (TMJ). In this study we evaluated the effects of intra-articular injection of exogenous VEGF in the TMJ in mice on the early stage. Forty-eight male Sprague-Dawley mice were equally divided into 3 groups. In the vegf group, the mice received an injection of VEGF solution (50 MUL) in the TMJ once a week over a period of 4 weeks. In the sham group, the mice received an injection of saline (50 MUL). The control group did not receive any injection. Four mice from each group were sacrificed at 1, 2, 4, and 8 weeks. Gradual prominent cartilage degeneration was observed in the vegf group. Additionally, this group showed higher expressions of metalloproteinase (MMP)-9, MMP-13, receptor activator of nuclear factor-kappa-B ligand (RANKL), and a higher number of apoptotic chondrocytes and VEGF receptor 2 (VEGFR2)-positive chondrocytes. Micro-computed tomography (CT) revealed prominent subchondral bone resorption in the vegf group, with a high number of osteoclasts in the subchondral bone. In vitro study demonstrated that VEGF can promote osteoclast differentiation. In conclusion, our study found that VEGF can initiate TMJ OA by destroying cartilage and subchondral bone. PMID- 26531674 TI - Effects of lentivirus-mediated shRNA targeting integrin-linked kinase on oral squamous cell carcinoma in vitro and in vivo. AB - Integrin-linked kinase (ILK), a highly conserved intracellular protein of serine/threonine protein kinase activities, which is associated with the integrin and growth factor receptor signaling pathway, is involved in the regulation of cell proliferation, apoptosis, differentiation, migration and epithelial mesenchymal transition (EMT). Findings of a previous study showed that ILK overexpression was strongly correlated with a more aggressive tumor phenotype, recurrence and poor survival for oral squamous cell carcinoma (OSCC) patients, as well as some EMT markers. In order to investigate the underlying mechanisms involved, a lentivirus-mediated short hairpin RNA (shRNA) was employed to downregulate ILK. The results showed that the knockdown of ILK inhibited cell growth, adhesion and invasion ability in vitro, and OSCC cells deficient of ILK were blocked in the S phase and underwent apoptosis. Additionally, ILK shRNA inhibited EMT by impairing the expression of Snail, Slug and Twist2 and enhacning E-cadherin expression. ILK shRNA suppressed the phosphorylation of downstream signaling targets Akt and GSk-3beta. In addition, the knockdown of ILK inhibited tumor growth, invasion and metastasis of xenograft tumors in vivo. These results suggested that ILK is a promising therapeutic target for the treatment of OSCC. PMID- 26531675 TI - Evolution and mutations of hepatitis B virus quasispecies in genotype B and C during vertical transmission. AB - Evolution patterns of HBV QS between genotype B and C during vertical transmission are not well understood. In this study, we enrolled 10 HBV infected mother-infant pairs (four pairs with genotype B, four pairs with genotype C, and two with co-infection) without anti-viral therapy. Serum HBV DNA of mothers and infants were sequenced, HBV QS complexity and diversity were analyzed, polymorphisms and mutation sites were recorded, and phylogenetic trees were performed. Our result showed that the QS complexities in P (amino acid), C/PreC (amino acid), and PreS1 (nucleotide) gene were significantly higher in mothers than in infants in pairs with genotype C (P < 0.05), however, full-length and other genes showed non-significant differences (P > 0.05). Unlike genotype C, QS complexity of P gene (nucleotide) was significantly higher in infants than in mothers (P < 0.05) in pairs with genotype B, similarly, QS complexities of full length and other genes (except Pre S2) were also higher in infants than in mothers but without significant differences (P > 0.05). QS diversities of full length and most genes in genotype B were comparable between mothers and their infants (P > 0.05), in pairs with genotype C, dS of P, X, RT genes, genetic distance of Pre S1 gene (amino acid) and dN of Pre S1 gene were significant higher in mothers than in infants (P < 0.05). Several HBV mutations correlated with immune escape, e antigen loss and drug resistance were observed in infants. The results indicated that differences of HBV QS evolution patterns between genotype B and C during vertical transmission might contribute to distinct prognosis. PMID- 26531676 TI - Peripheral oxidative stress markers in diabetes-related dementia. AB - AIMS: We previously found that there was a dementia subgroup with characteristics predominantly associated with diabetes mellitus (DM)-related metabolic abnormalities, referred to as "diabetes-related dementia (DrD)." We determined the possible role of oxidative stress in the pathophysiology of DrD. METHODS: In a 2013 study, we classified 175 patients with clinically diagnosed Alzheimer's disease (AD) and DM into four subgroups based on brain imaging. Among them, we measured endogenous plasma anti-oxidants, such as albumin, unconjugated bilirubin and uric acid, and urinary 8-hydroxy-2'-deoxyguanosine and 8-isoprostane in 58 patients of an AD group showing decreased regional cerebral blood flow of the parietotemporal lobe on single-photon emission computed tomography (AD+DM group), and in 35 patients of a DrD group showing neither decreased regional cerebral blood flow of the parietotemporal lobe nor cerebrovascular disease on magnetic resonance imaging, which is strongly associated with DM-related factors. A total of 31 patients with AD and without DM (AD-DM group) were enrolled as a control group. RESULTS: The DrD group showed a significant decrease in plasma levels of anti-oxidants, and a significant increase in urinary 8-hydroxy-2'-deoxyguanosine and 8-isoprostane levels in contrast to the AD-DM and AD+DM groups. Cognitive performance was negatively correlated with urinary 8-hydroxy-2'-deoxyguanosine and 8-isoprostane levels in the DrD group. CONCLUSIONS: These results strongly suggest that a decrease in anti-oxidant levels and an increase in oxidative damage might be involved in the pathophysiology and cognitive decline associated with DrD. Geriatr Gerontol Int 2016; 16: 1312-1318. PMID- 26531678 TI - CORRECTIONS. PMID- 26531677 TI - Focus Issue on Metabolism: Metabolites, Metabolites Everywhere. PMID- 26531679 TI - CORRECTIONS. PMID- 26531680 TI - Differential regulation of receptivity in two uterine horns of a recipient mouse following asynchronous embryo transfer. AB - Receptivity is a limited time in which uterine endometrium can establish a successful dialogue with blastocyst. This study was to investigate the effect of asynchronous embryo transfer on uterine receptivity in mice. Embryos under different stages were transferred into two oviduct sides of a recipient mouse on day 1 of pseudopregnancy. Our results showed the asynchronously transferred embryos can implant in all groups. Compared to zygote-transfer group, the length of implanted embryos is longer in 8-cell embryo- or blastocyst-transfer group. The levels of Snail and COX-2 immunostaining in blastocyst-transfer group are significantly stronger than that in zygote-transfer group. Embryos in blastocyst transfer group migrate faster than that in zygote-transfer group within uterus. Blastocysts are in a state of developmental delay after they are transferred into oviducts, and they are reactivated and implanted rapidly in uterus. The developmental rate to newborn in zygote-transfer group is obviously higher than that in blastocyst-transfer group, suggesting that a delay in embryo development and implantation will lead to a decrease of litter size. These results indicated that the window of implantation is differentially regulated in two uterine horns of a recipient by embryos at different stages. PMID- 26531681 TI - Physiological role of FolD (methylenetetrahydrofolate dehydrogenase), FchA (methenyltetrahydrofolate cyclohydrolase) and Fhs (formyltetrahydrofolate synthetase) from Clostridium perfringens in a heterologous model of Escherichia coli. AB - Most organisms possess bifunctional FolD [5,10-methylenetetrahydrofolate (5,10 CH2-THF) dehydrogenase-cyclohydrolase] to generate NADPH and 10 formyltetrahdrofolate (10-CHO-THF) required in various metabolic steps. In addition, some organisms including Clostridium perfringens possess another protein, Fhs (formyltetrahydrofolate synthetase), to synthesize 10-CHO-THF. Here, we show that unlike the bifunctional FolD of Escherichia coli (EcoFolD), and contrary to its annotated bifunctional nature, C. perfringens FolD (CpeFolD) is a monofunctional 5,10-CH2-THF dehydrogenase. The dehydrogenase activity of CpeFolD is about five times more efficient than that of EcoFolD. The 5,10 methenyltetrahydrofolate (5,10-CH+-THF) cyclohydrolase activity in C. perfringens is provided by another protein, FchA (5,10-CH+-THF cyclohydrolase), whose cyclohydrolase activity is ~ 10 times more efficient than that of EcoFolD. Kinetic parameters for CpeFhs were also determined for utilization of all of its substrates. Both CpeFolD and CpeFchA are required to substitute for the single bifunctional FolD in E. coli. The simultaneous presence of CpeFolD and CpeFchA is also necessary to rescue an E. coli folD deletion strain (harbouring CpeFhs support) for its formate and glycine auxotrophies, and to alleviate its susceptibility to trimethoprim (an antifolate drug) or UV light. The presence of the three clostridial proteins (FolD, FchA and Fhs) is required to maintain folate homeostasis in the cell. PMID- 26531682 TI - Kinetics of Protein Complex Dissociation Studied by Hydrogen/Deuterium Exchange and Mass Spectrometry. AB - The growing importance of protein aggregation diseases requires the development of new methods to elucidate the molecular features that are responsible for the incipient protein-protein interactions. Kinetic information from protein-protein association/dissociation reactions is particularly valuable for revealing mechanistic insight, but robust tools that can provide this information are somewhat lacking. In this work, we describe a hydrogen/deuterium exchange (HDX) based method that provides rate constant information for protein oligomer dissociation, using the well-studied beta-lactoglobulin (betaLG) dimer as a model system to validate our approach. By measuring the rate of exchange at different regions of the protein using top-down tandem mass spectrometry and fitting the resulting data to an appropriate mathematical model, we are able to extract the dimer's dissociation rate constant. We exploit the fact that regions of the protein that are part of the protein-protein interface have exchange patterns that are distinct from noninterfacial regions. This observation indicates that the HDX/MS method not only provides kinetic information but also could provide structural insight about the interface at the same time, which would be very valuable for previously uncharacterized protein-protein complexes. PMID- 26531683 TI - Formal Direct Cross-Coupling of Phenols with Amines. AB - The transition-metal-catalyzed amination of aryl halides has been the most powerful method for the formation of aryl amines over the past decades. Phenols are regarded as ideal alternatives to aryl halides as coupling partners in cross couplings. An efficient palladium-catalyzed formal cross-coupling of phenols with various amines and anilines has now been developed. A variety of substituted phenols were compatible with the standard reaction conditions. Secondary and tertiary aryl amines could thus be synthesized in moderate to excellent yields. PMID- 26531684 TI - The mitochondrial genome of the bloom-forming green alga Ulva prolifera. AB - From 2007 to 2015, massive green tides formed by Ulva prolifera O.F. Muller have broken out for nine consecutive years in the Yellow Sea of China. Here, we determined the complete mitochondrial genome sequence of U. prolifera. The circular U. prolifera mitogenome is 63 845 bp in size, with the overall A + T content of 66.04% which is similar to the other three ulvophyceans (60.66% 67.83%). The mitogenome encodes 74 genes and the coding sequences account for 77.3% of the genome. Nine introns are identified in five genes and each of these introns contains an ORF. Two long tandem repeats identified have a period of 11 bp with a copy number of 62.5 and 19.5, respectively. The genome organization of U. prolifera is similar to that in Ulva sp., and its reduced spacer region makes it more compact than the latter. The present data will provide important information on phylogenetics and molecular evolution of Ulva species. PMID- 26531685 TI - Antibacterial effects of nitric oxide on uropathogenic Escherichia coli during bladder epithelial cell colonization--a comparison with nitrofurantoin. PMID- 26531686 TI - Streptomyces hyaluromycini sp. nov., isolated from a tunicate (Molgula manhattensis). AB - A novel Gram-stain-positive actinomycete, designated MB-PO13(T), was isolated from a tunicate (Molgula manhattensis) collected in Tokyo Bay, Japan, and its taxonomic position was studied by a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that strain MB-PO13(T) was closely related to Streptomyces graminisoli JR-12(T) (99.72% 16S rRNA gene sequence similarity) and Streptomyces shenzhenensis 172115(T) (99.23%). The strain contained LL-diaminopimelic acid in the whole-cell hydrolysate. The predominant menaquinones were MK-9(H8) and MK-9(H6) and the major fatty acids were anteiso-C15:0, iso-C16:0, iso-C14:0 and C16:0. These data supported the affiliation of the novel strain to the genus Streptomyces. Meanwhile, results of DNA-DNA hybridization and physiological and biochemical tests indicated that strain MB-PO13(T) was distinguished from known Streptomyces type strains. Therefore, strain MB-PO13(T) represents a novel species of the genus Streptomyces for which the name Streptomyces hyaluromycini sp. nov. is proposed; the type strain is MB-PO13(T) (=NBRC 110483(T) =DSM 100105(T)). PMID- 26531687 TI - In situ precision electrospinning as an effective delivery technique for cyanoacrylate medical glue with high efficiency and low toxicity. AB - The side effects or toxicity of cyanoacrylate used in vivo have been argued since its first application in wound closure. We propose an airflow-assisted in situ precision electrospinning apparatus as an applicator and make a detailed comparison with traditional spraying via in vitro and in vivo experiments. This novel method can not only improve operational performance and safety by precisely depositing cyanoacrylate fibers onto a wound, but significantly reduce the dosage of cyanoacrylate by almost 80%. A white blood cell count, liver function test and histological analysis prove that the in situ precision electrospinning applicator produces a better postoperative outcome, e.g., minor hepatocyte injury, moderate inflammation and the significant ability for liver regeneration. This in situ precision electrospinning method may thus dramatically broaden both civilian and military applications of cyanoacrylates. PMID- 26531688 TI - Neonatal vaccination with bacillus Calmette-Guerin and hepatitis B vaccines modulates hippocampal synaptic plasticity in rats. AB - Immune activation can exert multiple effects on synaptic transmission. Our study demonstrates the influence of neonatal vaccination on hippocampal synaptic plasticity in rats under normal physiological conditions. The results revealed that neonatal BCG vaccination enhanced synaptic plasticity. In contrast, HBV hampered it. Furthermore, we found that the cytokine balance shifted in favour of the T helper type 1/T helper type 2 immune response in BCG/HBV-vaccinated rats in the periphery. The peripheral IFN-gamma:IL-4 ratio was positively correlated with BDNF and IGF-1 in the hippocampus. BCG raised IFN-gamma, IL-4, BDNF and IGF-1 and reduced IL-1beta, IL-6, and TNF-alpha in the hippocampus, whereas, HBV triggered the opposite effects. PMID- 26531689 TI - Chrysin suppresses human CD14(+) monocyte-derived dendritic cells and ameliorates experimental autoimmune encephalomyelitis. AB - Chrysin, a naturally flavonoid of plant, has various biological activities. However, the effects of chrysin on dendritic cells (DCs) and multiple sclerosis (MS) remain unknown. In this study, we demonstrate that chrysin inhibited human DC differentiation, maturation, function and the expression of the Th1 cells polarizing cytokines IFN-gamma and IL-12p35 form DCs. In addition, chrysin ameliorated experimental autoimmune encephalomyelitis (EAE), an animal model of MS, by reducing CNS inflammation and demyelination. Furthermore, chrysin suppressed DCs and Th1 cells in the EAE mice. Taken together, chrysin exerts anti inflammatory and immune suppressive effects, and suggests a possible therapeutic application of chrysin in MS. PMID- 26531690 TI - TRPC6 gene variants and neuropsychiatric lupus. AB - Neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) influence patients' quality of life and their survival. Little is known about the pathophysiological bases of NPSLE and accordingly there are no specific therapeutic agents to be employed in this setting. Genetic research in systemic lupus erythematosus (SLE) is rapidly evolving as a tool to find clues about the pathogenic determinants of the disease and of its manifestations. Here, we describe the association of a single nucleotide polymorphic variant of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) gene with protection from the development of NPSLE in a cohort of 106 patients with SLE. TRPC6 is involved in the regulation of N-methyl-d-aspartate (NMDA) receptor signalling, a major player in post-ischemic neuronal injury and in the pathogenesis of NPSLE. TRPC6 genetic variants are promising candidate predictors of nervous system involvement in SLE, whereas the TRPC6 pathway might constitute a potential novel therapeutic target. PMID- 26531692 TI - Aberrant decrease of microRNA19b regulates TSLP expression and contributes to Th17 cells development in myasthenia gravis related thymomas. AB - Myasthenia gravis (MG) is an organ-specific autoimmune disease. The imbalance of T helper type 17 cells (Th17) plays a key role in the pathogenesis of thymomatous MG. But the regulatory mechanism for Th17 cell development in MG-related thymoma remains undefined. Here we demonstrated that thymic stromal lymphopoietin (TSLP) is significantly decreased in thymomas. We also proved that TSLP was post trancriptionally regulated by microRNA-19b. The expression of microRNA-19b was negatively correlated with the expression of TSLP mRNA and protein in thymomas. This study indicated that the elevation of microRNA-19b suppressed TSLP expression and then influenced T cell development in thymomatous MG. PMID- 26531691 TI - Loss of CCR2 expressing non-classical monocytes are associated with cognitive impairment in antiretroviral therapy-naive HIV-infected Thais. AB - HIV DNA in monocytes has been linked to HIV-associated neurocognitive disorders (HAND), however, characterization of monocyte subsets associated with HAND remains unclear. We completed a prospective study of antiretroviral therapy naive, HIV-infected Thais, with varying degrees of cognitive impairment, compared to HIV-uninfected controls. Monocyte subsets' CCR2, CCR5 and CD163 expression were profiled and inflammatory markers in plasma and cerebrospinal fluid (CSF), measured. Lower numbers of CCR2(+)non-classical monocytes were associated with worse neuropsychological test performance (r=0.43, p=0.024). CCR2(+)non-classical monocyte count inversely correlated with CSF neopterin (r=-0.43, p=0.035) and plasma TNF-alpha levels (r=-0.40, p=0.041). These data benchmark CCR2(+)non classical monocytes as an independent index of cognitive impairment. PMID- 26531693 TI - Behavioral and systemic consequences of long-term inflammatory challenge. AB - Inflammatory reactions are involved in a diversity of diseases, including major depressive disorder. Cytokines act as intercellular signaling molecules and mediators of inflammation between the periphery and the brain. Within the brain, evidence from animal studies of acute inflammation has shown that elevated cytokine levels are linked to behavioral responses of sickness and depression like behavior. Although chronic inflammation is more translational to human depression than acute studies, little is known on central cytokine expression and associated behavioral responses following chronic immune challenges. The present study assessed behavioral changes and a selection of cytokines in the brain and in the blood in rats randomized to receive a single or 8week administration with either lipopolysaccharide (LPS, 600MUg/kg, i.p.) or saline. Acute and long-term LPS treatments caused similar sickness and depression-like behavior. Chronic LPS administration did not have an effect on blood cytokine levels, indicating endotoxin tolerance, whereas increased fasting blood glucose was observed, indicating insulin resistance, a metabolic consequence of chronic inflammation. While a single LPS injection produced a generalized cytokine response in the brain, long-term LPS administration produced a specific central cytokine response with increased interleukin (IL)-1beta and interferon (IFN)-gamma. These cytokines can explain the behavioral changes observed, and could indicate microglia activation, although future studies are needed to uncover this assumption. Taken together, although the behavioral outcome was similar between acute and chronic LPS administration, the central cytokine response was distinct. As the long-term LPS paradigm also posed a metabolic demand, this setting may reflect a more translational insight into inflammatory reactions in human depression, and could prove useful for assessing cytokine down-stream effects and experimental antidepressant drug products. PMID- 26531694 TI - Long-distance effects of inflammation on differentiation of adult spinal cord neural stem/progenitor cells. AB - Studies in multiple sclerosis have demonstrated that normal-appearing white matter can harbor pathological changes. Here we investigated the effects of neuroinflammation, modeled by experimental autoimmune encephalomyelitis (EAE) on neural stem/progenitor cells (NPCs) located distally to inflammatory foci. We observed that EAE-derived NPCs had a lower capacity to differentiate into oligodendrocytes and an increased neuronal differentiation than control NPCs. This finding was corroborated with changes in gene expression of early differentiation genes. We conclude that inflammation has a long range effect on the NPCs in the diseased central nervous system, reaching NPC populations outside the lesion sites. PMID- 26531696 TI - Daily fingolimod administration may cause lymphopenia but alternate-day administration may be too little to inhibit disease activity. AB - CD28/CTLA-4-CD80/CD86 molecules play an important role in the regulation of T cells activation. Defects in proteins involved in this pathway may lead to the development of autoimmune diseases in which T cells are involved. In this case control study (336 multiple sclerosis (MS) patients and 322 controls) we investigated the possible association of eleven polymorphisms in CD28, CTLA-4, CD80 and CD86 genes with susceptibility to MS and/or its progression. We also took into account HLA-DRB1*15:01 status. Moreover, this study aimed to determinethe possible gene-gene interactions between examined SNPs associated with the susceptibility to MS and its outcome. Our investigation revealed that in HLA-DRB1*15:01 negative individuals, G allele in rs231775A NGof CTLA-4 gene was associatedwith higher risk ofmultiple sclerosis. Additionally, the association of rs2715267T NGof CD86 gene withMS susceptibilitywas detected. In details, carriers of G allele at this polymorphic site possessed higher risk of MS in comparison to TT homozygotes. On the other hand, the lower risk of MS was observed in individuals carrying A allele at the rs1599795T N A polymorphic site of CD80. Furthermore, the analysis revealed an interactionbetween three polymorphisms: rs3116496T N C (CD28), rs6641T N G (CD80) and rs17281995G N C (CD86), associated with the age of MS onset. PMID- 26531697 TI - Microvesicles in the brain: Biomarker, messenger or mediator? AB - Microvesicles (MVs) are cell-derived vesicles produced after membrane remodeling of eukaryotic cells during activation or apoptosis. MVs are considered a novel biomarker/messenger for many diseases. Neurons, astrocytes, microglia, as well as neural stem cells, have been described to release MVs, many studies have demonstrated the involvement of platelets and endothelial MVs in some central nervous diseases. This review is focused on understanding the role of MVs in the brain; new findings demonstrated that MVs can contribute to the onset and progression of some neurodegenerative and neuroinflammatory diseases, as well as to the development and regeneration of the nervous system. PMID- 26531695 TI - Social disruption alters pain and cognition in an animal model of multiple sclerosis. AB - Although pain and cognitive deficits are widespread and debilitating symptoms of multiple sclerosis (MS), they remain poorly understood. Theiler's murine encephalomyelitis virus (TMEV) infection is an animal model of MS where disease course is exacerbated by prior stressors. Here chronic infection coupled with prior social stress increased pain behavior and impaired hippocampal-dependent memory consolidation during the demyelinating phase of disease in SJL mice. These results suggest that the TMEV model may be useful in investigating pain and cognitive impairments in MS. However, in contrast to prior Balb/cJ studies, stress failed to consistently alter behavioral and physiological indicators of disease course. PMID- 26531698 TI - Polymorphisms in CD28, CTLA-4, CD80 and CD86 genes may influence the risk of multiple sclerosis and its age of onset. AB - CD28/CTLA-4-CD80/CD86 molecules play an important role in the regulation of T cells activation. Defects in proteins involved in this pathway may lead to the development of autoimmune diseases in which T cells are involved. In this case control study (336 multiple sclerosis (MS) patients and 322 controls) we investigated the possible association of eleven polymorphisms in CD28, CTLA-4, CD80 and CD86 genes with susceptibility to MS and/or its progression. We also took into account HLA-DRB1*15:01 status. Moreover, this study aimed to determine the possible gene-gene interactions between examined SNPs associated with the susceptibility to MS and its outcome. Our investigation revealed that in HLA DRB1*15:01 negative individuals, G allele in rs231775A NGof CTLA-4 gene was associatedwith higher risk ofmultiple sclerosis. Additionally, the association of rs2715267T NGof CD86 gene withMS susceptibilitywas detected. In details, carriers of G allele at this polymorphic site possessed higher risk of MS in comparison to TT homozygotes. On the other hand, the lower risk of MS was observed in individuals carrying A allele at the rs1599795T N A polymorphic site of CD80. Furthermore, the analysis revealed an interaction between three polymorphisms: rs3116496T N C (CD28), rs6641T N G (CD80) and rs17281995G N C (CD86), associated with the age of MS onset. PMID- 26531699 TI - Paraneoplastic syndrome-associated neuronal antibodies in adult ADHD. AB - A high seroprevalence of Yo antibodies targeting cerebellar Purkinje cells was recently reported in children with attention deficit/hyperactivity disorder (ADHD). We investigated the presence of 8 paraneoplastic neurological syndrome (PNS)-associated antibodies including anti-Yo in 169 adult ADHD patients. No associations between ADHD and serum Yo antibodies or other antibodies associated with PNS were found. However, 10 out of 48 ADHD patient sera analyzed by immunofluorescence presented antibodies targeting cerebellar Purkinje cells. This reactivity probably represents the presence of low levels of antibodies against multiple cellular hitherto unknown antigens with little to no clinical significance. PMID- 26531700 TI - Body mass index influence interferon-beta treatment response in multiple sclerosis. AB - Obesity is a possible risk factor of multiple sclerosis (MS), but the association between obesity and MS disease activity has not been explored. In a cohort of 86 MS patients, 80% of overweight or obese patients (BMI>=25kg/m(2)) had MRI activity compared to 48% of the normal-weight patients (BMI<25kg/m(2)) (p=0.001) during interferon-beta treatment. NEDA-status (no evidence of disease activity) was defined as a composite that consisted of absence of any relapses, sustained disability-progression and MRI-activity. Among normal-weight patients 26% obtained NEDA-status compared to only 13% of patients with BMI >25 (p=0.05). This may indicate that BMI affects interferon-beta treatment response. PMID- 26531701 TI - Peripheral blood non-MAIT CD8+CD161hi cells are decreased in relapsing-remitting multiple sclerosis patients treated with interferon beta. AB - CD8+CD161hi cells, comprising MAIT and non-MAIT cells, have been involved in multiple sclerosis (MS) pathogenesis. Here, we investigated the frequency of CD8+CD161hi, MAIT and non-MAIT cells by flow cytometry in peripheral blood samples from 41 untreated MS patients, 48 patients receiving disease modifying therapies, and 17 healthy controls (HC). IFNbeta treatment was associated with a decrease in the frequency of Tc17 cells compared to untreated patients (p=0.019). No significant differences were observed between untreated MS patients and HC for any of the study cell populations. These results suggest previously unknown mechanisms of action of IFNbeta. PMID- 26531702 TI - Systemic Staphylococcus aureus infection in restraint stressed mice modulates impaired immune response resulting in improved behavioral activities. AB - Stress leads to immune malfunction and increased susceptibility to infection resulting in impaired cognitive behavior and depression. Working with an animal model of Staphylococcus aureus infection and restraint stress we demonstrated impaired immune response and altered behavior against the S. aureus infection after exposure to acute or chronic restraint stress. This enhanced the resistance of mice to S. aureus infection via inhibiting the production of pro-inflammatory cytokines, free radicals, and upregulating corticosterone and anti-inflammatory cytokine production, resulting in altered exploratory behavior, compared to non stressed infected group (P<0.05), thereby helping the animals to recover from depressive-like symptoms due to stress. PMID- 26531703 TI - Association of interleukin-1 gene cluster polymorphisms and haplotypes with multiple sclerosis in an Iranian population. AB - Multiple sclerosis (MS) is a multi-factorial autoimmune disease of the central nervous system. The exact etiology of MS is still unknown. Due to the important roles that cytokines play as mediators in immune and inflammatory responses, we have evaluated the association of IL-1 gene cluster polymorphisms and haplotypes with MS susceptibility in 306 unrelated MS patients and 312 healthy matched controls. A significant association was found for the IL-1beta +3953 T allele [OR=1.43, 95% CI (1.14-1.79), P value=0.002, Pc=0.01] and for IL-1beta +3953 T/T genotype and MS risk [OR=1.92, 95% CI (1.25-2.96), P value=0.005, Pc=0.01]. Interestingly, the genotypes of the polymorphisms remained significant under recessive, co-recessive and dominant models. However, no significant differences were found between MS patients and controls in the genotype and allele frequencies of the IL-1beta -511, -31 and IL-1Ra polymorphisms. Haplotype analysis for IL-1beta -31 and IL-1beta -511, with moderate linkage disequilibrium (LD), using the EM algorithm revealed a significant global association of haplotype differences between the two groups. Lower presence of two haplotypes (H3: C-T and H4: T-C) was observed in the MS patients than healthy controls. However, after applying Bonferroni's correction the differences were not significant. To our knowledge, this is the first study reporting the association of the IL-1beta +3953 gene polymorphism and MS susceptibility. PMID- 26531704 TI - Serum interleukin-27 expression in patients with myasthenia gravis. AB - Myasthenia gravis (MG)(1) is an autoimmune disease directed at the neuromuscular junction, and cytokines are thought to contribute to its immunopathogenesis. Interleukin-27 (IL-27)(2) plays a complex and pleiotropic role in immune responses associated with T helper cells. To assess the role of IL-27 in MG, we determined serum IL-27 levels in MG patients (n=32) compared to healthy controls (n=50). The median serum IL-27 level was significantly higher in MG patients (35.947pg/mL) than in controls (19.885pg/mL). Furthermore, serum IL-27 was significantly higher in early onset MG. This study suggests the possibility that IL-27 might contribute to MG pathogenesis or immunoregulation. PMID- 26531705 TI - Monitoring oligoclonal immunoglobulins in cerebral spinal fluid using microLC-ESI Q-TOF mass spectrometry. AB - Our group has previously shown that mass spectrometry can be used to detect and quantify monoclonal and polyclonal immunoglobulin light chains in serum and urine from patients with monoclonal gammopathies and polyclonal hypergammaglobinemia. Here we demonstrate the use of the methodology, also referred to as monoclonal immunoglobulin Rapid Accurate Mass Measurement?with (miRAMM), to detect oligoclonal immunoglobulins above the polyclonal background in cerebral spinal fluid (CSF) and serum. We compared the findings for 56 paired CSF and serum samples analyzed by IgG IEF and miRAMM. The two methods were in agreement with 54 samples having concordant results (22 positive and 34 negative) and 2 that were positive by IgG IEF but negative by miRAMM. In addition to identifying oligoclonal immunoglobulins, miRAMM can be used to quantify and isotype each specific monoclonal immunoglobulin in CSF. This methodology has the potential to transform the way the inflammatory response is monitored in the CNS compartment. PMID- 26531706 TI - Perspectives on research activity in the USA on Cancer Precision Medicine. AB - The National Cancer Institute-Molecular Analysis for Therapy Choice trial is a clinical trial that will analyze various genetic statuses of patients' tumors to determine whether they contain abnormalities which can be a target for an available drug. National Cancer Institute-Molecular Analysis for Therapy Choice seeks to determine whether improved outcomes can be achieved when cancer treatments are personalized based on molecular abnormalities found in individual patients. As a master protocol, or basket trial, National Cancer Institute Molecular Analysis for Therapy Choice can add or remove treatments as indicated over the duration of the study. Each treatment will be used in a unique arm, or sub-study, of the trial. The trial initially has 10 arms, each of which will enroll patients to a specific molecularly targeted treatment. It is ultimately anticipated that 20-25 drugs or combination treatments will be tested. To be eligible for the study, participants must have an advanced solid tumor or lymphoma that is no longer responding or never responded to the standard therapy. National Cancer Institute-Molecular Analysis for Therapy Choice investigators plan to obtain tumor biopsy specimens from as many as 3000 patients initially. To identify multiple genetic abnormalities that may respond to the targeted drugs selected for the trial, next-generation deoxyribonucleic acid and ribonucleic acid sequencing will be done in the genetic testing laboratories, analyzing for >4000 different variants across 143 genes. The drugs included in the trial have all either been approved by the US Food and Drug Administration for another cancer indication or are still being tested in other clinical trials, but have shown some clinical levels of evidence against tumors with a particular genetic alteration. PMID- 26531707 TI - Salmonella grows vigorously on seafood and expresses its virulence and stress genes at different temperature exposure. AB - BACKGROUND: Seafood is not considered the natural habitat of Salmonella except the river fish, but still, the incidence of Salmonella in seafood is in a steady rise. By extending our understanding of Salmonella growth dynamics and pathogenomics in seafood, we may able to improve seafood safety and offer better strategies to protect the public health. The current study was thus aimed to assess the growth and multiplication of non-typhoidal and typhoidal Salmonella serovars on seafood and further sought to evaluate their virulence and stress genes expression while in contact with seafood at varying temperature exposure. RESULTS: Salmonella enterica Weltevreden and Salmonella enterica Typhi were left to grow on fish fillets at -20, 4, room temperature (RT) and 45 degrees C for a period of one week. Total RNA from both Salmonella serovars were extracted and qRT-PCR based relative gene expression approach was used to detect the expression of rpoE, invA, stn and fimA genes at four different temperature conditions studied on incubation days 0, 1, 3, 5 and 7. Salmonella Weltevreden growth on seafood was increased ~4 log10 at RT and 45 degrees C, nevertheless, nearly 2 and >4 log 10 reduction was observed in cell count stored at 4 and -20 degrees C on seafood, respectively. Growth pattern of Salmonella Typhi in seafood has shown identical pattern at RT and 45 degrees C, however, growth was sharply reduced at 4 and -20 degrees C as compared to the Salmonella Weltevreden. Total RNA of Salmonella Weltevreden was in the range from 1.3 to 17.6 MUg/MUl and maximum concentration was obtained at 45 degrees C on day 3. Similarly, RNA concentration of Salmonella Typhi was ranged from 1.2 to 11.8 MUg/MUl and maximum concentration was obtained at 45 degrees C on day 3. The study highlighted that expression of invA and stn genes of Salmonella Weltevreden was >8-fold upregulated at RT, whereas, fimA gene was increasingly down regulated at room temperature. Storage of Salmonella Weltevreden at 45 degrees C on seafood resulted in an increased expression (>13 -fold) of stn genes on day 1 followed by down regulation on days 3, 5, and 7. Nevertheless, other genes i.e. fimA, invA and rpo remained downregulated throughout the storage period. More intense upregulation was observed for invA and stn genes of Salmonella Typhi at RT and 45 degrees C. Further, incubating Salmonella Weltevreden at 4 degrees C resulted in down regulation in the expression of rpoE, invA and stn genes. Regarding Salmonella Typhi, fimA and stn genes were upregulated on day one, in addition, an increased expression of fimA was noted on day 3. At -20 degrees C, there was no obvious expression of target genes of Salmonella Weltevreden and Salmonella Typhi when stored along with seafood. CONCLUSION: Here we demonstrate that nutritional constituents and water content available in seafood has become useful growth ingredients for the proliferation of Salmonella in a temperature dependent manner. Although, it was absence of serovar specific growth pattern of non typhoidal and typhoidal Salmonella in seafood, there was observation of diverse expression profile of stress and virulent genes in non-typhoidal and typhoidal Salmonella serovars. In presence of seafood, the induced expression of Salmonella virulent genes at ambient temperature is most likely to be impacted by increased risk of seafood borne illness associated with Salmonella. PMID- 26531708 TI - Use of a Flexible Intubating Scope in Combination with a Channeled Video Laryngoscope for Managing a Difficult Airway in the Emergency Department. AB - BACKGROUND: Difficulty with intubation is not uncommon in the emergency setting. Video laryngoscopes (VLs) are commonly used to manage the difficult airway in the emergency department (ED). Intubation using a flexible bronchoscope, while considered the gold standard for managing the anticipated difficult airway in the operating room, is not commonly used in the ED. CASE: We present a case describing VL-assisted flexible scope intubation performed in the ED as a novel feasible approach to managing the difficult airway. A 65-year-old male, post cardiac arrest, with multiple unsuccessful attempts at prehospital intubation had rapid sequence intubation (RSI) performed and, despite obtaining a view with a King VisionTM VL, the skilled operator was unable to advance the endotracheal tube (ETT). An AmbuTM aScope3 flexible intubating scope (FIS) was placed through the ETT loaded in the channel of the King Vision and advanced through the cords to a position proximal to the carina. The ETT was then advanced easily over the FIS and down the trachea. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although video laryngoscopy is commonly used in the ED, intubation can prove difficult, despite having an adequate view of the glottis. Use of an FIS, however, through a channeled VL makes navigation of the ETT easier and facilitates tube advancement, which can be difficult with VL. Channeled VL assisted use of an FIS is a viable option for managing the difficult airway. PMID- 26531709 TI - Horizontal Slide Creates Less Cervical Motion When Centering an Injured Patient on a Spine Board. AB - BACKGROUND: A patient with a suspected cervical spine injury may be at risk for secondary neurologic injury when initially placed and repositioned to the center of the spine board. OBJECTIVES: We sought to determine which centering adjustment best limits cervical spine movement and minimizes the chance for secondary injury. METHODS: Using five lightly embalmed cadaveric specimens with a created global instability at C5-C6, motion sensors were anchored to the anterior surface of the vertebral bodies. Three repositioning methods were used to center the cadavers on the spine board: horizontal slide, diagonal slide, and V-adjustment. An electromagnetic tracking device measured angular (degrees) and translation (millimeters) motions at the C5-C6 level during each of the three centering adjustments. The dependent variables were angular motion (flexion-extension, axial rotation, lateral flexion) and translational displacement (anteroposterior, axial, and medial-lateral). RESULTS: The nonuniform condition produced significantly less flexion-extension than the uniform condition (p = 0.048). The horizontal slide adjustment produced less cervical flexion-extension (p = 0.015), lateral bending (p = 0.003), and axial rotation (p = 0.034) than the V adjustment. Similarly, translation was significantly less with the horizontal adjustment than with the V-adjustment; medial-lateral (p = 0.017), axial (p < 0.001), and anteroposterior (p = 0.006). CONCLUSIONS: Of the three adjustments, our team found that horizontal slide was also easier to complete than the other methods. The horizontal slide best limited cervical spine motion and may be the most helpful for minimizing secondary injury based on the study findings. PMID- 26531710 TI - Effects of NO3 (-) and PO4 (3-) on the release of geogenic arsenic and antimony in agricultural wetland soil: a field and laboratory approach. AB - The dynamics of arsenic (As) and antimony (Sb) in wetland soil periodically submitted to agricultural pressure as well as the impact of soil enrichment with NO3 (-) (50 mg L(-1)) and PO4 (3-) (20 mg L(-1)) on As and Sb release were evaluated at both field and laboratory scales. The results showed that As and Sb exhibited different temporal behaviors, depending on the study scale. At field scale, As release (up to 93 MUg L(-1)) occurred under Fe-reducing conditions, whereas Sb release was favored under oxidizing conditions (up to 5 MUg L(-1)) and particularity when dissolved organic carbon (DOC) increased in soil pore water (up to 92.8 mg L(-1)). At laboratory scale, As and Sb release was much higher under reducing conditions (up to 138 and 1 MUg L(-1), respectively) compared to oxic conditions (up to 6 and 0.5 MUg L(-1), respectively) and was enhanced by NO3 (-) and PO4 (3-) addition (increased by a factor of 2.3 for As and 1.6 for Sb). The higher release of As and Sb in the enriched reduced soil compared to the non enriched soil was probably induced by the combined effect of PO4 (3-) and HCO3 ( ) which compete for the same binding sites of soil surfaces. Modeling results using Visual Minteq were in accordance with experimental results regarding As but failed in simulating the effects of PO4 (3-) and HCO3 (-) on Sb release. PMID- 26531711 TI - Response of invertebrates from the hyporheic zone of chalk rivers to eutrophication and land use. AB - Whereas the response of lotic benthic macroinvertebrates to different environmental stressors is a widespread practice nowadays in assessing the water and habitat quality, the use of hyporheic zone invertebrates is still in its infancy. In this study, classification and regression trees analysis were employed in order to assess the ecological requirements and the potential as bioindicators for the hyporheic zone invertebrates inhabiting four lowland chalk rivers (south England) with contrasting eutrophication levels (based on surface nitrate concentrations) and magnitude of land use (based on percentage of fine sediments load and median interstitial space). Samples of fauna, water and sediment were sampled twice, during low (summer) and high (winter) groundwater level, at depths of 20 and 35 cm. Certain groups of invertebrates (Glossosomatidae and Psychomyiidae caddisflies, and riffle beetles) proved to be good indicators of rural catchments, moderately eutrophic and with high fine sediment load. A diverse community dominated by microcrustaceans (copepods and ostracods) were found as good indicators of highly eutrophic urban streams, with moderate-high fine sediment load. However, the use of other taxonomic groups (e.g. chironomids, oligochaetes, nematodes, water mites and the amphipod Gammarus pulex), very widespread in the hyporheic zone of all sampled rivers, is of limited use because of their high tolerance to the analysed stressors. We recommend the use of certain taxonomic groups (comprising both meiofauna and macroinvertebrates) dwelling in the chalk hyporheic zone as indicators of eutrophication and colmation and, along with routine benthic sampling protocols, for a more comprehensive water and habitat quality assessment of chalk rivers. PMID- 26531712 TI - Mechanisms of biochar-mediated alleviation of toxicity of trace elements in plants: a critical review. AB - Trace elements (TEs) contamination is one of the main abiotic stresses which limit plant growth and deteriorate the food quality by their entry into food chain. In recent, biochar (BC) soil amendment has been widely reported for the reduction of TE(s) uptake and toxicity in plants. This review summarizes the role of BC in enhancing TE(s) tolerance in plants. Under TE(s) stress, BC application increased plant growth, biomass, photosynthetic pigments, grain yield, and quality. The key mechanisms evoked are immobilization of TE(s) in the soil, increase in soil pH, alteration of TE(s) redox state in the soil, and improvement in soil physical and biological properties under TE(s) stress. However, these mechanisms vary with plant species, genotypes, growth conditions, duration of stress imposed, BC type, and preparation methods. This review highlights the potential for improving plant resistance to TE(s) stress by BC application and provides a theoretical basis for application of BC in TE(s) contaminated soils worldwide. PMID- 26531713 TI - Current content of selected pollutants in moss, humus, soil and bark and long term radial growth of pine trees in the Mezaparks forest in Riga. AB - The aim of this study was to evaluate the use of various indicators in the assessment of environmental pollution and to determine the response of pine to changes of pollution levels. Mezaparks is a part of Riga that has been subject to various long-term effects of atmospheric pollution and, in particular, historically from a large superphosphate factory. To determine the spatial distribution of pollution, moss, pine bark and soil O and B horizons were used as sorbents in this study, as well as the additional annual increment of pine trees. The current spatial distribution of pollution is best shown by heavy metal accumulation in mosses and the long-term accumulation of P2O5 pollution by the soil O horizon. The methodological problems of using these sorbents were explored in the study. Environmental pollution and its changes could be associated with the tree growth ring annual additional increment of Mezaparks pine forest stands. The additional increment increased after the closing of the Riga superphosphate factory. PMID- 26531714 TI - Urban eutrophication and its spurring conditions in the Murchison Bay of Lake Victoria. AB - The efficiency of Lake Victoria in providing its ecosystem services to riparian states, both immediate and along the Nile river basin, is strongly related to its water quality. Over the past few decades, eutrophication has increased in the lake arising from increased inflow of nutrients. This study was carried out in the Murchison Bay area of Lake Victoria with the aims of assessing the progress of eutrophication nutrient enrichment into the lake between 1990 and 2014. Using Landsat satellite floating algae index (FAI) products and data from laboratory analysis of water samples, the study revealed that floating algae reoccurred periodically with coverage varying between 1 and 18 km(2). The findings also indicated that the range of nitrate-nitrogen concentrations increased greatly with maximum concentrations recorded at 31.2 mg l(-1) in 2007 from 0.084 mg l(-1) in 1990. The soluble reactive phosphorus concentration range showed a maximum of 1.45 mg l(-1) in 2007 from 0.043 mg l(-1) in 1990. The chlorophyll levels increased from an average of 17 MUg l(-1) in 1992 by threefold in 1996 but had however declined and halved in intensity by 2011. The eutrophication that has occurred in Lake Victoria over the past decades has been due to pollution from industrial, residential, and agricultural areas within the catchment. PMID- 26531715 TI - Removal of polycyclic aromatic hydrocarbons (PAHs) from inorganic clay mineral: Bentonite. AB - There has been limited study of the removal of polycyclic aromatic hydrocarbons (PAHs) from inorganic clay minerals. Determining the amount of PAH removal is important in predicting their environmental fate. This study was carried out to the degradation and evaporation of PAHs from bentonite, which is an inorganic clay mineral. UV apparatus was designed specifically for the experiments. The impacts of temperature, UV, titanium dioxide (TiO2), and diethylamine (DEA) on PAH removal were determined. After 24 h, 75 and 44 % of ?12 PAH in the bentonite were removed with and without UV rays, respectively. DEA was more effective as a photocatalyst than TiO2 during UV application. The ?12 PAH removal ratio reached 88 % with the addition of DEA to the bentonite. It was concluded that PAHs were photodegraded at high ratios when the bentonite samples were exposed to UV radiation in the presence of a photocatalyst. At the end of all the PAH removal applications, higher evaporation ratios were obtained for 3-ring compounds than for heavier ones. More than 60 % of the amount of ?12 PAH evaporated consisted of 3-ring compounds. PMID- 26531716 TI - Enzymatic activities and arbuscular mycorrhizal colonization of Plantago lanceolata and Plantago major in a soil root zone under heavy metal stress. AB - The objectives of the present field study were to examine the soil enzyme activities in the soil root zones of Plantago lanceolata and Plantago major in different heavy metal contaminated stands. Moreover, the investigations concerned the intensity of root endophytic colonization and metal bioaccumulation in roots and shoots. The investigated Plantago species exhibited an excluder strategy, accumulating higher metal content in the roots than in the shoots. The heavy metal accumulation levels found in the two plantain species in this study were comparable to other plants suggested as phytostabilizers; therefore, the selected Plantago species may be applied in the phytostabilization of heavy metal contaminated areas. The lower level of soil enzymes (dehydrogenase, urease, acid, and alkaline phosphatase) as well as the higher bioavailability of metals in the root zone soil of the two plantain species were found in an area affected by smelting activity, where organic matter content in the soil was also the smallest. Mycorrhizal colonization on both species in the contaminated area was similar to colonization in non-contaminated stands. However, the lowest arbuscule occurrence and an absence of dark septate endophytes were found in the area affected by the smelting activity. It corresponded with the lowest plant cover observed in this stand. The assessment of enzyme activity, mycorrhizal colonization, and the chemical and physical properties of soils proved to be sensitive to differences between sites and between Plantago species. PMID- 26531717 TI - Gut to lung. PMID- 26531718 TI - Real friends: Faecalibacterium prausnitzii supports mucosal immune homeostasis. PMID- 26531719 TI - Octreotide in combination with AT-101 induces cytotoxicity and apoptosis through up-regulation of somatostatin receptors 2 and 5 in DU-145 prostate cancer cells. AB - Prostate cancer (PCa) is the most common type of cancer among males. Although survival rate of early-stage PCa is high, treatment options are very limited for recurrent disease. In this study, the possible synergistic cytotoxic and apoptotic effect of octreotide in combination with AT-101 was investigated in DU 145 hormone and drug refractory prostate cancer cell line. To enlighten the action mechanisms of the combination treatment, expression levels of somatostatin receptors 2 and 5 (SSTR2 and SSTR5) were also investigated. Cell viability was measured by XTT assay. Apoptosis was assessed through DNA fragmentation analysis and caspase 3/7 assay. mRNA and protein levels of SSTR2 and SSTR5 were evaluated by qRT-PCR and western blot analysis, respectively. Octreotide in combination with AT-101 inhibited cell viability and induced apoptosis synergistically in DU 145 cells as compared to any agent alone. Combination treatment increased both SSTR2 and SSTR5 mRNA and protein levels in DU-145 cells. The data suggest that this combination therapy may be a good candidate for patients with advanced metastatic PCa do not respond to androgen deprivation. PMID- 26531720 TI - Circulating miR-148/152 family as potential biomarkers in hepatocellular carcinoma. AB - Aberrant expressions of the miR-148/152 family (miR-148a, miR-148b, and miR-152) have been documented in many tumor tissues, including hepatocellular carcinoma (HCC). However, the expression pattern and clinical significance of circulating miR-148/152 family in HCC remain elusive. In this study, we conducted quantitative real-time polymerase chain reaction (qRT-PCR) to examine the levels of serum miR-148a, miR-148b, and miR-152 in 76 HCC cases, as well as 62 controls with benign liver diseases and 55 healthy volunteers. Our results showed that serum levels of three microRNAs (miRNAs) were significantly decreased in HCC cases than those in benign and healthy controls (all P < 0.05). Moreover, they showed strong correlations with each other in HCC group (r = 0.6716, 0.5381, and 0.7712; all P < 0.001). Receiver operating characteristic (ROC) analysis revealed that the combination of circulating miR-148/152 family had an increased area under the curve (AUC) = 0.940 (95 % confidence interval (CI), 0.886-0.973) with the sensitivity of 96.1 % and the specificity of 91.9 %, which were significantly higher than those of serum alpha-fetoprotein (AFP) and three miRNAs alone in differentiating HCC from benign liver diseases. In addition, serum miR-148a and miR-148b were significantly associated with tumor size (P = 0.011 and 0.037) and tumor-node-metastasis (TNM) stage (P < 0.001 and P = 0.034), yet serum miR-152 was only correlated with TNM stage (P = 0.009). Also, dynamic monitoring three miRNAs can help us predict recurrence or metastasis in HCC cases after surgical resection. Besides, Kaplan-Meier analyses demonstrated that the decreased serum miR-148a (P < 0.001) and miR-152 (P = 0.012) was closely correlated with shorten overall survival of HCC patients. Additionally, Cox regression model further indicated that serum miR-148a was strongly associated with the prognosis of HCC patients. Our study suggests that downregulated circulating miR-148/152 family can provide positive diagnostic value for HCC. Moreover, serum miR-148a might be as independent prognostic factor for HCC patients. PMID- 26531721 TI - Predictive value of blood lipid association with response to neoadjuvant chemoradiotherapy in colorectal cancer. AB - The aim of this research was to explore whether blood lipid parameters could predict tumor regression grading (TRG) and compare with the predictive value of carcinoembryonic antigen (CEA) in patients with locally advanced colorectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT). Between June 2011 and January 2015, the records of 176 patients with primary colorectal adenocarcinoma treated with nCRT followed by radical surgery were reviewed retrospectively. Total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and pre-CEA were measured before nCRT, and post-CEA was measured before surgery. A total of 129 (73.3 %) good responders (TRG 3-4) and 47 (26.7 %) poor responders (TRG 0-2) were assessed after the nCRT. TC, LDL, HDL, and DeltaCEA were 6.56 +/- 0.95, 3.08 +/- 0.72, and 1.43 +/- 0.25 mmol/L and -0.69 +/- 8.33 MUg/mL in poor responders compared with 5.15 +/- 1.29, 2.39 +/- 0.5, and 1.37 +/- 0.32 mmol/L and 16.67 +/- 30.18 MUg/mL in good responders, respectively (p < 0.05). TG, pre-CEA, and post-CEA were not significantly different. Multivariate logistic regression analysis revealed TC and DeltaCEA as independent factors in predicting TRG; TC showed a sensitivity of 62.79 %, a specificity of 91.49 %, a Youden index of 0.543, a cutoff value of 5.52, and an AUC of 0.800 compared with DeltaCEA (sensitivity 76.74 %, specificity 65.96 %, Youden index 0.427, and AUC 0.761). TC has a better predictive value than DeltaCEA and hence might serve as a predictor of TRG in LARC patients. PMID- 26531722 TI - Oncogenic potential of TSTA3 in breast cancer and its regulation by the tumor suppressors miR-125a-5p and miR-125b. AB - TSTA3 participates in enzyme metabolism and affects glycosylation processes, and abnormal glycosylation influences the malignant transformation of cells and tumor development. However, studies have not examined the molecular biological function of TSTA3 in breast cancer (BC). The expression of TSTA3 was examined in BC tissues and cell lines. Kaplan-Meier survival tests and Cox regression were used to analyze prognosis. TSTA3 depletion was used to analyze cell function. The upstream miRNAs of TSTA3 were predicted, and the downstream target gene was analyzed using a RT2 ProfilerTM PCR array. Our results show that TSTA3 was highly expressed in BC tissues and cells and was correlated with poor survival. The expression of TSTA3 was correlated with the TNM status (P < 0.01) and served as an independent prognostic factor (P = 0.041). TSTA3-siRNA decreased cell invasion and proliferation in vitro. miR-125a-5p and miR-125b are upstream targets of TSTA3, and a PCR array revealed that TSTA3 affects the CXCR4-CXCL12 genes. The findings suggest that miR-125a-5p/miR-125b suppress the expression of TSTA3, which controls cell proliferation and invasion by regulating CXCR4 expression. In conclusion, a high expression of TSTA3 exerts a proto-oncogenic effect during carcinogenesis and serves as an independent molecular marker for BC patients. PMID- 26531723 TI - The role of HE4 in endometrial cancer recurrence: how to choose the optimal follow-up program. AB - The aim of this study was to evaluate for the first time in the literature the role of HE4, at primary diagnosis, compared to CA125 as an indicator of endometrial cancer (EC) recurrence. Our study is a retrospective analysis of 252 EC patients treated, between January 2009 and July 2013, at the Division of Gynaecologic Oncology of Campus Bio-Medico University of Rome. Thirty-seven patients experienced recurrence. Median follow-up was 38 months. HE4 and CA125 levels were analyzed at primary diagnosis, during follow-up and either after histological or radiological confirmation of recurrent disease or at last registered visit, when patients returned to our Department with no evidence of recurrent disease. A statistically significant difference was observed between HE4 values at primary diagnosis and at recurrence, respectively, comparing recurrent and non-recurrent patients (p < 0.05), while CA125 values resulted not statistically significant (p = 0.08) at each time point. Considering the poor specificity of HE4 at threshold of 70 pmol/L at primary diagnosis, in our cohort of patients, we found out that HE4 cut-off of 201.3 pmol/L is able to correctly classify patients at high or low risk of EC recurrence, with a sensitivity of 80 % and a specificity of 91 % (PPV = 90.3 % and NPV = 90.8 %). In particular, HE4 performance improves in cases of endometrioid histotype. HE4 levels at primary diagnosis correlate with an increased risk of EC recurrence, particularly in cases of endometrioid histotype, and they may help to recognize patients who may need a more intensive follow-up. PMID- 26531725 TI - Early contact with animals is linked to reduced asthma risk, study shows. PMID- 26531724 TI - Role of histone deacetylase 3 in ankylosing spondylitis via negative feedback loop with microRNA-130a and enhancement of tumor necrosis factor-1alpha expression in peripheral blood mononuclear cells. AB - The present study was performed to investigate the molecular mechanism of ankylosing spondylitis (AS). The interaction between micro (mi)RNA-130a and its target tumor necrosis factor (TNF)-1alpha and histone deactylase (HDAC)3 was assessed in peripheral blood mononuclear cells (PBMCs) from AS patients. Increased HDAC3 and decreased miRNA-130a levels were observed in PBMCs from AS patients. HDAC3 knockdown or HDAC3 inhibition promoted the expression of miRNA 130a, and HDAC3 was recruited to the promoter region of the gene encoding miRNA 130a in PBMCs. In addition, miR-130a overexpression led to a decrease, whereas miR-130a inhibition led to an increase of TNF-1alpha expression in PBMCs. Furthermore, HDAC3 knockdown or HDAC3 inhibition was associated with simultaneous upregulation of the expression of miR-130a and downregulation of the expression of TNF-1alpha in PBMCs. These results indicated that HDAC3 was involved in the regulation of the underlying molecular mechanism of AS by forming a negative feedback loop with miR-130a and enhancement of TNF-1alpha expression. PMID- 26531726 TI - Use of progesterone in female reproduction: tradition and trends. PMID- 26531728 TI - Photoinduced spontaneous free-carrier generation in semiconducting single-walled carbon nanotubes. AB - Strong quantum confinement and low dielectric screening impart single-walled carbon nanotubes with exciton-binding energies substantially exceeding kBT at room temperature. Despite these large binding energies, reported photoluminescence quantum yields are typically low and some studies suggest that photoexcitation of carbon nanotube excitonic transitions can produce free charge carriers. Here we report the direct measurement of long-lived free-carrier generation in chirality-pure, single-walled carbon nanotubes in a low dielectric solvent. Time-resolved microwave conductivity enables contactless and quantitative measurement of the real and imaginary photoconductance of individually suspended nanotubes. The conditions of the microwave conductivity measurement allow us to avoid the complications of most previous measurements of nanotube free-carrier generation, including tube-tube/tube-electrode contact, dielectric screening by nearby excitons and many-body interactions. Even at low photon fluence (approximately 0.05 excitons per MUm length of tubes), we directly observe free carriers on excitation of the first and second carbon nanotube exciton transitions. PMID- 26531727 TI - Coevolutionary dynamics between tribe Cercopithecini tetherins and their lentiviruses. AB - Human immunodeficiency virus, a primate lentivirus (PLV), causes AIDS in humans, whereas most PLVs are less or not pathogenic in monkeys. These notions suggest that the co-evolutionary process of PLVs and their hosts associates with viral pathogenicity, and therefore, that elucidating the history of virus-host co evolution is one of the most intriguing topics in the field of virology. To address this, recent studies have focused on the interplay between intrinsic anti viral proteins, such as tetherin, and viral antagonists. Through an experimental phylogenetic approach, here we investigate the co-evolutionary interplay between tribe Cercopithecini tetherin and viral antagonists, Nef and Vpu. We reveal that tribe Cercopithecini tetherins are positively selected, possibly triggered by ancient Nef-like factor(s). We reconstruct the ancestral sequence of tribe Cercopithecini tetherin and demonstrate that all Nef proteins are capable of antagonizing ancestral Cercopithecini tetherin. Further, we consider the significance of evolutionary arms race between tribe Cercopithecini and their PLVs. PMID- 26531730 TI - Dermatitis caused by metal allergy after coil embolization for unruptured cerebral aneurysm. AB - We report a rare case of metal-induced dermatitis after coil embolization for cerebral aneurysm. A 51-year-old woman experienced a rash around the lips and neck 3 weeks after coil embolization. Judging from the clinical course and results of several patch tests, platinum coils were considered to have induced the dermatitis. Symptoms were relieved with administration of oral steroids. This represents the first report of metal-induced dermatitis after neuroendovascular treatment. The possibility of metal allergy was difficult to suspect preoperatively. However, early evaluation and referral are important when skin symptoms are observed postoperatively. PMID- 26531731 TI - Successful endovascular stroke therapy in a 103-year-old woman. AB - People older than 80 years of age constitute the most rapidly growing age group in the world. Several trials confirming superior efficacy of endovascular therapy did not have an upper age limit and showed favorable treatment effects, regardless of age. Current American Heart Association/American Stroke Association guidelines do not restrict treatment based on age as long as other eligibility criteria are met. A 103-year-old woman presented 2 h after stroke onset secondary to a left internal carotid artery terminus (ICA-T) occlusion. Admission National Institutes of Health Stoke Scale (NIHSS) score was 38, with no early ischemic changes on imaging, pre-stroke modified Rankin Scale score was 0, and she lived independently with minimal help. After initiation of intravenous thrombolysis, the patient underwent successful mechanical thrombectomy with Thombosis in Cerebral Infaction-3 recanalization. She showed remarkable recovery (NIHSS score of 1 at 48 h). Stroke onset to recanalization was 3 h 40 min. Our objective in documenting the oldest patient to successfully undergo stroke intervention is to corroborate that with the current evidence, appropriate patients undergoing rapid treatment may allow us to advance the limits of endovascular therapy. PMID- 26531732 TI - Successful surgical management of early esophageal cancer in a patient with cystic fibrosis post-bilateral lung transplantation. AB - We present the first reported case of successful surgical management of esophageal cancer post-lung transplantation for cystic fibrosis. This case of a 42-year-old man highlights the risk factors for esophageal adenocarcinoma associated with cystic fibrosis and lung transplantation, the management options for early esophageal cancer and the surgical option chosen to minimise respiratory risks. Individualised patient care may allow for curative surgical approaches, even where complex surgery is required. PMID- 26531734 TI - Buerger's disease. PMID- 26531733 TI - Neurofibromatosis 1-associated panhypopituitarism presenting as hypoglycaemic seizures and stroke-like symptoms. AB - A 37-year-old man with a known history of neurofibromatosis 1 (NF1) presented within 2 days of diarrhoeal illness followed by encephalopathy, facial twitching, hypoglycaemia, hypotension, tachycardia and low-grade fever. Examination showed multiple cafe-au-lait spots and neurofibromas over the trunk, arms and legs and receptive aphasia with right homonymous hemianopia, which resolved. Workup for cardiac, inflammatory and infectious aetiologies was unrevealing. A brain MRI showed gyral swelling with increased T2 fluid-attenuated inversion recovery signal and diffusion restriction in the left cerebral cortex. Neuroendocrine findings suggested panhypopituitarism with centrally derived adrenal insufficiency. Supportive treatment, hormone supplementation, antibiotics, antivirals and levetiracetam yielded clinical improvement. A follow-up brain MRI showed focal left parieto-occipital atrophy with findings of cortical laminar necrosis. In conclusion, we describe a case of NF1-associated panhypopituitarism presenting as hypoglycaemic seizures and stroke-like findings, hitherto unreported manifestations of NF1. Prompt recognition and treatment of these associated conditions can prevent devastating complications. PMID- 26531735 TI - Pulmonary oedema, think beyond the heart even in the presence of severe left ventricular systolic dysfunction. AB - We submit a case of a young patient with known severe left ventricular (LV) systolic impairment who presented with recurrent flash pulmonary oedema (FPO) requiring multiple high-dependency care admissions. Despite extensive optimisation of his underlying heart failure, the presentations remained frequent. Investigations for alternative diagnosis were not approached due to the presence of LV impairment and compliance being questioned. However, deteriorating renal function prompted further investigation with multiple imaging modalities, and an effective diagnosis of bilateral renal artery stenosis secondary to an aortoiliac thrombus was made. At the point of diagnosis, it was felt that rescue of renal function was unfeasible and thus the patient was started on anticoagulation, with initiation of peritoneal dialysis planned. This case highlights the importance of considering alternative diagnoses for the presentation of FPO even in the presence of LV impairment. If this patient had received a prompter diagnosis it is possible that the outcome would have been different. PMID- 26531736 TI - Resolution of tachyarrhythmia-related fetal hydrops after corticosteroid administration for fetal lung maturation. AB - A case of hydrops fetalis (HF) that resolved after corticosteroid therapy despite persisting fetal tachycardia of 190 bpm is reported. The fetus with confirmed normal karyotype had HF in the presence of atrial flutter and sustained ventricular rate of 200-210 bpm at gestational week (GW) 31(-6/7). Aetiologies of HF other than fetal tachyarrhythmia were unlikely in this infant. The patient's family declined pharmacological treatment with maternal digoxin and desired to continue pregnancy with only intensive monitoring of fetal condition. Maternal transplacental beta-methasone was given to facilitate fetal lung maturation. The fetal tachyarrhythmia ameliorated to 190 bpm at GW 32(-5/7) and HF gradually disappeared by birth. The otherwise healthy female neonate weighing 3050 g born at GW 37(-0/7) was successfully treated with cardioversion performed 60 min after birth. This case suggested that corticosteroid therapy contributed to the resolution of HF associated with tachyarrhythmia. PMID- 26531737 TI - Low-intensity pulsed ultrasound treatment as an alternative to vascular bone graft surgery for a 5-year-long ulnar non-union in a patient with haemochromatosis. AB - We present the case of a 75-year-old woman with haemochromatosis who developed a 5-year-long right ulnar non-union after a shortening osteotomy to correct a malunited Colles' fracture. Standard surgical treatment for ulnar non-unions was attempted on 19 March 2008 and again on 20 April 2009, but the non-union persisted on 8 May 2012, as confirmed by CT scan. Vascular bone grafting and refixation was then considered, but the patient declined this extensive operation, instead choosing to try non-invasive low-intensity pulsed ultrasound treatment with an Exogen device. Just 4 months later, complete union as confirmed by CT scan was achieved. This is the first case demonstrating the efficacy of ultrasound treatment for long-standing non-unions resistant to surgery in patients with haemochromatosis, a disorder where iron deposition can provide suboptimal circumstances for bone healing. Our finding suggests that low intensity pulsed ultrasound devices could be used as a first-line treatment for stable non-unions instead of revision surgery. PMID- 26531738 TI - Tricuspid and mitral endocarditis due to methicillin-resistant Staphylococcus aureus exhibiting vancomycin-creep phenomenon. AB - Right-sided infective endocarditis (RIE) is commonly due to Staphylococcus aureus and often involves the tricuspid valve (TV). A 31-year-old man with prior intravenous drug use presented with substernal pain, cough, dyspnoea and fever. Examination revealed a febrile, tachycardic male with peripheral infective endocarditis stigmata and right-heart failure. Laboratory parameters demonstrated leucocytosis, lactic acidosis and methicillin-resistant S. aureus (MRSA) bacteraemia. Echocardiography demonstrated multiple TV echodensities and chest imaging confirmed septic emboli. The MRSA species demonstrated 'vancomycin creep', necessitating therapy with daptomycin and ceftaroline. Owing to persistent bacteraemia and septic shock, the patient underwent TV surgery, but continued to have a poor postoperative course with subsequent death. Indications for surgical therapy of RIE are limited to the European guidelines and most data are extrapolated from left-heart disease. MRSA exhibiting vancomycin-creep portends a poorer prognosis and requires aggressive therapy. We advocate the use of ceftaroline salvage therapy with daptomycin, pending further trials. PMID- 26531739 TI - Immune recovery uveitis in a patient with previously undiagnosed cytomegalovirus retinitis. AB - A 40-year-old man presented to the emergency service of the Department of Ophthalmology, Fundacion Oftalmologica de Santander, Floridablanca, Colombia, with blurred vision in his right eye. Anamnesis revealed that he also had newly diagnosed stage C HIV. He had recently started highly active antiretroviral therapy (HAART). Examination disclosed intraocular inflammation, along with plain white peripheral non-exudative lesions with sparse haemorrhaging. The differential diagnosis included cytomegalovirus (CMV) retinitis and immune recovery uveitis (IRU). On follow-up, the patient's left eye presented with decreased visual acuity and increased vitreous haze. A vitrectomy with vitreous tap was performed for microbiological studies. PCR for CMV in the vitreous sample was negative. The patient was discharged with the final diagnosis of IRU. In HIV patients with uveitis, the knowledge of characteristic signs and symptoms of particular entities such as opportunistic infections and IRU will enable the clinician to give the appropriate treatment. PMID- 26531740 TI - Catecholamine-secreting paraganglioma: the challenges of perioperative management. AB - An asymptomatic 48-year-old man presented with a right-sided neck mass. A CT scan demonstrated a lesion at the carotid bifurcation and an angiogram showed splaying of the carotid arteries. His plasma metanephrines were raised confirming a catecholamine-secreting paraganglioma. Metaiodobenzylguanidine single-photon emission CT showed focal high tracer uptake in the right of the neck. Histology revealed a tumour, arising within a nerve, composed of oval-shaped cells arranged in nested (zellballen) as well as in trabecular patterns. Immunohistochemistry was positive for neuroendocrine markers chromogranin A, synaptophysin and CD56. Preoperative management included an endocrinologist initiating alpha-adrenergic and beta-adrenergic blockers. Intraoperatively, acute hypertension occurred whenever the tumour was manipulated. Close communication between the surgeons and the anaesthetist allowed for these episodes to be predicted and treated with fast acting antihypertensives such as sodium nitroprusside. Postoperatively, the patient recovered well and his antihypertensives were discontinued. PMID- 26531742 TI - A thyroid nodule mimic. PMID- 26531741 TI - Failure of oral penicillin as secondary prophylaxis for rheumatic heart disease: a lesson from a low-prevalence rheumatic fever region. AB - Our patient is an 18-year-old Caucasian woman from the UK who developed severe mitral stenosis on a history of childhood acute rheumatic fever (ARF) and rheumatic heart disease (RHD). She had been reporting of her oral penicillin secondary prophylaxis regimen since diagnosis. At the age of 15 years, a new murmur was discovered during routine cardiac follow-up. An echocardiogram confirmed moderate-severe mitral stenosis. One year later, her exercise tolerance significantly deteriorated and she subsequently underwent balloon valvuloplasty of her mitral valve to good effect. Our case emphasises the evidence base supporting the use of monthly intramuscular penicillin injection to prevent ARF recurrence and RHD progression; it also emphasises the reduced efficacy of oral penicillin prophylaxis in this context. It particularly resonates with regions of low rheumatic fever endemicity. The long-term cardiac sequelae of ARF can be devastating; prescribing the most effective secondary prophylaxis regimen is essential. PMID- 26531743 TI - General Surgery Resident Satisfaction on Cardiothoracic Rotations. AB - OBJECTIVE: General surgery residents' exposure to cardiothoracic (CT) surgery rotations has decreased, which may affect resident satisfaction. We surveyed general surgery graduates to assess the relationships among rotation satisfaction, CT disease exposure, rotation length, mentorship, and mistreatment. DESIGN: A survey assessing CT curriculum, exposure, mentorship, and satisfaction was forwarded to general surgery graduates from 17 residency programs. A Wilcoxon rank-sum test was used to assess statistical significance of ordinal level data. Statistical significance was defined as p < 0.05. SETTING: This study was conducted at the University of Michigan Health System in Ann Arbor, MI, a tertiary care center. PARTICIPANTS: The survey was sent to approximately 1300 graduates of general surgery residency programs who graduated between the years of 1999 to 2014. A total of 94 responses were completed and received. RESULTS: Receiving adequate exposure to CT procedures and disease management was significantly associated with higher satisfaction ratings for all procedures, particularly thoracotomy incisions (p < 0.001), empyemas and pleural effusions (p < 0.001), and lung cancer care (p < 0.001). The absence of mistreatment and good/very good mentorship were both positively associated with higher reported satisfaction (p = 0.018 and p < 0.001, respectively). Increased length of time on CT rotation was neither associated with improved levels of satisfaction nor with an improvement in the quality of mentorship. CONCLUSION: Rotation satisfaction is positively associated with procedure exposure, better mentorship, and the absence of mistreatment. Longer rotation length was not associated with satisfaction. Shorter rotations are not detrimental to training if they have focused clinical exposure and invested mentors to maximize resident satisfaction. These specific markers of rotation quality are useful in curricular design. PMID- 26531744 TI - Senior Surgical Resident Confidence in Performing Flexible Endoscopy: What Can We Do Differently? AB - INTRODUCTION: The American Board of Surgery endoscopy requirements for general surgery training are evolving. In 2006, the Residency Review Committee in Surgery increased the total number of endoscopy cases required before completion of general surgery residency training. This requirement is set to change further, given the new Flexible Endoscopic Curriculum that would be a requirement for applicants graduating surgical training during or after the 2017 to 2018 academic year. Given these changes, our goal was to evaluate the confidence of senior surgical residents performing flexible endoscopy. METHODS: A survey was developed and sent to general surgery residents nationally, querying them regarding demographics and program-specific characteristics; additionally they were asked to rate their confidence level in performing flexible upper endoscopy and colonoscopy on a Likert scale of 1 to 5. We then compared those residents who indicated confidence (Likert scale 4-5) to those who did not (Likert scale 1-3). For the purpose of this study, only senior (postgraduate year 4 and 5) general surgery residents were assessed. RESULTS: We received 1176 responses from senior surgical residents: 56% of these were postgraduate year 5 residents, 65% male, 68% from University Programs, and 56% from programs associated with a Veteran's Affairs Hospital; 33% were from programs in the Northeast, 29% in the South, 24% in the Midwest, and 14% in the West; 75% were going on to additional fellowship training after the completion of residency; 42% indicated that they would go into academic practice and 32% into private practice; 66.7% reported confidence performing upper endoscopy and 52.7% reported confidence performing colonoscopy. Male gender, overall operative volume, and graduating from a medium-sized program or program in the South were associated with increased confidence performing flexible endoscopy. CONCLUSIONS: A large percentage of senior residents do not report confidence in performing flexible endoscopy. Although increasing the number of cases required for graduation has likely helped improve the training of residents in endoscopy, additional improvements in training are required. The Flexible Endoscopic Curriculum helps standardize the curriculum and demonstrate that the graduating resident has the fundamental knowledge and skills required in the performance of endoscopy. Simulation training and dedicated endoscopic rotations during the course of residency training could help improve endoscopy training and proficiency for future graduating residents. PMID- 26531746 TI - Highlight report: biomarkers of acetaminophen-induced liver injury. PMID- 26531745 TI - Amorphous Sulfadoxine: A Physical Stability and Crystallization Kinetics Study. AB - Poor aqueous solubility of drugs and the improvement thereof has always been a challenge for the pharmaceutical industry. With this, one of the focuses of the pharmaceutical research scientist involves investigating possible metastable forms of a given drug to be incorporated into solid dosage forms. The rationale being, the improved solubility offered by the metastable solid-state forms of drugs. Solubility remains a major challenge for formulation scientists, especially with antimicrobial agents where the emergence of resistance is directly dependent on the concentration and duration of the parasite exposed to the drug. Sulfadoxine-pyrimethamine combination therapies are still the recommended treatments for uncomplicated Plasmodium falciparum malaria. The aim of this study was to prepare an amorphous form of sulfadoxine and to investigate the stability and recrystallization behavior thereof. The amorphous form was prepared by the well-known quench cooling of the melt. The physico-chemical properties and stability of amorphous sulfadoxine were studied using hot-stage microscopy (HSM), scanning electron microscopy (SEM), x-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), as well as microcalorimetry. The recrystallization kinetics were studied isothermally by applying the Johnson-Mehl-Avrami model and non-isothermally by applying the Kissinger model. The physical stabilization of the amorphous form was investigated using physical mixtures of amorphous sulfadoxine with polyvinylpyrrolidone-25 (PVP-25). It was proved that sulfadoxine is a good glass former with relative high physical stability; however, water acts as a strong plasticizer for amorphous sulfadoxine, detrimentally affecting the stability during exposure to high moisture conditions. PMID- 26531747 TI - Multisector Nutrition Program Governance and Implementation in Ethiopia: Opportunities and Challenges. AB - Governments globally are stressing both direct nutrition interventions combined with nutrition sensitive policies and programs to combat malnutrition. Governance at all levels has been identified as a critical element in ensuring success of national nutrition plans. For example, the most recent National Nutrition Program (NNP) in Ethiopia discusses the essentiality of governance and coordination at all levels. The research uses a qualitative study based on semi-structured interviews with key informant. The research discussed in this article focuses on governance structures from national to regional to district level in Ethiopia with an emphasis on translation of a strategy and implementation of the NNP. This article concentrates primarily on results from the national and regional levels. Data at both the national and regional levels indicate that there is general agreement on the nature of the nutrition problems in Ethiopia. At all levels of government, under nutrition, food insecurity, and micronutrient deficiencies were listed as the main nutrition problems. The challenges in governance and implementation identified at both the national and regional levels, however, varied. The implementation of the 2013 NNP was in its early stages at the time of this research. While there was palpable energy around the launch of the NNP, respondents indicated issues related to leadership, coordination, collaboration, advocacy, and budget would be challenges in sustaining momentum. PMID- 26531748 TI - From prospective biobanking to precision medicine: BIO-RAIDs - an EU study protocol in cervical cancer. AB - BACKGROUND: Cervical cancer (CC) is -second to breast cancer- a dominant cause of gynecological cancer-related deaths worldwide. CC tumor biopsies and blood samples are of easy access and vital for the development of future precision medicine strategies. DESIGN: BIO-RAIDs is a prospective multicenter European study, presently recruiting patients in 6 EU countries. Tumor and liquid biopsies from patients with previously non-treated cervical cancer (stages IB2-IV) are collected at defined time points. Patients receive standard primary treatment according to the stage of their disease. 700 patients are planned to be enrolled. The main objectives are the discovery of -dominant molecular alterations, signalling pathway activation, and -tumor micro-environment patterns that may predict response or resistance to treatment. An exhaustive molecular analysis is performed using 1 degrees Next generation sequencing, 2 degrees Reverse phase protein arrays and 3 degrees Immuno-histochemistry. DISCUSSION: The clinical study BIO-RAIDs is activated in all planned countries, 170 patients have been recruited till now. This study will make an important contribution towards precision medicine treatments in cervical cancer. The results will support the development of clinical practice guidelines for cervical cancer patients to improve their prognosis and their quality of life. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02428842 , registered 10 February 2015. PMID- 26531749 TI - Sucrose fed-batch strategy enhanced biomass, polysaccharide, and ganoderic acids production in fermentation of Ganoderma lucidum 5.26. AB - Ganoderma, as a Chinese traditional medicine, has multiple bioactivities. However, industrial production was limited due to low yield during Ganoderma fermentation. In this work, sucrose was found to greatly enhance intracellular polysaccharide (IPS) content and specific extracellular polysaccharide (EPS) production rate. The mechanism was studied by analyzing the activities of enzymes related to polysaccharide biosynthesis. The results revealed that sucrose regulated the activities of phosphoglucomutase and phosphoglucose isomerase. When glucose and sucrose mixture was used as carbon source, biomass, polysaccharide and ganoderic acids (GAs) production was greatly enhanced. A sucrose fed-batch strategy was developed in 10-L bioreactor, and was scaled up to 300-L bioreactor. The biomass, EPS and IPS production was 25.5, 2.9 and 4.8 g/L, respectively, which was the highest biomass and IPS production in pilot scale. This study provides information for further understanding the regulation mechanism of Ganoderma polysaccharide biosynthesis. It demonstrates that sucrose fed-batch is a useful strategy for enhancing Ganoderma biomass, polysaccharide and GAs production. PMID- 26531750 TI - Seizure outcome in patients with juvenile absence epilepsy. AB - The purpose of this study was to identify seizure outcome and factors potentially predictive for seizure outcome in patients with juvenile absence epilepsy (JAE). In this case-control study all patients with JAE were recruited at the outpatient epilepsy clinic at Shiraz University of Medical Sciences from 2008 till 2012. All patients had to be under the care of the epileptologist for at least 18 months. We divided the patients into two groups: patients who were seizure free in the last 12 months of their follow-up period and those who had any seizures. During the study period, 2750 patients with epilepsy were registered at our epilepsy clinic; 641 patients (23.3 %) had idiopathic generalized epilepsy (IGE). Among patients with IGE, 81 patients (12.6 %) were diagnosed as having JAE and of these, 33 patients (20 women and 13 men) were eligible to enter into the study. Ten patients (30.3 %) were seizure free in the last 12 months of their follow-up and 23 (69.6 %) patients reported at least one seizure of any type. We could not identify any factor to be associated with seizure outcome in these patients. All studies in the literature suffer from small number of patients; so does our study. Besides, they used different methodologies. A large multicenter study is required to explore the variables that predict seizure outcome in patients with juvenile absence epilepsy. This is particularly needed to provide an appropriate counselling for patients and their families and also to formulate better individualized treatment plans for the patients. PMID- 26531752 TI - The need for better linkage between administrative data and clinical datasets. PMID- 26531751 TI - Neurohumoral Integration of Cardiovascular Function by the Lamina Terminalis. AB - The mechanisms involved in cardiovascular regulation, such as vascular tone, fluid volume and blood osmolarity, are quite often mediated by signals circulating in the periphery, such as angiotensin II and sodium concentration. Research has identified areas within the lamina terminalis (LT), specifically the sensory circumventricular organs (CVOs), the subfornical organ and the organum vasculosum of the lamina terminalis, as playing crucial roles detecting and integrating information derived from these circulating signals. The median preoptic nucleus (MnPO) is a third integrative structure within the LT that influences cardiovascular homeostasis, although to date, its role is not as clearly elucidated. More recent studies have demonstrated that the CVOs are not only essential in the detection of traditional cardiovascular signals but also signals primarily considered to be important in the regulation of metabolic, reproductive and inflammatory processes that have now also been implicated in cardiovascular regulation. In this review, we highlight the critical roles played by the LT in the detection and integration of circulating signals that provide critical feedback control information contributing to cardiovascular regulation. PMID- 26531753 TI - Detection of Voice Pathology using Fractal Dimension in a Multiresolution Analysis of Normal and Disordered Speech Signals. AB - Voice disorders are associated with irregular vibrations of vocal folds. Based on the source filter theory of speech production, these irregular vibrations can be detected in a non-invasive way by analyzing the speech signal. In this paper we present a multiband approach for the detection of voice disorders given that the voice source generally interacts with the vocal tract in a non-linear way. In normal phonation, and assuming sustained phonation of a vowel, the lower frequencies of speech are heavily source dependent due to the low frequency glottal formant, while the higher frequencies are less dependent on the source signal. During abnormal phonation, this is still a valid, but turbulent noise of source, because of the irregular vibration, affects also higher frequencies. Motivated by such a model, we suggest a multiband approach based on a three-level discrete wavelet transformation (DWT) and in each band the fractal dimension (FD) of the estimated power spectrum is estimated. The experiments suggest that frequency band 1-1562 Hz, lower frequencies after level 3, exhibits a significant difference in the spectrum of a normal and pathological subject. With this band, a detection rate of 91.28 % is obtained with one feature, and the obtained result is higher than all other frequency bands. Moreover, an accuracy of 92.45 % and an area under receiver operating characteristic curve (AUC) of 95.06 % is acquired when the FD of all levels is fused. Likewise, when the FD of all levels is combined with 22 Multi-Dimensional Voice Program (MDVP) parameters, an improvement of 2.26 % in accuracy and 1.45 % in AUC is observed. PMID- 26531754 TI - A Decision Tree Based Classifier to Analyze Human Ovarian Cancer cDNA Microarray Datasets. AB - Ovarian cancer is the deadliest gynaecological disease because of the high mortality rate and there is no any symptom in cancer early stage. It was often the terminal cancer period when patients were diagnosed with ovarian cancer and thus delays a good opportunity of treatment. The current common method for detecting ovarian cancer is blood testing for analyzing the tumor marker CA-125 of serum. However, specificity and sensitivity of CA-125 are insufficient for early detection. Therefore, it has become an urgent issue to look for an efficient method which precisely detects the tumor markers for ovarian cancer. This study aims to find the target genes of ovarian cancer by different algorithms of information science. Feature selection and decision tree were applied to analyze 9600 ovarian cancer-related genes. After screening the target genes, candidate genes will be analyzed by Ingenuity Pathway Analysis (IPA) software to create a genetic pathway model and to understand the interactive relationship in the different pathological stages of ovarian cancer. Finally, this research found 9 oncogenes associated with ovarian cancer and some genes had not been discovered in previous studies. This system will assist medical staffs in diagnosis and treatment at cancer early stage and improve the patient's survival. PMID- 26531756 TI - Mammographic and clinical characteristics of different phenotypes of screen detected and interval breast cancers in a nationwide screening program. AB - In the context of a population-based screening program, we aimed to evaluate the major mammographic features and clinicopathological characteristics of breast tumors at diagnosis and the associations between them, focusing on tumors with the worst prognosis. We analyzed cancers diagnosed in a cohort of 645,764 women aged 45-69 years participating in seven population-based screening programs in Spain, between January 1, 2000 and December 31, 2006 and followed up until June 2009. We included all interval cancers and a sample of screen-detected cancers, whether invasive or in situ. We compared tumor-related information and breast density for different phenotypes (Triple-negative (TN), HER2+, Luminal B and Luminal A) in screen-detected and interval cancers. We used Chi-square or Fisher's exact test to compare major mammographic features of invasive versus in situ tumors, of screen-detected versus interval cancers, and of different types of interval cancers. We included 2582 tumors (1570 screen-detected and 1012 interval cancers). There were significant differences in the distribution of most clinicopathological variables between screen-detected and interval cancers. Invasive TN interval tumors were more common than other phenotypes in breasts with low mammographic density; three-quarters of these tumors presented as masses without associated calcifications. HER2+ tumors were more common in denser breasts and were associated with calcifications and multifocality. Architectural distortion was more common in Luminal A and Luminal B tumors. Certain radiologic findings are associated with pre-invasive lesions; these differ among invasive tumor phenotypes. We corroborate that TN and HER2+ cancers have distinctive appearances also in the context of population-based screening programs. This information can be useful for establishing protocols for diagnostic strategies in screening units. PMID- 26531757 TI - Regulation of the osteogenic and adipogenic differentiation of bone marrow derived stromal cells by extracellular uridine triphosphate: The role of P2Y2 receptor and ERK1/2 signaling. AB - An imbalance in the osteogenesis and adipogenesis of bone marrow-derived stromal cells (BMSCs) is a crucial pathological factor in the development of osteoporosis. Growing evidence suggests that extracellular nucleotide signaling involving the P2 receptors plays a significant role in bone metabolism. The aim of the present study was to investigate the effects of uridine triphosphate (UTP) on the osteogenic and adipogenic differentiation of BMSCs, and to elucidate the underlying mechanisms. The differentiation of the BMSCs was determined by measuring the mRNA and protein expression levels of osteogenic- and adipogenic related markers, alkaline phosphatase (ALP) staining, alizarin red staining and Oil Red O staining. The effects of UTP on BMSC differentiation were assayed using selective P2Y receptor antagonists, small interfering RNA (siRNA) and an intracellular signaling inhibitor. The incubation of the BMSCs with UTP resulted in a dose-dependent decrease in osteogenesis and an increase in adipogenesis, without affecting cell proliferation. Significantly, siRNA targeting the P2Y2 receptor prevented the effects of UTP, whereas the P2Y6 receptor antagonist (MRS2578) and siRNA targeting the P2Y4 receptor had little effect. The activation of P2Y receptors by UTP transduced to the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. This transduction was prevented by the mitogen activated protein kinase inhibitor (U0126) and siRNA targeting the P2Y2 receptor. U0126 prevented the effects of UTP on osteogenic- and adipogenic-related gene expression after 24 h of culture, as opposed to 3 to 7 days of culture. Thus, our data suggest that UTP suppresses the osteogenic and enhances the adipogenic differentiation of BMSCs by activating the P2Y2 receptor. The ERK1/2 signaling pathway mediates the early stages of this process. PMID- 26531755 TI - Pre-diagnostic polyphenol intake and breast cancer survival: the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. AB - The aim was to investigate the association between pre-diagnostic intakes of polyphenol classes (flavonoids, lignans, phenolic acids, stilbenes, and other polyphenols) in relation to breast cancer survival (all-cause and breast cancer specific mortality). We used data from the European Prospective Investigation into Cancer and Nutrition cohort. Pre-diagnostic usual diet was assessed using dietary questionnaires, and polyphenol intakes were estimated using the Phenol Explorer database. We followed 11,782 breast cancer cases from time of diagnosis until death, end of follow-up or last day of contact. During a median of 6 years, 1482 women died (753 of breast cancer). We related polyphenol intake to all-cause and breast cancer-specific mortality using Cox proportional hazard models with time since diagnosis as underlying time and strata for age and country. Among postmenopausal women, an intake of lignans in the highest versus lowest quartile was related to a 28 % lower risk of dying from breast (adjusted model: HR, quartile 4 vs. quartile 1, 0.72, 95 % CI 0.53; 0.98). In contrast, in premenopausal women, a positive association between lignan intake and all-cause mortality was found (adjusted model: HR, quartile 4 vs. quartile 1, 1.63, 95 % CI 1.03; 2.57). We found no association for other polyphenol classes. Intake of lignans before breast cancer diagnosis may be related to improved survival among postmenopausal women, but may on the contrary worsen the survival for premenopausal women. This suggests that the role of phytoestrogens in breast cancer survival is complex and may be dependent of menopausal status. PMID- 26531758 TI - MicroRNA-21 induces breast cancer cell invasion and migration by suppressing smad7 via EGF and TGF-beta pathways. AB - MicroRNA-21 (miR-21) upregulation, smad family member 7 (smad7) downregulation, epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) actions contribute to breast cancer cell aggressiveness. However, their correlation and the relevant molecular mechanisms involved remain to be elucidated. The present study was undertaken to determine the association of miR 21, smad7, EGF and TGF-beta with breast cancer cell invasion and migration and to identify the molecular mechanisms involved using immunohistochemistry and western blot analysis. In the present study, the plasma miR-21 levels were significantly increased in patients with breast cancer, as compared to the controls. Smad7 was confirmed to be a direct target of miR-21, by luciferase reporter and western blot assays. The downregulation of smad7 by miR-21 or sismad7 enhanced EGF dependent invasion and migration, as well as TGF-beta-dependent invasion and migration. The actions of miR-21 were abrogated by expressing a modified smad7 cDNA resistant to miR-21. Moreover, miR-21, EGF and TGF-beta combined to markedly increase cancer cell invasion and migration, and this effect was blocked by the combination of erlotinib (an EGF receptor kinase inhibitor) and SB505124 (a type I TGF-beta receptor inhibitor). A lower smad7 expression was identified in poorly differentiated breast cancers, as compared to well- to moderately differentiated breast cancers. Notably, antagonism of miR-21 decreased breast cancer cell proliferation and tumor growth in mouse models. In conclusion, our results demonstrated that plasma miR-21 levels may serve as a diagnostic marker in breast cancers, whereas miR-21 promotes breast cancer cell proliferation and invasion by suppressing smad7, which enhances EGF and TGF-beta pathways. PMID- 26531759 TI - Predicting pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a systematic review. AB - AIM: Approximately 20% of patients treated with neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer achieve a pathological complete response (pCR) while the remainder derive the benefit of improved local control and downstaging and a small proportion show a minimal response. The ability to predict which patients will benefit would allow for improved patient stratification directing therapy to those who are likely to achieve a good response, thereby avoiding ineffective treatment in those unlikely to benefit. METHOD: A systematic review of the English language literature was conducted to identify pathological factors, imaging modalities and molecular factors that predict pCR following chemoradiotherapy. PubMed, MEDLINE and Cochrane Database searches were conducted with the following keywords and MeSH search terms: 'rectal neoplasm', 'response', 'neoadjuvant', 'preoperative chemoradiation', 'tumor response'. After review of title and abstracts, 85 articles addressing the prediction of pCR were selected. RESULTS: Clear methods to predict pCR before chemoradiotherapy have not been defined. Clinical and radiological features of the primary cancer have limited ability to predict response. Molecular profiling holds the greatest potential to predict pCR but adoption of this technology will require greater concordance between cohorts for the biomarkers currently under investigation. CONCLUSION: At present no robust markers of the prediction of pCR have been identified and the topic remains an area for future research. This review critically evaluates existing literature providing an overview of the methods currently available to predict pCR to nCRT for locally advanced rectal cancer. The review also provides a comprehensive comparison of the accuracy of each modality. PMID- 26531760 TI - Case Report: Disparate flow in HeartMate II patient with extensive left ventricle repair. AB - This case study reports the operative management of a 63-year-old male patient following implantation of the HeartMate II (HMII) left ventricular assist device (LVAD), with a non-compliant left ventricle (LV) and a reduced right ventricular (RV) end-diastolic volume. Intraoperatively, the patient had a thin, fragile LV wall with laminated clot; a ventricular septal defect was encountered during removal of the clot. Along with an aortic valve repair, the LV and the septum were reconstructed with multiple bovine pericardium patches, thus, moderately reducing the RV and LV stroke volume. A difference in cardiac output via a Swan Ganz catheter (approximately 1.5 l/min) was observed as opposed to the HMII's estimated flow. The result was later replicated and verified ITALIC! in vitrovia the Donovan Mock Circulation System (DMCS), where about 2 l/min lower flow on the HMII system was observed. In conclusion, the HMII flow rate displayed can be inaccurate and should only be used for trending. PMID- 26531761 TI - TSLP expression in the skin is mediated via RARgamma-RXR pathways. AB - TSLP is an important trigger and initiator for various atopic diseases mainly atopic dermatitis (AD). Activators of nuclear hormone receptors like bioactive vitamin A and D derivatives are known to induce TSLP up-regulation in the skin. In this study, various combinations of synthetic specific agonists and antagonists of the retinoic acid receptors (RARs), retinoid X receptors (RXRs) and vitamin D receptor (VDR) were topically administered to mice. The aim of the study was to elucidate via which nuclear hormone receptor pathways TSLP is regulated and how this regulation is connected to the development and phenotype of atopic dermatitis. TSLP expression was monitored using QRT-PCR and serum TSLP levels using ELISA. Synthetic agonists of the VDR and RARgamma as well as the natural agonist all-trans retinoic acid (ATRA) increased TSLP expression in the skin, while an RXR agonist was not active. Treatments with antagonists of RXRs and RARs in addition to RARalpha-agonists reduced skin TSLP expression. Strong activation was found after a combination of a VDR and an RXR agonist (ca. 5 times induction) and even stronger by an RARgamma and an RXR agonist treatment (ca. 48 times induction). We conclude that besides VDR-mediated signaling mainly RARgamma RXR mediated pathways in the skin are important patho-physiological triggers for increased skin TSLP expression. We conclude that topical synthesized retinoids stimulated by internal or external triggers or topically applied induce TSLP production and are thereby important triggers for atopic dermatitis prevalence. PMID- 26531762 TI - Origins of contrasting copper coordination geometries in crystalline copper sulfate pentahydrate. AB - Metal-aqua ion ([M(H2O)n](X+)) formation is a fundamental step in mechanisms that are central to enzymatic and industrial catalysis. Past investigations of such ions have yielded a wealth of information regarding their properties, however questions still exist involving the exact structures of these complexes. A prominent example of this is hexaaqua copper(II) ([Cu(H2O)6](2+)), with the solution versus gas-phase configurations under debate. The differences are often attributed to the intermolecular interactions between the bulk solvent and the aquated complex, resulting in structures stabilized by extended hydrogen-bonding networks. Yet solution phase systems are difficult to study due to the lack of atomic-level positional details. Crystalline solids are ideal models for comparative study, as they contain fixed structures that can be fully characterized using diffraction techniques. Here, crystalline copper sulfate pentahydrate (CuSO4.5H2O), which contains two unique copper-water geometries, was studied in order to elucidate the origin of these contrasting hydrated metal envrionments. A combination of solid-state density functional theory and low temperature X-ray diffraction was used to probe the electronic origins of this phenomenon. This was accomplished through implementation of crystal orbital overlap population and crystal orbital Hamiltonian population analyses into a developmental version of the CRYSTAL14 software. These new computational methods help highlight the delicate interplay between electronic structure and metal water geometries. PMID- 26531763 TI - Expression of Signaling Molecules in Progressive Multifocal Leukoencephalopathy. AB - INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a debilitating demyelinating disease of the CNS caused by the infection and destruction of glial cells by JC virus (JCV) and is an AIDS-defining disease. Infection with JCV is common and most people acquire antibodies early in life. After initial infection, JCV remains in an asymptomatic persistent state and can be detected by PCR in many tissues including brain. A major question in PML pathogenesis is how the virus reactivates from persistence in HIV-1/AIDS. Our studies with primary cultures of glial cells have implicated transcription factors NF-kappaB and NFAT4, which bind to a unique site in the JCV noncoding control region and stimulate viral gene expression. Furthermore, these transcription factors are controlled by pathways downstream of proinflammatory cytokines, e.g., TNF-alpha activates NF-kappaB and stimulates JCV transcription. OBJECTIVES: We hypothesize that HIV-1/PML initiation may involve reactivation of JCV by cytokine disturbances in the brain such as occur in HIV-1/AIDS. In this study, the objective was to evaluate HIV-1/PML clinical samples for expression of TNF-alpha and its receptors and subcellular localization of NF-kappaB p65 and NFAT4 compared to non-PML controls. METHODS: We evaluated HIV-1/PML clinical samples and non-PML controls for expression of TNF-alpha and its receptors and subcellular localization of NF-kappaB p65 and NFAT4 using Western blot and immunohistochemistry. RESULTS: Consistent with our hypothesis, compared to non PML controls, HIV-1/PML tissue has high levels of TNF-alpha and TNFR1 expression and NF-kappaB and NFAT4 were preferentially localized to the nucleus. CONCLUSION: The involvement of TNF-alpha/NF-kappaB/NFAT4 signaling in JCV regulation that we reported from experiments in cultured human glial cells may be clinically relevant in PML. PMID- 26531764 TI - Changes in Serum Markers of Inflammation and Endothelial Activation in HIV Infected Antiretroviral Naive Patients Starting A Treatment with Abacavir Lamivudine or Tenofovir-Emtricitabine Plus Efavirenz. AB - BACKGROUND: The association between abacavir use and increased risk of myocardial infarction has been heavily debated, but cohort studies and randomized trials have provided conflicting results. Aim of our study is to compare the effect of abacavir and tenofovir on the inflammation and endothelial activation markers. METHODS: We performed an observational study of HIV-infected naive patients starting tenofovir/emtricitabine (group A) or abacavir/lamivudine (group B) plus efavirenz. In the present analysis, we measured serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble vascular adhesion molecule-1 (VCAM-1), soluble intercellular adhesion molecule-1 (ICAM-1), E-selectin and P-selectin at baseline and during a 48-week follow-up. RESULTS: As a whole, 118 patients (93 males; mean age +/- SD of 42.8 +/- 10.1 years) were enrolled: 61 in group A and 57 in group B. In group A at weeks 24 and 48 the mean concentrations of IL-6, TNF-alpha, ICAM-1, VCAM-1, E-selectin and Pselectin decreased significantly in comparison with respective baseline values. In group B at week 24 a significant increase in mean values of these markers was reported in comparison with group A, but after 48 weeks they significantly decreased in group B too and no significant differences between groups A and B were found. CONCLUSION: In our study, naive patients starting tenofovir/emtricitabine or abacavir/lamivudine plus efavirenz showed after 48 weeks a significant and comparable decrease in serum concentrations of IL-6, TNF alpha, ICAM-1, VCAM-1, Eselectin and P-selectin, while the mean level of hs-CRP did not change significantly in any group. PMID- 26531765 TI - Hippocampal unified multi-atlas network (HUMAN): protocol and scale validation of a novel segmentation tool. AB - In this study we present a novel fully automated Hippocampal Unified Multi-Atlas Networks (HUMAN) algorithm for the segmentation of the hippocampus in structural magnetic resonance imaging. In multi-atlas approaches atlas selection is of crucial importance for the accuracy of the segmentation. Here we present an optimized method based on the definition of a small peri-hippocampal region to target the atlas learning with linear and non-linear embedded manifolds. All atlases were co-registered to a data driven template resulting in a computationally efficient method that requires only one test registration. The optimal atlases identified were used to train dedicated artificial neural networks whose labels were then propagated and fused to obtain the final segmentation. To quantify data heterogeneity and protocol inherent effects, HUMAN was tested on two independent data sets provided by the Alzheimer's Disease Neuroimaging Initiative and the Open Access Series of Imaging Studies. HUMAN is accurate and achieves state-of-the-art performance (Dice[Formula: see text] and Dice[Formula: see text]). It is also a robust method that remains stable when applied to the whole hippocampus or to sub-regions (patches). HUMAN also compares favorably with a basic multi-atlas approach and a benchmark segmentation tool such as FreeSurfer. PMID- 26531766 TI - Modifying the thermal conductivity of small molecule organic semiconductor thin films with metal nanoparticles. AB - Thermal properties of organic semiconductors play a significant role in the performance and lifetime of organic electronic devices, especially for scaled-up large area applications. Here we employ silver nanoparticles (Ag NPs) to modify the thermal conductivity of the small molecule organic semiconductor, dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]thiophene (DNTT). The differential 3-omega method was used to measure the thermal conductivity of Ag-DNTT hybrid thin films. We find that the thermal conductivity of pure DNTT thin films do not vary with the deposition temperature over a range spanning 24 degrees C to 80 degrees C. The thermal conductivity of the Ag-DNTT hybrid thin film initially decreases and then increases when the Ag volume fraction increases from 0% to 32%. By applying the effective medium approximation to fit the experimental results of thermal conductivity, the extracted thermal boundary resistance of the Ag-DNTT interface is 1.14 +/- 0.98 * 10(-7) m(2)-K/W. Finite element simulations of thermal conductivity for realistic film morphologies show good agreement with experimental results and effective medium approximations. PMID- 26531767 TI - The distribution of positive work and power generation amongst the lower-limb joints during walking normalises following recovery from traumatic brain injury. AB - OBJECTIVE: To determine whether better walking performance following recovery from traumatic brain injury (TBI) is attributable to an accentuation of compensatory strategies or an improvement in the way positive work is done and power is generated by the lower-limb joints. SETTING: A large metropolitan rehabilitation hospital. PARTICIPANTS: Thirty-five ambulant people with extremely severe TBI who were attending physiotherapy for mobility limitations, and a comparative sample of 25 healthy controls (HC). DESIGN: Cross-sectional cohort study with six month follow-up. MAIN MEASURES: Positive work done and average power (i.e. over time) generation by the hip, knee and ankle during stance as well as self-selected gait velocity. RESULTS: In comparison to HCs, TBI participants walked at baseline with a significantly (p<.01) reduced contribution from the ankle to total lower-limb average power generation (and positive work done) during stance, and a significantly (p=.03) greater contribution from the hip. However, this compensatory strategy resolved over time such that at six month follow-up no significant differences in the relative contributions from the ankle and hip were identified for the TBI participants when compared to HCs. CONCLUSION: Better walking performance following recovery from TBI is attributable to an improvement in the way positive work is done and power is generated by the lower-limb joints rather than an accentuation of compensatory strategies. PMID- 26531768 TI - Recovery of gait after quadriceps muscle fatigue. AB - The aim of this study was to investigate the effect of recovery time after quadriceps muscle fatigue on gait in young adults. Forty young adults (20-40 years old) performed three 8-m gait trials at preferred velocity before and after muscle fatigue, and after 5, 10 and 20min of passive rest. In addition, at each time point, two maximal isometric voluntary contractions were preformed. Muscle fatigue was induced by repeated sit-to-stand transfers until task failure. Spatio temporal, kinetic and muscle activity parameters, measured in the central stride of each trial, were analyzed. Data were compared between before and after the muscle fatigue protocol and after the recovery periods by one-way repeated measures ANOVA. The voluntary force was decreased after the fatigue protocol (p<0.001) and after 5, 10 and 20min of recovery compared to before the fatigue protocol. Step width (p<0.001) and RMS of biceps femoris (p<0.05) were increased immediately after the fatigue protocol and remained increased after the recovery periods. In addition, stride duration was decreased immediately after the fatigue protocol compared to before and to after 10 and 20min of rest (p<0.001). The anterior-posterior propulsive impulse was also decreased after the fatigue protocol (p<0.001) and remained low after 5, 10 and 20min of rest. We conclude that 20min is not enough to see full recovery of gait after exhaustive quadriceps muscle fatigue. PMID- 26531769 TI - Biomarker triplet NAMPT/VEGF/HER2 as a de novo detection panel for the diagnosis and prognosis of human breast cancer. AB - The early detection of breast cancer, the most common malignant tumor disease in women worldwide, relies on mammography and self breast examination. Here we evaluated the concentration of nicotinamide phosphoribosyltransferase (NAMPT), vascular endothelial growth factor (VEGF) and human epidermal growth factor receptor-2 (HER2) in serum and their expression in breast tissues associated with the clinicopathological features of patients with benign and malignant breast tumors. The immunohistochemical analysis showed that NAMPT, VEGF and HER2 proteins were overexpressed in breast tumors. The highest expression was observed in malignant tumors, low in benign tumors and negative in the adjacent normal tissue, indicating that the triplets may be progression markers and correlated with each other. The detection rate of NAMPT, VEGF and HER2 alone in tissue was 54.17, 64.58 and 60.42%, respectively, and was increased to about 79% in double combination and to 90% in triple combination. The basal levels of serum NAMPT, VEGF and HER2 in healthy controls were 94.90+/-4.24 pg/ml, 87.02+/-2.41 pg/ml and 1.12+/-0.04 ng/ml, respectively, measured by ELISA and found to be increased by 6.64-, 1.76- and 2.52-fold, respectively, in patients with malignant breast tumor. These elevated serum levels of NAMPT, VEGF and HER2 in patients were decreased after tumor removal, suggesting that these molecules are the indicators of treatment efficacy. The combined measurement of these triplets together may improve the sensitivity of breast cancer diagnosis and may potentially be used as a testing panel for the detection of malignant tumors, the assessment of treatment effectiveness and the monitoring of the disease progression in patients with breast cancer. Thus, we propose that the biomarker triplet NAMPT/VEGF/HER2 can be used as a de novo detection panel for the diagnosis and prognosis of human breast cancer. PMID- 26531770 TI - Human cooperation in groups: variation begets variation. AB - Many experiments on human cooperation have revealed that individuals differ systematically in their tendency to cooperate with others. It has also been shown that individuals condition their behaviour on the overall cooperation level of their peers. Yet, little is known about how individuals respond to heterogeneity in cooperativeness in their neighbourhood. Here, we present an experimental study investigating whether and how people respond to heterogeneous behaviour in a public goods game. We find that a large majority of subjects does respond to heterogeneity in their group, but they respond in quite different ways. Most subjects contribute less to the public good when the contributions of their peers are more heterogeneous, but a substantial fraction of individuals consistently contributes more in this case. In addition, we find that individuals that respond positively to heterogeneity have a higher general cooperation tendency. The finding that social responsiveness occurs in different forms and is correlated with cooperativeness may have important implications for the outcome of cooperative interactions. PMID- 26531771 TI - Beyond osteogenesis imperfecta: Causes of fractures during infancy and childhood. AB - Fractures in infancy or early childhood require prompt evaluation with consideration of accidental or non-accidental trauma as well as a large number of genetic disorders that predispose to fractures. Bone fragility has been reported in more than 100 genetic disorders, including skeletal dysplasias, inborn errors of metabolism and congenital insensitivity to pain. Most of these disorders are rare but often have distinctive clinical or radiographic findings to assist in the diagnosis. Gene sequencing is available, albeit connective tissue and skeletal dysplasia panels and biochemical studies are only helpful in a minority of cases. This article presents the clinical, radiographic, and molecular profiles of the most common heritable disorders other than osteogenesis imperfecta with increased bone fragility. In addition, the clinicians must consider non-heritable influences such as extreme prematurity, prenatal viral infection and neoplasia in the diagnostic process. PMID- 26531772 TI - Three-dimensional localization of polymer nanoparticles in cells using ToF-SIMS. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) three-dimensional (3D) depth profiling and a novel background subtraction method were used to localize polymeric nanoparticles within cells. Results showed that ToF-SIMS 3D depth profiling is capable of localizing polymer nanoparticles within HeLa cells. ToF SIMS results compared well with optical images of cells incubated with fluorescently labeled polymer nanoparticles, with both imaging techniques demonstrating clustering of nanoparticles in punctate regions consistent with endosomal localization as anticipated based on the nanoparticle design. PMID- 26531773 TI - Safety and Effectiveness of SAF-R, a Novel Patient Positioning Device for Robot Assisted Pelvic Surgery in Trendelenburg Position. AB - PURPOSE: We found current robotic positioning devices to be inadequate and cumbersome. Furthermore, we realized there were no premarket well-designed studies to prove their safety and efficacy. In this prospective pilot study, we aimed to investigate the safety and effectiveness of a novel patient-positioning device (SAF-R) to secure the patient in Trendelenburg (T-burg) position for robot assisted pelvic surgery. PATIENTS AND METHODS: Sixteen patients undergoing robot assisted pelvic operation in T-burg position were enrolled. Patients were positioned using SAF-R board. Pressure sensor mats were used for real-time monitoring of the contact pressures and contact area on the shoulders and calves throughout the surgery. Data collection included patients' body mass index (BMI), time needed for positioning, total time in the T-burg position, contact pressure and contact area readings from the sensor mats, and the patient shifting distance on the table. Patients were also followed for 1-month postoperatively for any position-related adverse event. RESULTS: The median age of the patients was 56.5 years with median BMI of 27.3. The median positioning time was 6 minutes, duration of T-burg position was 3.5 hours, and patient shift on the table was 1 cm. The contact pressure over the shoulders was in the safe range (< 80 mm Hg) before and at the end of the surgery in all cases (right: 13.12 +/- 1.12 vs 20.25 +/- 1.56 mm Hg, left: 12.84 +/- 1.05 vs 19.60 +/- 1.09 mm Hg, p = 0.001). The changes in the mean contact pressure over the calves and the mean contact area for the shoulders and calves during the T-burg position were not significantly different. No significant position-related complication was detected during follow-up. CONCLUSIONS: SAF-R surgical board is a safe, reliable, and timesaving positioning device for patients undergoing robotic pelvic surgery in the T-burg position. PMID- 26531774 TI - Reply. PMID- 26531775 TI - Editorial Comment. PMID- 26531776 TI - PUGNAc induces protein ubiquitination in C2C12 myotube cells. AB - O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) regulates many cellular processes including the cell cycle, cell signaling, and protein trafficking. Dysregulation of O-GlcNAcylation may be involved in the development of insulin resistance and type 2 diabetes. Therefore, it is necessary to identify cellular proteins that are induced by elevated O-GlcNAcylation. Here, using adenosine 5' triphosphate affinity chromatography, we employed a proteomic approach in order to identify differentially expressed proteins in response to treatment with the O GlcNAcase inhibitor, O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N phenylcarbamate (PUGNAc), in mouse C2C12 myotube cells. Among 205 selected genes, we identified 68 nucleotide-binding proteins, 14 proteins that have adenosinetriphosphatase activity, and 10 proteins with ligase activity. Upregulation of proteins, including ubiquitin-activating enzyme E1, proteasome subunit 20S, cullin-associated NEDD8-dissociated protein 1, ezrin, and downregulation of the protein nucleoside diphosphate kinase B, were confirmed by western blot analysis. In particular, we found that the protein ubiquitination level in C2C12 cells was increased by PUGNAc treatment. This is the first report of quantitative proteomic profiles of myotube cells after treatment with PUGNAc, and our results demonstrate the potential to enhance understanding of the relationship between insulin resistance, O-GlcNAc, and PUGNAc in the future. PMID- 26531777 TI - All-fibre photonic signal generator for attosecond timing and ultralow-noise microwave. AB - High-impact frequency comb applications that are critically dependent on precise pulse timing (i.e., repetition rate) have recently emerged and include the synchronization of X-ray free-electron lasers, photonic analogue-to-digital conversion and photonic radar systems. These applications have used attosecond level timing jitter of free-running mode-locked lasers on a fast time scale within ~100 MUs. Maintaining attosecond-level absolute jitter over a significantly longer time scale can dramatically improve many high-precision comb applications. To date, ultrahigh quality-factor (Q) optical resonators have been used to achieve the highest-level repetition-rate stabilization of mode-locked lasers. However, ultrahigh-Q optical-resonator-based methods are often fragile, alignment sensitive and complex, which limits their widespread use. Here we demonstrate a fibre-delay line-based repetition-rate stabilization method that enables the all-fibre photonic generation of optical pulse trains with 980-as (20 fs) absolute r.m.s. timing jitter accumulated over 0.01 s (1 s). This simple approach is based on standard off-the-shelf fibre components and can therefore be readily used in various comb applications that require ultra-stable microwave frequency and attosecond optical timing. PMID- 26531778 TI - Ezrin-radixin-moesin-binding phosphoprotein-50 regulates EGF-induced AKT activation through interaction with EGFR and PTEN. AB - Dysregulated epidermal growth factor receptor (EGFR) signaling, especially EGFR/AKT signaling, plays important roles in tumorigenesis and progression, the study on intracellular regulation of this signaling pathway has great clinical significance. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is an important antagonist of AKT activity. Its regulation of AKT activity can be enhanced by ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50)-mediated PTEN/EBP50/platelet-derived growth factor receptor (PDGFR) complex. EBP50 was reported to bind to EGFR, and that it may also mediate the formation of PTEN/EGFR complex to regulate EGFR/AKT signaling. In this study, experiments were performed to verify the hypothesis. Results showed that PTEN co-immunoprecipitated with EGFR, demonstrating PTEN/EGFR complex can form in tissue. Further studies showed that EBP50 knockdown decreased the amount of PTEN/EGFR complex by GST pull-down assay, and EBP50 overexpression increased the amount of PTEN/EGFR complex in a dose-dependent manner. While PTEN mutant (V403A), which can not bind with EBP50, only slightly mediated the formation of PTEN/EGFR complex, confirming that EBP50 specifically mediated the formation of the PTEN/EGFR complex. Both PTEN (V403A) and EGFR (L1043/1063F) mutants can not bind with EBP50. The expression of PTEN (V403A) or EGFR (L1043/1063F) mutant in cells resulted in higher AKT activation level than their respective wild-types by EGF stimulation, indicating that EBP50 mediated PTEN/EGFR complex can effectively inhibit EGF-induced AKT activation. EGF stimulation of siEBP50 cells induced higher AKT activation level compared with control cells, further confirming EBP50-mediated PTEN/EGFR complex can more effectively inhibit EGF-induced AKT activation. These results demonstrated the PTEN/EGFR complex formed under the mediation of EBP50, revealing a novel mechanism for negative regulation of EGF-induced AKT pathway, which may be an important molecular target for antineoplastic therapy. PMID- 26531779 TI - Effects of spousal illness on self-rated health in older couples: Role of sex and proximity to adult children. AB - AIMS: The present study examined the impact of serious spousal illness or hospitalization on community-dwelling older adults' self-rated health (SRH), and explored the moderating effects of sex and residential proximity to adult children using a prospective and representative survey design. METHODS: The sample was obtained from a 2-year longitudinal survey of non-institutionalized men and women aged 65 years and older carried out in the Fukui Prefecture, Japan (n = 1573). The effect of serious spousal illness or hospitalization on SRH during the survey period was examined after controlling for baseline SRH, sex, age, socioeconomic status, chronic illness and other baseline covariates. RESULTS: Overall, 15.7% of respondents had experienced a serious spousal illness or hospitalization within the previous year. After controlling for covariates, spousal illness had a significant negative effect on SRH at follow-up (P = 0.031). More serious effects of spousal illness were found in older adults whose children lived farther than 30 min away than in couples who lived with their children (P = 0.009). However, there was no significant interaction effect between sex and spousal illness. CONCLUSIONS: Serious spousal illness could cause deterioration in the health of older spouses, particularly for older parents whose children live a distance away. Geriatr Gerontol Int 2016; 16: 1332-1338. PMID- 26531780 TI - Ensemble coding in amygdala circuits for associative learning. AB - Associative fear learning in the basolateral amygdala (BLA) is crucial for an animal's survival upon environmental threats. BLA neurons are defined on the basis of their projection target, genetic markers, and associated function. BLA principal neuron responses to threat signaling stimuli are potentiated upon associative fear learning, which is tightly controlled by defined interneuron subpopulations. In addition, BLA population activity correlates with behavioral states and threat or safety signals. BLA neuronal ensembles activated by different behavioral signals can be identified using immediate early gene markers. The next challenge will be to determine the activity patterns and coding properties of defined BLA ensembles in relation to the whole neuronal population. PMID- 26531781 TI - A Zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals Its Specific Role in Laterality Organ Function. AB - Establishing correct left-right asymmetry during embryonic development is crucial for proper asymmetric positioning of the organs. Congenital heart defects, such as dextrocardia, transposition of the arteries, and inflow or outflow tract malformations, comprise some of the most common birth defects and may be attributed to incorrect establishment of body laterality. Here, we identify new patients with dextrocardia who have mutations in CFAP53, a coiled-coil domain containing protein. To elucidate the mechanism by which CFAP53 regulates embryonic asymmetry, we used genome editing to generate cfap53 zebrafish mutants. Zebrafish cfap53 mutants have specific defects in organ laterality and randomization of asymmetric gene expression. We show that cfap53 is required for cilia rotation specifically in Kupffer's vesicle, the zebrafish laterality organ, providing a mechanism by which patients with CFAP53 mutations develop dextrocardia and heterotaxy, and confirming previous evidence that left-right asymmetry in humans is regulated through cilia-driven fluid flow in a laterality organ. PMID- 26531782 TI - Highly sensitive image-derived indices of water-stressed plants using hyperspectral imaging in SWIR and histogram analysis. AB - The optical signature of leaves is an important monitoring and predictive parameter for a variety of biotic and abiotic stresses, including drought. Such signatures derived from spectroscopic measurements provide vegetation indices - a quantitative method for assessing plant health. However, the commonly used metrics suffer from low sensitivity. Relatively small changes in water content in moderately stressed plants demand high-contrast imaging to distinguish affected plants. We present a new approach in deriving sensitive indices using hyperspectral imaging in a short-wave infrared range from 800 nm to 1600 nm. Our method, based on high spectral resolution (1.56 nm) instrumentation and image processing algorithms (quantitative histogram analysis), enables us to distinguish a moderate water stress equivalent of 20% relative water content (RWC). The identified image-derived indices 15XX nm/14XX nm (i.e. 1529 nm/1416 nm) were superior to common vegetation indices, such as WBI, MSI, and NDWI, with significantly better sensitivity, enabling early diagnostics of plant health. PMID- 26531783 TI - Surgical Aspects of Intraductal Papillary Mucinous Neoplasms of the Pancreas. AB - Intraductal papillary mucinous neoplasms (IPMN) play an important role mongst exocrine tumours of the pancreas due to several causes. Although they count for only 1% of all the tumours, they represent some 20-30% of all cystic neoplasms, a histologically defined group that has gained a lot of attention lately. IPMNs of the main or the secondary (branch) pancreatic ducts have remarkably different rates of malignant transformation, prognosis and thus indication for surgery. Prognosis of a ductal carcinoma developing from IPMN does not differ from classic ductal adenocarcinoma, with a very poor (10%) 5-year survival rate. However, prognosis of IPMN can still be regarded favourable, because the above rate can be as high as 70% if the tumour is non-invasive. This fact leads to the importance of diagnosing and resecting IPMN before its malignant transformation into an invasive carcinoma. PMID- 26531784 TI - Surgical Attitude in Patients with Secondary Hyperparathyroidism Undergoing Dialysis. AB - BACKGROUND: Secondary hyperparathyroidism (SHPT), develops, more or less in all the patients with chronic kidney disease. The pathology is even more severe as it intervenes in a suffering patient in whom the chronic kidney disease frequently associates severe comorbidities. General mortality is higher than in general population. The failure of the medical therapy is an indication for parathyroidectomy. METHODS: The study analyzed 200 patients with SHPT and chronic kidney disease, admitted in the clinic from October 2011 until January 2015.In this period, 179 (89.5 %) total-parathyroidectomies have been performed a long with 14 (7%) subtotal parathyroidectomies. Also 7 (3.5%) surgical interventions were incomplete. RESULTS: Overall mortality was 1% (2 patients) and postoperative specific morbidity 3.5% -4 local hemorrhagic complications and 3 cases of dysphonia have been encountered (12% if we include the reinterventions for recurrent hyperparathyroidism - 17 patients). CONCLUSIONS: Total parathyroidectomy is encumbered by a reduced number of postoperative complications and the risk of recurrent disease in almost nonexistent. The disadvantages of this surgical approach are the tendency of immediate postoperative hypocalcemia and long therm substitution with calcium and vitamine D. PMID- 26531785 TI - Technical Factors Involved in Parathyroid Surgery. AB - We aimed to investigate the frequency of ectopic and supernumerary parathyroid glands in our series of renal hyperparathyroidism. From October 2011 to November 2014, 202 patients with chronic renal failure and advanced SHPT nonresponsive to medical therapy were hospitalized in the General Surgery Department of the Carol Davila Nephrology Hospital. These patients underwent a number of 188 (93%) total parathyroidectomies and a number of 14 patients (7%) subtotal parathyroidectomies. Of these 202 patients, reoperation was carried out for 14 patients (7%) in which we identified ectopic and supernumerary parathyroid glands. Operative details and pathology results were prospectively collected and reviewed after we obtained informed consent for data and pictures use. In 188 patients (93% cases), four or more parathyroid glands were removed at the first operation. In 14 cases (7%) high PTH level persisted after the initial operation. In 22 of them (11%), supernumerary glands were found at the first operation and in 6 of them (3%) at the second operation. We conclude that extensive cervical exploration in addition with preoperative imaging tests, parathyroid ultrasound; scintigraphy with Tc will reduce secondary hyperparathyroidism surgery. PMID- 26531786 TI - Early Improvement in Glycemic Metabolism after Laparoscopic Sleeve Gastrectomy in Obese Patients - A Prospective Study. AB - BACKGROUND: according to W.H.O. in 2014 more than 600 million adults were obese, (more than doubled since 1980), and face a major risk for the onset of metabolic syndrome, including T2DM. Due to the poor control of glycemic imbalance for the conservative treatment of T2DM, the metabolic surgery was able to gain an important role in modern management of T2DM, with significant reported improvements or remissions for these patients. OBJECTIVE: to study the effects of laparoscopic sleeve gastrectomy (LSG) on glycemic metabolism in obese patients, with or without T2DM. METHODS: 60 consecutive patients were included in a prospective study and were submitted to laparoscopic sleeve gastrectomy in Ponderas Hospital between February - March 2013. BMI, waist circumference and glycemic parameters were studied at the moment of entering the study, 10 days after surgery and at 6 months follow up. RESULTS: the glycemic control was significantly improved starting with postoperative day 10. Statistically significant improvements were noticed after six months postoperatively in BMI values (p 0,0001), waist circumference (p 0,0001), glycemic levels (p 0,0001), insulin (p 0,0001), C-peptide (p 0,0001) and HOMA. CONCLUSIONS: a rapid induced improvement of glucose metabolism in both diabetic and non-diabetic patients occurs before a significant weight loss (POD 10). At 6 months, when associated with an important weight loss, both diabetic and non-diabetic patients present a furthermore improvement in glycemic metabolism, that enables us to consider that sleeve gastrectomy is an efficient method for a sustained improvement in the metabolic status of patients with obesity. These beneficial changes that can explain the remission of T2DM can also explain the prevention of T2DM after metabolic surgery. PMID- 26531787 TI - Laparoscopic Gastric Plication - One Year of Bariatric Surgery in the Emergency County Hospital of Baia Mare. AB - The main advantages of the laparoscopic gastric plication, in comparison to other bariatric surgery techniques, are the lowest costs and the fewest postopertive complications. This study shows our first year experience with this procedure in the Emergency County Hospital of Baia Mare. METHODS: The first 14 laparoscopic gastric pulications performed in 2014 were studied retrospectively: there were 13 women and one man, with age ranging from 25 to 60 years old and a body mass index (BMI) from 35,7 to 59,8. Postoperative, the patients' evolution was evaluated 9 days, 1 month, 3 months, 6 months, 1 year after the surgery and before writing this paper, taking into account excess weight loss percentage and comorbidities' progress. RESULTS: The average weight loss was 21,42 kg and the weight loss percentage was 36,52%. There were no postoperative complications in need of surgical reintervention. CONCLUSIONS: The results were very good, the costs were low and the postoperative complications had a low rate. Therefore, there is a recommendation on performing this surgery in every hospital equipped for laparoscopic surgery. PMID- 26531788 TI - Clinical Significance of Intraoperative Frozen Section Analysis of Pancreatic Cancer Surgical Margin at the Time of Pancreaticoduodenectomy. AB - BACKGROUND: Today, in the management of pancreas cancers, achieving an R0 resection is one of the most powerful independent predictors of long-term survival. The aim of this study is to assess the clinical significance of intraoperative frozen section analysis of the pancreatic surgical margin for pancreatic cancer during pancreaticoduodemectomy. MATERIAL AND METHODS: We conducted a retrospective analysis of prospectively collected data of 37 patients who were operated for pancreatic head cancer and who were evaluated for surgical margin by frozen section analysis intraoperatively, between September 2013 and August 2014 in our center. The intraoperative biopsy reports were compared with final pathological reports. RESULTS: The mean age of the patients was 64.55(19 82) years (range), the mean tumor size was 3.96(1.16-6.25) cm (range) and the mean harvested lymph node number was 18.52(9-45) (range). In the intraoperative frozen section, one patient was positive for surgical margin (%2.7) who underwent total or complementary pancreatectomy. CONCLUSION: To secure a tumor-free margin by frozen section, intraoperatively, may increase R0 resection rate in pancreas cancers. The preoperative estimation of tumor margin by endoscopic ultrasonography, computerized tomography or magnetic resonance imaging mostly correlate with intraoperative findings, however in suspected cases intraoperative frozen section for margin determination should be performed. PMID- 26531789 TI - Early-Stage Quantitative Analysis of the Effect of Laparoscopic versus Conventional Inguinal Hernia Repair on Physical Activity. AB - AIM: To compare the effects of laparoscopic versus conventional inguinal hernia repair techniques on patients physical activity. MATERIALS AND METHODS: Ninety three patients (between 20 and 59 years old) who presented with a need for inguinal hernia repair at the private Safa Hospital, General Surgery Clinic, were evaluated prospectively between November 2011 and March 2013. The patients mean age was 46.1 (+-12.9) years. They were divided into three groups according to hernia repair technique. Thirty underwent total extraperitoneal repair (TEP), 31 had transabdominalpreperitoneal repair (TAPP) and 32 had modified Bassiniprolene mesh grafting (MBPMG). All patients were examined in the physical therapy and rehabilitation unit just before and after the operation. Lower extremity muscles isokinetic and isometric functions were measured with the Cybex isokinetic testing device. Patients length of stay in hospital, need for analgesics in the postoperative period, visual analogue scale (VAS) scores, time of return to work and postoperative complications were also compared. RESULTS: Patients need for postoperative analgesics, the use of VAS scoring system (between 0 and 10), complication rates and the patients VAS scores on movement results were similar to those in the literature. On the postoperative third day, measurements recorded by the Cybex isokinetic testing device showed that the loss of strength in the lower extremities after the MBPMG procedure was greater than with TAPP and TEP. The isokinetic and isometric assessment of all cases revealed that postoperative mean muscle strength loss was two-thirds less in association with the laparoscopic procedure. Within a 95% confidence interval (CI), the significance of findings was accepted at P-values of less than 0.05 (p 0.05). CONCLUSION: The quantitative data showed that there is a more favourable impact from laparoscopic hernia repair versus open surgery on patients physical activity and return to active work. PMID- 26531790 TI - Surgical Site Infection: Re-assessment of the Risk Factors. AB - BACKGROUND: Surgical site infection (SSI) is a well-known complication of general surgery. Although overall SSI rate is relatively low, it is the most common nosocomial infection. SSI adversely affects patient outcomes and healthcare costs. METHODS: Patients who underwent general surgical procedures between 2003 and 2009 were included in the study. SSI diagnosed based on the National Nosocomial Infection Surveillance System (NNIS) criteria. Patients were classified into two groups: SSI (+) and SSI (-). Patient demographics, co morbidities, procedural details, and SSI type and treatment were evaluated. Multivariate analysis was performed to determine independent risk factors of SSI. RESULTS: In total, 4690 patients were included. Overall SSI rate was 4.09% (192/ 4690). Colorectal surgery was associated with the highest SSI rate (9.43%) followed by pilonidal sinus (8.79%), upper gastrointestinal (GI) (8.09%), hepatobiliary (6.68%), hernia (0.78%), and breast-thyroid (0.3%) surgery. Procedure type (pilonidal sinus, colorectal, hepatobiliary and upper GI surgery), prolonged preoperative hospital stay, higher ASA score, emergency surgery, dirty- infected wound class, experienced surgeon, prolonged operating time, presence of surgical drains, and intraoperative transfusion were determined as independent risk factors of SSI (p 0.05). CONCLUSION: Most of the determined risk factors were surgeon and procedure related. Reduced SSI rate and better outcomes can be achieved by controlling modifiable risk factors. PMID- 26531791 TI - Lung Sealing with the Sandwich-Technique: A New Surgical Method to Deal with the Emphysematous Lung. AB - The persistent air leak is a common and sometimes difficult to manage complication after major pulmonary resections. Especially in cases with lung emphysema spontaneous sealing of the lung surface under conservative therapy can be prolonged or even fail and a reoperation to close the damaged visceral pleura might be necessary. An ideal surgical solution to deal with this problem is not known, all of the techniques have advantages but also limitations and additional operations should be avoided in this group of frail patients. In this paper a new surgical method to seal the lung surface is presented based on two exemplary cases and our clinical experience. Basically, two stripes of fleece bounded fibrin based sealant are put on the visceral pleura parallel to the wound, which will be then closed by multiple stitches of absorbable suture line inserted through the stripes. Afterwards, a second layer of the same sealant will be placed over it to cover the suture with a narrow overlapping in all directions to the adjacent visceral pleura (Sandwich-Technique). In our experience, this technique can be used to successfully prevent or treat persistent air leaks especially in patients with lung emphysema in whom otherwise treatment options are limited. ABBREVIATIONS: VATS = video-assisted thoracoscopic surgery POD = postoperative day LVRS = lung volume reduction surgery FEV1 = forced expiratory volume in the first second DLCO = diffusing capacity of the lung for carbon monoxide. PMID- 26531792 TI - Traumatic Tricuspid Valve Rupture after Blunt Chest Trauma - A Case Report and Review of the Literature. AB - INTRODUCTION: Despite the high frequency of thoracic injuries secondary to traffic related accidents, the blunt cardiac valve rupture is extremely rare. METHOD: Case report and review of the literature using PubMed/MEDLINE and EMBASE databases. RESULT: A 38 year old female patient, victim of car accident was admitted. On primary survey the patient was conscious, cooperative and hemodynamic and respiratory stable. On secondary survey was found a bilateral open leg fracture and a seat belt sign. Whole body Computed Tomography revealed minimal haemorrhagic contusion of the cortex, left hemopneumothorax and right pneumothorax, bilateral rib fractures, liver contusion, left femoral neck fracture and fracture to the lumbar spinal column. After bilateral pleurostomy, the patient becomes hemodynamically unstable, but with no signs of external bleeding. The transthoracic echocardiography revealed an acute severe tricuspid regurgitation with hepatic veins reflux. After orthopaedic surgeries, the tricuspid valve rupture was managed by replacing the valve with a bioprostheses. The hospital stay was 122 days. CONCLUSION: Only a high index of suspicion may reveal blunt cardiac lesions as a cause for hemodynamic instability in acute setting. PMID- 26531793 TI - Endoscopic Removal of Duodenal Perforating Fishbone - A Case Report. AB - BACKGROUND: Accidental ingestion of foreign bodies is common in clinical practice. While perforation of the ileum and jejunum due to the ingested foreign body is common, duodenal perforation is rare. In this report, our experience with this rare entity is shared. CASE REPORT: Here we present a 31-year-old patient with gastrointestinal tract perforation at the second part of the duodenum due to an ingested fishbone. The patient was admitted to the emergency room with abdominal pain. Right upper quadrant tenderness was detected at physical examination, and leukocytosis on the laboratory test results. Ultra-sonography was not diagnostic, however, computerized tomo-graphy showed an ingested foreign body in the second part of the duodenum. A fishbone perforating the duodenum was retrieved by endoscopy. The patient was managed non-operatively, and discharged without any problems on the third day after endoscopy. CONCLUSION: Endoscopic removal and non-operative management may be feasible in carefully selected patients with duodenal perforated fishbone ingestion. PMID- 26531794 TI - Anemia as One of Presenting Symptoms in an Adult with Cyst and Torsion of the Omentum - A Case Report. AB - BACKGROUND: Torsion is an uncommon disorder of the omentum and cysts are one of the rarest causes of omental torsion. To our knowledge, this is the first report of a case of an omental cyst presenting with both omental torsion and anemia. CASE PRESENTATION: We herein present a case report of a 41 year old indian female patient who presented with anemia (hemoglobin concentration 6.5 g/dL) and intermittent abdominal pain caused by torsion of a hemorrhagic omental cyst. A computed tomography scan, showed an omental cyst with free fluid in the abdominal cavity. At abdominal exploration, 1.5 L of hemorrhagic fluid was confirmed in the abdominal cavity. The cyst and twisted omentum were removed en bloc. The patient had an uneventful postoperative course and was discharged on day 8. At her 2 month follow-up, she was no longer anemic (hemoglobin concentration 10.7 g/dL). CONCLUSION: Cases of anemia associated with omental torsion have been reported in children; however, to the best of our knowledge, this is the first reported case of such a presentation in an adult. In such patients, surgical removal is the treatment of choice. Persons with recurrent abdominal pain and anemia must be assessed carefully and their differential diagnosis should include omental torsion. Appropriate diagnosis and treatment help avoid complications. PMID- 26531795 TI - Enterocutaneous Fistula Occurring 15 Years after the Prosthetic Mesh Repair of a Recurrent Incisional Hernia - A Case Report. AB - A 78 year-old female patient who had been operated in 1999 for a recurrent large incisional hernia, with a 20/20 cm prosthetic mesh sutured to the lateral muscular layers of the abdominal wall, has had a favourable postoperative evolution for over 15 years. The patient was admitted in our clinic for a wound infection in January 2015. The clinical examination revealed a cutaneous fistula with large purulent drainage from the deep space; the outflow was between 30 and 50 ml/day. The fistulography identified the communication with the small bowel. The surgical procedure consisted of an enterectomy, which achieved the excision of 2 lesions of an ileal loop; one of them had a fragment of the prosthesis inside the lumen, while the other was strongly adherent to the internal surface of the prosthesis. An end-to-end anastomosis was then performed, as well as the large excision of the infected prosthesis. Finally, the only possible option was the skin closure. Postoperative recovery was uneventful, and the patient was discharged after 14 days; the reconstruction of the abdominal wall using a composite mesh is expected after few months. This clinical case is demonstrative for a rare and serious complication of a prosthetic mesh repair, which occurred after a very long period of normal clinical condition. PMID- 26531796 TI - Accurate Diagnosis of Sigmoid Colon Endometriosis by Immunohistochemistry and Transmission Electron Microscopy - A Case Report. AB - Endometriosis is described as the presence of functioning endometrial tissue at sites outside the uterus. Up to 15% ofwomen in their reproductive period are affected by this condition. Endometriosis is mostly foundon the uterosacral ligaments, inside the rectovaginalseptum or vagina, in the rectosigmoid area, ovarianfossa, pelvic peritoneum, ureters, and bladder, causinga distortion of the pelvic anatomy. Colonic involvement is rare but is usually found at the level of the rectum or the sigmoid colon. Acute presentation with intestinal obstruction or perforation is rare. While malignant transformation of endometrial lesions is rare, findings of dysplasia on pathology sections can give rise to questions of management. Immunohistochemistry and electron microscopy can help decision making. We present the case of a 38 year old woman with intestinal obstruction caused by sigmoid colon endometriosis with moderate dysplasia in which transmission electron microscopy was used for postoperative diagnosis. Detailed analysis of these cases, while logistically difficult, can prove useful in understanding the etiology and pathophysiology of the disease. PMID- 26531797 TI - Total Pelvic Exenteration for Recurrent Endometrial Sarcoma - A Case Report. AB - Endometrial stromal sarcomas are rare gynecologic malignancies characterized by the presence of cells that resemble those of the endometrial stroma during the prolipferative phase of the menstrual cycle. They are classified as low grade or high grade tumors depending on the mitotic index, the second one being usually associated with poor prognosis and high recurrence rate. We present the case of a 46-year-old patient who was previously submitted to surgery for an endometrial stromal sarcoma followed by adjuvant radiotherapy; 18 months later she was diagnosed with a pelvic recurrence invading the urinary bladder trigone and the rectosigmoid so she was submitted to a total pelvic exenteration. PMID- 26531798 TI - Humeral Neck Fracture after Electrocution - Case Report and Literature Review. AB - A case of left humeral neck fracture following electrocution is reported in a 56 year old man, associated with partial thickness burns on his left hand. A fracture after accidental electrical shock injury represents a very unusual situation, due to muscle contractions. Surgeons involved in the management of the electrocuted patients should be aware of the possibility of musculoskeletal injuries. Neglecting these injuries can lead to delay in diagnosis and to detrimental complications. PMID- 26531799 TI - Polarization behavior of polystyrene particles under direct current and low frequency (<1 kHz) electric fields in dielectrophoretic systems. AB - The relative polarization behavior of micron and submicron polystyrene particles was investigated under direct current and very low frequency (<1 kHz) alternating current electric fields. Relative polarization of particles with respect to the suspending medium is expressed in terms of the Clausius-Mossotti factor, a parameter of crucial importance in dielectrophoretic-based operations. Particle relative polarization was studied by employing insulator-based dielectrophoretic (iDEP) devices. The effects of particle size, medium conductivity, and frequency (10-1000 Hz) of the applied electric potential on particle response were assessed through experiments and mathematical modeling with COMSOL Multiphysics((r)). Particles of different sizes (100-1000 nm diameters) were introduced into iDEP devices fabricated from polydimethylsiloxane (PDMS) and their dielectrophoretic responses under direct and alternating current electric fields were recorded and analyzed in the form of images and videos. The results illustrated that particle polarizability and dielectrophoretic response depend greatly on particle size and the frequency of the electric field. Small particles tend to exhibit positive DEP at higher frequencies (200-1000 Hz), while large particles exhibit negative DEP at lower frequencies (20-200 Hz). These differences in relative polarization can be used for the design of iDEP-based separations and analysis of particle mixtures. PMID- 26531800 TI - Multijunction Capillary Isoelectric Focusing Device Combined with Online Membrane Assisted Buffer Exchanger Enables Isoelectric Point Fractionation of Intact Human Plasma Proteins for Biomarker Discovery. AB - Prefractionation of proteins is often employed to improve analysis specificity in proteomics. Prefractionation based on the isoelectric point (pI) is particularly attractive because pI is a well-defined parameter and it is orthogonal to hydrophobicity on which reversed-phase chromatography is based. However, direct capillary electrophoresis of blood proteins is challenging due to its high content of salts and charged small molecules. Here, we couple an online desalinator device to our multijunction capillary isoelectric focusing (MJ-CIEF) instrument and perform direct isoelectric separation of human blood plasma. In a proof-of-principle experiment, pooled samples of patients with progressive mild cognitive impairment and corresponding healthy controls were investigated. Injection of 3 MUL of plasma containing over 100 MUg of proteins into the desalinator was followed by pI fractionation with MJ-CIEF in less than 1 h. Shotgun proteomics of 12 collected fractions from each of the 5 replicates of pooled samples resulted in the identification and accurate quantification (median CV between the replicates is <4%) of nearly 365 protein groups from 4030 unique peptides (with <1% FDR for both peptides and proteins). The obtained results include several proteins previously reported as AD markers. The isoelectric point of each quantified protein was calculated using a set of 7 synthetic peptides spiked into the samples. Several proteins with a significant pI shift between their isoforms in the patient and control samples were identified. The presented method is straightforward, robust, and scalable; therefore, it can be used in both biological and clinical applications. PMID- 26531801 TI - Synthesis of 1D-glyconanomaterials by a hybrid noncovalent-covalent functionalization of single wall carbon nanotubes: a study of their selective interactions with lectins and with live cells. AB - To take full advantage of the remarkable applications of carbon nanotubes in different fields, there is a need to develop effective methods to improve their water dispersion and biocompatibility while maintaining their physical properties. In this sense, current approaches suffer from serious drawbacks such as loss of electronic structure together with low surface coverage in the case of covalent functionalizations, or instability of the dynamic hybrids obtained by non-covalent functionalizations. In the present work, we examined the molecular basis of an original strategy that combines the advantages of both functionalizations without their main drawbacks. The hierarchical self-assembly of diacetylenic-based neoglycolipids into highly organized and compacted rings around the nanotubes, followed by photopolymerization leads to the formation of nanotubes covered with glyconanorings with a shish kebab-type topology exposing the carbohydrate ligands to the water phase in a multivalent fashion. The glyconanotubes obtained are fully functional, and able to establish specific interactions with their cognate receptors. In fact, by taking advantage of this selective binding, an easy method to sense lectins as a working model of toxin detection was developed based on a simple analysis of TEM images. Remarkably, different experimental settings to assess cell membrane integrity, cell growth kinetics and cell cycle demonstrated the cellular biocompatibility of the sugar coated carbon nanotubes compared to pristine single-walled carbon nanotubes. PMID- 26531802 TI - Contribution of breast milk and formula to arsenic exposure during the first year of life in a US prospective cohort. AB - Arsenic is a carcinogen that can also affect the cardiac, respiratory, neurological and immune systems. Children have higher dietary arsenic exposure than adults owing to their more restricted diets and greater intake per unit body mass. We evaluated the potential contributions of breast milk and formula to arsenic exposure throughout the first year of life for 356 infants in the prospective New Hampshire Birth Cohort Study (NHBCS) using infant diets reported by telephone at 4, 8 and 12 months of age; measured household water arsenic concentrations; and literature data. Based on our central-tendency models, population-wide geometric mean (GM) estimated arsenic exposures in the NHBCS were relatively low, decreasing from 0.1 MUg/kg/day at 4 months of age to 0.07 MUg/kg/day at 12 months of age. At all three time points, exclusively formula-fed infants had GM arsenic exposures ~8 times higher than exclusively breastfed infants owing to arsenic in both tap water and formula powder. Estimated maximum exposures reached 9 MUg/kg/day among exclusively formula-fed infants in households with high tap water arsenic (80 MUg/l). Overall, modeled arsenic exposures via breast milk and formula were low throughout the first year of life, unless formula was prepared with arsenic-contaminated tap water. PMID- 26531803 TI - Emergency room visits associated with particulate concentration and Asian dust storms in metropolitan Taipei. AB - This study evaluated risks of emergency room visits (ERV) for all causes, circulatory diseases, and respiratory diseases associated with concentrations of particulate matter (PM10 and PM2.5) and Asian dust storms (ADS) from 2000 to 2008 in metropolitan Taipei. Cumulative 4-day (lag 0-3) relative risks (RR) and confidence intervals (CI) of cause-specific ERV associated with daily concentrations of PM10 or PM2.5 and ADS based on study period (ADS frequently inflicted period: 2000-2004 and less-inflicted period: 2005-2008) were estimated using a distributed lag non-linear model with Poisson distribution. Risks associated with ADS-inflicted season (winter and spring), strength (ratio of stations with Pollutant Standard Index above 100 is < 0.5 or >= 0.5), and duration (ADS lasting for 1-3 days or >= 4 days) were especially evaluated. In non-linear models, an increase in PM10 from 10 MUg/m(3) to 50 MUg/m(3) was associated with increased risk of ERV for all causes and respiratory disease with cumulative 4- day RR of 1.18 (95% CI: 1.13, 1.24) and 1.37 (95% CI: 1.23, 1.54), respectively. From 2005 to 2008, the cumulative 4-day RR for an ERV related to an increase in PM2.5 from 5 MUg/m(3) to 30 MUg/m(3) is 1.21 (95% CI: 1.03, 1.41) for respiratory diseases, and 1.15 (95% CI: 1.08, 1.22) for all causes. In comparison with normal days, elevated ERV of all causes and respiratory diseases was also associated with winter ADS (with corresponding RRs of 1.10 (95% CI: 1.07, 1.13) and 1.14 (95% CI: 1.08, 1.21)) and shorter and less area-affected ADS (with corresponding RRs of 1.07 (95% CI: 1.01, 1.10) and 1.09 (95% CI: 1.03, 1.14)) from 2000 to 2004. Results of this study demonstrate that population health risk varies not only with PM concentration, but also with the ADS characteristics. PMID- 26531804 TI - Phthalates and alternative plasticizers and potential for contact exposure from children's backpacks and toys. AB - This work focuses on the mass content of plasticizers in children's backpacks and toys, and their mass transfer from product surfaces to cotton wipes. The mass content of plasticizers in six backpacks and seven toys was measured by extracting them in tetrahydrofuran. Bis(2-ethylhexyl) terephthalate (DEHT) was the most common plasticizer, dominating the composition of plasticizers in four backpacks (average mass content in product polyvinyl chloride, 5.38 +/- 1.98% 25.5 +/- 3.54%) and six plastic toys (8.17 +/- 1.85%-21.2 +/- 1.11%). The surface of each product was wiped with three dry and three wet (by isopropanol) cotton wipes, so as to evaluate the mass transfer of plasticizers to clothing and human skin, respectively. DEHT was the most common plasticizer detected on wipe samples. There were strong correlations (backpacks r=0.90; plastic toys r=0.96) between average mass transfer of DEHT to wet wipes and its average mass content in the product. The mass transfers of the five dominant plasticizers in one backpack to both dry and wet wipes were also correlated (both r=1.00) with their mass contents. These results suggest that the mass transfer of plasticizers from products to clothing or human skin is strongly associated with their mass content. PMID- 26531805 TI - Outdoor ultrafine particle concentrations in front of fast food restaurants. AB - Ultrafine particles (UFPs) have been associated with negative effects on human health. Emissions from motor vehicles are the principal source of UFPs in urban air. A study in Vancouver suggested that UFP concentrations were related to density of fast food restaurants near the monitoring sites. A previous monitoring campaign could not separate the contribution of restaurants from road traffic. The main goal of this study has been the quantification of fast food restaurants' contribution to outdoor UFP concentrations. A portable particle number counter (DiscMini) has been used to carry out mobile monitoring in a largely pedestrianized area in the city center of Utrecht. A fixed route passing 17 fast food restaurants was followed on 8 days. UFP concentrations in front of the restaurants were 1.61 times higher than in a nearby square without any local sources used as control area and 1.22 times higher compared with all measurements conducted in between the restaurants. Adjustment for other sources such as passing mopeds, smokers or candles did not explain the increase. In conclusion, fast food restaurants result in significant increases in outdoor UFP concentrations in front of the restaurant. PMID- 26531806 TI - Prompting participation in health: Fostering favorable attitudes toward personal health records through message design. AB - OBJECTIVE: Personal health records (PHRs) offer many benefits. However, a relatively small amount of individuals take advantage of PHRs. This study examined how message composition influences attitudes toward electronic PHRs. METHODS: Participants (N=329) were randomly assigned to read one of two fictitious editorials proposing that all patients have PHRs. One version assigned linguistic agency (capacity for action) to PHRs (e.g.,PHRs can guard against long term health problems) and the other to humans (e.g.,people can guard themselves against long-term health problems). RESULTS: One-way analyses of variance revealed significant main effects of agency on perceptions of PHR benefits. Respondents reported feeling more comfortable using PHRs and perceived them as more effective at protecting patients when agency was assigned to PHRs rather than to humans. CONCLUSION: Messages with PHRs as the primary acting agents elicited favorable reactions about PHR use. Patients may be more willing to engage with this technology if the emphasis is put on what PHRs can do for patients. PRACTICE IMPLICATIONS: Providers and staff can make strategic choices about wording when discussing PHRs and healthcare. Attention to linguistic agency can help providers better engage patients in discussions about this topic and enable patients to become more proactive. PMID- 26531807 TI - Melatonin attenuates hypertension-induced renal injury partially through inhibiting oxidative stress in rats. AB - The aim of the present study was to investigate the protective effects of melatonin (MLT) on hypertension-induced renal injury and identify its mechanism of action. Twenty-four healthy male Wistar rats were divided into a sham control group (n=8), which was subjected to sham operation and received vehicle treatment (physiological saline intraperitoneally at 0.1 ml/100 g), a vehicle group (n=8), which was subjected to occlusion of the left renal artery and vehicle treatment, and the MLT group (n=8), which was subjected to occlusion of the left renal artery and treated with MLT (10 mg/kg/day). Pathological features of the renal tissues were determined using hematoxylin and eosin staining and Masson staining. Urine protein, serum creatinine (Scr), superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Immunohistochemical analysis was performed to determine the expression of heme oxygenase-1 (HO-1), intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS). Furthermore, reverse transcription polymerase chain reaction was conducted to determine the mRNA expression of HO-1, ICAM-1, eNOS and iNOS. A marked decrease in blood pressure was noticed in the MLT group at week 4 compared with that of the vehicle group (P<0.01). Furthermore, MLT treatment attenuated the infiltration of inflammatory cells and oedema/atrophy of renal tubules. MLT attenuated hypertension-induced increases in urine protein excretion, serum creatinine and MDA as well as decreases in SOD activity in renal tissues. Furthermore, MLT attenuated hypertension-induced increases in iNOS and ICAM-1 as well as decreases in eNOS and HO-1 expression at the mRNA and protein level. In conclusion, the results of the present study indicated that MLT had protective roles in hypertension-induced renal injury. Its mechanism of action is, at least in part, associated with the inhibition of oxidative stress. PMID- 26531808 TI - Automated image analysis for quantification of filamentous bacteria. AB - BACKGROUND: Antibiotics of the beta-lactam group are able to alter the shape of the bacterial cell wall, e.g. filamentation or a spheroplast formation. Early determination of antimicrobial susceptibility may be complicated by filamentation of bacteria as this can be falsely interpreted as growth in systems relying on colorimetry or turbidometry (such as Vitek-2, Phoenix, MicroScan WalkAway). The objective was to examine an automated image analysis algorithm for quantification of filamentous bacteria using the 3D digital microscopy imaging system, oCelloScope. RESULTS: Three E. coli strains displaying different resistant profiles and differences in filamentation kinetics were used to study a novel image analysis algorithm to quantify length of bacteria and bacterial filamentation. A total of 12 beta-lactam antibiotics or beta-lactam-beta lactamase inhibitor combinations were analyzed for their ability to induce filamentation. Filamentation peaked at approximately 120 min with an average cell length of 30 MUm. CONCLUSION: The automated image analysis algorithm showed a clear ability to rapidly detect and quantify beta-lactam-induced filamentation in E. coli. This rapid determination of beta-lactam-mediated morphological alterations may facilitate future development of fast and accurate AST systems, which in turn will enable early targeted antimicrobial therapy. Therefore, rapid detection of beta-lactam-mediated morphological changes may have important clinical implications. PMID- 26531809 TI - Association Between Pain and Functional Independence in Older Adults During and After Admission to Rehabilitation After an Acute Illness or Injury. AB - OBJECTIVES: To investigate the association between pain and functional independence in older adults during and after admission to rehabilitation after an acute illness or injury. DESIGN: Prospective, observational cohort study. SETTING: One community and one Veterans Affairs rehabilitation center. PARTICIPANTS: Individuals aged 65 and older admitted for rehabilitation after an acute illness or injury (postacute rehabilitation) (N = 245; mean age 80.6, 72% male)). MEASUREMENTS: Pain was assessed using the Geriatric Pain Measure (GPM, score 0-100). Functional independence was measured using the motor component of the Functional Independence Measure (mFIM, score 13-91). Both scores were obtained at admission; discharge; and 3-, 6-, and 9-month follow-up. In bivariate analyses, discharge GPM and persistent pain (lasting >3 months) were evaluated as predictors of mFIM score at 9 months. Applying a multilevel modeling (MLM) approach, individual deviations in GPM scores were used to predict variations in mFIM. RESULTS: At admission, 210 participants (87.9%) reported pain (16.3% mild (GPM<30); 49.3% moderate (GPM: 30-69); 22.1% severe (GPM>70)); 21.3% reported persistent pain after discharge. The bivariate analyses did not find statistically significant associations between discharge GPM or persistent pain and mFIM score at 9 months, but in the MLM analysis, deviations in GPM were significant predictors of deviations in mFIM score, suggesting that, when individuals experienced above-average levels of pain (GPM > their personal mean GPM), they also experienced worse functional independence (mFIM < their personal mean mFIM). CONCLUSION: Twenty-one percent of older adults undergoing postacute rehabilitation reported persistent pain after discharge from rehabilitation. The bivariate analysis did not find association between pain and functional independence, but MLM analysis showed that, when participants experienced more pain than their average, they had less functional independence. PMID- 26531810 TI - Systems biology-guided identification of synthetic lethal gene pairs and its potential use to discover antibiotic combinations. AB - Mathematical models of metabolism from bacterial systems biology have proven their utility across multiple fields, for example metabolic engineering, growth phenotype simulation, and biological discovery. The usefulness of the models stems from their ability to compute a link between genotype and phenotype, but their ability to accurately simulate gene-gene interactions has not been investigated extensively. Here we assess how accurately a metabolic model for Escherichia coli computes one particular type of gene-gene interaction, synthetic lethality, and find that the accuracy rate is between 25% and 43%. The most common failure modes were incorrect computation of single gene essentiality and biological information that was missing from the model. Moreover, we performed virtual and biological screening against several synthetic lethal pairs to explore whether two-compound formulations could be found that inhibit the growth of Gram-negative bacteria. One set of molecules was identified that, depending on the concentrations, inhibits E. coli and S. enterica serovar Typhimurium in an additive or antagonistic manner. These findings pinpoint specific ways in which to improve the predictive ability of metabolic models, and highlight one potential application of systems biology to drug discovery and translational medicine. PMID- 26531811 TI - Assembling an alkyl rotor to access abrupt and reversible crystalline deformation of a cobalt(II) complex. AB - Harnessing molecular motion to reversibly control macroscopic properties, such as shape and size, is a fascinating and challenging subject in materials science. Here we design a crystalline cobalt(II) complex with an n-butyl group on its ligands, which exhibits a reversible crystal deformation at a structural phase transition temperature. In the low-temperature phase, the molecular motion of the n-butyl group freezes. On heating, the n-butyl group rotates ca. 100 degrees around the C-C bond resulting in 6-7% expansion of the crystal size along the molecular packing direction. Importantly, crystal deformation is repeatedly observed without breaking the single-crystal state even though the shape change is considerable. Detailed structural analysis allows us to elucidate the underlying mechanism of this deformation. This work may mark a step towards converting the alkyl rotation to the macroscopic deformation in crystalline solids. PMID- 26531812 TI - Hematopoietic ABCA1 deletion promotes monocytosis and worsens diet-induced insulin resistance in mice. AB - Low-grade chronic inflammation plays an important role in the pathogenesis of obesity-induced insulin resistance. ABCA1 is essential for reverse cholesterol transport and HDL synthesis, and protects against macrophage inflammation. In the present study, the effects of ABCA1 deficiency in hematopoietic cells on diet induced inflammation and insulin resistance were tested in vivo using bone marrow transplanted (BMT)-WT and BMT-ABCA1(-/-) mice. When challenged with a high-fat high-carbohydrate diabetogenic diet with added cholesterol (HFHSC), BMT-ABCA1(-/ ) mice displayed enhanced insulin resistance and impaired glucose tolerance as compared with BMT-WT mice. The worsened insulin resistance and impaired glucose tolerance in BMT-ABCA1(-/-) mice were accompanied by increased macrophage accumulation and inflammation in adipose tissue and liver. Moreover, BMT-ABCA1(-/ ) mice had significantly higher hematopoietic stem cell proliferation, myeloid cell expansion, and monocytosis when challenged with the HFHSC diet. In vitro studies indicated that macrophages from ABCA1(-/-) mice showed significantly increased inflammatory responses induced by saturated fatty acids. Taken together, these studies point to an important role for hematopoietic ABCA1 in modulating a feed-forward mechanism in obesity such that inflamed tissue macrophages stimulate the production of more monocytes, leading to an exacerbation of inflammation and associated disease processes. PMID- 26531813 TI - Renoprotective effects of berberine and its potential effect on the expression of beta-arrestins and intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in streptozocin-diabetic nephropathy rats. AB - BACKGROUND: Berberine has been shown to exert protective effects against diabetic nephropathy (DN), but the mechanisms involved have not been fully characterized. The aim of the present study was to explore the effects of berberine on the expression of beta-arrestins, intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in DN rat kidneys and investigate the underlying molecular mechanisms. METHODS: To create the DN model, rats fed a high fat and high-glucose diet were injected with a single dose of streptozotocin (35 mg/kg, i.p.). Then, DN rats were either treated or not with berberine (50, 100, 200 mg/kg per day, i.g., 8 weeks). Periodic acid-Schiff staining was used to evaluate renal histopathological changes. Renal tissue levels of beta-arrestin 1 and beta-arrestin 2 were determined by Western blot analysis, whereas immunohistochemistry was used to determine renal ICAM-1 and VCAM-1 levels. RESULTS: Berberine (100, 200 mg/kg) ameliorated the histopathological changes in the diabetic kidney. Western blot analysis revealed significant increases in ICAM 1 and VCAM-1 levels in the kidneys of DN rats, which were reversed by treatment with 100 and 200 mg/kg berberine. In addition, berberine treatment (50, 100, 200 mg/kg) increased diabetic-induced decreases in beta-arrestin 1 and beta-arrestin 2. CONCLUSIONS: Berberine exhibited renoprotective effects in DN rats. The underlying molecular mechanisms may be associated with changes in the levels and regulation of beta-arrestin expression, as well as ICAM-1 and VCAM-1 levels in the rat kidney. PMID- 26531814 TI - Into the polymer brush regime through the "grafting-to" method: densely polymer grafted rodlike viruses with an unusual nematic liquid crystal behavior. AB - The current work reports an intriguing discovery of how the force exerted on protein complexes like filamentous viruses by the strong interchain repulsion of polymer brushes can induce subtle changes of the constituent subunits at the molecular scale. Such changes transform into the macroscopic rearrangement of the chiral ordering of the rodlike virus in three dimensions. For this, a straightforward "grafting-to" PEGylation method has been developed to densely graft a filamentous virus with poly(ethylene glycol) (PEG). The grafting density is so high that PEG is in the polymer brush regime, resulting in straight and thick rodlike particles with a thin viral backbone. Scission of the densely PEGylated viruses into fragments was observed due to the steric repulsion of the PEG brush, as facilitated by adsorption onto a mica surface. The high grafting density of PEG endows the virus with an isotropic-nematic (I-N) liquid crystal (LC) phase transition that is independent of the ionic strength and the densely PEGylated viruses enter into the nematic LC phase at much lower virus concentrations. Most importantly, while the intact virus and the one grafted with PEG of low grafting density can form a chiral nematic LC phase, the densely PEGylated viruses only form a pure nematic LC phase. This can be traced back to the secondary to tertiary structural change of the major coat protein of the virus, driven by the steric repulsion of the PEG brush. Quantitative parameters characterising the conformation of the grafted PEG derived from the grafting density or the I-N LC transition are elegantly consistent with the theoretical prediction. PMID- 26531815 TI - Blue carbon in human-dominated estuarine and shallow coastal systems. AB - Estuarine and shallow coastal systems (ESCS) are recognized as not only significant organic carbon reservoirs but also emitters of CO2 to the atmosphere through air-sea CO2 gas exchange, thus posing a dilemma on ESCS's role in climate change mitigation measures. However, some studies have shown that coastal waters take up atmospheric CO2 (Catm), although the magnitude and determinants remain unclear. We argue that the phenomenon of net uptake of Catm by ESCS is not unusual under a given set of terrestrial inputs and geophysical conditions. We assessed the key properties of systems that show the net Catm uptake and found that they are often characteristic of human-dominated systems: (1) input of high terrestrial nutrients, (2) input of treated wastewater in which labile carbon is highly removed, and (3) presence of hypoxia. We propose that human-dominated ESCS are worthy of investigation as a contributor to climate change mitigation. PMID- 26531816 TI - Reboxetine has no antidepressant effect at all. PMID- 26531819 TI - Modification of Vermiculite for the Preparation of Floating Adsorbent for Phosphate in Wastewater. AB - Floating adsorbents made from exfoliated vermiculite (EV) were tested for their ability to remove phosphate in aqueous solution. The modified vermiculites (MEV) were prepared with EV/glycerol ratio of 1/4 where glycerol contained 4 mol% H2SO4 and heated until designated temperatures. The highest specific surface area of 58.6 m(2)/g and carbon content of 62.2% were obtained for MEV heated at 580 degrees C and 380 degrees C, respectively. The dry density of MEV was decreased from 1.78 g/cm(3) (EV) to 0.25 g/cm(3), indicating these adsorbent floating characteristic. The MEV heated at 380 degrees C showed the highest Freundlich partition coefficient of 45.7 L/kg and the highest Langmuir sorption capacity of 714.3 mg/kg among other MEVs (476.2 mg/kg for MEV-580 and 181.8 mg/kg for MEV 780). Removal of phosphate using MEV heated at 380 degrees C was well explained by pseudo-second-order model and model parameters were comparable to other phosphate adsorption tests. PMID- 26531818 TI - Creatinine-based equations for the adjustment of drug dosage in an obese population. AB - AIM: For drug dosing adaptation, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend using estimated glomerular filtration rate (eGFR) by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, after 'de-indexation' by body surface area (BSA). In pharmacology, the Cockcroft-Gault (CG) equation is still recommended to adapt drug dosage. In the context of obesity, adjusted ideal body weight (AIBW) is sometimes preferred to actual body weight (ABW) for the CG equation. The aim of the present study was to compare the performance of the different GFR-estimating equations, non-indexed or de-indexed by BSA for the purpose of drug-dosage adaptation in obese patients. METHODS: We analysed data from patients with a body mass index (BMI) higher than 30 kg m(-2) who underwent a GFR measurement. eGFR was calculated using the CKD-EPI and Modification of Diet in Renal Disease (MDRD) equations, de-indexed by BSA, and the CG equation, using either ABW, AIBW or lean body weight (LBW) for the weight variable and compared with measured GFR, expressed in ml min(-1). RESULTS: In our population of obese patients, use of the AIBW instead of the ABW in the CG equation, markedly improved the overall accuracy of this equation [57% for CGABW and 79% for CGAIBW (P < 0.05)]. For high BMI (over 40 kg m(-2)), the accuracy of the CG equations is no different when using LBW than when using AIBW. The MDRD and CKD-EPI equations de-indexed by the BSA also performed well, with an overall higher accuracy for the MDRD de-indexed equation [(80% and 76%, respectively (P < 0.05)]. CONCLUSIONS: The de-indexed MDRD equation appeared to be the most suitable for estimating the non-indexed GFR for the purpose of drug dosage adaptation in obese patients. PMID- 26531820 TI - Incidence of aortic stenosis in subjects with normal and slightly elevated aortic gradients and flow. AB - OBJECTIVE: We aimed to describe the progression rate into manifest aortic stenosis (AS) in subjects with normal aortic valves or in an early phase of calcific aortic valve disease. METHODS: Participants were recruited from the Tromso Study, a population-based health survey. In our prospective cohort study, we performed two echocardiographical examinations (2001 and 2008) of a random sample of 1884 participants. AS was defined as a mean aortic valve gradient >=15 mm Hg or a peak flow exceeding 2.6 m/s. Those with lesser values were stratified into three groups based on mean gradients (cut-off 5 and 10 mm Hg) and peak aortic flow (cut-off 1.5 and 2 m/s). RESULTS: At baseline, 71 participants had gradients from 10 to 14.9 mm Hg, of whom 32.4% developed AS during follow-up. AS developed in only 3.6% of those with a baseline gradient of 5-9.9 mm Hg and in 0.3% of those with a gradient <5 mm Hg. Almost identical separations were obtained among the three flow velocity groups. Of the 45 subjects who developed incident AS, 56% acquired mild, 33% moderate and 11% severe AS. Their mean gradient progression rate was 2.7 mm Hg/year. CONCLUSIONS: The results support that subjects with a mean aortic valve gradient of 10-15 mm Hg or aortic flow >2.0 m/s should be followed routinely. This group identifies about half of those who develop AS in the following 7 years. PMID- 26531821 TI - ABCB1 gene variants, digoxin and risk of sudden cardiac death in a general population. AB - OBJECTIVE: The ATP-binding cassette B1 (ABCB1) gene encodes P-glycoprotein, a transport protein, which plays an important role in the bioavailability of digoxin. We aimed to investigate the interaction between variants within the ABCB1 gene and digoxin on the risk of sudden cardiac death (SCD). METHODS: Within the Rotterdam Study, a population-based cohort study in persons 45 years of age and older, we used Cox regression to analyse the association between three polymorphisms that have been associated with digoxin bioavailability, extracted from 1000-Genomes imputed ABCB1 genotypes and the risk of SCD, stratified by digoxin use. RESULTS: In a total study population of 10,932 persons, 419 SCDs occurred during a median follow-up of 9.8 years. In non-users of digoxin, the risk of SCD was not different across genotypes. In digoxin users, homozygous T allele carriers of C1236T (HR 1.90; 95% CI 1.09 to 3.30; allele frequency 0.43), G2677T (HR 1.89; 95% CI 1.10 to 3.24; allele frequency 0.44) and C3435T (HR 1.72; 95% CI 1.03 to 2.87; allele frequency 0.53) had a significantly increased risk of SCD in a recessive model. Interaction between the ABCB1 polymorphisms and digoxin use was significant for C1236T and G2677T in the age-adjusted and sex-adjusted model. CONCLUSIONS: In this study, we showed that in digoxin users variant alleles at each of the three loci in the ABCB1 gene were associated with an increased risk of SCD compared with digoxin users with none or one T allele. If replicated, the findings imply that the ABCB1 genotype modifies the risk of cardiac digoxin toxicity. PMID- 26531822 TI - Collaborator of alternative reading frame protein (CARF) regulates early processing of pre-ribosomal RNA by retaining XRN2 (5'-3' exoribonuclease) in the nucleoplasm. AB - Collaborator of alternative reading frame protein (CARF) associates directly with ARF, p53, and/or human double minute 2 protein (HDM2), a ubiquitin-protein ligase, without cofactors and regulates cell proliferation by forming a negative feedback loop. Although ARF, p53, and HDM2 also participate in the regulation of ribosome biogenesis, the involvement of CARF in this process remains unexplored. In this study, we demonstrate that CARF associates with 5'-3' exoribonuclease 2 (XRN2), which plays a major role in both the maturation of rRNA and the degradation of a variety of discarded pre-rRNA species. We show that overexpression of CARF increases the localization of XRN2 in the nucleoplasm and a concomitant suppression of pre-rRNA processing that leads to accumulation of the 5' extended from of 45S/47S pre-rRNA and 5'-01, A0-1 and E-2 fragments of pre rRNA transcript in the nucleolus. This was also observed upon XRN2 knockdown. Knockdown of CARF increased the amount of XRN2 in the nucleolar fraction as determined by cell fractionation and by immnocytochemical analysis. These observations suggest that CARF regulates early steps of pre-rRNA processing during ribosome biogenesis by controlling spatial distribution of XRN2 between the nucleoplasm and nucleolus. PMID- 26531823 TI - A dynamic intron retention program enriched in RNA processing genes regulates gene expression during terminal erythropoiesis. AB - Differentiating erythroblasts execute a dynamic alternative splicing program shown here to include extensive and diverse intron retention (IR) events. Cluster analysis revealed hundreds of developmentally-dynamic introns that exhibit increased IR in mature erythroblasts, and are enriched in functions related to RNA processing such as SF3B1 spliceosomal factor. Distinct, developmentally stable IR clusters are enriched in metal-ion binding functions and include mitoferrin genes SLC25A37 and SLC25A28 that are critical for iron homeostasis. Some IR transcripts are abundant, e.g. comprising ~50% of highly-expressed SLC25A37 and SF3B1 transcripts in late erythroblasts, and thereby limiting functional mRNA levels. IR transcripts tested were predominantly nuclear localized. Splice site strength correlated with IR among stable but not dynamic intron clusters, indicating distinct regulation of dynamically-increased IR in late erythroblasts. Retained introns were preferentially associated with alternative exons with premature termination codons (PTCs). High IR was observed in disease-causing genes including SF3B1 and the RNA binding protein FUS. Comparative studies demonstrated that the intron retention program in erythroblasts shares features with other tissues but ultimately is unique to erythropoiesis. We conclude that IR is a multi-dimensional set of processes that post-transcriptionally regulate diverse gene groups during normal erythropoiesis, misregulation of which could be responsible for human disease. PMID- 26531824 TI - DGIdb 2.0: mining clinically relevant drug-gene interactions. AB - The Drug-Gene Interaction Database (DGIdb, www.dgidb.org) is a web resource that consolidates disparate data sources describing drug-gene interactions and gene druggability. It provides an intuitive graphical user interface and a documented application programming interface (API) for querying these data. DGIdb was assembled through an extensive manual curation effort, reflecting the combined information of twenty-seven sources. For DGIdb 2.0, substantial updates have been made to increase content and improve its usefulness as a resource for mining clinically actionable drug targets. Specifically, nine new sources of drug-gene interactions have been added, including seven resources specifically focused on interactions linked to clinical trials. These additions have more than doubled the overall count of drug-gene interactions. The total number of druggable gene claims has also increased by 30%. Importantly, a majority of the unrestricted, publicly-accessible sources used in DGIdb are now automatically updated on a weekly basis, providing the most current information for these sources. Finally, a new web view and API have been developed to allow searching for interactions by drug identifiers to complement existing gene-based search functionality. With these updates, DGIdb represents a comprehensive and user friendly tool for mining the druggable genome for precision medicine hypothesis generation. PMID- 26531825 TI - Domain swapping between homologous bacterial small RNAs dissects processing and Hfq binding determinants and uncovers an aptamer for conditional RNase E cleavage. AB - In E. coli, small RNA GlmZ activates the glmS mRNA by base-pairing in an Hfq dependent manner. When not required, GlmZ is bound by adaptor protein RapZ and recruited to RNase E, which cleaves GlmZ in its base-pairing sequence. Small RNA GlmY counteracts cleavage of GlmZ by sequestration of RapZ. Although both sRNAs are highly homologous, only GlmZ specifically binds Hfq and undergoes cleavage by RNase E. We used domain swapping to identify the responsible modules. Two elements, the 3' terminal oligo(U) stretch and the base-pairing region enable GlmZ to interact with Hfq. Accordingly, Hfq inhibits cleavage of GlmZ, directing it to base-pairing. Intriguingly, the central stem loop of GlmZ is decisive for cleavage, whereas the sequence comprising the actual cleavage site is dispensable. Assisted by RapZ, RNase E cleaves any RNA fused to the 3' end of this module. These results suggest a novel mode for RNase E recognition, in which one of the required handholds in the substrate is replaced by an RNA binding protein. This device can generate RNAs of interest in their 5' monophosphorylated form on demand. As these species are rapidly degraded, this tool allows to regulate gene expression post-transcriptionally by modulation of RapZ levels. PMID- 26531826 TI - JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles. AB - JASPAR (http://jaspar.genereg.net) is an open-access database storing curated, non-redundant transcription factor (TF) binding profiles representing transcription factor binding preferences as position frequency matrices for multiple species in six taxonomic groups. For this 2016 release, we expanded the JASPAR CORE collection with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in fungi). The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. We updated the structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification. In addition, we introduced 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites. This new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, we provide the users with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. Finally, we provide the JASPAR2016 R/Bioconductor data package with the data of this release. PMID- 26531827 TI - Requirement for human Mps1/TTK in oxidative DNA damage repair and cell survival through MDM2 phosphorylation. AB - Human Mps1 (hMps1) is a protein kinase essential for mitotic checkpoints and the DNA damage response. Here, we present new evidence that hMps1 also participates in the repair of oxidative DNA lesions and cell survival through the MDM2-H2B axis. In response to oxidative stress, hMps1 phosphorylates MDM2, which in turn promotes histone H2B ubiquitination and chromatin decompaction. These events facilitate oxidative DNA damage repair and ATR-CHK1, but not ATM-CHK2 signaling. Depletion of hMps1 or MDM2 compromised H2B ubiquitination, DNA repair and cell survival. The impairment could be rescued by re-expression of WT but not the phospho-deficient MDM2 mutant, supporting the involvement of hMps1-dependent MDM2 phosphorylation in the oxidative stress response. In line with these findings, localization of RPA and base excision repair proteins to damage foci also requires MDM2 and hMps1. Significantly, like MDM2, hMps1 is upregulated in human sarcoma, suggesting high hMps1 and MDM2 expression may be beneficial for tumors constantly challenged by an oxidative micro-environment. Our study therefore identified an hMps1-MDM2-H2B signaling axis that likely plays a relevant role in tumor progression. PMID- 26531828 TI - EMERGE: a flexible modelling framework to predict genomic regulatory elements from genomic signatures. AB - Regulatory DNA elements, short genomic segments that regulate gene expression, have been implicated in developmental disorders and human disease. Despite this clinical urgency, only a small fraction of the regulatory DNA repertoire has been confirmed through reporter gene assays. The overall success rate of functional validation of candidate regulatory elements is low. Moreover, the number and diversity of datasets from which putative regulatory elements can be identified is large and rapidly increasing. We generated a flexible and user-friendly tool to integrate the information from different types of genomic datasets, e.g. ATAC seq, ChIP-seq, conservation, aiming to increase the ease and success rate of functional prediction. To this end, we developed the EMERGE program that merges all datasets that the user considers informative and uses a logistic regression framework, based on validated functional elements, to set optimal weights to these datasets. ROC curve analysis shows that a combination of datasets leads to improved prediction of tissue-specific enhancers in human, mouse and Drosophila genomes. Functional assays based on this prediction can be expected to have substantially higher success rates. The resulting integrated signal for prediction of functional elements can be plotted in a build-in genome browser or exported for further analysis. PMID- 26531829 TI - Impacts of nicorandil on infarct myocardium in comparison with nitrate: assessed by cardiac magnetic resonance imaging. AB - In this pilot study, we compared the infarct and edema size in acute myocardial infarction (MI) patients treated by nicorandil with those treated by nitrate, using cardiac magnetic resonance (CMR) imaging. Fifty-two acute MI patients who underwent emergency percutaneous coronary intervention (PCI) were enrolled, and were assigned to receive nicorandil or nitrate at random just before reperfusion. For the assessment of infarct and edema areas, short-axis delayed enhancement (DE) and T2-weight (T2w) CMR images were acquired 6.1 +/- 2.4 days after the onset of MI. A significant correlation was observed between the peak creatinine kinase (CK) level and the infarct size on DE CMR (r = 0.62, p < 0.05), as well as the edema size on T2w CMR (r = 0.70, p < 0.05) in patients treated by nicorandil (28 patients). A similar correlation was seen between the peak CK level and the infarct size on DE CMR (r = 0.84, p < 0.05), as well as the edema size on T2w CMR (r = 0.84, p < 0.05) in patients treated by nitrate (24 patients). The maximum CK level was significantly lower in patients treated by nicorandil rather than nitrate (1991 +/- 1402, 2785 +/- 2121 IU/L, respectively, p = 0.03). Both the edema size on T2w CMR and the infarct size on DE CMR were significantly smaller in patients treated by nicorandil rather than nitrate (17.7 +/- 9.9, 21.9 +/- 13.7 %; p = 0.03, 10.3 +/- 6.0, 12.7 +/- 6.9 %, p = 0.03, respectively). The presence and amount of microvascular obstruction were significantly smaller in patients treated by nicorandil rather than nitrate (39.2, 64.7 %; p = 0.03; 2.2 +/- 1.3, 3.4 +/- 1.5 cm(2); p = 0.02, respectively). Using CMR imaging, we demonstrated that the complementary use of intravenously and intracoronary administered nicorandil during PCI favorably acts more on the damaged myocardium after MI than nitrate. We need a further powered prospective study on the use of nicorandil. PMID- 26531830 TI - Clinical value of regression of electrocardiographic left ventricular hypertrophy after aortic valve replacement. AB - Electrocardiographic left ventricular hypertrophy (ECG-LVH) gradually regressed after aortic valve replacement (AVR) in patients with severe aortic stenosis. Sokolow-Lyon voltage (SV1 + RV5/6) is possibly the most widely used criterion for ECG-LVH. The aim of this study was to determine whether decrease in Sokolow-Lyon voltage reflects left ventricular reverse remodeling detected by echocardiography after AVR. Of 129 consecutive patients who underwent AVR for severe aortic stenosis, 38 patients with preoperative ECG-LVH, defined by SV1 + RV5/6 of >=3.5 mV, were enrolled in this study. Electrocardiography and echocardiography were performed preoperatively and 1 year postoperatively. The patients were divided into ECG-LVH regression group (n = 19) and non-regression group (n = 19) according to the median value of the absolute regression in SV1 + RV5/6. Multivariate logistic regression analysis was performed to assess determinants of ECG-LVH regression among echocardiographic indices. ECG-LVH regression group showed significantly greater decrease in left ventricular mass index and left ventricular dimensions than Non-regression group. ECG-LVH regression was independently determined by decrease in the left ventricular mass index [odds ratio (OR) 1.28, 95 % confidence interval (CI) 1.03-1.69, p = 0.048], left ventricular end-diastolic dimension (OR 1.18, 95 % CI 1.03-1.41, p = 0.014), and left ventricular end-systolic dimension (OR 1.24, 95 % CI 1.06-1.52, p = 0.0047). ECG-LVH regression could be a marker of the effect of AVR on both reducing the left ventricular mass index and left ventricular dimensions. The effect of AVR on reverse remodeling can be estimated, at least in part, by regression of ECG-LVH. PMID- 26531831 TI - WT1 Expression in Adult Acute Myeloid Leukemia: Assessing its Presence, Magnitude and Temporal Changes as Prognostic Factors. AB - Expression of the gene Wilms tumor 1 (WT1) has been suggested as a marker of minimal residual disease in acute myeloid leukemia (AML), but literature data are not without controversy. Our aim was to assess the presence, magnitude and temporal changes of WT1 expression as prognostic factors. 60 AML patients were followed until death or the end of the 6-year observation period. Blood samples were taken at diagnosis, post-induction, during remission and in case of a relapse. Using quantitative real-time PCR, we determined WT1 expression from each sample, normalized it against the endogenous control gene glyceraldehyde 3 phosphate dehydrogenase (GAPDH), and classified samples as negative, moderately positive or highly positive. We divided the patients into groups based on detected WT1 expression values, illustrated overall and disease-free survival on Kaplan-Meier curves, and compared differences between each group by the logrank test. Disappearance of WT1-positivity during chemotherapy had a favorable effect on survival. Interestingly, no difference was seen between the survivals of WT1 positive subgroups that expressed moderate or high levels of WT1 mRNA. A 1-log decrease in WT1 expression without becoming negative did not affect prognosis, either. Our results suggest that defining a cut-off value for WT1-positivity, rather than just using logarithmic figures of changes in gene expression, might have prognostic use in post-induction AML patients. We encourage further, larger scale studies. PMID- 26531832 TI - Inhibitors of phosphodiesterases PDE2, PDE3, and PDE4 do not increase the sinoatrial tachycardia of noradrenaline and prostaglandin PGE1 in mice. AB - Phosphodiesterases PDE2, PDE3, and PDE4 are expressed in murine sinoatrial cells. PDE3 and/or PDE4 reduce heart rate but apparently do not influence the tachycardia mediated through sinoatrial beta1- and beta2-adrenoceptors despite the high content of sinoatrial cAMP. The function of PDE2 is, however, uncertain. Prostaglandin PGE1 elicits sinoatrial tachycardia through EP receptors, but the control by phosphodiesterases is unknown. We investigated on spontaneously beating right atria of mice the effects of the PDE2 inhibitors Bay 60-7550 and EHNA on basal beating and the tachycardia produced by noradrenaline (3 nM) and PGE1 (1 MUM). Bay 60-7550 (1 MUM), but not EHNA (10 MUM), increased basal sinoatrial beating. EHNA also failed to produce tachycardia in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin (10 MUM), remaining inconclusive whether PDE2 reduces basal sinoatrial beating. Rolipram (10 MUM) and cilostamide (300 nM) caused moderate tachycardia. The tachycardia evoked by Bay 60-7550 was similar in the absence and presence of rolipram. Noradrenaline elicited stable tachycardia that was not increased by Bay 60-7550. A stable tachycardia caused by PGE1 was not increased by the inhibitors of PDE2, PDE3, and PDE4. Unlike PDE3 and PDE4 which reduce murine basal sinoatrial beating, a possible effect of PDE2 needs further research. The stable tachycardia produced by noradrenaline and PGE1, together with the lack potentiation by the inhibitors of PDE2, PDE3, and PDE4, suggests that cAMP generated at the receptor compartments is hardly hydrolyzed by these phophodiesterases. Evidence from human volunteers is consistent with this proposal. PMID- 26531833 TI - Possible role of thromboxane A2 in remote hind limb preconditioning-induced cardioprotection. AB - Remote hind limb preconditioning (RIPC) is a protective strategy in which short episodes of ischemia and reperfusion in a remote organ (hind limb) protects the target organ (heart) against sustained ischemic reperfusion injury. The present study was designed to investigate the possible role of thromboxane A2 in RIPC induced cardioprotection in rats. Remote hind limb preconditioning was performed by four episodes of 5 min of inflation and 5 min of deflation of pressure cuff. Occlusion of the hind limb with blood pressure cuff is most feasible, non invasive, clinically relevant, and safe method for inducing RIPC. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120-min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. The extent of myocardial infarct size along with the functional parameters including left ventricular developed pressure (LVDP), dp/dtmax, and dp/dtmin were also measured. Ozagrel (thromboxane synthase inhibitor) and seratrodast (thromboxane A2 receptor antagonist) were employed as pharmacological modulators of thromboxane A2. Remote hind limb preconditioning significantly attenuated ischemia/reperfusion-induced myocardial injury and produced cardioprotective effects. However, administration of ozagrel and seratrodast completely abolished the cardioprotective effects of RIPC suggesting the key role of thromboxane A2 in RIPC-induced cardioprotection. It may be concluded that brief episodes of preconditioning ischemia and reperfusion activates the thromboxane synthase enzyme that produces thromboxane A2, which may elicit cardioprotection either involving humoral or neurogenic pathway. PMID- 26531834 TI - The Effect of Capsaicin-Containing Food on the Swallowing Response. AB - The purpose of this study was to determine the effect of regular ingestion of capsaicin-containing food that is easily available in everyday life on the latency of the swallowing response (LSR). Pickled Napa cabbage was selected as the food for the present study. One portion (10 g) of pickled Napa cabbage provides 1.5 ug of capsaicin. Participants ingested pickled Napa cabbage (10 g) before every meal for 20 days (days 1-20). LSR was measured pre-intervention (day 0) and post-intervention (day 21). The participants then followed their regular diet, without foods containing red pepper, from day 21 to day 27, and LSR was measured on day 28 (follow-up LSR). Sixteen elderly participants (two male, 14 female; age 81.6 +/- 9.39 years) and 10 young participants (all female; age 21.6 +/- 0.52 years) participated in the study. The pre-intervention LSR was 2.04 +/- 1.60 s in elderly participants and 1.27 +/- 0.27 s in young participants. In the elderly group, the post-intervention LSR (day 21) was 1.47 +/- 1.05 the follow up LSR (day 28) was 1.99 +/- 1.80 s (p = 0.044 and 0.502, respectively, compared to pre-intervention). In the young group, the post-intervention and follow-up LSR values were 1.07 +/- 0.20 s and 1.04 +/- 0.10 s, respectively (p = 0.016 and 0.038, respectively, compared to pre-intervention). Swallowing function was improved by pickled Napa cabbage containing capsaicin, but capsaicin supplementation may need to be maintained to have an ongoing effect. PMID- 26531835 TI - Anti-allergic and anti-inflammatory effects of aqueous extract of Pogostemon cablin. AB - Allergic disease is caused by exposure to normally innocuous substances that activate mast cells. Mast cell-mediated allergic inflammation is closely related to a number of allergic disorders, such as anaphylaxis, allergic rhinitis, asthma and atopic dermatitis. The discovery of drugs for treating allergic disease is an interesting subject and important to human health. The aim of the present study was to investigate the anti-allergic and anti-inflammatory effects of the aqueous extract of Pogostemon cablin (Blanco) Benth (AEPC) (a member of the Labiatae family) using mast cells, and also to determine its possible mechanisms of action. An intraperitoneal injection of compound 48/80 or a serial injection of immunoglobulin E and antigen was used to induce anaphylaxis in mice. We found that AEPC inhibited compound 48/80-induced systemic and immunoglobulin E-mediated cutaneous anaphylaxis in a dose-dependent manner. The release of histamine from mast cells was reduced by AEPC, and this suppressive effect was associated with the regulation of calcium influx. In addition, AEPC attenuated the phorbol 12 myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated expression of pro-inflammatory cytokines in mast cells. The inhibitory effects of AEPC on pro-inflammatory cytokines were dependent on the activation of nuclear factor (NF)-kappaB and p38 mitogen-activated protein kinase (MAPK). AEPC blocked the PMACI-induced translocation of NF-kappaB into the nucleus by hindering the degradation of IkappaBalpha and the phosphorylation of p38 MAPK. Our results thus indicate that AEPC inhibits mast cell-mediated allergic inflammation by suppressing mast cell degranulation and the expression of pro-inflammatory cytokines caused by reduced intracellular calcium levels and the activation of NF kappaB and p38 MAPK. PMID- 26531836 TI - A positive feedback loop of p53/miR-19/TP53INP1 modulates pancreatic cancer cell proliferation and apoptosis. AB - Pancreatic cancer is a common malignancy whose prognosis and treatment of pancreatic cancer is extremely poor, with only 20% of patients reaching two years of survival. Previous findings have shown that the tumor suppressor p53 is involved in the development of various types of cancer, including pancreatic cancer. Additionally, p53 is able to activate TP53INP1 transcription by regulating several phenotypes of cancer cells. Using gain and loss-of-function assays, the aim of the present study was to examine the relationships between miR 19a/b and cancer development as well as potential underlying mechanisms. The results showed that miR-19a/b identified a positive feedback regulation of p53/TP53INP1 axis. Additionally, p53 upregulated the TP53INP1 level in pancreatic cancer cells. However, overexpressed miR-19a/b partially restored the TP53 function in the pancreatic cancer cells while miR-19a/b downregulated TP53INP1 protein by directly targeting 3'UTR of its mRNA at the post-transcriptional level. In addition, the patient tissues identified that the miR-19a/b level in pancreatic cancer tissues was conversely correlated with TP53 and TP53INP1 expression. The results provide evidence for revealing the molecular mechanism involved in the development of pancreatic cancer and may be useful in the identification of new therapeutic targets for pancreatic cancer. PMID- 26531837 TI - The Fusarium solani species complex: ubiquitous pathogens of agricultural importance. AB - Members of the Fusarium solani species complex (FSSC) are capable of causing disease in many agriculturally important crops. The genomes of some of these fungi include supernumerary chromosomes that are dispensable and encode host specific virulence factors. In addition to genomics, this review summarizes the known molecular mechanisms utilized by members of the FSSC in establishing disease. TAXONOMY: Kingdom Fungi; Phylum Ascomycota; Class Sordariomycetes; Order Hypocreales; Family Nectriaceae; Genus Fusarium. HOST RANGE: Members of the FSSC collectively have a very broad host range, and have been subdivided previously into formae speciales. Recent phylogenetic analysis has revealed that formae speciales correspond to biologically and phylogenetically distinct species. DISEASE SYMPTOMS: Typically, FSSC causes foot and/or root rot of the infected host plant, and the degree of necrosis correlates with the severity of the disease. Symptoms on above-ground portions of the plant can vary greatly depending on the specific FSSC pathogen and host plant, and the disease may manifest as wilting, stunting and chlorosis or lesions on the stem and/or leaves. CONTROL: Implementation of agricultural management practices, such as crop rotation and timing of planting, can reduce the risk of crop loss caused by FSSC. If available, the use of resistant varieties is another means to control disease in the field. USEFUL WEBSITES: http://genome.jgi-psf.org/Necha2/Necha2.home.html. PMID- 26531838 TI - The Role of Mediators in the Indirect Effects of Religiosity on Therapeutic Compliance in African Migrant HIV-Positive Patients. AB - This research investigates the indirect effects of religiosity (practice and belief) on therapeutic compliance in 81 HIV-positive patients who are migrants from sub-Saharan Africa (23 men and 58 women). Using analyses of mediation and standard multiple regression, including a resampling procedure by bootstrapping, the role of these mediators (magical-religious beliefs and nonuse of toxic substances) was tested. The results show that, through magical-religious beliefs, religiosity has a negative indirect effect, while with the nonuse of toxic substances, religious practice has a positive indirect effect. Beyond religiosity, the role of mediators is highlighted in the interaction with therapeutic compliance. PMID- 26531839 TI - Bispectral Index Versus Standard Monitoring in Sedation for Endoscopic Procedures: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Bispectral index (BIS ) monitoring has been used as an objective measurement tool for sedation depth and has been proposed as a guidance to reduce the risk of intraprocedural over-sedation. However, the results of several studies evaluating the benefits of BIS monitoring for gastrointestinal endoscopy were not consistent. AIMS: This meta-analysis aimed to assess the reduction in total consumption of administrated propofol and recovery time under BIS during gastrointestinal endoscopy. METHODS: Electronic databases (MEDLINE, EMBASE, WEB of SCIENCE, and the Cochrane Central Register of Controlled Trials) were searched for articles published through March 2015. After screening, the reviewers extracted information on 11 randomized controlled trials. A total of 1039 patients (526 in BIS and 513 in non-BIS group) were included in this study. RESULTS: Meta-analyses showed that the total propofol consumption (the pooled standardized mean difference [SMD]: -0.15, 95% confidence interval [CI]: -0.28 to -0.01) was significantly lower in the BIS group than in the non-BIS group, although mean propofol consumption was not significantly different. Recovery time (the pooled SMD: -0.04 [95% CI -0.46 to 0.38, P = 0.85]), procedure time (the pooled SMD: 0.13 [95% CI -0.03 to 0.29, P = 0.11]), adverse events, and satisfaction-related outcomes were not significantly superior in the BIS group when compared with the non-BIS group. CONCLUSIONS: This first meta-analysis showed that BIS monitoring appears to be an effective and safe method for avoiding unnecessary administration of propofol and for providing adequate sedation during endoscopic procedures. PMID- 26531840 TI - Accuracy of three hemoglobin A1c point-of-care systems for glucose monitoring in patients with diabetes mellitus. AB - OBJECTIVES: Use of hemoglobin A1c point-of-care devices in physician offices provides immediate results and reduces inconveniences for the patients. We compared the analytical performances of 3 point-of-care HbA1c analyzers to high pressure liquid chromatography (HPLC). MATERIAL AND METHODS: We preselected a pool of 40 EDTA-preserved whole blood samples from our laboratory with HbA1c results obtained by HPLC (mean 6.6% [49 mmol/mol] and range: 4.6-9.9% [27-87 mmol/mol]). Aliquots of theses samples were tested by Afinion AS100, DCA Vantage and In2it point-of-care systems. According the Clinical Laboratory Standards Institute EP-09 protocol we determined linearity (linear regression and correlation coefficient between point-of-care and reference methods), bias (Bland Altman analysis) and coefficient of variation (%). We used the acceptability criteria endorsed by the National Glycohemoglobin Standardization Program. RESULTS: The calculated correlation coefficients (r) were 0.98, 0.98 and 0.83 for Afinion AS100, DCA Vantage and In2it systems, respectively. The 95% confidence interval of the error between point-of-care systems and the reference method was 0.41% and +0.34% (p =.22) for Afinion AS100, -0.62% and +0.05% (p =.57) for DCA Vantage, and -1.15% and +1.26% (p<.001) for the In2it. The coefficients of variation for Afinion AS100, DCA Vantage and In2it systems were 1.80, 3.74 and 7.14%, respectively. CONCLUSION: Only the Afinion AS100 point-of-care system met all NGSP performance criteria. PMID- 26531841 TI - Numerical and clinical precision of continuous glucose monitoring in Colombian patients treated with insulin infusion pump with automated suspension in hypoglycemia. AB - OBJECTIVE: Insulin pump therapy associated with continuous glucose monitoring has shown a positive clinical impact on diabetes control and reduction of hypoglycemia episodes. There are descriptions of the performance of this device in other populations, but its precision and accuracy in Colombia and Latin America are unknown, especially in the routine outpatient setting. METHODS: Data from 33 type 1 and type 2 diabetes patients with sensor-augmented pump therapy with threshold suspend automation, MiniMed Paradigm(r) VeoTM (Medtronic, Northridge, California), managed at Hospital Universitario San Ignacio (Bogota, Colombia) and receiving outpatient treatment, were analyzed. Simultaneous data from continuous glucose monitoring and capillary blood glucose were compared, and their precision and accuracy were calculating with different methods, including Clarke error grid. RESULTS: Analyses included 2,262 continuous glucose monitoring -reference paired glucose values. A mean absolute relative difference of 20.1% was found for all measurements, with a value higher than 23% for glucose levels <=75mg/dL. Global compliance with the ISO criteria was 64.9%. It was higher for values >75mg/dl (68.3%, 1,308 of 1,916 readings), than for those <= 75mg/dl (49.4%, 171 of 346 readings). Clinical accuracy, as assessed by the Clarke error grid, showed that 91.77% of data were within the A and B zones (75.6% in hypoglycemia). CONCLUSIONS: A good numerical accuracy was found for continuous glucose monitoring in normo and hyperglycemia situations, with low precision in hypoglycemia. The clinical accuracy of the device was adequate, with no significant safety concerns for patients. PMID- 26531842 TI - Factors associated with length of hospital stay in minor and moderate burns at Popayan, Colombia. Analysis of a cohort study. AB - OBJECTIVE: To determine the independent contribution of prognostic factors to length of hospital stay of minor and moderate burn victims at the Hospital Universitario San Jose (HUSJ), Popayan, Colombia, 2000-2010. METHODS: This was a retrospective cohort study of minor and moderate burn victims admitted between 2000 and 2010, at the burn unit (HUSJ). This is a further analysis of a same cohort previously published in Burns. The following variables were recorded and analyzed: age, gender, origin, depth and extent of burn, causal agent, length of hospital stay and mortality. The main outcome under study was length of stay. Survival analysis was done to explore the association of covariates and length of hospital stay and Cox regression model to adjust the effect of covariates in the outcome. RESULTS: During the study period 2000-2010, 842 of 921 (91.5%) patients treated at the Burn Unit of HUSJ that had complete data were included. There were 520 (61.8%) males and 322 (38.2%) females with a male to female ratio of 1.6:1. Their median age was 9 years (IQR 3-28). The median of percent total body surface area burned (TBSA) was 12% (IQR 7-21) and the most common degree of burn was 2nd degree with 58% (488 patients). There were 12 deaths (censored data) and 830 patients were discharged alive. After multivariate adjustment, significant associations with length of hospital stay remained for age group, burn degree and extension of the burn. The strongest relationship found was for burn degree (2nd degree superficial vs. 3rd degree hazard ratio=2.66 CI 95% [2.13-3.33]). CONCLUSIONS: In patients admitted with mild and moderate burns at HUSJ, the main predictors of length of stay were age, burn degree and extension of the burn. PMID- 26531843 TI - Depression symptoms in burn patients. PMID- 26531844 TI - Burns teaching in UK medical schools: Is it enough? AB - BACKGROUND: Burns are frequently seen and managed in non-specialist settings. The crowding of the UK medical undergraduate curriculum may have resulted in the reduction of teaching on burns. AIM: To determine the burns education experience and the level of competence among UK final year medical students in assessing and acutely managing patients with burns. METHODS: An online questionnaire was circulated among UK final year medical students. RESULTS: There was a total of 348 respondents. The majority of the respondents (70%) have not received any specific teaching on how to manage patients with burns. Nearly two-thirds of the students (66%) have never seen a patient being managed for burns throughout their training. Over 90% of respondents stated that they would not feel confident in initially managing a burn in the emergency department. The majority of the respondents (57%) have not heard of the criteria for referring a burns patient for further specialist management. There was almost universal agreement about the importance of knowing how to manage a burn initially. CONCLUSIONS: There seems to be a lack of consistent undergraduate training in burns management and final year students lack the experience and knowledge to initially manage burns. PMID- 26531845 TI - Hypoxia induced HIF-1/HIF-2 activity alters trophoblast transcriptional regulation and promotes invasion. AB - Reduced or absent cytotrophoblast invasion of the maternal uterine spiral arterioles is a common clinical finding in studies of pregnancies complicated by preeclampsia, suggesting that the mechanisms mediating invasion of these cells is perturbed. The placenta initially develops in a low oxygen environment of 1-2% oxygen until after the 10th week of pregnancy. During this time oxygen concentration exerts a major influence over trophoblast activity and, hypoxia inducible factors are proposed to be one of many key regulators of first trimester trophoblast behaviour. We used a global gene expression microarray approach to identify signalling pathways and hypoxia-responsive genes of interest involved in invasion of the first trimester trophoblast cell line HTR8/SVneo under hypoxic conditions where HIF-1 was active. Additionally, first trimester placental samples from different gestational age groups were labelled with anti HIF-1alpha and HIF-2alpha to evaluate whether HIFs are differentially expressed and localised across two periods of placental development: (1) early first trimester characterised by hypoxia (6-8 weeks) and (2) late first trimester after initiation of maternal blood flow into the placenta (10-12 weeks). Invasion of HTR8/SVneo was assessed in real-time and was significantly increased in 1% compared with 5% and 21% oxygen and did not differ between 5% and 21% oxygen treatments. Eighty-eight genes were differentially expressed between cells cultured in 1% oxygen (where HIF-1alpha protein was localised to the nucleus) and 5% oxygen (where HIF-1alpha was mainly cytoplasmic). 65% of the genes were predicted to contain HIF-1alpha:HIF-1beta transcription factor binding sites. While HIF-2alpha staining intensity in trophoblasts of late first trimester placenta was higher than early first trimester (+57%) the percentage of positively stained trophoblast nuclei did not differ between the two time points. There was no difference in the expression level of any of the hypoxia responsive genes of interest, IGFBP3, P4HA1, P4HA2, ANGPTL4 and MMP1 between early and late first trimester placenta. While HIF-1alpha and its downstream targets are clearly induced in HTR8/SVneo during in vitro hypoxic conditions, it appears that hypoxia inducible factors and genes are not altered throughout the first 7-12 weeks of placental development, during which the onset of maternal blood flow to the intervillous space takes place. PMID- 26531846 TI - On-line MR imaging for dose validation of abdominal radiotherapy. AB - For quality assurance and adaptive radiotherapy, validation of the actual delivered dose is crucial.Intrafractional anatomy changes cannot be captured satisfactorily during treatment with hitherto available imaging modalitites. Consequently, dose calculations are based on the assumption of static anatomy throughout the treatment. However, intra- and interfraction anatomy is dynamic and changes can be significant.In this paper, we investigate the use of an MR linac as a dose tracking modality for the validation of treatments in abdominal targets where both respiratory and long-term peristaltic and drift motion occur.The on-line MR imaging capability of the modality provides the means to perform respiratory gating of both delivery and acquisition yielding a model-free respiratory motion management under free breathing conditions.In parallel to the treatment, the volumetric patient anatomy was captured and used to calculate the applied dose. Subsequently, the individual doses were warped back to the planning grid to obtain the actual dose accumulated over the entire treatment duration. Ultimately, the planned dose was validated by comparison with the accumulated dose.Representative for a site subject to breathing modulation, two kidney cases (25 Gy target dose) demonstrated the working principle on volunteer data and simulated delivery. The proposed workflow successfully showed its ability to track local dosimetric changes. Integration of the on-line anatomy information could reveal local dose variations -2.3-1.5 Gy in the target volume of a volunteer dataset. In the adjacent organs at risk, high local dose errors ranging from -2.5 to 1.9 Gy could be traced back. PMID- 26531847 TI - Subthalamic stimulation or subthalamic lesion for Parkinson's disease? A case report. PMID- 26531848 TI - Inferior oblique muscle paresis as a sign of myasthenia gravis. AB - Myasthenia gravis may affect any of the six extra-ocular muscles, masquerading as any type of ocular motor pathology. The frequency of involvement of each muscle is not well established in the medical literature. This study was designed to determine whether a specific muscle or combination of muscles tends to be predominantly affected. This retrospective review included 30 patients with a clinical diagnosis of myasthenia gravis who had extra-ocular muscle involvement with diplopia at presentation. The diagnosis was confirmed by at least one of the following tests: Tensilon test, acetylcholine receptor antibodies, thymoma on chest CT scan, or suggestive electromyography. Frequency of involvement of each muscle in this cohort was inferior oblique 19 (63.3%), lateral rectus nine (30%), superior rectus four (13.3%), inferior rectus six (20%), medial rectus four (13.3%), and superior oblique three (10%). The inferior oblique was involved more often than any other muscle (p<0.01). Eighteen (60%) patients had ptosis, six (20%) of whom had bilateral ptosis. Diagnosing myasthenia gravis can be difficult, because the disease may mimic every pupil-sparing pattern of ocular misalignment. In addition diplopia caused by paresis of the inferior oblique muscle is rarely encountered (other than as a part of oculomotor nerve palsy). Hence, when a patient presents with vertical diplopia resulting from an isolated inferior oblique palsy, myasthenic etiology should be highly suspected. PMID- 26531849 TI - Investigation of band gap narrowing in nitrogen-doped La2Ti2O7 with transient absorption spectroscopy. AB - Doping a semiconductor can extend the light absorption range, however, it usually introduces mid-gap states, reducing the charge carrier lifetime. This report shows that doping lanthanum dititinate (La2Ti2O7) with nitrogen extends the valence band edge by creating a continuum of dopant states, increasing the light absorption edge from 380 nm to 550 nm without adding mid-gap states. The dopant states are experimentally resolved in the excited state by correlating transient absorption spectroscopy with a supercontinuum probe and DFT prediction. The lack of mid-gap states is further confirmed by measuring the excited state lifetimes, which reveal the shifted band edge only increased carrier thermalization rates to the band edge and not interband charge recombination under both ultraviolet and visible excitation. Terahertz (time-domain) spectroscopy also reveals that the conduction mechanism remains unchanged after doping, suggesting the states are delocalized. PMID- 26531850 TI - Analysis of Documentation Speed Using Web-Based Medical Speech Recognition Technology: Randomized Controlled Trial. AB - BACKGROUND: Clinical documentation has undergone a change due to the usage of electronic health records. The core element is to capture clinical findings and document therapy electronically. Health care personnel spend a significant portion of their time on the computer. Alternatives to self-typing, such as speech recognition, are currently believed to increase documentation efficiency and quality, as well as satisfaction of health professionals while accomplishing clinical documentation, but few studies in this area have been published to date. OBJECTIVE: This study describes the effects of using a Web-based medical speech recognition system for clinical documentation in a university hospital on (1) documentation speed, (2) document length, and (3) physician satisfaction. METHODS: Reports of 28 physicians were randomized to be created with (intervention) or without (control) the assistance of a Web-based system of medical automatic speech recognition (ASR) in the German language. The documentation was entered into a browser's text area and the time to complete the documentation including all necessary corrections, correction effort, number of characters, and mood of participant were stored in a database. The underlying time comprised text entering, text correction, and finalization of the documentation event. Participants self-assessed their moods on a scale of 1-3 (1=good, 2=moderate, 3=bad). Statistical analysis was done using permutation tests. RESULTS: The number of clinical reports eligible for further analysis stood at 1455. Out of 1455 reports, 718 (49.35%) were assisted by ASR and 737 (50.65%) were not assisted by ASR. Average documentation speed without ASR was 173 (SD 101) characters per minute, while it was 217 (SD 120) characters per minute using ASR. The overall increase in documentation speed through Web-based ASR assistance was 26% (P=.04). Participants documented an average of 356 (SD 388) characters per report when not assisted by ASR and 649 (SD 561) characters per report when assisted by ASR. Participants' average mood rating was 1.3 (SD 0.6) using ASR assistance compared to 1.6 (SD 0.7) without ASR assistance (P<.001). CONCLUSIONS: We conclude that medical documentation with the assistance of Web-based speech recognition leads to an increase in documentation speed, document length, and participant mood when compared to self-typing. Speech recognition is a meaningful and effective tool for the clinical documentation process. PMID- 26531851 TI - Integrative taxonomy helps to reveal the mask of the genus Gynandropaa (Amphibia: Anura: Dicroglossidae). AB - Species of the genus Gynandropaa within the family Dicroglossidae are typical spiny frogs whose taxonomic status has long been in doubt. We used integrative methods, involving morphological and molecular analyses, to elucidate the phylogenetic relationships, and to determine identities and the geographic distribution of each valid species. We obtained DNA sequence data of 5 species of Gynandropaa (complete sequences of the mitochondrial NADH dehydrogenase subunit 2 [ND2] gene, and 890 bp of 12S rRNA and 16S rRNA partial sequences) from 37 localities (including the topotypes of 5 described species) and constructed Bayesian and maximum-likelihood trees to examine the patterns of phylogeography. A total of 28 morphological variables were taken on 624 specimens. Three clades with clear geographic patterns were recognized: clade C (from south-western Sichuan Province and central Yunnan Province), clade E (western Guizhou Province and eastern to central Yunnan Province) and clade W (western to southern Yunnan Province). Integrating morphological characteristics and distribution information, the clades W, E and C represent Gynandropaa yunnanensis, G. phrynoides and G. sichuanensis, respectively. We draw the following conclusions: (i) the taxon G. phrynoides, formerly evaluated as a junior synonym of G. yunnanensis, is revalidated herein at the rank of species; (ii) G. liui is a junior synonym of G. sichuanensis; and (iii) G. yunnanensis is a valid species while G. bourreti is probably a subspecies of G. yunnanensis, with the distribution range from Vietnam to southern Yunnan Province. This study clears up the taxonomic status of Gynandropaa and provides important information for understanding the evolution and conservation of these spiny frogs. PMID- 26531854 TI - Phenylpropanoids from the stems of Ephedra sinica. AB - Two new compounds of phenylpropanoids, (S)-N-((1R,2S)-1-hydroxy-1-phenylpropan-2 yl)-5-oxopyrrolidine-2-carboxamide (1) and (3R)-3-O-beta-d-glucopyranosyl-3 phenylpropanoic acid (2), were isolated from the stems of Ephedra sinica. Their structures were elucidated by in-depth examination of spectroscopic data, mainly including those from the 1D and 2D NMR and HRESIMS techniques, and chemical method. The absolute configurations of the two compounds were also corroborated through CD procedure. PMID- 26531852 TI - Abnormalities in synaptic dynamics during development in a mouse model of spinocerebellar ataxia type 1. AB - Late-onset neurodegenerative diseases are characterized by neurological symptoms and progressive neuronal death. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, causes the symptoms of neurodegenerative diseases. However, the mechanisms underlying the dysfunction that occurs prior to cell death remain unclear. To investigate the synaptic basis of this dysfunction, we employed in vivo two-photon imaging to analyse excitatory postsynaptic dendritic protrusions. We used Sca1(154Q/2Q) mice, an established knock-in mouse model of the polyglutamine disease spinocerebellar ataxia type 1 (SCA1), which replicates human SCA1 features including ataxia, cognitive impairment, and neuronal death. We found that Sca1(154Q/2Q) mice exhibited greater synaptic instability than controls, without synaptic loss, in the cerebral cortex, where obvious neuronal death is not observed, even before the onset of distinct symptoms. Interestingly, this abnormal synaptic instability was evident in Sca1(154Q/2Q) mice from the synaptic developmental stage, and persisted into adulthood. Expression of synaptic scaffolding proteins was also lower in Sca1(154Q/2Q) mice than controls before synaptic maturation. As symptoms progressed, synaptic loss became evident. These results indicate that aberrant synaptic instability, accompanied by decreased expression of scaffolding proteins during synaptic development, is a very early pathology that precedes distinct neurological symptoms and neuronal cell death in SCA1. PMID- 26531855 TI - Experimental Demonstration of Anomalous Field Enhancement in All-Dielectric Transition Magnetic Metamaterials. AB - Anomalous field enhancement accompanied by resonant absorption phenomenon was originally discussed in the context of plasma physics and in applications related to radio-communications between the ground and spacecraft returning to Earth. Indeed, there is a critical period of time when all communications are lost due to the reflection/absorption of electromagnetic waves by the sheath of plasma created by a high speed vehicle re-entering the atmosphere. While detailed experimental studies of these phenomena in space are challenging, the emergence of electromagnetic metamaterials enables researchers exceptional flexibility to study them in the laboratory environment. Here, we experimentally demonstrated the strong localized field enhancement of magnetic field for an electromagnetic wave propagating in Mie-resonance-based inhomogeneous metamaterials with magnetic permeability gradually changing from positive to negative values. Although these experiments were performed in the microwave frequency range, the proposed all dielectric approach to transition metamaterials can be extended to terahertz, infrared, and visible frequencies. We anticipate that these results, besides most basic science aspects, hold the potential for numerous applications, including low-intensity nonlinear transformation optics, topological photonics, and the broader area of surface and interface science. PMID- 26531856 TI - A (-)-norephedrine-based molecularly imprinted polymer for the solid-phase extraction of psychoactive phenylpropylamino alkaloids from Khat (Catha edulis Vahl. Endl.) chewing leaves. AB - A molecularly imprinted polymer (MIP) was prepared using (-)-norephedrine as the template, methacrylic acid as the functional monomer, ethylene glycol dimethacrylate as the cross-linker and chloroform as the porogen. The MIP was used as a selective sorbent in the molecularly imprinted solid-phase extraction (MIP-SPE) of the psychoactive phenylpropylamino alkaloids, norephedrine and its analogs, cathinone and cathine, from Khat (Catha edulis Vahl. Endl.) leaf extracts prior to HPLC-DAD analysis. The MIP was able to selectively extract the alkaloids from the aqueous extracts of Khat. Loading, washing and elution of the alkaloids bound to the MIP were evaluated under different conditions. The clean baseline of the Khat extract obtained after MIP-SPE confirmed that a selective and efficient sample clean-up was achieved. Good recoveries (90.0-107%) and precision (RSDs 2.3-3.2%) were obtained in the validation of the MIP-SPE-HPLC procedure. The content of the three alkaloids in Khat samples determined after treatment with MIP-SPE and a commercial Isolute C18 (EC) SPE cartridge were in good agreement. These findings indicate that MIP-SPE is a reliable method that can be used for sample pre-treatment for the determination of Khat alkaloids in plant extracts or similar matrices and could be applicable in pharmaceutical, forensic and biomedical laboratories. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26531857 TI - The safety of emergency medicine. AB - The patient safety movement has been active for over a decade, but the issue of patient safety in emergency care and the emergency department (ED) has only recently been brought into the forefront. The ED environment has traditionally been considered unsafe, but there is little data to support this assertion. This paper reviews the literature on patient safety and highlights the challenges associated with using the current evidence base to inform practice due to the variability in methods of measuring safety. Studies looking at safety in the ED report low rates for adverse events ranging from 3.6 to 32.6 events per 1000 attendances. The wide variation in reported rates on adverse events reflects the significant differences in methods of reporting and classifying safety incidents and harm between departments; standardisation in the ED context is urgently required to allow comparisons to be made between departments and to quantify the impact of specific interventions. We outline the key factors in emergency care which may hinder the provision of safer care and consider solutions which have evolved or been proposed to identify and mitigate against harm. Interventions such as team training, telephone follow-up, ED pharmacist interventions and rounding, all show some evidence of improving safety in the ED. We further highlight the need for a collaborative whole system approach as almost half of safety incidents in the ED are attributable to external factors, particularly those related to information flow, crowding, demand and boarding. PMID- 26531858 TI - Heimlich valve orientation error leading to radiographic tension pneumothorax: analysis of an error and a call for education, device redesign and regulatory action. AB - Medical errors are commonly multifactorial, with adverse clinical consequences often requiring the simultaneous failure of a series of protective layers, termed the Swiss Cheese model. Remedying and preventing future medical errors requires a series of steps, including detection, mitigation of patient harm, disclosure, reporting, root cause analysis, system modification, regulatory action, and engineering and manufacturing reforms. We describe this process applied to two cases of improper orientation of a Heimlich valve in a thoracostomy tube system, resulting in enlargement of an existing pneumothorax and the development of radiographic features of tension pneumothorax. We analyse elements contributing to the occurrence of the error and depict the implementation of reforms within our healthcare system and with regulatory authorities and the manufacturer. We identify features of the Heimlich valve promoting this error and suggest educational, design, and regulatory reforms for enhanced patient safety. PMID- 26531859 TI - Diagnostic errors related to acute abdominal pain in the emergency department. AB - OBJECTIVE: Diagnostic errors in the emergency department (ED) are harmful and costly. We reviewed a selected high-risk cohort of patients presenting to the ED with abdominal pain to evaluate for possible diagnostic errors and associated process breakdowns. DESIGN: We conducted a retrospective chart review of ED patients >18 years at an urban academic hospital. A computerised 'trigger' algorithm identified patients possibly at high risk for diagnostic errors to facilitate selective record reviews. The trigger determined patients to be at high risk because they: (1) presented to the ED with abdominal pain, and were discharged home and (2) had a return ED visit within 10 days that led to a hospitalisation. Diagnostic errors were defined as missed opportunities to make a correct or timely diagnosis based on the evidence available during the first ED visit, regardless of patient harm, and included errors that involved both ED and non-ED providers. Errors were determined by two independent record reviewers followed by team consensus in cases of disagreement. RESULTS: Diagnostic errors occurred in 35 of 100 high-risk cases. Over two-thirds had breakdowns involving the patient-provider encounter (most commonly history-taking or ordering additional tests) and/or follow-up and tracking of diagnostic information (most commonly follow-up of abnormal test results). The most frequently missed diagnoses were gallbladder pathology (n=10) and urinary infections (n=5). CONCLUSIONS: Diagnostic process breakdowns in ED patients with abdominal pain most commonly involved history-taking, ordering insufficient tests in the patient provider encounter and problems with follow-up of abnormal test results. PMID- 26531860 TI - Using voluntary reports from physicians to learn from diagnostic errors in emergency medicine. AB - OBJECTIVES: Diagnostic errors are common in the emergency department (ED), but few studies have comprehensively evaluated their types and origins. We analysed incidents reported by ED physicians to determine disease conditions, contributory factors and patient harm associated with ED-related diagnostic errors. METHODS: Between 1 March 2009 and 31 December 2013, ED physicians reported 509 incidents using a department-specific voluntary incident-reporting system that we implemented at two large academic hospital-affiliated EDs. For this study, we analysed 209 incidents related to diagnosis. A quality assurance team led by an ED physician champion reviewed each incident and interviewed physicians when necessary to confirm the presence/absence of diagnostic error and to determine the contributory factors. We generated descriptive statistics quantifying disease conditions involved, contributory factors and patient harm from errors. RESULTS: Among the 209 incidents, we identified 214 diagnostic errors associated with 65 unique diseases/conditions, including sepsis (9.6%), acute coronary syndrome (9.1%), fractures (8.6%) and vascular injuries (8.6%). Contributory factors included cognitive (n=317), system related (n=192) and non-remedial (n=106). Cognitive factors included faulty information verification (41.3%) and faulty information processing (30.6%) whereas system factors included high workload (34.4%) and inefficient ED processes (40.1%). Non-remediable factors included atypical presentation (31.3%) and the patients' inability to provide a history (31.3%). Most errors (75%) involved multiple factors. Major harm was associated with 34/209 (16.3%) of reported incidents. CONCLUSIONS: Most diagnostic errors in ED appeared to relate to common disease conditions. While sustaining diagnostic error reporting programmes might be challenging, our analysis reveals the potential value of such systems in identifying targets for improving patient safety in the ED. PMID- 26531861 TI - Can paediatric early warning scores (PEWS) be used to guide the need for hospital admission and predict significant illness in children presenting to the emergency department? An assessment of PEWS diagnostic accuracy using sensitivity and specificity. AB - OBJECTIVES: Designed to detect early deterioration of the hospitalised child, paediatric early warning scores (PEWS) validity in the emergency department (ED) is less validated. We aimed to evaluate sensitivity and specificity of two commonly used PEWS (Brighton and COAST) in predicting hospital admission and, for the first time, significant illness. METHODS: Retrospective analysis of PEWS data for paediatric ED attendances at St Mary's Hospital, London, UK, in November 2012. Patients with missing data were excluded. Diagnoses were grouped: medical and surgical. To classify diagnoses as significant, established guidelines were used and, where not available, common agreement between three acute paediatricians. RESULTS: 1921 patients were analysed. There were 211 admissions (11%). 1630 attendances were medical (86%) and 273 (14%) surgical. Brighton and COAST PEWS performed similarly. hospital admission: PEWS of >=3 was specific (93%) but poorly sensitive (32%). The area under the receiver operating curve (AUC) was low at 0.690. Significant illness: for medical illness, PEWS >=3 was highly specific (96%) but poorly sensitive (44%). The AUC was 0.754 and 0.755 for Brighton and COAST PEWS, respectively. Both scores performed poorly for predicting significant surgical illness (AUC 0.642). PEWS >=3 performed well in predicting significant respiratory illness: sensitivity 75%, specificity 91%. CONCLUSIONS: Both Brighton and COAST PEWS scores performed similarly. A score of >=3 has good specificity but poor sensitivity for predicting hospital admission and significant illness. Therefore, a high PEWS should be taken seriously but a low score is poor at ruling out the requirement for admission or serious underlying illness. PEWS was better at detecting significant medical illness compared with detecting the need for admission. PEWS performed poorly in detecting significant surgical illness. PEWS may be particularly useful in evaluating respiratory illness in a paediatric ED. PMID- 26531862 TI - Prevalence of emergency medical service utilisation in patients with out-of hospital cardiac arrest in Thailand. AB - BACKGROUND: Most patients with out-of-hospital cardiac arrest (OHCA) have grave outcomes. The efficacy of emergency medical services (EMS) may affect outcomes. However, no data exists in Thailand. OBJECTIVES: To ascertain the prevalence of EMS utilisation in patients with OHCA transferred to Siriraj Hospital and also to elucidate the rates of return of spontaneous circulation (ROSC), hospital admission and survival to hospital discharge. METHODS: This prospective cohort study was conducted in patients with OHCA at a university hospital in Bangkok, Thailand from May 2011 to February 2013. The data was gathered by interviewing bystanders. Data about the mode of transportation, reasons for EMS usage, response time, ROSC and 30-day mortality were collected. Patients with rigour mortis or livor mortis were excluded. The factors affecting ROSC and survival rate were determined by univariate analysis. RESULTS: One hundred and fifty-two patients were included. The prevalence of EMS usage was 14.5% (95% CI 9.3 to 21.0). The most common cause of non-usage of EMS was not knowing or forgetting an EMS number (49.2%). The proportion of bystanders having known an EMS number and using EMS was 34%. The ROSC and 30-day survival rates were 53.3% and 10.5%, respectively. Non-cardiac causes and witnessed arrests were associated with ROSC (p<0.05). CONCLUSIONS: The prevalence of EMS utilisation in OHCA at Siriraj Hospital was very low. This may affect the outcomes of patients with OHCA. Improving the EMS system by publicity to increase public awareness and providing life-support education nationwide may improve outcomes of patients with OHCA in Thailand. PMID- 26531863 TI - Developments in Surge Research Priorities: A Systematic Review of the Literature Following the Academic Emergency Medicine Consensus Conference, 2007-2015. AB - OBJECTIVES: In 2006, Academic Emergency Medicine (AEM) published a special issue summarizing the proceedings of the AEM consensus conference on the "Science of Surge." One major goal of the conference was to establish research priorities in the field of "disasters" surge. For this review, we wished to determine the progress toward the conference's identified research priorities: 1) defining criteria and methods for allocation of scarce resources, 2) identifying effective triage protocols, 3) determining decision-makers and means to evaluate response efficacy, 4) developing communication and information sharing strategies, and 5) identifying methods for evaluating workforce needs. METHODS: Specific criteria were developed in conjunction with library search experts. PubMed, Embase, Web of Science, Scopus, and the Cochrane Library databases were queried for peer reviewed articles from 2007 to 2015 addressing scientific advances related to the above five research priorities identified by AEM consensus conference. Abstracts and foreign language articles were excluded. Only articles with quantitative data on predefined outcomes were included; consensus panel recommendations on the above priorities were also included for the purposes of this review. Included study designs were randomized controlled trials, prospective, retrospective, qualitative (consensus panel), observational, cohort, case-control, or controlled before-and-after studies. Quality assessment was performed using a standardized tool for quantitative studies. RESULTS: Of the 2,484 unique articles identified by the search strategy, 313 articles appeared to be related to disaster surge. Following detailed text review, 50 articles with quantitative data and 11 concept papers (consensus conference recommendations) addressed at least one AEM consensus conference surge research priority. Outcomes included validation of the benchmark of 500 beds/million of population for disaster surge capacity, effectiveness of simulation- and Internet-based tools for forecasting of hospital and regional demand during disasters, effectiveness of reverse triage approaches, development of new disaster surge metrics, validation of mass critical care approaches (altered standards of care), use of telemedicine, and predictions of optimal hospital staffing levels for disaster surge events. Simulation tools appeared to provide some of the highest quality research. CONCLUSION: Disaster simulation studies have arguably revolutionized the study of disaster surge in the intervening years since the 2006 AEM Science of Surge conference, helping to validate some previously known disaster surge benchmarks and to generate new surge metrics. Use of reverse triage approaches and altered standards of care, as well as Internet-based tools such as Google Flu Trends, have also proven effective. However, there remains significant work to be done toward standardizing research methodologies and outcomes, as well as validating disaster surge metrics. PMID- 26531864 TI - Analysis of the TCP genes expressed in the inflorescence of the orchid Orchis italica. AB - TCP proteins are plant-specific transcription factors involved in many different processes. Because of their involvement in a large number of developmental pathways, their roles have been investigated in various plant species. However, there are almost no studies of this transcription factor family in orchids. Based on the available transcriptome of the inflorescence of the orchid Orchis italica, in the present study we identified 12 transcripts encoding TCP proteins. The phylogenetic analysis showed that they belong to different TCP classes (I and II) and groups (PCF, CIN and CYC/TB1), and that they display a number of conserved motifs when compared with the TCPs of Arabidopsis and Oryza. The presence of a specific cleavage site for the microRNA miRNA319, an important post transcriptional regulator of several TCP genes in other species, was demonstrated for one transcript of O. italica, and the analysis of the expression pattern of the TCP transcripts in different inflorescence organs and in leaf tissue suggests that some TCP transcripts of O. italica exert their role only in specific tissues, while others may play multiple roles in different tissues. In addition, the evolutionary analysis showed a general purifying selection acting on the coding region of these transcripts. PMID- 26531866 TI - Novel potential for the management of Alzheimer disease. AB - Pathologic characteristics of Alzheimer disease (AD) are beta-amyloid (Abeta) plaques, neurofibrillary tangles (NFT) and neurodegeneration. Currently, there is no cure for AD. Cilostazol, a selective inhibitor of type 3 phosphodiesterase, is likely to be a promising agent for AD. In the brain of the experimental animals it significantly reduced the Abeta amyloid plaques. Initial clinical reports on the effect of Cilostazol in AD patients are promising. In mice, stem cells favourably influence the pathogenetic process critical in AD, by reducing deposits of Abeta plaques. Clinical trials of the drug, called Betablock, are already underway in Britain. Successful management and resolution of AD in man will still require further intensive research (Fig. 4, Ref. 11). PMID- 26531867 TI - Reduced baroreflex sensitivity in patients with vasovagal syncope. AB - OBJECTIVES: The evidence is conflicting regarding the role of baroreflex in patients with vasovagal syncope. The aim of the study was to measure baroreflex sensitivity (BRS) and hemodynamic parameters during head up tilt test (HUT) with nitroglycerine stimulation. METHODS: Nitroglycerine stimulated HUT was performed in 51 patients with the history of recurrent syncope (mean age 46+/-19 years, 18 men, 23 women). Cardiac output (CO), stroke volume (SV), left-ventricular ejection time (LVET) and total peripheral resistance (TPR) were assessed during HUT by volume-clamp method using a beat-to-beat photopletysmography. Spontaneous BRS sensitivity was computed using a sequential BRS calculation. RESULTS: HUT was positive after nitroglycerine administration in 28 patients and negative in 23 patients. BRS was lower at the time of syncope in HUT positive group compared to end-test values in HUT negative group (0.54+/-0.27 vs 0.72+/-0.35, p=0.03). At the time of syncope, CO was significantly lower in HUT positive patients compared to HUT negative patients (2.6+/-1.4 vs 4.3+/-1.4 l/min, p<0.0001), similarly as SV (34.7+/-14.7 vs 49.2+/-19 ml, p=0.005). LVET was significantly higher in syncopal patients (282.27+/-26.2 vs 240.5+/-58.8 ms, p=0.002) and TPR did not differ between two groups. CONCLUSIONS: Reduced BRS may contribute to the development of the vasovagal syncope by inability to adequately counteract hypotension resulting from decreased cardiac output at the time of syncope (Tab. 3, Ref. 18). PMID- 26531865 TI - Short-term subcutaneous grass pollen immunotherapy under the umbrella of anti-IL 4: A randomized controlled trial. AB - BACKGROUND: Allergen immunotherapy is currently the only disease-modifying treatment available for allergic rhinitis and allergic asthma. OBJECTIVES: We sought to evaluate the induction of sustained tolerance to allergen when anti-IL 4 was combined with a suboptimal course of grass pollen subcutaneous immunotherapy (SCIT) using the allergen-induced skin late-phase response (LPR) and exploratory immune monitoring as surrogate markers of therapeutic response. METHODS: In this randomized, double-blind, 3-group parallel design trial, 37 participants with seasonal allergic rhinitis received suboptimal SCIT (30,000 standardized quality units) in combination with anti-IL-4 (VAK694) and suboptimal SCIT (30,000 standardized quality units) plus placebo antibody or double placebo (placebo SCIT and placebo antibody) restricted to 13 weeks before the grass pollen season. The primary end point was the size of the LPR at 12 months. Exploratory end points included measures of the immunomodulatory activity of treatment by using IL-4 and IL-10 FluoroSpot assays, flow cytometry of T cells, and measurement of IgE, IgG4, and facilitated antigen binding. RESULTS: Both active treatment arms led to a substantial and sustained reduction of the LPR with no additional suppression with addition of anti-IL-4. Treatment with anti-IL 4 and SCIT compared with SCIT alone led to a sustained reduction in allergen specific IL-4-producing cell counts (P < .01). Both active treatment arms led to induction of dual IL-4/IL-10-producing cells during the pollen season. CONCLUSION: The combination of anti-IL-4 with SCIT provided no additional benefit over SCIT alone in suppressing the allergen-induced skin LPR. A larger trial is needed to assess whether the observed ex vivo downregulation of TH2 responses might translate into clinical benefit. PMID- 26531868 TI - Elevated nucleosome level and oxidative stress in schizophrenia patients. AB - AIM: The aim of this study was to investigate the effect of oxidative stress on nucleosome levels and its relation with the clinical features in schizophrenia patients. MATERIAL AND METHOD: Thirty schizophrenia patients and 30 healthy controls were enrolled in this study. Patients were diagnosed with schizophrenia according to the 4th edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV). The control group consisted of 30 healthy subjects matched to the patients with regard to age and gender and who had no history of any psychiatric disorder. The severity of schizophrenia symptoms in the patients was evaluated using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Severity Scale (CGI-S). Physical and neurological examinations were performed in each of the patients and controls. RESULTS: Nucleosome, total oxidant levels and OSI values were higher in schizophrenia patients than in controls (p<0.05). There was no significant difference in the total antioxidant levels. There was a positive correlation between the nucleosome level and PANSS positive subscale (p=0.028, r=0.402). There was a positive correlation between TAS and age (p=0.025, r=0.289), PANSS total (p<0.001, r=0.604). There was a negative correlation between OSI and PANSS total (p=0.019, r=-0.427), PANSS positive subscale (p=0.043, r=-0.372). There was a negative correlation between TOS and PANS total (p=0.028, r=-0.402). CONCLUSION: In this study we found a correlation between nucleosome level and PANSS positive subscale. To our knowledge, this is the first study that evaluates oxidative stress and nucleosomes released from apoptotic cells together (Tab. 2, Ref. 50). PMID- 26531869 TI - Can a single lactate value predict adverse outcome in critically ill newborn? AB - OBJECTIVES: The aim of this study was to investigate the role of the lactic acidosis, as an early predictor of significant consequences and/or a fatal outcome in term neonates after a perinatal asphyxia. BACKGROUND: Severe perinatal asphyxia can generate multiple organ dysfunction and neonatal mortality. METHODS: In routine clinical practice, after an admission to the Intensive Care Unit, lactate concentration was determined in capillary blood samples during the first one to six hours after birth in 55 term newborns with the post-asphyxial hypoxic ischemic encephalopathy. The control group consisted of 36 healthy term neonates randomly selected in the maternity ward at the Gynecology and Obstetrics Clinic. RESULTS: Significantly higher concentrations of lactate (p 8.7 mmol/L with 80 % sensitivity and 82% specificity indicated the development of the hypoxic-ischemic encephalopathy stage II/III, while the lactate level>9.95 mmol/L was a predictor of death, with 75% sensitivity and 74.4% specificity. CONCLUSION: Determination of lactate concentrations in serum of term newborns associated with risk factors for the perinatal asphyxia is a useful tool in diagnosing metabolic disorders and ischemic damage, particularly severe clinical forms (Tab. 2, Fig. 3, Ref. 34). PMID- 26531870 TI - Increasing trend in syphilis. AB - OBJECTIVES: The aim of this study was to evaluate the epidemiological situation of syphilis in the Slovak Republic in the period of the past two decades. BACKGROUND: In last decade, the incidence of syphilis has decreased in European countries by 13%. However, several countries reported an increase in the trend of syphilis. METHODS: Cases of syphilis reported to the National Health Information Center in the Slovak Republic were statistically evaluated. RESULTS: In the first decade syphilis possessed an increase rate 262.5% and 127.6% in five subsequent year intervals, and then the rate fluctuated and showed minimal decrease in the last three years. The highest rate 7.3 per 100,000 population documented in 2009. The peak in the Bratislava region reached 36.36 in 2000. Epidemic was documented in marginalized group in East region. Early syphilis was the most frequent stage observed in both decades but late and no specified cases increased in the last period. The M/F rate was up to 1.7, the most frequently recorded age category was 15-24 years. CONCLUSION: These results indicate a requirement for developing a comprehensive control and educational program in the overall population, particularly in marginalized groups, and improving case management by health providers (Fig. 3, Ref. 20). PMID- 26531871 TI - Ultrastructural view of a promising anti TNF-alpha agent on hepatic ischaemia reperfusion injury. AB - BACKGROUND: Ischemia reperfusion causes injury to the liver cells during transplantation, trauma and emergency surgery. We investigated whether the anti TNF-alpha agent, etanercept, can reduce injury in an animal model of ischemia reperfusion owing to the fact that TNF-alpha plays a critical role in the process of inflammation. MATERIALS AND METHODS: Thirty rats were divided into three groups: sham (Group 1), control (Group 2), etanercept (5 mg/kg) treatment (Group 3). Ischemia-reperfusion model was carried out by clamping the hepatic pedicle for 45 min and then reperfusing the liver for 60 min. Etanercept (5 mg/kg) was injected intraperitoneally 5 min prior to reperfusion. At the end of the procedures, blood and liver tissue samples were obtained for biochemical and histopathological assessment. RESULTS: Control and treatment groups showed significant differences in hepatic function tests, plasma and tissue oxidative stress parameters. Samples in the control group histopathologically showed morphologic abnormalities specific to ischemia reperfusion. Histomorphologic findings in the treatment groups showed similar features as the sham group. CONCLUSIONS: Our evidence suggests that TNF-alpha plays a key role in liver ischemia reperfusion injury and etanercept may provide a novel therapeutic approach for patients undergoing liver surgical procedure (Tab. 3, Fig. 4, Ref. 22). PMID- 26531872 TI - TM4SF5-CTD-2354A18.1-miR-4697-3P may play a key role in the pathogenesis of gastric cancer. AB - AIMS: Our aim is to identify important lncRNAs and mRNAs which may play a key role in contributing to pathogenesis of gastric cancer. METHODS: Different LncRNAs and mRNAs are identified by microarray in gastric cancer tissue and corresponding normal tissues. The function and relationship of different LncRNAs and mRNAs is performed by GO analysis and Pathway analysis and made code-non-code network (CNC) by Pearson correlation coefficients (PCC). Then mRNA-miRNA relationship is predicted through mRNA-miRNA relationship software (http://www.targetscan.org). Lastly, mRNA-miRNA-LncRNA network is established for further research. RESULTS: The expression profiles of 3732 lncRNAs showed different expression (fold change (FC)>=2.0, p<0.05) in gastric cancer tissue and normal tissue and expression profiles of 3994 mRNAs also showed different expression (FC>=2.0, p<0.05) in gastric cancer and corresponding normal tissue. CONCLUSION: The expression of TM4SF5, CTD-2354A18.1 and miR-4697-3P is in balance at physiological conditions, however, the balance is disrupted by some situations, which may contribute to gastric cancer. GO analysis and Pathway analysis also showed TM4SF5 played an important role in proliferation, differentiation and apoptosis. Therefore, TM4SF5-miR-4697-3P- CTD-2354A18.1 may play a key role in the pathogenesis of gastric cancer (Tab. 2, Fig. 4, Ref. 30). PMID- 26531873 TI - Toxic effect of nano-zinc oxide. AB - INTRODUCTION: Nowadays, a lot of studies were carried out about side effects of nanoparticles especially nano-zinc oxide, but unfortunately, most of these studies have been conducted with high doses. MATERIAL AND METHODS: In the present study 36 male Wistar rats with approximate age of two months and weighing 300+/ 30 g were selected. After standard phases of preparation, injections were done intraperitoneally in chronic groups with zinc oxide nanoparticles (20 and 40 mg/kg) every other day and for acute groups with 200 and 400 mg/kg in a single dose. After the determined time for every group (21 days for chronic groups and 7 days for acute groups), blood samples were provided from rat hearts and also liver, kidney and testicular tissue were removed for histological studies. RESULTS: There were significant decreases in lymphocytes and platelet counts and significant increases in white blood cells count, hemoglobin and hematocrit in acute dose compared to control group and no difference in red blood cells count in all groups. A severe to slight damage was observed in liver tissue in all groups and tissue destruction was seen in kidney only in acute dose treated groups but no specific pathological effect in testis was observed (Fig. 8, Ref. 43). PMID- 26531874 TI - Imaging of deep venous thrombosis using radioactive-labeled tirofiban. AB - The development of radiolabeled small peptide or peptidomimetic ligands can bind platelets and their specific expressed receptor have been suggested as a new approach to detect the clot location and, more essentially, to determine the age and morphology of the evolving thrombus. This new approach is focused on the use of a series of radiolabeled platelet GPIIb/IIIa receptor antagonists. Tirofiban N (butylsulfonyl)- 4-O-(4-(4-piperidyl)-L-tyrosine is a non-peptide tyrosine derivate. The aim of the study was to introduce radioactive-labeled tirofiban as a specific imaging agent for acute DVT. The labeling was performed with technetium-99 in the presence of a stannous reducing agent. The labeled preparation showed fast blood clearance in a normal rat model (without induced thrombosis). More than 80% of the injected dose was eliminated from the circulation in the first hour after injection. Biodistribution and visualization of the labeled molecule was carried out using an experimental model of thrombosis in a male Wistar rat. Planar images were obtained 30 and 60 min after application of 2*10(6) imp/min 99m-technetium-tirofiban in the rat's tail vein. Sensitivity and specificity were determined using the ratio of 'left leg positive for DVT' to 'right leg negative for DVT'. The obtained ratio was 1.54 after 30 min and 5.04 after 60 min. These values were considered positive in the detection of acute DVT. The high DVT uptake shows that radiolabeled tirofiban in the introduced rat model can be a promising agent for imaging the deep venous thrombosis (Fig. 7, Ref. 25). PMID- 26531875 TI - Iloprost and vitamin C attenuates acute myocardial injury induced by suprarenal aortic ischemia-reperfusion in rabbits. AB - OBJECTIVE: The aim of this study was to evaluate antioxidant and cytoprotective effects of iloprost and Vitamin C in a distant organ after abdominal aorta ischemia-reperfusion injury. MATERIAL AND METHODS: Twenty-eight New Zealand rabbits weighing 2,400-2,800 g were used for this study. The rabbits were divided into four equal groups. These groups are control group, sham group, iloprost group, and iloprost+vitamin C group. Suprarenal aorta was occluded with a vascular clamp. Following 30 minutes of ischemia, the vascular clamp was removed. Rabbits in group 3 received 10 ng/kg/min iloprost and those in group 4 received 10 ng/kg/min iloprost and 10 mg/kg vitamin C. At the end of the reperfusion period, the rabbits were sacrificed by a high intraperitoneal dose of xylazine+ketamine injection. Myocardial tissue samples were taken for electron microscopic analysis. We evaluated SOD, MDA and catalase in myocardial tissue samples. RESULTS: Iloprost and iloprost+vitamin C groups significantly reduced the oxidative stress markers in tissue samples (p<0.05) and significantly decreased the myofibrillar injury and mitochondrial morphology changes in the myocardial tissue as shown with electron microscopy (p<0.05). Myocardial edema was significantly alleviated by iloprost and iloprost+vitamin C administration (p<0.05). CONCLUSIONS: This study clearly showed that myocardial injury and edema occurred after ischemia-reperfusion of abdominal aorta and that groups administered with iloprost and iloprost+vitamin C showed an attenuation of ischemia-reperfusion injury in distant organs (Tab. 3, Fig. 4, Ref. 30). PMID- 26531876 TI - Comparison of effects of classic LMA, cobraPLA and V-gel rabbit on QTc interval. AB - AIM: We aimed to compare the effects of three different supraglottic airway devices, the classic LMA, PLA, and V-gel, on hemodynamics and QTc in rabbits under general anesthesia. METHOD: The rabbits were divided into four groups: Group C (n=5) control group with no airway device used, Group L (n=5, classic LMA), Group P (n=5, CobraPLA) and Group V (n=5, V-gel-rabbit). Basal values of heart rate (HR), mean arterial pressure (MAP) and ECG for QTc interval were measured and the measurements were evaluated at 1, 5, 15, and 30 minutes after inserting the airway device RESULTS: The values of HR, MAP and QTc in Group V at minutes 1 and 5 were significantly different to those in Group L and Group P (p<0.05). DISCUSSION: The classic-LMA and cobraPLA cover a wide part of the perilaryngeal area with cuffs inflated to about 60 cmH2O of pressure resulting in mucosal compression. As V-gel rabbit does not have a cuff, it covers a smaller part of the laryngopharyngeal area, and thus does not cause mucosal compression, and the hemodynamic response is weaker. CONCLUSION: When comparing hemodynamic responses to other supraglottic airway devices, the response to V-gel rabbit is minimal and we consider that similar studies using the I-gel on humans are required (Fig. 5, Ref. 31). PMID- 26531877 TI - Characteristics of colonoscopic findings in the very elderly. AB - AIM: To determine the incidence and endoscopic types of colorectal lesions diagnosed with colonoscopy in elderly patients. METHODS: Consecutive Japanese patients who underwent colonic endoscopy between 1994 and 2007 (n = 5145; 2245 men and 2900 women, age 20-101 years) were examined retrospectively. Correlations between age, sex and number of lesions were analyzed. RESULTS: The incidence of advanced tumors was significantly correlated with increasing age in men (P = 0.02), and tumors were detected mainly in the sigmoid colon and rectum in both sexes. Right-sided colon cancer was significantly more common in women compared with men (P < 0.001). Polyps were detected throughout the colon, and their incidence was correlated significantly with increasing age in women (P = 0.01). Diverticula were frequently detected in the ascending and sigmoid colon in both sexes. Left-sided diverticula were significantly more common in women compared with men (P < 0.001). Lateral spreading tumors were detected mainly in the cecum in both sexes. Though the number of cases with angioectasia was small, angioectasia was slightly more common in the cecum and the ascending colon in women. CONCLUSIONS: In the present study, the incidence of advanced tumors correlated with increasing age in men, and right-sided cases were significantly more common in women than in men. The incidence of polyps correlated with increasing age in women. Left-sided diverticula were significantly more common in women than in men. Geriatr Gerontol Int 2016; 16: 1319-1323. PMID- 26531878 TI - The Concept of Peritraumatic Dissociation: A Qualitative Approach. AB - Peritraumatic dissociation has been considered an important feature for the development of post-traumatic stress disorders, but this concept remains widely unclear. To explore the peritraumatic experience, we interviewed eight victims of urban violence shortly after their traumatic events. The data collected were compared and analyzed according to the systematic set of procedures of Grounded Theory (GT). The alterations reported by participants were coded and categorized according to their perceptions of their inner and outer world, and the impressions of others involved, including the examiner's observations. The theoretical perspective for interpreting this study has parallels with Jaspers' psychopathology. Peritraumatic dissociation was conceived as a failure of synthesis among emerging stimuli from the internal and the external world, including the time-space flow structure, even when cognitive-perceptual tools remain intact. This synthesis qualifies the totality of the perceptual experience as coherent and meaningful to conscience, enabling possibilities for being/existing. PMID- 26531879 TI - Negotiating Collective and Individual Agency: A Qualitative Study of Young Women's Reproductive Health in Rural India. AB - The societal changes in India and the available variety of reproductive health services call for evidence to inform health systems how to satisfy young women's reproductive health needs. Inspired by Foucault's power idiom and Bandura's agency framework, we explore young women's opportunities to practice reproductive agency in the context of collective social expectations. We carried out in-depth interviews with 19 young women in rural Rajasthan. Our findings highlight how changes in notions of agency across generations enable young women's reproductive intentions and desires, and call for effective means of reproductive control. However, the taboo around sex without the intention to reproduce made contraceptive use unfeasible. Instead, abortions were the preferred method for reproductive control. In conclusion, safe abortion is key, along with the need to address the taboo around sex to enable use of "modern" contraception. This approach could prevent unintended pregnancies and expand young women's agency. PMID- 26531880 TI - Building Power Between Polarities: On the Space-in-Between. AB - In this article, I introduce the concept of the space-in-between. This space-in between is born of the realization that, between the expression of any two polarities (across dimensions such as emotion, thought, geography, and ideology), there exists a philosophical construct useful for framing thinking about practice, research, and managerial relationships in the health professions. Out of this construct emerge practical considerations useful for structuring the conduct of meaningful interpersonal and intercultural interactions. I describe how the idea of a space-in-between developed out of my medical practice, grew as a result of my experiences in international environments. and has found fulfillment in my ongoing work. I explore the application of a space-in-between in public health, medical anthropology, medical ethics, and global health. I review how, as a result of incorporating this space in their daily work, clinicians, educators, researchers, and managers can grow as leaders by sharing the presence that arises from the space-in-between them and the people in the communities they serve. PMID- 26531881 TI - Depression Narratives in Blogs: A Collaborative Quest for Coherence. AB - People with depression often suffer from severe social seclusion, and the lack of an agreed upon etiology for depression makes it difficult to satisfactorily narrate and "ritually control" it. Focusing on blogs by women with major depression, I delineate the ways in which bloggers publicly express and collaboratively reconstruct their depression narratives. Specifically, using thematic analysis, I argue that depression blogs uniquely bridge between the seclusion that characterizes depression and the exposure offered in blogs, and thus offer people a rare opportunity to publicly share very intimate depression narratives, form communal bonds with their readers, and collaboratively revise their narratives. Depression blogs are also shown to function as "narrative sandboxes"-protected spaces in which bloggers can temporarily and experimentally add or remove different sections from their illness narratives, assess the compatibility of different cultural frameworks, and interchangeably use various metaphors, in an attempt to satisfactorily explain depression. PMID- 26531882 TI - Vaginal Birth After Cesarean: Views of Women From Countries With High VBAC Rates. AB - Despite the consequences for women's health, a repeat cesarean section (CS) birth after a previous CS is common in Western countries. Vaginal Birth After Cesarean (VBAC) is recommended for most women, yet VBAC rates are decreasing and vary across maternity organizations and countries. We investigated women's views on factors of importance for improving the rate of VBAC in countries where VBAC rates are high. We interviewed 22 women who had experienced VBAC in Finland, the Netherlands, and Sweden. We used content analysis, which revealed five categories: receiving information from supportive clinicians, receiving professional support from a calm and confident midwife/obstetrician during childbirth, knowing the advantages of VBAC, letting go of the previous childbirth in preparation for the new birth, and viewing VBAC as the first alternative for all involved when no complications are present. These findings reflect not only women's needs but also sociocultural factors influencing their views on VBAC. PMID- 26531883 TI - Real-time monitoring of the penetration of amphiphilic acrylate copolymer in leather using a fluorescent copolymer as tracer. AB - A fluorescent tracer, poly (acrylic-co-stearyl acrylate-co-3-acryloyl fluorescein) [poly (AA-co-SA-co-Ac-Flu)], used for real-time monitoring the penetration of amphiphilic acrylate copolymer, poly (acrylic-co-stearyl acrylate) [poly (AA-co-SA)], in leather was synthesized by radical polymerization of acrylic, stearyl acrylate and fluorescent monomer, 3-acryloyl fluorescein (Ac Flu). The structure, molecular weight, introduced fluorescent group content and fluorescent characteristics of the fluorescent tracer and target copolymer, amphiphilic acrylate copolymer, were also characterized. The results show that the tracer presents the similar structural characteristics to the target and enough fluorescence intensity with 1.68 wt % of the fluorescent monomer introduced amount. The vertical section of the leather treated with the target copolymer mixing with 7% of the tracer exhibits evident fluorescence, and the change of fluorescence intensity along with the vertical section with treating time increasing can reflect the penetration depth of the target copolymer. The introduction of the fluorescent group in polymer structure through copolymerization with a limited amount of fluorescent monomer, Ac-Flu, is an effective way to make a tracer to monitor the penetration of the target in leather, which provides a new thought for the penetration research of syntans such as vinyl copolymer materials in leather manufacture. PMID- 26531884 TI - Self-screened high performance multi-layer MoS2 transistor formed by using a bottom graphene electrode. AB - We investigated the carrier transport in multi-layer MoS2 with consideration of the contact resistance (R(c)) and interlayer resistance (R(int)). A bottom graphene contact was suggested to overcome the degradation of I(d) modulation in a back gated multi-layer MoS2 field effect transistor (FET) due to the accumulated R(int) and increased R(c) with increasing thickness. As a result, non degraded drain current (I(d)) modulation with increasing flake thickness was achieved due to the non-cumulative R(int). Benefiting from the low R(c) induced by the negligible Schottky barrier at the graphene/MoS2 interface, the intrinsic carrier transport properties immune to R(c) were investigated in the multi-layer MoS2 FET. ~2 times the enhanced carrier mobility was attained from the self screened channel in the bottom graphene contacted device, compared to those with top metal contacts. PMID- 26531885 TI - Application of capacitively coupled contactless conductivity as an external detector for zone electrophoresis in poly(dimethylsiloxane) chips. AB - In this work, lab-made PDMS microfluidic chips were matched to a capacitively coupled contactless conductivity detector (C(4) D) having external in-plane electrodes (eDAQ, Australia). The advantages of this type of C(4) D are the choice to reversibly place or remove the microchip onto/from the detector and to freely variate the position of the detection (separation length) on the microchip. The thickness of the bottom layer of the PDMS chip was optimized to achieve sensitive detection during the electrophoretic separation. PDMS chips with 100 MUm bottom layer used with the C(4) D platform were tested by CZE of a mixture of seven anions and different types of real samples. Using split-flow pressure sample injection and effective length of 6.5 cm, the numbers of theoretical plates were in the range of 4000-6000 (63,000-93,000/m) and the LODs amounted to 3.66-14.7 MUmol/L (0.13-2.26 MUg/mL) for the studied anions. PMID- 26531887 TI - Optical fiber tip templating using direct focused ion beam milling. AB - We report on a method for integrating sub-wavelength resonant structures on top of optical fiber tip. Our fabrication technique is based on direct milling of the glass on the fiber facet by means of focused ion beam. The patterned fiber tip acts as a structured template for successive depositions of any responsive or functional overlay. The proposed method is validated by depositing on the patterned fiber a high refractive index material layer, to obtain a 'double layer' photonic crystal slab supporting guided resonances, appearing as peaks in the reflection spectrum. Morphological and optical characterizations are performed to investigate the effects of the fabrication process. Our results show how undesired effects, intrinsic to the fabrication procedure should be taken into account in order to guarantee a successful development of the device. Moreover, to demonstrate the flexibility of our approach and the possibility to engineering the resonances, a thin layer of gold is also deposited on the fiber tip, giving rise to a hybrid photonic-plasmonic structure with a complementary spectral response and different optical field distribution at the resonant wavelengths. Overall, this work represents a significant step forward the consolidation of Lab-on-Fiber Technology. PMID- 26531886 TI - Label-Free Isolation and mRNA Detection of Circulating Tumor Cells from Patients with Metastatic Lung Cancer for Disease Diagnosis and Monitoring Therapeutic Efficacy. AB - We develop an inertial-based microfluidic cell sorter combined with an integrated membrane filter, allowing for size-based, label-free, and high-efficiency separation and enrichment of circulating tumor cells (CTCs) in whole blood. The cell sorter is composed of a double spiral microchannel that hydrodynamically focuses and separates large CTCs from small blood cells. The focused CTCs with the equilibrium position around the midline of microchannel are further captured and enriched by a membrane filter (pore size of 8 MUm) attached at the middle outlet. This integrated microfluidic device can process 1 mL of whole blood containing spiked tumor cells (A549, human lung adenocarcinoma epithelial cell line) within 15 min, with the capture efficiency of 74.4% at the concentration as low as tens of A549 cells per mL of whole blood. This microfluidic cell sorter is further adopted for isolation of CTCs from peripheral blood samples of patients with metastatic lung cancer. The immunostaining and CK-19 mRNA detection are applied for identification of captured CTCs, showing that our method can detect 90% of metastatic lung cancer patients before therapy, whereas the commercially used system can only detect 40% of the same patients. We also use the expression of CK-19 mRNA from captured CTCs as an indicator for monitoring the therapeutic efficiency, which correlates well with X-ray computed tomography (CT) assessment of the disease. PMID- 26531888 TI - Identification of the metastasis potential and its associated genes in melanoma multinucleated giant cells using the PHA-ECM830 fusion method. AB - Malignant melanoma causes skin cancer with high rates of mortality. Multinucleated giant cells (MGCs) are frequently observed in tumor pathological analysis, especially in metastasized sites, and are related to poor prognosis. However, the role of MGCs in melanoma development and metastasis is currently unknown. In the present study, we obtained melanoma MGCs (M-MGCs) in vitro using the modified phytohaemagglutinin (PHA)-ECM830 electronic fusion method (fusion efficiency was significantly enhanced by adding PHA to agglutinate cells before electronic fusion). We found that M-MGCs showed decreased proliferation potential but increased pulmonary metastasis ability relative to the parental B16-F10 cells. Microarray and bioinformatics analysis showed that beta-tubulin gene group was significantly upregulated in MMGCs. A member of this gene group, TUBB2B, exhibited significantly enhanced expression, indicating that it may play an important role in melanoma metastasis. Our results provide novel insights into the properties of melanoma and they could contribute towards the design of new strategies for rapid diagnosis and treatment of this cancer. PMID- 26531889 TI - Ectopic expression of c-myc fails to overcome downregulation of telomerase activity induced by herbimycin A, but ectopic hTERT expression overcomes it. AB - Correction to: Leukemia (2000); 14: 1260-1265; doi: 10.1038/sj.leu.2401828. Since the publication of the above article the authors have identified an error in Figure 1. Figure 1 shows the modulation of telomerase activity by herbimycin A in K562 cells: (a) cell cycle and (b) telomerase activity, mRNA expressions of hTERT, hTERC, TEP-1, c-myc, cyclin D1 and b-actin, and c-Myc protein. The authors however wish to inform the readers that Figure 1b incorrectly shows hTERT mRNA, which is the result of herbimycin A treatment of cyclin-D1-transfected K562 cells (Figure 3b, hTERT mRNA). While preparing Figure 1, the authors mistakenly submitted a figure that used the incorrect photo data following confusion regarding file names. The correct figure can be found below: The authors wish to apologise for any inconvenience caused and confirm that the conclusions drawn from this research are not affected by this error. PMID- 26531890 TI - [This year 2015]. PMID- 26531891 TI - Catalpol preserves neural function and attenuates the pathology of Alzheimer's disease in mice. AB - Alzheimer's disease (AD) is the most common form of dementia and there currently are no effective treatment strategies available. Catalpol is an iridoid glucoside, and large quantities can be isolated from the genus Rehmannia (Orobanchaceae). The present study assessed whether catalpol had any protective effects against Alzheimer's disease using a murine model. Reactive oxygen species (ROS)-associated enzymes as well as soluble Abeta40 and Abeta42 were detected using kits. Thioflavin-S staining was performed to detect senile plaques and reverse-transcription quantitative polymerase chain reaction was used to assess iroquois homeobox protein 3 (IRX3) and obesity-associated genes, while western blot analysis was used for beta-secretase 1 (BACE1), insulin-degrading enzyme (IDE) and neprilysin (NEP) detection. The Morris water maze was used to detect the learning ability and spatial memory. The results revealed that catalpol was able to reduce the oxidative stress in the cerebral cortex by regulating the activities and concentration of ROS-associated enzymes superoxide dismutase, glutathione peroxidase and catalase, however not malondialdehyde. Catalpol was also identified to be able to reduce the levels of soluble Abeta40 and Abeta42 in the cerebral cortex and thus inhibit the formation of senile plaques. These effects were observed to be regulated by IDE, however not by BACE1 or NEP. It is suggested that catalpol is not capable of directly regulating the expression of IRX3 and obesity-associated genes. Subsequent to the treatment with catalpol, impairments in learning and memory were also observed to be relieved using the Morris water maze test. The results of the present study indicate that catalpol may be a potential drug for the treatment of neurodegenerative diseases such as AD. PMID- 26531892 TI - Treatment Access Barriers and Disparities Among Individuals with Co-Occurring Mental Health and Substance Use Disorders: An Integrative Literature Review. AB - The purpose of this integrative review is to examine and synthesize extant literature pertaining to barriers to substance abuse and mental health treatment for persons with co-occurring substance use and mental health disorders (COD). Electronic searches were conducted using ten scholarly databases. Thirty-six articles met inclusion criteria and were examined for this review. Narrative review of these articles resulted in the identification of two primary barriers to treatment access for individuals with COD: personal characteristics barriers and structural barriers. Clinical implications and directions for future research are discussed. In particular, additional studies on marginalized sub-populations are needed, specifically those that examine barriers to treatment access among older, non-White, non-heterosexual populations. PMID- 26531893 TI - The Adolescent Substance Abuse Goal Commitment (ASAGC) Questionnaire: An Examination of Clinical Utility and Psychometric Properties. AB - Commitment to change is an innovative potential mediator or mechanism of behavior change that has not been examined in adolescents with substance use disorders (SUD). The Adolescent Substance Abuse Goal Commitment (ASAGC) questionnaire is a 16-item measure developed to assess an individual's commitment to his/her stated treatment goal. The objectives of this study are to explore the research and clinical utility of the commitment construct as measured by the ASAGC. During sessions 3 and 9 of a 10-week SUD treatment, therapists completed the ASAGC for 170 13-18 year-old adolescents. An exploratory factor analysis was conducted on the ATAGC items. Concurrent validity with related constructs, self-efficacy and motivation for change, was examined as well. At both sessions, the factor analysis resulted in two scales--Commitment to Recovery and Commitment to Harm Reduction. The ASAGC scales were found to demonstrate a high level of internal consistency (alpha coefficients ranged from .92 to .96 over time). In contrast to the Commitment to Harm Reduction scale, the Commitment to Recovery scale consistently correlated with scales from the Situational Confidence Questionnaire assessing self-efficacy, evidencing concurrent validity. Similarly, the Commitment to Recovery scale was related to the Problem Recognition Questionnaire, providing further evidence of the validity of the ASAGC. The ASAGC is a reliable and valid clinical research instrument for the assessment of adolescents' commitment to their substance abuse treatment goal. Clinical researchers may take advantage of the clinical utility of the ASAGC including its ability to differentiate between commitment to abstinence versus commitment to harm reduction. PMID- 26531894 TI - Medications That Older Adults in Hospice Care in the United States Take, 2007. AB - OBJECTIVES: To describe medications that older adults in hospice with cancer, dementia, debility, heart disease, and lung disease take during the last week of life. DESIGN: Retrospective cross-sectional study. SETTING: Nationally representative sample of 695 U.S. hospices in the 2007 National Home and Hospice Care Survey. PARTICIPANTS: Individuals aged 65 and older with a primary diagnosis of cancer (49%), dementia (12%), debility (14%), heart disease (16%), or lung disease (10%) who received end-of-life care during their last week of life (N = 2,623). MEASUREMENTS: Medication data were obtained from hospice staff, who were asked, "What are the names of all the medications and drugs the patient was taking 7 days prior to and on the day of his or her death while in hospice? Please include any standing, routine, or PRN medications." RESULTS: The unweighted survey response rate was 71%. The average number of medications taken was 10.2. The most common therapeutic classes were analgesics (98%); antiemetic and antivertigo medications (78%); anxiolytics, sedatives, and hypnotics (76%); anticonvulsants (71%); and laxatives (53%). Approximately one-quarter of the individuals took proton pump inhibitors, anticoagulants, and antidepressants, and fewer than 20% took antacids and antibiotics. A smaller percentage of individuals with dementia and debility than of those with cancer took opioid analgesics. Individuals with heart disease were more likely than individuals in the other clinical cohorts to take diuretics, and those with lung disease were more likely than those in the other clinical cohorts to take bronchodilators. A higher percentage of individuals with dementia and with debility than with cancer and lung disease took antidepressants. CONCLUSION: People continue to receive disease focused therapies at the end of life rather than therapies exclusively for palliation of symptoms, suggesting that treatments may vary according to the person's primary diagnosis. PMID- 26531895 TI - Being Sherlock Holmes: Can we sense empathy from a brief sample of behaviour? AB - Mentalizing (otherwise known as 'theory of mind') involves a special process that is adapted for predicting and explaining the behaviour of others (targets) based on inferences about targets' beliefs and character. This research investigated how well participants made inferences about an especially apposite aspect of character, empathy. Participants were invited to make inferences of self-rated empathy after watching or listening to an unfamiliar target for a few seconds telling a scripted joke (or answering questions about him/herself or reading aloud a paragraph of promotional material). Across three studies, participants were good at identifying targets with low and high self-rated empathy but not good at identifying those who are average. Such inferences, especially of high self-rated empathy, seemed to be based mainly on clues in the target's behaviour, presented either in a video, a still photograph or in an audio track. However, participants were not as effective in guessing which targets had low or average self-rated empathy from a still photograph showing a neutral pose or from an audio track. We conclude with discussion of the scope and the adaptive value of this inferential ability. PMID- 26531898 TI - Analysis of the Relationship Between Patient-Reported Outcomes (Pros) and Clinical Outcomes In Metastatic Castration-Resistant Prostate Cancer (Mcrpc) Patients without Prior Chemotherapy. PMID- 26531896 TI - IFNL3 mRNA structure is remodeled by a functional non-coding polymorphism associated with hepatitis C virus clearance. AB - Polymorphisms near the interferon lambda 3 (IFNL3) gene strongly predict clearance of hepatitis C virus (HCV) infection. We analyzed a variant (rs4803217 G/T) located within the IFNL3 mRNA 3' untranslated region (UTR); the G allele (protective allele) is associated with elevated therapeutic HCV clearance. We show that the IFNL3 3' UTR represses mRNA translation and the rs4803217 allele modulates the extent of translational regulation. We analyzed the structures of IFNL3 variant mRNAs at nucleotide resolution by SHAPE-MaP. The rs4803217 G allele mRNA forms well-defined 3' UTR structure while the T allele mRNA is more dynamic. The observed differences between alleles are among the largest possible RNA structural alterations that can be induced by a single nucleotide change and transform the UTR from a single well-defined conformation to one with multiple dynamic interconverting structures. These data illustrate that non-coding genetic variants can have significant functional effects by impacting RNA structure. PMID- 26531897 TI - Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus. AB - The thymus has spatially distinct microenvironments, the cortex and the medulla, where the developing T-cells are selected to mature or die through the interaction with thymic stromal cells. To establish the immunological self in the thymus, medullary thymic epithelial cells (mTECs) express diverse sets of tissue specific self-antigens (TSAs). This ectopic expression of TSAs largely depends on the transcriptional regulator Aire, yet the mechanism controlling Aire expression itself remains unknown. Here, we show that Jmjd6, a dioxygenase that catalyses lysyl hydroxylation of splicing regulatory proteins, is critical for Aire expression. Although Jmjd6 deficiency does not affect abundance of Aire transcript, the intron 2 of Aire gene is not effectively spliced out in the absence of Jmjd6, resulting in marked reduction of mature Aire protein in mTECs and spontaneous development of multi-organ autoimmunity in mice. These results highlight the importance of intronic regulation in controlling Aire protein expression. PMID- 26531899 TI - Inflation, Inflexibility and Irrelevance - the Need for Inflation to be Accounted for in Icer Thresholds. PMID- 26531900 TI - Do evidence review groups bias nice decisions? PMID- 26531901 TI - The cancer drugs fund in england - undermining nice or efficient and good value for money? PMID- 26531902 TI - The german nice or the german nasty? an analysis of iqwig decisions and requirements for an 'added benefit'. PMID- 26531903 TI - The Cost of Molecular Diagnostic Testing in Oncology - a Workflow Analysis. PMID- 26531904 TI - Medical devices: have health technology assessment agencies started to focus more on them? PMID- 26531905 TI - Predictors of Positive Decision Outcomes by the Cancer Drugs Fund. PMID- 26531906 TI - The Burden of Cancer in Emerging Economies: Productivity Loss as an Alternative Perspective. PMID- 26531907 TI - The Esmo Magnitude of Clinical Benefit Scale for Novel Cancer Medicines - Correspondence with Prioritization Decisions In Updating the Israeli National List of Health Services. PMID- 26531908 TI - Prices of Pharmaceuticals Under a Generic Price Linkage System And a Reference Price System: Comparison of Austria and Finland. PMID- 26531909 TI - Decision Drivers in Health Technology Assessment in Hepatitis C. PMID- 26531910 TI - Predicting Post-Amnog Rebate Outcomes for Oncology Drugs. PMID- 26531911 TI - The Economic Impact of The use of Implantable Cardioverter Defibrillator In Primary Prevention. PMID- 26531912 TI - Cost-Effectiveness of 18f-Fdg Pet/Ct for Screening Distant Metastasis in Stage Ii/Iii Breast Cancer Patients of the UK, the United States and the Netherlands. PMID- 26531913 TI - Determinants of Orphan Drug Prices in France: Regression Analysis. PMID- 26531914 TI - Public Health Impact and cost-Effectiveness of Malaria routine Vaccination in Infants. PMID- 26531915 TI - Propensity Score Matching Does not Always Remove Confounding within an Economic Evaluation Based on a Non-Randomized Study. PMID- 26531916 TI - Partitioned Survival Versus State Transition Modeling in Oncology: a Case Study with Nivolumab in Advanced Melanoma. PMID- 26531917 TI - Avoiding Overestimation In Annualization of Event Risk from Risk Functions for use in Economic Modeling. PMID- 26531918 TI - Adjusting For Treatment Switching in Rcts - Identifying, Analysing and Justifying Appropriate Methods: a Case Study in Metastatic Melanoma. PMID- 26531919 TI - Cost of Paediatric Vaccine Administration in the United Kingdom (UK): a Time and Motion (T&M) Study. PMID- 26531920 TI - Basal Insulin Regimens: Systematic Review, Network Meta-Analysis, and Cost - Utility Analysis for the National Institute For Health and Care Excellence (Nice) Clinical Guideline on Type 1 Diabetes Mellitus in Adults. PMID- 26531921 TI - A Cost-Effectiveness Analysis of Novel Oral Anticoagulants for Primary Prevention of Venous Thromboembolic Disease. PMID- 26531922 TI - Economic Evaluation of Children Vaccination from 2 To 18 Years of age with the Live attenuated Influenza Vaccine ComparED with the Existing Vaccines in the Portuguese Setting. PMID- 26531923 TI - Cost-Effectiveness analysis of Quadrivalent Versus trivalent Influenza Vaccination In Germany - Linking a Dynamic Transmission Model with Health and Economic Outcomes. PMID- 26531924 TI - The Cost and Length of Stay of Hospital Emergency Department Visits for Chronic Heart Failure Patients in Canada. PMID- 26531925 TI - Survival and Rehospitalization After a First Hospitalization for Heart Failure: a Nationwide Population-Based Cohort Study using the French Egb Database. PMID- 26531926 TI - The Magnitude of Increased Cardiovascular (Cv) Risk Associated with Familial Hypercholesterolemia (Fh) for use in Economic Analyses. PMID- 26531927 TI - Assessing the Cost-Effectiveness of using Aclidinium Bromide 400 uG /Formoterol Fumarate Dihydrate 12 uG Compared to Aclidinium Bromide 400 uG in the Management of Moderate to Severe Chronic Obstructive Pulmonary Disease. PMID- 26531928 TI - A Cost Effectiveness Analysis of Nivolumab Compared to Ipilimumab for the Treatment of Braf Wild-Type Advanced Melanoma in Australia. PMID- 26531929 TI - A Review of Patient Registries in Heart Failure Across European Union-5 Countries. PMID- 26531930 TI - Access to New Therapies in Romania Through the Scorecard HTA System. PMID- 26531931 TI - Orphan Designations and Approvals in the EU, United States and Japan. PMID- 26531932 TI - The Economic Impact of an Hypothetical Rx-To-otc Switch in Spain. PMID- 26531933 TI - Access to Innovative Drugs in Patients with Metastatic Lung Cancer in French Public Hospitals (the Territoire Study). PMID- 26531934 TI - How ready are european payers for ema adaptive pathways? PMID- 26531935 TI - Understanding Key Drivers of Successful Hta Submission - Developing a Model. PMID- 26531936 TI - Regional Versus Centralized Hta: Implications for the Assessment of Cancer Drugs. PMID- 26531937 TI - Equivalence of Paper and Electronic Administration of Patient Reported Outcomes: a Comparison in Psoriatic Arthritis. PMID- 26531938 TI - Quantifying the Impact of Health-Related Quality of life (Hrql) on Medical Expenditures in Asthma, arthritis, Depression, Diabetes, and Migraine. PMID- 26531939 TI - Impact of Hta - an Irish Case Study. PMID- 26531940 TI - Network Meta-Analysis of Survival Data Using Fractional Polynomials - an Example with First Line Metastatic Renal cell cancer Treatments. PMID- 26531941 TI - The Relationship Between Glucose-Lowering Medications, Adherence, and Outcomes in Patients with Type 2 Diabetes. PMID- 26531942 TI - Comparison of Timed Automata with Discrete Event Simulation for Modeling Personalized Treatment Decisions: the Case of Metastatic Castration Resistant Prostate Cancer. PMID- 26531943 TI - Simulation optimisation of Treatment Sequences for Rheumatoid arthritis. PMID- 26531944 TI - Network Meta-Analysis of Biological Response Modifiers in Rheumatoid arthritis Including real World Evidence at Multiple time Points. PMID- 26531945 TI - condition Specific Utilities: Impact on Icer in a Markov Model for Multiple Sclerosis. PMID- 26531946 TI - Clinical And Economic Impact Of The Implementation Of Hpv 16/18 Genotyping Test For Cervical Cancer Screening In Mexican Healthcare System. PMID- 26531947 TI - Vivascope((c)) For Diagnosing Melanoma: A Systematic Review. PMID- 26531948 TI - A Cost Analysis Of Open Spina Bifida Detection In The First-Trimester. PMID- 26531949 TI - Cytogenetics And Dopamine Receptor (Drd2) Gene Polymorphism In Schizophrenia Patients. PMID- 26531950 TI - Systematic Review Of Thermal Massage Therapy For The Treatment Of Dry Eye Syndrome. PMID- 26531951 TI - Published Diagnostic Discordance Of Lymphoma And Potential For Impact On Patient Care. PMID- 26531952 TI - The Consequences Of Replacing The Fleischner Guidelines By A Software-Based Volume Doubling Time Technique: An Early-Stage Research. PMID- 26531953 TI - Assessing The Clinical And Economic Impact Of An Automated, On-Demand Immunoassay For The Diagnosis Of Heparin Induced Thrombocytopenia. PMID- 26531954 TI - Analysis Of Breast Cancer Patients' Clinical Pathway Being Diagnosed By Mammography Breast Screening Program. PMID- 26531955 TI - Health Outcomes Evaluation Of New Technologies In Clinical Practice: The Case Of The Minimally Invasive Insertable Cardiac Monitor. PMID- 26531956 TI - Exhaled Nitric Oxide For The Diagnosis Of Asthma In Adults And Children: A Systematic Review. PMID- 26531957 TI - Measuring Post-Partum Hemorrhage In Low-Resource Settings: The Diagnostic Validity Of Weighted Blood Loss Versus Quantitative Changes In Hemoglobin. PMID- 26531958 TI - The Safety And Tolerability Of The Fentanyl Iontophoretic Transdermal System Compared To Other Post-Operative Pain Modalities: A Systematic Review And Bayesian Network Meta-Analysis (Nma). PMID- 26531959 TI - Thrombectomy in the treatment of acute ischemic stroke: what effects do methodological differences in trial design have on comparability of outcomes? PMID- 26531960 TI - Network Meta-Analysis On Prevention Of Stroke For Patent Foramen Ovale Closure. PMID- 26531961 TI - Telemedicine Consultation In The Differential Diagnosis Simple Contact Dermatitis Due To Incontinence And Pressure Sores In Immobilized Patients With Urinary Incontinence - Clinical And Economic Analysis. PMID- 26531962 TI - Comparison Of T-Piece Resuscitator With Other Flow - Inflating Bags For Providing Positive Pressure Ventilation During Neonatal Resuscitation: A Systematic Review. PMID- 26531963 TI - The Effectiveness Of Wide Field Fluorescein Angiography : Systematic Reviews. PMID- 26531964 TI - Colonrectal Cancer Evaluation Of Italian Screening And Mortality. PMID- 26531965 TI - Risk Equation For Alcohol Related Consequences. PMID- 26531966 TI - To Access Independent Risk Cause Of Sudden Cardiac Death In Hemodialysis Patients. PMID- 26531967 TI - Innovative Methods For Early Diagnostic Of Cancer. PMID- 26531968 TI - A Budget Impact Analysis To Estimate The Economic Consequences Of An Increase Of Medication Compliance Related To A Potential Improvement Of The Inhalation Technique With Spiromax(r) Compared With Turbuhaler(r) In Moderate To Severe Asthmatic Patients In Spain. PMID- 26531969 TI - Budget Impact Analysis Of Phased Radiofrequency (Rf) Catheter Ablation System In The Treatment Of Atrial Fibrillation (Af) In Turkey. PMID- 26531970 TI - Estimating The Economic Consequences Of An Increased Medication Compliance Due To A Potential Improvement Of The Inhaler Technique With Spiromax(r) Compared With Turbuhaler(r) In Moderate To Severe Patients With Copd In Spain. PMID- 26531971 TI - Budget Impact Analysis Of N-Terminal Pro-B-Type Natriuretic Peptide Testing For The Diagnosis And Prognosis Of Heart Failure In Greece. PMID- 26531972 TI - Identifying The Optimal Use Of Ctcs In The Early Staging Phase Of Breast Cancer. PMID- 26531973 TI - Introduction Of An Organizational Model Of Telemedicine In Management Of Oral Anticoagulant Therapy: A Budget Impact Analysis From Italian Payer Perspective. PMID- 26531974 TI - Budget Impact Analysis Of High-Risk Hpv Dna (Hrhpv) Test With 16/18 Genotyping As A Primary Screening Method For Cervical Cancer In Greece. PMID- 26531975 TI - Endovascular Interventions For Treatment Of Femoropopliteal Peripheral Artery Disease: Updated Budget Impact Analysis For Germany Based On Latest Clincal Evidence. PMID- 26531976 TI - Potential For Cost Savings Associated With A Novel Ibs Blood Panel For Diagnosing Diarrhea Predominant Irritable Bowel Syndrome (Ibs-D): Italian Perspective. PMID- 26531977 TI - Clinical And Budget Impact Of Using A Molecular Test To Detect Kras Mutations In Metastatic Colorectal Cancer Patients In Denmark. PMID- 26531978 TI - The Potential For Improved Inhalation Technique With Duoresp(r) Spiromax(r) (Budesonide + Formoterol Fumarate Dihydrate) Compared With Commonly Prescribed Dry Powder Inhalers For The Management Of Asthma And Chronic Obstructive Pulmonary Disease In Spain: Estimated Impact On Number And Cost Of Unscheduled Healthcare Events. PMID- 26531979 TI - Impact Of A Novel Ibs Diagnostic Blood Panel For Mexico: Cost Implications To The Mexican Private Practice For Diarrhea Predominant Irritable Bowel Syndrome (Ibs D). PMID- 26531980 TI - Cost-Minimization For A Novel Ibs Diagnostic Blood Panel Versus Standard Exclusionary Diagnostic Testing For Diarrhea Predominant Irritable Bowel Syndrome: A United States Perspective. PMID- 26531981 TI - A Novel Ibs Diagnostic Blood Panel Can Enhance A Positive Diagnostic Strategy Versus A Strategy Of Exclusion For Patients With Diarrhea Predominant Irritable Bowel Syndrome (Ibs-D): Cost Implications For Denmark. PMID- 26531982 TI - Inclusion Of A Novel Ibs Blood Panel For Diagnosing Diarrhea Predominant Irritable Bowel Syndrome (Ibs-D): A Uk Perspective. PMID- 26531983 TI - The Cost Of Nutrition Alternatives For Premature Infants In The Neonatal Intensive Care Unit In Russia. PMID- 26531984 TI - Cost Consequences Of Single-Use And Re-Use Of Urinary Catheters Among Patients Performing Daily Intermittent Catheterization. PMID- 26531985 TI - Costs Analysis Of Pcr Unyverotm I60-Iti Technique For Detecting Microorganisms In Patients With Suspected Chronic Infection At Musculoskeletal Implants. PMID- 26531986 TI - Cost Saving Associated With Glucose Meter Accuraccy In Spain. PMID- 26531987 TI - One-Year Cost-Comparison Analysis Of AbsorbTM Everolimus Eluting Bioresorbable Vascular Scaffold And XienceTM Everolimus Eluting Stent: Based On Findings From Absorb Ii. PMID- 26531988 TI - Do Not Overlook Your Country-Specific Characteristics: The Case Of Baroreflex Activation Therapy (Bat) For The Treatment Of Resistant Hypertension. PMID- 26531989 TI - Estimating the additional indirect cost savings of a procalciton-algorithm in adult icu patients with sepsis, as achieved through reduction in antibiotic resistance and c. Difficile infections. PMID- 26531990 TI - Costs And Cost-Effectiveness Of Non-Invasive Prenatal Diagnosis (Nipt) For Detection Of Trisomy 21 In Sweden. PMID- 26531991 TI - Economic Benefits Of Endometrial Radiofrequency Ablation Compared With Other Endometrial Ablation Techniques In Women With Menorrhagia: A Retrospective Analysis With German Health Claims Data. PMID- 26531992 TI - Cost-Effectiveness Of Deep Brain Stimulation (Dbs) In The Management Of Advanced Parkinson's Disease: A Swedish Payer Perspective. PMID- 26531993 TI - Self-Reported Medication Costs In Patients Receiving Sacral Neuromodulation For Overactive Bladder. PMID- 26531994 TI - A Next-Generation Framework: Deciding On The Role Of Costs In The Clinical Use Of Targeted Gene Panels, Exome And Genome Sequencing. PMID- 26531995 TI - Cost Of Genome Analysis: The Sanger Sequencing Method. PMID- 26531996 TI - The Economics Of Critical Care Diagnostics: The Case Of Procalcitonin-Guided Care In Treatment Of Acute Respiratory Infection In The U.S. PMID- 26531997 TI - The Economic Burden Of Cardiac Complications Of Percutaneous Coronary Intervention In England: An Analysis Of Hospital Episode Statistics. PMID- 26531998 TI - Recurrent Laryngeal Carcinoma Pet Study (Relaps): Cost Analysis Of 18f-Fdg Pet In Patients With Suspected Recurrent Laryngeal Cancer Previously Treated With Radiotherapy. PMID- 26531999 TI - Clinical-Economic Modeling Analysis Of Human Papillomavirus (Hpv) Co-Testing With Genotyping Versus Primary Hpv Testing For Cervical Cancer Screening. PMID- 26532000 TI - Analysis Of Costs For Diagnosis And Differential Diagnosis Of Patients With Possible Temporomandibular Disorders In Ukrane. PMID- 26532001 TI - Finding The Optimal Screening Program For Unknown Atrial Fibrillation Using Simulation Models. PMID- 26532002 TI - Higher Accuracy Of Blood Glucose Monitoring Systems In Type 2 Insulin Treated Diabetic Patients In Spain: Clinical And Economic Impact. PMID- 26532003 TI - Hexaminolevulinate Blue-Light Flexible Cystoscopy In Addition To Standard White Light Cystoscopy In The Follow-Up Of Non-Muscle Invasive Bladder Cancer: Cost Consequences During Outpatient Surveillance In Sweden. PMID- 26532004 TI - A Microcosting Study Of Radiation Therapy In Localized Prostate Cancer Patients In A Hungarian Tertiary Oncology Center. PMID- 26532005 TI - A Decision Tree Model To Evaluate The Costs And Consequences Of Using Dual Antibiotic Bone Cement Versus Single Antibiotic Bone Cement In Hip Hemiarthroplasty. PMID- 26532006 TI - The Addition Of A Novel Colonoscope Device Improves Adenoma Detection In A German Screening Population Which May Result In Cost Savings Due To Fewer Cases Of Colorectal Cancer. PMID- 26532007 TI - Cost-Effectiveness Analysis Of Continuous Remote Monitoring Of Heart Failure Patients With Cardiac Electronic Implantable Device. PMID- 26532008 TI - Cost-Effectiveness Of Capnography Monitoring During Gastrointestinal Endoscopy Targeting Moderate Sedation. PMID- 26532009 TI - Cost-Effectiveness Analysis Of Capsule Endoscopy Using For Diagnosing Small Bowel Crohn's Disease. PMID- 26532010 TI - Economic Evaluation Of Individually Vs Vial-Packaged Strips For Glucose Monitoring. PMID- 26532011 TI - Increased Cost-Effectiveness Of Diagnostic Imaging In Patients With Suspected Cad By Using A New Clinical-Biohumoral Predictive Model Of Disease. PMID- 26532012 TI - Economic Analysis Of Epicup, An Epigenetic Test To Predict The Tissue Of Origin In Cancer Of Unknown Primary Site, From The Spanish Nhs Perspective. PMID- 26532013 TI - A Pct-Algorithm To Guide Antibiotic Therapy In Patients Hospitalized With Copd Exacerbations Leads To Net Cost Savings By Reducing Frequency And Duration Of Antibiotic Use As Compared To Current Practice. PMID- 26532014 TI - Economic Analysis Of Epicup, An Epigenetic Test To Predict The Tissue Of Origin In Cancer Of Unknown Primary Site, The Usa Payors Perspective. PMID- 26532015 TI - Economic Evaluation Of Oral Anticoagulation Therapies (Oat) In China. PMID- 26532016 TI - Economic Evaluation Of Four Schemes For Screening And Diagnosis Of Type 2 Diabetes In Adults In Colombia. PMID- 26532017 TI - Value of Antidrug Antibody Screening In Moderate-To-Severe Rheumatiod Arthritis Patients Who Failed Initial Tumor Necrosis Factor-Alpha Treatment. PMID- 26532018 TI - A Cost-Effective Analysis of The Optimum Number of Blood Culture for Adult Patients With Infection. PMID- 26532020 TI - A Cost-Effective Analysis of Revolution Ct for Patients With Acute Chest Pain. PMID- 26532019 TI - Cost-Effectiveness of A Left Atrial Appendage Closure Device In Patients With Non Valvular Atrial Fibrillation Unable or Unwilling to Tolerate Oral Anticoagulant Therapy In Italy And Spain. PMID- 26532021 TI - Modeling the cost-effectiveness of a new covered stent (willis) vs. Endovascular coil occlusion for the treatment of intracranial aneurysms in china. PMID- 26532022 TI - Cost-Effectiveness of Screening for Colorectal Cancer In Argentina. PMID- 26532023 TI - A Five-Year Model to Assess The Cost-Effectiveness of New Diagnostic Tests In The Early Diagnosis of Rheumatoid Arthritis. PMID- 26532024 TI - Early Stage Economic Evaluation of Caretoy System for Early Intervention In Preterm Infants At Risk of Neurodevelopmental Disorders. PMID- 26532025 TI - Cost Effectiveness Analysis of A Device to Monitor Levodopa-Induced Dyskinesia In Parkinson's Patients. PMID- 26532026 TI - The Cost-Effectiveness Analysis of Philips Motiva Telehealth System: A Comparison Between Home Telemonitoring, Nurse Telephone Support And Usual Care In Chronic Heart Failure. PMID- 26532027 TI - Cost-Effectiveness Analysis for The Use of The Ccp Score In The Management of Early Low Risk Prostate Cancer In The French Context. PMID- 26532028 TI - Cost-Effectiveness of Transcatheter Aortic Valve Replacement: Current Decision Analytic Models and Future Opportunities. PMID- 26532029 TI - Cost-Utility Analysis of Sacral Nerve Stimulation for The Treatment of Fecal Incontinence Refractory to Conservative Treatment: Looking for Optimal Treatment Path. PMID- 26532030 TI - Early Economic Evaluation of Short-Term Variability of Qt Intervals As A Potential Test for Predicting The Effectiveness of Icd Implantation In Patients With Heart Failure. PMID- 26532031 TI - A Cost-Effectiveness Model Evaluating Component-Resolved Diagnosis (Crd) Versus Standard Testing Method (Skin Prick Testing (Spt)) In The Diagnosis And Treatment of Allergic Rhinitis In The Netherlands. PMID- 26532032 TI - Early Economic Evaluation of A Hypothetical Perfect Test for Predicting The Effectiveness of Implantable Pacemaker-Defibrillator Devices (Crt-D) In Patients With Heart Failure. PMID- 26532033 TI - Cost-Effectiveness of Pen Devices For Nph Insulin Administration Compared With Syringe And Vial In Adult Patients With Diabetes Mellitus In Colombia. PMID- 26532034 TI - Cost-Utility of Hexaminolevulinate Blue Light Cystoscopy (Hal) Assisted Transurethral Resection of The Bladder Tumour (Turb) Compared to Turb With White Light Cystoscopy (Wlc) Alone In Patients With Non-Muscle Invasive Bladder Cancer (Nimbc) In Poland. PMID- 26532035 TI - Health-Economic Analysis of The Use of Sensor-Augmented Pump (Sap) Therapy In The Netherlands Compared to Insulin Pump Therapy Alone (Csii), In Type 1 Diabetic Patients. PMID- 26532036 TI - Long-Term Cost-Effectiveness of Transanal Irrigation In Patients With Neurogenic Bowel Dysfunction Who Have Failed Standard Bowel Care. PMID- 26532037 TI - Cost-Utility Analysis of Continuous Infusion Pump With Integrated Monitoring Compared With Multiple Daily Injection Treatment for Patients 15-Years or Older With Type 1 Diabetes Mellitus In Colombia. PMID- 26532038 TI - Reduction of Complications and Associated Costs for Type 2 Diabetic Patients Using Continuous Subcutaneous Insulin Infusion In The Uk. PMID- 26532039 TI - Cost-Effectiveness Analysis of Testing for Brca1 and Brca2 Mutations In Women Diagnosed With Ovarian Cancer and Their Female First- And Second Degree Relatives Using A Discrete Event Simulation: A Uk Health Service Perspective. PMID- 26532040 TI - Delayed Enhancement Cardiac Magnetic Resonance to Refine Patient Selection For Implantable Cardioverter Defibrillator Therapy In Primary Prevention - An Exploratory Cost-Effectiveness Analysis. PMID- 26532041 TI - Identifying The Most Cost-Effective Way of Diagnosing Asthma In Adults Using Multiple Tests - A Cost-Utility Analysis From The Nice Asthma Guideline. PMID- 26532042 TI - Economical and Organizational Impact of Adopting Different in Situ Hybridization Technologies to Assess HER2 Gene Amplification in Breast Cancer. PMID- 26532043 TI - Examining The Economic Impact of Laboratory Developed Testing In Flow Cytometry Immunophenotyping for Hematologic Malignancies: An Analysis of Health Resource Utilization. PMID- 26532044 TI - Risk Factors for Developing Diabetes As A Determinant of The Cost-Effectiveness of Using Coronary Calcium Score to Guide Primary Prevention With Statins. PMID- 26532045 TI - Copd Ics/Laba Treatment Inhalers and Their Impact on Adherence. PMID- 26532046 TI - Therapy Adherence In Patients With Multiple Sclerosis Using An Electronic Multidose Auto-Injection Device. PMID- 26532047 TI - Device Inhalators In Asthma and Their Impact on Treatment Adherence. PMID- 26532048 TI - The Importance of Inhaler Devices: An Incorrect Inhaler Technique Leads to Suboptimal Medication Compliance In Patients With Copd. PMID- 26532049 TI - Identification of Factors Involved In Medication Compliance: Incorrect Inhaler Technique of Asthma Treatment Leads to Poor Compliance. PMID- 26532050 TI - Evaluation of Inhaler Technique Mastery and Handling Errors With Spiromax(r), Easyhaler(r), And Turbuhaler(r) Devices (Finhaler). PMID- 26532051 TI - Evaluation of Inhaler Perception and Preference of Spiromax(r), Easyhaler(r), And Turbuhaler(r) Devices (Finhaler). PMID- 26532052 TI - Health State Utilities Associated With Attributes of Weekly Injection Devices for Treatment of Type 2 Diabetes. PMID- 26532053 TI - Health State Utilities Associated With Glucose Monitoring Devices. PMID- 26532054 TI - The Impact of Robotic Technology on Neuro-Rehabilitation: Preliminary Results on Acceptability And Effectiveness. PMID- 26532055 TI - Pen Devices for Insulin Administration Compared to Needle And Vial: Systematic Review of Literature and Meta-Analysis. PMID- 26532056 TI - The Assessment Of Value For Medical Devices: A Case Study On Injection Technique Education In Insulin Delivery. PMID- 26532057 TI - Reference Pricing For Laboratory Tests In The United States: Impact On Prices And Spending. PMID- 26532058 TI - Subjective Outcomes With Bone Conduction and Middle Ear Implants for Patients Wth Conductive or Mixed Hearing Loss. PMID- 26532059 TI - Preferences for Dry Powder Inhaler Attributes Among Patients With Asthma and Chronic Obstructive Pulmonary Disease From Five European Countries. PMID- 26532060 TI - Healthcare Associated Infections. Impact And Costs Of Diagnosis And Management Of Clostridium Difficile Infections (Cdi). The Experience Of A University Hospital In Rome. PMID- 26532061 TI - Knowledge On The Appropriate Technique Of Bloos Pressure Monitoring And Limits Of The Oscillometric Blood Pressure Measurement. PMID- 26532062 TI - Comparison Of Epidermal Growth Factor Receptor (Egfr) Tested And Not-Tested Metastatic Non-Small Cell Lung Cancer (Mnsclc) Patient Cohorts In Europe. PMID- 26532063 TI - Patterns Of Use Of Tests To Monitor Disease Activity Among Patients Currently Treated For Relapsing Remitting Multiple Sclerosis (Rrms) In Europe. PMID- 26532064 TI - Review Of Us Medicare System For Reimbursement Of New Medical Devices. PMID- 26532065 TI - Comparison Of Kras Tested And Not-Tested Metastatic Colorectal Cancer (Mcrc) Patient Cohorts In Europe. PMID- 26532066 TI - Modeling Of Clinical Pathways In The Implantation Of Cardioverter Defibrillators From 2006 To 2013 Using The French Hospital P.M.S.I. Database. PMID- 26532067 TI - How To Capture And Reward The Benefits Associated With Companion Diagnostics? PMID- 26532068 TI - New Nhi Reimbursement Coverage Paradigm Called 'Selective Reimbursement Scheme' On The Four Major Diseases In Korea. PMID- 26532069 TI - The Impact Of New Endovascular Therapies For Femoropopliteal Arterial Disease On Therapy Utilization And Case Volumes In Germany, 2009-2013. PMID- 26532070 TI - Medical Devices: Innovative Models To Access The Market Leveraging On Shared Infrastructure Among Payers And Pharmaceutical Companies. PMID- 26532071 TI - Virtual Consultation System To Enable Rare Diseases Diagnosis. PMID- 26532072 TI - Identifying Opportunities For Value-Based Contracting For Molecular Diagnostics As A Means To Improve Outcomes Of Hospital Acquired Infections. PMID- 26532073 TI - Accessing The Medical Devices Market In Egypt And Saudi Arabia: A Systematic Review Of Policies And Regulations. PMID- 26532074 TI - The Impact Of Self-Monitoring Of Blood Glucose (Smbg) On Prescription Costs In Newly Treated Type 2 Diabetes Melitus (T2dm): A Retrospective Cohort Analysis. PMID- 26532075 TI - The Medical Technologies Evaluation Programme (Mtep): An Analysis Of Notifications, Decision-Making And The Interpretation Of Claimed Healthcare System Benefits. PMID- 26532076 TI - When Is A Bone Fracture No Longer "Fresh"? PMID- 26532077 TI - What Is Ce Marking? How Technologies Are Classified, And How To Navigate The System. PMID- 26532078 TI - Re-Use Of Insulin Syringe Needles And Its Extra Disease Burden For Diabetic Patients In Beijing. PMID- 26532079 TI - Cost-Effectiveness Of Local Insufflation Of Warm Humidified Co2 During Open And Laparoscopic Colorectal Surgery. PMID- 26532080 TI - Economic Analysis Of Evarrest(r) Sealant Matrix Compared With Standard Of Care In Severe Soft Tissue Surgical Bleeding: A United Kingdom Hospital Perspective. PMID- 26532081 TI - Medical Devices: Why Do Some Pay More Than Others Do? Analysis Of Price Variation In French Public Hospital In 2013. PMID- 26532082 TI - Budget Impact Analysis Of Bioabsorbable Drug-Eluting Sinus Implants For Endoscopic Sinus Surgery. PMID- 26532083 TI - Economic Analysis Of Evicel(r) Compared With Standard Of Care For Dural Closure In Elective Cranial Surgery: A United Kingdom Hospital Perspective. PMID- 26532084 TI - Modelled U.K. And U.S. Analyses Demonstrate Sherlock 3cg(r) Tip Confirmation System For Peripherally Inserted Central Catheter Placement Is Associated With Favourable Health Economic Outcomes. PMID- 26532085 TI - Economic Analysis Of Evarrest(r) Sealant Matrix Compared With Standard Of Care In Severe Soft Tissue Surgical Bleeding: A German Hospital Perspective. PMID- 26532086 TI - Economic Analysis Of Evarrest(r) Sealant Matrix Compared With Standard Of Care In Severe Soft Tissue Surgical Bleeding: An Italian Hospital Perspective. PMID- 26532087 TI - Economic Justification Of Telemedicine Technology For Preventive Medical Examination Of The Population In Remote Regions In Russia. PMID- 26532088 TI - Using Real-World Hospital Purchasing And Consumption Data To Improve Healthcare Systems Efficiencies. PMID- 26532089 TI - Potential Economic Impact Of Inhalation Errors Due To Device Switch In Patients With Chronic Obstructive Pulmonary Disease And Asthma. PMID- 26532090 TI - Turkish Reimbursement System For Medical Devices. PMID- 26532091 TI - Medical Devices - Brest Forms. Cost And Quantity Characteristics Of Medical Devices In Slovakia 2009 - 2013. PMID- 26532092 TI - Multi European Country Cost Consequence Comparison Of Floseal Matrix And Surgiflo Thrombin In Major And Severe Spine Surgeries. PMID- 26532093 TI - Adoption Of Transcatheter Aortic Valve Replacement In Germany: Utilization Patterns And Case Volumes Compared To Surgical Aortic Valve Replacement In The Period 2009-2013. PMID- 26532094 TI - Companion Devices: Potential Routes To Market. PMID- 26532095 TI - Medical Devices For Ostomates. Cost And Quantity Characteristics In Slovakia 2009 - 2013. PMID- 26532096 TI - Compression Therapy Of Venous Insufficiency. Cost And Quantity Characteristics Of Medical Devices In Slovakia 2009 - 2013. PMID- 26532097 TI - Medical Devices For Patients With Incontinence. Cost And Quantity Characteristics In Slovakia 2009 - 2013. PMID- 26532098 TI - Medical Devices For Bandaging And Plasters. Cost And Quantity Characteristics In Slovakia 2009 - 2013. PMID- 26532099 TI - Medical Device Reimbursement Rules In Turkey: With Past And Current Practices, Looking Forward. PMID- 26532100 TI - Modeling Of Risks And Benefits Of Lung Cancer Screening Strategies Using Low-Dose Helical Ct (Ldct) Technology In Canada. PMID- 26532101 TI - Estimation Of Health Benefits Associated To Early Diagnosis And Treatment Of Copd. PMID- 26532102 TI - Nice Medical Technologies Evaluation Programme - Influence Of The Review On Uptake By Procurement Managers And Key Stakeholders. PMID- 26532103 TI - The Use Of Real World Evidence To Support Market Access Of Medical Devices - Implications For The German Setting. PMID- 26532104 TI - Costs Of Compression Therapy In Venous Leg Ulcers In Germany And Modelling Of The Economic Effects Of Regional Disparities In Health Care. PMID- 26532105 TI - Thermodilution Technique For Vascular Access Flow Measurement: A Systematic Review. PMID- 26532106 TI - An Analysis Of Drivers Of Positive And Negative Appraisals By Nice's Medical Technology Evaluation Programme (Mtep). PMID- 26532107 TI - Impact Of Her2 Testing Quality Improvement From A Health Economic Perspective. PMID- 26532108 TI - Unique Device Identifier System: The Impact Of The Portuguese Experience. PMID- 26532109 TI - Systematic Review On Efficacy Of The F-18 Fluoromisonidazole Pet Or Pet/Ct. PMID- 26532110 TI - The Link Between Proton Pump Inhibitors and Ischemic Heart Disease Could be Explained by Protopathic Bias: a Pharmacovigilance Analysis. PMID- 26532111 TI - Adverse Drug Reactions, Medication Adherence and Physicians' Prescribing Behavior: Which Relationship? a Database Analysis on Statin use. PMID- 26532112 TI - Lead Damage in the First-Year Following Cardiac Implantable Electronic Device (Cied) Replacement: Incidence and Costs Based on Device Type. PMID- 26532113 TI - Network Meta-Analysis of Oral Anticoagulants for Primary Prevention, Treatment and Secondary Prevention of Venous Thromboembolic Disease, and for Prevention of Stroke in Atrial Fibrillation. PMID- 26532114 TI - Clinical and Economic Impact of Chronic Heart Failure in General Practice: Analysis of 13.633 Patients. PMID- 26532115 TI - Assessment of a Predictive Risk Model for Classifying Patients with Multimorbidity in the Basque Country. PMID- 26532116 TI - Systematic Literature Review of the Burden of Illness in Hypertriglyceridemia. PMID- 26532117 TI - Cost-Effectiveness of Apixaban Compared to Low Molecular Weight Heparin/ Edoxaban for Treatment and Prevention of Recurrent Venous Thromboembolism. PMID- 26532118 TI - Trends and Correlates of Pulmonary Embolism in Hospitalized Spanish Patients. PMID- 26532119 TI - Patient Profile of New Users of Novel Oral Anticoagulants in non-Valvular Atrial Fibrillation (Nvaf): Real-World Evidence from Primary Care Data in Germany. PMID- 26532120 TI - Network Meta-Analysis to Assess Comparative Effectiveness of Beta-Blockers in Patients with Heart Failure and Reduced Ejection Fraction. PMID- 26532121 TI - Comparative Effectiveness of Triple Antihypertensive Combination Therapy for Patients with Resistant Hypertension In Taiwan. PMID- 26532122 TI - A Mixed Treatment Comparison (Mtc) to Compare the Efficacy of Anti-Thrombotic Agents in Treatment and Secondary Prevention of Venous Thromboembolism (Vte) in Patients with Deep Vein Thrombosis (Dvt). PMID- 26532123 TI - Real-World Effectiveness of Amlodipine/Valsartan/Hydroclorothiazide Single-Pill Combination in the Treatment of Patients with Essential Hypertension. PMID- 26532124 TI - Comparative Effectiveness of Ticagrelor Vs. Prasugrel in Patients with Acute Coronary Syndrome. PMID- 26532125 TI - Can Data Simulation Help Evaluate Hta Outcomes Over Time and Facilitate Early Decision-Making? a Case Study of Ticagrelor in Acute Coronary Syndrome in the Uk. PMID- 26532126 TI - Aspirin Versus Clopidogrel in Patients with Ischemic Stroke: a Cost and Effectiveness Comparison from Beijing Medical Insurance Database. PMID- 26532127 TI - A Mixed Treatment Comparison (Mtc) to Compare the Efficacy of Anti-Thrombotic Agents in the Acute Treatment of Venous Thromboembolism (Vte) in Patients with Active Cancer. PMID- 26532128 TI - Aspirin Versus Clopidogrel in Patients with Acute Myocardial Infarction: a Cost and Effectiveness Comparison from Beijing Medical Insurance Database. PMID- 26532129 TI - Network Meta-Analysis of Various Treatment Strategies in Resistant Hypertension. PMID- 26532130 TI - Systematic Review and Meta-Analysis of Self-Monitoring and Self-Management of Anticoagulation Therapy with Vitamin K Antagonists. PMID- 26532131 TI - Association Between Adherence to Evidence-Based Heart Failure Drug Treatment and One-Year All-Cause Hospitalization and All-Cause Mortality. PMID- 26532132 TI - Long-Term Increased Inpatient and Outpatient Visits Associated with Cardiovascular Events: a Large United States Real World Study. PMID- 26532133 TI - Preliminary Study of Safety and Efficacy of Warfarin Versus Dabigatran in Atrial Fibrillation Patients in a Tertiary Hospital in Malaysia. PMID- 26532134 TI - Co-Administration of Proton Pump Inhibitors in Chronic Aspirin Users and the Risk of Adverse Cardiovascular Events: a Population-Based Cohort Study. PMID- 26532135 TI - Relationship of Time in Therapeutic Range (Ttr) with Bleeding and Stroke Incidences of Warfarinised Patients with Pulmonary Embolism in a Tertiary Hospital in Malaysia. PMID- 26532136 TI - Effectiveness and Safety of New and Traditional Oral Anticoagulants in a Population-Based Cohort of New Users with Atrial Fibrillation. PMID- 26532137 TI - A One-Year Follow-Up of Patients with Acute Coronary Syndrome (Acs) and Diabetes Treated with Statins: Outcomes and Health Care Costs Supported by Italian National Health Service. PMID- 26532138 TI - Management of Statin Intolerance (Si) in Patients at High Risk for Cardiovascular (Cv) Events: Results of a Canadian Study. PMID- 26532139 TI - Demographics, Clinical Characteristics, and Treatment Patterns of Patients Newly Started on Prostacyclin Therapy for Pulmonary Arterial Hypertension. PMID- 26532140 TI - Clinical Characteristics, Lipid Treatment and Goal Attainment in a Familial Hypercholesterolemia Cohort in The Netherlands: a Cross Sectional Study. PMID- 26532141 TI - Patterns of Utilization and Cost of Prostacylins for Pulmonary Arterial Hypertension. PMID- 26532142 TI - Burden of Dyslipidaemia in Patients at High Risk for Cardiovascular (Cv) Events: Results of a Canadian Study. PMID- 26532143 TI - Association of Treatment with Carvedilol, Bisoprolol and Metoprolol on the Risk of Mortality and Hospital Admission Among Older Adults with Heart Failure. PMID- 26532144 TI - The Analyze of Consumption of Fixed Combinations of Drugs in Therapy of Hypertension. PMID- 26532145 TI - A Retrospective, Cross Sectional Study on the Prevalence of Hypertension and Treatment Status in Obese Patients Using a Healthcare Database in Japan. PMID- 26532146 TI - Epidemiology of Statin-Treated Patients with Uncontrolled Ldl Levels from Italian Administrative Official Databases. PMID- 26532147 TI - Epidemiology of Patients Affected by Acute Coronary Syndrome (Acs) Treated with Statins for Hypercholesterolemia from Italian Administrative Official Databases. PMID- 26532148 TI - A One-Year Follow-Up of Individuals with Diabetes at Very High Cv Risk Treated With Statins: Outcomes and Health Care Costs. PMID- 26532149 TI - Choice of Antithrombotic Drug in non-Valvular Atrial Fibrillation Patients in Real-World Practice. PMID- 26532150 TI - Heart Failure in a Health Area of Madrid, Spain. Description and Management from Electronic Medical Records. PMID- 26532151 TI - Hospital Readmissions and Mortality Patterns in a Cohort with Heart Failure: 1 Year Follow-Up from the Brazilian Public Healthcare System Database. PMID- 26532152 TI - Benefit-Risk of Vka for Atrial Fibrillation Before Doac: a Cohort Study in a Claims and Hospitalization Database. PMID- 26532153 TI - Epidemiological Burden and Management of Hypercholesterolemia in High Cardiovascular Risk Patients in Spain: a Comprehensive Picture from a Systematic Review of the Literature. PMID- 26532154 TI - Assessing Retrospective Data on the Management of Ischemic Stroke. PMID- 26532155 TI - Impact of Genetic Factors on Gastrointestinal Bleeding in a Prospective Cohort of new Warfarin users. PMID- 26532156 TI - Comparative Effectiveness on Cardiovascular Outcomes of Metformin Initial Therapy and Add-on Second-Line Drugs Among Patients with Type 2 Diabetes. PMID- 26532157 TI - Statin Use and Risk of New-Onset Type 2 Diabetes Mellitus and Cardiovascular Disease: a Nationwide Population-Based Observational Study Using National Claim Data. PMID- 26532158 TI - Cardiovascular Event Rates in a High-Risk General Population Cohort of 340,000 Individuals in the United Kingdom. PMID- 26532159 TI - Correlation of Triglycerides and Acute Pancreatitis: a Systematic Evidence Review. PMID- 26532160 TI - Incidence of Cardiovascular Events Following Myocardial Infarction in France: an Observational Analysis Using a Claims Database. PMID- 26532161 TI - A Comparison of Classification and Regression Trees and Logistic Regression for Predicting Death of Older Long-Term Care Users in Japan. PMID- 26532162 TI - Prediction Model for Functional Status at Discharge Following Rhabilitation After Intracerebral Hemorrhage. PMID- 26532163 TI - Hllkj. PMID- 26532164 TI - Simpson's Paradox: Why Smoking Reduces the Risk of Dying of Cardiovascular Disease. PMID- 26532165 TI - Budget Impact Model (Bim) Of Rivaroxaban In Comparison With Enoxaparin Plus Warfarin In The Treatment Of Venous Thromboembolism (Vte) Under The Perspective Of The Private Health System. PMID- 26532166 TI - Mortality Trends in Cardiovascular Disease: a New Model to Visualise the Contribution of Specific Diseases, Cohort Effects and Coding Changes to Overall Mortality Improvement. PMID- 26532167 TI - Cost Savings By The Use Of Bemiparin In The Treatment Of Patients With Venous Thromboembolism In Spain. PMID- 26532168 TI - An Assesment Of Enoxaparine Benefit On Healthcare Budget In Spain. PMID- 26532169 TI - Budget-Impact-Analysis Of Iron Treatment Using Intravenous Ferric Carboxymaltose In Patients With Chronic Heart Failure And Iron Deficiency In Austria. PMID- 26532170 TI - Budget Impact Analysis Of Tripliam For The Treatment Of Hypertension In Italy. PMID- 26532171 TI - Prescription Algorithms: Impact On Statins. PMID- 26532172 TI - Impact On Italian National Health Service Expenditure For The Treatment Of Venous Thromboembolism With Rivaroxaban. PMID- 26532173 TI - Hospitalization Expenses Analysis Of Chinese Stroke Patients With Urban Employee Basic Medical Insurance. PMID- 26532174 TI - Pharmacoeconomic Analysis Of Treatment Of Patients With Acute Coronary Syndrome Without St Segment Elevation In Ukraine. PMID- 26532175 TI - Hospital Cost Analysis Of Patients With Cardiovascular Events And Revascularisation Procedures In Spain. PMID- 26532176 TI - Medical Cost Of Patients With Non-Valvular Atrial Fibrillation (Nvaf) And Treated With Vitamin K Antagonists (Vkas) According To Inr Control Status In Spain. PMID- 26532177 TI - Development Of Prescription E-Protocols For Medicines And Integration On The Greek National E-Prescription System. PMID- 26532178 TI - Cost Of Illness In Aortic Stenosis Patients. PMID- 26532179 TI - Trends In Emergency Room Visits Due To Hyperkalemia In The United States. PMID- 26532180 TI - Economic Burden In Direct Costs Of Obesity And Overweight In Russia. PMID- 26532181 TI - Resource Utilisation And Costs In Patients With Post-Stroke Spasticity In The United Kingdom. PMID- 26532182 TI - Healthcare Costs Associated With Non-Valvular Atrial Fibrillation In Italy. PMID- 26532183 TI - Increased Costs Due To Myocardial Infarction (Mi) In France: An Observational Analysis Using A Claims Database. PMID- 26532184 TI - Medical Costs And Resources Consumption In Patients With Atrial Fibrillation: An Italian Observational Study. PMID- 26532185 TI - Systematic Litertaure Review Of Direct Health Care Costs For Cardiovascular Events Among European Patients With Dyslipidemia Or High Cardiovascular Risk. PMID- 26532186 TI - Estimating The Economic Burden Of Stroke In South India : A Cost-Of-Illness Study. PMID- 26532187 TI - Estimating The Burden Of Diabetes To The French National Health Insurance. PMID- 26532188 TI - Costs Of Cardiovascular (Cv) Events In The United Kingdom (Uk) Using Real-World Data. PMID- 26532189 TI - Analysis Of In-Hospital Resource Use After An Ischemic Stroke. PMID- 26532190 TI - Resource Utilization And Treatment Costs Of Stroke In Patients With Non-Valvular Atrial Fibrillation In Spain. PMID- 26532191 TI - Real World Evidence And Costs Of Chronic Heart Failure: Findings From 41,413 Patients Of The Arno Database. PMID- 26532192 TI - An Epidemiological Evaluation Of The Incidence Of Deep Venous Thrombosis And Pulmonary Embolism In Patients With Hip Or Knee Replacement Surgery And Of Its Impact On The Average Length Of Stay And Hospitalization Cost. PMID- 26532193 TI - Direct Treatment Costs Of Stroke In Turkey. PMID- 26532194 TI - Local Cost Study Of Treatment Of Venous Thromboembolism In Turkey. PMID- 26532195 TI - Economic Burden Of Acute Myocardial Infarction In Vietnam. PMID- 26532196 TI - Cost-Benefit Analysis Of Yindanxintai Dropping Pills In The Treatment Of Angina Pectoris Caused By Coronary Heart Disease. PMID- 26532197 TI - A Comparison Of Two Low-Molecular-Weight Heparins (Lmwhs) In Terms Of Cost Per Patient. PMID- 26532198 TI - The Cost Of Acute Care Hospitalizations Associated With Chronic Heart Failure In Canada. PMID- 26532199 TI - An Epidemiological Evaluation Of The Impact Of Percutaneous Coronary Interventions On The Hospitalization Cost, Length Of Stay And Mortality Of Patients Hospitalized With Acute Coronary Syndromes. PMID- 26532200 TI - Cost Benefits Of Incorporating Levosimendan Into Cardiac Surgery Practice: German Base Case. PMID- 26532201 TI - Is Edoxaban A Cost-Effective Alternative To Venous Thromboembolim Patients Treated With Vitamin K Antagonists In Spain? PMID- 26532202 TI - Cost-Effectiveness Of A Novel Pharmacist Guided Warfarin Pharmacogenetic Service. PMID- 26532203 TI - Cost-Effectiveness Of Combined Treatment With Alteplase (Rt-Pa) And Cerebrolysin In Acute Ischemic Hemispheric Stroke In Austria. PMID- 26532204 TI - Cost-Effectiveness Analysis Of Alternative Strategies Of Monitoring For Amiodarone-Related Thyroid Toxicity In Uk Primary Care. PMID- 26532205 TI - A Cost-Effectiveness Analysis Of Novel Oral Anticoagulants For Acute Treatment And Secondary Prevention Of Venous Thromboembolic Disease. PMID- 26532206 TI - Economic Evaluation Of Trimetazidine In The Management Of Chronic Stable Angina In Greece. PMID- 26532207 TI - The Cost-Effectiveness Of Novel Oral Anticoagulants For The Prevention Of Stroke In Atrial Fibrillation In England And Wales. PMID- 26532208 TI - The Cost-Effectiveness Of Treatment For Chronic Heart Failure: A Systematic Review. PMID- 26532209 TI - Development Of A Model To Provide Insight In The Value Of Fibrinogen Concentrate For Treating Excessive Bleedings During Complex Cardiovascular Surgery. PMID- 26532210 TI - Opportunistic Screening For Atrial Fibrillation In Primary Care - A Clinical And Cost-Effectiveness Analysis. PMID- 26532211 TI - Pharmacoeconomic Analysis Of Various Treatment Strategies For Patients With Chronic Venous Insufficiency Of The Lower Limbs. PMID- 26532212 TI - Comparison Of Overall Costs Between Alprostadil And Limb Amputation In Patients Affected By Peripheral Arterial Disease Stages Iii And Iv In Mexico. PMID- 26532213 TI - Cost-Effectiveness Of Ferric Carboxymaltose In Patients With Iron Deficiency And Chronic Heart Failure In Austria. PMID- 26532214 TI - Is Edoxaban Cost-Effective For Non-Valvular Atrial Fibrillation Patients Treated With Vitamin K Antagonists In Spain? PMID- 26532215 TI - Cost-Effectiveness Analysis Of Bemiparin Used As Acute Treatment For Deep Venous Thrombosis Without Pulmonary Embolism. PMID- 26532216 TI - Economic Evaluations Of New Oral Anticoagulants For The Prevention Of Venous Thromboembolism After Total Hip Or Total Knee Replacement. PMID- 26532217 TI - Dabigatran For The Treatment And Secondary Prevention Of Venous Thromboembolism. PMID- 26532218 TI - A Polypill Intervention To Improve Adherence For Secondary Cardiovascular Disease Prevention In Spain: A Cost-Effectiveness Study. PMID- 26532219 TI - Cost-Effectiveness Of The Non-Vitamin K Antagonist Oral Anticoagulants For Atrial Fibrillation In Portugal. PMID- 26532220 TI - The Cost-Effectiveness Of Bariatric Surgery In Germany. PMID- 26532221 TI - Clinical And Economic Analysis Of Effectiveness Of Fondaparinux Sodium In The Treatment Of Acute Coronary Syndrome. PMID- 26532222 TI - Development Of A Conceptual Model For Early Health Technology Assessment Of Tissue-Engineered Heart Valves. PMID- 26532223 TI - A Cost-Effectiveness Study On The Increased Intake Of Potassium And Vitamin B2 Among Adults In China. PMID- 26532224 TI - A New Cost-Effectiveness Modelling Approach In Chronic Heart Failure With Reduced Ejection Fraction. PMID- 26532225 TI - Cost-Minimization Analysis Of Rivaroxaban In Comparison To Enoxaparin Plus Warfarin For The Treatment Of Venous Thromboembolism (Vte) Under The Private Healthcare System Perspective. PMID- 26532226 TI - Clinical And Economic Impacts Of The Use Of A Prescription Assistance Software For Vitamin K Antagonist Treatment In French Management Of Atrial Fibrillation And Venous Thromboembolic Events. PMID- 26532227 TI - Cost-Effectiveness Of Edoxaban Compared With Warfarin For The Prevention Of Stroke And Systemic Embolic Events In The Uk. PMID- 26532228 TI - A Literature Review To Evaluate The Pharmacoeconomic Value Of Ranolazine For The Treatment Of Symptomatic Chronic Stable Angina. PMID- 26532229 TI - Cost-Utility Of Statin In Secondary Prevention: A Propensity Score Method Of Administrative Database. PMID- 26532230 TI - Cost-Utility Analysis Of Chocolate Consumption For Prevention Of Cardiometabolic Disease. PMID- 26532231 TI - Cost-Utility Of Ranolazine For The Symptomatic Treatment Of Patients With Chronic Angina Pectoris In Greece. PMID- 26532232 TI - Cost-Utility Analysis Of Apixaban In The Acute Treatment And Prevention Of Venous Thromboembolism In France. PMID- 26532233 TI - Resource Utilisation And Bleeding Events During Anticoagulation Treatment: Real World Findings From England. PMID- 26532234 TI - Cost-Effectiveness Of Edoxaban Compared With Other Licensed Noacs For The Prevention Of Stroke And Systemic Embolic Events In The Uk. PMID- 26532235 TI - Economic Evaluation Of A Pharmacogenomic Test For Statin-Induced Myopathy In Cardiovascular High-Risk Patients Initiating A Statin. PMID- 26532236 TI - Systematic Review Of Productivity Losses Associated With Cardiovascular Disease In Europe. PMID- 26532237 TI - Systematic Review Of Hyperkalemia Due To Angiotensin Enzyme Converting Inhibitors. PMID- 26532238 TI - Comparison Between The Interim Eq-5d-5l Score And The New Japanese Scoring In Stroke Patients. PMID- 26532239 TI - A Systematic Review Of Cardiovascular Event Utilities In Europe. PMID- 26532240 TI - Health-Related Quality Of Life In Heart Failure Patients: Health Utilities And Predictive Determinants. PMID- 26532241 TI - Quality Of Life Of Patients Experiencing Cancer-Associated Thrombosis. PMID- 26532242 TI - Quality Of Life And Emotional Impact Of A Fixed Dose Combination Of Antihypertensive Drugs In Patients With Uncontrolled Hypertension. PMID- 26532243 TI - Beliefs About Medicines In An Urban Community Health Center Hypertension Population. PMID- 26532244 TI - Design Of Three New Condition-Specific Questionnaires To Assess Quality Of Life, Symptoms And Treatment Satisfaction Of Patients With Abdominal Aortic Aneurysm: The Aneurysm-Dqol, Aneurysm-Srq And Aneurysm-Tsq. PMID- 26532245 TI - Assessment Of Patient-Reported Health Status In Chronic Thromboembolic Pulmonary Arterial Hypertension Patients Treated With Riociguat: 2-Year Results From The Chest-2 Extension Study. PMID- 26532246 TI - Assessment Of Patient-Reported Health Status In Pulmonary Arterial Hypertension Patients Treated With Riociguat: 2-Year Results From The Patent-2 Extension Study. PMID- 26532247 TI - Patient Utility Estimates In Patients At High Cardiovascular Risk. PMID- 26532248 TI - Study Of Knowledge, Attitude And Practice Of General Population Of Guntur Towards Silent Killer Diseases : Hypertension And Diabetes. PMID- 26532249 TI - Impact Of Heart Failure On Hospital Admissions And Mortality In Spain In The Period 2009-2013. PMID- 26532250 TI - A Discrete Choice Experiment (Dce) To Elicit Preferences For Attributes Of A Bedside Pharmacogenetic Test - Preliminary Results. PMID- 26532251 TI - Apheresis Treatment In German Patients With Severe Hypercholesterolemia - A Psychodrama Market Research. PMID- 26532252 TI - A Systematic Literature Review On The Impact Of Therapeutic Interventions On Quality Of Life In Systolic Hf Randomized Clinical Trials. PMID- 26532253 TI - Effect Of Intervention By Community Pharmacists On Awareness Of Continuing Treatment Among Patients With Hypertension. PMID- 26532254 TI - The Quality Of Life In Patients 12 Months After An Acute Coronary Syndrom: Results From The Pgrx-3 Real World Dataset. PMID- 26532255 TI - Simulating The Impact Of A Cardiovascular Prevention Program. PMID- 26532256 TI - Analysis Of Primary And Secondary Apr-Drg Codes Of An Ischemic Stroke Admission. PMID- 26532257 TI - A Triple Aim Framework For The Performance Assessment Of Disease Management Programs. PMID- 26532258 TI - Atrial Fibrillation And Anti-Coagulation Service Run By A Clinical Nurse Specialist. PMID- 26532259 TI - Novel Oral Anticoagulant Use In The Eu5: How Are Payer Policies And Physician Preferences Shaping The Prescribing Landscape? PMID- 26532260 TI - The Effect Of A Telephone Counseling Intervention By Pharmacist On Patients' Beliefs About Medicines And Blood Pressure Control. PMID- 26532261 TI - Effectiveness Of The St2 For Prognosis In Heart Failure: Systematic Reviews. PMID- 26532262 TI - Managing Patients With Statin-Associated Symptoms: Does Real-World Clinical Practice Align With Clinical Guidelines And Hta Recommendations In Europe? PMID- 26532263 TI - Factors Associated With The Duration Of Anticoagulation Therapy Following Acute Vte In England In General Practice: An Observational Study Using Cprd-Hes Databases. PMID- 26532264 TI - Real-World Identification Of European Patients With Statin-Associated Symptoms: Clinical Practice Compared With Clinical Guidelines. PMID- 26532265 TI - What Factors Influence Survival In Stroke: Turkey Case. PMID- 26532266 TI - Data Framework To Improve Relationship In Drugs Therapies Between Gps And Hospital Physicians. PMID- 26532267 TI - The Economic Aspect Of Warfarin Pharmacogenetics Introduction Into Health System. PMID- 26532268 TI - The Atlantic Divide In Coronary Heart Disease: Health Technologies Use In The Us And Portugal. PMID- 26532269 TI - Analysis Of Stroke Statistics In Turkey. PMID- 26532270 TI - Transitioning From Generic To Protected Brand Drug In Patients With Dm, Hypertension And Hyperlipidemia. PMID- 26532271 TI - Angiotensin Converting Enzyme Inhibitors Prescribing Pattern For Different Indications: A Population Based Study. PMID- 26532272 TI - Clinical Pathway And Health Care Resources Utilization Of A Patients Cohort At High Risk Of Cardiovascular Disease Of Local Healthcare Unit (Asln degrees 1) Of Milan: A Results Of Intervention On Secondary Prevention. PMID- 26532273 TI - The Economic Burden Of Poor Adherence To Statins In Belgium. PMID- 26532274 TI - Persistence To Vitamin-K Antagonists (Vka) And Novel Oral Anticoagulants (Noacs) In Non-Valvular Atrial Fibrillation (Nvaf): An Observational Study Using A Comprehensive Regional Database In Catalonia, Spain. PMID- 26532275 TI - Prescription Pattern Of Antihypertensive Agents In A Tertiary Care Teaching Hospital In Central Nepal. PMID- 26532276 TI - Anticoagulant Treatment After Vte In The Netherlands. PMID- 26532277 TI - Adherence With Therapeutic Guidelines In The Treatment Of Venous Thromboembolism And Pulmonary Embolism In Clinical Practice. Findings From The Victor Study. PMID- 26532278 TI - Are Spanish Regions Implementing The National Therapeutic Positioning Report (Tpr) Regarding New Oral Anticoagulants (Noac) In The Same Way? A Case Of Regional Variability In Drug Access. PMID- 26532279 TI - Pharmacoeconomic Analysis Of The Combined Homocysteine-Lowering And Standard Therapy Versus Standard Therapy Of Patients With Chd, Postpercutaneous Coronary Intervention (Pci) And B12 Deficiency. PMID- 26532280 TI - Disease Mapping And Spatial-Temporal Analysis Of Hospital Admissions Due To Heart Failure In Portugal. PMID- 26532281 TI - A Management View On Health Economics - Case Study On Network Meta Analyses (Nma) For Pulmonary Arterial Hypertension (Pah). PMID- 26532282 TI - Relationship Between Adherence To Post Percutaneous Coronary Intervention (Pci) Guidelines And Clinical Outcomes Of Post-Pci Patients In Hong Kong - A 5-Year Retrospective Cohort Study. PMID- 26532283 TI - Iron Deficiency In Patients With Chronic Heart Failure: A Systematic Literature Review. PMID- 26532284 TI - Investigating The Relationship Between "Severity Of Illness" And The "Modified Rankin Scale" In Ischemic Stroke Patients With Response Mapping. PMID- 26532285 TI - Total Cholesterol (Tc), Low-Density Lipoprotein Cholesterol (Ldl-C) And High Density Lipoprotein Cholesterol (Hdl-C) Levels In Patients With Hypertension (Ht), Diabetes (Dm), Both (Ht And Dm) And Chronic Kidney Disease (Ckd). PMID- 26532286 TI - Development Of Medical And Technological Documents On Standardization Of Medical Care In Cardiovascular Diseases In Ukraine. PMID- 26532287 TI - Heart Failure Management: A Nationwide Population-Based Cohort Study Using The French Egb Database. PMID- 26532288 TI - Risk Factors For Dementia Diagnosis In German Primary Care Practices. PMID- 26532289 TI - Does Use Of Antipsychotics Increase The Risk Of Death: A Systematic Review And Meta-Analysis Of Observational Studies. PMID- 26532290 TI - Lipid Modifying Therapy Treatment Patterns And Cholesterol Control After Cardiovascular Events In The United Kingdom. PMID- 26532291 TI - Revealed Opportunism: How Physicians Game Prior Authorization Protocols Until They Are Rescinded. PMID- 26532292 TI - Pilot Assessment Of Pharmaceuticals Based On The Eunethta Core Model For Rapid Relative Effectiveness Assessment. PMID- 26532293 TI - Cognitive Symptoms In Major Depressive Disorder And Their Italian Psychiatrists' Perception. PMID- 26532294 TI - Comparative Efficacy Of Ketamine And Other Pharmacological And Somatic Interventions In Adult Patients With Treatment-Resistant Depression: A Network Meta-Analysis. PMID- 26532295 TI - Longitudinal Modeling Of The Relationship Between Lisdexamfetamine Dimesylate And Health-Related Quality Of Life In Adults With Moderate To Severe Binge Eating Disorder. PMID- 26532296 TI - Longitudinal Modeling The Effect Of Lisdexamfetamine Dimesylate And Changes In Binge Eating Frequency On Disability In Patients With Binge Eating Disorder. PMID- 26532297 TI - Treatment Continuation And Treatment Characteristics Of Four Long Acting Antipsychotic Medications (Paliperidone Palmitate, Risperidone Microspheres, Olanzapine Pamoate And Haloperidol Decanoate) In The Netherlands. PMID- 26532298 TI - Effectiveness Of Supporting Informal Caregivers Of People With Dementia: A Systematic Review. PMID- 26532299 TI - Cost-Utility and Budget Impact Analyses Comparing Lurasidone with Aripiprazole in Adults with Schizophrenia in Scotland. PMID- 26532300 TI - Lurasidone in Adults with Schizophrenia in the UK: A Cost Consequence Analysis Considering Cost Implications of Improved Efficacy and Safety. PMID- 26532301 TI - Budget Impact Analysis of Introducing Lisdexamfetamine Dimesylate for the Treatment of Binge Eating Disorder in the United States. PMID- 26532302 TI - Mental Health Disorder Prevalence Trends In Germany: A Longitudinal Analysis. PMID- 26532303 TI - Prevalence Of Sleeping Pills Consumption And Its Association With Depressive Symptoms. PMID- 26532304 TI - Prescription Patterns Of Drugs For Attention-Deficit/Hyperactivity Disorders In Japanese Children And Adolescents. PMID- 26532305 TI - The Economic Burden of Pharmaceuticals in People Diagnosed with Depression, Anxiety-Related Disorder and Substance use in Australia. PMID- 26532306 TI - Costs of Mental Disorders in Poland and Their Complications. PMID- 26532307 TI - The Economic Burden of Mental Disorders in Korea. PMID- 26532308 TI - Observational Study of Resource use and Cost of Alzheimer's Disease in Europe (Geras) - 18-Month Results from the French Cohort. PMID- 26532309 TI - The Actual Cost of a "Forced Switch" of Psychiatric Patients to a New Therapy: a Markov Chain - Monte Carlo Simulation. PMID- 26532310 TI - Percentage Price Variation Among Antidepressant Drugs in Indian Market: an Economic Perspective. PMID- 26532311 TI - Economic Analysis of Paliperidone Long-Acting Acting Injectable for Chronic Schizophrenia in Portugal. PMID- 26532312 TI - Pharmacoeconomic Evaluation of Aripiprazole Once-Monthly Versus Paliperidone Palmitate in the UK: Findings From Qualify. PMID- 26532313 TI - Cost Effectiveness Analysis of Aripiprazole Once-Monthly Versus Paliperidone Palmitate in Spain. PMID- 26532314 TI - Cost-Effectiveness Analysis of the Information Technology Aided Relaps Prevention Programme in Schizophrenia (Itareps) in the Czech Republic. PMID- 26532315 TI - Study on Cost-Effectiveness Analysis for Treatment of Major Depression Disease: a Systematic Review of Literature From 2004-2014. PMID- 26532316 TI - Cost-Effectiveness Analysis of Opioid Substitution Treatment in Slovenia. PMID- 26532317 TI - A Systematic Review of Model-Based Economic Evaluations of Drug Substitution Therapies in Maintenance Treatment of Non-Prescription Opioid Dependence. PMID- 26532318 TI - Primary Care Dementia Clinic Reduces Societal Cost of Dementia: A Cost-Utility Analysis. PMID- 26532319 TI - Economic Burden in Studies Published in 2014: What Type of Mental Health Disorders and Outcomes Have Been Most Commonly Assessed? PMID- 26532320 TI - Evaluation of the Burden of Opioid Abuse Among us Veteran Patients. PMID- 26532321 TI - The Cost Effectiveness of Agomelatine in the Treatment of Major Depressive Disorder. PMID- 26532322 TI - Estimating the Impacts of Medication Adherence and Persistence on Costs and Hospitalization: the Case of Atypical Antipsychotics. PMID- 26532323 TI - Humanistic Burden in Dementia: Which Tools Were Most Commonly Used in Studies Published in Pubmed in 2014? PMID- 26532324 TI - Effect of Antidepressant-Base Treatment of Depressed Patients: an Observation Among Patients with Complete Adherence with Thai Depression Inventory and Lam Employment Absence and Productivity Scale in Psychiatric Hospitals. PMID- 26532325 TI - Pro Self-Assessment and Patient Retention in Major Depression Studies: Efficiency of a Direct-To-Patient Contact Approach. PMID- 26532326 TI - Development and Validation of A Patient-Reported Outcome Measure of the Psychological Impact of Submental Fat. PMID- 26532327 TI - Occupational Disability and Economic Deprivation of Individuals Suffering from Treated Mental Health Disorders. PMID- 26532328 TI - Patient, Caregiver and Treatment Factors Associated with Medication Satisfaction Among Treated Patients in the Caregiver Perspective on Pediatric Adhd (Cappa) Study in Europe. PMID- 26532329 TI - Opioid Addiction Treatment in the eu5: Market Access Levers for Emerging Brands Entering a Generic Market. PMID- 26532330 TI - Reducing Consumption Versus Maintaining Abstinence: Market Access Challenges Facing a Novel Treatment Pathway for Alcohol Addiction in the Eu5. PMID- 26532331 TI - Inequity in Access to Alzheimer Disease Indicated Treatment Across Different Geographic Areas of Turkey. PMID- 26532332 TI - Characteristics and Healthcare Resource use of Patients with Major Depressive Disorder Initiated on Snri Compared to Ssri In Beijing China. PMID- 26532333 TI - The Economic Consequences of the use of Antidepressants in Belgium: Prescribing Behavior and Misuse of Antidepressants. PMID- 26532334 TI - The Economic Consequences of the use of Antidepressants in Belgium. PMID- 26532335 TI - Depression: Highlight Molecules Used in Patients from Supplementary Health in Brazil. PMID- 26532336 TI - Drug Utilization Pattern of Lisdexamfetamine Dimesylate in Europe. PMID- 26532337 TI - Antidepressant use in Patients with Major Depressive Disorder: a Comparison of Treatment Resistant and Non-Treatment Resistant Episodes in the United Kingdom Using The Cprd Database. PMID- 26532338 TI - Risk of Incident Chronic Kidney Disease and End-Stage Renal Disease in Patients with Psoriasis: a Nationwide Population-Based Cohort Study. PMID- 26532339 TI - Integrated Clinical Pathway in Schizophrenia. PMID- 26532340 TI - Burden of Disease in Patients with Glaucoma in Brazil. PMID- 26532341 TI - Efficacy And Safety of Surgical Treatment Options for Primary Angle Closure Glaucoma: a Meta-Analysis of Randomised Controlled Trials. PMID- 26532342 TI - A Prospective Study to Compare Safety and Efficacy of Various Anti-Glaucoma Agents and Evaluate the Effect of Aerobic Exercise on Intra-Ocular Pressure in Newly Diagnosed Primary Open Angle Glaucoma Patients in a Tertiary Care Hospital. PMID- 26532343 TI - Skin Whitening Multiple Emulsions Loaded with Green Tea and Lotus Extracts: an Efficacy Study. PMID- 26532344 TI - Outcome of Harkany Thermal Water Completed Puva Therapy Versus Traditional Puva Therapy of Psoriatic Patients. PMID- 26532345 TI - Efficacy Comparison of Anti-Vegf and Laser Photocoagulation in the Treatment of Visual Impairment due to Diabetic Macular Edema: a Systematic Review and Network Meta-Analysis. PMID- 26532346 TI - Systematic Review and Mixed Treatment Comparison of Therapies for Diabetic Macular Edema. PMID- 26532347 TI - Higher Drug Survival Rates in Patients with Psoriasis Utilizing Etanercept Compared to Adalimumab - a Nationwide Population-Based Cohort Study in Sweden. PMID- 26532348 TI - Healthcare Pathways and Burden of Disease of Patients with Skin and Soft Tissue Infections (Sstis). PMID- 26532349 TI - Economic Burden of Pneumococcal Infections In Children Under Five Years Old. PMID- 26532350 TI - Biologic treatments for moderate-severe psoriasis. What efficacy gives you, cost should not take it away. PMID- 26532351 TI - Budget Impact Model of Omalizumab In The Treatment of Chronic Spontaneous Urticaria In Italy. PMID- 26532352 TI - Comparable Analysis of Prices for First Stage of Dental Implantation In Ukraine. PMID- 26532353 TI - Prevalence of Acne Vulgaris in Europe and Impact of Lifestyle Factors. PMID- 26532354 TI - Sun Exposure in Mexico: an Observational Study on Population Habits and Knowledge of Risks Associated with Such Exposure. PMID- 26532355 TI - Direct And Indirect Costs Associated to Retinal Vascular Diseases In Italy. A Probabilistic Cost of Illness Study. PMID- 26532356 TI - Costs Associated With The Management and Morbidity of Diabetic Macular Oedema and Macular Oedema Secondary to Retinal Vein Occlusion. PMID- 26532357 TI - The Cost-Of-Disease (Cod) In Diabetic Macular Edema (Dme) In Turkey: An Expert Panel Approach for Estimation of Costs. PMID- 26532358 TI - Sugar Free Gum In The Prevention of Caries: A Comparison of Germany and Finland. PMID- 26532359 TI - The Cost-Of-Disease (Cod) In Central Retinal Vein Occlusion (Crvo) In Turkey: An Expert Panel Approach For Estimation of Costs. PMID- 26532360 TI - The Cost-Of-Disease (Cod) In Wet Age-Related Macular Degeneration (Wamd) In Turkey: An Expert Panel Approach for Estimation of Costs. PMID- 26532361 TI - National Study to Assess The Costs of Patients With High Myopia With and Without Choroidal Neovascularisation. PMID- 26532362 TI - Estimation of Indirect (Work-Related Productivity) Costs Associated With Moderate To-Severe Plaque Psoriasis In Germany. PMID- 26532363 TI - Cost Effectiveness Analysis of Ranibizumab Compared to Aflibercept and Laser Intervention In Treatment of Diabetic Macular Edema (Dme) In The Czech Republic. PMID- 26532364 TI - Intravitrael Aflibercept Injection for The Treatment of Visual Impairment Due to Macular Oedema Secondary to Branch Retinal Vein Occlusion: Cost-Effectiveness Versus Ranibizumab. PMID- 26532365 TI - Cost-Utility Analysis of Apremilast for The Treatment of Moderate to Severe Plaque Psoriasis In The Italian Setting. PMID- 26532366 TI - Ranibizumab Vs. Verteporfin Photodynamic Therapy for The Treatment Of Myopic Choroidal Neovascularization: Cost Effectiveness Study In Portugal. PMID- 26532367 TI - Cost-Effectiveness of Apremilast In Moderate to Severe Psoriasis In Scotland. PMID- 26532368 TI - Cost-Effectiveness of Treatments for Wet Age-Related Macular Degeneration (Wamd) In The Netherlands, The Case of Intravitreal Aflibercept (Ivt-Afl) and Ranibizumab. PMID- 26532369 TI - Cost-Utility Analysis of Apremilast for The Treatment of Moderate to Severe Psoriasis In Spain. PMID- 26532370 TI - Cost-Effectiveness Analysis of Intravitreal Aflibercept In Diabetic Macular Oedema In Sweden. PMID- 26532371 TI - Drug Utilisation And Healthcare Resources Use In Patients With Psoriatic Arthritis And Psoriasis. PMID- 26532372 TI - Cost-Effectiveness of Ikervis(r) In Severe Dry Eye Disease In The Uk [Update]. PMID- 26532373 TI - Cost-Effectiveness Analysis of Intravitreal Aflibercept In The Treatment of Neovascular Age-Related Macular Degeneration In Greece. PMID- 26532374 TI - Cost-Effectiveness Analysis of Conbercept Versus Ranibizumab For The Treatment of Age-Related Macular Degeneration In China. PMID- 26532375 TI - Budget Impact Analysis of Apremilast on Moderate to Severe Psoriasis In Spain. PMID- 26532376 TI - Budget Impact Analysis of Apremilast In Patients With Psoriasis In The Italian Setting. PMID- 26532377 TI - Cost-effectiveness of Ranibizumab Vs. Dexamethasone Implant In Diabetic Macular Edema. PMID- 26532378 TI - Cost-Effectiveness Analysis of Topical Filed Treatment Therapies for The Treatment of Actinic Keratosis In Greece. PMID- 26532379 TI - Sugar Free Gum: Impact on Oral Health and Copayment In Germany. PMID- 26532380 TI - Cost-Effectiveness of Secukinumab Compared to Ustekinumab In Patients With Psoriasis From A Swedish Health Care Perspective. PMID- 26532381 TI - Adapalene 0.1% / Benzoyl Peroxide 2.5% + Doxycycline 200mg Is A Less Expensive Alternative Compared to Oral Isotretinoin for The Management of Severe Nodular Acne In Sweden. PMID- 26532382 TI - Cost-Utility of Omalizumab Compared With Standard of Care for The Treatment of Chronic Spontaneous Urticaria (Csu). PMID- 26532383 TI - Cost-Utility of Ranibizumab Versus Aflibercept for Treating Visual Impairment Due to Diabetic Macular Edema In Greece. PMID- 26532384 TI - Cost-Utility Analysis of Ingenol Mebutate Versus Imiquimod 5% for Actinic Keratosis Treatment In Spain. PMID- 26532385 TI - Health And Economic Outcomes Related to Delay Between Medical Indication and Treatment With Ranibizumab In Age-Related Macular Degeneration In Greece. PMID- 26532386 TI - Cost-Effectiveness Of Omalizumab In Chronic Spontaneous Urticaria In The Netherlands. PMID- 26532387 TI - Cost-Utility Analysis of Ingenol Mebutate Versus Diclofenac 3% for Actinic Keratosis Treatment In Spain. PMID- 26532388 TI - Healthcare Resource Utilisation Among Chronic Spontaneous/Idiopathic Urticaria Patients- Findings From The First International Burden of Illness Study (Assure Csu). PMID- 26532389 TI - Cost-Effectiveness Analysis of Secukinumab Compared to Ustekinumab In The Treatment of Moderate to Severe Plaque Psoriasis In The Czech Republic. PMID- 26532390 TI - Economic Burden of Chronic Spontaneous Urticaria And Psoriasis: Patients Perspective From Europe. PMID- 26532391 TI - A Cost-Effectiveness Analysis of Secukinumab 300 Mg Vs Current Therapies for The Treatment of Moderate to Severe Plaque Psoriasis In Italy. PMID- 26532392 TI - Characteristics of Acne Vulgaris In European Adolescents And Patients Perceptions. PMID- 26532393 TI - Impact of Alexithymia and Disease Characteristics on Work Productivity and Activity In Psoriasis Patients With Short Disease Duration: Epidepso Multicentre Study. PMID- 26532394 TI - Disease Burden, Outcomes and Costs Among Adults Admitted To Hospital In The United Kingdom (Uk) Due to Plaque Or Erythrodermic Psoriasis. PMID- 26532395 TI - Assessment of Dental Status and Perception Towards Oral Health Among Pharmacy Students In Quetta, Pakistan. PMID- 26532396 TI - Evaluation of Psoriasis Patients' Attitude to Risk: Benefit And Therapeutic Tradeoffs In Their Choice of Treatments. PMID- 26532397 TI - First Real-World Study Assessing Health Utility Values For Chronic Spontaneous/Idiopathic Urticaria Using The Eq-5d. PMID- 26532398 TI - Validation of The Spanish Version of The Urticaria Activity Score (Uas) and Its Use Over One Week (Uas7). PMID- 26532399 TI - Burden Of Infantile Hemangioma On Family: An International Cross-Sectional Study. PMID- 26532400 TI - Review of Patient Reported Outcomes In Glaucoma. PMID- 26532401 TI - Improved Visual Function Is Associated With Inflammation Reduction In Subjects With Non-Infectious Uveitis (Niu) of The Posterior Segment Treated With Intravitreal Sirolimus: ResultsFrom Sakura Study 1. PMID- 26532402 TI - Social Impact of Psoriasis In Spain: A Rasch Analysis From A Survey. PMID- 26532404 TI - Patient Diagnostic Therapeutic Pathway For Patients With Psoriasis The Organisational Analysis of 13 Excellence Centres Of The Tuscany Region (Italy). PMID- 26532403 TI - Work Productivity and Activity Impairment Among Chronic Spontaneous/Idiopathic Urticaria Patients: ResultsFrom The First International Burden of Illness Study (Assure-Csu). PMID- 26532405 TI - Does Health-Related Quality of Life Evaluation In Psoriasis Matter? A Review of Labels of Psoriasis Products Approved By The Fda and The Ema. PMID- 26532406 TI - The Value of Achieving Complete or Near Complete Resolution of Psoriasis. PMID- 26532407 TI - Quality Of Life And Perspectives Of Happiness In Middle-Aged And Older People With Dysphagia. PMID- 26532408 TI - Real-World Treatment Patterns of Ranibizumab Among Patients With Retinal Diseases In Canada: 5 Years Of Data. PMID- 26532409 TI - Price Fluctuations Across Lifecycle: Insights From The Anti-Vegf Market. PMID- 26532410 TI - Glaucoma: Highlight Molecules Used In Patients From Supplementary Health In Brazil. PMID- 26532411 TI - Treatment of Macular Edema: What's New? Evidence From An Hta Study Comparing Ranibizumab And Dexamethasone Implant. PMID- 26532413 TI - Selective Retina Therapy. PMID- 26532412 TI - Nationwide Trend Analysis of Targeted Therapies for Treatment Of Malignant Neoplasms of The Eye In Taiwan (2009-2016). PMID- 26532414 TI - Real World Skin Clearance Rates for Biologic Treatments In Patients With Moderate to Severe Plaque Psoriasis: Interim Results From A Large Prospective, Observational Study. PMID- 26532415 TI - Prospective Study Of Radiation Related Adverse Events And Its Management In Cancer Patients- A Pilot Study. PMID- 26532416 TI - Adverse Events Costs Associated With Erlotinib Or Afatinib In Non-Small Cell Lung Cancer (Nsclc) Patients With Egfr Mutation-Positive Tumours. PMID- 26532417 TI - Pharmacovigilance Of Anti-Neoplastic Agents In A Developing Country-A Report Through A Spontaneous Reporting & Contineous Monitoring System. PMID- 26532418 TI - Factors Influencing Treatment Duration In Metastatic Colorectic Cancer Patients Treated With Ziv-Aflibercept: A Real World View. PMID- 26532419 TI - Efficacy And Safety Profile Of Combined Targeted Therapy Against Egfr And Vegf In Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer: A Systematic Review And Meta-Analysis. PMID- 26532420 TI - A Systematic Review To Assess The Association Between The Use Of Antidepressants And Male-Only Cancers. PMID- 26532421 TI - SERIOUS POST-OPERATIVE INFECTIONS INCREASE RESOURCE UTILIZATION, LENGTH OF STAY, AND INPATIENT MORTALITY IN PEDIATRIC PATIENTS UNDERGOING BRAIN TUMOR RESECTION. PMID- 26532422 TI - Changes In The Mortality Rate During The Last Decade In The Fields Of Oncology In Hungary. PMID- 26532423 TI - Assessment Of Serious Adverse Reactions Among Patients On Tyrosine Kinase Inhibitors: Identification Of Significant Signals For Gastrointestinal Hemorrhage And Pulmonary Reactions. PMID- 26532424 TI - The Effect Of Glucose Lowering Drug Use On Overall Mortality Among Breast Cancer Patients. PMID- 26532425 TI - Prevalence Of Depression And Anxiety And Their Risk Factors In Women With Breast Cancer In German Primary Care. PMID- 26532426 TI - Mortality Reduction From Gastric Cancer By Endoscopic Screening: 6-Years Follow Up Of A Population-Based Cohort Study. PMID- 26532427 TI - Therapy Of Depression In Cancer And Non-Cancer Patients In German Neuropsychiatric Practices. PMID- 26532428 TI - Long-Term Trends In Descriptive Epidemiology Of Malignant Melanoma In The Slovak Republic. PMID- 26532429 TI - Patterns Of Metachronous Metastases After Curative Treatment Of Breast Cancer. PMID- 26532430 TI - Bayesian Network Meta-Analysis To Assess Relative Efficacy Of Ibrutinib Versus Idelalisib+Ofatumumab And Physician's Choice In Relapsed/Refractory Cll Patients. PMID- 26532431 TI - Assessment Of Major Molecular Response (Mmr) And Complete Cytogenetic Response (Ccyr) As Surrogate Outcomes Of Survival In Chronic Myeloid Leukemia Chronic Phase (Cml-Cp) Patients. PMID- 26532432 TI - Comparison Of Treatment Duration Among Targeted Agents In Renal Cell Carcinoma (Rcc). PMID- 26532433 TI - Evaluation Of Patterns Of Care In Renal Cell Carcinoma (Rcc): High Unmet Need Persists. PMID- 26532434 TI - TREATMENT STRATEGIES FOR ELDERLY PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA: A META-ANALYSIS AND INDIRECT TREATMENT COMPARISON. PMID- 26532435 TI - Comparative Efficacy Of Imatinib, Dasatinib And Nilotinib For Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (Cml-Cp): A Meta-Analysis And Indirect Comparison. PMID- 26532436 TI - Overall Survival (Os), Quality Of Life (Qol), And Neurocognitive Function (Nf) In Recurrent Glioblastoma Multiforme (Gbm): A Systematic Literature Review. PMID- 26532437 TI - Effects Of Lifestyle Interventions On Body Mass Index In Breast Cancer Patients. PMID- 26532438 TI - Clinical Effectiveness And Safety Of Robot-Assisted Laparoscopic Hysterectomy Versus Traditional Laparotomy For Endometrial Cancer: A Systematic Review. PMID- 26532439 TI - Overall Survival (Os) And Quality-Of-Life (Qol) Outcomes In Recurrent Or Metastatic Squamous Cell Carcinoma Of The Head And Neck (Scchn): A Systematic Literature Review. PMID- 26532440 TI - Lipegfilgrastim For Reduction Of Chemotherapy-Induced Neutropenia Related Events: A Meta-Analysis. PMID- 26532441 TI - Comparative Effectiveness Of Granulocyte Colony-Stimulating Factors (G-Csf) For Reducing Incidence Of Febrile Neutropenia (Fn) -Related Hospitalization: A Retrospective Cohort Study Using German Claims Data. PMID- 26532442 TI - Analysis Of Eribulin Mesylate Dosing Modifications Impact On Administration Persistence In Patients With Metastatic Breast Cancer (Mbc). PMID- 26532443 TI - A Systematic Literature Review To Identify And Compare Clinical Trials Evaluating Novel Therapeutic Agents In Post-Gemcitabine Advanced Pancreatic Cancer. PMID- 26532444 TI - A Real-World Analysis Of Korean Nation-Wide Database: Pattern, Adherence, And Associated Heatlhcare Costs Of Imatinib Among Patients With Chronic Myeloid Leukemia. PMID- 26532445 TI - New Drugs In Advanced Melanoma: Disparities In Requirements For Post-Launch Real Word Evidence In Europe. PMID- 26532446 TI - Real-World Analysis Of Tyrosin Kinase Inhibitor Treatemnt Patterns Among Patients With Chronic Myeloid Leukemia In Korea. PMID- 26532447 TI - A Description Of Real-World Treatment With Abiraterone Acetate In Metastatic Castration-Resistant Prostate Cancer Patients In The Post-Chemotherapy Setting In France And The Netherlands. PMID- 26532448 TI - Matching-Adjusted Indirect Treatment Comparison And Survival Extrapolation In Radioiodine-Refractory Differentiated Thyroid Cancer (Rai-Refractory Dtc): Updated Analysis. PMID- 26532449 TI - The Relative Efficacy And Safety Of Treatments In Second-Line Management Of Chronic Myeloid Leukaemia: Systematic Review And Network Meta-Analysis Feasibility Study. PMID- 26532450 TI - Eroltinib Plus Gemcitabine Compared With Gemcitabine Monotherapy In Patients With Pancreatic Cancer: A Real-World Analysis Of Korean Nationa-Wide Database. PMID- 26532451 TI - New Drugs In Non-Small Cell Lung Cancer: Disparities In Requirements For Post Launch Real-Word Evidence In Europe. PMID- 26532452 TI - Symptoms, Concomitant Conditions And Cardiac Risk In European Hydroxyurea Treated Polycythemia Vera Patients. PMID- 26532453 TI - Assessing The Level Of Resistance/Intolerance To Hydroxyurea Therapy Amongst Patients With Polycythemia Vera In Europe. PMID- 26532454 TI - Comparative Efficacy Of Treatments For Previously Treated Advanced Or Metastatic Non-Small Cell Lung Cancer (Nsclc): A Network Meta-Analysis. PMID- 26532455 TI - The Impact Of First-Line Tyrosine Kinase Inhibitors (Tkis) On Overall Survival In Patients With Advanced Non-Small Cell Lung Cancer (Nsclc) And Activating Epidermal Growth Factor Receptor (Egfr) Mutations: Meta-Analysis Of Major Randomized Trials By Mutation Type. PMID- 26532456 TI - Survival And Cost Among Photodynamic Therapy Patients With Non-Small Cell Lung Cancer. PMID- 26532457 TI - Effects Of Nutritional Supplement Usage On Mortality In Colorectal Cancer Patient With Abdominal Resection Surgery. PMID- 26532458 TI - A Cross-Sectional Epidemiological Cancer Registry In Egypt. PMID- 26532459 TI - Impact Of Cancer Diagnosis And Treatment On Glycaemic Control Among Individuals With Colorectal Cancer Using Glucose Lowering Drugs. PMID- 26532460 TI - The Treatment Patterns Of Castration Resistant Prostate Cancer In Japan. PMID- 26532461 TI - Use Pattern Narcotic Analgesics For Cancer Patient In South Korea : Claims Data Analysis. PMID- 26532462 TI - Changes In Glucose Lowering Drug Use Before And After A Cancer Diagnosis Among Individuals With Diabetes. PMID- 26532463 TI - The Ups And Downs Of Hpv-Related Cancers: Trends 2005-2014. PMID- 26532464 TI - Systematic Review Of Burden Of Cutaneous T-Cell Lymphoma. PMID- 26532465 TI - Evolution Of The Number Of Patients Treated For Metastatic Cancer Between 2003 And 2013 In France. PMID- 26532466 TI - PATIENT CHARACTERISTICS AND HEALTHCARE BURDEN OF CANCER HOSPITALIZATIONS IN THE UNITED STATES. PMID- 26532467 TI - Prevalence And Risk Factors Of Skin Cancer In Mexico: An Observational Study. PMID- 26532468 TI - Adjusting For Cross-Over In Oncology Trials: Approaches Taken To Support Drug Reimbursement In Australia. PMID- 26532469 TI - Statins Use And The Risk Of Hematological And Non-Hematological Malignancies: A Meta-Analysis Of 53 Observational Studies. PMID- 26532470 TI - The Effect Of Metformin Use And Mortality Among Those With Pancreatic Cancer And Type 2 Diabetes Mellitus: Findings From A Nationwide Population Retrospective Cohort Study. PMID- 26532471 TI - Systematic Review Of Burden Of Pancreatic Cancer. PMID- 26532472 TI - Epidemiology And Treatment Of Soft Tissue Sarcoma In The Eu5. PMID- 26532473 TI - Assessment Of Renal Function Among Patients With Bone Metastases From Solid Tumors. PMID- 26532474 TI - Improved Survival With Ipilimumab In Patients With Advanced Melanoma In Real World Clinical Practice: First Results Of The Dutch Melanoma Treatment Registry. PMID- 26532475 TI - Associations Of Metformin Use With Mortality And Disease Progression After Curative Hepatic Resection In Hepatocellular Carcinoma With Type 2 Diabetes Mellitus: A Nationwide Population-Based Study. PMID- 26532476 TI - When "Alive After 5 Years" Does Not Mean "Cured": International Patterns In Cancer 10- To 20- Year Relative Survival Rates. PMID- 26532477 TI - Safety And Insurance Premium Implications For Hospitals Based On Subcutaneous Versus Intravenous Administration Of Oncology / Hematology Therapies: Case Studies With Rituximab (Mabthera) And Trastuzumab (Herceptin). PMID- 26532478 TI - Improved Survival In Patients With Advanced Melanoma In Real-World Clinical Practice: First Results Of The Dutch Melanoma Treatment Registry. PMID- 26532479 TI - Mortality Trends In Cancers: A New Model To Visualise The Contribution Of Specific Diseases, Cohorts And Coding Changes To Overall Mortality Improvement. PMID- 26532480 TI - Evaluation Of 'Real-World' Ipilimumab Data In Ireland. PMID- 26532481 TI - Retrospective Comparison Of Real-Life Survival Data From Single Centre Trials - The Clinical Outcome Of Vemurafenib Therapy In Metastatic Melanoma Patients. PMID- 26532482 TI - The Budget Impact of Denosumab in the Treatment of Giant Cell Tumor of the Bone (Gctb) in Belgium. PMID- 26532483 TI - Budget Impact Analysis of Dasatinib as a Second-Line Therapy in Patients with Chronic Myelogenous Leukemia (Cml) in the Russian Federation. PMID- 26532484 TI - Economic Impact of the Detection of Medication Errors in Oncological Patients with Afebrile Neutropenia in a Cancer Hospital. PMID- 26532485 TI - What is the Most Cost-Effective way to Set-Up Organised Cervical Cancer Screening in France? a Budget Impact Analysis. PMID- 26532486 TI - Budget Impact Analysis or Pharmacological Therapy of Chronic Myeloid Leukemia (Cml) with Nilotinib as the Second-Line Treatment in Russian Federation. PMID- 26532487 TI - Pharmacoeconomic Analysis of the use of Everolimus Compared to Axitinib in Second Line Therapy of Patients with Metastatic Renal Cell Carcinoma. PMID- 26532488 TI - Cost Analysis in Implementing Rituximab for non-Hodgkins Lymphoma - Intravenously and Subcutaneously - in Patients with Social Coverage in Latam. PMID- 26532489 TI - Radio-223 in the Treatment of Metastatic Castration Resistant Prostate Cancer with Bone Metastases: Budget Impact Analysis of the National Health Service. PMID- 26532490 TI - An Assessment of Annual Costs of Patients Hospitalized for Spinal Tumors in France: Analysis Using the Pmsi Database. PMID- 26532491 TI - Healthcare Burden and Economic Cost of Hospitalisation During Chemotherapy for Adult Patients with Ph-Negative B-Precursor Relapsed or Refractory (R/R) Acute Lymphoblastic Leukaemia (All) in France. PMID- 26532492 TI - Retrospective Chart Review of Hospitalisations During Chemotherapy for Adult Patients with Ph-Negative B-Precursor Relapsed or Refractory (R/R) Acute Lymphoblastic Leukaemia (All) In Italy. PMID- 26532493 TI - Budget Impact Analysis of the Treatment of Chronic Myeloid Leukemia with Tyrosine Kinase Inhibitors - Nilotinib in the First and Second Lines of Therapy. PMID- 26532494 TI - Pharmacoeconomic Analysis of Urothelial Transitional Cell Cancer Treatment with Vinflunine in Patients Resistant to the Platinum-Based Treatment Regimes. PMID- 26532495 TI - Hospitalisations Among Adult Patients with Ph-Negative B-Precursor Relapsed or Refractory (R/R) Acute Lymphoblastic Leukaemia (All) Receiving Chemotherapy in Germany: A Retrospective Chart Review. PMID- 26532496 TI - A Trial-Based Economic Evaluation of Resource use and Costs in the Emilia Clinical Study. PMID- 26532497 TI - Pharmacoeconomic Analysis of Ferric Carboxymaltose in Patients with Colon Cancer and Anemia. PMID- 26532498 TI - Rituximab Sc Vs Rituximab Iv for non-Hodgkin's Lymphomas (Nhls): an Economic Evaluation for the Greek Healthcare System. PMID- 26532499 TI - Do Payers Equally Value the Cost Per Month of Overall Survival for Metastatic Castration Resistant Prostate Cancer within the Eu5? PMID- 26532500 TI - Pharmacoeconomical Characteristics of Different Strategies of Hemostasis During Extensive Hepatectomy. PMID- 26532501 TI - Cost Comparison of Oral Versus iv Vinorlbine in France in Advanced Breast Cancer. PMID- 26532502 TI - Five-Years Experience of Robotic Vs Laparoscopic Colorectal Cancer Surgery in a Single Center: Surgical Parameters and Costs. PMID- 26532503 TI - Costs to U.S. Health Insurers for Hematopoietic Stem Cell Transplant (Hct) Recipients with Double Stranded Dna (Dsdna) Virus Infections Following Transplant. PMID- 26532504 TI - Extended-Release Oxycodone Hydrochloride (Oxycontin(r)) for Cancer Pain Management: a Cost Analysis from the Brazilian Public and Private Healthcare Systems Perspectives. PMID- 26532505 TI - The Cost of Radiotherapy: What Do We Know? a Systematic Search of the Literature Between 1981 and 2015. PMID- 26532506 TI - Total Annual Cost Associated with Best Supportive Care of Patients with Unresectable Advanced Non-Small-Cell Lung Cancer Under Real-World-Conditions in Relation to Results of International Studies. PMID- 26532507 TI - A Cost-Effectiveness Analysis of Gefitinib as the First Line Treatment in Patients With Positive Egfr Mutation In Metastatic or Locally Advanced non-Small Cell. PMID- 26532508 TI - Analysis of Clinical and Economic Implications of Esmo 2014 Clinical Practice Guidelines for Metastatic Colorectal Cancer Treatment. PMID- 26532509 TI - Oral Vinorelbine Plus Cisplatin Versus Pemetrexed Plus Cisplatin as First-Line Treatment for Patients with Advanced non- Squamous non- Small Cell Lung Cancer: a Cost Minimization Analysis in Twelve European Countries. PMID- 26532510 TI - A Cost Comparison of Treatment with Abiraterone Acetate Plus Prednisone in the Pre Chemotherapy Setting Followed By Enzalutamide in the Post-Chemotherapy Setting Versus the Opposite Treatment Sequence in Metastatic Castration Resistant Prostate Cancer Patients With non-Visceral Metastases. PMID- 26532511 TI - The Economic Burden of Primary Brain Tumors in Canada. PMID- 26532512 TI - Decrease of Patient Costs in the Netherlands: a Cost of Illness Study in Metastatic Non Small Cell Lung Cancer (Nsclc). PMID- 26532513 TI - An Assessment of The Hospitalization Costs of Melanoma in France in the Advanced/Metastatic Setting: the Melissa Study (Melanoma in Hospital Costs Assessment). PMID- 26532514 TI - Burden of Disease of Ovarian Cancer in Spain. Ovarcost Study. PMID- 26532515 TI - The Societal and Economic Impact of Cervical Cancer in Brazil. PMID- 26532516 TI - Economic Burdens of the Top 10 Cancers During 2003-2012 in Taiwan. PMID- 26532517 TI - Direct Medical Costs Associated with Multiple Myeloma in Chinese Patients: Estimations from China Public Health Insurance Claim Data. PMID- 26532518 TI - The Life Time Cost-of-Disease (Cod) of Metastatic Colorectal Cancer (Mcrc) in Turkey: an Expert Panel Approach for Estimation of Costs. PMID- 26532519 TI - Cost and Cost-Effectiveness Data on Pancreatic Cancer: a Comprehensive Review of the Literature. PMID- 26532520 TI - The Economics of the Treatment and Follow-Up of Patients with Glioblastoma. PMID- 26532521 TI - Cost of Cervical Cancer and Cervical Intraepithelial Neoplasia in Croatia. PMID- 26532522 TI - A Systematic Literature Review of Economic Burden of Myelofibrosis. PMID- 26532523 TI - Economic and Humanistic Burden of Ductal Carcinoma in Situ. PMID- 26532524 TI - The Increasing Cost Burden of Obesity Related Cancer to Nhs England. PMID- 26532526 TI - Clinical and Economic Burden of Prostate Cancer. PMID- 26532525 TI - Medical Cost Associated with Treatment and Follow-Up of Pantients with Head and Neck Cancer. PMID- 26532527 TI - The Cost-of-Disease of Metastatic/Inoperable Gastrointestnal Stromal Tumors in Turkey: an Expert Panel Approach for Estimation of Costs. PMID- 26532528 TI - The Analysis of Inpatients Cost of Breast Cancer in China, 2011. PMID- 26532529 TI - Epidemiology and Burden of Multiple Myeloma in Japan: a Systematic Review. PMID- 26532530 TI - Resource Utilization Among Advanced Squamous and non-Squamous non-Small Cell Lung Cancer Patients Receiving Second-Line Treatment in France, Germany, Italy, and Spain: Results of A Retrospective Medical Chart Review. PMID- 26532531 TI - Treatment Sequencing Patterns And Costs of Care in Patients with Relapsed/Refractory Multiple Myeloma. PMID- 26532532 TI - Treatment Strategies, Health Care Resource use and Costs of Aggressive Histological types of non-Hodgkin Lymphomas in the Slovak Republic. Results from the Cross-Sectional Survey in the Haematology-Oncological Centers. PMID- 26532533 TI - Treatment Patterns and Health Care Resource use (Hcru) Associated with Repeatedly Treated Metastatic Squamous Cell Carcinoma of the Head and Neck (Scchn) in the United Kingdom (Uk). PMID- 26532534 TI - Health and Economic Burden of Breast Cancer Mortality in Younger Women Aged 18-44 Years in the United States, 1970-2012. PMID- 26532535 TI - Additional Cost of Vte In Patients with Cancer: an Approach Based Databases. PMID- 26532536 TI - Clinical, Mediciation and Economical Outcome Research of Advanced Colorectal Cancer Relapse Using Reimbursement and Cancer Registry Databases. PMID- 26532537 TI - The Management and Costs of Locally Advanced or Metastatic Alk-Positive Non-Small Cell Lung Cancer in Greece. PMID- 26532538 TI - Estimation of Direct Medical Costs Associated with Treatment of Metastatic Melanoma in Switzerland. PMID- 26532539 TI - Intermediate and Advanced Hepatocellular Carcinoma Management in four Italian Centers: Patterns of Treatment and Costs. PMID- 26532540 TI - Economic Burden of Patients with Alk+ Mutation non-Small Cell Lung Cancer After Treatment with Crizotinib: a Canadian Retrospective Observational Study. PMID- 26532541 TI - Health-Economic Comparison of a Gnrh-Antagonist (Degarelix) Vs. Gnrh-Agonists Considering the Number-Needed-to-Treat to Avoid Cardiovascular Events. PMID- 26532542 TI - Colorectal Cancer: the Importance of Being Right - a Model Investigating the Impact of Bowel Cleansing on Adenoma Detection in a German Screening Population. PMID- 26532543 TI - Prostatectomy: a Comparison of Cost-Benefit Analysis Between Open Surgery and Robotic Techniques. PMID- 26532544 TI - Resource Use and Cost of Chemotherapeutic Treatment for Metastatic Breast Cancer in the Netherlands. PMID- 26532545 TI - Cost Effectiveness of Bortezomib, Rituximab, Cyclophosphamide, Doxorubicin and Prednisone for the First-Line Treatment of Mantle Cell Lymphoma not Eligible for Stem Cell Transplantation: a Scottish Perspective. PMID- 26532546 TI - Cost-Effectiveness of Vemurafenib as a First-Line Treatment in Patients with Braf V600 Mutation-Positive Unresectable or Metastatic Melanoma in Spain. PMID- 26532547 TI - Cost-Effectiveness of Pembrolizumab for Unresectable Metastatic Melanoma After Progression with Ipilimumab in England. PMID- 26532548 TI - Revisiting The Simulation Evidence for the Incremental Cost-Effectiveness of Breast Cancer Screening of Average-Risk Women. PMID- 26532549 TI - Economic Assessment of Eribulin Against Treatment of Physician's Choice (Tpc) in Taiwan. PMID- 26532550 TI - Therapeutic and Economic Value of Everolimus Plus Exemestane for the Treatment of Postmenopausal Women with Hormone Receptor-Positive, Her2/Neu Negative Advanced Breast Cancer. PMID- 26532551 TI - Aflibercept in Combination with Folfiri in Patients with Metastatic Colorectal Cancer: Cost-Effectiveness Based on Velour Best Efficacy Subgroup Post-Hoc Analysis. PMID- 26532552 TI - Cost-Effectiveness of Cardioprotective Effect of Dexrazoxane (Cardioxane(r)) in Advanced/Metastatic Breast Cancer Patients Treated with Anthracycline-Based Chemotherapy in Mexico. PMID- 26532553 TI - Cost-Effectiveness Analysis Of Neo-Adjuvant Pertuzumab Therapy In Women With Locally Advanced, Inflammatory, Or Early Her2-Positive Breast Cancer In Italy. PMID- 26532554 TI - A Cost Utility Analysis Of Cetuximab For 1st-Line Treatment Of Ras Wild-Type Metastatic Colorectal Cancer: A Summary Of The Submission To All Wales Medicines Strategy Group (Awmsg). PMID- 26532555 TI - The Cost Effectiveness Of Idelalisib In Chronic Lymphocytic Leukaemia In England And Wales. PMID- 26532556 TI - Cost-Effectiveness Of Ceritinib In The Treatment Of Previously Treated Anaplastic Lymphoma Kinase-Positive (Alk+) Non-Small Cell Lung Cancer In The United Kingdom. PMID- 26532557 TI - The Cost-Effectiveness Of Regorafenib In The Treatment Of Metastatic/Inoperable Gastrointestinal Stromal Tumors In Turkey. PMID- 26532559 TI - A Scotland Based Cost-Effectiveness Analysis Of Idelalisib (Zydelig(r)) In Combination With Rituximab For The Treatment Of Adults With Chronic Lymphocytic Leukaemia Cll). PMID- 26532558 TI - Cost-Effectiveness Of Sunitinib As Second-Line Treatment For Gastrointestinal Stromal Tumor(Gist) In China. PMID- 26532560 TI - Cost-Effectiveness Of Ofatumumab Plus Chlorambucil In First-Line Chronic Lymphocytic Leukemia In The United Kingdom. PMID- 26532561 TI - Cost-Effectiveness Analysis Of Granulocyte Colony-Stimulating Factors For The Prophylaxis Of Chemotherapy-Induced Febrile Neutropenia In Patients With Breast Cancer In Greece. PMID- 26532562 TI - Cost-Effectiveness Of Bortizomib For Multiple Myeloma: A Systematic Review. PMID- 26532563 TI - Value Of Implementation Of Physical Exercise For Cancer Survivors. PMID- 26532564 TI - Pharmacoeconomics Of Ruxolitinib Therapy In Patients With Myelofibrosis. PMID- 26532565 TI - Cost-Effectiveness Analysis Of Pertuzumab For Metastatic Her2-Positive Breast Cancer In Japan. PMID- 26532566 TI - Consequences Of Biomarker Analysis On The Cost-Effectiveness Of Cetuximab In Combination With Irinotecan Based Chemotherapy For First-Line Treatment Of Metastatic Colorectal Cancer. Stratified Medicine At Work? PMID- 26532567 TI - Cost-Effectiveness Analysis Of Granulocyte Colony-Stimulating Factors For The Prophylaxis Of Chemotherapy-Induced Febrile Neutropenia In Patients With Non Hodgkin's Lymphoma In Greece. PMID- 26532568 TI - Cost-Effectiveness Of Nilotinib In Patients With Chronic Myeloid Leukaemia Eligible To Start The Treatment-Free Remission Phase In Italy. PMID- 26532569 TI - Estimating The Cost-Effectiveness Profile Of A Vaccination Programme With A Nine Valent Hpv Vaccine In Italy. PMID- 26532570 TI - A Cost-Effectiveness Analysis Of A Genomic Test Compared To Standard Of Care In Breast Cancer Patients In France. PMID- 26532571 TI - Cost-Effectiveness In The Second-Line Treatment Of Non-Small Cell Lung Cancer (Nsclc) In The Us. PMID- 26532572 TI - The Cost-Effectiveness Of Regorafenib In The Treatment Of Patients With Metastatic Colorectal Cancer (Mcrc) Who Have Progressed After Standard Therapies In Turkey. PMID- 26532573 TI - Comparative Efficacy And Costs Of Treatment Sequences In Metastatic Castration Resistant Prostate Cancer. PMID- 26532574 TI - Mammography For Breast Cancer Screening In India - A Health Technology Assessment. PMID- 26532576 TI - Pharmacoeconomic Analysis Of Afatinib As 1st-Line Treatment Of Metastatic Non Small Cell Lung Cancer With Del19 Mutation Of Egfr Gene. PMID- 26532575 TI - Cost-Effectiveness Of Directly Mailed Fobt Kits To Previous Responders Being Recalled For Screening. PMID- 26532577 TI - Cost-Effectiveness Of First-Line Tyrosine Kinase Inhibitors (Tkis) In Newly Diagnosed Chronic Myeloid Leukemia (Cml) Patients In Korea: Comparison Of Dasatinib (100mg), Nilotinib (600mg) And Imatinib (400mg). PMID- 26532578 TI - Cost Effectiveness Of Cetuximab In First Line Treatment Of Ras Wild-Type Metastatic Colorectal Cancer In The Uk: A Summary Of Economic Analyses Submitted To The National Institute For Health And Care Excellence (Nice). PMID- 26532579 TI - Systematic Review Of Cost Effectiveness Of Gefitinib In The Treatment Of Non Small Cell Lung Cancer In China. PMID- 26532580 TI - Economic Evaluation Of Pegfilgrastim As Prophylaxis For Febrile Neutropenia In Patients With Solid Tumors Or Lymphoma Receiving Chemotherapy In Mexico. PMID- 26532581 TI - Results Of A Dutch Cost-Effectiveness Model Of Radium-223 In Comparison To Cabazitaxel, Abiraterone, And Enzalutamide In Patients With Metastatic Castration Resistant Prostate Cancer Previously Treated With Docetaxel. PMID- 26532583 TI - Dasatinib, High-Dose Imatinib And Nilotinib In Chinese Patients With Chronic Phase Of Chronic Myeloid Leukemia With Imatinib-Resistance Or -Intolerance: An Economic Evaluation. PMID- 26532582 TI - Study On Cost-Effectiveness Analysis For Multiple Myeloma Treatment: A Systematic Review Of Literature From 2004-2014. PMID- 26532584 TI - Cost-Effectiveness Analysis Of Panitumumab + Folfox Compared To Cetuximab + Folfiri As First-Line Treatment For Patients With Wild-Type (Wt) Ras (Exons 2, 3, And 4 Of Kras And Nras) Metastatic Colorectal Cancer (Mcrc) In Colombia. PMID- 26532585 TI - Health Economics And Radium-223 (Xofigo(r)) In The Treatment Of Metastatic Castration-Resistant Prostate Cancer (Mcrpc). A Case History And A Systematic Review Of The Literature On Cost-Effectiveness Analysis (Cea). PMID- 26532586 TI - Cost-Effectiveness Of Idelalisib Plus Rituximab In Chronic Lymphocytic Leukaemia. PMID- 26532587 TI - Cost-Effectiveness Analysis Of Obinutuzumab/Chlorambucil Vs Rituximab/Chlorambucil In Treatment Of Chronic Lymphocytic Leukemia. PMID- 26532588 TI - Cost-Effectiveness Analysis Of Cetuximab And Panitumumab For First Line Treatment Of Metastatic Colorectal Cancer (Mcrc) In Wt Ras Patients In Spain. PMID- 26532589 TI - Economic Evaluations Of Glioblastoma. PMID- 26532590 TI - Economic Evaluation For Fluvestrant 500 Mg Im Versus Exemestene In Egyptian Patients With Metastatic Breast Cancer. PMID- 26532591 TI - Cost-Effectiveness Of Idelalisib In Combination With Rituximab For The Treatment Of Relapsed/Refractory Chronic Lymphocytic Leukemia (Cll) In Portugal. PMID- 26532592 TI - Fixed Combination Netupitant And Palonosetron Is A Cost-Effective Intervention For The Prevention Of Chemotherapy-Induced Nausea And Vomiting In The Uk. PMID- 26532593 TI - Adding Bevacizumab To Single-Agent Chemotherapy For The Treatment Of Platinum Resistant Recurrent Ovarian Cancer: A Cost-Effectiveness Analysis Of The Aurelia Trial. PMID- 26532594 TI - Literature Review Of Economic Evaluations Of Screening Tests For Breast Cancer. PMID- 26532595 TI - Cost-Effectiveness Of Ceritinib In Previously Treated Patients With Crizotinib In Anaplastic Lymphoma Kinase-Positive (Alk+) Non-Small Cell Lung Cancer In Canada. PMID- 26532596 TI - A Cost-Effectiveness Analysis Of Aspirin In The Primary Prevention Of Cardiovascular Diseases And Colorectal Cancer. PMID- 26532597 TI - Estimating The Public Health Impact Of A Vaccination Programme With A Nonavalent Hpv Vaccine In Germany. PMID- 26532598 TI - COST-EFFECTIVENESS ANALYSIS ON STARTING PATIENTS WITH CHRONIC MYELOID LEUKEMIA ON A HIGHLY POTENT TYROSINE KINASE INHIBITOR AND EARLY SWITCHING TO IMATINIB. PMID- 26532599 TI - Loss Of Opportunity Linked With The Suboptimal Coverage Rate Of Hpv Vaccination In France. PMID- 26532600 TI - Pharmacoeconomic Study Of The Use Of Rituximab For Subcutaneous Administration In The Treatment Of Follicular Lymphoma. PMID- 26532601 TI - Pharmacoeconomic Evaluation Of The Use Of Trastuzumab For Subcutaneous Administration Compared To Intravenous Dosage Form In The Treatment Of Breast Cancer. PMID- 26532602 TI - Subcutaneous Vs Intravenous Administration Of Trastuzumab In Her2+ Breast Cancer Patients: A Macedonian Cost-Minimization Analysis. PMID- 26532603 TI - COST-EFFECTIVENESS AND FEASIBILITY OF IMPLEMENTING MRI-GUIDED NEOADJUVANT CHEMOTHERAPY TO TREAT ER-POSITIVE HER2-NEGATIVE BREAST CANCERS IN THE NETHERLANDS. PMID- 26532604 TI - Cost-Effectiveness Analysis Of Obinutuzumab For Previously Untreated Chronic Lymphocytic Leukemia (Cll) In Portuguese Patients That Are Unsuitable For Full Dose Fludarabine Based Therapy. PMID- 26532605 TI - Economic Evaluation Of Oral Chemotherapy Regimen In Metastatic Breast Cancer Egyption Prospective. PMID- 26532606 TI - The Comparative Pharmacoeconomic Analysis Of Using Plerixafor For Stem Cell Mobilization For Autologous Peripheral Stem Cell Transplantation For Non Hodgkin's Lymphoma Patients. PMID- 26532607 TI - Cost-Effectiveness Of Cetuximab In First-Line Treatment Of Patients With Metastatic Colorectal Cancer In Belgium And The Netherlands. PMID- 26532608 TI - A Cost-Utility Analysis Of Nab-Paclitaxel (Abraxane) Plus Gemcitabine In Metastatic Pancreatic Cancer In Slovak Republic. PMID- 26532609 TI - ESTIMATION OF THE TRESHOLD PRICE OF REGORAFENIB IN THE TREATMENT OF UNRESECTABLE AND/OR METASTATIC GASTROINTESTINAL STROMAL TUMORS AFTER FAILURE ON IMATINIB AND SUNITINIB IN SPAIN: COST-UTILITY ANALYSIS. PMID- 26532610 TI - Efficiency Of Expenses Of Gefitinibum In Patients With Non-Small Cell Lung Cancer As A Second Line Therapy. PMID- 26532611 TI - Evaluation Of Resource Utilizaton For Chemotherapy Induced Nausea And Vomiting (Cinv) In Patients Treated With Anthracycline+Cyclophosphamide (Ac) For Solid Cancers With And Without Nk-1 Based Regimens. PMID- 26532612 TI - The Impact Of Pharmaceutical Innovation On Premature Cancer Mortality In Portugal. PMID- 26532613 TI - Predicting Future Need Of Resources For Adenoma Surveillance From A Population Based Colorectal Cancer Screening Program Through Discrete Event Simulation. PMID- 26532614 TI - Potential Savings To Eu Economy Due To Returning To Work Of Cancer Survivors With A Disability. PMID- 26532615 TI - Resource Utilization In Patients With Advanced Melanoma In France. PMID- 26532616 TI - Cancer And Premature Mortality In Ireland: An Employer's Perspective Following The Friction Cost Approach. PMID- 26532617 TI - Cognitive Debriefing And Usability Assessment Of The Eortc Qlq-C30 And Qlq-Br23 As Presented On Tablet And Handheld Devices. PMID- 26532618 TI - Systematic Review Of Adherence To Oncological Treatments. PMID- 26532619 TI - Direct Costs And Healthcare Resource Use Associated With Advanced Melanoma In Portugal. PMID- 26532620 TI - Descriptive Epidemiology And Treatment Strategies Used In Multiply Myeloma In The Slovak Republic. Results From The Cross-Sectional Survey In The Haematology Oncological Centers. PMID- 26532621 TI - Resource And Cost Savings Due To Subcutaneous Versus Intravenous Administration Of Oncology Therapies: Case Studies With Rituximab (Mabthera) And Trastuzumab (Herceptin). PMID- 26532622 TI - Long-Term Eq-5d Score For Patients With Metastatic Breast Cancer; Comparison Of First-Line Oral S-1 And Taxane Therapies In The Randomized "Select" Trial. PMID- 26532623 TI - Influence Of The Method Of Analysis On Estimates Of Qaly Treatment Difference: Phase Iii Trial Of Vinflunine Versus Best Supportive Care In Patients With Tccu. PMID- 26532624 TI - Prevalence And Reasons For Nonadherence To Aromatase Inhibitors In An Outpatient Oncology Clinic. PMID- 26532625 TI - Sensitivity Analysis In Discrete Choice Experiments For Rare Diseases - An Analysis Within The Piano-Study. PMID- 26532626 TI - Patient Preferences Concerning Alternative Net Treatment Options - The Piano Study. PMID- 26532627 TI - Alternative Regression Methods For Mapping Utilities In Oncology. PMID- 26532628 TI - Hrqol And Health Utility Impact On Patients With Newly Diagnosed Multiple Myeloma In Us And Europe: A Systematic Literature Review. PMID- 26532629 TI - Mapping Health State Utility Values From Eortc Data Collected From A Clinical Trial Population With Relapsed/Refractory Multiple Myeloma. PMID- 26532630 TI - Estimating Eortc-8d Health State Utility Values From Eortc Qlq-C30 Scores In Relapsed Multiple Myeloma. PMID- 26532631 TI - Impact Of Staging And Hormone Sensitivity On Quality Of Life In Us Prostate Cancer Patients. PMID- 26532632 TI - Field Monitoring Of The Z Benefits For Breast Cancer Of The Philippine Health Insurance Corporation. PMID- 26532633 TI - Prefmab: Final Analysis Of Patient Satisfaction With Subcutaneous Versus Intravenous Rituximab In Previously Untreated Cd20+ Diffuse Large B-Cell Lymphoma Or Follicular Lymphoma. PMID- 26532634 TI - Do European Patients Have A Shared Preference For The Benefits And Risks Of Medicines? PMID- 26532635 TI - Qualitative Interviews To Provide In-Depth Understanding Of The Impact Of Non Small Cell Lung Cancer (Nsclc) And Its Treatment On Of The Lives Of Patients And Their Families/Caregivers. PMID- 26532636 TI - Understanding The Impact Of Patient And Physician Preferences In Personalized Treatment For Melanoma Using A Discrete Choice Experiment. PMID- 26532637 TI - Preference Elicitation On Benefits And Risks Of Medicines Using A Discrete Choice Experiment. PMID- 26532638 TI - Is There A Relationship Between Patient-Reported Outcomes (Pros) And Clinical Outcomes In Metastatic Castration-Resistant Prostate Cancer (Mcrpc) Post Docetaxel? PMID- 26532639 TI - A Discrete Choice Experiment For Engaging Patients In Reimbursement Decision Making: Patient Preferences On Adjuvant Chemotherapy In Breast Cancer. PMID- 26532640 TI - Will Rating Scale Types And Disease Conditions Influence Concordance Between Cognitive Function Reported By Children And Their Parents? PMID- 26532641 TI - The Willingness Of Cancer Outpatients To Complete Patient-Reported Outcome Measures Outside Of The Clinic. PMID- 26532642 TI - Knowledge On Breast Cancer Among Women In Tolna And Baranya Counties, Hungary. PMID- 26532643 TI - Cancer Is Associated With Intraoperative And Postprocedural Complications And Disorders. PMID- 26532644 TI - TRANSLATION AND LINGUISTIC VALIDATION OF THE MODIFIED MYELOPROLIFERATIVE NEOPLASM SYMPTOM ASSESSMENT FORM - TOTAL SYMPTOM SCORE (MMPN-SAF TSS) FOR USE IN 26 COUNTRIES. PMID- 26532645 TI - Development Of A Patient-Reported Outcome (Pro) Assessment Of Core Non-Small Cell Lung Cancer (Nsclc) Symptoms. PMID- 26532646 TI - The Use Of Social Media To Generate Health Data For Effectiveness Research: A Scoping Review. PMID- 26532647 TI - The Impact Of Non-Muscle Invasive Bladder Cancer: Qualitative Research With Patients. PMID- 26532648 TI - Do Patient Reported Outcomes (Pro) In Oncology Matter In Health Technology Assessments (Hta)? PMID- 26532649 TI - Breast Cancer Patients' Perception On Health Impacts From Receiving Chemotherapy. PMID- 26532650 TI - How Can We Improve The Design Of Patient Preference Research In Oncology? A Case Study In Metastatic Castrate Resistant Prostate Cancer. PMID- 26532651 TI - Reducing The Barriers To Capturing Patient Reported Outcomes In Oncology Studies. PMID- 26532652 TI - Health-Related Quality Of Life And Treatment Satisfaction Among Patients Receiving Novel Anti-Androgen Therapies For The Treatment Of Metastatic Castrate Resistant Prostate Cancer (Mcrpc). PMID- 26532653 TI - The Finnish Versions Of The Lower-Limb Sections Of The Toronto Extremity Salvage Score And The Musculoskeletal Tumor Society Scale: A Pilot Study. PMID- 26532654 TI - Effects Of Adverse Events On Quality Of Life Scores In A Randomized Clinical Trial Of Adjuvant Chemotherapy For Breast Cancer: N-Sas Bc 02. PMID- 26532655 TI - Patients' Preferences Regarding The Setting Of Electronic Patient-Reported Outcome Assessments. PMID- 26532656 TI - Measurement Of Hope In Patients With Cancer. PMID- 26532657 TI - Development Of A Web-Based Quality Of Life Portal For Breast Cancer Patients. PMID- 26532658 TI - Health Related Quality Of Life Of Caregivers And Patients Treated For Metastatic Non-Small Cell Lung Cancer (Nsclc) With Oral Vinorelbine. PMID- 26532659 TI - Burden Of Advanced Breast Cancer For Patients And Caregiver In Europe: Comparisons Of Two Treatment Forms Of Vinorelbine, Oral And Intravenous. PMID- 26532660 TI - Predictors Of Utility Over Time Among Patients With Treatment-Naive Advanced Melanoma From The Phase 3 Checkmate 066 Trial. PMID- 26532661 TI - Cost-Utility Analysis Of Enzalutamide For Patients With Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer (Mcrpc) After Failure Of Androgen Deprivation Therapy (Adt). PMID- 26532662 TI - Eastern Cooperative Oncology Group (Ecog) Performance Status (Ps) Is An Independent Predictor Of Hrqol In Unresectable Or Metastatic Melanoma. PMID- 26532663 TI - Health-Related Quality Of Life In Bladder Cancer: A Systematic Literature Review. PMID- 26532664 TI - Quality Of Life In Adult Intradural Primary Spinal Cord Tumors: Short Form-36 Correlates With The Scales Of Mccormick And Aminoff-Logue. PMID- 26532665 TI - Health-Related Quality Of Life (Hrqol) Benefits Of Enzalutamide In Patients With Metastatic Castration-Resistant Prostate Cancer (Mcrpc): An In-Depth Analysis Of Eq-5d Data From The Prevail Trial. PMID- 26532666 TI - Structured Review Of Patient Quality Of Life Following Diagnosis With Prostate Cancer. PMID- 26532667 TI - Progressive Disease Does Not Impact Hrqol In Patients Receiving Nivolumab For The Treatment Of Unresectable Or Metastatic Melanoma. PMID- 26532668 TI - Quality Of Life In Patients With Breast Cancer In Slovakia. PMID- 26532669 TI - Quality Of Life In Patients With Kidney Cancer In Slovakia. PMID- 26532670 TI - Health Professional Students' Willingness To Pay For Human Papillomavirus Vaccination And Factors Influencing Their Decision In Malaysia. PMID- 26532671 TI - Search for Clinically and Economically Effective Lymphomas Treatment. PMID- 26532672 TI - Value of Assessing the Burden of Hospitalizations for Metastatic Melanoma in the era of Targeted Therapies: Analysis of the French National Hospital Database From 2008 To 2013. PMID- 26532673 TI - Burden of Metastatic Renal Cell Carcinoma in France From 2008 To 2013: Analysis of the French National Hospital Database. PMID- 26532674 TI - A Loss of Chance Index: a New Tool for Optimizing Patient Access to Innovative Drugs. PMID- 26532675 TI - Social Burden of Chronic Hcv Infection in Patients with Hepatocellular Carcinoma. PMID- 26532676 TI - Insurance Plan Switch Patterns Among Breast Cancer Patients Compared to Non Cancer Patients. PMID- 26532677 TI - Mapping the Diagnostic Pathway for Breast Cancer in England and Comparison to Europe. PMID- 26532678 TI - Quantifying Costs of Medical Personnel Involved with Radiation therapy Using Administrative Databases. PMID- 26532679 TI - Measuring the Importance of Decision Making Criteria for Anticancer Drug Reimbursement in Korea. PMID- 26532680 TI - Experiences with Price Competition of Biosimilar Drugs In Hungary in Case of Colony-Stimulating Factor Products. PMID- 26532681 TI - How Can Biosimilars Compete with Existing Biologics: update of the Results of a Previous Study. PMID- 26532682 TI - Appraising the Value of Lenvatinib for Radio-Iodine Refractory Differentiated Thyroid Cancer (Rr-Dtc): A Multi-Country Study Applying Holistic Multicriteria Decision Analysis (Mcda). PMID- 26532683 TI - Cost Per Qaly as a Potential Hurdle in Accessibility to Innovative Cancer Care in Selected Cee Countries. PMID- 26532684 TI - Are you at risk of cancer? Consider Where you live in england for Access to the Most Expensive Oncology Treatments. PMID- 26532685 TI - Cancer Drug Funding Decisions in the UK: Innovation And Value in the Biologics Era. PMID- 26532686 TI - Analysis of Evaluations Made by the uk Cancer Drug Fund Panel of Breast Cancer Treatments in Relation to Overall Scores and Final Cdf Decisions. PMID- 26532687 TI - Are Trends in Spending on Oncology Treatments Sustainable?: Analysis of Sales Patterns in Major Global Markets. PMID- 26532688 TI - Sipuleucel-T (Provenge(r)): Autopsy of an Innovative Change of Paradigm in Cancer Treatment. PMID- 26532689 TI - A New Pace for the Smc? PMID- 26532690 TI - The Italian Regional Access of New Cancer Drugs: An Example in Four Regions. PMID- 26532691 TI - Geographical Disparities in Colon Cancer Care in Europe: Implications for Access to Innovative Medicines Via the UK Cancer Drugs Fund. PMID- 26532692 TI - Drug use Among Elderly in the year Before Colon Cancer Diagnosis Versus Matched Cancer-Free Controls. PMID- 26532693 TI - Analysis of Eribulin Mesylate Utilzation in Patients with Metastatic Breast Cancer (Mbc) by Line of Therapy and Associated Changes Over Time. PMID- 26532694 TI - Descriptive Evaluation of Patient Characteristics and Health Care Resource Utilization of Patients Diagonsed with Malignant Neoplasm of Anus. PMID- 26532695 TI - Descriptive Evaluation of Patient Characteristics and Health Care Resource Utilization of Patients Diagonsed with Ovarian Cancer. PMID- 26532696 TI - Descripttive Evaluation of Patient Characteristics and Health Care Resource utilization of Patients Diagonsed with Breast Cancer. PMID- 26532697 TI - Patient Characteristics and Health Care Resource Utilization of Patients Diagonsed with Neoplasm of Colon. PMID- 26532698 TI - Chemotherapy Exposure and outcomes Among Patients Diagnosed with Chronic Lymphoid Leukemia. PMID- 26532699 TI - Priority issues and Recommendation Selection in Cancer Pain Management. PMID- 26532700 TI - Assessing the Gap Between Evidence Based Indications for Radiotherapy and Actual Practice in European Countries. PMID- 26532701 TI - Patient Characteristics and Health Care Resource Utilization of Patients Diagonsed with Prostate Cancer. PMID- 26532702 TI - Abstract Title: Descriptive Evaluation of Patient Characteristics and Health Care Resource Utilization of Patients Diagonsed with Malignant Neoplasm of Rectum. PMID- 26532703 TI - International Differences in the Role of Payer and Administrative Controls in Prescribing Decisions. PMID- 26532704 TI - Tiered Pricing in Oncology - Drivers for Improved Patient Access and Commercial Success. PMID- 26532705 TI - Building a Real World Data Network to Support Access to Oncology Medicines in France: the Personalised Reimbursement Models Initiative. PMID- 26532706 TI - Progressive Innovation in Oncology: Valuing Outcomes Beyond Survival. PMID- 26532707 TI - Health Care Resource use and Costs Among Polycythemia Vera Patients in the United States: Results from an Observational Cohort Study. PMID- 26532708 TI - The Prostate Cancer Registry: Analysis of Medical Resource Utilisation (Mru) in An International, Prospective, Observational Study of Men with Metastatic Castration-Resistant Prostate Cancer (Mcrpc). PMID- 26532709 TI - Using Geographic Information Systems and Multi-Criteria Decision Analysis to Address Spatially Explicit Problems in Healthcare Policy Decision Making. PMID- 26532710 TI - Use of Quality of Care (Qoc) Metrics Among Oncologists In the United States (Us). PMID- 26532711 TI - Switching to A 6-Monthly Triptorelin Formulation for Prostate Cancer (Pca) Reduces Patient-Nhs Interactions and Hospital Resource use: Real World Evidence (Rwe) from Project Deserve (Decapeptyl Service Evaluation). PMID- 26532712 TI - Cost-Effectiveness Analysis of Rituximab in Treatmenting Diffuse Large B-Cell Lymphoma in China. PMID- 26532713 TI - The Clinical and Economic Burden of Skeletal Related Events in Austria, Czech Republic, Germany, Greece, Italy, Spain and Switzerland: a Comparison Between the use of Denosumab and Zoledronic Acid In Patients with Prostate Cancer And Bone Metastases. PMID- 26532714 TI - The Clinical and Economic Burden of Skeletal Related Events in Austria, Czech Republic, Germany, Greece, Italy, Spain and Switzerland: A Comparison Between the use of Denosumab and Zoledronic acid in Patients With Breast Cancer and Bone Metastases. PMID- 26532715 TI - The Cancer Drugs Fund and Patient Acces Schemes within the UK: Increased Access to Oncology Medicines or Reduced Value For Money? PMID- 26532716 TI - Patient Count Forecasts of Advanced Non-Small Cell Lung Cancer: Results from the UK, Germany, France, Italy and Spain (Eu-5). PMID- 26532717 TI - Comparative Analysis of Expenditure of Drugs for Malignancy. PMID- 26532718 TI - Assessment of Burden and Economic Impact of the Vandetanib Restricted Distribution Program in Canada. PMID- 26532720 TI - Disease Prevalence and Healthcare Resources Consumption in Patients with Basal Cell Carcinoma in Italian Lhus. PMID- 26532719 TI - Impact of Drug's Presentation on Patients' Perception of Treatment's Risks & Benefits Through New Ordinal Gee Modelling Method: Results from Imi Protect Wp6. PMID- 26532721 TI - Results From a Time and Motion Study of Denosumab Subcutaneous Injection and Zoledronic Acid Intravenous Infusion in Patients with Metastatic Bone Disease From Italian Sites. PMID- 26532722 TI - A Time and Motion Study of Denosumab Subcutaneous Injection and Zoledronic Acid Intravenous Infusion in Patients with Metastatic Bone Disease in Belgium. PMID- 26532723 TI - Clinical And Health-Economic Criteria for the Assessment of New Immune-Oncologic Drugs in Spain. PMID- 26532724 TI - International Comparison of Internet Information Source in Breast Cancer. PMID- 26532725 TI - Cost of Questionnaire-Based Process to Identify Occupational Exposures Among Patients with Lung Cancer. PMID- 26532726 TI - Description of Baseline Characteristics of Patients Provided Cancer Care within a Novel Commercial Health Plan Cancer Care Quality Program in the First Year. PMID- 26532727 TI - Oncologist Support for American Society of Clinical Oncology (Asco) Consolidated Payments for Cancer Care Management in the United States (Us). PMID- 26532728 TI - G-Ba Does not Adjust Evidence Requirements in Early Benefit Assessment in Cases of Pre-Defined, Efficacy-Based Cross-Over Decisions in Oncology Trials. PMID- 26532729 TI - Qualitative Assessment of Societal Preferences for Market Access of Cancer Drugs. PMID- 26532730 TI - Price Structure Assessment of Selected Oncology Products in China, Taiwan, South Korea, Brazil, and Mexico. PMID- 26532731 TI - Impact on Time Gap Between Approval and Reimbursement of Target Therapy to Advanced Colorectal Cancer. PMID- 26532732 TI - Opportunities with Accelerated Approval Times, but Stumbles at Hta? the Impact of a Limited Evidence Package. PMID- 26532733 TI - Comparative Cost-Effectiveness of Drugs in Early Versus Late Stages of Cancer; Review of the Literature and a Case Study in Breast Cancer. PMID- 26532734 TI - Patient Reported Outcomes (Pro) in Postprogression Oncology: Implications in Health Technology Assessments (Hta) & Payer Decision Making. PMID- 26532735 TI - Does Budget Impact Affect Reimbursement Decisions Made by the Cancer Drugs Fund in England? PMID- 26532736 TI - 4+ Years of Amnog - Clinical Drivers for Successful Dossier Submissions in Oncology. PMID- 26532737 TI - Delays in Diagnosis of Breast Cancer in Greece: Findings from a Qualitative Study. PMID- 26532738 TI - From Diagnosis To Treatment And Survival: The Emotional Journey Of Patients With Breast Cancer. PMID- 26532739 TI - Real World Evidence in Oncology - Status Quo in Germany. PMID- 26532740 TI - What Lifecycle Management Lessons Can We Learn From Pd-1 Immuno-Oncology Therapies? PMID- 26532741 TI - A Pragmatic Approach to Data Source Selection for use In Real-World Evidence (Rwe) Generation. PMID- 26532742 TI - What Makes A Pharmaceutical Pricing & Reimbursement Process Patient-Centric? A Comparative Analysis Of 11 Systems. PMID- 26532743 TI - Differences And Similarities In Hta: A Comparative Analysis Of The Decision Making Processes For Cancer Drugs Across 4 Countries. PMID- 26532744 TI - French Health Technology Assessment Of Antineoplastic Drugs Indicated In The Treatment Of Solid Tumours: Perspective For Future Trends. PMID- 26532745 TI - Application Of Asco Value Framework Evaluations Of Net Health Benefit For Oncology Drugs Launched In The United States Between 2013 And 2015. PMID- 26532746 TI - How Has The Smc Patient And Clinician Engagement (Pace) Process Been Used In Assessments Of End-Of-Life Medicines And Medicines To Treat Very Rare Conditions? PMID- 26532747 TI - Female Breast Cancer: Burden Of Disease In Portugal. PMID- 26532748 TI - Trends In End-Of-Life Appraisals And Recommendations By Nice For Oncology Therapies. PMID- 26532749 TI - Payer/Hta Requirements In Metastatic Breast Cancer. PMID- 26532750 TI - Relationship Between The Prevalence Of Cancers In England And Wales And The Performance Of Technology Appraisals. PMID- 26532751 TI - To What Extent Do Payers' Assessment Of Clinically Relevant Outcomes Align With Clinicians In Oncology? PMID- 26532752 TI - Analysis Of Differences In Hta Reimbursement Decisions Of Stage Iv (Metastatic) Breast Cancer Medications Across Different Countries. PMID- 26532753 TI - Personalised Breast Screening: Key Drivers Of Cost Effectiveness. PMID- 26532754 TI - The Dutch Melanoma Treatment Registry As Blueprint For Using Registry Data To Improve Health Care Decision Making. PMID- 26532755 TI - Uptake Of Filgrastim 'Biosimilars' In The United States: Analysis Of A Medical Transcription Database Of Patient Office Visits. PMID- 26532756 TI - French Physician Sensitivity To And Consideration Of The Costs Of Cancer Treatment. PMID- 26532757 TI - Review Of The Current Status Of Ras Mutation Testing In Patients With Metastatic Colorectal Cancer (Mcrc): Flash-Ras Study. PMID- 26532758 TI - Evaluation Of Patient-Centered Care In Short-Term Cancer Survivors, Through The Patient Assessment Of Chronic Illness Care Questionnaire. PMID- 26532759 TI - Treatment Patterns Among Front-Line Glioblastoma Patients In Five European Countries. PMID- 26532760 TI - Current Treatment Patterns In Patients With Metastatic Melanoma: A Retrospective Claims Database Analysis In The United States (Us). PMID- 26532761 TI - Patient Characteristics And Treatment Patterns In Er+/Her2- Metastatic Breast Cancer In The Uk: Results From A Retrospective Medical Record Review. PMID- 26532762 TI - Access To Innovation And Economic Burden----A Case Of Non-Small Cell Lung Cancer In A Patient Access Program In Qingdao, China. PMID- 26532763 TI - Exploring Before And After Risk-Sharing Scheme Implementation During 8.5 Years Focused On Anticancer Drugs. PMID- 26532764 TI - Evaluation Of A Payment By Results Scheme In A Catalan Cancer Center: Gefinitib In Egfr Mutation-Positive Advanced Non-Small Cell Lung Cancer. PMID- 26532765 TI - Bone Pain And Bone Targeting Agent (Bta) Treatment Patterns In Patients With Bone Metastases (Bms) From Breast Cancer (Bc) In Real World Setting In Europe. PMID- 26532766 TI - Bone Pain And Bone Targeting Agent (Bta) Treatment Pattern In Patients With Bone Metastases (Bms) From Prostate Cancer (Pc) In Real World Setting In Europe. PMID- 26532767 TI - Torsade De Pointes And Qt Prolongation Could Result From Desloratadine Anti Allergy Treatment. PMID- 26532768 TI - A Comparative Study To Evaluate Treatment Patterns And Resulting Utility In Patients Of Head & Neck Cancers Under Private Payment Scheme And Government Scheme. PMID- 26532769 TI - Screening Guidelines And Cancer Stage: Early Findings From Medicare. PMID- 26532770 TI - Risk Of Pneumonia Associated With The Use Of Ics/Laba: A Retrospective Cohort Study In Korea. PMID- 26532771 TI - Prevalence And Burden Cost Of Adverse Drug Reactions (Adrs) In The Faculty Of Medicine Vajira Hospital Navaminthradhiraj University : A Research Implemented To Policy Recommendations. PMID- 26532772 TI - Bayesian Network Meta-Analysis To Assess The Comparative Efficacy And Safety Of Treatments For Severe Or Uncontrolled Asthma. PMID- 26532773 TI - Doctors' Failure In Observance Of The Copd Management Guidelines: The Czech Republic 2015 Update. PMID- 26532774 TI - Systematic Review And Meta-Analysis Of The Effectiveness And Safety Of Combination Therapy With Glycopirronium-Indacaterol Compared With Other First Line Therapies In Patients With Chronic Obstructive Pulmonary Disease. PMID- 26532775 TI - Bayesian Network Meta-Analysis To Assess The Comparative Efficacy And Safety Of Treatments For Chronic Obstructive Pulmonary Disease. PMID- 26532776 TI - Evolution Of Tiotropium Efficacy Vs. Placebo Over Time For The Maintenance Therapy Of Chronic Obstructive Pulmonary Disease: From Investigational Product To Active Reference. PMID- 26532777 TI - Can We Improve The Inhalation Techniques In Patient With Copd?. Tiepoc Study. PMID- 26532778 TI - Clinical Evaluation Of Kanakasava And Swasanandam Gulika In Bronchial Asthma. PMID- 26532779 TI - Use Of Xanthines In The Treatment Of Chronic Respiratory Diseases In Serbia, Compared With The Scandinavian Countries From 2004 To 2013. PMID- 26532780 TI - Comparative Effectiveness Analysis Of Mab In Asthma: The Importance Of Exacerbation Definition. PMID- 26532781 TI - Identification Of Subgroups With Low Rates Of Smoking Cessation In Israel. PMID- 26532782 TI - Pattern And Factors Associated With Readmission In Patients Hospitalized For Chronic Obstructive Pulmonary Disease In Taiwan. PMID- 26532783 TI - The Budget Impact Of Duoresp(r) Spiromax(r) Compared With Commonly Prescribed Dry Powder Inhalers For The Management Of Asthma And Chronic Obstructive Pulmonary Disease In Italy: Estimated Impact Of Inhalation Technique. PMID- 26532784 TI - Tioropium+Olodaterol Respimat; Budget Impact In The Uk. PMID- 26532785 TI - Management Of Sore Throat In Community Pharmacy In France: A National Observational Study. PMID- 26532786 TI - Burden Of Community-Acquired Pneumonia In Adults Over 18 Years Of Age. PMID- 26532787 TI - Cost Saving Study Of Five Grass Pollen Slit Tablet Versus Scit's & Symptomatic Treatment. PMID- 26532788 TI - Budget Impact Analysis Of Formoterol Easyhaler In The Treatment Of Asthma In Children In The Russian Federation. PMID- 26532789 TI - Budgetary Implications Of Introducing The Gsk Ellipta Portfolio For Copd In The Uk. PMID- 26532790 TI - The Budget Impact Of An Inhaler With Improved Features Compared To Spiriva(r) Handihaler(r) For The Management Of Chronic Obstructive Pulmonary Disease (Copd) In The Uk: Estimated Impact On Unscheduled Healthcare Costs And Inhaler Satisfaction. PMID- 26532791 TI - Estimating Seasonal Allergic Conjunctivitis Market Size And Spending. PMID- 26532792 TI - Pulmonary Arterial Hypertension (Pah): Real-World Treatment Patterns, Outcomes And Costs Based On World Health Organization (Who) Functional Class (Fc). PMID- 26532793 TI - To Study The Clinical Characteristics, Treatment Pattern And Factors Associated With The Total Hospital Cost In Acute Respiratory Distress Syndrome In Tertiary Care Hospital. PMID- 26532794 TI - Economic Analysis Of Cost Of Drug Treatment Involved In The Maintainance Therapy Of Copd. PMID- 26532795 TI - Clinical And Economic Benefits Associated With Less Use Of Fluticasone In Pediatric Patients With Persistent Asthma Treated With High Doses Of Specific Allergen Immunotherapy To Mites. PMID- 26532796 TI - Cost Consequence Of Preventive Treatment With Om 85 Bacterial Lysate Compared To The Same Patients Without Om 85 The Previous Year In Allergic Rhinitis, Asthma And Copd In Argentina. PMID- 26532797 TI - The Association Between Smoking Cessation Outpatient Visits And Total Medical Costs: An Analysis Of Japanese Employee Based Public Health Insurance Data. PMID- 26532798 TI - Cost Of Smoking In Asia. PMID- 26532799 TI - Examining Health System And Resource Utilization And Medical Management Of Patients Idiopathic Pulmonary Fibrosis In Ontario: A Preliminary Analysis. PMID- 26532800 TI - Clinical And Economic Burden Of Asthma And Chronic Obstructive Pulmonary Disease (Copd) In Poland: Estimated Impact Of Poor Inhalation Technique With Inhaled Corticosteroid And Long-Acting Beta Agonist Fixed-Dose Combinations. PMID- 26532801 TI - New Copd Medicinal Products Entrance Analysis And Their Influence On The Number And Cost Of Hospitalizatons Due To Copd Exacerbations. PMID- 26532802 TI - Burden Of Symptomatic Copd Patients In Spain: Data From Continuing To Confront Copd International Patient Survey 2012-2013. PMID- 26532803 TI - Can Qva149 Improve Short Term Outcomes In Patients With Copd Without Increasing The Overall Treatment Costs For The Portuguese Nhs? Optimizing Treatment Outcomes With A Responsible Use Of Limited Resources. PMID- 26532804 TI - The Potential Societal Cost Benefits Of Increasing Patient Satisfaction By Using An Inhaler With Improved Features Compared To Spiriva(r) Handihaler(r) For The Management Of Chronic Obstructive Pulmonary Disease (Copd) In The Uk. PMID- 26532805 TI - Updated Medication Costs From A Real-Life Cost-Effectiveness Evaluation Of Budesonide/Formoterol Maintenance And Reliever Therapy In Asthma Maintenance And Reliever Therapy In Asthma. PMID- 26532806 TI - Cost-Effectiveness Analysis Of The Fixed Combination Indacaterol/Glycopyrronium Vs. Tiotropium And Salmeterol/ Fluticasone In The Management Of Copd In Greece. PMID- 26532807 TI - Cost-Effectiveness Of Umeclidinium/Vilanterol In Symptomatic Copd Spanish Patients. PMID- 26532808 TI - Dual Bronchodilation With Qva149 In Patients With Severe And Very Severe Copd - Are There Incremental Benefits For Portuguese Patients And For The Portuguese Nhs When Compared With Current Treatment Options In Portugal? PMID- 26532809 TI - Economic Evaluation Of Fluticasone Propionate/Formoterol Fumarate (Flutiform(r)) Vs Fluticasone/Salmeterol And Budesonide/Formoterol In Spain. PMID- 26532810 TI - Cost-Effectiveness Of Tiotropium Vs Glycopyrronium In Moderate To Very Severe Copd In Spain. PMID- 26532811 TI - Cost - Effectiveness Analysis Of Budesonid Easyhaler In The Treatment Of Asthma In Children In The Russian Federation. PMID- 26532812 TI - Economic Evaluation Of Respiratory Medication Therapy Adherence Clinic (Rmtac) On Asthma Patients In Malaysia. PMID- 26532813 TI - Cost-Effectiveness Of Tiotropium In The Treatment Of Patients With Asthma. PMID- 26532814 TI - Sq(r) Hdm Slit-Tablets In Addition To Pharmacotherapy Are Cost-Effective Compared To Pharmacotherapy Only In Treating Patients With Allergic Asthma. PMID- 26532815 TI - Economic Evaluation Of Tiotropium For Severe Persistent Asthma In Portugal. PMID- 26532816 TI - Economic Evaluation Of Tiotropium Administrated Through The Respimat Inhaler As Add-On Therapy In Patients With Uncontrolled Severe Asthma In Poland. PMID- 26532817 TI - Cost-Effectiveness Of A 13-Valent Conjugate Pneumococcal Vaccination Program In Copd Patients Aged 50+ Years In Spain. PMID- 26532818 TI - Cost-Effectiveness Analysis Of Tobacco Dependence Treatment In The Czech Republic. PMID- 26532819 TI - A Systematic Review Of Markov Models Evaluating Multi-Component Disease Management Programs. PMID- 26532820 TI - Recent Trends In Anaphylaxis-Related Hospitalization In The United States. PMID- 26532821 TI - Measuring Generic Health-Related Quality Of Life And Impact Of Health Resource Utilization In Adults With Cystic Fibrosis. PMID- 26532822 TI - Assessing Copd Patients Burden Of Disease In A Fold-In-Fold-Out Discrete Choice Experiment. PMID- 26532823 TI - Mapping The St George's Respiratory Questionnaire To The Euroqol 5 Dimensions: A Study In Patients With Idiopathic Pulmonary Fibrosis. PMID- 26532824 TI - Patients' Priorities For Treatment In Moderate To Severe Copd. PMID- 26532825 TI - Patients' Priorities For Treatment In Severe Asthma. PMID- 26532826 TI - Patient-Reported Outcomes In Studies Published In 2014: Which Tools Have Been Most Commonly Used In Studies Of Respiratory Disorders? PMID- 26532827 TI - Systematic Review On The Correlation Between Lung Function Or Eosinophil Levels And Quality Of Life In Asthma. PMID- 26532828 TI - Systematic Literature Review And Critical Appraisal Of The Suitability Of The Outcome Measures Used In The Idiopathic Pulmonary Fibrosis. PMID- 26532829 TI - Assessment Of Knowledge And Awareness Regarding Asthma Among School Teachers In Quetta. PMID- 26532830 TI - Health Related Quality Of Life In Tb Patients Quetta, Pakistan. PMID- 26532831 TI - The Epipen4schools(r) Survey: Staff Training And Use Of Epinephrine Auto Injectors For The Treatment Of Anaphylaxis In Large Us School Districts. PMID- 26532832 TI - Prevalence Of Switching From Brand To Generic Asthma Medications. PMID- 26532833 TI - Copd Performance Indicators In An Integrated Care Program And Its Impact On Health Outcomes: The Recode Cluster Randomized Trial. PMID- 26532834 TI - Conditional Agreements For Innovative Therapies In Italy: The Case Of Pirfenidone. PMID- 26532835 TI - Title: Factors Influencing Consumers' Perceived Risk Of Tobacco Products. PMID- 26532836 TI - Resource Use And Exacerbations Of Chronic Obstructive Pulmonary Disease (Copd) By Gold Categories. PMID- 26532837 TI - Assesing The Net Fiscal Consequences Of Tobacco Use In A High Consumption And High Tobacco Tax Country: The Case Of Greece. PMID- 26532838 TI - Cost And Resource Utilization Of Uncontrolled And Persistent Asthma In Canada: A Systematic Literature Review. PMID- 26532839 TI - Availability Of Drugs Recommended By Global Initiative For Chronic Obstructive Lung Disease (Gold) For Ukrainian Patients With Copd. PMID- 26532840 TI - Do Clinical Guideline Implementations Reduce The Government Budget? A Clinical Guideline-Based Budget Impact Model In Reimbursement Of Inhaler Treatments In Copd. PMID- 26532841 TI - Study Of Acute Lower Respiratory Tract Infections In Children Of Age Group 1 Month To 5 Years. PMID- 26532842 TI - Effects Of Clinical Computing Systems During Consultations On Smoking Cessation - Evidence Landscape From Randomized And Quasi Randomized Trials. PMID- 26532843 TI - Physicians' Prescribing Pattern For Tuberculosis: Evidences From Community Pharmacies In Punjab, Pakistan. PMID- 26532844 TI - The Opportunities Of Internet Technology And Telemedicine In Interaction Between Doctor And Patient. PMID- 26532845 TI - Reliability Of Manufacturers' Budget Impact Estimates For Elimination Diet In Patients With Allergy To Cow's Milk In Poland. PMID- 26532846 TI - Resource Use And Health Care Costs Of Copd Patients At The End Of Life: A Systematic Review. PMID- 26532847 TI - Systematic Review On The Correlation Between Lung Function Or Eosinophil Levels And Health Care Resource Utilization In Asthma. PMID- 26532848 TI - Correlation Between Equation For Estimating Glomerular Filtration Rate: Chronic Kidney Disease Epidemiology Collaboration -Ckd -Epi, Cockcroft-Gault -Cg- And Modification Of Diet And Renal Disease -Mdrd4- In Colombia. PMID- 26532849 TI - Patterns Of Medication Use In Chronic Kidney Disease Stage 5d: Emphasis On Medications For The Management Of Ckd-Mbd. PMID- 26532850 TI - Data Mining Based On Real World Data In Chronic Kidney Disease Patients Not On Dialysis: The Key Role Of Early Hemoglobin Levels Control. PMID- 26532851 TI - Patient Benefits And Cost Savings Predicted For Mineralocorticoid-Receptor Antagonist Treatment Of Early And Advanced Diabetic Kidney Disease. PMID- 26532852 TI - Cyclosporine Is Not The Drug Of Choice For Renal Transplanted Patients And Increases The Risk Of Cardiovascular And Cerebrovascular Accidents. PMID- 26532853 TI - Do Socioeconomic Inequalities Impact The Social Cost Of Chronic Kidney Disease In Italy? PMID- 26532854 TI - Costs Of Overactive Bladder Symptoms Treatment With Solifenacin. PMID- 26532855 TI - Cost-Consequences Analysis Of Fesoterodine At Flexible-Dose In The Therapy Of Overactive Bladder In Routine Medical Practice. PMID- 26532856 TI - Economic Burden Of Adpkd From The Spanish Health System And Patient's Perspective: Advantages Of Delaying Dialysis. PMID- 26532857 TI - Prevalence Of Chronic Kidney Disease In India: A Systematic Review And Meta Analysis Of Observational Studies. PMID- 26532858 TI - Introduction Of Mirabegron In The Czech Republic From Payer's Perspective - 1 Year Overview. PMID- 26532859 TI - Hospital Costs Of Contrast-Induced Nephropathy. PMID- 26532860 TI - Investigating The Cost-Effectiveness Of Bacterial Whole-Genome Sequencing For Enabling Targeted Antibiotic Selection In Urinary Tract Infections. PMID- 26532861 TI - Projected Clinical And Economic Impact Of Grazoprevir (Gzr, Mk-5172)/Elbasvir (Ebr, Mk-8742) For Chronic Hcv Genotype 1 Infection In Chronic Kidney Disease. PMID- 26532862 TI - Cost-Effectiveness Of A Fixed-Dose Combination Of Solifenacin Plus Tamsulosin Ocas For The Treatment Of Lower Urinary Tract Symptoms Associated With Benign Prostatic Hyperplasia In Spain. PMID- 26532863 TI - Economic Evaluation Of Mirabegron Versus Antimuscarinic Treatments In Patients With Overactive Bladder From The Pespective Of The Spanish National Health Service. PMID- 26532864 TI - Pharmacoeconomic Analysis Of Everolimus Immunosupressive Therapy After Renal Transplantation. PMID- 26532865 TI - Hrqol And Utility In Nocturia Are Correlated To Number Of Voids. PMID- 26532866 TI - Delay Of Optimal Nocturia Treatment Is Costly: Results Of A Real World Survey Of Patients In Europe And The Usa. PMID- 26532867 TI - Pharmacoeconomic Analysis: Analysis Of Cost-Effectiveness Of Lanthanum-Carbonate (Lc) In Uncontrolled Hyperphosphatemia In Dialysis. PMID- 26532868 TI - Laparoscopic Surgery Versus Traditional Open Surgery For Kidney Implantation: A Cost-Effectiveness Model. PMID- 26532869 TI - Impact Of Nocturia On Quality Of Life - Mapping Of Sf-12 To Utility Values Using Clinical Trial Data. PMID- 26532870 TI - The Quality Of Life Of Parents Of Pediatric Kidney Transplantation Patients. PMID- 26532871 TI - Quality Of Life In Women Patients With Urinary Incontinence In Slovakia. PMID- 26532872 TI - Health-Related Quality Of Life (Hrqol) Measures In Autosomal Dominant Polycystic Kidney Disease (Adpkd). PMID- 26532873 TI - Validation Of The Overactive Bladder Questionnaire (Oab-Q; 1-Week Recall) In Medically Complex Elderly Adults With Overactive Bladder. PMID- 26532874 TI - Nocturia Work Productivity And Activity Impairment Compared To Other Common Chronic Diseases: A Systematic Review. PMID- 26532875 TI - Healthcare Resource Consumption And Costs Before And After Kidney Transplantation In Lombardy, Italy. PMID- 26532876 TI - Does Out-Patient Medical Insurance Policy Work Among Ckd Patients In Non-Dialysis Phases? Evidence From Two Sample Cities In China. PMID- 26532877 TI - A Concept For Best-Practice In Therapeutic Drug Monitoring (Tdm) For Kidney Transplant (K-Tx): Results From Q-Perior Study. PMID- 26532878 TI - Experiences With Price Competition Of Biosimilar Drugs In Hungary In Case Of Erythropoietin Products. PMID- 26532879 TI - Disease Burden And Costs Associated With Urinary Tract Infections In Type 2 Diabetes Mellitus Patients: An Analysis Based On A Large Sample Of 456,586 German Patients. PMID- 26532880 TI - Autosomal Polycystic Kidney Disease (Adpkd): Costs And Resource Utilisation In The Nordic Countries. PMID- 26532881 TI - Building Intentions with The Theory of Planned Behaviour: A Qualitative Assessment of Salient Beliefs About Pharmacy Value Added Services in Malaysia. PMID- 26532882 TI - Cross-Sectional Descriptive Study Of The Impact Of Anaemia In Patients With Chronic Kidney Disease On Healthcare Resource Utilisation And Work Productivity Across Europe. PMID- 26532883 TI - Economic Evaluation Of Health Spending And Health Outcomes In The Management Of Hemodialysis For Two Insurance Companies In Colombia. PMID- 26532884 TI - Analysis of Health Services Utilization among Elderly in Slovenia. PMID- 26532885 TI - Are The Elderly Citizens Ready for Assisted Living Technologies? an Italian Case Study. PMID- 26532886 TI - Patient Involvement with Pharmaceutical Industry Drug Development and Research: A Review of the Literature. PMID- 26532887 TI - Development, Test-Retest Reliability And Validity of the Pharmacy Value Added Services Questionnaire. PMID- 26532888 TI - Peculiarity, Environmental and Chronic Diseases: Using Ecological Models as a Framework for Analysising Risk Factors of Chronic Diseases. PMID- 26532889 TI - A New Methodology to Define the Scope of The French " Liste-En-Sus ". PMID- 26532890 TI - The Impact of Consumer-Directed Health Plans on Price Shopping. PMID- 26532891 TI - Investigating Levels of Bacterial Resistance and Antibiotic Consumption in the St. Petersburg State Medical University. PMID- 26532892 TI - The Impact of the increasing Penetration of on-Patent Medicines on the Greek Pharmaceutical Market. PMID- 26532893 TI - Epidemiological Data Presented in German Benefit Assessments - A Comparison between Pharmaceutical Companies and G-Ba. PMID- 26532894 TI - Systematic Review on Use of Economic Evidence in Clinical Guidelines. PMID- 26532895 TI - The Under-Recognised Human and Economic Impact of Chronic Rhinosinusitis. PMID- 26532896 TI - Prices Changes for Patent-Protected Innovative Drugs in the Top 5 Eu Pharmaceutical Markets. PMID- 26532897 TI - Outpatient Utilization and Quality Appraisal of Antibiotics in Turkey. PMID- 26532898 TI - Analysis of Biotechnology Drugs Market in Turkey. PMID- 26532899 TI - Costs of Adverse Drug Events: Systematic Review. PMID- 26532900 TI - Fast-Tracking Innovation: A Scorecard for The Fda's Expedited Review Process. PMID- 26532901 TI - Advanced Therapy Medicinal Products May Dramatically Impact Payers' Budget. PMID- 26532902 TI - Cost of Adverse Drug Events on Health Resources Utilizaton in Older Adult Singaporeans. PMID- 26532903 TI - Effect of Parallel Review Processes for the Marketing Authorization and Reimbursement to Patients and Budget. PMID- 26532904 TI - Policy Implications of Affordable Care Act on Us Market Access. PMID- 26532905 TI - How Reducing The Equivalence Band Cap to Base Price For Selected 15 Groups impacts saving and Price Erosion in Turkey: Preliminary Results. PMID- 26532906 TI - Market Access of Atmps: Overview and Expected Challenges. PMID- 26532907 TI - Defibrotide in Veno-Occlusive Disease in Public Hospitals of Paris: Funding Issues and Perspectives. PMID- 26532908 TI - Have Infliximab Discounted Prices in Norway Had an Impact on Prices Around the World? PMID- 26532909 TI - Compliance with the Recently Introduced System of Generic Substitution and Reference Pricing in Ireland; Implications for Further Policy Rollout. PMID- 26532910 TI - The End of the Exceptional Financing of Erythropoiesis-Stimulating Agents in French Hospitals: What are the Impacts For Public Hospitals of Paris ? PMID- 26532911 TI - Faster Drug Market Access In Italy: is Class C-Nn The Answer? PMID- 26532912 TI - The Expansion of Use of Discounted Prices for International Reference Pricing Purposes. PMID- 26532913 TI - The Evolving Landscape of Early Access Programmes: Comparisons and Implications for Market Access. PMID- 26532914 TI - Prma Reform in Poland - Impact on Pharmaceutical Industry and Market Access. PMID- 26532915 TI - Evaluation of Who/Inrud Prescribing Indicators and Prescribing Trend of Antibiotics in Accidents and Emergency Department, Bahawal Victoria Hospital, Bahawalpur, Pakistan. PMID- 26532916 TI - External Reference Pricing from the Perspective of Slovenia. PMID- 26532917 TI - Heterogeneity in Relative Efficacy Assessments (Rea) across European Hta Bodies: Opportunity for Improving Efficiency and Speed of Access to Patients? PMID- 26532918 TI - The Uk Pharmaceutical Price Regulation Scheme (Pprs) - Considerations of Voluntary Versus Statutory Regulations and How to Negotiate Pricing. PMID- 26532919 TI - Using Decision Making Clinical Scenarios to Appraise Preferences and Value Judgments in Health Technology Assessment (Hta). PMID- 26532920 TI - Drug Pricing Reform in China - Impact of the Reform from a Societal Perpsective. PMID- 26532921 TI - Current Process and Future Path for Health Economic Assessment of Pharmaceuticals in France. PMID- 26532922 TI - Drug Pricing Reform in China - An Analysis of Piloted Pricing Approaches in the Context of International Experience. PMID- 26532923 TI - Are the Irish Slower than they Think? A Systematic Analysis of all Recent Ncpe Appraisals. PMID- 26532924 TI - Could Giving Cost-Utility Hta Bodies Negotiating Powers Help Bridge The Gap between Cost-Containment and Broadening Coverage? A Systematic Review of all Swedish Nlt Appraisals of Hospital Pharmaceuticals. PMID- 26532925 TI - Closing the Gap Between Hta and Innovation Uptake in Finnish Hospitals. PMID- 26532926 TI - An Evaluation of a New Regional Decision making Process in Sweden for High-Cost Hospital Therapies. PMID- 26532927 TI - A Comparison of Time to Launch and Reimbursement for New Medicines across Developed Countries. PMID- 26532928 TI - Fda Breakthrough Status Versus Accelerated Approval - What's the Difference? PMID- 26532929 TI - Analysis of the Reports of the National Committee for Technology Incorporation (Conitec) in the Brazilian Public Health System (Sus), 2012-2015. PMID- 26532930 TI - Reimbursement of Telemedicine in Germany: Quo Vadis - Anything Beyond Selective Contracts? PMID- 26532931 TI - The British Isles Hta League Table 2014. PMID- 26532932 TI - Use of Incremental Cost-Effectiveness Ratio (Icer) in Recommending Technologies Incorporation in the Brazilian Public Health System (Sus), 2012-2015. PMID- 26532933 TI - Pricing Policy for Pharmaceuticals in Egypt: Challenges and Opportunities. PMID- 26532934 TI - Overview of Generics Policies and Penetration in Japan. PMID- 26532935 TI - Is The Proof of an Additional Benefit under amnog in Germany More Difficult for Certain Drugs than for Other Ones? PMID- 26532936 TI - Real World Data: Biologic Treatment for Naive Patient in the Lazio Region. PMID- 26532937 TI - Capturing Accurate Concomittant Medications Information in Global Trials. PMID- 26532938 TI - Prevalence and Perception of Use of Non-Prescription Medicines among Medical Student in Quetta, Pakistan. PMID- 26532939 TI - Drug Utilization Study On Indian Elderly Ambulatory Patients Using Who Prescribing Indicators. PMID- 26532940 TI - Dynamics of Public Outpatient Drug Expenditures in Austria, 2005-2015. PMID- 26532941 TI - Assessment of Who/Inrud Core Drug Use Indicators in two Tertiary Care Hospitals of Bahawalpur, Punjab, Pakistan. PMID- 26532942 TI - A Cross-Sectional Analysis of Recently Published Systematic Literature Reviews on Pharmacological Interventions in Oncology. PMID- 26532943 TI - Dispensing of Vitamin Products by Retail Pharmacies in South Africa. PMID- 26532944 TI - Biosimilar Substitution Policies: An Overview. PMID- 26532945 TI - Multiple Use Of Antibiotic In Post Operative Patients In Tertiary Care Hospital Of Quetta, Pakistan. PMID- 26532946 TI - Assessing Equity Of Health Service Utilization Of Rural Residents In China: A Case Study Of Z County, Shaanxi Province. PMID- 26532947 TI - The Intertemporal Changes Of Health Services Utilization During The Last Decade: The Case Of Austerity Inflicted On Greece. PMID- 26532948 TI - Assessing Equity Of Health Service Utilization Of Urban Residents In China: A Case Study Of B City, Shaanxi Province. PMID- 26532949 TI - All Qalys Are Equal, But Some Qalys Are More Equal Than Others; A Comparison Of The Nice End Of Life Criteria And Smc Pace Process. PMID- 26532950 TI - Causes And Cost Impact Of Variabilities On The A&E Ward Utilization Across Hospitals In Spain. PMID- 26532952 TI - Investigating The Accessibility Of Uninsured Population To Health Services In Greece. PMID- 26532951 TI - Differential Pricing For Pharmaceuticals: Overview Of A Widely Debated Pricing Concept And Key Challenges. PMID- 26532953 TI - Does China's New Medical Reform Improve Health Equity Of Rural Residents? Evidence From Household Surveys Before And After The Implementation Of New Medical Reform In Shaanxi Province, China. PMID- 26532954 TI - Assessing Japan's Three Early Access Programs Based On Recent Discussions: Scope And Financial Aid. PMID- 26532955 TI - Understanding The Underutilisation Of Evidence From Economic Evaluations In Healthcare: A Mixed Methods Design. PMID- 26532956 TI - Does The Atu Process Have An Impact On Time To Market Launch? PMID- 26532957 TI - Differences In Reimbursement Prices And Inequalities To Access Most Commonly Prescribed Medicines In Bosnia And Herzegovina. PMID- 26532958 TI - The Relationship Between Socioeconomic Characteristics And Self-Rated Health In Greece. PMID- 26532959 TI - Incorporation Of Evidence Based Medicine Into The European Observatory On Health Systems And Policies Document Describing The Health Systems Of Countries Not Belonging To The European Union. PMID- 26532960 TI - Assessing The Efficiency Of The Long-Term Care Hospital Units In Hungary Between 2006 And 2013. PMID- 26532961 TI - The Competition Between Drugstore And Primary Care And Treatment Choice Of Patients In The Context Of Essential Medicine Policy In Rural China. PMID- 26532962 TI - The United States Specialty Pharmacy Payor Landscape. PMID- 26532963 TI - Organs-On-Chips: Exploring The Utility Of Biosynthesised Organ Tissue To Improve Efficiency Of The Drug Development Process. PMID- 26532964 TI - The Current Landscape And Expected Changes In Formulary Management. PMID- 26532965 TI - Pharmacy Information System In Saudi Hospitals- How Far Is It To Meet Pharmacy Benefit Management Program Requierments? PMID- 26532966 TI - Health Services Utilization By Dengue Patient In Brazil, 2012 - 2013: A Multicenter Study. PMID- 26532967 TI - Treatment Costs In Primary And Secondary Healthcare In Finland. PMID- 26532968 TI - Role Of Budget Impact Analysis In Market Access Of Biosimilars. PMID- 26532969 TI - A Comparison Of Key Components Of The Hta Core Model And The Amcp Format. PMID- 26532970 TI - Does The Legal Regulation Of Promoting Pharmaceutical Parallel Imports Helps To Create Savings For The Statutory Health Insurance (Gkv) In Germany? PMID- 26532971 TI - General Assessment Of Unlicensed Antineoplastic And Immunomodulating Medicine Usage In Turkey. PMID- 26532972 TI - Economic Modelling Studies Published In 2014: Which Disease Areas Have Been The Main Focus Of Clinical Research? PMID- 26532973 TI - Disinvesting In Low-Value Care: Opportunities And Challenges. PMID- 26532974 TI - Use Of Budget Impact Analysis (Bia) In Economic Evaluations Of Drugs And Medical Devices Submitted To The French National Authority For Health (Has). PMID- 26532975 TI - Sick-Pay Expenditures In Hungary According To Major Disease Groups. PMID- 26532976 TI - Cost-Effectiveness Analyses In France, England And Canada: Comparative Analysis Of Structural Choices, Results And Perspectives. PMID- 26532977 TI - Costs Of Septic Shock In England, Wales And Northern Ireland In 2012. PMID- 26532978 TI - Biosimilars Entry And Price Development In Europe. PMID- 26532979 TI - Appraising The Cost Of Physician Visits And Technical Procedures In France In The Age Of Open Data. PMID- 26532980 TI - Trends Of Sick-Pay Benefits In Hungary Between 2005-2013. PMID- 26532981 TI - Reforming The Reformed - Hospital Pharmaceutical Expenditure In Greece Over The Crisis Era; Looking At What Has Been Achieved When Planning Ahead. PMID- 26532982 TI - Introducing Orange: An International Price Reference Tool. PMID- 26532983 TI - Economic Impact Of Drug-Related Morbidity In Sweden. PMID- 26532984 TI - Cost-Effectiveness Of Early Parenteral Versus Enteral Nutrition In Critically Ill Patients. PMID- 26532985 TI - Basic Attitude Of Japanese Physicians Towards Healthcare Resource Allocation In A Setting Of Budget Constraints. PMID- 26532986 TI - Economic Burden Outcomes In Studies Published In 2014: Which Disease Areas Have Been The Main Focus Of Clinical Research? PMID- 26532987 TI - General Assessment Of Unlicensed Medicine Usage In Turkey. PMID- 26532988 TI - In Greece, During 2009-2014, Public Pharmaceutical Expenditure Undoubtedly Fell; But On Whose Backs? PMID- 26532989 TI - Role Of Pharmacoeconomic Analysis In Pricing Decision In Japan. PMID- 26532990 TI - Systematic Review Of Economic Evaluations In Personalized Medicine. PMID- 26532991 TI - Economic Evaluation Of Fibrin Sealant Patch: A Proposal To Assess The Economic Value In Hemostasis And As A Surgical Sealant. PMID- 26532992 TI - How Pharmaceutical Cost Indicators Are Affected When Adjusted To Hospitals' Clinical Workload: Data Analysis For Greek Nhs Hospitals. PMID- 26532993 TI - Off-Patent Drugs Consumption And Expenditures In Italy: 2009-2013. PMID- 26532994 TI - Systematic Review Of Cost Effectiveness Of Ultra-Orphan Therapies. PMID- 26532995 TI - External And Internal Reference Pricing As Cost Containment Measures In Bulgaria. PMID- 26532996 TI - Investigating The Health-Economic Impact Of Biomarker-Driven Immunosuppression (Biodrim) Following Renal Transplantation. PMID- 26532997 TI - Changes Of Sick-Pay Expenditures In Hungary Between 2005-2013. PMID- 26532998 TI - Costing The National Health Insurance Program Prematurity Benefit Package: The Philippine Experience. PMID- 26532999 TI - Developing A Drug Price Reference Index In The Philippines. PMID- 26533000 TI - The Comparative Pharmacoeconomic Analysis Of Using Different Variants Of Balanced Crystalloids During Infusion Therapy. PMID- 26533001 TI - How Important Is The Time Factor? Saving Lives Using Fire And Rescue Services. PMID- 26533002 TI - Changes In The Prices Of Reference Biotechnology Products By The Penetration Of Biosimilars Into The Turkish Pharmaceutical Market. PMID- 26533003 TI - Defining Value When Launching Biosimilars Treatments Within European Healthcare Systems. PMID- 26533004 TI - Economic Evaluation Of The Use Of Human Albumin In A Brazilian Public Hospital. PMID- 26533005 TI - Josa Andras Hospital Complex Project - Cost-Benefit Analysis Of The Major Project Investment. PMID- 26533006 TI - The Influence Of The Revision Of The Medical Fee Schedule On National Hospital Organisation Hospitals In Japan. PMID- 26533007 TI - Prediction Of Future Health Insurance Expenditures In Hungary According To Population Forecast Scenarios. PMID- 26533008 TI - Cost-Savings And Cost-Utility Of An Ehr System Smartphone App In A Trauma Intensive Care Unit. PMID- 26533009 TI - Italian Healthcare Expenditure Trends From 2002 To 2013. PMID- 26533010 TI - The Impact Of Pharmaceutical Innovation On Longevity In Portugal, 2002-2010. PMID- 26533011 TI - Using An Economic Model To Choose Initial Appropriate Antibiotic Therapy Based On Differences In In-Vitro Susceptibility To Ceftolozane/Tazobactam And Piperacillin/Tazobactam. PMID- 26533012 TI - Drug Pricing Information Management: Development Of A Web Based E-Pricing System. PMID- 26533013 TI - General Assessment Of Unlicensed Antineoplastic And Immunomodulating Medicine Usage Subgroups In Turkey. PMID- 26533014 TI - Avoidable Hospitalizations Due To Medication Errors In Belgium. PMID- 26533015 TI - Healthcare Expenditure On Prevention In The Spending Review Era. PMID- 26533016 TI - Cost Of Multimorbidity: The Influence Of Ambulatory Pharmaceutical And Hospital Expenditure. PMID- 26533017 TI - The Economic Consequences Of The Use Of Antibiotics In Belgium. PMID- 26533018 TI - Following Norway, Which Market Will Be Next to See Extreme Biosimilar Discounting? PMID- 26533019 TI - Comparison of current and preferred status of hta implementation in central and eastern europen countries. PMID- 26533020 TI - Liste-En-Sus Reform In France - What are The Consequences? PMID- 26533021 TI - The Most Profitable Health Insurance "Company" In Turkey. PMID- 26533022 TI - Impact of A Payment By Results Access Scheme In Italy: Better Value For Money? PMID- 26533023 TI - Patient Access Schemes Within The Uk: A Retrospective Analysis. PMID- 26533024 TI - Methodology of International Comparison of Pharmaceutical Prices. PMID- 26533025 TI - Analysis of Nursing Activities And Health Care Need In Residential Social Care Institutions In Hungary. PMID- 26533026 TI - Impact of The Changes In The Portuguese Pharmacy Remuneration System. PMID- 26533027 TI - Evaluation of Fractures In The Elderly In Austria And Drug Risk Factor Analysis Based on Claims Data. PMID- 26533028 TI - Early Benefit Assessment And Uptake Of Pharmaceutical Innovations - Experiences From Germany 2011 To 2014. PMID- 26533029 TI - Use of Economic Evaluations of Health Technologies In Dutch Healthcare Decision Making: Barriers And Facilitators. PMID- 26533030 TI - Effectiveness of A Community-Based Falls Prevention Program For The Elderly. PMID- 26533031 TI - Hurdles That Impede Economic Evaluations of Health Care Interventions Tested By General Practitioners In Flanders: A Qualitative Study. PMID- 26533032 TI - Use of Health Services In Brazil: A Systematic Review And Meta-Analysis of Prevalence Studies. PMID- 26533033 TI - Success Rate of Including Medicines to The Reimbursement System In Slovakia. PMID- 26533035 TI - The Use Comparative Effectiveness Research And Evidence Based Medicine In Us Payor Decision Making. PMID- 26533034 TI - Association Between Depression And Discontinuation With Antidiabetic Drugs. PMID- 26533036 TI - A Study of Knowledge, Attitude And Practice of Community Pharmacists Towards Adverse Drug Reaction Reporting & Monitoring. PMID- 26533037 TI - Relationship Between Community Pharmacy Attribution And Patient's Outcomes In Healthcare Service of Home-Visiting. PMID- 26533038 TI - Systematic Review of Fda Breakthrough Therapy Designated Products. PMID- 26533039 TI - Impact of Clerkship Attachments on Students' Attitude Towards Pharmaceutical Care In Ethiopia. PMID- 26533040 TI - Taking Medication Safely: Implementing And Developing A Medication Review Program In German Community Pharmacies Over 4 Years. PMID- 26533041 TI - Observational (Obs), Pragmatic (Pra), And Indirect (Ind) Methodologies For Comparative Relative Effectiveness (Re) And Benefit-Risk (Br) Analyses. PMID- 26533042 TI - Isolation, Identification And Antimicrobial Susceptibility Testing of Salmonella From Selected Poultry Farms In Debre Zeit. PMID- 26533043 TI - Survey on Romanian Hospitals Financing Reveals Major Dysfunctions In Covering Drug Treatment During Hospitalization. PMID- 26533044 TI - Applying Karnofsky Performance Scale In Hospitalized Patients For Promoting Rational Therapy. PMID- 26533045 TI - Can Grapefruit Juice Make Safe Drugs Unsafe or Ineffective? An Evidence-Based Answer. PMID- 26533046 TI - An Overview of Reviews of The Clinical Effectiveness of Generic Chronic Disease Self Management Support Interventions. PMID- 26533047 TI - Real-World Data on Multiple Comorbidities Among Patients With Hepatitis C: Considerations for Patient Care And Prognosis. PMID- 26533048 TI - Efficiency Analysis of Surgical Staplers Compared to Manual Suture for Open And Laparoscopic Surgery. PMID- 26533049 TI - Influence of Some Factors on The Morphological Structure of Spermatozoa In Straight Intestine During Forensic - Medical Examination of Sodomy. PMID- 26533050 TI - Intra- And Extra-Organizational Factors Affecting Community Pharmacy Performance. PMID- 26533051 TI - Acceptance of Clinically Relevant Primary Study Endpoints In The German Health Technology Assessment Process: Analysis of Five Different Disease Areas. PMID- 26533052 TI - Validation of Periodic Safety Update Reporting System In A Tertiary Care Teaching Hospital Using Adverse Drug Reaction Monitoring of Three Commonly Prescribed Drugs. PMID- 26533053 TI - The Relationship Between Knowledge and Performance: The Case of Iran Community Pharmacies. PMID- 26533054 TI - Character of Toxic Damage of Liver In Influences of Substances of Mediator to Fetal Cells on Hepatocytes In Acute Liver Failure. PMID- 26533055 TI - Willing to Provide Medication Analysis? Predicting Pharmacists' Intention to Provide Medication Analysis In Community Pharmacies In Germany. PMID- 26533056 TI - Italian Law 326/2003 for The Reimbursement of Orphan and Life Saving Drugs Awaiting Market Entry: Approvals, Rejections And Methods In Aifa's Evaluation Process Between January 2013 And May 2015. PMID- 26533057 TI - Does A Shorter Protocol Time for Chest Pain Patients Impact Emergency Department Flow? A Queuing Model to Discuss Emergency Department Management Metrics. PMID- 26533058 TI - Can Patients Rely on Results of Physician Rating Websites When Selecting A Physician? - A Cross-Sectional Study Assessing The Association Between Online Ratings and Structural and Quality of Care Measures from Two German Physician Rating Websites. PMID- 26533059 TI - Relationship Between The Provision of Injection Services In Ambulatory Physician Offices And Prescribing Injectable Medicines In Iran. PMID- 26533060 TI - U.s. Payer Expectations for Reimbursement of Biosimilars. PMID- 26533061 TI - Understanding Local Commissioning Decisions on New Pharmacotherapies In The Uk. PMID- 26533062 TI - The Clinical and Economic Burden of Medication Errors In The Canadian Acute Care Setting: A Review of Published Studies. PMID- 26533063 TI - Performance of Drg-Based Reimbursement Policy In National Health Insurance : Eight Years' Experiences. PMID- 26533064 TI - Reimbursement of Orphan and Expensive Drugs In The Netherlands: Exploration of Essential Criteria In The Decision Making Process. PMID- 26533065 TI - Overview of Nub Process for In-Patient Drugs and Devices In German. PMID- 26533066 TI - A Simulation Analysis Using The Orange Price Reference Tool. PMID- 26533067 TI - The German Amnog Drug Reimbursement Process: Factors Associated With Gba Decisions About The Additional Benefit. PMID- 26533068 TI - Impact of Essential Health Benefit Benchmark Plans on Us Market Access. PMID- 26533069 TI - A Systematic Comparision of Iqwig Recommendations and G-Ba Decisions In The Amnog Process In Germany. PMID- 26533070 TI - Impact of Assessments of New Medicines By The Smc In England. PMID- 26533071 TI - Ultra Orphan and Cancer Drug Pricing Trends In The Us and The Uk. PMID- 26533072 TI - Discount Distribution Analysis of Original Medicines Which Has No Generics In Turkey. PMID- 26533073 TI - Regulations of The German Drug Market. PMID- 26533074 TI - Are Vaccinations Really Different to Pharmaceuticals With Respect to Market Access In Germany? PMID- 26533075 TI - Streamlining The Access Decision Process For German Patients to Receive Reimbursed Treatments In Another European Union Member State. PMID- 26533076 TI - Influence of Patient-Reported Outcomes (Pro) on Market Access Decisions In Markets With Centralized Healthcare Systems. PMID- 26533077 TI - Differences Between The Efficacy of Biosimilars and Originators - Analysis and Implications for The Cost-Effectiveness-Analysis From A Payers Perspective. PMID- 26533078 TI - Pharmacoeconomic Guideline for Positive Drug List Application Purposes Implemented In Bulgaria. PMID- 26533079 TI - Nub Status - An Analysis Comparing Results of 2015 Vs. 2014 - Leading Therapeutic Areas Confirmed. PMID- 26533080 TI - Qualitative and Quantitative Analysis of The Scottish Medicines Consortium (Smc) Advice. PMID- 26533081 TI - Assessing The Potential for Tiered Pricing of High Priced Therapies Within Argentina, Columbia, Mexico, Indonesia, and Thailand. PMID- 26533082 TI - A Comparison of on-Patent Medicine Prices Using An Eks Method. PMID- 26533083 TI - Impact of Healthcare Reforms on Pricing and Reimbursement In Turkey. PMID- 26533084 TI - Critical Analysis of Pricing and Reimbursement Process on The Basis of New Indroduced Pharmacoeconomic Guidelines In Bulgaria. PMID- 26533085 TI - Atc1 Group Discount Distribution Analysis of Original Medicines Which Has No Generics In Turkey. PMID- 26533086 TI - Quantitative Assessment of Canadian Provincial Public Funding Decisions for Oncology Drugs Following Pcodr Economic Evaluations for 2013 and 2014. PMID- 26533087 TI - Value Judgment of Health Interventions From Different Perspectives: Arguments and Criteria. PMID- 26533088 TI - Fda Breakthrough Medicines; Have They Caused Breakthrough Headaches for Hta Agencies? PMID- 26533089 TI - The Evolution of HTA as a Coverage Decision-Making Tool in the Middle East and North Africa Region. PMID- 26533090 TI - Orphan Drugs Assessment in Germany: A Comparison with Other International HTA Agencies. PMID- 26533091 TI - How Does The Additional Benefit Extent of Orphan Drugs Impact Price Negotiations In The German Outpatient Sector? PMID- 26533092 TI - Reimbursement and Pricing of Innovative Medicines: EU5 Policies and Implications for Market Access. PMID- 26533093 TI - Assessing Pharmaceuticals with Limited Evidence in Germany - Current Experience. PMID- 26533094 TI - Current Challenges and Opportunities to Market Access in Brazil, Argentina, Mexico and Colombia. PMID- 26533095 TI - From Centralized Marketing Authorization to National Reimbursement - A Challenging Journey for New Medical Products with Placebo Controlled Trials. PMID- 26533096 TI - Limitation of Benefit Assessments in Germany - Current Experience. PMID- 26533097 TI - An Analysis of German Amnog Re-View Assessments and Learnings for Manufacturers. PMID- 26533098 TI - Off-Label Use of Intravenous Immunoglogulins (IVIGS): Funding Mechanisms in France, Germany, Italy, Spain and the United Kingdom (EU5). PMID- 26533099 TI - Nice Patient Access Schemes - A Who, What, Why, When and How. PMID- 26533100 TI - Market Access Entry Agreements in the Italian Market Between January 2006 and April 2015. PMID- 26533101 TI - Measuring Health Care Performance on Equity: A Framework Using National Administrative Data from 2004/5 to 2011/12. PMID- 26533103 TI - Quality Analysis of Pharmacoeconomics Evaluation and Application Literature in China During 2009-2013. PMID- 26533102 TI - Methodological Gaps in the Assessment of the Utility and Burden of Risk Minimisation Interventions. PMID- 26533104 TI - Is Assignment of Financial Value Stimulating French Researchers of Paris Academic Hospitals to Publish in International Journals? Results of the Diazepam Survey. PMID- 26533105 TI - Challenges and Benefits of Conducting Value of Information Analysis from the Perspective of Industry: A Simulation Study. PMID- 26533106 TI - A Systematic Literature Review to Assess the Impact of Social Networks on Healthcare in India. PMID- 26533107 TI - Evaluation Study on Equalization of Basic Medical and Health Services in China. PMID- 26533108 TI - Global Publication Trends in Medical Nutrition Health Economics. PMID- 26533109 TI - A Pitcure of Private Health Insurance Policyholders in Italy. PMID- 26533110 TI - Ethical Requirements for the Conduct of Drug Utilisation Studies Involving AD Hoc Data Collection: An International Cross-Sectional Survey. PMID- 26533111 TI - The Survey of Physicians' Satisfaction of Implementing Interventions for Changing Prescribing Behavior Toward Rational Medicine Use-2014. PMID- 26533112 TI - An Economic Analysis of Informal Care Provision in Ireland. PMID- 26533113 TI - A Literature Study About Utilization of Oriental Medical Services. PMID- 26533114 TI - Building a Bridge Between Clinical Evidence Research and Patient Preference Research. PMID- 26533115 TI - Gender Differences in Physical Activity of Hungarian Adults: An Observatory Survey. PMID- 26533116 TI - Survey of the Hungarian Physiotherapists' Migration and Career Changing Behaviour. PMID- 26533117 TI - Tailoring Sponsor-Payer Engagement to Facilitate Effective and Fair Patient Access. PMID- 26533118 TI - Examination of the Effect of Clinical Practices among Nursing Students. PMID- 26533119 TI - Are Medicines Granted with a Conditional Approval by the European Medicines Agency Gaining Positive Assessment by Payers in France, Germany and the United Kingdom? PMID- 26533120 TI - Trends in Hospital Standardized Mortality Ratios in Japan. PMID- 26533121 TI - Consumer Interest in Adopting an Electronic Health Record (EHR) Mobile Application Based on the Risk that Identifiable Information is Leaked. PMID- 26533122 TI - A Handbook and a Toolkit for Hospital-Based Health Technology Assessment. PMID- 26533123 TI - The Ceesp Economic Evaluation: Can Clinical Efficacy and Cost-Effectiveness Co Exist in France. PMID- 26533124 TI - An Analysis of German G-BA Added Benefit Assessment Decisions Using the World Health Organization Daly Framework. PMID- 26533125 TI - Romania's New HTA System: What Progress have Innovative Drugs Made under the Points-Based System So Far? PMID- 26533126 TI - Direct Evidence Versus Lack of Direct Evidence and the Impact on HTA Acceptance. PMID- 26533127 TI - Health Technology Assessment Archetype: Implication on Launch Planning and Evidence Synthesis. PMID- 26533128 TI - Evaluating the Safety Impact of Light Emitting Diode (LED) Guided Drug Picking in an Outpatient Pharmacy. PMID- 26533129 TI - Evidence Review Group (ERG) Critique of Systematic Reviews (SR) Submitted to Nice as Part of Single Technology Appraisals (STA) or Multiple Technology Appraisals (MTA) in the Last Three Years. PMID- 26533130 TI - Assessment of Consumer Likelihood to Adopt an Electronic Health Record (EHR) Mobile Application and the Impact of Perceived Risk of Privacy Leaks. PMID- 26533131 TI - Evolution & Influence of HTA in Emerging Markets. PMID- 26533132 TI - Comparison between HTA Reports in Veneto and Emilia Romagna: Drugs Assessment Decision Criteria and Priorities. PMID- 26533133 TI - Nice Decision Making: To Appeal or not to Appeal? PMID- 26533134 TI - The Challenges of Carrying out an Indirect Comparison with Single-Arm Studies. PMID- 26533136 TI - Biosimilars: Accessing the Uk Market. PMID- 26533135 TI - Prevalence and Incidence Estimations in German amnog Applications - The Role of Real-World Evidence (RWE). PMID- 26533137 TI - Comparison of Economic Evaluation Between Three Major HTA Agencies. Is There a French Touch? PMID- 26533138 TI - Implementing the Full Economic Evaluations of Medicines in the HTA Programmes in Catalonia: First Steps and Future Perspectives. PMID- 26533139 TI - Analysis of Four Early Dialogues (ED) as Part of the Seed (Shaping European Early Dialogues) Pilot: Lessons Learnt and Way Forward. Sanofi's Perspective. PMID- 26533140 TI - Variability in Clinical Comparators and Standards of Care: Consequences for Pan European Relative Efficacy. PMID- 26533141 TI - The Use of Mobile Health Technology in Promoting Infant Vaccine Adherence - A Health Technology Assessment. PMID- 26533142 TI - Does Conditional Marketing Authorisation Influence Market Access in France, England, and Germany? PMID- 26533143 TI - Organizational Models of Hospital Based HTA: Empirical Evidence from Adhophta European Project. PMID- 26533144 TI - Innovation Ranking in France and Italy: Differences and their Impact on Pricing and Reimbursement Processes. PMID- 26533145 TI - Trends in Non-Submissions in the UK. PMID- 26533146 TI - A Retrospective Analysis of Time to Market Access and the Regional Impact of Spanish 'Place in Therapy' Reports. PMID- 26533147 TI - Health Technology Assessment Tools for Technologies Incorporation into Public Health System. PMID- 26533148 TI - Manufacturers' Reactions in Response to the New Requirement for Cost Effectiveness in France. PMID- 26533149 TI - Increasing Transparency and the Patient Voice in HTA of New Medicines. PMID- 26533150 TI - Steps Towards Introducing a System of Health Technologies Assessment in Ukraine. PMID- 26533151 TI - Identifying Practical Gaps to Comply with Cost-Effectiveness Guideline in Selecting Comparators in South Korea. PMID- 26533152 TI - Eunethta Tools and Methods - Facilitating Uptake by Training Activities. PMID- 26533153 TI - Making Collaborative Relative Effectiveness Assessments Relevant: Experience of 4 Eunethta Pilots Across Pharmaceuticals and Medical Devices. PMID- 26533154 TI - Current Perception of Upcoming Cost-Effectiveness Requirements in Japan: a Survey on the Perspective of Pharmaceutical Industry. PMID- 26533155 TI - The Cumulative Analysis of Checklist Questionnaires Filled Out by the Hungarian HTA Office. PMID- 26533156 TI - Assessing the Cost-Effectiveness of Therapies in the Third Quadrant on the Cost Effectiveness Plane. PMID- 26533157 TI - Eunethta Members: What are their Roles within the National Setting? PMID- 26533158 TI - Potential Societal Value of Biosimilars Adoption: The Example of UK. PMID- 26533159 TI - The Eu Patient Registry Landscape: Survey of Registry Profiles Through Parent Ja Research And Framework. PMID- 26533160 TI - Shaping European Early Dialogues: The Seed Project. PMID- 26533161 TI - Prevalnce of Cigrate Smooking And Allied Tobacco Products Among Universty Students In Quetta, Pakistan. PMID- 26533162 TI - Examination of Water Consumption: Knowledge About Water Consumption In Population of Batya And Pecs. PMID- 26533163 TI - Trends In Self-Rated Health Status Among Adults In Greece (2002-2015). PMID- 26533164 TI - Work Capacity And Health Status Test of Police Officers. PMID- 26533165 TI - The Impact of Social Networks on The Students Health. PMID- 26533166 TI - Regispt: Registry of Registries In Portugal. PMID- 26533167 TI - Antibiotic Prescription Practices of Pediatricians In Hospital Care In Cyprus. PMID- 26533168 TI - Assessment of Drug Use Pattern Using Who Prescribing And Patient Care Indicators In A Referral Hospital In Ethiopia. PMID- 26533169 TI - A Systematic Review of The Impact of Improved Housing Interventions on Health In Low And Middle Income Tropical Settings. PMID- 26533170 TI - Comparative Analysis of Physical Activity, Sense of Control And Self-Reported Health of Elderly In Cee Countries. PMID- 26533171 TI - Role of Economics, Health, And Social And Political Stability In Determining Health Outcomes. PMID- 26533172 TI - Attitudes of Medical Doctors And Pharmacists Toward Generic Substitution In Slovakia: First Results From Adopting The Law In 2012. PMID- 26533173 TI - Prescription Pattern of Outpatient Department of A Teaching Hospital Quetta, Pakistan. PMID- 26533174 TI - Assessment of Drug Prescribing Among Pregnant Women Attending Antenatal Out Patient Department of A Referral Hospital In Ethiopia. PMID- 26533175 TI - Medication Error Identification Rate Among Medical Students of Quetta City, Pakistan. PMID- 26533176 TI - The Use of Real World Evidence to Influence Practice: A Systematic Review of Cprd Studies In English Guidances And Guidelines. PMID- 26533177 TI - Economic Considerations In Clinical Guidelines - Are Patient Perspectives Considered? PMID- 26533178 TI - Efficiency Assessments of Pharmaceuticals and Medical Devices In France: A 2 Years Update. PMID- 26533179 TI - Irrational Drug Use Pattern In Hospitals. A Warning for Health Care System. PMID- 26533180 TI - Law Project 7169/2014 And Health Policy In Brazilian Supplemetary Sector. PMID- 26533181 TI - Health Technological Supports to Detect Medication Errors: The Saniarp Case Study. PMID- 26533182 TI - A Study on Health Care Professional's Sense of Ethics In Japan. PMID- 26533183 TI - The 5-Years European Price Stability Awarded to Innovative Medicines: Is It Verified In Practice? PMID- 26533184 TI - Efficacy-Effectiveness-Gap - Extent, Causes And Implications. PMID- 26533185 TI - Conflicts' Mediation Between Consumers and Health Plans: The Usage Profile of The Available Channels for Complaints. PMID- 26533186 TI - Effect of The Reorganization of The Intensive Care Units System In Hungary. PMID- 26533187 TI - The Relation Between Real Costs Of Drugs Temporarily Reimbursed In Mode Of Coverage With Evidence Development And Budget Impact Analysis Submitted As A Mandatory Requirement Of The Application. PMID- 26533188 TI - Review of Policies And Perspectives on Real-World Data for Drug Development and Assessment (Imi-Getreal Deliverable). PMID- 26533189 TI - Challenges Along The Road to Universal Health Coverage In Egypt, An Hio Perspective. PMID- 26533190 TI - Payer Vs. Industry Views on Managed Entry Agreements. PMID- 26533191 TI - A Review of Guidelines And Approaches to Performance-Based Risk-Sharing Agreements Across The Uk, Italy And The Netherlands. PMID- 26533192 TI - Using Financial Incentives to Motivate Stair Use In A Workplace Setting: Results From A Randomized Controlled Trial. PMID- 26533193 TI - Which Risk Share Agreements are Available and are Those Applied In Global Reimbursement Decisions? PMID- 26533194 TI - State of The Art of Medical Registers In Switzerland 2015: More Questions Than Answers. PMID- 26533195 TI - Health Economics In Immunization Decision-Making - Results From A Systematic Literature Research and A Stakeholder Symposium In Germany. PMID- 26533196 TI - Recent Update to Russia's Essential Drugs List and Seven Nosologies: Clinical Differentiation And Local Manufacturing Implications for New Drug Inclusion. PMID- 26533197 TI - Economic Sanctions And Market Access for Pharmaceuticals: Case Studies With Russia, Cuba And Iran. PMID- 26533198 TI - How to Institutionalize The "Knowledge to Action" Framework for Health Technology Assessment? PMID- 26533199 TI - Assessing The Esmo Magnitude of Clinical Benefit Scale From A Health Economics Perspective. PMID- 26533200 TI - The New Technology Cost-Effectiveness Checklist: Introducing A Practical Guideline For The Selection Of Health Technologies. PMID- 26533201 TI - Extension of Indication With Mature Products: Toward More Incentives Rewarding Innovation? PMID- 26533202 TI - Do Clinical Guidelines for Hernia Surgery Reduce Costs and Improve Patient Outcomes, and Do Surgeons Follow Them? PMID- 26533203 TI - Development of Hospital-Based Hta Unit Processes In The Czech Hospital Environment. PMID- 26533204 TI - Reforming Drug Pricing and Patient Access Systems to Support Universal Coverage In Developing Countries. PMID- 26533205 TI - The Irish Cost-Effectiveness Threshold: Does It Support Rational Rationing or Might It Lead to Unintended Harm of Ireland's Health System? PMID- 26533206 TI - Brexit and Grexit: Implications for The Pharmaceutical Industry. PMID- 26533207 TI - The Influence of "Has" Haute Autorite De Sante In The Reimbursement Decisions In Francophone Countries: The Case of North Africa Region. PMID- 26533208 TI - Tracking Drug Utilization Data to Enable Conditional Reimbursement of Medicines or Specific Indications In Romania: Analysis of The Requirement for An Effective Implementation. PMID- 26533209 TI - Targeted Combination Regimes In Oncology Challenges for Pricing and Reimbursment In Switzerland: Analysis of The Implication and Operational Requirement For Implementation of An Indication Code. PMID- 26533210 TI - The Trends In Orphan Drug Authorisation and Approval In Europe And In The United States - A Retrospective Study (2005-2014). PMID- 26533211 TI - Introduction of Formal Risk Sharing Agreements (Rsa): A Promising Solution for Sustainable and Predictable Pharmaceutical Expenditures In Bulgaria. PMID- 26533212 TI - Health Care Coverage Through Private Health Insurance. PMID- 26533213 TI - Sofosbuvir: The Failure of Pricing Policies In The European Union. PMID- 26533214 TI - Closing The Financial Gap of Antiretroviral and Hiv Supplies For Sustainability of Hiv National Response In The Dominican Republic. PMID- 26533215 TI - Patient Behaviour As A Cost Driver In The Management of Chronic Disease Patients. PMID- 26533216 TI - Comparison of Pharmaceutical Pricing and Reimbursement Systems In Turkey And Certain Other Eu Countries. PMID- 26533217 TI - Proposal for A Regulatory Framework for Health Apps to Ensure A Patient Centered Competition Between Providers. PMID- 26533218 TI - Need for New Pharmacoeconomics Policy for Regulating Prices of Medical Devices In India. PMID- 26533219 TI - Pricing and Reimbursement Policies of Turkey and Ukraine. PMID- 26533220 TI - Health Care Policy and Cost After Earthquake In Nepal. PMID- 26533221 TI - Health Proffessionals Involvement In Politics A Means to Improving Healthcare Delivery and Healthcare Legislations for Healthcare Seekers In Africa. PMID- 26533222 TI - The South African Guidelines for Pharmacoeconomic Submissions: A Review In Context of Existing Legislation and Challenges to Implementation. PMID- 26533223 TI - Is Oncology Drug Financial Toxicity A Specific Us Issue? PMID- 26533224 TI - Trends of Implementation of Hta In Kazakhstan. PMID- 26533225 TI - Adaptive Pathways May Expand The Gap Between Regulators And Payers. PMID- 26533226 TI - Market Access for Pharmaceuticals In Europe: Future Perspectives. PMID- 26533227 TI - A Conceptual Paper on Steps Needed to Reach Integrated Healthcare System In Egypt. PMID- 26533228 TI - Health System Research Opportunities for Assessment of The National Health Care System. PMID- 26533229 TI - Impact of Decision Making Based on The Matching The Quality of The Early Warning Indicators In Colombia During 2013 - 2014 Between Private And Public Ips and The Quantity of Affiliates By Regimen. PMID- 26533230 TI - Prevalence of Hepatitis C And Presence of Comorbidities In Sweden: A Nationwide Population-Based Register Study. PMID- 26533231 TI - Health Technology Assessment Practices In Turkey. PMID- 26533232 TI - Considering Evidence From Health Economics Within Immunization Decision-Making - A Semi Multiple Criteria Decision Approach Using The Decide Tool. PMID- 26533233 TI - Increase Arv Access for Plwha In Dominican Republic Through The Transition From Vertical Supply System to An Integrated National Pharmaceutical System. PMID- 26533234 TI - Evaluation of Average Cost-Effectiveness Ratios of Standards of Care Across Different Indications. PMID- 26533235 TI - Outcome Research to Investigate The Actual Status of Mrsa Infection And Usage of Anti-Mrsa Drugs In Real Clinical Settings In Japan : A Retrospective Database Study. PMID- 26533236 TI - Coping With Discrepancies In Epidemiological Data From Various Sources For Low Incidence Diseases: The Case Of Multidrug-Resistant Tuberculosis In Germany. PMID- 26533237 TI - Daclatasvir +Asunaprevir Versus Sofosbuvir/Ledipasvir for The Treatment of Chronic Hepatitis C Genotype 1 In Japanese Patients: A Matching-Adjusted Indirect Comparison. PMID- 26533238 TI - Probiotics Significantly Reduce Mortality In Preterm Newborns With Necrotising Enterocolitis: Results of Large Network Meta-Analysis. PMID- 26533239 TI - The Use of Single-Arm Evidence In The Comparative Efficacy of Interferon-Free Antivirals for Treatment-Naive Hepatitis C Genotype 1. PMID- 26533240 TI - Long Term Virological Outcomes of Hiv Infected Patients on Antiretroviral Treatment In Uganda. PMID- 26533241 TI - Adherence, Healthcare Resource Use (Hru) And Costs: A Comparison Of Single-Tablet Regimen (Str) Versus Multi-Tablet Regimen (Mtr) Containing Fixed Dose Combination (Fdc) Regimens. PMID- 26533242 TI - Public Health Outcomes of Paediatric Influenza Vaccination With An Intranasal Tetravalent Live Attenuated Vaccine In Belgium Using A Dynamic Transmission Model. PMID- 26533243 TI - Estimation of The Relative Efficacy of Licensed Regimens for Genotype-1 Hcv Infection Using A Mixed Treatment Comparison. PMID- 26533244 TI - Systematic Literature Review (Slr) And Network Meta-Analysis (Nma) Of Tenofovir/Emtricitabine (Tdf/Ftc) And Abacavir/Lamivudine (Abc/3tc) Backbone Regimens For Hiv-1. PMID- 26533245 TI - Appropriateness Score and Cost Evaluation In Hiv: The Aprosce System, on Field Clinical Evaluation. PMID- 26533246 TI - High Therapeutic Efficiency With Ledipasvir/Sofosbuvir For The Treatment Of Genotype 1 Chronic Hepatitis C In Portugal. PMID- 26533247 TI - Public Health And Economic Impact of A Quadrivalent Influenza Vaccine In Comparison to The Trivalent Influenza Vaccine In Brazil Over The Period Of 2010 - 2013. PMID- 26533248 TI - Indirect Comparison for E/C/F/Taf In Treatment Naive Hiv Patients. PMID- 26533249 TI - Modeling of Using Rilpivirine/ Tenofovir/ Emtricitabine In Treatment of Naive Hiv 1 Infected Patiens. PMID- 26533250 TI - Meta-Analysis of Mortality In Adults, Newborns and Older Children With Bacterial Infections And Sepsis When Treated By Igm-Enriched Intravenous Immunoglobulins And Standard Schemes. PMID- 26533251 TI - Budget Impact Analysis of Sofosbuvir-Based Regimens for The Treatment of Hiv/Hcv Co-Infected Patients In Northern Italy: The Liguria Region Simulation. PMID- 26533252 TI - Health Economic Impact of 13-Valent Pneumococcal Conjugate Vaccine In Finnish Home Care Customers >=50 Years With Underlying Chronic Medical Conditions. PMID- 26533253 TI - Age Related Consultation Rates of Clinically-Diagnosed Influenza And Acute Respiratory Illnesses Observed Through A Network of Gp Practices Across England. PMID- 26533254 TI - Cholera Death Audit In Ghana: A Medical Record Review of The 2014 Outbreak. PMID- 26533255 TI - Epidemiology of Hepatitis C Patients In Italian Local Health Units (Lhus). PMID- 26533256 TI - Epidemiological Data Used In Rotavirus Vaccination Cost-Effectiveness Analysis In Europe: A Literature Review Update. PMID- 26533257 TI - Cost Impact of The Delay of Broad-Spectrum Antimicrobial Agents De-Esclation on Surgical Wards. PMID- 26533258 TI - Budget Impact Analysis of The Use of Daclatasvir for The Treatment of Hepatitis C Virus (Hcv) Genotypes 3, In The Italian Setting. PMID- 26533259 TI - A Dynamic Model To Estimate The Budget Impact Of A Neumococcal Vaccination Program In Spain. PMID- 26533260 TI - A Systematic Literature Review of The Economic Implications of Acute Bacterial Skin And Skin Structure Infections (Absssis). PMID- 26533261 TI - Challenges In Economic Evaluation of Antibiotics In Health-Care Acquired Infections: A Targeted Review. PMID- 26533262 TI - Potential Long-Term Cost Savings In Treatment of Naive Hiv-Infected Patients With Rilpivirine/ Tenofovir/ Emtricitabine (Single Tablet Regimen) In The Russian Federation. PMID- 26533263 TI - Budget Impact Analysis And Long-Term Disease Implications Of Hepatitis C Treatments In Sweden. PMID- 26533264 TI - Reduction in Costs over two years when Treating with Darunavir/Ritonavir Compared to Atazanavir/Ritonavir in the UK. PMID- 26533265 TI - Direct Costs And Length of Stay In Patients With Methicillin Resistant Versus Methicillin Sensitive Staphylococcus Aureus Infection In A Tertiary Care Hospital In India. PMID- 26533266 TI - Comparison of Direct Hospitalization Costs and Length of Stay In Carbapenem Resistant Versus Carbapenem Sensitive Klebsiella Pneumoniae Infections In A Tertiary Care Hospital. PMID- 26533267 TI - Pharmacoeconomic Analysis of The Use of Voriconazole, Posaconazole And Micafungin In The Primary Prophylaxis of Invasive Fungal Infections In Recipients of Allogeneic Hematopoietic Stem Cell Transplants In Spain. PMID- 26533268 TI - Direct Medical Cost Associated With The Diagnosis and Treatment of Patients With Chronic Hepatitis-B In Three Large Metropolitan Cities In India - A Pilot Study. PMID- 26533269 TI - The Health And Medical Care Costs For Hospitalized All-Cause Pneumonia Among Children <2 Years, Pre And Postthe Introduction Of Prevenar13 In Sweden. PMID- 26533270 TI - Health-Economic Evaluation of Clostridium Difficile Infection (Cdi) And Epidemiology In England And Merseyside. PMID- 26533271 TI - Assessment of Direct Cost for Treatment of Influenza and Ari for Outpatient In Ukraine. PMID- 26533272 TI - Potential Health And Economic Impact Of Introducing A Dengue Vaccine In Malaysia: Assessment Using Dynamic Transmission Modelling. PMID- 26533273 TI - Economic Analysis of Outpatient Parenteral Antimicrobial Therapy (Opat): A Systematic Review. PMID- 26533274 TI - Cost Analysis of The Chronic Hcv-Related Cirrhosis In Bulgaria. PMID- 26533275 TI - The Cost of Treating Recurrent Clostridium Difficile Infection In Patients Attending Infectious Disease Clinics At Four Hospitals In Sweden. PMID- 26533276 TI - The Devil Is Not So Black As He Is Painted - The Future of Immunization In Poland. PMID- 26533277 TI - Cost-Effectiveness Analysis of Herpes Zoster Vaccination In Hong Kong. PMID- 26533278 TI - Pharmacoeconomic Evaluation of the Introduction of Routine Varicella Vaccination in Children in the United Kingdom. PMID- 26533279 TI - The Public Health Impact and Cost-Effectiveness of Pneumococcal Conjugate Vaccination In Estonia. PMID- 26533280 TI - Cost-Effectiveness of Pneumococcal Vaccination of Elderly In Germany. PMID- 26533281 TI - Pharmacoeconomic Analysis Of Anidulafungin, Micafungin, Caspofungin And Fluconazole In The Treatment Of Candidemia And/Or Invasive Candidiasis In Non Neutropenic Adult Patients In Spain. PMID- 26533282 TI - Cost-Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Among Patients Aged 65-84 Years With Co-Morbidities or Immunosuppression In Belgium. PMID- 26533283 TI - Herpes Zoster and Post-Herpetic Neuralgia Vaccination- Cost-Effectiveness Analysis In Portugal. PMID- 26533284 TI - Cost-Effectiveness of 18 Month Booster Dose of A Pertussis-Containing Vaccine on The Australian National Immunisation Program: A Dynamic Model-Based Analysis. PMID- 26533285 TI - Ledipasvir / Sofosbuvir for The Treatment of Chronic Hepatitis C: A Cost Effectiveness Analysis Across Different Genotype 1 Clinical Subgroups. PMID- 26533286 TI - Cost-Effectiveness Of Active Surveillance Of Carbapenem-Resistant Enterobacteriaceae In Intensive Care Units In Hong Kong. PMID- 26533287 TI - Cost-Effectiveness of Sofosbuvir and Ledipasvir In The Treatment of Patients With Hepatitis C. PMID- 26533288 TI - Rectal Culture Testing Before Transrectal Ultrasound-Guided Prostate Biopsy (Trusbx) In Hong Kong - A Cost-Effectiveness Analysis. PMID- 26533289 TI - Economic Evaluation Of The Rotavirus Vaccination Among Children Under 5 Years Of Age In Switzerland. PMID- 26533290 TI - Estimating The Cost-Effectiveness Profile of A Universal Vaccination Programme With A Nine-Valent Hpv Vaccine In Austria. PMID- 26533291 TI - Genotype 1 Hepatitis C Virus Treatments For Non-Cirrhotics In The Era Of All-Oral Direct-Acting Antivirals: A Cost-Effectiveness Analysis. PMID- 26533292 TI - Economic Evaluation of Targeted Antifungal Treatment Sequencing Strategies For Invasive Aspergillosis Based on Real World Data: The Case of Dutch Clinical Practice. PMID- 26533293 TI - Economic Evaluation of Voriconazole in the Treatment of Invasive Aspergillosis. PMID- 26533294 TI - Cost Per Patient With Sustained Viral Response for Ombitasvir/Paritaprevir/Ritonavir And Dasabuvir With or Without Ribavarin In Genotype 1 Patients With Chronic Hcv In The Netherlands. PMID- 26533295 TI - Cost-Effectiveness of Conjugate Pneumococcal Vaccination In Croatia. PMID- 26533296 TI - Cost-Effectiveness of Dolutegravir/Abacavir/Lamivudine in Hiv-1 Treatment Naive Patients in France. PMID- 26533297 TI - Cost Effectiveness Analysis of The Use of Daclatasvir for the Treatment of Hepatitis C Virus (Hcv) Genotypes 3 in Cirrhotic Patients Within the Italian National Health Service. PMID- 26533298 TI - Cost Effectiveness of Bedaquiline for Patients With Multi-Drug Resistant Tuberculosis in South Korea. PMID- 26533299 TI - Assessment of Compliance and Avoided Costs After Implementation of Equivalent Terapeutic Program for Candida Infection Treatment. PMID- 26533300 TI - Cost Analysis of Residual Viremia Detected by Two Real-Time Pcr Assays For Response-Guided (Dual Or Triple) Therapy of Hcv Genotype 1 Infection. PMID- 26533301 TI - High-Dose Inactivated Influenza Vaccine can Reduce Costs and Improve Outcomes Compared to Standard-Dose Inactivated Influenza Vaccine in Canadian Seniors. PMID- 26533302 TI - Broad Access to Treatment is Cost-Effective for Patients with Chronic Hepatitis C in England. PMID- 26533303 TI - Cost-Utility Analysis of Dolutegravir/Abacavir/Lamivudine (Dtg/Abc/3tc) as a Single Tablet Treatment of Naive Hiv Infected Patientss. PMID- 26533304 TI - Health Economic Evaluation of Different Vaccination Strategies Against Varicella and Herpes Zoster in Germany. PMID- 26533305 TI - Cost-Effectiveness of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir for Patients With Chronic Hcv in the Netherlands. PMID- 26533306 TI - Cost-Effectiveness Analysis of Quadrivalent Influenza Vaccine in Spain. PMID- 26533307 TI - Cost-Effectiveness of Ledipasvir/Sofosbuvir for the Treatment of Genotype 1 Or 4 Chronic Hepatitis C in England and Wales. PMID- 26533308 TI - Testing for Ns5a Resistance in Order to Optimize Antiviral Therapy With Simeprevir And Sofosbuvir 12 Weeks Appears Cost-Effective in Non-Cirrhotic Genotype 1 Hepatitis C Virus Treatment Experienced Patients. PMID- 26533309 TI - Pharmacoepidemiologic Modeling of Treatment Hiv-Infected Patients With Rilpivirine/ Tenofovir/ Emtricitabin (Single Tablet Regimen) in Russia. PMID- 26533310 TI - The Epidemiological and Cost Burden of Herpes Zoster (Hz) and Post-Herpetic Neuralgia (Phn) in the Uk. PMID- 26533311 TI - Public Health and Economic Benefits of Quadrivalent Influenza Vaccine in Panama. PMID- 26533312 TI - Economic evaluations in infectious disease: which infections, what settings and what type of economic evaluations were reported in papers published in 2014? PMID- 26533313 TI - Adherence to Antiretroviral Therapy Among Patients Lost-To-Follow Up: A Case of An Hiv Clinic in a Private-For-Profit Health Facility in Kampala, Uganda. PMID- 26533314 TI - Exploring Attitudes and Perceptions of Patients and Staff Towards a Fee For Service "After Hours" Clinic Supplementing Free Hiv Services in Uganda: A Qualitative Study. PMID- 26533315 TI - Health State Utilities of Risks Associated with Antiretroviral Treatment for Human Immunodeficiency Virus (Hiv). PMID- 26533316 TI - Disutilities Associated with Central Nervous System (Cns) Side Effects of Antiretroviral Therapy (Art) in Hiv. PMID- 26533317 TI - Public Health and Economic Benefits of Quadrivalent Influenza Vaccine in Colombia. PMID- 26533318 TI - Effect of Pharmacist Interventions and Patient Reported Outcomes on Highly active Antiretroviral Therapy Counseling in Indian Hiv Postive Patients : A Prospective Study. PMID- 26533319 TI - Multiple Pill Regimens, Single Tablet Regimens and Hiv+ Patients Quality of Life: Evidence from the Straq Study. PMID- 26533320 TI - Assessment of Hiv-Related Quality of Life in a Representative Sample Of French Patients using Multivariate Multi-Block Statistical Models. PMID- 26533321 TI - Psychometric Validation of the New International Questionnaire to Assess Health Related Quality of Life (Hrql) Specific to Viral Hepatitis C: Proqol-Hcv. PMID- 26533322 TI - Knowledge, Attitude and Perception of Polio (Poliomyelitis) among General Public in Pakistan. PMID- 26533323 TI - Real-World Hepatitis C Treatment Strategies in Denmark. PMID- 26533324 TI - A Systematic Review of Herpes Zoster Vaccine Acceptance. PMID- 26533325 TI - Indiscriminate Prescription of Antibiotics and an Urgent Need of Legislation- A Survey from Pakistan. PMID- 26533326 TI - Hiv Patient Preferences for Simplified Treatment Regimens. PMID- 26533327 TI - The Conceptual Framework of Quality of Sexual Life in Hiv and Hcv. PMID- 26533328 TI - Quality of Life Among Hiv Patients: Results from the Ianua Clinical Trial. PMID- 26533329 TI - Assessing the Cost-Effectiveness of Antiretroviral Treatments in Hiv: an Individual Patient Simulation Approach. PMID- 26533330 TI - The Impact of Societal Views on Market Access- Case Studies For Utilization of Hpv Vaccines in Cervical Cancer and Prep Hiv Preventive Therapy. PMID- 26533331 TI - Trends of Hpv Vaccine Uptake, Completion, and Adherence in the United States: 2006-2011. PMID- 26533332 TI - Steering vaccines through the uk system - what factors influence the likelihood of positive and negative recommendations? PMID- 26533333 TI - A Decision Options Approach to Antibiotic R&D Investment. PMID- 26533334 TI - Treatment Patterns and Characteristics of Medicare Beneficiaries with Hiv Related Cachexia. PMID- 26533335 TI - Descriptive Analysis of Drug Utilization among Chronic Hepatitis C Virus (Chc) Patients in the Us Commercially Insured Population. PMID- 26533336 TI - Characterisitcs and Drug Utilization among Treated Chronic Hepatitis C Virus (Chc) Patients with and without Chronic Kidney Disease (Ckd) in the Us. PMID- 26533337 TI - Adherence of hiv patients switching to emtricitabina+tenofovir disoproxil+rilpivirin. Real world evidence from italian administrative databases. PMID- 26533338 TI - Minimun Indicators To Evaluate Management and Clinical Results in Institutions Assisting Patients Living with Hiv in Colombia. PMID- 26533339 TI - How much is spent in vaccines across western europe countries? PMID- 26533341 TI - The Cost of Vaccination Throughout Life: A Pan-European Perspective. PMID- 26533340 TI - Decontamination and Infection Control of Nursing Tools and Patient Environment Regarding Nosocomialis Infections. PMID- 26533342 TI - Reliability of Manufacturers' Budget Impact Estimates for Chronic Hcv Gt1 Drugs in Poland. PMID- 26533343 TI - National Survey of Behavior, Attitudes and Practice of General Practitioners and Various Specialists Concerning Antimicrobial Use And Resistance in Respiratory Tract Infections. PMID- 26533344 TI - Are vaccines getting a fair deal? Health technology assessment of vaccines across europe. PMID- 26533345 TI - Willingness to Pay for Innovative Drugs: Anti-Hcv Treatment from the Italian National Health System Perspective. PMID- 26533346 TI - ANALYSIS OF Hiv - Infection in Kazakhstan. PMID- 26533347 TI - Identifying Research Gaps in Antimicrobial Resistance (Amr): Literature Review, Potential Research Questions and Study Designs. PMID- 26533348 TI - Do pneumococcal conjugate vaccines represent good value for money in a lower middle income country? A cost-utility analysis in the philippines. PMID- 26533349 TI - Scoring and Measurement Properties of a Tool to Assess Primary Care Physicians' Engagement in and Perceived Barriers to Vaccination: the 'Determinant of Intentions of Vaccination' (Diva(c)) Questionnaire. PMID- 26533350 TI - Monitoring Of Critical Laboratory Results To Improve Quality Of Patient Care In A Large Urban Clinic In Uganda. PMID- 26533351 TI - Cost Analysis of Two Methods for Improving the Quality of Care (Qoc) Scores in Paediatric Hospital Wards During Winter Periods. PMID- 26533352 TI - Exenatide Once Weekly Plus Metformin for the Treatment of Type 2 Diabetes Mellitus: A Network Meta-Analysis of Randomised Controlled Trials. PMID- 26533353 TI - Relationship between Glycaemic Burden and Micro- and Macrovascular Complications in Patients with Type 2 Diabetes Mellitus: A real-world study in the Pharmo Database Network. PMID- 26533354 TI - The Association of Waist Circumference and Microvascular Complications in Diabetic Patients in an Asian Population. PMID- 26533355 TI - Risk of New-Onset Diabetes Associated with Concomitant Antidepressant, Inhaled Corticosteroids, and Statin Use Among Medicaid Beneficiaries with COPD. PMID- 26533356 TI - Cost-Effectiveness Analysis Of Phid-Cv Routine Vaccination Programme Compared To Pcv-13 In Portugal. PMID- 26533357 TI - Network Meta-Analysis (NMA) to Assess Relative Efficacy Measured as Percentage of Patients Treated to HbA1c Target with Canagliflozin in Patients with Type 2 Diabetes Mellitus (T2DM) Inadequately Controlled on Metformin and Sulphonylurea (MET+SU). PMID- 26533358 TI - Liraglutide vs Other Daily GLP-1 Analogues in People with Type 2 Diabetes: A Network Meta-Analysis. PMID- 26533359 TI - Achievement of Glycaemic Targets with Canagliflozin in Triple Therapy in Patients with Type 2 Diabetes Mellitus (T2DM). PMID- 26533360 TI - Bayesian Network Meta-Analysis (NMA) to Assess the Relative Efficacy of Canagliflozin in Patients with Type 2 Diabetes Mellitus (T2DM) Inadequately Controlled with Insulin. PMID- 26533362 TI - Indirect Comparison to Evaluate the Efficacy and Safety of Dipeptidyl Peptidase-4 Inhibitors (DPP4I) and Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2I) Added to Insulin Therapy in Type 2 Diabetes. PMID- 26533361 TI - A Network Meta-Analysis (NMA) to Assess the Longer-Term Relative Efficacy of Canagliflozin in Patients with Type 2 Diabetes Inadequately Controlled on Metformin. PMID- 26533363 TI - A Multivariate Safety and Efficacy Analysis of Prescribing Information for Next Generation SGLT-2 Inhibitors in Type 2 Diabetes Treatment. PMID- 26533364 TI - "Efficacy and Safety Bariatric Surgery VS. Clinical Treatment in Control of Levels Glycemic and Remission Diabetes Mellitus Type II in Patients Obese". PMID- 26533365 TI - A Cross-Sectional Study on Insulin Treatments and Glycemic Control in Type 2 Diabetes in France, Italy, Germany, UK and Spain. PMID- 26533366 TI - Patterns of Pharmacological Treatment in Type 2 Diabetes in France in 2013. PMID- 26533367 TI - Prescription Patterns of Antidiabetic Treatment in the Elderly. Results from Southern Italy. PMID- 26533368 TI - Factors Associated with T2DM Treatment Choice Across Europe. PMID- 26533369 TI - Cardiovascular Outcomes of Antidiabetic Therapy - Results of a Literature Search. PMID- 26533370 TI - Factors Associated with the Risk of Diabetes-Related Events: A Retrospective Analysis. PMID- 26533371 TI - Impact of Socioeconomic Status on the Prevalence of Complications in Type 2 Diabetes in Indian Population: A Systematic Review. PMID- 26533372 TI - The Association of Waist Circumference with Glycaemic Control in Diabetic Patients in an Asian Population. PMID- 26533373 TI - Trends in Prevalence and Incidence Rates of Type 2 Diabetes Mellitus in Medicare Population. PMID- 26533374 TI - Risk of Fracture in Type 2 Diabetes Mellitus Patients: Meta-Analysis of Observational Studies. PMID- 26533375 TI - Budget Impact Analysis of Long-Acting Insulin Analogues in the Perspective of Brazilian Public Health System. PMID- 26533376 TI - The NHS Expenditure Managing Severe Hypoglycemia Episodes in Type 2 Diabetic Patients in Portugal. PMID- 26533377 TI - Costs for Diabetic Patients Receiving Dipeptidyl Peptidase-4 (DPP-4) Inhibitors in US Medicare and Commercial Insurance Plans. PMID- 26533378 TI - Heterogeneity in the Definition of Drug Induced Hypoglycemia in Clinical Trials: A Review. PMID- 26533379 TI - Impact of Overweight and Obesity in the Frequency Medical Complications During Pregnancy and Economic Burden in the High Risk Pregnancy in Mexico. PMID- 26533380 TI - Cost Analysis Study of Anti-Diabetic Fixed Dose Combination Drugs: An Indian Scenario. PMID- 26533381 TI - Economic Aspects in the Management of Diabetes in Italy. PMID- 26533382 TI - Pharmacy Cost Differences Associated with the Initiation of Exenatide Once-Weekly Compared to Liraglutide Once-Daily. PMID- 26533383 TI - Impact of Nurse-Led Telecoaching on the Annual Healthcare Utilization and Costs in People with Type 2 Diabetes in Belgium. Within-Trial Analysis of Health Insurance Data. PMID- 26533384 TI - Direct Cost of Uncomplicated Hypothyroidism During Pregnancy and Childbed in Czech Republic. PMID- 26533385 TI - Costs of Type 1 Diabetes Mellitus in Pediatric Patients in Spain: Chrystal Observational Study. PMID- 26533386 TI - The Indirect Costs of Types 1 Diabetes Mellitus Associated with Absenteeism in Poland in 2013. PMID- 26533387 TI - Pharmacoeconomic Evaluation of Geriatric Diabetics in a Tertiary Care Hospital: A Prospective Study. PMID- 26533388 TI - Type II Diabetes Complications' Cost in Estonia. PMID- 26533389 TI - Cost of Illness Study of Type 2 Diabetes Mellitus in the Newly Established Diabetology Outpatient Facility in the Czech Republic. PMID- 26533390 TI - Cost of Achieving Combined Improvements in HbA1c and Weight without Hypoglycaemia over 4 Years in a Post-Hoc Analysis of Dapagliflozin + MET Vs Glipizide + MET. PMID- 26533391 TI - Cost of Illness Analysis in Patients with Diabetic Foot Syndrome in Health Care of Republic of Belarus. PMID- 26533392 TI - Cost of Type 2 Diabetes According to Glucose-Lowering Medications in France. PMID- 26533393 TI - Hospitalization Cost and Length of Stay Associated with Ophthalmological Surgery Depending on the Diabetic Status. PMID- 26533394 TI - Productivity Loss Costs Attributable to Obesity in Working Patients with Diabetes in the US. PMID- 26533395 TI - Longitudinal Changes in Medical Services Costs from 2006 to 2012 for Newly Diagnosed T2D Patients. PMID- 26533396 TI - Direct Cost and Medication Usage Among Insured Type 2 Diabetes Patients with Chronic Kidney Disease under Hospitalization in Beijing and Tianjin, China. PMID- 26533397 TI - Association between Weight Change, Diabetes-Related Healthcare Costs, and HbA1c among Patients with Type 2 Diabetes. PMID- 26533398 TI - Direct Cost and Medication Usage in Elderly Type 2 Diabetic Patients under Hospitalization among Insured Urban Population in China. PMID- 26533399 TI - Cost of Medication Nonadherence in Patients with Diabetes Mellitus. PMID- 26533400 TI - Relationship between Spending on Diabetes Drugs and Occurrence of Risks Associated with Type 2 Diabetes in English General Practices. PMID- 26533401 TI - Cost-Effectiveness of Dapagliflozin as Add-on to Metformin for the Treatment of Type 2 Diabetes in Greece. PMID- 26533402 TI - Evaluating the Cost-Effectiveness of GLP-1 Receptor Agonists for the Treatment of Type 2 Diabetes in the UK. PMID- 26533403 TI - The Long-Term Cost-Effectiveness of Twice-Daily Exenatide with Insulin Glargine Versus Once-Daily Liraglutide with Insuline Detemir in Adult Patients with Type 2 Diabetes in Russia. PMID- 26533404 TI - Economic Burden of Type 2 Diabetes Mellitus Treatment Strategies: A Cost Consequence Analysis of Sitagliptin vs Sulfonylureas in Lombardy Region. PMID- 26533405 TI - The Cost-Effectiveness (CE) of Intravitreal Aflibercept (IVT-AFL) in the Treatment of Diabetic Macular Edema (DME) in Turkey. PMID- 26533406 TI - Cost-Effectiveness Analysis of Exenatide Once-Weekly Versus Dulaglutide, Liraglutide and Lixisenatide for the Treatment of Type 2 Diabetes Mellitus: An Analysis from the UK NHS Perspective. PMID- 26533407 TI - Cost-Effectiveness Analysis of Gestational Diabetes Mellitus Screening in Urban Chinese Setting. PMID- 26533408 TI - A Systematic Review of Cost-Effectiveness Models in Type 1 Diabetes Mellitus. PMID- 26533409 TI - Dapagliflozin Versus a Dipeptidyl Peptidase 4 Inhibitor (DPP4) Both Added to Metformin in Patients with Type 2 Diabetes Mellitus (T2DM): Impact on Health, Quality of Life and Costs in the Turkish Clinical Setting. PMID- 26533410 TI - Cost-Effectiveness of Dulaglutide 1.5mg Once Weekly for the Treatment of Patients with Type Two Diabetes Mellitus in Sweden. PMID- 26533411 TI - The Cost-Effectiveness of Canagliflozin (CANA) Versus Dapagliflozin (Dapa) 10mg and Empagliflozin (EMPA) 25mg in Patients with Type 2 Diabetes Mellitus (T2DM) as Monotherapy in the United Kingdom. PMID- 26533412 TI - Economic Evaluation of Second Line Oral Antidiabetics for Type 2 Diabetes in Colombia. PMID- 26533413 TI - Economic Evaluation of Saxagliptin in Combination with Metformin Versus Sitagliptin or Vildagliptin in Combination with Metformin in Patients with Type 2 Diabetes in Russia. PMID- 26533414 TI - Cost-Effectiveness of Sitagliptin Compared to Sulphonylurea as an Add-on to Metformin in the Treatment of Type 2 Diabetes in Greece. PMID- 26533415 TI - Cost of Reaching Defined HbA1c Target Using Canagliflozin Compared to Dapagliflozin as Add-On to Metformin in Patients with Type 2 Diabetes Mellitus (T2DM) in the United Arab Emirates (UAE). PMID- 26533416 TI - Cost-Effectiveness Analysis of Vildagliptin vs. Glimepiride as Add-On to Metformin in the Management of Type 2 Diabetes Mellitus in Greece. PMID- 26533417 TI - Economics Analysis of Dapagliflozin Compare to Sulfonylurea in the Treatment of Type 2 Diabetes Mellitus in Spain: Cost of Achieving Composite Endpoints. PMID- 26533418 TI - Cost-Effectiveness of Pasireotide Long-Acting in a Treatment of Acromegaly in Finland. Economic Evaluation Based on Finnish Auria Biobank Data on Health Care Resource Utilization. PMID- 26533419 TI - Cost-Utility Analysis of Insulin Analogues Compared with Multiple Daily Injections of Human Insulin for the Treatment of 15 Years Old or Older Patients with Type 1 Diabetes Mellitus in Colombia. PMID- 26533420 TI - Cost-Effectiveness of Increasing the Influenza Vaccination Rate in Adults with Type 2 Diabetes in Turkey. PMID- 26533421 TI - Cost Analysis of the Diabetic Treatment in Italy: The Role of Vildagliptin vs. Other Therapeutic Options in Patients with Type 2 Diabetes with Renal Insufficiency. PMID- 26533422 TI - Cost-Effectiveness Analysis of Exenatide Twice Daily (BID) Versus Insulin Glargine Once Daily (QD) as Add-on Therapy in Chinese Patients with Type 2 Diabetes Mellitus Inadequately Controlled by Oral Therapies. PMID- 26533423 TI - Economic Evaluation of The One-Step Scheme Compared With Two-Steps for Screening And Diagnosis of Gestational Diabetes In Colombia. PMID- 26533424 TI - Cost-Effectiveness of Rapid-Acting Analog Insulin for Type 1 Diabetes In The Uk Setting. PMID- 26533425 TI - Health Utilities Associated with Hypoglycemic Events in Type 2 Diabetes Mellitus (T2DM) Patients Receiving Basal-Bolus Insulin Therapy. PMID- 26533426 TI - Cost-Minimization Analysis (CMA) of Canagliflozin Compared to Glimepiride and Sitagliptin as Dual Therapy in Combination with Metformin. PMID- 26533427 TI - Understanding The Inter-Relationship Between Improved Glycaemic Control, Hypoglycaemia and Weight Change Within A Type 1 Diabetic Population. PMID- 26533428 TI - The Role of Selective Inhibitors of Sodium-Glucose Co-Conveyor Type 2 In Reducing of Vascular Aftereffects. PMID- 26533429 TI - The Cost of Non-Severe Hypoglycaemia In Europe. PMID- 26533430 TI - Impact of A Telephonic Outreach Program on Medication Adherence In Medicare Advantage Prescription Drug (Mapd) Plan Beneficiaries. PMID- 26533431 TI - Impact of Adherence to Oral Antidiabetics on All-Cause Mortality: A Population Based Study. PMID- 26533432 TI - Basal Insulin Persistence, Associated Factors, and Outcomes After Treatment Initiation Among People With Type 2 Diabetes Mellitus In Japan. PMID- 26533433 TI - Potential Barriers to Insulin Intensification Among Patients With Type 2 Diabetes: The Patient Perspective In Germany. PMID- 26533434 TI - Barriers to Intensification of Insulin Treatment In Patients With Type 2 Diabetes In The Netherlands: Assessing Patient Preferences And Behaviours. PMID- 26533435 TI - Patient Perspective on Convenience and Intensification of Insulin Treatment In Type 2 Diabetes In Italy. PMID- 26533436 TI - Adherence and Persistence In Patients Initiating Treatment With Injectable Therapies for Type 2 Diabetes Mellitus (T2dm) In Spain. PMID- 26533437 TI - Medication Adherance and Satisfaction With Treatment In Patients With Diabetes Mellitus Receiving Oral Combination Therapy: Data of A Real-World Study. PMID- 26533438 TI - Adherence to Initiated Basal Insulin Analog Treatment In Type 1 and 2 Diabetes. PMID- 26533439 TI - Association Between Knowledge and Medication Adherence In Patients With Type 2 Diabetes Mellitus In Pakistan. PMID- 26533440 TI - Experiences of Italian Patients With Diabetes: An Analysis of The Eu Roper Diabetes Study. PMID- 26533441 TI - Systematic Literature Review of Health State Utilities for Adults With Type 1 Diabetes. PMID- 26533442 TI - Assessment of Unmet Healthcare Needs In Diabetic Patients In Bulgaria. PMID- 26533443 TI - Does Treatment Adherence Correlates With Health-Related Quality of Life: Findings From A Cross Sectional Analysis of Type 2 Diabetes Mellitus Patients In Pakistan. PMID- 26533444 TI - Patient Preferences for Attributes of Type 2 Diabetes Mellitus (T2dm) Treatments In Spain. PMID- 26533445 TI - Evaluating Diabetes Patients' Preferences for Profiles of Glp-1 Treatments In The United Kingdom: A Discrete Choice Experiment. PMID- 26533446 TI - A Pilot Study Measuring Knowledge and Attitudes Towards Diabetes Mellitus In Kedah, Malaysia. PMID- 26533447 TI - Patient-Reported Frequency and Burden of Hypoglycaemia for Insulin-Treated Diabetes Patients In 5 Cities of China: A Cross-Section Study. PMID- 26533448 TI - Cross-Sectional Survey Study to Understand Behaviours, Thoughts and Perceptions of Mealtime Insulin Usage In Patients With Type 1 and Type 2 Diabetes. PMID- 26533449 TI - Ideglira Improves Health Utility Compared With Insulin Glargine In Patients With Type 2 Diabetes. PMID- 26533450 TI - Diareg - Diabetes Register Including Patient Reported Outcomes. PMID- 26533451 TI - Benefits And Risks of Vildagliptin/Metformin Versus Sulphonylureas/Metformin Combination Therapy In Type 2 Diabetes Mellitus (T2dm) From Patient's Perspective: Real-World Data. PMID- 26533452 TI - A Novel Tool to Measure The Subjective Burden of Acute Post-Prandial Hyperglycaemia (Pphg). PMID- 26533453 TI - Translation and Validation of The Polish Diabetic Foot Ulcer Scale - Short Form (Dfs-Sf). PMID- 26533454 TI - Rasch Analysis In The Development of A Specific Health-Related Quality of Life Questionnaire for Hypoglycemic Events In Diabetic Patients: The Qolhypo Questionnaire. PMID- 26533455 TI - Health-Related Quality of Life In Patients With Adrenal Insufficiency Receiving Plenadren Compared With Immediate-Release Hydrocortisone. PMID- 26533456 TI - Assessment of Health Related Quality of Life (Hrql) Using Eq-5d In Type 2 Diabetes Mellitus Patients In A University Teaching Hospital. PMID- 26533457 TI - A Cross-Sectional Assessment of Health-Related Quality of Life Among Type 2 Diabetic Patients In Pakistan. PMID- 26533458 TI - Health Related Quality of Life In Patients With Diabetic Foot Ulceration - Observational Study In Poland. PMID- 26533459 TI - Quantifying The Short-Term Impact of Changes In Hba1c, Weight And Insulin Regimen on Health Related Quality-of-Life. PMID- 26533460 TI - Willingness to Pay for One Quality Adjusted Life Years In Patients With Diabetes. PMID- 26533461 TI - Willingness to Pay for Quality-Adjusted Life Years In Patients With Diabete. PMID- 26533463 TI - Mobile Phone Use And Willingness To Pay For Sms For Diabetes In Bangladesh. PMID- 26533462 TI - Using The Transtheoretical Model to Enhance Self-Management Activities In Type 2 Diabetic Patients: A Systematic Review. PMID- 26533464 TI - Diabetes Conversation Maps and Health Outcomes: A Systematic Literature Review. PMID- 26533465 TI - Efficiency of A Personalized Care Model In Diabetes As An Example of Chronic Disease With Information and Communications Technology Support. PMID- 26533466 TI - Intensification of Basal Insulin Treatment Among Patients With Diabetes Mellitus Type 2 In The Netherlands. PMID- 26533467 TI - The Role of Education In The Management of Type 1 Diabetes Mellitus In England. PMID- 26533468 TI - The Impact of Healthcare Policy Based on Drug Plan Perspective Versus The Ministry of Health Perspective: A Case Study of The Odprn Recommendations of Restricting Reimbursement of Testosterone Replacement Therapy For Hypogonadism In Ontario, Canada. PMID- 26533469 TI - Diabetes In Turkey: Analysis of Patient Characteristics. PMID- 26533470 TI - Quantifying The Efficacy-Effectiveness-Gap Using The Example of Metformin. PMID- 26533471 TI - Do Free Medications Improve Observance Among Diabetic Patients? PMID- 26533472 TI - Do Access Restrictions Always Imply Cost Reduction? Case of Turkish Dpp4 Market In Treatment of Type Ii Diabetes. PMID- 26533473 TI - Improving The System of Healthcare Provision for Patients With Hypothyroidism In Ukraine. PMID- 26533474 TI - Analysis of The Consumption And Pharmacoeconomic Evaluation of Using Different Formulations of Alpha-Lipoic Acid In The Pharmaceutical Market of Ukraine. PMID- 26533475 TI - Healthcare Use and Expenditure for Diabetes In Bangladesh: A Matched-Case-Control Study. PMID- 26533476 TI - International Diabetes Management Practice Study (Idmps): Resource Use Associated With Type 2 Diabetes In Africa, Middle East, South Asia, Eurasia and Turkey. PMID- 26533477 TI - Epidemiology and Costs of Peripheral Arteriopathy In Diabetic Patients: A Population-Based Study. PMID- 26533478 TI - Burden of Disease of Diabetes Mellitus Typ-2 In Austria. PMID- 26533479 TI - Examining The Sociological Influences on Physician Prescribing Behavior of Type 2 Diabetic Medications In Us Outpatient Setting. PMID- 26533480 TI - Complementary and Alternative Medicines (Cam) Among Diabetes Patients: A Prospective Study From Pakistan. PMID- 26533481 TI - A Comparison of Market Access Evaluations for Type Ii Diabetes Mellitus In France and Germany: An Analysis Using The Prismaccess Database. PMID- 26533482 TI - Trio H's (Hyperglycemia, Hypertension, Hyperlipidemia): Undiagnosed Modifiable Risk Factors In Malaysia Rural Community. PMID- 26533483 TI - How to Determine The Target Population In Early Benefit Assessments In Germany? The Case of Diabetes Mellitus Type 2. PMID- 26533484 TI - Clinician-Reported Insights of Insulin Degludec Use In Germany and Four Supporting European Countries. PMID- 26533485 TI - An Analysis of Diabetic Medicine Utilization In Turkey. PMID- 26533486 TI - Importance of Hypoglycemia Barrier on The Treatment of Diabetes Mellitus (Dm) - Survey With Turkish Physicians. PMID- 26533487 TI - Blood Glucose Test Result From Employees At Health Clinic of Songino Khairkhan District. PMID- 26533488 TI - Effect of Patient-Education on Health-Related Quality of Life of Diabetic Foot Ulcer Patients In A Tertiarycare Hospital. PMID- 26533489 TI - Telemedicine Compared With Standard Care In Type 2 diabetes mellitus. A randomized Controlled Project In An Outpatient Clinic. PMID- 26533490 TI - Current Clinical Practice Correspondence With Treatment Guidelines In Patients With Type 2 Diabetes Mellitus. PMID- 26533491 TI - Vedolizumab In Ulcerative Colitis; A Budget Impact Model for A Novel Drug In A Recession Environment. PMID- 26533492 TI - Healthcare Pathways And Burden of Disease of Patients With Inflammatory Bowel Diseases (Ibd). PMID- 26533493 TI - Effects of Nutritional Supplement Usage on Mortality In Patient Underwent Abdominal Resection Surgery for Non-Oncological Conditions. PMID- 26533494 TI - Systematic Review of Esomeprazole for The Treatment of Gastroesophageal Reflux Disease. PMID- 26533495 TI - Quality of Care For Patients With Diabetes Mellitus (Dm) In Canada: Findings From A National Population-Based Survey. PMID- 26533496 TI - Cost Analysis of Proton Pump Inhibitors In The Treatment of Gastroesophageal Reflux Disease In Ukraine. PMID- 26533497 TI - Is Nice Too Optimistic About Savings From Faecal Calprotectin Testing? PMID- 26533498 TI - Optimal Treatment of Chron's Disease With Biologicals In A Western Balkan Country: Estimates of Cost/Utility By Markov Model And Budget Impact Analysis. PMID- 26533499 TI - Introduction of New Combination Therapy for Treatment of Experienced Hcv Gt1 Patients: Budget Impact Analysis, The Croatian Perspective. PMID- 26533500 TI - Vedolizumab In Crohn's Disease; A Budget Impact Model for A Novel Drug In A Recession Environment. PMID- 26533501 TI - Costs of Inflamatory Bowel Disease (Crohns Disease and Ulcerative Colitis) In Serbia. PMID- 26533502 TI - Strengths And Weaknesses of Current Clinical And Economic Evidence for The Comparison of Laparoscopic Versus Open Repair of Incisional Hernia. PMID- 26533503 TI - Pharmacoeconomic Analysis of Different Strategies of Replacement Therapy In Russian Patients With Pancreatic Exocrine Insufficiency. PMID- 26533504 TI - Economic Burden and Quality of Life of Moderate-To-Severe Irritable Bowel Syndrome With Constipation (Ibs-C) In Germany: Results From The Ibis-C Study. PMID- 26533505 TI - Real-World Medical Costs of Antiviral Therapy Among Patients With Chronic Hcv Infection and Advanced Hepatic Fibrosis. PMID- 26533506 TI - Economic Burden In Studies Published In 2014: What Type of Gastrointestinal Disorders, Interventions and Outcomes Have Been Most Commonly Assessed? PMID- 26533507 TI - The Cost-Effectiveness of Referring Patients With Irritable Bowel Syndrome To A Gastroenterologist In The Uk. PMID- 26533508 TI - Cost-Effectiveness of Esomeprazole Compared With Other Ppis Currently Reimbursed In Poland In The Treatment of Gerd. PMID- 26533509 TI - Persistence of Remission Among Patients With Inflammatory Bowel Disease After Adalimumab Therapy Is Stopped: Economic Implications. PMID- 26533510 TI - Evaluation of Cost of Managing Hepatitis C In Greece Across All Disease Stages and The Potential Value of Simeprevir Triple Regimen As A Treatment Option In The Early Stages. PMID- 26533511 TI - Modeling The Cost-Effectiveness of Ilaprazole Vs. Omeprazole for The Treatment of Newly Diagnosed Duodenal Ulcer Patients In China. PMID- 26533512 TI - Cost-Effectiveness of Everolimus In Liver Transplantation. PMID- 26533513 TI - Cost Effectiveness of Rifaximin-A 550mg In The Reduction of Recurrence of Overt Hepatic Encephalopathy In United Kingdom. PMID- 26533514 TI - Evaluating The Cost-Effectiveness of Prolonged-Release Tacrolimus Relative to Immediate-Release Tacrolimus In Liver Transplant Patients Based on Data From Routine Clinical Practice. PMID- 26533515 TI - Economic Assessment of Eltrombopag In The Treatment of Thrombocytopenia In Italy. PMID- 26533516 TI - Study on Cost-Effectiveness Analysis For Ulcerative Colitis Treatment: A Systematic Review of Literature From 2004-2014. PMID- 26533517 TI - Evaluation of The Cost Effectiveness of Rifaximin-a 550mg In The Reduction of Recurrence of Overt Hepatic Encephalopathy In Sweden. PMID- 26533518 TI - Should Sofosbuvir-Based All-Oral Treatment Be Considered In Elderly Chronic Hepatitis C Patients? PMID- 26533519 TI - Key Drivers of Cost Effectiveness In Crohn's Disease. PMID- 26533520 TI - Cost-Effectiveness of Simeprevir Vs. Telaprevir for The Triple Therapy of Hepatitis C In Kazakhstan. PMID- 26533521 TI - Earlier Detection And Treatment of Non-Alcoholic Fatty Liver Disease: An Economic Evaluation to Appraise An Innovative Diagnostic Pathway to Detect And Intervene Where There Are Known Risk Factors. PMID- 26533522 TI - Economic Evaluations of Treatments for Inflammatory Bowel Diseases. PMID- 26533523 TI - A Cost-Utility Analysis of Prolonged-Release Tacrolimus Relative to Immediate Release Tacrolimus and Ciclosporin In Liver Transplant Recipients In The Uk. PMID- 26533524 TI - Economic Evaluation of Infliximab for Treatment of Refractory Ulcerative Colitis In Iran: Cost-Effectiveness Analysis. PMID- 26533525 TI - Evaluation of The Cost Effectiveness of Rifaximin-A In The Reduction of Recurrence of Overt Hepatic Encephalopathy In Belgium. PMID- 26533526 TI - Economic Evaluation of Fecal Microbiota Transplantation for The Treatment of Recurrent Clostridium Difficile Infection In Australia. PMID- 26533527 TI - Cost-Effectiveness and Cost-Utility of Home-Based Hypnotherapy Using Compact Disc Versus Individual Hypnotherapy By A Therapist for Pediatric Irritable Bowel Syndrome and Functional Abdominal Pain (Syndrome). PMID- 26533528 TI - Modeling The Cost-Effectiveness of The All Oral, Direct-Acting Antiviral Regimen Daclatasvir Plus Sofosbuvir In Patients Co-Infected With Hepatitis C Virus (Hcv) And Hiv. PMID- 26533529 TI - Evaluation of The Cost Effectiveness and Societal Impact of Rifaximin-A 550mg In The Reduction of Recurrence of Overt Hepatic Encephalopathy In The Netherlands. PMID- 26533531 TI - Compound Attributes For Side Effect In Discrete Choice Experiments: Risk or Severity - What Is More Important to Hepatitis C Patients? PMID- 26533530 TI - Patients' Perception of Adherence to Therapy In Ulcerative Colitis: Results of A Survey to Specialized Centers. PMID- 26533532 TI - Health-Related Quality of Life In Patients With Inflammatory Bowel Disease In Poland (Application of The Eq-5d And Self-Assessment of Health State). PMID- 26533533 TI - A Cost-Utility Analysis of Different Oral Antiviral Medications In Patients With Chronic Hepatitis B In Iran: An Economic Micro-Simulation Decision Model. PMID- 26533534 TI - Systematic Literature Review of Health-Related Quality of Life In Patients Receiving Parenteral Nutrition. PMID- 26533535 TI - Health Related Quality of Life (Hrqol) In Patients Who Have Undergone Colectomy for Ulcerative Colitis: Impacts of Complications Post-Surgery. PMID- 26533536 TI - Translatability Assessment and Linguistic Validation of The Patient-Reported Outcome Instrument for Irritable Bowel Syndrome With Diarrhea (Ibs-D Pro). PMID- 26533537 TI - Development of A Validated Questionnaire Evaluating The Burden of The Haemorrhoidal Disease and Anal Fissure (Hemo-Fiss). PMID- 26533538 TI - Nutritional Aspects And Disinformation In Liver Disease: A Questionnaire-Based Survey In Italian Patients. PMID- 26533539 TI - Clinical Characteristics and Patterns of Care Among Patients With Genotype 1 (G1) Hepatitis C Virus In Europe (Eu). PMID- 26533540 TI - The Demographic Aspects of Turkish Chronic Hepatitis C Patients And The Treatment Initiation From A Physician's & Patient's Point of View. First Interim Analysis of Turkish Data From Mosaic Study (An International Multicenter Prospective Observational Study To Evaluate The Epidemiology, Humanistic And Economic Outcomes Oftreatment for Chronic Hepatitis C Virus). PMID- 26533541 TI - Life Quality of Young Adult Patients With Inflammable Bowel Disease. PMID- 26533542 TI - Diagnosis And Management of Moderate-To-Severe Irritable Bowel Syndrome With Constipation (Ibs-C) In Germany: Results From The Ibis-C Study. PMID- 26533543 TI - Health-Related Quality of Life, Work Productivity, and Daily Activity Among A Sample of Commercially Insured Patients With Irritable Bowel Syndrome With Constipation or Chronic Constipation In The United States. PMID- 26533544 TI - Models of The Impact of Major Liver Diseases on Eq-5d Visual Analogue Scale and Utility-Index: Convergences and Divergences. PMID- 26533545 TI - Health Technology Assessment In Chronic Hepatitis C: Assessment of Decision Landscape And Manufacturer Inputs In Six Agencies. PMID- 26533546 TI - Proton Pump Inhibitors In Italy: It's Time to Make A (Policy) Change. PMID- 26533547 TI - Assessing The Rationality of Costs of Drug Treatment of Nonalcoholic Steatohepatitis In The Hospital of Ukraine. PMID- 26533548 TI - The Burden of Moderate-To-Severe Irritable Bowel Syndrome With Constipation (Ibs C) In France: A Comparison With The European Results From The Ibis-C Observational Study. PMID- 26533549 TI - Medical Resource Utilisation of Australian Patients With Genotype 1 Chronic Hepatitis C: A Retrospective Observational Study. PMID- 26533550 TI - Trends In Health Technology Assessment Decisions Across The Globe: A Focus on Hepatitis C. PMID- 26533551 TI - Biologics In Ulcerative Colitis (Uc): Treatment Guidelines and Health Technology Assessments (Hta). PMID- 26533552 TI - Dose Escalation Among Ulcerative Colitis Patients Treated With Adalimumab In Sweden. PMID- 26533553 TI - Effects of Financial Incentives for Saving Drug Expenditures on Physician Prescription Behaviors. PMID- 26533554 TI - Comparison of Regulatory Labels And Hta Decisions for Chronic Hepatitis-C Therapies. PMID- 26533555 TI - Rheumatoid Arthritis and Ischemic Heart Disease In Patients From Blumenau - Brazil. PMID- 26533556 TI - Increased Risk of Osteoporosis In Depressed Patients: A Real World Data Study Conducted In Italy. PMID- 26533557 TI - Applying Weighted Cumulative Exposure Models to Patterns of Nonspecific Symptom Consultations for Early Diagnosis: A Primary Care Database Study of Knee Pain and Osteoarthritis. PMID- 26533558 TI - Clinical Effectiveness of Bisphosphonates for Prevention of Fragility Fractures: A Systematic Review and Network Meta-Analysis. PMID- 26533559 TI - Compliance With Allopurinol Among Hypertensive Patients With Gout Diagnosis and The Relationship to Onset of End-Stage Renal Disease. PMID- 26533560 TI - The Effect of Positioning The Lower Extremities on Postoperative Bleeding After Total Knee Replacement. PMID- 26533561 TI - Efficacy of Surgical Vs. Non-Surgical Treatment of Carpal Tunnel Syndrome (Cts): A Systematic Review. PMID- 26533562 TI - Using Active Techniques to Handle Chronic Low Back Pain Caused By Sedentary Work. PMID- 26533563 TI - The Effect of Szigetvar Thermal Water on Quality of Life of Patients With Rheumatic Diseases. PMID- 26533564 TI - Clinical Evaluation of Amritadi Guggulu and Mandoora Bhasma In Osteoarthritis Patients. PMID- 26533565 TI - Reduction In C-Reactive Protein With Biologic Drugs In Rheumatoid Arthritis and Spondylitis Patients In German Rheumatologist Practices. PMID- 26533566 TI - Effectiveness of Allopurinol In Achieving And Sustaining Target Serum Urate: An Analysis of A National Integrated U.S. Healthcare System. PMID- 26533567 TI - The Efficacy and Safety of Abatacept, Adalimumab, Etanercept And Tocilizumab are Comparable In Polyarticular Juvenile Idiopathic Arthritis. PMID- 26533568 TI - A Network Metanalysis Comparing The Efficacy of Biologics for The Treatment of Early Rheumatoid Arthritis. PMID- 26533569 TI - Mixed Treatment Comparison to Rank Antiresorptive Agents In Preventing New Non Vertebral Fractures In Postmenopausal Osteoporosis. PMID- 26533570 TI - New Possibility for Testing The Dynamic Stability of The Trunk and Lower Extremities. PMID- 26533571 TI - Characterization of Osteoporosis In Portugal - Treatment Patterns And Reasons for Under-Treatment and Non-Persistence With Pharmacological Treatments. PMID- 26533572 TI - Healthcare Pathways and Burden of Disease of Patients With Psoriasis and Psoriatic Arthritis. PMID- 26533573 TI - Baseline Characteristics of Rheumatoid Arthritis Patients Starting Certolizumab Pegol Therapy And Glucocorticoid Prescription In The Eclair Study In 2012-2013. PMID- 26533574 TI - Identification of Osteoporosis & Chronic Inflammatory Rheumatic Disease In French Claims Data. PMID- 26533575 TI - Risk Factors for Coronary Artery Disease In Patients With Rheumatoid Arthritis. PMID- 26533576 TI - Prevalence, Comorbidities and Burden of Severe Spondyloarthritis In France: Analysis of A National Public Health Insurance Database In 2012 In France. PMID- 26533577 TI - Wintertime Surgery Increases The Risk of Osteonecrosis After Internal Fixation of Femoral Neck Fracture. PMID- 26533578 TI - The Research on The Incidence of Kashin-Beck Disease and The Selenium Level In Children of Xunyi County. PMID- 26533579 TI - Budget Impact Analysis of Certolizumab Pegol for The Treatment of Active Psoriatic Arthritis In Greece. PMID- 26533580 TI - Budget Impact Analysis Of Tofacitinib For Rheumatoid Arthritis From The Perspective Of The Brazilian Private Healthcare System. PMID- 26533581 TI - The Research on The Relationship Between The Ovarian Function Damage With Fluorosis and The Protective Effect of Selenium. PMID- 26533582 TI - Relationship Between Gpx1 Pro198leu Polymorphism and Susceptibility of Kashin Beck Disease. PMID- 26533583 TI - Predictors of 10-Year Mortality After Primary Femoral Neck Fracture In Elderly Patients. PMID- 26533584 TI - Budget Impact Analysis of Implementing Tenders Between The Branded Infliximab And Its Biosimilars In The Public Hospitals of Paris. PMID- 26533585 TI - Budget Impact Analysis of An Etanercept Biosimilar for The Treatment of Rheumatoid Arthritis In Europe. PMID- 26533586 TI - Budget Impact Analysis of An Etanercept Biosimilar for The Treatment of All Licensed Etanercept Indications for Adults In Europe. PMID- 26533587 TI - Budget Impact Analysis of Certolizumab Pegol In The Treatment of Axial Spondyloarthritis In Greece. PMID- 26533588 TI - Budget Impact Analysis of Tocilizumab Versus Adalimumab As A First Line (1l) Monotherapy For The Treatment of Patients With Rheumatoid Arthritis (Ra) In Greece. PMID- 26533589 TI - Economic Evaluation of Chondroitin Sulfate and Non-Steroidal Antiinflammatory Drugs for The Treatment of Osteoarthritis. PMID- 26533590 TI - Economic Burden of Controlled Gout, Uncontrolled Gout, and Gout Exacerbated By Common Comorbidities: Results From The 2012-2013 National Health and Wellness Survey. PMID- 26533591 TI - Economic Evaluation of Tocilizumab Monotherapy Vs Adalimumab Monotherapy In Patients With Rheumatoid Arthritis In Italy. PMID- 26533592 TI - The Cost Burden of Monoclonal Antibody Therapy In An Athens Greece Tertiary Hospital. A Seven Year Cost Comparison Analysis. PMID- 26533593 TI - Extended-Release Oxycodone Hydrochloride (Oxycontin(r)) for Pain Management In Patients Undergoing Arthroplasty: A Cost Analysis From The Brazilian Public and Private Healthcare Systems Perspectives. PMID- 26533594 TI - Cost of Early Retirement Caused By Rheumatic Diseases In Portugal. PMID- 26533595 TI - Patient Characteristics and Disease Burden of Osteoporosis In Post Menopausal Women At Increased Risk of Fracture In Germany. PMID- 26533596 TI - Years of Working Life Lost Caused By Rheumatic Diseases In Portugal. PMID- 26533597 TI - The Impact of Biologic Therapy Versus Conventional Treatment on The Costs of Ankylosing Spondylitis Chronic Complications Under The Perspective of Brazilian Private Health Care System. PMID- 26533598 TI - Effect of Persistence of Biologic Therapy on Long Term Direct Healthcare Costs of Psoriatic Arthritis In Russian Plaque Psoriasis Patients. PMID- 26533599 TI - Health Care Resource Utilization and Direct Medical Cost for Patients With Osteoporotic Fractures In Tianjin, China. PMID- 26533600 TI - The Association Between Disease Activity And Indirect Costs of Absenteeism And Presenteeism Generated By Patients With Ankylosing Spondylitis In Polish Population. PMID- 26533601 TI - Years of Working Life Lost Caused By Osteoarthritis In Portugal. PMID- 26533602 TI - Predicting The Future Economic Burden of Hip Fractures In Norway-The Impact of Epidemiological Uncertainty. PMID- 26533603 TI - Burden of Spinal Diseases: Results From Register Study In Sweden. PMID- 26533604 TI - The Cost of Rehumatoid Diseases In Italy: Analysis From An Italian Administrative Database. PMID- 26533605 TI - Costs of Absenteeism In Ankylosing Spondylitis Based on Real-Life Data From Poland's Social Insurance Institution Database In 2013. PMID- 26533606 TI - A Pilot Study of Direct Costs for Patients With Rheumatoid Arthritis In Bulgaria. PMID- 26533608 TI - Persistence and Econ"Mic Impact of Etanercept and Adalimumab Dose Reduction In Rheumatoid Arthritis, Psoriatic Arthropathy and Ankylosing Spondylitis Patients With At Least 1 Year In Clinical Remission: Experience From 2 Spanish Teaching Hospitals During 5 Years of Follow-Up. PMID- 26533607 TI - How Pricing And Reimbursement Policies Affect The Budget Impact of The Treatment of Systemic Juvenile Idiopathic Arthritis In Turkey. PMID- 26533609 TI - Epidemiologic and Economic Burden Attributable to First Spinal Fusion Surgery: Analysis From An Administrative Database. PMID- 26533610 TI - Expected Lifetime Numbers, Risks, And Burden of Fractures for 50-Year Old Chinese Women. PMID- 26533611 TI - Cost-Utility of Certolizumab Pegol for The Treatment of Axial Spondyloarthritis In Greece. PMID- 26533612 TI - Healthcare Costs In Psoriatic Arthritis Patients Newly Initiated on Apremilast or Biologic Therapies. PMID- 26533613 TI - The Use of Real World Data to Build Economic Models: A Case Study of Osteoporosis. PMID- 26533614 TI - Cost-Effectiveness of Apremilast In Psoriatic Arthritis In Scotland. PMID- 26533615 TI - Cost-Effectiveness of Abatacept Compared to Adalimumab In Italy Based on A Head To-Head Outcomes Study In Rheumatoid Arthritis. PMID- 26533616 TI - A Review of Cost Effectiveness Studies of Rheumatoid Arthritis (Ra) Interventions In The Uk And Us. PMID- 26533617 TI - Cost-Utility Analysis of Apremilast for The Treatment of Psoriatic Arthritis Patients In Spain. PMID- 26533618 TI - Cost-Effectiveness of Certolizumab Pegol for The Treatment of Axial Spondyloarthritis In Turkey. PMID- 26533619 TI - Pharmacoeconomic Analysis of Different Strategies of Monotherapy With Biologic Therapies In Russian Patients With Rheumatoid Arthritis. PMID- 26533620 TI - Budget Impact Analysis of Apremilast In Patients With Psoriatic Arthritis In The Italian Setting. PMID- 26533621 TI - Biological Agents for Patients With Rheumatoid Arthritis Who Had Failed Treatment With Methotrexate In The Spanish Clinical Setting: A Cost-Effectiveness Analysis. PMID- 26533622 TI - Budget Impact Analysis of Apremilast In Patients With Psoriatic Arthritis In Spain. PMID- 26533623 TI - Cost-Utility Analysis of Apremilast for The Treatment of Psoriatic Arthritis In The Italian Setting. PMID- 26533624 TI - Cost-Effectiveness of Zoledronic Acid Versus Alendronic Acid In The Treatment of Osteoporosis In Postmenopausal Egyptian Patients: Decision Analysis. PMID- 26533625 TI - Cost-Effectiveness Analysis of Canacinumab In The Treatment of Patients Suffering From Systemic Juvenile Idiopathic Arthritis In Russian Federation. PMID- 26533626 TI - Assessment of Tofacitinib For Rheumatoid Arthritis From The Perspective of The Brazilian Healthcare System. PMID- 26533627 TI - Cost-Utility Analysis of Certolizumab Pegol for the Treatment of Active Psoriatic Arthritis in GREECE. PMID- 26533628 TI - Economic Evaluation of Tocilizumab Combination in the Treatment of the patients with Dmard-Ir Rheumatoid Arthritis in China. PMID- 26533629 TI - Controlling the Cost Spent on Expensive Biologic Agents: an Example of Net Monetary Savings By Dose Optimisation of Tumor Necrosis Factor Inhibitors in Rheumatoid Arthritis Patients. PMID- 26533630 TI - Telerehabilitation after Total Knee Replacement: Preliminary Cost-Effectiveness Analysis of an Innovative Device. PMID- 26533631 TI - Relationship between Pain, Functional Disability and Health-Related Quality of Life in Patient with Failed Back Surgery Syndrome Undergoing Spinal Cord Stimulation: Results from the Precise Study. PMID- 26533632 TI - The Effectiveness and Cost-Effectiveness of Hylan G-F 20 in Osteoarthritis of the Knee. PMID- 26533633 TI - Telerehabilitation after Total Knee Replacement: Preliminary Cost-Utility Analysis of an Innovative Device. PMID- 26533634 TI - Comparative Effectiveness and Cost-Effectiveness of Generic Alendronate, Risendronate, Denosumab and Zolendronic Acid for Secondary Prevention of Fragility Fractures - Perliminay Results. PMID- 26533635 TI - Cost-Effectiveness of Proton Pump Inhibitor Initiation Aimed to Prevent Upper Gastrointestinal Toxicity in Patients Using Low-Dose Acetylsalicylic Acid. PMID- 26533636 TI - Tocilizumab in Methotrexate-Naive Rheumatoid Arthritis - A Cost-Utility Model for Slovakia. PMID- 26533637 TI - Economic Analysis of Ustekinumab for Psoriatic Arthritis in Russia. PMID- 26533638 TI - Cost-Effectiveness of Biologics Compared to Conventional Disease-Modifying Antirheumatic Drugs for Treatment of Rheumatoid Arthritis in Finland. PMID- 26533639 TI - The Impact of Spa Therapy on Ambulatory Health Care Expenses of osteoarthritic Patients: The Preliminary Results of Ecotherm Study. PMID- 26533640 TI - Productivity Loss Due to Low Back Pain: Results from Swedish Registers. PMID- 26533641 TI - The Impact of Anti-Tnf (Etanercept) Therapy on Work Productivity in Patients with Rheumatoid Arthritis, Psoriatic Arthritis and Psoriasis in the Czech Republic. PMID- 26533642 TI - Dispensing Frequency among Patients with Rheumatoid Arthritis Treated with Rituximab in England. PMID- 26533643 TI - Cost-Utility Analysis of Potential Campylobacter Control Measures in the Food Chain of Indoor Broiler Chicken in the Eu. PMID- 26533644 TI - Systematic Review of Compliance to Bisphosphonates in Patients with Osteoporosis in Rct and Real Practice. PMID- 26533645 TI - Medication-Taking Behaviour in Women with Postmenopausal Osteoporosis (Op) Treated with Denosumab or Monthly Oral Bisphosphonates (Obps). PMID- 26533646 TI - Association of Medication Persistency with Route of Administration and Patient Cost-Sharing: Analysis of Commonly Used Biologics. PMID- 26533647 TI - Primary Non-Adherence to Antiosteoporotic Treatment and Associated Factors: A Prospective Cohort Study in Spain. PMID- 26533648 TI - An Economic Evaluation to Assess the Cost Effectiveness of the New Medicine Service in Improving Adherence in People Initiated on New Treatment for Gout. PMID- 26533649 TI - Review of Patient Reported Outcome Measures used in Clinical and Cost Effectiveness Studies to Measure Utilities in the Treatment of Psoriatic Arthritis and Ankylosing Spondylitis. PMID- 26533650 TI - How Do we Estimate Quality Adjusted Life Years (Qalys) in Rare Diseases? A Case Study in Hypophosphatasia. PMID- 26533651 TI - Understanding Patients' Socio-Economic Burden in Rheumatic Diseases. PMID- 26533652 TI - Assessment of Compliance among Patients with Arthritis. PMID- 26533653 TI - The Burden of Rheumatoid Arthritis in Russia. PMID- 26533654 TI - A Systematic Review of the Humanistic Burden of Gout. PMID- 26533655 TI - Validation of the English Version of the Forgotten Joint Score - 12 in Patients Undergoing Total Knee or Hip Arthroplasty. PMID- 26533656 TI - Factors Associated with Inadequate Pain Relief in Patients with Primary Knee Osteoarthritis in Portugal: An Analysis from the Survey of Osteoarthritis Real World Therapies (Sort). PMID- 26533657 TI - Patients' Preferences for Rheumatoid Arthritis Treatments and their Participation in the Treatment Decision-Making Process. A Systematic Review of the Literature. PMID- 26533658 TI - Patient Beliefs and Preferences in Treatment with Disease Modifying Anti Rheumatic Drugs. PMID- 26533659 TI - Patient Reported Outcome in Health Services Research: A Prospective Study of Orthopedic Surgery in Routine Care in Switzerland. PMID- 26533660 TI - Pro Claims in Fibromyalgia: A Review of the Labels of Products Approved by the Fda and the Ema. PMID- 26533661 TI - UNDERSTANDING THE RELATIONSHIP BETWEEN HEALTH ASSESSMENT QUESTIONNAIRE-DISABILITY INDEX (HAQ-DI), PSORIASIS AREA SEVERITY INDEX (PASI), AND QUALITY OF LIFE (QOL) AND ITS INFLUENCE ON COST-EFFECTIVENESS IN PSORIATIC ARTHRITIS (PSA). PMID- 26533662 TI - The Association between Disease Activity and Quality of Life among Patients with Ankylosing Spondylitis in Polish Population. PMID- 26533663 TI - Avoidable Burden and Unmet Need Associated with Non-Radiographic Axial Spondyloarthritis Treatment: A Cross-Sectional European Study in the Real World Setting. PMID- 26533664 TI - Burden Of Residual Skin and Joint Disease in Patients with Psoriatic Arthritis Treated with Biologics. PMID- 26533665 TI - Patient-Reported Outcomes in Studies Published in 2014: which Tools have been most Commonly Used in Studies of Musculoskeletal Disorders? PMID- 26533666 TI - Persistence to Therapy and the Associated Risk of Fractures with Antiosteoporotic Drugs. PMID- 26533667 TI - Estimating the Monetary Value of Relief of Tennis Elbow: A Contingent Valuation Study of Willingness-To-Pay. PMID- 26533668 TI - Clinical Responses in Joint and Skin Outcomes and Patient-Reported Outcomes are Associated with Increased Productivity in the Workplace and at Home in Psoriatic Arthritis Patients Treated with Certolizumab Pegol. PMID- 26533669 TI - Clinical Responses and Improvements in Patient-Reported Outcomes are Associated with Increased Productivity in the Workplace and at Home in Axial Spondyloarthritis Patients Treated with Certolizumab Pegol. PMID- 26533670 TI - Elderly Osteoporosis Suspects without Diagnosis - Interim Data from a German Geriatric Practice. PMID- 26533671 TI - Access to Biologics for Rheumatoid Arthritis in the Public Sector of a Latam Country. PMID- 26533672 TI - An Assessment of the Impact of Biosimilars on Access to Biologics Based on Primary Research, System Dynamics Modelling, and War Gaming. PMID- 26533673 TI - Adherence and Persistence to Allopurinol among Hypertensive Patients with Gout. PMID- 26533674 TI - Age-Rationing - Reality or Virtue? A Study in Autoimmune Disease. PMID- 26533675 TI - Access to Biological Therapies and Consumption Trends in Bosnia and Herzegovina. PMID- 26533676 TI - Prevention of Fragility Fractures in Osteoporotic Patients: Can the Secondary Therapy Help Contain Costs for Admissions? A Retrospective, Observational Case Control Study Based on Asl Pavia's Administrative Databases. PMID- 26533677 TI - Reliability of Manufacturers' Budget Impact Estimates for Severe Rheumatoid Arthritis Drugs in Poland. PMID- 26533678 TI - A Systematic Review of the Cost Burden of Gout. PMID- 26533679 TI - Number of Osteoporosis Patients with Pathological Fractures by Months in Outpatient Care in the Light of Physiotherapy Care in Hungary. PMID- 26533680 TI - Gender Differences in Medication Taking Behaviour: A Case of Osteoporosis. PMID- 26533681 TI - Number of Osteoporosis Patients with Pathological Fractures By Gender in Outpatient Care in the Light of Physiotherapy Care in Hungary. PMID- 26533682 TI - Characteristics of Patients Starting Biologic Treatments for Rheumatoid Arthritis in The Real World: Systematic Review. PMID- 26533683 TI - Self-Reported Rheumatic Diseases and Early Retirement in Portugal. PMID- 26533684 TI - Grand-4: The German Retrospective Analysis on Persistence in Women with Osteoporosis Treated with Bisphosphonates or Denosumab. PMID- 26533685 TI - Strategies -Based on Evidence- To Rationalize the High Cost Drugs National List in the Dominican Republic. PMID- 26533686 TI - Establishing the Value of Emerging Biosimilars. PMID- 26533687 TI - Join Progress A Efficiency Partnership Program on Knee Joint Replacement. PMID- 26533688 TI - Assessment of Risk Sharing Agreements (Rsas) in Select Global Markets with Specific Focus on Activities Surrounding Immunomodulators. PMID- 26533689 TI - A Web-Based Survey to Investigate the Extent of Awareness and Understanding for Biosimilar among Japanese Physicians and Pharmacists. PMID- 26533690 TI - Association of Adverse Events And Health Service Usage With Tapentadol Prolonged Release Treatment Compared With Morphine Controlled-Release (Cr) And Oxycodone Cr: A Uk Primary Care Observational Study. PMID- 26533691 TI - Clinical and Economic Burden of Pulmonary Excerbations In Patients With Cystic Fibrosis Who are Homozygous For The F508del Mutation. PMID- 26533692 TI - Effectiveness of A Referral Program for Early Arthritis Diagnosis At Primary Care Centers in Portugal - Preliminary Results from the Siara Study. PMID- 26533693 TI - Real-World Evidence of Iron Chelation Therapy In Transfusion-Dependent Mds Patients: A Portuguese Hospital Registry. PMID- 26533694 TI - Guillain-Barre Syndrome: Clinical Presentation, Treatment Pattern And Outcome. PMID- 26533695 TI - How are Pain Treatment Response Rates In Primary Care Influenced By Co Prescription of Cyp2d6 Inhibitors? PMID- 26533696 TI - A Systematic Literature Review And Network Meta-Analysis of Capsaicin 8% Patch Versus Oral Neuropathic Pain Medications for The Treatment of Painful Diabetic Peripheral Neuropathy. PMID- 26533697 TI - Efficacy of The Mica Antibody for Transplant Patients. PMID- 26533698 TI - Modeling The Impact of Potential Differences In Real-Wolrd Adherence With Extended-Half-Life Vs. Conventional Factor Viii And Ix on Bleeding. PMID- 26533699 TI - Comparison of Network Meta-Analysis and Traditional Meta-Analysis for Prevention of Relapses In Multiple Sclerosis. PMID- 26533700 TI - Assessing The Treatment of Peripheral Neuropathic Pain (Pnep) And Postherpetic Neuralgia (Phn) In China Using A Simulation Model. PMID- 26533701 TI - Systematic Review of Economic Evaluations In Multidisciplinary Pain Management Services for Managing People With Fibromyalgia or Chronic Widespread Pain. PMID- 26533702 TI - Factor Consumption for Prophylaxis and Treatment of Bleeding: Recombinant Factor Ix Fc Fusion Protein Compared With Conventional Recombinant Factor Ix. PMID- 26533703 TI - Comparisons of Factor Consumption for Routine Prophylaxis And Bleeding During Episodic Therapy With Recombinant Factor Viii Fc Fusion Protein and Conventional Recombinant Factor Viii. PMID- 26533704 TI - Cost Effectiveness of Multidisciplinary Pain Management Services for Chronic Back Pain: Systematic Review. PMID- 26533705 TI - Burden of Anemia Among Indian Women: A Systematic Review And Meta-Analysis of Literature. PMID- 26533706 TI - Prevalence of Antidepressants Prescribed to Tramadol Users In The Uk Primary Care Setting - A Prescription Sequence Symmetry Analysis. PMID- 26533707 TI - Prevalence and Cost of Myasthenia Gravis In The Medicare Beneficiary Sample. PMID- 26533708 TI - Sickness Funds Data Analyses on Prevalence & Incidence And Treatment of Waldenstrom's Macroglobulinemia (Wm) In Germany. PMID- 26533709 TI - Identification of Subgroups With Low Rates of Weight Loss In Israel. PMID- 26533710 TI - Assessment of Iron Deficiency And Anemia In Pregnant Women In France: An Observational Study. PMID- 26533711 TI - A Systematic Literature Review of Risk Prediction Models for Mortality, Complications and Diabetes Outcomes After Bariatric Surgery. PMID- 26533712 TI - Prevalence of Transthyretin Familial Amyloid Polyneuropathy In Portugal. PMID- 26533713 TI - Calculating The Prevalence of Urea Cycle Disorders In The Eu5 Using An Incidence Survival Model. PMID- 26533714 TI - Relationship Between Patient Characteristics and Outcomes In Patients With Multiple Myeloma. PMID- 26533715 TI - Budget Impact Analysis of Canacinumab In The Treatment of Patients With Muckle Wells Syndrome In The Russian Federation. PMID- 26533716 TI - Biologic Treatments for Moderate to Severe Naive Psoriatic Patients: A Budget Impact Analysis In Italy. PMID- 26533717 TI - Budget Impact Analysis of Dasatynib In Treatment of Adult Patients With Philadelphia Chromosome Positive (Ph+) Acute Lymbphoblastic Leukemia (All) With Resistance or Intolerance to Prior Therapy In Poland. PMID- 26533718 TI - Modelling The Likely Impact of The Obesity Epidemic on Mortality And Cause of Death In Older Adults. PMID- 26533719 TI - A Five Years Budget Impact Analysis of The Introduction of Adalimumab For Crohn's Disease Patients From The Perspective of The Brazilian Private Health Care System. PMID- 26533720 TI - Budget Impact Analysis of Blood Clotting Factor Concentrates In The Treatment of Von Willebrand Disease. PMID- 26533721 TI - Health Care Cost and Utilization Associated With Alpha-1 Antitrypsin Deficiency Among A Cohort of Medicare Beneficiaries With Copd. PMID- 26533722 TI - Pharmacoeconomic Analysis of Using Golimumab In The Care of Patients With Ulcerative Colitis. PMID- 26533723 TI - Economic Impact of Employment Status on The Social Cost of Morbid Obese Patients Submitted to Bariatric Surgery. PMID- 26533724 TI - Economic Evaluation of The Aranesp Application for Anemia Correction In Pathients With Chronical Renal Failure on Hemodialysis or Peritoneal Dialysis In Russia. PMID- 26533725 TI - Evicel and Bloodless Protocol In Orthopaedics Surgery Clinical Evidence And Cost- Analysis : Italian Experience Humanitas Research Hospital. PMID- 26533726 TI - Economic Evaluation and Added Value for Stakeholders of Switching From Rituximab Intravenous Injection to Rituximab Subcutaneous Injection In France. PMID- 26533727 TI - Idiopathic Pulmonary Fibrosis: Hospital Disease Management and Associated Costs. PMID- 26533728 TI - Direct Medical Costs Associated With Ankylosing Spondylitis In Chinese Patients: Estimations From China Public Health Insurance Claim Data. PMID- 26533729 TI - Costs of Absenteeism In Psoriatic and Enteropathic Arthropathies Based on Real Life Data From Poland's Social Insurance Institution Database In 2013. PMID- 26533730 TI - Pharmacoeconomic Considerations About Breakthrough Cancer Pain. PMID- 26533731 TI - Direct Cost of Myelodysplastic Syndromes Associated With A Deletion 5q Cytogenetic Abnormality (Del5q Mds) In Patients Who Are Red Blood Cell Transfusion Dependent In Mexico. PMID- 26533732 TI - The Indirect Costs of Inflammatory Bowel Disease (Crohn's Disease And Ulcerative Colitis) Associated With Absenteeism In Poland In 2013. PMID- 26533733 TI - Societal and Non-Healthcare Costs Associated With Atypical Haemolytic Uraemic Syndrome In The Uk: Results of A Patient Survey. PMID- 26533734 TI - The Budget Impact of Orphan Drugs In The Us and Canada: A 2007-2013 Midas Sales Data Analysis. PMID- 26533735 TI - Comparing The Cost-Effectiveness of Apcc Vs Rfviia In on-Demand Treatment of Bleeds In Hemophilia A Patients With Inhibitors: A Brazilian Public Health System Perspective. PMID- 26533736 TI - Analysis of Direct Costs Associated With Cystic Fibrosis In Single Center In Slovakia: 5 Years Review. PMID- 26533737 TI - Cost of Familial Mediterranean Fever (Fmf) Disease In Turkey. PMID- 26533738 TI - Analysis of The Cost of Invasive Fungal Infections In Patients With Hemopoetic Stem Cell Transplantation. PMID- 26533739 TI - Cost Analysis of Voriconazole Versus Liposomal Amphotericin B And Caspofungin for Primary Therapy of Invasive Aspergillosis Among High-Risk Hematologic Cancer Patients In Saudi Arabia. PMID- 26533740 TI - Assessing The Burden of Systemic Lupus Erythematosus In Belgium Using A Longitudinal Hospital Database. PMID- 26533741 TI - Biopharma Intervention Valuation: An Evidence-Based Appraisal Framework for Oncology Drugs. PMID- 26533742 TI - Cost-Effectiveness of Ponatinib Followed By Stem Cell Transplant Versus Best Supportive Care For Uk Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia After Failure of Dasatinib. PMID- 26533743 TI - Ambulatory Medicines Cost With Transthyretin Familial Amyloid Polyneuropathy In Portugal. PMID- 26533744 TI - Is Regenerative Medicine Cost-Effective? Evidences From The First Approved Stem Cell Based Product. PMID- 26533745 TI - The Cost-Effectiveness of Biologics for The Treatment of Inflammatory Bowel Diseases: A Systematic Review. PMID- 26533746 TI - Cost-Effectiveness Analysis of Ponatinib In The Treatment of Chronic-Phase Chronic Myeloid Leukemia (Cp-Cml) In Sweden. PMID- 26533747 TI - Re-Evaluating The Cost-Effectiveness of Screening For Congenital Adrenal Hyperplasia (Cah): The Sensitivity to Choice of Distributions In Probabilistic Sensitivity Analyses (Psas). PMID- 26533748 TI - Cost-Effectiveness Analysis of Romiplostim for The Treatment of Adult Chronic Immune Thrombocytopenic Purpura (Itp) In Brazil. PMID- 26533749 TI - Cost-Effectiveness of Manual Therapy Versus Physical Therapy In Patients With Sub Acute and Chronic Neck Pain: A Randomized Controlled Trial. PMID- 26533750 TI - Cost-Effectiveness of Ruxolitinib for The Treatment of Myelofibrosis In Finland. Economic Evaluation Based on Finnish Auria Biobank Data on Health Care Resource Utilization. PMID- 26533751 TI - Pharmacoeconomic Analysis of Treatment Patients With Craniocerebral Injury In Ukraine. PMID- 26533752 TI - An In Silico Health Economic Model Applied to Cryopyrin Associated Periodic Syndromes (Caps): Cost Effectiveness of Prevention Effects of Ultra-Orphan Drugs for Rare Diseases. PMID- 26533753 TI - Economic Evaluation of Lidocaine/Tetracaine Patch Versus Lidocaine/Prilocaine Cream for Topical Anaesthesia Before Vascular Access In Egypt. PMID- 26533754 TI - Cost-Utility of Bariatric Surgery In Belgium, Denmark, and Italy. PMID- 26533755 TI - Cost-Utility Analysis of Adalimumab for The Treatment of Moderate-To-Severe Ulcerative Colitis In Patients In Spain. PMID- 26533756 TI - Cost-Effectiveness Analysis of Pregabalin In The Treatment of Central Neuropathic Pain. PMID- 26533757 TI - Cost-Effectiveness Modelling for Neuropathic Pain Treatments: An Exploration to Identify Comparative Importance of Model Parameters. PMID- 26533758 TI - Cost-Minimization Analysis and Total Cost Analysis for A Weight Range In Crohn's Disease Treatment With Anti-Tnf Biologics Under Brazilian Private Health Care System Perspective. PMID- 26533759 TI - Cost-Effectiveness of Ustekinumab In The Treatment of Psoriasis In Finland. PMID- 26533760 TI - Cost-Effectiveness and Cost-Utility Analyses Comparing Strategies for Initial Treatment of Rheumatoid Arthritis Using Published Outcomes: Economic Lessons From The Tear Trial. PMID- 26533761 TI - Cost-Effectiveness Analysis of Tocilizumab Subcutaneous As First Line Biologic Monotherapy for Rheumatoid Arthritis Management In Greece. PMID- 26533762 TI - Cost-Effectiveness of Bariatric Surgery for The Treatment of Obesity In Australia. PMID- 26533763 TI - Cost-Utility Analysis of Antihemophilic Factor Rfviii-Fs for Secondary Prophylaxis Vs on-Demand Therapy In Severe Haemophilia A In Italy. PMID- 26533764 TI - Economic Evaluation of Dasatynib In Treatment of Adult Patients With Philadelphia Chromosome Positive (Ph+) Acute Lymbphoblastic Leukemia (All) With Resistance or Intolerance to Prior Therapy In Poland. PMID- 26533765 TI - Cost-Utility of Bariatric Surgery In France And Germany. PMID- 26533766 TI - Retrospective Cohort Study Using Data From The Uk Clinical Practice Research Datalink and Hospital Episode Statistics to Assess Unplanned Hospitalisation In Patients With Multiple Myeloma. PMID- 26533767 TI - Inpatient Burden Among Patients With Cystic Fibrosis Who Are Homozygous for The F508del Mutation. PMID- 26533768 TI - Transthyretin Familial Amyloid Polyneuropathy Impact on Health-Related Quality of Life. PMID- 26533769 TI - Health State Utilities for Gaucher Disease Type 1. PMID- 26533770 TI - Association Between Feeding Types and Iron Status In India. PMID- 26533771 TI - The Impact of Orthopaedic Surgery on The Quality of Life of Haemophilia Patients With or Without Inhibitors: A Systematic Review of The Literature. PMID- 26533772 TI - Ten Years of The International Pompe Survey: Patient Reported Outcomes As A Reliable Tool for Studying Treated and Untreated Children and Adults With Non Classic Pompe Disease. PMID- 26533773 TI - "First And Foremost Battle The Virus" - Patient Preferences In Antiviral Therapy For Hepatitis C. PMID- 26533774 TI - Social Utility Values for Pemphigus Vulgaris and Foliaceus: A Composite Time Trade-Off Study. PMID- 26533775 TI - Clustering Health Status Among Adults With Hemophilia Using Sf-12 Health Survey. PMID- 26533776 TI - Health States Worse Than Dead In An Elderly Population - Prevalence and The Significance of Chronic Pain. PMID- 26533777 TI - Impact of Weight Loss on Patient-Reported Outcomes In The Scale Obesity and Prediabetes Trial of Liraglutide 3.0 Mg As Adjunct to A Diet and Exercise (D&E) Programme. PMID- 26533778 TI - Assocations Between Pain Severity and Quality of Life Domains Among Those Diagnosed With Various Pain Types In Europe. PMID- 26533779 TI - Validation of A New Hemophilia-Specific Burden Scale for Caregivers of Children With Hemophilia In The Us - The Hemophilia Associated Caregiver Burden Scale (Hemocabtm). PMID- 26533780 TI - Opioids Switch In Chronic Pain: Impact Assessment Using Electronic Health Records. PMID- 26533781 TI - Assessing The Impact of Growth Hormone Deficiency (Ghd) In Children: Concept Elicitation Results Supporting The Development of The Treatment-Related Impact Measure for Childhood Ghd (Trim-Cghd). PMID- 26533782 TI - Cognitive Testing of A Modified Version of The Faces Pain Scale-Revised In Children With Sickle-Cell Disease. PMID- 26533783 TI - Reporting Instruments of Patient Reported Outcomes In Orphan Disease. PMID- 26533784 TI - Impact of Pain Severity on Patient-Reported Outcomes of Individuals With Chronic Lower Back Pain In Japan. PMID- 26533785 TI - Health-Related Quality of Life In Patients With Transthyretin Familial Amyloid Polyneuropathy. PMID- 26533786 TI - Evaluation of Patients' Quality of Life of Preoperation and Early Postoperation After Total Hip and Knee Arthroplasty. PMID- 26533787 TI - The Relationship Between Disease Severity and Quality of Life In Patients With Moderate to Severe Psoriasis. PMID- 26533788 TI - Medical Care And Costs of Patients With Systemic Lupus Erythematosus In Taiwan. PMID- 26533789 TI - Towards Creating A National System of Care for Patients With Orphan Diseases. PMID- 26533790 TI - Assessing The Treatment Burden for Growth Hormone Deficiency (Ghd) In Children: Concept Elicitation Results Supporting The Development of The Treatment Burden Measure for Childhood Ghd (Tb-Cghd). PMID- 26533791 TI - Health-Related Quality of Life (Hrqol) In Splenectomized Immune Thrombocytopenia (Itp) Patients - A Targeted Literature Review. PMID- 26533792 TI - Impact of Blood Transfusions on Hospital Length of Stay and Mortality: A Single Center Experience. PMID- 26533793 TI - The Rheumatologist's Perspective In Diagnostic Course and Management of Familial Mediterranean Fever. PMID- 26533795 TI - The Rise of Orphan Drugs In Europe Vs The United States: Comparing Orphan Drug Designations Between The Ema And Fda. PMID- 26533794 TI - Convergent Validity of New Disease Assessment Instruments (Dai) In Systemic Lupus Erythematosus (Sle) In Relation to Sledai-2k. PMID- 26533796 TI - Analysis of Government Procurements of Medicines for Rare Diseases In Russia. PMID- 26533797 TI - Comparative Analysis of The Reimbursement Landscape of Orphan Drugs on An International Level. PMID- 26533798 TI - Similarities and Differences In Orphan Drug Reimbursement In 16 European Countries. PMID- 26533799 TI - Reimbursed Price of Orphan Drugs: A Value Based Framework. PMID- 26533800 TI - Horizontal Vs. Vertical Equity: Market Access of Orphan Drugs In France and Uk. PMID- 26533801 TI - Orphan Drug Regulation In The Usa, European Union, Japan and South Korea: A Comparative Analysis. PMID- 26533802 TI - Economic Impact of The End of The Market Exclusivity for Orphan Drugs. PMID- 26533803 TI - Value Assessment and Pricing Frameworks for Rare Disease Treatments: New Approaches From The Literature. PMID- 26533804 TI - Recommendations and Reimbursement Status of Orphan Drugs In Ue Countries. PMID- 26533805 TI - Experts Consensus on The Future of Rare Diseases Care and Orphan Drugs Access In Spain: A Delphi Study. PMID- 26533806 TI - Anaesthesia In Developing Countries. PMID- 26533807 TI - Hospitalizations In Hyperchylomicronemia Patients In Quebec, Canada; Results From A Real-World Observational Study. PMID- 26533808 TI - Reversal of Neuromuscular Blockade: A Discrete Event Simulation Model of Clinical and Operating Room Efficiency Outcomes of Sugammadex Versus Neostigmine In Canada. PMID- 26533809 TI - Healthcare Resource Utilization Costs Related to Anaemia Management In Chronic Kidney Disease Non-Dialysed Patients: A Retrospective Clinical and Administrative Database Analysis. PMID- 26533810 TI - The Feasibility of Applying Definitions of Persistent Opioid Utilisation to Quantify The Persistency of Tramadol Users. PMID- 26533811 TI - Market Access Trends In Rare Disease Approvals In Europe From 2005 To 2014. PMID- 26533812 TI - Diagnosis of Liver Diseases Among Individual With Hepatic Dysfunction Detected By Annual Health Checkup Based on Claims Data In Japan. PMID- 26533813 TI - Patient Understanding and Attitudes About Biosimilars: An International Cross Sectional Survey. PMID- 26533814 TI - Healthcare Resource Consumption and Cost of Care In Patients With Autosomal Dominant Polycystic Disease (Adpkd) In Italy. PMID- 26533815 TI - The Italian 648/96 List: Approvals, Rejections and Methods In Aifa's Evaluation Process Between January 2013 and May 2015. PMID- 26533816 TI - Challenges for Assessing The Economic Value of Orphan Drugs - A Literature Review of Current And Alternative Approaches. PMID- 26533817 TI - Orphan and Ultra-Orphan Technologies: European and Australian Payer Perceptions. PMID- 26533818 TI - Does A New Pharmacoeconomic Model Is Demanded for Obesity's Pharmacotherapy Assessment? PMID- 26533820 TI - The Contribution of Informal Caregiver Burden to Hta In Hematological Cancers In France, Germany, and The Us. PMID- 26533819 TI - Comprehensive Review of Orphan Drugs Post-Amnog In Germany. PMID- 26533821 TI - Epidemiology And Healthcare Services Utilization for Rare Diseases In Italy. PMID- 26533822 TI - Assessment of Real-World Treatment Patterns and Outcomes In Relapsed or Refractory Multiple Myeloma: Evidence From A Brief Multi-Country Survey of European Physicians. PMID- 26533823 TI - Cart Analysis As A Tool To Determine Optimal Treatment Intensification Time In Diabetes. PMID- 26533824 TI - Characteristics Associated With Annual Bleeding Frequency Among Hemophilia Patients In The United States. PMID- 26533825 TI - Selection Of Statistical Approach In Understanding The Role Of Contrast Media In Inpatient Interventional Cardiovascular Procedures. PMID- 26533826 TI - How To Conduct Economic Evaluations Of New Treatments For Advanced Cancer When Overall Survival Data Are Not Available? Results From A Systematic Literature Review. PMID- 26533827 TI - A Study On Cytogenetic And Molecular Analysis Of Presenilin 1 (Ps1) Gene In Alzheimer's Disease. PMID- 26533828 TI - How Good Are Physicians And Chart Reviews At Capturing Health Resources And Drug Utilisation By Patients? Results Of The Pgrx-3 Prospective Real World Dataset Validation Study. PMID- 26533829 TI - Comparison Of Treatment-Related Adverse Events Recorded In Administrative Claims Data With Those Recorded In Electronic Medical Records For Multiple Myeloma Patients. PMID- 26533830 TI - The Acceptance Of Morbidity Endpoints In The Amnog Process In Germany: Are There Greater Hurdles For Substances Within Oncology? PMID- 26533831 TI - Non-Comparative Trials To Supplement Network Meta-Analyses Using Arm-Specific Meta-Regression: An Application To Combination Therapies In Hiv. PMID- 26533832 TI - The Value Of Progression-Free Survival (Pfs) As An Endpoint In Oncology Trials. PMID- 26533833 TI - Network Meta-Analysis Of Multiple Outcomes Incorporating Dose-Related Constraints: Application To Overactive Bladder Syndrome. PMID- 26533834 TI - Critical Appraisal Of Real World Evidence - A Review Of Recommended And Commonly Used Tools. PMID- 26533835 TI - Does Attrition In Subject-Based Studies Of Drug Safety Lead To Bias Related To Morbidity? PMID- 26533836 TI - Estimation of The Progression of Colon Cancer By Japanese Large-Scale Insurance Benefits Data Analysis. PMID- 26533837 TI - Beyond The Middle: Evaluating Surrogacy Of Clinical Trial Endpoints Across Trial Durations. PMID- 26533838 TI - Machine Learning For Identifying Potentially Undiagnosed Post-Stroke Spasticity Patients In United Kingdom. PMID- 26533839 TI - Stakeholder Views On The Acceptability Of Real-World Evidence For Informing Trial Design And Assessment Of Relative Effectiveness Of New Medicines. PMID- 26533840 TI - Knowledge And Awareness Of Breast Cancer Among Young Women Living In South India. PMID- 26533841 TI - Analysis Of Evidence Data About Adding Succinic Acid To The Various Medicines. PMID- 26533842 TI - Objective Data In Parkinson's Disease Therapy Management - A Retrospective Analysis Of The Parkinson's Kinetigraph (Pkg) Database. PMID- 26533843 TI - Patient Versus General Population Health State Valuations: A Case Study Of Low Back Pain. PMID- 26533844 TI - Outcomes Used In Clinical Studies In Adult Hematoncology: Ten Years Of Publications In Pubmed. PMID- 26533845 TI - The Use Of Real World Evidence (Rwe) To Investigate The Overall Treatment Effects Of Different Lines Of Therapy In Rheumatoid Arthritis. PMID- 26533846 TI - Time Ratios Or Hazard Ratios: Accelerating Toward A New Approach? PMID- 26533847 TI - Pangaea 2.0: State Of The Art Multiple Sclerosis Patient Management In Daily Clinical Practice. A New 3-Year Observational Study Of Patients Receiving Fingolimod. PMID- 26533848 TI - Stochastic Multicriteria Acceptability Analysis In A Bayesian Framework. PMID- 26533849 TI - Vial Sizes Of Pharmaceuticals For Infusion - The Potential For Cost Reductions And Reduced Wastage By Optimising Fill Volumes. PMID- 26533850 TI - A Novel Itc Approach: Matching Patient-Level Data To Study-Level Summary Means And Variances. PMID- 26533851 TI - A Comparison Of Fat Grafting Methods On Operating Room Efficiency And Cost. PMID- 26533852 TI - Method Comparison Of Censoring Cost Analyses. PMID- 26533853 TI - Multivariate Network Meta-Analysis: An Example In Type 2 Diabetes For The Analysis Of Glycaemic Control. PMID- 26533854 TI - Comparison Of Different Costing Methods. PMID- 26533855 TI - Including Human Resource Constraints In Health Economic Evaluations. PMID- 26533856 TI - Quantifying The Cost And Quality Of Life Implications Of Adverse Events Associated With Long-Term Oral Corticosteroid Use. PMID- 26533857 TI - Comparing Cost-Effectiveness Of Emerging Drugs In Advanced Cancer Without Hazard Ratios For Progression. PMID- 26533858 TI - Consistency In Search Strategies For Systematic Literature Reviews In Nice Submissions. PMID- 26533859 TI - Identification Of Items For A Standardised Resource-Use Measure: Review Of Current Instruments. PMID- 26533860 TI - Multiple To Single Transition Probability: Hcv-Based Example. PMID- 26533861 TI - Construction Of Simulation Techniques For Development Of Optimal Cervical Cancer Screening Strategies: Experience Of Ukraine. PMID- 26533862 TI - Structure Of Health-Related Direct Costs In Ukraine - The First Step Of Analysis. PMID- 26533863 TI - The Cost Of Treatment Of The New Antiviral Therapies Against The Hepatitis C Virus. PMID- 26533864 TI - Resource Use Measurement In Trials Conducted In Care Homes: A Study Of Level-Of Agreement Between Data Collected From Gp Records And Care Home Records. PMID- 26533865 TI - Are Qalys An Appropriate Measure To Use When Evaluating Public Health Interventions In The Uk? PMID- 26533866 TI - Budget Impact Analysis In The Uk Setting - Know Your Audience. PMID- 26533867 TI - Different Models For Different Payers - Are We Moving Towards Or Away From Universal Economic Models? PMID- 26533868 TI - Bayesian Econometric Modelling Of Observational Data For Cost-Effectiveness Analysis. PMID- 26533869 TI - Societal Burden And Impact On Health Related Quality Of Life (Hrqol) Of Non-Small Cell Lung Cancer (Nsclc) In Europe. PMID- 26533870 TI - The Economic Impact Of Shape Formula For The Children Of Overweight And Obese Mothers. PMID- 26533871 TI - Estimating Lifetime Medical Costs From Censored Claims Data. PMID- 26533872 TI - Comparison Of Comorbidity Measures To Predict Economic Outcomes In A Large Uk Primary Care Database. PMID- 26533873 TI - Effect Of Fingolimod On Disease Progressions, Relapse Rate And Brain Atrophy In Multiple Sclerosis Patients: Review Of Literature And Pharmacoeconomic Considerations. PMID- 26533874 TI - Generating Costing Algorithms For Oncology Drugs Using Administrative Databases. PMID- 26533875 TI - Oncology Literature Bank For Cancers And Therapies For Heor: Concept And Utilization Of Oncolitbank. PMID- 26533876 TI - Pharmaceutical Products And Vaccines Discussed In Social Media: Which Ones Are Patients Talking About? PMID- 26533877 TI - "Big Data" In Alzheimer's Disease Research: An Environmental Scan. PMID- 26533878 TI - Hunting For Randomised Controlled Trials (Rcts): A Comparison Of Search Filters Designed To Identify Rcts. PMID- 26533879 TI - Indirect Treatment Comparison (Itc) To Demonstrate The Utility Of Oncolitbank: An Oncology Literature Registry. PMID- 26533880 TI - Methotdological Difficulties Of Compliance Analyses Based On Real-World Data. PMID- 26533881 TI - Utility And Metrics Of Natural Language Processing On Identifying Patients For Pharmacoepidemiologic Studies. PMID- 26533882 TI - Review Of Comorbidity Measures To Predict Economic Outcomes In Real-Life Database Studies. PMID- 26533883 TI - The Nationwide Osmed Health-Db Database. A Tool To Support Healthcare Decision Making And Real-World Evidence Generation. PMID- 26533884 TI - The Pediatric Asthma Patient Registry In Implementation Of Long Term Follow Up. PMID- 26533885 TI - Development Of An International Observational Study Programme To Describe The Management And Outcomes Of Mild Stroke And Transient Ischaemic Attack In Routine Clinical Practice. PMID- 26533886 TI - Health Technology Assessment Needs Information Technology: The Experience From The First Italian Study On The Da Vinci Surgical Robot. PMID- 26533887 TI - Management Of Soft Tissue Sarcoma (Sts) In France - A Retrospective Analysis Of The French Clinical Biological Sarcoma Database (Gsf-Geto). PMID- 26533888 TI - The Remote Monitoring Technologies In The Patient Risk Management. PMID- 26533889 TI - Modeling The Burden of Abdominal Aortic Aneurysm (Aaa) In Europe In 2013. PMID- 26533890 TI - Patient Heterogeneity In Cost-Effectiveness Models for Chronic Obstructive Pulmonary Disease (Copd): are Current Models Suitable to Evaluate Personalized Medicine. PMID- 26533891 TI - Generalized Implementation of Em Algorithm for Estimation of Transition Probability Matrix. PMID- 26533892 TI - Burden Of Epilepsy In Colombia. PMID- 26533893 TI - Using Machine Learning To Populate A Markov Model By Mining Big Data Directly From Hospital Ehrs - An Application To Dynamically Predict Hospital-Acquired Pressure Ulcers. PMID- 26533894 TI - Contrasting Model Predicted Life Expectancy In Patients With Type 2 Diabetes Across Different Mortality Risk Prediction Models Versus Data From The Canadian Chronic Disease Surveillance System. PMID- 26533895 TI - Contrasting Predictions of Cardiovascular Incidence Derived From Alternative Risk Prediction Models In Type 1 Diabetes. PMID- 26533896 TI - Validation of A Markov Model for Economic Evaluation of Screening and Preventive Interventions In Alzheimer's Disease In Denmark. PMID- 26533897 TI - Cost-Effectiveness of Escalating to Natalizumab or Switching Among Immunomodulators In Relapsing-Remitting Multiple Sclerosis In Italy. PMID- 26533898 TI - The Efficiency Path: An Estimation of Cost-Effectiveness Thresholds for 185 Countries Based on Per Capita Health Expenditures and Life Expectancy. PMID- 26533899 TI - Review of Economic Models for The Evaluation of Biologic Dmards In Rheumatoid Arthritis. PMID- 26533900 TI - Best Practices for Network Meta-Analysis Methodology: Comparative Effectiveness of Interferon-Beta Therapies In Relapsing-Remitting Multiple Sclerosis. PMID- 26533901 TI - How to Handle Levels of Evidence In Health Economic Modelling. PMID- 26533902 TI - Investigating The Value of Patient Level Data to Inform Estimates of Adpkd Progression Generated Within The Adpkd Outcomes Model. PMID- 26533903 TI - Investigating The Impact of Structural Changes In A Nice Single Technology Appraisal Cost-Effectiveness Model. PMID- 26533904 TI - Adapting Literature-Based Remission Rates for Chronic Spontaneous/Idiopathic Urticaria to The Needs of A Health Economic Model: A Kaplan-Meier Approach. PMID- 26533905 TI - The Importance of Accounting for Baseline Hypoglycaemia Frequency When Modelling Hypoglycaemia Disutility In Type 1 Diabetes Mellitus. PMID- 26533906 TI - Challenges to The Economic Modelling of Macular Oedema Due to Retinal Vein Occlusion And Diabetes. PMID- 26533907 TI - Impact of Uncertainty In Predicted Risks on The Cost-Effectiveness of Risk Stratified Preventive Treatment Strategies. PMID- 26533908 TI - Cost-Effectiveness Analysis of Delayed-Release Dimethyl-Fumarate In The Treatment of Relapsing-Remitting Multiple Sclerosis In Italy. PMID- 26533909 TI - Validating Approaches to Modelling End-Stage Renal Disease Using The Ims Core Diabetes Model. PMID- 26533910 TI - Development of A Cost-Effectiveness Analysis Framework for Modeling Treatment of Alzheimer's Disease And Mild Cognitive Impairment. PMID- 26533911 TI - Validation of Fracture Risk Model In Japanese Women Compared With Frax. PMID- 26533912 TI - Development and Validation of A Conceptual Model of Multiple Myeloma. PMID- 26533913 TI - The Impact of Baseline Hba1c and Hba1c Trajectories on Time to Therapy Escalation In Type 2 Diabetes Mellitus. PMID- 26533914 TI - Expert Perspective on The Treatment of Functional Dyspepsia And Motility Disorders: A Multi-Criteria Decision Analysis Using The Analytic Hierarchy Process (Ahp). PMID- 26533915 TI - Selecting Evidence-Based Preventive Treatment Thresholds By Optimizing Preferred Outcomes. PMID- 26533916 TI - A Comparison of Discrete Event Simulation (Des) Versus Markov Models With A Practical Application to Human-Immunodeficiency Virus (Hiv). PMID- 26533917 TI - Modeling Treatment Sequences In Health Technology Assessments. PMID- 26533918 TI - Budget Impact Analysis of Cerebrolysin In The Treatment of Acute Ischemic Stroke of Moderate and Severe Degrees of Severity In The Russian Federation. PMID- 26533919 TI - A Comparison of Three Survival Models to Estimate The Cost-Effectiveness of Cancer Immunotherapy In The Treatment of Advanced Melanoma. PMID- 26533920 TI - Economic and Clinical Impact of Secondhand Smoking In Korea. PMID- 26533921 TI - Implementation of Population Dynamics In Modelling Health And Budget Impact of An Intervention for A Chronic Disease With Multiple Disease Subtypes. PMID- 26533922 TI - Modeling The Natural History of Secondary-Progressive Multiple Sclerosis: A New Modeling Approach Using Discrete Event Simulation. PMID- 26533923 TI - Better Reimbursement Decision-Making Based on Expected Cost-Effectiveness: Using Value of Information Decision Analysis to Improve The Design and Efficacy of A Phase Iii Program for Erlotinib. PMID- 26533924 TI - Budget Impact Analysis of Delayed-Release Dimethylfumarate In The Treatment of Relapsing-Remitting Multiple Sclerosis In Italy. PMID- 26533925 TI - Investigating The Impact of Contemporary Risk Factors for Diabetes Complications and Their Evolution on Risk Prediction Using The Ukpds 82 Equations. PMID- 26533926 TI - Impact of Grexit on Pharmaceutical Pricing: An International Reference Pricing Analysis. PMID- 26533927 TI - Eight Ways to Improve The Interpretation and Reporting of Cost-Effectiveness Analyses of Screening Interventions. PMID- 26533928 TI - Development of A Conceptual Model of Multiple Myeloma for Use In Economic Modelling: A Systematic Literature Review to Identify The Evidence Base. PMID- 26533929 TI - Quantitative Assessment of Therapeutic Value of Innovative Medical Technologies: Methodology and Preliminary Results. PMID- 26533930 TI - Simulating Individual Patient Level Data Using An Illness-Death Modelling Framework In Order to Adjust for Treatment Switching When Only Summary Data Are Available. PMID- 26533931 TI - Markov Modeling of Hiv Infection In Russian Population. PMID- 26533932 TI - Timed Automata Modeling of The Personalized Treatment Decisions In Metastatic Castration Resistant Prostate Cancer. PMID- 26533933 TI - Surgery As An Outcome In Cost-Effectiveness Analysis. PMID- 26533934 TI - The Role of Patient Level Data In Assessing Health Economic Value: A Case Study Using Edge and The Core Diabetes Model. PMID- 26533935 TI - Verification and Validation of Health Economic Models for Diabetes. PMID- 26533936 TI - Impact of Poverty on Multidimensional Infant Mortality Rate In Brazil. PMID- 26533937 TI - Decision-Analytic Modeling Studies: An Overview for Clinicians Using Dlbcl As An Example. PMID- 26533938 TI - Zrx Mcdm: A Fully Flexible Tool to Support The Local Adaptation of Multiple Criteria Decision Criteria In Health Care. PMID- 26533939 TI - Cost-Effectivness Analysis of Shizophrenia Treatment With Haloperidol , Olanzapine And Risperidone In Bosnia and Hercegovina ,Republic of Srpska By Application of The Markov Model. PMID- 26533940 TI - Reviewing The Cost-Effectiveness of Chemotherapy and Targeted Therapy for Metastatic Breast Cancer. PMID- 26533941 TI - Patent Expiry and Generic Pricing: The Impact on Cost- Effectiveness Results. PMID- 26533942 TI - Model-Based Techniques In The Early Phases of The Medical Device Development: A Systematic Literature Review. PMID- 26533943 TI - Physicians' Choice As A Comparator In Clinical Trials: Challenges for Pharmacoeconomic Modelling of Innovative Treatments to Support Health Technology Assessments. PMID- 26533944 TI - Assessment of Validation of Health-Economics Decision Models In Intervention Studies of Seasonal Influenza and Breast Cancer. PMID- 26533945 TI - Sensitivity Analysis: How Much Impact Does It Have on The Nice Decision Making Process? PMID- 26533946 TI - How to Model Survival In Cost-Effectiveness Analysis? Differences Between Markov and Partitioned Survival Analysis Models. PMID- 26533947 TI - Evaluation of The Effect of Crude Leaves Extract of Indigofera Spicata Forssk.(Fabaceae) on Blood Glucose Level of Normoglycemic, Oral Glucose Loaded and Alloxan Induced Diabetic Rodents. PMID- 26533948 TI - Disease Progression In Rheumatoid Arthritis: Key Element for Cost-Effectiveness Modelling. PMID- 26533949 TI - Conditional Copula Models With Applications to Biomarkers In Rheumatoid Arthritis. PMID- 26533950 TI - Using Machine Learning to Detect Patients With Undiagnosed Rare Diseases: An Application of Support Vector Machines to A Rare Oncology Disease. PMID- 26533951 TI - Health Economic Programming Using Royston-Parmar "Hazard Rate" Models: Providing Flexibility and Speed for Event Modelling In Cohort and Des Models. PMID- 26533952 TI - The Futility of Cost-Efficacy Analysis. PMID- 26533953 TI - The Limitations of Icers In Screening Interventions and The Relative Net Benefit Alternative. PMID- 26533954 TI - Cost-Effectiveness Analysis of Cerebrolysin In The Treatment of Patients With Acute Ischemic Stroke Moderate and Severe Degrees of Severity In The Russian Federation. PMID- 26533955 TI - Operational Validation of Health Economic Decision Analytic Models. PMID- 26533956 TI - A Systematic Review and Taxonomy of Economic Evaluations of Pharmaceuticals Licensed on The Basis of Uncontrolled Clinical Studies. PMID- 26533958 TI - Methods for Determining Patient Pathway and Resource Use In Complex Abdominal Wall Reconstruction. PMID- 26533957 TI - Humanistic Burden of Chronic Spontaneous Urticaria in Comparison to Psoriasis: European Perspective. PMID- 26533959 TI - Scoring and Responsiveness of the Self-Assessment of Treatment Version Ii Questionnaire in Patients with Painful Diabetic Peripheral Neuropathy. PMID- 26533960 TI - Issues Affecting Quality of Life and Disease Burden in Lipoprotein Lipase Deficiency (Lpld) - First Step Towards a Pro Measure in Lpld. PMID- 26533961 TI - Mapping the Beck Depression Inventory to the Eq-5d-3l in Patients with Depressive Disorders. PMID- 26533962 TI - Recommendations for Analysis of Patient Reported Outcomes (Pro) Efficacy Data When Evaluating Treatment Benefit. PMID- 26533963 TI - Incremental Quality Adjusted Life Years (Qaly) Analysis in Absence of Head to Head and Health Related Quality of Life (Hrqol) Data: a Case Study in Thyroid Cancer. PMID- 26533964 TI - Internal Structure of the Minnesota Living with Heart Failure Questionnaire. PMID- 26533965 TI - Improvements in Patient-Reported outcomes Following 52 Weeks of Treatment with Certolizumab Pegol in Combination with Methotrexate in Dmard-Naive Patients with Severe, Active and Progressive Rheumatoid Arthritis: Results from the C-Early Randomized, Double-Blind, Controlled Phase 3 Study. PMID- 26533966 TI - Cultural Adaptation Into Spanish (Spain) of the Questionnaire "Overactive Bladder - Family Impact Measure (Oab-Fim)". PMID- 26533967 TI - Development and Validation of a Questionnaire Assessing the fears and Beliefs of Patients Suffering from Chronic Rheumatic Diseases. PMID- 26533968 TI - Physical Functioning and Pain in Chronic Low Back Pain: a Systematic Review of Psychometric Properties of Various Outcomes Measures. PMID- 26533969 TI - Development of a Prediction Model of Disease Activity in Support of Clinical Practice - the Acrodat Experience. PMID- 26533970 TI - A Validity and Reliability Study of the Poverty Related Quality of Life Questionnaire in a Turkish Patient Population. PMID- 26533971 TI - Valuation of the Eq-5d-5l with Composite Time Trade-off for the German Population. PMID- 26533972 TI - Quality of Life Issues Important to Patients with Haematological Malignancies. PMID- 26533973 TI - Comparison of Two Methods for Estimation of Work Limitation Scores from Health Status Measures. PMID- 26533974 TI - Quality of Life Instruments used to Measure Job-Related Stress: a Systematic Review. PMID- 26533975 TI - Measuring the Impact of Multiple Sclerosis: Enhancing the Performance of the Msis 29 and Msws-12. PMID- 26533976 TI - 'How Does that Make You feel?' - the Ambiguity of Translating Depression. PMID- 26533977 TI - Improvements in Workplace and Household Productivity Following 52 Weeks of Treatment with Certolizumab Pegol in Combination with Methotrexate in Dmard-Naive Patients with Severe, Active and Progressive Rheumatoid Arthritis: Results from the C-Early Randomized, Double-Blind, Controlled Phase 3 Study. PMID- 26533978 TI - The Impact of Severe Asthma on the Quality of Life: a Systematc Review. PMID- 26533979 TI - Content Validity of the Current Health Satisfaction Questionnaire (Ches-Q) Among People Living with Type 2 Diabetes Mellitus (T2dm) and Comorbid Chronic Kidney Disease (Ckd). PMID- 26533980 TI - Assessing the Translatability of the Term "Distressed". PMID- 26533981 TI - Demonstrating Methods for Handling Missing Patient Reported Outcome (Pro) Data in Clinical Trial Data Analysis. PMID- 26533982 TI - When is it Evening, When is it Night? why it is Challenging to Translate Times of the Day in Clinical Translations. PMID- 26533983 TI - Qualitative Equivalence Between Paper and Ediary Versions and Usability of 4 Pro Questionnaires for Uterine Fibroids. PMID- 26533984 TI - External Validity of the Well-Being Related to Food Questionnaire (Well-Bfq(c)): Variations According to the Subjects' Nutritional Status. PMID- 26533985 TI - Methods to Account for Follow-Up Time Differences when Calculating Qalys from Randomised Controlled Trials. PMID- 26533986 TI - Validation of a Short "Occupational Disability Index" As a Measure for Disease Impacts on Work Performance and Occupational Handicaps. PMID- 26533987 TI - Modelling Methods for Eq-5d - a Fitting Time for Change. PMID- 26533988 TI - Measuring Preference-Based Patient Benefit of Medical Devices: a New Instrument for Health Economic Assessments. PMID- 26533989 TI - How French Subjects Describe Well-Being from food and Eating Habits? Development, and Scoring Definition of the well-Being Related to food Questionnaire (Well Bfq(c)). PMID- 26533990 TI - Psychometric Validation of the Multidimensional Dyspnea Profile (Mdp) Questionnaire. PMID- 26533991 TI - Survey of Neurologist's Current Practices in Evaluation of Multiple Sclerosis to Identify Domains for a New Clinician-Reported Measure. PMID- 26533992 TI - Assessment of Content Equivalence and Usability Between the Paper and Electronic Versions of the Psoriasis Symptom and Sign Diary (Pssd) Among Subjects with Plaque Psoriasis. PMID- 26533993 TI - Development of a Discrete Choice Experiment to Assess Patients' and Professionals' Preferences for Home Enteral Nutrition. PMID- 26533994 TI - Measuring the Impact of Secondary Progressive Multiple Sclerosis (Spms) in the Ascend Trial: Equating the Msis-29, Msws-12, Abilhand-56 and Sf-36. PMID- 26533995 TI - What Do we Mean When we Talk About "U.S. Spanish"? PMID- 26533996 TI - Development of a Preference-Based Instrument: Compared with Eq-5d. PMID- 26533997 TI - Developing and Validating a New Tool: Physicians' Barriers, Attitudes and Practices Towards Applying Smoking Cessation Interventions in Their Clinics. PMID- 26533998 TI - Comparison of a Profile and Multi-Profile Best Worst Scaling Task: a Preference Study in Parkinson's Patients. PMID- 26533999 TI - Translation and Cultural Adaptation Difficulties Encountered During Linguistic Validation of the Habitual Activity Estimation Scale (Haes). PMID- 26534000 TI - Development of an Eq-5d Respiratory Bolt-on. PMID- 26534001 TI - Methotrexate Adherence Questionnaire: a New Tool to Assess Adherence in Patients Treated with Methotrexate. PMID- 26534002 TI - The Effect of Stress and Coping Resources on Predicting Quality of Life of Graduate Students. PMID- 26534003 TI - Does One Size Fit All? - Challenges Faced when Adapting Translations for an Electronic Platform. PMID- 26534004 TI - Tools for Measuring Workability - Results Derived from Literature and Expert Interviews. PMID- 26534005 TI - The Most Frequent Fears and Beliefs of 226 Patients with Rheumatoid Arthritis or Spondyloarthritis, Using a Novel Questionnaire. PMID- 26534006 TI - Patient Reported Outcomes in the Development of new Medications for Type 2 Diabetes: a Review of Recently Approved Products. PMID- 26534007 TI - The Maps Reporting Statement for Studies Mapping onto Generic Preference-Based outcome Measures. PMID- 26534008 TI - Avoiding Anything 'Abnormal' in the Translation of 'Usually'. PMID- 26534009 TI - Mapping of the 16-Item Sort form Version of the Menopause Cervantes Health Related-Quality-of-Life Scale onto the Eq-5d-3l. PMID- 26534010 TI - Qualitative Equivalence Between Paper and Ediary Versions and Usability of 6 Pro Questionnaires for Endometriosis. PMID- 26534011 TI - Happiness Effects on Health-State Valuations. PMID- 26534012 TI - Assessing Outcomes for Cost-Utility Analyses in Mental Health Interventions: Comparison of Multi-Attribute Utility Instrument Eq-5d with Mental Health Specific Outcomes Ghq12. PMID- 26534013 TI - Translation and Linguistic Validation of the Caregiver Quality of Life Cystic Fibrosis Scale (Cqolcf) and the Multidimensional Scale of Perceived Social Support (Mspss) for use in Germany and the United Kingdom (Uk). PMID- 26534014 TI - Monitored Cognitive Debriefing Interviews: a Case Study. PMID- 26534015 TI - Development of a Measure to Assess Severity of Mps Ii: the Disease Severity Score. PMID- 26534016 TI - Migration of the Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (Fsiq-Rms(tm)) from Paper to an Electronic Diary Format. PMID- 26534017 TI - Measurement Invariance of the Whoqol-Old Module Across Different Demographic Groups in Taiwan's Elderly People. PMID- 26534018 TI - Cost Analysis Study of Oral Anti-Diabetic Drugs Available in Indian Govt Generic (Jan Aushadhi,Jeevandhara ) Drugs and Brand Drugs Market in Rural / Urban Area of Guntur, Andhrapradesh, India. PMID- 26534019 TI - Empirical Evidence for Identifying Best Practices in Translatability Assessment as a Proactive Tool for Enhancing the Quality of Pro and Hrqol Translation and Linguistic Validation. PMID- 26534020 TI - Anchoring Bias in Tto Valuations. PMID- 26534021 TI - Something Old, Something Borrowed, Something New: a Direct Comparison of Three Qualitative Elicitation Methods. PMID- 26534022 TI - Interpreting Results from Bayesian Network Meta-Analyses (Nma): A Guide for Non Statisticians. PMID- 26534023 TI - Telephone Versus face-to-face Interviews for Patient-Reported Outcome Instrument Development. PMID- 26534024 TI - Performance Score Extraction from Panel Data for Multi-Criteria Decision Analysis (Mcda) Using a Regression-Based Approach. PMID- 26534025 TI - Non-Adherence and Non-Persistence Should be Analyzed Separately: The Example of Methotrexate (Mtx) Therapy in the Therapy of Newly Treated Rheumatoid Arthritis in Germany. PMID- 26534026 TI - Using Tangent Line Segments to Determine Statistical Differences between Survival Curves at a Single Point in Time. PMID- 26534027 TI - A Method Based on the Remaining Value of Perfect Information for the Sample Size Calculation in Randomized Trial-Based Cost-Effectiveness Analyses. PMID- 26534028 TI - The Use of Indirect Comparisons in Medicines Evaluation for their Access To Reimbursement by the Has. PMID- 26534029 TI - Simulated Treatment Comparison of Time-To-Event (And Other Non-Linear) Outcomes. PMID- 26534030 TI - The Use and Acceptance of Meta-Analysis of Survival Outcomes to Support Health Technology Assessment Submissions in the Uk. PMID- 26534031 TI - Meta-Analysis to Support Technology Submissions to Health Technology Assessment Authorities: Criticisms By Nice And Evidence Review Groups in the Uk. PMID- 26534032 TI - Alternatives To Winbugs for Network Meta-Analysis. PMID- 26534033 TI - Using Machine Learning Techniques To Classify Oecd Countries According to Health Expenditures. PMID- 26534034 TI - Disproportionality Measures Used in Signal Detection: An Assessment on Pharmacovigilance Adverse Event Reporting System Data. PMID- 26534035 TI - Correcting for Switching to Second Line Treatment in the Survival Analysis: An Example of the Use of Inverse Probability of Censoring Weighted Analysis. PMID- 26534036 TI - The Use of Propensity Score Matching Does Not Protect Against Regression Artifacts (Regression Towards The Mean). PMID- 26534037 TI - Indirect Comparisons in Benefit Assessment. PMID- 26534038 TI - The Use of Interquartile Deviation in Establishing Delphi Panel Consensus: A Prioritization of Intravenous Immunoglobulin Utilization. PMID- 26534039 TI - Network Meta-Analysis for Health Technology Submissions Worldwide: A Report Checklist for Network Meta Analysis Best Practices Globally. PMID- 26534040 TI - Transparency and Reproducibility of Supplementary Search Methods in Nice Single Technology Appraisal Manufacturer Submissions. PMID- 26534041 TI - Application of Simple Imputation Techniques for Missing Pairwise Contrasts from Multi-Arm Trials when Using Frequentist Network Meta Analysis. PMID- 26534042 TI - Increasing Precision of Real-World Data Estimates: The Importance of A Step-Wise Process to Limit Data Collection Errors And Data Incompleteness. PMID- 26534043 TI - Evaluation of Quality Assessment Tools for Non-Randomised Controlled Trials Assessing Surgical Interventions: A Systematic Review of Systematic Reviews. PMID- 26534044 TI - A Comprehensive Disease Model of Polycystic Ovary Syndrome (Pcos). PMID- 26534045 TI - Incidence and Prevalence Estimations Based on Claims Data - New Methodological Considerations. PMID- 26534046 TI - Statistical Assessment of a Case-Finding Algorithm for Identifying Non-Small Cell Lung Cancer (Nsclc) Patients in Administrative Claims Databases. PMID- 26534047 TI - Systematic Literature Review of Adjunctive Anti-Epileptic Drug Trials In Patients With Primary Generalized Tonic-Clonic Seizures Illustrates Changes in Standard of Care Over 12-20 Years. PMID- 26534048 TI - Do We Need to Strengthen Study Design in Observational Studies? PMID- 26534049 TI - Economic Study Design for the Optimize Study on Orbital Atherectomy and Drug Coated Balloon Devices for the Treatment of Below-The-Knee Peripheral Arterial Disease. PMID- 26534050 TI - Methodological Considerations for the Implementation of A European Mandated Retrospective Drug Utilisation Study (Dus) to Investigate the Use of Dexmedetomidine (Dexdor(r)) in Clinical Practice. PMID- 26534051 TI - Trial Design and Market Access Implications: Outcomes from Comparator Choice. PMID- 26534052 TI - The Diabetes Telephone Study: Design and Challenges of a Pragmatic Cluster Randomized Trial to Improve Diabetic Peripheral Neuropathy Treatment. PMID- 26534053 TI - Use of Simulation to Assess the Impact of a Remote Monitoring System. PMID- 26534054 TI - Can Actigraphy Outcome Measures From Existing Clinical Trials Provide A Framework for Sleep and Activity Endpoint Standards in the Clinical Trial of the Future? PMID- 26534055 TI - A Mixed Methods Study of Researchers' Experiences of Developing Core Outcome Sets. PMID- 26534056 TI - Using Incentives to Improve Health-Related Behaviours: A Review of Incentive Based Trials. PMID- 26534057 TI - Translation into Russian and Validation of the Cochrane Questionnarie to Assess Risks of Systematic Biases in Randomized Controlled Trials. PMID- 26534058 TI - Lets Talk! Is Chatter on Social Media Amongst Participants Compromising Clinical Trials? PMID- 26534059 TI - Modelling Health Benefits Associated to Early Diagnosis and Treatment of Copd. PMID- 26534060 TI - Representing the Threshold in the Cost-Effectiveness Plane: Proposing a New Graphical Convention. PMID- 26534061 TI - Predictive Analysis of Factors Influencing Health Technology Assessment Recommendation: A Literature Review. PMID- 26534062 TI - Quality Assessment of Diagnostic Studies: Study Designs Leading to High and Low Risk of Bias. PMID- 26534063 TI - How to Calculate Value of Information in Seconds Using 'Savi', the Sheffield Accelerated Value of Information Web App. PMID- 26534064 TI - Filling the Gap Between Risk/Benefit Assessment for Drugs and Risk Assessment for Consumer Goods. PMID- 26534065 TI - The Power of the Patient Voice: Formalising Qualitative Data in the Drug Approval Process. PMID- 26534066 TI - Early Health Economic Assessment in Innovation Partnerships: Lessons from the European Innovation Partnership on Active and Healthy Ageing. PMID- 26534067 TI - Capturing Quality of Life (Qol) Data in Rare Indications: Case Study in Radioiodine-Refractory Thyroid Cancer (Rr-Dtc). PMID- 26534068 TI - Nordic Longitudinal Data from Electronic Medical Records and Full Population National Registers: Unique Opportunities for New Insights in Benefit of Diabetes Patients. PMID- 26534069 TI - New Standards to Derive Preference-Based Hrqol Values. PMID- 26534070 TI - A Practical Guide To Adding Patient Heterogeneity Into Phase Iii Trials: Results from Imi Getreal Wp2. PMID- 26534071 TI - Rapid and Automated Test for Connectedness of Evidence Networks in Network Meta Analysis. PMID- 26534072 TI - The Need to Revise Discount Rates in Belgium, The Netherlands, Poland and the Uk. PMID- 26534073 TI - The Challenges in Evaluating the Cost-Effectiveness of Complex Interventions. PMID- 26534074 TI - Establshing The Cost-Effectiveness of Genomic-Based Diagnostic Tests: Are Current Methods Sufficient and Appropriate? PMID- 26534075 TI - A Cost-Effective Enhanced Retrospective Observational Study Methodology to Capture Economic Burden Evidence in a Rare Disease Using Non-Tuberculous Mycobacteria Infection as a Model. PMID- 26534076 TI - The Vaccine Portfolio Management Model as an Efficiency Tool for Japan. PMID- 26534077 TI - Applying Symptom-Based Utility Functions in Health Economic Modelling: A Case Study of Uterine Fibroids. PMID- 26534078 TI - Qualitative Discussion on Issues of Patient-Reported Outcome Assessment in Post Marketing Surveillance for Diseases in the Elderly. PMID- 26534079 TI - A Conceptual Search Filter to Identify Real-World Evidence. PMID- 26534080 TI - Methodological Guidelines for Economic Drug Evaluation Studies in Portugal: Major Gaps and New Topics in the Studies Evaluated Between 2010 and 2014. PMID- 26534081 TI - From Phase Ii Studies to Hta Submissions: Optimal Use of Evidence for Informed Decisions. PMID- 26534082 TI - Validation of Social Media Analysis for Outcomes Research: Identification of Drivers of Switches between oral and Injectable Therapies for Multiple Sclerosis. PMID- 26534083 TI - A Framework for Prioritizing Research Investments in Precision Medicine. PMID- 26534084 TI - Development of A Precis-2 Scoring Grid: How Pragmatic are Pragmatic Trials of Surgical and Pharmaceutical Interventions? PMID- 26534085 TI - Full Economic Assessment of Rotavirus Vaccination Using the Health Economic Cauliflower Toolbox. PMID- 26534086 TI - Use of A Multi-Decision Criteria Analysis to Support Healthcare Decision-Making for Private Payers in Brazil: Development of a Model To Guide Reimbursement Decisions. PMID- 26534087 TI - How Insurance Claim Data Can Help in Health Outcomes Research: an Indian Perspective. PMID- 26534088 TI - Modelling to Determine the Price and Identify Critical Data Gaps During Vaccine Development. PMID- 26534089 TI - Exploring the Use of Value of Information Methods to Prioritise Research to Address the Treatment Uncertainties Identified By the James Lind Alliance Priority Setting Partnerships. PMID- 26534090 TI - Can Advances in Health Monitors Lead to Health Being Looked at as A Commodity? PMID- 26534091 TI - Practical Considerations in the Application of Statistical Methods for Treatment Switching. PMID- 26534092 TI - A Method to Evaluate Uncertainty Due to Unknown Parameter Correlation in Stochastic Decision Models. PMID- 26534093 TI - Moving Beyond the Picos: Appropriate Comparative Observational Data Selection Can Facilitate Meta-Analysis of Relative Treatment Effects. PMID- 26534094 TI - Human Health Damage Modelling in Life Cycle Assessment: A Valuable Addition to the Evaluation of Medical Interventions? PMID- 26534095 TI - Possible Applications of Real World Evidence in Safety Operations. PMID- 26534096 TI - Assessing Heterogeneity Across Groups of Clinical Trials Based on Aggregate Data. PMID- 26534097 TI - Public Consultations: A Tool for the Inclusion of Society in the Brazilian Hta Process. PMID- 26534098 TI - Value-Based Pricing Scheme for new Technology in Consideration of Cost Effectiveness Dominance to the Control. PMID- 26534099 TI - Hta Studies for Medical Devices Incorporating Their Moral Ageing. PMID- 26534100 TI - Clinical Multi-Criteria Decision Assessment (Cmda): A Proposal for Applying Mcda to Compare Treatments in a Simultaneous, Transparent and Overall Way. PMID- 26534101 TI - Prevention and Treatment of Missing Data in Real World Research. PMID- 26534102 TI - Sugammadex: The Right Option for the Efficiency of the Operating Room? A Methodology for Cost / Benefit Analysis in Comparison to the Routine Choice for Reversal. PMID- 26534103 TI - A Cost-Effectiveness Analysis of Hospital Pharmacist Review in Older Patients. PMID- 26534104 TI - Comparison of Bazedoxifene/Conjugated Oestrogens Vs Current Therapies in the Treatment of Postmenopausal Symptoms: Systematic Review and Meta-Analysis. PMID- 26534105 TI - Practices of Substance Abuse and Risky Sexual Behavior Among Adama Science and Technology University Undergraduate Students in 2012/13 Academic Years. PMID- 26534106 TI - Examining Prescribing Patterns in Older Patients with Acute Illness. PMID- 26534107 TI - Prevalence of Self-Medication and Its Reason Among Pharmacy Students in India: A cross-sectional study. PMID- 26534108 TI - Prevalence and Incidence of Malnutrition Among Geriatrics Population in Turkey. PMID- 26534109 TI - The Burden of Adult Pneumococcal Disease in 50+ Population in Hungary. PMID- 26534110 TI - Cost-Effectiveness Analysis of Botulinum Toxin Type a Treatment for Cerebral Palsy. PMID- 26534111 TI - Bemfola(r) Can Potentially Reduce Drug Wastage and Associated Costs of Intertility Treatment. PMID- 26534112 TI - Implant Versus Oral Contraception Use: 3-Years Budget Impact Analysis for the National Heal System in Portugal. PMID- 26534113 TI - Risk Factors and Causes of Intrauterine Death. PMID- 26534114 TI - Estimating the Lifetime Indirect Cost of Childhood Overweight and Obesity: A Markov Modelling Study. PMID- 26534115 TI - Cost Study of Assisted Reproductive Technologies in Ukraine. PMID- 26534116 TI - A Cost-Effectiveness Evaluation Comparing Biosimilar Bemfola to Gonal-F for the Treatment of Infertility in an Italian Contest. PMID- 26534117 TI - Cost-Effectiveness of Nexplanon(r) (Etonogestrel Implant) Compared to other Reimbursed Contraceptive Methods in France Based on Real Life Data. PMID- 26534118 TI - Analysis of Preeclampsia Prevention in Real Practice and the Need to Improve Information Support of Doctors in Ukraine. PMID- 26534119 TI - Economic Impact of Treating Chinese Postmenopausal Women with 17-beta-Estradiol Combined Hormone Replacment Therapy (Hrt) Compared with the Alternative Practices. PMID- 26534120 TI - Cost-Efficiency of of National Drug Information Center Through Ministry of Healh Hotline Calling Services (937) in Saudi Arabia: Application of a Mercian Model. PMID- 26534121 TI - Population Cost-Effectiveness of a Parenting Program for the Treatment of Conduct Disorders: a Modelling Study to Assist Priority Setting in Australia. PMID- 26534122 TI - Biossimilars, Are they Really Cost Saving? The Case of Recombinant Human Follicle Stimulating Hormone in Portugal. PMID- 26534123 TI - The Comparative Pharmacoeconomic Analysis of Using Korifollitropin Alfa with Ganirelix and Follitropin Alfa with Cetrorelix for Ovarian Stimulation. PMID- 26534124 TI - Examining the Economic Burden and Health Care Utilization of Menopausal Women in the U.S. Medicaid Population. PMID- 26534125 TI - Cost-Effectiveness of Recommended Medical Intervention for Treatment of Dysmenorrhea and Endometriosis in Japan Setting. PMID- 26534126 TI - Cost-Effectiveness of Conjugated Estrogens/Bazedoxifene for the Treatment of Vasomotor Symptoms in the United States. PMID- 26534127 TI - Review of Adherence Measures for use in Phase Iv Studies and Recommendations for a new Standardized Generic Measure. PMID- 26534128 TI - Sistematic Review on Personal Predictors of Adherence to Medication. The Cumple-Q Scale. PMID- 26534129 TI - Patient-Centered Reasons for Primary Non-Adherence as Derived from the Peer Reviewed Literature. PMID- 26534130 TI - Inconsistency in the Valuations of Euroqol Eq-5d-5l Health States in China was More Related to Interviewer and to Interview Process than to Respondents' Characteristics. PMID- 26534131 TI - A Novel Method for Calculating Medication Adherence to Poly-Pharmacotherapy by Linking General Practice Prescribing Data and Pharmacy Dispensing Records. PMID- 26534132 TI - Utility Values for Health Technology Assessment: Learning Lessons from Economic Models of Pharmaceuticals Submitted to the French National Authority for Health (Has). PMID- 26534133 TI - Time Trade-Off Utility Values in Mild and Severe Primary Dysmenorrhea. PMID- 26534134 TI - A National Eq-5d Value Set for Hungary - a Model Methodology ? PMID- 26534135 TI - Valuation of Eq-5d Health States by Pharmacy Students in Poland (Comparison of Different Methods and with General Population). PMID- 26534136 TI - Japanese Population Norms for Preference-Based Measures: Eq-5d-3l, Eq-5d-5l, And Sf-6d. PMID- 26534137 TI - Engaging Patients with E-Clinical Technology: Incorporating Patient Preferences into Disease Management and Care. PMID- 26534138 TI - Evaluation of Inpatients'satisfaction in Pafos General Hospital, Cyprus. PMID- 26534139 TI - Cross-Country Profile of Adult Caregivers. PMID- 26534140 TI - Patient-Reported Outcomes within Health Technology Assessment Decision Making: Current Status and Implications for Future Policy. PMID- 26534141 TI - Health Status and Quality of Life Among Nurses. PMID- 26534142 TI - Review and Comparison of Eq-5d-3l Valuation Studies. PMID- 26534143 TI - Connection Between the way of Parenting and the Behavior of Adolescents in the Light of a Survey in Hungary. PMID- 26534144 TI - Results of the Eq-5d-3l Valuation Project for Ireland. PMID- 26534145 TI - Preferences for Using Phone Calls, Text Messaging, and Email to Communicate with Physicians Among Patients with four chronic diseases. PMID- 26534146 TI - Patient use of Eclinical Technology to Research, Track, And Self-Manage Chronic Disease. PMID- 26534147 TI - Aligning Patient Centred Evidence Generation Across the Drug Development Lifecycle. PMID- 26534148 TI - Knowledge Regarding Harmful Effects of Child Vaccination and Reasons of Non Vaccination Among Married Population of Mastung, Pakistan. PMID- 26534149 TI - Assessment of Effective Incentives for Blood Donations. How can citizens be Motivated to donate Blood? PMID- 26534150 TI - Investigation of the Living and its Impact to the Pregnants. PMID- 26534151 TI - The Importance of the Communicator for an Integrated Care Program - A Comparative Preference Analysis with Discrete Choice Experiments. PMID- 26534152 TI - Experienced Vs. Hypothetical Health States Preferences Using Eq-5d 3l And 5l Versions: A National Study. PMID- 26534153 TI - Research And Evaluation of the Self-Treatment Process with the Non-Steroidal Anti Inflammatory Drugs in the Republic of Armenia. PMID- 26534154 TI - The Conceptual Framework and Content Validity of the Polycystic Ovary Syndrome Patient Reported Outcome (Pcos-Pro) Scale. PMID- 26534156 TI - Patient-Reported Outcomes in Studies Published in 2014: Which Disease Areas Have Been the Main Focus of Clinical Research? PMID- 26534155 TI - The Oxford Participation & Activities Questionnaire (Ox-Paq): Psychometric Analysis. PMID- 26534157 TI - Where is Your Abdomen? Patient-Reported Abdomen Locations and Implications for Patient-Reported Outcome Assessments. PMID- 26534158 TI - Patients' and Health Professionals' Preferences Regarding Intravenous Vs Subcutaneous Drug Administration: A Literature Review. PMID- 26534159 TI - Therapeutic Reference Pricing System In Slovenia From The Patients' Perspective. PMID- 26534160 TI - Satisfaction with life of general population of pakistan. A nation wide survey. PMID- 26534161 TI - Comparison of Patient-Reported Outcomes Requirements in Medical Guidelines for Pain, Migraine, Rheumatoid Arthritis, and Systemic Lupus Erythematosus: Europe Vs. United States. PMID- 26534162 TI - Usability Testing of an Integrated Glucometer and Handheld Electronic Patient Reported Outcome System. PMID- 26534163 TI - Differentials In Contraceptive Use Among Currently Married Women By Socio Demographic Characteristics In Western Kenya. PMID- 26534164 TI - Capturing Emotional Concepts During Concept Elicitation. PMID- 26534165 TI - Inadequate Treatment of Post-Surgical Pain May Result in Extended Hospitalization Period. PMID- 26534166 TI - Assessment of The Association Between Sleep Behaviors and Experiential Outcomes Among A Multinational Adult Population. PMID- 26534167 TI - Students' Knowledge and Perceptions Towards Quality Use of Medicines: A Descriptive Analysis From Universiti Sains Malaysia. PMID- 26534168 TI - Validity and Responsiveness of Preference Based Measures: A Critical Overview of Reviews. PMID- 26534169 TI - Linguistic Validation of The Emphasis-10 Questionnaire: A Patient-Reported Outcome Instrument For Assessing Qol In Pulmonary Hypertension (Ph). PMID- 26534170 TI - Promis((r)) Physical Function Multilingual Translations: Progress And Outlook. PMID- 26534171 TI - Tea Consumption and Health-Related Quality of Life In Elderly Adults. PMID- 26534172 TI - Children's Medication In The Nordic Countries - Survey on National Administrative Register Data. PMID- 26534173 TI - Contraception Patterns In France: A Real-World Database Analysis. PMID- 26534174 TI - Haemodialysis Versus Non-Dialysis Therapy Among Older Adults With Stage 5 Chronic Kidney Disease: A Comparison of Health-Related Quality of Life. PMID- 26534175 TI - Examination of Stress and Psychosomatic Symptoms In Terms of Nurses' Quality of Life. PMID- 26534176 TI - Health-Related Quality of Life of People From Low-Income Families In Hong Kong, China. PMID- 26534177 TI - Anti-Dementia Medicine Dispensing Patterns: A Community Pharmacy Database Analysis. PMID- 26534178 TI - Characteristics of Geriatric Patients Diagnosed With Multiple Sclerosis Taking Disease Modifying Agents In The United States. PMID- 26534179 TI - Inappropriate Drug Prescription: Still on-Going Among Malaysian Older Adults. PMID- 26534180 TI - Role of Puppet Plays In Improving Children's Knowledge About Hand Washing and Using Normal Saline to Rinse Nose and Throat. PMID- 26534181 TI - The Drivers of Facility-Based Immunization Performance and Costs. An Application to Moldova. PMID- 26534182 TI - Psychiatric Healthcare Utilization and Related Costs In Newly Diagnosed Individuals With Autism Spectrum Disorder (Asd) In Quebec (Canada). PMID- 26534183 TI - Value Assessment for Genetic Testing of Drug Variation In An Elderly Population. PMID- 26534184 TI - Stimulant Use and Cardiovascular Risk Among Children And Adolescents With Adhd: What Product Labeling Does, or Does Not, Tell Us. PMID- 26534185 TI - The Analysis of Telemedicine Technologies In Pediatric Patients. PMID- 26534186 TI - The 3-Arm Strategy for Readmission Prevention: Automated Predictive Modeling, Readmission Prevention Intervention, and Monitoring. PMID- 26534187 TI - Patients Experience At Hospital Discharge and Readmissions. PMID- 26534188 TI - The Association of Early Exposure to Phenols and Neuro-Behavior Developemnt In School-Aged Children. PMID- 26534189 TI - Socioeconomic Burden of Autism In Children In Greece. PMID- 26534190 TI - Determinants of Women's Choice of Place of Intrapartum Care In Uganda: An Analysis of Secondary Data From Udhs. PMID- 26534191 TI - Dispensing of The Combination of Amoxicillin With Clavulanic Acid to Elderly Patients: A Database Analysis. PMID- 26534192 TI - Examination of Knowledge About Hpv Infection Among Mothers and Daughters. PMID- 26534193 TI - Indirect Comparison of Onabotulinum Vs. Oral Triptans for The Phrophylaxis Treatment of Chronic Migraine. PMID- 26534194 TI - The Burden of Illness of Congenital Adrenal Hyperplasia In The United Kingdom: A Retrospective, Observational Study. PMID- 26534195 TI - Twenty-Year Trends In Diagnosis and Treatment of Alzheimer's Disease. PMID- 26534196 TI - 36 Months Pangaea: A 5-Year Non-Interventional Study of Safety, Efficacy and Pharmacoeconomic Data for Fingolimod Patients In Daily Clinical Practice. PMID- 26534197 TI - Idntification of Chromosomal Alteration and Association Study of Mthfr Gene Mutations In Autism. PMID- 26534198 TI - A Study on Cytogenetic Analyses and Mecp2 Mutation With Dopamine And Serotonin In Rett Syndrome (Rtt). PMID- 26534199 TI - The Effectiveness of Cbl Gene Mutation Test for Diagnosis In Juvenile Myelomonocytic Leukemia: Systematic Reviews. PMID- 26534200 TI - Adjusted Indirect Comparison of Oral Multiple Sclerosis Agents. PMID- 26534201 TI - Epidemiology and Current Treatment of Neuromyelitis Optica: A Systematic Review. PMID- 26534202 TI - Ranking of Disease-Modifying Therapies for Multiple Sclerosis. PMID- 26534203 TI - Comparative Effectiveness Using A Matching-Adjusted Indirect Comparison Between Delayed-Release Dimethyl Fumarate and Fingolimod for The Treatment of Relapsing Remitting Multiple Sclerosis. PMID- 26534204 TI - Confirmed Disability Improvement In Patients With Active Multiple Sclerosis Treated With Fingolimod Versus Brace: A Matched Comparison of Treatments From The Pangaea And Pearl Registry Studies. PMID- 26534205 TI - Variation In State-Level Vs. National Incidence In Rare Genetic Disease: A Monte Carlo Simulation to Examine Sampling Variation As A Primary Explanation In Congenital Adrenal Hyperplasia. PMID- 26534206 TI - Cost Offsets Associated With Rebif Use In First-Line Rrms: An Analysis Based on The Cochrane Collaboration Review And Real-World Persistence Data. PMID- 26534207 TI - Budget Impact of Perampanel for The Treatment of Patients With Partial-Onset Seizures (Pos) In Russia. PMID- 26534208 TI - Glatiramer Acetate 40 Mg/Ml Three Times A Week for The Treatment of Relapsing Forms of Multiple Sclerosis: Potential Cost Benefits of A Regimen With Infrequent Injections Which May Minimise Switching to The Newly-Introduced First-Line and Second-Line Disease Modifying Therapies. PMID- 26534209 TI - Forecasting The Prevalence of Status Epilepticus and Its Subtypes In Europe, 2015 2024. PMID- 26534210 TI - Social Demographic Characteristics and Direct Medical Costs For Patients With Parkinson's Disease In Korea : Big Data Analysis From The National Health Insurance Claims Dataset. PMID- 26534211 TI - Cost Offset Analysis of Interferon Beta Disease Modifying Therapies In Relapsing Remitting Multiple Sclerosis. PMID- 26534212 TI - Budget Impact Analysis of Botulinum Toxin Type A Treatment for Cerebral Palsy In The Russian Federation. PMID- 26534213 TI - Budget Impact Analysis for Peginterferon Beta-1a In Relapsing Remitting Multiple Sclerosis In Italy. PMID- 26534214 TI - The Budget Impact Analysis of Adjunctive Therapy for Patients With Partial Epilepsy. PMID- 26534215 TI - Budget Impact Analysis of Pramipexole Extended Release Monotherapy In Early Parkinson'S Disease. PMID- 26534216 TI - Real-World Data And Budget Impact Analysis for Incobotulinum Toxin A and Onabotulinum Toxin A for Upper Limb Post-Stroke Spasticity At A Uk Centre. PMID- 26534217 TI - Excess Costs Associated With Possible Misdiagnosis of Alzheimer's Disease Among Patients With Vascular Dementia In Italy. PMID- 26534218 TI - Newer Antiepileptic Drugs Dispensed By Community Pharmacies: Generic Prescribing and Cost. PMID- 26534219 TI - Treatment Costs and Patterns In Patients With Multiple Sclerosis Treated With Prolonged-Release Fampridine In Germany. PMID- 26534220 TI - Costs of Illness of Multiple Sclerosis In Sweden - A Population-Based Register Study. PMID- 26534221 TI - Cost of Drug-Related Monitoring Requirements for Glatiramer Acetate and Other Multiple Sclerosis Disease-Modifying Therapies (Dmts). PMID- 26534222 TI - Health Care Resource Utilization and Direct Medical Costs Among Patients With Epilepsy In Tianjin, China. PMID- 26534223 TI - The Indirect Costs of Multiple Sclerosis Associated With Absenteeism In Poland In 2013. PMID- 26534224 TI - An Update on Healthcare Resource Use and Economic Burden In Alzheimer's Disease In The United States (Us) From A Medicare Sample Analysis. PMID- 26534225 TI - The Cost of Patients With Relapsing-Remitting Multiple Sclerosis Who Develop Neutralizing Antibodies While Treated With Interferon Beta. PMID- 26534226 TI - The Economic Burden of Brain Disorders In Korea. PMID- 26534227 TI - Cost Implications of Further Limiting or Increasing Generic Prescribing of Antiepileptics In English And Welsh General Practices. PMID- 26534228 TI - Analysis of Expenditure In Multiple Sclerosis Disease Modifying Therapies Evolution Between 2004-2014 In Spain. PMID- 26534229 TI - Adapting The Adpkd Outcomes Model to Predict Cost Consequence In Italian Patients With Autosomal Dominant Polycystic Kidney Disease (Adpkd) Treated With Jinarc (Tolvaptan). PMID- 26534230 TI - Cost-Effectiveness Analysis of Delayed-Release Dimethyl Fumarate for The Treatment of Relapsing Remitting Multiple Sclerosis In Spain. PMID- 26534231 TI - Real-World Assessment of Relapse, Medical Costs and Persistency of Multiple Sclerosis Patients Treated With Subcutaneous Interferon beta-1a. PMID- 26534232 TI - Exploring Cost-Effectiveness Heterogeneity By State: Using State-Level Vs. National Disease Incidence In Newborn Screening (Nbs) Cost-Effectiveness Analysis of Congenital Adrenal Hyperplasia (Cah). PMID- 26534233 TI - Cost-Effectiveness Analysis of Peginterferon Beta-1a In The Treatment of Relapsing-Remitting Multiple Sclerosis In Scotland. PMID- 26534234 TI - Cost-Effectiveness of First-Line Disease-Modifying Therapies (Dmts) For Relapsing Remitting Ms (Rrms). PMID- 26534235 TI - Cost-Effectiveness Analysis of Peginterferon Beta-1a In The Treatment of Relapsing-Remitting Multiple Sclerosis In Ireland. PMID- 26534236 TI - Cost-Effectiveness Analysis of Glybera for The Treatment of Lipoprotein Lipase Deficiency. PMID- 26534237 TI - Cost-Effectiveness Analysis of Ginkgo Biloba Extract (Egb761(r) - Tanakan(r)) for The Treatment of Dementia In The Czech Republic. PMID- 26534238 TI - Systematic Review of Economic Evaluations of Treatments In Epilepsy. PMID- 26534239 TI - Abobotulinumtoxin A In The Management of Cervical Dystonia In The United Kingdom: A Cost-Effectiveness Analysis. PMID- 26534240 TI - Cost-Effectiveness of New Therapies for Multiple Sclerosis In Spain. PMID- 26534241 TI - Cost Effectiveness of Sodium Oxybate In Treatment of Cataplexy In Patients With Narcolepy In Turkey. PMID- 26534242 TI - Cost-Effectiveness Analysis of Pramipexole Extended Release Monotherapy In Early Parkinson'S Disease. PMID- 26534243 TI - The Cost Effectiveness of Delayed-Release Dimethyl Fumarate Versus Interferon Beta-1b In A Swedish Setting. PMID- 26534244 TI - Cost-Effectiveness of Dimethyl Fumarate Treatment for Relapsing-Remitting Multiple Sclerosis From A Danish Perspective. PMID- 26534245 TI - A Cost-Effectiveness Analysis of Fingolimod Versus Dimethyl Fumarate As A Second Line Disease Modifying Treatment In Patients With Highly Active Relapsing Remitting Multiple Sclerosis. PMID- 26534246 TI - Cost-Effectiveness Analysis of Peginterferon Beta-1a In Italian Relapsing Remitting Multiple Sclerosis Management. PMID- 26534247 TI - Cost-Utility Analysis of Delayed-Release Dimethyl Fumerate For The Treatment of Relapsing-Remitting Multiple Sclerosis In Portugal. PMID- 26534248 TI - Cost-Utility Analysis of Pramipexole Extended Release Monotherapy In Early Parkinson'S Disease. PMID- 26534249 TI - Evaluation of The Burden of Parkinson's Disease In Medicare And Linked Long Term Care Population. PMID- 26534250 TI - The Impact of Increasing Multiple Sclerosis (Ms) Severity Level on Employment and Caregiver Burden. PMID- 26534251 TI - Cost-Utility of Fingolimod Compared With Dimethyl Fumarate (Dmf) In Highly Active Relapsing Remitting Multiple Sclerosis (Rrms) In England: Comparison of A Markov and Discrete Event Simulation Model. PMID- 26534252 TI - Differences In Work Productivity Activity Imparment In Rrms Patients Initiated on Oral Dmf or Platform Therapies In Europe and Us. PMID- 26534253 TI - Cost-Effectiveness of Incobotulinumtoxin-A With Flexible Treatment Intervals Compared to Onabotulinumtoxin-A In The Management of Blepharospasm And Cervical Dystonia. PMID- 26534254 TI - Comparing Resource Use In Alzheimer's Disease Across Three European Countries - 18-Month Results of The Geras Study. PMID- 26534255 TI - Adherence to Inhaled Antibiotics for The Treatment of Chronic Pseudomonas Aeruginosa Infection In Patients With Cystic Fibrosis: A Systematic Literature Review. PMID- 26534256 TI - Comparison of Compliance And Discontinuation Rates Among Ms Patients Treated With Fingolimod and Other Disease-Modifying Therapies: A Canadian Retrospective Claims Analysis. PMID- 26534257 TI - How Useful are Eq-5d And Zbi In Assessing The Impact of Caring for Alzheimer's Disease Patients? PMID- 26534258 TI - Systematic Literature Review of Health State Utility Values In Patients With Migraine. PMID- 26534259 TI - Treatment Satisfaction With Disease Modifying Therapies In Multiple Sclerosis: A Systematic Review of Studies Using The Treatment Satisfaction Questionnaire For Medication (Tsqm). PMID- 26534260 TI - A Comparison of Stated Preferences for Injectable Disease-Modifying Treatments for Multiple Sclerosis: Compliant Vs. Non-Compliant Patients. PMID- 26534261 TI - Us Rrms Patient Preferences for Multiple Sclerosis Treatments: An Online Survey. PMID- 26534262 TI - Preferences of Patients With Multiple Sclerosis for Attributes of Disease Modifying Drugs In Decision-Making: A Nominal Group Technique And Best-Worst Scaling. PMID- 26534263 TI - Using A Mixed Methods Approach to Develop A Discrete Choice Experiment In Multiple Sclerosis. PMID- 26534264 TI - The International Development of The Modified Hyperphagia Questionnaire. PMID- 26534265 TI - Association Between Self-Administered Expanded Disease Severity Scale (Edss) and Multiple Sclerosis Impact Scale (Msis-29): Results from The Burden of Illness In Patients With Multiple Sclerosis In Finland (Defense) Study. PMID- 26534266 TI - Health-Related Quality of Life In Double-Blind Phase Iii Studies of Brivaracetam As Adjunctive Therapy of Partial-Onset Seizures. PMID- 26534267 TI - Challenges In Translating The Multiple Sclerosis International Quality of Life (Musiqol) Questionnaire In 57 Languages. PMID- 26534268 TI - Relapsing Remitting Multiple Sclerosis Patients Initiated on Oral Dmf Report A Better Quality of Life Compared to Patients on Platform Therapies As Measured By Eq-5d. PMID- 26534269 TI - Differences In Disease Specific Hrqol In Rrms Patients Initiated on Oral Dmf Or Platform Therapies In Europe And Us. PMID- 26534270 TI - A Systematic Review of The Humanistic Burden of Disease In Patients With Fabry Disease. PMID- 26534271 TI - Does Crgs Provide Proper Guides for An Efficient Pharmaceutical Prescription In Alzheimer Patients? PMID- 26534272 TI - Development of A Screening Tool to Support Identification of Patients With Secondary Progressive Multiple Sclerosis (Spms). PMID- 26534273 TI - Costs Associated With Patients Diagnosed With Relapsing Remitting Multiple Sclerosis Taking Once Daily Fingolimod Capsules In The United States. PMID- 26534274 TI - Muscular Dystrophy Patients With Severe Renal Dysfunction: Analysis Of Ace Inhibitor Use. PMID- 26534275 TI - Quantifying The Impact of Treatment on The Public Health Burden of Adpkd: A Uk Case Study Using The Adpkd Outcomes Model. PMID- 26534276 TI - Over-Prescription Of Fingolimod In Germany. PMID- 26534277 TI - Treatment Patterns, Resource Utilization And Costs In Muscular Dystrophy Patients: Analysis Using Administrative Claims Data. PMID- 26534278 TI - Characteristics of Patients With Relapsing Remitting Multiple Sclerosis Taking Once Daily Fingolimod Capsules In The United States. PMID- 26534279 TI - Characteristics of Patients With Relapsing Remitting Multiple Sclerosis Taking Disease Modifying Agents. PMID- 26534280 TI - Differences In Multiple Sclerosis Relapse Rates Based On Patient Adherence, Average Daily Dose, And Persistence With Disease-Modifying Therapy: Observations Based on Real-World Data. PMID- 26534281 TI - Inequalities In Access to Treatment for Multiple Sclerosis In England Continue Despite Service Improvement Initiatives And Policy Reforms. PMID- 26534282 TI - Natalizumab Use In Multiple Sclerosis: A Real World Evidence (Rwe) Analysis of Its Impact on Nhs Resources In England. PMID- 26534283 TI - Health Care Costs Associated With Geriatric Patients Diagnosed With Multiple Sclerosis Taking Disease Modifying Agents In The United States. PMID- 26534284 TI - Development of Ms Budget Manager: A Practical Tool to Assist Alternative Stakeholders At Multiple Decision Levels In The Forecast And Financial Management For Multiple Sclerosis (Ms). PMID- 26534285 TI - Humanistic and Economic Burden of Focal Drug-Refractory Epilepsy In Europe. PMID- 26534286 TI - Impact of Ongoing National Health Technology Assessment Challenges on Patient Access to New Therapies for Multiple Sclerosis In Germany And The Uk. PMID- 26534287 TI - A Long Term Analysis of The Clinical And Cost Effectiveness of Glatiramer Acetate From The Uk Multiple Sclerosis Risk Sharing Scheme. PMID- 26534288 TI - Characteristics of Patients With Relapsing Remitting Multiple Sclerosis (Rrms) Taking Injectable and Oral Disease Modifying Treatments (Dmt) In Europe (Eu). PMID- 26534289 TI - Adherence to Glatiramer Acetate 40 Mg Versus Oral Disease-Modifying Therapies for Multiple Sclerosis. PMID- 26534290 TI - Comparison of Patients With Relapsing Remitting Multiple Sclerosis (Rrms) Treated With Disease Modifying Treatments (Dmt) In Europe (Eu) And The United States (Us). PMID- 26534291 TI - Access To The Procedure Care of Colorectal Cancer In Brazilian Public Health System: Use Of Diagnosis Resources In Sao Paulo State. PMID- 26534292 TI - Asociacion Significativa Entre La Enfermedad Voluminosa Cercana A Craneo Y Neuroeje Y La Infiltracion Secundaria A Sistema Nervioso Central En Pacientes Con Linfoma Difuso De Celulas Grandes B. PMID- 26534293 TI - Profile of Colorectal Cancer Treatment Within The Brazilian Public Setting: Analysis Of Datasus Aq Database. PMID- 26534294 TI - Costo De Cancer De Colon Avanzado En Los Establecimientos Hospitalarios Del Peru. PMID- 26534295 TI - Cost-Effectiveness Analysis For Cervical Cancer Screening Using Hpv Tests In Chile. PMID- 26534296 TI - Evaluacion Del Costo-Efectividad Y Costo-Utilidad Del Uso De Rivaroxaban En Pacientes Con Fibrilacion Auricular No Valvular Frente A Warfarina En El Contexto Ecuatoriano. PMID- 26534297 TI - Projected Economic Impact of Increased Use of Biologic Treatments For Rheumatoid Arthritis In Argentina, Colombia, And Mexico Over 10 Years. PMID- 26534298 TI - Evaluacion Costo-Utilidad De Dos Alternativas De Vacunacion Para El Virus Del Papiloma Humano (Vph) En La Prevencion Del Cancer Cervical Uterino. PMID- 26534299 TI - Analisis De Costo-Utilidad De Pcv13 Versus Ppsv23 En Adultos De 65 Anos Y Mas. PMID- 26534300 TI - Methodological Changes In Burden of Infectious Disease Estimation: The Case of Pneumococcal Infection In Colombia. PMID- 26534301 TI - Cost Effectiveness of Drug Coated Balloon Versus Percutaneous Transluminal Balloon Angioplasty In The Treatment of Peripheral Arterial Disease In Lower Limbs In Brazil. PMID- 26534302 TI - Estimating The Supply And Demand Of Butantan Dengue Vaccine In Brazil. PMID- 26534303 TI - Economic Costs of Bacterial Meningitis: A Systematic Review. PMID- 26534304 TI - Evaluacion Economica Del Cardio-Desfibrilador Implantable Comparado Con La Terapia Farmacologica Optima Para El Tratamiento De Los Pacientes Con Falla Cardiaca En Colombia. PMID- 26534305 TI - Medical Devices - From Licensing To Coverage: Highlights From Argentina, Brazil, Colombia, And Mexico. PMID- 26534306 TI - Stapled Haemorrhoidopexy To Treat Hemorrhoids Grade Iii And Iv: A Systematic Review And Meta-Analysis. PMID- 26534307 TI - Potential Public Resource Savings In Brazil: The Somatropin Case. PMID- 26534308 TI - Cost Reduction For A Health System Through Decreasing Number Of Eligible Patients For Biological Therapy In Patients With Rheumatoid Arthritis Using The Treat To Target Recommendations. PMID- 26534309 TI - Competition And Strategic Regulation In The Argentine Pharmaceutical Market: A Comparative Study Of Six Therapeutic Classes. PMID- 26534310 TI - Treatment Patterns And Budgetary Impact of Chemotherapy Drugs In A Brazilian Private Health Plan (Php). PMID- 26534311 TI - Impact of Major Changes To The Brazilian Health Care System Utilizing The Heat Maps Project. PMID- 26534312 TI - Association of Adherence Status As Measured Using Two Single-Item Physician Administered Methods With Cardiovascular Risk In Patients Taking Antihypertensive Medication. PMID- 26534313 TI - Apixaban In Patients With Atrial Fibrillation: Patient Characteristics Of The Latin America Cohort From A Multinational Clinical Trial. PMID- 26534314 TI - Aretaeus: Retrospective Study Of Medication Usage Patterns Following The Diagnosis Of Type 2 Diabetes In Latin America. PMID- 26534315 TI - Hospitalization Costs of Type 2 Diabetes Mellitus (T2dm) Patients In A Public Hospital In Brazil. PMID- 26534316 TI - Financial Impact of Hospital Expenditure In Chronic Diseases For Seguro Popular. PMID- 26534317 TI - Economics of Diabetes Mellitus: Theory And Evidence For Brazilian Data In 2008. PMID- 26534318 TI - Barriers To Participation In Trials Of Cancer: A Survey On Clinical Research Perception. PMID- 26534319 TI - Proceso De Incorporacion De Farmacos A La Lista Positiva De Medicamentos (Lpm) Para Los Prestadores Integrales De Salud: Experiencia En El Ministerio De Salud Publica (Msp) De Uruguay. PMID- 26534320 TI - Rapid Increase of Health Litigation As A Means of Market Access For Innovative Medicines In Colombia And The Potential Role Of Health Technology Assessment. PMID- 26534321 TI - From Law To Reality: Measuring Time-To-Access Of Conitec Approved Drugs In Brazilian Public Health Care System (Sus) In The State Of Parana. PMID- 26534322 TI - An Eq-5d-5l Value Set Based On Uruguayan Population Preferences: Report Of The First Experience In Latin America. PMID- 26534323 TI - Standardization Process Of Raw Datasus And Consumption Analysis Of Oncology Therapies In The Brazil Public Health Care System: A Comparison Between Raw And Standardized Dataset In Colorectal And Lung Cancer. PMID- 26534324 TI - Comparison of Social Eq-5d Time Trade-Off Values In Chile 2008-2013: Do Geographical Differences Really Matter? PMID- 26534325 TI - Extracting And Using Data From Electronic Medical Records (Emr) To Monitor Quality Of Care And Prescription Patterns For Diabetes Prevention And Control In Outpatient Clinics Of Low And Mid Resources Countries: The Case Of Colima, Mexico. PMID- 26534326 TI - Cost-Effectiveness Analysis For Cervical Cancer Screening Using Hpv Tests In Brazil. PMID- 26534327 TI - An Undeveloped Picture: The Availability Of Utility Valuations In Latin America - How Will They Affect Qalys? PMID- 26534328 TI - What does Copd Exacerbation Means for Patients and for Healthcare? PMID- 26534329 TI - Espesor Corneal Central En Personas Sanas En Chile Y Correlacion Entre Distintos Metodos De Medicion. PMID- 26534330 TI - Modelo De Caracterizacion De Una Poblacion Afiliada A Una Asegurada En Colombia, Mediante Una Metodologia De Agrupacion Por Riesgo. PMID- 26534331 TI - Rivaroxavan+Enoxiparina Comparado A Enoxiparina En Pacientes Postoperador De Remplazo Articular De Rodilla Y Cadera. PMID- 26534332 TI - Exploring Variation in Cost-Effectiveness Estimates in Studies that Evaluate Adult Pneumococcal Vaccination in Latin America. PMID- 26534333 TI - Cost-Benefit Analysis of Whole Body Bone Scintilography in the Pre-Trasnplant Assesment of Adult Patients Beares of Hepatocellular Carcinoma in a Liver Tranaplant List in the South of Brazil. PMID- 26534334 TI - Morbidades E Custos Das Internacoes Hospitalares Do Sistema Unico De Saude Para Doencas Cronicas Em Maringa, Parana, Brasil. PMID- 26534335 TI - A Systematic Review of Economic Evaluations in Latin America: Assessing the Factors that affect Adaptation and Transferability of Results. PMID- 26534336 TI - Budget Impact Analysis of Drugs: Systematic Review. PMID- 26534337 TI - Propuesta De Un Indicador Que Valore La Carga De Enfermedad Desde La Perspectiva Del Riesgo Y Costos En Una Entidad Promotora De Salud Colombiana. PMID- 26534338 TI - Avaliacao Do Impacto Economico De Afastamentos Laborais Por Cancer De Mama . Analise Preliminar Singular Institucional. PMID- 26534339 TI - Cholic Acid Decreases the Distribution Coefficient of Simvastastin: A Potential for Increasing Simvastatin Bioavailability. PMID- 26534340 TI - Applied Comparison of Meta-Analysis Techniques. PMID- 26534341 TI - Perfil Del Gasto De Bolsillo En Medicamentos Esenciales En Panama, 2014. PMID- 26534342 TI - Tabagismo Em Universitarios: Uma Revisao Sistematica Da Literatura. PMID- 26534343 TI - Calibration of Piecewise Markov Models Using a Change-Point Analysis Through an Iterative Convex Optimization Algorithm. PMID- 26534344 TI - Trends of Research Related Brazil Published in Ispor Meetings: A Bibliometric Analysis from 1998 to 2014. PMID- 26534345 TI - Comparison of Chronic Hepatitis C Treatment Efficacy in Randomized Controlled Trials and Real-Life Studies - Influence of Study Design in the Sustained Virological Response: A Systematic Review of Published Literature. PMID- 26534346 TI - Engaging Hispanic Caregivers in Research: A Framework to Design Culturally Sensitive Approaches for Engagement in Patient-Centered Outcomes Research. PMID- 26534347 TI - Pharmacovigilance in Oncology: Knowledge and Perception on Adverse Events Reporting in Brazil. PMID- 26534348 TI - Eficacia Y Seguridad Del Uso Del Cetuximab En Pacientes Con Cancer Colorrectal Metastasico. PMID- 26534349 TI - O Metodo Paraconsistente Como Suporte As Tomadas De Decisao Em Saude. PMID- 26534350 TI - Trastuzumab Emtansine for Her2 Positive Breast Cancer Patients: an Updated Systematic Review. PMID- 26534351 TI - Optimizacion De La Quimioterapia En El Cancer Epidermoide De Pulmon Avanzado, Antimetabolitos O Taxanos? PMID- 26534352 TI - Comparacao De Tratamentos Para Cancer De Cabeca E Pescoco Ajustado Por Escore De Propensao: Radioterapia Versus Cirurgia+Radioterapia. PMID- 26534353 TI - Hematological Toxicities Associated with Pazopanib use in Cancer Patients: A Meta Analysis. PMID- 26534354 TI - Utilizacao Do Escore De Propensao Na Comparacao De Duas Opc'es Terapeuticas Em Pacientes Com Carcinoma Epiderm"Ide De Cabeca E Pescoco, Brasil 1998-2008. PMID- 26534355 TI - Eficacia De Docetaxel En Pacientes Con Cancer De Prostata Resistente A Castraci"N En Primera Linea De Tratamiento. PMID- 26534356 TI - Factores Pronosticos De Sobrevida En La Neoplasia Trofoblastica Gestacional. PMID- 26534357 TI - Impacto En La Supervivencia De La Gestion Y Atencion De Pacientes Con Cancer De Prostata. Instituto De Cancerologia Las Americas, Medellin (Colombia), 2013. PMID- 26534358 TI - Indicacao Do Medicamento Talidomida Para O Tratamento De Mieloma Multiplo: Uma Avaliacao Para Atualizacao Da Rename. PMID- 26534359 TI - Real-World Patient Characteristics, Treatment Patterns, and Survival among Locally-Advanced/Metastatic Alk+ Non-Small Cell Lung Cancer Patients in Latin America. PMID- 26534360 TI - The Economic Value Proposition of Hand-Sewn Suture Versus Stapled Anastomoses During Right Colon Surgery. PMID- 26534361 TI - Impacto Economico Del Uso De Vismodegib En El Tratamiento De Pacientes Con Carcinoma Basocelular Localmente Avanzado En Venezuela. PMID- 26534362 TI - Budget Impact Analysis of Carfilzomib for the Treatment of Relapsed Refractory Multiple Myeloma (Mm) in Mexico. PMID- 26534363 TI - Estimating the Budget Impact of Switching from Bortezomib Intravenous (Iv) to Bortezomib Subcutaneous (Sq) in the Treatment of Relapsed/Refractory Multiple Myeloma (Mm) in Mexico. PMID- 26534364 TI - A Budget Impact Model Estimating the Financial Impact of Increased Use of Generic Bortezomib Intravenous (Iv) in the Treatment of Relapsed/Refractory Multiple Myeloma (Mm) in Venezuela. PMID- 26534365 TI - Impact of Indiscriminate Use of Pump Infusion Set (Pis) on the Cost of Chemotherapy Treatments: A Cost Minimization Study. PMID- 26534366 TI - The Cost-Effectiveness of Bendamustine-Rituximab (Ben-R) Versus R-Chop for the First Line Treatment of Patients with Indolent Non-Hodgkin's Lymphoma (Inhl) in Colombia. PMID- 26534367 TI - Costo De Cancer De Prostata En Los Establecimientos Hospitalarios Del Peru. PMID- 26534368 TI - Costo De Cancer De Mama En Los Establecimientos De Salud Del Peru. PMID- 26534369 TI - The Relative Clinical and Economic Value of Ipilimumab in the Treatment of Metastatic Melanoma Versus Other Anti-Cancer Agents for Metastatic Diseases from a Brazilian Private Health Care System Perspective. PMID- 26534370 TI - Comparison of Cost of Treatment of Selected Cancers with Patented Drugs: India Versus its Neighbors. PMID- 26534371 TI - Cost Distribution Analysis Related to the Use of Tyrisine-Kinase Inhibitors (Tki) and the Combination of Pemetrexed/Cisplatin in the Treatment of Non-Small Cell Lung Cancer (Nsclc) Locally Advanced or Metastatic in Presence of Epidermal Growth Factor Receptor (Egfr) Mutations in a Mexican Institutional Context. PMID- 26534372 TI - Breast Cancer in Brazil: Hospitalization Costs. PMID- 26534373 TI - The Burden of Cancer in Jamaica. PMID- 26534374 TI - Costo De Cancer Gastrico Avanzado En Los Establecimientos Hospitalarios Del Peru. PMID- 26534375 TI - Costo De Cancer De Cuello Uterino En Los Establecimientos De Salud Del Peru. PMID- 26534376 TI - Impacto Economico Del Tratamiento De Cancer De Cuello Uterino. PMID- 26534377 TI - Cost Analysis of Voriconazole Versus Liposomal Amphotericin B for Primary Therapy of Invasive Aspergillosis among High-Risk Hematologic Cancer Patients in Brazil. PMID- 26534378 TI - Costo-Efectividad De Octreotide Lar Comparado Con Terapia De Soporte Usual Para El Tratamiento De Tumores Neuroendocrinos De Intestino Medio En Colombia. PMID- 26534379 TI - Economic, Public Health, And Humanistic Impact of a Quadrivalent Human Papillomavirus (Hpv6/11/16/18) Vaccination Program For Females And Males Age 9-11 Years in Mexico. PMID- 26534380 TI - Costo-Efectividad De Toracotomia Versus Videotoracoscopia En Pacientes Con Cancer De Pulmon De Celula No Pequena En Estadio I. PMID- 26534381 TI - Cost-Effectiveness of Ceritinib Versus Current Therapies for Chemotherapy Experienced Anaplastic Lymphoma Kinase Positive Non-Small Cell Lung Cancer Patients in Mexico. PMID- 26534382 TI - Panitumumab + Mfolfox6 Versus Bevacizumab + Mfolfox6 As First-Line Treatment of Wild-Type Ras Metastatic Colorectal Cancer: A Cost-Effectiveness Analysis from the Brazilian Private Healthcare System Perspective. PMID- 26534383 TI - Costo En Salud En La Intervencion De Prevencion Y Control De Cancer En El Instituto Nacional De Enfermedades Neoplasicas, 2010-2014. PMID- 26534384 TI - Evaluacion Economica De La Adicion De Pertuzumab Al Tratamiento De Trastuzumab+Docetaxel En Pacientes Con Cancer De Mama Her2 Positivo Metastasico Frente Al Tratamiento Con Trastuzumab+Docetaxel+Placebo, En El Contexto Venezolano. PMID- 26534385 TI - Evaluacion Economica Del Uso De Trastuzumab-Emtansine Para El Manejo De Pacientes Con Cancer De Mama Her2 Positivo Avanzado Con Tratamiento Previo Con Trastuzumab Y Un Taxano Por Separado O En Combinacion, Para Venezuela. PMID- 26534386 TI - Costo Efectividad De La Adici"N De Bevacizumab Al Esquema De Primera Linea De Quimioterapia Carboplatino + Paclitaxel En Pacientes Con Cancer De Pulm"N De Celula No Pequena No Escamosa Con Ecog Entre 0 Y 1. PMID- 26534387 TI - Analisis De Costo Efectividad Del Uso De Sorafenib En Pacientes Con Carcinoma Hepatocelular En Estadios Avanzados, Para El Contexto Ecuatoriano. PMID- 26534388 TI - Cost Effectiveness Analysis of Eribulin Mesylate (Halaven(r)) as a Treatment for Metastatic Breast Cancer in Mexico. PMID- 26534389 TI - Cost-Effectiveness of Vemurafenib Vs Ipilimumab Plus Dacarbacine in the Treatment of Non-Resectable Metastasic Melanoma with Braf600e Mutation in Colombia. PMID- 26534390 TI - Analisis De Minimizacion De Costos Del Uso De Trastuzumab Subcutaneo Frente A Trastuzumab Intravenoso En El Tratamiento De Cancer De Mama Temprano En Mujeres Con Her2 Positivo Para Venezuela. PMID- 26534391 TI - Evaluacion Economica De Leuprorelina 45 Mg En El Tratamiento De Cancer De Prostata Avanzado. PMID- 26534392 TI - Federal Purchases of Imatinib Mesylate, Trastuzumab and L-Asparaginase in Brazil, 2004-2013. PMID- 26534393 TI - Analisis Costo-Utilidad Del Manejo Integral De Las Pacientes Con Carcinoma De Seno Tratadas Con Reconstruccion De Seno Inmediata Vs. Diferida En Colombia. PMID- 26534394 TI - Evaluacion De Costo-Utilidad Del Uso De Cetuximab Como Ultima Linea De Tratamiento Del Cancer Colorrectal Metastasico. PMID- 26534395 TI - Health-Related Quality of Life in Patients with Localized Prostate Cancer Using Eq- 5d- 3l. PMID- 26534396 TI - Relationship Between Non Compliance to Claim Medication in Pharmacy and Incidence of Hospitalizations in Patients with Breast Cancer. PMID- 26534397 TI - Body Image and Sexual Problem in Young Breast Cancer Patients in South Indian Population. PMID- 26534398 TI - Differences In Pharmacists' Skin Cancer Prevention Strategies by Age and Gender. PMID- 26534400 TI - Identifying Current Treatment Practices In Non-Hodgkin's Lymphoma. PMID- 26534399 TI - Access Inequalities between Private and Public Insurance Among Cancer Patients: Results of a National Survey in Brazil. PMID- 26534401 TI - Patterns of Care For Metastatic Pancreatic Cancer: Real World Data From The Brazilian Private Health System (Phs). PMID- 26534402 TI - Diagnoses And Treatment Patterns For Non-Small Cell Lung Cancer (Nsclc) Within The Private Health System In Brazil. PMID- 26534403 TI - Utilizacion De Servicios De Salud Para El Tratamiento De Cancer De Estomago En Venezuela. PMID- 26534404 TI - Utilizacion De Servicios De Salud Para El Tratamiento De Cancer De Pulmon En Venezuela. PMID- 26534405 TI - High-Cost Oncologic Medication Access: Why Is Latin America Falling Behind? Case Study In Non-Small Cell Lung Cancer (NSCLC). PMID- 26534406 TI - Regulatory Approval for Oncology Products In Brazil: A Comparison Between The Fda And Anvisa Approval Timelines. PMID- 26534407 TI - Real World Data On Colony-Stimulating Factors (Csf) In Oncology: Patterns Of Use In Brazil. PMID- 26534408 TI - The impact of the u.s. Odac decision on avastin prescribing for metastatic breast cancer. PMID- 26534409 TI - Analisis Del Comportamiento Del Cancer De Mama En Una Aseguradora Colombiana. PMID- 26534410 TI - Exploratory Analysis of Apac Values Versus Recommended Treatment Guidelines For Metastatic Non-Small Cell Lung Cancer (Mnsclc) In The Brazilian Public Healthcare System. PMID- 26534411 TI - Evolution of Treatment Paradigms In Metastatic Castrate-Resistant Prostate Cancer. PMID- 26534412 TI - A Pharmacoeconomic Analysis of Costs From The Tumor Bank of The Instituto Nacional De Cancerologia Mexico. PMID- 26534413 TI - An Open Label, One Arm Study To Evaluate The Efficacy And Safety of Cerebrolysin In Patients With Acute Severe Ischemic Stroke In Mexico. PMID- 26534414 TI - Effectiveness of the st2 for prognosis in heart failure: systematic reviews. PMID- 26534415 TI - Costo-Efectividad De Un Programa De Nefroproteccion En Una Cohorte De 17.000 Pacientes Con Enfermedad Renal Cronica Afiliados A Una Aseguradora En Salud En Colombia. PMID- 26534416 TI - Change In The Demographic Profile And Impact In The Mortality Of Melanoma And Lung Cancer In Puerto Rico 2000-2010. PMID- 26534417 TI - Sobrevida De Cinco Anos E Fatores Associados Ao Cancer De Boca Para Pacientes Em Tratamento Oncol"Gico Ambulatorial Pelo Sistema Unico De Saude, Brasil. PMID- 26534418 TI - Budget Impact Analysis of The Use of Tenecteplase In The Treatment of Acute Myocardial Infarction In Mexico. PMID- 26534419 TI - Burden of Heart Failure In Latin America: A Systematic Review And Meta-Analysis. PMID- 26534420 TI - Budget Impact Analysis of The Use of Alteplase In The Treatment of Acute Ischaemic Stroke In Mexico. PMID- 26534421 TI - Impacto Orcamentario Do Everolimo, Sirolimo E Tacrolimo Para Imunossupressao Em Transplantados Cardiacos No Sistema Publico De Saude Do Brasil. PMID- 26534422 TI - Antipsychotic Exposure And Risk of Stroke: A Systematic Review And Meta-Analysis of Observational Studies. PMID- 26534423 TI - A Physician-Centered Intervention To Improve Control of Blood Pressure: Systematic Review And Meta-Analysis. PMID- 26534424 TI - Cost-Effectiveness of Apixaban Versus Other New Oral Anticoagulants And Warfarin for Stroke Prevention In Atrial Fibrillation In Venezuela. PMID- 26534425 TI - Resource Use And Costs of Congestive Heart Failure Hospitalizations: A Retrospective Cohort Study In Argentina. PMID- 26534426 TI - Costo-Efectividad De Los Nuevos Anticoagulantes Orales En Pacientes Con Fibrilacion Auricular No Valvular En Colombia. PMID- 26534427 TI - Costo - Efectividad De Apixaban Con Otros Noacs (Dabigatran Y Rivaroxaban) En El Tratamiento De La Fibrilacion Auricular No Valvular (Fanv) En Pacientes De La Seguridad Social De Peru. PMID- 26534428 TI - Evaluation of The Annual Cost of Fixed-Dose Combination Drugs Used In Treatment of Hypertension In India: An Economic Perspective. PMID- 26534429 TI - Costo De Hipertension Arterial En Los Establecimientos De Salud Del Peru. PMID- 26534430 TI - Evaluacion De Costo De Efectividad Y Costo Utilidad Del Uso De Rivaroxaban En Pacientes Sometidos Quirurgicamente Por Reemplazo De Cadera Y Rodilla, Frente A Enoxaparina En El Contexto Ecuatoriano. PMID- 26534431 TI - Analisis de costo-efectividad de la warfarina vs. Dabigatran etexilato en fibrilacion auricular en ecuador. PMID- 26534432 TI - Cost-Effectiveness of Apixaban Versus Other Noacs And Warfarin, During Hospitalization In The Private Brazilian Health System. PMID- 26534433 TI - Cost-Effectiveness of Palivizumab In Children With Congenital Heart Disease In Mexico. PMID- 26534434 TI - Analisis De Costo Efectividad Y Costo Utilidad De La Adicion De Rivaroxaban En El Tratamiento De Pacientes Con Sindrome Coronario Agudo En Colombia. PMID- 26534435 TI - Indicadores De Nefroporteccion: Herramienta Para Evaluar Resultados En Gestion De Riesgo Para Pacientes Con Enfermedad Renal Cronica, Hipertension Y/O Diabetes Mellitus En Colombia. PMID- 26534436 TI - Gastos En Salud En La Intervencion De Tratamiento Y Control De Pacientes Con Hipertension Arterial Del Programa Presupuestal De Enfermedades No Transmisibles En El Peru-2012-2014. PMID- 26534437 TI - Design And Evaluation of Transdermal Patch of Felodipine. PMID- 26534438 TI - Economic Evaluation for The Decision Making Process of Implementing of Pharmaceutical Care for The Treatment of Hypertension In The Brazilian Health System: Stage I - Direct-Costs Analysis. PMID- 26534439 TI - Association Among Calendar Packaging And Medication Adherence: Findings From A Focus Group Discussion Among Hypertensive Patients In Penang, Malaysia. PMID- 26534440 TI - Evaluacion Economica Del Uso De Rivaroxaban Como Profilaxis En Cirugia De Reemplazo Total De Cadera Y/O De Rodilla Frente A Enoxaparina, En Colombia. PMID- 26534441 TI - Effectiveness and Side Effects of Oseltamivir for Influenza Treatment: A Meta Analysis of Meta-Analysis. PMID- 26534442 TI - Consumo De Benzodiazepinas En La Poblacion Geriatrica Atendida En El Hospital Clinico Regional De Concepcion. PMID- 26534443 TI - Evaluaci"N De La Prescripci"N Medica De Antihipertensivos En Los Medicos Cardi"Logos Del Hospital Nacional Edgardo Rebagliati Martins, Lima (Peru). PMID- 26534444 TI - Mortality Due To Cardiovascular Disease In Colombia, 1998-2011. PMID- 26534445 TI - Causas Y Factores Asociados Al Delirium En Pacientes Mayores De 65 Anos Que Solicitan Atencion Medica De Urgencias. PMID- 26534446 TI - Contraception Patterns In Brazil: 2012 National Survey Data. PMID- 26534447 TI - Mortality In A University Pediatric Hospital In Colombia 2000 - 2014. PMID- 26534448 TI - Determinantes Socioeconomicos De La Nutricion Infantil En Colombia. PMID- 26534449 TI - The Issue for Sexuality After Cervix Cancer Treatment Among Woman. PMID- 26534450 TI - Consensus of Clinical Practices And Associated Costs To Diagnose And Treat Genital Warts Caused By Human Papilloma Virus (Hpv) In Ecuador: Results From A Panel Of Experts. PMID- 26534451 TI - Costo En Salud De La Intervenci"N En La Atenci"N Del Parto Normal En El Peru 2009 Y 2014. PMID- 26534452 TI - Evaluacion De Costo-Efectividad De Un Programa De Cuidados Integrales Post-Alta Tipo Hospital De Dia Para Adultos Mayores Comparado Con El Manejo Estandar En El Sistema Publico. PMID- 26534453 TI - Cost-Effectiveness Of Palivizumab In Premature Infants And Children With Chronic Lung Disease In Mexico. PMID- 26534454 TI - Economic Evaluation of Ulipristal Acetate For The Treatment of Patients With Moderate And Severe Symptoms of Uterine Fibroids Before Surgery In Mexico. PMID- 26534455 TI - Costo En Salud Del Programa Presupuestal De Salud Materno Neonatal Para Reducir La Tasa De Mortalidad Materna Y Neonatal En El Peru, 2009 - 2014. PMID- 26534456 TI - An Eq-5d-3l Value Set For Trinidad And Tobago. PMID- 26534457 TI - Evaluacion Costo-Efectividad Del Uso Del Regimen Combinado De Mifepristona Y Misoprostol Para Aborto Incompleto O Diferido En Mujeres Con Embarazos De Hasta 12 Semanas De Gestacion En Instituciones De Salud Publica En Mexico. PMID- 26534458 TI - Cost-Effectiveness of Quadrivalent Human Papilloma Virus (Hpv6/11/16/18) Vaccination In Ecuador. PMID- 26534459 TI - Knowledge And Contraceptive Use Among Currently Married Women Aged 15-49 In Western Kenya. PMID- 26534460 TI - Cambios En La Percepcion De La Calidad De Vida Relacionada Con La Salud Por Diferencias En El Acceso Y El Regimen De Afiliacion En Bogota. PMID- 26534461 TI - Health Related Quality Of Life In A Community Dwelling Elderly Sample In Brazil. PMID- 26534462 TI - Interregional Valuation Of Patient Satisfaction With Pharmaceutical Care As A Tool For Increasing Quality Management In Community Pharmacy And Patients Quality Of Life. PMID- 26534463 TI - Valuation of Patient Satisfaction With Pharmaceutical Care As A Tool For Increasing Quality Management In Community Pharmacy And Patient's Quality Of Life. PMID- 26534464 TI - Knowledge, Attitude And Practices Towards Medication Use Among Post-Graduate Pharmacy Students. PMID- 26534465 TI - Characteristics of Pediatric Patients With Relapsing Remitting Multiple Sclerosis Taking Disease Modifying Agents. PMID- 26534466 TI - Envelhecimento Populacional E As Politicas Publicas De Saude No Brasil. PMID- 26534467 TI - Avaliacao Da Eficacia E Seguranca Do Ibuprofeno Versus Demais Anti-Inflamat"Rios Nao Esteroidais, No Tratamento De Recem-Nascidos Prematuros Com Persistencia Do Canal Arterial. PMID- 26534468 TI - Impact of Negative Symptoms on Quality of Life in Patients with Schizophrenia. PMID- 26534469 TI - Generic Drugs Adoption In Turkish Healthcare System. PMID- 26534470 TI - Avaliacao De Tecnologias No Tratamento Da Depressao Maior: Overview Sobre A Eficacia E Seguranca Da Duloxetina, Venlafaxina E Trazodona Comparados A Fluoxetina. PMID- 26534471 TI - Evidence of Efficacy and Safety of Methylphenidate in the Treatment of Children or Adolescents with Attention Deficit Disorder and Hyperactivity (Adhd). PMID- 26534472 TI - Comparative Tolerability of New Antipsychotic Drugs in Schizophrenia: A Systematic Review and Meta-Analysis. PMID- 26534473 TI - Lagrange Method for Budget Optimization Analysis in Resource Allocation for Antipsychotic Therapies in Colombia. PMID- 26534474 TI - Costo De Enfermedades Mentales Prevalentes En Peru. PMID- 26534475 TI - Costs of Relapse of Schizophrenia for the Argentinian Health System. PMID- 26534476 TI - Uso De Recursos Medicos En La Intervencion De Examenes De Tamizaje Y Tratamiento De Pacientes Con Problemas Y Trastornos De Salud Mental 2012-2013. PMID- 26534477 TI - Evaluacion Economica Del Seguimiento Farmacoterapeutico En Pacientes Con Trastorno Afectivo Bipolar I. PMID- 26534478 TI - Individual and Societal Burden of Non-Adherence to Antidepressants in Brazil. PMID- 26534479 TI - Healthcare Access Differences between Public and Private Insurance Coverage Among Patients with Depression in Brazil. PMID- 26534480 TI - Costs of Relapse of Schizophrenia for Colombian Health System. PMID- 26534481 TI - Costo De Tuberculosis En Los Establecimientos De Salud Del Peru. PMID- 26534482 TI - Cost of Illness (Out of Pocket Costs Paid By Patient) for T.B in Quetta City, Pakistan. PMID- 26534483 TI - Public Health and Economic Impact of 13-Valent Pneumococcal Conjugate Vaccine (Pcv13) in Public and Private System Versus Ppsv23 and No Vaccination in Older Adults. PMID- 26534484 TI - Out Hospital Drug Consumption in Therapy of Obstructive Pulmonary Disease in Serbia in the Period from 2007 to 2012. PMID- 26534485 TI - Fluticasone Propionate Versus Budesonide or Beclomethasone As Monotherapy Treatment for Asthma Patients - A Systematic Review. PMID- 26534486 TI - Evaluation Analysis of Smoking Population in Ulaanbaatar. PMID- 26534487 TI - Tratamiento Ambulatorio Versus Hospitalario Relacionado A Agudizaciones En Pacientes Con Asma Desde Una Perspectiva Institucional Publica Mexicana. PMID- 26534488 TI - Evaluacion Economica De Los Principales Esteroides Intranasales Utilizados Para El Tratamiento De Pacientes Pediatricos Con Rinitis Alergica En Colombia. PMID- 26534489 TI - Costo - efectividad de la combinacion de glicopirronio/indacaterol vs. Salmeterol/ fluticasona (combinacion de dosis fija - cdf) en el manejo de los pacientes con enfermedad pulmonar obstructiva cronica (epoc) en colombia (sur america). PMID- 26534490 TI - A Prospective Prescription Cost Analysis of Asthma Medication. PMID- 26534491 TI - Burden of Cost in Bronchiolitis Obliterans Syndrome (Bos): Predictions for the Next Decade. PMID- 26534492 TI - Cost-Effective Evaluation of Pirfenidone for Treating Idiopathic Pulmonary Fibrosis in Mexico. PMID- 26534493 TI - Evaluacion economica de tres terapias para la enfermedad pulmonar obstructiva cronica en chile. Analisis de costo utilidad. PMID- 26534494 TI - Impact of a Pharmacotherapeutic Follow-Up Program on the Cost-Month-Patient, Stratified By Risk-Pharmacological Type. PMID- 26534495 TI - Revision Sistematica De Estudios De Costo Efectividad De Intervenciones Sanitarias Para La Cesacion Del Habito Tabaquico. PMID- 26534496 TI - Characteristics and Outcomes of Patients with Dengue Viral Infection During The Hospitalization At Tertiary Care Hospital. PMID- 26534497 TI - Determinantes Socioeconomicos De La Obesidad En Escolares Y Adolescentes En Colombia: Un Analisis Regional. PMID- 26534498 TI - Cost-Minimisation Analysis of Dexmedetomidine Versus Propofol in Mechanical Ventilated Patients at Icu. PMID- 26534499 TI - Systematic Review and Cost-Effectiveness Analysis of Drug Used in Obesity Treatment in Brazil, Under Health System Perspective. PMID- 26534500 TI - Cost-Effectiveness of Romiplostim As First-Line Primary Immune Thrombocytopenia (Itp) Treatment in Adult Splenectomised Patients Who are Refractory to Other Treatments and As Second-Line Itp Treatment in Adult Non-Splenectomised Patients Where Surgery is Contraindicated in Colombia. PMID- 26534501 TI - Burden of Cost in Chronic Graft Versus Host Disease Following Hematopoietic Stem Cell Transplantation: Predictions for the Next Decade. PMID- 26534502 TI - Acromegaly Patients with Inadequate Response to Maximum Dose Octreotide-Lar Who Progress to Treatment with Pegvisomant: Economic Evaluation and Incremental Budget Impact Analysis from the Public Perspective to Sao Paulo State. PMID- 26534503 TI - Matters of Weight: Financial Burden of Overweight and Obesity in Mexico. PMID- 26534504 TI - Nuevas Moleculas Registradas En Chile Durante El Ano 2014. PMID- 26534505 TI - Cost-minimization analysis of the carboxymaltose ferric (i.v.) Compared with sacarato ferric (i.v.) in the treatment of anemia under suplementary health care perspective. PMID- 26534506 TI - Cost-Minimization Analyses of Adalimumab Compared with Selective Immunosuppressive Cytokines Blockers and Inhibitors of Tumor Necrosis Factor Alpha Indicated for the Treatment of Rheumatoid Arthritis, Psoriasis and Crohn's Disease in the Private Market in Mexico. PMID- 26534507 TI - Weight Loss Treatment Patterns in Mexico. PMID- 26534508 TI - The Burden of Obesity in Mexico: Prevalence, Comorbidities, and Associations With Quality of Life, Resource Utilization and Productivity. PMID- 26534509 TI - Leptospirosis; A Zoonotic, Morbid and Fatal Disease: A Record Viewing Study. PMID- 26534510 TI - Acessibilidade De Obesos M"Rbidos Usuarios Do Sistema Publico De Saude No Brasil. PMID- 26534511 TI - Mortality Rate and Premature Mortality Due to Systemic Erythematosus Lupus (Sle) in Latin America, Us and England and Wales. PMID- 26534512 TI - Crisis Economica Y Gradiente Social De La Obesidad En Espana. PMID- 26534513 TI - Caracterizacion De La Poblacion Con Diagnostico De Hemofilia De Un Programa De Seguimiento A Pacientes De Un Grupo De Empresas Administradoras De Planes De Beneficio Colombianas. PMID- 26534514 TI - Costo En Salud En La Intervenci"N De Suplemento De Hierro En Ninos De 6 A Menos De 36 Meses De Edad Para Reducir La Anemia En El Peru, 2009-2014. PMID- 26534515 TI - Analisis Del Comportamiento De La Drepanocitosis En Colombia, Desde La Perspectiva Del Uso De Servicios De Salud. PMID- 26534516 TI - Anthropometric Study on Mongolians with Metabolic Syndrome. PMID- 26534517 TI - Perfil Alimentario Segun Estado Nutricional De Estudiantes Universitarios De Valparaiso, Chile. PMID- 26534518 TI - Meses Evitados De Dialisis En Una Poblaci"N Con Enfermedad Renal Cr"Nica Estadio 5 Con Intervenci"N Predialitica En Colombia. PMID- 26534519 TI - Analisis Comparativo De Los Procesos De Decision De Cobertura De Medicamentos Para Enfermedades Raras En Los Paises De La Ocde. PMID- 26534520 TI - Costo Efectividad De La Hemodialisis En Los Prestadores De Servicios De Dos Aseguradoras A Traves De La Evaluacion De Indicadores Minimos Para El Analisis De Resultados Clinicos De La Terapia Dialitica En Colombia. PMID- 26534521 TI - Anemia Treatment Cost in Patients with Chronic Kidney Disease (A-Ckd) In The Mexican Social Security Institute (Imss). PMID- 26534522 TI - Short And Long-Term Economic Impact of Secondary Hyperparathyroidism Treatment in Chronic Kidney Disease in Carlos Andrade Marin Hospital (Ecuador). PMID- 26534523 TI - Evaluacion Economica Del Manejo Farmacologico Del Paciente Con Hiperplasia Prostatica Benigna En Colombia. PMID- 26534524 TI - Analise De Custo-Utilidade Em Pacientes Com Insuficiencia Renal Cronica Submetidos A Terapia Renal Substitutiva (Trs). PMID- 26534525 TI - Dialise Planejada E A Utilizacao Regular Da Atencao Primaria A Saude Entre Os Pacientes Diabeticos Do Municipio De Belo Horizonte, Minas Gerais, Brasil. PMID- 26534526 TI - Gasto de Bolsillo en Salud y Medicamentos en Chile: Analisis Comparativo de Los Periodos 1997, 2007 y 2012. PMID- 26534527 TI - Determinant Factors of the Administrative Pathway to Access Medicines in the Brazilian Health System. PMID- 26534528 TI - Patients' choice of providers as a signal of quality of care. Evidence of twelve public hospitals in the province of buenos aires, argentina. PMID- 26534529 TI - Biosimilar Trials: Patient Recruitment and Barriers in Brazil. PMID- 26534530 TI - Efeitos da Atencao Farmaceutica nos Resultados em Saude Dos Pacientes: Revisao Sistematica Com Meta-Analises. PMID- 26534531 TI - Avaliacao das Demandas da Isotretinoina Para o Tratamento da Acne Grave no Sistema Unico de Saude (Sus), Brasil. PMID- 26534532 TI - Analise da Producao de Avaliacao de Tecnologias Em Saude do Centro Colaborador do Sistema Unico de Saude (Sus), Brasil - Uma Parceria Entre o Governo E A Academia. PMID- 26534533 TI - Politicas de Acesso ao Medicamento no Sistema Publico de Saude no Brasil. PMID- 26534534 TI - A Perspective on the use of Health Technology Assessment in Brazil and Mexico. PMID- 26534535 TI - A Participacao do Departamento de Ciencia e Tecnologia do Ministerio da Saude Na Revisao e Atualizacao da Rename. PMID- 26534536 TI - Prescribing Patterns for upper Respiratory Tract Infections: A Prescription Review of Primary Care Practice in Kota Setar District, Kedah, Malaysia. PMID- 26534537 TI - La Canasta Basica de Medicamentos Como Estrategia Para Mejorar el Acceso y Costo de Los Medicamentos en Panama. PMID- 26534538 TI - Gasto de Bolsillo y Gasto Catastrofico en Salud en Hogares de Cartagena de Indias, Colombia. PMID- 26534539 TI - Equity in Access to High Cost Drugs in Uruguay. PMID- 26534540 TI - Determinantes y Barreras Socioeconomicas del Acceso A Los Servicios de Salud en Las Regiones de Colombia. PMID- 26534541 TI - Access to Healthcare Among International Immigrants in Chile: Repeated Cross Sectional Analysis of Casen Survey 2006-2009-2011. PMID- 26534542 TI - Pesquisa Nacional de Acesso a Medicamentos no Brasil - Percepcao dos Usuarios da Atencao Basica do Sistema Unico de Saude. PMID- 26534543 TI - Identificacao Sistematica de Lacunas de Pesquisa no Ambito da Saude Mental Pelo Ministerio da Saude do Brasil. PMID- 26534544 TI - Impacto Orcamentario do Everolimo e Sirolimo para Imunossupressao em Transplantados Hepaticos no Sistema Publico de Saude do Brasil. PMID- 26534545 TI - Differences in Price of Medicines Available from Pharmaceutical Companies and "Jan Aushadhi" Stores. PMID- 26534546 TI - Potentially inadequate Medication (Pim) Effects on Adverse Drug Events (Ades) and Costs: Hospital Universitario Austral (Hua). PMID- 26534547 TI - Retos Metodol"Gicos de Las Politicas de Fijaci"N de Precios de Referencia Para Grupos de Medicamentos de Utilidad Terapeutica Similar. PMID- 26534548 TI - Scoping Review of Publicly Available Performance Information in Argentina, Chile and Colombia. PMID- 26534549 TI - Caracterizacion de Pacientes Con Multiples Enfermedades Cronicas desde la Perspectiva Del Aseguramiento en Colombia. PMID- 26534550 TI - Institutional Development Program of the Brazilian National Health System. PMID- 26534552 TI - Costos Unitarios de Servicios Brindados Por Una Unidad de Salud de la Familia: Evidencia en el Caso Paraguayo. PMID- 26534551 TI - Immunisation in Latin America: Factors Preventing Uptake of Cost-Effective Vaccines. PMID- 26534553 TI - Pharmaceutical Cost-Containment Strategies - Opinions of the Pharmaceutical Industry and Hta Bodies in Latin America. PMID- 26534554 TI - Evaluacion Economica del uso de La Gasa Sintetica Frente a la Gasa de Algodon de Pieza Unica En El Manejo de Heridas en Colombia. PMID- 26534555 TI - Analisis del impacto economico de la adopcion de una tecnica minimamente invasiva para la reparacion de hernia ventral. Perspectivas de 4 paises de latinamerica. PMID- 26534556 TI - Determinacao do Impacto Orcamentario no Modelo de Pagamento de Medicamentos Em Uma Operadora de Planos de Saude: Buscando Novas Estrategias Para Minimizar Os Custos. PMID- 26534557 TI - O Processo de Contratualizacao do Hospital Universitario da Ufjf no Contexto do Sus. PMID- 26534558 TI - Evaluacion Economica del uso de Un Paquete de Tres Torundas de Algodon Esteriles Frente a Toallas Impregnadas Con Solucion Antiseptica Como Estrategia de Antisepsia en Venopuncion. PMID- 26534559 TI - Cambio de Copago de Medicamentos en Espana y Desigualdad. PMID- 26534560 TI - Study on Quality of Nursing Care and Assessment of Safety. PMID- 26534561 TI - Implicac'es Entre os Gastos Com a Producao Ambulatorial em Media Complexidade E A Atencao Basica. PMID- 26534562 TI - Analisis Del Modelo de Toma de Decisiones Sobre Cobertura de Medicamentos en Chile. PMID- 26534563 TI - Considerations for the Adoption of the who-Choice Cost-Effectiveness Threshold in Latin America. PMID- 26534564 TI - Climate Measurement of Patient Safety in the Health Service-Portuguese Version of the Safety Attitudes Questionnaire Short Form 2006. PMID- 26534565 TI - Clinical Trial Trends in Latin America: communicable Versus Non-Communicable Disease. PMID- 26534566 TI - Analisis de Visiones y Percepciones de Potenciales Beneficiarios de la Institucionalizacion de un Proceso de Evaluacion de Tecnologias Sanitarias En Chile: un Estudio Cualitativo. PMID- 26534567 TI - Benchmarking Health Technology Assessment (Hta) Agencies for Setting Standards on Pharmacoeconomic, Pricing, Evidence, and General Submission Requirements: development of a Multidimensional Rating Scale. PMID- 26534568 TI - Brazilian Guideline for Academic Detailing: a Need to Improve Health Care. PMID- 26534569 TI - State and Prospects of Pharmacoeconomics Training in Ukraine. PMID- 26534570 TI - Governance, Decision-Making, and Universal Health Coverage: perceptions from Chilean Health Decision-Makers. PMID- 26534571 TI - Defining Market Access in Brazil: the Pharma Professionals' Perspective. PMID- 26534572 TI - Instrumentos Para la Incorporacion de la Evaluacion Economica, el Impacto Presupuestario y Los Esquemas de Pago por Resultados en el Servicio Catalan de Salud (Espana). PMID- 26534573 TI - Configuracion Espacial de La Vulnerabilidad Social de Inmigrantes Internacionales en Iquique 2002-2012 y Su Relacion Con La Localizacion de Red de Atencion Primaria de Salud. PMID- 26534574 TI - A Forma (in) Adequada do Aparato Vocal. PMID- 26534575 TI - A Quantitative Analysis of Ten Health Technology Assessment (Hta) Agencies for Attributes Driving Transparency of the Organization. PMID- 26534576 TI - A Streamlined Approach to Ethics Review in Brazil. PMID- 26534577 TI - Disinvestment Initiatives in Latin American Countries (Lac): a Systematic Literature Review (Slr). PMID- 26534578 TI - Estudio de La Implementacion de la Exigencia de Bioequivalencia Sobre el Consumo de Medicamentos Durante Agosto 2009 a Noviembre 2014 en Chile. PMID- 26534579 TI - Desarrollo e Implementaci"n de un Modelo de Auditoria Medica Basado en Garantia de Calidad y Supervisi"n Participativa en Ecuador. PMID- 26534580 TI - Incorporacion de Los Resultados de La Evaluacion Economica en Las Recomendaciones de Las Guias de Practica Clinica en Colombia. PMID- 26534581 TI - Campanas de Medicamentos; Instrumento Publicitario Que Atenta Contra Los Genericos y el Acceso a Medicamentos. PMID- 26534582 TI - The Structure of The Choroid Plexus of Adult and Children Brain Ventricles. PMID- 26534583 TI - Son utiles los enfoques de separacion de funciones y cadena de valor para mejorar la organizacion, regulacion y acceso a medicamentos? PMID- 26534584 TI - Aumento del Riesgo de Cancer por Efecto de Variaciones Acumuladas en la Exposici"n a la Radiacion en Estudios de Radiologia Convencional y Tomografia Computarizada en Pacientes Pediatricos. PMID- 26534585 TI - Developing Bilingual Certificate Programs in Clinical Pharmacy. PMID- 26534586 TI - Envolvimento do Publico no Processo de Incorporacao de Tecnologias no Sus. PMID- 26534587 TI - Analytical Representation of Utility Functions for Cervical Screening Strategies In Their Evaluation With "Cost-Utility" Method. PMID- 26534588 TI - Economic Benefits Associated With Nt-Probnp Test In Brazil and Mexico. PMID- 26534589 TI - Budget impact analysis of drug coated balloon vs. Percutaneous transluminal balloon angioplasty in the treatment of peripheral arterial disease in lower limbs in brazil. PMID- 26534590 TI - Reducing Insulin Syringe Reuse Can Help Lower Cost of Insulin Waste In Brazil. PMID- 26534591 TI - Budget Impact Model for Cervical Cancer Screening Using Hpv Tests In Chile. PMID- 26534592 TI - Effectiveness of The Antibiotic-Impregnated Catheters In Ventricular Drainage In Hydrocephalus Patients - A Systematic Review. PMID- 26534593 TI - Evaluaci"N De Costo-Efectividad De La Implementaci"N De Monitoreo Ambulatorio De Presi"N Arterial Versus Perfil De Presi"N Arterial Para El Diagn"Stico De Hipertensi"N En El Sistema Publico Chileno. PMID- 26534594 TI - Evaluacion Economica Completa Del Escaner Cervical Avanzado Como Agente Diagnostico En Pacientes Mexicanas Con Riesgo Asociado A Cancer De Cervix Por Vph En Mexico. PMID- 26534595 TI - Cost-Effectiveness of The Use of 18fdg-Pet/Ct In The Detection of Recurrent Differentiated Thyroid Cancer. PMID- 26534596 TI - Standards Of Surgical Materials Usage In Anterior Cruciate Ligament (Acl) Surgery In Brazil Under The Perspective Of The Private Health Care System. PMID- 26534597 TI - Costo Efectividad De Multiples Alternativas Diagn"Sticas En Pacientes Con Sospecha De Cancer De Pulm"N En Colombia. PMID- 26534598 TI - Comparacao De Custos E Efetividade Entre Ml- Flow E Baciloscopia Para Auxilio Diagn"Stico E Tratamento Da Hanseniase. PMID- 26534599 TI - Analisis De Costo Efectividad Del Diagnostico De La Distrofia Muscular De Duchenne O Becker En Colombia. PMID- 26534600 TI - Costo-Efectividad De La Cuantificaci"N De La Actividad Enzimatica En Leucocitos En Comparaci"N A Su No Realizaci"N Para La Confirmaci"N Diagn"Stica De La Mucopolisacaridosis Tipo Iva En Colombia. PMID- 26534601 TI - Costo-Efectividad Del Desfibrilador Externo Automatico (Dea) Comparado Con Reanimacion Cardiopulmonar Basica (Rcp) En Colombia. PMID- 26534602 TI - Custo-Efetividade Da Cintilografia Ossea De Corpo Inteiro Na Avaliacao Pre Transplante Hepatico De Pacientes Com Carcinoma Hepatocelular Na Regiao Sul Do Brasil. PMID- 26534603 TI - Economic Evaluation For The Rapid Test Dpp(r) Hiv-Syphilis Assay With Immunochromatography In Pregnant Women In Mexico. PMID- 26534604 TI - Cost-Effectiveness Analysis of One-Piece Drainable Pouch Versus Two-Piece Drainable Pouch For Colostomates Under The Perspective of Patient's Out-of-Pocket Expenses, In Brazil. PMID- 26534605 TI - Cost utility analysis of spinal cord stimulation vs. Reoperation in the treatment of failed back surgery syndrome in colombia. PMID- 26534606 TI - Evalucion Economica Completa Del Sistema De Terapia De Radiacion Con Rayos X Para El Tratamiento Cancer De Prostata De Alto Riesgo En Mexico. PMID- 26534607 TI - Psychometric Analysis And Validation of The Patient Satisfaction With Orthopaedic And Prosthetic Medical Devices, Modul Client Satisfaction With Device (Csd). PMID- 26534608 TI - Improving Patient Quality of Life By Verifying And Enhancing Quality of Orthopaedic And Prosthetic Medical Devices. PMID- 26534609 TI - Economic Value of Stemi Program Investment In Sao Paulo, Brazil. PMID- 26534610 TI - Consulta Aos Membros De Agencias Internacionais De Ats Como Estrategia De Intercambio Do Conhecimento Produzido - O Caso Do Pet-Tc. PMID- 26534611 TI - Economic Impact of A Volumetric Infusion Pump (Infusomat(r) Space) + Central Alarm Management (One View), In The Risk Prevention In Infusion Therapy In The Intensive Care Unit (Icu) In Mexico. PMID- 26534612 TI - La Hipoglucemia Incrementa El Gasto En Salud Y Deteriora La Productividad De Pacientes Con Diabetes Tipo 1 Y Tipo 2. PMID- 26534613 TI - Efetividade E Seguranca Da Glargina Vs Detemir E Nph No Tratamento De Pacientes Com Diabetes Tipo 1 - Revisao Sistematica E Metanalise. PMID- 26534614 TI - Efficacy And Safety of Antidiabetic Drugs Available on Brazilian Public Health System (Sus) - Regular Insulin, Nph Insulin, Metformin, Glibenclamide And Gliclazide - In Treatment of Type 2 Diabetes (T2dm) - Systematic Review And Meta Analysis. PMID- 26534615 TI - Efetividade Clinica Comparativa Do Analogo De Insulina Glargina Para Tratamento De Pacientes Acometidos Por Diabetes Mellitus Tipo 1. PMID- 26534616 TI - Costo De Diabetes Mellitus No Complicada En Los Establecimientos De Salud Del Peru. PMID- 26534617 TI - Impacto Presupuestario De Incorporar Linagliptina Para El Tratamiento De La Diabetes En Argentina. PMID- 26534618 TI - Analisis De Impacto Presupuestal De Detemir En Pacientes Diabeticos Tratados Con Insulinas Analogas. PMID- 26534619 TI - There Is Evidence of Increased Risk of Cancer In Patients Using Human Insulin Analogue Glargine For Treatment of Diabetes Mellitus - Overview Based Evaluation. PMID- 26534620 TI - Economic Burden of Type 2 Diabetes Mellitus For Mexico. PMID- 26534621 TI - Long-Acting Insulin Analogues A Systematic Review of Systematic Reviews. PMID- 26534622 TI - Uso de recursos y costos relacionados al tratamiento de complicaciones de la diabetes mellitus tipo 2 (dmt2) en colombia. Una estimacion basada en guias de practica clinica (gpc). PMID- 26534623 TI - Estimacion Del Costo De Tratamiento De Un Evento Moderado Versus Uno Severo De Hipoglucemia En Pacientes Con Diabetes Mellitus Tipo 2 En Mexico Desde La Opinion De Expertos. PMID- 26534624 TI - Incidencia E Importes Asociados A Las Atenciones Por Hipoglicemia Grave En Pacientes Con Diabetes Mellitus Tipo 2 En Tratamiento Con Antidiabeticos Orales En Ecuador. PMID- 26534625 TI - Cost-Effectiveness of Canagliflozin (Cana) Versus Sitagliptin (Sita) As Add-On To Metformin Plus Sulfonylurea In Patients With Type 2 Diabetes Mellitus (T2dm) In Brazil. PMID- 26534626 TI - Analisis De Costo-Efectividad De La Educacion De Pacientes Con Diabetes Tipo 2 Por Pares. PMID- 26534627 TI - Costo Efectividad Y Costo Utilidad Del Uso De Undecanoato De Testosterona Inyectable En Pacientes Con Hipogonadismo Y Diabetes Mellitus Tipo 2 En Colombia. PMID- 26534628 TI - Diabetes Duration and Severity and Labour Market Outcomes In Mexico. PMID- 26534629 TI - Type II Diabetes Prevalence, Hypoglycemia Episodes, and Hba1C Control In Brazil. PMID- 26534630 TI - Recent Hypoglycemia Episodes Are Associated With Poorer Quality Of Life, Healthcare Resource Use, And Work Impairment Among Patients With Type II Diabetes In Brazil. PMID- 26534631 TI - Use of Complementary And Alternative Medicines (Cam) In Diabetics Patients In Quetta. PMID- 26534632 TI - Purpose, Belief And Rate of Disclosure of Cam Use Among Diabetic Patients In Quetta, Pakistan. PMID- 26534633 TI - Resource Use And Direct Costs For Managing Hcv Genotype 1 Patients In Colombia. PMID- 26534634 TI - Willingness To Pay For Improved Clinical Outcomes And Reduced Treatment Burden Associated With Insulin Treatment In People With Type 2 Diabetes In South America. PMID- 26534635 TI - Assessment Of Pharmacist-Led Home-Based Educational Intervention Among Type 2 Diabetes Patients In The State of Penang, Malaysia. PMID- 26534636 TI - Estudio De Impacto Presupuestal De Daclatasvir Asociado A Asunaprevir Desde La Perspectiva Del Sistema De Salud Publico Chileno. PMID- 26534637 TI - Cost Analysis of Certolizumab Pegol Compared With Available Biologic Agents For Crohn's Disease In Mexico And Brazil. PMID- 26534638 TI - Terlipressin Versus Noradrenaline In The Treatment Of Hepatorenal Syndrome - Systematic Review With Meta-Analysis And Full Economic Evaluation. PMID- 26534639 TI - Custo-Efetividade Do Tenofovir Para O Tratamento Da Hepatite B Cronica Uma Revisao Sistematica. PMID- 26534640 TI - Economic Impact of Expanded Use of Biologic Therapy for Crohn's Disease In Latin American Countries. PMID- 26534641 TI - A hepatite c cronica diminui a qualidade de vida? PMID- 26534642 TI - Assessment of Complementary and Alternative Medicine Use In Hepatitis-C Patients In Quetta, Pakistan. PMID- 26534643 TI - Analysis of Cost Minimization of Adalimumab Compared With Infliximab for The Treatment of Ulcerative Colitis In The Public Market In Mexico. PMID- 26534644 TI - Associated Factors The Virologic Success In A Group of Patients With Human Immunodeficiency Virus, Managed By A Care Team Integral, Eps|Sura Medellin 2010 2013. PMID- 26534645 TI - Effect of Transfer Factor on The Reduction of The Number of Episodes of Recurrent Infections In Adult And Pediatric Patients From A Multicentre Observational Study. PMID- 26534646 TI - Malaria Diagnosis And Treatment Practice Following Introduction of Rapid Diagnostic Test In Selected Health Posts of Adama Woreda, East Shewa Zone, Oromia Region,Centeral Ethiopia. PMID- 26534647 TI - Does use of calcium channel blockers affect the risk of incident active tuberculosis disease? A nested case control study on a national health claim database. PMID- 26534648 TI - Utilizacion De Antibacterianos De Uso Restringido En Pacientes Adultos Hospitalizados En El Hospital Las Higueras - Talcahuano. PMID- 26534649 TI - Systematic Review And Meta-Analysis of Efficacy And Safety of Simeprevir And Sofosbuvir For Hcv Genotype 1 Infection. PMID- 26534650 TI - Estimaci"N de Costos Directos Asociados al Cambio de Terapia iv A oral en Infecci"N Complicada de Piel y Tejidos Blandos en Chile. PMID- 26534651 TI - Treatment Outcomes Among Hiv/Aids Patients Treated During Haart Therapy At Infectious Disease Clinic. PMID- 26534652 TI - Analisis de Impacto Presupuestal del uso de Daclatasvir+Asunaprevir en el Tratamiento de Pacientes Con Hepatitis C en Colombia. PMID- 26534653 TI - Increased Usage of Calcium Free Balanced Solutions (Bal) in Lieu of 0,9% Saline in Patients Meeting Sirs (Systemic Inflammatory Response Syndrome) Criteria: a Private Brazilian Hospital Perspective. PMID- 26534654 TI - Costos economicos de la otitis media aguda. Una revision de la literatura. PMID- 26534655 TI - Costo de Enfermedades Metaxenicas en Los Establecimientos de Salud del Peru. PMID- 26534656 TI - Costos de Hospitalizacion Por Infeccion Respiratoria Aguda Grave (Irag) en Guatemala. PMID- 26534657 TI - Measurement of the burden, resources use and health costs associated with herpes zoster and post-herpetic neuralgia in mexico. Master study. PMID- 26534658 TI - Analisis de Costo-Efectividad de Anidulafungina en el Tratamiento de la Candidiasis Invasiva en Colombia. PMID- 26534659 TI - Analisis de Costo-Efectividad de Las Vacuna Antineumococcicas Conjugadas en Colombia. PMID- 26534660 TI - Costos de Infeccion Respiratoria Aguda Grave Asociada Al Virus de La Influenza en Colombia. PMID- 26534661 TI - Costo-Efectividad De La Vacuna Contra El Dengue 2014. PMID- 26534662 TI - Evaluacion de Costo Efectividad de Dolutegravir (dtg) Vs Raltegravir (Ral) En Segunda Linea de Tratamiento en Pacientes Con Vih en Colombia. PMID- 26534663 TI - Analisis de Costo Efectividad y Costo Utilidad del uso de Daclatasvir+Asunaprevir en el Tratamiento de Pacientes Con Hepatitis C en Colombia, Desde La Perspectiva Del Tercer Pagador. PMID- 26534664 TI - Economic, Public Health, and Humanistic Impact of a Quadrivalent Human Papillomavirus (Hpv6/11/16/18) Vaccination Program for Females Age 9-11 Years in Mexico. PMID- 26534665 TI - Assessing the Public Health Impact and Cost Effectiveness of Pneumococcal Vaccines for Adults 65 Years of Age in Colombia. PMID- 26534666 TI - Economic Evaluation of Ertapenem in the Treatment of Intra-Abdominal Infections, from the Perspective of Imss. PMID- 26534667 TI - Simeprevir Plus Peginterferon/Ribavirin Cost-Effectiveness Analysis for the treatment of Chronic Genotype 1 Hepatitis C in Colombia. PMID- 26534668 TI - Cost Effectiveness of Triple Therapy for Adults Patients with Genotype 1 Chronic Hepatitis C. PMID- 26534669 TI - Simeprevir Plus Peginterferon/Ribavirin Cost-Effectiveness Analysis for the Treatment of Chronic Genotype 1 Hepatitis C in Mexico. PMID- 26534670 TI - Cost-Effectiveness Analysis of Simeprevir and Sofosbuvir Combination Therapy for the Treatment of Genotype 1 Hcv Patients in the Dominican Republic. PMID- 26534671 TI - Avaliacao da Adesao Ao Protocolo de Tratamento de Pessoas Vivendo Com Hiv/Aids: Conhecer Bem Para Cuidar Melhor. PMID- 26534672 TI - Beneficios Materiais Como Incentivo Para Reducao de Abandono de Tratamento de Tuberculose em Pessoas Vivendo em Situacao de Rua: Revisao de Analises Economicas. PMID- 26534673 TI - Costos de Medicamentos en el Marco de un Programa Presupuestal Para el Vih/Sida en Peru, 2012-2014. PMID- 26534674 TI - Financial Impact of Not Prescribing "By The Book": Art and Sustainability of Seguro Popular. PMID- 26534675 TI - Preliminary Outcomes of Health-Related Quality of Life in Hiv-Infected Naive Patients. PMID- 26534676 TI - The Association Between Tolerability Issues and Health Outcomes Among Patients with Hcv in Brazil. PMID- 26534677 TI - Quality of Life of Hiv-Infected Patients Attending to A University Infectious Diseases Clinic In Venezuela. PMID- 26534678 TI - Costo en Salud en la Intervencion de Atencion Integral de Personas Diagnosticadas Con Vih/Sida Para Reducir La Morbimortalidad Por Vih/Sida En El Peru, 2011-2014. PMID- 26534679 TI - Healthcare Resource Utilization Associated with Varicella in Argentina. PMID- 26534680 TI - Resistencia Antimicrobiana: Identificacao Das Pesquisas Brasileiras Fomentadas Para Suporte A Gestao No Pais. PMID- 26534681 TI - Occurrence of Treatment Interruption During Therapy with Biological Agents in Patients with Previous Anti-Tnf Failure in Rheumatoid Arthritis. PMID- 26534682 TI - Distribucion Geografica y Acceso a Terapias Biologicas en Pacientes Con Diagnostico de Artritis Reumatoide (Ar) en Colombia. PMID- 26534683 TI - Budget Impact of Golimumab iv for Rheumatoid Arthritis in the Chilean Private Sector. PMID- 26534684 TI - Analisis de Costo Efectividad y Costo Utilidad de Rituximab Como Tratamiento en Pacientes Con Artritis Reumatoide, Ante el Fallo o Intolerancia en Primera Linea de un Anti-Tnf, en el Contexto Venezolano. PMID- 26534685 TI - Analisis de Minimizacion de Costos de Tofacitinib en el Tratamiento de Pacientes Con Artritis Reumatoide Que Han Presentado Respuesta Inadecuada a Metotrexato en Colombia. PMID- 26534686 TI - Costo-Utilidad de Un Esquema Inicial de Tratamiento Con Tofacitinib Comparado Con Terapia Biologica Anti-Tnf en Pacientes Adultos Con Artritis Reumatoide Que Han Presentado Respuesta Inadecuada a Metotrexato en Venezuela. PMID- 26534688 TI - Impact of Financial Incentives on Access to Services and Quality of Care. PMID- 26534687 TI - Ankylosing Spondylitis Treatment and Follow-Up Costs in Colombia. PMID- 26534689 TI - Apresentacao do Programa Desfechos de um Hospital Privado de Sao Paulo, Brasil. PMID- 26534690 TI - Quality of Life in Patients After Total Hip Replacement. PMID- 26534691 TI - Caracterizacion de Pacientes Con Enfermedad Osteoarticular Desde La Perspectiva Del Aseguramiento en Colombia. PMID- 26534692 TI - Patterns of Care with Biological Drugs for Ankylosing Spondylitis: Real-World Data from the Private Healthcare Market in Brazil. PMID- 26534693 TI - Racial Disparities In total ankle arthroplasty Utilization and outcomes. PMID- 26534694 TI - Evaluacion Sobre Medicamentos y Actos Medicos Cubiertos Financieramente Por Resolucion Judicial- Fnr. PMID- 26534695 TI - Subject Recommendations for Improving Their Compliance and Engagement in Completing Daily Electronic Diaries in Osteoarthritis Clinical Trials. PMID- 26534696 TI - Desarrollo de Una Guia de Intervencion Psicologica Para Artritis Reumatoide en Colombia. PMID- 26534697 TI - Estimating the Opportunity Costs of Treating Meningitis in Selected Countries of Latin America. PMID- 26534698 TI - Rates of Adverse Events and Multiple Sclerosis Relapses Before and After Introduction of a Purported Generic Glatiramer Acetate in mexico: Results from a Large Patient Support Program in Mexico. PMID- 26534699 TI - Effect of Educational Intervention on Osteoporosis Knowledge Among University Female Students in Quetta, Pakistan. PMID- 26534700 TI - Prevalencia da Espondilite Anquilosante: Uma Revisao Sistematica. PMID- 26534701 TI - Healthcare Costs Associated with Patients Diagnosed with Relapsing Remitting Multiple Sclerosis. PMID- 26534702 TI - Health Care Resource Utilization Associated with Pediatric Patients Diagnosed with Relapsing Remitting Multiple Sclerosis. PMID- 26534703 TI - Heatlh Care Costs Associated with Patients Diagnosed with Relapsing Remitting Multiple Sclerosis Taking Once Daily Teriflunomide Tablets in the United States. PMID- 26534704 TI - Cost-Utility Analysis of Natalizumab as First-Line Treatment of Highly-Active Relapsing-Remitting Multiple Sclerosis in the Brazilian Public Healthcare System. PMID- 26534705 TI - Socioeconomic Impact of Immunoglobulin Replacement Therapy for Primary Immunodeficiency Patients on the Health Public System in Brazil: A Single Center Study. PMID- 26534706 TI - An Analysis of Medicine Procurement for Alzheimer's Disease in Brazil From Federal Purchases. PMID- 26534707 TI - National Estimates of Prevalence and Patterns of Psychotropic Polypharmacy Among Elderly Individuals with Parkinson's Disease in Nursing Home and Home Healthcare Settings in the United States. PMID- 26534708 TI - A Systematic Literature Review of Global Economic Evaluations of Rasagiline for Parkinson's Disease. PMID- 26534709 TI - Characteristics of Patients with Relapsing Remitting Multiple Sclerosis Taking once Daily Teriflunomide Tablets in the United States. PMID- 26534710 TI - Costo Efectividad de la Terapia Inmunomoduladora en Esclerosis Multiple Tipo Recaida Remision: Busqueda Sistematica de la Literatura. PMID- 26534711 TI - Adherence and Persistence among Patients Treated with First-Line Therapies for Relapsing-Remitting Multiple Sclerosis in Brazil. PMID- 26534712 TI - Cost-Effectiveness Analysis of Intravitreal Aflibercept Compared with Ranibizumab Prn in Patients with wet Age-Related Macular Degeneration (Wamd). PMID- 26534713 TI - Condicoes Socioeconomicoculturais Das Familias de Individuos Nascidos Com Fissura Labiopalatina. PMID- 26534714 TI - Acrysof Cachet Para la Correccion de Moderada a Alta Miopia: Una Revision Sistematica y Meta-Analisis. PMID- 26534715 TI - Estudio De Costo Efectividad Entre el Implante de Ahmed Versus el Implante de Baerveldt en Pacientes Operados De Glaucoma Cronico. PMID- 26534716 TI - Descriptive Evalaution of Characteristics of Patients Diagnosed with Relapsing Remitting Multiple Sclerosis and Taking Disease Modifying Agents. PMID- 26534717 TI - Implante de Ahmed Versus Implante de Baerveldt: Una Revision Sistematica y Meta Analisis. PMID- 26534718 TI - Analisis de Costo-Efectividad de Inyeccion Intravitrea de Ranibizumab Versus Aflibercept en el Tratamiento de la Perdida Visual Secundaria a Edema Macular Diabetico Desde la Perspectiva del Sistema de Salud en Colombia. PMID- 26534719 TI - Cost-Minimization Analysis of Intravitreal Aflibercept Compared with Ranibizumab on-Label In Patients with wet Age-Related Macular Degeneration (Wamd). PMID- 26534720 TI - Estimacion de Cambios en la Calidad de Vida Debido al Uso de Ocriplasmina en Pacientes Con Traccion Vitreomacular en Colombia. PMID- 26534721 TI - Interventions targeting sexual and reproductive health and rights outcomes of young people living with HIV: a comprehensive review of current interventions from sub-Saharan Africa. AB - BACKGROUND: A growing number of young people (ages 10-24) are living with HIV (YPLWH) in sub-Saharan Africa (SSA). These YPLWH have particular needs and challenges related to their sexual and reproductive health and rights (SRHR). Contextual factors including gender inequalities, violence, stigma, and discrimination and lack of tailored services undermine YPLWH's SRHR. OBJECTIVE: Understand the scope and impact of interventions targeting YPLWH to improve SRH related outcomes in SSA. DESIGN: We undertook a review to synthesise evaluated interventions (qualitative, quantitative, or mixed methods) aimed at improving the SRH outcomes of YPLWH in SSA with outcomes based on a World Health Organization framework of comprehensive SRHR approaches for women living with HIV. Using inclusion criteria, only six interventions were identified. RESULTS: Interventions sought to improve a range of direct and indirect SRH outcomes, including sexual behaviour, adherence, disclosure, and mental health. Four overarching issues emerged: 1) all interventions were structured according to cognitive behavioural therapy theories of behaviour change - while showing promise they do not tackle the wider gender, social, and economic contexts that shape YPLWH's SRH; 2) 'significant others' were included in two of the interventions, but further work needs to consider how to leverage parental/guardian support appropriately; 3) interventions only accessed young people who were already linked to care, participants were likely to have better SRH outcomes than those potentially more vulnerable YPLWH; and 4) none of the interventions explored the sexuality of young people. CONCLUSIONS: There have been a limited number of evaluated interventions to strengthen SRH of YPLWH in SSA, and gaps exist in addressing the SRHR needs of YPLWH. Intervention approaches require greater scope and depth, including the need to address structural and contextual challenges. PMID- 26534722 TI - Scaling-up NLP Pipelines to Process Large Corpora of Clinical Notes. AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Big Data and Analytics in Healthcare". OBJECTIVES: This paper describes the scale-up efforts at the VA Salt Lake City Health Care System to address processing large corpora of clinical notes through a natural language processing (NLP) pipeline. The use case described is a current project focused on detecting the presence of an indwelling urinary catheter in hospitalized patients and subsequent catheter-associated urinary tract infections. METHODS: An NLP algorithm using v3NLP was developed to detect the presence of an indwelling urinary catheter in hospitalized patients. The algorithm was tested on a small corpus of notes on patients for whom the presence or absence of a catheter was already known (reference standard). In planning for a scale-up, we estimated that the original algorithm would have taken 2.4 days to run on a larger corpus of notes for this project (550,000 notes), and 27 days for a corpus of 6 million records representative of a national sample of notes. We approached scaling-up NLP pipelines through three techniques: pipeline replication via multi-threading, intra-annotator threading for tasks that can be further decomposed, and remote annotator services which enable annotator scale-out. RESULTS: The scale-up resulted in reducing the average time to process a record from 206 milliseconds to 17 milliseconds or a 12- fold increase in performance when applied to a corpus of 550,000 notes. CONCLUSIONS: Purposely simplistic in nature, these scale-up efforts are the straight forward evolution from small scale NLP processing to larger scale extraction without incurring associated complexities that are inherited by the use of the underlying UIMA framework. These efforts represent generalizable and widely applicable techniques that will aid other computationally complex NLP pipelines that are of need to be scaled out for processing and analyzing big data. PMID- 26534723 TI - Effects of age and muscle action type on acute strength and power recovery following fatigue of the leg flexors. AB - Short-term strength and power recovery patterns following fatigue have received little research attention, particularly as they pertain to age-specific responses, and the leg flexors (i.e., hamstrings) muscle group. Thus, research is warranted addressing these issues because both age-related alterations in the neuromuscular system and mode of muscle action (e.g., eccentric, concentric, isometric) may differentially influence recovery responses from fatigue. The aim of this study was to investigate the strength and power recovery responses for eccentric, concentric, and isometric muscle actions of the leg flexors in young and older men following an isometric, intermittent fatigue-inducing protocol. Nineteen young (age = 25 +/- 3 years) and nineteen older (71 +/- 4) men performed maximal voluntary contractions (MVCs) for eccentric, concentric, and isometric muscle actions followed by a fatigue protocol of intermittent (0.6 duty cycle) isometric contractions of the leg flexors at 60% of isometric MVC. MVCs of each muscle action were performed at 0, 7, 15, and 30 min following fatigue. Peak torque (PT) and mean power values were calculated from the MVCs and the eccentric/concentric ratio (ECR) was derived. For PT and mean power, young men showed incomplete recovery at all time phases, whereas the older men had recovered by 7 min. Eccentric and isometric muscle actions showed incomplete recovery at all time phases, but concentric recovered by 7 min, independent of age. The ECR was depressed for up to 30 min following fatigue. More rapid and pronounced recovery in older men and concentric contractions may be related to physiological differences specific to aging and muscle action motor unit patterns. Individuals and clinicians may use these time course responses as a guide for recovery following activity-induced fatigue. PMID- 26534724 TI - Aging increases the susceptibility of cisplatin-induced nephrotoxicity. AB - Cisplatin (CDDP) nephrotoxicity is one of the most common side effects in cancer treatment, causing the disruption of chemotherapy. In this study, we analyzed the influence of nongenetic factors on CDDP-induced nephrotoxiciy using the data from 182 CDDP-treated and 52 carboplatin (CBP)-treated patients. The mean change of eGFR (100% to baseline) in CDDP-treated patients was -9.2%, which was significantly lower than that in the population with CBP therapy. By using the chi-squared test and multivariate logistic regression analysis, age (>=50 years) is found associated with CDDP-induced nephrotoxicity, with odds ratio (OR) of 9.167 and 11.771, respectively. Three- and 18-month-old mice were employed to study the age-dependent susceptibility of CDDP-induced nephrotoxicity. Biochemical parameters, histopathogical examination, and mRNA biomarkers indicated that old mice were subjected to more severe kidney injury. In addition, old mice accumulated more CDDP in kidney than young mice, and the protein level of CDDP efflux transporter, MATE1, in aged mice kidney was 35% of that in young mice. Moreover, inflammatory receptor TLR4 was higher in the kidney of old mice, indicating the alteration of inflammatory signaling in old mice. After CDDP administration, the induced alterations of TNF-alpha, ICAM-1, and TLR4 were more extensive in old mice. To summarize, aging increased the susceptibility of CDDP induced renal function decline or nephrotoxicity. PMID- 26534725 TI - Development and Evaluation of an Attractive Self-Marking Ovitrap to Measure Dispersal and Determine Skip Oviposition in Aedes albopictus (Diptera: Culicidae) Field Populations. AB - Aedes albopictus (Skuse) is a container-breeding species with considerable public health importance. To date, Ae. albopictus oviposition behavior has been assessed in outdoor conditions, but only with laboratory-reared specimens. In outdoor large-cage and field studies, we used an attractive self-marking ovipositional device to assess Ae. albopictus skip oviposition behavior. In field studies, 37 wild Ae. albopictus that visited an attractive self-marking ovisite were subsequently captured at a sticky ovitrap within a 4-d period. Because the average Ae. albopictus gonotrophic period is 4.5-6 d, the wild-caught Ae. albopictus visited at least two oviposition sites within a single gonotrophic period. This provided field-based indirect evidence of skip oviposition. The mean distance traveled (MDT) during the 20-d evaluations ranged from 58 to 78 m. The maximum observed distance traveled was 149 m, which was the outer edge of our trapping ability. As populations of Ae. albopictus increased, the MDT during the 4- and 20-d post-marking period increased significantly. Additional observations of wild-marked and captured Aedes triseriatus (Say) are discussed. PMID- 26534726 TI - Two-stage hepatectomy, a 10 years experience. AB - Colorectal tumor represents in Europe the second most common cause of cancer death. Surgical resection in case of colorectal liver metastasis remain for patients the only cure. In 2003, Jaeck et al. described a one or two-stage hepatectomy combined with PVE for initially non-resectable colorectal liver metastases. The aim of our study was to retrospectively review all patients who underwent to a two-stage hepatectomy for CLM and evaluate the safety and feasibility of the procedure. We review all patient who underwent two-stage hepatectomy for CLM in our center. From 2004 to March 2014, 57 patients were candidate for a two-stage hepatectomy for CLM. Thirty-two patients (55.9 %) were men and twenty-five women (44.1 %). Median age was 60.9 years old. In forty-six cases, the two-stage hepatectomy was completed. Of these 46 patients, 38 patients completed the procedure with a PVL and 8 underwent a secondary PVE. Seven patients were planned but did not performed PVL after intraoperative evaluation and neither PVE after secondary evaluation due to disease progression. Five cases were treated with a laparoscopic approach for the first step procedure. We had no death in this series. Ten patients developed complications after the first-stage operation and 18 patients had complications after the second stage. The median interval between the two stages was 66 days. Long-term overall survival was 52 months from the first liver surgery. This study demonstrated the feasibility of two-stage hepatectomy without postoperative mortality. In our last experience in selected patient, a laparoscopic first step should be performed. Patients selection is extremely important to propose the best therapeutic option for each one. PMID- 26534727 TI - Recent advances in new technologies and applications for molecular TEM. PMID- 26534728 TI - Correction. PMID- 26534729 TI - Six-year follow-up of the SPHERE RCT: secondary prevention of heart disease in general practice. AB - OBJECTIVE: To determine the long-term effectiveness of a complex intervention in primary care aimed at improving outcomes for patients with coronary heart disease. DESIGN: A 6-year follow-up of a cluster randomised controlled trial, which found after 18 months that both total and cardiovascular hospital admissions were significantly reduced in intervention practices (8% absolute reduction). SETTING: 48 general practices in the Republic of Ireland and Northern Ireland. PARTICIPANTS: 903 patients with established coronary heart disease at baseline in the original trial. INTERVENTION: The original intervention consisted of tailored practice and patient plans; training sessions for practitioners in medication prescribing and behavioural change; and regular patient recall system. Control practices provided usual care. Following the intervention period, all supports from the research team to intervention practices ceased. OUTCOME MEASURES: PRIMARY OUTCOME: hospital admissions, all cause and cardiovascular; secondary outcomes: mortality; blood pressure and cholesterol control. RESULTS: At 6-year follow-up, data were collected from practice records of 696 patients (77%). For those who had died, we censored their data at the point of death and cause of death was established. There were no significant differences between the intervention and control practices in either total (OR 0.83 (95% CI 0.54 to 1.28)) or cardiovascular hospital admissions (OR 0.91 (95% CI 0.49 to 1.65)). We confirmed mortality status of 886 of the original 903 patients (98%). There were no significant differences in mortality (15% in intervention and 16% in control) or in the proportions of patients above target control for systolic blood pressure or total cholesterol. CONCLUSIONS: Initial significant differences in the numbers of total and cardiovascular hospital admissions were not maintained at 6 years and no differences were found in mortality or blood pressure and cholesterol control. Policymakers need to continue to assess the effectiveness of previously efficacious programmes. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN24081411. PMID- 26534730 TI - Choosing Healthcare Options by Involving Canada's Elderly: a protocol for the CHOICE realist synthesis project on engaging older persons in healthcare decision making. AB - INTRODUCTION: While patient and citizen engagement has been recognised as a crucial element in healthcare reform, limited attention has been paid to how best to engage seniors-the fastest growing segment of the population and the largest users of the healthcare system. To improve the healthcare services for this population, seniors and their families need to be engaged as active partners in healthcare decision-making, research and planning. This synthesis aims to understand the underlying context and mechanisms needed to achieve meaningful engagement of older adults in healthcare decision-making, research and planning. METHODS AND ANALYSIS: The CHOICE Knowledge Synthesis Project: Choosing Healthcare Options by Involving Canada's Elderly aims to address this issue by synthesising current knowledge on patient, family, and caregiver engagement. A realist synthesis will support us to learn from other patient and citizen engagement initiatives, from previous research, and from seniors, families and caregivers themselves. The synthesis will guide development or adaptation of a framework, leading to the development of best practice guidelines and recommendations for engagement of older people and their families and caregivers in clinical decision making, healthcare delivery, planning and research. ETHICS AND DISSEMINATION: The components of this protocol involving consultation with patients or caregivers have received ethics clearance from the University of Waterloo, Office of Research Ethics (ORE#19094). After completion of the project, we will amalgamate the information collected into a knowledge synthesis report which will include best practice guidelines and recommendations for patient, family and caregiver engagement in clinical and health system planning and research contexts. RESULTS: Will be further disseminated to citizens, clinicians, researchers and policymakers with the help of our partners. TRIAL REGISTRATION NUMBER: CRD42015024749. PMID- 26534731 TI - What role do pharmacists play in mediating antibiotic use in hospitals? A qualitative study. AB - OBJECTIVE: To understand Australian hospital pharmacists' accounts of antibiotic use, and the potential role of pharmacy in antibiotic optimisation within a tertiary hospital setting. DESIGN, SETTING AND PARTICIPANTS: Qualitative study, utilising semistructured interviews with 19 pharmacists in two hospitals in Queensland, Australia in 2014. Data was analysed using the framework approach and supported by NVivo10 qualitative data analysis software. RESULTS: The results demonstrate that (1) pharmacists' attitudes are ambivalent towards the significance of antibiotic resistance with optimising antibiotic use perceived as low priority; (2) pharmacists' current capacity to influence antibiotic decision making is limited by the prescribing power of doctors and the perception of antibiotic use as a medical responsibility; and, (3) interprofessional and organisational barriers exist that prevent change in the hospital setting including medical hierarchies, limited contact with senior doctors and resource constraints resulting in insufficient pharmacy staffing to foster collaborative relationships and facilitate the uptake of their advice. DISCUSSION: While pharmacy is playing an increasingly important role in enhanced antibiotic governance and is a vital component of antimicrobial stewardship in Australia, role-based limitations, interprofessional dynamics and organisational/resource constraints in hospitals, if not urgently addressed, will continue to significantly limit the ability of pharmacy to influence antibiotic prescribing. PMID- 26534732 TI - An exploratory analysis of cigarette price premium, market share and consumer loyalty in relation to continued consumption versus cessation in a national US panel. AB - INTRODUCTION: Brand equity and consumer loyalty play a role in continued purchasing behaviour; however, this research has largely focused on non-addictive products without counter-marketing tactics. We examined the impact of brand equity (price premium, market share) and consumer loyalty (switching rates) on smoking cessation (discontinued cigarette purchases for 1 year) among smokers in a consumer panel. METHODS: In Spring 2015, we analysed 1077 cigarette-purchasing households in the Nielsen Homescan Panel. We analysed cessation in relation to brand equity, consumer loyalty, other purchasing behaviours (nicotine intake, frequency), sociodemographics and tobacco control activities (per state-specific data) over a 6-year period (2004-2009) using Cox proportional hazard modelling. RESULTS: The sample was 13.28% African-American; the average income was $52,334 (SD=31,445). The average price premium and market share of smokers' dominant brands were $1.31 (SD=0.49) and 15.41% (SD=19.15), respectively. The mean brand loyalty level was 0.90 (SD=0.17), indicating high loyalty. In our final model, a higher price premium and market share were associated with lower quit rates (p=0.039); however, an interaction effect suggested that greater market share was not associated with lower cessation rates for African-American smokers (p=0.006). Consumer loyalty was not associated with cessation. Other predictors of lower quit rates included a higher nicotine intake (p=0.006) and baseline purchase frequency (p<0.001). Tobacco control factors were not significantly associated. CONCLUSIONS: Smokers of high-equity cigarette brands are less likely to quit, perhaps due to strong brand-consumer relationships. Thus, continued efforts should aim to regulate tobacco marketing efforts in order to disrupt these relationships to promote cessation. PMID- 26534733 TI - Correction. PMID- 26534734 TI - Community-based interventions to prevent fatal overdose from illegal drugs: a systematic review protocol. AB - INTRODUCTION: Drug overdose is the most frequent cause of death among people who misuse illegal drugs. People who inject these drugs are 14-17 times more likely to die than their non-drug using peers. Various strategies to reduce drug-related deaths have failed to meet target reductions. Research into community-based interventions for preventing drug overdose deaths is promising. This review seeks to identify published studies describing community-based interventions and to evaluate their effectiveness at reducing drug overdose deaths. METHODS AND ANALYSIS: We will systematically search key electronic databases using a search strategy which groups terms into four facets: (1) Overdose event, (2) Drug classification, (3) Intervention and (4) Setting. Searches will be limited where possible to international literature published in English between 1998 and 2014. Data will be extracted by two independent reviewers using a predefined table adapted from the Cochrane Collaboration handbook. The quality of included studies will be evaluated using the Cochrane Collaboration's tool for assessing risk of bias. We will conduct a meta-analysis for variables which can be compared across studies, using statistical methods to control for heterogeneity where appropriate. Where clinical or statistical heterogeneity prevents a valid numerical synthesis, we will employ a narrative synthesis to describe community based interventions, their delivery and use and how effectively they prevent fatal overdoses. ETHICS AND DISSEMINATION: We will publish findings from this systematic review in a peer-reviewed scientific journal and present results at national and international conferences. It will be disseminated electronically and in print. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015017833. PMID- 26534735 TI - Perception of electronic cigarettes in the general population: does their usefulness outweigh their risks? AB - OBJECTIVE: To describe and compare the perceptions of the general population about the harmful effects of electronic cigarettes (e-cigarettes) on users and on those passively exposed to e-cigarettes and the perceptions about e-cigarette usefulness for reducing or eliminating tobacco smoking. DESIGN, SETTING, AND PARTICIPANTS: We analysed cross-sectional data from a longitudinal study of a representative sample of the general adult (>=16 years) population of Barcelona, Spain (336 men and 400 women). The fieldwork was conducted between May 2013 and February 2014. We computed the percentages, adjusted OR and their corresponding 95% CI among participants with some awareness of e-cigarettes (79.2% of the sample). PRIMARY AND SECONDARY OUTCOME MEASURES: We assessed the perception about harmfulness for e-cigarette users and for passively exposed non-e-cigarette users, as well as the perception of usefulness for smokers of cigarette cessation and reduction. RESULTS: In this sample, 40.1% thought that e-cigarettes had a harmful effect on users, and 27.1% thought that e-cigarettes had a harmful effect on passively exposed bystanders (p<0.001). Particularly, more never-smokers perceived that e-cigarettes had harmful effects on passively exposed bystanders than current smokers (34.4% vs 20.6%; OR=1.93, 95% CI 1.02 to 3.63). More people perceived e-cigarettes as being useful for reducing smoking than for quitting (50.6% vs 29.9%, p<0.001), as well as for reducing smoking than as being harmful to users (50.6% vs 40.1%, p=0.044). DISCUSSION: The perception that e-cigarettes are useful for reducing tobacco consumption was more prevalent than the perception that e-cigarettes are harmful to users and to those passively exposed to e-cigarettes. Advertisements and messages about the use of e-cigarettes and their harmful effects should be regulated and based on scientific evidence to avoid creating erroneous ideas about their use. PMID- 26534737 TI - Abstracts of Presentations from the 2015 Meeting of the American Association of Veterinary Anatomists, held July 17-19, at Washington State University in Pullman, Washington, USA. PMID- 26534738 TI - Impact of delirium on weaning from mechanical ventilation in medical patients. AB - BACKGROUND AND OBJECTIVE: Delirium is an important predictor of negative clinical outcomes in intensive care unit (ICU), including prolonged mechanical ventilation (MV). However, delirium has not yet proven to be directly linked to weaning difficulties. The objective of this cohort study was to evaluate the association between delirium, as observed on the day of the weaning trial, and subsequent weaning outcomes in medical patients. METHODS: This is a retrospective analysis with prospectively collected data on weaning from mechanical ventilation (MV) and delirium, as assessed by bedside ICU nurses using the Confusion Assessment Method for the ICU (CAM-ICU) between October 2011 and September 2013. RESULTS: During the study period, a total of 393 patients with MV support underwent a spontaneous breathing trial (SBT) according to the standardized protocol. Of these patients, 160 (40.7%) were diagnosed with delirium on the day of the first SBT. Patients without delirium were more successfully extubated than those with delirium (81.5% vs 69.4%, P = 0.005). Delirium was found to be associated with final weaning outcomes, including difficult (OR 1.962, 95% CI 1.201-3.205) and prolonged weaning (OR 2.318, 95% CI 1.272-4.226) when simple weaning was used as a reference category. After adjusting for potential confounding factors, delirium was still significantly associated with difficult weaning (adjusted OR 2.073, 95% CI 1.124-3.822), but not with prolonged weaning (adjusted OR 2.001, 95% CI 0.875 4.575). CONCLUSION: Delirium, as assessed by the CAM-ICU at the time of first weaning trial, was significantly associated with weaning difficulties in medical patients. PMID- 26534739 TI - Adjuvant chemotherapy in stage IB non-small cell lung carcinoma: A survival analysis. PMID- 26534740 TI - Is the COPD assessment test (CAT) effective in demonstrating the systemic inflammation and other components in COPD? AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is currently a complex, multicomponent disorder. The COPD Assessment Test (CAT) has been increasingly used to assess COPD patients. This study aims to investigate the relationship between CAT and inflammation markers and other COPD components. METHODS: We enrolled 110 stable COPD patients and 65 control subjects in this study. All patients completed the CAT questionnaire and the modified Medical Research Council (mMRC) dispnea scale. The quality of life of these patients was measured with St. George's Respiratory Questionnaire (SGRQ). Levels of TNFalpha, IL-6, CRP were determined in blood samples. RESULTS: In COPD patients, serum levels of TNFalpha (109.5 +/- 58 pg/ml), IL-6 (10.3 +/- 18 pg/ml), and C-reactive protein (CRP) (1.6 +/- 1.7 mg/L) were found to be significantly higher compared to controls (TNF-alpha: 14.6 +/- 18 pg/ml, IL-6: 2.14 +/- 1.9 pg/ml, CRP: 0.4 +/- 0.3mg/L, p<0.001). These markers were correlated with smoking (r from 0.27 to 0.35, p<0.001), FEV1 (r from -0.39 to -0.57, p<0.001), FVC (r from -0.32 to 0.37, p<0.001) and FEV1/FVC (r from -0.31 to -0.66, p<0.001). The CAT score correlated with GOLD spirometric stages, mMRC dyspnea score, number of exacerbations in the previous year and FEV1 (p<0.001). There was a significant correlation between levels of CRP and the CAT score (r=0.43, p<0.001) but no similar relationship between levels of TNFalpha and IL-6 and the CAT was observed. CONCLUSION: Systemic inflammation persists in the stable period of COPD. CRP, one of the inflammation markers, was correlated with the CAT. Further studies are required to confirm the relationship between CAT and biomarkers. PMID- 26534741 TI - Risk relation between rhinitis and acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Chronic inflammation that triggers endothelial dysfunction and atherosclerosis may promote the evolution of cardiovascular diseases, including acute ischemic stroke (AIS). In this study, we assessed the association between rhinitis (RN), an immunoglobulin E-related atopic disease, and the risk of AIS. METHODS: We used a Taiwan national insurance claims data set of 1 million enrollees to distinguish 61,899 patients with RN and 123,798 randomly selected age- and sex-matched controls from January 1, 2000, to December 31, 2010. Both cohorts were followed up until the occurrence of stroke or the end of follow-up. The risk of AIS was evaluated by using the Cox proportional hazards regression model. RESULTS: After adjustment of the relevant covariates, the RN group showed a lower risk of AIS (adjusted hazard ratio [aHR] 0.74 [95% confidence interval {CI}, 0.70-0.79]) compared with the control cohort at the end of follow-up. Among the participants without comorbidities, the RN cohort still had a lower risk of AIS compared with the control cohort (aHR 0.69 [95% CI, 0.59 0.81]). Moreover, in the three stratified age groups, RN was associated with a significantly decreased risk of AIS (ages <=49 years: aHR 0.77 [95% CI, 0.63 0.95]; ages 50-64 years: aHR 0.72 [95% CI, 0.64-0.81]; ages >=65 years: aHR 0.78 [95% CI, 0.71-0.85]). CONCLUSIONS: RN was associated with a decreased risk of developing AIS. Although a reduction in risk of AIS was observed, it warrants further consideration to prevent AIS in patients with RN. PMID- 26534742 TI - Serum eosinophil-derived neurotoxin: correlation with persistent airflow limitation in adults with house-dust mite allergic asthma. AB - BACKGROUND: The serum level of eosinophil-derived neurotoxin (EDN), a protein present in eosinophil granules, correlates with the severity of childhood asthma. However, the relationship between the serum EDN level and the severity of adult asthma has not been sufficiently investigated. OBJECTIVE: This study aimed to elucidate the correlation between the serum EDN level and markers of severity in adult asthma. METHODS: The subjects comprised 83 adult patients who had asthma and who were undergoing treatment. Of these patients, 40 were positive for house dust-specific immunoglobulin E (IgE) antibodies; 9 patients with severe adult asthma who were treated with omalizumab were included in the study. We measured the blood eosinophil count, serum EDN, and eosinophil cationic protein levels before investigating the correlations of these parameters with lung function and symptom score. RESULTS: There were no significant correlations between the blood eosinophil count or serum EDN or eosinophil cationic protein level with lung function and the symptom score in patients with asthma. However, serum EDN level was inversely correlated with the decrease percentage forced expiratory volume in 1 second (%FEV1) in patients positive for house-dust-specific IgE antibody (R = 0.54; p < 0.05), whereas no such correlation was observed in patients with negative results for house-dust-specific IgE antibody (R = 0.11; p = 0.468). A significant correlation was observed between a decrease in serum EDN level from baseline and lung function improvement after 8 weeks of omalizumab therapy (R = 0.77; p = 0.015). CONCLUSION: Serum EDN level may be a useful marker for monitoring persistent airflow limitation in adult patients with asthma who had positive results for house-dust-specific IgE antibodies. PMID- 26534743 TI - Popular on YouTube: a critical appraisal of the educational quality of information regarding asthma. AB - BACKGROUND: Asthma affects >300 million people globally, including 25 million in the United States. Patients with asthma frequently use the Internet as a source of information. YouTube is one of the three most popular Web sites. OBJECTIVE: To determine the educational quality of YouTube videos for asthma. METHODS: We performed a YouTube search by using the keyword "asthma." The 200 most frequently viewed relevant videos were included in the study. Asthma videos were analyzed for characteristics, source, and content. Source was further classified as asthma health care provider, other health care provider, patient, pharmaceutical company, and professional society and/or media. A scoring system was created to evaluate quality (-10 to 30 points). Negative points were assigned for misleading information. RESULTS: Two hundred videos were analyzed, with a median of 18,073.5 views, 31.5 likes, and 2 dislikes, which spanned a median of 172 seconds. More video presenters were male (60.5%). The most common type of video source was other health care providers (34.5%). The most common video content was alternative treatments (38.0%), including live-fish ingestion; reflexology; acupressure and/or acupuncture; Ayurveda; yoga; raw food, vegan, gluten-free diets; marijuana; Buteyko breathing; and salt therapy. Scores for videos supplied by asthma health care providers were statistically significantly different from other sources (p < 0.001) and had the highest average score (9.91). CONCLUSION: YouTube videos of asthma were frequently viewed but were a poor source of accurate health care information. Videos by asthma health care providers were rated highest in quality. The allergy/immunology community has a clear opportunity to enhance the value of educational material on YouTube. PMID- 26534744 TI - Correlation of skin barrier impairment in atopic dermatitis with aeroallergen sensitization. AB - BACKGROUND: Atopic dermatitis (AD) often predates the development of allergic sensitization in the so-called atopic march. Several studies have pointed out epidermal barrier impairment as a major cause of this evolution. OBJECTIVE: The present study aimed to assess atopic skin integrity by means of transepidermal water loss (TEWL) and Corneometer, and to investigate possible correlations between barrier integrity measurements and the degree of sensitization to aeroallergens (allergy score). METHODS: Sixty-one children (6 months to 17 years old) with AD were clinically evaluated by the Scoring Atopic Dermatitis index. TEWL and Corneometer evaluations were performed on lesion sites as well as on healthy skin. The subjects underwent skin-prick testing, and the severity of allergic sensitization was assessed for each patient by summing all wheal diameters (the allergy score). The same tests were performed in 20 children without AD. RESULTS: In patients with AD, TEWL and Corneometer results were found to be higher and lower, respectively, on eczematous areas in comparison with healthy skin, and differences were significantly correlated to the Scoring Atopic Dermatitis index (p < 0.0001 and p = 0.007, respectively). The TEWL result was significantly higher in nonlesional skin of the patients with AD compared with that of individuals without AD (p = 0.017). Of the patients with AD, 59% were sensitized to inhalant allergens; allergy scores were positively correlated with both AD duration (r = 0.63; p < 0.0001) and nonlesional skin TEWL values (r = 0.46; p = 0.002). No significant correlation was found between allergy scores and skin parameters in subjects without AD. CONCLUSION: Patients with AD are affected by barrier function impairment, even on noneczematous skin. This defect is associated with greater aeroallergen sensitization and may contribute to allergic respiratory symptom development. PMID- 26534745 TI - Expression of TLR2 and TLR4 on peripheral blood monocytes during exacerbation of atopic dermatitis. AB - BACKGROUND: In atopic dermatitis (AD), monocytes, which accumulate in the inflamed skin, are characterized by a significantly impaired Toll-like receptors (TLR) expression and TLR2-mediated cytokine secretion. However, data on expression of TLR on monocytes of peripheral blood (PB) in AD are not available. OBJECTIVE: To investigate TLR2 and TLR4 expression on PB monocytes during AD exacerbation and to assess the relationships between TLR expressions with AD clinical severity and with serum interleukin (IL) 4, IL-10, and IL-17a levels. METHODS: The objective Scoring Atopic Dermatitis index, TLR2 and TLR4 expression on CD14(+) human leukocyte antigen-DR (HLA-DR(+)) PB monocytes by flow cytometry, serum IL-4, IL-10, IL-17a (enzyme-linked immunosorbent assay) and total immunoglobulin E levels were measured at study entry and after 4 months in patients with AD and healthy controls. RESULTS: Eighty-two patients with AD, 35 women (45.1%) and 47 men (54.9%), mean (standard deviation [SD]) age, 42.2 +/- 11.5 years, were included. Thirty healthy volunteers served as controls. We observed a significant difference in the levels of TLR2 expression in the CD14(+) HLA-DR(+) PB monocytes of patients with AD (mean [SD], 51.6 +/- 23.1% and 264 +/- 118 cells/mm(3)) at exacerbation (but not at the end of the 4-month postexacerbation period) compared with the healthy control subjects (mean [SD], 22.3 +/- 10.6% and 105 +/- 50 cells/mm(3); p < 0.001). TLR4 expression in PB monocytes was significantly greater in AD (mean [SD], 50.1 +/- 20.9% and 275 +/- 114 cells/mm(3)) than in the healthy subjects (mean [SD], 31.2 +/- 8.7% and 147 +/- 41 cells/mm(3); p < 0.001) both at exacerbation and at the 4-month postexacerbation period. Significant correlations between TLR2(+) (but not TLR4(+)) PB monocytes and the objective Scoring Atopic Dermatitis index (r = 0.604, p < 0.001), serum levels of IL-17a and TLR2(+) PB monocytes (r = 0.416, p = 0.027), and IL-4 and TLR2(+) PB monocytes (r = -0.307, p = 0.014) were observed during AD exacerbation. CONCLUSION: PB CD14(+) HLA-DR(+) TLR2(+) monocytes might have a role in the skewing of a T-helper 2/T-helper 17-mediated immune response during AD flare. PMID- 26534746 TI - Asthma, allergy, and psychiatric disease. PMID- 26534747 TI - Severe asthma: epidemiology, burden of illness, and heterogeneity. AB - BACKGROUND: Patients with severe persistent asthma comprise only 5-10 % of the total asthma population, but account for a large proportion of asthma morbidity and health care expenditures. Among patients with severe asthma, higher costs can be expected in association with not well or poorly controlled asthma. OBJECTIVE: To summarize the evidence concerning the epidemiology, burden, and heterogeneity of severe asthma. METHODS: A literature search was performed to identify citations using the terms "severe asthma" and "epidemiology", "asthma control", "asthma" and "heterogeneity". RESULTS: Successful management of patients with severe asthma continues to be a major unmet need. One of the barriers to successful management is the heterogeneity of asthma. Asthma is not one disease; it is a disorder that can be subdivided into a number of different phenotypes and endotypes. A revised paradigm for asthma management, that entails categorization of asthma patients via use of "biomarkers", and prescribing targeted therapy, will supplant what has been a "one size fits all" approach to asthma management. CONCLUSION: The novel approach to asthma management, in which therapy will be more mechanism-specific based on phenotype/endotype, offers the potential for improved asthma care outcomes - particularly for patients with severe persistent asthma who are not well or poorly controlled. PMID- 26534748 TI - Hereditary angioedema: special consideration in children, women of childbearing age, and the elderly. AB - This review on hereditary angioedema (HAE) focused on special topics regarding HAE in children, women of childbearing age, and the elderly. HAE is a rare autosomal dominant bradykinin-mediated disorder characterized by recurrent attacks of subcutaneous or submucosal swelling that usually affects the face, upper airway, extremities, gastrointestinal tract, or genitalia. These recurrent attacks cause significant morbidity and can be life threatening, especially when the swelling affects the airway. Our objective was to summarize the published data available on the disease epidemiology, pathophysiology, clinical presentation, on demand and prophylactic therapy, and focus on management considerations for these special patient populations. Unique aspects of HAE in women with regard to contraception, hormone replacement therapy, pregnancy, lactation, and menopause were also reviewed. PMID- 26534749 TI - Allergies and suicidal behaviors: a systematic literature review. AB - BACKGROUND: Allergies are among the most common chronic conditions. In addition to physical and social impacts, a number of studies have consistently linked allergies to poor psychological outcomes, including depression and anxiety. OBJECTIVES: The aim of the present systematic literature review was to analyze the existing literature about the relationship between allergies and fatal and nonfatal suicidal behaviors. METHODS: Data sources include articles retrieved from Scopus, PubMed, ProQuest, and Web of Knowledge. Search terms: "suicid* and (allerg* or hay fever or atop* or eczema or aeroallergen*)" in English-language peer-reviewed journals between 1990 and 2014. ELIGIBILITY CRITERIA: Original research articles that provide empiric evidence about the potential link between allergies and suicidal behaviors. RESULTS: The initial search identified a total of 769 articles with 17 original research articles that present empiric evidence. Nine articles analyzed the relationship between allergies and fatal suicidal behavior, and nine analyzed nonfatal suicidal behaviors (one article included both). There currently is little research into the relationship between allergies and suicidal behavior. LIMITATIONS: The review was restricted to English-language articles published within the chosen time period; other limitations included the small number of articles that involve suicide mortality, and the fact that the majority of articles originated from the United States and Scandinavia. CONCLUSIONS: Analysis of the results indicates a link between allergies and suicidality, particularly suicide mortality; however, results for nonfatal suicidal behaviors are mixed. It is important that further research by using more rigorous study designs be carried out to lend strength to these findings. PMID- 26534750 TI - Evaluation of anxiety levels and factors associated with positive test results in patients with drug hypersensitivity. AB - BACKGROUND: High anxiety has been reported in patients with drug hypersensitivity reaction (DHR); however, its relationship with the test results was not studied previously. OBJECTIVE: We aimed to investigate the association of patient anxiety with the results of drug tests together with the other contributing factors. METHODS: Sixty-seven patients were included in the study between November 2012 and April 2013, in whom drug tests were performed after clinical evaluation and application of the Penn State Worry Questionnaire (PSWQ). RESULTS: The mean +/- standard deviation (SD) age was 43.5 +/- 12.9 years, and 73.1% of the patients were females. The patient group had significantly higher mean +/- SD PSWQ score than 35 control subjects without histories of DHRs and major psychiatric disorders (47.95 +/- 14.64 versus 40.22 +/- 11.86, p = 0.008). However, the mean +/- SD. PSWQ score of the patients with positive drug test results was not significantly different from the patients with negative drug test results (46.06 +/- 13.41 versus 50.47 +/- 18.02, p = 0.32). Panic attack symptoms were more common in the reactions with positive test results than in the reactions with negative test results (74.0% versus 48.9%, p = 0.01). However, presence of panic attack symptoms [odds ratio (OR): 1.25, 95% confidence interval (CI): 0.44-3.54; p = 0.67] was not found independently associated with positive test results in the multiple logistic regression model. CONCLUSION: Patients with DHR have high levels of anxiety; however, this is not related to the results of drug tests. Because panic reaction symptoms may accompany the objective symptoms of DHR, a complete clinical work-up is required before deciding whether the reaction is related to panic or a "true DHR." PMID- 26534751 TI - Anxiety but not depression symptoms are associated with greater perceived dyspnea in asthma during bronchoconstriction. AB - OBJECTIVE: To determine whether anxiety and depression are associated with greater respiratory discomfort in asthma. METHODS: Adults with asthma (n = 230) underwent methacholine (Mch) challenge. Anxiety and depression, asthma control, and quality of life were evaluated at study entry by using the Hospital Anxiety and Depression Scale, Asthma Control Test, and Asthma Quality of Life Questionnaire, respectively. Qualitative descriptors of breathlessness, dyspnea intensity (modified Borg scale and visual analog scale [VAS]), and other respiratory symptoms were evaluated before and after Mch challenge. RESULTS: Patients were classified as neither anxiety nor depression (NAD), anxiety only, depression only (D), or both anxiety and depression (AD) according to the Hospital Anxiety and Depression Scale score. Asthma Control Test and Asthma Control Test, and Asthma Quality of Life Questionnaire scores were lowest in the AD group (both p < 0.001). VAS scores for dyspnea and wheezing before Mch challenge were highest in the AD group (both p < 0.05). The increase in the modified Borg scale score after Mch challenge was higher in the AD group (mean [standard deviation] 2.5 +/- 2.0) than in the NAD (1.5 +/- 1.5) and D (0.8 +/- 0.9) groups (p = 0.006 and p = 0.003, respectively). Most descriptors of breathlessness were more prevalent in the anxiety only, D, and AD groups than in the NAD group. Multivariable logistic regression models indicated that anxiety increased the risk of dyspnea (odds ratio 1.10, p < 0.001 for the Borg score; odds ratio 3.84, p = 0.032 for the VAS score) but not for other respiratory symptoms. CONCLUSIONS: Anxiety but not depression was associated with greater perceived dyspnea intensity but not other measures of respiratory discomfort in individuals with asthma. Anxiety may shape the quality and intensity of dyspnea at a given respiratory load. PMID- 26534752 TI - Association between thyroid autoimmunity and recurrent angioedema in children. AB - BACKGROUND: The association between thyroid autoimmunity (TA) and idiopathic isolated angioedema (or angioedema without urticaria) has not been evaluated in either children or in adults up until now. We, therefore, aimed to investigate underlying or concomitant TA and/or autoimmune thyroid disease in children diagnosed with recurrent idiopathic angioedema. METHODS: Children who were consecutively diagnosed with recurrent idiopathic histaminergic acquired angioedema (IH-AAE) between January 2011 and January 2014 constituted the case group. A standard diagnostic and therapeutic algorithm was applied to all the patients with recurrent IH-AAE. Thyroid autoantibodies and thyroid function tests were measured in all the patients with recurrent IH-AAE and in healthy control groups. Prophylaxis with an antihistamine was started for patients with frequently recurrent IH-AAE. RESULTS: Eighty consecutive children with recurrent IH-AAE (49 boys; median age, 8.3 years) and 80 healthy children (39 boys; median, 8 years) were enrolled in this prospective, case-control study (p > 0.05 for age and sex). The IH-AAE group was significantly different than the control group with respect to TA (13.7% versus 2.5%, respectively; p = 0.009) but was similar with respect to autoimmune thyroid disease (3.7% versus 0%, respectively; p = 0.2). The median follow-up of the recurrent IH-AAE group was 34 months (range, 12 45 months). Patients with recurrent IH-AAE with and those without TA were not different with respect to either the need or the duration of antihistamine prophylaxis (p > 0.05 for both). CONCLUSIONS: Recurrent IH-AAE may be related to or associated with TA and/or autoimmune thyroid diseases in some children. However, exploring to see whether this association is a causal link or just an epiphenomenon deserves further investigation and longer follow-ups. PMID- 26534753 TI - Anticytokine autoantibodies in chronic rhinosinusitis. AB - BACKGROUND: Anticytokine autoantibodies (AAbs) involve a great panel of cytokines both in healthy subjects and in patients with various diseases, but their incidence and pathophysiologic role are widely debated. The issue of AAbs in chronic rhinosinusitis (CRS) has never been explored. OBJECTIVE: The aim of the study was to check AAbs in patients with CRS and with nasal polyps (CRSwNP) and patients with CRS and without nasal polyps (CRSsNP). METHODS: One-hundred subjects with CRS and 40 healthy controls were included. CRS severity was determined by the 22-item Sino-Nasal Outcome Test and Lund-Mackay scores. Levels of immunoglobulin A (IgA), secretory IgA, IgG, IgE, interleukin (IL) 1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and IL-17A, and AAbs levels in subjects' serum and nasal secretions (NS) were measured by the enzyme-linked immunosorbent assay. RESULTS: Forty-six patients with CRSsNP, 25 women (54.3%) and 21 men (45.7%), mean (standard deviation [SD]) ages 34.1 +/- 12.3 years; and 54 patients with CRSwNP, 24 women (44.4%) and 30 men (55.6%), mean (SD) ages 37.9 +/- 17.5 years. A group of 40 healthy subjects served as controls. In both CRSsNP and CRSwNP groups, serum and NS IL-1beta, IL-4, IL-5, IL-6, IL-8, IL-10, and IL-17A levels were higher compared with healthy controls, but there was no difference in the serum levels of cytokines between the CRSsNP and CRSwNP groups. Binding IgA antibodies against IL-1beta, IL-2, IL-5, and IL-8 were found at low levels in NS of both patients with CRSsNP and patients with CRSwNP. The highest levels of AAbs were detected against IL-5 (0.43 +/- 0.38 optical density values) and IL-17A (0.51 +/- 0.32 optical density values) in NS of patients with CRSwNP. In the CRSwNP group, a positive correlation was found between NS IL-5 and anti-IL-5 AAbs (r = 545; p < 0.001). Positive correlations between anti-IL-5 AAbs with NS total IgE (r = 0.424; p = 0.001) and with NS secretory IgA (r = 0.545; p < 0.001) were noted in the CRSwNP group. CONCLUSIONS: In patients with CRS, IgA class AAbs were detected in NS, whereas the highest levels of anti-IL-5 and anti-IL-17A AAbs were detected in patients with CRSwNP. Maybe these AAbs indicate disruption of immune tolerance and mucosal autoimmunity. PMID- 26534754 TI - Objective and subjective responses to a mechanical external nasal dilator in healthy children and children with nasal congestion. AB - BACKGROUND: Nasal congestion is a frequent symptom of allergic rhinitis. Mechanical external nasal dilators (MEND) can be applied to the outside of the nose to provide temporary relief from nasal stuffiness. OBJECTIVE: To assess the objective and subjective benefits and tolerability of MEND in healthy children and in children with nasal congestion due to allergic rhinitis. METHODS: Two studies were performed, one in healthy children and one in children with nasal congestion. The study of healthy children was a single-center, randomized, crossover study of two pediatric MEND variants, "tan" and "stars." The study of children with nasal congestion was a single-center assessment of the stars MEND. In both studies, nasal patency was measured via peak nasal inspiratory flow in the seated position and in the supine position at baseline and after the pediatric MEND was affixed to the nose. Assessment questions were administered at baseline and after MEND application, while seated and while supine, to evaluate subjective reduction in nasal blockage and tolerability. RESULTS: Thirty healthy and 26 children with nasal congestion were assessed. Pediatric MENDs showed a statistically significant improvement in peak nasal inspiratory flow for both healthy children and children with nasal congestion while seated and for healthy children while recumbent. Pediatric MENDs were perceived as decreasing nasal obstruction in both healthy children and children with nasal congestion in both positions, and there were statistically significant improvements in most subjective measures. Pediatric MENDs were well tolerated. CONCLUSIONS: Pediatric MENDs provided significant objective increases in nasal patency in healthy children and children with nasal congestion in the seated position and also subjective reduction in nasal airway stuffiness in both seated and supine positions; they were also well tolerated. PMID- 26534755 TI - Assessment of inspiratory flow in bronchial asthma by using a portable meter. AB - BACKGROUND: The use of inhalation systems for the administration of specific drugs allows the selective treatment of asthma through the respiratory tract, which affords a higher drug concentration in the target tissue and lesser systemic exposure. It is therefore important to know the quality of inspiratory flow in patients with asthma who are subjected or amenable to treatment because, in the case of dry powder inhalers (DPIs), the flow must be higher than in the case of pressurized canister inhalers. AIMS: To evaluate the mean inspiratory flow (L/min) in such patients. METHODS: A total of 2387 Spanish patients were included in a cross-sectional, multicenter, noninterventional epidemiologic study. Inspiratory flux measurements were made, and the Asthma Control Test, Airways 20, and Morisky-Green questionnaires were used. RESULTS: The mean (standard deviation) inspiratory flow value measured was 72.39 +/- 25.04 L/min, and the value was <60 L/min in 29.8% of the patients. The DPI was the most widely used device among the patients in the study (61.4%), although no significant difference was observed between DPI and metered dose inhaler devices in previous studies demonstrated no significant differences between DPI and metered dose inhaler devices in efficacy and safety profiles. Significant differences were recorded according to patient age and weight. Although this was not an objective data analysis it presented interesting results for discussion. CONCLUSIONS: Before selecting the inhalation system, and especially in older patients and in individuals who are overweight or sedentary, it is very important to ensure that the inspiratory flow is sufficient to guarantee optimal drug deposition to improve asthma control and thus patient quality of life. PMID- 26534756 TI - Omalizumab in the treatment of allergic bronchopulmonary aspergillosis: One center's experience with 14 cases. AB - BACKGROUND: Omalizumab has been a valuable option for patients with severe allergic asthma, but there are only case reports regarding effectiveness of omalizumab in patients with allergic bronchopulmonary aspergillosis (ABPA). OBJECTIVE: To evaluate the clinical and functional effectiveness of omalizumab in patients with asthma and ABPA in long-term follow-up. METHODS: The study was conducted as a retrospective chart review of patients with ABPA who were treated with omalizumab injections between December 2008 and June 2014. Once treatment with omalizumab was started, data were collected at three time points: at baseline, after 1 year, and, in June 2014, at the last follow-up. RESULTS: Fourteen patients with ABPA (seven women and seven men; mean [+/- standard deviation (SD)] age, 44.21 +/- 13.01 years) were included. The treatment period was 31.5 +/- 3.99 months (mean +/- SD). The difference between the baseline and the last evaluation of the mean percentage of forced expiratory volume in 1 second (FEV1) was significant (p = 0.02). The mean asthma control test score was increased at all-time points compared with the basal score (p = 0.001). After omalizumab treatment was initiated, the patients' mean oral corticosteroid dosage significantly decreased (p = 0.001). The baseline exacerbation rate was 2.7 +/- 1.5/y (mean +/- SD), and the hospitalization rate was 1.4/y, and both were zero at the last assessment (p = 0.001). Eleven of the patients (78.6%) responded perfectly, and three (21.4%) partially responded to treatment. The patients who had a total immunoglobulin E level of <1000 IU/mL seemed to be more responsive than those whose total immunoglobulin E level was >1000 IU/mL (p = 0.05). CONCLUSION: Omalizumab provided a clinically important reduction in exacerbations and steroid requirement, and improved asthma symptoms and pulmonary function parameters in patients with asthma and ABPA who had previously shown an unsatisfactory response to Global Initiative for Asthma step 4 treatment. PMID- 26534757 TI - Drug reaction with eosinophilia and systemic symptoms syndrome. AB - BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening adverse drug reaction. OBJECTIVE: To increase awareness of the potential for recurrence in patients with a history of DRESS syndrome and provide a brief review of the clinical characteristics, diagnosis, and management of this disease process. METHODS: The authors selected and reviewed salient articles on the topic and incorporated pertinent information from the patient's clinical course. RESULTS: A case of recurrent DRESS triggered by a structurally unrelated drug is presented, followed by discussion of the clinical characteristics, diagnosis, and management. Clinical pearls and pitfalls are emphasized for the practicing allergist, clinical immunologist, and fellow-in training. CONCLUSIONS: The most important steps in the treatment of this condition are the identification and removal of the offending agent. Providers should be aware of the potential for recurrent DRESS and recognize the importance of prompt management. PMID- 26534758 TI - A 17-month-old patient with severe anemia and respiratory distress. AB - Anemia can be caused by, or be associated with, many clinical conditions, including pulmonary diseases, some of which are rare and can be misdiagnosed. Nontraumatic pulmonary bleeding may be caused by a variety of conditions and results in anemia and pulmonary hemosiderosis, even when it is subtle. The differential diagnosis in such cases is extensive. We present the case of a diagnostic dilemma in a 17-month-old child hospitalized for severe anemia and respiratory distress in which the diagnosis was settled through an allergy/immunology consultation. PMID- 26534759 TI - For the patient. PMID- 26534760 TI - Authors' reply to Braithwaite and Elrington. PMID- 26534761 TI - Possible role of increased oxidative stress in pulmonary hypertension in experimental diaphragmatic hernia. AB - PURPOSE: Congenital diaphragmatic hernia (CDH) is one of the causes of respiratory failure in newborns due to lung hypoplasia and pulmonary abnormalities leading to pulmonary hypertension (PH). NAD(P)H oxidase (Nox) is a family of isoenzymes that generate reactive oxygen species (ROS) which can contribute to PH-induced vascular dysfunction. On the other hand, superoxide dismutase (SOD) 1-2 and catalase are the antioxidant enzymes that eliminate the excess of ROS in pulmonary vascular cells. Our aim is to examine whether PH associated with CDH is due to a dysregulation of ROS production in lungs from CDH fetuses. METHODS: Pregnant rats received either 100 mg nitrofen or vehicle on E9.5. Fetuses were recovered on E21. (1) Nox activity, (2) H2O2 production and (3) mRNA levels of Nox1, Nox2, Nox4, SOD1, SOD2 and catalase were analyzed in fetal lungs. RESULTS: Nox activity and Nox1 and Nox2 mRNA levels were increased in the lungs of fetuses with CDH. However, there were no changes in H2O2 production and Nox4 mRNA levels. SOD1, SOD2 and catalase were decreased. CONCLUSIONS: The raised oxidative stress due to increase in ROS generation by Nox isoenzymes and dysfunction of antioxidant enzymes seems to be a potential mechanism responsible on PH-associated with CDH. PMID- 26534762 TI - Demographics and prevalence of positive QuantiFERON-TB Gold In-Tube test in renal transplant candidates. AB - BACKGROUND: Latent tuberculosis infection (LTBI) screening prior to solid organ transplantation is standard of care. QuantiFERON-TB Gold In-Tube (QFT-GIT) test is the preferred diagnostic test for renal transplant candidates (RTC). QFT-GIT reversions and the potential delay of living-donor kidney transplantation (LDKT) because of QFT-GIT positivity have not been examined previously in RTC. METHODS: We evaluated the prevalence of positive QFT-GIT in RTC from January 1 through December 31, 2011. In addition, we examined the demographic and renal disease data differences between QFT-GIT-positive and -negative patients, changes in QFT GIT results, and positive QFT-GIT results reverting to negative. Lastly, we evaluated if QFT-GIT-positive patients were less likely to undergo LDKT within 6 months of QFT-GIT testing. RESULTS: In total, 722 RTC were analyzed, 16% of whom had positive QFT-GIT. The QFT-GIT-positive patients were more likely to be older and foreign-born, P < 0.0001. Haitians had the highest prevalence. Of the 119 QFT GIT-positive patients, 25% had low/intermediate-positive results and were more likely to revert to negative, compared with patients with high-positive QFT-GIT results (50% vs. 0%, P = 0.01). A trend was seen toward fewer QFT-GIT-positive patients undergoing LDKT, compared with QFT-GIT-negative patients (0% vs. 3%, P = 0.09). CONCLUSIONS: Our high prevalence was likely a result of the high number of foreign-born RTC. Half of our small subset of low/intermediate-positive QFT-GIT patients reverted to negative. QFT-GIT-positive patients were more likely to have their LDKT delayed. PMID- 26534763 TI - Highly efficient extraction of anthocyanins from grape skin using deep eutectic solvents as green and tunable media. AB - Deep eutectic solvents (DESs) were investigated as tunable, environmentally benign, yet superior extraction media to enhance the extraction of anthocyanins from grape skin, which is usually discarded as waste. Ten DESs containing choline chloride as hydrogen bond acceptor combined with different hydrogen bond donors were screened for high extraction efficiencies based on the anthocyanin extraction yields. As a result, citric acid, D-(+)-maltose, and fructose were selected as the effective DES components, and the newly designed DES, CM-6 that is composed of citric acid and D-(+)-maltose at 4:1 molar ratio, exhibited significantly higher levels of anthocyanin extraction yields than conventional extraction solvents such as 80% aqueous methanol. The final extraction method was established based on the ultrasound-assisted extraction under conditions optimized using response surface methodology. Its extraction yields were double or even higher than those of conventional methods that are time-consuming and use volatile organic solvents. Our method is truly a green method for anthocyanin extraction with great extraction efficiency using a minimal amount of time and solvent. Moreover, this study suggested that grape skin, the by-products of grape juice processing, could serve as a valuable source for safe, natural colorants or antioxidants by use of the eco-friendly extraction solvent, CM-6. PMID- 26534764 TI - Overexpression of lysine-specific demethylase 1 promotes androgen-independent transition of human prostate cancer LNCaP cells through activation of the AR signaling pathway and suppression of the p53 signaling pathway. AB - Lysine-specific demethylase 1 (LSD1) is the first defined histone demethylase, and was found to be closely correlated with the development and progression of various types of cancers, including prostate cancer (PCa). Previous research suggests that LSD1 is closely related with cell proliferation, angiogenesis, migration and invasion in PCa. However, it remains to be elucidated whether LSD1 is correlated with androgen-independent (AI) transition of PCa under androgen ablated conditions. The present study aimed to investigate the correlation of LSD1 expression with AI transition of human androgen-dependent PCa LNCaP cells. Our data showed that LSD1 was overexpressed in human PCa specimens and in AI PCa LNCaP-AI cells, which were established through a three-month continuous culture of LNCaP cells in androgen-deprived medium. Under androgen-deprived conditions, LNCaP-AI cells grew perfectly with less apoptosis and G0/G1 cell cycle arrest. Overexpression of LSD1 protected the LNCaP cells from androgen deprivation induced apoptosis and G0/G1 arrest, while knockdown of LSD1 drove LNCaP-AI cells into a higher rate of apoptosis and G0/G1 arrest. Furthermore, LSD1 was found to regulate the androgen receptor (AR) and p53 signaling pathways via demethylation, subsequently influencing apoptosis and cell cycle progression. These findings revealed that overexpression of LSD1 promoted AI transition of PCa LNCaP cells under androgen-ablated conditions via activation of the AR signaling pathway and suppression of the p53 signaling pathway. PMID- 26534765 TI - Orexin A-induced enhancement of attentional processing in rats: role of basal forebrain neurons. AB - RATIONALE: Orexins are neuropeptides released in multiple brain regions from neurons that originate within the lateral hypothalamus and contiguous perfornical area. The basal forebrain, a structure implicated in attentional processing, receives orexinergic inputs. Our previous work demonstrated that administration of an orexin-1 receptor antagonist, SB-334867, systemically or via infusion directly into the basal forebrain, can disrupt performance in a task that places explicit demands on attentional processing. OBJECTIVES: Given that the orexin-1 receptor binds orexin A with high affinity, we tested whether orexin A could enhance attention in rats. METHODS: Attentional performance was assessed using a task that required discrimination of variable duration visual signals from trials when no signal was presented. We also tested whether infusions of orexin A into the lateral ventricle could attenuate deficits following lesions of medial prefrontal cortical cholinergic projections that arise from the basal forebrain. RESULTS: Infusions of orexin A into the basal forebrain attenuated distracter induced decreases in attentional performance. Orexin A attenuated deficits in lesioned animals when a visual distracter was presented. CONCLUSION: The present results support the view that orexin A can enhance attentional performance via actions in the basal forebrain and may be beneficial for some conditions characterized by attentional dysfunction due to disruption of cortical cholinergic inputs. PMID- 26534766 TI - Nuclear factor-kappaB in glioblastoma: insights into regulators and targeted therapy. AB - Nuclear factor-kappaB (NF-kappaB) is a ubiquitous transcription factor that regulates multiple aspects of cancer formation, growth, and treatment response. Glioblastoma (GBM), the most common primary malignant tumor of the central nervous system, is characterized by molecular heterogeneity, resistance to therapy, and high NF-kappaB activity. In this review, we examine the mechanisms by which oncogenic pathways active in GBM impinge on the NF-kappaB system, discuss the role of NF-kappaB signaling in regulating the phenotypic properties that promote GBM and, finally, review the components of the NF-kappaB pathway that have been targeted for treatment in both preclinical studies and clinical trials. While a direct role for NF-kappaB in gliomagenesis has not been reported, the importance of this transcription factor in the overall malignant phenotype suggests that more rational and specific targeting of NF-kappaB-dependent pathways can make a significant contribution to the management of GBM. PMID- 26534767 TI - The use of facial modeling and analysis to objectively quantify facial redness. AB - BACKGROUND: The reproducible evaluation of facial redness is critical to the assessment of erythematotelangiectatic rosacea. Assessments have typically focused on the use of photography with the use of semi-quantitative grading scales based on evaluator rating. However, few studies have utilized computer based algorithms to evaluate facial redness. AIM: The purpose of this clinical study was to assess whether there is correlation between clinical grading of facial redness to the assessment of a quantitative computer-based facial modeling and measurement. MATERIAL AND METHODS: In this prospective study, a set of high resolution facial photographs and cross-polarized subsurface photographs for erythema detection were obtained for 31 study participants. A computer algorithm was then utilized to detect and quantify facial redness in the photographs and compare this to semi-quantitative evaluator-based grading for facial redness. RESULTS: There was a strong correlation between computer-based cross-polarized subsurface erythema quantification and clinical grading for redness intensity (Clinical Erythema Assessment), redness distribution, and overall redness severity (Modified Clinical Erythema Assessment). CONCLUSION: Overall, facial redness measurements by facial imaging and computer analysis correlated well to clinical grading scales for both redness intensity and distribution. Future studies should incorporate facial modeling and analysis tools for assessments in clinical studies to introduce greater objectivity and quantitative analysis in facial erythema-based analyses. PMID- 26534768 TI - Clinical outcome of endoscopic management of duodenal Dieulafoy's lesions: endoscopic band ligation versus endoscopic hemoclip placement. AB - BACKGROUND: The most appropriate type of endoscopic hemostasis for bleeding due to duodenal Dieulafoy's lesions (DLs) is not yet established. The aim of this study was to assess the efficacy of mechanical endoscopic hemostasis for duodenal DLs and long-term outcome after successful hemostasis, as well as to compare the efficacy and safety of endoscopic band ligation (EBL) and endoscopic hemoclip placement (EHP). METHODS: Patients admitted to the emergency unit with acute upper gastrointestinal bleeding from duodenal DLs were enrolled in this study. The data were collected prospectively, but data analysis was performed retrospectively. Twenty-four patients with duodenal DLs were treated with EBL (n = 11) or EHP (n = 13). RESULTS: There were no significant differences between groups with respect to clinical or endoscopic characteristics, apart from the number of epinephrine (three cases with EBL vs. 11 cases with EHP; p = 0.011). Primary hemostasis was achieved in all patients. Recurrent bleeding was observed in one patient (9.1 %) from the EBL group and in five patients (38.5 %) from the EHP group (p = 0.166). The recurrent bleeding in the patient from the EBL group was treated by EHP. In the EHP group, all five patients achieved successful secondary hemostasis by endoscopic treatment (EBL in two patients and EHP in three patients). There were no differences in secondary outcomes between the two groups, including the number of endoscopic sessions required, need for angiographic embolization or emergent surgery, transfusion requirements, or length of hospital stay. No complications occurred, and there was no recurrence of bleeding in either group during the follow-up period. CONCLUSIONS: Mechanical endoscopic treatments are effective and safe for the treatment of bleeding duodenal DLs. A large-scale, randomized, controlled study is required to confirm the efficacy and safety of EBL and EHP for the management of bleeding duodenal DLs. PMID- 26534769 TI - Transumbilical single-incision laparoscopic cholecystectomy: long-term review from a single center. AB - BACKGROUND: Currently, researches about single-incision laparoscopic cholecystectomy (SILC) are various, but long-term reviews assessing relevant complications after SILC with considerable amount of case series are rare. STUDY DESIGN: We retrospectively reviewed a large series of 529 patients undergoing SILC to assess the long-term postoperative recovery, including postoperative complications, retained symptoms, and quality of life. Finally, we assessed its associated risk factors related to SILC patients' recovery in the long term. RESULTS: During a mean follow-up period of 36.8 +/- 8.8 months after SILC, 402 (76.0 %) patients underwent complete resolution. Frequent diarrhea (12.1 %) and recurrent omphalitis (5.9 %) were most commonly seen among other complications and retained symptoms within overall the patients. We identified 1 (0.3 %) incision hernia and 1 (0.3 %) intra-abdominal abscess among overall the patients, while 3 (0.8 %) common bile duct stones and 1 (0.3 %) biliary pancreatitis among the patients with symptomatic cholelithiasis during long-term review period. No significant differences were identified between patients with symptomatic cholelithiasis and gallbladder polyps when considering other incidences (all p > 0.05). Patients undergoing SILC with older age (p = 0.023) or female gender (p = 0.020) contributed to complete resolution. CONCLUSIONS: SILC via traditional devices is feasible and safe with acceptable postoperative incidence rate in the long run. Patients with older age or female gender, who have no severe systemic diseases, tend to benefit more from the surgical intervention. PMID- 26534770 TI - Minimally invasive surgery versus percutaneous radio frequency ablation for the treatment of single small (<=3 cm) hepatocellular carcinoma: a case-control study. AB - BACKGROUND: Patients with single small hepatocellular carcinoma (HCC) can be managed by surgical resection or radio frequency ablation (RFA), with similar recurrence and survival rates. Recently, minimally invasive surgery (MIS) has been introduced in liver surgery, and the advantage/drawback balance between surgery and RFA needs reassessment. METHODS: Patients with Child-Pugh class A or B cirrhosis, and with single 1-3 cm HCC, undergoing MIS (laparoscopic or robot assisted) or RFA from July 1998 to December 2012 were compared. RESULTS: Overall, 45 patients underwent MIS, and 60 underwent RFA. Groups were not statistically different regarding type of underlying liver disease, HCC size, and AFP. However, RFA patients showed worse liver synthetic function with lower albumin and higher bilirubin serum levels, and higher ASA scores. Patients with HCC in segments 2-6 were more often treated by MIS. The incidence of complications was similar between groups (RFA: 6/60, 10 % vs. MIS: 5/45, 11 %, p = 0.854), and there was no measurable difference in the rate of procedure-related blood transfusions (RFA: 1/60, 1.7 % vs. MIS: 3/45, 6.7 %, p = 0.185). Local recurrence was only detected after RFA (11.7 %, p = 0.056, log-rank). Overall survival was higher in the MIS group (p = 0.042), with median survivals of 100 +/- 13.5 versus 68 +/- 15.9 months. CONCLUSION: The present data need further validation. Selected patients with single <=3-cm HCCs can be safely treated by MIS, without increased risk of perioperative complication, and with a lower risk of local recurrence. MIS should be especially favoured in patients with peripheral HCCs in segments 2-6, and/or when a histological assessment is desirable. PMID- 26534771 TI - Informing phenomenological structural bone remodelling with a mechanistic poroelastic model. AB - Studies suggest that fluid motion in the extracellular space may be involved in the cellular mechanosensitivity at play in the bone tissue adaptation process. Previously, the authors developed a mesoscale predictive structural model of the femur using truss elements to represent trabecular bone, relying on a phenomenological strain-based bone adaptation algorithm. In order to introduce a response to bending and shear, the authors considered the use of beam elements, requiring a new formulation of the bone adaptation drivers. The primary goal of the study presented here was to isolate phenomenological drivers based on the results of a mechanistic approach to be used with a beam element representation of trabecular bone in mesoscale structural modelling. A single-beam model and a microscale poroelastic model of a single trabecula were developed. A mechanistic iterative adaptation algorithm was implemented based on fluid motion velocity through the bone matrix pores to predict the remodelled geometries of the poroelastic trabecula under 42 different loading scenarios. Regression analyses were used to correlate the changes in poroelastic trabecula thickness and orientation to the initial strain outputs of the beam model. Linear (R(2) > 0.998) and third-order polynomial (R(2) > 0.98) relationships were found between change in cross section and axial strain at the central axis, and between beam reorientation and ratio of bending strain to axial strain, respectively. Implementing these relationships into the phenomenological predictive algorithm for the mesoscale structural femur has the potential to produce a model combining biofidelic structure and mechanical behaviour with computational efficiency. PMID- 26534772 TI - Modeling the biomechanics of fetal movements. AB - Fetal movements in the uterus are a natural part of development and are known to play an important role in normal musculoskeletal development. However, very little is known about the biomechanical stimuli that arise during movements in utero, despite these stimuli being crucial to normal bone and joint formation. Therefore, the objective of this study was to create a series of computational steps by which the forces generated during a kick in utero could be predicted from clinically observed fetal movements using novel cine-MRI data of three fetuses, aged 20-22 weeks. A custom tracking software was designed to characterize the movements of joints in utero, and average uterus deflection of [Formula: see text] mm due to kicking was calculated. These observed displacements provided boundary conditions for a finite element model of the uterine environment, predicting an average reaction force of [Formula: see text] N generated by a kick against the uterine wall. Finally, these data were applied as inputs for a musculoskeletal model of a fetal kick, resulting in predicted maximum forces in the muscles surrounding the hip joint of approximately 8 N, while higher maximum forces of approximately 21 N were predicted for the muscles surrounding the knee joint. This study provides a novel insight into the closed mechanical environment of the uterus, with an innovative method allowing elucidation of the biomechanical interaction of the developing fetus with its surroundings. PMID- 26534773 TI - The association between primary bacteremia of presumed gastrointestinal origin and nonalcoholic fatty liver disease. PMID- 26534774 TI - Light-Controlled Cellular Internalization and Cytotoxicity of Nucleic Acid Binding Agents: Studies in Vitro and in Zebrafish Embryos. AB - We synthesized octa-arginine conjugates of DNA-binding agents (bisbenzamidine, acridine and Thiazole Orange) and demonstrated that their DNA binding and cell internalization can be inhibited by appending a (negatively charged) oligoglutamic tail through a photolabile linker. UV irradiation released the parent conjugates, thus restoring cell internalization and biological activity. Assays with zebrafish embryos demonstrates the potential of this prodrug strategy for controlling in vivo cytotoxicity. PMID- 26534775 TI - Creating Youth-Supportive Communities: Outcomes from the Connect-to-Protect(r) (C2P) Structural Change Approach to Youth HIV Prevention. AB - Reducing HIV incidence among adolescents represents an urgent global priority. Structural change approaches to HIV prevention may reduce youth risk by addressing the economic, social, cultural, and political factors that elevate it. We assessed whether achievement of structural changes made by eight Connect-to Protect (C2P) coalitions were associated with improvements in youth's views of their community over the first 4 years of coalitions' mobilization. We recruited annual cross-sectional samples of targeted youth from each C2P community. We sampled youth in neighborhood venues. We interviewed a total of 2461 youth over 4 years. Males (66 %) and youth of color comprised the majority (52 % Hispanic/Latinos; 41 % African Americans) of those interviewed. By year 4, youth reported greater satisfaction with their community as a youth-supportive setting. They reported their needs were better met by available community resources compared with year 1. However, these findings were moderated by risk population such that those from communities where C2P focused on young men who have sex with men (YMSM) reported no changes over time whereas those from communities focused on other at-risk youth reported significant improvements over time in satisfaction and resource needs being met. Internalized HIV stigma increased over time among those from communities serving other at-risk youth and was unchanged among those from YMSM communities. The very different results we observe over time between communities focused on YMSM versus other at-risk youth may suggest it is unreasonable to assume identical chains of structural causality across youth populations who have such different historical relationships to HIV and who encounter very different kinds of entrenched discrimination within their communities. PMID- 26534776 TI - Online Self-Presentation on Facebook and Self Development During the College Transition. AB - Self-presentation, a central element of young people's identity development, now extends from face-to-face contexts to social networking sites. Online self presentation may change when youth transition to college, faced with the need to reclaim or redefine themselves in the new environment. Drawing on theories of self-presentation and self development, this study explores changes in youth's online self-presentation during their transition to a residential college. It also examines associations between online self-presentation and students' self esteem and self-concept clarity. We surveyed 218 college freshmen (M age = 18.07; 64 % female, 79 % White) at the beginning and again at the end of their first semester. Freshmen's Facebook self-presentation became less restricted later in the semester. Broad, deep, positive, and authentic Facebook self-presentation was positively associated with perceived support from the audience, which contributed to higher self-esteem contemporaneously, though not longitudinally. Intentional Facebook self-presentation engaged students in self-reflection, which was related to lower self-concept clarity concurrently but higher self-esteem longitudinally. Findings clarified the paths from multifaceted online self-presentation to self development via interpersonal and intrapersonal processes during college transition. PMID- 26534777 TI - From Vulnerability to Dignity: The RN Declaration of Self-Esteem. AB - BACKGROUND: Registered nurses (RNs) experience vulnerability from a variety of sources in today's healthcare organizations. While RN vulnerability can be associated with positive outcomes with patients and clients, vulnerability can also be dangerous to RNs as they struggle with outside forces that many feel they have no control over. AIMS: The study aims to maintain and enhance the dignity of RNs and provide a beacon to RNs who may have become wounded in the healthcare setting and/or their own profession. SETTING: The study was conducted in a conference entitled "Advancing Nursing Practice Through Change, Innovation and Creativity" held at a midsized university in western Canada. PARTICIPANTS: The participants were 115 administrators, members of RN regulatory bodies, nursing faculty, nurse educators, and staff nurses. METHODS: An activity entitled "Wild Thinking" gave participants an opportunity to reflect upon the conference and their personal experiences of change, innovation, and creativity they wished to see within the workplace. All responses were collected at the end of the activity, transcribed verbatim, and analyzed for themes. RESULTS: Arising from 16 themes, the RN Declaration of Self-Esteem was created. CONCLUSION: The RN Declaration of Self-Esteem may be helpful in promoting empowerment at the individual RN level as well as in the collective professional level. Janzen Mitchell Renton Currie Nordstrom. PMID- 26534778 TI - Regulation of SPRY3 by X chromosome and PAR2-linked promoters in an autism susceptibility region. PMID- 26534779 TI - DNA Triplexes That Bind Several Cofactor Molecules. AB - Invited for the cover of this issue are Sven Vollmer and Clemens Richert of the University of Stuttgart. The cover image hints at the analogy between a honey comb, as a macroscopic storage device, and DNA triplexes with designed binding sites, as molecular storage motifs that can release ATP to fuel a bioluminescence reaction. Read the full text of the article at 10.1002/chem.201503220. PMID- 26534780 TI - Carbonic anhydrase inhibitors: Design, synthesis, kinetic, docking and molecular dynamics analysis of novel glycine and phenylalanine sulfonamide derivatives. AB - The inhibition of two human cytosolic carbonic anhydrase isozymes I and II, with some novel glycine and phenylalanine sulfonamide derivatives were investigated. Newly synthesized compounds G1-4 and P1-4 showed effective inhibition profiles with KI values in the range of 14.66-315MUM for hCA I and of 18.31-143.8MUM against hCA II, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico docking studies were applied. Atomistic molecular dynamic simulations were performed for docking poses which utilize to illustrate the inhibition mechanism of used inhibitors into active site of CAII. These sulfonamide containing compounds generally were competitive inhibitors with 4 nitrophenylacetate as substrate. Some investigated compounds here showed effective hCA II inhibitory effects, in the same range as the clinically used sulfonamide, sulfanilamide or mafenide and might be used as leads for generating enzyme inhibitors possibly targeting other CA isoforms which have not been yet assayed for their interactions with such agents. PMID- 26534781 TI - Soft matter food physics--the physics of food and cooking. AB - This review discusses the (soft matter) physics of food. Although food is generally not considered as a typical model system for fundamental (soft matter) physics, a number of basic principles can be found in the interplay between the basic components of foods, water, oil/fat, proteins and carbohydrates. The review starts with the introduction and behavior of food-relevant molecules and discusses food-relevant properties and applications from their fundamental (multiscale) behavior. Typical food aspects from 'hard matter systems', such as chocolates or crystalline fats, to 'soft matter' in emulsions, dough, pasta and meat are covered and can be explained on a molecular basis. An important conclusion is the point that the macroscopic properties and the perception are defined by the molecular interplay on all length and time scales. PMID- 26534782 TI - Interfacial zippering-up of coiled-coil protein filaments. AB - Protein self-assembled materials find increasing use in medicine and nanotechnology. A challenge remains in our ability to tailor such materials at a given length scale. Here we report a de novo self-assembly topology which enables the engineering of filamentous protein nanostructures under morphological control. The rationale is exemplified by a ubiquitous self-assembly motif - an alpha-helical coiled-coil stagger. The stagger incorporates regularly spaced interfacial tryptophan residues, which allows it to zipper up into discrete filaments that bundle together without thickening by maturation. Using a combination of spectroscopy, microscopy, X-ray small-angle scattering and fibre diffraction methods we show that the precise positioning of tryptophan residues at the primary and secondary structure levels defines the extent of coiled-coil packing in resultant filaments. Applicable to other self-assembling systems, the rationale holds promise for the construction of advanced protein-based architectures and materials. PMID- 26534783 TI - A Mobile Phone App for Dietary Intake Assessment in Adolescents: An Evaluation Study. AB - BACKGROUND: There is a great need for dietary assessment methods that suit the adolescent lifestyle and give valid intake data. OBJECTIVE: To develop a mobile phone app and evaluate its ability to assess energy intake (EI) and total energy expenditure (TEE) compared with objectively measured TEE. Furthermore, to investigate the impact of factors on reporting accuracy of EI, and to compare dietary intake with a Web-based method. METHODS: Participants 14 to 16 years of age were recruited from year nine in schools in Gothenburg, Sweden. In total, 81 adolescents used the mobile phone app over 1 to 6 days. TEE was measured with the SenseWear Armband (SWA) during the same or proximate days. Individual factors were assessed with a questionnaire. A total of 15 participants also recorded dietary intake using a Web-based method. RESULTS: The mobile phone app underestimated EI by 29% on a group level (P<.001) compared to TEE measured with the SWA, and there was no significant correlation between EI and TEE. Accuracy of EI relative to TEE increased with a weekend day in the record (P=.007) and lower BMI z-score (P=.001). TEE assessed with the mobile phone app was 1.19 times the value of TEE measured by the SWA on a group level (P<.001), and the correlation between the methods was .75 (P<.001). Analysis of physical activity levels (PAL) from the mobile phone app stratified by gender showed that accuracy of the mobile phone app was higher among boys. EI, nutrients, and food groups assessed with the mobile phone app and Web-based method among 15 participants were not significantly different and several were significantly correlated, but strong conclusions cannot be drawn due to the low number of participants. CONCLUSIONS: By using a mobile phone dietary assessment app, on average 71% of adolescents' EI was captured. The accuracy of reported dietary intake was higher with lower BMI z score and if a weekend day was included in the record. The daily question in the mobile phone app about physical activity could accurately rank the participants' TEE. PMID- 26534784 TI - The influence of dementia on injury-related hospitalisations and outcomes in older adults. AB - INTRODUCTION: Injury is the most common reason for admission to hospital in people with dementia in Australia. However relatively little is known about the temporal trends and the hospital experience of people with dementia hospitalised for an injury. This population-based data linkage study compared the causes, temporal trends and health outcomes for injury-related hospitalisations in people with and without dementia. METHODS: Hospitalisation and death data for 235,612 individuals aged 65 years and over admitted to hospital for an injury over the ten year period (2003-2012) in New South Wales, Australia were probabilistically linked. Descriptive statistics including chi square tests, observed and age standardised admission rates and rate ratios (RRs) were calculated. Trends over time were analysed using negative binomial regression. RESULTS: There were 331,432 injury-related hospitalisations over the study period. Both the observed (RR 3.16; 95% CI 3.13-3.19) and age-standardised admission rate ratios (RR 1.78; 95% CI 1.77-1.79) were higher for people with dementia. Age-standardised rates increased by 3.5% (95% CI 3.1-3.9) per annum over the study period for people without dementia. In contrast, for people with dementia, rates increased by 2.4% (95% CI 1.8-3.1) per annum until 2007 and then decreased by 3.1% (95% CI -4.4 to 1.7) per annum from 2007 onwards. Compared to people without dementia, a higher proportion of people with dementia were hospitalised as a result of a fall (90.9% vs 75.2%, p<0.0001), sustained a fracture (57.2% vs 52.1%, p<0.0001), notably hip fracture (30.7% vs 14.7%, p<0.0001), had longer mean hospital lengths of stay (LOS) (16.5 vs 13.6 days), and higher 30-day mortality (8.7% vs 3.6% p<0.0001), although this pattern was not consistent across all injury types. CONCLUSIONS: People with dementia are disproportionately represented in injury-related hospitalisations, experience longer hospital LOS and have poorer outcomes. Ninety percent of hospitalisations for people with dementia were as a result of a fall, highlighting the importance of developing and implementing effective fall-related preventive strategies in this high risk population. PMID- 26534785 TI - In response: Disability after nondisplaced and minimally displaced radial head fractures [Injury 45 (2014) 2110-2119]. PMID- 26534786 TI - Pollen food syndrome amongst children with seasonal allergic rhinitis attending allergy clinic. AB - BACKGROUND: There is limited information regarding the onset and sensitization patterns of pollen food syndrome (PFS) in children. The aim was to explore this within children referred to a specialist allergy clinic at a London Tertiary Hospital. METHODS: A total of 54 patients with seasonal allergic rhinitis (SAR) were enrolled in equal numbers in three age groups; 0-5, 6-10, 11-15 years. Families completed a questionnaire on rhinitis, food symptoms and quality of life. Children underwent skin prick testing (SPT) to fresh fruits, nuts and a blood test for microarray analysis. RESULTS: Clinical diagnosis of PFS was made in 26/54 (48%), increasing with age (group 1 = 3 (17%), group 2 = 9 (50%), group 3 = 14 (78%) (p = 0.03)). Microarray demonstrates children aged 2.8 years sensitized to pan-allergens and 4.5 years symptomatic to pan-allergens. Peach, cherry, carrot and strawberry SPT had the highest sensitivity and NPV at 100%. The sensitivity of PR10 molecules on microarray was 92%, PPV 62% and NPV 87%. Microarray confirmed 69% of allergens on clinical history compared to 61% by SPT. Microarray and SPT had a 19% false-negative rate. The quality-of-life data showed moderate impact across all domains, and patients with PFS were significantly more likely to have increased anxiety over time spent preparing food (p = 0.029). CONCLUSIONS: We demonstrate that SAR occurs in children from 1.4 years and PFS from 4.5 years with a changing pattern of pan-allergen sensitization. Microarray and SPT have moderate concordance in confirming allergens. PFS impacts negatively on quality of life and should be assessed in all paediatric allergy patients. PMID- 26534787 TI - Transcriptional Impact of Rare and Private Copy Number Variants in Hypoplastic Left Heart Syndrome. AB - BACKGROUND: Hypoplastic left heart syndrome (HLHS) is a heterogeneous, lethal combination of congenital malformations characterized by severe underdevelopment of left heart structures, resulting in a univentricular circulation. The genetic determinants of this disorder are largely unknown. Evidence of copy number variants (CNVs) contributing to the genetic etiology of HLHS and other congenital heart defects has been mounting. However, the functional effects of such CNVs have not been examined, particularly in cases where the variant of interest is found in only a single patient. METHODS AND RESULTS: Whole-genome SNP microarrays were employed to detect CNVs in two patient cohorts (N = 70 total) predominantly diagnosed with some form of nonsyndromic HLHS. We discovered 16 rare or private variants adjacent to or overlapping 20 genes associated with cardiovascular or premature lethality phenotypes in mouse knockout models. We evaluated the impact of selected variants on the expression of nine of these genes through quantitative PCR on cDNA derived from patient heart tissue. Four genes displayed significantly altered expression in patients with an overlapping or proximal CNV verses patients without such CNVs. CONCLUSION: Rare and private genomic imbalances perturb transcription of genes that potentially affect cardiogenesis in a subset of nonsyndromic HLHS patients. PMID- 26534788 TI - Medication beliefs and structural barriers to treatment adherence among people living with HIV infection. AB - BACKGROUND: People living in poverty face multiple structural challenges to medication adherence including lack of transportation, inadequate housing and food insecurity. The degree to which individuals' motivations to remain adherent may overcome structural barriers has received limited attention. PURPOSE: To examine whether medication necessity and concerns beliefs predict antiretroviral therapy (ART) adherence over and above structural adherence barriers associated with poverty. METHODS: People living with HIV in a southern US city (N = 942) completed computerised interviews, an objective measure of adherence and HIV viral suppression obtained from medical records. Hierarchical logistic regression models were constructed to examine demographic and illness characteristics, structural barriers, mental health, substance use and medication necessity and concerns beliefs as predictors of ART adherence. RESULTS: In multivariable models, current drug use and medication necessity and concerns beliefs predicted treatment adherence over and above demographic, health, mental health and structural factors. CONCLUSIONS: Medication beliefs are proximal and powerful motivating factors that predict adherence. Adherence interventions should directly address medication beliefs in developing strategies to manage barriers facing people with HIV living in poverty. PMID- 26534790 TI - Dr Computer. PMID- 26534789 TI - Circulating miR-106a is a Novel Prognostic and Lymph Node Metastasis Indicator for Cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is a common biliary malignancy. Despite continuing advances, novel indicators are urgently needed to identify patients with a poor prognosis. Several microRNAs (miRNAs) have been reported to be dysregulated in CCA tissues. The purpose of the current study was to explore the potential use of certain miRNAs as serum indicators. A total of 157 individuals, including103 CCA patients, were recruited into this study. We first used qRT-PCR to evaluate 5 CCA related miRNAs in the serum of 95 individuals to identify significantly deregulated miRNAs. A logistic regression was used to analyse the potential variables influencing lymph node metastasis. Cox proportional hazards regression models were applied to determine the association between possible prognostic variables and overall survival (OS). We observed that decreased serum miR-106a confers a higher likelihood of lymph node metastasis [hazard ratio (HR) 18.3, 95% confidence interval (CI) 5.9-56.4, p < 0.01]. Additionally, lower circulating miR 106a levels (HR 5.1; 95% CI 2.2-11.8; p < 0.01) and non-radical surgery (HR 4.2; 95% CI 2.3-7.7; p < 0.01) were independent predictors for poor prognosis. Together, reduced expression of serum miR-106a is a powerful prognostic indicator for CCA patients. The dismal outcome of these CCA patients might correlate with a higher risk of lymph node metastasis. PMID- 26534791 TI - Diagnostic success with pitfalls. PMID- 26534792 TI - [Re: The practice consultant scheme at a crossroads]. PMID- 26534793 TI - [Re: Physician heroes--and antiheroes]. PMID- 26534794 TI - [S.C. Hoymork replies]. PMID- 26534795 TI - [Re: We should stop using the word demented]. PMID- 26534796 TI - [O. Aga replies]. PMID- 26534797 TI - [Re: The Norwegian Care Coordination Reform--what now?]. PMID- 26534798 TI - [A.Grimsmo replies]. PMID- 26534799 TI - [Re: An indispensable tool]. PMID- 26534800 TI - [E. Skovlund replies]. PMID- 26534801 TI - [Re: A woman in her 60s with itching arms]. PMID- 26534802 TI - [J.A. Halvorsen & K. Orstavik reply]. PMID- 26534803 TI - [Re: All suicides are not due to treatment failure]. PMID- 26534804 TI - [Obese, fat or just overweight?]. PMID- 26534805 TI - [An illogical and unfortunate side effect term]. PMID- 26534806 TI - [Cumulative summation in monitoring postoperative wound infections]. PMID- 26534807 TI - [In Process Citation]. PMID- 26534808 TI - [In Process Citation]. PMID- 26534809 TI - Clinical exome sequencing - Norwegian findings. AB - BACKGROUND: New DNA-sequencing technology is revolutionising medical diagnostics. Through the use of exome sequencing, it is now possible to sequence all human genes in parallel. This technology has been widely used in research over the last few years and is now also being applied to diagnostics. The aim of this study was to systematically examine initial experiences with diagnostic exome sequencing in Norway. MATERIAL AND METHOD: This is a retrospective observational study of the results of all exome sequencing performed by the Section of Medical Genetics at Telemark Hospital between December 2012 and October 2014, and includes 125 persons in 46 families. The majority of these families were being investigated for a syndrome (n = 35, 76%) or neurological disease (n = 9, 20%). RESULTS: Exome sequencing detected pathogenic sequence variants in 15 of 46 probands, and variants of unknown significance in 12 probands. Of the 100 patients who stated their wishes regarding feedback of any incidental findings, six indicated that they did not wish to receive such information. There were no incidental findings in this study, but neither were such sequence variants actively looked for. INTERPRETATION: Exome sequencing can enable more patients with syndromes or neurological diseases to receive a causal diagnosis, and to receive this diagnosis at an earlier stage. However, the patients in this study were quite highly selected, and the results must therefore be interpreted with caution. PMID- 26534810 TI - Hereditary peripheral neuropathies diagnosed by next-generation sequencing. AB - BACKGROUND: Next-generation sequencing (NGS) is a genetic technique used to determine the order of nucleotides in DNA. The technique has proved to be more efficient than the traditional method, Sanger sequencing, for sequencing multiple genes. NGS is now being used to diagnose disorders in which multiple genes are involved. This study has examined whether next-generation sequencing produces a greater number of positive diagnoses than its traditional counterpart in patients with suspected hereditary peripheral neuropathy. MATERIAL AND METHOD: This study is a retrospective review of samples from 103 patients investigated for hereditary peripheral neuropathy, received by Telemark Hospital in the period 2012-14. After exclusion of duplication/deletion of PMP22, 96 samples were analysed by NGS with physical enrichment of 52 hereditary peripheral neuropathy genes. RESULTS: A genetic cause was identified in 35 patients (34%) with peripheral neuropathy, of which 28 (27%) were point mutations identified by NGS. INTERPRETATION: Of the pathogenic point mutations identified in this study, 12 were in genes that would previously have been analysed by Sanger sequencing in our department, whereas 16 were in genes that would not previously have been tested. PMID- 26534811 TI - Lung cancer - changes in incidence by gender, age and county of residence 1984 2013. AB - BACKGROUND: The Cancer Registry of Norway has reported a decline in age standardised lung cancer rates for men and an unconfirmed levelling-off in the rate for women. This study describes the development in trends according to gender and age, nationwide as well as by county. MATERIAL AND METHOD: Data on lung cancer from the Cancer Registry of Norway and the NORDCAN website are presented as age-specific and age-standardised rates by gender and place of residence, with a main emphasis on the period 1984-2013. RESULTS: Out of 62,937 Norwegian lung cancer patients (1984-2013), altogether 63% were men. Nationally there was a decline in the rate for middle-aged men (50-69 years), but only a levelling-off in the oldest age group (>= 70 years). For women, the rates increased in both age groups, most markedly in the oldest one. The rates for older men in the Agder, Vestfold and Finnmark counties have remained above the national average for a prolonged period, and there are only modest signs of a decline among the middle-aged. Oslo is a clear exception, with a clear and sustained decline among men in both age groups. Vest-Agder county had the highest rate for women during the last five-year period, while the rates in Oslo are now at the national average. The national rates for middle-aged women and middle-aged men are converging, intersecting each other in Akershus county. INTERPRETATION: The large differences between genders, age groups, counties and nations in terms of trends in lung cancer indicate that through preventive efforts, we might have achieved much more in a shorter time. PMID- 26534812 TI - Congenital mirror movements of the hands. PMID- 26534813 TI - A woman in her 60s with large thrombotic masses in the aorta. PMID- 26534814 TI - A man with fever, urticaria, periorbital oedema and dry cough. PMID- 26534815 TI - [A forgotten pioneer]. PMID- 26534816 TI - The sea route to Europe - a Mediterranean massacre. PMID- 26534817 TI - [E-health and m-health]. PMID- 26534818 TI - [In Process Citation]. PMID- 26534820 TI - [The wonders of practical teaching]. PMID- 26534821 TI - [Interview when hiring interns]. PMID- 26534822 TI - [Surgical treatment of lumbar spinal stenosis]. PMID- 26534823 TI - [ESBL - risk factors and treatment]. PMID- 26534824 TI - Medication safety at the interface: evaluating risks associated with discharge prescriptions from mental health hospitals. AB - WHAT IS KNOWN AND OBJECTIVE: When compared to general hospitals, relatively little is known about the quality and safety of discharge prescriptions from specialist mental health settings. We aimed to investigate the quality and safety of discharge prescriptions written at mental health hospitals. METHODS: This study was undertaken on acute adult and later life inpatient units at three National Health Service (NHS) mental health trusts. Trained pharmacy teams prospectively reviewed all newly written discharge prescriptions over a 6-week period, recording the number of prescribing errors, clerical errors and errors involving lack of communication about medicines stopped during hospital admission. All prescribing errors were reviewed and validated by a multidisciplinary panel. Main outcome measures were the prevalence (95% CI) of prescribing errors, clerical errors and errors involving a lack of details about medicines stopped. Risk factors for prescribing and clerical errors were examined via logistic regression and results presented as odds ratios (OR) with corresponding 95% CI. RESULTS AND DISCUSSION: Of 274 discharge prescriptions, 259 contained a total of 1456 individually prescribed items. One in five [20.8% (95%CI 15.9-25.8%)] eligible discharge prescriptions and one in twenty [5.1% (95%CI 4.0-6.2%)] prescribed or omitted items were affected by at least one prescribing error. One or more clerical errors were found in 71.9% (95%CI 66.5 77.3%) of discharge prescriptions, and more than two-thirds [68.8% (95%CI 56.6 78.8%)] of eligible discharge prescriptions erroneously lacked information on medicines discontinued during hospital admission. Logistic regression analyses revealed that middle-grade [whole discharge prescription level OR 3.28 (3.03 3.56)] and senior [whole discharge OR 1.43 (1.04-1.96)] prescribers as well as electronic discharge prescription pro formas [whole discharge OR 2.43 (2.08 2.83)] were all associated with significantly higher risks of prescribing errors than junior prescribers and handwritten discharges, respectively. Similar findings were reported at the individually prescribed item level. Middle-grade prescribers were also more likely to make both non-psychotropic and psychotropic prescribing errors than their junior colleagues [individual item OR 4.24 (2.14 8.40) and OR 1.70 (1.16-2.48), respectively]. WHAT IS NEW AND CONCLUSION: Discharge prescriptions issued by mental health NHS hospitals are affected by high levels of prescribing, clerical and communication errors. Important targets for intervention have been identified to improve medication safety problems at care transfer. PMID- 26534825 TI - Improved cellular thermotolerance in cloned Holstein cattle derived with cytoplasts from a thermotolerant breed. AB - The objective of this study was to compare the thermotolerance of ear fibroblasts derived from various SCNT cattle. Specimens were produced from cloned embryos that had been reconstructed using donor cells (d) from the same Holstein cow (Hd) and the ooplasm (o) from Holstein cattle (Ho) or Taiwan yellow cattle (Yo). Polymorphism in the D-loop region of mitochondrial DNA in ear fibroblasts derived from SCNT cattle reconstructed with the Y ooplasm and H donor cells (SCNT-Yo-Hd) indicates that the cytoplasm originated from Bos indicus. The rates of apoptosis in heat-shocked ear fibroblasts derived from SCNT-Yo-Hd cattle (1.9%) and purebred Y cattle (1.5%) were significantly (P < 0.05) lower than those of cells derived from SCNT cattle reconstructed with the H ooplasm (SCNT-Ho-Hd: 3.4%), donor cells (4.0%), and purebred Holstein (4.1%) cattle. At the protein level, the relative abundances of apoptosis-inducing factor, B cell lymphoma 2 associated X protein, endonuclease G, cytochrome c, cysteinyl aspartate-specific proteinases 3, 8 and 9 in ear fibroblasts derived from SCNT-Yo-Hd cattle were significantly (P < 0.05) lower than those of cells derived from SCNT-Ho-Hd cattle after heat shock. In contrast, the relative abundances of heat shock proteins 27, 70 and B cell lymphoma 2 in ear fibroblasts derived from SCNT-Yo-Hd cattle were higher (P < 0.05) than those of fibroblasts derived from SCNT-Ho-Hd cattle. Moreover, heat-shocked ear fibroblasts derived from SCNT-Yo-Hd cattle have a significantly (P < 0.05) lower percentage of apoptosis-inducing factor-positive nuclei than do heat-shocked ear fibroblasts derived from SCNT-Ho-Hd cattle (11.1% vs. 18.5%). Taken together, these results report that ear fibroblasts derived from SCNT cattle reconstructed using the Y ooplasm are more thermotolerant than ear fibroblasts derived from SCNT cattle reconstructed using the H ooplasm. This is an indication that the cytoplasm may be a major determinant of thermal sensitivity in bovine ear fibroblasts. PMID- 26534826 TI - Failure of a single dose of medroxyprogesterone acetate to induce uterine infertility in postnatally treated domestic cats. AB - In mice and sheep, neonatal administration of progesterone or progestins inhibited development of uterine glands. The aims of the present study were (1) to describe uterine gland development on postnatal Days 6 to 8 and (2) to evaluate the effects of a single postnatal administration of a progestin on reproduction and adult uterine glands morphology and function in domestic cats. Necropsy was performed on three 1-week-old female cats which had died unrelated to this study. Ten female kittens were randomly assigned within the first 24 hours of birth to: medroxyprogesterone acetate 10 mg/animal subcutaneously (MPA; n = 6) or placebo (PLC; n = 4) and followed up until puberty when they were mated. Twenty-four days after the end of estrus, ovulation and pregnancy were diagnosed by serum progesterone measurement and ultrasonography, respectively. Then, all the cats were ovariohysterectomized. After necropsy or surgery, the excised organs were histologically evaluated. Seven queens ovulated (4 of 6 MPA and 3 of 4 PLC; P > 0.1) and were pregnant (P > 0.1). Four MPA cats presented endometrial hyperplasia and one of them developed a pyometra. The 1-week-old females presented uterine glands in the stage of budding and incipient penetration of the glandular epithelium into the underlying stroma. The MPA treated queens revealed that the area occupied by uterine glands per square micrometer (0.55 +/- 0.2 vs. 0.49 +/- 0.2; P > 0.1) and the height of the glandular epithelium (MUm; 24.5 +/- 6.7 vs. 24.4 +/- 7.2; P > 0.1) did not differ from those of the PLC group. Neither significant gross nor microscopical differences were also found for ovaries (P > 0.1). It is concluded that 1-week old kittens had an incipient stage of uterine gland development and that a single postnatal supraphysiological dose of MPA did not alter uterine adenogenesis in this species. Furthermore, this treatment seemed to predispose to uterine disease without prevention of fertility. PMID- 26534827 TI - Detection of genes encoding multidrug resistance and biofilm virulence factor in uterine pathogenic bacteria in postpartum dairy cows. AB - Reckless use of antibiotics and/or development of biofilm are the rationale for the development of multidrug resistance (MDR) of pathogenic bacteria. The objective of the present study was to detect MDR genes in Trueperella pyogenes and to detect biofilm virulence factor (VF) genes in Escherichia coli isolated from the uterus of postpartum dairy cows. Uterine secretions from different parity postpartum Holstein cows (n = 40) were collected using cytobrush technique after a sterile procedure from cows with varying degree of uterine inflammatory conditions. The cytobrush was stored in a specimen collector, placed in a cooler with ice, and transported to the laboratory within 2 hours. The pathogens were isolated and were identified initially by their colony morphology and biochemical characteristics. To further identify and classify the single species, and to determine the presence of MDR and VF genes, the genes fragments were amplified using the respective primers by either singleplex or multiplex polymerase chain reaction protocol, and amplicons were detected by electrophoresis method. T pyogenes was isolated in 17 of 40 (42.5%) cows in the study population as recognized by the 16S rRNA gene. Of the positive T pyogenes samples, 8 of 17 (42.1%) were positive for integron type 1 (intI I), and none were positive for integron type 2 (intI II). Of those 8 positive for intI I, six of eight (66.7%) were positive for amplicons aadA5 and aadA24-ORF1 at 1048 and 1608 bp, respectively, associated with specific drug resistance. Presence of addA5 indicated resistance to sulfadiazine, bacitracin, florfenicol, and ceftiofur. Presence of addA24-ORF1 indicated resistant to sulfadiazine, bacitracin, penicillin, clindamycin, and erythromycin. E coli was isolated in 18 of 40 (45.0%) cows in the study population. The genes for VF, Agn43a, and Agn43 b, associated with biofilm production, were found in 6 of 18 (33.3%) of the positive isolates. Both T pyogenes MDR gene and E coli biofilm VF existed in more severe form of uterine diseases than subclinical endometritis. In conclusion, 35% of T pyogenes isolates found were positive for a gene cassette associated with antibiotic resistance, and 33% of the E coli isolates contained genes for the VF associated with biofilm production. PMID- 26534828 TI - Is Unilateral Implant or Autologous Breast Reconstruction Better in Obtaining Breast Symmetry? AB - Unilateral breast reconstruction poses a special set of challenges to the reconstructive breast surgeon compared to bilateral reconstructions. No studies to date provide an objective comparison between autologous and implant based reconstructions in matching the contralateral breast. This study compares the quantitative postoperative results between unilateral implant and autologous flap reconstructions in matching the native breast in shape, size, and projection using three-dimensional (3D) imaging. Sixty-four patients who underwent unilateral mastectomy with tissue expander (TE)-implant (n = 34) or autologous microvascular free transverse rectus abdominus myocutaneous (TRAM; n = 18) or deep inferior epigastric artery perforator (DIEP; n = 12) flap (n = 30) reconstruction from 2007 to 2010 were analyzed. Key patient demographics and risk factors were collected. Using 3D scans of patients obtained during pre and postoperative visits including over 1 year follow-ups for both groups, 3D models were constructed and analyzed for total breast volume, anterior-posterior projection from the chest wall, and 3D comparison. No significant differences in mean age, body mass index, or total number of reconstructive surgeries were observed between the two groups (TE-implant: 52.2 +/- 10, 23.9 +/- 3.7, 3 +/- 0.9; autologous: 50.7 +/- 9.4, 25.4 +/- 3.9, 2.9 +/- 1.3; p > 0.05). The total volume difference between the reconstructed and contralateral breasts in the TE implant group was insignificant: 27.1 +/- 22.2 cc, similar to the autologous group: 29.5 +/- 24.7 cc, as was the variance of breast volume from the mean. In both groups, the reconstructed breast had a larger volume. A-P projections were similar between the contralateral and the reconstructed breasts in the TE-implant group: 72.5 +/- 3.21 mm versus 71.7 +/- 3.5 mm (p > 0.05). The autologous reconstructed breast had statistically insignificant but less A-P projection compared to the contralateral breast (81.9 +/- 16.1 mm versus 61.5 +/- 9.5 mm; p > 0.05). Variance of A-P projection from the mean was additionally insignificant between the contralateral and reconstructed breasts. Both groups produced similar asymmetry scores based on global 3D comparison (TE-implant: 2.24 +/- 0.3 mm; autologous: 1.96 +/- 0.2 mm; p > 0.05). Lastly, when the autologous group was further subdivided into TRAM and DIEP cohorts, no significant differences in breast volume, A-P projection or symmetry existed. Using 3D imaging, we demonstrate that both TE-implant and autologous reconstruction can achieve symmetrical surgical results with the same number of operations. This study demonstrates that breast symmetry, while an important consideration in the breast reconstruction algorithm, should not be the sole consideration in a patient' decision to proceed with autologous versus TE-implant reconstruction. PMID- 26534829 TI - Comparison of quality of sleep, depression, and life satisfaction between older adults in nursing homes and long-term care hospitals in Korea. AB - AIM: The purpose of the present study was to identify the sleep quality, depression, and life satisfaction between nursing home and long-term care hospital residents. METHODS: Data was collected through a structured questionnaire survey of 61 nursing home residents and 74 long-term care hospital residents. Descriptive statistics, t-test, chi2 -test, anova, Pearson's correlation were used to analyze the data. RESULTS: The residents living in a nursing home showed higher subjective health status and sleep quality than long term care hospital residents. Depression did not show a significant difference between them. However, there was a significant difference in depression score by subjective health status. Sleep quality and depression showed a significant negative correlation for both residents. In terms of depression and life satisfaction, nursing home residents showed a significant negative correlation, and long-term care hospital residents showed a significant positive correlation. CONCLUSIONS: These results show that environmental management is essential to enhance sleep quality, thus depression and subjective health status will be improved. Geriatr Gerontol Int 2017; 17: 142-149. PMID- 26534830 TI - Disadvantageous associations: Reversible spatial cueing effects in a discrimination task. AB - Current theories describe learning in terms of cognitive or associative mechanisms. To assess whether cognitive mechanisms interact with automaticity of associative processes we devised a shape-discrimination task in which participants received both explicit instructions and implicit information. Instructions further allowed for the inference that a first event would precede the target. Albeit irrelevant to respond, this event acted as response prime and implicit spatial cue (i.e. it predicted target location). To modulate cognitive involvement, in three experiments we manipulated modality and salience of the spatial cue. Results always showed evidence for a priming effect, confirming that the first stimulus was never ignored. More importantly, although participants failed to consciously recognize the association, responses to spatially cued trials became either slower or faster depending on salience of the first event. These findings provide an empirical demonstration that cognitive and associative learning mechanisms functionally co-exist and interact to regulate behaviour. PMID- 26534831 TI - Multiphoton imaging with a novel compact diode-pumped Ti:sapphire oscillator. AB - Multiphoton laser scanning microscopy commonly relies on bulky and expensive femtosecond lasers. We integrated a novel minimal-footprint Ti:sapphire oscillator, pumped by a frequency-doubled distributed Bragg reflector tapered diode laser, into a clinical multiphoton tomograph and evaluated its imaging capability using different biological samples, i.e. cell monolayers, corneal tissue, and human skin. With the novel laser, the realization of very compact Ti:sapphire-based systems for high-quality multiphoton imaging at a significantly size and weight compared to current systems will become possible. PMID- 26534832 TI - Cell rearrangement in transplanted human islets. AB - The major feature of the human pancreatic islet architecture is the organization of endocrine cells into clusters comprising central beta cells and peripheral alpha cells surrounded by vasculature. To have an insight into the mechanisms that govern this unique islet architecture, islet cells were isolated, and reaggregation of alpha and beta cells into islet-like structures (pseudoislets) after culture or transplantation into mice was studied by immunohistology. The pseudoislets formed in culture displayed an unusual cell arrangement, contrasting with the transplanted pseudoislets, which exhibited a cell arrangement similar to that observed in native pancreatic islet subunits. The pattern of revascularization and the distribution of extracellular matrix around transplanted pseudoislets were alike to those observed in native pancreatic islets. This organization of transplanted pseudoislets occurred also when revascularization was abolished by treating mice with an anti-VEGF antibody, but not when contact with extracellular matrix was prevented by encapsulation of pseudoislets within alginate hydrogel. These results indicate that the maintenance of islet cell arrangement is dependent on in vivo features such as extracellular matrix but independent of vascularization. PMID- 26534833 TI - Protein immobilization on the surface of polydimethylsiloxane and polymethyl methacrylate microfluidic devices. AB - PDMS and PMMA are two of the most used polymers in the fabrication of lab-on-chip or microfluidic devices. In order to use these polymers in biological applications, it is sometimes essential to be able to bind biomolecules such as proteins and DNA to the surface of these materials. In this work, we have evaluated a number of processes that have been developed to bind protein to PDMS surfaces which include passive adsorption, passive adsorption with glutaraldehyde cross-linking, (3-aminopropyl) triethoxysilane functionalization followed by glutaraldehyde or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride cross-linkers. It has been shown that the latter technique--using 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide hydrochloride--results in more than twice the bonding of protein to the surface of PDMS microchannels than proteins binding passively. We have also evaluated a few techniques that have been tested for the functionalization of PMMA microchannels where we have found that the use of polyethyleneimine (PEI) has led to the strongest protein-PMMA microchannel bond. We finally demonstrated the effect of PDMS curing methodology on protein adsorption to its surface, and showed that increased curing time is the factor that reduces passive adsorption the most. PMID- 26534834 TI - Compressible and monolithic microporous polymer sponges prepared via one-pot synthesis. AB - Compressible and monolithic microporous polymers (MPs) are reported. MPs were prepared as monoliths via a Sonogashira-Hagihara coupling reaction of 1,3,5 triethynylbenzene (TEB) with the bis(bromothiophene) monomer (PBT-Br). The polymers were reversibly compressible, and were easily cut into any form using a knife. Microscopy studies on the MPs revealed that the polymers had tubular microstructures, resembling those often found in marine sponges. Under compression, elastic buckling of the tube bundles was observed using an optical microscope. MP-0.8, which was synthesized using a 0.8:1 molar ratio of PBT-Br to TEB, showed microporosity with a BET surface area as high as 463 m(2)g(-1). The polymer was very hydrophobic, with a water contact angle of 145 degrees and absorbed 7-17 times its own weight of organic liquids. The absorbates were released by simple compression, allowing recyclable use of the polymer. MPs are potential precursors of structured carbon materials; for example, a partially graphitic material was obtained by pyrolysis of MP-0.8, which showed a similar tubular structure to that of MP-0.8. PMID- 26534835 TI - Family Satisfaction With Nursing Home Care. AB - This article explores the factor structure of a new family satisfaction with nursing home care instrument and determines the relationship of resident quality of life (QOL) and facility characteristics with family satisfaction. Data sources include (1) family satisfaction interviews ( n = 16,790 family members), (2) multidimensional survey of resident QOL ( n = 13,433 residents), and (3) facility characteristics ( n = 376 facilities). We used factor analysis to identify domains of family satisfaction and multivariate analyses to identify the role of facility-level characteristics and resident QOL on facility-mean values of family satisfaction. Four distinct domains were identified for family satisfaction: "care," "staff," "environment," and "food." Chain affiliation, higher resident acuity, more deficiencies, and large size were all associated with less family satisfaction, and resident QOL was a significant (albeit weak) predictor of family satisfaction. Results suggest that family member satisfaction is distinct from resident QOL but is associated with resident QOL and facility characteristics. PMID- 26534836 TI - Time-staggered inhibition of JNK effectively sensitizes chemoresistant ovarian cancer cells to cisplatin and paclitaxel. AB - Ovarian cancer is the most lethal gynecological malignancy, for which platinum- and taxane-based chemotherapy plays a major role. Chemoresistance of ovarian cancer poses a major obstacle to the successful management of this devastating disease; however, effective measures to overcome platinum and taxane resistance are yet to be established. In the present study, while investigating the mechanism underlying the chemoresistance of ovarian cancer, we found that JNK may have a key role in the resistance of ovarian cancer cells to cisplatin and paclitaxel. Importantly, whereas simultaneous application of a JNK inhibitor and either of the chemotherapeutic agents had contrasting effects for cisplatin (enhanced cytotoxicity) and paclitaxel (decreased cytotoxicity), JNK inhibitor treatment prior to chemotherapeutic agent application invariably enhanced the cytotoxicity of both drugs, suggesting that the basal JNK activity is commonly involved in the chemoresistance of ovarian cancer cells to cisplatin and paclitaxel in contrast to drug-induced JNK activity which may have different roles for these two drugs. Furthermore, we confirmed using non-transformed human and rodent fibroblasts that sequential application of the JNK inhibitor and the chemotherapeutic agents did not augment their toxicity. Thus, our findings highlight for the first time the possible differential roles of the basal and induced JNK activities in the chemoresistance of ovarian cancer cells and also suggest that time-staggered JNK inhibition may be a rational and promising strategy to overcome the resistance of ovarian cancer to platinum- and taxane based chemotherapy. PMID- 26534837 TI - External-Photocatalyst-Free Visible-Light-Mediated Synthesis of Indolizines. AB - A visible-light-mediated synthesis of valuable polycyclic indolizine heterocycles from easily accessed brominated pyridine and enol carbamate derivatives has been developed. This process, which operates at room temperature under irradiation from readily available light sources, does not require the addition of an external photocatalyst. Instead, an investigation into the reaction mechanism indicates that the indolizine products themselves may be in some way involved in mediating and accelerating their own formation. Preliminary studies also show that these simple heterocyclic compounds may be capable of facilitating other visible-light-mediated transformations. PMID- 26534838 TI - Caregiver Perspectives of Stigma Associated With Sickle Cell Disease in Adolescents. AB - Patients and families affected by various medical conditions report experiencing health-related stigma, which contributes to detrimental physical, psychological, and social outcomes. Sickle cell disease (SCD) is a genetic disorder that affects 89,000 individuals in the United States and is often associated with negative stereotypes and incorrect assumptions. The present study explored the perception of stigma as reported by caregivers of adolescents with SCD. DESIGN AND METHODS: Focus groups were conducted with 20 caregivers of patients with SCD. Focus groups were audio recorded and transcribed. The data were coded independently by two authors, and then reviewed conjointly until consensus was reached. RESULTS: Caregivers reported the perception of stigma in academic, medical, community, and family settings. They also reported internalized stigma including negative feelings toward having a child with SCD, feeling upset with others, and seeing negative emotions in their child due to SCD. Caregivers reported a general lack of knowledge about SCD across settings. CONCLUSION: These results demonstrated that stigma may affect individuals with SCD across multiple settings. These results also highlighted areas for intervention, with a focus on increasing communication and education toward medical providers, schools, and communities. PRACTICAL IMPLICATIONS: Interventions can utilize technology, social media, and advertisement campaigns. Additionally, support groups for patients with SCD may help decrease stigma and validate patients' experiences. PMID- 26534839 TI - Men dissociate sexual attraction from moral judgement more than women. AB - Would you find an opposite-sex individual physically less attractive if you knew that he/she was a bad person? Would you feel the same if you were a man or a woman? This study examined whether gender differences exist in the influence of moral judgements on heterosexual physical attraction. In a first Experiment, participants (N = 214) rated on attractiveness photographs of opposite-sex persons. Each photograph was paired with a "good" and a "bad" (from a moral point of view) sentence to depict a quality or activity of the displayed person (i.e., she/he is a defender of human rights in an NGO vs. she/he belongs to a terrorist group). Compared with women, men were significantly less influenced by sentence valence in their attractiveness ratings. A second Experiment (N = 105) using photographs of very attractive people showed the same pattern of results. The data suggest that sexual attraction is relatively less permeable to moral factors in men, and that this sex difference is consistent with an evolutionary approach to human sexuality. PMID- 26534840 TI - Probing Nanoscale Thermal Transport in Surfactant Solutions. AB - Surfactant solutions typically feature tunable nanoscale, internal structures. Although rarely utilized, they can be a powerful platform for probing thermal transport in nanoscale domains and across interfaces with nanometer-size radius. Here, we examine the structure and thermal transport in solution of AOT (Dioctyl sodium sulfosuccinate) in n-octane liquids using small-angle neutron scattering, thermal conductivity measurements, and molecular dynamics simulations. We report the first experimental observation of a minimum thermal conductivity occurring at the critical micelle concentration (CMC): the thermal conductivity of the surfactant solution decreases as AOT is added till the onset of micellization but increases as more AOT is added. The decrease of thermal conductivity with AOT loading in solutions in which AOT molecules are dispersed as monomers suggests that even the interfaces between individual oleophobic headgroup of AOT molecules and their surrounding non-polar octane molecules can hinder heat transfer. The increase of thermal conductivity with AOT loading after the onset of micellization indicates that the thermal transport in the core of AOT micelles and across the surfactant-oil interfaces, both of which span only a few nanometers, are efficient. PMID- 26534842 TI - Whose goal is it anyway? Self-directed goal setting for children with cerebral palsy. PMID- 26534841 TI - Localized reconstruction of subunits from electron cryomicroscopy images of macromolecular complexes. AB - Electron cryomicroscopy can yield near-atomic resolution structures of highly ordered macromolecular complexes. Often however some subunits bind in a flexible manner, have different symmetry from the rest of the complex, or are present in sub-stoichiometric amounts, limiting the attainable resolution. Here we report a general method for the localized three-dimensional reconstruction of such subunits. After determining the particle orientations, local areas corresponding to the subunits can be extracted and treated as single particles. We demonstrate the method using three examples including a flexible assembly and complexes harbouring subunits with either partial occupancy or mismatched symmetry. Most notably, the method allows accurate fitting of the monomeric RNA-dependent RNA polymerase bound at the threefold axis of symmetry inside a viral capsid, revealing for the first time its exact orientation and interactions with the capsid proteins. Localized reconstruction is expected to provide novel biological insights in a range of challenging biological systems. PMID- 26534843 TI - Integrated Data Repository Toolkit (IDRT). A Suite of Programs to Facilitate Health Analytics on Heterogeneous Medical Data. AB - BACKGROUND: In recent years, research data warehouses moved increasingly into the focus of interest of medical research. Nevertheless, there are only a few center independent infrastructure solutions available. They aim to provide a consolidated view on medical data from various sources such as clinical trials, electronic health records, epidemiological registries or longitudinal cohorts. The i2b2 framework is a well-established solution for such repositories, but it lacks support for importing and integrating clinical data and metadata. OBJECTIVES: The goal of this project was to develop a platform for easy integration and administration of data from heterogeneous sources, to provide capabilities for linking them to medical terminologies and to allow for transforming and mapping of data streams for user-specific views. METHODS: A suite of three tools has been developed: the i2b2 Wizard for simplifying administration of i2b2, the IDRT Import and Mapping Tool for loading clinical data from various formats like CSV, SQL, CDISC ODM or biobanks and the IDRT i2b2 Web Client Plugin for advanced export options. The Import and Mapping Tool also includes an ontology editor for rearranging and mapping patient data and structures as well as annotating clinical data with medical terminologies, primarily those used in Germany (ICD-10-GM, OPS, ICD-O, etc.). RESULTS: With the three tools functional, new i2b2-based research projects can be created, populated and customized to researcher's needs in a few hours. Amalgamating data and metadata from different databases can be managed easily. With regards to data privacy a pseudonymization service can be plugged in. Using common ontologies and reference terminologies rather than project-specific ones leads to a consistent understanding of the data semantics. CONCLUSIONS: i2b2's promise is to enable clinical researchers to devise and test new hypothesis even without a deep knowledge in statistical programing. The approach presented here has been tested in a number of scenarios with millions of observations and tens of thousands of patients. Initially mostly observant, trained researchers were able to construct new analyses on their own. Early feedback indicates that timely and extensive access to their "own" data is appreciated most, but it is also lowering the barrier for other tasks, for instance checking data quality and completeness (missing data, wrong coding). PMID- 26534844 TI - Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families. AB - INTRODUCTION: Gene panel testing for breast cancer susceptibility has become relatively cheap and accessible. However, the breast cancer risks associated with mutations in many genes included in these panels are unknown. METHODS: We performed custom-designed targeted sequencing covering the coding exons of 17 known and putative breast cancer susceptibility genes in 660 non-BRCA1/2 women with familial breast cancer. Putative deleterious mutations were genotyped in relevant family members to assess co-segregation of each variant with disease. We used maximum likelihood models to estimate the breast cancer risks associated with mutations in each of the genes. RESULTS: We found 31 putative deleterious mutations in 7 known breast cancer susceptibility genes (TP53, PALB2, ATM, CHEK2, CDH1, PTEN and STK11) in 45 cases, and 22 potential deleterious mutations in 31 cases in 8 other genes (BARD1, BRIP1, MRE11, NBN, RAD50, RAD51C, RAD51D and CDK4). The relevant variants were then genotyped in 558 family members. Assuming a constant relative risk of breast cancer across age groups, only variants in CDH1, CHEK2, PALB2 and TP53 showed evidence of a significantly increased risk of breast cancer, with some supportive evidence that mutations in ATM confer moderate risk. CONCLUSIONS: Panel testing for these breast cancer families provided additional relevant clinical information for <2% of families. We demonstrated that segregation analysis has some potential to help estimate the breast cancer risks associated with mutations in breast cancer susceptibility genes, but very large case-control sequencing studies and/or larger family-based studies will be needed to define the risks more accurately. PMID- 26534845 TI - The efficacy of objective and subjective predictors of driving performance during sleep restriction and circadian misalignment. AB - Fatigue is a significant contributor to motor-vehicle accidents and fatalities. Shift workers are particularly susceptible to fatigue-related risks as they are often sleep-restricted and required to commute around the clock. Simple assays of performance could provide useful indications of risk in fatigue management, but their effectiveness may be influenced by changes in their sensitivity to sleep loss across the day. The aim of this study was to evaluate the sensitivity of several neurobehavioral and subjective tasks to sleep restriction (SR) at different circadian phases and their efficacy as predictors of performance during a simulated driving task. Thirty-two volunteers (M+/-SD; 22.8+/-2.9 years) were time-isolated for 13-days and participated in one of two 14-h forced desynchrony protocols with sleep opportunities equivalent to 8h/24h (control) or 4h/24h (SR). At regular intervals during wake periods, participants completed a simulated driving task, several neurobehavioral tasks, including the psychomotor vigilance task (PVT), and subjective ratings, including a self-assessment measure of ability to perform. Scores transformed into standardized units relative to baseline were folded into circadian phase bins based on core body temperature. Sleep dose and circadian phase effect sizes were derived via mixed models analyses. Predictors of driving were identified with regressions. Performance was most sensitive to sleep restriction around the circadian nadir. The effects of sleep restriction around the circadian nadir were larger for simulated driving and neurobehavioral tasks than for subjective ratings. Tasks did not significantly predict driving performance during the control condition or around the acrophase during the SR condition. The PVT and self-assessed ability were the best predictors of simulated driving across circadian phases during SR. These results show that simple performance measures and self-monitoring explain a large proportion of the variance in driving when fatigue-risk is high. PMID- 26534846 TI - Is Talking to Your Car Dangerous? It Depends: Prologue to the Special Section. AB - Cognitive distraction represents an important and growing traffic safety issue, particularly with the increasing computerization of cars. The target paper in this special section describes a protocol for assessing the distraction potential of information and entertainment systems. Cognitive distraction has specific relevance to the challenges facing driving safety but also reflects the more pervasive challenge of generalizing findings in the face of complex contextual and compensatory influences. Peer commentaries from five driving safety experts sketch paths forward in assessing the distraction potential of in-vehicle information technology. A simple, definitive statement regarding the risk of talking to your car is appealing, but the complexity of driver behavior may make such a statement unachievable. PMID- 26534847 TI - Assessing Cognitive Distraction in the Automobile. AB - OBJECTIVE: The objective was to establish a systematic framework for measuring and understanding cognitive distraction in the automobile. BACKGROUND: Driver distraction from secondary in-vehicle activities is increasingly recognized as a significant source of injuries and fatalities on the roadway. METHOD: Across three studies, participants completed eight in-vehicle tasks commonly performed by the driver of an automobile. Primary, secondary, subjective, and physiological measures were collected and integrated into a cognitive distraction scale. RESULTS: In-vehicle activities, such as listening to the radio or an audio book, were associated with a low level of cognitive workload; the conversation activities of talking to a passenger in the vehicle or conversing with a friend on a handheld or hands-free cell phone were associated with a moderate level of cognitive workload; and using a speech-to-text interfaced e-mail system involved a high level of cognitive workload. CONCLUSION: The research established that there are significant impairments to driving that stem from the diversion of attention from the task of operating a motor vehicle and that the impairments to driving are directly related to the cognitive workload of these in-vehicle activities. Moreover, the adoption of voice-based systems in the vehicle may have unintended consequences that adversely affect traffic safety. APPLICATION: These findings can be used to help inform scientifically based policies on driver distraction, particularly as they relate to cognitive distraction stemming from the diversion of attention to other concurrent activities in the vehicle. PMID- 26534848 TI - On the Effects of Listening and Talking to Humans and Devices on Driving. AB - The body of research on cognitive distraction while driving is vast and spans many decades. To this research, the authors of the target article add three experiments that measure a number of cognitive tasks across laboratory, simulation, and on-road contexts. The pattern of decrements is similar across contexts, when expressed as an index, and when compared to previous research. Measurement, task, and generalizability issues arise from the approaches taken by the authors. For example, the use of "pure" cognitive tasks may not necessarily generalize to everyday driving behavior, wherein visual and physical distractions are inherently interleaved with cognitive tasks. A valuable contribution of the authors' future research on cognitive distractions would be to predict relative crash risk. PMID- 26534849 TI - Cognitive Workload ? Crash Risk: Rejoinder to Study by Strayer et al. (2015). AB - Strayer et al.'s article is a significant attempt to scale the cognitive workload of different potentially distracting tasks. It is tempting but not warranted to equate the workload with the relative risk of crash involvement. In this article, I list the reasons why the scaling should not be generalized to safety implications in real driving and argue for the combination of studies of maximal performance assessment (e.g., simulation) with behavioral assessment (e.g., naturalistic driving). PMID- 26534850 TI - Cognitive Distraction in the Wild: Next Steps-Addressing a Not-So-Humdrum Conundrum. AB - Strayer et al. in this volume show that increases in cognitive workload caused by drivers' involvement in distracting activities that allow them to keep their eyes on the road lead to decrements in indices of safe driving performance. Although there is agreement that in-vehicle tasks that require drivers to take their eyes off the road increase crash risk, there is mounting controversy about whether in vehicle tasks that do not require drivers to take their eyes off the forward roadway increase crash risk-thus the conundrum: How can there be an abundance of cognitively distracting activities and controversy about whether such activities increase crash risk? PMID- 26534851 TI - Driver Compensation: Impairment or Improvement? AB - Strayer et al.'s conclusion that their "cognitive distraction scale" for auditory vocal tasks indicates "significant impairments to driving" is not supported by their data. Additional analysis demonstrates that slower brake reaction times during auditory-vocal tasks were fully compensated for by longer following distances to the lead car. Naturalistic driving data demonstrate that cellular conversation decreases crash risk, the opposite of the article's assumption. Hence, the scale's internal and external validities for indicating driving impairment are highly questionable. PMID- 26534852 TI - Judging Thieves of Attention: Commentary on "Assessing Cognitive Distraction in the Automobile," by Strayer, Turrill, Cooper, Coleman, Medeiros-Ward, and Biondi (2015). AB - The laudable effort by Strayer and his colleagues to derive a systematic method to assess forms of cognitive distraction in the automobile is beset by the problem of nonstationary in driver response capacity. At the level of the overall goal of driving, this problem conflates actual on-road behavior; characterized by underspecified task satisficing, with our own understandable, scientifically inspired aspiration for measuring deterministic performance optimization. Measures of response conceived under this latter imperative are, at best, only shadowy reflections of the actual phenomenological experience involved in real world vehicle control. Whether we, as a research community, can resolve this issue remains uncertain. However, we believe we can mount a positive attack on what is arguably another equally important dimension of the collision problem. PMID- 26534853 TI - Driven to Distraction. AB - We address several themes that emerged in the commentaries related to our target article. First, we consider the relationship between cognitive distraction and crash risk. Second, we discuss the development of our cognitive distraction scale. Third, we weigh issues of self-regulation, appropriate baselines, and satisficing. Finally, we identify several areas where additional research is needed to refine our understanding of driver distraction and crash risk. PMID- 26534855 TI - Current and emerging practice of end-of-life care in British prisons: findings from an online survey of prison nurses. AB - BACKGROUND: There are concerns about prisoners and detainees not having equal access to end-of-life care while in prison. There is a lack of existing literature about the standards of end-of-life care in UK prisons. OBJECTIVES: The aim of this study was to investigate the views of current and former prison nurses with regard to the end-of-life care being provided in UK prisons. METHODS: Prison nurses were invited to participate in an online survey and asked about their role in the prison, prisoners' access to healthcare facilities, and any barriers and good practices to end-of-life care. The survey included open-ended and closed questions. The closed questions were analysed using descriptive statistics. The open-ended responses were coded and grouped into themes. RESULTS: 31 (N=31) prison nurses responded to the survey. The reported barriers to end-of life care included some prison regimes, lack of appropriate care and visiting facilities, lack of privacy and inadequate visiting hours. Respondents also reported examples of good practice, including having access to specialist palliative care and specialist equipment, and being able to receive visits from family and friends. CONCLUSIONS: The findings suggest that there is considerable variability in the end-of-life care provided to prisoners in the UK. Further research is needed in order to reduce the health inequalities and improve the quality of end-of-life care experienced by prisoners in the UK. PMID- 26534857 TI - Delayed access to clinical audit data has risks for patient care. PMID- 26534856 TI - A Western dietary pattern is associated with higher blood pressure in Iranian adolescents. AB - PURPOSE: The dietary determinants of adolescent blood pressure (BP) are not well understood. We determined the association between major dietary patterns and BP in a sample of Iranian adolescents. METHODS: This cross-sectional study was conducted among a representative sample (n = 557) of Shirazi adolescents aged 12 19 years. Participants' systolic and diastolic BP was measured using a validated oscillometric BP monitor. Usual dietary intakes during the past 12 months were assessed using a valid and reproducible 168-item semiquantitative food frequency questionnaire through face-to-face interviews. Principal component factor analysis was used to identify major dietary patterns based on a set of 25 predefined food groups. RESULTS: Overall, three major dietary patterns were identified, among which only the Western pattern (abundant in soft drinks, sweets and desserts, salt, mayonnaise, tea and coffee, salty snacks, high-fat dairy products, French fries, and red or processed meats) had a significant association with BP. After adjusting for potential confounders in the analysis of covariance models, multivariable adjusted means of the systolic and mean BP of subjects in the highest tertile of the Western pattern score were significantly higher than those in the lowest tertile (for systolic BP: mean difference 6.9 mmHg, P = 0.001; and for mean BP: mean difference 4.2 mmHg, P = 0.003). A similar but statistically insignificant difference was observed in terms of diastolic BP. CONCLUSIONS: The findings suggest that a Western dietary pattern is associated with higher BP in Iranian adolescents. However, additional large-scale prospective studies with adequate methodological quality are required to confirm these findings. PMID- 26534858 TI - A comparison between digital breast tomosynthesis and full-field digital mammography for the detection of breast cancers. AB - PURPOSE: To evaluate interobserver agreement in full-field digital mammography (FFDM) and digital breast tomosynthesis (DBT) in terms of both lesion detection and characterization, and to evaluate the cancer detection rate of standard two view FFDM compared to various combinations of DBT. MATERIALS AND METHODS: Thirty five women (mean age 59.7; range 50-80 years) with 37 breast cancers who underwent both two-view DBT and two-view FFDM were included. DBT images were obtained using an investigational prototype. We performed interobserver agreement analyses using kappa (k) statistics. The cancer detection rate of various combinations of DBT compared to standard two-view FFDM was estimated using a generalized estimation equation. RESULTS: There was fair to moderate agreement on detectability (k = 0.59-0.62) in both views of FFDM and DBT, while fair to substantial agreement was found for lesion location (k = 0.52-0.84) and fair to moderate agreement for lesion type (k = 0.46-0.70) and BI-RADS final assessment (k = 0.48-0.69). In generalized estimation equations, standard two-view FFDM was inferior to any combination of DBT. The detection rate ratio was significantly higher in the combined four views of DBT and FFDM compared to standard FFDM (p < 0.046). CONCLUSION: Our study showed good agreement in lesion detection and characterization between FFDM and DBT images. Our findings also demonstrated that combining DBT and FFDM is superior in detecting cancer compared to standard FFDM. PMID- 26534859 TI - Molecular diagnostics for precision medicine in breast cancer treatment: what does the future hold? PMID- 26534860 TI - Research commentary regarding Savage et al. entitled "Genome-wide association study identifies two susceptibility loci for osteosarcoma". PMID- 26534861 TI - A framework for the analysis of the security of supply of utilising carbon dioxide as a chemical feedstock. AB - Recent developments in catalysts have enhanced the potential for the utilisation of carbon dioxide as a chemical feedstock. Using the appropriate energy efficient catalyst enables a range of chemical pathways leading to desirable products. In doing so, CO2 provides an economically and environmentally beneficial source of C1 feedstock, while improving the issues relating to security of supply that are associated with fossil-based feedstocks. However, the dependence on catalysts brings other supply chains into consideration, supply chains that may also have security of supply issues. The choice of chemical pathways for specific products will therefore entail an assessment not only of economic factors but also the security of supply issues for the catalysts. This is a multi-criteria decision making problem. In this paper, we present a modified 4A framework based on the framework suggested by the Asian Pacific Energy Research centre for macro economic applications. The 4A methodology is named after the criteria used to compare alternatives: availability, acceptability, applicability and affordability. We have adapted this framework for the consideration of alternative chemical reaction processes using a micro-economic outlook. Data from a number of sources were collected and used to quantify each of the 4A criteria. A graphical representation of the assessments is used to support the decision maker in comparing alternatives. The framework not only allows for the comparison of processes but also highlights current limitations in the CCU processes. The framework presented can be used by a variety of stakeholders, including regulators, investors, and process industries, with the aim of identifying promising routes within a broader multi-criteria decision making process. PMID- 26534862 TI - Decade-Long Trends in 30-Day Rehospitalization Rates After Acute Myocardial Infarction. AB - BACKGROUND: There are limited data available describing relatively contemporary trends in 30-day rehospitalizations among patients who survive hospitalization after an acute myocardial infarction (AMI) in the community setting. We examined decade-long (2001-2011) trends in, and factors associated with, 30-day rehospitalizations in patients discharged from 3 central Massachusetts hospitals after AMI. METHODS AND RESULTS: Residents of the Worcester, MA, metropolitan area discharged after AMI from 3 central Massachusetts hospitals on a biennial basis between 2001 and 2011 comprised the study population (N=4810). Logistic regression analyses were used to examine the association between selected factors and 30-day rehospitalizations. The average age of this population was 69 years, 42% were women, and 92% were white. During the years under study, 18.5% of patients were rehospitalized within 30 days after hospital discharge. Crude 30 day rehospitalization rates decreased from 20.5% in 2001-2003 to 15.8% in 2009 2011. After adjusting for several patient characteristics, there was a reduced odds of being rehospitalized in 2009-2011 (odds ratio 0.74, 95% CI 0.61-0.91) compared with 2001-2003; this trend was slightly attenuated after further adjustment for hospital treatment practices. Female sex, having previously diagnosed heart failure and chronic kidney disease, and the development of in hospital cardiogenic shock and heart failure were associated with an increased odds of being rehospitalized. CONCLUSIONS: While the likelihood of subsequent short-term rehospitalizations remained frequent, we observed an encouraging decline during the most recent years under study. Several high-risk groups were identified for purposes of heightened surveillance and intervention efforts to reduce the likelihood of being readmitted. PMID- 26534863 TI - Incremental Bayesian Category Learning From Natural Language. AB - Models of category learning have been extensively studied in cognitive science and primarily tested on perceptual abstractions or artificial stimuli. In this paper, we focus on categories acquired from natural language stimuli, that is, words (e.g., chair is a member of the furniture category). We present a Bayesian model that, unlike previous work, learns both categories and their features in a single process. We model category induction as two interrelated subproblems: (a) the acquisition of features that discriminate among categories, and (b) the grouping of concepts into categories based on those features. Our model learns categories incrementally using particle filters, a sequential Monte Carlo method commonly used for approximate probabilistic inference that sequentially integrates newly observed data and can be viewed as a plausible mechanism for human learning. Experimental results show that our incremental learner obtains meaningful categories which yield a closer fit to behavioral data compared to related models while at the same time acquiring features which characterize the learned categories. (An earlier version of this work was published in Frermann and Lapata .). PMID- 26534864 TI - Statistical Approach to Decreasing the Error Rate of Noninvasive Prenatal Aneuploid Detection caused by Maternal Copy Number Variation. AB - Analyses of cell-free fetal DNA (cff-DNA) from maternal plasma using massively parallel sequencing enable the noninvasive detection of feto-placental chromosome aneuploidy; this technique has been widely used in clinics worldwide. Noninvasive prenatal tests (NIPT) based on cff-DNA have achieved very high accuracy; however, they suffer from maternal copy-number variations (CNV) that may cause false positives and false negatives. In this study, we developed an algorithm to exclude the effect of maternal CNV and refined the Z-score that is used to determine fetal aneuploidy. The simulation results showed that the algorithm is robust against variations of fetal concentration and maternal CNV size. We also introduced a method based on the discrepancy between feto-placental concentrations to help reduce the false-positive ratio. A total of 6615 pregnant women were enrolled in a prospective study to validate the accuracy of our method. All 106 fetuses with T21, 20 with T18, and three with T13 were tested using our method, with sensitivity of 100% and specificity of 99.97%. In the results, two cases with maternal duplications in chromosome 21, which were falsely predicted as T21 by the previous NIPT method, were correctly classified as normal by our algorithm, which demonstrated the effectiveness of our approach. PMID- 26534866 TI - Evaluation of the perforators of the anterior communicating artery (AComA) using routine cerebral 3D rotational angiography. AB - BACKGROUND: Damage to perforating branches of the anterior communicating artery (AComA) is a known complication of surgical or interventional treatment procedures for AComA aneurysm leading to neurologic deficits. In spite of the clinical relevance of these AComA branches, they have not been systematically analyzed using imaging techniques and most of our knowledge is based on post mortem injection studies or neurosurgical reports. We therefore analyzed three dimensional rotational angiography (3DRA) images of the AComA, and propose a first imaging definition of the microvascular structures surrounding the AComA. METHODS: Reconstructed 3D data derived from standard-of-care rotational angiography acquisitions (5 s DSA) were retrospectively analyzed. 20 patients undergoing selective cerebral angiography and 3DRA for therapy assessment were included in our study. 3DRA datasets were reconstructed and displayed using the volume rendering technique (VRT). Additionally, multiplanar reformatted CT-like cross-sectional images (MPR) were used to evaluate the number, size, and origin of the perforators of the AComA. RESULTS: Perforating branches of the AComA could be demonstrated in all cases with large interindividual variations in vessel visibility. MPRs appeared to be superior to total VRT volumes in the visualization of the perforating branches of the AComA. CONCLUSIONS: 3DRA can be used to visualize perforating branches of the AComA in vivo. Since damage to these perforators may result in neurologic deficits, visualization of these vessels prior to surgery or endovascular aneurysm treatment could help in the planning of therapeutic interventions. Further refinement of current imaging techniques will be necessary, however, to increase the reliability of small vessel angiography. PMID- 26534867 TI - Diagnosis of acute ischemia using dual energy CT after mechanical thrombectomy. AB - BACKGROUND AND PURPOSE: To assess the performance of dual energy unenhanced CT in the detection of acute ischemia after mechanical thrombectomy. METHODS: Retrospective study, approved by the local institutional review board, including all patients that underwent intra-arterial thrombectomy in our institution over a period of 2 years. The presence of acute ischemia and hemorrhage was evaluated by three readers. Sensitivity and specificity of the non-contrast CT weighted sum image (NCCT) and the virtual non-contrast reconstructed image (VNC) were estimated and compared using generalized estimating equations to account for the non-independence of regions in each patient. RESULTS: 58 patients (27 women and 31 men; mean age 70.4 years) were included in the study, yielding 580 regions of interest. Sensitivity and specificity in detecting acute ischemia were higher for all readers when using VNC, with a significant increase in sensitivity for two readers (p<0.001 and 0.01) and a significant increase in specificity in one reader (p<0.001). Specificity in detecting hemorrhage was excellent for all readers. CONCLUSIONS: Dual energy unenhanced CT VNC images were superior in the identification of acute ischemia in comparison with NCCT. PMID- 26534868 TI - Endovascular treatment of PICA aneurysms with a Low-profile Visualized Intraluminal Support (LVIS Jr) device. AB - OBJECTIVE: To describe the treatment of posterior inferior cerebellar artery (PICA) aneurysms with the Low-profile Visualized Intraluminal Support Device (LVIS Jr) stent. MATERIALS AND METHODS: The databases of three institutions were retrospectively reviewed. Patients who underwent endovascular treatment of PICA aneurysms using a reconstructive technique where the LVIS Jr stent was totally or partially deployed into the PICA were included in the analysis. Clinical presentation, aneurysm and PICA sizes, procedural complications, and clinical and angiographic follow-up information was recorded and analyzed. RESULTS: Seven patients who underwent endovascular treatment of PICA aneurysms with an LVIS Jr stent were identified. Four aneurysms were treated in the acute phase of subarachnoid hemorrhage (SAH). There were no symptomatic complications. One patient had spasm distal to the stent as a result of mechanical straightening of the vessel. One patient was treated in the acute phase of SAH and required a gycoprotein IIb/IIIa inhibitor after the stent was implanted. This patient needed to be re-treated to complete embolization. All patients had good clinical outcomes (Glasgow Outcome Scale 5). No in-stent stenosis or occlusion was seen on short-term angiographic follow-up and the aneurysms were occluded. CONCLUSIONS: This small series suggests that the use of a reconstructive technique with the LVIS Jr stent for the treatment of PICA aneurysms is feasible, safe and effective in the short term. PMID- 26534870 TI - Writing Across the Curriculum: Strategies to Improve the Writing Skills of Nursing Students. AB - BACKGROUND: Writing across the curriculum (WAC) is a strategy in which writing instruction occurs in classes outside of composition, literature, and other English courses. This literature review was conducted to identify and synthesize the peer-reviewed literature about WAC in nursing education. METHODS: The team performed searches of MEDLINE (PubMed), CINAHL Plus With Full Text, and ERIC for articles published between January 2003 and April 2014. A combination of Medical Subject Heading terms (or equivalent) and keywords were used to create the database search strategies. RESULTS: There were 48 articles that discussed WAC. Most of the papers described writing courses in nursing programs, strategies to teach writing to nursing students, and writing activities or assignments within nursing courses. High-level evidence examining the impact of writing strategies and exercises in courses and occurring across the curriculum was lacking. Only 18 (37.5%) of these papers were evaluative; most of the databased articles were either author observations or perceptions of changes in students' writing ability, or low-level research studies. CONCLUSIONS: Strategies, assignments, and courses intended to promote writing skills of nursing students were documented in this literature review; however, further evaluation is needed to determine which are most effective. Hawks Turner Derouin Hueckel Leonardelli Oermann. PMID- 26534869 TI - Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline. AB - Low insulin-like growth factor-1 (IGF-1) signaling is associated with improved longevity, but is paradoxically linked with several age-related diseases in humans. Insulin-like growth factor-1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF-1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole body insulin action in aging. Utilizing hyperinsulinemic-euglycemic clamps, we show that old insulin-resistant rats with age-related declines in IGF-1 level demonstrate markedly improved whole-body insulin action, when treated with central IGF-1, as compared to central vehicle or insulin (P < 0.05). Furthermore, central IGF-1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P < 0.05). Taken together, IGF-1 action in the brain and periphery provides a 'balance' between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at 'tipping the balance' of IGF-1 action centrally are the optimal approach to achieve healthy aging and longevity in humans. PMID- 26534871 TI - Root canal filling in primary molars without successors: Mineral trioxide aggregate versus gutta-percha/AH-Plus. AB - The aim of this study was to compare the clinical and radiographical success of mineral trioxide aggregate (MTA) and gutta-percha/AH-Plus used as a root canal filling material in primary second molars without successors. A total of 16 patients (9 girls, 7 boys) aged 6-13 years (mean: 10.5) were selected and randomly distributed into the treatment groups. Children were recalled for clinical and radiographic examination at 6, 12, 18, 24 and 36 months. Differences in treatment outcomes were analysed using chi-squared and Fisher's exact tests. Clinically, there was no significant difference in the success rates between the groups at the end of a 3-year follow-up period (MTA: 100%; Gutta-percha/AH-Plus: 70%) (P > 0.05). However, radiographically, there was a significant difference between the groups (MTA: 80%; gutta-percha/AH-Plus: 30%) (P < 0.05). The present study showed that MTA can be recommended for use in root canal treatment of primary molars without successors based on better radiographic success. PMID- 26534872 TI - Mentoring in Clinical-Translational Research: A Study of Participants in Master's Degree Programs. AB - Research projects in translational science are increasingly complex and require interdisciplinary collaborations. In the context of training translational researchers, this suggests that multiple mentors may be needed in different content areas. This study explored mentoring structure as it relates to perceived mentoring effectiveness and other characteristics of master's-level trainees in clinical-translational research training programs. A cross-sectional online survey of recent graduates of clinical research master's program was conducted. Of 73 surveys distributed, 56.2% (n = 41) complete responses were analyzed. Trainees were overwhelmingly positive about participation in their master's programs and the impact it had on their professional development. Overall the majority (>=75%) of trainees perceived they had effective mentoring in terms of developing skills needed for conducting clinical-translational research. Fewer trainees perceived effective mentoring in career development and work-life balance. In all 15 areas of mentoring effectiveness assessed, higher rates of perceived mentor effectiveness was seen among trainees with >=2 mentors compared to those with solo mentoring (SM). In addition, trainees with >=2 mentors perceived having effective mentoring in more mentoring aspects (median: 14.0; IQR: 12.0-15.0) than trainees with SM (median: 10.5; IQR: 8.0-14.5). Results from this survey suggest having >=2 mentors may be beneficial in fulfilling trainee expectations for mentoring in clinical-translational training. PMID- 26534873 TI - Risk of postpartum hemorrhage among Native American women. AB - OBJECTIVE: To assess whether Native American women have an increased risk of postpartum hemorrhage (PPH) after vaginal delivery. METHODS: In a retrospective study, medical charts were reviewed for patients who delivered vaginally at Rehoboth McKinley Hospital in Gallup, NM, USA, between June 1, 2009, and June 30, 2012. Ethnic origin had been determined by self-report. PPH was defined as a visually estimated blood loss of more than 500 mL. Multivariable logistic analysis was undertaken to identify factors independently associated with PPH. RESULTS: Among 1062 eligible patients, 751 (70.7%) were Native American and 311 (29.3%) were non-native (white, African American, or Hispanic). A significantly higher proportion of Native Americans than non-native women developed PPH (87 [11.6%] vs 22 [7.0%]; P=0.02). In multivariable analysis, Native American ethnic origin was an independent predictor of PPH (odds ratio 1.8, 95% confidence interval 1.1-3.0; P=0.02). In a comparison with white women only, PPH was significantly more frequent among Native American women (87/751 [11.6%] vs 13/194 [6.7%]; P=0.01). CONCLUSION: Native American women have a higher risk of PPH after vaginal delivery than do non-native women. PMID- 26534874 TI - Randomized double-blind placebo-controlled trial of buccal misoprostol to reduce the need for additional uterotonic drugs during cesarean delivery. AB - OBJECTIVE: To determine whether buccal misoprostol during cesarean delivery in conjunction with active management of the third stage of labor reduces the need for additional uterotonic drugs. METHOD: A double-blind, randomized, placebo controlled trial was performed in Monterrey, Mexico, between February 2008 and December 2013. Eligible women had risk factors for uterine atony and were to undergo cesarean delivery under epidural block. Using a computer-generated sequence and blocks of six, patients were randomly assigned to receive 400MUg misoprostol or 800MUg placebo buccally after cord clamping. Both groups received an intravenous oxytocin infusion. The primary outcome was the need for additional uterotonic drugs. Analyses were performed per protocol. Patients, investigators, and data analysts were masked to group assignment. RESULTS: A total of 120 women were included in analyses (60 in each group). At least one additional uterotonic drug was required in 24 (40%) women in the placebo group versus 6 (10%) women in the misoprostol group (relative risk 0.16; 95% confidence interval 0.06-0.44). No adverse effects due to misoprostol were recorded. CONCLUSION: Buccal misoprostol during cesarean delivery reduced the need for additional uterotonic drugs to treat uterine atony. ClinicalTrials.gov:NCT01733329. PMID- 26534875 TI - Stereoselective Synthesis of Trisubstituted Alkenes through Sequential Iron Catalyzed Reductive anti-Carbozincation of Terminal Alkynes and Base-Metal Catalyzed Negishi Cross-Coupling. AB - The stereoselective synthesis of trisubstituted alkenes is challenging. Here, we show that an iron-catalyzed anti-selective carbozincation of terminal alkynes can be combined with a base-metal-catalyzed cross-coupling to prepare trisubstituted alkenes in a one-pot reaction and with high regio- and stereocontrol. Cu-, Ni-, and Co-based catalytic systems are developed for the coupling of sp-, sp(2) -, and sp(3) -hybridized carbon electrophiles, respectively. The method encompasses a large substrate scope, as various alkynyl, aryl, alkenyl, acyl, and alkyl halides are suitable coupling partners. Compared with conventional carbometalation reactions of alkynes, the current method avoids pre-made organometallic reagents and has a distinct stereoselectivity. PMID- 26534876 TI - Targeted Intraoperative Radiotherapy for the Management of Ductal Carcinoma In Situ of the Breast. AB - Multiple long-term studies have demonstrated a propensity for breast cancer recurrences to develop near the site of the original breast cancer. Recognition of this local recurrence pattern laid the foundation for the development of accelerated partial breast irradiation (APBI) approaches designed to limit the radiation treatment field to the site of the malignancy. However, there is a paucity of data regarding the efficacy of APBI in general, and intraoperative radiotherapy (IORT), in particular, for the management of ductal carcinoma in situ (DCIS). As a result, use of APBI, remains controversial. A prospective nonrandomized trial was designed to determine if patients with pure DCIS considered eligible for concurrent IORT based on preoperative mammography and contrast-enhanced magnetic resonance imaging (CE-MRI) could be successfully treated using IORT with minimal need for additional therapy due to inadequate surgical margins or excessive tumor size. Between November 2007 and June 2014, 35 women underwent bilateral digital mammography and bilateral breast CE-MRI prior to selection for IORT. Patients were deemed eligible for IORT if their lesion was <=4 cm in maximal diameter on both digital mammography and CE-MRI, pure DCIS on minimally invasive breast biopsy or wide local excision, and considered resectable with clear surgical margins using breast-conserving surgery (BCS). Postoperatively, the DCIS lesion size determined by imaging was compared with lesion size and surgical margin status obtained from the surgical pathology specimen. Thirty-five patients completed IORT. Median patient age was 57 years (range 42-79 years) and median histologic lesion size was 15.6 mm (2-40 mm). No invasive cancer was identified. In more than half of the patients in our study (57.1%), MRI failed to detect a corresponding lesion. Nonetheless, 30 patients met criteria for negative margins (i.e., margins >=2 mm) whereas five patients had positive margins (<2 mm). Two of the five patients with positive margins underwent mastectomy due to extensive imaging-occult DCIS. Three of the five patients with positive margins underwent successful re-excision at a subsequent operation prior to subsequent whole breast irradiation. A total of 14.3% (5/35) of patients required some form of additional therapy. At 36 months median follow up (range of 2-83 months, average 42 months), only two patients experienced local recurrences of cancer (DCIS only), yielding a 5.7% local recurrence rate. No deaths or distant recurrences were observed. Imaging-occult DCIS is a challenge for IORT, as it is for all forms of breast-conserving therapy. Nonetheless, 91.4% of patients with DCIS were successfully managed with BCS and IORT alone, with relatively few patients requiring additional therapy. PMID- 26534877 TI - Lithium and renal and upper urinary tract tumors - results from a nationwide population-based study. AB - OBJECTIVES: A recent alarming finding suggested an increased risk of renal tumors among long-term lithium users. The objectives of the present study were to estimate rates of renal and upper urinary tract tumors (RUT), malignant and benign, among individuals exposed to successive prescriptions for lithium, anticonvulsants, and other psychotropic agents used for bipolar disorder, and among unexposed individuals. METHODS: This was a nationwide, population-based longitudinal study including time-specific data from all individuals exposed to lithium (n = 24,272) or anticonvulsants (n = 386,255), all individuals with a diagnosis of bipolar disorder (n = 9,651), and a randomly selected sample of 1,500,000 from the Danish population. The study period was from 1995 to 2012, inclusive. Outcomes were hazard rate ratios (HR) for RUT in three groups: (i) combined malignant and benign, (ii) malignant, and (iii) benign. Analyses were adjusted for the number of prescriptions for lithium/anticonvulsants, antipsychotic agents, antidepressants, and use of all other types of medication; age; gender; employment status; calendar year; and a diagnosis of bipolar disorder. RESULTS: Continued treatment with lithium was not associated with increased rates of RUT [adjusted HR malignant or benign: 0.67-1.18, p (trend) = 0.70; adjusted HR malignant: 0.61-1.34, p (trend) = 0.90; adjusted HR benign: 0.74-1.18, p (trend) = 0.70]. Similarly, continued treatment with anticonvulsants was not associated with increased rates of RUT [adjusted HR malignant or benign: 0.97-1.18, p (trend) = 0.10; adjusted HR malignant: 0.82-1.15, p (trend) = 0.80; adjusted HR benign: 0.94-1.36, p (trend) = 0.20]. The associations were confirmed among the 9,651 patients with a diagnosis of bipolar disorder. CONCLUSIONS: Treatment with lithium is not associated with increased rates of RUT. PMID- 26534878 TI - Glut-1 intensity and pattern of expression in thymic epithelial tumors are predictive of WHO subtypes. AB - OBJECTIVES: Glucose-transporter-1 (Glut-1) may be a useful marker for differentiating B3 thymomas and thymic carcinomas. Since the literature is limited, we undertook a study to evaluate its diagnostic value in a series of thymic epithelial tumors. MATERIALS AND METHODS: Glut-1 expression was studied by the group of pathologists linked to the French national oncological network RYTHMIC. Immunostaining was performed on a whole section of one paraffin block in a series of 92 successive surgical specimens. Patterns (focal, zonal, diffuse) and intensity of Glut-1 expression were assessed and compared with WHO histological subtypes. RESULTS: Expression was mainly restricted to epithelial cells. Immature T-lymphocytes were negative. A diffuse, moderate or strong staining was observed in most thymic carcinomas (15/16). In B3 thymomas (10/11) and in B3 thymomas borderline to thymic carcinomas (5/6), a moderate to strong zonal staining was observed at distance from vessels and fibrous septa. This pattern sometimes created the aspect of an anastomosing network in large cellular lobules. In B1 thymomas, immunostaining highlighted foci of medullary differentiation (7/8). B2 thymomas (n=25) were heterogeneous, with a spectrum of patterns ranging between those of B1 and B3 thymomas. Type A thymomas (n=5) mostly presented a weak positivity but one aggressive case showed zonal moderate/strong positivity. Most AB thymomas (15/17) showed weak to moderate immunostaining in spindle cell areas. In micronodular thymomas (n=3), epithelial cells and B-lymphocytes were weakly positive while follicular dendritic cells were strongly highlighted. One metaplastic thymoma displayed diffuse and moderate positivity. CONCLUSION: Glut-1 expression globally depended on histological subtypes and the staining patterns (diffuse or zonal) were different between thymic carcinomas and type B3 thymomas. A comparative study of Glut-1 expression in atypical versus conventional type A thymomas appears warranted. Otherwise, restriction to epithelial cells makes likely a correlation with clinical assessment of glucose uptake in lymphocyte-poor tumors. PMID- 26534879 TI - [Breastfeeding in Spain. A commitment by everyone]. PMID- 26534880 TI - [Microbiota and gastrointestinal diseases]. AB - The bacterial colonisation is established immediately after birth, through direct contact with maternal microbiota, and may be influenced during lactation. There is emerging evidence indicating that quantitative and qualitative changes on gut microbiota contribute to alterations in the mucosal activation of the immune system, leading to intra- or extra-intestinal diseases. A balance between pathogenic and beneficial microbiota throughout childhood and adolescence is important to gastrointestinal health, including protection against pathogens, inhibition of pathogens, nutrient processing (synthesis of vitamin K), stimulation of angiogenesis, and regulation of host fat storage. Probiotics can promote an intentional modulation of intestinal microbiota favouring the health of the host. A review is presented on the modulation of intestinal microbiota on prevention, and adjuvant treatment of some paediatric gastrointestinal diseases. PMID- 26534881 TI - Ultrastructure of spermatogenesis and mature spermatozoa in the flatworm Prosthiostomum siphunculus (Polycladida, Cotylea). AB - This is the first study investigating spermatogenesis and spermatozoan ultrastructure in the polyclad flatworm Prosthiostomum siphunculus. The testes are numerous and scattered as follicles ventrally between the digestive ramifications. Each follicle contains the different stages of sperm differentiation. Spermatocytes and spermatids derive from a spermatogonium and the spermatids remain connected by intercellular bridges. Chromatoid bodies are present in the cytoplasm of spermatogonia up to spermatids. During early spermiogenesis, a differentiation zone appears in the distal part of spermatids. A ring of microtubules extends along the entire sperm shaft just beneath the cell membrane. An intercentriolar body is present and gives rise to two axonemes, each with a 9 + "1" micro-tubular pattern. Development of the spermatid leads to cell elongation and formation of a filiform, mature spermatozoon with two free flagella and with cortical microtubules along the sperm shaft. The flagella exit the sperm shaft at different levels, a finding common for acotyleans, but so far unique for cotylean polyclads. The Golgi complex produces numerous electron-dense bodies of two types and of different sizes. These bodies are located around a perinuclear row of mitochondria. The elongated nucleus extends almost along the entire sperm body. The nucleus is wide in the proximal part and becomes narrow going towards the distal end. Thread-like chromatin mixed with electron-dense intranuclear spindle-shaped bodies are present throughout nucleus. The general sperm ultrastructure, the presence of intranuclear bodies and a second type of cytoplasmic electron-dense bodies may provide characters useful for phylogenetic analysis. PMID- 26534882 TI - Molecular Insights into the Thermal Stability of mAbs with Variable-Temperature Ion-Mobility Mass Spectrometry. AB - The aggregation of protein-based therapeutics such as monoclonal antibodies (mAbs) can affect the efficacy of the treatment and can even induce effects that are adverse to the patient. Protein engineering is used to shift the mAb away from an aggregation-prone state by increasing the thermodynamic stability of the native fold, which might in turn alter conformational flexibility. We have probed the thermal stability of three types of intact IgG molecules and two Fc-hinge fragments by using variable-temperature ion-mobility mass spectrometry (VT-IM MS). We observed changes in the conformations of isolated proteins as a function of temperature (300-550 K). The observed differences in thermal stability between IgG subclasses can be rationalized in terms of changes to higher-order structural organization mitigated by the hinge region. VT-IM-MS provides insights into mAbs structural thermodynamics and is presented as a promising tool for thermal stability studies for proteins of therapeutic interest. PMID- 26534883 TI - Capillary electrochromatography and nano-liquid chromatography coupled to nano electrospray ionization interface for the separation and identification of estrogenic compounds. AB - Nano-LC and CEC were coupled to MS through a nanospray or a pressurized liquid junction interface for the simultaneous separation and determination of 11 estrogenic compounds. Different stationary phases, that is, phenyl, C18, and C18 bidentate silica hydrate, were studied. For both techniques, the phenyl stationary phase was the best option, considering separation efficiency, selectivity, and resolution. Under the optimized conditions, the baseline separation of the target compounds (including estradiol and zearalanol epimers) was achieved in less than 20 min in nano-LC-MS and less than 13 min in CEC-MS. Molecular imprinted polymer SPE was used for extracting the target compounds from mineral water samples with the analysis of nano-LC-MS. The whole molecular imprinted polymer SPE nano-LC-MS method was validated through a recovery study at two levels of concentration. Sensitivity was improved by on-column focusing technique obtaining LODs in the range 1.4-55.4 ng/L. PMID- 26534884 TI - Teaching innovations in ultrasound-guided renal biopsy. PMID- 26534885 TI - Valvular calcifications in chronic kidney disease: Mineral and bone disease or previous cardiovascular risk? Response. PMID- 26534886 TI - Valvular calcifications in CKD: Mineral and bone disease or previous cardiovascular risk? PMID- 26534887 TI - The physics of Martian weather and climate: a review. AB - The planet Mars hosts an atmosphere that is perhaps the closest in terms of its meteorology and climate to that of the Earth. But Mars differs from Earth in its greater distance from the Sun, its smaller size, its lack of liquid oceans and its thinner atmosphere, composed mainly of CO(2). These factors give Mars a rather different climate to that of the Earth. In this article we review various aspects of the martian climate system from a physicist's viewpoint, focusing on the processes that control the martian environment and comparing these with corresponding processes on Earth. These include the radiative and thermodynamical processes that determine the surface temperature and vertical structure of the atmosphere, the fluid dynamics of its atmospheric motions, and the key cycles of mineral dust and volatile transport. In many ways, the climate of Mars is as complicated and diverse as that of the Earth, with complex nonlinear feedbacks that affect its response to variations in external forcing. Recent work has shown that the martian climate is anything but static, but is almost certainly in a continual state of transient response to slowly varying insolation associated with cyclic variations in its orbit and rotation. We conclude with a discussion of the physical processes underlying these long- term climate variations on Mars, and an overview of some of the most intriguing outstanding problems that should be a focus for future observational and theoretical studies. PMID- 26534888 TI - A flow injection chemiluminescence method for determination of nalidixic acid based on KMnO4-morin sensitized with CdS quantum dots. AB - A simple and sensitive flow injection chemiluminescence (CL) method was developed for determination of nalidixic acid by application of CdS quantum dots (QDs) in KMnO4-morin CL system in acidic medium. Optical and structural features of L cysteine capped CdS quantum dots which were synthesized via hydrothermal approach were investigated using X-ray diffraction (XRD), scanning electron microscopy (SEM), photoluminescence (PL), and ultraviolet-visible (UV-Vis) spectroscopy. Moreover, the potential mechanism of the proposed CL method was described using the results of the kinetic curves of CL systems, the spectra of CL, PL and UV-Vis analyses. The CL intensity of the KMnO4-morin-CdS QDs system was considerably increased in the presence of nalidixic acid. Under the optimum condition, the enhanced CL intensity was linearly proportional to the concentration of nalidixic acid in the range of 0.0013 to 21.0 mg L(-1), with a detection limit of (3sigma) 0.003 mg L(-1). Also, the proposed CL method was utilized for determination of nalidixic acid in environmental water samples, and commercial pharmaceutical formulation to approve its applicability. Furthermore, corona discharge ionization ion mobility spectrometry (CD-IMS) method was utilized for determination of nalidixic acid and the results of real sample analysis by two proposed methods were compared. Comparison the analytical features of these methods represented that the proposed CL method is preferable to CD-IMS method for determination of nalidixic acid due to its high sensitivity and precision. PMID- 26534889 TI - Comparison of the prevalence of sarcopenia using skeletal muscle mass index and calf circumference applying the European consensus definition in elderly Mexican women. AB - AIM: To compare the prevalence of sarcopenia using two indicators: skeletal muscle mass index (SMI) and calf circumference (CC) used in the algorithm proposed by the European Working Group on Sarcopenia in Mexican elderly women. METHODS: This was a cross-sectional study. Lean body mass was determined by dual energy X-ray absorptiometry. To define sarcopenia, the SMI was obtained using a cut-off value of 5.5 kg/m2 , and the CC cut-off was 31 cm. For gait speed and handgrip strength, the cut-off values were 0.8 m/s and 20 kg, respectively. RESULTS: A total of 137 women (mean age 73.8 +/- 6.7 years) participated in the study. The prevalence of sarcopenia was 14.6% using SMI and 11.0% using CC (P = 0.009). Body mass index was associated with a lower probability of sarcopenia applying SMI or CC (OR 0.75, P = 0.002 for SMI and OR 0.71, P = 0.004 for CC). Sarcopenia evaluated either with dual-energy X-ray absorptiometry or CC was not associated with physical performance, such as five times chair stand test, timed up and go test and short physical performance battery. Additionally, SMI was not associated with physical performance, five times chair stand test (P = 0.775) and timed up-and-go test (P = 0.341). CONCLUSIONS: The prevalence of sarcopenia in active elderly women was low. A higher prevalence of sarcopenia was detected using SMI compared with CC. It is important to identify the best methods to assess skeletal muscle mass to obtain a reliable diagnosis of sarcopenia. Geriatr Gerontol Int 2017; 17: 161-170. PMID- 26534890 TI - Liver capsule: Hepatitis C virus host cell entry. PMID- 26534891 TI - Genetic effects of multiple asthma loci identified by genomewide association studies on asthma and spirometric indices. AB - BACKGROUND: Genomewide association study (GWAS) published by GABRIEL consortium identified 10 asthma-associated loci. However, their relationship with lung functions is unclear. This study investigated the association between asthma traits and single-nucleotide polymorphisms (SNPs) of these GWAS loci. METHODS: Rs3894194 and rs9273349 were not genotyped due to unavailable TaqMan assays. Genetic associations of remaining eight SNPs were investigated in 903 school-age asthmatics and 1205 non-allergic controls. Four significant SNPs were then replicated in 479 adult asthmatics and 746 adult controls, and 1341 Chinese preschool children. Meta-analyses were performed by combining data from school age children and adults. Generalized multifactor dimensionality reduction (GMDR) was used to analyze their interactions for asthma traits. RESULTS: Childhood asthma was associated with GSDMB_rs2305480 (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.57-0.83). IL13_rs1295686 was associated with all asthma (OR 1.64, 95% CI 1.16-2.32) and early-onset asthma (OR 1.92, 95% CI 1.20-3.06) in adults, whereas GSDMB_rs2305480 was only associated with early-onset asthma (OR 0.69, 95% CI 0.49-0.96). According to meta-analyses, the minor allele of rs2305480 was inversely associated with FEV1 , FVC, and FEV1 /FVC (p < 0.01). GMDR analyses revealed 2-locus models of SLC22A5 with SMAD3 to modulate FEVt /FVC in both preschool children and adults, with IL13 to determine FVC in both school-age children and adults, and with IL2RB to modulate FEV1 /FVC in school-age children. CONCLUSIONS: IL13 and GSDMB are replicated as asthma genes. Rs2305480 of GSDMB is also associated with low FEV1 , FVC, and FEV1 /FVC among asthmatics. Moreover, SLC22A5, IL13, SMAD3, and GSDMB interact to modulate spirometric indices. PMID- 26534892 TI - The First Crystal Structure of a Reactive Dirhodium Carbene Complex and a Versatile Method for the Preparation of Gold Carbenes by Rhodium-to-Gold Transmetalation. AB - The dirhodium carbene derived from bis(4-methoxyphenyl)diazomethane and [Rh(tpa)4 ]?CH2 Cl2 (tpa=triphenylacetate) was characterized by UV, IR, and NMR spectroscopy, HRMS, as well as by X-ray diffraction. The isolated complex exhibits prototypical rhodium carbene reactivity in that it cyclopropanates 4 methoxystyrene at low temperature. Experimental structural information on this important type of reactive intermediate is extremely scarce and thus serves as a reference point for mechanistic discussions of rhodium catalysis in general. Moreover, dirhodium carbenes are shown to undergo remarkably facile carbene transfer on treatment with [LAuNTf2 ] (L=phosphine). This formal transmetalation opens a valuable new entry into gold carbene complexes that cannot easily be made otherwise; three fully characterized representatives illustrate this aspect. PMID- 26534893 TI - Quality of life in Duchenne muscular dystrophy: the disability paradox. PMID- 26534894 TI - Sample Taking and Direct Examination in Dermatomycoses. PMID- 26534895 TI - What is a microbiologist? A survey exploring the microbiology workforce. AB - Microbiology has a long tradition of making inspirational, world-changing discovery. Microbiology now plays essential roles in many disciplines, leading to some microbiologists raising concern over the apparent loss of identity. An electronic survey was undertaken to capture the scientific identity (based on scientific discipline) of people for whom microbiology forms a part of their profession, in addition to information regarding their first degree (title, country and year in which the degree was completed) and the sector in which they currently work. A total of 447 responses were collected, representing 52 countries from which they gained their first degree. Biology was the most common first degree title (of 32 titles provided), while microbiologist was the most common scientific identity (of 26 identities provided). The data collected in this study gives a snapshot of the multidisciplinarity, specialism and evolving nature of the microbiology academic workforce. While the most common scientific identity chosen in this study was that of a microbiologist, it appears that the microbiological workforce is contributed to by a range of different disciplines, highlighting the cross-cutting, multidisciplined and essential role microbiology has within scientific endeavour. Perhaps, we should be less concerned with labels, and celebrate the success with which our discipline has delivered. PMID- 26534896 TI - A novel endolysin disrupts Streptococcus suis with high efficiency. AB - Streptococcus suis serotype 2 (S. suis 2) is a zoonotic pathogen that exhibits high-level resistance and multi-drug resistance to classic antibiotics and causes serious human casualties and heavy economic losses in the swine industry worldwide. Therefore, alternative therapies or novel antibacterial agents need to be developed to combat this pathogen. A novel endolysin derived from the S. suis temperate phage phi7917, termed Ly7917, was identified, which had broad lytic activity against S. suis type 1, 2, 7 and 9. Ly7917 consisted of an N-terminal cysteine, histidine-dependent amidohydrolases/peptidase catalytic domain and C terminal SH3b cell wall binding domain. The endolysin maintained activity at high pH and its catalytic activity could be improved by addition of 10 MUM 1.5 mM Ca(2+). In animal studies, 90% of BALB/c mice challenged with typical virulent strain HA9801 of S. suis 2 were protected by Ly7917 treatment. The bacterial load in the blood of HA9801-challenged mice was efficiently reduced almost 50% by Ly7917 while that of penicillin-G-treated mice kept almost unchanged. Our data suggest that Ly7917 may be an alternative therapeutic agent for infections caused by virulent S. suis strains. PMID- 26534897 TI - Dilatation and curettage increases the risk of subsequent preterm birth: a systematic review and meta-analysis. AB - STUDY QUESTION: Could dilatation and curettage (D&C), used in the treatment of miscarriage and termination of pregnancy, increase the risk of subsequent preterm birth? SUMMARY ANSWER: A history of curettage in women is associated with an increased risk of preterm birth in a subsequent pregnancy compared with women without such history. WHAT IS KNOWN ALREADY: D&C is one of the most frequently performed procedures in obstetrics and gynaecology. Apart from the acknowledged but relatively rare adverse effects, such as cervical tears, bleeding, infection, perforation of the uterus, bowel or bladder, or Asherman syndrome, D&C has been suggested to also lead to an increased risk of preterm birth in the subsequent pregnancy. STUDY DESIGN, SIZE, DURATION: In the absence of randomized data, we conducted a systematic review and meta-analysis of cohort and case-control studies. PARTICIPANTS/MATERIALS, SETTING, METHODS: We searched OVID MEDLINE and OVID EMBASE form inception until 21 May 2014. We selected cohort and case-control studies comparing subsequent preterm birth in women who had a D&C for first trimester miscarriage or termination of pregnancy and a control group of women without a history of D&C. MAIN RESULTS AND THE ROLE OF CHANCE: We included 21 studies reporting on 1 853 017 women. In women with a history of D&C compared with those with no such history, the odds ratio (OR) for preterm birth <37 weeks was 1.29 (95% CI 1.17; 1.42), while for very preterm birth the ORs were 1.69 (95% CI 1.20; 2.38) for <32 weeks and 1.68 (95% CI 1.47; 1.92) for <28 weeks. The risk remained increased when the control group was limited to women with a medically managed miscarriage or induced abortion (OR 1.19, 95% CI 1.10; 1.28). For women with a history of multiple D&Cs compared with those with no D&C, the OR for preterm birth (<37 weeks) was 1.74 (95% CI 1.10; 2.76). For spontaneous preterm birth, the OR was 1.44 (95% CI 1.22; 1.69) for a history of D&C compared with no such history. LIMITATIONS, REASONS FOR CAUTION: There were no randomized controlled trials comparing women with and without a history of D&C and subsequent preterm birth. As a consequence, confounding may be present since the included studies were either cohort or case-control studies, not all of which corrected the results for possible confounding factors. WIDER IMPLICATIONS OF THE FINDINGS: This meta-analysis shows that D&C is associated with an increased risk of subsequent preterm birth. The increased risk in association with multiple D&Cs indicates a causal relationship. Despite the fact that confounding cannot be excluded, these data warrant caution in the use of D&C for miscarriage and termination of pregnancy, the more so since less invasive options are available. STUDY FUNDING/COMPETING INTERESTS: This study was funded by ZonMw, a Dutch organization for Health Research and Development, project number 80-82310-97 12066. PMID- 26534898 TI - Higher levels of procoagulant microparticles in women with recurrent miscarriage are not associated with antiphospholipid antibodies. AB - STUDY QUESTION: Are the levels of circulating cell-derived microparticles (cMPs) in patients with recurrent miscarriage (RM) associated with the antiphospholipid syndrome (APS)? SUMMARY ANSWER: cMPs in women with RM are not associated with antiphospholipid antibodies (aPLs). WHAT IS KNOWN ALREADY: Previous studies have focused on cMP levels in RM patients. Most studies have shown higher levels of cMPs in RM patients whereas others have reported lower levels. Data regarding cMPs in patients with the APS are scanty in the literature. STUDY DESIGN, SIZE, DURATION: A case-control study including three groups of patients. A total of 154 women were prospectively recruited from September 2009 to October 2013. Four patients refused to participate. The APS group consisted of 50 women that had been previously diagnosed with primary APS and had had >=3 consecutive first trimester miscarriages. The uRM group included 52 couples with >=3 consecutive first trimester miscarriages of unknown etiology. The fertile control (FER) group was composed of 52 healthy fertile women with no history of pregnancy losses. Miscarriage was defined as intrauterine pregnancy loss at <10 weeks' size on ultrasound. PARTICIPANTS/MATERIALS, SETTING, METHODS: Venous blood samples for coagulation studies and cMP determinations were obtained. All patients underwent a thrombophilia study. MAIN RESULTS AND THE ROLE OF CHANCE: cMP levels were significantly higher in the APS and uRM groups versus the FER group (P < 0.0001 and P = 0.009, respectively) (cMP number * 10(3)/ml plasma [mean +/- SD]: APS: 18.5 +/- 13.6; uRM: 16.3 +/- 13.8; FER: 9.7 +/- 4.6). There were no statistically significant differences in cMP levels between the APS and uRM groups. LIMITATIONS, REASONS FOR CAUTION: The sample size was arbitrarily decided according to previous studies analyzing cMPs in RM patients. Different cMP subtypes were not investigated. WIDER IMPLICATIONS OF THE FINDINGS: The present study adds further data on the subject showing that patients with RM, irrespective of testing positive for aPLs, have increased levels of cMPs compared with healthy fertile controls. The presence of elevated cMPs in RM women may reflect an ongoing systemic pathological, albeit asymptomatic, status that can become deleterious in the setting of pregnancy. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by grant from FIS-PI11/01560 within the 'Plan Nacional de I+D+I' and co-funded by the 'ISCIII-Subdireccion General de Evaluacion' and the 'Fondo Europeo de Desarrollo Regional (FEDER)'. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 26534900 TI - Edutainment's Impact on Health Promotion: Viewing The Biggest Loser Through the Social Cognitive Theory. AB - Through a critical rhetorical analysis using Bandura's social cognitive theory as a lens to view The Biggest Loser (TBL), this article illustrates the contradictions between the show's health promotional aims and its entertainment aims, which show the problems the show creates for health promotion practitioners working on obesity. The social cognitive theory constructs of observational learning, psychological determinants, and environmental determinants emerged from this reading of TBL as central to how the show masquerades as a health promotion tool. This reading reveals that TBL promotes a neoliberal construction of health and obesity that challenges the worldview that many health promotion campaigns take and, therefore, complicates our own efforts to combat obesity. With this revealed, it is suggested that TBL be incorporated into health promotion campaigns only as a foil. PMID- 26534899 TI - Developmental emergence of fear/threat learning: neurobiology, associations and timing. AB - Pavlovian fear or threat conditioning, where a neutral stimulus takes on aversive properties through pairing with an aversive stimulus, has been an important tool for exploring the neurobiology of learning. In the past decades, this neurobehavioral approach has been expanded to include the developing infant. Indeed, protracted postnatal brain development permits the exploration of how incorporating the amygdala, prefrontal cortex and hippocampus into this learning system impacts the acquisition and expression of aversive conditioning. Here, we review the developmental trajectory of these key brain areas involved in aversive conditioning and relate it to pups' transition to independence through weaning. Overall, the data suggests that adult-like features of threat learning emerge as the relevant brain areas become incorporated into this learning. Specifically, the developmental emergence of the amygdala permits cue learning and the emergence of the hippocampus permits context learning. We also describe unique features of learning in early life that block threat learning and enhance interaction with the mother or exploration of the environment. Finally, we describe the development of a sense of time within this learning and its involvement in creating associations. Together these data suggest that the development of threat learning is a useful tool for dissecting adult-like functioning of brain circuits, as well as providing unique insights into ecologically relevant developmental changes. PMID- 26534902 TI - Public Health England's troubled trail. PMID- 26534901 TI - Pancreatic Cancer Metabolism: Breaking It Down to Build It Back Up. AB - How do cancer cells escape tightly controlled regulatory circuits that link their proliferation to extracellular nutrient cues? An emerging theme in cancer biology is the hijacking of normal stress response mechanisms to enable growth even when nutrients are limiting. Pancreatic ductal adenocarcinoma (PDA) is the quintessential aggressive malignancy that thrives in nutrient-poor, hypoxic environments. PDAs overcome these limitations through appropriation of unorthodox strategies for fuel source acquisition and utilization. In addition, the interplay between evolving PDA and whole-body metabolism contributes to disease pathogenesis. Deciphering how these pathways function and integrate with one another can reveal novel angles of therapeutic attack. SIGNIFICANCE: Alterations in tumor cell and systemic metabolism are central to the biology of pancreatic cancer. Further investigation of these processes will provide important insights into how these tumors develop and grow, and suggest new approaches for its detection, prevention, and treatment. PMID- 26534903 TI - Cold loops applied to bipolar resectoscope: A safe "one-step" myomectomy for treatment of submucosal myomas with intramural development. AB - AIM: To assess the safety and efficacy of cold loop myomectomy applied to bipolar resectoscope to perform "one-step" myomectomy of submucosal myomas with intramural involvement. METHODS: Seventy-two patients with at least one symptomatic G1 or G2 myoma (Wamsteker's classification) underwent cold loop myomectomy from January 2011 to January 2013. All surgical procedures were performed using a 26Fr resectoscope and bipolar energy source. At one month after the procedure, all patients underwent an office hysteroscopy check-up. A subgroup of seven infertile patients underwent an office hysteroscopy every two-weeks to evaluate recovery time of the myometrial fovea. RESULTS: Resectoscopic myomectomies were successfully performed in one surgical step in 70 out of 72 patients without any significant complications. Overall, the mean diameter of resected myomas was 32.2 +/- 9 mm. Median operative time was 34.2 +/- 24.1 min. Median fluid deficit was 761.22 +/- 480.34 ml. The fovea was almost completely restored (>80%) six weeks after surgery in six of the seven infertile patients who underwent repeated follow-up office hysteroscopies every two weeks. CONCLUSIONS: Data from the present study show that the use of cold loops applied to bipolar resectoscope represent an effective, safe technique for "one-step" myomectomy of G1-G2 myomas, allowing rapid recovery of the myometrial fovea. PMID- 26534904 TI - Effect of flavored milk vs plain milk on total milk intake and nutrient provision in children. AB - Concerns surrounding added sugars and their effects on health have created a need to review the literature to assess consumption of flavored milk, consumer preferences for flavored milk, behavior related to the intake of flavored milk, and the effect of flavored milk on the diet and health of children. A review of the literature was performed using the following keywords: milk, flavored, flavoured, sweetened, and chocolate. The search was limited to articles published in English, studies conducted in children, and studies reporting on prevalence of consumption, trends in consumption, preferences for flavored milk, intakes of milk and nutrients, and health outcomes. Fifty-three studies were included. Flavored milk receives the highest palatability rating among children. Children drink more flavored milk than plain milk and, when flavored milk is not available, children drink less plain milk and, consequently, less milk overall. Consumers of flavored milk have a higher total milk intake. Micronutrient intake among consumers of flavored milk is similar to that among consumers of plain milk, while intakes of energy and sugars vary, owing to differences in reporting across studies. There is no association between flavored milk intake and weight status among normal-weight children, and some contradictory effects of flavored milk intake have been observed in subgroups of overweight children. Flavored milk is a palatable beverage choice that helps children to meet calcium targets. Further research to test the effect of flavored milk consumption among overweight children is warranted. PMID- 26534905 TI - Polymorphisms of dopamine pathway genes NRG1 and LMX1A are associated with cognitive performance in bipolar disorder. AB - OBJECTIVES: LIM homeobox transcription factor 1, alpha (LMX1A) and neuregulin 1 (NRG1) are susceptibility genes for schizophrenia that have been implicated in the dopaminergic pathway and have been associated with altered cognitive functioning. We hypothesized that single nucleotide polymorphisms (SNPs) in LMX1A and NRG1 would be associated with cognitive functioning in bipolar disorder. METHODS: In total, four SNPs were directly genotyped. Regression models with five aggregated cognitive domains and intelligence quotient (IQ) score were run using risk variants of LMX1A (rs11809911, rs4657412, rs6668493) and NRG1 (rs35753505) as predictors. Models were performed in a clinical sample of patients with bipolar disorder (n = 114) and healthy controls (n = 104). RESULTS: The risk variants of the rs11809911 SNP in LMX1A were negatively associated with IQ score and memory/learning, whereas the risk variants of rs35753505 in NRG1 were positively associated with IQ score (adjusted R(2) = 0.17, Q = 0.006) and memory/learning (adjusted R(2) = 0.24, Q = 0.001). The risk variants of the rs35753505 SNP in NRG1 were positively associated with language (adjusted R(2) = 0.11, Q = 0.006), visuospatial functions (adjusted R(2) = 0.23, Q = 0.001), and attention/speed (adjusted R(2) = 0.25, Q = 0.001). Results could not be replicated in controls. CONCLUSIONS: The risk variants of the rs35753505 SNP were associated with increased performance in several cognitive domains and IQ, whereas the risk variants of the rs11809911 SNP in LMX1A was associated with reduced IQ and memory/learning. PMID- 26534906 TI - First Occurrence of Tetrazines in Aqueous Solution: Electrochemistry and Fluorescence. AB - The photophysical and electrochemical properties of tetrazines substituted by linear 2,3-naphtalimide antennas and/or adamantane groups specifically dedicated to host-guest interactions with cyclodextrins are studied both in organic and aqueous media. In acetonitrile solvent, the reduction potential of tetrazine leading to the anion radical is shifted, depending on the electron-withdrawing power of the substituent of the tetrazines. Due to the hydrophobic character of these compounds, their solubilization in aqueous solution is achieved successively in presence of either beta-cyclodextrins or gold nanoparticules modified by beta-cyclodextrins. We demonstrate that the formation of the inclusion compound tetrazine-cyclodextrin allows the solubilization of the tetrazines in aqueous solution. The supramolecular assemblies obtained in water retain tetrazine's emission properties, yielding a yellow fluorescence. PMID- 26534907 TI - Constructing Visual Perception of Body Movement with the Motor Cortex. AB - The human brain readily perceives fluent movement from static input. Using functional magnetic resonance imaging, we investigated brain mechanisms that mediate fluent apparent biological motion (ABM) perception from sequences of body postures. We presented body and nonbody stimuli varying in objective sequence duration and fluency of apparent movement. Three body postures were ordered to produce a fluent (ABC) or a nonfluent (ACB) apparent movement. This enabled us to identify brain areas involved in the perceptual reconstruction of body movement from identical lower-level static input. Participants judged the duration of a rectangle containing body/nonbody sequences, as an implicit measure of movement fluency. For body stimuli, fluent apparent motion sequences produced subjectively longer durations than nonfluent sequences of the same objective duration. This difference was reduced for nonbody stimuli. This body-specific bias in duration perception was associated with increased blood oxygen level-dependent responses in the primary (M1) and supplementary motor areas. Moreover, fluent ABM was associated with increased functional connectivity between M1/SMA and right fusiform body area. We show that perceptual reconstruction of fluent movement from static body postures does not merely enlist areas traditionally associated with visual body processing, but involves cooperative recruitment of motor areas, consistent with a "motor way of seeing". PMID- 26534908 TI - Global Transcriptome Analysis of Primary Cerebrocortical Cells: Identification of Genes Regulated by Triiodothyronine in Specific Cell Types. AB - Thyroid hormones, thyroxine, and triiodothyronine (T3) are crucial for cerebral cortex development acting through regulation of gene expression. To define the transcriptional program under T3 regulation, we have performed RNA-Seq of T3 treated and untreated primary mouse cerebrocortical cells. The expression of 1145 genes or 7.7% of expressed genes was changed upon T3 addition, of which 371 responded to T3 in the presence of cycloheximide indicating direct transcriptional regulation. The results were compared with available transcriptomic datasets of defined cellular types. In this way, we could identify targets of T3 within genes enriched in astrocytes and neurons, in specific layers including the subplate, and in specific neurons such as prepronociceptin, cholecystokinin, or cortistatin neurons. The subplate and the prepronociceptin neurons appear as potentially major targets of T3 action. T3 upregulates mostly genes related to cell membrane events, such as G-protein signaling, neurotransmission, and ion transport and downregulates genes involved in nuclear events associated with the M phase of cell cycle, such as chromosome organization and segregation. Remarkably, the transcriptomic changes induced by T3 sustain the transition from fetal to adult patterns of gene expression. The results allow defining in molecular terms the elusive role of thyroid hormones on neocortical development. PMID- 26534909 TI - Adenosine A2A Receptors Modulate alpha-Synuclein Aggregation and Toxicity. AB - Abnormal accumulation of aggregated alpha-synuclein (aSyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and related synucleinopathies. Recent studies suggest a neuroprotective role of adenosine A2A receptor (A2AR) antagonists in PD. Nevertheless, the precise molecular mechanisms underlying this neuroprotection remain unclear. We assessed the impact of A2AR blockade or genetic deletion (A2AR KO) on synaptic plasticity and neuronal cell death induced by aSyn oligomers. We found that impairment of LTP associated with aSyn exposure was rescued in A2AR KO mice or upon A2AR blockade, through an NMDA receptor dependent mechanism. The mechanisms underlying these effects were evaluated in SH SY5Y cells overexpressing aSyn and rat primary neuronal cultures exposed to aSyn. Cell death in both conditions was prevented by selective A2AR antagonists. Interestingly, blockade of these receptors did not interfere with aSyn oligomerization but, instead, reduced the percentage of cells displaying aSyn inclusions. Altogether, our data raise the possibility that the well-documented effects of A2AR antagonists involve the control of the latter stages of aSyn aggregation, thereby preventing the associated neurotoxicity. These findings suggest that A2AR represent an important target for the development of effective drugs for the treatment of PD and related synucleinopathies. PMID- 26534910 TI - Bacterial protein toxins in human cancers. AB - Many bacteria causing persistent infections produce toxins whose mechanisms of action indicate that they could have a role in carcinogenesis. Some toxins, like CDT and colibactin, directly attack the genome by damaging DNA whereas others, as for example CNF1, CagA and BFT, impinge on key eukaryotic processes, such as cellular signalling and cell death. These bacterial toxins, together with other less known toxins, mimic carcinogens and tumour promoters. The aim of this review is to fulfil an up-to-date analysis of toxins with carcinogenic potential that have been already correlated to human cancers. Bacterial toxins-induced carcinogenesis represents an emerging aspect in bacteriology, and its significance is increasingly recognized. PMID- 26534911 TI - Superior septal approach for mitral valve surgery. AB - Superior septal approach is a very useful technique to address the mitral valve surgery. Since this approach virtually divides the left atrium in two parts between the ascending aorta and the superior vena cava, mitral valve exposure becomes quite easy. We present a case of mitral valve repair by means of this approach. PMID- 26534912 TI - Disseminated histoplasmosis in an immunocompetent individual: a myth or reality? PMID- 26534913 TI - Staining of hydatid elements: a useful adjunct in the diagnosis of hydatid disease. AB - Staining techniques have immeasurably aided diagnosis of hydatid disease on several instances. The use of staining techniques for their ability to aid in the morphological diagnosis of hydatid elements, especially at rare and uncommon sites, is discussed. PMID- 26534914 TI - Diffuse melanonychia as a clue to vitamin B12 deficiency. PMID- 26534915 TI - Qualitative evaluation of paediatric burn injury in Malawi: assessing opportunities for injury prevention. AB - INTRODUCTION: The burden of burn injury in sub-Saharan Africa is high and children bare a disproportional share of the injury burden. METHODS: This is a prospective qualitative study of paediatric burn survivors (age, <=8 years) admitted to Kamuzu Central Hospital (KCH) in Lilongwe, Malawi. RESULTS: There were a total of 72 guardians interviewed for the purpose of the study. The most frequent mechanisms of burn injury were flames and scalds in 44.4% and 38.9%, respectively. Mothers were present at the time of the burn injury in only 23.6% of cases, while 22.2% of children were unmonitored at the time of injury. A total of 55.6% of burn injuries was cooking-related. CONCLUSION: Burn prevention strategies are necessary for addressing the high rates of burns for children in sub-Saharan Africa. The must be focused on mothers and caregivers burn education in the home, particularly as it relates to cooking and parental oversight. PMID- 26534916 TI - The fate of end-stage renal disease patients after arteriovenous fistula creation in a northern Nigerian teaching hospital. AB - With few end-stage renal disease patients having access to dialysis, we sought to determine the average duration of survival of these patients, after creation of an arteriovenous fistula. Out of 36 patients, 26 had died a little over 6 months later. PMID- 26534917 TI - Duodenal tuberculosis: dig deep to diagnose. PMID- 26534918 TI - Do coping styles mediate the relationship between disability status and psychosocial loss in people with relapsing remitting multiple sclerosis? AB - The main aim of this cross-sectional study was to analyse the degree to which coping may act as a mediator between disability and psychosocial loss in people with relapsing remitting multiple sclerosis. Participants ( N = 158) completed measures of psychosocial loss and ways of coping. Disability status was evaluated by attending neurologists. Coping partially mediated the relationship between disability and psychosocial loss. Disability leads to the experience of psychosocial loss but it is not the sole factor determining the formation of psychosocial loss. Coping is also associated with such losses in multiple sclerosis. PMID- 26534919 TI - Mefloquine for malarial prophylaxis in military personnel. PMID- 26534920 TI - CXCR3+ Regulatory T Cells Control TH1 Responses in Crescentic GN. AB - Chemokines and chemokine receptors are implicated in regulatory T cell (Treg) trafficking to sites of inflammation and suppression of excessive immune responses in inflammatory and autoimmune diseases; however, the specific requirements for Treg migration into the inflamed organs and the positioning of these cells within the tissue are incompletely understood. Here, we report that Tregs expressing the TH1-associated chemokine receptor CXCR3 are enriched in the kidneys of patients with ANCA-associated crescentic GN and colocalize with CXCR3(+) effector T cells. To investigate the functional role of CXCR3(+) Tregs, we generated mice that lack CXCR3 in Tregs specifically (Foxp3(eGFP-Cre) * Cxcr3(fl/fl)) and induced experimental crescentic GN. Treg-specific deletion of CXCR3 resulted in reduced Treg recruitment to the kidney and an overwhelming TH1 immune response, with an aggravated course of the nephritis that was reversible on anti-IFNgamma treatment. Together, these findings show that a subset of Tregs expresses CXCR3 and thereby, acquires trafficking properties of pathogenic CXCR3(+) TH1 cells, allowing Treg localization and control of excessive TH1 responses at sites of inflammation. PMID- 26534921 TI - Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort. AB - To maximize clinical benefits of genetic screening of patients with nephrotic syndrome (NS) to diagnose monogenic causes, reliably distinguishing NS-causing variants from the background of rare, noncausal variants prevalent in all genomes is vital. To determine the prevalence of monogenic NS in a North American case cohort while accounting for background prevalence of genetic variation, we sequenced 21 implicated monogenic NS genes in 312 participants from the Nephrotic Syndrome Study Network and 61 putative controls from the 1000 Genomes Project (1000G). These analyses were extended to available sequence data from approximately 2500 subjects from the 1000G. A typical pathogenicity filter identified causal variants for NS in 4.2% of patients and 5.8% of subjects from the 1000G. We devised a more stringent pathogenicity filtering strategy, reducing background prevalence of causal variants to 1.5%. When applying this stringent filter to patients, prevalence of monogenic NS was 2.9%; of these patients, 67% were pediatric, and 44% had FSGS on biopsy. The rate of complete remission did not associate with monogenic classification. Thus, we identified factors contributing to inaccurate monogenic classification of NS and developed a more accurate variant filtering strategy. The prevalence and clinical correlates of monogenic NS in this sporadically affected cohort differ substantially from those reported for patients referred for genetic analysis. Particularly in unselected, population-based cases, considering putative causal variants in known NS genes from a probabilistic rather than a deterministic perspective may be more precise. We also introduce GeneVetter, a web tool for monogenic assessment of rare disease. PMID- 26534922 TI - The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes. AB - Epigenetic regulation of oxidative stress is emerging as a critical mediator of diabetic nephropathy. In diabetes, oxidative damage occurs when there is an imbalance between reactive oxygen species generation and enzymatic antioxidant repair. Here, we investigated the function of the histone methyltransferase enzyme enhancer of zeste homolog 2 (EZH2) in attenuating oxidative injury in podocytes, focusing on its regulation of the endogenous antioxidant inhibitor thioredoxin interacting protein (TxnIP). Pharmacologic or genetic depletion of EZH2 augmented TxnIP expression and oxidative stress in podocytes cultured under high-glucose conditions. Conversely, EZH2 upregulation through inhibition of its regulatory microRNA, microRNA-101, downregulated TxnIP and attenuated oxidative stress. In diabetic rats, depletion of EZH2 decreased histone 3 lysine 27 trimethylation (H3K27me3), increased glomerular TxnIP expression, induced podocyte injury, and augmented oxidative stress and proteinuria. Chromatin immunoprecipitation sequencing revealed H3K27me3 enrichment at the promoter of the transcription factor Pax6, which was upregulated on EZH2 depletion and bound to the TxnIP promoter, controlling expression of its gene product. In high glucose-exposed podocytes and the kidneys of diabetic rats, the lower EZH2 expression detected coincided with upregulation of Pax6 and TxnIP. Finally, in a gene expression array, TxnIP was among seven of 30,854 genes upregulated by high glucose, EZH2 depletion, and the combination thereof. Thus, EZH2 represses the transcription factor Pax6, which controls expression of the antioxidant inhibitor TxnIP, and in diabetes, downregulation of EZH2 promotes oxidative stress. These findings expand the extent to which epigenetic processes affect the diabetic kidney to include antioxidant repair. PMID- 26534923 TI - Megalin-Mediated Tubuloglomerular Alterations in High-Fat Diet-Induced Kidney Disease. AB - Obesity, an important risk factor for metabolic syndrome (MetS) and cardiovascular disease, is often complicated by CKD, which further increases cardiovascular risk and causes ESRD. To elucidate the mechanism underlying this relationship, we investigated the role of the endocytic receptor megalin in proximal tubule epithelial cells (PTECs). We studied a high-fat diet (HFD) induced obesity/MetS model using kidney-specific mosaic megalin knockout (KO) mice. Compared with control littermates fed a normal-fat diet, control littermates fed an HFD for 12 weeks showed autolysosomal dysfunction with autophagy impairment and increased expression of hypertrophy, lipid peroxidation, and senescence markers in PTECs of the S2 segment, peritubular capillary rarefaction with localized interstitial fibrosis, and glomerular hypertrophy with mesangial expansion. These were ameliorated in HFD-fed megalin KO mice, even though these mice had the same levels of obesity, dyslipidemia, and hyperglycemia as HFD-fed control mice. Intravital renal imaging of HFD-fed wild-type mice also demonstrated the accumulation of autofluorescent lipofuscin-like substances in PTECs of the S2 segment, accompanied by focal narrowing of tubular lumens and peritubular capillaries. In cultured PTECs, fatty acid-rich albumin induced the increased expression of genes encoding PDGF-B and monocyte chemoattractant protein-1 via megalin, with large (auto)lysosome formation, compared with fatty acid-depleted albumin. Collectively, the megalin-mediated endocytic handling of glomerular-filtered (lipo)toxic substances appears to be involved primarily in hypertrophic and senescent PTEC injury with autophagy impairment, causing peritubular capillary damage and retrograde glomerular alterations in HFD-induced kidney disease. Megalin could be a therapeutic target for obesity/MetS-related CKD, independently of weight, dyslipidemia, and hyperglycemia modification. PMID- 26534924 TI - 2-Deoxy-d-Glucose Ameliorates PKD Progression. AB - Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of ESRD for which there exists no approved therapy in the United States. Defective glucose metabolism has been identified as a feature of ADPKD, and inhibition of glycolysis using glucose analogs ameliorates aggressive PKD in preclinical models. Here, we investigated the effects of chronic treatment with low doses of the glucose analog 2-deoxy-d-glucose (2DG) on ADPKD progression in orthologous and slowly progressive murine models created by inducible inactivation of the Pkd1 gene postnatally. As previously reported, early inactivation (postnatal days 11 and 12) of Pkd1 resulted in PKD developing within weeks, whereas late inactivation (postnatal days 25-28) resulted in PKD developing in months. Irrespective of the timing of Pkd1 gene inactivation, cystic kidneys showed enhanced uptake of (13)C-glucose and conversion to (13)C-lactate. Administration of 2DG restored normal renal levels of the phosphorylated forms of AMP-activated protein kinase and its target acetyl-CoA carboxylase. Furthermore, 2DG greatly retarded disease progression in both model systems, reducing the increase in total kidney volume and cystic index and markedly reducing CD45-positive cell infiltration. Notably, chronic administration of low doses (100 mg/kg 5 days per week) of 2DG did not result in any obvious sign of toxicity as assessed by analysis of brain and heart histology as well as behavioral tests. Our data provide proof of principle support for the use of 2DG as a therapeutic strategy in ADPKD. PMID- 26534925 TI - Hemovascular Progenitors in the Kidney Require Sphingosine-1-Phosphate Receptor 1 for Vascular Development. AB - The close relationship between endothelial and hematopoietic precursors during early development of the vascular system suggested the possibility of a common yet elusive precursor for both cell types. Whether similar or related progenitors for endothelial and hematopoietic cells are present during organogenesis is unclear. Using inducible transgenic mice that specifically label endothelial and hematopoietic precursors, we performed fate-tracing studies combined with colony forming assays and crosstransplantation studies. We identified a progenitor, marked by the expression of helix-loop-helix transcription factor stem cell leukemia (SCL/Tal1). During organogenesis of the kidney, SCL/Tal1(+) progenitors gave rise to endothelium and blood precursors with multipotential colony-forming capacity. Furthermore, appropriate morphogenesis of the kidney vasculature, including glomerular capillary development, arterial mural cell coating, and lymphatic vessel development, required sphingosine 1-phosphate (S1P) signaling via the G protein-coupled S1P receptor 1 in these progenitors. Overall, these results show that SCL/Tal1(+) progenitors with hemogenic capacity originate and differentiate within the early embryonic kidney by hemovasculogenesis (the concomitant formation of blood and vessels) and underscore the importance of the S1P pathway in vascular development. PMID- 26534926 TI - Pharmacokinetics of Bedaquiline in Cerebrospinal Fluid and Serum in Multidrug Resistant Tuberculous Meningitis. PMID- 26534927 TI - Explicit and Implicit Positive Illusory Bias in Children With ADHD. AB - OBJECTIVE: Children with ADHD overestimate their own social and behavioral competence when using explicit self-report measures, a phenomenon known as Positive Illusory Bias (PIB). This study examined whether children with ADHD show PIB when self-perceptions are measured implicitly, reflecting associations that are relatively difficult to consciously control. METHOD: Participants were 23 children (ages 6.8-9.8) with ADHD and 55 typically developing (TD) children. Children's explicit self-perceptions of competence were measured via self-report on the Self-Perception Profile for Children; their implicit associations were assessed using an Implicit Association Test. Parent and teacher ratings formed an adult-reported composite indicator of children's competence, to which children's self-perceptions were compared. RESULTS: Children with ADHD overestimated their competence as compared with adult-informant reports on both explicit and implicit measures, whereas TD children tended to be accurate. CONCLUSION: Inflated self perceptions in children with ADHD may exist on an implicit level outside of conscious awareness. PMID- 26534928 TI - Vogt-Koyanagi-Harada syndrome and Crohn's disease: an exceptional association. AB - Vogt-Koyanagi-Harada disease (VKH) is a rare, multisystem disease of melanocyte containing organs. It is characterized by diffuse, granulomatous inflammation involving various organs. It has been reported to occur in association with other autoimmune disorders. We report the case of a female patient who was diagnosed with VKH at the age of 4 years and who was treated with corticosteroids until the age of 16. Twenty years later, Crohn's disease was diagnosed, with a severe flare up. Three cases of VKH associated with ulcerative colitis have previously been reported anecdotally but, to our knowledge, this is the first case occurring in association to Crohn's disease. PMID- 26534929 TI - Imaging panorama in postoperative complications after liver transplantation. AB - The liver is the second most-often transplanted solid organ after the kidney, so it is clear that liver disease is a common and serious problem around the globe. With the advancements in surgical, oncological and imaging techniques, orthotopic liver transplantation has become the first-line treatment for many patients with end-stage liver disease. Ultrasound, and Doppler are the most economical and cost effective imaging modalities for evaluating postoperative fluid collections and vascular complications. Computed tomography (CT) is used to confirm the findings of ultrasound and look for pulmonary complications. Magnetic resonance imaging (MRI) is used for the diagnosis of biliary complications, bile leaks and neurological complications. This article illustrates the imaging options for diagnosing the various complications that can be encountered in the postoperative period after liver transplantation. PMID- 26534930 TI - Incident impulse control disorder symptoms and dopamine transporter imaging in Parkinson disease. AB - OBJECTIVE: To describe the incidence of, and clinical and neurobiological risk factors for, new-onset impulse control disorder (ICD) symptoms and related behaviours in early Parkinson disease (PD). METHODS: The Parkinson's Progression Markers Initiative is an international, multicenter, prospective study of de novo patients with PD untreated at baseline and assessed annually, including serial dopamine transporter imaging (DAT-SPECT) and ICD assessment (Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease short form, QUIP). Participants were included if they screened negative on the QUIP at baseline. Kaplan-Meier curves and generalised estimating equations examined frequency and predictors of incident ICD symptoms. RESULTS: Participants were seen at baseline (n=320), year 1 (n=284), year 2 (n=217) and year 3 (n=96). Estimated cumulative incident rates of ICD symptoms and related behaviours were 8% (year 1), 18% (year 2) and 25% (year 3) and increased each year in those on dopamine replacement therapy (DRT) and decreased in those not on DRT. In participants on DRT, risk factors for incident ICD symptoms were younger age (OR=0.97, p=0.05), a greater decrease in right caudate (OR=4.03, p=0.01) and mean striatal (OR=6.90, p=0.04) DAT availability over the first year, and lower right putamen (OR=0.06, p=0.01) and mean total striatal (OR=0.25, p=0.04) DAT availability at any post-baseline visit. CONCLUSIONS: The rate of incident ICD symptoms increases with time and initiation of DRT in early PD. In this preliminary study, a greater decrease or lower DAT binding over time increases risk of incident ICD symptoms, conferring additional risk to those taking DRT. CLINICAL TRIAL REGISTRATION: NCT01141023. PMID- 26534931 TI - Excess BMP Signaling in Heterotopic Cartilage Forming in Prg4-null TMJ Discs. AB - Heterotopic cartilage develops in certain pathologic conditions, including those affecting the human temporomandibular joint (TMJ), but the underlying molecular mechanisms remain obscure. This is in part due to the fact that a reliable animal model of such TMJ diseases is not available. Here, we show that aberrant chondrocyte differentiation and ectopic cartilage formation occur spontaneously in proteoglycan 4 (Prg4) mutant TMJ discs without further invasive procedure. By 2 mo of age, mutant disc cells displayed chondrocyte transdifferentiation, accompanied by strong expression of cartilage master gene Sox9 and matrix genes aggrecan and type II collagen. By 6 mo, heterotopic cartilage had formed in the discs and expressed cartilage hypertrophic markers Runx2 and ColX. The ectopic tissue grew in size over time and exhibited regional mineralization by 12 mo. Bone morphogenetic protein (BMP) signaling was activated with the ectopic chondrogenic cells and chondrocytes, as indicated by phosphorylated Smad 1/5/8 nuclear staining and by elevated expression of Bmp2, Bmpr1b, Bmpr2, and BMP signaling target genes. Likewise, we found that upon treatment with recombinant human BMP 2 in high-density micromass culture, mutant disc cells differentiated into chondrocytes and synthesized cartilage matrix more robustly than control cells. Importantly, a specific kinase inhibitor of BMP receptors drastically attenuated chondrogenesis in recombinant human BMP 2-treated mutant disc cultures. Unexpectedly, we found that Prg4 was expressed at joint-associated sites, including disc/muscle insertion and muscle/bone interface, and all these structures were abnormal in Prg4 mutants. Our data indicate that Prg4 is needed for TMJ disc integrity and function and that its absence leads to ectopic chondrogenesis and cartilage formation in conjunction with abnormal BMP signaling. Our findings imply that the BMP signaling pathway could be a potential therapeutic target for prevention or inhibition of ectopic cartilage formation in TMJ disease. PMID- 26534932 TI - Right Ventricular Strain and Dyssynchrony Assessment in Arrhythmogenic Right Ventricular Cardiomyopathy: Cardiac Magnetic Resonance Feature-Tracking Study. AB - BACKGROUND: Analysis of right ventricular (RV) regional dysfunction by cardiac magnetic resonance (CMR) imaging in arrhythmogenic RV cardiomyopathy (ARVC) may be inadequate because of the complex contraction pattern of the RV. Aim of this study was to determine the use of RV strain and dyssynchrony assessment in ARVC using feature-tracking CMR analysis. METHODS AND RESULTS: Thirty-two consecutive patients with ARVC referred to CMR imaging were included. Thirty-two patients with idiopathic RV outflow tract arrhythmias and 32 control subjects, matched for age and sex to the ARVC group, were included for comparison purpose. CMR imaging was performed to assess biventricular function; feature-tracking analysis was applied to the cine CMR images to assess regional and global longitudinal, circumferential, and radial RV strains and RV dyssynchrony (defined as the SD of the time-to-peak strain of the RV segments). RV global longitudinal strain (-17+/ 5% versus -26+/-6% versus -29+/-6%; P<0.001), global circumferential strain (-9+/ 4% versus -12+/-4% versus -13+/-5%; P=0.001), and global radial strain (18 [12 26]% versus 22 [15-32]% versus 27 [20-39]%; P=0.015) were significantly lower and SD of the time-to-peak RV strain in all 3 directions were significantly higher among patients with ARVC compared with patients with RV outflow tract arrhythmias and controls. RV global longitudinal strain >-23.2%, SD of the time-to-peak RV longitudinal strain >113.1 ms, and SD of the time-to-peak RV circumferential strain >177.1 ms allowed correct identification of 88%, 75%, and 63% of ARVC patients with no or only minor CMR criteria for ARVC diagnosis. CONCLUSIONS: Strain analysis by feature-tracking CMR helps to objectively quantify global and regional RV dysfunction and RV dyssynchrony in patients with ARVC and provides incremental value over conventional cine CMR imaging. PMID- 26534933 TI - Progress in the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia by Cardiac Magnetic Resonance Imaging Using Feature Tracking. PMID- 26534934 TI - Effects of combined progesterone and 17beta-estradiol treatment on the transcriptome of cultured human myometrial smooth muscle cells. AB - A transcriptomic analysis of cultured human uterine smooth muscle cells (hUtSMCs) was performed to examine gene expression profiles in smooth muscle in an environment containing the two major steroid hormones that regulate the human myometrium in physiological states associated with estrous, pregnancy, labor, and pathophysiological states such as leiomyoma and endometrial cancer. hUtSMCs were treated with progesterone (P4) and 17beta-estradiol (E2) individually and in combination, in the presence and absence of RU486 (mifepristone). Transcription of many genes was modulated in the presence of P4 or E2 alone, but almost six times more genes were transcriptionally modulated in the presence of the P4/E2 hormone combination. In total 796 annotated genes were significantly differentially expressed in the presence of both P4 and E2 relative to their expression in untreated cells. Functional withdrawal of P4 by addition of RU486 effectively reversed almost all transcriptional changes caused by P4/E2 treatment. Gene ontology analysis of differentially expressed genes revealed a strong association between P4/E2 treatment and downregulated expression of genes involved in cell communication, signal transduction, channel activity, inflammatory response, and differentiation. Upregulated processes included cell survival, gene transcription, steroid hormone biosynthesis, muscle development, insulin receptor signaling, and cell growth. PMID- 26534935 TI - Genetic loci associated with nonobstructive coronary artery disease in Caucasian women. AB - Nonobstructive coronary artery disease (CAD) in women is associated with adverse cardiovascular (CV) outcomes; however, information regarding genetic variants that predispose women to nonobstructive CAD is lacking. Women from the Women's Ischemia Syndrome Evaluation (WISE) Study and the St. James Women Take Heart (WTH) Study were genotyped with the Cardio-MetaboChip. WISE enrolled women with symptoms and signs of ischemia referred for coronary angiography; WTH enrolled asymptomatic, community-based women without heart disease. Analyses were conducted with a case (WISE)--control (WTH) design and multivariate logistic regression models to investigate genetic variation associated with likelihood of nonobstructive CAD. One genetic marker, single nucleotide polymorphism (SNP) rs2301753 on chromosome 6 in RNF39, achieved chip-wide significance for nonobstructive CAD (P < 9.5 * 10(-7)). After adjusting for baseline characteristics, we found no variants achieved chip-wide significance. However, SNP rs2301753 on chromosome 6 in RNF39 was associated with reduced likelihood of nonobstructive CAD [odds ratio (OR) 0.42 and 95% confidence interval (CI) of 0.29 to 0.68], at a nominal level of P = 5.6 * 10(-6), while SNP rs12818945 in the ATP2B1 locus on chromosome 12 was associated with increased odds for nonobstructive CAD (OR 2.38 and 95% CI of 1.63 to 3.45) and nominal P = 5.8 * 10( 6). The functions of RNF39 and ATP2B1 raise the possibility that genes involved in cardio-dysfunction may contribute to nonobstructive CAD in Caucasian women and may provide insights into novel approaches for therapy and prevention. If replicated, incorporation of these genetic variants into diagnostic evaluation may identify women at high risk for nonobstructive CAD. PMID- 26534936 TI - Interference with PPARgamma in endothelium accelerates angiotensin II-induced endothelial dysfunction. AB - The ligand activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) in the endothelium regulates vascular function and blood pressure (BP). We previously reported that transgenic mice (E-V290M) with selectively targeted endothelial-specific expression of dominant negative PPARgamma exhibited endothelial dysfunction when treated with a high-fat diet, and exhibited an augmented pressor response to angiotensin II (ANG II). We hypothesize that interference with endothelial PPARgamma would exacerbate ANG II induced endothelial dysfunction. Endothelial function was examined in E-V290M mice infused with a subpressor dose of ANG II (120 ng.kg(-1).min(-1)) or saline for 2 wk. ANG II infusion significantly impaired the responses to the endothelium dependent agonist acetylcholine both in basilar and carotid arteries from E-V290M but not NT mice. This impairment was not due to increased BP, which was not significantly different in ANG II-infused E-V290M compared with NT mice. Superoxide levels, and expression of the pro-oxidant Nox2 gene was elevated, whereas expression of the anti-oxidant genes Catalase and SOD3 decreased in carotid arteries from ANG II-infused E-V290M mice. Increased p65 and decreased Ikappa-Balpha suggesting increased NF-kappaB activity was also observed in aorta from ANG II-infused E-V290M mice. The responses to acetylcholine were significantly improved both in basilar and carotid arteries after treatment with Tempol (1 mmol/l), a scavenger of superoxide. These findings provide evidence that interference with endothelial PPARgamma accelerates ANG II-mediated endothelial dysfunction both in cerebral and conduit arteries through an oxidative stress-dependent mechanism, suggesting a role for endothelial PPARgamma in protecting against ANG II-induced endothelial dysfunction. PMID- 26534937 TI - Pappa2 is linked to salt-sensitive hypertension in Dahl S rats. AB - A 1.37 Mbp region of chromosome 13 previously identified by exclusion mapping was consistently associated with a reduction of salt-induced hypertension in the Dahl salt-sensitive (SS) rat. This region contained five genes that were introgressed from the salt-insensitive Brown Norway (BN) rat. The goal of the present study was to further narrow that region to identify the gene(s) most likely to protect from salt-induced hypertension. The studies yielded a subcongenic SS rat strain containing a 0.71 Mbp insert from BN (26-P strain) in which salt-induced hypertension was reduced by 24 mmHg. The region contained two protein-coding genes (Astn1 and Pappa2) and a microRNA (miR-488). Pappa2 mRNA in the renal cortex of the protected 26-P was 6- to 10-fold greater than in SS fed a 0.4% NaCl diet but was reduced to levels observed in SS when fed 8.0% NaCl diet for 7 days. Compared with brain nuclei (NTS, RVLM, CVLM) and the adrenal gland, Pappa2 in the renal cortex was the only gene found to be differentially expressed between SS and 26-P and that responded to changes of salt diet. Immunohistochemistry studies found Pappa2 localized in the cytosol of the epithelial cells of the cortical thick ascending limbs. In more distal segments of the renal tubules, it was observed within tubular lumens and most notably bound to the apical membranes of the intercalated cells of collecting ducts. We conclude that we have identified a variant form of Pappa2 that can protect against salt-induced hypertension in the Dahl S rat. PMID- 26534938 TI - International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) for Lesions in the Minipig. AB - The International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) is a global project establishing diagnostic criteria and nomenclature for both proliferative and nonproliferative changes in laboratory animals. Nonrodent working groups (NRWGs) have been established for the dog, nonhuman primate, minipig, and the rabbit. The Global Editorial and Steering Committee (GESC) oversees the activities of the INHAND projects and is composed of toxicologic pathologists from all of the participating societies. In 2012, INHAND GESC began a collaboration with the U.S. Food and Drug Administration (USFDA) in adapting INHAND terminology for standardized nonclinical data submission to the FDA. The Standard for Exchange of Nonclinical Data is an implementation of the Clinical Data Interchange Standards Consortium Study Data Tabulation Model for nonclinical studies. The NRWG for the minipig consists of toxicologic and diagnostic pathologists from Japan, North America, and Europe, and the group has 15 members including a GESC representative. The NRWGs are reviewing the applicability of the rodent nomenclature for the species and providing terminology unique for the species as well as determining rodent terminology not appropriate for the species. This information will be published with representative illustrations and references. PMID- 26534939 TI - PDGFR Inhibition Results in Pericyte Depletion and Hemorrhage into the Corpus Luteum of the Rat Ovary. AB - The growth plate, ovary, adrenal gland, and rodent incisor tooth are sentinel organs for antiangiogenic effects since they respond reliably, quantitatively, and sensitively to inhibition of the vascular endothelial growth factor receptor (VEGFR). Here we report that treatment of rats with platelet-derived growth factor receptor beta (PDGFRbeta) inhibitors that target pericytes results in severe ovarian hemorrhage with degeneration and eventual rupture of the corpus luteum. Evaluation of the growth plate, adrenal gland, and incisor tooth that are typical target organs for antiangiogenic treatment in the rodent revealed no abnormalities. Histologically, the changes in the ovary were characterized by sinusoidal dilatation, increased vessel fragility, and hemorrhage into the corpus luteum. Immunocytochemical staining of vessels with alpha smooth muscle actin and CD31 that recognize pericytes and vascular endothelium, respectively, demonstrated that this effect was due to selective pericyte deficiency within corpora lutea. Further experiments in which rats were treated concurrently with both PDGFRbeta and VEGFR inhibitors ablated the hemorrhagic response, resulting instead in corpus luteum necrosis. These changes are consistent with the notion that selective pericyte loss in the primitive capillary network resulted in increased vessel fragility and hemorrhage, whereas concomitant VEGFR inhibition resulted in vessel regression and reduced vascular perfusion that restricted development of the hemorrhagic vessels. These results also highlight the utility of the rodent ovary to respond differentially to VEGFR and PDGFR inhibitors, which may provide useful information during routine safety assessment for determining target organ toxicity. PMID- 26534940 TI - Background Pathological Changes in Minipigs: A Comparison of the Incidence and Nature among Different Breeds and Populations of Minipigs. AB - Swine, especially the miniature swine or minipigs, are increasingly being used in preclinical safety assessment of small molecules, biopharmaceutical agents, and medical devices as an alternate nonrodent species. Although swine have been used extensively in biomedical research, there is a paucity of information in the current literature detailing the incidence of background lesions and differences in incidence between commonly used breeds. This article is a collaborative effort between multiple organizations to define and document lesions found in the common breeds of minipigs used for toxicological risk assessment in North America (NA) and the European Union (EU). We retrospectively assessed 10 years of historical control data from several institutions located in NA and EU, covering the period of 2004-2015. Here we report the background lesions with consideration of breed and geographical location. To our knowledge, this is the first report documenting spontaneous background lesions in commonly used breeds of swine in both NA and EU. This report serves as a resource to pathologists and will aid in interpretation of findings and differentiation of background from test article related changes. PMID- 26534941 TI - The Role of Chronic Exposure to Amoxicillin/Clavulanic Acid on the Developmental Enamel Defects in Mice. AB - Amoxicillin used in early childhood may be associated with enamel hypomineralization. Our aim was to assess disturbances of amelogenesis in mice lower incisors induced by chronic administration of amoxicillin/clavulanic acid (AMC). Twenty-eight C57BL/6 male mice, of similar age, randomly divided into a control and 3 treatment groups (n = 7) received subcutaneous injection, once per day, for 60 days: 50, 100, and 150 mg/kg BW of AMC. Scanning electron microscopy/energy dispersive X-ray spectroscopy analysis in AMC treatment groups showed higher content in F and a decrease in P and Ca. Morphology changes ranged from scratched patterns, and small isolated pits-like enamel loss, to generalized demineralized enamel surface, giving a rough, foamy, scaly, or even cracked eggshell appearance to the affected areas. Histological analysis showed disturbances of maturation ameloblasts, which were less organized, with increased amounts of clear vacuoles in the cytoplasm and slightly more elongated and less condensed nucleus. Additionally, they were often detached from the enamel matrix. Transitional ameloblasts formed underlying the cysts of varied sizes. In conclusion, AMC dose-dependently affect ameloblast functions especially in the maturation phase, causing hypomineralized enamel formation with quantitative and/or qualitative defects. PMID- 26534942 TI - Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys. AB - Cocaine abuse and obesity are serious public health problems, and studies suggest that both dopamine and serotonin systems are involved in regulating the consumption of drugs and food. Lorcaserin has serotonin (5-HT)2C receptor agonist actions, is approved by the U.S. Food and Drug Administration for treating obesity, and might be effective for treating cocaine abuse. These studies characterized the pharmacokinetic and behavioral profiles of lorcaserin (intragastric administration) and determined the effectiveness of lorcaserin to alter discriminative stimulus and reinforcing effects of cocaine (intravenous administration) in rhesus monkeys. Administered acutely, lorcaserin dose dependently increased the occurrence of yawning while decreasing spontaneous activity and operant responding for food. These effects appeared within 30-60 minutes of administration and began to dissipate by 240 minutes, a time course closely matching plasma concentrations of lorcaserin. In monkeys discriminating cocaine from saline, lorcaserin alone did not occasion cocaine-appropriate responding but shifted the cocaine dose-response curve to the right and down in two of three monkeys. When administered acutely, lorcaserin dose-dependently decreased the rate at which monkeys responded for infusions of cocaine. When administered chronically, 3.2 mg/kg lorcaserin reduced the rate of cocaine maintained responding by 50% for the duration of a 14-day treatment period. Together, these results show that lorcaserin attenuates the discriminative stimulus effects of cocaine after acute administration and the reinforcing effects of cocaine after acute and repeated administration, consistent with the view that it might have utility in treating cocaine abuse. PMID- 26534943 TI - A1 Adenosine Receptor-Mediated Inhibition of Parasympathetic Neuromuscular Transmission in Human and Murine Urinary Bladder. AB - The potential role of A1 adenosine receptors in modulating neuromuscular transmission in the detrusor muscle of the urinary bladder has been tested in human and murine preparations with the intent to determine the viability of using adenosine receptor agonists as adjuncts to treat overactive bladder. In human detrusor muscle preparations, contractile responses to electrical field stimulation were inhibited by the selective A1 adenosine receptor agonists 2 chloro-N(6)-cyclopentyladenosine, N(6)-cyclopentyladenosine (CPA), and adenosine (rank order of potency: 2-chloro-N(6)-cyclopentyladenosine > CPA > adenosine). Pretreatment with 8-cyclopentyl-3-[3-[[4(fluorosulphonyl)benzoyl]oxy]propyl]-1 propylxanthine, an irreversible A1 antagonist, blocked the effects of CPA, thus confirming the role of A1 receptors in human detrusor preparations. In murine detrusor muscle preparations, contractions evoked by electrical field stimulation were reduced by CPA or adenosine. Amplitudes of the P2X purinoceptor-mediated excitatory junctional potentials (EJPs) recorded with intracellular microelectrodes were reduced in amplitude by CPA and adenosine with no effect on the spontaneous EJP amplitudes, confirming the prejunctional action of these agents. 8-Cyclopentyltheophylline, a selective A1 receptor antagonist, reversed the effects of CPA on EJP amplitudes with no effect of spontaneous EJPs, confirming the role of A1 receptors in mediating these effects. PMID- 26534944 TI - Evaluation of oral maropitant as an antiemetic in cats receiving morphine and dexmedetomidine. AB - Objectives The aim of the study was to evaluate the antiemetic effects of maropitant, after oral administration, in cats receiving morphine and dexmedetomidine. Methods This prospective, blinded, randomized controlled trial involved 98 healthy female domestic shorthair cats. Cats were randomly assigned to receive maropitant PO 8 mg total (group M) administered 18 h prior to sedation with intramuscular dexmedetomidine 20 ug/kg and morphine 0.1 mg/kg, or no antiemetic treatment (group C). The occurrence of signs of nausea (sialorrhea and lip-licking), retching and emesis during the 30 mins following administration of dexmedetomidine and morphine was measured for each group. Results Two cats were excluded from the investigation. Cats in group M (n = 46) received an average of 2.5 mg/kg of maropitant PO. Compared with group C (n = 50), cats in group M had lower incidences of emesis (M: 4% vs C: 40%), retching (M: 8% vs C: 40%) and lip licking (M: 30% vs C: 52%) (all P <0.05). The incidence of sialorrhea was not different between groups (M: 21% vs C: 22%). Conclusions and relevance Maropitant 8 mg total PO was effective in reducing morphine and dexmedetomidine-induced emesis by 10-fold, when administered as early as 18 h in advance to healthy cats. Maropitant PO could be useful for administration the evening prior to a scheduled procedure requiring sedation/anesthesia to decrease the incidence of emesis. PMID- 26534945 TI - Renal abscesses in cats: six cases. AB - Case series summary Six cats were diagnosed with renal abscesses. Common clinical findings were lethargy, dehydration, abdominal pain and nephromegaly. Fever was noted in half of the cases. Diagnosis was established by ultrasonography, cytological examination and bacterial culture of abscess aspirates. At least one possible contributing factor could be identified in all cases. Antibiotics were consistently used and in two cats the abscess was surgically drained. The short term outcome was fair but the long-term outcome was dependent on the underlying condition. Relevance and novel information The results of this small case series suggest that renal abscess should be considered when nephromegaly and/or abdominal discomfort are noted. Diagnosis of renal abscess is straightforward when ultrasonography and fine-needle aspirate analysis can be performed. Medical treatment is assumed to be preferable but surgical treatment may be warranted on a case-by-case basis. Given that almost every affected cat was diagnosed with at least one comorbidity, a thorough evaluation is recommended for all cats with renal abscesses. PMID- 26534946 TI - Epidemiology of Mycoplasma genitalium in British men and women aged 16-44 years: evidence from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). AB - BACKGROUND: There are currently no large general population epidemiological studies of Mycoplasma genitalium (MG), which include prevalence, risk factors, symptoms and co-infection in men and women across a broad age range. METHODS: In 2010--12, we conducted the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3), a probability sample survey in Britain. Urine from 4507 sexually-experienced participants, aged 16-44 years, was tested for MG. RESULTS: MG prevalence was 1.2% [95% confidence interval (CI): 0.7-1.8%] in men and 1.3% (0.9-1.9%) in women. There were no positive MG tests in men aged 16-19, and prevalence peaked at 2.1% (1.2-3.7%) in men aged 25-34 years. In women, prevalence was highest in 16-19 year olds, at 2.4% (1.2-4.8%), and decreased with age. Men of Black ethnicity were more likely to test positive for MG [adjusted odds ratio (AOR) 12.1; 95% CI: 3.7-39.4). For both men and women, MG was strongly associated with reporting sexual risk behaviours (increasing number of total and new partners, and unsafe sex, in the past year). Women with MG were more likely to report post-coital bleeding (AOR 5.8; 95%CI 1.4-23.3). However, the majority of men (94.4%), and over half of women (56.2%) with MG did not report any sexually transmitted infection (STI) symptoms. Men with MG were more likely to report previously diagnosed gonorrhoea, syphilis or non-specific urethritis, and women previous trichomoniasis. CONCLUSIONS: This study strengthens evidence that MG is an STI. MG was identified in over 1% of the population, including in men with high-risk behaviours in older age groups that are often not included in STI prevention measures. PMID- 26534947 TI - Cohort Profile: UK COSMOS-a UK cohort for study of environment and health. PMID- 26534948 TI - The effect of using a pre-dive checklist on the incidence of diving mishaps in recreational scuba diving: a cluster-randomized trial. AB - BACKGROUND: Scuba diving mishaps, caused by equipment problems or human errors, increase the occurrence of injuries and fatalities while diving. Pre-dive checklists may mitigate mishaps. This study evaluated the effect of using a pre dive checklist on the incidence of diving mishaps in recreational divers. METHODS: A multi-location cluster-randomized trial with parallel groups and allocation concealment was conducted between 1 June and 17 August 2012. The participants had to be at least 18 years of age, permitted to dive by the dive operator and planning to dive on the day of participation. They were recruited at the pier and dive boats at four locations. The intervention group received a pre dive checklist and post-dive log. The control group received a post-dive log only. The outcomes, self-reported major and minor mishaps, were prompted by a post-dive questionnaire. Mishap rates per 100 dives were compared using Poisson regression with generalized estimating equations. Intent-to-treat, per-protocol and marginal structural model analyses were conducted. RESULTS: A total of 1043 divers (intervention = 617; control = 426) made 2041 dives, on 70 location-days (intervention = 40; control = 30) at four locations. Compared with the control group, the incidence of major mishaps decreased in the intervention group by 36%, minor mishaps by 26% and all mishaps by 32%. On average, there was one fewer mishap in every 25 intervention dives. CONCLUSIONS: In this trial, pre-dive checklist use prevented mishaps which could lead to injuries and fatalities. Pre dive checklists can increase diving safety and their use should be promoted. Trial Registration: ClinicalTrials.gov ID NCT01960738. PMID- 26534950 TI - Antisense Transcription of Retrotransposons in Drosophila: An Origin of Endogenous Small Interfering RNA Precursors. AB - Movement of transposons causes insertions, deletions, and chromosomal rearrangements potentially leading to premature lethality in Drosophila melanogaster. To repress these elements and combat genomic instability, eukaryotes have evolved several small RNA-mediated defense mechanisms. Specifically, in Drosophila somatic cells, endogenous small interfering (esi)RNAs suppress retrotransposon mobility. EsiRNAs are produced by Dicer-2 processing of double-stranded RNA precursors, yet the origins of these precursors are unknown. We show that most transposon families are transcribed in both the sense (S) and antisense (AS) direction in Dmel-2 cells. LTR retrotransposons Dm297, mdg1, and blood, and non-LTR retrotransposons juan and jockey transcripts, are generated from intraelement transcription start sites with canonical RNA polymerase II promoters. We also determined that retrotransposon antisense transcripts are less polyadenylated than sense. RNA-seq and small RNA-seq revealed that Dicer-2 RNA interference (RNAi) depletion causes a decrease in the number of esiRNAs mapping to retrotransposons and an increase in expression of both S and AS retrotransposon transcripts. These data support a model in which double-stranded RNA precursors are derived from convergent transcription and processed by Dicer-2 into esiRNAs that silence both sense and antisense retrotransposon transcripts. Reduction of sense retrotransposon transcripts potentially lowers element specific protein levels to prevent transposition. This mechanism preserves genomic integrity and is especially important for Drosophila fitness because mobile genetic elements are highly active. PMID- 26534951 TI - Divergent Residues Within Histone H3 Dictate a Unique Chromatin Structure in Saccharomyces cerevisiae. AB - Histones are among the most conserved proteins known, but organismal differences do exist. In this study, we examined the contribution that divergent amino acids within histone H3 make to cell growth and chromatin structure in Saccharomyces cerevisiae. We show that, while amino acids that define histone H3.3 are dispensable for yeast growth, substitution of residues within the histone H3 alpha3 helix with human counterparts results in a severe growth defect. Mutations within this domain also result in altered nucleosome positioning, both in vivo and in vitro, which is accompanied by increased preference for nucleosome favoring sequences. These results suggest that divergent amino acids within the histone H3 alpha3 helix play organismal roles in defining chromatin structure. PMID- 26534952 TI - The Splice Isoforms of the Drosophila Ecdysis Triggering Hormone Receptor Have Developmentally Distinct Roles. AB - To grow, insects must periodically shed their exoskeletons. This process, called ecdysis, is initiated by the endocrine release of Ecdysis Trigger Hormone (ETH) and has been extensively studied as a model for understanding the hormonal control of behavior. Understanding how ETH regulates ecdysis behavior, however, has been impeded by limited knowledge of the hormone's neuronal targets. An alternatively spliced gene encoding a G-protein-coupled receptor (ETHR) that is activated by ETH has been identified, and several lines of evidence support a role in ecdysis for its A-isoform. The function of a second ETHR isoform (ETHRB) remains unknown. Here we use the recently introduced "Trojan exon" technique to simultaneously mutate the ETHR gene and gain genetic access to the neurons that express its two isoforms. We show that ETHRA and ETHRB are expressed in largely distinct subsets of neurons and that ETHRA- but not ETHRB-expressing neurons are required for ecdysis at all developmental stages. However, both genetic and neuronal manipulations indicate an essential role for ETHRB at pupal and adult, but not larval, ecdysis. We also identify several functionally important subsets of ETHR-expressing neurons including one that coexpresses the peptide Leucokinin and regulates fluid balance to facilitate ecdysis at the pupal stage. The general strategy presented here of using a receptor gene as an entry point for genetic and neuronal manipulations should be useful in establishing patterns of functional connectivity in other hormonally regulated networks. PMID- 26534953 TI - Cardiovascular Disease: Another Hidden Cost of War? PMID- 26534954 TI - Trends in Use and Adverse Outcomes Associated with Transvenous Lead Removal in the United States. AB - BACKGROUND: Transvenous lead removal (TLR) has made significant progress with respect to innovation, efficacy, and safety. However, limited data exist regarding trends in use and adverse outcomes outside the centers of considerable experience for TLR. The aim of our study was to examine use patterns, frequency of adverse events, and influence of hospital volume on complications. METHODS AND RESULTS: Using the Nationwide Inpatient Sample, we identified 91 890 TLR procedures. We investigated common complications including pericardial complications (hemopericardium, cardiac tamponade, or pericardiocentesis), pneumothorax, stroke, vascular complications (consisting of hemorrhage/hematoma, incidents requiring surgical repair, and accidental arterial puncture), and in hospital deaths described with TLR, defining them by the validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code. We specifically assessed in-hospital death (2.2%), hemorrhage requiring transfusion (2.6%), vascular complications (2.0%), pericardial complications (1.4%), open heart surgery (0.2%), and postoperative respiratory failure (2.4%). Independent predictors of complications were female sex and device infections. Hospital volume was not independently associated with higher complications. There was a significant rise in overall complication rates over the study period. CONCLUSIONS: The overall complication rate in patients undergoing TLR was higher than previously reported. Female sex and device infections are associated with higher complications. Hospital volume was not associated with higher complication rates. The number of adverse events in the literature likely underestimates the actual number of complications associated with TLR. PMID- 26534955 TI - When You Have Nowhere to Look, You Look Where You Can. PMID- 26534956 TI - Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. AB - Pulmonary hypertension is associated with diverse cardiac, pulmonary, and systemic diseases in neonates, infants, and older children and contributes to significant morbidity and mortality. However, current approaches to caring for pediatric patients with pulmonary hypertension have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a panel of experienced clinicians and clinician-scientists was assembled to review the current literature and to make recommendations on the diagnosis, evaluation, and treatment of pediatric pulmonary hypertension. This publication presents the results of extensive literature reviews, discussions, and formal scoring of recommendations for the care of children with pulmonary hypertension. PMID- 26534957 TI - Immunometabolism: Cellular Metabolism Turns Immune Regulator. AB - Immune cells are highly dynamic in terms of their growth, proliferation, and effector functions as they respond to immunological challenges. Different immune cells can adopt distinct metabolic configurations that allow the cell to balance its requirements for energy, molecular biosynthesis, and longevity. However, in addition to facilitating immune cell responses, it is now becoming clear that cellular metabolism has direct roles in regulating immune cell function. This review article describes the distinct metabolic signatures of key immune cells, explains how these metabolic setups facilitate immune function, and discusses the emerging evidence that intracellular metabolism has an integral role in controlling immune responses. PMID- 26534958 TI - SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells. AB - Mitochondrial oxidative phosphorylation produces most of the energy in aerobic cells by coupling respiration to the production of ATP. Mitochondrial uncouplers, which reduce the proton gradient across the mitochondrial inner membrane, create a futile cycle of nutrient oxidation without generating ATP. Regulation of mitochondrial dysfunction and associated cellular bioenergetics has been recently identified as a promising target for anticancer therapy. Here, we show that SR4 is a novel mitochondrial uncoupler that causes dose-dependent increase in mitochondrial respiration and dissipation of mitochondrial membrane potential in HepG2 hepatocarcinoma cells. These effects were reversed by the recoupling agent 6-ketocholestanol but not cyclosporin A and were nonexistent in mitochondrial DNA depleted HepG2 cells. In isolated mouse liver mitochondria, SR4 similarly increased oxygen consumption independent of adenine nucleotide translocase and uncoupling proteins, decreased mitochondrial membrane potential, and promoted swelling of valinomycin-treated mitochondria in potassium acetate medium. Mitochondrial uncoupling in HepG2 cells by SR4 results in the reduction of cellular ATP production, increased ROS production, activation of the energy sensing enzyme AMPK, and inhibition of acetyl-CoA carboxylase and mammalian target of rapamycin signaling pathways, leading to cell cycle arrest and apoptosis. Global analysis of SR4-associated differential gene expression confirms these observations, including significant induction of apoptotic genes and down-regulation of cell cycle, mitochondrial, and oxidative phosphorylation pathway transcripts at 24 h post-treatment. Collectively, our studies demonstrate that the previously reported indirect activation of AMPK and in vitro anticancer properties of SR4 as well as its beneficial effects in both animal xenograft and obese mice models could be a direct consequence of its mitochondrial uncoupling activity. PMID- 26534959 TI - HIV-1-Tat Protein Inhibits SC35-mediated Tau Exon 10 Inclusion through Up regulation of DYRK1A Kinase. AB - The HIV-1 transactivator protein Tat is implicated in the neuronal damage that contributes to neurocognitive impairment affecting people living with HIV/AIDS. Aberrant splicing of TAU exon 10 results in tauopathies characterized by alterations in the proportion of TAU isoforms containing three (3R) or four (4R) microtubule-binding repeats. The splicing factor SC35/SRSF2 binds to nuclear RNA and facilitates the incorporation of exon 10 in the TAU molecule. Here, we utilized clinical samples, an animal model, and neuronal cell cultures and found that Tat promotes TAU 3R up-regulation through increased levels of phosphorylated SC35, which is retained in nuclear speckles. This mechanism involved Tat-mediated increased expression of DYRK1A and was prevented by DYRK1A silencing. In addition, we found that Tat associates with TAU RNA, further demonstrating that Tat interferes with host RNA metabolism in the absence of viral infection. Altogether, our data unravel a novel mechanism of Tat-mediated neuronal toxicity through dysregulation of the SC35-dependent alternative splicing of TAU exon 10. Furthermore, the increased immunostaining of DYRK1A in HIV+ brains without pathology points at dysregulation of DYRK1A as an early event in the neuronal complications of HIV infection. PMID- 26534960 TI - A Heme-responsive Regulator Controls Synthesis of Staphyloferrin B in Staphylococcus aureus. AB - Staphylococcus aureus possesses a multitude of mechanisms by which it can obtain iron during growth under iron starvation conditions. It expresses an effective heme acquisition system (the iron-regulated surface determinant system), it produces two carboxylate-type siderophores staphyloferrin A and staphyloferrin B (SB), and it expresses transporters for many other siderophores that it does not synthesize. The ferric uptake regulator protein regulates expression of genes encoding all of these systems. Mechanisms of fine-tuning expression of iron regulated genes, beyond simple iron regulation via ferric uptake regulator, have not been uncovered in this organism. Here, we identify the ninth gene of the sbn operon, sbnI, as encoding a ParB/Spo0J-like protein that is required for expression of genes in the sbn operon from sbnD onward. Expression of sbnD-I is drastically decreased in an sbnI mutant, and the mutant does not synthesize detectable SB during early phases of growth. Thus, SB-mediated iron acquisition is impaired in an sbnI mutant strain. We show that the protein forms dimers and tetramers in solution and binds to DNA within the sbnC coding region. Moreover, we show that SbnI binds heme and that heme-bound SbnI does not bind DNA. Finally, we show that providing exogenous heme to S. aureus growing in an iron-free medium results in delayed synthesis of SB. This is the first study in S. aureus that identifies a DNA-binding regulatory protein that senses heme to control gene expression for siderophore synthesis. PMID- 26534961 TI - Time-resolved Studies of IsdG Protein Identify Molecular Signposts along the Non canonical Heme Oxygenase Pathway. AB - IsdGs are heme monooxygenases that break open the tetrapyrrole, releasing the iron, and thereby allowing bacteria expressing this protein to use heme as a nutritional iron source. Little is currently known about the mechanism by which IsdGs degrade heme, although the products differ from those generated by canonical heme oxygenases. A synthesis of time-resolved techniques, including in proteo mass spectrometry and conventional and stopped-flow UV/visible spectroscopy, was used in conjunction with analytical methods to define the reaction steps mediated by IsdG from Staphylococcus aureus and their time scales. An apparent meso-hydroxyheme (forming with k = 0.6 min(-1), pH 7.4, 10 mm ascorbate, 10 MUm IsdG-heme, 22 degrees C) was identified as a likely common intermediate with the canonical heme oxygenases. Unlike heme oxygenases, this intermediate does not form with added H2O2 nor does it convert to verdoheme and CO. Rather, the next observable intermediates (k = 0.16 min(-1)) were a set of formyloxobilin isomers, similar to the mycobilin products of the IsdG homolog from Mycobacterium tuberculosis (MhuD). These converted in separate fast and slow phases to beta-/delta-staphylobilin isomers and formaldehyde (CH2O). Controlled release of this unusual C1 product may support IsdG's dual role as both an oxygenase and a sensor of heme availability in S. aureus. PMID- 26534962 TI - Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration. AB - Exosomes are cell-derived extracellular vesicles thought to promote intercellular communication by delivering specific content to target cells. The aim of this study was to determine whether endothelial cell (EC)-derived exosomes could regulate the phenotype of hepatic stellate cells (HSCs). Initial microarray studies showed that fibroblast growth factor 2 induced a 2.4-fold increase in mRNA levels of sphingosine kinase 1 (SK1). Exosomes derived from an SK1 overexpressing EC line increased HSC migration 3.2-fold. Migration was not conferred by the dominant negative SK1 exosome. Incubation of HSCs with exosomes was also associated with an 8.3-fold increase in phosphorylation of AKT and 2.5 fold increase in migration. Exosomes were found to express the matrix protein and integrin ligand fibronectin (FN) by Western blot analysis and transmission electron microscopy. Blockade of the FN-integrin interaction with a CD29 neutralizing antibody or the RGD peptide attenuated exosome-induced HSC AKT phosphorylation and migration. Inhibition of endocytosis with transfection of dynamin siRNA, the dominant negative dynamin GTPase construct Dyn2K44A, or the pharmacological inhibitor Dynasore significantly attenuated exosome-induced AKT phosphorylation. SK1 levels were increased in serum exosomes derived from mice with experimental liver fibrosis, and SK1 mRNA levels were up-regulated 2.5-fold in human liver cirrhosis patient samples. Finally, S1PR2 inhibition protected mice from CCl4-induced liver fibrosis. Therefore, EC-derived SK1-containing exosomes regulate HSC signaling and migration through FN-integrin-dependent exosome adherence and dynamin-dependent exosome internalization. These findings advance our understanding of EC/HSC cross-talk and identify exosomes as a potential target to attenuate pathobiology signals. PMID- 26534964 TI - Cleavage of Signal Regulatory Protein alpha (SIRPalpha) Enhances Inflammatory Signaling. AB - Signal regulatory protein alpha (SIRPalpha) is a membrane glycoprotein immunoreceptor abundant in cells of monocyte lineage. SIRPalpha ligation by a broadly expressed transmembrane protein, CD47, results in phosphorylation of the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, resulting in the inhibition of NF-kappaB signaling in macrophages. Here we observed that proteolysis of SIRPalpha during inflammation is regulated by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), resulting in the generation of a membrane-associated cleavage fragment in both THP-1 monocytes and human lung epithelia. We mapped a charge-dependent putative cleavage site near the membrane-proximal domain necessary for ADAM10-mediated cleavage. In addition, a secondary proteolytic cleavage within the membrane-associated SIRPalpha fragment by gamma-secretase was identified. Ectopic expression of a SIRPalpha mutant plasmid encoding a proteolytically resistant form in HeLa cells inhibited activation of the NF-kappaB pathway and suppressed STAT1 phosphorylation in response to TNFalpha to a greater extent than expression of wild-type SIRPalpha. Conversely, overexpression of plasmids encoding the proteolytically cleaved SIRPalpha fragments in cells resulted in enhanced STAT-1 and NF-kappaB pathway activation. Thus, the data suggest that combinatorial actions of ADAM10 and gamma secretase on SIRPalpha cleavage promote inflammatory signaling. PMID- 26534963 TI - The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways. AB - N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-beta pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di 2-pyridylketone class of thiosemicarbazones, namely di-2-pyridylketone 4,4 dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3 thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4 dimethyl-3-thiosemicarbazone, but was independent of this metastasis suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone. This observation demonstrates that small structural changes in thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors. PMID- 26534965 TI - Elucidating the Specificity Determinants of the AtxE2 Lasso Peptide Isopeptidase. AB - Lasso peptide isopeptidase is an enzyme that specifically hydrolyzes the isopeptide bond of lasso peptides, rendering these peptides linear. To carry out a detailed structure-activity analysis of the lasso peptide isopeptidase AtxE2 from Asticcacaulis excentricus, we solved NMR structures of its substrates astexin-2 and astexin-3. Using in vitro enzyme assays, we show that the C terminal tail portion of these peptides is dispensable with regards to isopeptidase activity. A collection of astexin-2 and astexin-3 variants with alanine substitutions at each position within the ring and the loop was constructed, and we showed that all of these peptides except for one were cleaved by the isopeptidase. Thus, much like the lasso peptide biosynthetic enzymes, lasso peptide isopeptidase has broad substrate specificity. Quantitative analysis of the cleavage reactions indicated that alanine substitutions in loop positions of these peptides led to reduced cleavage, suggesting that the loop is serving as a recognition element for the isopeptidase. PMID- 26534966 TI - Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors. AB - PURPOSE: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase I protocol. EXPERIMENTAL DESIGN: This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects <=21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. RESULTS: Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory solid tumors (n = 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T-cell populations. Six subjects had confirmed stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma). CONCLUSIONS: Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance. PMID- 26534968 TI - Candidate Reference Measurement Procedure for the Quantification of Total Serum Cortisol with LC-MS/MS. AB - BACKGROUND: Accurate measurement of serum cortisol is required to diagnose and treat adrenal disorders. Although certified reference materials (CRMs) are available to standardize cortisol measurements, External Quality Assessment (EQA) schemes still demonstrate a wide dispersion of results. We present a serum cortisol candidate reference measurement procedure that, through analysis of a Joint Committee for Traceability in Laboratory Medicine-listed panel of higher order CRMs, provides metrologically traceable results. METHOD: Isotope-labeled internal standard was added to samples before supported liquid extraction. Extracts were analyzed with LC-MS/MS in positive electrospray ionization mode. Multiple reaction monitoring was used to detect cortisol and its corresponding internal standard transitions. We measured samples in triplicate over 3 days and calculated the mean result. RESULTS: Mean intra- and interassay imprecision were 1.3% and 1.5%, respectively, for concentrations of 154, 510, and 769 nmol/L. Ionization efficiency studies and structural analog analysis proved the method to be robust against interferences. Through analysis of 34 CRMs (83-764 nmol/L), expanded measurement uncertainty was calculated to be 5% (95% CI). The mean bias between the measured and target CRM concentrations was statistically insignificant at -0.08%. CONCLUSIONS: The accuracy and low measurement uncertainty of this method qualify it as a CRM procedure. Metrological traceability has been achieved through the analysis of higher-order CRMs. This method could be used to underpin serum cortisol EQA schemes to provide samples with a traceable target value, enabling participating laboratories to determine the accuracy and measurement uncertainty of their assays. PMID- 26534967 TI - Treatment Response Assessment in IDH-Mutant Glioma Patients by Noninvasive 3D Functional Spectroscopic Mapping of 2-Hydroxyglutarate. AB - PURPOSE: Measurements of objective response rates are critical to evaluate new glioma therapies. The hallmark metabolic alteration in gliomas with mutant isocitrate dehydrogenase (IDH) is the overproduction of oncometabolite 2 hydroxyglutarate (2HG), which plays a key role in malignant transformation. 2HG represents an ideal biomarker to probe treatment response in IDH-mutant glioma patients, and we hypothesized a decrease in 2HG levels would be measureable by in vivo magnetic resonance spectroscopy (MRS) as a result of antitumor therapy. EXPERIMENTAL DESIGN: We report a prospective longitudinal imaging study performed in 25 IDH-mutant glioma patients receiving adjuvant radiation and chemotherapy. A newly developed 3D MRS imaging was used to noninvasively image 2HG. Paired Student t test was used to compare pre- and posttreatment tumor 2HG values. Test retest measurements were performed to determine the threshold for 2HG functional spectroscopic maps (fSM). Univariate and multivariate regression were performed to correlate 2HG changes with Karnofsky performance score (KPS). RESULTS: We found that mean 2HG (2HG/Cre) levels decreased significantly (median = 48.1%; 95% confidence interval = 27.3%-56.5%;P= 0.007) in the posttreatment scan. The volume of decreased 2HG correlates (R(2)= 0.88,P= 0.002) with clinical status evaluated by KPS. CONCLUSIONS: We demonstrate that dynamic measurements of 2HG are feasible by 3D fSM, and the decrease of 2HG levels can monitor treatment response in patients with IDH-mutant gliomas. Our results indicate that quantitative in vivo 2HG imaging may be used for precision medicine and early response assessment in clinical trials of therapies targeting IDH-mutant gliomas. PMID- 26534969 TI - Modafinil May Alleviate Poststroke Fatigue: A Randomized, Placebo-Controlled, Double-Blinded Trial. AB - BACKGROUND AND PURPOSE: Poststroke fatigue is common and reduces quality of life. Current evidence for intervention is limited, and this is the first placebo controlled trial to investigate treatment of poststroke fatigue with the wakefulness promoting drug modafinil. METHODS: The trial was randomized, double blinded, and placebo-controlled. Patients were treated with 400-mg modafinil or placebo for 90 days. Assessments were done at inclusion, 30, 90, and 180 days. The primary end point was fatigue at 90 days measured by the Multidimensional Fatigue Inventory-20 general fatigue domain. Secondary end points included the Fatigue Severity Scale, the Montreal Cognitive Assessment, the modified Rankin Scale and the Stroke-specific quality of Life questionnaire. Adult patients with a recent stroke achieving a score of >=12 on the Multidimensional Fatigue Inventory-20 general fatigue domain were consecutively included. Exclusion criteria were severe cognitive disabilities and contraindications for modafinil treatment. RESULTS: One thousand one hundred twenty-one patients with stroke were screened and 41 patients included, 21 received modafinil. The primary end point, the Multidimensional Fatigue Inventory-20 general fatigue score, did not differ between groups. Patients in the modafinil group obtained better scores on the Fatigue Severity Scale (P=0.02) and in some subscales of the stroke-specific quality of life questionnaire (0.0010.15): Na, Cl, creatine kinase, C-reactive protein, serum amyloid A, carbohydrate antigen 125, and parathyroid hormone were higher during the early follicular phase, while insulin, total cholesterol, and white blood cell were higher during the luteal phase. Significant associations of those test items with the four sex hormones were revealed. CONCLUSIONS: The menstrual cycle-related changes in laboratory test results were revealed in some commonly tested items other than sex hormones. The findings are of interest in understanding female physiology in relation to hormonal changes, but the magnitude of changes is rather small and not very relevant in interpreting test results. PMID- 26535009 TI - Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake. AB - Cholesterol is a lipid that is critical for steroid hormone production and the integrity of cellular membranes, and, as such, it is essential for cell growth. The epidermal growth factor receptor (EGFR) family member ERBB4, which forms signaling complexes with other EGFR family members, can undergo ligand-induced proteolytic cleavage to release a soluble intracellular domain (ICD) that enters the nucleus to modify transcription. We found that ERBB4 activates sterol regulatory element binding protein-2 (SREBP-2) to enhance low-density lipoprotein (LDL) uptake and cholesterol biosynthesis. Expression of the ERBB4 ICD in mammary epithelial cells or activation of ERBB4 with the ligand neuregulin 1 (NRG1) induced the expression of SREBP target genes involved in cholesterol biosynthesis, including HMGCR and HMGCS1, and lipid uptake, LDLR, which encodes the LDL receptor. Addition of NRG1 increased the abundance of the cleaved, mature form of SREBP-2 through a pathway that was blocked by addition of inhibitors of PI3K (phosphatidylinositol 3-kinase) or dual inhibition of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2, but not by inhibition of AKT or mTORC1. Pharmacological inhibition of the activity of SREBP site 1 protease or of all EGFR family members (with lapatinib), but not EGFR alone (with erlotinib), impaired NRG1-induced expression of cholesterol biosynthesis genes. Collectively, our findings indicated that activation of ERBB4 promotes SREBP-2-regulated cholesterol metabolism. The connections of EGFR and ERBB4 signaling with SREBP-2 regulated cholesterol metabolism are likely to be important in ERBB-regulated developmental processes and may contribute to metabolic remodeling in ERBB-driven cancers. PMID- 26535012 TI - Early Vascular Aging in Normotensive Patients With Systemic Lupus Erythematosus: Comparison With Young Patients Having Hypertension. AB - Connective tissue diseases, like systemic lupus erythematosus (SLE), are associated with early and accelerated atherosclerosis. Recently, the concept of "early vascular aging" (EVA) has been more widely accepted. Aortic stiffness is one of the important markers of EVA. We evaluated EVA and subclinical atherosclerosis, by measuring aortic pulse wave velocity (aPWV) and carotid intima-media thickness (cIMT), in 50 normotensive patients with SLE (mean age: 39 +/- 12 years). We compared these participants with 50 age- and sex-matched patients with essential hypertension (EH) and 20 healthy controls. Each participant underwent 24-hour ambulatory blood pressure monitoring (ABPM), aPWV, and cIMT measurements. Clinic and 24-hour ABPM values were significantly lower in patients with SLE and controls when compared with the participants having EH (all P < .0001), but aPWV and cIMT were significantly lower in the control group when compared with patients having SLE and EH (all P < .001). Overall, patients with SLE and EH had similar cIMT and aPWV values (P = .31 and P = .47, respectively). Our results suggest that SLE has a similar deleterious impact on EVA as EH. PMID- 26535014 TI - The Neutrophil-Lymphocyte Ratio and Inflammation. PMID- 26535013 TI - Carbondioxide-Aided Angiography Decreases Contrast Volume and Preserves Kidney Function in Peripheral Vascular Interventions. AB - Chronic kidney disease is a common comorbidity in patients with peripheral artery disease. We investigated the safety and efficacy of carbon dioxide (CO2) as supplemental contrast agent to decrease contrast volume during fluoroscopy-guided peripheral vascular procedures in routine angiological practice. We analyzed 191 consecutive interventions of the lower extremity in claudicants and critical limb ischemia (CLI) that were performed with iodinated contrast media (ICM) alone (n = 154) or with the aided or exclusive use of CO2 (n = 37). The technical success rate, total irradiation, and intervention time were not significantly different between ICM and CO2 No severe procedure-related complications occurred. The contrast volume was lower in CO2 than in ICM. Although kidney function, creatinine, and estimated glomerular filtration rate was lower in CO2 at baseline, the incidence of contrast-induced nephropathy was lower in CO2 compared to ICM. These data support CO2 as an alternative supplemental contrast agent that can be applied safely and efficiently to lower contrast volume during peripheral vascular interventions preventing kidney dysfunction even in patients with disease of the popliteal artery and below the knee and CLI. PMID- 26535015 TI - Are Child Cognitive Characteristics Strong Predictors of Responses to Intervention? A Meta-Analysis. AB - We conducted a meta-analysis of 28 studies comprising 39 samples to ask the question, "What is the magnitude of the association between various baseline child cognitive characteristics and response to reading intervention?" Studies were located via literature searches, contact with researchers in the field, and review of references from the National Reading Panel Report. Eligible participant populations included at-risk elementary school children enrolled in the third grade or below. Effects were analyzed using a shifting unit of analysis approach within three statistical models: cognitive characteristics predicting growth curve slope (Model 1, mean r = .31), gain (Model 2, mean r = .21), or postintervention reading controlling for preintervention reading (Model 3, mean r = .15). Effects were homogeneous within each model when effects were aggregated within study. The small size of the effects calls into question the practical significance and utility of using cognitive characteristics for prediction of response when baseline reading is available. PMID- 26535016 TI - [Not Available]. PMID- 26535017 TI - Good Intentions, Uncertain Outcomes: Physician Dispensing in Offices and Clinics. AB - Physician dispensing in offices and clinics raises concerns. PMID- 26535018 TI - Interstate Compounding Plan Jars Hospitals: The Definitions of "Distribution" and "Inordinate" Stir Concern. AB - The FDA's plan for interstate compounding jars hospitals. PMID- 26535019 TI - New Medical Devices. PMID- 26535020 TI - Pharmaceutical Approval Update. AB - Alirocumab (Praluent) for high cholesterol; flibanserin (Addyi) for sexual desire disorder in women; daclatasvir (Daklinza) for chronic hepatitis C virus (HCV) genotype 3 infection; and ombitasvir/paritaprevir/ritonavir (Technivie) for genotype 4 HCV infection without cirrhosis. PMID- 26535021 TI - Edoxaban (Savaysa): A Factor Xa Inhibitor. PMID- 26535022 TI - Congress Likely to Rein In 340B Drug Discount Program: The HRSA's Draft Guidance and a Proposed Rule Give Legislators an Opening. AB - Congress may be about to rein in the 340B drug program, which lets safety-net hospitals and community clinics use outpatient prescription sales to generate revenue. The Health Resources and Services Administration, which runs the program, has published draft guidance to clarify issues raised by federal watchdog agencies. PMID- 26535024 TI - Evaluation of Biosimilars for Formulary Inclusion: Factors for Consideration by P&T Committees. AB - P&T committees will play a key role in driving the adoption of biosimilars, which have unique characteristics compared with small-molecule generic drugs. Key elements of formulary review will include clinical parameters, product characteristics, and institutional considerations, which are among the issues covered in this article. PMID- 26535023 TI - Parkinson's Disease and Its Management: Part 3: Nondopaminergic and Nonpharmacological Treatment Options. AB - This installment of a five-part series reviews the role of nondopaminergic pharmacotherapies and adjunctive options-such as monoamine oxidase type B inhibitors, catechol-O-methyltransferase inhibitors, and anticholinergic agents in managing Parkinson's disease. Nonpharmacological treatments are also explored. PMID- 26535025 TI - Exploring Transitional Care: Evidence-Based Strategies for Improving Provider Communication and Reducing Readmissions. AB - The coordination of care as patients move from one health care setting to another is crucial to treatment, but breakdowns in the process lead to poor transitions, fragmented care, hospital readmissions, and increased costs. This article discusses evidence-based strategies for improving communication and reducing readmissions. PMID- 26535026 TI - CELF1 is Up-Regulated in Glioma and Promotes Glioma Cell Proliferation by Suppression of CDKN1B. AB - BACKGROUND: As a member of the CELF family, CELF1 (CUG-binding protein 1, CUGBP1) is involved in cardiac and embryonic development, skeletal muscle differentiation and mammary epithelial cell proliferation. CELF1 is also observed in many kinds of cancer and may play a great role in tumorigenesis and deterioration. However, the expression and mechanism of its function in human glioma remain unclear. METHODS: We examined CELF1 expression in 62 glioma patients by immunohistochemistry and Western blot. The association between the expression of CELF1 protein and clinicopathological characteristics was analysed using SPSS 17.0. Survival analyses were performed using the Kaplan-Meier method. Small interfering RNA was utilised to specifically knockdown CELF1 mRNA in U87 and U251 cells. Cell proliferation, cell cycle and cell apoptosis were tested by Cell Counting Kit-8 and flow cytometry. The expression of cell cycle-related gene CDKN1B was investigated by Western blot. The interactions between CELF1 and CDKN1B were detected with immune co-precipitation. Subcutaneous tumour models were used to study the effect of CELF1 on the growth of glioma cells in vivo. RESULTS: Our results showed that CELF1 protein was frequently up-regulated in human glioma tissues. The expression level of this protein was positively correlated with glioma World Health Organisation grade and inversely correlated with patient survival (P < 0.05). Knockdown of CELF1 inhibited the glioma cell cycle process and proliferation potential, possibly by down-regulating its target, CDKN1B protein. CONCLUSIONS: Results indicated that CELF1 may be a novel independent prognostic predictor of survival for glioma patients. It may promote glioma cell proliferation and cell cycle process during glioma carcinogenesis. PMID- 26535027 TI - Study of in Vitro and in Vivo Bone Formation in Composite Cryogels and the Influence of Electrical Stimulation. AB - This work studies osteoinduction and bone conduction in polyvinyl alcohol tetraethylorthosilicate-alginate-calcium oxide (PTAC) biocomposite cryogels along with the synergistic effect of electrical stimulation. In vitro osteoinduction of C2C12 myoblast towards osteogenic lineage is demonstrated through alkaline phosphatase assay, scanning electron microscopy and energy dispersive X-ray spectroscopy. These results were followed by in vivo implantation studies of PTAC biocomposite cryogel scaffolds in the bone conduction chamber model depicting bone formation after 24 days based on immunohistological staining for osteogenic markers, i.e., collagen type I (Col I), osteocalcin (OCN), osteopontin (OPN) and bone sialoprotein (BSP). Further, osteogenic differentiation of murine mesenchymal stem cells was studied with and without electrical stimulation. The q PCR analysis shows that the electrically stimulated cryogels exhibit ~ 6 folds higher collagen type I and ~ 10 folds higher osteopontin mRNA level, in comparison to the unstimulated cryogels. Thus, PTAC biocomposite cryogels present osteoinductive and osteoconductive properties during in vitro and in vivo studies and support osteogenic differentiation of mesenchymal stem cells under the influence of electrical stimulation. PMID- 26535028 TI - Time depended Bcl-2 inhibition might be useful for a targeted drug therapy. AB - BACKGROUND: Over expression of Bcl-2 is frequently observed in several types of cancers and it is one of the prognostic markers in breast cancer. The importance of the Bcl-2 protein as ideal therapeutic target is the dual role of inhibiting apoptosis and autophagy-mediated cell death. Thus, the bcl-2 targeting may be a strategy of choice to improve treatment efficacy and overcome drug resistance to cancer chemotherapy. For this reason, we designed the siRNA mediated silencing of the Bcl-2 gene in the MCF-7 breast cancer cell line. OBJECTIVES: The purpose of this research was to investigate the effective Bcl-2 gene silencing by our homemade siRNA, more than previous study. Our data demonstrated that specific inhibition of the Bcl-2 by siRNA induces approximately more than 90 % gene silencing. METHODS: MCF-7 Cell lines were treated by homemade Bcl-2siRNA for the first time and control siRNA that was transfected with nanoparticle. The cells harvested at 24, 48 and 72 h and transcription level of Bcl-2 was examined by Real Time -PCR analysis. The drug sensitivity was detected by using LDH assay test. Finally Anexin V-FITC test was performed for evaluation of apoptosis. RESULTS: In the present study, results showed that targeting the specific sequence of the Bcl-2 by our homemade siRNA in the MCF7 cell line and its effect was more obvious in 24 h in contrast to 48 and 72 h. CONCLUSIONS: However, we showed here a time dependent blocking of the bcl-2 transcript that might lead to cell dead due autophagy, and not necessarily to apoptosis. PMID- 26535029 TI - Proteomic analysis of Pteropus alecto kidney cells in response to the viral mimic, Poly I:C. AB - BACKGROUND: Bats are recognised as an important reservoir for a number of highly pathogenic zoonotic viruses. While many of these viruses cause severe and often fatal disease in humans, bats are able to coexist with these viruses without clinical signs of disease. The mechanism conferring this antiviral response is not fully understood. Here, we investigated the differential protein expression of immortalised Pteropus alecto kidney cells (PaKiT03) following transfection with the viral mimic, Poly I:C. Two complementary proteomic approaches, difference gel electrophoresis (DIGE) and isobaric tagging for relative and absolute quantitation (iTRAQ) were used to quantify changes in protein expression following Poly I:C stimulation at 4, 8 and 20 hr post treatment (hpt). RESULTS: The expression of ISG54 gene, a known responder to virus infection and Poly I:C treatment, was significantly induced in transfected cells compared with mock transfected cells. Through iTRAQ analysis we show that Poly I:C up-regulates key glycolytic enzymes at 4 hpt within PaKiT03 cells. In contrast, at 20 hpt PaKiT03 cells down-regulated ribosomal subunit proteins. The analysis with DIGE of Poly I:C transfected PaKiT03 cells showed over 215 individual spots differentially regulated, however only 25 spots could be unambiguously identified by LC-MS/MS. Immunoblotting confirmed the up-regulation of Eno1 and Tpi1 in PaKiT03 cells following Poly I:C transfection. A comparison with human cells (HEK293T and HeLa) and one additional bat cell line (PaLuT02), demonstrated that glycolytic pathways are also induced in these cell types, but at different intensities. CONCLUSION: The two techniques, DIGE and iTRAQ identified largely overlapping sets of differentially expressed proteins, however DIGE unambiguously identified significantly less proteins than iTRAQ. Poly I:C induced a rapid metabolic shift towards glycolysis within the PaKiT03 cells at 4 hpt, presumably as a consequence of increased energy requirements. On the other hand ribosomal subunit proteins were seen as down-regulated by iTRAQ, these proteins may be the limiting factors in the translational machinery available for virus replication. This study provides new insight into the antiviral response of bat cells, highlighting the importance of energy metabolism. PMID- 26535030 TI - DNA and chromosomal damage in coronary artery disease patients. AB - DNA and chromosomal damage in peripheral blood leukocytes of patients with coronary artery disease (CAD) were investigated by using the single cell gel electrophoresis assay /comet and cytokinesis- block micronucleus (CBMN) assays, respectively. The case-control study comprised patients with CAD (n = 46; average age 53.0 +/- 1.27 y) undergoing treatment at local hospitals, and healthy age-and sex-matched controls (n = 19; average age 54.21 +/- 0.91 y) from the general population. The results of the comet assay revealed that the mean values of DNA damage were significantly (p < 0.001) higher in CAD patients than in controls (Tail DNA% 11.55 +/- 0.38 vs. 5.31 +/- 0.44; Tail moment 6.17 +/- 0.31 vs. 2.93 +/- 0.21 AU; Olive tail moment 3.52 +/- 0.23 vs. 1.25 +/- 0.11 AU). The mean values of chromosomal damage were also significantly higher (p < 0.001) in CAD patients than in controls (Binucleated cells with MN- 28.15 +/- 1.18 vs. 18.16 +/ 2.59; micronuclei 29.52 +/- 1.21 vs. 18.68 +/- 2.64, respectively) while nuclear division index (1.48 +/- 0.01 vs. 1.63 +/- 0.01) was significantly higher (p < 0.001) in controls. The results of the present study indicate that coronary artery disease patients had increased levels of both, unrepaired (DNA) and repaired (chromosomal) genetic damage which may be a pathological consequence of the disease and/or the drug-treatment. This accumulation of DNA/chromosomal damage is of concern as it can lead to the development of cancer with increased chances of morbidity and mortality in the CAD patients. PMID- 26535031 TI - An up-to-date review of rutin and its biological and pharmacological activities. PMID- 26535032 TI - MicroRNAS in endometrial cancer: recent advances and potential clinical applications. AB - Endometrial cancer is a common malignant gynecological tumor, but there are few biomarkers that are useful for early and accurate diagnosis and few treatments other than surgery. However, use of microRNAs (miRNAs) that induces gene downregulation in cells may permit effective and minimally invasive diagnosis and treatment. In endometrial cancer cells, expression levels of miRNAs including miR 185, miR-210 and miR-423 are upregulated and those of miR-let7e, miR-30c and miR 221 are downregulated compared to normal tissues, and these miRNAs are involved in carcinogenesis, invasion and metastasis. miRNAs with expression changes such as miR-181b, miR-324-3p and miR-518b may be used as prognostic biomarkers and transfection of miR-152 may inhibit cancer growth. However, most current studies of miRNAs are at a basic level and further work is needed to establish clinical applications targeting miRNAs. PMID- 26535033 TI - A review on biological and chemical diversity in Berberis (Berberidaceae). AB - Berberis is an important genus and well known in the Indian as well as European systems of traditional medicine. It is used since ancient times for curing eye disease, fever, jaundice, rheumatism, vomiting during pregnancy, kidney and gall balder stones and various other ailments due to the presence of biologically active alkaloid berberine. Action of the root extracts of few species are believed to be as powerful as quinine in the treatment of malarial fever. A plethora of literature pertaining to the taxonomy, biology, chemistry, traditional and ethnic uses of Berberis in different countries and indigenous cultures was collected by both offline (library, journals, textbooks etc.) and online mode (electronic search of available databases). In addition to this, books on traditional medicine and ethno pharmacological knowledge were also referred to extract ancient uses of Berberis in different traditional medicine systems. Most of the folklore, traditional and ethno botanical claims about Berberis species were validated by broad spectrum in vitro and vivo pharmacological studies. The present article summarizes its usage in eye and liver disorder, fever, kidney and gall stones along with anticancer activity. This comprehensive review will not only help researchers for further evaluation but also provide substantial information for future exploitation of species to develop novel herbal formulations. PMID- 26535034 TI - Perspectives of tissues in silico. PMID- 26535035 TI - Protective effects of the aqueous extract of Crocus sativus against ethylene glycol induced nephrolithiasis in rats. AB - This study evaluated the possible protective effect of Crocus sativus L. (saffron) in the treatment of renal calculi. Aqueous extract of saffron (25, 50 and 100 mg/kg, daily) was administered intraperitoneally in two regimens of protective or curative, using male Wistar rats. Urolithiasis was induced by ethylene glycol (% 0.75) in drinking water. Urine was collected for biochemical analysis and the kidneys were prepared for total lipid peroxide and histological evaluation. Ethylene glycol feeding resulted in an increased urine output, renal excretion of oxalate and decreased excretion of citrate and magnesium. Saffron did not show diuretic effect; however, it significantly reduced the elevated urinary oxalate in prophylactic (50 and 100 mg/kg) and curative (100 mg/kg) studies. Only the high dose of prophylactic regimen restored citrate concentration of urine. Increased number of calcium oxalate crystals deposits in the kidney tissue of calculogenic rats was significantly reverted by the prophylactic and high dose of curative saffron treatment. Malondialdehyde (MDA, a lipid peroxidation product) in the kidneys was increased following the lithogenic treatment; however, prophylactic (50, 100 mg/kg) and curative (100 mg/kg) regimens with saffron reduced the elevated levels of MDA. Results in the current study indicate that saffron can protect against ethylene glycol induced calcium oxalate (CaOx) nephrolithiasis. The mechanisms underlying this effect are mediated possibly through effect on the urinary concentration of stone-forming constituents and an antioxidant effect. PMID- 26535036 TI - Comparison of five pretreatments for the production of fermentable sugars obtained from Pinus pseudostrobus L. wood. AB - To benefit from the use of a waste product such as pine sawdust from a sawmill in Michoacan, Mexico, five different pretreatments for the production of reducing sugars by enzymatic hydrolysis were evaluated (sodium hydroxide, sulfuric acid, steam explosion, organosolv and combined method nitric acid / sodium hydroxide). The main finding of the study was that the pretreatment with 6 % HNO3 and 1 % NaOH led to better yields than those obtained with sodium hydroxide, dilute sulfuric acid, steam explosion, and organosolv pretreatments. Also, HNO3 yields were maximized by the factorial method. With those results the maxima concentration of reducing sugar found was 97.83 +/- 1.59, obtained after pretreatment with 7.5 % HNO3 at 120 degrees C for 30 minutes; followed by 1 % of NaOH at 90 degrees C for 30 minutes at pH 4.5 for 168 hours with a load enzyme of 25 FPU/g of total carbohydrates. Comparing the results obtained by the authors with those reported in the literature, the combined method was found to be suitable for use in the exploitation of sawdust. PMID- 26535037 TI - Prediction of aromatase inhibitory activity using the efficient linear method (ELM). AB - Aromatase inhibition is an effective treatment strategy for breast cancer. Currently, several in silico methods have been developed for the prediction of aromatase inhibitors (AIs) using artificial neural network (ANN) or support vector machine (SVM). In spite of this, there are ample opportunities for further improvements by developing a simple and interpretable quantitative structure activity relationship (QSAR) method. Herein, an efficient linear method (ELM) is proposed for constructing a highly predictive QSAR model containing a spontaneous feature importance estimator. Briefly, ELM is a linear-based model with optimal parameters derived from genetic algorithm. Results showed that the simple ELM method displayed robust performance with 10-fold cross-validation MCC values of 0.64 and 0.56 for steroidal and non-steroidal AIs, respectively. Comparative analyses with other machine learning methods (i.e. ANN, SVM and decision tree) were also performed. A thorough analysis of informative molecular descriptors for both steroidal and non-steroidal AIs provided insights into the mechanism of action of compounds. Our findings suggest that the shape and polarizability of compounds may govern the inhibitory activity of both steroidal and non-steroidal types whereas the terminal primary C(sp3) functional group and electronegativity may be required for non-steroidal AIs. The R code of the ELM method is available at http://dx.doi.org/10.6084/m9.figshare.1274030. PMID- 26535038 TI - Phytomedical investigation of Najas minor All. in the view of the chemical constituents. AB - Plants are an abundant natural source of effective antibiotic compounds. Phytomedical investigations of certain plants haven't still been conducted. One of them is Najas minor (N. minor), an aquatic plant with confirmed allelopathy. Research conducted in this study showed the influence of water and ethyl acetate extracts of N. minor on microorganisms, in the view of chemical profiling of volatile constituents and the concentrations of total phenols, flavonoids and tannins. Antimicrobial activity was defined by determining minimum inhibitory and minimum microbicidal concentrations using microdilution method. Influence on bacterial biofilm formation was performed by tissue culture plate method. The total phenolics, flavonoids and condensed tannins were determined by Folin Ciocalteu, aluminum chloride and butanol-HCl colorimetric methods. Chemical profiling of volatile constituents was investigated by GC and GC-MS. Water extract didn't have antimicrobial activity below 5000 ug/mL. Ethyl acetate extract has shown strong antimicrobial activity on G+ bacteria - Staphylococcus aureus PMFKGB12 and Bacillus subtilis (MIC < 78.13 ug/mL). The best antibiofilm activity was obtained on Escherichia coli ATCC25922 (BIC50 at 719 ug/mL). Water extract had higher yield. Ethyl acetate extract had a significantly greater amount of total phenolics, flavonoids and tannins. As major constituent hexahydrofarnesyl acetone was identified. The ethyl acetate extract effected only G+ bacteria, but the biofilm formation of G-bacteria was suppressed. There was a connection between those in vivo and in vitro effects against pathogenic bacterial biofilm formation. All of this points to a so far unexplored potential of N. minor. PMID- 26535039 TI - Investigations on Leucas cephalotes (Roth.) Spreng. for inhibition of LPS-induced pro-inflammatory mediators in murine macrophages and in rat model. AB - Silica gel column chromatography fractionation of the dichloromethane extract (LCD) of Leucas cephalotes (Roth.) Spreng. led to the isolation of five compounds namely beta-sitosterol (1) + stigmasterol (2), lupeol (3), oleanolic acid (4) and laballenic acid (5). Also, gas chromatography-mass spectrometry (GC-MS) analysis of sub-fraction (LCD-F1) of this extract showed the presence of eleven (6-16) compounds. In addition to this, 3-5 and LCD-F1 were evaluated for lipopolysachharide (LPS)-induced nitric oxide (NO), tumor necrosis factor (TNF) alpha and interleukin (IL)-1beta production in RAW 264.7 and J774A.1 cells. Results directed that 4 and 5 were found to inhibit these mediators at half maximal inhibitory concentration of 17.12 to 57.20 MUM while IC50 for LCD-F1 was found to be 15.56 to 31.71 MUg/mL. Furthermore, LCD at a dose of 50, 100 and 400 mg/Kg was found to reduce significantly LPS induced tumor necrosis factor (TNF) alpha and interleukin (IL)-1beta production in female Sprague Dawley (SD) rats. All the results findings evoked that the anti-inflammatory effects of Leucas cephalotes is partially mediated through the suppression of pro-inflammatory mediators and hence can be utilized for the development of anti-inflammatory candidates. PMID- 26535040 TI - Serial measurement of lipid profile and inflammatory markers in patients with acute myocardial infarction. AB - Serum concentration of lipids and lipoproteins changes during the course of acute coronary syndrome as a consequence of the inflammatory response. The objective of this study was to evaluate the effect of acute myocardial infarction (AMI) on the levels of lipid profile and inflammatory markers. We investigated 400 patients with AMI who were admitted within 24 h of onset of symptoms. Serum levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and high density lipoprotein (HDL) were determined by standard enzymatic methods along with high sensitive C-reactive protein (hs-CRP) (latex enhanced immunoturbidimetric assay) and cytokines, interleukin (IL)-6 and IL-10 (quantitative ''sandwich'' enzyme-linked immunosorbent assay). The results indicate a trend of reduced TC, LDL, and HDL, and elevated TG levels, along with pro- and anti-inflammatory markers (p < 0.001), between day 1 and the day 2 serum samples of AMI patients. However, corrections in the serum levels have been observed at day 7. Our results demonstrate significant variations in the mean lipid levels and inflammatory markers between days 1, 2 and 7 after AMI. Therefore, it is recommended that the serum lipids should be assessed within 24 hours after infarction. Early treatment of hyperlipidemia provides potential benefits. Exact knowledge regarding baseline serum lipids and lipoprotein levels as well as their varying characteristics can provide a rational basis for clinical decisions about lipid lowering therapy. PMID- 26535041 TI - Apoptotic potential of C-phycoerythrin from Phormidium sp. A27DM and Halomicronema sp. A32DM on human lung carcinoma cells. AB - Phycobilisomes present in cyanobacteria are photosynthetic macromolecular protein complexes that are categorized into three types - phycoerythrins (high energy), phycocyanin (intermediate energy) and allophycocyanin (low energy). Structurally, they consist of alpha and beta protein subunits and open chain tetrapyrrole prosthetic group (bilin chromophore), known for its antioxidant properties and therapeutic potential against a variety of physiological ailments. Phycoerythrins (C-PE) were purified from cyanobacterial strains Phormidium sp. A27DM and Halomicronema sp. A32DM and their respective apoptotic potentials were assessed on A549 human lung carcinoma cells. Both strains of cyanobacteria were cultured and the C-PE from each strain was extracted, quantified and characterized. C-PE accounted for a dose dependent decrement in cell viability, mitochondrial membrane potential and an increment in lactate dehydrogenase release. Higher doses of C-PE (of both strains) accounted for loss of cell viability and nuclear pycnosis. These findings were further substantiated with flow cytometry that revealed a cell arrest at G0/G1 phase and a high percentage of cells undergoing apoptosis following C-PE treatment. These results confirm the efficacy of C-PE from Phormidium sp. or Halomicronema sp. in triggering apoptotic cell death. This study is the first to report on apoptotic property of C-PE against A549 human lung carcinoma cells and warrants further studies to establish its anti-cancer potential. PMID- 26535042 TI - Highlight report: Role of the circadian clock system in breast cancer. PMID- 26535043 TI - Calculated Antibiosis of Acute Cholangitis and Cholecystitis. AB - BACKGROUND: The aim of this article is to present the most recent suggestions for the therapy of acute cholangitis and cholecystitis based on a review of the current literature. METHODS: We performed a systematic literature search in the Medline, PubMed, and Google Scholar databases using the keywords mentioned above. This article is strongly influenced by the publication of the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07, TG13) in 2007 and 2013. These were the first practical guidelines targeting diagnosis and treatment of acute cholangitis and cholecystitis. These guidelines are based on the best published evidence and a consensus conference of international experts in the field. RESULTS AND CONCLUSION: Acute cholangitis and acute cholecystitis are common conditions that may result in progressively severe infection and death when not treated appropriately. Beside supportive therapy and antiobstructive measures, therapy with antimicrobial agents is an important component in the management of affected patients. Here, we discuss the use of antimicrobial agents that are suitable for the first-line management of these infections. Empirical therapy depends upon the knowledge of local microbial epidemiology and patient specific factors affecting the selection of appropriate agents. PMID- 26535044 TI - Perioperative Antibiotic Prophylaxis and Antimicrobial Therapy of Intra-Abdominal Infections. AB - BACKGROUND: The increase of antimicrobial resistances to first- and second-line antibiotics, especially of Gram-negative bacteria, and the lack of novel antimicrobial substances are a challenge in the treatment of intra-abdominal infections. METHODS: Review article. RESULTS: The efficacy and safety of perioperative antibiotic prophylaxis in visceral surgery has been demonstrated by several meta-analyses. Perioperative antibiotic prophylaxis is defined as a single administration of antibiotics shortly before a surgical intervention. A so called prolonged prophylaxis including the postoperative period (e.g. 1-3 days postoperatively) should be avoided as it does not reduce the number of wound infections and is associated with an increased risk of antimicrobial resistance and side effects. Antimicrobial management of severe intra-abdominal infections involves a delicate balance of optimizing empirical therapy which has been shown to improve outcomes while simultaneously reducing unnecessary use of antimicrobials. CONCLUSION: Antimicrobial resistance poses a serious threat to human health and requires a rational use of antibiotics to curb further spreading. This applies for perioperative prophylaxis as well as for the treatment of intra-abdominal infections. PMID- 26535045 TI - Verrucous Oesophageal Carcinoma: Single Case Report and Case Series Including 15 Patients - Issues for Consideration of Therapeutic Strategies. AB - BACKGROUND: Verrucous carcinomas (VC) of the oesophagus are a rarity. Due to their histological resemblance to squamous cell carcinoma, the diagnostic and treatment standards applicable to the latter have so far also been applied to VC as a disease entity. Quite limited data are available including two case series of 5 or 11 patients. The present study reports on a single case treated by local endoscopic therapy and a series of 15 patients, 9 of whom received local endoscopic therapy. METHODS: The data for patients diagnosed with VC of the oesophagus who had been treated from January 1999 to May 2011 were analysed retrospectively. RESULTS: 15 patients with the diagnosis of oesophageal VC were included. The male-female ratio was 3:1. 9 of 11 pT1-VC patients presented with the cardinal symptom dysphagia or odynophagia. For the majority of the patients, the growth pattern is one of extensive superficial expansion showing a median length of 9 cm (range: 2-22 cm). Surprisingly, none of the VC patients showed lymph node or distant metastasis. 9 of 15 VC patients received local endoscopic therapy; 4 were treated with curative intent and 5 were treated palliatively. 3 patients underwent oesophageal resection, and definitive chemoradiotherapy was administered in a further 3 patients. One severe complication, consisting of a postoperative anastomotic insufficiency with a fatal outcome, occurred in this group of patients. CONCLUSION: This is the largest published study describing patients diagnosed with VC of the oesophagus so far. The option of local endoscopic therapy and its results in 9 patients are reported for the first time. The superficial growth pattern of the tumour and the frequent absence of lymph node or distant metastasis suggest that endoscopic resection can be carried out as a diagnostic and/or therapeutic approach. Due to the rarity of this entity, the case numbers are unfortunately so limited that evidence-based recommendations are unlikely to become available even in the future. PMID- 26535046 TI - Cytoreductive Surgery and HIPEC in the Baltic States: An International Scientific Workshop with Live Surgery. AB - BACKGROUND: Around the globe a new interest in the multidisciplinary management of peritoneal metastases using neoadjuvant chemotherapy, cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and adjuvant systemic chemotherapy has occurred. The combined use of these treatment modalities has required the creation of centers of excellence to manage patients with peritoneal metastases with a high level of success as well as a low incidence of adverse events. METHODS: A 2-day workshop hosted by the Center of Abdominal Surgery, Vilnius University Hospital, with 230 participants was organized to explore the current practice in the Baltic states. Live surgery with video transmission initiated the efforts. Then, presentations by five experts from high-volume peritoneal surface malignancy centers were made and discussed. A summary of the efforts to date in Lithuania and Estonia was presented and collected for publication. RESULTS: The live surgery served as a focal point for all subsequent presentations. The five invited speakers reviewed the rationale, current literature, indications and contraindications, implementation, and current European guidelines for management. The results of CRS and HIPEC from five centers in Lithuania and Estonia currently active revealed 127 patients treated to date, half of whom carried a diagnosis of ovarian cancer. There was an incidence of major complications of 11.8% and a mortality of 1.6%. Data regarding long-term survival benefits will require further follow-up. CONCLUSIONS: Progress in peritoneal surface oncology in the Baltic states was confirmed. With a low morbidity and mortality, these clinical programs promise to provide continued benefit for patients with peritoneal metastases - a condition judged to be terminal in the past. PMID- 26535047 TI - Current status of sleep quality in Taiwan: a nationwide walk-in survey. AB - BACKGROUND: Sleep disorder plays an important role in the overall health care system, because it can be co-morbid with many other physical or mental disorders. In this study, we conducted a screening survey to determine the current status of sleep quality in the general population of Taiwan. METHODS: During the period 1 March 2010 to 30 April 2013, we collaborated with the Fo-Guang Shan Compassion Foundation's Mentality Protection Center (MPC) branches to conduct 53 walk-in screenings at the 59 branches distributed throughout Taiwan. We used the Pittsburgh Sleep Quality Index (PSQI) to assess multiple dimensions of sleep over a 1-month period after identifying the participants' age, sex, and residence location. The participants were identified to have poor sleep quality if their PSQI-T total score was greater than five. RESULTS: In total, 760 participants, 195 from northern, 289 from central, 228 from southern, and 48 from eastern Taiwan with an average age of 54.2 years (SD 14.7) were recruited. We found that 46.6 % of all participants had poor sleep quality and that there were significantly different proportions among the four areas. Besides, 11.6 % of all participants and 21.8 % of individuals with poor sleep quality had used sedatives/hypnotics to help them fall asleep in the past 4 weeks, and the proportion was highest in the eastern area. CONCLUSIONS: This survey suggested that the ratio of poor sleep quality in Taiwan is progressively increasing compared to the previous studies. In addition, there were significantly different proportions of individuals with poor sleep quality and hypnotics' uses among the four areas. PMID- 26535048 TI - Integrating technology into cognitive behavior therapy for adolescent depression: a pilot study. AB - BACKGROUND: Rapid advances in information technology and telecommunications have resulted in a dramatic increase in the use of mobile devices and the internet to enhance and facilitate access to treatment. Cognitive behavior therapy (CBT) is an empirically based treatment that is well suited for enhancement by new technologies, particularly with youth. To facilitate the dissemination of this evidence-based treatment, we developed a technology-enhanced CBT intervention for the treatment of adolescent depression consisting of (1) online therapist training (2) in-session use of tablets for teaching clients CBT concepts and skills, and (3) text messaging for between session homework reminders and self monitoring. METHODS: Eighteen licensed clinicians (social workers n = 7, psychologists n = 9) were randomized to have their patients receive either the intervention (CBT) or treatment as usual (TAU). Each clinician treated four adolescents for 12 weeks. Clinicians in the CBT arm completed an online tutorial on CBT treatment of adolescent depression, then received an iPad with access to patient education materials for teaching CBT concepts to patients during sessions. Individualized text messages were integrated into treatment for homework reminders, support, and outcomes measurement. Outcome measures included a 49-item multiple choice test for tutorial effectiveness; the system usability scale (SUS) for user satisfaction; quick inventory of depressive symptomatology adolescent version (QIDS-A-Pat); and clinician and patient ratings on the therapeutic alliance scale for adolescents (TASA). RESULTS: A significant increase in knowledge of CBT concepts was found after completing the tutorial, t(8) = 7.02, p < 0.001. Clinician and patient ratings of user satisfaction were high for both the iPad teaching tools, and the text messaging. Ninety-five percent of teens said reviewing their text messages with their therapist was helpful, and all said they would use text messaging in treatment again. Ratings of the therapeutic alliance were higher in the CBT arm t(131) = 4.03, p = 0.001. A significant reduction in depression was found in both groups [t(34) = 8.453, p < 0.001 and t(29) = 6.67, p < 0.001 for CBT and TAU, respectively). Clinical ratings of improvement were greater on all outcome measures for the CBT arm; however, none reached statistical significance. Effect sizes (Cohen's d) ranged from small (QIDS-A) to large (TASA). CONCLUSIONS: Results support the feasibility of this technology-enhanced CBT intervention as a means of improving CBT treatment of adolescent depression and may help address the critical shortage of therapists trained on empirically based treatments. PMID- 26535049 TI - Epidemiology and Treatment Guidelines of Negative Symptoms in Schizo-phrenia in Central and Eastern Europe: A Literature Review. AB - AIM: To gather and review data describing the epidemiology of schizophrenia and clinical guidelines for schizophrenia therapy in seven Central and Eastern European countries, with a focus on negative symptoms. Methods : A literature search was conducted which included publications from 1995 to 2012 that were indexed in key databases. Results : Reports of mean annual incidence of schizophrenia varied greatly, from 0.04 to 0.58 per 1,000 population. Lifetime prevalence varied from 0.4% to 1.4%. One study reported that at least one negative symptom was present in 57.6% of patients with schizophrenia and in 50 90% of individuals experiencing their first episode of schizophrenia. Primary negative symptoms were observed in 10-30% of patients. Mortality in patients with schizophrenia was greater than in the general population, with a standardized mortality ratio of 2.58-4.30. Reasons for higher risk of mortality in the schizophrenia population included increased suicide risk, effect of schizophrenia on lifestyle and environment, and presence of comorbidities. Clinical guidelines overall supported the use of second-generation antipsychotics in managing negative symptoms of schizophrenia, although improved therapeutic approaches are needed. Conclusion : Schizophrenia is one of the most common mental illnesses and poses a considerable burden on patients and healthcare resources alike. Negative symptoms are present in many patients and there is an unmet need to improve treatment offerings for negative symptoms beyond the use of second-generation antipsychotics and overall patient outcomes. PMID- 26535050 TI - Nervous Facilitation in Cardiodynamic Response of Exercising Athletes to Superimposed Mental Tasks: Implications in Depressive Disorder. AB - INTRODUCTION: Motor commands to perform exercise tasks may also induce activation of cardiovascular centres to supply the energy needs of the contracting muscles. Mental stressors per se may also influence cardiovascular homeostasis. We investigated the cardiovascular response of trained runners simultaneously engaged in mental and physical tasks to establish if aerobically trained subjects could develop, differently from untrained ones, nervous facilitation in the brain cardiovascular centre. Methods : Cardiovascular responses of 8 male middle distance runners (MDR), simultaneously engaged in mental (colour-word interference test) and physical (cycle ergometer exercise) tasks, were compared with those of 8 untrained subjects. Heart rate, cardiac (CI) and stroke indexes were assessed by impedance cardiography while arterial blood pressures were assessed with a brachial sphygmomanometer. Results : Only in MDR simultaneous engagement in mental and physical tasks induced a significant CI increase which was higher (p<0.05) than that obtained on summing CI values from each task separately performed. Conclusion : Aerobic training, when performed together with a mental effort, induced a CI oversupply which allowed a redundant oxygen delivery to satisfy a sudden fuel demand from exercising muscles by utilizing aerobic sources of ATP, thus shifting the anaerobic threshold towards a higher work load. From data of this study it may also be indirectly stated that, in patients with major depressive disorder, the promotion of regular low-intensity exercise together with mental engagement could ameliorate the perceived physical quality of life, thus reducing their heart risk associated with physical stress. PMID- 26535051 TI - Digital imaging of root traits (DIRT): a high-throughput computing and collaboration platform for field-based root phenomics. AB - BACKGROUND: Plant root systems are key drivers of plant function and yield. They are also under-explored targets to meet global food and energy demands. Many new technologies have been developed to characterize crop root system architecture (CRSA). These technologies have the potential to accelerate the progress in understanding the genetic control and environmental response of CRSA. Putting this potential into practice requires new methods and algorithms to analyze CRSA in digital images. Most prior approaches have solely focused on the estimation of root traits from images, yet no integrated platform exists that allows easy and intuitive access to trait extraction and analysis methods from images combined with storage solutions linked to metadata. Automated high-throughput phenotyping methods are increasingly used in laboratory-based efforts to link plant genotype with phenotype, whereas similar field-based studies remain predominantly manual low-throughput. DESCRIPTION: Here, we present an open-source phenomics platform "DIRT", as a means to integrate scalable supercomputing architectures into field experiments and analysis pipelines. DIRT is an online platform that enables researchers to store images of plant roots, measure dicot and monocot root traits under field conditions, and share data and results within collaborative teams and the broader community. The DIRT platform seamlessly connects end-users with large scale compute "commons" enabling the estimation and analysis of root phenotypes from field experiments of unprecedented size. CONCLUSION: DIRT is an automated high-throughput computing and collaboration platform for field based crop root phenomics. The platform is accessible at http://www.dirt.iplantcollaborative.org/ and hosted on the iPlant cyber-infrastructure using high-throughput grid computing resources of the Texas Advanced Computing Center (TACC). DIRT is a high volume central depository and high-throughput RSA trait computation platform for plant scientists working on crop roots. It enables scientists to store, manage and share crop root images with metadata and compute RSA traits from thousands of images in parallel. It makes high-throughput RSA trait computation available to the community with just a few button clicks. As such it enables plant scientists to spend more time on science rather than on technology. All stored and computed data is easily accessible to the public and broader scientific community. We hope that easy data accessibility will attract new tool developers and spur creative data usage that may even be applied to other fields of science. PMID- 26535052 TI - Management of respiratory disorders in a Chinese medicine teaching clinic in Australia: review of clinical records. AB - BACKGROUND: People seek Chinese medicine (CM) treatments for a variety of respiratory disorders, e.g., asthma and upper respiratory tract infection (URTI). No previous studies have reviewed the data available in medical records from Australian clinics. This study aims to identify the characteristics of patients with respiratory disorders who visited a CM teaching clinic at RMIT University in Melbourne, Australia. METHODS: Primary data from January 2010 to December 2011 were collected from patient records in a CM teaching clinic at RMIT University. Patient data, including demographics, primary complaint, clinical history, lifestyle, CM treatment, and adverse events, were analyzed with descriptive statistics and the Chi square test using SPSS version 21.0. RESULTS: From 1677 clinical records we identified 261 patients with respiratory disorders. The patients made a total of 842 visits (mean: 3.2 visits/patient; range: 1-34 visits) during the study period. The mean age of the patients was 38.5 +/- 17.9 years, and the majority were female (65.5 %). The most common respiratory disorders were URTI (27.8 %), cough (20.8 %), hay fever or allergic rhinitis (18.6 %), sinus congestion (11.2 %), and asthma (7.6 %). Acupuncture was given at almost all visits (97.5 %) and was frequently combined with herbs (64.0 %). Fifteen adverse events were reported, but none were considered severe. CONCLUSION: In the CM teaching clinic, respiratory conditions were a common presenting complaint of patients, and were safely treated with a combination of acupuncture and herbs. PMID- 26535053 TI - Self-administered acupressure for treating adult psychiatric patients with constipation: a randomized controlled trial. AB - BACKGROUND: Constipation has a high prevalence rate (>30 %) in psychiatric patients with psychotropic drugs. Common pharmacological and non-pharmacological interventions for constipation might have longer-term negative and adverse effects that would outweigh their short-term efficacy in symptom reduction. This randomized controlled trial aims to investigate the effect of self-administered acupressure for the management of constipation, in hospitalized psychiatric patients. METHODS: Seventy-eight patients were recruited in matched pairs in terms of gender, age and laxative use from five acute psychiatric wards in Hong Kong. Each of these matched pairs of patients was randomly assigned to either a self-administered acupressure (n = 39) or a sham group (n = 39), using computer generated random numbers. After baseline measurement, the intervention and sham group received the same training in self-administered acupressure and supervised practice once per day for 10 days, except light pressure on non-acupoints was taught to the sham group. The acupoints chosen for acupressure included Zhongwan (RN12), right and left Tianshu (ST25), right and left Quchi (LI11). Participants' symptoms and quality of life regarding constipation were measured at baseline and immediately and 2 weeks after completion of the interventions with constipation assessment scale and patient assessment of constipation quality of life questionnaire, respectively. RESULTS: After 2 weeks follow-up, participants who had received self-administered acupressure indicated significantly greater improvements in both symptom severity (P = 0.0003) and quality of life (P = 0.0004) when compared with the sham group. CONCLUSION: The psychiatric patients with constipation who practiced self-administered acupressure for 10 days improved their symptom severity and perceived quality of life immediately and 2 weeks after completion of the intervention in comparison with the sham group. TRIAL REGISTRATION: The trial was registered with the ClinicalTrials.gov (Reg. No: NCT02187640). PMID- 26535054 TI - A novel rat model of liver regeneration: possible role of cytokine induced neutrophil chemoattractant-1 in augmented liver regeneration. AB - BACKGROUND: Liver resection is the mainstay of treatment for most of the liver tumors. Liver has a unique capability to restore the lost volume following resection, however, most of the primary tumors grow in a liver with preexisting parenchymal diseases and secondary tumors often present in multiple liver lobes precluding a safe curative resection. Two-stage hepatectomy and portal vein ligation (PVL) are used to achieve a safer future remnant liver volume (FRLV), however, these procedures take several weeks to achieve adequate FRLV. A recently introduced faster alternative two-stage hepatectomy, also know as associated liver partitioning and portal vein ligation for staged hepatectomy (ALPPS), produces a desirable FRLV in days. METHODS: To have an insight into the mechanism of ALPPS associated liver regeneration, we reproduced a rat model of ALPPS and compared the results with the PVL group. RESULTS: Our results convincingly showed an advantage of the ALPPS procedure over PVL group in terms of early regeneration, however, in 1-week time the amount of regeneration was comparable. An early regeneration in the ALPPS group coincided with an early entry of hepatocytes into the cell proliferation phase, a significant increase in portal pressure and increase in hepatic enzymes in the ALPPS group compared with the PVL group. According to the protein array evaluation of 29 cytokines/chemokines, cytokine induced neutrophil chemoattractant-1 had the highest expression whereas IL-6 had the highest fold (>6 vs PVL group) expression at the early phase of regeneration in the ALPPS group. CONCLUSIONS: This unique rat model of ALPPS would help to improve our understanding about the liver generation process and also will help in further refinement of the ALPPS procedure for the clinical benefit. PMID- 26535055 TI - Patterns of HIV viremia and viral suppression before diagnosis of non-AIDS defining cancers in HIV-infected individuals. AB - BACKGROUND: The association between HIV viremia and non-AIDS-defining cancers (NADCs) is not well characterized. Viremia may contribute directly or indirectly to cancer development and may have a differential impact on various cancer types. Our objective was to characterize patterns of HIV viremia in a retrospective, urban, clinical cohort (N = 320) of patients diagnosed with NADCs. FINDINGS: The most common NADC's were lung (n = 60), prostate (n = 47), oropharyngeal (n = 32), liver (n = 29), and anal cancer (n = 20) and Hodgkin lymphoma (n = 18). In the year before cancer diagnosis, 66 % of all patients were virally suppressed. Patients with oropharyngeal (70 %) and prostate cancer (78 %) had a higher proportion of visits with suppressed viral loads. Patients diagnosed with anal cancer and Hodgkin lymphoma were infrequently virally suppressed and more frequently had viral loads >=5 log10 copies/ml in the ten years prior to cancer diagnosis. CONCLUSIONS: In this cohort of HIV-infected patients diagnosed with NADCs, there were important differences in the patterns and levels of viremia between the different NADCs in the ten years prior to cancer diagnosis. Patients with anal cancer and Hodgkin lymphoma had the highest proportion of high level viremia in the ten years before cancer and the lowest frequency of viral load suppression at cancer diagnosis. PMID- 26535056 TI - Child health in Syria: recognising the lasting effects of warfare on health. AB - The war in Syria, now in its fourth year, is one of the bloodiest in recent times. The legacy of war includes damage to the health of children that can last for decades and affect future generations. In this article we discuss the effects of the war on Syria's children, highlighting the less documented longer-term effects. In addition to their present suffering, these children, and their own children, are likely to face further challenges as a result of the current conflict. This is essential to understand both for effective interventions and for ethical reasons. PMID- 26535057 TI - An engineered cryptic Hxt11 sugar transporter facilitates glucose-xylose co consumption in Saccharomyces cerevisiae. AB - BACKGROUND: The yeast Saccharomyces cerevisiae is unable to ferment pentose sugars like d-xylose. Through the introduction of the respective metabolic pathway, S. cerevisiae is able to ferment xylose but first utilizes d-glucose before the d-xylose can be transported and metabolized. Low affinity d-xylose uptake occurs through the endogenous hexose (Hxt) transporters. For a more robust sugar fermentation, co-consumption of d-glucose and d-xylose is desired as d xylose fermentation is in particular prone to inhibition by compounds present in pretreated lignocellulosic feedstocks. RESULTS: Evolutionary engineering of a d xylose-fermenting S. cerevisiae strain lacking the major transporter HXT1-7 and GAL2 genes yielded a derivative that shows improved growth on xylose because of the expression of a normally cryptic HXT11 gene. Hxt11 also supported improved growth on d-xylose by the wild-type strain. Further selection for glucose insensitive growth on d-xylose employing a quadruple hexokinase deletion yielded mutations at N366 of Hxt11 that reversed the transporter specificity for d glucose into d-xylose while maintaining high d-xylose transport rates. The Hxt11 mutant enabled the efficient co-fermentation of xylose and glucose at industrially relevant sugar concentrations when expressed in a strain lacking the HXT1-7 and GAL2 genes. CONCLUSIONS: Hxt11 is a cryptic sugar transporter of S. cerevisiae that previously has not been associated with effective d-xylose transport. Mutagenesis of Hxt11 yielded transporters that show a better affinity for d-xylose as compared to d-glucose while maintaining high transport rates. d glucose and d-xylose co-consumption is due to a redistribution of the sugar transport flux while maintaining the total sugar conversion rate into ethanol. This method provides a single transporter solution for effective fermentation on lignocellulosic feedstocks. PMID- 26535058 TI - On predicting regulatory genes by analysis of functional networks in C. elegans. AB - BACKGROUND: Connectivity networks, which reflect multiple interactions between genes and proteins, possess not only a descriptive but also a predictive value, as new connections can be extrapolated and tested by means of computational analysis. Integration of different types of connectivity data (such as co expression and genetic interactions) in one network has proven to benefit 'guilt by association' analysis. However predictive values of connectives of different types, that had their specific functional meaning and topological characteristics were not obvious, and have been addressed in this analysis. METHODS: eQTL data for 3 experimental C.elegans age groups were retrieved from WormQTL. WormNet has been used to obtain pair-wise gene interactions. The Shortest Path Function (SPF) has been adopted for statistical validation of the co-expressed gene clusters and for computational prediction of their potential gene expression regulators from a network context. A new SPF-based algorithm has been applied to genetic interactions sub-networks adjacent to the clusters of co-expressed genes for ranking the most likely gene expression regulators causal to eQTLs. RESULTS: We have demonstrated that known co-expression and genetic interactions between C. elegans genes can be complementary in predicting gene expression regulators. Several algorithms were compared in respect to their predictive potential in different network connectivity contexts. We found that genes associated with eQTLs are highly clustered in a C. elegans co-expression sub-network, and their adjacent genetic interactions provide the optimal functional connectivity environment for application of the new SPF-based algorithm. It was successfully tested in the reverse-prediction analysis on groups of genes with known regulators and applied to co-expressed genes and experimentally observed expression quantitative trait loci (eQTLs). CONCLUSIONS: This analysis demonstrates differences in topology and connectivity of co-expression and genetic interactions sub-networks in WormNet. The modularity of less continuous genetic interaction network does not correspond to modularity of the dense network comprised by gene co-expression interactions. However the genetic interaction network can be used much more efficiently with the SPF method in prediction of potential regulators of gene expression. The developed method can be used for validation of functional significance of suggested eQTLs and a discovery of new regulatory modules. PMID- 26535059 TI - Vitamin A: a missing link in diabetes? AB - Vitamin A has a critical role in embryonic development, immunity and the visual cycle. In recent years, evidence has demonstrated that vitamin A can also regulate metabolic pathways implicated in the pathogenesis of obesity and diabetes. This has increased interest in the possible antiobesity and antidiabetic properties of natural and synthetic vitamin A derivatives. However, whether vitamin A deficiency or aberrations in vitamin A metabolism contribute to the pathogenesis of diabetes is not known. This perspective article will review what is currently known and new data regarding the link between vitamin A and the clinical manifestations of common and atypical forms of diabetes. PMID- 26535060 TI - Vertical Targeting of AKT and mTOR as Well as Dual Targeting of AKT and MEK Signaling Is Synergistic in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is the sixth most common cancer, and the third most common cause of cancer related death worldwide. The multi-kinase inhibitor Sorafenib represents the only systemic treatment option until today, and results from clinical trials with allosteric mTOR inhibitors were sobering. Since the PI3K/AKT/mTOR and RAF/MEK/ERK signaling pathways are frequently upregulated in HCC, we have analyzed the effects of AKT inhibitor MK-2206, MEK inhibitor AZD6244 (ARRY 142886) and mTOR kinase inhibitor AZD8055, given as single drugs or in combination, on proliferation and apoptosis of three HCC cell lines in vitro. We show that all three inhibitor combinations synergistically inhibit proliferation of the three HCC cell lines, with the strongest synergistic effect observed after vertical inhibition of AKT and mTORC1/2. We demonstrate that AKT kinase activity is restored 24h after blockade of mTORC1/2 by increased phosphorylation of T308, providing a rationale for combined targeting of AKT and mTOR inhibition in HCC. Our data suggest that a combination of inhibitors targeting those respective pathways may be a viable approach for future application in patients with hepatocellular carcinoma. PMID- 26535061 TI - May Circulating microRNAs be Gastric Cancer Diagnostic Biomarkers? AB - Gastric cancer (GC) is the third leading cause of cancer-related deaths. More than 80% of the diagnosis was made at the advanced stages of the disease, highlighting the urgent demand for novel biomarkers that can be used for early detection. Recently, a number of studies suggest that circulating microRNAs (miRNAs) could be potential biomarkers for GC diagnosis. Cancer-related circulating miRNAs, as well as tissue miRNAs, provide a hopeful prospect of detecting GC at early stages, and the prospective participation of miRNAs in biomarker development will enhance the sensitivity and specificity of diagnostic tests for GC. As miRNAs in blood are stable, their potential value as diagnostic biomarkers in GC has been explored over the past few years. However, due to the inconsistent or sometimes conflicting reports, large-scale prospective studies are needed to validate their potential applicability in GC diagnosis. This review summarizes the current development about potential miRNA biomarkers for GC diagnosis and the obstacles hindering their clinical usage. PMID- 26535062 TI - Expression Profiling Identifies Bezafibrate as Potential Therapeutic Drug for Lung Adenocarcinoma. AB - Drug-induced gene expression patterns that invert disease profiles have recently been illustrated to be a new strategy for drug-repositioning. In the present study, we validated this approach and focused on prediction of novel drugs for lung adenocarcinoma (AC), for which there is a pressing need to find novel therapeutic compounds. Firstly, connectivity map (CMap) analysis computationally predicted bezafibrate as a putative compound against lung AC. Then this hypothesis was verified by in vitro assays of anti-proliferation and cell cycle arrest. In silico docking evidence indicated that bezafibrate could target cyclin dependent kinase 2(CDK2), which regulates progression through the cell cycle. Furthermore, we found that bezafibrate can significantly down-regulate the expression of CDK2 mRNA and p-CDK2. Using a nude mice xenograft model, we also found that bezafibrate could inhibit tumor growth of lung AC in vivo. In conclusion, this study proposed bezafibrate as a potential therapeutic option for lung AC patients, illustrating the potential of in silico drug screening. PMID- 26535063 TI - The Expression of CD9 and PIK3CD is Associated with Prognosis of Follicular Lymphoma. AB - BACKGROUND: Follicular lymphoma (FL) frequently develops drug-resistance and transforms into more aggressive subtypes over time. It is urgent to find prognostic biomarkers and disclose signaling pathways that have potential to be drug targets. In this study, we investigated the association of FL prognosis with the expression of 2 proteins: PIK3CD, a PI3K pathway component, and CD9, a tetraspanin family member. METHOD: The expression of PIK3CD and CD9 were examined on 76 FL tumor tissues and 15 normal tissues with Immunohistochemistry. Chi square test, Cox proportional hazards model, and Kaplan-Meier estimates were used to analyze the relationships of CD9 and PIK3CD expression and major clinicopathological features. RESULT: PIK3CD expression was significantly higher, whereas CD9 expression was significantly lower in the 76 FL specimens than normal tissues. Concomitantly, low CD9 or high PIK3CD expression is associated with high degrees of Ann Arbor stages. In agreement with this, PIK3CD is an unfavorable and CD9 is a favorable factor for progression-free survival (PFS). Interestingly, PIK3CD expression is negatively correlated with CD9 expression, and the PIK3CD high/CD9-low was significantly associated with short PFS when the 2 factors were combined together. Lastly, CD9 expression was significant higher in patients with bone marrow infiltration (BMI) than those without BMI. CONCLUSION: Both CD9 and PIK3CD are prognostic markers of FL. The negative correlation between CD9 and PIK3CD expression suggests that there may be crosstalks of the 2 proteins in FL. PMID- 26535064 TI - MicroRNA-222 Controls Human Pancreatic Cancer Cell Line Capan-2 Proliferation by P57 Targeting. AB - Pancreatic cancer (PC) is one of the most common cancers and has a poor prognosis due to late diagnosis and ineffective therapeutic multimodality. MicroRNAs (miRNAs, miRs) are a group of non-coding, small RNAs with active biological activities. In our investigation, human pancreatic cancer cell line Capan-2 were transfected with miR-222 mimics, inhibitors or their negative controls. Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8), EdU incorporation assay and cell cycle determination by flow cytometry. MiR-222 and putative target gene expression levels including p27, p57 and PTEN were determined using quantitative reverse transcription polymerase chain reactions and Western blotting. Our results showed that miR-222 could lead to increased vitality and proliferative rate of Capan-2 cells, and also higher S-phase and lower G1-phase of cell cycle. Further, we found p57 at protein level, but not p27 nor PTEN, was regulated by miR-222 in Capan-2 cells. Finally, we co-transfected miR-222 inhibitor and p57 si-RNA into Capan-2 cells, and found that proliferation suppressing effects of miR-222 inhibitor on Capan-2 cells could be partially reversed by silencing p57. Our results indicate that miR-222 controls Capan-2 cell proliferation by targeting p57. This study provides a novel idea for developing effective therapeutic strategy for PC patients through inhibiting miR 222. PMID- 26535065 TI - A Fraction of CD133+ CNE2 Cells Is Made of Giant Cancer Cells with Morphological Evidence of Asymmetric Mitosis. AB - CD133 has been suggested as a broad-spectrum marker for cancer stem cells(CSCs). The present study investigated the expression of CD133 in biopsy tissues of nasopharyngeal carcinoma (NPC), NPC cell lines and the immortalized cell line NP69 by immunohistochemistry, flow cytometry and qRT-PCR. CD133+ cancer cells were isolated using magnetic-activated cell sorting technology. The study demonstrated that CD133+ cells are rare in NPC tissues and cell lines and that their self-renewal and proliferation abilities are stronger than those of CD133- cells and suggested that CD133+ NPC cells have characteristics of cancer stem cells. We further observed CD133+ cancer cells using a light microscope and scanning electron microscope. Generally, CD133+ cells are small, regular and round with small microvilli. On the other hand, CD133- cells are more polymorphic and larger with long micromicrovilli. Additionally, in some fields, several giant cancer cells (GCCs) in the CD133+ cell group were identified under the light microscope. Most of them were polynuclear cells. Under the scanning electron microscope, we found indefinite regular small bodies on the surface of or surrounding the giant cancer cells, some of which appeared to be creeping out the parental cells. This phenomenon was not observed in the CD133- cell groups. Through comparison with descriptions of apoptotic bodies in the literature and from the results of the acridine orange test, we propose that some of the small bodies are daughter cells of the GCCs. This phenomenon is a mode of division of cancer cells called neosis, or budding, which is a form of reproduction for simple organisms. Budding is satisfied with the rapid speed of tumor development. GCCs could be isolated by CD133 beads because the daughter cells have stem-cell characteristics and express stem-cell markers. PMID- 26535066 TI - High Expression of FGFR4 Enhances Tumor Growth and Metastasis in Nasopharyngeal Carcinoma. AB - BACKGROUND: FGF receptor (FGFR) family can be activated by FGFs and play important roles in regulating cell growth, differentiation, migration and angiogenesis. Recent studies suggested that FGFR4 could regulate several processes including tumor progression. Nasopharyngeal carcinoma (NPC) is a malignancy with a high occurrence in Southeast Asia and Southern China. However, the molecule mechanism and the potential roles of FGFR4 in NPC remain unknown Methods: Immunohistochemistry and western blot were used to investigate the expression of FGFR4 in NPC samples. Then we used statistical analysis to evaluate the diagnostic value and the associations of FGFR4 expression with clinical parameters. In vitro studies, the effects of FGFR4 on proliferation and migration of NPC cell line CNE2 were measured by the starvation-refeeding experiment, CCK8 assay, wounding healing assay and transwell migration assay. The changes of the epithelial-mesenchymal transition (EMT) markers in CNE2 cells after knocking down the expression of FGFR4 were measured by Western blot and immunofluorescence analysis. RESULTS: FGFR4 was overexpressed in NPC as compared with the inflammatory tissues. High expression of FGFR4 was correlated with Ki67 expression, clinical stages and prognosis in NPC patients (P<0.05).While in vitro, the upregulation of FGFR4 was accompanied with CNE2 cells released from serum starvation. Moreover, it could increase cell proliferation and migration by regulating EMT markers in CNE2 cells. CONCLUSION: Our data suggested that FGFR4 might induce NPC progression and act as a potential therapeutic target in NPC. PMID- 26535067 TI - CT120A Acts as an Oncogene in Head and Neck Squamous Cell Carcinoma. AB - Squamous cell carcinoma of the head and neck (HNSCC) is among the most frequent cancers worldwide. The etiology and pathogenesis of HNSCC are influenced by multiple genetic factors in addition to environmental and lifestyle-related factors. However, the mechanism underlying the HNSCC is still far from clear. The membrane associated gene CT120 was previously identified from chromosome 17p13.3 as a lung cancer-associated gene. Its function as an activator of the Erk and Akt signaling pathways in human lung cancer cell lines suggested that CT120 has an oncogenic function. However, there is no data in the literature on the role of CT120 in any other cancer type. Therefore, the aim of this study was to determine the expression rate and probable function of CT120 in HNSCC. Tumor tissues from 50 patients were analyzed by real-time quantitative RT-PCR to investigate the expression rate and by direct sequencing to differentiate the CT120A and CT120B variants. CT120 overexpression was observed in 58% of tumors compared to non cancerous tissue samples and this up-regulation was directly associated with the upregulation of the CT120A variant and with the stage of the disease (p=0.001). Our results indicate that the CT120 gene may function in the development of HNSCC. PMID- 26535068 TI - Onset Latency of Motor Evoked Potentials in Motor Cortical Mapping with Neuronavigated Transcranial Magnetic Stimulation. AB - Cortical motor mapping in pre-surgical applications can be performed using motor evoked potential (MEP) amplitudes evoked with neuronavigated transcranial magnetic stimulation. The MEP latency, which is a more stable parameter than the MEP amplitude, has not so far been utilized in motor mapping. The latency, however, may provide information about the stress in damaged motor pathways, e.g. compression by tumors, which cannot be observed from the MEP amplitudes. Thus, inclusion of this parameter could add valuable information to the presently used technique of MEP amplitude mapping. In this study, the functional cortical representations of first dorsal interosseous (FDI), abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles were mapped in both hemispheres of ten healthy righthanded volunteers. The cortical muscle representations were evaluated by the area and centre of gravity (CoG) by using MEP amplitudes and latencies. As expected, the latency and amplitude CoGs were congruent and were located in the centre of the maps but in a few subjects, instead of a single centre, several loci with short latencies were observed. In conclusion, MEP latencies may be useful in distinguishing the cortical representation areas with the most direct pathways from those pathways with prolonged latencies. However, the potential of latency mapping to identify stressed motor tract connections at the subcortical level will need to be verified in future studies with patients. PMID- 26535069 TI - The Impact of Deep Brain Stimulation on Sleep and Olfactory Function in Parkinson's Disease. AB - OBJECTIVE: Relatively little is known about the effects of deep brain stimulation on non-motor symptoms. The aim of this pilot study was to assess the impact of deep brain stimulation on sleep and olfactory function in Parkinson's disease. METHODS: Subjective sleep quality and olfactory testing were performed on 11 consecutive Parkinson's disease patients (eight men and three women) undergoing bilateral subthalamic nucleus stimulation. All patients consented to undergo clinical assessments prior to the procedure, and at regular intervals afterwards. RESULTS: Subjective sleep quality improved at six months following deep brain stimulation and this benefit was sustained in the majority of patients at later follow-up assessments. There was no significant change in olfactory function following deep brain stimulation. CONCLUSIONS: In addition to having beneficial effects on motor function and quality of life, bilateral subthalamic nucleus stimulation improves subjective sleep quality in Parkinson's disease. PMID- 26535070 TI - Diagnostic Value of Procalcitonin in ANCA-Associated Vasculitis (AAV) to Differentiate Between Disease Activity, Infection and Drug Hypersensitivity. AB - OBJECTIVE: Procalcitonin (PCT) is considered to be a specific marker for severe bacterial infections and sepsis. Elevated PCT levels have been reported in active autoimmune diseases without infection. The aim of this study was to assess the diagnostic value of PCT serum levels in ANCA-associated vasculitis (AAV) patients with respect to infection, disease activity and drug fever using a high sensitive PCT detection method. METHODS: In 53 AAV patients with elevated C-reactive protein (CRP) PCT was determined by the Thermo Scientific BRAHMS PCT sensitive KRYPTOR assay. Patients underwent standardized diagnostic procedures for evaluation of disease activity and infection. RESULTS: 53 patients with AAV and elevated CRP (7.7+/-6.9 mg/dl, PCT 0.34+/-1.02 ng/ml) were assessed, 10 had infection with elevated CRP levels of 11.2+/-10.2 mg/dl and PCT levels of 1.06+/ 2.07 ng/dl. 43 patients had no evidence of infection, 36 of them were presented with AAV with normal or only slightly positive PCT levels in active disease (n=36) (PCT 0.06+/-0.06 ng/ml). 7 patients had increased PCT levels due to azathioprine hypersensitivity (0.76+/-1.01 ng/ml). For discrimination between infection and vasculitis activity PCT was more useful than CRP with the best cut off at 0.1 ng/ml (sensitivity 60%, specificity 92%). CONCLUSION: In contrast to previous studies using semiquantitative PCT assays, the KRYPTOR performs better with respect to discrimination of infection from active AAV. In all patients assessed with active AAV (and without infection) PCT levels remained below the PCT reference limit (0.5 ng/ml) for infections. Drug hypersensitivity seems to be an important differential diagnosis in the setting of elevated CRP and PCT in patients who receive azathioprine. PMID- 26535071 TI - Refractive and Visual Outcomes of Different Intraocular Lenses with Femtosecond Laser Cataract Surgery: The Expectation of Independence from Spectacles. AB - PURPOSE: To evaluate the visual performance of different types of intraocular lens (IOL) in eyes submitted to femtosecond laser (FSL) cataract surgery and to analyze whether this technology could result in spectacles independence. DESIGN: Retrospective comparative case series. METHODS: Consecutive eyes that were scheduled for FSL cataract surgery were included in this study. After one month postoperative, patients were divided into two groups: cases that required prescription for eyeglasses and cases that did not require prescription. In addition, the patients were analyzed according to the type of IOL that was implanted (monofocal, monofocal toric, multifocal and multifocal toric). RESULTS: Thirty-five cataract surgeries were analyzed. Twenty-three eyes had a monofocal IOL implanted, and 12 had a multifocal IOL implanted. After 1 month, 12 cases required prescription (Group 1), and 23 did not require prescription (Group 2). The proportion of eyes that did not require corrective lenses was significantly greater (P = 0.02) in eyes that received multifocal IOL (91.67%) compared with those that received monofocal IOL (47.83%). Additionally, 100% of eyes that received multifocal toric IOL did not require eyeglasses at one month postoperatively. CONCLUSION: The FSL surgical precision associated with modern IOL technology may be an important factor related to vision satisfaction after cataract surgery. PMID- 26535072 TI - The Association Between Primary Open Angle Glaucoma and Clustered Components of Metabolic Syndrome. AB - PURPOSE: There is conflicting evidence whether components of metabolic syndrome (MetS) increase or decrease the risk of primary open-angle glaucoma (POAG). The aim of the present study was to determine the association between metabolic syndrome and primary open-angle glaucoma. METHODS: A total of 200 participants comprising 100 controls and 100 patients with POAG documented by clinical tests and examined by an experienced ophthalmologist using standard ophthalmologic equipment were included in the study. MetS was defined and based on ATP III criteria and POAG was defined by the criteria of the International Society of Geographic and Epidemiological Ophthalmology (ISGEO). The data were entered into the SPSS software and analyzed. RESULTS: The prevalence of MetS in the glaucoma group was 53% in comparison to 38% in the control group (p=0.037). MetS was associated with an increased odds ratio for an IOP higher than 21 mmHg (OR: 1.72; 95% CI 1.03-2.79; p=0.034). The mean IOP was 24.91+/-4.29 mmHg in the patients without MetS, and 27.23+/-4.81 mmHg in those with MetS (p=0.027). The mean values of CCT were 603.64+/-63.16 um in MetS patients and 579.27+/-72.87 um in controls (p=0.018). CONCLUSION: Data showed an increased prevalence of components of metabolic syndrome in patients with glaucoma. The mechanisms underlying these associations need to be established in future studies. Our results support the recommendation that patients with metabolic syndrome undergo regular ophthalmological exams to monitor for the onset or progression of glaucoma. PMID- 26535073 TI - Social, Relational and Network Determinants of Unprotected Anal Sex and HIV Testing Among Men Who Have Sex with Men in Beirut, Lebanon. AB - Social, relational and network determinants of condom use and HIV testing were examined among 213 men who have sex with men (MSM) in Beirut. 64% reported unprotected anal intercourse (UAI), including 23% who had UAI with unknown HIV status partners (UAIU); 62% had HIV-tested. In multivariate analysis, being in a relationship was associated with UAI and HIV testing; lower condom self-efficacy was associated with UAIU and HIV testing; gay discrimination was associated with UAIU; MSM disclosure was associated with UAI, UAIU and HIV testing; and network centralization was associated with HIV testing. Multi-level social factors influence sexual health in MSM. PMID- 26535074 TI - Strategies and Advancement in Antibody-Drug Conjugate Optimization for Targeted Cancer Therapeutics. AB - Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris((r)) (anti-CD30-drug conjugate) and Kadcyla((r)) (anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed. PMID- 26535075 TI - Lipid A as a Drug Target and Therapeutic Molecule. AB - In this review, lipid A, from its discovery to recent findings, is presented as a drug target and therapeutic molecule. First, the biosynthetic pathway for lipid A, the Raetz pathway, serves as a good drug target for antibiotic development. Several assay methods used to screen for inhibitors of lipid A synthesis will be presented, and some of the promising lead compounds will be described. Second, utilization of lipid A biosynthetic pathways by various bacterial species can generate modified lipid A molecules with therapeutic value. PMID- 26535076 TI - Pretreatment with Lycopene Attenuates Oxidative Stress-Induced Apoptosis in Human Mesenchymal Stem Cells. AB - Human mesenchymal stem cells (MSCs) have been used in cell-based therapy to promote revascularization after peripheral or myocardial ischemia. High levels of reactive oxygen species (ROS) are involved in the senescence and apoptosis of MSCs, causing defective neovascularization. Here, we examined the effect of the natural antioxidant lycopene on oxidative stress-induced apoptosis in MSCs. Although H2O2 (200 MUM) increased intracellular ROS levels in human MSCs, lycopene (10 MUM) pretreatment suppressed H2O2-induced ROS generation and increased survival. H2O2-induced ROS increased the levels of phosphorylated p38 mitogen activated protein kinase (MAPK), Jun-N-terminal kinase (JNK), ataxia telangiectasia mutated (ATM), and p53, which were inhibited by lycopene pretreatment. Furthermore, lycopene pretreatment decreased the expression of cleaved poly (ADP ribose) polymerase-1 (PARP-1) and caspase-3 and increased the expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax), which were induced by H2O2 treatment. Moreover, lycopene significantly increased manganese superoxide dismutase (MnSOD) expression and decreased cellular ROS levels via the PI3K-Akt pathway. Our findings show that lycopene pretreatment prevents ischemic injury by suppressing apoptosis-associated signal pathway and enhancing anti-oxidant protein, suggesting that lycopene could be developed as a beneficial broad-spectrum agent for the successful MSC transplantation in ischemic diseases. PMID- 26535077 TI - Vitamin C Stimulates Epidermal Ceramide Production by Regulating Its Metabolic Enzymes. AB - Ceramide is the most abundant lipid in the epidermis and plays a critical role in maintaining epidermal barrier function. Overall ceramide content in keratinocyte increases in parallel with differentiation, which is initiated by supplementation of calcium and/or vitamin C. However, the role of metabolic enzymes responsible for ceramide generation in response to vitamin C is still unclear. Here, we investigated whether vitamin C alters epidermal ceramide content by regulating the expression and/or activity of its metabolic enzymes. When human keratinocytes were grown in 1.2 mM calcium with vitamin C (50 MUg/ml) for 11 days, bulk ceramide content significantly increased in conjunction with terminal differentiation of keratinocytes as compared to vehicle controls (1.2 mM calcium alone). Synthesis of the ceramide fractions was enhanced by increased de novo ceramide synthesis pathway via serine palmitoyltransferase and ceramide synthase activations. Moreover, sphingosine-1-phosphate (S1P) hydrolysis pathway by action of S1P phosphatase was also stimulated by vitamin C supplementation, contributing, in part, to enhanced ceramide production. However, activity of sphingomyelinase, a hydrolase enzyme that converts sphingomyelin to ceramide, remained unaltered. Taken together, we demonstrate that vitamin C stimulates ceramide production in keratinocytes by modulating ceramide metabolic-related enzymes, and as a result, could improve overall epidermal barrier function. PMID- 26535078 TI - Simvastatin Reduces Lipopolysaccharides-Accelerated Cerebral Ischemic Injury via Inhibition of Nuclear Factor-kappa B Activity. AB - Preceding infection or inflammation such as bacterial meningitis has been associated with poor outcomes after stroke. Previously, we reported that intracorpus callosum microinjection of lipopolysaccharides (LPS) strongly accelerated the ischemia/reperfusion-evoked brain tissue damage via recruiting inflammatory cells into the ischemic lesion. Simvastatin, 3-hydroxy-3 methylgultaryl (HMG)-CoA reductase inhibitor, has been shown to reduce inflammatory responses in vascular diseases. Thus, we investigated whether simvastatin could reduce the LPS-accelerated ischemic injury. Simvastatin (20 mg/kg) was orally administered to rats prior to cerebral ischemic insults (4 times at 72, 48, 25, and 1-h pre-ischemia). LPS was microinjected into rat corpus callosum 1 day before the ischemic injury. Treatment of simvastatin reduced the LPS-accelerated infarct size by 73%, and decreased the ischemia/reperfusion induced expressions of pro-inflammatory mediators such as iNOS, COX-2 and IL 1beta in LPS-injected rat brains. However, simvastatin did not reduce the infiltration of microglial/macrophageal cells into the LPS-pretreated brain lesion. In vitro migration assay also showed that simvastatin did not inhibit the monocyte chemoattractant protein-1-evoked migration of microglial/macrophageal cells. Instead, simvastatin inhibited the nuclear translocation of NF-kappaB, a key signaling event in expressions of various proinflammatory mediators, by decreasing the degradation of IkappaB. The present results indicate that simvastatin may be beneficial particularly to the accelerated cerebral ischemic injury under inflammatory or infectious conditions. PMID- 26535079 TI - EP2 Induces p38 Phosphorylation via the Activation of Src in HEK 293 Cells. AB - Prostaglandin E2 (PGE2), a major product of cyclooxygenase, binds to four different prostaglandin E2 receptors (EP1, EP2, EP3, and EP4) which are G-protein coupled transmembrane receptors (GPCRs). Although GPCRs including EP receptors have been shown to be associated with their specific G proteins, recent evidences suggest that GPCRs can regulate MAPK signaling via non-G protein coupled pathways including Src. EP2 is differentially expressed in various tissues and the expression of EP2 is induced by extracellular stimuli. We hypothesized that an increased level of EP2 expression may affect MAPK signaling. The overexpression of EP2 in HEK 293 cells resulted in significant increase in intracellular cAMP levels response to treatment with butaprost, a specific EP2 agonist, while overexpression of EP2 alone did not increase intracellular cAMP levels. However, EP2 overexpression in the absence of PGE2 induced an increase in the level of p38 phosphorylation as well as the kinase activity of p38, suggesting that up regulation of EP2 may promote p38 activation via non-G protein coupled pathway. Inhibition of Src completely blocked EP2-induced p38 phosphorylation and overexpression of Src increased the level of p38 phosphorylation, indicating that Src is upstream kinase for EP2-induced p38 phosphorylation. EP2 overexpression also increased the Src activity and EP2 protein was co-immunoprecipitated with Src. Furthermore, sequential co-immunoprecipitation studies showed that EP2, Src, and beta-arrestin can form a complex. Our study found a novel pathway in which EP2 is associated with Src, regulating p38 pathway. PMID- 26535080 TI - Dimethyl Cardamonin Exhibits Anti-inflammatory Effects via Interfering with the PI3K-PDK1-PKCalpha Signaling Pathway. AB - Consumption of herbal tea [flower buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry (Myrtaceae)] is associated with health beneficial effects against multiple diseases including diabetes, asthma, and inflammatory bowel disease. Emerging evidences have reported that High mobility group box 1 (HMGB1) is considered as a key "late" proinflammatory factor by its unique secretion pattern in aforementioned diseases. Dimethyl cardamonin (2',4'-dihydroxy-6'-methoxy-3',5' dimethylchalcone, DMC) is a major ingredient of C. operculatus flower buds. In this study, the anti-inflammatory effects of DMC and its underlying molecular mechanisms were investigated on lipopolysaccharide (LPS)-induced macrophages. DMC notably suppressed the mRNA expressions of TNF-alpha, IL-1beta, IL-6, and HMGB1, and also markedly decreased their productions in a time- and dose-dependent manner. Intriguingly, DMC could notably reduce LPS-stimulated HMGB1 secretion and its nucleo-cytoplasmic translocation. Furthermore, DMC dose-dependently inhibited the activation of phosphatidylinositol 3-kinase (PI3K), phosphoinositide dependent kinase 1 (PDK1), and protein kinase C alpha (PKCalpha). All these data demonstrated that DMC had anti-inflammatory effects through reducing both early (TNF-alpha, IL-1beta, and IL-6) and late (HMGB1) cytokines expressions via interfering with the PI3K-PDK1-PKCalpha signaling pathway. PMID- 26535081 TI - Diphlorethohydroxycarmalol Suppresses Ultraviolet B-Induced Matrix Metalloproteinases via Inhibition of JNK and ERK Signaling in Human Keratinocytes. AB - Skin aging is the most readily observable process involved in human aging. Ultraviolet B (UVB) radiation causes photo-oxidation via generation of reactive oxygen species (ROS), thereby damaging the nucleus and cytoplasm of skin cells and ultimately leading to cell death. Recent studies have shown that high levels of solar UVB irradiation induce the synthesis of matrix metalloproteinases (MMPs) in skin fibroblasts, causing photo-aging and tumor progression. The MMP family is involved in the breakdown of extracellular matrix in normal physiological processes such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes such as arthritis and metastasis. We investigated the effect of diphlorethohydroxycarmalol (DPHC) against damage induced by UVB radiation in human skin keratinocytes. In UVB-irradiated cells, DPHC significantly reduced expression of MMP mRNA and protein, as well as activation of MMPs. Furthermore, DPHC reduced phosphorylation of ERK and JNK, which act upstream of c-Fos and c-Jun, respectively; consequently, DPHC inhibited the expression of c-Fos and c-Jun, which are key components of activator protein-1 (AP-1, up-regulator of MMPs). Additionally, DPHC abolished the DNA-binding activity of AP-1, and thereby prevented AP-1-mediated transcriptional activation. These data demonstrate that by inactivating ERK and JNK, DPHC inhibits induction of MMPs triggered by UVB radiation. PMID- 26535082 TI - Peptidoglycan Up-Regulates CXCL8 Expression via Multiple Pathways in Monocytes/Macrophages. AB - Peptidoglycan (PG), the gram positive bacterial pathogen-associated molecular patterns (PAMP), is detected in a high proportion in macrophage-rich atheromatous regions, and expression of chemokine CXCL8, which triggers monocyte arrest on early atherosclerotic endothelium, is elevated in monocytes/macrophages in human atherosclerotic lesion. The aim of this study was to investigate whether PG induced CXCL8 expression in the cell type and to determine cellular signaling pathways involved in that process. Exposure of THP-1 cell, human monocyte/macrophage cell line, to PG not only enhanced CXCL8 release but also profoundly induced il8 gene transcription. PG-induced release of CXCL8 and induction of il8 gene transcription were blocked by OxPAPC, an inhibitor of TLR 2/4 and TLR4, but not by polymyxin B, an inhibitor of LPS. PG-mediated CXCL8 release was significantly attenuated by inhibitors of PI3K-Akt-mTOR pathways. PKC inhibitors, MAPK inhibitors, and ROS quenchers also significantly attenuated expression of CXCL8. The present study proposes that PG contributes to inflammatory reaction and progression of atherosclerosis by inducing CXCL8 expression in monocytes/macrophages, and that TLR-2, PI3K-Akt-mTOR, PKC, ROS, and MAPK are actively involved in the process. PMID- 26535083 TI - Effect of Beta-Asarone on Impairment of Spatial Working Memory and Apoptosis in the Hippocampus of Rats Exposed to Chronic Corticosterone Administration. AB - beta-asarone (BAS) is an active component of Acori graminei rhizoma, a traditional medicine used clinically in treating dementia and chronic stress in Korea. However, the cognitive effects of BAS and its mechanism of action have remained elusive. The purpose of this study was to examine whether BAS improved spatial cognitive impairment induced in rats following chronic corticosterone (CORT) administration. CORT administration (40 mg/kg, i.p., 21 days) resulted in cognitive impairment in the avoidance conditioning test (AAT) and the Morris water maze (MWM) test that was reversed by BAS (200 mg/kg, i.p). Additionally, as assessed by immunohistochemistry and RT-PCR analysis, the administration of BAS significantly alleviated memory-associated decreases in the expression levels of brain-derived neurotrophic factor (BDNF) and cAMP-response element-binding protein (CREB) proteins and mRNAs in the hippocampus. Also, BAS administration significantly restored the expression of Bax and Bcl-2 mRNAs in the hippocampus. Thus, BAS may be an effective therapeutic for learning and memory disturbances, and its neuroprotective effect was mediated, in part, by normalizing the CORT response, resulting in regulation of BDNF and CREB functions and anti-apoptosis in rats. PMID- 26535084 TI - Lifespan Extending and Stress Resistant Properties of Vitexin from Vigna angularis in Caenorhabditis elegans. AB - Several theories emphasize that aging is closely related to oxidative stress and disease. The formation of excess ROS can lead to DNA damage and the acceleration of aging. Vigna angularis is one of the important medicinal plants in Korea. We isolated vitexin from V. angularis and elucidated the lifespan-extending effect of vitexin using the Caenorhabditis elegans model system. Vitexin showed potent lifespan extensive activity and it elevated the survival rates of nematodes against the stressful environments including heat and oxidative conditions. In addition, our results showed that vitexin was able to elevate antioxidant enzyme activities of worms and reduce intracellular ROS accumulation in a dose-dependent manner. These studies demonstrated that the increased stress tolerance of vitexin mediated nematode could be attributed to increased expressions of stress resistance proteins such as superoxide dismutase (SOD-3) and heat shock protein (HSP-16.2). In this work, we also studied whether vitexin-mediated longevity activity was associated with aging-related factors such as progeny, food intake, growth and movement. The data revealed that these factors were not affected by vitexin treatment except movement. Vitexin treatment improved the body movement of aged nematode, suggesting vitexin affects healthspan as well as lifespan of nematode. These results suggest that vitexin might be a probable candidate which could extend the human lifespan. PMID- 26535085 TI - Assessment of the Abuse Liability of Synthetic Cannabinoid Agonists JWH-030, JWH 175, and JWH-176. AB - The emergence and use of synthetic cannabinoids have greatly increased in recent years. These substances are easily dispensed over the internet and on the streets. Some synthetic cannabinoids were shown to have abuse liability and were subsequently regulated by authorities. However, there are compounds that are still not regulated probably due to the lack of abuse liability studies. In the present study, we assessed the abuse liability of three synthetic cannabinoids, namely JWH-030, JWH-175, and JWH-176. The abuse liability of these drugs was evaluated in two of the most widely used animal models for assessing the abuse potential of drugs, the conditioned place preference (CPP) and self administration (SA) test. In addition, the open-field test was utilized to assess the effects of repeated (7 days) treatment and abrupt cessation of these drugs on the psychomotor activity of animals. Results showed that JWH-175 (0.5 mg/kg), but not JWH-030 or JWH-176 at any dose, significantly decreased the locomotor activity of mice. This alteration in locomotor activity was only evident during acute exposure to the drug and was not observed during repeated treatment and abstinence. Similarly, only JWH-175 (0.1 mg/kg) produced significant CPP in rats. On the other hand, none of the drugs tested was self-administered by rats. Taken together, the present results indicate that JWH-175, but not JWH-030 and JWH-176, may have abuse potential. More importantly, our findings indicate the complex psychopharmacological effects of synthetic cannabinoids and the need to closely monitor the production, dispensation, and use of these substances. PMID- 26535086 TI - Neurotoxicity of Synthetic Cannabinoids JWH-081 and JWH-210. AB - Synthetic cannabinoids JWH-018 and JWH-250 in 'herbal incense' also called 'spice' were first introduced in many countries. Numerous synthetic cannabinoids with similar chemical structures emerged simultaneously and suddenly. Currently there are not sufficient data on their adverse effects including neurotoxicity. There are only anecdotal reports that suggest their toxicity. In the present study, we evaluated the neurotoxicity of two synthetic cannabinoids (JWH-081 and JWH-210) through observation of various behavioral changes and analysis of histopathological changes using experimental mice with various doses (0.1, 1, 5 mg/kg). In functional observation battery (FOB) test, animals treated with 5 mg/kg of JWH-081 or JWH-210 showed traction and tremor. Their locomotor activities and rotarod retention time were significantly (p<0.05) decreased. However, no significant change was observed in learning or memory function. In histopathological analysis, neural cells of the animals treated with the high dose (5 mg/kg) of JWH-081 or JWH-210 showed distorted nuclei and nucleus membranes in the core shell of nucleus accumbens, suggesting neurotoxicity. Our results suggest that JWH-081 and JWH-210 may be neurotoxic substances through changing neuronal cell damages, especially in the core shell part of nucleus accumbens. To confirm our findings, further studies are needed in the future. PMID- 26535087 TI - Pyogenic granuloma in relation to dental implants: Clinical and histopathological findings. AB - BACKGROUND: The occurrence of pyogenic granuloma in association to dental implants is rare and only five cases have been reported in the literature. MATERIAL AND METHODS: Patients charts were analyzed to select patients who had been diagnosed for pyogenic granuloma and its association with dental implants had been evaluated. The clinical status of the dental implants and the prosthesis had also been assessed. RESULTS: Clinical and histopathological diagnosis of pyogenic granuloma had been reached for soft mass growth in association with dental implants in 10 patients. Histological analysis of all samples was performed to obtain a firm diagnosis of finding against pyogenic granuloma lesions. Accumulation of dental plaque due to poor oral hygiene and improper design of the prosthesis had been related to the occurrence of pyogenic granuoloma. This lesion showed no predilection to specific surface type and had no significant association with marginal bone loss. CONCLUSIONS: Pyogenic granuloma should be included in the differential diagnosis of soft mass growth around dental implants. KEY WORDS: Reactive lesion, soft mass, pyogenic granuloma, dental implant, titanium. PMID- 26535088 TI - Panoramic radiographic study of mental foramen in selected dravidians of south Indian population: A hospital based study. AB - BACKGROUND: This study aimed at documenting information on appearance, size, horizontal and vertical locations of Mental Foramen (MF) in Panoramic Radiograph. We also analyzed the age and gender differences with radiographic appearance and location of MF. We evaluated these findings in our population and co-relate with results of previous studies. MATERIAL AND METHODS: 1662 panoramic radiographs were evaluated, of which 245 fulfilled the inclusion criteria. Each radiograph was traced to record the horizontal and vertical locations. The size of MF was recorded using digital caliper and its appearance was determined by visual examination. Chi-square and t-test were employed. RESULTS: The most common appearance of MF was continuous type and the tests showed significant difference with age and gender. The most frequent horizontal location of MF was "location c" with no statistical significant difference with age and gender. The MF was most commonly positioned mesially in relation to the apex of second premolar with no significant differences with gender. The vertical location of the foramen varied drastically with no statistical significant difference in both sides. The difference in dimensions on the left and right sides were not statistically significant. CONCLUSIONS: Determining the morphological appearance and positional variation of MF is important for isolation of mental nerves and vessels when administering local anesthesia and performing surgeries. We therefore stress the importance of accurate radiographic identification of MF and interpretation. Our research findings can be used as reference material by the dental practitioners of South India while performing clinical procedures that involve MF. KEY WORDS: Mental foramen, mental nerve, panoramic radiograph, mandible. PMID- 26535089 TI - The staining effect of different mouthwashes containing nanoparticles on dental enamel. AB - BACKGROUND: This study aimed to evaluate the effects of several mouthwashes containing nanoparticles on discoloration of dental enamel, and compare the results with that of 0.2% chlorhexidine (CHX). MATERIAL AND METHODS: Sixty intact premolars were randomly assigned to six groups. A spectrophotometer was used to measure the color of the teeth (T1) according to the CIELAB system. The specimens in groups 1 to 4 were then immersed in colloidal solutions containing nanoTiO2 (Group 1), nanoZnO (Group 2), nanoAg (Group 3) and nanoCuO (Group 4). In groups 5 and 6, a 0.2% CHX mouthwash and distilled water were used as positive and negative controls, respectively. After 24 hours of immersion, color determination was repeated (T2). The third color assessment was accomplished after brushing (T3). The L, a, and b values were recorded and the color change (?E) between different stages was calculated. RESULTS: ANOVA revealed significant between group differences in the color change between T1 and T2 stages, as well as between T1 and T3 time points (p<0.05), whereas the color change between T2 and T3 was not significantly different among the study groups (p=0.09). ?ET1-T3 was significantly lower in the specimens immersed in distilled water or CHX as compared to the nanoparticle-containing mouthwashes (p<0.05). The highest ?E value pertained to the specimens immersed in nanoZnO-containing solution. The TiO2 nanoparticles caused the lowest staining among the tested nanoparticles. CONCLUSIONS: The mouthwashes containing nanoparticles produced comparable or even greater enamel discoloration compared to CHX. Brushing had little effect on removal of induced stains. KEY WORDS: Nanoparticle, mouthrinse, mouthwash, staining, enamel, discoloration, chlorhexidine. PMID- 26535090 TI - Estimation of Pyruvic acid in serum and saliva among healthy and potentially malignant disorder subjects - a stepping stone for cancer screening? AB - BACKGROUND: According to Warburg's effect, the rate of glycolysis increases in cancerous cells. This will increase overall levels of pyruvic acid. The present on-going study was conducted to estimate the levels of pyruvic acid in saliva and serum in normal, oral PMD subjects. MATERIAL AND METHODS: A total of 50 subjects in healthy, PMD of the oral cavity individuals were selected based on clinical and histological criteria. Collected saliva and serum samples were subjected to pyruvic acid level estimation using biochemical analysis. RESULTS: Of the 50 participants 25 (13: Males; 12: Females) & 25 (16: Males; 9: Females) were PMD group. Independent samples t test showed statistically significant difference in serum & salivary pyruvic acid level in between 2 groups (p < 0.001 respectively). CONCLUSIONS: Estimation of pyruvic acid showed sequential increase in the level in PMD group compared to healthy. Hence the study results open new direction in cancer screening. KEY WORDS: Pyruvic acid, glycolysis, warburg's effect. PMID- 26535091 TI - Durability of solvent-free one-step self-etch adhesive under simulated intrapulpal pressure. AB - BACKGROUND: There are different solvents presented in simplified adhesives. Bond 1 SF has been developed, which contains neither water nor organic solvents, in order to eliminate technical issues in terms of evaporation of solvents and concerns for the durability of resin-dentin bond. Thus this study was conducted to evaluate the microtensile bond strength (?TBS) of solvent-free and ethanol based one-step self-etch adhesives to dentin under simulated intrapulpal pressure (IPP). MATERIAL AND METHODS: Occlusal surfaces of human molars were prepared to expose mid-dentin depth. Bond-1SF Solvent-Free SE [SF] and AdperTM easy one adhesives [AE] were applied on dentin specimens. Resin composite build up was done in increments. Then specimens were stored under simulated IPP 20 mmHg, immersed in artificial saliva at 37 oC for 24 hours (24h) and 6 months (6m). Specimens were sectioned into sticks of (1 mm2) to be tested for (?TBS) using a universal testing machine. Both fractured sections of each stick were inspected using a stereomicroscope at 40* magnification to determine the mode of failure. Data were statistically analyzed by Two-way ANOVA of Variance. RESULTS: There was no statistically significant difference between the mean ?TBS of both [SF] and [AE] adhesives at both aging periods, 24h and 6m (p< 0.1103) and (p< 0.7148) respectively. Only for [AE] there was statistical significance for aging periods (p< 0.0057*). The most represented modes of failure were adhesive failure at tooth side. CONCLUSIONS: Under simulated IPP solvent-free adhesive [SF] had comparable performance as ethanol-based adhesive [AE] when bonded to dentin substrate. KEY WORDS: Bond strength, dentin, simulated intrapulpal pressure, self etch adhesives, solvents. PMID- 26535092 TI - Hemodynamic changes following injection of local anesthetics with different concentrations of epinephrine during simple tooth extraction: A prospective randomized clinical trial. AB - BACKGROUND: Presence of epinephrine in local anesthetic cartridge increases the duration of local anesthesia (LA), decreases the risk of toxicity, and provides hemostasis. However, the unfavorable effects are increasing heart rate (HR) and raising blood pressure (BP). The aim was to evaluate hemodynamic changes in the BP, HR, and oxygen saturation (SpO2) of normal patients undergoing tooth extraction using LA with various epinephrine concentrations. MATERIAL AND METHODS: A prospective randomized clinical trial was conducted on 120 patients who were divided randomly into 3 parallel groups according to the LA received. Group 1: lidocaine 2% with epinephrine 1:80,000 (L80). Group 2: articaine 4% with epinephrine 1:100,000 (A100). Group 3: articaine 4% with epinephrine 1:200,000 (A200). INCLUSION CRITERIA: normal patients whose BP < 140/90. EXCLUSION CRITERIA: hypertension, cardiovascular disease, hyperthyroidism, pregnancy, and allergy to LA. BP, HR, and (SpO2) were evaluated in 3 different time points: 3 minutes before LA, 3 minutes after LA, and 3 minutes after extraction. RESULTS: Systolic blood pressure (SBP) significantly increased after injection of L80 and continued after extraction to be significant than pre-injection. SBP significantly increased after injection of A100 then decreased after extraction. In the group of A200, SBP insignificantly decreased after injection then increased after extraction. The increasing of SBP between time point 1and 2 was significantly higher in G1 than G3 (p=0.014). Diastolic blood pressure decreased after LA in the 3 groups; however it was significant only with L80, then increased after extraction for all. CONCLUSIONS: The changings of DBP, HR and SpO2 after anesthesia and extraction showed no significant difference among the three groups. However, A200 had significant lesser effect on SBP than L80 and the least effect on other parameters. Therefore, A200 is considered safer than L80 and A100 and is recommended for LA before teeth extraction in normal patient. KEY WORDS: Local anesthesia, lidocaine, epinephrine 1:80,000, articaine, epinephrine 1:100,000, epinephrine 1:200,000, tooth extraction. PMID- 26535093 TI - Role of serum interleukin-6 in deciding therapy for multidrug resistant oral lichen planus. AB - BACKGROUND: Oral lichen planus (OLP) is a T cell mediated immune response. T cells locally present in the involved tissues release cytokines like interleukin 6 (IL-6), which contributes to pathogenesis of OLP. Also IL-6 has been associated with multidrug resistance protein (MRP) expression by keratinocytes. Correspondingly, upregulation of MRP was found in OLP. We conducted this study to evaluate the effects of various drugs on serum IL-6 in OLP; and correlation of these effects with the nature of clinical response and resistance pattern seen in OLP lesions with various therapeutic modalities. Thus we evaluated the role of serum IL-6 in deciding therapy for multidrug resistant OLP. MATERIAL AND METHODS: Serum IL-6 was evaluated in 42 erosive OLP (EOLP) patients and 10 normal mucosa and 10 oral squamous cell carcinoma cases using ELISA technique. OLP patients were randomly divided into 3 groups of 14 patients each and were subjected to Pimecrolimus local application, oral Mycophenolate Mofetil (MMF) and Methotrexate (MTX) alongwith Pimecrolimus local application. IL-6 levels were evaluated before and after treatment. RESULTS: Serum IL-6 levels were raised above 3pg/ml in 26.19% erosive OLP (EOLP) cases (mean- 3.72+/-8.14). EOLP (5%) cases with IL-6 levels above 5pg/ml were resistant in MTX group. However significant decrease in serum IL-6 corresponding with the clinical resolution was seen in MMF group. CONCLUSIONS: Significantly raised IL-6 levels in EOLP reflect the chronic inflammatory nature of the disease. As serum IL-6 levels significantly decreased in MMF group, correspondingly no resistance to treatment was noted. However with MTX there was no significant decrease in IL-6 and resistance to treatment was noted in some, especially plaque type lesions. Thus IL-6 can be a possible biomarker in deciding the best possible therapy for treatment resistant OLP. KEY WORDS: Lichen planus, biological markers, cytokines, enzyme-linked immunosorbent assay, immunosuppressive agents. PMID- 26535094 TI - Effect of platform switching on the peri-implant bone: A finite element study. AB - BACKGROUND: There exists a relation between the presence and location of the micro-gap and the loss of peri implant bone. Several authors have shown that the treatments based on the use of platform switching result in less peri-implant bone loss and an increased tissue stability. The purpose of this study was to analyse the effect of the platform switching on the distribution of stresses on the peri-implant bone using the finite element method. MATERIAL AND METHODS: A realistic 3D full-mandible finite element model representing cortical bone and trabecular bone was used to study the distribution of the stress on the bone induced by an implant of diameter 4.1 mm. Two abutments were modelled. The first one, of diameter 4.1 mm, was used in the reference model to represent a conventional implant. The second one, of diameter 3.2 mm, was used to represent the implant with platform switching. Both models were subjected to axial and oblique masticatory loads. RESULTS: The analyses showed that, although no relevant differences can be found for the trabecular bone, the use of platform switching reduces the maximum stress level in the cortical bone by almost 36% with axial loads and by 40% with oblique loads. CONCLUSIONS: The full 3D Finite Element model, that can be used to investigate the influence of other parameters (implant diameter, connexion type, ...) on the biomechanical behaviour of the implant, showed that this stress reduction can be a biomechanical reasons to explain why the platform switching seems to reduce or eliminate crestal bone resorption after the prosthetic restoration. KEY WORDS: Dental implant, platform switching, finite element method. PMID- 26535095 TI - Comparison of the clinical effects of white brand toothbrushes versus Vitis Suave(r). AB - BACKGROUND: There has been an increase in the use of white label manual toothbrushes and a greater increase in inquiries for discomfort of the gingiva and mucosa. MATERIAL AND METHODS: A randomized, double-blind, cross-over clinical trial was made of four white brand toothbrushes versus a control brush (Vitis Suave(r)), with the recording of plaque index, bleeding upon probing, and gingival abrasions following utilization of the different brushes. RESULTS: All the brushes except Deliplus(r) were equally effective in terms of plaque removal (p<0.05). Vitis Suave(r) and Veckia(r) were the brushes associated to the greatest increase in minor abrasions (p<0.01), while Veckia(r), Carrefour(r) and Deluxe(r) significantly increased the number of medium intensity abrasions (p<0.05). These brushes also increased the number of large abrasions, though statistical significance was not reached in this case. CONCLUSIONS: The white brand brushes proved effective in controlling bacterial plaque, but were associated to more intense soft tissue abrasion. KEY WORDS: Gingival abrasions, manual tooth brushing, white brand, clinical effects. PMID- 26535096 TI - Comparative characterization of a novel cad-cam polymer-infiltrated-ceramic network. AB - BACKGROUND: The field of dental ceramics for CAD-CAM is enriched with a new innovative material composition having a porous three-dimensional structure of feldspathic ceramic infiltrated with acrylic resins.The aim of this study is to determine the mechanical properties of Polymer-Infiltrated-Ceramic-Network (PICN) and compare its performance with other ceramics and a nano-ceramic resin available for CAD-CAM systems. MATERIAL AND METHODS: In this study a total of five different materials for CAD-CAM were investigated. A polymer-infiltrated ceramic (Vita Enamic), a nano-ceramic resin (Lava Ultimate), a feldspathic ceramic (Mark II), a lithium disilicate ceramic (IPS-e max CAD) and finally a Leucite based ceramic (Empress - CAD). From CAD-CAM blocks, 120 bars (30 for each material cited above) were cut to measure the flexural strength with a three point-bending test. Strain at failure, fracture stress and Weibull modulus was calculated. Vickers hardness of each material was also measured. RESULTS: IPS EMAX presents mechanical properties significantly better from the other materials studied. Its strain at failure, flexural strength and hardness exhibited significantly higher values in comparison with the others. VITA ENAMIC and LAVA ULTIMATE stand out as the next most resistant materials. CONCLUSIONS: The flexural strength, elastic modulus similar to a tooth as well as having less hardness than ceramics make PICN materials an option to consider as a restorative material. KEY WORDS: Ceramic infiltrated with resin, CAD-CAM, Weibull modulus, flexural strength, micro hardness. PMID- 26535097 TI - Salivary gland dysfunction markers in type 2 diabetes mellitus patients. AB - BACKGROUND: Diabetes mellitus (DM) is a chronic disease of the carbohydrate metabolism that, when not rigorously controlled, compromises systemic and organ integrity, thereby causing renal diseases, blindness, neuropathy, arteriosclerosis, infections, and glandular dysfunction, including the salivary glands. The aim of this study was to determine the relationship between the qualitative and quantitative parameters of salivary alteration, which are indicators of salivary gland dysfunction, and the level of metabolic control of type 2 diabetes patients. MATERIAL AND METHODS: A convenience sample of 74 voluntary patients with type 2 DM was selected, each of whom donated a sample of unstimulated saliva. Salivary parameters such as salivary flow rate, protein concentration, pH, and xerostomia were studied. RESULTS: There is a positive relationship between the level of metabolic control measured with HbA1 and the protein concentration in saliva (Spearman rho = 0.329 and p = 0.004). The same assay showed an inverse correlation between HbA1 and pH (Spearman rho = -0.225 and p = 0.05). CONCLUSIONS: The protein concentration in saliva and, to a lesser extent, the pH may be useful as glandular dysfunction indicators in DM2 patients. KEY WORDS: Saliva, type 2 diabetes mellitus, pH, protein concentration, xerostomia. PMID- 26535098 TI - Effects of acids used in the microabrasion technique: Microhardness and confocal microscopy analysis. AB - BACKGROUND: This study evaluated the effects of the acids used in the microabrasion on enamel. MATERIAL AND METHODS: Seventy enamel/dentine blocks (25 mm2) of bovine incisors were divided into 7 groups (n=10). Experimental groups were treated by active/passive application of 35% H3PO4 (E1/E2) or 6.6% HCl (E3/E4). Control groups were treated by microabrasion with H3PO4+pumice (C5), HCl+silica (C6), or no treatment (C7). The superficial (SMH) and cross-sectional (CSMH; depths of 10, 25, 50, and 75 um) microhardness of enamel were analyzed. Morphology was evaluated by confocal laser-scanning microscopy (CLSM). Data were analyzed by analysis of variance (Proc Mixed), Tukey, and Dunnet tests (alpha=5%). RESULTS: Active application (E1 and E3) resulted in higher microhardness than passive application (E2 and E4), with no difference between acids. For most groups, the CSMH decreased as the depth increased. All experimental groups and negative controls (C5 and C6) showed significantly reduced CSMH values compared to the control. A significantly higher mean CSMH result was obtained with the active application of H3PO4 (E1) compared to HCl (E3). Passive application did not result in CSMH differences between acids. CLSM revealed the conditioning pattern for each group. CONCLUSIONS: Although the acids displayed an erosive action, use of microabrasive mixture led to less damage to the enamel layers. KEY WORDS: Enamel microabrasion, enamel microhardness, confocal laser scanning microscopy. PMID- 26535099 TI - Cartridge syringe vs computer controlled local anesthetic delivery system: Pain related behaviour over two sequential visits - a randomized controlled trial. AB - BACKGROUND: Local anesthetic injection is one of the most anxiety provoking procedure in dentistry. Knowledge about change in pain related behaviour during consecutive visits helps in and scheduling of treatment procedures and management of children in dental clinic. AIM: To compare the pain perception, behavioural response and the associated change in physiological parameters while receiving local anesthesia injection with cartridge syringe and computer controlled local anesthetic delivery system (CCLAD) over two consecutive visits. MATERIAL AND METHODS: In this randomized controlled cross over trial, 120 children aged 7 - 11 years were randomly divided into group A: receiving injections with CCLAD during first visit; group B: receiving injections with cartridge syringe during first visit. The physiological parameters (heart rate and blood pressure) were recorded before and during injection procedure. Objective evaluation of disruptive behaviour and subjective evaluation of pain perceived were done using Face Legs Activity Cry Consolability (FLACC) scale and modified facial image scale (FIS) respectively. RESULTS: No statistical difference in pain response (p= 0.164) and disruptive behaviour (p = 0.120) between cartridge syringe and CCLAD injections were seen during the first visit although the latter showed lesser scores. However, during the second visit there were significant increase in pain response (p = 0.004) and disruptive behaviour (p = 0.006) in cartridge syringe group with an associated increase in heart rate. CONCLUSIONS: Injections with CCLAD produced lesser pain ratings and disruptive behaviour than cartridge syringe in children irrespective of order of visit. KEY WORDS: Behaviour, cartridge syringe, CCLAD, local anesthesia. PMID- 26535100 TI - Evaluation of bond strength of orthodontic brackets without enamel etching. AB - BACKGROUND: To compare the shear bond strength of brackets with and without enamel etching. MATERIAL AND METHODS: In this study, 60 sound premolars were randomly divided into four different groups: 1- TXE group: Enamel etching+Transbond XT adhesive+ Transbond XT composite. 2- TXS group: Transbond plus self-etch adhesive+ Transbond XT composite. 3- PQ1E group: Enamel etching+ PQ1 adhesive+ Transbond XT composite. 4- PQ1 group: PQ1 adhesive+ Transbond XT composite. The shear bond strengths of brackets were evaluated using universal testing machine at cross head speed of 0.5 mm/min. The Adhesive Remnant Index (ARI) was also measured. One-way ANOVA, Tukey's post hoc, Kruskal-wallis and Mann Witney U test were used for data analysis. RESULTS: There was a significant difference between etched and unetched groups respect to SBS and ARI (p<0.05), however; no significant difference was observed between unetched group and self etch adhesive group (p>> 0.05). The shear bond strength of PQ1 group was the least but in acceptable range and its ARI was less than other groups. CONCLUSIONS: PQ1 adhesive can be used for bracket bonding without enamel etching with adequate bond strength and minimal ARI. KEY WORDS: Bracket, shear bond strength, filled-adhesive, self-etch adhesive. PMID- 26535101 TI - Evaluation of the efficacy of low-level laser in improving the symptoms of burning mouth syndrome. AB - BACKGROUND: Burning mouth syndrome (BMS) is common conditions that affects menopause women, patients suffer from sever burning sensation. Up to now there is no definitive treatment for this disease. Present study was undertaken to evaluate the efficacy of low-level laser (LLL) in improving the symptoms of burning mouth syndrome. MATERIAL AND METHODS: Twenty patients with BMS were enrolled in this study; they were divided in two groups randomly. In the laser group, in each patient, 10 areas on the oral mucosa were selected and underwent LLL irradiation at a wavelength of 630 nm, and a power of 30 mW for 10 seconds twice a week for 4 weeks. In the placebo group, silent/off laser therapy was carried out during the same period in the same areas. Burning sensation and quality of life were evaluated. RESULTS: Burning sensation severity and quality of life in the two groups after intervention were different significant statistically, (p= 0.004, p= 0.01 respectively) .Patients in laser group had better results. CONCLUSIONS: It can be concluded that low level laser might decrease the intensity of burning mouth syndrome. KEY WORDS: Pain, low-level laser, burning mouth syndrome, oral mucosa. PMID- 26535102 TI - Apixaban and oral implications. AB - BACKGROUND: Thrombotic disorders remain a leading cause of death in the Western world, and in this regard a number of anticoagulation treatment have been used, including heparins, fondaparinux, vitamin K antagonists (warfarin, acenocoumarol), and new oral anticoagulants such as apixaban. For years there has been great controversy regarding the use of anticoagulants in planning dental treatments that imply bleeding. The main concerns about using new oral anticoagulants in invasive dental procedures are bleeding due to the lack of an antidote, and the thrombotic risk of the disease for which anticoagulation was indicated in the first place. MATERIAL AND METHODS: A literature search was conducted through May 2014 using the keyword "apixaban" for publications in the ISI Web of Knowledge. The search was extended to other databases (PubMed, Scopus and the Cochrane Library). RESULTS: Based on the results of the different studies, apixaban seems to be a good alternative to conventional anticoagulation and a reasonable treatment option, though its main and most common adverse effect is bleeding. Dose adjustment is needed in some patients, though regular laboratory monitoring is not required. The use of the drug in different patient populations will define its final indications and doses. CONCLUSIONS: Regarding the use of apixaban in the dental setting, there is a compelling need for further clinical studies in order to establish more evidence-based guidelines for patients requiring antithrombotic treatment. KEY WORDS: Apixaban, dental treatment, dental implications. PMID- 26535103 TI - Post endodontic Aspergillosis in an immunocompetent individual. AB - Non-invasive aspergillosis in immunocompetent individuals subsequent to post endodontic treatment can involve the maxillary antrum. An early and accurate diagnosis will aid in prompt and effective treatment. A 35 year old female patient reported with a painful nasomaxillary swelling. Previous records revealed the failure of the endodontic treatment of maxillary left second premolar which was subsequently extracted. Root piece was accidently left behind which resulted in a painful nasomaxillary swelling. The extraction socket was curetted and tissue was sent for histopathological examination, which revealed abundant septate fungal hyphae with numerous spores characteristic of Aspergillus. The patient showed marked improvement in the symptoms with systemic itraconazole at 3 months follow up and complete resolution occurred within 6 months. Inclusion of aspergilloma infections in the differential diagnosis is advocated when patients present with post-endodontic nasomaxillary swelling. KEY WORDS: Aspergillosis, fungal sinusitis, post root canal treatment. PMID- 26535104 TI - Salivary gland choristoma in the buccinator muscle: A case report and literature review. AB - Salivary gland choristoma (SGCh) is defined as the presence of normal salivary tissue in an abnormal location. It is a rare entity in oral and maxillofacial region and its ethiology is unknown. The typical presentation of salivary gland heterotopia is an asymptomatic mass that may or may not produce saliva. Some examples of ectopic salivary tissue in the pituitary gland, in the lymph nodes, in the middle ear, in the neck, in the jaw, in the thyroid gland, in the mediastinum and in the rectum have been documented in literature. We report the case of a 61-year-old male presented with a bilateral tumorlike mass in the cheek. The mass was painless, of fibrous consistency and had size change with time. The histological diagnosis was salivary gland choristoma in the buccinator muscle. In this article, we will revise the characteristic of salivary gland heterotopias and we present a report case that has not been described in literature: a bilateral choristoma of salivary gland in the buccinator muscle, which should be included in the differential diagnosis of head and neck masses. KEY WORDS: Choristoma, heterotopias, ectopic tissue, salivary gland, buccinator muscle. PMID- 26535105 TI - Chronic neuropathic facial pain after intense pulsed light hair removal. Clinical features and pharmacological management. AB - Intense Pulsed Light (IPL) photodepilation is usually performed as a hair removal method. The treatment is recommended to be indicated by a physician, depending on each patient and on its characteristics. However, the use of laser devices by medical laypersons is frequent and it can suppose a risk of damage for the patients. Most side effects associated to IPL photodepilation are transient, minimal and disappear without sequelae. However, permanent side effects can occur. Some of the complications are laser related but many of them are caused by an operator error or mismanagement. In this work, we report a clinical case of a patient that developed a chronic neuropathic facial pain following IPL hair removal for unwanted hair in the upper lip. The specific diagnosis was painful post-traumatic trigeminal neuropathy, reference 13.1.2.3 according to the International Headache Society (IHS). KEY WORDS: Neuropathic facial pain, photodepilation, intense pulse light. PMID- 26535106 TI - Fluorescence-guided bone resection by using Visually Enhanced Lesion Scope in diffuse chronic sclerosingosteomyelitis of the mandible: Clinical and pathological evaluation. AB - Diffuse chronic sclerosingosteomyelitis (DCSO) is a refractory disease, becausethe etiology and pathogenesis remain poorly understood and to determine the border betweenunhealthy boneandhealthybone is difficult. However, progressive inflammation, clinical symptoms and a high recurrence rate of DCSO were the reasons for surgical treatment. We report a case of a 66-year old woman with DCSO of the right side of mandible who was treated with hemimandibulectomy and simultaneous reconstruction by vascularized free fibula flap. After preoperative administration of minocycline for 1 month, the bone fluorescence was successfully monitored by using a Visually Enhanced Lesion Scope (VELscope(r)). Intraoperatively, we could determine the resection boundaries. We investigated the clinical and histopathological findings. The fluorescence findings were well correlated with histopathological findings. Using a VELscope(r)was handy and useful to determine the border between DCSO lesion andhealthybone.The free fibula flap under the minocycline-derived bone fluorescence by using a VELscope(r)offered a good quality of mandibular bone and the successful management of an advanced and refractory DCSO. KEY WORDS: Fluorescence-guided bone resection, fibular free flap, osteomyelitis of the mandible, diffuse chronicosteomyelitis, VELscope(r). PMID- 26535107 TI - Coil Embolization of Intracranial Aneurysms: A Six-Month Follow-Up Study. AB - BACKGROUND: Rupture of the intracranial aneurysms is associated with a high risk of bleeding and a high incidence of mortality if left untreated. OBJECTIVES: The aim of this study is to report our experience in managing intracranial aneurysms using coil embolization and to report the 6-month follow-up outcome of the patients. PATIENTS AND METHODS: From January 2010 to December 2012, a series of 90 nonrandomized consecutive patients (mean age: 44.6 +/- 14.9 years) with intracranial aneurysms underwent endovascular coil embolization in our center. We excluded patients with dissecting, blood blister-like, or false aneurysms. All patients were evaluated by four-vessel angiography to determine the shape, size, number and location of the aneurysms. We recommended a six-month follow-up control angiography. However, only 38 of them participated in this follow-up imaging. The data were analyzed by chi-square, fisher exact and t-tests and alpha was considered lower than 5%. RESULTS: Immediately after the procedure, the total occlusion was seen in 76 (86.4%), subtotal occlusion in six (6.8%), and partial occlusion in six patients (6.8%). There was no significant relationship between the aneurysm size, aneurysm neck size, and location of the aneurysm with total or subtotal occlusions. Eleven patients (12.5%) experienced some complication during the procedure including two tears, three focal neurological signs, three vision disturbances, and three bleedings in the aneurysm. Major complications were significantly higher in the posterior aneurysm compared to the anterior ones (55.6% versus 44.4% of the major complications; P value = 0.015). Among patients who underwent control angiography, 34 patients (89.4%) had no change, two (5.3%) had new growth and two (5.3%) had widening of the neck after 6 months follow-up. Although aneurysms that remained unchanged after six months follow-up angiography had total occlusion after the procedure, it was 50% for aneurysms that had any changes in 6 months follow-up angiography (P value = 0.01). CONCLUSION: Coil embolization showed successful outcomes in the treatment of intracranial aneurysms with a low complication rate. PMID- 26535109 TI - Detecting miRNA Mentions and Relations in Biomedical Literature. AB - INTRODUCTION: MicroRNAs (miRNAs) have demonstrated their potential as post transcriptional gene expression regulators, participating in a wide spectrum of regulatory events such as apoptosis, differentiation, and stress response. Apart from the role of miRNAs in normal physiology, their dysregulation is implicated in a vast array of diseases. Dissection of miRNA-related associations are valuable for contemplating their mechanism in diseases, leading to the discovery of novel miRNAs for disease prognosis, diagnosis, and therapy. MOTIVATION: Apart from databases and prediction tools, miRNA-related information is largely available as unstructured text. Manual retrieval of these associations can be labor-intensive due to steadily growing number of publications. Despite the fact that several databases host miRNA-associations derived from text, lower sensitivity has motivated the need for an improvised framework. Additionally, the lack of a standard corpus for miRNA-relations has caused difficulty in evaluating the available systems. We propose methods to automatically extract mentions of miRNAs, species, genes/proteins, disease, and relations from scientific literature. Our generated corpora, along with dictionaries, and miRNA regular expression are freely available for academic purposes. To our knowledge, these resources are the most comprehensive developed so far. RESULTS: The identification of specific miRNA mentions reaches a recall of 0.94 and precision of 0.93. Extraction of miRNA-disease and miRNA-gene relations lead to an F 1 score of up to 0.76. A comparison of the information extracted by our approach to the databases miR2Disease and miRSel for the extraction of Alzheimer's disease related relations shows the capability of our proposed methods in identifying correct relations with improved sensitivity. The published resources and described methods can help the researchers for maximal retrieval of miRNA relations and generation of miRNA-regulatory networks. AVAILABILITY: The training and test corpora, annotation guidelines, developed dictionaries, and supplementary files are available at http://www.scai.fraunhofer.de/mirna corpora.html. PMID- 26535108 TI - Sex differences in Sjogren's syndrome: a comprehensive review of immune mechanisms. AB - Autoimmune diseases (ADs) are estimated to affect between 5 and 8 % of the US population, and approximately 80 % of these patients are women. Sjogren's syndrome (SS) is an AD that occurs predominately in women over men (16:1). The hallmark characteristic of SS is diminished secretory production from the primary exocrine gland and the lacrimal or salivary glands resulting in symptoms of dry eye and mouth. The disease is believed to be mediated by an inflammatory and autoantibody response directed against salivary and lacrimal gland tissues. This review will examine the literature on sex differences in the immune response of patients and animal models of Sjogren's syndrome in order to gain a better understanding of disease pathogenesis. PMID- 26535110 TI - Effect of environmental and cultural conditions in medium pH and plant growth performance of Douglas-fir ( Pseudotsuga menziesii) shoot culture. AB - The medium pH level of plant tissue culture has been shown to be essential to many aspects of explant development and growth. Sensitivity or tolerance of medium pH change in vitro varies accordingly to specific requirements of individual species. The objectives of this study are to 1) determine medium pH change over time in storage conditions and with presence of explants, 2) evaluate the effects of medium pH change and explant growth performance and 3) assess the effects of adding a pH stabilizer, 2-(N-morpholino)ethanesulfonic acid (MES) to Douglas-fir micropropagation medium. Spring buds, collected before breaking dormancy from juvenile and mature donor trees were utilized for these evaluations. Medium with or without MES, each at five medium pH levels was pre adjusted before adding MES, agar and autoclaving. Medium pH changes and explant growth parameters were measured at eight different incubation times. In general, medium with MES provided a more stable medium pH compared to pre-adjusted pH values under two storage conditions as well as with presence of explants over time. A general trend of decreasing medium pH over time was found comparing explants from juvenile and mature donor genotypes. Explant height and weight growth increased over time, but differ among explants from juvenile and mature donor genotypes. MES may help to maintain stable medium pH for bulk medium preparation. Our findings suggested a 21-day subculture practice may facilitate to sustain medium freshness, medium pH level and desirable explant growth. PMID- 26535111 TI - AGA: Interactive pipeline for reproducible gene expression and DNA methylation data analyses. AB - Automated Genomics Analysis (AGA) is an interactive program to analyze high throughput genomic data sets on a variety of platforms. An easy to use, point and click, guided pipeline is implemented to combine, define, and compare datasets, and customize their outputs. In contrast to other automated programs, AGA enables flexible selection of sample groups for comparison from complex sample annotations. Batch correction techniques are also included to further enable the combination of datasets from diverse studies in this comparison. AGA also allows users to save plots, tables and data, and log files containing key portions of the R script run for reproducible analyses. The link between the interface and R supports collaborative research, enabling advanced R users to extend preliminary analyses generated from bioinformatics novices. PMID- 26309728 TI - Non-invasive imaging to monitor lupus nephritis and neuropsychiatric systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect multiple different organs, including the kidneys and central nervous system (CNS). Conventional radiological examinations in SLE patients include volumetric/ anatomical computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound (US). The utility of these modalities is limited, however, due to the complexity of the disease. Furthermore, standard CT and MRI contrast agents are contraindicated in patients with renal impairment. Various radiologic methods are currently being developed to improve disease characterization in patients with SLE beyond simple anatomical endpoints. Physiological non-contrast MRI protocols have been developed to assess tissue oxygenation, glomerular filtration, renal perfusion, interstitial diffusion, and inflammation-driven fibrosis in lupus nephritis (LN) patients. For neurological symptoms, vessel size imaging (VSI, an MRI approach utilizing T2-relaxing iron oxide nanoparticles) has shown promise as a diagnostic tool. Molecular imaging probes (mostly for MRI and nuclear medicine imaging) have also been developed for diagnosing SLE with high sensitivity, and for monitoring disease activity. This paper reviews the challenges in evaluating disease activity in patients with LN and neuropsychiatric systemic lupus erythematosus (NPSLE). We describe novel MRI and positron-emission tomography (PET) molecular imaging protocols using targeted iron oxide nanoparticles and radioactive ligands, respectively, for detection of SLE-associated inflammation. PMID- 26535113 TI - Case Report: A case report highlighting bilateral EDB wasting as a clinical marker for lumbar canal stenosis. AB - Herein we discuss a case of a 55 year old male presenting with history suggestive of sciatica on the left leg. Straight leg raising (SLR) test was positive at 45 degrees on the left side. His ankle reflex was absent and the power of extensor hallusus longus (EHL) was 4/5 on the same side. MRI lumbosacral spine revealed left paramedian disc prolapsed on L4/L5 level with spinal canal diameter of 9mm.However since his bilateral extensor digitorm brevis (EDB) were wasted, we suspected associated lumbar canal stenosis and thereby opted for laminectomy and discectomy in this case. Intraoperatively dural wasting, hypertrophied facets and narrow canal were confirmed. Laminectomy, medial facectectomy and discectomy were carried out. The patient recovered uneventfully with resolution of his sciatica like pain. Bilateral EDB wasting thereby provides a clinical clue to the underlying lumbar canal stenosis and can help in making correct therapeutic decisions. PMID- 26535114 TI - The khmer software package: enabling efficient nucleotide sequence analysis. AB - The khmer package is a freely available software library for working efficiently with fixed length DNA words, or k-mers. khmer provides implementations of a probabilistic k-mer counting data structure, a compressible De Bruijn graph representation, De Bruijn graph partitioning, and digital normalization. khmer is implemented in C++ and Python, and is freely available under the BSD license at https://github.com/dib-lab/khmer/. PMID- 26535115 TI - Case Report: Compound heterozygous nonsense mutations in TRMT10A are associated with microcephaly, delayed development, and periventricular white matter hyperintensities. AB - Microcephaly is a fairly common feature observed in children with delayed development, defined as head circumference less than 2 standard deviations below the mean for age and gender. It may be the result of an acquired insult to the brain, such prenatal or perinatal brain injury (congenital infection or hypoxic ischemic encephalopathy), or be a part of a genetic syndrome. There are over 1000 conditions listed in OMIM (Online Mendelian Inheritance in Man) where microcephaly is a key finding; many of these are associated with specific somatic features and non-CNS anomalies. The term primary microcephaly is used when microcephaly and delayed development are the primary features, and they are not part of another recognized syndrome. In this case report, we present the clinical features of siblings (brother and sister) with primary microcephaly and delayed development, and subtle dysmorphic features. Both children had brain MRI studies that showed periventricular and subcortical T2/FLAIR hyperintensities, without signs of white matter volume loss, and no parenchymal calcifications by CT scan. The family was enrolled in a research study for whole exome sequencing of probands and parents. Analysis of variants determined that the children were compound heterozygotes for nonsense mutations, c.277C>T (p.Arg93*) and c.397C>T (p.Arg133*), in the TRMT10A gene. Mutations in this gene have only recently been reported in children with microcephaly and early onset diabetes mellitus. Our report adds to current knowledge of TRMT10A related neurodevelopmental disorders and demonstrates imaging findings suggestive of delayed or abnormal myelination of the white matter in this disorder. Accurate diagnosis through genomic testing, as in the children described here, allows for early detection and management of medical complications, such as diabetes mellitus. PMID- 26535116 TI - The association between Parkinson's disease and melanoma: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the association between Parkinson's disease (PD) and melanoma via systematic review and meta-analysis. METHODS: Comprehensive search in PubMed, Web of Science, Embase and four China databases (SinoMed, WanFang data, CNKI and VIP database) of epidemiologic evidences on PD and melanoma published before April 30, 2015. Studies which reported risk estimates of melanoma among PD patients or risk estimates of PD in patients with melanoma were included. Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated by random-effects models. Heterogeneity across studies was assessed using Cochran Q and I(2) statistics. Subgroup analyses and sensitivity analyses were conducted to evaluate sources of heterogeneity. Subgroup analyses were done according to temporal relationship, geographic region and gender respectively. We assessed publication bias using the Begg and Egger test. In addition, study appraisal was done using a scale for observational studies to ensure the quality of evidence. RESULTS: We identified 24 eligible studies on PD and melanoma with a total number of 292,275 PD patients: the pooled OR was 1.83 (95 % CI 1.46-2.30) overall, subgroup analyses by temporal relationship showed that risk of melanoma after PD diagnosis was significantly higher (OR 2.43, 95 % CI 1.77-3.32), but not before the diagnosis of PD (OR 1.09, 95 % CI 0.78-1.54). Subgroup analysis by geographic region showed that increased risk of melanoma in PD was found both in Europe (OR 1.44, 95 % CI 1.22-1.70) and in North America (OR 2.64, 95 % CI 1.63 4.28). Gender-specific subgroup analyses did not show difference between men (OR 1.64, 95 % CI 1.27-2.13) and women (OR 1.38, 95 % CI 1.04-1.82) in the risk of melanoma. In addition, we found the risk of non-melanoma skin cancers in PD was slightly higher (OR 1.20, 95 % CI 1.11-1.29) than general population. It was impossible to evaluate the association between PD and melanoma according to use of levodopa or gene polymorphism via meta-analysis since few observational or cohort studies have focused on it. CONCLUSIONS: An association between PD and melanoma was confirmed. Most of the evidences were of high quality, and the conclusion was robust. Further research is needed to explore the mechanisms underlying this relationship. PMID- 26535117 TI - Association between inflammatory airway disease of horses and exposure to respiratory viruses: a case control study. AB - BACKGROUND: Inflammatory airway disease (IAD) in horses, similar to asthma in humans, is a common cause of chronic poor respiratory health and exercise intolerance due to airway inflammation and exaggerated airway constrictive responses. Human rhinovirus is an important trigger for the development of asthma; a similar role for viral respiratory disease in equine IAD has not been established yet. METHODS: In a case-control study, horses with IAD (n = 24) were compared to control animals from comparable stabling environments (n = 14). Horses were classified using pulmonary function testing and bronchoalveolar lavage. PCR for equine rhinitis virus A and B (ERAV, ERBV), influenza virus (EIV), and herpesviruses 2, 4, and 5 (EHV-2, EHV-4, EHV-5) was performed on nasal swab, buffy coat from whole blood, and cells from BAL fluid (BALF), and serology were performed. Categorical variables were compared between IAD and control using Fisher's exact test; continuous variables were compared with an independent t test. For all analyses, a value of P <0.05 was considered significant. RESULTS: There was a significant association between diagnosis of IAD and history of cough (P = 0.001) and exercise intolerance (P = 0.003) but not between nasal discharge and IAD. Horses with IAD were significantly more likely to have a positive titer to ERAV (68 %) vs. control horses (32 %). Horses with IAD had higher log transformed titers to ERAV than did controls (2.28 +/- 0.18 v.1.50 +/- 0.25, P = 0.038). There was a significant association between nasal shedding (positive PCR) of EHV-2 and diagnosis of IAD (P = 0.002). CONCLUSIONS: IAD remains a persistent problem in the equine population and has strong similarities to the human disease, asthma, for which viral infection is an important trigger. The association between viral respiratory infection and development or exacerbation of IAD in this study suggests that viral infection may contribute to IAD susceptibility; there is, therefore, merit in further investigation into the relationship between respiratory virus exposure and development of IAD. PMID- 26535118 TI - The genetic epidemiology of diverticulosis and diverticular disease: Emerging evidence. AB - Diverticular disease (DD) is one of the most prevalent gastrointestinal disorders. The pathogenesis of diverticulosis and DD is controversially discussed. Current studies call the traditional concept of a fibre-deficient diet causing the development of diverticula into question. Data from two recent twin studies have provided conclusive evidence for a strong genetic component to diverticulosis. Although genomewide association studies have provided new insights into the polygenic architecture of human diseases, genomic research in diverticulosis and DD has just been started. This is an astonishing fact given the high morbidity and mortality of the disease, as well as the substantial economic burden on health care systems. For this review, we provide an update of the molecular pathobiology and summarise recent evidence supporting the hypothesis that distinct, yet unidentified genetic variants contribute to the development of diverticulosis and DD. PMID- 26535119 TI - Biologics in inflammatory bowel disease: what are the data? AB - BACKGROUND: Over the last decade, biologics have gained an important place for the treatment of moderate to severe inflammatory bowel disease (IBD), and many randomized control trials have evaluated their efficacy. AIM: The goal of this review is to analyze the results of these trials and to highlight the evidence and indications emerging from these studies for their implementation in the management of IBD patients. METHODS: A PubMed search was realized to screen high quality clinical trials studying biologic agents currently available in clinics for the treatment of IBD. Words used were: "infliximab," "adalimumab," "certolizumab," "golimumab," "natalizumab," "vedolizumab," "ustekinumab," "azathioprine," "methotrexate," "Crohn's disease," and "ulcerative colitis." RESULTS: In Crohn's disease, studies supporting induction and maintenance therapies were documented for infliximab, adalimumab, certolizumab, natalizumab, vedolizumab, and ustekinumab. Infliximab, adalimumab, and certolizumab have evidences for fistulizing Crohn's disease and only infliximab and adalimumab have evidences for mucosal healing. In ulcerative colitis, studies supporting induction, maintenance, and mucosal healing were found with infliximab, adalimumab, golimumab, and vedolizumab. Only infliximab was associated with evidences for combination therapy with thiopurine and acute severe colitis in ulcerative colitis. CONCLUSION: Management with biologics in IBD patients is well validated by high-quality clinical trials. PMID- 26535120 TI - Diagnostic methods for H. pylori infection: Choices, opportunities and pitfalls. PMID- 26535121 TI - A combined antral and corpus rapid urease testing protocol can increase diagnostic accuracy despite a low prevalence of Helicobacter pylori infection in patients undergoing routine gastroscopy. AB - BACKGROUND: The effects of an increased risk of sampling error and the lower prevalence of Helicobacter pylori infection on the diagnostic accuracy of standard invasive tests needs to be considered. Despite evidence of enhanced yield with additional biopsies, combined Rapid Urease Tests (RUTs) have not been widely adopted. We aimed to compare the diagnostic efficacy of a combined antral and corpus rapid urease test (RUT) to a single antral RUT in a low prevalence cohort. METHODS: Between August 2013 and April 2014 adult patients undergoing a scheduled gastroscopy were prospectively recruited. At endoscopy biopsies were taken and processed for single and combined RUTs, histology and culture using standard techniques. Infection was defined by positive culture or detection of Helicobacter like organisms on either antral or corpus samples. RESULTS: In all 123 patients were recruited. H. pylori prevalence was low at 36%, n = 44. There was a significant difference in positivity between single and combined RUTs, 20% (n = 25) versus 30% (n = 37), p = 0.0094, (95% CI 0.15-0.04). The number needed to treat (NNT) for an additional diagnosis of infection using a combined versus a single RUT is 4 (95% CI 2.2-11). The only factor associated with a reduction in RUT yield was regular proton pump inhibitor (PPI) use. Overall the sensitivity, specificity, positive and negative predictive value for any RUT test was 84%, 100%, 100% and 92% respectively. CONCLUSION: Our data suggests taking routine antral and corpus biopsies in conjunction with a combined RUT appears to optimizing H. pylori detection and overcome sampling error in a low prevalence population. PMID- 26535122 TI - Occult H. pylori infection partially explains 'false-positive' results of (13)C urea breath test. AB - BACKGROUND: In a previous study, UBiT-100 mg, (Otsuka, Spain), a commercial (13)C urea breath test omitting citric acid pre-treatment, had a high rate of false positive results; however, it is possible that UBiT detected low-density 'occult' infection missed by other routine reference tests. We aimed to validate previous results in a new cohort and to rule out the possibility that false-positive UBiT were due to an 'occult' infection missed by reference tests. METHODS: Dyspeptic patients (n = 272) were prospectively enrolled and UBiT was performed, according to the manufacturer's recommendations. Helicobacter pylori infection was determined by combining culture, histology and rapid urease test results. We calculated UBiT sensitivity, specificity, positive and negative predictive values (with 95% CI). In addition, we evaluated 'occult' H. pylori infection using two previously-validated polymerase chain reaction (PCR) methods for urease A (UreA) and 16 S sequences in gastric biopsies. We included 44 patients with a false positive UBiT, and two control groups of 25 patients each, that were positive and negative for all H. pylori tests. RESULTS: UBiT showed a false-positive rate of 17%, with a specificity of 83%. All the positive controls and 12 of 44 patients (27%) with false-positive UBiT were positive for all two PCR tests; by contrast, none of our negative controls had two positive PCR tests. CONCLUSIONS: UBiT suffers from a high rate of false-positive results and sub-optimal specificity, and the protocol skipping citric acid pre-treatment should be revised; however, low-density 'occult' H. pylori infection that was undetectable by conventional tests accounted for around 25% of the 'false-positive' results. PMID- 26535123 TI - Gender differences in symptoms in partial responders to proton pump inhibitors for gastro-oesophageal reflux disease. AB - BACKGROUND: Gender differences may exist in the symptom experience of patients with gastro-oesophageal reflux disease (GERD) who have a partial response to proton pump inhibitors (PPIs). OBJECTIVE: The purpose of this study was to analyse gender differences in partial responders to PPIs. METHODS: Patients with GERD who responded partially to PPIs (n = 580; NCT00703534) completed the Reflux Symptom Questionnaire 7-day recall (RESQ-7) and the Gastrointestinal Symptom Rating Scale (GSRS). Anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale. RESULTS: Women had significantly higher RESQ-7 domain scores than men for Heartburn (frequency: 4.3 vs 3.9; intensity: 3.1 vs 2.8), Burping (frequency: 4.9 vs 4.4; intensity: 3.1 vs 2.8) and Hoarseness, cough and difficulty swallowing (frequency: 2.6 vs 2.2; intensity: 1.8 vs 1.5), and had higher GSRS domain discomfort scores than men for Abdominal pain (3.51 vs 3.23), Indigestion (3.80 vs 3.45) and Constipation (2.69 vs 2.17) (all p < 0.05). Anxiety and depression were significantly more prevalent in women than in men. CONCLUSION: In this population of partial responders, women had more frequent/intense heartburn and extra-oesophageal symptoms and more discomfort from abdominal pain, indigestion and constipation than men. Comorbid anxiety and depression may contribute to the increased symptom burden in women. PMID- 26535124 TI - A phase II study of TRC105 in patients with hepatocellular carcinoma who have progressed on sorafenib. AB - BACKGROUND: Endoglin is an endothelial cell membrane receptor essential for angiogenesis and highly expressed on the vasculature of many tumor types, including hepatocellular carcinoma (HCC). TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis, and complements VEGF inhibitors. OBJECTIVE: The aim of this phase II study was to evaluate the efficacy of anti endoglin therapy with TRC105 in patients with advanced HCC, post-sorafenib. METHODS: Patients with HCC and compensated liver function (Childs-Pugh A/B7), ECOG 0/1, were enrolled to a single-arm, phase II study of TRC105 15 mg/kg IV every two weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal two-stage design was employed with a 50% four-month PFS target for progression to the second stage. Correlative biomarkers evaluated included DCE-MRI as well as plasma levels of angiogenic biomarkers and soluble CD105. RESULTS: A total accrual of 27 patients was planned. However, because of lack of efficacy and in accordance with the Simon two-stage design, 11 patients were enrolled. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N = 3) and epistaxis (G1; N = 4). One patient had a confirmed partial response by standard RECIST criteria and biologic response on DCE-MRI but the four-month PFS was insufficient to proceed to the second stage of the study. CONCLUSIONS: TRC105 was well tolerated in this HCC population following sorafenib. Although there was evidence of clinical activity, this did not meet prespecified criteria to proceed to the second stage. TRC105 development in HCC continues as combination therapy with sorafenib. PMID- 26535125 TI - Inflammatory bowel disease-specific pregnancy knowledge of gastroenterologists against general practitioners and obstetricians. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) tend to have smaller family sizes. Health care professionals (HCPs) may inadvertently provide inaccurate advice to patients resulting in voluntary childlessness or unfavourable pregnancy outcomes. OBJECTIVE: The study aims to objectively measure IBD-specific pregnancy-related knowledge of general practitioners (GPs) and obstetricians/gynaecologists (OB/GYNs) in comparison with gastroenterologists (GEs) using the validated Crohn's and Colitis Pregnancy Knowledge (CCPKnow) questionnaire. METHODS: GPs, OB/GYNs and GEs in two Australian states completed the CCPKnow (range 0-17) and demographic questionnaires. The CCPKnow addresses issues pertaining to conception, IBD inheritance, risk of congenital abnormalities, medication use in the peri-conceptual period, pregnancy and breastfeeding, and mode of delivery. RESULTS: In total, 337 HCPs responded. GPs (n = 188/2086) and OB/GYNs (n = 94/228) had significantly lower knowledge than GEs (n = 55/165) for the composite CCPKnow (medians 11, 13 and 17, respectively, p < 0.001), and almost all domains. GEs were the only group to attain a median CCPKnow score in the top category (14-17). More than 70% of GPs and OB/GYNs expressed discomfort with initiation of IBD medications around conception/pregnancy. GPs (43.6%) and OB/GYNs (45.7%) perceived thiopurine use to be unsafe during pregnancy and to cause serious harm to the baby. CONCLUSIONS: Our study demonstrates that GPs and OB/GYNs have inadequate and variable IBD specific pregnancy-related knowledge including use of IBD medications. These results support the need for GEs' prime role in a team-based management for IBD patients who are pregnant or planning pregnancy. PMID- 26535126 TI - Efficacy and safety of naloxegol in patients with opioid-induced constipation and laxative-inadequate response. AB - BACKGROUND: Treatment options for patients with opioid-induced constipation (OIC) and inadequate response to laxatives (LIR) are few. OBJECTIVE: Assess the efficacy and safety of orally administered naloxegol in patients with prospectively confirmed OIC and LIR. METHODS: We analyzed pooled data from two identical randomized, double-blind, placebo-controlled, Phase 3 trials of naloxegol in patients with non-cancer pain, OIC and LIR in which naloxegol (12.5 mg, n = 240; 25 mg, n = 241) or placebo (n = 239) were administered daily. We assessed the response rates, time to first post-dose laxation, spontaneous bowel movements (SBMs), OIC symptoms and patient-reported outcomes over 12 weeks. RESULTS: OIC response rates for the naloxegol 25-mg (p < 0.001) and the 12.5-mg (p = 0.005) LIR dose groups were higher than placebo. Median times to first post dose SBM were 7.6, 19.2 and 41.1 hours for the naloxegol 25 mg, naloxegol 12.5 mg and placebo groups, respectively. Other SBM measures, daily symptoms of OIC, and both the Patient Assessment of Constipation - Symptoms and Patient Assessment of Constipation-Quality of Life scores improved from baseline with naloxegol treatment. Changes from baseline in opioid dose, pain scores and opioid withdrawal scores were similar among treatment groups. CONCLUSIONS: Naloxegol was efficacious, generally safe and well tolerated in the patients with OIC and LIR, while preserving opioid analgesia. ClinicalTrials.gov identifiers: NCT01309841; NCT01323790. PMID- 26535127 TI - Continuous education in gastroenterology: the present and the future. PMID- 26535128 TI - UEG LINK Award from the National Societies to HaPanEU: Harmonising the diagnosis and treatment of Pancreatitis across EUrope. PMID- 26535129 TI - UEG Week in Vienna 2016-advancing science, linking people. PMID- 26535130 TI - Erratum to: A case of B-cell acute lymphoblastic leukemia in a child with Down syndrome bearing a t(2;12)(p12;p13) involving ETV6 and biallelic IGH@ rearrangements. AB - [This corrects the article DOI: 10.1186/s40364-015-0036-1.]. PMID- 26535131 TI - Severe paraneoplastic hypoglycemia secondary to a gastrointestinal stromal tumour masquerading as a stroke. AB - We report the case of a 70-year-old previously healthy female who presented acutely to the Accident and Emergency department with left-sided vasomotor symptoms including reduced muscle tone, weakness upon walking and slurred speech. Physical examination confirmed hemiparesis with VIIth nerve palsy and profound hepatomegaly. A random glucose was low at 1.7 mmol/l, which upon correction resolved her symptoms. In hindsight, the patient recalled having had similar episodes periodically over the past 3 months to which she did not give much attention. While hospitalized, she continued having episodes of symptomatic hypoglycaemia during most nights, requiring treatment with i.v. dextrose and/or glucagon. Blood tests including insulin and C-peptide were invariably suppressed, in correlation with low glucose. A Synacthen stimulation test was normal (Cort (0') 390 nmol/l, Cort (30') 773 nmol/l). A computed tomography scan showed multiple lobulated masses in the abdomen, liver and pelvis. An ultrasound guided biopsy of one of the pelvic masses was performed. Immunohistochemistry supported the diagnosis of a gastrointestinal stromal tumour (GIST) positive for CD34 and CD117. A diagnosis of a non islet cell tumour hypoglycaemia (NICTH) secondary to an IGF2 secreting GIST was confirmed with further biochemical investigations (IGF2=96.5 nmol/l; IGF2:IGF1 ratio 18.9, ULN <10). Treatment with growth hormone resolved the patient's hypoglycaemic symptoms and subsequent targeted therapy with Imatinib was successful in controlling disease progression over an 8-year observation period. LEARNING POINTS: NICTH can be a rare complication of GISTs that may manifest with severe hypoglycaemia and neuroglucopenic symptoms.NICTH can masquerade as other pathologies thus causing diagnostic confusion.Histological confirmation of GIST induced NICTH and exclusion of other conditions causing hypoglycaemia is essential.Mutational analysis of GISTs should be carried out in all cases as it guides treatment decision.Tailored management of hypoglycaemia, in this case using growth hormone and targeted cyto-reductive therapy, minimizes the risk of possible life-threatening complications. PMID- 26535132 TI - Prevalence of chronic kidney disease among the high risk population in South Western Ghana; a cross sectional study. AB - BACKGROUND: Chronic Kidney Disease (CKD) is a major global health problem. CKD is one of the most common complications of diabetes mellitus and hypertension and carries a risk of cardiovascular morbidity and mortality and progression to end stage kidney disease. OBJECTIVES: This study sought to use the 2012 Kidney Disease Improving Global Outcomes (KDIGO) definitions to establish the prevalence and risk factors for CKD among a high risk population in the Sekondi-Takoradi metropolis. DESIGN: Cross sectional study. SETTING: Effia-Nkwanta regional and the Takoradi Government hospitals in South Western Ghana. PATIENTS: Two hundred eight consecutive adults with diabetes, hypertension or both. MEASUREMENTS: Serum creatinine and urine albumin-creatinine ratio respectively. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) was used to estimate glomerular filtration rate (GFR). METHODS: CKD was classified according to KDIGO. RESULTS: The prevalence of CKD was 30 %: 27 % in patients with diabetes, 22 % in patients with hypertension only and 74 % in patients with both diabetes and hypertension. GFR category G3a CKD was most prevalent stage (9 %). Albuminuria was highest among people with diabetes (39 %). LIMITATIONS: A convenience sample of patients attending clinics. CONCLUSION: CKD was prevalent in these high-risk patients. PMID- 26535133 TI - Trends in treatment and outcomes of ankylosing spondylitis in outpatient rheumatological care in Germany between 2000 and 2012. AB - OBJECTIVES: To describe changes in drug treatment and clinical outcomes of ankylosing spondylitis (AS) during the past decade. METHODS: The national database of the German collaborative arthritis centres collects clinical and patient-derived data from unselected outpatients with inflammatory rheumatic diseases. Cross-sectional data from 2000 to 2012 of around 1000 patients with AS per year were compared with regard to clinical presentation and quality of life indicators. RESULTS: Non-steroidal anti-inflammatory drugs (NSAIDs) have been the predominant treatment choice in AS over the years with a prescription rate of 67% of patients in 2012. Currently, almost half of the patients with AS in German rheumatology centres are treated with tumour necrosis factor inhibitors (TNFi). Often, both treatments are used in combination (33%), followed by combinations of NSAIDs and synthetic disease modifying antirheumatic drugs (sDMARDs) with 23% or TNFi alone (21%). In 2012, 10% of patients each received NSAID or sDMARD monotherapy. Methotrexate, sulfasalazine, glucocorticoids and analgaesics alone or in combination with other treatments were given to 10% of patients, respectively. Over the years, we have seen remarkable improvements in disease control and patient reported outcomes. These developments are consistent with enhanced functional status, increasing employment rates and decreasing sick leave, hospitalisation and work disability. CONCLUSIONS: In the German rheumatology secondary/tertiary care setting, routine care of patients with AS has changed tremendously during the past decade. Increasingly, more efficacious treatment options are reflected in improved clinical outcomes, quality of life and participation in the labour force. PMID- 26535134 TI - Efficacy and safety of tabalumab, an anti-BAFF monoclonal antibody, in patients with moderate-to-severe rheumatoid arthritis and inadequate response to TNF inhibitors: results of a randomised, double-blind, placebo-controlled, phase 3 study. AB - BACKGROUND: Tabalumab is a human monoclonal antibody that neutralises B-cell activating factor. OBJECTIVES: To evaluate tabalumab efficacy and safety in patients with rheumatoid arthritis (RA). METHODS: This phase 3, randomised, double-blind, placebo-controlled study evaluated 456 patients with active RA after 24-week treatment with subcutaneous tabalumab (120 mg every 4 weeks (120/Q4W) or 90 mg every 2 weeks (90/Q2W)) versus placebo, with loading doses (240 or 180 mg) at week 0. Patients were allowed background disease-modifying antirheumatic drugs and previously discontinued >=1 tumour necrosis factor alpha inhibitors for lack of efficacy/intolerance. Primary end point was American College of Rheumatology 20% (ACR20) response at 24 weeks. This study was terminated early due to futility. RESULTS: Most patients had moderate-to-high baseline disease activity. There was no significant difference in week 24 ACR20 responses between 120/Q4W, 90/Q2W, and placebo (17.6%, 24.3%, 20%) per non responder imputation analysis. Mean percent changes in CD20+ B-cell count ( 10.8%, -9.6%, +10.9%) demonstrated expected pharmacodynamic effects. Treatment emergent adverse events (AEs) were similar (59.5%, 51.7%, 52.6%), as were AE discontinuations (2.6%, 2.7%, 2.6%), serious AEs (4.6%, 4.1%, 3.9%), serious infectious events (1.3%, 0, 0) and events of interest: infections (23.5%, 25.9%, 24%), injection site reactions (13.1%, 25.8%, 11%) and allergy/hypersensitivity (3.9%, 4.1%, 3.9%) reports. Incidence of treatment-emergent antidrug antibodies was similar to placebo (3.9%, 4.8%, 3.9%). No deaths or new/unexpected safety findings were reported. CONCLUSIONS: Tabalumab did not demonstrate clinical efficacy in patients with RA in this phase 3 study, despite evidence of biological activity. There were no notable differences in safety parameters between tabalumab treatment groups and placebo. TRIAL REGISTRATION NUMBER: NCT01202773. PMID- 26535135 TI - Estimating the monetary value of the annual productivity gained in patients with early rheumatoid arthritis receiving etanercept plus methotrexate: interim results from the PRIZE study. AB - OBJECTIVE: To measure and value the impact of combined etanercept (ETN) and methotrexate (MTX) therapy on work productivity in patients with early rheumatoid arthritis (RA) over 52 weeks. METHODS: MTX- and biological-naive patients with RA (symptom onset <=12 months; Disease Activity Score based on a 28-joint count (DAS28) >3.2) received open-label ETN50/MTX for 52 weeks. The Valuation of Lost Productivity (VOLP) questionnaire, measuring paid and unpaid work productivity impacts, was completed approximately every 13 weeks. Bootstrapping methods were used to test changes in VOLP outcomes over time. One-year productivity impacts were compared between responders (DAS28 <=3.2) at week 13 and non-responders using zero-inflated models for time loss and two-part models for total costs of lost productivity. RESULTS: 196 patients were employed at baseline and had >=1 follow-up with VOLP. Compared with baseline, at week 52, patients gained 33.4 h per 3 months in paid work and 4.2 h per week in unpaid work. Total monetary productivity gains were ?1322 per 3 months. Over the 1-year period, responders gained paid (231 h) and unpaid work loss (122 h) compared with non-responders, which amounted to a gain of ?3670 for responders. CONCLUSIONS: This is the first clinical trial to measure and value the impact of biological treatment on all the labour input components that affect overall productivity. Combination therapy with ETN50/MTX was associated with a significant productivity gain for patients with early RA who were still observed at week 52. Over the 1-year treatment period, responders at week 13 suffered significantly less productivity loss than non-responders suggesting this gain was related to treatment response. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number NCT00913458. PMID- 26535136 TI - Socioeconomic inequities in perceived health among patients with musculoskeletal disorders compared with other chronic disorders: results from a cross-sectional Dutch study. AB - OBJECTIVES: To explore the impact of socioeconomic factors on physical and mental health of patients with musculoskeletal disorders (MSKDs) and compare it across patients with other disorders. METHODS: A representative sample of the Dutch population (n=8904) completed a survey on sociodemographics, physician-diagnosed (co-) morbidities, and physical (physical component summary, PCS) and mental (mental component summary, MCS) subscales of SF-12 (outcome variables). Regression models were computed first in the total group of patients with MSKDs, with education, age, gender, origin and place of residence as independent variables, and, second, in individuals expected to have paid work, adding a variable on social status. Models were repeated for five other subgroups of chronic disorders (cardiovascular (CVD), diabetes, cancer, mental and respiratory) and for healthy individuals. RESULTS: MSKDs confirmed by a physician were reported by 1766 (20%) participants (mean age 59 years, 38% male), 547 (6%) respondents reported to have diabetes, 1855 (21%) CVD, 270 (3%) cancer, 526 (6%) mental disorders, 679 (8%) respiratory disorders and 4525 (51%) did not report any disease. In patients with MSKDs, (primary school vs university education ( 5.3 (PCS) and -3.3 (MCS)) and having a state subsidy vs paid work (-5.3 (PCS) and -4.7 (MCS)) were consistently associated with worse physical and mental health. Gender was only relevant for PCS (female vs male -2.1). Comparable differences in health by education and social status were observed in the other diseases, except for cancer. CONCLUSIONS: Education and social status in MSKD have the same strong and independent association with health as in other chronic diseases. These health gradients are unfair and partly avoidable, and require consorted attention and action in and outside healthcare. PMID- 26535137 TI - Association between diabetes mellitus and osteoarthritis: systematic literature review and meta-analysis. AB - OBJECTIVES: To investigate the prevalence of osteoarthritis (OA) in patients with diabetes mellitus (DM) and prevalence of DM in patients with OA and whether OA and DM are associated. DESIGN: A systematic literature review and meta-analysis. We included cohort, case-control and cross-sectional studies assessing the number of patients with DM and/or OA. The mean prevalence of OA among patients with DM and DM among patients with OA was calculated. Data from trials assessing an association of diabetes and OA were pooled and results are presented as unadjusted OR and 95% CI. RESULTS: From the 299 publications, we included 49 studies in the analysis, including 28 cross-sectional studies, 11 cohort studies and 10 case-control studies. In all, 21, 5 and 23 articles involved patients with OA exclusively, patients with DM and the general population, respectively. For 5788 patients with DM, the mean OA prevalence was 29.5+/-1.2%. For 645 089 patients with OA, the prevalence of DM was 14.4+/-0.1%. The risk of OA was greater in the DM than non-DM population (OR=1.46 (1.08 to 1.96), p=0.01), as was DM in the OA than non-OA population (OR=1.41 (1.21 to 1.65), p<0.00 001). Among the 12 studies reporting an OR adjusted on at least the body mass index, 5 showed no association of DM and OA and 7 identified DM as an independent risk factor. CONCLUSIONS: This meta-analysis highlights a high frequency of OA in patients with DM and an association between both diseases, representing a further step towards the individualisation of DM-related OA within a metabolic OA phenotype. PMID- 26535138 TI - Longer durations of antitumour necrosis factor treatment are associated with reduced risk of cardiovascular events in patients with rheumatoid arthritis. AB - OBJECTIVE: To assess the effects of treatment with antitumour necrosis factor (TNF) agents, methotrexate, or other non-biological disease-modifying antirheumatic drugs (DMARDs) on cardiovascular event risks among patients with rheumatoid arthritis (RA). METHODS: We conducted a retrospective study using data from the MarketScan claims database. Patients with RA with >=1 prescription for an index drug were included. Each patient's use of an index drug was calculated cumulatively as a time-varying exposure. The incidence of cardiovascular events among patients with RA was determined. Associations between drug exposures and occurrence of cardiovascular events were assessed with Cox proportional hazards models. RESULTS: Of 113 677 patients identified, 35.8%, 41.1% and 23.1% received anti-TNF agents, methotrexate and other DMARDs, respectively. Patients were treated for an average of 7.6 months; 2138 patients (1.9%) had a cardiovascular event following their index prescription. Each additional 6 months of anti-TNF therapy use versus non-use reduced the risk (HR; 95% CI) for any cardiovascular event by 12% (0.88; 0.81 to 0.95, p=0.002). Anti-TNF therapy was associated with a 13% and 12% reduction in cardiovascular events in patients aged >=50 years (0.87; 0.80 to 0.95, p=0.002) and in those without prior methotrexate use (0.88; 0.78 to 0.99, p=0.04), respectively. Cumulative use of 1, 2 or 3 years of anti TNF therapy versus non-use is expected to reduce cardiovascular event risks by 21%, 38% and 51%, respectively. CONCLUSIONS: Anti-TNF therapy was associated with a significantly lower risk of cardiovascular events among patients with RA, older patients with RA and patients without prior exposure to methotrexate. PMID- 26535139 TI - Accuracy of musculoskeletal imaging for the diagnosis of polymyalgia rheumatica: systematic review. AB - OBJECTIVES: To review the evidence for accuracy of imaging for diagnosis of polymyalgia rheumatica (PMR). METHODS: Searches included MEDLINE, EMBASE and PubMed. Evaluations of diagnostic accuracy of imaging tests for PMR were eligible, excluding reports with <10 PMR cases. Two authors independently extracted study data and three authors assessed methodological quality using modified QUADAS-2 criteria. RESULTS: 26 studies of 2370 patients were evaluated: 10 ultrasound scanning studies; 6 MRI studies; 1 USS and MRI study; 7 18 fluorodeoxyglucose-positron emission tomography (PET) studies; 1 plain radiography and 1 technetium scintigraphy study. In four ultrasound studies, subacromial-subdeltoid bursitis had sensitivity 80% (95% CI 55% to 93%) and specificity 68% (95% CI 60% to 75%), whereas bilateral subacromial-subdeltoid bursitis had sensitivity 66% (95% CI 43% to 87%) and specificity 89% (95% CI 66% to 97%). Sensitivity for ultrasound detection of trochanteric bursitis ranged from 21% to 100%. In four ultrasound studies reporting both subacromial subdeltoid bursitis and glenohumeral synovitis, detection of subacromial subdeltoid bursitis was more accurate than that of glenohumeral synovitis (p=0.004). MRI and PET/CT revealed additional areas of inflammation in the spine and pelvis, including focal areas between the vertebrae and anterior to the hip joint, but the number of controls with inflammatory disease was inadequate for precise specificity estimates. CONCLUSIONS: Subacromial-subdeltoid bursitis appears to be the most helpful ultrasound feature for PMR diagnosis, but interpretation is limited by study heterogeneity and methodological issues, including variability in blinding and potential bias due to case-control study designs. Recent MRI and PET/CT case-control studies, with blinded readers, yielded promising data requiring validation within a diagnostic cohort study. PMID- 26535140 TI - Relationship between tissue stress during gait in healthy volunteers and patterns of urate deposition and bone erosion in gout: a biomechanical computational modelling study. AB - OBJECTIVES: To determine whether patterns of high internal tissue stress during gait are associated with patterns of monosodium urate crystal deposition and bone erosion in gout. METHODS: We compared patterns of foot von Mises stress predicted computationally during gait in volunteers of normal and high body mass index (BMI) with patterns of urate deposition in gout and asymptomatic hyperuricaemia, and bone erosion in gout using dual-energy and conventional CT data. RESULTS: The highest average and peak von Mises stress during gait was observed at the third metatarsal (MT) head. Similar stress patterns were observed for high and low BMI groups. In contrast, for both urate deposition and bone erosion, the first MT head was most frequently affected, with very infrequent involvement of the third MT head. There was no clear relationship between average or peak von Mises stress patterns with patterns of urate deposition or bone erosion (-0.29>r<0.16). Addition of BMI into linear regression models did not alter the findings. CONCLUSIONS: These data do not support the concept that elevated internal tissue stress during biomechanical loading plays an important role in patterns of monosodium urate crystal deposition or structural damage in gout. PMID- 26535141 TI - Time to redefine erosive osteoarthritis. PMID- 26535142 TI - Detection of clinically manifest and silent synovitis in the hands and wrists by fluorescence optical imaging. AB - OBJECTIVES: The correct identification of synovitis is critical for achieving optimal therapy results. Fluorescence optical imaging (FOI) is a novel modality based on the use of an intravenous fluorophore, which enables fluorescent imaging of the hands and wrists with increased focal optical signal intensities in areas of high perfusion and/or capillary leakage. The study objective was to determine the diagnostic utility of FOI in detecting apparent and clinically non-apparent active synovitis. METHODS: Bilateral hand and wrist joints (n=872) of 26 patients with inflammatory arthritis assessed by standard clinical examination, musculoskeletal ultrasound (MSUS) and FOI were studied. Synovitis was defined as tender and swollen joints on clinical examination, presence of synovial thickening and intra-articular Doppler signals on MSUS, and abnormal focal optical signal intensities on FOI, respectively. Subclinical synovitis was defined as being clinically non-apparent, but positively inflamed on MSUS. RESULTS: Depending on the standard used to define inflammation, FOI ranged from 73-83% sensitive and 83-95% specific for detecting manifest synovitis. For detecting clinically silent synovitis, the sensitivity, specificity and positive and negative predictive values of FOI were 80%, 96%, 77% and 97%, respectively. CONCLUSIONS: The high degree of agreement between MSUS and FOI suggest its use in clinical practice, especially when MSUS is not available, in order to identify synovitis earlier and with greater confidence. FOI may be particularly useful in identifying patients with clinically non-apparent joint inflammation of the hands and/or wrists. PMID- 26535143 TI - Diagnostic value of ultrasound in calcium pyrophosphate deposition disease: a systematic review and meta-analysis. AB - OBJECTIVE: A systematic review and meta-analysis of data from cohort studies to analyse the diagnostic performances (ie, sensitivity and specificity) of ultrasound (US) for diagnosis of calcium pyrophosphate deposition (CPPD) disease with microscopic crystal detection used as a gold standard. METHODS: We performed a systematic review of articles published up to December 2014 using EMBASE, MEDLINE and Cochrane databases and abstracts from the past two EULAR and ACR annual meetings. Only studies reporting the performance of US for diagnosis of CPPD disease were selected. A meta-analysis involved the inverse variance method to evaluate global sensitivity and specificity of US. Statistical heterogeneity was assessed by the Cochran Q-test and I(2) values. RESULTS: The search resulted in 85 articles and 11 abstracts; 17 and 4, respectively, were selected for the systematic review. A total of 262 patients with CPPD disease and 335 controls from 4 original articles and 4 abstracts were included in the meta-analysis. The US diagnostic patterns most frequently recorded were thin hyperechoic bands in the hyaline cartilage (8 articles); hyperechoic spots in fibrous cartilage or in tendons (7 articles); and homogeneous hyperechoic nodules localised in bursa or articular recesses (4 articles). The meta-analysis revealed a heterogeneity of the data, with a sensitivity of 87.9% (95% CI 80.9% to 94.9%) and specificity of 91.5% (95% CI 85.5% to 97.5%) using a random model. CONCLUSIONS: This meta analysis confirmed that US has high sensitivity and specificity for the diagnosis of CPPD and may be a promising tool for the diagnosis and management of CPPD. PMID- 26535144 TI - Biologicals in rheumatoid arthritis: current and future. AB - The aim of the review is to highlight the current knowledge about established and new biologicals and to summarise recent advances by focusing on comparative efficacy, safety and possible discontinuation of treatment in patients with rheumatoid arthritis (RA). Up to now, comparative analyses showed only minor differences with respect to efficacy and safety among the established biologicals. Studies confirmed the excellent drug retention rate as well as efficacy and safety of approved biologicals including their use in monotherapy. Tapering and in some instances discontinuation of biologicals is possible in disease remission. In case of relapse, patients usually show full response after reintroduction of the same compound. The development of biologicals continues fast with several new biologicals targeting different or established cytokines or cellular subsets of the immune system. With several new biologicals in the pipeline and different formulations for established compounds, treatment options for RA will become even more versatile and sophisticated. Although we get closer to the aim of decreasing the proportion of refractory patients, many questions have to be addressed in the near future regarding emerging biosimilars and biologicals with new modes of action. PMID- 26535145 TI - Cardiovascular and selected comorbidities in early arthritis and early spondyloarthritis, a comparative study: results from the ESPOIR and DESIR cohorts. AB - OBJECTIVES: To investigate the prevalence of comorbidities in early rheumatoid arthritis (ERA) and early axial spondyloarthritis (ESpA) versus the general population. METHODS: Baseline data of 689 patients with ERA from the Etude et Suivi des Polyarthrites Indifferenciees Recentes (ESPOIR) cohort (age 48.2+/-12.1 years, symptoms duration 14.2+/-14.5 weeks) and 645 patients with ESpA from Devenir des Spondylarthropathies Indifferenciees Recentes (DESIR; age 32.8+/-8.4 years, axial symptoms duration 79.0+/-45.7 weeks) were analysed. Metabolic and cardiovascular diseases (CVD), infections and neoplasia were determined in each cohort. The prevalence (95% CI) of several comorbidities was compared with that in the French general population. For patients without CVD, the 10-year risk of developing CVD was calculated using the Framingham and SCORE equations. The heart age was calculated using the 2008 Framingham points system. RESULTS: 42% of patients with ERA and 20.3% of patients with ESpA had at least 1 comorbidity; the most common were arterial hypertension (AHT) and dyslipidaemia. AHT prevalence (95% CI) in ERA (18.2% (15.5% to 21.3%)), but not in ESpA (5.08% (3.57% to 7.14%)), was significantly increased (p<0.05) compared with the general population (7.58%). Prevalence of tuberculosis history was higher in ERA (4.7% (3.3% to 6.6%)), and ESpA (0.99% (0.4% to 2.3%)) than in the general population (0.02%; both p<0.05). No differences were observed in malignancies, coronary heart disease or diabetes. In ERA, among patients without a history of CVD, an intermediate to high CVD risk was found. The heart age exceeded the real age by 4.1+/-9.6 years in ERA and by 2.1+/-7.0 years in ESpA (p<0.001). CONCLUSIONS: We found an increased prevalence of AHT and tuberculosis history in ERA and ESpA, and an increased CVD risk. These results should prompt rheumatologists to check these comorbidities early in the disease. PMID- 26535146 TI - Delayed-release prednisone improves fatigue and health-related quality of life: findings from the CAPRA-2 double-blind randomised study in rheumatoid arthritis. AB - OBJECTIVES: Like morning stiffness, fatigue is a common, debilitating symptom of rheumatoid arthritis (RA). Delayed-release (DR) prednisone is designed for evening administration (approximately 22:00) and releases 4 h later to coincide with the rise of nocturnal inflammatory cytokines associated with development of morning stiffness. The impact of DR prednisone on fatigue and other related patient-reported outcomes was analysed with data obtained from the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA) 2 study. METHODS: Patients with symptomatic RA (n=350) despite treatment with a disease-modifying antirheumatic drug (DMARD) were randomised 2:1 to receive additional therapy with DR prednisone 5 mg or placebo once daily for 12 weeks. Fatigue was assessed using validated instruments: the fatigue scale of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and the vitality domain of the Short Form-36 (SF-36). General quality of life was assessed using the general score and individual domains of Functional Assessment of Cancer Therapy-General (FACT-G) and SF-36. RESULTS: The change from baseline to week 12 in FACIT-F score was statistically significantly different with DR prednisone/DMARD (3.8) versus placebo/DMARD (1.6; difference 2.2, p=0.0032). Improvement in FACIT-F score correlated positively with clinical response. Compared with placebo/DMARD, DR prednisone/DMARD showed a significantly greater improvement in SF-36 vitality score (5.6, p=0.001), physical component of SF-36 (2.3, p=0.0003) and general score with FACT-G (2.6, p=0.0233). CONCLUSIONS: DR prednisone in addition to a DMARD significantly improves fatigue and other aspects of health-related quality of life in patients with symptomatic RA compared with DMARD treatment alone. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00650078. PMID- 26535147 TI - Self-reported quality care for knee osteoarthritis: comparisons across Denmark, Norway, Portugal and the UK. AB - OBJECTIVES: To assess and compare patient perceived quality of osteoarthritis (OA) management in primary healthcare in Denmark, Norway, Portugal and the UK. METHODS: Participants consulting with clinical signs and symptoms of knee OA were identified in 30 general practices and invited to complete a cross-sectional survey including quality indicators (QI) for OA care. A QI was considered as eligible if the participant had checked 'Yes' or 'No', and as achieved if the participant had checked 'Yes' to the indicator. The median percentage (with IQR and range) of eligible QIs achieved by country was determined and compared in negative binominal regression analysis. Achievement of individual QIs by country was determined and compared using logistic regression analyses. RESULTS: A total of 354 participants self-reported QI achievement. The median percentage of eligible QIs achieved (checked 'Yes') was 48% (IQR 28%, 64%; range 0-100%) for the total sample with relatively similar medians across three of four countries. Achievement rates on individual QIs showed a large variation ranging from 11% (referral to services for losing weight) to 67% (information about the importance of exercise) with significant differences in achievement rates between the countries. CONCLUSIONS: The results indicated a potential for improvement in OA care in all four countries, but for somewhat different aspects of OA care. By exploring these differences and comparing healthcare services, ideas may be generated on how the quality might be improved across nations. Larger studies are needed to confirm and further explore the findings. PMID- 26535148 TI - Educational recommendations for the conduct, content and format of EULAR musculoskeletal ultrasound Teaching the Teachers Courses. AB - OBJECTIVE: To produce educational guidelines for the conduct, content and format of theoretical and practical teaching at EULAR musculoskeletal ultrasound (MSUS) Teaching the Teachers (TTT) Courses. METHODS: A Delphi-based procedure with 24 recommendations covering five main areas (Duration and place of the course; Faculty members; Content of the course; Evaluation of the teaching skills; TTT competency assessment) was distributed among a group of experts involved in MSUS teaching, in addition to an advisory educational expert being present. Consensus for each recommendation was considered achieved when the percentage of agreement was >75%. RESULTS: 21 of 24 invited participants responded to the first Delphi questionnaire (88% response rate). All 21 participants also responded to the second round. Agreement on 19 statements was obtained after two rounds. CONCLUSIONS: This project has led to the development of guidelines for the conduct, content and format of teaching at the EULAR MSUS TTT Courses that are organised annually, with the aim of training future teachers of EULAR MSUS Courses, EULAR Endorsed MSUS Courses, as well as national and local MSUS Courses. The presented work gives indications on how to homogenise the teaching at the MSUS TTT Courses, thus resolving current discrepancies in the field. PMID- 26535149 TI - Biosimilars: what do patients need to consider? AB - A view from the EULAR Standing Committee of People with Arthritis/Rheumatism in Europe (SCPARE) on some of the issues that patients might wish to consider about biosimilars in shared decision-making discussions with their rheumatologist. The paper also points to the need for more information on biosimilars being made available in lay language. PMID- 26535150 TI - Real-life assessment of the validity of patient global impression of change in fibromyalgia. AB - OBJECTIVES: Patient Global Rating of Change (GRC) scales are commonly used in routine clinical care given their ease of use, availability and short completion time. This analysis aimed at assessing the validity of Patient Global Impression of Change (PGIC), a GRC scale commonly used in fibromyalgia, in a Canadian real life setting. METHODS: 167 fibromyalgia patients with available PGIC data were recruited in 2005-2013 from a Canadian tertiary-care multidisciplinary clinic. In addition to PGIC, disease severity was assessed with: pain visual analogue scale (VAS); Patient Global Assessment (PGA); Fibromyalgia Impact Questionnaire (FIQ); Health Assessment Questionnaire (HAQ); McGill Pain Questionnaire; body map. Multivariate linear regression assessed the PGIC relationship with disease parameter improvement while adjusting for follow-up duration and baseline parameter levels. The Spearman's rank coefficient assessed parameter correlation. RESULTS: Higher PGIC scores were significantly (p<0.001) associated with greater improvement in pain, PGA, FIQ, HAQ and the body map. A statistically significant moderate positive correlation was observed between PGIC and FIQ improvement (r=0.423; p<0.001); correlation with all remaining disease severity measures was weak. Regression analysis confirmed a significant (p<0.001) positive association between improvement in all disease severity measures and PGIC. Baseline disease severity and follow-up duration were identified as significant independent predictors of PGIC rating. CONCLUSIONS: Despite that only a weak correlation was identified between PGIC and standard fibromyalgia outcomes improvement, in the absence of objective outcomes, PGIC remains a clinically relevant tool to assess perceived impact of disease management. However, our analysis suggests that outcome measures data should not be considered in isolation but, within the global clinical context. PMID- 26535151 TI - Tapering and discontinuation of methotrexate in patients with RA treated with TNF inhibitors: data from the DREAM registry. AB - OBJECTIVES: To study the number of patients that taper or discontinue concomitant methotrexate (MTX) in daily practice in patients with rheumatoid arthritis (RA) treated with tumour necrosis factor inhibitor (TNFi) and to analyse the effects of that adaption on disease activity and drug survival. METHODS: Data were collected from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. Patients who started their first TNFi were included in the study. Treatment effectiveness after MTX tapering or discontinuation was analysed using Disease Activity Score of 28 joints (DAS28). Drug survival of the TNFi was analysed using the Cox proportional hazard model with a time-dependent covariate. RESULTS: In 458 patients (34%), MTX was tapered, 126 patients (10%) discontinued MTX and 747 patients (56%) continued MTX at the same dose. On average, DAS28 improved after tapering MTX (-0.40, -0.45) and after stopping MTX (-0.28, -0.12) at 6 and 12 months. In the taper group, 21% of the patients relapsed (DAS28 increase >0.6), and in the discontinuation group this was 21% and 24% at 6 and 12 months, respectively. Patients who taper and discontinue MTX have a similar DAS28 score over time as patients who continue MTX. Moreover, there was no influence of tapering or discontinuation of MTX on long-term drug survival of TNFi. CONCLUSIONS: In daily practice, tapering or discontinuation of concomitant MTX in patients with RA treated with TNFi frequently occurs and it does not seem to influence the average DAS28 over time or the long-term TNFi drug survival. It appears that in daily clinical practice the correct patients are selected to taper or discontinue MTX. PMID- 26535152 TI - Education improves referral of patients suspected of having spondyloarthritis by general practitioners: a study with unannounced standardised patients in daily practice. AB - OBJECTIVES: To evaluate the practice performance of general practitioners (GPs) and GP residents in recognising and referring patients suspected for having axial or peripheral spondyloarthritis (SpA), and to investigate the influence of education on this performance. METHODS: GP (residents) were visited in two rounds by standardised patients (SPs) simulating axial SpA, peripheral SpA or carpal tunnel syndrome (CTS) with in between an educational intervention on SpA for part of the participants. Participants were unaware of the nature of the medical problem and study purpose. CTS was included as diversionary tactic. The primary outcome was >=40% improvement in (considering) referral of the SPs with SpA to the rheumatologist after education. Secondary outcomes included ordering additional diagnostic tests, correct recognition of SpA and identification of variables contributing to this. RESULTS: 68 participants (30 GPs and 38 GP residents) were included, of which 19 received education. The primary outcome was met. A significantly higher proportion of GP (residents) from the intervention group referred patients to the rheumatologist compared with the control group after education (change scores, axial SpA +71% vs +15% (p<0.01); peripheral SpA +48% vs 0% (p<0.001)). Participants who received education, more frequently correctly recognised SpA compared with controls (change scores, axial SpA +50% vs -5% (p<0.001); peripheral SpA +21% vs 0% (p=0.01). CONCLUSIONS: Recognition and referral of patients suspected for having SpA by GP (residents) is low, but targeted education markedly improved this. This supports the development of educational initiatives to improve recognition of SpA and hence referral to a rheumatologist. PMID- 26535153 TI - Lifestyle factors may modify the effect of disease activity on radiographic progression in patients with ankylosing spondylitis: a longitudinal analysis. AB - OBJECTIVES: To investigate the complex relationship between inflammation, mechanical stress and radiographic progression in patients with ankylosing spondylitis (AS), using job type as a proxy for continuous mechanical stress. METHODS: Patients from the Outcome in Ankylosing Spondylitis International Study were followed up for 12 years, with 2-yearly assessments. Two readers independently scored the X-rays according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Disease activity was assessed by the AS Disease Activity Score C reactive protein (ASDAS-CRP). The relationship between ASDAS and spinal radiographic progression was investigated with longitudinal analysis, with job type at baseline (physically demanding ('blue-collar') versus sedentary ('white-collar') labour) as a potential factor influencing this relationship. The effects of smoking status and socioeconomic factors were also investigated. RESULTS: In total, 184 patients were included in the analyses (70% males, 83% human leucocyte antigen-B27 positive, 39% smokers, 48% blue-collar workers (65/136 patients in whom data on job type were available)). The relationship between disease activity and radiographic progression was significantly and independently modified by job type: In 'blue-collar' workers versus 'white collar' workers, every additional unit of ASDAS resulted in an increase of 1.2 versus 0.2 mSASSS-units/2-years (p=0.014 for the difference between blue-collar and white-collar workers). In smokers versus non-smokers, every additional unit of ASDAS resulted in an increase of 1.9 versus 0.4 mSASSS-units/2-years. CONCLUSIONS: Physically demanding jobs may amplify the potentiating effects of inflammation on bone formation in AS. Smoking and socioeconomic factors most likely confound this relationship and may have separate effects on bone formation. PMID- 26535154 TI - Physiome-on-a-Chip: The Challenge of "Scaling" in Design, Operation, and Translation of Microphysiological Systems. AB - Scaling of a microphysiological system (MPS) or physiome-on-a-chip is arguably two interrelated, modeling-based activities: on-platform scaling and in vitro-in vivo translation. This dual approach reduces the need to perfectly rescale and mimic in vivo physiology, an aspiration that is both extremely challenging and not substantively meaningful because of uncertain relevance of any specific physiological condition. Accordingly, this perspective offers a tractable approach for designing interacting MPSs and relating in vitro results to analogous context in vivo. PMID- 26535155 TI - Physiologically Based Pharmacokinetic Model for Prediction of Leflunomide and Teriflunomide: Should Consideration Be Given to Cannalicular Efflux Transporters? PMID- 26535156 TI - Response to Physiologically Based Pharmacokinetic Model for Prediction of Leflunomide and Teriflunomide-Should Consideration Be Given to Cannalicular Efflux Transporters? PMID- 26535157 TI - Establishing Good Practices for Exposure-Response Analysis of Clinical Endpoints in Drug Development. AB - This tutorial aims at promoting good practices for exposure-response (E-R) analyses of clinical endpoints in drug development. The focus is on practical aspects of E-R analyses to assist modeling scientists with a process of performing such analyses in a consistent manner across individuals and projects and tailored to typical clinical drug development decisions. This includes general considerations for planning, conducting, and visualizing E-R analyses, and how these are linked to key questions. PMID- 26535158 TI - Relating Chemical Structure to Cellular Response: An Integrative Analysis of Gene Expression, Bioactivity, and Structural Data Across 11,000 Compounds. AB - A central premise in systems pharmacology is that structurally similar compounds have similar cellular responses; however, this principle often does not hold. One of the most widely used measures of cellular response is gene expression. By integrating gene expression data from Library of Integrated Network-based Cellular Signatures (LINCS) with chemical structure and bioactivity data from PubChem, we performed a large-scale correlation analysis of chemical structures and gene expression profiles of over 11,000 compounds taking into account confounding factors such as biological conditions (e.g., cell line, dose) and bioactivities. We found that structurally similar compounds do indeed yield similar gene expression profiles. There is an ~20% chance that two structurally similar compounds (Tanimoto Coefficient >= 0.85) share significantly similar gene expression profiles. Regardless of structural similarity, two compounds tend to share similar gene expression profiles in a cell line when they are administrated at a higher dose or when the cell line is sensitive to both compounds. PMID- 26535159 TI - Quantitative Systems Pharmacology Approaches Applied to Microphysiological Systems (MPS): Data Interpretation and Multi-MPS Integration. AB - Our goal in developing Microphysiological Systems (MPS) technology is to provide an improved approach for more predictive preclinical drug discovery via a highly integrated experimental/computational paradigm. Success will require quantitative characterization of MPSs and mechanistic analysis of experimental findings sufficient to translate resulting insights from in vitro to in vivo. We describe herein a systems pharmacology approach to MPS development and utilization that incorporates more mechanistic detail than traditional pharmacokinetic/pharmacodynamic (PK/PD) models. A series of studies illustrates diverse facets of our approach. First, we demonstrate two case studies: a PK data analysis and an inflammation response--focused on a single MPS, the liver/immune MPS. Building on the single MPS modeling, a theoretical investigation of a four MPS interactome then provides a quantitative way to consider several pharmacological concepts such as absorption, distribution, metabolism, and excretion in the design of multi-MPS interactome operation and experiments. PMID- 26535160 TI - Population Pharmacokinetics and Pharmacodynamics of Lampalizumab Administered Intravitreally to Patients With Geographic Atrophy. AB - Intravitreally administered lampalizumab is an investigational complement inhibitor directed against complement factor D (CFD) for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration. We sought to develop an integrated ocular and systemic pharmacokinetic/pharmacodynamic model for lampalizumab in patients with GA using the data from the clinical phase I and II studies. The kinetics of lampalizumab and CFD disposition were well described by the combined ocular/serum target-mediated drug disposition model using a quasi-steady-state approximation. This model takes into account the drug, target, and drug-target complex clearance, their transfer rates between ocular and serum compartments, and turnover kinetics of CFD. The constructed model provided a prediction of target occupancy in ocular tissues and supported that the two dosing regimens (10 mg q4w and 10 mg q6w) selected for the phase III studies are expected to be efficacious and able to achieve near-complete target engagement in the vitreous humor. PMID- 26535161 TI - Development of a Multicompartment Permeability-Limited Lung PBPK Model and Its Application in Predicting Pulmonary Pharmacokinetics of Antituberculosis Drugs. AB - Achieving sufficient concentrations of antituberculosis (TB) drugs in pulmonary tissue at the optimum time is still a challenge in developing therapeutic regimens for TB. A physiologically based pharmacokinetic model incorporating a multicompartment permeability-limited lung model was developed and used to simulate plasma and pulmonary concentrations of seven drugs. Passive permeability of drugs within the lung was predicted using an in vitro-in vivo extrapolation approach. Simulated epithelial lining fluid (ELF):plasma concentration ratios showed reasonable agreement with observed clinical data for rifampicin, isoniazid, ethambutol, and erythromycin. For clarithromycin, itraconazole and pyrazinamide the observed ELF:plasma ratios were significantly underpredicted. Sensitivity analyses showed that changing ELF pH or introducing efflux transporter activity between lung tissue and ELF can alter the ELF:plasma concentration ratios. The described model has shown utility in predicting the lung pharmacokinetics of anti-TB drugs and provides a framework for predicting pulmonary concentrations of novel anti-TB drugs. PMID- 26535162 TI - Predictors of Dental Cleaning Over a Two-year Time Period Around Pregnancy Among Asian and Native Hawaiian or Other Pacific Islander Race Subgroups in Hawai'i, 2009-2011. AB - Oral health disease is linked to several chronic diseases including adverse health outcomes around pregnancy. Optimizing a woman's oral health before, during, and after pregnancy can impact her health and the health of her children. Preventive, diagnostic, and restorative dental services can be done safely and effectively including during pregnancy. We examined data from the 2009-2011 Hawai'i Pregnancy Risk Assessment Monitoring System (PRAMS) to assess the prevalence of dental cleanings over an approximately 2 year (Median: 2.0 years, Range:1.6-2.5 years) time period (12 months before pregnancy, during pregnancy, and in the first few months postpartum) among 4,735 mothers who recently had a live birth. Adjusted prevalence ratios (APR) of dental cleanings were calculated for both race and Medicaid/QUEST insurance status adjusting for maternal age and education. During a two-year span before, during, and after pregnancy an estimated 60.8% of women had dental cleanings. Native Hawaiian (APR=0.87; 95% CI=0.80-0.93), Other Pacific Islander (0.70; 0.58-0.83), Filipino (0.90; 0.82 0.97), and Chinese (0.76; 0.63-0.93) mothers were less likely to have had dental cleanings compared to white mothers. Additionally, mothers with Medicaid/QUEST health insurance (0.73; 0.68-0.79) were less likely to have had cleanings. More than one-third of recently pregnant mothers did not have dental cleanings in the approximately two-year time period. Native Hawaiian, Other Pacific Islander, Filipino, and Chinese mothers and those on Medicaid/QUEST health insurance were less likely to receive regular dental care. Identification of the reasons why these populations do not seek regular dental care can inform programmatic efforts to improve oral health outcomes for women and families. PMID- 26535163 TI - Assessing Face Validity of a Food Behavior Checklist for Limited-resource Filipinos. AB - Diet-related chronic health conditions are prevalent in the Filipino American community; however, there is a lack of rigorously validated nutrition education evaluation tools in Tagalog for use in this population. This study aimed to develop and evaluate the face validity of a Tagalog-language food behavior checklist (FBC). A multi-step method was used, involving translation of questionnaire text from English to Tagalog by a team of professionals, creation of accompanying color photographs, cognitive testing with the target population, final review by the team of professionals, and assessment of readability. Subjects for cognitive testing were men (n=6) and women (n=14) 18 years or older in Hawai'i who received or were eligible to receive Supplemental Nutrition Assistance Program (SNAP) benefits, self-identified as Filipino, and preferred Tagalog rather than English. Participants were recruited from churches, the Filipino Center, and other community sites. Cognitive interviews revealed several issues with text and photographs, such as preferences for specific terms, and images that did not adequately illustrate the text. Image changes were made to reflect items most commonly consumed. The team of professionals agreed with participant suggestions. Assessment of readability revealed a reading level appropriate for a low-literacy population of grade 5.9. The multi-step process, which allowed members of the target audience to reveal the appropriateness of the questionnaire, yielded a Tagalog-language FBC found to have adequate face validity. After further evaluation of validity and reliability, this tool may be used to evaluate behavior change resulting from the United States Department of Agriculture's (USDA) nutrition education programs. PMID- 26535164 TI - Acute Rheumatic Carditis: A Rare Cause for Reversible Complete Heart Block. AB - A previously healthy 18-year-old man presented to the emergency department with weakness, fever, and joint pains and was found to have complete heart block with transient asystole requiring urgent transvenous pacing. After further workup, the patient was found to have complete heart block secondary to acute rheumatic carditis. The conduction system recovered in a step-wise fashion following treatment with Penicillin, and high dose Aspirin, without the need for permanent pacemaker placement. This case illustrates that acute rheumatic carditis, although rare, can present with advanced conduction system involvement, which is reversible if treatment is initiated. PMID- 26535165 TI - Medical School Hotline: The Magical World of Medicine. PMID- 26535166 TI - Insights in Public Health: Initiating Bicycle Sharing in Hawai'i: Lessons Learned from a Small Pilot Bike Share Program. AB - In 2011, a small pilot bike share program was established in the town core of Kailua, Hawai'i, with funding from the Hawai'i State Department of Health. The Kailua system consisted of two stations with 12 bicycles, and the goal was to secure additional funding to expand the station network in the future. Community feedback consistently indicated support for the bike share program. However, system metrics showed low levels of usage, averaging 41.5 rides per month (2011 2014). From observational data, users were primarily tourists. With minimal local staff, the bike share program had limited resources for promotion and education, which may have hindered potential use by local residents. Management of station operations and bike maintenance were additional, ongoing barriers to success. Despite the challenges, the pilot bike share program was valuable in several ways. It introduced the bike share concept to Hawai'i, thereby helping to build awareness and connect an initial network of stakeholders. Furthermore, the pilot bike share program informed the development of a larger bike share program for urban Honolulu. As limited information exists in the literature about the experiences of smaller bike share programs and their unique considerations, this article shares lessons learned for other communities interested in starting similar bike share programs. PMID- 26535168 TI - Novel Interventions in Children's Healthcare for Youth Hospitalized for Chronic Pain. AB - The purpose of this study was to pilot the implementation of the Novel Interventions in Children's Healthcare (NICH) program for youth with chronic pain who utilized a disproportionate amount of health care. Three youth (2 males and 1 female, aged 11 to 15 years) participated. The intervention consisted of a combination of family-based problem-solving, care coordination, and case management, with the inclusion of technology-assisted treatment delivery (e.g., text messages, video chat) to reduce costs. Both objective (i.e., hospitalization records) and subjective (e.g., interventionist reports) outcomes were examined to assess changes over the course of treatment. Two of the three youth demonstrated reductions in the number of days hospitalized and associated costs. In addition, interventionist reports indicated improved quality of life for family and youth served. Although further research is needed, NICH appears to be a promising intervention for youth with chronic pain and high health care utilization and shows the potential to result in improved youth health and reduced monetary costs for families, providers, and the healthcare system. PMID- 26535169 TI - Pyoderma gangrenosum following a routine caesarean section: Pseudo-infection in a caesarean wound. AB - A 22-year-old booked primigravida underwent lower segment caesarean section for breech presentation. She developed signs and symptoms of wound infection by the fourth postoperative day. This was initially managed with antibiotics and wound dressing, but debridement was later undertaken after consulting surgeons. This resulted in an alarming worsening of the wound with sudden and fast increase in its size along with systemic symptoms. Wound biopsy established the diagnosis of pyoderma gangrenosum. The patient's management included oral medication with prednisolone, cyclosporin and dapsone and wound care. There was a dramatic response to this treatment. The wound completely healed by the eighth postoperative month. The oral medications were tapered off slowly and stopped by that time. PMID- 26535170 TI - First Bahraini adolescent with anti-NMDAR-Ab encephalitis. AB - Anti-N-methyl-D-aspartate-receptor (NMDA-R) encephalitis is a new autoimmune, often paraneoplastic disorder that presents with complex neuropsychiatric symptoms. It was first described in 2007 by Dalmau et al. Our patient presented with headache, behavioral changes and then seizures with hallucinations. She was initially misdiagnosed to have schizophrenia and was prescribed antipsychotics. She deteriorated and developed further seizures with hypoventilation and choreoathetosis. Her blood investigations were positive for mycoplasma IGM. Her CSF studies showed high white cell counts, predominantly lymphocytes, and high anti-NMDA-R titre. Her brain MRI scans showed high tbl2 and FLAIR intensities in the grey and white matter of the left cerebellar hemisphere suggestive of acute disseminated encephalomyelitis. She responded to treatment with antibiotics, multiple antiepileptics, steroids and needed five sessions of plasmapheresis. There was no underlying malignancy on repeated scanning of the abdomen. She needed around one year for full recovery with intensive rehabilitation. The objective of this paper was to highlight the occurrence of this fairly new, challenging, easily missed, not-so-rare form of encephalitis often occurring in the absence of fever. PMID- 26535171 TI - The prevalence of psychological impact on caregivers of hospitalized patients: The forgotten part of the equation. AB - INTRODUCTION: Despite the large number of caregivers suffering from various psychiatric disorders, research on psychological symptoms among caregivers of hospitalized patients is lacking in Saudi populations. OBJECTIVES: The objective of this study is to determine the prevalence of depression, anxiety and stress among caregivers of hospitalized Saudi patients. METHODS: A cross-sectional study of depression, anxiety and stress among caregivers of hospitalized patients was conducted. Arabic speaking caregivers (n = 353) between the ages of 14 and 80 years were included in the study. The Depression Anxiety Stress Scales (DASS-21) test (Arabic version) was used to measure the three psychological symptoms. RESULTS: The study has shown high rates of depression, anxiety and stress among caregivers (72.8%, 76.5%, and 61.5%, respectively). Depression was found to be associated with long-term hospital stay (81.4% vs. 69.3%; p-value = 0.021) and family caregivers (75.4% vs. 46.9%, p-value = 0.001). Anxiety was found to be associated with family caregivers (78.8% vs. 53.1%; p-value = 0.001). The three psychological symptoms were higher among those with an age above 20 years old (p value < 0.05). Multivariate logistic models show the risk of the psychological symptoms increased with low-income, higher education, immediate relation to the patient, and older caregivers. CONCLUSIONS: The findings suggest that the prevalence of depression, anxiety and stress symptoms were very common among caregivers. The results showed that approximately 8 out of 10 caregivers suffer from at least one psychiatric disorder. Older, low socioeconomic status, and well educated caregivers were identified as being at higher risk of developing psychiatric symptoms. PMID- 26535172 TI - Evaluating psychosocial support needs of female cancer patients in the State of Qatar. AB - Patient perceived perceptions of psychosocial support are increasingly important to understanding appropriate holistic patient-centred care. Information is scarce regarding the attitudes of female cancer patients in Arab and Muslim populations. This study was undertaken in the State of Qatar among female cancer patients. The aim of this study was to investigate what extent women undergoing cancer treatment in the State of Qatar view the importance of psychosocial support? Another aim of this study was to determine which demographic indicators, if any, may predict for certain preferences in support. The authors hypothesized that a majority of female cancer patients will perceive psychosocial support as an important aspect. This study used English and Arabic questionnaires to glean data from female cancer patients attending clinics at the National Centre for Cancer Care and Research in Doha, Qatar. For the purpose of this study, psychosocial support was defined under four categories: 1) family support, 2) religious/spiritual support, 3) support groups 4) physician referred support. Results showed that 88% of female respondents rated psychosocial support categories as important. There was no significance between patient demographics and specific preferences for the support categories in the study. This study may provide some areas for future research that may shape guidelines for improving holistic patient care and in assisting the Supreme Health Council in meeting its targets for the Qatar National Cancer strategy, which states that cancer treatment should be patient-centred focusing on both medical and psychosocial needs of patients. PMID- 26535173 TI - Foreign body in the liver: Case report and review of literature. AB - Foreign bodies in the liver, although rare, have been described previously in the literature. While more common in children, adults may also swallow foreign bodies that can reach the liver by penetrating the stomach, duodenum or colon. We describe the case of a young lady who accidentally swallowed a needle, which was later found in the liver by abdominal X-ray and computed tomography (CT). It was removed intact by laparoscopy. A foreign body in the liver is a rare occurrence. Radiology is important in diagnosis through modalities including plain X-ray, ultrasonography and abdominal CT. Removal can be achieved by laparotomy or laparoscopy. PMID- 26535174 TI - A review of drug-induced acute angle closure glaucoma for non-ophthalmologists. AB - Acute angle closure glaucoma is an ophthalmic emergency and can lead to blindness if left untreated. Several types of drugs have the potential to precipitate acute angle closure glaucoma. These include adrenergic, cholinergic and anticholinergic, antidepressants, anticoagulants and sulfa-based agents. This article provides a basic overview of the risk factors and pathophysiologic mechanisms involved in angle closure glaucoma and focuses on drug-induced angle closure glaucoma for the non-ophthalmologist. A PubMed search limited to the English language was conducted to find relevant literature for the purpose of this article. Most attacks occur in subjects unaware that they are at risk due to innately narrow iridocorneal angles. Clinicians should always review medications in patients presenting with symptoms of acute angle closure glaucoma. The aim of this article is to bring this ophthalmic condition to the attention of clinicians, particularly those outside the field of ophthalmology who commonly prescribe these medications or see these patients prior to referring to ophthalmologists. PMID- 26535175 TI - A rare case of unusual migrated foreign bodies in kidney and their successful extraction using retrograde percutaneous nephrostomy. AB - Foreign body ingestion is a common presentation in the emergency room and most cases are without any major symptoms, or go unnoticed and later cause severe complications that can potentially threaten patient life. We report a case of multiple migrated metallic foreign bodies in the right kidney presenting as right renal colic and gross haematuria one year after its accidental ingestion, treated successfully with retrograde percutaneous nephrostomy. PMID- 26535176 TI - Nontuberculous mycobacterial infection presenting as empyema and life threatening pneumothorax: A challenging situation in the emergency department. AB - Nontuberculous mycobacterial infection in an immunocompetent young patient complicated with empyema and pneumothorax is rarely reported. A 36-year-old man presented to the emergency department with a history of worsening dyspnea and pleuritic chest pain. The patient had unstable vital signs on presentation, and was referred to the resuscitation area on a monitored bed. The patient had a chest x-ray (CXR) performed on a prior occasion at a primary health clinic, revealing pneumothorax and some fluid at the left costophrenic angle. On arrival at the hospital, bedside ultrasound was performed which confirmed the diagnosis of pneumothorax. His vital signs were pulse 153, BP 88/62, RR 50 breaths per minute and his oxygen saturation on air was 92%. Tension pneumothorax was diagnosed based on clinical presentation and given vital signs. It was managed immediately with needle decompression followed by chest tube insertion. The patient improved dramatically after needle decompression with stabilization of vital signs. A CXR was repeated post-needle decompression which showed an incompletely resolved pneumothorax with an increase in the size of the effusion. Iatrogenic haemothorax was a possible explanation for this increase in effusion size. Chest tube was successfully inserted in the fourth intercostal space just anterior to the midaxillary line under full aseptic precautions. The chest tube drained 1.4 liters of blood, which on analysis showed a low pH and elevated adenosine deaminase level. Two out of three sputum samples sent from the medical ward were positive for mycobacteria other than tuberculosis as confirmed on culture. The patient's symptoms improved with percutaneous tube drainage of hemopneumothorax and antituberculous medications. PMID- 26535177 TI - Diagnosis and clinical features of organic acidemias: A hospital-based study in a single center in Damascus, Syria. AB - BACKGROUND: Organic acidemias (OA) are a group of heterogeneous metabolic inherited disorders characterized by the accumulation of organic acids in body fluids and tissues. These are rare disorders and infrequently reported worldwide. In Syria, there is a lack of information regarding these disorders. OBJECTIVE: Our hospital-based study aimed to describe the pattern of clinical and demographic presenting features of organic acidemias among Syrian children and to shed light on the diagnostic experience of organic acidemias in the Children's Hospital of Damascus through a five year period. MATERIAL AND METHODS: We conducted a retrospective cohort study by reviewing the medical records of OA patients in the Children's Hospital of Damascus between 2008 and 2012. All cases were investigated by metabolic work up, including the acylcarnitine profile performed by tandem mass spectrometry (MS/MS) and quantitative urine organic acid analysis performed by gas chromatography mass spectrometry (GC-MS). RESULTS: A total of 70 OA confirmed cases were included in the study. There were 46 males and 31 females. Twenty-seven cases were diagnosed after the first year of life. Methylmalonic acidemia was the most frequent disorder (57.1%). There were relatively high rates of family history of unexplained death and OA confirmed cases (50%), consanguinity (74.2%) and mortality (21.4%). The most frequent symptoms were apnea or respiratory distress (65.7%) and vomiting (40%). CONCLUSION: The lack of specific confirmatory diagnostic tests being performed and the high mortality and consanguinity rates among OA patients suggests high incidence of OA in Syria. Further studies are needed to determine the actual incidence of OA and the cost-effectiveness of applying a governmental mandatory newborn screening program. PMID- 26535178 TI - Effects of witnessing or exposure to community violence on mental health of Iraqi men. AB - BACKGROUND: Iraq is consistently exposed to large-scale traumatic events such as successive wars since 1980 to the present day, economic sanctions, sustained organized violence, and terrorism. These unsafe circumstances have negatively impacted the psychosocial status of the Iraqi community. OBJECTIVE: To study the prevalence of witnessing or exposure to various types of violence, and its association with mental health problems in a sample of Iraqi men. METHODS: This is a cross-sectional study that was conducted from April to September 2014. The target population were men from different age groups that were collected through a convenience sampling technique from two large cities; Baghdad (the capital city) and Mosul (the second largest city in Iraq). The source of data was from different institutions, colleges and lay people. The data collection process was done using the Self-Reporting Questionnaire 20 which is recommended by the World Health Organization for screening psychiatric disturbances. RESULTS: A total of 480 Iraqi males agreed to participate in the study. The main type of violence reported was witnessing violence (55.4%), followed by exposure of friends or relatives to violence (51.4%), and witnessing or exposure to sexual assault was least reported (3.8%). The most frequent feeling recorded was of worry (72.9%), getting easily upset (65.4%), suffering from headaches (62.7%) and lethargy (59.4%). Severe psychological changes were evident in 68.5% of men, while moderate changes were present in 31.5%. Analysis of the feelings and behavioral changes in relation to the participants' history of exposure to violence revealed a significant association with witnessing shooting or stabbings, displacement, friends or relatives' exposure to violence, and viewing corpses. CONCLUSION: There is a high prevalence among Iraqi men of exposure to, or witnessing violence that showed an association with their mental condition, which, if proved causally, may be a leading cause for future devastating effects on their health, wellbeing and quality of life. PMID- 26535179 TI - Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: A five-year retrospective study in the Children's Hospital of Damascus, Syria. AB - BACKGROUND: Congenital adrenal hyperplasia (CAH) is one of the most common inherited metabolic disorders. 21-hydroxylase deficiency is responsible for the majority of cases (90-95%) and considered the most common cause of genital ambiguity. There are no statistics concerning the prevalence of this disorder in Syria, although the high rate of consanguineous marriages indicates a possible high prevalence. OBJECTIVES: This study aims to collect baseline information about CAH in Syria to evaluate the potential need of a screening program. SUBJECTS AND METHODS: All medical records of inpatients who had CAH as a final or presumptive diagnosis at the Children's Hospital of Damascus between 2008-2012, or were diagnosed elsewhere and then admitted at the hospital for the first time within the same period, were retrospectively reviewed and divided into two groups: confirmed and suspected cases. RESULTS: Eighty-nine cases were confirmed, 25 were still suspected. Of the 89 confirmed cases: 20 (22.5%) were males, 66 (74.1%) were females, and 3 were ambiguous. Sixty-one patients (68.5%) were of the salt wasting type and 28 (31.5%) were of the simple virilizing type. The mortality rate was 6.7%. Thirty-two females were assigned as males at birth. Seventeen cases (19.1%) underwent previous hospitalization. 69.7% of patients were not diagnosed during the first month of life. Of the 25 suspected cases: 12 were males, 8 were females and 5 were ambiguous. Confirmatory tests had not been performed because of death in 7 patients (28%) and early discharge upon parental request in another 7 patients (28%). CONCLUSION: A mandatory screening program for CAH in Syria seems necessary due to the obvious lack of awareness, delayed diagnosis and high expected prevalence. However, further efforts are needed to confirm the effectiveness of such a program in the Syrian society. PMID- 26535180 TI - Erratum: "Eating and Nutrition Habits in Young Competitive Athletes: A Comparison Between Soccer Players and Cyclists". AB - [This corrects the article on p. 44 in vol. 11, PMID: 25674549.]. PMID- 26535181 TI - Withdrawal of Papers. AB - [This retracts the article on p. 22 in vol. 5, PMID: 23905079.][This retracts the article on p. 57 in vol. 3, PMID: 23905053.]. PMID- 26535182 TI - Rugby and Shoulder Trauma: A Systematic Review. AB - Rugby is a popular contact sport worldwide. Collisions and tackles during matches and practices often lead to traumatic injuries of the shoulder. This review reports on the epidemiology of injuries, type of lesions and treatment of shoulder injuries, risk factors, such as player position, and return to sport activities. Electronic searches through PubMed (Medline), EMBASE, and Cochrane Library retrieved studies concerning shoulder injuries in rugby players. Data regarding incidence, type and mechanisms of lesion, risk factors and return to sport were extracted and analyzed. The main reported data were incidence, mechanism of injury and type of lesion. Most of the studies report tackle as the main event responsible for shoulder trauma (between 50% and 85%), while the main lesions reported were Bankart lesions, Superior Labral tear from Anterior to Posterior (SLAP tears), anterior dislocation and rotator cuff tears. Open or arthroscopic repair improve clinical outcomes. Shoulder lesions are common injuries in rugby players. Surgical treatment seems to be effective in for rotator cuff tears and shoulder instability. More and better designed studies are needed for a higher Level of Evidence analysis of this topic. PMID- 26535183 TI - Muscle Injuries: A Brief Guide to Classification and Management. AB - Muscle injuries are frequent in athletes. Despite their high incidence, advances in clinical diagnostic criteria and imaging, their optimal management and rehabilitation strategies are still debated in literature. Furthermore, reinjury rate is high after a muscle lesion, and an improper treatment or an early return to sports can increase the rate of reinjury and complications. Most muscle injuries are managed conservatively with excellent results, and surgery is normally advocated only for larger tears. This article reviews the current literature to provide physicians and rehabilitation specialists with the necessary basic tools to diagnose, classify and to treat muscle injuries. Based on anatomy, biomechanics, and imaging features of muscle injury, the use of a recently reported new classification system is also advocated. PMID- 26535184 TI - What the Young Physician Should Know About May-Thurner Syndrome. AB - May-Thurner syndrome (MTS) is an anatomically variable condition resulting in compression of the left common iliac vein between the right common iliac artery and the underlying spine with subsequent development of a left deep vein thrombosis (DVT). Although this syndrome is rare, its true prevalence is likely underestimated. Mainly, clinical symptoms and signs include, but are not limited to, pain, swelling, venous stasis ulcers, skin pigmentation changes and post thrombotic syndrome. Correct treatment is not well established and is based on clinical presentation. Staged thrombolysis with/without prophylactic retrievable inferior vena cava filter placement followed by angioplasty/stenting of the left iliac vein appears to be the best option in MTS patients with extensive DVT. The aim of this review is to present in a simple and didactic form all variable clinical presentations of MTS and to outline possible management within the current guidelines. PMID- 26535185 TI - High Density Lipoprotein Cholesterol Increasing Therapy: The Unmet Cardiovascular Need. AB - Despite aggressive strategies are now available to reduce LDL-cholesterol, the risk of cardiovascular events in patients with coronary artery disease remains substantial. Several preclinical and clinical studies have shown that drug therapy ultimately leads to a regression of the angiographic lesions but also results in a reduction in cardiovascular events. The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein (CEPT) inhibitors, torcetrapib and dalcetrapib, has led to considerable doubt about the value of the current strategy to raise high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These clinical results, as well as animal studies, have revealed the complexity of HDL metabolism, assessing a more important role of functional quality compared to circulating quantity of HDL. As a result, HDL-based therapeutic interventions that maintain or enhance HDL functionality, such as improving its main property, the reverse cholesterol transport, require closer investigation. In this review, we will discuss HDL metabolism and function, clinical-trial data available for HDL-raising agents, and potential strategies for future HDL-based therapies. PMID- 26535186 TI - Anterior Medial Meniscal Root Tears: A Novel Arthroscopic All Inside Repair. AB - BACKGROUND: Management of tears of the anterior and posterior roots of the meniscus is still controversial. We wish to propose a simple technique of suture anchor to repair tears of the anterior root of the medial meniscus. METHODS: Twelve patients, active males, underwent arthroscopic repair of the anterior meniscal horn between 2009 and 2011. All were assessed postoperatively at an average follow-up of 1 year after the index operation. RESULTS: At the last appointment, the average Lysholm scores was improved from a pre-operative average value of 48+/-17 to a postoperative value of 91+/-7 (P<0.001); five patients (45.3%) were scored as excellent (>=95), and 7 (54.6%) as good (85-94). At the last appointment, 8 of 9 active patients practiced sport at the same preoperative level, 1 (8.5%) had changed to lower level of activity. No technique related complications were evident. PMID- 26535187 TI - Teriparatide in Fracture Non-Unions. AB - BACKGROUND: The use of teriparatide in the management of fracture disorders is poorly documented. This study aims to show that teriparatide administration may improve the healing process in patients with nonunions after open fixation of traumatic fractures of the lower limb. METHODS: Four patients received Teriparatide for management of non-unions after open fixation of traumatic fractures of the lower limb. RESULTS: Teriparatide administration resulted in adequate bone callus over the site of nonunion in all the patients, and clinical and radiographic evidence of sound union. CONCLUSIONS: The efficacy of teriparatide in delayed or non unions is still unclear. It may induce an angiogenetic response which counteracts the features responsible for development of non-union. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26535188 TI - Role of Nitric Oxide in Glioblastoma Therapy: Another Step to Resolve the Terrible Puzzle ? AB - Glioblastoma Multiforme, the most common and aggressive primary brain tumor, remains incurable despite of the advent of modern surgical and medical treatments. This poor prognosis depends by the recurrence after surgery and intrinsic or acquired resistance to chemotherapy and radiotherapy. Nitric oxide is a small molecule that plays a key roles in glioma pathophysiology. Many researches showing that NO is involved in induction of apoptosis, radiosensitization and chemosensitization. Therefore, NO role, if clarified, may improve the knowledge about this unsolved puzzle called GBM. PMID- 26535189 TI - Unique Association of Rare Cardiovascular Disease in an Athlete With Ventricular Arrhythmias. AB - Ventricular arrhythmias are a leading cause of non-elegibility to competitive sport. The failure to detect a significant organic substrate in the initial stage of screening does not preclude the identification of structural pathologies in the follow-up by using advanced imaging techniques. Here we report the case of a senior athlete judged not elegible because an arrhythmia with the morphology consistent with the origin of the left ventricle, in which subsequent execution of a cardiac MR and a thoracic CT scan has allowed the identification of an unique association between an area of myocardial damage, probable site of origine of the arrhythma, and a rare aortic malformation. PMID- 26535190 TI - Communication between the musculocutaneous and median nerves in the arm: an anatomical study and clinical implications. AB - OBJECTIVE: To determine the frequency and features of communication between the musculocutaneous nerve (MCN) and median nerve (MN) in a sample of the Colombian population, and assess its clinical implication. METHODS: The arms of 53 cadaver specimens that had been subjected to necropsy at the National Institute of Forensic Medicine, in Bucaramanga, Colombia, were studied. The structures of the anterior compartment of the arm were dissected and characterized regarding the presence of communication between the MCN and MN. RESULTS: A communicating branch was found in 21/106 upper limbs (19.8%), occurring bilaterally in 10 (47.6%) and unilaterally in 11 (52.4%), without significant difference regarding the side of occurrence (p = 0.30). In 17% of the cases, there was MCN-MN communication in which the communicating branch was seen leaving the MCN after piercing the coracobrachialis muscle (Type I). In 2.8%, the connection was from the MN to the MCN (Type II). The length of the communicating branch was 57.8 +/- 33.4 mm. The distances from the proximal and distal points of this branch to the coracoid process were 138 +/- 39.4 mm and 188 +/- 48.3 mm, respectively. The communicating branch was located mostly in the middle third of the arm. CONCLUSIONS: The frequency of MCN-MN communication observed in the present study is in the middle of the range of what was reported in previous studies. MCN-MN connections need to be taken into account in diagnosing and managing peripheral nerve lesions of the upper limbs. PMID- 26535191 TI - The Sociedade Brasileira de Ortopedia e Traumatologia turns 80. PMID- 26535192 TI - Viscosupplementation for treating knee osteoarthrosis: review of the literature. AB - The aim here was to evaluate the evidence that might support or refute the use of intra-articular viscosupplementation in treating patients with symptomatic knee osteoarthrosis. A review of the literature was conducted using the Medline, PubMed and Cochrane Controlled Trial Register databases and Cochrane database systematic reviews (Cochrane Library). Only studies presenting a high level of evidence were taken into consideration. This study included analysis on randomized clinical trials that included at least 100 patients in each intervention group, meta-analyses and systematic reviews. Two meta-analyses, five systematic reviews and six randomized clinical trials fulfilled the inclusion criteria for this review. In the light of the best evidence available so far, there is no consensus for indicating or even for contraindicating the use of intra-articular viscosupplementation among patients with symptomatic knee osteoarthrosis (level of evidence I and degree of recommendation A). Further studies with appropriate methodology are needed to elucidate this matter. PMID- 26535193 TI - Reproducibility of the Tronzo and AO classifications for transtrochanteric fractures. AB - OBJECTIVE: To analyze the reproducibility of the Tronzo and AO classifications for transtrochanteric fractures. METHOD: This was a cross-sectional study in which the intraobserver and interobserver concordance between two readings made by 11 observers was analyzed. The analysis of the variations used the kappa statistical method. RESULTS: Moderate concordance was found in relation to the AO classification, while slight concordance was found for the Tronzo classification. CONCLUSION: This study found that the AO/Asif classification for transtrochanteric presented greater intra and interobserver reproducibility and that greater concordance was correlated with greater experience of the observers. Without division into subgroups, the AO/Asif classification was shown, as described in the literature, to be acceptable for clinical use in relation to transtrochanteric fractures of the femur, although it did not show absolute concordance, given that its concordance level was only moderate. Nonetheless, its concordance was better than that of the Tronzo classification. PMID- 26535194 TI - Intra and interobserver concordance of the AO classification system for fractures of the long bones in the pediatric population. AB - OBJECTIVE: The AO classification for fractures of the long bones in the pediatric population was developed and validated in 2006. However, the complexity of this system has limited its use in clinical practice and few studies in the literature have evaluated its reproducibility and applicability. The present study had the objective of determining the intra and interobserver agreement using the pediatric AO system, among physicians with different levels of experience. METHODS: After making the sample calculation, 108 consecutive radiographs on long bone fractures in patients aged 0-16 years, coming from the digital files of the quaternary-level hospital, were selected. The radiographs were classified by five examiners with different levels of experience after prior explanations about the system. A chart containing images from the classification was made available for consultation. The evaluations were made at two different times by each observer. The Fleiss kappa index was used to ascertain the intra and interobserver agreement. RESULTS: Intraobserver agreement that was at least substantial was obtained for all the items of the classification and it reached excellent levels for all observers in relation to five of the seven items considered. The interobserver evaluation presented excellent levels of agreement in two items, substantial in two items, moderate to substantial in one item and poor to moderate in one item. No influence from the observer's experience was observed with regard to obtaining higher or lower levels of agreement, either in the intraobserver or in the interobserver evaluation. CONCLUSIONS: In this study, the intra and interobserver agreement was considered to be good or excellent for the pediatric AO classification system, for the parameters of bone, segment, paired bone, subsegment, standard and deviation. However, the intra and interobserver agreement was statistically unsatisfactory for the parameter of severity/side of avulsion. The levels of agreement obtained did not depend on the observer's level of experience within pediatric orthopedics. PMID- 26535195 TI - Experimental trial on surgical treatment for transverse fractures of the proximal phalanx: technique using intramedullary conical compression screw versus lateral compression plate. AB - OBJECTIVE: To compare the mechanical parameters between two methods for stabilization through compression: 1.5 mm axial compression plate versus conical compression screw used as an intramedullary tutor. METHODS: Polyurethane models (Sawbone((r))) that simulated transverse fractures of the proximal phalanx were used. The models were divided into three groups: lateral plate, conical screw and no implant. RESULTS: Greater force was needed to result in fatigue in the synthesis using an intramedullary plate. Thus, this model was proven to be mechanically superior to the model with the lateral plate. CONCLUSION: Stabilization using the Acutrak((r)) screw for treating fractures in the model used in this trial presents mechanical results that are statistically significantly superior to those from the axial compression technique using the lateral plate (Aptus Hand((r))). PMID- 26535196 TI - Acromioclavicular dislocation: treatment and rehabilitation. Current perspectives and trends among Brazilian orthopedists. AB - OBJECTIVE: To evaluate the approaches and procedures used by Brazilian orthopedic surgeons in treatment and rehabilitation of acromioclavicular dislocation of the shoulder. METHODS: A questionnaire comprising eight closed questions that addressed topics relating to treatment and rehabilitation of acromioclavicular dislocation was applied to Brazilian orthopedic surgeons over the three days of the 45th Brazilian Congress of Orthopedics and Traumatology, in 2013. RESULTS: A total of 122 surgeons completely filled out the questionnaire and formed part of the sample analyzed. Most of them came from the southeastern region of the country. In this sample, 67% of the participants would choose surgical treatment for patients with grade 3 acromioclavicular dislocation. Regarding the preferred technique for surgical treatment of acute acromioclavicular dislocation, a majority of the surgeons used subcoracoid ligature with acromioclavicular fixation and transfer of the coracoacromial ligament (25.4%). Regarding complications found after surgery had been performed, 43.4% and 32.8% of the participants, respectively, stated that residual deformity of the operated joint and pain were the complications most seen during the postoperative period. CONCLUSIONS: Although there was no consensus regarding the treatment and rehabilitation of acromioclavicular dislocation, evolution had occurred in some of the topics analyzed in this questionnaire applied to Brazilian orthopedists. However, further controlled prospective studies are needed in order to evaluate the clinical and scientific benefit of these trends. PMID- 26535197 TI - Rotator cuff arthropathy: what functional results can be expected from reverse arthroplasty? AB - OBJECTIVE: To evaluate the functional results from reverse arthroplasty and its complications and relationships with types of injury. METHODS: Twenty-seven shoulders (26 women and one man) were treated. The patients were assessed using the UCLA functional scale. The implant used was the Delta Xtend Depuy((r)) model. The injuries were classified using the Seebauer method for the degree of arthroplasty and the Nerot method for notching. RESULT: The mean age was 77.4 years (range: 67-89) and the follow-up was 25.8 months (range: 6-51). The preoperative UCLA score was 10.1 (range: 6-15) and the postoperative UCLA score was 29.8 (range: 22-35), which was a statistically significant improvement (p < 0.001). According to the Seebauer classification, five patients were 1B, 19 were 2A and three were 2B. Fifteen cases presented complications (55.5%) and notching was the commonest of these, occurring in 14 patients (nine with grade 1 and five with grade 2), but this did not cause instability in any of them. Only one patient (3.7%) had a major complication, consisting of dislocation in the immediate postoperative period. Two patients (7.4%) said that they would undergo the procedure again. One patient (3.7%) underwent a revision procedure. CONCLUSION: Reverse arthroplasty was shown to be an excellent option for treating patients with rotator cuff arthropathy, with a low rate of major complications. Notching was a frequent complication, but in the majority of the cases, it did not present clinical repercussions. PMID- 26535198 TI - Evaluation of the quality of life of patients undergoing hemiarthroplasty of the hip. AB - OBJECTIVE: This was a comparative analysis on the quality of life of patients who underwent hemiarthroplasty of the hip, assessed before the operation and 3 and 6 months after the operation, by means of the SF-36 questionnaire (Medical Outcomes Study 36-Item Short Form health survey). METHODS: A prospective study was conducted on 12 patients with femoral neck fractures who underwent partial hip arthroplasty between June 2013 and July 2014. Female patients predominated (58.3%). The mean age was 83 years and, in 91.7%, the fracture was due to falling from a standing position. The SF-36 questionnaire was applied before the operation and 3 and 6 months after the operation. RESULTS: With regard to physical health, the patients presented low scores for functional capacity and physical aspects. They had good scores for the subitem of general state and high scores regarding pain. Vitality, social aspect and mental health had moderate scores and emotional aspects had a low score. CONCLUSION: With the sample analyzed here, we can say that the hip hemiarthroplasty procedure for cases of unstable femoral neck fractures, in patients with low functional demands analyzed over a postoperative period of 6 months, does indeed allow quality of life to be maintained. PMID- 26535199 TI - Injuries among amateur runners. AB - OBJECTIVES: To determine the frequency and severity of injuries that affect amateur runners. METHODS: This study was conducted by means of a questionnaire applied to 204 amateur runners. Individuals who were under the age of 18 years and those who were unpracticed runners were excluded. The data gathered comprised the number, type, site and degree of severity of the injuries and the individuals' age and sex. RESULTS: It was observed that male athletes predominated. The mean age was 32.6 +/- 9.3 years with a range from 18 to 68 years, and the injuries were classified as mild, keeping the athlete away from practicing running for fewer than eight days. Sprains, blisters and abrasions were the most frequent injuries, located most often on the lower limbs and predominantly on the feet. CONCLUSION: In practicing running, sprains, blisters and abrasions occur frequently, but are mild injuries. They mostly affect the lower limbs. PMID- 26535200 TI - Evaluation of intraoperative radioscopy on the coronal alignment of the tibial component in primary knee arthroplasty. AB - OBJECTIVES: The present study had the objective of evaluating the effect of the use of intraoperative radioscopy in cases of primary knee arthroplasty, on the final alignment of the tibial component. METHODS: Patients who underwent total knee arthroplasty (TKA) between April 13, 2013, and April 20, 2013, were included in the study. These patients were evaluated retrospectively and two groups were identified: one in which intraoperative radioscopy was used to assess the positioning of the tibial component during the surgery and the other in which this resource was not used. RESULTS: The mean angle of alignment of the tibial component in relation to the tibial diaphysis was greater in the group without use of intraoperative radioscopy (90.82) than in the group with radioscopy (90.63), which was a statistically significant result (p < 0.05). CONCLUSION: Use of intraoperative radioscopy during TKA produced a better mean angle of alignment between the tibial component and the tibial diaphysis, in comparison with nonuse. PMID- 26535201 TI - Saphenous nerve injury during harvesting of one or two hamstring tendons for anterior cruciate ligament reconstruction. AB - OBJECTIVE: The aim of this study was to assess whether harvesting of two hamstring tendons (semitendinosus and gracilis) has the same rate of nerve injury as harvesting of the semitendinosus tendon alone, used as a triple graft. METHODS: Changes in sensitivity relating to injury of the infrapatellar branch of the saphenous nerve were evaluated in 110 patients six months after they underwent anterior cruciate ligament (ACL) reconstruction using hamstring tendons. They were divided into two groups: one in which only the semitendinosus was used and the other, the semitendinosus and gracilis. RESULTS: The group in which only the semitendinosus was used as a graft presented a nerve injury rate of 36.1%. In the group in which the semitendinosus and gracilis tendons were used, 58.1% of the patients presented altered sensitivity. In the general assessment on all the patients, the nerve injury rate was 50.9%. CONCLUSION: Harvesting the semitendinosus alone and using it in triple form is a viable option for ACL reconstruction and may give rise to fewer nerve injuries relating to branches of the saphenous nerve. PMID- 26535202 TI - Patellar tendinopathy: late-stage results from surgical treatment. AB - OBJECTIVE: To evaluate the late-stage results from surgical treatment of patellar tendinopathy (PT), using the Visa score (Victorian Institute of Sport Tendon Study Group) and the Verheyden method. METHODS: This was a retrospective study in which the postoperative results from 12 patients (14 knees) who were operated between July 2002 and February 2011 were evaluated. The patients included in the study presented patellar tendinopathy that was refractory to conservative treatment, without any other concomitant lesions. Patients who were not properly followed up during the postoperative period were excluded. RESULTS: Using the Verheyden method, nine patients were considered to have very good results, two had good results and one had poor results. In relation to Visa, the mean was 92.4 points and only two patients had scores less than 70 points (66 and 55 points). CONCLUSION: When surgical treatment for patellar tendinopathy is correctly indicated, it has good long-term results. PMID- 26535203 TI - Clinical aspects of patients with traumatic lesions of the brachial plexus following surgical treatment. AB - OBJECTIVE: To evaluate sociodemographic and clinical aspects of patients undergoing operations due to traumatic lesions of the brachial plexus. METHOD: This was a retrospective study in which the medical files of a convenience sample of 48 patients operated between 2000 and 2010 were reviewed. The following were evaluated: (1) range of motion (ROM) of the shoulder, elbow and wrist/hand, in degrees; (2) grade of strength of the shoulder, elbow and wrist/hand; (3) sensitivity; and (4) visual analogue scale (VAS) (from 0 to 10). The Student's t, chi-square, Friedman, Wilcoxon and Kruskal-Wallis tests were used (p < 0.05). RESULTS: The patients' mean age was 30.6 years; 60.4% of them had suffered motorcycle accidents and 52.1%, multiple trauma. The mean length of time until surgery was 8.7 months (range: 2-48). Thirty-one patients (64.6%) presented complete rupture of the plexus. The frequent operation was neurosurgery in 39 cases (81.3%). The ROM achieved was >=30 degrees in 20 patients (41.6%), with a range from 30 degrees to 90 degrees and mean of 73 degrees (p = 0.001). Thirteen (27.1%) already had shoulder strength >=M3 (p = 0.001). Twenty-seven patients (56.2%) had elbow flexion >=80 degrees , with a range from 30 degrees to 160 degrees and mean of 80.6 degrees (p < 0.001). Twenty-two had strength >=M3 (p < 0.001). Twenty-two patients (45.8%) had wrist extension >=30 degrees starting from flexion of 45 degrees , with a range from 30 degrees to 90 degrees and mean of 70 degrees (p = 0.003). Twenty-seven (56.3%) presented wrist/hand extension strength >=M3 (p = 0.002). Forty-five (93.8%) had hypoesthesia and three (6.2%) had anesthesia (p = 0.006). The initial VAS was 4.5 (range: 1.0-9.0) and the final VAS was 3.0 (range: 1.0-7.0) (p < 0.001). CONCLUSION: Traumatic lesions of the brachial plexus were more prevalent among young adults (21-40 years), men, people living in urban areas, manual workers and motorcycle accidents, with multiple trauma and total rupture of the plexus. Neurosurgery, with a second procedure consisting of muscle-tendon transfer, was the commonest operation. Surgery for traumatic lesions of the brachial plexus resulted in significant improvement in the ROM and strength of the shoulder, elbow and wrist/hand, improvement of the sensitivity of the limb affected and reduction of the final pain. PMID- 26535204 TI - Analysis on the risk of contralateral proximal femoral epiphyseal slippage using the modified Oxford score. AB - OBJECTIVE: To determine the application of the modified Oxford score among patients with proximal femoral epiphyseal slippage (PFES) as an aid to indicating prophylactic surgical treatment on the contralateral hip. METHODS: Retrospective analysis on the medical files of patients attended at the institution where the authors work. From these, patients attended between 2008 and 2011 who presented unilateral PFES and were followed up for a minimum of two years were selected. Patients were excluded if they presented endocrine disease, metabolic disease, Down syndrome or radiographs that were inadequate for determining the modified Oxford score. The initial radiographs received scores ranging from 16 to 26. Statistical analysis was used to determine whether the scoring was predictive of future development of contralateral slippage. RESULTS: Among the 15 patients with unilateral PFES that were selected, five (33.3%) evolved with contralateral slippage. The patients were divided into two groups. Four patients were considered to present risk and three of them developed contralateral slippage. In the group that was considered not to present risk, there were 11 patients and two of these evolved with contralateral slippage. Thus, there was a tendency for the patients in the group that developed the disease to differ from the group that did not develop it, in relation to the risk classification. CONCLUSION: Although application of the modified Oxford score was not statistically significant in our sample, we noted a tendency toward contralateral slippage among hips with low scores. PMID- 26535205 TI - Syndrome of fascial incarceration of the long thoracic nerve: winged scapula. AB - OBJECTIVE: To analyze the results from early intervention surgery in patients with the syndrome of fascial incarceration of the long thoracic nerve and consequent winged scapula. METHODS: Six patients with a syndrome of nerve trapping without specific nerve strain limitations were followed up. RESULTS: The patients achieved improvement of their symptoms 6-20 months after the procedure. The motor symptoms completely disappeared, without any persistent pain. The medial deformity of the winged scapula improved in all cases, without any residual esthetic disorders. CONCLUSION: The approach of early surgical release seems to be a better predictor for recovery from non-traumatic paralysis of the anterior serratus muscle. PMID- 26535206 TI - Is arthrodesis still a good indication for non-inflammatory arthrosis of the wrist? AB - OBJECTIVE: The aim of this study was to objectively and subjectively evaluate wrist function after total arthrodesis, among patients with sequelae of non inflammatory arthritis who were treated with rigid internal fixation using a DCP plate. METHODS: Thirty-two patients with sequelae of non-inflammatory degenerative arthritis were treated using total arthrodesis of the wrist. Of these, two patients were treated with Kirschner wires and four discontinued the treatment, thus leaving 26 patients. The indication for arthrodesis of the wrist was the presence of intracarpal pathological conditions: eight wrists presented sequelae from fractures of the distal radius; 13 had sequelae from fractures of the scaphoid; and five had sequelae from Kienbock's disease. The cases were evaluated using the visual analogue scale (VAS), the muscle strength test, the Jebsen-Taylor functional test and the Buck-Gramcko test. RESULTS: It was observed that there were no significant differences at the level of 5%, in the variables of grip strength, VAS, Jebsen-Taylor functional test or Buck-Gramcko/Lohmann test, between the pathological conditions. CONCLUSION: Total arthrodesis of the wrist using a plate in the dorsal region was shown to be a safe and efficient technique for patients with different types of pathological arthrosis of the wrist, since it did not cause any important functional incapacity and brought great pain relief. PMID- 26535207 TI - The effect of platelet-rich plasma on the repair of muscle injuries in rats. AB - OBJECTIVE: The need for therapeutic options for muscle injuries, which are increasingly frequent among sports practitioners, was the motivation for this experimental study, which had the aim of evaluating the histological effects of platelet-rich plasma (PRP) on repairs to muscle tissues of rats. METHODS: PRP was obtained by means of double centrifugation of blood from five animals. In 30 rats, an injury was produced in the middle third of the belly of the gastrocnemius muscle of each hind limb. These injuries did not receive any treatment in six rats (12 legs). In 24 rats, 0.9% physiological serum was injected into the injury in the left leg and PRP into the injury in the right leg. Samples from the treated and untreated tissue were evaluated histologically 7 and 21 days after the procedures. RESULTS: The quantity of collagen in the injuries treated with PRP was significantly lower than that in the other injuries, in the evaluation made 7 days after the procedure, but it became equal to the other groups in the evaluation done on the 21st day. There was a significant increase (p < 0.001) in the quantity of collagen from the 7th to the 21st day in the injuries treated with PRP, but this was not seen in the injuries treated using other methods. The inflammatory process was shown to be more intense in the injuries treated with PRP than in the injuries of the other treatment groups, in the evaluation done 7 days after the procedure. However, the morphological aspects of these injuries were seen to be similar to those of the untreated injuries, 21 days after the procedure. CONCLUSION: PRP promoted complete tissue restitution between the 7th and 21st days in experimental muscle injuries. PMID- 26535208 TI - Reconstruction of chronic tearing of the distal triceps using the double-row configuration: technical note. AB - Tearing of the distal triceps is uncommon and may be difficult to diagnose, especially in situations of partial tearing. Imaging methods such as ultrasonography and magnetic resonance imaging should be used to confirm the diagnosis and define the extent of the injury. The preferred treatment for complete tearing of the triceps is surgical, unlike in cases of partial tearing, in which the treatment depends on factors such as pain, functional deficit and the patient's expectations. Here, we describe the case of a patient with partial tearing of the distal triceps after falling to the ground, which was not diagnosed at the time of first attendance and evolved with pain and great functional loss. The surgical procedure was performed nine months after the injury, with reconstruction of the triceps by means of reinforcement using the tendon of the ipsilateral semitendinosus and fixation in the olecranon using the double-row configuration. The patient remained immobilized using a sling for one week and then gains in passive range of motion (ROM) were introduced. Three weeks later, the patient was released for gains in active ROM. Muscle strengthening was started after 12 weeks. Six weeks after the surgical procedure, the patient was free from pain and presented complete ROM, grade V elbow extension force and hypertrophy of the triceps. The technique described here was shown to be useful for treating tears of the tendon of the distal triceps. PMID- 26535209 TI - Parosteal aneurysmal bone cyst. AB - The incidence of aneurysmal bone cysts is 0.14 cases per 100,000 individuals. Parosteal aneurysmal bone cysts are the least prevalent subtype and represent 7% of all aneurysmal bone cysts. We present the case of a 38-year-old male patient with pain and bulging in his right arm for eight months. He had previously been diagnosed as presenting giant-cell tumor, but his slides were reviewed and his condition was then diagnosed as parosteal aneurysmal bone cyst. The patient was treated with corticosteroid and calcitonin infiltration into the lesion and evolved with clinical and radiological improvement within the first five weeks after the operation. PMID- 26535210 TI - Arthroscopic treatment of synovial osteochondromatosis of the elbow. Case report and literature review. AB - Synovial osteochondromatosis is a benign proliferative disorder with metaplasia of the synovial membrane that affects the fibroblasts of the synovial joints, tendons and bursae. In literature, there are few descriptions of synovial osteochondromatosis of the elbow. The objective of this article was to report a case of synovial osteochondromatosis of the elbow in a patient aged 32, basketball athlete, in which surgical treatment was chosen because of the pain and functional limitation and stage of disease with multiple loose bodies. Patient 32, male, presented with pain and limitation of motion of the elbow. The range of passive motion was 100 degrees of flexion and 30 degrees extension. The range of active motion was 40-90 degrees . Magnetic resonance observed many loose bodies mainly in the posterior compartment in the olecranon fossa plus some chondral lesions in the capitellum. The arthroscopic treatment was chosen with two anteriors portals (medial and lateral) and two posterior portals (standard posterior and posterolateral) for easing loose bodies and osteoplasty of the olecranon fossa. The visual analog scale pain was 9-3 and its arc of active motion was 110 degrees to -20 degrees of flexion and extension. On a scale of performance from Mayo Clinic patients was 65 points preoperatively to 90 postoperatively with 9 months follow-up and the patient was satisfied with the treatment outcome. Arthroscopic treatment of synovial osteochondromatosis of the elbow is an effective and safe therapeutic management with low morbidity and early return to activities. PMID- 26535211 TI - 2015 Autumn Conference. PMID- 26535212 TI - Interaction between HSP 70 and iNOS in skeletal muscle injury and repair. AB - Muscle injuries are frequently occurred in various sports. The biological process and mechanism of muscle repair after injury are well known through the many studies. This study aimed at presenting heat shock protein and nitric oxide synthase are to respond to muscle damage and repair. This section discusses the results obtained through many articles. Heat shock proteins (HSPs) are considered to play an essential role in protecting cells from damage, preparing them to survive on new environmental challenges. In addition, exercise-induced changes such as heat shock, oxidative, metabolic, muscular, and cytokine stress seem to be responsible for the HSP response to exercise. Also, inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) for prolonged period and causes pathophysiological effects. Furthermore, iNOS is involved in processes such as cell injury, wound repair, embryogenesis, tissue differentiation, and suppression of tumorigenesis. In conclusion, the inhibition of HSP 70 on caspase-3 and apoptosis is associated with its inhibition on iNOS that leads to less NO production. PMID- 26535213 TI - Role of creatine supplementation in exercise-induced muscle damage: A mini review. AB - Muscle damage is induced by both high-intensity resistance and endurance exercise. Creatine is a widely used dietary supplement to improve exercise performance by reducing exercise-induced muscle damage. Many researchers have suggested that taking creatine reduces muscle damage by decreasing the inflammatory response and oxidative stress, regulating calcium homeostasis, and activating satellite cells. However, the underlying mechanisms of creatine and muscle damage have not been clarified. Therefore, this review discusses the regulatory effects of creatine on muscle damage by compiling the information collected from basic science and sports science research. PMID- 26535214 TI - Recommendations to the primary care practitioners and the patients for managing pelvic pain, especially in painful bladder syndrome for early and better prognosis. AB - Painful bladder syndrome (PBS) is a common disease presenting with chronic pelvic pain and discomfort with at least one urinary symptom with no identifiable cause. The etiology is still unknown, and the medication has limited effects on pelvic pain or other urinary symptoms. This article presents advanced insight regarding the approach to PBS, particularly pelvic pain for primary care practitioners and patients. We suggest six tips for medical staff and suspected patients for easy diagnosis and proper treatment of pelvic pain. These six tips cover: Self awareness of the disease; immediate urine culture test; specifying the location of pain urinary incontinence; frequency, or urgency without functional disorder of an overactive bladder helpful dietary control; complementary, and alternative medicine, and finding an expert. These tips might be helpful in advancing the schematic approach and in achieving better prognosis of PBS. Further study should be conducted to achieve better treatment for this disease, including development of a definitive test and diagnosis. PMID- 26535215 TI - Changes in blood lactate concentrations during taekwondo combat simulation. AB - The aim of this study was to analyze blood lactate response before, during and after simulated taekwondo fight in young male athletes. The experiment was composed of simulated official taekwondo fight. During the experiment a total of 7 blood samples (25 MUL) were collected that following: at rest, after 1st, 2nd, and 3rd rounds, and 3, 5, and 10 min after the end of combat. The results showed that blood lactate concentrations [Lac]B increased significantly after 1st, 2nd, and 3rd rounds of the combat compared to the rested values. The [Lac]B after 3rd round was higher when compared to 3, 5, and 10 min of recovery. After 10 min of passive recovery, the [Lac]B was significantly lesser than 3 and 5 min of recovery, and 2nd round. These data showed that taekwondo requires high activation of anaerobic lactic metabolism, and improves the ability to rapidly remove the lactate from blood. PMID- 26535216 TI - Dyspnea, depression and health related quality of life in pulmonary arterial hypertension patients. AB - Pulmonary arterial hypertension (PAH) is a rare and devastating disease which is characterized by worsening dyspnea and exercise tolerance. These patients are often found to have concomitant, depression, anxiety and impaired health-related quality of life (HRQOL). The interrelationship of dyspnea, depression and HRQOL in these patients is not well studied. Retrospective analysis was performed on 46 PAH patients (mean age 51.73). Patients completed Medical Outcomes Study Short - Form 36 V2 (SF-36) to measure HRQOL, Modified Medical Research Council (mMRC) Dyspnea Scale and Zung Depression Scale (ZDS). Physical Health Composite Scores (PCS) and Mental Health Composite Scores (MCS) were derived from SF-36. Spearman's correlation was computed to determine degree of correlation between pairs of scales. 46 patients (12 males, 34 females; median age 51.4 yr) with confirmed PAH were considered for the study of which 36 patients (9 males, 27 females, median age 50.1 yr), were eligible for further analysis. MMRC Dyspnea Scale Score was 1.0 (Q1 to Q3:1.0 to 2.0). Median MCS was 52.1 (Q1 to Q3:41.7 to 57.1) and PCS was 37.9 (Q1 to Q3: 30.7 to 49.6). There was a significant negative correlation between dyspnea and PCS (r =-0.660, P<0.0001) and MCS (r =-0.342, P<0.0411). The ZDS was available for 17 of these patients; their median score was 42.0 (Q1 to Q3: 33.0 to 46.0). There was a significant correlation between the ZDS and PCS (r =-0.578, P<0.0150,) MCS (r =-0.752, P<0.0005). Patients with PAH suffer from diminished HRQOL correlating with their dyspnea and underlying depression. PMID- 26535217 TI - Effect of regular swimming exercise on the physical composition, strength, and blood lipid of middle-aged women. AB - The purpose of this study is to define the effects of regular swimming exercise on the physical composition, physical strength, and blood lipids of middle-aged women. The subjects of this study are a total of 24 middle-aged women in the swimming group and the control group, with 12 women for each group. The swimming group performed swimming exercise for 60 min every time for 3 times a week, for a total of 12 weeks. For data processing, SPSS 21.0 statistics program was used to calculate the mean and standard deviation. For the difference verification on the change in mean for each group and between the groups, paired and independent t tests were respectively used. As a result, for physical composition, the body fat rate decreased in the swimming group. Moreover, the difference verification result showed a statistically significant difference between the groups. For physical strength, the difference verification result for each group showed that the swimming group had a statistically significant difference in flexibility and cardiovascular endurance. Moreover, the difference verification result between the groups showed a statistically significant difference only for flexibility. For blood lipids, as a result of the difference verification for each group, T-C and TG showed a significant decrease, and HDL-C, a significant increase. However, in the difference verification result between the groups, only T-C and TG showed a statistically significant difference. With these results, it is considered that regular swimming exercise is effective for improving the physical composition, physical strength, and blood lipids of middle-aged women. PMID- 26535218 TI - The effects of aquatic walking and jogging program on physical function and fall efficacy in patients with degenerative lumbar spinal stenosis. AB - The purpose of this study was to evaluate the effects of 12-week aqua walking and jogging program on muscle function, ankle range of motion (ROM), balance and fell efficacy in degenerative lumbar spinal stenosis (DLSS) patients. Six patients (2 males, 4 females) with DLSS participated in aquatic exercise program 3 times per week with each session of 60 min (warming-up, aqua walking, aqua jogging and cool down) at 1 m 20 cm-1 m 30 cm deep pool. Janda's muscle function test, ankle ROM, Berg balance scale (BBS) and fall efficacy scale (FES) were analyzed before and after the training intervention. We found significant increases in balance, muscle function, ankle ROM and fall efficacy after training intervention. In conclusion, aquatic exercise seems to affect physical function and fall efficacy positively in elderly DLSS patients. PMID- 26535219 TI - Effects of the combined PNF and deep breathing exercises on the ROM and the VAS score of a frozen shoulder patient: Single case study. AB - This study was conducted to examine the influence of combined exercise using proprioceptive neuromuscular facilitation (PNF) and deep breathing exercise on range of motion (ROM) and visual analog scale (VAS) score in acute frozen shoulder patient. The subject of this study was woman complained disabilities in daily routine due as a frozen left shoulder. The exercise program was composed of 11 sessions and continued four weeks. The program was composed of PNF and deep breathing exercise, and the subject was compared by passive ROM (shoulder flexion, abduction, and internal and external rotation) test and VAS score in shoulder movement before and after the exercise. The results showed that patient who practiced this program, the ROM of the shoulder joint increased and the VAS score decreased. Thus, this program was shown to be effective in suppressing pain and increasing the ROM of the shoulder joint in acute frozen shoulder patient. PMID- 26535220 TI - Association between exonic polymorphism (rs629849, Gly1619Arg) of IGF2R gene and obesity in Korean population. AB - The aim of this study is to investigate the relationship between single nucleotide polymorphisms (SNPs) and susceptibility to obesity. A previous study suggested that insulin-like growth factors (IGFs) may affect obesity and that IGFs regulate cellular signals by receptors that include the insulin-like growth factor 1 receptor (IGF1R) and the insulin-like growth factor 2 receptor (IGF2R). In this research, the rs3743262 and rs2229765 SNPs of IGF1R gene and rs629849 and rs1805075 SNPs of IG-F2R gene were genotyped in 120 overweight and obese patients with a BMI>=23 kg/m2 (Body Mass Index) and 123 healthy controls with a BMI of 18.5-23.0 kg/m2. Genotyping of each SNP was performed by direct sequencing. Among tested SNPs in IGF1R and IGF2R genes, rs629849 SNP of IGF2R gene showed significant association with obesity (OR=1.86, 95% CI=1.02-3.40, P=0.044 in codominant1 model; OR=1.99, 95% CI=1.10-3.57, P=0.020 in dominant model; OR=1.93, 95% CI=1.13-3.31, P=0.013 in log-additive model). And allele distribution between the control group and overweight/obese group also showed significant difference (OR=1.93, 95% CI=1.14-3.28, P=0.015). In conclusion, these results indicate that rs629849 SNP of IGF2R might be contributed to development of obesity in the Korean population. PMID- 26535221 TI - Is there a role for genetic risk assessment in the treatment of dyslipidemia in primary and secondary prevention of coronary heart disease? AB - Genetic variants have been associated with the risk of coronary heart disease (CHD). Mega et al studied the association of a genetic risk score based on 27 genetic variants with incidents of recurrent CHD, adjusting for traditional risk factors using data from a community based study and 4 randomized controlled trials of both primary and secondary prevention with statin therapy. When individuals were divided into low, intermediate and high genetic risk categories, a significant gradient in risk of incident and recurrent CHD was shown. PMID- 26535222 TI - The Burundi Heart Centre: From concept to design. AB - Burundi is one of the world's poorest nations, which is also reflected in its relative lack of cardiac facilities, particularly those catering to young children and adults. The authors discuss current efforts to build "The Burundi Heart Centre" to help address this challenge. In particular, they highlight how the project can act as a case study for a sustainable architecture that involves local people and uses locally available materials in a contemporary and innovative way. PMID- 26535223 TI - Percutaneous pulmonary valve implantation. PMID- 26535224 TI - Utility of mass spectrometry for the diagnosis of the unstable coronary plaque. AB - Mass spectrometry is a powerful technique that is used to identify unknown compounds, to quantify known materials, and to elucidate the structure and chemical properties of molecules. Recent advances in the accuracy and speed of the technology have allowed data acquisition for the global analysis of lipids from complex samples such as blood plasma or serum. Here, mass spectrometry as a tool is described, its limitations explained and its application to biomarker discovery in coronary artery disease is considered. In particular an application of mass spectrometry for the discovery of lipid biomarkers that may indicate plaque morphology that could lead to myocardial infarction is elucidated. PMID- 26535225 TI - Genetic modifiers to the PLN L39X mutation in a patient with DCM and sustained ventricular tachycardia? PMID- 26535226 TI - Open Access for Orthopaedic Sports Medicine. PMID- 26535227 TI - Tunnel Enlargement and Coalition After Anatomic Double-Bundle Anterior Cruciate Ligament Reconstruction With Hamstring Tendon Autografts: A Computed Tomography Study. AB - BACKGROUND: Tunnel enlargement and coalition following double-bundle anterior cruciate ligament (ACL) reconstruction with hamstring tendon autografts has not yet been sufficiently studied. HYPOTHESIS: The incidence and the degree of femoral tunnel enlargement will be significantly greater than those for tibial tunnel enlargement after anatomic double-bundle ACL reconstruction using hamstring tendon autografts. There will be no significant correlation between tunnel enlargement and coalition and the postoperative knee laxity. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Thirty-nine patients who underwent anatomic double-bundle ACL reconstruction using semitendinosus and gracilis tendon autografts were followed up for 1 year after surgery. The grafts were simultaneously fixed at 10 degrees of knee flexion with EndoButtons and spiked staples. All patients were examined with computed tomography and the standard clinical evaluation methods at 2 weeks and 1 year after surgery. RESULTS: The degree of tunnel enlargement of the femoral anteromedial and posterolateral tunnels averaged 10% to 11% and 7% to 9%, respectively, while that of the tibial anteromedial and posterolateral tunnels averaged 3% to 7% and 1% to 6%. The degree and incidence of the anteromedial and posterolateral tunnel enlargement were significantly greater in the femur than in the tibia (P < .0335 and P < .0405, respectively). On the femoral and tibial intra-articular surface, tunnel outlet coalition was found in 5% and 77% of the knees, respectively, at 1 year after surgery. There was no significant correlation between tunnel enlargement and coalition and the clinical outcome. CONCLUSION: The incidence and the degree of each tunnel enlargement in the femur were significantly greater than that in the tibia. However, the incidence of tunnel coalition in the femur was significantly less than that in the tibia after double-bundle ACL reconstruction with a transtibial technique. There was no significant correlation between tunnel enlargement and coalition and the clinical outcome. CLINICAL RELEVANCE: The present study provides orthopaedic surgeons with important information on double bundle ACL reconstruction with hamstring tendons. PMID- 26535228 TI - Predictors of Running-Related Injuries Among 930 Novice Runners: A 1-Year Prospective Follow-up Study. AB - BACKGROUND: To identify persons at high risk of sustaining running-related injuries, an evidence-based understanding of the risk factors associated with injury is needed. PURPOSE: To identify demographic and behavioral risk factors associated with running-related injuries. STUDY DESIGN: Observational prospective cohort study with a 1-year follow-up. METHODS: Exposures including sex, age, body mass index (BMI), behavior (Type A Self-Rating Inventory [TASRI]), running experience, other sports activity, previous running-related injuries, and other injuries not related to running were assessed prior to or at baseline. The outcome of interest was a running-related injury, defined as any musculoskeletal complaint of the lower extremity or back caused by running that restricted the amount of running (volume, duration, pace, or frequency) for at least 1 week. All participants quantified their running volume by global positioning system (GPS) and used a neutral running shoe. Time to first injury for each exposure variable was analyzed using a generalized linear model, with cumulative kilometers of the training sessions as the time scale. RESULTS: A total of 930 individuals were included in the study, of which 254 sustained a running-related injury during a total of 155.318 km of running. By calculating the cumulative injury risk differences (cIRDs) [95% confidence intervals] after 500 km of running, the TASRI Type B behavior (cIRD, 11.9% [-0.5%; 23.3%]; P = .04) was found to be a significant predictor of injury, while age between 45 and 65 years (cIRD, 14.7% [ 2.1%; 31.5%]; P = .08) and previous injuries not related to running (cIRD, 11.1% [-0.2%; 22.4%]; P = .05) were considered clinically interesting, although not statistically significant. In addition, chi(2) test results across 4 BMI groups also revealed a borderline significant relationship (P = .06). No significant or clinically relevant relationships were found for sex (P = .42), previous running related injury (P = .47), running experience (P = .30), and other sports activities (P = .30). CONCLUSION: The findings of the present study suggest BMI >30 kg/m(2), age between 45 and 65 years, noncompetitive behavior, and previous injuries not related to running are associated with increased risk of injury among novice runners, while BMI <20 kg/m(2) was protective. Still, the role of the risk factors in the causal mechanism leading to injury needs to be investigated. PMID- 26535229 TI - Differences in Knee Kinematics Between Awake and Anesthetized Patients During the Lachman and Pivot-Shift Tests for Anterior Cruciate Ligament Deficiency. AB - BACKGROUND: The Lachman and pivot-shift tests have been widely used for detecting anterior cruciate ligament (ACL) deficiency. However, it still remains unclear whether these manual tests can be quantified accurately while patients are awake. PURPOSE: To assess the differences in knee kinematics of awake and anesthetized patients. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 50 patients with unilateral ACL rupture were examined. Anteroposterior tibial translation was assessed using a KT-1000 arthrometer at maximal manual power. Anterior tibial translations during the manual Lachman test and the acceleration of tibial posterior translation (APT) during the pivot-shift test were also measured using an electromagnetic measurement system (EMS). All 3 measurements were performed on the day previous to surgery while the patients were awake and on the operative day before the surgery while the patients were under general anesthesia. RESULTS: The mean side-to-side difference in anteroposterior tibial translation was 5.6 +/- 2.6 mm in the awake state and 5.9 +/- 3.5 mm under anesthesia, indicating a nonsignificant difference. According to the EMS, the mean side-to-side difference in anteroposterior tibial translation during the Lachman test was 4.6 +/- 3.6 mm in the awake state and 6.9 +/- 4.3 mm under anesthesia, indicating a significant difference (P < .01). The mean APT during the pivot-shift test was -0.8 +/- 0.3 m/s(2) in intact knees and -1.1 +/- 0.4 m/s(2) in ACL-deficient knees when the patients were awake and was -0.7 +/- 0.2 m/s(2) and -1.7 +/- 1.0 m/s(2), respectively, when the patients were under anesthesia. In ACL-deficient knees, the APT pivot-shift test result was significantly higher when the patients were under anesthesia than when they were awake (P < .01). CONCLUSION: In ACL-deficient knees, the knee kinematics during the Lachman and pivot-shift tests is significantly affected by patient consciousness, and caution is needed in quantifying anterior knee laxity during these tests when the patients are awake. PMID- 26535230 TI - Rotator Cuff Weakness Is Not a Risk Factor for First-Time Anterior Glenohumeral Instability. AB - BACKGROUND: Shoulder instability is a common problem in young athletes and can lead to pain and decreased ability to participate in high-level activities. Little is known about the modifiable risk factors for glenohumeral joint instability. HYPOTHESIS: Isometric shoulder strength at baseline would be a modifiable risk factor associated with subsequent first-time anterior instability events. STUDY DESIGN: Cohort study. METHODS: Study participants were freshmen entering the United States Military Academy in June 2006. All participants completed bilateral isometric strength evaluations with a hand-held dynamometer at baseline upon entry into the study. Variables measured included internal and external rotation at 0 degrees (IR0, ER0) and internal and external rotation at 45 degrees of abduction (IR45, ER45). All subjects were followed for subsequent glenohumeral joint instability events until graduation in May 2010. Independent t tests were used to analyze the data. RESULTS: Baseline strength data were available for 1316 shoulders with no prior history of instability, of which 26 went on to have an acute first-time anterior shoulder instability event while the individuals were at the academy. There were no significant differences in mean strength between shoulders that did not go on to develop instability (uninjured; n = 1290) and those that did develop anterior instability (injured; n = 26). The mean strength values in pounds of force for uninjured and injured shoulders, respectively, were as follows: IR0 (49.80 vs 49.29; P = .88), ER0 (35.58 vs 33.66; P = .27), IR45 (47.38 vs 46.93; P = .88), and ER45 (40.08 vs 38.98; P = .59). CONCLUSION: No association was found between isometric shoulder strength measures at baseline and subsequent first-time anterior glenohumeral joint instability within the high-risk athletic population studied in this prospective cohort. PMID- 26535231 TI - Jockey Falls, Injuries, and Fatalities Associated With Thoroughbred and Quarter Horse Racing in California, 2007-2011. AB - BACKGROUND: Despite the popularity of the horse racing industry in the United States and the wide recognition that horse racing is one of the most hazardous occupations, little focused research into the prevention of falls by and injuries to jockeys has been conducted. PURPOSE: To describe the incidence rates and characteristics of falls and injuries to Thoroughbred and Quarter Horse racing jockeys in the state of California. STUDY DESIGN: Descriptive epidemiology study. METHODS: Data on race-day falls and injuries were extracted from jockey accident reports submitted to the California Horse Racing Board from January 2007 to December 2011. Denominator data, number of jockey race rides, were obtained from commercial and industry databases. Jockey fall, injury, and fatality incidence rates and ratios in Thoroughbred and Quarter Horse flat races were estimated using Poisson regression. Characteristics of falls and injuries are described and compared. RESULTS: In Thoroughbred races, 184 jockey injuries occurred from 360 reported jockey falls, 180,646 race rides, 23,500 races, and 3350 race meetings. In Quarter Horse races, 85 jockey injuries occurred from 145 jockey falls, 46,106 race rides, 6320 races, and 1053 race meetings. Jockey falls occurred at a rate of 1.99 falls per 1000 rides in Thoroughbred races, with 51% of falls resulting in jockey injury, and 3.14 falls per 1000 rides in Quarter Horse races, with 59% of falls resulting in jockey injury. The majority of falls occurred during a race, with catastrophic injury or sudden death of the horse reported as the most common cause in both Thoroughbred (29%) and Quarter Horse (44%) races. During the period studied, 1 jockey fatality resulted from a fall. Jockey fall rates were lower but injury rates were comparable to those reported internationally. CONCLUSION: On average, a licensed jockey in California can expect to have a fall every 502 rides in Thoroughbred races and every 318 rides in Quarter Horse races. While jockey fall rates were lower, injury rates were similar to those in other racing jurisdictions. The high proportion of jockey falls caused by horse fatalities should be further investigated. PMID- 26535232 TI - Risk Factors for Lower Extremity Tendinopathies in Military Personnel. AB - BACKGROUND: Overuse injuries have a significant impact on United States military service members, but research to date has been limited in its ability to assess occupational and behavioral risk factors. HYPOTHESIS/PURPOSE: To prospectively identify risk factors for the development of lower extremity tendinopathy and plantar fasciitis in United States military personnel. STUDY DESIGN: Descriptive epidemiology study. METHODS: Baseline data from the Millennium Cohort Study, a long-term observational cohort of military personnel, were utilized. Service members were enrolled in the cohort in 2001, 2004, and 2007. A total of 80,106 active-duty personnel were followed over 1 year for the development of patellar tendinopathy, Achilles tendinopathy, and plantar fasciitis. Regression analyses were used to estimate significant associations between each tendinopathy, plantar fasciitis, and demographic, behavioral, and occupational characteristics. RESULTS: Using medical records, 450 cases of Achilles tendinitis, 584 cases of patellar tendinopathy, and 1228 cases of plantar fasciitis were identified. Recent deployment was associated with an increased risk for developing plantar fasciitis (adjusted odds ratio [AOR], 1.27; 95% confidence interval [CI], 1.04 1.56). Moderate weekly alcohol consumption was marginally associated with an increased risk for Achilles tendinopathy (AOR, 1.33; 95% CI, 1.00-1.76). Overweight or obese individuals were more likely to develop Achilles tendinopathy and plantar fasciitis. CONCLUSION: Lower extremity tendinopathies and plantar fasciitis are common among military service members, and this study identified several modifiable risk factors for their occurrence. These potential risk factors could serve as the focus for future preventive and intervention studies. PMID- 26535233 TI - Platelet-Rich Plasma in Addition to Rehabilitation for Acute Hamstring Injuries in NFL Players: Clinical Effects and Time to Return to Play. AB - BACKGROUND: Platelet-rich plasma (PRP) injections have been proposed to hasten soft tissue healing. There is a lack of evidence in the current literature to support their efficacy in elite athletes. PURPOSE: To investigate the effects of the addition of PRP to rehabilitation in the treatment of acute hamstring injuries in professional National Football League (NFL) players and to report the time to return to play. STUDY DESIGN: Case control study. METHODS: Ten NFL players with similar hamstring injury patterns were retrospectively divided into 2 groups. The treatment group (PRP; n = 5) was injected with PRP and the control group (non-PRP; n = 5) was not injected; both groups completed a rehabilitation program. The PRP injections were administered under ultrasound guidance with precise localization of the injury site, within 24 to 48 hours of injury. Age, muscle involved, extent of injury, grading, and time to return to play were noted. Descriptive statistics and the exact Wilcoxon rank-sum test were used for data analysis. RESULTS: The mean age was 23 years (range, 22-27 years) for the PRP group and 26 years (range, 22-28 years) for the non-PRP group (P = .42). The median longitudinal extent of the injury was 14 cm (range, 9-18 cm) in the PRP group and 15 cm (range, 9-16 cm) in the non-PRP group (P = .77). The average transverse extent of the injury in the PRP and non-PRP groups was 4 cm (range, 1.6-6 cm) and 3.5 cm (range, 2-5 cm), respectively, and the respective average anteroposterior extent was 4 cm (range, 1.9-5 cm) and 2.9 cm (range, 1.5-4 cm). The long head of biceps femoris was most commonly involved (4 in each group), with a single tear of the semimembranosus in each group. The median injury classification was grade 2 in both groups. The median time to return to play was 20 days (range,16-30 days) in the PRP group and 17 days (range, 8-81 days) in the non-PRP group (P = .73). CONCLUSION: There were no significant differences in recovery from hamstring injury between treatment with PRP and routine rehabilitation. A larger, randomized controlled trial is warranted. PMID- 26535234 TI - Functional Outcome of Percutaneous Achilles Repair: Improvements in Achilles Tendon Total Rupture Score During the First Year. AB - BACKGROUND: Randomized studies have so far failed to show a difference in outcome between operative and nonoperative management of Achilles tendon rupture, provided that no rerupture occurs. Percutaneous Achilles repair has been suggested to result in superior patient satisfaction compared with open repair in patients with an acute Achilles tendon rupture, but there are no outcome data available with validated methods describing the progression of recovery during the first year. PURPOSE: To evaluate the outcome of patients with a ruptured Achilles tendon, managed by percutaneous repair, during the first year following repair with a valid, reliable, and responsive outcome measure. Furthermore, the effects of time between injury and surgery, age, and complications on outcome were also evaluated. STUDY DESIGN: Case series. METHODS: A total of 73 patients (60 males and 13 females) with a mean age of 45.5 years were included. Patient age, length of time between injury and surgery, and complications were documented. Patients were evaluated using the Achilles tendon Total Rupture Score (ATRS) at 3, 6, 9, and 12 months following repair. RESULTS: The median ATRS results at 3, 6, 9, and 12 months were 42.5, 73, 83, and 89, respectively. The number of patients who reported excellent or good scores (ATRS >84) at 3, 6, 9, and 12 months were 3%, 36%, 57%, and 69%, respectively. There were no significant differences in outcome at each time point for those patients undergoing early (<=48 hours) compared with late surgery or between those <65 and those >65 years of age. The complication rate was 13.5%. Patients who had a complication had a lower ATRS result at 3 months following surgery, but there were no differences after that time point. CONCLUSION: The patients in the present study reported marked improvement in function between 3 and 6 months following surgery, with continuing but less steep improvement up to 1 year following surgery. The presence of a complication other than rerupture did not affect the end-stage outcome but did affect that at 3 months following surgery. CLINICAL RELEVANCE: This study demonstrates improving scores with time over the first year following surgery, against which other treatment methods can be compared. PMID- 26535235 TI - Coracohumeral Distances and Correlation to Arm Rotation: An In Vivo 3-Dimensional Biplane Fluoroscopy Study. AB - BACKGROUND: Reduced coracohumeral distances have been reported to be associated with anterior shoulder disorders such as subscapularis tears, biceps tendon injuries, and leading edge supraspinatus tears. PURPOSE: To determine the variability in coracohumeral distance as a function of arm rotation in healthy male subjects. The null hypothesis was that no differences in coracohumeral distance would exist with respect to arm rotation. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 9 male participants who had full range of motion, strength, and no prior surgery or symptoms in their tested shoulders were enrolled in this institutional review board-approved study. Computed tomography scans of the shoulder were obtained for each subject. A dynamic biplane fluoroscopy system recorded internal and external shoulder rotation with the arm held in the neutral position. Three-dimensional reconstructions of each motion were generated, and the coracohumeral distance and coracoid index (lateral extension of the coracoid) were measured. RESULTS: The mean coracohumeral distance in neutral rotation was 12.7 +/- 2.1 mm. A significantly shorter minimum coracohumeral distance of 10.6 +/- 1.8 mm was achieved (P = .001) at a mean glenohumeral joint internal rotation angle of 36.6 degrees +/- 19.2 degrees . This corresponded to a reduction in coracohumeral distance of 16.4% (range, 6.6% 29.8%). The mean coracoid index was 14.2 +/- 6.8 mm. A moderate correlation (R = 0.75) existed between the coracohumeral distance and coracoid index. CONCLUSION: Coracohumeral distance was reduced during internal rotation. Decreased coracohumeral distance was correlated with larger coracoid indices. CLINICAL RELEVANCE: This study provides a reference value for coracohumeral distance in the healthy male population. Knowledge of how coracohumeral distance varies over the range of arm internal-external rotation may improve the clinical diagnosis and treatment plan for patients with anterior shoulder pathology, specifically subcoracoid impingement. Imaging of the coracohumeral distance during internal rotation with the hand at approximately midline should be considered to assess patients with anterior shoulder pain. PMID- 26535236 TI - Clinical Application of the "Glenoid Track" Concept for Defining Humeral Head Engagement in Anterior Shoulder Instability: A Preliminary Report. AB - BACKGROUND: The optimal treatment of Hill-Sachs injuries is difficult to determine and is potentiated by the finding that a Hill-Sachs injury becomes more important in the setting of glenoid bone loss, making engagement of the humeral head on the glenoid inherently easier. The "glenoid track" concept was developed to biomechanically quantify the effects of a combined glenoid and humeral head bony defects on instability. PURPOSE: To clinically evaluate humeral head engagement on the glenoid by utilizing glenoid track measurements of both humeral head and glenoid bone loss. STUDY DESIGN: Retrospective cohort. METHODS: A total of 205 patients with recurrent anterior shoulder instability were evaluated, and of these, 140 patients (68%; 9 females [6%] and 131 males [94%]) with a Hill Sachs lesion and a mean age of 27.6 years (range, 15-47 years; standard error of mean [SEM], 0.59) were included in the final magnetic resonance angiogram [MRA]) analysis. Bipolar bone loss measures of glenoid bone loss (sagittal oblique MRA) and multiple size measures of the Hill-Sachs injury (coronal, axial, and sagittal MRA) were recorded. Based on the extent of the bipolar lesion, patients were classified with glenoid track as either outside and engaging of the glenoid on the humeral head (OUT-E) or inside and nonengaging (IN-NE). The 2 groups were then compared with clinical evidence of engagement on examination under anesthesia (EUA) using video arthroscopy, number of dislocations, length of instability, and patient age. RESULTS: The mean glenoid bone loss was 7.6% (range, 0%-29%; SEM, 1.20%), and 31 of 140 (22%) patients demonstrated clinical engagement on EUA. Radiographically, 19 (13.4%) patients were determined to be OUT-E, while 121 (86.6%) were IN-NE and not expected to engage. Of those 19 patients with suggested radiographic engagement (OUT-E), 16 (84.5%) had clinical evidence of engagement versus only 12.4% that clinically engaged (15/121) without radiographic evidence of engagement (IN-NE) (P < .001). Younger age and a greater number of recurrence events were jointly predictive of a patient being classified as OUT-E (11.8 vs 6.4 dislocations; P = .015). CONCLUSION: This study demonstrates that glenohumeral engagement was well predicted based on preoperative glenoid and humeral head bone loss measurements using the glenoid track method. In addition, younger age and a greater number of recurrences were predictive of engagement. The glenoid track concept may be important to fully assess the overall risk for engagement prior to surgery and may help guide surgical decision making such as bony augmentation procedures. PMID- 26535237 TI - Operative Fixation of Chondral Loose Bodies in Osteochondritis Dissecans in the Knee: A Report of 5 Cases. AB - BACKGROUND: Osteochondritis dissecans (OCD) can progress to loose body formation, with or without subchondral bone attachment to the lesion. The efficacy of internal fixation of chondral loose bodies has not been determined. HYPOTHESIS: Operative fixation of cartilaginous loose bodies would result in (1) healed OCD at second-look arthroscopy, (2) restored cartilage appearance on magnetic resonance imaging (MRI), and (3) nearly normal knee function, as determined by patient-reported outcome scores. STUDY DESIGN: Retrospective case series; Level of evidence, 4. METHODS: Five patients who underwent cartilaginous loose body fixation were identified. Lesions were located on the lateral trochlea (n = 2) and medial femoral condyle (n = 3) (mean size, 2.5 cm(2)). Loose bodies were reattached with compression screws through mini-arthrotomy or arthroscopy. Patients were nonweightbearing for 12 weeks postoperatively. After 12 weeks, screws were removed arthroscopically, and OCD stability was evaluated. Three patients underwent MRI to determine articular cartilage status. Images were evaluated using the magnetic resonance observation of cartilage repair tissue (MOCART) score. Patients were interviewed and completed the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire. RESULTS: Four patients had stable lesions at 12 weeks after surgery. One patient had slight motion to one third of the lesion and stability to the remaining two-thirds. Three patients underwent an MRI. The mean time from surgery to MRI was 3.1 years. Mean MOCART score was 72.0 +/- 10.4. One patient required repeat arthroscopy 1 year after initial fixation for debridement and arthroscopic drilling of an incompletely healed area of the lesion. Four patients completed the KOOS questionnaire. The mean time to KOOS completion was 4.6 years. Mean KOOS subscales for knee pain (91.0 +/- 8.9), knee symptoms (83.0 +/- 7.9), and function in activities of daily living (91.9 +/- 10.6) were similar to published age-matched controls; however, scores for sports and recreation function (70.0 +/- 17.8) and knee-related quality of life (67.2 +/- 12.9) were lower. CONCLUSION: Operative fixation of chondral loose bodies, without macroscopically visible subchondral bone attachment, resulted in lesion stability at second-look arthroscopy. At final follow-up, patients had no substantial pain and normal function in activities of daily life compared with controls; however, knee-related quality of life and sport and recreation function were reduced, and 1 patient required reoperation for an unhealed portion of the lesion. PMID- 26535238 TI - Performance and Return to Sport After Anterior Cruciate Ligament Reconstruction in Male Major League Soccer Players. AB - BACKGROUND: Anterior cruciate ligament (ACL) rupture is a significant injury in male Major League Soccer (MLS) players in the United States. PURPOSE: To determine (1) return-to-sport (RTS) rate in MLS following ACL reconstruction (ACLR), (2) timing of RTS, (3) performance upon RTS, and (4) the difference in RTS and performance between players who underwent ACL reconstruction (ACLR) and controls. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: MLS players undergoing ACLR between 1996 and 2012 were evaluated. Player data were extracted from publically available sources. All demographic data were analyzed. A control group of players matched by age, body mass index (BMI), sex, position, performance, and MLS experience (occurred at 2.6 years into career, designated "index year") was selected from the MLS during the same years as those undergoing ACLR. The RTS and performance in the MLS were analyzed and compared between cases and controls. Student ttests were performed for analysis of within- and between group variables. RESULTS: A total of 52 players (57 knees) that met inclusion criteria underwent ACLR while in the MLS. Mean player age was 25.6 +/- 3.98 years. Forty players were able to resume play (77%). Of the 40 players (45 knees), 38 (43 knees; 95%) resumed play the season following ACLR (mean, 10 +/- 2.8 months after surgery). Mean career length in the MLS after ACLR was 4.0 +/- 2.8 years. The revision rate was 10%. There was a significant increase in the incidence of ACL tears in the MLS by year (P < .001), and there was a significantly (P= .002) greater number of ACL tears on the left knee as opposed to the right. Performance in the MLS upon RTS after ACLR was not significantly different versus preinjury. There was no significant difference in survival in the MLS between cases and controls after ACLR or index year. The only significant performance differences between cases and controls were that cases had significantly greater shots taken per season (P= .005) and assists (P= .005) than did controls after the index year. CONCLUSION: There is a high RTS rate in the MLS following ACLR. Nearly all players resumed play the season after surgery. Performance was not significantly different from preinjury. Only 2 performance measures (shots taken and assists) were significantly different between cases and controls. A significantly greater number of ACL tears occur in the left versus the right knee. PMID- 26535239 TI - Epidemiology of Hip Injuries in the National Basketball Association: A 24-Year Overview. AB - BACKGROUND: Professional athletes are subject to various injuries that are often dictated by the nature of their sport. Professional basketball players previously have been shown to sustain injuries throughout the musculoskeletal system, most commonly to the ankle and knee. PURPOSE: The purpose of this study was to report the epidemiology of injuries specific to the pelvis, hip, and thigh and their effect on games missed in professional basketball players. STUDY DESIGN: Descriptive epidemiological. METHODS: Records were recalled from the National Basketball Association epidemiological database for athletic-related pelvis, hip, or thigh injuries that occurred from the 1988-1989 through the 2011-2012 seasons. The primary information collected included anatomic location where the injury occurred, when in the course of the season injury occurred, specific pathology, date, activity at the time of injury, injury mechanism, number of practices and games missed, and whether surgery was required. The number of practices and games missed were summed to yield the number of days missed per episode. RESULTS: There were 2852 cases (14.6% of all athletic-related injuries) involving 967 individual players. In 1746 (61.2%) cases, injuries occurred during game competition. Across the course of this study, clinical incidence of injury to the pelvis, hip, or thigh was 1.50 per 100 players. The mean (+/-standard deviation) number of days missed per case was 6.3 +/- 10.2. The quadriceps group was the most commonly injured structure (contusions and strains) and had a significantly higher game related injury rate than other structures (0.96 per 100 athletic exposures, 95% confidence interval [CI] = 0.87-1.04). Players had the greatest risk (relative risk = 1.38, 95% CI = 1.26-1.52) of sustaining a strain than any other type of injury, with a game-related injury rate of 1.79 (95% CI = 1.67-1.90). The hamstring muscle group was the most frequently strained. Strains were more likely to occur in the preseason. CONCLUSION: Pelvis, hip, and thigh injuries in professional basketball players are commonly extra-articular strains and contusions and represent a significant burden of injury. The actual amount of intra-articular hip disorders may be underestimated, as the awareness of these disorders has increased only in the past decade. With the awareness of the types of injuries that occur in this region, focused injury prevention strategies may be beneficial to players and teams at all levels of competition, not only professional athletes. PMID- 26535240 TI - Anterior Limbus Vertebra and Intervertebral Disk Degeneration in Japanese Collegiate Gymnasts. AB - BACKGROUND: Magnetic resonance imaging (MRI) studies have shown that gymnasts have a high prevalence of radiological abnormalities, such as intervertebral disk degeneration (IDD) and anterior limbus vertebra (ALV). These 2 abnormalities may coexist at the same spinal level. However, the relationship between IDD and ALV remains unclear. HYPOTHESIS: A significant relationship exists between IDD and ALV in Japanese collegiate gymnasts. STUDY DESIGN: Case-control study. METHODS: A total of 104 Japanese collegiate gymnasts (70 men and 34 women; age, 19.7 +/- 1.0 years) with 11.8 +/- 3.6 years of sporting experience participated. T1- and T2 weighted MRIs were used to evaluate ALV and IDD. RESULTS: The prevalence among the gymnasts of IDD and ALV was 40.4% (42/104) and 20.2% (21/104), respectively. The prevalence of IDD was significantly higher in gymnasts with ALV than those without ALV, as determined using the chi-square test. Logistic regression analysis demonstrated a significant association between IDD and ALV (adjusted odds ratio [OR], 6.60; 95% confidence interval [CI], 2.14-20.35). IDD was further grouped by whether it was present in the upper lumbar region (L1-2, L2-3, and L3 4 disks) or in the lower lumbar region (L4-5 and L5-S1 disks). Upper IDD had a greater association with ALV (adjusted OR, 33.17; 95% CI, 7.09-155.25) than did lower IDD (adjusted OR, 6.71; 95% CI, 1.57-28.73). CONCLUSION: In Japanese collegiate gymnasts, ALV is a predictor of IDD, especially in the upper lumbar region. CLINICAL RELEVANCE: Information regarding ALV is important to prevent IDD in Japanese collegiate gymnasts. PMID- 26535241 TI - Iliopsoas Syndrome in Dancers. AB - BACKGROUND: Coxa saltans refers to a constellation of diagnoses that cause snapping of the hip and is a major cause of anterior hip pain in dancers. When the internal type is accompanied by weakness or pain, it is referred to as iliopsoas syndrome. Iliopsoas syndrome is the result of repetitive active hip flexion in abduction and can be confused with other hip pathology, most commonly of labral etiology. PURPOSE: To report the incidence, clinical findings, treatment protocol, and results of treatment for iliopsoas syndrome in a population of dancers. STUDY DESIGN: Retrospective case series; Level of evidence, 4. METHODS: A retrospective database review of 653 consecutive patients evaluated for musculoskeletal complaints over a 3-year period was completed. The diagnosis of iliopsoas syndrome was made based on anterior hip or groin pain, weakness with resisted hip flexion in abduction, or symptomatic clicking or snapping with a positive iliopsoas test. Patients identified with iliopsoas syndrome were further stratified according to age at time of onset, insidious versus acute onset, duration of symptoms, side of injury, presence of rest pain, pain with activities of daily living, and associated lower back pain. All patients diagnosed with iliopsoas syndrome underwent physical therapy, including hip flexor stretching and strengthening, pelvic mobilization, and modification of dance technique or exposure as required. RESULTS: A total of 49 dancers were diagnosed and treated for iliopsoas syndrome. Within this injured population of 653 patients, the incidence in female dancers was 9.2%, significantly higher than that in male dancers (3.2%). The mean age at the time of injury was 24.6 years. The incidence of iliopsoas syndrome in dancers younger than 18 years was 12.8%, compared with 7% in dancers older than 18 years. Student dancers had the highest incidence (14%), followed by amateur dancers (7.5%), while professional dancers had the lowest incidence (4.6%). All patients responded to conservative treatment, and no patients required corticosteroid injections or surgical intervention. CONCLUSION: This is the largest series reported to date of iliopsoas syndrome in the dance population, treated noninvasively. This study supports that conservative treatment with nonsteroidal anti-inflammatory medication, activity modification, and a physical therapy regimen specific to the iliopsoas should be the primary treatment for patients with iliopsoas syndrome. CLINICAL RELEVANCE: This study supports current literature and conservative treatment of iliopsoas syndrome diagnosis. Furthermore, this study gives specific information regarding incidence of iliopsoas syndrome in dance populations and provides a test for diagnosis and an algorithm for treatment. PMID- 26535242 TI - Posterolateral Bundle Reconstruction With Anteromedial Bundle Remnant Preservation in ACL Tears: Clinical and MRI Evaluation of 39 Patients With 24 Month Follow-up. AB - BACKGROUND: Augmentation consisting of a selective reconstruction of the ruptured bundle while preserving the remnant bundle has been proposed as a treatment option for partial anterior cruciate ligament (ACL) tears. Good clinical outcomes after selective anteromedial (AM) bundle augmentation have been reported, whereas little is known about selective reconstruction of the posterolateral (PL) bundle with preservation of the AM bundle remnant. PURPOSE: The purpose of this study was to evaluate the clinical outcomes and the magnetic resonance imaging (MRI) characteristics of selective PL bundle reconstruction with a median follow-up of 24 months. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: In a consecutive series of 741 ACL reconstructions, 44 patients underwent a selective PL bundle reconstruction with preservation of the AM remnant. Four patients with contralateral knee ligament surgery and 1 patient who sustained a traumatic rupture of his graft were excluded, leaving 39 patients for final evaluation. Clinical evaluation of knee function and laxity were recorded preoperatively and at a mean 24.2-month follow-up. Magnetic resonance imaging was performed on 35 patients at a mean 25.9-month follow-up for evaluation of graft and remnant bundle continuity, tunnel enlargement, and graft remodeling status by measuring the signal intensity of the graft (contrast/noise quotient [CNQ]). RESULTS: Tegner and Lysholm knee scores were significantly improved after surgery. The subjective International Knee Documentation Committee (IKDC) score was 43.5 +/- 16.6 preoperatively and 89.9 +/- 6.6 at the final follow-up (P < .01). The objective IKDC score was "B" for 17 patients, "C" for 21 patients, and "D" for 1 patient preoperatively, while it was "A" for 34 patients and "B" for 5 patients postoperatively (P < .01). The mean side-to-side anteroposterior laxity was 5 mm (range, 4-10 mm) preoperatively and 1.5 mm (range, -1 to 4 mm) at final follow-up (P < .01). On MRI, the graft was visible and continuous in all cases. No cyclops lesions were noted. The average CNQ for the PL graft and the AM remnant bundle was 3.2 +/- 1 and 2.9 +/- 1.2, respectively. Minimum bone tunnel enlargement was found. CONCLUSION: Selective PL bundle reconstruction restores knee stability and function. At final follow-up, MRI showed continuity of the PL graft without signs of dramatic tunnel enlargement or cyclops syndrome. PMID- 26535243 TI - A Retrospective Review of Anterior Cruciate Ligament Reconstruction Using Patellar Tendon: 25 Years of Experience. AB - BACKGROUND: The comparative data in the literature regarding rates of reoperation, revision ligament surgery, and contralateral surgery following anterior cruciate ligament reconstruction (ACLR) are variable and are often derived from studies with multiple surgeons, multiple centers, different surgical techniques, and a wide variety of graft choices. PURPOSE: To describe and analyze a single surgeon's experience with ACLR using bone-patellar tendon-bone (BPTB) as the primary graft choice over a 25-year period. STUDY DESIGN: Retrospective case series. METHODS: All patients who underwent ACLR from 1986 to 2012 were identified from a prospectively maintained database. Traditional follow-up was only for patients who sought subsequent surgery with the index surgeon or presented with contralateral ACL injury. Covariates of interest included age, sex, time, and graft selection. Outcomes of interest included reoperation rates after primary/revision ACLR, rate of revision ACLR, success of meniscal repair with concomitant ACLR, and the proportion of patients undergoing contralateral surgery. RESULTS: A total of 1981 patients (mean age, 29 years; 49% male) were identified. Of patients undergoing primary ACLR (n = 1809), 74% had BPTB autograft and 26% had a central third BPTB allograft. The mean age of patients undergoing autograft and allograft ACLR was 26 and 36 years, respectively (P < .05). Allograft tissue usage increased over time (P < .05). The rate of personal ACLR revision surgery was 1.7% (n = 30) for primary cases and 3.5% (n = 6) for revision cases. There were no significant differences in revision rates between primary autograft (1.6%) and allograft (2.0%) ACLR. With allograft use, the method of sterilization did not affect revision rates. The overall reoperation rate following primary ACLR was 10%; the 5-year reoperation rate was 7.7%. The reoperation rate was lower for primary cases reconstructed with allograft versus autograft (5% vs 12%) (P < .0001). Among primary ACLR cases, 332 patients (18%) underwent concomitant meniscal repair; 14% required revision meniscal surgery. The rate of contralateral ACLR was 6%. CONCLUSION: This information is useful for patients in the informed consent process, for perioperative decision making regarding graft choice, and for identifying patients who are at risk for injuring the uninvolved knee. The observed results in this series also emphasize that allograft ACLR can produce sustainable results with low complication rates in appropriately selected patients. PMID- 26535244 TI - A Magnetic Resonance Imaging Study of the Significance of the Distal Femoral Physis During Medial Patellofemoral Ligament Reconstruction. AB - BACKGROUND: Medial patellofemoral ligament (MPFL) reconstruction in adults often utilizes screw fixation in the distal femur. The aim was to define the safety of similar fixation in young patients, with respect to their open physis. PURPOSE: To define the age-related relationship between the femoral insertion of the MPFL and the medial aspect of the distal femoral physis on magnetic resonance imaging (MRI) scans. The study investigates whether screw fixation at this point is safe with respect to patient age and screw inclination. STUDY DESIGN: Cross-sectional study. METHODS: Retrospective review of the MRI scans of 159 skeletally immature patients. The femoral insertion of the MPFL was defined with respect to the distal femoral physis. The predicted paths of 2-cm screw fixation were simulated both parallel to the joint line and 45 degrees distally oblique; physeal and joint penetration were noted when present. Results are plotted against age and compared as quartile ranges. RESULTS: The femoral insertion of the MPFL was found to be distal to the distal femoral physis in all patients by an average of 10 mm (range, 2-16 mm). The mean distance increases slightly with age in a nonlinear relationship (r = 0.51, P < .001) from 9 mm at age 10 years to 12 mm by age 16 years. For the classic, parallel screw, the risk of physeal breach is high for all age groups (mean, 64%). For the novel, oblique screw, joint penetration and physeal breach were less prevalent (mean, 13%), and importantly, the vast majority of these breaches were in younger children (age <9 years 9 months). With oblique screws, older children were at significantly lower risk than younger children (<3% vs 48%; P < .001). CONCLUSION: This study accurately defines the relationship between the femoral insertion of the MPFL and the distal femoral physis in children and adolescents. A high risk of potentially poor outcomes was found during anatomic reconstruction of the MPFL in children utilizing classic (parallel) screw fixation, irrespective of age. However, in children older than 10 years, a 20-mm screw, from the anatomic MPFL insertion and directed 45 degrees distally oblique, should be safe in 98% of patients. PMID- 26535245 TI - Three-Dimensional Gait Analysis Following Achilles Tendon Rupture With Nonsurgical Treatment Reveals Long-Term Deficiencies in Muscle Strength and Function. AB - BACKGROUND: Precise long-term assessment of movement and physical function following Achilles tendon rupture is required for the development and evaluation of treatment, including different regimens of physical therapy. PURPOSE: To assess intermediate-term (<10 years by conventional thinking) objective measures of physical function following Achilles tendon rupture treated nonsurgically and to compare these with self-reported measures of physical function. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Two to 5 years after Achilles tendon rupture, 9 women and 43 men (mean age, 49.2 years; range, 26-68 years) were assessed by physical examination, performance of 1-legged jumps, and 3-dimensional gait analysis (including calculation of muscle work). Self-reported scores for foot function (Achilles tendon rupture score) and level of physical activity were collected. Twenty age- and sex-matched controls were assessed in the same manner. RESULTS: Physical examination of patients with the knee extended revealed 11.1 degrees of dorsiflexion on the injured side and 9.2 degrees on the uninjured side (P = .020), indicating gastrocnemius muscle lengthening. The 1 legged jump distance was shorter on the injured side (89.5 vs 96.2 cm; P < .001). Gait analysis showed higher peak dorsiflexion (14.3 degrees vs 13.3 degrees ; P = .016) and lower concentric (positive) plantar flexor work (16.6 vs 19.9 J/kg; P = .001) in the ankle on the uninjured side. At the same time, eccentric (negative) dorsiflexor work was higher on the injured side (13.2 vs 11.9 J/kg; P = .010). Self-perceived foot function and physical activity were lower in patients than in healthy controls (mean Achilles tendon rupture score, 78.6 and 99.8, respectively). CONCLUSION: Nonsurgically treated patients with Achilles tendon rupture showed signs of both anatomic and functional lengthening of the tendon. Attenuated muscle strength and function were present during walking as long as 2 to 5 years after rupture, as determined by 3-dimensional gait analysis. More extensive future studies involving patients having both surgical and nonsurgical treatment could provide additional valuable information. PMID- 26535246 TI - ACL Reconstruction Preserving the ACL Remnant Achieves Good Clinical Outcomes and Can Reduce Subsequent Graft Rupture. AB - BACKGROUND: Although anterior cruciate ligament (ACL) reconstruction techniques that preserve remnant tissues have been described, complete preservation may be difficult, with little known about its clinical advantages. PURPOSE: To compare clinical outcomes in patients undergoing ACL reconstruction with and without ACL remnant preservation. STUDY DESIGN: Case-control study. METHODS: Of 372 patients who underwent surgical treatment of an ACL injury between September 2006 and July 2010, 154 had no remaining identifiable ligament tissue and were excluded from this study. Attempts were made to preserve the ACL remnant as much as possible in the remaining 218 patients. These patients were divided into 2 groups: those in whom the remnant was preserved (group 1, n = 85) and those in whom the remnant was not preserved (group 2, n = 98). Patients were followed for at least 24 months. Outcomes, including graft rupture, were compared in the 2 groups. RESULTS: Time from injury to surgery was significantly shorter (7.3 +/- 16.3 vs 16.0 +/- 30.3 months; P < .05) and the preinjury Tegner activity was significantly higher (7.6 +/- 1.4 vs 7.1 +/- 1.2; P < .05; 95% confidence interval, 1.2-13.7) in group 1 than in group 2. The postoperative negative ratio of the pivot-shift test was similar in the 2 groups (87% vs 81%). Anterior stability of the knee, as measured by a KT-2000 arthrometer, was significantly better in group 1 than in group 2 (1.0 +/- 0.8 vs 1.3 +/- 1.0 mm; P < .05). ACL graft rupture occurred in 1 patient (1.1%) in group 1 and in 7 patients (7.1%) in group 2 (P < .05). Regression analysis showed that preservation of the remnant decreased the likelihood of graft rupture (odds ratio, 11.2; 95% confidence interval, 1.2-101.7). CONCLUSION: These findings confirmed that preserving the remnant tissue of the ACL may facilitate recovery of function and decrease graft rupture after primary reconstruction. PMID- 26535247 TI - Medium-Term Results After Treatment of Recalcitrant Lateral Epicondylitis: A Prospective, Randomized Study Comparing Open Release and Radiofrequency Microtenotomy. AB - BACKGROUND: Recalcitrant lateral epicondylitis (elbow extensor-origin tendinosis) is a common cause of elbow pain with many treatment options. In the present study, the medium-term results after open release and radiofrequency microtenotomy are reported. HYPOTHESIS: Microtenotomy would provide long-term pain relief that was as good as the open release method. STUDY DESIGN: Prospective, randomized trial. METHODS: Twenty-four patients randomized to either open release or microtenotomy were assessed after 5 to 7 years. Clinical examination and dynamic infrared thermography (DIRT) of both elbows were performed preoperatively and at the medium-term follow-up. Magnetic resonance imaging (MRI) of both elbows was performed at the medium-term follow-up. RESULTS: Significant pain reduction was found using a visual analog scale (VAS) at the medium-term follow-up in both groups compared with the preoperative assessment (P < .005). The Mayo Elbow Performance Score (MEPS) increased significantly in both groups (P < .01). The improvement in grip strength was not significant in either group. There was no significant difference between the groups in terms of VAS, strength, and the MEPS. On the DIRT examinations, there were significantly fewer hot spots at the medium-term follow-up than preoperatively (P = .0067, both study groups together). The MRI examinations revealed grade II changes in the operated elbow in 1 patient in each group at the medium-term follow-up, while all the other MRI examinations revealed a normal tendon. CONCLUSION: In this prospective, randomized trial with a medium-term follow-up, the results were similar after surgical release and microtenotomy in patients with recalcitrant lateral epicondylitis. The hypothesis was thus verified. PMID- 26535248 TI - Hospital Charges and Practice Patterns for General and Regional Anesthesia in Arthroscopic Anterior Cruciate Ligament Repair. AB - BACKGROUND: Anesthetic use for arthroscopic anterior cruciate ligament (ACL) reconstruction may display variability in hospital charges and utilization in the United States. PURPOSE: To evaluate practice patterns and hospital charges for anesthesia in arthroscopic ACL reconstruction. STUDY TYPE: Cross-sectional study. METHODS: The PearlDiver Patient Records Database, a national database of insurance billing records, was searched using the current procedural terminology (CPT) codes for arthroscopic ACL reconstruction in combination with different types of anesthesia. The search included the years between 2004 and 2009. Age, sex, number of procedures performed, geographic region, and hospital charges for each type of anesthesia were recorded and compared. Anesthetic types were categorized as general anesthesia (GA) only, GA with concomitant single femoral injection, GA with concomitant other regional anesthesia (RA), single femoral injection only, or other RA only. RESULTS: Between 2004 and 2009, a total of 53,968 arthroscopic reconstructive procedures were identified. The mean per patient hospital charge for GA alone, GA in combination with single femoral injection, GA in combination with other RA, single femoral injection alone, and RA alone was $1065 (63% of cases), $1614 (29%), $1849 (4%), $630 (3%), and $612 (1%), respectively. The use of GA in combination with RA or single femoral nerve injection significantly increased during this time period (P = .004 and P < .001, respectively). CONCLUSION: The mean per patient hospital charges for arthroscopic ACL reconstruction varied with the mode of anesthesia utilized, where regional anesthetic techniques alone were least expensive. RA alone was utilized infrequently, and there was a significant increase in the rate of utilization of GA in combination with any form of RA. CLINICAL RELEVANCE: This study provides information on current trends and hospital charges for anesthesia in arthroscopic ACL reconstruction. PMID- 26535249 TI - Functional Outcomes After Arthroscopic Scapulothoracic Bursectomy and Partial Superomedial Angle Scapulectomy. AB - BACKGROUND: Arthroscopic scapulothoracic bursectomy with partial superomedial angle scapulectomy has been described as a treatment for persistent scapulothoracic bursitis with varying results. PURPOSE: To evaluate patients after arthroscopic scapulothoracic bursectomy utilizing validated functional outcome instruments. STUDY DESIGN: Case series. METHODS: Fifteen patients underwent arthroscopic scapulothoracic bursectomy and partial superomedial angle scapulectomy. Thirteen patients were available for review at a mean 27-month follow-up (range, 13-65 months). Patients were evaluated preoperatively with a history, physical examination evaluating medial scapula border tenderness and crepitus, pain visual analog scale (VAS) score, and the simple shoulder test (SST). Postoperatively, patients were evaluated with all preoperative questionnaires as well as a satisfaction survey and the American Shoulder and Elbow Surgeons (ASES) score. RESULTS: SST scores improved significantly from a mean 7.7 +/- 3.1 preoperatively to 10.3 +/- 2.3 postoperatively (P = .03). VAS pain scores reduced significantly from 6.5 +/- 2.2 preoperatively to 2.3 +/- 2.4 postoperatively (P < .001). Ninety-two percent (12/13) of patients were satisfied, and 92% (12/13) stated they would have the surgical procedure performed again. The mean ASES postoperative score was 80.1 (range, 38-100). The 2 clinical failures (ASES scores <50) had either a workers' compensation claim with persistent medial border tenderness or ongoing rotator cuff disease. Despite lower ASES scores, these patients were still satisfied with the procedure and would undergo it again. CONCLUSION: Arthroscopic scapulothoracic bursectomy with partial superomedial angle scapulectomy provides significant improvements in pain and functional outcomes. Even in patients at risk for poorer clinical outcomes, patient satisfaction and willingness to undergo the surgical procedure again was still high. PMID- 26535250 TI - Evaluation of Joint Space Width and Narrowing After Isolated Partial Medial Meniscectomy for Degenerative Medial Meniscus Tears. AB - BACKGROUND: Few studies have evaluated the effect of existing articular cartilage damage and sex on joint space measurements after isolated degenerative medial meniscus tears. PURPOSE: To determine what factors affected joint space width and narrowing in patients after removal of isolated degenerative medial meniscus tears. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 62 patients (15 women and 47 men) with all ligaments intact, no previous surgery to either knee, and an isolated degenerative medial meniscus tear removed in 1 knee were examined. The mean age at examination was 58.2 years at a mean follow-up of 9.4 years (range, 4-20 years). Subjective results were obtained with the International Knee Documentation Committee (IKDC) knee survey. Radiographs were taken using 45 degrees weightbearing posteroanterior views. Midpoint and perceived minimum joint space width of the medial and lateral compartments of both knees were measured to the nearest 0.1 mm by 2 observers at different times, and they were blinded as to the previous measurements (Pearson intra- and interclass correlations, >0.93). Joint space narrowing was found by calculating the difference in joint space width between knees. Percentage of normal joint space loss was calculated by dividing joint space narrowing by the joint space width in the contralateral knee. Other factors considered were patient sex and Outerbridge grading of articular cartilage. RESULTS: Women had a mean 1.5 mm less normal joint space width than men in the involved and noninvolved knees (P < .01). Mean joint space narrowing was 0.7 mm for both measurements. The mean +/- standard deviation narrowing was 0.4 +/- 1.2 mm for patients with grade 0-2 damage and 1.1 +/- 1.3 for patients with grade 3-4 damage (P = .04). Five women (33%) and 3 men (6%) had narrowing of >50% of the normal joint space as measured in the noninjured knee (P = .016). The mean IKDC total score was 66.1 points for women, which was statistically significantly lower than the mean of 82.7 points for men (P < .01). CONCLUSION: Patients undergoing partial medial meniscectomy have greater joint space narrowing and lower subjective scores after surgery if they also have existing Outerbridge grade 3-4 damage. Women have less normal joint space than men, and more women than men experience >50% joint space narrowing after surgery. PMID- 26535251 TI - A Biomechanical Evaluation of the Kinetics for Multiple Pitching Techniques in College-Aged Pitchers. AB - BACKGROUND: There are a number of studies showing that fastball pitches place greater loads on the shoulder and elbow than the curveball; however, the results of these studies are inconsistent, especially in collegiate-level pitchers. There is also discussion that sliders may produce substantially greater loads than other breaking pitches, but there is little scientific evidence to support this claim. HYPOTHESIS: The curveball and slider/cutter produce greater moments on the shoulder and elbow compared with the fastball and change-up. STUDY DESIGN: Descriptive laboratory study. METHODS: Thirty-six collegiate pitchers were evaluated using motion analysis techniques. All subjects pitched a fastball and a change-up, 29 pitched a curveball, and 20 pitched a slider/cutter. Kinematic data were collected, and kinetic (joint moment) data were computed using standard protocols. A random-intercept, mixed-model regression analysis was used to assess differences in joint moments between pitch types. RESULTS: The greatest glenohumeral and elbow moments were found when pitchers were pitching the fastball (mean +/- standard deviation: 80.8 +/- 15.5 and 79.2 +/- 16.9 N.m, respectively) and the lowest when pitching the change-up (73.2 +/- 14.5 and 71.6 +/- 15.0 N.m, respectively). The moments produced by the slider/cutter and curveball were similar (74.9 +/- 16.4 and 75.6 +/- 15.5 N.m at the elbow, respectively) and significantly lower than the moments produced by the fastball (P < .0001). Results also indicate that the change-up produced the lowest joint moments compared with other pitch types. CONCLUSION: This study shows that the fastball and not the curveball or slider/cutter produced the greatest moments on the college pitcher's glenohumeral and elbow joints, as previously believed. The study also shows that the change-up may be the safest of the 4 pitch types analyzed. CLINICAL RELEVANCE: There is a long-held belief that throwing breaking pitches, specifically the slider and curveball, places additional stresses on the shoulder and elbow of skeletally mature pitchers. However, these results show that pitching breaking pitches may not be as detrimental to a college-aged pitcher as currently believed. PMID- 26535252 TI - Elbow Injuries in Youth Baseball Players Without Prior Elbow Pain: A 1-Year Prospective Study. AB - BACKGROUND: Many risk factors for throwing injuries have been proposed. However, little is known about the risk factors for elbow injuries, particularly on physeal injuries in youth baseball players without prior elbow pain. PURPOSE: To investigate the risk factors for elbow injuries with a focus on physeal injuries that could predispose youth baseball players without elbow pain to elbow injuries. STUDY DESIGN: A prospective epidemiology study. METHODS: In 2006, 449 players without prior elbow pain were observed prospectively for 1 season to study injury incidence in relation to specific risk factors. The average age was 10.1 years (range, 7-11 years). One year later, all players were examined by administering a questionnaire, physical examination, and radiographic examination. Data for the groups with and without elbow pain were analyzed using multivariate logistic regression models. RESULTS: Among the 449 participants, 30.5% reported episodes of elbow pain during the season. Of the players who reported elbow pain, 72.3% presented abnormal findings on physical examination, and of those players, 81.4% had radiographic abnormalities. Multivariate analysis showed that the age of 12 years (at 1-year examination), pitcher and catcher positions, and playing more than 100 games per year were risk factors for elbow pain. CONCLUSION: It is expected that 30% of youth baseball players have elbow pain each year, and nearly 60% of players with elbow pain exhibit radiographic abnormalities. The age of 12 years, pitcher and catcher positions, and playing more than 100 games per year are risk factors for elbow pain. PMID- 26535253 TI - Performance and Return to Sport After Anterior Cruciate Ligament Reconstruction in X-Games Skiers and Snowboarders. AB - BACKGROUND: Skiing and snowboarding have become increasingly popular since the inception of the winter X-Games in 1997. PURPOSE: To determine (1) rate of return to sport (RTS) to the winter X-Games following anterior cruciate ligament (ACL) reconstruction and (2) performance upon RTS following ACL reconstruction. HYPOTHESES: There is a high rate of RTS to the winter X-Games in subjects undergoing ACL reconstruction. There is no difference in performance upon RTS following ACL reconstruction versus preinjury. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Skiers and snowboarders competing in the winter X-Games who tore their ACL and underwent ACL reconstruction between 1997 and 2012 were evaluated. Athlete data were extracted from winter X-Games media websites, ESPN, injury reports, player profiles/biographies, and press releases. All athlete, knee, and surgical demographic data were analyzed. RTS and performance as it related to the number of gold, silver, and bronze medals won both pre- and postoperatively in the X-Games were analyzed. RESULTS: Fifteen skiers (19 knees) and 10 snowboarders (10 knees) were analyzed. There were 13 males and 12 females, with a mean subject age of 22.6 +/- 4.45 years. The rate of RTS in the X-Games following ACL reconstruction was 80% overall (20/25 subjects). The rate of RTS in winter X-Games following ACL reconstruction in skiers was 87% (13/15 subjects) and in snowboarders was 70% (7/10 subjects). The rate of RTS in winter X-Games following ACL reconstruction in males and females was 85% (11/13 subjects) and 75% (9/12 subjects), respectively. The rate of revision ACL reconstruction due to ACL tear following primary ACL reconstruction was 4% (1/25 subjects). There were more left- than right-sided tears (18 vs 11). Skiers and snowboarders competed in the X-Games for 3.84 +/- 2.73 and 3.40 +/- 2.84 years prior to ACL reconstruction and 2.56 +/- 2.06 and 7.29 +/- 3.30 years after ACL reconstruction, respectively. Skiers earned 22 medals prior to ACL reconstruction (9 gold, 5 silver, 8 bronze) and 24 medals after ACL reconstruction (16 gold, 2 silver, 6 bronze). Snowboarders earned 7 medals prior to ACL reconstruction (4 gold, 1 silver, 2 bronze) and 19 medals after ACL reconstruction (7 gold, 7 silver, 5 bronze). CONCLUSION: Winter X-Games skiers and snowboarders have a high rate of RTS after ACL reconstruction. Skiers earned a similar number of medals preinjury and postsurgery, while snowboarders earned more medals following surgery. PMID- 26535254 TI - Altitude Modulates Concussion Incidence: Implications for Optimizing Brain Compliance to Prevent Brain Injury in Athletes. AB - BACKGROUND: Recent research indicates that the volume and/or pressure of intracranial fluid, a physiology affected by one's altitude (ie, elevation above sea level), may be associated with the likelihood and/or severity of a concussion. The objective was to employ an epidemiological field investigation to evaluate the relationship between altitude and concussion rate in high school sports. HYPOTHESIS: Because of the physiologies that occur during acclimatization, including a decline in intracranial compliance (a "tighter fit"), increased altitude may be related to a reduction in concussion rates in high school athletes. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data on concussions and athlete exposures (AEs) between 2005-2006 and 2011-2012 were obtained from a large national sample of high schools (National High School Sports-Related Injury Surveillance System [High School RIO]) and were used to calculate total, competition, and practice concussion rates for aggregated sports and for football only. RESULTS: Altitude of participating schools ranged from 7 to 6903 ft (median, 600 ft), and a total of 5936 concussions occurred in 20,618,915 exposures (2.88 per 10,000 AEs). When concussion rates were dichotomized by altitude using the median, elevated altitude was associated with a reduction in concussion rates overall (rate ratio [RR], 1.31; P < .001), in competition (RR, 1.31; P < .001), and in practice (RR, 1.29; P < .001). Specifically, high school sports played at higher altitude demonstrated a 31% reduction (95% confidence interval [CI], 25%-38%) in the incidence of total reported concussions. Likewise, concussion rates at increased altitude were reduced 30% for overall exposures, 27% for competition exposures, and 28% for practice exposures in football players (P < .001). CONCLUSION: The results of this epidemiological investigation indicate increased physiological responses to altitude may be associated with a reduction in sports-related concussion rates, especially in collision sports. Future research that focuses on the potential prophylactic effect of optimizing outflow impedance and thus reduction of intracranial compliance (a "tighter fit") in humans is warranted to determine the most effective approaches to mitigate sport-related concussion, especially in football players. PMID- 26535255 TI - Magnetic Resonance Imaging Findings After Acute Patellar Dislocation in Children. AB - BACKGROUND: Acute patellar dislocation (APD) is a common knee injury in children. The pattern and frequency of injury to the medial patellofemoral ligament (MPFL) is different in pediatric compared with adult populations. PURPOSE: To report on injury patterns sustained to the MPFL after APD in children and to determine whether predisposing factors for APD cited in adults hold true in the pediatric population. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Magnetic resonance imaging (MRI) studies were reviewed for 36 children sustaining APD. Evidence of injury to the MPFL was documented, and when the MPFL was torn, the location of tear was determined. Presence of trochlear dysplasia, patella alta, tibial tubercle-trochlear groove (TTTG) distance, and thickness of the lateral patellofemoral retinaculum (LPR) were recorded and correlated with MPFL tear. RESULTS: Of the 36 patients sustaining APD, only 16 tore the MPFL. The location of MPFL tear was equally divided between the origin, the insertion, or both, with no case of midsubstance tear. There was a significant correlation identified between MPFL rupture and both LPR thickness greater than 3 mm and TTTG distance greater than 19 mm. CONCLUSION: The MPFL does not always tear in children who sustain APD, and the tear location is variable. A thickened LPR and increased TTTG distance predispose to MPFL tear. PMID- 26535256 TI - Return to Sport and Performance After Microfracture in the Knees of National Basketball Association Players. AB - BACKGROUND: Use of microfracture in the knees of National Basketball Association (NBA) players is controversial. HYPOTHESES: (1) There would be a high rate of return to sport (RTS) in NBA players following microfracture, (2) players would RTS the season following surgery, (3) preoperative player performance would not be significantly different on RTS, and (4) there would be no significant difference in RTS rate or postoperative performance in players undergoing microfracture in comparison with an age-, position-, NBA experience-, and performance-matched control group. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: NBA players undergoing microfracture were evaluated. Age-, body mass index-, position-, NBA experience-, and performance-matched controls were selected from the NBA during the same years as those undergoing microfracture. An index year was selected (controls) to match the number of seasons of NBA experience in microfracture cases. RTS and performance were analyzed and compared between cases and controls. Student t tests were performed for analysis of within and between-group variables. RESULTS: A total of 41 NBA players underwent microfracture and were compared with 41 demographic- and performance-matched controls. Rate of RTS after microfracture was 73% in the NBA and 83% in professional basketball (NBA, D-league, and International Basketball Federation [FIBA]). Time to RTS in NBA was 9.20 +/- 4.88 months. Seventy-one percent (29/41) of players RTS the season following microfracture. Length of NBA career following microfracture (4.10 +/- 3.91 years) was not significantly different from controls. After microfracture, case athletes played fewer games per season and with fewer points and steals per game (relative to premicrofracture; P < .05). Performance was better in control (after index year) versus case players (after microfracture) with regard to points per game, games played per season, and field goal and free throw percentage (P < .05). CONCLUSION: Eighty-three percent of NBA players undergoing microfracture returned to professional basketball. Career length was not significantly different between players undergoing microfracture and controls. However, following microfracture, players competed in fewer games per season with fewer points and steals. PMID- 26535257 TI - Idiopathic Cam Morphology Is Not Caused by Subclinical Slipped Capital Femoral Epiphysis: An MRI and CT Study. AB - BACKGROUND: Cam impingement as a known sequelae of slipped capital femoral epiphysis (SCFE) has led to speculation that subclinical SCFEs may be the causative factor in idiopathic cam morphology; alternatively, others have implicated an abnormal extension of the growth plate as a causative factor. HYPOTHESIS/PURPOSE: To investigate the growth plate tilt angle in 4 patient cohorts: normal patients, patients with idiopathic cam morphology (CamIP), patients with cam morphology secondary to known SCFE (CamSCFE), and patients with incidental findings of an asymptomatic cam (Camasymp). STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A database of 192 computed tomography scans of abdomens/pelvises of patients (ages, 5-19 years) with no known orthopaedic issues, reformatted to neutral tilt, inclination, and rotation, were utilized for the normal cohort, the Camasymp cohort, and to create an age- and sex-matched control cohort. In addition, a retrospective review of all patients treated for femoroacetabular impingement (FAI) with preoperative advance imaging was conducted, and patients were separated to CamIP and CamSCFE cohorts. The alpha angle and tilt angle were measured on each hip. Statistical analysis was performed. RESULTS: The mean tilt angle among the normal patients was 12.1 degrees , with 1.9% of the variation in tilt angle being explained by age; each additional year of age decreased the tilt angle by 0.27 degrees (P = .008). The tilt angle for the CamSCFE cohort (mean, 44.5 degrees ) was found to be significantly greater than both the CamIP cohort (mean, 5.9 degrees ; P < .001) and the control cohort (mean, 12.8 degrees ; P < .001). The tilt angle for the CamIP cohort was found to be significantly less than the control cohort (P = .003). The alpha angle and tilt angle were positively correlated in the CamIP cohort, but no correlation was found in the other cohorts. The mean tilt angle of the 18 hips in the Camasymp cohort was 13.9 degrees +/- 11.5 degrees (range, 12 degrees to 37 degrees ), with 12 hips (67%) in the tilt angle range of CamIP cohort and 6 in the tilt angle range of CamSCFE. CONCLUSION: The proximal femoral growth plate normally has a posterior tilt that becomes more anterior through maturation. Idiopathic cam morphology has a drastically different growth plate tilt angle than cam morphology secondary to SCFE, suggesting that a majority of idiopathic cam morphology is not the result of subclinical SCFEs. PMID- 26535258 TI - Analysis of Low-Field Magnetic Resonance Imaging Scanners for Evaluation of Knee Pathology Based on Arthroscopy. AB - BACKGROUND: In recent years, few studies have evaluated low-field magnetic resonance imaging (MRI) diagnoses compared with intraoperative findings of the knee. PURPOSE: To determine the accuracy and sensitivity of low-field MRI scanners in diagnosing pathology of the menisci, cruciate ligaments, and osteochondral surfaces. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: MRI examinations without intra-articular contrast were performed on 379 patients for knee pathologies over a 4-year period. The MRI examinations were done using a 0.2-tesla scanner utilizing a dedicated knee coil and read by 1 of 3 board-certified, musculoskeletal fellowship-trained radiologists. Within a mean time of 50 days after MRI, all patients underwent knee arthroscopy performed by 1 of 2 sports fellowship-trained orthopaedic surgeons. Operative notes from the knee arthroscopies were then reviewed by a single independent observer, and the intraoperative findings were compared with the MRI reports. RESULTS: For medial meniscus tears, the sensitivity, specificity, positive predictive value, and negative predictive value were 83%, 81%, 89%, and 71%, respectively. For lateral meniscus tears, the values were 51%, 93%, 84%, and 73%, respectively. For anterior cruciate ligament (ACL) tears, the values were 85%, 94%, 69%, and 97%, respectively. For osteochondral lesions, the values were 8%, 99%, 29%, and 94%, respectively. For posterior cruciate ligament (PCL) tears, the specificity and negative predictive value were 99% and 100%, respectively. CONCLUSION: Low-field MRI was an accurate tool for evaluation of medial meniscus and ACL tears. However, within the study population, it is not as effective in diagnosing lateral meniscus tears and showed a poor ability to detect osteochondral lesions. More information is needed to properly assess its ability to diagnose PCL tears. PMID- 26535259 TI - Anatomy and Histology of the Knee Anterolateral Ligament. AB - BACKGROUND: Reconstruction of the anterior cruciate ligament (ACL) is one of the most common procedures in orthopaedic surgery. However, even with advances in surgical techniques and implants, some patients still have residual anterolateral rotatory laxity after reconstruction. A thorough study of the anatomy of the anterolateral region of the knee is needed. PURPOSE: To study the anterolateral region and determine the measurements and points of attachments of the anterolateral ligament (ALL). STUDY DESIGN: Descriptive laboratory study. METHODS: Dissections of the anterolateral structures of the knee were performed in 20 human cadavers. After isolating the ALL, its length, thickness, width, and points of attachments were determined. The femoral attachment of the ALL was based on the anterior-posterior and proximal-distal distances from the attachment of the lateral collateral ligament (LCL). The tibial attachment point was based on the distance from the Gerdy tubercle to the fibular head and the distance from the lateral tibial plateau. The ligaments from the first 10 dissections were sent for histological analysis. RESULTS: The ALL was found in all 20 knees. The femoral attachment of the ALL at the lateral epicondyle averaged 3.5 mm distal and 2.2 mm anterior to the attachment of the LCL. Two distal attachments were observed: one inserts into the lateral meniscus, the other between the Gerdy tubercle and the fibular head, approximately 4.4 mm distal to the tibial articular cartilage. The mean measurements for the ligament were 37.3 mm (length), 7.4 mm (width), and 2.7 mm (thickness). The histological analysis of the ligaments revealed dense connective tissue. CONCLUSION: The ALL is consistently present in the anterolateral region of the knee. Its attachment to the femur is anterior and distal to the attachment of the LCL. Moving distally, it bifurcates at close to half of its length. The ALL features 2 distal attachments, one at the lateral meniscus and the other between the Gerdy tubercle and the fibular head. CLINICAL RELEVANCE: The ALL may be important in maintaining normal rotatory limits of knee motion; ALL rupture could be responsible for rotatory laxity after isolated intra-articular reconstruction of the ACL. PMID- 26535260 TI - Utility of the Pectoralis Major Index in the Diagnosis of Structurally Significant Pectoralis Major Tears. AB - BACKGROUND: Diagnosis of pectoralis major tears early in the acute phase is important for optimizing surgical repair and outcomes. However, physical examination of pectoralis major injuries can be misleading, often resulting in a potentially detrimental delay in surgical treatment. PURPOSE: To establish and validate a quantifiable clinical diagnostic test for structurally significant pectoralis major tears. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: A total of 50 healthy male participants (mean age, 43.3 +/- 11.9 years) with normal uninjured pectoralis major anatomy were examined. Digital photographs of all participants were taken in the "military press" starting position (90 degrees of shoulder abduction, 90 degrees of shoulder external rotation). The length between the ipsilateral nipple and the apex of the pectoralis major muscle curvature along the anterior axillary fold, known as the pectoralis major distance, was measured bilaterally. Two orthopaedic surgeons measured all photographs on 2 separate occasions. The pectoralis major index (PMI) was calculated as a ratio of pectoralis major distance values to establish normal values. The PMI was also calculated in a cohort of 19 male patients (mean age, 33.8 +/- 6.8 years) with a pectoralis major rupture to assess the diagnostic utility of this novel quantifiable physical examination technique. RESULTS: Mean (+/- standard deviation) PMI for the uninjured group was 1.0 +/- 0.07. A diagnostic threshold of a PMI <0.9 resulted in a sensitivity of 79%, specificity of 98%, and overall accuracy of 93% in identifying structurally significant pectoralis major ruptures. There was no correlation between PMI and age or activity level, including participation in sports and/or weight training. The PMI technique demonstrated good to excellent intrarater reliability (intraclass correlation coefficient [ICC] = 0.82, 0.74) and interrater reliability (ICC = 0.63, 0.76). CONCLUSION: The PMI technique is a simple, quantifiable, and accurate clinical diagnostic test for structurally significant pectoralis major tears. Routine application of the PMI technique by clinicians may improve accurate identification of structurally significant rupture and expedite referral to a surgical specialist for optimal treatment and outcome. PMID- 26535261 TI - The Anatomic Pattern of Injuries in Acute Inversion Ankle Sprains: A Magnetic Resonance Imaging Study. AB - BACKGROUND: There are little data on the incidence and patterns of injuries seen on magnetic resonance imaging (MRI) in acute inversion ankle sprains. This study may help in the understanding of the pathomechanics, natural history, and outcomes of this common injury. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: From June 2011 to June 2013, a total of 64 consecutive patients had MRI of the ankle performed for acute inversion injury to the ankle. All injuries/pathologies reported were recorded. RESULTS: Only 22% of patients had isolated lateral ligament complex injuries. Twenty-two percent of patients had other pathologies but no lateral ligament injury, and 53% had lateral ligament injuries in combination with other pathologies or injuries. The most common associated finding with lateral ligament injuries was bone bruising (76%) followed by deltoid ligament injury (50%). The overall incidence of bone bruising was 50%. Thirty percent of ankles had tendon pathology, 27% had deltoid ligament injury, and 22% had occult fractures. CONCLUSION: Isolated lateral ligament ankle injury is not as common as is believed. The pattern of injury seems complex, and most patients appear to have more injuries than expected. MRI reveals additional information that may have significance in terms of diagnosis, treatment, and prognosis in this common injury. PMID- 26535262 TI - Concussions From Youth Football: Results From NEISS Hospitals Over an 11-Year Time Frame, 2002-2012. AB - BACKGROUND: Youth football programs across the United States represent an at-risk population of approximately 3.5 million athletes for sports-related concussions. The frequency of concussions in this population is not known. STUDY DESIGN: Descriptive epidemiology study. METHODS: Over an 11-year span from January 2002 to December 2012, the authors reviewed the concussions sustained by athletes aged 5 to 13 years while playing football, as evaluated in emergency departments (EDs) in the United States and captured by the National Electronic Injury Surveillance System (NEISS) database of the US Consumer Product Safety Commission. RESULTS: There were 2028 (national estimate, 49,185) young football players evaluated in NEISS EDs with concussion from 2002 to 2012. There were 1987 (97.9%) males and 41 (2.1%) females, with a mean age of 11.2 years. The total number of concussions reported increased with age and by year. The majority of concussions were treated in the outpatient setting, with 1878 (91.7%) being treated and released. The total number of head-to-head injury mechanisms mirrored the total number of concussions by year, which increased throughout the 11-year span. The total number of players experiencing a loss of consciousness increased throughout the study period but did not match the total number of concussions over the 11-year time period. Fractures occurred in 11 (0.5%) patients, with 2 being severe (1 skull fracture and 1 thoracic compression fracture). CONCLUSION: Within the 5- to 13-year age range, there were a significant number of young athletes who presented to EDs with concussion as a result of playing organized football. Older children may be at greater risk for sustaining concussions, fractures, and catastrophic injuries while playing football when compared with younger children. CLINICAL RELEVANCE: Younger children are more susceptible to long-term sequelae from head injuries, and thus, improved monitoring systems for these athletes are needed to assist in monitoring patterns of injury, identifying risk factors, and driving the development of evidence-based prevention programs. PMID- 26535263 TI - Intrinsic Predictive Factors of Noncontact Lateral Ankle Sprain in Collegiate Athletes: A Case-Control Study. AB - BACKGROUND: Lateral ankle sprain (LAS) is one of the most common injuries in sports. Despite extensive research, intrinsic factors that predict initial and recurrent noncontact LAS remain undefined. PURPOSE: To identify the predictive factors of initial and recurrent noncontact LAS, focusing on ankle flexibility and/or alignment in collegiate athletes. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 191 athletes were assessed during the preseason for factors predictive of noncontact LAS. The baseline measurements included weightbearing dorsiflexion range of motion (ROM), leg-heel angle, foot internal rotation angle in plantar flexion, classification according to the mortise test, and navicular-medial malleolus (NMM) distance. Occurrence of noncontact LAS and participation in practice and games were prospectively recorded for 11 months. RESULTS: Of the 191 athletes assessed, 169 (145 males, 24 females) completed the study; 125 athletes had a history of ankle sprain. During the observational period, 16 athletes suffered noncontact LAS (0.58 per 1000 athlete-exposures) consisting of 4 initial sprains and 12 recurrences. The hazard ratio estimated by a Cox regression analysis showed that athletes with an NMM distance >=4.65 cm were 4.14 times more likely to suffer an initial noncontact LAS than were athletes with a shorter NMM distance (95% confidence interval, 1.12 14.30) and that athletes with a weightbearing dorsiflexion ROM >49.5 degrees were 1.12 times as likely to suffer a recurrent noncontact LAS compared with athletes with a lower ROM (95% confidence interval, 1.05-1.20). CONCLUSION: NMM distance predicts initial noncontact LAS, and weightbearing dorsiflexion ROM predicts recurrent noncontact LAS. PMID- 26535264 TI - Medial Epicondyle Morphology in Elite Overhead Athletes: A Closer Look Using 3 Dimensional Computer Simulation. AB - BACKGROUND: Prior studies have attempted to determine morphological characteristics of the medial epicondyle in overhead athletes, but no study has reported on precise quantitative differences between elite overhead athletes and control patients. HYPOTHESIS: The medial epicondyle in overhead athletes is larger in volume than those of control patients. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Computer simulation modeling from advanced (computed tomography/magnetic resonance imaging) imaging of the elbow of 37 patients (22 elite overhead athletes, 15 control patients) was performed to provide detailed assessment of the morphological characteristics of the medial epicondyle. Several quantitative metrics regarding the medial epicondyle were measured and compared across both cohorts, including that of epicondyle width (medial-lateral), height (superior-inferior), thickness (anterior-posterior), volume, percentage cortical volume, and morphology of the inferior slope of the epicondyle. RESULTS: The medial epicondyle in overhead athletes was significantly larger than that found in nonathlete controls (4976 vs 3682 mm(3); P = .001). There was no significance between the 2 cohorts in medial-lateral width (16.8 vs 16.6 mm; P = .68), but there was a difference in anterior-posterior thickness (16.96 vs 14.40 mm; P = .001) and superior-inferior height (39.55 vs 35.86 mm; P = .09) in athletes versus controls. The epicondyle volume was 97.9% cortical bone in athletes compared with 82.3% in control patients (P < .001). There were no differences in the morphology of the inferior epicondyle slope between the 2 groups. CONCLUSION: The medial epicondyle in overhead athletes is larger in volume and anterior-posterior thickness than those of control patients. Additionally, the medial epicondyle is comprised nearly entirely of cortical bone in overhead athletes. CLINICAL RELEVANCE: These quantitative findings support the theory of adaptive remodeling in skeletally immature overhead athletes. PMID- 26535265 TI - Are There Differences in Ice Hockey Injuries Between Sexes?: A Systematic Review. AB - BACKGROUND: Men's ice hockey allows for body checking, and women's ice hockey prohibits it. Studies have reported injury data on both sexes, but no systematic reviews have compared the injury patterns between male and female ice hockey players. HYPOTHESIS: Men's and women's ice hockey would have different types of injuries, and this difference would extend across the different age groups and levels of play. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: Three databases, 3 scientific journals, and selected bibliographies were searched to identify articles relevant to this study. Articles were further screened by the use of predetermined inclusion and exclusion criteria. Twenty-two studies met these criteria and were subsequently reviewed. RESULTS: Men sustained higher rates of injuries than women at all age levels, and both sexes sustained at least twice as many injuries in games than practices. Both sexes sustained most of their injuries from player contact. Men and women in college sustained most injuries to the head and face, and women suffered from higher percentages of concussion. At all ages and levels of play, men had higher rates of upper extremity injuries (shoulder), while women were found to sustain more injuries to the lower extremity (thigh, knee). CONCLUSION: Although findings showed men sustaining higher rates of injuries than women, the predominant mechanism of player contact was the same. The most common locations and types of injuries in female ice hockey players are comparable to other sports played by women, and similar interventions could offer protection against injury. CLINICAL RELEVANCE: Further studies that report injury data for women playing ice hockey at all levels will assist in understanding what prevention strategies should be implemented. PMID- 26535266 TI - Functional Performance Testing After Anterior Cruciate Ligament Reconstruction: A Systematic Review. AB - BACKGROUND: When to allow an athlete to return to unrestricted sporting activity after anterior cruciate ligament (ACL) reconstruction remains controversial. PURPOSE: To report the results of functional performance testing reported in the literature for individuals at differing time points following ACL reconstruction and to examine differences between graft types. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic review of Medline, Scopus, and Cochrane Central Register of Controlled Trials was performed using PRISMA guidelines. Inclusion criteria were English-language studies that examined any functional rehabilitation test from 6 months to 2 years following ACL reconstruction. All patient-, limb-, and knee-specific demographics were extracted from included investigations. All functional rehabilitation tests were analyzed and compared when applicable. RESULTS: The search term returned a total of 890 potential studies, with 88 meeting inclusion and exclusion criteria. A total of 4927 patients were included, of which 66% were male. The mean patient age was 26.5 +/- 3.4 years. The predominant graft choices for reconstruction were bone-patellar tendon-bone (BPTB) autograft (59.8%) and hamstring autograft (37.9%). The most commonly reported functional tests were the hop tests. The results of these functional tests, as reported in the Limb Symmetry Index (LSI), improved with increasing time, with nearly all results greater than 90% at 1 year following primary ACL reconstruction. At 6 months postoperatively, a number of isokinetic strength measurements failed to reach 80% LSI, most commonly isokinetic knee extension testing in both BPTB and hamstring autograft groups. The knee flexion strength deficit was significantly less in the BPTB autograft group as compared with those having hamstring autograft at 1 year postoperatively, while no significant differences were found in isokinetic extension strength between the 2 groups. CONCLUSION: Hop testing was the most commonly reported functional test following ACL reconstruction. Increases in performance on functional tests were predictably seen as time increased following surgery. Those with hamstring autografts may experience increased strength deficits with knee flexion versus those having BPTB autograft. These data provide information that may assist providers in determining timing of return to unrestricted sporting activity. PMID- 26535267 TI - The Epidemiology of Injuries in Mixed Martial Arts: A Systematic Review and Meta analysis. AB - BACKGROUND: Mixed martial arts (MMA) has experienced a surge in popularity since emerging in the 1990s, but the sport has also faced concomitant criticism from public, political, and medical holds. Notwithstanding the polarized discourse concerning the sport, no systematic review of the injury problems in MMA has been published to date. PURPOSE: To systematically review the epidemiologic data on injuries in MMA and to quantitatively estimate injury incidence and risk factor effect sizes. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 4. METHODS: Electronic searching of PubMed, Scopus, CINAHL, EMBASE, AMED, and SPORTDiscus databases to identify studies reporting on the epidemiology of injuries in MMA. Random-effects models were used to obtain pooled summary estimates of the injury incidence rate per 1000 athlete-exposures (IIRAE) and rate ratios with 95% confidence intervals (CIs). Heterogeneity was evaluated with the I (2) statistic. RESULTS: A total of 6 studies were eligible for inclusion in this review. The IIRAE summary estimate was found to be 228.7 (95% CI, 110.4 473.5). No studies reported injury severity. The most commonly injured anatomic region was the head (range, 66.8%-78.0%) followed by the wrist/hand (range, 6.0% 12.0%), while the most frequent injury types were laceration (range, 36.7% 59.4%), fracture (range, 7.4%-43.3%), and concussion (range, 3.8%-20.4%). The most notable risk factors pertained to the outcome of bouts. Losers incurred 3 times as many injuries as winners, and fighters in bouts ending with knockout or technical knockout incurred more than 2 times as many injuries as fighters in bouts ending with submission. CONCLUSION: Notwithstanding the paucity of data, the injury incidence in MMA appears to be greater than in most, if not all, other popular and commonly practiced combat sports. In general, the injury pattern in MMA is very similar to that in professional boxing but unlike that found in other combat sports such as judo and taekwondo. More epidemiologic research is urgently needed to improve the accuracy of the injury incidence estimate, to determine the injury severity, and to identify more risk factors for injury in MMA. PMID- 26535268 TI - Surface Replacement Arthroplasty of the Humeral Head in Young, Active Patients: Midterm Results. AB - BACKGROUND: The treatment of glenohumeral arthritis in young, active patients remains controversial. Standard total shoulder arthroplasty in this patient group has not obtained the same satisfaction rate as in older patients. One surgical option that has emerged is humeral resurfacing. HYPOTHESIS: Humeral head surface replacement arthroplasty (SRA) would provide satisfactory clinical outcomes in active patients, allowing them to maintain their normal lifestyle without activity restrictions. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: From 2004 to 2007, all consecutive surface replacement arthroplasties of the humerus performed at the authors' institution were identified and retrospectively reviewed, and 118 patients who underwent SRA during this time were identified. This study included patients younger than 60 years who wished to maintain an active lifestyle; 52 of the 118 patients met the inclusion criteria. University of California at Los Angeles (UCLA) shoulder scores and subjective shoulder value (SSV) scores were used to measure clinical outcomes at an average follow-up of 6 years (range, 4-8 years). Of the 52 patients meeting the inclusion criteria, 48 were contacted and examined for the study, with 4 patients lost to follow-up. RESULTS: The mean postoperative UCLA score was 28.03, with 1 patient requiring revision because of pain and glenoid wear. The mean SSV was 92% (range, 0%-100%), with 3 patients restricting their activity because of the shoulder. Forty-seven of the 48 contacted patients stated that, given the option, they would have the same surgery again. One patient required revision surgery because of pain. CONCLUSION: Surface replacement arthroplasty provided reasonable results in patients younger than 60 years with high activity demands with a low rate of revision at midterm follow-up. PMID- 26535269 TI - Knee Injuries in Downhill Skiers: A 6-Year Survey Study. AB - BACKGROUND: Knee injuries account for approximately one third of injuries in skiers. Researchers have proposed several mechanisms of knee injury in skiers. However, the frequencies of these mechanisms have varied in different studies. PURPOSE: To identify the most common knee injury mechanisms in recreational downhill skiers and to assess injury frequencies across several demographics. STUDY DESIGN: Descriptive epidemiology study. METHODS: Over 6 ski seasons, 541 patients with acute knee injuries completed a survey. Patients selected 1 of 6 injury classifications; age, sex, height, weight, years of experience, ability level, and ski binding release were also recorded. RESULTS: The overall injury distribution was valgus-external rotation (32.9%), phantom foot (22.5%), hyperextension (19.0%), boot induced (7.8%), collision (2.2%), and other (15.6%). The phantom foot mechanism was most common in ages 30 to 40 years (36.3% of all injuries within this mechanism; P < .01). Children and adults showed no significant difference in distribution of injury mechanism. Of 80 youth skiers, valgus-external rotation was most common (35.4%), followed by phantom foot (25.3%). Adult and youth skiers who identified as "advanced" skiers had a higher prevalence of valgus-external rotation than did less experienced skiers (51.5% of total valgus injuries; P < .01). Bindings released in 19.3% in adults and 53.7% in youths (P < .01) during injury. Female skiers comprised 60.0% of total respondents, but only 39.7% of injuries occurred in female children (P < .01). CONCLUSION: Valgus-external rotation is the most common injury mechanism for recreational skiers in general. Previous studies have suggested that the phantom foot injury is the most common injury, but in this series, it was the second most common, representing 22.5% of injuries in this study. Individuals between the ages of 30 and 40 years showed an increased risk for the phantom foot mechanism, and the prevalence of injuries was significantly higher for females compared with males in this cohort (P < .01). Children and adults appear to have similar mechanisms for ski-related knee injuries, with valgus-external rotation being most common and advanced skiers having the highest frequency of this mechanism. Binding release was more likely to occur in youth skiers. PMID- 26535270 TI - Characterization of Human Anterosuperior Acetabular Depression in Correlation With Labral Tears. AB - BACKGROUND: Labral tears often occur in the same quadrant of the acetabulum at a small depression previously referred to as the psoas valley. Understanding the anatomic variations of this depression could help us understand the etiology of labral tears. PURPOSE: To describe the location and dimensions of the depression located in the anterosuperior acetabular rim. The hypothesis was that the location of this depression would be consistent with the common location of acetabular labral tears described in the literature. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 240 pelvic specimens were divided into 2 groups (n = 120 for each) according to age (younger age group: 21.36 +/- 3.12 years [range, 14-24 years]; older age group: 42.30 +/- 10.27 years, [range, 25-60 years]).Specimens were also categorized based on sex (mean age: 31.93 +/- 12.31 years [male]; 32.08 +/- 13.66 years [female]) and race (mean age: 31.45 +/- 13.16 years [black]; 32.57 +/- 12.82 years [white]). The depth and width of the acetabular depression were measured using a digital caliper, and the location was measured using a goniometer. RESULTS: The psoas valley was observed in every specimen and was located in the anterosuperior quadrant of the acetabulum. Its depth was significantly greater (P < .001) in males (5.35 +/- 1.60 mm) than in females (3.95 +/- 1.31 mm). The width of the psoas valley was also greater (P < .001) in males (29.39 +/- 3.98 mm) than in females (24.49 +/- 4.80 mm). There were no differences in size or location of the depression between races or age groups. The psoas valley was located between 3.92 +/- 0.42 o'clock anteriorly and 2.12 +/- 0.77 o'clock posteriorly. CONCLUSION: The differences observed in the study data are believed to be a result of the different anatomic morphologies of the pelvis in males and females. This loss of bony support, caused by the depression, could be the underlying cause of weakening of the acetabular labrum as people age. CLINICAL RELEVANCE: The loss of bony support in the anterosuperior acetabular depression could contribute to the labral tears that commonly occur in this area. Understanding the normal anatomy of this area could be important in determining the risk of labral tears as well as treatment options. PMID- 26535271 TI - Cartilage Repair With or Without Meniscal Transplantation and Osteotomy for Lateral Compartment Chondral Defects of the Knee: Case Series With Minimum 2-Year Follow-up. AB - BACKGROUND: Treatment decision making for chondral defects in the knee is multifactorial. Articular cartilage pathology, malalignment, and meniscal deficiency must all be addressed to optimize surgical outcomes. PURPOSE: To determine whether significant clinical improvements in validated clinical outcome scores are observed at minimum 2-year follow-up after articular cartilage repair of focal articular cartilage defects of the lateral compartment of the knee with or without concurrent distal femoral osteotomy and lateral meniscus transplant. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Symptomatic adults who underwent surgical treatment (microfracture, autologous chondrocyte implantation [ACI], osteochondral autograft or allograft) of full-thickness lateral compartment chondral defects of the knee with or without a postmeniscectomy compartment or valgus malalignment by a single surgeon with minimum 2-year follow up were analyzed. Validated patient-reported and surgeon-measured outcomes were collected pre- and postsurgery. Pre- and postoperative outcomes were compared via Student t tests. RESULTS: Thirty-five subjects (mean age, 29.6 +/- 10.5 years) were analyzed. Patients had been symptomatic for 2.51 +/- 3.52 years prior to surgery and had undergone 2.11 +/- 1.18 surgeries prior to study enrollment, with a mean duration of follow-up of 3.65 +/- 1.71 years. The mean defect size was 4.42 +/- 2.06 cm(2). Surgeries included ACI (n = 18), osteochondral allograft (n = 14), osteochondral autograft (n = 2), and microfracture (n = 1). There were 18 subjects who underwent concomitant surgery (14 lateral meniscus transplant, 3 distal femoral osteotomy, and 1 combined). Statistically significant (P < .05) and clinically meaningful improvements were observed at final follow-up in Lysholm, subjective International Knee Documentation Committee (IKDS), Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales, Short Form-12 (SF-12) scores, and patient satisfaction. At follow-up, patients undergoing isolated articular cartilage surgery had a significantly higher KOOS quality of life subscore than did those undergoing articular cartilage surgery and lateral meniscus transplant (P = .039). Otherwise, there were no significant postoperative differences between the isolated and combined surgery groups in any outcome score. Five patients underwent 6 reoperations (1 revision osteochondral allograft, 5 chondroplasties). No patient was converted to knee arthroplasty. CONCLUSION: In patients with lateral compartment focal chondral defects with or without lateral meniscal deficiency and valgus malalignment, surgical cartilage repair and correction of concomitant pathology can significantly improve clinical outcomes at 2-year follow-up with no significant differences between isolated and combined surgery and a low rate of complications and reoperations. PMID- 26535272 TI - Risk for Revision After Anterior Cruciate Ligament Reconstruction Is Higher Among Adolescents: Results From the Danish Registry of Knee Ligament Reconstruction. AB - BACKGROUND: The number of children and adolescents with anterior cruciate ligament (ACL) reconstructions is increasing, and disturbing reports on high rerupture rates in this group have been noted. PURPOSE: To describe the outcome of ACL reconstruction in children and adolescents based on data from the Danish Knee Ligament Reconstruction Registry (DKRR). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data were retrieved from the DKRR, a national population based registry. The analysis was based on a population of 14,806 ACL reconstructed patients. The outcome was evaluated using risk of ACL revision, subjective outcome score (Knee injury and Osteoarthritis Outcome Score [KOOS]), Tegner function score, and objective knee laxity. Three age groups were defined (A, <13 years; B, 13-15 years; and C, 15-20 years) and compared with D, patients >=20 years (adults). There were 95 patients in group A, 327 in B, 2888 in C, and 11,496 in D. RESULTS: There was a significantly increased risk of revision surgery in the age groups B (6.7%) and C (4.9%) compared with the adults in group D (2.0%). Objective knee laxity did not differ between the 4 groups. Groups A, B, and C had a higher score on the combined KOOS symptoms, pain, sport, and quality of life subscales (KOOS4; 79.6, 76.6, and 73.1, respectively) compared with the adults (69.7). Group B had higher KOOS quality of life (76.6) and sports (71.1) scores than did group C (73.1 and 66.4, respectively). The Tegner activity score did not differ between the 4 groups. No impact of the use of extracortical graft fixation was detected in the youngest age group. CONCLUSION: Study results indicated an increased risk of graft failure in patients between 13 and 20 years of age. This is in contrast to the better subjective and equal objective knee score found in the same age groups. CLINICAL RELEVANCE: The new knowledge about the high revision rate among ACL-reconstructed teenagers is important for evidence-based preoperative information of ACL patients and their parents. PMID- 26535273 TI - Hip Morphology Characterization: Implications in Femoroacetabular Impingement in a Chilean Population. AB - BACKGROUND: Femoroacetabular impingement (FAI) is the result of a mechanical conflict in the hip joint, and its diagnosis is based on clinical and radiological parameters. To our knowledge, there are no published studies describing the radiologic characteristics of FAI in Latin American populations. PURPOSE: To describe the radiological features associated with FAI in an asymptomatic Chilean population. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: We prospectively recruited asymptomatic patients with no history or symptoms of hip pathology who underwent abdomen-pelvis computed tomography (CT) for a nonorthopaedic indication. The acetabular and femoral parameters related to FAI were measured. RESULTS: We studied 101 subjects (202 hips) with a mean age of 36.8 +/- 14.4 years. The mean center-edge angle was 39.4 degrees +/- 7.2 degrees . The crossover sign was present in 34 cases (33.7%). The mean alpha angle was 49.7 degrees +/- 8.3 degrees . Depending on the cut points chosen for FAI-related parameters, between 39.6% and 69.3% of an asymptomatic Chilean population were found to have morphological features related to FAI. CONCLUSION: Our findings suggest that the proposed pathological threshold values in the literature cannot be extrapolated to a Chilean population, and this must be taken into consideration when evaluating Latin American patients with hip pain. PMID- 26535274 TI - Postoperative Morbidity by Procedure and Patient Factors Influencing Major Complications Within 30 Days Following Shoulder Surgery. AB - BACKGROUND: Little data are available to prioritize quality improvement initiatives in shoulder surgery. PURPOSE: To stratify the risk for 30-day postoperative morbidity in commonly performed surgical procedures about the shoulder completed in a hospital setting and to determine patient factors associated with major complications. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This retrospective study utilized the National Surgical Quality Improvement Program (NSQIP) database from the years 2005 to 2010. Using Current Procedural Terminology codes, the database was queried for shoulder cases that were divided into 7 groups: arthroscopy without repair; arthroscopy with repair; arthroplasty; clavicle/acromioclavicular joint (AC) open reduction and internal fixation (ORIF)/repair; ORIF of proximal humeral fracture; open tendon release/repair; and open shoulder stabilization. The primary end point was any major complication, with secondary end points of incisional infection, return to the operating room, and venothromboembolism (VTE), all within 30 days of surgery. RESULTS: Overall, 11,086 cases were analyzed. The overall major complication rate was 2.1% (n = 234). Factors associated with major complications on multivariate analysis included: procedure performed (P < .001), emergency case (P < .001), pulmonary comorbidity (P < .001), preoperative blood transfusion (P = .033), transfer from an outside institution (P = .03), American Society of Anesthesiologists (ASA) score (P = .006), wound class (P < .001), dependent functional status (P = .027), and age older than 60 years (P = .01). After risk adjustment, open shoulder stabilization was associated with the greatest risk of major complications relative to arthroscopy without repair (odds ratio [OR], 5.56; P = .001), followed by ORIF of proximal humerus fracture (OR, 4.90; P < .001) and arthroplasty (OR, 4.40; P < .001). These 3 groups generated over 60% of all major complications. Open shoulder stabilization had the highest odds of reoperation (OR, 8.34; P < .001), while ORIF of proximal humerus fracture had the highest risk for VTE (OR, 6.47; P = .001) compared with the reference group of arthroscopy without repair. CONCLUSION: Multivariable analysis of the NSQIP database suggests that open shoulder stabilization, ORIF for proximal humerus fractures, and shoulder arthroplasty are associated with the highest risk of major complications within 30 days after shoulder surgery in a hospital setting. Age, functional status, ASA score, pulmonary comorbidity, emergency case, preoperative blood transfusion, and transfer from an outside institution are patient variables that significantly influence complication risk. PMID- 26535275 TI - Correlation Analysis of Potential Factors Influencing Graft Maturity After Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Postoperatively, signal changes of the reconstructed anterior cruciate ligament (ACL) graft on magnetic resonance imaging (MRI) images commonly occurs, which may be a cause for concern. The signal intensity changes are usually expressed by signal/noise quotient (SNQ) value, representing graft maturity. To date, little is known about the factors influencing the SNQ value of the reconstructed ACL graft. PURPOSE: To evaluate ACL graft SNQ value and associated factors after ACL reconstruction. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Male patients who underwent ACL reconstruction using autograft or allograft tendon from September 2004 to September 2011 were randomly invited to take part in this investigation, including functional scores, physical examination, and MRI scan. The femoral side graft was fixed with Endobutton CL or Rigidfix pins, and the tibial side graft was fixed with a bio-intrafix. SNQ values of each graft were measured on MRI to represent graft maturity. Sagittal ACL angle, ACL-Blumensaat line angle, and medial and lateral posterior tibial slope (PTS) were measured using MRI 3-dimensional dual-echo steady-state images. Potential risk factors, including age, body mass index, postoperative time, Tegner activity scale (TAS), sagittal ACL angle, ACL-Blumensaat line angle, medial PTS, lateral PTS, and primary graft diameter, were tested for their association with the graft SNQ value by multivariate stepwise regression analysis. RESULTS: A total of 104 male subjects (mean follow-up, 30.7 months) were examined, including 62 allograft and 42 autograft reconstructions. There was a significant association between graft SNQ and postoperative time (r = -0.431, P < .001), TAS (r = 0.295, P = .002), and ACL-Blumensaat line angle (r = -0.304, P = .002). Univariate regression analysis showed that TAS (beta = 6.15, P < .001) positively correlated, postoperative time (beta = -0.26, P < .001) negatively correlated, and ACL-Blumensaat line angle (beta = -0.40, P = .038) negatively correlated with graft SNQ. Multivariate stepwise regression analysis showed that TAS, postoperative time, ACL-Blumensaat line angle, and age were significant independent factors associated with graft SNQ. CONCLUSION: The graft SNQ value had a significant positive correlation with physical activity level and a significant negative correlation with postoperative time in this study. Males with a shorter postoperative time and a higher physical activity level had higher graft signal intensity postoperatively. PMID- 26535276 TI - Clinical and Biomechanical Evaluation of an All-Arthroscopic Suprapectoral Biceps Tenodesis. AB - BACKGROUND: Pathology of the long head of the biceps (LHB) is a well-recognized cause of shoulder pain in the adult population and can be managed surgically with tenotomy or tenodesis. PURPOSE: To compare the biomechanical strength of an all arthroscopic biceps tenodesis technique that places the LHB distal to the bicipital groove in the suprapectoral region with a more traditional mini-open subpectoral tenodesis. This study also evaluates the clinical outcomes of patients who underwent biceps tenodesis using the all-arthroscopic technique. STUDY DESIGN: Controlled laboratory study and case series; Level of evidence, 4. METHODS: For the biomechanical evaluation of the all-arthroscopic biceps tenodesis technique, in which the biceps tendon is secured to the suprapectoral region distal to the bicipital groove with an interference screw, 14 fresh-frozen human cadaveric shoulders (7 matched pairs) were used to compare load to failure and displacement at peak load with a traditional open subpectoral location. For the clinical evaluation, 49 consecutive patients (51 shoulders) with a mean follow-up of 2.4 years who underwent an all-arthroscopic biceps tenodesis were evaluated using the American Shoulder and Elbow Surgeons (ASES) score preoperatively and at last follow-up, as well as the University of California, Los Angeles (UCLA) Shoulder Score at last follow-up. RESULTS: On biomechanical evaluation, there was no significant difference in peak failure load, displacement at peak load, or displacement after cyclic testing between the arthroscopic suprapectoral and mini-open subpectoral groups. In the clinical evaluation, the mean preoperative ASES score was 65.4, compared with 87.1 at last follow-up. The mean UCLA score at last follow-up was 30.2. Forty-eight (94.1%) patients reported satisfaction with the surgery. In subgroup analysis comparing patients who had a rotator cuff repair or labral repair at time of tenodesis with patients who did not have either of these procedures, there were no significant differences in UCLA or ASES scores. CONCLUSION: The excellent biomechanical strength as well as the high rate of satisfaction after surgery and high ASES and UCLA postoperative scores make this technique a novel option for treatment of biceps tendon pathology. PMID- 26535277 TI - Is Tommy John Surgery Performed More Frequently in Major League Baseball Pitchers From Warm Weather Areas? AB - BACKGROUND: Medial ulnar collateral ligament (UCL) reconstruction is a common procedure performed on Major League Baseball (MLB) pitchers with symptomatic UCL insufficiency, frequently due to overuse. Warm weather climates afford youth pitchers the opportunity to throw year-round, potentially placing them at risk for overuse elbow injuries. PURPOSE/HYPOTHESIS: To determine whether the proportion of MLB pitchers who underwent medial UCL reconstruction and who pitched competitive youth baseball in warm weather areas is higher than those from cold weather areas. The hypothesis was that MLB pitchers from warm weather areas were more likely to undergo UCL reconstruction than pitchers from cold weather areas. STUDY DESIGN: Descriptive epidemiological study. METHODS: All MLB pitchers with symptomatic UCL deficiency who underwent UCL reconstruction as of June 1, 2014, were evaluated. The state/country where they played high school baseball was identified from online reference websites. Warm and cold weather areas were defined by latitude distance from the equator and mean annual temperatures. A chi-square test was used to compare the proportion of MLB pitchers from warm versus cold weather areas who underwent UCL reconstruction. The study was 99.6% powered to detect a 100% effect size (eg, 1% vs 2%) and 71.4% powered to detect a 50% effect size (eg, 1% vs 1.5%) with setting alpha = .05. RESULTS: A total of 247 pitchers were identified who had undergone UCL reconstruction; 139 (56.3%) pitched high school baseball in warm weather areas, 108 (43.7%) pitched in cold weather areas. A significantly higher proportion of pitchers who underwent UCL reconstruction (2.2% [95% CI, 1.9%-2.6%]) were from warm weather areas compared with cold weather areas (0.94% [95% CI, 0.78%-1.1%]) (P < .0001). Warm weather pitchers had a mean (+/-SD) age of 27.6 +/- 0.6 years and had played 4.0 +/- 0.6 seasons in MLB at the time of surgery, while cold weather pitchers were aged 28.4 +/- 0.8 years and had played 5.0 +/- 0.9 seasons in MLB (P = .089 and P = .047, respectively). CONCLUSION: MLB pitchers who played high school baseball in warm weather climates have undergone medial UCL reconstruction more frequently and earlier in their MLB careers than pitchers who played in cold weather areas. PMID- 26535278 TI - The Impact of Superior Labral Anterior to Posterior Lesions on Functional Status in Shoulder Instability: A Multicenter Cohort Study. AB - BACKGROUND: Type IV superior labral anterior to posterior (SLAP) lesions, which are superior labral detachments associated with Bankart tears, are reported to occur in up to 25% of recurrent shoulder instability patients. However, the clinical implications of this finding are debatable. PURPOSE: To determine whether there are any functional differences between anterior instability patients with and without type IV SLAP lesions at the time of presentation and at short-term follow-up after surgical intervention. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A prospective, multicenter database was established to follow the clinical evolution of patients with shoulder instability. Patients were diagnosed as having a type IV SLAP lesion at the time of arthroscopic Bankart surgery (SLAP+). These patients were compared with a group of patients who simply had a Bankart lesion (SLAP-). The 2 groups had their functional outcomes (Western Ontario Shoulder Instability Index [WOSI]; Disability of the Arm, Shoulder, and Hand [QuickDASH]; and Walch-Duplay) compared prior to surgery and 1 year postoperatively. RESULTS: A total of 103 subjects were included in the study; of these, 56 (43 men, 13 women) completed 1-year follow-up. Twenty-three subjects had a type IV SLAP tear, and most had this repaired along with their Bankart lesion. At baseline, SLAP+ subjects had inferior QuickDASH scores compared with SLAP- subjects (37.8 vs 29.0) as well as poorer pain subscores on both the WOSI and QuickDASH. At 1-year follow-up, however, there were no significant differences in any of the outcome measures. CONCLUSION: A type IV SLAP lesion can be expected in 22% of patients with recurrent shoulder instability. This finding implies that at baseline, the patient will have slightly worse functional scores related to pain. However, following surgical management of the labral pathology, these patients will have equivalent functional outcomes at short-term follow-up. CLINICAL RELEVANCE: With surgical management of the superior and anteroinferior labrum, patients with type IV SLAP lesions will do as well as those with only Bankart tears. Thus, the presence of SLAP lesions should not alter the decision to provide surgical management and should not change the prognosis for a specific patient. PMID- 26535279 TI - High School Athletes' Perceptions of Concussion. AB - BACKGROUND: The perception high school athletes have regarding concussions may influence their injury-reporting behavior, and if their perceptions are based on incorrect or incomplete information, they may be at risk for subsequent head injuries. PURPOSE: To determine whether the recent influx of concussion information has had a positive impact on high school athletes' knowledge of concussions, to determine their perceptions regarding the severity of a concussion injury, and to determine whether receiving correct information will potentially alter their future reporting behavior. STUDY DESIGN: Cross-sectional study; Level of evidence, 4. METHODS: A total of 454 high school athletes (212 females, 242 males; mean age, 15.7 +/- 1.15 years) from 6 different schools participated in an anonymous survey. The researchers met with teams individually at their high schools to collect data and provide an educational intervention regarding sports-related concussions. The survey questions assessed the athletes' personal injury histories and perceptions and knowledge of the severity of concussion injuries. RESULTS: There was a difference in the number of athletes who reported having their "bell rung" (n = 297) versus the number of athletes reporting at least 1 concussion (n = 172) (t (453) = -11.60, P = .000, d = 0.54). There was also a difference in the number of athletes who reported a history of at least 1 concussion at the beginning of the study session (n = 172) versus the number of athletes who reported at least 1 concussion at the end of the session (n = 292) (t (453) = -12.018, P = .000, d = 0.732). Fifty percent of athletes also stated that the importance of a game/event should dictate when they return to play. CONCLUSION: High school athletes continue to fail to realize when they have sustained a concussion. Additionally, athletes lack understanding regarding the severity and seriousness of a concussion. A better effort at formalized education must be made if the culture of sports is to change. CLINICAL RELEVANCE: Allied health care professionals need to continue to put forth a great effort in educating all student athletes on what a concussion is and the dangers of a concussion injury. Preseason meetings should be used as an opportunity to provide formalized education to all student athletes. PMID- 26535280 TI - Injuries in Competitive Dragon Boating. AB - BACKGROUND: Dragon boating is a fast-growing team water sport and involves forceful repetitive motions that predispose athletes to overuse injuries. Despite the rising popularity of the sport, there is a lack of studies on injury epidemiology in dragon boating. PURPOSE: To investigate the injury epidemiology in competitive dragon boating athletes. STUDY DESIGN: Descriptive epidemiological study. METHODS: A total of 95 dragon boaters (49 males, 46 females) representing their respective universities took part in this study. Data were collected retrospectively using a reliable and valid self-report questionnaire. The study period was from August 2012 to July 2013. RESULTS: A total of 104 musculoskeletal injuries were reported (3.82 injuries/1000 athlete-exposures), 99% of which occurred during training. The most commonly injured regions were the lower back (22.1%), shoulder (21.1%), and wrist (17.3%). The majority of injuries were due to overuse (56.3%), and incomplete muscle-tendon strain was the most prevalent type of injury (50.5%). The time loss from injuries varied. In addition, a significant majority of the dragon boating athletes incurred nonmusculoskeletal injuries, with abrasions (90.5%), blisters (78.9%), and sunburns (72.6%) being the most common. CONCLUSION: Competitive dragon boating has a moderately high injury incidence, and there seems to be a direct relationship between exposure time and injury rate. A majority of the injuries are overuse in nature, and the body parts most actively involved in paddling movement are at higher risk of injuries. The high incidence of nonmusculoskeletal injuries in dragon boaters suggested that these injuries are likely outcomes of participation in the sport. PMID- 26535281 TI - Biomechanical Comparison of Fracture Risk Created by 2 Different Clavicle Tunnel Preparations for Coracoclavicular Ligament Reconstruction. AB - BACKGROUND: An anatomic reconstruction of coracoclavicular (CC) ligaments typically requires drilling tunnels in the clavicle. An increase in fracture complications has been associated with graft tunnel position. A method of drilling clavicle tunnels that would better re-create anatomic function of the CC ligaments without increasing fracture risk would be an improvement. PURPOSE: To evaluate the feasibility of a novel single anterior-to-posterior tunnel technique and compare the biomechanical properties to the 2-tunnel technique in CC ligament reconstruction. The hypothesis was that the single tunnel will yield similar loads to failure as the 2-tunnel technique and better reproduce the native anatomy of the conoid and trapezoid ligaments. STUDY DESIGN: Controlled laboratory study. METHODS: Eight fresh-frozen matched pairs of human clavicles underwent testing. In 1 specimen of the matched pair, 2 bone tunnels were created as previously described. In the other, a single tunnel was placed obliquely from anterior to posterior. The relative position of the tunnels in relation to the conoid tuberosity was recorded. Specimens were tested on a materials testing machine. The ultimate load to failure, linear stiffness, distance of the conoid tuberosity to the conoid tunnel exit point, and mode of failure were recorded. RESULTS: The ultimate load to failure in the single-tunnel group and the 2-tunnel group was 457.2 +/- 139.8 and 488.8 +/- 170.6, respectively. There was no significant difference (P = .5). The linear stiffness in the single-tunnel group and the 2-tunnel group was 94.6 +/- 31.3 and 79.8 +/- 33.5, respectively. There was no significant difference (P = .2). The 2-tunnel group had a significantly longer average maximum distance from the conoid tuberosity to the conoid tunnel exit point than the single-tunnel group (6.0 +/- 2.1 vs 0.8 +/- 1.9 mm; P = .05). The single-tunnel group was consistently more anatomic with regard to its relationship to the conoid tuberosity than the 2-tunnel group. CONCLUSION: The single anterior-to-posterior clavicle tunnel had similar biomechanical properties to the 2-tunnel technique. However, the single-tunnel technique better reproduced the anatomic footprint of the conoid ligament. Utilizing this single-tunnel technique may yield an anatomic advantage that may also reduce the rate of complications caused by posterior wall blowout. CLINICAL RELEVANCE: Acromioclavicular joint injuries are common in collision sports. Surgical management is often indicated to reconstruct the joint. This study assesses the feasibility of a novel surgical approach. PMID- 26535282 TI - Meniscal Repair of Degenerative Horizontal Cleavage Tears Using Fibrin Clots: Clinical and Arthroscopic Outcomes in 10 Cases. AB - BACKGROUND: Presently, the treatment options available for patients with horizontal degenerative cleavage tears of the meniscus are limited. These tears are considered an indication for partial or subtotal meniscectomy because when the tear is located within an avascular area, it is difficult to induce healing. However, meniscectomy is not ideal because it disrupts the normal anatomical structure and function of the meniscus. PURPOSE: To examine the clinical and arthroscopic outcomes following meniscal repair of degenerative horizontal cleavage tears using fibrin clots. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Vertical sutures were placed in the meniscal tear, and the cleft was filled with fibrin clots before the sutures were tightened. We repaired 18 menisci in 18 consecutive eligible patients using a previously described technique. Three patients with anterior cruciate ligament (ACL) injury who underwent simultaneous ACL reconstruction and 5 patients who did not undergo follow-up arthroscopy within 12 months were excluded. The remaining 10 menisci in 10 patients were evaluated in this study. The mean age of the patients was 35.8 +/- 16.5 years, and the mean postoperative follow-up time was 40.8 +/- 5.4 months. Pre- and postoperative Lysholm scores, International Knee Documentation Committee (IKDC) subjective scores, and Tegner activity levels were compared. The arthroscopy findings were evaluated at a mean postoperative time of 6.7 +/- 2.9 months. RESULTS: The mean Lysholm score improved significantly from 69.3 +/- 16.3 points preoperatively to 95.4 +/- 3.6 points postoperatively (P < .005). The mean IKDC subjective score also improved significantly from 26.5% +/- 19.0% preoperatively to 87.8% +/- 7.5% postoperatively (P < .001). The Tegner activity level recovered to the preinjury level in 6 patients and to 1 level below the preinjury level in 4 patients. The follow-up arthroscopies showed complete healing in 7 patients (70%) and incomplete healing in 3 patients (30%). CONCLUSION: Meniscal repair of degenerative horizontal cleavage tears using fibrin clots resulted in improved Lysholm and IKDC subjective scores, but the complete healing rate on follow-up arthroscopy was only 70%. CLINICAL RELEVANCE: If we are to prevent osteoarthritis, we should minimize resection and restore the contact area of the meniscus to preserve the original shape. PMID- 26535283 TI - Glenoid Rim Anatomy: Risk for Glenoid Vault Perforation During Labral Repair. AB - BACKGROUND: Injuries to the glenoid labrum frequently require repair with anchors. Placing anchor devices arthroscopically can be challenging, and anchor malpositioning can complicate surgical outcomes. PURPOSE: To determine the safe insertion range and optimal insertion angle of glenoid labral anchors at various positions on the glenoid rim and to establish surgical guidelines that minimize risk of anchor perforation. STUDY DESIGN: Descriptive laboratory study. METHODS: Three-dimensional computed tomography scans of 30 normal cadaveric specimens were obtained. A virtual model of a generic labral anchor was inserted into the rim of the glenoid at the clockface positions represented by 12:00, 1:30, 3:00, 4:30, 6:00, 7:30, 9:00, and 10:30. At each position, the safe insertion range was the maximal range measured, and the optimal insertion angle was identified as the angle between the bisector of the safe insertion range and the glenoid face. RESULTS: Progressing in the clockwise direction, beginning at the 12:00 position, the safe insertion ranges (mean +/- SD ) were 55.9 degrees +/- 10.6 degrees , 63.6 degrees +/- 17.6 degrees , 47.7 degrees +/- 9.1 degrees , 46.1 degrees +/ 8 degrees , 73.9 degrees +/- 9.7 degrees , 40.9 degrees +/- 6.5 degrees , 40.4 degrees +/- 7.4 degrees , and 39.9 degrees +/- 7.1 degrees , respectively. The optimal insertion angles were 47.9 degrees +/- 7.6 degrees , 53.1 degrees +/- 10.9 degrees , 35.0 degrees +/- 4.4 degrees , 42.4 degrees +/- 4.9 degrees , 60.9 degrees +/- 8.4 degrees , 36.6 degrees +/- 5.9 degrees , 31.2 degrees +/- 4.9 degrees , 34.8 degrees +/- 4.6 degrees , respectively. CONCLUSION: Optimal insertion angles and safe insertion ranges varied significantly with respect to the position on the glenoid face. The safe insertion range and optimal insertion angle were found to be wider at the anterior glenoid as compared with the posterior glenoid. A posterolateral insertion angle was safer than an anterior insertion angle at the 10:30 position. CLINICAL RELEVANCE: Proper arthroscopic technique resulting in anchor insertion at the correct angle, depth, and location will prevent anchor-related glenohumeral complications such as glenoid perforation, cartilage damage, persistent pain, decreased range of motion, and failure of the reconstruction. PMID- 26535284 TI - Using the Amplitude of Pulse-Synchronous Intramuscular Pressure Oscillations When Diagnosing Chronic Anterior Compartment Syndrome. AB - BACKGROUND: To diagnose chronic anterior compartment syndrome (CACS) among patients with exercise-induced leg pain, intramuscular pressure (IMP) is regarded as the gold standard. Two recent studies have suggested that the evidence for commonly used IMP criteria are weak, and the validity has therefore come under question. PURPOSE: To evaluate whether the amplitude of pulse-synchronous IMP oscillations at rest after an exercise test is a reliable parameter that may aid in diagnosing CACS. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: A total of 89 consecutive patients with suspected CACS (mean age, 31 years) and 19 healthy subjects (mean age, 28 years) participated in this study. All participants performed an exercise test until they were unable to continue because of leg pain and/or muscle fatigue. The IMP was recorded continuously in the anterior compartment of the leg with a noninfusion pressure recording system, starting 15 to 30 seconds after discontinuation of exercise. To test the amplitude of pulse-synchronous IMP oscillations as an indicator of CACS, a peak to-peak amplitude of >2 mm Hg was chosen as the cutoff value. The clinical diagnosis of CACS was considered reference standard. RESULTS: The mean +/- SD IMP 1 minute after exercise was 54 +/- 16 mm Hg in 53 patients with CACS, 17 +/- 6 mm Hg in 36 non-CACS patients, and 18 +/- 5 mm Hg in control subjects. The mean amplitude of the oscillations was 7.1 +/- 3 mm Hg in patients with CACS, 1.3 +/- 0.9 mm Hg in non-CACS patients, and 1.5 +/- 0.6 mm Hg in control subjects 1 minute after exercise. The sensitivity of the amplitude to validate CACS was 96%, while the specificity was 94%. The positive predictive value was 96%, and the negative predictive value was 94%. CONCLUSION: The amplitude of the pulse synchronous IMP oscillations at rest after an exercise test that elicits a patient's leg pain and muscle fatigue has high sensitivity to identify an abnormally elevated IMP. CLINICAL RELEVANCE: Oscillations are easily recorded during clinical routine IMP measurements. They ascertain the diagnosis of CACS, corroborate the level of IMP, and ensure catheter patency. PMID- 26535285 TI - Thromboembolism Following Shoulder Arthroscopy: A Retrospective Review. AB - BACKGROUND: Thromboembolism following shoulder arthroscopy is considered an uncommon complication, with fewer than 50 cases reported in the literature. Arthroscopy of the shoulder is one of the most commonly performed orthopaedic procedures, with low associated risks. PURPOSE: To identify potential risk factors for the development of venous thromboembolism (VTE) following shoulder arthroscopy and to determine the overall incidence of this complication. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A retrospective case control review was performed of patients who developed symptomatic deep venous thrombosis (DVT) or pulmonary embolism (PE) following shoulder arthroscopy. Multiple surgeons from across North America were queried. For every case of DVT or PE identified, 2 control cases of shoulder arthroscopy were analyzed. The incidence of DVT/PE following shoulder arthroscopy was determined. A univariate analysis and a multivariate logistic regression model were conducted to identify any potential risk factors for the development of VTE following shoulder arthroscopy. RESULTS: A total of 17 surgeons participated in this study and had performed a total of 15,033 cases of shoulder arthroscopy from September 2002 through August 2011. Eleven of the 17 participating surgeons had had a patient with a VTE complication during this time frame. The incidence of VTE in the 15,033 cases was 0.15%; 22 patients of the 15,033 patients had a DVT (n = 15) and/or PE (n = 8). Forty-four control cases were also analyzed. Univariate and multivariate analyses were performed. No significant risk factors were identified other than patient positioning. All cases and controls were positioned in the beach-chair position for surgery. CONCLUSION: The results of this study show that although rare, VTE occurs following shoulder arthroscopy at a rate of 0.15%. The variables analyzed in the cases of VTE compared with the control cases did not show any significant risk factors. All cases were positioned in the beach-chair position. Further analysis of future cases is warranted. PMID- 26535286 TI - Treatment of Anterior Cruciate Ligament Injuries by Major League Soccer Team Physicians. AB - BACKGROUND: The treatment and rehabilitation procedures of anterior cruciate ligament (ACL) injuries in elite soccer players are controversial. Points of debate include surgical timing, technique, graft choice, rehabilitation, and return-to-sport criteria and timing. PURPOSE: To identify practice preferences among current Major League Soccer (MLS) team orthopaedic surgeons for ACL injuries. STUDY DESIGN: Cross-sectional study; Level of evidence, 4. METHODS: The survey was administered at the MLS team physician annual meeting in January 2013. At least 1 orthopaedic surgeon representative from each of the 19 clubs (16 from the United States, 3 from Canada) was in attendance. Teams with more than 1 affiliated orthopaedic surgeon were given an additional survey to be completed either at the meeting or returned via e-mail. Descriptive statistics, Wilcoxon Mann-Whitney (return-to-play parameters, running, and ball drills), and Fisher exact tests (graft selection, bracing, continuous passive motion) were applied to the various data sets from the survey responses. RESULTS: A 100% survey participation rate was achieved (22 team orthopaedic surgeons representing 19 MLS teams). A single-incision, arthroscopically assisted, single-bundle reconstruction was the most common technique (91%). Surgeons were split regarding femoral tunnel drilling (50% transtibial, 46% accessory medial). Autograft bone patellar tendon-bone (BPTB) was the most common preferred graft choice (68%). The biggest concerns about BPTB autograft and hamstring autograft were anterior knee pain (76%) and hamstring weakness (46%), respectively. Most surgeons did not recommend postoperative continuous passive motion (64%) or functional bracing (68%). Most surgeons permitted return to sport without restrictions at 6 to 8 months following surgery (82%). Surgeons who routinely used functional bracing after ACL surgery more frequently used hamstring autograft than those who used BPTB autograft (P = .04). CONCLUSION: This article successfully describes current management of ACL injuries among MLS team orthopaedic surgeons. The preference for single-bundle BPTB autograft is similar to published data in the National Football League and National Basketball Association. PMID- 26535287 TI - Results of Operative and Nonoperative Treatment of Rockwood Types III and V Acromioclavicular Joint Dislocation: A Prospective, Randomized Trial With an 18- to 20-Year Follow-up. AB - BACKGROUND: The optimal treatment of acute, complete dislocation of the acromioclavicular joint (ACJ) is still unresolved. PURPOSE: To determine the difference between operative and nonoperative treatment in acute Rockwood types III and V ACJ dislocation. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: In the operative treatment group, the ACJ was reduced and fixed with 2 transarticular Kirschner wires and ACJ ligament suturing. The Kirschner wires were extracted after 6 weeks. Nonoperatively treated patients received a reduction splint for 4 weeks. At the 18- to 20-year follow-up, the Constant, University of California at Los Angeles Shoulder Rating Scale (UCLA), Larsen, and Simple Shoulder Test (SST) scores were obtained, and clinical and radiographic examinations of both shoulders were performed. RESULTS: Twenty-five of 35 potential patients were examined at the 18- to 20-year follow-up. There were 11 patients with Rockwood type III and 14 with type V dislocations. Delayed surgical treatment for ACJ was used in 2 patients during follow-up: 1 in the operatively treated group and 1 in the nonoperatively treated group. Clinically, ACJs were statistically significantly less prominent or unstable in the operative group than in the nonoperative group (normal/prominent/unstable: 9/4/3 and 0/6/3, respectively; P = .02) and in the operative type III (P = .03) but not type V dislocation groups. In operatively and nonoperatively treated patients, the mean Constant scores were 83 and 85, UCLA scores 25 and 27, Larsen scores 11 and 11, and SST scores 11 and 12 at follow-up, respectively. There were no statistically significant differences in type III and type V dislocations. In the radiographic analysis, the ACJ was wider in the nonoperative than the operative group (8.3 vs 3.4 mm; P = .004), and in the type V dislocations (nonoperative vs operative: 8.5 vs 2.4 mm; P = .007). There was no statistically significant difference between study groups in the elevation of the lateral end of the clavicle. Both groups showed equal levels of radiologic signs of ACJ osteoarthritis and calcification of the coracoclavicular ligaments. CONCLUSION: Nonoperative treatment was shown to produce more prominent or unstable and radiographically wider ACJs than was operative treatment, but clinical results were equally good in the study groups at 18- to 20-year follow-up. Both treatment methods showed statistically significant radiographic elevations of the lateral clavicle when compared with a noninjured ACJ. PMID- 26535288 TI - Rectus Femoris Tendon Calcification: Arthroscopic Excision in 6 Top Amateur Athletes. AB - BACKGROUND: Since it was developed, hip arthroscopy has become the favored treatment for femoroacetabular impingement. Due to recent considerable improvements, the indications for this technique have been widely extended. Injuries of the rectus femoris tendon origin, after an acute phase, could result in a chronic tendinopathy with calcium hydroxyapatite crystal deposition, leading to pain and loss of function. Traditionally, this condition is addressed by local injection of anesthetic and corticosteroids or, when conservative measures fail, by open excision of the calcific lesion by an anterior approach. PURPOSE: To assess whether arthroscopic excision of calcification of the proximal rectus is a safe and effective treatment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Outcomes were studied from 6 top amateur athletes (age range, 30-43 years; mean, 32.6 years) affected by calcification of the proximal rectus who underwent arthroscopic excision of the calcification. Patients were preoperatively assessed radiographically, and diagnosis was confirmed by a 3 dimensional computed tomography scan. To evaluate the outcome, standardized hip rating scores were used pre- and postoperatively (at 6 and 12 months): the Hip disability and Osteoarthritis Outcome Score, Oxford Hip Score, and Modified Harris Hip Score. Moreover, visual analog scales (VAS) for pain, sport activity level (SAL), and activities of daily living (ADL) were also used. RESULTS: One year after surgery, all patients reported satisfactory outcomes, with 3 of 6 rating their return-to-sport level as high as preinjury level, and the remaining 3 with a percentage higher than 80%. Five patients ranked their ability to carry on daily activities at 100%. Statistical analysis showed significant improvement of the Oxford Hip Score, the Modified Harris Hip Score, and all 3 VAS subscales (pain, SAL, and ADL) from pre- to latest postoperative assessment (P < .05). CONCLUSION: Arthroscopic excision of rectus femoris tendon calcification yields satisfying results with few risks to the patient as well as rapid recovery. CLINICAL RELEVANCE: The recent improvements in hip arthroscopy give the opportunity to address an increasing number of hip conditions effectively and safely, with rapid recovery for the patient. Arthroscopic excision of rectus femoris tendon calcification can be considered a feasible option, with few risks to the patient, rapid recovery, and satisfying outcomes. PMID- 26535289 TI - Long-term Outcomes After Anterior Cruciate Ligament Reconstruction in Patients 60 Years and Older. AB - BACKGROUND: Studies evaluating the benefit of surgical reconstruction of the anterior cruciate ligament (ACL) in middle-aged patients have shown promising results, but study populations were limited primarily to patients who were 40 to 60 years old. Some authors have suggested that surgery may benefit these older patients. HYPOTHESIS: Patients aged >=60 years with functional instability after ACL injury would benefit from ACL reconstruction. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Medical records from 1984 through 2010 were searched for patients aged >=60 years who had undergone primary arthroscopic ACL reconstruction at a single institution. Fifteen patients (15 knees) were identified as meeting the above criteria. All patients were contacted for a telephone interview, and they completed Short Form-36 and modified Cincinnati Knee Score forms. One patient was deceased, and 1 had undergone revision to total knee arthroplasty. Among the remaining 13 patients, the mean age at surgery was 63.5 years (range, 60-73 years), and the mean patient age at the time of follow up was 73 years (range, 65-85 years). Preoperative radiographs showed no obvious evidence of arthritis in 10 (77%) of the 13 patients; small osteophytes without loss of joint space were seen in 3 (23%) patients. The mean length of follow up was 115.7 months (range, 53-193 months). RESULTS: At their last clinic visits, all 13 patients had regained full range of motion and returned to sports or exercise, such as tennis, golf, gym exercise, and yoga. Twelve patients reported no joint laxity. CONCLUSION: Patients aged >=60 years with symptomatic instability from ACL injury can have good to excellent subjective outcomes with surgical reconstruction. CLINICAL RELEVANCE: Physicians who treat active patients older than 60 years should not exclude ACL reconstruction based on the patient's age alone. PMID- 26535290 TI - Structural Properties of the Native Ligamentum Teres. AB - BACKGROUND: A majority of studies investigating the role of the ligamentum teres (LT) have focused primarily on anatomical and histological descriptions. To date, however, the structural properties of the LT have yet to be fully elucidated. PURPOSE: To investigate the structural properties of the native LT in a human cadaveric model. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 12 human cadaveric hemipelvises (mean age, 53.6 years; range, 34-63 years) were dissected free of all extra-articular soft tissues to isolate the LT and its acetabular and femoral attachments. A dynamic tensile testing machine distracted each femur in line with the fibers of the LT at a displacement-controlled rate of 0.5 mm/s. The anatomic dimensions, structural properties, and modes of failure were recorded. RESULTS: The LT achieved a mean yield load of 75 N and ultimate failure load of 204 N. The LT had mean lengths of 38.0 and 53.0 mm at its yield and failure points, respectively. The most common (75% of specimens) mechanism of failure was tearing at the fovea capitis. On average, the LT had a linear stiffness of 16 N/mm and elastic modulus of 9.24 MPa. The mean initial length and cross-sectional area were 32 mm and 59 mm(2), respectively. CONCLUSION: The human LT had a mean ultimate failure load of 204 N. Therefore, the results of this investigation, combined with recent biomechanical and outcomes studies, suggest that special consideration should be given to preserving the structural and corresponding biomechanical integrity of the LT during surgical intervention. CLINICAL RELEVANCE: The LT may be more important as a static stabilizer of the hip joint than previously recognized. Further studies are recommended to investigate the appropriate indications to perform surgical repair or reconstruction of the LT for preservation of hip stability and function. PMID- 26535291 TI - Psychometric Evaluation of the Lower Extremity Computerized Adaptive Test, the Modified Harris Hip Score, and the Hip Outcome Score. AB - BACKGROUND: The applicability and validity of many patient-reported outcome measures in the high-functioning population are not well understood. PURPOSE: To compare the psychometric properties of the modified Harris Hip Score (mHHS), the Hip Outcome Score activities of daily living subscale (HOS-ADL) and sports (HOS sports), and the Lower Extremity Computerized Adaptive Test (LE CAT). The hypotheses was that all instruments would perform well but that the LE CAT would show superiority psychometrically because a combination of CAT and a large item bank allows for a high degree of measurement precision. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: Data were collected from 472 advanced-age, active participants from the Huntsman World Senior Games in 2012. Validity evidences were examined through item fit, dimensionality, monotonicity, local independence, differential item functioning, person raw score to measure correlation, and instrument coverage (ie, ceiling and floor effects), and reliability evidences were examined through Cronbach alpha and person separation index. RESULTS: All instruments demonstrated good item fit, unidimensionality, monotonicity, local independence, and person raw score to measure correlations. The HOS-ADL had high ceiling effects of 36.02%, and the mHHS had ceiling effects of 27.54%. The LE CAT had ceiling effects of 8.47%, and the HOS-sports had no ceiling effects. None of the instruments had any floor effects. The mHHS had a very low Cronbach alpha of 0.41 and an extremely low person separation index of 0.08. Reliabilities for the LE CAT were excellent and for the HOS-ADL and HOS sports were good. CONCLUSION: The LE CAT showed better psychometric properties overall than the HOS-ADL, HOS-sports, and mHHS for the senior population. The mHHS demonstrated pronounced ceiling effects and poor reliabilities that should be of concern. The high ceiling effects for the HOS-ADL were also of concern. The LE CAT was superior in all psychometric aspects examined in this study. Future research should investigate the LE CAT for wider use in different populations. PMID- 26535292 TI - Evaluation of the Length and Isometric Pattern of the Anterolateral Ligament With Serial Computer Tomography. AB - BACKGROUND: Recent anatomical studies have identified the anterolateral ligament (ALL). Injury to this structure may lead to the presence of residual pivot shift in some reconstructions of the anterior cruciate ligament. The behavior of the length of this structure and its tension during range of motion has not been established and is essential when planning reconstruction. PURPOSE: To establish differences in the ALL length during range of knee motion. STUDY DESIGN: Descriptive laboratory study. METHODS: Ten unpaired cadavers were dissected. The attachments of the ALL were isolated. Its origin and insertion were marked with a 2 mm-diameter metallic sphere. Computed tomography scans were performed on the dissected parts under extension and 30 degrees , 60 degrees , and 90 degrees of flexion; measurements of the distance between the 2 markers were taken at all mentioned degrees of flexion. The distances between the points were compared. RESULTS: The mean ALL length increased with knee flexion. Its mean length at full extension and at 30 degrees , 60 degrees , and 90 degrees of flexion was 37.9 +/ 5.3, 39.3 +/- 5.4, 40.9 +/- 5.4, and 44.1 +/- 6.4 mm, respectively. The mean increase in length from 0 degrees to 30 degrees was 3.99% +/- 4.7%, from 30 degrees to 60 degrees was 4.20% +/- 3.2%, and from 60 degrees to 90 degrees was 7.45% +/- 4.8%. From full extension to 90 degrees of flexion, the ligament length increased on average 16.7% +/- 12.1%. From 60 degrees to 90 degrees of flexion, there was a significantly higher increase in the mean distance between the points compared with the flexion from 0 degrees to 30 degrees and from 30 degrees to 60 degrees . CONCLUSION: The ALL shows no isometric behavior during the range of motion of the knee. The ALL increases in length from full extension to 90 degrees of flexion by 16.7%, on average. The increase in length was greater from 60 degrees to 90 degrees than from 0 degrees to 30 degrees and from 30 degrees to 60 degrees . The increase in length at higher degrees of flexion suggests greater tension with increasing flexion. CLINICAL RELEVANCE: Knowledge of ALL behavior during the range of motion of the knee will allow for fixation (during its reconstruction) to be performed with a higher or lower tension, depending on the chosen degree of flexion. PMID- 26535293 TI - Macroscopic Anomalies and Pathological Findings in and Around the Achilles Tendon: Observations From 1661 Operations During a 40-Year Period. AB - BACKGROUND: Nonsurgical treatments for chronic Achilles tendinopathy (AT) results in unpredictable success rates. Surgical treatment may be chosen as reports show mostly encouraging but variable success rates depending on the pathology. The distribution of surgically confirmed pathologies in AT is largely unknown. PURPOSE: To ascertain the distributions of macroscopically observed anomalies in participants undergoing surgical treatment for chronic AT. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The main macroscopic pathologies of 1661 chronic Achilles tendon overuse injuries, which were diagnosed and surgically treated by a single surgeon, were reviewed. The surgeries were performed on professional and recreational athletes during the years 1976-1980, 1986-1990, 1996-2000, and 2006-2010. Surgical diagnoses, along with age- and sport-specific characteristics, were collected retrospectively from patient records. RESULTS: The relative proportion of tendinosis increased during the study period from 4.2% to 21%, and paratenonitis decreased from 50% to 26%. Retrocalcaneal pathologies were the most common surgically confirmed lesions at 30%, while the mean age at surgery increased by 11 years over the entire study period. CONCLUSION: Surgically confirmed pathologies in and around the Achilles tendon showed coherent changes, chronic paratenonitis, and retrocalcaneal problems as the most prevalent findings. The classification of midportion and insertional tendinopathy and retrocalcaneal bursitis in AT should strictly be used as a clinical diagnosis. During surgical evaluations, the diagnosis is further clarified as more specific pathologies may be identified. PMID- 26535294 TI - Incidence and Nature of Medical Attendance Injuries in English Community Rugby Union. AB - BACKGROUND: Previous research has identified injury patterns during community level rugby union match play, but none have investigated the frequency and reasons for on-field injury management. PURPOSE: To establish the frequency, reasons, and patterns of on-field injury management in English community rugby, including differences between different levels of play. STUDY DESIGN: Descriptive epidemiology study. METHODS: Over 3 seasons, injury information was collected from 46 (2009-2010), 67 (2010-2011), and 76 (2011-2012) English community clubs (Rugby Football Union [RFU] levels 3-9). Club injury management staff reported information for all medical attendances during match play, including details on the injury site and type, playing position (seasons 2010-2011 and 2011-2012 only), and whether the player was removed from play. Clubs were subdivided into groups A (RFU levels 3 and 4 [mainly semiprofessional]; n = 39), B (RFU levels 5 and 6 [mainly amateur]; n = 71), and C (RFU levels 7-9 [social and recreational]; n = 79) to differentiate playing levels. RESULTS: The overall medical attendance incidence was 229 per 1000 player-match hours (95% CI, 226-232), with 45 players removed per 1000 player-match hours (95% CI, 44-46). Attendance incidence for group A (294 per 1000 player-match hours; 95% CI, 287-301) was higher compared with group B (213; 95% CI, 208-218; P < .001) and C (204; 95% CI, 200-209; P < .001). There was a higher incidence of attendances to forwards (254; 95% CI, 249 259) compared with backs (191; 95% CI, 187-196; P < .001). The head was the most common specific site of injury (55 per 1000 player-match hours; 95% CI, 53-57) but the lower limb region overall accounted for most attendances (87; 95% CI, 85 89) and the greatest chance of removal from the pitch (22; 95% CI, 21-23). CONCLUSION: With the likelihood of 1 injury for each team per match severe enough for the player to leave the pitch and with at least 1 attendance for a head injury per match, there is clear evidence that pitch side staff should be trained to recognize potentially serious injuries. PMID- 26535295 TI - Development of a Valid and Reliable Knee Articular Cartilage Condition-Specific Study Methodological Quality Score. AB - BACKGROUND: Condition-specific questionnaires are important components in evaluation of outcomes of surgical interventions. No condition-specific study methodological quality questionnaire exists for evaluation of outcomes of articular cartilage surgery in the knee. PURPOSE: To develop a reliable and valid knee articular cartilage-specific study methodological quality questionnaire. STUDY DESIGN: Cross-sectional study. METHODS: A stepwise, a priori-designed framework was created for development of a novel questionnaire. Relevant items to the topic were identified and extracted from a recent systematic review of 194 investigations of knee articular cartilage surgery. In addition, relevant items from existing generic study methodological quality questionnaires were identified. Items for a preliminary questionnaire were generated. Redundant and irrelevant items were eliminated, and acceptable items modified. The instrument was pretested and items weighed. The instrument, the MARK score (Methodological quality of ARticular cartilage studies of the Knee), was tested for validity (criterion validity) and reliability (inter- and intraobserver). RESULTS: A 19 item, 3-domain MARK score was developed. The 100-point scale score demonstrated face validity (focus group of 8 orthopaedic surgeons) and criterion validity (strong correlation to Cochrane Quality Assessment score and Modified Coleman Methodology Score). Interobserver reliability for the overall score was good (intraclass correlation coefficient [ICC], 0.842), and for all individual items of the MARK score, acceptable to perfect (ICC, 0.70-1.000). Intraobserver reliability ICC assessed over a 3-week interval was strong for 2 reviewers (>=0.90). CONCLUSION: The MARK score is a valid and reliable knee articular cartilage condition-specific study methodological quality instrument. CLINICAL RELEVANCE: This condition-specific questionnaire may be used to evaluate the quality of studies reporting outcomes of articular cartilage surgery in the knee. PMID- 26535296 TI - Emerging Applications of Stem Cell and Regenerative Medicine to Sports Injuries. AB - BACKGROUND: The treatment of sports-related musculoskeletal injuries with stem cells has become more publicized because of recent reports of high-profile athletes undergoing stem cell procedures. There has been increased interest in defining the parameters of safety and efficacy and the indications for potential use of stem cells in clinical practice. PURPOSE: To review the role of regenerative medicine in the treatment of sports-related injuries. STUDY DESIGN: Review. METHOD: Relevant studies were identified through a PubMed search combining the terms stem cells and cartilage, ligament, tendon, muscle, and bone from January 2000 to August 2013. Studies and works cited in these studies were also reviewed. RESULTS: Treatment of sports-related injuries with stem cells shows potential for clinical efficacy from the data available from basic science and animal studies. CONCLUSION: Cell-based therapies and regenerative medicine offer safe and potentially efficacious treatment for sports-related musculoskeletal injuries. Basic science and preclinical studies that support the possibility of enhanced recovery from sports injuries using cell-based therapies are accumulating; however, more clinical evidence is necessary to define the indications and parameters for their use. Accordingly, exposing patients to cell based therapies could confer an unacceptable risk profile with minimal or no benefit. Continued clinical testing with animal models and clinical trials is necessary to determine the relative risks and benefits as well as the indications and methodology of treatment. PMID- 26535297 TI - Asymmetric Hip Rotation in Professional Baseball Pitchers. AB - BACKGROUND: There is a renewed interest in examining the association between hip range of motion and injury in athletes, and the data on baseball players are conflicting. Understanding whether asymmetrical hip rotation is a normal adaptation or a risk factor for injury will help therapists, trainers, and physicians develop rehabilitation programs to improve kinetic energy transfer and prevent injury. As our knowledge of hip pathology among baseball pitchers improves, establishing baselines for hip motion is critical in the further assessment of injury. HYPOTHESIS: Because of the repetitive nature of throwing sports and the adaptive changes documented in the shoulder, elite baseball pitchers would have characteristic patterns of hip internal and external rotations on their dominant throwing side (stance) and their nondominant side (stride) in extension. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Computer software was used to measure passive internal and external rotations on digital photographs of 111 professional baseball pitchers. RESULTS: In right-handed pitchers, there was significantly more internal rotation in the stance hip than the stride hip (32.2 degrees +/- 8.2 degrees vs 30.8 degrees +/- 8.4 degrees ; P = .0349) and significantly more external rotation in the stride hip than the stance hip (36.3 degrees +/- 7.7 degrees vs 30.8 degrees +/- 9.7 degrees ; P < .0001). While the mean difference in external rotation was 4.7 degrees , 32% of the subjects had a >10 degrees increase in external rotation on the stride hip relative to the stance hip. This population was statistically different from the remaining group for older age (P = .0053), lower body mass index (P = .0379), and more years in professional baseball (P = .0328). In the smaller number of left-handed pitchers, side-to-side differences in hip rotation were found but were not statistically significant. CONCLUSION: Pitchers showed more internal rotation on their stance hip and more external rotation on their stride hip. Although the mean differences are small, there is a subset of pitchers with defined characteristics in whom larger differences exist. PMID- 26535298 TI - Eccentric and Isometric Hip Adduction Strength in Male Soccer Players With and Without Adductor-Related Groin Pain: An Assessor-Blinded Comparison. AB - BACKGROUND: Adductor-related pain is the most common clinical finding in soccer players with groin pain and can be a long-standing problem affecting physical function and performance. Hip adductor weakness has been suggested to be associated with this clinical entity, although it has never been investigated. PURPOSE: To investigate whether isometric and eccentric hip strength are decreased in soccer players with adductor-related groin pain compared with asymptomatic soccer controls. The hypothesis was that players with adductor related groin pain would have lower isometric and eccentric hip adduction strength than players without adductor-related groin pain. STUDY DESIGN: Cross sectional study; Level of evidence, 3. METHODS: Male elite and subelite players from 40 teams were contacted. In total, 28 soccer players with adductor-related groin pain and 16 soccer players without adductor-related groin pain (asymptomatic controls) were included in the study. In primary analysis, the dominant legs of 21 soccer players with adductor-related groin pain (>=4 weeks duration) were compared with the dominant legs of 16 asymptomatic controls using a cross-sectional design. The mean age of the symptomatic players was 24.5 +/- 2.5 years, and the mean age of the asymptomatic controls was 22.9 +/- 2.4 years. Isometric hip strength (adduction, abduction, and flexion) and eccentric hip strength (adduction) were assessed with a handheld dynamometer using reliable test procedures and a blinded assessor. RESULTS: Eccentric hip adduction strength was lower in soccer players with adductor-related groin pain in the dominant leg (n = 21) compared with asymptomatic controls (n = 16), namely 2.47 +/- 0.49 versus 3.12 +/- 0.43 N.m/kg, respectively (P < .001). No other hip strength differences were observed between symptomatic players and asymptomatic controls for the dominant leg (P = .35-.84). CONCLUSION: Large eccentric hip adduction strength deficits were found in soccer players with adductor-related groin pain compared with asymptomatic soccer players, while no isometric strength differences were observed between the groups. PMID- 26535299 TI - Assessment of Injuries During Brazilian Jiu-Jitsu Competition. AB - BACKGROUND: Brazilian jiu-jitsu (BJJ) is a unique style of martial arts with rapid growth in the United States and internationally. Although studies have examined injuries in other martial arts and combat sports, to date, no published medical study has examined injuries in BJJ competitions. PURPOSE: (1) To estimate the incidence of injuries in BJJ competitions and (2) to identify and describe the types and mechanisms of injuries associated with competitive BJJ. STUDY DESIGN: Descriptive epidemiology study. METHODS: Injury data were obtained from records of on-site medical coverage at 8 statewide BJJ tournaments in Hawaii, USA, between 2005 and 2011. RESULTS: The identified injury incidence on the day of matches was 9.2 per 1000 exposures (46 injuries out of 5022 exposures, ie, match participations). Orthopaedic injuries were the most common and accounted for 78% of all injuries (n = 36), followed by costochondral or rib injuries (n = 7) and lacerations requiring medical care (n = 3). The elbow was found to be the joint most commonly injured during BJJ competitions, with the arm bar being the most common mechanism. We propose that this BJJ-specific injury mechanism, the "arm bar," be recognized as another mechanism of hyperextension injury to the elbow in sports. CONCLUSION: Comparison of the BJJ injury data with injury data reported for judo, taekwondo, wrestling, and mixed martial arts showed that BJJ competitors were at substantially lower risk of injury compared with these other sports. With orthopaedic injuries being most common and the elbow being the area most vulnerable to injury in BJJ, it is important that participants, referees, and physicians be properly educated about the unique mechanisms of injury that can occur, particularly to the elbow. PMID- 26535300 TI - Proximal Biceps Tenodesis: An Anatomic Study and Comparison of the Accuracy of Arthroscopic and Open Techniques Using Interference Screws. AB - PURPOSE: To (1) better define the anatomy of the proximal shoulder in relation to the long head of the biceps tendon, (2) compare the length-tension relationship of the biceps tendon in the native shoulder with that after arthroscopic and open tenodesis techniques using interference screws, and (3) provide surgical recommendations for both procedures based on study findings. STUDY DESIGN: Descriptive laboratory study. METHODS: Twenty fresh-frozen cadaveric shoulders were dissected for analysis. Initial anatomic measurements involving the proximal long head of the biceps tendon (BT) were made, which included: the labral origin to the superior bicipital groove (LO-SBG), the total tendon length (TTL), the musculotendinous junction (MTJ) to the inferior pectoralis major tendon border, the MTJ to the superior pectoralis major tendon border, and the biceps tendon diameter (BTD) at 2 different tenodesis locations. These same measurements were made again after completing a simulated suprapectoral arthroscopic and open subpectoral tenodesis, both with interference screw fixation. Statistical comparisons were then made between the native anatomy and that after tenodesis, with the goal of assessing the accuracy of re-establishing the normal length tension relationship of the long head of the BT after simulated arthroscopic suprapectoral and open subpectoral tenodesis with tenodesis screws. RESULTS: For all cadavers, the mean TTL was 104.1 mm. For the arthroscopic suprapectoral technique, the mean LO-SBG was 33.6 mm, and the mean tendon resection length was 12.8 mm in males and 5.0 mm in females. The mean BTD was 6.35 mm at the arthroscopic suprapectoral tenodesis site and 5.75 mm at the open subpectoral tenodesis site. Males were found to have statistically longer TTL and LO-SBG measurements (111.6 vs 96.5 mm [P = .027] and 37.2 vs 30.0 mm [P = .009], respectively). In the native shoulder, the mean distances from the MTJ to the superior and inferior borders of the pectoralis major tendon were 23.8 and 31.7 mm, respectively. No statistically significant differences were found in the location of the MTJ after simulated arthroscopic or open tenodesis with tenodesis screws as compared with the native shoulder. Mean hole depth in the open subpectoralis tenodesis was 22.4 mm (males) and 18.6 mm (females), with a mean of 20.5 mm for both sexes. CONCLUSION: This study better defines the anatomy of the proximal shoulder in relationship to the long head of the BT. Using our surgical techniques and recommendations, both arthroscopic and open tenodesis procedures adequately restored the native length-tension relationship of the long head of the biceps. Surgical recommendations are as follows: For arthroscopic suprapectoral tenodesis with tenodesis screws, the anatomic landmark of the SBG should be used. The tendon resection length should be approximately 1 cm in males and 5 mm in females when using a 25-mm tunnel. For subpectoral tenodesis, the site of tenodesis should be placed approximately 3 cm above the inferior border of the pectoralis major tendon in the bicipital groove; whipstitching and preserving approximately 2 cm of the biceps tendon above the MTJ is also recommended. The diameter of the screws in either location should be based on patient anatomy. However, this study shows the need for slightly longer screws for the subpectoral tenodesis, as the average hole depth was 20.5 mm. The system used in this study has 7 * 10-mm and 8 * 12-mm screws available. Based on study findings, a screw length of 15 to 18 mm may be needed. PMID- 26535301 TI - The Effect of Ulnar Collateral Ligament Reconstruction on Pitch Velocity in Major League Baseball Pitchers. AB - BACKGROUND: The medial ulnar collateral ligament (UCL) is the primary restraint to valgus load, and injury is commonly encountered as a result of overuse in throwing athletes. Reconstruction of this ligament has allowed for a high rate of return to sport for elite pitchers. Public perception of this procedure has resulted in a commonly held belief of increased throwing velocity following UCL reconstruction. HYPOTHESIS: Fastball velocity for Major League Baseball (MLB) pitchers is significantly decreased following UCL reconstruction. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 129 pitchers were identified as undergoing UCL reconstruction from publicly available reports, and a final group of 80 MLB pitchers were included for analysis. Statistics were collected, including pitch velocity, pitch selection, and performance outcomes. Pre- and postoperative statistics were compared using paired t tests to allow for evaluation of each pitcher relative to his baseline velocity and performance. RESULTS: Mean fastball velocity was significantly decreased following UCL reconstruction, with a presurgical mean velocity of 91.3 mph and postoperative velocity of 90.6 mph (P = .003). The greatest observed difference was in pitchers older than 35 years, with fastball velocity decreasing from 91.7 to 88.8 mph (P = .0048). Pitchers threw fewer fastballs after reconstruction. Pitch velocity for curveballs, changeups, and sliders did not change significantly after UCL reconstruction. Additionally, pitchers threw fewer innings and pitches following reconstruction and produced fewer wins above replacement relative to their preinjury state. CONCLUSION: Contrary to popular opinion, fastball velocity for MLB pitchers is significantly decreased following UCL reconstruction, which should reinforce the importance of preventing overuse injuries. PMID- 26535302 TI - Return to Play After Open Bankart Repair: A Systematic Review. AB - BACKGROUND: Results of open Bankart repair have been well reported. However, less information is available outlining the timetable for return to play (RTP) in athletes after this procedure. PURPOSE: To review the current literature regarding (1) the timetable recommended for athletes to RTP after an open Bankart repair and (2) the objective criteria on which the decision to allow an athlete to RTP is based. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A comprehensive literature search was conducted of all relevant English-language articles using the electronic databases OVID and PubMed between the years 1947 and 2012 to identify open Bankart repair. Two reviewers screened articles for eligibility based on the following criteria: (1) an open Bankart repair, (2) a minimum follow-up of at least 8 months, (3) any report that described the procedure in athletes, and (4) any report that described the time for an athlete to RTP. All relevant data were collected and analyzed with regard to number of patients; mean follow-up; Rowe, Constant, and American Shoulder and Elbow (ASES) scores; redislocation rate; and return-to-sport timing. RESULTS: In all, 559 relevant citations were identified, of which 29 articles met the inclusion criteria. The mean follow-up was 51.7 months (range, 8-162 months), and the mean age was 25.9 years (range, 21-31 years). The average Rowe score for all studies was 86.9 (range, 63-90). The average redislocation rate was 5.3%. Twenty-six of 29 studies cited a specific timetable for unrestricted RTP, with an average of 23.2 weeks (range, 12-36 weeks). Only 38% of authors reported sport-specific criteria for return to competition, with the majority allowing return to noncontact sports at 12 to 16 weeks, and the resumption of throwing/contact sports by 24 weeks. Three reports described specific functional parameters for RTP. CONCLUSION: The current review summarized return-to-play guidelines for athletic competition after open Bankart repair. These data may provide general guidelines to aid surgeons when determining the appropriate timetable to allow an athlete to return to unrestricted competition. PMID- 26535303 TI - Transtibial Tunnel Placement in Posterior Cruciate Ligament Reconstruction: How It Relates to the Anatomic Footprint. AB - BACKGROUND: It is common to place the posterior cruciate ligament (PCL) tibial tunnel with a transtibial technique using a guide that attempts to place the center of the tunnel 1 to 1.5 cm distal to the tibiofemoral joint. It is unknown how well this technique will re-create the native tibial footprint of the PCL. PURPOSE: To evaluate the accuracy of tibial tunnel placement using a transtibial technique. STUDY DESIGN: Controlled laboratory study. METHODS: Ten cadaveric knees from 10 donors underwent arthroscopic transtibial drilling of the tibial tunnel with use of a posteromedial portal for visualization. The transtibial guide was rested flush against the tibial spines to allow for the guide to be as distal as possible, which was between 1 and 1.5 cm distal to the tibiofemoral joint line. Using this technique, an attempt was made to place the tibial tunnels as close to the center of the PCL footprint as possible. All knees underwent computed tomography both pre- and postoperatively with a previously reported technique optimized for ligament evaluation. This allowed comparison of the anatomic PCL tibial footprint to the tibial tunnel aperture. The percentage of tunnel aperture contained within the native footprint as well as the distance from the center of the tunnel aperture to the center of the footprint was measured. RESULTS: The percentage of tunnel aperture contained within the native footprint was 45.9% +/- 23.1%. The distance from the center of the tibial tunnel aperture to the center of the tibial PCL footprint was 6.4 +/- 2.3 mm. The tunnels were almost always (9/10) distal (or inferior) to the native footprint and either slightly lateral (5/10) or centered (5/10) in a medial to lateral direction. CONCLUSION: This study demonstrates that using the transtibial drilling technique in the tibia for PCL reconstruction places approximately half of the tibial tunnel aperture within the tibial footprint. Generally, the tunnel is distal to the footprint. CLINICAL RELEVANCE: Consideration should be given to the fact that, using this transtibial technique, the tibial tunnel aperture is generally not placed in the center of the footprint. This may not be a negative issue, however, since there are other potential advantages from distal tunnel placement. PMID- 26535304 TI - Glenohumeral Function of the Long Head of the Biceps Muscle: An Electromyographic Analysis. AB - BACKGROUND: Optimal treatment of superior labral anterior-posterior (SLAP) tears is controversial, in part because the dynamic role of the long head of the biceps muscle (LHBM) in the glenohumeral joint is unclear. The aim of this study was to determine dynamic LHBM behavior during shoulder activity by studying (1) the electromyographic activity of the LHBM during shoulder motion, (2) the effect of elbow immobilization on this activity, and (3) the effect of a load applied to the distal humerus on this activity. HYPOTHESIS: The LHBM would not play a significant role in active glenohumeral range of motion. STUDY DESIGN: Controlled laboratory study. METHODS: Thirteen normal volunteers underwent surface electromyography (EMG) measurement of the LHBM, short head biceps muscle (SHBM), deltoid, infraspinatus, and brachioradialis during shoulder motion from the neutral position (0 degrees of rotation, flexion, and abduction) to 45 degrees of flexion, 90 degrees of flexion, 45 degrees of abduction, and 90 degrees of abduction. These motions were repeated both with and without splint immobilization of the forearm and elbow at 100 degrees of flexion and neutral rotation and with and without a 1-kg weight placed on the lateral distal humerus. RESULTS: Mean EMG activity within the LHBM and the SHBM was low (<=11.6% +/- 9.1%). LHBM activity was significant increased by flexion and abduction (P < .049 in all cases), while SHBM activity was not. EMG activity from the middle head of the deltoid was significantly increased by loading with the shoulder positioned away from the body (ie, in abduction or flexion). When compared with the unloaded state, the addition of a distal humeral load significantly increased LHBM activity in 45 degrees of abduction (P = .028) and 90 degrees of flexion (P = .033) despite forearm and elbow immobilization. The SHBM showed similar trends. CONCLUSION: In normal volunteers with forearm and elbow immobilization and application of a load to the distal humerus, LHBM EMG activity is increased by both glenohumeral flexion and abduction, suggesting that this muscle plays a dynamic role in glenohumeral motion with higher demand activities. CLINICAL RELEVANCE: Biceps tenodesis may result in dynamic change within the glenohumeral joint with higher demand activities. PMID- 26535305 TI - Time and Cost of Diagnosis for Symptomatic Femoroacetabular Impingement. AB - BACKGROUND: Femoroacetabular impingement (FAI) and labral tears are common causes of hip pain that are often not promptly or properly diagnosed. To our knowledge, no reports have defined the time and cost of diagnosis of labral tears associated with FAI. HYPOTHESIS: Patients with labral tears associated with FAI undergo extraneous diagnostic testing and pain and incur a significant amount of health care costs before they receive appropriate surgical management for their pathology. STUDY DESIGN: Economic and decision analysis; Level of evidence, 4. METHODS: A total of 78 patients diagnosed with symptomatic FAI were surveyed. A standardized questionnaire asked patients about time to diagnosis, symptoms, health care providers visited, imaging tests, and treatments prior to diagnosis. Costs were calculated based on 2012 national Medicare data. RESULTS: Patients in the cohort saw an average of 4.0 health care providers, had an average of 3.4 diagnostic imaging tests, and tried an average of 3.1 treatments prior to diagnosis. The average total amount spent per patient prior to diagnosis was US$2456.97. The calculated minimum cost of diagnosis, including a visit to an orthopaedic surgeon as well as an anteroposterior pelvis and lateral hip radiograph and 1 magnetic resonance arthrogram, was US$690.62. The average duration between onset of symptoms and diagnosis of labral tear was 32.0 months. CONCLUSION: The average amount of health care dollars spent per patient prior to receiving a diagnosis of acetabular labral tear was US$1766.35 higher than the calculated minimum cost. This figure is based on Medicare payment amounts, which may significantly underestimate the actual charges at many hospitals, thereby increasing the total cost of diagnosis. CLINICAL RELEVANCE: The costs and pain associated with this time, along with the potential long-term degradation of the hip joint, make it important for all health care professionals to recognize and appropriately manage or refer the patient. PMID- 26535306 TI - Etiology and Biomechanics of Tarsometatarsal Injuries in Professional Football Players: A Video Analysis. AB - BACKGROUND: Tarsometatarsal (TMT) dislocations are uncommon yet debilitating athletic injuries, particularly in American football. To date, the mechanisms of athletic TMT dislocation have been described only anecdotally. This lack of information confounds the development of preventative countermeasures. PURPOSE: To use video analysis to provide direct, independent identification of the etiologic and mechanistic variables responsible for TMT dislocations in professional football players. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Sixteen professional National Football League players who sustained publicly reported TMT dislocations were identified. Publicly broadcast game footage of the plays in which injury occurred was reviewed by a panel of 5 biomechanists. Consensus was reached regarding the details surrounding injury, and a weighting was assigned to each detail based on the panel's confidence. RESULTS: Roughly 90% of injuries occurred while the injured player was engaged with or by another player, a detail that has heretofore been undocumented. Few injuries resulted from direct loading of either the foot or the ipsilateral limb; however, the injured foot was frequently subjected to axial loading from ground engagement with the foot in plantar flexion and the toes dorsiflexed. Injurious loading was often due to external rotation of the midfoot (86%). Fifteen of 16 injuries were season ending. CONCLUSION: TMT dislocations are frequently associated with engagement by or with a second player but infrequently caused by a direct blow to the foot. Axial loading of the foot, external rotation, and pronation/supination are the most common conditions during injurious loading. PMID- 26535307 TI - Evaluation and Comparison of Femoral Tunnel Placement During Anterior Cruciate Ligament Reconstruction Using 3-Dimensional Computed Tomography: Effect of Notchplasty on Transtibial and Medial Portal Drilling. AB - BACKGROUND: Advocates of medial portal drilling claim that the transtibial technique results in a more vertical positioning of the graft, which could lead to subsequent failure and/or a residual pivot shift on postoperative examination. However, advocates of transtibial drilling state that with appropriate placement and adequate notchplasty, their technique places the graft in a more anatomically correct position on the wall, negating the resultant potential for pivot shift and early postoperative failure. HYPOTHESIS: Transtibial femoral drilling can adequately reproduce the femoral origin of the anterior cruciate ligament (ACL) and place the graft in an anatomical position equivalent to medial portal drilling. STUDY DESIGN: Controlled laboratory study. METHODS: Ten matched-pair cadaveric knees (N = 20) were scanned using computed tomography (CT), and 3 dimensional images of the native ACL origin were reconstructed. The matched pairs were then randomized into transtibial and medial portal groups. The femoral tunnel was drilled in each knee according to group. A bamboo skewer was placed in the femoral tunnel, and the knees underwent a second CT scan. Arthroscopic notchplasty was performed, and the femoral tunnels were redrilled. Radiographs confirmed placement, and the post-notchplasty tunnel was reamed with a 4-mm reamer. The knees underwent a third CT scan. CT scans compared femoral tunnel placement with the native ACL footprint before and after notchplasty. RESULTS: The post-notchplasty transtibial group revealed an average of 68.3% coverage of the native ACL femoral origin. The medial portal group revealed an average of 60.8% coverage, with 1 instance of perforation of the posterior cortex. There were no instances of perforation in the transtibial group. CONCLUSION: Both drilling techniques place the graft in an anatomically correct position. CLINICAL RELEVANCE: Transtibial drilling of the femur can adequately place the entry tunnel at the origin of the ACL's native footprint. PMID- 26535308 TI - Barefoot Running: The Effects of an 8-Week Barefoot Training Program. AB - BACKGROUND: It has been proposed that running barefoot can lead to improved strength and proprioception. However, the duration that a runner must train barefoot to observe these changes is unknown. HYPOTHESIS: Runners participating in a barefoot running program will have improved proprioception, increased lower extremity strength, and an increase in the volume or size of the intrinsic musculature of the feet. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: In this 8-week study, 29 runners with a mean age of 36.34 years were randomized into either a control group (n = 10) who completed training in their regular running shoes or to an experimental barefoot group (n = 14). Pretraining tests consisted of a volumetric measurement of the foot followed by a strength and dynamic balance assessment. Five subjects completed the pretests but did not complete the study for reasons not related to study outcomes. Participants then completed 8 weeks of training runs. They repeated the strength and dynamic balance assessment after 8 weeks. RESULTS: Significant changes from baseline to 8 weeks were observed within the barefoot group for single-leg hop (right, P = .0121; left, P = .0430) and reach and balance (right, P = .0029) and within the control group for single-left leg hop (P = .0286) and reach and balance (right, P = .0096; left, P = .0014). However, when comparing the differences in changes from baseline to 8 weeks between the barefoot and control groups, the improvements were not significant at the .05 level for all measures. CONCLUSION: Although statistically significant changes were not observed between the pre- and posttest evaluations in strength and proprioception with the 8-week low-intensity barefoot running regimen, this does not necessarily mean that these changes do not occur. It is possible that it may take months or years to observe these changes, and a short course such as this trial is insufficient. PMID- 26535309 TI - A Preliminary In Vivo Assessment of Anterior Cruciate Ligament-Deficient Knee Kinematics With the KneeM Device: A New Method to Assess Rotatory Laxity Using Open MRI. AB - BACKGROUND: Methods of objectively measuring rotational knee laxity are either experimental or difficult to use in daily practice. A new method has been developed to quantitatively assess rotatory laxity using an open MRI system and new tool, the KneeM device. PURPOSE/HYPOTHESIS: To perform a preliminary evaluation of a novel knee rotation measurement device to assess knee kinematics during flexion in an MRI field, in both anterior cruciate ligament (ACL) deficient and healthy contralateral knees. The hypothesis was that the KneeM device would allow in vivo reproduction and analysis of knee kinematics during flexion in healthy and ACL-deficient knees. STUDY DESIGN: Controlled laboratory study. METHODS: Ten subjects (7 men and 3 women; mean age +/- standard deviation, 32.3 +/- 9.4 years) with ACL-deficient knees and contralateral uninjured knees participated in the study. An open MRI was performed with the KneeM device at a mean 4.9 months (range, 3.0-7 months) after ACL injury. The device exerted on the knee an anterior drawer force of 100 N, with an internal rotation of 20 degrees , through the range of flexion (0 degrees , 20 degrees , 40 degrees , and 60 degrees ). Both ACL-deficient and healthy contralateral knees were analyzed using the Iwaki method. RESULTS: There was no statistical difference of anterior translation in the medial compartment between intact and ACL-deficient knees at all degrees of flexion. However, significant differences in the anterior translation of the lateral compartment were observed between ACL-deficient and intact contralateral knees at 0 degrees and 20 degrees of flexion (P = .005 and P = .002, respectively). Between 20 degrees and 40 degrees , the lateral plateau of ACL-deficient knees translated 7.7 mm posteriorly, whereas the medial compartment remained stable, reflecting a sudden external rotation of the lateral plateau under the femoral condyle. CONCLUSION: This preliminary study suggests that measurement of tibiofemoral movements in both compartments during flexion using the KneeM device was useful for quantifying rotatory laxity in ACL deficient knees. Moreover, this device seemed to allow a "mechanized pivot shift" and allowed reproduction of the "pivot" phase in the MRI field between 20 degrees and 40 degrees of flexion. CLINICAL RELEVANCE: This device could be used for diagnostic purposes or to investigate the outcomes of ACL reconstructions. PMID- 26535310 TI - Fluoroscopically Guided Peritendinous Corticosteroid Injection for Proximal Hamstring Tendinopathy: A Retrospective Review. AB - BACKGROUND: Proximal hamstring tendinopathy is an uncommon but debilitating cause of posterior thigh pain in athletes subjected to repetitive eccentric hamstring contraction, such as runners. Minimal data exist evaluating treatment options for proximal hamstring tendinopathy. PURPOSE: This retrospective study evaluates the effectiveness of fluoroscopically guided corticosteroid injections in treating proximal hamstring tendinopathy. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Eighteen athletes with 22 cases of magnetic resonance imaging-confirmed proximal hamstring tendinopathy were treated with corticosteroid injection and later contacted to evaluate the efficacy of the injection with the use of a questionnaire. RESULTS: The visual analog score decreased from 7.22 preinjection to 3.94 postinjection (P < .001), level of athletic participation increased from 28.76% to 68.82% (P < .001) at a mean follow-up of 21 months, and 38.8% of patients experienced complete resolution at a mean follow-up of 24.8 months. The mean lower extremity function score at the time of follow-up was 60. CONCLUSION: A trial of fluoroscopically guided corticosteroid injection is warranted in patients presenting with symptoms of proximal hamstring tendinopathy refractory to conservative therapy. PMID- 26535312 TI - Altitude Does Not Reduce Concussion Incidence: Letter to the Editor. PMID- 26535311 TI - Systematic Review of Biological Modulation of Healing in Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Whether biological modulation is effective to promote healing in anterior cruciate ligament (ACL) reconstruction remains unclear. PURPOSE: To perform a systematic review of both clinical and experimental evidence of preclinical animal studies on biological modulation to promote healing in ACL reconstruction. STUDY DESIGN: Systematic review; Level of evidence, 2. METHODS: A systematic search was performed using the PubMed, Ovid, and Scopus search engines. Inclusion criteria were clinical and animal studies involving subjects with ACL injury with the use of biological modulation to promote healing outcomes. Methodological quality of clinical studies was evaluated using the Critical Appraisal Skill Programme (CASP) appraisal tool, and animal studies were evaluated by a scoring system based on a published checklist of good animal studies. RESULTS: Ten clinical studies and 50 animal studies were included. Twenty-five included studies were regarded as good quality, with a methodological score >=5. These studies suggested that transforming growth factor-beta (TGF beta), mesenchymal stem cells, osteogenic factors, and modalities that reduce local inflammation may be beneficial to promote graft healing in ACL reconstruction. CONCLUSION: This systematic review suggests that biological modulation is able to promote healing on top of surgical treatment for ACL injuries. This treatment strategy chiefly works through promotion of healing at the tunnel-graft interface, but the integrity of the intra-articular midsubstance of the graft would be another target for biological modulation. PMID- 26535313 TI - Altitude Does Not Reduce Concussion Incidence: Response. PMID- 26535314 TI - Surgery for Patients With Recalcitrant Plantar Fasciitis: Good Results at Short-, Medium-, and Long-term Follow-up. AB - BACKGROUND: Plantar fasciitis is a common cause of foot pain, and although many episodes are self-limiting with short duration, 10% leave chronic symptoms. Recalcitrant cases can be managed surgically, with studies demonstrating good results in the short term but uncertainties over longer term outcomes. PURPOSE: To assess the outcome following surgical intervention for patients with plantar fasciitis. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Seventy-nine patients were identified from operative diaries undergoing plantar fasciotomy surgery between 1993 and 2009. They were contacted to investigate long-term results using self-reported outcome measures. RESULTS: Sixty-eight responses were received (86% response rate), with an average of 7 years (range, 1-15 years) of follow-up. Patients reported an average reduction in pain by visual analog scale of 79%, and 84% of patients were happy with the surgical results. Greater success was achieved in patients with shorter duration of symptoms preoperatively. No deterioration in success was seen over time. CONCLUSION: Plantar fasciotomy surgery for plantar fasciitis remains controversial, with biomechanical arguments against surgery; however, this article reports good success following surgery over a long follow-up period. The results of current operative techniques need to be fully investigated for longer term success, as do the outcomes of newer nonoperative management strategies. PMID- 26535315 TI - Concussions From 9 Youth Organized Sports: Results From NEISS Hospitals Over an 11-Year Time Frame, 2002-2012. AB - BACKGROUND: Youth sports programs are extremely popular throughout the United States, with children starting formal sports participation as young as 4 years. This places children at greater risk for concussions and other trauma. PURPOSE: To describe the epidemiology of concussions sustained during participation in 9 organized sports prior to participation in high school athletics. METHODS: Over an 11-year span from January 2002 to December 2012, the authors reviewed the concussions sustained by athletes aged 4 to 13 years while playing basketball, baseball, football, gymnastics, hockey, lacrosse, soccer, softball, and wrestling, as evaluated in emergency departments (EDs) in the United States and captured by the National Electronic Injury Surveillance System (NEISS) database of the US Consumer Product Safety Commission. STUDY DESIGN: Descriptive epidemiology study. RESULTS: There were 4864 (national estimate [NE] = 117,845) youth athletes evaluated in NEISS EDs as sustaining concussions from 2002 to 2012. Except for the year 2007, concussion frequencies trended upward throughout the 11-year time frame as well as with increasing age. Loss of consciousness (LOC) occurred in 499 cases (NE, 12,129; 10%). Football had the highest frequency of concussions, with 2013 (NE, 51,220; 41%), followed by basketball, with 977 (NE, 22,099; 20%), and soccer, with 801 (NE, 18,916; 17%). The majority of concussions were treated in the outpatient setting, with 4444 (91.4%) patients being treated and released; 412 (9%) patients required admission and were found to have increased frequencies of LOC (n = 17; 18.0%) compared with LOC in the total group (n = 499, 10%). The total number of player-to-player injury mechanisms mirrored the total number of concussions by year, which increased throughout the 11-year span, except for the year 2007. Subgroup analysis of athletes aged 4 to 7 years demonstrated a difference in the mechanism of injury distribution, with a ball-to-head mechanism increase of 5% from 15% to 20% and a player-to-other object mechanism of injury increase by more than double to 13% compared with the entire cohort over the 11-year time frame. CONCLUSION: Within the 4- to 13-year age range, there were a significant number of young athletes who presented to EDs with concussion as a result of playing organized sports. The 4- to 7-year age group had a disproportionately higher player-to-other object mechanism of injury. CLINICAL RELEVANCE: Younger children are more susceptible to long-term sequelae from head injuries, and therefore, improved systems of monitoring for these athletes are required to monitor the patterns of injury, identify risk factors, and develop evidence-based prevention programs. PMID- 26535316 TI - High Prevalence of Disc Degeneration and Spondylolysis in the Lumbar Spine of Professional Beach Volleyball Players. AB - BACKGROUND: Beach volleyball is an intensive sport with high impact on the lumbar spine. Low back pain (LBP) is frequent among elite players. Increased prevalence of pathological changes on magnetic resonance imaging (MRI) in the lumbar spine of elite athletes has been reported. HYPOTHESIS: There is an increased prevalence of disc degeneration and spondylolysis in the MRI of the lumbar spine of professional beach volleyball players. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Twenty-nine fully competitive professional male volleyball players (mean age, 28 years) completed outcomes questionnaires and underwent a complete clinical examination and an MRI of their lumbar spine. RESULTS: Whereas 86% of players suffered from LBP during their career, the incidence of LBP in the last 4 weeks was 35%. Pain rated using a visual analog scale (VAS) averaged 3 points (range, 0-8). Twenty-three of 29 players (79%) had at least 1 degenerated disc of Pfirrmann grade >=3. The most affected spinal levels were L4-5 in 14 (48%) and L5-S1 in 15 players (52%); both levels were involved in 5 players (17%). Six of 29 (21%) players showed a spondylolysis grade 4 according to the Hollenburg classification; there was evidence of spondylolisthesis in 2 players. There was no significant correlation between LBP and MRI abnormalities. CONCLUSION: In the lumbar spine MRI of professional beach volleyball players, the prevalence of disc degeneration is 79%. Spondylolysis (21%) is up to 3 times higher compared with the normal population. Abnormal MRI findings did not correlate with LBP, thus MRIs have to be interpreted with caution. PMID- 26535317 TI - Influence of Rotator Cuff Tear Size and Repair Technique on the Creation and Management of Dog Ear Deformities in a Transosseous-Equivalent Rotator Cuff Repair Model. AB - BACKGROUND: Redundancies in the rotator cuff tissue, commonly referred to as "dog ear" deformities, are frequently encountered during rotator cuff repair. Knowledge of how these deformities are created and their impact on rotator cuff footprint restoration is limited. PURPOSE: The goals of this study were to assess the impact of tear size and repair method on the creation and management of dog ear deformities in a human cadaveric model. STUDY DESIGN: Controlled laboratory study. METHODS: Crescent-shaped tears were systematically created in the supraspinatus tendon of 7 cadaveric shoulders with increasing medial to lateral widths (0.5, 1.0, and 1.5 cm). Repair of the 1.5-cm tear was performed on each shoulder with 3 methods in a randomized order: suture bridge, double-row repair with 2-mm fiber tape, and fiber tape with peripheral No. 2 nonabsorbable looped sutures. Resulting dog ear deformities were injected with an acrylic resin mixture, digitized 3-dimensionally (3D), and photographed perpendicular to the footprint with calibration. The volume, height, and width of the rotator cuff tissue not in contact with the greater tuberosity footprint were calculated using the volume injected, 3D reconstructions, and calibrated photographs. Comparisons were made between tear size, dog ear measurement technique, and repair method utilizing 2-way analysis of variance and Student-Newman-Keuls multiple-comparison tests. RESULTS: Utilizing 3D digitized and injection-derived volumes and dimensions, anterior dog ear volume, height, and width were significantly smaller for rotator cuff repair with peripheral looped sutures compared with a suture bridge (P < .05) or double-row repair with 2-mm fiber tape alone (P < .05). Similarly, posterior height and width were significantly smaller for repair with looped peripheral sutures compared with a suture bridge (P < .05). Dog ear volumes and heights trended larger for the 1.5-cm tear, but this was not statistically significant. CONCLUSION: When combined with a standard transosseous equivalent repair technique, peripheral No. 2 nonabsorbable looped sutures significantly decreased the volume, height, and width of dog ear deformities, better restoring the anatomic footprint of the rotator cuff. CLINICAL RELEVANCE: Dog ear deformities are commonly encountered during rotator cuff repair. Knowledge of a repair technique that reliably decreases their size, and thus increases contact at the anatomic footprint of the rotator cuff, will aid sports medicine surgeons in the management of these deformities. PMID- 26535318 TI - Lower Back Symptoms in Adolescent Soccer Players: Predictors of Functional Recovery. AB - BACKGROUND: There are little published data on factors relating to low back pain in the younger athletic population. HYPOTHESIS: Independent predictors of recovery and return to participation in sports could be determined by event analysis, which investigates the impacts of covariates, including age, position, and injury type, on the risk of delayed recovery after injury. STUDY DESIGN: Descriptive epidemiology study. METHODS: This study examined 41 English Premiership soccer academy squads consisting of 12,306 player seasons for the incidence of lower back injury, injury severity, and investigated time to recovery in relation to potential risk factors. Injury risk was assessed for different times in a match and season, mechanism of injury, player position, player age, and competitive compared with noncompetitive play. RESULTS: A total of 310 (3.0% of all injuries sustained in the population) lumbar spine injuries were recorded. Overall, 10,265 training days (median, 14 days; interquartile range, 8-30 days) were lost. The risk of injury increased as the first half progressed and was maintained throughout the second half with a contact mechanism and with increasing age. Neither competitive play compared with noncompetitive play nor player position had an effect on injury incidence. Prognostic factors for poor recovery were bony injuries and increasing age. CONCLUSION: These findings indicate that prolonged absence from training after a back injury is seen, especially in bony injuries and in older adolescents. It is suggested that there should be a low threshold for investigation of adolescent patients with back pain in the hope of early appropriate management of more severe diagnoses. PMID- 26535319 TI - Enlargement of Glenoid Defects in Traumatic Anterior Shoulder Instability: Influence of the Number of Recurrences and Type of Sport. AB - BACKGROUND: Large glenoid rim defects in patients with traumatic anterior shoulder instability are often regarded as a contraindication for arthroscopic Bankart repair, with a defect of 20% to 27% considered as the critical size. While recurrence of dislocations, male sex, and collision sports were reported to be the significant factors influencing large glenoid defects, the influences of subluxations and more detailed types of sports were not investigated. PURPOSE: To investigate the influence of the number of dislocations and subluxations and type of sport on the occurrence and size of glenoid defects in detail. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 223 shoulders (60 with primary instability, 163 with recurrent instability) were prospectively examined by computed tomography. Glenoid rim morphology was compared between primary and recurrent instability. In patients with recurrent instability, the relationship between the glenoid defect and the number of dislocations and subluxations was investigated. In addition, glenoid defects were compared among 49 male American football players, 41 male rugby players, 27 male baseball players, and 25 female athletes. RESULTS: The mean extent of the glenoid defect was 3.5% in shoulders with primary instability and 11.3% in those with recurrent instability. A glenoid defect was detected in 108 shoulders (66.2%) with recurrent instability versus 12 shoulders (20%) with primary instability. Regarding the influence of the total number of dislocations/subluxations, the average extent of the glenoid defect was 6.3% in 85 shoulders with 2 to 5 events, 12.9% in 34 shoulders with 6 to 10 events, and 19.6% in 44 shoulders with 11 or more events. The glenoid defect became significantly larger along with an increasing number of recurrences. Although recurrent subluxation without dislocation also influenced the glenoid defect size, the number of dislocations did not. The average extent of the glenoid defect was 12.0% in rugby players, 8.9% in American football players, 4.7% in female athletes, and 4.5% in baseball players. Glenoid defects were significantly smaller in male baseball players and female athletes than in male collision athletes. CONCLUSION: The glenoid defect is significantly enlarged by damage due to recurrent dislocation and subluxation; therefore, glenoid rim morphology differs markedly between primary and recurrent instability. Glenoid defect size is also influenced by sex and by the type of sport. PMID- 26535320 TI - Avoiding Complications and Technical Variability During Arthroscopically Assisted Transtibial ACL Reconstructions by Using a C-Arm With Image Intensifier. AB - BACKGROUND: Surgical reconstruction of the anterior cruciate ligament (ACL) can be complicated by incorrect and variable tunnel placement, graft tunnel mismatch, cortical breaches, and inadequate fixation due to screw divergence. This is the first report describing the use of a C-arm with image intensifier employed for the sole purpose of eliminating those complications during transtibial ACL reconstruction. PURPOSE: To determine if the use of a C-arm with image intensifier during arthroscopically assisted transtibial ACL reconstruction (IIAA TACLR) eliminated common complications associated with bone-patellar tendon-bone ACL reconstruction, including screw divergence, cortical breaches, graft-tunnel mismatch, and improper positioning of the femoral and tibial tunnels. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 110 consecutive patients (112 reconstructed knees) underwent identical IIAA-TACLR using a bone patellar tendon-bone autograft performed by a single surgeon. Intra- and postoperative radiographic images and operative reports were evaluated for each patient looking for evidence of cortical breeching and screw divergence. Precision of femoral tunnel placement was evaluated using a sector map modified from Bernard et al. Graft recession distance and tibial alpha angles were recorded. RESULTS: There were no femoral or tibial cortical breaches noted intraoperatively or on postoperative images. There were no instances of loss of fixation screw major thread engagement. There were no instances of graft-tunnel mismatch. The positions of the femoral tunnels were accurate and precise, falling into the desired sector of our location map (sector 1). Tibial alpha angles and graft recession distances varied widely. CONCLUSION: The use of the C-arm with image intensifier enabled accurate and precise tunnel placement and completely eliminated cortical breach, graft-tunnel mismatch, and screw divergence during IIAA-TACLR by allowing incremental adjustment of the tibial tunnel and knee flexion angle. Incremental adjustment was essential to accomplish this. Importantly, a C-arm with image intensifier can be used with any ACL reconstruction that incorporates tunnels in the technique, with the expectation of increase in accuracy and precision and the elimination of common complications. CLINICAL RELEVANCE: The use of an image intensifier during transtibial ACL reconstruction will substantially reduce the common complications associated with the procedure and improve both accuracy and precision of tibial and femoral tunnel placement. Use of an image intensifier unit is generalizable to an individual surgeon's preferences for graft choices and drilling techniques and will be especially valuable when the intercondylar architecture is altered from injury, time, or prior surgery. PMID- 26535321 TI - A Study of Epiphyses in the Young Prepubescent Knee Using Magnetic Resonance Imaging: Evaluation of Parameters for Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Questions have been raised concerning the safety of intra-articular anterior cruciate ligament (ACL) reconstruction in prepubescent children aged <7 years. However, normal values for the width of the lateral femoral condylar epiphysis and height of the tibial epiphysis have yet to be established through the use of magnetic resonance imaging (MRI). PURPOSE: To determine normal values for the width of the lateral femoral condylar epiphysis and height of the tibial epiphysis at the knee in prepubescent children aged <7 years by use of MRI and to compare this age group with an older cohort of prepubescent children aged <10 years. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: An electronic search was conducted for pediatric knee MRI examinations at the authors' institution from March 2003 to March 2013. The total and ossified lateral femoral condylar widths were determined on coronal proton density weighted images. The total and ossified tibial epiphyseal heights were recorded on the sagittal T1-weighted image best containing the ACL footplate. The intraclass correlation coefficient (ICC) was calculated to determine interobserver agreement. Knees were stratified by age into 2 groups: children between the ages of 3 and 6 years (group 1) and children between the ages of 7 and 9 years (group 2). Each cohort was further stratified by sex. RESULTS: Group 1 consisted of 10 children (mean age, 4.3 years) and group 2 consisted of 10 children (mean age, 8.5 years). There were a total of 20 knees. There was a statistically significant difference between groups 1 and 2 for the ossified lateral femoral condylar width where femoral tunnel location would be expected (20.00 +/- 4.20 vs 26.27 +/- 4.12 mm, respectively; P = .0035) and for total lateral femoral condylar width (25.57 +/- 3.47 vs 29.43 +/- 4.04 mm, respectively; P = .0339). No difference was found for total tibial epiphyseal height between the 2 groups. However, there was a difference between groups 1 and 2 for ossified tibial epiphyseal height (13.20 +/- 1.63 vs 15.27 +/- 0.94 mm, respectively; P = .0028). No difference was found for average ossified tibial epiphyseal height or ossified lateral femoral condylar width between boys and girls in the younger or older cohorts. The ICC was strong (>0.7) at femoral and tibial locations where tunnel placement would be expected. CONCLUSION: Prepubescent children <7 years old have smaller knee epiphyses than older prepubescent children, and on average, present with an osseous bone stock of 20 mm for lateral femoral condylar width and 13 mm for tibial epiphyseal height. Study results suggest that children aged <7 years possess enough osseous bone stock at the lateral femoral condyle to support transepiphyseal ACL reconstruction. However, future studies will be necessary to determine the safety and effectiveness of this procedure in children aged <7 years. CLINICAL RELEVANCE: ACL tears in children are more frequently being recognized by the orthopaedic community. The trend toward increasing participation in competitive and recreational sports has contributed to this phenomenon. Young patients with complete ACL tears and open growth plates often provide a management dilemma for surgeons who wish to perform reconstructive surgery. PMID- 26535322 TI - Osteochondritis Dissecans of the Humeral Capitellum: The Significance of Lesion Location. AB - BACKGROUND: There is a paucity of information regarding the effect of lesion location on surgical outcomes in the treatment of osteochondritis dissecans (OCD) of the humeral capitellum. PURPOSE: To survey the literature for conclusions that can be drawn regarding the effect of lesion location on treatment of capitellar OCD lesion. The hypothesis was that lesion severity and the need for more aggressive surgical interventions are increased for lesions that are located laterally on the capitellum. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: All studies from the past 20 years were determined using a literature search of PubMed, Scopus, and Cochrane databases. Included studies were clinical studies that specifically commented on the location of the OCD defect on the capitellum. Excluded studies were case reports, review articles, and those that did not include information regarding the location of the OCD lesion on the capitellum. RESULTS: Six studies met the inclusion criteria. Autograft reconstruction was found to yield reliable outcomes regardless of lesion location, as 87% (26/30) of lateral lesions had excellent or good outcomes using the Timmerman and Andrews score, while 91% (21/23) of central lesions had excellent or good outcomes. There was a trend toward improved outcomes with more aggressive surgical management of lateral lesions, specifically those involving the lateral cartilage margin. The failure rate for nonreconstructive operative management for lateral lesions was noted to be significant, as failure rates for peg fixation of lateral lesions was seen to be as high as 44% (4/9) in one of the studies. CONCLUSION: Studies regarding capitellar OCD lesion location, as it relates to symptom severity and surgical outcome, are limited. The literature suggests that lesions located on the lateral capitellum-particularly those involving the lateral cartilage margin-require more aggressive surgical management than those located medially. A refinement of the Takahara classification is proposed, which includes lesion location as a factor influencing surgical decision making. PMID- 26535323 TI - Characterization of the Supinator Tubercle for Lateral Ulnar Collateral Ligament Reconstruction. AB - BACKGROUND: Lateral ulnar collateral ligament (LUCL) reconstruction requires proper understanding and identification of anatomic structures about the lateral elbow. The insertion site of the LUCL is based on the supinator tubercle. PURPOSE: To characterize the supinator tubercle relative to other surrounding anatomic landmarks. STUDY DESIGN: Descriptive laboratory study. METHODS: Computed tomography (CT) scans of 10 adult elbows were retrospectively reviewed. These CT scans were converted into patient-specific 3-dimensional computer models. Using a user-defined coordinate system, an ulnar Cartesian coordinate system was defined with anatomic landmarks as reference points to standardize the position of each model. The length of the supinator crest was measured. Following this, the crest was examined for a distinct raised bony tuberosity that would be consistent with the supinator tubercle. If no distinctly raised tubercle was noted, the most prominent appearing location of the crest distal to the radial notch was considered the tubercle. The distance from the proximal radial head junction to the supinator tubercle was recorded. Finally, the distance from the supinator crest at the radial head junction to the posterior cortex in the sagittal plane was measured. RESULTS: The supinator tubercle was found to be prominent in 5 of 10 ulnar models. The supinator crest was 43.59 +/- 13.28 mm long, and the supinator tubercle lateral extrusion was 5.60 +/- 0.90 mm. The distance between the radial head junction and the supinator tubercle was found to be 15 +/- 2.37 mm, and the distance from the supinator crest at the radial head junction to the posterior cortex was 10.25 +/- 2.07 mm. CONCLUSION: The supinator tubercle is frequently not prominent or easily recognizable. Its relationship to other structures is of value. The proximal border of the radial head, residing 15 mm proximal to the most predictable location of the supinator tubercle, is a useful landmark when drilling tunnels during LUCL reconstructions. CLINICAL RELEVANCE: Results of this study may aid proper anatomic LUCL reconstruction. PMID- 26535324 TI - Changes in Health-Related Quality of Life and Knee Function After Knee Injury in Young Female Athletes. AB - BACKGROUND: Recent literature has called for greater attention to evidence-based practice in sports medicine with the documentation of overall status and impairments following injury. The prospective documentation of impairments associated with knee injuries in female athletes regarding their health-related quality of life (HRQoL) and knee function (KF) of high school and collegiate athletes is limited. Assessing the effect knee injuries have on young female athletes may allow clinicians to better understand the perspectives of the athletes who sustain these injuries. PURPOSE: To document the changes over 12 months in self-reported HRQoL and KF in young females who have sustained a knee injury. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A convenience sample of 242 females (mean age, 17.4 +/- 2.4 years) who injured their knee participating in sport or recreational activities was utilized. Injuries were categorized as anterior cruciate ligament tears (ACL), anterior knee pain (AKP), patellar instability (PAT), meniscus tear (MNT), iliotibial band syndrome (ITB), collateral ligament sprain (COL), and other (OTH). HRQoL was assessed with the Short Form-12 v 2.0 survey (SF-12) physical component summary (PCS) and mental component summary (MCS). KF was assessed with the 2000 International Knee Documentation Committee survey (IKDC). Dependent variables included the paired differences in the 2000 IKDC as well as SF-12 composite scores from preinjury through 12 months postdiagnosis. Paired differences were assessed with repeated measures analyses of variance (P <= .05). RESULTS: IKDC scores were lower through 12 months for ACL, AKP, and PAT; through 6 months for MNT; and through 3 months for COL and OTH. HRQoL PCS and MCS scores were lower through 3 to 12 months depending on the type of injury classification. CONCLUSION: Knee injuries can negatively affect KF and HRQoL for up to 12 months in young females. Sports medicine providers need to be aware of these impacts as they work to effectively treat individuals with these injuries. PMID- 26535325 TI - Injury Rate and Patterns Among CrossFit Athletes. AB - BACKGROUND: CrossFit is a type of competitive exercise program that has gained widespread recognition. To date, there have been no studies that have formally examined injury rates among CrossFit participants or factors that may contribute to injury rates. PURPOSE: To establish an injury rate among CrossFit participants and to identify trends and associations between injury rates and demographic categories, gym characteristics, and athletic abilities among CrossFit participants. STUDY DESIGN: Descriptive epidemiology study. METHODS: A survey was conducted, based on validated epidemiologic injury surveillance methods, to identify patterns of injury among CrossFit participants. It was sent to CrossFit gyms in Rochester, New York; New York City, New York; and Philadelphia, Pennsylvania, and made available via a posting on the main CrossFit website. Participants were encouraged to distribute it further, and as such, there were responses from a wide geographical location. Inclusion criteria included participating in CrossFit training at a CrossFit gym in the United States. Data were collected from October 2012 to February 2013. Data analysis was performed using Fisher exact tests and chi-square tests. RESULTS: A total of 486 CrossFit participants completed the survey, and 386 met the inclusion criteria. The overall injury rate was determined to be 19.4% (75/386). Males (53/231) were injured more frequently than females (21/150; P = .03). Across all exercises, injury rates were significantly different (P < .001), with shoulder (21/84), low back (12/84), and knee (11/84) being the most commonly injured overall. The shoulder was most commonly injured in gymnastic movements, and the low back was most commonly injured in power lifting movements. Most participants did not report prior injury (72/89; P < .001) or discomfort in the area (58/88; P < .001). Last, the injury rate was significantly decreased with trainer involvement (P = .028). CONCLUSION: The injury rate in CrossFit was approximately 20%. Males were more likely to sustain an injury than females. The involvement of trainers in coaching participants on their form and guiding them through the workout correlates with a decreased injury rate. The shoulder and lower back were the most commonly injured in gymnastic and power lifting movements, respectively. Participants reported primarily acute and fairly mild injuries. PMID- 26535326 TI - Specific Shoulder Pathoanatomy in Semiprofessional Water Polo Players: A Magnetic Resonance Imaging Study. AB - BACKGROUND: Shoulders of throwing and swimming athletes are highly stressed joints that often show structural abnormalities on magnetic resonance imaging (MRI). However, while water polo players exhibit a combination of throwing and swimming movements, a specific pattern of pathological findings has not been described. PURPOSE: To assess specific MRI abnormalities in shoulders of elite water polo players and to compare these findings with a healthy control group. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: After performing a power analysis, volunteers were recruited for this study. Both shoulders of 28 semiprofessional water polo players and 15 healthy volunteers were assessed clinically (based on the Constant score) and had bilateral shoulder MRIs. The shoulders were clustered into 3 groups: 28 throwing and 28 nonthrowing shoulders of water polo athletes and 30 shoulders of healthy control subjects. RESULTS: Twenty-eight male water polo players with an average age of 24 years and 15 healthy subjects (30 shoulders) with an average age of 31 years were examined. Compared with controls, significantly more MRI abnormalities in the water polo players' throwing shoulders could be found in the subscapularis, infraspinatus, and posterior labrum (P = .001, P = .024, and P = .041, respectively). Other structures showed no statistical differences between the 3 groups, including the supraspinatus tendon, which had abnormalities in 36% of throwing versus 32% of nonthrowing shoulders and 33% of control shoulders. All throwing shoulders showed abnormal findings in the MRI, but only 8 (29%) were symptomatic. CONCLUSION: The shoulders of semiprofessional water polo players demonstrated abnormalities in subscapularis and infraspinatus tendons that were not typical abnormalities for swimmers or throwing athletes. CLINICAL RELEVANCE: The throwing shoulders of water polo players have specific MRI changes. Clinical symptoms do not correlate with the MRI findings. PMID- 26535327 TI - Relationship Between Tightness of the Hip Joint and Elbow Pain in Adolescent Baseball Players. AB - BACKGROUND: Repetitive tensile stresses from valgus torque can induce elbow injury in adolescent baseball players. Insufficient hip range of motion (ROM) can change throwing mechanics, reducing the transfer of energy from the lower to the upper extremities. Thus, hip ROM limitations may force the upper extremities to bear the burden of a strong throw. Improper pitching mechanics caused by insufficient hip ROM are thought to increase valgus torque on the elbow when throwing, increasing the risk of elbow injury. PURPOSE: To investigate the relationship between elbow pain and hip ROM in adolescent baseball players. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 122 adolescent baseball players with a mean age of 12.0 years (range, 6-14 years) participated in this study. Elbow pain, hip flexion angle, and the internal rotation angles of the hip at 0 degrees and 90 degrees of flexion were assessed. Participants were divided into a pain group and a normal group based on the pain assessment, and each hip angle was compared between groups using Student t tests. P values <.05 were considered statistically significant. RESULTS: Thirty one of 122 players had elbow pain. The hip flexion angle of the trail leg was 121.9 degrees +/- 12.3 degrees for the normal group and 111.2 degrees +/- 11.3 degrees for the pain group (P = .0001). The plant leg hip flexion angles were 122.0 degrees +/- 12.4 degrees and 113.6 degrees +/- 11.3 degrees (P = .0014) for the normal and pain groups, respectively. The internal rotation angle at 0 degrees of hip flexion of the trail leg was 49.4 degrees +/- 12.6 degrees and 45.6 degrees +/- 8.8 degrees (not significant), and of the plant leg was 49.1 degrees +/- 12.5 degrees and 48.7 degrees +/- 11.5 degrees (not significant), for the normal and pain groups, respectively. The internal rotation of the trail leg at 90 degrees of hip flexion was 46.9 degrees +/- 13.3 degrees in the normal group and 36.1 degrees +/- 15.7 degrees in the pain group (P = .0005). In the plant leg, the internal rotation angle at 90 degrees of hip flexion was 46.9 degrees +/- 12.2 degrees and 36.4 degrees +/- 18.1 degrees for the normal and pain groups, respectively (P = .0013). CONCLUSION: Limitations to hip flexion and internal rotation at 90 degrees of hip flexion were risk factors for elbow injury. Differences in internal rotation angles between 0 degrees and 90 degrees of hip flexion may be important criteria for identifying adolescent baseball players at risk of elbow pain. PMID- 26535328 TI - Comparison of Pull-out Strength for Different Bone Block Length in a Porcine Anterior Cruciate Ligament Model. AB - BACKGROUND: Bone block length for bone-patellar tendon-bone (BPTB) anterior cruciate ligament (ACL) reconstruction has traditionally been 25 mm in length. The previous surgical technique did not require the surgeon to pay particular attention to the length of the bone block, and therefore, there is scant evidence in the literature describing ideal lengths. With the gaining popularity of accessory medial portal drilling of the femoral tunnel, concerns with tunnel length and graft shuttling have surfaced. Newer techniques have advised shortening of the femoral bone block to accommodate the shorter tunnel and for ease of bone block manipulation into the aperture of the tunnel. PURPOSE: To compare the effects of bone block length on the pull-out strength of patellar tendon grafts using metal interference screws in a porcine ACL reconstruction model. The hypothesis was that the pull-out strength of each length of bone block under cyclic and ultimate load to failure testing would surpass the physiologic loads experienced by a normal ACL. STUDY DESIGN: Controlled laboratory study. METHODS: This study used 27 unmatched porcine femurs and BPTB constructs. Specimens were randomly assigned to a 10-, 15-, or 20-mm bone block reconstruction and a cycle load of 100, 500, or 1000 cycles. This resulted in 9 specimen groups with 3 specimens in each group. A central composite design (CCD) for the test matrix was selected, as this was optimum for requiring relatively few experiments while still exploring the complete range of interest for 2 independent variables. Each reconstruction used a 7 * 20-mm titanium interference screw. All reconstructions were performed on the femoral side using 10-mm-wide patellar tendon grafts, and tensile tests were performed. The loading protocol started with a 20-N preload, then cyclic testing to the appropriate number of cycles in the elastic region between 50 and 150 N at a strain rate of 200 mm/min, and then ended with ultimate load-to-failure testing. Ultimate load to failure, peak stress, elongation, and stiffness were all recorded. The patellar tendon graft mode of failure was measured by visual inspection. RESULTS: During load-to failure testing, 5 of 9 graft constructs in the 10-mm group failed at the bone block, while 2 of 9 failed in the 15-mm group at this interface. In the 20-mm group, all 9 specimens failed at the tendon, and none failed at the bone block. There was a statistically significant difference in modes of failure between the bone block length groups in the reconstructed ACL grafts. Analysis indicates that a smaller bone block length graft is more likely to fail due to a bone block failure than a tendon failure. The average +/- standard deviation failure load for all specimens was 573 +/- 171 N. The mean failure loads for the 10-, 15-, and 20-mm groups were 614 +/- 110, 658 +/- 92, and 540 +/- 203 N, respectively. There was no statistical significance between the groups in any of these measurements. CONCLUSION: Bone blocks of 20 to 25 mm in length are normally used in surgical practice. Thus, the purpose of this study was to explore the effects of a smaller bone block length in the fixation strength of a graft. This study could not yield a significant difference in failure load for differently sized bone blocks. There was a significant tendency of shorter bone block lengths to fail due to bone block failure. CLINICAL RELEVANCE: Bone block failure was defined as slippage of the bone block or interference screw. These results show that using a smaller bone block may increase the likelihood of a graft failure in an ACL reconstruction. PMID- 26535329 TI - Single-Leg Balance Impairments Persist in Fully Operational Military Special Forces Operators With a Previous History of Low Back Pain. AB - BACKGROUND: Single-leg balance (SLB) can be chronically impaired after low back pain (LBP). Impaired SLB is a risk factor for recurrent LBP and lower extremity injury. In the United States military, the special forces operator (SFO) deploys on high-risk missions under extreme conditions, and impaired SLB can potentially threaten SFO safety and mission success. PURPOSE: To compare SLB in fully operational SFOs with and without a history of LBP. The hypothesis was that SLB deficits would be present in SFOs with a history of LBP. STUDY DESIGN: Cross sectional study; Level of evidence, 3. METHODS: A total of 226 SFOs were included in this analysis. Comparisons were made between SFOs with and without medical chart documented history of LBP (LBP group [n = 43]: mean age = 31.2 +/- 10.3 years, mean height = 177.3 +/- 7.2 cm, mean mass = 87.3 +/- 11.8 kg; healthy group [n = 183]: mean age = 28.0 +/- 6.0 years, mean height = 177.9 +/- 6.0 cm, mean mass = 84.9 +/- 8.8 kg). Bilateral SLB was tested (eyes open and eyes closed) in both groups using a force plate. The variability in the ground reaction forces was averaged across 3 trials for each leg for both conditions. Comparisons were made between legs in the LBP and between the LBP and healthy group (alpha = .05). RESULTS: There were significant between-group differences for each leg for both conditions, with the healthy group demonstrating better SLB compared with the LBP group. P values ranged from .01 to .03. CONCLUSION: Impaired SLB persists in SFOs with previously reported LBP. Balance assessments of individuals who report LBP may assist with designing targeted interventions to address potential deficits that may increase the risk of future injury. CLINICAL RELEVANCE: SFOs with a known history of LBP would benefit from examination of SLB and may benefit from balance training to resolve any deficits that may be present to lower the potential risk for future injury. PMID- 26535330 TI - Understanding the Acute Skin Injury Mechanism Caused by Player-Surface Contact During Soccer: A Survey and Systematic Review. AB - BACKGROUND: Superficial skin injuries are considered minor, and their incidence is probably underestimated. Insight into the incidence and mechanism of acute skin injury can be helpful in developing suitable preventive measures and safer playing surfaces for soccer and other field sports. PURPOSE: To gain insight into the incidence and severity of skin injuries related to soccer and to describe the skin injury mechanism due to player-surface contact. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: The prevention model by van Mechelen et al (1992) combined with the injury causation model of Bahr and Krosshaug (2005) were used as a framework for the survey to describe the skin injury incidence and mechanism caused by player-surface contact. RESULTS: The reviewed literature showed that common injury reporting methods are mainly based on time lost from participation or the need for medical attention. Because skin abrasions seldom lead to absence or medical attention, they are often not reported. When reported, the incidence of abrasion/laceration injuries varies from 0.8 to 6.1 injuries per 1000 player-hours. Wound assessment techniques such as the Skin Damage Area and Severity Index can be a valuable tool to obtain a more accurate estimation of the incidence and severity of acute skin injuries. CONCLUSION: The use of protective equipment, a skin lubricant, or wet surface conditions has a positive effect on preventing abrasion-type injuries from artificial turf surfaces. The literature also shows that essential biomechanical information of the sliding event is lacking, such as how energy is transferred to the area of contact. From a clinical and histological perspective, there are strong indications that a sliding-induced skin lesion is caused by mechanical rather than thermal injury to the skin. PMID- 26535331 TI - Arthroscopic Removal of Chronic Symptomatic Calcifications of the Supraspinatus Tendon Without Acromioplasty: Analysis of Postoperative Recovery and Outcome Factors. AB - BACKGROUND: Little knowledge exists on postoperative recovery of pain and shoulder function following arthroscopic removal of calcific deposits of the supraspinatus tendon (ACDSSP). Certain factors may influence outcome, including acromial morphology. PURPOSE: To examine postoperative recovery following ACDSSP without acromioplasty and to analyze influential outcome factors. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This prospective study evaluated 82 patients (105 shoulders) after ACDSSP without acromioplasty. Time periods for postoperative recovery of pain and subjective shoulder function were recorded. The absolute and normalized Constant scores (CSabs and CSnorm, respectively), Oxford Shoulder Score (OSS), DASH score (DS), and subjective shoulder value (SSV) were measured after a mean follow-up of 33.9 months. Analyzed outcome factors included localization of the calcific deposit (CD), acromial morphology, radiographic extent of CD removal, type of nonoperative treatment, and preoperative duration of symptoms. RESULTS: Mean duration of postoperative pain was 2.2 weeks. Recovery of subjective shoulder function required 11.1 weeks on average. Mean +/- standard deviation follow-up values were 91.1 +/- 8.3 for CSabs, 104.2% +/- 8.2% for CSnorm, 13.1 +/- 2.6 for OSS, 1.81 +/- 4.59 for DS, and 93.8% +/- 10.7% for SSV. Abduction was significantly (P = .008) lower in patients with type III (170 degrees +/- 17.5 degrees ) compared with type I (174 degrees +/- 20.7 degrees ) and type II (179 degrees +/- 4.5 degrees ) acromions. Also, abduction was significantly (P = .001) lower in patients with long-standing symptoms (>72 months). Minor calcific remnants were found in 19 of 105 shoulders (18.1%), but affected neither postoperative recovery nor outcome. CONCLUSION: ACDSSP without acromioplasty yielded favorable outcomes and effected fast remission of pain regardless of acromial morphology. However, recovery of subjective shoulder function required almost 3 months on average. Minimal restriction of abduction occurred in patients with hook-shaped acromions and long standing preoperative symptoms. The present data do not support routine performance of acromioplasty. PMID- 26535332 TI - Knee Dislocations: Lessons Learned From 20-Year Follow-up. AB - BACKGROUND: Traumatic knee dislocation is becoming more prevalent because of improved recognition and increased exposure to high-energy trauma, but long-term results are lacking. PURPOSE: To present 2 cases with minimum 20-year follow-up and a review of the literature to illustrate some of the fundamental principles in the management of the dislocated knee. STUDY DESIGN: Review and case reports. METHODS: Two patients with knee dislocations who underwent multiligamentous knee reconstruction were reviewed, with a minimum 20-year follow-up. These patients were brought back for a clinical evaluation using both subjective and objective measures. Subjective measures include the following scales: Lysholm, Tegner activity, visual analog scale (VAS), Short Form-36 (SF-36), International Knee Documentation Committee (IKDC), and a psychosocial questionnaire. Objective measures included ligamentous examination, radiographic evaluation (including Telos stress radiographs), and physical therapy assessment of function and stability. RESULTS: The mean follow-up was 22 years. One patient had a vascular injury requiring repair prior to ligament reconstruction. The average assessment scores were as follows: SF-36 physical health, 52; SF-36 mental health, 59; Lysholm, 92; IKDC, 86.5; VAS involved, 10.5 mm; and VAS uninvolved, 2.5 mm. Both patients had excellent stability and were functioning at high levels of activity for their age (eg, hiking, skydiving). Both patients had radiographic signs of arthritis, which lowered 1 subject's IKDC score to "C." CONCLUSION: Knee dislocations have rare long-term excellent results, and most intermediate-term studies show fair to good functional results. By following fundamental principles in the management of a dislocated knee, patients can be given the opportunity to function at high levels. Hopefully, continued advances in the evaluation and treatment of knee dislocations will improve the long-term outcomes for these patients in the future. PMID- 26535333 TI - Whole-Person Impairment in Younger Retired NFL Players: The Orthopaedic Toll of a Professional Football Career. AB - BACKGROUND: Professional American football is a physically demanding, high-impact sport with an elevated risk of injury. Orthopaedic injuries may impose acute, short-term or cumulative consequences throughout a player's lifetime. Several studies have addressed health and psychosocial concerns of an older, retired population of players in the National Football League (NFL); however, minimal research has examined the orthopaedic toll on younger, retired players. PURPOSE: This study reports total whole-person impairment (WPI) percentages in a cohort of younger, retired NFL players who presented for disability evaluations based on the use of standardized American Medical Association (AMA) impairment guidelines. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: During the study period of February 2011 to August 2013, 65 younger retired NFL players presented for impairment evaluations. The mean time between retirement and impairment evaluation was 3.1 years (range, 0.3-16.4 years). A complete history and physical examination was performed on all symptomatic joints. A retrospective chart review was conducted on 100% of presenting players to assess orthopaedic burden. Body part impairment (BPI) percentage for each affected joint was generated. The impairment data for each extremity were then combined with spine impairment data to create WPI percentage. Player demographics, including age, position, and playing time, were also recorded. RESULTS: The average WPI percentage was 37% (range, 19%-53%). Players participating in >30 games (n = 54) had a higher mean WPI percentage (38%) than those playing in <30 games (31%; n = 11) (P = .004). Players competing in >5 seasons (n = 46) were 2.4 times more likely to have a WPI of at least 37% (P = .007). The most common joints players reported as symptomatic were lumbar (n = 63; 97%) and cervical spine (n = 58; 89%). The mean age at evaluation was 33.5 years (range, 27-42 years), and the mean number of seasons played was 7.5 (range, 3-14 seasons). The mean number of games played was 98.4 (range, 2-236 games). CONCLUSION: This study demonstrated high WPI percentages related to symptomatic joints in a cohort of younger, retired NFL players. Further research is warranted to study potential cumulative physical and quality of life factors related to high impairment percentages in younger, retired NFL players. PMID- 26535334 TI - Position-Specific Hip and Knee Kinematics in NCAA Football Athletes. AB - BACKGROUND: Femoroacetabular impingement is a debilitating hip condition commonly affecting athletes playing American football. The condition is associated with reduced hip range of motion; however, little is known about the range-of-motion demands of football athletes. This knowledge is critical to effective management of this condition. PURPOSE: To (1) develop a normative database of game-like hip and knee kinematics used by football athletes and (2) analyze kinematic data by playing position. The hypothesis was that kinematics would be similar between running backs and defensive backs and between wide receivers and quarterbacks, and that linemen would perform the activities with the most erect lower limb posture. STUDY DESIGN: Descriptive laboratory study. METHODS: Forty National Collegiate Athletic Association (NCAA) football athletes, representing 5 playing positions (quarterback, defensive back, running back, wide receiver, offensive lineman), executed game-like maneuvers while lower body kinematics were recorded via optical motion capture. Passive hip range of motion at 90 degrees of hip flexion was assessed using a goniometer. Passive range of motion, athlete physical dimensions, hip function, and hip and knee rotations were submitted to 1 way analysis of variance to test for differences between playing positions. Correlations between maximal hip and knee kinematics and maximal hip kinematics and passive range of motion were also computed. RESULTS: Hip and knee kinematics were similar across positions. Significant differences arose with linemen, who used lower maximal knee flexion (mean +/- SD, 45.04 degrees +/- 7.27 degrees ) compared with running backs (61.20 degrees +/- 6.07 degrees ; P < .001) and wide receivers (54.67 degrees +/- 6.97 degrees ; P = .048) during the cut. No significant differences were found among positions for hip passive range of motion (overall means: 102 degrees +/- 15 degrees [flexion]; 25 degrees +/- 9 degrees [internal rotation]; 25 degrees +/- 8 degrees [external rotation]). Several maximal hip measures were found to negatively correlate with maximal knee kinematics. CONCLUSION: A normative database of hip and knee kinematics utilized by football athletes was developed. Position-specific analyses revealed that linemen use smaller joint motions when executing dynamic tasks but do not demonstrate passive range of motion deficits compared with other positions. CLINICAL RELEVANCE: Knowledge of requisite game-like hip and knee ranges of motion is critical for developing goals for nonoperative or surgical recovery of hip and knee range of motion in the symptomatic athlete. These data help to identify playing positions that require remedial hip-related strength and conditioning protocols. Negative correlations between hip and knee kinematics indicated that constrained hip motion, as seen in linemen, could promote injurious motions at the knee. PMID- 26535335 TI - Surgically Relevant Bony and Soft Tissue Anatomy of the Proximal Femur. AB - BACKGROUND: Hip endoscopy facilitates the treatment of extra-articular disorders of the proximal femur. Unfortunately, current knowledge of proximal femur anatomy is limited to qualitative descriptions and lacks surgically relevant landmarks. PURPOSE: To provide a quantitative and qualitative analysis of proximal femur anatomy in reference to surgically relevant bony landmarks. STUDY DESIGN: Descriptive laboratory study. METHODS: Fourteen cadaveric hemipelvises were dissected. A coordinate measuring device measured dimensions and interrelationships of the gluteal muscles, hip external rotators, pectineus, iliopsoas, and joint capsule in reference to osseous landmarks. RESULTS: The vastus tubercle, superomedial border of the greater trochanter, and femoral head neck junction were distinct and reliable osseous landmarks. The anteroinferior tip of the vastus tubercle was 17.1 mm (95% CI: 14.5, 19.8 mm) anteroinferior to the center of the gluteus medius lateral insertional footprint and was 22.9 mm (95% CI: 20.1, 25.7 mm) inferolateral to the center of the gluteus minimus insertional footprint. The insertions of the piriformis, conjoint tendon of the hip (superior gemellus, obturator internus, and inferior gemellus), and obturator externus were identified relative to the superomedial border of the greater trochanter. The relationship of the aforementioned footprints were 49% (95% CI: 43%, 54%), 42% (95% CI: 33%, 50%), and 64% (95% CI: 59%, 69%) from the anterior (0%) to posterior (100%) margins of the superomedial border of the greater trochanter, respectively. The hip joint capsule attached distally on the proximal femur 18.2 mm (95% CI: 14.2, 22.2 mm) from the head-neck junction medially on average. CONCLUSION: The vastus tubercle, superomedial border of the greater trochanter, and the femoral head-neck junction were reliable osseous landmarks for the identification of the tendinous and hip capsular insertions on the proximal femur. Knowledge of the interrelationships between these structures is essential for endoscopic navigation and anatomic surgical repair and reconstruction. CLINICAL RELEVANCE: The qualitative and quantitative clinically relevant anatomic data presented here will aid in the diagnosis of proximal femur pathology and will provide a template for anatomic repair or reconstruction. PMID- 26535336 TI - Preventive Effects of Eccentric Training on Acute Hamstring Muscle Injury in Professional Baseball. AB - BACKGROUND: Hamstring injuries are the second most common injury causing missed days in professional baseball field players. Recent studies have shown the preventive benefit of eccentric conditioning on the hamstring muscle group in injury prevention. Specifically, Nordic-type exercises have been shown to decrease the incidence of acute hamstring injuries in professional athletes. PURPOSE: This was a prospective study performed in coordination with a single Major League Baseball (MLB) organization (major and minor league teams) that targeted the effects of Nordic exercises on the incidence of acute hamstring injuries in the professional-level baseball player. STUDY DESIGN: Prospective cohort study; Level of evidence, 2. METHODS: The daily workouts of 283 professional baseball players throughout all levels of a single MLB organization were prospectively recorded. The intervention group participated in the Nordic exercise program and was compared with a randomly selected control group of professional athletes within the organization not participating in the exercise program. The incidence of hamstring injuries in both groups was compared, and the total number of days missed due to injury was compared with the 2 previous seasons. RESULTS: There were 10 hamstring injuries that occurred during the 2012 season among the 283 professional athletes that required removal from play. There were no injuries that occurred in the intervention group (n = 65, 0.00%; P = .0381). The number needed to treat (NNT) to prevent 1 hamstring injury was 11.3. The average repetitions per week of the injured group were assessed at multiple time points (2, 4, 6, and total weeks) prior to injury. There were significantly fewer repetitions per week performed in the injured group at all time points compared with overall average repetitions per week in the noninjured group (P = .0459, .0127, .0164, and .0299, respectively). After beginning the Nordic exercise program, there were 136 total days missed due to a hamstring injury during the 2012 season. This number was less than the 2011 season (273 days missed) and the 2010 season (309 days missed). CONCLUSION: Study results indicate the initiation of Nordic hamstring exercises may decrease the incidence of acute hamstring injuries and potentially decrease the total number of days missed due to injury in professional baseball players. CLINICAL RELEVANCE: The financial and competitive interest in professional baseball players is of large importance to the player, team, and fans. Prevention of injuries is as important to all parties involved as the treatment and rehabilitation following an injury. This prospective study shows the initiation of a simple, free exercise can reduce the incidence of hamstring injury in the professional-level baseball player. PMID- 26535337 TI - Clinical Implications of Changing Parameters on an Elliptical Trainer. AB - BACKGROUND: Specific weightbearing instructions continue to be a part of routine orthopaedic clinical practice on an injured or postoperative extremity. Researchers and clinicians have struggled to define the best weightbearing strategies to maximize clinical outcomes. PURPOSE: To investigate the average percentage body weight (APBW) values, weightbearing distribution percentages (WBDP), and cadence values on the entire foot, hindfoot, and forefoot during changing resistance and incline on an elliptical trainer, as well as to suggest clinical implications. STUDY DESIGN: Descriptive laboratory study. METHODS: An original research study was performed consisting of 30 asymptomatic subjects (mean age, 29.54 +/- 12.64 years; range, 21-69 years). The protocol included 3 consecutive tests of changing resistance and incline within a speed range of 70 to 95 steps/min. The SmartStep weightbearing gait analysis system was utilized to measure the values. RESULTS: The APBW values for the entire foot ranged between 70% and 81%, the hindfoot values were between 27% and 57%, and the forefoot values between 42% and 70%. With regard to WBDP, the forefoot remained planted on the pedal (stance phase) 2 to 3 times more as compared with the hindfoot raise in the swing phase. CONCLUSION: The study findings highlight the fact that elliptical training significantly reduces weightbearing in the hindfoot, forefoot, and entire foot even at higher levels of resistance and incline. CLINICAL RELEVANCE: Weightbearing on the hindfoot consistently displayed the lowest weightbearing values. Orthopaedic surgeons, now equipped with accurate weightbearing data, may recommend using the elliptical trainer as a weightbearing exercise early on following certain bony or soft tissue pathologies and lower limb surgical procedures. PMID- 26535338 TI - The Impact of Fatigue on the Kinematics of Collegiate Baseball Pitchers. AB - BACKGROUND: Many factors are believed to contribute to throwing injuries in baseball pitchers, in particular overuse and poor throwing mechanics. The impact of fatigue on pitching biomechanics in live-game situations is not well understood. HYPOTHESIS: Pitchers will demonstrate significant deviation in their pitching motions with increasing levels of fatigue. STUDY DESIGN: Descriptive laboratory study. METHODS: Eleven National Collegiate Athletic Association (NCAA) Division I collegiate baseball pitchers were filmed in multiple live-game situations throughout a single season using 2 orthogonal high-speed cameras at 120 Hz. The first fastball of each inning and, when available, the fastball subsequent to the 15th and 30th pitch of each inning were recorded and analyzed for 26 kinematic parameters. Pitch count and velocity were recorded. Kinematic differences were assessed for association with pitch count and subjective fatigue measures over the course of each inning and game through the season. RESULTS: Twenty-six games were recorded. Pitchers had a mean of 97.2 +/- 16.1 pitches per start and 1079 +/- 251 pitches per collegiate season. Increased hip lean at hand separation, elbow height at foot contact, and hip flexion and shoulder tilt at maximum external rotation were seen in innings lasting longer than 15 pitches. Maximum external rotation of the shoulder and elbow height at foot contact decreased over the course of a game. Hip lean at hand separation and elbow height at foot contact increased over the course of the season. Season pitch count was weakly correlated with increased shoulder external rotation and shoulder alignment at maximum external rotation and with shoulder abduction at ball release. Elbow flexion decreased with greater season pitch counts. CONCLUSION: Hip lean, elbow height, and shoulder external rotation were the most sensitive kinematic parameters to inning, game, and season fatigue. Pitch count and fatigue have a significant impact on live-game pitching kinematics. CLINICAL RELEVANCE: Fatigue likely alters pitching mechanics. Recognition of kinematic alterations may better demonstrate fatigue-related injury risk and may assist injury prevention in addition to standardized limitations of innings and pitches thrown. PMID- 26535339 TI - Small Multifidus Muscle Size Predicts Football Injuries. AB - BACKGROUND: In Australian football, lower limb injuries have had the highest incidence and prevalence rates. Previous studies have shown that football players with relatively more severe preseason and playing season hip, groin, and thigh injuries had a significantly smaller multifidus muscle compared with players with no lower limb injuries. Rehabilitation of the multifidus muscle, with restoration of its size and function, has been associated with decreased recurrence rates of episodic low back pain and decreased numbers of lower limb injuries in football players. Assessment of multifidus muscle size and function could potentially be incorporated into a model that could be used to predict injuries in football players. PURPOSE: To examine the robustness of multifidus muscle measurements as a predictor of lower limb injuries incurred by professional football players. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Ultrasound examinations were carried out on 259 male elite football players at the start of the preseason and 261 players at the start of the playing season. Injury data were obtained from records collected by the Australian Football League (AFL) club staff during the preseason and the playing season. RESULTS: Decreased size of the multifidus muscle at L5 consistently predicted injury in the preseason and playing season. Asymmetry of the multifidus muscle and low back pain were significantly related to lower limb injuries in the preseason, and having no preferred kicking leg was related to season injuries. Seasonal change in the size of the multifidus muscle indicating a decrease in muscle mass was linked to injury. Sensitivity and specificity of the model were 60.6% and 84.9% for the preseason and 91.8% and 45.8% for the playing season, respectively. CONCLUSION: A model was developed for prediction of lower limb injuries in football players with potential utility for club medical staff. Of particular note is the finding that changes in muscle size from the preseason to the playing season predicted injury. CLINICAL RELEVANCE: As size of the multifidus muscle has been shown to be modifiable with training and has been associated with reduced pain and occurrence of injuries, this information could be incorporated in current programs of injury prevention. PMID- 26535340 TI - Reconstruction of Hyaline Cartilage Deep Layer Properties in 3-Dimensional Cultures of Human Articular Chondrocytes. AB - BACKGROUND: Articular cartilage (AC) injuries and malformations are commonly noticed because of trauma or age-related degeneration. Many methods have been adopted for replacing or repairing the damaged tissue. Currently available AC repair methods, in several cases, fail to yield good-quality long-lasting results, perhaps because the reconstructed tissue lacks the cellular and matrix properties seen in hyaline cartilage (HC). PURPOSE: To reconstruct HC tissue from 2-dimensional (2D) and 3-dimensional (3D) cultures of AC-derived human chondrocytes that would specifically exhibit the cellular and biochemical properties of the deep layer of HC. STUDY DESIGN: Descriptive laboratory study. METHODS: Two-dimensional cultures of human AC-derived chondrocytes were established in classical medium (CM) and newly defined medium (NDM) and maintained for a period of 6 weeks. These cells were suspended in 2 mm-thick collagen I gels, placed in 24-well culture inserts, and further cultured up to 30 days. Properties of chondrocytes, grown in 2D cultures and the reconstructed 3D cartilage tissue, were studied by optical and scanning electron microscopic techniques, immunohistochemistry, and cartilage-specific gene expression profiling by reverse transcription polymerase chain reaction and were compared with those of the deep layer of native human AC. RESULTS: Two-dimensional chondrocyte cultures grown in NDM, in comparison with those grown in CM, showed more chondrocyte-specific gene activity and matrix properties. The NDM-grown chondrocytes in 3D cultures also showed better reproduction of deep layer properties of HC, as confirmed by microscopic and gene expression analysis. The method used in this study can yield cartilage tissue up to approximately 1.6 cm in diameter and 2 mm in thickness that satisfies the very low cell density and matrix composition properties present in the deep layer of normal HC. CONCLUSION: This study presents a novel and reproducible method for long-term culture of AC derived chondrocytes and reconstruction of cartilage tissue with properties similar to the deep layer of HC in vitro. CLINICAL RELEVANCE: The HC tissue obtained by the method described can be used to develop an implantable product for the replacement of damaged or malformed AC, especially in younger patients where the lesions are caused by trauma or mechanical stress. PMID- 26535341 TI - Analysis of Low-Field MRI Scanners for Evaluation of Shoulder Pathology Based on Arthroscopy. AB - BACKGROUND: Many studies have compared the diagnostic capabilities of low-field magnetic resonance imaging (MRI) scanners to high-field MRI scanners; however, few have evaluated the low-field MRI diagnoses compared with intraoperative findings. PURPOSE: To determine the accuracy and sensitivity of low-field MRI scanners in diagnosing lesions of the rotator cuff and glenoid labrum. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: Over a 2-year period, MRI examinations without intra-articular contrast were performed on 79 patients for shoulder pathologies using an in-office 0.2-T extremity scanner. The MRI examinations were read by board-certified, musculoskeletal fellowship-trained radiologists. All patients underwent shoulder arthroscopy performed by a single sports fellowship-trained orthopaedic surgeon within a mean time of 56 days (range, 8-188 days) after the MRI examination. The mean patient age was 54 years (range, 18-81 years). Operative notes from the shoulder arthroscopies were then retrospectively reviewed by a single blinded observer, and the intraoperative findings were compared with the MRI reports. RESULTS: For partial-thickness rotator cuff tears, the sensitivity, specificity, positive predictive value, and negative predictive value were 85%, 89%, 79%, and 92%, respectively. For full thickness rotator cuff tears, the respective values were 97%, 100%, 100%, and 98%. For anterior labral lesions, the values were 86%, 99%, 86%, and 99%, and for superior labral anterior-posterior (SLAP) lesions, the values were 20%, 100%, 100%, and 79%, respectively. CONCLUSION: Low-field MRI is an accurate tool for evaluation of partial- and full-thickness rotator cuff tears; however, it is not effective in diagnosing SLAP lesions. More information is needed to properly assess its ability to diagnose anterior and posterior labral lesions. PMID- 26535342 TI - Effect of Posterior Horn Medial Meniscus Root Tear on In Vivo Knee Kinematics. AB - BACKGROUND: Medial meniscus root tear (MMRT) is a recently recognized yet frequently missed meniscal tear pattern that biomechanically creates an environment approaching meniscal deficiency. HYPOTHESIS/PURPOSE: The purpose of this study was to assess the effect of MMRT on tibiofemoral kinematics and arthrokinematics during daily activities by comparing the injured knees of subjects with isolated MMRT to their uninjured contralateral knees. The hypothesis was that the injured knee will demonstrate significantly more lateral tibial translation and adduction than the uninjured knee, and that the medial compartment will exhibit significantly different arthrokinematics than the lateral compartment in the affected limb. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Seven subjects with isolated MMRT were recruited and volumetric, density-based 3-dimensional models of their distal femurs and proximal tibia were created from computed tomography scans. High-speed, biplane radiographs were obtained of both their affected and unaffected knees. Moving 3 dimensional models of tibiofemoral kinematics were calculated using model-based tracking to assess overall kinematic variables and specific measures of tibiofemoral joint contact. The affected knees of the subjects were then compared to their unaffected contralateral knees. RESULTS: Affected knees demonstrated significantly more lateral tibial translation than the uninjured contralateral limb in all dynamic activities. Additionally, the medial compartment displayed greater amounts of mobility than the lateral compartment in the injured limbs. CONCLUSION: This study suggests that MMRT causes significant changes in in vivo knee kinematics and arthrokinematics and that the magnitude of these changes is influenced by dynamic task difficulty. CLINICAL RELEVANCE: Medial meniscus root tears lead to significant changes in joint arthrokinematics, with increased lateral tibial translation and greater medial compartment excursion. With complete root tears, essentially 100% of circumferential fibers are lost. This study will further our knowledge of meniscal deficiency and osteoarthritis and provide a baseline for more common forms of medial meniscal injuries (vertical, horizontal, radial), with various degrees of circumferential fiber function remaining. PMID- 26535343 TI - Greater Polar Moment of Inertia at the Tibia in Athletes Who Develop Stress Fractures. AB - BACKGROUND: Several previous investigations have determined potential risk factors for stress fractures in athletes and military personnel. PURPOSE: To determine factors associated with the development of stress fractures in female athletes. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 88 female athletes (cross-country, n = 29; soccer, n = 15; swimming, n = 9; track and field, n = 14; volleyball, n = 12; and basketball, n = 9) aged 18 to 24 years were recruited to participate in a longitudinal bone study and had their left distal tibia at the 4%, 20%, and 66% sites scanned by peripheral quantitative computed tomography (pQCT). Patients included 23 athletes who developed stress fractures during the following year (cases). Whole body, hip, and spine scans were obtained using dual-energy x-ray absorptiometry (DXA). Analysis of covariance was used to determine differences in bone parameters between cases and controls after adjusting for height, lower leg length, lean mass, fat mass, and sport. RESULTS: No differences were observed between cases and controls in any of the DXA measurements. Cases had significantly greater unadjusted trabecular bone mineral content (BMC), greater polar moment of inertia (PMI) at the 20% site, and greater cortical BMC at the 66% site; however, after adjusting for covariates, the differences became nonsignificant. When analyses were repeated using all individuals who had ever had a stress fracture as cases (n = 31) and after controlling for covariates, periosteal circumference was greater in the cases than the controls (71.1 +/- 0.7 vs 69.4 +/- 0.5 mm, respectively; P = .04). CONCLUSION: A history of stress fractures is associated with larger bones. These findings are important because larger bones were previously reported to be protective against fractures and stress fractures, but study findings indicate that may not always be true. One explanation could be that individuals who sustain stress fractures have greater loading that results in greater periosteal circumference but also results in the development of stress fractures. PMID- 26535344 TI - Diagnosing Femoroacetabular Impingement From Plain Radiographs: Do Radiologists and Orthopaedic Surgeons Differ? AB - BACKGROUND: A diagnosis of femoroacetabular impingement (FAI) requires careful history and physical examination, as well as an accurate and reliable radiologic evaluation using plain radiographs as a screening modality. Radiographic markers in the diagnosis of FAI are numerous and not fully validated. In particular, reliability in their assessment across health care providers is unclear. PURPOSE: To determine inter- and intraobserver reliability between orthopaedic surgeons and musculoskeletal radiologists. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: Six physicians (3 orthopaedic surgeons, 3 musculoskeletal radiologists) independently evaluated a broad spectrum of FAI pathologies across 51 hip radiographs on 2 occasions separated by at least 4 weeks. Reviewers used 8 common criteria to diagnose FAI, including (1) pistol grip deformity, (2) size of alpha angle, (3) femoral head-neck offset, (4) posterior wall sign abnormality, (5) ischial spine sign abnormality, (6) coxa profunda abnormality, (7) crossover sign abnormality, and (8) acetabular protrusion. Agreement was calculated using the intraclass correlation coefficient (ICC). RESULTS: When establishing an FAI diagnosis, there was poor interobserver reliability between the surgeons and radiologists (ICC batch 1 = 0.33; ICC batch 2 = 0.15). In contrast, there was higher interobserver reliability within each specialty, ranging from fair to good (surgeons: ICC batch 1 = 0.72; ICC batch 2 = 0.70 vs radiologists: ICC batch 1 = 0.59; ICC batch 2 = 0.74). Orthopaedic surgeons had the highest interobserver reliability when identifying pistol-grip deformities (ICC = 0.81) or abnormal alpha angles (ICC = 0.81). Similarly, radiologists had the highest agreement for detecting pistol-grip deformities (ICC = 0.75). CONCLUSION: These results suggest that surgeons and radiologists agree among themselves, but there is a need to improve the reliability of radiographic interpretations for FAI between the 2 specialties. The observed degree of low reliability may ultimately lead to missed, delayed, or inappropriate treatments for patients with symptomatic FAI. PMID- 26535345 TI - Assessment of Osgood-Schlatter Disease and the Skeletal Maturation of the Distal Attachment of the Patellar Tendon in Preadolescent Males. AB - BACKGROUND: Osgood-Schlatter disease (OSD) is a traction apophysitis of the tibial tuberosity. Ultrasonography (US) is able to detect pathologic changes, such as cartilage swelling and fragmentation of the tibial tubercle ossification center. PURPOSE: To compare the US stages of tibial tuberosity development and the physical features and prevalence of OSD in this patient cohort. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Subjects included 238 males (n = 476 joints) with a mean age of 11.4 +/- 1.6 years (range, 7-14 years). The tibial tuberosity development on US was divided into 3 stages: the cartilaginous stage (stage C), apophyseal stage (stage A), and epiphyseal stage (stage E). It was then investigated whether the subjects had pain in the tibial tuberosity on application of pressure. Age, height, body weight, body mass index (BMI), heel buttock distance (HBD, cm), and straight-leg raise angle (SLRA) were evaluated. To confirm the diagnosis of OSD, the participant had to fulfill the following clinical criteria: pain with direct pressure on the tibial apophysis, fragmentation of the bone, and irregularity of the ossification center detected by US. RESULTS: The tibial tuberosity was stage C in 195 knees, stage A in 105 knees, and stage E in 176 knees. The subjects' heights, weights, and BMIs significantly increased with advancing development of the tibial tuberosity. The HBD increased in stage E (P < .01). The SLRA was not significantly different among groups. There was fragmentation of the bone and irregularity of the ossification center in 32 knees (6.8%): 0 in stage C, 21 (4.3%) in stage A, and 11 (2.3%) in stage E. Fragmentation of the bone and irregularity were observed significantly more often in stage A (P < .01). On the other hand, there were 10 joints with OSD (2.1%): 0 in stage C, 3 (0.6%) in stage A, and 7 (1.5%) in stage E. OSD was observed significantly more often in stage E than in the other stages (P < .05). CONCLUSION: The present study showed that the HBD increased from stage A to stage E. The prevalence of OSD was highest in stage E. PMID- 26535346 TI - Surgical Management of Symptomatic Olecranon Traction Spurs. AB - BACKGROUND: There is a paucity of information pertaining to the pathoanatomy and treatment of symptomatic olecranon traction spurs. PURPOSE: To describe the pathoanatomy of olecranon traction spur formation, a technique for spur resection, and a series of patients who failed conservative care and underwent operative treatment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Eleven patients (12 elbows) with a mean age of 42 years (range, 27-62 years) underwent excision of a painful olecranon traction spur after failing conservative care. Charts and imaging studies were reviewed. All patients returned for evaluation and new elbow radiographs at an average of 34 months (range, 10-78 months). Outcome measures included the Quick-Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire; the Mayo Elbow Performance Score (MEPS); visual analog scales (VAS) for pain and patient satisfaction; elbow motion; elbow strength; and elbow stability. RESULTS: The traction spur was found in the superficial fibers of the distal triceps tendon in all cases. The mean QuickDASH score was 3 (range, 0-23), the mean MEPS score was 96 (range, 80-100), the mean VAS pain score was 0.8 (range, 0-3), and the mean VAS satisfaction score was 9.6 (range, 7-10). Average elbow motion measured 3 degrees to 138 degrees (preoperative average, 5 degrees -139 degrees ). All patients exhibited normal elbow flexion and extension strength, and all elbows were deemed stable. Early postoperative complications involved a wound seroma in 1 case and olecranon bursitis in 1 case: both problems resolved without additional surgery. Two patients eventually developed a recurrent traction spur, 1 of whom underwent successful repeat spur excision 48 months after the index operation. CONCLUSION: Short- to mid-term patient and examiner-determined outcomes after olecranon traction spur resection were acceptable in our experience. Early postoperative complications and recurrent enthesophyte formation were uncommon. CLINICAL RELEVANCE: This study provides the treating physician with an improved understanding of the pathoanatomy of olecranon traction spur formation, a technique for spur resection, and information to review with patients regarding the outcome of surgical management. PMID- 26535347 TI - Prevalence and Incidence Rates Are Not the Same: Letter to the Editor. PMID- 26535348 TI - Prevalence and Incidence Rates Are Not the Same: Response. PMID- 26535349 TI - Injuries in Elite Men's Lacrosse: An Observational Study During the 2010 World Championships. AB - BACKGROUND: There are limited data on injuries sustained during men's lacrosse. As the sport gains popularity, practitioners will be more likely to treat lacrosse players. PURPOSE: To analyze data from the 2010 World Lacrosse Championships. STUDY DESIGN: Descriptive epidemiology study. METHODS: This was a prospective observational study of injuries reported during the 2010 World Lacrosse Championships. An injury surveillance questionnaire was completed, and data were categorized into body part injured, diagnosis, mechanism, and time of injury. RESULTS: Over 9 days, 667 players from 29 countries competed in 105 games. A total of 150 injuries were sustained by 129 individuals aged 16 to 46 years. Five times more injuries occurred during games than in training (69.3% [n = 104] vs 13.3% [n = 20]; rate ratio [95% CI] = 5.2 [4.9-5.5]), resulting in 39.5 injuries per 1000 hours played. The most frequent mechanism was contact (53.3%; n = 80), including direct impact with another player (30%; n = 45), with a stick (16.7%; n = 25), or with a ball (5.3%; n = 8). Change of direction and/or speed were the most common noncontact mechanisms (27.3%; n = 41). The most frequently reported injuries were contusions (32.0%; n = 48), sprains (22.7%; n = 34), and strains (22.7%; n = 34). The lower limb was the most injured body part (50.7%; n = 76) compared with the upper limb (23.3%; n = 35; rate ratio [95% CI] = 2.2 [2.1 2.3]). The ankle was the most injured joint (14.0%; n = 21), followed by the shoulder (10.0%; n = 15). CONCLUSION: As participation expands, health professionals may become more responsible for treating lacrosse players. Players are susceptible to a range of injuries. Familiarity with the common injury patterns could help treatment and prevention. Despite differences in rules during international competition, this study corroborates reports from North America. CLINICAL RELEVANCE: The epidemiology of men's lacrosse injuries needs to be documented and understood to effectively prevent injuries. The 2014 World Championships are to be held in Denver, Colorado (July 10-19, 2014), and it is important that practitioners treating players are aware of the differences in the international game. Publication of these data will allow for those planning lacrosse tournaments to do so more effectively. PMID- 26535350 TI - Vertical Tears of the Lateral Meniscus: Effects on In Vitro Tibiofemoral Joint Mechanics. AB - BACKGROUND: Lateral meniscal tears are often seen with acute anterior cruciate ligament (ACL) injury and may be left in situ, repaired, or treated with meniscectomy. Clinical studies have shown good outcomes with vertical tears left in situ and poor outcomes following meniscectomy. However, clinically relevant studies are needed to establish a biomechanical foundation for treatment of these tears, particularly regarding the effects of meniscectomy. PURPOSE: To compare tibiofemoral joint mechanics following vertical lateral meniscal tears and meniscectomies. We hypothesized that a peripheral vertical tear of the lateral meniscus would alter joint mechanics, increasing contact pressure and area, and that more drastic effects would be seen following meniscectomy, at higher knee flexion angles, and with increased loads. STUDY DESIGN: Controlled laboratory study. METHODS: Ten fresh-frozen cadaveric knees (average age, 55 +/- 12 years) were tested with 5 lateral meniscus states: intact, short vertical tear, extended vertical tear, posterior horn partial meniscectomy (rim intact), and posterior horn subtotal meniscectomy (rim excised). The specimens were loaded axially at knee flexion angles of 0 degrees , 30 degrees , and 60 degrees , and musculotendinous forces were applied, simulating a 2-legged squat. Intra articular contact pressures were measured using pressure-sensitive Fuji film. Kinematic data were acquired through digitization of fiducial markers. RESULTS: Vertical tears did not cause a significant change in contact pressure or area. Partial meniscectomy increased maximum contact pressures in the lateral compartment at 30 degrees and 60 degrees from 5.3 MPa to 7.2 MPa and 7.6 MPa, respectively (P = .02, P = .007). Subtotal meniscectomy (8.4 MPa) significantly increased contact pressure compared with partial meniscectomy (7.6 MPa) at 60 degrees (P = .04). Both meniscectomy states significantly increased contact pressures with increasing flexion from 0 degrees to 60 degrees (P < .001, P < .001). CONCLUSION: Vertical tears of the lateral meniscus during a simulated 2 legged squat did not significantly change contact pressures and areas compared with an intact meniscus. However, treating these tears with partial and complete meniscectomy significantly increased maximum contact pressures. CLINICAL RELEVANCE: Biomechanical evidence supports treating vertical lateral meniscus tears with meniscal-sparing techniques as opposed to meniscectomy, which may lead to progressive degenerative joint disease from altered joint biomechanics. PMID- 26535351 TI - Rates and Determinants of Return to Play After Anterior Cruciate Ligament Reconstruction in NCAA Division 1 College Football Athletes: A Study of the ACC, SEC, and PAC-12 Conferences. AB - BACKGROUND: For competitive athletes, return to play (RTP) and return to preinjury levels of performance after anterior cruciate ligament (ACL) reconstruction are the main goals of surgery. Although outcomes of ACL surgery are well studied, details on factors influencing RTP in elite college football players have not been evaluated thoroughly. PURPOSE: To determine the rate of RTP following ACL surgery among National Collegiate Athletic Association (NCAA) Division 1 collegiate football athletes and to examine variables that may affect these rates. The hypothesis was that the RTP rate in this cohort will be influenced by factors reflecting skill and accomplishment; that is, athletes higher on the depth chart, those on scholarship, and those later in their careers will have higher RTP rates. It was also predicted that graft type and concomitant procedures may have an effect on RTP rates. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Using athlete- and surgery-specific data from participating institutions in 3 major Division 1 college football conferences, information on athletes who had ACL reconstruction from 2004 through 2010 was collected. Statistical analyses were performed to determine the RTP rate as a function of the variables, such as depth chart position, in the data collected. RESULTS: Of the 184-player cohort, 82% of the athletes, including 94% of starters, were able to RTP. Rates were greater among athletes higher on the depth chart (P = .004) and on scholarship (P = .008). Year of eligibility also affected RTP rates (P = .047), which increased from the redshirt and freshman year to the sophomore and junior years, but then decreased slightly into the senior and fifth-year senior seasons. The use of an autograft versus allograft was associated with increased RTP (P = .045). There was no significant difference (P = .18) between players who underwent an isolated ACL reconstruction versus those who underwent additional procedures. CONCLUSION: More than 80% of football players at the Division 1 level were able to RTP following ACL reconstruction. Factors representative of a player's skill were associated with higher rates of RTP. Surgery-specific variables, in general, had no effect on RTP, except for the use of autograft, which was associated with a greater RTP rate. PMID- 26535352 TI - Medial Patellofemoral Ligament Reconstruction for Patellar Dislocation: A Systematic Review. AB - BACKGROUND: With improved understanding of the biomechanical importance of the medial patellofemoral ligament (MPFL), its reconstruction for patellar dislocation has become increasingly popular. The aim of this systematic review was to critically determine the effectiveness of MPFL reconstruction for patellar dislocation. HYPOTHESIS: MPFL reconstruction for patellar dislocation leads to a low redislocation rate with improved Kujala scores. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A literature search was performed using Embase and Medline (Ovid) databases. Inclusion criteria included first-time and recurrent patellar dislocation, subluxation, or persistent instability with a minimum follow-up of 12 months and documentation of postoperative redislocation rate or Kujala score. The studies were systematically appraised, and a meta analysis was performed. RESULTS: Twenty-two studies were included: 2 randomized controlled trials, 3 parallel case series, and 17 case series. There were a total of 655 knees in the review, with an age range at time of surgery from 11 to 52 years. The pooled postoperative redislocation rate from all 17 case series showed a mean of 2.44%. The pooled preoperative Kujala scores from 12 case series showed a mean of 51.6 (95% CI, 46.71-56.49). The pooled postoperative Kujala scores from 16 case series showed a mean of 87.77 (95% CI, 85.15-90.39). CONCLUSION: Although the studies were of low quality, the meta-analysis of 17 case series shows that MPFL reconstruction for recurrent patellar dislocation results in a significant improvement in Kujala scores, a low redislocation rate, and acceptable complication rate. Randomized trials would be needed to draw influences on the superiority of MPFL reconstruction compared with other treatments. PMID- 26535353 TI - Subacromial Injection Results in Further Scapular Dyskinesis. AB - BACKGROUND: Scapular kinematic movement patterns between patients with subacromial impingement and healthy controls have been extensively investigated. However, a high degree of variability has been reported in the literature pertaining to differences between these 2 groups. PURPOSE: To investigate the influence of subacromial pain on scapular kinematics. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 21 patients with stage 2 subacromial impingement who received local anesthetic injections as part of their normal treatment were recruited for this study. The postinjection kinematic data from these patients were compared with those of healthy age-, sex-, and arm dominance matched controls. RESULTS: Subacromial injections of anesthetics resulted in increased scapular anterior tilting; however, no changes were noted in upward or internal rotation. When compared with healthy controls, patients had greater anterior tilting and upward rotation of the scapula. CONCLUSION: The study findings indicate that the removal of pain in patients with impingement results in further dyskinesis of the scapula. CLINICAL RELEVANCE: Pain may be causing patients with subacromial impingement to limit scapular tilt and upward rotation, and movement limitations may continue after an anesthetic injection. PMID- 26535354 TI - Current Physical and Mental Health of Former Collegiate Athletes. AB - BACKGROUND: There is a dearth of research on the current health of former collegiate athletes. PURPOSE: To examine the current health and related correlates in a cohort of former collegiate athletes who played in a diverse range of men's and women's sports with various levels of contact. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Former collegiate athletes (N = 3657) were asked to complete an online questionnaire addressing sports history, medical history, and demographics. The questionnaire also included the Veterans RAND 12-Item Health Survey (VR-12), which yielded 2 composite scores for physical (PCS) and mental (MCS) health. The VR-12 PCS and MCS scores were compared with published US normative data using t tests and analyses of variance. RESULTS: Mean PCS and MCS scores of the 797 respondents with complete data (21.9% of target sample; average, 14.5 years since last played collegiate sport) were 53.0 +/- 6.1 and 51.7 +/- 9.4, respectively. When stratified by age and sex, PCS and MCS scores were similar to normative scores in the United States. Lower PCS scores were associated with sustaining >=3 concussions, playing in collision sports during college, and sustaining a career-ending injury (all, P < .001). No association was found between concussion and MCS scores (P = .06). Among former collegiate athletes, prevalent medical conditions included anxiety (16.2%), hypercholesterolemia/high cholesterol (10.6%), and depression (10.4%). Additionally, 5.8% screened positive for alcohol dependence, and 5.8% screened positive for disordered eating (eg, binge eating, purging). These findings were more prevalent than those reported by the World Health Organization as representative of the US population. Conversely, there was a lower prevalence of depression, bipolar disorders, and attention deficit disorder, with or without hyperactivity (ADD/ADHD), than in the World Health Organization US population data sample. CONCLUSION: Former collegiate athletes appear similar to the general US population on many aspects of mental and physical health. However, observed health deficits associated with previous sports injuries warrant ongoing monitoring of the health and well-being of former collegiate athletes. PMID- 26535355 TI - Incidence of Deep Venous Thrombosis After Tibial Tubercle Osteotomy: A Single Case Series Study. AB - BACKGROUND: Tibial tubercle osteotomy (TTO) is performed in a predominantly young and often female population due to the prevalence of patellofemoral disorders in this group. While considered a procedure that falls within the realm of sports surgeries, the procedure can carry significant morbidity, including infection, fracture, and deep vein thrombosis (DVT). The incidence of postoperative DVT in this population has not been described in the literature, although it has been mentioned anecdotally, and current guidelines do not address the issue of DVT prophylaxis in postoperative TTO patients. PURPOSE: To describe the incidence of DVT after TTO and identify any predisposing factors. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Subjects who had undergone TTO by the senior author from 2002 to 2013 were identified, and a retrospective chart review was performed. Those who presented with symptomatic DVT confirmed with ultrasonography were reported. Demographic data, as well as potential risk factors such as body mass index, family history of bleeding/clotting disorders, duration of the nonweightbearing period, total tourniquet time, use of contraceptive medication, smoking status, and use of anticoagulants, were collected from the chart and analyzed for correlation with development of DVT. RESULTS: A total of 156 patients were included in this study. Six patients were found to have developed symptomatic DVT during the first 6 weeks after surgery. The mean age at the time of surgery in the DVT group was 34.94 +/- 6.57 years, compared with 26.26 +/- 10.20 years in the non-DVT group (P = .04). Due to the small number of patients with positive findings, there was no statistically significant correlation between the development of DVT and factors such as nonweightbearing duration, tourniquet time, or the use of contraceptives. CONCLUSION: The incidence of postoperative DVT in arthroscopic and sports procedures has been thought to be low. This case series reported a rate of 3.8% with symptomatic DVT after TTO, and patients diagnosed with DVT were significantly older than unaffected patients. It is anticipated that the actual rate including asymptomatic DVT would be higher, as only 60% of patients with DVT are symptomatic. More studies are needed to define the actual incidence in this population. Given the number of common risk factors in this population, including nonweightbearing duration and the use of oral contraceptive pills, future studies may show the advantage of chemical prophylaxis for DVT in this group. PMID- 26535356 TI - Prevalence of Osteochondritis Dissecans of the Capitellum in Young Baseball Players: Results Based on Ultrasonographic Findings. AB - BACKGROUND: Osteochondritis dissecans (OCD) of the capitellum is a well recognized cause of elbow pain and disability in adolescent athletes. However, little is known about the prevalence of OCD in adolescent baseball players. PURPOSE: To determine the prevalence of OCD in baseball players aged 10 to 12 years based on ultrasonographic findings and to investigate the clinical characteristics of those with OCD lesions. STUDY DESIGN: Descriptive epidemiology study. METHODS: A total of 1040 players aged 10 to 12 years completed a questionnaire, ultrasound imaging, and radiographic examination to investigate OCD. Sonographic findings were classified into 5 grades (0, 1a, 1b, 2, and 3). Subjects with grade 1a, 1b, 2, or 3 were considered to have abnormal findings of the capitellum and were advised to undergo radiography. Radiographic and ultrasonographic findings were then compared. The prevalence of OCD was calculated, and differences by age and player position were determined. RESULTS: Of the 1040 players, 33 (3.2%) had an abnormal finding on initial ultrasonography screening, and all 33 agreed to undergo radiography. Of them, 22 (66.7%) were found to have OCD of the capitellum on radiographs, giving an overall prevalence of 2.1%. Seven subjects (31.8%) had no history of elbow pain. Based on the radiographic classification, 20 subjects (90.9%) had stage I lesions. Analysis of OCD by age and player position revealed no significant differences. CONCLUSION: The prevalence of OCD of the capitellum was 2.1% in 1000 baseball players aged 10 to 12 years, with no differences in prevalence according to age or player position. PMID- 26535357 TI - Meniscus Injuries Alter the Kinematics of Knees With Anterior Cruciate Ligament Deficiency. AB - BACKGROUND: Most knee joint biomechanics studies have involved knees with an isolated anterior cruciate ligament (ACL) injury. However, a large portion of patients with injured ACLs have accompanied meniscus tearing. In this study, the in vivo alteration of knee biomechanics after tearing the ACL with or without combined medial or lateral meniscus tear was investigated during stair-ascending activity. HYPOTHESIS: The kinematic behavior of ACL-deficient knees changes with a combined medial or lateral meniscus tear. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-one patients with injured ACLs (contralateral side intact) were recruited before undergoing ACL reconstruction. Among these patients, 5 had isolated ACL injuries (group I), 8 had combined ACL and medial meniscus injuries (group II), and 8 had combined ACL and lateral meniscus injuries (group III). Bilateral magnetic resonance scans were obtained on each patient to construct 3 dimensional anatomic knee models. Both knees were then scanned during stair climbing activity using a dual fluoroscopic imaging system. The knee kinematics during stair climbing were reproduced using a bone model image matching method. Anteroposterior and mediolateral translations and axial tibial rotation of the knee during stair ascent were then compared between the injured and intact contralateral knees of the patients. RESULTS: On average, injured knees in groups I and III showed more than 2 mm increased anterior tibial translation close to full knee extension. In group II, no statistically significant difference was observed between the injured and contralateral side in anteroposterior translation. Near full extension, in groups I and III, injured knees had less than 1 mm of increased medial tibial translation compared with the contralateral side, whereas in group II, a 1.0-mm increase in lateral tibial shift was observed in the injured knees. With regard to axial tibial rotation, group I showed an increased external tibial rotation (approximately 5 degrees ), group II had little variation, whereas group III had increased internal tibial rotation (approximately 3 degrees ). CONCLUSION: The results of this study demonstrate that a combined ACL/meniscus injury could alter the kinematics of ACL-injured knees in a different way compared with knees with isolated ACL tears, depending on the pattern of the meniscus tear. Considering the varying effect of meniscus injuries on knee joint kinematics, future studies might focus on specific treatment of patients with combined ACL and meniscus injuries to protect the joint from abnormal kinematics and subsequent postoperative cartilage degeneration. PMID- 26535358 TI - Delay to Reconstruction of the Adolescent Anterior Cruciate Ligament: The Socioeconomic Impact on Treatment. AB - BACKGROUND: A delay in pediatric and adolescent anterior cruciate ligament (ACL) reconstruction is associated with an increase in the number of concomitant meniscal and chondral injuries. Factors that contribute to this delay have not been well described. HYPOTHESIS: Socioeconomic and demographic factors are related to ACL surgery timing. STUDY METHODS: Cohort study; Level of evidence, 3. METHODS: All subjects who underwent primary ACL reconstruction at a single tertiary pediatric hospital between 2005 and 2012 were retrospectively reviewed. Variables included concomitant knee injuries (cartilage or meniscus injuries requiring additional operative treatment) and chronologic, demographic, and socioeconomic factors. Multivariable Cox proportional-hazards analyses were used to identify factors related to ACL surgery timing. RESULTS: The mean age of the 272 subjects was 15.2 +/- 2.12 years. Time to surgery was significantly different among subjects who required multiple additional surgical procedures at time of ACL reconstruction (median, 3.3 months) compared with subjects with 1 (median, 2.0 months) or no additional injuries (median, 1.6 months). Subjects underwent ACL reconstruction significantly sooner if they were older at the time of injury (hazard ratio [HR], 1.2 per 1 year; 95% CI, 1.1-1.2; P < .0001) or were covered by a commercial insurance plan (HR, 2.0; 95% CI, 1.6-2.6; P < .0001). Median time to ACL surgery was 1.5 months (95% CI, 1.3-1.7) for subjects with commercial insurance plans compared with 3.0 months (95% CI, 2.3-3.3) for subjects with noncommercial insurance coverage. CONCLUSION: The risk of delayed ACL surgery was significantly higher among pediatric and adolescent subjects who were less affluent, who were covered by a noncommercial insurance plan, and who were younger. This study also confirms previous studies that have reported an association between a delay in ACL surgery and the presence of additional knee injuries requiring operative treatment, accentuating the importance of timely care. CLINICAL RELEVANCE: Access to care is a current area of research interest and health policy formation. Information in this arena drives 2 important aspects of health: most immediately, care provided to patients, and over a broader scope, the policy that directs health care. The orthopaedic surgeon should be aware of the association between socioeconomic and demographic factors and ACL surgery timing to optimize outcomes. PMID- 26535359 TI - Performance and Return to Sport After Anterior Cruciate Ligament Reconstruction in National Hockey League Players. AB - BACKGROUND: Anterior cruciate ligament (ACL) rupture is a significant injury in male National Hockey League (NHL) players. PURPOSE: To determine (1) the return to sport (RTS) rate in the NHL following ACL reconstruction, (2) performance on RTS, and (3) the difference in RTS and performance between players who underwent ACL reconstruction and controls. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: NHL players undergoing ACL reconstruction were evaluated. All demographic data were analyzed. Matched controls were selected from the NHL during the same years as those undergoing ACL reconstruction. The "index year" (relative to the number of years of experience in the NHL) in controls was the same as the year that cases underwent ACL reconstruction. RTS and performance in the NHL were analyzed and compared between cases and controls. Student t tests were performed for analysis of within- and between-group variables. Bonferroni correction was used in the setting of multiple comparisons. RESULTS: A total of 36 players (37 knees) meeting the inclusion criteria underwent ACL reconstruction while in the NHL. Thirty-five players were able to RTS in the NHL (97%), and 1 player returned to the international Kontinental Hockey League. Of the players who RTS in the NHL, 100% were able to RTS the season after ACL reconstruction (mean, 7.8 +/- 2.4 months). Length of career in the NHL after ACL reconstruction was 4.47 +/- 3.3 years. The revision rate was 2.5%. There were significantly more cases playing in the NHL at 3 (P = .027) and 4 (P = .029) years following surgery compared with controls (index year). After ACL reconstruction, player performance was not significantly different from preinjury performance. Following ACL reconstruction (or index year in controls), cases played significantly more minutes, took more shots, had better shooting percentages, and scored more goals and points than did controls (P < .01 for all). Control players did not significantly outperform cases after ACL reconstruction in any performance measure. CONCLUSION: There is a high RTS rate in the NHL following ACL reconstruction. All players who RTS did so the season following surgery. Performance following ACL reconstruction was not significantly different from preinjury. Cases performed better than did controls in several performance measures. Controls did not outperform cases in any measured performance variable. PMID- 26535360 TI - Glenoid Bone Loss Measurement in Recurrent Shoulder Dislocation: Assessment of Measurement Agreement Between CT and MRI. AB - BACKGROUND: Shoulder instability can cause both soft tissue injury and bone defects, requiring both computed tomography (CT) and magnetic resonance imaging (MRI) for a thorough workup, which results in high patient costs and radiation exposure. Prior studies in cadaveric and nonclinical models have shown promise in assessing preoperative bone loss utilizing MRI. PURPOSE: To evaluate the utility of MRI in detecting and evaluating glenoid bone defects in a clinical setting. The aim was to establish whether similar information could be determined by utilizing MRI and CT in a population with recurrent instability. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: CT and MRI scans of 22 shoulders were read by 4 orthopaedic surgeons. The CT images were obtained on a 2 dimensional CT scanner. Vertical measurements were taken from the superior glenoid tubercle and directed inferiorly along the glenoid; horizontal measurements were taken across the widest part of the face of the glenoid and were perpendicular within one-half of 1 degrees to the vertical measurement. The same protocol was followed for MRI measurements. An intraclass correlation coefficient (ICC) was calculated. RESULTS: There was a moderate amount of agreement between examiners for the height measurements on MRI (ICC, 0.53) and a substantial agreement for the CT images (ICC, 0.64). The width measurements for MRI had a moderate amount of agreement (ICC, 0.41), while the CT images had a fair agreement (ICC, 0.39). The height measurements between the measurements of MRI and CT images had an overall ICC of 0.43, while the width measurements had an overall ICC of 0.41, both of which were considered a moderate amount of agreement. CONCLUSION: There is moderate correlation between MRI and CT scans when measuring the glenoid, indicating that taking the length-to-height ratio measurements across the glenoid is a promising way to estimate the glenoid defect. At present, a complete workup of a patient with shoulder instability includes both a CT scan and an MRI. Future research that establishes precisely how MRI misestimates CT measurements of the glenoid can perhaps obviate the need for 2 scans. PMID- 26535361 TI - Trends in the Management of Achilles Tendon Ruptures in the United States Medicare Population, 2005-2011. AB - BACKGROUND: Achilles tendon ruptures are one of the most commonly treated injuries by orthopaedic surgeons and general practitioners. Achilles tendon ruptures have classically been thought to affect the middle-aged "weekend warrior" participating in basketball, volleyball, soccer, or any other ground sport that requires speed and agility; however, with a more active elderly population, these tears are becoming more common in older patients. PURPOSE: To report trends in nonoperative and operative treatment of Achilles tendon tears in the United States from 2005 to 2011 in patients registered with a large Medicare database. STUDY DESIGN: Descriptive epidemiological study. METHODS: Patients who underwent nonoperative and operative treatment of Achilles tendon ruptures by either primary repair or primary repair with graft (International Classification of Diseases 9 [ICD-9] diagnosis code 727.67, Current Procedural Terminology [CPT] codes 27650 and 27652) for the years 2005 to 2011 were identified using the PearlDiver Medicare Database. Demographic and utilization data available within the database were extracted for patients who underwent nonoperative as well as operative treatment for Achilles tendon ruptures. Statistical analysis involved Student t tests, chi-square tests, and linear regression analyses, with statistical significance set at P < .05. RESULTS: From 2005 to 2011, there were a total of 14,127 Achilles tendon ruptures. Of these, 9814 were managed nonoperatively, 3531 were treated with primary repair, and 782 were treated with primary repair with graft. The incidence of Achilles tendon increased from 0.67 per 10,000 in 2005 to 1.08 per 10,000 in 2011 (P < .01). There was no significant difference in the number of Achilles ruptures between males (6636) and females (7582) (P > .05). There was an increase in the overall number of Achilles tendon ruptures over time (1689 in 2005 compared with 2788 in 2011; P < .001) but no difference in the percentage of Achilles ruptures treated operatively (P > .05). Older patients were more likely to be treated nonoperatively (P < .05). No differences in operative versus nonoperative treatment were seen between yearly quarter (P > .05), sex (P > .05), or region (P > .05). CONCLUSION: The incidence of Achilles tendon ruptures is increasing with time, but the trend in operative and nonoperative treatment has not changed between 2005 and 2011. Older patients, especially those older than 85 years, are more likely to be treated nonoperatively. No differences in treatment patterns were seen based on sex, region, or yearly quarter. PMID- 26535362 TI - Histological Evaluation of Regenerated Semitendinosus Tendon a Minimum of 6 Years After Harvest for Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Semitendinosus (ST) and/or gracilis (G) autografts are the most used grafts for anterior cruciate ligament (ACL) surgery. The tendons have been shown to be able to regenerate but with focal areas of scar tissue in the short term. There are no long-term histological studies of the regenerated tendons. HYPOTHESIS: In the long term, the regenerated ST tendon normalizes and has a similar histology as the contralateral nonharvested tendon. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: Eighteen patients (8 female, 10 male) who underwent ACL surgery using ipsilateral ST/G tendon autografts were included in this study. Percutaneous specimens were obtained from the regenerated ST tendon and the contralateral nonharvested ST tendon under ultrasonographic guidance at a median of 8.4 years (100.5 months; range, 77-129 months) after the harvest procedure. Specimens from the nonoperated side served as controls. The histology and presence of glycosaminoglycans (GAGs) were assessed using a light microscope and a semiquantitative grading system. RESULTS: Thirty-six biopsies were obtained (2 biopsies from each patient). In 5 biopsies, the amount of tissue was too small to analyze in the light microscope, and 1 patient had been operated on bilaterally and was therefore excluded. In total, 24 biopsies were included in the histological analysis. In overall terms, there were no significant differences between the regenerated and nonharvested ST tendon in terms of fiber structure, cellularity, vascularity, and level of GAGs a minimum 6 years after harvest of the ST tendon. However, 3 of the regenerated tendons displayed a loss of fiber structure. CONCLUSION: The ST tendon regenerates and may regain a histological appearance similar to that of the nonharvested contralateral tendon, as seen in this study a median of 8.4 years after harvesting. However, in some tendons, loss of fiber structure was found. PMID- 26535363 TI - Outcomes of Total Knee Arthroplasty After Osteochondral Allograft Transplantation. AB - BACKGROUND: Fresh osteochondral allograft (OCA) transplantation is an effective treatment for osteochondral defects. Some patients require further surgical intervention, such as total knee arthroplasty (TKA). The effects of prior OCA transplantation on TKA outcomes are unknown. PURPOSE: This study evaluated TKA failure rates after long-term follow-up and identified factors that may have contributed to an inferior outcome. Its aims were to (1) assess if having a prior OCA transplantation would increase the surgical complications of the subsequent TKA, (2) measure the infection and failure rates following TKA, (3) ascertain subjective outcomes scores from patients with intact TKA at latest follow-up, and (4) identify potential factors that contributed to inferior outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 35 patients who underwent TKA after OCA were identified. Pain, symptoms, function, and quality of life were evaluated using the Knee Society Function score and Knee injury and Osteoarthritis Outcome Score (KOOS). Associations between outcomes scores versus total number of surgeries before TKA were assessed using Spearman correlation. Patient characteristics (age, sex, total OCA area, presentation of osteoarthritis, and number of surgeries before TKA) were calculated between failures and nonfailures. RESULTS: For patients with TKA surviving at latest follow-up (n = 24), mean follow-up time was 9.2 +/- 4.3 years after TKA and 16.1 +/- 5.2 years after OCA. While TKA after OCA did not present a technical challenge in the operating room, there was a high failure rate (31.4%). Activities of daily living, as measured on KOOS, were negatively correlated with total number of surgeries before TKA (rho(2) = -0.5, P = .041). Patient age and number of surgeries before TKA influenced the failure rate, while sex and OCA area did not appear to be factors associated with inferior outcomes. CONCLUSION: Patients with multiple knee operations before TKA were more likely to experience functional limitations or TKA failure. The patients who experienced TKA failure were part of a challenging subset of young patients treated with numerous orthopaedic procedures, and while these patients had inferior results with TKA after OCA, the OCA transplantation extended the time before a TKA was required without adding surgical complications. PMID- 26535364 TI - Baseline Neurocognitive Performance in Professional Lacrosse Athletes. AB - BACKGROUND: Concussions have become a major public health concern for both youth and professional athletes. The long-term consequences of concussion can be debilitating or even life threatening. To reduce these concerns, baseline neurocognitive performance can aid decision making in postconcussion recovery and return to play for athletes sustaining concussions. To date, these data are not available for lacrosse athletes. PURPOSE: To present baseline neurocognitive performance for Major League Lacrosse (MLL) players and to determine differences between athletes with and without a history of concussion. STUDY DESIGN: Cross sectional study; Level of evidence, 3. METHODS: A retrospective review was conducted of Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) scores from MLL players who completed baseline testing from June 2010 to June 2011. Inclusion required a valid baseline test and no history of concussion in the 3 months prior to testing. Means +/- standard deviations were computed for all demographic variables and ImPACT composite scores including visual and verbal memory, reaction time, and visual motor processing speed. Independent-samples t tests were used to determine differences between athletes with and without a history of concussion. RESULTS: Valid baseline ImPACT testing was available for 235 MLL athletes (mean age, 25.1 +/- 3.0 years). Forty percent of MLL athletes (n = 94) reported a history of concussion, with 14% of those (n = 13) reporting a history of 3 or more previous concussions. There were no differences on any demographic variables between MLL athletes with and without a history of concussion. MLL athletes with a history of concussion had lower ImPACT composite scores than those without a history of concussion, although only the verbal memory composite was found to be statistically significant (MLL with concussion, 83.2 +/- 10.8 vs MLL without concussion, 86.9 +/- 9.5; P = .007). CONCLUSION: This study establishes baseline ImPACT scores for MLL and demonstrates that athletes with a history of concussion have poorer neurocognitive performance compared with MLL athletes without a history of concussion. CLINICAL RELEVANCE: These data can serve as normative values for subsequent testing following concussion to assess neurocognitive recovery. PMID- 26535365 TI - Impact of Patient Sex on Clinical Outcomes: Data From an Anterior Cruciate Ligament Reconstruction Registry, 2008-2013. AB - BACKGROUND: The Combined Quality Care Anterior Cruciate Ligament registry provides data for clinical research regarding primary anterior cruciate ligament (ACL) surgery. PURPOSE: To explore the data with regard to the clinical outcomes between sexes after ACL reconstruction in a Dutch population. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data involving patients diagnosed with an ACL tear and eligible for surgery were recorded. Isokinetic muscle strength, functional muscle performance, and anterior-posterior translation of the knee joint were documented preoperatively and at 3, 6, 9, and 12 months postoperatively. Patients completed the Knee Injury and Osteoarthritis Outcome Score (KOOS), Lysholm, and Tegner rating scales during each examination using a web-based questionnaire. RESULTS: Approximately 90% of ACL injuries occurred during sport activities. The mean (SD) age at surgery was 28 (11) years for both men and women, and the majority of patients were treated with hamstring tendon autografts (94%). Four percent received bone-patellar tendon-bone autografts, and 2% of the patients received other grafts. Preoperatively, the KOOS, Lysholm, and Tegner scores were significantly higher in males. Twelve months postoperatively, both sexes showed comparable isokinetic strength (P = .336), knee laxity (P = .680), and hop test for distance (P = .122) when comparing the injured with the uninjured side. Self-reported knee function was comparable between sexes as assessed by the KOOS (P = .202), Lysholm (P = .872), and Tegner (P = .767) questionnaires during the 12-month follow-up. CONCLUSION: One year after ACL surgery, all patients had improved greatly, showing only minor differences between sexes. The male group showed slightly better results when evaluating self reported knee questionnaires. Comparable outcomes and knee function between sexes can therefore be presumed with patients who are treated with hamstring tendon autografts in a Dutch population. CLINICAL RELEVANCE: These results can be used during the clinical evaluation of patients who are eligible for ACL reconstruction. PMID- 26535367 TI - Knee Function Assessment in Patients With Meniscus Injury: A Preliminary Study of Reproducibility, Response to Treatment, and Correlation With Patient-Reported Questionnaire Outcomes. AB - BACKGROUND: Outcomes of meniscus surgery are typically assessed with patient questionnaires that help capture symptoms and functional limitations but may not provide an accurate representation of underlying joint health. There are currently no performance-based measures of knee function in patients with symptomatic meniscus injury. PURPOSE: To assess the reproducibility, response to partial meniscectomy, and correlation with patient-reported questionnaire outcomes of novel performance-based knee function tests. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: A battery of 9 tests for activities that require knee movements essential for everyday living was developed. Intra- and interrater reproducibility was assessed in 50 meniscus tear patients completing the battery at 2 preoperative assessments with either the same or different examiners. Response to arthroscopic partial meniscectomy was evaluated in 35 of these patients 6 weeks after surgery. Subjects also completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee (IKDC) questionnaires pre- and postoperatively. RESULTS: The intrarater intraclass correlation coefficients (ICCs) were excellent for all tests (ICC > 0.8). Interrater ICC > 0.8 was observed for step-down, stair descent, star lunges, and timed treadmill travel. Performance on all tests improved significantly with surgery (P < .05), with the greatest improvement in sit-to-stand and stair ascent and descent. A greater percentage response to surgery was seen on questionnaire outcomes (20%-65%) than on performance-based tests (3%-15%). Moderate to poor correlations existed between the KOOS activities of daily living subscale and the performance-based tests (all ICCs <= 0.4). CONCLUSION: Performance-based knee function tests demonstrated good reproducibility and responsiveness in patients undergoing partial meniscectomy. CLINICAL RELEVANCE: As both patient perception and functional performance are determinants of patient outcomes, questionnaires and performance-based tests could be used simultaneously to provide complementary data to monitor short- and long-term outcomes after meniscus surgery. PMID- 26535366 TI - Clinical Outcome 3 Years After Autologous Chondrocyte Implantation Does Not Correlate With the Expression of a Predefined Gene Marker Set in Chondrocytes Prior to Implantation but Is Associated With Critical Signaling Pathways. AB - BACKGROUND: There is a need for tools to predict the chondrogenic potency of autologous cells for cartilage repair. PURPOSE: To evaluate previously proposed chondrogenic biomarkers and to identify new biomarkers in the chondrocyte transcriptome capable of predicting clinical success or failure after autologous chondrocyte implantation. STUDY DESIGN: Controlled laboratory study and case control study; Level of evidence, 3. METHODS: Five patients with clinical improvement after autologous chondrocyte implantation and 5 patients with graft failures 3 years after implantation were included. Surplus chondrocytes from the transplantation were frozen for each patient. Each chondrocyte sample was subsequently thawed at the same time point and cultured for 1 cell doubling, prior to RNA purification and global microarray analysis. The expression profiles of a set of predefined marker genes (ie, collagen type II alpha1 [COL2A1], bone morphogenic protein 2 [BMP2], fibroblast growth factor receptor 3 [FGFR3], aggrecan [ACAN], CD44, and activin receptor-like kinase receptor 1 [ACVRL1]) were also evaluated. RESULTS: No significant difference in expression of the predefined marker set was observed between the success and failure groups. Thirty nine genes were found to be induced, and 38 genes were found to be repressed between the 2 groups prior to autologous chondrocyte implantation, which have implications for cell-regulating pathways (eg, apoptosis, interleukin signaling, and beta-catenin regulation). CONCLUSION: No expressional differences that predict clinical outcome could be found in the present study, which may have implications for quality control assessments of autologous chondrocyte implantation. The subtle difference in gene expression regulation found between the 2 groups may strengthen the basis for further research, aiming at reliable biomarkers and quality control for tissue engineering in cartilage repair. CLINICAL RELEVANCE: The present study shows the possible limitations of using gene expression before transplantation to predict the chondrogenic and thus clinical potency of the cells. This result is especially important as the chondrogenic potential of the chondrocytes is currently part of quality control measures according to European and American legislations regarding advanced therapies. PMID- 26535368 TI - Trends in Anterior Cruciate Ligament Reconstruction in the United States. AB - BACKGROUND: The anterior cruciate ligament (ACL) is the most frequently injured ligament in the knee for which surgery is performed. United States national estimates of ACL reconstruction vary widely. PURPOSE: This study sought to use the most recently available Centers for Disease Control and Prevention data to investigate changes in the utilization of inpatient and ambulatory surgery for ACL tears in the United States. STUDY DESIGN: Descriptive epidemiology study. METHODS: The National Survey of Ambulatory Surgery, conducted in 1994, 1995, 1996, and 2006 (data from 1994, 1996, and 2006 were used in the study), and the National Hospital Discharge Survey, conducted between 1990 and 2007, were used to identify cases of ACL reconstruction. The data were analyzed for trends in demographics, treatment, and utilization. RESULTS: Between 1994 and 2006, the population-adjusted estimate of the rate of ACL reconstructions increased by 37% (33.0/100,000 capita or 86,837 total procedures to 45.1/100,000 capita or 134,421 total procedures). There was an increase in the proportion of females undergoing reconstruction in both the ambulatory (30% to 40%) and inpatient (29% to 47%) settings over the study period, with a 304% increase in the sex-adjusted estimate of the rate of female ambulatory procedures between 1994 and 2006. Age-adjusted estimates of the rates of ambulatory ACL reconstruction increased among all age groups, with a 924% increase in patients less than 15 years of age. Concurrent meniscectomy remained relatively constant in the ambulatory (37% to 40%) and inpatient (37% to 33%) settings between 1994 and 2007. Private insurance was the largest compensator, representing 77% of cases in 2006. Between 1994 and 2006, the use of peripheral nerve blocks during ambulatory surgery increased from 0.7% to 30.8%. CONCLUSION: The rate of ACL reconstruction increased dramatically between 1990 and 2007 based on the National Survey of Ambulatory Surgery and National Hospital Discharge Survey databases, which represents the most up-to date publicly available data. Knowledge of this increase and national practice patterns may aid policy makers and surgeons in appropriately allocating health care resources to ensure quality patient care. PMID- 26535369 TI - The Current State of Head and Neck Injuries in Extreme Sports. AB - BACKGROUND: Since their conception during the mid-1970s, international participation in extreme sports has grown rapidly. The recent death of extreme snowmobiler Caleb Moore at the 2013 Winter X Games has demonstrated the serious risks associated with these sports. PURPOSE: To examine the incidence and prevalence of head and neck injuries (HNIs) in extreme sports. STUDY DESIGN: Descriptive epidemiological study. METHODS: The National Electronic Injury Surveillance System (NEISS) was used to acquire data from 7 sports (2000-2011) that were included in the Winter and Summer X Games. Data from the NEISS database were collected for each individual sport per year and type of HNI. Cumulative data for overall incidence and injuries over the entire 11-year period were calculated. National estimates were determined using NEISS-weighted calculations. Incidence rates were calculated for extreme sports using data from Outdoor Foundation Participation Reports. RESULTS: Over 4 million injuries were reported between 2000 and 2011, of which 11.3% were HNIs. Of all HNIs, 83% were head injuries and 17% neck injuries. The 4 sports with the highest total incidence of HNI were skateboarding (129,600), snowboarding (97,527), skiing (83,313), and motocross (78,236). Severe HNI (cervical or skull fracture) accounted for 2.5% of extreme sports HNIs. Of these, skateboarding had the highest percentage of severe HNIs. CONCLUSION: The number of serious injuries suffered in extreme sports has increased as participation in the sports continues to grow. A greater awareness of the dangers associated with these sports offers an opportunity for sports medicine and orthopaedic physicians to advocate for safer equipment, improved on site medical care, and further research regarding extreme sports injuries. PMID- 26535370 TI - Autologous Hamstring Anterior Cruciate Ligament Graft Failure Using the Anteromedial Portal Technique With Suspensory Femoral Fixation: A Case Series of 7 Patients. AB - BACKGROUND: The anteromedial portal technique for drilling of the femoral tunnel during anterior cruciate ligament (ACL) reconstruction has been advocated by many surgeons as allowing improved access to the anatomical footprint. Furthermore, suspensory fixation of soft tissue grafts has become popularized because of complications associated with cross-pin fixation. Concerns regarding the use of both have recently arisen. PURPOSE: To raise awareness of the increased risk of graft failure when using the anteromedial portal technique with suspensory femoral fixation during ACL reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: From November 1998 to August 2012, a total of 465 primary ACL reconstructions were performed using quadrupled hamstring autograft tendons, with drilling of the femoral tunnel performed via the transtibial portal. Graft fixation on the femur was achieved with cross-pin fixation, while interference screw fixation was used on the tibia. From September 2012 to October 2013, there were 69 reconstructions performed through an anteromedial portal. While there was no change in graft choice, a change was made to using suspensory femoral fixation. No other surgical or postoperative rehabilitation changes were made. RESULTS: During the 14-year period in which ACL reconstructions were performed via the transtibial portal and with cross-pin fixation, 2 graft failures (0.4% failure rate) were reported. After switching to the anteromedial portal with suspensory fixation, 7 graft failures (10.1% failure rate) were reported over a 13-month period. These were 5 male and 2 female patients, with a mean age of 18.8 years-all elite athletes. The same surgical technique was used in all patients, and all patients had at least an 8 mm-diameter graft. Patients were cleared to return to sport at an average of 8.4 months postoperatively, after completing functional performance tests. Of the 7 patients, 6 sustained a rerupture of the graft within 2 weeks of returning to full competition. The final patient sustained a rerupture 10 months after being cleared to play. CONCLUSION: Compared with the transtibial technique with cross-pin graft fixation, there is an increased risk of graft failure when performing autologous hamstring ACL reconstructions using the anteromedial portal technique with cortical suspensory fixation. PMID- 26535371 TI - A Preseason Checklist for Predicting Elbow Injury in Little League Baseball Players. AB - BACKGROUND: Despite pitch count limits, the incidence of Little League elbow is increasing. A risk-evaluation tool capable of predicting which players are predisposed to throwing injury could potentially prevent injuries. PURPOSE: To investigate the effectiveness of a risk factor checklist for predicting elbow injury in Little League baseball players during 1 season. The hypothesis was that a preseason risk-evaluation checklist could predict which players were predisposed to elbow injury. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A preseason risk-evaluation checklist was distributed to Little League baseball teams in Japan. Six months later, a follow-up questionnaire was mailed to determine injuries sustained during the season. Logistic regression analysis was performed, assigning presence or absence of elbow injury during the season as the dependent variable, and an injury risk score (IRS) was developed based on the statistically significant variables. Receiver operating characteristic (ROC) curve analysis was conducted to determine the predictive validity of the checklist and the optimal cutoff IRS. RESULTS: Data from 389 Little League players were analyzed. Among them, 53 players experienced an elbow injury requiring medical treatment during the season. Six checklist items associated with a medical history of throwing injury, pitch volume, and arm fatigue were found to be significant. Responses to the items could predict the players who were susceptible to injury during the season, with a two-thirds cutoff value for a 6-item checklist (area under the curve, 0.810; sensitivity, 0.717; specificity, 0.771). CONCLUSION: Results from a 6-item preseason checklist can predict which Little League players are to sustain an elbow injury by the end of the season. CLINICAL RELEVANCE: The ability to predict which Little League baseball players are predisposed to elbow injury allows parents and coaches to initiate preventive measures in those players prior to and during the baseball season, which could lead to fewer elbow injuries. PMID- 26535372 TI - Surface Electromyography of the Forearm Musculature During the Windmill Softball Pitch. AB - BACKGROUND: Previous studies investigating the windmill softball pitch have focused primarily on shoulder musculature and function, collecting limited data on elbow and forearm musculature. Little information is available in the literature regarding the forearm. This study documents forearm muscle electromyographic (EMG) activity that has not been previously published. PURPOSE: Elbow and upper extremity overuse injuries are on the rise in fast-pitch softball pitchers. This study attempts to describe forearm muscle activity in softball pitchers during the windmill softball pitch. Overuse injuries can be prevented if a better understanding of mechanics is defined. STUDY DESIGN: Descriptive laboratory study. METHODS: Surface EMG and high-speed videography was used to study forearm muscle activation patterns during the windmill softball pitch on 10 female collegiate-level pitchers. Maximum voluntary isometric contraction of each muscle was used as a normalizing value. Each subject was tested during a single laboratory session per pitcher. Data included peak muscle activation, average muscle activation, and time to peak activation for 6 pitch types: fastball, changeup, riseball, curveball, screwball, and dropball. RESULTS: During the first 4 phases, muscle activity (seen as signal strength on the EMG recordings) was limited and static in nature. The greatest activation occurred in phases 5 and 6, with increased signal strength, evidence of stretch-shortening cycle, and different muscle characteristics with each pitch style. These 2 phases of the windmill pitch are where the arm is placed in the 6 o'clock position and then at release of the ball. The flexor carpi ulnaris signal strength was significantly greater than the other forearm flexors. Timing of phases 1 through 5 was successively shorter for each pitch. There was a secondary pattern of activation in the flexor carpi ulnaris in phase 4 for all pitches except the fastball and riseball. CONCLUSION: During the 6 pitches, the greatest muscular activity was in phases 5 and 6. Flexor carpi ulnaris activity was greatest among the muscles tested. The riseball had the highest peak activity, but the curveball and dropball had the highest average signal strength. This muscle activity correlates with increasing distraction in the elbow, suggesting that flexor muscles act to counterdistract the elbow as they do for the baseball pitch. CLINICAL RELEVANCE: Windmill pitchers are unique among overhead athletes as they throw, on average, more pitches per overhead athlete. Understanding the mechanics and physiology of the elbow in windmill pitchers is crucial to prevention and treatment of these increasingly common elbow injuries. This study establishes baseline data that will be useful to further prevent windmill pitch elbow injury. PMID- 26535373 TI - Troubleshooting the Femoral Attachment During Medial Patellofemoral Ligament Reconstruction: Location, Location, Location. AB - The medial patellofemoral ligament (MPFL) has been recognized as an important soft tissue restraint in preventing lateral patellar translation. As many patients with acute or chronic patellar instability will have a deficient MPFL, reconstruction of this ligament is becoming more common. Appropriately, significant research has been undertaken regarding graft biomechanics and techniques, as intraoperative errors in graft placement often result in poor patient outcomes. Although the research has not answered all of the dilemmas encountered during reconstruction, publications consistently emphasize the importance of re-establishing an anatomic femoral attachment. The purpose of this study was to briefly review the current literature on MPFL reconstruction. Graft selection and patellar graft attachment and fixation are discussed, but the main focus is the femoral attachment as this is where most errors are seen and, unfortunately, where getting it right appears to matter the most. Using a sawbones knee model, the concepts of an MPFL graft that is "high and tight" or "low and loose" are presented, with the goal of providing physicians with intraoperative tools to adjust an incorrectly placed femoral MPFL attachment. This model is also used to justify the recommendation of graft fixation in 30 degrees to 45 degrees of knee flexion. PMID- 26535374 TI - Arthroscopic Versus Open Stabilization for Anterior Shoulder Subluxations. AB - BACKGROUND: Most of the literature on shoulder instability focuses on patients experiencing anterior glenohumeral dislocation, with little known about the treatment of anterior subluxation events. PURPOSE: To determine the outcomes of surgical stabilization of patients with anterior glenohumeral subluxations and to compare open and arthroscopic approaches. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: We prospectively enrolled patients with anterior glenohumeral subluxations undergoing surgical stabilization. Patients were offered randomization between open and arthroscopic stabilization. Inclusion criteria included patients with anterior glenohumeral subluxations undergoing Bankart repair, while exclusions included the presence of glenoid or humeral bone loss, multidirectional instability, capsular tear/humeral avulsion of the glenohumeral ligament lesion, and rotator cuff tear requiring repair. Patients were randomized to an open Bankart repair through a subscapularis takedown or an arthroscopic Bankart repair, both using the same bioabsorbable suture anchors, and they were followed for a minimum of 2 years. Outcomes were evaluated with the Single Assessment Numeric Evaluation (SANE), Western Ontario Shoulder Instability Index (WOSI), American Shoulder and Elbow Surgeons Score (ASES), Simple Shoulder Test (SST), Rowe, and Tegner activity scores. RESULTS: A total of 26 patients were enrolled, with 7 being lost to follow-up. Complete follow-up data were available on 19 subjects (74%): 10 in the open group and 9 in the arthroscopic group. There were no significant differences noted between the randomized groups, with a 2-year WOSI score of 320 in the open subjects and 330 in the arthroscopic subjects, and similar findings in the other scoring scales. There were no cases of dislocation following surgery. There were 3 patients with recurrent instability (subluxations only) in each group at a mean of 17 months, for an overall recurrent subluxation rate of 31%. These subjects with recurrence had lower outcome scores (WOSI, 532; SANE, 88.4). The outcomes of the 9 subjects with <=3 subluxation events were superior to those of the 10 subjects with >3 events prior to stabilization. The patients with <=3 events had a WOSI score of 143, compared with 470 (P = .042), and an ASES mean score of 98.8, compared with 87.1 (P = .048). Four of the 6 patients with recurrent subluxations had sustained >3 subluxations prior to stabilization. CONCLUSION: Overall, patients with Bankart lesions resulting from an anterior glenohumeral subluxation event had excellent outcomes with surgical stabilization. The overall recurrence in the 19 subjects with at least 2-year follow-up was 6 cases (31%), with no instances of dislocation in this young, active cohort. There was no significant benefit to open or arthroscopic stabilization, and we did find that stabilization of subluxation patients with <=3 events resulted in superior outcomes compared with chronic recurrent subluxation patients with >3 events. We recommend early surgical stabilization of young athletes with Bankart lesions that result from anterior subluxation events. PMID- 26535375 TI - Arthroscopic Rotator Cuff Repair Using the Undersurface Technique: A 2-Year Comparative Study in 257 Patients. AB - BACKGROUND: Arthroscopic rotator cuff repair has traditionally been performed in the subacromial space from the bursal side of the tendon. The undersurface rotator cuff repair technique involves the arthroscope remaining in the glenohumeral joint, thus viewing the tendon from its undersurface during repair without a bursectomy or acromioplasty. PURPOSE: To compare the clinical and structural outcomes of undersurface rotator cuff repair with bursal-side repair. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective analysis of prospectively collected data was conducted on 2 cohorts of patients who had undergone arthroscopic rotator cuff repair with knotless suture anchors configured in a single-row formation using inverted mattress-style sutures from either the bursal side (n = 100) or undersurface (n = 165) of the supraspinatus tendon. Data were collected preoperatively, intraoperatively, and at 1 week, 6 weeks, 3 months, 6 months, and 2 years postoperatively. At each time point, patients completed a modified L'Insalata questionnaire to assess patient-ranked pain scores and were clinically examined using standardized tests. Ultrasound examination was performed at 6 months and 2 years to assess the integrity of the repair. RESULTS: At 2 years postoperatively, patients in both cohorts had significantly less pain and less difficulty with overhead activities compared with preoperative levels (P < .001). The type of repair performed (bursal or undersurface) did not affect the ability to perform overhead activities at 2 years. At 2 years, both groups also had similar retear rates (21% for bursal side, 23% for undersurface). The mean operative time for the arthroscopic rotator cuff repair was 32 minutes when performed from the bursal side and 20 minutes when performed from the undersurface (P < .001). CONCLUSION: Arthroscopic rotator cuff repair, whether performed from the subacromial space or glenohumeral joint, resulted in decreased levels of pain and difficulty with overhead activities at 2 years. The major difference between the 2 techniques was operative time, with the undersurface technique being performed significantly faster than the bursal-side repair technique. PMID- 26535376 TI - Surgical Management of Recurrent Musculotendinous Hamstring Injury in Professional Athletes. AB - BACKGROUND: Hamstring injury is the most common muscular lesion in athletes. The conservative treatment is well described, and surgical management is often indicated for proximal tendinous avulsions. To our knowledge, no surgical treatment has been proposed for failure of conservative treatment in musculotendinous hamstring lesions. PURPOSE: To describe the surgical management of proximal and distal hamstring musculotendinous junction lesions in professional athletes after failure of conservative treatment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A consecutive series of 10 professional athletes, including 4 soccer players, 4 rugby players, and 2 handball players, underwent surgical intervention between October 2010 and June 2014 for the treatment of recurrent musculotendinous hamstring injuries. All athletes had failed at least 3 months of conservative treatment for a recurrent musculotendinous hamstring injury. Surgical resection of the musculotendinous scar tissue was performed using a longitudinal muscular suture. Lower Extremity Functional Scale (LEFS) and Marx scores were obtained at the 3-month follow-up, and a final phone interview was completed to determine recurrence of hamstring injury and return to previous level of play. RESULTS: The mean age at surgery was 25.2 years (range, 19-35 years). The musculotendinous hamstring lesions involved 8 semitendinosus and 2 biceps femoris, with 6 injuries located proximally and 4 distally. Conservative treatment lasted a mean 5.1 months (range, 3-9 months) after last recurrence, and the patients had an average of 2.7 (range, 2-5) separate incidents of injury recurrence before surgical intervention was decided upon. At the 3-month follow-up, all patients had Marx activity scores of 16 and LEFS scores of 80. All 10 patients returned to the same level of play at a mean 3.4 months (range, 2-5 months). At a mean follow-up of 28.7 months, none of the athletes had suffered a recurrence. No surgical complication was encountered. CONCLUSION: In cases of failed conservative treatment of musculotendinous hamstring lesions, surgical intervention may be a viable treatment option in professional athletes and allows the patient to return to the same level of play. PMID- 26535377 TI - Predictors for Surgery in Shoulder Instability: A Retrospective Cohort Study Using the FEDS System. AB - BACKGROUND: Shoulder instability is a common cause of pain and dysfunction in young, active patients. While studies have analyzed risk factors for recurrent instability and failure after instability surgery, few have examined which variables are associated with initial surgery in this patient population. PURPOSE: To identify variables that may be associated with surgical intervention in patients with shoulder instability in the context of the FEDS (frequency, etiology, direction, severity) classification, a system that may be useful in the surgical treatment of shoulder instability patients. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: A database of patients treated for shoulder instability from 3 separate institutions from 2005 to 2010 was generated using International Classification of Diseases-9th Revision data. Data were collected via retrospective review. Injury data were categorized according to the FEDS system. Data were analyzed for significance, with the primary outcome of surgical intervention. Summary statistics were used to assess which variables were associated with eventual surgery. To test the unadjusted bivariate associations between shoulder surgery and each data point, Pearson chi-square tests were used for categorical variables and Wilcoxon tests were used for continuous variables. RESULTS: Over the study time period, 377 patients were treated for shoulder instability. Patients who had surgery were more likely younger, had recurrent instability, and had their initial injury while playing a sport. Most patients had anterior instability; however, there was a greater proportion of posterior instability patients in the operative group. Severity of dislocation, measured by whether the patient required help to relocate the shoulder, was not significantly associated with eventual surgery. While imaging was not available for all patients, surgical patients were more likely to have magnetic resonance imaging findings of anterior labral injury and less likely to have a supraspinatus or subscapularis tear. CONCLUSION: Patients who underwent surgery for shoulder instability were younger, more likely to have experienced recurrent instability, and more likely to have sustained their original injury while playing sports. The FEDS classification, particularly the frequency and etiology of the patient's shoulder instability, may be helpful in identifying patients with a higher likelihood of undergoing surgical treatment. PMID- 26535378 TI - Recurrent Fracture After Anterior Tension Band Plating With Bilateral Tibial Stress Fracture in a Basketball Player: A Case Report. PMID- 26535379 TI - Good Results After Hip Arthroscopy for Femoroacetabular Impingement in Top-Level Athletes. AB - BACKGROUND: Femoroacetabular impingement (FAI) is a common cause of hip pain and dysfunction among athletes. Although arthroscopic surgery is an established treatment option for FAI, there are few studies reporting detailed outcomes using validated outcome measurements specifically designed for young and active athletes. PURPOSE: To report outcomes 1 year after arthroscopic treatment of FAI in top-level athletes using validated outcome measurements adapted for a young and active population. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 85 top-level athletes (68 males, 17 females) with a mean (+/-SD) age of 25 +/- 5 years underwent arthroscopic surgery for FAI. All athletes who reported Hip Sports Activity Scale (HSAS) levels 7 or 8 (range, 0-8) prior to symptom onset were included. The cohort was prospectively evaluated using online web-based validated health-related patient-reported outcomes measures (HR-PROMs), including the short version of the International Hip Outcome Tool (iHOT-12), the Copenhagen Hip and Groin Outcome Score (HAGOS; 6 subscales), the EuroQOL 5 dimensions questionnaire (EQ-5D; 2 subscales), the Hip Sports Activity Scale (HSAS) for physical activity level, and a visual analog scale (VAS) for overall hip function. Furthermore, patients reported their overall satisfaction with treatment. RESULTS: The mean follow-up time was 12.3 +/- 0.6 months. Preoperative scores compared with those obtained at the 12-month follow-up revealed statistically and clinically significant improvements (P < .0001) for all measured outcomes: iHOT-12 (42 vs 73), VAS for global hip function (52 vs 77), HSAS (4.3 vs 5.7), EQ-5D index (0.60 vs 0.83), EQ-VAS (68 vs 82), and HAGOS subscales (60 vs 83, 50 vs 73, 66 vs 86, 39 vs 75, 27 vs 70, and 34 vs 67). At the 12-month follow-up, 79 athletes (93%) reported that they were satisfied with the outcome of surgery. At follow-up, 62 athletes (73%) had returned to competitive sports (HSAS levels 5-8) and 44 (52%) to their previous HSAS level of activity (HSAS level 7 or 8). Twenty-three athletes (27%) did not return to competitive sports (HSAS level <=4). Significantly lower levels of return to sports were seen with longer symptom duration (P < .05). CONCLUSION: Twelve months after surgery, arthroscopic treatment for FAI in top-level athletes resulted in statistically and clinically significant improvements at the group level in all outcome parameters for pain, symptoms, function, physical activity level, quality of life, and general health. One year after surgery, approximately 3 of 4 top-level athletes had returned to sports. PMID- 26535380 TI - Development of a Large Animal Model of Osteochondritis Dissecans of the Knee: A Pilot Study. AB - BACKGROUND: Treatment of osteochondritis dissecans (OCD) of the knee is challenging, and evidence for stage-dependent treatment options is lacking. Basic science approaches utilizing animal models have provided insight into the etiology of OCD but have yet to produce a reliable and reproducible large animal model of the disease on which to test new surgical strategies. PURPOSE/HYPOTHESES: The purpose of this study was to develop an animal model featuring an OCD-like lesion in terms of size, location, and International Cartilage Repair Society (ICRS) grading. The hypothesis was that surgical creation of an osteochondral defect followed by placement of a barrier between parent bone and progeny fragment would generate a reproducible OCD-like lesion. STUDY DESIGN: Controlled laboratory study. METHODS: Bilateral osteochondral lesions were created in the medial femoral condyles of 9 Yucatan minipigs. After lesion creation, a biodegradable membrane was interposed between the progeny and parent bone. Five different treatment groups were evaluated at 2 weeks: a control with no membrane (ctrl group; n = 4), a slowly degrading nanofibrous poly(? caprolactone) membrane (PCL group; n = 4), a fenestrated PCL membrane with 1.5-mm holes covering 25% of surface area (fenPCL group; n = 4), a collagen membrane (Bio-Gide) (CM group; n = 3), and a fenestrated CM (fenCM group; n = 3). Five unperturbed lateral condyles (1 from each treatment group) served as sham controls. After euthanasia on day 14, the lesion was evaluated by gross inspection, fluoroscopy, micro-computed tomography (micro-CT), and histology. To quantify changes between groups, a scoring system based on gross appearance (0 2), fluoroscopy (0-2), and micro-CT (0-6) was established. Micro-CT was used to quantify bone volume per total volume (BV/TV) in a defined region surrounding and inclusive of the defect. RESULTS: The no scaffold group showed healing of the subchondral bone at 2 weeks, with continuity of subchondral bone elements. Conversely, condyles treated with PCL or CM showed substantial remodeling, with loss of bone in both the progeny fragment and surrounding parent bone. When these membranes were fenestrated (fenPCL and fenCM groups), bone loss was less severe. Histological analysis showed no integration in the cartilage layer in any treatment group, while fibrous tissue formed between the parent and progeny fragments. Micro-CT showed significant differences in mean BV/TV between the PCL (27.4% +/- 2.3%) and the sham (47.7% +/- 1.4%) or no scaffold (54.9% +/- 15.1%) groups (P < .01 and P < .05, respectively). In addition, a significant difference in bone loss was evident between the PCL and fenPCL groups (mean BV/TV, 46.6% +/- 15.2%; P < .05), as well as between the PCL and fenCM (mean BV/TV, 50.9% +/- 3.5%) and fenPCL groups (P < .01). Grading by 6 blinded reviewers using an OCD scoring system with 3 subcategories showed a significant difference between control and PCL groups. CONCLUSION: This study successfully developed a large animal model of OCD-like lesions in the knee joint of Yucatan minipigs. The lesions generated matched characteristics of an ICRS grade 3 OCD lesion in humans. These findings set the stage for ongoing model refinement as well as exploration of novel interventional therapies to restore function and bone and cartilage patency in individuals affected by this rare but significant disease. CLINICAL RELEVANCE: This developed model will serve as a platform on which to further investigate the natural course as well as emerging treatment options for OCD. PMID- 26535381 TI - Reconstruction of the Posterolateral Corner After Sequential Sectioning Restores Knee Kinematics. AB - BACKGROUND: Various surgical techniques to treat posterolateral knee instability have been described. To date, the recommended treatment is an anatomic form of reconstruction in which the 3 key structures of the posterolateral corner (PLC) are addressed: the popliteofibular ligament, the popliteus tendon, and the lateral collateral ligament. PURPOSE/HYPOTHESIS: The purpose of this study was to identify the role of each key structure of the PLC in kinematics of the knee and to biomechanically analyze a single-graft, fibular-based reconstruction that replicates the femoral insertions of the lateral collateral ligament and popliteus to repair the PLC. The hypothesis was that knee kinematics can be reasonably restored using a single graft with a 2-strand "modified Larson" technique. STUDY DESIGN: Descriptive laboratory study. METHODS: Eight fresh frozen cadaveric knees were used in this study. We conducted sequential sectioning of the popliteofibular ligament (PFL) and then subsequently the popliteal tendon (PT), the lateral collateral ligament (LCL), and the anterior cruciate ligament (ACL). We then reconstructed the ACL first and then the posterolateral corner using the modified Larson technique. A surgical navigation system was used to measure varus laxity and external rotation at 0 degrees , 30 degrees , 60 degrees , and 90 degrees with a 9.8-N.m varus stress and 5-N.m external rotation force applied to the tibia. RESULTS: In extension, varus laxity increased only after the sectioning of the lateral collateral ligament. At 30 degrees of flexion, external rotation in varus and translation of the lateral tibial plateau increased after the isolated popliteofibular ligament section. From 60 degrees to 90 degrees of flexion, translation and mobility of the lateral plateau section increased after sectioning of the PFL. After reconstruction, we observed a restoration of external varus rotation in extension and translation of the lateral tibial plateau at 90 degrees of flexion. This technique provided kinematics similar to the normal knee. CONCLUSION: The PFL has a key role between 30 degrees and 90 degrees of flexion, and the lateral collateral ligament plays a role in extension. Reconstruction with the modified Larson technique restores these 2 complementary stabilizers of the knee. CLINICAL RELEVANCE: Although there are many different techniques to reconstruct the PLC deficient knee, this study indicates that a single-graft, fibular-based reconstruction of the LCL and PT may restore varus and external rotation laxity to the knee. PMID- 26535382 TI - Biceps Tenotomy Versus Tenodesis in Active Patients Younger Than 55 Years: Is There a Difference in Strength and Outcomes? AB - BACKGROUND: Proximal biceps pathology is a significant factor in shoulder pain. Surgical treatment options include biceps tenotomy and subpectoral biceps tenodesis. Tenotomy is a simple procedure, but it may produce visible deformity, subjective cramping, or loss of supination strength. Tenodesis is a comparatively technical procedure involving a longer recovery, but it has been hypothesized to achieve better outcomes in younger active patients (<55 years). HYPOTHESIS: This study investigated the outcomes of younger patients who underwent either a biceps tenotomy or tenodesis as part of treatment for shoulder pain. The hypothesis was that, apart from cosmetic deformity, there will be no difference in outcome between the 2 treatment options. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Isometric strength and endurance testing of operative and nonoperative shoulders for forearm supination (FS) and elbow flexion (EF) were tested utilizing an isometric dynamometer. Objective physical assessment was also performed. Subjective outcomes using the modified American Shoulder and Elbow Surgeons score (ASES); Disability of the Arm, Shoulder, and Hand (DASH); visual analog scale (VAS); and perceived biceps symptoms were collected. RESULTS: A total of 42 patients (22 tenotomy, 20 tenodesis) with an average follow-up of 3.3 years were studied. The average age at follow-up was 49.9 years. Thirty-five percent (7/20) of tenotomy patients exhibited a "Popeye" deformity, compared with 18.2% (4/22) of tenodesis patients. Strength prior to fatiguing exercise was similar between tenodesis and tenotomy for FS (6.9 vs 7.3 lbs; P < .05), EF in neutral (35.4 vs 35.4 lbs), and EF in supination (33.8 vs 34.2 lbs). Strength was not significantly different between groups for isometric strength and endurance measures. Subjective functional outcome measured by the DASH, ASES, and VAS scores were similar between groups. Frequency of complaints of cramping was higher in the tenotomy group (4/20 vs 1/22), and complaints of pain were higher in the tenodesis group (11/22 vs 5/20). CONCLUSION: Despite increased demands and activity placed on biceps function in a younger population, this study showed no differences in functional and subjective outcome measurements. The choice between biceps tenotomy and tenodesis for pathology of the proximal biceps tendon can continue to be based on surgeon and patient preference. PMID- 26535383 TI - Clinical Features That Predict the Need for Operative Intervention in Gluteus Medius Tears. AB - BACKGROUND: Gluteus medius tears are a common cause of lateral hip pain. Operative intervention is usually prescribed for patients with pain despite physical therapy and/or peritrochanteric injections. PURPOSE: To identify clinical features that predict operative intervention in gluteus medius tears. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: A matched-pair controlled study was conducted on patients who underwent endoscopic gluteus medius repairs from June 2008 to August 2014 for full-thickness tears. The exclusion criterion was previous hip disorders (eg, Legg-Calve-Perthes disease, avascular necrosis). The control group contained patients with full-thickness gluteus medius tears on magnetic resonance imaging (MRI) who did not require operative intervention. Both groups had a minimum trial of 3 months of nonoperative management. Matching criteria included age within 5 years, sex, and body mass index (BMI) class. The following clinical parameters were analyzed: presence of lateral-sided hip pain, duration of symptoms, power of resisted hip abduction, gait deviation (antalgic or Trendelenburg), greater trochanter tenderness, and hip passive range of abduction. RESULTS: Twenty-four patients who underwent isolated endoscopic gluteus medius repairs were identified; all patients were females, with a mean age of 65 years (range, 52-82 years) and mean BMI of 29.2 kg/m(2) (range, 21.55-44.398 kg/m(2)). The matched control cohort contained 12 females treated nonoperatively for gluteus medius tears with mean age of 66 years (range, 52-81 years) and mean BMI of 29.9 kg/m(2) (range, 20.20 43.59 kg/m(2)). There were significant differences between the groups in power of resisted abduction and presence of gait deviation. The operative cohort had a mean power grading of 3.63 (95% CI, 3.28-3.98) compared with 4.58 (95% CI, 4.29 4.87) for the matched cohort (P < .05). Abnormal gait was found in 75% of the operative cohort, compared with 33% of the matched cohort (P < .05). Specifically, 83.3% of the surgical cohort had a Trendelenburg gait, compared with 25% of the matched cohort (P = .002). The odds of requiring surgical intervention was 14-fold higher for patients with a gluteus medius tear and gait deviation compared with those without gait deviation. There were no significant differences in the other parameters. CONCLUSION: Reduced power of resisted abduction and the presence of gait deviation on initial evaluation of patients with gluteus medius tears increases the likelihood of surgical intervention. PMID- 26535384 TI - Sex-Specific Predictors of Intra-articular Injuries Observed During Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Male patients tend to have more meniscal and chondral injuries at the time of anterior cruciate ligament (ACL) reconstruction than females. No studies have examined sex-specific predictors of meniscal and chondral lesions in ACL injured patients. PURPOSE: To identify sex-specific predictors of meniscal and chondral lesions, as well as meniscal tear management, in patients undergoing ACL reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data were collected prospectively from 689 patients (56.2% males) undergoing ACL reconstruction between 2005 and 2014. Predictors of meniscal tears, meniscal tear management, and chondral injuries were determined using multivariate logistic regression models stratified by sex. Predictors were age, body mass index (BMI; 25-29.99 and >=30 vs <=24.99 kg/m(2)), mechanism (contact vs noncontact) and type (high-impact sports [basketball, football, soccer, and skiing] and other sports vs not sports-related) of injury, interval from injury to surgery (<=6 vs >6 weeks), and instability episodes (vs none). Odds ratios and 95% CIs were reported. RESULTS: Males had more lateral (46% vs 27.8%; P < .0001) and medial (40.2% vs 31.5%; P = .01) meniscal tears, as well as more lateral (72.1% vs 27.9%; P < .0001) and medial (61.4% vs 38.6%; P = .01) meniscectomies than females. For males, age predicted chondral injuries and medial meniscectomy; BMI >=30 kg/m(2) predicted medial meniscal tears; high-impact and other sports predicted medial meniscal tears, medial meniscectomies, and medial meniscal repairs; injuries <=6 weeks from surgery predicted lateral meniscal repairs; and instability episodes predicted medial meniscal tears, medial tears left in situ, medial meniscectomies, and medial meniscal repairs. For females, age predicted chondral injuries, BMI >=30 kg/m(2) predicted lateral meniscectomies and repairs, and instability episodes predicted medial meniscectomies. CONCLUSION: Sex differences were observed. For males, predictors included age, BMI, sports related injuries, injuries <=6 weeks from surgery, and instability episodes. For females, predictors included age, BMI, and instability episodes. PMID- 26535385 TI - The Supine Internal Rotation Test: A Pilot Study Evaluating Tibial Internal Rotation in Grade III Posterior Cruciate Ligament Tears. AB - BACKGROUND: Biomechanical studies have reported that the posterior cruciate ligament (PCL) functions as a restraint against excessive tibial internal rotation at higher degrees of knee flexion. PURPOSE: To investigate the use of a supine internal rotation (IR) test for the diagnosis of grade III PCL injuries. The hypothesis was that internal rotation would be greater in patients with grade III PCL injuries compared with other knee injuries and that the supine IR test would demonstrate excellent diagnostic accuracy. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: A consecutive series of 309 patients underwent arthroscopic and/or open knee ligament reconstruction surgery. Seven patients were excluded based on the inability to perform a side-to-side comparison of internal rotation. Tibial internal rotation was assessed bilaterally on 302 patients during examination under anesthesia by a single orthopaedic surgeon measuring tibial tubercle excursion (mm) while applying internal rotation torque. Internal rotation was graded from 0 to 4 at 60 degrees , 75 degrees , 90 degrees , 105 degrees , and 120 degrees of knee flexion. Data were collected and stored prospectively. The optimal threshold for the supine IR test was chosen based on maximization of the Youden index. Diagnostic accuracy parameters were calculated. Multiple logistic regression models were constructed to assess the influence of other knee pathologies on diagnostic accuracy. RESULTS: Examination of the 22 PCL-deficient knees demonstrated an increase in tibial internal rotation at 60 degrees , 75 degrees , 90 degrees , 105 degrees , and 120 degrees of knee flexion. The supine IR test had a sensitivity of 95.5%, a specificity of 97.1%, a positive predictive value of 72.4%, and a negative predictive value of 99.6% for the diagnosis of grade III PCL injuries. Posterolateral corner injury had a significant interaction with the supine IR test, increasing its sensitivity and decreasing its specificity. CONCLUSION: PCL deficient knees demonstrated an increase in the side-to-side difference in tibial internal rotation compared with other knee pathologies. The supine IR test offers high sensitivity and specificity for grade III PCL injuries and may represent a useful adjunct for diagnosing PCL injuries. PMID- 26535386 TI - Does Labral Size Correlate With Degree of Acetabular Dysplasia? AB - BACKGROUND: Hip dysplasia has been shown to be a cause of early arthritis. The decrease in bony coverage has shown increased stress on the acetabular labrum as it shares an increased load. PURPOSE/HYPOTHESIS: The purpose of this study was to divide a cohort of patients by radiographic measures of dysplastic and nondysplastic hips for comparison with regard to labral size at 4 anatomic locations. The hypothesis was that dysplastic hips will have significantly larger labral size compared with nondysplastic hips. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A prospective study was conducted at a single institution. A total of 130 patients underwent hip arthroscopy during the study period from September 2011 to February 2012. Intraoperatively, arthroscopic measurements were taken at 4 quadrants on the acetabular clockface: anterosuperior (12-3 o'clock), anteroinferior (3-6 o'clock), posterosuperior (9 12 o'clock), and posteroinferior (6-9 o'clock). Three radiographic parameters for dysplasia were used to substratify the study population base: lateral center-edge angle (LCEA) <=25 degrees and LCEA >25 degrees , acetabular inclination (AI) <=10 degrees and AI >10 degrees , and anterior center-edge angle (ACEA) <=20 degrees and ACEA >20 degrees . RESULTS: For the LCEA <=25 degrees group, there were 28 hips with mean LCEA of 20.96 degrees +/- 3.40 degrees . Patients with LCEA <=25 degrees had larger labral width in all 4 quadrants (P < .05). For AI >10 degrees , there were 12 hips with the mean AI 12.92 degrees +/- 2.50 degrees . Patients with AI >10 degrees had larger labral size in the posteroinferior quadrant only (P < .05). For ACEA <=20 degrees , there were 4 hips with a mean ACEA of 11.25 degrees +/- 5.19 degrees . The anteroinferior and posteroinferior quadrants had a significant increase in labral size when substratified by ACEA <=20 degrees (P < .05). CONCLUSION: Labral size was significantly larger in dysplastic hips compared with nondysplastic hips. The posteroinferior quadrant labrum was larger in size in dysplastic hips, as measured by any of the 3 radiographic measurements of dysplasia. Hips with LCEA <=25 degrees had larger labra in all 4 quadrants. PMID- 26535387 TI - Two Helpful MRI Signs for Evaluation of Posterolateral Bundle Tears of the Anterior Cruciate Ligament: A Pilot Study. AB - BACKGROUND: Diagnosis of partial anterior cruciate ligament (ACL) tears is difficult on magnetic resonance imaging (MRI), particularly the isolated tears of the posterolateral bundle. PURPOSE: To describe 2 MRI signs of partial ACL tear involving the posterolateral bundle on conventional knee MRI sequences, specifically, the "gap" and "footprint" signs. STUDY DESIGN: Case-control study. METHODS: We retrospectively reviewed the MRI appearance of the ACL in 11 patients with arthroscopically proven partial ACL tears isolated to the posterolateral bundle, as well as in 10 patients with arthroscopically proven intact ACLs, and evaluated for the presence of gap and/or footprint signs. RESULTS: There was high degree of sensitivity and specificity associated with the MRI findings of "gap" and "footprint" signs with arthroscopically proven isolated posterolateral bundle tears. CONCLUSION: Gap and footprint signs are suggestive of posterolateral bundle tear of the ACL, and the presence of 1 or both of these imaging findings should alert the radiologist to the possibility of a posterolateral bundle tear. PMID- 26535388 TI - The Importance of the Intercondylar Notch in Anterior Cruciate Ligament Tears. AB - BACKGROUND: The factors associated with anterior cruciate ligament (ACL) tears are not completely clear. Some studies have shown that patients with a narrow intercondylar notch have a predisposition for ACL tears. PURPOSE: To determine the relationship between the alpha angle and intercondylar notch width measurements and ACL tears. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 530 patients (308 with ACL rupture, 222 with healthy ACLs) were included in this study. The alpha angle and intercondylar width were measured from magnetic resonance images (MRIs). Binary logistic regression analysis was performed to determine the influence of the variables on ACL status (normal or torn). Odds ratios (ORs) and their respective 95% CIs were also calculated. RESULTS: No significant differences in patient age and the affected knee were found between patients with normal or torn ACLs. The mean alpha angle was higher in patients with a torn ACL than in those with an intact one (57.5 degrees +/- 5.5 degrees vs 56.2 degrees +/- 4.5 degrees ; P = .009). Intercondylar width was significantly lower in patients with a torn ACL than in those with an intact one (18.2 +/- 3.1 vs 19.5 +/- 3.6 mm; P < .001). A highly significant difference between men and women was found for mean intercondylar notch width (19.3 +/- 3.3 vs 17.4 +/- 3.1 mm; P < .001). In a logistic regression model, sex, intercondylar width, and alpha angle were statistically significant when adjusted for age. CONCLUSION: Study results suggest that the ACL tears are associated with a narrow intercondylar notch and a high alpha angle, and that tears occur more frequently in men than in women. CLINICAL RELEVANCE: The model proposed in this study could be used by the physician in the medical office as a tool to identify the risk factors that may predispose a patient for a potential ACL tear. PMID- 26535389 TI - SLAP Repairs With Combined Procedures Have Lower Failure Rate Than Isolated Repairs in a Military Population: Surgical Outcomes With Minimum 2-Year Follow up. AB - BACKGROUND: Injuries to the superior glenoid labrum represent a significant cause of shoulder pain among active patients. The physical requirements of military service may contribute to an increased risk of injury. Limited data are available regarding the success of superior labral anterior posterior (SLAP) repairs in an active military population. PURPOSE: To quantify the rate of clinical failure and surgical revision after isolated and combined SLAP repair. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All consecutive active-duty servicemembers undergoing arthroscopic repair of type II SLAP lesions at a single institution between 2006 and 2012 were identified. Patients with less than 2-year clinical follow-up and nonmilitary status were excluded. Demographic variables, surgical variables, and occupational outcomes were extracted from electronic medical records and confirmed with the US Army Physical Disability Agency database. Failure was defined as subsequent revision surgery or medical discharge with persistent shoulder complaints. RESULTS: A total of 192 patients with SLAP repair were identified with a mean follow-up of 50.0 months (SD, 17.0 months). Isolated SLAP repair occurred in 31.3% (n = 60) versus 68.8% (n = 132) with concomitant procedures. At final follow-up, 37.0% (n = 71) of patients reported some subjective activity-related shoulder pain. Postoperative return to duty occurred in 79.6% (n = 153), and only 20.3% (n = 39) were discharged with continuing shoulder disability. The combined rotator cuff repair (96%; P = .023) and anteroinferior labral repair group (88%; P = .056) had a higher rate of functional return than isolated SLAP repair (70%). Thirty-one (16.1%) patients were classified as surgical failure and required revision. Of these, the majority of patients undergoing biceps tenodesis (76%) returned to active duty, as compared with revision SLAP repair (17%). Lower demand occupation and the presence of combined shoulder injuries (P = .011 and .016, respectively) were significantly associated with a lower risk of medical discharge and revision surgery, respectively. CONCLUSION: Favorable outcomes can be anticipated in the majority of military servicemembers after arthroscopic SLAP repair, particularly with combined shoulder injuries. Revision surgery occurred in 16% of patients after primary SLAP repair. CLINICAL RELEVANCE: Isolated repair of unstable SLAP lesions and/or increased upper extremity demands are associated with higher failure rates in this population. PMID- 26535390 TI - Posterior Capsular Plication Constrains the Glenohumeral Joint by Drawing the Humeral Head Closer to the Glenoid and Resisting Abduction. AB - BACKGROUND: Shoulder pain is a common problem, with 30% to 50% of the American population affected annually. While the majority of these shoulder problems improve, there is a high rate of recurrence, as 54% of patients experience persistent symptoms 3 years after onset. PURPOSE: Posterior shoulder tightness has been shown to alter glenohumeral (GH) kinematics. Clinically, posterior shoulder contractures result in a significant loss of internal rotation and abduction (ABD). In this study, the effect of a posterior capsular contracture on GH kinematics was investigated using an intact cadaveric shoulder without violating the joint capsule or the rotator cuff. STUDY DESIGN: Controlled laboratory study. METHODS: Glenohumeral motion, humeral load, and subacromial contact pressure were measured in 6 fresh-frozen left shoulders during passive ABD from 60 degrees to 100 degrees using an automated robotic upper extremity testing system. Baseline values were compared with the experimental condition in which the full thickness of posterior tissues was plicated without decompressing the joint capsule. RESULTS: Posterior soft tissue plication resulted in increased compression between the humeral head and the glenoid (axial load) at 90 degrees of ABD. Throughout ABD, the posterior contracture increased the anterior and superior moment on the humeral head, but it did not change the GH kinematics in this intact model. As a result, there was no increase in the subacromial contact pressure during ABD with posterior plication. CONCLUSION: In an intact cadaveric shoulder, posterior contracture does not alter GH motion or subacromial contact pressure during passive ABD. By tightening the soft tissue envelope posteriorly, there is an increase in compressive load on the articular cartilage and anterior/superior force on the humeral head. These findings suggest that subacromial impingement in the setting of a posterior soft tissue contracture may result from alterations in scapulothoracic motion, not changes in GH kinematics. CLINICAL RELEVANCE: This investigation demonstrates that posterior capsular plication increases the axial load on the shoulder joint during ABD. While a significant difference from baseline was observed in the plicated condition, posterior capsular plication did not change GH motion or subacromial contact pressure significantly. PMID- 26535391 TI - Patients With Isolated PCL Injuries Improve From Surgery as Much as Patients With ACL Injuries After 2 Years. AB - BACKGROUND: Reports on outcome after posterior cruciate ligament (PCL) reconstruction often contain both isolated PCL and combined knee ligament injuries. This makes it difficult to conclude on the outcome after reconstruction of isolated PCL injuries. PURPOSE: To investigate the outcome after PCL reconstruction in patients with an isolated PCL injury and to compare this with the outcome of patients treated with reconstruction after isolated anterior cruciate ligament (ACL) injuries. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Seventy-one patients with an isolated PCL injury that was reconstructed surgically and who had registered in the Norwegian Knee Ligament Registry between 2004 and 2010 were included in this study. Patients with isolated ACL reconstructions (n = 9661) who had registered in the same period were included for comparison. Knee Injury and Osteoarthritis Outcome Score (KOOS) was used as the patient-reported outcome measure. Preoperative and 2-year postoperative KOOS scores were compared. Changes in KOOS score reported by the PCL patients were compared with changes reported by the ACL patients. RESULTS: At the 2-year postoperative follow-up of the PCL-reconstructed patients, the patient reported outcome was improved, measured by KOOS as follows: pain, 15.1 (95% CI, 8.5-21.8; P < .001); symptoms, 0.9 (95% CI, -6.6 to 8.3; P = .82); activities of daily living, 13.2 (95% CI, 6.6-13.9; P < .001); sports, 20.7 (95% CI, 11.8-29.4; P < .001); and quality of life, 26.6 (95% CI, 18.9-34.2; P < .001). According to the KOOS, the incremental improvements were similar for PCL and ACL patients. Time from injury to surgery was longer for the PCL patients compared with ACL patients (median, 21.5 vs 8.0 months; P < .001). CONCLUSION: Patients undergoing PCL reconstruction can expect the same improvements in KOOS score as patients undergoing ACL reconstruction. However, PCL patients start out with an inferior score on average and consequently end up at a lower score compared with ACL patients for all KOOS subscales. PMID- 26535392 TI - Factors Expressed in an Animal Model of Anteroinferior Glenohumeral Instability. AB - BACKGROUND: There is little information on the molecular factors important in healing and changes that occur in the glenoid labrum in response to injury. Using a novel animal model of acute anterior shoulder dislocation, this study characterizes the factors expressed in the glenoid labrum in response to injury and correlates their expression to glenohumeral stability. PURPOSE: To study the response of the glenoid labrum to injury both biomechanically and with immunohistochemical testing. METHODS: An injury to the anteroinferior labrum was surgically induced in 50 male Lewis rats. Rats were sacrificed at 3, 7, 14, 28, or 42 days. Immunolocalization experiments were performed to localize the expression of growth factors and cytokines. For biomechanical testing, dynamic stiffness for anterior and posterior laxity, load to failure, stiffness, and maximum load were recorded. Statistical differences were determined at P < .05. STUDY DESIGN: Descriptive laboratory study. RESULTS: Expression of interleukin-1 beta (IL-1beta), transforming growth factor-beta 1 (TGF-beta1), matrix metalloproteinase 3 (MMP3), and matrix metalloproteinase 13 (MMP13) were increased in injured compared with uninjured specimens. Collagen III expression was increased early and decreased with time. Biomechanical testing verified instability by demonstrating increased anterior displacement and decreased stiffness in injured shoulders at all time points. CONCLUSION: This novel animal model of acute anterior shoulder dislocation showed increased expression of IL 1beta, TGF-beta1, MMP3, MMP13, and collagen III in the injured labral tissue at early time points. Increased anterior laxity and decreased stiffness and maximum load to failure were seen after anterior labral injury, supporting the model's ability to re-create anterior glenohumeral instability. These data provide important information on the temporal changes occurring in a rat model of anterior glenohumeral dislocation. CLINICAL RELEVANCE: Identification of factors expressed in the anterior capsule and glenoid labrum in response to injury may lead to the development of novel agents that can be used to augment glenoid labrum healing and ultimately improve both surgical and nonsurgical treatment of this common shoulder injury. PMID- 26535393 TI - Tolerability and Efficacy of 3 Approaches to Intra-articular Corticosteroid Injections of the Knee for Osteoarthritis: A Randomized Controlled Trial. AB - BACKGROUND: Several studies have been performed suggesting that a superolateral approach to cortisone injections for symptomatic osteoarthritis of the knee is more accurate than anteromedial or anterolateral approaches, but there are little data to correlate clinical outcomes with these results. Additionally, there are minimal data to evaluate the pain of such procedures, and this consideration may impact physician preferences for a preferred approach to knee injection. PURPOSE: To determine the comparative efficacy and tolerability (patient comfort) of landmark-guided cortisone injections at 3 commonly used portals into the arthritic knee without effusion. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Adult, English-speaking patients presenting to a sports medicine clinic with knee pain attributed to radiographically proven grades I through III knee osteoarthritis were randomized to receive a cortisone injection via superolateral, anteromedial, or anterolateral approaches. Patients used a visual analog scale (VAS) to self-report comfort with the procedure. Western Ontario and McMaster Universities Arthritis Index (WOMAC) 3.1 VAS scores were used to establish baseline pain and dysfunction prior to the injection and at 1 and 4 weeks follow-up via mail. RESULTS: A total of 55 knees from 53 patients were randomized for injection using a superolateral approach (17 knees), an anteromedial approach (20 knees), and an anterolateral approach (18 knees). The mean VAS scores for procedural discomfort showed no significant differences between groups (superolateral, 39.1 +/- 28.5; anteromedial, 32.9 +/- 31.5; anterolateral, 33.1 +/- 26.6; P = .78). WOMAC scores at baseline were similar between groups as well (superolateral, 1051 +/- 686; anteromedial, 1450 +/- 573; anterolateral, 1378 +/- 673; P = .18). The WOMAC scores decreased at 1 and 4 weeks for all groups, with no significant differences in reduction between the 3 groups. CONCLUSION: Other studies have shown that the superolateral portal is the most accurate. This study did not assess accuracy, but it showed that all 3 knee injection sites studied have similar overall clinical benefit at 4-week follow up. Procedural pain was not significantly different between groups. PMID- 26535394 TI - Triceps Tendon Ruptures Requiring Surgical Repair in National Football League Players. AB - BACKGROUND: Complete triceps tendon ruptures are relatively rare in the general population but slightly more prevalent in professional football. One prior study found 11 complete ruptures over a 6-season period. HYPOTHESIS: Triceps ruptures occur more commonly in football linemen due to forced elbow flexion during an eccentric contraction and may occur more commonly with the increasing size and speed of professional players. Surgical repair allows full return to sports, but with a lengthy recovery time. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A search of the National Football League Injury Surveillance System (NFLISS) found a total of 37 triceps tendon ruptures requiring surgical repair from the years 2000 to 2009. Data were obtained for setting of injury, player position, activity causing injury, play type, time of game when injury occurred, height, weight, body mass index (BMI), and number of days lost from football. RESULTS: There were 37 players requiring surgical repair for triceps tendon ruptures over the 10-season period. The average height, weight, and BMI of the players were 75 inches, 292 pounds, and 36.5 kg/m(2), respectively. The majority of players were linemen (86%): 16 defensive, 15 offensive, and 1 tight end. The injury took place while blocking or being blocked in 29 players (78%) and while tackling or being tackled in 5 players (14%). Players missed an average of 165 days (range, 49-318 days) from football as a result of their injury and surgery. CONCLUSION: Triceps tendon tears requiring surgical repair are more common in professional football players than in the general population and are occurring more commonly than previously reported. Surgical repair allows return to play. CLINICAL RELEVANCE: Our study identifies the rate of triceps tendon tears requiring repair in the NFL according to position, identifying which players may be most at risk for this injury. PMID- 26535395 TI - Utility of Intra-articular Hip Injections for Femoroacetabular Impingement: A Systematic Review. AB - BACKGROUND: Femoroacetabular impingement (FAI) is a condition that is becoming increasingly recognized as a common etiology of hip pain in athletes, adolescents, and adults. However, history and clinical examination are often inconclusive in reaching a diagnosis, while imaging often detects asymptomatic abnormalities. Treatment has traditionally been limited to surgery, with the role of conservative management remaining unclear. PURPOSE: To evaluate the utility of the intra-articular hip injection in the diagnosis and management of FAI. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: MEDLINE, EMBASE, and PubMed databases were screened in duplicate for studies published between January 1946 and January 2014. Search terms included femoroacetabular impingement, hip impingement, and intra-articular injection. Quality assessment using the Methodological Index for Non-Randomized Studies (MINORS) scale was completed for all included studies. Data evaluated included study design, study objectives, number of hips, injected product, duration of pain relief, and outcomes measured. RESULTS: Our search yielded 8 studies involving 281 hips. Studies were categorized into diagnostic (4 studies), therapeutic (3 studies), and prognostic (1 study) applications. Patients with FAI and its degenerative sequelae obtained greater relief from diagnostic intra-articular hip injection than those without (P < .05). The diagnostic intra-articular injection performed under ultrasound guidance was better tolerated than injections performed under fluoroscopic guidance (pain rating, 5.6 vs 3.0; P < .1). Intra-articular injection of hyaluronic acid was the most effective at providing pain relief (in 23 patients), with significant improvements of functional outcome measures (Harris Hip Score, visual analog scale) present at 12 months. Pooled results with corticosteroid injection resulted in improvement in only 15% (9/60) of patients at 6 weeks. A negative response to intra-articular hip injection was a strong predictor for poor surgical outcomes. CONCLUSION: The results of this review suggest that (1) pain relief obtained from an intra-articular hip injection supports a diagnosis of FAI, (2) therapeutic relief at 12 months may be achieved, particularly with hyaluronic acid, and (3) a negative response to preoperative injections may predict poor short-term surgical outcomes. Additional large studies are required to build on the small number of studies included in this review, and further delineate the role of intra-articular hip injection in the management of FAI. PMID- 26535396 TI - Patellar Tendon-Trochlear Groove Angle Measurement: A New Method for Patellofemoral Rotational Analyses. AB - BACKGROUND: The tibial tubercle-trochlear groove (TT-TG) is used as the gold standard for patellofemoral malalignment. PURPOSE: To assess 3 patellar tendon trochlear groove (PT-TG) angle measurement techniques and the PT-TG distance measurement (tendinous cartilaginous TT-TG) as predictors of patellar instability. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: Three PT-TG angle measurements and the PT-TG distance were measured in 82 participants with patellar instability and 100 controls using magnetic resonance imaging (MRI). Measurement landmarks were the line tangent to the posterior femoral condyles, the deepest point of the trochlea, the transepicondylar line, and the patellar tendon center. All measurements were recorded once by 1 examiner, and the measurements were recorded twice by 2 examiners in a random group of 100 knees. Mean values and standard deviations (SDs) were obtained. Normality cutoff values were defined as 2 and 3 SDs above the mean in the control group. The sensitivity, specificity, and positive likelihood ratio (LR+) were calculated. Inter- and intrarater reliability were assessed based on the intraclass correlation coefficient (ICC). RESULTS: The measurements from the patellar instability and control groups, respectively, for angle 1 (16.4 degrees and 8.4 degrees ), angle 2 (31 degrees and 15.6 degrees ), angle 3 (30.8 degrees and 15.7 degrees ), PT-TG distance (14.5 and 8.4 mm), and patellar tilt (21.1 degrees and 7.5 degrees ) were significantly different (P < .05). The angle measurements showed greater sensitivity, specificity, and LR+ than the PT-TG distance. Inter- and intrarater ICC values were >0.95 for all measurements. CONCLUSION: The PT-TG angle and the PT-TG distance are reliable and are different between the patellar instability and control groups. PT-TG angles are more closely associated with patellar instability than PT-TG distance. CLINICAL RELEVANCE: PT-TG angle measurements show high reliability and association with patellar instability and can aid in the assessment of extensor mechanism malalignment. A more sensitive and specific evaluation of extensor mechanism malalignment can improve patient care by preventing both redislocation and abnormal tracking of overlooked malalignment and complications of unnecessary tibial tuberosity medialization. PMID- 26535397 TI - Controlled Laboratory Comparison Study of Motion With Football Equipment in a Destabilized Cervical Spine: Three Spine-Board Transfer Techniques. AB - BACKGROUND: Numerous studies have shown that there are better alternatives to log rolling patients with unstable spinal injuries, although this method is still commonly used for placing patients onto a spine board. No previous studies have examined transfer maneuvers involving an injured football player with equipment in place onto a spine board. PURPOSE: To test 3 different transfer maneuvers of an injured football player onto a spine board to determine which method most effectively minimizes spinal motion in an injured cervical spine model. STUDY DESIGN: Controlled laboratory study. METHODS: Five whole, lightly embalmed cadavers were fitted with shoulder pads and helmets and tested both before and after global instability was surgically created at C5-C6. An electromagnetic motion analysis device was used to assess the amount of angular and linear motion with sensors placed above and below the injured segment during transfer. Spine boarding techniques evaluated were the log roll, the lift and slide, and the 8 person lift. RESULTS: The 8-person lift technique resulted in the least amount of angular and linear motion for all planes tested as compared with the lift-and slide and log-roll techniques. This reached statistical significance for lateral bending (P = .031) and medial-lateral translation (P = .030) when compared with the log-roll maneuver. The lift-and-slide technique was significantly more effective at reducing motion than the log roll for axial rotation (P = .029) and lateral bending (P = .006). CONCLUSION: The log roll resulted in the most motion at an unstable cervical injury as compared with the other 2 spine-boarding techniques examined. The 8-person lift and lift-and-slide techniques may both be more effective than the log roll at reducing unwanted cervical spine motion when spine boarding an injured football player. Reduction of such motion is critical in the prevention of iatrogenic injury. PMID- 26535398 TI - Distal Insertions of the Biceps Femoris: A Quantitative Analysis. AB - BACKGROUND: Avulsion of the biceps femoris from the fibula and proximal tibia is encountered in clinical practice. While the anatomy of the primary posterolateral corner structures has been qualitatively and quantitatively described, a quantitative analysis regarding the insertions of the biceps femoris on the fibula and proximal tibia is lacking. PURPOSE: To quantitatively assess the insertions of the biceps femoris, fibular collateral ligament (FCL), and anterolateral ligament (ALL) on the fibula and proximal tibia as well as establish relationships among these structures and to pertinent surgical anatomy. STUDY DESIGN: Descriptive laboratory study. METHODS: Dissections were performed on 12 nonpaired, fresh-frozen cadaveric specimens identifying the biceps femoris, FCL, and ALL, and their insertions on the proximal tibia and fibula. The footprint areas, orientations, and distances from relevant osseous landmarks were measured using a 3-dimensional coordinate measurement device. RESULTS: Dissection produced 6 easily identifiable and reproducible anatomic footprints. Tibial footprints included the insertion of the ALL and an insertion of the biceps femoris (TBF). Fibular footprints included the insertion of the FCL, a distal insertion of the biceps femoris (DBF), a medial footprint of the biceps femoris (MBF), and a proximal footprint of the biceps femoris (PBF). The mean area of these footprints (95% CI) was as follows: ALL, 53.0 mm(2) (38.4-67.6); TBF, 93.9 mm(2) (72.0-115.8); FCL, 86.8 mm(2) (72.3-101.2); DBF, 119 mm(2) (91.1-146.9); MBF, 46.8 mm(2) (29.0-64.5); and PBF, 215 mm(2) (192.4-237.5). The mean distance (95% CI) from the Gerdy tubercle to the center of the ALL footprint was 24.3 mm (21.6-27.0) and to the center of the TBF was 22.5 mm (21.0-24.0). The center of the DBF was 8.68 mm (7.0-10.3) from the anterior border of the fibula, the center of the FCL was 14.6 mm (12.5-16.7) from the anterior border of the fibula and 20.7 mm (19.0-22.4) from the tip of the fibular styloid, and the center of the PBF was 8.96 mm (8.2-9.7) from the tip of the fibular styloid. CONCLUSION: A tibial footprint, distal fibular footprint, medial fibular footprint, and proximal fibular footprint were all consistent components of the insertion of the biceps femoris. Consistent relationships existed between the biceps femoris and insertions of the ALL and FCL. CLINICAL RELEVANCE: The size of these footprints and distances from pertinent surgical landmarks will guide repairs of biceps femoris avulsion injuries. PMID- 26535399 TI - Pathogenesis of Fifth Metatarsal Fractures in College Soccer Players. AB - BACKGROUND: The pathogenesis of fifth metatarsal stress fractures remains uncertain. HYPOTHESIS: Physical characteristics and environmental factors, which have received limited attention in the literature thus far, might be involved in the development of fifth metatarsal stress fractures. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: To test the study hypothesis, a medical examination and survey of the living environment of collegiate soccer players was conducted and correlated with the existence of fifth metatarsal stress fractures. The survey and measurements were conducted in 273 male athletes from the same college soccer team between 2005 and 2013. A medical examination comprising assessment of stature, body weight, body mass index, foot-arch height ratio, toe grip strength, quadriceps angle, leg-heel angle, functional reach test, single leg standing time with eyes closed, straight-leg raise angle, finger-floor distance, heel-buttock distance, ankle joint range of motion, and a general joint laxity test were performed once a year, along with a questionnaire survey. The survey was also repeated when a fifth metatarsal stress fracture was diagnosed. The study participants were separated into a fifth metatarsal stress fracture injury group and a noninjury group. The measurement items and survey items were compared, and the association between the factors and the presence or absence of injuries was analyzed. RESULTS: Toe-grip strength was significantly weaker in the injury group compared with the noninjury group, suggesting that weak toe-grip is associated with fifth metatarsal stress fracture (P < .05). In addition, fifth metatarsal stress fractures were more common in the nondominant leg (P < .05). Between-group comparisons of the other items showed no statistically significant differences. CONCLUSION: The association between weak toe-grip strength and fifth metatarsal fracture suggests that weak toe-grip may lead to an increase in the load applied onto the lateral side of the foot, resulting in stress fracture. The finding of stress fracture being more common in the nondominant leg needs further study. PMID- 26535400 TI - Orthopaedic Injuries in Equestrian Sports: A Current Concepts Review. AB - BACKGROUND: Despite the common nature of orthopaedic injuries in equestrian sports, there is no published review to specifically characterize orthopaedic injuries in equestrian athletes. PURPOSE: To characterize orthopaedic injury patterns in equine sports-related injuries and their treatment. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: This review was performed through a PubMed, EMBASE, and Scopus query (from 1978 to June 2014) in the English literature using search terms "(equine-related OR equestrian-related OR horse-related OR equestrian OR equestrians) AND (injury OR injuries)." Only full text studies reporting on orthopaedic injury patterns pertinent to equestrian sports in the United States (US) and the United Kingdom (UK) were included. Orthopaedic injuries were defined as those resulting in a fracture or dislocation. In all, 182 studies were excluded, leaving a total of 27 studies for evaluation. The studies included were analyzed for demographic and epidemiological data for orthopaedic injuries, including fractures and dislocations. Cranial and facial injuries were excluded from analysis. RESULTS: The majority of those injured in the US were female (64.5%). The leading cause of injury in the US was falling from a horse. The use of protective equipment seemed to vary widely, with helmet use ranging from less than 6% up to 66.7%. In the UK, fractures were found to account for 17.4% of reported injures, compared with 33.6% of injuries in the US. The majority of fractures in US riders occurred in the upper extremities (50.7%). CONCLUSION: This review helps characterize the epidemiology of equestrian injuries based on currently available data. PMID- 26535401 TI - Effect of Preheating and Precooling on the Flexural Strength and Modulus of Elasticity of Nanohybrid and Silorane-based Composite. AB - STATEMENT OF THE PROBLEM: Composite resin may be used in different temperatures; it is crucial to determine the effect of temperature on mechanical properties of nanohybrid and silorane-based composite. PURPOSE: This in vitro study compared the flexural strength and modulus of elasticity of nanohybrid and silorane-based resin composite, at 4C, room temperature (25C), and 45C. MATERIALS AND METHOD: In this experimental study, 60 specimens were prepared in a metal split mold (2*2*25mm). Two different resin composites, Filtek Z250 XT (3M/ ESPE) and Filtek P90 (3M/ESPE), were evaluated. The material were inserted into split molds at room temperature, 4C or 45C and cured with LED (1200 mW/cm(2)) for 20 seconds in four points (n=10). Then, a three-point bending test was performed using a universal testing machine at a crosshead speed of 0.5 mm/min for measuring the flexural strength and flexural modulus of samples. The data were analyzed by the two-way ANOVA and Tukey test (p< 0.05). RESULTS: The mean highest flexural strength was observed at 45C, showing statistically significant difference with flexural strength at 4C (p= 0.0001) and 25C (p= 0.003) regardless of the type of resin composite. The flexural modulus at 45C was highest, showing the statistically significant difference with flexural modulus at 4C (p= 0.0001) and 25C (p= 0.002). The flexural modulus was statistically different between nanohybrid and silorane-based resin composite (p= 0.01) in 25C and 45C, but there were no statistically significant differences between flexural strength of Filtek Z250 XT and Filtek P90 regardless of the temperatures (p= 0.062). CONCLUSION: Preheating the resin composite at 45C improves flexural strength and modulus of nanohybrid and silorane-based resin composite. However, flexural strength and modulus of the tested materials were not affected by precooling. The flexural modulus of nanohybrid resin composite was significantly higher than silorane based resin composite in 25C and 45C temperatures. PMID- 26535402 TI - Evaluation of Bond Strength of Pressed and Layered Veneering Ceramics to Nickel Chromium Alloy. AB - STATEMENT OF THE PROBLEM: The success of metal- ceramic- restorations (MCR) depends on the presence of strong bond between porcelain and metal substructure. PURPOSE: The purpose of this study was to evaluate the effect of hot pressing technique on the bond strength of a metal-porcelain composite in comparison to layering technique. MATERIALS AND METHOD: Thirty Nickel-Chromium specimens were produced by two methods; conventional porcelain layering on metal and hot pressing (n=15). Bond strengths of all specimens were assessed by the means of three-point bending test according to ISO 9693: 1999 (E) instructions. The data were analyzed using Students t-test (p< 0.001). RESULTS: The mean +/- SD bond strength of conventional and hot pressing technique was 48.29 +/- 6.02 and 56.52 +/- 4.97, respectively. Therefore, the conventional layering technique yielded significantly lower mean bond strength values than hot pressing technique (p< 0.001). CONCLUSION: This study showed that it is possible to improve metal porcelain bond strength significantly by applying an overpressure during porcelain firing. PMID- 26535403 TI - Acid and Alkaline Phosphatase Levels in GCF during Orthodontic Tooth Movement. AB - STATEMENT OF THE PROBLEM: The present constituents of gingival crevicular fluid (GCF) can reflect the changes occurring in underlying tissues. Considering variety of biologic bone markers, alkaline phosphatase and acid phosphatase have been examined as bone turn over markers in orthodontic tooth movement. PURPOSE: The current study designed in a longitudinal pattern to determine the changes of acid and alkaline phosphatase (ACP & ALP) in GCF during orthodontic tooth movement. MATERIALS AND METHOD: An upper canines from twelve patients (mean age: 14+/-2 years) undergoing extraction orthodontic treatment for distal movement served as the test tooth (DC), and its contralateral (CC) and antagonist (AC) canines were used as controls. The CC was included in orthodontic appliance without orthodontic force; the AC was free from any orthodontic appliance. The GCF around the experimental teeth was harvested from mesial and distal tooth sites immediately before appliance placement (T0), and 14 (T2) and 28 days (T3) after it and ALP and ACP concentration were determined spectrophotometrically. RESULTS: ALP concentration was elevated significantly in DC and CC groups at days 14 and 28 compared with the AC. In DC group, the ALP was significantly greater in mesial sites than distal site, while no significant changes were found between both sites of CC. The peak level of ALP was observed in mesial sites of DC at T2. Regarding ACP, significant elevation of this enzyme was seen in DC group both in mesial and distal sites at T2 and T3. The peak level of this enzyme was seen at T2. CONCLUSION: Monitoring simultaneous changes of ALP and ACP levels in GCF can reflect the tissue responses occur in periodontium during bone formation and bone resorption during orthodontic tooth movement, respectively. PMID- 26535404 TI - Identification of Mesenchymal Stem Cell Marker STRO-1 in Oral Reactive Lesions by Immunofluorescence Method. AB - STATEMENT OF THE PROBLEM: Stem cells are considered as new implement for tissue regeneration. Several niches in adult human body are colonized by multipotent stem cells but access to these potential reservoirs is often limited. Although human dental pulp stem cells isolated from healthy teeth have been extensively characterized, it is still unknown whether stem cells also exist in reactive lesions of oral cavity such as pyogenic granuloma and peripheral ossifying fibroma which are deliberated as inflammatory proliferation of different cell families. PURPOSE: The aim of this study was to explore for clues to see whether pyogenic granuloma or peripheral ossifying fibroma contain dental mesenchymal stem cell (DMSC). MATERIALS AND METHOD: Four pyogenic granuloma and four peripheral ossifying fibroma specimens were collected by excisional biopsy and preserved in PBS-EDTA at -86 degrees C. Then we cut them in 5um diameter using Cryostat. Having been rinsed with PBS, the samples were stained with a primary mouse anti-human STRO-1 monoclonal IgM antibody. Afterward, a secondary goat anti mouse IgM-FITC antibody was applied to detect STRO-1+ cells as probable stem cells by immunofluorescence technique. RESULTS: Immunofluorescence microscopy revealed presence of STRO-1+ cells in these lesions, particularly localized on perivascular zone. The negative control group was not glowing. CONCLUSION: Based on these results, it was found that reactive lesions of pyogenic granuloma and peripheral ossifying fibroma have STRO-1 positive cells, which raises the possibility that these cells may be DMSCs. PMID- 26535405 TI - The Effect of Four Surface Treatment Methods on the Shear Bond Strength of Metallic Brackets to the Fluorosed Enamel. AB - STATEMENT OF THE PROBLEM: Some studies have reported the bond strength to be significantly lower in fluorotic enamels than the non-fluorosed. PURPOSE: The purpose of this study was to evaluate the shear bond streongth of metallic brackets to non-fluorosed and fluorosed teeth after different enamel conditioning. MATERIALS AND METHOD: A total of 176 freshly extracted human premolars (88 non-fluorosed and 88 fluorosed teeth) were used in this study for bonding the metallic brackets. Teeth with moderate fluorosis were used according to Thylstrup and Fejereskov index (TFI). Eighty non-fluorosed and 80 fluorosed teeth (TFI=4-6) were randomly divided into 8 equal groups of 20 teeth each. The remaining 16 teeth were used for scanning electron microscopy observation. The enamel surface was conditioned by 4 methods: acid etching for 30 sec, acid etching for 120 sec, air abrasion followed by acid etching, and Er: YAG laser etching followed by acid etching. The morphology of etching patterns in different groups was studied under scanning electron microscope. RESULTS: The shear bond strength of fluorosed teeth to the brackets was significantly lower than non fluorosed ones (p= 0.003). The shear bond strength of laser-acid groups in both non-fluorosed and fluorosed teeth was significantly lower than other groups (p< 0.001). Weibull analysis indicated that the chance of failure under the applied force was different between fluorosed and non-fluorosed group. The scanning electron microscope observations revealed that the fluorosed teeth treated with phosphoric acid had fewer irregularities compared to non-fluorosed teeth. The most irregularities were detected in the teeth conditioned with phosphoric acid for 120 seconds. CONCLUSION: Fluorotic enamel adversely affects the bond strength of orthodontic brackets. None of the conditioning methods tested in this study could significantly improve shear bond strength of metallic brackets. Er: YAG laser conditioning followed by acid further reduced the bond strength in non fluorosed and fluorosed teeth. PMID- 26535406 TI - Comparison of the Effects of Two Different Drinks on Microhardness of a Silorane based Composite Resin. AB - STATEMENT OF THE PROBLEM: Acidic foods and drinks can erode composite resins. Silorane-based composite is a new low shrinkage composite with higher hydrophobicity which might resist the erosive effect of beverages. PURPOSE: The aim of this study was to determine the effects of 100% orange juice and non alcoholic carbonated beer on microhardness of a silorane-based composite in comparison with two methacrylate-based composite resins. MATERIALS AND METHOD: Ninety disc-shaped composite specimens were fabricated of Filtek P90, Filtek Z350 XT Enamel and Filtek Z250 (3M-ESPE) (n=30) and randomly divided into 3 subgroups of 10.Group 1 was immersed in distilled water, group 2 in 100% orange juice, and group 3 in non-alcoholic beer for 3 h/day. Primary, secondary and final Vickers microhardness tests were performed at the beginning of the study and 7 and 28 days later. Surface of 2 specimens in each group was evaluated under scanning electron microscope on day 28. Data were analyzed using repeated measures of ANOVA model (alpha=0.05). RESULTS: The primary and secondary microhardness of P90 was significantly lower than that of Z350, and Z250 (p< 0.001). Microhardness of Z350 was also lower than that of Z250 (p= 0.002). On day 28, microhardness of P90 was lower than Z250 and Z350 (p< 0.001); however, microhardness values of Z250 and Z350 were not significantly different (p= 0.054). Microhardness of specimens subjected to non-alcoholic beer was significantly lower than that of controls (p= 0.003). Meanwhile, the microhardness value of resins in orange juice was somewhere between the two mentioned values with no significant difference with any of them (p> 0.05). CONCLUSION: Although 28 days of immersion in 100% orange juice and non-alcoholic beer decreased the microhardness of all specimens, P90 experienced the greatest reduction of microhardness and non-alcoholic beer had the highest effect on reducing microhardness. PMID- 26535407 TI - A Profilometric Study to Assess the Role of Toothbrush and Toothpaste in Abrasion Process. AB - STATEMENT OF THE PROBLEM: Despite of many studies conducted on toothbrushes and toothpaste to find out the culprit for abrasion, there is no clear cut evidence to pin point the real cause for abrasion. PURPOSE: An in vitro assessment of the role of different types of toothbrushes (soft/ medium/hard) in abrasion process when used in conjunction with and without a dentifrice. MATERIALS AND METHOD: Forty five freshly extracted, sound, human incisor teeth were collected for this study. Enamel specimens of approximately 9 mm(2) were prepared by gross trimming of extracted teeth using a lathe machine (Baldor 340 Dental lathe; Ohio, USA). They were mounted on separate acrylic bases. The specimens were divided into three groups, each group containing 15 mounted specimens. Group 1 specimens were brushed with soft toothbrush; Group 2 brushed with medium toothbrush and Group 3 with hard toothbrush. Initially, all the mounted specimens in each group were brushed using dentifrice and then the same procedure was repeated with water as control. Profilometric readings were recorded pre and post to tooth brushing and the differences in readings served as proxy measure to assess surface abrasion. These values were then compared to each other. Kruskal Wallis and Mann-Whitney U test were performed. RESULTS: The results showed that brushing, with water alone, caused less abrasion than when toothpaste was added (p< 0.008). When brushed with water, the harder toothbrush caused more abrasion (higher Ra-value), but when toothpaste was added, the softer toothbrush caused more abrasion (p< 0.001). CONCLUSION: Besides supporting the fact that toothpaste is needed to create a significant abrasion, this study also showed that a softer toothbrush can cause more abrasion than harder ones. The flexibility of bristles is only secondary to abrasion process and abrasivity of dentifrice has an important role in abrasion process. PMID- 26535408 TI - A Retrospective Analysis of Oral Langerhans Cell Histiocytosis in an Iranian Population: a 20-year Evaluation. AB - STATEMENT OF THE PROBLEM: Langerhans cell histiocytosis is a rare disease with unknown pathogenesis and is characterized by local or disseminated proliferation of Langerhans cells. There is no previous investigation on prevalence of oral Langerhans cell histiocytosis in Iranian population. PURPOSE: The purpose of this study was to assess the relative frequency of oral Langerhans cell histiocytosis in an Iranian population and to compare the data with previous reports. MATERIALS AND METHOD: Pathology files of Oral and Maxillofacial Pathology Department of Dental School of Shahid Beheshti University of Medical Sciences from 1992 to 2012 were searched for cases recorded as oral Langerhans cell histiocytosis. A total number of 20 cases were found and the clinical information of patients was recorded. RESULTS: The relative frequency of oral Langerhans cell histiocytosis was 0.34% and the most common location was the posterior mandible. In addition, the mean age of patients was 27 years and there was a definite male predominance. Most lesions were localized and tooth mobility was the most common oral presentation. CONCLUSION: In Iranian population as in many other countries, the relative frequency of oral Langerhans cell histiocytosis is low. Moreover, tooth mobility and periodontal lesions are the frequent early signs of disease. Therefore, in patients with periodontal problems, good oral health, and no response to the treatment; Langerhans cell histiocytosis must be considered. Additionally, although most cases of oral Langerhans cell histiocytosis are localized, systemic involvement must also be considered and dental professionals have an important role in early detection of the disease. PMID- 26535409 TI - The Effectiveness of Home Water Purification Systems on the Amount of Fluoride in Drinking Water. AB - STATEMENT OF THE PROBLEM: Water purification systems for domestic use have drawn significant attention over the past few years. This can be related to the improvement of public health and concern for water contamination. PURPOSE: The aim of this study was to evaluate whether home water purification systems eliminate the essential materials such as fluoride besides filtrating the heavy ions and other unwanted particles out of water. MATERIALS AND METHOD: In this experimental study, six most frequently used commercial brands of water purifiers were evaluated and compared. Specimens were collected right before and after setting up the device, and 6 months later. Then, spectrophotometry (the Harrison device) was performed to compare fluoride clearance by each home water cleaner device. RESULTS: Based on the data collected from all water purification devices in different locations, the amount of fluoride was significantly different before and right after using home water purifier and six months later (p= 0.001 and p= 0.00, respectively). CONCLUSION: The filtration of water significantly decreased its fluoride concentration. The fluoride content of purified water was approximately as much as zero in some cases. PMID- 26535410 TI - Extragingival Pyogenic Granuloma: an Unusual Clinical Presentation. AB - Pyogenic granuloma is thought to represent an exuberant tissue reaction to local irritation. It occurs in second decade of life in young females. Clinically, oral pyogenic granuloma is a smooth or lobulated exophytic growth, pedunculated or sessile, which usually bleeds on provocation. Oral pyogenic granuloma preferentially affects the gingiva. On rare occasion, it can be found extragingivally on lips, tongue, buccal mucosa, and palate which may mimic more serious pathological conditions such as malignancies. This article reports an unusual case of extra gingival pyogenic granuloma occurring on the right buccal mucosa in a female patient and discusses the features that distinguish this lesion from other similar oral mucosal lesions. PMID- 26535411 TI - Clinical and Histopathologic Investigation of Periapical Actinomycosis with Cutaneous Lesion: a Case Report. AB - Management of an extra-radicular infection is a challenging procedure that requires surgical intervention. This report describes a patient with discharging cutaneous lesion that required apical surgery. A 40-year-old woman was referred to the Department of Endodontics, Shiraz Dental School with chief complaint of a cutaneous sinus tract. She had been treated by a dermatologist and an otolaryngologist. The patient had also received orthograde root canal treatment of tooth #16. Yet, the lesion was still discharging and the patient was scheduled for surgery. Histopathologic analysis of the lesion showed actinomycosis infection. A 36-month follow-up revealed clinical and radiographic healing. PMID- 26535412 TI - Basal Cell Adenoma of Palate, a Rare Occurrence with Review of Literature. AB - Basal cell adenoma is an uncommon benign epithelial neoplasm of salivary gland which derives its name from the basaloid appearance of tumor cells and accounting for 1-2 % of all salivary gland epithelial tumors. This tumor usually arises in the major salivary glands, with the parotid being the most frequent site of occurrence, followed by the upper lip; while it is very rare in the minor salivary glands. Microscopically, it is composed of isomorphic cells similar to basal cells with nuclear palisading. We report a case of BCA presenting as an asymptomatic swelling over the right side of palate of 55-year-old female patient. A follow-up of 1 year revealed no recurrence. This report emphasizes the rare site of occurrence of this tumor and briefly reviews the literature. PMID- 26535413 TI - Characterization of human breast cancer tissues by infrared imaging. AB - Fourier Transform InfraRed (FTIR) spectroscopy coupled to microscopy (IR imaging) has shown unique advantages in detecting morphological and molecular pathologic alterations in biological tissues. The aim of this study was to evaluate the potential of IR imaging as a diagnostic tool to identify characteristics of breast epithelial cells and the stroma. In this study a total of 19 breast tissue samples were obtained from 13 patients. For 6 of the patients, we also obtained Non-Adjacent Non-Tumor tissue samples. Infrared images were recorded on the main cell/tissue types identified in all breast tissue samples. Unsupervised Principal Component Analyses and supervised Partial Least Square Discriminant Analyses (PLS DA) were used to discriminate spectra. Leave-one-out cross-validation was used to evaluate the performance of PLS-DA models. Our results show that IR imaging coupled with PLS-DA can efficiently identify the main cell types present in FFPE breast tissue sections, i.e. epithelial cells, lymphocytes, connective tissue, vascular tissue and erythrocytes. A second PLS-DA model could distinguish normal and tumor breast epithelial cells in the breast tissue sections. A patient specific model reached particularly high sensitivity, specificity and MCC rates. Finally, we showed that the stroma located close or at distance from the tumor exhibits distinct spectral characteristics. In conclusion FTIR imaging combined with computational algorithms could be an accurate, rapid and objective tool to identify/quantify breast epithelial cells and differentiate tumor from normal breast tissue as well as normal from tumor-associated stroma, paving the way to the establishment of a potential complementary tool to ensure safe tumor margins. PMID- 26535414 TI - Quinones as novel chemiluminescent probes for the sensitive and selective determination of biothiols in biological fluids. AB - Altered plasma aminothiol concentrations are thought to be a valuable risk indicator and are interestingly utilized for routine clinical diagnosis and for the monitoring of various metabolic disorders and human diseases, and accordingly there is a need for an accurate and reliable assay capable of simultaneously determining aminothiols including glutathione (GSH), N-acetylcysteine (NAC), homocysteine (Hcys), and cysteine (Cys) in human plasma. Herein, a highly sensitive, selective, and very fast HPLC-chemiluminescence (HPLC-CL) coupled method is reported, exploiting for the first time the strong nucleophilicity and high reactivity of aminothiols toward quinones for a CL assay. The unique redox cycling capability of quinone and/or Michael addition adducts, thioether-quinone conjugates, was utilized to establish a novel analytical method based on the reaction of adducts with dithiothreitol (DTT) to liberate reactive oxygen species (ROS), which are detected by using a luminol-CL assay. Specimen preparation involved the derivatization of aminothiols with menadione (MQ) for 5 minutes at room temperature. A unique green chemistry synthesis of thioether-quinones in HEPES buffer (pH 8.5) was introduced by using our reaction methodology without needing any hazardous organic solvent or catalyst. The aminothiol-MQ adducts were separated using solid-phase extraction followed by isocratic elution on an ODS column. Linearity was observed in the range of 2.5-500, 5-500, 10-1500, and 20 2000 nM with detection limits (S/N of 3) of 3.8, 4.2, 8, and 16 (fmol per injection) for GSH, NAC, Hcys, and Cys, respectively. The method was successfully applied for the selective determination of aminothiols in human plasma from healthy people and patients with rheumatic arthritis and diabetes mellitus. The obtained results postulated the usefulness of our method for investigating the relationship between aminothiol metabolism and related human disorders. PMID- 26535415 TI - Emerging techniques in the isolation and characterization of extracellular vesicles and their roles in cancer diagnostics and prognostics. AB - Extracellular vesicles (EVs) are cell-derived nanovesicles, present in almost all types of body fluids, which play an important role in intercellular communication and are involved in the transport of biological signals for regulating diverse cellular functions. Due to the increasing clinical interest in the role of EVs in tumor promotion, various techniques for their isolation, detection, and characterization are being developed. In this review, we present an overview of the current EV isolation and characterization methods in addition to their applications and limitations. Furthermore, EVs as the potential emerging biomarkers in cancer management and their clinical implementation are briefly discussed. PMID- 26535416 TI - A membrane-activatable near-infrared fluorescent probe with ultra-photostability for mitochondrial membrane potentials. AB - Mitochondrial membrane potential (MMP) is a frequently used indicator for mitochondrial function. Herein, we report a photostable near-infrared (NIR) fluorescent dye for monitoring MMP. This new probe, named NIMAP, is non fluorescent in aqueous solution and can be activated by cell membranes, providing high fluorescence contrast and low background fluorescence. NIMAP has been validated for monitoring MMP in living mammalian cells and in mice. Due to the large fluorescence response, low fluorescence background, high photostability, and excellent tissue penetration resulting from red-shifted excitation and emission in the "optical window" above 600 nm, broad applications of this new probe are expected. PMID- 26535417 TI - Nanoparticle-assisted laser desorption/ionization using sinapic acid-modified iron oxide nanoparticles for mass spectrometry analysis. AB - Iron oxide-based nanoparticles (NP) were covalently modified with sinapic acid (SA) through a condensation reaction to assist the ionization of both large and small molecules. The morphology of SA-modified NPs (SA-NP) was characterized by transmission electron microscopy (TEM), and the modification of the NP surface with SA was confirmed using ultraviolet (UV) and infrared (IR) spectroscopy. The number of SA molecules was estimated to be 6 per NP. SA-NP-assisted laser desorption/ionization was carried out on small molecules, such as pesticides and plant hormones, and large molecules, such as peptides and proteins. A peptide fragment from degraded proteins was detected more efficiently compared with conventional methods. PMID- 26535418 TI - High durability and low toxicity antimicrobial coatings fabricated by quaternary ammonium silane copolymers. AB - Adhesion and subsequent growth of microorganisms on material surfaces are a major concern in many biomedical applications. Currently, various polymers are immobilized on material surfaces to prevent microbial colonization. However, there are several challenges with regard to the coating materials, including their inability to kill microorganisms, complexity of surface grafting, limited durability and toxicity towards humans. To address these challenges, we synthesize a novel quaternary ammonium silane (QAS) antimicrobial copolymer to confer the antimicrobial effect via a simple thermal-curing coating process. The QAS copolymers were less toxic to 3 human cell lines than a commercial antimicrobial QAS monomeric agent, namely, dimethyloctadecyl[3-(trimethoxysilyl) propyl]ammonium chloride (DTPAC). Moreover, the QAS coatings demonstrated superior antimicrobial efficacy and durability than those of the DTPAC coatings. In conclusion, the novel QAS copolymers are useful to prevent substrates from microbial infections, yet with low toxicity to humans and long durability. In addition, the synthetic process is potentially scalable for industrial applications. PMID- 26535419 TI - Perfluoroalkylchain conjugation as a new tactic for enhancing cell permeability of peptide nucleic acids (PNAs) via reducing the nanoparticle size. AB - Perfluoro undecanoyl chain conjugated peptide nucleic acids (PNAs) show 2.5 to 3 fold higher cellular uptake efficiency in NIH 3T3 and HeLa cells compared to simple undecanoyl PNAs. Fluorination of PNAs leads to the formation of lower size (~100-250 nm) nanoparticles compared to larger size (~500 nm) nanoparticles from non-fluorinated PNAs, thereby improving the efficiency of cell penetration. PMID- 26535420 TI - Cardiac and neurogenic syncope and atrial flutter misdiagnosed as ventricular tachycardia in a patient after myocardial infarction. PMID- 26535421 TI - Coronary artery bypass graft surgery in a 103-year-old female patient. PMID- 26535422 TI - Integrating mitochondrial translation into the cellular context. AB - Mitochondrial-encoded subunits of the oxidative phosphorylation system assemble with nuclear-encoded subunits into enzymatic complexes. Recent findings showed that mitochondrial translation is linked to other mitochondrial functions, as well as to cellular processes. The supply of mitochondrial-encoded proteins is coordinated by the coupling of mitochondrial protein synthesis with assembly of respiratory chain complexes. MicroRNAs imported from the cytoplasm into mitochondria were, surprisingly, found to act as regulators of mitochondrial translation. In turn, translation in mitochondria controls cellular proliferation, and mitochondrial ribosomal subunits contribute to the cytoplasmic stress response. Thus, translation in mitochondria is apparently integrated into cellular processes. PMID- 26535423 TI - Reply: To PMID 25858551. PMID- 26535425 TI - Response to the Commentary by Sobolewska et al. on Choi et al. PMID- 26535426 TI - Ross H. Musgrave, M.D., 1921 to 2014. PMID- 26535427 TI - [Editorial]. PMID- 26535424 TI - Acute Pain Medicine in the United States: A Status Report. AB - BACKGROUND: Consensus indicates that a comprehensive,multimodal, holistic approach is foundational to the practice of acute pain medicine (APM),but lack of uniform, evidence-based clinical pathways leads to undesirable variability throughout U. S. healthcare systems. Acute pain studies are inconsistently synthesized to guide educational programs. Advanced practice techniques involving regional anesthesia assume the presence of a physician-led, multidisciplinary acute pain service,which is often unavailable or inconsistently applied.This heterogeneity of educational and organizational standards may result in unnecessary patient pain and escalation of healthcare costs. METHODS: A multidisciplinary panel was nominated through the APM Shared Interest Group of the American Academy of Pain Medicine. The panel met in Chicago, IL, in July 2014, to identify gaps and set priorities in APM research and education. RESULTS: The panel identified three areas of critical need: 1) an open-source acute pain data registry and clinical support tool to inform clinical decision making and resource allocation and to enhance research efforts; 2) a strong professional APM identity as an accredited subspecialty; and 3) educational goals targeted toward third-party payers,hospital administrators, and other key stake holders to convey the importance of APM. CONCLUSION: This report is the first step in a 3-year initiative aimed at creating conditions and incentives for the optimal provision of APM services to facilitate and enhance the quality of patient recovery after surgery, illness, or trauma. The ultimate goal is to reduce the conversion of acute pain to the debilitating disease of chronic pain. PMID- 26535429 TI - [Editorial]. PMID- 26535428 TI - Human Interest. PMID- 26535430 TI - [Weaning from mechanical ventilation is an important part of the ventilation process]. AB - Mechanical ventilation is an important part of intensive care. It requires intense observation and has several severe complications. Weaning from mechanical ventilation should be started as soon as possible and immediately after the cause of the pulmonary dysfunction has been treated. Weaning is a continuous process with the aim of shortening the period of mechanical ventilation, and the progress can be managed by personnel-driven or automatic protocols. In this article we describe factors that predict a successful endotracheal extubation. PMID- 26535431 TI - [There is evidence for the use of cannabinoids for symptomatic treatment of multiple sclerosis]. AB - We identified 16 randomized placebo-controlled trials investigating cannabinoids as symptomatic treatment in multiple sclerosis (MS). There is evidence that nabiximols oromucosal spray may reduce subjective symptoms of spasticity and that dronabinol is effective against neuropathic pain in patients with MS. The existing treatment system in Denmark is in conformity with the existing data and there is not sufficient evidence to modify it. PMID- 26535432 TI - [Diagnosis and treatment of pancreatic cysts]. AB - Incidental cystic lesions of the pancreas are often detected due to the increased use of cross-sectional imaging. Since mucinous cysts have a malignant potential, whereas pseudocysts and serous cystadenomas are benign, the distinction is of key clinical importance. Current recommendations advocate the use of multiple imaging modalities (CT/MRI/endoscopic US/endoscopic US & fine-needle aspiration) during evaluation and follow-up. This review describes the most frequent cystic lesions of the pancreas and suggests a simple investigation and treatment algorithm. PMID- 26535433 TI - Recent trends in hospitalization and in-hospital mortality associated with traumatic brain injury in Canada: A nationwide, population-based study. AB - BACKGROUND: Traumatic brain injury (TBI) is the leading cause of traumatic death and disability worldwide.We examined nationwide trends in TBI-related hospitalizations and in-hospital mortality between April 2006 and March 2011 using a nationwide, population based database that is mandatory for all hospitals in Canada. METHODS: Trends in hospitalization rates for all acute hospital separations in Canada were analyzed using linear regression. Independent predictors of in-hospital mortality were evaluated using logistic regression. RESULTS: Hospitalization rates remained stable for children and young adults but increased considerably among elderly adults (age Q65 years). Falls and motor vehicle collisions (MVCs) were the most common causes of TBI hospitalizations. TBIs caused by falls increased by 24% (p = 0.01), while MVC-related hospitalization rates decreased by 18% (p = 0.03). Elderly adults were most vulnerable to falls and experienced the greatest increase (29%) in fall-related hospitalization rates. Young adults (ages, 15Y24 years) were most at risk for MVCs but experienced the greatest decline (28%) in MVC-related admissions. There were significant trends toward increasing age, injury severity, comorbidity, hospital length of stay, and rate of in-hospital mortality.However, multivariate regression showed that odds of death decreased over time after controlling for relevant factors. Injury severity, comorbidity, and advanced age were the most important predictors of in-hospital mortality for TBI inpatients. CONCLUSION: Hospitalizations for TBI are increasing in severity and involve older populations with more complex comorbidities. Although preventive strategies for MVC-related TBI are likely having some effects, there is a critical need for effective fall prevention strategies, especially among elderly adults. PMID- 26535434 TI - [Anaphylaxis]. AB - Anaphylaxis is a potentially life-threatening systemic allergic reaction involving several organ systems. Recognition of the reaction leading to prompt treatment is essential for a good outcome. The lifesaving treatment is intramuscular injection of adrenaline (0.3-0.5 mg for adults and children > 40 kg, 0.3 mg for children 20-40 kg and 0.15 mg for infants < 20 kg). The patient must be placed on the back with elevated lower extremities to improve cerebral and cardiac circulation. High dose oxygen and crystalloid fluid load are needed to improve oxygenation and cardiac output. PMID- 26535435 TI - [Angioedema]. AB - Angioedema may be an overlooked common disease. Angioedema comprises the idiopathic, the allergic, pseudo allergic, the physical form as well as the hereditary form. Diagnosis is simple when symptoms are classical (lips, eyes and tongue) but might be missed if symptoms are nonspecific such as dizziness or dyspnoea. However, the most striking observation reviewing the literature is the absence of original research on angioedema considering the high prevalence of the disease. From a patient and physician perspective more information and research on angioedema is needed. PMID- 26535436 TI - [Valproate can induce reversible encephalopathy]. AB - Valproate (VPA) is a widely used antiepileptic drug - also in the elderly. A female patient was diagnosed with epilepsy at the age 60 of years and treated with VPA for 16 years before developing tremor, rigidity, cognitive impairment and descending consciousness progressing to coma. After discontinuation of VPA she regained full consciousness, could talk and feed herself. The extrapyramidal and cognitive symptoms completely subsided during the following months. VPA induced encephalopathy is an uncommon but serious adverse effect that should be considered in patients with cognitive decline during VPA treatment. PMID- 26535437 TI - [In Process Citation]. PMID- 26535438 TI - [Not Available]. PMID- 26535439 TI - [In Process Citation]. PMID- 26535441 TI - [Not Available]. PMID- 26535440 TI - [In Process Citation]. PMID- 26535442 TI - [Not Available]. PMID- 26535443 TI - Adaptive and innate immune modulators of inflammation and autoimmunity. AB - Both genetic and environmental factors contribute to the pathogenesis of inflammatory and autoimmune diseases. The association of specific major histocompatibility complex (MHC) alleles with susceptibility to particular autoimmune diseases is well known, although the mechanistic aspects of this link are not fully unraveled yet. Furthermore, the prevalence of many autoimmune diseases is much higher in females than in males. Intensive efforts are currently being directed to defining the role of sex hormones, the hypothalamic-pituitary adrenal (HPA) axis, and other modifying factors in this sexual dimorphism. Among the environmental factors, emerging understanding of the interplay between the gut microbiota and the immune system has opened up a new frontier of biomedical research with a renewed perspective of host-environment interactions. In addition, besides specific T helper subsets and their cytokine products, the roles of the scavenger receptors, the inflammasome, the newer cytokines of the IL 1 (e.g., IL-33, IL-37) and IL-12 (e.g., IL-27, IL-35) families, and the soluble mediators produced by adipocytes (adipokines) (e.g., leptin, adiponectin) in the pathogenesis of inflammation, autoimmunity, and metabolic disorders are increasingly being realized. In this special issue, "Cytokines in Immune Pathology and Therapy," second volume, leading experts have shared their research work and perspectives on the above-mentioned cytokines and other modulators of inflammation and autoimmunity. An outline of 15 articles in volume 2 is presented here. Volume 1 of this special issue containing 14 articles was published recently. PMID- 26535444 TI - Accessing complex urologic surgery in the 21st century. PMID- 26535446 TI - NAVIGATING THE LITIGATION QUAGMIRE. PMID- 26535445 TI - Authors' Reply. PMID- 26535447 TI - Integrating QSAR and read-across for environmental assessment. AB - Read-across and QSAR have different traditions and drawbacks. We address here two main questions: (1) How do we solve the issue of the subjectivity in the evaluation of data and results, which may be particularly critical for read across, but may have a role also for the QSAR assessment? (2) How do we take advantage of the results of both approaches to support each other? The QSAR model starts from the training set. The presence of similar chemicals with property values close to that predicted can support the result. The approach in read across is the opposite. The assessment is focused on the few substances similar to the target. The data quality of the similar chemicals is fundamental. A risk is poor standardization in the definition of 'similarity', because different approaches may be applied. Inspired by the principles of high transparency and reproducibility, a new program for read-across, called ToxRead, has been developed and made freely available ( www.toxgate.eu ). The output of ToxRead can be compared and integrated with the output of QSAR, within a weight-of-evidence strategy. We discuss the evaluation and integration of ToxRead and QSAR with examples of the assessment of bioconcentration factors of chemicals. PMID- 26535448 TI - Modelling inhibition of avian aromatase by azole pesticides. AB - The potential effects of pesticides and their metabolites on the endocrine system are of major concern to wildlife and human health. In this context, the azole pesticides have earned special attention due to their cytochrome P450 aromatase inhibition potential. Cytochrome P450 aromatase (CYP19) catalyses the conversion of androstenedione and testosterone into oestrone and oestradiol, respectively. Thus, aromatase modulates the oestrogenic balance essential not only for females, but also for male physiology, including gonadal function. Its inhibition affects reproductive organs, fertility and sexual behaviour in humans and wildlife species. Several studies have shown that azole pesticides are able to inhibit human and fish aromatases but the information on birds is lacking. Consequently, it appeared to be of interest to estimate the aromatase inhibition of azoles in three different avian species, namely Gallus gallus, Coturnix coturnix japonica and Taeniopygia guttata. In the absence of the crystal structure of the aromatase enzyme in these bird species, homology models for the individual avian species were constructed using the crystal structure of human aromatase (hAr) (pdb: 3EQM) that showed high sequence similarity for G. gallus (82.0%), T. guttata (81.9%) and C. japonica (81.2%). A homology model with Oncorhynchus mykiss (81.9%) was also designed for comparison purpose. The homology-modelled aromatase for each avian and fish species and crystal structure of human aromatase were selected for docking 46 structurally diverse azoles and related compounds. We showed that the docking behaviour of the chemicals on the different aromatases was broadly the same. We also demonstrated that there was an acceptable level of correlation between the binding score values and the available aromatase inhibition data. This means that the homology models derived on bird and fish species can be used to approximate the potential inhibitory effects of azoles on their aromatase. PMID- 26535449 TI - A General Method for High-Performance Li-Ion Battery Electrodes from Colloidal Nanoparticles without the Introduction of Binders or Conductive-Carbon Additives: The Cases of MnS, Cu(2-x)S, and Ge. AB - In this work, we demonstrate a general lithium-ion battery electrode fabrication method for colloidal nanoparticles (NPs) using electrophoretic deposition (EPD). Our process is capable of forming robust electrodes from copper sulfide, manganese sulfide, and germanium NPs without the use of additives such as polymeric binders and conductive agents. After EPD, we show two postprocessing treatments ((NH4)2S and inert atmosphere heating) to effectively remove surfactant ligands and create a linked network of particles. The NP films fabricated by this simple process exhibit excellent electrochemical performance as lithium-ion battery electrodes. Additive-free Cu(2-x)S and MnS NP films show well-defined plateaus at ~1.7 V, demonstrating potential for use as cathode electrodes. Because of the absence of additives in the NP film, this additive free NP film is an ideal template for ex situ analyses of the particles to track particle morphology changes and deterioration as a result of Li ion cycling. To this end, we perform a size-dependent investigation of Cu(2-x)S NPs and demonstrate that there is no significant relationship between size and capacity when comparing small (3.8 nm), medium (22 nm), and large (75 nm) diameter Cu(2 x)S NPs up to 50 cycles; however, the 75 nm NPs show higher Coulombic efficiency. Ex situ TEM analysis suggests that Cu(2-x)S NPs eventually break into smaller particles (<10 nm), explaining a weak correlation between size and performance. We also report for the first time on additive-free Ge NP films, which show stable capacities for up to 50 cycles at 750 mAh/g. PMID- 26535450 TI - A Focus on Veterinary Immunology. PMID- 26535451 TI - Portrayal of gay characters in Bollywood cinema. AB - Hindi cinema production from India is the largest in the world. Cinema reflects the society which it portrays, and in turn influences social attitudes. Hindi cinema, often known as Bollywood, demonstrates deep roots in society. In the last decade homosexual behaviour was legalized by the Delhi High Court but subsequently deemed illegal by the Supreme Court. These changes reflect changes in social attitudes. In this paper we highlight social attitudes to homosexuality - both male and female - in the context of portrayal in Hindi cinema. Historically, cultural and social values and the attitudes towards sexuality in India have been sex positive, but over the past 200 years under the British colonial rule they became very negative and indeed punitive towards homosexuality and homosexual men and women in line with prevalent Victorian attitudes to sex and sexual activity. Various descriptions and sexual identities have been identified and described in the literature. In this paper we describe a small selection of films from Hindi cinema which depict homosexuality. These portrayals have been largely negative. We describe the possible reasons for this and the potential impact these portrayals may have on audiences. PMID- 26535452 TI - Copper-Mediated Living Radical Polymerization (Atom Transfer Radical Polymerization and Copper(0) Mediated Polymerization): From Fundamentals to Bioapplications. PMID- 26535453 TI - High Prevalence of Covert Infection With Gastrointestinal Helminths in Cats. AB - Fecal flotation is routinely used to identify feline helminth infections in clinical practice, but it is known to have limitations of sensitivity, particularly for cestodes. To determine the prevalence of helminths in a contemporary population of cats and evaluate the ability of fecal flotation to detect these infections, helminths were recovered from intestinal tracts removed from 116 adult cats humanely euthanized by an animal control shelter in northeastern Oklahoma. Results were compared to those of fecal flotation performed using both passive and centrifugal techniques. Helminths were identified in 78/116 (67.2%) cats, including Toxocara cati (48/116; 41.4%), Ancylostoma tubaeforme (8/116; 6.9%), Dipylidium caninum (40/116; 34.5%), and Taenia taeniaeformis (30/116; 25.9%). Cats with T. cati were significantly more likely to harbor T. taeniaeformis (P = .001) than cats without ascarids. Centrifugal fecal flotation with sugar solution identified 37/48 (77.1%) T. cati infections, 8/30 (26.7%) T. taeniaeformis infections, and no D. caninum infections. Proglottids were detected on external examination in 19.0% (12/63) of cats with cestodes. Cestodes were present in over half of the cats examined in this study, but the majority of these infections were not evident by the detection of external proglottids or recovery of characteristic stages on fecal flotation. PMID- 26535454 TI - Coagulase-Positive Staphylococcus: Prevalence and Antimicrobial Resistance. AB - Staphylococcus pseudintermedius is the most prevalent coagulase-positive Staphylococcus inhabitant of the skin and mucosa of dogs and cats, causing skin and soft tissue infections in these animals. In this study, coagulase-positive Staphylococcus species were isolated from companion animals, veterinary professionals, and objects from a clinical veterinary environment by using two particular culture media, Baird-Parker RPF agar and CHROMagar Staph aureus. Different morphology features of colonies on the media allowed the identification of the species, which was confirmed by performing a multiplex polymerase chain reaction (PCR). Among 23 animals, 15 (65.2%) harbored coagulase-positive Staphylococcus, being 12 Staphylococcus pseudintermedius carriers. Four out of 12 were methicillin-resistant S. pseudintermedius (MRSP). All veterinary professionals had coagulase-positive Staphylococcus (CoPS) species on their hands and two out of nine objects sampled harbored MRSP. The antimicrobial-resistance pattern was achieved for all isolates, revealing the presence of many multidrug resistant CoPS, particularly S. pseudintermedius . The combined analysis of the antimicrobial-resistance patterns shown by the isolates led to the hypothesis that there is a possible crosscontamination and dissemination of S. aureus and S. pseudintermedius species between the three types of carriers sampled in this study that could facilitate the spread of the methicillin-resistance phenotype. PMID- 26535455 TI - Retrospective Evaluation of Canine Dermatitis Secondary to Corynebacterium spp. AB - Corynebacterium species are considered nonpathogenic in canine dermatitis; however, potential clinical significance has been demonstrated in canine otitis externa and from a dog bite wound in a human. Objectives of this study were to identify the predominant Corynebacterium species present in lesions of canine dermatitis, assess pathogenic role, determine antimicrobial susceptibility, and evaluate clinical response. Of 37 isolates identified as Corynebacterium, 31 were Corynebacterium auriscanis . Most Corynebacterium isolates were susceptible to chloramphenicol (97%), tetracyclines (92%), and amikacin (89%); isolate susceptibilities to beta-lactams, trimethoprim-sulfonamides, and fluoroquinolones were <50%. Most cultures grew mixed populations of bacteria; C. auriscanis was the only organism isolated in three patients. At recheck, 2-8 wk after initial presentation, pleomorphic rods were absent or significantly decreased in all patients. Two of three C. auriscanis isolates were obtained in pure culture and were evaluable, meaning patient had an initial exam and recheck examination. Both patients were already on antimicrobials to which C. auriscanis was resistant in vitro. Both improved after doxycycline administration. C. auriscanis may act as an opportunistic pathogen in canine dermatitis and may not respond to antimicrobial therapy based on susceptibilities for other organisms in mixed infections. Occasionally, Corynebacterium isolated alone may be pathogenic. PMID- 26535456 TI - Seizures Associated With Hypocalcemia in a Yorkshire Terrier With Protein-Losing Enteropathy. AB - A 7 yr old, male, castrated, Yorkshire terrier was presented on emergency for an acute onset of seizure activity. The owner also reported that the dog had previously exhibited other symptoms, including intermittent vomiting, diarrhea, and anorexia for several yr. The initial workup revealed a marked decrease in ionized calcium and total protein. Further diagnostics revealed decreases in magnesium, 25 hydroxyvitamin D, albumin, and globulins, and an increased parathyroid hormone level. Intestinal biopsies revealed inflammatory bowel disease and lymphangiectasia. The dog received intravenous calcium gluconate for treatment of hypocalcemia followed by oral calcium and vitamin D supplementation. Seizure activity ceased once calcium levels approached the normal range. Medical and dietary therapy for lymphangiectasia and inflammatory bowel disease consisted of prednisone, rutin, and a low-fat diet. Decreased serum total ionized calcium levels have been reported previously in dogs with protein-losing enteropathies. Typically, the hypocalcemia is not associated with clinical signs. Severe clinical signs of hypocalcemia are rarely reported in dogs with protein-losing enteropathy, but seizures, facial twitching, and tremors can occur. When presented with a dog with a history of seizure activity, panhypoproteinemia, and hypocalcemia, protein-losing enteropathy should be included on the list of differential diagnoses. PMID- 26535457 TI - Surgical and Medical Treatment of Pyloric and Duodenal Pythiosis in a Dog. AB - A 5 yr old, male, neutered mixed-breed dog was referred for persistent vomiting 2 wk following a pyloric biopsy for a pyloric outflow obstruction. Histopathology at the time of initial surgery was suggestive of pythiosis. Following referral, the dog underwent radical surgical treatment with a Billroth II procedure, partial pancreatectomy, and cholecystoduodenostomy. Histopathology and serology confirmed the diagnosis of pythiosis and medical treatment consisting of itraconazole and terbinafine was started postoperatively. Serology titers were checked again at 8, 12, and 24 wk postoperatively revealing a positive response to treatment and no reoccurrence of pythiosis. Since surgery, the patient experienced waxing and waning elevations of liver values and laparoscopic liver biopsies 10 mo postoperatively revealed hepatic cirrhosis with fibrosis, bile duct hyperplasia, and chronic inflammation. This report documents successful treatment of pyloric/duodenal pythiosis and the long-term (17 mo) consequences associated with the Billroth II, partial pancreatectomy, and biliary rerouting in the dog. PMID- 26535458 TI - Synchronous Diaphragmatic Flutter Secondary to Primary Hypoparathyroidism in a Dog. AB - A 3 yr old, spayed, female miniature mchnauzer was presented for rhythmic, spontaneous contractions of the abdominal wall and across the costal arches. The rate of contractions coincided with the heart rate and increased during exercise. The dog was diagnosed with primary hypoparathyroidism based on low plasma ionized calcium and serum parathyroid hormone (PTH) concentrations. Fluoroscopic exam confirmed the diagnosis of a synchronous diaphragmatic flutter. Treatment of the hypocalcemia led to resolution of the diaphragmatic flutter. PMID- 26535459 TI - GM2 Gangliosidosis Variant 0 (Sandhoff Disease) in a Mixed-Breed Dog. AB - GM2 gangliosidosis variant 0 (Sandhoff disease, SD) is a fatal, progressive, neurodegenerative lysosomal storage disease caused by simultaneous deficiencies of acid beta-hexosaminidases A and B. Canine SD has so far been identified only in two purebreeds. In this article, we present the case of a 10 mo old, male dog of mixed breed that developed progressive neurological signs including ataxia, postural deficit, and visual deficits and finally died at the age of 21 mo. The dog was diagnosed with SD on the basis of the results of biochemical and histopathological analyses. This is the third report of canine SD and the first time it has been identified in a mixed breed. PMID- 26535460 TI - An Unusual Case of Metastatic Seminoma in a Dog. AB - An 8 yr old, reportedly castrated male Boston terrier presented with a history of generalized hyperesthesia and intermittent shifting leg lameness. Physical examination revealed a caudal abdominal mass and bilateral shoulder pain. A complete blood count, serum biochemistry panel, and urinalysis were unremarkable. Thoracic radiographs demonstrated bony proliferation and lysis of the third sternebra, an expansile lesion of the left tenth rib, and lucency in both proximal humeral metaphyses. Abdominal radiographs and ultrasound revealed a soft tissue mass within the caudoventral right abdomen. Ultrasonography also revealed an enlarged lymph node within the right retroperitoneal space. Exploratory laparotomy identified the mass as a retained testicle. A cryptorchidectomy, lymph node biopsy, and bilateral percutaneous core biopsies of the proximal humeri were performed. Histopathologic examination revealed malignant seminoma of the testicle with metastasis to lymph node and bone. Adjuvant chemotherapy was recommended, but it was declined by the owner. All follow-up was lost. This case highlights a unique case for causative hyperesthesia secondary to a novel site of metastasis from malignant seminoma. Metastasis to bone has not been reported in humans or dogs and represents a very unusual and aberrant variant of the normally relatively benign biological behavior of seminoma in the dog. PMID- 26535461 TI - Treatment of Gastrin-Secreting Tumor With Sustained-Release Octreotide Acetate in a Dog. AB - An 8 yr old, intact male Shiba Inu was presented with loose stool, polydipsia, hematuria, vomiting, and anorexia. On abdominal ultrasonography, numerous nodules were detected in the hepatic parenchyma distributed diffusely throughout all lobes. Excisional biopsy of one of the nodules was performed via exploratory laparotomy. A histopathological diagnosis of the lesion was carcinoid, and the tumor cells stained positive to chromogranin A and gastrin. The serum gastrin level of the dog was 45,613 pg/mL (reference range: 160-284). In addition to medical treatment with omeprazole(c) and famotidine(e), suppression of gastrin secretion was attempted with octreotide acetate. A test dose of octreotide acetate significantly decreased the serum gastrin level to approximately one third of the baseline in 2 hr and the effect lasted approximately for 6 hr. On day 21, treatment with sustained-release formulation of octreotide acetate(a) (5 mg intramuscular, q 4 wk) was initiated. The serum gastrin concentration gradually decreased over 32 days and then progressively increased in parallel with the progression of the hepatic nodules. The dog gradually developed recurrence of initial clinical signs, and was lost to follow-up on day 510. PMID- 26535462 TI - Orbital and Subcutaneous Emphysema Following Enucleation and Respiratory Distress in a Japanese Chin. AB - A 7 yr old, neutered male Japanese chin presented to the Cummings School of Veterinary Medicine at Tufts University (CSVMTU) for evaluation of chronic unilateral orbital swelling that worsened following an episode of respiratory distress. The left eye had been enucleated 5 yr previously. Intermittent mild-to moderate left orbital swelling had been noted by the owner since the initial surgery. Examination demonstrated a moderate-to-severe, soft, fluctuant swelling involving the left orbit with erythema of the overlying skin. Crepitus was noted over the occipital tuberosity. Computed tomography revealed a large volume of gas involving the left orbit. The gas extended caudally within the subcutaneous tissues to both hemimandibles, dorsal to the cranium, and partially surrounded the cranial neck. The presence of a mucosa-lined, air-filled space with a patent nasolacrimal duct was noted on orbital exploration. The lining was removed and the duct closed. Histopathology confirmed the presence of an epithelial lining. No recurrence of the swelling was observed on examination 8 wk after surgery. This is the first report documenting acute worsening of orbital swelling following an episode of respiratory distress. This case highlights the importance of addressing the nasolacrimal duct while performing an enculeation in a brachycephalic dog. PMID- 26535463 TI - Juvenile Diabetes Mellitus and Concurrent Exocrine Pancreatic Insufficiency in a Labrador Retriever: Long-Term Management. AB - A 3 mo old, female, entire Labrador retriever presented with vomiting, diarrhea, polyuria, polydipsia, polyphagia, and stunted growth. Diagnostics revealed the presence of juvenile diabetes mellitus and concurrent exocrine pancreatic insufficiency. Pancreatic histopathology showed severe pancreatic atrophy. Successful treatment was achieved with a combination of insulin and pancreatic enzymes. This report describes successful long-term treatment of juvenile diabetes mellitus and concurrent exocrine pancreatic insufficiency in a dog. PMID- 26535464 TI - Denervation of the Tensor Veli Palatini Muscle and Effusion in the Tympanic Cavity. AB - An English springer spaniel was presented for right-sided atrophy of the muscles of mastication, analgesia and paralysis of the face, and vestibular dysfunction. Neurological signs were consistent with a lesion involving the pons and rostral medulla resulting in deficits in the function of the trigeminal, facial, and vestibular nerves. MRI disclosed a right-sided extraparenchymal mass consistent with a trigeminal nerve sheath neoplasm that was compressing and invading the pons and medulla. Atrophy of the muscles of mastication, innervated by the trigeminal nerve, was also observed on MRI. Additionally, effusion was present in the ipsilateral tympanic cavity. Gross and microscopic evaluation of the right tensor veli palatini muscle (TVPM) was consistent with neurogenic atrophy. Effusion in the tympanic cavity was likely the result of an inability to open the auditory tube as a consequence of paralysis of the TVPM. Without the ability to open the auditory tube, gases present within the auditory tube and tympanic cavity may be absorbed, creating a negative pressure environment that leads to fluid transudation and effusion build up. To the authors' knowledge, this is the first report to document neurogenic atrophy of the TVPM with concurrent effusion in the ipsilateral tympanic cavity. PMID- 26535465 TI - Nanoparticle-Mediated, Light-Induced Phase Separations. AB - Nanoparticles that both absorb and scatter light, when dispersed in a liquid, absorb optical energy and heat a reduced fluid volume due to the combination of multiple scattering and optical absorption. This can induce a localized liquid vapor phase change within the reduced volume without the requirement of heating the entire fluid. For binary liquid mixtures, this process results in vaporization of the more volatile component of the mixture. When subsequently condensed, these two steps of vaporization and condensation constitute a distillation process mediated by nanoparticles and driven by optical illumination. Because it does not require the heating of a large volume of fluid, this process requires substantially less energy than traditional distillation using thermal sources. We investigated nanoparticle-mediated, light-induced distillation of ethanol-H2O and 1-propanol-H2O mixtures, using Au-SiO2 nanoshells as the absorber-scatterer nanoparticle and nanoparticle-resonant laser irradiation to drive the process. For ethanol-H2O mixtures, the mole fraction of ethanol obtained in the light-induced process is substantially higher than that obtained by conventional thermal distillation, essentially removing the ethanol H2O azeotrope that limits conventional distillation. In contrast, for 1-propanol H2O mixtures the distillate properties resulting from light-induced distillation were very similar to those obtained by thermal distillation. In the 1-propanol H2O system, a nanoparticle-mediated, light-induced liquid-liquid phase separation was also observed. PMID- 26535466 TI - Investigational new drugs for focal epilepsy. AB - For more than 30 years, antiepileptic drug development has been based on specific assumptions regarding the neurobiology of epilepsy but all marketed drugs have not changed the proportion of drug refractory patients. It is, therefore, evident that new molecular targets need to be identified. Advances in neurobiology and molecular pharmacology are bringing into the epilepsy field new neurochemical functions such as those modulated by cannabinoid, serotonin, melatonin and galanin receptors. Among all the different compounds, the melatonin type 3 receptor agonist beprodone and cannabidiol are those at the more advanced stage of development. Interestingly, despite the structural analogies with tetrahydrocannabinol, the anticonvulsant activity of cannabidiol is not mediated by an interaction with cannabinoid receptors. Neurosteroids represent another remarkable class of drugs, and among them, ganaxolone is at the most advanced stage of development. Furthermore, for the first time, potential disease modifying agents and techniques are entering the epilepsy market. Rapalogues such as everolimus and the antibiotic minocycline are currently under development for specific epileptic syndromes like tuberous sclerosis or Angelman syndrome. Finally, optogenetics, though still at an early stage of development, represents a futuristic therapeutic strategy for drug-refractory epilepsy. PMID- 26535467 TI - The ever-changing brain: Clinical implications. PMID- 26535468 TI - Optic Nerve Sheath Melanoma Presenting as a Central Retinal Vein Occlusion. AB - A 64-year-old woman, with a history of diabetes and melanoma, developed a central retinal vein occlusion (CRVO) in her left eye. On exam, she had severe disc edema with retinal nerve fiber layer thickening, and anterior deformation of the peripapillary retinal pigment epithelium (RPE)/Bruch membrane layer (ppRPE/BM) toward the vitreous on spectral domain optical coherence tomography (SD-OCT) suggesting an optic nerve sheath (ONS) meningioma. Magnetic resonance imaging findings and ONS biopsy later confirmed a metastatic melanoma. This case demonstrates that the shape of the RPE/BM on SD-OCT may aid in the decision to consider imaging in patients with isolated CRVO. PMID- 26535469 TI - GDNF-induced cerebellar toxicity: A brief review. AB - Recombinant-methionyl human glial cell line-derived neurotrophic factor (GDNF) is known for its neurorestorative and neuroprotective effects in rodent and primate models of Parkinson's disease (PD). When administered locally into the putamen of Parkinsonian subjects, early clinical studies showed its potential promise as a disease-modifying agent. However, the development of GDNF for the treatment of PD has been significantly clouded by findings of cerebellar toxicity after continuous intraputamenal high-dose administration in a 6-month treatment/3-month recovery toxicology study in rhesus monkeys. Specifically, multifocal cerebellar Purkinje cell loss affecting 1-21% of the cerebellar cortex was observed in 4 of 15 (26.7%; 95% confidence interval [CI]: 10.5-52.4%) animals treated at the highest dose level tested (3000MUg/month). No cerebellar toxicity was observed at lower doses (450 and 900MUg/month) in the same study, or at similar or higher doses (up to 10,000MUg/month) in subchronic or chronic toxicology studies testing intermittent intracerebroventricular administration. While seemingly associated with the use of GDNF, the pathogenesis of the cerebellar lesions has not been fully understood to date. This review integrates available information to evaluate potential pathogenic mechanisms and provide a consolidated assessment of the findings. While other explanations are considered, the existing evidence is most consistent with the hypothesis that leakage of GDNF into cerebrospinal fluid during chronic infusions into the putamen down-regulates GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF generates the observed lesions. The implications of these findings for clinical studies with GDNF are discussed. PMID- 26535470 TI - Approaches to the management of functional tricuspid regurgitation. AB - Functional tricuspid regurgitation (FTR) is an acquired valvular abnormality that is most frequently encountered during the evaluation and operative management of left-sided heart failure and left heart valve disease. Observational studies have demonstrated that uncorrected significant FTR during mitral valve surgery can result in inferior early and late outcomes due to progression of FTR and underlying right heart failure. The 2012 ESC/EACTS and 2014 ACC/AHA guidelines strongly encourage the surgical correction of greater than mild tricuspid regurgitation or tricuspid annular dilation greater than 4 cm in patients undergoing left-sided valve surgery. Prospective randomized trials are needed to bolster the evidence behind the current recommendations. Percutaneous therapies in development may eventually result in less invasive options for treating FTR. PMID- 26535471 TI - Surveillance of endemic foci of tick-borne encephalitis in Finland 1995-2013: evidence of emergence of new foci. AB - The geographical risk areas for tick-borne encephalitis (TBE) in Finland remained the same until the beginning of the 21st century, but a considerable geographical expansion has been observed in the past 10 years. In order to support public health measures, the present study describes the number of laboratory-confirmed TBE cases and laboratory tests conducted and the associated trends by hospital district, with a particular emphasis on the suspected geographical risk areas. An additional investigation was conducted on 1,957 clinical serum samples throughout the country taken from patients with neurological symptoms to screen for undiagnosed TBE cases. This study identified new TBE foci in Finland, reflecting the spread of the disease into new areas. Even in the most endemic municipalities, transmission of TBE to humans occurred in very specific and often small foci. The number of antibody tests for TBE virus more than doubled (an increase by 105%) between 2007 and 2013. Analysis of the number of tests also revealed areas in which the awareness of clinicians may be suboptimal at present. However, it appears that underdiagnosis of neuroinvasive TBE is not common. PMID- 26535472 TI - Can silicon substituted metal-free organic dyes achieve better efficiency compared to silicon free organic dyes? A computational study. AB - The power conversion efficiency of metal-free organic dyes in dye-sensitized solar cells (DSSCs) is now comparable to ruthenium-based polypyridyl and zinc based porphyrin dyes. We have computationally investigated the structural, electronic and optical properties of a series of metal free organic dyes and their corresponding silicon substituted dyes. The DFT and TD-DFT calculations revealed that silicon substituted organic dyes have higher efficiency than the corresponding silicon free organic dyes. The computational results showed that the presence of silole units as a spacer group can significantly affect the performance of DSSCs compared to typically using thiophene as a spacer unit. These results corroborate the experimental observations reported in the literature. The time-dependent density functional theory (TDDFT) calculations performed at the CPCM-CAM-B3LYP/6-31+G* level of theory showed better agreement with the experimental absorption spectra of some reported metal free organic dyes having silole in the spacer group compared to other functionals and are employed in this study. Indoline donor based dye 5 showed a much shorter absorption spectrum (absorption peak at 425 nm) and smaller electron injection driving force (DeltaGinjection = -1.77 eV) than the corresponding dye 8 containing silicon substituted indoline as a donor and a silole group as a spacer unit. lambdamax = 502 nm and DeltaGinjection = -1.82 eV calculated for dye 8 are much larger than the corresponding silicon free dye 5. The silicon based dye 8 helps in achieving a much lower DeltaGregeneration value than 5, which can facilitate the faster electron injection rate from the dye to the semiconductor TiO2. Dye 8 should also have a higher Voc value compared to other dyes (5-7) due to favourable interaction with the electrolyte (I(-)/I3(-)). The higher planarity and better conjugation in dye 8 facilitate the transfer of electrons from the dye molecules to the semiconductor TiO2. The calculations performed with phenyl protecting groups near the silicon center of the dye molecule 8 to diminish the dimerization process showed very similar optical properties as obtained with the corresponding unprotected dye system. The designed julolidine and pyrrolo-indolizine donor based dyes also showed a similar trend as observed for indoline donor based dyes. PMID- 26535473 TI - How Does the Body Affect the Mind? Role of Cardiorespiratory Coherence in the Spectrum of Emotions. AB - The brain is considered to be the primary generator and regulator of emotions; however, afferent signals originating throughout the body are detected by the autonomic nervous system (ANS) and brainstem, and, in turn, can modulate emotional processes. During stress and negative emotional states, levels of cardiorespiratory coherence (CRC) decrease, and a shift occurs toward sympathetic dominance. In contrast, CRC levels increase during more positive emotional states, and a shift occurs toward parasympathetic dominance. The dynamic changes in CRC that accompany different emotions can provide insights into how the activity of the limbic system and afferent feedback manifest as emotions. The authors propose that the brainstem and CRC are involved in important feedback mechanisms that modulate emotions and higher cortical areas. That mechanism may be one of many mechanisms that underlie the physiological and neurological changes that are experienced during pranayama and meditation and may support the use of those techniques to treat various mood disorders and reduce stress. PMID- 26535474 TI - School-based Yoga Programs in the United States: A Survey. AB - CONTEXT: Substantial interest has begun to emerge around the implementation of yoga interventions in schools. Researchers have found that yoga practices may enhance skills such as self-regulation and prosocial behavior, and lead to improvements in students' performance. These researchers, therefore, have proposed that contemplative practices have the potential to play a crucial role in enhancing the quality of US public education. OBJECTIVE: The purpose of the present study was to provide a summary and comparison of school-based yoga programs in the United States. DESIGN: Online, listserv, and database searches were conducted to identify programs, and information was collected regarding each program's scope of work, curriculum characteristics, teacher-certification and training requirements, implementation models, modes of operation, and geographical regions. SETTING: The online, listserv, and database searches took place in Boston, MA, USA, and New Haven, CT, USA. RESULTS: Thirty-six programs were identified that offer yoga in more than 940 schools across the United States, and more than 5400 instructors have been trained by these programs to offer yoga in educational settings. Despite some variability in the exact mode of implementation, training requirements, locations served, and grades covered, the majority of the programs share a common goal of teaching 4 basic elements of yoga: (1) physical postures, (2) breathing exercises, (3) relaxation techniques, and (4) mindfulness and meditation practices. The programs also teach a variety of additional educational, social-emotional, and didactic techniques to enhance students' mental and physical health and behavior. CONCLUSIONS: The fact that the present study was able to find a relatively large number of formal, school-based yoga programs currently being implemented in the United States suggests that the programs may be acceptable and feasible to implement. The results also suggest that the popularity of school-based yoga programs may continue to grow. PMID- 26535475 TI - SPECT Perfusion Imaging Demonstrates Improvement of Traumatic Brain Injury With Transcranial Near-infrared Laser Phototherapy. AB - Traumatic brain injury (TBI) is a growing health concern affecting civilians and military personnel. Near-infrared (NIR) light has shown benefits in animal models and human trials for stroke and in animal models for TBI. Diodes emitting low level NIR often have lacked therapeutic efficacy, perhaps failing to deliver sufficient radiant energy to the necessary depth. In this case report, a patient with moderate TBI documented in anatomical magnetic resonance imaging (MRI) and perfusion single-photon emission computed tomography (SPECT) received 20 NIR treatments in the course of 2 mo using a high-power NIR laser. Symptoms were monitored by clinical examination and a novel patient diary system specifically designed for this patient population. Clinical application of these levels of infrared energy for this patient with TBI yielded highly favorable outcomes with decreased depression, anxiety, headache, and insomnia, whereas cognition and quality of life improved. Neurological function appeared to improve based on changes in the SPECT by quantitative analysis. NIR in the power range of 10-15 W at 810 and 980 nm can safely and effectively treat chronic symptoms of TBI. PMID- 26535476 TI - Endoscopic cartilage tympanoplasty: A two-handed technique using an endoscope holder. AB - OBJECTIVES/HYPOTHESIS: Endoscopic ear surgery provides a minimally invasive approach to the middle ear. The disadvantage of endoscopic ear surgery is that it is a single-handed surgical technique. The nondominant hand of the surgeon is utilized for holding and manipulating the endoscope. This necessitated the need for the development of an endoscope holder that would allow both hands to be free for surgical manipulation. The aim of this article is to report our preliminary experience using our newly designed and developed endoscope holder, which allowed us to perform cartilage tympanoplasty utilizing both hands for surgery. STUDY DESIGN: Retrospective nonrandomized clinical study. METHODS: The endoscope holder was designed and developed to aid in endoscopic ear surgery and to overcome the disadvantage of single-handed endoscopic surgery. The design of the endoscope holder is described in detail, along with instructions on how it can be used. A total of 179 endoscope holder-assisted cartilage tympanoplasties were performed to evaluate the feasibility of a two-handed technique and to evaluate the results of surgery. RESULTS: In an early follow-up period ranging from 6 to 20 months, the graft take was seen in 174 ears, with one residual perforation and four recurrent perforations, giving a success rate of 97%. The endoscope holder eliminates the disadvantages of single-handed surgery and is a good option for those who wish to perform endoscopic ear surgery using both hands. CONCLUSION: The study reports the successful application and use of the endoscope holder in a two-handed technique of endoscopic tympanoplasty. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1893-1898, 2016. PMID- 26535477 TI - Is Abdominal Paracentesis Drainage Too Risky for Patients With Severe Acute Pancreatitis? PMID- 26535478 TI - Structural and Functional Changes in the Tight Junctions of Asymptomatic and Serology-negative First-degree Relatives of Patients With Celiac Disease. AB - BACKGROUND: Ten to 15% of first-degree relatives (FDRs) of celiac disease (CeD) patients develop CeD. Although intestinal barrier functions (intestinal permeability) are abnormal in the subset of serology-negative FDRs, what leads to the abnormal barrier function is not known. GOALS: To study the ultrastructure and functions of tight junctions in serology-negative FDRs of CeD patients. STUDY: The intestinal permeability was measured in 97 asymptomatic and anti tissue transglutaminase antibody (anti-tTG Ab)-negative FDRs (using the lactulose mannitol ratio) and in 75 controls. The ultrastructure of tight junctions using transmission electron microscopy, and the expression of key tight junction proteins (claudin-2, claudin-3, occludin, JAM-A, and ZO-1) and zonulin using real time PCR and immunohistochemistry were assessed in anti-tTG Ab-negative, HLA-DQ2/ DQ8-positive FDRs having normal villi and in disease controls. In addition, the serum zonulin level was measured in 172 anti-tTG Ab-negative FDRs and 198 controls. RESULTS: The intestinal permeability was significantly increased in FDRs than in controls. Ultrastructural abnormalities such as dilatation of the tight junction (P=0.004) and loss of the pentalaminar structure (P=0.001) were more common in FDRs than in disease controls. There was significant underexpression of tight junction proteins ZO-1 (P=0.040) and occludin (P=0.041) in FDRs. There was no significant difference in the serum zonulin level between FDRs and controls (P=0.154). CONCLUSIONS: Even asymptomatic, anti-tTG-Ab-negative FDRs with a normal villous histology have both ultrastructural and functional abnormalities in tight junctions. These findings are indirect evidence of the presence of tight junction abnormalities before the onset of the disease and may have therapeutic implications. PMID- 26535479 TI - The Role of the Acid Pocket in Gastroesophageal Reflux Disease. AB - Gastroesophageal reflux disease is one of the commonest chronic conditions in the western world and its prevalence is increasing worldwide. The discovery of the acid pocket explained the paradox of acid reflux occurring more frequently in the postprandial period despite intragastric acidity being low due to the buffering effect of the meal. The acid pocket was first described in 2001 when it was detected as an area of low pH immediately distal to the cardia using dual pH electrode pull-through studies 15 minutes after a meal. It was hypothesized that there was a local pocket of acid close to the gastroesophageal junction that escapes the buffering effect of the meal, and that this is the source of postprandial acidic reflux. The presence of the acid pocket has been confirmed in other studies using different techniques including high-resolution pHmetry, Bravo capsule, magnetic resonance imaging, and scintigraphy. This review aims to describe what we know about the acid pocket including its length, volume, fluid constituents, and its relationship to the lower esophageal sphincter and squamocolumnar junction. We will discuss the possible mechanisms that lead to the formation of the acid pocket and examine what differences exist in patients who suffer from acid reflux. Treatments for reflux disease that affect the acid pocket will also be discussed. PMID- 26535480 TI - Are Anti-Tumor Necrosis Factor Trough Levels Predictive of Mucosal Healing in Patients With Inflammatory Bowel Disease?: A Systematic Review and Meta-Analysis. AB - GOALS: Our primary goal was to evaluate whether anti-tumor necrosis factor (TNF) alpha trough levels above author-determined thresholds are associated with increased rates of mucosal healing among patients with Crohn's disease and ulcerative colitis. BACKGROUND: The introduction of anti-TNF agents has considerably advanced the approach to the management of patients with inflammatory bowel disease (IBD). As use of anti-TNF therapy has increased, there has been new interest in algorithms focused on the monitoring of pharmacodynamics and pharmacokinetics to improve outcomes. In addition, there has been an increased focus on mucosal healing as marker of treatment success. STUDY: We performed a systematic review and meta-analysis. The studies examined were restricted to randomized controlled trials and cohort studies with a high Jadad or Newcastle-Ottawa score. RESULTS: All pooled analyses were based on a random effects model. Data from 2 randomized controlled trials and 5 observational studies (n=652) were included in the meta-analysis. Among patients with IBD, anti TNF trough levels above prespecified values were associated with increased rates of mucosal healing (OR=5.57; 95% CI, 3.80-8.15). There was no heterogeneity detected (I=0, Q=5.88, df=6; P=0.436) and there was minimal evidence of publication bias present. CONCLUSIONS: There is a strong relationship between anti-TNF trough levels and increased rates of mucosal healing among patients with IBD. Given the increased emphasis on mucosal healing as an outcome in practice and clinical trials, continued focus on the proactive use of pharmacokinetic testing appears warranted. PMID- 26535481 TI - Use of the Conventional Side-viewing Duodenoscope for Successful Endoscopic Retrograde Cholangiopancreatography in Postgastrectomy Patients. AB - OBJECTIVES: The aim of this study was to evaluate the usefulness of the conventional side-viewing duodenoscope for successful endoscopic retrograde cholangiopancreatography (ERCP) in postgastrectomy patients. METHODS: A total of 220 consecutive patients with bile duct stones or a distal common bile duct stricture who had previously undergone gastrectomy and were referred for ERCP were analyzed for the outcome of their ERCP. All ERCP procedures were performed using a conventional side-viewing duodenoscope. In patients who had undergone a Billroth II gastroenterostomy and total gastrectomy with Roux-en-Y reconstruction, we also used the procedure of retrieval balloon-assisted enterography. RESULTS: The study group included 220 patients who had previously undergone gastrectomy (77 women and 143 men; mean age, 72.2 y; range, 11 to 93 y). The overall enterography success rate was 90.5% (199/220), and the diagnostic and ERCP success rates were both 88.6% (195/220). Endoscopy was unsuccessful in 21 patients who received Billroth II gastroenterostomy and Roux-en-Y reconstruction. After successful endoscopy, diagnostic and ERCP success was not achieved in 4 patients with Billroth II gastroenterostomy, with or without Braun anastomosis, due to cannulation failure. The procedure-related complication rate was 5.5% (12/220), including immediate bleeding (0.9%, 2/220), pancreatitis (4.1%, 9/220), and perforation (0.5%, 1/220). There were no procedure-related deaths. CONCLUSIONS: The side-viewing duodenoscope is a useful instrument for performing successful ERCP in patients postgastrectomy. In addition, retrieval balloon-assisted enterography may improve the enterography success rate in postgastrectomy patients with Billroth II and Roux-en-Y reconstruction. PMID- 26535482 TI - Screening and Survival in Familial Adenomatous Polyposis. PMID- 26535483 TI - A Brachioradialis Splitting Approach Sparing the Pronator Quadratus for Volar Plating of the Distal Radius. AB - Fractures of the distal radius account for up to 15% of all extremity fractures. Volar plating has become more popular, as it allows locking plate technology to be applied. Traditionally, access to the volar radius has been achieved through the approach of Henry using the interval between flexor carpi radialis and the radial artery, involving incising the radial border of the pronator quadratus (PQ). With this approach, PQ repair is difficult, and when attempted is often incomplete or tenuous, as it is a direct muscle-to-muscle repair. Theoretical advantages of repairing the PQ include the provision of plate coverage, a protective gliding layer, a well-vascularized coverage of the fracture fragments, and a protective barrier against deep infection in the case of superficial infection. Techniques have been developed to try and improve on the Henry approach. We have developed a surgical approach to volar plating that utilizes the anatomic relationship between brachioradialis and PQ in a way that allows simple and stable reattachment of the PQ muscle. We have termed the technique the "Brachioradialis splitting" approach. We present it here. PMID- 26535484 TI - A Surgeon of Indications. PMID- 26535485 TI - Optimal treatment of poor-risk renal cell carcinoma patients with mTOR inhibitors and anti-VEGFR agents. AB - Poor-risk metastatic renal cell carcinoma (RCC) includes a subgroup of patients with unfavorable prognosis, according to both the Motzer and Heng criteria. Overall, owing to the poor prognosis of these patients, the approach is still a challenge for the first and subsequent lines of treatment, particularly for rare histologies other than clear cell renal cell carcinoma. In this review, we investigated the present treatment option of poor-risk metastatic RCC. Areas covered are data with first and further line of therapy with mTOR inhibitors and other agents but without cytoreductive nephrectomy or rare histologies. The current data on systemic therapy in poor-risk metastatic RCC maintain temsirolimus as the preferred first-line therapy. New agents targeting immune checkpoints are being developed in clinical trials. PMID- 26535486 TI - Ethics and health promotion within policy and practice contexts in a small jurisdiction: perspectives from the Northern Territory. PMID- 26535487 TI - Evidence for a surface gold hydride on a nanostructured gold catalyst. AB - Inelastic neutron scattering shows formation of a surface Au-H species, of key importance for the study of catalytic mechanisms. Previous assignment of this feature in the infrared as a purely Ce(3+) transition is shown to be erroneous on reducing the catalyst using hydrogen and deuterium. PMID- 26535488 TI - Novel Speciation Method Based on Diffusive Gradients in Thin-Films for in Situ Measurement of Cr(VI) in Aquatic Systems. AB - Hexavalent chromium (Cr(VI)) is much more toxic and mobile than the trivalent species (Cr(III)) and consequently, in situ monitoring of Cr(VI) can improve the understanding of Cr biogeochemistry and toxicity in ecosystems. The passive diffusive gradients in thin-films (DGT) technique is a powerful tool for determining metal(loid) speciation, but a binding phase that absorbs only one specific species of Cr is needed. N-Methyl-d-glucamine (NMDG) functional resin was incorporated into the DGT binding phase for selective measurement of Cr(VI). This NMDG-DGT sampler exhibited a theoretically linear accumulation of Cr(VI), with negligible accumulation (<5%) of Cr(III), even after 72 h deployment. The good prediction of Cr(VI) concentration in synthetic freshwater with NMDG-DGT, even in the presence of 10-time more Cr(III), further indicated the sampler's reliability in selective detection of Cr(VI). Moreover, its high capacity for Cr(VI), which exceeded 230 MUg cm(-2), facilitates measurement of Cr(VI) in both uncontaminated natural waters and in slightly and heavily contaminated (ppm level) waters. Field deployment of the NMDG-DGT sampler in such waters allowed accurate measurement of time-averaged Cr(VI) concentration, indicating its robustness for in situ measurements of Cr speciation and its potential for further application in the risk assessment of Cr. PMID- 26535490 TI - The Need for Greater Regulation, Guidelines, and a Consensus Statement for Tattoo Aftercare. PMID- 26535489 TI - N-Terminal Extensions Retard Abeta42 Fibril Formation but Allow Cross-Seeding and Coaggregation with Abeta42. AB - Amyloid beta-protein (Abeta) sequence length variants with varying aggregation propensity coexist in vivo, where coaggregation and cross-catalysis phenomena may affect the aggregation process. Until recently, naturally occurring amyloid beta protein (Abeta) variants were believed to begin at or after the canonical beta secretase cleavage site within the amyloid beta-protein precursor. However, N terminally extended forms of Abeta (NTE-Abeta) were recently discovered and may contribute to Alzheimer's disease. Here, we have used thioflavin T fluorescence to study the aggregation kinetics of Abeta42 variants with N-terminal extensions of 5-40 residues, and transmission electron microscopy to analyze the end states. We find that all variants form amyloid fibrils of similar morphology as Abeta42, but the half-time of aggregation (t1/2) increases exponentially with extension length. Monte Carlo simulations of model peptides suggest that the retardation is due to an underlying general physicochemical effect involving reduced frequency of productive molecular encounters. Indeed, global kinetic analyses reveal that NTE-Abeta42s form fibrils via the same mechanism as Abeta42, but all microscopic rate constants (primary and secondary nucleation, elongation) are reduced for the N-terminally extended variants. Still, Abeta42 and NTE-Abeta42 coaggregate to form mixed fibrils and fibrils of either Abeta42 or NTE-Abeta42 catalyze aggregation of all monomers. NTE-Abeta42 monomers display reduced aggregation rate with all kinds of seeds implying that extended termini interfere with the ability of monomers to nucleate or elongate. Cross-seeding or coaggregation may therefore represent an important contribution in the in vivo formation of assemblies believed to be important in disease. PMID- 26535491 TI - Resonant cavity perturbation: a promising new method for the assessment of total body water in children. AB - The accurate measurement of total body water (TBW) in children has important clinical and nutritional applications. Resonant cavity perturbation (RCP) is a new method for estimating TBW. This method measures the dielectric properties of the body which are related to body water. For RCP measurements, each subject lay supine on a bed inside a screened room which acts as a resonant cavity. A network analyser measures the frequencies of two low-order cavity resonances of the room, with electric-field vectors that were respectively vertical and horizontal, the resonant frequency shifts relative to the empty room are then derived. These frequency shifts correlates with TBW. The aims of this present study were to (a) develop TBW(RCP) predictive equations for children using TBWdil as the criterion method, (b) cross-validate the derived equations, (c) determine precision of the TBW(RCP) method, and (d) compare the criterion method TBWdil with three methods of estimating TBW: RCP, MFBIS and anthropometry.Predictive equations, independent of sex, were developed with linear regression in a group of 36 children. The relationship between combined RCP frequency shifts and TBWdilution had an r2 = 0.90 and standard error of the estimate (SEE) =1.42 kg. Multiple regression analysis, that included a term for body mass index, only had a small effect on r2 = 0.93 and SEE = 1.25 kg. In vivo TBW precision for the vertical, horizontal and combined frequency modes ranged from 0.7 to 3.4%. Bland-Altman analysis indicated close agreement between the criterion method TBWdil and the three other methods of TBW estimation. Mean differences were TBW(RCP(2)) = 0.01 +/- /- 1.34 kg, TBW(MFBIS) = 0.45 +/- /- 1.35 kg, TBWAnthropometry = 0.29 +/- / 1.29 kg.Currently the RCP method does not significantly improve the prediction of TBW compared to MFBIS and anthropometry in this initial study. However the derived equation was independent of sex and body size had only a small effect. PMID- 26535492 TI - The diagnostic and prognostic potential of plasma extracellular vesicles for cardiovascular disease. AB - Cardiovascular disease (CVD) is the leading cause of death worldwide and its prevalence is expected to rise rapidly worldwide in the coming decades. Atherosclerosis, the syndrome underlying CVD, is a chronic progressive disease of the arteries already present at a young age. Strokes, heart attacks and heart failure are acute CVD events that occur after decades, however, and require timely diagnosis and treatment. Plasma extracellular vesicles (EVs) are microstructures with a lipid bilayer membrane involved in hemostasis, inflammation and injury. Both EV-counts and EV-content are associated with CVD and the identification of plasma EVs is a novel source of blood-based biomarkers with the potential to improve diagnosis and prognosis of CVD. Presented in this review is an overview of the current use of EVs in CVD and a discussion of the need for robust and easy isolation technologies for plasma EV subsets. This is needed to bring this promising field towards clinical application in the patient. PMID- 26535493 TI - Debunking the July Phenomenon: Are We Asking the Right Questions? PMID- 26535494 TI - 3D printed bioceramics for dual antibiotic delivery to treat implant-associated bone infection. AB - Surgical implant-associated bone infections (osteomyelitis) have severe clinical and socioeconomic consequences. Treatment of chronic bone infections often involves antibiotics given systemically and locally to the affected site in poly (methyl methacrylate) (PMMA) bone cement. Given the high antibiotic concentrations required to affect bacteria in biofilm, local delivery is important to achieve high doses at the infection site. PMMA is not suitable to locally-deliver some biofilm-specific antibiotics, including rifampin, due to interference with PMMA polymerisation. To examine the efficacy of localised, combinational antibiotic delivery compared to PMMA standards, we fabricated rifampin- and vancomycin-laden calcium phosphate scaffolds (CPS) by three dimensional (3D) printing to treat an implant-associated Staphylococcus aureus bone infection in a murine model. All vancomycin- and rifampin-laden CPS treatments significantly reduced the bacterial burden compared with vancomycin laden PMMA. The bones were bacteria culture negative in 50 % of the mice that received sustained release vancomycin- and rifampin-laden CPS. In contrast, 100 % of the bones treated with vancomycin monotherapy using PMMA or CPS were culture positive. Yet, the monotherapy CPS significantly reduced the bacterial metabolic load following revision compared to PMMA. Biofilm persisted on the fixation hardware, but the infection-induced bone destruction was significantly reduced by local rifampin delivery. These data demonstrate that, despite the challenging implant-retaining infection model, co-delivery of rifampin and vancomycin from 3D printed CPS, which is not possible with PMMA, significantly improved the outcomes of implant-associated osteomyelitis. However, biofilm persistence on the fixation hardware reaffirms the importance of implant exchange or other biofilm eradication strategies to complement local antibiotics. PMID- 26535495 TI - Traumatic Stress, Depression, and Recovery: Child and Parent Responses After Emergency Medical Care for Unintentional Injury. AB - OBJECTIVE: To assess psychological symptoms in injured children (aged 8-17 years) and their parents after emergency department (ED) care to examine the relationship between posttraumatic stress and depression symptoms, co-occurrence of symptoms within families, and the relationship of these symptoms to parent reported overall recovery. METHODS: Children and parents (n = 263 child-parent dyads) were enrolled during ED treatment for unintentional injury. Approximately 5 months later, children and parents (n = 178 dyads) completed standardized measures of posttraumatic stress and depression symptoms and parents reported on child overall recovery. RESULTS: Follow-up assessments found significant posttraumatic stress symptoms in 15% of children and 5% of parents, significant depression symptoms in 13% of children and 16% of parents, and problematic overall recovery in 17% of children. For both children and parents, posttraumatic stress and depression symptom severity were strongly associated. Child and parent symptoms were only modestly associated with each other, and there were few families in which both child and parent had significant posttraumatic stress or depression. Parent symptoms, but not child symptoms, were inversely associated with children's overall recovery. CONCLUSIONS: For about 1 in 6 children and parents, unintentional injury treated in the ED can be associated with negative psychological sequelae and suboptimal recovery. Within families, child and parent responses may differ; their relative association with overall recovery deserves additional research. To promote emotional recovery, ED clinicians should be aware of the potential psychological impact of unintentional injury, provide timely evidence-based anticipatory guidance, and communicate these concerns to primary care clinicians. PMID- 26535496 TI - Cardiopulmonary Resuscitation in Children With In-Hospital and Out-of-Hospital Cardiopulmonary Arrest: Multicenter Study From Turkey. AB - OBJECTIVES: The objectives of this study were to determine the causes, location of cardiopulmonary arrest (CPA) in children, and demographics of cardiopulmonary resuscitation (CPR) in Turkish pediatric emergency departments and pediatric intensive care units (PICUs) and to determine survival rates and morbidities for both in-hospital and out-of-hospital CPA. METHODS: This multicenter descriptive study was conducted prospectively between January 15 and July 15, 2011, at 18 centers (15 PICUs, 3 pediatric emergency departments) in Turkey. RESULTS: During the study period, 239 children had received CPR. Patients' average age was 42.4 (SD, 58.1) months. The most common cause of CPA was respiratory failure (119 patients [49.8%]). The location of CPA was the PICU in 168 (68.6%), hospital wards in 43 (18%), out-of-hospital in 24 (10%), and pediatric emergency department in 8 patients (3.3%). The CPR duration was 30.7 (SD, 23.6) minutes (range, 1-175 minutes) and return of spontaneous circulation was achieved in 107 patients (44.8%) after the first CPR. Finally, 58 patients (24.2%) were discharged from hospital; survival rates were 26% and 8% for in-hospital and out of-hospital CPA, respectively (P = 0.001). Surviving patients' average length of hospital stay was 27.4 (SD, 39.2) days. In surviving patients, 19 (32.1%) had neurologic disability. CONCLUSION: Pediatric CPA in both the in-hospital and out of-hospital setting has a poor outcome. PMID- 26535497 TI - Effects of Timing to Diagnosis and Appendectomy in Pediatric Appendicitis. AB - OBJECTIVES: Prospectively follow pediatric appendicitis patients to assess outcomes and rates of appendiceal perforations relative to duration of symptomatology and appendectomy timing. METHODS: Data were collected on the duration of symptomatology to diagnosis and from diagnosis to appendectomy. Symptomatology duration was evaluated in 24-hour increments, and diagnosis to appendectomy was evaluated in 3-hour intervals. Appendiceal perforation rates, hospital length of stay (LOS), and operating room (OR) times were evaluated. RESULTS: Data were analyzed on 230 patients. Average age was 9.3 years (+/-3.2), 93 (40%) were female, and 64 (28%) appendectomies were perforated. Perforations had a mean 10 minutes longer OR time (63 vs 50 minutes, P < 0.001) and a 57% increase in hospital LOS (3 days' interquartile range, 1-5 vs 1 day's interquartile range, 1-3; P < 0.001). From diagnosis to appendectomy, those taken 0 to 3 hours, 4 to 6 hours, or longer than 6 hours after diagnosis had no statistically significant difference in hospital LOS or perforation rates and no clinically significant difference in OR times. Symptomatology greater than 48 hours had hospital LOS 55.7% greater and 4.9 times increased odds for perforation than those 0 to 23 hours (P < 0.05).We found no effect on perforation rates, hospital LOS, or OR time when symptomatology duration was compared independently with timing of surgery. CONCLUSIONS: Pediatric patients with appendicitis presenting with greater than 48 hours of symptomatology had 4.9 times increased odds of perforation and 56% greater hospital LOS than those presenting within 0 to 23 hours. We were unable to demonstrate a difference in perforation rates based on emergency department LOS before surgery. PMID- 26535498 TI - Emergency Procedural Sedation With Propofol in Older Teenagers: Any Cause for Concern? AB - INTRODUCTION: Propofol is a standard for adult emergency department procedural sedation (EDPS). Use in pediatric patients remains controversial. Our primary objective was to investigate whether adverse events occurred more frequently in teenage pediatric patients receiving propofol for EDPS. METHODS: This retrospective study examines records from the Halifax Procedural Sedation Registry, collected between January 1, 2006 and May 31, 2013. Patients undergoing EDPS using propofol were divided into those aged 16 to 19 years (teenagers), 20 to 65 years (adults), and older than 65 years (seniors). The primary outcomes were the incidences of hypotension and hypoxia. RESULTS: Four thousand sixty three EDPSs were included in the analysis, of which 230 involved teenagers, 2853 adults (mean age, 43.0 years), and 980 seniors (mean age, 77.1). The teenage group was significantly less likely to develop hypotension or hypoxia. These differences were confirmed on multivariate analysis. Patients in the teenage group received higher doses of propofol per kilogram/minute than the other groups. No other differences met statistical significance. CONCLUSIONS: Teenage patients receiving EDPS with propofol had a lower incidence of adverse events, and both received and tolerated larger adjusted doses of medication than older patients. Satisfaction and duration of EDPS were similar. Concerns about propofol use in younger patients have not been supported by this study. We believe that these findings support the use of propofol for EDPS in older teenagers. PMID- 26535499 TI - Emergency Point-of-Care Ultrasound Detection of Papilledema in the Pediatric Emergency Department. AB - The application of emergency point-of-care ultrasound has been expanding in pediatric emergency medicine for a decade. In this case series, we describe the detection of papilledema in patients presenting to the pediatric emergency department using this technology and its potential impact on their clinical care. PMID- 26535500 TI - Tracheal Rupture: A Rare Complication of Endotracheal Intubation. AB - There are numerous immediate and delayed complications associated with endotracheal intubation. Tracheal rupture is a rare complication whose diagnosis is often delayed. This can result in significant morbidity and mortality. We present a case of therapeutic misadventure resulting in a significant tracheal rupture in a child intubated by helicopter emergency medical services after a near-drowning. This is followed by a review of endotracheal intubation related tracheal rupture. PMID- 26535501 TI - Pediatric Acute Bacterial Sinusitis: Diagnostic and Treatment Dilemmas. AB - Acute bacterial sinusitis (ABS) is a common complication of a simple upper respiratory infection. Acute bacterial sinusitis and an upper respiratory infection, however, have different management plans. This article will help clinicians establish when a diagnosis of ABS can be made based on the latest guidelines from the American Academy of Pediatrics. Also covered will be the pathophysiology of ABS, the role of diagnostic imaging, the recognition of complications of ABS, and treatment options. PMID- 26535503 TI - Rapid Electronic Provider Documentation Design and Implementation in an Academic Pediatric Emergency Department. AB - BACKGROUND: Many emergency departments are transitioning from paper charting to full electronic health records, which include both computerized provider order entry and provider documentation. Implementation of electronic provider documentation (EPD), in particular, has been challenging. Known benefits include legibility, medicolegal and compliance safeguards, and improved access to patient charts. Offsetting these benefits may be reductions in efficiency, patient throughput, and less provider-patient interaction. METHODS: We used a rapid design process coupled with Lean principles, simulation, aggressive training, and continuous process improvement to design and implement a novel EPD system with real-time voice recognition dictation in the pediatric emergency department (PED). We used statistical process control methodologies to compare mean PED lengths of stay (LOSs) for admitted and discharged patients before and after EPD GoLive. RESULTS: We were able to design, test, train, and implement a novel EPD to the PED within 7 months. There was special cause variation, with a 2.7% (5 minute) increase in overall LOS after EPD implementation. There was a temporary 9.3% (15-minute) increase in discharge LOS for 6 weeks after GoLive, with a subsequent return to a new baseline of 4.3% (7-minute) increase. There were no significant changes in admission LOS. There was overall consistent use of the voice recognition system several months after EPD rollout. There have been improving rates of compliance with chart completion over time, as a result of easier tracking and electronic reminders to complete. CONCLUSION: Despite the inherent challenges involved in transitioning from paper charting to EPD, our study showed that an academic ED, EPD, can be rapidly designed and implemented while not significantly negatively impacting ED metrics such as LOS. We had consistent use of the voice dictation system after implementation. Time spent documenting after clinical shift was not reliably captured and is an important area of future research for successful EPD implementation. PMID- 26535504 TI - Point-of-Care Ultrasound in the Evaluation of Pyogenic Flexor Tenosynovitis. AB - A 4-year-old girl presented to the emergency department for evaluation of finger swelling after a dog bite. Point-of-care ultrasound was used to diagnose pyogenic flexor tenosynovitis of the digit after visualizing a fluid collection within the flexor tendon sheath. The patient underwent emergent incision and drainage of the digit with good outcome. PMID- 26535505 TI - Posterior Fossa Epidural Hematoma. PMID- 26535506 TI - ECGs in the ED. PMID- 26535507 TI - Colloids for the Initial Management of Severe Sepsis and Septic Shock in Pediatric Patients: A Systematic Review. AB - AIM: The goal of this study was to perform a systematic review of the literature assessing the use of colloids for the initial treatment of severe sepsis and septic shock in pediatric patients. DESIGN: The PICO [Patient, Intervention, Comparison, Outcome] method was used for the selection of studies, and the Cochrane Bias Tool was used to analyze the quality of the selected studies. DATA SEARCH: Relevant studies were sought using the following databases: EMBASE (1980 to March 2014), PubMed (1970 to March 2014), Cochrane (1980 to March 2014), Web of Science, and Scopus. Searches used the following key words: isotonic solution, crystalloid, saline solution, colloid, resuscitation, fluid therapy, sepsis and septic shock, starch, and gelatin. The filters children and clinical trial were used when possible. REVIEW METHOD: Study selection was performed by 1 examiner. The selected articles were analyzed by 2 examiners who validated the articles according to the Cochrane Bias Tool. Discrepancies were resolved by consensus or by a third examiner. RESULT: A total of 110 articles were selected based on the key words. Of these, 99 were excluded because they assessed postoperative follow up, burn cases, cardiac surgery, or nutritional therapy or were review articles, guidelines, or editorials. One study was included after an analysis of previous reviews. A total of 12 articles were selected for analysis because they were reports of clinical trials conducted with prospective cohorts and they analyzed the use of crystalloids and colloids or colloids only in the initial treatment of severe sepsis or septic shock in children and adolescents. The total number of patients was 4375, and they ranged in age from 2 months to 15 years, with most patients between 5 and 15 years. Five studies assessed patients diagnosed with malaria, 5 assessed patients with dengue shock syndrome, 1 studied febrile diseases, and 1 examined the progression of patients with septic shock caused by various causes. CONCLUSIONS: The studies analyzed did not find evidence to suggest that the use of colloids is superior to crystalloids. In some studies, the fluid volume needed to achieve initial stabilization was smaller in the group given colloids. Crystalloids are the preferred therapeutic option because of their effectiveness, low cost, and wide availability. Colloids may be the first choice in cases of malaria when the central nervous system is affected. PMID- 26535508 TI - Preventing Suicidal Ideation in Medical Interns. PMID- 26535509 TI - The Future of Japan's Health System--Sustaining Good Health with Equity at Low Cost. PMID- 26535510 TI - New Math on Drug Cost-Effectiveness. PMID- 26535511 TI - A Delicate Balance--Pharmaceutical Innovation and Access. PMID- 26535512 TI - Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma. AB - BACKGROUND: Mantle-cell lymphoma is generally incurable. Initial treatment is not standardized but usually includes cytotoxic chemotherapy. Lenalidomide, an immunomodulatory compound, and rituximab, an anti-CD20 antibody, are active in patients with recurrent mantle-cell lymphoma. We evaluated lenalidomide plus rituximab as a first-line therapy. METHODS: We conducted a single-group, multicenter, phase 2 study with induction and maintenance phases. During the induction phase, lenalidomide was administered at a dose of 20 mg daily on days 1 through 21 of every 28-day cycle for 12 cycles; the dose was escalated to 25 mg daily after the first cycle if no dose-limiting adverse events occurred during the first cycle and was reduced to 15 mg daily during the maintenance phase. Rituximab was administered once weekly for the first 4 weeks and then once every other cycle until disease progression. The primary end point was the overall response rate. Secondary end points included outcomes related to safety, survival, and quality of life. RESULTS: A total of 38 participants were enrolled at four centers from July 2011 through April 2014. The median age was 65 years. On the basis of the Mantle Cell Lymphoma International Prognostic Index scores, the proportions of participants with low-risk, intermediate-risk, and high-risk disease at baseline were similar (34%, 34%, and 32%, respectively). The most common grade 3 or 4 adverse events were neutropenia (in 50% of the patients), rash (in 29%), thrombocytopenia (in 13%), an inflammatory syndrome ("tumor flare") (in 11%), anemia (in 11%), serum sickness (in 8%), and fatigue (in 8%). At the median follow-up of 30 months (through February 2015), the overall response rate among the participants who could be evaluated was 92% (95% confidence interval [CI], 78 to 98), and the complete response rate was 64% (95% CI, 46 to 79); median progression-free survival had not been reached. The 2-year progression-free survival was estimated to be 85% (95% CI, 67 to 94), and the 2 year overall survival 97% (95% CI, 79 to 99). A response to treatment was associated with improvement in quality of life. CONCLUSIONS: Combination biologic therapy consisting of lenalidomide plus rituximab was active as initial therapy for mantle-cell lymphoma. (Funded by Celgene and Weill Cornell Medical College; ClinicalTrials.gov number, NCT01472562.). PMID- 26535513 TI - Malignant Transformation of Hymenolepis nana in a Human Host. AB - Neoplasms occur naturally in invertebrates but are not known to develop in tapeworms. We observed nests of monomorphic, undifferentiated cells in samples from lymph-node and lung biopsies in a man infected with the human immunodeficiency virus (HIV). The morphologic features and invasive behavior of the cells were characteristic of cancer, but their small size suggested a nonhuman origin. A polymerase-chain-reaction (PCR) assay targeting eukaryotes identified Hymenolepis nana DNA. Although the cells were unrecognizable as tapeworm tissue, immunohistochemical staining and probe hybridization labeled the cells in situ. Comparative deep sequencing identified H. nana structural genomic variants that are compatible with mutations described in cancer. Invasion of human tissue by abnormal, proliferating, genetically altered tapeworm cells is a novel disease mechanism that links infection and cancer. PMID- 26535514 TI - Functional Dyspepsia. PMID- 26535515 TI - IMAGES IN CLINICAL MEDICINE. Acral Lentiginous Melanoma. PMID- 26535516 TI - CLINICAL PROBLEM-SOLVING. A Breakthrough Diagnosis. PMID- 26535517 TI - Regional Nodal Irradiation in Early-Stage Breast Cancer. PMID- 26535518 TI - Regional Nodal Irradiation in Early-Stage Breast Cancer. PMID- 26535519 TI - Regional Nodal Irradiation in Early-Stage Breast Cancer. PMID- 26535520 TI - Bornavirus Associated with Fatal Human Encephalitis. PMID- 26535521 TI - Bornavirus Associated with Fatal Human Encephalitis. PMID- 26535522 TI - Chagas' Disease. PMID- 26535523 TI - Chagas' Disease. PMID- 26535524 TI - Chagas' Disease. PMID- 26535525 TI - Heparin-Induced Thrombocytopenia. PMID- 26535526 TI - Heparin-Induced Thrombocytopenia. PMID- 26535527 TI - Heparin-Induced Thrombocytopenia. PMID- 26535528 TI - Mast Cells, Mastocytosis, and Related Disorders. PMID- 26535529 TI - Mast Cells, Mastocytosis, and Related Disorders. PMID- 26535530 TI - Mast Cells, Mastocytosis, and Related Disorders. PMID- 26535531 TI - Mast Cells, Mastocytosis, and Related Disorders. PMID- 26535532 TI - Bradyarrhythmias Associated with Sofosbuvir Treatment. PMID- 26535533 TI - Bradyarrhythmias Associated with Sofosbuvir Treatment. PMID- 26535534 TI - IMAGES IN CLINICAL MEDICINE. Apical Hypertrophic Cardiomyopathy. PMID- 26535535 TI - [The bacteriophage on hundred years of significant findings]. PMID- 26535536 TI - Make your own diagnosis A 6-year old child with hyperpigmented patches in the right arm and chest. PMID- 26535537 TI - Histoid leprosy with giant lesions of fingers and toes. AB - This work was conducted at the Facultad de Medicina, Universidad de La Sabana, and at the Facultad de Medicina, Universidad Surcolombiana. Histoid leprosy, a clinical and histological variant of multibacillary leprosy, may offer a challenging diagnosis even for experts. An 83-year-old woman presented with papular, nodular and tumor-like lesions of 3 years of evolution, affecting fingers, toes, hands, thighs and knees, and wide superficial ulcers in her lower calves. Cutaneous lymphoma was suspected. A biopsy of a nodule of the knee showed a diffuse dermal infiltrate with microvacuolated histiocytes, moderate numbers of lymphocytes and plasma cells. Cutaneous lymphoma was suggested. Immunohistochemistry (IHC) showed prominent CD68-positive macrophages, as well as CD3, CD8 and CD20 positive cells. Additional sections suggested cutaneous leishmaniasis. New biopsies were sent with the clinical diagnoses of cutaneous lymphoma, Kaposi's sarcoma or lepromatous leprosy, as the patient had madarosis. These biopsies showed atrophic epidermis, a thin Grenz zone and diffuse inflammation with fusiform cells and pale vacuolated macrophages. ZiehlNeelsen stain showed abundant solid phagocytized bacilli with no globii formation. Abundant bacilli were demonstrated in the first biopsy. Histoid leprosy was diagnosed. The patient received the WHO multidrug therapy with excellent results. We concluded that Ziehl Neelsen staining should be used in the presence of a diffuse dermal infiltrate with fusiform and vacuolated histiocytes, which suggests a tumor, and an IHC particularly rich in CD68-positive macrophages; this will reveal abundant bacilli if the lesion is leprosy. A good clinical pathological correlation is essential to establish a proper diagnosis and management of the patient. PMID- 26535538 TI - [Invasive pulmonary aspergillosis: A case report]. AB - The fungus Aspergillus spp. causes infections in immunocompromised hosts and produces a variety of clinical syndromes including lung tracheobronchial, chronic necrotizing pulmonary and allergic bronchopulmonary manifestations, as well as aspergilloma, depending on the type of host-fungus relationship involved. Aspergilloma is usually colonized by Aspergillus spp. lesions in the bronchial tree, while invasive forms are characterized by the presence of hyphae below its basement membrane. The objective of the present study was to describe the case of a pediatric patient with invasive pulmonary aspergillosis in the form of pseudomembranous tracheobronchitis, including the clinical course, diagnostic approach and paraclinical care provided. The patient was a 5-year-old female with a history of Fanconi anemia who presented with febrile neutropenia and pneumonia. Antibiotic treatment with cefepime provided no improvement in the patient's condition and computed tomography of the thorax revealed bibasilar pulmonary opacities. Bronchoalveolar lavage and a lesion biopsy were performed after diagnostic bronchoscopy showed a white exophytic lesion. Since pathologic examination revealed numerous septate fungal hyphae exhibiting 45 degrees branching compatible with Aspergillus spp., the patient was treated with voriconazole. Bronchoalveolar lavage culture produced fungi of the Aspergillus flavi complex. A review of pulmonary Aspergillus spp. infection in children is also included, with emphasis on the management and treatment of clinical syndromes. In pediatric patients with hematological diseases who present with febrile neutropenia and respiratory symptoms, it is essential to consider fungi as potential etiologic agents including Aspergillus spp., which is common and causes a variety of clinical syndromes. PMID- 26535539 TI - [Ecology of Aedes aegypti and Aedes albopictus in the Americas and disease transmission]. AB - The recent range expansion of the mosquito Aedes albopictus has been associated in some areas by declines in abundance or local elimination of Aedes aegypti, but the two species still coexist in large regions of the Americas. We offer a summary of the possible mechanisms responsible for the abundance and displacement pattern observed and of their significance in terms of disease transmission. Among these mechanisms we may mention the competition for limiting resources, the differences in the ability to withstand starvation, the apparent competition through differential effects of the parasite Ascogregarina taiwanensis, and the inhibition of Ae. aegypti egg development by Ae. albopictus larvae. Habitat segregation has been proposed as a mechanism promoting the coexistence of the two species through avoidance of direct competition. Aedes aegypti predominates in urban areas, Ae. albopictus in rural ones, and both species coexist in the suburbs. There is also evidence that in certain areas, habitat segregation in terms of distance from the coast can influence the distribution of both species. Another possible cause of the rapid disappearance of Ae. aegypti is reproductive interference between the species. According to this hypothesis, asymmetric effects of interspecific mating favor Ae. albopictus. This type of reproductive interference can result in the elimination of sympatric populations of the affected species and can be one of the major causes for the swiftness with which Ae. aegypti disappeared from some places in the Americas following invasions by Ae. albopictus. PMID- 26535540 TI - [Operation of government policies for the prevention and control of dengue: The cases of Arauca and Armenia]. AB - INTRODUCTION: Dengue is a growing public health problem in urban areas, given that its transmission is associated with the environment, as well as with the behaviour of individuals and communities. The model proposed by Ecohealth to study this problem includes the operation of government policies. OBJECTIVE: To describe the operation of policies to prevent and control dengue in two Colombian cities. MATERIALS AND METHODS: A qualitative study was conducted. Data was collected through interviews with officials who worked in the health and education sectors. The contents were processed with the Ethnograph software, using the proposals of the bottom-up model of implementation as analytical categories. RESULTS: A lack of coordination was identified between department and municipal offices, with few developments of the protocol for dengue and severe dengue in terms of community participation, communication strategies and studies of inhabitants' knowledge, attitudes and practices. The integrated management strategy was limited by the instability of human resources, limited intra institutional and cross-sectorial coordination and little emphasis on promotion interventions, both at the individual and population levels. CONCLUSIONS: Coordination between the departament and the municipality needs to be strengthened in the city of Arauca. Both here and in Armenia administration of human resources and interinstitutional coordination should be improved. Promotion of preventative measures should be strengthened to impact on the determinants of dengue. PMID- 26535541 TI - [Cerebral venous sinus thrombosis: Epidemiology, clinical characteristics, imaging and prognosis]. AB - INTRODUCTION: Cerebral venous sinus thrombosis represents 0.5 - 1% of all cerebrovascular diseases. OBJECTIVE: The aim of this study was to determine the epidemiological, clinical, and imaging features of the disease, as well as the outcomes of patients with cerebral venous sinus thrombosis, and to explore the characteristics associated with unfavorable patient outcomes. MATERIALS AND METHODS: In this cross-sectional, retrospective study, the medical records of 37 patients with cerebral venous sinus thrombosis were analyzed. RESULTS: Eighty-six percent of the patients were women, and the mean patient age was 41 years. The most frequently reported symptom was headache (86.5%); headache was the single presenting symptom in 40.5% of the patients. Sixty-eight percent of the patients had at least one risk factor, the most frequent of which was obesity (24.3%). A total of 43.2% of the patients had no focal neurological findings. The most common finding on computerized tomography (CT) was hyperdense venous sinuses; on Magnetic Resonance Imaging (MRI), the most common finding was venous infarction. On average, 2.27+/-1.3 sinuses were involved; most frequently, the transverse venous sinuses were affected. The average hospital stay was 7.8+/-3.6 days. At hospital discharge, the outcomes were favorable in 92% of the patients, and the mortality rate was 5.4%. CONCLUSIONS: Cerebral venous sinus thrombosis is a different type of cerebrovascular disorder, with distinct epidemiology, risk factors, clinical presentations and functional outcomes. The diagnosis is based on clinical suspicion because of the unspecific clinical presentation of the disease. PMID- 26535542 TI - [Comparative analysis of insulin glargine vs. insulin detemir: A cost minimization study applicable to Colombia]. AB - INTRODUCTION: More than 90% of subjects diagnosed with diabetes mellitus present with type 2, which is recognized for peripheral insulin resistance. OBJECTIVE: To determine the costs of achieving glycemic target with the use of basal insulin analogs, insulin glargine (IG) once a day vs. insulin detemir (ID) once or twice a day, with a cost minimization model built from a third-party payer perspective in Colombia. MATERIALS AND METHODS: A systematic review of comparative clinical trials between IG and ID in patients with insulin-resistant type 2 diabetes was performed to determine data of use, effectiveness and frequency of and adverse events. The goal of glycemic control (effectiveness measure) was defined as HbA1c=7%. The costs of insulin were extracted from the Integrated System of Medication Prices 2012 (Ministerio de Salud y Proteccion Social de Colombia) and the IMS Consulting Group mobile average cost for the past year as of December, 2012. Sensitivity analyses were performed via Montecarlo simulations for dose and medication costs (insulin). RESULTS: Five publications met inclusion criteria. The range of the difference between insulin doses was 3.2 IU to 33 IU. The percentage of patients requiring two ID doses was 12.6-100%. There were no significant differences in hypoglycemic events. For both retail and institutional channels, there was a higher differential cost between IG vs. ID favoring IG in 4 and 5 studies, respectively. For the retail channel only one study showed the opposite results. CONCLUSIONS: As only medication costs are considered, differences in insulin units between IG and ID result in a differential cost in favor of IG that makes it a cost/effective alternative. PMID- 26535543 TI - [Functional parameters and their association with gait speed in Chilean community dwelling older adults]. AB - INTRODUCTION: Gait speed is a test to measure functional capacity in older adults. Nevertheless, the factors influencing this variable are not well described in South American populations. OBJECTIVE: To determine the relationship between usual and maximal walking speed and functional parameters among Chilean community-dwelling older adults. MATERIALS AND METHODS: An observational, descriptive and cross-sectional study including 69 older adults was conducted. The usual and maximal gait speeds were associated with body composition (body mass index), upper limbs muscle strength (arm curl-ups), lower limbs muscle strength (30 seconds sit-to-stand test), global function (Barthel index), ankle flexibility (range of motion), dynamic balance (timed Up & Go test) and aerobic capacity (2 minutes walking test). RESULTS: The ankle flexibility, lower limbs strength and aerobic capacity influenced the maximal speed (R2 =0.65; p <0.001), while the usual speed was influenced by upper limbs and lower limbs strength and by the aerobic capacity (R2 = 0.51; p <0.001). CONCLUSION: The usual and maximal gait speeds are mostly influenced by the lower limbs muscle strength plus aerobic capacity. PMID- 26535544 TI - [High prevalence of cardiovascular disease risk factors in a pediatric population]. AB - INTRODUCTION: Cardiovascular disease risk factors begin in childhood. Their presence may predict cardiovascular disease in adulthood. OBJECTIVE: To determine the prevalence of cardiovascular disease risk factors in a group of nurses' children at a health facility in Bogota, Colombia. MATERIALS AND METHODS: A cross sectional, population-based observational study among 3-17 year-old individuals evaluated between June, 2011, and July, 2012. RESULTS: A total number of 118 children were included. The mean age was 7.4 years, with a standard deviation of 3.86; 72.0% of the children had a normal weight. Prevalence of cardiovascular risk factors was distributed as follows: inadequate food habits, 89.0%; sedentary lifestyle, 78.8%; family history of cardiovascular disease, 16.1%; overweight, 15.3%, and obesity, 12.7%. There were no significant differences in risk factors between boys and girls. Among overweight and obese children, sedentary lifestyle was present in 90.9%, and among normal-weight children, in 36.5% (p<0.001). Inadequate food habits were present in 84.8% of the overweight and obese children, and in 42.4% of those with normal weight (p<0.001). Among the study population, 97.5% had at least one risk factor and 42.4% presented 3 or more. The presence of 3 or more cardiovascular disease risk factors was higher in obese children, when compared to overweight (p<0.001) and normal-weight children (p<0.001). CONCLUSIONS: The results of this study indicate that there was a substantial burden of cardiovascular disease risk factors in the 3-17 year-old children included, particularly in those who were obese or overweight. PMID- 26535545 TI - [Prevalence of birth defects according to the level of care in two hospitals, Cali, Colombia, 2012-2013]. AB - INTRODUCTION: Birth defects are morphologic alterations diagnosed prenatal or postnatally. Surveillance systems have been used to estimate the prevalence in high complexity care centers; however, the variation of the prevalence among different complexity care centers remains unknown. OBJECTIVE: To compare the prevalence of birth defects among two different complexity care centers in Cali, Colombia. MATERIALS AND METHODS: A descriptive hospital-based study following the methodology of the Latin American Collaborative Study of Congenital Malformations was conducted during 20 months in a medium complexity hospital and a high complexity hospital. RESULTS: During the study period, 7,140 births were attended of which 225 had at least one birth defect. The prevalence of these was of 1.7% (IC95% 1.3-2.0) and 7.4% (IC95% 6.2-8.7) for the medium complexity hospital and the high complexity hospital, respectively. The highest frequencies for the high complexity care center were: ventricular septal defect, 10%; congenital hydronephrosis, 7%; abdominal wall defects, 6%, and hydrocephalus, 5%, while for the medium complexity were: polydactyly, 15%; preauricular skin tags, 8%; congenital talipes equino varus, 7%, and hemangioma, 6%. CONCLUSIONS: The prevalence of birth defects among different complexity care centers varies in quantity, type and severity of the anomaly diagnosed. The surveillance of birth defects is a useful tool for any level of care. It allows estimating more accurately the prevalence of the city, as well being a base for the planning and targeting of resources according to the prevalence of different congenital defects. PMID- 26535546 TI - [Detection of molecular targets on the phosphatidylinositol signaling pathway of Leishmania spp. through bioinformatics tools and mathematical modeling]. AB - INTRODUCTION: Leishmaniasis is a disease of high impact on public health. Research on drugs for its treatment is considered a priority by the World Health Organization. The phosphatidyl-inositol signaling pathway is interesting to explore because it is involved in the survival of the parasite, by controlling osmoregulation, transport through membranes, and activation of transcription factors. OBJECTIVE: To propose drug targets against the disease through bioinformatic analysis and mathematical modeling of this signaling pathway. MATERIALS AND METHODS: The phosphatidyl-inositol pathway proteins were characterized through Pfam and TriTrypDB databases. Subsequently, a similarity analysis with human proteins was performed using the OrthoMCL and InParanoid7 tools. Finally, a boolean model of the pathway was proposed using PROMOT and CellNetAnalyzer softwares. RESULTS: The phosphatidyl-inositol signaling pathway in Leishmania spp. was reconstructed and described. The similarity analysis determined the feasibility of the phosphatidyl-inositol pathway proteins as molecular targets. Mathematical models allowed integrating the elements of the path and predicted an inhibitor effect. The following were proposed as drug targets: inositol-3-phosphate-5-phosphatase, phosphatidylinositol-4-kinase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and Inositol-1P polyphosphate phosphatase. CONCLUSION: The phosphatidyl-inositol signaling pathway is robust from the point of view of the qualitative model and the proteins found. Thus, potential drug targets against leishmaniasis were identified. Subsequently we will seek to detect drugs against this set of proteins and validate them experimentally . PMID- 26535547 TI - [Entomological study of Trypanosoma cruzi vectors in the rural communities of Sucre state, Venezuela]. AB - INTRODUCTION: The ecological niche of Reduvidae vectors has been modified due to environmental changes and human encroachment into the rural areas. OBJECTIVE: This study evaluates the current entomological indices of triatomines responsible for Trypanosoma cruzi infection in Sucre State, Venezuela. MATERIALS AND METHODS: A cross-sectional and prospective study was conducted in 95 towns and 577 dwellings in the 15 municipalities of the state of Sucre, Venezuela, from August to November, 2008. Triatomine bugs were identified on the basis of morphological characteristics, and their feces examined for T. cruzi infection through direct microscopy. Positive slides were stained with Giemsa and parasites were identified by morphologic characterization. RESULTS: The entomological indices expressing the highest values were dispersion (16.67%) and household colonization (33.33%). The triatomine species captured were: Rhodnius prolixus , Rhodnius main intradomiciliary vector. CONCLUSIONS: Despite the low index of vector infection (1.72%), the existence of species with domiciliary and peridomiciliary reproductive success ensures the persistence of the epidemiological chain both for the disease and the parasite. PMID- 26535548 TI - [Estimation of Aedes aegypti (L.) (Diptera: Culicidae) productivity in households and public spaces in a dengue endemic city in Colombia]. AB - INTRODUCTION: Aedes aegypti is a vector for the dengue virus in Colombia. Its productivity can be estimated using pupal counts. OBJECTIVE: To determine Ae. aegypti productivity in households and public spaces in Girardot (Colombia) during both wet and dry seasons. MATERIALS AND METHODS: The amount of Ae. aegypti pupae was evaluated in 20 randomly selected clusters in Girardot, each consisting of 100 households and public spaces. Inspections were performed during the rainy (February-May, 2011), and dry (August-September, 2011) seasons. House, container, Breteau, person and hectare pupae indices were estimated. RESULTS: During the rainy season households contributed 94% to the total number of pupae (n=7,098) while only 6% (n=482) were found in public spaces. In the dry season, 98% (n=9,138) of pupae were found in households and 2% (n=223), in public spaces. Low water-storage tanks and tanks for washing purposes provided >87% of pupae in households, whereas jars, tires and sinks contained most pupae in public spaces. High pupal densities were observed in public spaces during the rainy season and in streets and schools in the dry season. There were no significant differences in the index per person (rainy season=1.0; dry season=1.3) or per hectare (rainy season=0.96, dry season=0.45) between seasons. CONCLUSIONS: High Ae. aegypti pupal densities were found inside households in low water-storage tanks and tanks for washing purposes during both the dry and rainy seasons. Public spaces provided more aquatic habitats during the rainy season. Vector control strategies targeting these containers could allow a more rational use of resources and increase efficiency. PMID- 26535549 TI - [Morphological abnormalities in the cibarium of Lutzomyia evansi (Diptera: Psychodidae, Phlebotominae) caught in Trujillo, Venezuela]. AB - INTRODUCTION: Lutzomyia evansi is a recognized vector of Leishmania infantum in Colombia and Venezuela. OBJECTIVE: To describe and illustrate the morphological abnormalities in Lu. evansi females captured in a rural focus of visceral leishmaniasis in Trujillo, Venezuela. MATERIALS AND METHODS: Phlebotomine sand flies were collected using CDC light traps, Shannon traps and aspiration in resting places. The identification was performed according to Young & Duncan (1994) and drawings were made using a microscope with camara lucida . RESULTS: Abnormalities in the cibarium of Lu. evansi were detected in 4 (0.12%) females of the 3,477 adults that were studied. CONCLUSION: Lutzomyia evansi can have uncommon morphological variants associated with an increase in the number of teeth in the cibarium and their arrangement, which may lead to errors in the taxonomic identification of anomalous specimens. The study of such deformities can serve to avoid taxonomic identification errors. PMID- 26535550 TI - [What everybody should know about good clinical practices]. AB - An increasing number of countries are adopting good clinical practices guidelines as part of the regulation of clinical studies to register pharmaceutical products and other health-related products. Consequently, all parties involved in the research and development of these products should know them, implement them and ensure their compliance. However, good clinical practices guidelines are just one of the initiatives seeking to achieve the highest ethical and scientific standards in health research and in other areas where humans are research subjects. This review defines such practices and their objectives presenting in a practical manner their legal framework in Colombia, and clarifying their application in studies where interventions use no medications or those that are not clinical trials. Finally, the work discusses the challenges to ensure that good clinical practices contribute to the protection of research participants, the education of trustworthy health professionals, and a culture of respect for human beings. PMID- 26535551 TI - Evaluation of direct microplate nitrate reductase assay as a rapid method for the detection of multiple and extensively tuberculosis drug resistance. AB - INTRODUCTION: Reports of Mycobacterium tuberculosis resistant to multiple drugs are increasing globally and laboratories are becoming increasingly aware of the need for drug susceptibility testing. In recent years, due to the long time required by conventional drug susceptibility testing, new approaches have been proposed for faster detection of drug resistance, such as the nitrate reductase assay, considered fast and inexpensive, making it a good diagnostic tool for low resource countries. OBJECTIVE: The present study proposed a fast direct colorimetric drug susceptibility testing method in a microplate format using solid medium. MATERIALS AND METHODS: The diagnostic accuracy was evaluated by comparing the proportion method with the direct nitrate reductase assay in plates. Frozen sputum samples, known to be positive, were decontaminated and processed by Petroff method. The decontaminated suspension was used to perform direct nitrate reductase assay in 7H11 medium using 1 u g/ml rifampicin (RIF), 0.2 ug/ml isoniazid (INH), 2 ug/ml ofloxacin (OFX), 6 ug/ml kanamycin (KAN), 2 ug/ml amikacin (AMK) and 10 ug/ml capreomycin (CAP). Eighty-four samples were tested and the results for 69% of them were available within 21 days. RESULTS: The sensitivity and specificity compared to the proportion method, was 98.5% and 100% for INH, 98.3% and 96.2% for RIF, 91.7% and 100% for KAN, 78.8% and 97.3% for OFX, 100% and 100% for AMK and CAP, respectively. CONCLUSION: The results lead to the conclusion that direct nitrate reductase assay, in this new format, is an accurate, quick and inexpensive method to determine the susceptibility profile of M. tuberculosis and may become an alternative for countries with limited resources. PMID- 26535552 TI - Realistic Simulation of Regional Myocardial Perfusion Defects for Cardiac SPECT Studies. AB - The current 3D XCAT phantom allows users to manually define the regional myocardial perfusion defect (MPD) as a simple pie-shaped wedge region with reduced activity level in the myocardium of left ventricle. To more accurately and realistically model the MPD, we have developed a new regional MPD model for the 3D XCAT phantom for myocardial perfusion SPECT (MP-SPECT) studies based on the location and the severity of the stenosis in a computer generated coronary arterial tree. First, we generated a detailed coronary arterial tree by extending the large proximal branches segmented from patient CT images to cover the whole heart using an iterative rule-based algorithm. Second, we determined the affected downstream vascular segments of a given stenosis. Third, we computed the activity of each myocardial region as a function of the inverse-distance-weighted average of the flow of the neighboring vascular segments. Fourth, we generated a series of bull's-eye maps of MP-SPECT images of different coronary artery stenosis scenarios. Fifth, we had expert physician readers to qualitatively assess the bull's-eye maps based on their similarity to typical clinical cases in terms of the shape, the extent, and the severity of the MPDs. Their input was used to iteratively revise the coronary artery tree model so that the MPDs were closely matched to those found in bull's-eye maps from patient studies. Finally, from our simulated MP-SPECT images, we observed that (1) the locations of the MPDs caused by stenoses at different main arteries were different largely according to their vascular territories, (2) a stenosis at a proximal branch produced a larger MPD than the one at a distal branch, and (3) a more severe stenosis produced a larger MPD than the less severe one. These observations were consistent to those found in clinical cases. Therefore, this new regional MPD model has enhanced the generation of realistic pathological MP-SPECT images using the XCAT phantom. When combining with the mechanical model of the myocardium, the new model can be extended for the simulation of 4D gated MP-SPECT simulation of a pathological heart with both perfusion and motion defects. PMID- 26535553 TI - Correction to: J Ocul Pharmacol Ther 2015;31(7);413-418; DOI: 10.1089/jop.2015.0017. PMID- 26535554 TI - Effects of acute O3 stress on PSII and PSI photochemistry of sensitive and resistant snap bean genotypes (Phaseolus vulgaris L.), probed by prompt chlorophyll "a" fluorescence and 820 nm modulated reflectance. AB - The response of PSII and PSI photochemistry to acute ozone (O3) stress was tested in a "model plant system", namely the O3 sensitive (S156) and O3 resistant (R123) genotype pairs of Phaseolus vulgaris L., during a phenological phase of higher O3 sensitivity (pod formation). The modulation of the photosynthetic activity during O3 stress was analysed by measuring gas exchanges, Prompt Fluorescence (PF, JIP test) and 820 nm Modulated Reflectance (MR), a novel techniques which specifically detects the changes in the redox state of P700 and plastocyanin. The results showed that, coherently with genotypic-specific O3 sensitivity, the response of the two snap bean genotypes differed for the intensity and time of onset of the considered physiological changes. In fact, despite leaf injury and gas exchanges reduction appeared concurrently in both genotypes, S156 showed a PSII down regulation already after the first day of fumigation (DOF), and an enhancement of Cyclic Electron Flow of PSI after the second DOF, whereas R123 showed only slight adjustments until the third DOF, when the activity of both photosystems was down-regulated. Despite these differences, it is possible to distinguish in both genotypes an early O3 response of the photochemical apparatus, involving PSII only, and a following response, in which PSI activity and content are also modulated. The measurement of the MR signal, performed simultaneously with the PF measurements and the JIP-test analysis, has allowed a better understanding of the role that PSI plays in the O3 stress response of the S156/R123 model plant system. PMID- 26535556 TI - The VivaSight-DL double-lumen tube with integrated camera. PMID- 26535555 TI - Risk prediction model for respiratory complications after lung resection: An observational multicentre study. AB - BACKGROUND: Patients undergoing lung surgery are at risk of postoperative pulmonary complications (PPCs). Identifying those patients is important to optimise individual perioperative management. The Clinical Prediction Rule for Pulmonary Complications (CPRPCs) after thoracic surgery, developed by the Memorial Sloan-Kettering Cancer Center, might be an ideal predictor. The hypothesis was that CPRPC performs well for the prediction of PPCs. OBJECTIVE: The aim of our study was to provide the external validation of the CPRPC after lung resection for primary tumours, before universal acceptance. In case of poor discrimination, we planned, as a second objective, to derive a new predictive index for PPCs. DESIGN: Retrospective, observational multicentre study. PATIENTS: A total of 559 adult consecutive patients who underwent pulmonary resection. Inclusion criteria were adult patients (aged over 17 years). SETTING: Thirteen Spanish hospitals during the first half of 2011. INTERVENTIONS: A record of the PPCs defined, as in the original publication, as the presence of any of the following events: atelectasis; pneumonia; pulmonary embolism; respiratory failure; and need for supplemental oxygen at hospital discharge. MAIN OUTCOME MEASURES: The performance of the CPRPC was determined in order to examine its ability to discriminate and calibrate the presence of PPCs. RESULTS: The study included 559 patients, of whom 75 (11.6%) suffered PPCs. The CPRPC did not show enough discriminatory power for our cohort area under the receiver operating characteristic (ROC) curve 0.47 (95% confidence interval 0.37 to 0.57)]. After a fitting step by stepwise multivariate logistic regression, we identified three main predictors of PPCs: age; smoking status; and predicted postoperative forced expiratory volume in 1 s. Combining them into a simple risk score, we were able to obtain an area under the ROC curve of 0.74 (95% confidence interval 0.68 to 0.79). CONCLUSION: In this external validation, the CPRPC performed poorly despite its simplicity. The CPRPC was not a useful scale in our cohort. In contrast, we used a more accurate score to predict the occurrence of PPCs in our cohort. It is based on age, smoking status and predicted postoperative forced expiratory volume in 1 s. We propose that our formula should be externally validated. PMID- 26535557 TI - Postanaesthesia pulmonary complications after use of muscle relaxants in Europe: Study protocol of the POPULAR study. PMID- 26535558 TI - Variability by country in the European Neuroanaesthesia and Critical Care Interest Group subarachnoid haemorrhage survey. PMID- 26535559 TI - Ultra-small mesoporous silica nanoparticles as efficient carriers for pH responsive releases of anti-cancer drugs. AB - Mesoporous silica has emerged as one of the most promising carriers for drug delivery systems. However, the synthesis of ultra-small mesoporous silica nanoparticles (UMSNs) and their application in drug delivery remains a significant challenge. Here, spherical UMSNs (~25 nm) have been synthesized and tested as drug carriers. Anti-cancer drugs mitoxantrone (MX), doxorubicin (DOX) and methotrexate (MTX) have been utilized as model drugs. The pH-responsive drug delivery system can be constructed based on electrostatic interactions between carriers and drug molecules. The UMSNs could store drugs under physiological conditions and release them under acidic conditions. Different pH-responsive release profiles were obtained in phosphate buffer solutions (PBSs) at the designed pH values (from 4.0 to 7.4). MX and DOX can be used in the pH-responsive delivery system, while MTX cannot be used. Furthermore, we found that the physiological stabilities of these drug molecules in UMSNs are in a decreasing order MX > DOX > MTX, which follows the order of their isoelectric point (pI) values. PMID- 26535560 TI - The impact of smoking on the effect of the rs4972593 genetic variant on end-stage renal disease. PMID- 26535562 TI - Comparison of the histopathological effects of two electrosurgical currents in an in vivo porcine model of esophageal endoscopic mucosal resection. AB - BACKGROUND AND STUDY AIMS: Stricture formation is the main limitation of endoscopic resection in the esophagus. The optimal electrosurgical current (ESC) for endoscopic resection in the esophagus and other gastrointestinal sites is unknown. There may be a relationship between the type of ESC used and the development of post-procedure esophageal stricture. Unlike the low power coagulating current (LPCC), the microprocessor-controlled current (MCC), which alternates between short pulse cutting and coagulation, avoids high peak voltages that are thought to result in deep thermal injury. The aim of this study was to determine the histopathological variables associated with these two commonly employed ESCs used for esophageal endoscopic resection. METHODS: Standardized endoscopic resection of normal mucosa by band mucosectomy was performed by a single endoscopist in 12 adult pigs. The procedures were randomized 1 : 1 to either LPCC (ERBE 100 C at 25 W) or MCC (ERBE Endocut Q, Effect 3). Necropsy and esophagectomy were performed at 72 hours after the procedure. Two histopathologists, who were blinded to the ESC allocation, independently assessed the presence and depth of ulceration, necrosis and inflammation. RESULTS: A total of 45 resections were analyzed. In the LPCC and MCC groups, ulceration extending into the muscularis propria was present in 9/24 (37.5 %) and 1/21 (4.8 %) resected specimens, respectively (P = 0.04). Necrosis extending into the muscularis propria was present in 13/24 (54.1 %) and 1/21 (4.8 %) resected specimens, respectively (P = 0.002). One case of microperforation with muscularis propria injury was noted in the LPCC group compared with none in the MCC group. The quantified mean depth of ulceration, necrosis, and acute inflammation was significantly greater in the LPCC group. CONCLUSIONS: In an in vivo porcine survival model of esophageal endoscopic mucosal resection, the use of MCC resulted in significantly less deep thermal ulceration, necrosis, and acute inflammation compared with LPCC. MCC should be used in preference over LPCC for esophageal endoscopic resection. PMID- 26535563 TI - Pilot randomized crossover study comparing the efficacy of transnasal disposable endosheath with standard endoscopy to detect Barrett's esophagus. AB - BACKGROUND AND STUDY AIMS: The transnasal endosheath endoscope is a new disposable technology with potential applicability to the primary care setting. The aim of this study was to evaluate the efficacy of transnasal endosheath endoscopy (TEE) for the detection of Barrett's esophagus, by comparing the diagnostic accuracy of TEE with that of standard endoscopy. PATIENTS AND METHODS: This was a prospective, randomized, crossover study performed in a single tertiary referral center. Consecutive patients undergoing surveillance for Barrett's esophagus or referred for diagnostic assessment were recruited. All patients were randomized to undergo TEE followed by standard endoscopy or the reverse. Endoscopy experiences and patient preferences were evaluated using a questionnaire. Endoscopic and histologic diagnosis of Barrett's esophagus, and optical image quality of both endoscopic procedures, were compared. RESULTS: A total of 21 of 25 patients completed the study. TEE had sensitivity and specificity of 100 % for an endoscopic diagnosis of Barrett's esophagus, and of 66.7 % and 100 %, respectively, for the histologic diagnosis of Barrett's esophagus. The mean optical quality of standard endoscopy was significantly better than that of TEE (7.11 +/- 0.42 vs. 4.06 +/- 0.27; P < 0.0001). However, following endoscopy, patients reported a significantly better experience with TEE compared with standard endoscopy (7.05 +/- 0.49 vs. 4.35 +/- 0.53; P = 0.0006), with 60 % preferring TEE and 25 % preferring sedated standard endoscopy. CONCLUSIONS: In this study, TEE had equal accuracy for an endoscopic diagnosis of Barrett's esophagus compared with standard endoscopy, at the expense of reduced image quality and a lower yield of intestinal metaplasia on biopsy. TEE was better tolerated and preferred by patients. Hence, TEE needs further evaluation in primary care as an initial diagnostic tool. PMID- 26535564 TI - Structure of the light-driven sodium pump KR2 and its implications for optogenetics. AB - A key and common process present in organisms from all domains of life is the maintenance of the ion gradient between the inside and the outside of the cell. The gradient is generated by various active transporters, among which are the light-driven ion pumps of the microbial rhodopsin family. Whereas the proton pumping and anion-pumping rhodopsins have been known for a long time, the cation (sodium) pumps were described only recently. Following the discovery, high resolution atomic structures of the pump KR2 were determined that revealed the complete ion translocation pathway, including the positions of the characteristic Asn-Asp-Gln (NDQ) triad, the unusual ion uptake cavity acting as a selectivity filter, the unique N-terminal alpha-helix, capping the ion release cavity, and unexpected flexibility of the retinal-binding pocket. The structures also revealed pentamerization of KR2 and binding of sodium ions at the interface. Finally, on the basis of the structures, potassium-pumping KR2 variants have been designed, making the findings even more important for optogenetic applications. In this Structural Snapshot, we analyse the implications of the structural findings for understanding the sodium translocation mechanism and application of the pump and its mutants in optogenetics. PMID- 26535565 TI - Outreach invitations for FIT and colonoscopy improve colorectal cancer screening rates: A randomized controlled trial in a safety-net health system. AB - BACKGROUND: The effectiveness of colorectal cancer (CRC) screening is limited by underuse, particularly among underserved populations. Among a racially diverse and socioeconomically disadvantaged cohort of patients, the authors compared the effectiveness of fecal immunochemical test (FIT) outreach and colonoscopy outreach to increase screening participation rates, compared with usual visit based care. METHODS: Patients aged 50 to 64 years who were not up-to-date with CRC screening but used primary care services in a large safety-net health system were randomly assigned to mailed FIT outreach (2400 patients), mailed colonoscopy outreach (2400 patients), or usual care with opportunistic visit-based screening (1199 patients). Patients who did not respond to outreach invitations within 2 weeks received follow-up telephone reminders. The primary outcome was CRC screening completion within 12 months after randomization. RESULTS: Baseline patient characteristics across the 3 groups were similar. Using intention-to screen analysis, screening participation rates were higher for FIT outreach (58.8%) and colonoscopy outreach (42.4%) than usual care (29.6%) (P <.001 for both). Screening participation with FIT outreach was higher than that for colonoscopy outreach (P <.001). Among responders, FIT outreach had a higher percentage of patients who responded before reminders (59.0% vs 29.7%; P <.001). Nearly one-half of patients in the colonoscopy outreach group crossed over to complete FIT via usual care, whereas <5% of patients in the FIT outreach group underwent usual-care colonoscopy. CONCLUSIONS: Mailed outreach invitations appear to significantly increase CRC screening rates among underserved populations. In the current study, FIT-based outreach was found to be more effective than colonoscopy-based outreach to increase 1-time screening participation. Studies with longer follow-up are needed to compare the effectiveness of outreach strategies for promoting completion of the entire screening process. PMID- 26535566 TI - Reorganization of Azospirillum brasilense cell membrane is mediated by lipid composition adjustment to maintain optimal fluidity during water deficit. AB - AIMS: We study the Azospirillum brasilense tolerance to water deficit and the dynamics of adaptive process at the level of the membrane. METHODS AND RESULTS: Azospirillum brasilense was exposed to polyethylene glycol (PEG) growth and PEG shock. Tolerance, phospholipids and fatty acid (FA) composition and membrane fluidity were determined. Azospirillum brasilense was able to grow in the presence of PEG; however, its viability was reduced. Cells grown with PEG showed membrane fluidity similar to those grown without, the lipid composition was modified, increasing phosphatidylcholine and decreasing phosphatidylethanolamine amounts. The unsaturation FAs degree was reduced. The dynamics of the adaptive response revealed a decrease in fluidity 20 min after the addition of PEG, indicating that the PEG has a fluidizing effect on the hydrophobic region of the cell membrane. Fluidity returned to initial values after 60 min of PEG exposure. CONCLUSION: Azospirillum brasilense is able to perceive osmotic changes by changing the membrane fluidity. This effect is offset by changes in the composition of membrane phospholipid and FA, contributing to the homeostasis of membrane fluidity under water deficit. SIGNIFICANCE AND IMPACT OF THE STUDY: This knowledge can be used to develop new Azospirillum brasilense formulations showing an adapted membrane to water deficit. PMID- 26535567 TI - Correction: Time Adaptation Shows Duration Selectivity in the Human Parietal Cortex. AB - [This corrects the article DOI: 10.1371/journal.pbio.1002262.]. PMID- 26535568 TI - Glutathione S-Transferase M1 and T1 Gene Polymorphisms in Patients with Chronic Plaque-Type Psoriasis: A Case-Control Study. AB - OBJECTIVE: To determine the role of glutathione S-transferase (GST) isoenzyme polymorphisms as susceptibility factors in patients with psoriasis in a Turkish cohort. SUBJECTS AND METHODS: In this case-control study, 105 patients with plaque-type psoriasis and 102 healthy controls were recruited from the dermatology outpatient clinics of two university hospitals. Genomic DNA was extracted from whole blood using a DZ DNA isolation kit. Multiplex PCR was used to determine GSTM1 and GSTT1 polymorphisms in the isolated DNAs. RESULTS: Of the 150 patients with psoriasis, 83 (79%) were identified with the GSTT1 genotype and 22 (21%) with the null genotype. Of the 102 patients in the control group, 69 (67.6%) subjects were identified with the GSTT1 genotype and 33 (32.4%) with the null genotype. There was no significant difference between the patient and control groups (p = 0.063). Regarding the GSTM1 polymorphism, 54 (51.4%) patients were identified with this genotype and 51 (48.6%) with the null genotype; in the control group, 50 (49%) were identified with this genotype and 52 (51%) with the null genotype. Again there was no statistically significant difference between the groups (p = 0.957). CONCLUSION: In this Turkish cohort of patients with psoriasis, neither GSTT1 nor GSTM1 polymorphisms were associated with disease susceptibility. Larger studies with a wider range of GST isoenzyme are needed. PMID- 26535569 TI - Lifestyle and Ice: The Relationship between Ecological Specialization and Response to Pleistocene Climate Change. AB - Major climatic changes in the Pleistocene had significant effects on marine organisms and the environments in which they lived. The presence of divergent patterns of demographic history even among phylogenetically closely-related species sharing climatic changes raises questions as to the respective influence of species-specific traits on population structure. In this work we tested whether the lifestyle of Antarctic notothenioid benthic and pelagic fish species from the Southern Ocean influenced the concerted population response to Pleistocene climatic fluctuations. This was done by a comparative analysis of sequence variation at the cyt b and S7 loci in nine newly sequenced and four re analysed species. We found that all species underwent more or less intensive changes in population size but we also found consistent differences between demographic histories of pelagic and benthic species. Contemporary pelagic populations are significantly more genetically diverse and bear traces of older demographic expansions than less diverse benthic species that show evidence of more recent population expansions. Our findings suggest that the lifestyles of different species have strong influences on their responses to the same environmental events. Our data, in conjunction with previous studies showing a constant diversification tempo of these species during the Pleistocene, support the hypothesis that Pleistocene glaciations had a smaller effect on pelagic species than on benthic species whose survival may have relied upon ephemeral refugia in shallow shelf waters. These findings suggest that the interaction between lifestyle and environmental changes should be considered in genetic analyses. PMID- 26535570 TI - Pervasive Local-Scale Tree-Soil Habitat Association in a Tropical Forest Community. AB - We examined tree-soil habitat associations in lowland forest communities at Paracou, French Guiana. We analyzed a large dataset assembling six permanent plots totaling 37.5 ha, in which extensive LIDAR-derived topographical data and soil chemical and physical data have been integrated with precise botanical determinations. Map of relative elevation from the nearest stream summarized both soil fertility and hydromorphic characteristics, with seasonally inundated bottomlands having higher soil phosphate content and base saturation, and plateaus having higher soil carbon, nitrogen and aluminum contents. We employed a statistical test of correlations between tree species density and environmental maps, by generating Monte Carlo simulations of random raster images that preserve autocorrelation of the original maps. Nearly three fourths of the 94 taxa with at least one stem per ha showed a significant correlation between tree density and relative elevation, revealing contrasted species-habitat associations in term of abundance, with seasonally inundated bottomlands (24.5% of species) and well drained plateaus (48.9% of species). We also observed species preferences for environments with or without steep slopes (13.8% and 10.6%, respectively). We observed that closely-related species were frequently associated with different soil habitats in this region (70% of the 14 genera with congeneric species that have a significant association test) suggesting species-habitat associations have arisen multiple times in this tree community. We also tested if species with similar habitat preferences shared functional strategies. We found that seasonally inundated forest specialists tended to have smaller stature (maximum diameter) than species found on plateaus. Our results underline the importance of tree-soil habitat associations in structuring diverse communities at fine spatial scales and suggest that additional studies are needed to disentangle community assembly mechanisms related to dispersal limitation, biotic interactions and environmental filtering from species-habitat associations. Moreover, they provide a framework to generalize across tropical forest sites. PMID- 26535571 TI - (E)-4-(3,4-Dimethoxyphenyl)but-3-en-1-ol Enhances Melanogenesis through Increasing Upstream Stimulating Factor-1-Mediated Tyrosinase Expression. AB - We investigated the potential melanogenic effect of compounds from Zingiber cassumunar Roxb. Our data revealed that chloroform-soluble extract of Z. cassumunar enhanced melanin synthesis in B16F10 melanoma cells. Among the components of the chloroform extract, (E)-4-(3,4-dimethoxyphenyl)but-3-en-1-ol (DMPB) increased melanogenesis in both B16F10 cells and human primary melanocytes. In B16F10 cells, DMPB enhanced the activation of ERK and p38, and the level of tyrosinase. Although the level of microphthalmia-associated transcription factor was unchanged in DMPB-treated B16F10 cells, DMPB increased levels and nuclear localization of upstream stimulating factor-1 (USF1). Consistently, DMPB-mediated melanin synthesis was diminished in USF1-knockdown cells. Furthermore, DMPB induced hyperpigmentation in brown guinea pigs in vivo. Together, these data suggest that DMPB may promote melanin synthesis via USF1 dependent fashion and could be used as a clinical therapeutic agent against hypopigmentation-associated diseases. PMID- 26535572 TI - Effect of C-Terminal S-Palmitoylation on D2 Dopamine Receptor Trafficking and Stability. AB - We have used bioorthogonal click chemistry (BCC), a sensitive non-isotopic labeling method, to analyze the palmitoylation status of the D2 dopamine receptor (D2R), a G protein-coupled receptor (GPCR) crucial for regulation of processes such as mood, reward, and motor control. By analyzing a series of D2R constructs containing mutations in cysteine residues, we found that palmitoylation of the D2R most likely occurs on the C-terminal cysteine residue (C443) of the polypeptide. D2Rs in which C443 was deleted showed significantly reduced palmitoylation levels, plasma membrane expression, and protein stability compared to wild-type D2Rs. Rather, the C443 deletion mutant appeared to accumulate in the Golgi, indicating that palmitoylation of the D2R is important for cell surface expression of the receptor. Using the full-length D2R as bait in a membrane yeast two-hybrid (MYTH) screen, we identified the palmitoyl acyltransferase (PAT) zDHHC4 as a D2R interacting protein. Co-immunoprecipitation analysis revealed that several other PATs, including zDHHC3 and zDHHC8, also interacted with the D2R and that each of the three PATs was capable of affecting the palmitoylation status of the D2R. Finally, biochemical analyses using D2R mutants and the palmitoylation blocker, 2-bromopalmitate indicate that palmitoylation of the receptor plays a role in stability of the D2R. PMID- 26535574 TI - Herpes Zoster as a Predictor of HIV Infection in Taiwan: A Population-Based Study. AB - This study aimed to investigate the association between herpes zoster (HZ) and human immunodeficiency virus (HIV). Data were retrieved from the Longitudinal Health Insurance Databases (LHID 2005 and 2010), Taiwan. The International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] codes were used to identify Hz from 2001-2004. Identification of HIV infection was from 2005-2010. The hazard ratios of HIV among herpes zoster infected and non-herpes zoster infected patients were estimated using multiple Cox proportional hazard model. In general, 19685 participants were identified with Hz. The HIV incidence rates (per 104 person-months) in herpes zoster infected and non-infected patients were 0.191(95% CI 0.130-0.280) and 0.079 (95% CI 0.074-0.084), respectively while the hazard ratio (HR) of HIV among infected individuals was 3.518 (95% CI 2.375 5.211). This study concludes that herpes zoster could be considered as a predictor of HIV infection especially among Asian populations, hence it is vital to test herpes zoster infected individuals for HIV antibodies. PMID- 26535573 TI - Multivariate PLS Modeling of Apicomplexan FabD-Ligand Interaction Space for Mapping Target-Specific Chemical Space and Pharmacophore Fingerprints. AB - Biomolecular recognition underlying drug-target interactions is determined by both binding affinity and specificity. Whilst, quantification of binding efficacy is possible, determining specificity remains a challenge, as it requires affinity data for multiple targets with the same ligand dataset. Thus, understanding the interaction space by mapping the target space to model its complementary chemical space through computational techniques are desirable. In this study, active site architecture of FabD drug target in two apicomplexan parasites viz. Plasmodium falciparum (PfFabD) and Toxoplasma gondii (TgFabD) is explored, followed by consensus docking calculations and identification of fifteen best hit compounds, most of which are found to be derivatives of natural products. Subsequently, machine learning techniques were applied on molecular descriptors of six FabD homologs and sixty ligands to induce distinct multivariate partial-least square models. The biological space of FabD mapped by the various chemical entities explain their interaction space in general. It also highlights the selective variations in FabD of apicomplexan parasites with that of the host. Furthermore, chemometric models revealed the principal chemical scaffolds in PfFabD and TgFabD as pyrrolidines and imidazoles, respectively, which render target specificity and improve binding affinity in combination with other functional descriptors conducive for the design and optimization of the leads. PMID- 26535576 TI - How Far into Europe Did Pikas (Lagomorpha: Ochotonidae) Go during the Pleistocene? New Evidence from Central Iberia. AB - This paper reports the first find of pika remains in the Iberian Peninsula, at a site in central Spain. A fragmented mandible of Ochotona cf. pusilla was unearthed from Layer 3 (deposited some 63.4+/-5.5 ka ago as determined by thermoluminescence) of the Buena Pinta Cave. This record establishes new limits for the genus geographic distribution during the Pleistocene, shifting the previous edge of its known range southwest by some 500 km. It also supports the idea that, even though Europe's alpine mountain ranges represented a barrier that prevented the dispersal into the south to this and other taxa of small mammals from central and eastern Europe, they were crossed or circumvented at the coldest time intervals of the end of the Middle Pleistocene and of the Late Pleistocene. During those periods both the reduction of the forest cover and the emersion of large areas of the continental shelf due to the drop of the sea level probably provided these species a way to surpass this barrier. The pika mandible was found accompanying the remains of other small mammals adapted to cold climates, indicating the presence of steppe environments in central Iberia during the Late Pleistocene. PMID- 26535577 TI - HORMESIS: A Fundamental Concept with Widespread Biological and Biomedical Applications. AB - Hormesis is a biphasic dose response with specific quantitative features for the amplitude and width of the stimulation. It is highly generalizable and independent of biological model, endpoint, inducing agent, level of biological organization and mechanism. Hormesis may be induced via a direct stimulation or by overcompensation to a disruption of homeostasis. The induction of hormesis by low-level stressor agents not only rapidly upregulates adaptive processes to repair damage but also protects the adapted system from damage due to a subsequent challenging dose (toxic) within a definable temporal window. The striking consistency of the amplitude of hormetic response suggests that hormesis provides a quantitative description of biological plasticity. Knowledge of hormesis has particular potential biomedical significance with respect to slowing or retarding both normal aging processes and the progression of severe neurological diseases. PMID- 26535575 TI - Impact of Statins on Gene Expression in Human Lung Tissues. AB - Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that alter the synthesis of cholesterol. Some studies have shown a significant association of statins with improved respiratory health outcomes of patients with asthma, chronic obstructive pulmonary disease and lung cancer. Here we hypothesize that statins impact gene expression in human lungs and may reveal the pleiotropic effects of statins that are taking place directly in lung tissues. Human lung tissues were obtained from patients who underwent lung resection or transplantation. Gene expression was measured on a custom Affymetrix array in a discovery cohort (n = 408) and two replication sets (n = 341 and 282). Gene expression was evaluated by linear regression between statin users and non-users, adjusting for age, gender, smoking status, and other covariables. The results of each cohort were combined in a meta-analysis and biological pathways were studied using Gene Set Enrichment Analysis. The discovery set included 141 statin users. The lung mRNA expression levels of eighteen and three genes were up-regulated and down-regulated in statin users (FDR < 0.05), respectively. Twelve of the up regulated genes were replicated in the first replication set, but none in the second (p-value < 0.05). Combining the discovery and replication sets into a meta analysis improved the significance of the 12 up-regulated genes, which includes genes encoding enzymes and membrane proteins involved in cholesterol biosynthesis. Canonical biological pathways altered by statins in the lung include cholesterol, steroid, and terpenoid backbone biosynthesis. No genes encoding inflammatory, proteases, pro-fibrotic or growth factors were altered by statins, suggesting that the direct effect of statin in the lung do not go beyond its antilipidemic action. Although more studies are needed with specific lung cell types and different classes and doses of statins, the improved health outcomes and survival observed in statin users with chronic lung diseases do not seem to be mediated through direct regulation of gene expression in the lung. PMID- 26535578 TI - Internal or External Stenting of the Ureterovesical Anastomosis in Renal Transplantation. AB - BACKGROUND: Stenting of the ureterovesical anastomosis reduces the incidence of urological complications (UCs) after renal transplantation, but there are multiple stenting techniques, and there is no consensus regarding which technique is preferred. The aim of this study was to compare an internal versus an external stenting technique on the incidence of UCs. METHODS: This is a retrospective analysis of 419 deceased donor renal transplantations performed between January 2008 and December 2013. Until 2011, 183 patients received an external stent through the ureterovesical anastomosis placed by suprapubic bladder puncture (SP stent). From 2011, 236 recipients received an internal double-J (JJ) stent. RESULTS: The rate of UC was 3.8% in JJ stents, compared to 9.3% in SP stents (p = 0.021). No difference in surgical ureter revision rate was observed between the groups (2.1 vs. 5.5%; p = 0.068). Urinary tract infection (UTI) rate and graft function were comparable between both groups. CONCLUSIONS: Internal JJ stenting significantly decreased the incidence of UC compared to an external SP stent. There was no difference in surgical ureter revision rate, UTI or graft function. PMID- 26535579 TI - Relationship between Urinary N-Desmethyl-Acetamiprid and Typical Symptoms including Neurological Findings: A Prevalence Case-Control Study. AB - Neonicotinoid insecticides are nicotinic acetylcholine receptor agonists used worldwide. Their environmental health effects including neurotoxicity are of concern. We previously determined a metabolite of acetamiprid, N-desmethyl acetamiprid in the urine of a patient, who exhibited some typical symptoms including neurological findings. We sought to investigate the association between urinary N-desmethyl-acetamiprid and the symptoms by a prevalence case-control study. Spot urine samples were collected from 35 symptomatic patients of unknown origin and 50 non-symptomatic volunteers (non-symptomatic group, NSG, 4-87 year old). Patients with recent memory loss, finger tremor, and more than five of six symptoms (headache, general fatigue, palpitation/chest pain, abdominal pain, muscle pain/weakness/spasm, and cough) were in the typical symptomatic group (TSG, n = 19, 5-69 year-old); the rest were in the atypical symptomatic group (ASG, n = 16, 5-78 year-old). N-desmethyl-acetamiprid and six neonicotinoids in the urine were quantified by liquid chromatography-tandem mass spectrometry. The detection of N-desmethyl-acetamiprid was the most frequent and highest in TSG (47.4%, 6.0 ppb (frequency, maximum)), followed by in ASG (12.5%, 4.4 ppb) and in NSG (6.0%, 2.2 ppb), however acetamiprid was not detected. Thiamethoxam was detected in TSG (31.6%, 1.4 ppb), in ASG (6.3%, 1.9 ppb), but not in NSG. Nitenpyram was detected in TSG (10.5%, 1.2 ppb), in ASG (6.3%, not quantified) and in NSG (2.0%, not quantified). Clothianidin was only detected in ASG (6.3%, not quantified), and in NSG (2.0%, 1.6 ppb). Thiacloprid was detected in ASG (6.3%, 0.1 ppb). The cases in TSG with detection of N-desmethyl-acetamiprid and thiamethoxam were aged 5 to 62 years and 13 to 62 years, respectively. Detection of N-desmethyl-acetamiprid was associated with increased prevalence of the symptoms (odds ratio: 14, 95% confidence interval: 3.5-57). Urinary N-desmethyl acetamiprid can be used as a biomarker for environmental exposure to acetamiprid. Further multi-centered clinical research in larger patients groups with more metabolites analysis is needed. PMID- 26535580 TI - Reliability and Minimum Detectable Change of Temporal-Spatial, Kinematic, and Dynamic Stability Measures during Perturbed Gait. AB - Temporal-spatial, kinematic variability, and dynamic stability measures collected during perturbation-based assessment paradigms are often used to identify dysfunction associated with gait instability. However, it remains unclear which measures are most reliable for detecting and tracking responses to perturbations. This study systematically determined the between-session reliability and minimum detectable change values of temporal-spatial, kinematic variability, and dynamic stability measures during three types of perturbed gait. Twenty young healthy adults completed two identical testing sessions two weeks apart, comprised of an unperturbed and three perturbed (cognitive, physical, and visual) walking conditions in a virtual reality environment. Within each session, perturbation responses were compared to unperturbed walking using paired t-tests. Between session reliability and minimum detectable change values were also calculated for each measure and condition. All temporal-spatial, kinematic variability and dynamic stability measures demonstrated fair to excellent between-session reliability. Minimal detectable change values, normalized to mean values ranged from 1-50%. Step width mean and variability measures demonstrated the greatest response to perturbations with excellent between-session reliability and low minimum detectable change values. Orbital stability measures demonstrated specificity to perturbation direction and sensitivity with excellent between session reliability and low minimum detectable change values. We observed substantially greater between-session reliability and lower minimum detectable change values for local stability measures than previously described which may be the result of averaging across trials within a session and using velocity versus acceleration data for reconstruction of state spaces. Across all perturbation types, temporal-spatial, orbital and local measures were the most reliable measures with the lowest minimum detectable change values, supporting their use for tracking changes over multiple testing sessions. The between-session reliability and minimum detectable change values reported here provide an objective means for interpreting changes in temporal-spatial, kinematic variability, and dynamic stability measures during perturbed walking which may assist in identifying instability. PMID- 26535581 TI - Embelin-Induced Phosphatidylserine Translocation in the Erythrocyte Cell Membrane. AB - BACKGROUND/AIMS: The antihelminthic, contraceptive, anti-inflammatory and anticancer phytochemical embelin is at least in part effective against malignancy by inducing suicidal death or apoptosis of tumor cells. Erythrocytes are similarly able to enter suicidal death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling of eryptosis includes increase of cytosolic Ca(2+)-activity ([Ca2+]i), ceramide formation, oxidative stress as well as activation of p38 kinase and protein kinase C (PKC). The present study tested, whether and how embelin induces eryptosis. METHODS: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ceramide abundance utilizing specific antibodies and reactive oxygen species (ROS) from 2',7' dichlorodihydrofluorescein diacetate (DCFDA) fluorescence. RESULTS: A 48 hours exposure of human erythrocytes to embelin (>=25 uM) significantly increased the percentage of annexin-V-binding cells and hemolysis. Embelin did not significantly modify [Ca2+]i. The effect of embelin on annexin-V-binding was not blunted by removal of extracellular Ca2+, by p38 kinase inhibitor SB203580 (2 uM) or by PKC inhibitor staurosporine (1 uM). Embelin did, however, significantly increase the ceramide abundance. CONCLUSIONS: Embelin stimulates phospholipid scrambling of the erythrocyte cell membrane, an effect involving ceramide formation. PMID- 26535582 TI - Assessment of Flooring Renovations on African Elephant (Loxodonta africana) Behavior and Glucocorticoid Response. AB - Captive African (Loxodonta africana) and Asian (Elephas maximus) elephants can experience foot pathologies and arthritis. As a preventative measure against these pathologies and to alleviate the potential discomfort due to concrete substrates, some zoological institutions have renovated elephant housing to increase the amount of natural or shock-absorbent substrates. The objective of this study was to compare behavioral (diurnal and nocturnal) and glucorticoid (e.g., serum cortisol) responses of three female African elephants before, during, and after renovation to their indoor housing floor to assess whether renovations had short-term effects on the elephants' behavior and stress physiology. Behavioral data were collected using scan-sampling methods, and activity budgets were constructed for each of the three elephants. In addition, the duration of all lying rest activities were recorded. Weekly serum cortisol concentrations were determined with enzyme immunoassay (EIA). Overall, eating was the most prevalent behavior exhibited outdoors during the day, while resting (either in a lying or standing position) were most common during the indoor, nocturnal periods. Although variation existed among the three elephants, all three females spent significantly more time walking and less time eating during the day after the completion of the renovations. The extent to which the three elephants exhibited nocturnal lying rest behavior varied among the elephants, with the oldest elephant exhibiting the least amount (an average of 13.2 +/- 2.8% of the nightly behavioral scans) compared to the two younger elephants (an average of 34.5 +/- 2.1% and 56.6 +/- 2.8% of the nightly behavioral scans). There was a significant increase in lying rest behavior for one elephant and standing rest for a second elephant following renovations. Baseline cortisol concentrations prior to renovations were 3.0 +/- 0.4 ng/ml, 4.5 +/- 0.5 ng/ml, and 4.9 +/- 0.5 ng/ml for the three elephants. Cortisol concentrations remained baseline for two of the elephants throughout and after the renovation period, while one elephant that was pregnant had elevated cortisol during construction. Cortisol concentrations for the pregnant elephant remained higher than baseline once she was introduced to the new flooring and allowed back into the building, but these values were closer to the cortisol concentrations before renovations than during construction. Our findings demonstrate that individual elephants can vary in their behavioral and physiological responses to exhibit modifications. Given that the elephants walked more during the day, two of the three elephants had an increase in rest behavior during the night, and there were minimal changes in cortisol response after the flooring renovations, we conclude that the flooring renovations overall had a positive impact on animal welfare. PMID- 26535583 TI - The Earliest Chinese Proto-Porcelain Excavated from Kiln Sites: An Elemental Analysis. AB - In June 2012, the Piaoshan kiln site was excavated in Huzhou, Zhejiang Province, which hitherto proved to be the earliest known Chinese proto-porcelain kiln. Judging from the decorative patterns of unearthed impressed stoneware and proto porcelain sherds, the site was determined to date to the late Xia (c. 2070-c. 1600 BC), the first dynasty of China. Here, we report on proton-induced X-ray emission analyses of 118 proto-porcelain and 35 impressed stoneware sherds from Piaoshan and five subsequent kiln sites in the vicinity. Using principal components analysis on the major chemical compositions, we reveal the relationships between impressed stoneware and proto-porcelain samples from the six kiln sites. The sherds from different sites have distinctive chemical profiles. The results indicate that the raw materials were procured locally. We find a developmental tendency for early glazes towards mature calcium-based glaze. It is most likely that woody plant ashes with increased calcia-potash ratios were applied to the formula. PMID- 26535584 TI - Correction: Feelings of Hopelessness in Midlife and Cognitive Health in Later Life: A Prospective Population-Based Cohort Study. PMID- 26535585 TI - Multimorbidities and Overprescription of Proton Pump Inhibitors in Older Patients. AB - OBJECTIVES: To determine whether there is an association between overprescription of proton pump inhibitors (PPIs) and multimorbidities in older patients. DESIGN: Multicenter prospective study. SETTING: Acute geriatric medicine at the University Hospital of Nantes and the Hospital of Saint-Nazaire. PARTICIPANTS: Older patients aged 75 and over hospitalized in acute geriatric medicine. MEASUREMENTS: Older patients in acute geriatric medicine who received proton pump inhibitors. Variables studied were individual multimorbidities, the burden of multimorbidity evaluated by the Cumulative Illness Rating Scale, age, sex, type of residence (living in nursing home or not), functional abilities (Lawton and Katz scales), nutritional status (Body Mass Index), and the type of concomitant medications (antiaggregant, corticosteroids', or anticoagulants). RESULTS: Overprescription of proton pump inhibitors was found in 73.9% older patients. In the full model, cardiac diseases (odds ratio [OR] = 4.17, p = 0.010), metabolic diseases (OR = 2.14, p = 0.042) and corticosteroids (OR = 5.39, p = 0.028) were significantly associated with overprescription of proton pump inhibitors. Esogastric diseases (OR = 0.49, p = 0.033) were negatively associated with overprescription of proton pump inhibitors. CONCLUSION: Cardiac diseases and metabolic diseases were significantly associated with overprescription of proton pump inhibitors. PMID- 26535586 TI - Conservation Planning for Coral Reefs Accounting for Climate Warming Disturbances. AB - Incorporating warming disturbances into the design of marine protected areas (MPAs) is fundamental to developing appropriate conservation actions that confer coral reef resilience. We propose an MPA design approach that includes spatially- and temporally-varying sea-surface temperature (SST) data, integrating both observed (1985-2009) and projected (2010-2099) time-series. We derived indices of acute (time under reduced ecosystem function following short-term events) and chronic thermal stress (rate of warming) and combined them to delineate thermal stress regimes. Coral reefs located on the Brazilian coast were used as a case study because they are considered a conservation priority in the southwestern Atlantic Ocean. We show that all coral reef areas in Brazil have experienced and are projected to continue to experience chronic warming, while acute events are expected to increase in frequency and intensity. We formulated quantitative conservation objectives for regimes of thermal stress. Based on these objectives, we then evaluated if/how they are achieved in existing Brazilian MPAs and identified priority areas where additional protection would reinforce resilience. Our results show that, although the current system of MPAs incorporates locations within some of our thermal-stress regimes, historical and future thermal refugia along the central coast are completely unprotected. Our approach is applicable to other marine ecosystems and adds to previous marine planning for climate change in two ways: (i) by demonstrating how to spatially configure MPAs that meet conservation objectives for warming disturbance using spatially- and temporally explicit data; and (ii) by strategically allocating different forms of spatial management (MPA types) intended to mitigate warming impacts and also enhance future resistance to climate warming. PMID- 26535587 TI - Efficient and Unbiased Estimation of Population Size. AB - Population sizing from still aerial pictures is of wide applicability in ecological and social sciences. The problem is long standing because current automatic detection and counting algorithms are known to fail in most cases, and exhaustive manual counting is tedious, slow, difficult to verify and unfeasible for large populations. An alternative is to multiply population density with some reference area but, unfortunately, sampling details, handling of edge effects, etc., are seldom described. For the first time we address the problem using principles of geometric sampling. These principles are old and solid, but largely unknown outside the areas of three dimensional microscopy and stereology. Here we adapt them to estimate the size of any population of individuals lying on an essentially planar area, e.g. people, animals, trees on a savanna, etc. The proposed design is unbiased irrespective of population size, pattern, perspective artifacts, etc. The implementation is very simple-it is based on the random superimposition of coarse quadrat grids. Also, an objective error assessment is often lacking. For the latter purpose the quadrat counts are often assumed to be independent. We demonstrate that this approach can perform very poorly, and we propose (and check via Monte Carlo resampling) a new theoretical error prediction formula. As far as efficiency, counting about 50 (100) individuals in 20 quadrats, can yield relative standard errors of about 8% (5%) in typical cases. This fact effectively breaks the barrier hitherto imposed by the current lack of automatic face detection algorithms, because semiautomatic sampling and manual counting becomes an attractive option. PMID- 26535588 TI - Drug Transporter Genetic Variants Are Not Associated with TDF-Related Renal Dysfunction in Patients with HIV-1 Infection: A Pharmacogenetic Study. AB - OBJECTIVE: To investigate whether single nucleotide polymorphisms (SNP) of drug transporter proteins for TDF is a risk factor for TDF-related renal function decrement. METHODS: This study investigated the association between 3 SNPs (ABCC2 24, 1249, and ABCB1 2677), which are shown to be associated with TDF-induced tubulopathy, and clinically important renal outcomes (>10ml/min/1.73m2 decrement in eGFR relative to baseline, >25% decrement in eGFR, and eGFR <60ml/min/1.73m2) in 703 HIV-1-infected Japanese patients who initiated TDF-containing antiretroviral therapy (ART). Genotyping was performed by allelic discrimination using TaqMan 5'-nuclease assays. RESULTS: 95% of the study patients were males and 66% were treatment-naive, with median CD4 count of 249/MUl, median baseline eGFR of 96ml/min/1.73m2 (IQR 84.6-109.2), and median exposure to TDF of 3.66 years (IQR 1.93-5.59). The frequencies of genotypes at -24, 1249 of ABCC2, and 2677 of ABCB1 were neither different between patients with decrement in eGFR of >10ml/min/1.73m2 and those without such decrement (ABCC2: -24, p = 0.53, 1249, p = 0.68; ABCB1: 2677, p = 0.74), nor between those without and with the other two renal outcomes (>25% decrement: ABCC2: -24, p = 0.83, 1249, p = 0.97, ABCB1: 2677, p = 0.40; eGFR <60ml/min/1.73m2: ABCC2: -24, p = 0.51, 1249, p = 0.81, ABCB1: 2677, p = 0.94). Logistic regression analysis showed that the risk genotype of the three SNPs were not associated with any of the three renal outcomes, respectively. Logistic regression model that applied either dominant, recessive, or additive model yielded the same results. CONCLUSIONS: SNPs of the drug transporters for TDF are not associated with clinically important renal outcomes in patients who initiated TDF-containing ART. PMID- 26535589 TI - Development of an Agent-Based Model (ABM) to Simulate the Immune System and Integration of a Regression Method to Estimate the Key ABM Parameters by Fitting the Experimental Data. AB - Agent-based models (ABM) and differential equations (DE) are two commonly used methods for immune system simulation. However, it is difficult for ABM to estimate key parameters of the model by incorporating experimental data, whereas the differential equation model is incapable of describing the complicated immune system in detail. To overcome these problems, we developed an integrated ABM regression model (IABMR). It can combine the advantages of ABM and DE by employing ABM to mimic the multi-scale immune system with various phenotypes and types of cells as well as using the input and output of ABM to build up the Loess regression for key parameter estimation. Next, we employed the greedy algorithm to estimate the key parameters of the ABM with respect to the same experimental data set and used ABM to describe a 3D immune system similar to previous studies that employed the DE model. These results indicate that IABMR not only has the potential to simulate the immune system at various scales, phenotypes and cell types, but can also accurately infer the key parameters like DE model. Therefore, this study innovatively developed a complex system development mechanism that could simulate the complicated immune system in detail like ABM and validate the reliability and efficiency of model like DE by fitting the experimental data. PMID- 26535590 TI - Meticillin-resistant Staphylococcus aureus CC398 is an increasing cause of disease in people with no livestock contact in Denmark, 1999 to 2011. AB - Livestock constitutes a potential reservoir of meticillin-resistant Staphylococcus aureus isolates belonging to a recently derived lineage within clonal complex 398 (MRSA CC398-IIa). Since its discovery in the early 2000s, this lineage has become a major cause of human disease in Europe, posing a serious public health challenge in countries with intensive livestock production. To retrace the history of human colonisation and infection with MRSA CC398-IIa in Denmark, we conducted a nationwide, retrospective study of MRSA isolates collected from 1999 to 2011. Among 7,429 MRSA isolates screened, we identified 416 MRSA CC398-IIa isolates. Of these, 148 were from people with infections, including 51 from patients reporting no livestock exposure. The first cases of MRSA CC398-IIa infection in Denmark occurred in 2004. Subsequently, the incidence of MRSA CC398-IIa infection showed a linear annual increase of 66% from 2004 to 2011 (from 0.09 to 1.1 per 100,000 person-years). There were clear temporal and spatial relationships between MRSA CC398-IIa-infected patients with and without livestock exposure. These findings suggest substantial dissemination of MRSA CC398-IIa from livestock or livestock workers into the Danish community and underscore the need for strategies to control its spread both on and off the farm. PMID- 26535591 TI - Graphene field effect transistors with niobium contacts and asymmetric transfer characteristics. AB - We fabricate back-gated field effect transistors using niobium electrodes on mechanically exfoliated monolayer graphene and perform electrical characterization in the pressure range from atmospheric down to 10(-4) mbar. We study the effect of room temperature vacuum degassing and report asymmetric transfer characteristics with a resistance plateau in the n-branch. We show that weakly chemisorbed Nb acts as p-dopant on graphene and explain the transistor characteristics by Nb/graphene interaction with unpinned Fermi level at the interface. PMID- 26535592 TI - Measuring exposure to sexually explicit media among young men who have sex with men: a pilot study. AB - Background Sexually explicit media (SEM) consumption may contribute to sexual risk-taking among young men who have sex with men (YMSM). METHODS: The prevalence and frequency of SEM consumption as well as associations with contextual and sexual risk characteristics among 61 YMSM were estimated. RESULTS: All participants (n=61, 100%) reported viewing SEM; 45 (74%) in the past week. There were no significant associations between viewing SEM in the past week and measured characteristics. CONCLUSION: SEM use among YMSM is extremely common. Future research should clarify potential relations between SEM and sexual risk taking with larger samples of YMSM and specific measures, including SEM content and amount. PMID- 26535593 TI - Febuxostat in the management of gout: a cost-effectiveness analysis. AB - OBJECTIVE: To determine the cost-effectiveness of febuxostat vs allopurinol for the management of gout. METHODS: A stochastic microsimulation cost-effectiveness model with a US private-payer perspective and 5-year time horizon was developed. Model flow based on guideline and real-world treatment paradigms incorporated gout flare, serum uric acid (sUA) testing, treatment titration, discontinuation, and adverse events, chronic kidney disease (CKD) incidence and progression, and type 2 diabetes mellitus (T2DM) incidence. Outcomes were estimated for the general gout population and for gout patients with CKD stages 3/4. Modeled treatment interventions were daily oral febuxostat 40-80 mg and allopurinol 100 300 mg. Baseline patient characteristics were taken from epidemiologic studies, efficacy data from randomized controlled trials, adverse event rates from package inserts, and costs from the literature, government sources, and expert opinion. Eight clinically-relevant incremental cost-effectiveness ratios were estimated: per patient reaching target sUA, per flare avoided, per CKD incidence, progression, stages 3/4 progression, and stage 5 progression avoided, per incident T2DM avoided, and per death avoided. RESULTS: Five-year incremental cost effectiveness ratios for the general gout population were $5377 per patient reaching target sUA, $1773 per flare avoided, $221,795 per incident CKD avoided, $29,063 per CKD progression avoided, $36,018 per progression to CKD 3/4 avoided, $71,426 per progression to CKD 5 avoided, $214,277 per incident T2DM avoided, and $217,971 per death avoided. In patients with CKD 3/4, febuxostat dominated allopurinol for all cost-effectiveness outcome measures. CONCLUSIONS: Febuxostat may be a cost-effective alternative to allopurinol, especially for patients with CKD stages 3 or 4. PMID- 26535594 TI - A Plea for Self-Critique in Rheumatology. AB - It had been shown that authors do not frequently acknowledge the limitations of the work that lead to scientific articles. Limitations of scientific reports are mainly of two kinds. First is the frank acknowledgment by the authors, with its reasons, of the category in which their article best belongs, like original, confirmatory,exploratory, and so forth. Second is an open discussion of validity. This second limitation might be more involved than generally considered. We also had the impression that the relative lack of self-critique was more true for articles in basic science. A formal survey of three leading rheumatology journals confirmed our hypothesis. The possible reasons for this relative lack in basic sciences is discussed as well as is how best to voice limitations. PMID- 26535595 TI - Improvement Thresholds for Morning Stiffness Duration in Patients Receiving Delayed- Versus Immediate-Release Prednisone for Rheumatoid Arthritis. AB - BACKGROUND: Morning stiffness, a common patient reported symptom in rheumatoid arthritis, is associated with an increase in early morning inflammatory cytokines and significant disability. Little is known about categorical morning stiffness responses to glucocorticoid use in rheumatoid arthritis patients. Chronic pain threshold models have indicated previously that response rates of 15% to 30% indicate minimally important relief, 40% to 50% indicate substantial pain relief, and greater than 70% represents extensive pain relief. The objective of the present analysis was to assess differences in the percentages of patients achieving 25%(minimally important change), 50% (substantial change), and 75% (extensive change) reduction in the duration of patient-reported morning stiffness between patients receiving DR- and IR-prednisone in the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) trial. MATERIALS AND METHODS: The CAPRA-1 trial was a 12-week, double-blind study followed by an additional 9-month open-label extension. Patients in the CAPRA-1 trial were randomized to IR-prednisone in the morning or DR-prednisone at bedtime in addition to stable disease modifying antirheumatic drug therapy. After the double blind phase, patients randomized to IR-prednisone (N =110) were switched to DR prednisone and followed at 3, 6, and 9 months in an open-label extension phase. Patients originally randomized to DR-prednisone (N = 97) continued that therapy in the open-label extension. Patient morning stiffness diary entries from 4 weeks before and 4 weeks after each scheduled visit were analyzed over 1 year for threshold response. The number of patients reaching threshold response (25%, 50%, and 75% improvement) and time to morning stiffness response were examined. RESULTS: The DR-prednisone arm had significantly more responders in all three morning stiffness threshold response categories at the end of the double-blind period compared with IR-prednisone (p <= 0.05). Patients who switched from IR- to DR-prednisone in the open-label extension had comparable responses in all categories within 3 months and significantly shorter time to response versus patients already receiving DR-prednisone. DISCUSSION: DR-prednisone produced significantly higher morning stiffness response rates compared with IR prednisone, as defined by 25%, 50%, and 75% improvement thresholds, at week 12. The time to reach these thresholds was quicker with DR-prednisone, and patients who switched to DR-prednisone from IR-prednisone achieved responses comparable to the continuous DR-prednisone group over 9 months of therapy. This analysis is the first to assess time-to-event and percentage threshold morning stiffness responses to differently timed glucocorticoid therapy and propose clinically meaningful response rates in RA patients. PMID- 26535596 TI - RheuMetric A Physician Checklist to Record Patient Levels of Inflammation, Damage and Distress as Quantitative Data Rather than as Narrative Impressions. AB - BACKGROUND: A physician global estimate of patient status (DOCGL) was designed to quantitate inflammatory activity but may be influenced by the presence of damage and distress. Therefore, three additional 0 to 10 visual analog scales (VAS) have been developed on a RheuMetric checklist to record physician estimates of inflammation (DOCINF), damage (DOCDAM), and distress (DOCSTR) (such as fibromyalgia and somatization). We analyzed patient scores on a multidimensional health assessment questionnaire (MDHAQ) and four RheuMetric physician estimates inpatients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), osteoarthritis (OA), and fibromyalgia (FM). METHODS: All patients with all diagnoses seen by Rush University Medical Center rheumatologists complete an MDHAQ and have four RheuMetric 0 to 10 VAS estimates for DOCGL, DOCINF, DOCDAM, and DOCSTR assigned by the rheumatologist at each visit. A random visit of 205 patients with RA (N = 50), OA (N = 67), SLE (N = 66), and FM (N = 32) was analyzed for mean MDHAQ scores, RheuMetric estimates, and Spearman correlations. RESULTS: Mean MDHAQ scores and DOCGL were highest for FM, followed by OA, RA, and SLE. Highest estimates and highest correlations with DOCGL were seen for DOCINF in RA, for DOCDAM in OA, and for DOCSTR in FM. DOCDAM estimates were higher than DOCINF in RA and SLE, suggesting that damage may be as severe a clinical problem as inflammation. DOCGL was correlated significantly with patient global estimate (PATGL) in RA, SLE, and OA, but not in FM. CONCLUSIONS: Physician estimates for inflammation, damage,and distress differ in different rheumatic diagnoses. Many patients have inflammation and damage or distress, or all three problems, reflecting challenges of rheumatology care. PMID- 26535597 TI - Analysis of Failure with the Use of Locked Plates for Stabilization of Proximal Humerus Fractures. AB - OBJECTIVE: To evaluate factors associated with complications in a series of patients with proximal humerus fractures treated with locked plating. DESIGN: Retrospective chart review. SETTING: Level 1 Trauma Center. PATIENTS AND METHODS: A retrospective review was performed on patients older than 18 years of age treated with a locked plate for a proximal humerus fracture between June 2007 and December 2011 in order to identify any factors associated with failure. Patients had a minimum of 6 months of clinical follow-up. RESULTS: 78 proximal humerus fractures in 78 patients were stabilized using a locked plate. Twenty-four patients were lost to follow-up, while 54 patients were available for 6-month minimum follow-up and comprised the study group. A healing complication occurred in 20 patients (37%) and consisted of loss of reduction (16), varus malunion (16), avascular necrosis (6) or implant penetration (1). Eleven of 54 patients (20%) required secondary surgery. Factors associated with a healing complication were number of fracture parts (p < 0.029), one or more comorbidities (p <0.016), three or more comorbidities (p < 0.038), and varus malreduction (p < 0.001). CONCLUSION: An overall complication rate of 37% was found in patients stabilized using a locked plate after sustaining a proximal humerus fracture. Factors associated with healing complications included increased number of fracture parts, increasing number of comorbidities, and initial varus malreduction. Patient selection for locked plating after proximal humerus fracture should incorporate many factors with meticulous attention to surgical technique. PMID- 26535598 TI - Limb Sparing Resection for Tumors Involving the Distal Humerus and Reconstruction with a Modular Endoprosthesis. AB - Tumors involving the distal humerus are extremely rare. Those tumors can be safely resected and then the extremity reconstructed. In this article, we present a series of patients treated with hinged semiconstrained modular distal humeral replacement for reconstruction following wide resection of tumors of the distal humerus. We retrospectively reviewed the charts of nine patients treated for tumors of the distal humerus between 2002 and 2013. The diagnoses consisted of three primaries, five metastatic, and one benign aggressive tumor. There were four male and five female patients ranging in age from 36 to 78 years old. Patients were followed for an average of 34 months (3 to 75 months). The functional status was rated using the Musculoskeletal Tumor Score System (MSTS). Five of the nine cases presented as a pathologic fracture. Six of the nine patients died of their diseases at a mean of 17 months after main surgery. Three patients were alive and disease-free at a mean follow-up of 69 months (63 to 75 months). Seven patients demonstrated significant improvement in their elbow pain after the endoprosthetic surgery. The MSTS score for the nine cases was 81% (63% to 97%). Tumors of the distal humerus can be safely resected through an anterior approach. Once the tumor is resected, the resultant defect is reconstructed with a modular semiconstrained prosthesis. This technique allows safe tumor resection with a low complication rate and good functional results. PMID- 26535599 TI - Risk Factors for Postoperative Venous Thromboembolism in Orthopaedic Spine Surgery, Hip Arthroplasty, and Knee Arthroplasty Patients. AB - BACKGROUND: Orthopaedic surgery is a major risk factor for venous thromboembolism (VTE) manifesting as deep vein thrombosis (DVT) or pulmonary embolism (PE). Various patient characteristics alter the likelihood of a postoperative VTE, and there is substantial ambiguity in current VTE prophylaxis guidelines. PURPOSE: To determine if particular patient characteristics are risk factors for VTE following major orthopaedic surgery. METHODS: Data was reviewed from 201 patients presenting with either a PE or DVT following spine surgery or joint replacement from October 2009 through June 2013. The following characteristics were reviewed for each patient: VTE event date, surgery date and type, comorbidities and pre existing conditions, calculated comorbidity level, body mass index, prophylaxis type, time to initiation of chemoprophylaxis, time to epidural removal, and VTE event type. The control patients were randomly selected from a group of 13,782 patients during the same period. RESULTS: A history of VTE (p < 0.0001), Factor V Leiden disorder (p = 0.04) and the use of general anesthesia (p =0.05) were significant risk factors for postoperative VTE. The frequency of VTE decreased following hip and knee arthroplasty during the study period and remained constant for spine surgery. DVTs occurred 14.2 days later than PEs (p < 0.0001). Over 90% of PEs and 33.3% to 75% of DVTs were diagnosed in the first week following surgery. CONCLUSIONS: A prior history of VTE, Factor V Leiden disorder and general anesthesia increases the risk of VTE postoperatively. The probability of PE beyond the second postoperative week is low. PMID- 26535600 TI - The Relationship between the School Function Assessment (SFA) and the Gross Motor Function Classification System (GMFCS) in Ambulatory Patients with Cerebral Palsy. AB - PURPOSE: Determine the relationship between the SFA and GMFCS in children with cerebral palsy (CP). METHODS: Through correlation, regression, and ANOVA analysis, data from 103 children were examined. A regression model was used to compare SFA-predicted versus actual GMFCS levels. One-way ANOVA was utilized to determine differences between SFA subscale scores in the context of GMFCS. RESULTS: A significant correlation between composite SFA scores and GMFCS levels (r = -0.847, p < 0.020) was observed. Subscale-SFA and GMFCS correlations included Regular Class (r = -0.338, p < 0.001), Physical Tasks Adaptation (Phys1; r = -0.340, p < 0.001) and Assistance (Phys2; r = -0.340, p < 0.001), Position (r = -0.338, p<0.001), Recreational Movement (RecMvmt; r = -0.387, p <0.0001), Manipulation Movement (ManMvmt; r = -0.494, p < 0.0001), and Up/Down Stairs (UDStairs; r = -0.453, p< 0.0001). Between predicated and actual GMFCS levels, no statistical difference was observed. One-way ANOVA demonstrated SFA differences at GMFCS levels: Phys1 (F= 5.32, p < 0.002), Phys2 (F = 4.54, p < 0.005), Position (F = 4.63, p < 0.004), RecMvmt (F = 7.92, p < 0.0001), ManMvmt (F = 13.50, p < 0.0001), and UDStairs (F = 6.18, p < 0.001). CONCLUSION: Utilizing both SFA-predicted and actual GMFCS levels may help determine if a child is performing at an expected level of daily function. PMID- 26535601 TI - The Unique Macroscopic Appearance of Gouty Arthritis of the Knee. AB - Patients with significant gouty arthritis can develop disabling joint pain secondary to monosodium urate (MSU) articular deposition. We report a case of white, chalky MSU crystal deposition covering the articular surfaces of the knee as discovered by total knee arthroplasty. A 65-year-old male with a history of gout presented with bilateral knee pain. His radiographic imaging was negative for gouty tophi, and he elected to undergo left total knee arthroplasty. Intraoperatively a distinct chalky, white paste consistent with MSU deposition was observed covering the articular surfaces of the knee consistent with the diagnosis of gouty arthritis. Gout is the most common inflammatory arthritis affecting more than 3 million people in the USA. The inflammation results from the phagocytosis of monosodium urate crystals (MSU) and the release of inflammatory cytokines within the joint. Gout progresses from acute to chronic over many years and frequently causes chronic arthropathy. When significant knee pain and disability is associated with gouty arthropathy, total knee arthroplasty is certainly an option. The pathological appearance of gouty joints is characteristic. Macroscopic examination of joints affected by gout reveals a nodular, white, chalky appearance. Polarized microscopy of gout demonstrates negative birefringent needle-shaped MSU crystals. In this case report, we describe the characteristic chalky, white MSU deposit that covers the articular surfaces of a knee joint in a patient with a history of gout undergoing total knee arthroplasty. The investigators have obtained the patient's informed written consent for print and electronic publication of the case report. PMID- 26535602 TI - A Case of Adult-Onset Still's Disease Treated with Monitoring of Serum Tacrolimus Levels. AB - Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. The mainstays of treatment are glucocorticoids (GCs) and non steroidal anti-inflammatory drugs, although most cases are refractory to these conventional therapies. Immunosuppressants,such as methotrexate (MTX), cyclosporine A, tumor necrosis factor-alpha blockers, an interleukin (IL)-1 blocker, and an IL-6, receptor blocker, have been suggested in previous reports for the treatment of steroid-resistant AOSD. We report herein the case of an AOSD patient who was successfully treated with tacrolimus, another immunosuppressant, in combination with GC and MTX. Blood concentrations of tacrolimus were monitored because of the narrow therapeutic window. PMID- 26535603 TI - Clinically Amyopathic Dermatomyositis Complicated by Pleural Effusion Case Report, Literature Review, and Proposed Mechanism. AB - Polymyositis-dermatomyositis (PM-DM) is a chronic inflammatory disorder that mainly involves muscles and skin. Clinically amyopathic dermatomyositis (CADM) is a unique subset of PM-DM with typical skin manifestations but little or no evidence of musculoskeletal involvement. Many cases of dermatomyositis and CADM are associated with internal malignancy, but pulmonary manifestations can also been seen; the most common of which is interstitial lung disease. Pleural effusion is a rare complication and may be difficult to differentiate from other causes, such as infections, heart failure, or malignancy. We report a patient with CADM complicated by rapidly progressive pleural effusions. Based on findings of this patient, as well as literature review, we suggest that the etiology of massive pleural effusion in this setting is most likely related to local immune pleuritis associated with underlying interstitial lung disease due to dermatomyositis. Optimal management should be individualized and may include immunosuppressive agents, as well as antimicrobials, and potentially other agents. PMID- 26535605 TI - A systematic review of Markov models evaluating multicomponent disease management programs in diabetes. AB - Diabetes is the most expensive chronic disease; therefore, disease management programs (DMPs) were introduced. The aim of this review is to determine whether Markov models are adequate to evaluate the cost-effectiveness of complex interventions such as DMPs. Additionally, the quality of the models was evaluated using Philips and Caro quality appraisals. The five reviewed models incorporated the DMP into the model differently: two models integrated effectiveness rates derived from one clinical trial/meta-analysis and three models combined interventions from different sources into a DMP. The results range from cost savings and a QALY gain to costs of US$85,087 per QALY. The Spearman's rank coefficient assesses no correlation between the quality appraisals. With restrictions to the data selection process, Markov models are adequate to determine the cost-effectiveness of DMPs; however, to allow prioritization of medical services, more flexibility in the models is necessary to enable the evaluation of single additional interventions. PMID- 26535604 TI - Comprehensive Cross-Linking Mass Spectrometry Reveals Parallel Orientation and Flexible Conformations of Plant HOP2-MND1. AB - The HOP2-MND1 heterodimer is essential for meiotic homologous recombination in plants and other eukaryotes and promotes the repair of DNA double-strand breaks. We investigated the conformational flexibility of HOP2-MND1, important for understanding the mechanistic details of the heterodimer, with chemical cross linking in combination with mass spectrometry (XL-MS). The final XL-MS workflow encompassed the use of complementary cross-linkers, quenching, digestion, size exclusion enrichment, and HCD-based LC-MS/MS detection prior to data evaluation. We applied two different homobifunctional amine-reactive cross-linkers (DSS and BS(2)G) and one zero-length heterobifunctional cross-linker (EDC). Cross-linked peptides of four biological replicates were analyzed prior to 3D structure prediction by protein threading and protein-protein docking for cross-link-guided molecular modeling. Miniaturization of the size-exclusion enrichment step reduced the required starting material, led to a high amount of cross-linked peptides, and allowed the analysis of replicates. The major interaction site of HOP2-MND1 was identified in the central coiled-coil domains, and an open colinear parallel arrangement of HOP2 and MND1 within the complex was predicted. Moreover, flexibility of the C-terminal capping helices of both complex partners was observed, suggesting the coexistence of a closed complex conformation in solution. PMID- 26535606 TI - Mechanically Responsive Molecular Crystals. PMID- 26535607 TI - Surface Recombination Limited Lifetimes of Photoexcited Carriers in Few-Layer Transition Metal Dichalcogenide MoS2. AB - We present results on photoexcited carrier lifetimes in few-layer transition metal dichalcogenide MoS2 using nondegenerate ultrafast optical pump-probe technique. Our results show a sharp increase of the carrier lifetimes with the number of layers in the sample. Carrier lifetimes increase from few tens of picoseconds in monolayer samples to more than a nanosecond in 10-layer samples. The inverse carrier lifetime was found to scale according to the probability of the carriers being present at the surface layers, as given by the carrier wave function in few layer samples, which can be treated as quantum wells. The carrier lifetimes were found to be largely independent of the temperature, and the inverse carrier lifetimes scaled linearly with the photoexcited carrier density. These observations are consistent with defect-assisted carrier recombination, in which the capture of electrons and holes by defects occurs via Auger scatterings. Our results suggest that carrier lifetimes in few-layer samples are surface recombination limited due to the much larger defect densities at surface layers compared with the inner layers. PMID- 26535608 TI - Au-S Bonding Revealed from the Characterization of Diatomic Gold Sulfide, AuS. AB - Gold monosulfide, AuS, has been detected and characterized in the gas phase using optical spectroscopy. The symmetries of the ground and low-lying electronic excited states have been determined by application of a synergy of hot and cold laser excitation techniques. The electronic spectra are assigned to progressions in four band systems associated with excitations from the X(2)Pii ((2sigma)(2)(2pi)(3)) ground state to the A(2)Sigma(+) state arising from the (2sigma)(1)(2pi)(4) configuration and to the a(4)Sigma(-), B(2)Sigma(-), and C(2)Deltai states arising from the (2sigma)(2)(2pi)(2)(3sigma*)(1) configuration. The bond length and dissociation energy of the ground X(2)Pii state are determined to be 2.156(2) A and 298 +/- 2 kJ/mol, respectively. A molecular orbital correlation diagram is used to rationalize the energy ordering of the excited states and the associated harmonic frequencies. PMID- 26535609 TI - Evaluating the comparative effectiveness of treatment sequences in oncology: a new approach. PMID- 26535610 TI - Screening for breast cancer with Breast-CT in a ProHTA simulation. AB - AIMS: The potential of dedicated Breast-CT is evaluated by simulating its impact onto the performance of the German breast cancer screening program. Attendance rates, cancer detection and economic implications are quantified. METHODS: Based on a prospective health technology assessment approach, we simulated screening in different scenarios. RESULTS: In the simulation, attendance rates increase from 54 to up to 72% due to reduced pain. Breast cancers will be detected earlier while nodal positives and distant recurrences decrease. Assuming no additional cost, cost savings of up to ?55 million in one screening period are computed. CONCLUSION: The simulation indicates that earlier cancer detection, fewer unnecessary biopsies and less pain are potential benefits of Breast-CT resulting in cost savings and higher attendance. PMID- 26535611 TI - A Rebeccamycin Analog Provides Plasmid-Encoded Niche Defense. AB - Bacterial symbionts of fungus-growing ants occupy a highly specialized ecological niche and face the constant existential threat of displacement by another strain of ant-adapted bacteria. As part of a systematic study of the small molecules underlying this fraternal competition, we discovered an analog of the antitumor agent rebeccamycin, a member of the increasingly important indolocarbazole family. While several gene clusters consistent with this molecule's newly reported modification had previously been identified in metagenomic studies, the metabolite itself has been cryptic. The biosynthetic gene cluster for 9 methoxyrebeccamycin is encoded on a plasmid in a manner reminiscent of plasmid derived peptide antimicrobials that commonly mediate antagonism among closely related Gram-negative bacteria. PMID- 26535612 TI - Pilot Study to Evaluate Compliance and Tolerability of Cranberry Capsules in Pregnancy for the Prevention of Asymptomatic Bacteriuria. AB - OBJECTIVES: To evaluate the compliance with and tolerability of daily cranberry capsule ingestion for asymptomatic bacteriuria (ASB) prevention in pregnancy. DESIGN: A total of 49 pregnant women from two sites were randomly assigned to cranberry or matching placebo, two doses daily, at gestational ages less than 16 weeks. Patients were followed monthly for urinary tract infection until delivery. Up to seven monthly visits were scheduled for each patient. Delivery data were evaluated. RESULTS: Of 38 evaluable patients, the mean compliance rate over the study period was 82% (range, 20%-100%). This compliance rate and the 74% of patients achieving good (>=75%) compliance were similar between those who received cranberry capsules and placebo. Compliance evaluation revealed that most patients stopped capsule consumption after 34-38 weeks of participation. Multivariate logistic regression and longitudinal analysis showed a significant interaction time effect with cranberry treatment. However, cranberry consumption was not a significant predictor of gastrointestinal intolerance or study withdrawal. Although 30% of patients withdrew for various reasons, only 1 withdrew because of intolerance to the cranberry capsules. Loss to follow-up was mostly due to provider change (9 of 49 [18%]) and therapy disinterest (4 of 49 [8%]). Seven cases of ASB occurred in 5 patients: 2 of 24 (8%) in the cranberry group and 3 of 25 (12%) in the placebo group. No cases of cystitis or pyelonephritis were observed. CONCLUSION: One third of pregnant women could not complete the study protocol for various reasons. Compliance with and tolerability of cranberry capsule ingestion appear good; these capsules provide a potentially effective means to prevent ASB in pregnancy. Further studies with large samples are necessary to confirm the findings. PMID- 26535613 TI - Advanced dual-energy CT for head and neck cancer imaging. AB - Dual energy computed tomography (DECT) is an advanced form of computed tomography (CT) in which simultaneous or near-simultaneous acquisitions are performed at two different peak energy levels, enabling material density and spectral attenuation characterization beyond what is possible with conventional CT scans. This article is a review of the current applications of DECT for the evaluation of head and neck cancer. The article will begin with a brief overview of different approaches to DECT scanning and address basic issues related to image quality and acquisition dose. This will be followed by a review of the use of different DECT reconstructions for improving head and neck squamous cell carcinoma visualization, evaluation of tumor extent, and invasion of critical structures. The article will conclude with a brief review of other emerging applications of DECT for evaluation of different head and neck cancers and advanced tumor analysis. PMID- 26535614 TI - Small Molecule CXCR3 Antagonists. AB - Chemokines and their receptors are known to play important roles in disease. More than 40 chemokine ligands and 20 chemokine receptors have been identified, but, to date, only two small molecule chemokine receptor antagonists have been approved by the FDA. The chemokine receptor CXCR3 was identified in 1996, and nearly 20 years later, new areas of CXCR3 disease biology continue to emerge. Several classes of small molecule CXCR3 antagonists have been developed, and two have shown efficacy in preclinical models of inflammatory disease. However, only one CXCR3 antagonist has been evaluated in clinical trials, and there remain many opportunities to further investigate known classes of CXCR3 antagonists and to identify new chemotypes. This Perspective reviews the known CXCR3 antagonists and considers future opportunities for the development of small molecules for clinical evaluation. PMID- 26535615 TI - Docetaxel for the treatment of bladder cancer. AB - INTRODUCTION: Docetaxel has had a significant impact on the management of urothelial carcinoma (UC). Multiple phase II trials have been conducted to evaluate the efficacy of docetaxel in the treatment of metastatic UC. Docetaxel is an accepted community standard for the therapy of platinum-treated patients with metastatic UC. AREAS COVERED: This review focuses on the data supporting a role for docetaxel in the therapy of advanced UC. It also explores the future development of docetaxel and describes the ongoing clinical trials in the treatment of UC. EXPERT OPINION: Docetaxel plays an important role as one of the standard agents used in the comparator arms of randomized trials evaluating new agents as salvage therapy for metastatic UC. Furthermore, biologic agents are being developed in chemo-biologic regimens using docetaxel as the platform. In the context of emerging novel agents such as T-cell checkpoint inhibitors, docetaxel may continue to play a role as a salvage therapy in select patients ineligible for immunotherapy or following checkpoint inhibitors. PMID- 26535616 TI - Metal Fluxes from Porewaters and Labile Sediment Phases for Predicting Metal Exposure and Bioaccumulation in Benthic Invertebrates. AB - The use of diffusive gradients in thin films (DGT) for predicting metal bioavailability was investigated by exposing the bivalve Tellina deltoidalis to an identical series of metal-contaminated sediments deployed simultaneously in the field and laboratory. To understand the differences in metal exposure occurring between laboratory- and field-based bioassays, we investigated changes in metal fluxes to DGT probes in sediments and in metal concentrations and partitioning to porewaters and overlying waters. DGT-metal fluxes (Cu, Pb, and Zn) were lower in the overlying waters of most field bioassays compared to the laboratory, causing differences in Pb and Zn bioaccumulation between bivalves exposed to laboratory and field conditions. Overall, DGT-metal fluxes provided predictions of metal bioaccumulation similar to those obtained using dilute-acid extractable metal measurements. This study demonstrates that, irrespective of the physicochemical properties of the sediment and type of exposure (laboratory or field), sediments pose a significant risk of bioaccumulation by T. deltoidalis when the Cu, Pb, and Zn DGT flux exceeds 3.5, 1.3, and 156 MUg/h/m(2), respectively. The results presented here support the use of the DGT technique for sediment quality assessment and the hypothesis that DGT-metal fluxes may potentially be useful surrogates for the lability of metals for all exposure routes. PMID- 26535617 TI - Photon upconversion and photocurrent generation via self-assembly at organic inorganic interfaces. AB - Molecular photon upconversion via triplet-triplet annihilation (TTA-UC), combining two or more low energy photons to generate a higher energy excited state, is an intriguing strategy to surpass the maximum efficiency for a single junction solar cell (<34%). Here, we introduce self-assembled bilayers on metal oxide surfaces as a strategy to facilitate TTA-UC emission and demonstrate direct charge separation of the upconverted state. A 3-fold enhancement in transient photocurrent is achieved at light intensities as low as two equivalent suns. This strategy is simple, modular and offers unprecedented geometric and spatial control of the donor-acceptor interactions at an interface. These results are a key stepping stone toward the realization of an efficient TTA-UC solar cell that can circumvent the Shockley-Queisser limit. PMID- 26535618 TI - Molecular characterization, tissue distribution, and immune reaction expression of karyopherins in the domestic silkworm (Bombyx mori). AB - Karyopherins, including alpha and beta types, are transport proteins in the eukaryotic cell that carry cargoes across nuclear pore complexes into or out of the nucleus. In this study, full open reading frames of one beta and three alpha types of karyopherin were cloned from cDNA of the domestic silkworm (Bombyx mori). The one beta and three alpha types' open reading frames were 2661, 1563, 1515, and 1551 base pairs long, respectively, and coded 886, 520, 504, and 516 amino acids, respectively. The alphas all had one importin-beta-binding (IBB) domain, and eight, four, or seven armadillo/beta-catenin-like repeats. The beta had 19 HEAT repeat domains, which constructed one importin-beta-N-terminal domain and one IBB domain. The recombinant proteins were expressed in Escherichia coli cells. The molecular weight of the beta type was approximately 100 kDa, and the alphas weighed approximately 60 kDa. Phylogenic tree construction revealed that the alphas could be classified into three known karyopherin-alpha subfamilies. We detected mRNA of the four karyopherins in normal 3rd day of 5th instar larvae, and in larvae injected with Gram-positive bacteria, Gram-negative bacteria, viruses, and fungi using real-time fluorescence quantitative reverse transcriptase-polymerase chain reaction, and found that the four karyopherins were widely distributed, but their expression levels were related to tissues type, the microbe injected, and the time point. PMID- 26535619 TI - Association of the GSTM1 null polymorphism with breast cancer in a Mexican population. AB - The glutathione S transferase (GST) family plays an important role in the processing of carcinogens. Data on the null GSTM1 genotype has revealed associations with cancer, and has been suggested to affect carcinogen metabolism and to contribute to tumor promotion in the mammary gland. We examined the role of the null GSTM1 genotype by comparing the genotypes of 276 healthy Mexican women with those of 558 Mexican women with breast cancer (BC). The genotype frequencies observed in the controls and patients with BC were 38 and 45% for the null GSTM1 genotype, respectively. The obtained odds ratio (OR) was 1.36, with a 95% confidence interval (95%CI) of 1.02-1.8, P = 0.04. The protective association was also evident upon analysis of the distributions of the null GSTM1 genotype in patients with positive chemotherapy response who had high plasma levels of glucose (OR 0.56, 95%CI = 0.33-0.94, P = 0.03). This study suggested that the null GSTM1 genotype is associated with BC susceptibility in the Mexican population analyzed. PMID- 26535620 TI - Association between the interleukin-6-174 G/C polymorphism and risk of ischemic stroke: a meta-analysis. AB - Numerous studies have evaluated the association between the -174 G/C polymorphism in the interleukin-6 (IL6) gene and ischemic stroke risk. However, the results have been inconsistent. In this study, we performed a meta-analysis to assess the association of the IL6 -174 G/C polymorphism with ischemic stroke. Published literatures from PubMed and Embase databases were retrieved. Pooled ORs with 95%CIs were calculated using fixed- or random-effect models. A total of seven case-control studies containing 2025 patients and 2174 controls were enrolled into this meta-analysis. In combined analysis, the results showed no significant association between the IL6 -174 G/C polymorphism and ischemic stroke risk in the overall population (GG vs CC: OR = 1.22, 95%CI = 0.50-3.01; TT vs TC: OR = 0.97, 95%CI = 0.81-1.15; dominant: OR = 0.98, 95%CI = 0.70-1.38; or recessive: OR = 1.24, 95%CI = 0.57-2.70) models. In the subgroup analysis by race, no significant associations between the -174 G/C polymorphism in the IL6 gene and ischemic stroke risk were found in Caucasians or Asians. No publication bias was found in the present study (all P > 0.05). Overall, the meta-analysis results suggested that the IL6 -174 G/C polymorphism was not associated with an increased risk of ischemic stroke. Further large and well-designed studies are needed to confirm this conclusion. PMID- 26535621 TI - A novel lumazine synthase molecule from Brucella significantly promotes the immune-stimulation effects of antigenic protein. AB - Brucella, an intracellular parasite that infects some livestock and humans, can damage or destroy the reproductive system of livestock. The syndrome is referred to as brucellosis and often occurs in pastoral areas; it is contagious from livestock to humans. In this study, the intact Brucella suis outer membrane protein 31 (omp31) gene was cloned, recombinantly expressed, and examined as a subunit vaccine candidate. The intact Brucella lumazine synthase (bls) gene was cloned and recombinantly expressed to study polymerization function in vitro. Non reducing gel electrophoresis showed that rBs-BLS existed in different forms in vitro, including as a dimer and a pentamer. An enzyme-linked immunosorbent assay result showed that rOmp31 protein could induce production of an antibody in rabbits. However, the rOmp31-BLS fusion protein could elicit a much higher antibody titer in rabbits; this construct involved fusion of the Omp31 molecule with the BLS molecule. Our results indicate that Omp31 is involved in immune stimulation, while BLS has a polymerizing function based on rOmp31-BLS fusion protein immunogenicity. These data suggest that Omp31 is an ideal subunit vaccine candidate and that the BLS molecule is a favorable transport vector for antigenic proteins. PMID- 26535622 TI - A framework radiation hybrid map of buffalo chromosome 1 ordering scaffolds from buffalo genome sequence assembly. AB - River buffalo chromosome 1 (BBU1) is a sub-metacentric chromosome homologous to bovine chromosomes 1 and 27. In this study, we constructed a new framework radiation hybrid (RH) map from BBU1 using BBURH5000 panel adding nine new genes (ADRB3, ATP2C1, COPB2, CRYGS, P2RY1, SLC5A3, SLC20A2, SST, and ZDHHC2) and one microsatellite (CSSM043) to the set of markers previously mapped on BBU1. The new framework RH map of BBU1 contained 141 markers (55 genes, 2 ESTs, 10 microsatellites, and 74 SNPs) distributed within one linkage group spanning 2832.62 centirays. Comparison of the RH map to sequences from bovine chromosomes 1 and 27 revealed an inversion close to the telomeric region. In addition, we ordered a set of 34 scaffolds from the buffalo genome assembly UMD_CASPUR_WB_2.0. The RH map could provide a valuable tool to order scaffolds from the buffalo genome sequence, contributing to its annotation. PMID- 26535623 TI - MTHFR C677T and A1298C polymorphisms as predictors of radiotherapy response in head and neck squamous cell carcinoma. AB - The C677T and A1298C polymorphisms in methylene-tetrahydrofolate reductase (MTHFR), which regulates the release of active folate in the body, may have reduced activity. Given that folate participates in important intracellular pathways, such as nucleotide synthesis and biomolecule methylation, it seems plausible that patients with head and neck squamous cell carcinoma (HNSCC) may respond differently to radiotherapy treatments, based on genetic polymor-phisms. Therefore, this study sought to understand the role of these polymorphisms in HNSCC patient radiotherapy response. Genotypes were detected by PCR-RFLP after extraction of DNA from peripheral blood lymphocytes. Survival curves were analyzed by the Kaplan- Meier model, and significant differences were analyzed by the Wil-coxon test. Response to radiotherapy in patients with laryngeal SCC was significantly associated with the MTHFR C677T polymorphism (P = 0.030). Indeed, the presence of at least one T allele decreases the mortality rate up to 3-fold. Therefore, we propose that MTHFR C677T may represent a putative biomarker for radiotherapy prognosis in la-ryngeal SCC patients. PMID- 26535624 TI - Effects of Cx43 gene modification on the proliferation and migration of the human lung squamous carcinoma cell line NCI-H226. AB - In this study, the human lung squamous carcinoma cell line NCI-H226 was transfected with the recombinant plasmid pBudCE4.1_Cx43 to explore the role of the Cx43 gene in cell growth, cell cycle, and tumor migration. pBudCE4.1-Cx43 was transfected into human lung squamous carcinoma NCI-H226 cells using Lipofectamine TM2000. The mRNA and protein expressions of Cx43 in the transfected cells were detected by reverse transcriptase polymerase chain reaction and western blot analysis. The cell-cell communication was detected using the scratch dye tracer method and the cell cycle was detected by flow cytometry. The CCK-8 proliferation, scratch healing, and cell invasion assays were performed to evaluate the effect of the Cx43 gene transfection on the proliferation, migration, and invasive abilities of NCI-H226 cells. Cx43 mRNA and protein expressions and the fluorescence intensity in the scratch healing test were significantly higher in the experimental group than those in the control and blank groups (P < 0.05 and < 0.01, respectively). The CCK-8 proliferation assay and the scratch healing experiment revealed significantly inhibited NCI-H226 cell proliferation (especially 72 h after incubation) and cell migration, respectively, in the experimental group, compared to the control and blank groups (P < 0.001 and <0.05, respectively). The transwell chamber test showed a statistically significant decrease in the invasive ability of NCI-H226 cells in the experimental group (P < 0.05). Therefore, Cx43 gene transfection could inhibit the migration of human lung squamous carcinoma cell line NCI-H226, thereby inhibiting tumor cell proliferation. PMID- 26535625 TI - Analysis of upland cotton (Gossypium hirsutum) response to Verticillium dahliae inoculation by transcriptome sequencing. AB - Verticillium wilt is one of the main diseases in cotton (Gossypium hirsutum), severely reduces yield and fiber quality, and is difficult to be con-trolled effectively. At present, the molecular mechanism that confers resistance to this disease is unclear. Transcriptome sequencing is an important method to detect resistance genes, explore metabolic pathways, and study resistance mechanisms. In this study, the transcriptome of a disease-resistant inbred cot-ton line inoculated with Verticillium dahliae was sequenced. A total of 126,402 unigenes were obtained using de novo assembly and data analysis, 99,712 (78.88%) of which were annotated into the Nr, Nt, Swiss-Prot, KEGG, COG, and GO databases. The expression patterns of 16 candidate disease-resis-tance genes showed that some genes were upregulated soon after V. dahliae inoculation and others were upregulated later, which may indicate instanta-neous basal defense and lagged specific defense, respectively. We conducted a preliminary analysis of the transcriptome database, which will contribute to further research regarding the cloning of disease-resistance genes. PMID- 26535626 TI - Cloning and transformation of INDUCER of CBF EXPRESSION1 (ICE1) in tomato. AB - The tomato plant (Solanum lycopersicum Mill.) is sensitive to cold, and low field temperatures can result in shortened growth periods and decreased crop yield. Transcription of CRT/DRE-binding factor (CBF) is regulated by INDUCER of CBF EXPRESSION1 (ICE1). CBF activates many downstream genes that confer cold tolerance on plants. ICE1 has been used in genetic engineering to improve cold resistance in several plant species. Here, ICE1 in a plant expression vector was used to transform a tissue-cultured rhubarb tomato variety using Agrobacterium tumefaciens. The transgenic and control plants were compared at 4 degrees C for 0, 24, and 72 h. We measured leaf physiological indicators related to cold resistance, including malondialdehyde (MDA) and proline (Pro) contents, and peroxidase (POD) and catalase (CAT) activities. At 72 h, the MDA content in transgenic plants was significantly lower than in control plants, indicating a lower membrane lipid injury. The Pro contents and the CAT and POD activities in the transgenic plants increased significantly compared with those of the control plants. For Pro, the increase continued over the prolonged stress exposure, while CAT and POD activities reached peak levels at 24 h. These results are consistent with the roles of Pro, CAT, and POD in defending the integrity of plant cells. Our study not only improves the cold resistance of tomato, but also provides the foundation for further research on the role of ICE1 as a transcription factor in plant cold resistance. PMID- 26535627 TI - Differentiation of four strains of Chinese soft-shelled turtle (Pelodiscus sinensis) based on high-resolution melting analysis of single nucleotide polymorphism sites in mitochondrial DNA. AB - The Chinese soft-shelled turtle (Pelodiscus sinensis) has been one of the most economically important aquatic animals in China for thousands of years, and several breeding strains have been formed. Since the morphological characteristics of some strains are similar, a rapid and accurate molecular method to differentiate between strains is required. In this study, partial sequences of mitochondrial DNA from four turtle strains, Taihu Lake Strain, Taiwan Strain, Japanese Strain, and Yellow River Strain, were amplified and sequenced based on selected strain-specific single nucleotide polymorphism (SNP) sites. The corresponding primers were designed and a high-resolution melting (HRM) technique was employed for genotyping these SNPs. The results indicated that a total of seven SNPs can be detected by HRM. Among these SNPs, one can be used for identifying the Taihu Lake Strain, one for the Japanese Strain, two for the Taiwan Strain, and three for the Yellow River Strain. This method is rapid and convenient, which offers technical support for strain identification and selective breeding in Chinese soft-shelled turtles. PMID- 26535628 TI - Mutational analysis of BRCA1/2 gene and pathologic characteristics from Kazakh population with sporadic breast cancer in northwestern China. AB - Mutations in the BRCA1/2 genes are associated with an increased risk of breast cancer, but no large-scale research have examined the BRCA1/2 mutations in Chinese Kazakh women. We evaluated the frequency and distributions of BRCA1 and BRCA2 gene mutations in Kazakh sporadic breast cancer patients and healthy women in China. The association between the clinical-pathologic features of Kazakh breast cancer patients and BRCA1/2 mutations were also investigated. Two unclassified variants (T539M and T1915M) and 16 polymorphisms were detected in this study, 4 of which (G356A, His743, Asn991Asp, Val1269) were detected more frequently in breast cancer patients than in healthy controls. We observed a higher prevalence of BRCA1/2 common sequence alterations and a large number of Kazakh women carrying multiple co-existing BRCA1/2 mutations. The prevalence of BRCA1 mutations was similar to that of BRCA2 mutations. Although no significant differences were observed, BRCA1/2 carriers were generally younger at diagnosis of wild-type breast cancer patients. BRCA1-associated Kazakh sporadic breast cancers present with high tumor grade, early stage, negative lymph node status, absence of estrogen receptor expression and progesterone-positive status. Estrogen receptor expression was the only predominant histological type in BRCA2 carriers. In this study, we determined the BRCA1 and BRCA2 gene mutation status and determined the association with clinical-pathologic characteristics in a Chinese Kazakh population. Larger population-based screening studies screening the entire coding region of BRCA1/2 are required to evaluate the breast cancer risk induced by the sequence alterations detected in this study. PMID- 26535629 TI - Differential responses of one hundred tomato genotypes grown under cadmium stress. AB - Due to increased global concern over the deleterious effects of toxic heavy metals in the environment, it has become necessary to develop plant genotypes that limit the uptake of heavy metals to aerial edible parts. To address this concern, we performed a glasshouse experiment to assess variations within tomato germplasm for cadmium (Cd) tolerance under control conditions and under simulated stress conditions. Significant differences (P < 0.01) were observed among all genotypes at both Cd levels (3 ppm and 6 ppm). Our analyses showed that the genotypes 9086, Roma, Sitara TS-01, pak0010990, CLN-2123A, Picdeneato, 0.006231, and 7035 gave the best yields with minimum Cd content in their fruit, whereas the genotypes 42-07, 17883, BL-1176-Riostone-1-1, Marmande, and 17882 had relatively low yields with higher metal contents. The heavy metal was found to accumulate first in the shoot, then fruit, leaf, and finally root in tolerant genotypes; in susceptible genotypes, the order was fruit, shoot, leaf, and root. The inter genotype differences in Cd uptake indicated the possibility of manipulating tomato genotypes to develop Cd tolerant tomato varieties or hybrids that allow safe use of a tomato crop grown on Cd contaminated soils. PMID- 26535630 TI - MicroRNA expression profile of a Malaysian Bajau family with familial mitochondrial neurogastrointestinal encephalomyopathy. AB - Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare, autosomal recessive disorder associated with mutations in the thymidine phosphorylase (TYMP) gene. The main objective of this study was to characterize the genetic profiles of the deceased proband's family members (N = 4) using DNA sequencing and to determine miRNA deregulation in MNGIE using miRNA microarray profiling and bioinformatic analysis. We found that the genetic profile of the younger sister showed similar TYMP gene mutations as that of the proband with the exception of a heterozygous mutation in exon 10. The miRNA microarray revealed 55 significantly up-regulated and 65 significantly down-regulated miRNAs. These miRNAs have been implicated in various mitochondrial dynamics such as energy metabolism, Krebs cycle, mitochondria-associated apoptosis, and mitophagy. In conclusion, we demonstrate that blood miRNAs are deregulated in the pathogenesis of MNGIE and these changes may have therapeutic implications. Further experimental studies will be required to elucidate the functional miRNA-mRNA interactions in MNGIE. PMID- 26535631 TI - Comparison of gSSR and EST-SSR markers for analyzing genetic variability among tomato cultivars (Solanum lycopersicum L.). AB - In order to study genetic variability and develop better strategies for the utilization of 48 tomato cultivars from America, China, the Netherlands, and Portugal, genomic simple sequence repeat (gSSR) and EST-derived SSR (EST-SSR) markers were applied. In all, 15 of 82 gSSR and 18 of 115 EST-SSR markers showed polymorphic loci. There were 995 and 2072 clear fragments amplified by polymorphic gSSR and EST-SSR markers, respectively. The total and average number of alleles detected by EST-SSRs (75, 4.2) was more than gSSRs (54, 3.6) as a result of some multi-locus EST-SSRs. A lower polymorphism information content value was found in gSSRs (0.529) compared to EST-SSRs (0.620). Similarity coefficient matrixes of the 48 tomato cultivars were established based on the gSSRs and EST-SSRs, and UPGMA dendrograms were constructed from the gSSRs and EST SSRs similarity coefficient matrixes. A high similarity was observed between the gSSRs and EST-SSRs dendrograms. Genetic variability of four tomato populations from different countries showed that the observed number of alleles and Nei's genetic diversity were highest in the American population, and the effective number of alleles was highest in the Dutch population. The estimated genetic structure showed some tomato cultivars from different countries shared a common genetic background, which might be related to gene flow. It was inferred that both gSSR and EST-SSR markers were effective to assess genetic variability of tomato cultivars, and the combination of both markers could be more effective for genetic diversity analysis in tomato. PMID- 26535632 TI - Elevated TrkA receptor expression is associated with all-trans retinoic acid induced neuroblastoma differentiation. AB - Neuroblastoma is the most common and one of the deadliest among pediatric tumors; however, a subset of infants with neuroblastoma display spontaneous regression. The mechanism of spontaneous regression remains to be elucidated. TrkA plays an essential role in the differentiation and functionality of neurons; abundant TrkA expression is associated with favorable prognosis of neuroblastoma. All-trans retinoic acid (ATRA), a first-line drug for acute promyelocytic leukemia (APL) treatment, has been shown to induce differentiation and inhibit cell growth. Neuroblastoma tissues in our hospital inpatient were collected, primary cell culture was performed, and the cells were separated and purified to be cell line. Trypan blue exclusion was used to count the numbers of cells alive, morphological changes were observed under the phase-contrast microscope. RT-PCR was used to determine the expression level of TrkA. In this study, a human neuroblastoma cell line was successfully established; in addition, we demonstrated that ATRA induces growth arrest and promotes the differentiation of neuroblastoma cells. In addition, ATRA was shown to significantly increase the levels of TrkA mRNA expression. Therefore, we concluded that the elevated expression of the TrkA receptor is associated with ATRA-induced growth arrest and differentiation o neuroblastoma cells. The results of this study provide a theoretical basis for the clinical application of differentiation-inducing ATRA for neuroblastoma therapy. PMID- 26535633 TI - Clinical significance of CD44 expression in children with hepatoblastoma. AB - The aim of this study was to investigate the expression of CD44 and its clinical significance in children suffering from hepatoblastoma (HB). CD44 expression was detected with immunohistochemistry staining in 30 samples from hepatoblastoma children and 10 normal liver tissue samples from normal children. The data obtained was statistically analyzed using the chi-square test, using the SPSS (v.11.0) software. The rate of CD44 expression was significantly higher (66.7%) in hepatoblastoma tissues than in normal liver tissues (chi(2) = 4.848, P < 0.05). The rate of CD44 expression was significantly higher in children with stage III or IV hepatoblastoma (83.3%) than that in children with stage I and II hepatoblastoma (chi(2) = 5.625, P < 0.05) (41.7%). Therefore, CD44 expression might play an important role in the pathogenesis, progression, and prognosis of HB in children. PMID- 26535634 TI - Biological activity of cytotoxic dendritic cells cocultured with cytokine-induced killer cells and their effect on acute leukemia cells. AB - We cocultured cytokine-induced killer (CIK) cells with dendritic cells (DCs) in vitro and investigated their proliferation, immunophenotype changes, secretory cytokine levels, and their antitumor effects on acute myeloid leukemia (AML) cells. DCs and CIK cells were acquired from healthy human peripheral blood mononuclear cells and cocultured as an experimental group, while CIK cells were cultured alone as a control group. Cell numbers were counted by trypan blue staining, cytotoxic activity was measured by a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, cell phenotypes were detected by flow cytometry, and secreted levels of INF-gamma and IL-12 were determined by enzyme linked immunosorbent assay. The proliferation activity in the experimental group was noticeably higher than in the control group (P < 0.05). Under the same conditions, the ratio of CD3(+)CD56(+) and CD3(+)CD8(+) double-positive CIK cells was significantly elevated when cocultured with DCs (P < 0.05). Compared with the control group, the experimental group had significantly higher levels of secreted INF-gamma and IL-12 in the supernatants after 3 days (P < 0.01 and P < 0.05, respectively). The antitumor effect of DC-CIK cells against leukemia cells was much higher than that of CIK cells at an effector-target ratio ranging from 2.5:1 to 20:1 (P < 0.05), and this effect was positively related to the effector-target ratio. The proliferation activity, level of secretory cytokines, and antitumor effect against AML cells of DC-CIK cells were significantly higher than in CIK cells. This study provides a theoretical and experimental basis for clinical immunotherapy using DC-CIK cells. PMID- 26535635 TI - Role of proteinase-activated receptor-1 gene polymorphisms in susceptibility to chronic obstructive pulmonary disease. AB - We conducted a case-control study to investigate the association between PAR1 gene polymorphisms and the development of chronic obstructive pulmonary disease (COPD). A total of 270 patients with COPD and 270 control subjects were consecutively recruited between March 2012 and March 2014. A polymerase chain reaction restriction fragment length polymorphism assay was used to assess the polymorphisms PAR1 IVS-14 A/T rs168753 and -506 I/D rs11267092. The frequency of the AA genotype in PAR1 IVS-14 A/T rs168753 was significantly higher than in the controls (chi(2) = 7.23, P = 0.03). By logistic regression analysis, we found that the AA genotype of PAR1 IVS-14 A/T rs168753 was associated with increased risk of COPD compared with the GG genotype. The adjusted OR (95%CI) was 2.00 (1.15-3.50) for the AA genotype. In conclusion, we found that the PAR1 IVS-14 A/T rs168753 polymorphism was associated with the development of COPD. PMID- 26535636 TI - Association between IL2/IL21 and SH2B3 polymorphisms and risk of celiac disease: a meta-analysis. AB - Celiac disease (CD) is a common autoimmune disorder characterized by heightened immunological response to ingested gluten. Certain gene polymorphisms of IL2/IL21 (rs6822844 and rs6840978) and SH2B3 (rs3184504) may influence susceptibility to CD, although the effects remain unclear. We performed a meta-analysis of the associations between rs6822844, rs6840978, and rs3184504 polymorphisms and CD risk. PubMed, EMBASE, and the China National Knowledge Infrastructure were searched. ORs and 95%CIs of each single nucleotide polymorphism (SNP) were estimated using the fixed-effect model if I(2) < 50% in the test of heterogeneity; otherwise, the random-effect model was used. Our meta-analysis included 12,986 CD cases and 28,733 controls from 16 independent samples, and the analysis of each SNP contained a subset of the total. We found that the minor allele T of both rs6822844 (T vs G, OR = 0.72, 95%CI = 0.67-0.78, P < 0.001) and rs6840978 (T vs C, OR = 0.76, 95%CI = 0.71-0.83, P < 0.001) in IL2/IL21 significantly decreased the risk of CD. However, the minor allele A of rs3184504 (A vs G, OR = 1.18, 95%CI = 1.12-1.24, P < 0.001) in SH2B3 significantly increased CD susceptibility. The estimated lambda values were 0.49, 0.50, and 0.53 for rs6822844, rs6840978, and rs3184504, respectively, suggesting that a co dominant model of genotype effect was most appropriate for the three SNPs. Our results support associations between the three SNPs and CD and provide a strong argument for further research. PMID- 26535637 TI - Association of the IL6 polymorphism rs1800796 with cancer risk: a meta-analysis. AB - The human IL6 [interleukin 6 (interferon, beta 2)] gene encodes IL-6, a cytokine which not only plays regulatory roles in inflammation, but may be also involved in the progression of cancer. Rs1800796 is a single nucleotide polymorphism (SNP) in the promoter region of IL6, and is associated with IL-6 production. A number of studies have been carried out to determine whether this SNP is associated with cancer risk. However, the results are inconsistent due to small sample sizes of individual studies and limited statistical power. Therefore, to evaluate the overall effect on all investigated cancer types, we conducted a meta-analysis by combining all available studies. Nineteen eligible case-control studies including 23,030 subjects (9,985 cases and 13,045 controls) were included for this meta analysis. Our study demonstrates that rs1800796 is significantly associated with cancer risk in three genetic models (allele G vs allele C, pooled OR = 1.182, P = 0.009; CG + GG vs CC, pooled OR = 1.333, P = 0.006; CG vs CC, pooled OR = 1.323, P = 0.007).Our meta-analysis suggests that polymorphism rs1800796 within the IL6 gene may be a potential risk factor for cancer. PMID- 26535638 TI - Genetic mechanism associated with congenital cytomegalovirus infection and analysis of effects of the infection on pregnancy outcome. AB - We aimed to compare the diagnostic value of various detection methods for cytomegalovirus (CMV) infection, to investigate the genetic mechanism associated with CMV infection in pregnant women, and to analyze the risk of sequelae development in fetuses with CMV infection. A total of 300 participants who had the same immunosuppressive regimen and received preemptive therapy for CMV infection were prospectively enrolled in this study; they included 289 vaccine trial participants. The gB-absorbed CMV IgG assay was performed for each vaccine trial participant. The healthy women were divided into 2 groups, and amniotic fluids were collected from them at 15-18 weeks of gestation to test for CMV seropositivity before conception by using IgM specific antibodies, CMV-DNA, and IgG analysis. In 104 cases, cord blood sera and urine specimens were also collected from the infants and examined. The sensitivity and specificity of immediate-early messenger RNA and pp67 (late) messenger RNA detection by the nucleic acid sequence-based amplification technique was comparable to those of virus isolation and PCR. Furthermore, an association between single nucleotide polymorphisms in the TLR-2 gene and congenital CMV infection was observed and confirmed. Moreover, CMV infection during early pregnancy has been shown to have a much more severe effect on the pregnancy outcome compared to infection during later stages of pregnancy. PMID- 26535639 TI - MicroRNA-122 is involved in oxidative stress in isoniazid-induced liver injury in mice. AB - Many studies have shown that the pathogenesis of liver injury includes oxidative stress. MicroRNA-122 may be a marker for the early diagnosis of drug-induced liver injury. However, the relationship between microRNA-122 and oxidative stress in anti-tuberculosis drug-induced liver injury remains unknown. We measured changes in tissue microRNA-122 levels and indices of oxidative stress during liver injury in mice after administration of isoniazid, a first-line anti tuberculosis drug. We quantified microRNA-122 expression and indices of oxidative stress at 7 time points, including 1, 3, and 5 days and 1, 2, 3, and 4 weeks. The tissue microRNA-122 levels and oxidative stress significantly changed at 3 and 5 days, suggesting that isoniazid-induced liver injury reduces oxidative stress and microRNA-122 expression compared to in the control group (P < 0.05). Notably, over the time course of isoniazid-induced liver injury, mitochondrial ribosome protein S11 gene, the target of microRNA-122, began to change at 5 days (P < 0.05). The tissue microRNA-122 profile may affect oxidative stress by regulating mitochondrial ribosome protein S11 gene during isoniazid-induced liver injury, which may contribute to the response mechanisms of microRNA-122 and oxidative stress. PMID- 26535640 TI - Mapping quantitative trait loci for five forage quality traits in a sorghum sudangrass hybrid. AB - The identification of quantitative trait loci (QTLs) affecting forage quality traits enables an understanding of the genetic mechanism of these loci. The aim of the present study was to detect QTLs for the whole-plant protein content (WP), whole-plant fat content (WF), neutral detergent fiber (NDF), acid detergent fiber (ADF), and whole-plant ash content (WA) using a population of 184 F2 individuals from a cross between sorghum Tx623A and sudangrass Sa. Correlation analysis was performed between the five forage quality traits. WP was found to be positively correlated with WF, NDF, and ADF. Furthermore, NDF was positively correlated with ADF but negatively correlated with WA. A genetic map with 124 SSR markers was constructed for QTL mapping. A total of 12 QTLs associated with the five forage quality traits were detected. Of these QTLs, qNDF3, qNDF8, and qADF8 explained more than 10% of the phenotypic variation. Additionally, although all of the QTLs exhibited additive and dominant effects, they mainly exhibited dominant effects. Our results provide important information for marker-assisted selection breeding of sorghum-sudangrass hybrids. PMID- 26535641 TI - Genomic identification of group A bZIP transcription factors and their responses to abiotic stress in carrot. AB - The basic-region/leucine-zipper (bZIP) family is one of the major transcription factor (TF) families associated with responses to abiotic stresses. Many members of group A in this family have been extensively examined and are reported to perform significant functions in ABA signaling as well as in responses to abiotic stresses. In this study, 10 bZIP factors in carrot were classified into group A based on their DNA-binding domains. The cis-acting regulatory elements and folding states of these 10 factors were analyzed. Evolutionary analysis of the group A members suggested their importance during the course of evolution in plants. In addition, cis-acting elements and the folding state of proteins were important for DNA binding and could affect gene expression. Quantitative RT-PCR was conducted to investigate the stress response of 10 genes encoding the group A factors. Six genes showed responses to abiotic stresses, while four genes showed other special phenomenon. The current analysis on group A bZIP family TFs in carrot is the first to investigate the TFs of Apiaceae via genome analysis. These results provide new information for future studies on carrot. PMID- 26535642 TI - Characterization of novel nitrate reductase-deficient mutants for transgenic Dunaliella salina systems. AB - The aim of the present study was to isolate and characterize novel nitrate reductase (NR)-deficient mutants, which may be useful for the transgenic manipulation of Dunaliella salina. Three NR-deficient mutants of D. salina, J-1, J-2, and J-3, were successfully isolated by screening for chlorate resistance after chemical mutagenesis with ethylnitrosourea. NR activity was not detected in the mutants and the expression of NR mRNA was significantly decreased. Growth analysis of D. salina strains grown in media containing different nitrogen sources revealed that these mutants were capable of utilizing nitrite and urea, but not nitrate as a nitrogen source, indicating that these mutants are indeed NR deficient. Mutation analysis of NR cDNA sequences revealed that there were 11 point mutations shared by the J-1, J-2, and J-3 mutants. Furthermore, the results of the functional complementation experiment showed that NR activity of transformant T-1 derived from J-1 was recovered to 48.1 % of that of the wild type D. salina. The findings of the present study indicate that nitrate may be used as a selective agent rather than antibiotics or herbicides for the isolated NR-deficient mutants in future transgenic D. salina systems. PMID- 26535643 TI - Protective effect of lyophilized recombinant human brain natriuretic peptide on renal ischemia/reperfusion injury in mice. AB - Brain natriuretic peptide (BNP) has a protective effect on acute injury of the heart, brain, and lung. However, its role in acute kidney injury (AKI) remains unclear. The aim of this study was to investigate the effect of lyophilized recombinant human BNP (lrh-BNP) on AKI and the underlying molecular mechanisms. An experimental model for AKI was established using an ischemia/reperfusion (I/R) procedure. Healthy adult BALB/c mice were randomized to the sham, I/R, and lrh BNP-treated post-I/R (BNP + I/R) groups. Post-operatively, the BNP + I/R group was subcutaneously injected with lrh-BNP (0.03 MUg.kg(-1).min(-1)), whereas the other groups received saline at the same dose. Serum creatinine (Scr) and blood urea nitrogen levels were examined; tissue staining was performed to evaluate the degree of I/R injury (IRI). Ki67 positive staining of renal tubular epithelial cells was observed using immunofluorescence confocal laser scanning to assess the effect of BNP on cell proliferation after IRI. Inflammatory factor expression levels were detected to evaluate the effect of BNP on renal inflammation. Compared with the sham group, the I/R group showed increased Scr levels, severe tubular injury of the renal outer medulla, increased Kim-1 mRNA expression, an increased number of infiltrative macrophages in the renal interstitium, and increased TNF-alpha, IL- 1beta, IL-6, MCP-1, and HIF-1alpha mRNA expression. BNP delivery significantly reduced all pathological changes in the I/R group. The protective role of BNP in murine renal IRI may be associated with its inhibition of renal interstitial inflammation and hypoxia and its promotion of renal tubule repair. PMID- 26535644 TI - Study of the expression of GABA(A) receptor in rats during acute lung injury caused by endotoxin. AB - The objective of the present study was to investigate the role of gamma aminobutyric acid type A receptor (GABA(A)R) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats. Thirty-two male wistar rats were randomly divided into four groups. Rats in the GABA group were pretreated with LPS and GABA, while those in the bicuculline (BIC) group were pretreated with LPS and bicuculline. We assessed the arterial blood gas, dry/wet ratio, and the level of tumor necrosis factor-alpha (TNF-alpha), IL-6, malondialdehyde, and superoxide dismutase 6 h after the immunization. Paraffin sections of samples were detected using the steptavidin-peroxidase method. Protein expression was detected using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blotting. PaO2 in the LPS group was significantly lower than that in the control rats. Activation of GABA-mediated signaling by GABA increased the expression of GABA(A)R in airway bronchial and alveolar epithelial cells. Blockade of the GABA(A)R by bicuculline limited the expression of this receptor. The GABA group rats had higher levels of tissue TNF-alpha and IL-6 than in ALI rats and control rats. The BIC group rats demonstrated an opposite expression level compared to the GABA group rats. Our results suggest that the GABA(A)R could aggravate the inflammatory response syndrome and oxidative stress in the lungs and play an essential role in LPS-induced acute lung injury. It provides a novel method to study the incidence and mortality of ALI during the peroperative period. PMID- 26535645 TI - Expression and function of PDGF-alpha in columnar epithelial cells of age-related cataracts patients. AB - We studied the expression and function of platelet-derived growth factor A (PDGF alpha) in the lens epithelial cells of cataracts patients. Ninety age-related cataracts patients were recruited in our hospital between January 2012 and January 2014. The expression levels of platelet-derived growth factor receptor (PDGFR) in the anterior capsule of the lens at different degrees of turbidity, and PDGF-alpha in the aqueous humor were detected. A human lens epithelium cell line was also cultured and studied. To investigate its function, PDGF-alpha was used to treat a PDGFR-silenced human lens epithelium cell line to observe changes in the proliferation, transfer, and epithelial mesenchymal transition (EMT). The expression of PDGF-alpha and its receptor increased in patients with more serious cataracts. Lens epithelium cells stimulated by PDGF-alpha showed greater proliferation and migration. The degree of EMT was also upregulated in cells stimulated by PDGF-alpha. However, silencing the expression of PDGFR inhibited the effects. The development and severity of age-related cataracts was related to the secretion and expression of PDGF-alpha. This may be a new therapeutic target for cataracts treatment. PMID- 26535646 TI - A rare PAX6 mutation in a Chinese family with congenital aniridia. AB - Aniridia is an autosomal dominant disorder characterized by the complete or partial loss of the iris and is almost associated with mutations in the paired box gene 6 (PAX6). We examined three generations of a Chinese family with congenital aniridia and observed genetic defects. Exons of PAX6 from 12 family members were amplified by polymerase chain reaction, sequenced, and compared with reference sequences in NCBI reference sequence database (http://www.ncbi.nlm.nih.gov/nuccore/NG_008679.1?from=5001&to=38170&report=genban ). A rare mutation c.2T>A (M1K) in exon 4 of PAX6 was identified in all affected family members but not in unaffected family members. Our results suggest that the c.2T>A (M1K) mutation may be responsible for the pathogenesis of congenital aniridia in this family. To our knowledge, this is the first report of the M1K mutation in PAX6 in a Chinese family with this disease and the second report worldwide. PMID- 26535647 TI - Genetic polymorphisms and retinal vein occlusion in an Italian population. AB - In this study, we assessed the prevalence of polymorphisms in genes involved in hyperhomocysteinemia or hemostasis to shed light on their role, if any, in retinal vein occlusion (RVO). We recruited 37 Italian patients (17 men and 20 women) with a diagnosis of central or branch RVO based on fundus examination and retinal fluorescein angiography, as well as 45 healthy controls. Risk factors and family history of RVO of all subjects were recorded. The distributions of polymorphisms in patients and controls were evaluated using the chi(2) test and OR. We confirmed an increased risk in subjects with dyslipidemia (high density lipoprotein <59 mg/dL: 17.8% of controls, 43.2% of patients, P = 0.0002; low density lipoprotein >130 mg/dL: 26.7% controls, 54.1% patients, P = 0.0002), arterial hypertension (60% controls, 75.7% patients, P = 0.023), and high body mass index (28.9% controls, 70.3% patients, P < 0.0001, and excluded involvement of the selected polymorphisms in RVO. Overall, the tested polymorphisms did not appear to be useful for assessing predisposition or for the diagnosis and prognosis of RVO. PMID- 26535648 TI - Cytotoxicity of 1-dodecyl-3-methylimidazolium bromide on HepG2 cells. AB - We evaluated the cytotoxicity of 1-dodecyl-3-methylimidazo-lium bromide ([C12mim][Br]) on HepG2 cells and its influence on plasma membrane permeability. The results showed that [C12mim][Br] inhibited HepG2 cell growth and decreased cell viability in a concentration-depen-dent manner. The results also revealed that [C12mim][Br] exposure induced apoptosis in [C12mim][Br]-treated HepG2 cells. In addition, the results showed that [C12mim][Br] increased membrane permeability in HepG2 cells. These results suggest that plasma membrane permeability may be responsible for apoptosis induced by [C12mim][Br] in HepG2 cells. PMID- 26535649 TI - Embryogenesis in the anthers of different ornamental pepper (Capsicum annuum L.) genotypes. AB - The aim of this study was to relate flower bud size with microspore developmental stages and the induction of embryos in the anthers of different ornamental pepper (Capsicum annuum L.) genotypes. Flower buds were randomly collected and visually divided into three classes based on both petal and sepal size. The length and diameter of the bud as well as the length of the petal, sepal, and anther were then measured. The microspore stage was also determined for each anther of the bud where it was found. The data were subjected to analysis of variance (P <= 0.01), and the means were separated by Tukey's test (P <= 0.01). The broad sense heritability, the CVg/CVe relation, and the Pearson correlation between characters were also determined. Anthers from 10 C. annuum genotypes were cultivated in four culture media types for the induction of embryos. The data were transformed by Arcsin (x) and subjected to analysis of variance (P <= 0.01), and the means were separated by Tukey's test (P <= 0.01). The majority of anthers in the second class had uninucleate microspores. No correlation was observed between bud size and the number of uninucleate microspores. Genotype 9 specimens grown in M2 medium induced the highest number of embryos (16) compared to the other treatments, which indicates a significant interaction effect between culture media and genotypes. PMID- 26535650 TI - Role of IL-17 gene polymorphisms in the susceptibility to gastric cancer. AB - We conducted a study to investigate the role of three IL-17 gene single nucleotide polymorphisms (SNP) (rs2275913G>A, rs3748067C>T, and rs763780 T>C) in the development of gastric cancer. A total of 252 patients with gastric cancer and 252 control subjects were collected between May 2012 and May 2014. The SNP genotyping of IL-17A rs2275913G>A and rs3748067C>T and IL-17F rs763780 T>C was performed using the Sequenom MassARRAY platform (Sequenom, San Diego, CA, USA) according to the manufacturer instructions. By conditional regression analysis, individuals carrying the AA and the GA+AA genotypes of rs2275913G>A were correlated with an elevated risk of gastric cancer when compared with those carrying the GG genotype, and the adjusted ORs (95%CIs) were 2.05 (1.13-3.76) for the AA genotype and 1.45 (1.03-2.08) for the GA+AA genotype. In conclusion, our results suggest that the IL-17A rs3748067C>T and IL-17F rs763780 T>C polymorphisms play an important role in the risk of gastric cancer in a Chinese population. PMID- 26535651 TI - Role of interleukin-6 gene polymorphisms in the development of prostate cancer. AB - We investigated the role of two functional polymorphisms, IL-6-174G>C (rs1800795) and IL-6-572C>G (rs1800796), in the development of prostate cancer. A total of 212 consecutive primary prostate cancer patients and 236 control subjects were recruited between May 2012 and May 2014. The IL-6-174G>C (rs1800795) and IL-6 572C>G (rs1800796) polymorphisms were assessed by polymerase chain reaction restriction fragment length polymorphism. The genotype distributions of IL-6 174G>C (rs1800795) and IL-6-572C>G (rs1800796) met the Hardy-Weinberg equilibrium in the controls. Unconditional logistic regression analyses showed that the GG genotype of IL-6-572C>G (rs1800796) was associated with an elevated risk of prostate cancer compared with the CC genotype, and the OR (95%CI) for the GG genotype was 2.06 (1.11-3.87). In conclusion, we suggest that the IL-6-572C>G (rs1800796) gene polymorphism influences the development of prostate cancer. PMID- 26535652 TI - Distribution of mitochondrial DNA fragments in the nuclear genome of the honeybee. AB - Nuclear mitochondrial pseudogenes (numts), which originated from mitochondrial DNA (mtDNA) insertions in the nuclear genome, have been detected in many species. The distribution of numts in the honeybee nuclear genome has not yet been fully reported. By referring to the whole honeybee mtDNA sequence and to the recent version of the honeybee nuclear genome, 236 reference sequences were identified by BLAST, with 90 unmapped. The size of the numts ranged from 219 to 3788 bp, and the homologous identity between numts and their corresponding mtDNA fragments varied from 71 to 93%. Furthermore, identified honeybee numts covered nearly all mitochondrial genes and were distributed over all chromosomes. This study provides useful information for further research related to mitochondrial genes and the evolution of the honeybee. PMID- 26535653 TI - Characterization and expression analysis of a cyclin B gene from black tiger shrimp (Penaeus monodon). AB - The open reading frame of black tiger shrimp (Penaeus monodon) cyclin B (Pmcyclin B) was identified, based on cDNA sequence registered in GenBank (accession No. EF015590). The target sequence was 1206 bp, corresponding to 401 amino acids. Two conserved signature sequences of the cyclin B gene family were found in the Pmcyclin B deduced aa sequence. Temporal expression of Pmcyclin B in different tissues, including ovary, lymphoid organ, brain, blood, muscle, heart, gill, hepatopancreas, and intestine, were quantified by quantitative real time PCR. Messenger RNA expression levels of Pmcyclin B were greatest in the ovary, compared to other tissues (P < 0.05). Temporal expression of Pmcyclin B in the ovary at six different developmental stages was investigated by real-time PCR; no significant difference was observed (P < 0.05). Recombinant Pmcyclin B protein and its polyclonal antibody were successfully produced. Western blot analysis revealed differential expression of Pmcyclin B in ovaries in developmental stages II to IV; a positive signal (45 kDa) was observed in all ovarian stages assessed, but was most intense at stage III. Pmcyclin B protein was assessed by immunohistochemistry and was localized to the cytoplasm of prophase oocytes at stage II and enriched in the nuclei of pro-metaphase oocytes at stages III and IV. Results from this study indicate that Pmcyclin B is constitutively expressed and plays an important role in ovarian maturation in P. monodon. PMID- 26535654 TI - Lack of association between the cyclooxygenase 2 -765G>C polymorphism and prostate cancer risk: a meta-analysis. AB - The aim of this study was to investigate the association between the cyclooxygenase 2 (COX2) -765G>C (rs20417) polymorphism and prostate cancer (PC) risk using meta-analysis. A systematic literature search was performed using the PubMed, Embase, Cochrane Library, and Google Scholar databases by using the terms "cyclooxygenase-2/COX-2/PTGs2", "polymorphism" or "variation", and "prostate" and "cancer" or "carcinoma" to identify relevant articles up to June 14, 2014. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were assessed for PC risk associated with COX2 -765G>C polymorphism using fixed- and random-effect models. We identified a total of nine publications, including 5952 cases and 5078 controls, to investigate the effect of COX2 -765G>C on PC risk, and found no significant association in any genetic model tested (CC vs GG: OR = 0.993, 95%CI = 0.923-1.068; GC+CC vs GG: OR = 1.041, 95%CI = 0.931-1.103; CC vs GC+GG: OR = 0.858, 95%CI = 0.689-1.067; CC vs GG: OR = 0.871, 95%CI = 0.689-1.086; GC vs GG: OR = 1.032, 95%CI = 0.945-1.127). Power analysis and tests for publication bias ensured the reliability of our results. This meta-analysis suggested that the functional COX2 -765G>C polymorphism, located in the COX2 gene promoter, is unlikely to be associated with PC risk. However, additional larger, well-designed studies are still required to reach a conclusive result on this issue. PMID- 26535655 TI - Sequence and phylogenetic analyses of the M and N genes of porcine epidemic diarrhea virus (PEDV) strains in Anhui Province, China. AB - To assess the homology and phylogenetic relationship between porcine epidemic diarrhea virus (PEDV) Anhui strains and other PEDV strains, molecular homology and phylogenetic analyses of Anhui PEDV field strains were compared with those of reference strains. The results revealed that the M and N genes of PEDV were 681 and 1326 bp long, respectively. The nucleotide sequences of the N genes of Anhui PEDV strains were 95.9-99.9% homologous with each other, and the deduced amino acid sequences were 92.5-99.8% homologous. Compared with the PEDV reference strains, the Anhui PEDV field strains had 94.1-99.5% nucleotide sequence homology in the N gene and 91.2-97.5% amino acid mutation homology in the N protein. The nucleotide sequences of the M genes of Anhui PEDV were 98.3-100% homologous, and the deduced amino acid sequences were 96.5-99.6% homologous. Compared with the PEDV reference strains, the Anhui PEDV field strains had 96.9-100% nucleotide sequence homology in the M gene and 96.5-99.6% amino acid homology in the M protein. The Anhui strains were genetically similar to USA strains (USA/Iowa/16465/2013 and USA/Indiana/17846/2013) but different from European (CV777;Br1/7), Korean (Chinju99), and Japanese (83p-5) strains. PMID- 26535656 TI - Significant interaction of APOE rs4420638 polymorphism with HDL-C and APOA-I levels in coronary heart disease in Han Chinese men. AB - Apolipoprotein E (APOE) is recognized for its importance in lipoprotein metabolism and cardiovascular disease. We evaluated the association between APOE rs4420638 genotypes and circulating lipid concentrations along with the risk of coronary heart disease (CHD). We conducted a case-control study involving 1508 individuals to investigate the contribution of rs4420638 to the risk of CHD in Han Chinese. In addition, we performed a meta-analysis to evaluate the association between rs4420638 and CHD in Europeans and Asians. The results show that rs4420638 is significantly correlated with increased CHD risk in male Han Chinese [P = 0.040, odds ratio (OR) = 1.34, 95% confidential interval (95%CI) = 1.01-1.78] and is likely to increase the risk of CHD under the dominant model in males (P = 0.036, OR = 1.38, 95%CI = 1.02-1.88). A further subgroup analysis by rs4420638 genotype found a significant association of rs4420638 AA with high density lipoprotein cholesterol (HDL-C) (P = 0.012) and APOA-I levels (P = 0.0001) in males. The meta-analysis suggests that rs4420638 significantly increases the risk of CHD (OR = 1.18, 95%CI = 1.14-1.22, P < 0.0001, fixed-effect method). Our case-control study shows that rs4420638 genotype AA has a significant association with the concentrations of circulating HDL-C and APOA-I in CHD in Han Chinese males. The meta-analysis suggests that rs4420638 is associated with CHD risk in Europeans and Asians. PMID- 26535657 TI - Analysis of biochemical compounds and differentially expressed genes of the anthocyanin biosynthetic pathway in variegated peach flowers. AB - Variegated plants are highly valuable in the floricultural market, yet the genetic mechanism underlying this attractive phenomenon has not been completely elucidated. In this study, we identified and measured different compounds in pink and white flower petals of peach (Prunus persica) by high-performance liquid chromatography and liquid chromatography/mass spectrometry analyses. No cyanidin based or pelargonidin-based compounds were detected in white petals, but high levels of these compounds were found in pink petals. Additionally, we sequenced and analyzed the expression of six key structural genes in the anthocyanin biosynthesis pathway (CHI, CHS, DFR, F3'H, ANS, and UFGT) in both white and pink petals. Quantitative real-time polymerase chain reaction revealed all six genes to be expressed at greatly reduced levels in white flower petals, relative to pink. No allelic variations were found in the transcribed sequences. However, alignment of transcribed and genomic sequences of the ANS gene detected alternative splicing, resulting in transcripts of 1.071 and 942 bp. Only the longer transcript was observed in white flower petals. Since ANS is the key intermediate enzyme catalyzing the colorless leucopelargonidin and leucocyanidin to substrates required for completion of anthocyanin biosynthesis, the ANS gene is implicated in flower color variegation and should be explored in future studies. This article, together with a previous transcriptome study, elucidates the mechanism underlying peach flower color variegation in terms of the key structural genes involved in anthocyanin biosynthesis. PMID- 26535658 TI - Effectiveness of muscle basal lamina carrying neural stem cells and olfactory ensheathing cells in spinal cord repair. AB - We examined the effect of muscle basal lamina (MBL) with neural stem cells (NSCs) and olfactory ensheathing cells (OECs) on spinal cord injury repair. Seventy-two Sprague-Dawley rats were subjected to spinal cord hemisection and divided into 6 groups. In blank control group (group A), the ends of the spinal cord hemisection model were flushed with physiological saline. In NSC transplantation group (B), OEC transplantation group (C), MBL with NSC transplantation group (D), MBL with OEC transplantation group (E), and MBL with NSC and OEC transplantation group (F), NSCs, OECs, MBL with NSCs, MBL with OECs, and MBL with NSCs and OECs were implanted into the ends of the hemisection model. Survival and migration of transplanted cells were detected by immunohistochemistry and immunofluorescence after 4 and 8 weeks. Hind limb function repair was evaluated by Bundle branch block score at various time points before and after surgery. MBL could promote NSC growth along its lumen and promote host cell advancement in the lumen, reducing local inflammatory responses. Using MBL with NSCs and/or OECs for spinal cord repair shows advantages over simple cell transplantation. Group F contained more nerve cells in muscle basal lamina than group E. This method is useful for forming more axons, synaptic connections, and signal transduction pathways. However, these new axons showed nerve demyelination, which may greatly limit nerve signal conduction. In group F, OECs could induce neural stem cells, axonal growth, and synaptic connection formation, but its role is limited. PMID- 26535659 TI - Influence of gossypol acetic acid on the growth of human adenoid cystic carcinoma ACC-M cells and the expression of DNA methyltransferase 1. AB - We investigated the effects of gossypol acetic acid (GAA) on the proliferation, apoptosis, and expression of DNA methyltransferase 1 (DNMT1) mRNA in human adenoid cystic carcinoma (ACC-M) cells in vitro. The proliferation and apoptosis of ACC-M cells after treatment with different concentrations of GAA were detected using Cell Counting Kit-8 and flow cytometry, respectively. DNMT1 mRNA expression was measured by real-time fluorescence quantitative polymerase chain reaction. The growth of ACC-M cells was inhibited after treatment with GAA for 24, 48, and 72 h. The apoptotic rates of ACC-M cells after treatment with GAA for 72 h were higher than those of control cells (without treatment) (P < 0.05). DNMT1 mRNA expression in ACC-M after treatment with GAA for 72 h was lower than that in control cells (P < 0.05). GAA had inhibitory effects on the proliferation and induced apoptosis of human ACC-M cells, while GAA also reduced the expression level of DNMT1 mRNA in ACC-M cells. PMID- 26535660 TI - NEDD4-1 and PTEN expression in keloid scarring. AB - Keloid scarring remains a major problem in plastic surgery. The aim of this study was to determine the expression of the PTEN tumor suppressor and NEDD4-1 genes in keloid tissue and explore their effect on the formation of such scarring. Twenty keloid patients were enrolled in the study and underwent surgical removal of keloid tissue. No patient had received chemotherapy and/or radiotherapy prior to treatment. PTEN and NEDD4-1 mRNA expression was detected by reverse transcription PCR, while PTEN protein expression was assessed using immunohistochemistry. Our results showed that levels of PTEN were significantly diminished in keloid samples (P < 0.05), whereas those of NEDD4-1 did not significantly differ between keloid tissue and normal skin (P > 0.05). Furthermore, we found that NEDD4-1 expression is high and inversely correlated with that of PTEN in keloids. Our results suggest that the PTEN/PI3K/AKT pathway may play an important role in keloid formation and reduces PTEN expression in such tissue. Finally, although NEDD4-1 has previously been identified as a factor in keloid susceptibility, and the protein for which it encodes is known to degrade PTEN by catalyzing its polyubiquitylation, the detailed mechanism behind its involvement in keloid formation needs to be further studied. PMID- 26535661 TI - Identification of molecular markers related to human alveolar bone cells and pathway analysis in diabetic patients. AB - Alveolar bone osteoblasts are widely used in dental and related research. They are easily affected by systemic diseases such as diabetes. However, the mechanism of diabetes-induced alveolar bone absorption remains unclear. This study systematically explored the changes in human alveolar bone cell-related gene expression and biological pathways, which may facilitate the investigation of its mechanism. Alveolar bone osteoblasts isolated from 5 male diabetics and 5 male healthy adults were cultured. Total RNA was extracted from these cells and subjected to gene microarray analysis. Differentially expressed genes were screened, and a gene interaction network was constructed. An enrichment pathway analysis was simultaneously performed on differentially expressed genes to identify the biological pathways associated with changes in the alveolar bone cells of diabetic humans. In total, we identified 147 mRNAs that were differentially expressed in diabetic alveolar bone cells (than in the normal cells; 91 upregulated and 36 downregulated mRNAs). The constructed co-expression network showed 3 pairs of significantly-expressed genes. High-enrichment pathway analysis identified 8 pathways that were affected by changes in gene expression; three of the significant pathways were related to metabolism (inositol phosphate metabolism, propanoate metabolism, and pyruvate metabolism). Here, we identified a few potential genes and biological pathways for the diagnosis and treatment of alveolar bone cells in diabetic patients. PMID- 26535662 TI - Diallel cross analysis of plesiomorphic traits in Triticum aestivum L. genotypes. AB - We conducted a 5 x 5 complete diallel cross experiment in bread wheat (Triticum aestivum) with the genotypes 6309, Chkwal-50, Dhrabi, Bhkhar-02, and FS-08. Our objective was to evaluate the type of gene action and the general and specific combining abilities required for various morphological traits in wheat. The results of analysis of variance revealed highly significant differences among genotypes for all the investigated traits. The results of joint regression analysis showed that the data for all the investigated traits fitted a simple additive dominance model. Graphical representation of variance and covariance suggested that most of the investigated traits were controlled by overdominance gene action. However, the peduncle length and plant height were controlled by additive gene action. Variety 6309 carried the highest number of dominant genes for the number of spikelets per spike, number of tillers per plant, plant height, number of fertile tillers per plant, and grain yield per plant. Chakwal-50 carried the highest number of recessive genes for grain yield per plant, number of tillers per plant, number of grains per spike, number of fertile tillers per plant, and plant height. Chakwal-50 and 6309 were the best general combiners for number of spikelets per spike, number of grains per spike, grain yield per plant, 1000-grain weight, number of fertile tillers per plant, and number of tillers per plant. On other hand, 6309 performed well in specific crosses with Chakwal-50, FS 08, and Bhakhar-02 for spike length and number of tillers per plant. PMID- 26535663 TI - Correlation between expression and significance of delta-catenin, CD31, and VEGF of non-small cell lung cancer. AB - We analyzed the expression and clinical significance of delta-catenin in non small cell lung cancer (NSCLC) and investigated prognosis using human lung cancer samples. Eighty-nine NSCLC patients underwent operation between January and March 2009. There were 53 cases of squamous cell carcinoma, 31 adenocarcinoma, and 5 large cell carcinoma. delta-Catenin in NSCLC patients was detected by immunohistochemistry and analyzed in combination with the clinicopathological characteristics of lung cancer. The relationship between delta-catenin and CD31, D2-40, and vascular endothelial growth factor (VEGF) was compared by immunohistochemistry and the chi(2) test. delta-Catenin appeared in the cytoplasm of adjacent bronchial epithelial cells, indicating negative expression. Positive delta-catenin expression in the cytoplasm of lung cancer tissues was 66.67% (52/78), which was significantly higher than in normal lung tissues. Kaplan-Meier survival analysis suggested that the mean survival time of patients with delta catenin-positive expression was significantly shorter than in those with negative expression, indicating that positive expression was closely related to poor prognosis of NSCLC. delta-Catenin was highly expressed in NSCLC mainly in the cytoplasm of lung cancer tissues. delta-Catenin-positive expression may be related to poor prognosis of NSCLC. High delta-catenin expression in NSCLC was positively correlated with high CD31 and VEGF expression, but not correlated with D2-40, suggesting that delta-catenin may be related to angiogenesis and not lymphangiogenesis. PMID- 26535664 TI - Interference on cytoplasmic polyadenylation element-binding proteins affects the invasion ability of glioma stem cells. AB - Glioma stem cells derived from primary cultures were divided into an experiment group, a control group, and a blank group and subjected to cytoplasmic polyadenilation element-binding protein (CPEBs) interference, transfection with empty vector, and normal culture, respectively, to compare their invasion abilities. Western blotting showed that siRNA-3 had the strongest interfering effect on CPEBs. CPEBs were expressed in the experiment group with green fluorescence at an expression rate of over 70%. Significantly lower CPEB expression was observed in the experiment group compared to in the control and blank groups (P < 0.05). After 48-h treatment, the apoptotic rate in the experiment group was 21.43%, which was significantly higher than that in the blank (0.51%) and control (1.43%) groups (P < 0.05). After 3 days of treatment, the experiment group grew significantly more slowly than did the control and blank groups (P < 0.05). The transwell invasion assay showed that significantly fewer cells in the experiment group penetrated the membrane than did cells in the control and blank groups (P < 0.05). After CPEB interference, the growth, proliferation, and invasion of glioma stem cells were substantially inhibited, providing support for targeted therapy of glioma and for improving prognosis. PMID- 26535665 TI - Biocompatibility of differently proportioned HA/PLGA/BMP-2 composite biomaterials in rabbits. AB - The aim of this study was to assess the histocompatibility of hydroxyapatite (HA)/poly(lactic-co-glycolic acid) (PLGA)/bone morphogenetic protein-2 (BMP-2) composite materials in rabbits. Thirty healthy New Zealand white rabbits were randomly divided into 3 groups (N = 10). HA/PLGA/BMP-2 composite materials with the HA/PLGA proportions of 1:1, 1:2, and 1:3 were implanted in the animals, which were subsequently sacrificed on the 30th and 60th days post-implantation to allow for differences in routine blood and biochemical indices to be assessed between the animal groups. The degree of biomaterial degradation was also assessed in the three groups. Thirty and 60 days after the implantation of titanium plates and composite materials, no rabbits succumbed to inflammatory reactions, adverse reactions, abnormal blood routine and biochemical indices, or unstable liver functions. The presence of newborn tissues was identified within the 60 days post implantation. No significant differences were observed between the three groups (P < 0.05). The wide clinical application of HA/PLGA/BMP-2 composite biomaterial, which is highly compatible with rabbits with no apparent effects on the animals, is highly feasible. PMID- 26535666 TI - Expression of PCA3 and PSA genes as a biomarker for differential diagnosis of nodular hyperplasia and prostate cancer. AB - We evaluated the expression of the PCA3 gene in urine from patients with nodular hyperplasia/benign prostatic hyperplasia (PNH) or adenocarcinoma type prostate cancer (PCa).The study included 59 men: 22 with PCa, 26 with PNH, and 11 with no alterations (controls). Patients' urine was collected following prostatic massage and quantified by quantitative real-time PCR for prostate cancer antigen 3 gene (PCA3) and prostate-specific antigen gene (PSA) expression with the ACTB gene for normalization. PCA3 gene expression was detected in 16 patients with PCa and 4 with PNH; in the control group, there was no expression of the gene. No significant difference was observed in the mean levels of PCA3 and PSA expression, the PCA3/PSA ratio, and the total PSA levels when the groups of patients with PCa and PNH were compared. The area under the receiver operating characteristic (ROC) curve was 0.625, 0.596, 0.559, and 0.503 for PCA3 and PSA expression, the PCA3/PSA ratio, and total PSA levels, respectively. The sensitivity and specificity of the PCA3 test were 73 and 85%, respectively. Considering the estimated cutoff values (0.2219 and 0.5007 for PCA3 and PCA3/PSA, respectively), we observed a significant difference between the frequency of individuals with values above in the PCa group compared with the PNH group (P < 0.001). We conclude that the qualitative PCA3 test could be applied to initial screening for differentiation between individuals with PCa or PNH and those without prostate changes. PMID- 26535667 TI - Blockade of S100A3 activity inhibits murine hair growth. AB - Using mouse gene expression microarray analysis, we obtained dynamic expression profiles of the whole genome in a depilation-induced hair growth mouse model. S100A3 expression increased during the anagen phase and returned to normal during the telogen phase. The effects of S100A3 blockade on the hair growth cycle were examined in mice after subcutaneous injection of an anti-mouse S100A3 antibody. Protein localization of S100A3 was confined to the hair shafts during the anagen phase and the sebaceous glands during the telogen phase. S100A3 blockade delayed hair follicle entry into the anagen phase, decreased hair elongation, and reduced the number of hair follicles in the subcutis, which correlated with the downregulated expression of hair growth induction-related genes in vivo. The present study demonstrates that anti-S100A3 antibody inhibits mouse hair growth, suggesting that S100A3 can be used as a target for hair loss treatment. PMID- 26535668 TI - Analysis of genetic traits for drought tolerance in maize. AB - Fifty-four genotypes of maize were crossed and evaluated in the field during the crop season in February 2012 under both normal and water stress conditions. To identify the major parameters responsible for variation among genotypes, single linkage cluster analysis and principle component analysis (PCA) were carried out. Thirteen characters were studied. The PCA showed that the first six components, with eigen values >1, contributed 82.30% of the variability among the genotypes under normal field irrigation conditions while other PCs (7-13) had eigen values less than 1. Under drought conditions, the first four PCs, with eigen values >1, contributed 64.79% of the variability among genotypes while the other PCs (5-13) had eigen values less than 1. In the absence of water stress, heritability ranged from 68% (sucrose content) to 99% (plant height) and genetic advance ranged between 158.43% for stomatal frequency and 0.87 for biological yield. Under drought conditions, the coefficient of variability (CV) was 1.43-7.79, whereas estimates of heritability ranged between 68% and 99% for sucrose content and leaf area, respectively. The values of genetic advance ranged between 153.41 for stomatal frequency and 0.47 for nitrogen content. CV was 1.52-7.38 under drought conditions. The results indicated that the plant characters studied were under the control of additive genetic effects and suggested that selection should lead to fast genetic improvements. Clusters with superior agronomic types were identified and could be exploited for the transfer of desirable genes to improve the yield potential of the maize crop. PMID- 26535669 TI - Proteomic analysis of susceptibility in intestinal stromal tumors. AB - We analyzed the susceptibility of intestinal stromal tumors using cell culture and proteomics. Human SGC7901 gastric cells were selected and divided into a blank control group (untransfected SGC7901 cells), a negative control group [SGC7901 cells transfected with negative interference control-small interfering RNA (siRNA)], and a COOH-terminus tensin-like molecule (CTEN)-siRNA-1 group (SGC7901 cells transfected with CTEN-siRNA-1). The cells were successfully transfected and subjected to analyses of cell proliferation, cell cycle, cell invasion, CTEN expression, and proteomics. The percentages of cells in the G0/G1, S, and G2/M phases were similar in the three groups (P > 0.05), and the OD values were also similar at 24, 48, and 72 h (P > 0.05). Compared with the levels in the blank and negative control groups, CTEN protein in the CTEN-siRNA-1 group decreased by 66 and 65%, respectively, and significantly fewer cells in the CTEN siRNA-1 group were capable of invasion (P < 0.05). Proteomic analysis showed that in the CTEN-siRNA-1 group, 283 proteins were upregulated and 242 were downregulated; from these, the expression levels of E-cadherin and ERK proteins changed significantly. Silencing the expression of CTEN in intestinal stromal tumor cells reduces their invasion capability. Moreover, silencing CTEN at different stages can also regulate the expression levels of E-cadherin and ERK proteins. PMID- 26535670 TI - Effects of beta 2 adrenergic agonists on axonal injury and mitochondrial metabolism in experimental autoimmune encephalomyelitis rats. AB - The primary aims of this study were to investigate mitochondrial metabolism during experimental allergic encephalomyelitis (EAE) animal model axonal injury and to determine the correlation among neurological function scores, pathological changes, and the activities of the BB isoenzyme of creatine kinase (CK-BB), catalase (CAT), and calpain in the brain tissues of EAE rats. Another goal was to preliminarily define the mechanism of mitochondrial metabolism resulting from the effect of beta 2 adrenergic agonists in the process of EAE animal model axonal damage. EAE was induced in specific pathogen free Wistar rats by guinea pig spinal cord homogenate, complete Freund's adjuvant, and pertussis vaccine. We recorded the behavioral change in EAE rats, detected pathological changes in central nervous tissue, and observed the changes of the CK-BB, CAT, and calpain in the EAE rat brain and spinal cord. The results indicated that the average neurologic function score increased in the EAE group compared to that of the controls (P < 0.01). In addition, CAT and CK-BB activities significantly decreased and the calpain activity significantly increased compared with those of the control group (P < 0.05). The decrease of the activity of central nervous CK BB and CAT content, as well as the increase of calpain activity at the highest time point were considered to be the consequences of EAE. Furthermore, the results revealed that use of salbutamol could alleviate disease symptoms and reduce the recurrence of the EAE disease. PMID- 26535671 TI - Identification and characterization of microsatellite markers from the tropical sea cucumber, Stichopus horrens (Selenka). AB - Tropical commercial sea cucumber Stichopus horrens is extensively distributed throughout the tropical Indo-Pacific region, and wild stocks have been severely depleted over the past decade. In this study, we used the microsatellite enrichment library of S. horrens to identify and characterize 13 microsatellite loci, including 11 polymorphic loci and 2 monomorphic loci. Among the 11 polymorphic loci, the number of alleles was 3-8. The observed and expected heterozygosity varied from 0.1364 to 0.8966 and from 0.1653 to 0.7551, respectively. Additionally, all 11 polymorphic loci showed moderate and high polymorphism with the polymorphism information content (0.271-0.7311). A total of 9 polymorphic loci were in Hardy-Weinberg equilibrium, except for 2 loci (adjusted P = 0.004545). Linkage disequilibrium was not detected in any pairs of polymorphic loci. The present study will be useful for studying genetic structure, population conservation, and breeding of wild S. horrens; moreover, our results contribute to the phylogeny and evolutionary research of Holothuroidea. PMID- 26535672 TI - Lenalidomide affect expression level of cereblon protein in multiple myeloma cell line RPMI8226. AB - We investigated the mechanisms of action of immuno-modulatory drug (lenalidomide) on the protein expression of cereblon (CRBN) and their therapeutic targets in the multiple myeloma cell line RPMI8226. The multiple myeloma cell line RPMI8226 was cultured and treated with different concentrations of lenalidomide and bortezomib to determine the proliferation inhibition rate, apoptosis rate, and protein expression of CRBN. The results revealed that both lenalidomide and bortezomib inhibited the proliferation of RPMI8226 and promoted cell apoptosis. However, the protein expression of CRBN decreased signifi-cantly after treatment with lenalidomide, while bortezomib had no effect on the expression of CRBN. We confirmed that CRBN may be a target of lenalidomide. PMID- 26535673 TI - Expression and localization of Luman/CREB3 in mouse embryos during the pre implantation period. AB - Luman/CREB3 is a transcription factor that is a member of the cAMP-response element-binding protein family of basic region-leucine zipper transcription factors. This protein interacts with host cell factor 1, which also associates with the herpes simplex virus protein VP16 to induce the transcription of herpes simplex virus. Currently, the physiological function of Luman/CREB3 in reproductive processes remains unclear. In this study, quantitative real-time PCR and immunofluorescence assays were used to investigate the expression and localization of Luman in mouse oocytes as well as in early embryonic development. Luman protein was detected in the germinal vesicle and metaphase II stage oocytes, and was distributed in the cytoplasm, nucleus, and polar body of the oocyte stage. However, Luman protein and mRNA expression levels were significantly (P < 0.05) increased before activation of the zygotic genome, and expression levels peaked in 4-cell embryos. Expression levels were significantly (P < 0.05) decreased following the 8-cell stage throughout the blastocyst stage. The Luman protein was also distributed in the nucleus and cytoplasm in the early preimplantation embryo and showed enhanced nuclear staining starting from the 2 cell stage embryo up to the 8-cell stage embryo. The differences in the expression and localization of Luman in mouse oocytes and early embryo suggested that Luman plays an important role in oocyte maturation and early embryonic development processes. PMID- 26535674 TI - Modification research on in wall of capillary copper tube with Norland optical adhesive 68 in a double stereo PCR microfluidic chip. AB - In this study, a Norland optical adhesive 68 (NOA68) film, approximately 2.2 MUm thick, was manufactured using ultraviolet solidified NOA68 in apparatus manufacturing film on the inwall of a capillary copper pipe, developed in our laboratory. The roughness of the inwall of capillary copper pipe was improved from Ra = 0.766 to 0.204 MUm and the contact angle was improved from approximately 96 degrees to 55 degrees , increasing hydrophilicity. Polymerase chain reaction experiments indicated that the ratio of work pressure in the microfluidic chip before modification to that after modification was 2.71/1, indicating that the extension efficiency increased. Our results provide a basis for the construction of a microform chip based on function integration. PMID- 26535675 TI - Association analysis of rs2275913G>A and rs763780T>C interleukin 17 polymorphisms in Chinese women with cervical cancer. AB - We conducted a case-control study with a relatively large sample size, and investigated the association between rs2275913G>A and rs763780T>C and the risk of cervical cancer. Three hundred and six newly diagnosed patients with histologically confirmed cervical cancer and 354 cancer-free control subjects were recruited from the Forestry General Hospital between May 2011 and May 2014. The gene polymorphisms rs2275913G>A and rs763780T>C were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. By unconditional logistic regression analysis, our study found that the AA genotype and the A allele of rs2275913 were associated with a higher risk of cervical cancer compared with the wild-type genotype, and the ORs (95%CIs) were 2.84 (1.57-5.23) and 1.55 (1.22-1.97), respectively. Compared with the G allele, the A allele of rs699947 was associated with a significantly increased risk of cervical cancer in subjects above 20 years and who were positive for human papillomavirus 16 (HPV-16) or HPV-18 infection. Patients with the A allele of rs2275913 had increased risk of cervical cancer, regardless of the number of births they had experienced or their smoking habits. We suggest that rs2275913 may play a role in the etiology of cervical cancer, although further large-sample studies are needed to confirm these observations. PMID- 26535676 TI - Genetic parameters of test-day milk yield in Guzera cattle under tropical conditions. AB - The objective of this study was to estimate genetic parameters for test-day milk yield (TDMY) in Guzera cows using random regression models. Additive and permanent environmental random effects were modeled by random regression on fourth- and fifth-order orthogonal Legendre polynomials, respectively. The residual variances were heterogeneous, with seven classes. Heritability estimates for TDMY ranged from 0.24 to 0.52, with higher heritabilities for yields during early lactation. Genetic correlations between TDMYs ranged from -0.03 to 0.95. The phenotypic and permanent environmental correlations were all positive, and the highest estimates were between adjacent TDMYs. The results suggest that TDMYs obtained with random regression models may be used as selection criteria for Guzera cattle. PMID- 26535677 TI - Effect of SERCA2a overexpression in the pericardium mediated by the AAV1 gene transfer on rapid atrial pacing in rabbits. AB - To study the effects of overexpression of the sarcoplasmic reticulum ATPase 2a (SERCA2a) gene on the activity and protein expression of SERCA2a after rapid atrial pacing (RAP) in New Zealand white rabbits. New Zealand white rabbits were randomly divided into a sham-operated group (group A), adeno-associated virus 1 (AAV1)/EGFP + atrial fibrillation (AF) model group (group B), or AVV1/SERCA2a + AF group (group C). The sham-operated group was used as a negative control. Each group consisted of 10 animals. Groups B and C were injected with 500 MUL of the AAV1-EGFP reporter gene and 500 MUL of the AAV1-SERCA2a target gene, respectively. Four weeks after AAV1-mediated gene transfer, the rabbits underwent 24 h of RAP to the right atrium. The animals were sacrificed and protein activity and protein expression in the myocardium were measured using the westernblot method. Four weeks after AAV1-mediated gene transfer, SERCA2a protein activity and expression were significantly higher in Group C than in Groups A and B (P < 0.05). RAP of the right atrium induced atrial fibrillation in rabbits, resulting in decreases in the activity and protein expression of SERCA2a. Pericardial AAV-1 mediated SERCA2a gene transfer resulted in the overexpression of SERCA2a, restoring SERCA2a activity and protein expression. PMID- 26535678 TI - Effects of exogenous protease supplementation on endogenous trypsin activity and gene expression in broilers. AB - Two hundred and forty one-day-old male broiler chickens (Ross-308) were fed corn soybean basal diets with 0, 40, 80, or 160 mg/kg of an acid protease preparation from 1 to 42 days of age, in order to investigate the effects of an exogenous enzyme on growth performance, pancreatic trypsin activity and mRNA expression. Average daily gain (ADG) was greatest in the 160-mg/kg treatment group at 1-21 days, which was significantly higher than that in the control. After 42 days, average daily feed intake (ADFI) and ADG had significantly increased in the 80- and 160-mg/kg treatments (P < 0.05), with the 80-mg/kg treatment group having the highest ADFI and ADG values. The feed conversion ratio was not affected. Dietary acid protease at 80 and 160 mg/kg significantly decreased trypsin activity in the pancreas (relative to the control group) by 35.71 and 47.29%, respectively (P < 0.05). After 42 days, trypsin mRNA expression in the pancreas had significantly decreased by 19.5% in the 80-mg/kg treatment group relative to the control (P < 0.05). After 21 and 42 days, the diet supplemented with 160 mg/kg acid protease significantly decreased pancreatic trypsin mRNA by 19.6 and 37.7%, respectively, compared to the control. There were the 40-mg/kg treatment group and the control. Our results suggest that the amount of acid protease in the diet significantly affects trypsin activity and mRNA expression in broilers. PMID- 26535679 TI - Tangeritin inhibits adipogenesis by down-regulating C/EBPalpha, C/EBPbeta, and PPARgamma expression in 3T3-L1 fat cells. AB - The treatment of obese patients is a topic investigated by an increasing number of researchers. This study aimed to elucidate the possible inhibitory effect of tangeritin on the development and function of fat cells. 3T3-L1 fat cells were grown to confluence and subjected to different concentrations of tangeritin. The most effective tangeritin inhibition concentration was determined by the MTT assay. The treated cells were subjected to real-time reverse transcriptase PCR and western blot analysis, to detect changes in the CCAAT/enhancer binding protein (C/EBP)alpha, C/EBPbeta, and peroxisome proliferator activated receptor (PPAR)gamma expression levels. The MTT assay revealed that the fat cell growth was inhibited at a 20 ng/mL concentration of tangeritin. The results of real-time PCR revealed a significant decrease in the expression of C/EBPalpha, C/EBPbeta, and PPARgamma mRNA, following the treatment with tangeritin. Western blot analysis also presented similar results at a protein level. Therefore, we concluded that tangeritin inhibits adipogenesis via the down-regulation of C/EBPalpha, C/EBPbeta, and PPARgamma mRNA and protein expression in 3T3-L1 cells. PMID- 26535680 TI - Molecular phylogeny of Colletotrichum (Sordariomycetes: Glomerellaceae) inferred from multiple gene sequences. AB - The genus Colletotrichum contains many important plant pathogens mainly distributed in tropical areas. Previous studies that utilized morphology or single genes have failed to resolve the phylogenetic relationships among the species. In this study, sequences of beta-tubulin, 28S ribosomal DNA, and ITS region from nine species were analyzed separately and combined to establish a fast method to infer the phylogeny of Colletotrichum using maximum parsimony, maximum likelihood, and Bayesian inference methods. The tree topologies inferred from the combined data set received higher bootstrap and posterior probability support than those inferred from the individual data sets. Obtained phylogenies highly supported C. capsici as the earliest diverging lineage followed by C. nymphaeae. The remaining seven species clustered into two distinct clades. Clade 1 consists of two monophyletic subclades: C. circinans, C. trichellum, and C. caudatum form one subclade and three accessions of C. dematium form another subclade. In Clade 2, C. incarnatum is in the basal-most clade. Three accessions of C. musae and C. caricae form a strongly supported clade indicating their close relationship. Spore shape analysis reveals an interesting evolutionary trend in the spore shape from acute- to obtuse-ended conidia and from curved to straight conidia in the sampled group of species. A quick and reliable way to infer the phylogeny of Colletotrichum based on combined DNA sequence data is presented in this paper. PMID- 26535681 TI - Isolation and characterization of novel polymorphic microsatellite markers for Epinephelus akaara. AB - In the present study, ten novel microsatellite markers were developed from an enriched-(CA)13 genomic library of Epinephelus akaara. The mean number of alleles per locus was 21.6, with a range of 12 to 33. Observed heterozygosity ranged from 0.767 to 0.967, and expected heterozygosity ranged from 0.831 to 0.975, with mean values of 0.877 and 0.923, respectively. Among the ten loci, three loci deviated from Hardy-Weinberg equilibrium after sequential Bonferroni's correction. These polymorphic microsatellite markers may be useful for studies on the population genetics of E. akaara. PMID- 26535682 TI - Drought-tolerant rice germplasm developed from an Oryza officinalis transformation-competent artificial chromosome clone. AB - Oryza officinalis has proven to be a natural gene reservoir for the improvement of domesticated rice as it carries many desirable traits; however, the transfer of elite genes to cultivated rice by conventional hybridization has been a challenge for rice breeders. In this study, the conserved sequence of plant stress-related NAC transcription factors was selected as a probe to screen the O. officinalis genomic transformation-competent artificial chromosome library by Southern blot; 11 positive transformation-competent artificial chromosome clones were subsequently detected. By Agrobacterium-mediated transformation, an indica rice variety, Huajingxian 74 (HJX74), was transformed with a TAC clone harboring a NAC gene-positive genomic fragment from O. officinalis. Molecular analysis revealed that the O. officinalis genomic fragment was integrated into the genome of HJX74. The transgenic lines exhibited high tolerance to drought stress. Our results demonstrate that the introduction of stress-related transformation competent artificial chromosome clones, coupled with a transgenic validation approach, is an effective method of transferring agronomically important genes from O. officinalis to cultivated rice. PMID- 26535683 TI - Screening of polymorphisms located in the FGF20 and TMEM175 genes in North Chinese Parkinson's disease patients. AB - Genome-wide association studies have reported numerous susceptibility loci for Parkinson's disease (PD). However, there have been few replication studies examining these loci in northern Chinese populations. To evaluate the relationships among 3 polymorphic markers located in the fibroblast growth factor 20 and transmembrane protein 175 genes and the genetic susceptibility to PD in northern Chinese subjects, 2 single nucleotide polymorphisms, and 1 insertion/deletion marker (rs591323 in FGF20; rs6599388 and rs142821586 in transmembrane protein 175 near the G-associated kinase/diacylglycerol kinase theta region) were investigated in 313 PD patients and 318 matched controls. Mismatched multiplex polymerase chain reaction-restriction fragment length polymorphism analysis as well as sequence-specific primer polymerase chain reaction and restriction fragment length polymorphism assays were performed. The genotypic frequency of rs591323 differed significantly between the patient and control groups; however, neither rs6599388 nor rs142821586 was associated with PD. We corrected the Hardy-Weinberg disequilibrium for rs6599388, which was previously reported to be common in 4 Asian descent populations into equilibrium status by simultaneously genotyping rs6599388 and rs142821586. In summary, we found that rs591323 was associated with PD but rs6599388 and rs142821586 were not associated with PD in a northern Chinese population. PMID- 26535684 TI - VEGF, eNOS, and ABCB1 genetic polymorphisms may increase the risk of osteonecrosis of the femoral head. AB - We investigated the associations between vascular endothelial growth factors (VEGF), endothelial nitric oxide synthase (eNOS), and ATP-binding cassette subfamily B member 1 transporter (ABCB1) polymorphisms and the risk of osteonecrosis of the femoral head (ONFH). Published studies were reviewed and analyzed based on predefined selection criteria. The strength of the association between VEGF, eNOS, and ABCB1 polymorphisms and ONFH risk was evaluated based on the odds ratio with corresponding 95%CIs. Meta-analysis was performed using the Comprehensive Meta-analysis 2.0 software. A total of 135 relevant articles were retrieved, of which 10 studies met the selection criteria, and included a total of 1025 patients with ONFH and 1730 healthy controls. The meta-analysis study results revealed that the VEGF rs2010963 G>C polymorphism increased the risk of ONFH, while the VEGF rs2010963 G>C and ABCB1 rs1045642 C>T polymorphisms increased the risk of ONFH under the allele model. In conclusion, the VEGF, eNOS, and ABCB1 polymorphisms may contribute to ONFH, but further studies including larger sample sizes are needed to confirm the results. PMID- 26535685 TI - Relationship between serum leptin levels and non-small cell lung carcinoma: a meta-analysis. AB - In this study, we analyzed the association between serum leptin levels and non small cell lung carcinoma (NSCLC). By examining English and Chinese databases, we identified potential relevant studies for statistical analysis. Human-associated case-control studies evaluating the association between serum leptin levels and NSCLC according to the random-effect model were retrieved and extracted data were statistically analyzed. We identified 7 case-control studies evaluating the correlation between serum leptin levels and NSCLC, which included 705 subjects (390 NSCLC patients and 315 healthy participants). Negative associations were investigated between serum leptin levels and NSCLC [standardized mean difference (SMD) = 0.96, 95% confidence interval (CI) = 0.13-1.79, P = 0.023). Ethnicity stratified analysis revealed there was no elevated leptin serum levels in NSCLC development in both Asians (SMD = 0.34, 95%CI = -0.10-0.79, P = 0.132) and Caucasians (SMD = 1.42, 95%CI = -0.09-2.93, P = 0.064). Sample size-stratified analysis of the association between serum leptin levels and NSCLC were found in studies of small sample size (SMD = 0.73, 95%CI = 0.04-1.41, P = 0.038), but not in studies of large sample size (SMD = 1.24, 95%CI = -0.52-3.01, P = 0.166). In the method-stratified subgroup analysis, serum leptin level was not correlated with NSCLC using a immunoradiometric assay method (SMD = 0.82, 95%CI = -1.38 3.03, P = 0.465). Determining the levels of the blood-based marker leptin may provide predictive information for NSCLC diagnosis. PMID- 26535686 TI - Abnormal metabolites related to bone marrow failure in aplastic anemia patients. AB - Metabolomics is the identification and quantitation of small molecules that are involved in metabolic reactions. Liquid chromatography-mass spectrometry (LC-MS) has enjoyed growing popularity as the platform for metabolomic studies due to high throughput, soft ionization, and good coverage of metabolites. Serum metabolites of aplastic anemia (AA) patients and healthy controls were investigated using LC-MS. A wavelet-based method was utilized to find and align LC-MS peaks. Principal component analysis, partial least squares discriminant analysis, and optimized potential for liquid simulations were used to identify differences in metabolite levels, and to reveal useful biomarkers. Thirty-two metabolites that were significantly altered were detected. Of these metabolites, 23 were successfully identified. In AA patients, metabolites involved amino acid biosynthesis, aminoacyl-tRNA biosynthesis, and ATP-binding cassette transporters were higher than normal, while the levels of metabolites involved in TCA cycles were lower than normal. These changes may be the primary cause or result of bone marrow failure in patients with AA. PMID- 26535687 TI - Multivariate analysis of test-day and total milk yield in goats. AB - The objective of this study was to estimate genetic parameters for 305-day cumulative milk yield (MY305) and its association with test-day milk yield (TDMY) in Saanen and Alpine goats in order to provide information that allows the use of TDMY as selection criteria. This was done using standard multi-trait and reduced rank models. Data from 1157 lactations, including the first three kiddings, and 5435 test-day records from 683 Saanen and 449 Alpine goats were used. MY305 was analyzed together with TDMY by multi-trait analysis, from the first to tenth test day, using records of the first three lactations as repeated measures. Three multi-trait models were used: a standard (SM) and two reduced rank models that fitted the first two (PC2) and three (PC3) genetic principal components. Akaike and Schwarz Bayesian information criteria were used to compare models. Heritability for TDMY estimated with the SM ranged from 0.20 to 0.66, whereas the range calculated from the PC2 model was 0.16 to 0.63. Genetic correlations between TDMY and MY305 were positive and moderate to high, ranging from 0.56 to 0.98 when estimated with the SM, and 0.91 to 1.00 when estimated with the PC2. The standard multi-trait model produced estimates that were more accurate than the reduced rank models. Although the SM provided the worst fit according to the two model selection criteria, it was the best in this dataset. PMID- 26535688 TI - Correlation between the development of calcium oxalate stones and polymorphisms in the fibronectin gene in the Uighur population of the Xinjiang region of China. AB - Here, we have investigated the correlation between calcium oxalate stone formation and Fn gene polymorphisms in urinary calculi patients among the Uighur population (Xinjiang region). In this case control study, genomic DNA extracted from the peripheral blood of 129 patients with calcium oxalate stones (patient group) and 94 normal people (control group) was used to genotype polymorphisms in the rs6725958, rs10202709, and rs35343655 sites of the Fn gene by polymerase chain reaction-restriction fragment length polymorphism. Subsequently, the association between different genotypes and susceptibility to calcium oxalate stone formation was compared among the patient and control groups. Single nucleotide polymorphisms (SNPs) were detected in the rs6725958, rs10202709, and rs35343655 sites of the Fn gene among the patient and control groups. The genotype distributions of the three loci complied with the Hardy-Weinberg equilibrium. The results of allele frequencies of the patient/control group for polymorphisms in the rs6725958 site of the Fn gene were C = 179 (69.92%)/119 (63.30%) and A = 77 (30.08%)/69 (36.70%), in the rs10202709 site were C = 245 (95.70%)/176 (93.63%) and T = 11 (4.30%)/12 (6.38%), and in the rs35343655 site of the Fn gene were A = 139 (54.30%)/87 (46.28%) and G = 117 (45.70%)/101 (53.72%). We observed no significant differences between the three SNPs and development of calcium oxalate stones. Polymorphisms in rs6725958, rs10202709, and rs35343655 of the Fn gene had no obvious effect on the susceptibility to the development of calcium oxalate stones in the Uighur population, residing in the Xinjiang region of China. PMID- 26535689 TI - Implicating the H63D polymorphism in the HFE gene in increased incidence of solid cancers: a meta-analysis. AB - A number of previous studies have demonstrated that the HFE H63D polymorphism is associated with increased risk of incidence multiple types of cancer, including colorectal cancer, breast cancer, liver cancer, pancreatic cancer, and gynecological malignant tumors. However, the clinical outcomes were inconsistent. Therefore, this meta-analysis was conducted to summarize the effect of the H63D variant on the incidence of solid tumor. PubMed and EMBASE databases were searched for articles associating the HFE H63D polymorphism with cancer risk. The relationships were evaluated by calculating the pooled odds ratios (ORs) with 95% confidence intervals (CIs). A total of 28 studies, including 7728 cancer cases and 11,895 controls, were identified. Statistically significant associations were identified between the HFE H63D polymorphism and solid cancer risk (CG vs CC, OR = 1.14, 95%CI = 1.07-1.23, P < 0.001; GG vs CC, OR = 1.28, 95%CI = 1.06-1.55, P = 0.010; CG/GG vs CC, OR = 1.16, 95%CI = 1.08-1.24, P < 0.001; GG vs CC/CG, OR = 1.24, 95%CI = 1.02-1.49, P = 0.027). In the subgroup analysis, we illustrated the effect of the H63D polymorphism on hepatocellular carcinoma and pancreatic cancer risk, particularly in the Asian and African subgroups; however, this was not observed in gynecological malignant tumors. In summary, this analysis provided strong evidence that the HFE H63D polymorphism may play a critical role in the increased aggressiveness of hepatocellular carcinoma and pancreatic cancer. PMID- 26535690 TI - MicroRNA-29a promotes apoptosis of monocytes by targeting STAT3 during sepsis. AB - Sepsis is a major cause of morbidity and mortality in critically ill patients. The sepsis syndrome results from a dysregulated inflammatory response to infection that leads to multiple-organ failure, but the underlying mechanisms remain poorly understood. More and more reports show that microRNAs (miRNAs) play an important role in sepsis. In the progression of this syndrome, cells change their behavior in response to cytokines stimulated by sepsis, such as interleukin 10 (IL-10). IL-10 can activate JAK2-STAT3 in the cells to protect them from damage. miR-29a is a potential miRNA directly targeting STAT3. In this study, we investigate the role of miR-29a in targeting STAT3 during sepsis. When cells were treated with IL-10, STAT3 was activated in monocytes, as determined using western blotting. It was verified that STAT3 was a new target gene of miR-29a. miR-29a could inhibit IL-10-induced cytokine release by targeting JAK-STAT3 in monocytes. In conclusion, this study demonstrates for the first time that miR-29a inhibits STAT3 in human monocytes during sepsis. PMID- 26535691 TI - Alpaca fiber growth is mediated by microRNA let-7b via down-regulation of target gene FGF5. AB - MicroRNAs are very small endogenous RNA molecules that play a crucial role in an array of biological processes, including regulation of skin morphogenesis. The microRNA let-7b is thought to modulate animal hair growth, by binding target genes that encode growth factors. Fibroblast growth factor 5 (FGF5) has been previously reported to be involved in the initiation of the catagen phase of hair growth. In this study, we combined previous reports with bioinformatic analysis techniques to identify and validate FGF5 and, using lucerifase assay, confirmed targeted binding of let-7b to FGF5. To investigate the interaction between let-7b and FGF5, alpaca skin fibroblasts were transfected with let-7b over-expression vectors, and then mRNA and protein expression levels of FGF5 and the gene encoding its receptor, FGFR1, were evaluated. Levels of FGF5 mRNA and protein were remarkably lower in transfected groups, as compared to controls. In summary, this study confirmed that let-7b acts as a regulator of skin morphogenesis, by directly targeting FGF5 and down-regulating its expression. It provides the evidence of hair growth regulated by miRNAs in animals and may have important applications in wool production. PMID- 26535692 TI - Cloning, characterization and expression analysis of coagulation factor II gene in grass carp (Ctenopharyngodon idella). AB - Here, we characterized the structure and function of the coagulation factor II (FII) gene in grass carp and determined its role in coagulation mechanisms. The FII gene EST was obtained using a constructed splenic transcriptome database; the full-length FII gene sequence was obtained by 3' and 5' RACE. The open reading frame (ORF) of FII was cloned and the full-length gene was found to be 1718 bp, with an ORF of 1572 bp; the gene contained a 25 bp 5'-untranslated region (UTR) and 108 bp 3'-UTR. The ORF encoded 524 amino acids, including 74 alkaline amino acids (arginine and lysine) and 69 acidic amino acids (aspartic acid and glutamic acid). The theoretical pI was 6.22. The calculated instability index (II) was 39.81, indicating that FII was a stable protein; the half-life period was predicted to be approximately 30 h. Amino acid sequence comparisons indicated that grass carp FII showed most similarity (71%) to FII of Takifugu rubripes, followed by Oplegnathus fasciatus (48% similarity) and Larimichthys crocea (47% similarity). A real-time reverse transcription PCR analysis showed that under normal circumstances, FII was most highly expressed in the liver, followed by the gill, spleen, thymus, and head-kidney (P < 0.001). After injection of the grass carp reovirus 873 (GCRV873), the pattern of FII expression was significantly altered (P < 0.001); gene expression was high after injection, suggesting a response involving the initiation of the coagulation system and defense of the body in combination with the platelet and complement system. PMID- 26535693 TI - Identification and characterization of the duck enteritis virus (DEV) US2 gene. AB - The US2 protein has been reported to contribute to duck enteritis virus (DEV) infection; however, its kinetics and localization during infection, and whether it is a component of virion, have not been previously reported. To elucidate the function of DEV US2, US2 was amplified by polymerase chain reaction (PCR) and inserted into pET-32a(+); this was expressed, the recombinant US2 protein was purified, and a polyclonal antibody generated. In addition, the kinetics and localization of the US2 gene and protein were determined by quantitative real time fluorescent PCR, ganciclovir (GCV), and cycloheximide (CHX) treatment, western-blot, and indirect immunofluorescence assay. The packaging of US2 into DEV virions was revealed by a protease protection assay. US2 was found to be transcribed 24 h post-infection (pi) and peaked at 72 h pi; the US2 protein was detected 48 h pi, except in the presence of GCV or CHX. US2 was packed into virions and also localized to the plasma membrane and cytoplasm in infected cells. The results showed that the DEV US2 is a late gene, and that its encoding protein could be a tegument component localized mainly in the cytoplasm. This study provides useful data for the further analysis of DEV US2, including an explanation for the genetic conservation among alphaherpesviruses. PMID- 26535694 TI - Methylation profile of SNRPN gene and its correlation with weight and chronological age. AB - Genomic imprinting is an important epigenetic phenomenon, wherein genes or gene clusters are marked by DNA methylation during gametogenesis. This plays a major role in several functions of normal cells, including cell differentiation, X chromosome inactivation, and the maintenance of chromatin structure, in mammalian development. The aim of this study was to investigate the possible differences in SNRPN gene methylation profiles in non-obese and obese individuals, and in children and adults. Our results did not reveal any statistical correlations between the DNA methylation profiles of the SNRPN gene in children or adult obese and non-obese groups. However, a comparison of the methylation levels with the chronological age revealed statistically significant differences between the means of methylation in adults and children (46.20 +/- 5.88 and 39.40 +/- 2.87, respectively; P < 0.001). Pearson's correlation analysis indicated a positive association between the level of DNA methylation and the chronological age (R2 = 0.326; P < 0.001). Therefore, we concluded that the methylation profile of the SNRPN promoter (in blood) is not a useful biomarker for determining the predisposition of an individual to obesity. Additionally, we have confirmed that SNRPN methylation increases with age, which raises further questions regarding the role of SNRPN expression during the aging process. PMID- 26535695 TI - RIG-I detects HIV-1 infection and mediates type I interferon response in human macrophages from patients with HIV-1-associated neurocognitive disorders. AB - The aim of this study was to explore the precise role of retinoic acid-inducible gene-I (RIG-I) signaling in human immunodeficiency virus type 1 (HIV-1)-infected macrophages from patients with HIV-1-associated neurocognitive disorders (HAND). Postmortem brain tissues were collected from patients with HIV-1-associated dementia and were compared to samples collected from HIV serum-positive patients without dementia and HIV serum-negative patients. A human monocyte-derived macrophage (MDM) primary culture system was established to evaluate the expression of RIG-I in these samples. Knockdown of RIG-I pathways genes was employed and STAT1 expression and phosphorylation levels were examined to explore the molecular mechanisms of HAND. The expression of RIG-I in postmortem brain tissue from HAND patients was significantly higher than in patients who were HIV serum-positive without dementia or HIV serum-negative. Moreover, we demonstrated that HIV-1 infection could result in a significant increase in the level of RIG-I in human MDMs. Moreover, a correlation was found between the increase in RIG-I expression and STAT1 expression and phosphorylation. Accordingly, knockdown of RIG-I decreased the phosphorylation of STAT1 and downregulated interferon-related genes. These observations highlight the importance of RIG-I signaling in anti-HIV innate immunity in macrophages, which may be beneficial for the treatment of HIV and aid in the understanding of the neuropathogenesis of HAND. PMID- 26535696 TI - Bone histomorphometry detection of autologous bone powder graft repair of partial mandibular defects in rabbits. AB - The aim of this study was to understand the effect of autologous bone powder graft repair of partial mandibular defects of rabbits by the quantitative detection of bone formation. New Zealand rabbits (N = 18) were selected as the test objects, and subjected to bilateral partial mandibular defect induction. One side of the mandibular defect acted as the test group, upon which the autologous bone powder backfilling graft was performed; the other side was put aside and acted as the negative control group. All used an autogenous control. At the twelfth postoperative week, the animals were sacrificed, and semi-automatic image analysis was used to conduct bone histomorphometric detection. Immediately subsequent, quantitative detection of bone formation was performed in the test group. Fluorescent perimeter percent, mineralization apposition rate, and bone formation rate were selected as the dynamic indicators; and trabecular area percent, trabecular thickness, trabecular number, and trabecular separation degree were selected as the static indicators for single factorial variance testing. It was found that the values of P are less than 0.05 between the test group and the control group, indicating that the effect of autologous bone powder graft repair on partial mandibular defects in rabbits was positive. PMID- 26535697 TI - Conjunctiva reconstruction by induced differentiation of human amniotic epithelial cells. AB - In this study, we aimed to investigate the feasibility of directed differentiation of human amniotic epithelial cells into conjunctival epithelium under specific conditions as well as of constructing tissue-engineered conjunctiva for ocular surface reconstruction. Human amniotic epithelial cells were cultured with induced denuded conjunctival matrix and conjunctival homogenate. Immunohistochemistry of cytokeratin-4, cytokeratin-13, and muc5ac as well as PAS staining were performed. The concentration of muc5ac at different times was measured using ELISA. The differentiated cells with quantum dots were transferred onto a denuded amniotic membrane to establish tissue-engineered conjunctiva and transplanted into a rabbit model with a conjunctival defect. After induction of human amniotic epithelial cells, differentiated cells showed conjunctival epithelium phenotype, while trace amounts of mu5ac in the culture medium measured by ELISA increased gradually within 1 to 7 days. Successfully tissue-engineered conjunctiva had similar structure as normal conjunctiva and was transplanted into a rabbit model with conjunctiva defect. After 2 weeks post surgery, conjunctiva grafts survived and were integrated. Immunohistochemistry showed conjunctival epithelium phenotype, positive cells were found in PAS staining. Thus, human amniotic epithelial cells could differentiate into conjunctival epithelium-like cells and goblet cells with partially physiological function, and we successfully restored ocular surface integrity in the rabbit model using tissue-engineered conjunctiva. PMID- 26535698 TI - TGF-beta1 and Serpine 1 expression changes in traumatic deep vein thrombosis. AB - The objective of this study was to investigate the expression changes of transforming growth factor beta1 (TGF-beta1) and Serpine 1 in rats with traumatic deep vein thrombosis (DVT). In total, 60 male Sprague Dawley rats were divided into model (N = 50) and control groups (Group A, N = 10). From the model group, 10 rats were randomly selected after modeling as the pre-thrombosis group (Group B, N = 10), and the remaining 40 rats in the model group were divided into the thrombosis (Group C) and no thrombosis groups (Group D) depending on whether DVT was apparent at 25 h after modeling. All rats were dissected and the total RNAs of the femoral veins were extracted. TGF-beta1 and Serpine 1 expression was detected by microarray and polymerase chain reaction (PCR) analyses, and the related signal pathways were analyzed using bioinformatic analysis. Of the 40 rats, DVT was evident in 23, yielding an incidence rate of 57.50%. TGF-beta1 and Serpine 1 expression increased significantly at 2.5 h after modeling, while DVT began to form at 25 h after modeling. Both PCR and microarray analysis showed that TGF-beta1 and Serpine 1 expression levels were significantly higher in the thrombosis group than in the other groups (P < 0.05). Bioinformatic analysis indicated that TGF-beta1 was an upstream regulatory gene of Serpine 1 and could induce Serpine 1 overexpression. Together, these results suggested that TGF-beta1 and Serpine 1 overexpression might play an important role in DVT formation and have predictive values. PMID- 26535699 TI - Effect of sphingosine-1-phosphate and myoblast transplantation on rat acute myocardial infarction. AB - In this study, we investigated the effects of sphingosine-1-phosphate (S1P) combined with myoblast transplantation on the treatment of acute myocardial infarction and provided a foundation for its clinical application. A rat model of acute myocardial infarction was established by ligating the anterior descending branch of the coronary artery. Serum-free media, myoblasts, myoblasts with S1P liposomes, or myoblasts with liposomes were then injected into the infarcted area. Apoptosis of the transplanted cells was assessed after 24 and 48 h, and changes in heart function and myocardial infarction area were assessed after 4 weeks. After transplantation of S1P into myoblasts, myocardial function was improved compared to that in the other groups. Specifically, the apoptosis of transplanted cells and the area of myocardial infarction decreased significantly (P < 0.01), while cardiac function significantly improved (P < 0.01). The efficacy of S1P and myoblast transplantation on acute myocardial infarction was significantly better than that in the control group (i.e., injection of myoblasts and liposomes) and the serum-free medium group, demonstrating the feasibility of joint S1P and myoblast transplantation for treating myocardial infarction. PMID- 26535700 TI - Effect of high-intensity exercise on interleukin-15 expression in rabbit synovia. AB - The objective of this study was to examine the effect of high-intensity exercise on interleukin-15 (IL-15) expression in rabbit synovia. We utilized 24 New Zealand white rabbits, which were randomly divided equally into high-intensity exercise and control groups. The former were forced to run for 60 min/day over 4 weeks at the speed of 30 m/min. The histological changes of cartilage and knee joint synovia were investigated with hematoxylin and eosin staining. Immunohistochemistry and enzyme-linked immunosorbent assays were performed to measure IL-15 expression. From these analyses, we identified knee articular cartilage damage and synovitis in the high-intensity exercise group. This group also exhibited higher IL-15 expression in their synovial fluid and tissues than was observed in the control group (P < 0.05). These results suggested that high intensity exercise might lead to synovitis and articular cartilage damage, and that IL-15 overexpression in synovia might be associated with post-traumatic osteoarthritis. PMID- 26535701 TI - Expression of macrophage migration-inhibitory factor in duodenal ulcer and its relation to Helicobacter pylori infection. AB - The aim of this study was to examine the expression of macrophage migration inhibitory factor (MIF) in duodenal ulcer epithelial cells and its relation to Helicobacter pylori (Hp) infection, and to discuss the pathogenic roles of MIF expression and Hp infection in duodenal ulcer. MIF protein and mRNA expression was examined in samples from patients with duodenal ulcer with and without Hp infection (N = 40 each, experimental group), and in normal duodenal bulb mucosal tissue (N = 40, control group) using immunohistochemistry and in situ hybridization. Patients without Hp infection received routine treatment, and treatment was provided to the patients positive for Hp to eradicate Hp infection. Hp and MIF expression levels before treatment and after the ulcer had been cured were compared. The positive rates of MIF protein and mRNA in patients with Hp infection before treatment were 67.5 and 65%, respectively, and were 18.9 and 21.6% in the 37 patients from whom Hp was eliminated. These were statistically different both before and after treatment compared with controls (P < 0.05). In the patients without Hp infection, the positive rates of MIF protein and mRNA expression before (45 and 47.5%, respectively) and after (32.5 and 30%) treatment were not significantly different (P > 0.05). The results of this study suggested that MIF is related to the development of duodenal ulcer, and that the presence of Hp is closely related with the expression of MIF in the duodenal mucosa and the development of duodenal ulcer. PMID- 26535702 TI - Genetic diversity of cultivated and wild tomatoes revealed by morphological traits and SSR markers. AB - In the current study, morphological traits and molecular markers were used to assess the genetic diversity of 29 cultivated tomatoes, 14 wild tomatoes and seven introgression lines. The three components of the principal component analysis (PCA) explained 78.54% of the total morphological variation in the 50 tomato genotypes assessed. Based on these morphological traits, a three dimensional PCA plot separated the 50 genotypes into distinct groups, and a dendrogram divided them into six clusters. Fifteen polymorphic genomic simple- sequence repeat (genomic-SSR) and 13 polymorphic expressed sequence tag-derived SSR (EST-SSR) markers amplified 1115 and 780 clear fragments, respectively. Genomic-SSRs detected a total of 64 alleles, with a mean of 4 alleles per primer, while EST-SSRs detected 52 alleles, with a mean of 4 alleles per primer. The polymorphism information content was slightly higher in genomic-SSRs (0.49) than in EST-SSRs (0.45). The mean similarity coefficient among the wild tomatoes was lower than the mean similarity coefficient among the cultivated tomatoes. The dendrogram based on genetic distance divided the 50 tomato genotypes into eight clusters. The Mantel test between genomic-SSR and EST-SSR matrices revealed a good correlation, whereas the morphological matrices and the molecular matrices were weakly correlated. We confirm the applicability of EST-SSRs in analyzing genetic diversity among cultivated and wild tomatoes. High variability of the 50 tomato genotypes was observed at the morphological and molecular level, indicating valuable tomato germplasm, especially in the wild tomatoes, which could be used for further genetic studies. PMID- 26535703 TI - Effects and mechanism of lipoic acid on beta-amyloid-intoxicated C6 glioma cells. AB - beta-amyloid peptides (Abetas) can exert neurotoxic effects through induction of oxidative damage, whereas lipoic acid (LA), a powerful antioxidant, can alleviate oxidative damage. In this study, we explored the effect and mechanism of action of LA on beta-amyloid-intoxicated C6 glioma cells. Cells were randomly divided into three groups: control (vehicle), Abeta, and LA + Abeta. The LA + Abeta group was treated with LA for 2 h, then both the Abeta-only and the LA + Abeta groups were incubated with 25 MUM Abeta for 24 h. Cell viability was measured by the MTT method. Mitochondrial reduced glutathione (GSH) and oxidized glutathione (GSSG) levels were detected by enzyme-linked immunosorbent assay (ELISA), and the GSH to GSSG ratio calculated. Real-time polymerase chain reaction and western blot analyses were used to detect MnSOD mRNA and protein, respectively. Abeta significantly inhibited C6 cell proliferation compared with the control group (P < 0.05). LA markedly increased cell viability compared with the Abeta group (P < 0.05). The increased GSSH and decreased GSH mitochondrial accumulation induced by Abeta was profoundly reversed by treatment with LA (P < 0.05). Abeta significantly reduced MnSOD expression compared to controls (P < 0.05), whereas LA pretreatment increased MnSOD expression compared with the Abeta-only group (P < 0.05); MnSOD protein levels showed similar patterns. These results suggest that LA might protect Abeta-intoxicated C6 glioma cells by alleviating oxidative damage, providing a new treatment strategy for neurodegenerative diseases. PMID- 26535704 TI - First cytogenetic study of Cavernicola pilosa Barber, 1937 (Hemiptera, Triatominae). AB - Cavernicola pilosa is a triatomine species that lives in caves and feeds on bat blood. This vector has a wide geographical distribution, and is found in Brazil, Colombia, Panama, Peru, and Venezuela. Little is known about the reproductive biology of this species, because most previous studies have only characterized its morphology, morphometry, ecology, and epidemiology. Therefore, this study aimed to obtain preliminary data related to spermatogenesis in C. pilosa by conducting cytogenetic analysis. Analysis of the heterochromatic pattern of C. pilosa during the initial prophases revealed that heterochromatic blocks are only present in the sex chromosomes. Based on the analyses of the meiotic metaphase and prophases, we found that the sex determination system of C. pilosa is XY and the chromosomes are holocentric. C. pilosa spermatids are filamentous and have long flagella. It was not possible to detect corpuscle or filament heteropycnosis in spermatids of this species. The initial cytogenetic data presented in this study are important in characterizing the spermatogenesis and heterochromatic patterns of C. pilosa. Our results suggest that adaptation to troglodytism did not result in differences in spermatogenesis in this vector. PMID- 26535705 TI - Photoperiod regulates the differential expression of KiSS-1 and GPR54 in various tissues and sexes of striped hamster. AB - In order to investigate how photoperiod affects the expression of KiSS-1/G protein-coupled receptor 54 (GPR54), the hypothalamus, the ovaries and testicles of the striped hamster were studied following photoperiod treatment and melatonin injection. We found that the melatonin concentration in the blood of the striped hamster was consistent with the treated photoperiods and that the photoperiod had significant effects on KiSS-1 expression, but the effect of photoperiod on GPR54 expression differed among tissues and sexes. The relative expression of KiSS-1 in the gonads of the male and female striped hamster was significantly higher than that in the hypothalamus, while the difference in GPR54 between the gonads and hypothalamus was inconsistent between the male and female striped hamster. In the striped hamster injected with melatonin, the expression level of KiSS-1 in the gonads and hypothalamus of the male and female striped hamster was significantly decreased; the expression level of GnRH in the gonads was also significantly decreased; the expression of GPR54 in the hypothalamus was increased. In the hypothalamus, a significant positive correlation existed between KiSS-1 and GnRH expression, while a negative correlation was observed between GPR54 and GnRH expression. These results suggest that the photoperiod-melatonin-KiSS-1-GnRH pathway plays an important role in the seasonal reproduction mechanism of the striped hamster. Additionally, photoperiod or melatonin may not be a direct regulatory factor of GPR54 expression. PMID- 26535706 TI - Vascular endothelial growth factor -634 G/C polymorphism and risk of cancer: an updated meta-analysis. AB - The association between vascular endothelial growth factor (VEGF) gene polymorphisms and risk of cancer has been investigated in several studies published previously; however, the individual results are inconclusive. Therefore, we performed a meta-analysis to establish evidence for an association between the VEGF -634 G/C polymorphism and risk of cancer. We searched PubMed, Medline, and Korean Studies Information Service System databases and identified 29 case-control studies, containing data of 25,324 individuals, for this meta analysis. The odds ratio (OR) and 95% confidence interval (95%CI) were used to determine the strength of the association. Overall, no significant association was detected in the allele model (G allele vs C allele, OR = 0.98, 95%CI = 0.93 1.03), dominant model (G/G+G/C vs C/C, OR = 1.00, 95%CI = 0.90-1.11), or recessive model (G/G vs G/C+C/C, OR = 0.96, 95%CI = 0.89-1.03). The meta-analysis results suggest that the VEGF -634 G/C polymorphism may not be related to the development of cancer. However, additional studies with larger sample size are required in order to provide supporting evidence. PMID- 26535707 TI - Molecular identification of Echinococcus granulosus on the Tibetan Plateau using mitochondrial DNA markers. AB - Cystic echinococcosis (CE) is an important worldwide zoonotic disease that causes large economic losses and human suffering. Echinococcus granulosus, the causative agent of CE, exhibits different genotypes in different locations. In order to identify its genotypes and analyze its genetic structure on the Tibetan Plateau, we collected 72 hydatid cysts from different intermediate hosts and amplified and sequenced their mitochondrial cytochrome c oxidase subunit 2 (cox2) genes. Seventy isolates were identified as the E. granulosus G1 genotype, while two isolates belonged to the G6 genotype. There were 18 haplotypes among the 70 E. granulosus isolates, which exhibited a star-like network pattern and shared a common haplotype (H1). There was little difference between geographical sub populations. Our results suggest that a recent E. granulosus population expansion occurred on the Tibetan Plateau, suggesting that E. granulosus was introduced into China. This study increases the basic molecular data needed for the molecular diagnosis, epidemiology, prevention, and control of Echinococcus diseases. PMID- 26535708 TI - Development of FQ-PCR method to determine the level of ADD1 expression in fatty and lean pigs. AB - To determine how adipocyte determination and differentiation factor 1 (ADD1), a gene involved in the determination of pork quality, is regulated in Laiwu and Large pigs, we used TaqMan fluorescence quantitative real-time polymerase chain reaction (FQ-PCR) to detect differential expression in the longissimus muscle of Laiwu (fatty) and Large White (lean) pigs. In this study, the ADD1 and GAPDH cDNA sequences were cloned using a T-A cloning assay, and the clone sequences were consistent with those deposited in GenBank. Thus, the target fragment was successfully recombined into the vector, and its integrity was maintained. The standard curve and regression equation were established through the optimized FQ PCR protocol. The standard curve of porcine ADD1 and GAPDH cDNA was determined, and its linear range extension could reach seven orders of magnitudes. The results showed that this method was used to quantify ADD1 expression in the longissimus muscle of two breeds of pig, and was found to be accurate, sensitive, and convenient. These results provide information regarding porcine ADD1 mRNA expression and the mechanism of adipocyte differentiation, and this study could help in the effort to meet the demands of consumers interested in the maintenance of health and prevention of obesity. Furthermore, it could lead to new approaches in the prevention and clinical treatment of this disease. PMID- 26535709 TI - ESR1 gene polymorphisms PvuII (rs2234693T>C) and XbaI (rs9340799A>G) may not be directly correlated with cardiovascular disease risk. AB - The aim of this meta-analysis was to evaluate the correlations between the estrogen receptor 1 (ESR1) gene polymorphisms PvuII (rs2234693T>C) and XbaI (rs9340799A>G) and the risk of cardiovascular disease (CVD). Case-control studies were screened and selected from a larger group of studies that were retrieved through a comprehensive search of scientific literature databases, which was complemented by manual searches. Data from studies selected were analyzed using the Comprehensive Meta-analysis 2.0 software. A total of 240 studies were initially retrieved and 10 studies were eventually included in the meta-analysis. These 10 case-control studies involved 7029 CVD patients (5001 myocardial infarction patients, 1223 coronary artery disease patients, 805 acute coronary syndromes patients) and 6901 healthy controls. We found no significant association between the PvuII (rs2234693T>C) and XbaI (rs9340799A>G) polymorphisms and CVD risk. We detected no significant associations under all genetic inheritance models tested, including the allele, dominant, homozygous, heterozygous, and recessive models, or for comparisons between the case group and control group (all P > 0.05). Our meta-analysis results strongly suggest that the ESR1 gene polymorphisms PvuII (rs2234693T>C) and XbaI (rs9340799A>G) are not associated with CVD risk. PMID- 26535710 TI - Genetic diversity analysis of faba bean (Vicia faba L.) germplasms using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. AB - To investigate genetic diversity and relationships of 101 faba bean (Vicia faba L.), landraces and varieties from different provinces of China and abroad were analyzed by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE). A total of 2625 unambiguous and stable bands from 101 germplasms were detected, and 36 different bands were classified according to the electrophoretic mobility patterns of the proteins as determined by the SDS-PAGE analysis, of which 16 were polymorphic. Besides the common bands, the protein bands of 92, 75, 62, 40, 34, 17, and 13 kDa presented the highest frequencies of 92.08, 90.10, 99.01, 95.05, 95.05, 98.02, and 95.05%, respectively. The other 29 polymorphic protein bands showed higher polymorphism with 16.09 polymorphic bands in average. The genetic similarity of the 101 genotypes tested varied from 0.6111 to 0.9722, with an average of 0.7122. Cluster analysis divided the 101 genotypes into six major clusters, which was consistent with the systematic classification of faba bean done in previous studies. The overall results indicated that SDS-PAGE was a useful tool for genetic diversity analysis and laid a solid foundation for future faba bean breeding. PMID- 26535711 TI - Linking lignocellulosic dietary patterns with gut microbial Enterotypes of Tsaitermes ampliceps and comparison with Mironasutitermes shangchengensis. AB - Tsaitermes ampliceps (lower termites) and Mironasutitermes shangchengensis (higher termites) are highly eusocial insects that thrive on recalcitrant lignocellulosic diets through nutritional symbioses with gut dwelling prokaryotes and eukaryotes. We used denaturing gradient gel electrophoresis and a 16S rRNA clone library to investigate i) how microbial communities adapt to lignocellulosic diets with different cellulose and lignin content, ii) the differences in the dominant gut microbial communities of the 2 types of termites. The results indicated that gut microbiota composition in T. ampliceps was profoundly affected by 2-week diet shifts. Comparison of these changes indicated that Bacteroidetes and Spirochaetes act in cellulose degradation, while Firmicutes were responsible for lignin degradation. Additionally, Proteobacteria consistently participated in energy production and balanced the gut environment. Bacteroidetes may function without hindgut protozoans in higher termites. The diversity of enteric microorganisms in M. shangchengensis was higher than that in T. ampliceps, possibly because of the more complicated survival mechanisms of higher termites. PMID- 26535712 TI - NLRP3 rs35829419 polymorphism is associated with increased susceptibility to multiple diseases in humans. AB - Using a meta-analysis framework, we investigated the association between the NLRP3 rs35829419 polymorphism and increased susceptibility to diverse diseases in humans. Relevant published studies were identified through a comprehensive and systematic electronic search, using the following scientific literature databases: Science Citation Index, the Cochrane Library, PubMed, Embase, CINAHL, Current Contents Index, Chinese Biomedical, the Chinese Journal Full-Text, and the Weipu Journal. Statistical analysis of data extracted from the selected high quality studies was performed using the Version 12.0 STATA software. A total of 13 case-control studies met our stringent inclusion and exclusion criteria for the present meta-analysis. These 13 high quality studies contained relevant information on 7719 patients with various diseases and 7094 healthy controls. Our meta-analysis results showed that the NLRP3 gene rs35829419 C>A polymorphism was associated with a significantly increased risk of developing multiple diseases in humans under 5 genetic models (all P < 0.05). Data stratification and subgroup analysis based on the disease type revealed that rs35829419 C>A carriers displayed a markedly increase susceptibility to leprosy, colorectal cancer, HIV-1 infection, rheumatoid arthritis, abdominal aortic aneurysms, inflammatory bowel disease, ulcerative colitis, and atopic dermatitis. In summary, our meta-analysis results revealed the first identified strong correlation between the NLRP3 rs35829419 polymorphism and increased susceptibility to various diseases in humans. PMID- 26535713 TI - Molecular barcoding of venomous snakes and species-specific multiplex PCR assay to identify snake groups for which antivenom is available in Thailand. AB - DNA barcodes of mitochondrial COI and Cytb genes were constructed from 54 specimens of 16 species for species identification. Intra- and interspecific sequence divergence of the COI gene (10 times) was greater than that of the Cytb gene (4 times), which suggests that the former gene may be a better marker than the latter for species delimitation in snakes. The COI barcode cut-off scores differed by more than 3% between most species, and the minimum interspecific divergence was greater than the maximum intraspecific divergence. Clustering analysis indicated that most species fell into monophyletic clades. These results suggest that these species could be reliably differentiated using COI DNA barcodes. Moreover, a novel species-specific multiplex PCR assay was developed to distinguish between Naja spp, Ophiophagus hannah, Trimeresurus spp, Hydrophiinae, Daboia siamensis, Bungarus fasciatus, and Calloselasma rhodostoma. Antivenom for these species is produced and kept by the Thai Red Cross for clinical use. Our novel PCR assay could easily be applied to venom and saliva samples and could be used effectively for the rapid and accurate identification of species during forensic work, conservation study, and medical research. PMID- 26535714 TI - Expression of Ras-related protein 25 predicts chemotherapy resistance and prognosis in advanced non-small cell lung cancer. AB - Ras-related protein 25 (Rab25) is involved in many human malignancies. However, its role in chemotherapy response and prognosis in advanced non-small cell lung cancer (NSCLC) remains unknown. Therefore, we investigated the relationship between Rab25 and chemotherapy sensitivity and prognosis in NSCLC. Rab25 expression was assessed using immunohistochemistry in 324 advanced NSCLC patients. Its correlations with clinical features were analyzed. Sensitivity to cisplatin (DDP) was compared between DDP-sensitive A549 and DDP-resistant A549/DDP cells. Furthermore, small interfering RNA (siRNA) targeting Rab25 was used for in vitro experiments. Patients with positive Rab25 expression had a significantly lower chemotherapy response rate (P = 0.004) and poorer overall survival (OS, P = 0.0012) than those with negative Rab25 expression. Multivariate analysis indicated that Rab25 expression was an independent prognostic factor for OS (P = 0.016). Moreover, Rab25 expression was significantly higher in A549/DDP cells than in A549 cells. Knockdown of Rab25 by siRNA suppressed cell migration and invasion. Cisplatin resistance in A549/DDP cells was also partially reversed by Rab25 silencing. Rab25 expression is a potential prognostic index for advanced NSCLC patients and its inhibition may improve chemosensitization in NSCLC treatment. PMID- 26535715 TI - Alternative splicing isoform of T cell factor 4K suppresses the proliferation and metastasis of non-small cell lung cancer cells. AB - The Wnt pathway has been implicated in the initiation, progression, and metastasis of lung cancer. T cell factor 4, a member of TCF/LEF family, acts as a transcriptional factor for Wnt pathways in lung cancer. Increasing amounts of evidence have shown that TCF-4 has multiple alternative splicing isoforms with transactivation or transrepression activity toward the Wnt pathway. Here, we found the presence of multiple TCF-4 isoforms in lung cancer cell lines and in normal bronchial epithelial cells. TCF-4K isoform expression was significantly decreased in lung cancer cells compared with normal bronchial epithelial cells and was identified as a transcriptional suppressor of the Wnt pathway in non small cell lung carcinoma (NSCLC). Overexpression of TCF-4K significantly inhibited the proliferation and migration of NSCLC cells. Collectively, our data indicate that TCF-4K functions as a tumor suppressor in NSCLC by down-regulating the Wnt pathway. PMID- 26535716 TI - Exploring laccase genes from plant pathogen genomes: a bioinformatic approach. AB - To date, research on laccases has mostly been focused on plant and fungal laccases and their current use in biotechnological applications. In contrast, little is known about laccases from plant pathogens, although recent rapid progress in whole genome sequencing of an increasing number of organisms has facilitated their identification and ascertainment of their origins. In this study, a comparative analysis was performed to elucidate the distribution of laccases among bacteria, fungi, and oomycetes, and, through comparison of their amino acids, to determine the relationships between them. We retrieved the laccase genes for the 20 publicly available plant pathogen genomes. From these, 125 laccase genes were identified in total, including seven in bacterial genomes, 101 in fungal genomes, and 17 in oomycete genomes. Most of the predicted protein models of these genes shared typical fungal laccase characteristics, possessing four conserved domains with one cysteine and ten histidine residues at these domains. Phylogenetic analysis illustrated that laccases from bacteria and oomycetes were grouped into two distinct clades, whereas fungal laccases clustered in three main clades. These results provide the theoretical groundwork regarding the role of laccases in plant pathogens and might be used to guide future research into these enzymes. PMID- 26535717 TI - 15-Deoxy-prostaglandin J2 anti-inflammation in a rat model of chronic obstructive pulmonary disease and human bronchial epithelial cells via Nrf2 activation. AB - Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates antioxidant and anti-inflammatory genes, and it plays a crucial role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Moreover, 15 deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) plays a protective role against oxidative stress and inflammation both in vivo and in vitro. In a previous study, we found that 15d-PGJ2 increased the expression of Nrf2 in a COPD rat model. This study aims to elucidate the role of 15d-PGJ2 in COPD pathogenesis and the relationship between Nrf2 and human bronchial epithelial (HBE) cells. Normal HBE (HBE) cells were cultured. Following cigarette smoke extract (CSE) stimulation, pre-incubation with or without small interfering RNA (siRNA) Nrf2, and stimulation with or without 15d-PGJ2, the expression levels of Nrf2, NF kappaBp65, and IL-8 were detected by reverse transcription-polymerase chain reaction and western blot, respectively. The expression of NF-kappaBp65 and IL-8 in CSE-stimulated normal HBE cells was inhibited by 15d-PGJ2 at both the mRNA level and the protein level. Moreover, the expression of Nrf2 in normal HBE cells was improved by 15d-PGJ2 at both the mRNA level and the protein level. However, the inhibitory or improving effects of 15d-PGJ2 were disengaged by siRNA Nrf2 at both the mRNA level and the protein level. 15d-PGJ2 possesses anti-inflammatory properties in the pathogenesis of COPD, and HBE cells stimulated by CSE via Nrf2 activation. PMID- 26535718 TI - Genetic divergence of sugarcane varieties collected in the region of Lavras, Minas Gerais, Brazil. AB - Genetic diversity among local accessions and varieties subsidize plant breeding programs, allowing the utilization of existing variability in plants that have already adapted to local climate conditions. An alternative to studying genetic variability is the study of diversity. The aim of this research was to study genetic diversity among sugarcane accessions and varieties used for the production of craft-distilled cachaca (distilled sugarcane alcohol) in the region of Lavras, Minas Gerais, Brazil. Using a one-way design, an experiment was conducted in the municipality of Perdoes, Minas Gerais to evaluate 35 regional accessions derived from germplasm collection expeditions and four varieties. Using morphological descriptions of 46 multicategorical sugarcane characteristics, dissimilarity and Tocher cluster method analyses were performed. Based on the results, it was concluded that genetic diversity exists among the accessions evaluated for the target traits. PMID- 26535719 TI - An let-7 KRAS rs712 polymorphism increases hepatocellular carcinoma risk. AB - KRAS, also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, acts as an intracellular signal transducer. The oncogenic KRAS mutation is an essential step in the development of many types of human cancers, including hepatocellular carcinoma. Here we aimed to investigate the relationship between KRAS rs712 polymorphisms and hepatocellular carcinoma susceptibility. Five-hundred-and fourteen participants were enrolled in a case-control study (262 cases and 252 normal subjects). The variants were distinguished using polymerase chain reaction restriction fragment length polymorphism. Significantly increased HCC risk was observed to be associated with the T allele of the rs712 locus (P = 0.049, OR = 1.35, 95%CI = 1.01-1.78). Further, HCC risk with the GT genotype (P = 0.015, OR = 1.64, 95%CI = 1.08-2.50) and the TT genotype (P = 0.015, OR = 2.56, 95%CI = 1.05 6.25) in a codominant model was significantly higher than that with the GG genotype. In a dominant model, significantly increased HCC susceptibility was also associated with T allele carriers (P = 0.006, OR = 1.75, 95%CI = 1.16-2.63). Moreover, we found that the frequency of the KRAS rs712 TT genotype was significantly higher in HBV-positive HCC patients than in HBV-negative HCC patients. PMID- 26535720 TI - In vivo and in vitro inhibitory action of 17beta-estradiol and environmental estrogen 4-nonylphenol on gonad-inhibiting hormone (GIH) expression in the eyestalks of Litopenaeus vannamei. AB - The gonad-inhibiting hormone (GIH) belongs to a neuropeptide family synthesized and released in an X-organ sinus gland complex of crustacean eyestalks. GIH inhibits crustacean ovarian maturation by suppressing vitellogenin (Vtg) synthesis, whereas estrogen is responsible for the stimulation of vitellogenesis (not established). In this study, the effects of 17beta-estradiol (E2, 10(-6) M), estrogen receptor antagonist tamoxifen (TAM, 10(-6), 10(-7), and 10(-8) M), and the environmental estrogen nonylphenol (NP, 1 MUg/L and 100 MUg/L) on LvGIH expression in the eyestalks of shrimp were determined by quantitative real-time PCR. Results showed that LvGIH expression decreased significantly during the L. vannamei ovarian maturation cycle. E2 and NP significantly reduced LvGIH transcripts in vivo, but TAM neutralized the inhibitory action of E2 in a dose dependent manner (P < 0.05). In addition, the LvGIH expression levels decreased significantly in a time-dependent manner (P < 0.05) when ovary fragments were cultured in vitro with E2. The results of this study suggested that estrogen regulates GIH expression in L. vannamei eyestalks. E2 promoted ovarian development not only by directly upregulating vitellogenesis in the hepatopancreas, but it was also capable of downregulating LvGIH expression, which indirectly resulted in the stimulation of L. vannamei vitellogenesis. PMID- 26535721 TI - Role of death receptors in the regulation of hepatocyte proliferation and apoptosis during rat liver regeneration. AB - The balance between hepatocyte proliferation and apoptosis is critical for liver homeostasis during liver regeneration. We created a rat liver regeneration model by partial hepatectomy (PH) to investigate the overall mechanism that regulates the proliferation and apoptosis of hepatocytes. The Rat Genome 230 2.0 Array was used to investigate changes in the expression levels of genes associated with the known proliferation or apoptosis signaling pathways. Ingenuity Pathway Analysis 9.0 was used to determine interactions among these signaling pathways. The results revealed that the expression levels of multiple key genes in three death receptor (DR) pathways, Fas/FasL, TNFR/TNFalpha, and DR6, were significantly altered in hepatocytes after PH. The expression level of the gene encoding DR6 increased by over 100-fold, whereas the levels of the genes encoding Fas, FasL, and TNFalpha were increased by 2-4-fold 12 h after PH. Fas/FasL, TNFR/TNFalpha, and DR6 are known to participate in numerous cellular events including cell proliferation and apoptosis. Our results suggest that the DR6 pathway plays a major role in the regulation of hepatocyte apoptosis, whereas Fas/FasL and TNFR/TNFalpha pathways may have roles in coordinating signaling activities between proliferation and apoptosis. PMID- 26535722 TI - Growth curves of carcass traits obtained by ultrasonography in three lines of Nellore cattle selected for body weight. AB - The effect of selection for postweaning weight was evaluated within the growth curve parameters for both growth and carcass traits. Records of 2404 Nellore animals from three selection lines were analyzed: two selection lines for high postweaning weight, selection (NeS) and traditional (NeT); and a control line (NeC) in which animals were selected for postweaning weight close to the average. Body weight (BW), hip height (HH), rib eye area (REA), back fat thickness (BFT), and rump fat thickness (RFT) were measured and records collected from animals 8 to 20 (males) and 11 to 26 (females) months of age. The parameters A (asymptotic value) and k (growth rate) were estimated using the nonlinear model procedure of the Statistical Analysis System program, which included fixed effect of line (NeS, NeT, and NeC) in the model, with the objective to evaluate differences in the estimated parameters between lines. Selected animals (NeS and NeT) showed higher growth rates than control line animals (NeC) for all traits. Line effect on curves parameters was significant (P < 0.001) for BW, HH, and REA in males, and for BFT and RFT in females. Selection for postweaning weight was effective in altering growth curves, resulting in animals with higher growth potential. PMID- 26535723 TI - Analysis of regulatory T cell subsets in the peripheral blood of immunoglobulin A nephropathy (IgAN) patients. AB - The aim of this study was to investigate the clinical significance of regulatory T cells (Tregs) and its subsets in immunoglobulin A nephropathy (IgAN) patients. Peripheral blood samples of 20 IgAN patients and 20 healthy individuals of similar ages were analyzed. Levels of Tregs and its subsets, namely nTregs and iTregs, were analyzed using flow cytometry. The number of Tregs in IgAN patients was significantly lower than that in the healthy controls. While significant reduction in iTregs primarily contributed to this effect (P < 0.01), nTreg levels did not significantly change (P > 0.05). The levels of serum IL-17, IL-10 and TGF beta were detected by ELISA method. The levels of IL-10 and TGF-beta in IgAN patients were lower (P < 0.05), whereas those of IL-17 in the IgAN group were higher (P < 0.05) than those in the controls. In conclusion, the change in Tregs count in the peripheral blood of IgAN patients is mainly caused by the reduction in iTregs, suggesting a substantial role in the prognosis and treatment of IgAN. PMID- 26535724 TI - Mitochondrial DNA dynamics during in vitro culture and pluripotency induction of a bovine Rho0 cell line. AB - Large number of cellular changes and diseases are related to mutations in the mitochondrial DNA copy number. Cell culture in the presence of ethidium bromide is a known way of depleting mitochondrial DNA and is a useful model for studying such conditions. Interestingly, the morphology of these depleted cells resembles that of pluripotent cells, as they present larger and fragmented mitochondria with poorly developed cristae. Herein, we aimed to study the mechanisms responsible for the control of mitochondrial DNA replication during mitochondrial DNA depletion mediated by ethidium bromide and during the in vitro induction of cellular pluripotency with exogenous transcription factor expression in a bovine model. This article reports the generation of a bovine Rho0 mesenchymal cell line and describes the analysis of mitochondrial DNA copy number in a time-dependent manner. The expression of apoptosis and mitochondrial-related genes in the cells during mitochondrial DNA repletion were also analyzed. The dynamics of mitochondrial DNA during both the depletion process and in vitro reprogramming are discussed. It was possible to obtain bovine mesenchymal cells almost completely depleted of their mitochondrial DNA content (over 90%). However, the production of induced pluripotent stem cells from the transduction of both control and Rho0 bovine mesenchymal cells with human reprograming factors was not successful. PMID- 26535725 TI - Phylogenetic analysis of DNA and RNA polymerases from a Moniliophthora perniciosa mitochondrial plasmid reveals probable lateral gene transfer. AB - The filamentous fungus Moniliophthora perniciosa is a hemibiotrophic basidiomycete that causes witches' broom disease of cacao (Theobroma cacao L.). Many fungal mitochondrial plasmids are DNA and RNA polymerase-encoding invertrons with terminal inverted repeats and 5'-linked proteins. The aim of this study was to carry out comparative and phylogenetic analyses of DNA and RNA polymerases for all known linear mitochondrial plasmids in fungi. We performed these analyses at both gene and protein levels and assessed differences between fungal and viral polymerases in order to test the lateral gene transfer (LGT) hypothesis. We analyzed all mitochondrial plasmids of the invertron type within the fungal clade, including five from Ascomycota, seven from Basidiomycota, and one from Chytridiomycota. All phylogenetic analyses generated similar tree topologies regardless of the methods and datasets used. It is likely that DNA and RNA polymerase genes were inserted into the mitochondrial genomes of the 13 fungal species examined in our study as a result of different LGT events. These findings are important for a better understanding of the evolutionary relationships between fungal mitochondrial plasmids. PMID- 26535726 TI - Development of microsatellite markers for Suriana maritima (Surianaceae) using next-generation sequencing technology. AB - Our objective was to develop microsatellite markers for use in assessing genetic variation in the small shrub or tree species Suriana maritima (Surianaceae). In China, this species is found only as a few fragmented populations and individuals on the Paracel Islands. Using next-generation genome sequencing methodology, we developed 17 novel microsatellite markers for S. maritima. Fifty-four individuals from six populations of S. maritima were examined for polymorphisms; only one allele was detected for each of the markers. Microsatellite loci developed indicate a complete absence of genetic diversity for S. maritima on the Paracel Islands in China. These markers will be useful for examining genetic variation among S. maritima populations in other areas of the world. PMID- 26535727 TI - Rapid microsatellite development in Gekko japonicus using sequenced restriction site associated DNA markers. AB - Twelve polymorphic microsatellite loci were isolated in the Japanese gecko, Gekko japonicus. We genotyped one population from Wenzhou, Zhejiang Province, China (N = 36). The mean number of observed alleles per locus was 7.3 (range 4 to 13). Observed and expected heterozygosity values ranged from 0.200 to 0.944 and from 0.395 to 0.797, respectively. One locus (GJ20) showed significant departure from Hardy-Weinberg equilibrium; no linkage disequilibrium was found between any two loci. These informative microsatellite markers will be useful for population genetic analyses of G. japonicus and other species in the genus Gekko. PMID- 26535728 TI - Heritability of predicted daily enteric methane emissions from growing Nellore cattle. AB - The objective of this study was to estimate the heritability of predicted daily enteric methane emissions (PME) from growing Nellore cattle. Dry matter intake (DMI) records of 955 Nellore animals that were born between 2004 and 2013, which were obtained in a postweaning performance test lasting 83 +/- 15 days, were used. The PME of each animal, obtained as MJ/day and converted to g/day, was estimated using three equations: PME1 (MJ/day) = 2.29 + 0.647 x DMI (kg/day), PME2 (MJ/day) = 3.96 + 0.561 x DMI (kg/day), and PME3 (MJ/day) = 4.41 + 0.50 x DMI (kg/day). The heritability (h2) of PME obtained using the three equations was identical to the h2 of DMI, regardless of whether the model included the effect of mid-test weight (h2 = 0.32 +/- 0.069) or not (h2 = 0.48 +/- 0.069). The equations were based exclusively on variations in DMI, and detected variations in this trait without taking into consideration individual differences in enteric methane emission caused by differences in fermentation and digestion capacity. Therefore, prediction equations of enteric methane emission from DMI are not adequate to estimate differences between animals. PMID- 26535729 TI - Pyridoxal 5?-phosphate-responsive epilepsy with novel mutations in the PNPO gene: a case report. AB - Pyridoxal 5'-phosphate (PLP)-responsive epilepsy is a rare autosomal recessive epileptic disorder caused by deficiency of pyridox(am)-ne 5'-phosphate oxidase (PNPO). Neonatal onset seizures in PLP responsive epilepsy are usually resistant to common anticonvulsants and pyridoxine, but respond to PLP. Various PNPO mutations are associated with this disorder. In this report, we have described a case of a female baby with neonatal onset seizures responding to PLP. Exome sequencing revealed that the patient was compound heterozygous for pathogenic mutations [c.546+1G>A (IVS5+1 G>A) and c.620delG (p.G207VfsX215)] in the PNPO gene. The c.546+1G>A was inherited from the mother while the c.620delG was inherited from the father. Both mutations were absent in 122 unrelated Thai controls. The results of this study indicated the presence of two newly identified mutations in this Thai patient with PLP-responsive epilepsy for the first time, expanding the mutational spectrum of PNPO. PMID- 26535730 TI - Effect of early vitamin D supplementation on asthma and the possible mechanisms. AB - Asthma is a chronic inflammatory disease of the airways with variable airflow obstruction and bronchial hyper-responsiveness. It is believed that Th2-derived cytokines orchestrate the asthmatic response and the maintenance of the balance of Th1/Th2 plays a crucial role in prevention of asthma. Moreover, 1,25(OH)2D3, the biologically activate form of vitamin D, was reported with an almost opposite role in prevention and treatment of asthma. Therefore, in this study, we elucidated the evaluations of in vivo anti-asthma effects when treated with different doses of vitamin D and validated the relationship between vitamin D and asthma. Our data demonstrated that intervention with the appropriate dose of 1,25(OH)2D3 in early life could improve pulmonary function and reduce eosinophil cell infiltration in the airways of rat asthma models. However, overdose might play a detrimental effect. Its mechanism may correlate with the effect of 1,25(OH)2D3 on interleukin (IL)-4, IL-12, IL-13, interferon-gamma, and ovalbumin specific immunoglobulin E secretion and the expression of p-JAK1/p-STAT6/SOCS5. PMID- 26535731 TI - Frequency of gray coat color in native Chinese horse breeds. AB - Gray horses are born colored, and they then gradually lose their hair pigmentation. Tremendous progress has been made in identifying the genes responsible for graying with age in horses in recent years. Results show that gray coat color in horses is caused by a 4.6-kb duplication in intron 6 of the syntaxin 17 gene (STX17), which constitutes a cis-acting-regulatory mutation. However, little is known about the gray phenotype in native Chinese horses. This study was conducted to explore the frequency distribution of the gray mutation in native Chinese horse breeds. A total of 489 samples from 14 native Chinese horse breeds were genotyped for the STX17 duplication using a simplified conventional PCR-based method. The results show that the gray mutation was present in 12 native Chinese horse breeds, except the Balikun and Guanzhong breeds. The Chakouyi and Hequ breeds had the highest frequency of the gray mutation (P(G) = 0.367 and P(G) = 0.274, respectively). There was no significant geographical difference in the distribution of gray coat color across native Chinese horse breeds. Our results suggest that gray is a common coat color in Chinese horses. PMID- 26535732 TI - Isolation and expression analysis of four HD-ZIP III family genes targeted by microRNA166 in peach. AB - MicroRNA166 (miR166) is known to have highly conserved targets that encode proteins of the class III homeodomain-leucine zipper (HD-ZIP III) family, in a broad range of plant species. To further understand the relationship between HD ZIP III genes and miR166, four HD-ZIP III family genes (PpHB14, PpHB15, PpHB8, and PpREV) were isolated from peach (Prunus persica) tissue and characterized. Spatio-temporal expression profiles of the genes were analyzed. Genes of the peach HD-ZIP III family were predicted to encode five conserved domains. Deduced amino acid sequences and tertiary structures of the four peach HD-ZIP III genes were highly conserved, with corresponding genes in Arabidopsis thaliana. The expression level of four targets displayed the opposite trend to that of miR166 throughout fruit development, with the exception of PpHB14 from 35 to 55 days after full bloom (DAFB). This finding indicates that miR166 may negatively regulate its four targets throughout fruit development. As for leaf and phloem, the same trend in expression level was observed between four targets and miR166 from 75 to 105 DAFB. However, the opposite trend was observed for the transcript level between four targets and miR166 from 35 to 55 DAFB. miRNA166 may negatively regulate four targets in some but not all developmental stages for a given tissue. The four genes studied were observed to have, exactly or generally, the same change tendency as individual tissue development, a finding that suggests genes of the HD-ZIP III family in peach may have complementary or cooperative functions in various tissues. PMID- 26535733 TI - Lack of association between rare mutations of the SIAE gene and rheumatoid arthritis in a Han Chinese population. AB - The function of rare genotypes encoding defective variants of sialic acid acetylesterase (SIAE) in some autoimmune diseases, including rheumatoid arthritis (RA), is ambiguous. We determined whether mutations in the SIAE gene are responsible for RA in a Han Chinese population.DNA was prepared from the venous leukocytes of 444 RA patients and 647 normal controls. The coding regions and adjacent intron sequences of SIAE were amplified by polymerase chain reaction. The products were then subjected to sequencing analysis. The detected variations were further evaluated in the normal controls and available family members by sequencing. Seven variants of RA were identified in this study, including four known single nucleotide polymorphisms SNPs (rs7941327, rs7941523, rs1942663, and rs12282107) and three novel SNPs. The genomic positions of the three novel SNPs are chr11:124013712, chr11:124023268, and chr11:124044505. No significant differences in the seven SNPs of SIAE were observed between patients with RA and controls in this cohort (P > 0.05). Three novel variations and four known SNPs in SIAE were detected in the Chinese RA patients and normal controls. Our results imply that SIAE does not play a major role in RA in this population. PMID- 26535734 TI - Comparative study of neural differentiation of bone marrow mesenchymal stem cells by different induction methods. AB - Neurogenic differentiation of bone marrow (BM) mesenchymal stem cells (MSCs) offers a new hope for patients with many neurological disorders. Several chemical inducers are employed to induce BMMSCs differentiation into nerve cells. In the present study, we compared different inducers [2-mercaptoethanol (BME), tretinoin (ATRA), dimethyl sulfoxide/butylated hydroxyanisole (DMSO/BHA), and indomethacin/3-isobutyl-1-methylxanthine (indomethacin/IBMX)] on the neurogenic differentiation of BMMSCs and aimed to identify a more efficient and safer method. The MSCs were first identified by their ability to adhere to plastic and by the expression of positive (CD44, CD90, and CD105) and negative (CD34) markers assessed by flow cytometry. The efficiency of the neurogenic differentiation was determined by assessing the mRNA and protein expression of nestin, microtubule associated protein-2 (MAP2), neuron specific enolase (NSE), and glial fibrillary acidic protein (GFAP) by reverse transcription-polymerase chain reaction and western-blot, respectively. The effect of these inducers on cell viability was also evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. This comprehensive study shows that indomethacin/IBMX is better than BME, DMSO/BHA, and ATRA both in terms of efficiency and safety, while BME suppressed the growth and proliferation of MSCs. PMID- 26535735 TI - Natural hybridization between Gossypium mustelinum and exotic allotetraploid cotton species. AB - Cotton has been collected in Brazil for decades for its conservation, evaluation, and the use of its genetic resources. Gossypium mustelinum is an allotetraploid cotton species that only occurs in Brazil, and little is known about its genetic potential for improvement. However, the species is threatened by habitat fragmentation and interspecific hybridization with exotic species of cotton. In this study, we investigated the rate of natural hybridization in two populations of G. mustelinum in Bahia, Brazil, with G. hirsutum and G. barbadense using a set of microsatellite markers. PMID- 26535736 TI - [The effect of determinant occupational and environmental factors in health]. PMID- 26535737 TI - [Proposal to establish an environmental contaminants surveillance system in Colombia]. AB - Environmental pollution is a growing problem that negatively impacts health with social and economic high costs. In this sense, coordinated surveillance of conditions, risks, exposures and health effects related to pollution is a useful tool to guide decision-making processes. The objective of this essay was to describe a surveillance system for environmental contaminants in Colombia and its design background. Using the technical guidelines proposed by the Pan American Health Organization, a literature review was conducted to identify the key elements to be included in such surveillance system and to establish which of these elements were already present in the Colombian context. Moreover, these findings were compared with successful experiences in Latin America. The surveillance system includes five components: Epidemiological, environmental and biological surveillance, clinical monitoring and recommendations to guide policies or interventions. The key factors for a successful surveillance system are: interdisciplinary and inter-sector work, clear definition of functions, activities, data sources and information flow. The implementation of the system will be efficient if the structures and tools existing in each country are taken into account. The most important stakeholders are inter-sector public health and environmental commissions and government institutions working in research and surveillance issues related to health, sanitation, environment, drugs and food regulation and control. In conclusion, Colombia has the technical resources and a normative framework to design and implement the surveillance system. However, stakeholders' coordination is essential to ensure the efficacy of the system so it may guide the implementation of cost-effective actions in environmental health. PMID- 26535738 TI - [Toward a national plan to control health effects of mercury in Colombia]. AB - INTRODUCTION: The problem of mercury effects on humans and the environment is global, and it has different impacts on health. It is necessary, therefore, to address this issue from a broad overview to identify populations at risk of exposure, health effects, the production processes involved and the actions aimed at reducing exposure and mitigating the impact. OBJECTIVE: To design a conceptual and operational framework to develop strategies for prevention, control and mitigation of mercury effects on health and on the environment in Colombia. MATERIALS AND METHODS: We conducted a two-phase study: a literature review following the Cochrane methodology and forums with national and international experts using a comprehensive planning methodology to identify priority actions and establish a national research agenda. RESULTS: The results of the review were structured into four components: mercury effects on health, legal framework in Colombia, emission inventory for the country and health plans and programs. We made recommendations for the design of an intervention plan considering five lines of action: technologies for exposure management, institutional strengthening for exposure prevention and control, strategies for strengthening diagnosis and care, health education on mercury risks, and knowledge generation. CONCLUSION: We detected information gaps, technical weaknesses, and the need of administrative and other resources in this field in Colombia. We proposed priority actions to reduce the economic, social and health impact from exposure to mercury. PMID- 26535739 TI - Laboratory genetic-based reference values for cholinesterase activity in a Colombian population: A step forward in personalized diagnostics. AB - INTRODUCTION: The determination of cholinesterase (ChE) activity has been commonly applied in the biomonitoring of exposure to organophosphate and carbamate pesticides. However, ChE activity is influenced by genetic factors. Integrating genotype and phenotype information in clinical laboratory tests would increase the accuracy of the reference values in well-defined populations. OBJECTIVE: To establish genetic-based reference values for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity in a Colombian population. MATERIALS AND METHODS: A total of 397 healthy adults from Bucaramanga were included in the study. AChE and BChE activities were measured in blood samples by potentiometry and spectrophotometry, respectively. Genotyping for ACHE rs17880573 and BCHE rs1803274 was performed using the TaqMan allelic discrimination assay. The statistical analyses to obtain the reference values were performed with the MedCalc(r) software. RESULTS: Allele frequencies were 10.58% for rs17880573 A and 8.82% for rs1803274 A. People with genotypes rs1803274 AA and AG showed a reduction of 20.69% and 10.92% respectively in mean BChE activity compared to people with genotype GG. No significant differences were identified in AChE activity between rs17880573 alleles or genotypes. In the overall sample, the corresponding reference values were as follows: for AChE activity, 0.62-0.98 D pH/h and for BChE activity, 4796.3-10321.1 U/L for people carrying the allele rs1803274A and 5768.2-11180.4 U/L for people carrying the genotype rs1803274 GG. CONCLUSION: We strongly recommend using these genetic-based reference values for ChE enzymes in our well-defined population in daily clinical practice. PMID- 26535740 TI - [Human mercury exposure and irregular menstrual cycles in relation to artisanal gold mining in Colombia]. AB - INTRODUCTION: Artisanal mining commonly extracts gold with an amalgamation process that uses mercury. The reproductive effects from exposure to elemental mercury used in gold mining have not been sufficiently studied. OBJECTIVE: To evaluate the effect of the exposure to elemental mercury used in gold mining on menstrual cycle regularity and the occurrence of miscarriages in Colombia. MATERIALS AND METHODS: An analytical cross-sectional study was conducted. The participants were female residents of gold mining districts, with a history of exposure to elemental mercury. Menstrual regularity and the occurrence of miscarriages were compared between these women and an unexposed group. Exposure and outcome variables were registered based on a questionnaire which was evaluated for its test-retest reproducibility. Prevalence rates were calculated using a binomial model and goodness-of-fit was evaluated. RESULTS: A total of 72 women exposed to mercury and 121 unexposed women participated. The average time of exposure to mercury among exposed women was 19.58 +/- 9.53 years. The adjusted prevalence of irregular menstruation over the last six months was higher in the group of women chronically exposed to mercury vapors (PR=1.59, 95% CI 0.93-2.73), while there was no difference in the proportion of women with a history of miscarriages. CONCLUSIONS: Exposure to elemental mercury used in artisanal gold mining may be associated with a higher prevalence of irregular menstrual cycles but not with the occurrence of miscarriage. PMID- 26535741 TI - [Biodiversity and depressive symptoms in Mexican adults: Exploration of beneficial environmental effects]. AB - INTRODUCTION: Depression is a highly prevalent illness among adults, and it is the second most frequently reported mental disorder in urban settings in Mexico. Exposure to natural environments and its components may improve the mental health of the population. OBJECTIVE: To evaluate the association between biodiversity indicators and the prevalence of depressive symptoms among the adult population (20 to 65 years of age) in Mexico. MATERIALS AND METHODS: Information from the Encuesta Nacional de Salud y Nutricion 2006 (ENSANUT 2006) and the Compendio de Estadisticas Ambientales 2008 was analyzed. A biodiversity index was constructed based on the species richness and ecoregions in each state. A multilevel logistic regression model was built with random intercepts and a multiple logistic regression was generated with clustering by state. RESULTS: The factors associated with depressive symptoms were being female, self-perceived as indigenous, lower education level, not living with a partner, lack of steady paid work, having a chronic illness and drinking alcohol. The biodiversity index was found to be inversely associated with the prevalence of depressive symptoms when defined as a continuous variable, and the results from the regression were grouped by state (OR=0.71; 95% CI = 0.59-0.87). CONCLUSIONS: Although the design was cross-sectional, this study adds to the evidence of the potential benefits to mental health from contact with nature and its components. PMID- 26535742 TI - Environmental and occupational health research and training needs in Colombia: A Delphi study. AB - INTRODUCTION: Environmental factors contribute with 16% of the burden of disease in Colombia. A main obstacle in implementing national and regional environmental and occupational health policies is the limited knowledge on the local ability to study and control the impact of harmful exposures on health. OBJECTIVE: To identify needs for research and training in environmental and occupational health in Colombia. MATERIALS AND METHODS: We conducted a three-round hybrid Delphi study. A group of environmental and occupational health Colombian experts (n=16) from government agencies, universities, and research centers was recruited to participate in the study. Expert's opinions on research and training needs were gathered through online questionnaires, followed by an in-person meeting. The percentage of agreement and the coefficient of variation were used to measure consensus. RESULTS: Air pollution and chemical products were considered the most important environmental and occupational exposures, due to their significant impact on chronic non-communicable diseases, such as respiratory diseases, cardiovascular diseases, and cancer. Research on the effects of outdoor air pollution on cardiovascular and respiratory diseases was considered of the greatest importance. Priority training areas included environmental and occupational health risk assessment, exposure modeling, advanced statistical methods, urban planning, occupational safety and hygiene, and epidemiology and toxicology. CONCLUSIONS: These findings provide a valuable input for the definition and implementation of national environmental and occupational health policies and for the development of a regional hub aimed at strengthening the capacity for research and training in Colombia. PMID- 26535743 TI - [Evaluation of exposure of auto painters to organic solvents in the city of Bogota]. AB - INTRODUCTION: Painters of automobiles are exposed to pure and mixed solvents that have been associated with neurological effects and carcinogenic mutations. OBJECTIVE: To characterize the health and work conditions of individuals who are occupationally exposed to organic solvents used in sheet metal and auto body shops in Bogota. MATERIALS AND METHODS: Descriptive, cross-sectional study that characterizes the health and work conditions of individuals exposed to organic solvents in sheet metal and auto body shops in Bogota. A group exposed to the solvents was compared to an unexposed group. Air concentrations of benzene, toluene and xylene (BTX) were determined, individual questionnaires were administered and phenylmercapturic, hippuric and ortho- and para-methylhippuric acids were measured in urine. The results of the measurements and the questionnaires were correlated to determine the exposure panorama. RESULTS: For the three BTX metabolites, statistically significant differences (p<0.001) were found between the population exposed to the solvents and the unexposed population. For the exposed population, positive correlations were found between toluene in air and hippuric acid in urine (rho=0.82) and between xylene in air and o-methylhippuric acid in urine (rho=0.76). Hippuric acid values exceeded permissible levels in 11 workers and p-methylhippuric acid exceeded permissible levels in 8 workers. None of the phenylmercapturic values exceeded the limit. CONCLUSION: Auto painters are exposed to high levels of organic solvents at the workplace and do not have adequate industrial health and safety conditions to perform their jobs. PMID- 26535744 TI - Work conditions and morbidity among coal miners in Guacheta, Colombia: The miners' perspective. AB - INTRODUCTION: Investigations in Colombia about work and health conditions in coal mining are scarce and few have focused on the perception of the exposed population and their behaviors in response to inherent risks. OBJECTIVE: To determine the association between work conditions and the perception of morbidity among coal miners in Guacheta, Cundinamarca. MATERIALS AND METHODS: A cross sectional study was performed with 154 workers selected randomly from the total registered with the municipality. Information about social and demographic characteristics and work and health conditions in the mines was gathered. The prevalence was estimated for respiratory, musculoskeletal and auditory disorders. The associations between certain work conditions, and events with a prevalence over 30% were explored using bivariate and multivariate analyses with Poisson regressions with robust variance. RESULTS: Workers were mostly men. Ages ranged from 18 to 77 years. Most frequently reported health problems were: back pain (46.1 %), pain in an upper limb (40.3%), pain in a lower limb (34.4 %), and respiratory (17.5 %) and auditory problems (13.6 %). Significant differences in perception were found depending on time on the job and underground or ground work conditions. CONCLUSIONS: The most recognized risks were those associated with musculoskeletal disorders since they were closer in time to the work performed (time discount). Some actions to identify psychological traits are proposed in order to improve risk perception among coal miners. PMID- 26535745 TI - [Mortality due to pesticide poisoning in Colombia, 1998-2011]. AB - INTRODUCTION: Poisoning due to pesticides is an important public health problem worldwide due its morbidity and mortality. In Colombia, there are no exact data on mortality due to pesticide poisoning. OBJECTIVE: To estimate the trend of mortality rate due to pesticide poisoning in Colombia between 1998 and 2011. MATERIALS AND METHODS: We carried out a descriptive analysis with the database reports of death as unintentional poisoning, self-inflicted intentional poisoning, aggression with pesticides, and poisoning with non-identified intentionality, population projections between 1998 and 2011, and rurality indexes. Crude and age-adjusted mortality rates were estimated and trends and Spearman coefficients were evaluated. RESULTS: A total of 4,835 deaths were registered (age-adjusted mortality rate of 2.38 deaths per 100,000 people). Mortality rates were higher in rural areas, for self-inflicted intentional poisoning, in men and in age groups between 15 and 39 years old. The trend has been decreasing since 2002. Municipality mortality rates due to unintentional poisoning and aggression correlated significantly with the rurality index in less rural municipalities. CONCLUSIONS: Mortality rates due to pesticide poisoning presented a mild decrease between 1998 and 2011. It is necessary to adjust and reinforce the measures conducive to reducing pesticide exposure in order to avoid poisoning and reduce mortality. PMID- 26535746 TI - [Sleep quality in an adult population exposed to the noise of El Dorado Airport, Bogota, 2012]. AB - INTRODUCTION: The airport of Bogota lies within the city and its expansion could produce an increase in adverse effects on the health of the inhabitants of Fontibon and Engativa districts due to the noise it generates. OBJECTIVE: To determine the prevalence of sleep disturbances and associated factors among residents of Fontibon exposed to this noise. MATERIALS AND METHODS: A cross sectional study design was used, involving a sample of 205 people aged 18 to 65, selected by means of stratified random sampling. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS). Descriptive statistics were carried out, as well as correlation tests between the different scales. RESULTS: A total of 60% of the residents reported poor quality sleep (PSQI>5), with a mean PSQI of 7.19 (SD=3.931), and the following pathological interruptions were found: subjective sleep quality, 27%; sleep latency, 39%; sleep duration, 33%; habitual sleep efficiency, 37%; sleep alterations, 30%; diurnal dysfunction, 40%, and use of sleeping medication, 5%. According to the Epworth Sleepiness Scale (ESS>10), 28% of residents reported daytime somnolence. Regarding the prevalence of poor quality sleep according to the Pittsburgh Sleep Quality Index, 17% of those who reported not being able to sleep because of noise associated this with air traffic. A correlation was observed between the index and the scale ( r =0.329, CI 95%: 0.20-0.44). CONCLUSIONS: Inhabitants of the district reported poor sleep quality due to exposure to noise, airport operations being one of the main generating sources. Noise mitigation strategies in the district need to be reviewed and the public health implications of the El Dorado Airport expansion should be considered. PMID- 26535747 TI - [Evaluation of human health risk for a population from Cali, Colombia, by exposure to lead, cadmium, mercury, 2,4-dichloro-phenoxyacetic acid and diuron associated with water and food consumption]. AB - INTRODUCTION: Exposure to pollutants such as pesticides and heavy metals has been linked to health problems. Several studies have revealed the presence of these contaminants in Cali; however, there is no information available about the main routes of exposure and risk of these contaminants. OBJECTIVE: To estimate the risk associated with the intake of cadmium, lead and mercury, and pesticides 2,4 D and diuron through the consumption of water and food in a population in Cali. MATERIALS AND METHODS: Population and environmental data were obtained, and a risk assessment was performed using United States Environmental Protection Agency guidelines. RESULTS: The concentrations of the evaluated pollutants were below permissible levels as established by the Colombian Ministerio de Ambiente, Vivienda y Desarrollo Territorial (3 ug/L -1 of cadmium; 10 ug/L -1 of lead; 1 ug/L -1 of mercury; 1 ug/L -1 of 2,4 D; 1 ug/L -1 of diuron). Salema butterfish ( Peprilus snyderi ) samples contained levels of cadmium between 20 and 80 ug/kg -1 , which are below the permissible limit set by the World Health Organization (100 ug/kg -1 ). The results of the risk assessment indicated that the carcinogenic and non-carcinogenic attributable risk to population health from the intake of food contaminants was below the maximum level permitted by the United States Environmental Protection Agency. CONCLUSIONS: It is believed that the findings in previous studies on pollutants may have been due to specific contamination events; therefore, monitoring and early warning about water intake is recommended. Furthermore, the report of cadmium being found in fish consumed as food suggests the need for quality control by regulators. PMID- 26535748 TI - [Prevalence of insomnia in adults aged 18 to 60 years and exposure to electromagnetic fields in households of Barranquilla, Colombia]. AB - INTRODUCTION: Insomnia, a sleep disorder that affects both individual and public health, has not been studied in Barranquilla. Prior studies about the effects of exposure to electromagnetic fields on sleep disorders are controversial. OBJECTIVE: To estimate the prevalence of insomnia symptoms in adults aged 18 to 60 years and its relation to the presence and intensity of electromagnetic fields in two neighborhoods of Barranquilla, Colombia. MATERIALS AND METHODS: A cross sectional study was carried out in 220 households located in two neighborhoods of Barranquilla, one with high exposure to radio and cell phone antennas and the other one with low exposure. After informed consent, a survey was applied among adults residing in 220 households to investigate the presence of insomnia symptoms, socio-demographic data and intake of medicines. When it was allowed, electromagnetic fields were measured with teslameters in bedrooms. The database was created in ExcelTM and the data analysis was done with SPSSTM, version 18. RESULTS: Insomnia, mainly of the mild type, was present in 74.5% of the total study population while 25.5% reported a normal sleep pattern. According to the sleeping test score we found a higher prevalence of insomnia in the neighborhood with greater exposure to radio antennas and cell towers (85.4%) than in the one with lower exposure (63.3%), prevalence ratio 1.34 (CI 95% 1.14-1.57). CONCLUSIONS: This study suggests a higher prevalence of insomnia among persons living in areas with higher exposure to electromagnetic fields where the number of radio antennas and cell towers was greater. PMID- 26535749 TI - [Influence of the climate variability on acute respiratory infections in the city of Bogota]. AB - INTRODUCTION: Acute respiratory infection is one of the most significant causes of morbidity in Bogota, and its burden of disease has increased in association with climate variability . OBJECTIVE: The aim of the study was to evaluate weekly trends of acute respiratory infection in relation to meteorological variables (temperature, relative humidity and cumulative rainfall) in Bogota during 2011 and 2012. MATERIALS AND METHODS: Epidemiological and meteorological data from 104 weeks were gathered. Temporal variability was taken into account including previous weeks and spatial variability was considered by studying each zone of the city separately (north, south, east, west). Statistical analysis was performed through Poisson dynamic regression models. RESULTS: The relative humidity had the greater impact on acute respiratory infection and its effects lasted between 8 to 10 weeks. Cumulative rainfall had effects only in the east zone, while the temperature presented mild effects across the four different zones of the city. CONCLUSION: Such results are the first step for the design of health-related early warning systems associated with climate variability. PMID- 26535750 TI - [Genotoxic effects in a human population exposed to heavy metals in the region of La Mojana, Colombia, 2013]. AB - INTRODUCTION: Mining is an economically important activity in Colombia which generates large quantities of residues containing potentially toxic elements such as heavy metals. These contaminate ecosystems and place human health at risk. La Mojana lies within one of the most biodiversity-rich zones on Earth and has been subjected to processes of contamination closely related to gold mining activities in the surrounding areas. OBJECTIVE: To evaluate genotoxicity in the population of La Mojana region exposed to heavy metals. MATERIALS AND METHODS: Genotoxic effects and their relationship with concentrations of heavy metals (mercury, cadmium and lead) in blood were evaluated among an exposed population and a control group. The exposed group comprised inhabitants of the municipalities of Guaranda, Sucre, Majagual and San Marcos; inhabitants of the municipality of Monteria were chosen as a control group. DNA damage was determined using the alkaline comet assay. Concentrations of mercury were determined by cold vapor atomic absorption spectrometry, and those of cadmium and lead by graphite furnace atomic absorption spectrometry. RESULTS: Concentrations of the heavy metals exceeded the limits permitted by the World Health Organization. Genotoxic effects were found in the exposed population, possibly associated with the presence of these metals in blood. Significant associations (p<0.05) were found between mercury and cadmium levels and damage to DNA. CONCLUSION: These results suggest that the genetic damage recorded among inhabitants of the region of La Mojana, Colombia, may be associated with the presence of heavy metals in the blood. PMID- 26535751 TI - [Preliminary survey to detect toxic substances in domestic potable water, Bogota and Soacha, 2012]. AB - INTRODUCTION: Significant alterations may be found in the water of Bogota's water supply system after its purification, specifically during its distribution and storage in home reservoirs, which makes it necessary to study the final quality of the domiciliary water consumed by users. OBJECTIVE: To conduct a preliminary study of toxic chemical substances in the water supplied by Bogota's water supply system in samples obtained from residential reservoirs and faucets. MATERIALS AND METHODS: Descriptive study made in 26 homes located in Bogota and Soacha. Two samplings were done during different seasons, each including a survey and the collection of water samples from domiciliary storage tanks and faucets. Samples were analyzed for basic physicochemical parameters, a screening test for organic and inorganic substances and the determination of heavy metals and residues of organophosphate pesticides and/or carbamates. RESULTS: Values obtained for conductivity, color and nitrates were acceptable, pH and turbidity were slightly high while residual chlorine levels were low; aluminum traces were found in 94% of the samples; 8% of the samples analyzed during the dry season showed organic compounds, compared to 66.7% during the rainy season, and just one positive result was obtained for inorganic compounds. Consequently, a medium risk level was observed in 11.5% of homes, low risk in 61.5% and no risk in 27.0%. CONCLUSION: The evidence showed deterioration of the domiciliary water by organic substances present in the reservoirs as well as in the water supply piping, probably caused by the formation of biofilms or organic polymers. Aluminum levels close to the top permissible limit can be explained by the presence of residual coagulants used during water treatment. PMID- 26535752 TI - [Respiratory symptoms associated with air pollution in five localities of Bogota, 2008-2011, a dynamic cohort study]. AB - INTRODUCTION: High levels of air pollution increase respiratory morbidity in children under five years of age. OBJECTIVE: To know the incidence of respiratory symptoms and its associated factors in five localities of Bogota. MATERIALS AND METHODS: A dynamic cohort study was undertaken with a sample size of 3,278 children from five localities split into two groups according to the degree of exposure to particulate matter. Monitoring was conducted at the outbreak of ten respiratory symptoms through a diary of those symptoms. Statistical analysis included incidence rate ratio (IRR) calculations and Poisson regression models for each assessed symptom. RESULTS: Cough was more frequent in the highly exposed group (lRR=1.23, Cl 95% 1.13-1.34). The most exposed group had higher incidence of expectoration (lRR=1.64, Cl= 95% 1.47-1.84). Wheezing was associated with high exposure to particulate matter (RR=2.29, Cl 95% 1.78-3.00), cottage industries (RR=1.29, Cl 95% 1.01-1.68) and age (RR=0.95, Cl 95% 0.94-0.96). Risk attributable to air pollution exposure fluctuated according to symptoms from 37% for nocturnal wheezing (Cl 95% 26-47.8) to 10.6 for cough (Cl 95% 6.3-15%). CONCLUSION: Extradomiciliary air pollution effects are potentiated by socioeconomic living and working conditions of people in Bogota. A broader conceptual public health approach and the strengthening of intersector actions are required to reduce health effects of air pollution. PMID- 26535753 TI - [Quality of water for human consumption and its association with morbimortality in Colombia, 2008-2012]. AB - INTRODUCTION: The quality of water for human consumption has been correlated with the occurrence of different diseases. Studying the relationship between these parameters would allow determining the impact of water quality on human health, and to direct preventative measures and promote environmental health. OBJECTIVE: To analyze the quality of water intended for human consumption and its association with morbimortality in Colombia, 2008-2012. MATERIALS AND METHODS: The database for surveillance of water quality was analyzed by means of descriptive statistics of the principal indicators (total coliforms, Escherichia coli , turbidity, color, pH, free residual chlorine and water quality risk index). The results were correlated with infant mortality and morbidity due to acute diarrheal diseases, foodborne diseases and hepatitis A. A risk map was prepared to identify those municipalities with the highest risk of water contamination and infant mortality. RESULTS: A high percentage of municipalities did not conform to existing standards for water potability values. Problems were identified that were related to presence of E. coli and total coliforms, as well as absence of free residual chlorine, a situation that was exacerbated in rural areas. Water quality showed a high correlation with infant mortality, highlighting its importance for children's health. CONCLUSION: Water quality was found to have an important impact on infant mortality. Improving water quality in Colombia will require policies that strengthen water supply systems in this country. Strengthening of environmental health surveillance programs is essential to guide actions aimed at improving water quality and exert a positive impact on health. PMID- 26535754 TI - [Ecological studies in environmental health: Beyond epidemiology]. AB - Ecological studies provide important and frequent sources of evidence of environmental health, since their unit of analysis is populations. This review summarizes the foundations of ecological studies with the premise that they can be performed using quantitative, qualitative or mixed methods. It presents the logic behind their design, their role in exploring causality, the variables and categories of analysis and the design principles and techniques used to collect data. Examples of ecological studies performed in Latin America are then presented, as well as some common methodological problems and options to address them. Lastly, the relevance of quantitative and qualitative ecological studies to environmental health as a way to overcome the dominance of conceptual and methodological individualism is highlighted, though ecological studies alone do not suffice for studying population health. PMID- 26535756 TI - Generation and Evaluation of a Simultaneous Cardiac and Respiratory Gated Rb-82 PET Simulation. AB - The goal is to generate and evaluate a simulated 4D Rb-82 PET dataset that realistically models simultaneous respiratory and cardiac motions for use to study the effects of the motions and their compensation using various gating schemes. Normal cardiac and respiratory (C&R) motions were simulated separately using the realistic 4D XCAT phantoms. The C&R motion cycles were divided into 24 and 48 equally-spaced time points, respectively. The simultaneous dual motions were modeled by 24 * 48 phantoms with different combinations of C&R motion phases. Almost noise-free projections of the heart, blood pool, lungs, liver, stomach, spleen, and the remaining body were simulated separately using the combined SimSET and GATE Monte Carlo simulation program which is 12 times faster than GATE alone. The projections were scaled and combined to simulate a typical Rb-82 myocardial perfusion (MP) PET patient study. The no gating, 6-frame respiratory gating only, 8-frame cardiac gating only, and simultaneous 6-frame respiratory and 8-frame cardiac gating schemes were applied. Each gated projection dataset was reconstructed using a 2D OS-EM without and with attenuation correction (AC) using an averaged and gated attenuation maps. The reconstructed images were evaluated in terms of artifactual non-uniformity in the MP polar map. Significant artifactual non-uniformity was found in the MP polar map over all gating scheme without AC. With AC, the artifactual decreases in both the anterior and inferior regions were reduced with respiratory gating. Cardiac motion alone did not cause significant artifactual non-uniformity. In addition, the combination of dual gating and AC using the gated attenuation map provided the most uniform MP polar map. We demonstrated the flexibility and utility of the 4D XCAT phantom set with simultaneous C&R motions. It is a powerful tool to study motion effects on MP PET studies and to evaluate C&R gating schemes, AC and quantitative 4D PET image reconstruction methods. PMID- 26535755 TI - Rationale and prospects for novel pneumococcal vaccines. AB - Streptococcus pneumoniae remains one of the most frequent bacterial causes of morbidity and mortality worldwide. National immunization programs implementing pneumococcal polysaccharide conjugate vaccines (PCVs) have successfully reduced rates of vaccine-type invasive disease and colonization both via direct effects in immunized children and, in some settings, indirect effects in unimmunized individuals. Limitations of the current PCV approach include the emergence of non vaccine serotypes contributing to carriage and invasive disease in high-PCV coverage settings and the high cost of goods of PCVs which limits their accessibility in developing countries where the burden of disease remains highest. Furthermore, the distribution of serotypes causing disease varies geographically and includes more serotypes than are currently covered in a single PCV formulation. Researchers have long been exploring the potential of genetically conserved non-capsular pneumococcal antigens as vaccine candidates that might overcome such limitations. To better evaluate the rationale of such approaches, an understanding of the mechanisms of immunity to the various phases of pneumococcal infection is of paramount importance. Herein we will review the evolving understanding of both vaccine-induced and naturally acquired immunity to pneumococcal colonization and infection and discuss how this informs current approaches using serotype-independent pneumococcal vaccine candidates. We will then review the alternative vaccine candidates that have been or are currently under evaluation in clinical trials. PMID- 26535757 TI - Mental Health is in the Hands of Nurses. PMID- 26535760 TI - Buspirone: Back to the Future. AB - Buspirone, first synthesized in 1968 and marketed in 1986, is a pharmacologically unique azapirone drug. It is effective for treating generalized anxiety, but not other anxiety disorders. Buspirone also is efficacious for depression, either alone or together with an antidepressant drug, and for treating adverse sexual effects. Studies of buspirone for substance use disorders have had disappointing outcomes, although it may be useful for treating coexisting anxiety and one controlled study suggested efficacy for heroin detoxification. Buspirone may be considered a treatment option for managing irritability, agitation, and aggression in older adult patients with dementia as well as in pediatric patients, although additional effectiveness studies are warranted. Buspirone and melatonin may synergistically promote neurogenesis, supporting the potential use of this combination for treating depression and cognitive impairment. PMID- 26535761 TI - Caring for Depression in Older Home Health Patients. AB - Depression is common in older home health patients and increases their risk of adverse outcomes. Depression screening is required by Medicare's Outcome and Assessment Information Set. The Depression Care for Patients at Home (CAREPATH) was developed as a feasible strategy for home health nurses to manage depression in their patients. The protocol builds on nurses' existing clinical skills and is designed to fit within routine home visits. Major components include ongoing clinical assessment, care coordination, medication management, education, and goal setting. In a randomized trial, Depression CAREPATH patients had greater improvement in depressive symptoms compared to usual care. The difference between groups was significant at 3 months, growing larger and more clinically meaningful over 1 year. The intervention had no impact on patient length of stay, number of home visits, or duration of visits. Thus, nurses can play a pivotal role in the long-term course and outcomes of patients with depression. PMID- 26535762 TI - Self-Rated Mental Health: Screening for Depression and Posttraumatic Stress Disorder Among Women Exposed to Perinatal Intimate Partner Violence. AB - The purpose of the current study was to evaluate the validity of a single-item, self-rated mental health (SRMH) measure in the identification of women at risk for depression and posttraumatic stress disorder (PTSD). Baseline data of 239 low income women participating in an intimate partner violence (IPV) intervention study were analyzed. PTSD was measured with the Davidson Trauma Scale. Risk for depression was determined using the Edinburgh Postnatal Depression Scale. SRMH was assessed with a single item asking participants to rate their mental health at the time of the baseline interview. Single-item measures can be an efficient way to increase the proportion of patients screened for mental health disorders. Although SRMH is not a strong indicator of PTSD, it may be useful in identifying pregnant women who are at increased risk for depression and need further comprehensive assessment in the clinical setting. Future research examining the use of SRMH among high-risk populations is needed. PMID- 26535763 TI - Reliability Testing of the Psychosocial Vital Signs Assessment Tool. AB - The current article describes preliminary psychometric testing of the Psychosocial Vital Signs (PVS) Assessment Tool, a tool for assessing psychosocial variables of health to enhance holistic patient-centered care. The five psychometric measurements of the PVS Assessment Tool include four patient self reporting items: (a) perception, (b) support, (c) coping, (d) anxiety, and one clinician observation item of (e) anxiety level. A simple psychometric design was used for testing the PVS Assessment Tool for internal reliability among the five measurement items and interrater reliability of the clinician observation item of anxiety level. A convenience sample of nursing students was used to test the tool. Thirty-two tools were used for testing internal reliability and 29 paired tools were used for interrater reliability testing of the clinician observation item. A Cronbach's alpha of 0.806 determined satisfactory internal reliability and a Cohen's kappa of 0.808 determined satisfactory interrater reliability. PMID- 26535764 TI - Management and Treatment of Attention-Deficit/Hyperactivity Disorder on College Campuses. AB - Attention-deficit/hyperactivity disorder (ADHD) on college campuses is a serious and often underdiagnosed condition. The current investigation analyzed current best practice guidelines for the management of ADHD in a mid-sized university in the Midwestern United States. Best practices were identified through a review of current evidence-based literature on ADHD management. A data collection tool was developed and used to organize data and determine adherence with best practice guidelines. Investigators revealed that policy and procedures followed best practice guidelines. Development and implementation of ADHD protocols on college campuses allows nurse practitioners to confidently provide safe, quality care to patients diagnosed with ADHD. PMID- 26535766 TI - Novel PPARgamma Modulator GED-0507-34 Levo Ameliorates Inflammation-driven Intestinal Fibrosis. AB - BACKGROUND: Intestinal fibrosis is mainly associated with Crohn's disease and is defined as a progressive and excessive deposition of extracellular matrix components. No specific antifibrotic therapies are available. In this study, we evaluate the antifibrotic effect of a novel 5-ASA analog able to activate the peroxisome proliferator-activated receptor gamma, named GED-0507-34 Levo. METHODS: Colonic fibrosis was induced in 110 C57BL/6 mice by 3 cycles of 2.5% (wt/vol) dextran sulfate sodium administration for 6 weeks. The preventive effects of oral daily GED (30 mg . kg(-1) . d(-1)) administration were evaluated using a macroscopic and histological score and also through biological endpoints. Expression of main markers of myofibroblasts activation was determined in transforming growth factor (TGF-beta)-stimulated intestinal fibroblasts and epithelial cells. RESULTS: GED improved macroscopic and microscopic intestinal lesions in dextran sulfate sodium-treated animals and reduced the profibrotic gene expression of Acta2, COL1a1, and Fn1 by 1.48-folds (P < 0.05), 1.93-folds (P < 0.005), and 1.03-fold (P < 0.05), respectively. It reduced protein levels of main markers of fibrosis (alpha-SMA and Collagen I-II) and the main TGF-beta/Smad pathway components. GED also decreased the interleukin-13 and connective tissue growth factor expression by 1.89-folds (P < 0.05) and 2.2-folds (P < 0.005), respectively. GED inhibited TGF-beta-induced activation of both fibroblast and intestinal epithelial cell lines, by regulating mRNA expression of alpha-SMA and fibronectin, and restoring the TGF-beta-induced loss of intestinal epithelial cell markers. GED treatment also reduced the TGF-beta and ACTA1 expression in primary human intestinal fibroblasts from ulcerative colitis patients. CONCLUSIONS: GED ameliorates intestinal fibrosis in dextran sulfate sodium induced chronic colitis in mice and regulates major profibrotic cellular and molecular mechanisms. PMID- 26535767 TI - Long-term Outcomes in Patients with Small Intestinal Strictures Secondary to Crohn's Disease After Double-balloon Endoscopy-assisted Balloon Dilation. AB - BACKGROUND: Crohn's disease (CD) strictures of the small intestine are a feared complication and difficult to treat because of difficulty gaining access to the stricture site. The development of double-balloon endoscopy (DBE) enabled access to the entire small intestine with interventional capabilities. The aim of this study was to assess the long-term outcomes in patients with small intestinal strictures secondary to CD after DBE-assisted endoscopic balloon dilation (EBD). METHODS: In this retrospective cohort study, DBE-assisted EBD was performed in 85 consecutive patients with CD strictures of the small intestine from 2002 to 2014. Follow-up data were available for 85 patients for a mean of 41.9 months (range, 0 141), and clinical outcomes were assessed. RESULTS: Overall, 321 DBE-assisted EBD sessions (473 procedures) were performed in 85 patients during the study period. Most CD strictures were de novo (97%). The surgery-free rate after initial DBE assisted EBD was 87.3% at 1 year and 78.1% at 3 years. The presence of a fistula was significantly associated with the need for surgical intervention (hazard ratio = 5.50, 95% confidence interval: 2.16-14.0, P < 0.01). The surgery-free interval in patients with a fistula was significantly shorter than in patients without a fistula (P < 0.01, log-rank test). CONCLUSIONS: DBE-assisted EBD provides a favorable long-term outcome in patients with small intestinal CD associated strictures. DBE-assisted EBD for CD strictures is a safe and effective treatment to avoid or postpone surgery over the long-term. PMID- 26535768 TI - Development and Evaluation of Simulation-Problem-Based Learning for Sex Education. AB - Nurses often encounter clients with sexual problems. A sexual problem is complicated and affects the quality of the client's life, and proper care requires the nurse to understand a variety of sex-related issues. Therefore, effective sex education for nursing students is necessary to prepare them for potential challenges from the client's sexual problems. In this study, we developed a simulation-problem-based sex education program for nursing students. The program immerses the students in a sex-related clinical situation to train them with nursing assessment, intervention skills, patient safety, patient privacy, and communication skills. To evaluate the effect of the program on the student's sexual knowledge and attitude, we provided the experimental group with simulation-problem-based sex education program along with traditional lectures, whereas the control group received only lectures. As a result, there were statistically significant differences in the improvement of knowledge (P < .05) and attitude (P < .05) of the two groups. The results show that the designed program effectively promotes nursing students' sexual knowledge and sexual attitude, and the simulation-problem-based learning is a practical and systematic approach to the sex education of nursing students. PMID- 26535769 TI - A Critical Review of the Theoretical Frameworks and the Conceptual Factors in the Adoption of Clinical Decision Support Systems. AB - The clinical decision support system is utilized to translate knowledge into evidence-based practice in clinical settings. Many studies have been conducted to understand users' adoption of the clinical decision support system. A critical review was conducted to understand the theoretical or conceptual frameworks used to inform the studies on the adoption of the clinical decision support system. The review identified 15 theoretical and conceptual frameworks using multiple hybrids of theories and concepts. The Technology Acceptance Model was the most frequently used baseline framework combined with frameworks such as the diffusion of innovation, social theory, longitudinal theory, and so on. The results from these articles yielded multiple concepts influencing the adoption of the clinical decision support system. These concepts can be recategorized into nine major concepts, namely, the information system, person (user or patient), social, organization, perceived benefits, emotions, trustability, relevance (fitness), and professionalism. None of the studies found all the nine concepts. That said, most of them have identified the information system, organization, and person concepts as three of its concepts affecting the use of the clinical decision support system. Within each of the concepts, its subconcepts were noted to be very varied. Yet each of these subconcepts has significantly contributed toward the different facets of the concepts. A pluralistic framework was built using the concepts and subconcepts to provide an overall framework construct for future study on the adoption of the clinical decision support system. PMID- 26535770 TI - FDG-PET/CT for Detection of Extramedullary Disease in 2 Pediatric Patients With AML. AB - Positron emission tomography combined with computed tomography (PET/CT) is a promising diagnostic procedure for the detection of extramedullary disease (EMD) in acute myeloid leukemia. We studied 2 children with acute myeloid leukemia who underwent PET to assess for EMD at diagnosis as well as in remission. We detected 5 EMD lesions in 2 cases with PET, only 2 of which were detectable on clinical examination. Our cases show PET's increased sensitivity over physical examination alone in assessing and monitoring the extent of this disease. PMID- 26535771 TI - Juvenile Idiopathic Inflammatory Myopathy in a Patient With Dyskeratosis Congenita Due to C16orf57 Mutation. AB - Dyskeratosis congenita (DC) is a rare inherited disorder characterized by reticular skin pigmentation, oral cavity leukoplakia, and nail dystrophy. A variety of noncutaneous (dental, pulmonary, gastrointestinal, neurological, genitourinary, ophthalmic, and skeletal) abnormalities also have been reported. An 8-year-old boy with DC developed juvenile idiopathic inflammatory myopathy. C16orf57 mutation was identified as a genetic cause of DC. Treatment with methylprednisolone was initiated, followed with methotrexate, prednisolone, and high-dose intravenous immunoglobulin treatment. This is the first report on a patient with juvenile idiopathic inflammatory myopathy and DC. PMID- 26535772 TI - Limited Role of Sinus CT in the Management of Febrile Pediatric HSCT Recipients. AB - Management guidelines have questioned the role of sinus computed tomography (CT). We reviewed 55 febrile episodes with sinus CT during 1 year after admission for hematopoietic stem cell transplant to determine predictive factors for positive sinus CT and the impact on management. Positive sinus CT findings were seen in 42% of febrile episodes. No characteristics were identified as predictors of a positive sinus CT. No other infectious source was identified in 17% of positive sinus CT episodes, with no pharmacotherapy modifications based solely on a positive sinus CT. Sinus CT should be examined in multicenter groups to develop practice guidelines. PMID- 26535773 TI - Incidence of Childhood Hodgkin Lymphoma in Mexico by Histologic Subtypes and Socioeconomic Regions. AB - BACKGROUND: Incidence rates of the histologic subtypes of Hodgkin lymphoma (HL) differed with socioeconomic conditions. MATERIALS AND METHODS: HL cases from the Register of Childhood Cancer (below 15 y of age) for 2 socioeconomic regions were analyzed. Central region has a high socioeconomic index; and the southern region a low index. The incidence rates (cases per million children/year) were estimated according to histologic subtypes, age groups, sex, clinical stages, time to diagnosis, and overall survival by regions. RESULTS: The overall incidence was greater in the south (6.8 vs. 4.6), principally due to higher incidence of mixed cellularity subtype (3.8 vs. 1.0). In the south, the highest incidence was found in the 5- to 9-year-old group (9.2), whereas in the central region it was found in the 10- to 14-year-old group (7.4). There was a delay of ~3 weeks in the time to diagnosis (P=0.36) in the south, but no difference in the percentage of advanced stages, adjusted by histologic subtype (61%, III and IV). The overall survival was 71%, differences were identified only for mixed cellularity cases (center=89.2 vs. south=61.5%, P=0.03). CONCLUSIONS: Incidences of HL subtypes differed in relation to socioeconomic conditions in Mexico. In the south, the incidence of mixed cellularity was higher and there was an earlier peak of presentation. PMID- 26535774 TI - Validation Study of the Composite Score to Identify Von Willebrand Disease in Children. AB - BACKGROUND: The diagnosis of type 1 von Willebrand disease (VWD) presents a diagnostic challenge in children. In fact, 25% or more of children with VWD may be diagnosed only after they experience postoperative bleeding. We previously described a 4-variable composite score that has 92.5% sensitivity and 95% specificity for diagnosing VWD in children with known VWD when 2 of 4 criteria are positive: (1) Tosetto bleeding score >= 1; (2) family history of VWD; (3) personal history of iron deficiency anemia; and/or (4) positive James early bleeding score. The purpose of this study was to prospectively validate a composite score of >= 2 for identifying children with VWD. PROCEDURE: Children without a previously diagnosed bleeding disorder presenting for hematology evaluation were enrolled. Sensitivity, specificity, positive, and negative predictive value of the composite score was determined. RESULTS: A total of 193 subjects were enrolled from 12 participating centers were included in the analysis. Forty-seven children had type 1 VWD, including 11 with von Willebrand Ristocetin Cofactor (VWF):RCo < 30 IU/dL, 14 subjects with a VWF:RCo 30 to 39 IU/dL, and 22 with a VWF:RCo 40 to 49 IU/dL. Including all 4 variables, a composite score of >= 2 had a sensitivity of 63.6% to 76.0%, specificity of 33.5% to 35.1%, negative predictive value of 76.9% to 93.8%, and positive predictive value of 5.5% to 25%. CONCLUSIONS: The negative predictive value of the composite score was robust, especially at lower VWF:RCo suggesting that VWD testing could be eliminated in nearly a third of children referred for VWD testing. PMID- 26535775 TI - Surgical Rehabilitation Techniques in Children with Poor Prognosis Short Bowel Syndrome. AB - Intestinal failure (IF) requires a multidisciplinary management based on nutritional support, surgical and medical rehabilitation, and transplantation. The aim of this study is to review our experience with surgical rehabilitation techniques (SRTs: enteroplasty, Bianchi, Serial Transverse Enteroplasty Procedure [STEP]) in patients with short bowel syndrome (SBS) and poor prognosis due to complex abdominal pathology. We performed a single-center retrospective study of patients with IF evaluated for intestinal transplantation in the Intestinal Rehabilitation Unit who underwent an SRT. Nonparametric tests were used for statistical analysis.A total of 205 patients (107 males/98 females) with mean age of 25 +/- 7 months were assessed for IF. A total of 433 laparotomies were performed on 130 patients including intestinal resection, enteroplasties, adhesiolysis, and transit reconstruction. SRT were performed in 22 patients: 12 enteroplasties, 8 STEPs, and 4 Bianchi procedures. All patients were parenteral nutrition (PN) dependent with different stages of liver disease: mild (13), moderate (5), and severe (4). The adaptation rate for patients who underwent enteroplasty, STEP, and Bianchi were 70, 63, and 25%, respectively, although the techniques are not comparable. Overall, intestinal adaptation was achieved in nine (41%) patients, and four (18%) patients showed significant reduction of PN needs. One child did not respond to SRT and did not meet transplantation criteria. The remaining eight (36%) patients were included on the waiting list for transplant: four were transplanted, two are still on the waiting list, and two died. Better outcomes were observed in milder cases of liver disease (mild 77%, moderate 40%, severe 25%) (p < 0.05). Conversely, a trend toward a poorer outcome was observed in cases with ultrashort bowel (p > 0.05). One patient required reoperation after a Bianchi procedure due to intestinal ischemia and six needed further re-STEP or adhesiolysis procedure several months later. The median follow-up was 62 (3-135) months. Overall mortality was 19%, and was due to end stage liver disease and/or central venous catheter-related sepsis. SRT led to intestinal adaptation in a significant number of patients with poor prognosis SBS referred for intestinal transplantation. However, SRT requires a multidisciplinary evaluation and should be attempted only in suitable cases. Careful assessment and optimal surgical timing is crucial to obtain a favorable outcome. PMID- 26535776 TI - Dactylitis: more than just arthritis. PMID- 26535777 TI - Serum Sclerostin Level Among Egyptian Rheumatoid Arthritis Patients: Relation to Disease Activity, Bone Mineral Density and Radiological Grading. AB -

INTRODUCTION: Bone loss in rheumatoid arthritis is caused by increased bone resorption without increasing bone formation. The Wnt pathway is important in the control of bone formation through the regulation of osteoblast activity. Sclerostin is an important regulator of the Wnt pathway by blocking Wnt binding to its receptor and thereby inhibiting bone formation. AIM: This study aimed to assess the serum sclerostin level in a group of Egyptian rheumatoid arthritis patients and to correlate its level with bone mineral density, disease activity and radiological grading. METHODS: Forty rheumatoid arthritis patients (mean age 48.9 +/- 11.6 years, disease duration 8 +/- 6.4 years) and 40 age and sex matched apparently healthy subjects were included. Serum sclerostin level was measured using Enzyme linked Immunosorbent Assay. Plain radiographs of hands and feet and dual-energy x-ray absorptiometry test were done for all patients. RESULTS: No significant difference was found between rheumatoid arthritis patients and healthy controls as regard mean value of sclerostin level. Postmenopausal healthy women had higher levels of sclerostin than premenopausal healthy women only. Serum sclerostin had significantly positive correlations with the age of onset and weight of rheumatoid arthritis patients and negative correlation with Erythrocyte Sedimentation Rate. No correlation was encountered between sclerostin level and bone mineral density, disease activity or radiographic grading. CONCLUSION: For better clarification of the role of sclerostin on bone mass in rheumatoid arthritis, larger sample size is needed. More studies on serum sclerostin levels among different grades of RA activity are encouraged.

. PMID- 26535778 TI - Chronic hyponatremia: a new risk factor for fragility fractures in the elderly? PMID- 26535779 TI - Clinical and Laboratory Characteristics of Pediatric Scorpion Stings: A Report From Southern Iran. AB - OBJECTIVE: Scorpion stings are a major public health problem in many countries, particularly in pediatrics. Children are more susceptible to severe clinical manifestations of envenomation. The aim of this study is to determine the epidemiological and clinical characteristics of pediatric scorpionism in Hormozgan province of Iran during 2012. METHOD: This was a cross-sectional study being conducted during 2010 in Hormozgan, the southern province of Iran. We included 350 patients admitted to emergency unit of the hospitals of 8 cities of Hormozgan with impression of scorpion envenomation. The clinical and epidemiological characteristics as well as the treatment and outcome were recorded. RESULTS: The prevalence rate of pediatric scorpion stings in the province was 1.8 in 1000 children. The mean age of the patients was 5.75 +/- 4.54 (range, 1-18) years. There were 208 (59.5%) boys and 142 (40.5%) girls among the patients. The most common site of sting was sole to knee in 94 (26.8%) followed by hand in 61 (17.4%) and fingers in 47 (13.4%). The most common presenting symptom was vomiting in 236 (67.4%) followed by localized pain in 131 (37.3%), erythema in 120 (34.2%), and edema in 119 (33.9%). The highest and lowest frequency occurred in July (17.7%) and January (3.2%), respectively. Nocturnal envenomations (53.7%) were more common than diurnal (46.3%). Most of scorpionism were mild (83.4%) that all evolved to cure, without any deaths. CONCLUSIONS: The results demonstrate the pediatric scorpionism is a public health problem in Hormozgan province of Iran, and special attention should be paid to prevention and treatment. PMID- 26535780 TI - Inhibition of FGFR Signaling With PD173074 Ameliorates Monocrotaline-induced Pulmonary Arterial Hypertension and Rescues BMPR-II Expression. AB - BACKGROUND: Numerous studies have demonstrated that fibroblast growth factor-2 (FGF-2) signaling may play a pivotal role in the development of pulmonary arterial hypertension (PAH). Excessive endothelial FGF-2 contributes to smooth muscle hyperplasia and disease progression. PD173074 is a potent FGF receptor 1 (FGFR-1) inhibitor that displays high activity and selectivity. The aim of this study was to investigate the effects of PD173074 on monocrotaline-induced PAH. We also evaluated whether FGFR-1 inhibition could attenuate bone morphogenetic protein type II receptor (BMPR-II) downregulation in the monocrotaline model. METHODS: PAH model was established by a single intraperitoneal injection of monocrotaline. And then a daily intraperitoneal injection of PD173074 (20 mg/kg) was administered from day 14 to day 28. Hemodynamic parameters, right ventricular hypertrophy index and morphometry were evaluated at day 28. Western blot and immunohistochemical analyses were used to determine the expression of FGF-2 and bone morphogenetic protein signaling in the lung tissue. RESULTS: The expression of FGF-2 and FGFR-1 was upregulated in lung tissue after monocrotaline injection and it was accompanied by hemodynamic changes and pulmonary vascular remodeling. PD173074 treatment ameliorated PAH and vascular remodeling. It decreased ERK1/2 activation and rescued total Akt expression, leading to a reduction in both proliferation and apoptosis in the lung. Besides, PD173074 rescued the expression of BMPR-II and p-Smad 1/5/8. CONCLUSION: These results suggest that PD173074 can alleviate monocrotaline-induced pulmonary arterial hypertension and it may be a useful option for PAH. Our data also suggest a role of FGF-2/bone morphogenetic protein signaling interaction in PAH. PMID- 26535781 TI - Conformational changes in the heat-induced crystallization of poly(2-isopropyl-2 oxazoline) in the solid state. AB - Poly(2-isopropyl-2-oxazoline) (PIPOZ) with an isomeric structure of poly(N isopropylacrylamide) (PNIPAM) represents an important class of stimuli-responsive synthetic polymers. Unlike PNIPAM, PIPOZ exhibits an unusual heat-induced crystallization behaviour at around 120 degrees C in the solid state, whose dynamic mechanism involving all group motions and conformational changes is still poorly understood. In this paper, IR spectroscopy in combination with two dimensional analysis methods - the perturbation correlation moving window (PCMW) and two-dimensional correlation spectroscopy (2DCOS) - was used to monitor and study the conformational changes in the crystallization of PIPOZ in the solid state. The incorporated water molecules are found to be not necessary to assist the solid-state crystallization of the PIPOZ film. PCMW and 2DCOS analyses reveal that following the breaking of minor CH3O[double bond, length as m-dash]C hydrogen bonds, all the group moieties exhibit highly synergetic motions during crystallization, and methylene groups on the backbone do not show significant changes throughout the crystallization process. Raman spectroscopic and molecular dynamics simulation results further support this conclusion. The chain alignment of PIPOZ chains is shown to be mainly achieved by the lateral distortion of coplanar side chains or the ordered chain arrangement of amide dipoles together with the torsion of the backbone through C-N linkages. Upon heating, gauche conformations of methylene groups on the backbone are always dominating, resulting in an ordered PIPOZ chain with alternate side chains and a slightly distorted backbone. PMID- 26535782 TI - Surface group modification and carrier transport properties of layered transition metal carbides (Ti2CT(x), T: -OH, -F and -O). AB - In spite of recent significant research into various two-dimensional (2D) materials after the emergence of graphene, the development of a new 2D material that provides both high mobility and an appropriate energy band gap (which are crucial for various device applications) remains elusive. In this report, we demonstrate that the carrier transport behaviour of 2D Ti2CTx, which belongs to the family of 2D transition metal carbides and nitrides, can be tuned by modifying the surface group Tx (-OH, -F, and -O). Our results show that 2D Ti2C(OH)xFy and Ti2COx films can be obtained via simple chemical treatment, thermal annealing, and mechanical exfoliation processes. For the first time, we study the carrier transport properties of 2D Ti2CTx field effect transistors (FETs), obtaining the high field effect carrier mobilities of 10(4) cm(2) V(-1) s(-1) at room temperature. The temperature dependent resistivity of the Ti2COx film exhibits semiconductor like Arrhenius behaviour at zero gate voltage, from which we estimate the energy gap of 80 meV. One interesting feature of the FETs based on transition metal carbides is that the field effect mobility at room temperature is less sensitive to the measured transport gaps, which may arise from the dominant charge transport of activated carriers over the narrow energy gaps of the transition metal carbides. Our results open up the possibility that new 2D materials with high mobilities and appropriate band gaps can be achieved, and broaden the range of electronic device applications of Ti2CTx films. PMID- 26535783 TI - Rapid preparation of single-layer transition metal dichalcogenide nanosheets via ultrasonication enhanced lithium intercalation. AB - In this report, we have developed a rapid and versatile ultrasonication enhanced lithium intercalation (ULI) method to prepare single-layer transition metal dichalcogenide nanosheets (TMDC NSs, including MoS2, WS2, and TiS2) by using n butyllithium (n-BuLi). PMID- 26535784 TI - Denominators count: supplementing surveillance data for genital Chlamydia trachomatis infection with testing data, Norway, 2007 to 2013. AB - As genital Chlamydia trachomatis (chlamydia) infection is often asymptomatic, surveillance of diagnosed cases is heavily influenced by the rate and distribution of testing. In 2007, we started supplementing case-based surveillance data from the Norwegian Surveillance System for Communicable Diseases (MSIS) with aggregated data on age group and sex of individuals tested. In this report, annual testing rates, diagnosis rates and proportion positive for chlamydia in Norway between 1990 and 2013 are presented. From 2007, rates are also stratified by age group and sex. The annual testing rate for chlamydia culminated in the early 1990s, with 8,035 tested per 100,000 population in 1991. It then declined to 5,312 per 100,000 in 2000 after which it remained relatively stable. Between 1990 and 2013 the annual rate of diagnosed cases increased 1.5 times from ca 300 to ca 450 per 100,000 population. The proportion of positive among the tested rose twofold from ca 4% in the 1990s to 8% in 2013. Data from 2007 to 2013 indicate that more women than men were tested (ratio: 2.56; 95% confidence interval (CI): 2.56-2.58) and diagnosed (1.54; 95% CI: 1.52-1.56). Among tested individuals above 14 years-old, the proportion positive was higher in men than women for all age groups. Too many tests are performed in women aged 30 years and older, where 49 of 50 tests are negative. Testing coverage is low (15%) among 15 to 24 year-old males. Information on sex and age-distribution among the tested helps to interpret surveillance data and provides indications on how to improve targeting of testing for chlamydia. Regular prevalence surveys may address remaining limitations of surveillance. PMID- 26535785 TI - Direct writing of CoFe alloy nanostructures by focused electron beam induced deposition from a heteronuclear precursor. AB - Recently, focused electron beam-induced deposition has been employed to prepare functional magnetic nanostructures with potential in nanomagnetic logic and sensing applications by using homonuclear precursor gases like Fe(CO)5 or Co2(CO)8. Here we show that an extension towards the fabrication of bi-metallic compounds is possible by using a single-source heteronuclear precursor gas. We have grown CoFe alloy magnetic nanostructures from the HFeCo3(CO)12 metal carbonyl precursor. The compositional analysis indicates that the samples contain about 80 at% of metal and 10 at% of carbon and oxygen. Four-probe magnetotransport measurements are carried out on nanowires of various sizes down to a width of 50 nm, for which a room temperature resistivity of 43 MUOmegacm is found. Micro-Hall magnetometry reveals that 50 nm * 250 nm nanobars of the material are ferromagnetic up to the highest measured temperature of 250 K. Finally, the transmission electron microscopy (TEM) microstructural investigation shows that the deposits consist of a bcc Co-Fe phase mixed with a FeCo2 O4 spinel oxide phase with nanograins of about 5 nm diameter. PMID- 26535786 TI - Quasi-Solid Electrolytes for High Temperature Lithium Ion Batteries. AB - Rechargeable batteries capable of operating at high temperatures have significant use in various targeted applications. Expanding the thermal stability of current lithium ion batteries requires replacing the electrolyte and separators with stable alternatives. Since solid-state electrolytes do not have a good electrode interface, we report here the development of a new class of quasi-solid-state electrolytes, which have the structural stability of a solid and the wettability of a liquid. Microflakes of clay particles drenched in a solution of lithiated room temperature ionic liquid forming a quasi-solid system has been demonstrated to have structural stability until 355 degrees C. With an ionic conductivity of ~3.35 mS cm(-1), the composite electrolyte has been shown to deliver stable electrochemical performance at 120 degrees C, and a rechargeable lithium battery with Li4Ti5O12 electrode has been tested to deliver reliable capacity for over several cycles of charge-discharge. PMID- 26535787 TI - Knowledge, attitudes and practices concerning Middle East respiratory syndrome among Umrah and Hajj pilgrims in Samsun, Turkey, 2015. AB - We performed a questionnaire study to determine knowledge, attitudes and practices concerning Middle East respiratory syndrome (MERS) among people intending to participate in the Hajj or Umrah Muslim pilgrimages. Of the 381 respondents aged between 17 and 85 years, 55% had never heard of MERS, while only one in three knew that it is a respiratory disease. Approximately half were insufficiently informed about protective measures. Prospective pilgrims do not seem prepared to take such precautions. PMID- 26535788 TI - Combined High-Density Lipoprotein Proteomic and Glycomic Profiles in Patients at Risk for Coronary Artery Disease. AB - OBJECTIVES: To test whether recently developed methods for comprehensive profiling of the high-density lipoprotein (HDL) glycome combined with the HDL proteome can distinguish individuals with coronary artery disease (CAD) from those without. METHODS: Twenty subjects at risk for CAD, who underwent diagnostic coronary arteriography, were analyzed. Ten subjects had CAD, and ten did not. HDL was extracted from fasting plasma samples by ultracentrifugation, followed by shotgun proteomic, glycomic, and ganglioside analyses using LC-MS. CAD vs non-CAD subjects' data were compared using univariate and multivariate statistics. RESULTS: Principal components analysis showed a clear separation of CAD and non CAD subjects, confirming that combined HDL proteomic and glycomic profiles distinguished at-risk subjects with atherosclerosis from those without. CAD patients had lower HDL apolipoprotein content (specifically ApoA-I, A-II, and E, p < 0.05), and lower serum amyloid A2 (SAA2, p = 0.020) and SAA4 (p = 0.007) but higher sialylated glycans (p < 0.05). CONCLUSION: Combined proteomic and glycomic profiling of isolated HDL was tested as a novel analytical approach for developing biomarkers of disease. In this pilot study we found that HDL proteome and glycome distinguished between individuals who had CAD from those who did not within a group of individuals equally at risk for heart disease. PMID- 26535789 TI - Transition State Charge Stabilization and Acid-Base Catalysis of mRNA Cleavage by the Endoribonuclease RelE. AB - The bacterial toxin RelE is a ribosome-dependent endoribonuclease. It is part of a type II toxin-antitoxin system that contributes to antibiotic resistance and biofilm formation. During amino acid starvation, RelE cleaves mRNA in the ribosomal A-site, globally inhibiting protein translation. RelE is structurally similar to microbial RNases that employ general acid-base catalysis to facilitate RNA cleavage. The RelE active site is atypical for acid-base catalysis, in that it is enriched with positively charged residues and lacks the prototypical histidine-glutamate catalytic pair, making the mechanism of mRNA cleavage unclear. In this study, we use a single-turnover kinetic analysis to measure the effect of pH and phosphorothioate substitution on the rate constant for cleavage of mRNA by wild-type RelE and seven active-site mutants. Mutation and thio effects indicate a major role for stabilization of increased negative change in the transition state by arginine 61. The wild-type RelE cleavage rate constant is pH-independent, but the reaction catalyzed by many of the mutants is strongly dependent on pH, suggestive of general acid-base catalysis. pH-rate curves indicate that wild-type RelE operates with the pK(a) of at least one catalytic residue significantly downshifted by the local environment. Mutation of any single active-site residue is sufficient to disrupt this microenvironment and revert the shifted pK(a) back above neutrality. pH-rate curves are consistent with K54 functioning as a general base and R81 as a general acid. The capacity of RelE to effect a large pK(a) shift and facilitate a common catalytic mechanism by uncommon means furthers our understanding of other atypical enzymatic active sites. PMID- 26535790 TI - Cost-effectiveness analysis of oxycodone with naloxone versus oxycodone alone for the management of moderate-to-severe pain in patients with opioid-induced constipation in Canada. AB - BACKGROUND: Approximately 20-30% of Canadians suffer from chronic pain. Guidelines for the management of chronic pain support the use of controlled release (CR) opioids to treat chronic pain. Although effective in managing chronic pain, oxycodone is associated with high rates of opioid-induced constipation (OIC). The cost-effectiveness of a combination of oxycodone for the management of pain and naloxone for the relief of OIC has not previously been evaluated for Canada. METHODS: A decision analytic model was developed to estimate the cost-utility of combination oxycodone/naloxone compared to oxycodone alone in four populations. Drug costs for managing pain and healthcare costs related to managing OIC were included in the analysis and the primary measure of effectiveness was quality adjusted life years (QALYs) derived from OIC rates observed in clinical trials. The analysis was conducted from a healthcare system perspective, used a 1-year time horizon, and results were expressed in 2015 Canadian dollars. RESULTS: In all four patient populations, there was a trade-off between slightly higher total expected costs for Targin treated patients compared to oxycodone treated patients, but also improved clinical benefits in terms of reduced OIC, which resulted in higher QALYs for patients. Although analgesic costs were found to be slightly higher for Targin treated patients, Targin also resulted in cost offsets to the healthcare system in terms of less rescue laxative drug use and other resources required for the management of OIC. The resulting 1-year cost-utility of Targin compared to oxycodone ranged from $2178 $7732 per QALY gained in the base case analysis, and it was found that these cost utility results remained robust and at low values throughout a series of one-way deterministic analyses of uncertainty. CONCLUSION: The clinical effectiveness of oxycodone/naloxone in managing pain and OIC compared to CR oxycodone alone resulted in low cost-utility estimates. PMID- 26535791 TI - Reversibility of Noble Metal-Catalyzed Aprotic Li-O2 Batteries. AB - The aprotic Li-O2 battery has attracted a great deal of interest because, theoretically, it can store far more energy than today's batteries. Toward unlocking the energy capabilities of this neotype energy storage system, noble metal-catalyzed high surface area carbon materials have been widely used as the O2 cathodes, and some of them exhibit excellent electrochemical performances in terms of round-trip efficiency and cycle life. However, whether these outstanding electrochemical performances are backed by the reversible formation/decomposition of Li2O2, i.e., the desired Li-O2 electrochemistry, remains unclear due to a lack of quantitative assays for the Li-O2 cells. Here, noble metal (Ru and Pd) catalyzed carbon nanotube (CNT) fabrics, prepared by magnetron sputtering, have been used as the O2 cathode in aprotic Li-O2 batteries. The catalyzed Li-O2 cells exhibited considerably high round-trip efficiency and prolonged cycle life, which could match or even surpass some of the best literature results. However, a combined analysis using differential electrochemical mass spectrometry and Fourier transform infrared spectroscopy, revealed that these catalyzed Li-O2 cells (particularly those based on Pd-CNT cathodes) did not work according to the desired Li-O2 electrochemistry. Instead the presence of noble metal catalysts impaired the cells' reversibility, as evidenced by the decreased O2 recovery efficiency (the ratio of the amount of O2 evolved during recharge/that consumed in the preceding discharge) coupled with increased CO2 evolution during charging. The results reported here provide new insights into the O2 electrochemistry in the aprotic Li-O2 batteries containing noble metal catalysts and exemplified the importance of the quantitative assays for the Li-O2 reactions in the course of pursuing truly rechargeable Li-O2 batteries. PMID- 26535792 TI - Air quality of nursing homes and its effect on the lung health of elderly residents. AB - In industrialized countries the elderly spend most of their time indoors. The elderly may be at a higher risk of suffering from indoor air pollution-related diseases compared to the rest of the population, because of their increased exposure to potential indoor risk factors. This editorial aims to critically analyze the recent literature regarding this important topic. Results of studies performed on the elderly living in nursing homes clearly highlight that they are at risk of respiratory health impairment, even at moderate air pollutant concentrations, particularly if they are over 80 years of age and living in poorly ventilated nursing homes. The future epidemiological research on ageing and respiratory diseases should investigate the underlying biological and physiological mechanisms, in addition to the adverse health effects of potential indoor risk factors, in order to help defining effective strategies for healthy ageing. PMID- 26535793 TI - Reply to staging classification for cancer of the ovary and fallopian tube should include in situ carcinoma. PMID- 26535794 TI - Mechanism of Bacillus subtilis spore inactivation by and resistance to supercritical CO2 plus peracetic acid. AB - AIMS: Determine how supercritical CO2 (scCO2 ) plus peracetic acid (PAA) inactivates Bacillus subtilis spores, factors important in spore resistance to scCO2 -PAA, and if spores inactivated by scCO2 -PAA are truly dead. METHODS AND RESULTS: Spores of wild-type B. subtilis and isogenic mutants lacking spore protective proteins were treated with scCO2 -PAA in liquid or dry at 35 degrees C. Wild-type wet spores (aqueous suspension) were more susceptible than dry spores. Treated spores were examined for viability (and were truly dead), dipicolinic acid (DPA), mutations, permeability to nucleic acid stains, germination under different conditions, energy metabolism and outgrowth. ScCO2 PAA-inactivated spores retained DPA, and survivors had no notable DNA damage. However, DPA was released from inactivated spores at a normally innocuous temperature (85 degrees C), and colony formation from treated spores was salt sensitive. The inactivated spores germinated but did not outgrow, and these germinated spores had altered plasma membrane permeability and defective energy metabolism. Wet or dry coat-defective spores had increased scCO2 -PAA sensitivity, and dry spores but not wet spores lacking DNA protective proteins were more scCO2 -PAA sensitive. CONCLUSIONS: These findings suggest that scCO2 PAA inactivates spores by damaging spores' inner membrane. The spore coat provided scCO2 -PAA resistance for both wet and dry spores. DNA protective proteins provided scCO2 -PAA resistance only for dry spores. SIGNIFICANCE AND IMPACT OF THE STUDY: These results provide information on mechanisms of spore inactivation of and resistance to scCO2 -PAA, an agent with increasing use in sterilization applications. PMID- 26535795 TI - Langerhans cell histiocytosis of the temporal bone: A review of 29 cases at a single center. AB - OBJECTIVES/HYPOTHESIS: Evaluate presentation, management, and clinical outcomes of patients with temporal bone Langerhans cell histiocytosis (LCH). STUDY DESIGN: Retrospective chart review. METHODS: Reviewed all patients with temporal bone LCH at a tertiary academic referral center between 1978 and 2014. Presentation, disease course, intervention, and clinical outcomes were analyzed. RESULTS: Between 1978 and 2014, 29 temporal bones in 20 patients (12 males; median age 32 years, range 1.3-88 years) were diagnosed with temporal bone LCH, representing 4% of all patients diagnosed with LCH at our institution during that time. Twelve (60%) patients presented purely with head and neck disease, nine (45%) with bilateral temporal bone involvement, seven (35%) with intracranial spread, and eight (40%) with multisystem disease. The most common presenting symptoms were otorrhea (n = 11; 55%) and subjective hearing loss (n = 10; 50%). Treatment included primary chemotherapy or radiation alone(n = 7; 35%), local resection alone (n = 2; 10%), and chemotherapy or radiation with surgery(n = 11; 55%). Ten patients suffered local or systemic relapse (50%; median 12 months). Median follow-up for patients was 31 months. One patient died secondary to pulmonary complications of multisystem LCH. CONCLUSIONS: LCH is an uncommon histiocytic disorder with a range of clinical manifestations and disease severity. Otologic involvement is rare, and frequently manifests with symptoms similar to otomastoiditis. Evaluation and close follow-up of both ears is important. Bilateral simultaneous or sequential LCH can be seen in up to 45% of cases. Patients with temporal bone LCH should be managed by a multidisciplinary team with treatment tailored to the patient. Relapse is more common in patients with multisystem involvement. Even in subjects with isolated otologic involvement, long-term follow-up is critical, with relapses occurring years beyond treatment. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1899-1904, 2016. PMID- 26535796 TI - Perceptions of misdiagnosis among women diagnosed with gestational diabetes. PMID- 26535797 TI - Ameliorative effect of trimetazidine on cisplatin-induced hepatotoxicity in rats. AB - This study was designed to evaluate the protective effects of trimetazidine (TMZ) against cisplatin (CP) induced liver damage in rats. Animals were distributed among 4 groups as follows: control group; TMZ group (20 mg/kg body mass, per oral), which was treated for 10 days; CP group (6 mg/kg, by intraperitoneal injection), which received a single injection; and the CP + TMZ group (20 mg/kg, per oral), which received TMZ 4 days before and 6 days after CP injection. The extent of hepatic damage was studied by assessing biochemical parameters and histopathological evaluation of the extracted liver tissue. The results revealed that liver enzymes were markedly elevated after injection of CP, as evident from significant increases in the serum levels of alanine transaminase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (gamma-GT), and lactate dehydrogenase (LDH), as well as marked changes to the liver architecture, with a significant decrease in serum levels of albumin. There were also marked changes to the antioxidant defense system, as indicated by significant decreases in total antioxidants and hepatic levels of reduced glutathione (GSH) and superoxide dismutase (SOD), together with a significant increase in lipid peroxidation. However, there was a significant increase in the activity of hepatic nuclear factor kappa B (NF-kappaB) as well as hepatic Bax protein expression. We conclude that TMZ protects against CP-induced liver damage through scavenging free radicals and anti-inflammatory and antiapoptotic effects, as well as through reducing NF-kappaB activation. PMID- 26535798 TI - Potential pitfalls of CRISPR/Cas9-mediated genome editing. AB - Recently, a novel technique named the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas)9 system has been rapidly developed. This genome editing tool has improved our ability tremendously with respect to exploring the pathogenesis of diseases and correcting disease mutations, as well as phenotypes. With a short guide RNA, Cas9 can be precisely directed to target sites, and functions as an endonuclease to efficiently produce breaks in DNA double strands. Over the past 30 years, CRISPR has evolved from the 'curious sequences of unknown biological function' into a promising genome editing tool. As a result of the incessant development in the CRISPR/Cas9 system, Cas9 co-expressed with custom guide RNAs has been successfully used in a variety of cells and organisms. This genome editing technology can also be applied to synthetic biology, functional genomic screening, transcriptional modulation and gene therapy. However, although CRISPR/Cas9 has a broad range of action in science, there are several aspects that affect its efficiency and specificity, including Cas9 activity, target site selection and short guide RNA design, delivery methods, off-target effects and the incidence of homology-directed repair. In the present review, we highlight the factors that affect the utilization of CRISPR/Cas9, as well as possible strategies for handling any problems. Addressing these issues will allow us to take better advantage of this technique. In addition, we also review the history and rapid development of the CRISPR/Cas system from the time of its initial discovery in 2012. PMID- 26535799 TI - Memory B Cell Divergences upon Immunization Against Streptococcus pneumoniae in HIV-1-Infected Adults. PMID- 26535800 TI - Electric-Field-Driven Dual Vacancies Evolution in Ultrathin Nanosheets Realizing Reversible Semiconductor to Half-Metal Transition. AB - Fabricating a flexible room-temperature ferromagnetic resistive-switching random access memory (RRAM) device is of fundamental importance to integrate nonvolatile memory and spintronics both in theory and practice for modern information technology and has the potential to bring about revolutionary new foldable information-storage devices. Here, we show that a relatively low operating voltage (+1.4 V/-1.5 V, the corresponding electric field is around 20,000 V/cm) drives the dual vacancies evolution in ultrathin SnO2 nanosheets at room temperature, which causes the reversible transition between semiconductor and half-metal, accompanyied by an abrupt conductivity change up to 10(3) times, exhibiting room-temperature ferromagnetism in two resistance states. Positron annihilation spectroscopy and electron spin resonance results show that the Sn/O dual vacancies in the ultrathin SnO2 nanosheets evolve to isolated Sn vacancy under electric field, accounting for the switching behavior of SnO2 ultrathin nanosheets; on the other hand, the different defect types correspond to different conduction natures, realizing the transition between semiconductor and half metal. Our result represents a crucial step to create new a information-storage device realizing the reversible transition between semiconductor and half-metal with flexibility and room-temperature ferromagnetism at low energy consumption. The as-obtained half-metal in the low-resistance state broadens the application of the device in spintronics and the semiconductor to half-metal transition on the basis of defects evolution and also opens up a new avenue for exploring random access memory mechanisms and finding new half-metals for spintronics. PMID- 26535801 TI - Vibrational Signature of a Single Water Molecule Adsorbed on Pt(111): Toward a Reliable Anharmonic Description. AB - In this study, we present a thorough benchmarking of our direct anharmonic vibrational variation-perturbation approach for adsorbed molecules on surfaces. We then use our method to describe the vibrational structure of a water molecule adsorbed on a Pt(111) surface and compare our results with the available experimental data. By using an explicitly correlated hybrid method to describe the molecule-surface interaction, we improve on the initial periodic PBE/DZP potential energy landscape and obtain vibrational frequencies that are of near experimental accuracy. We introduce an implementation of anharmonic z-polarized IR intensity calculation and explain the absence of antisymmetric O-H stretch in the experimental data for the adsorbed water molecule, while the symmetric O-H stretch is predicted to be visible. PMID- 26535802 TI - Kidney stones: flexible ureteroscopy. AB - INTRODUCTION: The age of peak incidence for stone disease is 20 to 40 years, although stones are seen in all age groups. There is a male to female ratio of 3:2. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of flexible ureteroscopy for the removal of renal stones? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 197 studies. After deduplication and removal of conference abstracts, 118 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 99 studies and the further review of 18 full publications. Of the 18 full articles evaluated, one systematic review and four RCTs were added at this update. We performed a GRADE evaluation for eight PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for four interventions, based on information relating to the effectiveness and safety of: flexible ureteroscopy (combined with snare or basket or laser lithotripsy) versus expectant management, flexible ureteroscopy (combined with snare or basket or laser lithotripsy) versus extracorporeal shockwave lithotripsy, flexible ureteroscopy (combined with snare or basket or laser lithotripsy) versus percutaneous nephrolithotomy. PMID- 26535803 TI - Effects of Removing Low-Frequency Electric Information on Speech Perception With Bimodal Hearing. AB - PURPOSE: The objective was to determine whether speech perception could be improved for bimodal listeners (those using a cochlear implant [CI] in one ear and hearing aid in the contralateral ear) by removing low-frequency information provided by the CI, thereby reducing acoustic-electric overlap. METHOD: Subjects were adult CI subjects with at least 1 year of CI experience. Nine subjects were evaluated in the CI-only condition (control condition), and 26 subjects were evaluated in the bimodal condition. CIs were programmed with 4 experimental programs in which the low cutoff frequency (LCF) was progressively raised. Speech perception was evaluated using Consonant-Nucleus-Consonant words in quiet, AzBio sentences in background babble, and spondee words in background babble. RESULTS: The CI-only group showed decreased speech perception in both quiet and noise as the LCF was raised. Bimodal subjects with better hearing in the hearing aid ear (< 60 dB HL at 250 and 500 Hz) performed best for words in quiet as the LCF was raised. In contrast, bimodal subjects with worse hearing (> 60 dB HL at 250 and 500 Hz) performed similarly to the CI-only group. CONCLUSIONS: These findings suggest that reducing low-frequency overlap of the CI and contralateral hearing aid may improve performance in quiet for some bimodal listeners with better hearing. PMID- 26535804 TI - A Novel Method of Neuromonitoring in Thyroidectomy and Parathyroidectomy Using Transcutaneous Intraoperative Vagal Stimulation. PMID- 26535805 TI - Use of Lithium and Anticonvulsants and the Rate of Chronic Kidney Disease: A Nationwide Population-Based Study. AB - IMPORTANCE: Lithium is the main mood stabilizing drug for bipolar disorder. However, it is controversial whether long-term maintenance treatment with lithium or other drugs for bipolar disorder causes chronic kidney disease (CKD). OBJECTIVE: To compare rates of CKD and in particular rates of end-stage CKD among individuals exposed to successive prescriptions of lithium, anticonvulsants, or other drugs used for bipolar disorder. DESIGN, SETTING, AND PARTICIPANTS: This is a Danish nationwide population-based study of 2 cohorts. Cohort 1 comprised a randomly selected sample of 1.5 million individuals among all persons who were registered in Denmark on January 1, 1995, all patients with a diagnosis of a single manic episode or bipolar disorder between January 1, 1994, and December 31, 2012 (n =10,591), and all patients exposed to either lithium (n = 26,731) or anticonvulsants (n=420,959). Cohort 2 included the subgroup of 10,591 patients diagnosed as having bipolar disorder. MAIN OUTCOMES AND MEASURES: Possible CKD, definite CKD, and end-stage CKD (defined as long-term dialysis or renal transplantation). RESULTS: A total of 14,727 (0.8%), 18,762 (1.0%), and 3407 (0.2%) in cohort 1 and 278 (2.6%), 319 (3.0%), and 62 (0.6%) in cohort 2 were diagnosed as having possible, definite, or end-stage CKD, respectively. Based on the total sample and not considering diagnoses, use of lithium was associated with an increased rate of definite CKD (0 prescriptions: hazard ratio [HR] = 1.09, 95% CI, 0.81-1.45; >=60 prescriptions: HR = 3.65, 95% CI, 2.64-5.05; P for trend < .001) and possible CKD (0 prescriptions: HR = 1.01, 95% CI, 0.79-1.30; >=60 prescriptions: HR = 2.88, 95% CI, 2.17-3.81; P for trend < .001), whereas use of anticonvulsants, antipsychotics, or antidepressants was not. Neither use of lithium nor use of any other drug class was associated with increasing rates of end-stage CKD. In patients with bipolar disorder, use of lithium was associated with an increased rate of definite CKD (1-2 prescriptions: HR = 0.89, 95% CI, 0.39-2.06; >=60 prescriptions: HR = 2.54, 95% CI, 1.81-3.57; P for trend < .001) or possible CKD (1-2 prescriptions: HR = 1.26, 95% CI, 0.65-2.43; >=60 prescriptions, HR = 2.48, 95% CI, 1.80-3.42; P for trend < .001), as was use of anticonvulsants (definite CKD, 1-2 prescriptions: HR = 1.23, 95% CI, 0.76-1.99; >=60 prescriptions, HR = 2.30, 95% CI, 1.53-3.44; P for trend < .001; possible CKD, 1-2 prescriptions: HR = 1.11, 95% CI, 0.70-1.76; >=60 prescriptions: HR = 1.97, 95% CI, 1.34-2.90; P for trend < .001). There was no such association with antipsychotics or antidepressants. Also in patients with bipolar disorder, use of lithium was not significantly associated with an increased rate of end-stage CKD, whereas use of anticonvulsants was (1-2 prescriptions, HR = 0 [95% CI, 0.00 infinity]; 30-39 prescriptions: HR = 3.23, 95% CI, 1.26-8.27; >=60 prescriptions: HR = 2.06, 95% CI, 0.82-5.16; P for trend = .002). CONCLUSIONS AND RELEVANCE: Maintenance treatment with lithium or anticonvulsants as practiced in modern care is associated with an increased rate of CKD. However, use of lithium is not associated with an increased rate of end-stage CKD. The associations between use of medication and CKD may at least partly be attributed to bias. PMID- 26535806 TI - Plasmodium falciparum kelch 13: a potential molecular marker for tackling artemisinin-resistant malaria parasites. AB - Although artemisinin combination therapies have been deployed as a first-line treatment for uncomplicated malaria in almost all endemic countries, artemisinin resistant parasites have emerged and have gradually spread across the Greater Mekong subregions. There is growing concern that the resistant parasites may migrate to or emerge indigenously in sub-Saharan Africa, which might provoke a global increase in malaria-associated morbidity and mortality. Therefore, development of molecular markers that enable identification of artemisinin resistance with high sensitivity is urgently required to combat this issue. In 2014, a potential artemisinin-resistance responsible gene, Plasmodium falciparum kelch13, was discovered. Here, we review the genetic features of P. falciparum kelch13 and discuss its related resistant mechanisms and potential as a molecular marker. PMID- 26535807 TI - Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells. AB - Collagen is the most abundant protein in animals. Its overproduction is associated with fibrosis and cancer metastasis. The stability of collagen relies on post-translational modifications, the most prevalent being the hydroxylation of collagen strands by collagen prolyl 4-hydroxylases (CP4Hs). Catalysis by CP4Hs enlists an iron cofactor to convert proline residues to 4-hydroxyproline residues, which are essential for the conformational stability of mature collagen. Ethyl 3,4-dihydroxybenzoate (EDHB) is commonly used as a "P4H" inhibitor in cells, but suffers from low potency, poor selectivity, and off target effects that cause iron deficiency. Dicarboxylates of 2,2'-bipyridine are among the most potent known CP4H inhibitors but suffer from a high affinity for free iron. A screen of biheteroaryl compounds revealed that replacing one pyridyl group with a thiazole moiety retains potency and enhances selectivity. A diester of 2-(5-carboxythiazol-2-yl)pyridine-5-carboxylic acid is bioavailable to human cells and inhibits collagen biosynthesis at concentrations that neither cause general toxicity nor disrupt iron homeostasis. These data anoint a potent and selective probe for CP4H and a potential lead for the development of a new class of antifibrotic and antimetastatic agents. PMID- 26535808 TI - Current and emerging drugs for interstitial cystitis/bladder pain syndrome (IC/BPS). AB - INTRODUCTION: Interstitial cystitis or bladder pain syndrome (IC/BPS) is a debilitating chronic disease characterized by suprapubic pain and lower urinary tract symptoms: however, the etiology is still unknown. Therefore, the long lasting, effective treatments of IC/BPS are still not established, and the treatment is sometimes empirically selected depending on practitioners' experience and preference. AREA COVERED: In this review we focus on the current treatments, ongoing clinical trials, and several potential new drugs based on the results of basic and clinical research studies. First, we discuss the potential etiologies of IC/BPS that include altered barrier lining, afferent and/or central nervous system abnormalities, possible contribution of inflammation or infection and abnormal urothelial signaling. Then, the current therapies of IC/BPS, either systemic or local, are reviewed by critical evaluation of the efficacy and shortcomings of each treatment. Finally, based on proposed etiologies of the disease, potential emerging drugs and treatments are discussed. EXPERT OPINION: Current therapies often fail to control the symptoms of IC/BPS. Several interventions including sustained drug release and retaining techniques, and drugs that act on afferent neural pathways are emerging and may be promising. In addition, phenotyping of IC/BPS patients based on cystoscopic findings (e.g., Hunner vs. non-Hunner lesion) or patients' symptoms would be important for further investigation of IC/BPS etiology and the evaluation of efficacy of new treatments. PMID- 26535809 TI - Blue Skies Bluer? AB - The largest U.S. environmental health risk is cardiopulmonary mortality from ambient PM2.5. The concentration-response (C-R) for ambient PM2.5 in the U.S. is generally assumed to be linear: from any initial baseline, a given concentration reduction would yield the same improvement in health risk. Recent evidence points to the perplexing possibility that the PM2.5 C-R for cardiopulmonary mortality and some other major endpoints might be supralinear: a given concentration reduction would yield greater improvements in health risk as the initial baseline becomes cleaner. We explore the implications of supralinearity for air policy, emphasizing U.S. CONDITIONS: If C-R is supralinear, an economically efficient PM2.5 target may be substantially more stringent than under current standards. Also, if a goal of air policy is to achieve the greatest health improvement per unit of PM2.5 reduction, the optimal policy might call for greater emission reductions in already-clean locales-making "blue skies bluer"-which may be at odds with environmental equity goals. Regardless of whether the C-R is linear or supralinear, the health benefits of attaining U.S. PM2.5 levels well below the current standard would be large. For the supralinear C-R considered here, attaining the current U.S. EPA standard, 12 MUg m(-3), would avert only ~17% (if C-R is linear: ~ 25%) of the total annual cardiopulmonary mortality attributable to PM2.5. PMID- 26535810 TI - Phytoestrogen consumption and risk for cognitive decline and dementia: With consideration of thyroid status and other possible mediators. AB - It is predicted that around 20% of the worlds population will be age 60 or above by 2050. Prevalence of cognitive decline and dementia is high in older adults and modifiable dietary factors may be able to reduce risk for these conditions. Phytoestrogens are bioactive plant chemicals found in soy, which have a similarity in structure to natural estradiol (the most abundant circulating estrogen). This structural likeness enables phytoestrogens to interact with estrogen receptors in the brain, potentially affecting cognition. However, findings in this domain are largely inconsistent, with approximately 50% of studies showing positive effects of phytoestrogens on cognition and the other half resulting in null/negative findings. This paper provides an updated review of the relationship between consumption of phytoestrogens and risk for cognitive decline and/or dementia. In particular, possible mediators were identified to explain discrepant findings and for consideration in future research. A case can be made for a link between phytoestrogen consumption, thyroid status and cognition in older age, although current findings in this area are very limited. Evidence suggests that inter-individual variants that can affect phytoestrogen bioavailability (and thus cognitive outcome) include age and ability to breakdown ingested phytoestrogens into their bioactive metabolites. Factors of the study design that must be taken into account are type of soy product, dosage, frequency of dietary intake and type of cognitive test used. Guidelines regarding optimal phytoestrogen dosage and frequency of intake are yet to be determined. PMID- 26535811 TI - Oxygen-glucose deprivation increases firing of unipolar brush cells and enhances spontaneous EPSCs in Purkinje cells in the vestibulo-cerebellum. AB - Unipolar brush cells (UBCs) are excitatory interneurons in the granular layer of the cerebellar cortex, which are predominantly distributed in the vestibulo cerebellar region. The unique firing properties and synaptic connections of UBCs may underlie lobular heterogeneity of excitability in the granular layer and the susceptibility to ischemia-induced excitotoxicity. In this study, we investigated the effects of oxygen-glucose deprivation (OGD) on the firing properties of UBCs and granule cells and spontaneous excitatory postsynaptic currents (sEPSCs) of Purkinje cells using whole-cell recordings. Short-term OGD induced increases in spontaneous firing of UBCs by causing membrane depolarization via the activation of NMDA receptors. UBC firing indirectly affected Purkinje cells by altering parallel fiber inputs of a subset granule cells, resulting in a marked increase in sEPSCs in Purkinje cells in vestibulo-cerebellar lobules IX-X, but not in lobules IV-VI, which have fewer UBCs. Similarly, the frequency and amplitude of sEPSCs in Purkinje cells were significantly greater in lobules IX-X than in IV VI, even in control conditions. These results reveal that UBCs play key roles in regulating local excitability in the granular layer, resulting in lobular heterogeneity in the susceptibility to ischemic insult in the cerebellum. PMID- 26535812 TI - Physician liability issues and telemedicine: Part 1 of 3. PMID- 26535813 TI - Langerhans cell histiocytosis involving the external auditory canal: An unusual ear tumor. PMID- 26535814 TI - Endoscopic view of a total ethmoidectomy prior to the FESS era. PMID- 26535815 TI - Laryngeal neurofibroma. PMID- 26535816 TI - Soft palate mass. PMID- 26535817 TI - "Cannonball" delayed pulmonary metastases in parotid adenoid cystic carcinoma. PMID- 26535818 TI - Angiolymphoid hyperplasia with eosinophilia. PMID- 26535819 TI - Globus sensation and laryngopharyngeal reflux. PMID- 26535820 TI - An intrathyroidal thyroglossal duct cyst. PMID- 26535821 TI - Comparison of SPECT/CT and planar MIBI in terms of operating time and cost in the surgical management of primary hyperparathyroidism. AB - We conducted a retrospective study to compare operating times and costs in patients who underwent guided parathyroidectomies with either (1) technetium-99m ((99m)Tc) multiplex ion-beam imaging (MIBI) parathyroid scintigraphy with single photon emission computed tomography/computed tomography (SPECT/CT) fusion images or (2) sestamibi dual-phase (99m)Tc MIBI planar parathyroid scintigraphy alone preoperatively. Our study population was made up of the first 24 patients at our facility who had undergone SPECT/CT parathyroid imaging with technetium-99m ((99m)Tc) MIBI and a group of 24 patients who had undergone MIBI planar imaging alone. Patient demographics, preoperative laboratory test results, operating times, and hospital charges were analyzed. We found that less operating time was required for the planar MIBI group than in the SPECT/CT group (mean: 135 vs. 158 min), although the difference was not statistically significant. Likewise, the total cost of treatment was lower in the planar MIBI group (mean: $10,035 vs. $11,592); the difference was statistically significant by one measure (p * 0.02, Wilcoxon rank sum test) but not by another (p * 0.06, Student t test). Although SPECT/CT is efficient for patients with small and difficult-to-localize adenomas, it has yet to demonstrate greater efficacy or cost-effectiveness than planar MIBI for routine parathyroidectomy in patients with primary hyperparathyroidism when an easily identifiable parathyroid adenoma is localized. PMID- 26535822 TI - Unusual primary tumors presenting as papillary carcinomas metastatic to the neck. AB - The presence of a metastatic papillary carcinoma in the neck is presumptive evidence of a primary thyroid neoplasm since neck metastases of other primary tumors are uncommon. Immunohistochemical studies may be required to diagnose these metastases. We report 2 cases in which an unrelated tumor mimicked a thyroid malignancy. Both patients had been referred for evaluation of enlarged lymph neck nodes without any other symptoms. In both cases, a lymph node biopsy identified a metastatic papillary adenocarcinoma that was believed to be consistent with a thyroid primary. Thyroidectomy was not performed in either case. Further investigations led to the diagnosis of other primary tumors that were unrelated to the thyroid; the unrelated primaries were an ovarian serous tumor in one patient and a papillary renal cell carcinoma in the other. PMID- 26535823 TI - Vascular malformation with phleboliths involving the parotid gland: A case report with a review of the literature. AB - Phleboliths within the parotid gland are exceedingly rare. We report a case of a venous malformation with multiple phleboliths that involved the left parotid gland and extended into the extraparotid tissue in a 43-year-old woman. We also review 13 similar cases that have been reported since 1948, and we highlight the significance of distinguishing phleboliths from sialoliths because management of the two can be entirely different. Phleboliths in and around the salivary glands primarily affect the parotid and submandibular glands in adult women. Patients can present with recurrent, intermittent swelling that may be associated with food intake and hyposalivation. Any sialolithiasis located outside of its most common location in the submandibular glands must be investigated thoroughly before surgery. PMID- 26535824 TI - Inferior turbinate augmentation with auricular cartilage for the treatment of empty nose syndrome. AB - Empty nose syndrome (ENS) is a potential complication of excessive resection of turbinate tissue. Patients with ENS complain of nasal obstruction despite a widely patent nasal cavity. Various implants, including autologous bone and biomaterials, have been used to reduce the width of the nasal cavity. Implantation of these grafts, however, has been limited by extrusion, infection, and resorption. We introduce a novel surgical technique that uses autologous auricular cartilage to augment the turbinate and to restore the natural airflow patterns of the nasal cavity. We present a representative case of ENS caused by excessive inferior turbinate reduction that was improved by turbinate augmentation with autologous auricular cartilage. PMID- 26535825 TI - Masseter flap for reconstruction of defects after excision of buccal mucosa cancers with intact mandible. AB - Among the reconstructive options available for buccal mucosa defects with an intact mandible, free flap with microvascular anastomosis is the best option. However, in the developing world, with poor resources, limited infrastructure, and high patient load, this cannot be offered to all patients. We report on the success of the masseter flap for reconstruction of such defects in carefully selected patients. Despite some known limitations, this flap is easy to learn and carries acceptable complications. The results of this flap may not be comparable to those of microvascular reconstructions, but they are better than those from other options such as skin graft, nasolabial flap, submental flap, etc., in terms of surgical time required, no donor site morbidity, and minimal aesthetic deformity. PMID- 26535826 TI - Laryngeal neuromas in a case of multiple endocrine neoplasia type 2B. AB - Mucosal neuromas of the larynx in the setting of multiple endocrine neoplasia type 2B (MEN-2B) are extremely rare; to the best of our knowledge, only 2 other cases have been previously reported in the world literature. We describe a new case, which occurred in a 30-year old woman who presented with dysphagia, dysphonia, and cough. On examination, she was found to have multiple laryngeal mucosal neuromas throughout the glottis and supraglottis. She underwent surgical resection of these lesions with resolution of her symptoms. PMID- 26535827 TI - Effects of different combinations of growth factors on the differentiation of neural stem cells into hair-like cells. AB - The differentiation of neural stem cells (NSCs) is influenced by a variety of factors. Therefore, it is important to explore the best external conditions that will induce NSCs to differentiate into hair cells. In this study, we investigated the best in vitro conditions for differentiation of NSCs derived from the hippocampus of newborn guinea pigs into hair-like cells. NSCs were separated and induced in different combinations of growth factors-in a control group and 7 combinations. Myosin VIIa-positive cells were detected to compare the effects of various combinations of growth factors on the differentiation of NSCs into hair like cells. NSCs were differentiated into hair-like cells in all groups, but cell growth was best in the basic fibroblast growth factor (bFGF) + epidermal growth factor (EGF) group and the bFGF + EGF + brain-derived neurotrophic factor (BDNF) group. The rates of myosin VIIa-positive cells in the 8 groups studied ranged from 13.53 to 22.71%, but the results in the bFGF+EGF and bFGF+EGF+BDNF groups had statistical significance compared with other groups (p < 0.05). While bFGF, EGF, and BDNF all can induce the differentiation of NSCs into hair-like cells, the synergies of bFGF+EGF and bFGF+EGF+BDNF are the best. PMID- 26535828 TI - An unusual presentation of a lingual dermoid cyst. AB - Dermoid cysts are rare lesions of the head and neck that usually present in children as an asymptomatic, slowly growing mass. We report a case that demonstrates that dermoid cysts can present later in life as a recurrent acute infection. Our patient was a 48-year-old man with a 22-year history of recurrent abscesses of the tongue and floor of the mouth that had required a tracheotomy and multiple hospitalizations. Magnetic resonance imaging performed between acute episodes revealed the presence of a 1.8-cm lesion within the tongue musculature. The patient underwent resection, and pathology was consistent with a lingual dermoid cyst. At 2 years of follow-up, he experienced no recurrence of symptoms. PMID- 26535829 TI - Noninvasive intraoperative angiography for reconstruction of head and neck defects. AB - Reconstruction of head and neck defects after cancer resection involves the use of local, pedicled musculocutaneous, and free flaps. Flap failure is often caused by vascular insufficiency, and it is associated with the presence of cardiovascular or peripheral vascular disease, a history of smoking, and previous radiation and/or surgery. Failure rates may be reduced by the use of indocyanine green near-infrared fluorescence laser angiography, which detects perfusion deficits intraoperatively. Although this technology has been validated in other fields, there is limited experience in the head and neck region. We present 3 cases in which different head and neck flaps were used along with this technology in patients at high risk for flap failure. All flaps were successfully implanted without perioperative or long-term complications. The increasing complexity, age, and comorbidities of the head and neck cancer population pose significant reconstructive challenges. This report demonstrates the feasibility of employing intraoperative angiography for local, pedicled, and free flaps. This noninvasive tool optimizes intraoperative planning and assesses viability, potentially lowering failure rates in high-risk patients. Identification of patients who most benefit from this technology warrants further investigation. PMID- 26535830 TI - Pitfalls in imaging the submandibular glands with PET/CT. AB - Imaging of the submandibular glands can provide vital information about malignant neoplastic processes. One of these modalities, fluorine-18 fluorodeoxyglucose positron-emission tomography/computed tomography (FDG-PET/CT), has become very important in the detection of malignancies because it provides functional and metabolic information as well as anatomic localization. However, there are several pitfalls associated with FDG-PET/CT in terms of salivary gland imaging. For example, a normal increase in the uptake of radiotracer might be mistaken for a neoplastic process. Other routine findings may include normal physiologic uptake in some structures, benign tumors and medical conditions, and iatrogenic abnormalities. We review a case in which compensatory hypertrophy of a submandibular gland was suspected to be a possible malignancy. PMID- 26535831 TI - Severe necrosis of the palate and nasal septum resulting from intranasal abuse of acetaminophen. AB - Intranasal drug abuse frequently leads to sinonasal complications, particularly sinus, nasal, and palatal necrosis. Classically, this type of necrosis has been linked to cocaine use, but the intranasal abuse of prescription narcotics and other pain medications can also lead to severe damage to the sinonasal tract. We describe a case of palatal and nasal septal necrosis resulting from intranasal acetaminophen abuse. The patient was a 34-year-old man with a remote history of polysubstance abuse who presented to the emergency department with worsening dysphagia and a recent history of exclusive intranasal acetaminophen abuse. He had an existing palatal fistula that was found to have dramatically increased in size. Examination revealed complete destruction of the soft palate and nasal septum and partial destruction of the hard palate. The areas of necrosis were surgically debrided. We describe the general clinical presentation and surgical outcome of this case. PMID- 26535832 TI - Extramedullary plasmacytoma associated with an ectopic tooth in the nasal cavity. AB - Extramedullary plasmacytoma and tooth eruption into the nasal cavity are both rare events. We report a case of plasmacytoma associated with an ectopic tooth. To the best of our knowledge, such a case has not been previously reported in the literature. A 63-year-old woman presented for evaluation of an 8-month history of a bloody nasal discharge from the posterior naris. Nasal endoscopy detected a slight eminence approximately 0.5 cm in diameter in the right nasal floor. Computed tomography demonstrated a tooth-like, high-attenuation shadow. A biopsy identified chronic inflammation of the mucosa and tissue. A diagnosis of an ectopic tooth in the right nasal cavity was initially considered. The mass and the tooth-like neoplasm were removed via nasal endoscopy. Immunohistochemistry of the excised mucosa showed strong positivity for kappa light chains, positivity for leukocyte common antigen and CD138, and negativity for lambda light chains, epithelial membrane antigen, CD1, and HMB-45. The final diagnosis was an extramedullary plasmacytoma in the right nasal cavity associated with an ectopic tooth. No bone metastasis was observed. Definitive radiotherapy was performed after the operation. During 40 months of follow-up, the patient exhibited no evidence of local recurrence or metastasis. The diagnosis in this case was made difficult by the nonspecific clinical manifestations, the presence of the ectopic tooth, and incorrect interpretation of preoperative histopathology. Physicians should maintain a clinical suspicion for the possibility that an ectopic tooth might be associated with a tumor. PMID- 26535833 TI - Chondroid chordoma of the sella turcica mimicking a pituitary adenoma. AB - We report an unusual case of a chondroid chordoma of the sella turcica that mimicked the clinical and radiologic presentation of the more common pituitary adenoma. A 50-year-old man presented with bitemporal visual field deficits. Magnetic resonance imaging (MRI) detected a sellar mass that was suggestive of a pituitary adenoma. However, the intraoperative appearance of the mass was not consistent with an adenoma, and frozen-section pathology was obtained. Pathology identified the mass as a malignant lesion. Based on this finding, the mass was treated more aggressively. Chondroid chordomas are rare and slowly growing but locally aggressive tumors. The prognosis depends on the ability to totally resect the mass, so differentiating this tumor from a benign lesion is critical. An intrasellar chordoma can be confused clinically and radiologically with a pituitary adenoma. These two lesions are nearly identical on MRI, although T2 weighted imaging sometimes demonstrates higher intensity with a chondroid chordoma. Computed tomography may be helpful in demonstrating bony destruction by these lesions, as can the presence of intralesional calcifications. Intraoperative findings of bony invasion or a purple-red color may also lead the surgeon to suspect a diagnosis other than pituitary adenoma. PMID- 26535834 TI - Letters to the Editor. PMID- 26535835 TI - Laryngeal tuberculosis: A public health concern. PMID- 26535836 TI - Laryngofissure for resection of a recurrent saccular cyst. PMID- 26535837 TI - A hyperpneumatized frontal sinus with middle meatal obstruction. PMID- 26535838 TI - An imaging study of the facial nerve canal in congenital aural atresia. AB - We conducted a prospective study to investigate the abnormalities of the facial nerve canal in patients with congenital aural atresia by computed tomography (CT). Our study population was made up of 99 patients--68 males and 31 females, aged 6 to 22 years (mean: 13.5)--who had unilateral congenital aural atresia without any inner ear malformations. We compared our findings in these patients with those in 50 controls-33 males and 17 females, aged 5 to 22 years (mean: 15.0)-who had normal ears. We classified the congenital aural atresia patients into three groups (A, B, and C) according to their Jahrsdoerfer grading scale score (>=8; 6 or 7; and <=5, respectively). The course of the facial nerve canal in both the controls and the study patients was determined by temporal bone CT with multiplanar reconstruction. The distances from different parts of the facial nerve canal to surrounding structures were also measured. The course of the facial nerve canal in the normal ears did not vary much, and there were no statistically significant differences according to head side and sex. In groups B and C, the tympanic segment, mastoid segment, and angle of the second genu of the facial nerve canal were all significantly smaller than those of the controls (p < 0.01 in all cases). Statistically, the tympanic segment of the facial nerve canal in patients with congenital aural atresia was downwardly displaced. The mastoid segment of the facial nerve canal in these patients was more anterior than that of the controls. We conclude that congenital aural atresia is often accompanied by abnormalities of the facial nerve canal, especially in the tympanic segment, the mastoid segment, and the second genu. We found that the lower the Jahrsdoerfer score was, the shorter the tympanic segment was and the more forward the mastoid segment was. PMID- 26535839 TI - Masters in Collective Health: pathway of challenges and possibilities. PMID- 26535840 TI - Work in the Healthcare Field: Artisanal or Industrial Models? AB - This text analyzes work within the health field and the differences and similarities with artisanal and industrial work models. In this framework, we consider the object of work, the worker, the work process, relational and organizational aspects, industrial logics, and ways of acquiring knowledge, influence of the general management theory, the role of language, symbolic aspects and enjoyment. The humanizing elements that care work maintains as a type of artisanal work are highlighted, and the costs, not just economic, of reducing care work to industrial logics, with a subsequent depersonalization of the process not just for the worker but also for the user, health teams, health institutions, and social groups are discussed. PMID- 26535841 TI - Production of Knowledge in the Master' Program in Collective Health of the Faculty of Nursing at Universidad de Antioquia, 1996-2013. AB - OBJECTIVE: This work sought to characterize the scientific production of the degree works in the Master' in Collective Health (MCH) of the Faculty of Nursing at Universidad de Antioquia, during the period from 1996 to 2013. METHODOLOGY: Ours was a descriptive, observational study, based on documentary research and content analysis. The work analyzed the degree works presented in the MCH since 1996 until 2013, reported in the library of the Faculty of Nursing, and the scientific articles published. These were reviewed manually using an instrument containing the variables of the characteristics of the works and articles. RESULTS: Some 51 degree works were included, corresponding to eight cohorts from the Master' in which 65 master' students have graduated and 61 professors have participated as counselors. The most common themes have been Gender and Health (27%) and Food and Nutrition Safety (16%). The most frequent populations object of study were women (14%) and population groups and/or community (14%). The methodologies used have been 90.2% qualitative, 3.9% quantitative, and 5.9% mixed. A total of 52.9% of the degree works were published as articles in scientific journals; of these, 46.49% corresponded to A2 journals, according to the classification by COLCIENCIAS. CONCLUSION: The characteristics of the degree works show increased dissemination in scientific journals, as well as diversification in the populations object of study and progress in the dissemination of the knowledge generated in the MCH, thus, contributing to progress in collective health in national and international settings. PMID- 26535842 TI - Violence against women: perceptions of nursing students' about the focus on the formation. AB - OBJECTIVE: Get to know the nursing undergraduates perception, from a public university in southern Brazil, on the inclusion of the theme violence against women in the curriculum and about that thematic approach during graduation. METHODOLOGY: Descriptive exploratory qualitative research, made with 18 students of Nursing Graduation in Federal de Santa Maria University. Semi-structured interview was made and its data was submitted to thematic analysis. RESULTS: From the undergraduates understanding, the theme integrates the curricular content in a punctual way and a reduced workload. There were found difficulties in the violence' identification and the actions to be developed. The participants suggest that the theme should be worked since the graduation' beginning, permeating the learning in collective health. CONCLUSION: The study shows the need to include violence as a transversal theme in curriculums in graduation courses of Nursing and Health. PMID- 26535843 TI - Gender Differences in the Interpretation of Experiences of Patients with Tuberculosis in Medellin, Colombia. AB - OBJECTIVE: This study sought to determine gender differences in the interpretation of tuberculosis (TB) in a group of patients from the city of Medellin. METHODOLOGY: This was a qualitative study, with the grounded theory method. Twelve semistructured interviews were applied to patients from both genders who were cured of TB. The sample was selected through convenience and for analysis the information was categorized through the Atlas Ti tool. RESULTS: Regarding the symptoms, the most reported is cough, but men manifest expectoration more frequently. Men overstated the symptoms, while women tend to minimize them. Women report mental impairment and emotional-type manifestations produced by the disease. Men and women expressed ignorance about the disease upon diagnosis. Both manifested fear of infection, work incapacity, loss of employment, rejection by others, and death. Also highlighted is the importance of family support and of the healthcare personnel. Women expressed shame in that others knew of their disease and mentioned greater intolerance with taking the medications. CONCLUSION: The gender role constructed culturally constitutes the central axis that explains how men and women interpret TB and can be modified by educational and accompaniment processes. Family support plays an important role in the healing process. Although common aspects exist, delving into the gender differences against the interpretation of TB may permit a different approach of the disease and better control of it. PMID- 26535844 TI - Experience of men in the context of Primary Health Care. AB - OBJECTIVES: To know the experience of male users' in the primary health care and to build data based theory that represents this experience. METHODOLOGY: This is a qualitative study, in which was used the reference of Grounded Theory and Symbolic Interactionism, respectively, methodological and theoretical. We interviewed 33 male users of three units of primary health care. RESULTS: After comparative analysis of data was built the data based theory feeling excluded, which includes: living with prejudice; living with the limitations of infra structure services; reflecting on the health service environment. The analysis showed the need for a change in logistics services and professionals' attitude guided in respectful and effective communication, the problem solving in readiness in attendance, in addressing gender issues. CONCLUSION: For to take care of men users of the Unified Health System and/or preserve their health, the construction of another rationality in health is imperative, based on reflection and respect for the autonomy and individuality of the male gender. PMID- 26535845 TI - Integrality: life principle and right to health. AB - OBJECTIVE: To understand the health integrality in the daily work of Family Health Strategy (FHS) and its concept according to the managers in Jequitinhonha Valley, Minas Gerais, Brazil. METHODOLOGY: This is a multiple case study of holistic and qualitative approach based on the Quotidian Comprehensive Sociology. The subjects were workers of the Family Health Strategy teams, the support team and managers in a total of 48. RESULTS: The results show the integrality as a principle of life and right to health and to contemplate it in the quotidian of doings in health, others principles of the Unified Health System may be addressed consecutively. The universal right to health care needs is declared in contemplation of integrity of being, the idealization of a subject-centered care, one that is our aim in health care, which signals a step towards a change of attitude in seeking comprehensive care. CONCLUSION: It is considered that the principle of integrality is a difficult accomplishment in its dimensions. PMID- 26535846 TI - Social determination of the oral health-disease process: a social-historical approach in four Latin American countries. AB - OBJECTIVE: This study sought to contrast the perspectives on the social determination of oral health present in the scientific literature published in Colombia, Brazil, Ecuador, and Mexico since 1970 until 2012. METHODOLOGY: This was a cross-sectional descriptive study on the Latin American scientific production published in specialized databases between 1970 and 2012. RESULTS: The social determination of oral health in Latin America is characterized by the conflict among the players when seeking to overcome the limitations and traditional perspectives in health. The differences among the countries studied are explained by the existing relationship among research, higher education, and the socio-political trajectories of the countries and the similarities by health systems that have permitted accumulation of inequities in health. In Brazil, the concern for the individual and collective in local settings is important, while in Ecuador, Mexico, and Colombia the explanation based on the social determinants of the diseases predominates. CONCLUSION: The view of the social determination of the oral health-disease process in Latin America is characterized by a continuous dispute between emancipation and accumulation approaches. The scant impact of social determination in oral health obeys to the history of the odontology profession, the predominance of care policies and services of technical care nature. PMID- 26535847 TI - Health profile of freedom-deprived men in the prison system. AB - OBJECTIVE: To understand the needs and health profile of men incarcerated in the Pau dos Ferros Regional Criminal Complex (Rio Grande do Norte, Brazil). METHODOLOGY: Quanti-qualitative research conducted with 30 men incarcerated in November 2012. Semi-structured interviews were the primary data collection method. Descriptive statistics and thematic analysis of the speeches were used for data analysis. RESULTS: The participants' health profile, resulting from deficits in living conditions prior to their imprisonment, is heightened by the degrading conditions of their prison stay, and plays a role in their exclusion and lack of care when admitted as prisoners. The disorders and symptoms most often self-reported by participants were: headache (86.6%), respiratory infections (66.6%), diarrhea (60.0%), stress (60.0%), and depression or deep sadness (56.6%). The responses showed that there is a social gap, especially related to health care, in the prison complex. CONCLUSION: We recognize a need to ensure the physical and moral integrity of inmates, which is compromised by life in prison; the inmates' health problems and needs differ from those of the general population, and require solutions; the inmates' health-disease process deteriorates due to the mere situation of entering the prison system; the inmates' health problems and health needs are treated with palliative and / or no assistance by those legally responsible for their protection; few human and financial resources exist to ensure health actions for the inmates; and there are no interventions or actions of disease prevention and health promotion. PMID- 26535848 TI - The school health program: teachers' perceptions. AB - OBJECTIVE: Understand teachers' perception of a school health program and its relationship with health education activities developed at school. METHODOLOGY: Descriptive qualitative study, in which interviews with 10 teachers at a public school in the city of Barbalha, Ceara, Brazil were conducted. Data were analyzed in thematic categories. RESULTS: Teachers perceived the School Health Program as welfare, without integration between teachers and health professionals, and being of no interest to teenagers. Educational activities at school and their relationship to the program were perceived as clinical evaluations that were not integrated into the actions already developed at school. CONCLUSION: A weakness was found in the lack of integration of actions performed by different agents. Therefore, there is a need for a closer relationship between them in order to optimize efforts to promote school health. PMID- 26535849 TI - "Not worth doing prenatal care": an ethnographic study of a low-income community. AB - OBJECTIVE: The aim of this study was to explore the reasons why pregnant women do not seek prenatal care (PNC). METHODOLOGY: The ethnographic method was used in a low-income Brazilian community. Ethnographic interviews were performed with 11 postpartum women who did not seek PNC in their last pregnancy. RESULTS: The cultural sub-themes used to express reasons for not seeking PNC included: "I found out I was pregnant too late and did not have enough time to receive PNC," "I did not receive PNC because I had to hide the pregnancy to avoid problems," "I had to address urgent issues and could not seek PNC," "The services are not good and going to the doctor when not ill is only for rich people," and cultural theme: "PNC is not worth pursuing: it is unnecessary and there are too many obstacles to receiving it." CONCLUSION: The main strategies that should be considered to increase adherence to PNC are better access and integrality through the use of adequate management criteria. PMID- 26535850 TI - Nursing care of patients during the dying process: a painful professional and human function. AB - OBJECTIVE: This work sought to describe the care functions of nurses with patients during the dying process. METHODOLOGY: This was a qualitative study with ethnographic approach stemming from the analysis of the culture of nurses; it was conducted in the city of Medellin, Colombia. Theoretical saturation was obtained with 23 interviews. RESULTS: Nurses feel the duty to care for patients throughout the vital cycle through functions defined as: serving, helping, accompanying, offering support, advocating, educating, and representing, which they identify as indispensable. They also perceive as their own the social responsibility for some issues related to death and due to this they get involved at the personal level, appropriate care and are affected as persons. CONCLUSION: Patient care during dying processes transcends the limits of the nurse' professional functions to become a human obligation. PMID- 26535851 TI - The experience of nursing students facing death and dying. AB - OBJECTIVE: To understand the phenomenon experienced by nursing students in their academic practices in view of death and dying. METHODOLOGY: This was a qualitative study, based on Martin Heidegger' existential phenomenology, undertaken at a public University in Alagoas, Brazil, between August and October 2013. Seven senior students of nursing were interviewed. RESULTS: The phenomenological analysis yielded the following existential themes: Facing death and dying in academic practice; Acknowledging impotence in the face of death; Glimpsing the possibility of solicitude; Interacting with the family in view of the loss; Experiencing spirituality in the face of dying. CONCLUSION: It is deduced that, during the academic education, the theme involving death and dying has been addressed insufficiently, without precisely attending to all the demands of the nursing students during care in the dying process. PMID- 26535852 TI - Risk factors for cardiovascular diseases in adolescents. AB - OBJECTIVE: Identify risk factors for cardiovascular disease in adolescents. METHODOLOGY: Descriptive cross-sectional study, conducted from May to September 2012, in the public schools of the city of Picos (Piaui State, Brazil). The sample consisted of 320 adolescents 10-19 years. RESULTS: As to gender, 60% were female. With regard to blood pressure values, 15.3% of participants had altered blood pressure values (6.9% with hypertension) and, in relation to nutritional status, 15.6% were overweight and 5.3% obese. None of the variables showed statistically significant differences according to sex. Correlation were found between the variables: family history of hypertension with arm circumference and triceps skinfold; maternal education with triceps skinfold thickness and diastolic blood pressure; uptime with body mass index, arm circumference, waist hip ratio and heart rate; birth weight with body mass index and arm circumference. CONCLUSION: A significant proportion of adolescent respondents had risk factors for cardiovascular disease. Nursing should lead the adoption of interventions that promote the improvement of healthy lifestyle in adolescence, thus avoiding not only cardiovascular disease, but also other chronic diseases that can develop. PMID- 26535853 TI - Metabolic syndrome prevalence in elderly of urban and rural communities participants in the HIPERDIA in the city of Coimbra/MG, Brazil. AB - OBJECTIVE: To identify the prevalence of metabolic syndrome (MS), and the influence of gender and place of residence for elders served by the Family Health Strategy in the municipality of Coimbra (Minas Gerais state, Brazil). METHODOLOGY: The sample consisted of 435 individuals of both sexes, with mean of age 72 +/- 8 years. RESULTS: Women had higher prevalence rates of MS (urban= 40%, rural= 37%) with differences (p<0.05, = 0.168 and 0.284) for men (urban= 13%, rural= 22%). Odds Ratio for SM was significant in age groups over 65 years in urban areas, with women having higher chances compared with men (OR=3.07 times), becoming 5.8 times aged 75 to 79 years. Women are more exposed to obesity (urban= 80.4 %, rural= 78.6%) than men, regardless of place of residence (p<0.05, =0.46 and 0.47 respectively), and the urban women are still exposed to hypertension (65%, p= 0.022, = 0.12). CONCLUSION: The prevalence of MS and exposure to risk factors such as obesity and hypertension was higher in women, mainly in urban areas. Health professionals, like nurses, should note that the elderly population in urban areas have greater exposure to risk factors for MS, which should strengthen educational programs that promote healthy lifestyles. PMID- 26535854 TI - Nursing students attitudes across the suicidal behavior. AB - OBJECTIVE: Examine the attitudes of nursing students with the suicidal behavior before and after a training course on the subject. METHODOLOGY: Performed quantitative, cross-sectional study, with 58 nursing students from a public university in Minas Gerais (Brazil) who participated in training on the theme. For data collection were used the Questionnaire of Attitudes Before Suicidal Behavior. The questionnaire was applied just before the start and the end of the training measuring attitudes toward suicidal behavior. RESULTS: Were found statistically significant differences in negative feelings factors on the patient and perception of professional competence (p <0.05). The right factor to suicide was not significantly different among nursing students. CONCLUSION: The academic training may have influenced positively the desired changes regarding the attitudes of nursing students across the suicidal behavior. PMID- 26535855 TI - Quality of life of children and adolescents with cancer: revision of studies literature that used the Pediatric Quality Of Life Inventory. AB - OBJECTIVE: To assess the quality of life of children and adolescents with cancer of studies that applied the Pediatric Quality of Life Inventory 3.0 Cancer Module. METHODOLOGY: The study was carried out on the basis of data Scopus Web of Science, BIREME, EBSCO host and Psychoinfo of articles in Spanish, English and Portuguese, and published from 1998 to 2013 that used the Pediatric Quality of life Inventory 3.0 Cancer Module. RESULTS: 21 articles were selected, of which 47.6% were carried out in America, and 61.9% of editions comprehended from 2011 to 2013. The scores variation by dimensions and in general was probably related for the selection of comparison groups, as the diversity of inclusion criteria and variants may be observed for the analysis in each study. The existence of a standard dimension could not be verified either for children s /adolescents reports or for parents. CONCLUSION: It is concluded that the scores averages by dimensions in general have not achieved values below 30 and the largest scores by dimension are above 80. It is suggested that the treatment anxiety dimension in children s and adolescents s reports may have obtained the largest scores within each study, that is lesser than the difficulty of the children and adolescents in face of the treatment and cancer. Nursing becomes a constant presence in the life of children and adolescents with cancer and it may provide a better quality of life for developing nursing activities and the team may demistify, clarify and help in all phases of the illness and treatment. PMID- 26535856 TI - Sexual debut in young adults in Cali as transition: keys for care. AB - OBJECTIVES: This work sought to understand sexual debut as a transitional process in the lives of a group of young adults and to interpret the meaning of this transition for them. METHODOLOGY: This was a qualitative research with 18 life stories of students from different socio-economic backgrounds and with diverse sexual orientations. RESULTS: According to the middle-range theory of transitions, sexual debut can be considered a developmental transition. The initiative can be their own, motivated by desire, or coerced by pressure from a partner or peers in which case underlay power relations either by age or hierarchy. Its features are shaped by the individual's abilities, knowledge, and uncertainties, as much as by the circumstances surrounding the event and the socio-cultural precepts towards the topic. It is valued as a healthy transitional process when it is agreed upon by both members of the couple, planned and flows into symmetrical relations. CONCLUSION: The theory of transitions and analysis of the context are useful in understanding the phenomenon because the subjective experience is framed within normative, appreciative, and socio-cultural constructions. Nursing, as discipline, requires elements like those provided by this research to interpret the dynamics, meanings, as well as subjective and social processes in the sexual evolution of people in different contexts and historical moments. PMID- 26535857 TI - Episiotomy: perceptions from adolescent puerperae. AB - OBJECTIVE: To identify the perception of the teenager puerperas regarding the practice of episiotomy. METHODOLOGY: This is a study with qualitative nature developed with 11 teenage puerperas in the Obstetrics Unit of one hospital located in the metropolitan region of Sao Paulo, Brazil. RESULTS: Teens knew of the existence of episiotomy, but they unaware the reasons for its realization. Pain, discomfort and burning were negative repercussions presented, but most of them believe that assisted procedure in their delivery showing confidence in the professional who carried it out. CONCLUSION: Adolescents have different perceptions on the practice of the episiotomy, ranging from resignation to outrage. PMID- 26535858 TI - Historic perspectives from anthropology. Reflections proposed to Transcultural Nursing. AB - History brings together meanings related to earlier periods, being aware of the past as a panorama to reread the present. Madeleine Leininger presented in 1970 an implicit and respectful message to the Nursing Profession when introducing Nursing and Anthropology. Two Worlds to Blend. Implicitly: Nursing you disregard culture. This article shows the absence of the history of anthropology and of nursing within Transcultural Nursing and it includes how education has influenced theoretic, methodological, and comparative approaches giving researchers the responsibility to decide their fundamentals. Berthoud (2001) has inspired the anthropological and historic perspectives of the author, thus universalism, relativism, and comparison are presented. PMID- 26535860 TI - Erratum. PMID- 26535859 TI - Pathological Changes Associated with Eggs and Larvae of Unionicola sp. (Acari: Unionicolidae) Infecting Strophitus connasaugaensis (Bivalvia: Unionidae) from Alabama Creeks. AB - We detail gross and histopathological changes associated with infection by the eggs, larvae, and cuticular remnants of Unionicola sp. in the mantle, gill, and visceral mass of 25 Alabama creekmussels, Strophitus connasaugaensis, collected during May 2010 through July 2012 from 2 Alabama streams. A multitude (estimated mean intensity >100) of mite eggs and larvae typically infected mantle, gill, and visceral mass integument. Pathology associated with eggs (prevalence = 0.57) and larvae (prevalence = 0.39) typically consisted of localized distension of the infection site; a host response to these infections was indeterminate. However, larval mites embedded in suprabranchial connective tissues were typically encapsulated (prevalence = 0.89). Mite remnants (prevalence = 0.5) occurred in mantle, gill, visceral mass integument, foot, heart, pericardial gland, intestinal lamina propria, and were typically encapsulated. We speculate that S. connasaugaensis clears some infections but is recolonized by autoinfection or horizontal dispersal of mites in the stream. Noteworthy is that high-intensity infections seemingly do not markedly impact the histological picture of mussel tissues, indicating that mites are relatively benign symbionts that are of little concern to mussels under normal environmental conditions. PMID- 26535861 TI - Alternative Framings, Countervailing Visions: Locating the "P" in Professional Identity Formation. AB - Professional identity formation in medical education is referenced increasingly as an object for educational reform. The authors introduce core concepts from two largely untapped literatures on identity and formation, contrasting framings on occupational preparation from within the organizational socialization literature with issues of socialization and professional acculturation from a military sciences perspective.The organizational sciences literature emphasizes socializing a workforce to "fit in," raising questions about how organization values might clash with core professional values concerning patient primary and social justice. The military literature, in turn, advances the notions of professional identity as a collective property, and that a particular social other (the public) must participate in shaping the group's identity as a profession.The authors extrapolate from these reviews that the training of physicians-as-professionals, and thus issues of socialization and identity formation, require intentionality and specificity around these contrasting issues. In turn, they argue that medical educators must attend to socializing trainees to a professional group identity while at the same time producing health care professionals who retain the capacity to resist the bureaucratic application of standardized solutions to contemporary problems. Educators must thus strive to identify the skills, knowledge, and attitudes necessary that will allow physicians-qua-professionals to function as a quasi-subversive work force and to disrupt the very system that helped to shape their identity, so that they may fulfill their mission to their patients. PMID- 26535862 TI - Comparing Open-Book and Closed-Book Examinations: A Systematic Review. AB - PURPOSE: To compare the relative utility of open-book examinations (OBEs) and closed-book examinations (CBEs) given the rapid expansion and accessibility of knowledge. METHOD: A systematic review of peer-reviewed articles retrieved from MEDLINE, ERIC, Embase, and PsycINFO (through June 2013). In 2013-2014, articles that met inclusion criteria were reviewed by at least two investigators and coded for six outcome categories: (1) examination preparation, (2) test anxiety, (3) exam performance, (4) psychometrics and logistics, (5) testing effects, and (6) public perception. RESULTS: From 4,192 identified studies, 37 were included. The level of learner and subject studied varied. The frequency of each outcome category was as follows: (1) exam preparation (n = 20; 54%); (2) test anxiety (n = 14; 38%); (3) exam performance (n = 30; 81%); (4) psychometrics and logistics (n = 5; 14%); (5) testing effects (n = 24; 65%); and (6) public perception (n = 5; 14%). Preexamination outcome findings were equivocal, but students may prepare more extensively for CBEs. For during-examination outcomes, examinees appear to take longer to complete OBEs. Studies addressing examination performance favored CBE, particularly when preparation for CBE was greater than for OBE. Postexamination outcomes suggest little difference in testing effects or public perception. CONCLUSIONS: Given the data available, there does not appear to be sufficient evidence for exclusively using CBE or OBE. As such, a combined approach could become a more significant part of testing protocols as licensing bodies seek ways to assess competencies other than the maintenance of medical knowledge. PMID- 26535863 TI - Development of a Health Professions Education Research-Specific Institutional Review Board Template. AB - PROBLEM: Health professions education (HPE) has become a core component of the mission of academic health centers (AHCs) nationwide. The volume of HPE research projects being reviewed has increased, presenting new challenges for institutional review boards (IRBs). As HPE research becomes increasingly sophisticated in its design and methods, IRBs and researchers alike have a duty to better understand its unique characteristics. Researchers must be better able to conceptualize and describe their research to IRBs, and IRBs should be able to provide timely review and assure protection of research subjects (or participants). APPROACH: The creation of HPE research-specific IRB templates may be one way to improve the interactions between education researchers and IRBs. This report describes the development and early implementation of an HPE research specific IRB template at Duke University from 2013 to 2014. OUTCOMES: Early adopters have noted increased ease of preparation and submission, while IRB staff have reported improved proposal clarity and more attention to protecting learners as research participants. Focus during educational or training sessions about the new template has shifted-from merely a description of the new submission process to a more comprehensive education series that includes discussion of regulatory definitions, examination of case studies, and opportunity for audience feedback. NEXT STEPS: Continued collection of quantitative and qualitative data regarding the implementation of this IRB template will help its developers more precisely describe its effects on HPE research projects. Formalizing and streamlining the interactions between HPE researchers and IRBs is an important goal for all AHCs. PMID- 26535864 TI - The Effects of Resident Peer- and Self-Chart Review on Outpatient Laboratory Result Follow-up. AB - PURPOSE: Performing and teaching appropriate follow-up of outpatient laboratory results (LRs) is a challenge. The authors tested peer-review among residents as a potentially valuable intervention. METHOD: Investigators assigned residents to perform self-review (n = 27), peer-review (n = 21), or self- + peer-review (n = 30) of outpatient charts. They also compared residence performance with that of historical controls (n = 20). In September 2012, residents examined 10 LRs from April 2012 onward. A second review in November 2012 ascertained whether performing chart review improved residents' practice behaviors. RESULTS: Initially, the least-square (LS) mean number of LRs without documentation of follow-up per resident in the self-, peer-, and self- + peer-review group was, respectively, 0.5 (SD 1.0), 1.0 (SD 1.7), and 0.9 (SD 1.3), and post intervention, this was 1.0 (SD 0.2), 0.3 (SD 0.2), and 0.6 (SD 0.2) (self- versus peer-review P = .03). Initially the LS mean follow-up time per resident in the self-, peer-, and self- + peer-review group was, respectively, 4.2 (SD 1.2), 6.9 (SD 1.4), and 5.9 (SD 1.2) days, and after the intervention, LS mean time was 5.0 (SD 0.5), 2.5 (SD 0.6), and 3.9 (SD 0.5) days (self- versus peer-review P < .01). Self-review was not associated with significant improvements in practice. CONCLUSIONS: In this comparison of self- and peer-review, only residents who performed peer-review demonstrated significant improvements in their documentation practices. These findings support the use of resident peer-review in improving LR follow-up, and potentially, in other, broader resident quality improvement initiatives. PMID- 26535865 TI - AM Last Page. Health Professions Education Must Change: What Educators Need to Know about the Changing Clinical Context. PMID- 26535866 TI - Leveraging Trainees to Improve Quality and Safety at the Point of Care: Three Models for Engagement. AB - Trainees, as frontline providers who are acutely aware of quality improvement (QI) opportunities and patient safety (PS) issues, are key partners in achieving institutional quality and safety goals. However, as academic medical centers accelerate their initiatives to prioritize QI and PS, trainees have not always been engaged in these efforts. This article describes the development of an organizing framework with three suggested models of varying scopes and time horizons to effectively involve trainees in the quality and safety work of their training institutions. The proposed models, which were developed through a literature review, expert interviews with key stakeholders, and iterative testing, are (1) short-term, team-based, rapid-cycle initiatives; (2) medium term, unit-based initiatives; and (3) long-term, health-system-wide initiatives. For each, the authors describe the objective, scope, duration, role of faculty leaders, steps for implementation in the clinical setting, pros and cons, and examples in the clinical setting. There are many barriers to designing the ideal training environments that fully engage trainees in QI/PS efforts, including lack of protected time for faculty mentors, time restrictions due to rotation-based training, and structural challenges. However, one of the most promising strategies for overcoming these barriers is integrating QI/PS principles into routine clinical care. These models provide opportunities for trainees to successfully learn and apply quality and safety principles to routine clinical care at the team, unit, and system level. PMID- 26535867 TI - Academic Medical Centers Forming Accountable Care Organizations and Partnering With Community Providers: The Experience of the Johns Hopkins Medicine Alliance for Patients. AB - Academic medical centers (AMCs)--which include teaching hospital(s) and additional care delivery entities--that form accountable care organizations (ACOs) must decide whether to partner with other provider entities, such as community practices. Indeed, 67% (33/49) of AMC ACOs through the Medicare Shared Savings Program through 2014 are believed to include an outside community practice. There are opportunities for both the AMC and the community partners in pursuing such relationships, including possible alignment around shared goals and adding ACO beneficiaries. To create the Johns Hopkins Medicine Alliance for Patients (JMAP), in January 2014, Johns Hopkins Medicine chose to partner with two community primary care groups and one cardiology practice to support clinical integration while adding approximately 60 providers and 5,000 Medicare beneficiaries. The principal initial interventions within JMAP included care coordination for high-risk beneficiaries and later, in 2014, generating dashboards of ACO quality measures to facilitate quality improvement and early efforts at incorporating clinical pathways and Choosing Wisely recommendations. Additional interventions began in 2015.The principal initial challenges JMAP faced were data integration, generation of quality measure reports among disparate electronic medical records, receiving and then analyzing claims data, and seeking to achieve provider engagement; all these affected timely deployment of the early interventions. JMAP also created three regional advisory councils as a forum promoting engagement of local leadership. Network strategies among AMCs, including adding community practices in a nonemployment model, will continue to require thoughtful strategic planning and a keen understanding of local context. PMID- 26535868 TI - Institutional Conflict of Interest Policies at U.S. Academic Research Institutions. AB - PURPOSE: Institutional conflicts of interest (ICOIs) occur when the institution or leaders with authority to act on behalf of the institution have conflicts of interest (COIs) that may threaten the objectivity, integrity, or trustworthiness of research because they could impact institutional decision making. The purpose of this study was to gather and analyze information about the ICOI policies of the top 100 U.S. academic research institutions, ranked according to total research funding. METHOD: From May-June 2014, the authors attempted to obtain ICOI policy information for the top 100 U.S. academic research institutions from publicly available Web sites or via e-mail inquiry. If an ICOI policy was not found, the institutions' online COI policies were examined. Data on each institution's total research funding, national funding rank, public versus private status, and involvement in clinical research were collected. The authors developed a coding system for categorizing the ICOI policies and used it to code the policies for nine items. Interrater agreement and P values were assessed. RESULTS: Only 28/100 (28.0%) institutions had an ICOI policy. ICOI policies varied among the 28 institutions. Having an ICOI policy was positively associated with total research funding and national funding ranking but not with public versus private status or involvement in clinical research. CONCLUSIONS: Although most U.S. medical schools have policies that address ICOIs, most of the top academic research institutions do not. Federal regulation and guidance may be necessary to encourage institutions to adopt ICOI policies and establish a standard form of ICOI review. PMID- 26535869 TI - Fecal Calprotectin Measured By Patients at Home Using Smartphones--A New Clinical Tool in Monitoring Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Fecal calprotectin is a reliable noninvasive marker for intestinal inflammation usable for monitoring patients with inflammatory bowel disease. Tests are usually performed by enzyme-linked immunosorbent assay (ELISA), which is time consuming and delays results, thus limiting its use in clinical practice. Our aim was to evaluate CalproSmart, a new rapid test for fecal calprotectin performed by patients themselves at home, and compare it to gold standard ELISA. METHODS: A total of 221 patients with inflammatory bowel disease (115 ulcerative colitis and 106 Crohn's disease) were included. The CalproSmart test involves extraction of feces, application to the lateral flow device, and taking a picture with a smartphone after 10 minutes of incubation. Results appear on the screen within seconds. Patients were instructed at inclusion and had a video guide of the procedure as support. When using CalproSmart at home, patients also sent in 2 fecal samples to be analyzed by ELISA. RESULTS: Totally, 894 fecal calprotectin results were obtained by ELISA, and 632 of them from CalproSmart. The correlation coefficient was 0.685, higher for academics than nonacademics (0.768 versus 0.637; P = 0.0037). The intra-assay and interassay coefficients of variation of the CalproSmart test were 4.42% and 12.49%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value were 82%, 85%, 47%, and 97%, respectively, with an optimal cutoff at 150 MUg/g. CONCLUSIONS: The CalproSmart test performed by patients with inflammatory bowel disease for fast assessment of gut inflammation seems a reliable alternative to ELISA and presents a new way of monitoring patients by eHealth. PMID- 26535870 TI - Probing the Association of Pancreatitis in Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) has been increasingly diagnosed in children and adults. Similarly, acute and chronic pancreatitis are increasingly prevalent conditions with potentially devastating consequences. There is a growing body of literature linking these 2 conditions. The purpose of this review is to provide a comprehensive outline of the association between IBD and pancreatitis and to explore their putative pathophysiology. Based on the collective reports, 2 outstanding reasons for pancreatitis in patients with IBD are medications and IBD complications. PMID- 26535871 TI - Long-Term Outcomes after Imatinib Mesylate Discontinuation in Chronic Myeloid Leukemia Patients with Undetectable Minimal Residual Disease. AB - BACKGROUND: Imatinib mesylate (IM) discontinuation is under active investigation in chronic myeloid leukemia-chronic phase (CML-CP) patients with undetectable minimal residual disease (UMRD). However, limited data exist on the long-term outcomes following IM discontinuation in patients treated with frontline IM therapy. METHODS: We consecutively enrolled patients with CML-CP who discontinued IM after achieving UMRD for >=12 months between June 2009 and January 2013. RESULTS: Nineteen patients (8 male, 11 female) were included. After IM discontinuation, 14 patients (74%) lost UMRD after a median of 4.0 months. Of the 14 patients with molecular relapses, 12 (86%) relapsed within the first 9 months after IM discontinuation and 2 (14%) relapsed at 20.5 and 22.8 months, respectively. No molecular relapse was observed after 2 years of IM discontinuation. With a median follow-up of 58.1 months (range 23.0-66.5), the estimated UMRD persistence rate at 5 years was 23.7%. IM was readministered in all patients with molecular relapse, and 12 patients (86%) reachieved UMRD at a median of 5.3 months. A high-risk Sokal score, delayed UMRD achievement and short term IM therapy were significantly associated with molecular relapse. CONCLUSION: These findings suggest that IM discontinuation in patients who achieved UMRD after frontline IM therapy resulted in favorable long-term outcomes in terms of safety and feasibility. PMID- 26535872 TI - Acute Effects of Vitamin D3 Supplementation on Muscle Strength in Judoka Athletes: A Randomized Placebo-Controlled, Double-Blind Trial. AB - OBJECTIVE: Indoor athletes have been shown to be prone to vitamin D3 deficiency. The aim of the study was to examine the acute effects of vitamin D supplementation on muscle function using isokinetic dynamometry. DESIGN: Randomized placebo-controlled, double-blind study. SETTING: Institutional. PARTICIPANTS: Adult male white national level judoka athletes (n = 22) who were involved in full-time training. Exclusion criteria were vitamin supplementation, overseas travel to sunny climes, and/or an injury incurred during the last 3 months before testing. INTERVENTIONS: Subjects were randomly allocated to the treatment (150 000IU vitamin D3) or placebo and given blinded supplements by an independent researcher. Participants were tested twice, 8 days apart, on a Monday morning before the start of judo training and after 2 days of rest. A 5 to 7 mL of blood sample was collected followed by isokinetic concentric quadriceps and hamstring muscle function assessments on the right leg at 30 and 200 degrees .s. MAIN OUTCOME MEASURES: Repeated-measures analysis of variance was used to analyze isokinetic muscle force and serum 25(OH)D3. Regression to the mean was used to examine changes in 25(OH)D3 levels over the study period. RESULTS: The treatment group demonstrated a significant increase in serum 25(OH)D levels (34%, P <= 0.001) and muscle strength (13%, P = 0.01) between days 1 and 8. No significant differences were found for the placebo group for the same period. CONCLUSIONS: A single bolus of 150 000IU vitamin D3 had a significant positive effect on serum 25(OH)D levels and muscle function in vitamin D insufficient elite indoor athletes. CLINICAL RELEVANCE: Serum 25(OH)D3 levels of indoor athletes should be monitored throughout the year and especially during winter months. Beneficial responses, in muscle strength and serum 25(OH)D3, to 1 dose of vitamin D3 supplementation can be observed within 1 week of ingestion. Muscle strength is linked to serum 25(OH)D levels. PMID- 26535873 TI - Fetal Diagnosis of Rhombencephalosynapsis. PMID- 26535874 TI - Prof. Jean Francois Marie Aicardi (1926-2015). PMID- 26535875 TI - Prof. Bengt Hagberg (1923-2015). PMID- 26535876 TI - Intrathecal Anti-GalC Antibodies in Bickerstaff Brain Stem Encephalitis. PMID- 26535877 TI - Early-Onset Severe Encephalopathy with Epilepsy: The BRAT1 Gene Should Be Added to the List of Causes. AB - A variety of pathologies can underlie early-onset severe encephalopathy with epilepsy. To aid the diagnostic process in such patients we present an overview of causes, including the rapidly expanding list of genes involved. When no explanation is found, whole-exome sequencing (WES) can be used in an attempt to identify gene defects in patients suspected to suffer from a genetic form. We describe three siblings, born to consanguineous parents, with a lethal severe epileptic encephalopathy with early-infantile onset, including their magnetic resonance imaging, electroencephalography and, in one case, neuropathological findings. Using WES a homozygous frameshift mutation in the BRAT1 gene, c.638dup p.(Val214Glyfs*189), was identified. We present our cases in the context of all published cases with mutations in the BRAT1 gene and conclude that BRAT1 should be added to the growing list of genes related to early-onset severe encephalopathy with epilepsy. PMID- 26535878 TI - Immunogenicity and Safety of a Booster Dose of a Live Attenuated Japanese Encephalitis Chimeric Vaccine Given 1 Year After Primary Immunization in Healthy Children in the Republic of Korea. AB - BACKGROUND: This study evaluated the effect of a booster vaccination of a new, live attenuated, Japanese encephalitis chimeric vaccine (JE-CV). Previously this vaccine has been used as a booster 12 months after priming with an inactivated vaccine and at >24 months after priming with the same JE-CV. This study evaluates the immunogenicity and safety of the JE-CV given at 12-24 months after JE-CV priming. METHODS: Phase III, open-label study in the Republic of Korea in which 119 children previously vaccinated with JE-CV at 12-24 months of age received a JE-CV booster at 12-24 months after primary vaccination. JE neutralizing antibody titers were measured using >50% plaque reduction neutralization test prebooster and 1 month postbooster vaccination. Seroprotection (SP) was defined as >=10 (1/dil). Safety was assessed for 28 days postvaccination by parental reports. Serious adverse events were monitored for 6 months postvaccination. RESULTS: Antibody persistence was high prebooster (SP rate 93.5%). There was a strong anamnestic response postbooster vaccination, with an SP rate of 100% and a >50 fold increase in geometric mean titer from the prebooster level. Both antibody persistence and the booster response were independent of whether the booster was given at 12-17 or 18-24 months. The safety profile was good and comparable with the primary vaccination; there were no vaccine-related serious adverse events and no deaths. CONCLUSIONS: This study confirms the suitability of a JE-CV booster vaccination at 12-24 months after a primary dose of the same vaccine given at 12 24 months of age in children in the Republic of Korea. PMID- 26535879 TI - Coxiella burnetii Endocarditis in a Child Caused by a New Genotype. AB - Coxiella burnetii endocarditis is a rare diagnosis in children. We present a case of Q fever endocarditis due to a new genotype, MST 54, and review recent literature on Q fever infections in children. Practitioners should consider Q fever in culture-negative endocarditis, particularly in children with congenital heart disease and history of travel or residence in endemic regions. PMID- 26535880 TI - Bergeyella zoohelcum Associated with Abscess and Cellulitis After a Dog Bite. AB - Cat and dog bites are a common cause of injury in young children. Bergeyella zoohelcum is a rarely reported zoonotic pathogen that is a part of cat and dog oral flora. We present a case of a child with B. zoohelcum abscess and cellulitis after a dog bite and review previously reported cases. PMID- 26535881 TI - Incidence and Outcome of Group B Streptococcal Sepsis in Infants in Switzerland. AB - The incidence and outcome of group B streptococcal (GBS) sepsis were assessed prospectively between September 2011 and February 2015 in all tertiary care pediatric hospitals of Switzerland. We describe a low incidence of GBS early onset sepsis (0.12/1000 livebirths) and a predominance of GBS late-onset sepsis (0.36/1000 livebirths), a pattern that has not been reported in other countries. PMID- 26535882 TI - A Positive Role of Cytokine-Induced Killer Cell Therapy on Gastric Cancer Therapy in a Chinese Population: A Systematic Meta-Analysis. AB - BACKGROUND: Chemotherapy and radiation therapy provide limited improvement in survival of gastric cancer patients after tumor resection. It is essential to develop a novel therapeutics for gastric cancer. In the recent years, cytokine induced killer cells (CIKs)-based adoptive immune therapy has been explored in gastric cancer patients. Due to the small number of patients included in each clinical trial and low-power statistical analysis, the effectiveness of this approach is still unclear. To address this issue, we systemically analyzed the relevant clinical trial data published in recent years by powerful statistical meta-analysis. MATERIAL AND METHODS: Clinical data was searched by multiple electronic databases with a term "gastric cancer" and "cytokine-induced killer cells". Six relevant clinical trials with case-control studies were extracted for our meta-analysis, including 318 patients receiving CIK cell therapy and 369 patients receiving conventional therapy. RESULTS: Overall survival (OS) and odds ratio (OR) were analyzed for patients at 1, 2, 3, and 5 years post-CIK cell therapy and post-conventional therapy. Heterogeneity and publication bias were analyzed for included data quality and publication bias. Our meta-analysis from 6 clinical trials suggests that CIK cell therapy significantly increased 5-year OS from 27+/-2.44% to 49+/-7.62% (p<0.05) and 5-year OR up to 1.77 (p<0.05). The increased 5-year survival rate was also highly correlated with the increased CD3+ T cell number and ratio of CD4+/CD8+ in the CIK treated patients. CONCLUSIONS: CIK cell therapy significantly increased 5-year survival rate compared to conventional chemotherapy among gastric cancer patients. The study provides powerful statistical evidence for large-scale clinical trials with CIK cell therapy. PMID- 26535883 TI - Youth Safety Perceptions of Weight Control Behaviors. AB - OBJECTIVE: Youth attempting to lose weight may engage in a variety of weight control behaviors (WCBs), some of which are viewed as healthy WCBs (HWCBs), whereas others are viewed as unhealthy WCBs (UWCBs). This study sought to examine youth perceptions of which WCBs are safe versus unsafe ways to lose weight. Furthermore, youth safety perceptions of WCBs and body mass index (BMI) z-scores were examined in relation to how often youth engage in these WCBs. METHOD: Participants were 219 youth (aged 10-17 years) attending a primary care clinic appointment. Participants completed questionnaires about the frequency of their own WCB use and whether they perceived each WCB as a safe way to lose weight. RESULTS: Results revealed differences in safety perceptions across weight status groups for certain HWCBs and UWCBs. Youth perception of WCBs as safe ways to lose weight was associated with more frequent engagement in WCBs. Furthermore, an interaction between youth safety perception of HWCBs and youth BMI z-scores was related to greater engagement in HWCBs, such that the relationship between safety perception and engagement was only significant for youth who are overweight/obese. The moderation model explained 36.95% of the variance in engagement in HWCBs. The moderation model was also significant for UWCBs (r = .35). CONCLUSION: This study identifies youth safety perception of WCBs as a mechanism that may lead to increased youth engagement in WCBs. Health care providers should educate both youth and family members about safe versus unsafe WCBs. PMID- 26535884 TI - Neurodevelopment of Two-Year-Old Children Exposed to Metformin and Insulin in Gestational Diabetes Mellitus. AB - OBJECTIVE: To compare cognitive, language, and motor skills and results of neurological examination in 2-year-old children born to mothers with gestational diabetes mellitus treated with metformin with those treated with insulin. METHOD: The children of mothers with gestational diabetes mellitus randomized to metformin (n = 75) or insulin (n = 71) treatment during pregnancy were examined by standardized developmental and neurological measures; the Bayley Scales of Infant and Toddler Development (Bayley-III) and the Hammersmith Infant Neurological Examination. RESULTS: There were no significant differences between the metformin and insulin groups in the Bayley Scales of Infant and Toddler Development (Bayley-III) test of cognitive scale (p = .12), receptive communication (p = .14) or expressive communication (p = .75), fine motor scale (p = .10) or gross motor scale (p = .13), or the global scores of Hammersmith Infant Neurological Examination (p = .14). None of the children had a clinically significant developmental problem. However, compared with age-adjusted norms, a trend for weaker language performance was observed in both study groups. CONCLUSION: No differences in neurodevelopmental outcome were seen in 2-year-old children born to mothers with gestational diabetes mellitus (GDM) treated with insulin or metformin during pregnancy. The results suggest that children born to mothers with GDM and exposed to metformin in utero do not systematically need extensive formal neurodevelopmental assessment in early childhood. PMID- 26535885 TI - Why Is It Important to Protect Children with Mental Disorders from Medical Cannabis? PMID- 26535886 TI - The Knowledge Gaps for Medical Marijuana in Pediatric Conditions. PMID- 26535887 TI - Should Surgical Burs Be Used as Single-Use Devices to Avoid Cross Infection? A Case-Control Study. AB - OBJECTIVE: The purpose of this study was to evaluate and compare the rate of bacterial contamination of reused and new unused burs after different sterilization sessions. MATERIALS AND METHODS: The test group consisted of 40 used fissure burs, and the control group of 40 unused new fissure burs (total n = 80). The burs from both groups were precleaned according to standard protocols and then subjected to two sterilization sessions (high- and low-steam pressure autoclaving). After each sterilization session, the burs were transferred into incubation tubes which contained thioglycollate culture medium and were monitored daily for a period of 48 h to detect any bacterial growth. Data were collected and statistical analysis was done using Fisher's exact test. RESULTS: Of the 40 burs of the test group, 2 burs (5%) showed positive bacterial growth, whereas no bur from the control group showed any sign of bacterial growth after high pressure autoclaving. The colony structure and Gram staining were compatible with the growth of Staphylococcus epidermis. After a second sterilization session at low-pressure steam autoclaving, no bacterial growth was observed for the test group, but 1 bur (2.5%) from the control group showed bacterial growth and Gram positive staining matched well with the growth of Brevibacterium species. CONCLUSIONS: The new and unused burs were 100% sterile after high-pressure steam autoclaving, whereas 5% of the reused burs appeared positive with bacterial contamination. After low-pressure steam autoclaving, reused burs were 100% sterile, but 1 new bur demonstrated bacterial contamination. PMID- 26535888 TI - Endocrine Disrupters and the Safety of Food Chains. AB - Endocrine disrupters (ED) are a heterogeneous group of chemicals including persistent contaminants, pesticides, as well as compounds present in consumer products and natural substances. For most ED, the food chain is a current major exposure route for the general population. ED can enter the food chain through the living environment (e.g., feeds, fertilizers) of food-producing organisms, be directly employed in food production (e.g., pesticides) or be released from food contact materials (such as bisphenol A or phthalates); in addition, the endocrine disruption potential of some natural compounds in edible plants, including the so called phytoestrogens, should not be overlooked. An exposure assessment has to consider the specific liability of food commodities to contamination with specific ED (e.g., polychlorinated and polybrominated chemicals in lipid-rich foods). The paper discusses the main toxicological research issues in order to support the risk assessment of ED in food chains, including: the potential for additive, 'cocktail' effects (as from multiple pesticide residues); the long-term effects on target body systems (e.g., reproductive, nervous) elicited by exposure during prenatal as well as postnatal life stage windows, and toxicant/nutrient interactions (e.g., thyroid-targeting ED and iodine status). Food safety systems should exploit the available knowledge to improve prevention of long-term risks along the whole food chain. PMID- 26535889 TI - Ebolavirus Vaccines: Progress in the Fight Against Ebola Virus Disease. AB - Ebolaviruses are highly infectious pathogens that cause lethal Ebola virus disease (EVD) in humans and non-human primates (NHPs). Due to their high pathogenicity and transmissibility, as well as the potential to be misused as a bioterrorism agent, ebolaviruses would threaten the health of global populations if not controlled. In this review, we describe the origin and structure of ebolaviruses and the development of vaccines from the beginning of the 1980s, including conventional ebolavirus vaccines, DNA vaccines, Ebola virus-like particles (VLPs), vaccinia virus-based vaccines, Venezuelan equine encephalitis virus (VEEV)-like replicon particles, Kunjin virus-based vaccine, recombinant Zaire Ebolavirusx2206;VP30, recombinant cytomegalovirus (CMV)-based vaccines, recombinant rabies virus (RABV)-based vaccines, recombinant paramyxovirus-based vaccines, adenovirus-based vaccines and vesicular stomatitis virus (VSV)-based vaccines. No licensed vaccine or specific treatment is currently available to counteract ebolavirus infection, although DNA plasmids and several viral vector approaches have been evaluated as promising vaccine platforms. These vaccine candidates have been confirmed to be successful in protecting NHPs against lethal infection. Moreover, these vaccine candidates were successfully advanced to clinical trials. The present review provides an update of the current research on Ebola vaccines, with the aim of providing an overview on current prospects in the fight against EVD. PMID- 26535890 TI - Health Insurance Status as a Barrier to Ideal Cardiovascular Health for U.S. Adults: Data from the National Health and Nutrition Examination Survey (NHANES). AB - BACKGROUND: Little is known about the association between cardiovascular (CV) health and health insurance status. We hypothesized that U.S. adults without health insurance coverage would have a lower likelihood of ideal cardiovascular health. METHODS AND RESULTS: Using National Health and Nutrition Examination Survey (NHANES) data from 2007-2010, we examined the relationship between health insurance status and ideal CV health in U.S. adults aged >=19 years and <65 (N = 3304). Ideal CV health was defined by the American Heart Association (AHA) as the absence of clinically manifested CV disease and the simultaneous presence of 6-7 "ideal" CV health factors and behaviors. Logistic regression modeling was used to determine the relationship between health insurance status and the odds of ideal CV health. Of the U.S. adult population, 5.4% attained ideal CV health, and 23.5% were without health insurance coverage. Those without health insurance coverage were more likely to be young (p<0.0001), male (p<0.0001), non-white (p<0.0001), with less than a high school degree (p<0.0001), have a poverty-to-income ratio less than 1 (p<0.0001) and unemployed (p<0.0001) compared to those with coverage. Lack of health insurance coverage was associated with a lower likelihood of ideal CV health; however, this relationship was attenuated by socioeconomic status. CONCLUSIONS: U.S. adults without health insurance coverage are less likely to have ideal CV health. Population-based strategies and interventions directed at the community-level may be one way to improve overall CV health and reach this at risk group. PMID- 26535891 TI - Immunisation of Sheep with Bovine Viral Diarrhoea Virus, E2 Protein Using a Freeze-Dried Hollow Silica Mesoporous Nanoparticle Formulation. AB - Bovine viral diarrhoea virus 1 (BVDV-1) is arguably the most important viral disease of cattle. It is associated with reproductive, respiratory and chronic diseases in cattle across the world. In this study we have investigated the capacity of the major immunological determinant of BVDV-1, the E2 protein combined with hollow type mesoporous silica nanoparticles with surface amino functionalisation (HMSA), to stimulate immune responses in sheep. The current work also investigated the immunogenicity of the E2 nanoformulation before and after freeze-drying processes. The optimal excipient formulation for freeze drying of the E2 nanoformulation was determined to be 5% trehalose and 1% glycine. This excipient formulation preserved both the E2 protein integrity and HMSA particle structure. Sheep were immunised three times at three week intervals by subcutaneous injection with 500 MUg E2 adsorbed to 6.2 mg HMSA as either a non freeze-dried or freeze-dried nanoformulation. The capacity of both nanovaccine formulations to generate humoral (antibody) and cell-mediated responses in sheep were compared to the responses in sheep immunisation with Opti-E2 (500 MUg) together with the conventional adjuvant Quil-A (1 mg), a saponin from the Molina tree (Quillaja saponira). The level of the antibody responses detected to both the non-freeze-dried and freeze-dried Opti-E2/HMSA nanoformulations were similar to those obtained for Opti-E2 plus Quil-A, demonstrating the E2 nanoformulations were immunogenic in a large animal, and freeze-drying did not affect the immunogenicity of the E2 antigen. Importantly, it was demonstrated that the long term cell-mediated immune responses were detectable up to four months after immunisation. The cell-mediated immune responses were consistently high in all sheep immunised with the freeze-dried Opti-E2/HMSA nanovaccine formulation (>2,290 SFU/million cells) compared to the non-freeze-dried nanovaccine formulation (213-500 SFU/million cells). This study is the first to demonstrate that a freeze-dried silica mesoporous nanovaccine formulation gives balanced immune responses in a production animal. PMID- 26535892 TI - SOX2 and SOX2-MYC Reprogramming Process of Fibroblasts to the Neural Stem Cells Compromised by Senescence. AB - Tumorigenic potential of induced pluripotent stem cells (iPSCs) infiltrating population of induced neural stem cells (iNSCs) generated from iPSCs may limit their medical applications. To overcome such a difficulty, direct reprogramming of adult somatic cells into iNSCs was proposed. The aim of this study was the systematic comparison of induced neural cells (iNc) obtained with different methods-direct reprogramming of human adult fibroblasts with either SOX2 (SiNSc like) or SOX2 and c-MYC (SMiNSc-like) and induced pluripotent stem cells differentiation to ebiNSc-in terms of gene expression profile, differentiation potential as well as proliferation properties. Immunocytochemistry and real-time PCR analyses were used to evaluate gene expression profile and differentiation potential of various iNc types. Bromodeoxyuridine (BrdU) incorporation and senescence-associated beta-galactosidase (SA-beta-gal) assays were used to estimate proliferation potential. All three types of iNc were capable of neuronal differentiation; however, astrocytic differentiation was possible only in case of ebiNSc. Contrary to ebiNSc generation, the direct reprogramming was rarely a propitious process, despite 100% transduction efficiency. The potency of direct iNSCs-like cells generation was lower as compared to iNSCs obtained by iPSCs differentiation, and only slightly improved when c-MYC was added. Directly reprogrammed iNSCs-like cells were lacking the ability to differentiate into astrocytic cells and characterized by poor efficiency of neuronal cells formation. Such features indicated that these cells could not be fully reprogrammed, as confirmed mainly with senescence detection. Importantly, SiNSc like and SMiNSc-like cells were unable to achieve the long-term survival and became senescent, which limits their possible therapeutic applicability. Our results suggest that iNSCs-like cells, generated in the direct reprogramming attempts, were either not fully reprogrammed or reprogrammed only into neuronal progenitors, mainly because of the inaccuracies of currently available protocols. PMID- 26535893 TI - New Crocodyliforms from Southwestern Europe and Definition of a Diverse Clade of European Late Cretaceous Basal Eusuchians. AB - The late Campanian-early Maastrichtian site of Lo Hueco (Cuenca, Spain) has provided a set of well-preserved crocodyliform skull and lower jaw remains, which are described here and assigned to a new basal eusuchian taxon, Lohuecosuchus megadontos gen. et sp. nov. The reevaluation of a complete skull from the synchronous site of Fox-Amphoux (Department of Var, France) allows us to define a second species of this new genus. Phylogenetic analysis places Lohuecosuchus in a clade exclusively composed by European Late Cretaceous taxa. This new clade, defined here as Allodaposuchidae, is recognized as the sister group of Hylaeochampsidae, also comprised of European Cretaceous forms. Allodaposuchidae and Hylaeochampsidae are grouped in a clade identified as the sister group of Crocodylia, the only crocodyliform lineage that reaches our days. Allodaposuchidae shows a vicariant distribution pattern in the European Late Cretaceous archipelago, with several Ibero-Armorican forms more closely related to each other than with to Romanian Allodaposuchus precedens. PMID- 26535895 TI - First Direct Dating for the Construction and Modification of the Baphuon Temple Mountain in Angkor, Cambodia. AB - Architecture represents key evidence of dynastic practice and change in the archaeological world. Chronologies for many important buildings and sequences, including the iconic temples of medieval Angkor in Cambodia, are based solely on indirect associations from inscriptions and architectural styles. The Baphuon temple, one of the last major buildings in Angkor without textual or scientifically-derived chronological evidence, is crucial both for the context and date of its construction and the period when its western facade was modified into a unique, gigantic Reclining Buddha. Its construction was part of a major dynastic change and florescence of the Hindu-Mahayana Buddhist state and the modification is the key evidence of Theravada Buddhist power after Angkor's decline in the 15th century. Using a newly-developed approach based on AMS radiocarbon dating to directly date four iron crampons integrated into the structure we present the first direct evidence for the history of the Baphuon. Comprehensive study of ferrous elements shows that both construction and modification were critically earlier than expected. The Baphuon can now be considered as the major temple associated with the imperial reformations and territorial consolidation of Suryavarman I (1010-1050 AD) for whom no previous building to legitimize his reign could be identified. The Theravada Buddhist modification is a hundred years prior to the conventional 16th century estimation and is not associated with renewed use of Angkor. Instead it relates to the enigmatic Ayutthayan occupation of Angkor in the 1430s and 40s during a major period of climatic instability. Accurately dating iron with relatively low carbon content is a decisive step to test long-standing assumptions about architectural histories and political processes for states that incorporated iron into buildings (e.g., Ancient Greece, medieval India). Furthermore, this new approach has the potential to revise chronologies related to iron consumption practices since the origins of ferrous metallurgy three millennia ago. PMID- 26535894 TI - DNA Methylation Modulates Nociceptive Sensitization after Incision. AB - DNA methylation is a key epigenetic mechanism controlling DNA accessibility and gene expression. Blockade of DNA methylation can significantly affect pain behaviors implicated in neuropathic and inflammatory pain. However, the role of DNA methylation with regard to postoperative pain has not yet been explored. In this study we sought to investigate the role of DNA methylation in modulating incisional pain and identify possible targets under DNA methylation and contributing to incisional pain. DNA methyltranferase (DNMT) inhibitor 5-Aza-2' deoxycytidine significantly reduced incision-induced mechanical allodynia and thermal sensitivity. Aza-2'-deoxycytidine also reduced hindpaw swelling after incision, suggesting an anti-inflammatory effect. Global DNA methylation and DNMT3b expression were increased in skin after incision, but none of DNMT1, DNMT3a or DNMT3b was altered in spinal cord or DRG. The expression of proopiomelanocortin Pomc encoding beta-endorphin and Oprm1 encoding the mu-opioid receptor were upregulated peripherally after incision; moreover, Oprm1 expression was further increased under DNMT inhibitor treatment. Finally, local peripheral injection of the opioid receptor antagonist naloxone significantly exacerbated incision-induced mechanical hypersensitivity. These results suggest that DNA methylation is functionally relevant to incisional nociceptive sensitization, and that mu-opioid receptor signaling might be one methylation regulated pathway controlling sensitization after incision. PMID- 26535896 TI - A Unifying Probabilistic View of Associative Learning. AB - Two important ideas about associative learning have emerged in recent decades: (1) Animals are Bayesian learners, tracking their uncertainty about associations; and (2) animals acquire long-term reward predictions through reinforcement learning. Both of these ideas are normative, in the sense that they are derived from rational design principles. They are also descriptive, capturing a wide range of empirical phenomena that troubled earlier theories. This article describes a unifying framework encompassing Bayesian and reinforcement learning theories of associative learning. Each perspective captures a different aspect of associative learning, and their synthesis offers insight into phenomena that neither perspective can explain on its own. PMID- 26535897 TI - Inositol Polyphosphate-4-Phosphatase Type I Negatively Regulates Phagocytosis via Dephosphorylation of Phagosomal PtdIns(3,4)P2. AB - Phagocytosis is a highly conserved process whereby phagocytic cells engulf pathogens and apoptotic bodies. The present study focused on the role of inositol polyphosphate-4-phosphatase type I (Inpp4a) in phagocytosis. Raw264.7 cells that express shRNA against Inpp4a (shInpp4a cells) showed significantly increased phagocytic activity. The introduction of shRNA-resistant human Inpp4a abolished this increase. Macrophages from Inpp4a knockout mice showed similar increases in the phagocytic activity. Inpp4a was recruited to the phagosome membrane by a mechanism other than the direct interaction with Rab5. PtdIns(3,4)P2 increased on the phagosome of shInpp4a cells, while PtdIns(3)P significantly decreased. The results indicate that Inpp4a negatively regulates the phagocytic activity of macrophages as a member of the sequential dephosphorylation system that metabolizes phagosomal PtdIns(3,4,5)P3 to PtdIns(3)P. PMID- 26535898 TI - Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association. AB - Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA) are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T). Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444) or group 2 (missense, excluding mutations at Arg444). Significant differences were found in the clinical severity score (P = 0.005), prevalence of laryngeal (P = 0.040) and facial (P = 0.013) oedema, and long-term prophylaxis (P = 0.023) between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038). Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a clear effect on C1-INH function might be responsible for a more severe disease phenotype. PMID- 26535899 TI - Ocular Hypotensive Effects of the ATP-Sensitive Potassium Channel Opener Cromakalim in Human and Murine Experimental Model Systems. AB - Elevated intraocular pressure (IOP) is the most prevalent and only treatable risk factor for glaucoma, a leading cause of irreversible blindness worldwide. Unfortunately, all current therapeutics used to treat elevated IOP and glaucoma have significant and sometimes irreversible side effects necessitating the development of novel compounds. We evaluated the IOP lowering ability of the broad spectrum KATP channel opener cromakalim. Cultured human anterior segments when treated with 2 MUM cromakalim showed a decrease in pressure (19.33 +/- 2.78 mmHg at 0 hours to 13.22 +/- 2.64 mmHg at 24 hours; p<0.001) when compared to vehicle treated controls (15.89 +/- 5.33 mmHg at 0 h to 15.56 +/- 4.88 mmHg at 24 hours; p = 0.89). In wild-type C57BL/6 mice, cromakalim reduced IOP by 18.75 +/- 2.22% compared to vehicle treated contralateral eyes (17.01 +/- 0.32 mmHg at 0 hours to 13.82 +/- 0.37 mmHg at 24 hours; n = 10, p = 0.002). Cromakalim demonstrated an additive effect when used in conjunction with latanoprost free acid, a common ocular hypotensive drug prescribed to patients with elevated IOP. To examine KATP channel subunit specificity, Kir6.2(-/-) mice were treated with cromakalim, but unlike wild-type animals, no change in IOP was noted. Histologic analysis of treated and control eyes in cultured human anterior segments and in mice showed similar cell numbers and extracellular matrix integrity within the trabecular meshwork, with no disruptions in the inner and outer walls of Schlemm's canal. Together, these studies suggest that cromakalim is a potent ocular hypotensive agent that lowers IOP via activation of Kir6.2 containing KATP channels, its effect is additive when used in combination with the commonly used glaucoma drug latanoprost, and is not toxic to cells and tissues of the aqueous humor outflow pathway, making it a candidate for future therapeutic development. PMID- 26535900 TI - Being Sticker Rich: Numerical Context Influences Children's Sharing Behavior. AB - Young children spontaneously share resources with anonymous recipients, but little is known about the specific circumstances that promote or hinder these prosocial tendencies. Children (ages 3-11) received a small (12) or large (30) number of stickers, and were then given the opportunity to share their windfall with either one or multiple anonymous recipients (Dictator Game). Whether a child chose to share or not varied as a function of age, but was uninfluenced by numerical context. Moreover, children's giving was consistent with a proportion based account, such that children typically donated a similar proportion (but different absolute number) of the resources given to them, regardless of whether they originally received a small or large windfall. The proportion of resources donated, however, did vary based on the number of recipients with whom they were allowed to share, such that on average, children shared more when there were more recipients available, particularly when they had more resources, suggesting they take others into consideration when making prosocial decisions. Finally, results indicated that a child's gender also predicted sharing behavior, with males generally sharing more resources than females. Together, findings suggest that the numerical contexts under which children are asked to share, as well as the quantity of resources that they have to share, may interact to promote (or hinder) altruistic behaviors throughout childhood. PMID- 26535901 TI - Humans but Not Chimpanzees Vary Face-Scanning Patterns Depending on Contexts during Action Observation. AB - Human and nonhuman primates comprehend the actions of other individuals by detecting social cues, including others' goal-directed motor actions and faces. However, little is known about how this information is integrated with action understanding. Here, we present the ontogenetic and evolutionary foundations of this capacity by comparing face-scanning patterns of chimpanzees and humans as they viewed goal-directed human actions within contexts that differ in whether or not the predicted goal is achieved. Human adults and children attend to the actor's face during action sequences, and this tendency is particularly pronounced in adults when observing that the predicted goal is not achieved. Chimpanzees rarely attend to the actor's face during the goal-directed action, regardless of whether the predicted action goal is achieved or not. These results suggest that in humans, but not chimpanzees, attention to actor's faces conveying referential information toward the target object indicates the process of observers making inferences about the intentionality of an action. Furthermore, this remarkable predisposition to observe others' actions by integrating the prediction of action goals and the actor's intention is developmentally acquired. PMID- 26535902 TI - Simulation Assisted Analysis of the Intrinsic Stiffness for Short DNA Molecules Imaged with Scanning Atomic Force Microscopy. AB - Studying the mechanical properties of short segments of dsDNA can provide insight into various biophysical phenomena, from DNA looping to the organization of nucleosomes. Scanning atomic force microscopy (AFM) is able to acquire images of single DNA molecules with near-basepair resolution. From many images, one may use equilibrium statistical mechanics to quantify the intrinsic stiffness (or persistence length) of the DNA. However, this approach is highly dependent upon both the correct microscopic polymer model and a correct image analysis of DNA contours. These complications have led to significant debate over the flexibility of dsDNA at short length scales. We first show how to extract accurate measures of DNA contour lengths by calibrating to DNA traces of simulated AFM data. After this calibration, we show that DNA adsorbed on an aminopropyl-mica surface behaves as a worm-like chain (WLC) for contour lengths as small as ~20 nm. We also show that a DNA binding protein can modify the mechanics of the DNA from that of a WLC. PMID- 26535903 TI - Correction: A New Chronology for the Bronze Age of Northeastern Thailand and Its Implications for Southeast Asian Prehistory. PMID- 26535904 TI - Development and Validation of the Behavioral Tendencies Questionnaire. AB - At a fundamental level, taxonomy of behavior and behavioral tendencies can be described in terms of approach, avoid, or equivocate (i.e., neither approach nor avoid). While there are numerous theories of personality, temperament, and character, few seem to take advantage of parsimonious taxonomy. The present study sought to implement this taxonomy by creating a questionnaire based on a categorization of behavioral temperaments/tendencies first identified in Buddhist accounts over fifteen hundred years ago. Items were developed using historical and contemporary texts of the behavioral temperaments, described as "Greedy/Faithful", "Aversive/Discerning", and "Deluded/Speculative". To both maintain this categorical typology and benefit from the advantageous properties of forced-choice response format (e.g., reduction of response biases), binary pairwise preferences for items were modeled using Latent Class Analysis (LCA). One sample (n1 = 394) was used to estimate the item parameters, and the second sample (n2 = 504) was used to classify the participants using the established parameters and cross-validate the classification against multiple other measures. The cross-validated measure exhibited good nomothetic span (construct-consistent relationships with related measures) that seemed to corroborate the ideas present in the original Buddhist source documents. The final 13-block questionnaire created from the best performing items (the Behavioral Tendencies Questionnaire or BTQ) is a psychometrically valid questionnaire that is historically consistent, based in behavioral tendencies, and promises practical and clinical utility particularly in settings that teach and study meditation practices such as Mindfulness Based Stress Reduction (MBSR). PMID- 26535905 TI - Carboranyl-Chlorin e6 as a Potent Antimicrobial Photosensitizer. AB - Antimicrobial photodynamic inactivation is currently being widely considered as alternative to antibiotic chemotherapy of infective diseases, attracting much attention to design of novel effective photosensitizers. Carboranyl-chlorin-e6 (the conjugate of chlorin e6 with carborane), applied here for the first time for antimicrobial photodynamic inactivation, appeared to be much stronger than chlorin e6 against Gram-positive bacteria, such as Bacillus subtilis, Staphyllococcus aureus and Mycobacterium sp. Confocal fluorescence spectroscopy and membrane leakage experiments indicated that bacteria cell death upon photodynamic treatment with carboranyl-chlorin-e6 is caused by loss of cell membrane integrity. The enhanced photobactericidal activity was attributed to the increased accumulation of the conjugate by bacterial cells, as evaluated both by centrifugation and fluorescence correlation spectroscopy. Gram-negative bacteria were rather resistant to antimicrobial photodynamic inactivation mediated by carboranyl-chlorin-e6. Unlike chlorin e6, the conjugate showed higher (compared to the wild-type strain) dark toxicity with Escherichia coli DeltatolC mutant, deficient in TolC-requiring multidrug efflux transporters. PMID- 26535906 TI - Impact of Acute Sleep Deprivation on Sarcasm Detection. AB - There is growing evidence that sleep plays a pivotal role on health, cognition and emotional regulation. However, the interplay between sleep and social cognition remains an uncharted research area. In particular, little is known about the impact of sleep deprivation on sarcasm detection, an ability which, once altered, may hamper everyday social interactions. The aim of this study is to determine whether sleep-deprived participants are as able as sleep-rested participants to adopt another perspective in gauging sarcastic statements. At 9am, after a whole night of sleep (n = 15) or a sleep deprivation night (n = 15), participants had to read the description of an event happening to a group of friends. An ambiguous voicemail message left by one of the friends on another's phone was then presented, and participants had to decide whether the recipient would perceive the message as sincere or as sarcastic. Messages were uttered with a neutral intonation and were either: (1) sarcastic from both the participant's and the addressee's perspectives (i.e. both had access to the relevant background knowledge to gauge the message as sarcastic), (2) sarcastic from the participant's but not from the addressee's perspective (i.e. the addressee lacked context knowledge to detect sarcasm) or (3) sincere. A fourth category consisted in messages sarcastic from both the participant's and from the addressee's perspective, uttered with a sarcastic tone. Although sleep-deprived participants were as accurate as sleep-rested participants in interpreting the voice message, they were also slower. Blunted reaction time was not fully explained by generalized cognitive slowing after sleep deprivation; rather, it could reflect a compensatory mechanism supporting normative accuracy level in sarcasm understanding. Introducing prosodic cues compensated for increased processing difficulties in sarcasm detection after sleep deprivation. Our findings support the hypothesis that sleep deprivation might damage the flow of social interactions by slowing perspective-taking processes. PMID- 26535907 TI - Metal-organic frameworks for photocatalysis. AB - Photocatalysis is a promising technology to convert solar energy into chemical energy. Recently, metal-organic frameworks (MOFs) have emerged as novel photocatalysts owing to their inherent structural characteristics of a large surface area and a well-ordered porous structure. Most importantly, via modulation of the organic linker/metal clusters or incorporation with metal/complex catalysts, not only the reactant adsorption and light absorption but also the charge separation and reactant activation will be largely promoted, leading to superior photocatalytic performance. In this article, we will first introduce the photophysical/chemical properties of MOFs; then various strategies of modification of MOFs towards better photocatalytic activity will be presented; finally, we will address the challenge and further perspective in MOF-based photocatalysis. PMID- 26535908 TI - Synthesis and biological evaluation of analogs of AAL(S) for use as ceramide synthase 1 inhibitors. AB - A convergent synthesis to access hydrophobic tail analogs and head group modifications of AAL(S) is described. The analogs synthesised were evaluated for their ability to inhibit ceramide synthase 1 and for their cytotoxicity in K562 cells. Our results have identified inhibitors which are non-cytotoxic yet maintain CerS1 inhibition. PMID- 26535910 TI - How Well Do Computer-Generated Faces Tap Face Expertise? AB - The use of computer-generated (CG) stimuli in face processing research is proliferating due to the ease with which faces can be generated, standardised and manipulated. However there has been surprisingly little research into whether CG faces are processed in the same way as photographs of real faces. The present study assessed how well CG faces tap face identity expertise by investigating whether two indicators of face expertise are reduced for CG faces when compared to face photographs. These indicators were accuracy for identification of own race faces and the other-race effect (ORE)-the well-established finding that own race faces are recognised more accurately than other-race faces. In Experiment 1 Caucasian and Asian participants completed a recognition memory task for own- and other-race real and CG faces. Overall accuracy for own-race faces was dramatically reduced for CG compared to real faces and the ORE was significantly and substantially attenuated for CG faces. Experiment 2 investigated perceptual discrimination for own- and other-race real and CG faces with Caucasian and Asian participants. Here again, accuracy for own-race faces was significantly reduced for CG compared to real faces. However the ORE was not affected by format. Together these results signal that CG faces of the type tested here do not fully tap face expertise. Technological advancement may, in the future, produce CG faces that are equivalent to real photographs. Until then caution is advised when interpreting results obtained using CG faces. PMID- 26535909 TI - 2-Hydroxypropyl-beta-Cyclodextrin Acts as a Novel Anticancer Agent. AB - 2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) is a cyclic oligosaccharide that is widely used as an enabling excipient in pharmaceutical formulations, but also as a cholesterol modifier. HP-beta-CyD has recently been approved for the treatment of Niemann-Pick Type C disease, a lysosomal lipid storage disorder, and is used in clinical practice. Since cholesterol accumulation and/or dysregulated cholesterol metabolism has been described in various malignancies, including leukemia, we hypothesized that HP-beta-CyD itself might have anticancer effects. This study provides evidence that HP-beta-CyD inhibits leukemic cell proliferation at physiologically available doses. First, we identified the potency of HP-beta-CyD in vitro against various leukemic cell lines derived from acute myeloid leukemia (AML), acute lymphoblastic leukemia and chronic myeloid leukemia (CML). HP-beta-CyD treatment reduced intracellular cholesterol resulting in significant leukemic cell growth inhibition through G2/M cell-cycle arrest and apoptosis. Intraperitoneal injection of HP-beta-CyD significantly improved survival in leukemia mouse models. Importantly, HP-beta-CyD also showed anticancer effects against CML cells expressing a T315I BCR-ABL mutation (that confers resistance to most ABL tyrosine kinase inhibitors), and hypoxia-adapted CML cells that have characteristics of leukemic stem cells. In addition, colony forming ability of human primary AML and CML cells was inhibited by HP-beta-CyD. Systemic administration of HP-beta-CyD to mice had no significant adverse effects. These data suggest that HP-beta-CyD is a promising anticancer agent regardless of disease or cellular characteristics. PMID- 26535911 TI - Effectiveness of seasonal influenza vaccine in preventing laboratory-confirmed influenza in primary care in the United Kingdom: 2014/15 end of season results. AB - The 2014/15 influenza season in the United Kingdom (UK) was characterised by circulation of predominantly antigenically and genetically drifted influenza A(H3N2) and B viruses. A universal paediatric influenza vaccination programme using a quadrivalent live attenuated influenza vaccine (LAIV) has recently been introduced in the UK. This study aims to measure the end-of-season influenza vaccine effectiveness (VE), including for LAIV, using the test negative case control design. The overall adjusted VE against all influenza was 34.3% (95% confidence interval (CI) 17.8 to 47.5); for A(H3N2) 29.3% (95% CI: 8.6 to 45.3) and for B 46.3% (95% CI: 13.9 to 66.5). For those aged under 18 years, influenza A(H3N2) LAIV VE was 35% (95% CI: -29.9 to 67.5), whereas for influenza B the LAIV VE was 100% (95% CI:17.0 to 100.0). Although the VE against influenza A(H3N2) infection was low, there was still evidence of significant protection, together with moderate, significant protection against drifted circulating influenza B viruses. LAIV provided non-significant positive protection against influenza A, with significant protection against B. Further work to assess the population impact of the vaccine programme across the UK is underway. PMID- 26535912 TI - Nanometre-scale identification of grain boundaries in MoS2 through molecular decoration. AB - In this paper, we address the challenge of identifying grain boundaries on the molybdenum disulphide (MoS2) surface at the nanometre scale using a simple self assembled monolayer (SAM) decoration method. Combined with atomic force microscopy, octadecylphosphonic acid monolayers readily reveal grain boundaries in MoS2 at ambient conditions, without the need of atomic resolution measurements under vacuum. Additional ab initio calculations allow us to obtain the preferred orientation of the SAM structure relative to the MoS2 beneath, and therefore, together with the experiments, the MoS2 crystalline orientations at the grain boundaries. The proposed method enables the visualization of grain boundaries with sub-micrometer resolution for nanodevice investigation and failure analysis. PMID- 26535913 TI - Carbon-Coated Gold Nanorods: A Facile Route to Biocompatible Materials for Photothermal Applications. AB - Gold nanorods and their core-shell nanocomposites have been widely studied because of their well-defined anisotropy and unique optical properties and applications. This study demonstrates a facile hydrothermal synthesis strategy for generating carbon coating on gold nanorods (AuNRs@C) under mild conditions (<200 degrees C), where the carbon shell is composed of polymerized sugar molecules (glucose). The structure and composition of the produced core-shell nanocomposites were characterized using advanced microscopic and spectroscopic techniques. The functional properties, particularly the photothermal and biocompatibility properties of the produced AuNRs@C, were quantified to assess their potential in photothermal hyperthermia. These AuNRs@C were tested in vitro (under representative treatment conditions) using near-infrared (NIR) light irradiation. It was found that the AuNRs produced here exhibit exemplary heat generation capability. Temperature changes of 10.5, 9, and 8 degrees C for AuNRs@C were observed with carbon shell thicknesses of 10, 17, and 25 nm, respectively, at a concentration of 50 MUM, after 600 s of irradiation with a laser power of 0.17 W/cm(2). In addition, the synthesized AuNRs@C also exhibit good biocompatibility toward two soft tissue sarcoma cell lines (HT1080, a fibrosarcoma; and GCT, a fibrous histiocytoma). The cell viability study shows that AuNRs@C (at a concentration of <0.1 mg/mL) core-shell particles induce significantly lower cytotoxicity on both HT1080 and GCT cell lines, as compared with cetyltrimethylammonium bromide (CTAB)-capped AuNRs. Furthermore, similar to PEG-modified AuNRs, they are also safe to both HT1080 and GCT cell lines. This biocompatibility results from a surface full of -OH or -COH groups, which are suitable for linking and are nontoxic Therefore, the AuNRs@C represent a viable alternative to PEG-coated AuNRs for facile synthesis and improved photothermal conversion. Overall, these findings open up a new class of carbon-coated nanostructures that are biocompatible and could potentially be employed in a wide range of biomedical applications. PMID- 26535914 TI - Interactions and Aggregation of Charged Nanoparticles in Uncharged Polymer Solutions. AB - We employ an extension of the single chain in mean field simulation method to study mixtures of charged particles and uncharged polymers. We examine the effect of particle charge, polymer concentration, and particle volume fraction on the resulting particle aggregates. The structures of aggregates were characterized using particle-particle radial distribution functions and cluster size distributions. We observe that the level of aggregation between particles increases with increasing particle volume fraction and polymer concentration and decreasing particle charge. At intermediate regimes of particle volume fraction and polymer concentrations, we observe the formation of equilibrium clusters with a preferred size. We also examined the influence of manybody effects on the structure of a charged particle-polymer system. Our results indicate that the effective two-body approximation overpredicts the aggregation between particles even at dilute particle concentrations. Such effects are thought to be a consequence of the interplay between the respective manybody effects on the depletion and electrostatic interactions. PMID- 26535915 TI - Human case of West Nile neuroinvasive disease in Portugal, summer 2015. AB - A case of West Nile virus (WNV) infection was reported in the Algarve region, Portugal, in the first week of September 2015. WNV is known to circulate in Portugal, with occasional reports in horses and birds (2004 to 2011) and very sporadically human cases (in 2004 and in 2010). Here we present the clinical and laboratory aspects related to the first human case of West Nile neuroinvasive disease reported in Portugal. PMID- 26535916 TI - Key Role of the Adenylate Moiety and Integrity of the Adenylate-Binding Site for the NAD(+)/H Binding to Mitochondrial Apoptosis-Inducing Factor. AB - Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein with pro-life and pro-death activities, which plays critical roles in mitochondrial energy metabolism and caspase-independent apoptosis. Defects in AIF structure or expression can cause mitochondrial abnormalities leading to mitochondrial defects and neurodegeneration. The mechanism of AIF-induced apoptosis was extensively investigated, whereas the mitochondrial function of AIF is poorly understood. A unique feature of AIF is the ability to form a tight, air-stable charge-transfer (CT) complex upon reaction with NADH and to undergo a conformational switch leading to dimerization, proposed to be important for its vital and lethal functions. Although some aspects of interaction of AIF with NAD(+)/H have been analyzed, its precise mechanism is not fully understood. We investigated how the oxidized and photoreduced wild-type and G307A and -E variants of murine AIF associate with NAD(+)/H and nicotinamide mononucleotide (NMN(+)/H) to determine the role of the adenylate moiety in the binding process. Our results indicate that (i) the adenylate moiety of NAD(+)/H is crucial for the association with AIF and for the subsequent structural reorganization of the complex, but not for protein dimerization, (ii) FAD reduction rather than binding of NAD(+)/H to AIF initiates conformational rearrangement, and (iii) alteration of the adenylate binding site by the G307E (equivalent to a pathological G308E mutation in human AIF) or G307A replacements decrease the affinity and association rate of NAD(+)/H, which, in turn, perturbs CT complex formation and protein dimerization but has no influence on the conformational switch in the regulatory peptide. PMID- 26535917 TI - Systematic review of models used in economic analyses in moderate-to-severe asthma and COPD. AB - BACKGROUND: Respiratory diseases exert a substantial burden on society, with newer drugs increasingly adding to the burden. Economic models are often used, but seldom reviewed. PURPOSE: To summarize economic models used in economic analyses of drugs treating moderate-to-severe/very severe asthma or chronic obstructive pulmonary disease (COPD). METHODS: This study searched Medline and Embase from inception to the end of February 2015 for cost-effectiveness/utility analyses that examined at least one drug against placebo, another drug, or other standard therapy in asthma or COPD. Two reviewers independently searched and extracted data with differences adjudicated via consensus discussion. Data extracted included model used and its qualities, validation methods, treatments compared, disease severity, analytic perspective, time horizon, data collection (pro- or retrospective), input rates and sources, costs and sources, planned sensitivity analyses, criteria for cost-effectiveness, reported outcomes, and sponsor. RESULTS: This study analyzed 53 articles; 14 (25%) on asthma and 39 (75%) COPD. Markov models were commonly used for both asthma and COPD-related economic evaluations. Relatively few studies validated their model. For asthma related studies, 10 examined inhaled corticosteroids and nine studied omalizumab. Placebo or standard therapy was the comparison in 11 studies and active drugs in the remainder. CONCLUSIONS: Few studies include validation of their models. Furthermore, controversy concerning some results was uncovered in this study, which needs to be avoided in the future. PMID- 26535918 TI - NADPH Oxidase-Dependent Mechanism Explains How Arsenic and Other Oxidants Can Activate Aryl Hydrocarbon Receptor Signaling. AB - The mechanisms explaining arsenic toxicity are not well understood, but physiological consequences of stimulated aryl hydrocarbon receptor (AHR) signaling both directly and through cross-talk with other pathways have been indicated. The aim of this study was to establish how arsenic interacts with AHR mediated transcription. The human hepatoma cell line (HepG2-XRE-Luc) carrying a luciferase reporter under the control of two AHR response elements (AHREs) and immortalized human keratinocytes (HaCaT) were exposed to sodium arsenite (NaAsO2; As(3+)), alone or in combination with the endogenous high affinity AHR ligand 6 formylindolo[3,2-b]carbazole (FICZ). Luciferase activity, cytochrome P4501A1 (CYP1A1) activity, oxidative stress-related responses, metabolic clearance of FICZ, and NADPH oxidase (NOX) activity as well as nuclear factor (erythroid derived 2)-like 2 (Nrf2)-dependent gene expression were measured. Arsenic inhibited CYP1A1 enzyme activity and reduced the metabolic clearance of FICZ. Arsenic also led to activated CYP1A1 transcription but only in cells grown in medium containing trace amounts of the endogenous ligand FICZ, pointing to an indirect mechanism of activation. Initially, arsenic caused dose-dependent inhibition of FICZ-activated AHR signaling, disturbed intracellular GSH status, and increased expression of oxidative stress-related genes. Silencing of NOX4, addition of N-acetylcystein, or pretreatment with arsenic itself attenuated the initial dose-dependent inhibition of AHR signaling. Arsenic pretreatment led to elevated GSH levels and sensitized the cells to ligand-dependent AHR signaling, while silencing of Nrf2 significantly reduced arsenic-mediated activation of the AHR. In addition, influence of NOX on AHR activation was also observed in cells treated with the SH-reactive metals cadmium, mercury, and nickel. Together, the results suggest that SH-reactive agents via a new and possibly general NOX/H2O2 dependent mechanism can interfere with the endogenous regulation of the AHR. PMID- 26535919 TI - Correction to "Development of a Concise Synthesis of (+)-Ingenol". PMID- 26535920 TI - Cryptochrome 1b: a possible inducer of visual lateralization in pigeons? AB - The visual system of adult pigeons shows a lateralization of object discrimination with a left hemispheric dominance on the behavioural, physiological and anatomical levels. The crucial trigger for the establishment of this asymmetry is the position of the embryo inside the egg, which exposes the right eye to light falling through the egg shell. As a result, the right-sided retina is more strongly stimulated with light during embryonic development. However, it is unknown how this embryonic light stimulation is transduced to the brain as rods and cones are not yet functional. A possible solution could be the blue-light-sensitive molecule cryptochrome 1 (Cry1), which is expressed in retinal ganglion cells (RGCs) of several mammalian and avian species. RGCs have been shown to be functional during the time of induction of asymmetry and possess projections to primary visual areas. Therefore, Cry1-containing RGCs could be responsible for induction of asymmetry. The aim of this study was to identify the expression pattern of the Cry1 subtype Cry1b in the retina of embryonic, post hatch and adult pigeons by immunohistochemical staining and to show whether Cry1b containing RGCs project to the optic tectum. Cry1b-positive cells were indeed mainly found in the RGC layer and to lesser extent in the inner nuclear layer at all ages, including the embryonic stage. Tracing in adult animals revealed that at least a subset of Cry1b-containing RGCs project to the optic tectum. Thus, Cry1b-containing RGCs within the embryonic retina could be involved in the induction of asymmetries in the visual system of pigeons. PMID- 26535921 TI - Charging/Discharging Nanomorphology Asymmetry and Rate-Dependent Capacity Degradation in Li-Oxygen Battery. AB - Liquid-cell in situ transmission electron microscopy (TEM) observations of the charge/discharge reactions of nonaqueous Li-oxygen battery cathode were performed with ~5 nm spatial resolution. The discharging reaction occurred at the interface between the electrolyte and the reaction product, whereas in charging, the reactant was decomposed at the contact with the gold current collector, indicating that the lithium ion diffusivity/electronic conductivity is the limiting factor in discharging/charging, respectively, which is a root cause for the asymmetry in discharging/charging overpotential. Detachments of lithium oxide particles from the current collector into the liquid electrolyte are frequently seen when the cell was discharged at high overpotentials, with loss of active materials into liquid electrolyte ("flotsam") under minute liquid flow agitation, as the lithium peroxide dendritic trees are shown to be fragile mechanically and electrically. Our result implies that enhancing the binding force between the reaction products and the current collector to maintain robust electronic conduction is a key for improving the battery performance. This work demonstrated for the first time the in situ TEM observation of a three-phase-reaction involving gold electrode, lithium oxides, DMSO electrolyte and lithium salt, and O2 gas. The technique described in this work is not limited to Li-oxygen battery but also can be potentially used in other applications involving gas/liquid/solid electrochemical reactions. PMID- 26535922 TI - Enterovirus D-68: an emerging cause of infection. AB - The outbreak of Enterovirus D-68 (EV-D68) in the United States in 2014 raised great interest due to it affecting large numbers of people and because patients presented with severe respiratory and/or central nervous system involvement. Many studies have tried to evaluate the biologic and genetic characteristics of this virus, its association with disease development and the possibility of infection prevention and therapy. The main aim of this paper is to discuss what is presently known and what might be expected in the future regarding EV-D68. We highlight that further studies are needed to precisely define the epidemiology and total burden of EV-D68, the real age prevalence, and the factors that may lead to negative outcomes in some patients and not in others. Moreover, if recently reported clinical data are confirmed, specific efficacious prophylactic and therapeutic measures should be urgently developed. PMID- 26535923 TI - Staging classification for cancer of the ovary and fallopian tube should include in situ carcinoma. PMID- 26535924 TI - Molecular Detection of Legionella spp. and their associations with Mycobacterium spp., Pseudomonas aeruginosa and amoeba hosts in a drinking water distribution system. AB - AIMS: This study investigated waterborne opportunistic pathogens (OPs) including potential hosts, and evaluated the use of Legionella spp. for indicating microbial water quality for OPs within a full-scale operating drinking water distribution system (DWDS). METHODS AND RESULTS: To investigate the occurrence of specific microbial pathogens within a major city DWDS we examined large volume (90 l drinking water) ultrafiltration (UF) concentrates collected from six sites between February, 2012 and June, 2013. The detection frequency and concentration estimates by qPCR were: Legionella spp. (57%/85 cell equivalent, CE l(-1) ), Mycobacterium spp. (88%/324 CE l(-1) ), Pseudomonas aeruginosa (24%/2 CE l(-1) ), Vermamoeba vermiformis (24%/2 CE l(-1) ) and Acanthamoeba spp. (42%/5 cyst equivalent, CE l(-1) ). There was no detection of the following microorganisms: human faecal indicator Bacteroides (HF183), Salmonella enterica, Campylobacter spp., Escherichia coli O157:H7, Giardia intestinalis, Cryptosporidium spp. or Naegleria fowleri. There were significant correlations between the qPCR signals of Legionella spp. and Mycobacterium spp., and their potential hosts V. vermiformis and Acanthamoeba spp. Sequencing of Legionella spp. demonstrated limited diversity, with most sequences coming from two dominant groups, of which the larger dominant group was an unidentified species. Other known species including Legionella pneumophila were detected, but at low frequency. The densities of Legionella spp. and Mycobacterium spp. were generally higher (17 and 324 folds, respectively) for distal sites relative to the entry point to the DWDS. CONCLUSIONS: Legionella spp. occurred, had significant growth and were strongly associated with free-living amoebae (FLA) and Mycobacterium spp., suggesting that Legionella spp. could provide a useful DWDS monitoring role to indicate potential conditions for non-faecal OPs. SIGNIFICANCE AND IMPACT OF THE STUDY: The results provide insight into microbial pathogen detection that may aid in the monitoring of microbial water quality within DWDS prior to customer exposures. PMID- 26535925 TI - What is the optimal perioperative management of antiplatelet therapy? PMID- 26535926 TI - Assessing Insulin Delivery Device Satisfaction in Patients with Type 1 and Type 2 Diabetes. AB - Over the past several decades, insulin treatment has changed drastically, not only with the development of further insulin analogs but also with the introduction of novel insulin delivery devices such as pumps and pens. In addition, adjunct devices such as continuous glucose monitors and sensor augmented pumps have become increasingly used in clinical care, increasing the volume of information available to patients and providers. However, with the development of new devices it has become clear that along with the many benefits of these advances, the use of these devices can also present a burden to people with diabetes. For example, some patients report being overwhelmed by too much data when using continuous glucose monitors. Furthermore, there are concerns regarding the accuracy of some of these new devices, particularly for glucose monitoring. As a result, some patients may choose not to use available devices, despite the recognized benefits. Therefore, it is critical to understand how the various insulin delivery devices available currently and in the future affect patients in terms of their diabetes management and perceived burdens and to understand which patient characteristics may predict a lack of satisfaction with these devices. This critical gap in our knowledge is addressed in an article in this issue of the journal through the development of a questionnaire that allows for a better understanding of the impact of insulin delivery devices on quality of life and diabetes management among both type 1 diabetes and insulin-dependent type 2 diabetes patients. The novelty, as well as limitations, of this new instrument for the assessment of insulin delivery device satisfaction are discussed. PMID- 26535927 TI - The Future of the Artificial Pancreas. PMID- 26535928 TI - Accuracy of CGM During Closed-Loop Home Studies. PMID- 26535929 TI - Evaluation of the Average Daily Risk Range as a Measure of Glycemic Variability in Youths with Type 1 Diabetes. AB - OBJECTIVE: The Average Daily Risk Range (ADRR) is a measure of glycemic variability (GV) developed for adults with diabetes. Although the ADRR is increasingly being reported in pediatric diabetes research and may also be used in clinical management, it has never been examined for its sensitivity to predicting hyper- and hypoglycemia in youths or compared for its predictive ability with other measures of GV in youths. Thus, we present predictive validity data for the ADRR in youths with type 1 diabetes. MATERIALS AND METHODS: Glucometer data for 436 youths (mean age, 11.8+/-3.8 years) were collected from a clinical database. Using these data, we computed the ADRR, SD of blood glucose, coefficient of variation of blood glucose, Low Blood Glucose Index, High Blood Glucose Index, the percentage of glucose values >=70 and <=180 mg/dL, the percentage of high glucose values >180 mg/dL and >400 mg/dL, and the percentage of low glucose values <70 mg/dL and <40 mg/dL in Month 1. We then compared these with episodes of hypo- and hyperglycemia in Month 2. RESULTS: The ADRR showed good concurrent validity with other measures of GV in youths experiencing hyperglycemic events but limited predictive validity in general and specifically with future hypoglycemic events. The percentages of current hyper- and hypoglycemic episodes appeared to be stronger predictors of future hyper- and hypoglycemic episodes, respectively. CONCLUSIONS: In a large pediatric sample, the ADRR was not the strongest predictor of future glycemic excursion. The percentages of current hyper- and hypoglycemic episodes appear to be stronger predictors. PMID- 26535930 TI - Summarising the health effects of breastfeeding. PMID- 26535931 TI - Multilevel developmental perspectives on child maltreatment. PMID- 26535932 TI - Multilevel developmental approaches to understanding the effects of child maltreatment: Recent advances and future challenges. AB - Recent research in the field of child maltreatment has begun to shed new light on the emergence of health problems in children by emphasizing the responsiveness of developmental processes to children's environmental and biological contexts. Here, I highlight recent trends in the field with an emphasis on the effects of early life stress across multiple levels of developmental domains. PMID- 26535933 TI - Measuring adolescents' exposure to victimization: The Environmental Risk (E-Risk) Longitudinal Twin Study. AB - This paper presents multilevel findings on adolescents' victimization exposure from a large longitudinal cohort of twins. Data were obtained from the Environmental Risk (E-Risk) Longitudinal Twin Study, an epidemiological study of 2,232 children (1,116 twin pairs) followed to 18 years of age (with 93% retention). To assess adolescent victimization, we combined best practices in survey research on victimization with optimal approaches to measuring life stress and traumatic experiences, and introduce a reliable system for coding severity of victimization. One in three children experienced at least one type of severe victimization during adolescence (crime victimization, peer/sibling victimization, Internet/mobile phone victimization, sexual victimization, family violence, maltreatment, or neglect), and most types of victimization were more prevalent among children from low socioeconomic backgrounds. Exposure to multiple victimization types was common, as was revictimization; over half of those physically maltreated in childhood were also exposed to severe physical violence in adolescence. Biometric twin analyses revealed that environmental factors had the greatest influence on most types of victimization, while severe physical maltreatment from caregivers during adolescence was predominantly influenced by heritable factors. The findings from this study showcase how distinct levels of victimization measurement can be harmonized in large-scale studies of health and development. PMID- 26535934 TI - Individual, family, and culture level contributions to child physical abuse and neglect: A longitudinal study in nine countries. AB - This study advances understanding of predictors of child abuse and neglect at multiple levels of influence. Mothers, fathers, and children (N = 1,418 families, M age of children = 8.29 years) were interviewed annually in three waves in 13 cultural groups in nine countries (China, Colombia, Italy, Jordan, Kenya, Philippines, Sweden, Thailand, and the United States). Multilevel models were estimated to examine predictors of (a) within-family differences across the three time points, (b) between-family within-culture differences, and (c) between cultural group differences in mothers' and fathers' reports of corporal punishment and children's reports of their parents' neglect. These analyses addressed to what extent mothers' and fathers' use of corporal punishment and children's perceptions of their parents' neglect were predicted by parents' belief in the necessity of using corporal punishment, parents' perception of the normativeness of corporal punishment in their community, parents' progressive parenting attitudes, parents' endorsement of aggression, parents' education, children's externalizing problems, and children's internalizing problems at each of the three levels. Individual-level predictors (especially child externalizing behaviors) as well as cultural-level predictors (especially normativeness of corporal punishment in the community) predicted corporal punishment and neglect. Findings are framed in an international context that considers how abuse and neglect are defined by the global community and how countries have attempted to prevent abuse and neglect. PMID- 26535935 TI - Intergenerational transmission of maltreatment: A multilevel examination. AB - Despite the commonly held belief that there is a high degree of intergenerational continuity in maltreatment, studies to date suggest a mixed pattern of findings. One reason for the variance in findings may be related to the measurement approach used, which includes a range of self-report and official indicators of maltreatment and both cross-sectional and longitudinal designs. This study attempted to shed light on the phenomenon of intergenerational continuity of maltreatment by examining multiple indicators of perpetration of maltreatment in young adults and multiple risk factors across different levels within an individual's social ecology. The sample included 166 women who had been placed in out-of-home care as adolescents (>85% had a substantiated maltreatment incident) and followed into young adulthood, and included three waves of adolescent data and six waves of young adult data collected across 10 years. The participants were originally recruited during adolescence as part of a randomized controlled trial examining the efficacy of the Treatment Foster Care Oregon intervention. Analyses revealed weak to modest associations among the three indicators of perpetration of maltreatment in young adulthood, that is, official child welfare records, self-reported child welfare system involvement, and self-reported maltreatment (r = .03-.51). Further, different patterns of prediction emerged as a function of the measurement approach. Adolescent delinquency was a significant predictor of subsequent self-reported child welfare contact, and young adult partner risk was a significant predictor of perpetration of maltreatment as indexed by both official child welfare records and self-reported child welfare contact. In addition, women who were originally assigned to the intervention condition reported perpetrating less maltreatment during young adulthood. Implications for measurement and interventions related to reducing the risk for intergenerational transmission of risk are discussed. PMID- 26535936 TI - Multigenerational links between mothers' experiences of autonomy in childhood and preschoolers' respiratory sinus arrhythmia: Variations by maltreatment status. AB - Despite burgeoning evidence linking early exposure to child maltreatment (CM) to deficits in self-regulation, the pathways to strong regulatory development in these children are not well understood, and significant heterogeneity is observed in their outcomes. Experiences of autonomy may play a key role in transmitting self-regulatory capacity across generations and help explain individual differences in maltreatment outcomes. In this study, we investigated multigenerational associations between Generation 1 (G1)-Generation 2 (G2) mothers' early experience of warmth and autonomy in relation to their own mothers and their Generation 3 (G3) children's autonomic physiological regulation in CM (n = 85) and non-CM (n = 128) families. We found that G2 mothers who recalled greater autonomy in their childhood relationship with their G1 mothers had preschool-age G3 children with higher respiratory sinus arrhythmia at baseline when alone while engaged in individual challenge tasks, during social exchanges with their mother in joint challenge tasks, and during the portions of the strange situation procedure when the mother was present. Although no clear mediators of this association emerged, multigenerational links among G1-G2 relations, maternal representations of her child, child behavior, and child respiratory sinus arrhythmia differed by maltreatment status, thus possibly representing important targets for future research and intervention. PMID- 26535937 TI - Cortisol profiles: A test for adaptive calibration of the stress response system in maltreated and nonmaltreated youth. AB - Throughout the life span, exposure to chronic stress such as child maltreatment is thought to contribute to future dysfunction of the stress response system (SRS) through the process of adaptive calibration. Dysfunction of the SRS is associated with numerous health and behavior problems, so it is important to understand under what conditions and what time frame adaptive calibration occurs. The present study tested for adaptive calibration of the SRS in a sample of maltreated (n = 303) and nonmaltreated (n = 151) youth during the important developmental period of adolescence. Data were used from Waves 2, 3, and 4 of a larger study of the consequences of maltreatment on health and well-being. At each time point, participants underwent the Trier Social Stress Test for Children and provided a baseline and four poststressor saliva samples to measure cortisol reactivity. Adaptive calibration was tested by performing a latent profile analysis using the five samples of salivary cortisol provided at each time point, and testing whether maltreatment status predicted the likelihood of profile membership at Time 2, Time 3, and Time 4. Three cortisol profiles emerged from the data at each time point (blunted, moderate, and elevated), and results indicated that maltreated youth were more likely than nonmaltreated youth to present with the blunted cortisol profile compared to the moderate and elevated profiles at Time 2 and Time 3, even after controlling for recent exposure to violence and trauma. At Time 4, there was no longer a difference in profile membership between maltreated and nonmaltreated youth, suggesting adaptive calibration may be a lengthy process requiring a period of years to become evident. Overall, the findings provide support for adaptive calibration and offer insight into the conditions under which adaptive calibration occurs. PMID- 26535938 TI - A multilevel prediction of physiological response to challenge: Interactions among child maltreatment, neighborhood crime, endothelial nitric oxide synthase gene (eNOS), and GABA(A) receptor subunit alpha-6 gene (GABRA6). AB - Physiological response to stress has been linked to a variety of healthy and pathological conditions. The current study conducted a multilevel examination of interactions among environmental toxins (i.e., neighborhood crime and child maltreatment) and specific genetic polymorphisms of the endothelial nitric oxide synthase gene (eNOS) and GABA(A) receptor subunit alpha-6 gene (GABRA6). One hundred eighty-six children were recruited at age 4. The presence or absence of child maltreatment as well as the amount of crime that occurred in their neighborhood during the previous year were determined at that time. At age 9, the children were brought to the lab, where their physiological response to a cognitive challenge (i.e., change in the amplitude of the respiratory sinus arrhythmia) was assessed and DNA samples were collected for subsequent genotyping. The results confirmed that complex Gene * Gene, Environment * Environment, and Gene * Environment interactions were associated with different patterns of respiratory sinus arrhythmia reactivity. The implications for future research and evidence-based intervention are discussed. PMID- 26535939 TI - Developmental pathways from child maltreatment to adolescent marijuana dependence: Examining moderation by FK506 binding protein 5 gene (FKBP5). AB - The current study examined the prospective association between child maltreatment and the development of substance use disorder in adolescence with the aim of investigating pathways underlying this relation, as well as genetic moderation of these developmental mechanisms. Specifically, we tested whether youth who experienced maltreatment prior to age 8 were at risk for the development of marijuana dependence in adolescence by way of a childhood externalizing pathway and a childhood internalizing pathway. Moreover, we tested whether variation in FK506 binding protein 5 gene (FKBP5) CATT haplotype moderated these pathways. The participants were 326 children (n =179 maltreated; n = 147 nonmaltreated) assessed across two waves of data collection (childhood: ages 7-9 and adolescence: ages 15-18). Results indicated that higher levels of child externalizing symptoms significantly mediated the effect of child maltreatment on adolescent marijuana dependence symptoms for individuals with one or two copies of the FKBP5 CATT haplotype only. We did not find support for an internalizing pathway from child maltreatment to adolescent marijuana dependence, nor did we find evidence of moderation of the internalizing pathway by FKBP5 haplotype variation. Findings extend previous research by demonstrating that whether a maltreated child will traverse an externalizing pathway toward substance use disorder in adolescence is dependent on FKBP5 genetic variation. PMID- 26535940 TI - Symptoms of major depressive disorder subsequent to child maltreatment: Examining change across multiple levels of analysis to identify transdiagnostic risk pathways. AB - Major depressive disorder (MDD) is a prevalent psychiatric condition in the child maltreatment population. However, not all children who have been maltreated will develop MDD or MDD symptoms, suggesting the presence of unique risk pathways that explain how certain children develop MDD symptoms when others do not. The current study tested several candidate risk pathways to MDD symptoms following child maltreatment: neuroendocrine, autonomic, affective, and emotion regulation. Female adolescents (N = 110; age range = 14-19) were recruited into a substantiated child maltreatment or comparison condition and completed a laboratory stressor, saliva samples, and measures of emotion regulation, negative affect, and MDD symptoms. MDD symptoms were reassessed 18 months later. Mediational modeling revealed that emotion regulation was the only significant indirect effect of the relationship between child maltreatment and subsequent MDD symptoms, demonstrating that children exposed to maltreatment had greater difficulties managing affective states that in turn led to more severe MDD symptoms. These results highlight the importance of emotion dysregulation as a central risk pathway to MDD following child maltreatment. Areas of future research and implications for optimizing prevention and clinical intervention through the direct targeting of transdiagnostic risk pathways are discussed. PMID- 26535941 TI - Maternal elaborative reminiscing mediates the effect of child maltreatment on behavioral and physiological functioning. AB - Theoretical and empirical evidence suggest that the way in which parents discuss everyday emotional experiences with their young children (i.e., elaborative reminiscing) has significant implications for child cognitive and socioemotional functioning, and that maltreating parents have a particularly difficult time in engaging in this type of dialogue. This dyadic interactional exchange, therefore, has the potential to be an important process variable linking child maltreatment to developmental outcomes at multiple levels of analysis. The current investigation evaluated the role of maternal elaborative reminiscing in associations between maltreatment and child cognitive, emotional, and physiological functioning. Participants included 43 maltreated and 49 nonmaltreated children (aged 3-6) and their mothers. Dyads participated in a joint reminiscing task about four past emotional events, and children participated in assessments of receptive language and emotion knowledge. Child salivary cortisol was also collected from children three times a day (waking, midday, and bedtime) on 2 consecutive days to assess daily levels and diurnal decline. Results indicated that maltreating mothers engaged in significantly less elaborative reminiscing than did nonmaltreating mothers. Maternal elaborative reminiscing mediated associations between child maltreatment and child receptive language and child emotion knowledge. In addition, there was support for an indirect pathway between child maltreatment and child cortisol diurnal decline through maternal elaborative reminiscing. Directions for future research are discussed, and potential clinical implications are addressed. PMID- 26535942 TI - Child maltreatment, callous-unemotional traits, and defensive responding in high risk children: An investigation of emotion-modulated startle response. AB - Child maltreatment is associated with disruptions in physiological arousal, emotion regulation, and defensive responses to cues of threat and distress, as well as increased risk for callous unemotional (CU) traits and externalizing behavior. Developmental models of CU traits have focused on biological and genetic risk factors that contribute to hypoarousal and antisocial behavior, but have focused less on environmental influences (Blair, 2004; Daversa, 2010; Hare, Frazell, & Cox, 1978; Krueger, 2000; Shirtcliff et al., 2009; Viding, Fontaine, & McCrory, 2012). The aim of the present investigation was to measure the independent and combined effects of child maltreatment and high CU traits on emotion-modulated startle response in children. Participants consisted of 132 low income maltreated (n = 60) and nonmaltreated (n = 72) children between 8 and 12 years old who attended a summer camp program. Acoustic startle response (ASR) was elicited in response to a 110-dB 50-ms probe while children viewed a slideshow of pleasant, neutral, and unpleasant IAPS images. Maltreatment status was assessed through examination of Department of Human Services records. CU traits were measured using counselor reports from the Inventory of Callous and Unemotional Traits (Frick, 2004), and conduct problems were measured using counselor and child self-report. We found no significant differences in emotion-modulated startle in the overall sample. However, significant differences in ASR by maltreatment status, maltreatment subtype, and level of CU traits were apparent. Results indicated differential physiological responses for maltreated and nonmaltreated children based on CU traits, including a pathway of hypoarousal for nonmaltreated/high CU children that differed markedly from a more normative physiological trajectory for maltreated/high CU children. Further, we found heightened ASR for emotionally and physically neglected children with high CU and elevated antisocial behavior in these children. Results provide further support for differential trajectories by which experience and biology may influence the development of antisocial behavior in youth and highlight potential avenues for intervention. PMID- 26535943 TI - Harsh parent-child conflict is associated with decreased anti-inflammatory gene expression and increased symptom severity in children with asthma. AB - Asthma is a chronic respiratory disorder that affects over 7 million children in the United States. Evidence indicates that family stressors are associated with worsening of asthma symptoms, and some research suggests that these stressful experiences engender changes in children's immune systems in ways that exacerbate airway inflammation and contribute to both acute and chronic asthma symptoms. We examined the association between observed experiences of parent-child conflict and the expression of signaling molecules involved in the transduction of anti inflammatory signals that regulate airway inflammation and obstruction. Fifty seven children and their parents participated in a conflict task, and coders rated interactions for evidence of harsh and supportive behaviors. Children reported on their perceptions of parental support and reported on their daily asthma symptoms for 2 weeks. We collected peripheral blood in children to measure leukocyte expression of messenger RNA for the glucocorticoid receptor and the beta2-adrenergic receptor. Analyses revealed that harsh conflict behaviors were associated with decreased expression of both messenger RNAs and more severe asthma symptoms. Neither supportive behaviors nor perceived parental support was associated with gene expression or asthma symptoms. These findings suggest that harsh interactions with parents are associated with downregulation of key anti inflammatory signaling molecules and difficulties breathing in children with asthma. Children with asthma who are also victims of maltreatment may be particularly susceptible to transcriptional changes in immune cells that could worsen asthma over time. PMID- 26535944 TI - Posterior structural brain volumes differ in maltreated youth with and without chronic posttraumatic stress disorder. AB - Magnetic resonance imaging studies of maltreated children with posttraumatic stress disorder (PTSD) suggest that maltreatment-related PTSD is associated with adverse brain development. Maltreated youth resilient to chronic PTSD were not previously investigated and may elucidate neuromechanisms of the stress diathesis that leads to resilience to chronic PTSD. In this cross-sectional study, anatomical volumetric and corpus callosum diffusion tensor imaging measures were examined using magnetic resonance imaging in maltreated youth with chronic PTSD (N = 38), without PTSD (N = 35), and nonmaltreated participants (n = 59). Groups were sociodemographically similar. Participants underwent assessments for strict inclusion/exclusion criteria and psychopathology. Maltreated youth with PTSD were psychobiologically different from maltreated youth without PTSD and nonmaltreated controls. Maltreated youth with PTSD had smaller posterior cerebral and cerebellar gray matter volumes than did maltreated youth without PTSD and nonmaltreated participants. Cerebral and cerebellar gray matter volumes inversely correlated with PTSD symptoms. Posterior corpus callosum microstructure in pediatric maltreatment-related PTSD differed compared to maltreated youth without PTSD and controls. The group differences remained significant when controlling for psychopathology, numbers of Axis I disorders, and trauma load. Alterations of these posterior brain structures may result from a shared trauma-related mechanism or an inherent vulnerability that mediates the pathway from chronic PTSD to comorbidity. PMID- 26535945 TI - Long-term consequences of childhood maltreatment: Altered amygdala functional connectivity. AB - Childhood maltreatment is a serious individual, familial, and societal threat that compromises healthy development and is associated with lasting alterations to emotion perception, processing, and regulation (Cicchetti & Curtis, 2005; Pollak, Cicchetti, Hornung, & Reed, 2000; Pollak & Tolley-Schell, 2003). Individuals with a history of maltreatment show altered structural and functional brain development in both frontal and limbic structures (Hart & Rubia, 2012). In particular, previous research has identified hyperactive amygdala responsivity associated with childhood maltreatment (e.g., Dannlowski et al., 2012). However, less is known about the impact of maltreatment on the relationship between the amygdala and other brain regions. The present study employed an emotion processing functional magnetic resonance imaging task to examine task-based activation and functional connectivity in adults who experienced maltreatment as children. The sample included adults with a history of substantiated childhood maltreatment (n = 33) and comparison adults (n = 38) who were well matched on demographic variables, all of whom have been studied prospectively since childhood. The maltreated group exhibited greater activation than comparison participants in the prefrontal cortex and basal ganglia. In addition, maltreated adults showed increased amygdala connectivity with the hippocampus and prefrontal cortex. The results suggest that the intense early stress of childhood maltreatment is associated with lasting alterations to frontolimbic circuitry. PMID- 26535946 TI - Sex differences in socioemotional functioning, attentional bias, and gray matter volume in maltreated children: A multilevel investigation. AB - While maltreatment is known to impact social and emotional functioning, threat processing, and neural structure, the potentially dimorphic influence of sex on these outcomes remains relatively understudied. We investigated sex differences across these domains in a large community sample of children aged 10 to 14 years (n = 122) comprising 62 children with verified maltreatment experience and 60 well-matched nonmaltreated peers. The maltreated group relative to the nonmaltreated comparison group exhibited poorer social and emotional functioning (more peer problems and heightened emotional reactivity). Cognitively, they displayed a pattern of attentional avoidance of threat in a visual dot-probe task. Similar patterns were observed in males and females in these domains. Reduced gray matter volume was found to characterize the maltreated group in the medial orbitofrontal cortex, bilateral middle temporal lobes, and bilateral supramarginal gyrus; sex differences were observed only in the supramarginal gyrus. In addition, a disordinal interaction between maltreatment exposure and sex was found in the postcentral gyrus. Finally, attentional avoidance to threat mediated the relationship between maltreatment and emotional reactivity, and medial orbitofrontal cortex gray matter volume mediated the relationship between maltreatment and peer functioning. Similar mediation patterns were observed across sexes. This study highlights the utility of combining multiple levels of analysis when studying the "latent vulnerability" engendered by childhood maltreatment and yields tentative findings regarding a neural basis of sex differences in long-term outcomes for maltreated children. PMID- 26535947 TI - Lower structural integrity of the uncinate fasciculus is associated with a history of child maltreatment and future psychological vulnerability to stress. AB - The experience of child maltreatment is a significant risk factor for the development of later internalizing disorders such as depression and anxiety. This risk is particularly heightened after exposure to additional, more contemporaneous stress. While behavioral evidence exists for such "stress sensitization," little is known about the mechanisms mediating such relationships, particularly within the brain. Here we report that the experience of child maltreatment independent of recent life stress, gender, and age is associated with reduced structural integrity of the uncinate fasciculus, a major white matter pathway between the amygdala and ventromedial prefrontal cortex, in young adults. We further demonstrate that individuals with lower uncinate fasciculus integrity at baseline who subsequently experience stressful life events report higher levels of internalizing symptomatology at follow-up. Our findings suggest a novel neurobiological mechanism linking child maltreatment with later internalizing symptoms, specifically altered structural connectivity within the brain's threat-detection and emotion-regulation circuitry. PMID- 26535948 TI - Child maltreatment, impulsivity, and antisocial behavior in African American children: Moderation effects from a cumulative dopaminergic gene index. AB - A model examining the effects of an increasing number of maltreatment subtypes experienced on antisocial behavior, as mediated by impulsivity and moderated by a polygenic index of dopaminergic genotypes, was investigated. An African American sample of children (N = 1,012, M age = 10.07) with and without maltreatment histories participated. Indicators of aggression, delinquency, and disruptive peer behavior were obtained from peer- and counselor-rated measures to form a latent variable of antisocial behavior; impulsivity was assessed by counselor report. Five genotypes in four dopaminergic genes (dopamine receptors D4, D2, known as DRD4, DRD2; dopamine active transporter 1, known as DAT1; and catechol-O methyltransferase, known as COMT) conferring heightened environmental sensitivity were combined into one polygenic index. Using structural equation modeling, a first-stage, moderated-mediation model was evaluated. Age and sex were entered as covariates, both as main effects and in interaction with maltreatment and the gene index. The model had excellent fit: chi2 (32, N = 1,012) = 86.51, p < .001; comparative fit index = 0.982, Tucker-Lewis index = 0.977, root mean square error of approximation = 0.041, and standardized root mean square residual = 0.022. The effect of maltreatment subtypes on antisocial behavior was partially mediated by impulsivity (beta = 0.173, p < .001), and these relations were moderated by the number of differentiating dopaminergic genotypes. Specifically, a significant Gene * Environment interaction (beta = 0.016, p = .013) indicated that the relation between maltreatment and impulsivity was stronger as children evinced more differentiating genotypes, thereby strengthening the mediational effect of impulsivity on antisocial behavior. These findings elucidate the manner by which maltreated children develop early signs of antisocial behavior, and the genetic mechanisms involved in greater vulnerability for maladaptation in impulse control within the context of child maltreatment. PMID- 26535949 TI - Childhood maltreatment and methylation of FK506 binding protein 5 gene (FKBP5). AB - A growing body of evidence suggests that alterations of the stress response system may be a mechanism by which childhood maltreatment alters risk for psychopathology. FK506 binding protein 51 (FKBP5) binds to the glucocorticoid receptor and alters its ability to respond to stress signaling. The aim of the present study was to examine methylation of the FKBP5 gene (FKBP5), and the role of an FKBP5 genetic variant, in relation to childhood maltreatment in a sample of impoverished preschool-aged children. One hundred seventy-four families participated in this study, including 69 with child welfare documentation of moderate to severe maltreatment in the past 6 months. The children, who ranged in age from 3 to 5 years, were racially and ethnically diverse. Structured record review and interviews in the home were used to assess a history of maltreatment, other traumas, and contextual life stressors; and a composite variable assessed the number exposures to these adversities. Methylation of two sites in intron 7 of FKBP5 was measured via sodium bisulfite pyrosequencing. Maltreated children had significantly lower levels of methylation at both CpG sites (p < .05). Lifetime contextual stress exposure showed a trend for lower levels of methylation at one of the sites, and a trend for an interaction with the FKBP5 polymorphism. A composite adversity variable was associated with lower levels of methylation at one of the sites as well (p < .05). FKBP5 alters glucocorticoid receptor responsiveness, and FKBP5 gene methylation may be a mechanism of the biobehavioral effects of adverse exposures in young children. PMID- 26535950 TI - A transactional approach to preventing early childhood neglect: The Family Check Up as a public health strategy. AB - This study examined the hypothesis that a brief, strengths-based home visiting strategy can promote positive engagement between caregiver and child and thereby reduce various forms of early childhood neglect. A total of 731 low-income families receiving services through the Women, Infants, and Children nutritional supplement program were randomized to the Women, Infants, and Children as usual or the Family Check-Up intervention. Assessments and intervention services were delivered in the home environment at ages 2, 3, 4, and 5. During the assessments, staff videotaped caregiver-child interactions and rated various features of the home environment, including the physical appropriateness of the home setting for children. Trained observers later coded the videotapes, unaware of the family's intervention condition. Specific caregiver-child interaction patterns were coded and macroratings were made of the caregiver's affection, monitoring, and involvement with the child. An intention to treat design revealed that randomization to the Family Check-Up increased duration of positive engagement between caregivers and children by age 3, which in turn was prognostic of less neglect of the child at age 4, controlling for family adversity. It was also found that family adversity moderated the impact of the intervention, such that the families with the most adverse circumstances were highly responsive to the intervention. Families with the highest levels of adversity exhibited the strongest mediation between positive engagement and reduction of neglect. Findings are discussed with respect to developmental theory and their potential implications for a public health approach to the prevention of early childhood maltreatment. PMID- 26535951 TI - Mechanisms of change: Testing how preventative interventions impact psychological and physiological stress functioning in mothers in neglectful families. AB - The present study applies a multilevel approach to an examination of the effect of two randomized preventive interventions with mothers in neglectful families who are also contending with elevated levels of impoverishment and ecological risk. Specifically, we examined how participation in either child-parent psychotherapy (CPP) or psychoeducational parenting intervention (PPI) was associated with reductions in maternal psychological parenting stress and in turn physiological stress system functioning when compared to mothers involved in standard community services as well as a demographic comparison group of nonmaltreating mothers. The resulting group sizes in the current investigation were 44 for CPP, 34 for PPI, 27 for community services, and 52 for nonmaltreating mothers. Mothers and their 13-month-old infants were randomly assigned to intervention group at baseline. Mothers completed assessments on stress within the parenting role at baseline and postintervention. Basal cortisol was sampled at postintervention and 1-year follow-up. Latent difference score analyses examined change in these constructs over time. Results suggested that mothers within the CPP intervention experienced significant declines in child-related parenting stress, while mothers in the PPI intervention reported declines in parent-related parenting stress. In turn, significant decreases in stress within the CPP mothers were further associated with adaptive basal cortisol functioning at 1-year postintervention. The results highlight the value of delineating how participation in preventive interventions aimed at ameliorating child maltreatment in neglectful families within the context of poverty may operate through improvements in psychological and physiological stress functioning. Findings are discussed with respect to the importance of multilevel assessments of intervention process and outcome. PMID- 26535952 TI - Betulinic Acid: Recent Advances in Chemical Modifications, Effective Delivery, and Molecular Mechanisms of a Promising Anticancer Therapy. AB - An important method of drug discovery is examination of diverse life forms, including medicinal plants and natural products or bioactive compounds isolated from these sources. In cancer research, lead structures of compounds from natural sources can be used to design novel chemotherapies with enhanced biological properties. Betulinic acid (3beta-hydroxy-lup-20(29)-en-28-oic acid or BetA) is a naturally occurring pentacyclic triterpene with a wide variety of biological activities, including potent antitumor properties. Non-malignant cells and normal tissues are not affected by BetA. Because BetA exerts its effects directly on the mitochondrion and triggers death of cancerous cells, it is an important alternative when certain chemotherapy drugs fail. Mitochondrion-targeted agents such as BetA hold great promise to circumvent drug resistance in human cancers. BetA is being developed by a large network of clinical trial groups with the support of the U.S. National Cancer Institute. This article discusses recent advances in research into anticancer activity of BetA, relevant modes of delivery, and the agent's therapeutic efficacy, mechanism of action, and future perspective as a pipeline anticancer drug. BetA is a potentially important agent in cancer therapeutics. PMID- 26535953 TI - Incisor display during speech and smile: Age and gender correlations. AB - OBJECTIVES: To evaluate age- and gender-related changes in the soft tissues, incisors, and gingival display during rest, speech, and posed smile. MATERIALS AND METHODS: A total of 265 participants (122 men, 143 women) ranging in age from 19 years to 60 years were recruited for this study. Participants were divided into one of the following four age groups: 19 to 24 years, 25 to 34 years, 35 to 44 years, and 45 to 60 years. Image capture was performed using standardized videographic methods. Each video produced pictures where measurements were performed: rest, speech, and smile positions. RESULTS: A statistically significant gender dimorphism was apparent in most of the variables. There was a significant increase in the upper lip length and lip commissures height with aging and more markedly in men. A greater exposure of mandibular incisor with increasing age was a feature in both genders. With increasing age there was a significant decrease in maxillary incisor display, especially for men. CONCLUSIONS: After 25 years of age there is significant difference in the aging process between men and women. Gingival and maxillary incisor display during speech and smile is a youthful and feminine characteristic. PMID- 26535954 TI - Engineered Asymmetric Heterogeneous Membrane: A Concentration-Gradient-Driven Energy Harvesting Device. AB - Engineered asymmetric membranes for intelligent molecular and ionic transport control at the nanoscale have gained significant attention and offer prospects for broad application in nanofluidics, energy conversion, and biosensors. Therefore, it is desirable to construct a high-performance heterogeneous membrane capable of coordinating highly selective and rectified ionic transport with a simple, versatile, engineered method to mimic the delicate functionality of biological channels. Here, we demonstrate an engineered asymmetric heterogeneous membrane by combining a porous block copolymer (BCP) membrane, polystyrene-b poly(4-vinylpyridine) (PS48400-b-P4VP21300), with a track-etched asymmetric porous polyethylene terephthalate membrane. The introduction of chemical, geometrical, and electrostatic heterostructures provides our heterogeneous membrane with excellent anion selectivity and ultrahigh ionic rectification with a ratio of ca. 1075, which is considerably higher than that of existing ionic rectifying systems. This anion-selective heterogeneous membrane was further developed into an energy conversion device to harvest the energy stored in an electrochemical concentration gradient. The concentration polarization phenomenon that commonly exists in traditional reverse electrodialysis can be eliminated with an asymmetric bipolar structure, which considerably increases the output power density. This work presents an important paradigm for the use of versatile BCPs in nanofluidic systems and opens new and promising routes to various breakthroughs in the fields of chemistry, materials science, bioscience, and nanotechnology. PMID- 26535955 TI - Combined Experimental and Theoretical Study on the Formation of the Elusive 2 Methyl-1-silacycloprop-2-enylidene Molecule under Single Collision Conditions via Reactions of the Silylidyne Radical (SiH; X(2)Pi) with Allene (H2CCCH2; X(1)A1) and D4-Allene (D2CCCD2; X(1)A1). AB - The crossed molecular beam reactions of the ground-state silylidyne radical (SiH; X(2)Pi) with allene (H2CCCH2; X(1)A1) and D4-allene (D2CCCD2; X(1)A1) were carried out at collision energies of 30 kJ mol(-1). Electronic structure calculations propose that the reaction of silylidyne with allene has no entrance barrier and is initiated by silylidyne addition to the pi electron density of allene either to one carbon atom (C1/C2) or to both carbon atoms simultaneously via indirect (complex forming) reaction dynamics. The initially formed addition complexes isomerize via two distinct reaction pathways, both leading eventually to a cyclic SiC3H5 intermediate. The latter decomposes through a loose exit transition state via an atomic hydrogen loss perpendicularly to the plane of the decomposing complex (sideways scattering) in an overall exoergic reaction (experimentally: -19 +/- 13 kJ mol(-1); computationally: -5 +/- 3 kJ mol(-1)). This hydrogen loss yields the hitherto elusive 2-methyl-1-silacycloprop-2 enylidene molecule (c-SiC3H4), which can be derived from the closed-shell cyclopropenylidene molecule (c-C3H2) by replacing a hydrogen atom with a methyl group and the carbene carbon atom by the isovalent silicon atom. The synthesis of the 2-methyl-1-silacycloprop-2-enylidene molecule in the bimolecular gas-phase reaction of silylidyne with allene enriches our understanding toward the formation of organosilicon species in the gas phase of the interstellar medium in particular via exoergic reactions of no entrance barrier. This facile route to 2 methyl-1-silacycloprop-2-enylidene via a silylidyne radical reaction with allene opens up a versatile approach to form hitherto poorly characterized silicon bearing species in extraterrestrial environments; this reaction class might represent the missing link, leading from silicon-bearing radicals via organosilicon chemistry eventually to silicon-carbon-rich interstellar grains even in cold molecular clouds where temperatures are as low as 10 K. PMID- 26535956 TI - Functional Near-Infrared Spectroscopy Brain Imaging Investigation of Phonological Awareness and Passage Comprehension Abilities in Adult Recipients of Cochlear Implants. AB - PURPOSE: The aim of this study was to examine how the brains of individuals with cochlear implants (CIs) respond to spoken language tasks that underlie successful language acquisition and processing. METHOD: During functional near-infrared spectroscopy imaging, CI recipients with hearing impairment (n = 10, mean age: 52.7 +/- 17.3 years) and controls with normal hearing (n = 10, mean age: 50.6 +/- 17.2 years) completed auditory tasks-phonological awareness and passage comprehension-commonly used to investigate neurodevelopmental disorders of language and literacy. RESULTS: The 2 groups had similar reaction time and performance on experimental tasks, although participants with CIs had lower accuracy than controls. Overall, both CI recipients and controls exhibited similar patterns of brain activation during the tasks. CONCLUSIONS: The results demonstrate that CI recipients show an overall neurotypical pattern of activation during auditory language tasks on which individuals with neurodevelopmental language learning impairments (e.g., dyslexia) tend to show atypical brain activation. These findings suggest that advancements in functional near-infrared spectroscopy neuroimaging with CI recipients may help shed new light on how varying types of difficulties in language processing affect brain organization for language. PMID- 26535957 TI - Underlying Mechanisms of Postoperative Pain After Laparoscopic Surgery. PMID- 26535958 TI - Web-Based Cognitive Behavioral Therapy Intervention for the Prevention of Suicidal Ideation in Medical Interns: A Randomized Clinical Trial. AB - IMPORTANCE: In the United States, approximately 1 physician dies by suicide every day. Training physicians are at particularly high risk, with suicidal ideation increasing more than 4-fold during the first 3 months of internship year. Despite this increase, to our knowledge, very few efforts have been made to prevent the escalation of suicidal thoughts among training physicians. OBJECTIVE: To assess the effectiveness of a web-based cognitive behavioral therapy (wCBT) program delivered prior to the start of internship year in the prevention of suicidal ideation in medical interns. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial conducted at 2 university hospitals with 199 interns from multiple specialties during academic years 2009-2010 or 2011-2012. The current study was conducted from May 2009 to June 2010 and May 2011 to June 2012, and data were analyzed using intent-to-treat principles, including last observation carried forward. INTERVENTIONS: Interns were randomly assigned to 2 study groups (wCBT and attention-control group [ACG]), and completed study activities lasting 30 minutes each week for 4 weeks prior to starting internship year. Participants assigned to wCBT completed online CBT modules and those assigned to ACG received emails with general information about depression, suicidal thinking, and local mental health professionals. MAIN OUTCOMES AND MEASURES: The Patient Health Questionnaire-9 was used to assess suicidal ideation (ie, "thoughts that you would be better off dead or hurting yourself in some way") prior to the start of intern year and at 3-month intervals throughout the year. RESULTS: A total of 62.2% of interns (199 of 320) agreed to take part in the study; 100 were assigned to the wCBT group and 99 to the ACG. During at least 1 point over the course of internship year, 12% of interns (12 of 100) assigned to wCBT endorsed suicidal ideation compared with 21.2% of interns (21 of 99) assigned to ACG. After adjusting for covariates identified a priori that have previously shown to increase the risk for suicidal ideation, interns assigned to wCBT were less likely to endorse suicidal ideation during internship year (relative risk, 0.40; 95% CI, 0.17- 0.91; P = .03) compared with those assigned to ACG. CONCLUSIONS AND RELEVANCE: This study demonstrates that a free, easily accessible, brief wCBT program is associated with reduced likelihood of suicidal ideation among medical interns. Prevention programs with these characteristics could be easily disseminated to medical training programs across the country. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12610000628044. PMID- 26535959 TI - Infection control implications of heterogeneous resistance mechanisms in carbapenem-resistant Enterobacteriaceae (CRE). AB - The Centers for Disease Control and Prevention (CDC) defines carbapenem-resistant Enterobacteriaceae (CRE) based upon a phenotypic demonstration of carbapenem resistance. However, considerable heterogeneity exists within this definitional umbrella. CRE may mechanistically differ by whether they do or do not produce carbapenemases. Moreover, patients can acquire CRE through multiple pathways: endogenously through antibiotic selective pressure on intestinal microbiota, exogenously through horizontal transmission or through a combination of these factors. Some evidence suggests that non-carbapenemase-producing CRE may be more frequently acquired by antibiotic exposure and carbapenemase-producing CRE via horizontal transmission, but definitive data are lacking. This review examines types of CRE resistance mechanisms, antibiotic exposure and horizontal transmission pathways of CRE acquisition, and the implications of these heterogeneities to the development of evidence-based CRE healthcare epidemiology policies. In our Expert Commentary & Five-Year View, we outline specific nosocomial CRE knowledge gaps and potential methodological approaches for their resolution. PMID- 26535960 TI - Pharmacokinetic considerations in the use of antivirals in neonates. AB - INTRODUCTION: Neonatal patients, because of the inability of their immune system to properly respond to microbial challenge, are highly susceptible to viral infections. Immunoglobulins, monoclonal antibody and antiviral drugs are used for prophylaxis and treatment of viral diseases in neonates. Neonates and, especially, preterm infants differ in drug absorption, distribution, metabolism and excretion from adults and older children. AREAS COVERED: This review will evaluate deficiencies of neonatal immune responses to microbial challenge that predispose newborns to viral infections, clinical manifestations and the treatment of viral diseases in neonates. We focus on published studies describing antiviral drug pharmacokinetics in neonates and make recommendations on the dosing of these drugs, allowing achievement of maximal clinical benefits in neonates. EXPERT OPINION: While some efforts were undertaken to study pharmacokinetics and pharmacodynamics of antiviral drugs, much more needs to be done. Current data indicate that the pharmacokinetics of antiviral drugs may vary significantly depending on gestational age, maturation processes of drug metabolizing enzymes and renal clearance. Specifics of pharmacokinetics of antiviral drugs need to be taken into consideration when they are prescribed to neonates and infants. PMID- 26535961 TI - B-Methylated Amine-Boranes: Substituent Redistribution, Catalytic Dehydrogenation, and Facile Metal-Free Hydrogen Transfer Reactions. AB - Although the dehydrogenation chemistry of amine-boranes substituted at nitrogen has attracted considerable attention, much less is known about the reactivity of their B-substituted analogues. When the B-methylated amine-borane adducts, RR'NH.BH2Me (1a: R = R' = H; 1b: R = Me, R' = H; 1c: R = R' = Me; 1d: R = R' = iPr), were heated to 70 degrees C in solution (THF or toluene), redistribution reactions were observed involving the apparent scrambling of the methyl and hydrogen substituents on boron to afford a mixture of the species RR'NH.BH3-xMex (x = 0-3). These reactions were postulated to arise via amine-borane dissociation followed by the reversible formation of diborane intermediates and adduct reformation. Dehydrocoupling of 1a-1d with Rh(I), Ir(III), and Ni(0) precatalysts in THF at 20 degrees C resulted in an array of products, including aminoborane RR'N?BHMe, cyclic diborazane [RR'N-BHMe]2, and borazine [RN-BMe]3 based on analysis by in situ (11)B NMR spectroscopy, with peak assignments further supported by density functional theory (DFT) calculations. Significantly, very rapid, metal-free hydrogen transfer between 1a and the monomeric aminoborane, iPr2N?BH2, to yield iPr2NH.BH3 (together with dehydrogenation products derived from 1a) was complete within only 10 min at 20 degrees C in THF, substantially faster than for the N-substituted analogue MeNH2.BH3. DFT calculations revealed that the hydrogen transfer proceeded via a concerted mechanism through a cyclic six-membered transition state analogous to that previously reported for the reaction of the N-dimethyl species Me2NH.BH3 and iPr2N?BH2. However, as a result of the presence of an electron donating methyl substituent on boron rather than on nitrogen, the process was more thermodynamically favorable and the activation energy barrier was reduced. PMID- 26535962 TI - Complex Coacervate Core Micelles with Spectroscopic Labels for Diffusometric Probing of Biopolymer Networks. AB - We present the design, preparation, and characterization of two types of complex coacervate core micelles (C3Ms) with cross-linked cores and spectroscopic labels and demonstrate their use as diffusional probes to investigate the microstructure of percolating biopolymer networks. The first type consists of poly(allylamine hydrochloride) (PAH) and poly(ethylene oxide)-poly(methacrylic acid) (PEO-b PMAA), labeled with ATTO 488 fluorescent dyes. We show that the size of these probes can be tuned by choosing the length of the PEO-PMAA chains. ATTO 488 labeled PEO113-PMAA15 micelles are very bright with 18 dye molecules incorporated into their cores. The second type is a (19)F-labeled micelle, for which we used PAH and a (19)F-labeled diblock copolymer tailor-made from poly(ethylene oxide) poly(acrylic acid) (mPEO79-b-PAA14). These micelles contain approximately 4 wt % of (19)F and can be detected by (19)F NMR. The (19)F labels are placed at the end of a small spacer to allow for the necessary rotational mobility. We used these ATTO- and (19)F-labeled micelles to probe the microstructures of a transient gel (xanthan gum) and a cross-linked, heterogeneous gel (kappa-carrageenan). For the transient gel, sensitive optical diffusometry methods, including fluorescence correlation spectroscopy, fluorescence recovery after photobleaching, and super resolution single nanoparticle tracking, allowed us to measure the diffusion coefficient in networks with increasing density. From these measurements, we determined the diameters of the constituent xanthan fibers. In the heterogeneous kappa-carrageenan gels, bimodal nanoparticle diffusion was observed, which is a signpost of microstructural heterogeneity of the network. PMID- 26535963 TI - Sperm Aneuploidy in Faroese Men with Lifetime Exposure to Dichlorodiphenyldichloroethylene (p,p'-DDE) and Polychlorinated Biphenyl (PCB) Pollutants. AB - BACKGROUND: Although it is known that sperm aneuploidy contributes to early pregnancy losses and congenital abnormalities, the causes are unknown and environmental contaminants are suspected. OBJECTIVES: Our goal was to evaluate associations between lifetime exposure to organochlorines, specifically dichlorodiphenyldicholorethylene (p,p'-DDE) and polychlorinated biphenyls (PCBs), and sperm aneuploidy in men from the general population of the Faroe Islands, a population with a known history of organochlorine exposures. METHODS: Serum and semen samples from men (n = 90) 22-44 years old who participated in Faroe Islands health studies were analyzed for p,p'-DDE and PCBs 118, 138, 153, and 180 and adjusted for total lipids. Cord blood and age-14 serum were available for a subgroup (n = 40) and were also analyzed for p,p'-DDE and PCBs. Sperm fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 was used to determine rates of XX18, XY18, YY18, and total disomy. Multivariable adjusted Poisson models were used to estimate the relationship between organochlorine exposure and sperm disomy outcomes. RESULTS: Adult p,p'-DDE and total PCB serum concentrations were both associated with significantly increased rates of XX18, XY18, and total disomy. Age-14 p,p'-DDE and PCB concentrations were both associated with significantly increased rates of XX, XY, and total disomy in adulthood. Associations between cord blood concentrations of p,p'-DDE and PCBs and sperm disomy in adulthood were not consistently significant. CONCLUSIONS: Organochlorine exposures measured at age 14 and in adulthood were associated with sperm disomy in this sample of high-exposure men, suggesting that the impacts of persistent pollutants on testicular maturation and function require further investigation. CITATION: Perry MJ, Young HA, Grandjean P, Halling J, Petersen MS, Martenies SE, Karimi P, Weihe P. 2016. Sperm aneuploidy in Faroese men with lifetime exposure to dichlorodiphenyldichloroethylene (p,p'-DDE) and polychlorinated biphenyl (PCB) pollutants. Environ Health Perspect 124:951-956; http://dx.doi.org/10.1289/ehp.1509779. PMID- 26535964 TI - Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: Restorative effect of pharmacological intervention. AB - Major depression is a complex disease that originates from the interaction between a genetic background of susceptibility and environmental factors such as stress. At molecular level, it is characterized by dysfunctions of multiple systems including neurotransmitters, hormones, signalling pathways, neurotrophic and neuroplastic molecules and - more recently - inflammatory mediators. Accordingly, in the present study we used the chronic mild stress (CMS) paradigm in the rat to elucidate to what extent brain inflammation may contribute to the development and/or the maintenance of an anhedonic phenotype and how pharmacological intervention may interfere with such behavioral and molecular stress-induced alterations. To this aim, adult male rats were exposed to CMS for 2 weeks and the cerebral expression of several mediators of the inflammatory system was evaluated in the hippocampus and prefrontal cortex of both stressed and control animals in parallel with the sucrose intake. Next, the animals that showed a decreased sucrose consumption were exposed to five further weeks of CMS and treated with the antidepressants imipramine or agomelatine, or the antipsychotic lurasidone. Our results demonstrate that only the stressed animals that were characterized by a deficit in sucrose intake showed increased expression of the pro-inflammatory cytokines IL-1beta, IL-6 and up-regulation of markers and mediators of microglia activation such as CD11b, CX3CL1 and its receptor CX3CR1 in comparison with stress-resilient animals. Some of these molecular alterations persisted also after longer stress exposure and were modulated, similarly to the behavioral effects of CMS, by chronic pharmacological treatment. These data suggest that neuroinflammation may have a key role in the pathological consequences of stress exposure, thus contributing to the subject's vulnerability for depression. PMID- 26535965 TI - Driving carbon flux through exogenous butyryl-CoA: Acetate CoA-transferase to produce butyric acid at high titer in Thermobifida fusca. AB - Butyric acid, a 4-carbon short chain fatty acid, is widely used in chemical, food, and pharmaceutical industries. The low activity of butyryl-CoA: acetate CoA transferase in Thermobifida fusca muS, a thermophilic actinobacterium whose optimal temperature was 55 degrees C, was found to hinder the accumulation of high yield of butyric acid. In order to solve this problem, an exogenous butyryl CoA: acetate CoA-transferase gene (actA) from Thermoanaerobacterium thermosaccharolyticum DSM571 was integrated into the chromosome of T. fusca muS by replacing celR gene, forming T. fusca muS-1. We demonstrated that on 5g/L cellulose, the yield of butyric acid by the engineered muS-1 strain was increased by 42.9 % compared to the muS strain. On 100g/L of cellulose, the muS-1 strain could consume 90.5% of total cellulose in 144h, with 33.2g/L butyric acid produced. Furthermore, on the mix substrates including the major components of biomass: cellulose, xylose, mannose and galactose, 70.4g/L butyric acid was produced in 168h by fed-batch fermentation. To validate the ability of fermenting biomass, the muS-1 strain was grown on the milled corn stover ranging from 200 to 250MUm. The muS-1 strain had the highest butyrate titer 17.1g/L on 90g/L corn stover. PMID- 26535966 TI - Balancing opioid-induced gastrointestinal side effects with pain management: Insights from the online community. AB - Opioids cause gastrointestinal (GI) symptoms such as nausea, vomiting, pain, and (in 40 percent) constipation that diminish patients' quality of life. Outside traditional surveys, little is known about the opioid-induced constipation (OIC) patient experience and its impact on pain management. The purpose of this study was to use data from social media platforms to qualitatively examine patient beliefs about OIC and other prominent GI side effects, their impact on effective pain management and doctor-patient interaction. The authors collected Tweets from March 25 to July 31, 2014, and e-forum posts from health-related social networking sites regardless of timestamp. The authors identified specific keywords related to opioids and GI side effects to locate relevant content in the dataset, which was then manually coded using ATLAS.ti software. The authors examined 2,519,868 Tweets and more than 1.8 billion e-forum posts, of which, 88,586 Tweets and 9,767 posts satisfied the search criteria. Three thousand three individuals experienced opioidinduced GI side effects, mostly related to phenanthrenes (n = 1,589), and 1,274 (42.4 percent) individuals described constipation. Over-the-counter medications and nonevidence-based natural approaches were most commonly used to alleviate constipation. Many individuals questioned, rotated, reduced, or stopped their opioid treatments as a result of their GI side effects. Investigation of social media reveals a struggle to balance pain management with opioid-induced GI side effects, especially constipation. Individuals are often unprepared to treat OIC, to modify opioid regiments without medical advice, and to resort to using natural remedies and treatments lacking scientific evidence of effectiveness. These results identify opportunities to improve physician-patient communication and explore effective treatment alternatives. PMID- 26535967 TI - Tolerability and efficacy of tapentadol extended release in elderly patients >= 75 years of age with chronic osteoarthritis knee or low back pain. AB - OBJECTIVE: Management of chronic pain in elderly adult patients is often complicated by analgesic medication-related side effects. This post hoc analysis of pooled data evaluated the tolerability and analgesic efficacy of tapentadol extended release (ER) compared with oxycodone controlled release (CR) in elderly adult patients (>= 75 years of age) with moderate to severe, chronic osteoarthritis knee or low back pain. METHODS: Data were pooled from three similarly designed, randomized, doubleblind, placebo- and active-controlled, phase 3 studies of tapentadol ER for moderate to severe, chronic osteoarthritis knee (NCT00421928, NCT00486811) or low back (NCT00449176) pain, and data for patients >= 75 years of age were evaluated. Each study consisted of a 3-week titration and 12-week maintenance period. Patients received placebo, tapentadol ER (100-250 mg bid), or oxycodone HCl CR (20-50 mg bid). Tolerability was evaluated using adverse event reporting. Efficacy was evaluated using pain intensity ratings (11-point numerical rating scale). RESULTS: For patients >= 75 years of age (n = 210), incidences of gastrointestinal treatment-emergent adverse events (TEAEs) overall and TEAEs of vomiting and the composite of nausea and/or vomiting were significantly lower in the tapentadol ER group compared with the oxycodone CR group (all p <= 0.0206). Tapentadol ER treatment was associated with significant reductions in pain intensity from baseline to week 15 compared with placebo (p = 0.0075); differences between the oxycodone CR and placebo groups failed to reach statistical significance (p = 0.1195), likely related to a higher treatment discontinuation rate in the oxycodone CR group. No significant differences were observed between the tapentadol ER and oxycodone CR groups in the change in pain intensity from baseline to week 15 (p = 0.2135). CONCLUSIONS: In elderly adult patients >= 75 years of age with moderate to severe, chronic osteoarthritis knee or low back pain, tapentadol ER (100-250 mg bid) provided significant pain relief compared with placebo and had a better overall gastrointestinal tolerability profile than oxycodone CR. PMID- 26535968 TI - A pharmacokinetic evaluation of single and multiple doses of extended-release hydrocodone bitartrate in subjects experiencing surgical or osteoarthritic pain. AB - OBJECTIVES: To assess the single-dose and steady-state pharmacokinetics of a single-entity hydrocodone extended-release (ER) formulation in patients enrolled in two separate phase 2 clinical studies. SETTING: Both studies were multicenter clinical studies. SUBJECTS AND INTERVENTIONS: In study 1, 115 subjects with postsurgical pain (bunionectomy) received single doses of 10, 20, 30, or 40 mg hydrocodone-ER, 10 mg hydrocodone/325 mg acetaminophen immediate-release (IR), or placebo. In study 2, 37 subjects with osteoarthritic pain received doses of 10, 20, 30, or 40 mg of hydrocodone- ER twice-daily for 7 days. Venous blood samples were taken periodically up to 24 hours postdosing after the single dose (study 1) or after 7 days of dosing (study 2) and were assayed for concentrations of hydrocodone and its major metabolites. MAIN OUTCOME MEASURES: Standard pharmacokinetic parameters were estimated by noncompartmental analysis methods. RESULTS: Following a single dose of hydrocodone-ER, Tmax was prolonged to approximately 6 hours at all dose levels of hydrocodone-ER compared with 2.9 hours for the IR formulation. All doses of hydrocodone-ER formulations provided prolonged and sustained release of hydrocodone throughout the 12-hour dosing interval with reduced peak-to-trough fluctuation at steady state compared with hydrocodone/acetaminophen-IR comparator. Both single-dose and steadystate mean Cmax and AUClast values showed reasonable dose-proportionality. Norhydrocodone and hydromorphone plasma concentrations were 32-38 percent and <2.1 percent, respectively, of hydrocodone concentrations in both studies. CONCLUSIONS: The sustained plasma concentrations of hydrocodone support twice-daily dosing with a 12-hour dosing interval. PMID- 26535969 TI - Relationship between change in pain intensity and functional outcomes in patients with chronic pain receiving twice daily extended-release hydrocodone bitartrate. AB - OBJECTIVE: Evaluate levels of pain relief achieved in patients with chronic pain treated with hydrocodone-extended release (HC-ER) up to 48 weeks and show that these levels were associated with secondary functional and global outcomes. DESIGN: Post hoc analyses were based on a previously reported study that started with an open-label conversion/titration phase for <= 6 weeks followed by an openlabel 48-week treatment phase. SETTING: Private practice and institutional pain centers. PARTICIPANTS: Three hundred ninety-one opioid-experienced subjects with moderate to severe pain for >= 3 months. INTERVENTIONS: Individualized doses (20-300 mg) of extended-release hydrocodone every 12 hours. MAIN OUTCOME: Almost 60 percent (232/391) of subjects achieved moderate or substantial levels of pain relief (>= 30 percent reduction in pain score) during the study. RESULTS: Subjects who achieved moderate or substantial pain relief demonstrated significant (p <0.001) improvements in Oswestry Disability Inventory (ODI), all pain interference outcomes, and Subject Global Assessment of Medication. Subjects with substantial pain relief had decreases in ODI, Hospital Anxiety and Depression Scale (HADS) anxiety, and HADS depression scores of -13.4 +/- 14.92, 1.9 +/- 3.37, and -1.7 +/- 3.26, respectively. The five most commonly reported treatment-emergent adverse events were constipation (12.5 percent), back pain (11.1 percent), nausea (9.9 percent), vomiting (9.7 percent), and arthralgia (7.8 percent) and are consistent with opioid therapy. CONCLUSIONS: Moderate or substantial levels of pain relief were associated with the greatest functional improvements in patients treated with HC-ER. These results may help define success of opioid therapy and determine if it should be continued or an alternative treatment should be tried. PMID- 26535970 TI - Twelve-month, open-label assessment of long-term safety and abuse potential of hydrocodone extended-release formulated with abuse-deterrence technology in patients with chronic pain. AB - OBJECTIVE: To evaluate long-term safety of hydrocodone extended-release (ER) formulated with CIMA((r)) Abuse-Deterrence Technology platform. DESIGN: Phase 3, open-label study. SETTING: Sixty-one US study centers. PATIENTS: Patients with chronic pain newly enrolled or rolled over from a 12-week, placebo-controlled hydrocodone ER study; 330 patients enrolled, 329 patients received study drug, and 189 completed the study. INTERVENTION: After titrating to an analgesic dose (15-90 mg every 12 hours), patients received <= 52 weeks of open-label treatment. MAIN OUTCOME MEASURES: SAFETY: adverse events (AEs), vital signs, laboratory values, electrocardiograms, and audiometry. Abuse potential: drug loss and diversion, Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP R), Addiction Behaviors Checklist (ABC), Current Opioid Misuse Measure (COMM) questionnaires, and Patient Global Assessment (PGA) of pain control. RESULTS: Of 329 patients who received >= 1 hydrocodone ER dose, 284 (86 percent) reported >= 1 AE and 27 (8 percent) experienced >= 1 serious AE. Sixty-two (19 percent) patients withdrew because of AEs, and two AEs leading to death were reported. No serious AEs or AEs leading to death were considered treatment related by the investigator. There were no clinically meaningful trends in other safety assessments. SOAPP-R, ABC, and COMM scores demonstrated low risk of aberrant drug related behavior. Good/excellent PGA responses were reported by 20 percent of patients at baseline and 75 percent at endpoint. The incidence of drug loss (11 percent) and diversion (2 percent) was low. CONCLUSIONS: Hydrocodone ER demonstrated acceptable safety when administered for <= 12 months in patients with chronic pain. Low occurrence of aberrant drugrelated behavior may support the abuse-deterrence properties of hydrocodone ER. PMID- 26535971 TI - Assessment of the use of oral fluid as a matrix for drug monitoring in patients undergoing treatment for opioid addiction. AB - Drug testing is an important clinical tool that is available to physicians who are assessing the effectiveness of drug treatment as well as patient compliance to the administered program. While urine has traditionally been the matrix of choice for drug monitoring, oral fluid, a filtrate of the blood, has shown great promise as an alternative matrix for such applications. Oral fluid collection can be accomplished without the need for highly trained medical staff through the use of a simple, noninvasive oral fluid collection device, which obtains an adequate sample in only a few minutes. There has been a significant amount of research performed on the use of oral fluid for forensic toxicology application; however, more studies assessing the use of oral fluid drug testing are required to validate its ability to achieve clinical drug monitoring goals. Testing for various drugs in oral fluid may yield a different result when compared to the same drugs in urine, requiring an assessment of the utility of oral fluid for such practices. The purpose of this study was to examine the application of oral fluid drug testing in patients undergoing buprenorphine treatment for opioid dependence. A retrospective analysis of drug testing results obtained from 6,928 patients (4,560 unobserved urine collections and 2,368 observed oral fluid collections) monitored for heroin metabolite, amphetamine, benzodiazepines, buprenorphine, tetrahydrocannabinol, cocaine, codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone was completed. Results of this statistical exercise indicated that patients undergoing observed oral fluid collection tested positive more frequently than those unobserved urine collections for several illicit drugs and prescription medications targeted. Oral fluid was shown to detect illicit drug use as well as noncompliance in this patient population under the studied conditions more often than the urine specimens. PMID- 26535972 TI - Opioid rotation: A case example using methadone in spinal cord injury. AB - Opioid rotation is a practice used when patients with chronic pain have insufficient analgesia, experience unwanted opioid-related adverse reactions, or other pharmacologic challenges with their current opioid. Methadone is an opioid with unique pharmacological properties, which render it clinically distinct from other opioids. The drug's potential clinical benefits in treating nociceptive and neuropathic pain are coupled with risks of serious, life-threatening adverse reactions. Its unique pharmacokinetic profile contributes added complexity; therefore, clinicians should be experienced with its dosing and monitoring. This report discusses the successful use of methadone during opioid rotation for chronic pain secondary to spinal cord injury. PMID- 26535973 TI - Furosemide as a potential unintended urine drug screen confounder during methadone maintenance treatment. AB - Patients receiving chronic methadone maintenance treatment (MMT) for addiction are closely monitored for signs of relapse. Urine drug screen (UDS) comprises a major component of ongoing patient assessment. As patients continue with MMT, developing medical conditions may necessitate addition of medications that interfere with UDS. Although widely accepted as masking agents, little guidance is available regarding management of patients receiving MMT with legitimate medical need for diuretics. The following describes a case in which furosemide clinically interfered with UDS interpretation for a patient receiving MMT. Potential management strategies are also discussed. PMID- 26535974 TI - Ecophysiology of Fusarium temperatum isolated from maize in Argentina. AB - The effect of water activity (aw = 0.95, 0.98 and 0.995), temperature (15, 25 and 30 degrees C), incubation time (7, 14, 21 and 28 days), and their interactions on growth and moniliformin (MON), beauvericin (BEA), fusaproliferin (FUS) and fumonisin B1 (FB1) production by two strains of Fusarium temperatum isolated from Argentinean maize were determined in vitro on sterile layers of maize grains. The results showed that there was a wide range of conditions for growth and mycotoxins production by F. temperatum. Both strains were found to grow faster with increasing aw and at 30 degrees C. In relation to mycotoxin production, the two strains produced more FUS than the other mycotoxins regardless of aw or temperature evaluated (maximum = 50,000 MUg g(-1)). For FUS, MON and BEA, the maximum levels were observed at 0.98 aw and 30 degrees C (50,000, 5000 and 2000 MUg g(-1) respectively). The lowest levels for these three mycotoxins were detected at 15 degrees C and 0.95 aw (1700 and 100 MUg g(-1) for FUS and MON respectively), and at 0.98 aw (400 MUg g(-1) for BEA). The maximum levels of FB1 were produced at 15 degrees C and 0.98 aw (1000 MUg g(-1)). At all aw and temperatures combinations evaluated there was an increase in toxin concentrations with time incubation. The maximum levels were detected at 21 days. Statistical analyses of aw, temperature, incubation time, and the two- and three-way interactions between them showed significant effects on mycotoxins production by F. temperatum. For its versatility on growth and mycotoxin production, F. temperatum represents a toxicological risk for maize in the field and also during grain storage. PMID- 26535975 TI - Association of Metabolic Syndrome with Chronic Kidney Disease in Elderly Japanese Women: Comparison by Estimation of Glomerular Filtration Rate from Creatinine, Cystatin C, and Both. AB - BACKGROUND: Associations between metabolic syndrome (MetS) and chronic kidney disease (CKD) has not been extensively studied in elderly Asians, who in general have lower body mass index (BMI) than European populations. METHODS: A cross sectional analysis was conducted including 159 community-living elderly Japanese women. MetS was defined by the modified National Cholesterol Education Program Adult Treatment Panel III criteria, but using a BMI >=25 kg/m(2) instead of waist circumference and renal function was assessed according to the Kidney Disease Outcomes Quality Initiative CKD classification. Creatinine-based and cystatin C based estimated glomerular filtration rate (eGFR) and the average of the two eGFRS were used. RESULTS: Prevalence of CKD was much higher when creatinine-based eGFR was used than the prevalence obtained when cystatin-C based equations were used (46.5% vs. 12.6%, P < 0.001). Eighteen (11.3%) women met MetS criteria. Both the presence of MetS and the number of MetS components were associated with higher prevalence of CKD using the average eGFR (all P < 0.05) but not using creatinine-based (P = 0.86) and cystatin C-based (P = 0.12) eGFR alone. Lower average eGFR and higher prevalence of CKD using average eGFR were evident in even women with only one MetS component, 89% of whom had elevated blood pressure. CONCLUSIONS: Prevalence of CKD varied substantially depending on the used equation. In nonobese, elderly Japanese women, both the presence of MetS and the number of MetS components were associated with higher prevalence of CKD and elevated blood pressure may play an important role in these associations. These findings should be confirmed in studies employing more participants with MetS diagnosed using standard criteria (waist circumference instead of BMI). PMID- 26535976 TI - Comparative Transcriptomic Analyses of Three Species of Placobdella (Rhynchobdellida: Glossiphoniidae) Confirms a Single Origin of Blood Feeding in Leeches. AB - One of the recalcitrant questions regarding the evolutionary history of clitellate annelids involves the feeding preference of the common ancestor of extant rhynchobdellid (proboscis bearing) and arhynchobdellid (jaw bearing) leeches. Whereas early evidence, based on morphological data, pointed towards independent acquisitions of blood feeding in the 2 orders, molecular-based phylogenetic data suggest that the ancestor of modern leeches was a sanguivore. Here, we use a comparative transcriptomic approach in order to increase our understanding of the diversity of anticoagulation factors for 3 species of the genus Placobdella, for which comparative data have been lacking, and inspect these in light of archetypal anticoagulant data for both arhynchobdellid and other rhynchobdellid species. Notwithstanding the varying levels of host specificity displayed by the 3 different species of Placobdella, transcriptomic profiles with respect to anticoagulation factors were largely similar -this despite the fact that Placobdella kwetlumye only retains a single pair of salivary glands, as opposed to the 2 pairs more common in the genus. Results show that 9 different anticoagulant proteins and an additional 5 putative antihemostasis proteins are expressed in salivary secretions of the 3 species. In particular, an ortholog of the archetypal, single-copy, anticoagulant hirudin (not previously available as comparative data for rhynchobdellids) is present in at least 2 of 3 species examined, corroborating the notion of a single origin of blood feeding in the ancestral leech. PMID- 26535977 TI - The Predictive Value of Preschool Language Assessments on Academic Achievement: A 10-Year Longitudinal Study of Icelandic Children. AB - PURPOSE: The purpose of this study was to investigate the relationship between language knowledge at 5 years of age and later academic achievement throughout compulsory school in Iceland. METHOD: Between 1997 and 1998, 267 Icelandic preschool children aged from 5;4 (years;months) to 5;10 were tested with the HLJOM-2 (an Icelandic test of phonological awareness; Simonardottir, Einarsdottir, & Bjornsdottir, 2002) and the Icelandic version of the Test of Language Development-Primary: Second Edition (TOLD-2P; oral comprehension tasks; Simonardottir, Gudmundsson, Skulason, & Petursdottir, 1995). In 2011 these individuals, now aged 18-19 years, were contacted again. Of the original 267 participants, 221 (83%) gave permission to link their results from the preschool language assessments with their performance on national tests in 4th, 7th, and 10th grades. RESULTS: The results showed strong correlation between phonological awareness (as measured by the HLJOM-2) and academic achievement (Icelandic and mathematics) in 4th, 7th, and 10th grades. There was also a significant but lower correlation with oral comprehension skills, as measured with the TOLD-2P. Regression analysis showed that the preschool oral-language assessments in phonological awareness and oral comprehension explained between 35% and 43% of variability in scores on national tests in Icelandic and between 20% and 39% of variability in scores in mathematics. CONCLUSION: Preschool language knowledge is a reliable predictor of later academic achievement. PMID- 26535978 TI - The Importance of Being Cured: A Chronic Myeloid Leukemia Perspective. PMID- 26535979 TI - Pseudomyxoma-type Invasion in Gastrointestinal Adenocarcinomas of Endometrium and Cervix: A Report of 2 Cases. AB - This paper presents a clinicopathologic and immunohistochemical report of 2 gastrointestinal-type tumors, one in the endometrium and the other in the cervix. Both showed extensive invasion into the pelvic structures with acellular mucin, identical to pseudomyxoma but in the absence of appendiceal or ovarian tumors. Case 1 was an 81-yr-old female with a Stage III endometrial gastrointestinal-type adenocarcinoma who had had an endometrial polyp with intestinal metaplasia 4 years previously. Case 2 was a 68-yr-old female with Stage IIIB endocervical gastrointestinal-type adenocarcinoma. Both were associated with a pseudomyxoma type of invasion, which in the endometrial case was transmural through the myometrium, and in the cervical case involved parametria, pelvic floor, and lymph nodes. Immunohistochemically, both tumors had a gastrointestinal phenotype coexpressing cytokeratins 7 and 20, CDX2, villin, MUC2, MUC5AC, and MUC6 and were negative for human papillomavirus, analyzed by real-time polymerase chain reaction. The first case exemplifies intestinal endometrial metaplasia as a precursor lesion of the rare gastrointestinal type of adenocarcinoma and also proves its progression into carcinoma. The second case exemplifies the highly aggressive nature of cervical invasion forming mucin lakes. Extensive pseudomyxoma in the uterus and cervix was associated with high clinical stages with marked lymphovascular invasion and lymph node metastases. PMID- 26535980 TI - Aberrant Expression of the Cell Polarity Regulator aPKClambda/iota is Associated With Disease Progression in Cervical Intraepithelial Neoplasia (CIN): A Possible Marker for Predicting CIN Prognosis. AB - Atypical protein kinase C lambda/iota (aPKClambda/iota) is a regulator of epithelial cellular polarity. It is also overexpressed in several cancers and functions in cell proliferation and invasion. Therefore, we hypothesized that aPKClambda/iota may be involved in development and progression of cervical intraepithelial neoplasia (CIN), the precancerous disease of cervical cancer induced by human papillomavirus. To do this, we investigated the relationship between aPKClambda/iota expression and CIN. aPKClambda/iota expression level and subcellular localization were assessed in 192 CIN biopsy samples and 13 normal epithelial samples using immunohistochemistry. aPKClambda/iota overexpression (normal epithelium, 7.7%; CIN1, 41.7%; CIN2/3, 76.4%) and aPKClambda/iota nuclear localization (normal epithelium, 0.0%; CIN1, 36.9%; CIN2/3, 78.7%) were higher in CIN samples than normal samples (P<0.05), suggesting that CIN grade is related to aPKClambda/iota overexpression and nuclear localization. Then, 140 CIN cases were retrospectively analyzed for 4-yr cumulative disease progression and regression rates using the Cox proportional hazards model. CIN1 cases with aPKClambda/iota overexpression or aPKClambda/iota nuclear localization had a higher progression rate than CIN1 cases with normal aPKClambda/iota expression levels or cytoplasmic localization (62.5% vs. 9.7% and 63.1% vs. 9.4%, respectively; P<0.001). Multivariate analysis indicated that human papillomavirus types 16 and 18, aPKClambda/iota overexpression (hazard ratio=4.26; 95% confidence interval, 1.50 12.1; P=0.007), and aPKClambda/iota nuclear localization (hazard ratio=3.59; 95% confidence interval, 1.24-10.4; P=0.019) were independent risk factors for CIN1 progression. In conclusion, aPKClambda/iota could be useful for the therapeutic management of patients with CIN, particularly those with non-human papillomavirus 16/18 types. PMID- 26535981 TI - GHRH Receptor Expression in Malignant Mixed Mullerian Tumors: A Potentially Targetable Biopredictor. AB - Malignant mixed Mullerian tumors (MMMTs) are aggressive malignant neoplasms with a high recurrence rate and poor prognosis. Despite advances in adjuvant therapies in recent years, the prognosis of these tumors has not improved. Growth hormone releasing hormone (GHRH) is produced by a variety of malignant tumors and acts as a growth factor in an autocrine/paracrine manner. Its function requires the presence of its receptors to exert its effects on neoplastic cells. In this study, we evaluated the expression of GHRH receptors (GHRH-R) in a group of MMMTs. Thirty-one examples of MMMTs from endometrium, ovary, uterine tube, and pelvic peritoneum were retrieved from the files of Department of Pathology at the University of Miami, Jackson Memorial Hospital. Immunohistochemistry for GHRH-R was performed on paraffin sections and the staining results were evaluated separately in both epithelial and mesenchymal components of each tumor. The presence of pituitary type growth hormone-releasing hormone receptor mRNA and that of its biologically active splice variant were also evaluated by RT-PCR in 6 of the tumors. Positive immunohistochemical reaction for GHRH-R was detected in 30 tumors (96%). The epithelial and sarcomatous components were positive in 30 (96%), whereas one endometrial tumor was negative in both components. The mRNA for GHRH-R and its splice variant was found in all 6 tested tumors. This study shows that GHRH-R is expressed by the majority of MMMTs in both epithelial and mesenchymal components. This finding could potentially serve as a basis for therapeutic approaches using synthetic peptide antagonists of GHRH-R that have shown significant efficacy with minimal side effects in experimental models. PMID- 26535982 TI - Vulval Microglandular Adenosis-like Neoplasm With Chondromyxoid Stroma: Report of a Unique Case. AB - Microglandular adenosis of the breast is an uncommon lesion which can mimic tubular carcinoma. It is composed of small round tubules lined by a single layer of flat or cuboidal epithelial cells, often with eosinophilic colloid-like material within the lumen. The absence of a myoepithelial cell layer and preservation of basement membrane around the tubules are characteristic features. We report the first case of a vulval "neoplasm" in a 60-yr-old woman showing features identical to microglandular adenosis of the breast except for the presence of an unusual chondromyxoid stroma. This case reinforces the analogy between vulval lesions derived from anogenital mammary-like glands and breast lesions and also adds a new entity to the list of lesions arising from these glands. PMID- 26535983 TI - The Impact on Survival of an Extensive Sex Cord-like Component in Mullerian Adenosarcomas: A Study Comprising 6 Cases. AB - Mullerian adenosarcomas are uncommon tumors of the female genital tract characterized by a synchronous proliferation of benign glands and sarcomatous stroma. In general, uterine Mullerian adenosarcomas are associated with a low risk of recurrence. The presence of "stromal overgrowth" (SO), historically defined by an estimate of the volume of sarcoma growing independently of epithelium, is associated with deep myometrial invasion, presence of heterologous elements, and poor outcomes. Very rarely, the stromal component can harbor foci resembling ovarian sex cord tumors (FROSCT). The aim of this study was to determine whether the presence of an extensive FROSCT component in Mullerian adenosarcomas has an impact on survival, akin to more typical types of SO. Six patients were included in this study. Age ranged from 39 to 71 yr. Five patients presented with uterine lesions (4 intracavitary, 1 isthmic), and 1 was located in the ovary. Tumors ranging in size from 2.5 to 19 cm were all diagnosed as Stage I. Morphologically, all had prominent FROSCT-like components that comprised 60% to 90% of tumor volume. Immunohistochemically, the FROSCT component was positive for CAM 5.2, vimentin, WT1, CD56, alpha-inhibin, calretinin, androgen and progesterone receptors, alpha-actin, and desmin. All patients are alive without disease at 26 to 102 mo. Compared with adenosarcomas with typical forms of SO, FROSCT overgrowth is low grade and not associated with recurrence or metastasis in this small series. Therefore, Mullerian adenosarcoma with extensive FROSCT should not be equated with SO. PMID- 26535984 TI - Invasive Complete Hydatidiform Moles: Analysis of a Case Series With Genotyping. AB - Complete hydatidiform moles (CHM) are purely androgenetic conceptions, with most (~85%) arising from fertilization of an egg lacking maternal DNA by a single sperm that duplicates (homozygous/monospermic 46,XX) and a small subset arising via fertilization by 2 sperms (heterozygous/dispermic 46,XY or 46,XX). It remains controversial if heterozygous/dispermic CHMs have a significantly greater risk of persistent gestational trophoblastic disease. Analysis of zygosity of CHMs with and without invasion at presentation, including invasive CHMs with concurrent atypical trophoblastic proliferations concerning for or consistent with choriocarcinoma, has not been specifically addressed. In a prospective series of 1024 products of conception specimens subjected to immunohistochemical analysis of p57 expression and molecular genotyping with short tandem-repeat markers, 288 CHMs were diagnosed, of which 126 were genotyped, including 16 invasive CHMs. Zygosity was compared between those with and without invasion. Of the 16 study cases, 12 (75%) were homozygous/monospermic XX and 4 (25%) were heterozygous/dispermic (3 XY and 1 XX). Of the 110 genotyped noninvasive CHMs, 96 (87%) were homozygous/monospermic XX and 14 (13%) were heterozygous/dispermic (12 XY, 2 XX). Comparison of the zygosity results for the invasive CHMs (study group) with the noninvasive CHMs in the database did not demonstrate a statistically significant difference (P=0.24, Fisher exact test). In addition, of the 3 cases associated with metastatic gestational trophoblastic disease (pulmonary nodules) at presentation, 2 were homozygous/monospermic XX, indicating that this form is not without risk of significant gestational trophoblastic disease. Thus, the current study has demonstrated a higher frequency of heterozygous/dispermic CHMs among invasive cases compared with those lacking invasion, but does not support the use of zygosity data for risk assessment of CHMs. A persistent, unresolved diagnostic challenge identified in some invasive CHMs is interpretation of accompanying florid atypical trophoblastic proliferations which raise concern for choriocarcinoma. Future studies should address the need for reproducible diagnostic criteria and molecular biomarkers for distinguishing florid hyperplastic from malignant neoplastic trophoblastic proliferations. PMID- 26535985 TI - Clinical Significance of Positive Pelvic Washings in Uterine Papillary Serous Carcinoma Confined to an Endometrial Polyp. AB - Uterine papillary serous carcinoma (UPSC) represents 10% of endometrial carcinomas. Significant number of patients initially present with extrauterine disease. The role of adjuvant treatment in low stage, especially polyp-confined UPSC is controversial. This multi-institutional study evaluated the significance of positive pelvic washing (PW) and adjuvant treatment on disease recurrence in a setting of endometrial polyp-confined UPSC. Surgical pathology files from 3 institutions were searched for cases of endometrial polyp-confined UPSC. Following histologic review, cases were clinically staged as Stage I, without myoinvasion or lymphovascular invasion. Clinicopathologic characteristics, results of PW, and type of adjuvant therapy were recorded. Statistical analysis using the Kaplan-Meier method for survival and Fisher exact test were performed. Thirty-three patients were included in the study. All patients were diagnosed with polyp-confined UPSC. The size of the polyp ranged from 0.3 to 4.3 cm. PW was positive for tumor cells in 8/33 (24%) patients. Twenty-two patients (66.6%) received some type of adjuvant treatment. Six patients (18%) developed recurrent disease. There was no significant difference in disease-free survival in the patients receiving adjuvant treatment versus not (P=0.375). However, there was significant association (P=0.0013) between positive PW and disease recurrence. Data are conflicting whether positive PW affects prognosis in low-stage endometrial carcinomas. Our study showed that in UPSC, malignant cells can be present in PW without lymphovascular invasion or myoinvasion and may have negative prognostic implication. Our data also reflect the controversies in the role of adjuvant treatment in endometrium-confined UPSC. PMID- 26535986 TI - Nontuberculous Mycobacterial Infection in the Uterine Cervix Mimics Invasive Cervical Cancer in Immunocompetent Woman. AB - Nontuberculous mycobacterial (NTM) infection is increasing across the world. Although the most common clinical manifestation of NTM disease is lung disease, a rare form of disseminated NTM disease has also been documented. Disseminated NTM usually develops in severely immunocompromised individuals, especially those with advanced AIDS. This manifestation is rare in non-HIV-infected hosts and is associated with immunosuppressed conditions. However, recent reports have suggested that disseminated NTM disease in immunocompetent patients without HIV infection has been increasing. Dissemination may involve any organ system, but a case in the female genital tract has never been reported. We report a case in a 67-yr-old previously healthy woman who presented with a disseminated NTM infection in the uterine cervix. The primary presentation was general fatigue and body weight loss. The patient also presented with a mass formation that mimicked cervical cancer on magnetic resonance imaging. In addition to the cervical mass, the patient presented with a mass formation in the omentum; wall thickening of the vagina, bladder, and ureter; and retention of pleural/peritoneal fluid. Vaginal cytology was negative. A diagnosis was made only after detecting acid fast bacilli in a biopsy specimen of cervical mass, which was conducted under suspicion of cervical malignancy. Then, Mycobacterium avium was confirmed in a polymerase chain reaction test of cervical tissue. After administration of antimycobacterial therapy, the mass and other findings on magnetic resonance imaging disappeared. Infection in multiple organs leads to the diagnosis of disseminated NTM. This case indicates that, for prompt and accurate diagnosis, efforts to detect specific lesions by an imaging study and to confirm diagnosis pathologically are equally important, especially when local cytology is not convincing. The clinical course of this case may serve as a useful reference in the diagnosis and treatment of NTM. PMID- 26535987 TI - Immunohistochemistry in the Diagnosis of Mucinous Neoplasms Involving the Ovary: The Added Value of SATB2 and Biomarker Discovery Through Protein Expression Database Mining. AB - Immunohistochemistry is frequently used to identify ovarian mucinous neoplasms as primary or metastatic; however, there is significant overlap in expression patterns. We compared traditional markers (CK7, CK20, CDX2, PAX8, estrogen receptor, beta-catenin, MUC1, MUC2, and MUC5AC) to 2 novel proteins identified through mining of the Human Protein Atlas expression database: SATB2 and POF1B. The study cohort included 49 primary gastrointestinal (GI) mucinous adenocarcinomas (19 colorectal, 15 gastric, 15 pancreatobiliary), 60 primary ovarian mucinous neoplasms (19 cystadenomas, 21 borderline tumors, 20 adenocarcinomas), and 19 metastatic carcinomas to the ovary (14 lower and 5 upper GI primaries). Immunohistochemistry was performed on tissue microarrays, scored and interpreted as negative (absent or focal/weak) or positive. Metastatic tumors were frequently unilateral (42.8% of tumors from lower and 40% of tumors from upper tract) and >=10 cm (85.7% of tumors from lower and 80% of tumors from upper tract). CK7 was positive in 88.5% upper GI and 88.3% primary ovarian compared with 24.3% lower GI neoplasms. CK20 and CDX2 were positive in 84.8% and 100% of lower GI tumors, respectively; however, expression was also common in upper GI (CK20 42.8%, CDX2 50%) and primary ovarian neoplasms (CK20 65.7%, CDX2 38.3%). Conversely, SATB2 was more specific for lower GI origin, being positive in 78.8% lower GI but only 11.5% upper GI and 1.7% primary ovarian neoplasms. PAX8 expression was common in primary ovarian neoplasms (75% of all neoplasms, 65% of carcinomas); only 1 (1.5%) GI tumor was positive. MUC2 and beta-catenin were frequently positive in lower GI tumors (96.9% and 51.5%, respectively). Estrogen receptor expression was only seen in primary ovarian neoplasms (13.3%). Nuclear premature ovarian failure 1B (POF1B) expression was seen in malignant tumors regardless of their origin. A panel including CK7, SATB2, and PAX8 separated primary from secondary GI neoplasms with up to 77.1% sensitivity and 99% specificity, outperforming tumor laterality and size. Second-line markers such as CDX2, MUC2, estrogen receptor, MUC1, and beta-catenin increased the sensitivity of immunohistochemistry in excluding lower GI origin. Biomarker search using proteomic databases has a value in diagnostic pathology, as shown with SATB2; however, as seen with POF1B, expression profiles in these databases are not always reproduced in larger cohorts. PMID- 26535988 TI - Prognostic Factors as a Function of Disease-free Interval After Definitive (Chemo)radiation for Non-Small Cell Lung Cancer Using Conditional Survival Analysis. AB - PURPOSE: We analyzed overall and disease-free survival (OS and DFS) after definitive (chemo)radiation for stage III non-small cell lung cancer with 2 statistical methods: Kaplan-Meier (KM) analysis, with diagnosis as index date, and conditional survival (CS) analysis, with a variety of disease-free index dates, and determined whether prognostic factors varied based on the reference date. MATERIALS AND METHODS: All 651 patients analyzed received definitive (chemo)radiotherapy for stage III non-small cell lung cancer in November 1998 to December 2010 at a single institution; all had Karnofsky performance status scores >=60 and received >=60 Gy. OS and DFS were first calculated with the KM method, and then CS was used to calculate 2 outcomes: OS conditioned on DFS time (OS|DFS) and DFS conditioned on DFS time (DFS|DFS). Factors predicting OS and DFS conditioned on 1-, 2-, and 3-year DFS were sought in univariate and multivariate analyses. RESULTS: KM analysis produced 1-, 2-, and 3-year DFS rates of 48%, 30%, and 26%; OS rates were 64%, 41%, and 29%. By CS analysis, both OS|DFS and DFS|DFS showed an increase in 5-year OS after 6 months, and CS after 30 months approached 100%. On multivariate analyses, age and concurrent chemoradiation predicted OS|DFS; age, smoking history, tumor histology, disease stage, and radiation dose predicted DFS|DFS. CONCLUSIONS: CS analysis showed that the probability of long term survival increases sharply after 6 months with no evidence of disease; factors predicting survival differed based on the method and endpoint used. PMID- 26535989 TI - Preoperative Radiosurgery for Soft Tissue Sarcoma. AB - OBJECTIVES: Preoperative radiation followed by surgical resection is a standard treatment for soft tissue sarcomas (STSs). The conventional method of radiation is 5 weeks to approximately 50 Gy. We report on our initial experience and phase II single-arm study assessing 5 fractions of stereotactic body radiotherapy (SBRT), followed by surgical resection for STS. METHODS: Thirteen patients and 14 tumors were treated with preoperative SBRT; tumors were mostly poorly differentiated (5) or myxoid (5) and were located on the leg (10), arm (2) or groin (2). The median tumor size in greatest dimension was 7.6 cm (maximum 16 cm). Twelve patients received 35 Gy in 5 fractions; for 2 deeper tumors the dose was 40 Gy in 5 fractions. Ten patients were administered 0.5 cm bolus to improve the dose. Gross tumor volume was expanded 0.5 cm radially and 3 cm along the tissue plane. Treatment was to an isodose line (median 81%) and was delivered every other day. Maximum dose to the skin was 46 Gy (median 41 Gy). RESULTS: The median follow-up period was 279 days. Surgical resection occurred a median of 37 days after completion of SBRT. Four patients had acute toxicity consisting of 2 grade 2 and 2 grade 3 skin reactions; all cases of skin toxicity resolved by the time of surgery. Percent tumor necrosis ranged from 10% to 95% (median 60%). All patients had negative margins. Planned vacuum-assisted wound closure was used in 4 patients; there were no other major wound complications. There was 1 local recurrence and 7 distant recurrences. CONCLUSION: This is the initial experience of radiosurgery for preoperative treatment of STSs. We have found this to be well tolerated, convenient for the patients, and a much shorter treatment course, allowing patients to undergo surgery and subsequent chemotherapy quicker. Surgical complications and control rates are satisfactory. The initial results are encouraging for further investigation. PMID- 26535990 TI - The Birth of the Illegitimate Linear No-Threshold Model: An Invalid Paradigm for Estimating Risk Following Low-dose Radiation Exposure. AB - This paper examines the birthing process of the linear no-threshold model with respect to genetic effects and carcinogenesis. This model was conceived >70 years ago but still remains a foundational element within much of the scientific thought regarding exposure to low-dose ionizing radiation. This model is used today to provide risk estimates for cancer resulting from any exposure to ionizing radiation down to zero dose, risk estimates that are only theoretical and, as yet, have never been conclusively demonstrated by empirical evidence. We are literally bathed every second of every day in low-dose radiation exposure due to natural background radiation, exposures that vary annually from a few mGy to 260 mGy, depending upon where one lives on the planet. Irrespective of the level of background exposure to a given population, no associated health effects have been documented to date anywhere in the world. In fact, people in the United States are living longer today than ever before, likely due to always improving levels of medical care, including even more radiation exposure from diagnostic medical radiation (eg, x-ray and computed tomography imaging examinations) which are well within the background dose range across the globe. Yet, the persistent use of the linear no-threshold model for risk assessment by regulators and advisory bodies continues to drive an unfounded fear of any low-dose radiation exposure, as well as excessive expenditures on putative but unneeded and wasteful safety measures. PMID- 26535991 TI - To What Extent Does Radiotherapy Improve the Quality of Life of Patients With Bone Metastasis?: A Prospective, Single-Institutional Study. AB - PURPOSE/OBJECTIVES: Radiation therapy (RT) is an effective method of palliating painful bone metastases and improves the quality of life (QoL) of these patients. The purpose of this trial is 2-fold: to quantify the impact of RT in the QoL of patients with bone metastasis and to compare the QoL results between the most used schemes of RT at our Centre. MATERIALS AND METHODS: A consecutive sample of patients with bone metastasis treated with RT in the Complejo Hospitalario de Navarra, Spain, was addressed between January 2011 and November 2012. The QoL was measured with the Quality of Life Questionnaire-C15-Palliative questionnaire, a short version of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 for palliative care. Two assessments were proposed for each patient: one on the first day of the treatment and the other one a month after the end of the radiotherapy sessions. One hundred and sixteen patients completed the first questionnaire and 75 completed the second one (65%). RESULTS: Significant differences appeared in 9 domains, with better QoL in the second assessment. Five areas (physical functioning, global, fatigue, nausea, dyspnea, and constipation) showed little change (between 5 and 9 points), 3 (emotional functioning, insomnia, and appetite loss) showed moderate change (10 to 20 points), and 1 (pain) showed a very positive change (>30 points).When we compare the QoL scores between the 2 most used schemes of RT (30 Gy/10 fractions vs. 20 Gy/4 to 5 fractions), there are no significant differences in any QoL areas (and in 2 areas P was near 0.05). CONCLUSIONS: Palliative RT is a very active treatment for patients with bone metastasis regardless of age, location, primary tumor, or RT scheme. RT significantly improves the QoL, fundamentally by controlling pain and reducing analgesic use. Shorter schemes of RT produce at least-if not better-the same effect on QL than longer schemes (30 Gy). PMID- 26535992 TI - Does Delaying Surgical Resection After Neoadjuvant Chemoradiation Impact Clinical Outcomes in Locally Advanced Rectal Adenocarcinoma?: A Single-Institution Experience. AB - OBJECTIVES: Surgical resection for locally advanced rectal adenocarcinoma commonly occurs 6 to 10 weeks after completion of neoadjuvant chemoradiation (nCRT). We sought to determine the optimal timing of surgery related to the pathologic complete response rate and survival endpoints. METHODS: The study is a retrospective analysis of 92 patients treated with nCRT followed by surgery from 2004 to 2011 at our institution. Univariate and multivariate analyses were performed to assess the impact of timing of surgery on locoregional control, distant failure (DF), disease-free survival, and overall survival (OS). RESULTS: Time-to-surgery was <=8 weeks (group A) in 72% (median 6.1 wk) and >8 weeks (group B) in 28% (median 8.9 wk) of patients. No significant differences in patient characteristics, locoregional control, or pathologic complete response rates were noted between the groups. Univariate analysis revealed that group B had significantly shorter time to DF (group B, median 33 mo; group A, median not reached, P=0.047) and shorter OS compared with group A (group B, median 52 mo; group A, median not reached, P=0.03). Multivariate analysis revealed that increased time-to-surgery showed a significant increase in DF (HR=2.96, P=0.02) and trends toward worse OS (HR=2.81, P=0.108) and disease-free survival (HR=2.08, P=0.098). CONCLUSIONS: We found that delaying surgical resection longer than 8 weeks after nCRT was associated with an increased risk of DF. This study, in combination with a recent larger study, questions the recent trend in promoting surgical delay beyond the traditional 6 to 10 weeks. Larger, prospective databases or randomized studies may better clarify surgical timing following nCRT in rectal adenocarcinoma. PMID- 26535993 TI - A Phase II Study of Biweekly Cisplatin, Fixed-Dose-Rate Gemcitabine and Infusional 5-Fluorouracil in Patients With Metastatic Pancreatic and Biliary Cancers. AB - OBJECTIVES: Combinations of gemcitabine, 5-fluorouracil (5-FU), and platinum have demonstrated improved outcomes compared with singlet chemotherapy in pancreatic and biliary cancers. This phase II study examined efficacy and safety of a novel schedule of cisplatin, fixed-dose-rate gemcitabine and infusional 5-FU. MATERIALS AND METHODS: Patients with metastatic adenocarcinoma of the pancreas or biliary tract, previously untreated or having received 1 cytotoxic regimen for advanced disease, were treated with gemcitabine 1000 mg/m intravenously (IV) over 100 minutes, cisplatin 35 mg/m IV over 30 minutes, and 5-FU 2400 mg/m IV over 48 hours on day 1 of a 14-day cycle. Patients were treated until disease progression or for 12 cycles. After 12 cycles, patients with stable or responding disease could continue gemcitabine and 5-FU. The primary endpoint was objective response. RESULTS: Thirty-nine patients were treated: 8 with biliary cancer (all untreated) and 31 with pancreatic cancer (17 untreated, 14 previously treated). Best response in 25 untreated patients was partial response in 40%, stable disease in 40%, and progressive disease in 20%. In 14 previously treated pancreatic patients, best response was partial response in 7%, stable disease in 50%, and progressive disease in 43%. Median overall survival in untreated patients was 10.3 versus 4.9 months in previously treated patients. Adverse events were primarily uncomplicated hematologic toxicity, >=grade 3 neutropenia (54%), anemia (21%), and thrombocytopenia (13%). CONCLUSION: Biweekly cisplatin, fixed-dose rate gemcitabine, and infusional 5-FU demonstrated a high response rate and were well tolerated, encouraging further investigation of this regimen in metastatic pancreatic and biliary cancers. PMID- 26535994 TI - Whole Versus Partial Bladder Radiation: Use of an Image-guided Hypofractionated IMRT Bladder-preservation Protocol. AB - OBJECTIVES: To report our institutional experience using definitive chemoradiation via whole bladder (WB) and partial bladder (PB) treatment in muscle-invasive bladder cancer. Combining intensity-modulated radiation therapy with image-guidance can improve the therapeutic ratio. MATERIALS AND METHODS: Retrospective analysis of 26 patients with clinical stage T2-4 N0-2 M0 urothelial cancer treated in 2009 to 2012; 16 received WB radiation and 10 received PB radiation. PB/tumor boost volume included visibly thickened bladder wall or tumor localized on cystoscopy. WB radiation delivered 45 to 50.4 Gy to bladder/lymph nodes, then sequential 19.8 to 21.6 Gy tumor boost (1.8 Gy/fx). PB radiation was 45 to 50 Gy to lymph nodes (1.8 to 2 Gy/fx) and simultaneous integrated boost to 55 to 62.5 Gy to tumor only (2.2 to 2.5 Gy/fx). The primary endpoint was local control, defined as no muscle-invasive recurrence. Secondary endpoints were overall survival, toxicity, and cost. RESULTS: Mean age was 77 and median follow up was 20 months. Freedom from local recurrence was 86% at 2 years (PB 100%, WB 77%). Overall survival was 80% at 1 year (PB 88%, WB 75%), and 55% at 2 years (PB 70%, WB 48%, P=0.38). Failure was predominantly distant. Toxicities were minimal (3 late grade 3 ureteral, 1 acute grade 4 renal), and all resolved. No cystectomies were performed for toxicity. Hypofractionation reduces treatment time and costs by one third. CONCLUSIONS: Image-guided hypofractionated PB radiation provides local control with similar survival to WB therapy, with minimal toxicity. Hypofractionation also offers time and cost advantages. Our results need to be validated in a larger, multi-institutional cohort. PMID- 26535995 TI - The inflammatory cytokine TWEAK decreases PGC-1alpha expression and mitochondrial function in acute kidney injury. AB - Studies of mitochondria-targeted nephroprotective agents suggest a key role of mitochondrial injury in AKI. Here we tested whether an improved perception of factors responsible for mitochondrial biogenesis may provide clues to novel therapeutic approaches to AKI. TWEAK is an inflammatory cytokine which is upregulated in AKI. Transcriptomic analysis of TWEAK-stimulated cultured murine tubular epithelial cells and folic acid-induced AKI in mice identified downregulation of peroxisome proliferator- activated receptor-gamma coactivador 1alpha (PGC-1alpha) and its target genes (mitochondrial proteins Ndufs1, Sdha, and Tfam) as a shared feature. Neutralizing anti-TWEAK antibodies prevented the decrease in kidney PGC-1alpha and its targets during AKI. TWEAK stimulation decreased kidney PGC-1alpha expression in healthy mice and decreased expression of PGC-1alpha and its targets as well as mitochondrial membrane potential in cultured tubular cells. Adenoviral-mediated PGC-1alpha overexpression prevented TWEAK-induced downregulation of PGC-1alpha-dependent genes and the decrease in mitochondrial membrane potential. TWEAK promoted histone H3 deacetylation at the murine PGC-1alpha promoter. TWEAK-induced downregulation of PGC-1alpha was prevented by histone deacetylase or NF-kappaB inhibitors. Thus, TWEAK decreases PGC-1alpha and target gene expression in tubular cells in vivo and in vitro. Approaches that preserve mitochondrial function during kidney injury may be therapeutic for AKI. PMID- 26535996 TI - Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition. AB - Elucidation of acute kidney diseases and disorders (AKD), including acute kidney injury (AKI), is important to prevent their progression to chronic kidney disease. Current animal AKI models are often too severe for use in evaluating human AKI. Therefore, new animal models of mild kidney injury are needed. Here a new clinically relevant animal model using multiple low doses of cisplatin (CP) was used to evaluate AKD. When 10 mg/kg CP was administered intraperitoneally once weekly for three times to L-type fatty acid-binding protein (L-FABP) transgenic mice, moderate renal interstitial fibrosis and tubule dilatation occurred, accompanied by brush-border loss. Urinary L-FABP, a promising biomarker of AKI, changed more drastically than blood urea nitrogen or creatinine. Preventing fibrosis in organs was also studied. Oral administration of a recently reported selective semicarbazide-sensitive amine oxidase inhibitor, PXS-4728A, for 1 week attenuated kidney injury and interstitial fibrosis compared with vehicle. Inhibition of renal lipid accumulation in semicarbazide-sensitive amine oxidase inhibitor-treated mice, together with reduced oxidative stress and L-FABP suppression in proximal tubules, suggested an antifibrotic effect of semicarbazide-sensitive amine oxidase inhibition in this CP-AKD model, a representative onco-nephrology. Thus, semicarbazide-sensitive amine oxidase inhibitors may be promising candidates for the prevention of chronic kidney disease in patients using CP to treat malignancy. PMID- 26535997 TI - Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. AB - Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with chronic kidney disease (CKD), but the mechanisms are poorly understood. Here we tested whether inflammation and iron deficiency regulate FGF23. In wild-type mice, acute inflammation induced by single injections of heat killed Brucella abortus or interleukin-1beta (IL-1beta) decreased serum iron within 6 h, and was accompanied by significant increases in osseous Fgf23 mRNA expression and serum levels of C-terminal FGF23, but no changes in intact FGF23. Chronic inflammation induced by repeated bacteria or IL-1beta injections decreased serum iron, increased osseous Fgf23 mRNA, and serum C-terminal FGF23, but modestly increased biologically active, intact FGF23 serum levels. Chronic iron deficiency mimicked chronic inflammation. Increased osseous FGF23 cleavage rather than a prolonged half-life of C-terminal FGF23 fragments accounted for the elevated C-terminal FGF23 but near-normal intact FGF23 levels in inflammation. IL 1beta injection increased Fgf23 mRNA and C-terminal FGF23 levels similarly in wildtype and Col4a3(ko) mice with CKD but markedly increased intact FGF23 levels only in the CKD mice. Inflammation increased Fgf23 transcription by activating Hif1alpha signaling. Thus, inflammation and iron deficiency stimulate FGF23 production. Simultaneous upregulation of FGF23 cleavage in osteocytes maintains near-normal levels of biologically active, intact circulating FGF23, whereas downregulated or impaired FGF23 cleavage may contribute to elevated intact serum FGF23 in CKD. PMID- 26535998 TI - Phenotyping by magnetic resonance imaging nondestructively measures glomerular number and volume distribution in mice with and without nephron reduction. AB - Reduced nephron mass is strongly linked to susceptibility to chronic renal and cardiovascular diseases. There are currently no tools to identify nephropenia in clinical or preclinical diagnostics. Such new methods could uncover novel mechanisms and therapies for chronic kidney disease (CKD) and reveal how variation among traits can affect renal function and morphology. Here we used cationized ferritin (CF)-enhanced MRI (CFE-MRI) to investigate the relationship between glomerular number (Nglom) and volume (Vglom) in kidneys of healthy wild type mice and mice with oligosyndactylism (Os/+), a model of congenital nephron reduction. Mice were injected with CF and perfused, and the resected kidneys were imaged with 7T MRI to detect CF-labeled glomeruli. CFE-MRI was used to measure the intrarenal distribution of individual glomerular volumes and revealed two major populations of glomeruli distinguished by size. Spatial mapping revealed that the largest glomeruli were located in the juxtamedullary region in both wild type and Os/+ mice and the smallest population located in the cortex. Os/+ mice had about a 50% reduction and 35% increase of Nglom and Vglom, respectively, in both glomerular populations compared with wild type, consistent with glomerular hypertrophy in the Os/+ mice. Thus, we provide a foundation for whole-kidney, MRI based phenotyping of mouse renal glomerular morphology and provide new potential for quantitative human renal diagnostics. PMID- 26535999 TI - The prevalence and clinical significance of C1q-binding donor-specific anti-HLA antibodies early and late after kidney transplantation. AB - We aimed to determine the prevalence and clinical significance of complement binding donor-specific antibodies (DSA) detected up to 30 years after kidney transplantation. Group 1 patients included 284 consecutive DSA negative patients who underwent kidney transplantation after 1 May 2009. Group 2 included 405 patients transplanted before this date and followed at our center with functioning allografts. DSA were tested using Luminex Single Antigen and the C1q assay. In Group 1 patients, who were monitored prospectively, 31 (11%) developed de novo DSA during a median follow-up of 2.5 (1.9, 3.6) years. Of these, 11 (4%) had C1q+ and 20 (7%) had C1q negative DSA. In Group 2 patients, 77 (19%) displayed DSA. Among these, 33 (8%) had C1q+ and 44 (11%) had C1q negative DSA. The incidence of acute antibody-mediated rejection (AMR) was significantly higher in C1q+DSA patients in both Group 1 (45%) and Group 2 (15%) compared with C1q negative DSA (5% and 2%) and DSA negative patients (1% and 3%; P < 0.001 and P = 0.001). The incidence of chronic AMR was 36% (Group 1) and 51% (Group 2) in patients with C1q+DSA. In contrast, chronic AMR occurred in 5% and 25% of C1q negative DSA, and 2% and 6% of DSA negative Group 1 and 2 patients, respectively (P < 0.001). Although the graft survival was lower in Group 1 C1q+DSA patients (73%) compared with C1q negative DSA (95%) and DSA negative (94%) patients, the difference was not statistically significant by Kaplan-Meier survival analysis (P = 0.21). Our results indicated that the presence of C1q+ DSA was associated with acute and chronic AMR. PMID- 26536000 TI - Kallistatin protects against diabetic nephropathy in db/db mice by suppressing AGE-RAGE-induced oxidative stress. AB - Kallistatin is a serine protease inhibitor with anti-inflammatory, anti angiogenic, and anti-oxidative properties. Since oxidative stress plays a critical role in the pathogenesis of diabetic nephropathy, we studied the effect and mechanisms of action of kallistatin superinduction. Using ultrasound microbubble-mediated gene transfer, kallistatin overexpression was induced in kidney tubules. In db/db mice, kallistatin overexpression reduced serum creatinine and BUN levels, ameliorated glomerulosclerosis and tubulointerstitial injury, and attenuated renal fibrosis by inhibiting TGF-beta signaling. Additionally, downstream PAI-1 and collagens I and IV expression were reduced and kallistatin partially suppressed renal inflammation by inhibiting NF-kappaB signaling and decreasing tissue kallikrein activity. Kallistatin lowered blood pressure and attenuated oxidative stress as evidenced by suppressed levels of NADPH oxidase 4, and oxidative markers (nitrotyrosine, 8-hydroxydeoxyguanosine, and malondialdehyde) in diabetic renal tissue. Kallistatin also inhibited RAGE expression in the diabetic kidney and AGE-stimulated cultured proximal tubular cells. Reduced AGE-induced reactive oxygen species generation reflected an anti oxidative mechanism via the AGE-RAGE-reactive oxygen species axis. These results indicate a renoprotective role of kallistatin against diabetic nephropathy by multiple mechanisms including suppression of oxidative stress, anti-fibrotic and anti-inflammatory actions, and blood pressure lowering. PMID- 26536001 TI - Is There an Additional Value of Using Somatostatin Receptor Subtype 2a Immunohistochemistry Compared to Somatostatin Receptor Scintigraphy Uptake in Predicting Gastroenteropancreatic Neuroendocrine Tumor Response? AB - BACKGROUND AND AIMS: It is unknown whether tumoral somatostatin receptor subtype 2a (sst2a) immunohistochemistry (IHC) has additional value compared to somatostatin receptor scintigraphy (SRS) uptake using OctreoScan(r) in predicting response to peptide receptor radiotherapy using 177Lu-octreotate (PRRT) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The aims of this study were: (1) to establish the percentage of sst2a immunopositivity in GEP-NET samples of PRRT-treated patients, (2) to determine the relationship between best GEP-NET response using RECIST 1.0 criteria 1 year after PRRT and tumoral sst2a IHC, and (3) to compare characteristics of patients with sst2a IHC negative and -positive tumors. METHODS: All 73 consecutive patients were selected for PRRT based on a positive SRS. Radiological response was scored according to RECIST 1.0 criteria. sst2a status was detected on tumor samples by IHC. RESULTS: In total, 93% of GEP-NET samples showed sst2a IHC positivity. No statistically significant relationship was observed between in vitro sst2a expression and in vivo best GEP-NET response 1 year after PRRT (p = 0.47). Sex, primary tumor site, disease stage, ENETS TNM classification, Ki-67 index, highest serum chromogranin A level, and highest neuron-specific enolase level were not significantly different between patients with negative and positive sst2a tumoral IHC with the exception of age at diagnosis (p = 0.007). CONCLUSIONS: sst2a IHC of tumor samples has no additional value compared to SRS uptake using OctreoScan(r) in predicting tumor response after PRRT. PMID- 26536002 TI - Transcription Factor-7-Like 2 Gene Variants Affect the Metabolic Phenotypes of Polycystic Ovary Syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrinopathy, which shares genetic features with type 2 diabetes mellitus (T2DM). Insofar as transcription factor 7-like 2 (TCF7L2) is consistently replicated T2DM susceptibility locus, this study evaluates whether common TCF7L2 variants are associated with PCOS and related metabolic features. METHODS: The association between TCF7L2 rs4506565, rs7903146, rs12243326, and rs12255372 SNPs and PCOS was tested in 242 women with PCOS and in 236 control women. RESULTS: The allelic distribution of rs4506565, rs7903146, rs12243326, and rs12255372 TCF7L2 variants was not significantly different between women with PCOS and control women. The genotype distribution of the 4 TCF7L2 loci was comparable between PCOS cases and controls, irrespective of the genetic analysis model used (additive, dominant, recessive). Carriage of rs4506565 minor allele correlated with free insulin and homeostasis model assessment of insulin resistance, while the presence of rs12243326 and rs12255372 minor allele correlated with waist changes. Four-locus (rs4506565-rs7903146, rs12243326, and rs12255372) haplotype analysis identified PCOS-susceptible (ACTG) and -protective (TTTG) haplotypes, which remained significant after controlling for multiple comparisons and for key covariates. CONCLUSIONS: Although individual TCF7L2 variants were not associated with the presence of PCOS in Bahraini women, specific TCF7L2 haplotypes were identified, which were both positively and negatively associated with PCOS. PMID- 26536003 TI - Associations of Leu72Met Polymorphism of Preproghrelin with Ratios of Plasma Lipids Are Diversified by a High-Carbohydrate Diet in Healthy Chinese Adolescents. AB - BACKGROUND/AIMS: The association of preproghrelin Leu72Met polymorphism with plasma lipids profile was inconsistently reported and needs more studies to be confirmed. Our study was to investigate the changes of plasma lipids ratios after a high-carbohydrate (high-CHO) diet in healthy Chinese adolescents with different genotypes of this polymorphism. METHODS: Fifty-three healthy university students were given a washout diet of 54.1% carbohydrate for 7 days, followed by a high CHO diet of 70.1% carbohydrate for 6 days. The anthropometric and biological parameters were analyzed at baseline and before and after the high-CHO diet. RESULTS: When compared with those before the high-CHO diet, body mass index (BMI) decreased in the male and female Met72 allele carriers. Decreased low-/high density lipoprotein cholesterol (LDL-C/HDL-C) was observed in all participants except the female subjects with the Leu72Leu genotype. TG/HDL-C and log (TG/HDL C) were increased only in the female subjects with the Leu72Leu genotype. CONCLUSION: These results suggest that the Met72 allele of preproghrelin Leu72Met polymorphism may be associated with decreased BMI induced by the high-CHO diet in male and female adolescents, while the Leu72 allele with increased TG/HDL-C and log (TG/HDL-C) in the female adolescents only. Furthermore, the decreasing effect of the high-CHO diet on LDL/HDL-C may be eliminated in the female Leu72Leu homozygotes. PMID- 26536005 TI - ["Within the Psychotherapeutic Service System ... we Want to Promote Group Psychotherapy"]. PMID- 26536004 TI - Inhibition of KIF14 Suppresses Tumor Cell Growth and Promotes Apoptosis in Human Glioblastoma. AB - BACKGROUND/AIMS: The mitotic kinesin superfamily protein KIF14 is essential for cytokinesis and chromosome segregation, and increased KIF14 expression is related to a variety of human cancers. However, the role of KIF14 in the development and malignant progression of astrocytomas and the underlying mechanisms remain unclear. The present study examined the relation between KIF14 and the pathogenesis of malignant astrocytoma. METHODS AND RESULTS: The role of KIF14 in astrocytoma development and progression was investigated by analyzing KIF14 expression using SYBR Green quantitative real-time RT-PCR, western blotting and immunohistochemistry in human astrocytoma and normal brain tissues. KIF14 expression was higher in astrocytoma samples, and was positively correlated with pathological grade and proliferative activity indicated by Ki-67 staining. SiRNA knockdown of KIF14 inhibited tumor growth in vitro and in vivo, attenuated anchorage-independent growth, and induced G2/M phase arrest, cytokinesis failure and apoptosis in glioblastoma cell lines in association with decreased AKT phosphorylation and activity. CONCLUSIONS: The upregulation of KIF14 in astrocytoma is associated with disease severity, and suppression of KIF14 inhibits cell proliferation and induces apoptosis through a mechanism involving the inactivation of AKT signaling, suggesting that KIF14 plays an important role in astrocytoma tumorigenesis and could be a promising molecular target for anticancer therapy. PMID- 26536006 TI - [What Does Inclusion Mean?]. PMID- 26536007 TI - Postnatal Depressive Symptoms Among Mothers and Fathers of Infants Born Preterm: Prevalence and Impacts on Children's Early Cognitive Function. AB - OBJECTIVE: Preterm birth is associated with lower cognitive functioning. One potential pathway is postnatal parental depression. The authors assessed depressive symptoms in mothers and fathers after preterm birth, and identified the impacts of both prematurity and parental depressive symptoms on children's early cognitive function. METHOD: Data were from the nationally representative Early Childhood Longitudinal Study, Birth Cohort (n = 5350). Depressive symptoms at 9 months were assessed by the Center for Epidemiologic Studies Depression Scale (CESD) and children's cognitive function at 24 months by the Bayley Short Form, Research Edition. Weighted generalized estimating equation models examined the extent to which preterm birth, and mothers' and fathers' postnatal depressive symptoms impacted children's cognitive function at 24 months, and whether the association between preterm birth and 24-month cognitive function was mediated by parental depressive symptoms. RESULTS: At 9 months, fathers of very preterm (<32 weeks gestation) and moderate/late preterm (32-37 weeks gestation) infants had higher CESD scores than fathers of term-born (>=37 weeks gestation) infants (p value = .02); preterm birth was not associated with maternal depressive symptoms. In multivariable analyses, preterm birth was associated with lower cognitive function at 24 months; this association was unaffected by adjustment for parental depressive symptoms. Fathers', but not mothers', postnatal depressive symptoms predicted lower cognitive function in the fully adjusted model (beta = -0.11, 95% confidence interval, -0.18 to -0.03). CONCLUSION: Fathers of preterm infants have more postnatal depressive symptomology than fathers of term-born infants. Fathers' depressive symptoms also negatively impact children's early cognitive function. The national findings support early identification and treatment of fathers of preterm infants with depressive symptoms. PMID- 26536008 TI - Advancing Continence in Typically Developing Children: Adapting the Procedures of Foxx and Azrin for Primary Care. AB - OBJECTIVE: To (1) identify and summarize procedures of Foxx and Azrin's classic toilet training protocol that continue to be used in training typically developing children and (2) adapt recent findings with the original Foxx and Azrin procedures to inform practical suggestions for the rapid toilet training of typically developing children in the primary care setting. METHOD: Literature searches of PsychINFO and MEDLINE databases used the search terms "(toilet* OR potty* AND train*)." Selection criteria were only peer-reviewed experimental articles that evaluated intensive toilet training with typically developing children. Exclusion criteria were (1) nonpeer reviewed research, (2) studies addressing encopresis and/or enuresis, (3) studies excluding typically developing children, and (4) studies evaluating toilet training during infancy. RESULTS: In addition to the study of Foxx and Azrin, only 4 publications met the above criteria. Toilet training procedures from each article were reviewed to determine which toilet training methods were similar to components described by Foxx and Azrin. Common training elements include increasing the frequency of learning opportunities through fluid loading and having differential consequences for being dry versus being wet and for voiding in the toilet versus elsewhere. CONCLUSION: There is little research on intensive toilet training of typically developing children. Practice sits and positive reinforcement for voids in the toilet are commonplace, consistent with the Foxx and Azrin protocol, whereas positive practice as a corrective procedure for wetting accidents often is omitted. Fluid loading and differential consequences for being dry versus being wet and for voiding in the toilet also are suggested procedures, consistent with the Foxx and Azrin protocol. PMID- 26536009 TI - Electronic Medical Record Adoption: The Effect on Efficiency, Completeness, and Accuracy in an Academic Orthopaedic Practice. AB - INTRODUCTION: The electronic medical record (EMR) is the new platform for documenting health information. The purpose of this study is to evaluate the impact of the EMR on efficiency, completeness, accuracy, and surgeon attitude in the orthopaedic program of a training hospital. METHODS: Sixty paper charts were compared with 60 EMRs. Pre-EMR and post-EMR billing data was used to determine outpatient clinic volume and the number of providers seeing patients per month. Completeness was evaluated by noting the presence of items from a predetermined list of clinical information pertinent to each diagnosis. Age and side of injury was used to evaluate note accuracy. A survey was used to evaluate surgeon's attitudes regarding the EMR. RESULTS: There was no difference in monthly volume pre-EMR and post-EMR. There was an increase in the number of providers needed to see patients, equating to a 19% reduction in the number of patient visits per provider. The EMR was 1.3 times more likely to include pertinent clinical information. Both paper charts and the EMR were highly accurate. The surgeon attitude survey revealed concerns regarding clinic efficiency, increased "off hours" record keeping, and decreased clinic teaching. DISCUSSION: EMR is an important and essential component of medical care delivery. Record completion and accuracy were similar across medical record types. The use of EMR led to a 19% reduction in patients per provider. Creating the record in the clinic setting appears to detract from patient interaction, and resident/fellow education time. A more focused, specialty designed, EMR may be more efficient for an orthopaedic practice. Future EMR technology should allow a focused EMR designed for specialties that is efficient to create but that can be electronically converted into a "master record" that meets the needs of an associated larger organization. LEVEL OF EVIDENCE: Level III-retrospective comparative study. PMID- 26536010 TI - Transgluteal Approach for Drainage of Obturator Internus Abscess in Pediatric Patients. AB - BACKGROUND: Of the locations of peripelvic pyomyositis, infection of the obturator musculature poses a difficult challenge for operative drainage. The anatomic location of the obturator muscles, especially the obturator internus, complicates operative debridement as the surgical approach must safely bypass a large number of neurovascular structures. Realizing the challenges and risks of approaches to the obturator musculature, the purpose of our study was to review a novel, yet simple, posterior approach to the obturator internus. METHODS: We reviewed a case series of children (age 0 to 18 y), who presented to our institution with obturator internus pyomyositis. The patients' demographics, vital signs, laboratory data, and radiographic findings from the initial evaluation were reviewed. Blood and intraoperative culture results were collected. Duration of symptoms and length of hospital stay were also reviewed. Cases of suspected obturator internus abscess were confirmed by magnetic resonance imaging of the pelvis. All patients in this study who met the operative indications were debrided using the posterior transgluteal approach. RESULTS: Five patients were identified who met criteria for isolated obturator internus pyomyositis. Four out of the 5 patients met operative indications and underwent drainage through a transgluteal approach. One patient responded well to antibiotic treatment; therefore, no surgery was indicated. Purulence was expressed in all 4 operative cases. Hospital length of stay ranged from 6 to 14 days. All patients were treated with an IV antibiotic course for 3 to 6 weeks. All patients returned to normal function and activity levels. There were no surgical complications. CONCLUSIONS: This case series has reviewed a new technique for the drainage of an isolated obturator internus abscess. The transgluteal posterior approach is a simple approach that is performed through a single incision with minimal soft-tissue dissection. It avoids the risks and challenges posed by other approaches. Most importantly, our case series, although small, in our experience, has shown that it is a safe and effective approach for drainage of obturator internus abscess. LEVEL OF EVIDENCE: Level IV. PMID- 26536011 TI - Early Outcomes of Pediatric Elbow Dislocation-Risk Factors Associated With Morbidity. AB - INTRODUCTION: Ulnohumeral elbow dislocation is a rare elbow injury in children. We reviewed a large cohort of pediatric ulnohumeral elbow dislocations and sought to identify risk factors associated with poor functional outcomes. METHODS: Medical charts and radiographs were reviewed for all acute pediatric ulnohumeral elbow dislocations evaluated at our facility during a 7-year period. Charts were abstracted for demographics, injury characteristics, treatments, and complications. Functional outcomes were assessed at minimum 6-week follow-up using a combination of symptoms and elbow range of motion (Roberts criteria). RESULTS: A total of 145 cases qualified for inclusion and were analyzed. The average age at injury was 11 years (range, 5 to 18 y), with equal distribution between male and female individuals. Concomitant elbow fractures were identified in 114 (80%) cases; the most common was the medial epicondyle (80/134, 60%). Treatment consisted of open reduction and fixation of associated fracture(s) in 59% of fracture cases. At an average follow-up of 3.7 months, the average range of motion was -5-degree extension to 126-degree flexion. Immobilization for longer than 2 weeks resulted in a loss of elbow extension (P<0.001). Functional outcomes as assessed by the Roberts criteria were good or excellent in 90% of cases. Risk factors associated with less than excellent functional outcomes included the presence of multiple fractures (P=0.001), the need for operative intervention (P=0.01), and the duration of immobilization (P=0.03). Complications requiring further treatment occurred in 16 cases (11%). Patients without complication resulted in a higher proportion of "excellent" functional outcomes (76%) compared with those with a complication (40%) (P<0.001). CONCLUSIONS: The majority of pediatric ulnohumeral elbow dislocations experience good to excellent functional outcomes by early follow-up. Risk factors associated with less than excellent functional outcomes include the presence of multiple associated fractures, operative intervention, and prolonged immobilization. Complications requiring operative intervention are not rare, and have a significant effect on functional outcomes. LEVEL OF EVIDENCE: Level IV-prognostic. PMID- 26536012 TI - TREATMENT OF RETINOPATHY AND MACULAR EDEMA SECONDARY TO A CAROTID-CAVERNOUS FISTULA. AB - PURPOSE: To present a case report on a patient with retinal complications from a carotid-cavernous fistula. METHODS: Observational case report. RESULTS: A 26-year old patient sustained head trauma following a motorcycle accident. Examination and retinal imaging demonstrated a venous stasis retinopathy with cystoid macular edema. The edema resolved with aflibercept, but not with bevacizumab. CONCLUSION: The patient was diagnosed with venous stasis retinopathy secondary to carotid cavernous fistula. Pathologic findings completely resolved with appropriate management. PMID- 26536013 TI - DEVELOPMENT OF CHRONIC SUBRETINAL FLUID IN KEARNS-SAYRE SYNDROME. AB - BACKGROUND/PURPOSE: To report a novel ophthalmic finding of the development of chronic subretinal fluid in a patient with Kearns-Sayre syndrome. METHODS: An observational case report with funduscopic, angiographic, neurophysiologic, and optical coherence tomographic correlation. RESULTS: An 11-year-old male with bilateral hearing loss, cerebellar dysfunction, short stature, low weight, ptosis, external ophthalmoplegia, and pigmentary retinopathy of both eyes developed chronic subretinal fluid below the central macula. This fluid has remained for more than 1.5 years. Genetic testing revealed a heteroplasmic 7,797 base pair mitochondrial deletion (m. 7638-1543del7797). CONCLUSIONS: The authors report a novel physical finding of subfoveal fluid in a patient with Kearns-Sayre syndrome. The pathophysiologic etiology of this fluid and its localization to the subfoveal retina remains unclear. Patients with pigmentary retinopathy related to mitochondrial disorders should be monitored for the development of subretinal fluid, which can contribute to vision loss. PMID- 26536014 TI - Genome-Wide Analysis of Microsatellite Markers Based on Sequenced Database in Chinese Spring Wheat (Triticum aestivum L.). AB - Microsatellites or simple sequence repeats (SSRs) are distributed across both prokaryotic and eukaryotic genomes and have been widely used for genetic studies and molecular marker-assisted breeding in crops. Though an ordered draft sequence of hexaploid bread wheat have been announced, the researches about systemic analysis of SSRs for wheat still have not been reported so far. In the present study, we identified 364,347 SSRs from among 10,603,760 sequences of the Chinese spring wheat (CSW) genome, which were present at a density of 36.68 SSR/Mb. In total, we detected 488 types of motifs ranging from di- to hexanucleotides, among which dinucleotide repeats dominated, accounting for approximately 42.52% of the genome. The density of tri- to hexanucleotide repeats was 24.97%, 4.62%, 3.25% and 24.65%, respectively. AG/CT, AAG/CTT, AGAT/ATCT, AAAAG/CTTTT and AAAATT/AATTTT were the most frequent repeats among di- to hexanucleotide repeats. Among the 21 chromosomes of CSW, the density of repeats was highest on chromosome 2D and lowest on chromosome 3A. The proportions of di-, tri-, tetra-, penta- and hexanucleotide repeats on each chromosome, and even on the whole genome, were almost identical. In addition, 295,267 SSR markers were successfully developed from the 21 chromosomes of CSW, which cover the entire genome at a density of 29.73 per Mb. All of the SSR markers were validated by reverse electronic Polymerase Chain Reaction (re-PCR); 70,564 (23.9%) were found to be monomorphic and 224,703 (76.1%) were found to be polymorphic. A total of 45 monomorphic markers were selected randomly for validation purposes; 24 (53.3%) amplified one locus, 8 (17.8%) amplified multiple identical loci, and 13 (28.9%) did not amplify any fragments from the genomic DNA of CSW. Then a dendrogram was generated based on the 24 monomorphic SSR markers among 20 wheat cultivars and three species of its diploid ancestors showing that monomorphic SSR markers represented a promising source to increase the number of genetic markers available for the wheat genome. The results of this study will be useful for investigating the genetic diversity and evolution among wheat and related species. At the same time, the results will facilitate comparative genomic studies and marker-assisted breeding (MAS) in plants. PMID- 26536015 TI - Tir Is Essential for the Recruitment of Tks5 to Enteropathogenic Escherichia coli Pedestals. AB - Enteropathogenic Escherichia coli (EPEC) is a bacterial pathogen that infects the epithelial lining of the small intestine and causes diarrhea. Upon attachment to the intestinal epithelium, EPEC uses a Type III Secretion System to inject its own high affinity receptor Translocated intimin receptor (Tir) into the host cell. Tir facilitates tight adhesion and recruitment of actin-regulating proteins leading to formation of an actin pedestal beneath the infecting bacterium. The pedestal has several similarities with podosomes, which are basolateral actin rich extensions found in some migrating animal cells. Formation of podosomes is dependent upon the early podosome-specific scavenger protein Tks5, which is involved in actin recruitment. Although Tks5 is expressed in epithelial cells, and podosomes and EPEC pedestals share many components in their structure and mechanism of formation, the potential role of Tks5 in EPEC infections has not been studied. The aim of this study was to determine the subcellular localization of Tks5 in epithelial cells and to investigate if Tks5 is recruited to the EPEC pedestal. In an epithelial MDCK cell line stably expressing Tks5-EGFP, Tks5 localized to actin bundles. Upon infection, EPEC recruited Tks5-EGFP. Tir, but not Tir phosphorylation was essential for the recruitment. Time-lapse microscopy revealed that Tks5-EGFP was recruited instantly upon EPEC attachment to host cells, simultaneously with actin and N-WASp. EPEC infection of cells expressing a DeltaPX-Tks5 deletion version of Tks5 showed that EPEC was able to both infect and form pedestals when the PX domain was deleted from Tks5. Future investigations will clarify the role of Tks5 in EPEC infection and pedestal formation. PMID- 26536016 TI - Recognizing the Symptoms of Mental Illness following Concussions in the Sports Community: A Need for Improvement. AB - OBJECTIVE: To evaluate the awareness of concussion-related symptoms amongst members of the sports community in Canada. METHODS: A cross-sectional national electronic survey was conducted. Youth athletes, parents, coaches and medical professionals across Canada were recruited through mailing lists from sports related opt-in marketing databases. Participants were asked to identify, from a list of options, the symptoms of a concussion. The proportion of identified symptoms (categorized as physical, cognitive, mental health-related and overall) as well as participant factors associated with symptom recognition were analyzed. RESULTS: The survey elicited 6,937 responses. Most of the respondents (92.1%) completed the English language survey, were male (57.7%), 35-54 years of age (61.7%), with post-secondary education (58.2%), or high reported yearly household income (>$80,000; 53.0%). There were respondents from all provinces and territories with the majority of respondents from Ontario (35.2%) or British Columbia (19.1%). While participants identified most of the physical (mean = 84.2% of symptoms) and cognitive (mean = 91.2% of symptoms), they on average only identified 53.5% of the mental health-related symptoms of concussions. Respondents who were older, with higher education and household income, or resided in the Northwest Territories or Alberta identified significantly more of the mental health-related symptoms listed. INTERPRETATION: While Canadian youth athletes, parents, coaches and medical professionals are able to identify most of the physical and cognitive symptoms associated with concussion, identification of mental health-related symptoms of concussion is still lagging. PMID- 26536017 TI - Comparison Between Dysport and Prosigne in the Treatment of Cervical Dystonia. AB - Cervical dystonia is the most frequent type of primary focal dystonia and treatment with botulinum toxin (BTX) is currently the criterion standard. OBJECTIVE: In this study, we compared the safety and efficacy of the following 2 formulations of BTXs available in Brazil: abobotulinumtoxin A (Dysport) and Lanzhou BTX type A (Prosigne), during a follow-up of 13 months. METHODS: We conducted a prospective, randomized, double blind trial with 1 group being treated with Dysport and the other with Prosigne. RESULTS: Fourteen patients were randomized to receive Dysport and 20 patients to receive Prosigne, each patient was followed during 13 months and received 5 injections of BTX in this period. The dose equivalency used was 3 U of Dysport for 1 U of Prosigne. After each treatment session, we assessed improvement with the Clinician Interview-Based Impression of Change scale and asked about adverse effects and duration of improvement. We also used the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) before and after the first and fifth treatment sessions. After the first injection, mean TWSTRS values reduced 12.78 points in the Dysport group and 9.98 in the Prosigne group (P = 0.38). After the last injection, the reduction in TWSTRS values was 11.87 points for Dysport and 11.35 points for Prosigne (P = 0.86). CONCLUSIONS: Our data showed similar efficacy and safety profiles when comparing both toxins in the treatment of cervical dystonia. PMID- 26536018 TI - Antidepressant-Induced Sleep Bruxism: Prevalence, Incidence, and Related Factors. AB - OBJECTIVE: The relationship between sleep bruxism and antidepressant drugs in patients remains unclear. In this study, we aimed to investigate the incidence rate of antidepressant-related bruxism and to examine whether antidepressant use is associated with this adverse effect in the patients. METHODS: The study sample was gathered from 2 hospitals. A total of 807 patients who met the inclusion criteria were included in the study. The sample was divided into 2 groups: the antidepressant group (n = 506) and the control group (n = 301). Sleep bruxism was established with reports from the study participants on the basis of the International Classification of Sleep Disorders: Diagnosis and Coding Manual Second Edition. RESULTS: The prevalence of bruxism was significantly higher in the antidepressant group (24.3%) than in the control group (15.3%). The incidence of antidepressant-induced bruxism was 14.0%. The antidepressants most associated with bruxism were paroxetine, venlafaxine, and duloxetine. The patients experiencing antidepressant-induced bruxism had higher age compared with those who did not experience this adverse effect. CONCLUSIONS: The results of the present study suggest that bruxism is frequently observed in women taking antidepressants and that it seems to be associated with antidepressant use at least in some patients. PMID- 26536019 TI - Effect of Memantine on Cognitive Performance in Patients Under Electroconvulsive Therapy: A Double-Blind Randomized Clinical Trial. AB - OBJECTIVES: Various strategies such as adding cholinesterase inhibitors are used to reduce cognitive impairments during electroconvulsive therapy. In this study, we aimed to assess the effectiveness and safety of memantine as an N-methyl-D aspartate receptor antagonist in the prevention of cognitive deficits due to ECT. METHODS: Thirty-eight adult patients with various mental disorders were randomized to memantine (10 mg/day initially and 20 mg/day at the end of the first week) or placebo during the ECT period. Mini Mental Status Examination, Digit Span Subtest, and backward memory span of Wechsler Adult Intelligence Scale were used to assess the cognitive functions 24 hours before and after ECT. Subjective ratings of side effects were obtained in the first, second, and fourth week of the treatment. RESULTS: The mean Mini Mental Status Examination score relatively increased in the intervention group showing a significant improvement with memantine (P < 0.001). The direct digit span had decreased in the control group, whereas no significant change was observed in the intervention group (P < 0.001). Backward memory span test showed a decrease in the control group after the ECT sessions, whereas a relative increase was observed in the intervention group (P = 0.001). The most frequently reported side effects in the intervention group did not differ significantly from the control group. CONCLUSIONS: This initial study showed that cognitive performance was enhanced in patients receiving memantine during ECT, indicating the possible role of the glutamatergic system in creating ECT-induced deficits. Larger long-term studies are necessary for understanding the role of the glutamatergic system in these disorders. PMID- 26536020 TI - Rotigotine Transdermal Patch Does Not Make Parkinson Disease Patients Sleepy During Daytime. AB - OBJECTIVES: To assess quantitatively the influence of rotigotine transdermal patch on daytime sleepiness, the most common adverse event by non-ergot dopamine agonists (DAs), in Parkinson disease (PD) patients. METHODS: An open-label study enrolled PD patients with unsatisfactory control of motor symptoms. Treatment with rotigotine transdermal patch was titrated to optimal dose (4-8 mg/24 hours) over 2 to 4 weeks. Primary outcome was Epworth Sleepiness Scale (ESS) for daytime sleepiness. Secondary outcomes included Hoehn&Yahr stage, time spent with dyskinesia, Clinical Global Impression of Improvement (CGI-I) of motor symptoms, adverse events, and compliance. RESULTS: The subjects were 31 PD patients (age 72 +/- 8, Hoehn &Yahr stage 2.7 +/- 0.9, mean +/- SD). The ESS did not increase after rotigotine treatment (7.2 +/- 4.9 before treatment, 6.2 +/- 4.0 with 4 mg/24 hour, and 8.1 +/- 6.4 with 8 mg/24 hour). The CGI-I score improved after treatment; responder rate reached 88.9% with 8 mg/24 hours. No patients showed worsening in other secondary outcomes. In 13 patients treated with equivalent doses of rotigotine switched from other DAs (pramipexole, ropinirole, and cabergoline), ESS did not increase after treatment (10.0 +/- 4.6 before and 8.6 +/- 4.5 after treatment) and decreased without worsening of CGI-I in 54% patients. Other secondary outcomes did not worsen after treatment. CONCLUSIONS: Twenty four-hour transdermal delivery of rotigotine at doses up to 8 mg/24 hours does not worsen the daytime sleepiness in PD patients and often improves it when switched from other non-ergot DAs. This is achieved together with satisfactory improvement in motor symptoms, demonstrating that this new modality of non-ergot DA is well tolerated and beneficial in PD patients. PMID- 26536021 TI - Safety, Tolerability, and Pharmacokinetics of Fosphenytoin Loading in Patients With Subarachnoid Hemorrhage. AB - OBJECTIVE: Fosphenytoin is frequently used for the rapid delivery of phenytoin in subarachnoid hemorrhage (SAH) patients. The present study was performed to investigate the safety, tolerability, and pharmacokinetic profiles of rapid intravenous loading of fosphenytoin in SAH patients. METHODS: Fosphenytoin was administered intravenously as a single loading dose of 20 mg phenytoin equivalent/kg at an infusion rate of 150 mg PE/min to 30 adult patients with SAH, who experienced seizures or had a clinical suspicion of nonconvulsive seizures. Serum concentrations of free phenytoin were determined, and adverse events were assessed at 0, 10, 20 minutes, and 24 hours after the infusion of fosphenytoin. RESULTS: Four patients experienced transient lowering of blood pressure, but other adverse events were not observed. All patients achieved the therapeutic level of free phenytoin (1-2 mg/L) at the end of infusion, but most patients (28/30) entered the markedly supratherapeutic range and the mean serum concentration was 17.7 +/- 8.13 mg/L; higher serum concentration was maintained up to 20 minutes after infusion (mean concentration; 3.46 +/- 3.75 mg/L). At 24 hours after loading, a majority of the patients (25/30) maintained their levels within the therapeutic range of free phenytoin. CONCLUSIONS: Rapid intravenous loading of fosphenytoin was well tolerated and effective in promptly achieving the therapeutic level of free phenytoin, but most patients experienced overshoot of free phenytoin at the end of infusion. Because increased serum concentrations may increase the risk of cardiovascular complications, additional studies are needed to determine the optimal dose and infusion rate of fosphenytoin in SAH patients. PMID- 26536022 TI - A Randomized Controlled Trial of Subcutaneous Apomorphine for Parkinson Disease: A Repeat Dose and Pharmacokinetic Study. AB - OBJECTIVES: This study is the first controlled trial to evaluate the efficacy and safety of subcutaneous apomorphine in Japanese patients with advanced Parkinson disease. METHODS: A phase II, multicenter, randomized, double-blind, parallel group trial was undertaken in 16 patients with advanced Parkinson disease with wearing-off phenomenon to compare subcutaneous apomorphine versus placebo. The maintenance dose of apomorphine (1-6 mg per dose), determined individually for each patient by titration, was additionally administered 3 times at 2-hour intervals in the multiple-dose phase in which pharmacokinetics was evaluated. RESULTS: The mean (SD) maintenance apomorphine dose was 3.4 (1.4) mg (range, 2-6 mg). The change in the Unified Parkinson's Disease Rating Scale motor score 20 minutes after maintenance dose administration was significantly greater in the apomorphine group than in the placebo group (least squares mean, -24.0 vs -4.1, P = 0.021). Apomorphine treatment resulted in an "on" state approximately 20 minutes after dose administration, lasting for approximately 60 minutes. Apomorphine was rapidly absorbed, with the maximum plasma concentration (Cmax) reached in 0.367 to 0.383 hour. It was quickly eliminated with a half-life of 0.520 to 0.793 hour, suggesting no accumulation during multiple-dose phase. The Cmax of apomorphine at effective dose was presumed to be approximately 20 ng/mL. Apomorphine was well tolerated. CONCLUSIONS: Subcutaneous apomorphine is expected to provide a new treatment option in Japan as a rescue therapy. Two-hour interval injections did not cause reduced responses, and effective blood concentration was presumed to be approximately 20 ng/mL similar, to the previous study conducted at North America. PMID- 26536023 TI - Recurrent and Alternating Pisa Syndrome. AB - OBJECTIVES: The aims of the study were to report the case of a male patient who developed a first episode of Pisa syndrome (PS) to the right side and a second episode to the left side and to discuss the hypothesis that states that denervation is one of the main mechanisms implicated in the development of PS. METHODS: We report on the case of a 71-year-old patient with Parkinson disease who developed PS to the right side while on dopaminergic treatment with pramipexol and levodopa. The dopamine agonist was discontinued and the postural abnormality was corrected increasing the levodopa dose. Six years later, while on ropinirole and levodopa, he developed PS again but this time the lean was to the left. Even though the dopamine agonist was discontinued, this condition failed to improve. CONCLUSIONS: Mechanisms other than denervation and its relationship with the more or less affected side contribute to the development of the syndrome.This is the first report of a case of recurrent alternating PS and highlights the need for research on this topic to better understand this disorder. PMID- 26536024 TI - Validation of a Novel Collection Device for Non-Invasive Urine Sampling from Free Ranging Animals. AB - Recent advances in non-invasively collected samples have opened up new and exciting opportunities for wildlife research. Different types of samples, however, involve different limitations and certain physiological markers (e.g., C peptide, oxytocin) can only be reliably measured from urine. Common collection methods for urine to date work best for arboreal animals and large volumes of urine. Sufficient recovery of urine is thus still difficult for wildlife biologists, particularly for terrestrial and small bodied animals. We tested three collection devices (two commercially available saliva swabs, Salivette synthetic and cotton, and cotton First aid swabs) against a control to permit the collection of small volumes of urine from the ground. We collected urine samples from captive and wild macaques, and humans, measured volume recovery, and analyzed concentrates of selected physiological markers (creatinine, C-peptide, and neopterin). The Salivette synthetic device was superior to the two alternative devices. Concentrations of creatinine, absolute C-peptide, C-peptide per creatinine, absolute neopterin, and neopterin per creatinine measured in samples collected with this device did not differ significantly from the control and were also strongly correlated to it. Fluid recovery was also best for this device. The least suitable device is the First aid collection device; we found that while absolute C-peptide and C-peptide per creatinine concentrations did not differ significantly from the control, creatinine concentrations were significantly lower than the control. In addition, these concentrations were either not or weakly correlated to the control. The Salivette cotton device provided intermediate results, although these concentrations were strongly correlated to the control. Salivette synthetic swabs seem to be useful devices for the collection of small amounts of urine from the ground destined for the assessment of physiological parameters. They thus provide new opportunities for field studies to incorporate physiological markers, particularly on smaller bodied and terrestrial animals and where urine collection is difficult. PMID- 26536025 TI - Prostate Cancer Heterogeneous High-Metastatic Multi-Organ-Colonizing Chemo Resistant Variants Selected by Serial Metastatic Passage in Nude Mice Are Highly Enriched for Multinucleate Giant Cells. AB - In order to further understand the role of tumor heterogeneity in metastasis and chemo-resistance, high metastatic PC-3 human prostate cancer variants were selected by injecting parental PC-3 cells, expressing green fluorescent protein (GFP) in the footpad of nude mice, which then metastasize to inguinal lymph nodes. The PC-3-GFP cells which metastasized to the inguinal lymph nodes were collected and were re-injected to the footpad. After 6 such cycles, the PC-3-GFP cells collected from inguinal lymph nodes (PC-3-GFP-LN) were again injected to the footpad. PC-3-GFP-LN showed 100% metastasis to major lymph nodes (popliteal, inguinal, axillary, and cervical), and 100% metastasis to bone and lung. The percent of giant cell variants was enriched in PC-3-GFP-LN-6 compared to parental cells and increased with each cycle of selection, which in turn had increased metastasis. PC-3-GFP-LN-6 cells were resistant to 5-fluorouracil, doxorubicin and cisplatinum, compared to parental PC-3. However, PC-3-GFP-LN-6 was sensitive to the traditional Chinese medicine (TCM) herbal mixture LQ, similar to the parental cells. These results suggest that PC-3 tumors are heterogenous and that subpopulations of highly metastatic, drug-resistant cells can be step-wise selected using a mouse model of tumor progression. PMID- 26536026 TI - Music and Language Syntax Interact in Broca's Area: An fMRI Study. AB - Instrumental music and language are both syntactic systems, employing complex, hierarchically-structured sequences built using implicit structural norms. This organization allows listeners to understand the role of individual words or tones in the context of an unfolding sentence or melody. Previous studies suggest that the brain mechanisms of syntactic processing may be partly shared between music and language. However, functional neuroimaging evidence for anatomical overlap of brain activity involved in linguistic and musical syntactic processing has been lacking. In the present study we used functional magnetic resonance imaging (fMRI) in conjunction with an interference paradigm based on sung sentences. We show that the processing demands of musical syntax (harmony) and language syntax interact in Broca's area in the left inferior frontal gyrus (without leading to music and language main effects). A language main effect in Broca's area only emerged in the complex music harmony condition, suggesting that (with our stimuli and tasks) a language effect only becomes visible under conditions of increased demands on shared neural resources. In contrast to previous studies, our design allows us to rule out that the observed neural interaction is due to: (1) general attention mechanisms, as a psychoacoustic auditory anomaly behaved unlike the harmonic manipulation, (2) error processing, as the language and the music stimuli contained no structural errors. The current results thus suggest that two different cognitive domains-music and language-might draw on the same high level syntactic integration resources in Broca's area. PMID- 26536027 TI - Loss of Metabotropic Glutamate Receptor 5 Function on Peripheral Benzodiazepine Receptor in Mice Prenatally Exposed to LPS. AB - Parental microglial induced neuroinflammation, triggered by bacterial- or viral infections, can induce neuropsychiatric disorders like schizophrenia and autism to offspring in animal models. Recent investigations suggest that microglia, the resident immune cells of the brain, provides a link between neurotransmission, immune cell activation, brain inflammation and neuronal dysfunction seen with the offspring. Relatively little is known about how reduction of brain inflammation and restoration of glial function are associated with diminution of brain degeneration and behavioral deficits in offspring. Increased mGluR5 expression and the long-lasting excitotoxic effects of the neurotoxin during brain development are associated with the glial dysfunctions. We investigated the relationship of mGluR5 and PBR and how they regulate glial function and inflammatory processes in mice prenatally exposed to LPS (120MUg/kg, between gestational days 15 and 17), an inflammatory model of a psychiatric disorder. Using PET imaging, we showed that pharmacological activation of mGluR5 during 5 weeks reduced expression of classic inflammation marker PBR in many brain areas and that this molecular association was not present in LPS-exposed offspring. The post-mortem analysis revealed that the down regulation of PBR was mediated through activation of mGluR5 in astrocytes. In addition, we demonstrated that this interaction is defective in a mouse model of the psychiatric deficit offering a novel insight of mGluR5 involvement to brain related disorders and PBR related imaging studies. In conclusion, mGluR5 driven glutamatergic activity regulates astrocytic functions associated with PBR (cholesterol transport, neurosteroidogenesis, glial phenotype) during maturation and could be associated with neuropsychiatric disorders in offspring. PMID- 26536028 TI - Interactive Effects of Indigestible Carbohydrates, Protein Type, and Protein Level on Biomarkers of Large Intestine Health in Rats. AB - The effects of indigestible carbohydrates, protein type, and protein level on large intestine health were examined in rats. For 21 days, 12 groups of six 12 week-old male Wistar rats were fed diets with casein (CAS), or potato protein concentrate (PPC), providing 14% (lower protein level; LP), or 20% (higher protein level; HP) protein, and containing cellulose, resistant potato starch, or pectin. Fermentation end-products, pH, and beta-glucuronidase levels in cecal digesta, and ammonia levels in colonic digesta were determined. Cecal digesta, tissue weights, cecal and colon morphology, and colonocyte DNA damage were also analyzed. Digesta pH was lower, whereas relative mass of cecal tissue and digesta were higher in rats fed pectin diets than in those fed cellulose. Cecal parameters were greater in rats fed PPC and HP diets than in those fed CAS and LP diets, respectively. Short-chain fatty acid (SCFA) concentrations were unaffected by protein or carbohydrate type. Total SCFA, acetic acid, and propionic acid concentrations were greater in rats fed LP diets than in those fed HP. Cecal pool of isobutyric and isovaleric acids was greater in rats fed PPC than in those fed CAS diets. PPC diets decreased phenol concentration and increased ammonia concentration in cecal and colonic digesta, respectively. Cecal crypt depth was greater in rats fed PPC and HP diets, and was unaffected by carbohydrates; whereas colonic crypt depth was greater in rats fed cellulose. Myenteron thickness in the cecum was unaffected by nutrition, but was greater in the colon of rats fed cellulose. Colonocyte DNA damage was greater in rats fed LP diets than in those fed HP diets, and was unaffected by carbohydrate or protein type. It was found that nutritional factors decreasing cecal digesta weight contribute to greater phenol production, increased DNA damage, and reduced ammonia concentration in the colon. PMID- 26536029 TI - Neural Sequence Generation Using Spatiotemporal Patterns of Inhibition. AB - Stereotyped sequences of neural activity are thought to underlie reproducible behaviors and cognitive processes ranging from memory recall to arm movement. One of the most prominent theoretical models of neural sequence generation is the synfire chain, in which pulses of synchronized spiking activity propagate robustly along a chain of cells connected by highly redundant feedforward excitation. But recent experimental observations in the avian song production pathway during song generation have shown excitatory activity interacting strongly with the firing patterns of inhibitory neurons, suggesting a process of sequence generation more complex than feedforward excitation. Here we propose a model of sequence generation inspired by these observations in which a pulse travels along a spatially recurrent excitatory chain, passing repeatedly through zones of local feedback inhibition. In this model, synchrony and robust timing are maintained not through redundant excitatory connections, but rather through the interaction between the pulse and the spatiotemporal pattern of inhibition that it creates as it circulates the network. These results suggest that spatially and temporally structured inhibition may play a key role in sequence generation. PMID- 26536030 TI - Development and Validation of the Body Size Scale for Assessing Body Weight Perception in African Populations. AB - BACKGROUND: The social valorisation of overweight in African populations could promote high-risk eating behaviours and therefore become a risk factor of obesity. However, existing scales to assess body image are usually not accurate enough to allow comparative studies of body weight perception in different African populations. This study aimed to develop and validate the Body Size Scale (BSS) to estimate African body weight perception. METHODS: Anthropometric measures of 80 Cameroonians and 81 Senegalese were used to evaluate three criteria of adiposity: body mass index (BMI), overall percentage of fat, and endomorphy (fat component of the somatotype). To develop the BSS, the participants were photographed in full face and profile positions. Models were selected for their representativeness of the wide variability in adiposity with a progressive increase along the scale. Then, for the validation protocol, participants self-administered the BSS to assess self-perceived current body size (CBS), desired body size (DBS) and provide a "body self-satisfaction index." This protocol included construct validity, test-retest reliability and convergent validity and was carried out with three independent samples of respectively 201, 103 and 1115 Cameroonians. RESULTS: The BSS comprises two sex-specific scales of photos of 9 models each, and ordered by increasing adiposity. Most participants were able to correctly order the BSS by increasing adiposity, using three different words to define body size. Test-retest reliability was consistent in estimating CBS, DBS and the "body self-satisfaction index." The CBS was highly correlated to the objective BMI, and two different indexes assessed with the BSS were consistent with declarations obtained in interviews. CONCLUSION: The BSS is the first scale with photos of real African models taken in both full face and profile and representing a wide and representative variability in adiposity. The validation protocol proved its reliability for estimating body weight perception in Africans. PMID- 26536031 TI - Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines. AB - BACKGROUND: BCRP/ABCG2 emerged as an important multidrug resistance protein, because it confers resistance to several classes of cancer chemotherapeutic agents and to a number of novel molecularly-targeted therapeutics such as tyrosine kinase inhibitors. Gefitinib is an orally active, selective EGFR tyrosine kinase inhibitor used in the treatment of patients with advanced non small cell lung cancer (NSCLC) carrying activating EGFR mutations. Membrane transporters may affect the distribution and accumulation of gefitinib in tumour cells; in particular a reduced intracellular level of the drug may result from poor uptake, enhanced efflux or increased metabolism. AIM: The present study, performed in a panel of NSCLC cell lines expressing different ABCG2 plasma membrane levels, was designed to investigate the effect of the efflux transporter ABCG2 on intracellular gefitinib accumulation, by dissecting the contribution of uptake and efflux processes. METHODS AND RESULTS: Our findings indicate that gefitinib, in lung cancer cells, inhibits ABCG2 activity, as previously reported. In addition, we suggest that ABCG2 silencing or overexpression affects intracellular gefitinib content by modulating the uptake rather than the efflux. Similarly, overexpression of ABCG2 affected the expression of a number of drug transporters, altering the functional activities of nutrient and drug transport systems, in particular inhibiting MPP, glucose and glutamine uptake. CONCLUSIONS: Therefore, we conclude that gefitinib is an inhibitor but not a substrate for ABCG2 and that ABCG2 overexpression may modulate the expression and activity of other transporters involved in the uptake of different substrates into the cells. PMID- 26536032 TI - Additive Renoprotection by Pioglitazone and Fenofibrate against Inflammatory, Oxidative and Apoptotic Manifestations of Cisplatin Nephrotoxicity: Modulation by PPARs. AB - Nephrotoxicity is a major side effect for the antineoplastic drug cisplatin. Here, we employed pharmacological, biochemical, and molecular studies to investigate the role of peroxisome proliferator-activated receptors (PPARs) in cisplatin nephrotoxicity. Rats were treated with a single i.p. dose of cisplatin (5 mg/kg) alone or combined with pioglitazone (PPARgamma agonist), fenofibrate (PPARalpha agonist), pioglitazone plus fenofibrate, or thalidomide (Tumor necrosis factor-alpha inhibitor; TNF-alpha). Cisplatin nephrotoxicity was evidenced by rises in renal indices of functional (blood urea nitrogen, BUN, and creatinine), inflammatory (TNF-alpha, interleukin 6, IL-6), oxidative (increased malondialdehyde, MDA, and decreased superoxide dismutase, SOD and nitric oxide metabolites, NOx), apoptotic (caspase 3), and histological (glomerular atrophy, acute tubular necrosis and vacuolation) profiles. Cisplatin effects were partly abolished upon concurrent exposure to pioglitazone, fenofibrate, or thalidomide; more renoprotection was observed in rats treated with pioglitazaone plus fenofibrate. Immunostaining showed that renal expressions of PPARalpha and PPARgamma were reduced by cisplatin and restored to vehicle-treated values after simultaneous treatment with pioglitazone or fenofibrate. Fenofibrate or pioglitazone renoprotection remained unaltered after concurrent blockade of PPARalpha (GW6471) and PPARgamma (GW9662), respectively. To complement the rat studies, we also report that in human embryonic kidney cells (HEK293 cells), increases caused by cisplatin in inflammatory, apoptotic, and oxidative biomarkers were (i) partly improved after exposure to pioglitazone, fenofibrate, or thalidomide, and (ii) completely disappeared in cells treated with a combination of all three drugs. These data establish that the combined use of pioglitazone and fenofibrate additively improved manifestations of cisplatin nephrotoxicity through perhaps GW6471/GW9662-insensitive mechanisms. PMID- 26536033 TI - Taxonomic Synopsis of the Ponto-Mediterranean Ants of Temnothorax nylanderi Species-Group. AB - In the current revisionary work, the Temnothorax nylanderi species-group of myrmicine ants is characterized. Eighteen species belonging to this group in the Ponto-Mediterranean region are described or redefined based on an integrative approach that combines exploratory analyses of morphometric data and of a 658bp fragment of the mitochondrial gene for the cytochrome c oxidase subunit I (CO I). The species group is subdivided into five species complexes: T. angustifrons complex, T. lichtensteini complex, T. nylanderi complex, T. parvulus complex, T. sordidulus complex, and two species, T. angulinodis sp. n. and T. flavicornis (Emery, 1870) form their own lineages. We describe seven new species (T. angulinodis sp. n., T. angustifrons sp. n., T. ariadnae sp. n., T. helenae sp. n., T. lucidus sp. n., T. similis sp. n., T. subtilis sp. n.), raise T. tergestinus (FINZI, 1928) stat.n. to species level, and propose a new junior synonymy for T. saxonicus (SEIFERT, 1995) syn.n. (junior synonym of T. tergestinus). We describe the worker caste and provide high quality images and distributional maps for all eighteen species. Furthermore, we provide a decision tree as an alternative identification key that visually gives an overview of this species-group. We make the first application to Formicidae of the Semantic Phenotype approach that has been used in previous taxonomic revisions. PMID- 26536034 TI - Broadening of Virus-Specific CD8+ T-Cell Responses Is Indicative of Residual Viral Replication in Aviremic SIV Controllers. AB - Control of HIV replication is a rare immunological event, providing clues to understand the viral control mechanism. CD8+ T-cell responses are crucial for virus control, but it is unclear whether lasting HIV containment can be achieved after establishment of infection. Here, we describe lasting SIV containment in a macaque AIDS model. Analysis of ten rhesus macaques that controlled viremia for 2 years post-infection found accumulation of proviral gag and nef CD8+ T-cell escape mutations in four of them. These four controllers mounted CD8+ T cells targeting Gag, Nef, and other viral proteins at 4 months, suggesting that broadening of CD8+ T-cell targets can be an indicator of the beginning of viral control failure. The remaining six aviremic SIV controllers, however, harbored proviruses without mutations and showed no or little broadening of their CD8+ T cell responses in the chronic phase. Indeed, three of the latter six exhibiting no change in CD8+ T-cell targets showed gradual decreases in SIV-specific CD8+ T cell frequencies, implying a concomitant reduction in viral replication. Thus, stability of the breadth of virus-specific CD8+ T-cell responses may represent a status of lasting HIV containment by CD8+ T cells. PMID- 26536035 TI - Tuberculosis Infection in the United States: Prevalence Estimates from the National Health and Nutrition Examination Survey, 2011-2012. AB - BACKGROUND: Reexamining the prevalence of persons infected with tuberculosis (TB) is important to determine trends over time. In 2011-2012 a TB component was included in the National Health and Nutrition Examination Survey (NHANES) to estimate the reservoir of persons infected with TB. METHODS: Civilian, noninstitutionalized U.S. population survey participants aged 6 years and older were interviewed regarding their TB history and eligibility for the tuberculin skin test (TST) and interferon gamma release assay (IGRA) blood test. Once eligibility was confirmed, both tests were conducted. Prevalence and numbers of TST positive (10 mm or greater), IGRA positive, and both TST and IGRA positive were calculated by adjusting for the complex survey design after applying corrections for item nonresponse and digit preference in TST induration measurements. To examine TST positivity over time, data from NHANES 1999-2000 were reanalyzed using the same statistical methods. The TST was performed using Tubersol, a commercially available purified protein derivative (PPD), rather than PPD-S, which was the antigen used in NHANES 1999-2000. Prior patient history of TB vaccination was not collected in this study nor were patients examined for the presence of a Bacillus of Calmette and Guerin (BCG) vaccine scar. RESULTS: For NHANES 2011-2012, TST and IGRA results were available for 6,128 (78.4%) and 7,107 (90.9%) eligible participants, respectively. There was no significant difference between the percentage of the U.S. population that was TST positive in 2011-2012 (4.7% [95% CI 3.4-6.3]; 13,276,000 persons) compared with 1999-2000 (4.3%; 3.5 5.3). In 2011-2012 the percentage that was IGRA positive was 5.0% (4.2-5.8) and double TST and IGRA positivity was 2.1% (1.5-2.8). The point estimate of IGRA positivity prevalence in foreign-born persons (15.9%; 13.5-18.7) was lower than for TST (20.5%; 16.1-25.8) in 2011-2012. The point estimate of IGRA positivity prevalence in U.S.-born persons (2.8%; 2.0-3.8) was higher than for TST (1.5%; 0.9-2.6). CONCLUSIONS: No statistically significant decline in the overall estimated prevalence of TST positivity was detected from 1999-2000 to 2011-2012. The prevalence of TB infection, whether measured by TST or IGRA, remains lower among persons born in the United States compared with foreign-born persons. PMID- 26536036 TI - Age-Related Changes in Electroencephalographic Signal Complexity. AB - The study of active and healthy aging is a primary focus for social and neuroscientific communities. Here, we move a step forward in assessing electrophysiological neuronal activity changes in the brain with healthy aging. To this end, electroencephalographic (EEG) resting state activity was acquired in 40 healthy subjects (age 16-85). We evaluated Fractal Dimension (FD) according to the Higuchi algorithm, a measure which quantifies the presence of statistical similarity at different scales in temporal fluctuations of EEG signals. Our results showed that FD increases from age twenty to age fifty and then decreases. The curve that best fits the changes in FD values across age over the whole sample is a parabola, with the vertex located around age fifty. Moreover, FD changes are site specific, with interhemispheric FD asymmetry being pronounced in elderly individuals in the frontal and central regions. The present results indicate that fractal dimension well describes the modulations of brain activity with age. Since fractal dimension has been proposed to be related to the complexity of the signal dynamics, our data demonstrate that the complexity of neuronal electric activity changes across the life span of an individual, with a steady increase during young adulthood and a decrease in the elderly population. PMID- 26536037 TI - Evaluating Computer Screen Time and Its Possible Link to Psychopathology in the Context of Age: A Cross-Sectional Study of Parents and Children. AB - BACKGROUND: Several studies have suggested that high levels of computer use are linked to psychopathology. However, there is ambiguity about what should be considered normal or over-use of computers. Furthermore, the nature of the link between computer usage and psychopathology is controversial. The current study utilized the context of age to address these questions. Our hypothesis was that the context of age will be paramount for differentiating normal from excessive use, and that this context will allow a better understanding of the link to psychopathology. METHODS: In a cross-sectional study, 185 parents and children aged 3-18 years were recruited in clinical and community settings. They were asked to fill out questionnaires regarding demographics, functional and academic variables, computer use as well as psychiatric screening questionnaires. Using a regression model, we identified 3 groups of normal-use, over-use and under-use and examined known factors as putative differentiators between the over-users and the other groups. RESULTS: After modeling computer screen time according to age, factors linked to over-use were: decreased socialization (OR 3.24, Confidence interval [CI] 1.23-8.55, p = 0.018), difficulty to disengage from the computer (OR 1.56, CI 1.07-2.28, p = 0.022) and age, though borderline-significant (OR 1.1 each year, CI 0.99-1.22, p = 0.058). While psychopathology was not linked to over use, post-hoc analysis revealed that the link between increased computer screen time and psychopathology was age-dependent and solidified as age progressed (p = 0.007). Unlike computer usage, the use of small-screens and smartphones was not associated with psychopathology. CONCLUSIONS: The results suggest that computer screen time follows an age-based course. We conclude that differentiating normal from over-use as well as defining over-use as a possible marker for psychiatric difficulties must be performed within the context of age. If verified by additional studies, future research should integrate those views in order to better understand the intricacies of computer over-use. PMID- 26536038 TI - Regulation of Guinea Pig Detrusor Smooth Muscle Excitability by 17beta-Estradiol: The Role of the Large Conductance Voltage- and Ca2+-Activated K+ Channels. AB - Estrogen replacement therapies have been suggested to be beneficial in alleviating symptoms of overactive bladder. However, the precise regulatory mechanisms of estrogen in urinary bladder smooth muscle (UBSM) at the cellular level remain unknown. Large conductance voltage- and Ca2+-activated K+ (BK) channels, which are key regulators of UBSM function, are suggested to be non genomic targets of estrogens. This study provides an electrophysiological investigation into the role of UBSM BK channels as direct targets for 17beta estradiol, the principle estrogen in human circulation. Single BK channel recordings on inside-out excised membrane patches and perforated whole cell patch clamp were applied in combination with the BK channel selective inhibitor paxilline to elucidate the mechanism of regulation of BK channel activity by 17beta-estradiol in freshly-isolated guinea pig UBSM cells. 17beta-Estradiol (100 nM) significantly increased the amplitude of depolarization-induced whole cell steady-state BK currents and the frequency of spontaneous transient BK currents in freshly-isolated UBSM cells. The increase in whole cell BK currents by 17beta estradiol was eliminated upon blocking BK channels with paxilline. 17beta Estradiol (100 nM) significantly increased (~3-fold) the single BK channel open probability, indicating direct 17beta-estradiol-BK channel interactions. 17beta Estradiol (100 nM) caused a significant hyperpolarization of the membrane potential of UBSM cells, and this hyperpolarization was reversed by blocking the BK channels with paxilline. 17beta-Estradiol (100 nM) had no effects on L-type voltage-gated Ca2+ channel currents recorded under perforated patch-clamp conditions. This study reveals a new regulatory mechanism in the urinary bladder whereby BK channels are directly activated by 17beta-estradiol to reduce UBSM cell excitability. PMID- 26536039 TI - A viologen-functionalized chiral Eu-MOF as a platform for multifunctional switchable material. AB - A novel viologen-functionalized chiral europium-based metal-organic framework (Eu MOF) that possesses multi-switchable features including photochromism, photo modulated luminescence, photoswitchable NLO and piezoelectric properties has been obtained for the first time. PMID- 26536040 TI - Assessing the HIV-1 Epidemic in Brazilian Drug Users: A Molecular Epidemiology Approach. AB - Person who inject illicit substances have an important role in HIV-1 blood and sexual transmission and together with person who uses heavy non-injecting drugs may have less than optimal adherence to anti-retroviral treatment and eventually could transmit resistant HIV variants. Unfortunately, molecular biology data on such key population remain fragmentary in most low and middle-income countries. The aim of the present study was to assess HIV infection rates, evaluate HIV-1 genetic diversity, drug resistance, and to identify HIV transmission clusters in heavy drug users (DUs). For this purpose, DUs were recruited in the context of a Respondent-Driven Sampling (RDS) study in different Brazilian cities during 2009. Overall, 2,812 individuals were tested for HIV, and 168 (6%) of them were positive, of which 19 (11.3%) were classified as recent seroconverters, corresponding to an estimated incidence rate of 1.58%/year (95% CI 0.92-2.43%). Neighbor joining phylogenetic trees from env and pol regions and bootscan analyses were employed to subtype the virus from132 HIV-1-infected individuals. HIV-1 subtype B was prevalent in most of the cities under analysis, followed by BF recombinants (9%-35%). HIV-1 subtype C was the most prevalent in Curitiba (46%) and Itajai (86%) and was also detected in Brasilia (9%) and Campo Grande (20%). Pure HIV-1F infections were detected in Rio de Janeiro (9%), Recife (6%), Salvador (6%) and Brasilia (9%). Clusters of HIV transmission were assessed by Maximum likelihood analyses and were cross-compared with the RDS network structure. Drug resistance mutations were verified in 12.2% of DUs. Our findings reinforce the importance of the permanent HIV-1 surveillance in distinct Brazilian cities due to viral resistance and increasing subtype heterogeneity all over Brazil, with relevant implications in terms of treatment monitoring, prophylaxis and vaccine development. PMID- 26536041 TI - Ab initio pressure-dependent reaction kinetics of methyl propanoate radicals. AB - The unimolecular dissociation and isomerization kinetics of the three methyl propanoate (MP) radicals, CH3CH2C(=O)OCH2 (MP-m), CH3CHC(=O)OCH3 (MP-alpha), and CH2CH2C(=O)OCH3 (MP-beta), are theoretically investigated using high-level ab initio methods and the Rice-Ramsperger-Kassel-Marcus (RRKM)/master equation (ME) theory. Stationary-point energies are obtained using the coupled cluster singles and doubles with perturbative triples correction (CCSD(T)), multi-reference singles and doubles configuration interaction (MRSDCI) with the Davidson-Silver (DS) correction, and multi-reference averaged coupled pair functional (MRACPF2) theories. The isomerization barriers between the three radicals are predicted to be generally lower than the corresponding bond dissociation channels, leading to a strongly coupled reaction system in subsequent kinetics studies. The phenomenological temperature- and pressure-dependent rate coefficients are computed using the RRKM/ME theory over a temperature range of 500 to 2000 K and at a pressure range of 0.01 atm to the high-pressure limit, which are then fitted to modified Arrhenius expressions. The beta-scission rate coefficients of MP alpha to CH3CHC(=O) and CH3O[combining dot above] are predicted to be the smallest because of its highest activation energy among all studied unimolecular reactions channels. Analysis of branching fractions shows that both MP-m and MP alpha radicals mainly decompose to the bimolecular products CH3CH2C(=O) and H2CO, whereas the MP-beta radical primarily decomposes via cleavage of a C-C bond to form C2H4 and CH3OC(=O). The isomerization channels dominate at low temperatures, the branching fractions of which decrease with increasing temperature and become very minor at about 2000 K. Our accurate rate coefficients and branching fractions help to illuminate the unique combustion properties of MP. PMID- 26536042 TI - Ongoing increasing temporal and geographical trends of the incidence of extended spectrum beta-lactamase-producing Enterobacteriaceae infections in France, 2009 to 2013. AB - Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) are a major focus of multidrug-resistant organisms (MRO) surveillance programmes in France. To describe the temporal and geographical trends of these pathogens, we conducted an epidemiological study based on data extracted from the nationwide MRO surveillance network from 2009 to 2013. During this time, the incidence of ESBL-E infections in French hospitals increased by 73%, from 0.35 to 0.60 per 1,000 patient days (PD) (p<0.001) and ESBL-E bacteraemia by 77%, from 0.03 to 0.05 per 1,000 PD (p<0.001). The incidence of ESBL-E infections was higher in intensive-care units (1.62 to 2.44 per 1,000 PD (p<0.001)) than in recovery and long-term care facilities (0.20 to 0.31 per 1,000 PD (p<0.001)). Escherichia coli was the most frequent extended-spectrum beta-lactamase-producing (ESBL) pathogen, representing 59% (26,238/44,425) of all ESBL isolates, followed by Klebsiella pneumoniae (20%; 8,856/44,425) in 2013. The most frequent infection was urinary tract infection, for all species. The incidence of ESBL-E varied by region but showed an upward trend overall. Reinforcement of control measures for halting the spread of such MRO is crucial. PMID- 26536043 TI - Variation in breast cancer care quality in New York and California based on race/ethnicity and Medicaid enrollment. AB - BACKGROUND: Racial/ethnic and socioeconomic disparities persist in part because our current understanding of the care provided to minority and disadvantaged populations is limited. The authors evaluated the quality of breast cancer care in 2 large states to understand the disparities experienced by African Americans, Hispanics, Asian/Pacific Islanders (APIs), and Medicaid enrollees and to prioritize remediation strategies. METHODS: Statewide cancer registry data for 80,436 women in New York and 121,233 women in California who were diagnosed during 2004 to 2009 with stage 0 through III breast cancer were used to assess underuse and overuse of surgery, radiation, chemotherapy, and hormone therapy based on 34 quality measures. Concordance values were compared across racial/ethnic and Medicaid-enrollment groups. Multivariable models were used to quantify disparities across groups for each treatment in each state. RESULTS: Overall concordance was 76% for underuse measures and 87% for overuse measures. The proportions of patients who received care concordant with all relevant measures were 35% in New York and 33% in California. Compared with whites, African Americans were less likely to receive recommended surgery, radiation, and hormone therapy; Hispanics and APIs were usually more likely to receive recommended chemotherapy. Across states, the same racial/ethnic groups did not always experience the same disparities. Medicaid enrollment was associated with decreased likelihood of receiving all recommended treatments, except chemotherapy, in both states. Overuse was evident for hormone therapy and axillary surgery but was not associated with race/ethnicity or Medicaid enrollment. CONCLUSIONS: Patient-level measures of quality identify substantial problems with care quality and meaningful disparities. Remediating these problems will require prioritizing low-performing measures and targeting high-risk populations, possibly in different ways for different regions. PMID- 26536044 TI - Response to: impact of tiotropium on exacerbations versus glycopyrronium and QVA149. PMID- 26536045 TI - Healthcare providers' experiences screening for intimate partner violence among migrant and seasonal farmworking women: A phenomenological study. AB - BACKGROUND: Migrant and seasonal farmworking (MSFW) women patients experience substantially more intimate partner violence (IPV) than the general population, but few health-care providers screen patients for IPV. While researchers have examined screening practices in health-care settings, none have exclusively focused on MSFW women. OBJECTIVE: The aim of this phenomenological study was to explore the experiences of health-care providers who have screened for and/or addressed IPV with MSFW women patients. DESIGN: Researchers utilized descriptive phenomenology to capture the lived experiences of these health-care providers. Data were analysed using Colaizzi's seven-stage framework. SETTING AND PARTICIPANTS: Interviews were conducted with nine female participants - all of whom: (i) were clinically active health-care providers within the MSFW community, (ii) were bilingual in English and Spanish or had access to a translator, (iii) had treated MSFW patients who had experienced IPV and (iv) were at least 18 years of age. RESULTS: Participants' experiences were reflected in four emergent themes: (i) provider-centered factors, (ii) patient-centered factors, (iii) clinic-centered factors and (iv) community-centered factors. Participants described barriers to establish routine IPV assessment, decrease patient ambivalence and increase on-site support and community resources. DISCUSSION AND CONCLUSIONS: This study aimed to generate a greater understanding of the experiences of health-care providers with screening for and addressing IPV with MSFW patients. Implications and recommendations for research, clinical practice and policy are provided. PMID- 26536046 TI - Photonic Applications of Metal-Dielectric Heterostructured Nanomaterials. AB - Metal materials, supporting plasmon modes on their surface, can confine the optical field at deep subwavelength scale, which is desired for photonic integration. However, their intrinsic high Ohmic losses make it impossible to construct the whole circuit solely with the metal materials. Integrating the plasmonic components with dielectric materials may offer a solution to this dilemma. With outstanding active optical performance, these dielectric components not only can greatly reduce the optical losses of the entire circuits but also offer an efficient way to launch the surface plasmon polaritons through the evanescent field coupling or the direct exciton-plasmon conversion. Furthermore, the cooperative interaction between metal and dielectric materials would bring vast novel optical phenomena and functional photonic devices. In this review, the synergistic effects among metal and dielectric materials in various heterostructures as well as their related applications are highlighted. Comprehensive understanding on their synergistic interactions would offer useful guidance for the design and fabrication of the ultracompact novel optical devices. PMID- 26536047 TI - Size-dependent surface effects in maghemite nanoparticles and its impact on interparticle interactions in dense assemblies. AB - The question of the dominant interparticle magnetic interaction type in random closely packed assemblies of different diameter (6.2-11.5 nm) bare maghemite nanoparticles (NPs) is addressed. Single-particle magnetic properties such as particle anisotropy and exchange bias field are first of all studied in dilute (reference) systems of these same NPs, where interparticle interactions are neglible. Substantial surface spin disorder is revealed in all particles except the smallest, viz. for diameters d = 8-11.5 nm but not for d = 6.2-6.3 nm. X-ray diffraction analysis points to a crystallographic origin of this effect. The study of closely packed assemblies of the d >= 8 nm particles observes collective (superspin) freezing that clearly appears to be governed by interparticle dipole interactions. However, the dense assemblies of the smallest particles exhibit freezing temperatures that are higher than expected from a simple (dipole) extrapolation of the corresponding temperatures found in the d >= 8 nm assemblies. It is suggested that the nature of the dominant interparticle interaction in these smaller particle assemblies is superexchange, whereby the lack of significant surface spin disorder allows this mechanism to become important at the level of interacting superspins. PMID- 26536048 TI - SilverCatalyzed Cascade Carboxylation and Cyclization of Trimethyl(2-methylenebut 3-yn-1-yl)silane Derivatives. AB - C-C bond-forming carboxylation and cyclization of trimethyl(2-methylenebut-3-yn-1 yl)silane derivatives and carbon dioxide was developed. Silver catalysts and CsF promoted the reaction to afford the corresponding 2-furanone and 2-pyrone derivatives in good-to-high yields. The structure of the 2-furanone was confirmed by single-crystal X-ray crystallography, which revealed that the geometry of the exo-olefin was that of a Z-isomer. When an aromatic ring-substituted alkyne was used, 2-furanone derivatives were selectively obtained via 5-exo-dig cyclization, whereas the reaction of alkyl-substituted alkynes produced 2-pyrone derivatives with high selectivity. PMID- 26536049 TI - Hospital-based Clostridium difficile infection surveillance reveals high proportions of PCR ribotypes 027 and 176 in different areas of Poland, 2011 to 2013. AB - As part of the European Clostridium difficile infections (CDI) surveillance Network (ECDIS-Net), which aims to build capacity for CDI surveillance in Europe, we constructed a new network of hospital-based laboratories in Poland. We performed a survey in 13 randomly selected hospital-laboratories in different sites of the country to determine their annual CDI incidence rates from 2011 to 2013. Information on C. difficile laboratory diagnostic testing and indications for testing was also collected. Moreover, for 2012 and 2013 respectively, participating hospital-laboratories sent all consecutive isolates from CDI patients between February and March to the Anaerobe Laboratory in Warsaw for further molecular characterisation, including the detection of toxin-encoding genes and polymerase chain reaction (PCR)-ribotyping. Within the network, the mean annual hospital CDI incidence rates were 6.1, 8.6 and 9.6 CDI per 10,000 patient-days in 2011, 2012, and 2013 respectively. Six of the 13 laboratories tested specimens only on the request of a physician, five tested samples of antibiotic-associated diarrhoea or samples from patients who developed diarrhoea more than two days after admission (nosocomial diarrhoea), while two tested all submitted diarrhoeal faecal samples. Most laboratories (9/13) used tests to detect glutamate dehydrogenase and toxin A/B either separately or in combination. In the two periods of molecular surveillance, a total of 166 strains were characterised. Of these, 159 were toxigenic and the majority belonged to two PCR ribotypes: 027 (n=99; 62%) and the closely related ribotype 176 (n=22; 14%). The annual frequency of PCR-ribotype 027 was not significantly different during the surveillance periods (62.9% in 2012; 61.8% in 2013). Our results indicate that CDIs caused by PCR-ribotype 027 predominate in Polish hospitals participating in the surveillance, with the closely related 176 ribotype being the second most common agent of infection. PMID- 26536050 TI - Intact working memory in non-manifesting LRRK2 carriers--an fMRI study. AB - Cognitive impairments are prevalent in patients with Parkinson's disease. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of genetic Parkinsonism. Non-manifesting carriers of the G2019S mutation in the LRRK2 gene were found to have lower executive functions as measured by the Stroop task. This exploratory study aimed to assess whether the cognitive impairment in non-manifesting carriers is specific for executive functions or includes other cognitive domains such as working memory. We recruited 77 non manifesting first-degree relatives of Parkinson's disease patients (38 carriers). A block-design fMRI N-back task, with 0-back, 2-back and 3-back conditions, was used in order to assess working memory. Participants were well matched on the Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test, Unified Parkinson's Disease Rating Scale part III, digit span, age, gender and Beck Depression Inventory. The task achieved the overall expected effect in both groups with longer reaction times and lower accuracy rates with increasing task demands. However, no whole-brain or region-of-interest between-groups differences were found on any of the task conditions. These results indicate that non-manifesting carriers of the G2019S mutation in the LRRK2 gene have a specific cognitive profile with executive functions, as assessed by the Stroop task, demonstrating significant impairment but with working memory, as assessed with the N-back task, remaining relatively intact. These finding shed light on the pre motor cognitive changes in this unique 'at risk' population and should enable more focused cognitive assessments of these cohorts. PMID- 26536051 TI - What's new about Acta Oncologica for 2016? PMID- 26536053 TI - Evaluating Sense Codon Reassignment with a Simple Fluorescence Screen. AB - Understanding the interactions that drive the fidelity of the genetic code and the limits to which modifications can be made without breaking the translational system has practical implications for understanding the molecular mechanisms of evolution as well as expanding the set of encodable amino acids, particularly those with chemistries not provided by Nature. Because 61 sense codons encode 20 amino acids, reassigning the meaning of sense codons provides an avenue for biosynthetic modification of proteins, furthering both fundamental and applied biochemical research. We developed a simple screen that exploits the absolute requirement for fluorescence of an active site tyrosine in green fluorescent protein (GFP) to probe the pliability of the degeneracy of the genetic code. Our screen monitors the restoration of the fluorophore of GFP by incorporation of a tyrosine in response to a sense codon typically assigned another meaning in the genetic code. We evaluated sense codon reassignment at four of the 21 sense codons read through wobble interactions in Escherichia coli using the Methanocaldococcus jannaschii orthogonal tRNA/aminoacyl tRNA synthetase pair originally developed and commonly used for amber stop codon suppression. By changing only the anticodon of the orthogonal tRNA, we achieved sense codon reassignment efficiencies between 1% (Phe UUU) and 6% (Lys AAG). Each of the orthogonal tRNAs preferentially decoded the codon traditionally read via a wobble interaction in E. coli with the exception of the orthogonal tRNA with an AUG anticodon, which incorporated tyrosine in response to both the His CAU and His CAC codons with approximately equal frequencies. We applied our screen in a high throughput manner to evaluate a 10(9)-member combined tRNA/aminoacyl tRNA synthetase library to identify improved sense codon reassigning variants for the Lys AAG codon. A single rapid screen with the ability to broadly evaluate reassignable codons will facilitate identification and improvement of the combinations of sense codons and orthogonal pairs that display efficient reassignment. PMID- 26536054 TI - Mesostructure-Induced Selectivity in CO2 Reduction Catalysis. AB - Gold inverse opal (Au-IO) thin films are active for CO2 reduction to CO with high efficiency at modest overpotentials and high selectivity relative to hydrogen evolution. The specific activity for hydrogen evolution diminishes by 10-fold with increasing porous film thickness, while CO evolution activity is largely unchanged. We demonstrate that the origin of hydrogen suppression in Au-IO films stems from the generation of diffusional gradients within the pores of the mesostructured electrode rather than changes in surface faceting or Au grain size. For electrodes with optimal mesoporosity, 99% selectivity for CO evolution can be obtained at overpotentials as low as 0.4 V. These results establish electrode mesostructuring as a complementary method for tuning selectivity in CO2 to-fuels catalysis. PMID- 26536055 TI - Next-Generation Sequencing of Matched Primary and Metastatic Rectal Adenocarcinomas Demonstrates Minimal Mutation Gain and Concordance to Colonic Adenocarcinomas. AB - CONTEXT: -Colorectal carcinoma is the third most common cause of cancer death in males and females in the United States. Rectal adenocarcinoma can have distinct therapeutic and surgical management from colonic adenocarcinoma owing to its location and anatomic considerations. OBJECTIVE: -To determine the oncologic driver mutations and better understand the molecular pathogenesis of rectal adenocarcinoma in relation to colon adenocarcinoma. DESIGN: -Next-generation sequencing was performed on 20 cases of primary rectal adenocarcinoma with a paired lymph node or solid organ metastasis by using an amplicon-based assay of more than 2800 Catalogue of Somatic Mutations in Cancer (COSMIC)-identified somatic mutations. RESULTS: -Next-generation sequencing data were obtained on both the primary tumor and metastasis from 16 patients. Most rectal adenocarcinoma cases demonstrated identical mutations in the primary tumor and metastasis (13 of 16, 81%). The mutations identified, listed in order of frequency, included TP53, KRAS, APC, FBXW7, GNAS, FGFR3, BRAF, NRAS, PIK3CA, and SMAD4. CONCLUSIONS: -The somatic mutations identified in our rectal adenocarcinoma cohort showed a strong correlation to those previously characterized in colonic adenocarcinoma. In addition, most rectal adenocarcinomas harbored identical somatic mutations in both the primary tumor and metastasis. These findings demonstrate evidence that rectal adenocarcinoma follows a similar molecular pathogenesis as colonic adenocarcinoma and that sampling either the primary or metastatic lesion is valid for initial evaluation of somatic mutations and selection of possible targeted therapy. PMID- 26536056 TI - Anharmonic Vibrational Treatment Exclusively in Curvilinear Valence Coordinates: The Case of Formamide. AB - A highly correlated approach using curvilinear valence coordinates is applied to calculate the vibrational fundamentals and some combination modes of the formamide molecule with high accuracy. A series of potential energy surfaces (PESs) has been generated by AGAPES, a program for adaptive generation of adiabatic PESs, at various electronic structure qualities until excellent nonaccidental agreement with the experimentally assigned fundamental transitions was reached at the CCSDT(T)-F12a/aug-cc-pVTZ level of theory using the improved relaxation method of the Heidelberg multiconfiguration time-dependent Hartree (MCTDH) package in connection with an exact expression for the kinetic energy in valence coordinates generated by the TANA program. By comparison of the overtone series nu1-3nu1 to experiment, we demonstrate that the known problems concerning the floppy nu1 wagging motion are solved within this approach. The potential energy coupling as well as the vibrational coupling in curvilinear coordinates is discussed together with the efficiency of this approach. PMID- 26536058 TI - Chemoselection combined with alternating chemoradiotherapy or surgery for hypopharyngeal cancer. AB - OBJECTIVES/HYPOTHESIS: In order to make possible organ preservation, since 2007 our hospital has performed induction chemotherapy (ICT) with cisplatin and 5 fluorouracil (PF) for hypopharyngeal cancer as chemoselection, followed by alternating chemoradiotherapy (ACRT) with docetaxel, cisplatin, and 5 fluorouracil in (TPF) good responders and curative surgery was used in poor responders. METHODS: Twenty-six patients with stage III to stage IVB hypopharyngeal cancer received ICT. Eleven of the patients were classified as poor responders and received curative surgery. The remaining 15 patients were classified as good responders. Three of these patients underwent curative surgery, and the remaining 12 underwent ACRT. RESULTS: The primary lesions in the 12 ACRT patients responded completely to treatment without severe late toxicities. The estimated 3-year laryngectomy-free rate for all 26 patients was 23%. The estimated 3-year overall survival rates for all 26 patients, 12 patients treated with ACRT, and 14 patients who underwent curative surgery, were 79%, 75%, and 84%, respectively. CONCLUSION: The patients who underwent ACRT showed no significant difference in overall survival compared with the patients who underwent curative surgery. All the patients were able to proceed with this series of therapy, indicating that ICT with PF could be a feasible tool for choosing good responders. Because ACRT with TPF had a high response rate and fewer severe toxicities, this treatment could be safe and have enough impact to control hypopharyngeal cancer in good responders. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1349-1353, 2016. PMID- 26536057 TI - Effects of Group Psychotherapy, Individual Counseling, Methylphenidate, and Placebo in the Treatment of Adult Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial. AB - IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high prevalence in adulthood. There is a recognized need to assess the efficacy of psychotherapy in adult ADHD. OBJECTIVE: To evaluate the efficacy of cognitive behavioral group psychotherapy (GPT) compared with individual clinical management (CM) and that of methylphenidate hydrochloride compared with placebo. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter, randomized clinical trial of 18- to 58-year-old outpatients with ADHD from 7 German study centers. Patients were recruited between January 2007 and August 2010, treatment was finalized in August 2011, and final follow-up assessments occurred in March 2013. INTERVENTIONS: Sessions of GPT and CM were held weekly for the first 12 weeks and monthly thereafter (9 months). Patients received either methylphenidate or placebo for 1 year. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in the ADHD Index of the Conners Adult ADHD Rating Scale from baseline to the end of the 3-month intensive treatment (blinded observer ratings). Secondary outcomes included ADHD ratings after 1 year, blinded observer ratings using the Clinical Global Impression Scale, and self-ratings of depression. RESULTS: Among 1480 prescreened patients, 518 were assessed for eligibility, 433 were centrally randomized, and 419 were analyzed as randomized. After 3 months, the ADHD Index all-group baseline mean of 20.6 improved to adjusted means of 17.6 for GPT and 16.5 for CM, with no significant difference between groups. Methylphenidate (adjusted mean, 16.2) was superior to placebo (adjusted mean, 17.9) (difference, -1.7; 97.5% CI, 3.0 to -0.4; P = .003). After 1 year, treatment effects remained essentially stable. Descriptive analyses showed that methylphenidate was superior to placebo in patients assigned to GPT (difference, -1.7; 95% CI, -3.2 to -0.1; P = .04) or CM (difference, -1.7; 95% CI, -3.3 to -0.2; P = .03). Regarding depression, no significant differences were found. In contrast, GPT was superior to CM for all visits in the Clinical Global Impression global assessment of effectiveness. CONCLUSION AND RELEVANCE: Highly structured group intervention did not outperform individual CM with regard to the primary outcome. Psychological interventions resulted in better outcomes during a 1-year period when combined with methylphenidate as compared with placebo. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN54096201. PMID- 26536059 TI - Association Between American Board of Surgery In-Training Examination Scores and Resident Performance. AB - IMPORTANCE: The American Board of Surgery In-Training Examination (ABSITE) is designed to measure progress, applied medical knowledge, and clinical management; results may determine promotion and fellowship candidacy for general surgery residents. Evaluations are mandated by the Accreditation Council for Graduate Medical Education but are administered at the discretion of individual institutions and are not standardized. It is unclear whether the ABSITE and evaluations form a reasonable assessment of resident performance. OBJECTIVE: To determine whether favorable evaluations are associated with ABSITE performance. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of preliminary and categorical residents in postgraduate years (PGYs) 1 through 5 training in a single university-based general surgery program from July 1, 2011, through June 30, 2014, who took the ABSITE. EXPOSURES: Evaluation overall performance and subset evaluation performance in the following categories: patient care, technical skills, problem-based learning, interpersonal and communication skills, professionalism, systems-based practice, and medical knowledge. MAIN OUTCOMES AND MEASURES: Passing the ABSITE (>=30th percentile) and ranking in the top 30% of scores at our institution. RESULTS: The study population comprised residents in PGY 1 (n = 44), PGY 2 (n = 31), PGY 3 (n = 26), PGY 4 (n = 25), and PGY 5 (n = 24) during the 4-year study period (N = 150). Evaluations had less variation than the ABSITE percentile (SD = 5.06 vs 28.82, respectively). Neither annual nor subset evaluation scores were significantly associated with passing the ABSITE (n = 102; for annual evaluation, odds ratio = 0.949; 95% CI, 0.884-1.019; P = .15) or receiving a top 30% score (n = 45; for annual evaluation, odds ratio = 1.036; 95% CI, 0.964-1.113; P = .33). There was no difference in mean evaluation score between those who passed vs failed the ABSITE (mean [SD] evaluation score, 91.77 [5.10] vs 93.04 [4.80], respectively; P = .14) or between those who received a top 30% score vs those who did not (mean [SD] evaluation score, 92.78 [4.83] vs 91.92 [5.11], respectively; P = .33). There was no correlation between annual evaluation score and ABSITE percentile (r(2) = 0.014; P = .15), percentage correct unadjusted for PGY level (r(2) = 0.019; P = .09), or percentage correct adjusted for PGY level (r(2) = 0.429; P = .91). CONCLUSIONS AND RELEVANCE: Favorable evaluations do not correlate with ABSITE scores, nor do they predict passing. Evaluations do not show much discriminatory ability. It is unclear whether individual resident evaluations and ABSITE scores fully assess competency in residents or allow comparisons to be made across programs. Creation of a uniform evaluation system that encompasses the necessary subjective feedback from faculty with the objective measure of the ABSITE is warranted. PMID- 26536060 TI - The molecular origin and evolution of dim-light vision in mammals. AB - The nocturnal origin of mammals is a longstanding hypothesis that is considered instrumental for the evolution of endothermy, a potential key innovation in this successful clade. This hypothesis is primarily based on indirect anatomical inference from fossils. Here, we reconstruct the evolutionary history of rhodopsin--the vertebrate visual pigment mediating the first step in phototransduction at low-light levels--via codon-based model tests for selection, combined with gene resurrection methods that allow for the study of ancient proteins. Rhodopsin coding sequences were reconstructed for three key nodes: Amniota, Mammalia, and Theria. When expressed in vitro, all sequences generated stable visual pigments with lambdaMAX values similar to the well-studied bovine rhodopsin. Retinal release rates of mammalian and therian ancestral rhodopsins, measured via fluorescence spectroscopy, were significantly slower than those of the amniote ancestor, indicating altered molecular function possibly related to nocturnality. Positive selection along the therian branch suggests adaptive evolution in rhodopsin concurrent with therian ecological diversification events during the Mesozoic that allowed for an exploration of the environment at varying light levels. PMID- 26536061 TI - A Phase 1, Multi-Center, Open-Label, Dose-Escalation Study of 131I-CLR1404 in Subjects with Relapsed or Refractory Advanced Solid Malignancies. AB - This study explores the imaging and therapeutic properties of a novel radiopharmaceutical, (131)I-CLR1404. Phase 1a data demonstrated safety and tumor localization by SPECT-CT. This 1b study assessed safety, imaging characteristics, and possible antineoplastic properties and provided further proof-of-concept of phospholipid ether analogues' retention within tumors. A total of 10 patients received (131)I-CLR1404 in an adaptive dose-escalation design. Imaging characteristics were consistent with prior studies, showing tumor uptake in primary tumors and metastases. At doses of 31.25 mCi/m(2) and greater, DLTs were thrombocytopenia and neutropenia. Disease-specific studies are underway to identify cancers most likely to benefit from (131)I-CLR1404 monotherapy. PMID- 26536062 TI - Ophthalmoscopic-Perspectively Distorted Optic Disc Diameters and Real Disc Diameters. AB - PURPOSE: To investigate the difference between two-dimensionally measured disc diameters (DDs) based on fundus images and three-dimensionally measured DDs based on enhanced depth imaging optical coherence tomography (EDI-OCT). METHODS: The DDs were three-dimensionally measured on EDI-OCT images of optic nerve heads and two-dimensionally measured on near-infrared reflectance fundus images in 90 normal eyes of 90 subjects. Disc rotation around sagittal axis was defined as the angle between maximal DD and vertical axis. Disc rotation around horizontal and vertical axes was defined as cosine of DD on fundus images divided by DD on EDI OCT images. RESULTS: Mean optic disc rotation around vertical axis was 14.4 +/- 9.3 degrees , rotation around sagittal axis was 23.0 +/- 21.3 degrees , and rotation around horizontal axis was 4.7 +/- 6.6 degrees . Horizontal, vertical, minimal, and maximal DDs as measured three-dimensionally were significantly (P < 0.001) higher than those measured two-dimensionally. Difference between three dimensional and two-dimensional measurement of horizontal DD and vertical DD was associated with axial length (r = 0.38; P < 0.001, and r = 0.23; P = 0.03, respectively). Difference between three-dimensional and two-dimensional measurements was larger (P < 0.001) for horizontal DD (69.6 +/- 68.1 MUm) than for vertical DD (14.8 +/- 25.6 MUm). Correspondingly, the ratio of maximal-to minimal DD (ovality index) was significantly larger (P < 0.001) for two dimensional (1.33 +/- 0.21) than for three-dimensional (1.27 +/- 0.16) measurements. CONCLUSIONS: Two-dimensional measurement of DDs leads to falsely low results, more for horizontal DD than for vertical DD. The discrepancy between low two-dimensional compared to three-dimensional disc measurements increases with longer axial length. The angle of disc rotation around vertical and horizontal axes can be measured with EDI-OCT imaging. PMID- 26536063 TI - The synthesis of heterosaccharides related to the fucoidan from Chordaria flagelliformis bearing an alpha-L-fucofuranosyl unit. AB - Sulfated polysaccharides, fucoidans, from brown algae are built up mainly of alpha-L-fucopyranosyl units and form a group of natural biopolymers with a wide spectrum of biological activities. Systematic synthesis of oligosaccharides representing fucoidans' fragments gives molecular probes for detecting pharmacophores within fucoidan polysaccharide chains. Recently, it was discovered that the fucoidan from brown seaweed Chordaria flagelliformis contains not only alpha-L-fucopyranosyl units but also alpha-L-fucofuranosyl ones. To establish the influence of the unusual alpha-L-fucofuranose residue on the biological activity and conformational properties of fucoidans, the synthesis of selectively O sulfated pentasaccharides, which represent the main repeating unit of the fucoidan from C. flagelliformis, was performed. The features of the synthesis were the use of the pyranoside-into-furanoside rearrangement to prepare the fucofuranoside precursor and remote stereocontrolling participation of O-acyl groups to manage stereoselective alpha-bond formation in glycosylation reactions. PMID- 26536064 TI - Dengue in children: a systematic review of clinical and laboratory factors associated with severity. AB - Dengue is a potentially life-threatening illness, and children are at higher risk of severity. This review aimed to systematize the identified clinical and laboratory parameters associated with severe dengue in children, as monitoring these signs and fluid-replacement therapy are actually the cornerstones of dengue treatment. Of the 527 studies initially reviewed, 21 were selected as follows: three cohort studies, three case-control studies, 14 cross-sectional studies and one not defined. Eighteen studies were carried out in Asia and three in the Americas. Hepatomegaly, lethargy, abdominal pain, bleeding, hemoconcentration and thrombocytopenia, all referenced as warning signs in the WHO 2009 Guidelines, were the clinical and laboratory parameters independently associated with severity in more than one study. The recognition of these known warning signs associated to severe dengue disease underlines the usefulness of the WHO 2009 classification. PMID- 26536065 TI - Increased carrier mobility and lifetime in CdSe quantum dot thin films through surface trap passivation and doping. AB - Passivating surface defects and controlling the carrier concentration and mobility in quantum dot (QD) thin films is prerequisite to designing electronic and optoelectronic devices. We investigate the effect of introducing indium in CdSe QD thin films on the dark mobility and the photogenerated carrier mobility and lifetime using field-effect transistor (FET) and time-resolved microwave conductivity (TRMC) measurements. We evaporate indium films ranging from 1 to 11 nm in thickness on top of approximately 40 nm thick thiocyanate-capped CdSe QD thin films and anneal the QD films at 300 degrees C to densify and drive diffusion of indium through the films. As the amount of indium increases, the FET and TRMC mobilities and the TRMC lifetime increase. The increase in mobility and lifetime is consistent with increased indium passivating midgap and band-tail trap states and doping the films, shifting the Fermi energy closer to and into the conduction band. PMID- 26536066 TI - Developing an Australian health and aged care research agenda: a systematic review of evidence at the subacute interface. AB - Objective The aim of the present study was to systematically review articles describing recent interventions that aimed to improve access and outcomes for older people at the interface between health and aged care, with a focus on subacute care programs of palliative care, rehabilitation, geriatric evaluation and management (GEM) and psychogeriatrics. Methods Australian studies published between 2008 and 2013were evaluated using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and National Health and Medical Research Council of Australia (NHMRC) guidelines. Included studies were summarised according to focus areas and results discussed in the current Australian subacute health care context. Results Eleven Australian research articles were identified. Three did not achieve any NHMRC rating level because of methodological approach. Focus areas included: discharge planning; information management or communication; rehabilitation; hospital treatment in residential care; screening and intervention; and Telehealth. Interventions were primarily system centred; only three studies featured patient-level outcome measures. Conclusions There is limited high-quality research investigating the effectiveness of interventions at the health and aged care interface of subacute care. Further research is needed. What is known about the topic? Subacute care offers important healthcare programs for older people, operating at the interface between health and aged care. However, for the most part this has not been subject to research scrutiny. What does this paper add? Identified studies were predominantly hospital oriented and designed to avoid hospital admission and associated costs. Locally integrated, collaborative and multidiscipline based interventions improve system-level outcomes. Alternative and individualised models of care, particularly when provided in their home setting, yields positive outcomes for older people. What are the implications for practitioners? Health and aged care reforms and related research agenda must include the perspectives and experiences of patients and/or carers accessing subacute care programs, yet these are under-reported. The present review highlights opportunities to improve the quality of existing evidence and create a research agenda for the future. PMID- 26536067 TI - Aliphatic C-C Bond Cleavage of alpha-Hydroxy Ketones by Non-Heme Iron(II) Complexes: Mechanistic Insight into the Reaction Catalyzed by 2,4' Dihydroxyacetophenone Dioxygenase. AB - 2,4'-Dihydroxyacetophenone dioxygenase (DAD) is a bacterial non-heme enzyme that carries out oxygenative aliphatic C-C bond cleavage of 2,4'-dihydroxyacetophenone (an alpha-hydroxy ketone) with the incorporation of both the oxygen atoms of dioxygen into the cleavage products. The crystal structure of the iron enzyme DAD has recently been determined, but very little is known about the mechanism of the C-C bond cleavage reaction. With the objective of gaining insights into the mechanism of the reaction catalyzed by DAD, six new biomimetic iron(II)-alpha hydroxy ketone complexes, [(Tp(Ph2))Fe(II)(PHAP)] (1), [(Tp(Ph2))Fe(II)(HCH)] (2), [(Tp(Ph2))Fe(II)(HBME)] (3), [(Tp(Ph2))Fe(II)(CHPE)] (4), [(6-Me3 TPA)Fe(II)(PHAP)](+) (5), and [(6-Me3-TPA)Fe(II)(HCH)](+) (6) (Tp(Ph2) = hydrotris(3,5-diphenylpyrazol-1-yl)borate, 6-Me3-TPA = tris(6-methyl-2 pyridylmethyl)amine, PHAP-H = 2-phenyl-2-hydroxyacetophenone, HCH-H = 2 hydroxycyclohexanone, HBME-H = 2-hydroxy-1,2-bis(4-methoxyphenyl)ethanone, and CHPE-H = 1-(4-chlorophenyl)-2-hydroxy-2-phenylethanone), have been isolated and characterized. The single-crystal X-ray structure of 2 shows a five-coordinate iron(II) complex with one tridentate facial ligand and a monoanionic bidentate alpha-hydroxy ketone, resulting in a distorted-square-pyramidal coordination geometry at the iron center. The iron(II) complexes react with dioxygen to oxidatively cleave the aliphatic C-C bonds of the coordinated alpha-hydroxy ketones to afford 2 equiv of carboxylic acids. Mechanistic studies reveal that the C-C bond cleavage reaction proceeds through an intradiol pathway. Additionally, the coordinated alpha-hydroxy ketones in all of the complexes, except in complex 4, undergo two-electron oxidation to form the corresponding 1,2 diketones. However, the yields of 1,2-diketones are higher with the iron complexes of the tripodal N4 ligand (6-Me3-TPA) in comparison to the facial N3 ligand (Tp(Ph2)). These results strongly support the natural selection of a facial N3 environment at the active site of the iron enzyme DAD. PMID- 26536068 TI - Advancing pharmacotherapy for treating Huntington's disease: a review of the existing literature. AB - INTRODUCTION: Huntington's disease (HD) is an incurable chronic neurodegenerative disorder that typically presents in mid-life with a range of motor, cognitive and affective problems. Patients are currently managed using a combination of drug treatments and non-pharmacological therapies but at present there is no "gold standard" treatment for any aspect of the disease. AREAS COVERED: In this review the empirical evidence supporting the use of drugs commonly used to treat HD was discussed. In particular, we focus on therapeutics that have either reached phase 3 clinical trials or are already in clinical use. EXPERT OPINION: The results confirmed that there is a striking lack of evidence to support the efficacy of the drugs currently used in the management of HD. In fact, many drugs are prescribed on the basis of case reports, open label studies, small double blind placebo control trials of limited duration, or personal clinical experience. However of late, the establishment of large international databases, capturing all patients and their clinical details regardless of stage or geographical location has led to an increase in the number of clinical trials conducted on new therapies. Unfortunately, the same is not true for the existing therapies which look set to remain untested for the foreseeable future. PMID- 26536069 TI - Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor. AB - All serine proteases hydrolyze peptide bonds by the same basic mechanism and have very similar active sites, in spite of the fact that individual proteases have different physiological functions. We here report a strategy for designing high affinity and high-specificity serine protease inhibitors using a versatile peptide scaffold, a 10-mer peptide, mupain-1 (CPAYSRYLDC). Mupain-1 was previously reported as a specific inhibitor of murine urokinase-type plasminogen activator (Ki = 0.55 MUM) without measurable affinity to plasma kallikrein (Ki > 1000 MUM). On the basis of a structure-based rational design, we substituted five residues of mupain-1 and converted it to a potent plasma kallikrein inhibitor (Ki = 0.014 MUM). X-ray crystal structure analysis showed that the new peptide was able to adapt a new set of enzyme surface interactions by a slightly changed backbone conformation. Thus, with an appropriate re-engineering, mupain-1 can be redesigned to specific inhibitors of other serine proteases. PMID- 26536070 TI - Impact of Alkyl Chain Length on the Transition of Hexagonal Liquid Crystal Wormlike Micelle-Gel in Ionic Liquid-Type Surfactant Aqueous Solutions without Any Additive. AB - The search for functional supramolecular aggregations with different structure has attracted interest of chemists because they have the potential in industrial and technological application. Hydrophobic interaction has great influence on the formation of these aggregations, such as hexagonal liquid crystals, wormlike micelles, hydrogels, etc. So a systematical investigation was done to investigate the influence of alkyl chain length of surfactants on the aggregation behavior in water. The aggregation behavior of 1-hexadecyl-3-alkyl imidazolium bromide and water has been systematically investigated. These ionic liquid surfactants are denoted as C16-Cn (n = 2, 3, 4, 6, 8, 9, 10, 12, 14, 16). The rheological behavior and microstructure were characterized via a combination of rheology, cryo-etch scanning electron microscopy, polarization optical microscopy, and X ray crystallography. The alkyl chain has great influence on the formation of surfactant aggregates in water at the molecular level. With increasing alkyl chain length, different aggregates, such as hexagonal liquid crystals, wormlike micelles, and hydrogels can be fabricated: C16-C2 aqueous solution only forms hexagonal liquid crystal; C16-C3 aqueous solution forms wormlike micelle and hexagonal liquid crystal; C16-C4, C16-C6 and C16-C8 aqueous solutions only form wormlike micelle; C16-C9 aqueous solution experiences a transition between wormlike micelle and hydrogel; C16-C10, C16-C12, C16-C14 and C16-C16 only form hydrogel. The mechanism of the transition of different aggregation with increasing alkyl chain length was also proposed. PMID- 26536071 TI - Reform of Clinical Research Regulations, Finally. PMID- 26536072 TI - Benchmarking road safety performance: Identifying a meaningful reference (best-in class). AB - For road safety improvement, comparing and benchmarking performance are widely advocated as the emerging and preferred approaches. However, there is currently no universally agreed upon approach for the process of road safety benchmarking, and performing the practice successfully is by no means easy. This is especially true for the two core activities of which: (1) developing a set of road safety performance indicators (SPIs) and combining them into a composite index; and (2) identifying a meaningful reference (best-in-class), one which has already obtained outstanding road safety practices. To this end, a scientific technique that can combine the multi-dimensional safety performance indicators (SPIs) into an overall index, and subsequently can identify the 'best-in-class' is urgently required. In this paper, the Entropy-embedded RSR (Rank-sum ratio), an innovative, scientific and systematic methodology is investigated with the aim of conducting the above two core tasks in an integrative and concise procedure, more specifically in a 'one-stop' way. Using a combination of results from other methods (e.g. the SUNflower approach) and other measures (e.g. Human Development Index) as a relevant reference, a given set of European countries are robustly ranked and grouped into several classes based on the composite Road Safety Index. Within each class the 'best-in-class' is then identified. By benchmarking road safety performance, the results serve to promote best practice, encourage the adoption of successful road safety strategies and measures and, more importantly, inspire the kind of political leadership needed to create a road transport system that maximizes safety. PMID- 26536073 TI - Are anxiety and fear separable emotions in driving? A laboratory study of behavioural and physiological responses to different driving environments. AB - Research into anxiety and driving has indicated that those higher in anxiety are potentially more dangerous on the roads. However, simulator findings suggest that conclusions are mixed at best. It is possible that anxiety is becoming confused with fear, which has a focus on more clearly defined sources of threat from the environment, as opposed to the internal, thought-related process associated with anxiety. This research aimed to measure feelings of fear, as well as physiological and attentional reactions to increasing levels of accident risk. Trait anxiety was also measured to see if it interacted with levels of risk or its associated reactions. Participants watched videos of driving scenarios with varying levels of accident risk and had to rate how much fear they would feel if they were the driver of the car, whilst skin conductance, heart rate, and eye movements were recorded. Analysis of the data suggested that perceptions of fear increased with increasing levels of accident risk, and skin conductance reflected this pattern. Eye movements, when considered alongside reaction times, indicated different patterns of performance according to different dangerous situations. These effects were independent of trait anxiety, which was only associated with higher rates of disliking driving and use of maladaptive coping mechanisms on questionnaires. It is concluded that these results could provide useful evidence in support for training-based programmes; it may also be beneficial to study trait anxiety within a more immersive driving environment and on a larger scale. PMID- 26536074 TI - The impact of Val108/158Met polymorphism of catechol-O-methyltransferase on brain oscillations during working memory. AB - This study investigated whether catechol-O-methyltransferase (COMT) Val/Met polymorphism was associated with variation in event-related desynchronization/synchronization (ERD/ERS) of responses during working memory (WM). 11 Val/Val and 11 Met/Met homozygous participants underwent magnetoencephalography (MEG) while performing a WM task. In contrast to small effects behaviourally, during the delay period Val/Val individuals showed lower ERS in the gamma band (Hz 30-50) in frontal regions, increased ERS in the alpha band (Hz 8-12) in the right frontal and parietal regions and increased ERD in the beta band (Hz 14-30) in the left fronto-temporal regions as compared with Met/Met homozygous individuals. During the response period Val/Val participants showed greater beta ERD in the prefrontal and parietotemporal regions. These results demonstrate that COMT genotype has a strong impact on brain responses (oscillatory activity) during WM performance likely a consequence of compensatory activity during the delay and response periods. PMID- 26536075 TI - Lycium chinensis Mill attenuates glutamate induced oxidative toxicity in PC12 cells by increasing antioxidant defense enzymes and down regulating ROS and Ca(2+) generation. AB - Lycium chinensis Mill is a famous traditional Chinese medicine which displays several medicinal activities including antioxidant and neuroprotective activities. However, the mechanism of action towards the neuroprotective action has not been fully elucidated. This work was aimed at investigating the neuroprotective effects of L. chinensis Mill against glutamate-induced oxidative neurotoxicity in PC12 cells. Oxidative cell death was induced with 5mM glutamate in PC12 cells. Cell viability, LDH release, intracellular Ca(2+) concentration, reactive oxygen species (ROS) accumulation, GSH-Px, CAT and SOD antioxidant enzyme levels were measured. Our results indicated that pretreatment of PC12 cells with L. chinensis Mill extracts markedly attenuated the loss of cell viability, the release of lactate dehydrogenase (LDH), Ca(2+) overload, ROS generation, and cell apoptosis induced by glutamate toxicity. Furthermore, L. chinensis Mill extracts also significantly increased the levels of innate antioxidant enzymes GSH-Px, SOD and CAT in glutamate-induced PC12 cells. Conclusively, our results provided substantial evidence that L. chinensis Mill protected PC12 cells against glutamate-induced cell death by attenuating ROS generation, Ca(2+) influx, and increased the antioxidant defense capacity of PC12 cells against oxidative stress damages, suggesting the possible potential of extracts from the plant as sources of bioactive molecules in the treatment of neurodegenerative disorders. PMID- 26536076 TI - A model of the Ebola epidemics in West Africa incorporating age of infection. AB - A model of an Ebola epidemic is developed with infected individuals structured according to disease age. The transmission of the infection is tracked by disease age through an initial incubation (exposed) phase, followed by an infectious phase with variable transmission infectiousness. The removal of infected individuals is dependent on disease age, with three types of removal rates: (1) removal due to hospitalization (isolation), (2) removal due to mortality separate from hospitalization, and (3) removal due to recovery separate from hospitalization. The model is applied to the Ebola epidemics in Sierra Leone and Guinea. Model simulations indicate that successive stages of increased and earlier hospitalization of cases have resulted in mitigation of the epidemics. PMID- 26536077 TI - A sublexical training study for spelling in a biliterate Greek- and English speaking child. AB - RI is an emergent trilingual boy, literate in Greek and English, with difficulties in reading and spelling in both languages. Assessment with non literacy tests revealed a deficit in phonological ability and in visual memory for sequentially presented characters. RI took part in a training programme that targeted sublexical spelling processes. Post-intervention assessment revealed improvement in reading and spelling in Greek but not in English. Assessments of lexical and sublexical skills showed improvement in nonword spelling and nonword reading for Greek. For English, there was some indication of improvement in nonword reading at delayed post-intervention testing, but no evidence of improvement in nonword spelling. Possible reasons for the difference in outcome for the two languages are considered, including the level of transparency of written Greek and English. PMID- 26536078 TI - Is There Any Benefit of Neuromonitoring During Descending and Thoracoabdominal Aortic Aneurysm Repair? AB - OBJECTIVE: Paraplegia remains the most feared and a devastating complication after descending and thoracoabdominal aneurysm operative repair (DTA and TAAAR). Neuromonitoring, particularly use of motor-evoked potentials (MEPs), for this surgery has gained popularity. However, ambiguity remains regarding its use and benefit. We systematically reviewed the literature to assess the benefit and applicability of neuromonitoring in DTA and TAAAR. METHODS: Electronic searches were performed on 4 major databases from inception until February 2014 to identify relevant studies. Eligibility decisions, method quality, data extraction, and analysis were performed according to predefined clinical criteria and end points. RESULTS: Among the studies matching our inclusion criteria, 1297 patients had MEP monitoring during DTA and TAAAR. In-hospital mortality was low (6.9% +/- 3.6). Immediate neurological deficit was low (3.5% +/- 2.6). In one third of patients (30.4% +/- 14.2), the MEPs dropped below threshold, which were 30.4% and 29.4% with threshold levels of 75% and 50%, respectively. A range of surgical techniques were applied after reduction in MEPs. Most patients whose MEPs dropped and remained below threshold had immediate permanent neurological deficit (92.0% +/- 23.6). Somatosensory-evoked potentials were reported in one third of papers with little association between loss of somatosensory-evoked potentials and permanent neurological deficit (16.7% +/- 28.9%). CONCLUSIONS: We demonstrate that MEPs are useful at predicting paraplegia in patients who lose their MEPs and do not regain them intraoperatively. To date, there is no consensus regarding the applicability and use of MEPs. Current evidence does not mandate or support MEP use. PMID- 26536079 TI - Endovascular Repair of a Ruptured Aortic Extra-anatomic Bypass Pseudoaneurysm After Previous Coarctation Surgery. AB - We present a short case of a total endovascular repair of a ruptured thoracic pseudoaneurysm after previous coarctation aortic conduit bypass surgery. A 67 year-old man with two previous coarctation repairs many years ago was admitted with chest pain, dyspnea, and hemoptysis. Computed tomography showed a rupture in the distal anastomosis of the thoracic extra-anatomic graft. Successful treatment was achieved by placement of an endovascular stent graft between the old graft and the native aorta and with a vascular plug occlusion of the native aorta. PMID- 26536080 TI - Modified Tightening for Figure-of-Eight Sternal Wiring Closure. AB - This is a simple and quick method for the tightening of figure-of-eight wires routinely used for sternal closure. This technique gives a stable approximation, adequate reduction, and immobilization, providing higher strength and rigidity compared with conventional figure-of-eight closure. The advantage of this technique is that it tightens all the four wires equally, thus avoiding loose loops. PMID- 26536081 TI - Integration of Partial Information Within and Across Modalities: Contributions to Spoken and Written Sentence Recognition. AB - PURPOSE: This study evaluated the extent to which partial spoken or written information facilitates sentence recognition under degraded unimodal and multimodal conditions. METHOD: Twenty young adults with typical hearing completed sentence recognition tasks in unimodal and multimodal conditions across 3 proportions of preservation. In the unimodal condition, performance was examined when only interrupted text or interrupted speech stimuli were available. In the multimodal condition, performance was examined when both interrupted text and interrupted speech stimuli were concurrently presented. Sentence recognition scores were obtained from simultaneous and delayed response conditions. RESULTS: Significantly better performance was obtained for unimodal speech-only compared with text-only conditions across all proportions preserved. The multimodal condition revealed better performance when responses were delayed. During simultaneous responses, participants received equal benefit from speech information when the text was moderately and significantly degraded. The benefit from text in degraded auditory environments occurred only when speech was highly degraded. CONCLUSIONS: The speech signal, compared with text, is robust against degradation likely due to its continuous, versus discrete, features. Allowing time for offline linguistic processing is beneficial for the recognition of partial sensory information in unimodal and multimodal conditions. Despite the perceptual differences between the 2 modalities, the results highlight the utility of multimodal speech + text signals. PMID- 26536082 TI - Distinguishing Right Ventricular Cardiomyopathy From Idiopathic Right Ventricular Outflow Tract Tachycardia with T-wave Alternans. AB - BACKGROUND: The 2 predominant etiologies of right ventricular tachycardia (VT) are arrhythmogenic right ventricular cardiomyopathy (ARVC) and idiopathic VT arising from the right ventricular outflow tract. Discrimination between these 2 entities is critical, as their prognoses and therapeutic options differ. The microvolt T-wave alternans (TWA) is widely used to predict lethal ventricular arrhythmias in various diseases. However, the clinical significance of TWA in patients with VT originating from the right ventricle has been unknown. This study aims to investigate the possible role of TWA to discriminate ARVC from idiopathic right ventricular outflow tract tachycardia (RVOT-VT). METHODS: This study enrolled 38 patients (23 male, 43 +/- 16 years) with VT originating from the right ventricle. TWA was measured during exercise testing using the modified moving average method. TWA results were compared among patients with ARVC and RVOT-VT. RESULTS: Twenty-five patients (16 male, 42 +/- 16 years) met the Task Force criteria for the diagnosis of ARVC, and 13 patients (7 male, 45 +/- 14 years) had idiopathic RVOT-VT. Twenty patients with ARVC had positive TWA test, whereas only 1 patient with RVOT-VT had (80% versus 8%, P < 0.001). CONCLUSIONS: In patients with VT of right ventricle origin, positive TWA test supports the diagnosis of ARVC. PMID- 26536083 TI - Effect of a More Permeable Dialysis Membrane on ESA Resistance in Hemodialysis Patients--A Pilot Investigation. AB - BACKGROUND/AIMS: Hemodialysis (HD) patients often show impaired response to erythropoiesis-stimulating agents (ESAs). Extended HD membrane permeability may potentially improve ESA response. METHODS: Twenty-four prevalent HD patients were randomly assigned to 12 weeks use of high cut-off (HCO) membrane (in every second dialysis treatment) or continued treatment with high-flux membrane. We monitored changes in hemoglobin (Hb), ESA dose, and key biochemical markers. RESULTS: The Hb level increased in the study group (from 11.6 +/- 1.0 to 12.5 +/- 1.5 g/dl; p = 0.038) but was stable in the control group. Variation over time in ESA dose and ESA resistance index did not differ between groups. HCO membrane usage for 12 weeks led to decreased hepcidin level, from 303 +/- 189 to 157 +/- 83 ng/ml (p = 0.024); serum albumin level decreased and stabilized 15 +/- 6% below baseline. CONCLUSIONS: These results indicate that use of a more permeable dialysis membrane may improve ESA responsiveness in iron-replete HD patients. Extensive albumin removal may preclude long-term use of the HCO membrane. PMID- 26536084 TI - Perioperative Outcomes of Minimally Invasive Aortic Valve Replacement through Right Anterior Minithoracotomy. AB - Background The aim of the study was to analyze perioperative outcomes after minimally invasive aortic valve replacement through right anterior minithoracotomy (RAT-AVR). Patient selection criteria, anesthesia protocol, and surgical technique are presented. Methods A retrospective analysis of 194 patients electively scheduled for RAT-AVR was performed between January 2009 and June 2013. For preoperative planning, computed tomography was performed. Results Among studied patients, there were 48.5% females and 51.5% males with a mean age of 69.9 +/- 9.2 years. The predicted mortality calculated with EuroSCORE II was 3.2 +/- 0.9%, and observed mortality of RAT-AVR patients was 1.5%. Finally, RAT AVR surgery was performed on 97.9% of patients (n = 190). Reasons for conversions to median sternotomy were bleeding from aortotomy site (n = 4) and from the right ventricle after epicardial pacing wire placement (n = 1), pleural adhesions (n = 2), and ascending aorta hidden under the sternum (n = 2). The second intercostal space was chosen for surgical access in 97.9% of patients.There were 3.6% reoperations for bleeding: aortotomy place (n = 1), epicardial pacing wire placement (n = 3), right lung tear (n = 2), and intercostal vessels (n = 1). The intensive care unit and hospital length of stays were 1.3 +/- 1.2 and 5.7 +/- 1.4 days, respectively. Strokes were present in 1.5% of patients. The perioperative complications rate diminished with time, occurring in 44.9% of the patients between 2009 and 2010 and in 15.6% of patients in 2013. Conclusions RAT-AVR can be safely performed without increased morbidity and mortality. Reduced complication rates over time reflect a learning curve. PMID- 26536085 TI - A Systematic Review of Early Results Following Synchronous or Staged Carotid Artery Stenting and Coronary Artery Bypass Grafting. AB - Background The optimal management of patients with concomitant coronary artery disease (CAD) and severe carotid artery stenosis remains a controversy. We performed a systematic review of studies comparing early outcomes of synchronous or staged carotid artery stenting (CAS) and coronary artery bypass grafting (CABG) in the treatment of patients with concomitant CAD and severe carotid artery stenosis. Methods Multiple databases were systematically searched to identify studies of synchronous or staged CAS and CABG in the treatment of concomitant severe carotid and coronary artery disease published from 2005 to 2015. The quality of studies was assessed using the MINORS scale. The demographic data, risk factors, 30-day outcomes, and antiplatelet strategy were extracted. Results 23 studies were identified with a total of 873 and 459 patients in the staged and synchronous group, respectively. The observed overall death/stroke/MI rate was 8.5% (95% CI: 7.6-9.4%) in staged group and 4.8% (95% CI: 3.8-5.8%) in synchronous group. It seems that the synchronous group has better 30-day outcomes, but these data could not be compared statistically. Conclusion Our systematic review suggests either synchronous or staged CAS and CABG can be chosen for the treatment of concomitant carotid and coronary artery disease. It seems that the synchronous approach is relatively convenient and the antiplatelet strategy is relatively definite. For these patients, hybrid revascularization by synchronous CAS and CABG might be a feasible and promising therapeutic strategy. Our conclusions and the quality of the existing data suggest that a randomized controlled trial is needed to define the best treatment for patients with concomitant carotid and coronary artery disease. PMID- 26536086 TI - Large and small vessel disease and other aspects of hypertension. PMID- 26536087 TI - Essential hypertension in the pathogenesis of age-related macular degeneration: a review of the current evidence. AB - Age-related macular degeneration (AMD) is one of the main causes of vision loss, especially in the elderly. The involvement of essential hypertension in its pathogenesis has been well covered in the literature since it was first recognized. Hemodynamic abnormalities appear to contribute to AMD, with the renin angiotensin system playing a significant role. Many studies have demonstrated that high blood pressure is associated with lower choroidal blood flow and disturbed vascular homeostasis in these patients. In addition, AMD is characterized by abnormal neovascularization, to which angiotensin II and growth factors make a large contribution. Most epidemiological studies have found essential hypertension to be a risk factor for AMD. However, although all agree that the strongest predisposing factors are age and smoking, overall there is some inconsistency regarding the exact role of hypertension in its pathogenesis. In particular, there are no data in the literature to support the view that antihypertensive medication and the successful management of hypertension have a positive effect on the clinical outcome of AMD. This reinforces the data indicating that the cause of AMD is multifactorial and suggests that, although essential hypertension probably plays a role, in itself it is unlikely to be a major contributor to the future occurrence of AMD. PMID- 26536088 TI - Aging and pulse pressure widening: the inseparable duo? PMID- 26536089 TI - Dual renin-angiotensin system blockade and vascular remodeling: is this a real advantage for vascular protection? PMID- 26536090 TI - Modulation of CaV1.2 calcium channel by neuropeptide W regulates vascular myogenic tone via G protein-coupled receptor 7. AB - OBJECTIVE: Neuropeptide W (NPW), an endogenous ligand for the G protein-coupled receptor 7 (GPR7), was first found to make important roles in central nerve system. In periphery, NPW was also present and regulated intracellular calcium homeostasis by L-type calcium channels. This study was designed to discover the effects of NPW-GPR7 on the function of CaV1.2 calcium channels in the vascular smooth muscle cells (VSMCs) and vasotone of arterial vessels. METHODS: By whole cell patch clamp, we studied the effects of NPW-23, the active form of NPW, on the CaV1.2 channels in the heterologously transfected human embryonic kidney 293 cells and VSMCs isolated from rat. Living system was used to explore the physiological function of NPW-23 in arterial myogenic tone. To investigate the pathological relevance, NPW mRNA level of mesenteric arteries was measured in the hypertensive and normotensive rats. RESULTS: NPW's receptor GPR7 was coexpressed with CaV1.2 channels in arterial smooth muscle. NPW-23 increased the ICa,L in transfected human embryonic kidney 293 cells and VSMCs via GPR7, which could be abrogated by phospholipase C (PLC)/protein kinase C (PKC) inhibitors, not protein kinase A or protein kinase G inhibitor. After NPW-23 application, the expression of pan phospho-PKC was increased; moreover, intracellular diacylglycerol level, the second messenger catalyzed by PLC, was increased 1.5-2-fold. Application with NPW-23 increased pressure-induced vasotone of the rat mesenteric arteries. Importantly, the expression of NPW was decreased in the hypertensive rats. CONCLUSION: NPW-23 regulates ICa,L via GPR7, which is mediated by PLC/PKC signaling, and such a mechanism plays a role in modulating vascular myogenic tone, which may involve in the development of vascular hypertension. PMID- 26536091 TI - Normoaldosteronemic aldosterone-producing adenoma: immunochemical characterization and diagnostic implications. AB - BACKGROUND: A high aldosterone-renin ratio (ARR) is commonly used to identify primary aldosteronism, but the ARR is high when renin is low, even if plasma aldosterone concentration values are normal, suggesting the existence of 'normoaldosteronemic' primary aldosteronism. However, most such cases did not undergo adrenalectomy; moreover, because of the lack of antibody for the human CYP11B2 (aldosterone synthase), conclusive demonstration of a normoaldosteronemic aldosterone-producing adenoma was not possible thus far. METHOD: In 2003, a lady presented with severe hypertension a right adrenal nodule, low renin, high ARR, but normal plasma aldosterone concentration. As adrenal vein sampling showed lateralized aldosterone secretion, she underwent left adrenalectomy, which consistently normalized blood pressure (BP) and renin during 11-year follow-up. RESULT AND CONCLUSION: The development of a novel monoclonal antibody for the human CYP11B2 in 2014 allowed immunochemically identification of a CYP11B2 positive adenoma in the resected adrenal. Moreover, this case unequivocally demonstrates for the first time the existence of normoaldosteronemic aldosterone producing adenoma, which suggests that many cases of 'low renin-essential hypertension' might instead have a surgically curable form of primary aldosteronism. PMID- 26536092 TI - Foot detection and distances by different methods: implications for pulse wave velocity values. PMID- 26536093 TI - Reply. PMID- 26536094 TI - Reduced arterial stiffness may contribute to angiotensin-converting enzyme inhibitor induced improvements in walking time in peripheral arterial disease patients: Retraction. AB - J Hypertension 2008, 26:1037-1042. The following authors, Drs A.M. Dart, A. Lawler, P.A. Blombery, Prof. B.A. Kingwell, have requested retraction of a paper by A.A. Ahimastos et al. An investigation by the Research Conduct Office of the Baker Heart and Diabetes Institute found irregularities in a study, including falsification of patients' records and misrepresentation of results, from which this article was derived. On the basis of this investigation the Baker Heart and Diabetes Institute strongly supports retraction and points out the co-authors asking for retraction were found not be involved in the research misconduct. The article is retracted. PMID- 26536095 TI - Redesigning Health Care Organizations: The Influence of Government Policy and Methods of Payment. AB - Over the last 5 years, there has been a growing trend toward consolidation in the health care field. As reimbursement moves from a fee-for-service model to a value based model, there will be continued pressure on physicians to either be a hospital employee or to be in a large multidisciplinary practice. This is largely due to the Accountable Care Act, which directs payers to utilize population-based cost analyses, rather than an individual patient-based analysis. To succeed in this environment, practices will have to break down traditional organizational barriers to create evidence-based algorithms for the treatment of individual diagnoses from the initial onset of symptoms until the resolution of symptoms. PMID- 26536097 TI - Novel Techniques in the Surgical Treatment of Acromegaly: Applications and Efficacy. AB - Since the establishment of transsphenoidal microsurgery as the operative treatment of choice in most patients with acromegaly 40 years ago, a few novel technical developments have evolved. Their application, utility and efficacy will be briefly discussed in this review article, based on an analysis of published results and the authors' personal experience. The endoscope was additionally used to search for residual tumours in locations which could not be visualised with the operating microscope. In many centres it has by now fully replaced the operating microscope. Extended endoscopic operations hardly have limits in respect to accessible pathology. Overall, the results and complications reported from microsurgical and endoscopic series are comparable. Intraoperative magnetic resonance imaging allows depicting the completeness of a tumour resection. While in many patients additional tumour resections are performed on the basis of intraoperative imaging, the improvements in hormonal remission rates reported are less impressive. Neuronavigation uses imaging data to improve the surgeon's orientation, and it is certainly a major asset to the inexperienced. In high caseload centres it is mainly appreciated in anatomical variants and reoperations. While the Doppler probe is a valuable and easily affordable gadget to avoid vascular arterial injury, intraoperative ultrasound imaging of tumour extension has a much poorer resolution than magnetic resonance imaging and is thus not widely implemented. The clinical value of intraoperative growth hormone measurements is controversially discussed. In summary, the application of modern technology has only led to a minor improvement of results, but it has widened the spectrum of accessible pathologies and increased the safety of the procedures for the patient. It is expected that outcomes will continue to improve as novel techniques and concepts are being developed. PMID- 26536099 TI - CHOROIDAL THICKENING IN PATIENTS WITH CUTICULAR DRUSEN COMBINED WITH VITELLIFORM MACULAR DETACHMENT. AB - PURPOSE: To analyze the subfoveal choroidal thickness (SFCT) in patients with cuticular drusen. METHODS: Retrospective, monocentric, study of consecutive patients examined with enhanced depth imaging spectral domain optical coherence tomography (EDI SD-OCT, Cirrus, Zeiss) between 2009 and 2014 in a tertiary care center. Measurements of the height of the subfoveal vitelliform detachment and SFCT were manually performed. RESULTS: Thirteen patients, 3 men and 10 women, aged from 35 to 73 (mean: 53.6 years) were selected. For the 24 eyes without macular atrophy at first visit, SFCT ranged from 195 to 559 um (mean +/- SD = 317.5 +/- 93). The SFCT was significantly thicker in 12 eyes with vitelliform macular detachment at presentation (369 +/- 96, median = 368.5) than in 12 eyes without (266 +/- 58, median = 257.5) (P = 0.007), whereas the 2 groups did not differ in age (P = 0.35) or refractive error (P = 0.56). No correlation was observed between SFCT and the height of the foveal detachment. For 10 eyes followed up longer than 24 months (mean: 38.9 months), the SFCT significantly decreased over time, from 375 +/- 96 (median = 368.5) to 303 +/- 138 (median = 319) um (P = 0.022). CONCLUSION: Eyes with cuticular drusen combined with vitelliform macular detachment present with choroidal thickening, suggesting that the choroidal vasculature may play a role in the occurrence of macular detachments in patients with cuticular drusen. The life cycle of these vitelliform lesions evolves from translucent subretinal fluid to the accumulation of yellowish material eventually resolving and leading to atrophy with marked and rapid thinning of the choroid. PMID- 26536100 TI - Radial Retinal Incisions for Complex Pediatric Traumatic Macular Holes. PMID- 26536101 TI - ULTRA-WIDEFIELD IMAGING OF POSTERIOR SEGMENT PATHOLOGY IN THE SETTING OF THE BOSTON KERATOPROSTHESIS. AB - PURPOSE: To evaluate the ability to visualize and document posterior segment pathology through the Boston keratoprosthesis (KPro) using the Optos P200Tx ultra widefield (UWF) scanning laser ophthalmoscope. METHODS: A retrospective chart review was conducted of patients who underwent Boston Type I keratoprosthesis implantation and who subsequently were imaged with an UWF system. Ultra-widefield images were reviewed to evaluate for vitreoretinal pathology and were compared with the clinical examination. RESULTS: In this series of 10 patients (10 eyes), 100% of vitreoretinal pathology found on clinical examination was detectable using the Optos system. In 4 cases (40%), UWF imaging provided superior detection of pathology compared with the clinical examination by imaging through retroprosthetic membranes (3 cases) and by detection of a retinal detachment (one case). In 1 case (10%), B-scan ultrasonography was needed to characterize vitreoretinal pathology that could not be definitively distinguished on UWF imaging and was difficult to detect on clinical examination. Ultra-widefield imaging detected the following vitreoretinal pathologies in KPro eyes: retinal hemorrhage, epiretinal membrane, retinal detachment, proliferative diabetic retinopathy, and choroidal folds. CONCLUSION: Ultra-widefield imaging provides a high-resolution view of the posterior pole and periphery despite the limitations of imaging through the narrow optic of Boston Type I keratoprosthesis, and it may improve visualization through retroprosthetic membranes. Detection and documentation of vitreoretinal complications in the setting of a permanent keratoprosthesis may be enhanced using UWF imaging. PMID- 26536102 TI - A Breast Tissue Protein Expression Profile Contributing to Early Parity-Induced Protection Against Breast Cancer. AB - BACKGROUND/AIMS: Early parity reduces breast cancer risk, whereas, late parity and nulliparity increase breast cancer risk. Despite substantial efforts to understand the protective effects of early parity, the precise molecular circuitry responsible for these changes is not yet fully defined. METHODS: Here, we have conducted the first study assessing protein expression profiles in normal breast tissue of healthy early parous, late parous, and nulliparous women. Breast tissue biopsies were obtained from 132 healthy parous and nulliparous volunteers. These samples were subjected to global protein expression profiling and immunohistochemistry. GeneSpring and MetaCore bioinformatics analysis software were used to identify protein expression profiles associated with early parity (low risk) versus late/nulliparity (high risk). RESULTS: Early parity reduces expression of key proteins involved in mitogenic signaling pathways in breast tissue through down regulation of EGFR1/3, ESR1, AKT1, ATF, Fos, and SRC. Early parity is also characterized by greater genomic stability and reduced tissue inflammation based on differential expression of aurora kinases, p53, RAD52, BRCA1, MAPKAPK-2, ATF-1, ICAM1, and NF-kappaB compared to late and nulli parity. CONCLUSIONS: Early parity reduces basal cell proliferation in breast tissue, which translates to enhanced genomic stability, reduced cellular stress/inflammation, and thus reduced breast cancer risk. PMID- 26536103 TI - Errata. PMID- 26536104 TI - Methyl Sulfone Blocked Multiple Hypoxia- and Non-Hypoxia-Induced Metastatic Targets in Breast Cancer Cells and Melanoma Cells. AB - Metastatic cancer causes 90% of cancer deaths. Unlike many primary tumors, metastatic tumors cannot be cured by surgery alone. Metastatic cancer requires chemotherapy. However, metastatic cells are not easily killed by chemotherapy. These problems with chemotherapy are caused in part by the metastatic cell niche: hypoxia. Here we show that the molecule, methyl sulfone, normalized metastatic metabolism of hypoxic breast cancer and melanoma cells by altering several metabolic functions of the cells. Under hypoxia, methyl sulfone decreased expression of the master regulator of hypoxia, HIF-1alpha, and reduced levels of the glycolytic enzymes, PKM2, LDHA, GLUT1, the pro-angiogenic protein, VEGF, and the iron-sulfur metabolism molecules, miR-210 and transferrin, all of which promote metastasis. Conversely, methyl sulfone increased levels of ISCU1/2 and ferroportin, proteins associated with iron-sulfur cluster biogenesis and iron homeostasis in normal cells. These data identify methyl sulfone as a multi targeting molecule that blocks the survival/proliferative effect of hypoxia on metastatic cells and brings normality back to cellular metabolism. PMID- 26536105 TI - Demonstration of Therapeutic Equivalence of Fluconazole Generic Products in the Neutropenic Mouse Model of Disseminated Candidiasis. AB - Some generics of antibacterials fail therapeutic equivalence despite being pharmaceutical equivalents of their innovators, but data are scarce with antifungals. We used the neutropenic mice model of disseminated candidiasis to challenge the therapeutic equivalence of three generic products of fluconazole compared with the innovator in terms of concentration of the active pharmaceutical ingredient, analytical chemistry (liquid chromatography/mass spectrometry), in vitro susceptibility testing, single-dose serum pharmacokinetics in infected mice, and in vivo pharmacodynamics. Neutropenic, five week-old, murine pathogen free male mice of the strain Udea:ICR(CD-2) were injected in the tail vein with Candida albicans GRP-0144 (MIC = 0.25 mg/L) or Candida albicans CIB-19177 (MIC = 4 mg/L). Subcutaneous therapy with fluconazole (generics or innovator) and sterile saline (untreated controls) started 2 h after infection and ended 24 h later, with doses ranging from no effect to maximal effect (1 to 128 mg/kg per day) divided every 3 or 6 hours. The Hill's model was fitted to the data by nonlinear regression, and results from each group compared by curve fitting analysis. All products were identical in terms of concentration, chromatographic and spectrographic profiles, MICs, mouse pharmacokinetics, and in vivo pharmacodynamic parameters. In conclusion, the generic products studied were pharmaceutically and therapeutically equivalent to the innovator of fluconazole. PMID- 26536106 TI - Antiaggregation Potential of Padina gymnospora against the Toxic Alzheimer's Beta Amyloid Peptide 25-35 and Cholinesterase Inhibitory Property of Its Bioactive Compounds. AB - Inhibition of beta-amyloid (Abeta) aggregation in the cerebral cortex of the brain is a promising therapeutic and defensive strategy in identification of disease modifying agents for Alzheimer's disease (AD). Since natural products are considered as the current alternative trend for the discovery of AD drugs, the present study aims at the evaluation of anti-amyloidogenic potential of the marine seaweed Padina gymnospora. Prevention of aggregation and disaggregation of the mature fibril formation of Abeta 25-35 by acetone extracts of P. gymnospora (ACTPG) was evaluated in two phases by Thioflavin T assay. The results were further confirmed by confocal laser scanning microscopy (CLSM) analysis and Fourier transform infrared (FTIR) spectroscopic analysis. The results of antiaggregation and disaggregation assay showed that the increase in fluorescence intensity of aggregated Abeta and the co-treatment of ACTPG (250 MUg/ml) with Abeta 25-35, an extensive decrease in the fluorescence intensity was observed in both phases, which suggests that ACTPG prevents the oligomers formation and disaggregation of mature fibrils. In addition, ACTPG was subjected to column chromatography and the bioactivity was screened based on the cholinesterase inhibitory activity. Finally, the active fraction was subjected to LC-MS/MS analysis for the identification of bioactive compounds. Overall, the results suggest that the bioactive compound alpha bisabolol present in the alga might be responsible for the observed cholinesterase inhibition with the IC50 value < 10 MUg/ml for both AChE and BuChE when compared to standard drug donepezil (IC50 value < 6 MUg/ml) and support its use for the treatment of neurological disorders. PMID- 26536107 TI - Antibiotics: Homed to the hideout. PMID- 26536108 TI - Brain cancer: Tumour cells on neighbourhood watch. PMID- 26536109 TI - Basomedial amygdala mediates top-down control of anxiety and fear. AB - Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway. PMID- 26536112 TI - The effects of life history and sexual selection on male and female plumage colouration. AB - Classical sexual selection theory provides a well-supported conceptual framework for understanding the evolution and signalling function of male ornaments. It predicts that males obtain greater fitness benefits than females through multiple mating because sperm are cheaper to produce than eggs. Sexual selection should therefore lead to the evolution of male-biased secondary sexual characters. However, females of many species are also highly ornamented. The view that this is due to a correlated genetic response to selection on males was widely accepted as an explanation for female ornamentation for over 100 years and current theoretical and empirical evidence suggests that genetic constraints can limit sex-specific trait evolution. Alternatively, female ornamentation can be the outcome of direct selection for signalling needs. Since few studies have explored interspecific patterns of both male and female elaboration, our understanding of the evolution of animal ornamentation remains incomplete, especially over broad taxonomic scales. Here we use a new method to quantify plumage colour of all ~6,000 species of passerine birds to determine the main evolutionary drivers of ornamental colouration in both sexes. We found that conspecific male and female colour elaboration are strongly correlated, suggesting that evolutionary changes in one sex are constrained by changes in the other sex. Both sexes are more ornamented in larger species and in species living in tropical environments. Ornamentation in females (but not males) is increased in cooperative breeders- species in which female-female competition for reproductive opportunities and other resources related to breeding may be high. Finally, strong sexual selection on males has antagonistic effects, causing an increase in male colouration but a considerably more pronounced reduction in female ornamentation. Our results indicate that although there may be genetic constraints to sexually independent colour evolution, both female and male ornamentation are strongly and often differentially related to morphological, social and life-history variables. PMID- 26536111 TI - Brain tumour cells interconnect to a functional and resistant network. AB - Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease. PMID- 26536113 TI - Climate change: A rewired food web. PMID- 26536114 TI - Novel antibody-antibiotic conjugate eliminates intracellular S. aureus. AB - Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S. aureus within host cells may provide a reservoir relatively protected from antibiotics, thus enabling long-term colonization of the host and explaining clinical failures and relapses after antibiotic therapy. Here we confirm that intracellular reservoirs of S. aureus in mice comprise a virulent subset of bacteria that can establish infection even in the presence of vancomycin, and we introduce a novel therapeutic that effectively kills intracellular S. aureus. This antibody-antibiotic conjugate consists of an anti S. aureus antibody conjugated to a highly efficacious antibiotic that is activated only after it is released in the proteolytic environment of the phagolysosome. The antibody-antibiotic conjugate is superior to vancomycin for treatment of bacteraemia and provides direct evidence that intracellular S. aureus represents an important component of invasive infections. PMID- 26536115 TI - Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A. AB - It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents. HCV non structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with in vitro activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed in vitro has translated into clinical efficacy, with HCV RNA declining by ~3-4 log10 in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated in vivo using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle. PMID- 26536117 TI - Targeted Expression of Channelrhodopsin-2 to the Axon Initial Segment Alters the Temporal Firing Properties of Retinal Ganglion Cells. AB - The axon initial segment (AIS) is essential for initiating action potentials and maintaining neuronal excitability in axon-bearing neurons in the CNS. There is increasing interest in the targeting of optogenetic tools to subcellular compartments, including the AIS, to gain precise control of neuronal activity for basic research and clinical applications. In particular, targeted expression of optogenetic tools in retinal ganglion cells (RGCs) has been explored as an approach for restoring vision after photoreceptor degeneration. Thus, understanding the effects of such targeting on spiking abilities and/or patterns is important. Here, we examined the effects of recombinant adeno-associated virus (rAAV)-mediated targeted expression of channelrhodopsin-2 (ChR2)-GFP with a NaV channel motif in mouse RGCs. We found that this targeted expression disrupted NaV channel clustering at the AIS and converted the spike firing patterns of RGCs from sustained to transient. Our results suggest that the clustering of membrane channels, including NaV channels, at the AIS is important for the ability of RGCs to generate sustained spike firing. Additionally, the targeting of optogenetic tools to the AIS with the NaV channel motif may offer a way to create transient light responses in RGCs for vision restoration. PMID- 26536118 TI - Flow-Based Single Cell Deposition for High-Throughput Screening of Protein Libraries. AB - The identification and engineering of proteins having refined or novel characteristics is an important area of research in many scientific fields. Protein modelling has enabled the rational design of unique proteins, but high throughput screening of large libraries is still required to identify proteins with potentially valuable properties. Here we report on the development and evaluation of a novel fluorescent activated cell sorting based screening platform. Single bacterial cells, expressing a protein library to be screened, are electronically sorted and deposited onto plates containing solid nutrient growth media in a dense matrix format of between 44 and 195 colonies/cm2. We show that this matrix format is readily applicable to machine interrogation (<30 seconds per plate) and subsequent bioinformatic analysis (~60 seconds per plate) thus enabling the high-throughput screening of the protein library. We evaluate this platform and show that bacteria containing a bioluminescent protein can be spectrally analysed using an optical imager, and a rare clone (0.5% population) can successfully be identified, picked and further characterised. To further enhance this screening platform, we have developed a prototype electronic sort stream multiplexer, that when integrated into a commercial flow cytometric sorter, increases the rate of colony deposition by 89.2% to 24 colonies per second. We believe that the screening platform described here is potentially the foundation of a new generation of high-throughput screening technologies for proteins. PMID- 26536119 TI - Association between Dietary Magnesium Intake and Hyperuricemia. AB - OBJECTIVE: To examine the cross-sectional associations between dietary magnesium (Mg) intake and hyperuricemia (HU). METHODS: 5168 subjects were included in this study. Dietary intake was assessed using a validated semi-quantitative food frequency questionnaire. Hyperuricemia (HU) was defined as uric acid >= 416 MUmol/L for male population and >= 360 MUmol/L for female. A multivariable logistic analysis model was applied to test the associations after adjusting a number of potential confounding factors. RESULTS: The relative odds of the overall prevalence of HU were decreased by 0.57 times in the fourth quintile of Mg intake (OR 0.57, 95% CI 0.35-0.94) and 0.55 times in the fifth quintile (OR 0.55, 95% CI 0.30-1.01) comparing with the lowest quintile, and P for trend was 0.091. The results of multivariable linear regression also suggested a significant inverse association between serum uric acid and Mg intake (beta = 0.028, P = 0.022). For male, the relative odds of HU were decreased by 0.62 times in the third quintile of Mg intake (OR 0.62, 95% CI 0.40-0.97), 0.40 times in the fourth quintile (OR 0.40, 95% CI 0.23-0.72) and 0.35 times in the fifth quintile (OR 0.35, 95% CI 0.17-0.71) comparing with the lowest quintile, and P for trend was 0.006. Multivariable adjusted inverse association was also existed between serum uric acid and Mg intake in male population (beta = -0.061, P = 0.002). However, no significant association was observed between dietary Mg intake and HU for female. CONCLUSIONS: The findings of this cross-sectional study indicated that dietary Mg intake is inversely associated with HU, independent of some major confounding factors. In addition, this association remains valid for the male subgroup, but not for the female subgroup. LEVEL OF EVIDENCE: LevelIII, cross sectional study. PMID- 26536116 TI - Measurement of interaction between antiprotons. AB - One of the primary goals of nuclear physics is to understand the force between nucleons, which is a necessary step for understanding the structure of nuclei and how nuclei interact with each other. Rutherford discovered the atomic nucleus in 1911, and the large body of knowledge about the nuclear force that has since been acquired was derived from studies made on nucleons or nuclei. Although antinuclei up to antihelium-4 have been discovered and their masses measured, little is known directly about the nuclear force between antinucleons. Here, we study antiproton pair correlations among data collected by the STAR experiment at the Relativistic Heavy Ion Collider (RHIC), where gold ions are collided with a centre-of-mass energy of 200 gigaelectronvolts per nucleon pair. Antiprotons are abundantly produced in such collisions, thus making it feasible to study details of the antiproton-antiproton interaction. By applying a technique similar to Hanbury Brown and Twiss intensity interferometry, we show that the force between two antiprotons is attractive. In addition, we report two key parameters that characterize the corresponding strong interaction: the scattering length and the effective range of the interaction. Our measured parameters are consistent within errors with the corresponding values for proton-proton interactions. Our results provide direct information on the interaction between two antiprotons, one of the simplest systems of antinucleons, and so are fundamental to understanding the structure of more-complex antinuclei and their properties. PMID- 26536120 TI - Intra- and Intersession Repeatability of an Optical Quality and Intraocular Scattering Measurement System in Children. AB - PURPOSE: To evaluate intra- and intersession repeatability of objective optical quality and intraocular scattering measurements with a double-pass system in children. METHODS: Forty-two eyes of 42 children were included in the study. An optical quality analysis system (OQAS) was used to measure optical quality parameters, including modulation transfer function cutoff frequency (MTFcutoff), Strehl ratio (SR), OQAS values (OV) at 3 different contrasts and objective scatter index (OSI). Three measurement sessions with 10-min intervals were operated by the same technician, and in each session four consecutive measurements were obtained. RESULTS: Mean values for MTFcutoff, SR and OSI were 46.85 +/- 7.45cpd, 0.27 +/- 0.06 and 0.34 +/- 0.22 respectively. 1) The intraclass correlation coefficients were ranged from 0.89 to 0.97 and coefficients of variation from 0.06 to 0.16 for all the parameters in the first session; the relative repeatability were 11.1% (MTFcutoff), 22.5% (SR), 10.9% (OV100%), 16.6% (OV2%), 22.4% (OV9%) and 56.3% (OSI). Similar results were found in the second and third sessions. 2) Bland-Altman analysis showed that narrow 95% confidence intervals (compared between the first and second sessions) ranged from -5.42 to 5.28 (MTFcutoff), -0.05 to 0.07 (SR), -0.18 to 0.18 (OV100%), -0.26 to 0.29 (OV20%), -0.33 to 0.39 (OV9%) and -0.11 to 0.09 (OSI); the comparison between any two of the three sessions showed similar results. CONCLUSION: Measurements of optical quality and intraocular scattering in children by the double-pass system showed good intra- and intersession repeatability. Retinal image quality is high and intraocular scattering is low in children. PMID- 26536122 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/2325967113512467.]. PMID- 26536121 TI - Genome-Wide Annotation and Comparative Analysis of Cytochrome P450 Monooxygenases in Basidiomycete Biotrophic Plant Pathogens. AB - Fungi are an exceptional source of diverse and novel cytochrome P450 monooxygenases (P450s), heme-thiolate proteins, with catalytic versatility. Agaricomycotina saprophytes have yielded most of the available information on basidiomycete P450s. This resulted in observing similar P450 family types in basidiomycetes with few differences in P450 families among Agaricomycotina saprophytes. The present study demonstrated the presence of unique P450 family patterns in basidiomycete biotrophic plant pathogens that could possibly have originated from the adaptation of these species to different ecological niches (host influence). Systematic analysis of P450s in basidiomycete biotrophic plant pathogens belonging to three different orders, Agaricomycotina (Armillaria mellea), Pucciniomycotina (Melampsora laricis-populina, M. lini, Mixia osmundae and Puccinia graminis) and Ustilaginomycotina (Ustilago maydis, Sporisorium reilianum and Tilletiaria anomala), revealed the presence of numerous putative P450s ranging from 267 (A. mellea) to 14 (M. osmundae). Analysis of P450 families revealed the presence of 41 new P450 families and 27 new P450 subfamilies in these biotrophic plant pathogens. Order-level comparison of P450 families between biotrophic plant pathogens revealed the presence of unique P450 family patterns in these organisms, possibly reflecting the characteristics of their order. Further comparison of P450 families with basidiomycete non-pathogens confirmed that biotrophic plant pathogens harbour the unique P450 families in their genomes. The CYP63, CYP5037, CYP5136, CYP5137 and CYP5341 P450 families were expanded in A. mellea when compared to other Agaricomycotina saprophytes and the CYP5221 and CYP5233 P450 families in P. graminis and M. laricis-populina. The present study revealed that expansion of these P450 families is due to paralogous evolution of member P450s. The presence of unique P450 families in these organisms serves as evidence of how a host/ecological niche can influence shaping the P450 content of an organism. The present study initiates our understanding of P450 family patterns in basidiomycete biotrophic plant pathogens. PMID- 26536123 TI - Direct Measurements of Local Coupling between Myosin Molecules Are Consistent with a Model of Muscle Activation. AB - Muscle contracts due to ATP-dependent interactions of myosin motors with thin filaments composed of the proteins actin, troponin, and tropomyosin. Contraction is initiated when calcium binds to troponin, which changes conformation and displaces tropomyosin, a filamentous protein that wraps around the actin filament, thereby exposing myosin binding sites on actin. Myosin motors interact with each other indirectly via tropomyosin, since myosin binding to actin locally displaces tropomyosin and thereby facilitates binding of nearby myosin. Defining and modeling this local coupling between myosin motors is an open problem in muscle modeling and, more broadly, a requirement to understanding the connection between muscle contraction at the molecular and macro scale. It is challenging to directly observe this coupling, and such measurements have only recently been made. Analysis of these data suggests that two myosin heads are required to activate the thin filament. This result contrasts with a theoretical model, which reproduces several indirect measurements of coupling between myosin, that assumes a single myosin head can activate the thin filament. To understand this apparent discrepancy, we incorporated the model into stochastic simulations of the experiments, which generated simulated data that were then analyzed identically to the experimental measurements. By varying a single parameter, good agreement between simulation and experiment was established. The conclusion that two myosin molecules are required to activate the thin filament arises from an assumption, made during data analysis, that the intensity of the fluorescent tags attached to myosin varies depending on experimental condition. We provide an alternative explanation that reconciles theory and experiment without assuming that the intensity of the fluorescent tags varies. PMID- 26536124 TI - Global Food Demand Scenarios for the 21st Century. AB - Long-term food demand scenarios are an important tool for studying global food security and for analysing the environmental impacts of agriculture. We provide a simple and transparent method to create scenarios for future plant-based and animal-based calorie demand, using time-dependent regression models between calorie demand and income. The scenarios can be customized to a specific storyline by using different input data for gross domestic product (GDP) and population projections and by assuming different functional forms of the regressions. Our results confirm that total calorie demand increases with income, but we also found a non-income related positive time-trend. The share of animal based calories is estimated to rise strongly with income for low-income groups. For high income groups, two ambiguous relations between income and the share of animal-based products are consistent with historical data: First, a positive relation with a strong negative time-trend and second a negative relation with a slight negative time-trend. The fits of our regressions are highly significant and our results compare well to other food demand estimates. The method is exemplarily used to construct four food demand scenarios until the year 2100 based on the storylines of the IPCC Special Report on Emissions Scenarios (SRES). We find in all scenarios a strong increase of global food demand until 2050 with an increasing share of animal-based products, especially in developing countries. PMID- 26536125 TI - Polyphenylsilole multilayers--an insight from X-ray electron spectroscopy and density functional theory. AB - We present a combined investigation by means of X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine-structure (NEXAFS) spectroscopy of condensed multilayers of two polyphenylsiloles, namely hexaphenylsilole (HPS) and tetraphenylsilole (TPS). Both compounds exhibit very similar spectroscopic signatures, whose interpretation is aided by density functional theory (DFT) calculations. High-resolution XPS spectra of the Si 2p and C 1s core levels of these multilayers indicate a positively charged silicon ion flanked by two negatively charged adjacent carbon atoms in the silole core of both molecules. This result is corroborated quantitatively by DFT calculations on isolated HPS (TPS) molecules, which show a natural bond orbital partial charge of +1.67 e (+1.58 e) on the silicon and -0.34 e (-0.58 e) on the two neighbouring carbon atoms in the silole ring. These charges are conserved in direct contact with a Cu(111) substrate for films of submonolayer coverage, as evidenced by the Si 2p XPS data. The C K-edge NEXAFS spectra of HPS and TPS multilayers exhibit distinct and differing features. Their main characteristics reappear in the simulated spectra and are assigned to the different inequivalent carbon species in the molecule. The angle-dependent measurements hardly reveal any dichroism, i.e., the molecular pi-systems are not uniformly oriented parallel or perpendicular with respect to the surface. Changes in the growth conditions of TPS, i.e., a reduction of the substrate temperature from 240 K to 80 K during deposition, lead to a broadening of both XPS and NEXAFS signatures, as well as an upward shift of the Si 2p and C 1s binding energies, indicative of a less ordered growth mode at low temperature. PMID- 26536127 TI - A simple route to phosphamethine cyanines from S,N-heterocyclic carbenes. AB - Although salts of thiazolium cations are known, many readily prepared iodide salts have eluded spectroscopic and structural characterization; herein, data for a variety of such salts are reported. It has been demonstrated that thiazolium cations can be deprotonated to generate S,N-heterocyclic carbenes and their "electron rich olefin" dimers, but use of the former has been largely overshadowed by that of the more common N-heterocyclic carbenes. We report herein that the deprotonation of thiazolium iodides and their subsequent reaction with a conveniently prepared triphosphenium precursor grants phosphamethine cyanine cations with solid-state geometry and electronic structure unlike those of NHC stabilized cations. Protection of the phosphorus atom in such ions with elemental sulfur provides an air- and moisture-stable dithiophosphinium salt. PMID- 26536126 TI - Cell Lysis in S. pombe ura4 Mutants Is Suppressed by Loss of Functional Pub1, Which Regulates the Uracil Transporter Fur4. AB - Schizosaccharomyces pombe Deltaura4 cells lyse when grown on YPD medium. A S. pombe non-essential gene deletion library was screened to determine suppressors of the lysis phenotype. Deletion of the pub1 gene, which encoded E3 ubiquitin ligase, strongly suppressed cell lysis in Deltaura4 cells. The Deltapub1 cells displayed high sensitivity to 5-fluorouracil, a toxic analog of uracil, and this sensitivity was suppressed by deletion of fur4, which encoded a uracil transporter. Fur4 localized primarily to the Golgi apparatus and vacuoles in wild type cells, but localization was predominantly at the plasma membrane in Deltapub1 cells. Fur4 was necessary for the utilization of extracellular uracil, cytosine, or UMP. Uracil uptake activity increased in the Deltapub1 strain in a Fur4-dependent manner. In addition, uracil starvation was critical for induction of cell lysis of Deltaura4 strains and uracil supplementation suppressed lysis. In summary, the increased uracil uptake ability of Deltapub1 cells, where Fur4 was predominantly localized to the plasma membrane, resulted in suppression of cell lysis in the Deltaura4 background. PMID- 26536128 TI - The Skeleton Forming Proteome of an Early Branching Metazoan: A Molecular Survey of the Biomineralization Components Employed by the Coralline Sponge Vaceletia Sp. AB - The ability to construct a mineralized skeleton was a major innovation for the Metazoa during their evolution in the late Precambrian/early Cambrian. Porifera (sponges) hold an informative position for efforts aimed at unraveling the origins of this ability because they are widely regarded to be the earliest branching metazoans, and are among the first multi-cellular animals to display the ability to biomineralize in the fossil record. Very few biomineralization associated proteins have been identified in sponges so far, with no transcriptome or proteome scale surveys yet available. In order to understand what genetic repertoire may have been present in the last common ancestor of the Metazoa (LCAM), and that may have contributed to the evolution of the ability to biocalcify, we have studied the skeletal proteome of the coralline demosponge Vaceletia sp. and compare this to other metazoan biomineralizing proteomes. We bring some spatial resolution to this analysis by dividing Vaceletia's aragonitic calcium carbonate skeleton into "head" and "stalk" regions. With our approach we were able to identify 40 proteins from both the head and stalk regions, with many of these sharing some similarity to previously identified gene products from other organisms. Among these proteins are known biomineralization compounds, such as carbonic anhydrase, spherulin, extracellular matrix proteins and very acidic proteins. This report provides the first proteome scale analysis of a calcified poriferan skeletal proteome, and its composition clearly demonstrates that the LCAM contributed several key enzymes and matrix proteins to its descendants that supported the metazoan ability to biocalcify. However, lineage specific evolution is also likely to have contributed significantly to the ability of disparate metazoan lineages to biocalcify. PMID- 26536129 TI - Antibacterial Evaluation of Synthetic Thiazole Compounds In Vitro and In Vivo in a Methicillin-Resistant Staphylococcus aureus (MRSA) Skin Infection Mouse Model. AB - The emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA), including strains resistant to current antibiotics, has contributed to an increase in the number of skin infections reported in humans in recent years. New therapeutic options are needed to counter this public health challenge. The aim of the present study was to examine the potential of thiazole compounds synthesized by our research group to be used topically to treat MRSA skin and wound infections. The broth microdilution method confirmed that the lead thiazole compound and four analogues are capable of inhibiting MRSA growth at concentrations as low as 1.3 MUg/mL. Additionally, three compounds exhibited a synergistic relationship when combined with the topical antibiotic mupirocin against MRSA in vitro via the checkerboard assay. Thus the thiazole compounds have potential to be used alone or in combination with mupirocin against MRSA. When tested against human keratinocytes, four derivatives of the lead compound demonstrated an improved toxicity profile (were found to be non-toxic up to a concentration of 20 MUg/mL). Utilizing a murine skin infection model, we confirmed that the lead compound and three analogues exhibited potent antimicrobial activity in vivo, with similar capability as the antibiotic mupirocin, as they reduced the burden of MRSA present in skin wounds by more than 90%. Taken altogether, the present study provides important evidence that these thiazole compounds warrant further investigation for development as novel topical antimicrobials to treat MRSA skin infections. PMID- 26536130 TI - Aging Is Accompanied by a Blunted Muscle Protein Synthetic Response to Protein Ingestion. AB - PURPOSE: Progressive loss of skeletal muscle mass with aging (sarcopenia) forms a global health concern. It has been suggested that an impaired capacity to increase muscle protein synthesis rates in response to protein intake is a key contributor to sarcopenia. We assessed whether differences in post-absorptive and/or post-prandial muscle protein synthesis rates exist between large cohorts of healthy young and older men. PROCEDURES: We performed a cross-sectional, retrospective study comparing in vivo post-absorptive muscle protein synthesis rates determined with stable isotope methodologies between 34 healthy young (22+/ 1 y) and 72 older (75+/-1 y) men, and post-prandial muscle protein synthesis rates between 35 healthy young (22+/-1 y) and 40 older (74+/-1 y) men. FINDINGS: Post-absorptive muscle protein synthesis rates did not differ significantly between the young and older group. Post-prandial muscle protein synthesis rates were 16% lower in the older subjects when compared with the young. Muscle protein synthesis rates were >3 fold more responsive to dietary protein ingestion in the young. Irrespective of age, there was a strong negative correlation between post absorptive muscle protein synthesis rates and the increase in muscle protein synthesis rate following protein ingestion. CONCLUSIONS: Aging is associated with the development of muscle anabolic inflexibility which represents a key physiological mechanism underpinning sarcopenia. PMID- 26536131 TI - Detection of influenza A(H3N2) clade 3C.2a viruses in patients with suspected mumps in British Columbia, Canada, during the 2014/15 influenza season. PMID- 26536132 TI - Failure of Arm Movement Control in Stroke Patients, Characterized by Loss of Complexity. AB - We study the mechanism of human arm-posture control by means of nonlinear dynamics and quantitative time series analysis methods. Utilizing linear and nonlinear measures in combination, we find that pathological tremors emerge in patient dynamics and serve as a main feature discriminating between normal and patient groups. The deterministic structure accompanied with loss of complexity inherent in the tremor dynamics is also revealed. To probe the underlying mechanism of the arm-posture dynamics, we further analyze the coupling patterns between joints and components, and discuss their roles in breaking of the organization structure. As a result, we elucidate the mechanisms in the arm posture dynamics of normal subjects responding to the gravitational force and for the reduction of the dynamic degrees of freedom in the patient dynamics. This study provides an integrated framework for the origin of the loss of complexity in the dynamics of patients as well as the coupling structure in the arm-posture dynamics. PMID- 26536133 TI - Gender Differentials in Self-Rated Health and Self-Reported Disability among Adults in India. AB - BACKGROUND: The extant literature on gender differentials in health in developed countries suggests that women outlive men at all ages, but women report poorer health than men. It is well established that Indian women live longer than men, but few studies have been conducted to understand the gender dimension in self rated health and self-reported disability. The present study investigates gender differentials in self-rated health (SRH) and self-reported disability (SRD) among adults in India, using a nationally representative data. METHODS: Using data on 10,736 respondents aged 18 and older in the 2007 WHO Study on Global Ageing and Adult Health in India, prevalence estimates of SRH are calculated separately for men and women by socio-economic and demographic characteristics. The association of SRH with gender is tested using a multinomial logistic regression method. SRD is assessed using 20 activities of daily living (ADL). Further, gender differences in total life expectancy (TLE), disability life expectancy (DLE) and the proportion of life spent with a disability at various adult ages are measured. RESULTS: The relative risk of reporting poor health by women was significantly higher than men (relative risk ratio: 1.660; 95% confidence Interval (CI): 1.430-1.927) after adjusting for socio-economic and demographic characteristics. Women reported higher prevalence of severe and extreme disability than men in 14 measures out of a total20 ADL measures. Women aged less than 60 years reported two times more than men in SRD >= 5 ADLs. Finally, both DLE and proportion of life spent with a disability were substantially higher for women irrespective of their ages. CONCLUSION: Indian women live longer but report poorer health than men. A substantial gender differential is found in self reported disability. This makes for an urgent call to health researchers and policy makers for gender-sensitive programs. PMID- 26536134 TI - Evolutionary Analysis and Classification of OATs, OCTs, OCTNs, and Other SLC22 Transporters: Structure-Function Implications and Analysis of Sequence Motifs. AB - The SLC22 family includes organic anion transporters (OATs), organic cation transporters (OCTs) and organic carnitine and zwitterion transporters (OCTNs). These are often referred to as drug transporters even though they interact with many endogenous metabolites and signaling molecules (Nigam, S.K., Nature Reviews Drug Discovery, 14:29-44, 2015). Phylogenetic analysis of SLC22 supports the view that these transporters may have evolved over 450 million years ago. Many OAT members were found to appear after a major expansion of the SLC22 family in mammals, suggesting a physiological and/or toxicological role during the mammalian radiation. Putative SLC22 orthologs exist in worms, sea urchins, flies, and ciona. At least six groups of SLC22 exist. OATs and OCTs form two Major clades of SLC22, within which (apart from Oat and Oct subclades), there are also clear Oat-like, Octn, and Oct-related subclades, as well as a distantly related group we term "Oat-related" (which may have different functions). Based on available data, it is arguable whether SLC22A18, which is related to bacterial drug-proton antiporters, should be assigned to SLC22. Disease-causing mutations, single nucleotide polymorphisms (SNPs) and other functionally analyzed mutations in OAT1, OAT3, URAT1, OCT1, OCT2, OCTN1, and OCTN2 map to the first extracellular domain, the large central intracellular domain, and transmembrane domains 9 and 10. These regions are highly conserved within subclades, but not between subclades, and may be necessary for SLC22 transporter function and functional diversification. Our results not only link function to evolutionarily conserved motifs but indicate the need for a revised sub-classification of SLC22. PMID- 26536135 TI - Structural and Functional Brain Connectivity of People with Obesity and Prediction of Body Mass Index Using Connectivity. AB - Obesity is a medical condition affecting billions of people. Various neuroimaging methods including magnetic resonance imaging (MRI) have been used to obtain information about obesity. We adopted a multi-modal approach combining diffusion tensor imaging (DTI) and resting state functional MRI (rs-fMRI) to incorporate complementary information and thus better investigate the brains of non-healthy weight subjects. The objective of this study was to explore multi-modal neuroimaging and use it to predict a practical clinical score, body mass index (BMI). Connectivity analysis was applied to DTI and rs-fMRI. Significant regions and associated imaging features were identified based on group-wise differences between healthy weight and non-healthy weight subjects. Six DTI-driven connections and 10 rs-fMRI-driven connectivities were identified. DTI-driven connections better reflected group-wise differences than did rs-fMRI-driven connectivity. We predicted BMI values using multi-modal imaging features in a partial least-square regression framework (percent error 15.0%). Our study identified brain regions and imaging features that can adequately explain BMI. We identified potentially good imaging biomarker candidates for obesity-related diseases. PMID- 26536136 TI - Methods for the postoperative management of the thoracic oncology patients: lessons from the clinic. AB - Oncological thoracic surgery comprises challenging procedures not only from a surgical point of view but also regarding the postoperative management. The most significant procedures performed for malignancy are those requiring resection of the lung, the pleura, the esophagus, mediastinal structures, the chest wall and airways. Especially after major procedures, postoperative complications occur frequently and usually require a multidisciplinary approach involving thoracic surgeons, anesthesiologists, pulmonologist, physiotherapists and oncologists. Thus, a proper postoperative management is as important as the surgical procedure to achieve the best outcome following surgery. In this article, we provide an overview of the basic principles for management of postoperative imaging and drain system and review the main postoperative complications following thoracic surgery, focusing also on new strategies to prevent them. PMID- 26536137 TI - In Situ Formation of Disorder-Engineered TiO2(B)-Anatase Heterophase Junction for Enhanced Photocatalytic Hydrogen Evolution. AB - Hydrogenation of semiconductors is an efficient way to increase their photocatalytic activity by forming disorder-engineered structures. Herein, we report a facile hydrogenation process of TiO2(B) nanobelts to in situ generate TiO2(B)-anatase heterophase junction with a disordered surface shell. The catalyst exhibits an excellent performance for photocatalytic hydrogen evolution under the simulated solar light irradiation (~580 MUmol h(-1), 0.02 g photocatalyst). The atomically well-matched heterophase junction, along with the disorder-engineered surface shell, promotes the separation of electron-hole and inhibits their recombination. This strategy can be further employed to design other disorder-engineered composite photocatalysts for solar energy utilization. PMID- 26536138 TI - MANAGEMENT OF CATECHOLAMINE-SECRETING TUMORS IN PREGNANCY: A REVIEW. AB - OBJECTIVE: Catecholamine-secreting tumors (pheochromocytomas and paragangliomas) presenting during pregnancy are extremely rare, but they can be fatal to both mother and fetus. Recent discoveries in the genetic background of these tumors are expected to address an increasing number of at-risk women to prenatal diagnosis. METHODS: The literature was reviewed in order to provide clinicians with a practical and updated guide on how to manage this life-threatening condition. RESULTS: The clinical presentation of catecholamine-secreting tumors can be deceptive and mimic common disorders of pregnancy. Silent catecholamine secreting tumors can become evident during pregnancy, and hypertension cannot be considered a hallmark for this condition: some women may be normotensive or develop orthostatic hypotension. Biochemical screening includes measurement of plasma free metanephrines or urinary fractioned metanephrines. Measurement of catecholamines, dopamine, and methoxytyramine can provide further information on tumor biology, location, and prognosis. Diagnostic imaging is limited, and medical treatment requires a cautious balance between hemodynamic control and effects on the fetoplacental unit. Several genes have been associated with syndromes including catecholamine-secreting tumors, and positive genetic testing can correlate with tumor behavior. Timing and modalities for tumor removal and delivery, including anesthetic management, depend on gestational age, maternal and fetal wellbeing, control of catecholamine excess, suspicion of multiple or malignant disease, and surgical accessibility to the tumor. CONCLUSION: A timely diagnosis and a multidisciplinary approach are the keys to improve pregnancy outcomes in patients with a catecholamine-secreting tumor; each case should be managed in a tertiary referral center. PMID- 26536139 TI - A Case Presentation. PMID- 26536140 TI - IMPACT OF ETHNIC BACKGROUND ON CLINICAL CHARACTERISTICS AND CARDIOVASCULAR RISK FACTORS AMONG PATIENTS WITH PRIMARY HYPERPARATHYROIDISM. AB - OBJECTIVE: To compare initial laboratory values and cardiovascular risk factors (CRF) among patients with primary hyperparathyroidism (PHPT) of different ethnic backgrounds. METHODS: In this retrospective study, we reviewed 500 charts of PHPT patients who presented at Robert Wood Johnson University Hospital from January 2000 to December 2013. Among these patients were 46 African Americans (AA), 31 Asians (A), 19 Hispanics (H), and 404 Caucasians (C). The following characteristics were compared between the groups: age; body mass index (BMI); levels of serum calcium, intact parathyroid hormone (iPTH), 25-OH vitamin D, and 24-hour urine calcium; and parathyroid adenoma weight. Presence of CRF including BMI, diabetes mellitus, hypertension, and hyperlipidemia were also recorded for comparison. Associations of adenoma weight and several other parameters were also assessed. RESULTS: Among different ethnic groups, AA patients with PHPT had higher iPTH levels compared to the A and C groups (P<.05), while 25-OHD levels were lower in the AA compared to the A and C groups (P<.05). Adenoma weight was significantly greater in AA than in C and A PHPT patients (P<.01). Adenoma weight was positively correlated with iPTH levels (r = 0.493, P <.001) and serum calcium levels (r = 0.255, P<.01). The group BMIs were C: 29.5 +/- 6.9, AA: 33.8 +/- 10, A: 24.7 +/- 3.3, and H: 30.2 +/- 6.6. AA patients had a lower rate of renal stones (9%) compared to other groups (21-29%, P<.05). CONCLUSION: The results of our study indicate that AA patients with PHPT presented with a more severe PHPT profile but had lower 24-hour urine calcium and fewer renal stones. AA patients with PHPT also had higher prevalence of CRF when compared to A and C. PMID- 26536141 TI - Evaluation of a novel portable x-ray fluorescence screening tool for detection of arsenic exposure. AB - A new portable x-ray fluorescence (XRF) screening tool was evaluated for its effectiveness in arsenic (As) quantification in human finger and toe nails ([Formula: see text]). Nail samples were measured for total As concentration by XRF and inductively coupled plasma-mass spectrometry (ICP-MS). Using concordance correlation coefficient (CCC), kappa, diagnostic sensitivity (Sn) and specificity (Sp), and linear regression analyses, the concentration of As measured by XRF was compared to ICP-MS. The CCC peaked for scaled values of fingernail samples, at 0.424 (95% CI: 0.065-0.784). The largest kappa value, 0.400 (95% CI: -0.282 1.000), was found at a 1.3 MUg g(-1) cut-off concentration, for fingernails only, and the largest kappa at a clinically relevant cut-off concentration of 1.0 MUg g(-1) was 0.237 (95% CI: -0.068-0.543), again in fingernails. Analyses generally showed excellent XRF Sn (up to 100%, 95% CI: 48-100%), but low Sp (up to 30% for the same analysis, 95% CI: 14-50%). Portable XRF shows some potential for use as a screening tool with fingernail samples. The difference between XRF and ICP-MS measurements decreased as sample mass increased to 30 mg. While this novel method of As detection in nails has shown relatively high agreement in some scenarios, this portable XRF is not currently considered suitable as a substitute for ICP MS. PMID- 26536142 TI - Hauser-Heck: Efficient Synthesis of gamma-Aryl-beta-ketoesters en Route to Substituted Naphthalenes. AB - gamma-Aryl-beta-ketoesters can be prepared in one step from aryl bromides and bis(trimethylsilyl) enol ethers using catalytic amounts of Pd(dba)2/t-Bu3P and stoichiometric amounts of Bu3SnF. The wide range of gamma-(hetero)aryl-beta ketoesters that can be obtained illustrate the scope and limitations of this novel Hauser-Heck combination. gamma-Aryl-beta-ketoesters with a 1,3-dioxane acetal in the ortho position can easily be transformed into the hydroxy naphthoate in very good yield. Aqueous formic acid at 65 degrees C provides optimal conditions for this deprotective aromatization. PMID- 26536143 TI - Ovarian steroids alter dopamine receptor populations in the medial preoptic area of female rats: implications for sexual motivation, desire, and behaviour. AB - Dopamine (DA) transmission in the medial preoptic area (mPOA) plays a critical role in the control of appetitive sexual behaviour in the female rat. We have shown previously that a DA D1 receptor (D1R)-mediated excitatory state appears to occur in females primed with estradiol benzoate (EB) and progesterone (P), whereas a DA D2 receptor (D2R)-mediated inhibitory state appears to occur in females primed only with EB. The present experiment employed three techniques to better understand what changes occur to DA receptors (DARs) in the mPOA under different hormonal profiles. Ovariectomized females were randomly assigned to one of three steroid treatment groups: EB + P (10 and 500 MUg, respectively), EB + Oil, or the control (Oil + Oil), with hormone injections administered at 48 and 4 h prior to euthanizing. First, the number of neurons in the mPOA that contained D1R or D2R was assessed using immunohistochemistry. Second, the mPOA and two control areas (the prelimbic cortex and caudate putamen) were analysed for DAR protein levels using western blot, and DAR functional binding levels using autoradiography. Ovarian steroid hormones affected the two DAR subtypes in opposite ways in the mPOA. All three techniques supported previous behavioural findings that females primed with EB have a lower D1R : D2R ratio, and thus a D2R mediated system, and females primed with EB + P have a higher D1R : D2R ratio, and thus a D1R-mediated system. This provides strong evidence for a DA-driven pathway of female sexual motivation, desire, and behaviour that is modified by different hormone priming regimens. PMID- 26536144 TI - A Ferredoxin Disulfide Reductase Delivers Electrons to the Methanosarcina barkeri Class III Ribonucleotide Reductase. AB - Two subtypes of class III anaerobic ribonucleotide reductases (RNRs) studied so far couple the reduction of ribonucleotides to the oxidation of formate, or the oxidation of NADPH via thioredoxin and thioredoxin reductase. Certain methanogenic archaea contain a phylogenetically distinct third subtype of class III RNR, with distinct active-site residues. Here we report the cloning and recombinant expression of the Methanosarcina barkeri class III RNR and show that the electrons required for ribonucleotide reduction can be delivered by a [4Fe 4S] protein ferredoxin disulfide reductase, and a conserved thioredoxin-like protein NrdH present in the RNR operon. The diversity of class III RNRs reflects the diversity of electron carriers used in anaerobic metabolism. PMID- 26536145 TI - INFANT AVOIDANCE DURING A TACTILE TASK PREDICTS AUTISM SPECTRUM BEHAVIORS IN TODDLERHOOD. AB - The experience of touch is critical for early communication and social interaction; infants who show aversion to touch may be at risk for atypical development and behavior problems. The current study aimed to clarify predictive associations between infant responses to tactile stimuli and toddler autism spectrum, internalizing, and externalizing behaviors. This study measured 9-month old infants' (N = 561; 58% male) avoidance and negative affect during a novel tactile task in which parents painted infants' hands and feet and pressed them to paper to make a picture. Parent reports on the Pervasive Developmental Problems (PDP), Internalizing, and Externalizing scales of the Child Behavior Checklist were used to measure toddler behaviors at 18 months. Infant observed avoidance and negative affect were significantly correlated; however, avoidance predicted subsequent PDP scores only, independent of negative affect, which did not predict any toddler behaviors. Findings suggest that incorporating measures of responses to touch in the study of early social interaction may provide an important and discriminating construct for identifying children at greater risk for social impairments related to autism spectrum behaviors. PMID- 26536146 TI - Inhibitory effects of retigabine, a Kv7 channel activator, on mechanosensitive primary bladder afferent activities and nociceptive behaviors in rats. AB - AIMS: Kv7 voltage-gated potassium channels have been suggested to modulate mechano-afferent transduction and nociception in the bladder. We investigated the effects of retigabine, a Kv7 channel activator, on rhythmic bladder contractions (RBCs), and single-unit afferent activities (SAAs) of the primary bladder mechanosensitive afferent nerve fibers in urethane-anesthetized rats. In addition, the effects of pretreatment with retigabine on the nociceptive behaviors provoked by an intravesical instillation of resiniferatoxin (RTX) were evaluated in the conscious condition. METHODS: Female Sprague-Dawley rats were used. Under urethane anesthesia, saline was instilled into the bladder until RBCs were induced reproducibly. Then, the effects of intravenous, cumulative administrations of retigabine (0.1-3 mg/kg) or vehicle (saline) on RBCs were assessed. In separate animals, SAAs of Adelta- and C-fibers were identified by electrical stimulation of the pelvic nerve and by bladder distention with saline. After baseline recording, vehicle or retigabine (0.01-1 mg/kg) was administered intravenously and further recordings were performed. Under pretreatment with vehicle or retigabine (3 mg/kg intraperitoneally), the frequencies of lower abdominal licking and freezing were counted and scored as the bladder nociceptive behaviors induced by intravesical RTX instillation (3 uM, 0.3 ml). RESULTS: Retigabine dose-dependently decreased both the frequency and the amplitude of RBCs and SAAs of both Adelta- and C-fibers. The effect on RBCs was more potent on the frequency than the amplitude. Retigabine inhibited the RTX-induced abdominal licking, but not freezing. CONCLUSION: Kv7 channels are likely to be implicated in inhibition of bladder mechano- and nociceptive sensory transduction. Neurourol. Urodynam. 36:280-285, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26536147 TI - Six-Coordinate Zinc Porphyrins for Template-Directed Synthesis of Spiro-Fused Nanorings. AB - Five-coordinate geometry is the standard binding mode of zinc porphyrins with pyridine ligands. Here we show that pseudo-octahedral six-coordinate zinc porphyrin complexes can also be formed in solution, by taking advantage of the chelate effect. UV-vis-NIR titrations indicate that the strength of this second coordination is ca. 6-8 kJ mol(-1). We have used the formation of six-coordinate zinc porphyrin complexes to achieve the template-directed synthesis of a 3D pi conjugated spiro-fused array of 11 porphyrin units, covalently connected in a nontrivial topology. Time-resolved fluorescence anisotropy experiments show that electronic excitation delocalizes between the two perpendicular nanorings of this spiro-system within the experimental time-resolution of 270 fs. PMID- 26536148 TI - Domain Motion Enhanced (DoME) Model for Efficient Conformational Sampling of Multidomain Proteins. AB - Large conformational changes of multidomain proteins are difficult to simulate using all-atom molecular dynamics (MD) due to the slow time scale. We show that a simple modification of the structure-based coarse-grained (CG) model enables a stable and efficient MD simulation of those proteins. "Motion Tree", a tree diagram that describes conformational changes between two structures in a protein, provides information on rigid structural units (domains) and the magnitudes of domain motions. In our new CG model, which we call the DoME (domain motion enhanced) model, interdomain interactions are defined as being inversely proportional to the magnitude of the domain motions in the diagram, whereas intradomain interactions are kept constant. We applied the DoME model in combination with the Go model to simulations of adenylate kinase (AdK). The results of the DoME-Go simulation are consistent with an all-atom MD simulation for 10 MUs as well as known experimental data. Unlike the conventional Go model, the DoME-Go model yields stable simulation trajectories against temperature changes and conformational transitions are easily sampled despite domain rigidity. Evidently, identification of domains and their interfaces is useful approach for CG modeling of multidomain proteins. PMID- 26536149 TI - A Bayesian missing data framework for generalized multiple outcome mixed treatment comparisons. AB - Bayesian statistical approaches to mixed treatment comparisons (MTCs) are becoming more popular because of their flexibility and interpretability. Many randomized clinical trials report multiple outcomes with possible inherent correlations. Moreover, MTC data are typically sparse (although richer than standard meta-analysis, comparing only two treatments), and researchers often choose study arms based upon which treatments emerge as superior in previous trials. In this paper, we summarize existing hierarchical Bayesian methods for MTCs with a single outcome and introduce novel Bayesian approaches for multiple outcomes simultaneously, rather than in separate MTC analyses. We do this by incorporating partially observed data and its correlation structure between outcomes through contrast-based and arm-based parameterizations that consider any unobserved treatment arms as missing data to be imputed. We also extend the model to apply to all types of generalized linear model outcomes, such as count or continuous responses. We offer a simulation study under various missingness mechanisms (e.g., missing completely at random, missing at random, and missing not at random) providing evidence that our models outperform existing models in terms of bias, mean squared error, and coverage probability then illustrate our methods with a real MTC dataset. We close with a discussion of our results, several contentious issues in MTC analysis, and a few avenues for future methodological development. PMID- 26536150 TI - Painful and Pruritic Papules in the Gray Shading of a Tattoo. PMID- 26536151 TI - The benefits of recycling: how photosynthetic bark can increase drought tolerance. PMID- 26536152 TI - Corrigendum. PMID- 26536153 TI - Corrigendum. PMID- 26536154 TI - Self-reported Determinants of Access to Surgical Care in 3 Developing Countries. AB - IMPORTANCE: Surgical care is recognized as a growing component of global public health. OBJECTIVE: To assess self-reported barriers to access of surgical care in Sierra Leone, Rwanda, and Nepal using the validated Surgeons OverSeas Assessment of Surgical Need tool. DESIGN, SETTING, AND PARTICIPANTS: Data for this cross sectional, cluster-based population survey were collected from households in Rwanda (October 2011), Sierra Leone (January 2012), and Nepal (May and June 2014) using the Surgeons OverSeas Assessment of Surgical Need tool. MAIN OUTCOMES AND MEASURES: Basic demographic information, cost and mode of transportation to health care facilities, and barriers to access to surgical care of persons dying within the past year were analyzed. RESULTS: A total of 4822 households were surveyed in Nepal, Rwanda, and Sierra Leone. Primary health care facilities were commonly reached rapidly by foot (>70%), transportation to secondary facilities differed by country, and public transportation was ubiquitously required for access to a tertiary care facility (46%-82% of respondents). Reasons for not seeking surgical care when needed included no money for health care (Sierra Leone: n = 103; 55%), a person dying before health care could be arranged (all countries: 32%-43%), no health care facility available (Nepal: n = 11; 42%), and a lack of trust in health care (Rwanda: n = 6; 26%). CONCLUSIONS AND RELEVANCE: Self-reported determinants of access to surgical care vary widely among Sierra Leone, Rwanda, and Nepal, although commonalities exist. Understanding the epidemiology of barriers to surgical care is essential to effectively provide surgical service as a public health commodity in developing countries. PMID- 26536155 TI - Site-Specific Protein N- and O-Glycosylation Analysis by a C18-Porous Graphitized Carbon-Liquid Chromatography-Electrospray Ionization Mass Spectrometry Approach Using Pronase Treated Glycopeptides. AB - The analysis of N- and O-glycopeptides remains challenging due to the microheterogeneity (different glycoforms attached to one glycosylation site) and macroheterogeneity (site occupancy) of the glycoprotein. Trypsin is by far the most commonly used protease in glycoproteomic studies; however, it often results in long peptides that can harbor more than one glycan which may hamper site identification. The use of unspecific proteases such as Pronase can largely overcome this problem by generating glycopeptides with a small peptide portion. While the resulting glycopeptides are very useful for tandem mass spectrometric investigation, the analysis with conventional 1D-LC-ESI-MS/MS approaches can lead to incomplete glycosylation coverage because of the very heterogeneous physicochemical properties of the glycopeptides depending on the peptide sequence as well as the size and charges of the glycan moiety. Here, we describe a universal workflow for site-specific N- and O-glycopeptide analysis of Pronase treated glycoproteins with integrated, sequential C18 reverse phase and porous graphitized carbon-LC-ESI-QTOF-MS/MS employing a combination of lower- and enhanced-energy collision-induced dissociation. The approach was evaluated on glycoprotein standards and also applied to investigate the glycosylation of human IgG3 providing details on the hitherto uncharacterized glycosylation site Asn392 of the CH3 domain. This analytical tool can be applied to a variety of glycoproteins for site-specific N- and O-glycopeptide analysis, resulting in a good glycopeptide coverage within a single sample run and, thus, requiring only small amounts of sample. PMID- 26536156 TI - TranQuill sling snoreplasty for snoring: A single-arm pilot study for safety and effectiveness. AB - OBJECTIVES/HYPOTHESIS: Determine safety and efficacy of the TranQuill Sling Snoreplasty (TSS) (Surgical Specialties Corp., Vancouver, BC, Canada) for the treatment of snoring in adults with benign snoring or mild obstructive sleep apnea. STUDY DESIGN: Prospective, unblinded, single-center pilot study. METHODS: From February 2014 to July 2014, 20 adult patients with chronic, disruptive snoring assessed by bed partner were recruited to undergo TSS. Subjects with apnea hypopnea index < 15, minimum oxygen saturation > 85%, and body mass index (BMI) < 32 were included. Outcomes were assessed comparing the results of quality of-life questionnaires, bed partner-assessed snoring, pain visual analog scales, WatchPAT (Itamar Medical Ltd, Caesarea Ind. Park, Israel) home sleep studies, and flexible endoscopy at baseline and 90-day follow-up. RESULTS: Thirteen males and seven females were enrolled. Average age was 49.1 (range 31-67) and BMI of 25.8 +/- 2.66. TranQuill Sling Snoreplasty significantly reduced snoring symptom scores from 8.70 +/- 4.27 to 6.42 +/- 4.14, P = 0.012. Snoring visual analog scores demonstrated reduction of 17.8 mm (59.4 mm +/- 22.1 to 41.6 mm +/- 29.2), P = 0.0184. Thirty-five percent (7/20) of subjects reported complications related to the trial, with no serious adverse events. CONCLUSION: TranQuill Sling Snoreplasty is a safe therapy that improves snoring symptoms in most adult subjects with benign snoring or mild sleep apnea. Further study is required to better identify patients likely to respond to the therapy. PMID- 26536157 TI - Proteomic Profiling of Serum-Derived Exosomes from Ethnically Diverse Prostate Cancer Patients. AB - Prostate cancer (PCa) remains the most frequently diagnosed male malignancy in Western countries and the second most common cause of male cancer death in the United States. The relatively elevated PCa incidence and mortality among African American men makes this cancer type a challenging health disparity disease. To increase the chance for successful trea tment, earlier detection and prediction of tumor aggress iveness will be important and need to be resolved. This study demonstrates that small membrane-bound vesicles shed from the tumor called exosomes contain ethnically and tumor-specific biomarkers, and could be exploited for their diagnostic and therapeutic potential. PMID- 26536160 TI - Experimental and theoretical studies of spectroscopic properties of simple symmetrically substituted diphenylbuta-1,3-diyne derivatives. AB - A series of symmetrically substituted diphenylbuta-1,3-diyne (DPB) derivatives possessing electron-donating (N,N-dimethylamino or methoxy) or electron-accepting (nitrile, ester or aldehyde) groups have been prepared and studied with emphasis on their spectral and photophysical properties. The photophysical characteristics of these compounds have been studied in relation to their structures and influence of solvents or temperature. The observed spectral and photophysical properties are explained with the help of potential energy maps in the ground and excited states obtained from density functional theory (DFT, B3LYP, def2TZVP basis set) calculations. The structure-property relationship of all of the compounds is discussed and compared with appropriate diphenylacetylene derivatives. PMID- 26536161 TI - Amorfrutins are efficient modulators of peroxisome proliferator-activated receptor gamma (PPARgamma) with potent antidiabetic and anticancer properties: a patent evaluation of WO2014177593 A1. AB - INTRODUCTION: PPARgamma is an essential regulator of lipid, glucose, and insulin metabolism. PPARgamma full agonists, such as thiazolidinediones, are the mainstay drugs for the treatment of type 2 diabetes; however, undesirable clinical side effects have contributed to poor compliance with therapy and limited their full therapeutic potential. In the last few years, many efforts have been made in the discovery and development of selective PPARgamma modulators (SPPARgammaMs) as safer alternatives to PPARgamma full agonists. AREAS COVERED: This application claims the plant-derived amorfrutins or their synthetic analogs as SPPARgammaMs with potential to exhibit glucose-lowering effects without provoking side effects associated with full PPARgamma activation. Specifically, the in vivo glucose lowering properties of the high-affinity SPPARgammaM amorfrutin B are described. Moreover, examples of this class of compounds exhibit interesting antiproliferative activities. EXPERT OPINION: The patent (WO2014177593 A1) under discussion proposes enriching functional food products or phytomedical extracts with safe licorice extracts, containing sufficient amounts of amorfrutins, with the ultimate goal of inhibiting the early development of disorders such as insulin resistance. Interestingly, some example compounds show anticancer properties in colon, prostate, and breast malignancies. However, further in vivo investigations of the claimed compounds for these specific indications will be necessary to definitively support their clinical applications. PMID- 26536162 TI - Using DNA origami nanostructures to determine absolute cross sections for UV photon-induced DNA strand breakage. AB - We have characterized ultraviolet (UV) photon-induced DNA strand break processes by determination of absolute cross sections for photoabsorption and for sequence specific DNA single strand breakage induced by photons in an energy range from 6.50 to 8.94 eV. These represent the lowest-energy photons able to induce DNA strand breaks. Oligonucleotide targets are immobilized on a UV transparent substrate in controlled quantities through attachment to DNA origami templates. Photon-induced dissociation of single DNA strands is visualized and quantified using atomic force microscopy. The obtained quantum yields for strand breakage vary between 0.06 and 0.5, indicating highly efficient DNA strand breakage by UV photons, which is clearly dependent on the photon energy. Above the ionization threshold strand breakage becomes clearly the dominant form of DNA radiation damage, which is then also dependent on the nucleotide sequence. PMID- 26536163 TI - Normalising advance care planning in a general medicine service of a tertiary hospital: an exploratory study. AB - Objective The aim of the present study was to develop, implement and explore the effects of a program in advance care planning (ACP) within a tertiary hospital general medicine service. Methods Before-after exploratory mixed-methods analysis was conducted of an ACP program comprising seven components designed to overcome well-documented barriers to ACP in clinical practice. The results of pre-ACP program audits performed in June 2014 were compared with those of post-ACP audits performed over 5 months from July to November 2014. The main outcome measure was the number of advance care plans completed in patients considered eligible for ACP based on a life expectancy of 12 months or less as assessed by two prognostication instruments. Questionnaire surveys ascertained staff perceptions of ACP and the usefulness of training and resources in ACP. Results Pre-ACP program analysis of 166 consecutive patients deemed eligible for ACP revealed that only 1% had a documented advance care plan. Following ACP implementation, 115 of 215 (53%) potentially eligible patients were considered able to participate in ACP discussions and were approached to do so before discharge, of whom 89 (77.4%) completed an advance care plan, whereas 26 (23.6%) declined. This equated to an overall completion rate for all potentially eligible patients of 41% compared to 1% pre-ACP (P<0.001). Major barriers to ACP perceived by at least 30% of questionnaire respondents included the reluctance of patients and family to discuss ACP, insufficient time to initiate or complete ACP, patient and/or family factors that rendered ACP impractical, inadequate communication skills around end-of-life issues, confusion about who was primarily responsible for conducting ACP and difficulty using ACP documentation forms. Enabling factors included dedicated ACP workshops, facilitator and resource packages for staff, and ACP brochures for patients and family. Conclusion A multifaceted ACP program in a general medicine service led to completion of an advance care plan in more than three of four patients considered eligible for, and who participated in, ACP. However, although program components were tailored to overcome known barriers to ACP, staff indicated ongoing difficulties, with less than half of ACP eligible patients completing advance care plans. What is known about this topic? Advance care planning is increasingly recognised as an important part of hospital care for older patients with advanced chronic disease. However, research indicates that ACP discussions are rare in hospital settings because of various barriers that are not adequately addressed in the design of ACP programs. What does this paper add? The present exploratory study of the development, implementation and evaluation of an ACP program in a tertiary hospital general medicine service shows that program components designed to overcome specific barriers to ACP discussions was associated with a >75% completion rate of advance care plans among ACP-eligible patients who participated in ACP discussions. Dedicated staff training and resources in ACP, employment of an ACP facilitator and ready access to ACP documentation forms were important enabling strategies. What are the implications for practitioners? Hospital units caring for significant numbers of older patients with limited life expectancy can implement ACP programs that help normalise ACP discussions within routine clinical care. PMID- 26536164 TI - Ba3Pt4Al4-Structure, Properties, and Theoretical and NMR Spectroscopic Investigations of a Complex Platinide Featuring Heterocubane [Pt4Al4] Units. AB - Ba3Pt4Al4 was prepared from the elements in niobium ampules and crystallizes in an orthorhombic structure, space group Cmcm (oP44, a = 1073.07(3), b = 812.30(3), c = 1182.69(3) pm) isopointal to the Zintl phase A2Zn5As4 (A = K, Rb). The structure features strands of distorted [Pt4Al4] heterocubane-like units connected by condensation over Pt/Al edges. These are arranged in a hexagonal rod packing by further condensation over Pt and Al atoms with the barium atoms located inside cavities of the [Pt4Al4](delta-) framework. Structural relaxation confirmed the electronic stability of the new phase, while band structure calculations indicate metallic behavior. Crystal orbital Hamilton bonding analysis coupled with Bader effective charge analysis suggest a polar intermetallic phase in which strong Al-Pt covalent bonds are present, while a significant electron transfer from Ba to the [Pt4Al4](delta-) network is found. By X-ray photoelectron spectroscopy measurements the Pt 4f5/2 and 4f7/2 energies for Ba3Pt4Al4 were found in the range of those of elemental Pt due to the electron transfer of Ba, while PtAl and PtAl2 show a pronounced shift toward a more cationic platinum state. (27)Al magic-angle spinning NMR investigations verified the two independent crystallographic Al sites with differently distorted tetrahedrally coordinated [AlPt4] units. Peak assignments could be made based on both geometrical considerations and in relation to electric field gradient calculations. PMID- 26536165 TI - Cabozantinib for the treatment of progressive metastatic medullary thyroid cancer. AB - Cabozantinib (XL-184) is a potent inhibitor of MET, VEGFR 2/KDR, RET and other receptor tyrosine kinases, such as KIT, AXL and FLT3. Its efficacy against MTC has been demonstrated in a prospective, randomized, placebo-controlled study (EXAM). Cabozantinib comparing to placebo significantly prolonged progression free survival both in hereditary and sporadic MTC, 11.2 vs 4.0 months, respectively. Final analysis showed no global differences in overall survival (OS) between cabozantinib and placebo. However, in a subgroup with RET M918T mutation the difference in OS was significant: 44.3 vs 18.9 months, respectively. Among the most frequent cabozantinib-related adverse events (AEs), observed in >30% of patients were diarrhea, palmar-plantar erythrodysesthesia, decreased weight, decreased appetite, nausea, fatigue, dysgeusia, hair color changes and hypertension. Expert Commentary: Cabozantinib constitutes an effective treatment option with acceptable toxicity in MTC patients showing either germinal or sporadic tumor RET M918T mutation as the drug prolonged OS in these subjects. PMID- 26536166 TI - Exchangeable Mimics of DPPC and DPPG Exhibiting Similar Nearest-Neighbor Interactions in Fluid Bilayers. AB - The interactions between an exchangeable mimic of 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC), Phos(+/-), with an exchangeable mimic of cholesterol, Chol, have been analyzed in fluid bilayers by means of nearest-neighbor recognition measurements. These interactions have been found to be very similar to those of an exchangeable mimic of 1,2-dipalmitoyl-sn-glycerol-3-phospho-(1'rac glycerol) (DPPG), Phos(-), interacting with Chol. Thus, both phospholipids have a similar preference for becoming nearest-neighbors of Chol in the liquid-ordered (l0) phase, and both mix, ideally, with Chol in the liquid-disordered (ld) phase. These findings, together with the almost negligible screening effects found for the latter, provide strong evidence that electrostatic forces play a minor role in the preference that both phospholipids have in becoming a favored nearest neighbor of Chol. They also imply that the main driving force for forming the liquid-ordered phase, and for defining the lateral organization of this phase, is an intrinsic affinity that high-melting lipids and cholesterol have for each other. PMID- 26536167 TI - Incidence of invasive pneumococcal disease in 5-15 year old children with and without comorbidities in Germany after the introduction of PCV13: Implications for vaccinating children with comorbidities. AB - OBJECTIVE: To describe the burden of suffering from IPD in children aged 5-15 years with and without comorbidities up to 5 years after the introduction of PCV13 in Germany and to identify the potential benefit for PCV13 and PPV23 vaccination. METHODS: The surveillance of IPD for children <16 years was based on two independently reporting sources: active surveillance in pediatric hospitals and a laboratory-based sentinel surveillance system. CASE DEFINITION: IPD with cultural detection of pneumococci at a physiologically sterile site in children from 2010 to 2014 in Germany. Incidence was estimated by capture-recapture analysis with stratification by absence/presence of comorbidities. Coverage of the observed serotypes by different vaccines was assessed. RESULTS: 142 (Capture recapture-corrected: 437) cases were reported: 72.5% were healthy children and 27.5% had a comorbidity. The incidence of IPD related to children with comorbidities was 0.2 per 100,000. One third of these cases had serotypes not included in either vaccine. The remaining cases might benefit from pneumococcal vaccination but one third of all cases was not vaccinated. The additional potential benefit of PPV23 compared to PCV13 with respect to coverage was 10%. CONCLUSION: The incidence of IPD in children with comorbidities in Germany is low. Pneumococcal vaccination uptake in children with comorbidities should be increased, although only about two-thirds of the cases might be preventable by presently available vaccines. PMID- 26536168 TI - Testing multiple hypotheses with skewed alternatives. AB - In many practical cases of multiple hypothesis problems, it can be expected that the alternatives are not symmetrically distributed. If it is known a priori that the distributions of the alternatives are skewed, we show that this information yields high power procedures as compared to the procedures based on symmetric alternatives when testing multiple hypotheses. We propose a Bayesian decision theoretic rule for multiple directional hypothesis testing, when the alternatives are distributed as skewed, under a constraint on a mixed directional false discovery rate. We compare the proposed rule with a frequentist's rule of Benjamini and Yekutieli (2005) using simulations. We apply our method to a well studied HIV dataset. PMID- 26536170 TI - Neonatal BCG vaccination of mice improves neurogenesis and behavior in early life. AB - Bacillus Calmette-Guerin (BCG) is administered to neonates worldwide, but it is still unknown whether this neonatal vaccination affects brain development during early postnatal life, despite the close association of the immune system with the brain. Newborn C57BL/6 mice were injected subcutaneously with BCG or phosphate buffered saline (PBS) and their mood status and spatial cognition were observed at four and eight weeks (w) old. The mice were also subjected to tests at 2 and 6 w to examine BCG's effects on neurogenesis, the hippocampal microglia phenotype and number, and the expression of hippocampal neuroimmune molecules and peripheral cytokines. The BCG-injected mice showed better behavioral performances at 4 w. We observed elevated neurogenesis, M2 microglial activation and a neurotrophic profile of neuroimmune molecules [more interferon (IFN)-gamma, interleukin (IL)-4, transforming growth factor (TGF)-beta, brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF)-1 and less tumor necrosis factor (TNF)-alpha and IL-1beta] in the hippocampus of the 2-w-old BCG mice. In the periphery, BCG induced a T helper (Th)-1 serum response. At the individual level, there were positive correlations between the serum IFN-gamma/IL 4 ratio and the levels of neurotrophins and neurogenesis in the hippocampus. These findings suggest that neonatal BCG vaccination improved neurogenesis and mouse behavior in early life by affecting the neuroimmune milieu in the brain, which may be associated with a systemic Th1 bias. PMID- 26536171 TI - Imitation dynamics of vaccine decision-making behaviours based on the game theory. AB - Based on game theory, we propose an age-structured model to investigate the imitation dynamics of vaccine uptake. We first obtain the existence and local stability of equilibria. We show that Hopf bifurcation can occur. We also establish the global stability of the boundary equilibria and persistence of the disease. The theoretical results are supported by numerical simulations. PMID- 26536172 TI - The Role of Somatosensory Information in Speech Perception: Imitation Improves Recognition of Disordered Speech. AB - PURPOSE: Perceptual learning paradigms involving written feedback appear to be a viable clinical tool to reduce the intelligibility burden of dysarthria. The underlying theoretical assumption is that pairing the degraded acoustics with the intended lexical targets facilitates a remapping of existing mental representations in the lexicon. This study investigated whether ties to mental representations can be strengthened by way of a somatosensory motor trace. METHOD: Following an intelligibility pretest, 100 participants were assigned to 1 of 5 experimental groups. The control group received no training, but the other 4 groups received training with dysarthric speech under conditions involving a unique combination of auditory targets, written feedback, and/or a vocal imitation task. All participants then completed an intelligibility posttest. RESULTS: Training improved intelligibility of dysarthric speech, with the largest improvements observed when the auditory targets were accompanied by both written feedback and an imitation task. Further, a significant relationship between intelligibility improvement and imitation accuracy was identified. CONCLUSIONS: This study suggests that somatosensory information can strengthen the activation of speech sound maps of dysarthric speech. The findings, therefore, implicate a bidirectional relationship between speech perception and speech production as well as advance our understanding of the mechanisms that underlie perceptual learning of degraded speech. PMID- 26536173 TI - Preterm Infants' Mothers' Experiences With Milk Expression and Breastfeeding: An Integrative Review. AB - BACKGROUND: Preterm infants' mothers face several challenges when providing critical breast milk for their infants; therefore, sensitive and evidence-based counseling and support are needed. However, a general view of the experiences preterm infants' mothers can face during their infants' hospitalization and after discharge is lacking. PURPOSE: The aim of this integrative review was to explore practical and emotional experiences of preterm infants' mothers with respect to breast milk expression and breastfeeding, from the birth of the preterm infant, during the neonatal intensive care unit (NICU) stay, and postdischarge until the cessation of breastfeeding. METHODS/SEARCH STRATEGY: A systematic literature search from MEDLINE, CINAHL, PsycInfo, and Cochrane databases were performed. The search resulted in 20 qualitative and 3 quantitative studies. The data were analyzed by thematic analysis. FINDINGS: Coping was the central theme in mothers' experiences. The benefits of breast milk served both as a supportive factor and an obstructive factor for the mothers, and breastfeeding was used to rebuild connection and motherhood. Simultaneously, the mothers needed to cope with new demands, interfering NICU environment, demanding expressing, and difficulties with breastfeeding. IMPLICATIONS FOR PRACTICE: Expressing and breastfeeding are important for the mothers to contribute to their infants' care and to rebuild the interrupted connection. Evidence-based and sensitive informational and practical counseling are vital for the mothers. Intensive emotional support is important during encountered problems and during cessation. IMPLICATIONS FOR RESEARCH: Future research is needed about mothers' experiences using supplementation methods, test-weighing, exploring experiences of mothers of late-preterm infants, and the validity of the concept of coping with this phenomenon. PMID- 26536174 TI - Council of International Neonatal Nurses (COINN) Global Neonatal Provider Database Initiative (CGNPD): Results From an Implementation Focus Group. AB - BACKGROUND: The neonatal nurses are the key component of the essential workforce necessary to address the healthcare needs of the infants globally. The paucity of the data regarding the availability and training of the neonatal workforce challenges the stakeholders at the regional, national, and global levels. The lack of these data makes strategic planning for initiatives especially in low resourced countries difficult. Up-to-date data are critically needed to describe the role neonatal nurses play in global newborn health outcomes. PURPOSE: The purpose of the COINN Global Neonatal Provider Database Initiative (CGNPD) was to develop a workforce database by developing survey questions, conducting a focus group to determine the key reasons such a database was needed and how best to implement it, and incorporating these comments into the workforce survey and launch. Pilot testing of the draft survey instrument was done. This article reports on the findings from the focus group and the development of the survey. METHODS: A qualitative design using the focus group method was used. The focus group discussions were guided by semi-structured interview questions that had been developed prior to the focus group by neonatal experts. A convenience sample of 14 members from the international delegates and project advisory members who attended the COINN 2013 in Belfast, Northern Ireland, participated. These participants represented 10 countries. Thematic analysis was conducted using verbatim transcripts of the focus group data. RESULTS: Four main themes emerged: (1) the invisibility of neonatal nurses, (2) benchmarking needs for quality and standards, (3) need for partnership to implement the database, and (4) setting priorities for variables needed for the most salient database. IMPLICATIONS FOR PRACTICE: The questionnaire examined participants' perceptions of the significance of and the future utilization of the workforce database and elements that should be included in the survey. IMPLICATIONS FOR RESEARCH: The global neonatal workforce database is needed to describe who the neonatal nurses are in each country, what they do, how they are trained, and where they work. The data from the focus group aided in the development of the workforce survey that has been pilot tested and provides critical information to guide COINN's global implementation of the database project. PMID- 26536175 TI - A role of goals for social inhibition of return? AB - The social inhibition of return (sIOR) effect refers to the finding that response initiation times are longer if a movement is executed to a location where another person has responded to just before. Previous studies have examined the influence of the goal of the action on sIOR. In these studies, however, the movement endpoint and to-be-attained goal (e.g., touching/pressing a response key) were at the same spatial location. In the present two experiments, we disentangled movement endpoint and goal's identity and locations by means of introducing action effects that followed directly from a movement. Similar methods were previously shown powerful enough to clearly show the importance of action goals for other phenomena-a finding consistent with effect-based theories of action control, such as the ideomotor theory. The results of the present study revealed that sIOR was shaped by the movement endpoint location, not the goal's identity or location. That is, in both experiments, an sIOR effect was observed, but the magnitude of the sIOR effect was not modulated by repetitions/switches of goals or their locations. Thus, results indicate that goals play a negligible role in the emergence of the sIOR and, consequently, highlight the importance of action observation for the emergence of the sIOR effect. PMID- 26536176 TI - [Not Available]. PMID- 26536177 TI - [Not Available]. PMID- 26536178 TI - Development of a Disease-Modifying OA Drug (DMOAD) in Knee Osteoarthritis: The Example of Sprifermin. PMID- 26536169 TI - Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. AB - BACKGROUND: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist. METHODS: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis. RESULTS: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH). CONCLUSIONS: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.). PMID- 26536179 TI - From Bone Cell Biology to Novel Therapies of Osteoporosis. PMID- 26536180 TI - [Not Available]. PMID- 26536181 TI - [Not Available]. PMID- 26536182 TI - [Not Available]. PMID- 26536183 TI - [Not Available]. PMID- 26536184 TI - [Not Available]. PMID- 26536185 TI - [Not Available]. PMID- 26536186 TI - [Not Available]. PMID- 26536187 TI - [Not Available]. PMID- 26536188 TI - [Not Available]. PMID- 26536189 TI - [Not Available]. PMID- 26536190 TI - [Not Available]. PMID- 26536192 TI - Survival After Sublobar Resection Versus Lobectomy for Clinical Stage IA Lung Cancer: Analysis From the National Cancer Database. PMID- 26536194 TI - The Influence of the Evolution of First-Line Chemotherapy on Steadily Improving Survival in Advanced Non-Small-Cell Lung Cancer Clinical Trials. AB - Over the past three decades, survival in advanced non-small-cell lung cancer (NSCLC) clinical trials has doubled with an increase in 1-year survival from 25% to 50 to 55%. This has been mainly attributed to improvements in systemic therapy. Although modern first-line chemotherapy regimens have more favorable toxicity profiles, a statistically significant improvement in overall survival has not been demonstrated in existing meta-analyses of second-generation versus third-generation combinations. Moreover, pivotal trials demonstrating statistically significant survival superiority of third-generation regimens are consistently not reproducible even for nonsquamous populations using pemetrexed platinum combinations. As enhancement in the efficacy of first-line systemic therapy in patients without identifiable driver mutations is questionable, other factors are discussed that explain the doubling of 1-year survival reported in clinical trials. These factors include second-line or third-line therapy, maintenance chemotherapy, performance status selection, stage migration, sex migration, improved treatment of brain metastases, and better palliative care. PMID- 26536193 TI - The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. AB - INTRODUCTION: The aim of this study is to analyze all metastatic (M) categories of the current tumor, node, and metastasis (TNM) classification of lung cancer with the objective of providing suggestions for modifications of the M component in the next edition of the TNM classification for lung cancer. METHODS: The new International Association for the Study of Lung Cancer lung cancer database was created from 94,708 patients diagnosed as having lung cancer between 1999 and 2010. Including further patients submitted through the electronic data capture system to Cancer Research and Biostatistics until 2012, all together 1059 non small-cell lung cancer cases were available for a detailed analysis of the clinical M categories. Overall survival was calculated using the Kaplan-Meier method, and prognosis was assessed using a Cox proportional hazards regression analysis. RESULTS: No significant differences were found among the M1a (metastases within the chest cavity) descriptors. However, when M1b (distant metastases outside the chest cavity) were assessed according to the number of metastases, tumors with a single metastasis in a single organ had significantly better prognosis than those with multiple metastases in one or several organs. CONCLUSIONS: In this revision of the TNM classification, cases with pleural/pericardial effusions, contralateral/bilateral lung nodules, contralateral/bilateral pleural nodules, or a combination of multiple of these parameters should continue to be grouped as M1a category. Single metastatic lesions in a single distant organ should be newly designated to the M1b category. Multiple lesions in a single organ or multiple lesions in multiple organs should be reclassified as M1c category. This new division can serve as a first step into providing rational definitions for an oligometastatic disease stage in non-small cell lung cancer in the future. PMID- 26536195 TI - Clinicopathological and Survival Analysis of Japanese Patients with Resected Non Small-Cell Lung Cancer Harboring NKX2-1, SETDB1, MET, HER2, SOX2, FGFR1, or PIK3CA Gene Amplification. AB - INTRODUCTION: Gene amplification is an important genetic change in cancer cells. We investigated the prevalence, clinicopathological characteristics, and prognostic value of NKX2-1 (also known as TTF-1), SETDB1, MET, HER2, SOX2, FGFR1, and PIK3CA amplification in Japanese patients with non-small-cell lung cancer (NSCLC). METHODS: The copy numbers of the seven above-mentioned genes were assessed using fluorescence in situ hybridization in a tissue microarray containing 282 surgically resected NSCLC specimens (164 adenocarcinoma [AC], 99 squamous cell carcinoma [SCC], and 19 others). Clinicopathological information were obtained from the medical records. RESULTS: NKX2-1, SETDB1, MET, HER2, SOX2, FGFR1, and PIK3CA gene amplification were observed in 30 of 277 (10.8%), 16 of 280 (5.7%), 38 of 278 (13.7%), 8 of 270 (3.0%), 34 of 278 (12.2%), 18 of 282 (6.4%), and 53 of 278 (19.1%) cases, respectively. Coamplification was detected in 16 of 156 (10.3%) AC patients and 35 of 93 (37.6%) SCC patients (p < 0.0001). NKX2-1 amplification was significantly related to an AC histology (p = 0.004), whereas SOX2, FGFR1, and PIK3CA amplifications were related to a SCC histology (p < 0.0001). Within the ACs, NKX2-1 and SETDB1 amplifications were markers of a shorter survival period. A multivariate Cox proportional hazards model revealed that NKX2-1 amplification was an independent predictor of poor survival (hazard ratio, 2.938; 95% confidence interval, 1.434-6.022; p = 0.003). Coamplification had impact on patient outcome in AC but not in entire NSCLC and SCC. CONCLUSIONS: The amplification status differed among the histological types of NSCLC. NKX2-1 amplification was an independent and the most practically important predictor of a poor prognosis among Japanese patients with AC. PMID- 26536196 TI - Clinical Implications of Variant ALK FISH Rearrangement Patterns. AB - INTRODUCTION: Break-apart fluorescence in situ hybridization (FISH) is the FDA approved assay for detecting anaplastic lymphoma kinase (ALK) rearrangements in non-small-cell lung cancer (NSCLC), identifying patients who can gain dramatic benefit from ALK kinase inhibitors. Assay interpretation can be technically challenging, and either splitting of the 5' and 3' probes or loss of the 5' probe constitute rearrangement. We hypothesized that there may be clinical differences depending on rearrangement pattern on FISH. METHODS: An IRB-approved database of NSCLC patients at Dana-Farber Cancer Institute was queried for ALK rearrangement. Clinical characteristics and response to crizotinib were reviewed. Immunohistochemistry (IHC) and targeted next-generation sequencing (NGS) were obtained when available. RESULTS: Of 1614 NSCLC patients with ALK testing, 82 patients (5.1%) had ALK rearrangement by FISH: 30 patients with split signals, 25 patients with 5' deletion, and 27 patients with details unavailable. Patients with 5' deletion were older (p = 0.01) and tended to have more extensive smoking histories (p = 0.08). IHC was positive for ALK rearrangement in all 27 patients with FISH split signals, whereas three of 21 patients with FISH 5' deletion had negative IHC (p = 0.05). Targeted NGS on two of three cases with discordant FISH and IHC results did not identify ALK rearrangement, instead finding driver mutations in EGFR and KRAS. Patients with 5' deletion treated with crizotinib had a smaller magnitude of tumor response (p = 0.03). CONCLUSIONS: Patients with 5' deletion on ALK FISH harbor features less typical of ALK-rearranged tumors, potentially indicating that some cases with this variant are false positives. Corroborative testing with IHC or NGS may be beneficial. PMID- 26536197 TI - Spontaneous Pulmonary Torsion Secondary to Left Upper Lobe Malignancy. PMID- 26536198 TI - An Uncommon Presentation of Brain Metastases in a Lung Cancer Patient. PMID- 26536199 TI - Pruritus as a Paraneoplastic Symptom of Thymoma. PMID- 26536200 TI - Cytogenetic Assessment of the Rat Cell Line CLS-ACI-1: An in vitro Cell Model for Mycn Overexpression. AB - Breast cancer is a complex and heterogeneous disease, and the establishment of cell models in order to properly study the disease at the molecular and cellular level is of utmost importance. Here, we present the cytogenetic characterization and gene expression analysis of the tumoral mammary rat cell line CLS-ACI-1. The use of banding and molecular cytogenetic techniques allowed the description of the complex CLS-ACI-1 karyotype and the identification of breakpoints in clonal chromosome rearrangements. Moreover, a Mycn and Erbb2 comparative expression analysis by RT-qPCR was performed, revealing a high expression level of Mycn in CLS-ACI-1 cells. Moreover, a considerable number of putative mutated genes and chromosome alterations detected through cytogenetic analysis seem to be in the MYCN biological network. Therefore, the CLS-ACI-1 cell line is presented as a promising cell model for the study of the role of MYCN in breast cancer and also as a tool for developing appropriate cancer therapies, namely for Mycn targeting. PMID- 26536202 TI - DIVERSE AND TISSUE-SPECIFIC MITOCHONDRIAL RESPIRATORY RESPONSE IN A MOUSE MODEL OF SEPSIS-INDUCED MULTIPLE ORGAN FAILURE. AB - Mitochondrial function is thought to play a role in sepsis-induced multiple organ failure. However, the temporal and organ-specific alterations in mitochondrial function have yet to be fully elucidated. Many studies show reduced phosphorylating capacity, while others have indicated that mitochondrial respiration is enhanced. The objective of this study was to evaluate the temporal dynamics of brain and liver mitochondrial function in a mouse model of sepsis.Sepsis was induced by cecal ligation and puncture. Controls were sham operated. Using high-resolution respirometry, brain and liver homogenates from 31 C57BL/6 mice were analyzed at either 6 or 24 h. Reactive oxygen species (ROS) production was simultaneously measured in brain samples using fluorometry.Septic brain tissue exhibited an early increased uncoupling of respiration. Temporal changes between the two time points were diminutive and no difference in ROS production was detected.Liver homogenate from the septic mice displayed a significant increase in the respiratory control ratio at 6 h. In the 24-h group, the rate of maximal oxidative phosphorylation, as well as LEAK respiration, was significantly increased compared with controls and the resultant respiratory control ratio was also significantly increased. Maximal protonophore-induced respiratory (uncoupled) capacity was similar between the two treatment groups.The present study suggests a diverse and tissue-specific mitochondrial respiratory response to sepsis. The brain displayed an early impaired mitochondrial respiratory efficiency. In the liver the primary finding was a substantial activation of the maximal phosphorylating capacity. PMID- 26536201 TI - SYSTEM-WIDE MAPPING OF ACTIVATED CIRCUITRY IN EXPERIMENTAL SYSTEMIC INFLAMMATORY RESPONSE SYNDROME. AB - Sepsis-induced multiple organ dysfunction syndrome (MODS) is a major cause of morbidity and mortality in critically ill patients and remains impervious to most therapeutic interventions. We utilized a clinically relevant murine model of systemic inflammatory response syndrome (SIRS) during early MODS induced by ventilator-associated pneumonia to systematically delineate pathways dysregulated in lung, liver, and kidney. We focused on processes commonly activated across at risk organs and constructed an SIRS-associated network based on connectivity among the gene members of these functionally coherent pathways. Our analyses led to the identification of several putative drivers of early MODS whose expression was regulated by epidermal growth factor receptor. Our unbiased, integrative method is a promising approach to unravel mechanisms in system-wide disorders afflicting multiple compartments such as sepsis-induced MODS, and identify putative therapeutic targets. PMID- 26536203 TI - VISFATIN PROMOTES FOAM CELL FORMATION BY DYSREGULATING CD36, SRA, ABCA1, AND ABCG1 EXPRESSION IN RAW264.7 MACROPHAGES. AB - BACKGROUND: Visfatin is produced in and secreted from adipocytes. Increased circulating visfatin level is observed in obese subjects. Previous studies demonstrated that visfatin was involved in obesity-related cardiovascular diseases. AIMS: This study aims to explore the regulatory effects of adipokine visfatin on foam cell formation, a key step in the development of atherosclerosis. METHODS: Effect of visfatin on protein and mRNA expression of scavenger receptor and ATP binding cassette transporter in RAW264.7 macrophages were measured by western blotting and real-time RT-PCR. To confirm the influence of visfatin-regulated scavenger receptor and ATP binding cassette transporter to foam cell formation, the visfatin-caused changes of ox-LDL uptake, cholesterol efflux, and foam cell formation were determined. RESULTS: Visfatin significantly increased the expression of CD36 and scavenger receptor A (SRA), decreased the expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1), and had no effect on the expression of SR-B1. Visfatin increased oxidized-LDL (ox LDL) uptake and decreased cholesterol efflux, which increased foam cell formation. The PI3K inhibitor LY294002 blocked the effect of visfatin on the protein and mRNA expression levels of CD36, SRA, and ABCG1 and ox-LDL uptake and cholesterol efflux. The ERK inhibitor PD98059 also prevented visfatin-induced ABCA1 instability and subsequently decreased cholesterol efflux. CONCLUSIONS: Visfatin upregulated CD36 and SRA expression and downregulated ABCA1 and ABCG1 expression, subsequently increased ox-LDL uptake and decreased cholesterol efflux, and finally promoted foam cell formation via the PI3K- and ERK-dependent pathways. PMID- 26536205 TI - Review of nonsurgical/minimally invasive treatments and open myomectomy for uterine fibroids. AB - PURPOSE OF REVIEW: The main purpose of this review is to collect the most recent evidence with regards to safety and effectiveness of the nonsurgical and minimally invasive treatment options for uterine fibroids. RECENT FINDINGS: Among the nonsurgical options, uterine artery embolization (UAE), and in eligible patients, magnetic resonance-guided high-intensity focused ultrasound (MRgFUS) are emerging as effective alternatives to surgical options for treatment of symptomatic fibroids. MRgFUS is comparable to UAE, and appears to be a cost effective treatment option, especially in older women, although long-term data are awaited. The transvaginal route for radiofrequency ablation is a promising new nonsurgical alternative, which needs to be studied in larger trials to establish its safety and efficacy.The laparoscopic myomectomy results in less postoperative pain, reduced febrile morbidity, and shorter hospital stay when compared with open laparotomy. The newer robotic approach is comparable to traditional laparoscopic technique in short surgical outcomes but is associated with higher costs. Hysteroscopic myoma resection is an effective surgical intervention for submucous fibroids and prior misoprostol use can help in reducing cervical lacerations. SUMMARY: UAE and MRgFUS can be offered as an alternative nonsurgical option for eligible women with symptomatic fibroids. Laparoscopic myomectomy remains a safe and effective surgical option with advantage of less postoperative pain and faster recovery compared with open laparotomy for women who wish to retain their fertility options. PMID- 26536204 TI - Age and Long-Term Hormone Treatment Effects on the Ultrastructural Morphology of the Median Eminence of Female Rhesus Macaques. AB - The median eminence (ME) of the hypothalamus comprises the hypothalamic nerve terminals, glia (especially tanycytes) and the portal capillary vasculature that transports hypothalamic neurohormones to the anterior pituitary gland. The ultrastructure of the ME is dynamically regulated by hormones and undergoes organizational changes during development and reproductive cycles in adult females, but relatively little is known about the ME during aging, especially in nonhuman primates. Therefore, we used a novel transmission scanning electron microscopy technique to examine the cytoarchitecture of the ME of young and aged female rhesus macaques in a preclinical monkey model of menopausal hormone treatments. Rhesus macaques were ovariectomized and treated for 2 years with vehicle, estradiol (E2), or estradiol + progesterone (E2 + P4). While the overall cytoarchitecture of the ME underwent relatively few changes with age and hormones, changes to some features of neural and glial components near the portal capillaries were observed. Specifically, large neuroterminal size was greater in aged compared to young adult animals, an effect that was mitigated or reversed by E2 alone but not by E2 + P4 treatment. Overall glial size and the density and tissue fraction of the largest subset of glia were greater in aged monkeys, and in some cases reversed by E2 treatment. Mitochondrial size was decreased by E2, but not E2 + P4, only in aged macaques. These results contrast substantially with work in rodents, suggesting that the ME of aging macaques is less vulnerable to age-related disorganization, and that the effects of E2 on monkeys' ME are age specific. PMID- 26536206 TI - Management of fibroids in perimenopausal women. AB - PURPOSE OF REVIEW: This article reviews fibroids management in the perimenopausal period, and addresses future directions in care. RECENT FINDINGS: Aromatase inhibitors, selective estrogen receptor modulators and antiprogestogens for medical management and minimally surgical techniques are promising treatments. SUMMARY: The disease and the symptoms may persist in the peri and postmenopausal periods. The assumption that they will resolve with the onset of the menopause is too simplistic and not always valid. The number of perimenopausal women who wish to retain their uterus for reasons other than childbearing is increasing. The accurate diagnosis of these conditions may result in minor surgical or medical treatments being directed at the specific pathology and may avoid the need for major surgery. PMID- 26536207 TI - Current management of myomas: the place of medical therapy with the advent of selective progesterone receptor modulators. AB - PURPOSE OF REVIEW: To review the current management of myomas with the advent of selective progesterone receptor modulators. RECENT FINDINGS: Selective progesterone receptor modulators have proved effective and recent publications on the use of ulipristal acetate (UPA) have analyzed the performance of long-term intermittent utilization of 10 mg UPA given in repeated courses of 3 months. This long-term intermittent therapy maximizes the efficacy of UPA. Indeed, control of bleeding is achieved sooner after each course. With each subsequent course, a statistically greater number of patients show a fibroid volume reduction of more than 50%. SUMMARY: The choice of therapy is influenced by different factors, such as the severity of symptoms, tumor characteristics, age, and wish to preserve the uterus (and fertility). Use of UPA will undoubtedly modify the surgical approach. PMID- 26536208 TI - Update in family planning: hardware and software improvements. PMID- 26536209 TI - Immediate postpartum provision of long-acting reversible contraception. AB - PURPOSE OF REVIEW: The objective of this review is to describe current literature regarding the role and characteristics of long-acting reversible contraception (LARC) used immediately postpartum. RECENT FINDINGS: Copper and levonorgestrel intrauterine devices (IUDs) inserted immediately postpartum at the time of both vaginal and cesarean deliveries are associated with higher rates of continuation at 6-12 months when compared with IUDs placed at the postpartum visit (4-8 weeks after delivery), despite higher rates of expulsion. IUDs and contraceptive implants are cost-effective when used immediately postpartum, and they are associated with longer interpregnancy intervals. There is limited evidence regarding the effects of immediate postpartum LARC on breastfeeding. SUMMARY: Use of LARC methods in the immediate postpartum period is both effective and safe, and could reduce unmet need for contraception during this time. More research is needed to explore various immediate postpartum IUD insertion methods and the effects of immediate postpartum progestin-containing LARC on breastfeeding. PMID- 26536210 TI - Update on long-acting reversible methods. AB - PURPOSE OF REVIEW: The last several years have seen a number of important clinical and academic advances in long-acting reversible contraceptive (LARC) methods, such that many professional medical organizations now recommend these methods as first-line contraception for all women. RECENT FINDINGS: Recent data support the use of LARC in a variety of special circumstances including adolescents, nulliparous women and immediately postpartum and postabortion. Evidence also shows that traditional methods of pain control with intrauterine device (IUD) insertion and cervical preparation prior to insertion may not be warranted. Further, the extended use of IUDs is safer and more effective than previously realized. SUMMARY: The rising uptake of LARC methods in the United States has the potential to dramatically decrease undesired pregnancies and abortion rates, and should be considered an effective option in the majority of women. PMID- 26536211 TI - Hormonal contraceptive use and women's risk of HIV acquisition: priorities emerging from recent data. AB - PURPOSE OF REVIEW: Understanding whether hormonal contraception increases women's risk of HIV acquisition is a public health priority. This review summarizes recent epidemiologic and biologic data, and considers the implications of new evidence on research and programmatic efforts. RECENT FINDINGS: Two secondary analyses of HIV prevention trials demonstrated increased HIV risk among depot medroxyprogesterone acetate (DMPA) users compared with nonhormonal/no method users and norethisterone enanthate (NET-EN) users. A study of women in serodiscordant partnerships found no significant association for DMPA or implants. Two meta-analyses found elevated risks of HIV among DMPA users compared with nonhormonal/no method users, with no association for NET-EN or combined oral contraceptive pills. In-vitro and animal model studies identified plausible biological mechanisms by which progestin exposure could increase risk of HIV, depending on the type and dose of progestin, but such mechanisms have not been definitively observed in humans. SUMMARY: Recent epidemiologic and biologic evidence on hormonal contraception and HIV suggests a harmful profile for DMPA but not combined oral contraceptives. In limited data, NET-EN appears safer than DMPA. More research is needed on other progestin-based methods, especially implants and Sayana Press. Future priorities include updating modeling studies with new pooled estimates, continued basic science to understand biological mechanisms, expanding contraceptive choice, and identifying effective ways to promote dual method use. PMID- 26536212 TI - The use of pulsed CO2 lasers for the treatment of vulvovaginal atrophy. AB - PURPOSE OF REVIEW: This article reviews the literature regarding the safety and efficacy of the use of a pulsed CO2 laser for the treatment of vulvovaginal atrophy (VVA). RECENT FINDINGS: Prospective observational studies have demonstrated histological changes after the use of pulsed CO2 laser vaginally in atrophic conditions. Increased collagen and extracellular matrix production has been reported together with an increase in the thickness of the vaginal epithelium with the formation of new papilla. Three different observational studies reported a significant improvement of VVA assessed subjectively (with a 10-point visual analogue scale) and objectively (using the Vaginal Health Index) after a cycle of three treatments of pulsed CO2 laser. Also sexual function (assessed with the Female Sexual Function Index) and quality of life (evaluated with the SF12 questionnaire) significantly improved. No complications or side effects were reported during or after the laser procedure that was performed in an outpatient setting. SUMMARY: Increasing evidence with histological and clinical data supports the use of pulsed CO2 lasers in the treatment of VVA; however, no randomized control trial (sham versus treatment) has yet been produced and no data on the duration of therapy are currently available. PMID- 26536214 TI - Confounders of Cardioprotection by Remote Ischemic Preconditioning in Patients Undergoing Coronary Artery Bypass Grafting. AB - OBJECTIVES: Remote ischemic conditioning (RIC) by repetitive blood pressure cuff inflation/deflation around a limb provides cardioprotection in patients undergoing coronary artery bypass grafting (CABG). Cardioprotection is confounded by risk factors, comorbidities and comedications. We aimed to identify confounders that possibly attenuate the protection provided by RIC. METHODS: In a retrospective analysis of our single-center, randomized, double-blind trial of patients undergoing elective CABG with/without RIC prior to ischemic cardioplegic arrest, we analyzed demographics, medications and intraoperative variables. The primary end point was myocardial injury, as reflected by the area under the curve for serum troponin I (TnI) from baseline to 72 h after surgery. RESULTS: In models with 2 independent variables and in the multivariate analysis, age and aortic cross-clamp time impacted on TnI release. Subgroup analyses confirmed RIC induced protection in all age tertiles. There was no protection with an aortic cross-clamp time <=56 min (RIC/control = 1.026 not significant), but there was protection with 57-75 min (RIC/control = 0.757; p = 0.0348) and >=76 min (RIC/control = 0.735; p = 0.0277). Gender, beta-blockers, statins, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and intraoperative nitroglycerine did not impact on TnI release. CONCLUSION: Age, gender, beta-blockers, statins, ACE inhibitors, ARBs and intraoperative nitroglycerine have no significant impact on RIC-induced cardioprotection during CABG. However, greater myocardial ischemia/reperfusion injury at longer cross clamp time facilitates the detection of protection by RIC. PMID- 26536215 TI - Big data in biomedicine. PMID- 26536216 TI - Cancer: Reshaping the cancer clinic. PMID- 26536217 TI - Mobile data: Made to measure. PMID- 26536218 TI - Deep phenotyping: The details of disease. PMID- 26536219 TI - Perspective: Sustaining the big-data ecosystem. PMID- 26536220 TI - Q&A: Perry Nisen. Better insights, better drugs. PMID- 26536221 TI - Big data in biomedicine: 4 big questions. PMID- 26536222 TI - Big data: The power of petabytes. PMID- 26536223 TI - Q&A: Mark Caulfield. National genomics. PMID- 26536224 TI - Proteomics: High-protein research. PMID- 26536225 TI - Collaborations: Mining the motherlodes. PMID- 26536226 TI - Characteristics of Misclassified CT Perfusion Ischemic Core in Patients with Acute Ischemic Stroke. AB - BACKGROUND: CT perfusion (CTP) is used to estimate the extent of ischemic core and penumbra in patients with acute ischemic stroke. CTP reliability, however, is limited. This study aims to identify regions misclassified as ischemic core on CTP, using infarct on follow-up noncontrast CT. We aim to assess differences in volumetric and perfusion characteristics in these regions compared to areas that ended up as infarct on follow-up. MATERIALS AND METHODS: This study included 35 patients with >100 mm brain coverage CTP. CTP processing was performed using Philips software (IntelliSpace 7.0). Final infarct was automatically segmented on follow-up noncontrast CT and used as reference. CTP and follow-up noncontrast CT image data were registered. This allowed classification of ischemic lesion agreement (core on CTP: rMTT>=145%, aCBV<2.0 ml/100g and infarct on follow-up noncontrast CT) and misclassified ischemic core (core on CTP, not identified on follow-up noncontrast CT) regions. False discovery ratio (FDR), defined as misclassified ischemic core volume divided by total CTP ischemic core volume, was calculated. Absolute and relative CTP parameters (CBV, CBF, and MTT) were calculated for both misclassified CTP ischemic core and ischemic lesion agreement regions and compared using paired rank-sum tests. RESULTS: Median total CTP ischemic core volume was 49.7ml (IQR:29.9ml-132ml); median misclassified ischemic core volume was 30.4ml (IQR:20.9ml-77.0ml). Median FDR between patients was 62% (IQR:49%-80%). Median relative mean transit time was 243% (IQR:198%-289%) and 342% (IQR:249%-432%) for misclassified and ischemic lesion agreement regions, respectively. Median absolute cerebral blood volume was 1.59 (IQR:1.43-1.79) ml/100g (P<0.01) and 1.38 (IQR:1.15-1.49) ml/100g (P<0.01) for misclassified ischemic core and ischemic lesion agreement, respectively. All CTP parameter values differed significantly. CONCLUSION: For all patients a considerable region of the CTP ischemic core is misclassified. CTP parameters significantly differed between ischemic lesion agreement and misclassified CTP ischemic core, suggesting that CTP analysis may benefit from revisions. PMID- 26536227 TI - Network Science Based Quantification of Resilience Demonstrated on the Indian Railways Network. AB - The structure, interdependence, and fragility of systems ranging from power-grids and transportation to ecology, climate, biology and even human communities and the Internet have been examined through network science. While response to perturbations has been quantified, recovery strategies for perturbed networks have usually been either discussed conceptually or through anecdotal case studies. Here we develop a network science based quantitative framework for measuring, comparing and interpreting hazard responses as well as recovery strategies. The framework, motivated by the recently proposed temporal resilience paradigm, is demonstrated with the Indian Railways Network. Simulations inspired by the 2004 Indian Ocean Tsunami and the 2012 North Indian blackout as well as a cyber-physical attack scenario illustrate hazard responses and effectiveness of proposed recovery strategies. Multiple metrics are used to generate various recovery strategies, which are simply sequences in which system components should be recovered after a disruption. Quantitative evaluation of these strategies suggests that faster and more efficient recovery is possible through network centrality measures. Optimal recovery strategies may be different per hazard, per community within a network, and for different measures of partial recovery. In addition, topological characterization provides a means for interpreting the comparative performance of proposed recovery strategies. The methods can be directly extended to other Large-Scale Critical Lifeline Infrastructure Networks including transportation, water, energy and communications systems that are threatened by natural or human-induced hazards, including cascading failures. Furthermore, the quantitative framework developed here can generalize across natural, engineered and human systems, offering an actionable and generalizable approach for emergency management in particular as well as for network resilience in general. PMID- 26536230 TI - E-Cigarette Affects the Metabolome of Primary Normal Human Bronchial Epithelial Cells. AB - E-cigarettes are widely believed to be safer than conventional cigarettes and have been even suggested as aids for smoking cessation. However, while reasonable with some regards, this judgment is not yet supported by adequate biomedical research data. Since bronchial epithelial cells are the immediate target of inhaled toxicants, we hypothesized that exposure to e-cigarettes may affect the metabolome of human bronchial epithelial cells (HBEC) and that the changes are, at least in part, induced by oxidant-driven mechanisms. Therefore, we evaluated the effect of e-cigarette liquid (ECL) on the metabolome of HBEC and examined the potency of antioxidants to protect the cells. We assessed the changes of the intracellular metabolome upon treatment with ECL in comparison of the effect of cigarette smoke condensate (CSC) with mass spectrometry and principal component analysis on air-liquid interface model of normal HBEC. Thereafter, we evaluated the capability of the novel antioxidant tetrapeptide O-methyl-l-tyrosinyl-gamma-l glutamyl-l-cysteinylglycine (UPF1) to attenuate the effect of ECL. ECL caused a significant shift in the metabolome that gradually gained its maximum by the 5th hour and receded by the 7th hour. A second alteration followed at the 13th hour. Treatment with CSC caused a significant initial shift already by the 1st hour. ECL, but not CSC, significantly increased the concentrations of arginine, histidine, and xanthine. ECL, in parallel with CSC, increased the content of adenosine diphosphate and decreased that of three lipid species from the phosphatidylcholine family. UPF1 partially counteracted the ECL-induced deviations, UPF1's maximum effect occurred at the 5th hour. The data support our hypothesis that ECL profoundly alters the metabolome of HBEC in a manner, which is comparable and partially overlapping with the effect of CSC. Hence, our results do not support the concept of harmlessness of e-cigarettes. PMID- 26536229 TI - Expression of CCL20 and Its Corresponding Receptor CCR6 Is Enhanced in Active Inflammatory Bowel Disease, and TLR3 Mediates CCL20 Expression in Colonic Epithelial Cells. AB - BACKGROUND: The chemokine CCL20 and its receptor CCR6 are putative drug targets in inflammatory bowel disease, and CCL20 is a novel IBD predilection gene. Previous findings on the CCL20 response in these diseases are divergent. This study was undertaken to examine CCL20 and CCR6 during active and inactive disease, and mechanisms for CCL20 regulation by the innate immune system. As TLR3 has recently emerged as a possible mediator of CCL20 production, we hypothesised that this TLR plays an important role in enterocytic CCL20 production. METHODS: A large microarray study on colonic pinch biopsies from active and inactive ulcerative colitis and Crohn's disease provided background information. CCL20 and CCR6 were localized and their expression levels assessed in biopsies using in situ hybridization and immunohistochemistry. Regulation of CCL20 was studied in the HT29 cell line using a panel of pattern recognition receptor ligands followed by a TLR3 siRNA assay. RESULTS: CCL20 and CCR6 mRNA abundances were increased during active inflammation (CCL20 5.4-fold in ulcerative colitis and 4.2-fold in Crohn's disease; CCR6 1.8 and 2.0, respectively). CCL20 and CCR6 mRNA positive immune cells in lamina propria were more numerous, and CCL20 immunoreactivity increased massively in the epithelial cells during active inflammation for both diseases. TLR3 stimulation potently induced upregulation and release of CCL20 from HT29 cells, and TLR3 silencing reduced CCL20 mRNA and protein levels. CONCLUSIONS: The CCL20-CCR6 axis is involved during active inflammation in both ulcerative colitis and Crohn's disease. The epithelial cells seem particularly involved in the CCL20 response, and results from this study strongly suggest that the innate immune system is important for activation of the epithelium, especially through TLR3. PMID- 26536231 TI - Examining Temporal Sample Scale and Model Choice with Spatial Capture-Recapture Models in the Common Leopard Panthera pardus. AB - Many large carnivores occupy a wide geographic distribution, and face threats from habitat loss and fragmentation, poaching, prey depletion, and human wildlife conflicts. Conservation requires robust techniques for estimating population densities and trends, but the elusive nature and low densities of many large carnivores make them difficult to detect. Spatial capture-recapture (SCR) models provide a means for handling imperfect detectability, while linking population estimates to individual movement patterns to provide more accurate estimates than standard approaches. Within this framework, we investigate the effect of different sample interval lengths on density estimates, using simulations and a common leopard (Panthera pardus) model system. We apply Bayesian SCR methods to 89 simulated datasets and camera-trapping data from 22 leopards captured 82 times during winter 2010-2011 in Royal Manas National Park, Bhutan. We show that sample interval length from daily, weekly, monthly or quarterly periods did not appreciably affect median abundance or density, but did influence precision. We observed the largest gains in precision when moving from quarterly to shorter intervals. We therefore recommend daily sampling intervals for monitoring rare or elusive species where practicable, but note that monthly or quarterly sample periods can have similar informative value. We further develop a novel application of Bayes factors to select models where multiple ecological factors are integrated into density estimation. Our simulations demonstrate that these methods can help identify the "true" explanatory mechanisms underlying the data. Using this method, we found strong evidence for sex-specific movement distributions in leopards, suggesting that sexual patterns of space-use influence density. This model estimated a density of 10.0 leopards/100 km2 (95% credibility interval: 6.25-15.93), comparable to contemporary estimates in Asia. These SCR methods provide a guide to monitor and observe the effect of management interventions on leopards and other species of conservation interest. PMID- 26536232 TI - Dynamics of a Tularemia Outbreak in a Closely Monitored Free-Roaming Population of Wild House Mice. AB - Infectious disease outbreaks can be devastating because of their sudden occurrence, as well as the complexity of monitoring and controlling them. Outbreaks in wildlife are even more challenging to observe and describe, especially when small animals or secretive species are involved. Modeling such infectious disease events is relevant to investigating their dynamics and is critical for decision makers to accomplish outbreak management. Tularemia, caused by the bacterium Francisella tularensis, is a potentially lethal zoonosis. Of the few animal outbreaks that have been reported in the literature, only those affecting zoo animals have been closely monitored. Here, we report the first estimation of the basic reproduction number R0 of an outbreak in wildlife caused by F. tularensis using quantitative modeling based on a susceptible-infected recovered framework. We applied that model to data collected during an extensive investigation of an outbreak of tularemia caused by F. tularensis subsp. holarctica (also designated as type B) in a closely monitored, free-roaming house mouse (Mus musculus domesticus) population in Switzerland. Based on our model and assumptions, the best estimated basic reproduction number R0 of the current outbreak is 1.33. Our results suggest that tularemia can cause severe outbreaks in small rodents. We also concluded that the outbreak self-exhausted in approximately three months without administrating antibiotics. PMID- 26536233 TI - Inhibitory Effects of KP-A159, a Thiazolopyridine Derivative, on Osteoclast Differentiation, Function, and Inflammatory Bone Loss via Suppression of RANKL Induced MAP Kinase Signaling Pathway. AB - Abnormally elevated formation and activation of osteoclasts are primary causes for a majority of skeletal diseases. In this study, we found that KP-A159, a newly synthesized thiazolopyridine derivative, inhibited osteoclast differentiation and function in vitro, and inflammatory bone loss in vivo. KP A159 did not cause a cytotoxic response in bone marrow macrophages (BMMs), but significantly inhibited the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts induced by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL). KP A159 also dramatically inhibited the expression of marker genes related to osteoclast differentiation, including TRAP (Acp5), cathepsin K (Ctsk), dendritic cell-specific transmembrane protein (Dcstamp), matrix metallopeptidase 9 (Mmp9), and nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1). Moreover, actin ring and resorption pit formation were inhibited by KP-A159. Analysis of the signaling pathway involved showed that KP-A159 inhibited RANKL-induced activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinase kinase1/2 (MEK1/2). In a mouse inflammatory bone loss model, KP-A159 significantly rescued lipopolysaccharide (LPS)-induced bone loss by suppressing osteoclast numbers. Therefore, KP-A159 targets osteoclasts, and may be a potential candidate compound for prevention and/or treatment of inflammatory bone loss. PMID- 26536234 TI - Chemical modification of graphene aerogels for electrochemical capacitor applications. AB - Graphene aerogel is a relatively new type of aerogel that is ideal for energy storage applications because of its large surface area, high electrical conductivity and good chemical stability. Also, three dimensional interconnected macropores offer many advantages such as low density, fast ion and mass transfer, and easy access to storage sites. Such features allow graphene aerogels to be intensively applied for electrochemical capacitor applications. Despite the growing interest in graphene aerogel-based electrochemical capacitors, however, the graphene aerogels still suffer from their low capacitive performances and high fragility. Both relatively low capacitance and brittleness of physically crosslinked graphene aerogels remain a critical challenge. Until now, a number of alternative attempts have been devoted to overcome these shortcomings. In this perspective, we summarize the recent research progress towards the development of advanced graphene aerogel-based electrochemical capacitors according to the different approaches (e.g. porosity, composition and structure controls). Then, the recently proposed chemical strategies to improve the capacitive performances and mechanical durability of graphene aerogels for practical applications are highlighted. Finally, the current challenges and perspectives in this emerging material are also discussed. PMID- 26536235 TI - Influence of Visual Motion, Suggestion, and Illusory Motion on Self-Motion Perception in the Horizontal Plane. AB - A moving visual field can induce the feeling of self-motion or vection. Illusory motion from static repeated asymmetric patterns creates a compelling visual motion stimulus, but it is unclear if such illusory motion can induce a feeling of self-motion or alter self-motion perception. In these experiments, human subjects reported the perceived direction of self-motion for sway translation and yaw rotation at the end of a period of viewing set visual stimuli coordinated with varying inertial stimuli. This tested the hypothesis that illusory visual motion would influence self-motion perception in the horizontal plane. Trials were arranged into 5 blocks based on stimulus type: moving star field with yaw rotation, moving star field with sway translation, illusory motion with yaw, illusory motion with sway, and static arrows with sway. Static arrows were used to evaluate the effect of cognitive suggestion on self-motion perception. Each trial had a control condition; the illusory motion controls were altered versions of the experimental image, which removed the illusory motion effect. For the moving visual stimulus, controls were carried out in a dark room. With the arrow visual stimulus, controls were a gray screen. In blocks containing a visual stimulus there was an 8s viewing interval with the inertial stimulus occurring over the final 1s. This allowed measurement of the visual illusion perception using objective methods. When no visual stimulus was present, only the 1s motion stimulus was presented. Eight women and five men (mean age 37) participated. To assess for a shift in self-motion perception, the effect of each visual stimulus on the self-motion stimulus (cm/s) at which subjects were equally likely to report motion in either direction was measured. Significant effects were seen for moving star fields for both translation (p = 0.001) and rotation (p<0.001), and arrows (p = 0.02). For the visual motion stimuli, inertial motion perception was shifted in the direction consistent with the visual stimulus. Arrows had a small effect on self-motion perception driven by a minority of subjects. There was no significant effect of illusory motion on self-motion perception for either translation or rotation (p>0.1 for both). Thus, although a true moving visual field can induce self-motion, results of this study show that illusory motion does not. PMID- 26536236 TI - Which one is faster? A kinetic investigation of Pd and Ni catalyzed Negishi-type oxidative coupling reactions. AB - The difference between Pd and Ni has been investigated based on the Negishi-type oxidative coupling reactions in which reductive elimination was proved to be the rate determining step. Although DFT calculations illustrate that the Pd catalyzed reaction should be faster than the Ni catalyzed reaction under these conditions, kinetic experiments indicate that the reaction rate of Pd and Ni is dependent on the concentration of the catalyst precursor. The Pd catalyzed reaction is faster than the Ni catalyzed reaction only when the precursor concentration is as low as 1 * 10(-7) M. PMID- 26536237 TI - Anaplastic Lymphoma Kinase Acts in the Drosophila Mushroom Body to Negatively Regulate Sleep. AB - Though evidence is mounting that a major function of sleep is to maintain brain plasticity and consolidate memory, little is known about the molecular pathways by which learning and sleep processes intercept. Anaplastic lymphoma kinase (Alk), the gene encoding a tyrosine receptor kinase whose inadvertent activation is the cause of many cancers, is implicated in synapse formation and cognitive functions. In particular, Alk genetically interacts with Neurofibromatosis 1 (Nf1) to regulate growth and associative learning in flies. We show that Alk mutants have increased sleep. Using a targeted RNAi screen we localized the negative effects of Alk on sleep to the mushroom body, a structure important for both sleep and memory. We also report that mutations in Nf1 produce a sexually dimorphic short sleep phenotype, and suppress the long sleep phenotype of Alk. Thus Alk and Nf1 interact in both learning and sleep regulation, highlighting a common pathway in these two processes. PMID- 26536238 TI - Immobilization of Dystrophin and Laminin alpha2-Chain Deficient Zebrafish Larvae In Vivo Prevents the Development of Muscular Dystrophy. AB - Muscular dystrophies are often caused by genetic alterations in the dystrophin dystroglycan complex or its extracellular ligands. These structures are associated with the cell membrane and provide mechanical links between the cytoskeleton and the matrix. Mechanical stress is considered a pathological mechanism and muscle immobilization has been shown to be beneficial in some mouse models of muscular dystrophy. The zebrafish enables novel and less complex models to examine the effects of extended immobilization or muscle relaxation in vivo in different dystrophy models. We have examined effects of immobilization in larvae from two zebrafish strains with muscular dystrophy, the Sapje dystrophin deficient and the Candyfloss laminin alpha2-chain-deficient strains. Larvae (4 days post fertilization, dpf) of both mutants have significantly lower active force in vitro, alterations in the muscle structure with gaps between muscle fibers and altered birefringence patterns compared to their normal siblings. Complete immobilization (18 hrs to 4 dpf) was achieved using a small molecular inhibitor of actin-myosin interaction (BTS, 50 MUM). This treatment resulted in a significantly weaker active contraction at 4 dpf in both mutated larvae and normal siblings, most likely reflecting a general effect of immobilization on myofibrillogenesis. The immobilization also significantly reduced the structural damage in the mutated strains, showing that muscle activity is an important pathological mechanism. Following one-day washout of BTS, muscle tension partly recovered in the Candyfloss siblings and caused structural damage in these mutants, indicating activity-induced muscle recovery and damage, respectively. PMID- 26536239 TI - From SARS to Ebola--10 years of disease prevention and control at ECDC. PMID- 26536240 TI - Differentiation and Distribution of Marrow Stem Cells in Flex-Flow Environments Demonstrate Support of the Valvular Phenotype. AB - For treatment of critical heart valve diseases, prosthetic valves perform fairly well in most adults; however, for pediatric patients, there is the added requirement that the replacement valve grows with the child, thus extremely limiting current treatment options. Tissue engineered heart valves (TEHV), such as those derived from autologous bone marrow stem cells (BMSCs), have the potential to recapitulate native valve architecture and accommodate somatic growth. However, a fundamental pre-cursor in promoting directed integration with native tissues rather than random, uncontrolled growth requires an understanding of BMSC mechanobiological responses to valve-relevant mechanical environments. Here, we report on the responses of human BMSC-seeded polymer constructs to the valve-relevant stress states of: (i) steady flow alone, (ii) cyclic flexure alone, and (iii) the combination of cyclic flexure and steady flow (flex-flow). BMSCs were seeded onto a PGA: PLLA polymer scaffold and cultured in static culture for 8 days. Subsequently, the aforementioned mechanical conditions, (groups consisting of steady flow alone-850ml/min, cyclic flexure alone-1 Hz, and flex-flow-850ml/min and 1 Hz) were applied for an additional two weeks. We found samples from the flex-flow group exhibited a valve-like distribution of cells that expressed endothelial (preference to the surfaces) and myofibroblast (preference to the intermediate region) phenotypes. We interpret that this was likely due to the presence of both appreciable fluid-induced shear stress magnitudes and oscillatory shear stresses, which were concomitantly imparted onto the samples. These results indicate that flex-flow mechanical environments support directed in vitro differentiation of BMSCs uniquely towards a heart valve phenotype, as evident by cellular distribution and expression of specific gene markers. A priori guidance of BMSC-derived, engineered tissue growth under flex flow conditions may serve to subsequently promote controlled, engineered to native tissue integration processes in vivo necessary for successful long-term valve remodeling. PMID- 26536241 TI - Settlement-Size Scaling among Prehistoric Hunter-Gatherer Settlement Systems in the New World. AB - Settlement size predicts extreme variation in the rates and magnitudes of many social and ecological processes in human societies. Yet, the factors that drive human settlement-size variation remain poorly understood. Size variation among economically integrated settlements tends to be heavy tailed such that the smallest settlements are extremely common and the largest settlements extremely large and rare. The upper tail of this size distribution is often formalized mathematically as a power-law function. Explanations for this scaling structure in human settlement systems tend to emphasize complex socioeconomic processes including agriculture, manufacturing, and warfare-behaviors that tend to differentially nucleate and disperse populations hierarchically among settlements. But, the degree to which heavy-tailed settlement-size variation requires such complex behaviors remains unclear. By examining the settlement patterns of eight prehistoric New World hunter-gatherer settlement systems spanning three distinct environmental contexts, this analysis explores the degree to which heavy-tailed settlement-size scaling depends on the aforementioned socioeconomic complexities. Surprisingly, the analysis finds that power-law models offer plausible and parsimonious statistical descriptions of prehistoric hunter-gatherer settlement-size variation. This finding reveals that incipient forms of hierarchical settlement structure may have preceded socioeconomic complexity in human societies and points to a need for additional research to explicate how mobile foragers came to exhibit settlement patterns that are more commonly associated with hierarchical organization. We propose that hunter gatherer mobility with preferential attachment to previously occupied locations may account for the observed structure in site-size variation. PMID- 26536242 TI - Correction: Specialist Insect Herbivore and Light Availability Do Not Interact in the Evolution of an Invasive Plant. PMID- 26536244 TI - Understanding Acceptable Level of Risk: Incorporating the Economic Cost of Under Managing Invasive Species. AB - Management of nonindigenous species includes prevention, early detection and rapid response and control. Early detection and rapid response depend on prioritizing and monitoring sites at risk for arrival or secondary spread of nonindigenous species. Such monitoring efforts require sufficient biosecurity budgets to be effective and meet management or policy directives for reduced risk of introduction. Such consideration of risk reduction is rarely considered, however. Here, we review the concepts of acceptable level of risk (ALOR) and associated costs with respect to nonindigenous species and present a framework for aligning risk reduction priorities with available biosecurity resources. We conclude that available biosecurity resources may be insufficient to attain stated and desired risk reduction. This outcome highlights the need to consider policy and management directives when beginning a biosecurity program to determine the feasibility of risk reduction goals, given available resources. PMID- 26536243 TI - Monetary Value of Diet Is Associated with Dietary Quality and Nutrient Adequacy among Urban Adults, Differentially by Sex, Race and Poverty Status. AB - OBJECTIVE: The association between monetary value of the diet (MVD, $/day) with dietary quality was examined using a large sample of urban US adults, differentially by socio-demographic factors. METHODS: This was a cross-sectional study of 2,111 participants, aged 30-64y, using data from the Healthy Aging in Neighborhoods of Diversity across the Life Span Study. Dietary quality indices included Healthy Eating Index-2010 (HEI-2010) and Mean Adequacy Ratio (MAR), (two 24-hr recalls). A national food price database was used to estimate MVD. Multiple linear/logistic regression analyses were conducted stratifying separately by sex, race and poverty status. RESULTS: Women had significantly higher HEI-2010 scores than men (43.35 vs 41.57 out of 100, respectively), whereas MAR scores were higher for men (76.8 vs 69.9, out of 100), reflecting energy intake gender differentials. Importantly, a $3/day higher MVD (IQR: $3.70/d (Q1) to $6.62/d (Q4)) was associated with a 4.98+/-0.35 higher total HEI-2010 and a 3.88+/-0.37 higher MAR score, after energy-adjustment and control for key confounders. For HEI-2010 and MAR, stronger associations were observed among participants above poverty and among women, whilethe MVD vs. HEI-2010 association was additionally stronger among Whites. Sex and poverty status differentials were observed for many MAR and some HEI-2010 components. CONCLUSIONS: Despite positive associations between measures of dietary quality and MVD, particularly above poverty and among women, approaching compliance with the Dietary Guidelines (80 or more for HEI 2010) requires a substantially higher MVD. Thus, nutrition education may further improve people's decision-making regarding food venues and dietary choices. PMID- 26536245 TI - Pregnancy Augments G Protein Estrogen Receptor (GPER) Induced Vasodilation in Rat Uterine Arteries via the Nitric Oxide - cGMP Signaling Pathway. AB - BACKGROUND: The regulation of vascular tone in the uterine circulation is a key determinant of appropriate uteroplacental blood perfusion and successful pregnancy outcome. Estrogens, which increase in the maternal circulation throughout pregnancy, can exert acute vasodilatory actions. Recently a third estrogen receptor named GPER (G protein-coupled estrogen receptor) was identified and, although several studies have shown vasodilatory effects in several vascular beds, nothing is known about its role in the uterine vasculature. AIM: The aim of this study was to determine the function of GPER in uterine arteries mainly during pregnancy. Uterine arteries were isolated from nonpregnant and pregnant rats. METHODS: Vessels were contracted with phenylephrine and then incubated with incremental doses (10-12-10-5 M) of the selective GPER agonist G1. RESULTS: G1 induced a dose-dependent vasodilation which was: 1) significantly increased in pregnancy, 2) endothelium-dependent, 3) primarily mediated by NO/cGMP pathway and 4) unaffected by BKca channel inhibition. CONCLUSION: This is the first study to show the potential importance of GPER signaling in reducing uterine vascular tone during pregnancy. GPER may therefore play a previously unrecognized role in the regulation of uteroplacental blood flow and normal fetus growth. PMID- 26536246 TI - Microbial Gene Abundance and Expression Patterns across a River to Ocean Salinity Gradient. AB - Microbial communities mediate the biogeochemical cycles that drive ecosystems, and it is important to understand how these communities are affected by changing environmental conditions, especially in complex coastal zones. As fresh and marine waters mix in estuaries and river plumes, the salinity, temperature, and nutrient gradients that are generated strongly influence bacterioplankton community structure, yet, a parallel change in functional diversity has not been described. Metagenomic and metatranscriptomic analyses were conducted on five water samples spanning the salinity gradient of the Columbia River coastal margin, including river, estuary, plume, and ocean, in August 2010. Samples were pre-filtered through 3 MUm filters and collected on 0.2 MUm filters, thus results were focused on changes among free-living microbial communities. Results from metagenomic 16S rRNA sequences showed taxonomically distinct bacterial communities in river, estuary, and coastal ocean. Despite the strong salinity gradient observed over sampling locations (0 to 33), the functional gene profiles in the metagenomes were very similar from river to ocean with an average similarity of 82%. The metatranscriptomes, however, had an average similarity of 31%. Although differences were few among the metagenomes, we observed a change from river to ocean in the abundance of genes encoding for catabolic pathways, osmoregulators, and metal transporters. Additionally, genes specifying both bacterial oxygenic and anoxygenic photosynthesis were abundant and expressed in the estuary and plume. Denitrification genes were found throughout the Columbia River coastal margin, and most highly expressed in the estuary. Across a river to ocean gradient, the free-living microbial community followed three different patterns of diversity: 1) the taxonomy of the community changed strongly with salinity, 2) metabolic potential was highly similar across samples, with few differences in functional gene abundance from river to ocean, and 3) gene expression was highly variable and generally was independent of changes in salinity. PMID- 26536248 TI - Stable and Simple Immobilization of Proteinase K Inside Glass Tubes and Microfluidic Channels. AB - Engyodontium album proteinase K (proK) is widely used for degrading proteinaceous impurities during the isolation of nucleic acids from biological samples, or in proteomics and prion research. Toward applications of proK in flow reactors, a simple method for the stable immobilization of proK inside glass micropipette tubes was developed. The immobilization of the enzyme was achieved by adsorption of a dendronized polymer-enzyme conjugate from aqueous solution. This conjugate was first synthesized from a polycationic dendronized polymer (denpol) and proK and consisted, on average, of 2000 denpol repeating units and 140 proK molecules, which were attached along the denpol chain via stable bis-aryl hydrazone bonds. Although the immobilization of proK inside the tube was based on nonspecific, noncovalent interactions only, the immobilized proK did not leak from the tube and remained active during prolonged storage at 4 degrees C and during continuous operation at 25 degrees C and pH = 7.0. The procedure developed was successfully applied for the immobilization of proK on a glass/PDMS (polydimethylsiloxane) microchip, which is a requirement for applications in the field of proK-based protein analysis with such type of microfluidic devices. PMID- 26536247 TI - Deciphering Mineral Homeostasis in Barley Seed Transfer Cells at Transcriptional Level. AB - In addition to the micronutrient inadequacy of staple crops for optimal human nutrition, a global downtrend in crop-quality has emerged from intensive breeding for yield. This trend will be aggravated by elevated levels of the greenhouse gas carbon dioxide. Therefore, crop biofortification is inevitable to ensure a sustainable supply of minerals to the large part of human population who is dietary dependent on staple crops. This requires a thorough understanding of plant-mineral interactions due to the complexity of mineral homeostasis. Employing RNA sequencing, we here communicate transfer cell specific effects of excess iron and zinc during grain filling in our model crop plant barley. Responding to alterations in mineral contents, we found a long range of different genes and transcripts. Among them, it is worth to highlight the auxin and ethylene signaling factors Arfs, Abcbs, Cand1, Hps4, Hac1, Ecr1, and Ctr1, diurnal fluctuation components Sdg2, Imb1, Lip1, and PhyC, retroelements, sulfur homeostasis components Amp1, Hmt3, Eil3, and Vip1, mineral trafficking components Med16, Cnnm4, Aha2, Clpc1, and Pcbps, and vacuole organization factors Ymr155W, RabG3F, Vps4, and Cbl3. Our analysis introduces new interactors and signifies a broad spectrum of regulatory levels from chromatin remodeling to intracellular protein sorting mechanisms active in the plant mineral homeostasis. The results highlight the importance of storage proteins in metal ion toxicity-resistance and chelation. Interestingly, the protein sorting and recycling factors Exoc7, Cdc1, Sec23A, and Rab11A contributed to the response as well as the polar distributors of metal-transporters ensuring the directional flow of minerals. Alternative isoform switching was found important for plant adaptation and occurred among transcripts coding for identical proteins as well as transcripts coding for protein isoforms. We also identified differences in the alternative-isoform preference between the treatments, indicating metal-affinity shifts among isoforms of metal transporters. Most important, we found the zinc treatment to impair both photosynthesis and respiration. A wide range of transcriptional changes including stress-related genes and negative feedback loops emphasize the importance to withhold mineral contents below certain cellular levels which otherwise might lead to agronomical impeding side-effects. By illustrating new mechanisms, genes, and transcripts, this report provides a solid platform towards understanding the complex network of plant mineral homeostasis. PMID- 26536249 TI - Massive parallel sequencing in sarcoma pathobiology: state of the art and perspectives. AB - Sarcomas are an aggressive and highly heterogeneous group of mesenchymal malignancies with different morphologies and clinical behavior. Current therapeutic strategies remain unsatisfactory. Cytogenetic and molecular characterization of these tumors is resulting in the breakdown of the classical histopathological categories into molecular subgroups that better define sarcoma pathobiology and pave the way to more precise diagnostic criteria and novel therapeutic opportunities. The purpose of this short review is to summarize the state-of-the-art on the exploitation of massive parallel sequencing technologies, also known as next generation sequencing, in the elucidation of sarcoma pathobiology and to discuss how these applications may impact on diagnosis, prognosis and therapy of these tumors. PMID- 26536250 TI - Preparation of o-Fluorophenols from Nonaromatic Precursors: Mechanistic Considerations for Adaptation to Fluorine-18 Radiolabeling. AB - The preparation of fluorine-18 labeled o-fluorophenols at high specific activity is challenging and requires use of [(18)F]fluoride ion as the radioisotope source. As a novel, alternative approach, we found that treatment of alpha diazocyclohexenones with Selectfluor and Et3N.3HF followed by HF elimination and tautomerization afforded o-fluorophenols regioselectively and rapidly. To adapt this chemistry to (18)F radiolabeling, using bromine electrophiles in place of Selectfluor gave the o-fluorophenol via an alpha-bromo-alpha-fluoroketone intermediate in lower but still reasonable yields. PMID- 26536251 TI - Diffuse reflectance spectroscopy for the measurement of tissue oxygen saturation. AB - Tissue oxygen saturation (StO2) is a useful parameter for medical applications. A spectroscopic method has been developed to detect pathologic tissues, due to a lack of normal blood circulation, by measuring StO2. In this study, human blood samples with different levels of oxygen saturation have been prepared and spectra were acquired using an optical fiber probe to investigate the correlation between the oxygen saturation levels and the spectra. A linear correlation between the oxygen saturation and ratio of the intensities (760 nm to 790 nm) of the spectra acquired from blood samples has been found. In a validation study, oxygen saturations of the blood samples were estimated from the spectroscopic measurements with an error of 2.9%. It has also been shown that the linear dependence between the ratio and the oxygen saturation of the blood samples was valid for the blood samples with different hematocrits. Spectra were acquired from the forearms of 30 healthy volunteers to estimate StO2 prior to, at the beginning of, after 2 min, and at the release of total vascular occlusion. The average StO2 of a forearm before and after the two minutes occlusion was significantly different. The results suggested that optical reflectance spectroscopy is a sensitive method to estimate the StO2 levels of human tissue. The technique developed to measure StO2 has potential to detect ischemia in real time. PMID- 26536252 TI - Staying Together: Protein Molecules in Mesoscopic Clusters. PMID- 26536253 TI - Analysis and Interpretation of Superresolution Single-Particle Trajectories. AB - A large number (tens of thousands) of single molecular trajectories on a cell membrane can now be collected by superresolution methods. The data contains information about the diffusive motion of molecule, proteins, or receptors and here we review methods for its recovery by statistical analysis of the data. The information includes the forces, organization of the membrane, the diffusion tensor, the long-time behavior of the trajectories, and more. To recover the long time behavior and statistics of long trajectories, a stochastic model of their nonequilibrium motion is required. Modeling and data analysis serve extracting novel biophysical features at an unprecedented spatiotemporal resolution. The review presents data analysis, modeling, and stochastic simulations applied in particular on surface receptors evolving in neuronal cells. PMID- 26536254 TI - Optimal Drift Correction for Superresolution Localization Microscopy with Bayesian Inference. AB - Single-molecule-localization-based superresolution microscopy requires accurate sample drift correction to achieve good results. Common approaches for drift compensation include using fiducial markers and direct drift estimation by image correlation. The former increases the experimental complexity and the latter estimates drift at a reduced temporal resolution. Here, we present, to our knowledge, a new approach for drift correction based on the Bayesian statistical framework. The technique has the advantage of being able to calculate the drifts for every image frame of the data set directly from the single-molecule coordinates. We present the theoretical foundation of the algorithm and an implementation that achieves significantly higher accuracy than image-correlation based estimations. PMID- 26536255 TI - Force-Induced Unfolding of Leucine-Rich Repeats of Glycoprotein Ibalpha Strengthens Ligand Interaction. AB - Leucine-rich repeat (LRR) is a versatile motif widely present in adhesive proteins and signal-transducing receptors. The concave structure formed by a group of LRRs is thought to facilitate binding to globular protein domains with increased affinities. However, little is known about the conformational dynamics of LRRs in such a structure, e.g., whether and how force induces conformational changes in LRRs to regulate protein binding and signal transduction. Here we investigated the platelet glycoprotein Ibalpha (GPIbalpha), a demonstrated mechanoreceptor with known crystal structures for the N-terminal domain (GPIbalphaN), as a model for LRR-containing proteins using a combined method of steered molecular dynamics simulations and single-molecule force spectroscopy with a biomembrane force probe. We found that force-induced unfolding of GPIbalphaN starts with LRR2-4 and propagates to other LRRs. Importantly, force dependent lifetimes of individual VWF-A1 bonds with GPIbalpha are prolonged after LRR unfolding. Enhancement of protein-protein interactions by force-induced LRR unfolding may be a phenomenon of interest in biology. PMID- 26536256 TI - Predictive Spatiotemporal Manipulation of Signaling Perturbations Using Optogenetics. AB - Recently developed optogenetic methods promise to revolutionize cell biology by allowing signaling perturbations to be controlled in space and time with light. However, a quantitative analysis of the relationship between a custom-defined illumination pattern and the resulting signaling perturbation is lacking. Here, we characterize the biophysical processes governing the localized recruitment of the Cryptochrome CRY2 to its membrane-anchored CIBN partner. We develop a quantitative framework and present simple procedures that enable predictive manipulation of protein distributions on the plasma membrane with a spatial resolution of 5 MUm. We show that protein gradients of desired levels can be established in a few tens of seconds and then steadily maintained. These protein gradients can be entirely relocalized in a few minutes. We apply our approach to the control of the Cdc42 Rho GTPase activity. By inducing strong localized signaling perturbation, we are able to monitor the initiation of cell polarity and migration with a remarkable reproducibility despite cell-to-cell variability. PMID- 26536257 TI - Referenced Single-Molecule Measurements Differentiate between GPCR Oligomerization States. AB - The extent to which Rhodopsin family G-protein-coupled receptors (GPCRs) form invariant oligomers is contentious. Recent single-molecule fluorescence imaging studies mostly argue against the existence of constitutive receptor dimers and instead suggest that GPCRs only dimerize transiently, if at all. However, whether or not even transient dimers exist is not always clear due to difficulties in unambiguously distinguishing genuine interactions from chance colocalizations, particularly with respect to short-lived events. Previous single-molecule studies have depended critically on calculations of chance colocalization rates and/or comparison with unfixed control proteins whose diffusional behavior may or may not differ from that of the test receptor. Here, we describe a single-molecule imaging assay that 1) utilizes comparisons with well-characterized control proteins, i.e., the monomer CD86 and the homodimer CD28, and 2) relies on cell fixation to limit artifacts arising from differences in the distribution and diffusion of test proteins versus these controls. The improved assay reliably reports the stoichiometry of the Glutamate-family GPCR dimer, gamma-amino butyric acid receptor b2, whereas two Rhodopsin-family GPCRs, beta2-adrenergic receptor and mCannR2, exhibit colocalization levels comparable to those of CD86 monomers, strengthening the case against invariant GPCR oligomerization. PMID- 26536258 TI - A Chemomechanical Model of Matrix and Nuclear Rigidity Regulation of Focal Adhesion Size. AB - In this work, a chemomechanical model describing the growth dynamics of cell matrix adhesion structures (i.e., focal adhesions (FAs)) is developed. We show that there are three regimes for FA evolution depending on their size. Specifically, nascent adhesions with initial lengths below a critical value that are yet to engage in actin fibers will dissolve, whereas bigger ones will grow into mature FAs with a steady state size. In adhesions where growth surpasses the steady state size, disassembly will occur until their sizes are reduced to the equilibrium state. This finding arises from the fact that polymerization of adhesion proteins is force-dependent. Under actomyosin contraction, individual integrin bonds within small FAs (i.e., nascent adhesions or focal complexes) must transmit higher loads while the phenomenon of stress concentration occurs at the edge of large adhesion patches. As such, an effective stiffness of the FA extracellular matrix complex that is either too small or too large will be relatively low, resulting in a limited actomyosin pulling force developed at the edge that is insufficient to prevent disassembly. Furthermore, it is found that a stiffer extracellular matrix and/or nucleus, as well as a stronger chemomechanical feedback, will induce larger adhesions along with a higher level of contraction force. Interestingly, switching the extracellular side from an elastic half-space, corresponding to some widely used in vitro gel substrates, to a one-dimensional fiber (as in the case of cells anchoring to a fibrous scaffold in vivo) does not qualitative change these conclusions. Our model predictions are in good agreement with a variety of experimental observations obtained in this study as well as those reported in the literature. Furthermore, this new model, to our knowledge, provides a framework with which to understand how both intracellular and extracellular perturbations lead to changes in adhesion structure number and size. PMID- 26536259 TI - A Combination of Actin Treadmilling and Cross-Linking Drives Contraction of Random Actomyosin Arrays. AB - We investigate computationally the self-organization and contraction of an initially random actomyosin ring. In the framework of a detailed physical model for a ring of cross-linked actin filaments and myosin-II clusters, we derive the force balance equations and solve them numerically. We find that to contract, actin filaments have to treadmill and to be sufficiently cross linked, and myosin has to be processive. The simulations reveal how contraction scales with mechanochemical parameters. For example, they show that the ring made of longer filaments generates greater force but contracts slower. The model predicts that the ring contracts with a constant rate proportional to the initial ring radius if either myosin is released from the ring during contraction and actin filaments shorten, or if myosin is retained in the ring, while the actin filament number decreases. We demonstrate that a balance of actin nucleation and compression dependent disassembly can also sustain contraction. Finally, the model demonstrates that with time pattern formation takes place in the ring, worsening the contractile process. The more random the actin dynamics are, the higher the contractility will be. PMID- 26536260 TI - Feedback Regulation of Intracellular Hydrostatic Pressure in Surface Cells of the Lens. AB - In wild-type lenses from various species, an intracellular hydrostatic pressure gradient goes from ~340 mmHg in central fiber cells to 0 mmHg in surface cells. This gradient drives a center-to-surface flow of intracellular fluid. In lenses in which gap-junction coupling is increased, the central pressure is lower, whereas if gap-junction coupling is reduced, the central pressure is higher but surface pressure is always zero. Recently, we found that surface cell pressure was elevated in PTEN null lenses. This suggested disruption of a feedback control system that normally maintained zero surface cell pressure. Our purpose in this study was to investigate and characterize this feedback control system. We measured intracellular hydrostatic pressures in mouse lenses using a microelectrode/manometer-based system. We found that all feedback went through transport by the Na/K ATPase, which adjusted surface cell osmolarity such that pressure was maintained at zero. We traced the regulation of Na/K ATPase activity back to either TRPV4, which sensed positive pressure and stimulated activity, or TRPV1, which sensed negative pressure and inhibited activity. The inhibitory effect of TRPV1 on Na/K pumps was shown to signal through activation of the PI3K/AKT axis. The stimulatory effect of TRPV4 was shown in previous studies to go through a different signal transduction path. Thus, there is a local two legged feedback control system for pressure in lens surface cells. The surface pressure provides a pedestal on which the pressure gradient sits, so surface pressure determines the absolute value of pressure at each radial location. We speculate that the absolute value of intracellular pressure may set the radial gradient in the refractive index, which is essential for visual acuity. PMID- 26536261 TI - Functional and Modeling Studies of the Transmembrane Region of the TRPM8 Channel. AB - Members of the transient receptor potential (TRP) ion channel family act as polymodal cellular sensors, which aid in regulating Ca(2+) homeostasis. Within the TRP family, TRPM8 is the cold receptor that forms a nonselective homotetrameric cation channel. In the absence of TRPM8 crystal structure, little is known about the relationship between structure and function. Inferences of TRPM8 structure have come from mutagenesis experiments coupled to electrophysiology, mainly regarding the fourth transmembrane helix (S4), which constitutes a moderate voltage-sensing domain, and about cold sensor and phosphatidylinositol 4,5-bisphosphate binding sites, which are both located in the C-terminus of TRPM8. In this study, we use a combination of molecular modeling and experimental techniques to examine the structure of the TRPM8 transmembrane and pore helix region including the conducting conformation of the selectivity filter. The model is consistent with a large amount of functional data and was further tested by mutagenesis. We present structural insight into the role of residues involved in intra- and intersubunit interactions and their link with the channel activity, sensitivity to icilin, menthol and cold, and impact on channel oligomerization. PMID- 26536262 TI - Importance of the Voltage Dependence of Cardiac Na/K ATPase Isozymes. AB - Cardiac cells express more than one isoform of the Na, K-ATPase (NKA), the heteromeric enzyme that creates the Na(+) and K(+) gradients across the plasmalemma. Cardiac isozymes contain one catalytic alpha-subunit isoform (alpha1, alpha2, or alpha3) associated with an auxiliary beta-subunit isoform (beta1 or beta2). Past studies using biochemical approaches have revealed minor kinetic differences between isozymes formed by different alpha-beta isoform combinations; these results make it difficult to understand the physiological requirement for multiple isoforms. In intact cells, however, NKA enzymes operate in a more complex environment, which includes a substantial transmembrane potential. We evaluated the voltage dependence of human cardiac NKA isozymes expressed in Xenopus oocytes, and of native NKA isozymes in rat ventricular myocytes, using normal mammalian physiological concentrations of Na(+)o and K(+)o. We demonstrate that although alpha1 and alpha3 pumps are functional at all physiologically relevant voltages, alpha2beta1 pumps and alpha2beta2 pumps are inhibited by ~75% and ~95%, respectively, at resting membrane potentials, and only activate appreciably upon depolarization. Furthermore, phospholemman (FXYD1) inhibits pump function without significantly altering the pump's voltage dependence. Our observations provide a simple explanation for the physiological relevance of the alpha2 subunit (~20% of total alpha subunits in rat ventricle): they act as a reserve and are recruited into action for extra pumping during the long-lasting cardiac action potential, where most of the Na(+) entry occurs. This strong voltage dependence of alpha2 pumps also helps explain how cardiotonic steroids, which block NKA pumps, can be a beneficial treatment for heart failure: by only inhibiting the alpha2 pumps, they selectively reduce NKA activity during the cardiac action potential, leading to an increase in systolic Ca(2+), due to reduced extrusion through the Na/Ca exchanger, without affecting resting Na(+) and Ca(2+) concentrations. PMID- 26536263 TI - Phosphatidylserine-Dependent Catalysis of Stalk and Pore Formation by Synaptobrevin JMR-TMD Peptide. AB - Although the importance of a SNARE complex in neurotransmitter release is widely accepted, there exist different views on how the complex promotes fusion. One hypothesis is that the SNARE complex's ability to bring membranes into contact is sufficient for fusion, another points to possible roles of juxtamembrane regions (JMRs) and transmembrane domains (TMDs) in catalyzing lipid rearrangement, and another notes the complex's presumed ability to bend membranes near the point of contact. Here, we performed experiments with highly curved vesicles brought into contact using low concentrations of polyethylene glycol (PEG) to investigate the influence of the synaptobrevin (SB) TMD with an attached JMR (SB-JMR-TMD) on the rates of stalk and pore formation during vesicle fusion. SB-JMR-TMD enhanced the rates of stalk and fusion pore (FP) formation in a sharply sigmoidal fashion. We observed an optimal influence at an average of three peptides per vesicle, but only with phosphatidylserine (PS)-containing vesicles. Approximately three SB-JMR TMDs per vesicle optimally ordered the bilayer interior and excluded water in a similar sigmoidal fashion. The catalytic influences of hexadecane and SB-JMR-TMD on fusion kinetics showed little in common, suggesting different mechanisms. Both kinetic and membrane structure measurements support the hypotheses that SB-JMR TMD 1) catalyzes initial intermediate formation as a result of its basic JMR disrupting ordered interbilayer water and permitting closer interbilayer approach, and 2) catalyzes pore formation by forming a membrane-spanning complex that increases curvature stress at the circumference of the hemifused diaphragm of the prepore intermediate state. PMID- 26536264 TI - Structural Changes and Proapoptotic Peroxidase Activity of Cardiolipin-Bound Mitochondrial Cytochrome c. AB - The cellular process of intrinsic apoptosis relies on the peroxidation of mitochondrial lipids as a critical molecular signal. Lipid peroxidation is connected to increases in mitochondrial reactive oxygen species, but there is also a required role for mitochondrial cytochrome c (cyt-c). In apoptotic mitochondria, cyt-c gains a new function as a lipid peroxidase that catalyzes the reactive oxygen species-mediated chemical modification of the mitochondrial lipid cardiolipin (CL). This peroxidase activity is caused by a conformational change in the protein, resulting from interactions between cyt-c and CL. The nature of the conformational change and how it causes this gain-of-function remain uncertain. Via a combination of functional, structural, and biophysical experiments we investigate the structure and peroxidase activity of cyt-c in its membrane-bound state. We reconstituted cyt-c with CL-containing lipid vesicles, and determined the increase in peroxidase activity resulting from membrane binding. We combined these assays of CL-induced proapoptotic activity with structural and dynamic studies of the membrane-bound protein via solid-state NMR and optical spectroscopy. Multidimensional magic angle spinning (MAS) solid-state NMR of uniformly (13)C,(15)N-labeled protein was used to detect site-specific conformational changes in oxidized and reduced horse heart cyt-c bound to CL containing lipid bilayers. MAS NMR and Fourier transform infrared measurements show that the peripherally membrane-bound cyt-c experiences significant dynamics, but also retains most or all of its secondary structure. Moreover, in two dimensional and three-dimensional MAS NMR spectra the CL-bound cyt-c displays a spectral resolution, and thus structural homogeneity, that is inconsistent with extensive membrane-induced unfolding. Cyt-c is found to interact primarily with the membrane interface, without significantly disrupting the lipid bilayer. Thus, membrane binding results in cyt-c gaining the increased peroxidase activity that represents its pivotal proapoptotic function, but we do not observe evidence for large-scale unfolding or penetration into the membrane core. PMID- 26536265 TI - Elementary Energy Transfer Pathways in Allochromatium vinosum Photosynthetic Membranes. AB - Allochromatium vinosum (formerly Chromatium vinosum) purple bacteria are known to adapt their light-harvesting strategy during growth according to environmental factors such as temperature and average light intensity. Under low light illumination or low ambient temperature conditions, most of the LH2 complexes in the photosynthetic membranes form a B820 exciton with reduced spectral overlap with LH1. To elucidate the reason for this light and temperature adaptation of the LH2 electronic structure, we performed broadband femtosecond transient absorption spectroscopy as a function of excitation wavelength in A. vinosum membranes. A target analysis of the acquired data yielded individual rate constants for all relevant elementary energy transfer (ET) processes. We found that the ET dynamics in high-light-grown membranes was well described by a homogeneous model, with forward and backward rate constants independent of the pump wavelength. Thus, the overall B800->B850->B890-> Reaction Center ET cascade is well described by simple triexponential kinetics. In the low-light-grown membranes, we found that the elementary backward transfer rate constant from B890 to B820 was strongly reduced compared with the corresponding constant from B890 to B850 in high-light-grown samples. The ET dynamics of low-light-grown membranes was strongly dependent on the pump wavelength, clearly showing that the excitation memory is not lost throughout the exciton lifetime. The observed pump energy dependence of the forward and backward ET rate constants suggests exciton diffusion via B850-> B850 transfer steps, making the overall ET dynamics nonexponential. Our results show that disorder plays a crucial role in our understanding of low-light adaptation in A. vinosum. PMID- 26536266 TI - Tuning the Photocycle Kinetics of Bacteriorhodopsin in Lipid Nanodiscs. AB - Monodisperse lipid nanodiscs are particularly suitable for characterizing membrane protein in near-native environment. To study the lipid-composition dependence of photocycle kinetics of bacteriorhodopsin (bR), transient absorption spectroscopy was utilized to monitor the evolution of the photocycle intermediates of bR reconstituted in nanodiscs composed of different ratios of the zwitterionic lipid (DMPC, dimyristoyl phosphatidylcholine; DOPC, dioleoyl phosphatidylcholine) to the negatively charged lipid (DOPG, dioleoyl phosphatidylglycerol; DMPG, dimyristoyl phosphatidylglycerol). The characterization of ion-exchange chromatography showed that the negative surface charge of nanodiscs increased as the content of DOPG or DMPG was increased. The steady-state absorption contours of the light-adapted monomeric bR in nanodiscs composed of different lipid ratios exhibited highly similar absorption features of the retinal moiety at 560 nm, referring to the conservation of the tertiary structure of bR in nanodiscs of different lipid compositions. In addition, transient absorption contours showed that the photocycle kinetics of bR was significantly retarded and the transient populations of intermediates N and O were decreased as the content of DMPG or DOPG was reduced. This observation could be attributed to the negatively charged lipid heads of DMPG and DOPG, exhibiting similar proton relay capability as the native phosphatidylglycerol (PG) analog lipids in the purple membrane. In this work, we not only demonstrated the usefulness of nanodiscs as a membrane-mimicking system, but also showed that the surrounding lipids play a crucial role in altering the biological functions, e.g., the ion translocation kinetics of the transmembrane proteins. PMID- 26536267 TI - Miscibility of Sphingomyelins and Phosphatidylcholines in Unsaturated Phosphatidylcholine Bilayers. AB - Polyunsaturated phospholipids are common in biological membranes and affect the lateral structure of bilayers. We have examined how saturated sphingomyelin (SM; palmitoyl and stearoyl SM (PSM and SSM, respectively)) and phosphatidylcholine (PC; dipalmitoyl PC and 1-palmitoyl-2-stearoyl PC (DPPC and PSPC, respectively)) segregate laterally to form ordered gel phases in increasingly unsaturated PC bilayers (sn-1: 16:0 and sn-2: 18:1...22:6; or sn-1 and sn-2: 18:1...22:6). The formation of gel phases was determined from the lifetime analysis of trans parinaric acid. Using calorimetry, we also determined gel phase formation by PSM and DPPC in unsaturated PC mixed bilayers. Comparing PSM with DPPC, we observed that PSM formed a gel phase with less order than DPPC at comparable bilayer concentrations. The same was true when SSM was compared with PSPC. Furthermore, we observed that at equal saturated phospholipid concentration, the gel phases formed were less ordered in unsaturated PCs having 16:0 in sn-1, as compared to PCs having unsaturated acyl chains in both sn-1 and sn-2. The gel phases formed by the saturated phospholipids in unsaturated PC bilayers did not appear to achieve properties similar to pure saturated phospholipid bilayers, suggesting that complete lateral phase separation did not occur. Based on scanning calorimetry analysis, the melting of the gel phases formed by PSM and DPPC in unsaturated PC mixed bilayers (at 45 mol % saturated phospholipid) had low cooperativity and hence most likely were of mixed composition, in good agreement with trans-parinaric acid lifetime data. We conclude that both interfacial properties of the saturated phospholipids and their chain length, as well as the presence of 16:0 in sn-1 of the unsaturated PCs and the total number of cis unsaturations and acyl chain length (18 to 22) of the unsaturated PCs, all affected the formation of gel phases enriched in saturated phospholipids, under the conditions used. PMID- 26536268 TI - Hemagglutinin Spatial Distribution Shifts in Response to Cholesterol in the Influenza Viral Envelope. AB - Influenza virus delivers its genome to the host cytoplasm via a process of membrane fusion mediated by the viral hemagglutinin protein. Optimal fusion likely requires multiple hemagglutinin trimers, so the spatial distribution of hemagglutinin on the viral envelope may influence fusion mechanism. We have previously shown that moderate depletion of cholesterol from the influenza viral envelope accelerates fusion kinetics even though it decreases fusion efficiency, both in a reversible manner. Here, we use electron cryo-microscopy to measure how the hemagglutinin lateral density in the viral envelope changes with cholesterol extraction. We extract this information by measuring the radial distribution function of electron density in >4000 viral images per sample, assigning hemagglutinin density by comparing images with and without anti-HA Fab bound. On average, hemagglutinin trimers move closer together: we estimate that the typical trimer-trimer spacing reduces from 94 to 84 A when ~90% of cholesterol is removed from the viral membrane. Upon restoration of viral envelope cholesterol, this spacing once again expands. This finding can qualitatively explain the observed changes to fusion kinetics: contemporary models from single-virus microscopy are that fusion requires the engagement of several hemagglutinin trimers in close proximity. If removing cholesterol increases the lateral density of hemagglutinin, this should result in an increase in the rate of fusion. PMID- 26536269 TI - Plasma Membrane Organization of Epidermal Growth Factor Receptor in Resting and Ligand-Bound States. AB - The spatial arrangement of the epidermal growth factor receptor (EGFR) on the cellular plasma membrane is one of the prime factors that control its downstream signaling pathways and related functions. However, the molecular organization, which spans the scale from nanometers to micrometer-size clusters, has not been resolved in detail, mainly due to a lack of techniques with the required spatiotemporal resolution. Therefore, we used imaging total internal reflection fluorescence correlation spectroscopy to investigate EGFR dynamics on live CHO-K1 plasma membranes in resting and ligand-bound states. In combination with the fluorescence correlation spectroscopy diffusion law, this provides information on the subresolution organization of EGFR on cell membranes. We found that overall EGFR organization is sensitive to both cholesterol and the actin cytoskeleton. EGFR in the resting state is partly trapped in cholesterol-containing domains, whereas another fraction exhibits cholesterol independent trapping on the membrane. Disruption of the cytoskeleton leads to a broader range of EGFR diffusion coefficients and a reduction of hop diffusion. In the ligand-bound state we found a dose-dependent behavior. At 10 ng/mL EGF the EGFR is endocytosed and recycled to the membrane, whereas diffusion and organization do not change significantly. At 100 ng/mL EGF the EGFR forms clusters, which are subsequently internalized, whereas outside the clusters diffusivity increases and the organization of the receptor remains unchanged. After disruption of cholesterol containing domains or actin cytoskeleton, EGF induces microscopic EGFR clusters on the membrane and endocytosis is inhibited. PMID- 26536270 TI - Class A Plexins Are Organized as Preformed Inactive Dimers on the Cell Surface. AB - Plexins are single-pass transmembrane receptors that bind the axon guidance molecules semaphorins. Single-pass transmembrane proteins are an important class of receptors that display a wide variety of activation mechanisms, often involving ligand-dependent dimerization or conformational changes. Resolving the activation mechanism and dimerization state of these receptors is extremely challenging, especially in a live-cell environment. Here, we report on the dimerization state of PlexinA4 and its response to activation by semaphorin binding. Semaphorins are dimeric molecules that activate plexin by binding two copies of plexin simultaneously and inducing formation of a specific active dimer of plexin. An open question is whether there are preexisting plexin dimers that could act as autoinhibitory complexes. We address these questions with pulsed interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS). PIE-FCCS is a two-color fluorescence microscopy method that is directly sensitive to protein dimerization in a live-cell environment. With PIE-FCCS, we show that inactive PlexinA4 is dimerized in the live-cell plasma membrane. By comparing the cross correlation of full-length PlexinA4 to control proteins and plexin mutants, we show that dimerization of inactive PlexinA4 requires the Sema domain, but not the cytoplasmic domain. Ligand stimulation with Sema6A does not change the degree of cross correlation, indicating that plexin activation does not lead to higher order oligomerization. Together, the results suggest that semaphorin activates plexin by disrupting an inhibitory plexin dimer and inducing the active dimer. PMID- 26536271 TI - Electrostatic Similarity Analysis of Human beta-Defensin Binding in the Melanocortin System. AB - The beta-defensins are a class of small cationic proteins that serve as components of numerous systems in vertebrate biology, including the immune and melanocortin systems. Human beta-defensin 3 (HBD3), which is produced in the skin, has been found to bind to melanocortin receptors 1 and 4 through complementary electrostatics, a unique mechanism of ligand-receptor interaction. This finding indicates that electrostatics alone, and not specific amino acid contact points, could be sufficient for function in this ligand-receptor system, and further suggests that other small peptide ligands could interact with these receptors in a similar fashion. Here, we conducted molecular-similarity analyses and functional studies of additional members of the human beta-defensin family, examining their potential as ligands of melanocortin-1 receptor, through selection based on their electrostatic similarity to HBD3. Using Poisson Boltzmann electrostatic calculations and molecular-similarity analysis, we identified members of the human beta-defensin family that are both similar and dissimilar to HBD3 in terms of electrostatic potential. Synthesis and functional testing of a subset of these beta-defensins showed that peptides with an HBD3 like electrostatic character bound to melanocortin receptors with high affinity, whereas those that were anticorrelated to HBD3 showed no binding affinity. These findings expand on the central role of electrostatics in the control of this ligand-receptor system and further demonstrate the utility of employing molecular similarity analysis. Additionally, we identified several new potential ligands of melanocortin-1 receptor, which may have implications for our understanding of the role defensins play in melanocortin physiology. PMID- 26536272 TI - Lack of Dependence of the Sizes of the Mesoscopic Protein Clusters on Electrostatics. AB - Protein-rich clusters of steady submicron size and narrow size distribution exist in protein solutions in apparent violation of the classical laws of phase equilibrium. Even though they contain a minor fraction of the total protein, evidence suggests that they may serve as essential precursors for the nucleation of ordered solids such as crystals, sickle-cell hemoglobin polymers, and amyloid fibrils. The cluster formation mechanism remains elusive. We use the highly basic protein lysozyme at nearly neutral and lower pH as a model and explore the response of the cluster population to the electrostatic forces, which govern numerous biophysical phenomena, including crystallization and fibrillization. We tune the strength of intermolecular electrostatic forces by varying the solution ionic strength I and pH and find that despite the weaker repulsion at higher I and pH, the cluster size remains constant. Cluster responses to the presence of urea and ethanol demonstrate that cluster formation is controlled by hydrophobic interactions between the peptide backbones, exposed to the solvent after partial protein unfolding that may lead to transient protein oligomers. These findings reveal that the mechanism of the mesoscopic clusters is fundamentally different from those underlying the two main classes of ordered protein solid phases, crystals and amyloid fibrils, and partial unfolding of the protein chain may play a significant role. PMID- 26536273 TI - Biophysical Studies of Bacterial Topoisomerases Substantiate Their Binding Modes to an Inhibitor. AB - Bacterial DNA topoisomerases are essential for bacterial growth and are attractive, important targets for developing antibacterial drugs. Consequently, different potent inhibitors that target bacterial topoisomerases have been developed. However, the development of potent broad-spectrum inhibitors against both Gram-positive (G(+)) and Gram-negative (G(-)) bacteria has proven challenging. In this study, we carried out biophysical studies to better understand the molecular interactions between a potent bis-pyridylurea inhibitor and the active domains of the E-subunits of topoisomerase IV (ParE) from a G(+) strain (Streptococcus pneumoniae (sParE)) and a G(-) strain (Pseudomonas aeruginosa (pParE)). NMR results demonstrated that the inhibitor forms a tight complex with ParEs and the resulting complexes adopt structural conformations similar to those observed for free ParEs in solution. Further chemical-shift perturbation experiments and NOE analyses indicated that there are four regions in ParE that are important for inhibitor binding, namely, alpha2, the loop between beta2 and alpha3, and the beta2 and beta6 strands. Surface plasmon resonance showed that this inhibitor binds to sParE with a higher KD than pParE. Point mutations in alpha2 of ParE, such as A52S (sParE), affected its binding affinity with the inhibitor. Taken together, these results provide a better understanding of the development of broad-spectrum antibacterial agents. PMID- 26536274 TI - Substrate Binding Specifically Modulates Domain Arrangements in Adenylate Kinase. AB - The enzyme adenylate kinase (ADK) features two substrate binding domains that undergo large-scale motions during catalysis. In the apo state, the enzyme preferentially adopts a globally open state with accessible binding sites. Binding of two substrate molecules (AMP + ATP or ADP + ADP) results in a closed domain conformation, allowing efficient phosphoryl-transfer catalysis. We employed molecular dynamics simulations to systematically investigate how the individual domain motions are modulated by the binding of substrates. Two dimensional free-energy landscapes were calculated along the opening of the two flexible lid domains for apo and holo ADK as well as for all single natural substrates bound to one of the two binding sites of ADK. The simulations reveal a strong dependence of the conformational ensembles on type and binding position of the bound substrates and a nonsymmetric behavior of the lid domains. Altogether, the ensembles suggest that, upon initial substrate binding to the corresponding lid site, the opposing lid is maintained open and accessible for subsequent substrate binding. In contrast, ATP binding to the AMP-lid induces global domain closing, preventing further substrate binding to the ATP-lid site. This might constitute a mechanism by which the enzyme avoids the formation of a stable but enzymatically unproductive state. PMID- 26536275 TI - Tomography of a Cryo-immobilized Yeast Cell Using Ptychographic Coherent X-Ray Diffractive Imaging. AB - The structural investigation of noncrystalline, soft biological matter using x rays is of rapidly increasing interest. Large-scale x-ray sources, such as synchrotrons and x-ray free electron lasers, are becoming ever brighter and make the study of such weakly scattering materials more feasible. Variants of coherent diffractive imaging (CDI) are particularly attractive, as the absence of an objective lens between sample and detector ensures that no x-ray photons scattered by a sample are lost in a limited-efficiency imaging system. Furthermore, the reconstructed complex image contains quantitative density information, most directly accessible through its phase, which is proportional to the projected electron density of the sample. If applied in three dimensions, CDI can thus recover the sample's electron density distribution. As the extension to three dimensions is accompanied by a considerable dose applied to the sample, cryogenic cooling is necessary to optimize the structural preservation of a unique sample in the beam. This, however, imposes considerable technical challenges on the experimental realization. Here, we show a route toward the solution of these challenges using ptychographic CDI (PCDI), a scanning variant of coherent imaging. We present an experimental demonstration of the combination of three-dimensional structure determination through PCDI with a cryogenically cooled biological sample--a budding yeast cell (Saccharomyces cerevisiae)--using hard (7.9 keV) synchrotron x-rays. This proof-of-principle demonstration in particular illustrates the potential of PCDI for highly sensitive, quantitative three-dimensional density determination of cryogenically cooled, hydrated, and unstained biological matter and paves the way to future studies of unique, nonreproducible biological cells at higher resolution. PMID- 26536276 TI - Poly(lactic acid)-Based in Situ Microfibrillar Composites with Enhanced Crystallization Kinetics, Mechanical Properties, Rheological Behavior, and Foaming Ability. AB - Melt blending is one of the most promising techniques for eliminating poly(lactic acid)'s (PLA) numerous drawbacks. However, success in a typical melt blending process is usually achieved through the inclusion of high concentrations of a second polymeric phase which can compromise PLA's green nature. In a pioneering study, we introduce the production of in situ microfibrillar PLA/polyamide-6 (PA6) blends as a cost-effective and efficient technique for improving PLA's properties while minimizing the required PA6 content. Predominantly biobased products, with only 3 wt % of in situ generated PA6 microfibrils (diameter ~200 nm), were shown to have dramatically improved crystallization kinetics, mechanical properties, melt elasticity and strength, and foaming-ability compared with PLA. Crucially, the microfibrillar blends were produced using an environmentally friendly and cost-effective process. Both of these qualities are essential in guarantying the viability of the proposed technique for overcoming the obstacles associated with the vast commercialization of PLA. PMID- 26536277 TI - FATHERS' AND MOTHERS' REPRESENTATIONS OF THE INFANT: ASSOCIATIONS WITH PRENATAL RISK FACTORS. AB - Parents' representations of their infants consist of parents' subjective experiences of how they perceive their infants. They provide important information about the quality of the parent-infant relationship and are closely related to parenting behavior and infant attachment. Previous studies have shown that parents' representations emerge during pregnancy. However, little is known about prenatal (risk) factors that are related to parents' representations. In a prospective study, 308 mothers and 243 fathers were followed during pregnancy and postpartum. Prenatal risk factors were assessed with an adapted version of the Dunedin Family Services Indicator (T.G. Egan et al., ; R.C. Muir et al., ). At 26 weeks' gestation and 6 months' postpartum, parents' representations of their children were assessed with the Working Model of the Child Interview (C.H. Zeanah, D. Benoit, L. Hirshberg, M.L. Barton, & C. Regan). Results showed stability between pre- and postnatal representations, with fathers having more disengaged representations than did mothers. In addition, prenatal risk factors of parenting problems were associated with the quality of parents' prenatal (only in mothers) and postnatal representations. This study provides valuable information concerning parents at risk of developing nonbalanced representations of their children. In clinical practice, these families could be monitored more intensively and may be supported in developing a more optimal parent-infant relationship. PMID- 26536278 TI - Effects of environmental enrichment and stereotypic behavior on maternal behavior and infant viability in a model carnivore, the American mink (Neovison vison). AB - In several species, stress compromises maternal behaviors that are important for infant viability (e.g. licking and grooming). Understanding how stress in captivity affects maternal behavior could therefore be beneficial, especially for carnivores in zoos and breeding centers where infant mortality is often high. We used a model carnivore--American mink--to test two hypotheses, namely that maternal investment and/or behavior is i. improved by environmental enrichment; and ii. compromised by stereotypic behavior. We observed 22 females raised in an indoor facility, 9 enriched, 13 non-enriched. At birth, and at post-natal day 20 when altricial infants were still fully dependent on their mothers, the following offspring variables were recorded: litter size, infant mortality, litter sex ratio (post-natal day 1), and weight. Maternal behavior was assessed by recording nest shape (post-natal day 1), and the frequency of licking and grooming (post natal days 1-7). Non-enriched females stereotyped more, had female-skewed litters at birth, and tended to make poorer, flatter nests. Maternal licking and grooming showed large, stable individual differences, but appeared unaffected by enrichment. High levels of maternal stereotypic behavior predicted slower offspring growth, replicating previous findings for farmed mink. Nevertheless, enrichment did not significantly increase infant growth rates nor decrease infant mortality. Due to small sample sizes, our study now needs replicating, particularly to explore the potential benefits of enrichment on nest building, sex ratio effects, and the implications of maternal licking and grooming for offspring stress reactivity. Findings could then apply to endangered mustelids like the European mink. PMID- 26536279 TI - Dissection and dissection-associated required experiences improve student performance in gross anatomy: Differences among quartiles. AB - To promote student learning, educational strategies should provide multiple levels of engagement with the subject matter. This study investigated examination data from five first year medical gross anatomy class cohorts (692 students) to determine if enhanced student performance was correlated with learning through dissection in a course that used a rotating dissection schedule coupled with peer teaching and other associated experiences. When students performed two of five weekly dissections for a given unit, their average scores on both laboratory and written examinations tended to increase as compared to when they had completed only one week of dissection (P < 0.01). However, these performance gains differed across the class strata and were related to the amount of dissection completed. Students in the upper quartile (UQS) of the class benefited when they had dissected once (92.8%) or twice (92.4%), and these scores were significantly higher than those attained when learning from peers (90.3%, P < 0.01). Students in the lower quartile (LQS) benefited most from the dissection experiences, where practical examination performance was better (77.8% and 80.5%) than when these students learned material from their peers (73.7%, P < 0.01). Although UQS benefited from dissection, LQS benefited to a greater extent in both the practical and written examinations with dissection. Although limited, these data suggest that dissection, coupled with associated educational activities, is an effective pedagogical strategy for learning. Further investigation is required to evaluate the concomitant benefits of peer teaching that are associated with the dissection experience. Anat Sci Educ 9: 238-246. (c) 2015 American Association of Anatomists. PMID- 26536280 TI - Primary Melanoma of the Penis in 3 Patients With Lichen Sclerosus. PMID- 26536281 TI - Reproductive isolation between Zaluzianskya species: the influence of volatiles and flower orientation on hawkmoth foraging choices. AB - Floral trait differences between related species may play a key role in reproductive isolation imposed by pollinators. Volatile emissions can influence pollinator choice, but how they act in combination with traits such as flower orientation is rarely studied. We compared flower-opening patterns, morphology, colour, orientation and volatile emissions for two closely related species of Zaluzianskya and their natural hybrids. Hawkmoth pollinators were tested for preference between flowers of the two species, and between flowers with manipulations of volatiles or orientation. Flowers of Z. natalensis and Z. microsiphon open at night and day, respectively, but they overlap during early evening, when hawkmoths showed a strong preference for Z. natalensis. The species have similar flower size and colour, but Z. natalensis emits more floral volatiles in the evening and presents flowers vertically face-up as opposed to horizontally in Z. microsiphon, whereas natural hybrids are intermediate. Adding methyl benzoate and linalool to flowers of Z. microsiphon did not increase hawkmoth attraction, but re-orientation of flowers to face vertically increased attraction when scent cues were present, whereas re-orientation of Z. natalensis flowers to face horizontally decreased attraction. This study highlights the importance of flower orientation in imposing reproductive isolation. PMID- 26536282 TI - Evaluation of the Perceived Association Between Resident Turnover and the Outcomes of Patients Who Undergo Emergency General Surgery: Questioning the July Phenomenon. AB - IMPORTANCE: The influx of new surgical residents and interns at the beginning of the academic year is assumed to be associated with poor outcomes. Referred to as the July phenomenon, this occurrence has been anecdotally associated with increases in the frequency of medical errors due to intern inexperience. Studies in various surgical specialties provide conflicting results. OBJECTIVE: To determine whether an association between the July phenomenon and outcomes exists among a nationally representative sample of patients who underwent emergency general surgery (EGS). DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of data from the 2007-2011 Nationwide Inpatient Sample. Data on adult patients (>=16 years of age) presenting to teaching hospitals with a principal diagnosis of an EGS condition, as defined by the American Association for the Surgery of Trauma, were retrospectively analyzed. The patients who were included in our study were dichotomized into early (July-August) vs late (September-June) management. The original analyses were conducted in March 2015. MAIN OUTCOMES AND MEASURES: Risk-adjusted multivariable regression based on calculated propensity scores was assessed for associations with differences in in-hospital mortality, complications, length of stay, and total hospital cost. RESULTS: A total of 1,433,528 patients who underwent EGS were included, weighted to represent 7,095,045 patients from 581 teaching hospitals nationwide; 17.6% were managed early. Relative to patients managed later, early patients had marginally lower risk-adjusted odds of mortality (odds ratio [OR], 0.96 [95% CI, 0.92-0.99]), complications (OR, 0.98 [95% CI, 0.96-0.99]), and developing a secondary EGS condition (OR, 0.97 [95% CI, 0.97-0.98]). Length of stay and total hospital cost were comparable between the 2 groups (P > .05). CONCLUSIONS AND RELEVANCE: Contrary to expectations, the EGS patients who were managed early fared equally well, if not better, than the EGS patients who were managed later. Potentially attributable to increased manpower and/or hypervigilance on the part of supervising senior residents or attending physicians, the results suggest that concerns among EGS patients related to the July phenomenon are unfounded. PMID- 26536283 TI - Photocatalytic Stability of Single- and Few-Layer MoS2. AB - MoS2 crystals exhibit excellent catalytic properties and great potential for photocatalytic production of solar fuels such as hydrogen gas. In this regard, the photocatalytic stability of exfoliated single- and few-layer MoS2 immersed in water is investigated by MU-Raman spectroscopy. We find that while the basal plane of MoS2 can be treated as stable under photocatalytic conditions, the edge sites and presumably also defect sites are highly affected by a photoinduced corrosion process. The edge sites of MoS2 monolayers are significantly more resistant to photocatalytic degradation compared to MoS2 multilayer edge sites. The photostability of MoS2 edge sites depends on the photon energy with respect to the band gap in MoS2 and also on the presence of oxygen in the electrolyte. These findings are interpreted in the framework of an oxidation process converting MoS2 into MoOx in the presence of oxygen and photoinduced charge carriers. The high stability of the MoS2 basal plane under photocatalytic treatment under visible light irradiation of extreme light intensities on the order of P ~ 10 mW/MUm(2) substantiates MoS2's potential as photocatalyst for solar hydrogen production. PMID- 26536284 TI - Radiosurgery for Pediatric Brain Tumors. AB - The utility of radiosurgery for pediatric brain tumors is not well known. For children, radiosurgery may have an important role for treating unresectable tumors, residual disease, or tumors in the recurrent setting that have received prior radiotherapy. The available evidence demonstrates utility for some children with primary brain tumors resulting in good local control. Radiosurgery can be considered for limited residual disease or focal recurrences. However, the potential toxicities are unique and not insignificant. Therefore, prospective studies need to be performed to develop guidelines for indications and treatment for children and reduce toxicity in this population. PMID- 26536286 TI - Mitogen-Activated Protein Kinase Pathway: Genetic Analysis of 95 Adrenocortical Tumors. AB - Mitogen-activated protein kinase (MAPK) pathway is often deregulated in adrenocortical tumors (ACT) but with no concrete data confirming alteration rate. The objective of this study was to evaluate genetic alterations in key components of MAPK pathway. We found one BRAF mutation (p.V600E) and four HRAS silent mutations. No alteration was found in NRAS, KRAS, EGFR genes. The patient carrying BRAF mutation was further characterized by investigating his biomolecular and clinico-pathological findings. Therefore, even if MAPK signaling is activated in ACT, our results suggest that genetic alterations do not seem to represent a frequent mechanism of ACT tumorigenesis. PMID- 26536285 TI - Disease homogeneity and treatment heterogeneity in idiopathic subglottic stenosis. AB - OBJECTIVES/HYPOTHESIS: Idiopathic subglottic stenosis (iSGS) is a rare and potentially life-threatening disease marked by recurrent and progressive airway obstruction frequently requiring repeated surgery to stabilize the airway. Unknown etiology and low disease prevalence have limited the ability to characterize the natural history of iSGS and resulted in variability in surgical management. It is uncertain how this variation relates to clinical outcomes. STUDY DESIGN: Medical record abstraction. METHODS: Utilizing an international, multi-institutional collaborative, we collected retrospective data on patient characteristics, treatment, and clinical outcomes. We investigated variation between and within open and endoscopic treatment approaches and assessed therapeutic outcomes; specifically, disease recurrence and need for tracheostomy at last follow-up. RESULTS: Strikingly, 479 iSGS patients across 10 participating centers were nearly exclusively female (98%, 95% confidence interval [CI], 96.1 99.6), Caucasian (95%, 95% CI, 92.2-98.8), and otherwise healthy (mean age adjusted Charlson Comorbidity Index 1.5; 95% CI, 1.44-1.69). The patients presented at a mean age of 50 years (95% CI, 48.8-51.1). A total of 80.2% were managed endoscopically, whereas 19.8% underwent open reconstruction. Endoscopic surgery had a significantly higher rate of disease recurrence than the open approach (chi(2) = 4.09, P = 0.043). Tracheostomy was avoided in 97% of patients irrespective of surgical approach (95% CI, 94.5-99.8). Interestingly, there were outliers in rates of disease recurrence between centers using similar treatment approaches. CONCLUSION: Idiopathic subglottic stenosis patients are surprisingly homogeneous. The heterogeneity of treatment approaches and the observed outliers in disease recurrence rates between centers raises the potential for improved clinical outcomes through a detailed understanding of the processes of care. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1390-1396, 2016. PMID- 26536287 TI - Cellular resilience. AB - Cellular resilience describes the ability of a cell to cope with environmental changes such as toxicant exposure. If cellular metabolism does not collapse directly after the hit or end in programmed cell death, the ensuing stress responses promote a new homeostasis under stress. The processes of reverting "back to normal" and reversal of apoptosis ("anastasis") have been studied little at the cellular level. Cell types show astonishingly similar vulnerability to most toxicants, except for those that require a very specific target, metabolism or mechanism present only in specific cell types. The majority of chemicals triggers "general cytotoxicity" in any cell at similar concentrations. We hypothesize that cells differ less in their vulnerability to a given toxicant than in their resilience (coping with the "hit"). In many cases, cells do not return to the naive state after a toxic insult. The phenomena of "pre conditioning", "tolerance" and "hormesis" describe this for low-dose exposures to toxicants that render the cell more resistant to subsequent hits. The defense and resilience programs include epigenetic changes that leave a "memory/scar" - an alteration as a consequence of the stress the cell has experienced. These memories might have long-term consequences, both positive (resistance) and negative, that contribute to chronic and delayed manifestations of hazard and, ultimately, disease. This article calls for more systematic analyses of how cells cope with toxic perturbations in the long-term after stressor withdrawal. A technical prerequisite for these are stable (organotypic) cultures and a characterization of stress response molecular networks. PMID- 26536288 TI - Animal use for science in Europe. AB - To investigate long-term trends of animal use, the EU animal use statistics from the 15 countries that have been in the EU since 1995 plus respective data from Switzerland were analyzed. The overall number of animals used for scientific purposes in these countries, i.e., about 11 million/year, remained relatively constant between 1995 and 2011, with net increases in Germany and the UK and net decreases in Belgium, Denmark, Italy, Finland, the Netherlands and Sweden. The relatively low and constant numbers of experimental animals used for safety assessment (toxicology, 8%) may be due to the particularly intensive research on alternative methods in this area. The many efficiently working NGOs, multiple initiatives of the European Parliament, and coordinated activities of industry and the European Commission may have contributed to keeping the animal numbers in this field in check. Basic biological science, and research and development for medicine, veterinary and dentistry together currently make up 65% of animal use in science. Although the total numbers have remained relatively constant, consumption of transgenic animals has increased drastically; in Germany transgenic animals accounted for 30% of total animal use in 2011. Therefore, more focus on alternatives to the use of animals in biomedical research, in particular on transgenic animals, will be important in the future. One initiative designed to provide inter-sector information exchange for future actions is the "MEP - 3Rs scientists pairing scheme" initiated in 2015 by CAAT-Europe and MEP Pietikainen. PMID- 26536289 TI - Erratum: Regulatory Acceptance and Use of Serology for Inactivated Veterinary Rabies Vaccines. PMID- 26536290 TI - Quality assurance of metabolomics. AB - Metabolomics promises a holistic phenotypic characterization of biological responses to toxicants. This technology is based on advanced chemical analytical tools with reasonable throughput, including mass-spectroscopy and NMR. Quality assurance, however - from experimental design, sample preparation, metabolite identification, to bioinformatics data-mining - is urgently needed to assure both quality of metabolomics data and reproducibility of biological models. In contrast to microarray-based transcriptomics, where consensus on quality assurance and reporting standards has been fostered over the last two decades, quality assurance of metabolomics is only now emerging. Regulatory use in safety sciences, and even proper scientific use of these technologies, demand quality assurance. In an effort to promote this discussion, an expert workshop discussed the quality assurance needs of metabolomics. The goals for this workshop were 1) to consider the challenges associated with metabolomics as an emerging science, with an emphasis on its application in toxicology and 2) to identify the key issues to be addressed in order to establish and implement quality assurance procedures in metabolomics-based toxicology. Consensus has still to be achieved regarding best practices to make sure sound, useful, and relevant information is derived from these new tools. PMID- 26536292 TI - First training on alternatives to animal experimentation in Tunisia. PMID- 26536291 TI - Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology. AB - Models of the outer epithelia of the human body - namely the skin, the intestine and the lung - have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report. PMID- 26536293 TI - No alternatives? Animal experimentation and the future of research. PMID- 26536294 TI - Finding opportunities in the area of Alternative Methods to Animal Testing for Romania and inauguration of the Romanian Center for Alternative Test Methods (ROCAM). PMID- 26536295 TI - Risk assessment scores for patients with upper gastrointestinal bleeding and their use in clinical practice. AB - Upper gastrointestinal bleeding (UGIB) is a common cause for emergency admission to hospital representing a significant clinical as well as economic burden. UGIB encompasses a wide range of severities from life-threatening exsanguination to minor bleeding that may not require hospital admission. Patients with UGIB are often initially assessed and managed by junior doctors and non gastroenterologists. Several risk scores have been created for the assessment of these patients, some requiring endoscopic data for calculation and others that are calculable from clinical data alone. A key question in clinical practice is how to accurately identify patients with UGIB at high risk of adverse outcome. Patients considered high risk are more likely to experience adverse outcomes and will require urgent intervention. In contrast, those patients with UGIB who are considered to be low risk could potentially be managed on an outpatient basis. The Glasgow Blatchford Score (GBS) appears best at identifying patients at low risk of requiring intervention or death and therefore may be best for use in clinical practice, allowing outpatient management in low risk cases. There has been some debate as to the optimal GBS cut-off score for safely identifying this low-risk group. Many guidelines suggest that patients with a GBS of zero can be safely managed as outpatients, but more recent studies have suggested that this threshold could potentially be safely increased to <=1. Most other patients require inpatient endoscopy within 24 h and the full Rockall score remains important for risk assessment following endoscopy, particularly as it includes the endoscopic diagnosis. A minority of patients will require emergency endoscopy following resuscitation, but at present there is no evidence that risk scores can accurately identify this very high-risk group. Studies have shown the latest risk assessment score, the AIMS65, looks promising in the prediction of mortality. However, to date there is no data on the use of the AIMS65 in identifying low risk patients for possible outpatient management. PMID- 26536296 TI - A theoretical exploration on electronically excited states of protonated furan and thiophene. AB - The geometry, electronic structures and potential energy profiles of protonated furan and thiophene have been extensively investigated, using the RI-MP2 and RI CC2 methods. According to RI-CC2 calculated results, the adiabatic S1((1)pipi*) S0 transition energies of protonated furan and thiophene, have been predicted to be 4.41 eV and 3.70 eV respectively. Thus, protonation is accompanied by a large red shift effect on the first (1)pipi* transition of the title systems (DeltaE > 1.5 eV). The significant spectral-movements, predicted based on the calculated results of this work, indicate an essential effect of protonation on the geometry, electronic structures and optical characters of the five membered heterocyclic systems. In addition, it has been found that excitation of protonated furan and thiophene, with sufficient excess energy above the band origin of S1((1)pipi*)-S0 transition, is accompanied by the S-C or O-C bond breaking. This mechanism is mostly governed by a dissociative (1)pisigma* PE profile in both protonated systems. PMID- 26536297 TI - Australian physiotherapy workforce at a glance: a narrative review. AB - Background The ability of the physiotherapy workforce to meet the growing demand in the Australian community is uncertain, despite increasing tertiary students and numbers of registered physiotherapists annually. Objectives The present narrative literature review investigates what is known about the Australian physiotherapy workforce, what factors contribute to attrition from the profession and what strategies could be implemented to improve retention of skilled physiotherapists. Methods A literature search of five databases identified 24 articles that informed the content of the present review. The articles were reviewed and content summarised according to focus areas and results discussed in the current Australian healthcare context. Results Although many factors of attrition are inevitable, the present review identified some potentially modifiable factors of attrition. Strategies to improve retention of skilled physiotherapists were broadly grouped into improving professional support in the workforce and assisting the re-entry process for physiotherapists seeking to return to the workforce. Conclusion Increasing retention of qualified and skilled physiotherapists nationally will help build workforce capacity, meeting the needs of the growing, changing and aging community. What is known about the topic? The demand for physiotherapists is growing significantly in Australia and the ability of the workforce to meet growing demands is uncertain. What does this paper add? Many physiotherapists in Australia leave the workforce and the profession early in their careers. Addressing modifiable factors of attrition could help improve the retention of practitioners and skills in the profession, building workforce capacity. What are the implications for practitioners? Professional support for current physiotherapists is crucial. Re-entry physiotherapists should be supported with flexible return-to-work programs, refresher training and mentorship. PMID- 26536298 TI - Regio- and Stereoselective 1,3-Dipolar Cycloaddition of Cyclic Azomethine Imines to Platinum(IV)-Bound Nitriles Giving Delta(2)-1,2,4-Triazoline Species. AB - The complex trans-[PtCl4(EtCN)2] (14) reacts smoothly at 25 degrees C with the stable cyclic azomethine imines R(1)CH?N(a)NC(O)CH(NHC(O)C6H4R(3))C(b)H(C6H4R(2))((a-b)) [R(1)/R(2)/R(3) = p Me/H/H (8); p-Me/p-Me/H (9); p-Me/p-MeO/H (10); p-Me/p-Cl/p-Cl (11); p-MeO/p-Me/H (12); p-MeO/p-Cl/m-Me (13)], and the reaction proceeds as stereoselective 1,3 dipolar cycloaddition to one of the EtCN ligands accomplishing the monocycloadducts trans [PtCl4(EtCN){N(a)?C(Et)N(b)C(O)CH(NHC(O)C6H4R(3))CH(C6H4R(2))N(c)C(d)HR(1)}])((a d;b-c)) [R(1)/R(2)/R(3) = p-Me/H/H (15); p-Me/p-Me/H (16); p-Me/p-MeO/H (17); p Me/p-Cl/p-Cl (18); p-MeO/p-Me/H (19); p-MeO/p-Cl/m-Me (20)]. Inspection of the obtained and literature data indicate that the cycloaddition of the azomethine imines to the C=N bonds of HCN and of Pt(IV)-bound EtCN has different regioselectivity leading to Delta(2)-1,2,3-triazolines and Delta(2)-1,2,4 triazolines, respectively. Platinum(II) species trans [PtCl2(EtCN){N(a)?C(Et)N(b)C(O)CH(NHC(O)C6H4R(3))CH(C6H4R(2))N(c)C(d)HR(1)}]((a d;b-c)) [R(1)/R(2)/R(3) = p-Me/H/H (21); p-Me/p-Me/H (22); p-Me/p-MeO/H (23); p Me/p-Cl/p-Cl (24); p-MeO/p-Me/H (25); p-MeO/p-Cl/m-Me (26)] were obtained by a one-pot procedure from 14 and 8-13 followed by addition of the phosphorus ylide Ph3P?CHCO2Me. Delta(2)-1,2,4-Triazolines N(a)?C(Et)N(b)C(O)CH(NHC(O)C6H4R(3))CH(C6H4R(2))N(c)C(d)HR(1(a-d;b-c)) [R(1)/R(2)/R(3) = p-Me/H/H (27); p-Me/p-Me/H (28); p-Me/p-MeO/H (29); p-Me/p-Cl/p Cl (30); p-MeO/p-Me/H (31); p-MeO/p-Cl/m-Me (32)] were liberated from 21-26 by the treatment with bis(diphenylphosphyno)ethane (dppe). Platinum(II) complexes 21 26 were characterized by elemental analyses (C, H, N), high-resolution electrospray ionization mass spectrometry (ESI-MS), and IR and (1)H and (13)C{(1)H} NMR spectroscopies and single crystal X-ray diffraction in the solid state for 25.CH3OH, 26.(CHCl3)0.84. The structure of 26 was also determined by COSY-90 and NOESY NMR methods in solution. Quantitative evaluation of several pairs of interproton distances obtained by NMR and X-ray diffraction agrees well with each other and with those obtained by the MM+ calculation method. Platinum(IV) complexes 15-20 were characterized by (1)H NMR spectroscopy. Metal free 6,7-dihydropyrazolo[1,2-a][1,2,4]triazoles (27-32) were characterized by high-resolution ESI-MS and IR and (1)H and (13)C{(1)H} NMR spectroscopies and single crystal X-ray diffraction for 29.CDCl3. Theoretical density functional theory calculations were carried out for the investigation of the reaction mechanism, interpretation of the reactivity of Pt-bound and free nitriles toward azomethine imines and analysis of the regio- and stereoselectivity origin. PMID- 26536299 TI - Laquinimod (ABR-215062) for the treatment of relapsing multiple sclerosis. AB - Laquinimod (ABR-215062) is an oral immunomodulatory agent developed for the treatment of relapsing multiple sclerosis (MS). Laquinimod is a derivative of the drug roquinimex, but lacks the unacceptable side effect profile of this drug which was documented in previous MS trials. Preclinical studies in experimental models of MS, both of autoimmune neuroinflammation and of toxin induced demyelination show a multitude of immunomodulatory and anti-inflammatory effects, including some that are effective directly in the central nervous system. Phase I study results confirmed the safety and tolerability of laquinimod, and phase II and III studies provide a picture of a consistent albeit moderate effect on relapse rate and new lesion development on magnetic resonance imaging combined with a stronger effect on sustained progression and brain atrophy. These findings make laquinimod a potentially useful future treatment of MS. PMID- 26536300 TI - Magnetic-Responsive Release Controlled by Hot Spot Effect. AB - Magnetically triggered drug delivery nanodevices have attracted great attention in nanomedicine, as they can feature as smart carriers releasing their payload at clinician's will. The key principle of these devices is based on the properties of magnetic cores to generate thermal energy in the presence of an alternating magnetic field. Then, the temperature increase triggers the drug release. Despite this potential, the rapid heat dissipation in living tissues is a serious hindrance for their clinical application. It is hypothesized that magnetic cores could act as hot spots, this is, produce enough heat to trigger the release without the necessity to increase the global temperature. Herein, a nanocarrier has been designed to respond when the temperature reaches 43 degrees C. This material has been able to release its payload under an alternating magnetic field without the need of increasing the global temperature of the environment, proving the efficacy of the hot spot mechanism in magnetic-responsive drug delivery devices. PMID- 26536301 TI - The House and the ACA--A Lawsuit over Cost-Sharing Reductions. PMID- 26536302 TI - Coronary atherosclerosis and risk of acute coronary syndromes in chronic kidney disease using angioscopy and the kidney disease: Improving Global Outcomes (KDIGO) classification. AB - OBJECTIVE: This 8-year follow-up cohort study evaluated and compared the degree of coronary atherosclerosis in chronic kidney disease (CKD) according to the Kidney Disease: Improving Global Outcomes (KDIGO) classification using multivessel angioscopy and investigated the impact of the vulnerability of coronary arteries on the relationship between the classification and risk of acute coronary syndromes (ACS). METHODS: We studied 89 coronary artery disease patients who underwent angioscopic observation of multiple coronary arteries. The patients were divided into 3 groups: Risk 0, 1, and 2 were equivalent to low risk, moderately high risk, and high and severely high risk, respectively. We examined the frequencies of complex and yellow plaques. Furthermore, we followed all patients for de novo ACS, dividing into two groups according to the existence of vulnerable coronary atherosclerosis (VCA) based on angioscopic findings. RESULTS: The number of yellow plaques per vessel, maximum yellow grade, number of complex plaques per vessel, and cumulative incidence of ACS in all patients were significantly associated with Risk grade progression (p < 0.05 for trend). Among the patients with VCA, Risk 2 had a higher incidence of ACS than Risk0 (p < 0.014) and Risk 1 (p < 0.007), whereas Risk 0 and Risk 1 had similar outcomes. Among the patients without VCA, no de novo ACS events were seen regardless of the Risk group. CONCLUSIONS: Coronary atherosclerosis progressed in the early stages of CKD, and once it reached to a vulnerable stage, advanced CKD patients had a synergistically increased risk of ACS. PMID- 26536303 TI - Oral microbiota in patients with atherosclerosis. AB - BACKGROUND AND AIMS: Recent evidence suggests that the microbiota may be considered as an environmental factor that contributes to the development of atherosclerosis. Periodontal disease has been associated with cardio- and cerebrovascular events, and inflammation in the periodontium is suggested to increase the systemic inflammatory level of the host, which may in turn influence plaque composition and rupture. We previously showed that bacteria from the oral cavity and the gut could be found in atherosclerotic plaques. METHODS: To elucidate whether the oral microbiota composition differed between patients with asymptomatic and symptomatic atherosclerosis we performed pyrosequencing of the oral microbiota of 92 individuals including patients with asymptomatic and symptomatic atherosclerosis and control individuals without carotid plaques or previous stroke or myocardial infarction. RESULTS: The overall microbial structure was similar in controls and atherosclerosis patients, but patients with symptomatic atherosclerosis had higher relative abundance of Anaeroglobus (mean 0.040% (SD 0.049)) than the control group (0.010% (SD 0.028)) (P = 0.03). Using linear regression analysis, we found that Parvimonas associated positively with uCRP and Capnocytophaga, Catonella and Lactobacillus associated with blood lipid markers. In conclusion, abundance of Anaeroglobus in the oral cavity could be associated with symptomatic atherosclerosis. PMID- 26536304 TI - A progressive-duration schedule of reinforcement. AB - We describe a schedule of reinforcement involving systematic, within-session increases in response-duration requirements. Rats received access to appetitive reinforcers for depressing and holding down a response lever. Duration requirements increased after each reinforcer delivery. Sessions ended when reinforcement criteria were unmet for a period of ten minutes. Breaking points, defined as the terminal duration requirement in effect prior to the end of the session, stabilized when environmental conditions were held constant. Breaking points were sensitive to manipulations of both food deprivation and reinforcer quality. Analogous to progressive-ratio schedules, progressive-duration schedules may provide an assay for measuring the amount of behavior an organism will emit for a given reinforcer under current motivational conditions. PMID- 26536308 TI - Visualizing the Propagation of Acute Lung Injury. AB - BACKGROUND: Mechanical ventilation worsens acute respiratory distress syndrome, but this secondary "ventilator-associated" injury is variable and difficult to predict. The authors aimed to visualize the propagation of such ventilator induced injury, in the presence (and absence) of a primary underlying lung injury, and to determine the predictors of propagation. METHODS: Anesthetized rats (n = 20) received acid aspiration (hydrochloric acid) followed by ventilation with moderate tidal volume (V(T)). In animals surviving ventilation for at least 2 h, propagation of injury was quantified by using serial computed tomography. Baseline lung status was assessed by oxygenation, lung weight, and lung strain (V(T)/expiratory lung volume). Separate groups of rats without hydrochloric acid aspiration were ventilated with large (n = 10) or moderate (n = 6) V(T). RESULTS: In 15 rats surviving longer than 2 h, computed tomography opacities spread outward from the initial site of injury. Propagation was associated with higher baseline strain (propagation vs. no propagation [mean +/- SD]: 1.52 +/- 0.13 vs. 1.16 +/- 0.20, P < 0.01) but similar oxygenation and lung weight. Propagation did not occur where baseline strain was less than 1.29. In healthy animals, large V(T) caused injury that was propagated inward from the lung periphery; in the absence of preexisting injury, propagation did not occur where strain was less than 2.0. CONCLUSIONS: Compared with healthy lungs, underlying injury causes propagation to occur at a lower strain threshold and it originates at the site of injury; this suggests that tissue around the primary lesion is more sensitive. Understanding how injury is propagated may ultimately facilitate a more individualized monitoring or management. PMID- 26536309 TI - Kinetic Role of Carbon in Solid-State Synthesis of Zirconium Diboride using Nanolaminates: Nanocalorimetry Experiments and First-Principles Calculations. AB - Reactive nanolaminates afford a promising route for the low-temperature synthesis of zirconium diboride, an ultrahigh-temperature ceramic with metallic properties. Although the addition of carbon is known to facilitate sintering of ZrB2, its effect on the kinetics of the formation reaction has not been elucidated. We have employed a combined approach of nanocalorimetry and first-principles theoretical studies to investigate the kinetic role of carbon in the synthesis of ZrB2 using B4C/Zr reactive nanolaminates. Structural characterization of the laminates by XRD and TEM reveal that the reaction proceeds via interdiffusion of the B4C and Zr layers, which produces an amorphous Zr3B4C alloy. This amorphous alloy then crystallizes to form a supersaturated ZrB2(C) compound. A kinetic analysis shows that carbon lowers the energy barriers for both interdiffusion and crystallization by more than 20%. Energetic calculations based on first principles modeling suggest that the reduction of the diffusion barrier may be attributed to the stronger bonding between Zr and C as compared to the bonding between Zr and B. PMID- 26536310 TI - A Simplified Whole-Organ CT Perfusion Technique with Biphasic Acquisition: Preliminary Investigation of Accuracy and Protocol Feasibility in Kidneys. AB - PURPOSE: To determine the feasibility and accuracy of a protocol for calculating whole-organ renal perfusion (renal blood flow [RBF]) and regional perfusion on the basis of biphasic computed tomography (CT), with concurrent dynamic contrast material-enhanced (DCE) CT perfusion serving as the reference standard. MATERIALS AND METHODS: This prospective study was approved by the institutional review board, and written informed consent was obtained from all patients. Biphasic CT of the kidneys, including precontrast and arterial phase imaging, was integrated with a first-pass dynamic volume CT protocol and performed and analyzed in 23 patients suspected of having renal artery stenosis. The perfusion value derived from biphasic CT was calculated as CT number enhancement divided by the area under the arterial input function and compared with the DCE CT perfusion data by using the paired t test, correlation analysis, and Bland-Altman plots. Correlation analysis was made between the RBF and the extent of renal artery stenosis. All postprocessing was independently performed by two observers and then averaged as the final result. RESULTS: Mean +/- standard deviation biphasic and DCE CT perfusion data for RBF were 425.62 mL/min +/- 124.74 and 419.81 mL/min +/- 121.13, respectively (P = .53), and for regional perfusion they were 271.15 mL/min per 100 mL +/- 82.21 and 266.33 mL/min per 100 mL +/- 74.40, respectively (P = .31). Good correlation and agreement were shown between biphasic and DCE CT perfusion for RBF (r = 0.93; +/-10% variation from mean perfusion data [P < .001]) and for regional perfusion (r = 0.90; +/-13% variation from mean perfusion data [P < .001]). The extent of renal artery stenosis was negatively correlated with RBF with biphasic CT perfusion (r = -0.81, P = .012). CONCLUSION: Biphasic CT perfusion is clinically feasible and provides perfusion data comparable to DCE CT perfusion data at both global and regional levels in the kidney. Online supplemental material is available for this article. PMID- 26536311 TI - White Matter Degeneration with Aging: Longitudinal Diffusion MR Imaging Analysis. AB - PURPOSE: To determine longitudinally the rate of change in diffusion-tensor imaging (DTI) parameters of white matter microstructure with aging and to investigate whether cardiovascular risk factors influence this longitudinal change. MATERIALS AND METHODS: This prospective population-based cohort study was approved by a dedicated ethics committee overseen by the national government, and all participants gave written informed consent. Community-dwelling participants without dementia were examined by using a research-dedicated 1.5-T magnetic resonance (MR) imager on two separate visits that were, on average, 2.0 years apart. Among 810 persons who were eligible for imaging at baseline, longitudinal imaging data were available for 501 persons (mean age, 69.9 years; age range, 64.1-91.1 years). Changes in normal-appearing white matter DTI characteristics in the tract centers were analyzed globally to investigate diffuse patterns of change and then locally by using voxelwise multilinear regression. The influence of cardiovascular risk factors was assessed by treating them as additional determinants in both analyses. RESULTS: Over the 2.0-year follow-up interval, global fractional anisotropy (FA) decreased by 0.0042 (P < .001), while mean diffusivity (MD) increased by 8.1 * 10(-6) mm(2)/sec (P < .001). Voxelwise analysis of the brain white matter skeleton showed an average decrease of 0.0082 (Pmean = .002) in FA in 57% of skeleton voxels. The sensorimotor pathway, however, showed an increase of 0.0078 (Pmean = .009) in FA. MD increased by 10.8 * 10(-6)mm(2)/sec (Pmean < .001) on average in 79% of white matter skeleton voxels. Additionally, white matter degeneration was more pronounced in older persons. Cardiovascular risk factors were generally not associated with longitudinal changes in white matter microstructure. CONCLUSION: Longitudinal diffusion analysis indicates widespread microstructural deterioration of the normal-appearing white matter in normal aging, with relative sparing of sensorimotor fibers. PMID- 26536312 TI - Is food allergen analysis flawed? Health and supply chain risks and a proposed framework to address urgent analytical needs. AB - Food allergy is an increasing problem for those affected, their families or carers, the food industry and for regulators. The food supply chain is highly vulnerable to fraud involving food allergens, risking fatalities and severe reputational damage to the food industry. Many facets are being pursued to ameliorate the difficulties including better food labelling and the concept of thresholds of elicitation of allergy symptoms as risk management tools. These efforts depend to a high degree on the ability reliably to detect and quantify food allergens; yet all current analytical approaches exhibit severe deficiencies that jeopardise accurate results being produced particularly in terms of the risks of false positive and false negative reporting. If we fail to realise the promise of current risk assessment and risk management of food allergens through lack of the ability to measure food allergens reproducibly and with traceability to an international unit of measurement, the analytical community will have failed a significant societal challenge. Three distinct but interrelated areas of analytical work are urgently needed to address the substantial gaps identified: (a) a coordinated international programme for the production of properly characterised clinically relevant reference materials and calibrants for food allergen analysis; (b) an international programme to widen the scope of proteomics and genomics bioinformatics for the genera containing the major allergens to address problems in ELISA, MS and DNA methods; (c) the initiation of a coordinated international programme leading to reference methods for allergen proteins that provide results traceable to the SI. This article describes in more detail food allergy, the risks of inapplicable or flawed allergen analyses with examples and a proposed framework, including clinically relevant incurred allergen concentrations, to address the currently unmet and urgently required analytical requirements. Support for the above recommendations from food authorities, business organisations and National Measurement Institutes is important; however transparent international coordination is essential. Thus our recommendations are primarily addressed to the European Commission, the Health and Food Safety Directorate, DG Sante. A global multidisciplinary consortium is required to provide a curated suite of data including genomic and proteomic data on key allergenic food sources, made publically available on line. PMID- 26536313 TI - Associations of Genetically Determined Continental Ancestry With CD4+ Count and Plasma HIV-1 RNA Beyond Self-Reported Race and Ethnicity. AB - BACKGROUND: Ancestry informative markers (AIMs) measure genetic admixtures within an individual beyond self-reported racial/ethnic (SRR) groups. Here, we used genetically determined ancestry (GDA) across SRR groups and examine associations between GDA and HIV-1 RNA and CD4 counts in HIV-positive children in the United States. METHODS: Forty-one AIMs, developed to distinguish 7 continental regions, were detected by real-time PCR in 994 HIV-positive, antiretroviral naive children. GDA was estimated comparing each individual's genotypes to allele frequencies found in a large set of reference individuals originating from global populations using STRUCTURE. The means of GDA were calculated for each category of SRR. Linear regression was used to model GDA on CD4 count and log10 RNA, adjusting for SRR and age. RESULTS: Subjects were 61% black, 25% Hispanic, 13% white, and 1.3% Unknown. The mean age was 2.3 years (45% male), mean CD4 count of 981 cells per cubic millimeter, and mean log10 RNA of 5.11. Marked heterogeneity was found for all SRR groups with high admixture for Hispanics. In adjusted linear regression models, subjects with 100% European ancestry were estimated to have 0.33 higher log10 RNA levels (95% CI: 0.03 to 0.62, P = 0.028) and 253 CD4 cells per cubic millimeter lower (95% CI: -517 to 11, P = 0.06) in CD4 count, compared to subjects with 100% African ancestry. CONCLUSION: Marked continental admixture was found among this cohort of HIV-infected children from the United States. GDA contributed to differences in RNA and CD4 counts beyond SRR and should be considered when outcomes associated with HIV infection are likely to have a genetic component. PMID- 26536315 TI - Participants' Explanations for Nonadherence in the FEM-PrEP Clinical Trial. AB - BACKGROUND: FEM-PrEP-a clinical trial of daily, oral emtricitabine/tenofovir disoproxil fumarate for HIV prevention among women in sub-Saharan Africa-did not show a reduction in HIV acquisition because of low adherence to the study pill. We conducted a follow-up study to identify reasons for nonadherence. METHODS: Qualitative, semistructured interviews (n = 88) and quantitative, audio computer assisted self-interviews (n = 224) were conducted with former FEM-PrEP participants in Bondo, Kenya, and Pretoria, South Africa. Thematic analysis was used to analyze the qualitative data, and descriptive statistics were used to describe audio computer-assisted self-interviews responses. Data are presented within the 5 categories of Ickovics' and Meisler's conceptual framework on adherence: (1) the individual, (2) trial characteristics and study pill regimen, (3) patient-provider relationship, (4) clinical setting, and (5) the disease. RESULTS: Participants' explanations for nonadherence were primarily situated within 3 of the framework's 5 categories: (1) the individual, (2) trial characteristics and study pill regimen, and (3) the disease. Concerns about the investigational nature of the drug being tested and side effects were the prominent reasons reported for nonadherence. Participants also described being discouraged from taking the study pill by members of the community, their sexual partners, and other participants, primarily because of these same concerns. Limited acceptability of the pill's attributes influenced nonadherence for some participants as did concerns about HIV-related stigma. In addition, many participants reported that others continued in FEM-PrEP while not taking the study pill because of the trial's ancillary benefits and visit reimbursement factors related to the clinical setting. Negative patient-provider relationships were infrequently reported as a factor that influenced nonadherence. CONCLUSIONS: Despite substantial study staff engagement with participants and communities, concerns about the study pill and discouragement from others seemed to have influenced nonadherence considerably. Alternative study designs or procedures and enhanced community engagement paradigms may be needed in future studies. PMID- 26536316 TI - Use of Abacavir and Risk of Cardiovascular Disease Among HIV-Infected Individuals. AB - BACKGROUND: Evidence is conflicting about the association of abacavir use and cardiovascular disease (CVD) among HIV-infected individuals. Previous studies may have been biased by the preferential initiation or continuation of abacavir in patients with renal dysfunction. METHODS: We conducted a cohort study in Kaiser Permanente California during 1998-2011, following HIV-infected adults initiating antiretroviral therapy until the earliest of CVD (ie, coronary heart disease or ischemic stroke), health plan disenrollment, death, or end of study. We used inverse-probability weighting to fit marginal structural models to estimate hazard ratios (HRs) for CVD comparing regimens with and without abacavir. Propensity score models included demographics, HIV-specific factors, and CVD risk factors, including alcohol/drug use, smoking, overweight/obesity, diabetes, lipid lowering and hypertension therapy, and renal dysfunction (ie, estimated glomerular filtration rate <60 mL.min.1.73 m). RESULTS: Among 8154 subjects, 178 had >=1 CVD event, with 24/704 (3.4%) in the abacavir group and 154/7450 (2.1%) in the group initiating regimens without abacavir. Abacavir users had more renal dysfunction at antiretroviral therapy initiation (7.0% vs. 3.3%, P < 0.001). Compared with patients initiating regimens without abacavir, abacavir users had a 2.2-fold higher risk of CVD in intention-to-treat analysis [HR 2.2, 95% confidence interval (CI): 1.4 to 3.5], a 2.7-fold higher risk when remaining on their initial regimens for >=1 year (HR 2.7, 95% CI: 1.5 to 5.0), and a 2.1-fold higher risk in per-protocol analysis (HR 2.1, 95% CI: 0.9 to 5.0). CONCLUSIONS: Abacavir was associated with an over 2-fold increased risk of CVD, which was not explained by renal dysfunction or other CVD risk factors. PMID- 26536317 TI - Implementation and Operational Research: CD4 Count Monitoring Frequency and Risk of CD4 Count Dropping Below 200 Cells Per Cubic Millimeter Among Stable HIV Infected Patients in New York City, 2007-2013. AB - INTRODUCTION: The evidence has begun to mount for diminishing the frequency of CD4 count testing. To determine whether these observations were applicable to an urban US population, we used New York City (NYC) surveillance data to explore CD4 testing among stable patients in NYC, 2007-2013. METHODS: We constructed a population-based retrospective open cohort analysis of NYC HIV surveillance data. HIV+ patients aged >= 13 years with stable viral suppression (>= 1 viral load the previous year; all <400 copies per milliliter) and immune status (>= 1 CD4 the previous year; all >= 200 cells per cubic millimeter) entered the cohort the following year beginning January 1, 2007. Each subsequent year, eligible patients not previously included entered the cohort on January 1. Outcomes were annual frequency of CD4 monitoring and probability of maintaining CD4 >= 200 cells per cubic millimeter. A multivariable Cox model identified factors associated with maintaining CD4 >= 200 cells per cubic millimeter. RESULTS: During 1.9 years of observation (median), 62,039 patients entered the cohort. The mean annual number of CD4 measurements among stable patients was 2.8 and varied little by year or characteristic. Two years after entering, 93.4% and 97.8% of those with initial CD4 350-499 and CD4 >= 500 cells per cubic millimeter, respectively, maintained CD4 >= 200 cells per cubic millimeter. Compared to those with initial CD4 >= 500 cells per cubic millimeter, those with CD4 200-349 cells per cubic millimeter and CD4 350-499 cells per cubic millimeter were more likely to have a CD4 <200 cells per cubic millimeter, controlling for sex, race, age, HIV risk group, and diagnosis year. CONCLUSIONS: In a population-based US cohort with well-controlled HIV, the probability of maintaining CD4 >= 200 cells per cubic millimeter for >= 2 years was >90% among those with initial CD4 >= 350 cells per cubic millimeter, suggesting that limited CD4 monitoring in these patients is appropriate. PMID- 26536318 TI - Comparing HIV Case Detection in Prison During Opt-In vs. Opt-Out Testing Policies. PMID- 26536319 TI - Rosuvastatin Is Effective to Decrease CD8 T-Cell Activation Only in HIV-Infected Patients With High Residual T-Cell Activation Under Antiretroviral Therapy. AB - OBJECTIVE: The aim of the trial was to evaluate in patients under antiretroviral therapy (ART) the effect of rosuvastatin on cellular and soluble markers of immune activation/inflammation, as well as to identify patients who better benefit from statin administration. METHODS: IMEA-043-CESAR was a phase II open label pilot trial that enrolled patients under suppressive ART and CD4 <500/mm. Patients received rosuvastatin (20 mg/d) for 12 weeks. The primary outcome was the variation at week 12 (W12) in the proportion of CD38HLA-DRCD8 T lymphocytes. Secondary outcomes included evolution of other markers of T-cell activation and of inflammatory biomarkers between baseline, W12, and W24. RESULTS: Fifty patients were enrolled; end points were available for 43 patients. When considering all patients, the proportion of CD38HLA-DRCD8 T cells did not significantly decline throughout the follow-up. However, the proportion of CD38CD8T cells significantly decreased at W12 [median percentage change of -22.2% (-32.3; +1.4)]. Principal component analysis allowed identification of 3 groups of patients based on their baseline activation/inflammation profiles, 1 group with elevated levels of CD8 T-cell activation, and a small group with high levels of systemic inflammation and low levels of T-cell activation. Half of the patients exhibited relatively low levels of inflammation and activation. The proportion of activated CD8 T cells significantly decreased only in the particular group of patients with high baseline CD8 T-cell activation. CONCLUSIONS: This study shows that combining rosuvastatin with effective ART can result in a sustained decrease in CD8 T-cell activation and highlights the importance of identifying patients who can benefit from specific immunotherapeutic strategies. PMID- 26536320 TI - Hepatitis C Virus Antibody Testing: Result Availability at Time of Discharge for Emergency Department Patients. PMID- 26536322 TI - Veteran's Administration Care Continuum Uses the Wrong Denominator. PMID- 26536321 TI - Clear Links Between Starting Methamphetamine and Increasing Sexual Risk Behavior: A Cohort Study Among Men Who Have Sex With Men. AB - BACKGROUND: It remains unclear if methamphetamine is merely associated with high risk behavior or if methamphetamine use causes high-risk behavior. Determining this would require a randomized controlled trial, which is clearly not ethical. A possible surrogate would be to investigate individuals before and after starting the use of methamphetamine. METHODS: We performed a cohort study to analyze recent self-reported methamphetamine use and sexual risk behavior among 8905 men who have sex with men (MSM) receiving the "Early Test," a community-based HIV screening program in San Diego, CA, between April 2008 and July 2014 (total 17,272 testing encounters). Sexual risk behavior was evaluated using a previously published risk behavior score [San Diego Early Test (SDET) score] that predicts risk of HIV acquisition. RESULTS: Methamphetamine use during the last 12 months (hereafter, recent-meth) was reported by 754/8905 unique MSM (8.5%). SDET scores were significantly higher in the 754 MSM with recent-meth use compared with the 5922 MSM who reported that they have never used methamphetamine (P < 0.001). Eighty-two repeat testers initiated methamphetamine between testing encounter, with significantly higher SDET scores after starting methamphetamine [median 5 (interquartile range, 2-7) at recent-meth versus median 3 (interquartile range, 0 5) at never-meth; P < 0.001, respectively]. CONCLUSIONS: Given the ethical impossibility of conducting a randomized controlled trial, the results presented here provide the strongest evidence yet that initiation of methamphetamine use increases sexual risk behavior among HIV-uninfected MSM. Until more effective prevention or treatment interventions are available for methamphetamine users, HIV-uninfected MSM who use methamphetamine may represent ideal candidates for alternative effective prevention interventions (ie, preexposure prophylaxis). PMID- 26536323 TI - Additional Indicators to Measure New HIV Diagnoses: A Response to Chow et al. PMID- 26536324 TI - Preaching to the Choir. PMID- 26536325 TI - New Research Providing Direction for Vascular Access Device Decision Making. PMID- 26536326 TI - Oral Abstracts and Educational Posters: INS 2015 Annual Convention and Industrial Exhibition May 16-21, 2015. PMID- 26536327 TI - The Effect of Acupressure on Pain and Anxiety Caused by Venipuncture. AB - The aim of this study was to determine the effect of massage of acupoints on pain and anxiety caused by venipuncture. In this double-blind clinical trial, 187 patients who were admitted to a hospital in Khorramabad, Iran, were selected and randomly divided into 3 groups: acupressure, placebo, and control. Blood samples were obtained twice from each patient in the 3 groups: once by the routine method from the left arm and once by performing interventions from the right arm. Results showed significant differences in pain scores (P = .004) between the 3 groups after the intervention only. No significant differences between the 3 groups were found after the intervention with regard to pulse rate, systolic blood pressure, or diastolic blood pressure (P > .05). The application of acupressure at the right acupoints may relieve pain caused by venipuncture. Although further studies are needed to confirm the findings of this study, it is recommended that nurses use this safe method to increase quality of nursing care and patient satisfaction. PMID- 26536328 TI - The Patient Experience With Shared Decision Making: A Qualitative Descriptive Study. AB - Shared decision making is a process characterized by a partnership between a nurse and a patient. The existence of a relationship does not ensure shared decision making. Little is known about what nurses need to know and do for this experience to take place. A qualitative descriptive study was implemented using Coalizzi's method. Semistructured interviews were held with patients, and 3 themes were uncovered. The findings suggest that a nurse's conduct aimed at drawing patients in and inviting them to participate in a conversation leads toward shared decisions. Infusion nurses may find this information useful as they engage their patients in shared decisions. PMID- 26536329 TI - Evaluating the Evidence for Midline Catheter Use in the Newborn Intensive Care Unit. AB - When deciding which vascular access devices (VADs) are appropriate for patients in newborn intensive care units (NICUs), clinical providers may have difficulty reaching consensus because of a lack of evidence-based recommendations. The aim of this literature review is to evaluate current research and practice pertaining to midline catheter (MC) use in NICU patients. Discussion of the literature review includes information pertaining to the historical perspective of MC use, devices currently in use, common sites for placement, average dwell times, associated costs, and acceptable fluids and medications for infusion through MCs. Conclusive findings suggest that MCs are not an appropriate VAD for NICU patients because of insufficient high-level evidence demonstrating safety and efficacy. Randomized controlled trials are needed to evaluate current MC practice in the NICU and the rates of infection and extravasation associated with their use. PMID- 26536330 TI - Implementing an Evidence-Based Practice Project in the Prevention of Peripheral Intravenous Site Infiltrations in Children. AB - More than 90% of hospitalized patients require peripheral intravenous (IV) access for the delivery of fluids, nutrition, or medication. Peripheral IV site complications, such as infiltration and phlebitis, account for the greatest risk to most patients receiving infusion therapy. These complications may result in substantial acute or chronic injury, which may be further exacerbated if the affected individual is a child. Evidence suggests that the implementation of bedside-nurse training and more frequent assessment will reduce the risk for peripheral IV site complications. This project evaluates the implementation of these interventions on a pediatric acute care unit. PMID- 26536331 TI - Oral Delivery of Therapeutic Proteins and Peptides: An Overview of Current Technologies and Recommendations for Bridging from Approved Intravenous or Subcutaneous Administration to Novel Oral Regimens. AB - Since the early 1980s, therapeutic proteins and peptides have become established as an important class of pharmaceuticals. Due to their low oral bioavailability, which results from pre-systemic degradation and poor gastrointestinal absorption, most therapeutic proteins and peptides are administered intravenously. While subcutaneous formulations of some therapeutic proteins and peptides have been shown to improve patient convenience and reduce medical resource utilization, oral administration is generally the preferred administration route. Some therapeutic proteins and peptides employing novel oral delivery technologies have reached late-stage clinical development. To develop a new oral formulation of a therapeutic protein or peptide currently marketed as an injectable product, technical, nonclinical, and clinical studies are required to demonstrate similar safety and efficacy compared with the existing administration route. Since there is little experience with oral therapeutic proteins and peptides, this review provides recommendations for bridging from an approved intravenous or subcutaneous regimen to novel oral administration of the same therapeutic protein or peptide, based on precedents from intravenous-to-subcutaneous bridging approaches for trastuzumab, rituximab, tocilizumab, and bortezomib. If the pharmacokinetic/pharmacodynamic relationship is well characterized, demonstration of comparability in prespecified pharmacokinetic parameters might form a basis for establishing similar efficacy and safety of the oral formulation vs. the reference product. Although oral administration of therapeutic proteins and peptides remains challenging, given recent progress with novel delivery technologies, intravenous/subcutaneous-to-oral nonclinical and clinical bridging programs may soon be utilized to support approval of new oral formulations. PMID- 26536332 TI - Possibilities for Shortening the CAHPS Clinician and Group Survey. AB - BACKGROUND: The Consumer Assessment of Healthcare Providers and Systems (CAHPS) Clinician and Group adult survey (CG-CAHPS) includes 34 items used to monitor the quality of ambulatory care from the patient's perspective. CG-CAHPS includes items assessing access to care, provider communication, and courtesy and respect of office staff. Stakeholders have expressed concerns about the length of the CG CAHPS survey. OBJECTIVES: This paper explores the impact on reliability and validity of the CAHPS domain scores of reducing the numbers of items used to assess the 3 core CG-CAHPS domains (Provider Communication, Access to Care, and Courteous and Helpful Office Staff). RESEARCH DESIGN: CG-CAHPS data reported here consist of 136,725 patients across 4 datasets including ambulatory clinics, patient-centered medical homes, and Accountable Care Organizations. Analyses are conducted in parallel across the 4 settings to allow evaluations across data source. ANALYSES: Multiple regression and ANOVA techniques were used to evaluate reliability for shorter sets of items. Site-level correlations with the overall rating of the provider were compared to evaluate the impact on validity. The change in practices' rank-ordering as a function of domain revision is also reported. RESULTS: Findings suggest that the Provider Communication (6 items) and Access (5 items) domains can be reduced to as few as 2 items each and Office Staff (2 items) can be reduced to a single item without a substantial loss in reliability or content. CONCLUSIONS: The performance of several of the reduced length options for CG-CAHPS domains closely matches the full versions and may be useful in health care settings where the full-length survey is impractical due to time or cost constraints. PMID- 26536333 TI - Biofilm Formation and Susceptibility to Polymyxin B by a Highly Prevalent Clone of Multidrug-Resistant Acinetobacter baumannii from a Mexican Tertiary Care Hospital. AB - BACKGROUND: Acinetobacter baumannii has emerged as a major cause of hospital associated infections with increased morbidity and mortality among those affected. METHODS: A total of 85 isolates of a highly prevalent multidrug resistant clone, identified during the period 2007-2011, were analyzed for biofilm formation on a polystyrene surface. The minimal inhibitory concentration was determined by the Sensititre System, the agar disk diffusion method and then read by means of the BIOMIC system and serial dilutions on Muller-Hinton agar. RESULTS: In this study, covering a period of 5 years (2007-2011), we demonstrate that a particular clone emerged as the most prevalent, with an associated lethality of 28.2%. We demonstrate that 92.9% of strains corresponding to this clone are biofilm producers. Our results also demonstrate that all isolates were 100% susceptible to polymyxin B. CONCLUSION: Our study suggests that the high prevalence and lethality of this multidrug-resistant clone of A. baumannii and its persistence over close to 5 years in a Mexican tertiary hospital environment can be explained in part by the ability of these clinical isolates of A. baumannii to form biofilms. PMID- 26536334 TI - Variety is the spice of life. PMID- 26536335 TI - Swallowing assessment and management pre and post head and neck cancer treatment. AB - PURPOSE OF REVIEW: Head and neck cancer (HNC) imposes significant structural, functional, and cosmetic burdens upon those affected. Although advances in multimodality organ preservation therapy have assisted in ameliorating a number of previous treatment-related sequelae, dysphagia remains a foremost concern for members of the multidisciplinary team. Given its acute and long-term impact on physical and psychological wellbeing, and subsequent bearing on delivery of treatment, treatment-related morbidity and overall mortality, prompt recognition, and accurate assessment and optimization of management are pivotal. RECENT FINDINGS: Qualitative research has provided greater insight into the psychosocial burdens dysphagia imposes on HNC patients and carers, highlighting the need for holistic strategies of management. There is a growing body of evidence to support dietary alterations and preventive swallowing exercise regimens for maintenance of oral intake throughout and following HNC therapy. The role of prophylactic enteral feeding, however, remains uncertain, with conflicting institutional data and lack of high-quality prospective studies for meaningful systematic literature assessment. Endoscopic surgical techniques hold promise in relieving stricture related dysphagia; however, multiple treatments are required and recurrence is common. SUMMARY: Swallowing rehabilitation encompassing education, dietary modification, and swallowing exercises comprise the mainstay of current evidence based dysphagia management in HNC patients. PMID- 26536338 TI - The Principles of Magic Applied to Healthcare Simulation. AB - STATEMENT: Five principles of magic are described that directly relate to enhancing participant engagement in the healthcare simulation setting. The principles discussed are the following: reality is in the mind of the participant, attention is easily misdirected, perception can be manipulated, various cognitive biases can be exploited, and focus must be captured. Using these principles in a healthcare simulation can help fill gaps in fidelity and bring a participant to a point where the situation and events make sense to them, they feel that they are in an appropriate environment, and they are willing to forgive the natural flaws of the simulation itself. Misuse of illusions beyond the purpose of filling fidelity gaps can break trust with the teacher and lead to disengagement of the participant. PMID- 26536339 TI - Effects of Low- Versus High-Fidelity Simulations on the Cognitive Burden and Performance of Entry-Level Paramedicine Students: A Mixed-Methods Comparison Trial Using Eye-Tracking, Continuous Heart Rate, Difficulty Rating Scales, Video Observation and Interviews. AB - INTRODUCTION: High-fidelity simulation-based training is often avoided for early stage students because of the assumption that while practicing newly learned skills, they are ill suited to processing multiple demands, which can lead to "cognitive overload" and poorer learning outcomes. We tested this assumption using a mixed-methods experimental design manipulating psychological immersion. METHODS: Thirty-nine randomly assigned first-year paramedicine students completed low- or high-environmental fidelity simulations [low-environmental fidelity simulations (LF(en)S) vs. high-environmental fidelity simulation (HF(en)S)] involving a manikin with obstructed airway (SimMan3G). Psychological immersion and cognitive burden were determined via continuous heart rate, eye tracking, self-report questionnaire (National Aeronautics and Space Administration Task Load Index), independent observation, and postsimulation interviews. Performance was assessed by successful location of obstruction and time-to-termination. RESULTS: Eye tracking confirmed that students attended to multiple, concurrent stimuli in HF(en)S and interviews consistently suggested that they experienced greater psychological immersion and cognitive burden than their LF(en)S counterparts. This was confirmed by significantly higher mean heart rate (P < 0.001) and National Aeronautics and Space Administration Task Load Index mental demand (P < 0.05). Although group allocation did not influence the proportion of students who ultimately revived the patient (58% vs. 30%, P < 0.10), the HF(en)S students did so significantly more quickly (P < 0.01). The LF(en)S students had low immersion resulting in greater assessment anxiety. CONCLUSIONS: High environmental fidelity simulation engendered immersion and a sense of urgency in students, whereas LF(en)S created assessment anxiety and slower performance. We conclude that once early-stage students have learned the basics of a clinical skill, throwing them in the "deep end" of high-fidelity simulation creates significant additional cognitive burden but this has considerable educational merit. PMID- 26536340 TI - A Systematic Review of Serious Games in Training Health Care Professionals. AB - STATEMENT: Serious games are computer-based games designed for training purposes. They are poised to expand their role in medical education. This systematic review, conducted in accordance with PRISMA guidelines, aimed to synthesize current serious gaming trends in health care training, especially those pertaining to developmental methodologies and game evaluation. PubMed, EMBASE, and Cochrane databases were queried for relevant documents published through December 2014. Of the 3737 publications identified, 48 of them, covering 42 serious games, were included. From 2007 to 2014, they demonstrate a growth from 2 games and 2 genres to 42 games and 8 genres. Overall, study design was heterogeneous and methodological quality by MERQSI score averaged 10.5/18, which is modest. Seventy-nine percent of serious games were evaluated for training outcomes. As the number of serious games for health care training continues to grow, having schemas that organize how educators approach their development and evaluation is essential for their success. PMID- 26536341 TI - The Effect of Model Fidelity on Learning Outcomes of a Simulation-Based Education Program for Central Venous Catheter Insertion. AB - INTRODUCTION: Simulation-based education for central venous catheter (CVC) insertion has been repeatedly documented to improve performance, but the impact of simulation model fidelity has not been described. The aim of this study was to examine the impact of the physical fidelity of the simulation model on learning outcomes for a simulation-based education program for CVC insertion. METHODS: Forty consecutive residents rotating through the medical intensive care unit of an academic medical center completed a simulation-based education program for CVC insertion. The curriculum was designed in accordance with the principles of deliberate practice and mastery learning. Each resident underwent baseline skills testing and was then randomized to training on a commercially available CVC model with high physical fidelity (High-Fi group) or a simply constructed model with low physical fidelity (Low-Fi group) in a noninferiority trial. Upon completion of their medical intensive care unit rotation 4 weeks later, residents returned for repeat skills testing on the high-fidelity model using a 26-item checklist. RESULTS: The mean (SD) posttraining score on the 26-item checklist for the Low-Fi group was 23.8 (2.2) (91.5%) and was not inferior to the mean (SD) score for the High-Fi group of 22.5 (2.6) (86.5%) (P < 0.0001). Residents in both groups judged the training program to be highly useful despite perceiving a lesser degree of physical realism in the low-fidelity model compared with the high-fidelity model (P = 0.05). CONCLUSIONS: Simulation-based education using equipment with low physical fidelity can achieve learning outcomes comparable with those with high fidelity equipment, as long as other aspects of fidelity are maintained and robust educational principles are applied during the design of the curriculum. PMID- 26536343 TI - The Importance of Deception in Simulation: An Imperative to Train in Realism. PMID- 26536342 TI - Developing a Simulation-Based Mastery Learning Curriculum: Lessons From 11 Years of Advanced Cardiac Life Support. AB - STATEMENT: Curriculum development in medical education should follow a planned, systematic approach fitted to the needs and conditions of a local institutional environment and its learners. This article describes the development and maintenance of a simulation-based medical education curriculum on advanced cardiac life support skills and its transformation to a mastery learning program. Curriculum development used the Kern 6-step model involving problem identification and general needs assessment, targeted needs assessment, goals and objectives, educational strategies, implementation, and evaluation and feedback. Curriculum maintenance and enhancement and dissemination are also addressed. Transformation of the simulation-based medical education curriculum to a mastery learning program was accomplished after a 2-year phase-in trial. A series of studies spanning 11 years was performed to adjust the curriculum, improve checklist outcome measures, and evaluate curriculum effects as learning outcomes among internal medicine residents and improved patient care practices. We anticipate wide adoption of the mastery learning model for skill and knowledge acquisition and maintenance in medical education settings. PMID- 26536344 TI - Very High Intrapartum Fever in Term Pregnancies and Adverse Obstetric and Neonatal Outcomes. AB - BACKGROUND: Intrapartum fever is a well-known risk factor for adverse perinatal outcomes. Maternal intrapartum fever >=39.0 degrees C at term is a rare event during labor, and there is scarce evidence regarding its implications. OBJECTIVES: To investigate the association between very high intrapartum maternal fever and perinatal outcomes in term pregnancies. METHODS: A retrospective cohort analysis including 43,560 term, singleton live births in two medical centers between the years 2003 and 2011 was performed. We compared parturients who experienced a maximal intrapartum fever of <38.0 degrees C with two subgroups of parturients who experienced respective maximal fevers of 38.0-38.9 degrees C and >=39 degrees C. Adjusted risks for adverse perinatal outcomes were calculated by using multiple logistic regression models to control for confounders. RESULTS: Compared with normal intrapartum temperature, intrapartum fever >=39.0 degrees C was associated with an extremely elevated risk for neonatal sepsis 16.08 (95% CI: 2.15, 120.3) as well as with low Apgar scores and neonatal intensive care unit admissions (p < 0.001). Additionally, very high intrapartum fever was related to significantly higher risk for operative delivery (p < 0.001). CONCLUSIONS: Extremely elevated intrapartum fever is an important indicator of severe neonatal morbidity and operative delivery. PMID- 26536345 TI - Mitochondrial Regulation of Inflammasome Activation in Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is characterized by enhanced chronic airway and lung inflammatory responses to noxious particles or gases. It is a major unmet medical need worldwide, and in Western society is strongly associated with exposure to cigarette smoke (CS). CS-induced inflammation is believed to be a key immune driver in the pathogenesis of COPD. Since the concept of inflammasomes was first introduced nearly a decade ago, these have been increasingly recognized as a central player in innate immune and inflammatory responses. In addition, studies have emerged demonstrating that mitochondrial innate immune signaling plays an important role in CS-induced inflammasome activation, pulmonary inflammation and tissue remodeling responses. Here, recent discoveries about inflammasome activation and mitochondrial biology and their role in COPD pathogenesis are reviewed. In addition, the current limitations of our understanding of this theme and future research directions are discussed. PMID- 26536346 TI - Differential Effect of the Ratio of Right Ventricular Volume to Left Ventricular Volume in Children with Repaired Tetralogy of Fallot. AB - We aimed to compare the diagnostic value of indexed right ventricular end diastolic volume (RVEDVi) and the ratio of right ventricle volume to left ventricle volume (RV/LV ratio) in prediction of the severity of pulmonary regurgitation (PR) expressed as the PR fraction (PRF) after surgery of tetralogy of Fallot (TOF). Forty-one patients with repaired TOF were included in the study. RVEDVi, LVEDVi, RV/LV ratio, PRF and ejection fraction were measured with magnetic resonance imaging. A PRF of more than 20% was considered significant. The predictive capability of two markers (RVEDVi and RV/LV ratio) for significant PR was compared using multivariate linear regression analysis and receiver operating characteristic (ROC) analysis. Both the RV/LV ratio and RVEDVi showed a correlation with PRF (r = 0.526/0.321, p = 0.001/0.041) in the correlation analysis, but in multivariate regression analysis the only independent predictor of PRF was the RV/LV ratio (F = 14.890, p = 0.001). ROC analysis revealed that a better discrimination of significant PR (>20%) from slight types (=20%) PR can be reached with the RV/LV ratio than RVEDVi (AUC = 0.805/0.709, p = 0.01). The RV/LV ratio was better than RVEDVi at differentiating mild from moderate PR (p = 0.006 vs. p = 0.153), and proved superior over RVEDVi in predicting PR based on the PRF criterion. PMID- 26536348 TI - Concurrent Mutations in ATM and Genes Associated with Common gamma Chain Signaling in Peripheral T Cell Lymphoma. AB - Peripheral T cell lymphoma (PTCL) is a heterogeneous malignancy with poor response to current therapeutic strategies and incompletely characterized genetics. We conducted whole exome sequencing of matched PTCL and non-malignant samples from 12 patients, spanning 8 subtypes, to identify potential oncogenic mutations in PTCL. Analysis of the mutations identified using computational algorithms, CHASM, PolyPhen2, PROVEAN, and MutationAssessor to predict the impact of these mutations on protein function and PTCL tumorigenesis, revealed 104 somatic mutations that were selected as high impact by all four algorithms. Our analysis identified recurrent somatic missense or nonsense mutations in 70 genes, 9 of which contained mutations predicted significant by all 4 algorithms: ATM, RUNX1T1, WDR17, NTRK3, TP53, TRMT12, CACNA2D1, INTS8, and KCNH8. We observed somatic mutations in ATM (ataxia telangiectasia-mutated) in 5 out of the 12 samples and mutations in the common gamma chain (gammac) signaling pathway (JAK3, IL2RG, STAT5B) in 3 samples, all of which also harbored mutations in ATM. Our findings contribute insights into the genetics of PTCL and suggest a relationship between gammac signaling and ATM in T cell malignancy. PMID- 26536349 TI - Adaptive (TINT) Changes in the Tumor Bearing Organ Are Related to Prostate Tumor Size and Aggressiveness. AB - In order to grow, tumors need to induce supportive alterations in the tumor bearing organ, by us named tumor instructed normal tissue (TINT) changes. We now examined if the nature and magnitude of these responses were related to tumor size and aggressiveness. Three different Dunning rat prostate tumor cells were implanted into the prostate of immune-competent rats; 1) fast growing and metastatic MatLyLu tumor cells 2) fast growing and poorly metastatic AT-1 tumor cells, and 3) slow growing and non-metastatic G tumor cells. All tumor types induced increases in macrophage, mast cell and vascular densities and in vascular cell-proliferation in the tumor-bearing prostate lobe compared to controls. These increases occurred in parallel with tumor growth. The most pronounced and rapid responses were seen in the prostate tissue surrounding MatLyLu tumors. They were, also when small, particularly effective in attracting macrophages and stimulating growth of not only micro-vessels but also small arteries and veins compared to the less aggressive AT-1 and G tumors. The nature and magnitude of tumor-induced changes in the tumor-bearing organ are related to tumor size but also to tumor aggressiveness. These findings, supported by previous observation in patient samples, suggest that one additional way to evaluate prostate tumor aggressiveness could be to monitor its effect on adjacent tissues. PMID- 26536350 TI - Potential Compounds for Oral Cancer Treatment: Resveratrol, Nimbolide, Lovastatin, Bortezomib, Vorinostat, Berberine, Pterostilbene, Deguelin, Andrographolide, and Colchicine. AB - Oral cancer is one of the main causes of cancer-related deaths in South-Asian countries. There are very limited treatment options available for oral cancer. Research endeavors focused on discovery and development of novel therapies for oral cancer, is necessary to control the ever rising oral cancer related mortalities. We mined the large pool of compounds from the publicly available compound databases, to identify potential therapeutic compounds for oral cancer. Over 84 million compounds were screened for the possible anti-cancer activity by custom build SVM classifier. The molecular targets of the predicted anti-cancer compounds were mined from reliable sources like experimental bioassays studies associated with the compound, and from protein-compound interaction databases. Therapeutic compounds from DrugBank, and a list of natural anti-cancer compounds derived from literature mining of published studies, were used for building partial least squares regression model. The regression model thus built, was used for the estimation of oral cancer specific weights based on the molecular targets. These weights were used to compute scores for screening the predicted anti-cancer compounds for their potential to treat oral cancer. The list of potential compounds was annotated with corresponding physicochemical properties, cancer specific bioactivity evidences, and literature evidences. In all, 288 compounds with the potential to treat oral cancer were identified in the current study. The majority of the compounds in this list are natural products, which are well-tolerated and have minimal side-effects compared to the synthetic counterparts. Some of the potential therapeutic compounds identified in the current study are resveratrol, nimbolide, lovastatin, bortezomib, vorinostat, berberine, pterostilbene, deguelin, andrographolide, and colchicine. PMID- 26536351 TI - Regional Differences in Intervention Coverage and Health System Strength in Tanzania. AB - BACKGROUND: Assessments of subnational progress and performance coverage within countries should be an integral part of health sector reviews, using recent data from multiple sources on health system strength and coverage. METHOD: As part of the midterm review of the national health sector strategic plan of Tanzania mainland, summary measures of health system strength and coverage of interventions were developed for all 21 regions, focusing on the priority indicators of the national plan. Household surveys, health facility data and administrative databases were used to compute the regional scores. FINDINGS: Regional Millennium Development Goal (MDG) intervention coverage, based on 19 indicators, ranged from 47% in Shinyanga in the northwest to 71% in Dar es Salaam region. Regions in the eastern half of the country have higher coverage than in the western half of mainland. The MDG coverage score is strongly positively correlated with health systems strength (r = 0.84). Controlling for socioeconomic status in a multivariate analysis has no impact on the association between the MDG coverage score and health system strength. During 1991-2010 intervention coverage improved considerably in all regions, but the absolute gap between the regions did not change during the past two decades, with a gap of 22% between the top and bottom three regions. INTERPRETATION: The assessment of regional progress and performance in 21 regions of mainland Tanzania showed considerable inequalities in coverage and health system strength and allowed the identification of high and low-performing regions. Using summary measures derived from administrative, health facility and survey data, a subnational picture of progress and performance can be obtained for use in regular health sector reviews. PMID- 26536352 TI - Experimental Investigation on the Morphology and Adhesion Mechanism of Leech Posterior Suckers. AB - The posterior sucker of a leech represents a fascinating natural system that allows the leech to adhere to different terrains and substrates. However, the mechanism of adhesion and desorption has not yet to be elucidated. In order to better understand how the adhesion is performed, we analyzed the surface structure, adsorption movements, the muscles' distribution, physical characteristics, and the adsorption force of the leech posterior suckers by experimental investigation. Three conclusions can be drawn based on the obtained experimental results. First, the adhesion by the posterior sucker is wet adhesion, because the surface of the posterior sucker is smooth and the sealing can only be achieved on wet surfaces. Second, the deformation texture, consisting of soft collagen tissues and highly ductile epidermal tissues, plays a key role in adhering to rough surfaces. Finally, the adhesion and desorption is achieved by the synergetic operation of six muscle fibers working in different directions. Concrete saying, directional deformation of the collagen/epithermal interface driven by spatially-distributed muscle fibers facilitates the excretion of fluids in the sucker venter, thus allowing liquid sealing. Furthermore, we found that the adhesion strength is directly related to the size of the contact surface which is generated and affected by the sucker deformation. Such an underlying physical mechanism offers potential cues for developing innovative bio-inspired artificial adhesion systems. PMID- 26536353 TI - Photophysical deactivation pathways in adenine oligonucleotides. AB - In this work we study deactivation processes in adenine oligomers after absorption of UV radiation using Quantum Mechanics combined with Molecular Mechanics (QM/MM). Correlated electronic structure methods appropriate for describing the excited states are used to describe a pi-stacked dimer of adenine bases incorporated into (dA)20(dT)20. The results of these calculations reveal three different types of excited state minima which play a role in deactivation processes. Within this set of minima there are minima where the excited state is localized on one adenine (monomer-like) as well as minima where the excited state is delocalized on two adenines, forming different types of excimers and bonded excimers of varying but inter-related character. The proximity of their energies reveals that the minima can decay into one another along a flat potential energy surface dependent on the interbase separation. Additionally, analysis of the emissive energies and other physical properties, including theoretical anisotropy calculations, and comparison with fluorescence experiments, provides evidence that excimers play an important role in long-lived signals in adenine oligonucleotides while the subpicosecond decay is attributed to monomer-like minima. The necessity for a close approach of the nucleobases reveals that the deactivation mechanism is tied to macro-molecular motion. PMID- 26536355 TI - Blue copper protein analogue: synthesis and characterization of copper complexes of the N2S2 macrocycle 1,8-dithia-4,11-diazacyclotetradecane. AB - To improve understanding of copper at the active site of Type 1 copper proteins, Cu(I) and Cu(II) complexes of 1,8-dithia-4,11-diazacyclotetradecane, shown in , have been successfully isolated and structurally characterized by X-ray crystallography. In these compounds, both Cu(I) and Cu(II) are centered in the plane of the macrocycle containing two sulphur and two nitrogen heteroatoms comprising the distorted tetrahedral/square planar coordination geometry. The UV/VIS spectra, electrochemistry and EPR properties have been obtained for the Cu(II) complex 2. Three absorption bands at 295 nm, 354 nm, and 545 nm are observed in aqueous solution at a pH of 5. These bands have been assigned to the N -> Cu(II) and S -> Cu(II) charge transfer bands and the d-d transitions respectively. The Cu(I/II) redox midpoint potential of complex 2 in CH3CN is +403 mV versus NHE. PMID- 26536354 TI - Impact of Malaria Control on Mortality and Anemia among Tanzanian Children Less than Five Years of Age, 1999-2010. AB - BACKGROUND: Mainland Tanzania scaled up multiple malaria control interventions between 1999 and 2010. We evaluated whether, and to what extent, reductions in all-cause under-five child mortality (U5CM) tracked with malaria control intensification during this period. METHODS: Four nationally representative household surveys permitted trend analysis for malaria intervention coverage, severe anemia (hemoglobin <8 g/dL) prevalence (SAP) among children 6-59 months, and U5CM rates stratified by background characteristics, age, and malaria endemicity. Prevalence of contextual factors (e.g., vaccination, nutrition) likely to influence U5CM were also assessed. Population attributable risk percentage (PAR%) estimates for malaria interventions and contextual factors that changed over time were used to estimate magnitude of impact on U5CM. RESULTS: Household ownership of insecticide-treated nets (ITNs) rose from near zero in 1999 to 64% (95% CI, 61.7-65.2) in 2010. Intermittent preventive treatment of malaria in pregnancy reached 26% (95% CI, 23.6-28.0) by 2010. Sulfadoxine pyrimethamine replaced chloroquine in 2002 and artemisinin-based combination therapy was introduced in 2007. SAP among children 6-59 months declined 50% between 2005 (11.1%; 95% CI, 10.0-12.3%) and 2010 (5.5%; 95% CI, 4.7-6.4%) and U5CM declined by 45% between baseline (1995-9) and endpoint (2005-9), from 148 to 81 deaths/1000 live births, respectively. Mortality declined 55% among children 1 23 months of age in higher malaria endemicity areas. A large reduction in U5CM was attributable to ITNs (PAR% = 11) with other malaria interventions adding further gains. Multiple contextual factors also contributed to survival gains. CONCLUSION: Marked declines in U5CM occurred in Tanzania between 1999 and 2010 with high impact from ITNs and ACTs. High-risk children (1-24 months of age in high malaria endemicity) experienced the greatest declines in mortality and SAP. Malaria control should remain a policy priority to sustain and further accelerate progress in child survival. PMID- 26536356 TI - Anatomic Characteristics Associated with Head Splitting in Cabbage (Brassica oleracea var. capitata L.). AB - Cabbage belonging to Brassicaceae family is one of the most important vegetables cultivated worldwide. The economically important part of cabbage crop is head, formed by leaves which may be of splitting and non-splitting types. Cabbage varieties showing head splitting causes huge loss to the farmers and therefore finding the molecular and structural basis of splitting types would be helpful to breeders. To determine which anatomical characteristics were related to head splitting in cabbage, we analyzed two contrasting cabbage lines and their offspring using a field emission scanning electron microscope. The inbred line "747" is an early head-splitting type, while the inbred line "748" is a head splitting-resistant type. The petiole cells of "747" seems to be larger than those of "748" at maturity; however, there was no significant difference in petiole cell size at both pre-heading and maturity stages. The lower epidermis cells of "747" were larger than those of "748" at the pre-heading and maturity stages. "747" had thinner epidermis cell wall than "748" at maturity stage, however, there was no difference of the epidermis cell wall thickness in the two lines at the pre-heading stage. The head-splitting plants in the F1 and F2 population inherited the larger cell size and thinner cell walls of epidermis cells in the petiole. In the petiole cell walls of "747" and the F1 and F2 plants that formed splitting heads, the cellulose microfibrils were loose and had separated from each other. These findings verified that anomalous cellulose microfibrils, larger cell size and thinner-walled epidermis cells are important genetic factors that make cabbage heads prone to splitting. PMID- 26536357 TI - Prevalence, genotyping and macrolide resistance of Mycoplasma pneumoniae among isolates of patients with respiratory tract infections, Central Slovenia, 2006 to 2014. AB - In this retrospective study we employed real-time polymerase chain reaction (PCR) to analyse the occurrence of Mycoplasma pneumoniae among upper and lower respiratory tract infections (RTI) in the Central Region of Slovenia between January 2006 and December 2014. We also used a culture and pyrosequencing approach to genotype strains and infer their potential macrolide resistance. Of a total 9,431 tested samples from in- and out-patient with RTI, 1,255 (13%) were found to be positive by M. pneumoniae PCR. The proportion of positive samples was 19% (947/5,092)among children (<=16 years-old) and 7% (308/4,339) among adults (>16 years-old). Overall, among those PCR tested, the highest proportions of M. pneumonia infections during the study period were observed in 2010 and 2014. In these two years, 18% (218/1,237) and 25% (721/2,844) of samples were positive respectively,indicating epidemic periods. From the 1,255 M. pneumoniae PCR positive samples, 783 (614 from paediatric and 169 from adult patients) were successfully cultured. Of these, 40% (312/783) were constituted of strains belonging to the P1 type II genomic group, while 60% (469/783) contained strains of the P1 type I group. Two isolates comprised both P1 type Iand II strains. Results of a genotype analysis by year,showed that the dominant M. pneumoniae P1 type during the 2010 epidemic was P1 type II (82% of isolates;81/99), which was replaced by P1 type I in the 2014 epidemic (75%; 384/510). This observation could indicate that the two epidemics may have been driven by a type shift phenomenon, although both types remained present in the studied population during the assessed period of time. Only 1% of strains (7/783) were found to harbour an A2063G mutation in the 23S rRNA gene,which confers macrolide resistance, suggesting that the occurrence of M. pneumoniae macrolide resistance still seems to be sporadic in our geographic area. PMID- 26536358 TI - PyMYB10 and PyMYB10.1 Interact with bHLH to Enhance Anthocyanin Accumulation in Pears. AB - Color is an important agronomic trait of pears, and the anthocyanin content of fruit is immensely significant for pear coloring. In this study, an anthocyanin activating R2R3-MYB transcription factor gene, PyMYB10.1, was isolated from fruits of red sand pear (Pyrus pyrifolia cv. Aoguan). Alignments of the nucleotide and amino acid sequences suggested that PyMYB10.1 was involved in anthocyanin regulation. Similar to PyMYB10, PyMYB10.1 was predominantly expressed in red tissues, including the skin, leaf and flower, but it was minimally expressed in non-red fruit flesh. The expression of this gene could be induced by light. Dual-luciferase assays indicated that both PyMYB10 and PyMYB10.1 activated the AtDFR promoter. The activation of AtDFR increased to a greater extent when combined with a bHLH co-factor, such as PybHLH, MrbHLH1, MrbHLH2, or AtbHLH2. However, the response of this activation depended on the protein complex formed. PyMYB10-AtbHLH2 activated the AtDFR promoter to a greater extent than other combinations of proteins. PyMYB10-AtbHLH2 also induced the highest anthocyanin accumulation in tobacco transient-expression assays. Moreover, PybHLH interacted with PyMYB10 and PyMYB10.1. These results suggest that both PyMYB10 and PyMYB10.1 are positive anthocyanin biosynthesis regulators in pears that act via the formation of a ternary complex with PybHLH. The functional characterization of PyMYB10 and PyMYB10.1 will aid further understanding of the anthocyanin regulation in pears. PMID- 26536359 TI - Leaderless Transcripts and Small Proteins Are Common Features of the Mycobacterial Translational Landscape. AB - RNA-seq technologies have provided significant insight into the transcription networks of mycobacteria. However, such studies provide no definitive information on the translational landscape. Here, we use a combination of high-throughput transcriptome and proteome-profiling approaches to more rigorously understand protein expression in two mycobacterial species. RNA-seq and ribosome profiling in Mycobacterium smegmatis, and transcription start site (TSS) mapping and N terminal peptide mass spectrometry in Mycobacterium tuberculosis, provide complementary, empirical datasets to examine the congruence of transcription and translation in the Mycobacterium genus. We find that nearly one-quarter of mycobacterial transcripts are leaderless, lacking a 5' untranslated region (UTR) and Shine-Dalgarno ribosome-binding site. Our data indicate that leaderless translation is a major feature of mycobacterial genomes and is comparably robust to leadered initiation. Using translational reporters to systematically probe the cis-sequence requirements of leaderless translation initiation in mycobacteria, we find that an ATG or GTG at the mRNA 5' end is both necessary and sufficient. This criterion, together with our ribosome occupancy data, suggests that mycobacteria encode hundreds of small, unannotated proteins at the 5' ends of transcripts. The conservation of small proteins in both mycobacterial species tested suggests that some play important roles in mycobacterial physiology. Our translational-reporter system further indicates that mycobacterial leadered translation initiation requires a Shine Dalgarno site in the 5' UTR and that ATG, GTG, TTG, and ATT codons can robustly initiate translation. Our combined approaches provide the first comprehensive view of mycobacterial gene structures and their non-canonical mechanisms of protein expression. PMID- 26536360 TI - Nuclear Markers Reveal Predominantly North to South Gene Flow in Ixodes scapularis, the Tick Vector of the Lyme Disease Spirochete. AB - Ixodes scapularis, the tick vector of the Lyme disease spirochete, is distributed over most of the eastern United States, but >80% of all Lyme disease cases occur in the northeast. The role that genetic differences between northern and southern tick populations play in explaining this disparate distribution of Lyme disease cases is unclear. The present study was conducted with 1,155 SNP markers in eight nuclear genes; the 16S mitochondrial gene was examined for comparison with earlier studies. We examined 350 I. scapularis from 7 states covering a representative area of the species. A demographic analysis using Bayesian Extended Skyline Analysis suggested that I. scapularis populations in Mississippi and Georgia began expanding 500,000 years ago, those in Florida and North Carolina 200,000 years ago and those from Maryland and New Jersey only during the past 50,000 years with an accompanying bottleneck. Wisconsin populations only began expanding in the last 20,000 years. Analysis of current migration patterns suggests large amounts of gene flow in northern collections and equally high rates of gene flow among southern collections. In contrast there is restricted and unidirectional gene flow between northern and southern collections, mostly occurring from northern into southern populations. Northern populations are characterized by nymphs that quest above the leaf litter, are easy to collect by flagging, frequently feed on mammals such as rodents and shrews, commonly attach to people, and about 25% of which are infected with B. burgdorferi. If there is a genetic basis for these behaviors, then the patterns detected in this study are of concern because they suggest that northern I. scapularis populations with a greater ability to vector B. burgdorferi to humans are expanding south. PMID- 26536361 TI - FL3, a Synthetic Flavagline and Ligand of Prohibitins, Protects Cardiomyocytes via STAT3 from Doxorubicin Toxicity. AB - AIMS: The clinical use of doxorubicin for the treatment of cancer is limited by its cardiotoxicity. Flavaglines are natural products that have both potent anticancer and cardioprotective properties. A synthetic analog of flavaglines, FL3, efficiently protects mice from the cardiotoxicity of doxorubicin. The mechanism underlying this cardioprotective effect has yet to be elucidated. METHODS AND RESULTS: Here, we show that FL3 binds to the scaffold proteins prohibitins (PHBs) and thus promotes their translocation to mitochondria in the H9c2 cardiomyocytes. FL3 induces heterodimerization of PHB1 with STAT3, thereby ensuring cardioprotection from doxorubicin toxicity. This interaction is associated with phosphorylation of STAT3. A JAK2 inhibitor, WP1066, suppresses both the phosphorylation of STAT3 and the protective effect of FL3 in cardiomyocytes. The involvement of PHBs in the FL3-mediated cardioprotection was confirmed by means of small interfering RNAs (siRNAs) targeting PHB1 and PHB2. The siRNA knockdown of PHBs inhibits both phosphorylation of STAT3 and the cardioprotective effect of FL3. CONCLUSION: Activation of mitochondrial STAT3/PHB1 complex by PHB ligands may be a new strategy against doxorubicin induced cardiotoxicity and possibly other cardiac problems. PMID- 26536362 TI - Chick Begging Calls Reflect Degree of Hunger in Three Auk Species (Charadriiformes: Alcidae). AB - Begging behaviour is an important element in the parent-offspring conflict; it has been studied in many avian species. However, the majority of the studies have been entirely based on the call counts, and they agreed that vocal activity was a good indicator of chick's nutritional need and/or condition. Fewer researches were dedicated to the temporal-frequency variables of the begging calls themselves and they showed contrary results. Here begging behaviour in three burrow nested, uniparous species of auks (Alcidae) was studied. These objects provide an opportunity to study the signalling value of begging calls in the absence of important confounding factors such as nestling competition and predation pressure. I recorded calls of individual chicks in two conditions: during natural feeding and after experimental four-hour food deprivation. I found that almost all measured acoustic variables contain information about the chick's state in all studied species. The hungry chicks produced calls higher in fundamental frequency and power variables and at higher calling rate compared to naturally feeding chicks. The effect of food deprivation on most acoustic variables exceeded both the effects of individuality and species. In all studied species, the frequency variables were stronger affected by hunger than the calling rate and call durations. I suppose that such strong change of acoustic variables after food deprivation can be explained by absence of vocal individual identification in these birds. As parents do not need to check individuality of the chick in the burrow, which they find visually during the day time, the chicks could use all of the acoustic variables to communicate about their nutritional needs. PMID- 26536363 TI - A male preponderance in patients with Indian post kala-azar dermal leishmaniasis is associated with increased circulating levels of testosterone. AB - BACKGROUND: Post kala-azar dermal leishmaniasis (PKDL) is a neglected parasitic disease that occurs after apparent cure from visceral leishmaniasis (VL) and poses a challenge for elimination of VL, being its proposed reservoir. Several epidemiological studies have proposed that sex hormones may account for the increased susceptibility of males towards infectious diseases, including leishmaniasis; however, the role of testosterone and sex bias, if any, in PKDL has not been evaluated. METHODS: The study population included 87 patients with PKDL and 39 with VL; levels of testosterone were measured by competitive enzyme linked immunosorbent assay along with their levels of antileishmanial immunoglobulin and IgG. The association of testosterone, if any, was then correlated with age, gender, humoral response, lesional profile, disease duration, and lag period. RESULTS: A male predominance was evident in PKDL, not in VL; importantly, this male bias was predominant postpubertal, strongly indicative of an association between sex hormone and disease progression. Male patients with PKDL had significantly higher levels of testosterone, which regressed significantly with miltefosine, not with sodium antimony gluconate. Additionally, a significant correlation was found between plasma testosterone and antileishmanial IgG. CONCLUSION: Taken together, our study has established a male dominance in PKDL, which showed a strong association with testosterone. This information should be taken into consideration for disease monitoring and control. PMID- 26536364 TI - Correction: Rapid Changes in Cortical and Subcortical Brain Regions after Early Bilateral Enucleation in the Mouse. PMID- 26536365 TI - Primates, Provisioning and Plants: Impacts of Human Cultural Behaviours on Primate Ecological Functions. AB - Human provisioning of wildlife with food is a widespread global practice that occurs in multiple socio-cultural circumstances. Provisioning may indirectly alter ecosystem functioning through changes in the eco-ethology of animals, but few studies have quantified this aspect. Provisioning of primates by humans is known to impact their activity budgets, diets and ranging patterns. Primates are also keystone species in tropical forests through their role as seed dispersers; yet there is no information on how provisioning might affect primate ecological functions. The rhesus macaque is a major human-commensal species but is also an important seed disperser in the wild. In this study, we investigated the potential impacts of provisioning on the role of rhesus macaques as seed dispersers in the Buxa Tiger Reserve, India. We studied a troop of macaques which were provisioned for a part of the year and were dependent on natural resources for the rest. We observed feeding behaviour, seed handling techniques and ranging patterns of the macaques and monitored availability of wild fruits. Irrespective of fruit availability, frugivory and seed dispersal activities decreased when the macaques were provisioned. Provisioned macaques also had shortened daily ranges implying shorter dispersal distances. Finally, during provisioning periods, seeds were deposited on tarmac roads that were unconducive for germination. Provisioning promotes human-primate conflict, as commensal primates are often involved in aggressive encounters with humans over resources, leading to negative consequences for both parties involved. Preventing or curbing provisioning is not an easy task as feeding wild animals is a socio-cultural tradition across much of South and South-East Asia, including India. We recommend the initiation of literacy programmes that educate lay citizens about the ill-effects of provisioning and strongly caution them against the practice. PMID- 26536366 TI - A Bayesian Developmental Approach to Robotic Goal-Based Imitation Learning. AB - A fundamental challenge in robotics today is building robots that can learn new skills by observing humans and imitating human actions. We propose a new Bayesian approach to robotic learning by imitation inspired by the developmental hypothesis that children use self-experience to bootstrap the process of intention recognition and goal-based imitation. Our approach allows an autonomous agent to: (i) learn probabilistic models of actions through self-discovery and experience, (ii) utilize these learned models for inferring the goals of human actions, and (iii) perform goal-based imitation for robotic learning and human robot collaboration. Such an approach allows a robot to leverage its increasing repertoire of learned behaviors to interpret increasingly complex human actions and use the inferred goals for imitation, even when the robot has very different actuators from humans. We demonstrate our approach using two different scenarios: (i) a simulated robot that learns human-like gaze following behavior, and (ii) a robot that learns to imitate human actions in a tabletop organization task. In both cases, the agent learns a probabilistic model of its own actions, and uses this model for goal inference and goal-based imitation. We also show that the robotic agent can use its probabilistic model to seek human assistance when it recognizes that its inferred actions are too uncertain, risky, or impossible to perform, thereby opening the door to human-robot collaboration. PMID- 26536367 TI - The Dual Challenges of Generality and Specificity When Developing Environmental DNA Markers for Species and Subspecies of Oncorhynchus. AB - Environmental DNA (eDNA) sampling is a powerful tool for detecting invasive and native aquatic species. Often, species of conservation interest co-occur with other, closely related taxa. Here, we developed qPCR (quantitative PCR) markers which distinguish westslope cutthroat trout (Oncorhynchus clarkii lewsi), Yellowstone cutthroat trout (O. clarkii bouvieri), and rainbow trout (O. mykiss), which are of conservation interest both as native species and as invasive species across each other's native ranges. We found that local polymorphisms within westslope cutthroat trout and rainbow trout posed a challenge to designing assays that are generally applicable across the range of these widely-distributed species. Further, poorly-resolved taxonomies of Yellowstone cutthroat trout and Bonneville cutthroat trout (O. c. utah) prevented design of an assay that distinguishes these recognized taxa. The issues of intraspecific polymorphism and unresolved taxonomy for eDNA assay design addressed in this study are likely to be general problems for closely-related taxa. Prior to field application, we recommend that future studies sample populations and test assays more broadly than has been typical of published eDNA assays to date. PMID- 26536368 TI - Selective SERS Sensing Modulated by Functionalized Mesoporous Films. AB - A hybrid material comprising metal nanoparticles embedded in functionalized mesoporous thin films was constructed, and its use as a selective SERS-based sensor was demonstrated. The presence of specific functional groups in the pore network allows control over the surface chemistry of the pores, tuning the selectivity for specific molecules. Amino-functionalized hybrid mesoporous thin films were used in a proof of concept experiment, to discern the presence of methylene blue (MB) in mixtures with acid blue (AB), with no need for any sample pretreatment step. Selective detection of MB was possible through entrapment of AB in the mesoporous matrix, based on its high affinity for amino groups. The sensor selectivity can be tuned by varying the solution pH, rendering a pH responsive surface and thus, selective SERS-based sensing. The developed sensors allow specific detection of molecules in complex matrixes. PMID- 26536369 TI - Trapping the Pasture Odorscape Using Open-Air Solid-Phase Micro Extraction, a Tool to Assess Grassland Value. AB - Besides supporting cattle feeding, grasslands are home to a diversity of plants and insects that interact with each other by emitting volatile compounds. The aim of this work was to develop a method to determine permanent grassland odorscape and relate it to flower-visiting insects. Two grasslands were chosen for their contrasting levels of botanical diversity, resulting from differing grazing managements. Measurements were made over two periods of three consecutive days at the beginning of grazing, and just after the cows had left the plots. Volatile compounds were trapped using solid-phase microextraction (SPME) fibers exposed eight hours a day in three exclosures per plot, and then analyzed by gas chromatography-mass spectrometry (GC-MS). Insects were trapped using pan traps and a net, sorted and counted. The open air SPME method yielded volatile compound profiles that were richer than maize field profiles, comprising the common green leaf volatiles (GLV) and more specific ones. Differences between the odorscapes of the two grasslands were found, but they were not as marked as expected from their botanical composition. By contrast, there were sharp differences between the two periods, resulting from the combined effects of changes in weather conditions, plant phenological stage and grazing progress. Several correlations between insect counts and volatile compounds were found. Although their correlation coefficients were low, some of them were confirmed when tested by Spearman rank correlation, and could be logically explained. This method of grassland odorscape deserves to be developed because it can provide information on many aspects of grassland function and on the stresses that grassland plants undergo. PMID- 26536370 TI - The evolving role of radiotherapy in treatment of oligometastatic NSCLC. AB - Non-small cell lung cancer (NSCLC) patients with metastases limited in site and number, termed oligometastases, may represent a unique subpopulation of advanced NSCLC with improved prognosis. The optimal management of these patients remains unclear with the treatment approach currently undergoing a paradigm shift. The potential benefit of aggressive metastasis directed local treatment with surgery and/or radiotherapy (RT) in combination with systemic therapy is bolstered predominantly by retrospective analyses but also by a growing number of non randomized prospective studies regarding the use of ablative RT techniques including stereotactic body radiotherapy (SBRT), alternatively termed stereotactic ablative radiotherapy (SABR), directed at the primary tumor (if present) and all metastatic sites. Long-term survival is possible in a subset of patients treated aggressively in this manner. The challenge for the clinical oncology community moving forward is appropriately selecting patients for this treatment approach based on clinical, imaging, and molecular features and increasing enrollment of patients to prospective clinical trials to more definitively determine the added benefit and appropriate timing of aggressive metastasis directed therapy in the oligometastatic setting. PMID- 26536110 TI - Sex-dependent dominance at a single locus maintains variation in age at maturity in salmon. AB - Males and females share many traits that have a common genetic basis; however, selection on these traits often differs between the sexes, leading to sexual conflict. Under such sexual antagonism, theory predicts the evolution of genetic architectures that resolve this sexual conflict. Yet, despite intense theoretical and empirical interest, the specific loci underlying sexually antagonistic phenotypes have rarely been identified, limiting our understanding of how sexual conflict impacts genome evolution and the maintenance of genetic diversity. Here we identify a large effect locus controlling age at maturity in Atlantic salmon (Salmo salar), an important fitness trait in which selection favours earlier maturation in males than females, and show it is a clear example of sex-dependent dominance that reduces intralocus sexual conflict and maintains adaptive variation in wild populations. Using high-density single nucleotide polymorphism data across 57 wild populations and whole genome re-sequencing, we find that the vestigial-like family member 3 gene (VGLL3) exhibits sex-dependent dominance in salmon, promoting earlier and later maturation in males and females, respectively. VGLL3, an adiposity regulator associated with size and age at maturity in humans, explained 39% of phenotypic variation, an unexpectedly large proportion for what is usually considered a highly polygenic trait. Such large effects are predicted under balancing selection from either sexually antagonistic or spatially varying selection. Our results provide the first empirical example of dominance reversal allowing greater optimization of phenotypes within each sex, contributing to the resolution of sexual conflict in a major and widespread evolutionary trade-off between age and size at maturity. They also provide key empirical evidence for how variation in reproductive strategies can be maintained over large geographical scales. We anticipate these findings will have a substantial impact on population management in a range of harvested species where trends towards earlier maturation have been observed. PMID- 26536371 TI - Bi(OTf)3 Mediated exo-Olefin Isomerization of alpha-Benzoyl beta-Styrylsulfones. AB - Bi(OTf)3-mediated stereoselective exo-olefin isomerization of alpha-benzoyl beta styrylsulfones 5 in MeNO2 afforded alpha-benzoyl alpha-cinnamylsulfones 6 in moderate to good yields. PMID- 26536373 TI - Prescription Stimulants and PTSD Among U.S. Military Service Members. AB - Posttraumatic stress disorder (PTSD) is a prevalent condition among military service members and civilians who have experienced traumatic events. Stimulant use has been postulated to increase the risk of incident PTSD; however, research in this area is lacking. In this study, the association between receipt of prescription stimulants and PTSD was examined in a secondary analysis among active duty U.S. military members (n = 25,971), participating in the Millennium Cohort Study, who completed a baseline (2001-2003) and two follow-up surveys (between 2004-2008). Prescription stimulant data were obtained from the military Pharmacy Data Transaction Service. PTSD was assessed using the PTSD Checklist Civilian Version and incident PTSD was defined as meeting the criteria at follow up among those who did not have a history of PTSD at baseline. Overall, 1,215 (4.7%) persons developed new-onset PTSD during follow-up. Receipt of prescription stimulants were significantly associated with incident PTSD, hazard ratio = 5.09, 95% confidence interval [3.05, 8.50], after adjusting for sociodemographic factors, military characteristics, attention-deficit/hyperactivity disorder, baseline mental and physical health status, deployment experiences, and physical/sexual trauma. Findings suggested that prescription stimulants are associated with incident PTSD among military personnel; these data may inform the underlying pathogenesis of and preventive strategies for PTSD. PMID- 26536372 TI - Transfer of Dicamba Tolerance from Sinapis arvensis to Brassica napus via Embryo Rescue and Recurrent Backcross Breeding. AB - Auxinic herbicides (e.g. dicamba) are extensively used in agriculture to selectively control broadleaf weeds. Although cultivated species of Brassicaceae (e.g. Canola) are susceptible to auxinic herbicides, some biotypes of Sinapis arvensis (wild mustard) were found dicamba resistant in Canada. In this research, dicamba tolerance from wild mustard was introgressed into canola through embryo rescue followed by conventional breeding. Intergeneric hybrids between S. arvensis (2n = 18) and B. napus (2n = 38) were produced through embryo rescue. Embryo formation and hybrid plant regeneration was achieved. Transfer of dicamba tolerance from S. arvensis into the hybrid plants was determined by molecular analysis and at the whole plant level. Dicamba tolerance was introgressed into B. napus by backcrossing for seven generations. Homozygous dicamba-tolerant B. napus lines were identified. The ploidy of the hybrid progeny was assessed by flow cytometry. Finally, introgression of the piece of DNA possibly containing the dicamba tolerance gene into B. napus was confirmed using florescence in situ hybridization (FISH). This research demonstrates for the first time stable introgression of dicamba tolerance from S. arvensis into B. napus via in vitro embryo rescue followed by repeated backcross breeding. Creation of dicamba tolerant B. napus varieties by this approach may have potential to provide options to growers to choose a desirable herbicide-tolerant technology. Furthermore, adoption of such technology facilitates effective weed control, less tillage, and possibly minimize evolution of herbicide resistant weeds. PMID- 26536374 TI - Remote Oxidation of Aliphatic C-H Bonds in Nitrogen-Containing Molecules. AB - Nitrogen heterocycles are ubiquitous in natural products and pharmaceuticals. Herein, we disclose a nitrogen complexation strategy that employs a strong Bronsted acid (HBF4) or an azaphilic Lewis acid (BF3) to enable remote, non directed C(sp(3))-H oxidations of tertiary, secondary, and primary amine- and pyridine-containing molecules with tunable iron catalysts. Imides resist oxidation and promote remote functionalization. PMID- 26536375 TI - Catheter-based acoustic interrogation device for real-time monitoring of the dynamics of the lower esophageal sphincter: in vitro and pilot canine studies. AB - This paper presents a novel minimally-invasive catheter-based acoustic interrogation device for real-time monitoring the dynamics of the lower esophageal sphincter (LES). Dysfunction of the LES could result gastrointestinal (GI) diseases, such as gastroesophageal reflux disease (GERD). A micro-oscillator actively emitting sound wave at 16 kHz is located at one side of the LES, and a miniature microphone is located at the other side of the LES to capture the sound generated from the oscillator. Thus, the dynamics of the opening and closing of the LES can be monitored. The device was tested in vitro by utilizing a custom designed LES simulator, as well as in vivo in a pilot canine model. In the in vitro test, the sound was captured by the microphone and its strength was correlated with the level of LES opening and closing which was controlled by the simulator. The measurements showed statistically significant (p < 0.05) Pearson correlation coefficients (0.905 on the average in quiet environment and 0.736 on the average in noisy environment, DOF = 9). In the in vivo test, the LES was forced open and closed by a transoral endoscope, which was monitored in real-time by a transpyloric endoscope inserted from the duodenum and positioned into the distal stomach. Frame-by-frame video analysis validated the interrelation between the sound strength and the LES opening and closing. The LES dynamics monitored by the proposed device has the potential to become a valuable minimally-invasive technique for understanding LES dysfunction. PMID- 26536376 TI - The Challenges of Polydisperse SAXS Data Analysis: Two SAXS Studies of PICK1 Produce Different Structural Models. PMID- 26536377 TI - Response to The Challenges of Polydisperse SAXS Data Analysis: Two Different SAXS Studies of PICK1 Produce Different Structural Models. PMID- 26536378 TI - A PH Domain with Dual Phospholipid Binding Sites Regulates the ARF GAP, ASAP1. AB - In this issue of Structure, Jian et al. (2015) report the crystal structures of the apo- and dibutyryl-PI(4,5)P2 bound forms of the PH domain from the ARF GAP, ASAP1. This PH domain has two anionic phospholipid binding sites proposed to work in concert to regulate ASAP1 GAP activity. PMID- 26536379 TI - TRIBBLES: A Twist in the Pseudokinase Tail. AB - TRIB1, a homolog of Drosophila Tribbles, regulates the stability of transcription factors through physical interaction with the ubiquitin E3 ligase COP1. In this issue of Structure, Murphy et al. (2015) report the first X-ray analysis of the TRIB1 pseudokinase domain and its C-terminal COP1-binding extension. PMID- 26536381 TI - Calcium Phosphate Mineralization in Cellulose Derivative/Poly(acrylic acid) Composites Having a Chiral Nematic Mesomorphic Structure. AB - Calcium phosphate mineralization was conducted by using polymer composites of liquid-crystalline (ethyl)cellulose (EC) or (hydroxypropyl)cellulose (HPC) with poly(acrylic acid) (PAA) as a scaffolding medium for the inorganic deposition. The EC/PAA and HPC/PAA samples were prepared in colored film form from EC and HPC lyotropic liquid crystals of left-handed and right-handed chiral nematics, respectively, by polymerization and cross-linking of acrylic acid as the main solvent component. The mineralization was allowed to proceed in a batchwise operation by soaking the liquid-crystalline films in an aqueous salt solution containing the relevant ions, Ca(2+) and HPO4(2-). The calcium phosphate deposited EC/PAA and HPC/PAA composites (weight gain, typically 15-25% and 6-11%, respectively) retained the chiral nematic organization of the respective original handedness but exhibited selective light-reflection of longer wavelengths relative to that of the corresponding nonmineralized samples. From X-ray diffraction and energy-dispersive X-ray spectroscopy measurements, it was deduced that the calcium and phosphorus were incorporated inside the polymer matrices in three forms: amorphous calcium phosphate, hydroxyapatite, and a certain complex of PAA-Ca(2+). Dynamic mechanical analysis and thermogravimetry revealed that the inorganic hybridization remarkably enhanced the thermal and mechanical performance of the optically functionalized cellulosic/synthetic polymer composites; however, the effect was more drastic in the EC/PAA series rather than the HPC/PAA series, reflecting the difference in the deposited mineral amount between the two. PMID- 26536382 TI - Fast myelin water fraction estimation using 2D multislice CPMG. AB - PURPOSE: T2 relaxometry based on multiexponential fitting to a single slice multiecho sequence has been the most common MRI technique for myelin water fraction mapping, where the short T2 is associated with myelin water. However, very long acquisition times and physically unrealistic models for T2 distribution are limitations of this approach. We present a novel framework for myelin imaging which substantially increases the imaging speed and myelin water fraction estimation accuracy. METHOD: We used the 2D multislice Carr-Purcell-Meiboom-Gill sequence to increase the volume coverage. To compensate for nonideal slice profiles, we numerically solved the Bloch equations for a range of T2 and B1 inhomogeneity scales to construct the bases for the estimation of the T2 distribution. We used a finite mixture of continuous parametric distributions to describe the complete T2 spectrum and used the constrained variable projection optimization algorithm to estimate myelin water fraction. To validate our model, synthetic, phantom, and in vivo brain experiments were conducted. RESULTS: Using the Bloch equations, we can model the slice profile and construct the forward model of the T2 curve. Our method estimated myelin water fraction with smaller error than the nonnegative least squares algorithm. CONCLUSIONS: The proposed framework can be used for reliable whole brain myelin imaging with a resolution of 2*2*4 mm3 in ~17 min. Magn Reson Med 76:1301-1313, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26536384 TI - Treatment of Refractory Pityriasis Rubra Pilaris With Novel Phosphodiesterase 4 (PDE4) Inhibitor Apremilast. PMID- 26536383 TI - Transcranial magnetic stimulation in autism spectrum disorder: Challenges, promise, and roadmap for future research. AB - Autism Spectrum Disorder (ASD) is a behaviorally defined complex neurodevelopmental syndrome characterized by impairments in social communication, by the presence of restricted and repetitive behaviors, interests and activities, and by abnormalities in sensory reactivity. Transcranial magnetic stimulation (TMS) is a promising, emerging tool for the study and potential treatment of ASD. Recent studies suggest that TMS measures provide rapid and noninvasive pathophysiological ASD biomarkers. Furthermore, repetitive TMS (rTMS) may represent a novel treatment strategy for reducing some of the core and associated ASD symptoms. However, the available literature on the TMS use in ASD is preliminary, composed of studies with methodological limitations. Thus, off-label clinical rTMS use for therapeutic interventions in ASD without an investigational device exemption and outside of an IRB approved research trial is premature pending further, adequately powered and controlled trials. Leaders in this field have gathered annually for a two-day conference (prior to the 2014 and 2015 International Meeting for Autism Research, IMFAR) to share recent progress, promote collaboration across laboratories, and establish consensus on protocols. Here we review the literature in the use of TMS in ASD in the context of the unique challenges required for the study and exploration of treatment strategies in this population. We also suggest future directions for this field of investigations. While its true potential in ASD has yet to be delineated, TMS represents an innovative research tool and a novel, possibly transformative approach to the treatment of neurodevelopmental disorders. PMID- 26536385 TI - Increasing nondonors' intention to give blood: addressing common barriers. AB - BACKGROUND: Recruiting new donors is a challenging experience for most blood collection agencies. A modest proportion of the population is eligible to give blood and few of these individuals volunteer. The goal of this study was to examine the effects of brief behavioral interventions on nondonors' intention to give blood, by addressing some commonly reported obstacles. STUDY DESIGN AND METHODS: A total of 244 young adults who were eligible to give blood but had never done so participated in the study. They were assigned randomly to an applied tension (AT) instruction condition, a relaxation instruction condition, a Web browsing condition, or a no-treatment control condition. After the 20-minute experimental intervention, half watched three short injection and blood draw videos and the others sat quietly. Intention to give blood and different cognitive constructs associated with blood donation were measured using a Theory of Planned Behavior questionnaire. RESULTS: Participants in all three active conditions had significantly greater increases in intention to donate blood compared to controls, although those who learned AT had greater increases than Web browsing. Bootstrapping tests of mediation indicated particular importance of increased perceived behavioral control in AT and relaxation treatment effects. Follow-up analyses revealed a significant association between degree of within session increase in intention and subsequent blood clinic attendance. CONCLUSION: These results suggest that simple interventions can be effective in increasing nondonors' intention to donate blood and, perhaps, actual attendance. The mediational analyses suggest that interventions can selectively target different barriers associated with blood donation. PMID- 26536386 TI - The Surgeon Cost Report Card: A Novel Cost-Performance Feedback Tool. PMID- 26536387 TI - Quantitative Analysis of the Local Phase Transitions Induced by Laser Heating. AB - Functional imaging enabled by scanning probe microscopy (SPM) allows investigations of nanoscale material properties under a wide range of external conditions, including temperature. However, a number of shortcomings preclude the use of the most common material heating techniques, thereby limiting precise temperature measurements. Here we discuss an approach to local laser heating on the micron scale and its applicability for SPM. We applied local heating coupled with piezoresponse force microscopy and confocal Raman spectroscopy for nanoscale investigations of a ferroelectric-paraelectric phase transition in the copper indium thiophosphate layered ferroelectric. Bayesian linear unmixing applied to experimental results allowed extraction of the Raman spectra of different material phases and enabled temperature calibration in the heated region. The obtained results enable a systematic approach for studying temperature-dependent material functionalities in heretofore unavailable temperature regimes. PMID- 26536388 TI - Cellularized Cellular Solids via Freeze-Casting. AB - The elaboration of metabolically active cell-containing materials is a decisive step toward the successful application of cell based technologies. The present work unveils a new process allowing to simultaneously encapsulate living cells and shaping cell-containing materials into solid-state macroporous foams with precisely controlled morphology. Our strategy is based on freeze casting, an ice templating materials processing technique that has recently emerged for the structuration of colloids into macroporous materials. Our results indicate that it is possible to combine the precise structuration of the materials with cellular metabolic activity for the model organism Saccharomyces cerevisiae. PMID- 26536389 TI - BRAF inhibitors in BRAF-V600 mutated primary neuroepithelial brain tumors. AB - INTRODUCTION: Primary neuroepithelial brain tumors encompass a wide variety of glial and glioneuronal neoplasms. Malignant tumors, tumors located in surgically inaccessible locations (e.g., eloquent brain areas, deep structures, brain stem) and recurrent or progressive tumors pose considerable treatment challenges and are candidates for novel therapeutics based on molecular insights. Small kinase inhibitors of v-RAF murine sarcoma viral oncogene homologue B1 (BRAF) have shown considerable antineoplastic activity in some tumor types harboring activating BRAF-V600 mutations (e.g., melanoma) and promising data are emerging on BRAF inhibitor therapy of mutation-bearing primary brain tumors. AREAS COVERED: This review summarizes the available data on BRAF-V600 point mutations and the antineoplastic activity and toxicity profiles of BRAF inhibitors in neuroepithelial brain tumors including diffuse gliomas (glioblastomas, astrocytomas, oligodendrogliomas), pilocytic astrocytomas, pleomorphic xanthoastrocytomas and gangliogliomas. EXPERT OPINION: Activating BRAF-V600 mutations are recurrently found in several glial and glioneuronal brain tumors and the available data indicate that BRAF inhibitors are active and well tolerated in such tumors. Thus, BRAF inhibitors represent a novel and promising therapeutic opportunity that may alter the disease course of molecularly selected CNS neoplasms in a clinically meaningful way. However, so far the evidence is anecdotal and prospective clinical studies should be conducted. PMID- 26536390 TI - Predicting depth of electrode insertion by cochlear measurements on computed tomography scans. AB - OBJECTIVES/HYPOTHESIS: To evaluate the effectiveness of cochlear measures obtained by high-resolution computed tomography (HRCT) scan in predicting depth of cochlear implant insertion. STUDY DESIGN: Retrospective case review. METHODS: Patients who underwent cochlear implantation in an academic referral center between 2010 and 2013 were considered. Inclusion criteria included available preoperative HRCT scan and complete operative data. Subjects with labyrinthitis ossificans, cochlear hypoplasia, or major inner ear malformations were excluded. Subsequently, measures of cochlear height in the coronal plane and basal turn width in the axial plane were obtained using electronic calipers of the stored digital HRCT images by a blinded investigator. The insertion was considered deep when the electrode was placed at least 23 mm into the cochlea. Subjects were divided into those who had a deep insertion and those who did not. Regression analyses were done to associate cochlear measures with deep insertion. RESULTS: A deep insertion was possible in 25 patients out of 35. There was no statistically significant association between deep insertion and age at implantation, gender, and type of cochleostomy. The mean cochlear height was 6.22 mm (standard deviation [SD] = 0.32 mm) and 5.80 mm (SD = 0.3mm) in subjects with and without deep insertion, respectively (Student t test, P = .0015). Only cochlear height showed an association with deep insertion (logistic regression, P = .0007). For a cochlear height of 6.27 mm, the probability of deep insertion was 0.90. CONCLUSIONS: Linear measurements of standard CT scans of the cochlea can predict the depth of insertion and may help the selection of the appropriate electrode array preoperatively. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1656-1661, 2016. PMID- 26536391 TI - Understanding geometric instabilities in thin films via a multi-layer model. AB - When a thin stiff film adhered to a compliant substrate is subject to compressive stresses, the film will experience a geometric instability and buckle out of plane. For high film/substrate stiffness ratios with relatively low levels of strain, the primary mode of instability will either be wrinkling or buckling delamination depending on the material and geometric properties of the system. Previous works approach these systems by treating the film and substrate as homogenous layers, either consistently perfectly attached, or perfectly unattached at interfacial flaws. However, this approach neglects systems where the film and substrate are uniformly weakly attached or where interfacial layers due to surface modifications in either the film or substrate are present. Here we demonstrate a method for accounting for these additional thin surface layers via an analytical solution verified by numerical results. The main outcome of this work is an improved understanding of how these layers influence global behavior. We demonstrate the utility of our model with applications ranging from buckling based metrology in ultrathin films, to an improved understanding of the formation of a novel surface in carbon nanotube bio-interface films. Moving forward, this model can be used to interpret experimental results, particularly for systems which deviate from traditional behavior, and aid in the evaluation and design of future film/substrate systems. PMID- 26536392 TI - Development and oversight of ethical health promotion quality assurance and evaluation activities involving human participants. AB - ISSUE ADDRESSED: This paper considers the role of ethics and ethics review processes in the development of health promotion quality assurance and evaluation activities involving human participants. CONTENT: The Australian National Health and Medical Research Council (NHMRC) National Statement on Ethical Conduct in Human Research and associated documents provide the framework for the ethical conduct and independent review of research (including quality assurance and evaluation) involving humans in Australia. Identifying the level of risk to which participants may be exposed by participation in quality assurance and evaluation activities is essential for health promotion workers undertaking such activities. Organisations can establish processes other than review by a Human Research Ethics Committee for negligible and low risk research activities. Health promotion quality assurance and evaluation activities often involve negligible and low risk to participants. Seven triggers that indicate the need for ethics review of quality assurance and evaluation activities and a procedural checklist for developing ethical quality assurance and evaluation activities are provided. CONCLUSION: Health promotion workers should be familiar with the NHMRC's National Statement on Ethical Conduct in Human Research. When ethical considerations underpin the planning and conduct of all quality assurance and evaluation from the very beginning, the activity is the better for it, independent 'ethics approval' can mostly be secured without much trouble and workers' frustration levels are reduced. So what? Health promotion quality assurance and evaluation activities must be ethically justified. Health promotion workers should be familiar with the NHMRC's National Statement on Ethical Conduct in Human Research and should use it when developing health promotion quality assurance and evaluation activities. PMID- 26536393 TI - Addressing a "Black Box" of Bottom-Up Synthesis: Revealing the Structures of Growing Colloidal-Nanocrystal Nuclei. AB - In bottom-up synthesis, products from reactions of structural building units rapidly pass from soluble molecular complexes to nanoscale intermediates, whose solution-state structures defy elucidation by any routine method. To address this, electron diffraction is used to reveal the structures of cryogenically "trapped" colloidal nanocrystals. PMID- 26536394 TI - Prognostic value of non-invasive stress testing for coronary artery disease in obese patients. AB - Detecting coronary artery disease (CAD) in obese patients remains a challenge but can have substantial prognostic implications for this patient group. Until now, sufficient data was not available on which to base the selection of the imaging modality in obese patients. The decision on which imaging modality to use should therefore follow the general guidelines. In this article, the authors discuss the prognostic value of the different non-invasive stress testing methods for CAD in obese patients. PMID- 26536395 TI - Experimental Investigation and Thermodynamic Assessment of Phase Equilibria in the PLLA/Dioxane/Water Ternary System for Applications in the Biomedical Field. AB - Fundamental understanding of thermodynamic of phase separation plays a key role in tuning the desired features of biomedical devices. In particular, phase separation of ternary solution is of remarkable interest in processes to obtain biodegradable and biocompatible architectures applied as artificial devices to repair, replace, or support damaged tissues or organs. In these perspectives, thermally induced phase separation (TIPS) is the most widely used technique to obtained porous morphologies and, in addition, among different ternary systems, polylactic acid (PLLA)/dioxane/water has given promising results and has been largely studied. However, to increase the control of TIPS-based processes and architectures, an investigation of the basic energetic phenomena occurring during phase separation is still required. Here we propose an experimental investigation of the selected ternary system by using isothermal titration calorimetric approach at different solvent/antisolvent ratio and a thermodynamic explanation related to the polymer-solvents interactions in terms of energetic contribution to the phase separation process. Furthermore, relevant information about the phase diagrams and interaction parameters of the studied systems are furnished in terms of liquid-liquid miscibility gap. Indeed, polymer-solvents interactions are responsible for the mechanism of the phase separation process and, therefore, of the final features of the morphologies; the knowledge of such data is fundamental to control processes for the production of membranes, scaffolds and several nanostructures. The behavior of the polymer at different solvent/nonsolvent ratios is discussed in terms of solvation mechanism and a preliminary contribution to the understanding of the role of the hydrogen bonding in the interface phenomena is also reported. It is the first time that thermodynamic data of a ternary system are collected by mean of nano-isothermal titration calorimetry (nano-ITC). Supporting Information is available. PMID- 26536396 TI - Assessment of a computer-based Taenia solium health education tool 'The Vicious Worm' on knowledge uptake among professionals and their attitudes towards the program. AB - Health education has been recognised as a specific intervention tool for control of Taenia solium taeniosis/cysticercosis but evaluation of the efficacy of the tool remains. The aim of our study was to assess the effect of a computer-based T. solium health education tool 'The Vicious Worm' on knowledge uptake among professionals and investigate attitudes towards the program. The study was carried out between March and May 2014 in Mbeya Region, Tanzania, where T. solium is endemic. The study was a pre and post assessment of a health education tool based on questionnaire surveys and focus group discussions to investigate knowledge and attitudes. A total of 79 study subjects participated in the study including study subjects from both health- and agriculture sector. The health education consisted of 11/2h individual practice with the computer program. The baseline questionnaire showed an overall knowledge on aspects of acquisition and transmission of T. solium infections (78%), porcine cysticercosis treatment (77%), human tapeworm in general (72%), neurocysticercosis in general (49%), and porcine cysticercosis diagnosis (48%). However, there was a lack of knowledge on acquisition of neurocysticercosis (15%), prevention of T. solium taeniosis/cysticercosis (28%), and relation between porcine cysticercosis, human cysticercosis, and taeniosis (32%). Overall, the study subject's knowledge was significantly improved both immediately after (p=0.001) and two weeks after (p<0.001) the health education and knowledge regarding specific aspects was significantly improved in most aspects immediately after and two weeks after the health education. The focus group discussions showed positive attitudes towards the program and the study subjects found 'The Vicious Worm' efficient, simple, and appealing. The study revealed a good effect of 'The Vicious Worm' suggesting that it could be a useful health education tool, which should be further assessed and thereafter integrated in T. solium taeniosis/cysticercosis control. PMID- 26536397 TI - Inhibition of acetylcholinesterase and cytochrome oxidase activity in Fasciola gigantica cercaria by phytoconstituents. AB - Fasciolosis is an important cattle and human disease caused by Fasciola hepatica and Fasciola gigantica. One of the possible methods to control this problem is to interrupt the life cycle of Fasciola by killing its larva (redia and cercaria) in host snail. Molecular identification of cercaria larva of F. gigantica was done by comparing the nucleotide sequencing with adult F. gigantica. It was noted that nucleotide sequencing of cercaria larva and adult F. gigantica were 99% same. Every month during the year 2011-2012, in vivo treatment with 60% of 4 h LC50 of phyto cercaricides citral, ferulic acid, umbelliferone, azadirachtin and allicin caused significant inhibition of acetylcholinesterase (AChE) and cytochrome oxidase activity in the treated cercaria larva of F. gigantica. Whereas, activity of both enzymes were not significantly altered in the nervous tissues of vector snail Lymnaea acuminata exposed to same treatments. Maximum reduction in AChE (1.35% of control in month of June) and cytochrome oxidase (3.71% of control in the month of July) activity were noted in the cercaria exposed to 60% of 4 h LC50 of azadirachtin and allicin, respectively. PMID- 26536398 TI - A Never-Ending Battle. PMID- 26536399 TI - From placement to prison revisited: Do mental health services disrupt the delinquency pipeline among Latino, African American and Caucasian youth in the child welfare system? AB - Racial and ethnic disparities in delinquency among child welfare-involved youth are well documented. However, less is known about the mechanisms through which these disparities occur. This study explores the extent to which sets of variables predict the occurrence of juvenile delinquency and whether race/ethnicity moderates the strength of the relationships between (1) social, emotional, and behavioral (SEB) problems and delinquency and (2) mental health service use and delinquency. We used a nationally representative sample of 727 African American, Caucasian, and Latino youth between the ages of 12-17 who were referred to the child welfare system. Controlling for age, gender, placement instability, maltreatment history, poverty, and urbanicity, linear regression analyses revealed that African American and Latino youth engaged in more delinquent acts than Caucasian youth did. However, service use decreased the likelihood of engaging in more delinquent acts for African Americans. Additional efforts are needed to illuminate and address the contextual and organizational barriers to delivering effective mental health services as a strategy to reduce racial disparities in delinquent behavior. PMID- 26536400 TI - Acute iron overload leads to hypothalamic-pituitary-gonadal axis abnormalities in female rats. AB - Iron plays a critical role in a mammal's physiological processes. However, iron tissue deposits have been shown to act as endocrine disrupters. Studies that evaluate the effect of acute iron overload on hypothalamic-pituitary-gonadal (HPG) axis health are particularly sparse. This study demonstrates that acute iron overload leads to HPG axis abnormalities, including iron accumulation and impairment in reproductive tract morphology. Female rats were treated with iron dextran (Fe rats) to assess their HPG morphophysiology. The increasing serum iron levels due to iron-dextran treatment were positively correlated with higher iron accumulation in the HPG axis and uterus of Fe rats than in control rats. An increase in the production of superoxide anions was observed in the pituitary, uterus and ovary of Fe rats. Morphophysiological reproductive tract abnormalities, such as abnormal ovarian follicular development and the reduction of serum estrogen levels, were observed in Fe rats. In addition, a significant negative correlation was obtained between ovary superoxide anion and serum estrogen levels. Together, these data provide in vivo evidence that acute iron overload is toxic for the HPG axis, a finding that may be associated with the subsequent development of the risk of reproductive dysfunction. PMID- 26536401 TI - The Continuing Quest for Meaningful Faculty Evaluations of Residents. PMID- 26536402 TI - MU-Rainbow: CdSe Nanocrystal Photoluminescence Gradients via Laser Spike Annealing for Kinetic Investigations and Tunable Device Design. AB - Much of the promise of nanomaterials derives from their size-dependent, and hence tunable, properties. Impressive advances have been made in the synthesis of nanoscale building blocks with precisely tailored size, shape and composition. Significant attention is now turning toward creating thin film structures in which size-dependent properties can be spatially programmed with high fidelity. Nonequilibrium processing techniques present exciting opportunities to create nanostructured thin films with unprecedented spatial control over their optical and electronic properties. Here, we demonstrate single scan laser spike annealing (ssLSA) on CdSe nanocrystal (NC) thin films as an experimental test bed to illustrate how the size-dependent photoluminescence (PL) emission can be tuned throughout the visible range and in spatially defined profiles during a single annealing step. Through control of the annealing temperature and time, we discovered that NC fusion is a kinetically limited process with a constant activation energy in over 2 orders of magnitude of NC growth rate. To underscore the broader technological implications of this work, we demonstrate the scalability of LSA to process large area NC films with periodically modulated PL emission, resulting in tunable emission properties of a large area film. New insights into the processing-structure-property relationships presented here offer significant advances in our fundamental understanding of kinetics of nanomaterials as well as technological implications for the production of nanomaterial films. PMID- 26536403 TI - Virtual Monochromatic Images from Dual-Energy Multidetector CT: Variance in CT Numbers from the Same Lesion between Single-Source Projection-based and Dual Source Image-based Implementations. AB - PURPOSE: To determine the variance in virtual monochromatic computed tomography (CT) numbers from the same lesion, comparing the two clinically available dual energy multidetector CT hardware implementations (single-source projection-based and dual-source image-based), in a phantom-based simulated abdominal environment. MATERIALS AND METHODS: This phantom-based study was exempt from institutional review board oversight. Polyethylene terephthalate spheres (15 and 18 mm) with two iodine-to-saline dilutions (0.8 and 1.2 mg of iodine per millilliter) were serially suspended in a cylindrical polypropylene bottle filled with diluted iodinated contrast material. The bottle was placed into a 36-cm-wide torso-shaped water phantom simulating the abdomen of a medium-sized patient. Dual-energy (80/140 kVp) and single-energy (100 and 120 kVp) scans were obtained with single source and dual-source multidetector CT implementations. Virtual monochromatic images were reconstructed at energy levels of 40-140 keV (in 10-keV increments) in either the projection-space or image-space domain. A multivariate regression analysis approach was used to investigate the effect of energy level, lesion size, lesion iodine content, and implementation type on measured CT numbers. RESULTS: There were significant differences in the attenuation values measured in the simulated lesions with the single-source projection-based platform and the dual-source image-based implementation (P < .001 for all comparisons). The magnitude of these differences was greatest at lower monochromatic energy levels and at lower iodine concentrations (average difference at 40 keV: 25.7 HU; average difference at 140 keV: 7 HU). The monochromatic energy level and the lesion iodine concentration had a significant effect on the difference in the measured attenuation values between the two implementations, which indicates that the two imaging platforms respond differently to changes in investigated variables (P < .001 for all comparisons). CONCLUSION: There is a statistically significant variance in virtual monochromatic CT numbers from the same lesion examined with single-source projection-based and dual-source image-based implementations. The magnitude of the variance is a function of the selected energy level and the lesion iodine content. PMID- 26536404 TI - Indirect Cost and Harm Attributable to Oral 13-Hour Inpatient Corticosteroid Prophylaxis before Contrast-enhanced CT. AB - PURPOSE: To estimate the effect of an oral 13-hour inpatient corticosteroid premedication regimen on length of stay, hospital cost, and hospital-acquired infections (HAIs) by using a combination of real and hypothetical study populations. MATERIALS AND METHODS: Institutional review board approval was obtained and informed consent waived for this HIPAA-compliant retrospective study. Inpatients who received an oral 13-hour corticosteroid premedication regimen before contrast material-enhanced CT (n = 1424) from 2008 to 2013 were matched by age, sex, and year when CT was performed to a control cohort (n = 1425) of patients who underwent contrast-enhanced CT without premedication and who had similar rates of 13 comorbid diseases. Length of stay in the hospital and time from admission to CT were compared by using the Mann-Whitney U test. Rates of prospectively reported HAIs were compared by using chi(2) tests. The indirect cost and risk of HAI with premedication were estimated by using published data. RESULTS: Premedicated inpatients had a significantly longer median length of stay (+25 hours; 158 vs 133 hours, P < .001), a significantly longer median time to CT (+25 hours, 42 vs 17 hours, respectively; P < .001), and a significantly greater risk of HAI (5.1% [72 of 1424] vs 3.1% [44 of 1424], respectively; P = .008) compared with nonpremedicated control subjects. On the basis of these data and existing references, the prolonged length of stay was estimated to result in 0.04 HAI-related deaths and a cost of $159 131 (in U.S. dollars) for each prevented reaction of any severity and 32 HAI-related deaths and a cost of $131 211 400 for each prevented reaction-related death. CONCLUSION: Oral 13-hour inpatient corticosteroid prophylaxis is associated with substantial cost relative to its modest benefit, and may cause more indirect harm than the direct harm that it prevents. PMID- 26536405 TI - Safe Handling of Chemotherapeutic Agents in the Treatment of Nonmalignant Diseases. AB - Chemotherapy administration was once limited to inpatient oncology units. Over time, outpatient facilities, physicians' private offices, and patients' homes have become popular areas to administer chemotherapeutic agents. Chemotherapy has been successful in treating malignancies and recently has been proved to be effective in nononcology patients as well. The expanded use of these agents has created the need to amplify safe handling practices among health care providers. Evidence indicates that there is a heightened awareness of safe handling practices and the increased availability of the necessary tools. However, health care professionals resist protecting themselves. To avoid the potential risks associated with working with these agents, it is imperative to appreciate the dangers of these hazardous medications, to adhere to the safety mechanisms, and to use the available safety resources on a daily basis. Continuous education of health care providers is fundamental to ensuring safety and positive outcomes. Safe handling procedures can be implemented by adhering to the current standards and integrating them into policies and procedure manuals at practicing institutions. PMID- 26536406 TI - Chronotherapeutic Drug Delivery. AB - Living organisms follow a circadian rhythm in which physiological processes such as hormonal secretion, metabolism, heart rate, and renal output are affected by the time of day. Chronotherapy coordinates drug delivery with the circadian rhythm to enhance effectiveness and mitigate adverse effects and is achieved by delivering a drug when the system is most susceptible. Cancer is a chronotherapeutic disorder. Cancer treatment requires high doses of intravenous medication to kill cancerous cells; however, normal cells are also killed, creating intolerable side effects. This review shows that chronotherapy can play a vital role in the quality of life and survival rate for oncology patients. PMID- 26536407 TI - NIOSH Safe Handling of Hazardous Drugs Guidelines Becomes State Law. AB - Although guidelines for protecting health care workers from the dangers of hazardous drugs have been in existence for more than 25 years, there is tremendous inconsistency in compliance by oncology professionals. One reason for the discrepancy is the voluntary, nonpunitive nature of these guidelines. In 2012, Washington State became the first in the United States to mandate and enforce the National Institute for Occupational Safety and Health guidelines. PMID- 26536408 TI - Evaluation of Safe Infusion Devices for Antineoplastic Administration. AB - Nurses endure daily low-level exposure to cytotoxic drugs, which can lead to significant absorption with potential harmful consequences. New sterile medical devices called cytotoxic safe infusion systems (CSISs), intended by their manufacturers to improve safety and quality of cytotoxic drug infusions, have been made commercially available. CSISs from 3 manufacturers were tested in 2 cancer units and compared with standard infusion sets. The aim of this study is to evaluate the devices regarding occupational exposure, quality of the infusion, and economic aspects. PMID- 26536409 TI - A Message from Mary Alexander. PMID- 26536410 TI - Multiple Endocrine Neoplasia Syndromes. AB - Multiple endocrine neoplasia (MEN) is a term used to describe a group of hereditary carcinoma syndromes. Patients carrying a characteristic autosomal dominant gene aberration exhibit various endocrine carcinomas, as well as other anatomical abnormalities. Unfortunately, familial endocrine carcinoma patients are too often unrecognized by primary care providers, resulting in delayed diagnosis and treatment, with profound consequences related to morbidity and mortality. This article will introduce the various MEN syndromes and the infusion nurse's role in the care of these individuals and their families. PMID- 26536411 TI - Rituximab Faster Infusion for Patients With Non-Hodgkin's Lymphoma in the United States: Implications for Nursing Practice. AB - The majority of follicular non-Hodgkin's lymphoma patients in the United States receive an initial treatment strategy that includes the infusion of rituximab. Data from a phase III multicenter clinical trial led to the 2012 US Food and Drug Administration approval of a 90-minute infusion of rituximab (Rituxan) starting at Cycle 2 for patients with non-Hodgkin's lymphoma who did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1. A review of literature was undertaken to identify existing evidence regarding both the safety of rituximab faster infusion and its impact on nursing practice. The aim of this article is to stimulate discussion and lead to implementation of evidence-based nursing practices to improve the delivery of patient care. PMID- 26536412 TI - Eliminating Extravasation Events: A Multidisciplinary Approach. AB - Administration of chemotherapy agents can give rise to many safety issues. Extravasation of a vesicant agent causes tissue blistering and necrosis. This complication of chemotherapy administration causes additional pain and suffering in patients who are already suffering with a diagnosis of cancer. Nurses hold key responsibilities for educating patients about administration issues and following practice standards to minimize the risk of extravasation. Defining a path of shared responsibilities among team members is a critical step in assuring the safe administration of drugs classified as vesicants. This article describes a clinical practice change that is used at a large midwestern academic medical cancer center. This practice and policy change has resulted in a 90% reduction in the administration of vesicant agents peripherally, with no occurrence of extravasations in the first 6 months of implementation. PMID- 26536413 TI - The Impact of Postmeningitic Labyrinthitis Ossificans on Speech Performance After Pediatric Cochlear Implantation. AB - OBJECTIVE: 1) To characterize pediatric cochlear implant performance in patients with hearing loss secondary to bacterial meningitis. 2) To evaluate performance differences in patients with and without labyrinthitis ossificans (LO). STUDY DESIGN: Retrospective case review. SETTING: A large university-based multidisciplinary cochlear implant program. PATIENTS: Forty-nine patients with hearing loss from bacterial meningitis who received cochlear implants from 1991 to 2011. Thirty-nine patients had adequate data for analysis. INTERVENTION: Cochlear implantation with postoperative performance evaluation. MAIN OUTCOME MEASURE(S): Speech perception category (SPC). RESULTS: Nineteen (48.7%) patients had intraoperative evidence of LO. Fourteen patients (70.0%) without LO compared with seven (36.8%) with LO developed open-set speech after implantation. There was a trend toward better postimplant SPC outcomes in patients without LO that did not reach statistical significance (p = 0.17). The presence of LO negatively correlated with classroom placement (p < 0.05). Analysis of each group individually demonstrated statistically significant improvement in pre- versus postimplant SPC outcomes (p < 0.001). CONCLUSION: The presence of LO may negatively affect performance in pediatric patients receiving a cochlear implant for hearing loss secondary to bacterial meningitis. PMID- 26536414 TI - Impact of Elevation of Temporal Lobe During Middle Fossa Acoustic Neuroma Surgery on Contralateral Speech Discrimination. AB - AIM: For middle fossa acoustic neuroma approach, retractors are needed to elevate the temporal lobe to be able to access the internal auditory meatus. The temporal lobe hosts the primary and secondary auditory fields. The question arises regarding whether this elevation affects the functionality of the auditory cortex. MATERIAL AND METHODS: In patients, who underwent acoustic neuroma surgery, contralateral speech discrimination was tested pre- and postsurgery using different speech discrimination tests. Results of patients with a middle fossa approach were compared with patients with a translabyrinthine approach. RESULTS: No major differences between the translabyrinthine and the middle fossa approach could be detected. CONCLUSION: Elevation of the temporal lobe during middle fossa approach for acoustic neuroma surgery does not lead to short-term impaired contralateral speech discrimination compared with translabyrinthine approach. PMID- 26536415 TI - Management of Geniculate Ganglion Hemangiomas: Case Series and Systematic Review of the Literature. AB - OBJECTIVE: To analyze facial nerve (FN) outcomes based on duration of FN palsy and surgical strategy in patients with geniculate ganglion hemangiomas (GGH). STUDY DESIGN: Case series and systematic review of the literature. SETTING: Tertiary care center. SUBJECTS AND METHODS: All patients undergoing surgical resection of GGH from 1992 to 2014 were studied and a review of the English literature was performed. RESULTS: One hundred twenty unique patients (mean age 41.4 yrs, 44% female) were identified with GGH: 8 in the current series and 112 from the literature review. Of these patients, 94% presented with FN weakness, 18% reported hemifacial spasm, and 16% had hearing loss at presentation. Eleven patients underwent an initial period of observation, 6 of which experienced either growth or progression of FN dysfunction. One hundred fourteen subjects ultimately underwent surgical intervention. The average preoperative House Brackmann (HB) score was 4.6 and the mean duration of preoperative FN palsy was 27 months (range, 1-132). The average postoperative HB score was 3.5 at the last follow-up. Anatomical FN preservation was reported in 44% of patients. Duration of FN palsy <=12 months was associated with better pre- and postoperative FN outcome (HB 4.1 vs 5.1, p = 0.01 and 2.9 vs 4.0, p < 0.001, respectively). FN preservation was also associated with better postoperative FN outcome compared with interposition grafting (HB 2.6 vs 3.9, p < 0.001). CONCLUSION: GGHs are rare benign vascular malformations that present with progressive FN palsy. In most patients, early surgical intervention should be considered since shorter duration of FN paralysis and anatomical preservation of the FN are significant predictors of final FN outcome. PMID- 26536416 TI - Immunocytochemical localization of the calcium-binding proteins calbindin D28K, calretinin, and parvalbumin in bat visual cortex. AB - It is a common misconception that bats are blind, and various studies have suggested that bats have visual abilities. The purpose of this study was to investigate the cytoarchitecture of calbindin D28K (CB)-, calretinin (CR)-, and parvalbumin (PV)-immunoreactive (IR) neurons in the bat visual cortex using immunocytochemistry. The highest density of CB- and PV-IR neurons was located in layer IV of the visual cortex. The majority of CB- and PV-IR neurons were characterized by a stellate or round/oval shape. CR-IR neurons were predominantly located in layers II/III, and the cells were principally round/oval in shape. Two color immunofluorescence revealed that 65.96%, 24.24%, and 77.00% of the CB-, CR , and PV-IR neurons, respectively, contained gamma-aminobutyric acid (GABA). We observed calcium-binding protein (CBP)-IR neurons in specific layers of the bat visual cortex and in specific cell types. Many of the CBP-IR neurons were GABAergic interneurons. These data provide useful clues to aid in understanding the functional aspects of the bat visual system. PMID- 26536418 TI - Vascularized composite allotransplantation still remains an emerging field after 17 years. PMID- 26536419 TI - Immunopathology of rejection: do the rules of solid organ apply to vascularized composite allotransplantation? AB - PURPOSE OF REVIEW: As both the number of vascularized composite allotransplants (VCAs) recipients and the duration of their follow-up are limited, immunopathology of VCA rejection remains incompletely understood. VCAs have several immunological peculiarities, which make inaccurate a direct extrapolation of all rules established for solid organs. RECENT FINDINGS: Despite their bone marrow content, VCA do not induce chimerism in recipient and are therefore not spontaneously tolerated. Skin compartment of VCA contains a high density of antigen-presenting cells (APCs), some with self-renewal capacity. Donor APCs are responsible for continuous direct allosensitization of recipient's T cells that explains the high incidence of skin T-cell-mediated rejection and their occurrence beyond 1 year.Regenerative capability of the skin prevents the development of chronic rejection of this compartment as long as immunosuppression is maintained. In contrast, VCA can develop graft arteriosclerosis, which could be because of T cell and/or chronic antibody-mediated rejection (AMR). VCA recipients can indeed develop donor-specific antibodies (DSA). Whether DSA can also trigger acute AMR of VCA remains to be clarified. SUMMARY: A better understanding of the specificities of the immunopathology of VCA rejection should pave the way for the rationalization of immunosuppressive strategies aiming at optimizing long-term outcome. PMID- 26536420 TI - Tolerance induction via mixed chimerism in vascularized composite allotransplantation: is it time for clinical application? AB - PURPOSE OF REVIEW: The present review summarizes current data on the induction of immunologic tolerance through mixed hematopoietic chimerism relevant to applying this approach to vascularized composite allotransplantation. RECENT FINDINGS: Clinical allograft tolerance has been achieved recently for kidney transplants, using nonmyeloablative conditioning regimens and bone marrow transplantation from living donors. The mixed chimerism attained in these studies was either transient or durable, and both permitted tolerance of the renal allografts to be achieved across MHC-matched and MHC-mismatched barriers. In order to extend these protocols to deceased donor transplants across full MHC-mismatched combinations, as will be required for vascularized composite allografts (VCA), a delayed tolerance protocol has recently been developed, in which the donor bone marrow is given 4 months posttransplant. Recent primate studies of kidney transplants using this protocol have been successful and have demonstrated that strategies to abrogate memory T cells may be helpful. SUMMARY: Induction of tolerance in renal allograft transplantation has been achieved clinically, via mixed chimerism protocols. Modifications of these protocols for transplants, which require use of deceased donors across full MHC mismatches, have shown promise in preclinical models. It is therefore appropriate to consider evaluation of these protocols in clinical trials for kidney transplants, and if successful, for VCA. PMID- 26536421 TI - Premise and promise of mesenchymal stem cell-based therapies in clinical vascularized composite allotransplantation. AB - PURPOSE OF REVIEW: Over the past decade, clinical vascularized composite allotransplantation (VCA) has enabled functional and quality of life restoration in a wide range of indications secondary to devastating tissue loss. However, the spectre of toxicity and long-term complications of chronic immunosuppression has curtailed the momentum of VCA. This study summarizes the literature evidence behind successful mesenchymal stem cell (MSC)-based cell therapies highlighting their multipronged immunomodulatory, restorative and regenerative characteristics with special emphasis towards VCA applications. RECENT FINDINGS: Experimental and clinical studies in solid organs and VCA have confirmed that MSCs facilitate immunosuppression-free allograft survival or tolerance, stimulate peripheral nerve regeneration, attenuate ischaemia-reperfusion injury, and improve tissue healing after surgery. It has been hypothesized that MSC-induced long-term operational tolerance in experimental VCA is mediated by induction of mixed donor specific chimerism and regulatory T-cell mechanisms. All these characteristics of MSCs could thus help expand the scope and clinical feasibility of VCA. SUMMARY: Cellular therapies, especially those focusing on MSCs, are emerging in solid organ transplantation including VCA. Although some clinical trials have begun to assess the effects of MSCs in solid organ transplantation, much scientific domain remains uncharted, especially for VCA. PMID- 26536422 TI - Facial transplantation: worth the risks? A look at evolution of indications over the last decade. AB - PURPOSE OF REVIEW: The first face transplant was performed 10 years ago by Dubernard and his team in France. Since then, surgeons have continued to push the frontiers of vascularized composite allotransplantation and broaden the indications for face transplantation. In this review, we summarize some of the recent successes and failures in facial transplantation from the point of view of indications. RECENT FINDINGS: Recent literature includes case reports on face transplants in sensitized patient, with simultaneous bilateral upper extremity transplants, positive HIV status, and postmalignancy. Additionally, we summarize some of the outcomes of face transplants, including chronic rejection and latent viral infections. SUMMARY: Facial injuries vary widely, thus candidacy for face transplant should be assessed based on current guidelines, and a case-by-case basis. Although sensitization to donor-specific antigens should not be an absolute contraindication for facial allotransplantation, along with other comorbidities such as positive HIV status, history of malignancy should be evaluated cautiously. Additionally, multiple case studies advice against simultaneous transplantation of multiple vascularized composite allotransplantations. Other considerations include psychological health, social support, and availability for long-term follow-up. Ultimately, face transplant is not simply a surgery; it is a lifelong commitment between a patient and his/her medical team. PMID- 26536423 TI - Uterus transplantation. AB - PURPOSE OF REVIEW: The recent first live birth after human uterus transplantation (UTx) is a proof-of-concept of UTx as a factual treatment for women with absolute uterine factor infertility. This review summarizes the 15-year-long translational UTx research project, from the beginning in rodents until the first human UTx live birth in 2014. It also gives detailed information about the 11 human UTx cases performed so far. RECENT FINDINGS: The first live birth after UTx in any species was demonstrated already in 2003, in the syngeneic mouse model. Subsequent studies, in rats, large domestic species, and in nonhuman primates optimized the UTx procedure in regards to surgery, immunosuppression, rejection diagnosis, and pregnancy. Worldwide, only 11 human UTx attempts have been performed. The first two single cases were unsuccessful and performed with no research preparations. The following nine transplantations were completed within a clinical UTx trial in 2013. So far, four healthy babies have been born from this cohort and additional patients are pregnant. SUMMARY: Uterus transplantation, still at its early experimental stage, has the potential to become the first true treatment for the around 1.5 million women worldwide that are infertile because of absence of the uterus or presence of a nonfunctional uterus. PMID- 26536424 TI - Editorial. PMID- 26536425 TI - Intravenous immunoglobulin in kidney transplantation. AB - PURPOSE OF REVIEW: Antibody-mediated injury of renal allografts has assumed increasing importance with the availability of potent immunosuppressants directed against T-lymphocytes. Intravenous immunoglobulin (IVIG) has been used for prevention and treatment of antibody-mediated rejection. The review summarizes recent advances that shed light on mechanisms of action of IVIG and outlines current roles of IVIG in kidney transplantation. RECENT FINDINGS: Observational studies support the use of IVIG for desensitization and treatment of acute rejection. Most studies are small and uncontrolled, but a matched case-control study reported a better survival with incompatible live-donor kidney transplant after desensitization using IVIG-containing regimens compared with dialysis or waiting for compatible transplant. Recent data indicate that variations in glycosylation and amino acid sequence cause the crystallizable fragment of immunoglobulin G to assume specific conformations that have high affinity for canonical crystallizable fragment receptors (FcR) or a newly discovered class of FcRs, labelled type II FcRs. Signaling through type II FcRs appears to trigger anti-inflammatory pathways. SUMMARY: Recent discoveries expand our understanding of the mechanism of action of IVIG. Future research is expected to clarify the relevance of these findings to humans and could lead to the development of novel immunomodulatory agents. PMID- 26536426 TI - Alemtuzumab (Campath-1H) experience in kidney transplantation what we have learned; current practices; and scope for the future? AB - PURPOSE OF REVIEW: Alemtuzumab (Campath) usage as a preconditioning agent in kidney transplantation has gained considerable interest in the recent future. Alemtuzumab is currently available only by special request from Sanofi through its Campath distribution program. It is restricted to transplant programs with prior and continued experience with the agent. There may be a resurgence of interest for the utilization of this agent because of its ease of administration, and less cost and comparable or improved outcome in comparison to other induction agents. RECENT FINDINGS: Alemtuzumab when combined with standard calcineurin inhibitor and mycophenolate mofetil is well tolerated and efficacious as an induction therapy and allows for long-term steroid avoidance in high-risk renal transplant recipients. SUMMARY: The transplant community has advanced through a learning curve with the use of alemtuzumab over time; starting from an agent that was tried out to induce proper tolerance, minimization of nephrotoxic calcineurin inhibitors, and currently as a comparable depletional therapy that can reduce acute rejection in high-risk kidney transplant recipients. PMID- 26536427 TI - Eculizumab use in kidney transplantation. AB - PURPOSE OF REVIEW: Eculizumab suppresses the effector functions of the complement system and represents a therapeutic breakthrough for patients with paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome (aHUS). Safety monitoring is ongoing; so far, most notable is the expected increase in infection risk with encapsulated organisms. Despite potential applicability in multiple complement-mediated disorders, the off-label use of eculizumab has been limited, mainly by its prohibitive cost. The purpose of this review is to summarize the current data relevant to the use of eculizumab in kidney transplantation. RECENT FINDINGS: In aHUS, prone to high rates of recurrence and allograft loss, eculizumab has made the most notable therapeutic impact. Further clarification of complement defects may help predict therapeutic responses and hopefully guide treatment duration. In C3 glomerulopathies, the clinical response to eculizumab appears more heterogeneous and less effective in processes mediated by upstream to C5 complement deregulation. A large clinical trial of eculizumab for prevention of delayed graft function is ongoing. In antibody-mediated rejection, the role of eculizumab is unclear as its use has been limited to very complex, mostly presensitized, patients in mixed combinations of therapeutic modalities. SUMMARY: Overall, eculizumab has raised awareness of complement-mediated disorders as an exciting, new therapeutic option with multiple potential applications in kidney transplantation. Further research is needed to develop a better understanding of eculizumab applicability, efficacy, and treatment monitoring and beyond, to future therapeutic tools targeting the complement. PMID- 26536428 TI - Bortezomib in kidney transplantation. AB - PURPOSE OF REVIEW: The purpose of this review is to evaluate the effectiveness of bortezomib in the recent literature for the prevention and treatment of kidney transplant rejection. RECENT FINDINGS: Several studies have analyzed bortezomib alone and in comparison to more traditional immunosuppressive agents during the last 2 years. If administered prior to transplant or soon thereafter, bortezomib appears to lower donor-specific antibody levels and improves graft survival. Its role as a treatment option for antibody-mediated rejection after transplant remains unclear, with limited evidence supporting its long-term success. SUMMARY: Bortezomib appears to be a promising early desensitizing agent in the world of kidney transplantation and high short-term success rates have been observed. However, additional randomized trials would be useful to more conclusively demonstrate its effectiveness and optimal administration time in relation to transplant surgery. PMID- 26536429 TI - Extended release once a day tacrolimus. AB - PURPOSE OF REVIEW: This article provides an update of the literature on the use of extended release once-daily tacrolimus in solid organ transplant recipients. RECENT FINDINGS: Medication nonadherence occurs in a substantial proportion of patients posttransplant and is associated with worse outcomes. Multiple daily dosing is associated with an increased risk for nonadherence. Several studies have indicated once-daily dosing of medications and reduced complexity improve medication adherence. The extended release formulations of tacrolimus have been developed with the potential benefits of improving adherence, and hence safety and outcomes. Astagraf XLTM (Advagraf in Europe) and Envarsus XR. are the two extended release once-daily tacrolimus formulations that have recently become available for clinical use and provide promising alternatives to the treatment choices available for immunosuppression in solid organ transplant recipients. SUMMARY: Although extended release tacrolimus shows promise in improving patient adherence to transplant medication therapy, further studies are needed to confirm improved compliance and to assess long-term safety and efficacy. PMID- 26536430 TI - Pluripotent stem cell applications for regenerative medicine. AB - PURPOSE OF REVIEW: In this review, we summarize the current status of clinical trials using therapeutic cells produced from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). We also discuss combined cell and gene therapy via correction of defined mutations in human pluripotent stem cells and provide commentary on key obstacles facing widescale clinical adoption of pluripotent stem cell-based therapy. RECENT FINDINGS: Initial data suggest that hESC/hiPSC-derived cell products used for retinal repair and spinal cord injury are safe for human use. Early-stage studies for treatment of cardiac injury and diabetes are also in progress. However, there remain key concerns regarding the safety and efficacy of these cells that need to be addressed in additional well designed clinical trials. Advances using the clustered regulatory interspaced short palindromic repeats (CRISPR)/Cas9 gene-editing system offer an improved tool for more rapid and on-target gene correction of genetic diseases. Combined gene and cell therapy using human pluripotent stem cells may provide an additional curative approach for disabling or lethal genetic and degenerative diseases wherein there are currently limited therapeutic opportunities. SUMMARY: Human pluripotent stem cells are emerging as a promising tool to produce cells and tissues suitable for regenerative therapy for a variety of genetic and degenerative diseases. PMID- 26536431 TI - Beta-cell replacement therapy: current outcomes and future landscape. AB - PURPOSE OF REVIEW: This article provides a summary of the current outcomes of beta-cell replacement strategies, an algorithm for choosing a specific modality while highlighting associated advantages and disadvantages, and outlines remaining challenges and areas of active investigation in beta-cell replacement therapy. RECENT FINDINGS: The most recent reports of islet cell allotransplantation have shown improvements over previous eras and now rival some outcomes of pancreas alone transplantation. Active areas of investigation are focused on improving techniques for islet isolation, graft monitoring, and managing challenges posed by the innate and alloimmune systems. SUMMARY: Patients with insulin-dependent diabetes who continue to experience life threatening hypoglycemia despite maximal medical management can benefit from beta-cell replacement. Emerging nontransplant technologies have not provided a physiologic euglycemic state to the extent offered by transplantation. Islet transplantation eliminates hypoglycemic episodes/unawareness, facilitates normalization of hemoglobin A1c (HbA1c), decreases microvascular disease progression, and improves quality of life for patients with problematic diabetes. Mid- and long-term outcomes of islet transplantation performed at expert centers approximate those of registry reports of solitary pancreas transplant, whereas the complication profile is quite favorable. PMID- 26536434 TI - The 100 Most Influential Publications in Cervical Spine Research. AB - STUDY DESIGN: Bibliometric study of current literature. OBJECTIVE: To identify and analyze the 100 most cited publications in cervical spine research. SUMMARY OF BACKGROUND DATA: The cervical spine is a dynamic field of research with many advances made within the last century. The literature has, however, never been comprehensively analyzed to identify and compare the most influential articles as measured by the number of citations. METHODS: All databases of the Thomson Reuters Web of Knowledge were utilized in a two-step approach. First, the 150 most cited cervical spine studies up to and including 2014 were identified using four keywords. Second, all keywords related to the cervical spine found in the 150 studies (n = 38) were used to conduct a second search of the database. The top 100 most cited articles were hereby selected for further analysis of current and past citations, authorship, geographic origin, article type, and level of evidence. RESULTS: Total citations for the 100 studies identified ranged from 173 to 879. They were published in the time frame 1952 to 2008 in a total of 30 different journals. Most studies (n = 42) were published in the decade 1991-2000. Level of evidence ranged from 1 to 5 with 39 studies in the level 4 category. A total of 13 researchers were first author more than once and nine researchers senior author more than once. The two-step approach with a secondary widening of search terms yielded an additional 27 studies, including the first ranking article. CONCLUSION: This bibliometric study is likely to include some of the most important milestones in the field of cervical spine research of the last 100 years. PMID- 26536435 TI - Comparison of Clinical Outcomes in the National Neurosurgery Quality and Outcomes Database for Open Versus Minimally Invasive Transforaminal Lumbar Interbody Fusion. AB - STUDY DESIGN: A retrospective database review. OBJECTIVE: The aim of this study was to compare data on various pain and functional outcomes for patients who underwent minimally invasive transforaminal lumbar interbody fusion (MiTLIF) and those who had open TLIF to better delineate which patients may benefit from each procedure. SUMMARY OF BACKGROUND DATA: TLIF is a highly successful technique for the treatment of patients with degenerative instability or deformity. Minimally invasive approaches have been developed in an effort to improve outcomes by reducing tissue trauma and minimizing surgical time and blood loss. Although these approaches have been compared in the literature, there continues to be a debate about which patients may benefit from each procedure, and there is a dearth of information regarding short-term outcomes such as disposition status. METHODS: We used the National Neurosurgery Quality and Outcomes Database (N2QOD) to assess outcomes of patients who underwent open or MiTLIF at a single institution from 2012 to 2014. Primary outcomes included Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) scores, and secondary outcomes included hospital length of stay, blood loss, discharge status, and return to work. RESULTS: We identified 98 patients with 3- and 12-month follow-up records. The open and MiTLIF groups had similar improvements in ODI and VAS at 3 and 12 months. MiTLIF patients had a significantly longer hospital stay (5.0 vs. 3.8 days for open TLIF, P < 0.001) and were more likely to discharge to a location other than home (P < 0.021). Open TLIF patients had shorter mean operative time (235 vs. 329 minutes for MiTLIF, P < 0.001) and more blood loss (307 vs. 120.2 mL for MiTLIF, P < 0.001). CONCLUSION: Although each approach demonstrated advantages and disadvantages, outcome measures at short-term follow-up were largely equivalent, suggesting that the selection of procedure should be based on which approach will offer the superior individual outcome. LEVEL OF EVIDENCE: 4. PMID- 26536436 TI - Lumbar Lordosis Minus Thoracic Kyphosis: Remain Constant in Adolescent Idiopathic Scoliosis Patients Before and After Correction Surgery. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To explore the relationship between the change of lumbar lordosis (LL) and thoracic kyphosis (TK) in AIS patients after correction surgery. SUMMARY OF BACKGROUND DATA: TK tends to decrease in Lenke 1 and Lenke 2 AIS patients after correction surgery using pedicle screws, with the compensation of LL decrease. We hypothesize that lumbar lordosis minus thoracic kyphosis (LL-TK) remains constant after correction surgery to achieve the sagittal balance in AIS patients. METHODS: Medical records of Lenke 1 or Lenke 2 AIS patients who received posterior correction surgery using pedicle screws in our hospital from January 2010 to January 2013 were reviewed. General characters of patients and radiological parameters were evaluated before the surgery and at two years' follow-up. Correlation analysis between TK and LL was conducted. LL-TK and the change of LL and TK were analyzed at preoperation and final follow-up. RESULTS: A total of 76 Lenke 1 and Lenke 2 AIS patients were included. Both TK and LL decreased significantly after correction surgery (P = 0.019 and P = 0.040, respectively). There were significant correlations between TK and LL before and after surgery, respectively (preoperative: r = 0.234, P = 0.042; postoperative: r = 0.310, P = 0.006). Preoperative and postoperative LL-TK was 23.80 degrees and 25.09 degrees , respectively, and no significant difference of LL-TK was observed (P = 0.372). The same tendency was observed in the change of LL and TK, and significant correlation was also found between the change of TK and LL (r = 0.626, P = 0.002). CONCLUSION: The same change of LL and TK and no significant difference in LL-TK indicated that LL-TK might be an important compensatory mechanism in keeping sagittal balance. PMID- 26536437 TI - Identification of Preliminary Prognostic Indicators for Back Rehabilitation in Patients With Nonspecific Chronic Low Back Pain: A Retrospective Cohort Study. AB - STUDY DESIGN: Retrospective Cohort. OBJECTIVE: Our aim was to identify prognostic indicators for success after a back rehabilitation program (BR) in patients with nonspecific chronic low back pain (CLBP). SUMMARY OF BACKGROUND DATA: Exercise therapy is recommended for patients with nonspecific CLBP. Consensus on the type of exercises is lacking, largely due to heterogeneity in the studied patient samples. The identification of subgroups through the identification of prognostic indicators is therefore needed. To our knowledge, no specific prognostic indicators for BR are described in the literature. METHODS: We retrospectively analyzed the patient files of 49 nonspecific CLBP patients who followed a BR. Patients were selected based on predefined in- and exclusion criteria. All underwent 43 therapy sessions, two times per week. Primary outcome measure and dependent variable was the change in Oswestry Disability Questionnaire (ODI) score. Potential predictive variables were tested for association with the primary outcome and consequently entered in a logistic regression model. RESULTS: In this study, the posthoc calculated power was 91%. Based on the change in ODI scores, 24 patients were considered as therapy success (eight points or 50% improvement on change in ODI score) and 25 as therapy failure. Univariate and multiple regression analysis revealed only one significant prognostic indicator: higher scores on the physical function subscale of the SF36 (PF-SF36) corresponded with high risk of therapy failure (odds ratio of 0.791 (95% CI = .662-0.945); sensitivity of 0.79, and specificity of 0.68). CONCLUSION: Potentially, the preset exercises of the BR in this study design were not appropriate for the identified subgroup. The results of this study should be replicated in a RCT design that conforms to the necessary methodological steps in the identification of prognostic indicators and clinical prediction rules (CPRs). PMID- 26536438 TI - Risks for Vascular Injury During Anterior Cervical Spine Surgery: Prevalence of a Medial Loop of Vertebral Artery and Internal Carotid Artery. AB - STUDY DESIGN: Observational study using a retrospective single-institute database. OBJECTIVE: To investigate the prevalence of a medial loop (ML) of the vertebral artery (VA) and internal carotid artery (ICA), which might be an anatomical risk factor for arterial injury in anterior cervical surgeries. SUMMARY OF BACKGROUND DATA: Anterior cervical spine surgeries are generally considered to be safe and effective. VA injury is one of the most serious complications during anterior procedures. Several articles have reported this complication, which might be because of the anomalous course of VA at V2 segment. The prevalence and anatomical features of those high-risk cases were, however, not investigated. METHODS: Consecutive Japanese subjects, who underwent contrast enhanced computed tomography (CT) or computed tomographic angiography (CTA) for reasons other than evaluation of cervical artery disease from November 2011 to October 2012 in our institution, were reviewed. Exclusion criteria included poor images, past surgery, and endovascular intervention of cervical spine and its vessels. The definition of ML was set as the course of VA and ICA extended medially inside the uncovertebral joint. We also investigated whether those anomalous courses were detectable by plain CT. RESULTS: A total of 1251 subjects with age ranging from 14 to 93 years with a mean of 56.1 years were surveyed. Among them, 1054 subjects were eligible and the others were excluded. A total of 421 subjects were male, and 633 were female. There were 10 cases (1%) with an ML of the VA, and 2 (0.2%) cases with a medial loop of internal carotid artery. Five of the 10 cases with a medial loop of vertebral artery were aberrant into the vertebral body, which were detectable by plain CT. Importantly, the other five cases could not be seen on the CT. CONCLUSION: One percent of all subjects showed higher anatomical risk for VA and ICA injury during anterior surgery, half of which were undetectable by plain CT. Preoperative evaluation for vascular anatomy may be necessary for safer surgical treatment. LEVEL OF EVIDENCE: 4. PMID- 26536439 TI - Cervical Sagittal Alignment in Scheuermann Disease. AB - STUDY DESIGN: Retrospective evaluation of radiographs. OBJECTIVE: The aim of this study was to assess sagittal cervical balance in patients with the two types Scheuermann disease (SD). SUMMARY OF BACKGROUND DATA: The structural hyperkyphosis characterizing SD may be localized in the thoracic (SDT) or thoraco lumbar (SDTL) spine segments. This may affect sagittal cervical balance. METHODS: Seventy-one patients (41 males and 30 females), aged 16.3 +/- 3.8 years with SD, were enrolled into the study. On standing lateral long-cassette radiographs, the following measurements were made: C0-2 angle, C2-7 angle (CL), C1-C2 angle, relative rotation angle (RRA)-measured at levels from C2 to C7, cervical tilt (CT), thoracic inlet angle (TIA), T1 slope, neck tilt (NT), C0-angle, cranial offset (CO), and cranial tilt (CRT). Comparison with t test was performed with significance level P < 0.05. RESULTS: There were 38 SDT and 33 SDTL patients. In SDT, the T1 slope was significantly greater than that in SDTL (38.1 degrees vs. 28.9 degrees ; P = 0.0002), and consequently CL (-19.8 degrees vs. -8.9 degrees ; P = 0.0160), CT (29.8 degrees vs. 24.3 degrees ; P = 0.0190), and TIA (81.9 degrees vs. 71.1 degrees ; P = 0.0022) in SDT were significantly greater as well. The difference in CL was expressed mainly in C6-C5 (-4.8 degrees vs. -1.4 degrees ; P = 0.0146) and C5-C4 (-4.4 degrees ; vs. -1.5 degrees P = 0.0464) segments. There were no significant differences in proximal cervical lordosis: C0 2 angle (-21.6 degrees vs. -20.8 degrees ; P = 0.7597), C1-C2 angle (-30.8 degrees vs. -27.5 degrees ; P = 0.1746), C3-C2 (-5.4 degrees vs. -5.1 degrees ; P = 0.7976), and C4-C3 (3.5 degrees vs. -1.5 degrees ; P = 0.1464) segments. There was no significant difference in cranial parameters C0-angle, CRT, and CO. CONCLUSION: Scheuermann disease type has an influence on cervical sagittal balance. Localization of structural kyphosis affects the T1 slope as well as C2 C7 lordosis, cervical tilt, and thoracic inlet angle. Significant difference in C2-C7 lordosis in comparison to similar C0-2 lordosis demonstrates that compensation is present in subaxial cervical spine. Position of the head center of gravity is not dependent on the SD type. LEVEL OF EVIDENCE: 4. PMID- 26536440 TI - Influence of the Preoperative Neurological Status on Survival After the Surgical Treatment of Symptomatic Spinal Metastases With Spinal Cord Compression. AB - STUDY DESIGN: Consecutive case-series. OBJECTIVE: The main purpose of this study was to analyze the relationship between the preoperative neurological status and subsequent survival of patients undergoing surgical treatment for symptomatic spinal metastases. SUMMARY OF BACKGROUND DATA: The survival of cancer patients has increased over recent years with improvements in oncologic therapy. As many as 70% of cancer patients develop spinal metastases and ~10% of all cancer patients are treated for metastatic spinal cord compression. METHODS: We retrospectively analyzed 166 patients who underwent surgery for symptomatic spinal metastases in our department between 2005 and 2012. The evaluated factors were age, primary tumor aggressiveness (slow, moderate, rapid growing), spinal location (cervical, thoracic, lumbar, and sacral), operation type (posterior decompression, anterior or posterior instrumented procedure, and radical combined instrumented surgery), preoperative evaluation using the revised Tokuhashi scoring system (<9, 9-11, and 12-15), pre- and postoperative neurological status according to the Frankel score (A-C and D-E), and the site of the main spinal cord compression (anterior, posterior, or combined). Postoperative complication and recurrence rate were also monitored. RESULTS: The mean age of the patients was 62 +/- 12 years. The median survival time after surgery was 16.0 months. Preoperative neurological status influenced survival time significantly; the median survival was 5.1 months in Frankel A-C and 28.2 months in Frankel D-E (P < 0.001). Improvement on the Frankel scale did not influence the survival time (P = 0.131). When the patients' age was <65 years this related to a significantly longer survival time (P = 0.046). The Tokuhashi score predicted patient's survival independently (P < 0.001). The other factors had no statistical significance. CONCLUSION: The most important factors influencing postoperative survival time of these patients with symptomatic spinal metastases was the preoperative neurological condition and the Tokuhashi scoring system, which together represents a useful tool for planning the extent of surgical treatment. PMID- 26536441 TI - Comparison of Cervical Range-of-Motion Restriction and Craniofacial Tissue Interface Pressure With 2 Adjustable and 2 Standard Cervical Collars. AB - STUDY DESIGN: Randomized controlled trial. OBJECTIVE: The aim of the study was to compare and contrast the restrictiveness and tissue-interface pressure (TIP) characteristics of 2 standard and 2 adjustable cervical collars. SUMMARY OF BACKGROUND DATA: This study compared the restrictiveness and TIP of 4 commercially available cervical collars (2 standard and 2 adjustable). Adjustable collars offer potential advantages of individualized fit for patients and decreased inventory for institutions. The overall goal was to determine whether the adjustable collars provided the same benefits of cervical range-of-motion (CROM) restriction as the standard collars without increasing TIP and risk of pressure-related complications. METHODS: A total of 48 adult volunteer subjects (24 men and 24 women) were fitted with 4 collars (Aspen, Aspen Vista, Miami J, and Miami J Advanced) in random order. Data collection included assessment of CROM restrictiveness and measurement of TIP on the mandible and occiput in upright and supine positions. The experimental, repeated measures design stratified the sample by body mass index (BMI) and sex. RESULTS: All collars restricted CROM as compared with no collar (P <= 0.001 each). Aspen was more restrictive than Aspen Vista and Miami J in 4 movement planes (P <= 0.003 each), but not significantly different from Miami J Advanced. The Miami J standard collar was associated with significantly lower peak TIPs on all sites and in all positions compared with Aspen (P <= 0.001), Miami J Advanced (P < 0.001), and Aspen Vista (P = 0.01 for mandible site and upright position, P < 0.001 for remaining sites and positions). Increased peak TIP correlated with high BMI across all collar types, but was significantly lower for the Miami J collar than the Aspen collar. CONCLUSION: All collars, compared with no collar, significantly restricted CROM. Although the collar-to-collar comparisons were statistically significant, the differences may have little clinical significance in the acutely injured trauma patient. The Miami J standard collar had the lowest overall TIP in both sites and positions. Ongoing effort should be devoted to staff education in proper sizing and fit, particularly for patients with high BMI. PMID- 26536442 TI - The Position of the Aorta Relative to the Vertebrae in Patients With Lenke Type 1 Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: A computed tomography study. OBJECTIVE: The aim of the study was to clarify the position of the aorta relative to the spine in patients with Lenke type 1 adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Several authors have examined the position of the aorta in patients with scoliosis; however, their analysis included several types of curve. There is a possibility that the position of the aorta differs according to the scoliosis curve type. METHODS: Thirty-eight patients with Lenke type 1 were analyzed. The angle (left pedicle aorta [LtP-Ao] angle) and distance (LtP-Ao distance) from the insertion point of the left pedicle screw to the aorta were measured from T4 through L2. The measured data were evaluated from 4 levels above to 4 levels below the apical vertebra. The difference between lumbar modifiers A and C was examined. Dangerous pedicles, which were defined as those in which the aorta entered the expected area based on the screw direction error and length, were counted from T10 to L2. RESULTS: The aorta was located posterolaterally and adjacent to the vertebra at the middle thoracic level, and anteromedially and distant at the thoracolumbar level. LtP-Ao angle was largest at 1 level above the apical vertebra, and LtP-Ao distance was shortest at 2 levels above. LtP-Ao angle of Lenke 1A was significantly larger than 1C from T11 to L2, and LtP-Ao distance of 1A was significantly shorter than 1C from T11 to L1. When the screw length was 40 mm and the direction error was within 10 degrees , there were a large number of dangerous pedicles at T11, regardless of the lumbar modifier. CONCLUSION: The direction error has a potential risk of injuring the aorta around the apical vertebra. The selection of screws of the proper length is necessary to avoid a breach of the anterior vertebral wall at thoracolumbar level, especially at T11. LEVEL OF EVIDENCE: 3. PMID- 26536443 TI - Preoperative Cognitive-Behavioral Patient Education Versus Standard Care for Lumbar Spinal Fusion Patients: Economic Evaluation Alongside a Randomized Controlled Trial. AB - STUDY DESIGN: A cost-effectiveness analysis conducted alongside a randomized clinical trial. OBJECTIVE: To assess the cost-effectiveness of a preoperative cognitive-behavioral therapy (CBT) intervention compared to usual care for patients undergoing lumbar spinal fusion surgery (LSF). SUMMARY OF BACKGROUND DATA: The clinical effectiveness of a preoperative CBT intervention for patients undergoing LSF has been investigated in a randomized clinical trial. Economic evaluation is however essential for decision makers to make informed choices regarding allocation of scarce resources. METHODS: 90 patients undergoing LSF were randomly allocated to usual care (control group) or usual care plus a preoperative CBT intervention (CBT group). Outcome parameters included quality adjusted life years (QALY), based on the EQ-5D, and pain-related disability, based on the Oswestry disability index (ODI). Health care use and productivity loss were estimated from national registers. RESULTS: One year after LSF the estimated QALY was significantly better for the CBT group with 0.710 (95% CI 0.670; 0.749) versus 0.636 (95% CI 0.5573; 0.687). For the ODI, the CBT group reported significantly larger disability reductions at 3 months (P = 0.003) and 6 months (P = 0.047), but not at 1 year (P = 0.082). There was no difference in the overall costs of the two groups (-?89 (95% CI -12,080; 11,902)), leading to a 70% probability of the CBT intervention being cost-effective at a willingness-to-pay of ?40,000 for one additional QALY. For an additional gain of 15 ODI points the probability was 90% at a threshold of ?10,000. These results remained largely unaffected by relevant sensitivity analyses, confirming the robustness of findings. CONCLUSION: Preoperative CBT appears to be more effective and cost neutral when considering the overall health care sector and labor market perspective, supporting the implementation of preoperative CBT in the course of treatment for LSF surgery in a Danish context. PMID- 26536444 TI - Nonoperative Management in Neurologically Intact Thoracolumbar Burst Fractures: Clinical and Radiographic Outcomes. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The identification of factors that lead to the failure of nonoperative management in neurologically intact thoracolumbar burst fractures. SUMMARY OF BACKGROUND DATA: The treatment of thoracolumbar burst fractures (TLBF) can be controversial, particularly in the neurologically intact. Surgery for intact burst fractures has been advocated for early mobilization and a shorter hospital stay. These goals, however, have not always been achieved, rejuvenating an interest in nonoperative treatment. METHODS: Sixty-eight neurologically intact patients with burst fractures of the thoracolumbar junction (T11-L2), and a thoracolumbar injury classification and severity score (TLICS) of 2, were treated at our institution. Based on CT scans, patients were scored based on the load-sharing classification (LSC) scale. Initial treatment consisted of bracing in clamshell thoracolumbar orthosis and gradual mobilization. RESULTS: Owing to pain limiting mobilization, 18 patients failed nonoperative management and required instrumentation. Those who failed nonsurgical management were significantly more kyphotic (8 degrees +/- 10) and stenotic (52% +/- 14%) than those successfully treated nonoperatively (3 degrees +/- 7 and 63 +/- 12%, respectively). The LSC score of those undergoing surgery (6.9 +/- 1.1) was also greater than those successfully treated nonoperatively (5.8 +/- 1.3, P = 0.006). Length of hospitalization was longer, and hospital charges higher in those requiring surgery compared to the nonoperative group. At follow-up there was no difference between groups in the visual analog score for pain (VAS) or the Oswestry disability index. CONCLUSION: Owing to pain limiting mobilization, a quarter of neurologically intact patients with thoracolumbar burst fractures and a TLICS score of 2 failed nonsurgical management. The greater the kyphosis, stenosis, and fragmentation of the fracture, the more likely patients required surgery. In addition to the TLICS classification, other radiographic and clinical parameters should be included in selecting appropriate treatment strategy. The cost savings with nonoperative treatment of intact burst fractures, when appropriate, are significant. PMID- 26536445 TI - Relatively Large Cervical Spinal Cord for Spinal Canal is a Risk factor for Development of Cervical Spinal Cord Compression: A Cross-Sectional Study of 1211 Subjects. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVE: This study aims to investigate the correlation of the cervical canal and spinal cord size, and evaluate whether the size of the spinal cord relative to the spinal canal is a risk factor for development of cervical spinal cord compression (SCC). SUMMARY OF BACKGROUND DATA: There is little knowledge regarding the relationship between cervical bony canal and spinal cord diameters. Although developmental canal stenosis has been recognized as a risk factor for SCC, the size of the spinal cord relative to the spinal canal has not been similarly discussed. METHODS: Cervical canal anteroposterior (AP) diameters on X-rays and AP diameters and cross-sectional areas of dural sacs and spinal cords on magnetic resonance imaging (MRI) were measured in 1211 healthy volunteers. Correlation between cervical canal diameter on X-rays and AP diameter and cross-sectional area of dural sacs and spinal cords on MRI were assessed. The ratio of the AP diameter of the spinal cord/dural sac was compared between subjects with and without SCC. RESULTS: Spinal canal diameters were not highly correlated with spinal cord AP diameters and cross sectional areas, although spinal canal diameters were significantly correlated with dural sac AP diameters. The individual difference in the ratio of the AP diameter of the spinal cord/dural sac was large (35%-93%), and the ratio was significantly larger in the subjects with SCC. An AP diameter ratio more than 62% at the C2 to C3 disc level is a risk factor for developing SCC. CONCLUSION: The spinal cord diameter was independent of the spinal canal diameter and the relative size of a spinal cord and spinal canal differed on an individual basis. In addition, the ratio of spinal cord/dural sac in subjects with SCC was significantly larger. Therefore, a relatively large spinal cord could be a risk factor for SCC. PMID- 26536446 TI - Instrumented Lumbar Corpectomy and Spinal Reconstruction Comparing rhBMP 2/Compression-Resistant Matrix, rhBMP-2/Absorbable Collagen Sponge/Ceramic Granules Mixture, and Autograft in Two Different Devices: A Study in Sheep. AB - STUDY DESIGN: Fusion success with rhBMP-2 and autograft in titanium or PEEK corpectomy devices was evaluated in a sheep lumbar corpectomy model. The 6 treatment groups included titanium mesh or PEEK corpectomy devices filled with rhBMP-2 on a compression-resistant matrix (CRM) carrier; rhBMP-2 in a morselized absorbable collagen sponge (ACS) carrier combined with resorbable ceramic granules; and autograft. OBJECTIVE: The aim of this study was to determine fusion rates associated with 2 different preparations of rhBMP-2 as well as autograft in an instrumented ovine lumbar corpectomy model 6 months postoperatively. SUMMARY OF BACKGROUND DATA: Vertebral reconstruction with corpectomy devices requires bone graft. Bone graft substitutes have the potential to avoid a second operation, donor site pain, and attendant morbidity associated with autograft. METHODS: Twenty-four sheep in 6 treatment groups underwent lumbar corpectomy via a retroperitoneal trans-psoas approach. Spines were reconstructed with autograft, rhBMP-2 on a CRM, or rhBMP-2 on an ACS mixed with ceramic granules. Grafting materials were placed in either a titanium mesh or PEEK conduit in spines with internal fixation. Computed tomographic (CT) scans were evaluated for fusion. Undecalcified histology was used to evaluate for fusion as well as the amount and extent of graft incorporation and graft resorption. RESULTS: Regardless of corpectomy device used, rhBMP-2/CRM or rhBMP-2/ACS with MASTERGRAFT resulted in a 100% fusion rate. The autograft group had a lower (75%) radiographic fusion rate. Using either preparation of rhBMP-2 resulted in the length of the defect filling with solid bone. Autograft fragments and ceramic granules were incorporated into the fusion masses with much of the ceramic granules being resorbed by 6 months. CONCLUSION: Both of the rhBMP-2 formulations have the potential to effect bony fusion and vertebral reconstruction within the corpectomy devices. PMID- 26536447 TI - Short Segment Spinal Instrumentation With Index Vertebra Pedicle Screw Placement for Pathologies Involving the Anterior and Middle Vertebral Column Is as Effective as Long Segment Stabilization With Cage Reconstruction: A Biomechanical Study. AB - STUDY DESIGN: An in vitro, cadaveric biomechanical study. OBJECTIVE: The aim of the present study was to compare single-segment posterior instrumentation and fracture-level screws with single/multilevel posterior fixation and corpectomy in a simulated, unstable burst fracture model. SUMMARY OF BACKGROUND DATA: The optimal extent of instrumentation for surgical cases of non-neoplastic vertebral body pathologies remains uncertain. Although several clinical studies demonstrate advantages of short segment instrumentation with index-level screws over more extensive corpectomy and anterior-posterior techniques, a comprehensive biomechanical comparison of these techniques is currently lacking. METHODS: Six bovine spines (T11-L5) were tested in flexion, extension, lateral bending (LB), and axial rotation (AR) following simulated burst fracture at L2. Posterior instrumentation included 1 level above/below (1LF) and 2 levels above/below fracture level (2LF), intermediate or index screws at fracture level (FF), and cross-connectors above/below fracture level (CC). Anterior corpectomy devices included expandable corpectomy spacers with/without integrated screws, ACDi and ACD, respectively FORTIFY-Integrated/FORTIFY; Globus Medical, Inc., PA. Constructs were tested in the following order: (1) Intact; (2) 1LF; (3) 1LF and CC; (4) 1LF and FF; (5) 1LF, CC, and FF; (6) 2LF; (7) 2LF and CC; (8) 2LF and FF; (9) 2LF, CC, and FF; (10) 2LF and ACD; (11) 2LF, ACD, and CC; (12) 1LF and ACDi; (13) 1LF, ACDi, and CC. RESULTS: During flexion, all constructs except 1LF reduced motion relative to intact (P <= 0.05). Anterior support was most stable, but no differences were found between constructs (P >= 0.05). Every construct reduced motion in extension, though no differences were found between constructs and intact (P >= 0.05). During LB, all constructs reduced motion relative to intact (P <= 0.05); 2LF constructs further reduced motion (P <= 0.05). No construct returned AR motion to intact, with significant increases in 1LF and ACDi, 2LF and ACD, and 2LF, ACD, and CC (P <= 0.05). Cross-connectors and fracture screws reinforced each other in posterior-only constructs, providing maximum stability (P >= 0.05). CONCLUSIONS: This biomechanical comparison study found no significant superiority of combined anterior-posterior constructs over short segment fracture screw fixation, only multilevel posterior instrumentation with and without anterior support, providing increased stability in LB. Biomechanical equivalency suggests that short segment fracture screw intervention may provide appropriate stabilization for non-neoplastic pathologies involving the anterior and middle vertebral columns. LEVEL OF EVIDENCE: 2. PMID- 26536448 TI - Variations in the high-mobility group-A2 gene (HMGA2) are associated with idiopathic short stature. AB - BACKGROUND: Several association studies confirmed high-mobility group-A2 gene (HMGA2) polymorphisms as the most relevant variants contributing to height variability. Animal models and deletions in humans suggest that alterations of HMGA2 might be relevant in causing short stature. Together, these observations led us to investigate the involvement of HMGA2 in idiopathic short stature (ISS) through an association study and a mutation screening. METHODS: We conducted an association study (155 ISS patients and 318 normal stature controls) with three HMGA2 single-nucleotide polymorphisms (SNPs) (SNPs rs1042725, rs7968682, and rs7968902) using a TaqMan-based assay. The patients were then analyzed by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) to detect point mutations and genomic micro-rearrangements. RESULTS: Considering a recessive model, an OR value >1 was observed for genotypes rs7968682 TT (Odds ratio (OR) = 1.72, confidence interval (CI): 1.14-2.58) and rs1042725 TT (OR = 1.51, CI: 1.00-2.28) in accordance to the effect exhibited by the single alleles in the general population. None of the patients carried possibly causative HMGA2 mutations. CONCLUSION: Besides the already known role in determining variability in human height, HMGA2 polymorphisms also contribute to susceptibility to ISS. Moreover, we here report the first mutation screening performed in ISS concluding that HMGA2 has not a significant impact on the monogenic form of ISS. PMID- 26536449 TI - Plasma MASP-1 concentration and its relationship to recovery from coronary artery lesion in children with Kawasaki disease. AB - BACKGROUND: This study investigated prognostic factors for early recovery of coronary artery lesion (CAL) in children with Kawasaki disease (KD). METHODS: Patients hospitalized for KD were enrolled less than 2 wk from the onset of illness and divided into two groups: KD with CAL and KD without CAL. The CAL group was further divided into two subgroups according to the degree of CAL: mild (n = 31) and moderate/severe (n = 6) and further divided into two subgroups according to the age: younger than 1 y (n = 9) and older than 1 y (n = 28). Lectin pathway-related factors MASP-1, CD59, and C5b-9 were measured, along with C-reactive protein, white blood cell counts, erythrocyte sedimentation rate, and platelet count. Patients were followed up for 3 mo. Correlation between the measured factors and the length of time of recovery from CAL was analyzed. RESULTS: Plasma concentrations of MASP-1 in the CAL group were significantly lower than those without CAL. MASP-1 and gender positively correlated with the recovery time of CAL. There was no difference in MASP-1 between mild and moderate/severe CAL. At 3-mo follow-up, there was a positive correlation between plasma MASP-1 concentration and recovery time of the patients with CAL older than 1 y. CONCLUSION: Plasma MASP-1 concentration at the early stage of KD is predictive of length of time of recovery from CAL. PMID- 26536450 TI - Triggering of Suicidal Erythrocyte Death by Topotecan. AB - BACKGROUND/AIMS: The topoisomerase I inhibitor topotecan is used as treatment of various malignancies. The substance is effective by triggering tumor cell apoptosis. In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis, a suicidal death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the outer face of the erythrocyte membrane. Signaling leading to eryptosis include Ca(2+)-entry and ceramide formation. The present study explored, whether and how topotecan induces eryptosis. METHODS: Phosphatidylserine abundance at the erythrocyte surface was estimated from annexin V binding, cell volume from forward scatter, and ceramide abundance utilizing specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to topotecan significantly increased the percentage of annexin-V binding cells and significantly decreased forward scatter. The effect of topotecan was paralleled by a significant increase of ceramide abundance. The effect of topotecan on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca2+. CONCLUSIONS: Topotecan stimulated cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect paralleled by increase of ceramide abundance and partially dependent on entry of extracellular Ca2+. PMID- 26536452 TI - Comparison between Outcomes of Vitrectomy in Granulomatous and Nongranulomatous Uveitis. AB - PURPOSE: The aim of this study was to compare the outcomes of vitrectomy in granulomatous uveitis and nongranulomatous uveitis insufficiently managed by immunosuppressive therapy. METHODS: Thirty-eight eyes with granulomatous uveitis and 17 eyes with nongranulomatous uveitis that underwent vitrectomy for ocular complications between July 2006 and August 2012 were reviewed retrospectively. Visual acuity and ocular inflammation scores before and 6 months after surgery were compared. Patients treated with vitrectomy alone and those in whom vitrectomy was combined with phacoemulsification were analyzed separately. RESULTS: The mean visual acuity improved significantly both in granulomatous and nongranulomatous uveitis. In granulomatous uveitis, the mean inflammation scores decreased significantly both in the anterior segment and in the posterior segment. In nongranulomatous uveitis, the mean inflammation score in the posterior segment decreased significantly, although it did not change in the anterior segment. CONCLUSION: Vitrectomy was effective for treating ocular complications both in granulomatous uveitis and nongranulomatous uveitis, with favorable outcomes of improved visual acuity and decreased uveitis activity. PMID- 26536453 TI - Knowledge of the Relationships between Oral Health, Diabetes, Body Mass Index and Lifestyle among Students at the Kuwait University Health Sciences Center, Kuwait. AB - OBJECTIVES: To evaluate the level of knowledge regarding the relationships between oral health, diabetes, body mass index (BMI; obesity) and lifestyle among students of the Health Sciences Center (HSC), Kuwait, and to explore any possible correlation between students' oral health knowledge, BMI and lifestyle choices. SUBJECTS AND METHODS: A stratified random sample was proportionally selected according to the size of each faculty from the 1,799 students. The questionnaire was divided into 3 sections (i.e. demographics, evaluation of oral health knowledge in relation to diabetes, and evaluation of diabetes knowledge in relation to lifestyle) and distributed to 532 students. Oral health knowledge was categorized as limited, reasonable or knowledgeable. Lifestyle was classified as healthy or nonhealthy. The BMI was calculated as weight (kg) divided by the square of the height (m). ANOVA and chi2 tests were used to test for differences between independent variables. A Pearson correlation coefficient test was used to assess correlations. p < 0.05 was considered statistically significant. RESULTS: Of the 532 questionnaires, 498 (93.6%) were completed. The mean knowledge score was 47.7 +/- 25.2; of the 498 students, 235 (47.3%) had a BMI within the normal range, 184 (37.0%) were pre-obese and 67 (13.5%) were obese. Of the 498 students, 244 (49%) had a healthy lifestyle. There was no correlation between oral health knowledge and the other variables; however, there was a correlation between lifestyle and obesity. CONCLUSION: In this study, the majority of the students had limited knowledge of oral health in association with diabetes and lifestyle. More than half of the students fell in the pre-obese/obese range. PMID- 26536454 TI - Remote Ischaemic Preconditioning and Confounders of Cardioprotection. PMID- 26536455 TI - Shikimic acid ozonolysis kinetics of the transition from liquid aqueous solution to highly viscous glass. AB - Ageing of particulate organic matter affects the composition and properties of atmospheric aerosol particles. Driven by temperature and humidity, the organic fraction can vary its physical state between liquid and amorphous solid, or rarely even crystalline. These transitions can influence the reaction kinetics due to limitations of mass transport in such (semi-) solid states, which in turn may influence the chemical ageing of particles containing such compounds. We have used coated wall flow tube experiments to investigate the reaction kinetics of the ozonolysis of shikimic acid, which serves as a proxy for oxygenated, water soluble organic matter and can form a glass at room temperature. Particular attention was paid to how the presence of water influences the reaction, since it acts a plasticiser and thereby induces changes in the physical state. We analysed the results by means of a traditional resistor model, which assumes steady-state conditions. The ozonolysis rate of shikimic acid is strongly increased in the presence of water, a fact we attribute to the increased transport of O3 and shikimic acid through the condensed phase at lower viscosities. The analysis using the resistor model suggests that the system undergoes both surface and bulk reaction. The second-order rate coefficient of the bulk reaction is 3.7 (+1.5/ 3.2) * 10(3) L mol(-1) s(-1). At low humidity and long timescales, the resistor model fails to describe the measurements appropriately. The persistent O3 uptake at very low humidity suggests contribution of a self-reaction of O3 on the surface. PMID- 26536456 TI - Monitoring the Antioxidant Mediated Chemosensitization and ARE-Signaling in Triple Negative Breast Cancer Therapy. AB - Chemotherapy often fails due to cellular detoxifying mechanisms, including phase II enzymes. Activation of Nrf2-Keap1 pathway induces phase-II enzymes expression through ARE-signaling and prevents cancer development. Nrf2-overexpression in cancer cells results in chemo- and/or radioresistance. This necessitates understanding of Nrf2-regulation, and identification of Nrf2 activators/inhibitors sensitizing cancer cells to improve chemotherapy. N terminal 435-amino acids of Nrf2 are crucial for Keap1 binding during ubiquitination. Identification of a minimum Nrf2-domain required for Keap1 binding without altering endogenous ARE-signaling would be a novel tool to study Nrf2-signaling. Current study developed firefly-luciferase reporter fusion with N terminal Nrf2-domain of different lengths and examined its response to Nrf2 activators in cells. The results identified FLuc2 fusion with N-terminal 100-aa of Nrf2 is sufficient for measuring Nrf2-activation in cancer cells. We used MDA MB231 cells expressing this particular construct for studying antioxidant induced Nrf2-activation and chemosensitization in triple-negative breast cancer therapy. While antioxidant EGCG showed chemosensitization of MDA-MB231 cells to cisplatin by activating Nrf2-ARE signaling, PTS, another antioxidant showed chemoprotection. Tumor xenograft study in mouse demonstrates that combinational treatment by cisplatin/EGCG resulted in tumor growth reduction, compared to cisplatin alone treatment. The results of this study highlight the importance of identifying selective combination of antioxidants/chemotherapeutic agents for customized treatment strategy. PMID- 26536457 TI - Copper and nickel bind via two distinct kinetic mechanisms to a CsoR metalloregulator. AB - The intricate interplay between polypeptide and metal ion binding underscores many of life's fundamental processes. Metalloregulators recognise and bind cognate metal ions during cellular metal stress, evoking a transcriptional response so as to maintain metal ion homeostasis. Members of the copper sensitive operon repressor (CsoR) family of metalloregulators bind to their operator DNA in the absence of a bound metal ion, but on binding Cu(I) an allosteric conformational switch is induced that causes dissociation of the bound DNA. Other divalent metal ions are capable of binding to CsoR members but do not induce the allosteric response observed with Cu(I). The thermodynamics of Cu(I) binding has been studied in this family of metalloregulators, but the binding kinetics and mechanism of Cu(I) or a non-cognate metal ion is unknown. In the present study we have used stopped-flow absorbance kinetics and site-directed variants of the CsoR from Streptomyces lividans to monitor binding of Cu(I) and non-cognate Ni(II). The variants have been designed to individually replace known metal ion binding ligands and also to test the role of a histidine residue (His103) close, but not considered part of the Cu(I) first coordination sphere. Cu(I)/Ni(II) ion displacement studies have also been investigated. The kinetic data are most consistent with the existence of two distinct mechanisms that account for Cu(I) and Ni(II) ion binding to this CsoR. In particular Ni(II) has two binding sites; one that has identical amino acid coordination as the Cu(I) binding site and the second involving His103, a residue determined here not to be involved in the mechanism of Cu(I) binding. PMID- 26536458 TI - Phylogenetic and Molecular Clock Analysis of Dengue Serotype 1 and 3 from New Delhi, India. AB - Dengue fever is the most prevalent arboviral disease in the tropical and sub tropical regions of the world. The present report describes molecular detection and serotyping of dengue viruses in acute phase blood samples collected from New Delhi, India. Phylogenetic and molecular clock analysis of dengue virus serotype 1 and 3 strains were also investigated. Dengue virus infection was detected in 68.87% out of 604 samples tested by RT-PCR between 2011 & 2014. Dengue serotype 1 was detected in 25.48% samples, dengue serotype 2 in 79.56% samples and dengue serotype 3 in 11.29% samples. Dengue serotype 4 was not detected. Co-infection by more than one dengue serotype was detected in 18.26% samples. Envelope gene of 29 DENV-1 and 14 DENV-3 strains were sequenced in the study. All the DENV-1 strains grouped with the American African genotype. All DENV-3 strains were found to belong to Genotype III. Nucleotide substitution rates of dengue 1 and 3 viruses were determined in the study. Time to the most recent common ancestor (TMRCA) of dengue 1 viruses was determined to be 132 years. TMRCA of DENV-3 viruses was estimated to be 149 years. Bayesian skyline plots were constructed for Indian DENV-1 and 3 strains which showed a decrease in population size since 2005 in case of DENV- 1 strains while no change was observed in recent years in case of DENV-3 strains. The study also revealed a change in the dominating serotype in Delhi, India in recent years. The study will be helpful in formulating control strategies for the outbreaks. In addition, it will also assist in tracking the movement and evolution of this emerging virus. PMID- 26536459 TI - Integrated Analysis of Thyroid Cancer Public Datasets Reveals Role of Post Transcriptional Regulation on Tumor Progression by Targeting of Immune System Mediators. AB - Papillary thyroid carcinoma (PTC) is a well-differentiated thyroid tumor that accounts for approximately 80% of thyroid cancer cases. On other hand, anaplastic thyroid carcinoma (ATC) is a less frequent, but aggressive subtype, with poor prognosis. MicroRNAs (miRNAs), small non-coding RNAs, have emerged as potent post transcriptional regulators of gene expression, which modulate the expression of cancer-related genes. Computational analyses estimate that a single miRNA may modulate hundreds of mRNA targets and, at the same time, cooperate with others to regulate one single mRNA transcript. Due to the large number of predicted targets and possible interactions, only a small number of miRNAs have characterized biological roles, and the panorama of miRNA-mediated regulation in thyroid cancer remains to be understood. Taking into consideration the large amount of gene expression data deposited in public databases we aligned miRNA target prediction and gene expression data from public PTC and ATC datasets to construct a network of post-transcriptional regulation in thyroid cancer. After a gene set enrichment analysis we identified signaling pathways and biological processes potentially modulated by the miRNAs deregulated in PTC and ATC. Our results show miRNA-mRNA interaction that could contribute with the de-regulation of key tumor-host mediators, such as extra-cellular matrix molecules, interleukins and interleukin receptors, which could drive a more aggressive behavior and tumor progression. Moreover, our analysis through The Cancer Genome Atlas (TCGA) database revealed that aberrant expression of ECM and cytokines genes is frequent in PTC and is associated with aggressive behavior and decreased overall survival rate. In conclusion, we shed light on the post-transcriptional regulation of gene expression in differentiated and undifferentiated thyroid cancers, revealing a potential role of miRNAs in modulation of tumor-host interaction molecules, particularly ECM molecules and immune system mediators, which could stimulate crosstalk between tumors and the immune system to generate a more aggressive behavior. We propose a novel putative miRNA:mRNA network that could lead to a new path toward functional studies. PMID- 26536460 TI - A Qualitative Study to Appraise Patients and Family Members Perceptions, Knowledge, and Attitudes towards Venous Thromboembolism Risk. AB - OBJECTIVE: This study aimed to examine perception, knowledge and concerns developed by patients and their family as regards venous thromboembolism (VTE) risk. METHODS: We conducted a qualitative study. Participants were: (1) patients with unprovoked VTE with either factor V Leiden mutation or G20210A prothrombin gene mutation or not; and (2) their first-degree relatives. Interviews took place mostly at Brest University Hospital. Participants produced narratives of the patient's illness, stressing their perception of the disorder, its mechanisms, etiology, circumstances and risk factors. Interviews were audiotaped and transcribed verbatim. On an ongoing basis, central themes were identified and data from narratives were categorized by these themes. RESULTS: A total of ten patients and 25 first-degree relatives were interviewed. Analyses of patient's narratives suggested 4 main themes: (1) concerns about initial symptoms and suspicion of VTE. The longer the duration of the initial phase, the more likely anxiety took place and persisted after diagnosis; (2) underestimation of potential life-threatening episode once being managed in emergency; (3) possible biographical disruption with inability to cope with the event; and (4) secondary prevention attitudes motivated by remains of the episode and favoring general prevention attitudes. Analyses of the first-degree relatives narratives suggested 3 main themes: (1) common interpretation of the VTE episode shared within the family; (2) diverse and sometimes confusing interpretation of the genetic status; and, (3) interpretation of clinical signs linked to VTE transmission within the family. CONCLUSIONS: Construction of the risk of VTE is based on patient's initial experience and shared within the family. Collection of narratives illustrates the gap between these perceptions and current medical knowledge. These results support the need to collect the perceptions of the VTE episode and its consequences, as a prerequisite to any health education process. PMID- 26536461 TI - Pleiotropic Anti-Angiogenic and Anti-Oncogenic Activities of the Novel Mithralog Demycarosyl-3D-beta-D-Digitoxosyl-Mithramycin SK (EC-8042). AB - Demycarosyl-3D-beta-D-digitoxosyl-mithramycin SK (DIG-MSK) is a recently isolated analogue of mithramycin A (MTA) that showed differences with MTA in the DNA binding strength and selectivity. These differences correlated with a better therapeutic index and less toxicity in animal studies. Herein, we show that DIG MSK displays a potent anti-tumor activity against different types of cancer cell lines, ovarian tumor cells being particularly sensitive to this drug. Of relevance, DIG-MSK exerts low toxicity on fibroblasts and peripheral blood mononuclear cells, this toxicity being significantly lower than that of MTA. In correlation with its antitumor activity, DIG-MSK strongly inhibited Sp1-mediated transcription and endogenous Sp1 mRNA expression, which correlated with the inhibition of the expression of key Sp1-regulated genes involved in tumorigenesis, including VEGFA, BCL2L1 (Bcl-XL), hTERT, BRCA2, MYC and SRC in several ovarian cells. Significantly, DIG-MSK was a stronger inhibitor of VEGFA expression than MTA. Accordingly, DIG-MSK also exhibited potent anti-angiogenic activity on microvascular endothelial cells. Likewise, it significantly inhibited the gene expression of VEGFR1, VEGFR2, FGFR, PDGFB and PDGFRA and, additionally, it induced the expression of the anti-angiogenic factors angiostatin and tunstatin. These effects correlated with a pro-apoptotic effect on proliferating microvascular endothelial cells and the inhibition of the formation of endothelial capillary structures. Overall, the pleiotropic activity of DIG-MSK in inhibiting key oncogenic and angiogenic pathways, together with its low toxicity profile, highlight the therapeutic potential of this new drug. PMID- 26536462 TI - The Evaluation of Corrective Reconstruction Method For Reduced Acquisition Time and Various Anatomies of Perfusion Defect Using Channelized Hotelling Observer for Myocardial Perfusion SPECT. AB - We evaluated the effect of conventional and corrective image reconstruction methods on reduced acquisition time for detecting a myocardial perfusion (MP) defect in MP SPECT using the Channelized Hotelling Observer (CHO). Using the 4D Extended Cardiac-Torso (XCAT) phantom, we simulated realistic transmural and endocardial MP defects in various location and size. Realistic Tc-99m Sestamibi MP projection data were generated using an analytical projector that included the effects of attenuation (A), collimator-detector response (D) and scatter (S) for various count levels simulating different acquisition times. They were reconstructed using the 3D FBP without correction and a 3D OS-EM method with ADS correction followed by a smoothing filter with various cut-off frequencies. The CHO followed by receiver operating characteristics (ROC) methodology was applied to the reconstructed images to evaluate the detectability of a MP defect in each method for different defect anatomies and count levels. Areas under the ROC curve (AUC) were computed to assess the changes in the MP defect detection. The results showed that the 3D OS-EM with ADS corrections showed significantly less changes in AUC value and gave overall higher AUC values than FBP at all cut-off frequencies of the post smoothing filter, count levels and MP defect sizes. The difference in AUC increased towards less smoothed images where the 3D OS-EM with correction was able to provide similar AUC values with 20 - 40% reduction in acquisition time compared to FBP. The AUC values for smaller MP defects were lower for both reconstruction methods with smaller differences. We concluded that the 3D OS-EM with ADS corrections provides higher performance in the MP defect detection task. It allows increased reduction of acquisition time without loss of MP defect detection in MP SPECT compared to the conventional FBP method especially towards less smoothed images. PMID- 26536463 TI - Presence of antibodies but no evidence for circulation of MERS-CoV in dromedaries on the Canary Islands, 2015. AB - In 2012, a new betacoronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), was identified in humans. Several studies confirmed dromedary camels to be a potential reservoir and a source for human infection. Camels located on the Canary Islands were included in those studies and ca 10% of them were positive for MERS-CoV-specific antibodies. However, these findings could not be correctly interpreted because epidemiological information was not provided. Thus, further investigations were necessary to clarify these results. A total of 170 camels were investigated in this survey, of which seven (4.1%) were seropositive by ELISA. Epidemiological information revealed that all seropositive camels had been imported from Africa 20 or more years prior. We conclude that seropositive camels had contact with MERS-CoV in Africa and that there is no shedding of the virus among camels or people around the farms on the Canary Islands. However, the presence of antibodies in the camel herds should be monitored. PMID- 26536465 TI - Large-Scale Transcriptome Analysis of Cucumber and Botrytis cinerea during Infection. AB - Cucumber gray mold caused by Botrytis cinerea is considered one of the most serious cucumber diseases. With the advent of Hi-seq technology, it is possible to study the plant-pathogen interaction at the transcriptome level. To the best of our knowledge, this is the first application of RNA-seq to identify cucumber and B. cinerea differentially expressed genes (DEGs) before and after the plant pathogen interaction. In total, 248,908,688 raw reads were generated; after removing low-quality reads and those containing adapter and poly-N, 238,341,648 clean reads remained to map the reference genome. There were 3,512 cucumber DEGs and 1,735 B. cinerea DEGs. GO enrichment and KEGG enrichment analysis were performed on these DEGs to study the interaction between cucumber and B. cinerea. To verify the reliability and accuracy of our transcriptome data, 5 cucumber DEGs and 5 B. cinerea DEGs were chosen for RT-PCR verification. This is the first systematic transcriptome analysis of components related to the B. cinerea cucumber interaction. Functional genes and putative pathways identified herein will increase our understanding of the mechanism of the pathogen-host interaction. PMID- 26536464 TI - Green Tea Extract Rich in Epigallocatechin-3-Gallate Prevents Fatty Liver by AMPK Activation via LKB1 in Mice Fed a High-Fat Diet. AB - Supplementation with epigallocatechin-3-gallate has been determined to aid in the prevention of obesity. Decaffeinated green tea extract appears to restore a normal hepatic metabolic profile and attenuate high-fat diet (HFD)-induced effects, thereby preventing non-alcoholic fatty liver disease in mice. Mice were maintained on either a control diet (CD) or HFD for 16 weeks and supplemented with either water or green tea extract (50 mg/kg/day). The body mass increase, serum adiponectin level, and lipid profile were measured over the course of the treatment. Furthermore, the AMPK pathway protein expression in the liver was measured. From the fourth week, the weight gain in the CD + green tea extract (CE) group was lower than that in the CD + water (CW) group. From the eighth week, the weight gain in the HFD + water (HFW) group was found to be higher than that in the CW group. Moreover, the weight gain in the HFD + green tea extract (HFE) group was found to be lower than that in the HFW group. Carcass lipid content was found to be higher in the HFW group than that in the CW and HFE groups. Serum analysis showed reduced non-esterified fatty acid level in the CE and HFE groups as compared with their corresponding placebo groups. Increased adiponectin level was observed in the same groups. Increased VLDL-TG secretion was observed in the HFW group as compared with the CW and HFE groups. Increased protein expression of AdipoR2, SIRT1, pLKB1, and pAMPK was observed in the HFE group, which explained the reduced expression of ACC, FAS, SREBP-1, and ChREBP in this group. These results indicate that the effects of decaffeinated green tea extract may be related to the activation of AMPK via LKB1 in the liver of HFD-fed mice. PMID- 26536466 TI - A Peptide to Reduce Pulmonary Edema in a Rat Model of Lung Transplantation. AB - BACKGROUND: Despite significant advances in organ preservation, surgical techniques and perioperative care, primary graft dysfunction is a serious medical problem in transplantation medicine in general and a specific problem in patients undergoing lung transplantation. As a result, patients develop lung edema, causing reduced tissue oxygenation capacity, reduced lung compliance and increased requirements for mechanical ventilatory support. Yet, there is no effective strategy available to protect the grafted organ from stress reactions induced by ischemia/reperfusion and by the surgical procedure itself. METHODS: We assessed the effect of a cingulin-derived peptide, XIB13 or a random peptide in an established rat model of allogeneic lung transplantation. Donor lungs and recipients received therapeutic peptide at the time of transplantation and outcome was analyzed 100min and 28 days post grafting. RESULTS: XIB13 improved blood oxygenation and reduced vascular leak 100min post grafting. Even after 28 days, lung edema was significantly reduced by XIB13 and lungs had reduced fibrotic or necrotic zones. Moreover, the induction of an allogeneic T cell response was delayed indicating a reduced antigen exchange between the donor and the host. CONCLUSIONS: In summary, we provide a new tool to strengthen endothelial barrier function thereby improving outcomes in lung transplantation. PMID- 26536467 TI - Gestural Communication and Mating Tactics in Wild Chimpanzees. AB - The extent to which primates can flexibly adjust the production of gestural communication according to the presence and visual attention of the audience provides key insights into the social cognition underpinning gestural communication, such as an understanding of third party relationships. Gestures given in a mating context provide an ideal area for examining this flexibility, as frequently the interests of a male signaller, a female recipient and a rival male bystander conflict. Dominant chimpanzee males seek to monopolize matings, but subordinate males may use gestural communication flexibly to achieve matings despite their low rank. Here we show that the production of mating gestures in wild male East African chimpanzees (Pan troglodytes schweunfurthii) was influenced by a conflict of interest with females, which in turn was influenced by the presence and visual attention of rival males. When the conflict of interest was low (the rival male was present and looking away), chimpanzees used visual/ tactile gestures over auditory gestures. However, when the conflict of interest was high (the rival male was absent, or was present and looking at the signaller) chimpanzees used auditory gestures over visual/ tactile gestures. Further, the production of mating gestures was more common when the number of oestrous and non-oestrus females in the party increased, when the female was visually perceptive and when there was no wind. Females played an active role in mating behaviour, approaching for copulations more often when the number of oestrus females in the party increased and when the rival male was absent, or was present and looking away. Examining how social and ecological factors affect mating tactics in primates may thus contribute to understanding the previously unexplained reproductive success of subordinate male chimpanzees. PMID- 26536468 TI - Simulation Models of Leaf Area Index and Yield for Cotton Grown with Different Soil Conditioners. AB - Simulation models of leaf area index (LAI) and yield for cotton can provide a theoretical foundation for predicting future variations in yield. This paper analyses the increase in LAI and the relationships between LAI, dry matter, and yield for cotton under three soil conditioners near Korla, Xinjiang, China. Dynamic changes in cotton LAI were evaluated using modified logistic, Gaussian, modified Gaussian, log normal, and cubic polynomial models. Universal models for simulating the relative leaf area index (RLAI) were established in which the application rate of soil conditioner was used to estimate the maximum LAI (LAIm). In addition, the relationships between LAIm and dry matter mass, yield, and the harvest index were investigated, and a simulation model for yield is proposed. A feasibility analysis of the models indicated that the cubic polynomial and Gaussian models were less accurate than the other three models for simulating increases in RLAI. Despite significant differences in LAIs under the type and amount of soil conditioner applied, LAIm could be described by aboveground dry matter using Michaelis-Menten kinetics. Moreover, the simulation model for cotton yield based on LAIm and the harvest index presented in this work provided important theoretical insights for improving water use efficiency in cotton cultivation and for identifying optimal application rates of soil conditioners. PMID- 26536469 TI - Differences in the Prevalence of Obesity, Smoking and Alcohol in the United States Nationwide Inpatient Sample and the Behavioral Risk Factor Surveillance System. AB - BACKGROUND: The lack of adequate and standardized recording of leading risk factors for morbidity and mortality in medical records have downstream effects on research based on administrative databases. The measurement of healthcare is increasingly based on risk-adjusted outcomes derived from coded comorbidities in these databases. However inaccurate or haphazard assessment of risk factors for morbidity and mortality in medical record codes can have tremendous implications for quality improvement and healthcare reform. OBJECTIVE: We aimed to compare the prevalence of obesity, overweight, tobacco use and alcohol abuse of a large administrative database with a direct data collection survey. MATERIALS AND METHODS: We used the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for four leading risk factors in the United States Nationwide Inpatient Sample (NIS) to compare them with a direct survey in the Behavioral Risk Factor Surveillance System (BRFSS) in 2011. After confirming normality of the risk factors, we calculated the national and state estimates and Pearson's correlation coefficient for obesity, overweight, tobacco use and alcohol abuse between NIS and BRFSS. RESULTS: Compared with direct participant questioning in BRFSS, NIS reported substantially lower prevalence of obesity (p<0.01), overweight (p<0.01), and alcohol abuse (p<0.01), but not tobacco use (p = 0.18). The correlation between NIS and BRFSS was 0.27 for obesity (p = 0.06), 0.09 for overweight (p = 0.55), 0.62 for tobacco use (p<0.01) and 0.40 for alcohol abuse (p<0.01). CONCLUSIONS: The prevalence of obesity, overweight, tobacco smoking and alcohol abuse based on codes is not consistent with prevalence based on direct questioning. The accuracy of these important measures of health and morbidity in databases is critical for healthcare reform policies. PMID- 26536470 TI - Identification of Four-Jointed Box 1 (FJX1)-Specific Peptides for Immunotherapy of Nasopharyngeal Carcinoma. AB - Nasopharyngeal carcinoma (NPC) is highly prevalent in South East Asia and China. The poor outcome is due to late presentation, recurrence, distant metastasis and limited therapeutic options. For improved treatment outcome, immunotherapeutic approaches focusing on dendritic and autologous cytotoxic T-cell based therapies have been developed, but cost and infrastructure remain barriers for implementing these in low-resource settings. As our prior observations had found that four jointed box 1 (FJX1), a tumor antigen, is overexpressed in NPCs, we investigated if short 9-20 amino acid sequence specific peptides matching to FJX1 requiring only intramuscular immunization to train host immune systems would be a better treatment option for this disease. Thus, we designed 8 FJX1-specific peptides and implemented an assay system to first, assess the binding of these peptides to HLA A2 molecules on T2 cells. After, ELISPOT assays were used to determine the peptides immunogenicity and ability to induce potential cytotoxicity activity towards cancer cells. Also, T-cell proliferation assay was used to evaluate the potential of MHC class II peptides to stimulate the expansion of isolated T cells. Our results demonstrate that these peptides are immunogenic and peptide stimulated T-cells were able to induce peptide-specific cytolytic activity specifically against FJX1-expressing cancer cells. In addition, we demonstrated that the MHC class II peptides were capable of inducing T-cell proliferation. Our results suggest that these peptides are capable of inducing specific cytotoxic cytokines secretion against FJX1-expressing cancer cells and serve as a potential vaccine-based therapy for NPC patients. PMID- 26536471 TI - Different Placebos, Different Mechanisms, Different Outcomes: Lessons for Clinical Trials. AB - Clinical trials use placebos with the assumption that they are inert, thus all placebos are considered to be equal. Here we show that this assumption is wrong and that different placebo procedures are associated to different therapeutic rituals which, in turn, trigger different mechanisms and produce different therapeutic outcomes. We studied high altitude, or hypobaric hypoxia, headache, in which two different placebos were administered. The first was placebo oxygen inhaled through a mask, whereas the second was placebo aspirin swallowed with a pill. Both placebos were given after a conditioning procedure, whereby either real oxygen or real aspirin was administered for three consecutive sessions to reduce headache pain. We found that after real oxygen conditioning, placebo oxygen induced pain relief along with a reduction in ventilation, blood alkalosis and salivary prostaglandin (PG)E2, yet without any increase in blood oxygen saturation (SO2). By contrast, after real aspirin conditioning, placebo aspirin induced pain relief through the inhibition of all the products of cyclooxygenase, that is, PGD2, PGE2, PGF2, PGI2, thromboxane (TX)A2, without affecting ventilation and blood alkalosis. Therefore, two different placebos, associated to two different therapeutic rituals, used two different pathways to reduce headache pain. The analgesic effect following placebo oxygen was superior to placebo aspirin. These findings show that different placebos may use different mechanisms to reduce high altitude headache, depending on the therapeutic ritual and the route of administration. In clinical trials, placebos and outcome measures should be selected very carefully in order not to incur in wrong interpretations. PMID- 26536472 TI - Correction: Pre-Conception Dyslipidemia Is Associated with Development of Preeclampsia and Gestational Diabetes Mellitus. PMID- 26536473 TI - In Situ Control of Underwater-Pinning of Organic Droplets on a Surfactant-Doped Conjugated Polymer Surface. AB - Controlling the pinning of organic droplets on solid surfaces is of fundamental and practical interest in the field of material science and engineering, which has numerous applications such as surface cleaning, water treatment, and microfluidics. Here, a rapid in situ control of pinning and actuation of organic droplets is demonstrated on dodecylbenzenesulfonate-doped polypyrrole (PPy(DBS)) surfaces in an aqueous environment via an electrochemical redox process. A dramatic change of the pinning results from the transport of DBS(-) molecules between the PPy(DBS) surface and the aqueous environment, as well as from a simultaneous alternation of the surface oleophobicity to organic liquids during the redox process. This in situ control of the droplet pinning enables a stop-and go droplet actuation, applicable to both polar and apolar organic droplets, at low voltages (~0.9 V) with an extremely low roll-off angle (~0.4 degrees ). PMID- 26536474 TI - Daily heterosexism experiences and well-being among LGB young adults: The moderating role of attachment style. AB - This study examined within-person links between daily heterosexism experiences and well-being among lesbian, gay, and bisexual young adults, and tested the hypothesis that attachment insecurity amplifies the negative impact of heterosexism on well-being. A sample of 82 lesbian, gay, and bisexual young adults completed a measure of attachment style at the start of the study, and then reported on heterosexism experiences and facets of well-being in Internet surveys at the end of each day for 7-10 consecutive days (total of 706 days in the sample). Multilevel regression was used to test the interaction between attachment variables (anxiety and avoidance) and the presence of everyday heterosexism experiences in predicting 3 facets of daily well-being (self assurance, anger, and fear). Results indicated that attachment variables moderated the within-person link between daily heterosexism experiences and well being for anger and fear but not for self-assurance. As hypothesized, daily heterosexism was positively related to daily anger and fear for people with higher levels of avoidance but not those with lower levels of avoidance (controlling for previous day levels of well-being). Contrary to hypothesis, however, daily heterosexism was positively associated with anger and fear for participants with low levels of attachment anxiety but not for those with higher levels of attachment anxiety. Analyses also revealed no links between the attachment variables and frequency of heterosexism experiences. (PsycINFO Database Record PMID- 26536475 TI - Recurrent abdominal panniculitis in a Peruvian man. PMID- 26536476 TI - Loss of CD24 in Mice Leads to Metabolic Dysfunctions and a Reduction in White Adipocyte Tissue. AB - CD24 is a glycophosphatidylinositol (GPI)-linked cell surface receptor that is involved in regulating the survival or differentiation of several different cell types. CD24 has been used to identify pre-adipocytes that are able to reconstitute white adipose tissue (WAT) in vivo. Moreover, we recently found that the dynamic upregulation of CD24 in vitro during early phases of adipogenesis is necessary for mature adipocyte development. To determine the role of CD24 in adipocyte development in vivo, we evaluated the development of the inguinal and interscapular subcutaneous WAT and the epididymal visceral WAT in mice with a homozygous deletion of CD24 (CD24KO). We observed a significant decrease in WAT mass of 40% to 74% in WAT mass from both visceral and subcutaneous depots in male mice, with no significant effect in female mice, compared to wild-type (WT) sex- and age-matched controls. We also found that CD24KO mice had increased fasting glucose and free fatty acids, decreased fasting insulin, and plasma leptin. No major differences were observed in the sensitivity to insulin or glucose, or in circulating triglycerides, total cholesterol, HDL-cholesterol, or LDL-cholesterol levels between WT and CD24KO mice. Challenging the CD24KO mice with either high sucrose (35%) or high fat (45%) diets that promote increased adiposity, increased WAT mass and fasting insulin, adiponectin and leptin levels, as well as reduced the sensitivity to insulin and glucose, to the levels of WT mice on the same diets. The CD24-mediated reduction in fat pad size was due to a reduction in adipocyte cell size in all depots with no significant reduction pre-adipocyte or adipocyte cell number. Thus, we have clearly demonstrated that the global absence of CD24 affects adipocyte cell size in vivo in a sex- and diet-dependent manner, as well as causing metabolic disturbances in glucose homeostasis and free fatty acid levels. PMID- 26536477 TI - Nab-paclitaxel in patients with metastatic melanoma. AB - Cutaneous melanoma is one of the most aggressive and resistant malignancies in humans. Until recently, progress in the treatment of metastatic melanoma remained dormant for nearly two decades. However, recent advances in immune and targeted therapeutic approaches have led to dramatic and paradigm-shifting advances in the management of metastatic melanoma, that are now leading the way for other malignancies. With the advent of these new therapeutic options, chemotherapy is no longer favored as a first line strategy in metastatic melanoma, but continues to play a role in the salvage treatment of patients that have become refractory to immune-based or targeted therapies. Nab-paclitaxel, a solvent-free alternative to solvent-based paclitaxel, has shown in several trials to be active in metastatic melanoma. Herein, we summarize the role of nab-paclitaxel in the management of patients with advanced melanoma. PMID- 26536478 TI - Mangroves Enhance Reef Fish Abundance at the Caribbean Regional Scale. AB - Several studies conducted at the scale of islands, or small sections of continental coastlines, have suggested that mangrove habitats serve to enhance fish abundances on coral reefs, mainly by providing nursery grounds for several ontogenetically-migrating species. However, evidence of such enhancement at a regional scale has not been reported, and recently, some researchers have questioned the mangrove-reef subsidy effect. In the present study, using two different regression approaches, we pursued two questions related to mangrove reef connectivity at the Caribbean regional scale: (1) Are reef fish abundances limited by mangrove forest area?; and (2) Are mean reef fish abundances proportional to mangrove forest area after taking human population density and latitude into account? Specifically, we tested for Caribbean-wide mangrove forest area effects on the abundances of 12 reef fishes that have been previously characterized as "mangrove-dependent". Analyzed were data from an ongoing, long term (20-year) citizen-scientist fish monitoring program; coastal human population censuses; and several wetland forest information sources. Quantile regression results supported the notion that mangrove forest area limits the abundance of eight of the 12 fishes examined. Linear mixed-effects regression results, which considered potential human (fishing and habitat degradation) and latitudinal influences, suggested that average reef fish densities of at least six of the 12 focal fishes were directly proportional to mangrove forest area. Recent work questioning the mangrove-reef fish subsidy effect likely reflects a failure to: (1) focus analyses on species that use mangroves as nurseries, (2) consider more than the mean fish abundance response to mangrove forest extent; and/or (3) quantitatively account for potentially confounding human impacts, such as fishing pressure and habitat degradation. Our study is the first to demonstrate at a large regional scale (i.e., the Wider Caribbean) that greater mangrove forest size generally functions to increase the densities on neighboring reefs of those fishes that use these shallow, vegetated habitats as nurseries. PMID- 26536479 TI - The Missing C1-C5 Cycloaromatization Reaction: Triplet State Antiaromaticity Relief and Self-Terminating Photorelease of Formaldehyde for Synthesis of Fulvenes from Enynes. AB - The last missing example of the four archetypical cycloaromatizations of enediynes and enynes was discovered by combining a twisted alkene excited state with a new self-terminating path for intramolecular conversion of diradicals into closed-shell products. Photoexcitation of aromatic enynes to a twisted alkene triplet state creates a unique stereoelectronic situation, which is facilitated by the relief of excited state antiaromaticity of the benzene ring. This enables the usually unfavorable 5-endo-trig cyclization and merges it with 5-exo-dig closure. The 1,4-diradical product of the C1-C5 cyclization undergoes internal H atom transfer that is coupled with the fragmentation of an exocyclic C-C bond. This sequence provides efficient access to benzofulvenes from enynes and expands the utility of self-terminating aromatizing enyne cascades to photochemical reactions. The key feature of this self-terminating reaction is that, despite the involvement of radical species in the key cyclization step, no external radical sources or quenchers are needed to provide the products. In these cascades, both radical centers are formed transiently and converted to the closed-shell products via intramolecular H-transfer and C-C bond fragmentation. Furthermore, incorporating C-C bond cleavage into the photochemical self-terminating cyclizations of enynes opens a new way for the use of alkenes as alkyne equivalents in organic synthesis. PMID- 26536480 TI - Permutation Lempel-Ziv complexity measure of electroencephalogram in GABAergic anaesthetics. AB - Monitoring the brain state in anaesthesia is crucial for clinical doctors. In this study, we propose a novel nonlinear method, the permutation Lempel-Ziv complexity (PLZC) index, which describes the complexity in the electroencephalographic (EEG) signal to quantify the effect of GABAergic anaesthetics on brain activities.We applied the PLZC to two EEG data sets that were recorded under sevoflurane and propofol anaesthesia. The results are compared with traditional mean value-based Lempel-Ziv complexity (LZC), permutation entropy (PE), composite PE index (CPEI), response entropy (RE), state entropy (SE) and bispectral index (BIS) or SynchFastSlow (SFS, derived from BIS). Pharmacokinetic/pharmacodynamic (PK/PD) modelling and prediction probability (Pk) were used to assess the performance of the proposed method for tracking GABAergic anaesthetic concentrations.We found that PLZC correlates closely with the anaesthetic drug effect. When applied in sevoflurane anaesthesia, the coefficient of determination R2 between the PLZC values and the sevoflurane effect site concentrations was (0.90 +/- 0.07), mean +/- standard deviation), and the prediction probability Pk was (0.85 +/- 0.04). These values were higher than those for the other indices. While in propofol anaesthesia, the value of R2 between PLZC and the effect site concentrations was (0.89 +/- 0.07), and the Pk was (0.86 +/- 0.28), which were close to those for CPEI but better than those for the others.PLZC based on electroencephalogram signals can be used as a new index to characterize the depth of anaesthesia. This index outperformed LZC, PE, CPEI, RE, SE, and BIS or SFS in tracking drug concentration changes during GABAergic anaesthetics.PLZC is a potentially superior method for applications in intra operative monitoring. PMID- 26536481 TI - Patterns of Natural and Human-Caused Mortality Factors of a Rare Forest Carnivore, the Fisher (Pekania pennanti) in California. AB - Wildlife populations of conservation concern are limited in distribution, population size and persistence by various factors, including mortality. The fisher (Pekania pennanti), a North American mid-sized carnivore whose range in the western Pacific United States has retracted considerably in the past century, was proposed for threatened status protection in late 2014 under the United States Endangered Species Act by the United States Fish and Wildlife Service in its West Coast Distinct Population Segment. We investigated mortality in 167 fishers from two genetically and geographically distinct sub-populations in California within this West Coast Distinct Population Segment using a combination of gross necropsy, histology, toxicology and molecular methods. Overall, predation (70%), natural disease (16%), toxicant poisoning (10%) and, less commonly, vehicular strike (2%) and other anthropogenic causes (2%) were causes of mortality observed. We documented both an increase in mortality to (57% increase) and exposure (6%) from pesticides in fishers in just the past three years, highlighting further that toxicants from marijuana cultivation still pose a threat. Additionally, exposure to multiple rodenticides significantly increased the likelihood of mortality from rodenticide poisoning. Poisoning was significantly more common in male than female fishers and was 7 times more likely than disease to kill males. Based on necropsy findings, suspected causes of mortality based on field evidence alone tended to underestimate the frequency of disease-related mortalities. This study is the first comprehensive investigation of mortality causes of fishers and provides essential information to assist in the conservation of this species. PMID- 26536482 TI - Effect of Deuteration on Phase Behavior of Supported Phospholipid Bilayers: A Spectroelectrochemical Study. AB - Differences in molecular organization of two sides of a chemically symmetric, planar bilayer supported on a Au(111) substrate have been monitored with charge density measurements and in situ polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS). Isotopic substitution of the hydrogen atoms in the hydrocarbon chains with deuterium atoms in one monolayer was employed to allow the monitoring of C-H vibrations from that monolayer alone. Charge density measurements of bilayers formed from dimyristoylphosphatidylethanolamine (DMPE) showed that the effect of placing the deuterated layer next to the substrate or electrolyte had little impact on the electrical barrier properties. In situ PM IRRAS studies revealed that the structure of the two monolayers was the same at negative potentials, where the bilayer is separated from the Au substrate, but different at more positive potentials or small charge densities, where the bilayer is expected to be directly adsorbed on the Au surface. Thus, the differences observed for the related molecule dimyristoylphosphatidylcholine (DMPC) persist in planar structures, although to a lesser extent. A small but observable variation in the tilt angle was also apparent in the spectra of both isotopically asymmetric DMPE bilayers during the electrochemical phase transition. The fact that this effect was not previously observed for hydrogenous bilayers means that the dynamic behavior of deuterated DMPE and/or of bilayers composed of different monolayers is different from that of hydrogenous DMPE bilayers. These results have implications for future studies in which isotopic substitution is used to extract selectively information from one layer or component of lipid bilayers in spectroscopic or neutron measurements. PMID- 26536483 TI - Acute Oxygen Sensing--Inching Ever Closer to an Elusive Mechanism. AB - The carotid body has long been recognized as the body's primary acute oxygen sensor. For decades, this organ has been reluctant to reveal mechanisms underlying its sensory activity. In this issue of Cell Metabolism, Fernandez Aguera et al. (2015) take us closer to a fuller understanding of this fundamental process. PMID- 26536484 TI - Harnessing Genes and Diet to Fine-Tune the Gut Microbial Fitness. AB - Microbe communication with host mammalian cells and external factors such as diet influences this multifaceted ecosystem. A recent study shows that interactions between microbial genes and dietary elements are dynamic processes that may help to characterize an organism's niche and eventually its impact on the overall community and host metabolism. PMID- 26536485 TI - Molecular Regulation of Circadian Rhythms by Polyamines. AB - In this issue of Cell Metabolism, Zwighaft and colleagues (Zwighaft et al., 2015) describe a novel mechanism through which intracellular polyamines regulate circadian rhythms. These findings are significant, as they add yet another layer of complexity to the interplay between environmental, dietary, and organismal factors in the molecular control of daily behavioral oscillations. PMID- 26536486 TI - Metabolic Mechanisms of Drug Resistance in Leukemia. AB - Tumor cells frequently undergo metabolic reprogramming, but it is unknown how these metabolic changes relate to drug resistance. A recent article now demonstrates that PI3K/AKT signaling causes a metabolic switch from glutaminolysis to aerobic glycolysis in Notch-dependent T cell acute lymphoblastic leukemia (T-ALL). PMID- 26536487 TI - A Model for Selection of Eyespots on Butterfly Wings. AB - UNSOLVED PROBLEM: The development of eyespots on the wing surface of butterflies of the family Nympalidae is one of the most studied examples of biological pattern formation.However, little is known about the mechanism that determines the number and precise locations of eyespots on the wing. Eyespots develop around signaling centers, called foci, that are located equidistant from wing veins along the midline of a wing cell (an area bounded by veins). A fundamental question that remains unsolved is, why a certain wing cell develops an eyespot, while other wing cells do not. KEY IDEA AND MODEL: We illustrate that the key to understanding focus point selection may be in the venation system of the wing disc. Our main hypothesis is that changes in morphogen concentration along the proximal boundary veins of wing cells govern focus point selection. Based on previous studies, we focus on a spatially two-dimensional reaction-diffusion system model posed in the interior of each wing cell that describes the formation of focus points. Using finite element based numerical simulations, we demonstrate that variation in the proximal boundary condition is sufficient to robustly select whether an eyespot focus point forms in otherwise identical wing cells. We also illustrate that this behavior is robust to small perturbations in the parameters and geometry and moderate levels of noise. Hence, we suggest that an anterior-posterior pattern of morphogen concentration along the proximal vein may be the main determinant of the distribution of focus points on the wing surface. In order to complete our model, we propose a two stage reaction-diffusion system model, in which an one-dimensional surface reaction-diffusion system, posed on the proximal vein, generates the morphogen concentrations that act as non homogeneous Dirichlet (i.e., fixed) boundary conditions for the two-dimensional reaction-diffusion model posed in the wing cells. The two-stage model appears capable of generating focus point distributions observed in nature. RESULT: We therefore conclude that changes in the proximal boundary conditions are sufficient to explain the empirically observed distribution of eyespot focus points on the entire wing surface. The model predicts, subject to experimental verification, that the source strength of the activator at the proximal boundary should be lower in wing cells in which focus points form than in those that lack focus points. The model suggests that the number and locations of eyespot foci on the wing disc could be largely controlled by two kinds of gradients along two different directions, that is, the first one is the gradient in spatially varying parameters such as the reaction rate along the anterior-posterior direction on the proximal boundary of the wing cells, and the second one is the gradient in source values of the activator along the veins in the proximal-distal direction of the wing cell. PMID- 26536488 TI - Feasibility and Efficacy of an mHealth Game for Managing Anxiety: "Flowy" Randomized Controlled Pilot Trial and Design Evaluation. AB - OBJECTIVE: Meeting the complex needs of patients with chronic common mental health disorders (CMHDs) may be the greatest challenge facing organized medical practice. On the basis of a well-established and proven theoretical foundation for controlled respiration as a behavioral intervention for CMHDs, as well as preliminary evidence that gamification can improve health outcomes through increasing patient engagement, this randomized controlled pilot study evaluated the feasibility and clinical efficacy of a mobile health game called "Flowy" ( www.flowygame.com ) that digitally delivered breathing retraining exercises for anxiety, panic, and hyperventilation symptom management. MATERIALS AND METHODS: We designed an unblinded, Web-based, parallel-group randomized controlled trial focusing on feasibility, clinical efficacy, and design proof of concept. In the intervention condition (n = 31), participants received free access to "Flowy" for 4 weeks. In the control condition (n = 32), participants were placed on a waitlist for 4 weeks before being offered free access to "Flowy." Online measurements using psychological self-report questionnaires were made at 2 and 4 weeks post-baseline. RESULTS: At trial conclusion, participants found "Flowy" acceptable as an anxiety management intervention. "Flowy" engaged participants sufficiently to endorse proactive gameplay. Intent-to-treat analysis revealed a reduction in anxiety, panic, and self-report hyperventilation scores in both trial arms, with the intervention arm experiencing greater quality of life. Participants perceived "Flowy" as a fun and useful intervention, proactively used "Flowy" as part of their care, and would recommend "Flowy" to family and friends. CONCLUSIONS: Our results suggest that a digital delivery of breathing retraining exercises through a mobile health game can manage anxiety, panic, and hyperventilation symptoms associated with CMHDs. PMID- 26536489 TI - Designed Modular Proteins as Scaffolds To Stabilize Fluorescent Nanoclusters. AB - Proteins have been used as templates to stabilize fluorescent metal nanoclusters thus obtaining stable fluorescent structures, and their fluorescent properties being modulated by the type of protein employed. Designed consensus tetratricopeptide repeat (CTPR) proteins are suited candidates as templates for the stabilization of metal nanoclusters due to their modular structural and functional properties. Here, we have studied the ability of CTPR proteins to stabilize fluorescent gold nanoclusters giving rise to designed functional hybrid nanostructures. First, we have investigated the influence of the number of CTPR units, as well as the presence of cysteine residues in the CTPR protein, on the fluorescent properties of the protein-stabilized gold nanoclusters. Synthetic protocols to retain the protein structure and function have been developed, since the structural and functional integrity of the protein template is critical for further applications. Finally, as a proof-of-concept, a CTPR module with specific binding capabilities has been used to stabilize gold nanoclusters with positive results. Remarkably, the protein-stabilized gold nanocluster obtained combines both the fluorescence properties of the nanoclusters and the functional properties of the protein. The fluorescence changes in nanoclusters fluorescence have been successfully used as a sensor to detect when the specific ligand was recognized by the CTPR module. PMID- 26536490 TI - Correction to Source Contributions to Wintertime Elemental and Organic Carbon in the Western Arctic Based on Radiocarbon and Tracer Apportionment. PMID- 26536491 TI - Postprandial capillary-venous glucose gradient in Type 1 diabetes: magnitude and clinical associations in a real world setting. AB - AIMS: To determine the magnitude of the peripheral glucose gradient in patients with Type 1 diabetes in a real world setting and to explore its relationship with insulin dose and macronutrient intake. METHODS: All patients used mealtime analogue insulin. The glucose gradient was assessed using antecubital fossa venous and finger-stick capillary samples, collected concurrently at room temperature. Baseline sampling occurred before the administration of an insulin dose and breakfast of the patient's choosing. Breakfast was consumed an average of 15 min after baseline. The macronutrient content of breakfast was documented. Sampling was repeated 1 and 2 h after baseline. RESULTS: The mean (95% CI) plasma capillary-venous glucose gradient values for 43 patients were: pre-breakfast, 0.21 (0.08-0.34) mmol/l; 1 h after baseline, 0.87 (0.66-1.07) mmol/l; and 2 h after baseline, 0.52 (0.33-0.71) mmol/l. Glucose gradient and dietary carbohydrate intake (g/kg body weight) were positively correlated at both 1 h (P < 0.01) and 2 h after baseline (P < 0.01). No relationship was observed between this gradient and mealtime insulin dose, or the glucose concentration at either time point. CONCLUSIONS: In patients with Type 1 diabetes, a clinically significant glucose gradient is present after the ingestion of a carbohydrate rich meal. As postprandial capillary and venous plasma glucose concentrations are not equivalent, defining the site of sample collection is important. PMID- 26536492 TI - Patch Testing for Methylisothiazolinone and Methylchloroisothiazolinone Methylisothiazolinone Contact Allergy. AB - IMPORTANCE: Contact allergy to methylisothiazolinone (MI) or to the combined formulation of methylchloroisothiazolinone and MI (MCI-MI) has increased significantly, with a frequency of as much as 11.1% in patients with dermatitis; however, few cohort studies in the US population have been reported. OBJECTIVE: To investigate the prevalence of contact allergies to MI and MCI-MI and the outcomes of patients with positive patch test reactions to MI and MCI-MI. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of all consecutive patients (n = 703) presenting with possible allergic contact dermatitis and subsequently undergoing patch testing at a tertiary referral center from January 1, 2012, through November 30, 2014. Patch testing used the North American Contact Dermatitis Group standard series. The MCI-MI concentration was 100 ppm; the MI concentration in the screening series increased from 200 to 2000 ppm in January 2013. Demographic data, exposures, and outcomes were reported for patients with positive patch test reactions to MI and/or MCI-MI. Data were analyzed from December 1, 2014, through January 31, 2015. MAIN OUTCOMES AND MEASURES: Positive patch test reaction to MI and/or MCI-MI and identification of the relevance of contact allergy to these preservatives. Follow-up after allergen avoidance was determined when available. RESULTS: Of the 703 patients who underwent patch testing, contact allergy to MI and/or MCI-MI occurred in 57 patients (8.1%), with 35 reactions to MI only, 5 reactions to MCI-MI only, and 17 reactions to both. Prevalence of contact allergy to MI increased from 6 of 236 patients (2.5%) in 2012 to 16 of 235 patients (6.8%) in 2014. The most commonly affected sites were the hands and face. Contact allergy to MI and/or MCI-MI was occupationally related in 4 cases. Cosmetics, soaps and cleansers (including wet wipes), and hair care products accounted for all identified sources. Twenty-three patients had follow-up data, and 17 of these (74%) improved with allergen avoidance. CONCLUSIONS AND RELEVANCE: The increasing prevalence of contact allergy to MI alone supports its addition to the standard series to identify cases missed by testing only for MCI-MI. Recent regulations by the European Commission have banned MCI-MI in all leave-on body products as of July 16, 2015. Currently recommended US regulations are less stringent; however, US regulatory agencies must act to ensure patient safety. PMID- 26536493 TI - Albumin versus solvent/detergent-treated pooled plasma as replacement fluid for long-term plasma exchange therapy in a patient with primary hypertriglyceridemia and recurrent hyperlipidemic pancreatitis. AB - BACKGROUND: Chylomicronemia syndrome is a metabolic condition characterized by severe fasting hypertrigliceridemia (>= 1000 mg/dL) and other clinical features including chronic abdominal pain and recurrent acute pancreatitis. In patients with acute or recurrent pancreatitis, plasma exchange (PEx) is indicated for the treatment of acute disease and prevention of recurrence. The use of plasma instead of albumin as replacement fluid has been suggested for its putative ability to replace the deficient enzyme possibly leading to better clinical improvement. CASE REPORT: A 40-year-old man with chylomicronemia syndrome due to a newly identified loss-of-function mutation in the lipoprotein lipase (LPL) gene (IVS2, c.250-1G/C) has been treated at our hospital since the age of 13. From age 18 to age 34, the patient had five episodes of acute pancreatitis while his triglyceride (TG) levels were extremely high (2500-4000 mg/dL). As the TG levels remained stable over 4000 mg/dL despite the maximum medical treatment, the patient started long-term PEx treatment on a weekly basIs. Both albumin and plasma have been used as replacement solution. Thirty months from the beginning of this treatment, no episode of acute pancreatitis has been reported, and the chronic abdominal pain fully disappeared. No differences were observed between the use of albumin or plasma as replacement solution. CONCLUSION: Long-term PEx is effective in preventing the recurrence of acute pancreatitis and in treatment of chronic abdominal pain in this patient with chylomicronemia syndrome. Plasma is not more effective than albumin in lipid reduction, likely because of its extremely low enzyme content. Therefore, in patients with LPL deficiency serum albumin should be preferred to plasma as replacement fluid because of the low rate of side effects and reduced costs. PMID- 26536494 TI - Methodological Challenges in Solving Geographic Disparity in Liver Allocation. PMID- 26536495 TI - Spectroscopic Signatures of AA' and AB Stacking of Chemical Vapor Deposited Bilayer MoS2. AB - Prominent resonance Raman and photoluminescence spectroscopic differences between AA' and AB stacked bilayer molybdenum disulfide (MoS2) grown by chemical vapor deposition are reported. Bilayer MoS2 islands consisting of the two stacking orders were obtained under identical growth conditions. Resonance Raman and photoluminescence spectra of AA' and AB stacked bilayer MoS2 were obtained on Au nanopyramid surfaces under strong plasmon resonance. Both resonance Raman and photoluminescence spectra show distinct features indicating clear differences in interlayer interaction between these two phases. The implication of these findings on device applications based on spin and valley degrees of freedom will be discussed. PMID- 26536496 TI - Fc-Small Molecule Antibody Mimetics. AB - Antibody therapeutics are a promising drug class due to their high specificity and favorable pharmacokinetics. While there are many methods for the development of antibodies specific to disease associated antigens, selecting antibodies against functional epitopes with high specificity and affinity can be difficult for certain epitopes. We describe a generalizable method for synthesizing antibody mimetics by site specifically conjugating small molecules (with high affinity and specificity to disease associated antigens) to an Fc fragment to develop drugs with the benefits of an antibody. As a proof of concept, an E269pAcPhe Fc antibody Fc fragment was produced and subsequently site specifically labeled with a linker-modified folic acid compound to generate an Fc folic acid antibody-mimetic. This was chosen as the model system because the high affinity folate receptor FR-alpha is highly expressed in a number of cancer types including breast and ovarian cancer. The specificity of the Fc-folic acid conjugate was assessed via flowcytometry with the folate-receptor positive breast cancer cell line MDA-MB-231 by measuring Fc-folic acid binding in both the absence and presence of an excess of folic acid. Fc-small molecule conjugates could be developed into a unique class of antibody-like therapeutics. PMID- 26536497 TI - IL-1alpha and inflammasome-independent IL-1beta promote neutrophil infiltration following alum vaccination. AB - Despite its long record of successful use in human vaccines, the mechanisms underlying the immunomodulatory effects of alum are not fully understood. Alum is a potent inducer of interleukin-1 (IL-1) secretion in vitro in dendritic cells and macrophages via Nucleotide-binding domain and leucine-rich repeat-containing (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome activation. However, the contribution of IL-1 to alum-induced innate and adaptive immune responses is controversial and the role of IL-1alpha following alum injection has not been addressed. This study shows that IL-1 is dispensable for alum-induced antibody and CD8 T cell responses to ovalbumin. However, IL-1 is essential for neutrophil infiltration into the injection site, while recruitment of inflammatory monocytes and eosinophils is IL-1 independent. Both IL-1alpha and IL-1beta are released at the site of injection and contribute to the neutrophil response. Surprisingly, these effects are NLRP3-inflammasome independent as is the infiltration of other cell populations. However, while NLRP3 and caspase 1 were dispensable, alum induced IL-1beta at the injection site was dependent on the cysteine protease cathepsin S. Overall, these data demonstrate a previously unreported role for cathepsin S in IL-1beta secretion, show that inflammasome formation is dispensable for alum-induced innate immunity and reveal that IL-1alpha and IL 1beta are both necessary for alum-induced neutrophil influx in vivo. PMID- 26536499 TI - Laryngeal cryptococcosis: Literature review and guidelines for laser ablation of fungal lesions. AB - OBJECTIVES/HYPOTHESIS: To describe the demographics, clinical manifestations, diagnosis, treatment, and outcomes of laryngeal cryptococcosis. Antifungal therapy guidelines are provided and the use of laser ablation is discussed. DATA SOURCES: PubMed, OVID MEDLINE, and Embase databases and one patient who presented to our institution's otolaryngology department. REVIEW METHODS: A review of the English-language international medical literature was conducted using the terms ("larynx" or "laryngeal diseases") and ("Cryptococcus" or "cryptococcosis") to identify reported cases of laryngeal cryptococcosis. Databases were searched from inception through January 2015. RESULTS: Eighteen cases were identified and reviewed, including the first reported case of potassium-titanyl-phosphate laser ablation. All patients presented with hoarseness, and two (11%) presented with acute airway obstruction that required tracheotomy. Six patients (33%) were immunocompromised, including three (17%) who had an underlying human immunodeficiency virus infection. Seven cases (39%) described an exophytic mass. Histopathology indicated pseudoepitheliomatous hyperplasia in seven of the 17 reported results (41%). Methenamine silver stain was used in 12 of the 15 described cases (80%) to identify the fungus. Lumbar puncture results were reported for seven patients, none of whom had meningitis. Antifungal therapy was used in 15 cases (83%), and two (11%) received additional laser ablation treatment. Eleven patients (61%) had complete resolution. CONCLUSIONS: Laryngeal cryptococcosis is a rare cause of persistent hoarseness. Most patients have complete resolution after treatment. For complex and obstructive cases, laser ablation coupled with antifungal therapy can successfully manage laryngeal cryptococcosis in select patients. LEVEL OF EVIDENCE: NA Laryngoscope, 126:1625 1629, 2016. PMID- 26536498 TI - Investigational drugs to treat methicillin-resistant Staphylococcus aureus. AB - INTRODUCTION: Staphylococcus aureus remains one of the leading causes of morbidity and mortality worldwide. This is to a large extent due to antibiotic resistant strains, in particular methicillin-resistant S. aureus (MRSA). While the toll of invasive MRSA infections appears to decrease in U.S. hospitals, the rate of community-associated MRSA infections remains constant and there is a surge of MRSA in many other countries, a situation that calls for continuing if not increased efforts to find novel strategies to combat MRSA infections. AREAS COVERED: This review provides an overview of current investigational drugs and therapeutic antibodies against S. aureus in early clinical development (up to phase II clinical development). It includes a short description of the mechanism of action and a presentation of microbiological and clinical data. EXPERT OPINION: Increased recent antibiotic development efforts and results from pathogenesis research have led to several new antibiotics and therapies, such as anti-virulence drugs, as well as a more informed selection of targets for vaccination efforts against MRSA. This developing portfolio of novel anti staphylococcal drugs will hopefully provide us with additional and more efficient ways to combat MRSA infections in the near future and prevent us from running out of treatment options, even if new resistances arise. PMID- 26536500 TI - Renal oxidative stress and renal CD8(+) T-cell infiltration in mercuric chloride induced nephropathy in rats: role of angiotensin II. AB - Mercuric chloride (HgCl2) induces kidney damage, in part, through oxidative stress. A role for angiotensin II (Ang II) in pro-inflammatory events in a model of acute HgCl2-induced nephropathy was reported. Ang II is a potent oxidative stress inducer; however, its role in oxidative/anti-oxidative events in HgCl2 induced nephropathy remains unknown. The aim of this study was to determine the role of Ang II in the oxidative stress and renal infiltration of CD8(+) T-cells after an acute HgCl2 intoxication. Three groups of Sprague Dawley rats were treated with a single subcutaneous dose of 2.5 mg/kg HgCl2: for 3 days prior to and for 4 days after that injection, rats in one group received Losartan (30 mg/kg), in another group Enalapril (30 mg/kg) or normal saline in the last group. Two other groups of drug-treated rats received saline in place of HgCl2. A final group of rats received saline in place of HgCl2 and the test drugs. All treatments were via gastric gavage. At 96 h after the vehicle/HgCl2 injection, blood and kidney samples were harvested. Renal sections were homogenized for measures of malondialdehyde (MDA), reduced glutathione (GSH) and catalase activity. Frozen sections were studied for the presence of superoxide anion ([Formula: see text]) and CD8(+) T-cells. HgCl2-treated rats had increased interstitial and tubular expression of [Formula: see text], high levels of MDA, normal catalase activity and GSH content, increased levels of interstitial CD8(+) T-cells and an increased percentage of necrotic tubules. Anti-Ang II treatments diminished the HgCl2-induced increases in interstitial [Formula: see text], CD8(+) T-cells and tubular damage and increased catalase and GSH expression above that due to HgCl2 alone; the HgCl2-induced high MDA levels were unaffected by the drugs. These data provide new information regarding the potential role of Ang II in the oxidative stress and renal CD8(+) T-cell infiltration that occur during HgCl2 nephropathy. PMID- 26536501 TI - Getting the most from routinely collected data. PMID- 26536502 TI - Routinely collected data as a strategic resource for research: priorities for methods and workforce. AB - In the era of 'big data', research using routinely collected data offers greater potential than ever before to drive health system effectiveness and efficiency, and population health improvement. In Australia, the policy environment, and emerging frameworks and processes for data governance and access, increasingly support the use of routinely collected data for research. Capitalising on this strategic resource requires investment in both research methods and research workforce. Priorities for methods development include validation studies, techniques for analysing complex longitudinal data, exploration of bias introduced through linkage error, and a robust toolkit to evaluate policies and programs using 'natural experiments'. Priorities for workforce development include broadening the skills base of the existing research workforce, and the formation of new, larger, interdisciplinary research teams to incorporate capabilities in computer science, partnership research, research translation and the 'business' aspects of research. Large-scale, long-term partnership approaches involving government, industry and researchers offer the most promising way to maximise returns on investment in research using routinely collected data. PMID- 26536503 TI - Unleashing the power of administrative health data: the Scottish model. AB - Data and information generated through the provision and administration of health and social care provide potentially valuable untapped resources that can contribute to the development of effective and efficient services. We describe the Scottish system, which seeks to unleash, at scale, the power of administrative and health service data as part of the UK-wide Farr Institute of Health Informatics Research program. The 'Scottish model' balances current public attitudes and views around the use of administrative and health data for research purposes with researchers' data requirements, and does so within Scotland's legal framework. The past 3 years has seen the completion of more than 150 projects by researchers from industry (17%), academia (53%) and health service providers (30%). In the future, the aim will be to ensure that research findings are disseminated widely and used to both improve health service provision and further develop public trust. PMID- 26536504 TI - A feasibility study using geographic access to general practices and routinely collected data in public health and health services research. AB - BACKGROUND: Advances in geographic information systems (GIS) and increased availability of routinely collected data have the potential to contribute to public health and health services research. The aim of this feasibility study was to explore the use of GIS to measure access to general practices and its relationship to selected antenatal behaviours. METHODS: We obtained the Perinatal Data Collection, 2004-2008, for South Western Sydney Local Health District from the New South Wales Ministry of Health. Using a GIS, we generated circular and polygon-based 1 km and 2 km road network buffers from a maternal residential address and then calculated the number of general practices within those buffers (density measures). Distances to general practices from maternal residences were also calculated in the GIS as another measure of geographic access to general practices (proximity measures). We used generalised estimating equations logistic regression to examine associations between access to general practices, and smoking during pregnancy and late first antenatal visit. RESULTS: The numbers of general practices within circular buffers were significantly greater than within polygon-based road network buffers. The average distance to the five closest general practices from a mother's residence was 2.3 km +/- 3.0 km (median 1.4 km, range 0.05 km to 40.0 km). For two of the five measures of access, a higher number of general practices was associated with increased risk for late first antenatal visit. However, the associations were weak, with odds ratios very close to unity. Choice of metrics of geographic access to general practices did not alter the associations with smoking during pregnancy or late first antenatal visit. CONCLUSION: GIS can be used to quantify measures of geographic access to health services for public health and health services research. Geographic access to general practices was generally not associated with smoking during pregnancy or late first antenatal visit. GIS and routinely collected health data can be used to answer novel questions in public health and health services research. PMID- 26536505 TI - Medicare Benefits Schedule data to monitor influenza immunisation in Australian adults. AB - INTRODUCTION: In Australia, adult immunisation coverage is primarily monitored via periodic telephone surveys that rely on self-reported immunisation status. All Australian residents are eligible for Medicare, so we examined the feasibility of using immunisation-specific Medicare Benefits Schedule (MBS) item numbers to monitor and estimate adult influenza immunisation coverage. METHODS: Baseline questionnaire data from 267 129 participants from the 45 and Up Study, a prospective cohort study, were linked to data containing information on individual MBS immunisation-specific items from 2006 to 2011. Temporal trends in recording of these items were examined. Self-reported influenza immunisation status obtained from a follow-up questionnaire from 27 036 participants was then compared with the MBS immunisation records. RESULTS: From 2006 to 2011, the pattern of MBS immunisation claims was consistent with self-reported influenza immunisation trends, with annual peaks occurring from March to May. There was fair agreement between MBS immunisation records and self-reported influenza immunisation: 48.8% (95% CI 47.1, 50.4) of participants who self-reported influenza immunisation had a matching MBS record, and 79.6% (95% CI 78.8, 80.4) who reported never having influenza immunisation had no matching MBS record. However, compared with self-reported influenza vaccination for people aged >=65 years from the 2009 Adult Immunisation Telephone Survey (74.6%), the proportion of participants aged >65 years with an MBS immunisation record was low, with an annual median of 39.3% (range 28.3%-62.1%). CONCLUSION: MBS immunisation item data are readily available and may be useful to monitor trends in adult influenza immunisation, but they are likely to substantially underestimate coverage. Other approaches, such as capture of general practitioner-delivered influenza vaccine doses or a whole-of-life immunisation register, are needed to comprehensively monitor and estimate adult immunisation coverage for influenza and other recommended adult vaccines. PMID- 26536506 TI - Ascertaining severe perineal trauma and associated risk factors by comparing birth data with multiple sources. AB - OBJECTIVES: Population data are often used to monitor severe perineal trauma trends and investigate risk factors. Within New South Wales (NSW), two different datasets can be used, the Perinatal Data Collection ('birth' data) or a linked dataset combining birth data with the Admitted Patient Data Collection ('hospital' data). Severe perineal trauma can be ascertained by birth data alone, or by hospital International Classification of Diseases Australian Modification (ICD-10-AM) diagnosis and procedure coding in the linked dataset. The aim of this study was to compare rates and risk factors for severe perineal trauma using birth data alone versus using linked data. METHODS: The study population consisted of all vaginal births in NSW between 2001 and 2011. Perineal injury coding in birth data was revised in 2006, so data were analysed separately for 2001-06 and 2006-11. Rates of severe perineal injury over time were compared in birth data alone versus linked data. Kappa and agreement statistics were calculated. Risk factor distributions (maternal age, primiparity, instrumental birth, birthweight >=4 kg, Asian country of birth and episiotomy) were compared between women with severe perineal trauma identified by birth data alone, and those identified by linked data. Multivariable logistic regression was used to calculate the adjusted odds ratios (aORs) of severe perineal trauma. RESULTS: Among 697 202 women with vaginal births, 2.1% were identified with severe perineal trauma by birth data alone, and 2.6% by linked data. The rate discrepancy was higher among earlier data (1.7% for birth data, 2.4% for linked data). Kappa for earlier data was 0.78 (95% CI 0.78, 0.79), and 0.89 (95% CI 0.89, 0.89) for more recent data. With the exception of episiotomy, differences in risk factor distributions were small, with similar aORs. The aOR of severe perineal trauma for episiotomy was higher using linked data (1.33, 95% CI 1.27, 1.40) compared with birth data (1.02, 95% CI 0.97, 1.08). CONCLUSIONS: Although discrepancies in ascertainment of severe perineal trauma improved after revision of birth data coding in 2006, higher ascertainment by linked data was still evident for recent data. There were also higher risk estimates of severe perineal trauma with episiotomy by linked data than by birth data. PMID- 26536507 TI - Comprehensive sector-wide strategies to prevent and control obesity: what are the potential health and broader societal benefits? A case study from Australia. AB - AIM: Several countries have recently established multistakeholder strategies to prevent or control overweight and obesity; however, studies have not yet been done on their effectiveness and likely impact. This study's objectives were to (i) explore sector-wide benefits and impacts likely to accrue from implementing an obesity prevention strategy in the Australian state of New South Wales; (ii) discuss the wider implications of the findings for research and practice; and (iii) strengthen the case for sustained implementation of a comprehensive, intersectoral approach. METHOD: A case study approach, including evidence reviews and illustrative epidemiological models, was used to show potential benefits from meeting selected targets and objectives specified in the strategy. RESULTS: For adults, improved health outcomes potentially include reductions in all-cause mortality, cardiovascular disease, type 2 diabetes, various cancers, osteoarthritis, infant mortality and healthcare costs. Potential benefits beyond the health sector involve disability payments, absenteeism, worker productivity, workplace injuries and insurance claims. For children and adolescents, improved health outcomes potentially include metabolic risk factors, dental health, prehypertension/hypertension, cardiovascular disease risk factors, depression, rates of mortality in hospitalised children, bullying and otitis media. CONCLUSION: Sector-wide health, social and economic benefits from successful implementation of multisector obesity prevention strategies are likely to be substantial if specified targets are achieved. Epidemiological modelling described in this paper for selected examples provides illustrative rather than comprehensive evidence for potential benefits. Process evaluation of the extent of implementation of these multisectoral strategies, together with the accumulated data on intervention effectiveness, will determine their potential population health benefit. Quantifying the health and social benefits that are likely to accrue if comprehensive sector-wide obesity prevention and control strategies are established can strengthen advocacy for their sustained implementation. PMID- 26536508 TI - Using Australian Pharmaceutical Benefits Scheme data for pharmacoepidemiological research: challenges and approaches. AB - The Pharmaceutical Benefits Scheme (PBS) dataset provides detailed information about subsidised medicines dispensed in Australia and is increasingly used for pharmacoepidemiological research. Use of the PBS dataset provides unique opportunities for such research, but comes with its own set of challenges that must be considered and addressed. This paper outlines some issues that commonly arise when using PBS data - relating to accurate identification of medicine dispensings and how to define medicine exposure - and suggests some possible approaches for dealing with them. The paper is intended as an introductory resource for researchers. PMID- 26536509 TI - Outbreak-related Hendra virus infection in a NSW pet dog. AB - Hendra virus (HeV) infection is a zoonosis of importance in Australia. An outbreak of HeV occurred on the mid-north coast region of New South Wales (NSW) in June and July 2013. Four unvaccinated horses on four separate properties were confirmed to have HeV infection. A pet dog that had close contact with one of the horses was also confirmed to be infected with HeV. This paper documents the response to the canine infection and the resulting change to the public health management of HeV infection. PMID- 26536510 TI - Linkage of routinely collected data in practice: the Centre for Health Record Linkage. PMID- 26536511 TI - A New Minister for Cities and Built Environment welcomed. PMID- 26536512 TI - Tech teams harness data to win innovation awards. PMID- 26536513 TI - NSW to create whole-of-government data centre. PMID- 26536514 TI - Dr. Lewis' 10-Year Audit. AB - Kaufman pediatrician Charles Turner Lewis, MD, battled fraud allegations levied against him by the Office of Inspector General (OIG) from 2005 to 2008 and emerged victorious. To his dismay, he is once again on the receiving end of an OIG letter alleging Medicaid overpayment. The 2015 Texas Legislature responded to TMA's call for improvements in OIG Medicaid fraud investigations of physicians with passage of Senate Bill 207. Organized medicine hopes the law's safeguards will afford due process to doctors under investigation. PMID- 26536515 TI - Texas Medical Schools Beef Up Nutrition Education. AB - With lifestyle-related diseases on the rise, some medical schools help to arm future doctors with the nutrition knowledge they'll need. Texas medical schools and residency programs are getting ahead of the curve in addressing this public health-meets-medical-education issue, with medical students often leading the charge. PMID- 26536516 TI - Foot Soldiers. AB - Fifteen Texas physicians participate in Walk With a Doc, a fitness program that fosters relationships among physicians and their patients. Given the program's initial success, the Texas Medical Association is looking to expand it. PMID- 26536517 TI - Creating Leaders. AB - Participants in the Texas Medical Association's Accountable Care Leadership Program learn about communication skills, teamwork, and population health management. The program helps physicians adapt in a rapidly changing environment that demands more accountability and proof of value for the health care dollar. The program targets early- to mid-career practicing physicians who recognize they need new tools to survive and thrive in the new environment. PMID- 26536518 TI - Border Battle. AB - The Texas Medical Association, the Texas Alliance for Patient Access, and other organizations ask for reversal of a court ruling that allows a Texas negligence case to proceed in New Mexico. The case is sounding alarms all over Texas' medical community, conjuring fears that if the Supreme Court upholds the application of New Mexico law, it could have a significant impact on Texas doctors who operate near the state's vast borders and treat out-of-state patients. PMID- 26536519 TI - Mitigation of Adverse Clinical Events of a Narrow Target Therapeutic Index Compound through Modified Release Formulation Design: An in Vitro, in Vivo, in Silico, and Clinical Pharmacokinetic Analysis. AB - BMS-914392 is a tricyclic pyranoquinoline BCS class 2 weak base that demonstrates high solubility in low pH environments. Initial clinical studies indicated that rapid release of high dose BMS-914392 led to transient adverse events associated with peak plasma concentrations. A modified release (MR) formulation strategy was proposed to suppress the peak blood concentration and maintain total exposure to overcome the adverse effects. Three modified release prototype formulations were developed and tested via a USP 3 dissolution method to verify that each formulation can effectively slow the release of BMS-914392. A pharmacokinetic (PK) absorption model was employed to guide the formulation development and selection. Simulations showed good agreement with plasma levels measured after oral dosing in dogs. Identification of key formulation factors to achieve release rates suitable for blunting peak blood levels without diminishing exposure were achieved through combined preclinical data and use of GastroPlus simulations. PK absorption model refinements based on phase 1 data, dog pharmacokinetic results, and in vitro data provided reliable predictions of human absorption profiles and variability in patients. All three prototype formulations demonstrated lower maximum plasma concentrations of BMS-914392 and maintained satisfactory relative bioavailability. Both the PK absorption model and subsequent clinical data indicated that an acidified hydrophilic matrix MR formulation had the greatest potential to reduce the incidence of adverse events and showed the best exposure profile in fasted state healthy subjects with and without famotidine coadministration. The risk based development process achieved successful screening and selection of a suitable modified release formulation to enable clinical efficacy trials. PMID- 26536520 TI - Patients electing medical vs surgical treatment: emotional domain of the Rhinosinusitis Disability Index associates with treatment selection. AB - BACKGROUND: The Rhinosinusitis Disability Index (RSDI) consists of multiple subdomains shown to be useful in studying chronic rhinosinusitis (CRS). The objective of this study was to determine if RSDI subdomain scores are associated with selection of treatment modality (endoscopic sinus surgery [ESS] or continued medical management [CMM]) in subjects with CRS. METHODS: Patients with CRS were prospectively enrolled into a multi-institutional cohort study. Following an initial period of medical management, patients elected to undergo treatment with either ESS or CMM. Baseline RSDI total and subdomain scores were compared between patients electing different treatment modalities. RESULTS: A total of 684 subjects were enrolled with 122 (17.8%) electing CMM and 562 (82.2%) electing ESS. When compared to patients undergoing CMM, patients electing ESS exhibited significantly higher mean baseline RSDI total scores (mean +/- standard deviation [SD]: 48.1 +/- 24.9 vs 40.1 +/- 24.1; p = 0.001) and subdomain scores (emotional: 13.2 +/- 9.1 vs 10.4 +/- 8.3; p = 0.001; functional: 15.3 +/- 8.9 vs 12.6 +/- 8.4; p = 0.002; and physical: 19.6 +/- 9.3 vs 17.1 +/- 9.6; p = 0.007). Emotional subdomain scores were found to be the most associated with choice of treatment modality. CONCLUSION: Patients with CRS electing ESS had worse baseline RSDI total and subdomain scores compared to those electing CMM. Although both rhinologic and nonrhinologic symptoms contributed to the selection of treatment modality, emotional symptoms appeared to exhibit the greatest influence on patient-centered treatment decisions. PMID- 26536521 TI - Why a GME Squeeze Is Unlikely. PMID- 26536522 TI - 'Troubling' moments in health promotion: unpacking the ethics of empowerment. AB - ISSUE ADDRESSED: Concepts of empowerment feature strongly in global health discourses. Empowerment is frequently advocated as a positive approach to addressing individual and community-level health needs. Despite its popularity, relatively little has been said about the unintended consequences of empowerment, which may give rise to some troubling ethical issues or, indeed, result in outcomes that may not be considered health promoting. METHODS: Drawing on current uses of empowerment within health promotion, along with insights from an ethnographic study on young people's health, this paper raises some critical questions about the ethics of empowerment. By doing so, the paper troubles the idea that empowerment is a 'good thing' without some careful attention to the varying ways in which the ethics of empowerment may unfold in practice. RESULTS: Findings revealed young people's different perspectives on health and priorities for health promotion. The present analysis highlights how these alternative framings prompt a number of ethical tensions for understanding and operationalising empowerment. CONCLUSIONS: In conclusion, the findings underscore the importance of promoting ethical reflexivity in health promotion and, crucially, attending to the unintended and potentially ethically problematic consequences of empowerment. So what? This paper raises some critical questions about the ethics of empowerment and calls for a more thorough engagement with the unintended consequences of empowerment within health promotion. PMID- 26536523 TI - Parietal damage impairs learning of a visuomotor tracking skill. AB - This study evaluated the consequences of damage to the parietal lobe for learning a visuomotor tracking skill. Thirty subjects with a single unilateral brain lesion (13 with and 17 without parietal damage) and 23 demographically comparable healthy subjects performed the Rotary Pursuit task. For each group, time on target increased significantly across the four learning blocks. Subjects with parietal lesions had smaller improvements on the Rotary Pursuit from the 1st to the 4th block than subjects with lesions in other brain areas and healthy comparison subjects. The improvements on task performance from the 1st to the 2nd and from the 1st to the 3rd learning blocks were similar between groups. The parietal lobe appears to play an important role in the acquisition of a new visuomotor tracking skill, in particular during a relatively late phase of learning. PMID- 26536524 TI - The role of multimodality imaging in the selection of patients for aortic valve repair. AB - Aortic valve sparing surgery for aortic regurgitation and/or aortopathy serves as an alternative to aortic valve and root replacement. One of the advantages of aortic valve sparing surgery over conventional replacement is that there is no need for life-long anticoagulation, which is particularly attractive in young patients who may receive a mechanical prosthesis otherwise. However, successful aortic valve repair requires high expertise. At present, reparability is determined intraoperatively by direct surgical inspection. Preoperative imaging techniques might improve the patient selection for aortic valve repair. The mechanism of aortic regurgitation, aortic valve morphology and calcification and aortic root dimensions are all of importance when aortic valve repair is considered. The present review focuses on the role of imaging techniques in determining aortic valve reparability. PMID- 26536525 TI - Smoke signals: New reports reflect "staggering" increases in youth e-cigarette usage. PMID- 26536526 TI - Treatment improves for localized prostate cancer. PMID- 26536527 TI - US colorectal cancer death rates decline except in 3 geographic "hot spots". PMID- 26536528 TI - Disc-shaped polyoxyethylene glycol glycerides gel nanoparticles as novel protein delivery vehicles. AB - Disc-shaped nanoparticles with high aspect ratios have been reported to show preferential cellular uptake in vitro by mammalian cells. However, engineering and producing such disc-shaped nanoparticles are often complex. This study reports for the first time the use of a single, approved pharmaceutical excipient to prepare stable disc-shaped nanoparticles with a high aspect ratio via a simple, organic solvent free process. These disc-shaped nanoparticles were formed by fragmentation of stearoyl macrogol-32 glycerides (Gelucire 50/13) hydrogels. The nanoparticles showed good physical stability as a result of their outer coating of polyethylene glycol (PEG) that is a part of Gelucire composition. Using lysozyme as a model hydrophilic protein, these nanoparticles demonstrated a good loading capacity for hydrophilic macromolecules, mainly via surface adsorption. As a result of the higher hydrophobicity of the core of the nano discs, the loading efficiency of hydrophobic model components, such as Coumarin 6, was significantly increased in comparison to the model hydrophilic compound. These Gelucire nano-discs exhibited no cytotoxicity at the tested level of 600MUg/ml for Caco-2 cells. Rapid in vitro cellular uptake of the disc-shaped nanoparticles by Caco-2 cells was observed. This rapid internalisation was attributed to the high aspect ratio of the disc-shape nanoparticles which provides a high contact surface area between the particles and cells and may lower the strain energy required for membrane deformation during uptake. The results of this study demonstrate the promising potential of Gelucire nano-discs as effective nanocarriers for drug delivery and which can be manufactured using a simple solvent-free process. PMID- 26536529 TI - Twin screw wet granulation: Effect of process and formulation variables on powder caking during production. AB - This work focuses on monitoring the behaviour and the mass of the built up/caking of powder during wet granulation using Twin Screw Granulator (TSG). The variables changed during this work are; powder (alpha-lactose monohydrate and microcrystalline cellulose (MCC)), the screw configuration (conveying and kneading elements) and the weight percentage of hydroxypropyl-methyl cellulose (HPMC) dissolved in the granulation liquid (i.e. changing liquid viscosity). Additionally, the effect of these variables on the size distribution, of the granules produced, was determined. The experiments were conducted using an acrylic transparent barrel. A stainless steel barrel was then used to conduct the two extreme granulation liquid viscosities with two different screw configurations, using lactose only. This was done to compare the findings to those obtained from the transparent barrel for validation purpose. These variables showed to affect the behaviour and the mass of the powder caking as well as the size distribution of granules. Overall, the use of kneading element resulted in uniform behaviour in caking with higher mass. Furthermore, increasing the amount of HPMC resulted in a reduction of the mass of powder caking for lactose, while showing inconsistent trend for MCC. Furthermore, lactose showed to have a greater tendency to cake in comparison to MCC. The results, for lactose, obtained from the stainless steel barrel compared well with their corresponding conditions from the transparent barrel, as the screw configuration and HPMC mass varied. PMID- 26536530 TI - Starch-free grewia gum matrices: Compaction, swelling, erosion and drug release behaviour. AB - Polysaccharides are suitable for application as hydrophilic matrices because of their ability to hydrate and swell upon contact with fluids, forming a gel layer which controls drug release. When extracted from plants, polysaccharides often contain significant quantities of starch that impacts upon their functional properties. This study aimed to evaluate differences in swelling, erosion and drug release from matrix tablets prepared from grewia gum (GG) and starch-free grewia gum (GDS) extracted from the stems of Grewia mollis. HPMC was used as a control polymer with theophylline as a model drug. Swelling, erosion, and in vitro release were performed in deionized water, pH 1.2 and pH 6.8 media. The Vergnaud and Krosmeyer-Peppas model were used for swelling and drug release kinetics, respectively. However, linear regression technique was used to determine the erosion rate. GDS compacts were significantly harder than the native GG and HPMC compacts. GDS matrices exhibited the fastest erosion and drug release in deionised water and phosphate buffer compared with the GG and HPMC. At pH 1.2, GDS exhibited greater swelling than erosion, and drug release was similar to GG and HPMC. This highlights the potential of GDS as a matrix for controlled release similar to HPMC and GG at pH 1.2 but with a more rapid release at pH 6.8. GDS may have wider application in reinforcing compacts with relatively low mechanical strength. PMID- 26536531 TI - Functional stability of 3D8 scFv, a nucleic acid-hydrolyzing single chain antibody, under different biochemical and physical conditions. AB - 3D8 single-chain Fv (scFv) is a catalytic nucleic acid antibody with anti-viral activity against a broad spectrum of viruses. Here we investigated the functional stability of 3D8 scFv to provide a basis for engineering a 3D8 scFv derivative and for developing stable formulations with improved stability and potential use as an anti-viral agent. The stability of 3D8 scFv was assessed by measuring its DNA-hydrolyzing activity under different biochemical and physical conditions using a fluorescence resonance energy transfer (FRET)-based method. In addition, the anti-influenza (H9N2) effect of 3D8 scFv was evaluated in A549 cells. 3D8 scFv was stable at 50 degrees C for 6h at pH 7.2, for 3 days at pH 4-10 at 37 degrees C and 30 days at pH 4-8 at 37 degrees C. The stability was not affected by a reducing condition, freeze-thawing for up to 30 cycles, or lyophilization. Evaluation of the anti-virus effect showed that cells treated with 32-128 units of 3D8 scFv showed a 50% decrease in influenza replication compared to untreated cells. Based on its enzymatic stability in various biochemical and physical environments, 3D8 scFv holds good potential for development as an anti-viral therapeutic. PMID- 26536532 TI - Synthesis and biological evaluation of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives. AB - Research activities on the oxazolidinone antibacterial class of compounds continue to focus on developing newer derivatives with improved potency, broad spectrum activity and safety profiles superior to linezolid. Among the safety concerns with the oxazolidinone antibacterial agents is inhibition of monoamine oxidases (MAO) resulting from their structural similarity with toloxatone, a known MAO inhibitor. Diverse substitution patterns at the C-5 position of the oxazolidinone ring have been shown to significantly affect both antibacterial activity and MAO inhibition to varying degrees. Also, the antibacterial activity of compounds containing iron-chelating functionalities, such as the hydroxamic acids, 8-hydroxyquinolines and catechols have been correlated to their ability to alter iron intake and/or metabolism. Hence a series of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives were synthesized and evaluated for their antibacterial and MAO-A and -B inhibitory activities. The compounds were devoid of significant antibacterial activity but most demonstrated moderate MAO-A and -B inhibitory activities. Computer modeling studies revealed that the lack of potent antibacterial activity was due to significant steric interaction between the hydroxamic acid N-OH oxygen atom and one of the G2540 5'-phosphate oxygen atoms at the bacterial ribosomal binding site. Therefore, the replacement of the 5 acetamidomethyl group of linezolid with the 5-(N-hydroxyacetamido)methyl group present in the hydroxamic acid oxazolidinone derivatives was concluded to be detrimental to antibacterial activity. Furthermore, the 5-(hydroxamic acid)methyl oxazolidinone derivatives were also less active as MAO-A and -B inhibitors compared with linezolid and the selective inhibitors clorgyline and pargyline. In general, the 5-(hydroxamic acid)methyl oxazolidinone derivatives demonstrated moderate but selective MAO-B inhibitory activity. PMID- 26536533 TI - Access to Surgical Care in Developing Countries. PMID- 26536534 TI - Synergistic Strain Engineering Effect of Hybrid Plasmonic, Catalytic, and Magnetic Core-Shell Nanocrystals. AB - Hybrid core-shell nanocrystals, consisting of distinct components, represent an emerging functional material system, which could facilitate synergistic coupling effects via integrating drastically different functionalities. Here we report a unique strain engineering effect induced by phase transformation between plasmonic core and magnetic shell materials, which leads to a facile surface reconstruction of bimetallic core-shell nanocrystals to enhance their synergistic magnetic and catalytic properties. This advancement dramatically results in two orders of magnitude enhancement in magnetic coercivity and significant improvement in catalytic activity. Mechanistic studies involving the kinetic measurement and theoretical modeling uncover a structural distortion and surface rearrangement mechanism during the core-shell phase transformation pathway. This facile methodology could potentially open up the new design of multifunctional artificial hybrid nanostructures by the combination of phase transformation and surface engineering for emerging technological applications. PMID- 26536535 TI - Acoustic Characterization of Axial Flow Left Ventricular Assist Device Operation In Vitro and In Vivo. AB - The use of left ventricular assist devices (LVADs), implantable pumps used to supplement cardiac output, has become an increasingly common and effective treatment for advanced heart failure. Although modern continuous-flow LVADs improve quality of life and survival more than medical management of heart failure, device malfunction remains a common concern. Improved noninvasive methods for assessment of LVAD function are needed to detect device complications. An electronic stethoscope was used to record sounds from the HeartMate II axial flow pump in vitro and in vivo. The data were then uploaded to a computer and analyzed using two types of acoustic analysis software. Left ventricular assist device acoustics were quantified and were related to pump speed, acoustic environment, and inflow and outflow graft patency. Peak frequency values measured in vivo were found to correlate strongly with both predicted values and in vitro measurements (r > 0.999). Plots of the area under the acoustic spectrum curve, obtained by integrating over 50 Hz increments, showed strong correlations between in vivo and in vitro measurements (r > 0.966). Device thrombosis was found to be associated with reduced LVAD acoustic amplitude in two patients who underwent surgical device exchange. PMID- 26536536 TI - Effects of Osmotic Changes on Measuring Relative Blood Volume: Comparison of Three Hemodialysis Devices. AB - Recording the relative blood volume is a standard feature of modern dialysis devices. Three different measurement systems are incorporated in currently available dialysis machines. The Gambro-Hospal group and Nikkiso feature blood volume monitors based on different optical methods. The Fresenius Medical Care machines perform blood volume monitoring with an ultrasonic method. On grounds of clinical evidence suggesting a malfunction of the optical methods in the presence of sodium changes, we compared these three systems. Under the tested conditions, both optical systems show opposite and nonplausible courses of blood volume changes. The ultrasonic system seems to be less susceptible to osmotic changes. PMID- 26536537 TI - Heart Procurement from a Donor on Venovenous ECMO Support. AB - We report the case of a 37-year-old woman with acute respiratory distress syndrome and became a candidate for organ donation after anoxic brain injury and was on a venovenous extracorporeal membrane oxygenation (VV-ECMO) support. On preoperative evaluation and gross examination, the donor's heart was acceptable for heart transplantation to a 62-year-old female patient with a history of nonischemic cardiomyopathy with a HeartMate II mechanical assist device. Orthotopic heart transplantation was successfully performed in the recipient. We report a case that suggests that the procurement of a heart from a donor on ECMO support can potentially expand the donor heart pool in carefully selected patients. PMID- 26536538 TI - Quantification of training load during one-, two- and three-game week schedules in professional soccer players from the English Premier League: implications for carbohydrate periodisation. AB - Muscle glycogen is the predominant energy source for soccer match play, though its importance for soccer training (where lower loads are observed) is not well known. In an attempt to better inform carbohydrate (CHO) guidelines, we quantified training load in English Premier League soccer players (n = 12) during a one-, two- and three-game week schedule (weekly training frequency was four, four and two, respectively). In a one-game week, training load was progressively reduced (P < 0.05) in 3 days prior to match day (total distance = 5223 +/- 406, 3097 +/- 149 and 2912 +/- 192 m for day 1, 2 and 3, respectively). Whilst daily training load and periodisation was similar in the one- and two-game weeks, total accumulative distance (inclusive of both match and training load) was higher in a two-game week (32.5 +/- 4.1 km) versus one-game week (25.9 +/- 2 km). In contrast, daily training total distance was lower in the three-game week (2422 +/ 251 m) versus the one- and two-game weeks, though accumulative weekly distance was highest in this week (35.5 +/- 2.4 km) and more time (P < 0.05) was spent in speed zones >14.4 km . h(-1) (14%, 18% and 23% in the one-, two- and three-game weeks, respectively). Considering that high CHO availability improves physical match performance but high CHO availability attenuates molecular pathways regulating training adaptation (especially considering the low daily customary loads reported here, e.g., 3-5 km per day), we suggest daily CHO intake should be periodised according to weekly training and match schedules. PMID- 26536539 TI - The Use of CO2 Fractional Photothermolysis for the Treatment of Burn Scars. AB - A recent advancement in the treatment of burn scars has been the use of the carbon dioxide (CO2) laser to perform fractional photothermolysis. In this analysis, we describe our results and patient-reported outcomes with the use of fractional CO2 laser for the treatment of burn-related scarring. We performed a retrospective study of all patients who underwent CO2 laser procedures for treatment of symptomatic burn scars and skin grafts at one accredited regional burn center. Burn injury and laser treatment demographics, as well as complications, are reported. A questionnaire was administered to all patients and included patient-reported outcome measures aimed at understanding the patient experience and their subjective response to treatment. A total of 387 CO2 laser procedures were performed on 131 patients for the treatment of symptomatic burn scars and skin grafts between October 1, 2011, and May 1, 2014 (average, 2.95 procedures/patient; range, 1-11). Average time between injury and first laser was 597.35 days (range, 60-13,475). Average time between laser treatments (when multiple) was 117.73 days (range, 22-514). There were no infections requiring treatment with oral antibiotics. Overall patient satisfaction with laser therapy was 96.7%. Patients reported reductions in neuropathic pain, tightness (contracture), and pruritus (54.0, 50.6, and 49.0%, respectively). Fractional photothermolysis utilizing the CO2 laser is a safe and effective modality for the treatment of symptomatic burn scars, donor sites, and skin grafts. Patient satisfaction with this procedure is high, and complications are low. Significant improvements in scar appearance, pliability, tightness, neuropathic pain, and pruritus were commonly reported. PMID- 26536540 TI - The Hennepin Score: Quantification of Frostbite Management Efficacy. AB - For those at risk for cold-related injury, frostbite contributes significant morbidity through loss of limbs and digits. Frostbite injury generally affects distal extremities first and spreads proximally as the time of exposure increases. The Hennepin score is a tool to quantify injury and tissue loss of frostbite injury, similar to TBSA calculators in burn patients. Application of the Hennepin score allows for a clear picture of the effect of treatment through calculation of a salvage rate. The authors found high reliability between raters using the Hennepin score worksheet, suggesting consistency with applying the score to frostbite injury and outcomes (intraclass correlation, 0.93; confidence interval, 0.88-0.97). The Hennepin score allows for a standard means to accurately measure injury and outcomes, which will aid in the study of treatment outcomes of frostbite injuries. PMID- 26536541 TI - A Retrospective Analysis of Clinical Laboratory Interferences Caused by Frequently Administered Medications in Burn Patients. AB - The goal of this study is to quantify the number of medications administered to burn patients and identify potential drugs interfering with laboratory testing. The authors reviewed the medical records of 12 adult (age >= 18 years) burn patients with more than 20% TBSA burns from an existing glucose control database at our institution. Dose, interval, and route of medications administered from admission to discontinuation of intensive insulin therapy were recorded. Interfering drugs were identified based on established clinical chemistry literature. The retrospective cohort of adult burn patients exhibited a mean (SD) age of 37.9 (3.0) years. Mean TBSA burn was 51.3 (9.3)%. Disease severity determined by the average multiple organ dysfunction score was 5.4 (0.2). Mean and median medications administered per day were 42.1 (9.5) and 49 (with a daily range of 0-65), respectively. A total of 666 potential laboratory test interferences caused by medications were identified. There were 261 different effects (eg, increased glucose, decreased potassium). Multiple interferences, 71.0% (475/666), were caused by more than one medication. Investigation of the number of medications administered to a burn patient and delineation of potential laboratory test interferences has not been conducted in burn patients. Given the substantial number of medications administered to burn patients, physicians and laboratory personnel should work together to identify potential interferences and define appropriate countermeasures while enhancing the laboratorians understanding of this unique population. This synergistic partnership can lead to intelligent support tools and potentially autocorrecting instruments. PMID- 26536542 TI - Intracarotid Etomidate Decreases the Interhemispheric Synchronization in Electroencephalogram (EEG) During the Wada Test. AB - BACKGROUND: The Wada test is a diagnostic method to anesthetize 1 cerebral hemisphere and assess the language and memory functions of awake contralateral hemisphere before temporal lobectomy in patients with epilepsy. The effects of an ipsilateral injection of etomidate on the functional properties of contralateral hemisphere are not known. Our aim was to characterize the electroencephalographic (EEG) effects after intracarotid injection of etomidate and to determine the changes in synchronization between the ipsilateral and contralateral hemispheres. MATERIALS AND METHODS: We retrospectively analyzed EEG data from 15 patients who underwent Wada test with etomidate. Continuous EEG data from 4 electrodes (2 anterior [F3, F4] and 2 posterior [P3, P4]) were analyzed. After artifact rejection, we measured the amplitudes of delta (1 to 4 Hz) and alpha (7 to 13 Hz) waves and the changes in the interhemispheric synchronization before, during, and after etomidate injection. RESULTS: Ipsilateral injection of etomidate causes EEG changes in both hemispheres with increased amplitude of delta waves anteriorly and the alpha waves posteriorly. However this effect of etomidate is not uniform. Although there was a decrease in the interhemispheric synchronization of delta waves, there was no change in the synchronization of the alpha waves. CONCLUSIONS: Our study showed that the EEG effects of intracarotid ipsilateral injection of etomidate is not uniform in both hemispheres. Decrease in the interhemispheric synchronization of delta waves might serve as an indicator of ipsilateral effect of etomidate on the brain. Additional studies are needed to confirm our findings. PMID- 26536543 TI - ILMA as an Alternative to Face Mask Ventilation in a Case of Nasal Chondrosarcoma. PMID- 26536544 TI - Mirror Image Acute Subdural Hematoma Complicating Preexisting Bilateral Chronic Subdural Hematoma After Spinal Anesthesia. PMID- 26536545 TI - A Novel Method to Identify the Start and End of the Winter Surge in Demand for Pediatric Intensive Care in Real Time. AB - OBJECTIVE: Implementation of winter surge management in intensive care is hampered by the annual variability in the start and duration of the winter surge. We aimed to develop a real-time monitoring system that could identify the start promptly and accurately predict the end of the winter surge in a pediatric intensive care setting. DESIGN: We adapted a method from the stock market called "Bollinger bands" to compare current levels of demand for pediatric intensive care services to thresholds based on medium-term average demand. Algorithms to identify the start and end of the surge were developed using Bollinger bands and pragmatic considerations. The method was applied to a specific pediatric intensive care service: the North Thames Children's Acute Transport Service using eight winters of data (2005-2012) to tune the algorithms and one winter to test the final method (2013/2014). SETTING: A regional specialized pediatric retrieval service based in London, United Kingdom. MEASUREMENTS AND MAIN RESULTS: The optimal Bollinger band thresholds were 1.2 and 1 SDs above and below a 41-day moving average of demand, respectively. A simple linear model was found to predict the end of the surge and overall surge demand volume as soon as the start had been identified. Applying the method to the validation winter of 2013/2014 showed excellent performance, with the surge identified from November 18, 2013, to January 4, 2014. CONCLUSIONS: We have developed and tested a novel method to identify the start and predict the end of the winter surge in emergency demand for pediatric intensive care. PMID- 26536546 TI - Association Between Extracorporeal Membrane Oxygenation Center Volume and Mortality Among Children With Heart Disease: Propensity and Risk Modeling. AB - OBJECTIVES: To evaluate the relationship between extracorporeal membrane oxygenation center volume and mortality in children undergoing heart operations using propensity score matching in a multiinstitutional cohort. DESIGN: Post hoc analysis of data from an existing national database, Pediatric Health Information System. Propensity score matching was performed to 1-1-1 match patients in low volume (0-30 cases per year), medium-volume (31-50 cases per year), and high volume (> 50 cases per year) categories. We tested the sensitivity of our findings by repeating the primary analyses using traditional statistical techniques (traditional regression-based methods and covariate adjustment using propensity score). SETTING: Forty-two children's hospitals across the Unites States. PATIENTS: Patients 18 years old or younger receiving extracorporeal membrane oxygenation before or after pediatric heart operation at a Pediatric Health Information System participating hospital (2004-2013) were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 3,502 from 42 hospitals qualified for inclusion. Using propensity score matching, 1,962 patients were matched 1-1-1 to compare the three volume categories (654 patients in each category). Overall mortality was 1,493 patients (43%). Before matching and adjustment, low- and medium-volume centers were associated with higher mortality (low versus high volume: unadjusted odds ratio, 1.99; 95% CI, 1.68 2.36; p < 0.001). After matching, there was no significant association between center volume and mortality in unadjusted and adjusted analyses (low versus high volume: unadjusted odds ratio, 1.06; 95% CI, 0.85-1.32; p = 0.62 and adjusted odds ratio, 0.97; 95% CI, 0.63-1.50; p = 0.90). This relationship remained similar for analyses using traditional statistical techniques (regression adjustment, low versus high volume: adjusted odds ratio, 1.23; 95% CI, 0.80-1.89; p = 0.35 and covariate adjustment using propensity score, low versus high volume: adjusted odds ratio, 1.16; 95% CI, 0.77-1.74; p = 0.49). CONCLUSIONS: We demonstrated no relationship between extracorporeal membrane oxygenation center volume and mortality. Further analyses are needed to evaluate this relationship. PMID- 26536547 TI - Family Involvement in PICU Rounds: Reality or Rhetoric? PMID- 26536548 TI - Treatment of Parental Post-Traumatic Stress Disorder After PICU Admission: Who, What, Where, When? PMID- 26536549 TI - Bereaved Parents' Decisions About Organ Donation: Known Knowns and Known Unknowns. PMID- 26536550 TI - A New Band in Town: A Novel Approach to Identify Seasonal Surge in the PICU. PMID- 26536551 TI - Gastrointestinal Complications in the PICU: Is Disease the Only Culprit? PMID- 26536552 TI - Failed Extubation in Cardiac Patients: Not Just Case-Mix and Beware of Slow Progression. PMID- 26536553 TI - Pediatric Index of Cardiac Surgical Intensive Care Mortality: A New Severity of Illness Score for Cardiac Surgical Patients in ICUs. PMID- 26536554 TI - Targeting Glycemic Control After Pediatric Cardiac Surgery. PMID- 26536555 TI - The Ventilator Is a Vasoactive. PMID- 26536556 TI - Do You Know How Much Is Delivered to Your Patient's Lungs? Accurate Measurement of Effective Tidal Volumes Should Be Standard of Care in Infants and Children. PMID- 26536557 TI - Looking for Tips on Central Venous Catheter Insertion? Try Ultrasound. PMID- 26536558 TI - Unplanned Expenses: Paying for Unplanned Extubations. PMID- 26536559 TI - The authors reply. PMID- 26536560 TI - Morbidity and Mortality Conferences in Pediatric Critical Care. PMID- 26536561 TI - The authors reply. PMID- 26536562 TI - Transport of the Newborn: Different Realities in the World. PMID- 26536563 TI - The authors reply. PMID- 26536564 TI - Unilateral or Bilateral, That's the Question. PMID- 26536565 TI - The authors reply. PMID- 26536566 TI - Using Time Series Analysis to Predict Cardiac Arrest in a PICU. AB - OBJECTIVES: To build and test cardiac arrest prediction models in a PICU, using time series analysis as input, and to measure changes in prediction accuracy attributable to different classes of time series data. DESIGN: Retrospective cohort study. SETTING: Thirty-one bed academic PICU that provides care for medical and general surgical (not congenital heart surgery) patients. SUBJECTS: Patients experiencing a cardiac arrest in the PICU and requiring external cardiac massage for at least 2 minutes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred three cases of cardiac arrest and 109 control cases were used to prepare a baseline dataset that consisted of 1,025 variables in four data classes: multivariate, raw time series, clinical calculations, and time series trend analysis. We trained 20 arrest prediction models using a matrix of five feature sets (combinations of data classes) with four modeling algorithms: linear regression, decision tree, neural network, and support vector machine. The reference model (multivariate data with regression algorithm) had an accuracy of 78% and 87% area under the receiver operating characteristic curve. The best model (multivariate + trend analysis data with support vector machine algorithm) had an accuracy of 94% and 98% area under the receiver operating characteristic curve. CONCLUSIONS: Cardiac arrest predictions based on a traditional model built with multivariate data and a regression algorithm misclassified cases 3.7 times more frequently than predictions that included time series trend analysis and built with a support vector machine algorithm. Although the final model lacks the specificity necessary for clinical application, we have demonstrated how information from time series data can be used to increase the accuracy of clinical prediction models. PMID- 26536567 TI - Corrigendum: Origins of power-law degree distribution in the heterogeneity of human activity in social networks. PMID- 26536569 TI - Hair regeneration using adipose-derived stem cells. AB - Adipose-derived stem cells (ASCs) have been used in tissue repair and regeneration. Recently, it was reported that ASC transplantation promotes hair growth in animal experiments, and a conditioned medium of ASCs (ASC-CM) induced the proliferation of hair-compositing cells in vitro. However, ASCs and their conditioned medium have shown limited effectiveness in clinical settings. ASC preconditioning is one strategy that can be used to enhance the efficacy of ASCs and ASC-CM. Therefore, we highlighted the functional role of ASCs in hair cycle progression and also the advantages and disadvantages of their application in hair regeneration. In addition, we introduced novel ASC preconditioning methods to enhance hair regeneration using ASC stimulators, such as vitamin C, platelet derived growth factor, hypoxia, and ultraviolet B. PMID- 26536570 TI - Fast fabrication of copper nanowire transparent electrodes by a high intensity pulsed light sintering technique in air. AB - Copper nanowire transparent electrodes have received increasing interest due to the low price and nearly equal electrical conductivity compared with other TEs based on silver nanowires and indium tin oxide (ITO). However, a post-treatment at high temperature in an inert atmosphere or a vacuum environment was necessary to improve the conductivity of Cu NW TEs due to the easy oxidation of copper in air atmosphere, which greatly cancelled out the low price advantage of Cu NWs. Here, a high intensity pulsed light technique was introduced to sinter and simultaneously deoxygenate these Cu NWs into a highly conductive network at room temperature in air. The strong light absorption capacity of Cu NWs enabled the welding of the nanowires at contact spots, as well as the removal of the thin layer of residual organic compounds, oxides and hydroxide of copper even in air. The Cu NW TE with a sheet resistance of 22.9 Ohm sq(-1) and a transparency of 81.8% at 550 nm has been successfully fabricated within only 6 milliseconds exposure treatment, which is superior to other films treated at high temperature in a hydrogen atmosphere. The HIPL process was simple, convenient and fast to fabricate easily oxidized Cu NW TEs in large scale in an air atmosphere, which will largely extend the application of cheap Cu NW TEs. PMID- 26536571 TI - Andrographolide Attenuates LPS-Induced Cardiac Malfunctions Through Inhibition of IkappaB Phosphorylation and Apoptosis in Mice. AB - BACKGROUND/AIMS: Cardiac malfunction is a common complication in sepsis and significantly increases the mortality of patients in septic shock. However, no studies have examined whether andrographolide (And) reduces LPS-induced myocardial malfunction. METHODS: Left ventricular systolic and diastolic functions were examined using echocardiography. TNF-alpha and IL-1beta protein levels were detected by an enzyme-linked immunosorbent assay (ELISA). NO oxidation products were determined using Griess reagent. Protein expression levels of inhibitors of NF-kappaBalpha (IkappaB) and phospho-IkappaB were determined via Western blot. Oxidative injury was determined by measuring myocardial lipid peroxidation and superoxide dismutase activity. Cardiac apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nickend-labeling (TUNEL) and cardiac caspase 3/7 activity. RESULTS: And blunted LPS-induced myocardial malfunctions in mice. LPS induced TNF-alpha, IL-1beta, and NO production as well as I-kappaB phosphorylation. Cardiac apoptosis was attenuated via incubation with And, but the extent of oxidative injury remained unaffected. CONCLUSION: And prevents LPS-induced cardiac malfunctions in mice by inhibiting TNF-alpha, IL-1beta, and NO production, IkappaB phosphorylation, and cardiac apoptosis, indicating that And may be a potential agent for preventing myocardial malfunction during sepsis. PMID- 26536572 TI - A portable device for recording evoked potentials, optimized for pattern ERG. AB - Recording evoked potentials in un-anesthetized animals and people is a powerful technique to non-invasively measure the function of neurons. As such, the primary output neurons of the eye can be assessed by the pattern electroretinogram (PERG). Currently, electro-physiologic setups to perform PERG or related recordings are costly, complicated, and non-portable. Here, we design a simple steady-state PERG system, based off an Arduino board. The amplifier is built on a shield that fits over a microcontroller board, an Arduino, which digitizes the signal and sends it to a computer that presents stimuli then records and analyzes the evoked potentials. We used the device to record PERG accurately with a sensitivity as low as half a microvolt. The device has also been designed to implement other evoked potential recordings. This simple device can be quickly constructed and used for experiments in moving systems. Additionally, this device can be used to expose students in underserved areas to research technology that they would otherwise not have access to. PMID- 26536573 TI - Disordered eating and body image issues and their associated factors among adolescents in urban secondary schools in Sarawak, Malaysia. AB - Eating disorders are common health issues among the adolescents. The objective of this study was to determine the prevalence of eating disorders and their relationship with body mass index, body part satisfaction and perception on body weight among urban secondary school children. It was a cross-sectional study conducted in Kuching, Sarawak. Data was collected using a self-administered questionnaire that consist of the Eating Attitude Test-26 (EAT-26), perception on body part satisfaction and body weight, and anthropometric measurement. Data was entered and analysed using SPSS version 22. A total of 329 respondents participated in this study with 59% females and 60.5% Malays. There were 14.3% of the respondents overweight and obese, with higher percentage among males (19.3%). About 18.5% of the respondents were found to be at risk of eating disorders with higher prevalence among males (19.3%). More females reported to have higher prevalence of body part dissatisfaction (46.9%) and body weight (37.6%) compared to males (40%, 28.1%). The statistical results indicated there were significant associations between EAT-26 and body mass index (BMI) (p=0.039), body part satisfaction (p=0.004), and perception of body weight (p=0.038). Eating disorders are becoming more prevalent amongst adolescents, particularly among males. As eating disorder are strongly associated with adolescent mental and physical health, intervention programme on their developmental challenges and issues for both males and females should be in place particularly in the school education syllabus. PMID- 26536574 TI - Knowledge and perception of young adults in Nigeria on effectiveness of condom use in prevention of sexually transmitted infections. AB - BACKGROUND: Although sexually transmitted infections (STIs) are a global health problem affecting every region of the world, the higher prevalence and mortality rate of STIs in developing countries of the world, like Nigeria, make them serious public health issues in this region. OBJECTIVE: The aim of this study is to assess the knowledge and perception of young adults in Nigeria on the role of condom (both male and female condoms) as a preventive measure against STIs during heterosexual and homosexual intercourse. MATERIALS AND METHODS: Data was collected from participants selected from the northern and southern Nigeria using self-administered questionnaire specifically designed for this study. RESULTS: Knowledge of condom efficacy in STI prevention was satisfactory. However, knowledge and practice of the correct use of condom was poor. Only 47.1% of the 102 participants in this study reported correct condom use of wearing condoms before staring intercourse and removing condoms after ejaculation. As a strategy to include the experiences, knowledge and perception of men who have sex with men, this study asked the question on condom use during anal sex. Only 24.4% of the male participants indicated they have never had anal sex while for females, the percentage was more than half (53.5%). Condom use during anal sex was low with only 20.6% of participants reporting condom use during anal sex. Negative perceptions about condom use - such as that condom use promotes sexual promiscuity, and not using condoms with steady sexual partners - were significant in this study. Also, condom use errors were common in this study. CONCLUSION: There is a wide gap in knowledge of correct condom use in this population. There is need for interventions that address the issue of condom use during anal and same-sex sexual intercourse in this population. PMID- 26536575 TI - Media exposure, interactive health literacy, and adolescents' susceptibility to future smoking. AB - BACKGROUND: Few studies have investigated interactive health literacy (IHL)'s relationship with adolescents' smoking-related behavior. This study investigated IHL's association with adolescents' susceptibility to future smoking. MATERIALS AND METHODS: We conducted a school-based cross-sectional study of Japanese students enrolled in public junior high school, grades 7-9 (n=1937), who completed a self-report questionnaire. Variables were grade, gender, media exposure [television (TV), internet, and magazines], IHL (interest in learning about health, understanding what they hear about health, trying to follow what is taught about health), and susceptibility to future smoking. RESULTS: Significant findings were: [1] media exposure was positively associated with adolescents' susceptibility to future smoking (TV: p<0.01, internet: p<0.01, magazines: p<0.01); [2] IHL was negatively associated with adolescents' susceptibility to future smoking (interest in learning about health: p<0.001; understanding what they hear about health: p<0.05; trying to follow what is taught about health: p<0.001). IHL's influence on susceptibility to future smoking was found to be marginally stronger than that of media exposure. CONCLUSION: School health education programs that promote adolescents' IHL may effectively reduce adolescents' susceptibility to future smoking. PMID- 26536576 TI - Adolescent suicide and testosterone. AB - Completed suicide is much more common in men than in women. Its incidence rises precipitously in adolescence. One biological hypothesis that accounts for the increased frequency of completed suicide in men is that the male sex hormone testosterone partially mediates the observed increase in suicide frequency among men. It is the aim of this communication to review the relevant literature and to describe putative biological mechanisms for this association. Specifically, we propose that the impairment wrought by of high levels of testosterone in the adolescent upon the emotion regulation system contribute to an account for these findings. Herein, we describe this neural system and the specific effects of testosterone upon the system. We conclude with a discussion of clinical implications and applications with an aim of stimulating further research. PMID- 26536577 TI - Racial/ethnic disparity in obesity among US youth, 1999-2013. AB - BACKGROUND: One fundamental goal in the Healthy People 2020 is to achieve health equity and eliminate disparities. OBJECTIVE: To examine the annual trends in racial/ethnic disparity in obesity among US youth from 1999 to 2013. SUBJECTS: Nationally representative sample of 108,811 students in grades 9th-12th from the Youth Risk Behavior Surveillance System (YRBSS) 1999-2013 surveys. METHODS: Body mass index (BMI) was calculated based on self-reported height and weight. Obesity in youth is defined as BMI at or above 95th sex- and age-specific percentile of the 2000 Centers for Disease Control and Prevention growth charts. Multiple logistic regressions were conducted to estimate the annual prevalence of obesity by race/ethnicity, adjusted for gender and age group and accounted for the YRBSS survey design. Between-group variance (BGV) was used to measure absolute racial/ethnic disparity in obesity, and the mean log deviation (MLD) and the Theil Index (T) were used to measure relative racial/ethnic disparity in obesity, weighted by corresponding racial/ethnic population size. RESULTS: The obesity prevalence among non-Hispanic Whites, non-Hispanic African Americans, non Hispanic other race or multi-race, and Hispanic increased from 10.05%, 12.31%, 10.25%, and 13.24% in 1999 to 13.14%, 15.76%, 10.87%, and 15.20% in 2013, respectively. Both absolute and relative racial/ethnic disparity in obesity increased initially since 1999 but then steadily declined starting from mid-2000s back to around its original level by 2013. CONCLUSION: The obesity epidemic in youth is marked by salient and persistent disparity pertaining to race/ethnicity. No improvement on racial/ethnic disparity in obesity among American youth was observed during 1999-2013. PMID- 26536578 TI - Successful treatment of short stature with growth hormone replacement therapy in a patient with anorexia nervosa. AB - A 19-year-old woman visited our outpatient clinic requesting treatment for short stature. She had been repeatedly hospitalized at a psychiatric unit and was subsequently diagnosed with anorexia nervosa (AN). She was 139.3 cm (-3.6 SD) tall and weighed 25.5 kg (23% lower than standard weight). She had primary amenorrhea and her bone age (BA) was 11.8 years. She had low insulin-like growth factor (IGF)-I (80 ng/mL) and a basal growth hormone (GH) level of 1.47 ng/mL. Treatment with recombinant GH was initiated. At 22 years of age, she was 152.2 cm (-1.1 SD) tall and weighed 39.7 kg. As she had shown a favorable response to GH treatment, therapy was discontinued. We suggest that it is worthwhile treating AN patients with GH replacement therapy for short stature, once low IGF-I levels without GH resistance, delayed puberty, delay in BA, and nutritional stabilization are taken into consideration. PMID- 26536579 TI - Implicit emotion regulation: linking childhood oppositional defiant disorder with adult depression and bipolar disorder? PMID- 26536580 TI - Turner syndrome - working together with patients and their families. PMID- 26536581 TI - Discriminant indices for distinguishing thalassemia and iron deficiency in patients with microcytic anemia: a meta-analysis. AB - BACKGROUND: More than 40 mathematical indices have been proposed in the hematological literature for discriminating between iron deficiency anemia and thalassemia trait in subjects with microcytic red blood cells (RBCs). None of these discriminant indices is 100% sensitive and specific and also the ranking of the discriminant indices is not consistent. Therefore, we decided to conduct the first meta-analysis of the most frequently used discriminant indices. METHODS: An extensive literature search yielded 99 articles dealing with 12 indices that were investigated five or more times. For each discriminant index we calculated the diagnostic odds ratio (DOR) and summary ROC analysis was done for comparing the performance of the indices. RESULTS: The ratio of microcytic to hypochromic RBCs (M/H ratio) showed the best performance, DOR=100.8. This was significantly higher than that of all other indices investigated. The RBC index scored second (DOR=47.0), closely followed by the Sirdah index (DOR=46.7) and the Ehsani index (DOR=44.7). Subsequently, there was a group of four indices with intermediate and three with lower DOR. The lowest performance (DOR=6.8) was found for the RDW (Bessman index). Overall, the indices performed better for adults than for children. CONCLUSIONS: The M/H ratio outperformed all other discriminant indices for discriminating between iron deficiency anemia and thalassemia trait. Although its sensitivity and specificity are not high enough for making a definitive diagnosis, it is certainly of value for identifying those subjects with microcytic RBC in whom diagnostic tests for confirming thalassemia are indicated. PMID- 26536582 TI - Quantity quotient reporting. Comparison of various models. AB - Quantity quotient (QQ) reporting has been proposed by several authors to improve or support the present situation of presenting quantitative laboratory results. This proposal is based on a concept (symmetrical model) known from the intelligence quotient, which was developed to make intelligence tests comparable. In laboratory medicine, however, most measurands follow a non-symmetrical (skewed) distribution, leading to a compression of the QQ values at the lower end of the reference interval. This effect can be avoided by several alternatives. Three models considering non-symmetrical distributions are compared with the symmetrical model in the present study. The corresponding algorithms can be easily handled on the Excel platform. Graphical presentation of the QQ allows a quick overview of test results if they occur in a large number. PMID- 26536583 TI - Effect of age and gender on reference intervals of red blood cell distribution width (RDW) and mean red cell volume (MCV). AB - BACKGROUND: Red blood cell distribution width (RDW) was recently shown to be age dependent when using Sysmex XE-2100 hematology analyzers. As measuring RDW is subject to technology, we have investigated if this relation also exists when using a different hematology analyzer, Abbott CELL-DYN Sapphire. In addition, as RDW is generally expressed relative to mean red blood cell volume (MCV), we have explored how MCV influences the age-dependency of RDW. METHODS: We measured RDW and MCV in a large cohort and calculated RDW-SD (the "absolute" RDW), which does not contain MCV. For establishing reference intervals we used Bhattacharya statistics. RESULTS: In our study cohort of 8089 individuals we found a strong association between RDW and age, but not with gender. Also MCV showed an age related increase over the entire age range. The conventional RDW increased by 6% from the youngest to oldest age class, whereas RDW-SD increased by nearly 15%. This difference was caused by a mean age-related increase in MCV of 6.6%. Age dependent reference intervals were established for RDW, RDW-SD and MCV. CONCLUSIONS: The age-dependency of RDW seems to be a universal biological feature rather than related with a single type of hematology analyzer. As not only RDW, but also MCV increases with age, we propose that future studies on the prognostic significance of RDW take its age-dependency into account and focus on RDW-SD as a potential marker of adverse events in many clinical conditions. PMID- 26536584 TI - Misleading high-sensitivity troponin algorithm for NSTEMI in the ESC guidelines. PMID- 26536585 TI - Construction of Ni(II)Ln(III)M(III) (Ln = Gd(III), Tb(III); M = Fe(III), Cr(III)) clusters showing slow magnetic relaxations. AB - Four heterotrimetallic 3d-3d'-4f complexes, [Ni(L)Gd(H2O)4][Cr(CN)6]CH3OH.2H2O (1), [Ni(L)Tb(H2O)4][Cr(CN)6]CH3OH.2H2O (2), [Ni(L)Gd(H2O)4][Fe(CN)6].3H2O (3), and [Ni(L)Tb(H2O)4][Fe(CN)6]CH3OH.2H2O (4) (H2L = N,N-ethylenebis(3 methoxysalicylaldiimine)), were synthesized and characterized structurally and magnetically. The X-ray structural analysis revealed that these complexes are isostructural, in which Ni(II)Ln(III)M(III) (Ln = Tb(III), Gd(III); M = Fe(III), Cr(III)) is arranged in trinuclear clusters. Then, these clusters further interact with each other via weak hydrogen bonds to form high dimensional supramolecular networks. Magnetic investigation indicates that the Ni(II) centers are diamagnetic. Dominant antiferromagnetic coupling is presented in complexes 1 and 3. An ac magnetic susceptibility measurement indicates that complexes 2 and 4 show typical field induced slow magnetic relaxation, which might be caused by the magnetic anisotropy of the central Tb(III) ions. PMID- 26536586 TI - Nornicotine and Nicotine Induced Neovascularization via Increased VEGF/PEDF Ratio. AB - PURPOSE: The purpose of the current study was to evaluate the influences of nornicotine and nicotine (NT) in cigarette smoke on the expression of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in retinal pigment epithelium cells and human umbilical vein endothelial cells (HUVECs). Furthermore, the angiogenic behaviors of endothelial cells under nornicotine and NT treatment were assessed by using in vitro methods. METHODS: ARPE-19 cells and HUVECs were treated with different concentrations of either nornicotine or NT for different periods of time. The cell proliferative effect was investigated by using the method of MTT analysis. HUVEC migration and tube formation were assessed by using the scratch assay and Matrigel models. The expressions of VEGF and PEDF gene and protein in both types of cells were examined by real-time RT-PCR and Western blot. RESULTS: There was no proliferation of ARPE-19 cells following treatment with various concentrations of nornicotine or NT. In contrast, nornicotine or NT significantly stimulated HUVEC proliferation, migration and tube formation. Nornicotine and NT upregulated the expression of VEGF but suppressed the expression of PEDF at both mRNA and protein levels in a dose- and time-dependent manner in ARPE-19 cells and HUVECs. CONCLUSIONS: Our results demonstrate that nornicotine and NT promoted endothelial cellular proliferation, migration and tube formation of HUVECs in vitro. These effects might be partly due to simultaneous modulation of VEGF/PEDF signaling in ARPE-19 cells and HUVECs. PMID- 26536587 TI - Further Evidence for the Utility of Electrophysiological Methods for the Detection of Subclinical Stage Retinal and Optic Nerve Involvement in Diabetes. AB - OBJECTIVE: To assess the utility of visual electrophysiological methods, visual evoked potentials (VEPs) and pattern electroretinograms (PERGs) were recorded for the detection of subclinical optic nerve and retinal involvement in patients with diabetes mellitus. SUBJECTS AND METHODS: The data of 63 patients (126 eyes) with no vascular retinopathy or optic neuropathy were retrospectively analyzed. The patients were divided into polyneuropathic/nonpolyneuropathic groups to differentiate between early and late subclinical stages. The recorded parameters were compared with local reference values. RESULTS: 116 eyes (92%) had VEP and 76 (60%) had PERG abnormalities. The most frequent alteration was latency delay, but waveform and amplitude irregularities were also observed. The simultaneous use of the two methods allowed us to differentiate abnormal VEPs of purely optic nerve origin from those reflecting retinal involvement. CONCLUSIONS: We suggest that regular electrophysiological screening should receive more attention in the ophthalmological care of diabetic patients. PMID- 26536588 TI - Anti-Caries Effect of Arginine-Containing Formulations in vivo: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To assess the anti-caries effect of arginine-containing formulations in vivo on caries lesions compared with fluorides or placebo. METHODS: Randomized or quasi-randomized human clinical trials wherein arginine was delivered by any method were considered. The MEDLINE, Web of Science, EMBASE, Cochrane Library, and CBM databases were searched to identify relevant articles published up to December 2014. Grey literature was also searched. Two authors performed data extraction independently and in duplicate using data collection forms. Each included study was assessed using the Cochrane risk of bias assessment tool. RESULTS: Of the 470 studies screened, 31 full articles were scrutinized and assessed for eligibility. Ten studies (n = 15,546 participants) were selected for final inclusion. The meta-analysis results (n = 7 studies) demonstrated a synergistic effect of arginine when used in conjunction with fluoride on early coronal and root caries compared with placebo or fluoride alone. No specific side effects related to arginine usage were identified. CONCLUSIONS: When used in combination with a calcium compound and fluoride, arginine potentially provides a superior anti-caries effect compared with matched formulations of fluoride alone. However, the level of evidence was downgraded because of risks of bias and potential publication bias. In the future, more high quality, non-industry supported clinical studies in this research area are required before any definitive recommendations can be made. PMID- 26536589 TI - Tetrazine-Containing Amino Acid for Peptide Modification and Live Cell Labeling. AB - A novel amino acid derivative 3-(4-(1, 2, 4, 5-tetrazine-3-yl) phenyl)-2 aminopropanoic acid was synthesized in this study. The compound possessed better water-solubility and was synthesized more easily compared with the well-known and commercially available 3-(p-benzylamino)-1, 2, 4, 5-tetrazine. Tetrazine containing amino acid showed excellent stability in biological media and might be used for cancer cell labeling. Moreover, the compound remained relatively stable in 50% TFA/DCM with little decomposition after prolonged exposure at room temperature. The compound could be utilized as phenylalanine or tyrosine analogue in peptide modification, and the tetrazine-containing peptide demonstrated more significant biological activity than that of the parent peptide. The combination of tetrazine group and amino acid offered broad development prospects of the bioorthogonal labeling and peptide synthesis. PMID- 26536590 TI - Transactivation of ErbB Family of Receptor Tyrosine Kinases Is Inhibited by Angiotensin-(1-7) via Its Mas Receptor. AB - Transactivation of the epidermal growth factor receptor (EGFR or ErbB) family members, namely EGFR and ErbB2, appears important in the development of diabetes induced vascular dysfunction. Angiotensin-(1-7) [Ang-(1-7)] can prevent the development of hyperglycemia-induced vascular complications partly through inhibiting EGFR transactivation. Here, we investigated whether Ang-(1-7) can inhibit transactivation of ErbB2 as well as other ErbB receptors in vivo and in vitro. Streptozotocin-induced diabetic rats were chronically treated with Ang-(1 7) or AG825, a selective ErbB2 inhibitor, for 4 weeks and mechanistic studies performed in the isolated mesenteric vasculature bed as well as in cultured vascular smooth muscle cells (VSMCs). Ang-(1-7) or AG825 treatment inhibited diabetes-induced phosphorylation of ErbB2 receptor at tyrosine residues Y1221/22, Y1248, Y877, as well as downstream signaling via ERK1/2, p38 MAPK, ROCK, eNOS and IkB-alpha in the mesenteric vascular bed. In VSMCs cultured in high glucose (25 mM), Ang-(1-7) inhibited src-dependent ErbB2 transactivation that was opposed by the selective Mas receptor antagonist, D-Pro7-Ang-(1-7). Ang-(1-7) via Mas receptor also inhibited both Angiotensin II- and noradrenaline/norephinephrine induced transactivation of ErbB2 and/or EGFR receptors. Further, hyperglycemia induced transactivation of ErbB3 and ErbB4 receptors could be attenuated by Ang (1-7) that could be prevented by D-Pro7-Ang-(1-7) in VSMC. These data suggest that Ang-(1-7) via its Mas receptor acts as a pan-ErbB inhibitor and might represent a novel general mechanism by which Ang-(1-7) exerts its beneficial effects in many disease states including diabetes-induced vascular complications. PMID- 26536591 TI - Attraction to Carbon Dioxide from Feeding Resources and Conspecific Neighbours in Larvae of the Rhinoceros Beetle Trypoxylus dichotomus. AB - Saprophagous (feeding on decaying matter) insects often use carbon dioxide (CO2) as a cue for finding food. Humus-feeding larvae of the giant rhinoceros beetle Trypoxylus dichotomus exhibit a clumped distribution in natural microhabitats, but the mechanisms driving the distribution were unknown. Herein, I examined whether larvae use CO2 as a cue for fermented humus and aggregate in the vicinity of the food. I found that (i) larvae of T. dichotomus are strongly attracted to CO2, (ii) larvae orient toward highly fermented humus when given a choice between highly and poorly fermented humus, (iii) the highly fermented humus emits more CO2 than the poorly fermented humus, and (iv) larvae grow larger when fed highly fermented humus rather than poorly fermented humus. The clumped distribution of larvae is probably formed along the concentration gradient of CO2 induced by heterogeneity of fermented organic materials in soil. My laboratory experiments also revealed that larvae are chemically attracted to each other. Moreover, CO2 concentrations in soil were increased by the larval respiration, and small amounts of CO2 (much less than emitted during respiration by a single larva) were sufficient for larval attraction. These results suggest that not only response to fermented food resources, but also respiratory CO2 from conspecifics may lead to aggregation. Enhanced densities resulted in reduced weight gain under experimental conditions. However, exploiting a high-value resource at enhanced densities still led to greater body weight compared to individually exploiting a low-value resource. This demonstrates the adaptive value of the response to CO2 sources in this species. PMID- 26536592 TI - Direct and Conceptual Replications of Burgmer & Englich (2012): Power May Have Little to No Effect on Motor Performance. AB - Burgmer and Englich (2012) have reported that manipulating feelings of power can substantially improve performance on two motor tasks: golf and darts. We conducted two high-powered direct replications of the effects of power on golf, two online conceptual replications using mirror-tracing as a performance measure, and an additional conceptual replication using a cognitive performance measure (word-search). Overall, we found little to no effect of power on motor skill (d = 0.09, 95% CI[-0.07, 0.22], n = 603). We varied task difficulty, re-analyzed data without participants showing weak responses on manipulation checks, and tried adjusting performance scores for age, gender, and initial task skill. None of these secondary analyses revealed a strong effect of power on performance. A meta analysis integrating our data with Burgmer & Englich leaves open the possibility that manipulating power could provide a modest boost in motor skill (d = 0.19, 95% CI [0.001, 0.38], n = 685). Unfortunately, the pattern of performance changes we observed was unrelated to group differences in perceived and rated power, suggesting that what motor effects do occur with this protocol may not be directly related to the construct of power. [Burgmer, P., &Englich, B. (2012). Bullseye!: How Power Improves Motor Performance. Social Psychological and Personality Science, 4(2), 224-232.]. PMID- 26536593 TI - Quorum Sensing Peptides Selectively Penetrate the Blood-Brain Barrier. AB - Bacteria communicate with each other by the use of signaling molecules, a process called 'quorum sensing'. One group of quorum sensing molecules includes the oligopeptides, which are mainly produced by Gram-positive bacteria. Recently, these quorum sensing peptides were found to biologically influence mammalian cells, promoting i.a. metastasis of cancer cells. Moreover, it was found that bacteria can influence different central nervous system related disorders as well, e.g. anxiety, depression and autism. Research currently focuses on the role of bacterial metabolites in this bacteria-brain interaction, with the role of the quorum sensing peptides not yet known. Here, three chemically diverse quorum sensing peptides were investigated for their brain influx (multiple time regression technique) and efflux properties in an in vivo mouse model (ICR-CD-1) to determine blood-brain transfer properties: PhrCACET1 demonstrated comparatively a very high initial influx into the mouse brain (Kin = 20.87 MUl/(g*min)), while brain penetrabilities of BIP-2 and PhrANTH2 were found to be low (Kin = 2.68 MUl/(g*min)) and very low (Kin = 0.18 MUl/(g*min)), respectively. All three quorum sensing peptides were metabolically stable in plasma (in vitro) during the experimental time frame and no significant brain efflux was observed. Initial tissue distribution data showed remarkably high liver accumulation of BIP 2 as well. Our results thus support the potential role of some quorum sensing peptides in different neurological disorders, thereby enlarging our knowledge about the microbiome-brain axis. PMID- 26536594 TI - Development of a 4D Digital Phantom for Tracer Kinetic Modeling and Analysis of Dynamic Perfusion PET and SPECT Simulation Studies. AB - The goal is to develop a 4D digital perfusion cardiac-torso (PCAT) phantom, a tracer kinetic extension of the XCAT phantom, by modeling the time activity curves (TACs) of individual organ regions in the phantom for dynamic perfusion PET and SPECT simulation studies. The PCAT phantom is based on a generalized compartmental model, which accepts the blood input function, multiple series or parallel compartments, the bidirectional rate constants between the compartments, the blood volume in the tissue, the extraction curves, and other properties of a specific tracer. Based on the kinetic differential equations of the compartmental model, the TACs of the targeted organ regions were determined. For a specific time point, a voxelized anatomical realistic phantom, which with or without the cardiac and respiratory motions, was generated and the activity concentrations in the organ regions were assigned according to the corresponding TACs. According to the dynamic scanning protocol, multiple phantoms at different acquisition time points, which could have uniform or non-uniform time intervals, were generated. When combining the dynamic phantoms with realistic projection simulator, realistic dynamic projection data could be generated by easily adopting to various scanning protocols and imaging systems. With the availability of the "known truth", the activity map of the targeted organ regions, the TACs, the estimated rate constants and other kinetic parameters, from the projection data and the reconstructed images could be quantitatively evaluated. We demonstrate the usefulness of the 4D PCAT phantom in initial simulation studies in dynamic myocardial perfusion PET imaging with different tracers. The PCAT phantom was found to be an important bridge between the creation of TACs and the generation of simulated projection data. It is a useful simulation tool to study different kinetic analysis methods, acquisition protocols, reconstruction methods, and imaging parameter settings. PMID- 26536595 TI - Localization of Physical Activity in Primary School Children Using Accelerometry and Global Positioning System. AB - BACKGROUND: Ecological approaches have highlighted the importance of the built environment as a factor affecting physical activity. However, knowledge on children's activity patterns is still incomplete. Particularly, data on the spatial context of physical activity is limited, which limits the potential to design location-based interventions effectively. Using global positioning system (GPS) and accelerometry, this study aimed to identify locations where children engage in moderate-vigorous physical activity (MVPA). METHODS: Participants included 119 children (11-14 years, 57% girls) from public schools in Winterthur, Switzerland. During a regular school week between February and April 2013, children wore an accelerometer and GPS sensor for seven consecutive days. Time matched accelerometer and GPS data was mapped with a geographic information system and each data point was assigned to one of seven defined activity settings. Both the absolute amount of MVPA and proportion of time in MVPA were calculated for every setting. Multilevel analyses accounting for the hierarchical structure of the data were conducted to investigate any gender differences. RESULTS: Children achieved most MVPA on streets (34.5%) and on school grounds (33.4%). The proportion children spent in MVPA was highest in recreational facilities (19.4%), at other schools (19.2%) and on streets (18.6%). Boys accumulated significantly more MVPA overall and on other school grounds (p < 0.05) and showed a significantly higher proportion of time in MVPA at own school and outside of Winterthur (p < 0.05). CONCLUSIONS: The results indicate the importance of streets and school grounds as activity-promoting environments. The high use of streets may be an indicator for active transportation, which appears to contribute to an active lifestyle in both genders. In contrast, the school setting is more likely to encourage physical activity in boys. Recreational facilities seem to be conducive for MVPA among both genders, although infrequently visited during the week of measurement. PMID- 26536596 TI - Simulation-Based Evaluation of the Performances of an Algorithm for Detecting Abnormal Disease-Related Features in Cattle Mortality Records. AB - We performed a simulation study to evaluate the performances of an anomaly detection algorithm considered in the frame of an automated surveillance system of cattle mortality. The method consisted in a combination of temporal regression and spatial cluster detection which allows identifying, for a given week, clusters of spatial units showing an excess of deaths in comparison with their own historical fluctuations. First, we simulated 1,000 outbreaks of a disease causing extra deaths in the French cattle population (about 200,000 herds and 20 million cattle) according to a model mimicking the spreading patterns of an infectious disease and injected these disease-related extra deaths in an authentic mortality dataset, spanning from January 2005 to January 2010. Second, we applied our algorithm on each of the 1,000 semi-synthetic datasets to identify clusters of spatial units showing an excess of deaths considering their own historical fluctuations. Third, we verified if the clusters identified by the algorithm did contain simulated extra deaths in order to evaluate the ability of the algorithm to identify unusual mortality clusters caused by an outbreak. Among the 1,000 simulations, the median duration of simulated outbreaks was 8 weeks, with a median number of 5,627 simulated deaths and 441 infected herds. Within the 12-week trial period, 73% of the simulated outbreaks were detected, with a median timeliness of 1 week, and a mean of 1.4 weeks. The proportion of outbreak weeks flagged by an alarm was 61% (i.e. sensitivity) whereas one in three alarms was a true alarm (i.e. positive predictive value). The performances of the detection algorithm were evaluated for alternative combination of epidemiologic parameters. The results of our study confirmed that in certain conditions automated algorithms could help identifying abnormal cattle mortality increases possibly related to unidentified health events. PMID- 26536597 TI - The Orthology Clause in the Next Generation Sequencing Era: Novel Reference Genes Identified by RNA-seq in Humans Improve Normalization of Neonatal Equine Ovary RT qPCR Data. AB - BACKGROUND: Vertebrate evolution is accompanied by a substantial conservation of transcriptional programs with more than a third of unique orthologous genes showing constrained levels of expression. Moreover, there are genes and exons exhibiting excellent expression stability according to RNA-seq data across a panel of eighteen tissues including the ovary (Human Body Map 2.0). RESULTS: We hypothesized that orthologs of these exons would also be highly uniformly expressed across neonatal ovaries of the horse, which would render them appropriate reference genes (RGs) for normalization of reverse transcription quantitative PCR (RT-qPCR) data in this context. The expression stability of eleven novel RGs (C1orf43, CHMP2A, EMC7, GPI, PSMB2, PSMB4, RAB7A, REEP5, SNRPD3, VCP and VPS29) was assessed by RT-qPCR in ovaries of seven neonatal fillies and compared to that of the expressed repetitive element ERE-B, two universal (OAZ1 and RPS29) and four traditional RGs (ACTB, GAPDH, UBB and B2M). Expression stability analyzed with the software tool RefFinder top ranked the normalization factor constituted of the genes SNRPD3 and VCP, a gene pair that is not co expressed according to COEXPRESdb and GeneMANIA. The traditional RGs GAPDH, B2M, ACTB and UBB were only ranked 3rd and 12th to 14th, respectively. CONCLUSIONS: The functional diversity of the novel RGs likely facilitates expression studies over a wide range of physiological and pathological contexts related to the neonatal equine ovary. In addition, this study augments the potential for RT-qPCR based profiling of human samples by introducing seven new human RG assays (C1orf43, CHMP2A, EMC7, GPI, RAB7A, VPS29 and UBB). PMID- 26536598 TI - Mapping Individual Brain Networks Using Statistical Similarity in Regional Morphology from MRI. AB - Representing brain morphology as a network has the advantage that the regional morphology of 'isolated' structures can be described statistically based on graph theory. However, very few studies have investigated brain morphology from the holistic perspective of complex networks, particularly in individual brains. We proposed a new network framework for individual brain morphology. Technically, in the new network, nodes are defined as regions based on a brain atlas, and edges are estimated using our newly-developed inter-regional relation measure based on regional morphological distributions. This implementation allows nodes in the brain network to be functionally/anatomically homogeneous but different with respect to shape and size. We first demonstrated the new network framework in a healthy sample. Thereafter, we studied the graph-theoretical properties of the networks obtained and compared the results with previous morphological, anatomical, and functional networks. The robustness of the method was assessed via measurement of the reliability of the network metrics using a test-retest dataset. Finally, to illustrate potential applications, the networks were used to measure age-related changes in commonly used network metrics. Results suggest that the proposed method could provide a concise description of brain organization at a network level and be used to investigate interindividual variability in brain morphology from the perspective of complex networks. Furthermore, the method could open a new window into modeling the complexly distributed brain and facilitate the emerging field of human connectomics. PMID- 26536599 TI - Survival of Hepatitis C Virus in Syringes Is Dependent on the Design of the Syringe-Needle and Dead Space Volume. AB - BACKGROUND: Many people who inject drugs (PWID) use syringes with detachable needles, which have high dead space (HDS). Contaminated HDS blood may substantially contribute to the transmission of HIV, hepatitis C (HCV), and other blood-borne viruses within this population. Newly designed low dead space (LDS) syringe-needle combinations seek to reduce blood-borne virus transmission among PWID. We evaluated the infectivity of HCV-contaminated residual volumes recovered from two LDS syringe-needle combinations. METHODS: We tested two different design approaches to reducing the dead space. One added a piston to the plunger; the other reduced the dead space within the needle. The two approaches cannot be combined. Recovery of genotype-2a reporter HCV from LDS syringe-needle combinations was compared to recovery from insulin syringes with fixed needles and standard HDS syringe-needle combinations. Recovery of HCV from syringes was determined immediately following their contamination with HCV-spiked plasma, after storage at 22 degrees C for up to 1 week, or after rinsing with water. RESULTS: Insulin syringes with fixed needles had the lowest proportion of HCV positive syringes before and after storage. HCV recovery after immediate use ranged from 47%+/-4% HCV-positive 1 mL insulin syringes with 27-gauge 1/2 inch needles to 98%+/-1% HCV-positive HDS 2 mL syringes with 23-gauge 11/4 inch detachable needles. LDS combinations yielded recoveries ranging from 65%+/-5% to 93%+/-3%. Recovery was lower in combinations containing LDS needles than LDS syringes. After 3 days of storage, as much as 6-fold differences in virus recovery was observed, with HCV recovery being lower in combinations containing LDS needles. Most combinations with detachable needles required multiple rinses to reduce HCV infectivity to undetectable levels whereas a single rinse of insulin syringes was sufficient. CONCLUSIONS: Our study, the first to assess the infectivity of HCV in residual volumes of LDS syringes and needles available to PWID, demonstrates that LDS syringe-needle combination still has the greater potential for HCV transmission than insulin syringes with fixed needles. Improved LDS designs may be able to further reduce HCV recovery, but based on the designed tested, LDS needles and syringes remain intermediate between fixed-needle syringes and HDS combinations in reducing exposure to HCV. PMID- 26536601 TI - 'Skullduggery': Lions Align and Their Mandibles Rock! AB - South Africa has legally exported substantial quantities of lion bones to Southeast Asia and China since 2008, apparently as part of the multinational trade substituting bones and body parts of other large cats for those of the tiger in wine and other health tonics. The legal sale of lion bones may mask an illegal trade, the size of which is only partially known. An observed component of the illegal trade is that quantities of skeletons are sometimes declared falsely/fraudulently on CITES export permits. Furthermore, there are emerging concerns that bones from tigers reared in captivity in South Africa and elsewhere are being laundered as lion bones using CITES Appendix II permits. There is therefore a need for tools to monitor the trade in lion body parts and to distinguish between lions and tigers. Our research indicates that it is possible to use skeletons, skulls and cranial sutures to detect misdeclarations in the lion bone trade. It is also possible to use the average mass of a lion skeleton to corroborate the numbers of skeletons declared on CITES permits, relative to the weight of the consolidated consignments stated on the air waybills. When the mass of consolidated consignments of skeletons destined for export was regressed against the number of skeletons in that consignment, there was a strong correlation between the variables (r2 = 0.992) that can be used as a predictor of the accuracy of a declaration on a CITES permit. Additionally, the skulls of lions and tigers differ: two cranial sutures of lions align and their mandibles rock when placed on a flat surface, whereas the cranial sutures of tigers are not aligned and their mandibles rest naturally on two contact points. These two morphological differences between the skulls of tigers and lions are easy to observe at a glance and provide a method for distinguishing between the species if illegal trade in the bones is suspected and the skulls are present. These identifications should ideally be confirmed by a DNA test to provide rigorous evidence to prosecute offenders violating CITES regulations. PMID- 26536600 TI - Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease. AB - OBJECTIVE: To search for biomarkers to differentiate primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). METHODS: We isolated glomeruli from kidney biopsies of 6 patients with adult-onset steroid sensitiveFSGS and 5 patients with MCD, and compared the profiles of glomerular transcriptomes between the two groups of patients using microarray analysis. RESULTS: Analysis of differential expressed genes (DEGs) revealed that up regulated DEGs in FSGS patients compared with MCD patients were primarily involved in spermatogenesis, gamete generation, regulation of muscle contraction, response to unfolded protein, cell proliferation and skeletal system development. The down-regulated DEGs were primarily related to metabolic process, intracellular transport, oxidation/reduction andestablishment of intracellular localization. We validated the expression of the top 6 up-regulated and top 6 down-regulated DEGs using real-time PCR. Membrane metallo-endopeptidase (MME) is a down-regulated gene that was previously identified as a key gene for kidney development. Immunostaining confirmed that the protein expression of MME decreased significantly in FSGS kidneys compared with MCD kidneys. CONCLUSIONS: This report was the first study to examine transcriptomes in Chinese patients with various glomerular diseases. Expressions of MME both in RNA and protein level decreased significantly in glomeruli of FSGS kidneys compared with MCD kidneys. Our data suggested that MME might play a role in the normal physiological function of podocytes and a decrease in MME expression might be related to podocyte injury. We also identified genes and pathways specific for FSGS versus MCD, and our data could help identify potential new biomarkers for the differential diagnosis between these two diseases. PMID- 26536602 TI - Scleredema adultorum of Buschke with prominent periorbital edema in a Tunisian patient with diabetes mellitus: a case report. PMID- 26536603 TI - Molecular and Morphological Evidence Challenges the Records of the Extant Liverwort Ptilidium pulcherrimum in Eocene Baltic Amber. AB - Preservation of liverworts in amber, a fossilized tree resin, is often exquisite. Twenty-three fossil species of liverworts have been described to date from Eocene (35-50 Ma) Baltic amber. In addition, two inclusions have been assigned to the extant species Ptilidium pulcherrimum (Ptilidiales or Porellales). However, the presence of the boreal P. pulcherrimum in the subtropical or warm-temperate Baltic amber forest challenges the phytogeographical interpretation of the Eocene flora. A re-investigation of one of the fossils believed to be P. pulcherrimum reveals that this specimen in fact represents the first fossil evidence of the genus Tetralophozia, and thus is re-described here as Tetralophozia groehnii sp. nov. A second fossil initially assigned to P. pulcherrimum is apparently lost, and can be reassessed only based on the original description and illustrations. This fossil is morphologically similar to the extant North Pacific endemic Ptilidium californicum, rather than P. pulcherrimum. Divergence time estimates based on chloroplast DNA sequences provide evidence of a Miocene origin of P. pulcherrimum, and thus also argue against the presence of this taxon in the Eocene. Ptilidium californicum originated 25-43 Ma ago. As a result, we cannot rule out that the Eocene fossil belongs to P. californicum. Alternatively, the fossil might represent a stem lineage element of Ptilidium or an early crown group species with morphological similarities to P. californicum. PMID- 26536604 TI - Correction: An Evaluation of Prediction Equations for the 6 Minute Walk Test in Healthy European Adults Aged 50-85 Years. PMID- 26536605 TI - Levels and Patterns of Objectively Assessed Physical Activity and Compliance with Different Public Health Guidelines in University Students. AB - BACKGROUND: Physical activity (PA) is associated with health enhancement. The aim of this study was to assess: 1) levels and patterns of PA in university students by using accelerometers; and 2) the percentage of fulfilment of PA recommendations for adults, according to different public health guidelines. METHODS: Observational cross-sectional study (Cuenca's Adults Study) involving 296 (206 women) healthy Spanish university students aged 18-25 years old. Participants wore the ActiGraph GT1M accelerometer for seven consecutive days. Total PA, steps and time spent in sedentary time, light, moderate, vigorous, and moderate to vigorous PA (MVPA) was assessed, and the prevalence of sufficient PA was calculated according to various public health guidelines. RESULTS: No sex differences in total PA were found. University students were more sedentary during weekend days than weekdays (p<0.05). Only 30.3% of participants accumulated 30 min/day at least five days a week of MVPA. A total of 5.4% of students met the recommendation of 150 min/week of MVPA or 75 min/week of vigorous PA, in PA bouts of at least 10 min. using the same definition, but on five or more days a week, only 0.5% students were found to meet the recommendation. In addition, only 0.5% of students met the recommendation of 30 min/day of MVPA, at least five days a week and in bouts of at least 10 min. Finally, 28.1% of the students met the recommendation of 10,000 steps/day. CONCLUSIONS: Our study shows a high incidence of sedentary time in university students. The number of students meeting PA recommendations significantly differed depending on the recommendation proposed. Specific strategies to promote PA in this population are necessary as well as an agreement as to which PA guidelines should be used. PMID- 26536606 TI - Urbanization Increases Pathogen Pressure on Feral and Managed Honey Bees. AB - Given the role of infectious disease in global pollinator decline, there is a need to understand factors that shape pathogen susceptibility and transmission in bees. Here we ask how urbanization affects the immune response and pathogen load of feral and managed colonies of honey bees (Apis mellifera Linnaeus), the predominant economically important pollinator worldwide. Using quantitative real time PCR, we measured expression of 4 immune genes and relative abundance of 10 honey bee pathogens. We also measured worker survival in a laboratory bioassay. We found that pathogen pressure on honey bees increased with urbanization and management, and the probability of worker survival declined 3-fold along our urbanization gradient. The effect of management on pathogens appears to be mediated by immunity, with feral bees expressing immune genes at nearly twice the levels of managed bees following an immune challenge. The effect of urbanization, however, was not linked with immunity; instead, urbanization may favor viability and transmission of some disease agents. Feral colonies, with lower disease burdens and stronger immune responses, may illuminate ways to improve honey bee management. The previously unexamined effects of urbanization on honey-bee disease are concerning, suggesting that urban areas may favor problematic diseases of pollinators. PMID- 26536607 TI - Paliurus Fruits from the Oligocene of South China and Their Phytogeographic Implications. AB - Paliurus favonii Unger is recognized and described based on fruits from the Oligocene Ningming flora of Guangxi, South China. Characteristics of the present specimens include circular winged fruits that are 10.0-11.5 mm in diameter with a central endocarp at 3.0 to 4.0 mm in diameter. The specimens fall into the morphological range of the fossil species P. favonii, which has been observed in other Cenozoic sites in the Northern Hemisphere. The present discovery represents the lowest latitude distribution of P. favonii in the world, and we are presenting the first P. favonii fossil described with detailed cuticular characteristics from China. Further, this finding demonstrates that the genus existed in the Oligocene Ningming region, South China, and provides new information for understanding the fossil history. The dispersal mode for winged fossils demonstrates that wind dispersal is well-represented in the Oligocene Ningming flora. PMID- 26536608 TI - Diet Overlap and Foraging Activity between Feral Pigs and Native Peccaries in the Pantanal. AB - Inter-specific competition is considered one of the main selective pressures affecting species distribution and coexistence. Different species vary in the way they forage in order to minimize encounters with their competitors and with their predators. However, it is still poorly known whether and how native species change their foraging behavior in the presence of exotic species, particularly in South America. Here we compare diet overlap of fruits and foraging activity period of two sympatric native ungulates (the white-lipped peccary, Tayassu pecari, and the collared peccary, Pecari tajacu) with the invasive feral pig (Sus scrofa) in the Brazilian Pantanal. We found high diet overlap between white lipped peccaries and feral pigs, but low overlap between collared peccaries and feral pigs. Furthermore, we found that feral pigs may influence the foraging period of both native peccaries, but in different ways. In the absence of feral pigs, collared peccary activity peaks in the early evening, possibly allowing them to avoid white-lipped peccary activity peaks, which occur in the morning. In the presence of feral pigs, collared peccaries forage mostly in early morning, while white-lipped peccaries forage throughout the day. Our results indicate that collared peccaries may avoid foraging at the same time as white-lipped peccaries. However, they forage during the same periods as feral pigs, with whom they have lower diet overlap. Our study highlights how an exotic species may alter interactions between native species by interfering in their foraging periods. PMID- 26536609 TI - MRI-determined liver proton density fat fraction, with MRS validation: Comparison of regions of interest sampling methods in patients with type 2 diabetes. AB - PURPOSE: To assess the agreement between published magnetic resonance imaging (MRI)-based regions of interest (ROI) sampling methods using liver mean proton density fat fraction (PDFF) as the reference standard. MATERIALS AND METHODS: This retrospective, internal review board-approved study was conducted in 35 patients with type 2 diabetes. Liver PDFF was measured by magnetic resonance spectroscopy (MRS) using a stimulated-echo acquisition mode sequence and MRI using a multiecho spoiled gradient-recalled echo sequence at 3.0T. ROI sampling methods reported in the literature were reproduced and liver mean PDFF obtained by whole-liver segmentation was used as the reference standard. Intraclass correlation coefficients (ICCs), Bland-Altman analysis, repeated-measures analysis of variance (ANOVA), and paired t-tests were performed. RESULTS: ICC between MRS and MRI-PDFF was 0.916. Bland-Altman analysis showed excellent intermethod agreement with a bias of -1.5 +/- 2.8%. The repeated-measures ANOVA found no systematic variation of PDFF among the nine liver segments. The correlation between liver mean PDFF and ROI sampling methods was very good to excellent (0.873 to 0.975). Paired t-tests revealed significant differences (P < 0.05) with ROI sampling methods that exclusively or predominantly sampled the right lobe. Significant correlations with mean PDFF were found with sampling methods that included higher number of segments, total area equal or larger than 5 cm(2) , or sampled both lobes (P = 0.001, 0.023, and 0.002, respectively). CONCLUSION: MRI-PDFF quantification methods should sample each liver segment in both lobes and include a total surface area equal or larger than 5 cm(2) to provide a close estimate of the liver mean PDFF. PMID- 26536610 TI - Rare mimic of pedal osteomyelitis in a patient with diabetes. AB - BACKGROUND: Diabetic foot infections are an important cause of hospitalization, health expenditure and mortality. Bone biopsy is the gold standard for diagnosing diabetic foot osteomyelitis but it is not routinely performed in most centres. Instead, a combination of history, examination, biochemical and radiological findings are used to make the diagnosis. CASE REPORT: Here, we report a case mimicking diabetic foot osteomyelitis, where the histology was crucial in acquiring the correct diagnosis. CONCLUSION: The absence of ulceration in cases of presumed diabetic foot osteomyelitis should raise suspicion of potential rare mimics of osteomyelitis and bone biopsy should be considered to further evaluate the underlying etiology prior to any definitive surgical management. PMID- 26536611 TI - Real-time measurement of platelet shape change by light scattering under riboflavin and ultraviolet light treatment. AB - BACKGROUND: The adoption of pathogen reduction technologies (PRTs) is considered for the implementation of safer platelet (PLT) transfusion. However, the effects of PRT treatment including irradiation with ultraviolet (UV) light on PLT shape have not yet been fully clarified. STUDY DESIGN AND METHODS: Leukoreduced PLT concentrates (PCs) were treated with riboflavin and UV light (Mirasol PRT, TerumoBCT). PLT shape and adenosine diphosphate (ADP)-induced shape change were evaluated by a light scattering method where the amplitude of the scattered signal intensity was measured as the indicator of the proportion of discoid PLTs. Using a modified fluorometer, the real-time effects of different wavelengths of UV light on PLT shape were examined over the range of 300 to 360 nm at the same dose. RESULTS: The proportion of discoid PLTs in the Mirasol PRT-treated PCs decreased immediately after treatment. The difference in the proportion between PRT-treated and untreated PLTs became larger with storage. Although this modification correlated significantly with the pH decrease and P-selectin expression, the Mirasol PRT-treated PLTs retained sufficient ability to undergo an ADP-induced shape change. In the study using the modified fluorometer, the proportion of discoid PLTs significantly decreased with the wavelength (< 320 nm) of irradiated UV light. CONCLUSION: Mirasol PRT treatment of PCs decreases the proportion of discoid PLTs, which seemed to be caused by the irradiation with UV light of short wavelengths (< 320 nm), not that of long wavelengths (>= 320 nm) in the Mirasol PRT system. Modification of UV light wavelength may improve the quality of PRT-treated PCs. PMID- 26536612 TI - Virtual Clinical Trials, an Essential Step in Increasing the Effectiveness of the Drug Development Process. AB - Every patient is different--his/her genomes, environment, disease history and exposure to drugs. Tumours, in particular, are often heterogeneous in their genetic make-up and their response to drugs, both within and between samples. Classic clinical trials basically ignore this complexity or, as in stratified medicine, attempt to reduce it to an analysis of a small number of still enormously heterogeneous patient groups. Medicine, however, is not the only area in which we are faced with such complex 'n = 1' (every individual case is different) situations. The weather we experience today, characterised by tens of terabytes of measurement data, has never occurred before and will never occur again. Similar to the situation in medicine, we cannot predict the development of today's weather by looking for identical weather conditions in the past, and we cannot, in real life, test drugs for every individual patient in clinical trials with large numbers of biologically identical patient replicas. We can, however, do it with the help of models duplicating the 'n = 1' situation on the computer, an approach which will also have to be used in both patient treatment and prevention as well as drug development in the future if we do not want to continue to make dangerous and expensive mistakes in real life. PMID- 26536613 TI - Association of Patient Risk Factors and Frequency of Nevus-Associated Cutaneous Melanomas. AB - IMPORTANCE: The reported frequencies of associations between primary cutaneous melanomas and melanocytic nevi vary widely between 4% and 72%. However, earlier histopathologic studies were limited by their retrospective design and did not assess the influence of important patient-related risk factors. OBJECTIVES: To identify the frequency of nevus-associated melanomas and correlate patient- and melanoma-related factors. DESIGN, SETTING, AND PARTICIPANTS: A prospective, single-center, observational study with systematic documentation of melanoma risk factors, clinical and dermoscopic criteria of excised lesions, and results of histopathologic examination was conducted at a university-based dermatology clinic. Participants included 832 patients at high risk for developing melanoma. Evaluation was performed at regular intervals between April 1, 1997, and May 31, 2012, and data analysis was conducted between September 1, 2012, and December 31, 2013. MAIN OUTCOMES AND MEASURES: Assessment of the frequency of nevus-associated melanoma and the influence of patient- and melanoma-related factors on their manifestation. RESULTS: During the study, 190 melanomas (81 [42.6%] in situ and 109 [57.4%] invasive) were diagnosed in 113 of the 832 patients (13.6%); there were 42 women (37.2%) and 71 men (62.8%). The median (SD) Breslow thickness of invasive melanomas was 0.42 (0.43) mm. Histopathologic examination revealed remnants of melanocytic nevi in 103 melanomas (54.2%). Most nevus-associated melanomas were found on the trunk (67 [65.1%]); however, statistical significance for the localization was not present (P = .06). In univariate analyses, reported as odds ratios (95% CIs), nevus-associated melanomas were found significantly more frequently in patients of lower melanoma risk (risk group 1 [>50 common and/or <= 3 atypical nevi], 2.75 [1.14-6.64]; P = .02), with more than 100 nevi (1.63 [1.02-3.60]; P = .04), or with the diagnosis of in situ melanoma (14.01 [6.14-31.96]; P < .001). In contrast, nevus-associated melanomas were found significantly less frequently in patients with 1 or more previous melanomas (0.28 [0.21-0.83]; P = .005). All other factors (eg, age, skin type, hair color, and melanoma thickness) showed no significant influence on the manifestation of nevus associated melanomas. These observations were confirmed in a separate analysis including all 109 invasive melanomas. Multivariate regression analysis identified 3 independent patient-related factors (high nevus count, low risk for melanoma, and female sex) and 1 melanoma-related factor (in situ melanoma) to be indicative of a significantly increased probability of nevus-associated melanomas. CONCLUSIONS AND RELEVANCE: In this prospective study of a high-risk patient cohort, 54.2% of primary melanomas were associated with melanocytic nevi. Patients with many nevi and without previous melanomas or traits of familial atypical mole and multiple melanoma syndrome had a higher frequency of nevus associated melanomas. These patients could thus benefit from sequential digital dermoscopy in addition to total-body photography. PMID- 26536614 TI - Anti-Inflammation of N-Benzyl-4-Bromobenzamide in Lipopolysaccharide-Induced Human Gingival Fibroblasts. AB - OBJECTIVE: To evaluate the effect of N-benzyl-4-bromobenzamide (NBBA) on lipopolysaccharide (LPS)-induced IL-6 and prostaglandin E2 (PGE2) production in human gingival fibroblasts (HGFs). MATERIAL AND METHODS: The benzamide compound was synthesized. The condition for IL-6 production of HGFs after induction with LPS was optimized. The HGFs were incubated with NBBA (10 ug/ml) for 30 min before LPS (1 MUg/ml) was added. After 24 h of incubation time, the culture media were harvested and their IL-6 and PGE2 contents were determined using an enzyme-linked immunosorbent assay. Prednisolone (PDS) and NS-398 were used as positive controls. Statistical analysis of the IL-6 and PGE2 contents was performed using the ANOVA test followed by the Tukey multiple-comparisons test to compare replicate means. p < 0.001 was considered statistically significant. RESULTS: The maximum IL-6 production was achieved when HGFs were exposed to 1 MUg/ml of LPS for 24 h, which was inhibited by the IL-6 immunosuppressant PDS. The benzamide compound, NBBA, exhibited a potent anti-IL-6 activity with inhibition of 35.6 +/- 0.5%, significantly different from in the LPS-induced HGFs (p < 0.001). In addition, it inhibited 75.6 +/- 0.52% PGE2 production. Cell viability was not significantly affected by treatment with NBBA at a concentration <10 ug/ml (p < 0.001). CONCLUSIONS: NBBA exhibited an inhibitory effect on the production of IL 6 and PGE2 in LPS-induced HGFs. It could serve as a compound with inhibiting inflammatory activity in periodontal disease. PMID- 26536615 TI - Exenatide Facilitates Recovery from Oxaliplatin-Induced Peripheral Neuropathy in Rats. AB - BACKGROUND: Oxaliplatin has widely been used as a key drug in the treatment of colorectal cancer; however, it causes peripheral neuropathy. Exenatide, a glucagon-like peptide-1 (GLP-1) agonist, is an incretin mimetic secreted from ileal L cells, which is clinically used to treat type 2 diabetes mellitus. GLP-1 receptor agonists have been reported to exhibit neuroprotective effects on the central and peripheral nervous systems. In this study, we investigated the effects of exenatide on oxaliplatin-induced neuropathy in rats and cultured cells. METHODS: Oxaliplatin (4 mg/kg) was administered intravenously twice per week for 4 weeks, and mechanical allodynia was evaluated using the von Frey test in rats. Axonal degeneration was assessed by toluidine blue staining of sciatic nerves. RESULTS: Repeated administration of oxaliplatin caused mechanical allodynia from day 14 to 49. Although the co-administration of extended-release exenatide (100 MUg/kg) could not inhibit the incidence of oxaliplatin-induced mechanical allodynia, it facilitated recovery from the oxaliplatin-induced neuropathy with reparation of axonal degeneration. Inhibition of neurite outgrowth was evaluated in cultured pheochromocytoma 12 (PC12) cells. Exenatide inhibited oxaliplatin-induced neurite degeneration, but did not affect oxaliplatin-induced cell injury in cultured PC12 cells. Additionally, extended release exenatide had no effect on the anti-tumor activity of oxaliplatin in cultured murine colon adenocarcinoma 26 (C-26) cells or C-26 cell-implanted mice. CONCLUSION: These results suggest that exenatide may be useful for treating peripheral neuropathy induced by oxaliplatin in colorectal cancer patients with type 2 diabetes. PMID- 26536616 TI - Infection of Human Retinal Pigment Epithelium with Chlamydia trachomatis. AB - PURPOSE: Little is known about the susceptibility of posterior segment tissues, particularly the human retinal pigment epithelium (hRPE), to Chlamydia trachomatis. The purpose of the study was to investigate the possibility of infecting the hRPE with Chlamydia trachomatis, and to examine the infectivity of different Chlamydia trachomatis clinical isolates for hRPE cells and the hRPE cell response to the infection. METHODS: Cultured hRPE and McCoy cells were inoculated with eight Chlamydia trachomatis (serovar E) clinical isolates at multiplicity of infection (MOI) of 2.0 or 0.3. To detect Chlamydia trachomatis, samples were stained immunohistochemically with anti-major outer membrane protein antibodies at 24h, 48h, and 72h postinoculation (PI). The changes in the expression of signaling molecules and proteins of cytoskeleton and extracellular matrix in hRPE cells were examined immunohistochemically. RESULTS: All eight clinical isolates demonstrated ability to infect hRPE cells. At equal MOI of 0.3, the infectivity of Chlamydia trachomatis clinical isolates for RPE culture was found to be at least as high as that for McCoy cell culture. At 24h PI, the percentage of inclusion-containing cells varied from 1.5 +/- 0.52 to 14.6 +/- 3.3% in hRPE cell culture infected at MOI of 2.0 against 0.37 +/- 0.34 to 8.9 +/- 0.2% in McCoy cell culture infected at MOI of 0.3. Collagen type I, collagen type IV, basic fibroblast growth factor, transforming growth factor-beta and interleukin-8 expression at 48h PI were maximally increased, by 2.1-, 1.3-, 1.5-, 1.5- and 1.6-fold, respectively, in the Chlamydia trachomatis-infected compared with control hRPE cell culture specimens (P < 0.05). CONCLUSIONS: This study, for the first time, proved the possibility of infecting hRPE cultured cells with Chlamydia trachomatis, which leads to proproliferative and proinflammatory changes in the expression of signaling molecules and extracellular matrix components. PMID- 26536617 TI - A Descriptive in vitro Electron Microscopic Study of Acidic Fluoride-Treated Enamel: Potential Anti-Erosion Effects. AB - This study aimed to investigate the surface zones of acidic fluoride-treated enamel. Human teeth were each divided into three or four enamel specimens that were treated for 10 min with solutions of 0.2 and 0.4% HF (pH 3.09 and 2.94), 1.74% SnF2 (pH 2.9), 0.68% TiF4 (pH 1.6) and 0.84% NaF (pH 4.5). Untreated specimens functioned as negative controls. The microstructure and elemental composition of the surface zones were studied by scanning electron microscopy/energy-dispersive X-ray (EDX) analysis, transmission electron microscopy (TEM) and nanospot-EDX following cross-sectional preparation using focused ion beam technology. TEM/EDX analyses of NaF-treated specimens showed a 500-nm-thick closed surface film containing 20-40 at% (atomic percent) F. HF treated specimens had a distinct surface film 200-600 nm thick (dense, not globular) containing 45-47 at% F. TiF4-treated specimens had a surface film of 200-300 nm in thickness containing 8-11 at% Ti but no detectable fluoride. SnF2 treated specimens had a modified surface enamel layer varying in thickness from 200 to 800 nm with an inhomogeneous distribution of Sn. Local spots were detected with as high as 8 at% Sn (30 wt%, weight percent). The results suggest that the reaction mechanisms of SnF2 and TiF4 solutions with dental enamel differ from those occurring after enamel exposure to acidulated NaF and HF solutions. While the HF and NaF treatments resulted in the formation of CaF2-like material as shown by EDX, no significant surface fluoridation was found for SnF2 and TiF4 solutions within the TEM/EDX detection limits. These results suggest that the erosion-protective mechanisms of these latter compounds probably relate more to the formation of hardly soluble and acid-resistant reaction surface films and less to surface fluoride incorporation. PMID- 26536618 TI - Objectively Measured Daily Steps and Subsequent Long Term All-Cause Mortality: The Tasped Prospective Cohort Study. AB - BACKGROUND: Self-reported physical activity has been inversely associated with mortality but the effect of objectively measured step activity on mortality has never been evaluated. The objective is to determine the prospective association of daily step activity on mortality among free-living adults. METHODS AND FINDINGS: Cohort study of free-living adults residing in Tasmania, Australia between 2000 and 2005 who participated in one of three cohort studies (n = 2 576 total participants). Daily step activity by pedometer at baseline at a mean of 58.8 years of age, and for a subset, repeated monitoring was available 3.7 (SD 1.3) years later (n = 1 679). All-cause mortality (n = 219 deaths) was ascertained by record-linkage to the Australian National Death Index; 90% of participants were followed-up over ten years, until June 2011. Higher daily step count at baseline was linearly associated with lower all-cause mortality (adjusted hazard ratio AHR, 0.94; 95% CI, 0.90 to 0.98 per 1 000 steps; P = 0.004). Risk was altered little by removing deaths occurring in the first two years. Increasing baseline daily steps from sedentary to 10 000 steps a day was associated with a 46% (95% CI, 18% to 65%; P = 0.004) lower risk of mortality in the decade of follow-up. In addition, those who increased their daily steps over the monitoring period had a substantial reduction in mortality risk, after adjusting for baseline daily step count (AHR, 0.39; 95% CI, 0.22 to 0.72; P = 0.002), or other factors (AHR, 0.38; 95% CI, 0.21-0.70; P = 0.002). CONCLUSIONS: Higher daily step count was linearly associated with subsequent long term mortality among free living adults. These data are the first to quantify mortality reductions using an objective measure of physical activity in a free living population. They strongly underscore the importance of physical inactivity as a major public health problem. PMID- 26536619 TI - Placebo Devices as Effective Control Methods in Acupuncture Clinical Trials: A Systematic Review. AB - While the use of acupuncture has been recognised by the World Health Organisation, its efficacy for many of the common clinical conditions is still undergoing validation through randomised controlled trials (RCTs). A credible placebo control for such RCTs to enable meaningful evaluation of its efficacy is to be established. While several non-penetrating acupuncture placebo devices, namely the Streitberger, the Park and the Takakura Devices, have been developed and used in RCTs, their suitability as inert placebo controls needs to be rigorously determined. This article systematically reviews these devices as placebo interventions. Electronic searches were conducted on four English and two Chinese databases from their inceptions to July 2014; hand searches of relevant references were also conducted. RCTs, in English or Chinese language, comparing acupuncture with one of the aforementioned devices as the control intervention on human participants with any clinical condition and evaluating clinically related outcomes were included. Thirty-six studies were included for qualitative analysis while 14 were in the meta-analysis. The meta-analysis does not support the notion of either the Streitberger or the Park Device being inert control interventions while none of the studies involving the Takakura Device was included in the meta analysis. Sixteen studies reported the occurrence of adverse events, with no significant difference between verum and placebo acupuncture. Author-reported blinding credibility showed that participant blinding was successful in most cases; however, when blinding index was calculated, only one study, which utilised the Park Device, seemed to have an ideal blinding scenario. Although the blinding index could not be calculated for the Takakura Device, it was the only device reported to enable practitioner blinding. There are limitations with each of the placebo devices and more rigorous studies are needed to further evaluate their effects and blinding credibility. PMID- 26536620 TI - Dose-Dependent Mutation Rates Determine Optimum Erlotinib Dosing Strategies for EGFR Mutant Non-Small Cell Lung Cancer Patients. AB - BACKGROUND: The advent of targeted therapy for cancer treatment has brought about a paradigm shift in the clinical management of human malignancies. Agents such as erlotinib used for EGFR-mutant non-small cell lung cancer or imatinib for chronic myeloid leukemia, for instance, lead to rapid tumor responses. Unfortunately, however, resistance often emerges and renders these agents ineffective after a variable amount of time. The FDA-approved dosing schedules for these drugs were not designed to optimally prevent the emergence of resistance. To this end, we have previously utilized evolutionary mathematical modeling of treatment responses to elucidate the dosing schedules best able to prevent or delay the onset of resistance. Here we expand on our approaches by taking into account dose dependent mutation rates at which resistant cells emerge. The relationship between the serum drug concentration and the rate at which resistance mutations arise can lead to non-intuitive results about the best dose administration strategies to prevent or delay the emergence of resistance. METHODS: We used mathematical modeling, available clinical trial data, and different considerations of the relationship between mutation rate and drug concentration to predict the effectiveness of different dosing strategies. RESULTS: We designed several distinct measures to interrogate the effects of different treatment dosing strategies and found that a low-dose continuous strategy coupled with high dose pulses leads to the maximal delay until clinically observable resistance. Furthermore, the response to treatment is robust against different assumptions of the mutation rate as a function of drug concentration. CONCLUSIONS: For new and existing targeted drugs, our methodology can be employed to compare the effectiveness of different dose administration schedules and investigate the influence of changing mutation rates on outcomes. PMID- 26536621 TI - The Safety of Lithium. PMID- 26536622 TI - Coagulation disorders - recent lessons from clinical conditions. PMID- 26536623 TI - [The ambivalence of progress - do we need a less-is-more strategy?**. **Extract from the programmtic opening speech delivered at the 59th Annual GTH Congress 2015]. AB - Economizing health care systems has led to industrialized hospitals. The consequences and side effects are substantial and rather promote costs explosion due to the dictated increase in cases and efficiency. Hence, position sensing and change in direction are required. Effective ways to find out of the current crisis are discussed. PMID- 26536624 TI - Radiocesium accumulation properties of Chengiopanax sciadophylloides. AB - Through the assessments of radioactive contamination after the Fukushima Dai-ichi Nuclear Power Plant (F1NPP) accident, it has been reported that some sprouts of Chengiopanax sciadophylloides (Franch. et Sav.) at the site contained radiocesium (((134),)(137)Cs) at higher concentrations than the other plants. To assess the phytoremediation properties of C. sciadophylloides for (137)Cs decontamination, we aimed to quantify the (137)Cs accumulation in C. sciadophylloides. We measured the (137)Cs concentrations in various organs of C. sciadophylloides collected from the forest in the town of Kawamata, Fukushima prefecture, together with the concentrations of other elements [potassium (K), rubidium, (133)Cs, calcium, strontium, and manganese] present. In addition, we compared the foliar concentrations of these elements in C. sciadophylloides with those in four different deciduous tree species. The mean of foliar (137)Cs concentration in C. sciadophylloides was 28.1 kBq kg(-1) DW, one order of magnitude higher than that found in the other species. The (137)Cs concentrations were in the order of leaves > bark > wood. The wood of the treetop, leaf scars, and roots contained higher amounts of (137)Cs than that of the trunk. From the distribution of (137)Cs in C. sciadophylloides, we confirmed that (137)Cs tends to accumulate in the young growing parts. The difference in the distribution of (137)Cs and (133)Cs indicated that surface uptake of (137)Cs occurs. A significant correlation between K and (137)Cs concentrations in each organ was found, which suggested that (137)Cs in the plant body is transferred through the same pathway as K. On the other hand, there was no correlation between foliar K and (137)Cs concentrations, implying that the uptake ratio of K to (137)Cs was different for each individual. To determine the factors driving specific (137)Cs accumulation and/or the variability of the ratio between K and (137)Cs, the distribution of (137)Cs and the root in soil, the difference of the expression of transporter, and the existence of mycorrhizal fungi should be considered. However, further research is required. PMID- 26536625 TI - Composition of Carotenoids and Flavonoids in Narcissus Cultivars and their Relationship with Flower Color. AB - Narcissus is widely used for cut flowers and potted plants, and is one of the most important commercial bulbous flowers in the floricultural industry. In this study, ten carotenoid and eighteen flavonoid compounds from the perianths and coronas of fifteen narcissus cultivars were measured by HPLC-APCI-MS/MS and UPLC Q-TOF-MS/MS. Among these, six carotenoids, a total of seventeen flavonols and chlorogenic acid were identified in narcissus for the first time. A multivariate analysis was used to explore the relationship between flower color and pigment composition. We found that all-trans-violaxanthin and total carotenoid content were the main factors that affected flower color. These investigations could provide a global view of flower color formation and a theoretical basis for hybridization breeding in narcissus. PMID- 26536626 TI - Cost-Effectiveness and Cost Thresholds of Generic and Brand Drugs in a National Chronic Hepatitis B Treatment Program in China. AB - Chronic liver disease and liver cancer associated with chronic hepatitis B (CHB) are leading causes of death among adults in China. Although newborn hepatitis B immunization has successfully reduced the prevalence of CHB in children, about 100 million Chinese adults remain chronically infected. If left unmanaged, 15-25% will die from liver cancer or liver cirrhosis. Antiviral treatment is not necessary for all patients with CHB, but when it is indicated, good response to treatment would prevent disease progression and reduce disease mortality and morbidity, and costly complications. The aim of this study is to analyze the cost effectiveness of generic and brand antiviral drugs for CHB treatment in China, and assessing various thresholds at which a highly potent, low resistance antiviral drug would be cost-saving and/or cost-effective to introduce in a national treatment program. We developed a Markov simulation model of disease progression using effectiveness and cost data from the medical literature. We measured life-time costs, quality adjusted life years (QALYs), incremental cost effectiveness ratios (ICERs), and clinical outcomes. The no treatment strategy incurred the highest health care costs ($12,932-$25,293) per patient, and the worst health outcomes, compared to the antiviral treatment strategies. Monotherapy with either entecavir or tenofovir yielded the most QALYs (14.10 19.02) for both HBeAg-positive and negative patients, with or without cirrhosis. Threshold analysis showed entercavir or tenofovir treatment would be cost saving if the drug price is $32-75 (195-460 RMB) per month, highly cost-effective at $62 110 (379-670 RMB) per month and cost-effective at $63-120 (384-734 RMB) per month. This study can support policy decisions regarding the implementation of a national health program for chronic hepatitis B treatment in China at the population level. PMID- 26536627 TI - Generation of Novel Chimeric Mice with Humanized Livers by Using Hemizygous cDNA uPA/SCID Mice. AB - We have used homozygous albumin enhancer/promoter-driven urokinase-type plasminogen activator/severe combined immunodeficient (uPA/SCID) mice as hosts for chimeric mice with humanized livers. However, uPA/SCID mice show four disadvantages: the human hepatocytes (h-heps) replacement index in mouse liver is decreased due to deletion of uPA transgene by homologous recombination, kidney disorders are likely to develop, body size is small, and hemizygotes cannot be used as hosts as more frequent homologous recombination than homozygotes. To solve these disadvantages, we have established a novel host strain that has a transgene containing albumin promoter/enhancer and urokinase-type plasminogen activator cDNA and has a SCID background (cDNA-uPA/SCID). We applied the embryonic stem cell technique to simultaneously generate a number of transgenic lines, and found the line with the most appropriate levels of uPA expression-not detrimental but with a sufficiently damaged liver. We transplanted h-heps into homozygous and hemizygous cDNA-uPA/SCID mice via the spleen, and monitored their human albumin (h-alb) levels and body weight. Blood h-alb levels and body weight gradually increased in the hemizygous cDNA-uPA/SCID mice and were maintained until they were approximately 30 weeks old. By contrast, blood h-alb levels and body weight in uPA/SCID chimeric mice decreased from 16 weeks of age onwards. A similar decrease in body weight was observed in the homozygous cDNA-uPA/SCID genotype, but h-alb levels were maintained until they were approximately 30 weeks old. Microarray analyses revealed identical h-heps gene expression profiles in homozygous and hemizygous cDNA-uPA/SCID mice were identical to that observed in the uPA/SCID mice. Furthermore, like uPA/SCID chimeric mice, homozygous and hemizygous cDNA-uPA/SCID chimeric mice were successfully infected with hepatitis B virus and C virus. These results indicate that hemizygous cDNA-uPA/SCID mice may be novel and useful hosts for producing chimeric mice for use in future long term studies, including hepatitis virus infection analysis or drug toxicity studies. PMID- 26536628 TI - Influence of the Lactotripeptides Isoleucine-Proline-Proline and Valine-Proline Proline on Systolic Blood Pressure in Japanese Subjects: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: The lactotripeptides isoleucine-proline-proline (IPP) and valine proline-proline (VPP) have been shown to decrease systolic blood pressure (SBP) in several populations, but the size of the effect varies among studies. We performed a meta-analysis including all published studies to evaluate the SBP lowering effect of IPP/VPP in Japanese subjects more comprehensively. METHODS AND FINDINGS: Eligible randomized controlled trials were searched for within four bibliographic databases, including two Japanese ones. Eighteen studies (including a total of 1194 subjects) were included in the meta-analysis. A random effect model using the restricted maximum likelihood (REML) estimator was used for the analysis. The analysis showed that consumption of IPP/VPP induced a significant reduction in SBP as compared with placebo in Japanese subjects, with an estimated effect of -5.63 mm Hg (95% CI, -6.87 to -4.39, P<0.0001) and no evidence of publication bias. A significant heterogeneity between series was evident, which could be explained by a significant influence of the baseline blood pressure status of the subjects, the effect of IPP/VPP on SBP being stronger in hypertensive subjects (-8.35 mm Hg, P<0.0001) than in non-hypertensive subjects ( 3.42mm Hg, P<0.0001). Furthermore, the effect of IPP/VPP on SBP remained significant when limiting the analysis to series that tested the usual doses of IPP/VPP consumed daily (below 5 mg/d), with estimated effects of -6.01 mm Hg in the overall population and -3.32 mm Hg in non-hypertensive subjects. CONCLUSIONS: Results from this meta-analysis show that IPP/VPP lactotripeptides can significantly reduce office SBP in Japanese subjects with or without overt hypertension, and for doses that can potentially be consumed as an everyday supplement. This suggests that these peptides could play a role in controlling blood pressure in Japanese subjects. The systematic review protocol was published on the PROSPERO register (CRD42014014322). PMID- 26536629 TI - Correlations between ASCC3 Gene Polymorphisms and Chronic Hepatitis B in a Chinese Han Population. AB - We have previously identified 8 SNPs in Han Chinese HBV carriers that are associated with disease progression. Although not well studied, genetic factors may also play a significant role in developing chronic HBV disease after exposure. We extend the effect of these eight SNPs on persistent HBV infection in this study. A total of 875 unrelated Han Chinese, 493 chronic hepatitis B subjects (CHB) and 382 HBV clearance individuals (Clear), were recruited from Hubei Province from September 2007 to March 2010. SNPs were verified by using TaqMan 7900HT Sequence Detection System. By using multiple logistic regression analysis, each of the 8 SNP associations was tested using 3 different genetic models (Dominant, Recessive and Additive model), in 4 types of analyses (full sample, men, women, age stratified). A Bonferroni correction was used to account for multiple statistical tests for each SNP association (P<0.05/8 = 0.0063). A significant correlation was observed at SNP rs10485138 located in ASCC3 gene in female patients (OR, 0.445; 95% CI, 0.253-0.784; P = 0.005). Females bearing C allele infected by HBV had an increased susceptibility to CHB compared with those T allele carriers. Our results indicated that SNP rs10485138 located in ASCC3 gene was associated with persistent HBV infection in Han Chinese. PMID- 26536630 TI - Role of peroxynitrite induced structural changes on H2B histone by physicochemical method. AB - Histones are small highly conserved cationic proteins which bind DNA and remain confined in the nucleus. These histones are quite vulnerable to oxidizing and nitrating agents. Peroxynitrite is a powerful oxidant and nitrating agent present in the biological system. In this study, peroxynitrite-induced nitration and oxidation of H2B was assessed by various physicochemical techniques. The carbonyl content and dityrosine were markedly elevated in peroxynitrite-modified H2B histone as compared to the native histone. Cross-linking of H2B was evident on polyacrylamide gel electrophoresis. 3-Nitrotyrosine was present only in peroxynitrite-modified H2B revealed by HPLC. The results showed that peroxynitrite-mediated nitration and oxidation in H2B histone exhibited hyperchromicity, decrease of tyrosine fluorescence accompanied by increase in ANS binding specific fluorescence, loss of beta-sheet structure, appearance of new peak in FT-IR, increase in melting temperature and also loss of alpha-helix to produce a partially folded structure in comparison to intrinsically disordered structure of native H2B histone. We concluded that the H2B histone, a constituent of core histones, is highly sensitive to peroxynitrite and can adopt different structures under nitrosative and oxidative stress in order to protect the packaged DNA from the deleterious insult of peroxynitrite. PMID- 26536632 TI - [Therapy for thalassemia and sickle-cell disease]. PMID- 26536631 TI - Methamphetamine-induced deficits in social interaction are not observed following abstinence from single or repeated exposures. AB - The purpose of the current study was to assess social interaction (SI) following acute and repeated methamphetamine (MA) administration. Rats were injected with 5.0 mg/kg of MA and SI was tested 30 min or 24 h later. In another group of animals, MA sensitization was induced using 5.0 mg/kg of MA, and SI was assessed after 1 or 30 days of abstinence. SI was reduced in rats injected with MA 30 min, but not 24 h, before testing, compared with saline controls. Impaired SI was observed in combination with active avoidance of the conspecific animal. Repeated injections of MA progressively reduced locomotor activity and increased stereotypy, indicating that animals were sensitized. However, no differences in SI were observed 24 h or 30 days following the induction of sensitization. The absence of detectable differences in SI following MA sensitization may be attributable to the relatively short regimen used to induce sensitization. However, the current series of experiments provides evidence that an acute injection of MA decreases SI and simultaneously increases avoidance behavior, which supports a link between psychostimulant use and impaired social functioning. These data suggest that the acute injection model may provide a useful model to explore the neural basis of impaired social functioning and antisocial behavior. PMID- 26536633 TI - [Response]. PMID- 26536634 TI - [Does a decreased renal function reduce hearing capacity?]. PMID- 26536635 TI - [Endoscopic papillotomy doesn't increase cancer risk]. PMID- 26536636 TI - [37-year old pregnant woman with dyspnea and variable ECG-alterations]. PMID- 26536637 TI - [60-year old man with progressive cough and dyspnea after seasonal flu shot]. PMID- 26536638 TI - [Does an ICD-implantation make sense in older patients?]. PMID- 26536639 TI - [Metformin is commonly used in patients with renal impairment]. PMID- 26536640 TI - [63-year old patient with anginous symptoms and dyspnea]. PMID- 26536641 TI - [Underestimated osteoporosis: New directions in diagnosis and therapy]. PMID- 26536642 TI - [Vitamin D supplementation for everybody everytime?]. AB - Only few foods contain vitamin D in higher concentrations. Therefore, the main source of vitamin D is the dermal synthesis under the influence of UVB-light. By enzymatic hydroxylation vitamin D is converted to 25-hydroxy-vitamin D and finally to the active hormone 1,25-dihydroxy-vitamin D, which plays an important role in calcium- and bone metabolism. Vitamin D-deficiency can result in demineralisation of the bone. The vitamin D-receptor is expressed by all nucleated cells of the body and vitamin D regulates many cellular functions. Sublinical vitamin D-deficiency is common even in the normal population resulting in a risk situation for at least osteoporosis and falls in older people. This is the reason for fortification of food in some countries by vitamin D. Also in Germany vitamin D-deficiency can be detected in many people leading to the question: is vitamin D supplementation necessary for everyone? PMID- 26536643 TI - [Diagnosing osteoporosis: what is new in the 2014 DVO guideline?]. AB - Suitable diagnostic strategies beyond general measures of fracture prevention which allow the identification of those individuals who are likely to benefit most from medical treatment are of utmost importance for an efficient treatment of osteoporosis. Since 2003 the "Dachverband Osteologie" (DVO) provides recommendations for the diagnostics and treatment of osteoporosis in German speaking regions. The most recent update was in November 2014. The DVO guideline provides detailed recommendations for a diagnostic examination depending on age, gender, and the presence and strength of clinical risk factors. The number of clinical fractures risks on which the diagnostic and therapeutic recommendations of the DVO guideline 2014 are based has increased in comparison to the DVO guideline 2009. In addition to the fracture risks listed in the previous version of the DVO guideline the list now also includes monoclonal gammopathy of unknown significance, ankylosing spondylitis, COPD, heart failure, celiac disease, type 2 diabetes mellitus, long-term treatment with proton pump inhibitors and a treatment with high-dose inhaled glucocorticoids. For all persons with an increased fracture risk the guideline recommends a diagnostic workup, comprising medical history, clinical examination including assessment of fall risk, DXA measurements at the lumbar spine, proximal total femur and femoral neck, blood analysis and, if indicated, appropriate imaging procedures. The trabecular bone score offers a new diagnostic option for fracture prediction. PMID- 26536644 TI - [Therapy of osteoporosis: towards personalized treatment?]. AB - Osteoporosis is the most common clinical disorder of bone metabolism. With regard to the growing spectrum of therapy options, treatment decisions should be made on an individual basis, taking into account the relative benefits and risks in different patient populations. Prioritization of drugs should be based on the form (primary / secondary) and severity of osteoporosis, sex, age, the specific contraindications and precautions of use of the various available medications and in particular, existing comorbidities. PMID- 26536645 TI - [Critical care ultrasound of the thorax - what is the procedure?]. AB - Despite the limitations (especially that ultrasound does not penetrate air containing lung tissue) ultrasound of the thorax is a very suitable method as a complementary or even primary diagnostic tool. Bedside availability and no radiation exposure are real advantages. However we always have to keep in mind that we are blind for deeper lung processes that do not have contact to the visceral pleura.This article illustrates where and how to look for pathologies and what we have to expect in patients. According to symptoms such as dyspnea, dyspnea with fever and thorax pain with and without trauma, the sonographic morphology of important illnesses in emergency situation are described. The use of ultrasound can help to distinguish between differential diagnosis such as acute exacerbation of COPD vs. heart failure, pleuritis vs. pulmonary embolism, rip fracture vs. "simple" bone contusion and blunt chest trauma with or without pneumothorax. PMID- 26536646 TI - [Non-celiac disease non-wheat allergy wheat sensitivity]. AB - Non-celiac non-wheat allergy wheat sensitivity is regarded as discrete glutensensitivity diagnosed after the exclusion of celiac disease and wheat allergy. Due to the absence of reliable biomarkers no exact prevalence rates are known and estimations range between 0,5-6 %. Soon after ingestion of wheat, patients complain of intestinal symptoms mainly bloating, abdominal pain, diarrhea or nausea which improve fast under glutenfree diet. Often extraintestinal manifestation as tiredness, muscle or joint pain, headache and depression are reported. Actually, there are no serological markers and no intestinal mucosal damage was found in patients. The underlying mechanism of the disease is completely unknown and beside of gluten other wheat proteins as well as amylase-trypsin-inhibitor or short chain sugars are discussed as triggers. In addition, the involvement of the intestinal microbiome in pathology of glutensensitivity must be considered. PMID- 26536647 TI - [New occupational diseases in Germany]. AB - Every physician is legally required to officially report potential occupational diseases in case of reasonable suspicion.Due to these legal reporting requirements, knowledge about occupational diseases including necessary actualizations is essential for all physicians. In January 2015 the third regulation to change the Ordinance on Occupational Diseases came into force, adding four new diseases to the existing list of occupational diseases. New diseases include a laryngeal carcinoma caused by intensive and perennial exposition to aerosols containing sulphuric acid, and squamos-cell carcinoma or multiple actinic keratosis of the skin caused by natural UV radiation. Furthermore the carpal tunnel syndrome, a pressure damage of the Nervus medianus, caused by repetitive manual tasks with flexion and extension of wrists has been added as well as the hypothenar- and thenar-hammer-syndrome which are vascular damages of the hand caused by shock-type application of force. PMID- 26536648 TI - [Generation Y and the quality of internal medicine - are there any solutions for a serious dilemma?]. PMID- 26536649 TI - [Yellow-nail-Syndrome associated with chronic sinusitis and recurrent pneumonias]. AB - HISTORY AND CLINICAL FINDINGS: In a 58-year-old man progressive yellowing of all nails was associated with the diagnosis of chronic rhinosinusitis and COPD, later the COPD exacerbated with pneumonias. INVESTIGATIONS: Repeated fungal cultures and polymerase chain reactions to detect fungal DNA in order to exclude Onychomycosis, chest X-ray, computed tomography of the lung, extended pulmonary function tests, ECG, echocardiography and abdominal ultrasonography were performed and had normal results. TREATMENT AND COURSE: Normal fingernails regrew after a 6 month-course of vitamin E intake, most of the toenails remained coloured and thickened. After the initial presentation at the dermatological outpatient department the pulmonary situation remained stable, there was no need for additional pulmonary interventions. CONCLUSION: Yellowing of all nails is a diagnostic sign of the Yellow-nail-Syndrome, which is associated with respiratory diseases, the treatment is often difficult and also an interdisciplinary approach is needed. PMID- 26536650 TI - [Other countries, other customs - understanding patients with a migration background]. PMID- 26536651 TI - [Symptom experience of patients after allogenic renal transplantation]. AB - BACKGROUND: Quality of life and medication adherence of patients after renal transplantation (RTx) is most affected by problems associated with immunosuppressive symptoms. However, these problems are often underestimated in frequency and level of distress by professionals involved in transplantation. The aim of this study was to determine symptom occurrence and distress associated with current immunosuppressive medication following RTx. METHOD: A cross sectional study was conducted to assess symptom experience using the Modified Transplant Symptom Occurrence and Symptom Distress Scale-Revised 59 with bivariate subgroup analysis. RESULTS: 605 renal transplant recipients completed the survey. The most common symptoms were dry skin, erectile problems, bruises, muscle weakness and tiredness. The erectile problems, menstrual problems, sores or warts around genitals, feelings of anxiety and joint pain appeared to be the most distressing symptoms. A significantly higher level of symptom prevalence and distress was associated with a number of sociodemographic, disease-related and drug-related factors. CONCLUSION: The study results increase awareness for a careful symptom assessment and provide the basis for strategies to control symptoms. That should lead to improved quality of life and medication adherence with long patient and graft survival. PMID- 26536652 TI - [The availability of living wills in an interdisciplinary emergency department: results of a patient survey]. AB - INTRODUCTION: Despite an increasing attention to living wills, the effects of such living wills on patient care in the emergency departments remains unknown. MATERIAL AND METHODS: All patients who were admitted to our emergency department between September 24th, 2014 and November 23th, 2014 were asked, whether they have signed living wills previously and if so, whether they have it on hand at admission. RESULTS: 496 patients (229 men (46.2 %), 267 women (53.8 %)) with a mean age of 64.9 +/- 18.8 years were included in this survey. 138 patients (27.8 %) had a living will but only 16 patients (3.2 %) had it on hand.Altogether, the existence of living wills increased with an increasing patient's age; only 5 of 117 patients aged 50 years old or younger (4,3 %) had a living will, but 133 of 379 patients older than 50 years (35,1 %). DISCUSSION AND CONCLUSION: Despite an obviously broad acceptance of living wills especially in the elderly population, there are hardly any consequences on the daily patient care in an emergency department by now, as hardly any patient has hers or his living will on hand at admission. We therefore see the need for further educational work to guarantee that living wills get adequate priority in patient care at emergency departments. PMID- 26536653 TI - Hypericum perforatum use during pregnancy and pregnancy outcome. AB - Hypericum perforatum (HP; also known as St. John's Wort) is one of the most commonly used herbal therapies in the management of depressive illness. The aim of this study was to evaluate the potential side effects of HP during pregnancy on pregnancy outcome. Using data from the Danish National Birth Cohort (DNBC), we investigated outcomes among 38 HP exposed pregnancies compared to a group of 90,128 women. Associations between HP use and gestational age, preterm birth, birth weight, malformations and Apgar scores were investigated. Preterm birth did not differ across the groups. While the prevalence of malformations in the HP exposed group was slightly higher (8.1%) than observed in the control groups (3.3%; p=0.13), this was based on only three cases and was not of any specific pattern. PMID- 26536654 TI - A Simulation Study of the Effect of Phase-Shift on Dual Gated Myocardial Perfusion ECT. AB - We evaluated the effect of relative phase-shift of cardiac and respiratory (C&R) motions in myocardial perfusion (MP) ECT. Previously, we generated a set of realistic 3D XCAT (eXtended CArdiac Torso) phantoms that model simultaneous C&R motions for use in the study of new data acquisition methods and corrective image reconstruction techniques for improved gated MP ECT, including PET and SPECT. The respiratory motion (RM) over a respiration cycle was modeled using 24 equally spaced time frames while the cardiac beating motion (CBM) over a cardiac cycle was divided into 48 equally-spaced time frames for each of the 24 RM phases. Almost noise-free projection datasets were generated separately from the heart, blood pool, lungs, liver, kidneys, stomach, gall bladder and remaining body at each of the 24 * 48 time points using Monte Carlo simulation techniques that include the effect of collimator detector response, photon attenuation and scatter. To demonstrate the effect of relative phase-shift, a typical 99mTc Sestamibi MP SPECT projection dataset were generated. They were then scaled and combined to model different degrees of relative C&R phase shifting and grouped into 6 respiratory-gates with 8 cardiac-gates. Each projection was reconstructed using a 3D OS-EM without and with attenuation correction using an averaged and phase-mismatched gated attenuation maps. The image artifacts of the reconstructed images were compared by visual inspection of the MP polar maps. The results showed significant changes of artifactual non-uniformity in the polar maps for off-phase of RM compared to those of CBM. The changes in the polar maps also demonstrated the effect of phase shifting accordingly. We conclude that the 4D XCAT phantom dataset with simultaneous C&R motions provides a powerful tool in the study of the effects of C&R motions with relative phase shifts, and development of C&R gating schemes and motion correction methods for improved ECT/CT imaging. PMID- 26536655 TI - Genome-Wide DNA Methylation Patterns of Bovine Blastocysts Developed In Vivo from Embryos Completed Different Stages of Development In Vitro. AB - Early embryonic loss and altered gene expression in in vitro produced blastocysts are believed to be partly caused by aberrant DNA methylation. However, specific embryonic stage which is sensitive to in vitro culture conditions to alter the DNA methylation profile of the resulting blastocysts remained unclear. Therefore, the aim of this study was to investigate the stage specific effect of in vitro culture environment on the DNA methylation response of the resulting blastocysts. For this, embryos cultured in vitro until zygote (ZY), 4-cell (4C) or 16-cell (16C) were transferred to recipients and the blastocysts were recovery at day 7 of the estrous cycle. Another embryo group was cultured in vitro until blastocyst stage (IVP). Genome-wide DNA methylation profiles of ZY, 4C, 16C and IVP blastocyst groups were then determined with reference to blastocysts developed completely under in vivo condition (VO) using EmbryoGENE DNA Methylation Array. To assess the contribution of methylation changes on gene expression patterns, the DNA methylation data was superimposed to the transcriptome profile data. The degree of DNA methylation dysregulation in the promoter and/or gene body regions of the resulting blastocysts was correlated with successive stages of development the embryos advanced under in vitro culture before transfer to the in vivo condition. Genomic enrichment analysis revealed that in 4C and 16C blastocyst groups, hypermethylated loci were outpacing the hypomethylated ones in intronic, exonic, promoter and proximal promoter regions, whereas the reverse was observed in ZY blastocyst group. However, in the IVP group, as much hypermethylated as hypomethylated probes were detected in gene body and promoter regions. In addition, gene ontology analysis indicated that differentially methylated regions were found to affected several biological functions including ATP binding in the ZY group, programmed cell death in the 4C, glycolysis in 16C and genetic imprinting and chromosome segregation in IVP blastocyst groups. Furthermore, 1.6, 3.4, 3.9 and 9.4% of the differentially methylated regions that were overlapped to the transcriptome profile data were negatively correlated with the gene expression patterns in ZY, 4C, 16C and IVP blastocyst groups, respectively. Therefore, this finding indicated that suboptimal culture condition during preimplantation embryo development induced changes in the DNA methylation landscape of the resulting blastocysts in a stage dependent manner and the altered DNA methylation pattern was only partly explained the observed aberrant gene expression patterns of the blastocysts. PMID- 26536656 TI - Male fertility following spinal cord injury: an update. AB - Spinal cord injury (SCI) occurs most often in young men at the peak of their reproductive health. The majority of men with SCI cannot father children naturally. Three major complications contribute to infertility in men with SCI: erectile dysfunction, ejaculatory dysfunction, and abnormal semen quality. Erectile dysfunction can be managed by regimens available to the general population, including oral administration of phosphodiesterase-5 (PDE-5) inhibitors, intracavernosal injections, vacuum devices, and penile prostheses. Semen may be obtained from anejaculatory men with SCI via the medically assisted ejaculation methods of penile vibratory stimulation (PVS) or electroejaculation (EEJ). Sperm retrieval is also possible via prostate massage or surgical sperm retrieval. Most men with SCI have abnormal semen quality characterized by normal sperm concentrations but abnormally low sperm motility and viability. Accessory gland dysfunction has been proposed as the cause of these abnormalities. Leukocytospermia is evident in most SCI patients. Additionally, elevated concentrations of pro-inflammatory cytokines and elevated concentrations of inflammasome components are found in their semen. Neutralization of these constituents has resulted in improved sperm motility. There is a recent and alarming trend in the management of infertility in couples with SCI male partners. Although many men with SCI have sufficient motile sperm in their ejaculates for attempting intrauterine insemination (IUI) or even intravaginal insemination, surgical sperm retrieval is often introduced as the first and only sperm retrieval method for these couples. Surgical sperm retrieval commits the couple to the most advanced, expensive, and invasive method of assisted conception: in vitro fertilization with intracytoplasmic sperm injection (IVF/ICSI). Couples should be informed of all options, including semen retrieval by PVS or EEJ. Intravaginal insemination or IUI should be considered when indicated. PMID- 26536657 TI - HRD1 suppresses the growth and metastasis of breast cancer cells by promoting IGF 1R degradation. AB - HRD1 (3-hydroxy-3-methylglutaryl reductase degradation) is an E3 ubiquitin ligase. We found that HRD1 was significantly downregulated in 170 breast cancer tissues. Low tumoral HRD1 expression was correlated with clinicopathological characteristics and a shorter survival in breast cancer patients. P65 specifically bound to the HRD1 promoter and inhibited HRD1 expression. Suppression of NF-kappaB activity reversed IL-6-induced downregulation of HRD1 expression. HRD1 interacted with IGF-1R and promoted its ubiquitination and degradation by the proteasome. Overexpression of HRD1 resulted in the inhibition of growth, migration and invasion of breast cancer cells in vitro and in vivo. Furthermore, HRD1 attenuated IL-6-induced epithelial-mesenchymal transition in MCF10A cells. These findings uncover a novel role for HRD1 in breast cancer. PMID- 26536658 TI - HOXB9 induction of mesenchymal-to-epithelial transition in gastric carcinoma is negatively regulated by its hexapeptide motif. AB - HOXB9, a transcription factor, plays an important role in development. While HOXB9 has been implicated in tumorigenesis and metastasis, its mechanisms are variable and its role in gastric carcinoma (GC) remains unclear. In the present study, we demonstrated that the expression of HOXB9 decreased in gastric carcinoma and was associated with malignancy and metastasis. Re-expression of HOXB9 in gastric cell lines resulted in the suppression of cell proliferation, migration, and invasion, which was accompanied by the induction of mesenchymal-to epithelial transition (MET). Comparative sequence analysis and examination of a HOXB9 structural model indicated that three sites might possibly be involved in MET regulation. The in vitro study of HOXB9 mutants showed that these were unable to inhibit MET induction. However, when overexpressing a HOXB9 mutant lacking the hexapeptide motif, a more potent MET induction and tumor suppression was observed compared to that of the wild-type, indicating that the presence of the hexapeptide motif reduced HOXB9 MET induction and tumor suppression activity. Therefore, the results of the present study suggested that HOXB9 is a tumor suppressor in gastric carcinoma, and its activity was controlled by different regulatory mechanisms such as the hexapeptide motif as a "brake" in this case. The results of these regulatory effects could lead to either oncogenic or tumor suppressive roles of HOXB9, depending on the context of the particular type of cancer involved. PMID- 26536659 TI - Phosphorylation of nucleophosmin at threonine 234/237 is associated with HCC metastasis. AB - Hepatocellular carcinoma (HCC) is frequently complicated by the occurrence of intrahepatic and extrahepatic metastases, leading to poor prognosis. To improve the prognosis for HCC patients, there is an urgent need to understand the molecular mechanisms of metastasis in HCC. Since protein Serine/Threonine phosphorylation emerges to be an important posttranslational modification critical in signaling process associated with cell proliferation, survival and metastasis, we employed a pair of primary tumor-derived and corresponding lung metastatic counterparts (PLC/PRF/5-PT and PLC/PRF/5-LM) and aimed to identify these changes using CelluSpot Serine/Threonine kinase peptide array. Upon analysis, we found phosphorylated level of nucleophosmin (NPM) at Threonine 234/237 (p-NPM-Thr234/237) had remarkably high level in metastatic HCC cells (PLC LM) than the corresponding primary HCC cell line (PLC-PT). Similar observation was observed in another match primary and their metastatic counterparts (MHCC-97L and MHCC-97H). By immunohistochemical staining, p-NPM-Thr234/237 was consistently found to be preferentially expressed in metastatic HCCs when compared with primary HCC in 28 HCC cases (p < 0.0001). By overexpressing Flag-tagged NPM and its phosphorylation site mutant (Thr234/237A) into low p-NPM-Thr234/237 expressing cells (Hep3B and Huh7) using a lentiviral based approach, we demonstrated that p-NPM-Thr234/237 is critical in invasion and migration of HCC cells, and this effect was mediated by cyclin-dependent kinase 1 (CDK1). Wild type NPM was found to physically interact with a metastatic gene, ROCK2, and defective in Thr234/237 phosphorylation decreased its binding affinity, resulting in decrease in ROCK2 mediated signaling pathway. Identification of CDK1/p NPM/ROCK2 signaling pathway provides a novel target for molecular therapy against HCC metastasis. PMID- 26536660 TI - Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer. AB - Although the role of acyl-CoA synthetase 4 (ACSL4) in mediating an aggressive phenotype is well accepted, there is little evidence as to the early steps through which ACSL4 increases tumor growth and progression. In this study, and by means of the stable transfection of MCF-7 cells with ACSL4 using the tetracycline Tet-Off system (MCF-7 Tet-Off/ACSL4), we identify the mTOR pathway as one of the main specific signatures of ACSL4 expression and demonstrate the partial involvement of the lipoxygenase pathway in the activation of mTOR. The specificity of ACSL4 action on mTOR signaling is also determined by doxycycline inhibition of ACSL4 expression in MCF-7 Tet-Off/ACSL4 cells, by the expression of ACSL4 in the non-aggressive T47D breast cancer cell line and by knocking down this enzyme expression in the MDA-MB-231 breast cancer cells, which constitutively express ACSL4. ACSL4 regulates components of the two complexes of the mTOR pathway (mTORC1/2), along with upstream regulators and substrates.We show that mTOR inhibitor rapamycin and ACSL4 inhibitor rosiglitazone can act in combination to inhibit cell growth. In addition, we demonstrate a synergistic effect on cell growth inhibition by the combination of rosiglitazone and tamoxifen, an estrogen receptor alpha (ERalpha) inhibitor. Remarkably, this synergistic effect is also evident in the triple negative MDA-MB-231 cells in vitro and in vivo.These results suggest that ACSL4 could be a target to restore tumor hormone dependence in tumors with poor prognosis for disease-free and overall survival, in which no effective specifically targeted therapy is readily available. PMID- 26536661 TI - Distribution of metastatic disease in the brain in relation to the hippocampus: a retrospective single-center analysis of 6064 metastases in 632 patients. AB - This study aimed to investigate the patterns of brain metastasis and to explore the risk factors affecting hippocampus metastasis (HM). We retrospectively analyzed the clinical information of patients with metastatic disease in the brain. The associations between clinicopathologic variables with HM and peri hippocampal metastasis (PHM) were evaluated in univariate and multivariate regression analyses. A total of 632 patients with 6064 metastatic lesions were recruited into the present study. Of these, 4.1% (26/632) of patients developed HM, and 5.5% (35/632) of patients developed PHM. Only 0.5% (31/6064) of metastatic lesions were located in the hippocampus and 0.6% (37/6064) were in the PHM. Age <=60 years was an independent risk factor for HM (odds ratio [OR]: 2.602, 95% confidence interval [CI]: 1.115-6.076, P = 0.027) and PHM (OR: 2.555, 95%CI: 1.229-5.310, P = 0.012) in univariate and multivariate analyses. The hippocampus is a rare site of brain metastasis. Younger patients (age <=60 years) had increased risk of developing HM and PHM. The current study provides the opportunity to investigate the clinical feasibility of hippocampal sparing whole brain radiation therapy, especially in older patients. PMID- 26536662 TI - MiR224-3p inhibits hypoxia-induced autophagy by targeting autophagy-related genes in human glioblastoma cells. AB - Human glioblastoma multiforme (GBM) is a malignant solid tumor characterized by severe hypoxia. Autophagy plays a protective role in cancer cells under hypoxia. However, the microRNA (miRNA)-related molecular mechanisms underlying hypoxia reduced autophagy remain poorly understood in GBM. In this study, we performed a miRNA microarray analysis on GBM cells and found that numerous miRNAs were differentially expressed under hypoxic conditions. Further research showed that miR224-3p, one of the significantly down-regulated miRNAs, was involved in regulating hypoxia-induced autophagy in GBM cells. Overexpression of miR224-3p abolished hypoxia-induced autophagy, whereas knocking down endogenous miR224-3p increased autophagic activity under normoxia. In addition, we demonstrated that miR224-3p inhibited autophagy by directly suppressing the expression of two autophagy-related genes (ATGs), ATG5 and FAK family-interacting protein of 200 kDa (FIP200). Furthermore, in vitro, miR224-3p attenuated cell proliferation and promoted hypoxia-induced apoptosis, and in vivo, overexpression of miR224-3p inhibited tumorigenesis of GBM cells. Collectively, our study identified a novel hypoxia-down-regulated miRNA, miR224-3p, as a key modulator of autophagy by inhibiting ATGs in GBM cells. PMID- 26536663 TI - Ack1 overexpression promotes metastasis and indicates poor prognosis of hepatocellular carcinoma. AB - Despite the substantial data supporting the oncogenic role of Ack1, the predictive value and biologic role of Ack1 in hepatocellular carcinoma (HCC) metastasis remains unknown. In this study, both correlations of Ack1 expression with prognosis of HCC, and the role of Ack1 in metastasis of HCC were investigated in vitro and in vivo. Our results showed that Ack1 was overexpressed in human HCC tissues and cell lines. High Ack1 expression was associated with HCC metastasis and determined as a significant and independent prognostic factor for HCC after liver resection. Ack1 promoted HCC invasion and metastasis in vitro and in vivo. Mechanistically, we confirmed that Ack1 enhanced invasion and metastasis of HCC via EMT by mediating AKT phosphorylation. In conclusion, our study shows Ack1 is a novel prognostic biomarker for HCC and promotes metastasis of HCC via EMT by activating AKT signaling. PMID- 26536664 TI - Imaging the distribution of an antibody-drug conjugate constituent targeting mesothelin with 89Zr and IRDye 800CW in mice bearing human pancreatic tumor xenografts. AB - Mesothelin is a tumor differentiation antigen expressed by epithelial tumors, including pancreatic cancer. Currently, mesothelin is being targeted with an antibody-drug conjugate (ADC) consisting of a mesothelin-specific antibody coupled to a highly potent chemotherapeutic drug. Considering the toxicity of the ADC and reduced accessibility of pancreatic tumors, non-invasive imaging could provide necessary information. We therefore developed a zirconium-89 (89Zr) labeled anti-mesothelin antibody (89Zr-AMA) to study its biodistribution in human pancreatic tumor bearing mice. Biodistribution and dose-finding of 89Zr-AMA were studied 144 h after tracer injection in mice with subcutaneously xenografted HPAC. MicroPET imaging was performed 24, 72 and 144 h after tracer injection in mice bearing HPAC or Capan-2. Tumor uptake and organ distribution of 89Zr-AMA were compared with nonspecific 111In-IgG. Biodistribution analyses revealed a dose-dependent 89Zr-AMA tumor uptake. Tumor uptake of 89Zr-AMA was higher than 111In-IgG using the lowest tracer dose. MicroPET showed increased tumor uptake over 6 days, whereas activity in blood pool and other tissues decreased. Immunohistochemistry showed that mesothelin was expressed by the HPAC and CAPAN-2 tumors and fluorescence microscopy revealed that AMA-800CW was present in tumor cell cytoplasm. 89Zr-AMA tumor uptake is antigen-specific in mesothelin expressing tumors. 89Zr-AMA PET provides non-invasive, real-time information about AMA distribution and tumor targeting. PMID- 26536665 TI - Dual mTOR inhibitor MLN0128 suppresses Merkel cell carcinoma (MCC) xenograft tumor growth. AB - Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. Pathologic activation of PI3K/mTOR pathway and elevated expression of c-Myc are frequently detected in MCC. Yet, there is no targeted therapy presently available for this lethal disease. Recently, MLN0128, a second-generation dual TORC1/2 inhibitor is shown to have therapeutic efficacy in preclinical studies. MLN0128 is currently in clinical trials as a potential therapy for advanced cancers. Here we characterize the therapeutic efficacy of MLN0128 in the preclinical setting of MCC and delineate downstream targets of mTORC1/2 in MCC cellular systems. MLN0128 significantly attenuates xenograft MCC tumor growth independent of Merkel cell polyomavirus. Moreover, MLN0128 markedly diminishes MCC cell proliferation and induces apoptosis. Further investigations indicate that senescence does not contribute to MLN0128-mediated repression of xenograft MCC tumor growth. Finally, we also observe robust antitumor effects of MLN0128 when administered as a dual therapy with JQ1, a bromodomain protein BRD4 inhibitor. These results suggest dual blockade of PI3K/mTOR pathway and c-Myc axis is effective in the control of MCC tumor growth. Our results demonstrate that MLN0128 is potent as monotherapy or as a member of combination therapy with JQ1 for advanced MCC. PMID- 26536666 TI - Key Edaphic Properties Largely Explain Temporal and Geographic Variation in Soil Microbial Communities across Four Biomes. AB - Soil microbial communities play a critical role in nutrient transformation and storage in all ecosystems. Quantifying the seasonal and long-term temporal extent of genetic and functional variation of soil microorganisms in response to biotic and abiotic changes within and across ecosystems will inform our understanding of the effect of climate change on these processes. We examined spatial and seasonal variation in microbial communities based on 16S rRNA gene sequencing and phospholipid fatty acid (PLFA) composition across four biomes: a tropical broadleaf forest (Hawaii), taiga (Alaska), semiarid grassland-shrubland (Utah), and a subtropical coniferous forest (Florida). In this study, we used a team based instructional approach leveraging the iPlant Collaborative to examine publicly available National Ecological Observatory Network (NEON) 16S gene and PLFA measurements that quantify microbial diversity, composition, and growth. Both profiling techniques revealed that microbial communities grouped strongly by ecosystem and were predominately influenced by three edaphic factors: pH, soil water content, and cation exchange capacity. Temporal variability of microbial communities differed by profiling technique; 16S-based community measurements showed significant temporal variability only in the subtropical coniferous forest communities, specifically through changes within subgroups of Acidobacteria. Conversely, PLFA-based community measurements showed seasonal shifts in taiga and tropical broadleaf forest systems. These differences may be due to the premise that 16S-based measurements are predominantly influenced by large shifts in the abiotic soil environment, while PLFA-based analyses reflect the metabolically active fraction of the microbial community, which is more sensitive to local disturbances and biotic interactions. To address the technical issue of the response of soil microbial communities to sample storage temperature, we compared 16S-based community structure in soils stored at -80 degrees C and -20 degrees C and found no significant differences in community composition based on storage temperature. Free, open access datasets and data sharing platforms are powerful tools for integrating research and teaching in undergraduate and graduate student classrooms. They are a valuable resource for fostering interdisciplinary collaborations, testing ecological theory, model development and validation, and generating novel hypotheses. Training in data analysis and interpretation of large datasets in university classrooms through project-based learning improves the learning experience for students and enables their use of these significant resources throughout their careers. PMID- 26536667 TI - The Use of an Invasive Species Habitat by a Small Folivorous Primate: Implications for Lemur Conservation in Madagascar. AB - The lemurs of Madagascar are among the most threatened mammalian taxa in the world, with habitat loss due to shifting cultivation and timber harvest heavily contributing to their precarious state. Deforestation often leads to fragmentation, resulting in mixed-habitat matrices throughout a landscape where disturbed areas are prone to invasion by exotic plants. Our study site, the Mandena littoral forest (southeast Madagascar), is a matrix of littoral forest, littoral swamp, and Melaleuca swamp habitats. Here, Melaleuca quinquenervia has invaded the wetland ecosystem, creating a mono-dominant habitat that currently provides the only potential habitat corridor between forest fragments. We sought to understand the role of this invasive Melaleuca swamp on the behavioral ecology of a threatened, small-bodied folivore, the southern bamboo lemur (Hapalemur meridionalis). We collected botanical and behavioral data on four groups of H. meridionalis between January and December 2013. Our results confirm Melaleuca swamp as an important part of their home range: while lemurs seasonally limited activities to certain habitats, all groups were capable of utilizing this invasive habitat for feeding and resting. Furthermore, the fact that Hapalemur use an invasive plant species as a dispersal corridor increases our knowledge of their ecological flexibility, and may be useful in the conservation management of remaining threatened populations. PMID- 26536668 TI - Timing of hemodynamic changes during transnasal endoscopic surgery. AB - OBJECTIVES/HYPOTHESIS: Although considered less invasive and therefore less morbid than laryngoscopy under general anesthesia, prior research shows that transnasal flexible endoscopic (TNFE) procedures are associated with a significant increase in heart rate and blood pressure. The purpose of this review was to identify the most stimulating portion of the procedure to potentially provide a target for directed pharmacotherapy to ensure hemodynamic stability. STUDY DESIGN: Retrospective chart review. METHODS: Retrospective chart review of adult patients who underwent upper airway intervention in the larynx and trachea by TNFE. Vital signs recorded at 5-minute intervals throughout the procedure were examined and analyzed by Wilcoxon signed rank test and Wilcoxon rank sum test. RESULTS: For heart rate and systolic and diastolic blood pressure, the median change in value was 13 beats per minute (P < 0.0001), 27 mm of mercury (P < 0.0001), and 26.5 mm of mercury (P < 0.0001), respectively. The most significant change in heart rate and saturation was during the application of nasal and laryngeal anesthetic, as well as during the positioning of the scope. Blood pressures were elevated during the procedure itself. With respect to comorbidities, underlying asthma and coronary artery disease were associated with a greater percent change in the heart rate (P = 0.05 for both). CONCLUSION: There are significant vital sign changes during transnasal endoscopic procedures. Changes in heart rate and oxygen saturation tended to occur during preparation, whereas blood pressure was elevated during the laryngeal intervention. For patients with asthma, the percent change was greater, and perhaps a more controlled environment is warranted. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2047 2050, 2016. PMID- 26536669 TI - Correction: Increased Perfusion in Normal Appearing White Matter in High Inflammatory Multiple Sclerosis Patients. PMID- 26536670 TI - Role of Tellurite Resistance Operon in Filamentous Growth of Yersinia pestis in Macrophages. AB - BACKGROUND: Yersinia pestis initiates infection by parasitism of host macrophages. In response to macrophage infections, intracellular Y. pestis can assume a filamentous cellular morphology which may mediate resistance to host cell innate immune responses. We previously observed the expression of Y. pestis tellurite resistance proteins TerD and TerE from the terZABCDE operon during macrophage infections. Others have observed a filamentous response associated with expression of tellurite resistance operon in Escherichia coli exposed to tellurite. Therefore, in this study we examine the potential role of Y. pestis tellurite resistance operon in filamentous cellular morphology during macrophage infections. PRINCIPAL FINDINGS: In vitro treatment of Y. pestis culture with sodium tellurite (Na2TeO3) caused the bacterial cells to assume a filamentous phenotype similar to the filamentous phenotype observed during macrophage infections. A deletion mutant for genes terZAB abolished the filamentous morphologic response to tellurite exposure or intracellular parasitism, but without affecting tellurite resistance. However, a terZABCDE deletion mutant abolished both filamentous morphologic response and tellurite resistance. Complementation of the terZABCDE deletion mutant with terCDE, but not terZAB, partially restored tellurite resistance. When the terZABCDE deletion mutant was complemented with terZAB or terCDE, Y. pestis exhibited filamentous morphology during macrophage infections as well as while these complemented genes were being expressed under an in vitro condition. Further in E. coli, expression of Y. pestis terZAB, but not terCDE, conferred a filamentous phenotype. CONCLUSIONS: These findings support the role of Y. pestis terZAB mediation of the filamentous response phenotype; whereas, terCDE confers tellurite resistance. Although the beneficial role of filamentous morphological responses by Y. pestis during macrophage infections is yet to be fully defined, it may be a bacterial adaptive strategy to macrophage associated stresses. PMID- 26536671 TI - Single Base-Resolution Methylome of the Dizygotic Sheep. AB - Sheep is an important livestock in the world for meat, dairy and wool production. The third version of sheep reference genome has been recently assembled, but sheep DNA methylome has not been profiled yet. In this study, we report the comprehensive sheep methylome with 94.38% cytosine coverage at single base resolution by sequencing DNA samples from Longissimus dorsi of dizygotic Sunit sheep, which were bred in different habitats. We also compared methylomes between the twin sheep. DNA methylation status at genome-scale differentially methylated regions (DMRs), functional genomic regions and 248 DMR-containing genes were identified between the twin sheep. Gene ontology (GO) and KEGG annotations of these genes were performed to discover computationally predicted function. Lipid metabolism, sexual maturity and tumor-associated categories were observed to significantly enrich DMR-containing genes. These findings could be used to illustrate the relationship between phenotypic variations and gene methylation patterns. PMID- 26536672 TI - Postoperative Structural Brain Changes and Cognitive Dysfunction in Patients with Breast Cancer. AB - OBJECTIVE: The primary purpose of this study was to clarify the influence of the early response to surgery on brain structure and cognitive function in patients with breast cancer. It was hypothesized that the structure of the thalamus would change during the early response after surgery due to the effects of anesthesia and would represent one aspect of an intermediate phenotype of postoperative cognitive dysfunction (POCD). METHODS: We examined 32 postmenopausal females with breast cancer and 20 age-matched controls. We assessed their cognitive function (attention, memory, and executive function), and performed brain structural MRI 1.5 +/- 0.5 days before and 5.6 +/- 1.2 days after surgery. RESULTS: We found a significant interaction between regional grey matter volume (rGMV) in the thalamus (P < 0.05, familywise error (FWE), small volume correction (SVC)) and one attention domain subtest (P = 0.001, Bonferroni correction) after surgery in the patient group compared with the control group. Furthermore, the changes in attention were significantly associated with sevoflurane anesthetic dose (r2 = 0.247, beta = -0.471, P = 0.032) and marginally associated with rGMV changes in the thalamus (P = 0.07, FWE, SVC) in the Pt group. CONCLUSION: Our findings suggest that alterations in brain structure, particularly in the thalamus, may occur shortly after surgery and may be associated with attentional dysfunction. This early postoperative response to anesthesia may represent an intermediate phenotype of POCD. It was assumed that patients experiencing other risk factors of POCD, such as the severity of surgery, the occurrence of complications, and pre-existing cognitive impairments, would develop clinical POCD with broad and multiple types of cognitive dysfunction. PMID- 26536674 TI - [How anti-osteoporotic drugs work to improve bone metabolism]. PMID- 26536673 TI - Piscine Reovirus: Genomic and Molecular Phylogenetic Analysis from Farmed and Wild Salmonids Collected on the Canada/US Pacific Coast. AB - Piscine reovirus (PRV) is a double stranded non-enveloped RNA virus detected in farmed and wild salmonids. This study examined the phylogenetic relationships among different PRV sequence types present in samples from salmonids in Western Canada and the US, including Alaska (US), British Columbia (Canada) and Washington State (US). Tissues testing positive for PRV were partially sequenced for segment S1, producing 71 sequences that grouped into 10 unique sequence types. Sequence analysis revealed no identifiable geographical or temporal variation among the sequence types. Identical sequence types were found in fish sampled in 2001, 2005 and 2014. In addition, PRV positive samples from fish derived from Alaska, British Columbia and Washington State share identical sequence types. Comparative analysis of the phylogenetic tree indicated that Canada/US Pacific Northwest sequences formed a subgroup with some Norwegian sequence types (group II), distinct from other Norwegian and Chilean sequences (groups I, III and IV). Representative PRV positive samples from farmed and wild fish in British Columbia and Washington State were subjected to genome sequencing using next generation sequencing methods. Individual analysis of each of the 10 partial segments indicated that the Canadian and US PRV sequence types clustered separately from available whole genome sequences of some Norwegian and Chilean sequences for all segments except the segment S4. In summary, PRV was genetically homogenous over a large geographic distance (Alaska to Washington State), and the sequence types were relatively stable over a 13 year period. PMID- 26536675 TI - [Health benefits and demerits of calcium nutrition or supplementation in older people]. AB - The benefit of calcium nutrition for health has been believed for a long time. In fact, higher calcium intake is associated with reduction of blood pressure, rate of bone loss after menopause and mild risk reduction of fracture. Since calcium intake from food has not been achieved to be the recommended level, calcium supplementation is widely used especially in the US. However, calcium supplementation has been reported to increase in vascular events, recently. On the other hand, calcium nutrition from foods have not been reported any harmful effect on health. Therefore, calcium effects on health seemed to be composite effects of other nutrients taking together with calcium. PMID- 26536676 TI - The Authors Respond. PMID- 26536677 TI - The Authors Respond. PMID- 26536678 TI - [Reconstruction of the 1/4 defect on upper-lip vermilion with a lower-lip vermilion compound tissue flap]. AB - OBJECTIVE: To investigate the reconstruction of 1/4 defect on upper-lip vermilion with a lower-lip vermilion compound tissue flap pedicled at oral commissure. METHORDS: At the first stage, the lower lip mucosal flap pedicled by inferior labial artery was transposed to reconstruct the defect on upper lip vermilion and tubercle. The defect at the donor site was closed directly. At the second stage, the flap pedicle was cut off and revised. RESULTS: 6 patients were treated with satisfactory aesthetic results. All the flaps survived completely. The oral commissure kept normal with no obvious scar at the donor sites. CONCLUSIONS: The modified crosslip vermilion flap pedicled at oral commissure has the advantages of avoiding inconvenience in feeding, speaking and cleaning. The procedure is simple with available blood supply. Both aesthetic and functional results are satisfactory. PMID- 26536679 TI - [Clinical application of expanded flap based on the cutaneous branch of transverse cervical artery]. AB - OBJECTIVE: To investigate the clinical application of expanded flap based on cutaneous branch of transverse cervical artery for reconstruction of cervical cicatricial contracture. METHODS: Based on the clinical anatomy of cutaneous branch of transverse cervical artery flap, we design the corresponding subclavicular area for expansion. The incision was usually located at the anterior axillary fold, 5-8 cm in length. The expander was implanted under the deep fascial layer, without injury of the vascular pedicle. Fixation sutures were put about 1 cm apart from the incision to prevent the expander from transposition and exposure. After expansion, the cervical cicatricial contracture was excised and released. According to the defect, the expanded flap based on the cutaneous branch of transverse cervical artery was designed, with the pedicle located at the posterior margin of sternocleidomastoid and 1. 8 cm above median point of clavicle. "S" shape incision was made at the location of vascular pedicle. Subcutaneous dissection was performed 1.5 cm in width along the incision on both sides. Then the flap was harvested under the deep fascial layer and rotated to cover defect without tension. It was not necessary to dissect the vascular pedicle further. The defect at donor site was closed directly. RESULTS: 17 cases were treated with the island flap. The contracture of the cervical scar was corrected completely with aesthetic appearance. CONCLUSIONS: Expanded flap based on cutaneous branch of transverse cervical artery has reliable blood supply. It' s an ideal flap for the treatment of cervical cicatricial contracture. PMID- 26536680 TI - [Quantitative analysis based on three-dimensional CT in the contouring surgery of craniofacial fibrous dysplasia]. AB - OBJECTIVE: To investigate the quantitative analysis based on three-dimensional computed tomography (3D-CT) in contouring surgery of complex craniofacial fibrous dysplasia (FD). METHODS: 14 patients with craniofacial FD underwent 3D-CT scan. Axial images of patients with craniofacial FD were reconstructed into 3D model by using Mimics 10.0. Anatomical landmarks were located and the coordinate of the landmarks obtained. The differences between the right landmarks and the left were calculated and analyzed. Quantitative contouring surgery was performed based on the quantitative analysis result. RESULTS: With the detail data from the 3D-CT analysis, the surgery of contouring was more safe and accurate with less operation time, less bleeding and good results. CONCLUSIONS: The method of 3D CT quantitative analysis can provide precise information in the diagnosis and treatment planning of craniofacial deformity. Based on the result of 3D-CT quantitative analysis, the operations can be performed more accurately and safely with good symmetric consequence. PMID- 26536681 TI - [Clinical application of preoperative imaging evaluation in the anterolateral thigh flap transplantation: comparison of computed tomography angiography, digital subtract angiography and magnetic resonance angiography]. AB - OBJECTIVE: To evaluate the value of three preoperative imaging methods in the anterolateral thigh flap (ALT) transplantation. METHODS: According to preoperative imaging, patients who underwent the ALT flap transplantation were divided into three groups: computed tomography angiography (CTA) group, digital subtract angiography ( DSA) group and magnetic resonance angiography (MRA) group. There were fifteen cases in each group. We compared the imaging quality of the ALT artery among these groups and recorded the parameters of lateral femoral circumflex artery, descending branches and perforators including type, course and size. The results from images were compared with intraoperative findings. The success rate and complications were also recorded. RESULTS: The preoperative imaging accuracy of the types of the lateral femoral circumflex artery and descending branch was more than 92.3%, with no significant different between any two of three groups (P > 0.05). The difference in diameters of descending branches and perforators from preoperative measurement and from intraoperative measurement was also not significant between any two of the three groups; the success rate and complications were not also obviously different (P > 0.05 , P > 0.05, respectively). CONCLUSIONS: Preoperative mapping using CTA, DSA and MRA is a feasible and reliable method for the flap design in ALT transplantation. As a preoperative evaluation means, CTA and MRA may replace DSA in the ALT transplantation. PMID- 26536682 TI - [Application of "tennis racket" flap with fascial pedicle on the healthy chest for the radiation ulcer after surgical treatment of breast carcinoma]. AB - OBJECTIVE: To introduce the application of "tennis racket" flap with fascial pedicle on the healthy chest for radiation ulcer after surgical treatment of breast cancer. METHODS: The " tennis racket" flap was designed on the healthy chest along the cartilage with fascia pedicle near the sternum. 9 cases were treated. The flaps size ranged from 5.0 cm x 3.5 cm to 13 cm x 11 cm with pedicle size of 2-8 cm in length and 2.0-3.0 cm in width. RESULTS: All the 9 flaps survived completely with satisfactory appearance. The patients were followed up for 2 months to 3 years without ulcer reoccurrence. CONCLUSIONS: The "tennis racket" flap has a slender fascial pedicle without major blood vessel. It has the advantages of good flexibility for rotation and large flap size for the reconstruction of the radiation ulcer after surgical treatment of breast cancer. PMID- 26536683 TI - [Clinical application of venous nutrition flap pedicled by medial plantar artery of the hallux on the medical aspect of the foot]. AB - OBJECTIVE: To introduce the clinical application of venous nutrition flap pedicled by medial plantar artery of the hallux on the medical aspect of the foot. METHODS: Based on the anastomoses between the medial plantar artery of the hallux and the nutritional vein, the flap was designed with the perforator of medial plantar artery adjacent to the first metatarsal bone as the rotation point. The flap axis was along the vein at the medial aspect of the foot between rotation point and medial malleolus. RESULTS: 5 cases were treated with primary healing and complete survival flaps. The patients were followed up for 1-12 months with good match of texture and color. CONCLUSIONS: The venous nutrition flap pedicled by medial plantar artery of the hallux on the medical aspect of the foot can be transpositioned to repair the defect at forefoot. PMID- 26536684 TI - [Repair of lower extremity soft tissue defect with free musculo-cutaneous flaps bridging with healthy contralateral posterior tibial vessel]. AB - OBJECTIVE: To observe the clinical effects of free musculo-cutaneous flap bridging with contralateral posterior tibial vessel on repair of lower extremity soft tissue defect. METHODS: From February 2006 to June 2013, 10 patients with soft tissue defect on lower shank and foot were included. The posterior tibial vessel on healthy lower extremity was chosen as recipient vessel and anastomosed with free latissimus dorsi musculo-cutaneous flap, or free latissimus dorsi musculo-cutaneous flap combined with thoracic-umbilical skin flap or anterolateral femoral musculo-cutaneous flap. The retrograde bridged flap was transposed to repair defect on contralateral lower shank and foot. The wound area ranged from 40 cm x 21 cm to 22 cm x 15 cm, with flap size from 48 cm x 26 cm to 25 cm x 18 cm. Meanwhile the defects on donor sites were covered with skin graft and both lower extremities were fixed with kirschner wires at middle tibia and calcaneus. The kirschner wires were removed at 4 weeks and pedicles were cut off 5-8 weeks postoperatively. Six patients received posterior tibial vessel reanastomosis at the same time of pedicle cutting. RESULTS: All the 10 flaps survived and 3 patients received thinning of flaps due to excessive thickness. During the follow-up period of 3 months to 2 years follow up, the ambulatory function of injured legs recovered gradually with satisfactory appearance. The reanastomosed posterior tibial vessel on the healthy side was recovered. CONCLUSIONS: Appropriate bridged musculo-cutaneous flaps is suitable for extensive soft tissue defect of lower shank and foot. It is a safe and effective method for limb salvage. PMID- 26536685 TI - [Clinical application of free perforator hypothenar flap for thumb pulp defect]. AB - OBJECTIVE: To summarize the therapeutic effect of free perforator hypothenar flap for thumb pulp defect. METHODS: From Jun. 2012 to Mar. 2013,8 cases with thumb pulp defect accompanied with exposure of phalanges ans tendons were treated by free ipsilateral perforator hypothenar flap. The flaps were 1.4 cm x 2.0 cm-1.8 cm x 2.2 cm in size. Ulnar finger artery in the flap was anastomosed with thumb artery. The accompanied veins and superficial veins were respectively anastomosed with thumb dorsal veins. Nerve branches in flaps were sutured with unilateral finger nerve to reconstruct flap feeling with 9-0 thread. Wounds in the hypothenar donor site were sutured directly. RESULTS: All the flaps survived completely with primary healing both in donor and recipient area. 8 cases (8 fingers) were followed up for 6-13 months (average 9 months). The flaps appearance, texture were good. The two-point discrimination distance on flap was 7-10 mm. The active and passive movement of thumb joints was normal. There was no complain about the feeling at the donor site. Linear scar was left on the donor site. Patients hand grip strength was not decreased. CONCLUSIONS: The free perforator hypothenar flap which has constant vascular anatomy is a new method for thumb soft tissue defect with less morbidity to donor site. The operative procedures are relatively simple. PMID- 26536686 TI - [Reconstruction of thumb II-III degree defect by big toe wrap-around flap combined with second toe proximal interphalangeal joint]. AB - OBJECTIVE: To investigate the reconstruction of thumb II-III degree defect by big toe wrap-around flap combined with second toe proximal interphalangeal joint. METHODS: Between May 2004 to July 2012, 25 cases with thumbs II-III degree defects were treated. The ipsilateral big toe wrap-around flap combined with second toe proximal interphalangeal joint was designed to reconstruct the thumb defects based on the thumb size on the healthy side. The distal end of hallux was covered by flap at tibial side. The wound at the fibula side was covered by skin graft and flap. The bone defect at the second toe was filled with remnant hallux or iliac bone. RESULTS: All the 25 reconstructed thumbs survived completely. The patients were followed up for 6-26 months without any joint degeneration. According to the finger reconstruction functional criterion publicized by China Medical Association, the finger function was assessed as excellent in 10 case, good in 11 cases, poor in 4 cases. Joint necrosis happened in 2 cases and bone malunion in 2 cases. The 4 cases received dead bone debridement and iliac bone graft. No malfunction occurred in the donor site. CONCLUSIONS: Our surgical method is a currently effective way to reconstruct II-III degree thumb defects. Satisfactory functional and cosmetic results can be achieved both in donor site and recipient site. PMID- 26536687 TI - [The application of the dorsal metacarpal perforator sliding flap for web-space reconstruction in congenital syndactyly]. AB - OBJECTIVE: To investigate the application of the dorsal metacarpal perforator sliding flap for web-space reconstruction in congenital syndactyly. METHODS: According to the size and shape of skin defect at the web space after division operation of syndactyly, the corresponding intermetacarpal perforator sliding flap was designed. The edge of the flap was cut off, but its underlying tissue was not dissected. From May 2007 to November 2012, 28 web-spaces in 15 patients with syndactyly (10 male and 5 female) were reconstructed. RESULTS: All the 28 flaps survived completely. The flap size ranged from 3 cm x 2 cm to 1.5 cm x 1.0 cm. 14 cases with 26 flaps were followed up for 10-22 months (average, 14.5 month). The reconstructed web spaces had normal appearance and movement range. The 2-point discrimination distance was 9-13 mm (average, 11 mm). According to the Swanson Standard, 18 fingers were graded as excellent, 8 as good and 2 as fair (excellent and good, 92.6%, 26/28). CONCLUSIONS: Reconstruction of web-space in syndactyly with the dorsal metacarpal perforator flap has the advantages of easy handling, good cosmetic and functional results. PMID- 26536688 TI - [Crosslinking sodium hyaluronate gel with different ratio of molecular weight for subcutaneous injection: animal experimental study and clinical trials subcutaneous injection]. AB - OBJECTIVE: To investigate the biocompatibility and degradation rate of crosslinking sodium hyaluronate gel with different ratio of molecular weight, so as to choose the effective, safe and totally degraded hyaluronate gel for aesthetic injection. METHODS: (1) Compound colloid was formed by cross-linking the divinyl sulphone and sodium hyaluronate with different molecular weight (4 x 10(5), 8 x 10(5), 10 x 10(5), 12 x 10(5)). (2) Healthy level KM mice was randomly divided into two groups to receive hyaluronic acid gel or liquid injection. Each group was subdivided into three subgroup to receive hyaluronic acid with different molecular weight. The biocompatibility and degradation rate, of hyaluronate were observed at 7, 90, 180 days after injection. At the same time, different molecular weight of sodium hyaluronate gel is sealed or exposed respectively under the low temperature preservation to observe its natural degradation rate. (3) The most stable colloid was selected as aesthetic injector for volunteers to observe the aesthetic effect. RESULTS: The sodium hyaluronate gel with molecular of 4 x 10(5) was completely degraded 90 days later. The sodium hyaluronate gel with molecular of 8 x 10(5) was completely degraded 180 days later. The sodium hyaluronate gel with molecular of 10 x 10(5) was degraded to 90.0% after 180 days. The sodium hyaluronate liquid can be degraded completely within 7 days. The colloid could be kept for at least 12 months when sealed under low temperature, but was totally degraded when exposed for I d. Sodium hyaluronate gel with molecular 10 x 10(5) was confirmed to be kept for at least 6 months in animal experiment and clinical trials. CONCLUSIONS: Under the same condition of material ratio, the higher the molecular weight is, the lower the degradation rate is. But the liquidity of gel is not good for injection when molecular weight is too large. It suggests that Sodium hyaluronate gel with molecular 10 x 10(5) maybe the best choice in cosmetic injections. PMID- 26536689 TI - [The eyelid morphology analysis of 2,183 outpatients in plastic surgery clinic]. AB - OBJECTIVE: To explore the eyelid's characteristics of outpatients who visited the plastic surgery clinic in 3rd Hospital of Peking University. METHODS: From Jan. 2007 to Feb. 2011, we collected facial images and general data of 2,183 outpatients, and divided them into groups according to their genders. The eyelid images were analyzed and epicanthus or foldless eyelid were recorded. Then the incidence rates of epicanthus and foldless eyelid were calculated. RESULTS: In 2,183 patients (4,366 eyes), the incidence rate of epicanthus is 86.1% (3,760/4,366), and the incidence rate of foldless eyelid is 35.3% (1,541/4,366). In 178 males (356 eyes) and 2,005 females patients (4,010 eyes), the incidence rates of epicanthus are 78.4% (279/356) and 86.8% (3,481/4,010), respectively. The incidence rates of foldless eyelid are 48.0% (171/356) and 34.2% (1,370/4,010), respectively. CONCLUSIONS: The incidence rates of epicanthus and foldless eyelid are relatively high for the outpatient population in the plastic surgery clinic of Third Hospital of Peking University. PMID- 26536690 TI - [Experimental study of the influence of expanded capsule on biomechanics of autograftedcostal cartilage]. AB - OBJECTIVE: To explore the effect of the expanded capsule on biomechanics of the transplanted autologous costal cartilage. METHODS: Ten New Zealand white rabbits aged 3 months were involved and four 15 ml tissue expanders were implanted symmetrically on the back of each rabbit. After 1 month, expanded capsules were removed (experimental group) on the left side and were reserved (control group) on the right side. Meanwhile, the 6th and 7th costal cartilage without the perichondrium were taken out and each cartilage was divided into two pieces and put under the expanded capsule symmetrically. The cartilage at the upper sides and lower sides were taken out at 4 weeks and 8 weeks later, respectively. All the cartilages were sculptured for the demand of the machine text. The tension and compression property of the cartilages were assessed by the material testing machine (Instron 5967) and the results were analyzed statistically. RESULTS: 8 weeks lateral, the average ultimate tension strength was (4. 954 + 2. 8) MPa in experimental group and (2.939 + 0.842) MPa in control group. The average compressive strength was (58.74 +/- 13.77) MPa in experimental group, and (47.61 +/- 11.41) MPa in control group. The biomechanics property of the cartilages in the experimental group is better than the control group, and the differences were statistically significant. CONCLUSIONS: Removing the expanded capsule is benefical to maintain the biomechanics of autologous costal cartilage. PMID- 26536691 TI - [Effect of adipose tissue extract on promoting angiogenesis and adipogenesis in tissue engineering chamber in vivo]. AB - OBJECTIVE: To evaluate the influence of adipose tissue extract on inducing angiogenesis and adipogenesis in adipose tissue engineering chamber in vivo. METHODS: 6 months' healthy New Zealand rabbits (n = 64) were picked. The inguinal fat pads were cultured, centrifuged, filtered, and the liquid was called adipose tissue extract (ATE). Two adipose tissue engineering chamber were built in the rabbit's back. A week later, 0.2 ml normal saline (control group, left) and 0. 2 ml ATE (experimental group, right) was respectively injected into the chamber. The contents were evaluated morphometrically, histologically and immunohistochemically 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks and 7 weeks after injection. 8 rabbits were observed each time. The data regarding the number of the volume of fat flap and blood capillary at each time point were analyzed by paired t test. RESULTS: After injection, new tissue volume was significantly increased in the experimental group [(5.12 +/- 0.22) ml], compared with that in control group [(4.90 +/- 0.15) ml]. Early angiogenesis was also increased after ATE injection and the total number of capillaries reached peak 1 week after injection, which was (72.80 +/- 9.67) in experimental group and (51.40 +/- 6.09) in control group. In the mid-term of experimental period, earlier adipogenesis appeared in experimental group. In the later period, the outer capsule of the new construction was thinner in experimental group which reduced the suppression of the adipogenesis. CONCLUSIONS: ATE can promote the angiogenesis and adipogenesis in the chamber, and reduce the capsule contracturing, so as to induce the large volume of adipose tissue regeneration PMID- 26536692 TI - [Comparison between stapled and traditional suture closure total laryngectomy]. AB - OBJECTIVE: To compare the clinical results between stapled and traditional suture closure total laryngectomy. METHOD: Fifty-three cases of laryngeal cancer with total laryngectomy were divided into 2 groups: 32 cases with traditional suture closure total laryngectomy (group A) and 21 cases with stapled total laryngectomy group (group B). Compare two groups in pharyngeal fistula, postoperative bleeding, dysphagia, and nasal regurgitation. RESULT: There was no difference of postoperative pharyngeal fistula between group A and B (P>0. 05). The incidence of dysphagia, nasal regurgitation, and postoperative bleeding in group B were 23. 8%, 14. 3% and 14. 3% respectively, which were obviously higher than that in group A (P<0. 05). CONCLUSION: Stapled total laryngectomy has the advantages of reducing the operative time and simplifying the operation with some disadvantages such as higher standards of operation indications, higher incidence of dysphagia, higher nasal regurgitation, higher postoperative bleeding, and poor medical economic profit. Traditional suture closure total laryngectomy is recommended in clinical practice. PMID- 26536693 TI - [The influence factors of sound pressure level parameters in patients with simple snoring and obstructive sleep apnea hypopnea syndrom]. AB - OBJECTIVE: To discuss the main influence factors of sound pressure level parameters in patients with simple snoring (SS) and obstructive sleep apnea hypopnea syndrom (OSAHS). METHOD: Eighty-four cases with snoring disease underwent polysomnography and simultaneously snoring sound pressure level recording. The correlations between AHI, age, BMI, abdomen circumference, neck circumference, the lowest oxygen saturation total apnea time and sound pressure level parameters: equivalent continuous sound level(LAeq)and maximum sound pressure level(L10) were analyzed. RESULT: LAeq was significantly correlated to AHI (P= 0. 000) and BMI (P= 0. 007), and the odd ratios of AHI and BMI were 5. 74,2. 09 respectively, but it was unrelated to age, abdomen circumference, neck circumference, the lowest oxygen saturation and total apnea time. A significantly association also existed between L10 and AHI(P=0. 000), BMI(P=0. 032), and the odd ratios were 4. 11 and 2. 33 respectively. Other factors had nothing to do with L10. CONCLUSION: The main factors which affect the snoring sound pressure level parameters LAeq and L10 are AHI and BMI. PMID- 26536694 TI - [To explore the method of exposure of recurrent laryngeal nerve in thyroid second operation]. AB - OBJECTIVE: To discuss the safe approach to exposure of the recurrent laryngeal nerve (RLN) in thyroid second operation. METHOD: The data of 153 patients with thyroid second operation were analyzed retrospectively to compare the effectiveness of superior and inferior approach in the exposure of RLN. RESULT: A total of 177 RLNs were exposed in 153 cases. Among those 39 RLNs were exposed by superior approach, 34 by inferior approach after failure of superior approach, and 104 by inferior approach. CONCLUSION: In thyroid second operation, inferior approach is a safe and efficient method to expose RLN. Trachea and esophagus are the most important anatomical landmarks to look for the left RLN. Innominate artery and common carotid artery are the most important anatomical landmarks to look for right RLN. PMID- 26536695 TI - [To study the correlation between hyoid movement and openness of upper esophageal sphincter]. AB - OBJECTIVE: To discuss the effect of age on hyoid movement and the openness of UES in swallowing process, and to investigate the correlation between hyoid movement and openness of UES. METHOD: The X-ray dynamic swallowing videofluoroscopy was performed on 100 healthy adult volunteers(20-74 years). They were divided into three groups: young (ages 20 to 45), middle-aged (45 to 65) and older (65 and up). Then the software Avidemux 2. 5 and Image J were used to measure the time and distance of hyoid movement, and the maximal opening of the UES in swallowing process. RESULT: The time of hyoid moving to the maximal displacement was delayed along with the ages, and there were significant differences among the three groups (P<. 05). The staying time of hyoid in the maximal displacement gradually shortened along with the ages, and there was significant difference between young and older group, so was the middle-aged and older group(P<0. 05). The maximum antedisplacement of hyoid decreased with age, and significant differences were found between young and the middle-aged group and between oung and older group (P<0. 05). The maximal degree of UES opening decreased with the increase of age, and significant difference was found between young and older group (P<0. 05). The upper displacement of hyoid was not related to UES opening(P>0. 05), however, the antedisplacement of hyoid had significant relation to UES opening in the three groups (P<0. 05). CONCLUSION: In swallowing process, the time and space parameters of hyoid movement and the maximal degree of UES opening were related to age. There was significant difference between the antedisplacement of hyoid and the openness of UES (P<0. 05). PMID- 26536696 TI - [The preliminary study of the origin characters of snore in simple snorers]. AB - OBJECTIVE: to investigate the origin characters of snore in simple snorers and provide the basis for its treatment. METHOD: Thirty-two simple snorers diagnosed by polysomnography were induced to sleep by propofol and dexmedetomidine, then we observed the vibration sites, pattern and concomitant collapse of soft tissue in pharyngeal cavity by nasendoscopy. RESULT: Thirteen cases showed palatal fluttering only, and 1 case showed vibration of epiglottis only. Six cases showed palatal fluttering with vibration of epiglottis, and 2 cases showed palatal fluttering with vibration of epiglottis and tongue base. Five cases showed palatal fluttering with vibration of pharyngeal lateral wall, and 5 cases showed palatal fluttering with vibration of lateral wall, epiglottis and tongue base together. Palate and pharyngeal lateral wall vibrated strongly and always collapsed with vibrating, but epiglottis and tongue base usually vibrated slightly and seldom collapsed. CONCLUSION: The palatal fluttering is the main source of snoring sounds for most simple snorers, then followed by vibration of palatal and pharyngeal lateral wall together. The site of collapse in pharyngeal cavity is consistent with the main site of vibration. PMID- 26536697 TI - [The effect of binaural bi-modal fitting on speech recognition of cochlear implant recipients with low frequency electrodes incompletely implanted]. AB - OBJECTIVE: To study the effect of binaural bi-modal fitting (one cochlear implant and a contralateral hearing aid) on speech recognition of cochlear implant recipients with low frequency electrodes incompletely implanted. METHOD: A total of 15 cochlear implant(CI) users who have low residual hearing (250 Hz 45-90 dBHL, 500 Hz 75 - 100 dBHL) of their non surgery ears. We closed the top three electrodes to simulate the state of low-frequency electrodes incompletely implanted by fitting software. (1) The same tester received twice speech recognition tests in incompletely implanted state, one test used single CI model and the other used binaural bi-modal fitting model. (2)The same tester received above twice speech recognition tests again, but in completely implanted state. Then we compared the results of tests. RESULT: The CI users used binaural bi modal fitting have higher speech recognition score than the same users used unilateral cochlear implant model in low-frequency electrodes incompletely implanted state(P<0. 05). The gap between the scores of the tests by using two usage patterns in low frequency electrodes incompletely implanted state was more than that in completely implanted state (P<0. 05). CONCLUSION: Binaural bi-modal fitting can help CI users to improve their speech recognition ability in low frequency electrodes incompletely implanted state. PMID- 26536698 TI - [The changes of parathyroid hormone and serum calcium after total thyroidectomy]. AB - OBJECTIVE: To explore the changes of parathyroid hormone (PTH) and serum calcium alter total thyroidectomy and summarize the methods to prevent and treat the hypoparathyroidism and hypocalcernia. METHOD: Seventy-three patients with total thyroidectomy in our hospital were divided into three groups according to the scope of the operation. The serum concentrations of PTH and calcium were measured and compared before surgery and after surgery 1 h, 1 d, 3 d and 5 d. RESULT: In three groups, the serum concentrations of PTH and calcium were significantly decreased (P<0. 05) after surgery and low serum PTH and hypocalcemia occured. The severity of low serum PTH and hypocalcemia was as follows: total thyroidectomy with bilateral compartment lymph node dissection (CLND)>total thyroidectomy with unilateral CLND>total thyroidectomy. The differences were statistically significant. The levels of PTH after surgery 1 hour and 1 day were effective to predict hypocalcemia. CONCLUSION: Total thyroidectomy can affect the parathyroid function. The greater the scope of surgery, the higher the possibility of postoperative hypoparathyroidism. The reasonable operative procedures and more protection of parathyroid during operation can reduce the incidence of hypoparathyroidism. The level of postoperative PTH can be used as a predictive index of hypocalcemia. PMID- 26536699 TI - [Application of endotracheal intubation in the rescue of children with severe trachea and bronchial foreign body]. AB - OBJECTIVE: To discuss the application of endotracheal intubation in the rescue of children with severe trachea and bronchial foreign body. By observing the patient's clinical pathological characteristics, the diagnosis and treatment experience were summarized. METHOD: A retrospective analysis of 10 children with severe tracheal and bronchial foreign bodies were performed. They were given emergency intubation and cardiopulmonary resuscitation to relieve respiratory and circulatory failure after reaching hospital. After the restoration of spontaneous respiration, oxygen saturation increased by more than 90 percent and vital signs stable, the foreigh body was removed with bronchoscopy. The role of endotracheal intubation before and after the treatment of tracheal and bronchial foreign bodies in children was observed. RESULT: Ten cases of children were rescued successfully. No one died and the complications such as cerebral palsy, pneumothorax and pneumomediastinum didn't happened. CONCLUSION: For the children with severe tracheal and bronchial foreign body, endotracheal intubation can establish effective ventilation in a shorter period of time. The earlier endotracheal intubation, the shorter time required and the higher success rate. Endotracheal intubation can increase the survival rate of children with cardiopulmonary resuscitation, and can reduce disability. PMID- 26536700 TI - [Comparison of the effects of different analgesic methods after UPPP]. AB - OBJECTIVE: To explore the effects of different analgesia methods after UPPP. METHOD: Ninety cases of patients uvulopalatopharyngoplasty were divided into 3 groups randomly, and 30 cases in each group. The group A was the blank control group without any analgesia measures. The cases in group B were treated with intramuscular injection of parecoxib sodium 40 mg after surgery immediately, and continued injecting 40 mg after 12 hours, 24 hours and 36 hours respectively. 100 mg tramadol replaced 40 mg parecoxib sodium in group C. The VAS scoring was performed after surgery 12, 24, 36, 48, 72, 96 hours in 3 groups, and we observed adverse reaction such as lethargy, nausea, vomiting, dizziness, skin rash and so on. RESULT: The group B and C reduced the pain significantly compared with blank control group. The pain scores in group B were significantly decreased than that in group C (P<. 05). CONCLUSION: The analgesic effect of parecoxib sodium after UPPP is significant and better than tramadol. It is worthy to use widely in clinical due to its better effect and less side effect. PMID- 26536701 TI - [Analysis of clinical diagnosis and treatment of 112 cases of parapharyngeal space tumors]. AB - OBJECTIVE: To explore the diagnosis, treatment and surgical approaches of parapharyngeal space tumors. METHOD: This retrospective study consisted of 112 patients with parapharyngeal space tumors underwent surgeries. The data included clinical symptoms and signs, pathological types, imaging examinations, surgical approaches and postoperative complications. RESULT: Computerized tomography (CT), magnetic resonance imaging (MRD and digital subtraction angiography (DSA) made clear the tumor size, localization and its relation to adjacent structures. The postoperative histopathology varied and showed benign in 98 cases consisting of salivary gland tumors (52 cases), neurogenic tumors(33 cases) and other types (13 cases). During the 3 years follow-up period, local recurrence appeared in 3 patients with salivary pleomorphic adenoma and 1 patient with neurofibromatosis. These recurrent tumor cases were cured with second surgery. In 14 patients with malignant tumors reported, 8 cases survived for 5 years, 2 cases (1 adenoid cystic carcinoma and 1 carcinoma in pleornorphic adenoma) recurred in the two and a half years cured with second surgery affiliated radiation therapy through 3 years follow-up time and the rest were followed up 1 to 3 years without recurrence. Peripheral facial paralysis was observed in 25 patients, and 3 patients experienced hypoglossal nerve palsy. Only 1 patient encountered vagus nerve injury, and 2 patients appeared Horner's syndrome, and 4 patients endured Frey syndrome. Gills leakage was discovered in 3 cases and cavity infection was noted in 1 patient. CONCLUSION: CT, MRI and DSA were important in the diagnosis and differential diagnosis of parapharyngeal space tumors. The key to successful treatment is knowing the anatomy of the parapharyngeal space, preoperative assessment and appropriate surgical approach. PMID- 26536702 TI - [The therapeutic effect of proton pump inhibitor on alleviation of hoarseness symptoms in patients with laryngopharyngeal reflux]. AB - OBJECTIVE: To analyze the therapeutic effect of proton pump inhibitor(PPI) on alleviation of hoarseness symptoms in patients with laryngopharyngeal reflux(LPR). METHOD: The LPR outpatients in ENT department of our hospital(60 cases)complained of hoarseness were enrolled in the study from August of 2013 to October of 2014. All of them were randomly divided into group A and B. The individuals in group A (30 cases) taked golden voice capsule to treat for 3 months, while the individuals in group B (30 cases) taked golden voice capsule and omeprazole to treat for 3 months. The data about reflux symptom index (RSI), reflux finding score (RFS) and voice handicap index (VHI)from the first month to the third month after treatment were recorded and compared group A with group B. RESULT: The scores of RSI and RFS in patients (60 cases) before treatment were significantly correlated with their VHI (r=0. 823, P<0. 01; r=0. 873, P<0. 01). The score changes of RSI and VHI from the first to the third month after treatment in group B were significantly higher than those in group A (P<0. 01). Meanwhile, the score changes of RFS from the third month after treatment in group B were significantly higher than those in group A (t=8. 307, P<. 01), but the differences were not significant for RFS from the first to the second month after treatment between group A and group B(t=1. 128, P>0. 05; t=0. 376, P> 0. 05). CONCLUSION: PPI therapy could significantly alleviate the hoarseness symptom in LPR patients. PMID- 26536703 TI - [The assessed value of 64 slice spiral CT perfusion imaging in laryngeal squamous cell carcinoma after chemotherapy and radiotherapy]. AB - OBJECTIVE: To study the assessed value of 64 slice spiral CT perfusion imaging (CTPI) in laryngeal squamous cell carcinoma after chemotherapy and radiotherapy. METHOD: Forty five patients diagnosed with local advanced laryngeal squamous cell carcinoma were selected. Conventional CT and CTPI were performed before treatment and at the time of radiation dose up to 40 Gy. Blood flow, blood volume, mean transit time and surface permeability were measured at the same time. According to the decrease of tumor volume in final examination, patients were divided into sensitive group and insensitive group. The tumor perfusion indexes were compared between groups. RESULT: Blood flow, blood volume, surface permeability after 40Gy treatment were lower than before treatment in both sensitive group and the insensitive group ascended(P<0. 05). The AUC of ROC of blood flow, blood volume, mean transit time and surface permeability were 0. 804, 0. 843, 0. 852 and 0. 826. The sensitivity, specificity and accuracy of blood flow was 89. 7%, 86.8% and 90. 9%. There were 100. 0%, 91. 4% and 93. 7% in blood volume; 100. 0%, 67. 7% and 88. 3% in mean transit time; 91. 2%, 69. 4% and 90. 6% in surface permeability(P<0. 01). CONCLUSION: Sixty-four slice spiral CT perfusion imaging is able to assess tumor status of laryngeal squamous cell carcinoma after chemotherapy and radiotherapy effectively. PMID- 26536704 TI - [Comparison the application of 3D versus 2D laparoscopic thyroidectomy via modified chest and mammary areola approach]. AB - OBJECTIVE: To explore the safety, effectiveness and feasibility of 3D laparoscopy in thyroidectomy via modified chest and mammary areola approach comparing with 2D. METHOD: Twenty six cases received 3D laparoscopic thyroidectomy (3D group) and 34 cases experienced 2D (2D group). We compared the indexes about general status, operation time, operative blood loss, duration and overall volume of postoperative drainage, complications, etc between two groups. RESULT: Eight cases of thyroid cancer were detected in 3D group and 3 cases in 2D group. While there was no statistical difference between two groups with respect to other observation indexes such as other general status, operation time, operative blood loss, duration and overall volume of postoperative drainage, complications, etc. CONCLUSION: 3D laparoscopic thyroidectomy via modified chest and mammary areola approach is a safe, effective and feasible procedure, and it may substitute the place of 2D in the future. PMID- 26536705 TI - [Application of endoscopic nasal lateral wall dissection in lesions of the maxillary sinus]. AB - OBJECTIVE: To investigate the application of endoscopic nasal lateral wall dissection in lesions of the maxillary sinus. METHOD: Ten hospitalized patients with the maxillary sinus lesions were treated with the endoscopic nasal lateral wall dissection. RESULT: All 10 patients were unilateral invasion. Among them, 7 cases were inverted papilloma, 2 cases were recurrent antrochoanal polyps, 1 case was sinusal tooth. The tumors and antrochoanal polyps originated from the every part of the maxillary sinus wall during operation, especially from the anterior and media wall. During 10-62 months follow-up,epithelization of nasal occured and the shape of inferior turbinate was well. All of them had no epiphora. CONCLUSION: Endoscopic nasal lateral wall dissection can remain the function of nasal lacrimal duct and nasal cavity,and may provide a new minimally invasive approach for complete resection of lesions of nasal cavity and the maxillary sinus. PMID- 26536706 TI - [The effect of TLR4/MyD88/NF-kappaB signaling pathway on proliferation and apoptosis in human nasopharyngeal carcinoma 5-8F cells induced by LPS]. AB - OBJECTIVE: To evaluate the effects of NF-kappaB activation on the proliferation and apoptosis throughTLR4/MyD88 signaling pathway in human nasopharyngeal carcinoma (NPC) 5-8F cell lines. METHOD: TLR4 induced by LPS is inhibited by PE anti-human. Real-Time Quantitative PCR and Western blot were employed to evaluate the efficacy of mRNA level and protein expression. The growth inhibition rate of 5-8F by Celecoxib was evaluated with MTT method. The cell cycle and apoptosis were measured with flow cytometric method (FCM). RESULT: By using the specific inhibitor, the protein and gene expression of NF-kappaB and MyD88 were both significantly lower than the control group (P<. 05). Meanwhile, the down rugulation of NF-kappaB could inhibit proliferation of NPC 5-8F cells and promote their apoptosis (P<0. 05). CONCLUSION: By inhibiting TLR4 / MyD88 signaling pathway, the expression of NF-kappaB in NPC 5-8F cells could decrease, then the cell proliferation was inhibited and cell apoptosis was induced. The results showed that TLR4 / MyD88 / NF-kappaB induced by LPS is an important pathway in the genesis and development of NPC. This study provides evidence for targeting research of NPC. PMID- 26536707 TI - [The effect of MDR1 (P-gp) and ABCG2 on the drug resistance in Hep 2 cells]. AB - OBJECTIVE: To study the effect of MDR1 (P-gp) and ABCG2 on the drug resistance in Hep 2 cells. METHOD: Flow cytometry was used to detect the variations of the antitumor drugs accumulation and discharging, and activity variations when MDR1 and ABCG2 inhibitors were used in Hep-2. RESULT: The accumulation and discharging of mitoxantrone was significantly higher than the control group when ABCG2 inhibitor FTC was used in Hep-2 (P<0. 05). In contrast, P-gp did not appear similar case; To the mitoxantrone and cisplatin, there was no statistical correlation about activity of Hep-2 between P-gp or ABCG2 antagonist and the control; To the doxorubicin, combining FTC and P-gp, the activity of Hep-2 was higher than the control and difference was significant (P<. 05), In contrast, FTC and P-gp did not appear similar case when used alone; To the 5-FU, when PGP used, the activity of Hep-2 was higher than that in the control and difference was significant (P<0. 05), In con- trast, FTC and FTC+P-gp did not appear similar case; To the paclitaxel, when P-gp or FTC+P-gp used, the activity of Hep-2 was higher than that in the control and difference was significant(P<0. 05). CONCLUSION: ABCG2 may lead to drug resistance mainly by changing the ability of cell in accumulating and discharging chemotherapy drugs. P-gp has other way. P-gp and ABCG2 play different roles in different drug resistance. PMID- 26536708 TI - [The expression and clinical significance of EphA2 and E-cadherin in papillary thyroid carcinoma]. AB - OBJECTIVE: To investigate the expression and clinical significance of EphA2 and E cadherin proteins in papillary thyroid carcinoma tissues, and to explore the relationship between them. METHOD: Using immunohistochemical SP/PV method, we detected the expression of EphA2 and E cadherin in tumors of 43 papillary thyroid carcinomas, 11 thyroid adenoma and 10 normal thyroid tissues, then studied their relationships with clinic pathological factors. RESULT: The total positive rates of EphA2 and E cadherin expression were 58. 14% and 32. 56% in papillary thyroid carcinoma tissues, 18. 18% and 81. 81% in thyroid adenoma.tissues and they were 10. 00% and 100. 00% in normal thyroid tissues respectively. The positive expression of EphA2 in carcinoma tissues was higher than in the thyroid adenoma tissues and normal thyroid tissues (P<0. 05) and the positive expression of E cadherin in carcinoma tissues was lower than that in the thyroid adenoma tissues and normal thyroid tissues (P<0. 05). The positive expression of EphA2 and E cadherin was associated with lymph node metastasis and histological grade (P<0. 05), but it was not associated with all the clinic-pathological factors including age, sex and the tumor size (P>0. 05). In papillary thyroid carcinoma tissues, the expression of EphA2 was negatively correlated with the expression of E cadherin protein (r= -0. 416, P<0. 01). CONCLUSION: EphA2 and E cadherin may be involved in carcinogenesis and development of papillary thyroid carcinoma. PMID- 26536709 TI - [The effect of sodium salicylate on the expression of GABAa receptor subunits in cochlear spiral ganglion neurons]. AB - OBJECTIVE: To investigate mRNA expression of GABAa receptor(GABAaR) subunits in the rat cochlear spiral ganglion neurons (SGN) and explore the effect of sodium salicylate (SS) on the expression of GABAaR subunits. METHOD: The realtime fluorescent quantitative PCR (FQ-PCR) was used to detect mRNA expression of twelve GABAaR subunits in the newborn rat SGN and then investigate mRNA expression of GABAaR subunits after treatment with 5 mmol/L SS for 15 min, 30 min, 1 h, 3 h and 6 h in the primary culture SGN. RESULT: (1) GABAaR subunits of alpha1-6, beta1-3, and gamma1-3 were detected in the SGN, and the expression of GABAaR subunits was lower than those in the cerebral cortex. In the subunit alpha family of GABAaR, the expression rank was alpha2>alpha3/alpha5>alpha4>a1>alpha6, and the expression of alpha3 and alpha5 had no difference (P>0. 05). In the subunit beta family, the expression rank was beta3>beta2>beta1. In the subunit gamma family, the expression rank was gamma1>gamma2>gamma3. (2) The expression of all subunits of GABAa receptor was obviously fluctuated excepting subunit alpha5 after treatment with SS. At 15 min post-SS, alpha1, alpha2 , beta1 and gamma1-3 were upregulated, and alpha3 was downregulated; At 30 min post-SS, alpha3, beta1 and beta3 were upregulated, and gamma1 was downregulated; At 1 h post-SS, beta2 was upregulated and gamma3 was downregulated; At 3 h post-SS, beta1 and beta2 were upregulated, and alpha3 and gamma2 were downregulated; At 6 h post-SS, alphal, alpha3 ,beta2, beta3 and gamma1 were upregulated, and alpha2, alpha4 and beta1 were downregulated. CONCLUSION: The mRNA of GABAaR was expressed in the rat SGN, and the expression of GABAaR subunits was lower in SGN than the cerebral cortex. SS could alter the GABAaR expression quantity in rat SGN; Most of the subunits expression were elevated obviously in the early post SS (15 min), followed by a slight fluctuation. PMID- 26536710 TI - [The application of self-made needle electrocautery in laryngomicrosurgery]. PMID- 26536711 TI - [The analysis of therapeutic effect of pingyangmycin injection on treating 31 patients with pharyngolaryngeal venous malformation]. PMID- 26536712 TI - [The misdiagnostic analysis of one subglottic primary laryngeal malignant lymphoma case]. PMID- 26536713 TI - [A case of infant with giant parapharyngeal space rhabdomyosarcoma]. AB - Rhabdomyosarcoma is a kind of skeletal muscle ifferentiation tendency of primitive mesenchymal malignant tumor. It is common in pediatric malignant pleomorphic rhabdomyosarcoma, and its prognosis is poor. It is easy to relapse, and its predilection sites in head and face were around the eyes, the external auditory meatus, nasal cavity and paranasal sinuses. We should take comprehensive treatment including surgical operation, radiotherapy and chemotherapy drug combination for embryonal rhabdomyosarcoma. PMID- 26536714 TI - [A case of subglottic osteoma]. AB - A 41 years female patient was hospitalized with hoarseness for three months, without cough, expectoration and dyspnea. The symptom had no relief by application of antibiotics. Electronic laryngoscope showed that there were the grey neoplasms under subglottic anteriou commissure with broad base and slightly rough surface, and bilateral vocal cords were normal; throat CT showed subglottic irregular high density and calcification. The subglottal tumor resection was performed under the general anesthesia and laryngoscope CO2 laser assisted. In the operation, we found that the tumor was hard with surface of thin mucosa tissue, and there was white bone tissue under it. The removing tumor was about 0. 8 cm X 0. 6 cm X 0. 3 cm and was diagnosed as subglottic osteoma by pathologic examine. There was no recurrence in three months follow-up. PMID- 26536715 TI - [A case of proptosis by traumatic delayed meningo-encephalocele]. AB - A case of traumatic delayed meningo-encephalocele suffered orbital fracture, but bony defects in frontal sinus had not been found on CT scanning. We treated the patient with surgery of intranasal endoscopy and repaired the skull base defect successfully during the first attempt. There was no recurrence in 10 months followed up. The leak site may not correlate with imaging in traumatic delayed meningo-encephalocele by comparing operative findings with the imaging estimate and endoscopy. Therefore, endoscopical approaching is effective in seeking and treatment. PMID- 26536716 TI - [Two cases of neck region Kimura's disease]. AB - Kimura's disease is a rare, benign, slow-growing chronic inflammatory swelling with a predilection for the head and neck region and is almost always with peripheral blood eosinophilia and elevated serum IgE levels. It is endemic in Asian males and rare in Western people. Surgical excision of the lesion is the first line therapy. Drug and radiation therapy have to be considered for the refractory lesions. PMID- 26536717 TI - [Schwannoma of submandibular gland: a case report]. AB - A case of Schwannoma in the submandibular gland was reported which had been misdiagnosed as pleomorphic adenoma before operation. The tumor was originated from lingual nerve which in turn invaded the Schwann membrane near the submandibular ganglion. PMID- 26536718 TI - [The influence factors and meanings of tracheotomy after cervical spinal cord injury]. AB - Cervical spinal cord injury is a common and serious disease in clinic, and tracheotomy combined with mechanical ventilation is an effective way to prevent respiratory complications. Although tracheotomy is used widely, there are not unified indications of tracheotomy after cervical spinal cord injury in the practical application. At the same time, the advantages and disadvantages of the application of tracheotomy in patients with cervical spinal cord injury are still on dispute. Based on the recent literature, we summarize the influence factors and meanings of tracheotomy after cervical spinal cord injury. PMID- 26536719 TI - [The diagnosis and treatment progress of lymphatic malformations of the head and neck in children]. AB - Lymphatic malformations including macrocystic and microcystic malformation are congenital benign vascular disease. The incidence in children is much higher than adults and they most often occur in head and neck. There are a variety of diagnosis and treatment methods in lymphatic malformations. This paper reviewed the recent literatures with respect to the pathology, imaging and treatment of the lymphatic malformations in children. And we detailed the advantage and disadvantage of surgical excision, sclerotherapy, laser ablation and drug treatment of lymphatic malformations particularly in children. Surgical excision continues to be integral to treat in many cases when the lesions involve the eye socket or are large enough to affect breathing, but it should not be overused without consideration of the histologic types and extent. In addition, cervicofacial macrocystic lesions tend to sclerotherapy while superficial mucosal microsystic lesions are amenable to laser therapy. In order to obtain the best treatment outcomes, the treatment protocol should be individualized and comprehensive. PMID- 26536720 TI - [Magnetic resonance imaging of prostate cancer]. AB - Prostate cancer has varying prognoses.The extremes of the disease spectrum involve well-differentiated prostate cancer that can be considered almost normal ageing without any significant effect on the patient's prognosis, and poorly differentiated, invasive carcinoma that requires active treatment. The selection of an appropriate line of treatment for each patient requires reliable assessment of the extent, aggressiveness and risk of recurrence of the disease. Multiparametric magnetic resonance imaging has improved the detection of prostate cancer and the assessment of its aggressiveness and local extent. Magnetic resonance imaging enables the detection of the most suspicious target for taking a biopsy specimen. PMID- 26536721 TI - [Where to find a suitable red cell product, if the patient has a rare blood group?]. AB - A rare blood group and the associated anti-red cell antibody against a very common blood group factor make it significantly more difficult to find suitable red cell products, possibly endangering the additional treatment of the patient. The need of rare blood should be anticipated early enough. The availability of red cells is secured by extensive blood group studies among blood donors, by donor registers, freezing of rare red cells and through international collaboration. The determination of rare blood groups by genotyping provides a longed-for addition to the investigational repertoire of both patients and blood donors. Systematic freezing of red cells was started in Finland in 2010. PMID- 26536722 TI - [Effect of MRSA on treatment and care in Finland - applications for compensation and complaints in 1993 to 2012]. AB - Events involving applications for compensation or filing a complaint in a MRSA case in Finland by patients or family members were studied for over a twenty-year period. The number of cases found was 305. Of the applications, only 7% resulted in compensation, and none of the complaints led to a change in decision. The discontentment was more commonly associated with the possible MRSA-induced impairment of the given treatment or limitations in freedom than with the fear of the direct health effects of the infection. In order to avoid problems, essential aspects include an intimate knowledge of guidelines among those working in the treatment and care sector, and proper informing of the patients about the effects of MRA on life. PMID- 26536723 TI - [Electronically or face to face - quicker and more facile services for the client]. AB - While many services have moved or are moving to the Net, the standard of activity of the healthcare still continues to be based on booking an appointment and face to-face consultation. Electronic services may solve the availability problem in basic healthcare. The client and the producer of a health service can meet electronically both synchronically at the same time and non-synchronically, i.e. through communicating at a time that is best suited for each. The asymmetry of information changes when the patient and the professional have access to the same information. The expansion of virtual services presents a challenge to our training, which is based on a chain advancing from anamnesis to status, investigations and treatment plan. PMID- 26536724 TI - [Mobile technology and health applications, what are they?]. AB - There are almost as many mobile telephone connections in the world as there are people. A vast number of mHealth apps related to health and welfare are available and can be used by mobile phones, smart phones and tablets. By applying features adapted from games, the applications are endowed with user engagement, motivation and encouragement. Data security, patient safety and reliability play a key role as the number of mobile applications within healthcare is growing. In support of the development and introduction of novel health applications in the future, a culture of experimentation provides a standard of activity that is effective, illustrative and engaging. PMID- 26536725 TI - [Electronic means for the assessment and treatment of own health status]. AB - Independent management of affairs electronically without encountering a customer servant is part of everyday life. Citizens, patients and healthcare customers are willing to assess their health status and need for health services, taking care of treatment on one's own initiative, when this is possible. The benefit of electronic services is accessibility at all times of the day and immediate reception to the computer or mobile device of feedback concerning one's own status. The development and support of independent care will require novel working practices from healthcare professionals as well. PMID- 26536726 TI - [Online therapies - what is known about their functionality]. AB - Online therapies are partly automated therapies, in which psychotherapeutic contents have been complemented with computer-aided presentational and educational contents, with a therapist giving support to the progress of the patient. As methods, these therapeutic programs incorporate therapeutic methods that have proven effective, such as remodeling of thoughts, activation of behavior and exposure, empathy, strengthening of cooperative relationship and motivation, and general support for self-reflection. For instance, online therapies already constitute part of the Finnish treatment guidelines on depression. Online therapies are available throughout Finland for the essential psychiatric illnesses. PMID- 26536727 TI - [Self-service check-in and visit tracking - easier outpatient visits]. AB - The patient self-service check-in and visit tracking system developed in close co operation with the vendor and experts of Oulu University Hospital facilitates the management of the increasing number of outpatient visits. It helps physicians and nurses in keeping up with the patient flow. Furthermore, it reduces the amount of work needed for the enrolment of patients. Time stamps - a by-product of the use of the system - provide information about the functioning of the outpatient unit and the patient process. PMID- 26536728 TI - [Introduction of Kanta services between 2010 and 2014]. AB - National Kanta Services are at the deployment stage. The use of electronic prescription has become established and will be mandatory in 2017. Public health care organizations send data to the national Patient Data Repository in a large scale, and private health care is carrying out preparations in order to implement and start using the service. As part of Patient Data Repository services, a national Patient Data Management service has been accessible to citizens since 2010 and will be extended in 2015. Patient Data Management service patient summary for health care professionals is in development and will be implemented in 2016-2018. A user interface service My Kanta pages has been accessible to citizens since May 2010. A user interface for health care professionals (Kelain) to access Kanta Services is in development. Social welfare data repository will be developed as part of the national Kanta Services. PMID- 26536729 TI - [The Update of Obesity Syndrome: Molecular Mechanism. Pathophysiology and Therapies. Editorial: Obesity disease and its pathogenesis]. PMID- 26536730 TI - [The Update of Obesity Syndrome: Molecular Mechanism, Pathophysiology and Therapies. Topics: I. Recent Topics on Diagnosis and Pathophysiology of the Obesity Syndrome: 1. Obesity secondary to endocrinological disorders]. PMID- 26536731 TI - [The Update of Obesity Syndrome: Molecular Mechanism, Pathophysiology and Therapies. Topics: I. Recent Topics on Diagnosis and Pathophysiology of the Obesity Syndrome; 2. Progress in genomic and epigenetic medicine against obesity]. PMID- 26536732 TI - [The Update of Obesity Syndrome: Molecular Mechanism. Pathophysiology and Therapies. Topics: I. Recent Topics of Diagnosis and Pathophysiology of the Obesity Syndrome; 3. Gut microbiome and obesity]. PMID- 26536733 TI - [The Update of Obesity Syndrome: Molecular Mechanism, Pathophysiology and Therapies. Topics: I. Recent Topics on Diagnosis and Pathophysiology of the Obesity Syndrome; 4. Circadian rhythm disorders and obesity]. PMID- 26536734 TI - [The Update of Obesity Syndrome: Molecular Mechanism, Pathophysiology and Therapies. Topics: I. Recent Topics on Diagnosis and Pathophysiology of the Obesity Syndrome; 5. Feeding regulatory substances and obesity]. PMID- 26536735 TI - [The Update of Obesity Syndrome: Molecular Mechanism, Pathophysiology and Therapies. Topics: II. Recent Topics on Care and Treatment of the Obesity Syndrome; 1. Diet therapy for obesity]. PMID- 26536736 TI - [The Update of Obesity Syndrome: Molecular Mechanism, Pathophysiology and Therapies. Topics: II. Recent Topics on Care and Treatment of the Obesity Syndrome; 2. Exercise and cognitive behavioral therapy for obesity]. PMID- 26536737 TI - [The Update of Obesity Syndrome: Molecular Mechanism, Pathophysiology and Therapies. Topics: II. Recent Topics on Care and Treatment of the Obesity Syndrome; 3. Pharmacotherapy of obesity]. PMID- 26536738 TI - [The Update of Obesity Syndrome: Molecular Mechaniam, Pathophysiology and Therapies. Topics: II. Recent Topics on Care and Treatment of the Obesity Syndrome; 4. Bariatric surgery]. PMID- 26536739 TI - [Discussion Meeting on Care and Treatment of Obesity Syndrome: Latest Approach through Nutrition, Diets, Exercise, Lifestyle Modification and Psychological Aspects]. PMID- 26536740 TI - [Case Report; Long-term treatment with etanercept induced systemic sarcoidosis in a patient with rheumatoid arthritis]. PMID- 26536741 TI - [Case Report: A case of living-donor kidney transplantation from a heterozygote mother to a hemizygote son of Fabry disease diagnosed by donated allograft biopsy]. PMID- 26536742 TI - [The Cutting-edge of Medicine; Countermeasure and control issues for measles elimination]. PMID- 26536743 TI - [The Cutting-edge of Medicine; Progress and the issue toward the imaging of arthritis]. PMID- 26536744 TI - [How Does the Physician Interpret the Patient's Narrative as It Relates to the Physical Exam?; Chest pain]. PMID- 26536745 TI - [Series: Physicians and Disaster Medical Care; The report of mini-symposium on disaster medicine]. PMID- 26536746 TI - [Series: Physicians and Disaster Medical Care; The past history of the Disaster Medical Working Group of the Japanese Society of Internal Medicine]. PMID- 26536747 TI - [Series: Physicians and Disaster Medical Care; The 111th annual scientific meeting of the Japanese Society of Internal Medicine, Mini-symposium on disaster medicine; Questionnaire on how the medical subspecialty societies have responded for the Great East Japan Earthquake]. PMID- 26536748 TI - [Patient-Centered Medical Home: Suggestions for the Health Care Delivery System Reform in Japan: Guidelines for Patient-Centered Medical Home (PCMH) recognition and accreditation programs]. PMID- 26536749 TI - [Comprehensive risk management chart for the prevention of cerebro- and cardiovascular diseases]. PMID- 26536750 TI - Community, Family and Kin: Current Themes and Approaches. PMID- 26536751 TI - Maternal Mortality in Six East Anglian Parishes, 1539-1619. AB - This study examines the maternal mortality rate in six early modern rural parishes of East Anglia where a midwife was known to be practicing. Register entries from the six parishes are translated and transcribed and maternal outcomes established and discussed. Midwives and their families are researched to establish marital status, parity and social standing. Maternal mortality is calculated and differing rates for women experiencing multiple births, stillbirths and base births examined. PMID- 26536752 TI - Few Deaths before Baptism: Clerical Policy, Private Baptism and the Registration of Births in Georgian Westminster: a Paradox Resolved. AB - The evident lengthening of the interval between birth and baptism over the eighteenth century has often been assumed to have increased the risk that young infants died before baptism. Using burial records that include burials of unbaptised infants and give age at death we demonstrate that very few infants who survived the first few days of life escaped baptism in the parish of St. Martin in the Fields, despite a very profound lengthening of the delay between birth and baptism over the second half of the eighteenth century. Examination of baptism fee books indicates that perhaps a third of all infants were baptized privately in the parish and a pamphlet dispute between the vicar and one of his clerks provides extraordinary evidence of the extent to which baptism was a process rather than a single event. Our analysis suggests that it was the registration of baptism that was delayed, with no affect on the risk of death before baptism. PMID- 26536753 TI - Why was Infant Mortality so High in Eastern England in the mid Nineteenth Century? AB - This paper re-examines the high rates of infant mortality observed in rural areas of eastern England in the early years of civil registration. Infant mortality rates in some rural registration districts in the East Riding of Yorkshire, Cambridgeshire and Norfolk were higher than those in the mill towns of Lancashire. After describing the areas affected, this paper considers three potential explanations: environmental factors, poor-quality child care associated with the employment of women in agriculture, and the possibility that the high rates were the artefactual consequence of migrant women workers bringing their children to these areas. These explanations are then assessed using a range of evidence. In the absence of reliable cause of death data, recourse is had to three alternative approaches. The first involves the use of the exceptionally detailed tabulations of ages at death within the first year of life provided in the Registrar General's Annual Reports for the 1840s to assess whether the 'excess' infant deaths in rural areas of eastern England happened in the immediate post-natal period or later in the first year of life. Second, data on the seasonality of mortality in the 1840s are examined to see whether the zone of 'excess' infant mortality manifested a distinctive seasonal pattern. Finally, a regression approach is employed involving the addition of covariates to regression models. The conclusion is that no single factor was responsible for the 'excess' infant mortality, but a plausible account can be constructed which blends elements of all three of the potential explanations mentioned above with the specific historical context of these areas of eastern England. PMID- 26536754 TI - Marriage Horizons at Woodstock--A Revised Approach. AB - The double logarithmic straight-line representation of marriage horizon data is a useful tool for their comparison. Current practice is to exclude intra-parochial couples from the calculations. This note argues that these couples should be included and demonstrates that the results of doing so produce significantly improved correlation coefficients. PMID- 26536755 TI - The Carnegie Dietary Survey of Interwar Britain. AB - This research note describes an under-used collection of papers which document interwar income, nutrition and health in Britain which were created in the administration of the Carnegie Dietary Survey by John Boyd-Orr in the Rowett Institute with funding from the Carnegie United Kingdom Trust. The survey was conducted in 16 rural and urban places across England and Scotland between 1937 9, and are now held at the Specialist Collections Centre at the University of Aberdeen. While the importance of the survey in informing knowledge about nutrition and the development of rationing has been acknowledged in the field of social medicine, the survey data has primarily been used by epidemiological scientists and economic historians. After outlining the survey's past influences and uses, this item details the possible ways the data could be used by social, economic and local population historians. PMID- 26536756 TI - [Progress in quantitative methods based on liquid chromatography-mass spectrometry for drug metabolizing enzymes in human liver microsomes]. AB - Cytochrome P450 (CYP) enzymes and uridine 5-diphospho-glucuronosyltransferase (UGT) enzymes are critical enzymes for drug metabolism. Both chemical drugs and traditional Chinese medicines are converted to more readily excreted compounds by drug metabolizing enzymes in human livers. Because of the disparate expression of CYP and UGT enzymes among different individuals, accurate quantification of these enzymes is essential for drug pharmacology, drug-drug interactions and drug clinical applications. The research progress in quantitative methods based on liquid chromatography-mass spectrometry for drug metabolizing enzymes in human liver microsomes in the recent decade is reviewed. PMID- 26536757 TI - [Influence of the distortion of gradient profile on peak width in gradient liquid chromatography]. AB - In gradient liquid chromatography, the gradient profile may be distorted because of the effects of solvent mixing and axial dispersion. Such effects will be significant especially when stepwise gradient and linear gradient with high slope are applied. In this work, we discussed the influence of the distortion of gradient profile on the peak width. Firstly, the chromatographic peaks were measured under linear and stepwise gradient conditions where a C18 column was used as the stationary phase, a mixture of methanol and water as the mobile phase, and biphenyl and acetophenone as the samples. Then, the response of methanol under corresponding conditions was recorded by disconnecting the column and the detection wavelength was set at 205 nm. The gradient profile at the column inlet was calculated from the methanol response profile. The theoretical values of the peak width were calculated from the set gradient profile and the gradient profile obtained at the column inlet respectively. The theoretical values were compared with the experimental ones. It is shown that the distortion of gradient profile does affect the peak width. When such influence is taken into account, the theoretical and experimental values of the peak width are well consistent. PMID- 26536758 TI - [A simple preparation method of an electric heating apparatus for heating capillary chromatographic columns and its application in liquid chromatography mass spectrometry system]. AB - For deep coverage of proteome, especially in performing qualitative identification and quantitative analysis of low-abundance proteins, the most commonly used method is the application of a longer capillary chromatographic column or a capillary column packed with smaller particle sizes. However, this causes another problem, the very high back pressure which results in liquid leaks in some connection parts in a liquid chromatograph. To solve this problem, an electric heating apparatus was developed to raise the temperature of a capillary column for reducing its back pressure, which was further applied in a capillary high performance liquid chromatography-tandem mass spectrometry system (cHPLC MS/MS), and evaluated in the terms of chromatographic column back pressure and chromatographic column efficiency using bovine serum albumin (BSA) tryptic digests and yeast tryptic digests, separately. The results showed that at the optimum current, our electric heating apparatus could reduce the column pressure of a capillary column packed with 3 um packing materials by at least 50% during the separation of BSA tryptic digestion and yeast tryptic digestion, compared with that without electric heating. The column efficiency was also increased slightly. This suggested that the electric heating apparatus can significantly reduce the column pressure, which provides an efficient way to use capillary chromatographic columns packed with smaller sizes of particles at a lower pressure. PMID- 26536759 TI - [Simultaneous determination of ten benzotriazole ultraviolet stabilizers in food contact plastic materials by solid phase extraction and ultra performance liquid chromatography with tandem mass spectrometry]. AB - A sensitive method was developed for the simultaneous determination of ten benzotriazole ultraviolet stabilizers in food contact plastic materials by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The sample was extracted by methanol-dichloromethane, and purified by a C18 solid phase extraction (SPE) column. The separation was performed by using water containing 0. 1% (v/v) formic acid and methanol as the mobile phases with gradient elution at a flow rate of 0. 3 mL/min. The electrospray ionization (ESI) source in positive ion mode was used for the analysis of the ten benzotriazole ultraviolet stabilizers in multiple reaction monitoring (MRM) mode. The results showed that the standard curves were obtained with good correlation coefficients (r2 > 0.996) in their linear concentration ranges. The limits of detection (LODs, S/N = 3) for the ten benzotriazole ultraviolet stabilizers were in the range of 0.6-1.6 ug/kg. The mean recoveries for the ten benzotriazole ultraviolet stabilizers at three spiked levels (low, medium and high) were 75.2%-85.3% with relative standard deviations of 1.0%-5.7%. Ten kinds of food contact plastic materials were tested, and 2,2'-methylenebis (6-(benzotriazol-2-yl)-4-tert octylphenol) (UV-360) was found in a sample of polyethylene (PE) material. The method is accurate, simple, rapid and feasible for the simultaneous determination of benzotriazole ultraviolet stabilizers in food plastic materials. PMID- 26536760 TI - [Determination of anthocyanins in the peel of sweet cherry by ultra performance liquid chromatography tandem mass spectrometry]. AB - A method for the determination of seven anthocyanins in the peel of sweet cherry was developed by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The sample was extracted by methanol containing 0.1% (v/v) hydrochloric acid, and then purified by AB-8 macroporous resins. The separation was carried out on a Phenomenex Kinetex column (100 mm x 4.6 mm, 2.6 Rm) with mobile phase of 0.1% (v/v) formic acid aqueous solution containing 5 mmol/L ammonium formate and methanol. The sample solution was detected by UPLC-MS/MS with ESI under positive ion and multi reaction monitoring (MRM) modes. The results showed that the limits of quantification (LOQs) for the seven target compounds were 0.26-1.42 ug/kg. The seven anthocyanin standards showed a good linearity in the range of 0-100 ug/L with the correlation coefficients (r2) of 0.996 4-0.999 3. The average recoveries of the seven anthocyanins were 97.2% 105.4%, and the relative standard deviations (RSDs) were 1.9%-5.8%. The mature fruit samples of sweet cherry red variety "Tieton" and the yellow variety "13-33" were analyzed by this method. The results showed that the anthocyanin composition and contents were significantly different between the two varieties. This method can be used for rapid identification and the determination of anthocyanin components in sweet cherry fruits due to its simple operation, high sensitivity, good reproducibility and covering a wide range of anthocyanins. PMID- 26536761 TI - [Direct analysis of 38 polyphenols in wine by ultra high performance liquid chromatography-linear ion trap/orbitrap high resolution mass spectrometry]. AB - Wine has been described previously as a rich source of polyphenols. However, an accurate screening of its complete phenolic profile is still lacking. In the present work, the analysis of 38 polyphenols in wine using ultra high performance liquid chromatography-linear ion trap/orbitrap high resolution mass spectrometry (UPLC-LTQ/Orbitrap MS) was explored. Wines were directly detected. The sample was loaded onto a Thermo Hypersil Gold C18 column (100 mmx 2.1 mm, 1.9 um) using a gradient elution of acetonitrile/water containing 0. 1% (v/v) formic acid for the separation. UPLC-LTQ/Orbitrap mass spectrometer acquired full scan MS date for quantification, and data dependent MS2 product ion spectra for identification and/ or confirmation. The regression coefficients (R2) for the calibration curves (two orders of magnitude up to the lowest calibration level) in the study were >= 0.99. The limits of detection for the 38 compounds were 0.002-0.50 mg/kg. The average recoveries at three spiked levels were in the range of 90%-102% with the relative standard deviations (RSDs) of 0.51%-2.56%. Mass errors were always <= 5 ppm. This procedure was then successfully applied to the analysis of the polyphenols in wines. PMID- 26536762 TI - [Determination of five avermectins in bovine liver by on-line solid-phase extraction with hydrophobic monolithic column coupled with high performance liquid chromatography-tandem mass spectrometry]. AB - A method based on on-line solid-phase extraction (SPE) with hydrophobic monolithic column coupled with high performance liquid chromatography-tandem mass spectrometry was developed for the simultaneous determination of five avermectins in bovine liver. A poly(butyl methacrylate-co-ethylene dimethacrylate) monolithic column was used as the sorbent. The parameters influenced on on-line SPE and separation process such as the loading mobile phase, the eluting flow rate and the solvent for the separation were investigated in detail. Blank samples, spiked samples, matrix effect and recovery experiments were investigated to evaluate the extraction efficiency and potential interfering compounds originating from the matrix. Under the optimized conditions, the method showed a linear range of 1-100 ug/L and the quantification limit of 5 ug/kg for each analyte. The presented method gave recoveries of 77.4%-98.4%. The relative standard deviations of intra day and inter-day were 4.46%-8.03% and 4.79%-8.68%, respectively. Moreover, no significant changes were found in the extraction performance after more than 400 usages on one monolithic column, and even on the monoliths with various batches. The feasibility of the developed poly (butyl methacrylate-coethylene dimethacrylate) monolithic column based on the on-line SPE method for the determination of avermectins was further demonstrated by the analysis of real samples. PMID- 26536763 TI - [Rapid determination of 204 pesticide residues in tea by ultra performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry]. AB - An analytical method was established for the simultaneous determination of 204 pesticide residues in tea by ultra performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-Q-TOF/MS). The samples were extracted with acetonitrile, and cleaned-up by solid phase extraction (SPE) with a Carb-PSA cartridge, eluted with acetonitrile-toluene (3:1, v/v), determined by UPLC-Q-TOF/MS and quantified by external standard method. A data base of the accurate mass numbers and a library which contains the 204 pesticides were established. The automatic retrieval of detection results was carried on according to the characteristics of the compound, such as accurate mass, retention time, isotopic ratio, and so on. Based on the above results, the qualitative identifications of the 204 pesticides were accomplished without the contrast of standard substances. The results indicated that this method can be used to determine the 204 pesticides in tea. At the three spiked levels of 10, 20, 50 ug/kg, mean recoveries for the 204 pesticides in tea were between 68. 1% and 117. 2%, with the relative standard deviations (RSDs) ranging from 3.1% to 18.9%. The limits of quantification for the 204 pesticides were lower than 10 ug/kg. The method has been applied to four positive samples, and the results generally accord with the detection results by the method of GB/T 23205-2008. This method has the characteristics of high efficiency, as well as high sensitivity and accuracy, which can meet the requirement of the determination of the 204 pesticides in tea. PMID- 26536764 TI - [Metabolic profiling analysis of amino metabolites in plant extract based on pre column derivatization-ultra high performance liquid chromatography-mass spectrometry]. AB - Amino metabolites are important compounds that play a key role in plant growth and development. A metabolic profiling analysis method of amino metabolites in plant extract was developed based on pre-column derivatization-ultra high performance liquid chromatography- mass spectrometry. Using the tobacco leaf as an example, a total of 87 amino metabolites, including amino acids, amines, peptides, alkaloids etc. were detected. The repeatability of the method was good with RSDs of 85 amino metabolites between 1. 5% and 18. 8%. Forty-three amino metabolites validated by standard samples showed good linearity with the correlation coefficients of 0.993-0.999, covered linear range of four orders of magnitude. The limits of detection were 0.03-6.58 ng/mL. The intra-day and inter day precisions were 0.7%-15.6% and 0.8%-22.9%, respectively. The recoveries were 74.4%-122.7%. The influence of topping on metabolic profiling of amino metabolites in fresh tobacco was investigated using the developed method. The results showed that the amino metabolites in the upper tobacco leaves were most affected than those in the middle and lower leaves. Metabolism of amino metabolites in the upper leaves after topping was mainly towards the alkaloid synthesis. The method integrated the advantages of triple quadrupole mass spectrometry and high resolution quadrupole-time of flight mass spectrometry. It can be used for metabolic profiling analysis of amino metabolites in plant extract with high sensitivity and selectivity. PMID- 26536765 TI - [Determination of seven phthalate metabolites in human urine by high performance liquid chromatography-tandem mass spectrometry]. AB - A method has been developed for the analysis of seven metabolites of phthalates in human urine by high performance liquid chromatography-tandem mass spectrometry ( HPLC-MS/MS). The urine samples were hydrolyzed with glucuronidase followed by purification with solid-phase extraction (SPE) cartridges. Both 0. 1% formic acid in water (v/v) and 0.1% formic acid in acetonitrile were used as the mobile phases in a gradient mode. The chromatographic separation was achieved on a phenyl column. Mass detection was then conducted by electrospray ionization in negative ion mode and multiple reaction monitoring mode. The components were quantified by stable isotope-labelled (13C-) phthalate monoester internal standards. The calibration curves of the seven phthalates metabolites showed good linear relationships in the range of 0.2-200.0 ug/L (r > 0.999 76). The recoveries at three levels were from 88.8% to 108.9% with relative standard deviations no more than 17.05%. The limits of detection of the method were 13.43 80.2 ng/L. The limits of quantification were 44.77-267.37 ng/L. This method was successfully applied to the determination of metabolism of phthalates in human urine with efficiency, increased accuracy and high sensitivity. PMID- 26536766 TI - [Determination of peptide and protein diversity in venom of the spider Selenocosmia jiafu by high performance liquid chromatography and mass spectrometry]. AB - Selenocosmia jiafu (S. jiafu) is recently identified as a new species of spider in P. R. China. These medium bodied venomous spiders are distributed mainly in the hilly areas of southwest of China, mostly at Yunnan and Guangxi Provinces. In order to understand the composition of the S. jiafu venom, we performed a preliminary analysis of this venom using reversed-phase high performance liquid chromatography (RP-HPLC), matrix-assisted laser-desorption/ionization time-of flight mass spectrometry (MALDI-TOF-MS) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The S. jiafu venom was separated by RP-HPLC in an analytical C18 column (phenomenex 100 A, 250 mm x 4.6 mm, 5 um) equilibrated with solution A (distilled water with 0.1% trifluoroacetic acid), using a gradient from 0% to 50% of solution B (acetonitrile with 0.1% trifluoroacetic acid) over 50 min with a flow rate of 1 mL/min. The isolated venom proteins were treated with in-gel digestion separated by SDS- PAGE and then identified by liquid chromatography-electrospray ionization quadrupole-time of flight mass spectrometry (LC-ESI-QTOF-MS) techniques. The results show that more than 40 fractions eluted were monitored at 215 nm in the RP-HPLC chromatogram of the venom of the spider S. jiafu. Most of the fractions were eluted with retention times of 5-15 min and 25-40 min, corresponding to 5%-15% and 25%-40% acetonitrile, respectively. The venom contains 238 peptides that follow a bimodal distribution, with about 62.5% of the peptides having a relative molecular mass of 3,000-4,500 and about 33.2% of the peptides having a relative molecular mass of 1,000-3,000. This distribution model is rather different from those of peptides from other tarantula spider venoms analyzed. To explore the relative molecular mass distribution of the venom proteins, the venom was analyzed by SDS PAGE using standard protocols. Except for peptides with relative molecular mass lower than 10,000, the SDS-PAGE electrophoresis revealed three more obvious bands around 50, 72 and 90 kD respectively. Further MS analysis indicated that there are mainly hemocyanin, potassium ion channel protein, calcium protease and so on. Altogether, this study not only indicated there are many peptides and proteins in the S. jiafu venom, but also provided a basis for further case-by-case investigation of peptide toxins from this venom. PMID- 26536767 TI - Solidified floating organic drop microextraction combined with high performance liquid chromatography for the determination of carbamazepine in human plasma and urine samples. AB - Solidified floating organic drop microextraction (SFODME) in combination with high performance liquid chromatography was used for separation/preconcentration and determination of carbamazepine (CBZ) in human plasma and urine samples. Parameters that affect the extraction efficiency such as the type and volume of extraction solvent, ionic strength, sodium hydroxide concentration, stirring rate, sample volume and extraction time, were investigated and optimized. Under the optimum conditions (extraction solvent, 40 uL of 1-undecanol; sodium hydroxide concentration, 1 mol/L; temperature, 50 degrees C; stirring speed, 400 r/min; sample volume, 8 mL; sodium chloride concentration, 3% (w/v) and extraction time, 60 min) the calibration curve was found to be linear in the mass concentration range of 0.4-700.0 ug/L. The limit of detection (LOD) was 0. 1 ug/L and the relative standard deviation (RSD) for six replicate extraction and determination of carbamazepine at 100 ug/L level was found to be 4.1%. The method was successfully applied to the determination of CBZ in human plasma and urine samples. PMID- 26536768 TI - Comparison among three anion exchange chromatographic supports to capture erythropoietin from cell culture supernatant. AB - Affinity and ion exchange conventional chromatography have been used to capture erythropoietin (EPO) from mammalian cell culture supernatant. Currently, chromatographic adsorbent perfusion is available, however a limited number of applications have been found in the literature. In this work, three anion exchange chromatographic supports (gel, membrane and monolithic) were evaluated in the capture step of the recombinant erythropoietin purification process. The influences of load and flow rate on each support performance were analyzed. Also the purity of the EPO molecules was determined. A productivity analysis, as a decision tool for larger scale implementation, was done. As a conclusion, the evaluated supports are technically suitable to capture EPO with adequate recovery and good purity. However, the monolithic column admits high operating velocity, showing the highest adsorption capacity and productivity. PMID- 26536769 TI - [Enantioseparation of 3alpha-acyloxy-6beta-acetoxyltropane compounds with Chiralpak AD and Chiralcel OD-H chiral stationary phases]. AB - Six 3alpha-acyloxy-6beta-acetoxyltropane compounds were enantioseparated by high performance liquid chromatography with amylose-based chiral stationary phase Chiralpak AD and cellulose-based chiral stationary phase Chiralcel OD-H in the normal phase mode, using various mixtures of n-hexane-isopropanol as mobile phases. The enantiomers 6 were completely separated on a Chiralpak AD column. While the enantiomers 1, 4 and 3 got complete, baseline and basic separation respectively on a Chiralcel OD-H column. However, the enantiomers 6 were partially separated on the Chiralcel OD-H column and enantiomers 1 could not be separated on the Chiralpak AD column. This indicated that the cave structure of chiral stationary phase exerted great effect on the resolutions. The enantiomers 5 could not be separated on both of the chiral stationary phases. The main possible mechanism of chiral resolution involves in spatial adaptability and molecular interactions between chiral stationary phases and compounds. The substituents in C-3alpha position of 3alpha-acyloxy-6beta-acetoxyltropane compounds play an important role in spatial adaptability. And it was suggested that the steric hindrance effect of the substituent in C-3alpha position was the key factor of determining the selective recognition of chiral stationary phase to the enantiomers of 3alpha-acyloxy-6beta-acetoxyltropane compounds. Besides, the molecular interaction, such as pi-pi interaction, also exerts great influence to the chiral resolution. This study provides a reference for the enantioseparation of many other tropane derivatives. PMID- 26536770 TI - [Rapid determination of thiabendazole and carbendazim in concentrated fruit juices by ultra-high performance liquid chromatography-tandem mass spectrometry]. AB - A method was developed for the rapid determination of thiabendazole and carbendazim residues in concentrated fruit juices by using ultra-high performance liquid chromatography (UHPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS), and quantified by matrix-matched standard solution in external standard method. The residues in the samples were extracted by ethyl acetate, and then analyzed by using UHPLC-MS/MS in multiple reaction monitoring (MRM) mode via positive electrospray ionization with an Waters ACQUITY UPLC BEH C18 column (50 mm x 2.1 mm, 1.7 um) as the analytical column. Good linearities were obtained in the range of 0.5-10 ug/kg for both pesticides with correlation coefficients greater than 0. 99. The recovery experiments were carried out by spiking standards into blank samples of apple, peach, orange, pear, grape juices at three levels of 0.5, 1.0 and 5.0 ug/kg. The recoveries of thiabendazole and carbendazim were from 76.98% to 108.7% with the relative standard deviations (RSD) of 2.95%-9.99%. For both pesticides in different matrices, the limits of detection (S/N = 3) were in the range of 0.12-0.23 ug/kg. Meanwhile, the pyrolysis mechanism and matrix effects for the determination of thiabendazole and carbendazim in concentrated fruit juices were investigated in this study. The method is simple, rapid and accurate, and can be used for the routine analysis of thiabendazole and carbendazim in concentrated fruit juices. PMID- 26536771 TI - [Determination of dimethyl yellow and diethyl yellow in yuba and dried beancurd by modified QuEChERS method and liquid chromatography-tandem mass spectrometry]. AB - A modified QuEChERS (quick, easy, cheap, effective, rugged and safe) method followed by liquid chromatography-tandem mass spectrometric analysis was developed for the determination of dimethyl yellow and diethyl yellow in yuba and dried beancurd. Yuba and dried beancurd samples were soaked by deionized water, then acetonitrile was added to extract the analytes. Sodium chloride and anhydrous magnesium sulfate were added for liquid-liquid separation. The extracts were cleaned-up by dispersive solid-phase using N-propyl diethylamine. The analytes were separated by liquid chromatography and determined by mass spectrometry. External standard method was used for quantification. The recoveries of dimethyl yellow were in the range of 73.5%-84.5% at spiked levels of 0.3, 1 and 10 kg/kg and the recoveries of diethyl yellow were in range of 70.5%-81.2% at spiked levels of 0.1,1 and 10 ug/kg; relative standard deviations of the method were lower than 11%. The limit of detection and the limit of quantification of dimethyl yellow were 0.1 ug/kg and 0.3 ug/kg, respectively; the limit of detection and the limit of quantification of diethyl yellow were 0.05 ug/kg and 0.1 ug/kg, respectively. This method can be used in rapid screening and quantitative analysis of dimethyl yellow and diethyl yellow in yuba and dried beancurd. PMID- 26536772 TI - [Simultaneous determination of monosaccharide and oligosacpharide in rice wine by high performance anion exchange chromatography with integrated pulsed amperometric detection and the establishment of their fingerprints]. AB - An analytical method for the determination of glucose, fructose, isomaltose, isomaltotriose, maltose, panose and maltotriose was developed by high performance anion exchange chromatography coupled with integrated pulsed amperometric detection. The analysis was performed on a CarboPaTM 10 column with gradient elution of NaOH-NaOAc as mobile phases. The seven sugars were well separated in less than 26 min and showed good linear correlation coefficients between 0.5 and 50 mg/L. The detection limits (LODs) were 0.1 g/L. The recoveries ranged from 76.5% to 108.4% at different spiked levels. The relative standard deviations were between 3.02% and 8.23%. The established method was applied in determining the seven sugars in different batches of Shaoxing Jiafan rice wines from different manufacturers. The standard fingerprints were established by median values using the obtained results. Similarities of the fingerprints of the samples to the standard were calculated by using angle cosine. The results showed that the similarities of wines from different manufacturers were significantly different, so the method could be used for the identification of rice wines from different manufacturers. PMID- 26536773 TI - Selective separation and determination of isoproterenol on thin layers of bismuth silicate ion-exchanger. AB - A simple and sensitive method for the separation and determination of isoproterenol from other doping drugs has been developed on thin layers of bismuth silicate, a synthetic inorganic ion exchanger as adsorbent in thin layer chromatography (TLC). A mixture of methanol and 0.1 mol/L formic acid (3:7, v/v) was employed as the mobile phase. The development time was 32 min. The quantitative measurement were performed with a Camag TLC Scanner-3 at wavelength (lambda) of 410 nm. The isoproterenol recovery in this procedure was 98.9%. The linear correlation coefficient was greater than 0. 987 1 and the relative standard deviation (RSD) was less than 0.94. The limit of detection (LOD) and limit of quantification ( LOQ) were 7.7 x 10(-7) mol/L and 3.85 x 10(-6) mol/L, respectively. This method has been applied in the determination of isoproterenol in dosage forms and in biological fluids. PMID- 26536774 TI - [A Case of Secondary Cryofibrinogenemia with Cholangiocarcinoma and Deep Venous Thrombosis]. AB - Cryofibrinogen (CF) is a type of cryoprotein (CP) that can precipitate in cooled plasma but not in serum, and resolves upon warming. We identified a case of secondary cryofibrinogenemia with cholangiocarcinoma and deep venous thrombosis. The patient's cryocrit measured using a Wintrobe tube was 19% in sodium citrate plasma stored for 7 days at 4 degrees C. We performed quantitative analysis of plasma proteins (fibrinogen, IgG, IgA, IgM, C3, C4, alpha1-antitrypsin, and C reactive protein) before and after precipitation for 12 hours at 4 degrees C. The plasma fibrinogen concentration decreased by 16.7% (120 mg/dL --> 100 mg/dL), whereas the others were unaffected by precipitation. The CP purified from the patient's plasma was washed three times with saline and subjected to Western blot and Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE) analyses. Western blot analysis indicated that the purified CP was composed of not only fibrinogen but also fibronectin, alpha1-antitrypsin, alpha2 macroglobulin, coagulation factor VIII, and IgG, IgA, and IgM. Interestingly, SDS PAGE analysis showed that the molecular weight of the patient's CF differed from that of purified normal fibrinogen (340 KDa) and consisted of several low molecular-weight bands (50-250 KDa). From these results, we speculated that CF found in this case was a mixture of degradated fibrinogen and some plasma proteins. In summary, cryofibrinogenemia is a rare and under-recognized disease. Sample information in routine clinical practice is valuable to diagnose this disease. PMID- 26536775 TI - [Factors Affecting Non-Specific Reaction in Latex Agglutination Turbidimetric Immunoassay for Detection of Matrix Metalloproteinase-3]. AB - PURPOSE: Measurement of matrix metalloproteinase-3(MMP-3), a marker for rheumatoid arthritis, by means of latex agglutination turbidimetric immunoassay (LTIA), has come to replace ELISA kit, but pre-improvement LTIA kit S(Sekisui Medical) frequently shows false values resulting from non-specific reactions. We analyzed factors influencing the frequency of non-specific reactions for MMP-3 detection using various methods. METHOD: Serum MMP-3 levels were measured in 1,214 routine samples or 57 panels with various immunoserological abnormalities by means of pre-improvement and improved kit S, LTIA kit E (Eiken Chemical) and ELISA kit. Non-specific reaction samples were selected either from the routine samples based on the results of correlativity tests between the kits and of dilution linearity tests, or from 57 panels with immunoserological abnormalities based on the results of recovery tests. To explore the factors causing non- specific reactions, titers of rheumatoid factor (RF), immunoglobulins and four heterophil antibodies were measured in these samples. In addition, changes in findings as a result of reduction treatment or IgM absorption were examined in selected samples to clarify the effect of heterophil antibodies. RESULTS: Samples which showed suspected false values probably due to non-specific reaction numbered 75, 15, 5 and 17 as measured with pre-improvement kit S, improved kit S, kit E and ELISA kit, respectively. Kit S also showed high rate of deviation in recovery tests on panels with immunoserological abnormalities. Rate of RF titer in samples with non-specific reactions was higher than that of other factors. Non specific reaction could be inhibited in two samples as a result of reduction treatment or absorption of IgM subtype. CONCLUSION: Pre-improvement kit S showed a higher rate of non-specific reactions than other kits. The most common cause of non-specific reactions is thought to be high RF titer, but high levels of IgM, including heterophil antibodies, may also affect the values of MMP-3. PMID- 26536776 TI - [A Patient with Early-Stage Multiple System Atrophy Showing Augmented Nystagmus in Light]. AB - The ability to fix the eyes on a target, visual fixation, is important for the maintenance of equilibrium. The visual suppression (VS) test is one method of measuring the function of visual fixation. The test records caloric nystagmus by electrooculography, and the maximum slow phase velocity of caloric nystagmus in darkness is compared with the slow phase velocity in light with eyes fixed. Lesions of the cerebellum, brain stem, and cerebrum cause abnormalities of VS. We report a patient whose VS became a clue in the diagnosis of a disorder of the central nervous system. A 54-year-old man complained of dizziness, which gradually increased in frequency over 5 months. He visited several clinics, where vestibular neutritis and cervical spondylosis were suspected and treated without improvement. Although a pure-tone auditory test revealed bilateral normal hearing, a caloric test showed a weak response and VS was lost with augmentation of caloric nystagmus in light on both sides. Both eye tracking and optokinetic nystagmus tests were abnormal. Although magnetic resonance imaging showed no abnormalities, single photon emission computed tomography revealed decreased blood flow in the parietal area. VS of caloric nystagmus towards the side of a lesion is reduced or abolished after unilateral flocculus damage, and is abolished bilaterally after bilateral flocculus damage. In the case of a parietal lobe or pontine lesion, VS is strongly abolished, and even augmentation of caloric nystagmus may be observed. In the present case, the patient was diagnosed with multiple-system atrophy after onset of dizziness. PMID- 26536777 TI - [Mass Screening for Inborn Errors of Metabolism]. AB - Neonatal mass screening is a project aiming at the prevention of disorders by discovering and treating diseases which damage health left untreated in all newborns. The bacterial inhibition assay (BIA) was developed in about .1961 and used as the Guthrie method for a long time, but it was replaced by tandem mass spectrometry due to the recent development of mass spectrometers, and its nationwide introduction in Japan was completed. With this introduction, 13 diseases were newly included in screening. Fatty acid and organic acid metabolic disorders and urea cycle disorders were included, and favorable results have been obtained. PMID- 26536778 TI - [Gastroenterological Cancer Diagnosis by Metabolomics-Discovery of Pancreatic Cancer Biomarker]. AB - The field of omics involves comprehensive investigations based on genomics, transcriptomics, proteomics, and metabolomics, and omics studies have developed rapidly. Metabolomics, metabolome analysis, involves technology to analyze the concentrations of low-molecular-weight metabolites comprehensively, and has recently rapidly developed along with improvements in analytical technology. Therefore, metabolome analysis is just beginning to be applied to not only food science and environmental research fields but also medical research. In the medical research field, especially, metabolome analysis plays an important role in novel disease biomarker discovery. The metabolome represents the endpoint of the omics cascade and, therefore, is considered to be closer to the phenotype. In addition, there is also a possibility that the metabolome is affected by exogenous factors such as environmental and food factors, as well as endogenous factors such as DNA/mRNA/protein. Therefore, metabolome analysis can be a useful approach for discovering effective biomarkers. Here, we explain the characteristics of metabolome analysis, and also outline metabolome analysis using a liquid chromatograph mass spectrometer (LC-MS), gas chromatograph mass spectrometer (GC-MS), capillary electrophoresis mass spectrometer (CE-MS), and matrix-assisted laser desorption ionization mass spectrometer (MALDI-MS). Then, we describe the findings of studies that used metabolome analysis in an attempt to discover biomarker candidates for pancreatic cancer, and discuss metabolome analysis-based disease diagnosis. PMID- 26536779 TI - [Assessment of Vitamin D Metabolism by LC-MS/MS]. AB - Vitamin D is pro-hormone that has important roles in calcium metabolism in the intestine, kidneys, and bone. Many studies have indicated that vitamin D deficiency causes not only rickets and osteomalacia, but also increases the risk of various diseases such as cancer and autoimmune disease. Of the many vitamin D metabolites, 25-hydroxyvitamin D[25OH-D], 1alpha,25-dihydroxyvitamin D[1,25(OH)2 D], and 24,25-dihydroxyvitamin D [24,25 (OH) 2-D] are important for assessing vitamin D metabolism. They are circulating, biologically active, and major inactive forms of vitamin D metabolite, respectively. Immunoassays are widely used for the measurement of serum/plasma vitamin D metabolites. With such an assay, however, the accurate quantification of these metabolites is difficult because of cross-reactivity. Liquid chromatography-tandem mass spectrometry [LC MS/MS] is the gold standard method for analyzing these metabolites due to its high sensitivity and selectivity. Derivatization with a Cookson-type reagent is a key technique for robust and sensitive analysis by LC-MS/MS. A Cookson-type reagent rapidly and quantitatively reacts with the s-cis-diene structure of vitamin D metabolites, and markedly enhances the ionization efficiency. Using a recently developed Cookson-type reagent (DAPTAD), we successfully established an LC-MS/MS-based method for analyzing serum vitamin D metabolites including 250H-D, 1,25 (OH) 2-D, and 24,25 (OH) 2-D. Thus, LC-MS/MS can be a powerful tool for the accurate determination of vitamin D metabolism. In this review, we describe the advantages of LC-MS/MS for the determination of vitamin D metabolites. PMID- 26536780 TI - [Rapid Identification of Infectious Microorganisms in Clinical Samples by MALDI TOF MS Analysis]. AB - Matrix-laser desorption ionization time-of flight/mass spectrometry (MALDI-TOF MS) is a powerful tool for the detection of target molecules in body fluids. Recently, the MALDI-TOF MS technique was applied for the rapid detection of protein profiles in cultured strains, and has rapid, simple, and universal advantages over the conventional technique. MALDI mass patterns were compared with the unique ribosomal 16S protein profiles of standard microorganism strains in a commercial database. Although this present MS technique has already been adopted as a routine method for the identification of general bacteria in the clinical laboratory field, there are still many problems to overcome regarding current challenges, necessitating the identification of more valuable species of microorganism. As the first step, we have begun the standardization of sample preparation to identify species causing infectious diseases by MALDI-TOF MS. In this special issue, we summarize the challenges in the modified preparation of clinical samples, such as blood, urine, and sputum, in our laboratory to rapidly diagnose severe infectious disease, and describe the current trends in clinical microbiology. PMID- 26536781 TI - [Imaging Mass Spectrometry in Histopathologic Analysis]. AB - Matrix-assisted laser desorption/ionization (MALDI)-imaging mass spectrometry (IMS) enables visualization of the distribution of a range of biomolecules by integrating biochemical information from mass spectrometry with positional information from microscopy. IMS identifies a target molecule. In addition, IMS enables global analysis of biomolecules containing unknown molecules by detecting the ratio of the molecular weight to electric charge without any target, which makes it possible to identify novel molecules. IMS generates data on the distribution of lipids and small molecules in tissues, which is difficult to visualize with either conventional counter-staining or immunohistochemistry. In this review, we firstly introduce the principle of imaging mass spectrometry and recent advances in the sample preparation method. Secondly, we present findings regarding biological samples, especially pathological ones. Finally, we discuss the limitations and problems of the IMS technique and clinical application, such as in drug development. PMID- 26536782 TI - [GWAS of Rheumatoid Arthritis and Drug Discovery]. AB - We have conducted genome-wide association studies (GWAS) for rheumatoid arthritis (RA). We previously found that myelin basic protein (MBP) is associated with RA. One of the MBP isoforms (Golli-MBP) is expressed not only in nerve cells, but also in hematopoietic cells, and may negatively regulate T-cell receptor signaling. We expanded the GWAS level by collaborating with laboratories in Japan and then throughout the world. Meta-analysis of GWAS data resulted in the identification of -100 genomic loci associated with RA development. The -100 genomic loci contain -400 candidate genes, and it is not easy to find out which genes actually play important roles in RA. By incorporating available public databases, we succeeded in narrowing down the susceptibility genes from 377 to 98. We also showed that regulatory T cells are associated with RA based on the combination of the histone methylation database and our mega-GWAS results. Protein-protein interaction and drug discovery databases gave us information that some of the drugs have already been developed as therapeutic medicines for RA, and some of them were used for diseases other than RA. These drugs may be used for RA in the near future (drug repurposing). The combination of biological databases and GWAS results may be a novel method to identify new therapeutic targets. PMID- 26536783 TI - [A Novel Clinical Entity "Anti-PIT-1 Antibody Syndrome"--Autoimmunity against a Transcription Factor]. AB - Autoimmunity against the pituitary has been observed in patients with hypophysitis. Although various autoantibodies against pituitary proteins have been reported, it is known that most of them are markers for the disease. Recently, a unique autoantibody against pituitary transcription factor PIT-1 (POU1F1) was detected in patients with an acquired combined pituitary hormone deficiency characterized by a specific defect in growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH). The antibody has been suggested to be involved in the pathogenesis because PIT-1 is an essential transcription factor that plays a role in the differentiation and maintenance of GH-, PRL-, and TSH-producing cells and mutations in the PIT-1 gene, resulting in a specific defect in these hormones. This syndrome was found to be a novel clinical entity; therefore, it was named 'anti-PIT-1 antibody syndrome'. Circulating anti-PIT-1 antibody and various autoantibodies were detected with multiple endocrine organopathy, meeting the definition of autoimmune polyglandular syndrome. Mechanistically, cytotoxic T lymphocytes that specifically react with PIT-1 protein play an important role in the development of this syndrome. In this review, we discuss the clinical aspects and pathophysiology of anti-PIT-1 antibody syndrome. PMID- 26536784 TI - [Metabolomics for Biomarker Discovery in Systemic Lupus Erythematosus]. AB - Metabolomics is the identification and quantification of the metabolome, all low molecular-weight metabolites in a biological sample. Cell metabolism is known to have a marked impact on the function of various immune cells. We recently examined the differences in the serum metabolome between patients with systemic lupus erythematosus (SLE) and healthy subjects, using gas chromatography/mass spectrometry (GC/MS), and sought to identify candidates for metabolic biomarkers. We found that the levels of 25 metabolites were significantly different in SLE patients compared to healthy controls. A two-dimensional plot of the principal component analysis scores showed distinct clustering for the two subject groups. Multivariate analysis revealed that variations in the levels of glutamic acid, urea, tyrosine, phosphate and glycerol markedly contributed to the observed separation of metabolomic profiles of the SLE patients and healthy controls. A number of metabolites showed different changes between SLE and rheumatoid arthritis. Furthermore, the serum levels of glutamic acid were significantly correlated with the SLE disease activity index score in the patient group. These findings suggest that GC/MS-based serum metabolomics can serve as a novel diagnostic and monitoring tool for autoimmune diseases, and the pattern of variation in metabolite levels may be useful for understanding the pathophysiology of the diseases and developing novel therapeutic strategies. PMID- 26536785 TI - [Clinical Personnel Training in Laboratory Medicine in Chiba University Hospital during the Past 15 Years]. AB - During the past 15 years, various approaches have been adopted for medical personnel training in the Division of Laboratory Medicine, Chiba University Hospital. Medical personnel have been encouraged to enter the Graduate School of Medicine, Chiba University. At present, 14 of them have successfully completed the Ph.D. program and 16 have been awarded a master's degree. In our unit, clinical proteomics is a principal research subject, and we have identified a number of biomarker candidates in collaboration with clinical units. In Chiba University Hospital, all clinical laboratory physicians are certified as medical geneticists and are in charge of the Division of Clinical Genetics as well. We have treated a total of 1,009 patients, including those with hereditary neuromuscular diseases, familial cancers, and prenatal diagnoses. We have also encouraged medical technologists to become certified as genetic counselors, which may be a promising subspecialty for medical technologists. Mass spectrometry (MS) is a powerful analytical tool used in an increasing number of clinical laboratories around the world. Liquid chromatography (LC) coupled with tandem mass spectrometry (MS/MS) has been used for newborn screening, toxicology, therapeutic drug monitoring endocrinology, and, more recently, for the measurement of targeted proteins and peptides. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) has proven to be a rapid and reliable tool for identifying microorganisms. The Japanese Society for Medical Mass Spectrometry has started to certify medical mass spectrometrists, which could be another promising subspecialty for medical technologists. PMID- 26536786 TI - [Authorized Qualifications of Staff Conducting Examinations in the Field of Clinical Microbiology]. AB - Because of the increase in healthcare-associated infections, appearance of highly resistant bacteria, and that of emerging/re-emerging infectious diseases, it is necessary for the skills of clinical microbiological technologists and the associated technology to be improved. Technologist in Microbiology (4,717 certified) and Specialist in Microbiology (58 certified) are authorized qualifications in the field of examination for clinical microbiology, with a history of 60 years, and Clinical Microbiological Technologist (670 certified) and Infection Control Microbiological Technologist (ICMT) (528 certified) are necessary qualifications to become a member of an infection control team. As problems to be resolved, clarifying the relationships among the authorized qualifications, reconsidering the fairness of evaluating written examinations, and further consideration of the administration method for an increasing number of examinees need to be tackled. PMID- 26536787 TI - [Regarding Authorized Qualifications in Sonography]. AB - Today, I will talk about the profession "Ultrasound Technologist." The written examination to gain this license includes clinical questions (35 questions including those using photographs; 70 minutes to answer) and basic questions related to ultrasound for medical use (35 questions including those requiring calculation; 70 minutes to answer). The answer to each question is selected from 5 alternatives. The questions used in the examination are not officially disclosed. The minimum score needed to pass the examination is 60 points for both the test with clinical questions and that with basic questions. My practice to prepare for the basic questions related to ultrasound for medical use involved attempting to answer a collection of questions while understanding physical phenomena by watching animations on the related Internet homepage. I wrote down how to approach the questions (including those requiring calculation), together with comments and answers to each of them. Basic questions about ultrasound for medical use differ little from year to year because there are few questions reflecting highlights or specific topics prevailing in a given year. So, to prepare for basic questions, I think it is important to become familiar with the trends of questions and how to answer them through repeating mock tests many times. Preparing for clinical questions is very difficult. Although many collections of clinical questions are available at bookstores, I have the impression that most of the questions in these collections have already been used in past examinations, and there is now a tendency for more precise clinical questions targeting specific areas to be adopted for the examination. The questions adopted in the past are becoming outdated, while the techniques of ultrasonography are continuing to advance. So, clinical questions are being increasingly adopted that cover recent topics in this field. In any event, knowledge covering extensive areas is needed to prepare for the clinical questions. For those who desire to attain the license "ultrasound technologist" despite insufficient clinical experience, the only possible approach may be to read through collections of questions and reference books. PMID- 26536788 TI - [The I.G. Farben laboratory at the Gunzburg mental hospital. Epilepsy research during the NS-regime and the postwar period]. AB - The purpose of this study is to evaluate the activities of the I.G. Farben laboratory at the former "Heil- und Pflegeanstalt" Gunzburg. This laboratory was established to test the newly developed epilepsy drug "Citrullamon" and its derivatives. Specifically, the type and manner of the various experiments were examined to determine whether the suspicions of unethical human experimentation could be identified. The commercial and medical activities between I.G. Farben and the Heil- und Pflegeanstalt, including the specific roles of the senior physician Wilhelm Leinisch and the I.G. Farben chemist Arno Grosse, are reviewed. PMID- 26536789 TI - [The "modernization" of health education in both German states between 1949 and 1975. The example of smoking]. AB - Using the example of smoking, this article scrutinizes the notions of order, educational conduct and images of subjects in the health education of both German states between 1949 and the mid 70s. Drawing on archival sources, publications and educational media from both health ministries, the Deutsches Hygiene-Museum and the Bundeszentrale fur gesundheitliche Aufklarung I reconstruct the organizational, conceptual and medial shift of health education from "citizenship" to a technology of communication and public relation, needing "scientification" in the 1960s. New epidemiological evidence fostered the belief in an efficacious prevention of manly coded and with smoking associated cardio vascular diseases by forming healthy behavior. This went hand in hand with the increase of state responsibility for the health of its citizens and the import of new knowledge stemming from social research and new methodological expertise from advertising. At the same time the ideal of a comprehensible citizen shifted into a "socialist personality" that was to be shaped by a hierarchical and consistent education in the German Democratic Republic. In the Federal Republic of Germany the general principle of the self-determined citizen unfolded the antagonism of health education between individual emancipation and imposition. PMID- 26536790 TI - [The oldest statutes of the Faculty of Medicine of the University of Rostock]. AB - The statutes of the Faculties of Medicine of the Universities Rostock and Butzow are in the process of being edited and translated from Latin in to German. This article gives the first critical examination of the oldest statutes of the Faculty of Medicine of the Alma Mater Rostochiensis. PMID- 26536791 TI - Flood pulse influence on phytoplankton community of the Aksu Stream, Giresun, Turkey. AB - Flood pulse influence on phytoplankton communities of the Aksu Stream, Giresun, Turkey were studied between December 2008 and December 2009. The phytoplankton communities consisted of 54 species. The number of species and diversity of phytoplankton showed seasonal variation, being high in rainy season. As a consequence of the flood which occurred twice in July 2009, phytoplankton environment changed physically and chemically, which resulted in an alteration in the composition of phytoplankton community. The phytoplankton community that existed previous to the flood event, had been dominated by Hantzschia amphioxys but was replaced by Nitzschia palea and a teratological form of Fragilaria sp. Presence of teratological form of diatom in the stream indicated unfavourable conditions in this region. PMID- 26536792 TI - Screening of different Trichoderma species against agriculturally important foliar plant pathogens. AB - Different isolates of Trichoderma were isolated from soil samples which were collected from different part of India. These isolates were grouped into four Trichoderma species viz., Trichoderma asperellum (Ta), T. harzianum (Th), T. pseudokoningii (Tp) and T. longibrachiatum (Tl) based on their morphological characters. Identification of the above isolates was also confirmed through ITS region analysis. These Trichoderma isolates were tested for in vitro biological control of Alternaria solani, Bipolaris oryzae, Pyricularia oryzae and Sclerotinia scierotiorum which cause serious diseases like early blight (target spot) of tomato and potato, brown leaf spot disease in rice, rice blast disease, and white mold disease in different plants. Under in vitro conditions, all the four species of Trichoderma (10 isolates) proved 100% potential inhibition against rice blast pathogen Pyracularia oryzae. T. harzianum (Th-01) and T. asperellum (Ta-10) were effective with 86.6% and 97.7%, growth inhibition of B. oryzae, respectively. Among others, T. pseudokoningii (Tp-08) and T. Iongibrachiatum (Tl-09) species were particularly efficient in inhibiting growth of S. sclerotiorum by 97.8% and 93.3%. T. Iongibrachiatum (TI-06 and TI-07) inhibited maximum mycelial growth of A. solani by 87.6% and 84.75. However, all the T. harzianum isolates showed significantly higher inhibition against S. sclerotiorum (CD value 9.430), causing white mold disease. This study led to the selection of potential Trichoderma isolates against rice blast, early blight, brown leaf spot in rice and white mold disease in different crops. PMID- 26536793 TI - Acute and subchronic toxicity of metal complex azo acid dye and anionic surfactant oil on fish Oreochromis niloticus. AB - The acute toxicity study of metal complex dark green azo acid dye, anionic surfactant oil and their mixture determined the 96 hr LC50, and fish behaviours. Subchronic toxicity determined haematology parameters and concentrations of copper and chromium in blood. The 96 hr LC50 was determined by probit analysis and subchronic toxicity was conducted in 90 days. No mortalities were observed in control and anionic surfactant oil treatments. The 96 hr LC50 value of mixture was 26.7 mg I(-1) (95% CL = 20.7 - 46.8) and that of metal complex dark green azo acid dye was not met as the percentage of dead was below 50% of tested organisms. In a treatment of anionic surfactant oil and that of mixture observed behaviours were respiration response, uncoordinated movement, loss of equilibrium, erratic posture and loss of responsiveness. Subchronic toxicity indicated fluctuations in number of erythrocytes, leukocytes and thrombocytes in all chemical treatments. Erythrocyte morphology such as anisocytosis, erythrocytes hypertrophy, karyolysis, cytoplasm vacuolation, ghost cell were observed in fish blood in all chemical treatments. An inverse relation was observed between total copper and chromium concentration in blood. However, the toxicity effect was chemical dose dependent and length of exposure. PMID- 26536794 TI - Tidal variation of phytoplankton in the coastal waters of South Andaman, India. AB - Tidal variations of phytoplankton were studied at two stations i.e., Station 1 (Science Centre) and Station 2 (Junglighat Bay) during the period of December 2010 to February 2011 in the coastal waters of South Andaman Islands, India. Phytoplankton biomass (Chlorophyll-a) was observed low (avg. 0.02- 0.1 mg m(-3)) at the stations during the sampling period. Low values of dissolved oxygen and biochemical oxygen demand were recorded during low tide. In all 114 species belonging to 42 genera of diatoms, 16 genera of dinoflagellates and 4 genera of cyanobacteria were identified. Phytoplankton population density ranged from 827cells I(-1) to 11,790 cells l(-1) and was high during high tide in comparison to low tide. Diatoms were dominant (70.86-88.0%) and contributed more towards phytoplankton biomass followed by dinoflagellates (10.8-19.53%) and cyanobacteria (0.73-9.4%). Dinoflagellates were visualised more in the samples when diatom population had declined. Diversity indices such as species diversity (H') ranged from 0.68-3.1; species richness (d) varied from 2.18-6.54 and Pielou's evenness (J') ranged from 0.24-0.94. H' was more during high tide than at low tide at Station 2. On the other hand, low diversity and equitability in phytoplankton population were observed at Station 1 during the month of January, 2011. It may be due to dominance of mono specific cells of Rhizosolenia sp. The study indicates low production of phytoplankton in coastal waters. Variation of tides may leave implications on sampling, because it has an influence on species diversity and proportion of specific micro algal groups at different times. PMID- 26536795 TI - Effect of Mentha pulegium extract and 8-hydroxy quinoline sulphate to extend the quality and vase life of rose (Rosa hybrid) cut flower. AB - Rose is an ornamental plant which contains one of the world's top cut flowers. Vase life of cut rose flower is short. Extracts of Mentha pulegium and 8-hydroxy quinoline sulphate (8-HQS) were used as two preservative solutions, aiming to extend the vase life of cut rose (Rosa hybrid L.) flowers. Rose flowers were treated with a vase solution containing the extract of M. pulegium, at concentrations of 0, 10, 20 and 30%, in combination with 8-HQS at concentrations of 0, 200, 400 and 600 mg l(-1). Longevity of cut roses flowers was determined on the basis of wilting and chlorophyll retention. Cut roses flowers were kept at room temperature (20 +/- 2 degrees C) under normal day light and natural ventilation. The vase life of cut flowers studied was prolonged by all 8-HQS and extract treatments. The best concentration of 8-HQS and extractwere 400 mg l(-1) and 10%, respectively. Our results indicated that the flowers treated with the extract and 8-HQS had longer vase life, higher rate of solution uptake and lower SPAD value (total chlorophyll) compared to the control. Also, cut flowers treated with the extract and 8-HQS had least bacterial colonies. The greatest longevity of vase life by 11.20 and 10.25 days was related to 400 mg I(-1) 8-HQS and 10% of extract, respectively. These treatments improved cut vase life more than the control treatment. The maximum solution uptake (1.85 ml g(-1) f.wt.) and minimum SPAD value (2.19) were calculated in 30% extract along with 200 mg l(-1) 8-HQS, and 200 mg l(-1) 8-HQS, respectively. The lowest number of bacterial colonies (55.75) was obtained in treatment of 600 mg l(-1) 8-HQS. Flower quality of specimens treated with extract and 8-HQS was better than those of the control. The experiments were repeated three times with three replicates and a completely randomized design had been used. The present study concludes that it would be possible to use preservative solutions containing extract of M. pulegium L. and 8 HQS to extend vase life of cut rose (R. hybrida L.) flowers. PMID- 26536796 TI - Forest biomass flow for fuel wood, fodder and timber security among tribal communities of Jharkhand. AB - The study investigated extraction and consumption pattern of fuel wood, fodder and timber and forest biomass flow for fuel wood, fodder and timber security among tribal communities in Bundu block of Ranchi district in Jharkhand (India). The study is based on personal interviews of the selected respondents through structured interview schedule, personal observations and participatory rural appraisal tools i.e. key informant interviews and focus group discussions carried out in the sample villages, using multi-stage random sampling technique. The study revealed that the total extraction of fuel wood from different sources in villages was 2978.40 tons annum(-1), at the rate of 0.68 tons per capita annum( 1), which was mostly consumed in cooking followed by cottage industries, heating, community functions and others. The average fodder requirement per household was around 47.77 kg day(-1) with a total requirement of 14227.34 tons annum(-1). The average timber requirement per household was computed to be 0.346 m3 annum(-1) accounting for a total timber demand of 282.49 m3 annum(-1), which is mostly utilized in housing, followed by agricultural implements, rural furniture, carts and carriages, fencing, cattle shed/ store house and others. Forest biomass is the major source of fuel wood, fodder and timber for the primitive societies of the area contributing 1533.28 tons annum(-1) (51.48%) of the total fuel wood requirement, 6971.55 tons annum(-1) (49.00%) of the total fodder requirement and 136.36 m3 annum(-1) (48.27%) of the total timber requirement. The forest biomass is exposed to enormous pressure for securing the needs by the aboriginal people, posing great threat to biodiversity and environment of the region. Therefore, forest biomass conservation through intervention of alternative avenues is imperative to keep pace with the current development and future challenges in the area. PMID- 26536797 TI - Bioavailability and dissipation of anthracene from soil with different alkalinity and salinity. AB - Bioavailability of contaminants, such as anthracene (Anthra), a polycyclic aromatic hydrocarbon (PAHs), and their removal from soil has been related to their extractability with non-exhaustive techniques, such as hydroxypropyl-beta cyclodextrin (HPCD) or n-butanol. Anthra was extracted with HPCD, n-butanol and by exhaustive ultrasonic extraction method from sterilized and unsterilized alkaline soil of the former lake Texcoco, having pH ranging from pH 8.2 to 10.1 and electrolytic conductivity varying from 1.2 dS m(-1) to 95.2 dS m(-1), respectively. About 24.4 and 37.6% of Anthra was removed biologically from soil as estimated by exhaustive technique after 56 days. The percentage of Anthra that was removed from soil by exhaustive technique was not related to the amount thatwas extractable with HPCD or n-butanol. It was found that the Anthra extractable with n-butanol or HPCD did not correlate well with the removal of the contaminant from soil. In this study, the removal of Anthra from soil could not be predicted by the amount of Anthra that was extracted with n-butanol or HPCD . PMID- 26536798 TI - Effect of lambda cyhalothrin and temephos on detoxification enzyme systems in Culex quinquefasciatus (Diptera: Culicidae). AB - Mosquitoes serve as vector for transmitting diseases. Among mosquitoes, Culex quinquefasciatus transmits lymphatic filariasis, yellow fever Japanese encephalitis etc. Application of chemical insecticides is still the best option for vector control programmes. Continuous use of these chemicals on mosquito reduces its effects. The present study determined the baseline susceptibility of Cx. quinquefasciatus in response to lambda-cyhalothrin and temephos treatments. In addition, the biochemical mechanisms and zymogram analysis involved in insecticide detoxification among larval mosquitoes were studied. The larval bioassay indicated high LC50 value for lambda-cyhalothrin (0.1484ppm) as compared to temephos (0.01092ppm). While AChE assay showed increased activity in temephos treatments, glutathione reductase (GR) and esterase levels were increased at both the treatments. Esterase quantitative analysis revealed the expression of three bands at 43kDa, 67kDa and 245kDa. The findings suggest that insensitivity of AChE, esterase and high GR activity may play an important role in developing resistance to synthetic pyrethroid and organophosphate insecticides in Cx. quinquefasciatus population. PMID- 26536799 TI - Studies on long-term impact of STCR based integrated fertilizer use on pearl millet (Pennisetum glaucum)-wheat (Triticum aestivum) cropping system in semi arid condition of India. AB - A long-term field experiment on pearl millet - wheat cropping system with soil test crop response correlation (STCR) based fertilizer application was initiated during kharif- 2003 on a sandy loam soil (Typic Halustept) at a research farm of Indian Agricultural Research Institute, New Delhi. The aim of the experiment was to study the impact of STCR based integrated fertilizer application for targeted yield of pearl millet - wheat cropping sequence yield and changes in soil health. The result showed a significant and positive impact of integrated use of the fertilizerwith FYM on productivity of the cropping sequence and soil fertility. The STCR based integrated fertilizer recommendations with FYM produced significantly higher grain and straw yields of pearl millet and wheat crops as compared to other treatments. The highest average (2003 to 2010-11) grain and straw yield of pearl millet (2.85 and 6.59 t ha(-1)) and wheat (5.32 and 7.17 t ha(-1)) was recorded with the application of STCR based integrated fertilizer recommendations (T2) for targeted level of yield 2.5 and 5.0 ha(-1), respectively. Average increase in grain and straw yield of pearl millet was 203 and 197% and 196 and 193% of wheat under T2 treatment over control (T4). After harvest of wheat crops (2010-11), the physical, biological properties and fertility status i.e. available N, P and K of soil were improved in the treatments where STCR based integrated fertilizer dose with 10 t FYM (T2) and FYM @20 t ha(-1)(T1) were applied in both the crops and were significantly higher as compared to T3 treatment except available phosphorus. Economic analysis based on average yield of eight cropping sequence (2003 to 2010-11), pearl millet - wheat cropping sequence gave maximum net return of Rs. 100,907 ha(-1) yr(-1) and total return of Rs. 64,992/ ha(-1)yr(-1) over control with STCR based integrated fertilizer recommendations (T2). It is concluded that STCR based integrated fertilizer can be adopted by the farmers of arid region for getting higher yield, profit and improving soil health. PMID- 26536800 TI - Effects of exogenous salicylic acid on growth characteristics and biochemical content of wheat seeds under arsenic stress. AB - The present study illustrates the phytotoxic effect of As on wheat seedlings and pre-application of salicylic acid in alleviating toxic effect of arsenic. Wheat seedlings treated with different concentrations (50-400 MUM) of arsenic decreased the germination rate (34.7% and 86.9%), root and coleptile length, fresh and dry weight of roots and coleoptile, chlorophyll (67%) and protein content (27.1%), while increased proline and MDA content. However, pretreatment with 1mM saliycilic acid partially alleviated the toxic effect of arsenic on germination parameters and significantly reduced the proline (181.2%) and MDA (80%) content thereby increasing chlorophyll and protein content in As stressed wheat plants (p < 0.01 or p < 0.05). The data suggests that saliycilic acid reduced the damaging effects generated by As and enhanced the tolerance of wheat plants to arsenic toxicity. PMID- 26536801 TI - Application of response surface methodology for optimization of polygalacturonase production by Aspergillus niger. AB - Polygalacturonase (PG) degrades pectin into D-galacturonic acid monomers and is used widely in food industry especially for juice clarification. In the present study,. fermentation conditions for polygalacturonase production by Asgergillus niger NAIMCCF-02958, using mango peel as substrate, were optimized using the 2(3) factorial design with central composite rotatable experimental design (CCRD) of response surface methodology (RSM). The maximum PG activity 723.66 U g(-1) was achieved under pH 4.0, temperature 30 degrees C and 2% inoculum by response surface curve. The experimental value of PG activity wkas higher 607.65 U g(-1) than the predicted value 511.75 U g(-1). Under the proposed optimized conditions, the determination coefficient (R2) was equal to 0.66 indicating that the model could explain 66% of the total variation as well as establish the relationship between the variables and the responses. ANOVA analysis and the three dimensional plots also confirmed interactions among the parameters. PMID- 26536802 TI - Responses of microbial respiration to nitrogen addition in two alpine soils in the Qinghai-Tibetan Plateau. AB - An incubation experiment was conducted to examine the effects of nitrogen (N) application on microbial respiration in alpine meadow and alpine shrub soils from eastern of Qinghai-Tibetan Plateau. Four different levels of nitrogen fertilization were selected in this study: control (CK, 0 mg N g(-1)), low (LN, 0.04 mg N g(-1)), medium (MN, 0.16 mg N g(-1)), high (HN, 0.4 mg N g(-1)). The results showed that microbial respiration was higher in alpine shrub than in alpine meadow soil, regardless of the rate of N application. Total microbial respiration overthe course of incubation period decreased in both soils with HN and MN treatments relative to control, but no significant differences were observed in soils with LN treatments. There was significantly positive correlation between total microbial respiration and dissolved organic carbon concentration in both soils. The results indicated that DOC may be a useful indicator of microbial respiration rate in alpine soils and the increasing N inputs could drive a negative feedback to global warming effects of carbon dioxide emitted to the atmosphere in alpine soils. PMID- 26536803 TI - Effect of mixture of Trichoderma isolates on biochemical parameter in tomato fruits against Sclerotinia sclerotiorum rot of tomato plant. AB - Experiments revealed that a mixture of Trichoderma harzianum isolates, BHU51 and BHU105 showed lowest mean disease rating (MDR) of 1.70 and 1.62% and per cent disease reduction (PDR) by 41.00 and 44.84% during the year 2008-09 and 2009-10, respectively. Shoot length, chlorophyll content and yield was also recorded highest in the mixture of BHU51+ BHU105 treatment followed by single Tichoderma treatments while lowest was found in pathogen inoculated control. The nutritional quality such as lycopene content, protein and carbohydrate was recorded highest in BHU51+ BHU105 treatment. The antioxidant activity and free radical scavenging ability of tomato fruit extract was also recorded. The results indicated that maximum 1,1-diphenyl -2-pycryl-hydrazyl (DPPH) radical scavenging activity (47.86%), ferrous ion chelation capacity (50.81%), hydroxyl radical scavenging ability (49.18%) and reducing power 0.203 O.D. at wavelength 700 nm was maximum for BHU51+ BHU105 treatment, followed by single Trichoderma treated treatments while these were recorded lowest in pathogen inoculated control. PMID- 26536804 TI - Effect of chlormequat (cycocel) on the growth of ornamental cabbage and kale (Brassica oleracea) cultivars 'Kamome White' and 'Nagoya Red'. AB - The effect of concentration and application method of chlormequat (cycocel), a plant growth retardant, on plant height and some other traits in Brassica oleracea cultivars 'Kamome White' and 'Nagoya Red' was assessed. Plant growth retardants are commonly applied to limit stem elongation and produce a more compact plant. The experiment was done as a factorial in randomized completely blocks design (RCBD) with four replications. Plants (40 days after transplanting) were sprayed and drenched with 500, 1000 and 1500 mg l(-1) cycocel. In each experiment, control untreated plants. Data were recorded the 60 and 90 days after transplanting. Based on analysis of variance (ANOVA), the effect of different treatments and their interaction on all traits was significant at 0.05 or 0.01 level of probability. Treatment of 1500 mg I(-1) cycocel resulted in about 50 and 20% shorter plants than control plants, 60 and 90 days after transplant. The growth of Brassica oleracea cultivar 'Kamome White' and 'Nagoya Red' decreased with increased cycocel concentration. Foliar sprays of cycocel controlled plant height of both cultivars. Results indicated that the shortest plants (9.94 and 11.59 cm) were those sprayed with 1500 mg l(-1) cycocel in cultivar 'Kamome White' after 60 and 90 days, respectively. The largest number of leaves (33.94) and highest leaf diameter (9.39 cm) occurred in cv. 'Nagoya Red', when drench was used. Maximum dry matter (14.31%) accumulated in cv. 'Nagoya Red', treated with spray. PMID- 26536805 TI - Evaluation of post-germinative lipid peroxidation and enzymatic antioxidant potential in lead absorbing oat (Avena sativa) seedlings. AB - The objective of the present research was to study the impact of lead (Pb) on growth, metal uptake and antioxidative potential of oat seeds under metal stress. To achieve these objectives, few experiments were conducted to assess the effect of this particular metal on various anti-oxidative enzymes, during initial metabolism after germination, in presence of lead. Pb is not an oxido-reducing metal, the oxidative stress induced by Pb in growing oat seedlings appears to be an indirect effect of Pb toxicity, leading to production of ROS with simultaneous decrease in tissue levels of superoxide dismutase and catalase. Content of free radical like superoxide anion and metabolite such as H2O2 were found to be more in plumule as compared to radical and endosperm of oat seedling. In response to various concentrations of lead ranging from 25-400 ppm, activities of peroxidase, glutathione peroxidase and ascorbate peroxidase were induced in plumule, radical and cotyledon on the 3rd, 6th and 9th days after germination. Growth parameters like length, fresh weight and dry weight were substantially affected in addition to reduced germination upto 49% only. The results indicated that even at the lowest concentration tested, a low inhibition of growth was obtained. PMID- 26536806 TI - Molecular analysis of dinucleotide microsatellite in growth hormone gene of Asian seabass (Lates calcarifer) from Mumbal, India. AB - In the present study, out of four alleles amplified from seabass (Lates calcarifer) genome inhabiting Mumbai water by PCR using growth hormone (GH) gene specific primers, two DNA fragments (SGMS1, 233 bp and SGMS2, 239 bp) were eluted from gel, cloned using pTZ57R (2.886 kb) vector into E. coli DH5alpha, characterized by restriction endonuclease analysis and sequenced by automated DNA sequencer. After blasting and multiple alignment of the above sequences, SGMS1 showed 97% and SGMS2 93.3% homology with promoter region of GH gene containing microsatellite of Australian seabass and 94.6% homology between both the fragments. These sequences SGMS1 and SGMS2 were submitted to NCBI GenBank. On blasting, these sequences with gene databases, SGMS1 and SGMS2 showed partial homologies with Seriola quinqueradiata (26.9%, 12.9%), flounder (15.8%, 15.8%), Oreochromis nilotica (23%, 7.9%), Oreochromis mossambicus (23%, 7.9%) and Danio rerio (8.2%, 7.5%). Critical analysis showed the presence of microsatellite (CA)16 and (CA)19 repeats in fragments SGMS1 and SGMS2, respectively in seabass from Mumbai water in comparison to (CA)14 repeats from the Australian seabass. Further, on sequence comparison, single nucleotide mismatches detected at their several positions in relation to seabass GH gene of Australia. These nucleotide variations detected in SGMS1 and SGMS2 in comparison to those of the Australian seabass may be due to mutations owing to environmental or habitat changes that seem to have definite potentials for development of genetic markers, which would be useful for identification and selection of superior germplasm with desirable commercial traits such as high growth rate. PMID- 26536807 TI - Accumulation of heavy metals in the fish, Oreochromis niloticus and Poecilia latipinna and their concentration in water and sediment of dam lake of Wadi Namar, Saudi Arabia. AB - The present study reports the accumulation of heavy metals like Cu, Hg, Cd, Pb and Cr in different tissues viz. liver, kidney, gills and muscles of Oreochromisniloticus and Poecilia latipinna from two sites in dam lake of Wadi Namar. Water and sediment samples were also collected from two sites for heavy metal analysis. Metal concentration in water and sediment samples of both the sites were observed in the following order: Cu>Cr>Pb>Cd>Hg; however, their concentration was found to be more at site 2 as compared to site 1. The order of metal accumulation in different tissues of O. niloticus and P. latipinna was in the following order: Cu>Cr>Pb>Cd>Hg at both the sites, while liver accumulated maximum amounts of metals followed by kidney, gills and muscles. The results showed the site 2 was more polluted by metals than Site 1 and O. niloticus accumulated greater amount of metals than P. latipinna. PMID- 26536808 TI - Phosphate solubilizing and indole-3-acetic acid producing bacteria from the soil of Garhwal Himalaya aimed to improve the growth of rice. AB - In the present study, soil bacteria from rainfed agriculture field of Garhwal Himalaya, just prior to sowing of summer crop, were isolated and initially tested for solubilization of inorganic phosphate, production of indole acetic acid (IAA) and siderophore. Two bacterial isolates, having efficient P- solubilizing activity in solid medium, were identified using 16S rRNA sequence analysis as Pseudomonas koreensis strainYB1 Arthrobacter nitroguajacolicus strainYB3 and three bacterial isolates, producing high amount of IAA in liquid medium, were identified as Klebsiella oxytoca strainYB2 and two strain of Arthrobacter nitroguajacolicus, strainYB4 and YB5, respectively. In culture medium supplemented with L-Tryptophan, Klebsiella oxytoca produced high amount of IAA (337.44 MUg l(-1)). The selected five bacterial strains were further tested for tricalcium phosphate (TCP) solubilizing abilities at three different incubation temperature viz., 4 degrees C, 10 degrees C and 28 degrees C, under in vitro conditions. At 28 degrees C, three bacterial strains Pseudomonas koreensis, Arthrobacter nitroguajacolicus strainYB4 and Klebsiella oxytoca solubilized the phosphate efficiently. At 10 degrees C only two strains, Pseudomonas koreensis and Arthrobacter nitroguajacolicus strainYB4 solubilized phosphate efficiently as compared to other strains. These five bacterial strains were tested for nitrogen, catalase activity, starch and cellulose hydrolysis as well as growth promotion activity on rice, under controlled conditions. All the five bacterial strains efficiently increased the biomass and phosphorus uptake in Swama and Swarna sub1 varieties of rice. PMID- 26536809 TI - Assessment of exchange of crop in view of change climate and International Treaties. AB - To meet the UN millennium development goal of reducing the number of hungry people to half by 2015, there is utmost need to breed potentially high yielding varieties to match up the requirement along with corrective measures to bridge the gap between the potential yield and yield harvested by farmers. The scenario has changed from free access to limited access of plant genetic resources (PGR) and therefore, it is important to understand the issues in view of national and international agreements, intellectual property rights (IPR'S), climate change conditions and expanded scope of breeders and farmers rights for developed genotypes. For efficient management of PGR, developing countries need to understand the implications of PGR related IPR'S as stronger IPR'S in developed countries could have harmful effects by reduced exchange of genetic resources from developed countries. Keeping in view the existing realities every possible effort should be taken for enrichment of crop gene pool by introducing them from each and every corner of the globe. Keeping these facts in view this paper describes the priorities for introduction and exchange of important crop groups/crops along with some of their potential wild and weedy relatives and thrust has been given to generate awareness among the workers engaged in the breeders/crop improvement works. Information provided in this presentation can be utilized by prospective crop improvement works to plan to meet out the nationalfood security. PMID- 26536810 TI - Effect of no-tillage and tillage on the ecology of mite, Acarina (Oribatida) in two different farming systems of paddy field in Cachar district of Assam. AB - The present investigation was carried out in Cachar district of Assam over a period of one year (January 2011 - December 2011) to understand the seasonal ecology of Acarina (Oribatida) in rice (Oryza sativa L.) cultivated fields. Population of Oribatida was found to be maximum during August 2011, both in no tillage (6.32 +/- 0.66 No./m2 x 100(2)) and tillage (5.30 +/- 0.71 No./M2 x 100(2)) sites in Dorgakona area whereas the peak was recorded during August 2011, both in no-tillage (5.38 +/- 0.75 No./m(2) x 100(2)) and tillage (4.69 +/- 0.77 No./m2 x 100(2)) in Durby area of study sites. Least population was encountered during January 2011, in both no-tillage (0.98 +/- 0.28 +/- No./m2 x 100(2)) and tillage (0.98 +/- 0.30 No/m2 x 100(2)) sites in Dorgakona area whereas the same was found during November 2011 in no-tillage (0.57 +/- 0.31 No.m/2 x 100(2)) and in February 2011 in tillage (0.45 +/- 0.21 No./m2 x 100(2)) sites of Durby area. Linear regression analysis with all the environmental variables showed positive and significant influence on the population dynamics whereas relative humidity (R2 = 0.26 p > 0.05) in Dorgakona no-tillage and tillage (R2 = 0.19 P > 0.05) sites and relative humidity in tillage site (R2 = 0.27 P > 0.05) in Durby area showed no influence. Multiple regression analysis showed that the combined effect of climatic variables having a significant influence (p < 0.05) on the oribatid mite population in no-tillage and tillage systems in both the study sites. Rainfall, relative humidity and temperature facilitated the soil moisture, microbial activity and litter decomposition, which in turn may favour the reproduction and growth rate of the species. Among microclimatic conditions all the parameters showed positive and significant influence (P < 0.05) on the population in no-tillage and tillage system on both the sites except pH which showed negative correlation with the population. One way ANOVA revealed significant difference (F = 6.53, P < 0.01) of the Oribatid population between the systems. PMID- 26536811 TI - A comparative study on three methods of soil quality evaluation of microtopography in the semi-arid Loess Plateau, China. AB - Three soil property test data of microtopography in the semi-arid Loess Plateau were used to compare the following three soil quality evaluation methods: correlation coefficient method, factor analysis method and Nemoro index method. The results of these methods were analyzed and compared to determine the most suitable method for comprehensive evaluation of soil quality. While correlation coefficient method and factor analysis method produced similar results, Nemoro index method showed several differences from the othertwo methods and exhibited higher sensitivity in its assessment results. The soil quality index (SQI) parameters of three methods showed consistent scales and variation trends among the various microtopographies, and there was a highly significant linear positive correlation between the SQI parameters of any two given methods. This result suggested that the three methods were all reliable and could be employed for comprehensive assessment of soil quality of microtopography in the study region. However, the Nemoro index method involves relatively uncomplicated mathematics and is very easy to absorb, and thus should be preferentially employed when three grading standards can be identified. The factor analysis method is the next most preferable, followed by correlation coefficient method. PMID- 26536812 TI - Role of nurse shrubs for restoration planting of two conifers in southeast of Mu Us Sandland, China. AB - Two-year-old pine seedlings, Pinus tabulaeformis and Pinus sylvestris were planted under the canopies of three shrub species and in open areas to test for facilitation during seedling establishment in southeast of Mu Us Sandland in northern part of Shaanxi, China. Pine seedlings establishment were assessed three times within three consecutive growing seasons. Height, area and volume of shrubs were measured. Microclimate conditions (light intensity, air temperature and soil temperature and moisture) were recorded in four microhabitats. Near surface light intensity, air temperature and soil temperature were lower under shrubs, which led to higher soil moisture and pine seedlings under the canopy of shrub species. Pine seedlings survival was remarkably higher when planted under the canopy of shrub species (65.7% for P. tabulaeformis and 60.6% for P. sylvestris) as compared with open areas (22.4% for P. tabulaeformis and 38% for P. sylvestris). P. tabulaeformis with shade-tolerance trait expressed high survival of seedlings as compared to that of P. sylvestris seedlings under the canopy of shrub species (Tukey test, P < 0.05). Leguminous shrub (Caragana korshinskii and Amorpha fruticosa) showed continuously facilitation during moderate drought stress (summer 2012, 2013 and 2014), but dense and small shrub (Caragana korshinskii) reduced the establishment of seedlings possibly for light competition. Salix cheilophila showed a facilitation effect in growing seasons, but the effect of allelopathy led to high mortality of seedlings under their canopy. in addition, two pine growths were not inhibited when planted under three shrubs. In conclusions, nurse-shrub facilitation can be used as an effective restoration strategy in this sandland. However, use of shrubs as nurse plants depends on their canopy structure and ecological impacts; the selection of target species depends on their shade tolerance traits. PMID- 26536813 TI - Indole-2-carboxamide derivatives: a patent evaluation of WO2015036412A1. AB - INTRODUCTION: Hippocampal neurogenesis in adults is a new and attractive target for the treatment and prevention of neurodegenerative and neuro-psychiatric diseases. Recently, neurogenesis stimulating activity was observed in some of the commonly used small molecule drugs such as antidepressants and atypical antipsychotics. Stimulation of neurogenesis is attractive mainly due to its wide scope of application, ranging from depressions, schizophrenia, dementia, Parkinson's and Alzheimer's Disease to various brain injuries. AREAS COVERED: New compounds based on 7-phenyl or 7-pyridinyl-1H-indole-2-carboxamide showed interesting neural stem cell proliferation inducing activity in vitro and were claimed as potential therapeutics for various neurodegenerative and neuropsychiatric diseases as well as brain injuries. The potential of the presented compounds is evaluated with respect to other small molecule neurogenesis inducers in literature. EXPERT OPINION: Nanomolar in vitro activities of presented compounds and their favorable physico-chemical properties, giving a fair chance of good oral bioavailability and sufficient CNS penetration, make these compounds promising drug candidates. The biggest drawback of the presented application is the absence of pharmacokinetics, toxicity and in vivo activity data. On the other hand, the high number of applications in this area (seven published in last two years) indicates that Hoffmann-La Roche takes it seriously. PMID- 26536814 TI - Cyclospora infection linked to travel to Mexico, June to September 2015. AB - Cyclospora cayetanensis was identified in 176 returned travellers from the Riviera Maya region of Mexico between 1 June and 22 September 2015; 79 in the United Kingdom (UK) and 97 in Canada. UK cases completed a food exposure questionnaire. This increase in reported Cyclospora cases highlights risks of gastrointestinal infections through travelling, limitations in Cyclospora surveillance and the need for improved hygiene in the production of food consumed in holiday resorts. PMID- 26536815 TI - Neoadjuvant chemotherapy in cervical cancer in pregnancy. AB - Cervical cancer is the most common gynecological cancer encountered in pregnancy. The standard treatment of early cervical cancer is usually surgical removal of the cervix (in selected cases) or, more commonly, the uterus. However, when cervical cancer develops during pregnancy, definitive surgical treatment often needs to be postponed until the fetus reaches maturity. Neoadjuvant chemotherapy (NACT) is an innovative approach in the management of these patients. It helps in controlling the disease and delaying delivery. The paper presents a literature review of the history of NACT, as well as practice points and agenda for further research. PMID- 26536816 TI - Hollow Nanostructured Metal Silicates with Tunable Properties for Lithium Ion Battery Anodes. AB - Hollow nanostructured materials have attracted considerable interest as lithium ion battery electrodes because of their good electrochemical properties. In this study, we developed a general procedure for the synthesis of hollow nanostructured metal silicates via a hydrothermal process using silica nanoparticles as templates. The morphology and composition of hollow nanostructured metal silicates could be controlled by changing the metal precursor. The as-prepared hierarchical hollow nanostructures with diameters of ~100-200 nm were composed of variously shaped primary particles such as hollow nanospheres, solid nanoparticles, and thin nanosheets. Furthermore, different primary nanoparticles could be combined to form hybrid hierarchical hollow nanostructures. When hollow nanostructured metal silicates were applied as anode materials for lithium ion batteries, all samples exhibited good cyclic stability during 300 cycles, as well as tunable electrochemical properties. PMID- 26536817 TI - Co2Fe6B2/MgO-based perpendicular spin-transfer-torque magnetic-tunnel-junction spin-valve without [Co/Pt] n lower synthetic-antiferromagnetic layer. AB - We design a Co2Fe6B2/MgO-based p-MTJ spin-valve without a [Co/Pt] n lower synthetic-antiferromagnetic (SyAF) layer to greatly reduce the 12-inch wafer fabrication cost of the p-MTJ spin-valve. This spin-valve achieve a tunneling magnetoresistance (TMR) of 158% and an exchange field (H ex) of 1.4 kOe at an ex situ annealing temperature of >350 degrees C, which ensures writing error immunity. In particular, the TMR ratio strongly depends on the body-center-cubic capping-layer nanoscale thickness (t bcc), i.e., the TMR ratio peaks at t bcc = 0.6 nm. PMID- 26536820 TI - Buccal corridor airway adjunct for intermaxillary fixation. PMID- 26536818 TI - Orexin/Hypocretin-1 Receptor Antagonism Selectively Reduces Cue-Induced Feeding in Sated Rats and Recruits Medial Prefrontal Cortex and Thalamus. AB - The orexin/hypocretin system is important for reward-seeking behaviors, however less is known about its function in non-homeostatic feeding. Environmental influences, particularly cues for food can stimulate feeding in the absence of hunger and lead to maladaptive overeating behavior. The key components of the neural network that mediates this cue-induced overeating in sated rats include lateral hypothalamus, amygdala, and medial prefrontal cortex (mPFC), yet the neuropharmacological mechanisms within this network remain unknown. The current study investigated a causal role for orexin in cue-driven feeding, and examined the neural substrates through which orexin mediates this effect. Systemic administration of the orexin-1 receptor (OX1R) antagonist SB-334867 had no effect on baseline eating, but significantly reduced cue-driven consumption in sated rats. Complementary neural analysis revealed that decreased cue-induced feeding under SB-334867 increased Fos expression in mPFC and paraventricular thalamus. These results demonstrate that OX1R signaling critically regulates cue-induced feeding, and suggest orexin is acting through prefrontal cortical and thalamic sites to drive eating in the absence of hunger. These findings inform our understanding of how food-associated cues override signals from the body to promote overeating, and indicate OX1R antagonism as a potential pharmacologic target for treatment of disordered eating in humans. PMID- 26536821 TI - Neuropsychiatric presentations and outcomes in children and adolescents with primary brain tumours: Systematic review. AB - OBJECTIVE: The purpose of this study was to systematically review the literature relating to the neuropsychiatric symptoms at presentation and outcome of childhood brain tumours. METHODS: Seven online databases pertaining to the neuropsychiatric presentation and outcomes of childhood CNS tumours were searched and PRISMA guidelines were followed. Temporal limits were not applied to the searches. RESULTS: There were 1879 relevant search results in total. After discovering the large body of both primary and secondary research in the field of cognitive and neuropsychological outcomes of brain tumours in children, these studies were excluded. Quality-of-life studies were excluded for the same reason. Thirty-one papers were chosen for discussion in this review. CONCLUSION: This timely systematic review concluded that neuropsychiatric presentations are common in children with CNS tumours-with the presence of behavioural and psychological symptoms in up to 57% of cases, their frequency varies according to age of onset and is strongly associated with time since diagnosis. The findings highlight the necessity for routine psychological and psychiatric screenings of children with suspected brain tumours and at follow-up and a number of clinical recommendations to this effect are listed. PMID- 26536823 TI - Immunoregulation in larval Echinococcus multilocularis infection. AB - Alveolar echinococcosis (AE) is a clinically very severe zoonotic helminthic disease, characterized by a chronic progressive hepatic damage caused by the continuous proliferation of the larval stage (metacestode) of Echinococcus multilocularis. The proliferative potential of the parasite metacestode tissue is dependent on the nature/function of the periparasitic immune-mediated processes of the host. Immune tolerance and/or down-regulation of immunity are a marked characteristic increasingly observed when disease develops towards its chronic (late) stage of infection. In this context, explorative studies have clearly shown that T regulatory (Treg) cells play an important role in modulating and orchestrating inflammatory/immune reactions in AE, yielding a largely Th2-biased response, and finally allowing thus long-term parasite survival, proliferation and maturation. AE is fatal if not treated appropriately, but the current benzimidazole chemotherapy is far from optimal, and novel options for control are needed. Future research should focus on the elucidation of the crucial immunological events that lead to anergy in AE, and focus on providing a scientific basis for the development of novel and more effective immunotherapeutical options to support cure AE by abrogating anergy, anticipating also that a combination of immuno- and chemotherapy could provide a synergistic therapeutical effect. PMID- 26536822 TI - The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation. AB - Changes in the enzymatic activity of protein arginine methyltransferase (PRMT) 5 have been associated with cancer; however, the protein's role in acute myeloid leukemia (AML) has not been fully evaluated. Here, we show that increased PRMT5 activity enhanced AML growth in vitro and in vivo while PRMT5 downregulation reduced it. In AML cells, PRMT5 interacted with Sp1 in a transcription repressor complex and silenced miR-29b preferentially via dimethylation of histone 4 arginine residue H4R3. As Sp1 is also a bona fide target of miR-29b, the miR silencing resulted in increased Sp1. This event in turn led to transcription activation of FLT3, a gene that encodes a receptor tyrosine kinase. Inhibition of PRMT5 via sh/siRNA or a first-in-class small-molecule inhibitor (HLCL-61) resulted in significantly increased expression of miR-29b and consequent suppression of Sp1 and FLT3 in AML cells. As a result, significant antileukemic activity was achieved. Collectively, our data support a novel leukemogenic mechanism in AML where PRMT5 mediates both silencing and transcription of genes that participate in a 'yin-yang' functional network supporting leukemia growth. As FLT3 is often mutated in AML and pharmacologic inhibition of PRMT5 appears feasible, the PRMT5-miR-29b-FLT3 network should be further explored as a novel therapeutic target for AML. PMID- 26536824 TI - Development of a methodology to describe udder conformation in sows. AB - The aim of this study was to develop a methodology to measure sow udder conformation to use in studying the correlation between udder traits and piglet survival, health and performance. The steps in the investigation were (i) to assess the repeatability of measures, (ii) to determine if there was an important difference between the two sides of the udder, (iii) to assess the extent of variation between sows, and finally (iv) to verify if the measures differ in a systematic way over the days shortly before farrowing. A total of 24 sows were scored for six conformation traits of the udder measured twice a day, every day from the sows' entrance into the farrowing crates until farrowing (1 to 4 days later). The data were recorded from both sides when the sow was lying and when she was standing. The measurements taken were: inter-teat distance within the same row (SAMER; mm between the adjacent teat bases); distance from the base of the teats to the abdominal midline, recorded only in a lying posture (B); distance between the teat base and the adjacent teat on the opposite row, recorded only in a standing posture (OPPR), distance from the base of the teats to the ground (FLOOR); teat length (LEN) measured from the tip to the base, and diameter (DIA) measured at the tip of the teat. Intraclass correlation coefficients (ICC) revealed that most udder conformation traits were highly repeatable (ICC>0.8); only DIA and FLOOR had lower repeatability (ICC=0.7). Measurements did not differ by side. In general, the greatest proportion of variance occurred at the sow level. Traits changed little in the days before farrowing, except for a change 1 day before farrowing in DIA, FLOOR and OPPR. Measures which used anatomical landmarks as the reference point were more reliable than those using the floor of the pen. Udder conformation measures can be used as a reliable phenotype for further study. They can be collected on any day shortly before farrowing, and only from one side and in one posture to save time. PMID- 26536826 TI - Synthesis of geminal bis- and tristriazoles: exploration of unconventional azide chemistry. AB - A range of geminal bis- and tristriazoles are presented. These rare and hardly studied compound classes were easily synthesized using ethyl 2,2-diazido-3 oxobutanoate as the common starting point. Firstly, CuAAC-reaction with an alkyne afforded the corresponding deacetylated bistriazoles. Upon further azidation yielding azidomethylenebistriazoles, a second CuAAC-functionalization then led to the creation of the geminal tristriazole compounds. PMID- 26536825 TI - Precision medicine for cancer with next-generation functional diagnostics. AB - Precision medicine is about matching the right drugs to the right patients. Although this approach is technology agnostic, in cancer there is a tendency to make precision medicine synonymous with genomics. However, genome-based cancer therapeutic matching is limited by incomplete biological understanding of the relationship between phenotype and cancer genotype. This limitation can be addressed by functional testing of live patient tumour cells exposed to potential therapies. Recently, several 'next-generation' functional diagnostic technologies have been reported, including novel methods for tumour manipulation, molecularly precise assays of tumour responses and device-based in situ approaches; these address the limitations of the older generation of chemosensitivity tests. The promise of these new technologies suggests a future diagnostic strategy that integrates functional testing with next-generation sequencing and immunoprofiling to precisely match combination therapies to individual cancer patients. PMID- 26536827 TI - Lichen planus pigmentosus: a retrospective clinico-epidemiologic study with emphasis on the rare follicular variant. PMID- 26536828 TI - The maturation mechanism of gamma-glutamyl transpeptidases: Insights from the crystal structure of a precursor mimic of the enzyme from Bacillus licheniformis and from site-directed mutagenesis studies. AB - gamma-Glutamyl transpeptidases (gamma-GTs) are members of N-terminal nucleophile hydrolase superfamily. They are synthetized as single-chain precursors, which are then cleaved to form mature enzymes. Basic aspects of autocatalytic processing of these pro-enzymes are still unknown. Here we describe the X-ray structure of the precursor mimic of Bacillus licheniformis gamma-GT (BlGT), obtained by mutating catalytically important threonine to alanine (T399A-BlGT), and report results of autoprocessing of mutants of His401, Thr415, Thr417, Glu419 and Arg571. Data suggest that Thr417 is in a competent position to activate the catalytic threonine (Thr399) for nucleophilic attack of the scissile peptide bond and that Thr415 plays a major role in assisting the process. On the basis of these new structural results, a possible mechanism of autoprocessing is proposed. This mechanism, which guesses the existence of a six-membered transition state involving one carbonyl and two hydroxyl groups, is in agreement with all the available experimental data collected on gamma-GTs from different species and with our new Ala-scanning mutagenesis data. PMID- 26536829 TI - The relationship between insomnia with short sleep duration is associated with hypercholesterolemia: a cross-sectional study. AB - AIM: To examine the association between insomnia with short sleep duration and hypercholesterolemia in Taiwanese adults. BACKGROUND: Previous studies mostly focused on the association between sleep duration and hyperlipidemia, but the results were not consistent. Besides, very few studies extensively examined the association between insomnia and hypercholesterolemia. This study hypothesized that insomnia with short sleep duration is associated with hypercholesterolemia. DESIGN: Secondary data analysis. This study analysed the latest database of the cross-sectional Nutrition and Health Survey in Taiwan which was released on 2011 (data collected between 2005-2008) and collected data using stratified three staged probability sampling design. METHODS: This study analysed 1533 participants aged between 19-64 (733 males and 800 females) and used logistic regression model to calculate the odds ratio and the 95% confidence interval of insomnia with short sleep duration to hypercholesterolemia. Controlled confounders included age, gender, sample weight, body mass index, waist circumference, fasting plasma glucose, hypertension and diabetes. RESULTS: Insomnia with 5-6 hours of sleep duration was significantly associated with hypercholesterolemia. The odds ratio of mild insomnia or moderate/severe insomnia with 5-6 hours of sleep duration to hypercholesterolemia was higher, compared with the reference group (without insomnia and >6 hours of sleep duration). CONCLUSION: Insomnia with short sleep duration was associated with increased odds of hypercholesterolemia. Caregivers in clinical practice should watch out for the effect brought by this novel factor. PMID- 26536830 TI - Universal roles of hydrogen in electrochemical performance of graphene: high rate capacity and atomistic origins. AB - Atomic hydrogen exists ubiquitously in graphene materials made by chemical methods. Yet determining the effect of hydrogen on the electrochemical performance of graphene remains a significant challenge. Here we report the experimental observations of high rate capacity in hydrogen-treated 3-dimensional (3D) graphene nanofoam electrodes for lithium ion batteries. Structural and electronic characterization suggests that defect sites and hydrogen play synergistic roles in disrupting sp(2) graphene to facilitate fast lithium transport and reversible surface binding, as evidenced by the fast charge transfer kinetics and increased capacitive contribution in hydrogen-treated 3D graphene. In concert with experiments, multiscale calculations reveal that defect complexes in graphene are prerequisite for low-temperature hydrogenation, and that the hydrogenation of defective or functionalized sites at strained domain boundaries plays a beneficial role in improving rate capacity by opening gaps to facilitate easier Li penetration. Additional reversible capacity is provided by enhanced lithium binding near hydrogen-terminated edge sites. These findings provide qualitative insights in helping the design of graphene-based materials for high-power electrodes. PMID- 26536831 TI - Artifact-suppressed optimal three-dimensional T1 - and T2 *-weighted dual-echo imaging. AB - PURPOSE: To develop a new artifact-suppressed optimal three-dimensional (3D) T1 - and T2 *-weighted dual-echo imaging. METHODS: We optimized flip angles for 3D T1 and T2 *-weighted imaging by conventional dual-echo in vivo experiments and computer simulations, and then implemented a dual-echo sequence with an echo specific k-space reordering scheme to satisfy the optimal flip angles for both T1 and T2 * contrast. We also proposed two strategies to suppress ringing artifacts induced by the abrupt flip angle jumps in the proposed dual echo sequence: (i) implementing smooth transition regions and (ii) discarding the k-space regions of the abrupt flip angle jumps as dummy phase-encoding steps. RESULTS: The optimal flip angles measured from experiments were different between T1 - and T2 * weighted contrast, in agreement with simulations. The echo-specific k-space reordered dual-echo sequence showed optimal T1 and T2 * contrast simultaneously, but also showed ringing artifacts because of high flip-angle changes between k space regions. The two proposed strategies effectively suppressed the ringing artifacts. CONCLUSION: The proposed 3D dual-echo sequence provided optimal T1 and T2 * contrast simultaneously with no artifacts and thus is potentially applicable to routine clinical applications for simultaneous high resolution T1 - and T2 * weighted imaging. Magn Reson Med 76:1504-1511, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26536832 TI - Life history and dynamics of a platypus (Ornithorhynchus anatinus) population: four decades of mark-recapture surveys. AB - Knowledge of the life-history and population dynamics of Australia's iconic and evolutionarily distinct platypus (Ornithorhynchus anatinus) remains poor. We marked-recaptured 812 unique platypuses (total 1,622 captures), over four decades (1973-2014) in the Shoalhaven River, Australia. Strong sex-age differences were observed in life-history, including morphology and longevity. Apparent survival of adult females (Phi = 0.76) were higher than adult males (Phi = 0.57), as in juveniles: females Phi = 0.27, males Phi = 0.13. Females were highly likely to remain in the same pool (adult: P = 0.85, juvenile: P = 0.88), while residency rates were lower for males (adult: P = 0.74, juvenile: P = 0.46). We combined survival, movement and life-histories to develop population viability models and test the impact of a range of life-history parameters. While using estimated apparent survival produced unviable populations (mean population growth rate r = 0.23, extinction within 20 years), considering residency rates to adjust survival estimates, indicated more stable populations (r = 0.004, p = 0.04 of 100-year extinction). Further sensitivity analyses highlighted adult female survival and overall success of dispersal as most affecting viability. Findings provide robust life-history and viability estimates for a difficult study species. These could support developing large-scale population dynamics models required to underpin a much needed national risk assessment for the platypus, already declining in parts of its current distribution. PMID- 26536833 TI - Probing individual point defects in graphene via near-field Raman scattering. AB - The Raman scattering D-peak in graphene is spatially localised in close proximity to defects. Here, we demonstrate the capability of tip-enhanced Raman spectroscopy (TERS) to probe individual point defects, even for a graphene layer with an extremely low defect density. This is of practical interest for future graphene electronic devices. The measured TERS spectra enable a direct determination of the average inter-defect distance within the graphene sheet. Analysis of the TERS enhancement factor of the graphene Raman peaks highlights the preferential enhancement and symmetry-dependent selectivity of the D-peak intensity caused by zero-dimensional Raman scatterers. PMID- 26536834 TI - N-acetylcysteine inhibits in vivo oxidation of native low-density lipoprotein. AB - Low-density lipoprotein (LDL) is non-atherogenic, while oxidized LDL (ox-LDL) is critical to atherosclerosis. N-acetylcysteine (NAC) has anti-atherosclerotic effect with largely unknown mechanisms. The present study aimed to determine if NAC could attenuate in vivo LDL oxidation and inhibit atherosclerosis. A single dose of human native LDL was injected intravenously into male C57BL/6 mice with and without NAC treatment. Serum human ox-LDL was detected 30 min after injection, reached the peak in 3 hours, and became undetectable in 12 hours. NAC treatment significantly reduced serum ox-LDL level without detectable serum ox LDL 6 hours after LDL injection. No difference in ox-LDL clearance was observed in NAC-treated animals. NAC treatment also significantly decreased serum ox-LDL level in patients with coronary artery diseases and hyperlipidemia without effect on LDL level. Intracellular and extracellular reactive oxidative species (ROS) production was significantly increased in the animals treated with native LDL, or ox-LDL and in hyperlipidemic LDL receptor knockout (LDLR(-/-)) mice that was effectively prevented with NAC treatment. NAC also significantly reduced atherosclerotic plaque formation in hyperlipidemic LDLR(-/-) mice. NAC attenuated in vivo oxidation of native LDL and ROS formation from ox-LDL associated with decreased atherosclerotic plaque formation in hyperlipidemia. PMID- 26536835 TI - NBu4SH provides a convenient source of HS(-) soluble in organic solution for H2S and anion-binding research. AB - Hydrogen sulfide (H2S) has gained significant interest within the scientific community due to its expanding roles in different (patho)physiological processes. Despite this importance, the chemical mechanisms by which H2S exerts its action remain under-scrutinized. Biomimetic investigations in organic solution offer the potential to clarify these mechanisms and to delineate the differential reactivity between H2S and HS(-). However, such studies are hampered by the lack of readily-available sources of HS(-) that are soluble in organic solution. Here we present a simple method for preparing analytically pure tetrabutylammonium hydrosulfide (NBu4SH), which we anticipate will be of significant utility to researchers in the H2S and anion-binding communities. PMID- 26536836 TI - Governing GMOs in the USA: science, law and public health. AB - Controversy surrounds the production and consumption of genetically modified organisms (GMOs). Proponents argue that GMO food sources represent the only viable solution to food shortages in an ever-growing global population. Science reports no harm from GMO use and consumption so far. Opponents fear the potentially negative impact that GMO development and use could have on the environment and consumers, and are concerned about the lack of data on the long term effects of GMO use. We discuss the development of GMO food sources, the history of legislation and policy for the labeling requirements of GMO food products, and the health, environmental, and legal rationale for and against GMO food labeling. The Food and Drug Administration regulates food with GMOs within a coordinated framework of federal agencies. Despite mounting scientific evidence that GMO foods are substantially equivalent to traditionally bred food sources, debate remains over the appropriateness of GMO food labeling. In fact, food manufacturers have mounted a First Amendment challenge against Vermont's passage of a law that requires GMO labeling. Mandatory GMO labeling is not supported by science. Compulsory GMO labels may not only hinder the development of agricultural biotechnology, but may also exacerbate the misconception that GMOs endanger people's health. PMID- 26536838 TI - Precision medicine in the age of big data: The present and future role of large scale unbiased sequencing in drug discovery and development. AB - High throughput molecular and functional profiling of patients is a key driver of precision medicine. DNA and RNA characterization has been enabled at unprecedented cost and scale through rapid, disruptive progress in sequencing technology, but challenges persist in data management and interpretation. We analyze the state-of-the-art of large-scale unbiased sequencing in drug discovery and development, including technology, application, ethical, regulatory, policy and commercial considerations, and discuss issues of LUS implementation in clinical and regulatory practice. PMID- 26536839 TI - Barnyard grasses were processed with rice around 10000 years ago. AB - Rice (Oryza sativa) is regarded as the only grass that was selected for cultivation and eventual domestication in the Yangtze basin of China. Although both macro-fossils and micro-fossils of rice have been recovered from the Early Neolithic site of Shangshan, dating to more than 10,000 years before present (BP), we report evidence of phytolith and starch microfossils taken from stone tools, both for grinding and cutting, and cultural layers, that indicating barnyard grass (Echinochloa spp.) was a major subsistence resource, alongside smaller quantities of acorn starches (Lithocarpus/Quercus sensu lato) and water chestnuts (Trapa). This evidence suggests that early managed wetland environments were initially harvested for multiple grain species including barnyard grasses as well as rice, and indicate that the emergence of rice as the favoured cultivated grass and ultimately the key domesticate of the Yangtze basin was a protracted process. PMID- 26536840 TI - Variable selection in covariate dependent random partition models: an application to urinary tract infection. AB - Lower urinary tract symptoms can indicate the presence of urinary tract infection (UTI), a condition that if it becomes chronic requires expensive and time consuming care as well as leading to reduced quality of life. Detecting the presence and gravity of an infection from the earliest symptoms is then highly valuable. Typically, white blood cell (WBC) count measured in a sample of urine is used to assess UTI. We consider clinical data from 1341 patients in their first visit in which UTI (i.e. WBC >= 1) is diagnosed. In addition, for each patient, a clinical profile of 34 symptoms was recorded. In this paper, we propose a Bayesian nonparametric regression model based on the Dirichlet process prior aimed at providing the clinicians with a meaningful clustering of the patients based on both the WBC (response variable) and possible patterns within the symptoms profiles (covariates). This is achieved by assuming a probability model for the symptoms as well as for the response variable. To identify the symptoms most associated to UTI, we specify a spike and slab base measure for the regression coefficients: this induces dependence of symptoms selection on cluster assignment. Posterior inference is performed through Markov Chain Monte Carlo methods. PMID- 26536841 TI - Phenotypic plasticity and constraint along the upper and lower limb diaphyses of Homo sapiens. AB - OBJECTIVES: Morphological variation along the human limb reflects complex structural trade-offs between bone strength and mass. Here we assess how varying levels of plasticity and constraint affect this structure and influence the response to habitual loading along the diaphysis. MATERIALS AND METHODS: Cross sectional geometric properties including total area, cortical area, and rigidity were compared from the upper (humerus: 50% of length, radius: 66%, 50%, 4%) and lower (tibia: 50%, 38%, 4%) limbs of male varsity-level athletes and matched controls with distinct habitual loading histories. RESULTS: Geometric properties among cricketers and swimmers were significantly greater at the humeral midshaft, mid-proximal radius, and radial midshaft compared to controls. By contrast, no significant differences were found among athletes or controls at the distal radius. The tibial midshafts of hockey players and runners also displayed greater area and rigidity compared to controls. Differences in geometry among the three groups became less pronounced distally, where structure was comparable among athletes and controls at 4% of tibial length. Additionally, coefficients of variation revealed that variation among athletes of the same sport was highest distally in both the upper and lower limb and lowest at midshaft, where structure most closely reflected the activity pattern of each loading group. DISCUSSION: These results support previous research suggesting that distal limb sections are more tightly constrained by safety factors compared to midshafts and proximal sections. Overall, it appears that plasticity and constraint vary not only between limb segments in correspondence to known activity patterns, but also along specific sections of the diaphysis. PMID- 26536842 TI - A framework for estimating the sensitivity of eDNA surveys. AB - Imperfect sensitivity, or imperfect detection, is a feature of all survey methods that needs to be accounted for when interpreting survey results. Detection of environmental DNA (eDNA) is increasingly being used to infer species distributions, yet the sensitivity of the technique has not been fully evaluated. Sensitivity, or the probability of detecting target DNA given it is present at a site, will depend on both the survey method and the concentration and dispersion of target DNA molecules at a site. We present a model to estimate target DNA concentration and dispersion at survey sites and to estimate the sensitivity of an eDNA survey method. We fitted this model to data from a species-specific eDNA survey for Oriental weatherloach, Misgurnus anguillicaudatus, at three sites sampled in both autumn and spring. The concentration of target DNA molecules was similar at all three sites in autumn but much higher at two sites in spring. Our analysis showed the survey method had >=95% sensitivity at sites where target DNA concentrations were >=11 molecules per litre. We show how these data can be used to compare sampling schemes that differ in the number of field samples collected per site and number of PCR replicates per sample to achieve >=95% sensitivity at a given target DNA concentration. These models allow researchers to quantify the sensitivity of eDNA survey methods to optimize the probability of detecting target species, and to compare DNA concentrations spatially and temporarily. PMID- 26536843 TI - No effect of an early intervention after mild traumatic brain injury on activity and participation: A randomized controlled trial. AB - OBJECTIVE: To evaluate measures of activity, participation and quality of life 3 months after mild traumatic brain injury and the effect of an early intervention for patients with an estimated high risk for problems after mild traumatic brain injury. PATIENTS: Consecutive patients attending the emergency room with mild traumatic brain injury. DESIGN: Randomized controlled trial. METHODS: Patients reporting < 3 symptoms after 10 days were considered to have a low risk for prolonged problems. Patients with >= 3 symptoms (high-risk patients) were randomized to a visit to a physician or treatment-as-usual. Data on self-reported limitations in activity, restrictions in participation, and quality of life were collected for all patients at 3 months. RESULTS: At 3 months post-injury, low risk patients reported good quality of life and significantly fewer problems in everyday life compared with high-risk patients. The intervention had no effect on activity, participation or quality of life. CONCLUSION: Patients who report few symptoms early after mild traumatic brain injury are likely to have a good outcome regarding activity and participation. The intervention offered in this study, focusing on reassurance of a good outcome and treatment of comorbidities, had no effect. PMID- 26536844 TI - miR-27 impairs the adipogenic lineage commitment via targeting lysyl oxidase. AB - OBJECTIVE: The recruitment and commitment of mesenchymal stem cells and their terminal differentiation into adipocytes are the main pathways for increasing adipocyte cell numbers during obesity. Our previous studies have shown that lysyl oxidase (Lox) is upregulated and functions as an essential factor during bone morphogenetic protein 4 (BMP4) -induced C3H10T1/2 cell adipocytic lineage commitment. However, the mechanism of Lox regulation during adipogenic lineage commitment has remained largely unestablished. METHODS: Samples of adipose tissue from humans with different BMI and C57BL/6 mice with a high-fat diet were used to compare microRNA-27 (miR-27) expression level associated with obesity. Taqman assays were used for miR-27 expression detection and Oil Red O staining for adipogenesis analysis. RESULTS: A negative correlation was identified between Lox expression level and miR-27 expression in both BMP4-treated C3H10T1/2 cells and human subcutaneous adipose tissues. A Lox 3' UTR luciferase reporter assay showed that miR-27 directly targeted Lox. Furthermore, overexpression of miR-27 impaired BMP4-induced upregulation of Lox and adipocytic commitment, which could be rescued by overexpression of mature Lox. Conversely, miR-27 inhibition by specific inhibitors increased Lox expression and adipocytic commitment. CONCLUSIONS: Taken together, these results suggest a novel role for miR-27 in repressing adipogenic lineage commitment by targeting Lox. PMID- 26536845 TI - Anatomical and functional connectivity in the default mode network of post traumatic stress disorder patients after civilian and military-related trauma. AB - Posttraumatic stress disorder (PTSD) is characterized by unwanted intrusive thoughts and hyperarousal at rest. As these core symptoms reflect disturbance in resting-state mechanisms, we investigated the functional and anatomical involvement of the default mode network (DMN) in this disorder. The relation between symptomatology and trauma characteristics was considered. Twenty PTSD patients and 20 matched trauma-exposed controls that were exposed to a similar traumatic event were recruited for this study. In each group, 10 patients were exposed to military trauma, and 10 to civilian trauma. PTSD, anxiety, and depression symptom severity were assessed. DMN maps were identified in resting state scans using independent component analysis. Regions of interest (medial prefrontal, precuneus, and bilateral inferior parietal) were defined and average z-scores were extracted for use in the statistical analysis. The medial prefrontal and the precuneus regions were used for cingulum tractography whose integrity was measured and compared between groups. Similar functional and anatomical connectivity patterns were identified in the DMN of PTSD patients and trauma-exposed controls. In the PTSD group, functional and anatomical connectivity parameters were strongly correlated with clinical measures, and there was evidence of coupling between the anatomical and functional properties. Type of trauma and time from trauma were found to modulate connectivity patterns. To conclude, anatomical and functional connectivity patterns are related to PTSD symptoms and trauma characteristics influence connectivity beyond clinical symptoms. Hum Brain Mapp 37:589-599, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26536846 TI - Strong Specific Inhibition of UDP-glucuronosyltransferase 2B7 by Atractylenolide I and III. AB - Drug-metabolizing enzymes inhibition-based drug-drug interaction remains to be the key limiting factor for the research and development of efficient herbal components to become clinical drugs. The present study aims to determine the inhibition of uridine 5'-diphospho-glucuronosyltransferases (UGTs) isoforms by two important efficient herbal ingredients isolated from Atractylodes macrocephala Koidz, atractylenolide I and III. In vitro recombinant UGTs catalysed glucuronidation of 4-methylumbelliferone was used to determine the inhibition capability and kinetics of atractylenolide I and III towards UGT2B7, and in silico docking method was employed to explain the possible mechanism. Atractylenolide I and III exhibited specific inhibition towards UGT2B7, with negligible influence towards other UGT isoforms. Atractylenolide I exerted stronger inhibition potential than atractylenolide III towards UGT2B7, which is attributed to the different hydrogen bonds and hydrophobic interactions. Inhibition kinetic analysis was performed for the inhibition of atractylenolide I towards UGT2B7. Inhibition kinetic determination showed that atractylenolide I competitively inhibited UGT2B7, and inhibition kinetic parameter (Ki) was calculated to be 6.4 MUM. In combination of the maximum plasma concentration of atractylenolide I after oral administration of 50 mg/kg atractylenolide I, the area under the plasma concentration-time curve ration AUCi /AUC was calculated to be 1.17, indicating the highly possible drug-drug interaction between atractylenolide I and drugs mainly undergoing UGT2B7-catalysed metabolism. PMID- 26536847 TI - Botulinum neurotoxin effects on masseter muscle fibre in WNIN obese rats-Scanning electron microscope analysis. AB - WNIN/Ob obese mutant rats are unique in comparison to similar rodent models of obesity established in the West. The present study is aimed to evaluate the masticatory function and histological changes in masseter muscle fibres treated with botulinum toxin type A (BoNT/A) in WNIN/Ob rats. Twelve WNIN/Ob obese rats and 12 lean rats at 35 days of age were taken and divided into four groups (6 rats in each group): Group-I (WNIN/Ob) and Group-II (lean) rats were injected with BoNT/A (1 unit) into right side of masseter muscle. For control left masseter of both phenotypes was injected with saline. Group-III (WNIN/Ob) and Group-IV (lean) rats were without any treatment. Growth and food intake was monitored daily for 45 days. Rats were euthanized and gross necropsy was carried out to check any abnormalities. Masseter muscles were dissected and mean muscle mass was recorded. Small portion of muscle was stored in 10% formalin for hematoxylin-eosin (H&E) staining and remaining tissue stored in gluteraldehyde for scanning electron microscopy (SEM). There is a significant decrease in the body weights and food intake of BoNT/A treated obese rats. The H&E staining of the masseter muscle in both groups showed normal morphology and orientation. The SEM analysis showed that, fibre size in BoNT/A treated masseter muscle of obese rats increased more than the saline treated side and in control rats. The increase in the muscle fibre size and transition of muscle fibre subtypes may be due to the reduced masticatory function of the masseter muscle. SCANNING 38:396 402, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26536848 TI - The immobilization of human spermatozoa by STAT3 inhibitory compound V results from an excessive intracellular amount of reactive oxygen species. AB - We previously showed that Stattic V (Stat3 inhibitory compound V) reduces human sperm motility and cellular ATP levels, increases intracellular Ca(2+) concentration, and promotes mitochondrial membrane depolarization resulting in increased levels of extracellular reactive oxygen species (ROS). As these alterations in cellular function are highly similar to what is observed in a cell undergoing apoptosis, our goal was to determine if the immobilizing effect of Stattic V on spermatozoa results from apoptosis or was because of an oxidative stress. To address this question, spermatozoa were incubated with Stattic V in combination with a caspase inhibitor, a proteasome inhibitor or a cell permeant ROS scavenger. Following incubation in different conditions, sperm motility was evaluated by CASA, acrosomal integrity by FITC conjugated Pisum sativum agglutinin (PSA-FITC) labeling, intracellular pH, and mitochondrial superoxide production by flow cytometry using BCECF and MitoSoxRed dye, respectively. Levels of reduced thiols were assessed by iodoacetamidofluorescein staining on total and on sperm surface proteins, and protein tyrosine phosphorylation was evaluated by western blot. The loss in sperm motility induced by Stattic V was associated with a slight intracellular acidification and an important increase in intracellular superoxide anion. Unlike caspase and proteasome inhibitors, low molecular weight thiols, such as N-acetyl-L-cysteine (NAC), prevented Stattic V-induced sperm immobilization and increase responsiveness to acrosome reaction inducers. NAC also efficiently prevented the production of superoxide anion, mitochondrial membrane depolarization, intracellular acidification and the oxidation of protein free thiols caused by Stattic V. These results show that the deleterious effects of Stattic V on sperm functions are caused directly or indirectly by excessive intracellular ROS production without causing sperm apoptosis or necrosis. PMID- 26536849 TI - A Mononuclear Uranium(IV) Single-Molecule Magnet with an Azobenzene Radical Ligand. AB - A tetravalent uranium compound with a radical azobenzene ligand, namely, [{(SiMe2 NPh)3 -tacn}U(IV) (eta(2) -N2 Ph2 (.) )] (2), was obtained by one-electron reduction of azobenzene by the trivalent uranium compound [U(III) {(SiMe2 NPh)3 tacn}] (1). Compound 2 was characterized by single-crystal X-ray diffraction and (1) H NMR, IR, and UV/Vis/NIR spectroscopy. The magnetic properties of 2 and precursor 1 were studied by static magnetization and ac susceptibility measurements, which for the former revealed single-molecule magnet behaviour for the first time in a mononuclear U(IV) compound, whereas trivalent uranium compound 1 does not exhibit slow relaxation of the magnetization at low temperatures. A first approximation to the magnetic behaviour of these compounds was attempted by combining an effective electrostatic model with a phenomenological approach using the full single-ion Hamiltonian. PMID- 26536850 TI - The exotic wasp Megastigmus transvaalensis (Hymenoptera: Torymidae): first record and damage on the Brazilian peppertree, Schinus terebinthifolius drupes, in Sao Paulo, Brazil. AB - This paper records the first report of Megastigmus transvaalensis Hussey (Hymenoptera: Torymidae) in Brazilian peppertree, Schinus terebinthifolius Raddi (Anacardiaceae) drupes in Sorocaba, state of Sao Paulo, Brazil. This wasp is an invasive species and was found damaging S. terebinthifolius drupes in urban areas (35.0 +/- 15.8%), natural forests (21.5 +/- 10.2%) and restoration areas (15.8 +/ 8.4%). The bio-ecology and damage caused by M. transvaalensis in the S. terebinthifolius drupes warrants further study focused upon the management of this phytophagous wasp. Megastigmus transvaalensis has a potential to be disseminated throughout Brazil and is posing a threat to the natural regeneration of S. terebinthifolius in the native forests and restoration areas and ecological regions of this country. PMID- 26536851 TI - A comparative study: use of a Brain-computer Interface (BCI) device by people with cerebral palsy in interaction with computers. AB - This article presents a comparative study among people with cerebral palsy and healthy controls, of various ages, using a Brain-computer Interface (BCI) device. The research is qualitative in its approach. Researchers worked with Observational Case Studies. People with cerebral palsy and healthy controls were evaluated in Portugal and in Brazil. The study aimed to develop a study for product evaluation in order to perceive whether people with cerebral palsy could interact with the computer and compare whether their performance is similar to that of healthy controls when using the Brain-computer Interface. Ultimately, it was found that there are no significant differences between people with cerebral palsy in the two countries, as well as between populations without cerebral palsy (healthy controls). PMID- 26536852 TI - Tropane alkaloids and calystegines as chemotaxonomic markers in the Solanaceae. AB - This study assessed the occurrence and distribution of tropane alkaloids and calystegines in genera of the family Solanaceae to identify patterns of distribution and make evolutionary inferences. A database of tropane alkaloids and calystegines occurrences was constructed from the results of a search of scientific websites and a hand search of periodicals. The terms "Solanaceae", "tropane alkaloids", and "calystegines" were used as index terms for a full-text article search unrestricted by date of publications. The number of occurrence and chemical diversity indices were calculated and cluster analysis and principal components analysis were performed. Overall, 996 occurrences were reported, 879 of tropane alkaloids (88.3%) and 117 of calystegines (11.7%). The calystegines were significantly more relevant than tropane alkaloids for characterization of distinct groups of genera on both analyses performed here. This corroborates the trend toward a chemical dichotomy observed on database analysis and somewhat reinforces the correlation between geographic distribution and occurrence of secondary metabolites, as the presence of calystegines alone (without tropane alkaloids) was only reported in genera that have South America as their center of diversity. PMID- 26536853 TI - Olfaction in the fruit-eating bats Artibeus lituratus and Carollia perspicillata: an experimental analysis. AB - Studies suggest that frugivorous bats search and select fruit mainly by olfaction so that they can be attracted by smell alone. The aim of this study was to evaluate, in captivity, the behavioural response (number of foraging attempts) of Artibeus lituratus and Carollia perspicillata offered essential oils extracted from ripe fruit of Ficus insipida (Moraceae) and Piper hispidum (Piperaceae) as well as intact fruit wrapped in gauze to attract bats with reduced visual stimuli. Based on previous reports, we hypothesized that A.lituratus would exhibit preference for Ficus fruits/oil while C. perspicillata would prefer Piper fruit/oil. Four arrangements of these attractants were tested in triplicate: P. hispidum fruit vs. F. insipida fruit, P.hispidum oil vs. F. insipida oil, P. hispidum oil vs. F. insipida fruit and P. hispidum fruit vs. F. insipida oil. As expected, in all tests, A. lituratus showed the highest number of foraging attempts in F. insipida while C. perspicillata in those of P. hispidum. Based on the number of foraging attempts both species exhibited a positive response to their favorite fruit genera, though the differences were not always statistically significant. The results confirm the importance of smell in fruit choice by these species. PMID- 26536854 TI - Animal performance and carcass characteristics from confined lambs fed on concentrate feed and additives. AB - The number of sheep flocks in Brazil is increasing. It is known that lambs must be slaughtered when young for producing quality meat. The current study evaluated the inclusion of protected methionine, protected lysine, lysophospholipid and amylolytic enzymes in a diet to lambs and their effects on weight gain and quantitative carcass traits at slaughtering. Eighty non-castrated male crossbred Dorper x Santa Ines lambs, 20.57 +/- 4.33 kg live weight, were used. The feedlot lasted 64 days and 60 animals were slaughtered. There were no differences for live weight, daily feed intake, feed conversion and average daily weight gain at the first 28 days of feedlot. From the 28th day lysophospholipid treatment presented the highest live weight. Lysophospholipid and amylolytic enzyme presented the best performance in average daily gain, followed by protected methionine, control and protected lysine. Lysophospholipid treatment presented higher daily feed intake rates than protected lysine and protected methionine. Feed conversion was lower for amylolytic enzyme and higher for control. No changing in carcass traits was reported due to additives. Better performance may be achieved with feedlot lambs fed on diets with the addition of amylolytic enzyme and lysophospholipid at the finishing phase. PMID- 26536855 TI - Dialogues between social and natural sciences: contribution to the debate on socio-environmental conflicts. AB - In this article, I argue that attempting to solve real problems is a possible approach to bring social and natural sciences together, and suggest that - as Environmental Impact Assessment necessarily brings together social and environmental issues - this debate is a strong candidate for such a task. The argument is based on a general discussion about the possibilities and limitations of Environmental Impact Assessments, the social-environmental impacts of mining activities and three case studies. The analysis of the cases indicates possibilities and limitations of the dialogue between scientists from various areas - and of the collaboration with social movements and affected communities - in avoiding negative impacts of mining projects and, eventually, increasing their sustainability. PMID- 26536856 TI - Coral-based climate records from tropical South Atlantic: 2009/2010 ENSO event in C and O isotopes from Porites corals (Rocas Atoll, Brazil). AB - Coral skeletons contain records of past environmental conditions due to their long life span and well calibrated geochemical signatures. C and O isotope records of corals are especially interesting, because they can highlight multidecadal variability of local climate conditions beyond the instrumental record, with high fidelity and sub-annual resolution. Although, in order to get an optimal geochemical signal in coral skeleton, sampling strategies must be followed. Here we report one of the first coral-based isotopic record from the Equatorial South Atlantic from two colonies of Porites astreoides from the Rocas Atoll (offshore Brazil), a new location for climate reconstruction. We present time series of isotopic variation from profiles along the corallite valley of one colony and the apex of the corallite fan of the other colony. Significant differences in the isotopic values between the two colonies are observed, yet both record the 2009/2010 El Nino event - a period of widespread coral bleaching as anomalously negative delta18O values (up to -1 permil). delta13C is found to be measurably affected by the El Nino event in one colony, by more positive values (+0.39 0/00), and together with a bloom of endolithic algae, may indicate physiological alteration of this colony. Our findings indicate that corals from the Rocas Atoll can be used for monitoring climate oscillations in the tropical South Atlantic Ocean. PMID- 26536857 TI - Coronary Pan-Ischemia as a First Sign of a Fulminant Host-Versus-Graft Reaction Eight Years After Orthotopic Heart Transplantation. AB - Acute graft rejection in patients after heart transplantation can cause arrhythmias and acute angina pectoris with electrocardiographic ST-segment elevation. We report a case of a 53-year old female patient who had undergone cardiac transplantation 8 years previously. She developed bradycardia with co existent ST-segment elevation caused by a histologically proven acute graft rejection. After administration of methylprednisolone and immune absorption leading to initial clinical improvement, the patient died unexpectedly. The reasons remain unclear, but a degeneration of the conduction system as well as impaired blood flow in the right coronary caused by cellular and humoral rejection most likely have both contributed. PMID- 26536858 TI - Simultaneous bilateral total knee arthroplasty in patients with haemophilia: a safe and cost-effective procedure? AB - INTRODUCTION: Haemophilic arthropathy of the knee is usually a bilateral affliction. The patients usually refer for treatment in young ages and do not have major comorbidities, being fit for bilateral simultaneous total knee arthroplasty. AIM: In this study, we assessed the safety and cost-effectiveness of simultaneous bilateral surgery in patients with haemophilia. METHODS: Between April 2010 and April 2012, eight patients (16 knees) underwent bilateral simultaneous and 19 patients (19 knees) underwent unilateral total knee arthroplasty (TKA) at our institution. We compared the range of motion and flexion contracture, KSS, WOMAC knee score and SF36 quality of life score between two groups. The duration of hospital stay, coagulation factor consumption and all inpatient costs were recorded. The average follow-up was 26 and 29 months in unilateral and bilateral groups respectively. RESULTS: At the conclusion of the study, the KSS and WOMAC and SF36 scores were not significantly different between the two groups. Mean ROM and flexion contracture did not differ significantly. The mean length of hospital stay was 15 days for bilateral patients and 12 days for unilateral patients, the difference being non-significant. None of our patients needed transfusion in any group. The cost of simultaneous bilateral TKA was about half of the expenses of staged bilateral TKA. CONCLUSION: Simultaneous bilateral TKA seems to be a safe and cost-effective approach without increasing the rate of complications in patients' bilateral haemophilic knee arthropathy. The procedure is, at least, as effective as staged unilateral knee arthroplasty in improving the patients' quality of life. PMID- 26536859 TI - Bariatric surgery for women of reproductive age. PMID- 26536860 TI - Estimation of evolutionary parameters using short, random and partial sequences from mixed samples of anonymous individuals. AB - BACKGROUND: Over the last decade, next generation sequencing (NGS) has become widely available, and is now the sequencing technology of choice for most researchers. Nonetheless, NGS presents a challenge for the evolutionary biologists who wish to estimate evolutionary genetic parameters from a mixed sample of unlabelled or untagged individuals, especially when the reconstruction of full length haplotypes can be unreliable. We propose two novel approaches, least squares estimation (LS) and Approximate Bayesian Computation Markov chain Monte Carlo estimation (ABC-MCMC), to infer evolutionary genetic parameters from a collection of short-read sequences obtained from a mixed sample of anonymous DNA using the frequencies of nucleotides at each site only without reconstructing the full-length alignment nor the phylogeny. RESULTS: We used simulations to evaluate the performance of these algorithms, and our results demonstrate that LS performs poorly because bootstrap 95% Confidence Intervals (CIs) tend to under- or over-estimate the true values of the parameters. In contrast, ABC-MCMC 95% Highest Posterior Density (HPD) intervals recovered from ABC-MCMC enclosed the true parameter values with a rate approximately equivalent to that obtained using BEAST, a program that implements a Bayesian MCMC estimation of evolutionary parameters using full-length sequences. Because there is a loss of information with the use of sitewise nucleotide frequencies alone, the ABC-MCMC 95% HPDs are larger than those obtained by BEAST. CONCLUSION: We propose two novel algorithms to estimate evolutionary genetic parameters based on the proportion of each nucleotide. The LS method cannot be recommended as a standalone method for evolutionary parameter estimation. On the other hand, parameters recovered by ABC MCMC are comparable to those obtained using BEAST, but with larger 95% HPDs. One major advantage of ABC-MCMC is that computational time scales linearly with the number of short-read sequences, and is independent of the number of full-length sequences in the original data. This allows us to perform the analysis on NGS datasets with large numbers of short read fragments. The source code for ABC-MCMC is available at https://github.com/stevenhwu/SF-ABC. PMID- 26536861 TI - Amsterdam tool for clinical medication review: development and testing of a comprehensive tool for pharmacists and general practitioners. AB - BACKGROUND: Drug-related problems are prevalent among older patients, and substantially increase the risk of morbidity, (re-)hospitalisation and mortality. To detect drug-related problems and optimize treatment primary caregivers should periodically review the medication of older patients. The aim was to develop a structured, comprehensive but practicable tool to facilitate and support the reviewing of medication of older patients with a chronic disease by pharmacists and general practitioners. METHODS: A tool facilitating clinical medication review by community pharmacists was developed on the basis of treatment guidelines, literature data on drug-related problems. For the identification of drug-related problems from the patient's perspective, a script for structured interviews was developed. The tool was optimized by means of a Delphi method with an expert panel and testing in a trial. RESULTS: The medication review tool consists of a comprehensive checklist of 124 drug-related problems divided by 20 sections according to physiological systems and diseases, and includes a structured interview script for a patient interviews. CONCLUSION: A structured, comprehensive and practical tool to assist pharmacists and general practitioners to perform clinical medication review including a list of potential drug-related problems in older patients with chronic disease, as well as a script for structured patient interviews, was developed. PMID- 26536862 TI - A simplified universal approach to COH protocol for IVF: ultrashort flare GnRH agonist/GnRH-antagonist protocol with tailored mode and timing of final follicular maturation. AB - Recently, several new promising modifications have been introduced to clinical practice that may simplify and optimize IVF outcome. In the present opinion paper we present a simplified approach to controlled ovarian hyperstimulation protocol (COH), which combines the benefits of the ultrashort flare GnRH agonist/GnRH antagonist protocol and the personalized tailored mode and timing of ovulation triggering, aiming to improve IVF outcome while eliminating of severe OHSS.In patients at risk to develop severe ovarian hyperstimulation syndrome (OHSS), GnRH agonist (GnRHa) trigger if offered for final follicular maturation. While in those achieving >=20 oocytes, the freeze all policy with the subsequent frozen thawed embryo transfers (ET) is recommended, in those where less than 20 oocytes are retrieved, patients are re-evaluated 3 days after oocyte retrieval (day of ET) for signs of early moderate OHSS. If no early signs of OHSS developed, one embryo was transferred, and the patients are instructed to inject 1500 IU of HCG. In cases where signs of early moderate OHSS appear, the freeze all policy is recommended.In Patients not at risk to develop severe OHSS- three different modes of concomitant administration of both GnRHa and a standard bolus of hCG (5000 10,000 units) prior to oocyte retrieval were suggested. Standard hCG dose concomitant with GnRHa (dual trigger), 35-37 h before oocyte retrieval is offered to normal responders patients, resulting in improved oocyte/embryo quality and IVF outcome. GnRHa 40 h and standard hCG added 34 h prior to oocyte retrieval (double trigger), respectively are offered to patients demonstrating abnormal final follicular maturation despite normal response to COH. The double trigger results in significantly higher number of oocytes retrieved, higher proportions of the number of oocytes retrieved to the number of follicles >10 mm and >14 mm in diameter on day of hCG administration, higher number of MII oocytes and proportion of MII oocytes per number of oocytes retrieved, with the consequent significantly increased number of top-quality embryos, as compared to the hCG only trigger cycles. Standard hCG dose concomitant with GnRHa (dual trigger), 34 h before oocyte retrieval should be offered to poor responders patients, aiming to overcome premature luteinization, while achieving high yield of mature oocytes.Further studies are required to support this new concept prior to its implementation as a universal COH protocol to IVF practice. PMID- 26536863 TI - TaNAC29, a NAC transcription factor from wheat, enhances salt and drought tolerance in transgenic Arabidopsis. AB - BACKGROUND: NAC (NAM, ATAF, and CUC) transcription factors play important roles in plant biological processes, including phytohormone homeostasis, plant development, and in responses to various environmental stresses. METHODS: TaNAC29 was introduced into Arabidopsis using the Agrobacterium tumefaciens-mediated floral dipping method. TaNAC29-overexpression plants were subjected to salt and drought stresses for examining gene functions. To investigate tolerant mechanisms involved in the salt and drought responses, expression of related marker genes analyses were conducted, and related physiological indices were also measured. Expressions of genes were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: A novel NAC transcription factor gene, designated TaNAC29, was isolated from bread wheat (Triticum aestivum). Sequence alignment suggested that TaNAC29 might be located on chromosome 2BS. TaNAC29 was localized to the nucleus in wheat protoplasts, and proved to have transcriptional activation activities in yeast. TaNAC29 was expressed at a higher level in the leaves, and expression levels were much higher in senescent leaves, indicating that TaNAC29 might be involved in the senescence process. TaNAC29 transcripts were increased following treatments with salt, PEG6000, H2O2, and abscisic acid (ABA). To examine TaNAC29 function, transgenic Arabidopsis plants overexpressing TaNAC29 were generated. Germination and root length assays of transgenic plants demonstrated that TaNAC29 overexpression plants had enhanced tolerances to high salinity and dehydration, and exhibited an ABA-hypersensitive response. When grown in the greenhouse, TaNAC29-overexpression plants showed the same tolerance response to salt and drought stresses at both the vegetative and reproductive period, and had delayed bolting and flowering in the reproductive period. Moreover, TaNAC29 overexpression plants accumulated lesser malondialdehyde (MDA), H2O2, while had higher superoxide dismutase (SOD) and catalase (CAT) activities under high salinity and/or dehydration stress. CONCLUSIONS: Our results demonstrate that TaNAC29 plays important roles in the senescence process and response to salt and drought stresses. ABA signal pathway and antioxidant enzyme systems are involved in TaNAC29-mediated stress tolerance mechanisms. PMID- 26536864 TI - The H19 Long non-coding RNA in cancer initiation, progression and metastasis - a proposed unifying theory. AB - The imprinted oncofetal long non-coding RNA (lncRNA) H19 is expressed in the embryo, down-regulated at birth and then reappears in tumors. Its role in tumor initiation and progression has long been a subject of controversy, although accumulating data suggest that H19 is one of the major genes in cancer. It is actively involved in all stages of tumorigenesis and is expressed in almost every human cancer. In this review we delineate the various functions of H19 during the different stages in the complex process of tumor progression. H19 up-regulation allows cells to enter a "selfish" survival mode in response to stress conditions, such as destabilization of the genome and hypoxia, by accelerating their proliferation rate and increasing overall cellular resistance to stress. This response is tightly correlated with nullification, dysfunction or significant down-regulation of the master tumor suppressor gene P53. The growing evidence of H19's involvement in both proliferation and differentiation processes, together with its involvement in epithelial to mesenchymal transition (EMT) and also mesenchymal to epithelial transition (MET), has led us to conclude that some of the recent disputes and discrepancies arising from current research findings can be resolved from a viewpoint supporting the oncogenic properties of H19. According to a holistic approach, the versatile, seemingly contradictory functions of H19 are essential to, and differentially harnessed by, the tumor cell depending on its context within the process of tumor progression. PMID- 26536865 TI - Women's experience with home-based self-sampling for human papillomavirus testing. AB - BACKGROUND: Increasing cervical screening coverage by reaching inadequately screened groups is essential for improving the effectiveness of cervical screening programs. Offering HPV self-sampling to women who are never or under screened can improve screening participation, however participation varies widely between settings. Information on women's experience with self-sampling and preferences for future self-sampling screening is essential for programs to optimize participation. METHODS: The survey was conducted as part of a larger trial ("iPap") investigating the effect of HPV self-sampling on participation of never and under-screened women in Victoria, Australia. Questionnaires were mailed to a) most women who participated in the self-sampling to document their experience with and preference for self-sampling in future, and b) a sample of the women who did not participate asking reasons for non-participation and suggestions for enabling participation. Reasons for not having a previous Pap test were also explored. RESULTS: About half the women who collected a self sample for the iPap trial returned the subsequent questionnaire (746/1521). Common reasons for not having cervical screening were that having Pap test performed by a doctor was embarrassing (18 %), not having the time (14 %), or that a Pap test was painful and uncomfortable (11 %). Most (94 %) found the home based self-sampling less embarrassing, less uncomfortable (90 %) and more convenient (98%) compared with their last Pap test experience (if they had one); however, many were unsure about the test accuracy (57 %). Women who self-sampled thought the instructions were clear (98 %), it was easy to use the swab (95 %), and were generally confident that they did the test correctly (81 %). Most preferred to take the self-sample at home in the future (88 %) because it was simple and did not require a doctor's appointment. Few women (126/1946, 7 %) who did not return a self-sample in the iPap trial returned the questionnaire. Their main reason for not screening was having had a hysterectomy. CONCLUSIONS: Home based self-sampling can overcome emotional and practical barriers to Pap test and increase participation in cervical screening despite some women's concerns about test accuracy. Mailing to eligible women and assuring women about test accuracy could further optimize participation in screening. PMID- 26536866 TI - Mammalian prion protein (PrP) forms conformationally different amyloid intracellular aggregates in bacteria. AB - BACKGROUND: An increasing number of proteins are being shown to assemble into amyloid structures that lead to pathological states. Among them, mammalian prions outstand due to their ability to transmit the pathogenic conformation, becoming thus infectious. The structural conversion of the cellular prion protein (PrP(C)), into its misfolded pathogenic form (PrP(Sc)) is the central event of prion-driven pathologies. The study of the structural properties of intracellular amyloid aggregates in general and of prion-like ones in particular is a challenging task. In this context, the evidence that the inclusion bodies formed by amyloid proteins in bacteria display amyloid-like structural and functional properties make them a privileged system to model intracellular amyloid aggregation. RESULTS: Here we provide the first demonstration that recombinant murine PrP and its C-terminal domain (90-231) attain amyloid conformations inside bacteria. Moreover, the inclusions formed by these two PrP proteins display conformational diversity, since they differ in fibril morphology, binding affinity to amyloid dyes, stability, resistance to proteinase K digestion and neurotoxicity. CONCLUSIONS: Overall, our results suggest that modelling PrP amyloid formation in microbial cell factories might open an avenue for a better understanding of the structural features modulating the pathogenic impact of this intriguing protein. PMID- 26536867 TI - Real-time safety surveillance of seasonal influenza vaccines in children, Australia, 2015. AB - Increased febrile reactions in Australian children from one influenza vaccine brand in 2010 diminished confidence in influenza immunisation, highlighting the need for improved vaccine safety surveillance. AusVaxSafety, a national vaccine safety surveillance system collected adverse events in young children for 2015 influenza vaccine brands in real time through parent/carer reports via SMS/email. Weekly cumulative data on 3,340 children demonstrated low rates of fever (4.4%) and medical attendance (1.1%). Fever was more frequent with concomitant vaccination. PMID- 26536868 TI - Learning to walk with an adaptive gain proportional myoelectric controller for a robotic ankle exoskeleton. AB - BACKGROUND: Robotic ankle exoskeletons can provide assistance to users and reduce metabolic power during walking. Our research group has investigated the use of proportional myoelectric control for controlling robotic ankle exoskeletons. Previously, these controllers have relied on a constant gain to map user's muscle activity to actuation control signals. A constant gain may act as a constraint on the user, so we designed a controller that dynamically adapts the gain to the user's myoelectric amplitude. We hypothesized that an adaptive gain proportional myoelectric controller would reduce metabolic energy expenditure compared to walking with the ankle exoskeleton unpowered because users could choose their preferred control gain. METHODS: We tested eight healthy subjects walking with the adaptive gain proportional myoelectric controller with bilateral ankle exoskeletons. The adaptive gain was updated each stride such that on average the user's peak muscle activity was mapped to maximal power output of the exoskeleton. All subjects participated in three identical training sessions where they walked on a treadmill for 50 minutes (30 minutes of which the exoskeleton was powered) at 1.2 ms(-1). We calculated and analyzed metabolic energy consumption, muscle recruitment, inverse kinematics, inverse dynamics, and exoskeleton mechanics. RESULTS: Using our controller, subjects achieved a metabolic reduction similar to that seen in previous work in about a third of the training time. The resulting controller gain was lower than that seen in previous work (beta=1.50+/-0.14 versus a constant beta=2). The adapted gain allowed users more total ankle joint power than that of unassisted walking, increasing ankle power in exchange for a decrease in hip power. CONCLUSIONS: Our findings indicate that humans prefer to walk with greater ankle mechanical power output than their unassisted gait when provided with an ankle exoskeleton using an adaptive controller. This suggests that robotic assistance from an exoskeleton can allow humans to adopt gait patterns different from their normal choices for locomotion. In our specific experiment, subjects increased ankle power and decreased hip power to walk with a reduction in metabolic cost. Future exoskeleton devices that rely on proportional myolectric control are likely to demonstrate improved performance by including an adaptive gain. PMID- 26536869 TI - Traumatic dental injuries in a university hospital: a four-year retrospective study. AB - BACKGROUND: Traumatic dental injuries present complex injuries of the dentoalveolar system. Aim of this study was to investigate the frequency and patterns of traumatic dental injuries in a University dental emergency service over four years. METHODS: A retrospective investigation on all dental trauma patients presenting at the dental emergency service of the University Medical Center Mainz, Germany between 01/2010 and 12/2013 was conducted. Demographic data, the cause and type of trauma and the initial therapy were analyzed. RESULTS: Out of 16,301 patients, 1,305 patients (8 %; average age 14.7 years +/ 15.7; 60.1 % male, 39.9 % female) came due to trauma. 63.9 % of the traumas occurred on weekends. The most frequent reason for injuries was falls (54.6 %). No correlation could be found between the cause and the kind of trauma. In 48.6 % of the cases only one tooth was involved, in 33.5 % two. The permanent dentition was traumatized in 56.6 % of cases, the deciduous teeth in 41.1 %. The most frequently affected tooth was the central upper incisor (61.0 %). Hard-tissue injuries were significantly more frequent in the permanent dentition, while periodontal injuries were seen significantly more often in the deciduous dentition. CONCLUSION: Eight percent of all patients seeking help at the dental emergency service presented with trauma, meaning that dental traumatology is one of the major topics in emergencies. To improve the quality of care, further public education, expert knowledge among dental professionals and a well structured emergency service are necessary. PMID- 26536870 TI - Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover. AB - Adjuvant therapy for hormone receptor (HR) positive postmenopausal breast cancer patients includes aromatase inhibitors (AI). While both the non-steroidal AI letrozole and the steroidal AI exemestane decrease serum estrogen concentrations, there is evidence that exemestane may be less detrimental to bone. We hypothesized that single nucleotide polymorphisms (SNP) predict effects of AIs on bone turnover. Early stage HR-positive breast cancer patients were enrolled in a randomized trial of exemestane versus letrozole. Effects of AI on bone mineral density (BMD) and bone turnover markers (BTM), and associations between SNPs in 24 candidate genes and changes in BMD or BTM were determined. Of the 503 enrolled patients, paired BMD data were available for 123 and 101 patients treated with letrozole and exemestane, respectively, and paired BTM data were available for 175 and 173 patients, respectively. The mean change in lumbar spine BMD was significantly greater for letrozole-treated (-3.2 %) compared to exemestane treated patients (-1.0 %) (p = 0.0016). Urine N-telopeptide was significantly increased in patients treated with exemestane (p = 0.001) but not letrozole. Two SNPs (rs4870061 and rs9322335) in ESR1 and one SNP (rs10140457) in ESR2 were associated with decreased BMD in letrozole-treated patients. In the exemestane treated patients, SNPs in ESR1 (Rs2813543) and CYP19A1 (Rs6493497) were associated with decreased bone density. Exemestane had a less negative impact on bone density compared to letrozole, and the effects of AI therapy on bone may be impacted by genetic variants in the ER pathway. PMID- 26536871 TI - SOLTI NeoPARP: a phase II randomized study of two schedules of iniparib plus paclitaxel versus paclitaxel alone as neoadjuvant therapy in patients with triple negative breast cancer. AB - Iniparib is an investigational agent with antitumor activity of controversial mechanism of action. Two previous trials in advanced triple-negative breast cancer (TNBC) in combination with gemcitabine and carboplatin showed some evidence of efficacy that was not confirmed. This phase II randomized neoadjuvant study was designed to explore its activity and tolerability with weekly paclitaxel (PTX) as neoadjuvant treatment in TNBC patients. 141 patients with Stage II-IIIA TNBC were randomly assigned to receive PTX (80 mg/m(2), d1; n = 47) alone or in combination with iniparib, either once-weekly (PWI) (11.2 mg/kg, d1; n = 46) or twice-weekly (PTI) (5.6 mg/kg, d1, 4; n = 48) for 12 weeks. Primary endpoint was pathologic complete response (pCR) in the breast. pCR rate was similar among the three arms (21, 22, and 19 % for PTX, PWI, and PTI, respectively). Secondary efficacy endpoints were comparable: pCR in breast and axilla (21, 17, and 19 %); best overall response in the breast (60, 61, and 63 %); and breast conservation rate (53, 54, and 50 %). Slightly more patients in the PTI arm presented grade 3/4 neutropenia (4, 0, and 10 %). Grade 1/2 (28, 22, and 29 %), but no grade 3/4 neuropathy, was observed. There were no differences in serious adverse events and treatment-emergent adverse events leading to treatment discontinuation among the three arms. Addition of iniparib to weekly PTX did not add relevant antitumor activity or toxicity. These results do not support further evaluation of the combination of iniparib at these doses plus paclitaxel in early TNBC. PMID- 26536872 TI - Deletion of a gene cluster for [Ni-Fe] hydrogenase maturation in the anaerobic hyperthermophilic bacterium Caldicellulosiruptor bescii identifies its role in hydrogen metabolism. AB - The anaerobic, hyperthermophlic, cellulolytic bacterium Caldicellulosiruptor bescii grows optimally at ~80 degrees C and effectively degrades plant biomass without conventional pretreatment. It utilizes a variety of carbohydrate carbon sources, including both C5 and C6 sugars, released from plant biomass and produces lactate, acetate, CO2, and H2 as primary fermentation products. The C. bescii genome encodes two hydrogenases, a bifurcating [Fe-Fe] hydrogenase and a [Ni-Fe] hydrogenase. The [Ni-Fe] hydrogenase is the most widely distributed in nature and is predicted to catalyze hydrogen production and to pump protons across the cellular membrane creating proton motive force. Hydrogenases are the key enzymes in hydrogen metabolism and their crystal structure reveals complexity in the organization of their prosthetic groups suggesting extensive maturation of the primary protein. Here, we report the deletion of a cluster of genes, hypABFCDE, required for maturation of the [Ni-Fe] hydrogenase. These proteins are specific for the hydrogenases they modify and are required for hydrogenase activity. The deletion strain grew more slowly than the wild type or the parent strain and produced slightly less hydrogen overall, but more hydrogen per mole of cellobiose. Acetate yield per mole of cellobiose was increased ~67 % and ethanol yield per mole of cellobiose was decreased ~39 %. These data suggest that the primary role of the [Ni-Fe] hydrogenase is to generate a proton gradient in the membrane driving ATP synthesis and is not the primary enzyme for hydrogen catalysis. In its absence, ATP is generated from increased acetate production resulting in more hydrogen produced per mole of cellobiose. PMID- 26536873 TI - Investigation of the characteristics of biofilms grown in gas-phase biofilters with and without ozone injection by CLSM technique. AB - Recently, ozone injection technique was developed as a novel biomass control method to reduce bed clogging in biofilters treating volatile organic compounds (VOCs). However, the effects of ozone on the characteristics of biofilms are still unknown. In this study, two identical lab-scale biofilters treating gaseous toluene were operated in parallel except that one was continuously injected with 200 mg/m(3) ozone. Four glass slides were placed inside each biofilter on day 57 and then were taken out sequentially after 1, 2, 4, and 6 weeks of cultivation. The biofilms grown on the glass slides were stained by the ViaGramTM Red + Bacterial Gram Stain and Viability Kit and observed through the confocal laser scanning microscopy (CLSM). According to the CLSM images of 1, 2, and 4 weeks, the ozonated biofilm was significantly thinner than the control biofilm, which demonstrated that ozone could effectively control the biomass in the biofilter. For the biofilter without ozone injection, the ratios of viable cells (0.51~0.89) and the ratios of Gram-positive bacteria (0.22~0.57) both decreased within 4 weeks of cultivation. The CLSM image analysis results also demonstrated that a continuous injection of 200 mg/m(3) ozone was able to significantly enhance the ratio of viable cells to 0.77~0.97 and allow the dominance of Gram-positive bacteria in the biofilms with the ratio 0.46~0.88 instead of Gram-negative bacteria. For the 6-week samples, the biofilm thickness of the control system was reduced significantly which indicated the detachment of accumulated biofilms might occur in the samples without ozone. PMID- 26536874 TI - Identification and characterization of a mesophilic phytase highly resilient to high-temperatures from a fungus-garden associated metagenome. AB - Phytases are enzymes degrading phytic acid and thereby releasing inorganic phosphate. While the phytases reported to date are majorly from culturable microorganisms, the fast-growing quantity of publicly available metagenomic data generated in the last decade has enabled bioinformatic mining of phytases in numerous data mines derived from a variety of ecosystems throughout the world. In this study, we are interested in the histidine acid phosphatase (HAP) family phytases present in insect-cultivated fungus gardens. Using bioinformatic approaches, 11 putative HAP phytase genes were initially screened from 18 publicly available metagenomes of fungus gardens and were further overexpressed in Escherichia coli. One phytase from a south pine beetle fungus garden showed the highest activity and was then chosen for further study. Biochemical characterization showed that the phytase is mesophilic but possesses strong ability to withstand high temperatures. To our knowledge, it has the longest half life time at 100 degrees C (27 min) and at 80 degrees C (2.1 h) as compared to all the thermostable phytases publicly reported to date. After 100 degrees C incubation for 15 min, more than 93 % of the activity was retained. The activity was 3102 MUmol P/min/mg at 37 degrees C and 4135 MUmol P/min/mg at 52.5 degrees C, which is higher than all the known thermostable phytases. For the high activity level demonstrated at mesophilic temperatures as well as the high resilience to high temperatures, the phytase might be promising for potential application as an additive enzyme in animal feed. PMID- 26536875 TI - Engineering resistance to phage GVE3 in Geobacillus thermoglucosidasius. AB - Geobacillus thermoglucosidasius is a promising platform organism for the production of biofuels and other metabolites of interest. G. thermoglucosidasius fermentations could be subject to bacteriophage-related failure and financial loss. We develop two strains resistant to a recently described G. thermoglucosidasius-infecting phage GVE3. The phage-encoded immunity gene, imm, was overexpressed in the host leading to phage resistance. A phage-resistant mutant was isolated following expression of a putative anti-repressor-like protein and phage challenge. A point mutation was identified in the polysaccharide pyruvyl transferase, csaB. A double crossover knockout mutation of csaB confirmed its role in the phage resistance phenotype. These resistance mechanisms appear to prevent phage DNA injection and/or lysogenic conversion rather than just reducing efficiency of plating, as no phage DNA could be detected in resistant bacteria challenged with GVE3 and no plaques observed even at high phage titers. Not only do the strains developed here shed light on the biological relationship between the GVE3 phage and its host, they could be employed by those looking to make use of this organism for metabolite production, with reduced occurrence of GVE3-related failure. PMID- 26536876 TI - TNF-alpha produced by SEC2 mutant (SAM-3)-activated human T cells induces apoptosis of HepG2 cells. AB - Staphylococcal enterotoxins C2 (SEC2) is a classical model of superantigens (SAg), which has the powerful ability to activate T cells as well as induce massive cytokine production. This property makes SEC2 and its mutants well concerned as a potential new immune-regulatory agent for cancer therapy. We previously constructed a SEC2 mutant named SAM-3, which had prominently antitumor activity in BALB/c mice model. But, the underlying molecular mechanism for stimulation of human peripheral blood mononuclear cells (PBMCs) and antitumor effect on human tumor cells induced by SAM-3 is not clear. Here, we showed that SAM-3 could activate human TCR Vbeta 12, 13A, 14, 15, 17, and 20 CD8(+) subgroup T cells, which secreted the cytokines IL-2, IFN-gamma, and TNF-alpha, and exhibit stimulation activity in a dose-dependent manner. TNF-alpha secreted from activated T cells could induce apoptosis and G1-phase arrest and lead to the antitumor effect in HepG2 cells. Meanwhile, SAM-3 upregulated the expression of tumor necrosis factor receptor 1 (TNFR1) mRNA and activity of caspase-3 and caspase-8. We also found that the antitumor activity and activity of caspase-3 and caspase-8 were decreased when the neutralizing TNF-alpha monoclonal antibody presented. These data suggest that TNF-alpha secreted by SAM-3-activated T cells is an important factor in inducing apoptosis in HepG2 cells. PMID- 26536877 TI - Global metabolomic responses of Nitrosomonas europaea 19718 to cold stress and altered ammonia feeding patterns. AB - The model ammonia-oxidizing bacterium Nitrosomonas europaea represents one of the environmentally and biotechnologically significant microorganisms. Genome-based studies over the last decade have led to many intriguing discoveries about its cellular biochemistry and physiology. However, knowledge regarding the regulation of overall metabolic routes in response to various environmental stresses is limited due to a lack of comprehensive, time-resolved metabolomic analyses. In this study, gas chromatography-mass spectrometry (GC-MS)-based metabolic profiling was performed to characterize the temporal variations of N. europaea 19718 intercellular metabolites in response to varied temperature (23 and 10 degrees C) and ammonia feeding patterns (shock loading and continuous feeding of 20 mg N/L). Approximately 87 metabolites were successfully identified and mapped to the existing pathways of N. europaea 19718, allowing interpretation of the influence of temperature and feeding pattern on metabolite levels. In general, varied temperature had a more profound influence on the overall metabolism than varied feeding patterns. Total extracellular metabolite concentrations (relative to internal standards and normalized to biomass weight) were lower under cold stress and shock loading conditions compared with the control (continuous feeding at 23 degrees C). Cold stress caused the widespread downregulation of metabolites involved in central carbon metabolism, amino acid, and lipid synthesis (e.g., malonic acid, succinic acid, putrescine, and phosphonolpyruvate). Metabolites that showed differences under varied feeding patterns were mainly involved in nucleotide acid, amino acid, and lipid metabolism (e.g., adenine, uracil, and spermidine). This study highlighted the roles of central carbon and nitrogen metabolism in countering cold stress and altered ammonia availability. In addition, transcriptomic, proteomic, and metabolomic data from three studies on N. europaea were compared to achieve a holistic view of some important synergy and interconnectivity among different cellular components (RNA, protein, and metabolites) during ammonia starvation. PMID- 26536878 TI - Dehalococcoides abundance and alternate electron acceptor effects on large, flow through trichloroethene dechlorinating columns. AB - Trichloroethene (TCE) in groundwater is a major health concern and biostimulation/bioaugmentation-based strategies have been evaluated to achieve complete reductive dechlorination with varying success. Different carbon sources were hypothesized to stimulate different extents of TCE reductive dechlorination. Ecological conditions that developed different dechlorination stages were investigated by quantitating Dehalococcoides 16S rRNA (Dhc) and reductive dehalogenase gene abundance, and by describing biogeochemical properties of laboratory columns in response to this biostimulation. Eight large columns (183 cm * 15.2 cm), packed with aquifer material from Hill AFB, Utah, that were continuously fed TCE for 7.5 years. Duplicate columns were biostimulated with whey or one of two different Newman Zone(r) emulsified oil formulations containing either nonionic surfactant (EOLN) or standard surfactant (EOL). Two columns were non-stimulated controls. Complete (whey amended), partial (EOLN amended), limited (EOL), and non-TCE dehalogenating systems (controls) developed over the course of the study. Bioaugmentation of half of the columns with Bachman Road culture 3 years prior to dismantling did not influence the extent of TCE dehalogenation. Multivariate analysis clustered samples by biostimulation treatments and extent of TCE dehalogenation. Dhc, tceA, and bvcA gene concentrations did not show a consistent relationship with TCE dehalogenation but the vcrA gene was more abundant in completely dehalogenating, whey-treated columns. The whey columns developed strongly reducing conditions producing Fe(II), sulfide, and methane. Biostimulation with different carbon and energy sources can support high concentrations of diverse Dhc, but carbon addition has a major influence on biogeochemical processes effecting the extent of TCE dehalogenation. PMID- 26536879 TI - Metabolic flux analysis model for optimizing xylose conversion into ethanol by the natural C5-fermenting yeast Candida shehatae. AB - A metabolic flux analysis (MFA) model was developed to optimize the xylose conversion into ethanol using Candida shehatae strain. This metabolic model was compartmented and constructed with xylose as carbon substrate integrating the enzymatic duality of the first step of xylose degradation via an algebraic coefficient. The model included the pentose phosphate pathway, glycolysis, synthesis of major metabolites like ethanol, acetic acid and glycerol, the tricarboxylic acid cycle as well as the respiratory chain, the cofactor balance, and the maintenance. The biomass composition and thus production were integrated considering the major biochemical synthesis reactions from monomers to each constitutive macromolecule (i.e., proteins, lipids, polysaccharides, nucleic acids). The construction of the model resulted into a 122-linear equation system to be resolved. A first experiment allowed was to verify the accuracy of the model by comparing calculated and experimental data. The metabolic model was utilized to determine the theoretical yield taking into account oxido-reductive balance and to optimize ethanol production. The maximal theoretical yield was calculated at 0.62 Cmolethanol/Cmolxylose for an oxygen requirement of 0.33 moloxygen/molxylose linked to the cofactors of the xylose reductase. Cultivations in chemostat mode allowed the fine tuning of both xylose and oxygen uptakes and showed that lower was the oxygen/xylose ratio, higher was the ethanol production yield. The best experimental ethanol production yield (0.51 Cmolethanol/Cmolxylose) was obtained for an oxygen supply of 0.47 moloxygen/molxylose. PMID- 26536880 TI - Biochemical and physicochemical processes contributing to the removal of endocrine-disrupting chemicals and pharmaceuticals by the aquatic ascomycete Phoma sp. UHH 5-1-03. AB - The environmentally widespread micropollutants bisphenol A (BPA), carbamazepine (CBZ), 17alpha-ethinylestradiol (EE2), diclofenac (DF), sulfamethoxazole (SMX), technical nonylphenol (t-NP) and triclosan (TCS) were used to assess the potential of the laccase-producing freshwater ascomycete Phoma sp. strain UHH 5-1 03 for micropollutant removal and to provide quantitative insights into the mechanisms involved. Biotransformation rates observed with whole fungal cells followed the rank order EE2 ? BPA > TCS > t-NP > DF > SMX > CBZ. Biosorption onto fungal mycelia was prominent for BPA, EE2, TCS and t-NP and insignificant for CBZ, DF and SMX. Enzymatic removal rates investigated with cell-free, laccase containing culture supernatants of Phoma sp. followed the rank order EE2 > BPA > DF > t-NP > TCS and were insignificant for SMX and CBZ. Mass spectrometry assisted investigations addressing metabolite formation from unlabelled and (13)C6-labelled DF and SMX yielded DF metabolites indicating hydroxylation, cyclisation and decarboxylation reactions, as well as oxidative coupling typical for laccase reactions. For SMX, several products characterised by lower molecular masses than the parent compound were found, and indications for deamination and formamide formation were obtained. Summarising, the obtained results suggest that the extracellular laccase of Phoma sp. largely contributes to fungal biotransformation of EE2, BPA, DF, TCS and t-NP, together with cell-associated enzymes such as, e.g. cytochrome P450 monooxygenases suggested by the appearance of hydroxylated metabolites from DF. Laccase does not seem to play any role in the metabolisation of SMX and CBZ, where yet to be identified cell-associated enzymes have to be considered instead. PMID- 26536881 TI - Wide disparity of clinical genetics services and EU rare disease research funding across Europe. AB - The origins of clinical genetics services vary throughout Europe with some emerging from paediatric medicine and others from an academic laboratory setting. In 2011, the cross-border patients' rights directive recommended the creation of European Research Networks (ERNs) to improve patient care throughout EU. In 2013, the EU recommendation on the care for rare diseases came into place. The process of designating EU centres of expertise in rare diseases is being implemented to allow centres to enter ERNs. Hence, this is an opportune time to reflect on the current status of genetic services and research funding throughout Europe as 80 % of rare diseases have a genetic origin. Our aims were to determine (a) whether EU countries are prepared in terms of appropriate clinical genetic staffing to fulfil the European Union Committee of Experts on Rare Diseases (EUCERD) criteria that will allow national centres to be designated as centres of expertise, (b) which EU countries are successful in grant submissions to EU rare disease research funding and (c) country of origin of researchers from the EU presenting their research work as a spoken presentation at the European Society of Human Genetics annual conference. Our results show there is wide disparity of staffing levels per head of population in clinical genetics units throughout Europe. EU rare disease research funding is not being distributed equitably and the opportunity to present research is skewed with many countries not achieving spoken presentations despite abstract submissions. Inequity in the care of patients with rare diseases exists in Europe. Many countries will struggle to designate centres of expertise as their staffing mix and levels will not meet the EUCERD criteria which may prevent them from entering ERNs. The establishment of a small number of centres of expertise centrally, which is welcome, should not occur at the expense of an overall improvement in EU rare disease patient care. Caution should be observed to ensure that the inequity gap that already exists does not widen with the development of ERNs. PMID- 26536882 TI - The Essentials of Cardiac Computerized Tomography. AB - Cardiac computerized tomography (CT) has evolved from a research tool to an important diagnostic investigation in cardiology, and is now recommended in European, US, and UK guidelines. This review is designed to give the reader an overview of the current state of cardiac CT. The role of cardiac CT is multifaceted, and includes risk stratification, disease detection, coronary plaque quantification, defining congenital heart disease, planning for structural intervention, and, more recently, assessment of ischemia. This paper addresses basic principles as well as newer evidence. PMID- 26536883 TI - Isolation, cloning, and characterization of a novel Sorghum dehydrin (SbDhn2) protein. AB - Plants can produce their own set of defense molecules in an attempt to survive under stressed conditions. Dehydrins play a considerable role in protecting the plants under varied stress situations. We have isolated a novel SK3 type dehydrin from Sorghum capable of protecting the enzyme lactate dehydrogenase in vitro under both cold and high temperature. This protein showed non-canonical migration in a sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) due to the high hydrophilicity of the protein. The high percentage of glycine and histidine residues present in the protein sequence is responsible for the radical scavenging activity of the protein. The protein also exhibited binding affinity to metal ions owing to the histidine-rich motifs, therefore chelating the metal ions and making them unavailable to systems responsible for generation of reactive oxygen species (ROS). In the presence of specific metal ions, the protein showed reversible aggregation with certain degree of protease resistivity along with induction of secondary structures. The resistivity of the protein to degradation might be implicated in stress situations, thus leading to an increase in the shelf life of the protein. Association with metal ions like copper and zinc at a fairly low concentration increased the protective effect of the SbDHN2 protein for lactate dehydrogenase (LDH) activity to a considerable extent. The synthesis of this dehydrin in stressed plants might help the plant in rendering stress tolerance. PMID- 26536884 TI - Risk of anastomotic leakage with nonsteroidal anti-inflammatory drugs within an enhanced recovery program. AB - INTRODUCTION: Anastomotic leakage is a serious complication after colorectal resection. Recent studies suggest that nonsteroidal anti-inflammatory drugs may increase the risk of anastomotic leakage. We investigated this association in our enhanced recovery population. MATERIAL AND METHODS: Patients undergoing an elective colon or rectal resection with primary anastomosis because of malignancy and treated within our enhanced recovery program were included. Univariable and multivariable logistic regression analyses were used to study risk factors for anastomotic leakage. RESULTS: Between 2006 and 2013, 856 patients were included. The anastomotic leakage rate was significantly higher in the group that received nonsteroidal anti-inflammatory drugs compared to patients who did not: 9.2 vs. 5.3%, p = 0.038. This higher rate was only seen in patients receiving diclofenac: for colonic resections, 11.8 vs. 6.0%, p = 0.016; for rectal resections, 13.1 vs. 0%, p = 0.017. Only male sex (odds ratio 2.20, p = 0.005) was also independently associated with anastomotic leakage. CONCLUSION: The results of this study are in line with other comparable studies in the literature, showing an increased risk for anastomotic leakage with diclofenac. The use of diclofenac in colorectal surgery can no longer be recommended. Alternatives for postoperative analgesia need to be explored within an enhanced recovery program. PMID- 26536885 TI - Survey of the Definition of Fetal Viability and the Availability, Indications, and Decision Making Processes for Post-Viability Termination of Pregnancy for Fetal Abnormalities and Health Conditions in Canada. AB - The purpose of this study was to explore the definition of fetal viability and the availability, indications, and decision making processes for post-viability termination of pregnancy for fetal abnormalities and health conditions in Canada. An online survey of members of the Canadian Association of Genetic Counsellors, the Canadian College of Medical Geneticists, and the Canadian Society for Maternal-Fetal Medicine who provide direct counselling to, or management of, prenatal patients in Canada (total sample size 815). Results of this study showed that the majority of respondents indicated that their centre will offer post viability termination of pregnancy (98/123; 80 %). Sixty-seven percent (68/101) of respondents reported the definition of fetal viability to be 24 weeks' gestation. Most respondents reported that a collaborative decision making process was used to determine if post-viability termination of pregnancy would be offered (136/170; 80 %). For conditions presumed to be lethal/likely lethal, the majority of respondents would "sometimes" or "always" offer post-viability termination of pregnancy, whereas for conditions presumed to have a mild effect, the majority of respondents would "rarely" or "never" offer post-viability termination of pregnancy. Ninety percent (77/86) of respondents reported that perinatal hospice is offered as an alternative to termination of pregnancy. In conclusion, this study suggests that although post-viability termination is available in many provinces in Canada, variation in the definition of fetal viability and indications appear to exist. While these variations may lead to unequal access to post-viability termination of pregnancy across Canada, they might also represent the complexity of the decision making process and the importance of examining individual factors to ensure that the most appropriate decision is made in each case. PMID- 26536886 TI - Review of Commercially Available Epilepsy Genetic Panels. AB - Next generation sequencing panels have revolutionized the diagnostic approach to patients with epilepsy. There are several commercial epilepsy panels available. We assessed the list of genes tested and consent forms for epilepsy panels available at seven laboratories. The panels varied in the number of genes included (70-465 genes). In some panels, genes not currently associated with epilepsy were included (up to 4 % of panel content). The panels also included genes for lysosomal storage disorders (6-12 %), congenital disorders of glycosylation (0-8.5 %), metabolic disorders (3.5-34 %), neurological syndromes (18-43 %) and multisystemic genetic syndromes (6.4-21 %). Informed consents differed significantly between laboratories ranging from basic information about genetic testing and possible results to information about insurance, genetic counseling and familial testing, and incidental findings.Our findings suggest that it is important to consider the range of genes offered on epilepsy panels and their predicted phenotypes in an effort toward improving the informed consent process. PMID- 26536887 TI - Should psychiatric hospitals completely ban smoking? PMID- 26536888 TI - Research Progress Concerning Fungal and Bacterial beta-Xylosidases. AB - In the present review, we briefly summarize the biotechnological applications of microbial beta-xylosidases in the processing of agro-industrial residues into fuels and chemicals and report the importance of using immobilization techniques to study the enzyme. The advantages of utilizing genes that encode beta xylosidases are readily apparent in the bioconversion of abundant, inexpensive, and renewable resources into economically important products, such as xylitol and bioethanol. We highlight recent research characterizing fungal and bacterial beta xylosidases, including the use of classical biochemical methods such as purification, heterologous recombinant protein expression, and metagenomic approaches to discovery beta-xylosidases, with focus on enzyme molecular and kinetic properties. In addition, we discuss the relevance of using experimental design optimization methodologies to increase the efficacy of these enzymes for use with residual biomass. Finally, we emphasize more extensively the advances in the regulatory mechanisms governing beta-xylosidase gene expression and xylose metabolism in gram-negative and gram-positive bacteria and fungi. Unlike previous reviews, this revision covers recent research concerning the various features of bacterial and fungal beta-xylosidases with a greater emphasis on their biochemical characteristics and how the genes that encode these enzymes can be better exploited to obtain products of biotechnological interest via the application of different technical approaches. PMID- 26536889 TI - Ipsi- and contralateral frontal cortex oxygenation during handgrip task does not follow decrease on maximal force output. AB - The effect of fatiguing exercise on the ipsi- and contralateral frontal cortex has not been fully clarified. The purpose of this study was to investigate by near-infrared spectroscopy (NIRS) the frontal cortex oxygenation response to a prolonged fatiguing repetitive handgrip exercise performed at maximal voluntary contraction. It was found a significant oxyhemoglobin concentration ([HbO2]) increase (p < 0.05), accompanied by a smaller and delayed deoxyhemoglobin concentration ([Hb]) decrease (p < 0.05), in both hemispheres. Then, it was indicated higher delayed oxygenation in ipsilateral oxygenation compared to contralateral oxygenation. These results provide further evidence that the complemental interaction between the ipsilateral and contralateral cortex during the fatiguing maximal exercise. PMID- 26536890 TI - Diversity analysis and genomic prediction of Sclerotinia resistance in sunflower using a new 25 K SNP genotyping array. AB - KEY MESSAGE: We have developed a SNP array for sunflower containing more than 25 K markers, representing single loci mostly in or near transcribed regions of the genome. The array was successfully applied to genotype a diversity panel of lines, hybrids, and mapping populations and represented well the genetic diversity of cultivated sunflower. Results of PCoA and population substructure analysis underlined the complexity of the genetic composition of current elite breeding material. The performance of this genotyping platform for genome-based prediction of phenotypes and detection of QTL with improved resolution could be demonstrated based on the re-evaluation of a population segregating for resistance to Sclerotinia midstalk rot. Given our results, the newly developed 25 K SNP array is expected to be of great utility for the most important applications in genome-based sunflower breeding and research. ABSTRACT: Genotyping with a large number of molecular markers is a prerequisite to conduct genome-based genetic analyses with high precision. Here, we report the design and performance of a 25 K SNP genotyping array for sunflower (Helianthus annuus L.). SNPs were discovered based on variant calling in de novo assembled, UniGene-based contigs of sunflower derived from whole genome sequencing and amplicon sequences originating from four and 48 inbred lines, respectively. After inclusion of publically available transcriptome-derived SNPs, in silico design of the Illumina((r)) Infinium iSelect HD BeadChip yielded successful assays for 22,299 predominantly haplotype-specific SNPs. The array was validated in a sunflower diversity panel including inbred lines, open-pollinated varieties, introgression lines, landraces, recombinant inbred lines, and F2 populations. Validation provided 20,502 high-quality bi-allelic SNPs with stable cluster performance whereby each SNP marker represents a single locus mostly in or near transcribed regions of the sunflower genome. Analyses of population structure and quantitative resistance to Sclerotinia midstalk rot demonstrate that this array represents a significant improvement over currently available genomic tools for genetic diversity analyses, genome-wide marker-trait association studies, and genetic mapping in sunflower. PMID- 26536891 TI - Association analysis of grapevine bunch traits using a comprehensive approach. AB - KEY MESSAGE: A set of SNP markers associated to bunch compactness and related traits were identified in grapevine. ABSTRACT: Bunch compactness plays an important role in the sanitary status and perceived quality of table and wine grapes, being influenced by cultural practices and by environmental and genetic factors, which are mostly unknown. In this work, we took advantage of genetic, genomic and bioinformatic advances to analyze part of its molecular basis through a combination of transcriptomic and association analyses. Results from different transcriptomic comparisons between loose and compact grapevine clones were analyzed to select a set of candidate genes likely involved in the observed variation for bunch compactness. Up to 183 genes were sequenced in a grapevine collection, and 7032 single nucleotide polymorphisms (SNPs) were detected in more than 100 varieties with a frequency of the minor allele over 5%. They were used to test their association in three consecutive seasons with bunch compactness and two of its most influencing factors: total berry number and length of the first ramification of the rachis. Only one SNP was associated with berry number in two seasons, suggesting the high sensitiveness of this trait to seasonal environmental changes. On the other hand, we found a set of SNPs associated with both the first ramification length and bunch compactness in various seasons, in several genes which had not previously related to bunch compactness or bunch compactness-related traits. They are proposed as interesting candidates for further functional analyses aimed to verify the results obtained in this work, as a previous step to their inclusion in marker-assisted selection strategies. PMID- 26536892 TI - The Antidiabetic Effects of The Bioactive Flavonoid (Kaempferol-3-O-beta-D-6{P- Coumaroyl} Glucopyranoside) Isolated From Allium cepa. AB - BACKGROUND: Allium cepa has been in use in traditional medicine in the treatment of diabetes mellitus. The aqueous and ethanolic extracts have been found effective in lowering blood glucose levels in experimental diabetic rats and guinea pigs. METHODS: The study was carried out to isolate the active principle responsible for the observed hypoglycaemic effect in experimental animals. Freeze dried aqueous extract of Allium cepa was separated into various fractions using column chromatography with silica gel as a stationary phase. The column was eluted with various ratios of mixtures of hexane, chloroform, ethyl acetate and methanol. These column fractions obtained were tested for hypoglycaemic effects in alloxan-induced diabetic male rats. The identified active fraction was further separated by means of preparative thin layer chromatography (P-TLC) using silica gel as stationary phase and mixture of solvents chloroform, ethyl acetate, and methanol in the ratio of 10: 4: 1 respectively as the mobile phase. Pre-coated P TLC plates were used and the fraction bands were identified under u.v. lamp and by spraying with concentrated sulphuric acidvanillin reagent. The isolated bands (Rf 0.438) were scrapped off from the P-TLC plates, redissolved in absolute methanol, filtered and concentrated to dryness. RESULTS: The isolated compound's structure was determined be means of one and two dimensional nuclear magnetic resonance spectroscopy as well as comparison with literature data. The isolated compound given at 25 mg/kg dose reduced blood glucose in diabetic rats in manner which was comparable to the effect obtained with 2 mg/kg of glibenclamide (p < 0.05). The structure of the compound was found to be that of kaempferol- 3-O-beta - D 6{P-coumaroyl} glucopyranoside. CONCLUSION: The research findings have supported the claims that extracts of Allium cepa possess glucose lowering properties in experimental diabetic animals. PMID- 26536893 TI - Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency. AB - OBJECTIVE: On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. METHODS: We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7-47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional (31)P NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. RESULTS: Patients with GLUT1-DS experienced a mean of 30.8 (+/- 27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (+/- 2.9, 76% motor events) during the treatment phase (p = 0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (+/- 21.9, 52% motor events; p = 0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p = 0.021), and deteriorated when triheptanoin was withdrawn. CONCLUSIONS: Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS. TRIAL REGISTRATION NUMBER: NCT02014883. PMID- 26536895 TI - The need for quality assurance of health apps. PMID- 26536894 TI - A novel technique using potassium permanganate and reflectance confocal microscopy to image biofilm extracellular polymeric matrix reveals non-eDNA networks in Pseudomonas aeruginosa biofilms. AB - Biofilms are etiologically important in the development of chronic medical and dental infections. The biofilm extracellular polymeric substance (EPS) determines biofilm structure and allows bacteria in biofilms to adapt to changes in mechanical loads such as fluid shear. However, EPS components are difficult to visualize microscopically because of their low density and molecular complexity. Here, we tested potassium permanganate, KMnO4, for use as a non-specific EPS contrast-enhancing stain using confocal laser scanning microscopy in reflectance mode. We demonstrate that KMnO4 reacted with EPS components of various strains of Pseudomonas, Staphylococcus and Streptococcus, yielding brown MnO2 precipitate deposition on the EPS, which was quantifiable using data from the laser reflection detector. Furthermore, the MnO2 signal could be quantified in combination with fluorescent nucleic acid staining. COMSTAT image analysis indicated that KMnO4 staining increased the estimated biovolume over that determined by nucleic acid staining alone for all strains tested, and revealed non-eDNA EPS networks in Pseudomonas aeruginosa biofilm. In vitro and in vivo testing indicated that KMnO4 reacted with poly-N-acetylglucosamine and Pseudomonas Pel polysaccharide, but did not react strongly with DNA or alginate. KMnO4 staining may have application as a research tool and for diagnostic potential for biofilms in clinical samples. PMID- 26536896 TI - Spatial methods for infectious disease outbreak investigations: systematic literature review. AB - Investigations of infectious disease outbreaks are conventionally framed in terms of person, time and place. Although geographic information systems have increased the range of tools available, spatial analyses are used relatively infrequently. We conducted a systematic review of published reports of outbreak investigations worldwide to estimate the prevalence of spatial methods, describe the techniques applied and explore their utility. We identified 80 reports using spatial methods published between 1979 and 2013, ca 0.4% of the total number of published outbreaks. Environmental or waterborne infections were the most commonly investigated, and most reports were from the United Kingdom. A range of techniques were used, including simple dot maps, cluster analyses and modelling approaches. Spatial tools were usefully applied throughout investigations, from initial confirmation of the outbreak to describing and analysing cases and communicating findings. They provided valuable insights that led to public health actions, but there is scope for much wider implementation and development of new methods. PMID- 26536897 TI - Thioredoxin, an antioxidant redox protein, in ovarian follicles of women undergoing in vitro fertilization. AB - Oxidative stress has a bidirectional role in the development and maturation of zygotes and embryos. Reduction-oxidation reactions and regulatory proteins, such as thioredoxin (TRX) and thioredoxin reductase (TRXR), are intimately involved in the regulation of oxidative stress. The aim of this study was to determine the levels of TRX mRNA and protein in ovarian follicles collected from women undergoing in vitro fertilization (IVF) and to assess these levels relative to follicle size, presence of oocytes, and responsiveness to superovulation. Follicular fluid (FF) and/or granulosa cells (GCs) from large and small follicles were collected at the time of ovum pick-up from 42 IVF patients enrolled in this study. We divided the patients into normal and poor responders (NR and PR, respectively) based on the serum estradiol levels on the day of human chorionic gonadotropin (hCG) administration. We also compared the TRX concentration in FF (FF-TRX) between oocyte-containing follicles (Oc+) and empty follicles (Oc-). The transcript levels of TRX, but not TRXR, were significantly higher in GCs derived from follicles collected from NR than PR, as determined by semi-quantitative RT PCR analysis. In NR, the FF-TRX was significantly higher in Oc+ follicles than in Oc- follicles and also in large Oc+ follicles than in large Oc- follicles. Unlike NR, PR exhibited no positive association with elevated FF-TRX and presence of oocytes. Based on its collective anti-oxidative, cytoprotective, and cytokine like properties of TRX, TRX is likely to be involved in the optimal growth and maturation of ovarian follicles and responsiveness to hyperstimulation. PMID- 26536898 TI - Clinical significance of screening for subclinical Cushing's disease in patients with pituitary tumors. AB - Cushing's syndrome (CS) is a clinical state caused by chronic excess of glucocorticoid, and results in hypertension, impaired glucose tolerance, and dyslipidemia. Recently, a mild state of pituitary CS without typical Cushingoid appearance (subclinical Cushing's disease; SCD) has been identified. However, the true prevalence of SCD and its effect on metabolic disorders remain obscure. The aim of this prospective study was to determine the prevalence of SCD according to the guideline proposed by the working group of the Japanese Ministry of Health, Welfare and Labor, and to assess the outcome of surgery on metabolic disorders. The prevalence of SCD was investigated in 105 consecutive patients diagnosed with pituitary adenomas by MRI. ACTH-dependent hypercortisolism was diagnosed based on the results of the 0.5 mg dexamethasone suppression test (serum cortisol >3.0 MUg/dL) plus one positive finding of the following two tests: midnight serum cortisol level >5.0 MUg/dL or ACTH increase >50% after 1-deamino-5-D-arginine vasopressin (DDAVP) challenge. The final diagnosis of SCD was established by positive staining for ACTH in surgically-excised pituitary adenoma. Three patients (4.8%) were diagnosed with SCD among 62 patients with pituitary adenoma. Transsphenoidal adenomectomy partially resulted in improvement of blood pressure and glucose metabolism in SCD patients. Our results emphasize the importance of SCD screening in patients with pituitary tumors, especially in those patients with metabolic disorders. PMID- 26536899 TI - Educating Patients about CKD: The Path to Self-Management and Patient-Centered Care. AB - Patient education is associated with better patient outcomes and supported by international guidelines and organizations, but a range of barriers prevent widespread implementation of comprehensive education for people with progressive kidney disease, especially in the United States. Among United States patients, obstacles to education include the complex nature of kidney disease information, low baseline awareness, limited health literacy and numeracy, limited availability of CKD information, and lack of readiness to learn. For providers, lack of time and clinical confidence combine with competing education priorities and confusion about diagnosing CKD to limit educational efforts. At the system level, lack of provider incentives, limited availability of practical decision support tools, and lack of established interdisciplinary care models inhibit patient education. Despite these barriers, innovative education approaches for people with CKD exist, including self-management support, shared decision making, use of digital media, and engaging families and communities. Education efficiency may be increased by focusing on people with progressive disease, establishing interdisciplinary care management including community health workers, and providing education in group settings. New educational approaches are being developed through research and quality improvement efforts, but challenges to evaluating public awareness and patient education programs inhibit identification of successful strategies for broader implementation. However, growing interest in improving patient-centered outcomes may provide new approaches to effective education of people with CKD. PMID- 26536900 TI - Educational Tools: Thinking Outside the Box. AB - The understanding, study, and use of educational tools and their application to the education of adults in professional fields are increasingly important. In this review, we have compiled a description of educational tools on the basis of the teaching and learning setting: the classroom, simulation center, hospital or clinic, and independent learning space. When available, examples of tools used in nephrology are provided. We emphasize that time should be taken to consider the goals of the educational activity and the type of learners and use the most appropriate tools needed to meet the goals. Constant reassessment of tools is important to discover innovation and reforms that improve teaching and learning. PMID- 26536901 TI - Translating Genetic Risk Loci Into Molecular Risk Mechanisms for Schizophrenia. PMID- 26536902 TI - Cannabis Use Is Associated With Increased Psychotic Symptoms and Poorer Psychosocial Functioning in First-Episode Psychosis: A Report From the UK National EDEN Study. AB - OBJECTIVE: The use of cannabis during the early stage of psychosis has been linked with increased psychotic symptoms. This study aimed to examine the use of cannabis in the 12 months following a first-episode of psychosis (FEP) and the link with symptomatic course and outcome over 1 year post psychosis onset. DESIGN AND SETTING: One thousand twenty-seven FEP patients were recruited upon inception to specialized early intervention services (EIS) for psychosis in the United Kingdom. Participants completed assessments at baseline, 6 and 12 months. RESULTS: The results indicate that the use of cannabis was significantly associated with increased severity of psychotic symptoms, mania, depression and poorer psychosocial functioning. Continued use of cannabis following the FEP was associated with poorer outcome at 1 year for Positive and Negative Syndrome Scale total score, negative psychotic symptoms, depression and psychosocial functioning, an effect not explained by age, gender, duration of untreated psychosis, age of psychosis onset, ethnicity or other substance use. CONCLUSION: This is the largest cohort study of FEP patients receiving care within EIS. Cannabis use, particularly "continued use," was associated with poorer symptomatic and functional outcome during the FEP. The results highlight the need for effective and early intervention for cannabis use in FEP. PMID- 26536903 TI - Onset and Regression of Pregnancy-Induced Cardiac Alterations in Gestationally Hypertensive Mice: The Role of the Natriuretic Peptide System. AB - Pregnancy induces cardiovascular adaptations in response to increased volume overload. Aside from the hemodynamic changes that occur during pregnancy, the maternal heart also undergoes structural changes. However, cardiac modulation in pregnancies complicated by gestational hypertension is incompletely understood. The objectives of the current investigation were to determine the role of the natriuretic peptide (NP) system in pregnancy and to assess alterations in pregnancy-induced cardiac hypertrophy between gestationally hypertensive and normotensive dams. Previously we have shown that mice lacking the expression of atrial NP (ANP; ANP(-/-)) exhibit a gestational hypertensive phenotype. In the current study, female ANP(+/+) and ANP(-/-) mice were mated with ANP(+/+) males. Changes in cardiac size and weight were evaluated across pregnancy at Gestational Days 15.5 and 17.5 and Postnatal Days 7, 14, and 28. Nonpregnant mice were used as controls. Physical measurement recordings and histological analyses demonstrated peak cardiac hypertrophy occurring at 14 days postpartum in both ANP(+/+) and ANP(-/-) dams with little to no change during pregnancy. Additionally, left ventricular expression of the renin-angiotensin system (RAS) and NP system was quantified by real-time quantitative polymerase chain reaction. Up-regulation of Agt and AT(1a) genes was observed late in pregnancy, while Nppa and Nppb genes were significantly up-regulated postpartum. Our data suggest that pregnancy-induced cardiac hypertrophy may be influenced by the RAS throughout gestation and by the NP system postpartum. Further investigations are required to gain a complete understanding of the mechanistic aspects of pregnancy-induced cardiac hypertrophy. PMID- 26536904 TI - Sry-Independent Overexpression of Sox9 Supports Spermatogenesis and Fertility in the Mouse. AB - The Y chromosome gene Sry is responsible for sex determination in mammals and initiates a cascade of events that direct differentiation of bipotential genital ridges toward male-specific fate. Sox9 is an autosomal gene and a primary downstream target of SRY. The activation of Sox9 in the absence of Sry is sufficient for initiation of male-specific sex determination. Sry-to-Sox9 replacement has mostly been studied in the context of sex determination during early embryogenesis. Here, we tested whether Sry-to-Sox9 replacement affects male fertility in adulthood. We examined males with the Y chromosome carrying a deletion removing the endogenous Sry, with testes determination driven either by the Sox9 (XY(Tdym1)Sox9) or the Sry (XY(Tdym1)Sry) transgenes as well as wild type males (XY). XY(Tdym1)Sox9 males had reduced testes size, altered testes shape and vasculature, and increased incidence of defects in seminiferous epithelium underlying the coelomic blood vessel region when compared to XY(Tdym1)Sry and XY. There were no differences between XY(Tdym1)Sry and XY(Tdym1)Sox9 males in respect to sperm number, motility, morphology, and ability to fertilize oocytes in vitro, but for some parameters, transgenic males were impaired when compared to XY. In fecundity trials, XY(Tdym1)Sry, XY(Tdym1)Sox9, and XY males yielded similar average numbers of pups and litters. Overall, our findings support that males lacking the testis determinant Sry can be fertile and reinforce the notion that Sry does not play a role in mature gonads. Although transgenic Sox9 overexpression in the absence of Sry results in certain testicular abnormalities, it does not translate into fertility impairment. PMID- 26536905 TI - Depletion of Intracellular Thiols and Increased Production of 4-Hydroxynonenal that Occur During Cryopreservation of Stallion Spermatozoa Lead to Caspase Activation, Loss of Motility, and Cell Death. AB - Oxidative stress has been linked to sperm death and the accelerated senescence of cryopreserved spermatozoa. However, the molecular mechanisms behind this phenomenon remain poorly understood. Reactive oxygen species (ROS) are considered relevant signaling molecules for sperm function, only becoming detrimental when ROS homeostasis is lost. We hereby hypothesize that a major component of the alteration of ROS homeostasis in cryopreserved spermatozoa is the exhaustion of intrinsic antioxidant defense mechanisms. To test this hypothesis, semen from seven stallions was frozen using a standard technique. The parameters of sperm quality (motility, velocity, and membrane integrity) and markers of sperm senescence (caspase 3, 4-hydroxynonenal, and mitochondrial membrane potential) were assessed before and after cryopreservation. Changes in the intracellular thiol content were also monitored. Cryopreservation caused significant increases in senescence markers as well as dramatic depletion of intracellular thiols to less than half of the initial values (P < 0.001) postthaw. Interestingly, very high and positive correlations were observed among thiol levels with sperm functionality postthaw: total motility (r = 0.931, P < 0.001), progressive motility (r = 0.904, P < 0.001), and percentage of live spermatozoa without active caspase 3 (r = 0.996, P < 0.001). In contrast, negative correlations were detected between active caspase 3 and thiol content both in living (r = -0.896) and dead (r = -0.940) spermatozoa; additionally, 4-hydroxynonenal levels were negatively correlated with thiol levels (r = -0.856). In conclusion, sperm functionality postthaw correlates with the maintenance of adequate levels of intracellular thiols. The accelerated senescence of thawed spermatozoa is related to oxidative and electrophilic stress induced by increased production of 4 hydroxynoneal in thawed samples once intracellular thiols are depleted. PMID- 26536906 TI - Experiences from a communication training programme of paid carers in a residential rehabilitation centre for people with traumatic brain injury. AB - PURPOSE: To determine the impact of a communication training programme by exploring the experiences of paid carers who attended the programme in a residential rehabilitation centre for people with traumatic brain injury (TBI). METHOD: Five paid carers attended a communication training programme which comprised 17 hours (across 8 weeks). Semi-structured interviews were conducted pre- and post-training. Analysis used a generic procedure with constant comparative analysis to identify categories across and within interview transcripts. RESULTS: Paid carers described improved knowledge and use of strategies, improved communication, positive emotional experiences and barriers and facilitators to consider for future communication training programmes. CONCLUSION: Training communication skills of paid carers in a residential rehabilitation centre had a positive impact on their conversations with people with TBI. These positive changes support quantitative findings for the effectiveness of communication training. PMID- 26536907 TI - Follow-up on oral and cervical human papillomavirus prevalence 2013-2015 in youth at a youth clinic in Stockholm, Sweden. PMID- 26536908 TI - Dissociation and mindfulness in patients with auditory verbal hallucinations. AB - The very few studies relating mindfulness and dissociation have found a negative association between them (depersonalization and absorption). However, all of these studies have been done in nonclinical populations, and there are no data on the relationship between these variables in psychiatric patients with auditory hallucinations. This study was designed to study the relationship between mindfulness and the two dissociative variables, absorption and depersonalization, as well as their predictive power for the severity of auditory hallucinations and the distress they cause in a clinical population. A total of 55 psychiatric patients with hallucinations were given the following tests: the Mindful Attention Awareness Scale (K. Brown & R. Ryan, 2003), the Tellegen Absorption Scale (A. Tellegen & G. Atkinson, 1974), the Cambridge Depersonalization Scale (M. Sierra & G. E. Berrios, 2000), the Psychotic Symptom Rating Scales (G. Haddock, J. McCarron, N. Tarrier, & E. B. Faragher, 1999), and the Positive and Negative Syndrome Scale (S. R. Kay, L. A. Opler, & J.-P. Lindenmayer, 1988). A significant negative correlation was found between mindfulness and the dissociative variables and between mindfulness and the distress caused by the hallucinations. A positive correlation was found between absorption and distress caused by hallucinations and between depersonalization and the severity of hallucinations. Finally, the variable with the most predictive power for severity of the voices was depersonalization, and the variable with the most predictive power for distress caused by the voices was mindfulness. Interventions addressing training in mindfulness techniques could diminish the distress associated with hearing voices. PMID- 26536909 TI - White Light from a Light-Emitting Electrochemical Cell: Controlling the Energy Transfer in a Conjugated Polymer/Triplet-Emitter Blend. AB - We report on the attainment of broadband white light emission from a host-guest light-emitting electrochemical cell, comprising a blue-emitting conjugated polymer as the majority host and a red-emitting small-molecule triplet emitter as the minority guest. An analysis of the energy structure reveals that host-to guest energy transfer can be effectuated by both Forster and Dexter processes, and through a careful optimization of the active material composition partial energy transfer and white emission is accomplished at a low guest concentration of 0.5%. By adding a small amount of a yellow-emitting conjugated polymer to the active material, white light emission with a high color rendering index of 79, and an efficiency of 4.3 cd/A at significant luminance (>200 cd/m(2)), is realized. PMID- 26536910 TI - Beneficial Effects of Hypoxic Preconditioning on Human Umbilical Cord Mesenchymal Stem Cells. AB - As human umbilical cord mesenchymal stem cells (hUC-MSCs) transplanation may be promising in heart failure treatment, it is important to know whether hypoxic preconditioning (HP) promote hUC-MSCs proliferation and differentiation and protect them against chemical hypoxic damages. This study aimed to investigate the effects of HP on proliferation and differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs). The study also aimed to confirm our hypothesis that HP could promote hUC-MSCs proliferation and differentiation to cardiomyocyte like cells as well as effectively protecting hUC-MSCs and cardiomyocyte-like cells against chemical hypoxic damages. Isolated hUC-MSCs were cultured in hypoxia at 1%, 3% and 5% O2 for 72 hours. 5-azacytidine (5-AZA) induced differentiation of hUC-MSCs to cardiomyocyte-like cells was determined by streptavidin-perosidase (SP) immunohistochemical staining and the content of troponin (TnI). Flow cytometry was used to measure cell cycle in hUC-MSCs and cardiomyocyte-like cells. The mitochondrial membrane potential (DeltaPsi(m)) and mitochondrial Ca2+ concentration ([Ca2+](m)), were measured in hUC-MSCs and cardiomyocyte-like cells during chemical hypoxia induced by cobalt chloride (100 MUmol/L). HP optimally promoted the proliferation of hUC-MSCs at 3% O2 and enhanced the differentiation of hUC-MSCs to cardiomyocyte-like cells by 5-AZA in a concentration-dependent manner. The cell cycle distribution of cardiomyocyte like cells, but not hUC-MSCs, was clearly changed by HP. Chemical hypoxic damage, decreased DeltaPsi(m) and increased [Ca2+](m), were alleviated significantly in HP-treated cells compared with the normaxia-treated cells. The results demonstrate that HP promoted hUC-MSCs proliferation and differentiation to cardiomyocyte-like cells, and protected both cell types against chemical hypoxic damage. PMID- 26536911 TI - Why is There so Much Controversy Regarding the Population Health Impact of the Great Recession? Reflections on Three Case Studies. AB - In the aftermath of the Great Recession, public health scholars have grown increasingly interested in studying the health consequences of macroeconomic change. Reflecting existing debates on the nature of this relationship, research on the effects of the recent economic crisis has sparked considerable controversy. On the one hand there is evidence to support the notion that macroeconomic downturns are associated with positive health outcomes. On the other hand, a growing number of studies warn that the current economic crisis can be expected to pose serious problems for the public's health. This article contributes to this debate through a review of recent evidence from three case studies: Iceland, Spain, and Greece. It shows that the economic crisis has negatively impacted some population health indicators (e.g., mental health) in all three countries, but especially in Greece. Available evidence defies deterministic conclusions, including increasingly "conventional" claims about economic downturns improving life expectancy and reducing mortality. While our results echo previous research in finding that the relationship between economic crises and population health is complex, they also indicate that this complexity is not arbitrary. On the contrary, changing social and political contexts provide meaningful, if partial, explanations for the perplexing nature of recent empirical findings. PMID- 26536912 TI - Support for National Health Insurance Seven Years Into Massachusetts Healthcare Reform: Views of Populations Targeted by the Reform. AB - Before the Affordable Care Act (ACA), many surveys showed majority support for national health insurance (NHI), also known as single payer; however, little is currently known about views of the ACA's targeted population. Massachusetts residents have had seven years of experience with state health care reform that became the model for the ACA. We surveyed 1,151 adults visiting safety-net emergency departments in Massachusetts in late 2013 on their preference for NHI or the Massachusetts reform and on their experiences with insurance. Most of the patients surveyed were low-income and non-white. The majority of patients (72.0%) preferred NHI to the Massachusetts reform. Support for NHI among those with public insurance, commercial insurance, and no insurance was 68.9%, 70.3%, and 86.3%, respectively (p < .001). Support for NHI was higher among patients dissatisfied with their insurance plan (83.3% vs. 68.9%, p = .014), who delayed medical care (81.2% vs. 69.6%, p < .001) or avoided purchasing medications due to cost (87.3% vs. 71.4%; p = .01). Majority support for NHI was observed in every demographic subgroup. Given the strong support for NHI among disadvantaged Massachusetts patients seven years after state health reform, a reappraisal of the ACA's ability to meet the needs of underserved patients is warranted. PMID- 26536913 TI - Medical Causes and Consequences of Home Foreclosures. AB - The objective of this study was to elucidate the medical causes and consequences of foreclosure. We surveyed 90 households undergoing foreclosure in 2013-2014 in Maricopa County, Arizona on two occasions approximately five months apart. At baseline, median monthly household income was $3,000, and median mortgage payment $1,350. Only 10% of respondents lacked health insurance when surveyed, although 28% had experienced a gap in coverage within the past two years. Fifty-seven percent identified a medical debt or another medical cause of their foreclosure, and 54% had taken on new debt to pay medical bills; 10% had mortgaged their home for this reason. Although 57% of respondents had a chronic condition requiring ongoing care, more than half reported delaying or skipping a needed medical visit. At follow-up, one-third of respondents had been unable to afford food, and 3 respondents reported becoming homeless; 46% said foreclosure had worsened their health; and 63% had already incurred new medical debts. Medical debt and medical problems frequently contribute to foreclosure, even among insured families. Foreclosure compromises access to care and basic necessities like food and shelter, and worsens self-reported health. PMID- 26536914 TI - Sexual Health Knowledge and Needs: Young Muslim Women in Melbourne, Australia. AB - In this article, we discuss the sexual health knowledge and needs among young Muslim women living in Melbourne, Australia. Eleven young Muslim women were individually interviewed about issues relating to sexual health knowledge and needs, access to sexual health services, and their experiences of balancing their lives in relation to sexual health. Findings revealed a marked influence of religion and culture on sexual health of young Muslim women. They often faced challenges balancing Muslim culture, Australian culture, and Islamic religion. Our findings have implications for health services in a multicultural society. They could be used to promote culturally sensitive sexual health services for young Muslim women in Australia and elsewhere. PMID- 26536915 TI - Can Geographic Bridging Social Capital Improve the Health of People Who Live in Deprived Urban Neighborhoods? AB - The growing number of people living in deprived urban neighborhoods, which often have unhealthy environments, is of growing concern to inequality researchers. Social capital could be a resource to help such communities get ahead. In this study, we examined the differential effects of bonding and bridging social capital on self-rated health using two operational definitions, which we call personal and geographic social capital. Bonding and bridging social capital were operationally distinguished as respondents' perceived similarity to other members of a group with respect to personal characteristics (personal social capital) or as structural similarity with respect to geographical location (geographic social capital). The results showed that although both bonding and bridging social capital as defined by person-based criteria were associated with increased odds of self-rated health compared to those who reported zero participation, when defined by place-based criteria, only bridging social capital was associated with increased odds of self-rated health; no clear association was found between health and belonging to groups within the neighborhood, so-called geographic bonding social capital. The present study suggests that geographic bridging social capital can function as linking social capital that enables an upward approach depending on the political and economic contexts of urbanization. PMID- 26536916 TI - Quantification of NS1 dengue biomarker in serum via optomagnetic nanocluster detection. AB - Dengue is a tropical vector-borne disease without cure or vaccine that progressively spreads into regions with temperate climates. Diagnostic tools amenable to resource-limited settings would be highly valuable for epidemiologic control and containment during outbreaks. Here, we present a novel low-cost automated biosensing platform for detection of dengue fever biomarker NS1 and demonstrate it on NS1 spiked in human serum. Magnetic nanoparticles (MNPs) are coated with high-affinity monoclonal antibodies against NS1 via bio-orthogonal Cu free 'click' chemistry on an anti-fouling surface molecular architecture. The presence of the target antigen NS1 triggers MNP agglutination and the formation of nanoclusters with rapid kinetics enhanced by external magnetic actuation. The amount and size of the nanoclusters correlate with the target concentration and can be quantified using an optomagnetic readout method. The resulting automated dengue fever assay takes just 8 minutes, requires 6 MUL of serum sample and shows a limit of detection of 25 ng/mL with an upper detection range of 20000 ng/mL. The technology holds a great potential to be applied to NS1 detection in patient samples. As the assay is implemented on a low-cost microfluidic disc the platform is suited for further expansion to multiplexed detection of a wide panel of biomarkers. PMID- 26536917 TI - The functional gene composition and metabolic potential of coral-associated microbial communities. AB - The phylogenetic diversity of coral-associated microbes has been extensively examined, but some contention remains regarding whether coral-associated microbial communities are species-specific or site-specific. It is suggested that corals may associate with microbes in terms of function, although little is known about the differences in coral-associated microbial functional gene composition and metabolic potential among coral species. Here, 16S rRNA Illumina sequencing and functional gene array (GeoChip 5.0) were used to assess coral-associated microbial communities. Our results indicate that both host species and environmental variables significantly correlate with shifts in the microbial community structure and functional potential. Functional genes related to key biogeochemical cycles including carbon, nitrogen, sulfur and phosphorus cycling, metal homeostasis, organic remediation, antibiotic resistance and secondary metabolism were shown to significantly vary between and among the four study corals (Galaxea astreata, Porites lutea, Porites andrewsi and Pavona decussata). Genes specific for anammox were also detected for the first time in the coral holobiont and positively correlated with ammonium. This study reveals that variability in the functional potential of coral-associated microbial communities is largely driven by changes in environmental factors and further demonstrates the importance of linking environmental parameters with genomic data in complex environmental systems. PMID- 26536919 TI - Care for the carers. PMID- 26536918 TI - Targeting the Nuclear Export Protein XPO1/CRM1 Reverses Epithelial to Mesenchymal Transition. AB - Here we demonstrate for the first time that targeted inhibition of nuclear exporter protein exportin 1 (XPO1) also known as chromosome maintenance region 1 (CRM1) by Selective Inhibitor of Nuclear Export (SINE) compounds results in reversal of EMT in snail-transduced primary human mammary epithelial cells (HMECs). SINE compounds selinexor (KPT-330) and KPT-185, leptomycin B (LMB as +ve control) but not KPT-301 (-ve control) reverse EMT, suppress mesenchymal markers and consequently induce growth inhibition, apoptosis and prevent spheroid formation. SINE treatment resulted in nuclear retention of snail regulator FBXL5 that was concurrent with suppression of snail and down-regulation of mesenchymal markers. FBXL5 siRNA or transfection with cys528 mut-Xpo1 (lacking SINE binding site) markedly abrogated SINE activity highlighting an XPO1 and FBXL5 mediated mechanism of action. Silencing XPO1 or snail caused re-expression of FBXL5 as well as EMT reversal. Pathway analysis on SINE treated HMECs further verified the involvement of additional F-Box family proteins and confirmed the suppression of snail network. Oral administration of selinexor (15 mg/kg p.o. QoDx3/week for 3weeks) resulted in complete cures (no tumor rebound at 120 days) of HMLER-Snail xenografts. These findings raise the unique possibility of blocking EMT at the nuclear pore. PMID- 26536920 TI - Ills of the system. PMID- 26536921 TI - Smooth operator. PMID- 26536922 TI - Avoid major disasters by welcoming minor change. PMID- 26536934 TI - Historic Rosetta mission to end with crash into comet. PMID- 26536933 TI - Memory-boosting devices tested in humans. PMID- 26536935 TI - Indonesia blazes threaten endangered orangutans. PMID- 26536936 TI - Synthetic biology lures Silicon Valley investors. PMID- 26536937 TI - Software predicts slew of fiendish crystal structures. PMID- 26536938 TI - Indian scientists join protests over killings of prominent secularists. PMID- 26536939 TI - Correction. PMID- 26536940 TI - The big baby experiment. PMID- 26536941 TI - The greatest vanishing act in prehistoric America. PMID- 26536942 TI - Informatics: Make sense of health data. PMID- 26536943 TI - Society: Build digital democracy. PMID- 26536947 TI - Vehicle emissions: Volkswagen and the road to Paris. PMID- 26536948 TI - Bovine tuberculosis: DEFRA responds to badger-cull critique. PMID- 26536949 TI - China emissions: stop subsidizing emitters. PMID- 26536950 TI - China emissions: alter energy markets. PMID- 26536951 TI - Animal welfare: Europe's first '3Rs' governmental centre. PMID- 26536952 TI - Sustainability: Australia at the crossroads. PMID- 26536953 TI - Materials science: Droplets leap into action. PMID- 26536954 TI - Metabolism: Light on leptin link to lipolysis. PMID- 26536955 TI - Quantum physics: Quantum sound waves stick together. PMID- 26536956 TI - Australia is 'free to choose' economic growth and falling environmental pressures. AB - Over two centuries of economic growth have put undeniable pressure on the ecological systems that underpin human well-being. While it is agreed that these pressures are increasing, views divide on how they may be alleviated. Some suggest technological advances will automatically keep us from transgressing key environmental thresholds; others that policy reform can reconcile economic and ecological goals; while a third school argues that only a fundamental shift in societal values can keep human demands within the Earth's ecological limits. Here we use novel integrated analysis of the energy-water-food nexus, rural land use (including biodiversity), material flows and climate change to explore whether mounting ecological pressures in Australia can be reversed, while the population grows and living standards improve. We show that, in the right circumstances, economic and environmental outcomes can be decoupled. Although economic growth is strong across all scenarios, environmental performance varies widely: pressures are projected to more than double, stabilize or fall markedly by 2050. However, we find no evidence that decoupling will occur automatically. Nor do we find that a shift in societal values is required. Rather, extensions of current policies that mobilize technology and incentivize reduced pressure account for the majority of differences in environmental performance. Our results show that Australia can make great progress towards sustainable prosperity, if it chooses to do so. PMID- 26536957 TI - Episodic molecular outflow in the very young protostellar cluster Serpens South. AB - The loss of mass from protostars, in the form of a jet or outflow, is a necessary counterpart to protostellar mass accretion. Outflow ejection events probably vary in their velocity and/or in the rate of mass loss. Such 'episodic' ejection events have been observed during the class 0 protostellar phase (the early accretion stage), and continue during the subsequent class I phase that marks the first one million years of star formation. Previously observed episodic-ejection sources were relatively isolated; however, the most common sites of star formation are clusters. Outflows link protostars with their environment and provide a viable source of the turbulence that is necessary for regulating star formation in clusters, but it is not known how an accretion-driven jet or outflow in a clustered environment manifests itself in its earliest stage. This early stage is important in establishing the initial conditions for momentum and energy transfer to the environment as the protostar and cluster evolve. Here we report that an outflow from a young, class 0 protostar, at the hub of the very active and filamentary Serpens South protostellar cluster, shows unambiguous episodic events. The (12)C(16)O (J = 2-1) emission from the protostar reveals 22 distinct features of outflow ejecta, the most recent having the highest velocity. The outflow forms bipolar lobes--one of the first detectable signs of star formation- which originate from the peak of 1-mm continuum emission. Emission from the surrounding C(18)O envelope shows kinematics consistent with rotation and an infall of material onto the protostar. The data suggest that episodic, accretion driven outflow begins in the earliest phase of protostellar evolution, and that the outflow remains intact in a very clustered environment, probably providing efficient momentum transfer for driving turbulence. PMID- 26536958 TI - Hong-Ou-Mandel interference of two phonons in trapped ions. AB - The quantum statistics of bosons and fermions manifest themselves in the manner in which two indistinguishable particles interfere quantum mechanically. When two photons, which are bosonic particles, enter a beam-splitter with one photon in each input port, they bunch together at either of the two output ports. The corresponding disappearance of the coincidence count is the Hong-Ou-Mandel effect. Here we show the phonon counterpart of this effect in a system of trapped ion phonons, which are collective excitations derived by quantizing vibrational motions that obey Bose-Einstein statistics. We realize a beam-splitter transformation of the phonons by employing the mutual Coulomb repulsion between ions, and perform a two-phonon quantum interference experiment using that transformation. We observe an almost perfect disappearance of the phonon coincidence between two ion sites, confirming that phonons can be considered indistinguishable bosonic particles. The two-particle interference demonstrated here is purely a quantum effect, without a classical counterpart, hence it should be possible to demonstrate the existence of entanglement on this basis. We attempt to generate an entangled state of phonons at the centre of the Hong-Ou Mandel dip in the coincidence temporal profile, under the assumption that the entangled phonon state is successfully generated if the fidelity of the analysis pulses is taken into account adequately. Two-phonon interference, as demonstrated here, proves the bosonic nature of phonons in a trapped-ion system. It opens the way to establishing phonon modes as carriers of quantum information in their own right, and could have implications for the quantum simulation of bosonic particles and analogue quantum computation via boson sampling. PMID- 26536959 TI - Spontaneous droplet trampolining on rigid superhydrophobic surfaces. AB - Spontaneous removal of condensed matter from surfaces is exploited in nature and in a broad range of technologies to achieve self-cleaning, anti-icing and condensation control. But despite much progress, our understanding of the phenomena leading to such behaviour remains incomplete, which makes it challenging to rationally design surfaces that benefit from its manifestation. Here we show that water droplets resting on superhydrophobic textured surfaces in a low-pressure environment can self-remove through sudden spontaneous levitation and subsequent trampoline-like bouncing behaviour, in which sequential collisions with the surface accelerate the droplets. These collisions have restitution coefficients (ratios of relative speeds after and before collision) greater than unity despite complete rigidity of the surface, and thus seemingly violate the second law of thermodynamics. However, these restitution coefficients result from an overpressure beneath the droplet produced by fast droplet vaporization while substrate adhesion and surface texture restrict vapour flow. We also show that the high vaporization rates experienced by the droplets and the associated cooling can result in freezing from a supercooled state that triggers a sudden increase in vaporization, which in turn boosts the levitation process. This effect can spontaneously remove surface icing by lifting away icy drops the moment they freeze. Although these observations are relevant only to systems in a low-pressure environment, they show how surface texturing can produce droplet surface interactions that prohibit liquid and freezing water-droplet retention on surfaces. PMID- 26536960 TI - Eight ways to clean a digital library. PMID- 26536962 TI - Trends in presentation, management and survival of patients with de novo metastatic breast cancer in a Southeast Asian setting. AB - Up to 25% of breast cancer patients in Asia present with de novo metastatic disease. We examined the survival trends of Asian patients with metastatic breast cancer over fifteen years. The impact of changes in patient's demography, tumor characteristics, tumor burden, and treatment on survival trend were examined. Patients with de novo metastatic breast cancer from three hospitals in Malaysia and Singapore (N = 856) were grouped by year of diagnosis: 1996-2000, 2001-2005 and 2006-2010. Step-wise multivariable Poisson regression was used to estimate the contribution of above-mentioned factors on the survival trend. Proportions of patients presenting with metastatic breast cancer were 10% in 1996-2000, 7% in 2001-2005, and 9% in 2006-2010. Patients in 2006-2010 were significantly older, appeared to have higher disease burden, and received more chemotherapy, endocrine therapy, and surgery of primary tumor. The three-year relative survival in the above periods were 20.6% (95% CI: 13.9%-28.2%), 28.8% (95% CI: 23.4%-34.2%), and 33.6% (95% CI: 28.8%-38.5%), respectively. Adjustment for treatment considerably attenuated the relative excess risk of mortality in recent years, compared to other factors. Substantial improvements in survival were observed in patients with de novo metastatic breast cancer in this study. PMID- 26536963 TI - Prevalence of work-related musculoskeletal disorders among physical therapists. AB - BACKGROUND: Health professions like dentistry, nursing and physical therapy have been reported at high risk for developing work-related musculoskeletal disorders. Results of studies conducted in these occupational groups may help formulate prevention strategies. However, no such data among physical therapists has been reported in India. MATERIAL AND METHODS: We conducted an online survey among 100 physiotherapists in Delhi. RESULTS: The response rate was 75%. The prevalence of work-related musculoskeletal disorders is found to be high since 92% of them reported to feel some pain after joining physical therapy which affects daily activities and even sometimes forces them to change their work. Physical therapists specialty, gender, furniture used in clinic and duration of patient contact are found to be related to the pain development (p<0.05). CONCLUSIONS: We need to emphasize the role of ergonomics and techniques of patient handling in development of work-related pain symptoms. PMID- 26536964 TI - A study on respiratory problems and pulmonary function indexes among cement industry workers in Mashhad, Iran. AB - BACKGROUND: The respiratory system is the most vulnerable system in the cement industry. This study was conducted to determine the effects of occupational exposure to cement dust on the respiratory system more thoroughly. MATERIAL AND METHODS: In this cross sectional study an interviewer-administered questionnaire on socio-demographic characteristics and respiratory symptoms was completed and pulmonary function tests were carried out on 100 exposed and 120 non-exposed workers at the cement factory in Mashhad, Iran. The data was statistically analyzed by SPSS 16. RESULTS: The mean of age and work duration in the exposed group was 37.5+/-6.3 and 10.7+/-5.4 years compared with the non-exposed group that was 36.1+/-7.1 and 10.1+/-5.7 years, respectively. Levels of exposure to inhalable cement dust in the exposed group were 23.13 mg/m3 (higher than national occupational exposure limits for such particles). Among the exposed group, respiratory symptoms as cough (6% vs. 0.8% of the non-exposed) and sputum (7% vs. 0.8% of the nonexposed) were significantly more prevalent (p<0.05). Forced expiratory flow 25-75% (FEF25-75%) was significantly lower in the exposed workers compared with non-exposed ones (p<0.05). Also forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) and FEF25-75% had a reverse correlation with the length of employment (p=0.000 and p=0.003, respectively). CONCLUSIONS: The findings of this study showed that occupational exposure to cement dust could be a significant factor of respiratory system dysfunction. Strict implementation of a respiratory protection program is recommended in cement industries. PMID- 26536965 TI - Exposure to excessive sounds during orchestra rehearsals and temporary hearing changes in hearing among musicians. AB - BACKGROUND: It has been shown that musicians are at risk of noise-induced hearing loss. The aim of the study has been to evaluate the temporary changes of hearing in the case of orchestral musicians after group rehearsals. MATERIAL AND METHODS: The study group comprised 18 orchestral musicians, aged 30-58 years old (mean: 40 years old) having 12-40 years (mean: 22 years) of professional experience. The temporary changes in hearing after group rehearsals were determined using transient-evoked otoacoustic emissions (TEOAEs). Noise exposures during group rehearsals were also evaluated. RESULTS: Musicians' hearing threshold levels were higher (worse) than expected for the equivalent non-noise-exposed population. Moreover, the high frequency notched audiograms were observed in some of them. After rehearsals, during which musicians were exposed to orchestral noise at A weighted equivalent-continuous sound pressure level (normalized to 8-h working day) varied from 75.6-83.1 dB (mean: 79.4 dB). The significant post-exposure reductions of TEOAE amplitudes (approx. 0.7 dB) both for the total response and frequency bands of 2000 and 3000 Hz were noted. However, there were no significant differences between pre- and postexposure reproducibility of TEOAE. CONCLUSIONS: Obtained results have confirmed that orchestral musicians are at risk of hearing loss due to their professional activities, even at exposures to orchestral noise less than the limit values for occupational noise. PMID- 26536966 TI - [Assessment of vocal intensity in lecturers depending on acoustic properties of lecture rooms]. AB - BACKGROUND: Lombard's effect increases the level of vocal intensity in the environment, in which noise occurs. This article presents the results of the author's own study of vocal intensity level and A-weighted sound pressure level of background noise during normal lectures. The aim of the study was to define whether above-mentioned parameters depend on acoustic properties of rooms (classrooms or lecture rooms) and to define how many lectors speak with raised voice. MATERIAL AND METHODS: The study was performed in a group of 50 teachers and lecturers in 10 classrooms with cubature of 160-430 m3 and reverberation time of 0.37-1.3 s (group A consisted of 3 rooms which fulfilled, group B consisted of 3 rooms which almost fulfilled and group C consisted of 4 rooms which did not fulfill criteria based on reverberation time (maximum permissible value is 0.6 0.8 s according to PN-B-02151-4:2015). Criteria of raising voice were based on vocal intensity level (maximum value: 65 dB according to EN ISO 9921:2003). The values of above-mentioned parameters were determined from modes of A--weighted sound pressure level distributions during lectures. RESULTS: Great differentiation of vocal intensity level between lectors was found. In classrooms of group A lectors were not using raised voice, in group B--21%, and in group C- 60% of lectors were using raised voice. CONCLUSIONS: It was observed that acoustic properties of classrooms (defined by reverberation time) exert their effect on lecturer's vocal intensity level (i.e., raising voice), which may contribute to the increased risk of vocal tract illnesses. The occurrence of Lombard's effect in groups of teachers and lecturers, conducting lectures in rooms, was evidenced. PMID- 26536967 TI - [Influence of spectral interferences on the results of quartz determination by infrared spectrometry]. AB - BACKGROUND: Determination of quartz by Fourier transform infrared spectrometry (FTIR) is not specific: the obtained results are influenced by matrix components, some of which cause spectral interference. The aim of the study was to evaluate the effect of dust components responsible for spectral interference with quartz on the results of its determinations, and to develop methods to minimize the effects of interferences. MATERIAL AND METHODS: Investigation of interferent effects were conducted using respirable dusts: quartz SRM 1878a, cristobalite SRM 1879a, synthetic amorphous silica (Zeosil) and feldspar, albite and kaolinite. For the study 17 mixtures with quartz and interferents at concentrations from 10 to 90% were prepared. Determinations of quartz were carried out by the KBr disc method. RESULTS: In mixtures of quartz with interferents, the results based on bands 798-779 cm-1 were overestimated by 10-55%, while those based on band 695 cm 1 were closer to the true content of quartz. It was found that the best methods able to decrease the impact of spectral interference are: scaled subtraction of IR spectra of feldspar or kaolinite analysed in nonashed samples, correction curve for kaolinite also investigated in nonashed samples with quartz-content calculation based on band 695 cm-1 in mixtures with cristobalite, amorphous silica or kaolinite in ashed samples. CONCLUSIONS: The study indicates the need to identify spectral interferences in dust when determining crystalline silica by FT-IR and to take actions to minimize their impact on the obtained results. PMID- 26536968 TI - [Fibers as carriers of microbial particles]. AB - BACKGROUND: The aim of the study was to assess the ability of natural, synthetic and semi-synthetic fibers to transport microbial particles. MATERIAL AND METHODS: The simultaneously settled dust and aerosol sampling was carried out in 3 industrial facilities processing natural (cotton, silk, flax, hemp), synthetic (polyamide, polyester, polyacrylonitrile, polypropylene) and semi-synthetic (viscose) fibrous materials; 2 stables where horses and sheep were bred; 4 homes where dogs or cats were kept and 1 zoo lion pavilion. All samples were laboratory analyzed for their microbiological purity. The isolated strains were qualitatively identified. To identify the structure and arrangement of fibers that may support transport of microbial particles, a scanning electron microscopy analysis was performed. RESULTS: Both settled and airborne fibers transported analogous microorganisms. All synthetic, semi-synthetic and silk fibers, present as separated threads with smooth surface, were free from microbial contamination. Natural fibers with loose packing and rough surface (e.g., wool, horse hair), sheaf packing and septated surface (e.g., flax, hemp) or present as twisted ribbons with corrugated surface (cotton) were able to carry up to 9*10(5) cfu/g aerobic bacteria, 3.4*10(4) cfu/g anaerobic bacteria and 6.3*10(4) cfu/g of fungi, including pathogenic strains classified by Directive 2000/54/EC in hazard group 2. CONCLUSIONS: As plant and animal fibers are contaminated with a significant number of microorganisms, including pathogens, all of them should be mechanically eliminated from the environment. In factories, if the manufacturing process allows, they should be replaced by synthetic or semi-synthetic fibers. To avoid unwanted exposure to harmful microbial agents on fibers, the containment measures that efficiently limit their presence and dissemination in both occupational and non-occupational environments should be introduced. PMID- 26536969 TI - [Mental health status of drivers--Motor vehicle accidents perpetrators]. AB - BACKGROUND: This study aimed at exploring the phenomenon of motor vehicle accidents (MVA). The following research questions were addressed: what are the immediate reactions to accidents among MVA perpetrators, do MVA perpetrators develop posttraumatic stress symptoms, and what are the differences between high and low symptomatic signs in terms of socio-demographics and accident features? MATERIAL AND METHODS: Post-traumatic stress disorder (PTSD) questionnaire by Watson et al. in the Polish adaptation was applied to assess PTSD and its subclinical symptoms. The information on the MVA nature, declared MVA causes, drivers' reactions after MVA, as well as on the age, education and history of driving in the study group was collected. The results of psychological examination obtained from 209 MVA perpetrators were analyzed. The examination took place at least 1 month after the accident. RESULTS: In 1/3 of the study group no physiological reactions were observed directly after the accident, while 46% of respondents experienced trembling and shaking and about 30% of subjects were crying or having tears in their eyes. Compassion for the injured and victims, guilt, helplessness and fear were the most common among immediate psychological reactions related to the accident. On the day of psychological examination 11.2% of drivers met diagnostic criteria for PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV). Drivers showing low and high PTSD symptoms did not differ in terms of age, education, and subjective perception of accident cause. Women were significantly overrepresented it the group meeting the diagnostic criteria for PTSD. CONCLUSIONS: The results of the study indicate the need to carry on systematic screening for mental health problems in drivers involved in serious MVA as a part of strategy for improving road safety. PMID- 26536970 TI - [Serum cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE ) and cytochrome c oxidase (COX) in copper mine miners potentially expose d to hydrogen sulfide]. AB - BACKGROUND: The aim of the study was to evaluate serum levels of the target enzyme for H2S toxicity--cytochrome c oxidase (COX) and enzymes involved in the synthesis of H2S--cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) in copper mine miners. MATERIAL AND METHODS: The initial and basic study was conducted respectively in 237 and 88 miners, working in 2 mining shafts: I- no H2S emissions recorded in the last 10 years (study group A) and II--H2S emissions occurred (study group B). A medical examination was performed and 10 ml of blood was collected from miners immediately after exiting the mine. RESULTS: There were no clinical or biochemical changes typical for H2S toxicity. Sulfhemoglobine was undetectable and there were no changes in the red-ox system. However, in group B, regulatory changes were found; a tendency to higher concentration of CBS and CSE, a higher activity of angiotensin converting enzyme (ACE) compared to group A (p<0.05) and a linear relationship between ACE and CSE (r=0.6927; p<0.001). It has been shown that cigarette smoking decreases COX (p<0.05), however, in miners working in shaft II, the decreased level of COX may result also from the presence of H2S in the gaseous emissions. CONCLUSIONS: COX concentration can be a sensitive indicator of exposure to H2S. The measurements of blood H2S concentrations carried out in workplaces should explain the cause of the changes observed in the COX, CBS and CSE activity. PMID- 26536971 TI - [Nurses' professionalism as a component of evaluation of parents/caregivers satisfaction with nursing care]. AB - BACKGROUND: Professionalism in nursing means the provision of medical and nursing services based on the best knowledge and skills, as well as on great responsibility for the undertaken actions. The opinions of patients and their families concerning professionalism, reflected in the level of satisfaction, contribute to the improvement of the quality of services offered. MATERIAL AND METHODS: The study covered 120 parents/caregivers of children hospitalized in a pediatric ward. Diagnostic survey method was applied in the research. The standardized questionnaire for evaluation of the level of parents/caregivers satisfaction with nursing care (Latour et al.) adjusted to the conditions of Polish pediatric hospital services and subjected to validation was adopted as a research tool. Statistical analysis was performed using the Mann-Whitney U test and Kruskal-Wallis test. A value of p<=0.05 was considered to indicate statistical significance. The respondents were selected at random. The parents/caregivers received the questionnaire the day before the child's discharge. RESULTS: The parents/caregivers generally evaluated the professionalism of nursing care in positive terms (4.3). They expressed higher satisfaction with respect showed by nurses for patients (4.7), while lower satisfaction with nurses introducing themselves (3.2). A high level of satisfaction was obtained with respect to the parents/caregivers' opinions pertaining to cooperation within a therapeutic team (4.6), organization of nurses' work (4.6), and quality of nursing care (4.6). CONCLUSIONS: Parents/caregivers expressed their satisfaction with the professionalism of nursing care. Education of respondents, frequency and reasons for hospitalization among children proved to be the variables that significantly differed the opinions of parents/caregivers concerning the selected criteria for professionalism of nursing care. No correlation was found between the duration of hospitalization, children's age, place of parents/caregivers residence, and the level of satisfaction with professionalism of nursing care. PMID- 26536972 TI - [Occurrence of radon in the Polish underground tourist routes]. AB - BACKGROUND: There are about 200 underground tourist routes in Poland. There are caves, mines or underground structures. This paper presents the results of the research intended to identify the extent of the occurrence of radon concentrations in underground areas of tourist routes. MATERIAL AND METHODS: We conducted the measurement of periodic concentrations of radon (1-2 months) in the summer using type Tastrak trace detectors. We determined the average concentrations of radon in air in 66 underground tourist routes in Poland. RESULTS: The research results comprise 259 determinations of average radon concentrations in 66 routes. The arithmetic average of the results was 1610 Bqm 3, and the maximum measured concentration was over 20,000 Bqm-3. The minimum concentration was 100 Bqm-3 (threshold method) considering the arithmetic average of the measurements. It was found that in 67% of the routes, the average concentration of radon has exceeded 300 Bqm-3 and in 22 underground routes it exceeded 1000 Bqm-3. CONCLUSIONS: Radon which occurs in many Polish underground tourist routes may be an organizational, legal and health problem. It is necessary to develop a program of measures to reduce radon concentrations in underground routes, especially routes located in the former mines. PMID- 26536973 TI - [The type of employment contract and employees' health and occupational functioning--The review of studies]. AB - From over 2 decades intensive research concerning temporary workers has been carried out in Europe and outside Europe. Despite having the highest rate of temporary workers in Europe, the studies on this topic are very rare in Poland. The aim of the study was to review the existing research on the relations between temporary work and employees' health and occupational functioning. The main conclusion from this review is that there is a significant inconsistency between the results of the studies included in this review due to such factors as heterogeneity of the group "temporary workers," cultural and generational differences between temporary workers, as well as different economic context in which those studies had been carried out. The main recommendations for the future research is thus to take into account the personal preferences for performing temporary work and to use more complex study design. PMID- 26536974 TI - [New sector of employment--a review of data on nanoproduction, research and development in the field of nanotechnology in Poland]. AB - Nanotechnology is currently one of the fastest developing areas of science, focusing on the design, manufacture and use of nanomaterials. The term "nanomaterial" means any product made of nanometer-size (1-100 nm) structures. Due to the small size and unique properties of the applied nanomaterials there is a growing interest in their aplication in various fields of industry and science. In Poland, there are very few companies that carry on nanotechnology activities. Research institutes, universities and research units of the Polish Academy of Sciences predominate in these activities. PMID- 26536975 TI - [Selected work-related nephropathies]. AB - Infections, high temperature and many of the toxic substances can cause kidney damage. Acute kidney injury is a well known complication of some work-related diseases, e.g., lead intoxication. Chronic kidney disease can also be caused by some occupational factors. Three work-related nephropathies, in which causal connection with work has been proved, are discussed in this article. There are different risk factors of nephrolithiasis, lead nephropathy and silica nephropathy, but each of them can cause chronic kidney disease. Prevention of these nephropaties seems to be relatively simple. The principles of protection from the toxic effects of heavy metals and silica dust are very specific. The most important prevention of kidney stones is correct fluid intake. In addition to providing adequate quantities of drinking water, it is also important to educate exposed workers and assure enough rest breaks at work. PMID- 26536976 TI - [Good practice in occupational health services--Certification of stroke as an accident at work. Need for secondary prevention in people returning to work after acute cerebrovascular events]. AB - The classification of an acute vascular episode, both heart infarct and stroke, as an accident at work poses difficulties not only for post accidental teams, but also to occupational health professionals, experts and judges at labor and social insurance courts. This article presents the case of a 41-year-old office worker, whose job involved client services. While attending a very aggressive customer she developed solid stress that resulted in symptoms of the central nervous system (headache, speech disturbances). During her hospitalisation at the neurological unit ischemic stroke with transient mixed type aphasia was diagnosed. Magnetic resonance imaging (MRI) scan of the head revealed subacute ischemia. After an analysis of the accident circumstances, the employer's post accidental team decided that ischemic stroke had been an accident at work, because it was a sudden incident due to an external cause inducing work-related traumatic stroke. As a primary cause tough stress and emotional strain due to the situation developed while attending the customer were acknowledged. During control medical check up after 5 months the patient was found to be fit for work, so she could return to work. However, it should be noted that such a check up examination of subjects returning to work after stroke must be holistic, including the evaluation of job predispositions and health education aimed at secondary prevention of heart and vascular diseases with special reference to their risk factors. PMID- 26536977 TI - Immune-mediated Skin Inflammation is Similar in Severe Atopic Dermatitis Patients With or Without Filaggrin Mutation. AB - Inflammatory cytokines can impair the skin barrier, but the question as to whether barrier alterations affect keratinocyte immune responses remains unanswered. The aim of this study was to investigate whether immune-mediated skin inflammation differs between severe atopic dermatitis patients with or without filaggrin mutation. The levels of filaggrin, inflammatory T helper 2 polarizing cytokines (thymic stromal lymphopoietin (TSLP) and interleukin 33 (IL-33)) and chemokine (C-C motif) ligand 27 (CCL27), histological severity markers, T and dendritic cell counts in biopsies from lesional skin of severe atopic dermatitis patients with and without filaggrin mutation and healthy skin were quantified by immunohistochemistry. The results were confirmed by quantitative PCR analyses. No significant differences were found between the 2 patient groups. Expression of atopic dermatitis-specific cytokines showed significant correlation with histological severity. These findings suggest that the immune-mediated skin inflammation (represented by keratinocyte-derived factors, T cell and dendritic cell counts) is similar in the 2 patient groups with severe atopic dermatitis, and that immune activation is connected to the severity of the disease rather than to the origin of barrier alterations. PMID- 26536978 TI - Biophysical and economic water productivity of dual-purpose cattle farming. AB - This study analyzes key factors influencing water productivity in cattle rearing, particularly in contexts characterized by water scarcity. This was done through year-round monitoring of on-farm practices within five smallholder farms located in the Saiss area (northern Morocco). The on-farm monitoring protocol consisted of characterizing: (i) volumes of water used for fodder production and distinguished by source (rainfall, surface irrigation and groundwater), (ii) virtual water contained in off-farm feed resources, (iii) total forage biomass production, (iv) dietary rations fed to lactating cows and their calves and (v) milk output and live weight gain. Findings reveal a mean water footprint of 1.62+/-0.81 and 8.44+/-1.09 m3/kg of milk and of live weight gain, respectively. Groundwater represented only 13.1% and 2.2% of the total water used to get milk and live weight gain, respectively, while rainfall represented 53.0% and 48.1% of the total water for milk and live weight gain, respectively. The remaining water volumes used came from surface irrigation water (7.4% for milk and 4.0% for live weight gain) and from virtual water (26.5% for milk and 44.7% for live weight gain). The results also revealed a relatively small gross margin per m3 of water used by the herd, not exceeding an average value of US $ 0.05, when considering both milk and live weight. Given the large variability in farm performances, which affect water productivity in cattle rearing throughout the production process, we highlight the potential for introducing a series of interventions that are aimed at saving water, while concurrently improving efficiency in milk production and live weight gain. These interventions should target the chain of production functions that are implemented throughout the process of water productivity in cattle rearing. Moreover, these interventions are of particular importance given our findings that livestock production depends largely upon rainfall, rather than groundwater, in an area afflicted with sustained droughts, overexploitation of groundwater resources and growing water scarcity. PMID- 26536979 TI - Cardiovascular Autonomic Dysfunction in Patients with Morbid Obesity. AB - BACKGROUND: Morbid obesity is directly related to deterioration in cardiorespiratory capacity, including changes in cardiovascular autonomic modulation. OBJECTIVE: This study aimed to assess the cardiovascular autonomic function in morbidly obese individuals. METHODS: Cross-sectional study, including two groups of participants: Group I, composed by 50 morbidly obese subjects, and Group II, composed by 30 nonobese subjects. The autonomic function was assessed by heart rate variability in the time domain (standard deviation of all normal RR intervals [SDNN]; standard deviation of the normal R-R intervals [SDNN]; square root of the mean squared differences of successive R-R intervals [RMSSD]; and the percentage of interval differences of successive R-R intervals greater than 50 milliseconds [pNN50] than the adjacent interval), and in the frequency domain (high frequency [HF]; low frequency [LF]: integration of power spectral density function in high frequency and low frequency ranges respectively). Between-group comparisons were performed by the Student's t-test, with a level of significance of 5%. RESULTS: Obese subjects had lower values of SDNN (40.0 +/- 18.0 ms vs. 70.0 +/- 27.8 ms; p = 0.0004), RMSSD (23.7 +/- 13.0 ms vs. 40.3 +/- 22.4 ms; p = 0.0030), pNN50 (14.8 +/- 10.4 % vs. 25.9 +/- 7.2%; p = 0.0061) and HF (30.0 +/- 17.5 Hz vs. 51.7 +/- 25.5 Hz; p = 0.0023) than controls. Mean LF/HF ratio was higher in Group I (5.0 +/- 2.8 vs. 1.0 +/- 0.9; p = 0.0189), indicating changes in the sympathovagal balance. No statistical difference in LF was observed between Group I and Group II (50.1 +/- 30.2 Hz vs. 40.9 +/- 23.9 Hz; p = 0.9013). CONCLUSION: morbidly obese individuals have increased sympathetic activity and reduced parasympathetic activity, featuring cardiovascular autonomic dysfunction. PMID- 26536980 TI - Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio are Predictors of Heart Failure. AB - BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are inflammatory markers used as prognostic factors in various diseases. The aims of this study were to compare the PLR and the NLR of heart failure (HF) patients with those of age-sex matched controls, to evaluate the predictive value of those markers in detecting HF, and to demonstrate the effect of NLR and PLR on mortality in HF patients during follow-up. METHODS: This study included 56 HF patients and 40 controls without HF. All subjects underwent transthoracic echocardiography to evaluate cardiac functions. The NLR and the PLR were calculated as the ratio of neutrophil count to lymphocyte count and as the ratio of platelet count to lymphocyte count, respectively. All HF patients were followed after their discharge from the hospital to evaluate mortality, cerebrovascular events, and re-hospitalization. RESULTS: The NLR and the PLR of HF patients were significantly higher compared to those of the controls (p < 0.01). There was an inverse correlation between the NLR and the left ventricular ejection fraction of the study population (r: -0.409, p < 0.001). The best cut off value of NLR to predict HF was 3.0, with 86.3% sensitivity and 77.5% specificity, and the best cut-off value of PLR to predict HF was 137.3, with 70% sensitivity and 60% specificity. Only NLR was an independent predictor of mortality in HF patients. A cut-off value of 5.1 for NLR can predict death in HF patients with 75% sensitivity and 62% specificity during a 12.8-month follow-up period on average. CONCLUSION: NLR and PLR were higher in HF patients than in age sex matched controls. However, NLR and PLR were not sufficient to establish a diagnosis of HF. NLR can be used to predict mortality during the follow-up of HF patients. PMID- 26536981 TI - Can heart rate turbulance be used to assess stable coronary artery disease and its severity? PMID- 26536982 TI - Protective effect of elevated bilirubin levels on cardiovascular disease in patients with Gilbert syndrome. PMID- 26536983 TI - Heart rate turbulence in patients with stable coronary artery disease and its relationship with the severity of the disease. AB - OBJECTIVE: Heart rate turbulence (HRT) indicates the impairment of cardiac autonomic function. With the literature containing insufficient information on HRT in stable coronary artery disease (CAD), this study aimed to investigate the role of HRT in patients with stable CAD. METHODS: The study included 58 patients (mean age: 58.9 +/- 10.0 years; 25 male) with documented CAD and demonstrating ventricular premature complexes on Holter monitoring, and a control group of 52 patients (mean age: 55.9 +/- 9.3 years; 36 male) with no history of CAD and demonstrating ventricular premature complexes. HRT parameters such as turbulence onset (TO) and slope (TS) were analyzed. Angiographic Gensini score were used to evaluate CAD severity. RESULTS: There was a significant difference in HRT parameters between the 2 groups. TO: 0.47 +/- 1.52% vs. -1.61 +/- 2.0% (p=0.001) and TS: 4.7 +/- 3.0 vs. 6.4 +/- 3.7 ms/RR (p=0.009) in patients with CAD and control group respectively. Given also that TO >= 0% and TS <= 2.5 ms/ RR values are considered abnormal, there was significant difference between the two groups; TO abnormal: 27 patients (46.6%) vs. 7 patients (13.5%), p=0.001, and TS abnormal: 15 patients (25.9%) vs. 4 patients (7.7%), (p=0.004) in CAD patients and control group respectively. A positive correlation was detected between TO and Gensini score (r=0.282, p=0.001) and a negative correlation detected between TS and Gensini score (r=-0.287, p=0.001). CONCLUSION: The study demonstrated that HRT variables are impaired in patients with stable CAD when compared to those in the control group, and that these variables also correlate with severity of CAD. PMID- 26536984 TI - Evaluation of aortic stiffness in Gilbert syndrome patients: a protective effect of elevated bilirubin levels. AB - OBJECTIVE: Gilbert's syndrome (GS) is an autosomal recessive disease that is characterized by an increase in indirect bilirubin (IB). The incidence of atherosclerotic heart disease is decreased in GS. This study aimed to investigate the relation between pulse wave velocity (PWV) and the presence of GS. METHODS: The study included 58 GS patients (32 females, age; 27.12 +/- 7.27 years, 26 males, age; 26.63 +/- 5.84 years) admitted to the internal medicine clinic of the hospital. The control group included 58 healthy individuals (35 females [27.33 +/ 8.06 years old, p=0.716] and 23 males [27.38 +/- 6.91 years old, p=0.923]). PWV of both groups was measured from the right carotid and femoral arteries. RESULTS: Mean age of the GS group was 26.03 +/- 8.22 years, while that of the healthy group was 26.60 +/- 5.84 years. The GS group's diastolic blood pressure and PWV were significantly lower than those of the control group: 67.76 +/- 8.59 mmHg vs 71.72 +/- 7.28 mmHg; p=0.008, and 5.63 +/- 1.12 m/s vs 6.18 +/- 1.22 m/s; p=0.014 respectively. The GS group's high density lipoprotein (HDL) level was significantly higher than that of the control group: 1.4 +/- 0.3 mmol/L vs 1.2 +/ 0.3 mmol/L, p=0.029. CONCLUSION: This study found PWV among GS patients to be lower than that among non-smoking and aged-matched healthy controls. PMID- 26536985 TI - The use of flecainide in critical neonates and infants with incessant supraventricular tachycardias. AB - OBJECTIVE: This study aimed to evaluate the efficacy of flecainide therapy in neonates and infants with drug resistant incessant supraventricular tachycardia. METHODS: The study included 11 neonates and infants who received medical and/or ablation therapy between January 2010 and December 2013. Mean patient age and weight were 101.6 +/- 96 days and 5.3 +/- 1.9 kg respectively. Of the 12 patients, 5 underwent ablation between January 2010 and December 2011, and 6 were treated medically between January 2012 and December 2013. Mean follow-up time was 18 months (6 months-4 years). RESULTS: The antiarrhythmic agent flecainide only became available in Turkey in 2012, and the most noteworthy point was its addition to the therapy administered prior to ablation (adenosine, esmolol propranolol, propafenone, amiodarone and cardioversion). In all 6 patients admitted between January 2012 and December 2013, refractory SVT was successfully treated with the administration of a triple therapy regimen of esmolol propranolol, amiodarone and flecainide. One patient with myocarditis developed an atrial flutter complicated by a concealed accessory pathway and was put on extracorporeal membrane oxygenation (ECMO) support due to cardiopulmonary failure. The SVT was terminated, but the patient died on the fifteenth day of ECMO support. One patient with recurrent tachycardia, who had previously undergone ablation for a complex cardiac anomaly and Wolf-Parkinson-White syndrome, was treated with ablation again. No recurrence of tachycardia was observed in any of the other 9 patients. CONCLUSION: It appears that the use of propranolol-esmolol and amiodarone combined with flecainide in the medical treatment of drug-resistant SVT may reduce the need for ablation in critical neonates and infants. PMID- 26536986 TI - Relationship between red cell distribution width and contrast-induced nephropathy in patients who underwent primary percutaneous coronary intervention. AB - OBJECTIVE: This study evaluated the relationship between contrast-induced nephropathy (CIN) and red cell distribution width (RDW) in patients who underwent primary percutaneous coronary intervention (PCI). METHODS: A total of 359 patients with ST elevation myocardial infarction (STEMI) who had undergone primary PCI were included in the study. An increase of 25% in serum creatinine value after 48 h, or an increase of >0.5 mg/dL in the basal value was defined as CIN. RESULTS: Of the patients included in the study, 49 (13.8%) developed CIN. Compared to the CIN-negative group, CIN-positive patients had increased RDW values (16.9 +/- 2.00 and 14.8 +/- 2.14 respectively, p<0.001). The latter were also older patients, and had increased age rates of diabetes mellitus, baseline creatinine, ?-creatinine and amount of contrast media were higher and left ventricular ejection fraction and baseline glomerular filtration rate (GFR) were lower in the CIN-positive group than in the CIN-negative group. A statistically weak correlation was found between RDW and change in creatinine levels (? creatinine) (r=0.250, p=0.002). Diabetes mellitus (odds ratio [OR]: 3.252, 95% CI=1.184-8.951, p=0.022), high RDW (OR: 1.716, 95% CI=1.363-2.157, p<0.001), baseline low GFR (OR: 0.941, 95% CI=0.925-0.971, p<0.001), ?-creatinine (OR: 1.197, 95% CI=1.061-2.986, p=0.006) and increased amount of contrast media (OR: 1.187, 95% CI=1.048-3.02, p=0.001) used were observed as independent predictors of CIN. CONCLUSION: The study found diabetes mellitus, high RDW, basal low GFR, ? creatinine and increased contrast amount used to be the independent predictors of CIN in STEMI patients who underwent PCI. PMID- 26536987 TI - The relationship between epicardial adipose tissue and P wave and QT dispersions. AB - OBJECTIVE: Epicardial adipose tissue (EAT) secretes various pro-inflammatory and atherogenic mediators that have several endocrine and paracrine effects on heart. This study investigated the influence of EAT on QT and P wave dispersions (QTd, PWd), as simple, non-invasive tools of proarrhythmia on surface ECG. METHODS: This was a cross-sectional study and included 70 patients with normal coronary arteries who underwent 12-derivation electrocardiography, echocardiography and biochemical examinations in order for QTd, PWd, and EAT thickness to be measured. RESULTS: Median EAT thickness was 4.1 mm. Correlation analyses revealed that EAT was significantly associated with age (r=0.412, p<0.001), weight (r=0.262, p=0.028), body mass index (r=0.396, p<0.001), left atrium diameter (r=0.518, p<0.001), fasting plasma glucose (r=0.245, p=0.041), maximum P wave duration (r=0.343, p=0.004), minimum P wave duration (r=0.275, p=0.021) and PWd (r=0.265, p=0.026). No relation was found between study parameters and QTd. However, P wave dispersion was significantly related to EAT thickness (r=0.265, p=0.026), left atrium diameter (r=0.483, p<0.001), and the triglyceride levels (r=0.267, p=0.028). Multiple linear regression analyses revealed left atrial diameter as the only independent predictor of PWd. CONCLUSION: A significant association between EAT and PWd was demonstrated in the study. While EAT is related to both increased PWd and left atrial size, left atrial diameter seems to be more important than EAT for prediction of atrial fibrillation (AF) in patients with normal coronary arteries. PMID- 26536988 TI - [Evaluation of post-operative flow and diameter changes in brachial and ulnar arteries in coronary artery bypass surgery patients in which the radial artery is used as graft]. AB - OBJECTIVE: The radial artery is widely used in coronary bypass surgery. In these patients, forearm and hand circulation is provided by the ulnar artery. This study aimed to investigate post-operative changes in flow and diameter in brachial and ulnar arteries in patients undergoing coronary bypass surgery in which the radial artery is used as graft. METHODS: Between September 2007 and September 2008, 20 patients (16 men, 4 women; mean age 57.8 years; range 44 to 70 years) underwent elective coronary bypass surgery at our clinic. The radial artery was used as graft in all cases. Pre-operatively, adequacy of the ulnar artery for forearm circulation was investigated by Allen test and duplex ultrasonography. Basal flow and diameter values of the brachial and ulnar arteries were measured. Control duplex ultrasound measurements were performed at three months post-operatively. Flow and diameter changes in the brachial and ulnar arteries were recorded. RESULTS: Significant increase was shown in ulnar artery flow and diameter values in post-operative measurements. A significant increase was observed in brachial artery diameter, accompanied by a relative decrease in flow value. There were no mortality or ischemic complications in our study. Transient paresthesia as a neurological complication was observed in 4 patients. CONCLUSION: Radial artery use for coronary bypass surgery leads to significant changes in ulnar and brachial arteries. All flow and diameter changes can be detected by color Doppler ultrasonography in the early stages. These adaptation mechanisms show that the radial artery can be safely harvested as graft material. PMID- 26536989 TI - Resistant spontaneous coronary artery spasm. AB - Coronary artery spasm should always be suspected in patients who have myocardial infarction with normal coronary arteries. This case report presents a 33-year-old woman with anterior myocardial infarction, whose coronary angiograph revealed normal left anterior descending artery and new onset complete occlusion of the circumflex artery at the time of the procedure. Nitroglycerin up to 800 mcg was administered without success. In such resistant cases, when all efforts fail, including prompt recognition and application of vasodilator drugs, retracting the catheter and waiting may play a role. PMID- 26536990 TI - [Late development of double-chambered right ventricle after repair of a ventricular septal defect]. AB - Double-chambered right ventricle is a rare heart defect causing right ventricular outflow tract (RVOT) obstruction. In this malformation, the right ventricle is divided into two chambers by a fibromuscular band. A 12-year old female patient who had undergone repair of a ventricular septal defect at 5 months old was admitted to our hospital with complaints of dyspnea and fatigue. The patient was diagnosed with an isolated double-chambered right ventricle and surgical correction was successfully performed. Post-operative transesophageal echocardiography showed no residual gradients across the RVOT. Following an uneventful recovery, the patient was discharged five days after surgery. PMID- 26536991 TI - Arrhythmogenic right ventricular cardiomyopathy in monozygotic twin sisters, and persistent left superior vena cava in one complicating implantation of ICD. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized histologically by fibro-fatty replacement of heart muscle, and clinically by ventricular arrhythmias and right ventricular dysfunction. This report presents monozygotic twins with ARVC, suggesting a genetic abnormality as the most probable cause. PMID- 26536992 TI - A case of Mobitz type II atrioventricular block due to Nerium oleander poisoning successfully managed with digoxin-specific Fab antibody fragments. AB - Nerium oleander is a popular ornamental plant grown in many tropical and subtropical countries and in the Mediterranean region. It is dangerous because it has been shown to contain several types of cardiac glycosides, and hence can cause cardiac arrhythmias resembling digoxin in their toxicologic manifestations. We report a patient presenting to our hospital with Mobitz type II atrioventricular block after drinking herbal tea prepared from oleander leaves. Three hours after admission, a 200-mg empiric dose of digoxin-specific Fab antibody fragments was administered intravenously over 30 minutes. A 12-lead electrocardiogram (ECG) revealed sinus rhythm at the end of infusion. After 72 hours, the patient was discharged without any symptoms. PMID- 26536993 TI - A case of transcatheter aortic valve implantation complication with total femoral artery thrombosis due to failure of the ProStar device. AB - Vascular complications in transfemoral transcatheter aortic valve implantation are relatively frequent and there is increased morbidity and mortality risk in the procedure. This report presents successful surgical repair of a femoral artery thrombosis case following an implantation procedure. PMID- 26536994 TI - Volumetric and functional assessment of a left ventricular aneurysm from a single acquisition by three-dimensional speckle-tracking echocardiography (from the MAGYAR-Path Study). AB - Three-dimensional speckle-tracking echocardiography (3DSTE) is accepted as a reliable and feasible method in the quantification of left ventricular (LV) volumes, strains and rotational characteristics. This case aimed to demonstrate the diagnostic importance of 3DSTE in volumetric and functional assessment of an LV aneurysm. PMID- 26536995 TI - Case images: A rare variation in drainage of total anomalous pulmonary venous return. PMID- 26536996 TI - Case images: Successful treatment with anticoagulant therapy of a thrombus trapped in a patent foramen ovale in a patient with acute pulmonary embolism. PMID- 26536997 TI - Case images: Aortic valve papillary fibroelastoma presenting as transient ischemic attack. PMID- 26536998 TI - [Letter to the Editor: Evaluation of lead extraction procedures using the Evolution MechanicalDilatator Sheath lead extraction system: A single centre experience]. PMID- 26536999 TI - Letter to the Editor: What about pleiotropic modifiers of the pre-procedural pro inflammatory and pro-oxidant milieu in patients undergoing drug eluting stent implantation? PMID- 26537000 TI - A boron difluoride dye showing the aggregation-induced emission feature and high sensitivity to intra- and extra-cellular pH changes. AB - A novel AIE-active boron difluoride fluorescent probe P3T was designed and synthesized. P3T exhibited high sensitivity to intra- and extra-cellular pH changes. Furthermore, a Forster resonance energy transfer (FRET) system was constructed, where P3T acted as a donor fluorophore and DOX as the acceptor. PMID- 26537002 TI - Structural flexibility in crystallized matter: from history to applications. AB - The large reversible flexibility of hybrid crystallized matter is relatively new. After briefly recalling the history of this discovery, the article will analyze the different parameters influencing this phenomenon. They relate first to the various structural characteristics of the framework, in both its inorganic and organic parts. The influence of the energies of the guest-guest and host-guest interactions is then analyzed. Once the reasons are explained, a third section will be devoted to the various physical properties of these flexible solids. The last section concerns recent industrial applications of this family of solids. PMID- 26537003 TI - Biochar-amended potting medium reduces the susceptibility of rice to root-knot nematode infections. AB - BACKGROUND: Biochar is a solid coproduct of biomass pyrolysis, and soil amended with biochar has been shown to enhance the productivity of various crops and induce systemic plant resistance to fungal pathogens. The aim of this study was to explore the ability of wood biochar to induce resistance to the root-knot nematode (RKN) Meloidogyne graminicola in rice (Oryza sativa cv. Nipponbare) and examine its histochemical and molecular impact on plant defense mechanisms. RESULTS: A 1.2 % concentration of biochar added to the potting medium of rice was found to be the most effective at reducing nematode development in rice roots, whereas direct toxic effects of biochar exudates on nematode viability, infectivity or development were not observed. The increased plant resistance was associated with biochar-primed H2O2 accumulation as well as with the transcriptional enhancement of genes involved in the ethylene (ET) signaling pathway. The increased susceptibility of the Ein2b-RNAi line, which is deficient in ET signaling, further confirmed that biochar-induced priming acts at least partly through ET signaling. CONCLUSION: These results suggest that biochar amendments protect rice plants challenged by nematodes. This priming effect partially depends on the ET signaling pathway and enhanced H2O2 accumulation. PMID- 26537004 TI - miR-377-dependent BCL-xL regulation drives chemotherapeutic resistance in B-cell lymphoid malignancies. AB - BACKGROUND: BCL-xL is an anti-apoptotic BCL-2 family protein that inhibits apoptosis and is overexpressed in many cancers. We have reported that acquired resistance to the BCL-2 inhibitor ABT-199 (venetoclax) is associated with increased BCL-xL expression. Yet, how BCL-xL mediates chemoresistance in hematopoietic malignancies is not clear. This finding may help in design of new strategies for therapeutic intervention to overcome acquired chemoresistance mediated by BCL-xL. RESULTS: We now show that the increased BCL-xL expression was inversely correlated with that of miR-377 in ABT-199-resistant cells. This finding was also extended to a panel of B-cell lymphoid lines and primary chronic lymphocytic leukemia (CLL) cells. miR-377 suppressed BCL-xL expression by recognizing two binding sites in the BCL-xL 3'-UTR. Mutation of these two miR-377 consensus-binding sites completely abolished its regulatory effect. Expression of a miR-377 mimic downregulated BCL-xL protein expression and significantly increased apoptotic cell death. Expression of a miR-377 inhibitor restored BCL-xL protein expression and limited cell death caused by the hypomethylating agent 5 azacytidine. Thus, miR-377-dependent BCL-xL regulation drives acquired therapeutic resistance to ABT-199. We further show that CLL patients who received a diverse array of chemotherapy regimens also had significantly higher BCL-xL and lower miR377 expression, indicating that exposure to chemotherapy might trigger transcriptional silencing of miR-377, which results in high levels of BCL-xL. Importantly, CLL patients with high BCL-xL/low miR-377 expression had an advanced tumor stage. Moreover, the high BCL-xL expression correlated with short treatment free survival in 76 CLL patients. miR-377 is located at 14q32 in the DLK1-DIO3 region, which encodes the largest tumor suppressor miRNA cluster in humans. Examination of five additional 14q32 miRNAs revealed that the majority were significantly down-regulated in most CLL patients as well as in ABT-199-resistant cell lines. Remarkably, four of these miRNAs had significantly decreased expression in chemotherapy-treated CLL patients as compared to those untreated. These findings indicate a reduced expression of multiple miRNAs that may reflect a global silencing of this miRNA cluster in therapy-resistant lymphoid cells. CONCLUSIONS: These findings reveal a novel mechanism by which down-regulation of miR-377 increases BCL-xL expression, promoting chemotherapy resistance in B-cell lymphoid malignancies. PMID- 26537005 TI - Completeness of T, N, M and stage grouping for all cancers in the Mallorca Cancer Registry. AB - BACKGROUND: TNM staging of cancer is used to establish the treatment and prognosis for cancer patients, and also allows the assessment of screening programmes and hospital performance. Collection of staging data is becoming a cornerstone for cancer registries. The objective of the study was to assess the completeness of T, N, M and stage grouping registration for all cancers in the Mallorca Cancer Registry in 2006-2008 and to explore differences in T, N, M and stage grouping completeness by site, gender, age and type of hospital. METHODS: All invasive cancer cases during the period 2006-2008 were selected. DCO, as well as children's cancers, CNS, unknown primary tumours and some haematological cases were excluded. T, N, M and stage grouping were collected separately and followed UICC (International Union Against Cancer) 7th edition guidelines. For T and N, we registered whether they were pathological or clinical. RESULTS: Ten thousand two hundred fifty-seven cases were registered. After exclusions, the study was performed with 9283 cases; 39.4 % of whom were women and 60.6 % were men. T was obtained in 48.6 % cases, N in 36.5 %, M in 40 % and stage in 37.9 %. T and N were pathological in 71 % of cases. Stage completeness exceeded 50 % in lung, colon, ovary and oesophagus, although T also exceeded 50 % at other sites, including rectum, larynx, colon, breast, bladder and melanoma. No differences were found in TNM or stage completeness by gender. Completeness was lower in younger and older patients, and in cases diagnosed in private clinics. CONCLUSIONS: T, N, M and stage grouping data collection in population-based cancer registries is feasible and desirable. PMID- 26537006 TI - Post resuscitation care--some words of caution and a call for action. AB - This fall the European Resuscitation Council (ERC) and the European Cardiology Society (ESC) publish updated post resuscitation care guidelines. For these guidelines to have an impact they must be implemented into daily clinical practice. Newer studies imply that differences in hospital care explain much of the observed differences in survival after out-of-hospital cardiac arrest. A recent Nordic (Denmark, Finland, Iceland, Norway, Sweden) survey suggests worrisome variations in post resuscitation care provided and should urge us all to act in the coming years. One important step will be to build up resuscitation systems with integrated cardiac arrest centres in all the 5 Nordic countries and benchmark process of care, financial implications and survival. PMID- 26537007 TI - Detection of a novel astrovirus from a black-naped monarch (Hypothymis azurea) in Cambodia. AB - BACKGROUND: Astroviruses are comprised of two genera with Avastrovirus infecting birds and Mamastrovirus infecting mammals. Avastroviruses have primarily been associated with infections of poultry, especially chicken, turkey, duck, and guineafowl production systems, but also infect wading birds and doves. Outcomes result in a spectrum of disease, ranging from asymptomatic shedding to gastroenteritis with diarrhea, stunting, failure to thrive and death. FINDINGS: Virological surveillance was conducted in birds from two sites in Cambodia in 2010. Samples were screened for influenza, astroviruses, coronaviruses, flaviviruses, and paramyxoviruses. A total of 199 birds were tested and an astrovirus was detected in a black-naped monarch (Hypothymis azurea). CONCLUSIONS: This is the first astrovirus detection in a passerine bird. Phylogenetic analysis and nucleotide distances suggest that this avastrovirus forms a distinct lineage and may constitute a fourth avastrovirus group. PMID- 26537008 TI - Updating contextualized clinical practice guidelines on stroke rehabilitation and low back pain management using a novel assessment framework that standardizes decisions. AB - BACKGROUND: Clinical practice guidelines need to be regularly updated with current literature in order to remain relevant. This paper reports on the approach taken by the Philippine Academy of Rehabilitation Medicine (PARM). This dovetails with its writing guide, which underpinned its foundational work in contextualizing guidelines for stroke and low back pain (LBP) in 2011. METHODS: Working groups of Filipino rehabilitation physicians and allied health practitioners met to reconsider and modify, where indicated, the 'typical' Filipino patient care pathways established in the foundation guidelines. New clinical guidelines on stroke and low back pain which had been published internationally in the last 3 years were identified using a search of electronic databases. The methodological quality of each guideline was assessed using the iCAHE Guideline Quality Checklist, and only those guidelines which provided full text references, evidence hierarchy and quality appraisal of the included literature, were included in the PARM update. Each of the PARM-endorsed recommendations was then reviewed, in light of new literature presented in the included clinical guidelines. A novel standard updating approach was developed based on the criteria reported by Johnston et al. (Int J Technol Assess Health Care 19(4):646-655, 2003) and then modified to incorporate wording from the foundational PARM writing guide. The new updating tool was debated, pilot-tested and agreed upon by the PARM working groups, before being applied to the guideline updating process. RESULTS: Ten new guidelines on stroke and eleven for low back pain were identified. Guideline quality scores were moderate to good, however not all guidelines comprehensively linked the evidence body underpinning recommendations with the literature. Consequently only five stroke and four low back pain guidelines were included. The modified PARM updating guide was applied by all working groups to ensure standardization of the wording of updated recommendations and the underpinning evidence bases. CONCLUSIONS: The updating tool provides a simple, standard and novel approach that incorporates evidence hierarchy and quality, and wordings of recommendations. It could be used efficiently by other guideline updaters particularly in developing countries, where resources for guideline development and updates are limited. When many people are involved in guideline writing, there is always the possibility of 'slippage' in use of wording and interpretation of evidence. The PARM updating tool provides a mechanism for maintaining a standard process for guideline updating processes that can be followed by clinicians with basic training in evidence-based practice principles. PMID- 26537009 TI - Impact of chrysosplenetin on the pharmacokinetics and anti-malarial efficacy of artemisinin against Plasmodium berghei as well as in vitro CYP450 enzymatic activities in rat liver microsome. AB - BACKGROUND: Artemisinin (ART) is an efficacious and safe anti-malarial drugs but has low oral bioavailability and auto-induction profiles during multiple dosing. The pharmacokinetic disadvantages have been found to partially depend on the induction of cytochrome P-450 enzymes by ART and resulted in the therapeutic failure due to insufficient drug levels. The present study, therefore, investigated the impacts of chrysosplenetin (CHR), a polymethoxylated flavonoid from Artemisia annua, on the pharmacokinetics and the anti-malarial efficacy of ART against Plasmodium berghei. The inhibition of CHR on enzymatic activity of CYP1A2, CYP2A, CYP2C19, CYP2D6, CYP2E1, and CYP3A in rat liver microsome was also investigated. IC50, Km, Ki, and inhibitory type of CHR were respectively calculated. METHODS: Twenty rats were randomly divided into four groups and received three-day oral doses of ART in absence or presence of CHR (in ratio of 1:0, 1:1, 1:2, and 1:4, respectively). Plasma samples were separately harvested for ART pharmacokinetics analysis using a valid liquid chromatography tandem mass spectrometric (LC-MS/MS) method. Female Kunming mice were inoculated by P. berghei K173 strain and pre-exposed to three-day oral administration of ART with or without CHR as pharmacokinetics protocol. Giemsa staining method was applied to calculate percent parasitaemia (%) and inhibition (%). In vitro rat liver microsomal model was employed to elucidate the inhibitory effect of CHR on CYP1A2, CYP2A, CYP2C19, CYP2D6, CYP2E1, and CYP3A. RESULTS: The AUC0-t, Cmax, and t 1/2 of ART increased significantly (P < 0.05 or P < 0.01) as well as declined CLz (P < 0.05 or P < 0.01) after three-day oral doses of ART in presence of CHR (1:2) when compared with ART alone. Also, parasitaemia (%) remarkably attenuated 1.59 folds with 1.63-fold augmented inhibition (%) when the ratio between ART and CHR reached 1:2. CHR itself had no anti-malarial efficacy (P > 0.05). CHR inhibited in vitro activity of CYP1A2 and CYP2C19 (P < 0.01, IC50 = 4.61 and 6.23 MUM) in a concentration-response manner. The inhibition did not emerge on CYP2E1 and CYP3A until the CHR concentration exceeded 4.0 MUM (P < 0.01, IC50 = 28.17 and 3.38 uM). CHR has no impact on CYP 2A and CYP2D6 (P > 0.05). The inhibition types of CHR on CYP1A2 and CYP3A belonged to noncompetitive and uncompetitive, respectively. CONCLUSIONS: Co-administration of ART with CHR in ratio of 1:2 achieved a synergic anti-malarial effect partly because of the noncompetitive or uncompetitive inhibition of CHR of drug-metabolism enzymes, especially CYP3A which is closely related to the auto-induction of ART. PMID- 26537010 TI - Stabilizer-Guided Inhibition of Protein-Protein Interactions. AB - The discovery of novel protein-protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compounds, which target different though proximal regions of the protein interface. In principle, protein-stabilizer complexes can guide the design of PPI inhibitors (and vice versa). In the present work, we combine X-ray crystallographic data from both stabilizer and inhibitor co-crystal complexes of the adapter protein 14-3-3 to characterize, down to the atomic scale, inhibitors of the 14-3-3/Tau PPI, a potential drug target to treat Alzheimer's disease. The most potent compound notably inhibited the binding of phosphorylated full-length Tau to 14-3-3 according to NMR spectroscopy studies. Our work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer-protein complexes while potentially enabling access to new synthetically tractable stabilizers of 14-3-3 and other PPIs. PMID- 26537011 TI - Non-alcoholic fatty liver disease fibrosis score in patients with psoriasis. AB - BACKGROUND: Patients with psoriasis are at risk of non-alcoholic fatty liver disease (NAFLD) and likely liver fibrosis. OBJECTIVE: Investigate the prevalence of NAFLD in patients with psoriasis and measure their risk of liver fibrosis. METHOD: One hundred and twenty-four patients with psoriasis and 79 healthy controls were included in this cross-sectional study. NAFLD was diagnosed in the presence of characteristic sonographic features of fatty liver after excluding other secondary causes of chronic liver disease. NAFLD fibrosis score (NAFLD-FS) was scored in those with NAFLD to measure the risk of advanced liver fibrosis. RESULTS: Prevalence of NAFLD was greater in patients with psoriasis than in controls (44% vs. 26%, P < 0.001). NAFLD-FS was higher in patients with psoriasis than in controls, suggesting a higher risk of liver fibrosis in those with psoriasis (-1.57 +/- 1.4 vs. -3.10 +/- 1.5, mean +/- SD, P < 0.0001). Psoriasis resulted in a significant predictor of advanced liver fibrosis independently of age, sex, BMI, hypertension and diabetes in the multivariate analysis. CONCLUSIONS: Patients with psoriasis should be screened for common causes of liver disease, including NAFLD and liver fibrosis. PMID- 26537012 TI - Patterns of blood component use in cirrhosis: a nationwide study. AB - BACKGROUND & AIMS: Cirrhosis is a complex acquired disorder of coagulation and frequent indication for transfusion of blood components. We characterised blood component use in patients with cirrhosis and compared this to transfusion guidelines. METHODS: All National Health Service trusts with representation on the British Society of Gastroenterology membership list were invited to take part. Data were collected prospectively on consecutive, unselected, hospitalised admissions with cirrhosis over 28 days. Detailed information was recorded for patients receiving blood components including indication (for bleeding or prophylaxis), type of component, laboratory indices triggering transfusion, complications, thromboembolic events and clinical outcome to day 28. RESULTS: Data on 1313 consecutive patients with cirrhosis were collected from 85 hospitals. A total of 391/1313 (30%) were transfused a blood component; in 238/391 (61%), this was for treatment of bleeding and in 153/391 (39%) for prophylaxis of bleeding. In 48/185 (26%) cases with bleeding, the haemoglobin threshold was >80 g/L prior to red blood cell transfusion. In the prophylaxis group, 238/391 (61%) received transfusion in response to an abnormal haematological value in the absence of any planned procedure. In patients transfused for procedural prophylaxis, 10/34 (29%) received fresh frozen plasma at an International Normalised Ratio lower than the threshold where a benefit would be anticipated. An in-patient thromboembolic event was recorded in 3% (35/1313) and 10% (138/1313) died by day 28. CONCLUSIONS: One-third of hospitalised patients with cirrhosis were transfused. Strategies for Patient Blood Management should include ensuring transfusion practice is consistent with guidelines and greater emphasis on alternatives to transfusion. PMID- 26537013 TI - Stress measurement among charge nurses: developing a cross-cultural tool. AB - AIM: The aim of this study was to develop a cross-cultural tool for the measurement of stress among charge nurses in general hospitals. BACKGROUND: Studies of the specific stressors unique to different nursing roles are few, particularly those related to hospital charge nurses. The Charge Nurse Stress Questionnaire is a well-validated Israeli-developed scale. However, it has not been tested cross-culturally. DESIGN: A descriptive methodological study was conducted in Israel, Ohio and Thailand. METHOD: A total of 2616 nurses from 23 hospitals (small to large size) completed the questionnaire between 2011-2013. The questionnaire was translated into English and Thai. To establish tool validity and reliability, content validity, internal consistency reliability, exploratory and confirmatory factor analysis were performed. RESULTS: Analyses resulted in a final abbreviated version of the questionnaire with 25 items and four stress subscales. Internal consistency for the subscales indicated very good internal consistency. CONCLUSIONS: We developed a self-reported, cross-cultural, valid and reliable tool for evaluating the specific stressors of the role of charge nurses. A rigorous assessment of charge nurse stress provides a good basis for planning tailored stress reduction interventions. It is recommended to further use the tool in different settings across different countries. PMID- 26537014 TI - Integrated patient and tumor genetic testing for individualized cancer therapy. AB - Tumor genome analysis is transforming cancer treatment by enabling identification of specific oncogenic drivers and selection of effective targeted agents. Meanwhile, patient genome analysis is being employed across therapeutic areas to inform selection of appropriate drugs and doses for treatment safety. Integration of patient genome analysis concurrent with preemptive tumor genetic testing will enable oncologists to make informed treatment decisions to select the right dose of the right drug for each patient and their tumor. PMID- 26537015 TI - NMR characterization of novel pyranoanthocyanins derived from the pulp of Panax quinquefolius L. (North American ginseng). AB - Three major pigments (one natural and two derived) were determined to be present in the berry pulp of Panax quinquefolius L. (North American ginseng). The first was a simple anthocyanin (pelargonidin 3-O-lathyroside) along with two novel pyranoanthocyanins, structurally similar to those recently discovered in Staghorn sumac. The three anthocyanins were structurally characterized using NMR (1 H, gCOSY, gHSQC, gHMBC, TOCSY, ROESY, and 13 C DEPTq135) and High Resolution MS. All three anthocyanins had the disaccharide lathyrose (2-O-(beta-D-xylopyranosyl) beta-D-galactopyranoside) attached at the 3-O position. In the tradition of naming novel anthocyanin aglycones based on botanical origin, the new pyranoanthocyanin aglycones have been given the common names Panaxidin A (pelaragonidin-4-vinylcatechol) and Panaxidin B (pelargonidin-4-vinylphenol). Copyright (c) 2015 Her Majesty the Queen in Right of Canada Magnetic Resonance in Chemistry (c) 2015 John Wiley & Sons, Ltd. PMID- 26537016 TI - What is the role of individual accountability in patient safety? A multi-site ethnographic study. AB - An enduring debate concerns how responsibility for patient safety should be distributed between organisational systems and individual professionals. Though rule-based, calculus-like approaches intended to support a 'just culture' have become popular, they perpetuate an asocial and atomised account. In this article, we use insights from practice theory--which sees organisational phenomena as accomplished in everyday actions, with individual agency and structural conditions as a mutually constitutive, dynamic duality--along with contributions from the political science and ethics literature as a starting point for analysis. Presenting ethnographic data from five hospitals, three in one high income country and two in low-income countries, we offer an empirically informed, normative rethinking of the role of personal accountability, identifying the collective nature of the healthcare enterprise and the extent to which patient safety depends on contributions from many hands. We show that moral responsibility for actions and behaviours is an irreducible element of professional practice, but that individuals are not somehow 'outside' and separate from 'systems': they create, modify and are subject to the social forces that are an inescapable feature of any organisational system; each element acts on the other. Our work illustrates starkly the structuring effects of the broader institutional and socioeconomic context on opportunities to 'be good'. These findings imply that one of the key responsibilities of organisations and wider institutions in relation to patient safety is the fostering of the conditions of moral community. PMID- 26537017 TI - Inference for correlated effect sizes using multiple univariate meta-analyses. AB - Multivariate meta-analysis, which involves jointly analyzing multiple and correlated outcomes from separate studies, has received a great deal of attention. One reason to prefer the multivariate approach is its ability to account for the dependence between multiple estimates from the same study. However, nearly all the existing methods for analyzing multivariate meta-analytic data require the knowledge of the within-study correlations, which are usually unavailable in practice. We propose a simple non-iterative method that can be used for the analysis of multivariate meta-analysis datasets, that has no convergence problems, and does not require the use of within-study correlations. Our approach uses standard univariate methods for the marginal effects but also provides valid joint inference for multiple parameters. The proposed method can directly handle missing outcomes under missing completely at random assumption. Simulation studies show that the proposed method provides unbiased estimates, well-estimated standard errors, and confidence intervals with good coverage probability. Furthermore, the proposed method is found to maintain high relative efficiency compared with conventional multivariate meta-analyses where the within study correlations are known. We illustrate the proposed method through two real meta-analyses where functions of the estimated effects are of interest. PMID- 26537018 TI - Neural representation of emotion regulation goals. AB - The use of top-down cognitive control mechanisms to regulate emotional responses as circumstances change is critical for mental and physical health. Several theoretical models of emotion regulation have been postulated; it remains unclear, however, in which brain regions emotion regulation goals (e.g., the downregulation of fear) are represented. Here, we examined the neural mechanisms of regulating emotion using fMRI and identified brain regions representing reappraisal goals. Using a multimethodological analysis approach, combining standard activation-based and pattern-information analyses, we identified a distributed network of lateral frontal, temporal, and parietal regions implicated in reappraisal and within it, a core system that represents reappraisal goals in an abstract, stimulus-independent fashion. Within this core system, the neural pattern-separability in a subset of regions including the left inferior frontal gyrus, middle temporal gyrus, and inferior parietal lobe was related to the success in emotion regulation. Those brain regions might link the prefrontal control regions with the subcortical affective regions. Given the strong association of this subsystem with inner speech functions and semantic memory, we conclude that those cognitive mechanisms may be used for orchestrating emotion regulation. Hum Brain Mapp 37:600-620, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26537019 TI - Genomics is changing personal healthcare and medicine: the dawn of iPH (individualized preventive healthcare). AB - This opinion piece focuses on the convergence of information technology (IT) in the form of personal monitors, especially smart phones and possibly also smart watches, individual genomic information and preventive healthcare and medicine. This may benefit each one of us not only individually but also society as a whole through iPH (individualized preventive healthcare). This shift driven by genomic and other technologies may well also change the relationship between patient and physician by empowering the former but giving him/her also much more individual responsibility. PMID- 26537020 TI - Ectomycorrhizal fungal mycelia turnover in a longleaf pine forest. AB - Elucidation of the patterns and controls of carbon (C) flow and nitrogen (N) cycling in forests has been hindered by a poor understanding of ectomycorrhizal fungal mycelia (EFM) dynamics. In this study, EFM standing biomass (based on soil ergosterol concentrations), production (based on ergosterol accrual in ingrowth cores), and turnover rate (the quotient of annual production and average standing biomass estimates) were assessed in a 25-yr-old longleaf pine (Pinus palustris) plantation where C flow was manipulated by foliar scorching and N fertilization for 5 yr before study initiation. In the controls, EFM standing biomass was 30 +/ 7 g m(-2) , production was 279 +/- 63 g m(-2) yr(-1) , and turnover rate was 10 +/- 3 times yr(-1) . The scorched * fertilized treatment had significantly higher EFM standing biomass (38 +/- 8 g m(-2) ), significantly lower production (205 +/- 28 g m(-2) yr(-1) ), and a trend of decreased turnover rate (6 +/- 1 times yr( 1) ). The EFM turnover estimates, which are among the first reported for natural systems, indicate that EFM are a dynamic component of ecosystems, and that conventional assessments have probably underestimated the role of EFM in C flow and nutrient cycling. PMID- 26537021 TI - Dual 4- and 5-phosphatase activities regulate SopB-dependent phosphoinositide dynamics to promote bacterial entry. AB - Salmonella are able to invade non-phagocytic cells such as intestinal epithelial cells by modulating the host actin cytoskeleton to produce membrane ruffles. Two type III effector proteins SopB and SopE play key roles to this modulation. SopE is a known guanine nucleotide exchange factor (GEF) capable of activating Rac1 and CDC42. SopB is a phosphatidylinositol 4-phosphatase and 5-phosphatase promoting membrane ruffles and invasion of Salmonella through undefined mechanisms. Previous studies have demonstrated that the 4-phosphatase activity of SopB is required for PtdIns-3-phosphate (PtdIns(3)P) accumulation and SopB mediated invasion. We show here that both the 4-phosphatase as well as the 5 phosphatase activities of SopB are essential in ruffle formation and subsequent invasion. We found that the 5-phosphatase activity of SopB is likely responsible for generating PtdIns-3,4-bisphosphate (PtdIns(3,4)P(2)) and subsequent recruitment of sorting nexin 9 (SNX9), an actin modulating protein. Intriguingly, the 4-phosphatase activity is responsible for the dephosphorylation of PtdIns(3,4)P(2) into PtdIns(3)P. Alone, neither activity is sufficient for ruffling but when acting in conjunction with one another, the 4-phosphatase and 5 phosphatase activities led to SNX9-mediated ruffling and Salmonella invasion. This work reveals the unique ability of bacterial effector protein SopB to utilize both its 4- and 5-phosphatase activities to regulate phosphoinositide dynamics to promote bacterial entry. PMID- 26537022 TI - Characterization of the voltage-gated sodium channel of the Asian citrus psyllid, Diaphorina citri. AB - The Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Liviidae), is an important insect pest of citrus. It is the vector of 'Candidatus' Liberibacter asiaticus, a phloem-limited bacterium that infects citrus, resulting in the disease Huanglongbing (HLB). Disease management relies heavily on suppression of D. citri populations with insecticides, including pyrethroids. In recent annual surveys to monitor insecticide resistance, reduced susceptibility to fenpropathrin was identified in several field populations of D. citri. The primary target of pyrethroids is the voltage-gated sodium channel (VGSC). The VGSC is prone to target-site insensitivity because of mutations that either reduce pyrethroid binding and/or alter gating kinetics. These mutations, known as knockdown resistance or kdr, have been reported in a wide diversity of arthropod species. Alternative splicing, in combination with kdr mutations, has been also associated with reduced pyrethroid efficacy. Here we report the molecular characterization of the VGSC in D. citri along with a survey of alternative splicing across developmental stages of this species. Previous studies demonstrated that D. citri has an exquisite enzymatic arsenal to detoxify insecticides resulting in reduced efficacy. The results from the current investigation demonstrate that target-site insensitivity is also a potential basis for insecticide resistance to pyrethroids in D. citri. The VGSC sequence and its molecular characterization should facilitate early elucidation of the underlying cause of an established case of resistance to pyrethroids. This is the first characterization of a VGSC from a hemipteran to this level of detail, with the majority of the previous studies on dipterans and lepidopterans. PMID- 26537023 TI - Genetic analysis of infectious diseases: estimating gene effects for susceptibility and infectivity. AB - BACKGROUND: Genetic selection of livestock against infectious diseases can complement existing interventions to control infectious diseases. Most genetic approaches that aim at reducing disease prevalence assume that individual disease status (infected/not-infected) is solely a function of its susceptibility to a particular pathogen. However, individual infectivity also affects the risk and prevalence of an infection in a population. Variation in susceptibility and infectivity between hosts affects transmission of an infection in the population, which is usually measured by the value of the basic reproduction ratio R 0 . R 0 is an important epidemiological parameter that determines the risk and prevalence of infectious diseases. An individual's breeding value for R 0 is a function of its genes that influence both susceptibility and infectivity. Thus, to estimate the effects of genes on R 0 , we need to estimate the effects of genes on individual susceptibility and infectivity. To that end, we developed a generalized linear model (GLM) to estimate relative effects of genes for susceptibility and infectivity. A simulation was performed to investigate bias and precision of the estimates, the effect of R 0 , the size of the effects of genes for susceptibility and infectivity, and relatedness among group mates on bias and precision. We considered two bi-allelic loci that affect, respectively, the individuals' susceptibility only and individuals' infectivity only. RESULTS: A GLM with complementary log-log link function can be used to estimate the relative effects of genes on the individual's susceptibility and infectivity. The model was developed from an equation that describes the probability of an individual to become infected as a function of its own susceptibility genotype and infectivity genotypes of all its infected group mates. Results show that bias is smaller when R 0 ranges approximately from 1.8 to 3.1 and relatedness among group mates is higher. With larger effects, both absolute and relative standard deviations become clearly smaller, but the relative bias remains the same. CONCLUSIONS: We developed a GLM to estimate the relative effect of genes that affect individual susceptibility and infectivity. This model can be used in genome-wide association studies that aim at identifying genes that influence the prevalence of infectious diseases. PMID- 26537024 TI - Tuning Helical Chirality in Polycyclic Ladder Systems. AB - Conceptually and experimentally, a new set of helical model compounds is presented herein that allow correlations between structural features and their expression in the secondary structure to be investigated. A cross-linked oligomer with two strands of mismatching lengths connected in a ladder-type fashion serves as a model system. Compensation for the dimensional mismatch leads to the adoption of a helical arrangement. A strategically placed relay ensures the continuity and uniformity of the helix. Upon exchanging the heteroatomic linkage, the helix responds by increasing or decreasing the torsion of the backbone. Inversion of the relay's substitution pattern causes a distortion of the structure, while maintaining the directionality of the helix. Based on a short synthetic protocol with a modular precursor, four closely related "Gelander" oligomers (Gelander is the German word for bannister) were accessed and fully characterized. XRD analysis for one representative of each helical arrangement and complementary computational studies for the remaining derivatives allowed the impact of the alterations on the secondary structures to be studied. Isolation of pure enantiomers of all new Gelander oligomers provided insight into the racemization kinetics and estimation of the racemization barrier. In silico simulation of the electronic circular dichroism spectra of the model compounds enabled the helicity of the isolated samples to be assigned. PMID- 26537025 TI - Using megestrol acetate to ameliorate protein-energy wasting in chronic kidney disease. AB - BACKGROUND: Various populations are affected by chronic kidney disease (CKD), and a low dose appetite stimulant megestrol acetate (MA) is sometimes recommended in patients with CKD to ameliorate protein-energy wasting (PEW). Patients with CKD are at greater risk of developing PEW since the progression of their disease can cause decreased nutrient intake, catabolic effects, systemic inflammation and metabolic changes. Providers can detect PEW in CKD by identifying low serum levels <=3.8 g/dl of albumin, <30 mg/dl of transthyretin, or <100 mg/dl of cholesterol. Other characteristics include BMI <22 kg/m(2) (for <=65 years), unintentional weight loss of >=5% in three months or >=10% in six months, body fat percentage <10%, with muscle wasting of a reduction of >=5% in three months or >=10% in six months of muscle mass. METHOD: A review of research was completed and data collected from small population-based retrospective studies to determine the effect of MA. RESULTS: Clinical trials demonstrated the effectiveness of MA by showing increases in BMI up to 9%, albumin levels up to 1.1 g/dl, with reported protein and energy intake increases from 27% to 42%. There are potential adverse effects of using MA in CKD. CONCLUSION: After reviewing the available literature, the benefits of using MA should be evaluated against the potential side effects. For further examination of MA's potential benefits, long-term, prospective, large clinical trials should be carried out. PMID- 26537026 TI - Clinical relevance of preformed IgG and IgM antibodies against donor endothelial progenitor cells in recipients of living donor kidney grafts. AB - BACKGROUND: Literature reports suggest that non-HLA-antibodies against human endothelial progenitor cells (EPC) can be detected in pre-transplant recipient serum and that EPC antibodies can have a deleterious influence on the graft. METHODS: We investigated 71 renal transplant recipients from living donors for a possible influence of pre-transplant donor-specific IgG and/or IgM recipient antibodies against EPC of the donor using the flow cytometric XM-ONE cross-match. RESULTS: Eight of the 71 patients developed acute biopsy-proven rejection. Two of these patients showed IgM antibodies against EPC prior to transplantation while the other six patients had neither IgG nor IgM EPC antibodies. Conversely, pre transplant IgG or IgM antibodies against EPC were detected in 19 patients without acute rejection (3 * both IgG and IgM, 1 * IgG and 15 * IgM). The remaining 44 patients had neither EPC antibodies nor experienced rejection. Comparing serum creatinine levels at one month and one yr post-transplant within and among the three patient groups revealed that serum creatinine levels were similar in patients with or without EPC antibodies (p > 0.05). CONCLUSION: In this series of 71 recipients with living donor kidneys, pre-transplant EPC antibodies detected with the XM-ONE test kit were neither associated with acute rejection nor with graft function at one month or one yr. PMID- 26537027 TI - Mothers' feeding behaviors in infancy: Do they predict child weight trajectories? AB - OBJECTIVE: To determine associations between mothers' feeding behaviors in infancy and children's weight from infancy through to toddlerhood in urban, low income, minority families and to explore the contribution of concerns about infant eating/weight. METHODS: One hundred sixty-nine mother-infant dyads (88% African-American) were recruited from an inner city pediatric practice. Questionnaires measuring restrictive feeding, pressuring to eat, and concerns about infant overeating/weight and undereating/weight were administered, and infants weighed and measured, at 6-12 months. Anthropometric data up to 30 months were obtained from multiple (8.9 +/- 2.6) well-child visits, with 84% completing 11 visits. RESULTS: Higher pressuring was associated with lower weight-for-length z-scores (WLZ) over the period from baseline out to 30 months and higher restriction with higher child WLZ over the same period. Pressuring and concern about infant undereating/weight were independently associated with WLZ, but the relationship between restrictive feeding and WLZ was reduced by accounting for concern about infant overeating/weight. Child weight trajectories were not influenced by feeding behavior. CONCLUSIONS: Mothers restricted heavier infants and pressured leaner infants to eat, and the relationship between restriction and higher infant weight was mediated by concern about infant overeating/weight. Correcting misperceptions and discussing feeding with mothers reporting concern may help prevent excessive early weight gain. PMID- 26537028 TI - An informative prior probability distribution of the gompertz parameters for bayesian approaches in paleodemography. AB - OBJECTIVES: In paleodemography, the Bayesian approach has been suggested to provide an effective means by which mortality profiles of past populations can be adequately estimated, and thus avoid problems of "age-mimicry" inherent in conventional approaches. In this study, we propose an application of the Gompertz model using an "informative" prior probability distribution by revising a recent example of the Bayesian approach based on an "uninformative" distribution. METHODS: Life-table data of 134 human populations including those of contemporary hunter-gatherers were used to determine the Gompertz parameters of each population. In each population, we used both raw life-table data and the Gompertz parameters to calculate some demographic values such as the mean life-span, to confirm representativeness of the model. Then, the correlation between the two Gompertz parameters (the Strehler-Mildvan correlation) was re-established. We incorporated the correlation into the Bayesian approach as an "informative" prior probability distribution, and tested its effectiveness using simulated data. RESULTS: Our analyses showed that the mean life-span (>= age 15) and the proportion of living persons aging over 45 were well-reproduced by the Gompertz model. The simulation showed that using the correlation as an informative prior provides a narrower estimation range in the Bayesian approach than does the uninformative prior. CONCLUSIONS: The Gompertz model can be assumed to accurately estimate the mean life-span and/or the proportion of old people in a population. We suggest that the Strehler-Mildvan correlation can be used as a useful constraint in demographic reconstructions of past human populations. PMID- 26537029 TI - The effect of political generation on identity and social change: Age cohort consequences. AB - In this article, we explore how political generation affects the ways in which diverse individuals come together and change their social and personal identities. Drawing on 52 in-depth interviews with members of the Red Hat Society, we show that women draw on their political generation, and the gains of the women's movement specifically, to oppose cultural constructions of aging. The Red Hat Society provides a "free space" for women to foster a collective identity that both visibly challenges aging norms and provides its members new standards for self-approval. We conclude by highlighting the importance of focusing on political generation to understand collective action over the life course and call for more scholarship on the function of political generation in social change. PMID- 26537030 TI - Prevalence of Schistosomes and Soil-Transmitted Helminths among Schoolchildren in Lake Victoria Basin, Tanzania. AB - The objectives of this study was to conduct a survey on schistosomiasis and soil transmitted helminth (STH) infections in order to come up with feasible control strategies in Lake Victoria basin, Tanzania. Depending on the size of the school, 150-200 schoolchildren were recruited for the study. Duplicate Kato-Katz stool smears were prepared from each child and microscopically examined for Schistosoma mansoni and STHs. Urine specimens were examined for Schistosoma haematobium eggs using the filtration technique. After the survey, mass drug administration was done using praziquantel and albendazole for schistosomiasis and STHs infections, respectively. A total of 5,952 schoolchildren from 36 schools were recruited for the study and had their stool and urine specimens examined. Out of 5,952 schoolchildren, 898 (15.1%) were positive for S. mansoni, 754 (12.6%) for hookworms, 188 (3.2%) for Ascaris lumblicoides, and 5 (0.008%) for Trichuris trichiura. Out of 5,826 schoolchildren who provided urine samples, 519 (8.9%) were positive for S. haematobium eggs. The results revealed that intestinal schistosomiasis, urogenital schistosomiasis, and STH infections are highly prevalent throughought the lake basin. The high prevalence of intestinal and urogenital schistosomisiasis in the study area was a function of the distance from Lake Victoria, the former being more prevalent at localities close to the lake, whilst the latter is more so away from it. Control of schistosomiasis and STHs in the study area requires an integrated strategy that involves provision of health education to communities, regular treatments, and provision of adequate safe water supply and sanitation facilities. PMID- 26537031 TI - Prevalence of Schistosomes and Soil-Transmitted Helminths and Morbidity Associated with Schistosomiasis among Adult Population in Lake Victoria Basin, Tanzania. AB - The objective of this study was to carry out a community survey on schistosomiais and soil-transmitted helminth (STH) infections in order to suggest feasible and effective intervention strategies in Lake Victoria basin, Tanzania. A total of 37 communities selected from 23 districts of the 4 regions in the Lake Victoria basin of Tanzania were involved in the study. From each of the selected locality, 50 adult community members, 25 males and 25 females, were recruited for the study. Each study participant was requested to submit stool and urine specimens. From each stool specimen, duplicate Kato-Katz thick smears were prepared and microscopically examined for Schistosoma mansoni and STH eggs. Urine specimens were processed by the filtration technique and microscopically examined for Schistosoma haematobium eggs. Ultrasound examination for morbidity due to schistosomiasis was performed. Mass treatment was done using praziquantel and albendazole for schistosome and STHs infections, respectively. Out of 1,606 adults who provided stool specimens, 199 (12.4%) were positive for S. mansoni, 349 (21.7%) for hookworms, 133 (8.3%) for Ascaris lumbricoides, and 33 (2.0%) for Trichuris trichiura. Out of 1,400 participants who provided urine specimens, 25 (1.8%) were positive for S. haematobium eggs. Because of the co-endemicity of these afflictions and their impact on vulnerable population groups, the helminthiasis could be simultaneously treated with 2 drugs, praziquantel for schistosomiasis and albendazole for STHs. PMID- 26537032 TI - Integrated Schistosomiasis and Soil-Transmitted Helminthiasis Control over Five Years on Kome Island, Tanzania. AB - Integrated control strategies are important for sustainable control of schistosomiasis and soil-transmitted helminthiasis, despite their challenges for their effective implementation. With the support of Good Neighbors International in collaboration with National Institute of Medical Research, Mwanza, Tanzania, integrated control applying mass drug administration (MDA), health education using PHAST, and improved safe water supply has been implemented on Kome Island over 5 years for controlling schistosomiasis and soil-transmitted helminths (STHs). Baseline surveys for schistosomiasis and STHs was conducted before implementation of any integrated control strategies, followed by 4 cross sectional follow-up surveys on randomly selected samples of schoolchildren and adults in 10 primary schools and 8 villages, respectively, on Kome islands. Those follow-up surveys were conducted for impact evaluation after introduction of control strategies interventions in the study area. Five rounds of MDA have been implemented from 2009 along with PHAST and improved water supply with pumped wells as other control strategies for complementing MDA. A remarkable steady decline of schistosomiasis and STHs was observed from 2009 to 2012 with significant trends in their prevalence decline, and thereafter infection rate has remained at a low sustainable control. By the third follow-up survey in 2012, Schistosoma mansoni infection prevalence was reduced by 90.5% and hookworm by 93.3% among schoolchildren while in adults the corresponding reduction was 83.2% and 56.9%, respectively. Integrated control strategies have successfully reduced S. mansoni and STH infection status to a lower level. This study further suggests that monitoring and evaluation is a crucial component of any large-scale STH and schistosomiasis intervention. PMID- 26537033 TI - Schistosoma mansoni-Related Hepatosplenic Morbidity in Adult Population on Kome Island, Sengerema District, Tanzania. AB - Schistosomiasis is one of the important neglected tropical diseases (NTDs) in Tanzania, particularly in Lake Victoria zone. This baseline survey was a part of the main study of integrated control of schistosomiasis and soil-transmitted helminths (STHs) aimed at describing morbidity patterns due to intestinal schistosomiasis among adults living on Kome Island, Sengerema District, Tanzania. Total 388 adults from Kome Islands (about 50 people from each village) aged between 12 and 85 years, were examined by abdominal ultrasound according to the Niamey protocol. Liver image patterns (LIPs) A and B were considered normal, and C-F as distinct periportal fibrosis (PPF). The overall prevalence of PPF was 42.2%; much higher in males than in females (47.0% in male vs 34.4% in females, P=0.007). Abnormal increase of segmental branch wall thickness (SBWT) and dilated portal vein diameter (PVD) were also more common in males than in females. Hepatosplenomegaly was frequently encountered; 68.1% had left liver lobe hepatomegaly and 55.2% had splenomegaly. Schistosoma mansoni-related morbidity is quite high among adults in this community justifying the implementation of integrated control strategies through mass drug administration, improved water supply (pumped wells), and health education that had already started in the study area. PMID- 26537034 TI - Improved Socio-Economic Status of a Community Population Following Schistosomiasis and Intestinal Worm Control Interventions on Kome Island, North Western Tanzania. AB - Research on micro-level assessment of the changes of socio-economic status following health interventions is very scarce. The use of household asset data to determine wealth indices is a common procedure for estimating socio-economic position in resource poor settings. In such settings information about income is usually lacking, and the collection of individual consumption or expenditure data would require in-depth interviews, posing a considerable risk of bias. In this study, we determined the socio-economic status of 213 households in a community population in an island in the north-western Tanzania before and 3 year after implementation of a participatory hygiene and sanitation transformation (PHAST) intervention to control schistosomiasis and intestinal worm infections. We constructed a household 'wealth index' based housing construction features (e.g., type of roof, walls, and floor) and durable assets ownership (e.g., bicycle, radio, etc.). We employed principal components analysis and classified households into wealth quintiles. The study revealed that asset variables with positive factor scores were associated with higher socio-economic status, whereas asset variables with negative factor scores were associated with lower socio-economic status. Overall, households which were rated as the poorest and very poor were on the decrease, whereas those rated as poor, less poor, and the least poor were on the increase after PHAST intervention. This decrease/increase was significant. The median shifted from -0.4376677 to 0.5001073, and the mean from -0.2605787 (SD; 2.005688) to 0.2605787 (SD; 1.831199). The difference in socio-economic status of the people between the 2 phases was highly statistically significant (P<0.001). We argue that finding of this study should be treated with caution as there were other interventions to control schistosomiasis and intestinal worm infections which were running concurrently on Kome Island apart from PHAST intervention. PMID- 26537035 TI - Improved Perceptions and Practices Related to Schistosomiasis and Intestinal Worm Infections Following PHAST Intervention on Kome Island, North-Western Tanzania. AB - Schistosomiasis and intestinal worm infections are widespread diseases of public health importance in Tanzania. A study on perceptions and practices related to schistosomiasis and intestinal worm infections was undertaken among a community population of Kome Island in Sengerema District, north-western Tanzania, where intestinal schistosomiasis and intestinal worm infections are endemic. Schistosomiasis and intestinal worm-related perceptions and practices were assessed before and 3 years after implementation of a participatory hygiene and sanitation transformation (PHAST) intervention as a control measure. Data were obtained from baseline and post-intervention knowledge, attitudes, and practices (KAP) questionnaire surveys conducted twice in 2009 and 2012 among 82 individuals aged >=15 years. We found significant increases in respondents' knowledge of the cause, transmission, symptoms, health consequences, and prevention of schistosomiasis and intestinal worm infections after PHAST intervention. The increase in respondents' knowledge on almost all aspects of the said infections was translated into actions to control schistosomiasis and intestinal worm infections. This has not been achieved by chance, but due to well-designed and locally-adapted PHAST intervention. We conclude that despite criticisms, PHAST approach is still useful in empowering communities to control water, sanitation, and hygiene related infectious diseases such as schistosomiasis and intestinal worm infections. PMID- 26537036 TI - High Malaria Prevalence among Schoolchildren on Kome Island, Tanzania. AB - In order to determine the status of malaria among schoolchildren on Kome Island (Lake Victoria), near Mwanza, Tanzania, a total of 244 schoolchildren in 10 primary schools were subjected to a blood survey using the fingerprick method. The subjected schoolchildren were 123 boys and 121 girls who were 6-8 years of age. Only 1 blood smear was prepared for each child. The overall prevalence of malaria was 38.1% (93 positives), and sex difference was not remarkable. However, the positive rate was the highest in Izindabo Primary School (51.4%) followed by Isenyi Primary School (48.3%) and Bugoro Primary School (46.7%). The lowest prevalence was found in Muungano Primary School (16.7%) and Nyamiswi Primary School (16.7%). These differences were highly correlated with the location of the school on the Island; those located in the peripheral area revealed higher prevalences while those located in the central area showed lower prevalences. Plasmodium falciparum was the predominant species (38.1%; 93/244), with a small proportion of them mixed-infected with Plasmodium vivax (1.6%; 4/244). The results revealed that malaria is highly prevalent among primary schoolchildren on Kome Island, Tanzania, and there is an urgent need to control malaria in this area. PMID- 26537037 TI - Plasmodium knowlesi as a Threat to Global Public Health. AB - Malaria is a tropical disease caused by protozoans of the Plasmodium genus. Delayed diagnosis and misdiagnosis are strongly associated with higher mortality. In recent years, a greater importance is attributed to Plasmodium knowlesi, a species found mainly in Southeast Asia. Routine parasitological diagnostics are associated with certain limitations and difficulties in unambiguous determination of the parasite species based only on microscopic image. Recently, molecular techniques have been increasingly used for predictive diagnosis. The aim of the study is to draw attention to the risk of travelling to knowlesi malaria endemic areas and to raise awareness among personnel involved in the therapeutic process. PMID- 26537038 TI - DEAD/DExH-Box RNA Helicases in Selected Human Parasites. AB - DEAD/DExH-box RNA helicases catalyze the folding and remodeling of RNA molecules in prokaryotic and eukaryotic cells, as well as in many viruses. They are characterized by the presence of the helicase domain with conserved motifs that are essential for ATP binding and hydrolysis, RNA interaction, and unwinding activities. Large families of DEAD/DExH-box proteins have been described in different organisms, and their role in all molecular processes involving RNA, from transcriptional regulation to mRNA decay, have been described. This review aims to summarize the current knowledge about DEAD/DExH-box proteins in selected protozoan and nematode parasites of medical importance worldwide, such as Plasmodium falciparum, Leishmania spp., Trypanosoma spp., Giardia lamblia, Entamoeba histolytica, and Brugia malayi. We discuss the functional characterization of several proteins in an attempt to understand better the molecular mechanisms involving RNA in these pathogens. The current data also highlight that DEAD/DExH-box RNA helicases might represent feasible drug targets due to their vital role in parasite growth and development. PMID- 26537039 TI - Activation of MAPK Is Required for ROS Generation and Exocytosis in HMC-1 Cells Induced by Trichomonas vaginalis-Derived Secretory Products. AB - Trichomonas vaginalis is a flagellated protozoan parasite that causes vaginitis and cervicitis in women and asymptomatic urethritis and prostatitis in men. Mast cells have been reported to be predominant in vaginal smears and vaginal walls of patients infected with T. vaginalis. Mitogen-activated protein kinase (MAPK), activated by various stimuli, have been shown to regulate the transcriptional activity of various cytokine genes in mast cells. In this study, we investigated whether MAPK is involved in ROS generation and exocytotic degranulation in HMC-1 cells induced by T. vaginalis-derived secretory products (TvSP). We found that TvSP induces the activation of MAPK and NADPH oxidase in HMC-1 cells. Stimulation with TvSP induced phosphorylation of MAPK and p47(phox) in HMC-1 cells. Stimulation with TvSP also induced up-regulation of CD63, a marker for exocytosis, along the surfaces of human mast cells. Pretreatment with MAPK inhibitors strongly inhibited TvSP-induced ROS generation and exocytotic degranulation. Finally, our results suggest that TvSP induces intracellular ROS generation and exocytotic degranulation in HMC-1 via MAPK signaling. PMID- 26537040 TI - Seropositivity of Toxoplasmosis in Pregnant Women by ELISA at Minia University Hospital, Egypt. AB - Toxoplasmosis is considered as an important risk factor for bad obstetric history (BOH) and one of the major causes of congenitally acquired infections. The present study aimed to estimate the seropositivity of T. gondii infection and associated risk factors among the attendees of high risk pregnancy and low risk antenatal care clinic of Minia Maternity and Pediatric University Hospital, Minia, Egypt. The study was carried out from April 2013 to April 2014 through 2 phases, the first phase was case-control study, and the second phase was follow up with intervention. A total of 120 high risk pregnant and 120 normal pregnant females were submitted to clinical examinations, serological screening for anti Toxoplasma IgM and IgG antibodies by ELISA, and an interview questionnaire. Seropositive cases were subjected to spiramycin course treatment. The results showed that the seroprevalence of toxoplasmosis in high-risk pregnancy group was 50.8%, which was significantly different from that of normal pregnancy group (P<0.05). Analysis of seropositive women in relation to BOH showed that abortion was the commonest form of the pregnancy wastage (56.5%). The high prevalence of T. gondii seropositive cases was observed in the age group of 21-30 years. Post delivery adverse outcome was observed in 80.3% of high-risk pregnancy group compared to 20% of normal pregnancy group. There was a statistically significant relationship between seropositivity and living in rural area, low socioeconomic level, and undercooked meat consumption (P<0.05). Serological screening for anti Toxoplasma antibodies should be routine tests especially among high-risk pregnant women. PMID- 26537041 TI - Identification and Prevalence of Globocephalus samoensis (Nematoda: Ancylostomatidae) among Wild Boars (Sus scrofa coreanus) from Southwestern Regions of Korea. AB - This study describes the first record of Globocephalus samoensis (Nematoda: Ancylostomatidae) recovered in wild boars from southwestern regions of Korea. Gastrointestinal tracts of 111 Korean wild boars (Sus scrofa coreanus) hunted from mountains in Suncheon-si, Gwangyang-si, and Boseong-gun between 2009 and 2012 were examined for their visceral helminths. G. samoensis, as identified by morphological characteristics of the head and tail, were recovered from the small intestine of 51 (45.9%) wild boars. Worms were found from 7 of 28 wild boars (25.0%) from Suncheon-si, 40 of 79 (50.6%) from Gwangyang-si, and all 4 (100%) from Boseong-gun. The length of adult females was 7.2+/-0.5 mm, and the thickest part of the body measured the average 0.47+/-0.03 mm, while those of males were 6.52+/-0.19 and 0.37+/-0.02 mm, respectively. The buccal cavity was equipped with a pair of large and bicuspid subventral lancets near the base of the capsule. The average length of spicules of males was 0.45+/-0.02 mm. By the present study, G. samoensis is recorded for the first time in southwestern regions of Korea. Additionally, morphological characteristics and identification keys provided in the present study will be helpful in the faunistic and taxonomic studies for strongylid nematodes in both domestic and wild pigs. The infection of G. samoensis apparently did not elicit pathologic lesions, as revealed by macroscopic observation during the autopsy of all wild boars in this study. PMID- 26537042 TI - Larval Gnathostoma spinigerum Detected in Asian Swamp Eels, Monopterus albus, Purchased from a Local Market in Yangon, Myanmar. AB - The present study was performed to determine the infection status of swamp eels with Gnathostoma sp. larvae in Myanmar. We purchased total 37 Asian swamp eels, Monopterus albus, from a local market in Yangon in June and December 2013 and 2014. All collected eels were transferred with ice to our laboratory and each of them was examined by the artificial digestion technique. A total of 401 larval gnathostomes (1-96 larvae/eel) were detected in 33 (89.2%) swamp eels. Most of the larvae (n=383; 95.5%) were found in the muscle. The remaining 18 larvae were detected in the viscera. The advanced third-stage larvae (AdL3) were 2.3-4.4 mm long and 0.25-0.425 mm wide. The characteristic head bulb (0.093 * 0.221 mm in average size) with 4 rows of hooklets, muscular long esophagus (1.025 mm), and 2 pairs of cervical sacs (0.574 mm) were observed by light microscopy. The average number of hooklets in the 1st, 2nd, 3rd, and 4th rows was 41, 45, 48, and 51, respectively. As scanning electron microscopic findings, the characteristic 4-5 rows of hooklets on the head bulb, a cervical papilla, tegumental spines regularly arranged in the transverse striations, and an anus were well observed. Based on these morphological characters, they were identified as the AdL3 of Gnathostoma spinigerum. By the present study, it has been confirmed for the first time that Asian swamp eels, M. albus, from Yangon, Myanmar are heavily infected with G. spinigerum larvae. PMID- 26537043 TI - Metagonimus yokogawai (Trematoda: Heterophyidae): From Discovery to Designation of a Neotype. AB - Metagonimus yokogawai (Katsurada, 1912) Katsurada, 1912 (Trematoda: Heterophyidae) is parasitic in the small intestine of mammals including man and birds in Far Eastern Russia, Korea, Japan, China, and Taiwan. In the present study, the metacercariae and adults of M. yokogawai were redescribed to designate a neotype of this fluke together with reviews of previous studies including study histories from the first discovery to now. We particularly, attempted to review the study histories and morphological descriptions of M. yokogawai for the species validity, and compared with the morphological characteristics and life cycles of the closely related species, Metagonimus takahashii and Metagonimus miyatai. Finally, we proposed a differential key for the 8 known Metagonimus species distributed in East Asia. Metacercariae were obtained from the body muscles of sweetfish (Plecoglossus altivelis) collected in the Asahi River at Takebe-cho, Kita-ku, Okayama City, Okayama Prefecture, Japan. Adults were recovered from the small intestine of Syrian golden hamsters, to which the metacercariae had been fed 14 days before. A neotype was selected out of the present adult specimens. The Asahi River at Takebo-cho became the type locality of M. yokogawai. In conclusion, the present review shows that M. yokogawai, M. takahashii, and M. miyatai are valid and discriminated by means of morphological characteristics. PMID- 26537044 TI - Monitoring of Fasciola Species Contamination in Water Dropwort by cox1 Mitochondrial and ITS-2 rDNA Sequencing Analysis. AB - Fascioliasis, a food-borne trematode zoonosis, is a disease primarily in cattle and sheep and occasionally in humans. Water dropwort (Oenanthe javanica), an aquatic perennial herb, is a common second intermediate host of Fasciola, and the fresh stems and leaves are widely used as a seasoning in the Korean diet. However, no information regarding Fasciola species contamination in water dropwort is available. Here, we collected 500 samples of water dropwort in 3 areas in Korea during February and March 2015, and the water dropwort contamination of Fasciola species was monitored by DNA sequencing analysis of the Fasciola hepatica and Fasciola gigantica specific mitochondrial cytochrome c oxidase subunit 1 (cox1) and nuclear ribosomal internal transcribed spacer 2 (ITS 2). Among the 500 samples assessed, the presence of F. hepatica cox1 and 1TS-2 markers were detected in 2 samples, and F. hepatica contamination was confirmed by sequencing analysis. The nucleotide sequences of cox1 PCR products from the 2 F. hepatica-contaminated samples were 96.5% identical to the F. hepatica cox1 sequences in GenBank, whereas F. gigantica cox1 sequences were 46.8% similar with the sequence detected from the cox1 positive samples. However, F. gigantica cox1 and ITS-2 markers were not detected by PCR in the 500 samples of water dropwort. Collectively, in this survey of the water dropwort contamination with Fasciola species, very low prevalence of F. hepatica contamination was detected in the samples. PMID- 26537045 TI - Infections of Larval Stages of Dicrocoelium dendriticum and Brachylaima sp. in Brown Garden Snail, Helix aspersa, in Turkey. AB - The aim of this study was to determine the presence and prevalence of larval stages of Dicrocoelium dendriticum and Brachylaima sp. in the first intermediate host, a species of land snail, Helix aspersa, in Turkey. A total of 211 snails were collected in April-May 2014 from pastures in Mersin District. Larval stages of D. dendriticum were identified under a light microscope. Hepatopancreas from naturally infected H. aspersa snails were examined histologically. The prevalence of larval stages of D. dendriticum and Brachylaima sp. in H. aspersa snails was found to be 2.4% and 1.9%, respectively, in Mersin, Turkey. Cercariae were not matured in sporocysts at the beginning of April; however, it was observed that cercariae matured and started to leave sporocysts by early-May. Thus, it was concluded that H. aspersa acts as an intermediate host to D. dendriticumin and Brachylaima sp. in Mersin, Turkey. A digenean trematode Brachylaima sp. was seen for the first time in Turkey. PMID- 26537046 TI - Detection of Tick-Borne Pathogens in the Korean Water Deer (Hydropotes inermis argyropus) from Jeonbuk Province, Korea. AB - The objective of this study was to investigate the prevalence of tick-borne pathogens in the Korean water deer (Hydropotes inermis argyropus). Pathogens were identified using PCR which included Anaplasma, Ehrlichia, Rickettsia, and Theileria. Rickettsia was not detected, whereas Anaplasma, Ehrlichia, and Theileria infections were detected in 4, 2, and 8 animals, respectively. The most prevalent pathogen was Theileria. Of the 8 Theileria-positive animals, 2 were mixed-infected with 3 pathogens (Anaplasma, Ehrlichia, and Theileria) and another 2 animals showed mixed-infection with 2 pathogens (Anaplasma and Theileria). Sequencing analysis was used to verify the PCR results. The pathogens found in this study were identified as Anaplasma phagocytophilum, Ehrlichia canis, and Theileria sp. To the best of our knowledge, this is the first report identifying these 3 pathogens in the Korean water deer. Our results suggest that the Korean water deer may serve as a major reservoir for these tick-borne pathogens, leading to spread of tick-borne diseases to domestic animals, livestock, and humans. Further studies are needed to investigate their roles in this respect. PMID- 26537047 TI - OsHAL3, a Blue Light-Responsive Protein, Interacts with the Floral Regulator Hd1 to Activate Flowering in Rice. AB - In flowering plants, photoperiodic flowering is controlled by a complicated network. Light is one of the most important environmental stimuli that control the timing of the transition from vegetative growth to reproductive development. Several photoreceptors, including PHYA, PHYB, CRY2, and FKF1 in Arabidopsis and their homologs (OsPHYA, OsPHYB, OsPHYC, and OsCRY2) in rice, have been identified to be related to flowering. Our previous study suggests that OsHAL3, a flavin mononucleotide-binding protein, may function as a blue-light sensor. Here, we report the identification of OsHAL3 as a positive regulator of flowering in rice. OsHAL3 overexpression lines exhibited an early flowering phenotype, whereas downregulation of OsHAL3 expression by RNA interference delayed flowering under an inductive photoperiod (short-day conditions). The change in flowering time was not accompanied by altered Hd1 expression but rather by reduced accumulation of Hd3a and MADS14 transcripts. OsHAL3 and Hd1 colocalized in the nucleus and physically interacted in vivo under the dark, whereas their interaction was inhibited by white or blue light. Moreover, OsHAL3 directly bound to the promoter of Hd3a, especially before dawn. We conclude that OsHAL3, a novel light responsive protein, plays an essential role in photoperiodic control of flowering time in rice, which is probably mediated by forming a complex with Hd1. Our findings open up new perspectives on the photoperiodic flowering pathway. PMID- 26537048 TI - Structural Analyses of Short-Chain Prenyltransferases Identify an Evolutionarily Conserved GFPPS Clade in Brassicaceae Plants. AB - Terpenoids are the largest and most diverse class of plant-specialized metabolites, which function in diverse physiological processes during plant development. In the biosynthesis of plant terpenoids, short-chain prenyltransferases (SC-PTs), together with terpene synthases (TPSs), play critical roles in determining terpenoid diversity. SC-PTs biosynthesize prenyl pyrophosphates with different chain lengths, and these compounds are the direct precursors of terpenoids. Arabidopsis thaliana possesses a subgroup of SC-PTs whose functions are not clearly known. In this study, we focus on 10 geranylgeranyl pyrophosphate synthase-like [GGPPSL] proteins, which are commonly thought to produce GGPP [C20]. We found that a subset of members of the Arabidopsis GGPPSL gene family have undergone neo-functionalization: GGPPSL6, 7, 9, and 10 mainly have geranylfarnesyl pyrophosphate synthase activity (C25; renamed AtGFPPS1, 2, 3, and 4), and GGPPSL8 produces even longer chain prenyl pyrophosphate (>= C30; renamed polyprenyl pyrophosphate synthase 2, AtPPPS2). By solving the crystal structures of AtGFPPS2, AtPPPS2, and AtGGPPS11, we reveal the product chain-length determination mechanism of SC-PTs and interpret it as a "three floors" model. Using this model, we identified a novel GFPPS clade distributed in Brassicaceae plants and found that the GFPPS gene typically occurs in tandem with a gene encoding a TPS, forming a GFPPS-TPS gene cluster. PMID- 26537049 TI - Amyloid burden and sleep blood pressure in amnestic mild cognitive impairment. AB - OBJECTIVE: To determine whether cortical beta-amyloid (Abeta) deposition is associated with circadian blood pressure (BP) profiles and dynamic cerebral blood flow (CBF) regulation in patients with amnestic mild cognitive impairment (aMCI). METHODS: Forty participants with aMCI were included in this study. Cortical Abeta depositions were measured by (18)F-florbetapir PET and expressed as the standardized uptake value ratio (SUVR) relative to the cerebellum. Circadian BP profiles were measured by 24-hour ambulatory monitoring during awake and sleep periods. The dipping status of sleep BP (i.e., the percent changes from the awake BP) was calculated and dichotomized into the dipper (>=10%) and nondipper (<10%) groups. Dynamic CBF regulation was assessed by a transfer function analysis between beat-to-beat changes in BP and CBF velocity measured from the middle cerebral artery during a repeated sit-stand maneuver. RESULTS: Age was positively correlated with a greater Abeta deposition in the posterior cingulate, precuneus, and mean cortex. Accounting for the age effect, attenuated reductions in sleep systolic BP were associated with higher levels of posterior cingulate SUVR. Consistently, the nondippers exhibited a higher SUVR in the posterior cingulate than the dippers. Transfer function gain between changes in BP and CBF velocity was diminished in the nondippers, and moreover those individuals with a lower gain exhibited a higher SUVR in the posterior cingulate. CONCLUSIONS: Attenuated reductions in sleep BP are associated with a greater Abeta burden in the posterior cingulate and altered dynamic CBF regulation in patients with aMCI. PMID- 26537050 TI - Dipping to clear amyloid: Cerebrovascular reactivity and neurodegeneration--cause or effect? PMID- 26537051 TI - Quality of life in patients with TIA and minor ischemic stroke. AB - OBJECTIVE: We investigated health-related quality of life (HRQOL) in patients with TIA and minor ischemic stroke (MIS) using Neuro-QOL, a validated, patient reported outcome measurement system. METHODS: Consecutive patients with TIA or MIS who had (1) modified Rankin Scale (mRS) score of 0 or 1 at baseline, (2) initial NIH Stroke Scale score of <=5, (3) no acute reperfusion treatment, and (4) 3-month follow-up, were recruited. Recurrent stroke, disability by mRS and Barthel Index, and Neuro-QOL scores in 5 prespecified domains were prospectively recorded. We assessed the proportion of patients with impaired HRQOL, defined as T scores more than 0.5 SD worse than the general population average, and identified predictors of impaired HRQOL using logistic regression. RESULTS: Among 332 patients who met study criteria (mean age 65.7 years, 52.4% male), 47 (14.2%) had recurrent stroke within 90 days and 41 (12.3%) were disabled (mRS >1 or Barthel Index <95) at 3 months. Any HRQOL impairment was noted in 119 patients (35.8%). In multivariate analysis, age (adjusted odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01-1.04), initial NIH Stroke Scale score (adjusted OR 1.39, 95% CI 1.17-1.64), recurrent stroke (adjusted OR 2.10, 95% CI 1.06-4.13), and proxy reporting (adjusted OR 3.94, 95% CI 1.54-10.10) were independent predictors of impaired HRQOL at 3 months. CONCLUSIONS: Impairment in HRQOL is common at 3 months after MIS and TIA. Predictors of impaired HRQOL include age, index stroke severity, and recurrent stroke. Future studies should include HRQOL measures in outcome assessment, as these may be more sensitive to mild deficits than traditional disability scales. PMID- 26537052 TI - Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons. AB - OBJECTIVE: We tested the hypothesis that cerebral amyloid angiopathy (CAA) is related to Alzheimer disease (AD) dementia and decline in multiple cognitive systems in old age, independent of AD plaque and tangle pathology and other common age-related neuropathologies. METHODS: Participants (n = 1,113) came from 2 longitudinal clinical-pathologic studies of aging, the Rush Memory and Aging Project and the Religious Orders Study. All underwent annual clinical evaluations including detailed cognitive testing for a mean of 7.1 years before death. Clinical diagnoses of AD were established after reviewing all clinical data, blinded to neuropathologic information. Neuropathologic examinations provided measures of CAA, AD pathology, macroscopic infarcts, microinfarcts, and neocortical Lewy bodies. The association of CAA with AD dementia was examined using logistic regression models, and its association with cognitive decline was examined using linear mixed models. RESULTS: CAA was common, present in 78.9% of participants, and moderately related to AD pathology (rho = 0.401, p < 0.0001). In analyses adjusted for plaques, tangles, and other common age-related neuropathologies, CAA was associated with an increased odds of AD dementia (odds ratio = 1.237, 95% confidence interval 1.082-1.414) and an increased rate of decline in global cognition, perceptual speed, episodic memory, and semantic memory. The associations of CAA with cognitive outcomes were not driven by the presence of capillary involvement. CONCLUSIONS: CAA is an important determinant of AD dementia and decline in multiple cognitive systems in old age. PMID- 26537053 TI - Raloxifene for women with Alzheimer disease: A randomized controlled pilot trial. AB - OBJECTIVE: To determine whether raloxifene, a selective estrogen receptor modulator, improves cognitive function compared with placebo in women with Alzheimer disease (AD) and to provide an estimate of cognitive effect. METHODS: This pilot study was conducted as a randomized, double-blind, placebo-controlled trial, with a planned treatment of 12 months. Women with late-onset AD of mild to moderate severity were randomly allocated to high-dose (120 mg) oral raloxifene or identical placebo provided once daily. The primary outcome compared between treatment groups at 12 months was change in the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog). RESULTS: Forty-two women randomized to raloxifene or placebo were included in intent-to-treat analyses (mean age 76 years, range 68-84), and 39 women contributed 12-month outcomes. ADAS-cog change scores at 12 months did not differ significantly between treatment groups (standardized difference 0.03, 95% confidence interval -0.39 to 0.44, 2-tailed p = 0.89). Raloxifene and placebo groups did not differ significantly on secondary analyses of dementia rating, activities of daily living, behavior, or a global cognition composite score. Caregiver burden and caregiver distress were similar in both groups. CONCLUSIONS: Results on the primary outcome showed no cognitive benefits in the raloxifene-treated group. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for women with AD, raloxifene does not have a significant cognitive effect. The study lacked the precision to exclude a small effect. PMID- 26537054 TI - Dramatic worsening of adult-onset X-linked adrenoleukodystrophy after head trauma. PMID- 26537055 TI - Sensitivity to acute cerebral ischemic injury in migraineurs: A retrospective case-control study. AB - OBJECTIVE: Migraine, particularly with aura, is a risk factor for ischemic stroke. Recent data in migraine mutant mice suggest that cerebral hyperexcitability associated with migraine accelerates recruitment of ischemic penumbra into the core, resulting in faster infarct growth compared with wild type. We hypothesized that individuals with a history of migraine are more likely to exhibit increased recruitment of ischemic tissue into the infarct in acute stroke. METHODS: In this retrospective case-control study, we identified participants with reliably documented migraine history, measured lesion volumes on diffusion-weighted and perfusion-weighted MRI obtained within 72 hours of symptom onset, calculated the proportion of ischemic tissue on perfusion-weighted imaging (PWI) hyperintense on diffusion-weighted imaging (DWI), and compared the proportion of patients with no-mismatch pattern defined as DWI lesion >83% of PWI lesion. RESULTS: Migraineurs (n = 45) were younger, more often female, less likely to have vascular risk factors, and more often had cervical artery dissection, but otherwise did not differ from controls (n = 27). A significantly larger proportion of migraineurs had no-mismatch pattern, indicating that the entire perfusion defect was recruited into the infarct by the time of MRI (22% vs 4% of migraineurs and controls, respectively; p = 0.044). The difference was even more prominent in migraineurs with aura (36% vs 4%, p = 0.019). The association between migraine and no-mismatch pattern persisted after adjustment for time to MRI (p = 0.041). CONCLUSIONS: This case-control study supports the hypothesis that a history of migraine, particularly with aura, is associated with a no mismatch pattern during acute ischemic stroke, consistent with data obtained in migraine mutant mice. PMID- 26537057 TI - Migraine makes the stroke grow faster? PMID- 26537056 TI - ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations. AB - OBJECTIVE: To investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 (ADCY5)-related dyskinesia and genotype-phenotype relationship. METHODS: We analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases. RESULTS: We identified 3 new families and 12 new sporadic cases with ADCY5 mutations. These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In 2 unrelated families, a p.A726T mutation in the first cytoplasmic domain (C1) causes a relatively mild disorder of prominent facial and hand dystonia and chorea. Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia. Somatic mosaicism is usually associated with a less severe phenotype. In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea. The progenitor, whose childhood-onset episodic movement disorder almost disappeared in adulthood, was mosaic for the mutation. CONCLUSIONS: ADCY5-related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements. Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis. PMID- 26537058 TI - Endovascular vs medical management of acute ischemic stroke. AB - OBJECTIVE: To compare the outcomes between endovascular and medical management of acute ischemic stroke in recent randomized controlled trials (RCT). METHODS: A systematic literature review was performed, and multicenter, prospective RCTs published from January 1, 2013, to May 1, 2015, directly comparing endovascular therapy to medical management for patients with acute ischemic stroke were included. Meta-analyses of modified Rankin Scale (mRS) and mortality at 90 days and symptomatic intracranial hemorrhage (sICH) for endovascular therapy and medical management were performed. RESULTS: Eight multicenter, prospective RCTs (Interventional Management of Stroke [IMS] III, Local Versus Systemic Thrombolysis for Acute Ischemic Stroke [SYNTHESIS] Expansion, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy [MR RESCUE], Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands [MR CLEAN], Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness [ESCAPE], Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra Arterial [EXTEND-IA], Solitaire With the Intention For Thrombectomy as Primary Endovascular Treatment [SWIFT PRIME], and Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours [REVASCAT]) comprising 2,423 patients were included. Meta-analysis of pooled data demonstrated functional independence (mRS 0-2) at 90 days in favor of endovascular therapy (odds ratio [OR] = 1.71; p = 0.005). Subgroup analysis of the 6 trials with large vessel occlusion (LVO) criteria also demonstrated functional independence at 90 days in favor of endovascular therapy (OR = 2.23; p < 0.00001). Subgroup analysis of the 5 trials that primarily utilized stent retriever devices (>=70%) in the intervention arm demonstrated functional independence at 90 days in favor of endovascular therapy (OR = 2.39; p < 0.00001). No difference was found for mortality at 90 days and sICH between endovascular therapy and medical management in all analyses and subgroup analyses. CONCLUSIONS: This meta-analysis provides strong evidence that endovascular intervention combined with medical management, including IV tissue plasminogen activator for eligible patients, improves the outcomes of appropriately selected patients with acute ischemic stroke in the setting of LVO. PMID- 26537059 TI - Survival advantage associated with multimodal therapy in women with node-positive (stage-IIIC) uterine papillary serous carcinoma: a National Cancer Database study. AB - OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer. Adjuvant chemotherapy (CT) has become standard care in treatment of women with advanced-stage UPSC, but the role of consolidative radiotherapy (RT) is unclear. This study aims to evaluate survival outcomes of multimodal therapy. DESIGN: Retrospective cohort study using a National Cancer Database (NCDB). SETTING: United States of America. SAMPLE: A total of 1816 women diagnosed with UPSC. METHODS: All women diagnosed with surgically staged FIGO (International Federation of Gynecology and Obstetrics) stage-IIIC UPSC were identified in the NCDB from January 1998 to December 2010. Overall survival (OS) was estimated using the Kaplan-Meier method. Univariate and multivariable analyses were performed to identify and control for prognostic factors. MAIN OUTCOME MEASURE: Overall survival. RESULTS: A total of 398 057 cases of uterine cancer were identified, 22 106 of which were UPSC. Of these women, 14 093 underwent lymph-node examination, 2902 (20.6%) were found to have stage-IIIC disease, and 1816 received chemotherapy. Younger age and higher number of total lymph nodes examined were independently predictive of receiving multimodality (CT + RT) therapy, compared with CT only. Median OS was 33.6 and 42.6 months, for the CT and CT + RT groups, respectively (P < 0.0005). Exploratory univariate analyses found age, comorbidity index, tumour size, and number of dissected and positive lymph nodes to be also associated with survival. Multivariable analysis controlling for the above found the use of consolidative radiotherapy to be independently predictive of improved OS, with a hazard ratio of 0.69 (95% confidence interval, 95% CI 0.56-0.84). CONCLUSIONS: Patients with stage-IIIC UPSC may benefit from multimodal treatment that includes adjuvant radiotherapy in addition to chemotherapy. TWEETABLE ABSTRACT: In this study of 1816 women with uterine papillary serous cancer, adjuvant radiotherapy increased survival. PMID- 26537060 TI - Nano-sized precipitate stability and its controlling factors in a NiAl strengthened ferritic alloy. AB - Coherent B2-ordered NiAl-type precipitates have been used to reinforce solid solution body-centered-cubic iron for high-temperature application in fossil energy power plants. In this study, we investigate the stability of nano-sized precipitates in a NiAl-strengthened ferritic alloy at 700-950 degrees C using ultra-small angle X-ray scattering and electron microscopies. Here we show that the coarsening kinetics of NiAl-type precipitates is in excellent agreement with the ripening model in multicomponent alloys. We further demonstrate that the interfacial energy between the matrix and NiAl-type precipitates is strongly dependent on differences in the matrix/precipitate compositions. Our results profile the ripening process in multicomponent alloys by illustrating controlling factors of interfacial energy, diffusivities, and element partitioning. The study provides guidelines to design and develop high-temperature alloys with stable microstructures for long-term service. PMID- 26537061 TI - Interaction between hepatic membrane type 1 matrix metalloproteinase and acireductone dioxygenase 1 regulates hepatitis C virus infection. AB - Membrane type 1 matrix metalloproteinase (MT1-MMP) binds to and regulates the function of tetraspanin-enriched microdomains. It also physically interacts with claudin-1 and acireductone dioxygenase 1 (ADI1), both associated with hepatitis C virus (HCV) cell entry. Here, we examined hepatic expression of MT1-MMP, ADI1 and claudin-1 as well as their physical interaction in relation to serum or intrahepatic HCV-RNA levels. A total of 104 liver biopsies obtained from chronic hepatitis C patients and 84 liver tissues obtained from noncancerous parts of surgically removed HCV-related hepatocellular carcinoma were analysed. Positive cytoplasmic ADI1 in liver biopsies was associated with higher serum HCV-RNA levels (P = 0.009). Positive MT1-MMP and ADI1 interaction assessed by co immunoprecipitation was associated with lower tissue HCV-RNA levels (P = 0.009). Hepatic HCV-RNA levels were positively associated with ADI1 levels in the MT1-MMP and ADI1 co-immunoprecipitates (P = 0.030). Overexpression of MT1-MMP in Huh7.5 cells suppressed cell entry of HCV pseudoparticles as well as HCVcc infection. The suppression effect could be reversed by co-expression of ADI1 in a dose dependent manner. In summary, clinical and cell-based experiments suggested that physical interaction between MT1-MMP and ADI1 led to suppression of HCV infection. This inhibitory effect could be reversed by ADI1 overexpression. PMID- 26537062 TI - Sporadic versus inflammatory bowel disease-related colorectal adenocarcinoma: lessons learned from a single institution experience. AB - PURPOSE: Inflammatory bowel disease (IBD) - related colorectal adenocarcinoma (CAC) is known to impose a less favorable prognosis than its sporadic counterpart. The determining factor in the prognosis of IBD patients is the early endoscopic detection of commonly occult pre-cancerous lesions. This retrospective study attempted to highlight the distinctive features of IBD-related CAC, as well as the importance of implementing an acceptable surveillance protocol in IBD patients. METHODS: The medical records and biopsies of all IBD patients undergoing surgery and of surgical patients with sporadic CAC, admitted in the 5 year period 2010-2014, were examined. Overall, 26 clinicopathological parameters were collected and compared between the two groups. RESULTS: A total of 370 patients with sporadic CAC and 103 patients with IBD were included in the study, of which 8.7% (9/103) proved to have CAC. Cancer in IBD patients appeared at a younger age, had a larger maximum diameter and was more likely to have multiple synchronous locations and a signet-ring cell differentiation (p<0.05). Only 25% of IBD patients with CAC had previously followed correct surveillance. CONCLUSIONS: The aggressive features of IBD-related CAC, as well as the rising incidence of poorly-surveilled IBD patients that eventually progress to cancer, reflect the necessity of establishing dedicated IBD centers for their optimal follow-up. PMID- 26537063 TI - Is resection indicated in gastric cancer deemed curable preoperatively but found to be advanced intraoperatively? AB - PURPOSE: This study was designed to evaluate the value of resection and to analyze clinicopathologic data on gastric cancer patients who were evaluated as curable preoperatively but diagnosed as advanced intraoperatively. METHODS: A retrospective analysis was performed on clinical, surgical, and pathological data of 264 patients who had undergone surgery for gastric cancer between January 2008 and October 2012. The patients who were diagnosed in advanced stages during surgical exploration were accepted into the study group. Patients were categorized into the following two groups: non-resection group (NRG) and resection group (RG). We compared the clinicopathologic features of the two groups and investigated the prognostic factors by performing univariate and multivariate analyses. RESULTS: A total of 79 patients diagnosed with advanced disease in surgical exploration were evaluated. There were 40 patients (50.6%) in the NRG and 39 patients (49.4%) in the RG. The difference in median overall survival between the NRG and the RG was statistically significant (1.7 vs 5 months; p=0.001). In multivariate analysis, age less than 70 years, gastric resection, adjuvant chemotherapy, and male gender were found to be favorable significant independent prognostic factors for overall survival. CONCLUSION: Resection seems to be associated with improved overall survival in patients who were diagnosed as advanced intraoperatively. Therefore, patient and tumor-related factors should be taken into consideration before planning resection. Randomized controlled studies are required. PMID- 26537064 TI - Is there a correlation between peripheral blood expression of angiogenic transcriptional factors/receptors and colorectal cancer? AB - PURPOSE: The aim of this study was to evaluate whether there is a correlation between peripheral blood expression of angiogenic transcriptional factors/receptors and colorectal cancer (CRC). METHODS: Eighty six blood samples collected from patients with CRC (N=42), adenomas and/or hyperplastic polyps(AP, N=30) and individuals without colon pathology (control group/CTR, N=14) were used for this study. Twelve transcription factors and receptors were assessed by qRT PCR in a case-control study. The molecules with a minimum of 30% differences in gene expression for CRC and AP compared to CTR were then analyzed separately for each sample. Gene expression was evaluated relatively to the CTR after normalization to the large ribosomal protein PO (RPLPO) housekeeping gene, and the differential expression between studied groups was assessed by ANOVA. RESULTS: Seven out of 12 genes presented differences in expression between 10-29% in CRC and/or AP compared to CTR. Considering the selection criteria, we further individually evaluated the levels of expression of 5 genes that had a minimum of 30% expression in the case-control study. Our data showed a significant up regulation of platelet derived growth factor (PDGF) C in the blood of the patients with CRC compared to CTR (p=0.007). Likewise, clusterin (CLU) was significantly up-regulated both in CRC and AP groups compared to healthy subjects (p=0.01). For VEGFR1, PDGFRA and TGFB1 we didn't find significantly differential expression between any of the studied groups, even if increased levels were observed in both CRC and AP vs CTR. CONCLUSIONS: The results of our study indicated that increased blood level of PDGFC mRNA was associated with the presence of CRC (p=0.007). Additionally, high levels of circulating CLU mRNA were observed in both malignant and benign colorectal pathologies. PMID- 26537065 TI - Outcomes of first-line long-acting octreotide treatment in non-functional, advanced gastroenteropancreatic neuroendocrine tumors. AB - PURPOSE: Benefits of somatostatin analogues have been mostly studied in mixed samples of patients including both functional and non-functional neuroendocrine tumors. This study aimed to examine the response of patients with non-functional metastatic or inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that received first-line treatment with the somatostatin analogue octreotide LAR. METHODS: The medical records of 23 patients with locally inoperable or metastatic non-functional neuroendocrine tumors who received octreotide LAR (long acting release) treatment were retrospectively reviewed for clinical data and disease course. All patients had received first-line octreotide LAR 30 mg for 4 weeks. Progression free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively. RESULTS: All patients were followed for a median of 47 months. Mean PFS and OS were 25.0 +/- 3.4 months (95% CI: 18.4-31.5) and 71.3 +/- 9.5 months (95% CI: 52.7-89.9), respectively, with an estimated 5 year OS of 58%. Patients with <= 25% of hepatic tumor load had better PFS when compared to patients with >25% hepatic tumor load (32.2 +/- 6.2 vs 19.4 +/- 2.7 months, p=0.043). During treatment, the following adverse events developed: skin reaction (N=1, 4.3%), cholestasis (N=1, 4.3%), grade 1 diarrhea (N=1, 4.3%), and newly onset diabetes (N=3; 13.0%). CONCLUSION: Octreotide LAR seems to be an effective treatment option with acceptable tolerability for patients with well differentiated non-functional GEP-NETs. Survival benefits warrant further testing in future large-scale prospective trials. PMID- 26537066 TI - The importance of choice of resection procedures in T1 and T2 stage of carcinoma of the ampulla of Vater. AB - PURPOSE: The ampulla of Vater (AV), with its strategic location and its remarkable predisposition to the development of various malignant tumors, makes it very challenging for surgery. In this study we aimed to examine the prognostic factors in the treatment of early-stage carcinoma of the AV as well as to contribute to the choice of optimal surgical procedure. METHODS: We analyzed 109 AV patients, hospitalized at the Clinical Center of Serbia from January 1999 to December 2008 and we compared the clinicopathological features, analyzed intra- and postoperative data, recurrences and survival, according to duodenopancreatectomy (DP) or local resection (LR). RESULTS: DP was performed in 83 and LR in 26 patients. Overall survival (OS) was significantly influenced by the pathological (p) tumor stage (pT1/T2 vs pT3/T4), pathological nodal stage (pN0 vs pN1), perineural and vascular invasion, grade of tumor differentiation (G1 vs G3), and resection margin status (R0 vs R1). Kaplan-Meier analysis showed 64% 5-year overall survival of patients with pT1/T2 stage in the group with DP, and 58% in the group with LR (p>0.05). Survival analysis of pN1 patients in these two groups showed statistically significant difference (DP 49.67 vs LR 28.68 months, p<0.05). Postoperative complications occurred more frequently in patients treated with DP, compared with LR. Tumor recurrence occurred in 23.07% of LR patients and in 4.0% of DP patients, in pT1/T2 stage. The rate of in-hospital mortality was not significantly different in DP (9.78%) vs LR (0%) patients (p>0.05). CONCLUSION: Resection is mandatory for all proven AV tumors, and DP is the treatment choice. LR, due to reduced morbidity and mortality, might be recommended in elderly patients with comorbidities and in patients with stage pT1/T2, pN0 and well differentiated (G1,G2) tumors. PMID- 26537067 TI - Clinical study of autofluorescence imaging combined with narrow band imaging in diagnosing early gastric cancer and precancerous lesions. AB - PURPOSE: To evaluate the diagnostic values of autofluorescence imaging (AFI) combined with narrow band imaging (NBI) in diagnosing early gastric cancer and precancerous lesions. METHODS: 140 patients were investigated for lesions such as gastric mucosal roughness, erosion, plaque, abnormal color, bump or pitting by conventional endoscopy. AFI endoscope was used for the observation, and the endoscopic diagnosis was performed according to the fluorescence forms under the endoscopic AFI mode, as well as the changes of gastric mucosal capillaries and gastric pits under the NBI mode. The corresponding lesions were also biopsied for pathological examination. RESULTS: 78 patients were diagnosed as gastritis (including superficial and atrophic gastritis), 45 as intestinal metaplasia, 6 as dysplasia, and 11 as early gastric cancer. The sensitivity and specificity of AFI NBI combination were 88.89 and 91.58% in the diagnosis of intestinal metaplasia; 83.33 and 98.51% for dysplasia; and 90.91 and 99.22% for early gastric cancer. All of them were significantly higher than the simple fluorescence endoscopy. CONCLUSIONS: The AFI-NBI combination could improve the detection rate of early gastric cancer and precancerous lesions. PMID- 26537068 TI - Association of THADA, FOXP4, GPRC6A/RFX6 genes and 8q24 risk alleles with prostate cancer in Northern Chinese men. AB - PURPOSE: Prostate cancer (PCa) is one of the most common malignancies in males, and multiple genetic studies have confirmed association with susceptibility to PCa. However, the risk conferred in men living in China is unkown. We selected 6 previously identified variants as candidates to define their association with PCa in Chinese men. METHODS: We genotyped 6 single nucleotide polymorphisms (SNPs) (rs1465618, rs1983891, rs339331, rs16901966, rs1447295 and rs10090154) using high resolution melting (HRM) analysis and assessed their association with PCa risk in a case-control study of 481 patients and 480 controls in a Chinese population. In addition, the individual and cumulative contribution for the risk of PCa and clinical covariates were analysed. RESULTS: We found that 5 of the 6 genetic variants were associated with PCa risk. The T allele of rs339331 and the G allele of rs16901966 showed a significant association with PCa susceptibility: OR (95%CI)= 0.78 (0.64-0.94), p<0.009 and OR (95%CI)= 0.66 (0.54-0.81), p<0.0001, as well as A allele of rs1447295 (OR [95%CI]=1.46 (1.17-1.84), p<0.001) and T allele of rs10090154 (OR [95%CI]= 0.58 (0.46-0.74), p<0.0001). rs339331(T) was associated with a 0.71-fold and 1.42-fold increase of PCa risk by dominant model (p=0.007) and recessive model (p=0.007). rs16901966 (G) was associated with a 0.51-fold and 1.98-fold increase of PCa risk by dominant model (p=0.006) and recessive model (p=0.0058). rs10090154 (T) was associated with a 1.89-fold and 0.53-fold increase of PCa risk by dominant model (p=0.000006) and recessive model (p=0.000006). And, rs1983891(C) was associated with a 0.77-fold increase of PCa risk by recessive model (p=0.045). rs1447295 was associated with a 1.57-fold increase of PCa risk by dominant model (p=0.008). rs1465618 showed no significant association with PCa. The cumulative effects test of risk alleles (rs rs1983891, rs339331, rs16901966, rs1447295 and rs10090154) showed an increasing risk to PCa in a frequency-dependent manner (ptrend=0.001), and men with more than 3 risk alleles had the most significant susceptibility to PCa (OR=1.99, p=0.001), compared with those who had one risk allele (OR=1.17, p=0.486). CONCLUSION: Our results provide further support for association of the THADA, FOXP4, GPRC6A/RFX6 and 8q24 genes with Pca in Asian populations. Further work is still required to determine the functional variations and finally clarify the underlying biological mechanisms. PMID- 26537069 TI - Prophylactic intravesical chemotherapy decreases bladder tumor recurrence after nephroureterectomy for primary upper tract urothelial carcinoma: A systematic review and meta-analysis. AB - PURPOSE: A high incidence of bladder tumor (BT) occurs after radical nephroureterectomy (NU) for primary upper tract urothelial carcinoma (UTUC). Although some studies have shown that prophylactic intravesical chemotherapy could prevent BT recurrence, it has not become standard practice at this stage. The purpose of this study was to evaluate the effect of intravesical instillation chemotherapy in preventing BT recurrence in patients with primary UTUC after nephroureterectomy. METHODS: A comprehensive literature search was performed in July 2014 using the Medline, Embase, and Cochrane Library databases, as well as the China National Knowledge Infrastructure and Wanfang Data. All clinical trials compared the effect of prophylactic intravesical chemotherapy after radical NU for primary UTUC. Analysis was performed using the Stata 12.0 SE software. RESULTS: Eight trials were analyzed with a total of 979 patients including 521 patients receiving intravesical chemotherapy instillation and 458 without instillation. The BT incidence rate was 125 out of 521 patients (24.0%) with intravesical instillation chemotherapy after NU, and 169 out of 458 patients (36.9%) without intravesical chemotherapy after NU. Compared with those who didn't receive instillation, the pooled odds ratio (OR) of BT recurrence was 0.45 (95% confidence interval/CI 0.34-0.61, p<0.0001) in instillation patients. In the sub-analyses, the OR of single instillation was similar to repeated instillations (0.48 and 0.42). The OR of beginning the first instillation within 24 hrs, 48 hrs and 2 weeks was 0.34, 0.48 and 0.46, respectively. CONCLUSIONS: This systematic review demonstrates that prophylactic intravesical instillation chemotherapy can prevent BT recurrence in primary UTUC patients after NU. It also suggests that single instillation may have a similar effect to repeated instillations. The first instillation beginning within 24 hrs seems to show lower BT recurrence than at 48 hrs or 2 weeks. However, given that some limitations exist, well-designed randomized controlled trials are needed to further evaluate these results. PMID- 26537070 TI - Can transrectal ultrasound-guided biopsy of the prostate with extended 14-core scheme improve the predictive accuracy of Gleason score and tumor site in prostate cancer treatment? AB - PURPOSE: Several studies have reported upgrading of patients with Gleason score (GS) at the time of prostate biopsy to GS following radical prostatectomy (RP). We reviewed the predictive accuracy of extended 14-core prostate biopsies, in terms of GS and tumor location in patients with prostate cancer (PCa) treated by RP. METHODS: We retrospectively reviewed 163 patients who underwent RP for clinically localized PCa. Preoperatively, all patients underwent a transrectal ultrasound-guided biopsy of the prostate (TRUSBP) with 14-core scheme for suspected PCa. According to GS, patients were categorized as low (GS 2-6), moderate (GS 7), and high (GS 8-10). A comparison between GS and tumor laterality of the needle biopsy and RP specimens was carried out. RESULTS: Bioptic GS was low (<= 6) in 55.9%, moderate (7) in 34.9%, and high (>=8) in 9.2% of the patients. Pathological GS was 40.5, 46.6, and 12.9%, respectively. Of the 66 patients with low GS by RP, 41 (62.1%) were in agreement with TRUSBP, whereas 25 (37.9%) were underestimated by TRUSBP. Of the 76 patients with moderate GS by RP, 47 were in agreement with TRUSBP (61.8%), and 4 were underestimated by TRUSBP (5.3%). In the assessment of tumor laterality, TRUSBP falsely showed 51 cases as unilateral tumors, whereas RP diagnosed that both sides had PCa (p<0.001). CONCLUSION: These data are in line with those of the literature, although the group of low-risk tumors remained the same only in 40.5% of the cases. Therefore, we conclude that this type of biopsy (14-core TRUSBP) should not be used alone to guide therapy in PCa. PMID- 26537071 TI - Effect of metformin on the proliferation and apoptosis of the renal cancer cell line 786-O and the underlying mechanisms. AB - PURPOSE: To investigate the effects of metformin (Met) on the proliferation and apoptosis of a renal carcinoma cell line and study the underlying mechanisms. METHODS: Renal cell carcinoma (RCC) line 786-O was cultured with media containing different concentrations of Met. The proliferation and apoptosis of 786-O cells were detected by the MTT method and flow cytometry, respectively. The invasion of 786-O cells was detected by scratch test, and the expression of pro-apoptotic proteins was determined by Western blot assay. RESULTS: The proliferation rates of 786-O cells with Met concentrations of 10, 15, and 20 mM were decreased by 62.8, 61.7, and 65.1%, respectively, with no significant difference among these concentrations (p>0.05). Twenty-four hrs after the scratch assay, the mean migration index in the control group and Met treatment group was 51.6% +/- 5.9 and 28.1% +/- 4.3, and that after 48 hrs was 92.2% +/- 6.4 and 68.0% +/- 4.9, respectively (p<0.05). At low serum concentration, the percentage of apoptotic cells in the Met treatment group (17.6%) was significantly higher (p<0.05) than that in the control group (5.2%). Met (10 mM) treatment significantly increased the expression of Caspase-3 and Bax proteins in 786-O cells (p<0.05). CONCLUSIONS: Metformin may be a potential drug of choice in the treatment of metastatic RCC. PMID- 26537072 TI - JAK/STAT pathway interacts with intercellular cell adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) while prostate cancer stem cells form tumor spheroids. AB - PURPOSE: JAK/STAT is an evolutionarily conserved pathway and very important for second messenger system. This pathway is important in malignant transformation and accumulated evidence indicates that this pathway is involved in tumorigenesis and progression of several cancers. It was possible to assume that activation of JAK/STAT pathway is associated with increase in the expressions of ICAM/1 and VCAM-1. In this study we hypothesized that when cells were maintained as spheroids or monolayers, the structure of cancer stem cells (CSCs) could show differentiation when compared with non-CSCs. METHODS: DU-145 human prostate cancer cells were cultured using the Ege University molecular embryology laboratory medium supplemented with 10% fetal bovine serum. Clusters of differentiation 133 (CD133)(+high)/CD44(+high) prostate CSCs were isolated from the DU145 cell line by using BD FACSAria. CD133//CD44+ CSCs were cultured until confluent with 3% noble agar. The expression of these proteins in CSCs and non CSCs was analyzed by immunohistochemistry. RESULTS: Different expression profiles were observed in the conventional two-dimensional (2D) and three-dimensional (3D) experimental model system when CSCs and non-CSCs were compared. Human prostate CSCs exhibited intense ICAM-1 and VCAM-1 immunoreaction when compared with non CSCs. These findings were supported by the fact that VCAM-1 on the surface of cancer cells binds to its counterreceptor, the alpha4beta1 integrin (also known as very-late antigen, VLA-4), on metastasis-associated macrophages, triggering VCAM-1-mediated activation of the phosphoinositide 3-kinase growth and survival pathway in cancer cells. CONCLUSIONS: The results of this study showed that changes in JAK/STAT pathway are related with adhesion molecules and could affect cancer progression. PMID- 26537073 TI - Protein tyrosine phosphatase nonreceptor type 12 suppresses the proliferation of renal cell carcinoma by inhibiting the activity of the PI3K/mTOR pathway. AB - PURPOSE: To determine the expression and functions of protein tyrosine phosphatase nonreceptor type 12 (PTPN12) in renal cell carcinoma (RCC). METHODS: All RCC tissue and corresponding normal kidney tissue from 116 RCC patients undergoing radical nephrectomy were examined. PTPN12 expression was detected by immunohistochemistry, and PTPN12 mRNA expression by real-time polymerase chain reaction (RT-PCR). PTPN12 expression was increased by stable transfection with a pcDEF3 vector containing full-length cDNA of PTPN12 and was decreased by RNAi in 4 RCC cell lines. Proliferative analysis of RCC cells was done using a WST-1 assay and animal xenograft study. RESULTS: PTPN12 expression in RCC tissue was significantly decreased compared with normal kidney tissue, and was overexpressed in larger tumors, metastasis, and high pathological grades. CONCLUSIONS: PTPN12 expression decreases in human RCC, it is involved in progression and metastasis, and is an independent prognostic factor in RCC. Restoring PTPN12 activity could be a new therapeutic approach in advanced RCC. PMID- 26537074 TI - High selectivity of PI3Kbeta inhibitors in SETD2-mutated renal clear cell carcinoma. AB - PURPOSE: Clear cell renal cell carcinoma (ccRCC) is characterized with frequent mutations of SETD2 gene and our purpose was to explore targeted therapy for this entity. METHODS: By bioinformatic investigation of two major databases, the Genomics of Drug Sensitivity in Cancer (GDSC) database and The Cancer Genome Atlas (TCGA) database, we identified the selective PI3Kbeta inhibitors TGX221 and AZD6482 as selective inhibitors for ccRCC with SETD2 mutations, with AZD6482 additionally targeting PIK3CA and CDK6 mutations. RESULTS: Further investigation on AZD6482 profile revealed that mutations in RB1, KRAS, NRAS and APC contributed in drug resistance. Changes in both AZD6482-sensitive and -resistant gene sets showed limited impact on prognosis. Western blotting showed AZD6482 did not induce changes in a panel of major downstream effectors of AKT, but substantially increased PMS2 level. AZD6482 also selectively inhibited migration, invasiveness, and colony formation of ccRCC cells with SETD2 mutations. Integrative network analysis revealed complex interactions between these genes except SETD2. CONCLUSION: AZD6482 is a novel inhibitor with high selectivity for ccRCC SETD2 mutations. Increased activity of PI3K/AKT/PMS2 could play a role in SETD2 mutated ccRCC. PMID- 26537075 TI - Excellent clinical outcome of triple-negative breast cancer in younger and older women. AB - PURPOSE: To compare the histopathological features and survival of triple negative breast carcinomas (TBNC) in younger and older women. METHODS: We documented 312 patients with TBNC between 2008 and 2013. The histopathological and clinical features of women who were 35 years old or younger (N=53) were compared to those of women who were 60 years old and older (N=58). Patients were administered adjuvant or neoadjuvant chemotherapy, and adjuvant radiotherapy. RESULTS: We diagnosed and treated a total of 312 patients with TNBC. The median follow-up was 38 months (mean +/-SD:37.36; range: 0.2-383.4). The median age of the younger patients was 32 years (mean +/-SD:31.6 +/- 3.72; range:19-36) and of older patients 67 years (mean +/-SD: 68.21 +/- 6.78; range:60-84). The tumor size in young patients was larger than in older patients (p=0.001). More comorbid diseases were observed in older patients than in younger ones (p=0.001). There was no difference in the histological grades, lymphovascular invasion, stage and nodal involvement between the two groups. Local / distant metastases were found in 11 (40.7%) patients in the young patient group and in 16 (59.3%) in old patient group (p=0.704). Three (5.4%) patients died from each group. No significant difference in terms of disease-free survival (DFS) and overall survival (OS) (p=0.914, p=0.939, respectively) was noticed. CONCLUSION: This study showed that older and younger patients with TNBC had similar survival with neoadjuvant and adjuvant chemotherapy and adjuvant radiotherapy, which may be due to similar histopathologic features and intrinsic tumors' activity. PMID- 26537076 TI - Is there any relation between PET-CT SUVmax value and prognostic factors in locally advanced breast cancer? AB - PURPOSE: To investigate the relation between PET-CT SUVmax value and prognostic factors in locally advanced breast cancer. METHODS: Data of 73 patients were retrospectively analyzed. Relations between SUVmax value, clinical stage, tumor grade and breast cancer molecular subtypes were analyzed by using one-way ANOVA and x(2) tests. Correlations between age, ki-67 scores and SUVmax were evaluated by using Pearson's correlation test. A p value <0.05 was considered statistically significant. RESULTS: Median SUVmax values for clinical stages 1, 2 and 3 were 5 (range 2.1-4.1), 10.6 (range 2.9-19.6), and 12.2 (range 3.2-23.3), respectively. Statistically significant difference was noticed between stage 1 and 2 (p=0.014) and stage 1 and 3 (p=0.001). Median SUVmax values of triple negative, luminal A, luminal B and non-luminal HER2 positive groups were 14.4 (range 6.6-23.3), 8.2 (range 2.1-18.2), 10.1 (range 3.5-19.6), and 14 (range 4.1-22.9), respectively. Statistically significant differences were noticed in SUVmax values between triple-negative and luminal A groups (p=0.005) and between non-luminal HER2 positive and luminal A groups (p=0.02). Median SUVmax values of grade 1, 2 and 3 were 5.7 (range 2.1-18.2), 9.5 (range 2.2-21.3), and 11.6 (range 3.5-23), respectively. Statistically significant difference was noticed only between SUVmax values of grade 1 and 3 (p=0.035). There was negative correlation between age and SUVmax value (r=-0.23, p=0.047) and positive correlation between ki-67 and SUVmax value (r=0.43, p=0.016). CONCLUSION: There were significant positive relations between PET-CT SUVmax value and clinical stage, tumor grade, and certain breast cancer molecular subtypes (triple-negative and non-luminal HER2 positive groups. Moreover, positive correlation was found between SUVmax value and ki-67 and negative correlation between SUVmax value and age. PMID- 26537077 TI - Elevated survivin mediated multidrug resistance and reduced apoptosis in breast cancer stem cells. AB - PURPOSE: Overexpression of survivin in breast cancer cells is associated with aberrant inhibition of apoptosis which leads to massive proliferation of cancer cells. Downregulation of survivin by the anticancer agent prodigiosin can efficiently induce apoptosis in cancer cells. METHODS: The levels of survivin expression in breast cancer stem like side population (SP) cells were assessed. Analyzed were also the rate of apoptosis, drug resistance and the efficiency of clone formation of breast cancer SP cells after treatment with progiosin. RESULTS: Breast cancer samples contained about 2.7% of cancer stem like SP cells which possessed elevated mRNA expression of stem cell proteins Oct-4, EpCAM and ABC transporter ABCG2, essential for the maintenance of SP cells. Furthermore, the SP cells displayed overexpression of survivin in conjunction with reduced apoptosis and increased multidrug resistance. After treatment with prodigiosin, the SP cells became more sensitive to apoptosis and to several chemotherapeutic agents. CONCLUSION: These data suggest that increased expression of survivin in SP cells is one of the major factors involved in apoptosis and resistance to chemotherapy. PMID- 26537078 TI - Predictors determining the status of axilla in breast cancer: Where is PET/CT on that? AB - PURPOSE: 18 F-FDG PET/CT has an acceptable specificity but a low sensitivity on the prediction of axillary lymph node (ALN) metastasis in breast cancer. We analyzed the factors that could possibly affect this prediction. METHODS: The records of 270 patients with T1-2 invasive breast cancer who underwent surgery, 116 of whom had been evaluated by preoperative 18 F-FDG PET/CT were reviewed. Prediction of ALN status by PET/CT according to tumor stage, estrogen receptor (ER), progesterone receptor (PgR) and HER2 status, histology, age and sentinel node properties was assessed. RESULTS: ALN metastasis was present in 62 of 131 T1 (43.7%) and 106 of 142 T2 tumors (74.6%), 20 of 46 (43.5%) ER(-) and 146 of 222 (65.8%) ER(+) tumors, 38 of 71 (53.5%) PgR(-) and 127 of 200 (63.5%) PgR(+) tumors. On multivariate analysis only the tumor size (>2 cm) independently correlated with ALN metastasis (Odds ratio/OR=3.1). None of the other parameters had statistical significance in terms of ALN prediction on FDG-PET/CT. CONCLUSION: Though T2 tumors showed increased tendency to metastasize to the axilla, prediction of ALN metastasis in preoperative FDG-PET/CT was not associated with any of the predictive factors. PMID- 26537079 TI - Gene expression characteristics of breast cancer stem cells. AB - PURPOSE: Breast cancer stem cells have been found to be responsible for tumorigenic potential and resistance to therapy. This study aimed at comparing gene expression profiles in breast cancer, based on the differences of stem cells in their biological characteristics. METHODS: Four breast cancer cell lines with different molecular and biological characteristics were used to analyze 84 breast cancer-related gene expressions. These were the ductal human epithelial breast cancer cell line T47D (HTB-133) with metastatic origin, the invasive ductal human breast carcinoma cell line MDA-MB-231 (HTB-26), the ductal human epithelial breast cancer cell line BT-474 (HTB-20) and the human metastatic breast adenocarcinoma cell line MCF-7 (HTB-22). RESULTS: There were significant differences between the breast cancer cells and the stem cells, particularly in angiogenesis, migration, proliferation and the expression of the DNA repair genes. CONCLUSION: These data indicated the absence of a general cancer stem cell in breast cancer. Our study supports the use of the term "breast cancer initiating cells" instead of breast cancer stem cells. All of these genetic differences should be taken into account in the planning of final therapeutic approach. PMID- 26537080 TI - Early tumor-cell gene expression changes may predict the response to first-line bortezomib-based therapy in patients with newly diagnosed multiple myeloma. AB - PURPOSE: Maximizing the response rate to first-line therapy in patients with multiple myeloma (MM) is important because it leads to improved outcome. Gene expression studies have identified prognostic gene sets in patients receiving bortezomib-based therapy. Comparison of the lists of genes derived from two gene expression-based models (GEP70, GEP80) showed that they overlap in three genes, namely PSMD4, BIRC5, and KIAA1754. An unanswered question is whether early gene expression changes can be used as predictors of the response to first-line bortezomib. In this study we aimed to examine the predictive value of gene expression changes for the depth of response after bortezomib-based therapy in newly diagnosed MM. METHODS: We prospectively assessed the relation between early PSMD4, BIRC5, and KIAA1754 gene expression changes (before therapy and one week later) and the response rate after bortezomib-based therapy in 25 patients with newly diagnosed MM. Gene expression was studied by RT-PCR on CD138-selected plasma cells, and changes were recorded as upregulation, downregulation, or unchanged. RESULTS: Whereas baseline prognostic factors including genetic lesions and stage were not predictive of the response rate, we found that early BIRC5 and KIAA1754 gene-expression changes were significantly associated with the depth of response to bortezomib (p=0.001 and p<0.001, respectively). PSMD4 was not predictive of the depth of response. KIAA1754 upregulation was linked to complete remission (CR) or very good partial remission (VGPR). BIRC5 upregulation was linked to stable disease (SD) or progressive disease (PD). We also observed that BIRC5 upregulation was associated with worse progression-free survival (PFS). CONCLUSIONS: Our results suggest that BIRC5 and KIAA1754 gene-expression changes may predict the response to bortezomib-based therapy. These data may have relevance for the stratification and early adaptation of first-line treatment in patients with newly diagnosed MM. PMID- 26537081 TI - Utility of flow cytometric kappa and lambda light chain analysis of peripheral blood. AB - PURPOSE: Monoclonality in the peripheral blood can be shown by flow cytometric analysis of kappa (kappa) and lambda (lambda) light chain ratio of B lymphocytes. We aimed to show the utility of this method in patients with unknown causes of lymphadenopathy and/or splenomegaly. METHODS: This method was performed in 81 adult patients with undefined causes of lymphadenopathy and splenomegaly. RESULTS: 18 (22%) of these patients had clonality and all of them were diagnosed as B cell lymphoma later. None of the patients with benign causes had clonality in the peripheral blood. We could not find any relationship between presence of clonality and type and stage of lymphoma and bone marrow involvement. CONCLUSION: This method is easy to perform, cheap and non-invasive and yet it can give valuable information about the malignant nature of a suspected disease. If there is a sign of clonality in the peripheral blood, more invasive diagnostic procedures should be performed rather than watch and wait. PMID- 26537082 TI - Additive anticancer effects of chrysin and low dose cisplatin in human malignant glioma cell (U87) proliferation and evaluation of the mechanistic pathway. AB - PURPOSE: To evaluate the anticancer effect of chrysin and its additive combination with low-dose cisplatin in human glioma (U87) cancer cells and to study its underlying mechanism. METHODS: Inverted phase and fluorescence microscopic studies were done to demonstrate the effect of chrysin and its combination with cisplatin on cellular morphology and apoptosis. Annexin V-FITC assay was used to quantify the extent of apoptosis in chrysin and chrysin+cisplatin treated cells. Flow cytometry using propidium iodide (PI) as a staining agent was used to study the effect of chrysin and its combination with cisplatin on cell cycle phase distribution. RESULTS: The results showed chrysin brought about a potent and dose-dependent antiproliferative effect in human glioma cancer cells. However, the combination of chrysin with low dose cisplatin led to a much higher growth inhibitory effects indicating an additive effect between the two compounds. The combined effect of chrysin and cisplatin also gave rise to a greater apoptosis induction as well as cell cycle arrest in comparison to the treatment by chrysin or cisplatin alone. Fluorescence microscopy as well as inverted phase contrast microscopy also revealed that the combination of chrysin plus cisplatin resulted in greater apoptosis induction as well as cell morphology alterations. Combination treatment of chrysin and cisplatin resulted in greater percentage of cells in early as well as in late apoptotic stages. The combination effect was also seen in mitochondrial membrane potential loss. CONCLUSION: Chrysin additively potentiates the antiproliferative, cell cycle arrest and apoptotic activity of cisplatin in human glioma cancer (U87) cells. PMID- 26537083 TI - Downregulation of miR-195 via cyclosporin A in human glioblastoma cells. AB - PURPOSE: Cyclosporin A (CsA) is a potent immunosuppressive agent. MicroRNAs (miRs) which post-transcriptionally regulate gene expression are non-coding RNAs. The aim of this study was to investigate the effects of CsA on 88 miRs expression changes in glioma cells (U-87 MG). METHODS: CsA was used in U-87 MG glioma cells in doses of 10, 30 and 60 MUM. Cytotoxic assays and determination of IC50 dose of CsA were performed. Relative quantification of 88 miRs was performed by real time RT-PCR. The fold changes of miRs determined and alterations in the miR expressions were compared with CsA-treated and CsA- free U-87 MG glioma cells. RESULTS: In U-87 MG cells treated with CsA, the IC50 dose was 10 MUM. Seventeen of 88 human miRs were downregulated compared to the untreated control group by using miRs array. It was found that the expression levels of several miRs, in particular miR-195, was significantly decreased in CsA-treated U-87 MG cells. CONCLUSION: This study revealed a significant role of miR-195 in the molecular pathology of glioma cells which can also implicate potential application of miR 195 in cancer therapy. Rather than downregulation of miR-195 alone to exhibit cytotoxicity, treatment with CsA could be more effective especially on temozolomide-resistant cells. PMID- 26537084 TI - Antioxidant, anticancer and apoptotic effects of the Bupleurum chinense root extract in HO-8910 ovarian cancer cells. AB - PURPOSE: The purpose of this study was to evaluate the anticancer, apoptotic and antioxidant properties of Bupleurum chinense (B.C) root extract against human epithelial ovarian cancer cells (HO-8910) in vitro. METHODS: MTT assay was used to evaluate the cell viability of HO-8910 cells after treatment with different B.C extract doses. Apoptotic and morphological effects induced by the extract were demonstrated by inverted phase contrast microscopy and fluorescence microscopy. The percentage of apoptotic cells was quantified by Annexin V/PI double staining assay. Flow cytometry using rhodamine-123 dye was used to measure disruption of mitochondrial membrane potential (Deltapsim). Gel electrophoresis was used to study the effects of the extract on DNA fragmentation. The antioxidant activity of the extract using 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazolin-6-sulphonic acid) (ABTS) radical scavenging assays was also evaluated. RESULTS: The results showed that B.C extract could induce potent and dose-dependent cytotoxic effects on the HO-8910 cells as demonstrated by MTT assay. The extract also induced cell shrinkage, chromatin condensation and membrane blebbing which are the hallmark of apoptosis. The average proportion of Annexin V-staining positive cells (total apoptotic cells) significantly increased from 9.4% in control cells to 18.5, 28.2 and 50.5% in 20, 80 and 120 MUg/ml B.C extract-treated cells respectively. Different doses of the extract (20, 80 and 120 MUg/ml) after 48 hrs exposure led to a substantial increase in DNA fragmentation.The number of cells with disrupted Deltapsim increased from 6.6% in untreated (control cells) to 14.2, 42.1 and 73.4% in 20, 80 and 120 MUg/ml in extract-treated cells, respectively CONCLUSION: The anticancer effects of Bupleurum chinense extract were mediated through the induction of apoptosis, DNA fragmentation and disruption of mitochondrial membrane potential. PMID- 26537085 TI - Constitutive secretion of Interleukin-4 dictates CD133+ side population cells to resist drug treatment and cell death. AB - PURPOSE: In the present study, we made an attempt to elucidate the role of oversecretion of interleukin-4 (IL-4) in cancer stem cells (CSCs) of head and neck squamous cell carcinoma (HNSCC). METHODS: HNSCC samples were analyzed for the presence of CSCs by flow cytometry. In addition, we have performed drug and apoptosis resistance assays to determine the role of IL-4 in CSCs. RESULTS: HNSCC samples contained 3.3% of CD133+ cancer stem like side population (SP) cells in HNSCC which displayed infinite cell proliferation and they had high self-renewal capacity. These CD133+ cells displayed enhanced expression of IL-4, which promoted multidrug and apoptosis resistance. After neutralizing IL-4, the CD133+ SP cells became more sensitive to drug treatment and apoptosis. CONCLUSIONS: Our data suggest that the autocrine secretion of IL-4 is a potential target for the development of novel anticancer drugs to prevent the CSCs-mediated therapy failure and tumorigenesis. PMID- 26537086 TI - Analysis of 50 cases of operated giant thoracic tumors. AB - PURPOSE: To study the experience of the surgical treatment of giant thoracic tumors and the ways to overcome intraoperative and postoperative difficulties. METHODS: A retrospective analysis of the data from 50 patients operated with giant thoracic tumors (26 men and 24 women; age range 0.5-77 years) was carried out. All patients were treated with different surgical resections. The resected tumors weighed between 628 and 2586 g (mean 1973) and the intraoperative blood loss was 400-1500 ml. RESULTS: The tumor was successfully resected in all patients. Forty-eight (96%) patients were treated and discharged after the operation. Two (4%) patients developed postoperative pulmonary edema; one of them died due to disseminated intravascular coagulation (DIC) and the other one was discharged after full recovery. During follow up, one patient died of an abdominal metastasis of malignant mesothelioma 1 year after operation, and another one with mature teratoma died 4 months after the operation but the cause of death was unknown. The success of surgical resection was not related to the pathological tumor type. The surgical treatment was determined by the invasion and distant metastasis of giant thoracic tumors and surrounding tissues. CONCLUSIONS: Patients with giant thoracic tumors often have severe symptoms that cannot be managed with conservative treatment. However, surgery can completely resolve the symptoms. In order to fully reveal the operative field, the incision has to be as close as possible to the tumor. Various surgical techniques, such as complete, segmented, or major portion incisions, can be used, and attention should be paid to avoid major intraoperative bleeding. Preventive measures against re-expansion pulmonary edema should be applied as soon as possible after the surgery. PMID- 26537087 TI - Prescription consisting of Vitamin C and Baicalin inhibits tumor growth by enhancing the antioxidant capacity in vivo. AB - PURPOSE: To explore the antitumor effect of prescription consisting of Vitamin C (Vc) and Baicalin (PVB). METHODS: To explore the antitumor effect of PVB, using U14 cervical tumor-bearing mice model was used and the drugs were administrated through the gavages. Spectrophotometry was used to determine the content of superoxide dismutase (SOD), malondialdehyde (MDA) and cytokines IL-2, Il-4 and IFN-gamma. RESULTS: PVB had a better antitumor effect than baicalin and Vc used alone with an inhibition rate of 58.18% (p<0.05); PVB significantly improved the spleen index (p<0.01), and significantly reduced MDA content (p<0.01) but increased SOD activity in liver tissue and serum (p<0.01). CONCLUSIONS: PVB shows better antitumor effect than Vc and baicalin used alone, and it can significantly enhance the immunity and antioxidant capacity of the mice. PMID- 26537088 TI - Conflicting interests involved in the process of publishing in biomedical journals. AB - This short discussion on conflicting interests in publishing is designed to help all participants (authors, editors and peer reviewers) in the publication of biomedical papers. Authors who submit manuscripts to a journal are responsible for the overall quality and integrity of the paper. The main goal of the editor is to provide readers with the most relevant information by insuring proper presentation and interpretation of scientific data. The editor informs readers on potential conflicting interests of the authors to enable the reader to judge a paper in a more informative way. However, the editor must also consider potential conflicting interests of peer reviewers. If a peer reviewer has a potential conflicting interest in evaluating a manuscript, he/she should not accept the job of reviewing it. If the editor or any member of the executive board has a similar conflict of interest for an article under consideration, including an editorial for this journal, such persons should not participate in the vote to endorse the article, and the journal should publish a note to that effect. When an article is published in the local language for a "small scientific community" there is always a risk that peer review could reflect personal relationships and animosities. Blinding the reviewer to the author(s) might eliminate a reviewer's conflict of interests, but this is not always possible or even desirable. A better solution would be to have the journal publish all scientific articles in English. This would provide both wider readership and a larger group of international reviewers. To gain better reviewers, the journal staff could educate young local investigators by publishing educational articles. Advantages and disadvantages of publishing a statement on conflicting interests are discussed. PMID- 26537089 TI - Breast cancer and high-grade glioma: link or coincidence? PMID- 26537090 TI - Does eribulin mesylate cause recurrent transient diplopia? PMID- 26537091 TI - May there be a role for hormonal manipulation for treatment of hormone receptor negative breast cancer? PMID- 26537092 TI - Simultaneous genital & oropharyngeal HPV-related infection with Topoisomerase IIa overexpression. PMID- 26537093 TI - Uterine cancer in the writings of ancient Greek physicians. AB - In this article, we present the views on uterine cancer of the ancient Greek physicians. We emphasize on uterine's cancer aetiology according to the dominant in antiquity humoural theory, on its surgical treatment suggested by Soranus of Ephesus, and in the vivid description provided by Aretaeus of Cappadocia. During that period, uterine cancer was considered as an incurable and painful malignancy and its approach was mainly palliative. PMID- 26537094 TI - Hypothalamic-pituitary-adrenal axis activity is associated with the prevalence of chronic kidney disease in diabetic patients. AB - Progression of chronic kidney disease (CKD) in diabetic patients can occur through enhanced hypothalamic-pituitary-adrenal (HPA) axis activity. The purpose of our study was to determine whether HPA axis activity influences the prevalence of CKD in patients with type 2 diabetes mellitus. Seventy-seven diabetic patients (mean age, 60 years) were enrolled. CKD was defined by K/DOQI criteria, and serum cortisol level was measured after the 1 mg overnight dexamethasone suppression test (F-DST). F-DST values were significantly negatively correlated with estimated glomerular filtration rate (eGFR), and significantly positively correlated with cystatin C level and spot urine albumin to creatinine ratio in simple and multiple regression analyses. The subjects were divided into 3 groups (low, middle, and high) according to the F-DST, and the odds for CKD were 8.7 fold (95% confidence interval 2.56 to 29.6, P=0.01) and 12.5-fold (95% confidence interval 3.3 to 47.9, P<0.001) higher in subjects in the middle and high groups than those in the low group, respectively. In multivariate regression analysis, subjects in the middle group and high group (compared to those in the low group) had 13.0-fold (95% confidence interval, 2.9 to 58.8 and P=0.001) and 14.7-fold (95% confidence interval, 2.8 to 78.5 and P=0.002), respectively, higher risk for CKD. In conclusion, F-DST values have a relationship with decreased eGFR and increased cystatin C or albumin excretion involved in CKD, and enhanced HPA axis activity may be an independent risk factor for CKD in patients with type 2 diabetes mellitus. PMID- 26537095 TI - Patient Preferences for Treatment of Basal Cell Carcinoma: Importance of Cure and Cosmetic Outcome. AB - Treatment options for localized resectable basal cell carcinoma (BCC) include micrographically controlled surgery, simple excision, curettage, laser ablation, cryosurgery, imiquimod, 5-fluorouracil, photodynamic therapy and radiotherapy. The aim of this study was to assess the preferences of patients with BCC for outcome (cure and recurrence rate, cosmetic outcome, risk of temporary and permanent complications) and process attributes (type of therapy, treatment location, anaesthesia, method of wound closure, duration of wound healing, out-of pocket costs) of these treatments with conjoint analysis. Participants (n = 124) attached greatest importance to recurrence rate (relative importance score (RIS) = 17.28), followed by cosmetic outcome (RIS = 16.90) and cure rate (RIS = 15.02). Participants with BCC on the head or neck were particularly interested in cosmetic outcome. Those with a recurrence were willing to trade risk of recurrence, treatment location and duration of wound healing for a better cosmetic result. In summary, participants particularly valued cure and cosmetic outcome, although preferences varied with individual and tumour-associated characteristics. PMID- 26537096 TI - A Comparative Evaluation of Parent Training for Parents of Adolescents with Developmental Disorders. AB - BACKGROUND: In the present study, we evaluated the effectiveness of a parent training (PT) program in Japan for parents of adolescents with developmental disorders (DDs). In Japan, there were no separate programs for parents of children with DDs in early adolescence and beginning to assert their independence from their families despite the many parent-child conflicts and secondary disorders arising from the children. METHODS: The parents of forty-four adolescent children ranging in ages from ten to seventeen were assigned to either a control group or an experimental group. The program comprised two hour biweekly sessions for three months. The program we examined in this program are: how to praise, stress management for parents, cognitive restructuring, how to scold, problem-solving communication training and how to make a behavior contract. To compare the effectiveness of this program in the control and experimental groups, two-way analysis of variance was used to analyze data collected using psychological assessment scales such as the Strengths and Difficulties Questionnaire (SDQ), the Child Behavior Checklist (CBCL), the Conflict Behavior Questionnaire for Parents (CBQ), and the Beck Depression Inventory (BDI-II). RESULTS: The results showed a significant difference between pre- and post test scores on CBCL, BDI-II, and CBQ, but not on SDQ. The findings indicate that children's behavioral problems and parent-child conflict in the experimental group were improved at the end of the program. CONCLUSION: Accordingly, special programs are needed for adolescent PT as well as PT programs for children with DDs. PMID- 26537097 TI - Apolipoprotein A1 -75 G/A and +83 C/T polymorphisms and renal cancer risk. AB - BACKGROUND: Apolipoprotein A1 (ApoA1) is the major apoprotein constituent of high density lipoprotein that can play important roles in tumor invasion and metastasis. The objective of the present study was to evaluate the association of two genetic variants (-75 G/A and +83 C/T) of APOA1 with predisposition to renal cancer. METHODS: A total of 432 subjects, including 216 pathologically-proven renal cancer cases and 216 age- and gender-matched healthy controls, were recruited into this hospital-based case-control study. Genotyping of the APOA1 was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) combined with gel electrophoresis, and then confirmed by direct sequencing. RESULTS: Patients with renal cancer had a significantly higher frequency of APOA1 -75 AA genotype [odds ratio (OR) = 2.10, 95% confidence interval (CI) = 1.18, 3.75; P = 0.01] and APOA1 -75 A allele (OR =1.40, 95% CI = 1.05, 1.87; P = 0.02) than controls. When stratifying by the distant metastasis status, patients with distant metastasis had a significantly higher frequency of APOA1 -75 AA genotype genotype (OR =2.20, 95% CI = 1.04, 4.68; P = 0.04). CONCLUSION: This study is, to our knowledge, the first to examine prospectively an increased risk role of APOA1 -75 AA genotype and APOA1 -75 A allele in renal cancer susceptibility. PMID- 26537098 TI - Thrombosed cor triatriatum sinistrum mimicking left atrial mass and causing unilateral pulmonary edema. AB - 46 year old female with history of progressive shortness of breath for 3 years associated with recurrent right lung infiltrates and hemoptisis. A computed tomography of the chest showed a left atrial mass suggestive of atrial myxoma confirmed with transesophageal echocardiogram. Contrary with findings from a dedicated EKG gated cardiac computed tomography suggestive of cor triatriatum with associated thrombus and less likely a neoplasm; findings later on confirmed during surgery. Cardiac CT offers superior spatial resolution and multi-planar image reconstructions, allowing improved characterization of cardiac structures and cardiac masses compared to other traditional cardiovascular imaging modalities. PMID- 26537099 TI - Surgical options to treat constipation: A brief overview. AB - Patients with intractable chronic constipation should be evaluated with physiological tests after structural disorders and extracolonic causes have been excluded. Conservative treatment options should be tried unstintingly. It should be pointed out that especially new drugs such as prucalopride and linaclotide seem to be a big step forward in treating patients with chronic constipation. If surgery is indicated, for many years subtotal colectomy with IRA was the treatment of choice, although segmental resections were also a good option for isolated megasigmoid, sigmoidocele or recurrent sigmoid volvulus. Nowadays, less invasive procedures like sacral nerve modulation (SNM) should be tried first. If unsuccessful, colectomy can still be considered. In general, patients with a gastrointestinal dysmotility syndrome (GID) should not be offered any surgical options because of their anticipated poor results. Moreover, patients with psychiatric disorders should be actively discouraged from resection, as they tend to have a poorer prognosis. Patients must be counseled that pain and/or bloating will likely persist even if surgery normalizes bowel frequency. Patients with associated problems may be better served by having a stoma without resection as both a therapeutic maneuver and a diagnostic trial. Colectomy is not an option for the treatment of pain and/or abdominal bloating. In most cases outlet obstruction can be treated successfully with a conservative approach. However, nowadays there are also a variety of surgical options on the market. Each technique has its special place in the armamentarium of a colorectal surgeon but its exact role is not defined yet.The aim of this article is to give a brief overview, how to diagnose and treat chronic constipation from the standpoint of a colorectal surgeon.Surgical treatment of chronic constipation is not routine and is performed only in exceptional cases. But one thing first: a "too long gut" (dolichocolon) per se is never an indication for surgery. The aim of this manuscript is to give a brief overview about possible mechanisms of constipation, diagnostic methods and tools and the various conservative and operative treatment options. Moreover, please always keep in mind that constipation may not only be a symptom, but even a distinct disease! PMID- 26537100 TI - [Gastric stump cancer--unicentric analysis of 7 patients]. AB - INTRODUCTION: Gastric stump cancer accounts for 14% of all gastric carcinomas. Originally this term included patients who previously underwent surgery due to peptic ulcer disease but today gastric stump cancer also includes patients diagnosed some time after primary gastric resection due to gastric cancer. The incidence is increasing. Gastric stump cancer is associated with poor prognosis and its reported resecability is around 40%. METHODS: We retrospectively analyzed the data of 7 patients with a preoperatively histologically confirmed stump cancer who had been operated at the Department of Surgery at Novy Jicin Hospital during 2006-2014. RESULTS: We operated 5 men and 2 women with the median age of 70 years (5580). The primary surgical resection in all our patients was BII gastric resection due to peptic ulcer disease, and GSC had evolved within a median of 38 years (3246) after primary intervention. None of the patients had been regularly screened by endoscopy following primary surgery. We performed five curative resections (four total gastrectomies, one subtotal gastrectomy). Our resecability rate was 71%. In two cases, only explorative laparotomy was performed due to generalisation of the malignancy. Two patients from the resected group died after 30 and 34 months due to progression of their disease; the other three patients are still alive after 17, 19 and 88 months. CONCLUSION: Gastric stump cancer is a malignancy often diagnosed in its late stages. Regural endoscopic screening after primary gastric resection for benign disease can lead to diagnosis at an earlier stage, thereby improving the resection rate and overall survival. This also applies to long-term follow-up of patients with primary subtotal gastrectomy for cancer. Lymphatic metastasizing of the carcinoma can often be different due to the previous surgical intervention and altered anatomy. This must be taken into account during operations. PMID- 26537101 TI - [Cholecystostomy--an obsolete or relevant treatment?]. AB - INTRODUCTION: Percutaneous cholecystostomy is considered to be an emergency treatment option when conservative treatment of acute cholecystitis fails in elderly and critically ill patients. The question is: to what extent is this technique still up-to-date or obsolete. METHODS: We retrospectively reviewed data of patients who underwent a computer tomography (CT) guided percutaneous cholecystostomy between 1/20101/2015. We analyzed the patient data, the success rate, complications of the procedure, short- and long-term outcomes. RESULTS: 30 patients undergoing CT-guided percutaneous cholecystostomy at the Department of Surgery, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital during the study period were enrolled. The study group included 21 females (70%) and 9 males (30%) with mean age of 78 years (SD+/ 12.3), median 82 years (range 3493 years). Percutaneous cholecystostomy was indicated for patients with severe cholecystitis/empyema of the gallbladder not responding to conservative therapy who were poor candidates for operative cholecystectomy. Of these, 23 patients (77%) were successfully treated with initial percutaneous cholecystostomy whereas 7 patients (23%) experienced treatment failure - one was subsequently successfully treated with repeated percutaneous cholecystostomy and six underwent emergency cholecystectomy. The mean length of stay was 16.5 days (SD+/-8.2), median 15 days (7-49 days). The total 30-day mortality was 17%, and indication-related mortality was 10%. Three patients (10%) had a recurrence. One patient required repeated percutaneous drainage, the second recovered on conservative treatment and the third patient underwent acute cholecystectomy. Only one patient (3%) underwent delayed laparoscopic cholecystectomy without complications. CONCLUSION: CT guided percutaneous cholecystostomy is a safe and effective therapeutic modality in patients unfit for surgery. PMID- 26537102 TI - [The use of hybrid revascularization procedures for the therapy of multilevel lower extremity arterial disease--analysis of single center experience]. AB - INTRODUCTION: The goal of this study was to evaluate our experience and results of single staged hybrid procedures for revascularization of lower extremities affected by multilevel arterial occlusive disease. We analysed the effect of the indication and type of reconstruction on patency. METHOD: Patients were retrospectively reviewed. Data collection was conducted prospectively. Patients were divided into 5 groups based on the type of hybrid reconstruction. Group "1" included patients who underwent transluminal angioplasty (TA)+/-stenting of iliac arteries with endarterectomy (EA) and patch arterioplasty of the femoral bifurcation (35 patients; 27.6 %). Group "2" included patients who underwent TA+/ stenting of iliac arteries with infrainguinal bypass (15 patients; 11.8 %). Group "3" consisted of patients who underwent TA+/-stenting of outflow lower extremity arteries: superficial femoral artery+/-popliteal artery+/-crural arteries in combination with EA and patch arterioplasty of the femoral bifurcation (52 patients; 40.9 %). Group "4" represented patients who underwent infrainguinal bypass surgery in combination with TA distal to the site of open reconstruction (3 patients; 2.4%). Group "5" represented a heterogenous population of patients who underwent a hybrid reconstruction which did not belong to any of the 4 previously mentioned groups (22 patients; 17.3 %). The patients were divided into 3 groups based on the indication criteria of the intervention: Patients with acute limb ischemia (ALI) were put into group "ALI". Patients with critical limb ischemia (CLI) were put into group "CLI". Patients with claudications were put into group "II". Patency analyses were performed using Kaplan-Meier life tables. Differences in patency rates between the different groups of patients were determined using the log-rank test. Statistical analysis was performed using the software IBM SPSS Statistics 21.0. RESULTS: The study included 127 patients who underwent 127 hybrid arterial procedures. Technical and clinical success rates were 96.9% and 98.4%. 30-day perioperative mortality rate was 3.1%. The primary (PP), assisted-primary (APP) and secondary patency (SP) results at 2 years were the best amongst the patients from groups "1" and "3". These patients underwent patch arterioplasty+/-EA of the femoral bifurcation in combination with transluminal angioplasty of inflow or outflow arteries of the lower extremity. The resulting PP, APP and SP rates at 2 years in group "1" were 80.6%, 84.3% and 84.3%. Patency rates in group "3" in the same order at 2 years were 81.1 %, 82.8% and 86.3%. Significantly lower patency rates were achieved in patients from groups "2" and "5". The resulting PP, APP and SP rates in group "2" at 2 years were 39.4%, 59.1% and 59.1%; in group "5" at 2 years they were 30.4%, 49.2% and 70.7%. Taking into account the effect of the indication on patency rates, we found that patients from group "CLI" had the best APP and SP rates at 2 years: 81.6% and 86.2%. Only the PP rate at 2 years was the best in group "II" (patients with claudications): 71.1%. Patients who underwent their operations because of acute limb ischemia (group "ALI") achieved the worst results among these 3 groups. Their PP, APP and SP rates at 2 years were 33.7%, 46.2% and 45.5%. Patients from the group "CLI" had the best amputation-free survival at 2 years: 89.1% amongst the 3 groups subdivided according to the indication for the intervention ("II" 81.9%; "ALI" 61.4%). Overall survival and amputation-free survival at 2 years were 93.2% and 82.3%, respectively, for the whole studied population. CONCLUSION: The hybrid procedure is an intervention which combines endovascular and open reconstruction performed at the same time. Hybrid procedures provide effective therapy for patients with multilevel lower extremity arterial disease. They have low complication rates, periprocedural morbidity and mortality. Using these procedures, we are able to achieve good limb salvage rates and patency rates irrespective of the form of chronic limb ischemia (claudications, critical limb ischemia). Results for patients with acute limb ischemia are inferior. The combination of patch arterioplasty+/-endarterectomy of the femoral bifurcation with transluminal angioplasty of inflow or outflow limb arteries is our hybrid procedure of choice with the most favourable results. PMID- 26537103 TI - [Choledochal cyst]. AB - Choledochal cyst is a rare disease with a considerably higher incidence found in the Asian population. Although its etiology is not completely known, the disease is believed to be associated with anomalies in the anatomy of the biliary tract. While being a benign unit, it is considered as a precancerosis with the risk of conversion to the biliary tract carcinoma. Radical surgical removal with biliary tract reconstruction is the only curative solution. The authors present the case report of a patient with choledochal cyst type I according to Todani PMID- 26537104 TI - [Extraintestinal GIST--case report]. AB - Gastrointestinal stromal tumors (GISTs) represent the majority of mesenchymal neoplasms of the gastrointestinal tract. Extragastrointestinal stromal tumors (EGISTs), which are neoplasms with histological and immunohistological features overlapping with those of GISTs, are found in the abdomen outside of the gastrointestinal tract with no connection to the gastric or intestinal wall. We present a case of EGIST arising in the mesentery of a 68 years old patient. PMID- 26537105 TI - Phylogenetic and epidemiological analysis of measles outbreaks in Denmark, 2013 to 2014. AB - Despite the introduction of safe, effective vaccines decades ago and joint global public health efforts to eliminate measles, this vaccine-preventable disease continues to pose threats to children's health worldwide. During 2013 and 2014, measles virus was introduced into Denmark through several independent importations. This resulted in a number of secondary cases (n=7), with two clusters in 2013 and one in 2014. In total, there were 44 cases of measles. Most cases (n=41) were laboratory confirmed by detection of measles virus genome by real-time reverse transcription (RT)-PCR and IgM antibodies. The viruses from confirmed cases were genotyped by sequencing. Only one genotype circulated each year, i.e. D8 and B3, respectively. Sequencing of measles virus from different clinical specimens from the same patients revealed that sequence variants of measles viruses might co-exist and co-transmit during an outbreak. The majority of the cases were unvaccinated (n=27) or recipients of one dose of measles-mumps rubella (MMR) vaccine (n=7). In addition, two fully vaccinated adult cases were reported in 2014. We demonstrate the transmission of measles virus in a population in which the two-dose MMR vaccination coverage rate was 80% and how even vaccinated individuals may be at risk of contracting measles once transmission has been established. PMID- 26537106 TI - Enduring deficits in memory and neuronal pathology after blast-induced traumatic brain injury. AB - Few preclinical studies have assessed the long-term neuropathology and behavioral deficits after sustaining blast-induced neurotrauma (BINT). Previous studies have shown extensive astrogliosis and cell death at acute stages (<7 days) but the temporal response at a chronic stage has yet to be ascertained. Here, we used behavioral assays, immmunohistochemistry and neurochemistry in limbic areas such as the amygdala (Amy), Hippocampus (Hipp), nucleus accumbens (Nac), and prefrontal cortex (PFC), to determine the long-term effects of a single blast exposure. Behavioral results identified elevated avoidance behavior and decreased short-term memory at either one or three months after a single blast event. At three months after BINT, markers for neurodegeneration (FJB) and microglia activation (Iba-1) increased while index of mature neurons (NeuN) significantly decreased in all brain regions examined. Gliosis (GFAP) increased in all regions except the Nac but only PFC was positive for apoptosis (caspase-3). At three months, tau was selectively elevated in the PFC and Hipp whereas alpha-synuclein transiently increased in the Hipp at one month after blast exposure. The composite neurochemical measure, myo-inositol+glycine/creatine, was consistently increased in each brain region three months following blast. Overall, a single blast event resulted in enduring long-term effects on behavior and neuropathological sequelae. PMID- 26537107 TI - The quest for a new methodology for dementia care research. PMID- 26537108 TI - A sequential logic gate-based "smart probe" for selective monitoring of Cu(2+), Fe(3+) and CN(-)/F(-)via differential analyses. AB - A sequential logic gate-based probe has been constructed for the detection of Cu(2+), Fe(3+), CN(-) and F(-) at ppm levels which potentially meets real-world challenges through a simple synthetic route, with rapid response, water based activity, visualization by the naked eye, regenerative action, high selectivity and multiple readout for precise analysis. PMID- 26537109 TI - Bioactive Phenylpropanoids, Phenolic Acid and Phytosterol from Landolphia owariensis P. Beauv Stringy Seed Pulp. AB - Landolphia owariensis P. Beauv is economically important for latex/rubber and folklore medicine. Its stringy seed pulp is freely eaten by humans and animals. Thus, L. owariensis stringy seed pulp was extracted serially with hexane and acetone to isolate and characterize its active pharmaceutical ingredients. Solvent/solvent partition and chromatographic separations afforded four bioactive compounds, (E)-3-(3,4-Dihydroxylcinnamoyl)quinic acid [(E)-Chlorogenic acid], I; (E)-3-(3,4-Dihydroxylcinnamoyl)quinic acid methyl ester [(E)-Chlorogenic acid methyl ester], II; 3,4-Dihydroxylbenzoic acid, (Protocatechuic acid), III; and 22,23-Dihydrostigmaster-3beta-ol (3beta-Sitosterol) (IV). Structures of I, II and III were assigned by combinations of high-performance liquid chromatography ultraviolet-visible spectroscopy, 1D and 2D nuclear magnetic resonance spectroscopy, high-performance liquid chromatography-mass spectrometry and reference to published literatures, while compound IV was identified by chemical methods and gas chromatography-mass spectrometry. The phenylpropanoids and phenolic acid (compounds I, II and III) are notable standard antioxidants with confirmed hepatic-protective activity and other exciting biological activities. Compound IV has been reported to possess anti-inflammatory activity, anti-colon cancer action and a cholesterol-lowering effect. The described compounds are important medicinal constituents of L. owariensis stringy seed pulp, and this is the first major report on the phytochemistry of L. owariensis P. Beauv. PMID- 26537110 TI - Identification and comprehensive analyses of the CBL and CIPK gene families in wheat (Triticum aestivum L.). AB - BACKGROUND: Calcineurin B-like (CBL) proteins belong to a unique group of calcium sensors in plant that decode the Ca(2+) signature by interacting with CBL interacting protein kinases (CIPKs). Although CBL-CIPK complexes have been shown to play important roles in the responses to various stresses in plants, little is known about their functions in wheat. RESULTS: A total of seven TaCBL and 20 TaCIPK genes were amplified from bread wheat, Triticum aestivum cv. Chinese Spring. Reverse-transcriptase-polymerase chain reaction (RT-PCR) and in silico expression analyses showed that TaCBL and TaCIPK genes were expressed at different levels in different tissues, or maintained at nearly constant expression levels during the whole life cycle of the wheat plant. Some TaCBL and TaCIPK genes showed up- or down-regulated expressions during seed germination. Preferential interactions between TaCBLs and TaCIPKs were observed in yeast two hybrid and bimolecular fluorescence complementation experiments. Analyses of a deletion series of TaCIPK proteins with amino acid variations at the C-terminus provided new insights into the specificity of the interactions between TaCIPKs and TaCBLs, and indicated that the TaCBL-TaCIPK signaling pathway is very complex in wheat because of its hexaploid genome. The expressions of many TaCBLs and TaCIPKs were responsive to abiotic stresses (salt, cold, and simulated drought) and abscisic acid treatment. Transgenic Arabidopsis plants overexpressing TaCIPK24 exhibited improved salt tolerance through increased Na(+) efflux and an enhanced reactive oxygen species scavenging capacity. CONCLUSIONS: These results contribute to our understanding of the functions of CBL-CIPK complexes and provide the basis for selecting appropriate genes for in-depth functional studies of CBL-CIPK in wheat. PMID- 26537111 TI - The impact of comorbid disease history on all-cause and cancer-specific mortality in myeloid leukemia and myeloma - a Swedish population-based study. AB - BACKGROUND: Comorbidity increases overall mortality in patients diagnosed with hematological malignancies. The impact of comorbidity on cancer-specific mortality, taking competing risks into account, has not been evaluated. METHODS: Using the Swedish Cancer Register, we identified patients aged >18 years with a first diagnosis of acute myeloid leukemia (AML, N = 2,550), chronic myeloid leukemia (CML, N = 1,000) or myeloma (N = 4,584) 2002-2009. Comorbid disease history was assessed through in- and out-patient care as defined in the Charlson comorbidity index. Mortality rate ratios (MRR) were estimated through 2012 using Poisson regression. Probabilities of cancer-specific death were computed using flexible parametric survival models. RESULTS: Comorbidity was associated with increased all-cause as well as cancer-specific mortality (cancer-specific MRR: AML = 1.27, 95 % CI: 1.15-1.40; CML = 1.28, 0.96-1.70; myeloma = 1.17, 1.08-1.28) compared with patients without comorbidity. Disorders associated with higher cancer-specific mortality were renal disease (in patients with AML, CML and myeloma), cerebrovascular conditions, dementia, psychiatric disease (AML, myeloma), liver and rheumatic disease (AML), cardiovascular and pulmonary disease (myeloma). The difference in the probability of cancer-specific death, comparing patients with and without comorbidity, was largest among AML patients <70 years, whereas in myeloma the difference did not vary by age among the elderly. The probability of cancer-specific death was generally higher than other-cause death even in older age groups, irrespective of comorbidity. CONCLUSION: Comorbidities associated with organ failure or cognitive function are associated with poorer prognosis in several hematological malignancies, likely due to lower treatment tolerability. The results highlight the need for a better balance between treatment toxicity and efficacy in comorbid and elderly AML, CML and myeloma patients. PMID- 26537112 TI - New Permian fauna from tropical Gondwana. AB - Terrestrial vertebrates are first known to colonize high-latitude regions during the middle Permian (Guadalupian) about 270 million years ago, following the Pennsylvanian Gondwanan continental glaciation. However, despite over 150 years of study in these areas, the biogeographic origins of these rich communities of land-dwelling vertebrates remain obscure. Here we report on a new early Permian continental tetrapod fauna from South America in tropical Western Gondwana that sheds new light on patterns of tetrapod distribution. Northeastern Brazil hosted an extensive lacustrine system inhabited by a unique community of temnospondyl amphibians and reptiles that considerably expand the known temporal and geographic ranges of key subgroups. Our findings demonstrate that tetrapod groups common in later Permian and Triassic temperate communities were already present in tropical Gondwana by the early Permian (Cisuralian). This new fauna constitutes a new biogeographic province with North American affinities and clearly demonstrates that tetrapod dispersal into Gondwana was already underway at the beginning of the Permian. PMID- 26537113 TI - Venous Endothelial Marker COUP-TFII Regulates the Distinct Pathologic Potentials of Adult Arteries and Veins. AB - Arteries and veins have very different susceptibility to certain vascular diseases such as atherosclerosis and vascular calcification. The molecular mechanisms of these differences are not fully understood. In this study, we discovered that COUP-TFII, a transcription factor critical for establishing the venous identity during embryonic vascular development, also regulates the pathophysiological functions of adult blood vessels, especially those directly related to vascular diseases. Specifically, we found that suppression of COUP TFII in venous ECs switched its phenotype toward pro-atherogenic by up-regulating the expression of inflammatory genes and down-regulating anti-thrombotic genes. ECs with COUP-TFII knockdown also readily undergo endothelial-to-mesenchymal transition (EndoMT) and subsequent osteogenic differentiation with dramatically increased osteogenic transcriptional program and calcium deposition. Consistently, over-expression of COUP-TFII led to the completely opposite effects. In vivo validation of these pro-atherogenic and osteogenic genes also demonstrates a broad consistent differential expression pattern in mouse aorta vs. vena cava ECs, which cannot be explained by the difference in hemodynamic flow. These data reveal phenotypic modulation by different levels of COUP-TFII in arterial and venous ECs, and suggest COUP-TFII may play an important role in the different susceptibilities of arteries and veins to vascular diseases such as atherosclerosis and vascular calcification. PMID- 26537114 TI - Inferior vena cava diameters and collapsibility index reveal early volume depletion in a blood donor model. AB - BACKGROUND: Changes of volume status can be readily inferred from variations in diameter of the inferior vena cava (IVC) measured by ultrasound. However the effect of IVC changes following acute blood loss are not fully established. In this study, three different approaches to measuring IVC variables were compared in healthy blood donors, as a model of acute volume depletion, in order to establish their relative ability to detect acute blood loss. METHODS: Inspiratory and expiratory IVC diameters were measured before and after blood donation in hepatic long axis, hepatic short axis and renal short axis views using a 2-5 MHz curvilinear probe. All measurements were recorded and examined in real-time and post-processing sessions. RESULTS: All windows performed satisfactorily but the renal window approach was feasible in only 30 out of 47 subjects. After blood donation, IVC diameters decreased in hepatic long axis, hepatic short axis and renal short axis (expiratory: -19.9, -18.0, -26.5 %; CI 95 %: 14.5-24.1; 13.1 22.9; 16.0-35.9, respectively) (inspiratory: -31.1, -31.6, -36.5 %; CI 95 %: 21.3 40.1; 18.8-45.2; 23.4-46.0, respectively), whereas the IVC collapsibility index increased by 21.6, 22.6 and 19.3 % (CI 95 %: 11.6-42.9; 18.5-39.5; 7.7-30.0). IVC diameters appeared to return to pre-donation values within 20 min but this was only detected by the hepatic long axis view. CONCLUSIONS: IVC diameter and collapsibility index variations, as measured in M mode, consistently detect volume changes after blood donation. The longitudinal mid-hepatic approach performed better by allowing a panoramic view, avoiding anatomical aberrancies at fixed points and permitting to identify the best possible perpendicular plane to the IVC. In addition, it was able to detect time-dependent physiological volume replacement. In contrast, in our hands, the renal window could not be visualized consistently well. PMID- 26537115 TI - Fibroblast growth factor 8 regulates postnatal development of paraventricular nucleus neuroendocrine cells. AB - BACKGROUND: Fibroblast growth factors (FGFs) are crucial signaling molecules that direct the development of the vertebrate brain. FGF8 gene signaling in particular, may be important for the development of the hypothalamus-pituitary adrenal (HPA)-axis. Indeed, newborn Fgf8 hypomorphic mice harbor a major reduction in the number of vasopressin (VP) neurons in the paraventricular nucleus (PVN), the central output component of the HPA-axis. Additionally, recent studies indicated that adult heterozygous ((+/neo)) Fgf8 hypomorphic mice exhibit more anxiety-like behaviors than wildtype (WT) mice. These studies led us to investigate whether Fgf8 hypomorphy abrogated VP and/or corticotropin-releasing hormone (CRH) neuronal development in the postnatal day (PN) 21 and adult mouse PVN. Furthermore, we studied whether Fgf8 hypomorphy disrupted HPA responsiveness in these mice. METHODS: Using immunohistochemistry, we examined the development of VP and CRH neurons located in the PVN of PN 21 and adult Fgf8 (+/neo) mice. Moreover, we used a restraint stress (RS) paradigm and measured corticosterone levels with enzyme immunoassays in order to assess HPA axis activation. RESULTS: The number of VP neurons in the PVN did not differ between WT and Fgf8 (+/neo) mice on PN 21 and in adulthood. In contrast, CRH immunoreactivity was much higher in Fgf8 (+/neo) mice than in WT mice on PN 21, this difference was no longer shown in adult mice. RS caused a higher increase in corticosterone levels in adult Fgf8 (+/neo) mice than in WT mice after 15 min, but no difference was seen after 45 min. CONCLUSIONS: First, Fgf8 hypomorphy did not eliminate VP and CRH neurons in the mouse PVN, but rather disrupted the postnatal timing of neuropeptide expression onset in PVN neurons. Second, Fgf8 hypomorphy may, in part, be an explanation for affective disorders involving hyperactivity of the HPA axis, such as anxiety. PMID- 26537116 TI - Comparison of Bone Tissue Elements Between Normal and Osteoarthritic Pelvic Bones in Dogs. AB - Physiochemical analysis of bones affected with osteoarthritis (OA) can be used to better understand the etiology of this disease. We investigated the percentage of chemical elements in canine pelvic bone affected with varying degrees of OA using a handheld X-ray fluorescence (XRF) analyzer that discriminates magnesium (Mg(12)) through bismuth (Bi(83)). A total of 45 pelvic bones, including both ilium and subchondral acetabular bone plates, were categorized as normal (n = 20), mild grade OA (n = 5), moderate grade OA (n = 15), and severe grade OA (n = 5). In normal pelvic, seven elements (P, Ca, Mn, Ag, Cd, Sn, and Sb) differed (p < 0.005) in percentage between ilium and acetabulum. Comparisons among the four OA groups found Mn and Fe to be highest in severe grades (p < 0.05) in both ilium and acetabulum. Three heavy metals (Ag, Sn, and Sb) were detected in high percentages (p < 0.05) in the severe OA group in the acetabulum, but in ilium only Sn was high (p < 0.05) in severe OA. In conclusion, the percentages of several elements differed between pelvic types in dogs, and also with increasing severity of OA. The finding of high Mn and Fe in severe grade OA bone suggests these two elements may be useful in future studies of the etiology and pathophysiology of OA. PMID- 26537117 TI - Rumen Microorganisms Decrease Bioavailability of Inorganic Selenium Supplements. AB - Despite the availability of selenium (Se)-enriched trace mineral supplements, we have observed low Se status in cattle and sheep offered traditional inorganic Se supplements. Reasons for this may include inadequate intake or low bioavailability of inorganic Se sources. The objective of this study was to determine whether rumen microorganisms (RMO) alter the bioavailability of Se sources commonly used in Se supplements. Rumen microorganisms were isolated from ewes (n = 4) and incubated ex vivo with no Se (control), with inorganic Na selenite or Na selenate, or with organic selenomethionine (SeMet). Total Se incorporated into RMO and the amount of elemental Se formed were determined under equivalent conditions. Incorporation of Se from Na selenite, Na selenate, or SeMet into RMO was measured as fold change compared with control (no added Se). Incorporation of Se into microbial mass was greater for SeMet (13.2-fold greater than no-Se control) compared with inorganic Se supplements (P = 0.02); no differences were observed between inorganic Na selenate (3.3-fold greater than no Se control) and Na selenite (3.5-fold greater than no-Se control; P = 0.97). Formation of non-bioavailable, elemental Se was less for RMO incubated with SeMet compared with inorganic Se sources (P = 0.01); no differences were observed between Na selenate and Na selenite (P = 0.09). The clinical importance of these results is that the oral bioavailability of organic SeMet should be greater compared with inorganic Se sources because of greater RMO incorporation of Se and decreased formation of elemental Se by RMO. PMID- 26537118 TI - Effects of Oral Administration of CrCl3 on the Contents of Ca, Mg, Mn, Fe, Cu, and Zn in the Liver, Kidney, and Heart of Chicken. AB - This study aimed to investigate the effects of oral administration of trivalent chromium on the contents of Ca, Mg, Mn, Fe, Cu, and Zn in the heart, liver, and kidney. Different levels of 1/8, 1/4, and 1/2 LD50 (LD50 = 5000 mg/kg body mass) CrCl3 milligrams per kilogram body mass daily were added into the water to establish the chronic poisoning model. Ca, Mg, Mn, Fe, Cu, and Zn were detected with the flame atomic absorption spectrometry in the organs exposed 14, 28, and 42 days to CrCl3, respectively. Results showed that Cr was accumulated in the heart, liver, and kidney significantly (P < 0.05) with extended time and dose. The contents of Ca and Fe increased, whereas those of Mg, Mn, Cu, and Zn decreased in the heart, liver, and kidney of each treated group, which had a dose and time-dependent relationship, but the contents of Mg and Zn in the heart took on a fluctuated change. These particular observations were different from those in the control group. In conclusion, the oral administration of CrCl3 could change the contents of Ca, Mg, Mn, Fe, Cu, and Zn in the heart, liver, and kidney, which may cause disorders in the absorption and metabolism of the metal elements of chickens. PMID- 26537119 TI - Metformin and prostate cancer mortality: a meta-analysis. AB - PURPOSE: Observational studies report conflicting results on the association between metformin exposure and prostate cancer outcomes. This meta-analysis summarizes studies reporting overall survival, prostate cancer-specific mortality, and biochemical recurrence. METHODS: PubMed and Embase were systematically reviewed to identify studies investigating the association between metformin use and clinical endpoints among men with prostate cancer while taking confounding by diabetes diagnosis into account. Pooled risk estimates (hazard ratios, HRs) and 95 % confidence intervals (CIs) were calculated using random effects models. Sensitivity analyses for quality components and factors for heterogeneity were conducted. RESULTS: Of 549 articles identified, nine retrospective cohort studies representing 9,186 patients were included. There was significant heterogeneity between studies, and studies differed in quality. Metformin use was associated with improved overall survival in studies with clear risk window definition (HR 0.88, 95 % CI 0.86-0.90, p < 0.001) and in studies with potential immortal time bias (HR 0.52, 95 % CI 0.41-0.65, p < 0.001). No significant association with prostate cancer-specific mortality was detected (HR 0.76, 95 % CI 0.44-1.31, p = 0.33). Metformin use was associated with a decreased risk of biochemical recurrence (HR 0.79, 95 % CI 0.63-1.00, p = 0.047). CONCLUSIONS: This meta-analysis suggests a benefit of metformin in men with diabetes and prostate cancer. However, further carefully designed studies are needed to confirm findings and to assess potential generalization to non diabetic, non-white, and less aggressively treated men with prostate cancer. PMID- 26537120 TI - Comprehensive capture of cutaneous melanoma by the Ontario Cancer Registry: validation study using community pathology reports. AB - Melanoma is often managed outside hospital settings, creating the potential for underreporting to cancer registries. To our knowledge, completeness of melanoma capture in cancer registries has not been assessed using external data sources since the 1980s. We evaluated the melanoma capture rate from 1993 to 2009 in a provincial cancer registry. We identified all melanoma diagnoses in pathology reports from a major community laboratory in Ontario, Canada. Pathologically confirmed diagnoses were linked to Ontario Cancer Registry (OCR) records using health insurance numbers. We calculated capture rates as the proportion of patients with melanoma confirmed by a pathology report, with a corresponding melanoma diagnosis in OCR. OCR captured 3,798 of 4,275 (88.8, 95 % confidence interval: 87.9, 89.8 %) invasive melanoma diagnoses over the 17-year period. Annual capture rates of 94 % or higher were found for over half the study period. Among all 29,133 melanoma diagnoses in OCR, 27.6 % were registered based on a pathology report alone, compared with 3.4 % for non-cutaneous malignancies. This suggests that comprehensive capture of melanoma cases by a provincial cancer registry is achievable using source data from community laboratories. There is a need for ongoing validation to ensure data remain accurate and complete to reliably inform clinical care, research, and policy. PMID- 26537121 TI - Systematic review of human immunodeficiency virus (HIV) knowledge measurement instruments used on the Arabian Peninsula. AB - BACKGROUND: In 1984, the Kingdom of Saudi Arabia (KSA) began surveillance for human immunodeficiency virus (HIV) incidence and prevalence. However, no culturally-appropriate standardized questionnaire has been developed to measure HIV prevention knowledge in this population. Evidence exists that married Saudi women are especially at higher risk for infection, but lack knowledge of HIV modes of transmission and underestimate their personal risk of becoming infected. The objective of this paper is to present a critical review of existing HIV knowledge measurement tools developed for the KSA and other Arabian Peninsula populations, and to utilize this review to guide the development of a culturally- and gender-sensitive tool. Studies included were in English reporting results of a quantitative survey instrument as either an interview or self-reported questionnaire with questions about knowledge of HIV or AIDS. Surveys must have been given in English or Arabic, and must have been done in a population in the KSA or the Arabian Peninsula. The following data sources were searched for eligible studies: Google Scholar, Google Web, PubMed, PLoS, WHO publications, UN publications, news, and other peer-reviewed publication databases. RESULTS: Sixteen articles met criteria, and of these, 10 (63 %) were conducted in a KSA population, and a majority of the articles studied students of primary, secondary, or post-secondary schools (n = 9, 56 %). Five studies included only men, while the other 11 included both sexes. CONCLUSIONS: The KSA's public health goals should more specifically focus on measuring and improving knowledge in high risk populations such as married women-an option currently limited by commonly available measurement instruments. PMID- 26537122 TI - Extensively and pan-drug resistant Pseudomonas aeruginosa keratitis: clinical features, risk factors, and outcome. AB - BACKGROUND: Emergence of multi-drug resistant (MDR), extensively drug resistant (XDR), and pan-drug resistant (PDR) strains of Pseudomonas aeruginosa pose a significant therapeutic challenge. Managing XDR and PDR Pseudomonas aeruginosa keratitis would be extremely difficult due to paucity of safe and effective topical medications. We aim to describe the clinical features, risk factors, and outcome of XDR and PDR Pseudomonas aeruginosa keratitis. METHODS: A retrospective chart review of consecutive cases of XDR and PDR Pseudomonas aeruginosa keratitis were identified from Ocular Microbiology Department. XDR and PDR were defined based on criteria established by Centers for Disease Control and European Centre for Disease Prevention and Control. The following data was collected: age, gender, occupation, symptom duration, systemic and ocular risk factors, infiltrate characteristics, antimicrobial susceptibility, complications, surgical interventions, presenting, and final visual acuity and final outcome. Complete success was defined as resolution of the infiltrate with scar formation on medical treatment alone. Partial success was the resolution following tissue adhesive application. Failure was an inadequate response to medical therapy with progressive increase in infiltrate, corneal melting, and/or perforation necessitating one or more therapeutic penetrating keratoplasties or evisceration. RESULTS: Fifteen eyes of 13 patients were included. Seven (53.8 %) were male with left eye involvement in nine (60 %) cases. Most common risk factors were bandage contact lens (6, 40 %), topical steroids (5, 33.3 %), previous therapeutic graft (4, 26.6 %), and ocular surface disorder (OSD) following Stevens Johnson Syndrome (SJS) (4, 26.6 %). Of 15 isolates, six (40 %) were sensitive only to imipenem, three (20 %) to colistin, two (13.3 %) to neomycin, one (6.7 %) each to imipenem and colistin, imipenem and ceftazidime, and azithromycin respectively. One isolate was resistant to all antibiotics. Complete success was noted in two (16.67 %), partial success in three (25 %) and failure in seven (58.33 %) eyes. Five (33.3 %) eyes healed on imipenem (three eyes), azithromycin (one eye), and imipenem and colistin (one eye). CONCLUSION: XDR and PDR Pseudomonas aeruginosa keratitis are extremely difficult to treat. Globe salvage was possible in all cases; however, more than half required therapeutic grafts. Close monitoring of patients with known ocular and systemic factors is warranted. PMID- 26537123 TI - Inter-device size variation of small choroidal nevi measured using stereographic projection ultra-widefield imaging and optical coherence tomography. AB - PURPOSE: Our purpose was to compare the tumor sizes of small choroidal nevi using ultra-widefield imaging (UWF) and different optical coherence tomography systems. METHODS: Thirteen choroidal nevi were measured using automatic and manual segmentation techniques, including enhanced depth imaging spectral-domain optical coherence tomography (EDI-SDOCT) and 1050 nm swept source OCT (SSOCT), to compare to measurements obtained using the Optos projection ultra-widefield fundus (UWF) imaging technique. Segmentation artifacts were evaluated for all 13 cases, alongside an additional 12 choroidal nevi, using SSOCT. RESULTS: In tumor eyes, segmentation artifacts for the choroid-sclera interface were found in 42 % of SSOCT scans. EDI-SDOCT can underestimate tumor dimensions and differs up to -8.41 % compared to UWF imaging and by 1.25 % compared to SSOCT cases. The horizontal length of the nevi showed an average difference between EDI-SDOCT and SSOCT of +/ 9.38 %. Measured markers showed an average difference in length of +/- 12.51 %. The average tumor thickness showed a difference of +/- 11.47 %. Comparisons between EDI-SDOCT/UWF, SSOCT/EDI-SDOCT, and marker EDI-SDOCT/SSOCT showed significant mean differences of -122 MUm (CI: -212 to -31 MUm, p = 0.013), 134 MUm (CI: 65-203 MUm, p = 0.0012), and -193 MUm (CI: -345 to -41 MUm, p = 0.017), whereas SSOCT/UWF showed no significant difference with a measurement of 13 MUm (CI: -69-95 MUm, p = 0.74). CONCLUSIONS: Automatic segmentation of nevi requires much caution, because a choroidal tumor can trigger many artifacts. It would be beneficial to monitor choroidal nevi using the same type of OCT technology, because a tumor is displayed differently. PMID- 26537124 TI - Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes. AB - AIMS/HYPOTHESIS: Normal glucose metabolism depends on pancreatic secretion of insulin and glucagon. The bihormonal hypothesis states that while lack of insulin leads to glucose underutilisation, glucagon excess is the principal factor in diabetic glucose overproduction. A recent study reported that streptozotocin treated glucagon receptor knockout mice have normal glucose tolerance. We investigated the impact of acute disruption of glucagon secretin or action in a mouse model of severe diabetes by three different approaches: (1) alpha cell elimination; (2) glucagon immunoneutralisation; and (3) glucagon receptor antagonism, in order to evaluate the effect of these on glucose tolerance. METHODS: Severe diabetes was induced in transgenic and wild-type mice by streptozotocin. Glucose metabolism was investigated using OGTT in transgenic mice with the human diphtheria toxin receptor expressed in proglucagon producing cells allowing for diphtheria toxin (DT)-induced alpha cell ablation and in mice treated with either a specific high affinity glucagon antibody or a specific glucagon receptor antagonist. RESULTS: Near-total alpha cell elimination was induced in transgenic mice upon DT administration and resulted in a massive decrease in pancreatic glucagon content. Oral glucose tolerance in diabetic mice was neither affected by glucagon immunoneutralisation, glucagon receptor antagonism, nor alpha cell removal, but did not deteriorate further compared with mice with intact alpha cell mass. CONCLUSIONS/INTERPRETATION: Disruption of glucagon action/secretion did not improve glucose tolerance in diabetic mice. Near-total alpha cell elimination may have prevented further deterioration. Our findings support insulin lack as the major factor underlying hyperglycaemia in beta cell-deficient diabetes. PMID- 26537125 TI - Multiple comparisons analysis of serological data from an area of low Plasmodium falciparum transmission. AB - BACKGROUND: As a nation reduces the burden of falciparum malaria, identifying areas of transmission becomes increasingly difficult. Over the past decade, the field of utilizing malaria serological assays to measure exposure has grown rapidly, and a variety of serological methods for data acquisition and analysis of human IgG against falciparum antigens are available. Here, different immunoassays and statistical methods are utilized to analyse samples from a low transmission setting and directly compare the estimates generated. METHODS: A subset of samples (n = 580) from a 2012 Haitian nationwide malaria survey was employed as sample population of low falciparum endemicity. In addition to the Haitian samples, samples from 247 US residents were used as a reference population of 'true seronegatives'. Data acquisition was performed through standard ELISA and bead-based multiplex assays assaying for IgG antibodies to the Plasmodium falciparum antigens MSP-1p19, MSP-1p42(D), MSP-1p42(F), and AMA-1. Appropriate parametric distributions and seropositivity cutoff values were determined by statistical measures. RESULTS: Data from both assays showed a strong positive skew, and the lognormal distribution was found to be an appropriate statistical fit to the Haitian and American populations. The American samples served as a good serological true negative population for the multiplex assay, but not for ELISA-based data. Mixture model approaches to determine seronegative and seropositive populations from the Haitian data showed a high degree of distribution overlap-likely due to the historical low falciparum transmission in this nation. Different fittings to the reversible catalytic model resulted depending upon the immunoassay utilized and seropositivity cutoff method employed. Data were also analysed through fitting to penalized B-splines, presenting another possible analytical tool for the analysis of malaria serological data. CONCLUSIONS: Standardization of serological techniques and analyses may prove difficult as some tools can prove to be more useful depending on the area and parasite in question, making clear interpretation a vital pursuit. The presented analysis in the low-endemic nation of Haiti found malaria naive US residents to be an appropriate seronegative reference population for the multiplex assay, and this assay providing consistent estimates between MSP-1 and AMA-1 antigens of percent seropositives for this low-endemic population. PMID- 26537126 TI - Sepsis impairs microvascular autoregulation and delays capillary response within hypoxic capillaries. AB - INTRODUCTION: The microcirculation supplies oxygen (O2) and nutrients to all cells with the red blood cell (RBC) acting as both a deliverer and sensor of O2. In sepsis, a proinflammatory disease with microvascular complications, small blood vessel alterations are associated with multi-organ dysfunction and poor septic patient outcome. We hypothesized that microvascular autoregulation existing at three levels: over the entire capillary network, within a capillary and within the erythrocyte-was impaired during onset of sepsis. This study had three objectives: 1) measure capillary response time within hypoxic capillaries, 2) test the null hypothesis that RBC O2-dependent adenosine triphosphate (ATP) efflux was not altered by sepsis and 3) develop a framework of a pathophysiological model. METHODS: This was an animal study, comparing sepsis with control, set in a university laboratory. Acute hypotensive sepsis was studied using cecal ligation and perforation (CLP) with a 6-hour end-point. Rat hindlimb skeletal muscle microcirculation was imaged, and capillary RBC supply rate (SR = RBC/s), RBC hemoglobin O2 saturation (SO2) and O2 supply rate (qO2 = pLO2/s) were quantified. Arterial NOx (nitrite + nitrate) and RBC O2-dependent ATP efflux were measured using a nitric oxide (NO) analyzer and gas exchanger, respectively. RESULTS: Sepsis increased capillary stopped-flow (p = 0.001) and increased plasma lactate (p < 0.001). Increased plasma NOx (p < 0.001) was related to increased capillary RBC supply rate (p = 0.027). Analysis of 30-second SR-SO2-qO2 profiles revealed a shift towards decreased (p < 0.05) O2 supply rates in some capillaries. Moreover, we detected a three- to fourfold increase (p < 0.05) in capillary response time within hypoxic capillaries (capillary flow states where RBC SO2 < 20 %). Additionally, sepsis decreased the erythrocyte's ability to respond to hypoxic environments, as normalized RBC O2-dependent ATP efflux decreased by 62.5 % (p < 0.001). CONCLUSIONS: Sepsis impaired microvascular autoregulation at both the individual capillary and erythrocyte level, seemingly uncoupling the RBC acting as an "O2 sensor" from microvascular autoregulation. Impaired microvascular autoregulation was manifested by increased capillary stopped-flow, increased capillary response time within hypoxic capillaries, decreased capillary O2 supply rate and decreased RBC O2-dependent ATP efflux. This loss of local microvascular control was partially off-set by increased capillary RBC supply rate, which correlated with increased plasma NOx. PMID- 26537127 TI - Involvement of opsins in mammalian sperm thermotaxis. AB - A unique characteristic of mammalian sperm thermotaxis is extreme temperature sensitivity, manifested by the capacity of spermatozoa to respond to temperature changes of <0.0006 degrees C as they swim their body-length distance. The identity of the sensing system that confers this exceptional sensitivity on spermatozoa is not known. Here we show that the temperature-sensing system of mammalian spermatozoa involves opsins, known to be G-protein-coupled receptors that act as photosensors in vision. We demonstrate by molecular, immunological, and functional approaches that opsins are present in human and mouse spermatozoa at specific sites, which depend on the species and the opsin type, and that they are involved in sperm thermotaxis via two signalling pathways-the phospholipase C and the cyclic-nucleotide pathways. Our results suggest that, depending on the context and the tissue, mammalian opsins act not only as photosensors but also as thermosensors. PMID- 26537128 TI - Eldecalcitol prevents endothelial dysfunction in postmenopausal osteoporosis model rats. AB - Postmenopausal women have high incidence of cardiovascular events as estrogen deficiency can cause endothelial dysfunction. Vitamin D is reported to be beneficial on endothelial function, but it remains controversial whether vitamin D is effective for endothelial dysfunction under the treatment for osteoporosis in postmenopausal women. The aim of this study was to evaluate the endothelial protective effect of eldecalcitol (ELD) in ovariectomized (OVX) rats. ELD (20 ng/kg) was orally administrated five times a week for 4 weeks from 1 day after surgery. After that, flow-mediated dilation (FMD) as an indicator of endothelial function was measured by high-resolution ultrasound in the femoral artery of living rats. ELD ameliorated the reduction of FMD in OVX rats. ELD inhibited the increase in NOX4, nitrotyrosine, and p65 and the decrease in dimer/monomer ratio of nitric oxide synthase in OVX rat femoral arteries. ELD also prevented the decrease in peroxisome proliferator-activated receptor gamma (PPARgamma) in femoral arteries and cultured endothelial cells. Although PPARgamma is known to inhibit osteoblastogenesis, ELD understandably increased bone mineral density of OVX rats without increase in PPARgamma in bone marrow. These results suggest that ELD prevented the deterioration of endothelial function under condition of preventing bone loss in OVX rats. This endothelial protective effect of ELD might be exerted through improvement of endothelial nitric oxide synthase uncoupling, which is mediated by an antioxidative effect through normalization of vascular PPARgamma/NF-kappaB signaling. PMID- 26537129 TI - Authors' reply to Fountain and colleagues. PMID- 26537130 TI - Implementation of an Anesthesia Information Management System in an Ambulatory Surgery Center. AB - Anesthesia information management systems (AIMS) are increasingly being implemented throughout the United States. However, little information exists on the implementation process for AIMS within ambulatory surgery centers (ASC). The objectives of this descriptive study are to document: 1) the phases of implementation of an AIMS at an ASC; and 2) lessons learnt from a socio-technical perspective. The ASC, within the Veterans Health Administration (VHA), has hosted an AIMS since 2008. As a quality improvement effort, we implemented a new version of the AIMS. This new version involved fundamental software changes to enhance clinical care such as real-time importing of laboratory data and total hardware exchange. The pre-implementation phase involved coordinated preparation over six months between multiple informatics teams along with local leadership. During this time, we conducted component, integration, and validation testing to ensure correct data flow from medical devices to AIMS and centralized databases. The implementation phase occurred in September 2014 over three days and was successful. Over the next several months, during post-implementation phase, we addressed residual items like latency of the application. Important lessons learnt from the implementation included the utility of partnering early with executive leadership; ensuring end user acceptance of new clinical workflow; continuous testing of data flow; use of a staged rollout; and providing additional personnel throughout implementation. Implementation of an AIMS at an ASC can utilize methods developed for large hospitals. However, issues unique to an ASC such as limited number of support personnel and distinctive workflows must be considered. PMID- 26537131 TI - From Cues to Nudge: A Knowledge-Based Framework for Surveillance of Healthcare Associated Infections. AB - We propose an integrated semantic web framework consisting of formal ontologies, web services, a reasoner and a rule engine that together recommend appropriate level of patient-care based on the defined semantic rules and guidelines. The classification of healthcare-associated infections within the HAIKU (Hospital Acquired Infections - Knowledge in Use) framework enables hospitals to consistently follow the standards along with their routine clinical practice and diagnosis coding to improve quality of care and patient safety. The HAI ontology (HAIO) groups over thousands of codes into a consistent hierarchy of concepts, along with relationships and axioms to capture knowledge on hospital-associated infections and complications with focus on the big four types, surgical site infections (SSIs), catheter-associated urinary tract infection (CAUTI); hospital acquired pneumonia, and blood stream infection. By employing statistical inferencing in our study we use a set of heuristics to define the rule axioms to improve the SSI case detection. We also demonstrate how the occurrence of an SSI is identified using semantic e-triggers. The e-triggers will be used to improve our risk assessment of post-operative surgical site infections (SSIs) for patients undergoing certain type of surgeries (e.g., coronary artery bypass graft surgery (CABG)). PMID- 26537132 TI - Dispersion-Corrected Density Functional Theory Investigations of Structural and Electronic Properties of Bulk MoS2: Effect of Uniaxial Strain. AB - Strain-dependent structural and electronic properties of MoS2 materials are investigated using first principles calculations. The structural and electronic band structures of the MoS2 with relaxed unit cells are optimized and calculated by the dispersion-corrected density functional theory (DFT-D2). Calculations within the local density approximation (LDA) and GGA using PAW potentials were also performed for specific cases for the purpose of comparison. The effect of strain on the band gap and the dependence of formation energy on strain of MoS2 are also studied and discussed using the DFT-D2 method. In bulk MoS2, the orbitals shift towards the higher/lower energy area when strain is applied along the z/x direction, respectively. The energy splitting of Mo4d states is in the range from 0 to 2 eV, which is due to the reduction of the electronic band gap of MoS2. PMID- 26537133 TI - Identification of the palliative phase in people with dementia: a variety of opinions between healthcare professionals. AB - BACKGROUND: People with dementia can benefit from a palliative care approach. Recommendations, such as those of the EAPC have been proposed to strengthen the provision of palliative care for this group of patients. Yet, it remains challenging for professionals to identify when a person with dementia is in need of palliative care. The objective of this study therefore was to explore when professionals in long-term care settings consider a person with dementia in need of palliative care. METHODS: Teams with in total 84 professionals working in 13 long-term care settings from 6 countries (France, Germany, Italy, Norway, Poland and the Netherlands) received a case-vignette concerning a person with dementia recently admitted to a nursing home. Teams were asked to discuss when they considered people with dementia eligible for palliative care. The constant comparative method was used to analyse their answers. RESULTS: Three different time points in the disease trajectory when people with dementia were considered to be eligible for palliative care were extracted: (1) early in the disease trajectory; (2) when signs and symptoms of advanced dementia are present; and (3) from the time point that curative treatment of co-morbidities is futile. Yet, none of these time points was uniformly considered by the professional teams across Europe. In some cases, professionals working in the same nursing home didn't even reach consensus when considering persons with dementia eligible for palliative care. CONCLUSION: The results of the study identified that professionals across Europe have different opinions regarding the time point when to consider a person with dementia in need of palliative care. PMID- 26537134 TI - The Colorado Longitudinal Twin Study of Reading Difficulties and ADHD: Etiologies of Comorbidity and Stability. AB - Approximately 60% of children with reading difficulties (RD) meet criteria for at least one co-occurring disorder. The most common of these, attention deficit hyperactivity disorder (ADHD), occurs in 20-40% of individuals with RD. Recent studies have suggested that genetic influences are responsible. To assess the genetic etiologies of RD and the comorbidity of RD and two ADHD symptom dimensions -- inattention (IN) and hyperactivity/impulsivity (H/I) -- we are conducting the first longitudinal twin study of RD and ADHD. Data from twin pairs in which at least one member of the pair met criteria for proband status for RD at initial assessment, and were reassessed 5 years later, were subjected to DeFries-Fulker (DF) analysis. Analyses of reading composite data indicated that over 60% of the proband deficit at initial assessment was due to genetic influences, and that reading deficits at follow-up were due substantially to the same genetic influences. When a bivariate DF model was fitted to reading performance and IN data, genetic influences accounted for 60% of contemporaneous comorbidity and over 60% of the longitudinal relationship. In contrast, analysis of the comorbidity between reading performance and H/I indicated that common genetic influences accounted for only about 20% of the contemporaneous and about 10% of the longitudinal relationships. Results indicate that (1) genetic influences on RD are substantial and highly stable; (2) the comorbidity between RD and IN is due largely to genetic influences, both contemporaneously and longitudinally; and (3) genetic influences contribute significantly less to the comorbidity between RD and H/I. PMID- 26537135 TI - ALPPS: past, present and future. PMID- 26537136 TI - Hernioplasty with and without mesh: analysis of the immediate complications in a randomized controlled clinical trial. AB - BACKGROUND: Inguinal hernia repair is the most common procedure in general surgery and 80,000 operations are performed annually in Great Britain, 100,000 in France and 700,000 in the US. Given its high frequency has a major impact, both in the medical and economic aspects. AIM: Analyze the immediate postoperative complications comparing mesh versus non mesh hernioplasty. METHOD: Randomized control trial, with the enrollment of 263 patients underwent surgery for inguinal hernia randomized by randomization table. Treatment (mesh, Lichtenstein or without mesh, Bassini technique) was assigned using sequentially numbered opaque envelopes having fulfilled the inclusion criteria. The variables analyzed were: postoperative pain, seroma, hematoma, infection, return to normal activities and recurrence. RESULTS: The mean age was 55.5 years, 88% patients were male and 12% female. The pain was higher in patients operated with mesh. CONCLUSIONS: The inguinal hernia repair mesh group had less immediate postoperative complications and significantly earlier return to work than hernioplasty without mesh, this being one of the most important conclusions. PMID- 26537137 TI - Evaluation of risk factors affecting anastomotic leakage after repair of esophageal atresia. AB - BACKGROUND: Anastomotic leak are reported among neonates who underwent esophageal atresia. AIM: To find risk factors of anastomotic leakage in patients underwent esophageal repair. METHODS: All cases with esophageal atresia were included. In this case control study, patients were classified in two groups according to presence or absence of anastomotic leaks. Duration of study was 10 years. RESULTS: Sixty-one cases were included. Mean+/-SD age at time of surgery in patients with leakage and without leakage was 9.50+/-7.25 and 8.83+/-6.93 respectively (p=.670). Blood transfusion and two layer anastomosis had significant correlation with anastomotic leakage. CONCLUSION: Blood transfusion and double layer anastomosis are associated with higher rate of anastomotic leakage. PMID- 26537138 TI - Lactate as predictor of mortality in polytrauma. AB - BACKGROUND: The lactate is a product of anaerobic metabolism; it can be used as a marker on demand and availability of oxygen. Changes in lactate levels can be effectively used as a marker in resuscitation maneuvers, even in patients with stable vital signs. AIM: To verify the lactate clearance as a predictor of mortality in trauma patients, in need of intensive care. METHOD: A total of 851 patients were admitted in ICU, in which 146 were victims of multiple trauma; due to the exclusion criteria, were included 117. RESULTS: Patients were 87% male, mean age 32.4 years, motorcycle drivers, Glasgow coma scale between 3-8, affected by cranial trauma, followed by abdominal trauma. Was verified mortality up to 48 h and global mortality, that did not show statistical relationship between lactate clearance and mortality (p=0.928). CONCLUSION: There is no correlation between admission lactate or lactate clearance and mortality in patients treated with multiple trauma. PMID- 26537139 TI - AIR score assessment for acute appendicitis. AB - BACKGROUND: Acute appendicitis is the most common cause of acute abdomen. Approximately 7% of the population will be affected by this condition during full life. The development of AIR score may contribute to diagnosis associating easy clinical criteria and two simple laboratory tests. AIM: To evaluate the score AIR (Appendicitis Inflammatory Response score) as a tool for the diagnosis and prediction of severity of acute appendicitis. METHOD: Were evaluated all patients undergoing surgical appendectomy. From 273 patients, 126 were excluded due to exclusion criteria. All patients were submitted o AIR score. RESULTS: The value of the C-reactive protein and the percentage of leukocytes segmented blood count showed a direct relationship with the phase of acute appendicitis. CONCLUSION: As for the laboratory criteria, serum C-reactive protein and assessment of the percentage of the polymorphonuclear leukocytes count were important to diagnosis and disease stratification. PMID- 26537140 TI - Lower esophageal sphincter pressure measurement under standardized inspiratory maneuveurs. AB - BACKGROUND: Through rhythmic variations, the diaphragm influence lower esophageal sphincter (LES) pressure acting as an external sphincter. LES pressure recording is characterized by increased pressure in inspiration due to contraction of the diaphragmatic crura that involves the sphincter. AIM: To describe a method of measuring LES pressure during standardized inspiratory maneuvers with increasing loads. METHODS: The study population comprised of eight healthy female volunteers (average age of 31.5 years). An esophageal high-resolution manometry and impedance system was used for measuring the LES pressure during 3-second inspiratory efforts under 12, 24 and 48 cm H2O loads (Threshold maneuvers). RESULTS: There was a significant difference between the average maximum LES pressure and the average maximum basal LES pressure during the first (76.19+/ 17.92 difference, p=0.0008), second (86.92+/-19.01 difference, p=0.0004), and third seconds of the maneuver (90.86+/-17.93 difference, p=0.0002), with 12, 24 and 48 cmH2O loads. CONCLUSION: This maneuver is a standardization of the inspiratory LES pressure and may better differentiate patients with reflux disease from healthy individuals, and may also be useful for monitoring the treatment of these patients through inspiratory muscle training. PMID- 26537141 TI - Critical analysis of experimental model for study of adhesions after incisional hernias induced in rats' and repair of abdominal wall with different biomaterials. AB - BACKGROUND: Adhesions induced by biomaterials experimentally implanted in the abdominal cavity are basically studied by primary repair of different abdominal wall defects or by the correction of incisional hernias previously performed with no precise definition of the most appropriate model. AIM: To describe the adhesions which occur after the development of incisional hernias, before the prosthesis implantation, in an experimental model to study the changes induced by different meshes. METHODS: Incisional hernias were performed in 10 rats with hernia orifices of standardized dimensions, obtained by the median incision of the abdominal wall and eversion of the defect edges. Ten days after the procedure adhesions of abdominal structures were found when hernias were repaired with different meshes. RESULTS: The results showed hernia sac well defined in all rats ten days after the initial procedure. Adhesions of the greater omentum occurred in five animals of which two also showed adhesions of small bowel loops besides the omentum, and another two showed liver adhesions as well as the greater omentum, numbers with statistical significance by Student's t test (p<0.05). CONCLUSION: Although it reproduces the real clinical situation, the choice of experimental model of incisional hernia repair previously induced implies important adhesions, with possible repercussions in the evaluation of the second operation, when different implants of synthetic materials are used. PMID- 26537142 TI - The prevalence of HLA DQ2 and DQ8 in patients with celiac disease, in family and in general population. AB - BACKGROUND: Celiac disease is an enteropathy characterized by gluten sensitivity and broad clinical aspect. Has a multifactorial cause and depends on genetic, immunological and environmental factors for its development. The genetic influence is given mostly by the human leukocyte antigens HLA DQ2 and DQ8. AIM: To evaluate the prevalence of human leukocyte antigens DQ2 and DQ8 in three different groups: patients with celiac disease, first-degree relatives and the general population. METHOD: Retrospective analysis that evaluated serologic and endoscopic data of 74 patients with celiac disease and 109 non-celiac, which were subdivided into two subgroups: non-celiac who had first-degree relatives with celiac and non-celiac who did not. All patients underwent laboratory examination for screening genetic sensitivity given by HLA DQ2 and HLA DQ8 by. RESULTS: The presence of HLA DQ2 and DQ8 was identified in 98,4% of 74 celiac patients, of which 79,7% had only HLA DQ2; 8,1% had only HLA DQ8 and 10,8% had both antigens histocompatibility. In the group of relatives of celiac patients, were included 29 patients; among them, 89,6% had HLA DQ2 and/or DQ8; 76% only the HLA DQ2, 10,3% only HLA DQ8 and 3,4% presented both human leukocyte antigens (HLA). CONCLUSION: HLA DQ2/DQ8 was present in 98,4% of celiac patients; 89,6% relatives of celiac family and in 55,4% of people from the general population without family celiac. PMID- 26537143 TI - Copaiba oil influences ventral hernia repair with Vicryl(r) mesh? AB - BACKGROUND: The use of meshes in hernia surgical repair promoted revolution in the surgical area; however, some difficulties had come, such as a large area of fibrosis, greater postoperative pain and risk of infection. The search for new substances that minimize these effects should be encouraged. Medicinal plants stand out due possible active ingredients that can act on these problems. AIM: To check the copaiba oil influence in the repair of abdominal defects in rats corrected with Vicryl(c) mesh. METHOD: Twenty-four Wistar rats were submitted to an abdominal defect and corrected with Vicryl(c) mesh. They were distributed into two groups: control and copaiba via gavage, administered for seven days after surgery. The analysis of the animals took place on 8, 15 and 22 postoperative days. It analyzed the amount of adhesions and microscopic analysis of the mesh. RESULTS: There was no statistical difference regarding the amount of adhesions. All animals had signs of acute inflammation. In the control group, there were fewer macrophages in animals of the 8th compared to other days and greater amount of necrosis on day 8 than on day 22. In the copaiba group, the number of gigantocytes increased compared to the days analyzed. CONCLUSION: Copaiba oil showed an improvement in the inflammatory response accelerating its beginning; however, did not affect the amount of abdominal adhesions or collagen fibers. PMID- 26537144 TI - Standardized clinical pathways for esophagectomy are not a reality in Brazil, even with a high prevalence of esophageal cancer and achalasia. AB - BACKGROUND: The adoption of standardized protocols and specialized multidisciplinary teams for esophagectomy involve changes in routines with the implantation of expensive clinical practices and deviations from ingrained treatment philosophies. AIM: To evaluate the prevalence of standardized protocols and specialized multidisciplinary teams in Sao Paulo state, Brazil. METHODS: Institutions that routinely perform esophagectomies in Sao Paulo were contacted and questioned about the work team involved in the procedure and the presence of standardized routines in the preoperatory care. RESULTS: Fifteen centers answered the questionnaire: 10 (67%) public institutions and five (33%) private. There were seven (47%) medical schools, six (40%) with a residency program and two (13%) nonacademic institutions. The mean number of esophagectomies per year was 23. There was a multidisciplinary pre-operative team in nine (60%). There was a multidisciplinary postoperative team in 11 (73%). Early mobilization protocol was adopted in 12 (80%) institutions, early feeding in 13 (87%), routinely epidural in seven (47%), analgesia protocol in seven (47%), hydric restriction in six (40%), early extubation in six (40%), standardized hospitalization time in four (27%) and standardized intensive care time in two (13%). CONCLUSION: The prevalence of standardized protocols and specialized teams is very low in Sao Paulo state, Brazil. The presence of specialized surgeons is a reality and standardized protocols related directly to surgeons have higher frequency than those related to other professionals in the multidisciplinary team. PMID- 26537145 TI - Total lymphocyte count and serum albumin as predictors of nutritional risk in surgical patients. AB - BACKGROUND: Early detection of changes in nutritional status is important for a better approach to the surgical patient. There are several nutritional measures in clinical practice, but there is not a complete method for determining the nutritional status, so, health professionals should only choose the best method to use. AIM: To evaluate the total lymphocyte count and albumin as predictors of identification of nutritional risk in surgical patients. METHODS: Prospective longitudinal study was conducted with 69 patients undergoing surgery of the gastrointestinal tract. The assessment of nutritional status was evaluated by objective methods (anthropometry and biochemical tests) and subjective methods (subjective global assessment). RESULTS: All parameters used in the nutritional assessment detected a high prevalence of malnutrition, with the exception of BMI which detected only 7.2% (n=5). The albumin (p=0.01), the total lymphocytes count (p=0.02), the percentage of adequacy of skinfolds (p<0.002) and the subjective global assessment (p<0.001) proved to be useful as predictors of risk of postoperative complications, since the smaller the values of albumin and lymphocyte count and higher the score the subjective global assessment were higher risks of surgical complications. CONCLUSIONS: A high prevalence of malnutrition was found, except for BMI. The use of albumin and total lymphocyte count were good predictor for the risk of postoperative complications and when used with other methods of assessing the nutritional status, such as the subjective global assessment and the percentage of adequacy of skinfolds, can be useful for identification of nutritional risk and postoperative complications. PMID- 26537146 TI - Late results of esophagogastric devascularization and splenectomy associated with endoscopic treatment in patients with schistosomiasis. AB - BACKGROUND: Schistosomiasis is endemic problem in Brazil affecting about three to four million people, and digestive hemorrhage caused by esophageal varices rupture is the main complication of the disease. Surgical treatment has become a therapeutic option, especially for secondary prophylaxis after at least one episode of bleeding. The surgical technique used by the vast majority of surgeons for the prevention of rebleeding is esophagogastric devascularization and splenectomy. Although with good postoperative results, rebleeding rate is significant, showing the need to follow-up endoscopy in all patients. AIM: To evaluate long-term results of patients submitted to esophagogastric devascularization and splenectomy and postoperative endoscopic treatment regarding esophageal varices caliber and rebleeding rates. METHODS: A retrospective study of 12 patients underwent esophagogastric devascularization and splenectomy followed for more than five years. RESULTS: All patients showed varices size reduction, and no patient had postoperative bleeding recurrence. CONCLUSION: Esophagogastric devascularization and splenectomy decreased significantly the esophageal variceal size when associated with endoscopic follow up, being effective for bleeding recurrence prophylaxis. PMID- 26537147 TI - Early oral re-feeding on oncology patients submitted to gastrectomy for gastric cancer. AB - BACKGROUND: There is no advantage in maintaining patients on oral fasting after gastrointestinal elective resection. The early feeding up to 48 h can be beneficial, because it reduces infectious complications and hospital stay. AIM: Evaluate the evolution and tolerance of early oral diet in postoperative period after gastrectomy for gastric cancer. METHODS: Anthropometric assessment was performed on the day of surgery, weight, height, body mass index and weight loss were measured. Acceptance of diet was evaluated as food intake (amount accepted) and gastrointestinal symptoms such as nausea, vomiting, constipation, diarrhea, abdominal distension, postoperative complications and hospital stay. RESULTS: The sample consisted of 23 patients, 17 with partial gastrectomy and six with total gastrectomy. In the assessment of nutritional status 9% were malnourished, 54.5% normal weight, 9% overweight and 27.2% obese, but 54% had weight loss. There was good acceptance of the diet in 96,9% of the sample. Nausea and abdominal distension were present in 4,3% and 65.2% constipation. Surgical complications according to the Clavien scalle, 13% had grade V, 4.3% grade IIIA, 8.7% grade I and 73% did not have complications. The length of hospital stay was 5+/-2.2 days. CONCLUSION: Early postoperative re-feeding in total and partial gastrectomy was well tolerated by patients. PMID- 26537148 TI - White box: low cost box for laparoscopic training. AB - BACKGROUND: Laparoscopic surgery is a reality in almost all surgical centers. Although with initial greater technical difficulty for surgeons, the rapid return to activities, less postoperative pain and higher quality aesthetic stimulates surgeons to evolve technically in this area. However, unlike open surgery where learning opportunities are more accessible, the laparoscopic training represents a challenge in surgeon formation. AIM: To present a low cost model for laparoscopic training box. METHODS: This model is based in easily accessible materials; the equipment can be easily found based on chrome mini jet and passes rubber thread and a webcam attached to an aluminum handle. RESULTS: It can be finalized in two days costing R$ 280,00 (US$ 90). CONCLUSION: It is possible to stimulate a larger number of surgeons to have self training in laparoscopy at low cost seeking to improve their surgical skills outside the operating room. PMID- 26537149 TI - Acute pancreatitis gravity predictive factors: which and when to use them? AB - INTRODUCTION: Acute pancreatitis has as its main causes lithiasic biliary disease and alcohol abuse. Most of the time, the disease shows a self-limiting course, with a rapid recovery, only with supportive treatment. However, in a significant percentage of cases, it runs with important local and systemic complications associated with high mortality rates. AIM: To present the current state of the use of these prognostic factors (predictive scores) of gravity, as the time of application, complexity and specificity. METHOD: A non-systematic literature review through 28 papers, with emphasis on 13 articles published in indexed journals between 2008 and 2013 using Lilacs, Medline, Pubmed. RESULTS: Several clinical, laboratory analysis, molecular and image variables can predict the development of severe acute pancreatitis. Some of them by themselves can be determinant to the progression of the disease to a more severe form, such as obesity, hematocrit, age and smoking. Hematocrit with a value lower than 44% and serum urea lower than 20 mg/dl, both at admission, appear as risk factors for pancreatic necrosis. But the PCR differentiates mild cases of serious ones in the first 24 h. Multifactorial scores measured on admission and during the first 48 h of hospitalization have been used in intensive care units, being the most ones used: Ranson, Apache II, Glasgow, Iget and Saps II. CONCLUSION: Acute pancreatitis is a disease in which several prognostic factors are employed being useful in predicting mortality and on the development of the severe form. It is suggested that the association of a multifactorial score, especially the Saps II associated with Iget, may increase the prognosis accuracy. However, the professional's preferences, the experience on the service as well as the available tools, are factors that have determined the choice of the most suitable predictive score. PMID- 26537150 TI - Late acute rejection in liver transplant: a systematic review. AB - INTRODUCTION: Late acute rejection leads to worse patient and graft survival after liver transplantation. AIM: To analyze the reported results published in recent years by leading transplant centers in evaluating late acute rejection and update the clinical manifestations, diagnosis and treatment of liver transplantation. METHOD: Systematic literature review through Medline-PubMed database with headings related to late acute rejection in articles published until November 2013 was done. Were analyzed demographics, immunosuppression, rejection, infection and graft and patient survival rates. RESULTS: Late acute rejection in liver transplantation showed poor results mainly regarding patient and graft survival. Almost all of these cohort studies were retrospective and descriptive. The incidence of late acute rejection varied from 7-40% in these studies. Late acute rejection was one cause for graft loss and resulted in different outcomes with worse patient and graft survival after liver transplant. Late acute rejection has been variably defined and may be a cause of chronic rejection with worse prognosis. Late acute rejection occurs during a period in which the goal is to maintain lower immunosuppression after liver transplantation. CONCLUSION: The current articles show the importance of late acute rejection. The real benefit is based on early diagnosis and adequate treatment at the onset until late follow up after liver transplantation. PMID- 26537151 TI - Endoscopic stent for treatment of esophagojejunostomy fistula. PMID- 26537152 TI - Associating liver radiofrequency and portal vein ligation for staged hepatectomy. PMID- 26537153 TI - Gallbladder cancer as incidental finding in two stage resolution of gallstone ileus. PMID- 26537154 TI - Comparative effectiveness of lumbar epidural steroid injections using particulate vs. non-particulate steroid: an intra-individual comparative study. AB - OBJECTIVES: To perform an intra-individual comparison for the effectiveness of lumbar epidural steroid injection (ESI) between injections using particulate (triamcinolone) and non-particulate (dexamethasone) steroid. MATERIALS AND METHODS: This study included 162 patients(M:F = 60:102, mean age 66.3 years) who underwent lumbar ESI using dexamethasone(ESI_DEXA) from April 2013 to May 2013 and who had previously underwent lumbar ESI using triamcinolone(ESI_TRIAM) within 1 year. Degree of relative satisfaction, injection-free interval and injection frequency were determined. Subgroup analyses were also done according to the diagnosis, approach-methods, patients' ages and sex. RESULTS: Eighty-seven of 139 patients (62.6 %) responded that the effect of ESI_TRIAM was better than that of ESI_DEXA (p = 0.004). In the four subgroups-patients with herniated intervertebral disc (HIVD), who underwent transforaminal ESI, were under age 70 and were male patients-the proportion of patients who preferred ESI_TRIAM was significantly greater than the proportion patients who preferred ESI_DEXA in terms of relative satisfaction (p < 0.05). The injection-free interval of ESI_TRIAM was significantly longer than that of ESI_DEXA (p = 0.01). In the subgroup analyses, the patient groups HIVD, who underwent transforaminal ESI, under age 70 and female patients with longer injection-free interval of ESI_TRIAM than ESI_DEXA were statistically significant (p < 0.05). Other factors were not significant. CONCLUSION: The relative satisfaction with ESI_TRIAM was significantly better than that with ESI_DEXA in the same patient, and the injection-free interval after ESI_TRIAM was significantly longer than that after ESI_DEXA. PMID- 26537155 TI - The separate and combined effects of monoamine oxidase A inhibition and nicotine on resting state EEG. AB - While nicotine is often associated with the neuropsychological effects of tobacco smoke, the robust monoamine oxidase (MAO) inhibition observed in chronic smokers is also likely to play a role. Electroencephalographically-indexed alterations in baseline neural oscillations by nicotine have previously been reported in both smokers and non-smokers, however, little is known about the effects of MAO inhibition in combination with nicotine on resting state EEG. In a sample of 24 healthy non-smoking males, the effects of 6 mg nicotine gum, as well as MAO-A inhibition via 75 mg moclobemide, were investigated in separate and combined conditions over four separate test sessions. Drug effects were observed in the alpha2, beta2, and theta band frequencies. Nicotine increased alpha2 power, and moclobemide decreased beta2 power. Theta power was decreased most robustly by the combination of both drugs. Therefore, this study demonstrated that the nicotinic and MAO inhibiting properties of tobacco may differentially influence fast-wave oscillations (alpha2 and beta2), while acting in synergy to influence theta oscillations. PMID- 26537156 TI - Efficacy of dexamethasone versus bevacizumab on regression of hard exudates in diabetic maculopathy: data from the BEVORDEX randomised clinical trial. AB - OBJECTIVE: To report the effect of bevacizumab versus dexamethasone on hard exudates (HEX) in diabetic macular oedema (DME). DESIGN: Post hoc analysis of 24 month data from the Randomised clinical trial of BEVacizumab OR DEXamethasone for diabetic macular oedema (BEVORDEX) phase 2 multicentre randomised clinical trial. Eyes with centre-involving DME resistant to or unlikely to benefit from macular laser therapy were included. Eyes were randomly assigned to bevacizumab every 4 weeks or Ozurdex dexamethasone implant (DEX) every 16 weeks, both as required. The 68 eyes from 48 patients that completed 24-month follow-up were analysed. Two masked graders assessed extent and location of HEX on baseline, 12-month and 24 month foveal-centred colour fundus photographs using validated grading software. RESULTS: Macular HEX was present in 60% of study eyes. Of these, 21 eyes were treated with DEX and 20 eyes with bevacizumab. Both treatments led to reduction in area of macular HEX at 12 months and 24 months. There was greater regression of HEX from the foveal centre in DEX-treated eyes (median change +890 um, IQR=1040 um) than bevacizumab-treated eyes (median change +7.0 um, IQR=590 um) at 12 months (p=0.04) but the difference was no longer statistically significant (p=0.10) by 24 months (DEX +1400 um, IQR=1590 um; bevacizumab +20 um, IQR=2680 um). Reassuringly, no study eye developed HEX at the foveal centre, a visually devastating consequence of diabetic maculopathy. CONCLUSIONS: Bevacizumab and DEX were effective in reducing area of HEX in eyes with DME. DEX provided more rapid regression of HEX from the foveal centre although bevacizumab-treated eyes started to catch up by 24 months. Distance from the foveal centre as well as total area of macular HEX should be assessed when evaluating treatments for foveal-threatening HEX. TRIAL REGISTRATION NUMBER: NCT01298076; Post-results. PMID- 26537157 TI - Nucleic-acid-programmed Ag-nanoclusters as a generic platform for visualization of latent fingerprints and exogenous substances. AB - We display a nucleic acid controlled AgNC platform for latent fingerprint visualization. The versatile emission of aptamer-modified AgNCs was regulated by the nearby DNA regions. Multi-color images for simultaneous visualization of fingerprints and exogenous components were successfully obtained. A quantitative detection strategy for exogenous substances in fingerprints was also established. PMID- 26537158 TI - Availability of prescription zopiclone over the internet. PMID- 26537159 TI - Fast and background-free three-dimensional (3D) live-cell imaging with lanthanide doped upconverting nanoparticles. AB - We report on the development of a three-dimensional (3D) live-cell imaging technique with high spatiotemporal resolution using lanthanide-doped upconverting nanoparticles (UCNPs). It employs the sectioning capability of confocal microscopy except that the two-dimensional (2D) section images are acquired by wide-field epi-fluorescence microscopy. Although epi-fluorescence images are contaminated with the out-of-focus background in general, the near-infrared (NIR) excitation used for the excitation of UCNPs does not generate any autofluorescence, which helps to lower the background. Moreover, the image blurring due to defocusing was naturally eliminated in the image reconstruction process. The 3D images were used to investigate the cellular dynamics such as nuclear uptake and single-particle tracking that require 3D description. PMID- 26537160 TI - Treatment of Nontraumatic Rotator Cuff Tears: A Randomized Controlled Trial with Two Years of Clinical and Imaging Follow-up. AB - BACKGROUND: The optimal treatment for symptomatic, nontraumatic rotator cuff tear is unknown. The purpose of this trial was to compare the effectiveness of physiotherapy, acromioplasty, and rotator cuff repair for this condition. We hypothesized that rotator cuff repair yields superior results compared with other treatment modalities. METHODS: One hundred and eighty shoulders with symptomatic, nontraumatic, supraspinatus tears were randomized into one of three cumulatively designed intervention groups: the physiotherapy-only group (denoted as Group 1), the acromioplasty and physiotherapy group (denoted as Group 2), and the rotator cuff repair, acromioplasty, and physiotherapy group (denoted as Group 3). The Constant score was the primary outcome measure. Secondary outcome measures were visual analog scale for pain, patient satisfaction, rotator cuff integrity in a control imaging investigation, and cost of treatment. RESULTS: One hundred and sixty-seven shoulders (160 patients) were available for analysis at two years. There were no significant differences (p = 0.38) in the mean change of Constant score: 18.4 points (95% confidence interval, 14.2 to 22.6 points) in Group 1, 20.5 points (95% confidence interval, 16.4 to 24.6 points) in Group 2, and 22.6 points (95% confidence interval, 18.4 to 26.8 points) in Group 3. There were no significant differences in visual analog scale for pain scores (p = 0.45) and patient satisfaction (p = 0.28) between the groups. At two years, the mean sagittal size of the tendon tear was significantly smaller (p < 0.01) in Group 3 (4.2 mm) compared with Groups 1 and 2 (11.0 mm). Rotator cuff repair and acromioplasty were significantly more expensive than physiotherapy only (p < 0.01). CONCLUSIONS: There was no significant difference in clinical outcome between the three interventions at the two-year follow-up. The potential progression of the rotator cuff tear, especially in the non-repaired treatment groups, warrants further follow-up. On the basis of our findings, conservative treatment is a reasonable option for the primary initial treatment for isolated, symptomatic, nontraumatic, supraspinatus tears in older patients. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence. PMID- 26537161 TI - ProDisc-C Total Disc Replacement Versus Anterior Cervical Discectomy and Fusion for Single-Level Symptomatic Cervical Disc Disease: Seven-Year Follow-up of the Prospective Randomized U.S. Food and Drug Administration Investigational Device Exemption Study. AB - BACKGROUND: In patients with single-level cervical degenerative disc disease, total disc arthroplasty can relieve radicular pain and preserve functional motion between two vertebrae. We compared the efficacy and safety of cervical total disc arthroplasty with that of anterior cervical discectomy and fusion (ACDF) for the treatment of single-level cervical degenerative disc disease between C3-C4 and C6 C7. METHODS: Two hundred and nine patients at thirteen sites were randomly treated with either total disc arthroplasty with ProDisc-C (n = 103) or with ACDF (n = 106). Patients were assessed preoperatively; at six weeks and three, six, twelve, eighteen, and twenty-four months postoperatively; and then annually until seven years postoperatively. Outcome measures included the Neck Disability Index (NDI), the Short Form-36 (SF-36), postoperative neurologic parameters, secondary surgical procedures, adverse events, neck and arm pain, and satisfaction scores. RESULTS: At seven years, the overall follow-up rate was 92% (152 of 165). There were no significant differences in demographic factors, follow-up rate, or patient-reported outcomes between groups. Both procedures were effective in reducing neck and arm pain and improving and maintaining function and health related quality of life. Neurologic status was improved or maintained in 88% and 89% of the patients in the ProDisc-C and ACDF groups, respectively. After seven years of follow-up, thirty secondary surgical procedures had been performed in nineteen (18%) of 106 patients in the ACDF group compared with seven secondary surgical procedures in seven (7%) of 103 patients in the ProDisc-C group (p = 0.0099). There were no significant differences in the rates of any device-related adverse events between the groups. CONCLUSIONS: Total disc arthroplasty with ProDisc-C is a safe and effective surgical treatment of single-level symptomatic cervical degenerative disc disease. Clinical outcomes after total disc arthroplasty with ProDisc-C were similar to those after ACDF. Patients treated with ProDisc-C had a lower probability of subsequent surgery, suggesting that total disc arthroplasty provides durable results and has the potential to slow the rate of adjacent-level disease. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 26537162 TI - Morbidity and Mortality Associated with Geriatric Ankle Fractures: A Medicare Part A Claims Database Analysis. AB - BACKGROUND: The purpose of this study was to examine the incidence of adverse events in elderly patients who required inpatient admission after sustaining an ankle fracture and to consider these data in relation to geriatric hip fracture and other geriatric patient admissions. METHODS: A retrospective cohort study of patients admitted with an ankle fracture, a hip fracture, or any other diagnosis was performed with the Medicare Part A database for 2008. The primary outcome measure was the one-year mortality rate, examined with multivariate analysis factoring for both patient age and preexisting comorbidity. Secondary outcome measures analyzed additional morbidity as reflected by length of stay, discharge disposition, readmissions, and medical complications. RESULTS: There were 19,648 patients with ankle fractures, 193,980 patients with hip fractures, and 5,801,831 patients with other admitting diagnoses. Significant differences (p < 0.001) were noted in both age and comorbidity status between the group with ankle fractures and the group with hip fractures. The one-year mortality after admission was 11.9% for patients with ankle fracture, 28.2% for patients with hip fracture, and 21.5% for patients with any other admission. Upon using multivariate analysis to account for both age and comorbidity, the hazard ratio for one-year mortality associated with fracture was 1.088 for patients with hip fracture and 0.557 for patients with ankle fracture. CONCLUSIONS: Even after selecting for admitted patients and accounting for both age and comorbidity, geriatric patients with ankle fractures were found to have a lower one-year morbidity compared with geriatric patients who had sustained a hip fracture or alternative admitting diagnoses. Geriatric patients with ankle fractures are likely healthier and more active in ways that are not captured by simply accounting for age and comorbidity. These findings may support more aggressive definitive management of such injuries in this population. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26537163 TI - Incidence Trends in the Diagnosis of Giant Cell Tumor of Bone in Sweden Since 1958. AB - BACKGROUND: The Swedish Cancer Registry (founded in 1958) constitutes a unique resource for epidemiological studies of giant cell tumor of bone with potential for use for population-based studies of incidence over time. The aim of this study was to provide what we believe is the first modern population-based assessment of the incidence trends of giant cell tumor, a unique osteoclastogenic lytic stromal tumor with both benign and malignant histological forms, and to compare the findings with data from the same registry on osteosarcoma, a tumor that may display similar histological characteristics. METHODS: Cases were identified with use of codes for pathological bone tumor (International Classification of Diseases [ICD]-7 196). Specific morphological coding distinguishes benign (PAD 741) from malignant giant cell tumor (PAD 746) and osteosarcoma (PAD 766). RESULTS: During the period of 1958 to 2011, 4625 bone tumors were reported, including 505 giant cell tumors (383 benign and 122 malignant) and 1152 osteosarcomas. From 1958 to 1982 the ratio of malignant to benign giant cell tumors was 1.3, whereas from 1983 to 2011 the ratio inverted to 0.09, suggesting a change in the reporting or diagnosis of malignant or benign cases. Cases of giant cell tumor diagnosed from 1983 to 2011 displayed an age and sex distribution (median age at diagnosis, 34.0 years; 54% female) that were consistent with those in large published case series but differed from those in 1958 to 1982 (median age at diagnosis, 31.5 years; 48% female). The most current data (1983 to 2011) showed the giant cell tumor incidence in Sweden to be 1.3 per million per year, while the osteosarcoma incidence was 2.3 per million per year. CONCLUSIONS: Early Swedish Cancer Registry data (1958 to 1982) revealed a higher proportion of malignant giant cell tumors than seen in large sequential case series and a distinct age and sex profile compared with more recent data (1983 to 2011). This likely represents changes in the diagnostic workup and introduction of multidisciplinary review of giant-cell-containing tumors around 1982. Recent data may reflect the impact of expert centralized biopsy and multidisciplinary case review and more comprehensive reporting of benign giant cell tumors. PMID- 26537164 TI - ACL Graft Position Affects in Situ Graft Force Following ACL Reconstruction. AB - BACKGROUND: The purpose of our study was to evaluate the relationship between graft placement and in situ graft force after anterior cruciate ligament (ACL) reconstruction. METHODS: Magnetic resonance imaging (MRI) was obtained for twelve human cadaveric knees. The knees, in intact and deficient-ACL states, were subjected to external loading conditions as follows: an anterior tibial load of 89 N at 0 degrees , 15 degrees , 30 degrees , 45 degrees , 60 degrees , and 90 degrees of flexion and a combined rotatory (simulated pivot-shift) load of 5 Nm of internal tibial torque and 7 Nm of valgus torque at 0 degrees , 15 degrees , and 30 degrees of flexion. Three ACL reconstructions were performed in a randomized order: from the center of the tibial insertion site to the center of the femoral insertion site (Mid), the center of the tibial insertion site to a more vertical femoral position (S1), and the center of the tibial insertion site to an even more vertical femoral position (S2). The reconstructions were tested following the same protocol used for the intact state, and graft in situ force was calculated for the two loadings at each flexion angle. MRI was used to measure the graft inclination angle after each ACL reconstruction. RESULTS: The mean inclination angle (and standard deviation) was 51.7 degrees +/- 5.0 degrees for the native ACL, 51.6 degrees +/- 4.1 degrees for the Mid reconstruction (p = 0.85), 58.7 degrees +/- 5.4 degrees for S1 (p < 0.001), and 64.7 degrees +/- 6.5 degrees for S2 (p < 0.001). At 0 degrees , 15 degrees , and 30 degrees of knee flexion, the Mid reconstruction showed in situ graft force that was closer to that of the native ACL during both anterior tibial loading and simulated pivot shift loading than was the case for S1 and S2 reconstructions. At greater flexion angles, S1 and S2 had in situ graft force that was closer to that of the native ACL than was the case for the Mid reconstruction. CONCLUSIONS: Anatomic ACL reconstruction exposes grafts to higher loads at lower angles of knee flexion. CLINICAL RELEVANCE: Rehabilitation and return to sports progression may need to be modified to protect an anatomically placed graft after ACL reconstruction. PMID- 26537165 TI - Incidence, Risk Factors, and Causes for Thirty-Day Unplanned Readmissions Following Primary Lower-Extremity Amputation in Patients with Diabetes. AB - BACKGROUND: The Centers for Medicare & Medicaid Services targeted thirty-day readmissions as a quality-of-care measure. Hospitals can be penalized on unplanned readmissions. Given the frequency of amputation in diabetic patients and our changing health-care system, the purpose of this study was to determine the incidence, risk factors, and causes for unplanned thirty-day readmissions following primary lower-extremity amputation in diabetic patients. METHODS: Patients with a diagnosis of diabetes undergoing primary lower-extremity amputation between 2002 and 2013 were retrospectively identified in a single center patient database. Chart review determined patient factors including comorbidities, hemoglobin A1c level, amputation level, and demographic characteristics. Patients were divided into groups with and without unplanned readmission within thirty days postoperatively. Univariate and multivariate logistic regression analyses were used to compare cohorts and to identify variables associated with readmission. RESULTS: Overall, forty-six (10.5%) of 439 diabetic patients undergoing primary lower-extremity amputation had an unplanned thirty-day readmission. The top reason for readmission was a major surgical event requiring reoperation (37.0%), followed by medical events (28.3%) and minor surgical events (28.3%). In the univariate analysis, discharge on antibiotics (p = 0.002), smoking (p = 0.003), chronic kidney disease (p = 0.002), peripheral vascular disease (p = 0.002), and higher Charlson Comorbidity Index (p = 0.001) were each associated with readmission. In the multivariate analysis, diagnosis of gangrene (odds ratio [OR], 2.95 [95% confidence interval (95% CI), 1.37 to 6.35]), discharge on antibiotics (OR, 4.48 [95% CI, 1.71 to 11.74]), smoking (OR, 3.22 [95% CI, 1.40 to 7.36]), chronic kidney disease (OR, 2.82 [95% CI, 1.30 to 6.15]), and peripheral vascular disease (OR, 2.47 [95% CI, 1.08 to 5.67]) were independently associated with readmission. CONCLUSIONS: Thirty-day readmission rates following primary lower-extremity amputation in patients with diabetes were high at >10%. Both medical and surgical complications, many of which were unavoidable, contributed to readmission. Quality-reporting metrics should include these risk factors to avoid undeservedly penalizing surgeons and hospitals caring for this patient population. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26537166 TI - Clinical Outcomes of Semiconstrained Total Elbow Arthroplasty in Patients Who Were Forty Years of Age or Younger. AB - BACKGROUND: Total elbow arthroplasty is not commonly used in young patients with advanced arthritis because of concerns regarding implant loosening and clinical failure. Until now, to our knowledge, there have only been a few studies on the outcome in younger patients undergoing total elbow arthroplasty. METHODS: Twenty three elbows in patients forty years of age or younger who underwent total elbow arthroplasty were reviewed retrospectively. There were nine elbows with posttraumatic arthritis and fourteen elbows with nontraumatic arthritis. The mean patient age at the time of the surgical procedure was thirty-three years (range, twenty to forty years), and the mean follow-up duration was 129 months (range, eighty-five to 227 months). RESULTS: At the time of the latest follow-up, pain during motion decreased from a mean visual analog scale score (and standard deviation) of 5.8 +/- 1.8 cm preoperatively to 1.6 +/- 1.1 cm postoperatively (p < 0.001), and the mean Mayo Elbow Performance Score increased from 32.0 +/- 9.4 points preoperatively to 81.1 +/- 13.7 points postoperatively (p < 0.001). The mean subjective patients' satisfaction score was 83.5 +/- 11.7 points. The mean flexion-extension arc in the posttraumatic arthritis group increased from 37.8 degrees +/- 30.3 degrees preoperatively to 120.6 degrees +/- 11.3 degrees at the time of the latest follow-up, whereas that in the nontraumatic arthritis group increased from 24.3 degrees +/- 27.6 degrees to 96.4 degrees +/- 21.2 degrees (p < 0.001 for both). At the time of the latest follow-up, the loosening rate was 13% and mild-to-moderate bushing wear was observed in four elbows (17%). A revision surgical procedure was performed in five elbows (22%), of which three had revision surgery after fifteen postoperative years. The overall implant survival rates were 95% at the eight-year follow-up and 89% at the fifteen-year follow-up. CONCLUSIONS: Despite concerns regarding the longevity of total elbow replacements in young patients, long-term follow-up after total elbow arthroplasty showed significant functional improvement and pain relief. Although a desirable range of motion after the surgical procedure was difficult to achieve in patients with preoperative ankylosis, total elbow arthroplasty in selected young patients showed acceptable loosening, reoperation, and implant survival rates. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26537167 TI - Effect of Fibrin Formulation on Initial Strength of Tendon Repair and Migration of Bone Marrow Stromal Cells in Vitro. AB - BACKGROUND: Cell-based tissue engineering techniques have been introduced to improve tendon repair outcomes. The purpose of this study was to determine optimal concentrations of fibrinogen and thrombin for use as a scaffold to deliver stromal cells to the tendon repair site. METHODS: Lacerated flexor digitorum profundus tendons from forty canine forepaws underwent simulated repair with fibrin gel interposition. The tendons were divided into five groups with different ratios of fibrinogen (mg/mL) to thrombin (NIH units/mL) used to form the gels. These ratios, which ranged from those found in normal hemostasis to those used clinically as adhesives, were 5:25 (the physiological ratio, used as a control), 40:250 (a low adhesive concentration of fibrinogen and a low adhesive concentration of thrombin [low-low group]), 80:250 (high-low group), 40:500 (low high group), and 80:500 (high-high group). The failure load and tensile stiffness at time zero, compressive stiffness of the fibrin gel, and cell viability and migration were evaluated. RESULTS: The failure loads of the high-low and high high groups were significantly higher than that of the control group. The tensile stiffness of the high-high group was significantly higher than that of the control group. The high-low and high-high groups had significantly higher compressive stiffness than the other groups. While there was no significant difference among the groups regarding cell viability, the cells in the control, low-low, and low-high gels were spindle-shaped whereas those in the high-low and high-high groups were rounded. Cells migrated across scratch gaps within twenty four hours in the control, low-low, and low-high groups, but not in the high-low and high-high groups. CONCLUSIONS: Higher concentrations of fibrinogen resulted in stronger and stiffer gels, but the strength was far less than that of a tendon suture and these gels were associated with a more rounded cell morphology and reduced cell migration. Therefore, lower concentrations of fibrinogen should be used if a fibrin gel is employed to deliver cells for tendon repair. CLINICAL RELEVANCE: Concentrations of fibrinogen lower than those used in fibrin glue may be more appropriate if fibrin is employed to create a cell delivery matrix for tendon repair. PMID- 26537168 TI - Database and Registry Research in Orthopaedic Surgery: Part 2: Clinical Registry Data. AB - The use of large-scale national databases for observational research in orthopaedic surgery has grown substantially in the last decade, and the data sets can be categorized as either administrative claims or clinical registries. Clinical registries contain secondary data on patients with a specific diagnosis or procedure. The data are typically used for patient outcome surveillance to improve patient safety and health-care quality. Registries used in orthopaedic research exist at the regional, national, and international levels, and many were designed to specifically collect outcomes relevant to orthopaedics, such as short term surgical complications, longer-term outcomes (implant survival or reoperations), and patient-reported outcomes. Although heterogeneous, clinical registries-in contrast to claims data-typically have a more robust list of variables, with relatively precise prospective data input, management infrastructure, and reporting systems. Some weaknesses of clinical registries include a smaller number of patients, inconstant follow-up duration, and use of sampling methods that may limit generalizability. Within the U.S., national joint registry adoption has lagged international joint registries. Given the changing health-care environment, it is likely that clinical registries will provide valuable information that has the potential to influence clinical practice improvement and health-care policy in the future. PMID- 26537169 TI - Quality and Safety in Orthopaedics: Learning and Teaching at the Same Time: AOA Critical Issues. AB - Increasing attention has been placed on providing higher quality and safer patient care. This requires the development of a new set of competencies to better understand and navigate the system and lead the orthopaedic team. While still trying to learn and develop these competencies, the academic orthopaedist is also expected to model and teach them.The orthopaedic surgeon must understand what is being measured and why, both for purposes of providing better care and to eliminate unnecessary expense in the system. Metrics currently include hospital acquired conditions, "never events," and thirty-day readmission rates. More will undoubtedly follow.Although commitment and excellence at the individual level are essential, the orthopaedist must think at the systems level to provide the highest value of care. A work culture characterized by respect and trust is essential to improved communication, teamwork, and confidential peer review. An increasing number of resources, both in print and electronic format, are available for us to understand what we can do now to improve quality and safety.Resident education in quality and safety is a fundamental component of the systems-based practice competency, the Next Accreditation System, and the Clinical Learning Environment Review. This needs to be longitudinally integrated into the curriculum and applied parallel to the development of resident knowledge and skill, and will be best learned if resident learning is experiential and taught within a genuine culture of quality and safety. PMID- 26537170 TI - Initial Nonoperative Care Is Reasonable for Older Patients: Commentary on an article by Juha Kukkonen, MD, PhD, et al.: "Treatment of Nontraumatic Rotator Cuff Tears. A Randomized Controlled Trial with Two Years of Clinical and Imaging Follow-up". PMID- 26537171 TI - Cervical Disc Replacement: Are We There Yet? Commentary on an article by Michael E. Janssen, DO, et al.: "ProDisc-C Total Disc Replacement Versus Anterior Cervical Discectomy and Fusion for Single-Level Symptomatic Cervical Disc Disease. Seven-Year Follow-up of the Prospective Randomized U.S. Food and Drug Administration Investigational Device Exemption Study". PMID- 26537172 TI - Manual control of catalytic reactions: Reactions by an apoenzyme gel and a cofactor gel. AB - Enzymes play a vital role in catalysing almost all chemical reactions that occur in biological systems. Some enzymes must form complexes with non-protein molecules called cofactors to express catalytic activities. Although the control of catalytic reactions via apoenzyme-cofactor complexes has attracted significant attention, the reports have been limited to the microscale. Here, we report a system to express catalytic activity by adhesion of an apoenzyme gel and a cofactor gel. The apoenzyme and cofactor gels act as catalysts when they form a gel assembly, but they lose catalytic ability upon manual dissociation. We successfully construct a system with switchable catalytic activity via adhesion and separation of the apoenzyme gel with the cofactor gel. We expect that this methodology can be applied to regulate the functional activities of enzymes that bear cofactors in their active sites, such as the oxygen transport of haemoglobin or myoglobin and the electron transport of cytochromes. PMID- 26537173 TI - Phosphine-Catalyzed beta,gamma-Umpolung Domino Reaction of Allenic Esters: Facile Synthesis of Tetrahydrobenzofuranones Bearing a Chiral Tetrasubstituted Stereogenic Carbon Center. AB - An enantio-, diastereo-, regio-, and chemoselective phosphine-catalyzed beta,gamma-umpolung domino reaction of allenic esters with dienones has been developed for the first time. The designed sequence, involving oxy-Michael and Rauhut-Currier reactions, produced highly functionalized tetrahydrobenzofuranones, bearing a chiral tetrasubstituted stereogenic center, in up to 96 % ee. PMID- 26537174 TI - A study on the AMACR catalysed elimination reaction and its application to inhibitor testing. AB - alpha-Methylacyl-CoA racemase (AMACR; P504S) catalyses a key step in the degradation of branched-chain fatty acids and is important for the pharmacological activation of Ibuprofen and related drugs. Levels of AMACR are increased in prostate and other cancers, and it is a drug target. Development of AMACR as a drug target is hampered by lack of a convenient assay. AMACR irreversibly catalyses the elimination of HF from 3-fluoro-2-methylacyl-CoA substrates, and this reaction was investigated for use as an assay. Several known inhibitors and alternative substrates reduced conversion of 3-fluoro-2 methyldecanoyl-CoA by AMACR, as determined by (1)H NMR. The greatest reduction of activity was observed with known potent inhibitors. A series of novel acyl-CoA esters with aromatic side chains were synthesised for testing as chromophoric substrates. These acyl-CoA esters were converted to unsaturated products by AMACR, but their use was limited by non-enzymatic elimination. Fluoride sensors were also investigated as a method of quantifying released fluoride and thus AMACR activity. These sensors generally suffered from high background signal and lacked reproducibility under the assay conditions. In summary, the elimination reaction can be used to characterise inhibitors, but it was not possible to develop a convenient colorimetric or fluorescent assay using 3-fluoro-2 methylacyl-CoA substrates. PMID- 26537176 TI - Surgical outcomes after laparoscopic or robotic liver resection in hepatocellular carcinoma: a propensity-score matched analysis with conventional open liver resection. AB - BACKGROUND: This study was designed to compare perioperative and oncologic outcomes between minimally invasive liver resection (MILR) and conventional open liver resection (COLR) for hepatocellular carcinoma (HCC) using a propensity score matched analysis. METHODS: Ninety-nine patients who received MILR were matched with 198 patients treated with COLR out of 928 patients with HCC who received curative liver resection from 2002 to 2012. A multivariable logistic model based on factors related to the patient, tumor, and surgical procedure was used to estimate a propensity score. RESULTS: The MILR group experienced significantly less intraoperative blood loss (mean: 389.55 vs 580.66 mL; P = 0.008), lower complication rates (13.1% vs 24.7%; P = 0.020), and a shorter length of hospital stay (mean: 8.40 vs 13.39 days; P < 0.001). The two groups did not differ significantly in disease-free (P = 0.701) or overall survival (P = 0.086). CONCLUSIONS: MILR produced better perioperative and comparable oncologic outcomes than COLR for HCC. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26537175 TI - The SENSE Study (Sleep and Education: learning New Skills Early): a community cognitive-behavioural therapy and mindfulness-based sleep intervention to prevent depression and improve cardiac health in adolescence. AB - BACKGROUND: Sleep problems are a major risk factor for the emergence of depression in adolescence. The aim of this study was to test whether an intervention for improving sleep habits could prevent the emergence of depression, and improve well-being and cardiovascular indices amongst at-risk adolescents. METHODS/DESIGN: A longitudinal randomised controlled trial (RCT) is being conducted across Victorian Secondary Schools in Melbourne, Australia. Adolescents (aged 12-17 years) were defined as at-risk for depression if they reported high levels of anxiety and sleep problems on in-school screening questionnaires and had no prior history of depression (assessed by clinical diagnostic interview). Eligible participants were randomised into either a sleep improvement intervention (based on cognitive behavioral and mindfulness principles) or an active control condition teaching study skills. Both programs consisted of seven 90 minute-long sessions over seven weeks. All participants were required to complete a battery of mood and sleep questionnaires, seven-days of actigraphy, and sleep diary entry at pre- and post-intervention. Participants also completed a cardiovascular assessment and two days of saliva collection at pre-intervention. Participants will repeat all assessments at two-year follow up (ongoing). DISCUSSION: This will be the first efficacy trial of a selective group based sleep intervention for the prevention of depression in an adolescent community sample. If effective, the program could be disseminated in schools and greatly improve health outcomes for anxious adolescents. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612001177842. Date of Registration: 06-Nov-2012. PMID- 26537177 TI - Correction of aberrant imprinting by allele-specific epigenome editing. AB - Imprinting disorders are caused by the loss of the normal allele-specific DNA methylation at imprinting centers. Epigenetic editing is a promising approach to alter DNA methylation at defined genomic target regions. The novel development of CRISPR-Cas9-based DNA binding domains may allow for an allele-specific editing of DNA methylation at imprinted loci, for the first time offering a rational approach for correction of the molecular defects in imprinting disorders. PMID- 26537178 TI - Incidence and risk of peripheral neuropathy with nab-paclitaxel in patients with cancer: a meta-analysis. AB - Nab-paclitaxel, a Cremophor EL-free formulation of paclitaxel, is used to treat various malignancies. Peripheral neuropathy is one of its major toxicities, although the overall incidence remains unclear. We performed a meta-analysis to calculate the incidence of peripheral neuropathy in cancer patients treated with nab-paclitaxel and to compare the relative risk (RR) with conventional taxanes. The electronic databases were searched for relevant clinical trials. Eligible studies included phase II and III prospective clinical trials of cancer patients treated with nab-paclitaxel with toxicity profile on peripheral neuropathy. Statistical analyses were done to calculate summary incidences, RRs and 95% confidence intervals (CI), using fixed-effects or random-effects models based on the heterogeneity of the included studies. Nineteen trials were selected for the meta-analysis, yielding a total of 2878 cancer patients. The overall incidences of peripheral neuropathy (all-grade) was 51.0% (95% CI: 45.1-57.6%), and that of high-grade peripheral neuropathy was 12.4% (9.8-15.7%). The RRs of peripheral neuropathy of nab-paclitaxel compared to taxanes were not increased for all-grade and high-grade peripheral neuropathy. Nab-paclitaxel is associated with an increased risk of developing peripheral neuropathy. Future clinical studies are still needed to investigate the risk reduction and possible use of nab paclitaxel. PMID- 26537179 TI - BRANE Cut: biologically-related a priori network enhancement with graph cuts for gene regulatory network inference. AB - BACKGROUND: Inferring gene networks from high-throughput data constitutes an important step in the discovery of relevant regulatory relationships in organism cells. Despite the large number of available Gene Regulatory Network inference methods, the problem remains challenging: the underdetermination in the space of possible solutions requires additional constraints that incorporate a priori information on gene interactions. METHODS: Weighting all possible pairwise gene relationships by a probability of edge presence, we formulate the regulatory network inference as a discrete variational problem on graphs. We enforce biologically plausible coupling between groups and types of genes by minimizing an edge labeling functional coding for a priori structures. The optimization is carried out with Graph cuts, an approach popular in image processing and computer vision. We compare the inferred regulatory networks to results achieved by the mutual-information-based Context Likelihood of Relatedness (CLR) method and by the state-of-the-art GENIE3, winner of the DREAM4 multifactorial challenge. RESULTS: Our BRANE Cut approach infers more accurately the five DREAM4 in silico networks (with improvements from 6% to 11%). On a real Escherichia coli compendium, an improvement of 11.8% compared to CLR and 3% compared to GENIE3 is obtained in terms of Area Under Precision-Recall curve. Up to 48 additional verified interactions are obtained over GENIE3 for a given precision. On this dataset involving 4345 genes, our method achieves a performance similar to that of GENIE3, while being more than seven times faster. The BRANE Cut code is available at: http://www-syscom.univ-mlv.fr/~pirayre/Codes-GRN-BRANE-cut.html. CONCLUSIONS: BRANE Cut is a weighted graph thresholding method. Using biologically sound penalties and data-driven parameters, it improves three state of-the art GRN inference methods. It is applicable as a generic network inference post-processing, due to its computational efficiency. PMID- 26537180 TI - Group sequential testing of the predictive accuracy of a continuous biomarker with unknown prevalence. AB - Group sequential testing procedures have been proposed as an approach to conserving resources in biomarker validation studies. Previously, we derived the asymptotic properties of the sequential empirical positive predictive value (PPV) and negative predictive value (NPV) curves, which summarize the predictive accuracy of a continuous marker, under case-control sampling. A limitation of this approach is that the prevalence cannot be estimated from a case-control study and must be assumed known. In this paper, we consider group sequential testing of the predictive accuracy of a continuous biomarker with unknown prevalence. First, we develop asymptotic theory for the sequential empirical PPV and NPV curves when the prevalence must be estimated, rather than assumed known in a case-control study. We then discuss how our results can be combined with standard group sequential methods to develop group sequential testing procedures and bias-adjusted estimators for the PPV and NPV curve. The small sample properties of the proposed group sequential testing procedures and estimators are evaluated by simulation, and we illustrate our approach in the context of a study to validate a novel biomarker for prostate cancer. PMID- 26537181 TI - Building research capacity and productivity among advanced practice nurses: an evaluation of the Community of Practice model. AB - AIM: The aim of this study was to evaluate Wenger's Community of Practice as a framework for building research capacity and productivity. BACKGROUND: While research productivity is an expected domain in influential models of advanced nursing practice, internationally it remains largely unmet. Establishment of nursing research capacity precedes productivity and consequently, there is a strong imperative to identify successful capacity-building models for nursing focussed research in busy clinical environments. DESIGN: Prospective, longitudinal, qualitative descriptive design was used in this study. METHODS: Bruyn's participant observation framed evaluation of a Community of Practice comprising 25 advanced practice nurses. Data from focus groups, education evaluations, blog/email transcripts and field observations, collected between 2007 and 2014, were analysed using a qualitative descriptive method. FINDINGS: The Community of Practice model invited differing levels of participation, allowed for evolution of the research community and created a rhythm of research related interactions and enduring research relationships. Participants described the value of research for their patients and families and the significance of the developing research culture in providing richness to their practice and visibility of their work to multidisciplinary colleagues. Extensive examples of research dissemination and enrolment in doctoral programmes further confirmed this value. CONCLUSION: A Community of Practice framework is a powerful model enabling research capacity and productivity evidenced by publication. In developing a solid foundation for a nursing research culture, it should be recognized that research skills, confidence and growth develop over an extended period of time and success depends on skilled coordination and leadership. PMID- 26537182 TI - HbA1c After a Short Period of Monotherapy With Metformin Identifies Durable Glycemic Control Among Adolescents With Type 2 Diabetes. AB - OBJECTIVE: To determine whether clinically accessible parameters early in the course of youth-onset type 2 diabetes predict likelihood of durable control on oral therapy. RESEARCH DESIGN AND METHODS: TODAY was a randomized clinical trial of adolescents with type 2 diabetes. Two groups, including participants from all three treatments, were defined for analysis: (1) those who remained in glycemic control for at least 48 months of follow-up and (2) those who lost glycemic control before 48 months. Outcome group was analyzed in univariate and multivariate models as a function of baseline characteristics (age, sex, race/ethnicity, socioeconomic status, BMI, waist circumference, Tanner stage, disease duration, depressive symptoms) and biochemical measures (HbA1c, C peptide, lean and fat body mass, insulin inverse, insulinogenic index). Receiver operating characteristic curves were used to analyze HbA1c cut points. RESULTS: In multivariate models including factors significant in univariate analysis, only HbA1c and insulinogenic index at randomization remained significant (P < 0.0001 and P = 0.0002, respectively). An HbA1c cutoff of 6.3% (45 mmol/mol) (positive likelihood ratio [PLR] 3.7) was identified that optimally distinguished the groups; sex-specific cutoffs were 6.3% (45 mmol/mol) for females (PLR 4.4) and 5.6% (38 mmol/mol) for males (PLR 2.1). CONCLUSIONS: Identifying youth with type 2 diabetes at risk for rapid loss of glycemic control would allow more targeted therapy. HbA1c is a clinically accessible measure to identify high risk for loss of glycemic control on oral therapy. Adolescents with type 2 diabetes unable to attain a non-diabetes range HbA1c on metformin are at increased risk for rapid loss of glycemic control. PMID- 26537183 TI - Effect of the GLP-1 Receptor Agonist Lixisenatide on Counterregulatory Responses to Hypoglycemia in Subjects With Insulin-Treated Type 2 Diabetes. AB - OBJECTIVE: Counterregulatory responses are critical to prevent hypoglycemia in subjects with type 2 diabetes. This is particularly important in insulin-treated patients. This study explored the effect of the glucagon-like peptide 1 receptor agonist lixisenatide on the hormonal counterregulatory responses to insulin induced hypoglycemia when added to basal insulin therapy in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: The study was a single-center, double blind, randomized, placebo-controlled crossover study involving 18 subjects with type 2 diabetes (11 males) with a mean age of 55 years, diabetes duration of 12 years, HbA1c level of 7.7%, fasting blood glucose (FBG) concentration of 9.7 mmol/L, and a BMI of 33 kg/m(2), who were treated with basal insulin (mean duration 7 years, daily dose 39 units/day) and metformin (mean daily dose 2.1 g). Subjects received treatment with lixisenatide or placebo for 6 weeks in random order, with a 4-week washout period in between. After 6 weeks of treatment, subjects underwent a two-step hyperinsulinemic hypoglycemic clamp at 3.5 and 2.8 mmol/L. RESULTS: After 6 weeks of treatment, HbA1c and FBG levels were lower after lixisenatide therapy than after placebo therapy. At the hypoglycemic level of 3.5 mmol/L, glucagon and epinephrine levels were significantly lower during lixisenatide treatment than during placebo treatment, whereas at 2.8 mmol/L glucagon and epinephrine levels did not differ between the subjects. Cortisol, pancreatic polypeptide, and norepinephrine levels did not differ significantly between the treatments. CONCLUSIONS: Glucagon and epinephrine levels are reduced by lixisenatide at a concentration of 3.5 mmol/L, but their counterregulatory responses to deep hypoglycemia at a concentration of 2.8 mmol/L are sustained during treatment with lixisenatide in combination with basal insulin. PMID- 26537184 TI - Infections and interaction rituals in the organisation: clinician accounts of speaking up or remaining silent in the face of threats to patient safety. AB - Clinician silence in the face of known threats to patient safety is a source of growing concern. Current explanations for the difficulties clinicians have of speaking up are conceptualised at the individual or organisational level, with little attention paid to the space between--the interaction context. Drawing on 103 interviews with clinicians at one hospital in the United States this article examines how clinicians talk about speaking up or not in the face of breaches in infection prevention technique. Accounts are analysed using a microsociological lens as stories of interaction, through which respondents appeal to situational and organisational realities of medical work that serve to justify speaking up or remaining silent. Analysis of these accounts reveals three influences on the decision to speak up, shaped by background conditions in the organisation; mutual focus of attention, interactional path dependence and the presence of an audience. These findings suggest that the decision to speak up in a clinical setting is dynamic, highly context-dependent, embedded in the interaction rituals that suffuse everyday work and constrained by organisational dynamics. This article develops a more sophisticated and distinctly sociological understanding of the reasons why speaking up in healthcare is so difficult. PMID- 26537185 TI - The NEEDLELESS MICROJET: a novel device for hypertrophic scar remodelling on the forehead. PMID- 26537187 TI - An NMR study of new cardiac glycoside derivatives. PMID- 26537186 TI - Arsenic Promotes NF-Kappab-Mediated Fibroblast Dysfunction and Matrix Remodeling to Impair Muscle Stem Cell Function. AB - Arsenic is a global health hazard that impacts over 140 million individuals worldwide. Epidemiological studies reveal prominent muscle dysfunction and mobility declines following arsenic exposure; yet, mechanisms underlying such declines are unknown. The objective of this study was to test the novel hypothesis that arsenic drives a maladaptive fibroblast phenotype to promote pathogenic myomatrix remodeling and compromise the muscle stem (satellite) cell (MuSC) niche. Mice were exposed to environmentally relevant levels of arsenic in drinking water before receiving a local muscle injury. Arsenic-exposed muscles displayed pathogenic matrix remodeling, defective myofiber regeneration and impaired functional recovery, relative to controls. When naive human MuSCs were seeded onto three-dimensional decellularized muscle constructs derived from arsenic-exposed muscles, cells displayed an increased fibrogenic conversion and decreased myogenicity, compared with cells seeded onto control constructs. Consistent with myomatrix alterations, fibroblasts isolated from arsenic-exposed muscle displayed sustained expression of matrix remodeling genes, the majority of which were mediated by NF-kappaB. Inhibition of NF-kappaB during arsenic exposure preserved normal myofiber structure and functional recovery after injury, suggesting that NF-kappaB signaling serves as an important mechanism of action for the deleterious effects of arsenic on tissue healing. Taken together, the results from this study implicate myomatrix biophysical and/or biochemical characteristics as culprits in arsenic-induced MuSC dysfunction and impaired muscle regeneration. It is anticipated that these findings may aid in the development of strategies to prevent or revert the effects of arsenic on tissue healing and, more broadly, provide insight into the influence of the native myomatrix on stem cell behavior. PMID- 26537188 TI - Patient activation with knowledge, self-management and confidence in chronic kidney disease. AB - BACKGROUND: Chronic kidney disease is a growing health problem on a global scale. The increasing prevalence of chronic kidney disease presents an urgent need to better understand the knowledge, confidence and engagement in self-managing the disease. OBJECTIVES: This study examined group differences in patient activation and health-related quality of life, knowledge, self-management and confidence with managing chronic disease across all five stages of chronic kidney disease. DESIGN: The study employed a descriptive correlational design. SETTINGS: Participants were recruited from five primary care, three nephrology clinics and one dialysis centre in two Midwestern cities in the United States. PARTICIPANTS: The convenience sample included 85 adults with hypertension, diabetes mellitus and chronic kidney disease, including kidney failure, who spoke English. MEASUREMENTS: Seven measurements were used to collect data via telephone interviews with participants not receiving haemodialysis, and face-to-face interviews with those receiving haemodialysis at the beginning of their treatment session. RESULTS: Analyses indicated that half the participants were female (50.58%), the mean age was 63.21 years (SD = 13.11), and participants with chronic kidney disease stage 3 were the most activated. Post hoc differences were significant in patient activation and blood pressure self-management and anxiety across chronic kidney disease stages, excluding stage 5. CONCLUSION: Engaging patients in the self-management of their health care and enhancing patients' ability to self-manage their blood pressure may work to preserve kidney health. Healthcare providers should collaborate with patients to develop strategies that will maintain patients' health-related quality of life, like reducing anxiety as kidney disease progress. PMID- 26537189 TI - Photoprotective Potential of Penta-O-Galloyl-beta-DGlucose by Targeting NF-kappaB and MAPK Signaling in UVB Radiation-Induced Human Dermal Fibroblasts and Mouse Skin. AB - Exposure of the skin to ultraviolet radiation can cause skin damage with various pathological changes including inflammation. In the present study, we identified the skin-protective activity of 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (pentagalloyl glucose, PGG) in ultraviolet B (UVB) radiation-induced human dermal fibroblasts and mouse skin. PGG exhibited antioxidant activity with regard to intracellular reactive oxygen species (ROS) generation as well as ROS and reactive nitrogen species (RNS) scavenging. Furthermore, PGG exhibited anti inflammatory activity, inhibiting the activation of nuclear factor-kappaB (NF kappaB) and mitogen-activated protein kinase (MAPK) signaling, resulting in inhibition of the expression of pro-inflammatory mediators. Topical application of PGG followed by chronic exposure to UVB radiation in the dorsal skin of hairless mice resulted in a significant decrease in the progression of inflammatory skin damages, leading to inhibited activation of NF-kappaB signaling and expression of pro-inflammatory mediators. The present study demonstrated that PGG protected from skin damage induced by UVB radiation, and thus, may be a potential candidate for the prevention of environmental stimuli-induced inflammatory skin damage. PMID- 26537190 TI - Resveratrol Induces Glioma Cell Apoptosis through Activation of Tristetraprolin. AB - Tristetraprolin (TTP) is an AU-rich elements (AREs)-binding protein, which regulates the decay of AREs-containing mRNAs such as proto-oncogenes, anti apoptotic genes and immune regulatory genes. Despite the low expression of TTP in various human cancers, the mechanism involving suppressed expression of TTP is not fully understood. Here, we demonstrate that Resveratrol (3,5,4' trihydroxystilbene, Res), a naturally occurring compound, induces glioma cell apoptosis through activation of tristetraprolin (TTP). Res increased TTP expression in U87MG human glioma cells. Res-induced TTP destabilized the urokinase plasminogen activator and urokinase plasminogen activator receptor mRNAs by binding to the ARE regions containing the 3' untranslated regions of their mRNAs. Furthermore, TTP induced by Res suppressed cell growth and induced apoptosis in the human glioma cells. Because of its regulation of TTP expression, these findings suggest that the bioactive dietary compound Res can be used as a novel anti-cancer agent for the treatment of human malignant gliomas. PMID- 26537191 TI - Blockade of Retinol Metabolism Protects T Cell-Induced Hepatitis by Increasing Migration of Regulatory T Cells. AB - Retinols are metabolized into retinoic acids by alcohol dehydrogenase (ADH) and retinaldehyde dehydrogenase (Raldh). However, their roles have yet to be clarified in hepatitis despite enriched retinols in hepatic stellate cells (HSCs). Therefore, we investigated the effects of retinols on Concanavalin A (Con A)-mediated hepatitis. Con A was injected into wild type (WT), Raldh1 knock-out (Raldh1(-/-)), CCL2(-/-) and CCR2(-/-) mice. For migration study of regulatory T cells (Tregs), we used in vivo and ex vivo adoptive transfer systems. Blockade of retinol metabolism in mice given 4-methylpyrazole, an inhibitor of ADH, and ablated Raldh1 gene manifested increased migration of Tregs, eventually protected against Con A-mediated hepatitis by decreasing interferon-gamma in T cells. Moreover, interferon-gamma treatment increased the expression of ADH3 and Raldh1, but it suppressed that of CCL2 and IL-6 in HSCs. However, the expression of CCL2 and IL-6 was inversely increased upon the pharmacologic or genetic ablation of ADH3 and Raldh1 in HSCs. Indeed, IL-6 treatment increased CCR2 expression of Tregs. In migration assay, ablated CCR2 in Tregs showed reduced migration to HSCs. In adoptive transfer of Tregs in vivo and ex vivo, Raldh1-deficient mice showed more increased migration of Tregs than WT mice. Furthermore, inhibited retinol metabolism increased survival rate (75%) compared with that of the controls (25%) in Con A-induced hepatitis. These results suggest that blockade of retinol metabolism protects against acute liver injury by increased Treg migration, and it may represent a novel therapeutic strategy to control T cell mediated acute hepatitis. PMID- 26537192 TI - Identification of the 187 bp EphA7 Genomic DNA as the Dorsal Midline-Specific Enhancer of the Diencephalon and Mesencephalon. AB - EphA7 is a key molecule in regulating the development of the dien- and mesencephalon. To get insight into the mechanism of how EphA7 gene expression is regulated during the dorsal specification of the dien- and mesencephalon, we investigated the cis-acting regulatory sequence driving EphA7 to the dorsal midline of the dien- and mesencephalon. Transgenic LacZ reporter analysis, using overlapping EphA7 BACs, was used to narrow down the dorsal midline-specific enhancer, revealing the 25.3 kb genomic region as the enhancer candidate. Strikingly, this genomic DNA was located far downstream of the EphA7 transcription start site, +302.6 kb to +327.9 kb. Further enhancer mapping, using comparative genomic analysis and transgenic methods, showed that the 187 bp genomic DNA alone, approximately 305 kb downstream of the EphA7 transcription start site, was sufficient to act as the dorsal midline-specific enhancer of EphA7. Importantly, our results indicate that the 187 bp dorsal midline-specific enhancer is critically regulated by homeobox transcription factors during the development of the dien- and mesencephalon. PMID- 26537193 TI - TM-25659-Induced Activation of FGF21 Level Decreases Insulin Resistance and Inflammation in Skeletal Muscle via GCN2 Pathways. AB - The TAZ activator 2-butyl-5-methyl-6-(pyridine-3-yl)-3-[2'-(1H-tetrazole-5-yl) biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine] (TM-25659) inhibits adipocyte differentiation by interacting with peroxisome proliferator-activated receptor gamma. TM-25659 was previously shown to decrease weight gain in a high fat (HF) diet-induced obesity (DIO) mouse model. However, the fundamental mechanisms underlying the effects of TM-25659 remain unknown. Therefore, we investigated the effects of TM-25659 on skeletal muscle functions in C2 myotubes and C57BL/6J mice. We studied the molecular mechanisms underlying the contribution of TM-25659 to palmitate (PA)-induced insulin resistance in C2 myotubes. TM-25659 improved PA induced insulin resistance and inflammation in C2 myotubes. In addition, TM-25659 increased FGF21 mRNA expression, protein levels, and FGF21 secretion in C2 myotubes via activation of GCN2 pathways (GCN2-phosphoeIF2alpha-ATF4 and FGF21). This beneficial effect of TM-25659 was diminished by FGF21 siRNA. C57BL/6J mice were fed a HF diet for 30 weeks. The HF-diet group was randomly divided into two groups for the next 14 days: the HF-diet and HF-diet + TM-25659 groups. The HF diet + TM-25659-treated mice showed improvements in their fasting blood glucose levels, insulin sensitivity, insulin-stimulated Akt phosphorylation, and inflammation, but neither body weight nor food intake was affected. The HF diet + TM-25659-treated mice also exhibited increased expression of both FGF21 mRNA and protein. These data indicate that TM-25659 may be beneficial for treating insulin resistance by inducing FGF21 in models of PA-induced insulin resistance and HF diet-induced insulin resistance. PMID- 26537195 TI - Hetero-pi-Dimers of Phenalenyls. AB - Homogeneous pi-stacking dimers of phenalenyl and its derivatives have gained tremendous interest as components of conducting organic materials. For the first time, we investigate theoretically heterogeneous phenalenyl pi-dimers. Key parameters, including charge transfer, interaction energy, singly occupied molecular orbital (SOMO) energy, and spin density, are studied with the help of density functional theory. We find that the amount of charge transfer between the two monomers in phenalenyl pi-dimers correlates with the difference in the SOMO energies of the constituent monomers, where the SOMO energy plays the role of a monomer (group) electronegativity index. Charge transfer plays an important role in stabilizing the heterodimers while maintaining a significant diradicaloid character. For five heterodimers the interaction energy is found to be as large as -30 to -50 kcal mol(-1) . The presented correlation between the monomer SOMO energy levels and their stability can provide a simple predictive tool to design new highly stable pi-stacking heterodimers. PMID- 26537194 TI - Gain of a New Exon by a Lineage-Specific Alu Element-Integration Event in the BCS1L Gene during Primate Evolution. AB - BCS1L gene encodes mitochondrial protein and is a member of conserved AAA protein family. This gene is involved in the incorporation of Rieske FeS and Qcr10p into complex III of respiratory chain. In our previous study, AluYRa2-derived alternative transcript in rhesus monkey genome was identified. However, this transcript has not been reported in human genome. In present study, we conducted evolutionary analysis of AluYRa2-exonized transcript with various primate genomic DNAs and cDNAs from humans, rhesus monkeys, and crab-eating monkeys. Remarkably, our results show that AluYRa2 element has only been integrated into genomes of Macaca species. This Macaca lineage-specific integration of AluYRa2 element led to exonization event in the first intron region of BCS1L gene by producing a conserved 3' splice site. Intriguingly, in rhesus and crab-eating monkeys, more diverse transcript variants by alternative splicing (AS) events, including exon skipping and different 5' splice sites from humans, were identified. Alignment of amino acid sequences revealed that AluYRa2-exonized transcript has short N terminal peptides. Therefore, AS events play a major role in the generation of various transcripts and proteins during primate evolution. In particular, lineage specific integration of Alu elements and species-specific Alu-derived exonization events could be important sources of gene diversification in primates. PMID- 26537196 TI - 'Patients with multiple myeloma have excellent long-term outcomes after recovery from dialysis-dependent acute kidney injury'. PMID- 26537197 TI - Intravenous iron: barriers and facilitators to its use at nine maternity hospitals in New South Wales, Australia. AB - BACKGROUND: Anaemia in pregnancy is mostly due to iron deficiency, and the use of intravenous (IV) iron is gaining acceptance as a treatment option. Recently released obstetric transfusion guidelines recommend IV iron for obstetric patients in certain situations, including when oral formulations are poorly tolerated, unlikely to be well absorbed, or when rapid restoration of iron stores is required. AIMS: To identify barriers and facilitators to the use of IV iron in pregnancy among nine maternity hospitals in New South Wales, Australia. MATERIALS & METHODS: A qualitative research study was undertaken using semi-structured interviews. Nine maternity units were chosen to cover a range of clinical settings and obstetric blood transfusion rates. Interviews were conducted with haematologists, obstetricians and midwives, and included questions about the use of IV iron in each institution. Interviews were transcribed and coded, and NVivo software was used to develop themes. RESULTS: A total of 125 interviews were conducted: 61 with doctors. The use of IV iron differed between hospitals and individual doctors. There were hospital/pharmaceutical, clinician and patient factors which acted as either barriers or facilitators to the use of IV iron. Where perceived barriers outweighed facilitators in a particular hospital, doctors were less likely to use IV iron. DISCUSSION: The use of IV iron, as perceived by doctors, differed across hospitals. There are some potentially modifiable barriers to the use of IV iron that may need to be addressed for IV iron to be available to obstetric patients not tolerating oral formulations or requiring rapid restoration of iron stores. PMID- 26537198 TI - Dose response of exercise training following roux-en-Y gastric bypass surgery: A randomized trial. AB - OBJECTIVE: Roux-en-Y gastric bypass (RYGB) surgery can cause profound weight loss and improve overall cardiometabolic risk factors. Exercise (EX) training following RYGB can provide additional improvements in insulin sensitivity (SI ) and cardiorespiratory fitness. However, it remains unknown whether a specific amount of EX post-RYGB is required to achieve additional benefits. METHODS: We performed a post hoc analysis of participants who were randomized into either a 6 month structured EX program or a health education control (CON). The EX group (n = 56) was divided into tertiles according to the amount of weekly exercise performed, compared with CON (n = 42): low-EX = 54 +/- 8; middle-EX = 129 +/- 4; and high-EX = 286 +/- 40 min per week. RESULTS: The high-EX lost a significantly greater amount of body weight, total fat mass, and abdominal deep subcutaneous abdominal fat compared with CON (P < 0.005). SI improved to a greater extent in both the middle-EX and high-EX compared with CON (P < 0.04). Physical fitness (VO2 max) significantly improved in the high-EX (9.3% +/- 4.2%) compared with CON (-6.0 +/- 2.4%) (P < 0.001). Skeletal muscle mitochondrial State 4 (P < 0.002) and 3 (P < 0.04) respiration was significantly higher in the high-EX compared with CON. CONCLUSIONS: A modest volume of structured exercise provides additional improvements in insulin sensitivity following RYGB, but higher volumes of exercise are required to induce additional weight loss, changes in body composition, and improvements in cardiorespiratory fitness and skeletal muscle mitochondrial capacity. PMID- 26537199 TI - Optimization of a nano-enzymatic reactor for on-line tryptic digestion of polypeptide conjugates by capillary electrophoresis. AB - This work aims at studying the optimization of an on-line capillary electrophoresis (CE)-based tryptic digestion methodology for the analysis of therapeutic polypeptides (PP). With this methodology, a mixture of surrogate peptide fragments and amino acid were produced on-line by trypsin cleavage (enzymatic digestion) and subsequently analyzed using the same capillary. The resulting automation of all steps such as injection, mixing, incubation, separation and detection minimizes the possible errors and saves experimental time. In this paper, we first study the differents parameters influencing PP cleavage inside the capillary (plug length, reactant concentration, incubation time, diffusion and electrophoretic plugs mixing). In a second part, the optimization of the electrophoretic separation conditions of generated hydrolysis products (nature, pH and ionic strength (I) of the background electrolyte (BGE)) is described. Using the optimized conditions, excellent repeatability was obtained in terms of separation (migration times) and proteolysis (number of products from enzymatic hydrolysis and corresponding amounts) demonstrating the robustness of the proposed methodology. PMID- 26537200 TI - Age-dependent changes of stress and strain in the human heart valve and their relation with collagen remodeling. AB - In order to create tissue-engineered heart valves with long-term functionality, it is essential to fully understand collagen remodeling during neo-tissue formation. Collagen remodeling is thought to maintain mechanical tissue homeostasis. Yet, the driving factor of collagen remodeling remains unidentified. In this study, we determined the collagen architecture and the geometric and mechanical properties of human native semilunar heart valves of fetal to adult age using confocal microscopy, micro-indentation and inverse finite element analysis. The outcomes were used to predict age-dependent changes in stress and stretch in the heart valves via finite element modeling. The results indicated that the circumferential stresses are different between the aortic and pulmonary valve, and, moreover, that the stress increases considerably over time in the aortic valve. Strikingly, relatively small differences were found in stretch with time and between the aortic and pulmonary valve, particularly in the circumferential direction, which is the main determinant of the collagen fiber stretch. Therefore, we suggest that collagen remodeling in the human heart valve maintains a stretch-driven homeostasis. Next to these novel insights, the unique human data set created in this study provides valuable input for the development of numerical models of collagen remodeling and optimization of tissue engineering. STATEMENT OF SIGNIFICANCE: Annually, over 280,000 heart valve replacements are performed worldwide. Tissue engineering has the potential to provide valvular disease patients with living valve substitutes that can last a lifetime. Valve functionality is mainly determined by the collagen architecture. Hence, understanding collagen remodeling is crucial for creating tissue engineered valves with long-term functionality. In this study, we determined the structural and material properties of human native heart valves of fetal to adult age to gain insight into the mechanical stimuli responsible for collagen remodeling. The age-dependent evolutionary changes in mechanical state of the native valve suggest that collagen remodeling in heart valves is a stretch-driven process. PMID- 26537201 TI - Cell sheets prepared via gel-sol transition of calcium RGD-alginate. AB - The formation of layered tissues through the use of cell sheet harvesting has recently emerged as a potentially viable approach for clinical tissue engineering applications. Since the demonstration of effective cell sheet formation using temperature responsive substrates, a number of different stimuli have been utilized to facilitate cell sheet detachment. Each approach has differing advantages and disadvantages. Herein we demonstrate the ability of calcium alginate hydrogels to function as an effective substrate for cell sheet formation. By conjugating the integrin binding peptide sequence RGD to the alginate and crosslinking it with calcium ions, the hydrogel formed supported the attachment and growth of both 3T3 fibroblasts and human corneal epithelial cells (HCECs). Once the cells had grown to confluence, exposing the calcium alginate to the chelating agent citrate caused the release of a consolidated cell sheet. When HCEC sheets were stacked, the cell layers adhered to each other and the cells began to integrate. STATEMENT OF SIGNIFICANCE: Herein we describe a simple and inexpensive process for creating cell sheets using the ability of calcium alginate hydrogels to be dissolved under mild conditions. The alginate was first modified to possess cell attachment sites and in this demonstration of feasibility we employed an RGD peptide, but other peptides could be readily attached. The modified alginate was then formed into stable hydrogels through a drying and re-hydration step, and used as a substrate to grow confluent cell sheets of human corneal epithelial cells and 3T3 fibroblasts as examples. The cell sheets were released through chelating the calcium using citrate. The cell cell connections were retained following this release and the cell sheets interconnect and grew following being stacked. PMID- 26537202 TI - Label-free mapping of microstructural organisation in self-aligning cellular collagen hydrogels using image correlation spectroscopy. AB - Hydrogels have emerged as promising biomaterials for regenerative medicine. Despite major advances, tissue engineers have faced challenges in studying the complex dynamics of cell-mediated hydrogel remodelling. Second harmonic generation (SHG) microscopy has been a pivotal tool for non-invasive visualization of collagen type I hydrogels. By taking into account the typical polarization SHG effect, we recently proposed an alternative image correlation spectroscopy (ICS) model to quantify characteristics of randomly oriented collagen fibrils. However, fibril alignment is an important feature in many tissues that needs to be monitored for effective assembly of anisotropic tissue constructs. Here we extended our previous approach to include the orientation distribution of fibrils in cellular hydrogels and show the power of this model in two biologically relevant applications. Using a collagen hydrogel contraction assay, we were able to capture cell-induced hydrogel modifications at the microscopic scale and link these to changes in overall gel dimensions over time. After 24h, the collagen density was about 3 times higher than the initial density, which was of the same order as the decrease in hydrogel area. We also showed that the orientation parameters recovered from our automated ICS model match values obtained from manual measurements. Furthermore, regions axial to cellular processes aligned at least 1.5 times faster compared with adjacent zones. Being able to capture minor temporal and spatial changes in hydrogel density and collagen fibril orientation, we demonstrated the sensitivity of this extended ICS model to deconstruct a complex environment and support its potential for tissue engineering research. STATEMENT OF SIGNIFICANCE: It is generally accepted that looking beyond bulk hydrogel composition is key in understanding the mechanisms that influence the mechanical and biological properties of artificial tissues. In this manuscript, we performed label-free non-invasive imaging and extended a robust automated analysis method to characterize the microstructural organisation of cellular hydrogel systems. We underpin the sensitivity of this technique by capturing minor changes in collagen density and fibril orientation in biologically relevant systems over time. Therefore, we believe that this method is applicable in fundamental cell-matrix research and has high-throughput potential in screening arrays of hydrogel scaffolds, making it an interesting tool for future tissue engineering research. PMID- 26537203 TI - Porous, Dexamethasone-loaded polyurethane coatings extend performance window of implantable glucose sensors in vivo. AB - Continuous glucose sensors offer the promise of tight glycemic control for insulin dependent diabetics; however, utilization of such systems has been hindered by issues of tissue compatibility. Here we report on the in vivo performance of implanted glucose sensors coated with Dexamethasone-loaded (Dex loaded) porous coatings employed to mediate the tissue-sensor interface. Two animal studies were conducted to (1) characterize the tissue modifying effects of the porous Dex-loaded coatings deployed on sensor surrogate implants and (2) investigate the effects of the same coatings on the in vivo performance of Medtronic MiniMed SOF-SENSORTM glucose sensors. The tissue response to implants was evaluated by quantifying macrophage infiltration, blood vessel formation, and collagen density around implants. Sensor function was assessed by measuring changes in sensor sensitivity and time lag, calculating the Mean Absolute Relative Difference (MARD) for each sensor treatment, and performing functional glucose challenge test at relevant time points. Implants treated with porous Dex loaded coatings diminished inflammation and enhanced vascularization of the tissue surrounding the implants. Functional sensors with Dex-loaded porous coatings showed enhanced sensor sensitivity over a 21-day period when compared to controls. Enhanced sensor sensitivity was accompanied with an increase in sensor signal lag and MARD score. These results indicate that Dex-loaded porous coatings were able to elicit an attenuated tissue response, and that such tissue microenvironment could be conducive towards extending the performance window of glucose sensors in vivo. STATEMENT OF SIGNIFICANCE: In the present article, a coating to extend the functionality of implantable glucose sensors in vivo was developed. Our study showed that the delivery of an anti-inflammatory agent with the presentation of micro-sized topographical cues from coatings may lead to improved long-term glucose sensor function in vivo. We believe that improved function of sensors treated with the novel coatings was a result of the observed decreases in inflammatory cell density and increases in vessel density of the tissue adjacent to the devices. Furthermore, extending the in vivo functionality of implantable glucose sensors may lead to greater adoption of these devices by diabetic patients. PMID- 26537204 TI - A transgenic embryonic sexing system for the Australian sheep blow fly Lucilia cuprina. AB - Genetic approaches, including the sterile insect technique (SIT), have previously been considered for control of the Australian sheep blow fly Lucilia cuprina, a major pest of sheep. In an SIT program, females consume 50% of the diet but are ineffective as control agents and compete with females in the field for mating with sterile males, thereby decreasing the efficiency of the program. Consequently, transgenic sexing strains of L. cuprina were developed that produce 100% males when raised on diet that lacks tetracycline. However, as females die mostly at the pupal stage, rearing costs would not be significantly reduced. Here we report the development of transgenic embryonic sexing strains of L. cuprina. In these strains, the Lsbnk cellularization gene promoter drives high levels of expression of the tetracycline transactivator (tTA) in the early embryo. In the absence of tetracycline, tTA activates expression of the Lshid proapoptotic gene, leading to death of the embryo. Sex-specific RNA splicing of Lshid transcripts ensures that only female embryos die. Embryonic sexing strains were also made by combining the Lsbnk-tTA and tetO-Lshid components into a single gene construct, which will facilitate transfer of the technology to other major calliphorid livestock pests. PMID- 26537205 TI - Alteration of the DNA methylation status of donor cells impairs the developmental competence of porcine cloned embryos. AB - Nuclear reprogramming induced by somatic cell nuclear transfer is an inefficient process, and donor cell DNA methylation status is thought to be a major factor affecting cloning efficiency. Here, the role of donor cell DNA methylation status regulated by 5-aza-2'-deoxycytidine (5-aza-dC) or 5-methyl-2'-deoxycytidine-5' triphosphate (5-methyl-dCTP) in the early development of porcine cloned embryos was investigated. Our results showed that 5-aza-dC or 5-methyl-dCTP significantly reduced or increased the global methylation levels and altered the methylation and expression levels of key genes in donor cells. However, the development of cloned embryos derived from these cells was reduced. Furthermore, disrupted pseudo-pronucleus formation and transcripts of early embryo development-related genes were observed in cloned embryos derived from these cells. In conclusion, our results demonstrated that alteration of the DNA methylation status of donor cells by 5-aza-dC or 5-methyl-dCTP disrupted nuclear reprogramming and impaired the developmental competence of porcine cloned embryos. PMID- 26537206 TI - Behaviour change techniques to change the postnatal eating and physical activity behaviours of women who are obese: a qualitative study. AB - OBJECTIVE: To explore the experiences of postnatal women who are obese [body mass index (BMI) >= 30 kg/m(2) ] in relation to making behaviour changes and use of behaviour change techniques (BCTs). DESIGN: Qualitative interview study. SETTING: Greater Manchester, UK. POPULATION OR SAMPLE: Women who were 1 year postnatal aged >=18 years, who had an uncomplicated singleton pregnancy, and an antenatal booking BMI >= 30 kg/m(2) . METHODS: Eighteen semi-structured, audio-recorded interviews were conducted by a research midwife with women who volunteered to be interviewed 1 year after taking part in a pilot randomised controlled trial. The six stages of thematic analysis were followed to understand the qualitative data. The Behavior Change Technique Taxonomy (version 1) was used to label the behaviour change techniques (BCTs) reported by women. MAIN OUTCOME MEASURES: Themes derived from 1-year postnatal interview transcripts. RESULTS: Two themes were evident: 1. A focused approach to postnatal weight management: women reported making specific changes to their eating and physical activity behaviours, and 2. Need for support: six BCTs were reported as helping women make changes to their eating and physical activity behaviours; three were reported more frequently than others: Self-monitoring of behaviour (2.3), Prompts/cues (7.1) and Social support (unspecified; 3.1). All of the BCTs required support from others for their delivery; food diaries were the most popular delivery method. CONCLUSION: Behaviour change techniques are useful to postnatal women who are obese, and have the potential to improve their physical and mental wellbeing. Midwives and obstetricians should be aware of such techniques, to encourage positive changes. PMID- 26537207 TI - Secondary sentinel lymph node tracing technique: a new method for tracing lymph nodes in radical gastrectomy for advanced gastric cancer. AB - OBJECTIVE: To explore the feasibility and clinical value of secondary sentinel lymph node (SSLN) tracing technique in radical gastrectomy for advanced gastric cancer (AGC). METHODS: From January 2009 to June 2011, 247 patients who suffered from gastric angle cancer with metastasis in No. 3 group lymph nodes were divided randomly into groups A and B. Methylthioninium chloride was injected into the peripheral tissue of the metastatic No. 3 group lymph nodes of 138 patients in group A before tumor resections. SSLNs were traced and individual lymphadenectomies were carried out based on the biopsy results of the SSLNs. Standard D2 radical gastrectomies were carried out directly on 109 patients in group B. Postoperative follow-up and survival analysis were carried out for patients in both groups. RESULTS: SSLNs were found in 114 (82.6%) patients in group A. Ninety of those patients (78.9%) demonstrated existing metastasis in SSLNs. According to Kaplan-Meier's method, the postoperative 3-year cumulative survival rates were 63.5% and 47.5%, and the median survival time were 40 and 36 months for the patients of groups A and B, respectively (P<0.05). CONCLUSIONS: The SSLN tracing technique is feasible in radical gastrectomy for AGC. It gives surgeons important information about the terminal status of lymph node metastasis and provides some scientific basis for individual lymphadenectomy. PMID- 26537208 TI - Potential candidate cells for constructing tissue-engineered lacrimal duct epithelium: a histological and cytological study in rabbits. AB - OBJECTIVE: Injury and deficiency of the lacrimal duct epithelium (LDE) can lead to a variety of lacrimal diseases. The purpose of this study was to characterize potential candidate cells for constructing a tissue-engineered LDE. METHODS: Different areas of the conjunctiva and lacrimal duct tissue were removed from male adult New Zealand white rabbits for histological evaluation. Hematoxylin and eosin staining and immunohistochemical staining of cytokeratin AE1+AE3, cytokeratin 4, Ki-67, and MUC5AC were observed by light microscopy. The surface morphologies of different epithelial tissues and cellular structures were examined using field-emission scanning electron microscopy and transmission electron microscopy. Epithelial cells were isolated from tissues and identified by specific markers. In vitro, proliferative ability and Western blot analyses of the proliferating cell nuclear antigen (PCNA) of different epithelial cells cultured in identical environments were investigated and compared. RESULTS: Histologically, the epithelial specific markers, cytokeratin AE1+AE3 and cytokeratin 4, were expressed in the conjunctiva epithelium and the LDE. Notably, highly proliferative cells stained with Ki-67 were concentrated under the epithelium in a dome structure of the posterior palpebral conjunctiva. Differentiated goblet cells were also found to a lesser extent in this region. Primary palpebral and fornical conjunctival epithelial cells (PFCECs), bulbar conjunctival epithelial cells (BCECs), and lacrimal duct epithelial cells (LDECs) were successfully separated from tissues. In vitro, rabbit PFCECs and LDECs grew faster and expressed more PCNA than BCECs. CONCLUSIONS: PFCECs are anatomically similar to LDECs. They also have similar morphological characteristics, immune phenotypes, and proliferation features. PFCECs are therefore potential candidate cells to replace LDECs in tissue engineering to treat lacrimal duct diseases. PMID- 26537209 TI - Repair of articular cartilage defects in rabbits through tissue-engineered cartilage constructed with chitosan hydrogel and chondrocytes. AB - OBJECTIVE: In our previous work, we prepared a type of chitosan hydrogel with excellent biocompatibility. In this study, tissue-engineered cartilage constructed with this chitosan hydrogel and costal chondrocytes was used to repair the articular cartilage defects. METHODS: Chitosan hydrogels were prepared with a crosslinker formed by combining 1,6-diisocyanatohexane and polyethylene glycol. Chitosan hydrogel scaffold was seeded with rabbit chondrocytes that had been cultured for one week in vitro to form the preliminary tissue-engineered cartilage. This preliminary tissue-engineered cartilage was then transplanted into the defective rabbit articular cartilage. There were three treatment groups: the experimental group received preliminary tissue-engineered cartilage; the blank group received pure chitosan hydrogels; and, the control group had received no implantation. The knee joints were harvested at predetermined time. The repaired cartilage was analyzed through gross morphology, histologically and immunohistochemically. The repairs were scored according to the international cartilage repair society (ICRS) standard. RESULTS: The gross morphology results suggested that the defects were repaired completely in the experimental group after twelve weeks. The regenerated tissue connected closely with subchondral bone and the boundary with normal tissue was fuzzy. The cartilage lacuna in the regenerated tissue was similar to normal cartilage lacuna. The results of ICRS gross and histological grading showed that there were significant differences among the three groups (P<0.05). CONCLUSIONS: Chondrocytes implanted in the scaffold can adhere, proliferate, and secrete extracellular matrix. The novel tissue-engineered cartilage constructed in our research can completely repair the structure of damaged articular cartilage. PMID- 26537210 TI - Feasibility of diagnosing unstable plaque in patients with acute coronary syndrome using iMap-IVUS. AB - OBJECTIVE: To compare the plaque composition between stable and unstable plaques, characterize unstable plaque by using iMap-intravascular ultrasound (IVUS), and quantify the diagnostic criteria for unstable plaque. METHODS: Thirty-three acute coronary syndrome (ACS) patients who had undergone coronary angiography and IVUS from February 19, 2014 to December 19, 2014 at Peking University People's Hospital were enrolled in the study. Baseline data were collected. The patients were divided into two groups according to their gray-scale IVUS imaging, stable plaque and unstable plaque. A difference-in-difference evaluation was performed using the baseline data and off-line iMap imaging results between the two groups. A receiver operating characteristic (ROC) curve was constructed to obtain the optimal cut-off value to diagnose unstable plaque. RESULTS: Percentages of fibrotic and necrotic tissues, absolute values of lipidic, necrotic, and calcified tissues, and plaque burden were independent predictors for unstable plaque. Absolute necrotic area was the best predictor and exhibited the highest diagnostic value for plaque vulnerability (area under the curve (AUC)=0.806, P=0.000, 95% CI (0.718, 0.894)). The cut-off score for predicting unstable plaque was 4.0 mm(2). CONCLUSIONS: This study attempted to propose a cut-off value based on absolute necrotic area using iMap-IVUS to predict plaque vulnerability in patients with ACS. This score might provide a valuable reference for diagnosing unstable plaque. PMID- 26537211 TI - Clinical analysis of pharyngeal musculature and genioglossus exercising to treat obstructive sleep apnea and hypopnea syndrome. AB - OBJECTIVE: To evaluate the effect of pharyngeal musculature and genioglossus exercising on obstructive sleep apnea and hypopnea syndrome (OSAHS). METHODS: We conducted a non-randomized retrospective clinical trial of 75 patients with OSAHS. Fifty-four patients were managed by exercising of the pharyngeal musculature and genioglossus (exercising group). Twenty-one patients, who refused to undertake any treatment, were defined as the control group. We took the Epworth Sleepiness Scale (ESS), checked patients' polysomnography, and took 320 detector computed tomography (CT) before treatment. Six and twelve months later, we made records of apnea hypopnea index (AHI), lowest arterial oxygen saturation (LSaO2), body mass index (BMI), the shortest sagittal diameter, and transverse diameter, and the effective rates of exercising were calculated and compared with the 21 patients without any treatment (control group) at the same time. SPSS 10.0 was used to analyze the data. RESULTS: Before treatment, the ESS value was 7.67; 6 and 12 months later, the values were 3.54 and 3.25, respectively in the exercising group. AHI was decreased to 15.36 after 6 months and 13.79 after 12 months from 22.84 at the beginning. LSaO2 values were up to 81.18% after 6 months and 81.93% after 12 months from 74.05% at the beginning. There were significant differences in ESS scores, AHI, and LSaO2 between pre-treatment and post treatment in the exercising group (P<0.05). However, there was no statistical difference in all the parameters between 6 and 12 months of exercising. The effective rates were 70.37% and 74.07% after 6- and 12-month exercising, respectively. There were significant differences between the exercising and control groups (P<0.0001). There was no statistical difference in the effective rate of the exercising group between 6 and 12 months of exercising (P>0.05). At 12 months of exercising, the compliance of the anteroposterior pharyngeal wall of the retropalatal area was lower (P<0.01) than that before treatment. There was no significant change of BMI in either group. CONCLUSIONS: Exercising pharyngeal musculature and genioglossus is a kind of non-invasive and cost-effective method to treat some OSAHS patients, especially those who are old, without surgical complications, and especially mild and moderate OSAHS patients who do not want to take surgery and continuous positive airway pressure (CPAP) treatment. In addition, exercising pharyngeal musculature and genioglossus can be considered as remedial treatment of OSAHS to surgery and other therapies. PMID- 26537212 TI - Morphological and physiological comparison of taxa comprising the Sporothrix schenckii complex. AB - Based on recent molecular data, it has been suggested that Sporothrix globosa is the main causal agent of sporotrichosis in China. The objective of this study was to compare the morphology, growth characteristics, patterns of carbon source usage, and susceptibility to antifungal agents among Sporothrix strains. A total of 15 clinical strains confirmed to be S. globosa, from three different regions of China, and 11 ex-type strains from the CBS-KNAW biodiversity center were obtained. The elongated conidia of S. pallida, S. variecibatus, S. schenckii, and S. schenckii luriei were clearly different from the subglobose and globose conidia of S. globosa strains. S. schenckii is able to assimilate sucrose, raffinose, and ribitol. Susceptibility profiles of these Sporothrix species were evaluated by measuring minimum inhibitory concentrations (MICs). Fluconazole, itraconazole, terbinafine, and amphotericin B showed good activity against most S. globosa clinical isolates from China. Potassium iodide also showed a low MIC against S. pallida, while fluconazole showed a high MIC for S. mexicana, S. humicola, S. globosa, S. schenckii, and S. inflata; these strains might be considered tolerant. The species showed differences in susceptibility to antifungal drugs and should therefore be properly identified during diagnosis prior to designing therapeutic strategies. PMID- 26537213 TI - Impact of type 2 diabetes on the plasma levels of vascular endothelial growth factor and its soluble receptors type 1 and type 2 in patients with peripheral arterial disease. AB - OBJECTIVE: Type 2 diabetes coexistent with lower extremity artery disease (peripheral arterial disease (PAD)) can be observed in numerous patients. The mechanism compensating for ischemia and contributing to healing is angiogenesis the process of forming new blood vessels. The purpose of this study was to assess the likely impact of type 2 diabetes on the plasma levels of proangiogenic factor (vascular endothelial growth factor A (VEGF-A)) and angiogenesis inhibitors (soluble VEGF receptors type 1 and type 2 (sVEGFR-1 and sVEGFR-2)) in patients with PAD. METHODS: Among 46 patients with PAD under pharmacological therapy (non invasive), we identified, based on medical history, a subgroup with coexistent type 2 diabetes (PAD-DM2+, n=15) and without diabetes (PAD-DM2-, n=31). The control group consisted of 30 healthy subjects. Plasma levels of VEGF-A, sVEGFR 1, and sVEGFR-2 were measured using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: The subgroups of PAD-DM2+ and PAD-DM2- revealed significantly higher concentrations of VEGF-A (P=0.000 007 and P=0.000 000 1, respectively) and significantly lower sVEGFR-2 levels (P=0.02 and P=0.000 01, respectively), when compared with the control group. Patients with PAD and coexistent diabetes tended to have a lower level of VEGF-A and higher levels of sVEGFR-1 and sVEGFR-2 comparable with non-diabetic patients. CONCLUSIONS: The coexistence of type 2 diabetes and PAD is demonstrated by a tendency to a lower plasma level of proangiogenic factor (VEGF-A) and higher levels of angiogenesis inhibitors (sVEGFR-1 and sVEGFR-2) at the same time. Regardless of the coexistence of type 2 diabetes, hypoxia appears to be a crucial factor stimulating the processes of angiogenesis in PAD patients comparable with healthy individuals, whereas hyperglycemia may have a negative impact on angiogenesis in lower limbs. PMID- 26537214 TI - A novel large deletion mutation of FERMT1 gene in a Chinese patient with Kindler syndrome. AB - Kindler syndrome (KS; OMIM 173650) is a rare autosomal recessive skin disorder, which results in symptoms including blistering, epidermal atrophy, increased risk of cancer, and poor wound healing. The majority of mutations of the disease determining gene (FERMT1 gene) are single nucleotide substitutions, including missense mutations, nonsense mutations, etc. Large deletion mutations are seldom reported. To determine the mutation in the FERMT1 gene associated with a 7-year old Chinese patient who presented clinical manifestation of KS, we performed direct sequencing of all the exons of FERMT1 gene. For the exons 2-6 without amplicons, we analyzed the copy numbers using quantitative real-time polymerase chain reaction (qRT-PCR) with specific primers. The deletion breakpoints were sublocalized and the range of deletion was confirmed by PCR and direct sequencing. In this study, we identified a new 17-kb deletion mutation spanning the introns 1-6 of FERMT1 gene in a Chinese patient with severe KS phenotypes. Her parents were carriers of the same mutation. Our study reported a newly identified large deletion mutation of FERMT1 gene involved in KS, which further enriched the mutation spectrum of the FERMT1 gene. PMID- 26537215 TI - Clinical and molecular genetic analysis of a Chinese family with congenital X linked adrenal hypoplasia caused by novel mutation 1268delA in the DAX-1 gene. AB - Congenital X-linked adrenal hypoplasia (AHC) is a rare disease characterized by primary adrenal insufficiency before adolescence and by hypogonadotropic hypogonadism (HHG) during adolescence. In this paper, we present a Chinese family with AHC. Two brothers, misdiagnosed with adrenal insufficiency of unknown etiology at the age of 9, were correctly diagnosed with AHC when delayed puberty, HHG, and testicular defects were observed. We investigated the clinical features and identified the dosage-sensitive sex reversal AHC critical region of the X chromosome gene 1 (DAX-1) mutation in this kindred. Direct sequencing of the DAX 1 gene revealed that the two siblings have a novel mutation (1268delA) of which their mother is a heterozygous carrier. This mutation causes a frameshift and a premature stop codon at position 436, encoding a truncated protein. It is important to increase knowledge of the mutational spectrum in genes related to this disease, linking phenotype to genotype. PMID- 26537216 TI - A case report on indirect transmission of human rabies. AB - At present, virus infection is still a common threat to public health in developing countries. Human rabies remains a matter of great global concern with a case-fatality of almost 100%. The rabies virus belongs to the neurotropic type of virus of the Lyssavirus genus, and the disease presents as a deteriorating encephalomyelitis and is endemic throughout much of the world, particularly in Africa and Asia. Previous data have shown that, globally, approximately 59 000 human deaths are caused by rabies per year. Fortunately, human rabies can be treated through the timely administration of post-exposure prophylaxis (PEP). These days immunization using the rabies vaccine has become standard practice for individuals who have suffered bites or scratches from an animal, or who have been exposed to the body fluids of an infected animal. However, we have recently encountered a case of human rabies which arose through a rare transmission method, and we believe that lessons can and should be learnt from this incident. PMID- 26537217 TI - Peripheral and prefrontal stress system markers and risk of relapse in alcoholism. AB - Previous research has shown that hyperactivation in ventral medial prefrontal cortex (VmPFC) and rostral anterior cingulate cortex (rACC) and high cortisol to corticotrophin ratio (cort:ACTH ratio) during neutral-relaxed states predict relapse in alcohol-dependent (AD) patients. Other studies have shown that VmPFC/rACC deactivation and blunted cortisol release to stress and alcohol cues are predictive of time to relapse and relapse severity. However, no previous study has assessed the relationship between these markers of central and peripheral nervous system dysfunction in AD participants and their potential joint effects on relapse risk. Forty early abstinent, treatment engaged AD patients underwent a laboratory experiment with exposure to neutral, alcohol and stress cues and a separate functional magnetic resonance imaging scan with similar cue exposure. Neutral-relaxed state cort:ACTH ratio was significantly associated with VmPFC hyperreactivity to neutral-relaxing cues, and also with hypoactivation in response to alcohol and stress cues in AD patients. Basal heart rate, neutral cort:ACTH ratio and neutral VmPFC hyperreactivty were each associated with risk of relapse. However, abnormal VmPFC activation and elevated cort:ACTH ratio overlap in predicting risk for relapse, and dysfunctional VmPFC response was the sole significant predictor of odds of relapse in a joint model of relapse risk. These findings suggest that the cort:ACTH ratio may serve as a peripheral marker of VmPFC brain dysfunction, while aberrant VmPFC responses need further evaluation as a potential biomarker of alcohol relapse risk in clinical outcome studies. PMID- 26537218 TI - Supplementation of krill oil with high phospholipid content increases sum of EPA and DHA in erythrocytes compared with low phospholipid krill oil. AB - BACKGROUND: Bioavailability of krill oil has been suggested to be higher than fish oil as much of the EPA and DHA in krill oil are bound to phospholipids (PL). Hence, PL content in krill oil might play an important role in incorporation of n 3 PUFA into the RBC, conferring properties that render it effective in reducing cardiovascular disease (CVD) risk. The objective of the present trial was to test the effect of different amounts of PL in krill oil on the bioavailability of EPA and DHA, assessed as the rate of increase of n-3 PUFA in plasma and RBC, in healthy volunteers. METHODS AND DESIGN: In a semi randomized crossover single blind design study, 20 healthy participants consumed various oils consisting of 1.5 g/day of low PL krill oil (LPL), 3 g/day of high PL krill oil (HPL) or 3 g/day of a placebo, corn oil, for 4 weeks each separated by 8 week washout periods. Both LPL and HPL delivered 600 mg of total n-3 PUFA/day along with 600 and 1200 mg/day of PL, respectively. RESULTS: Changes in plasma EPA, DPA, DHA, total n-3 PUFA, n-6:n-3 ratio and EPA + DHA concentrations between LPL and HPL krill oil supplementations were observed to be similar. Intake of both forms of krill oils increased the RBC level of EPA (p < 0.001) along with reduced n-6 PUFA (LPL: p < 0.001: HPL: p = 0.007) compared to control. HPL consumption increased (p < 0.001) RBC concentrations of EPA, DPA, total and n-3 PUFA compared with LPL. Furthermore, although LPL did not alter RBC n-6:n-3 ratio or the sum of EPA and DHA compared to control, HPL intake decreased (p < 0.001) n-6:n-3 ratio relative to control with elevated (p < 0.001) sum of EPA and DHA compared to control as well as to LPL krill oil consumption. HPL krill oil intake elevated (p < 0.005) plasma total and LDL cholesterol concentrations compared to control, while LPL krill oil did not alter total and LDL cholesterol, relative to control. CONCLUSIONS: The results indicate that krill oil with higher PL levels could lead to enhanced bioavailability of n-3 PUFA compared to krill oil with lower PL levels. TRIAL REGISTRATION: Clinicaltrials.gov# NCT01323036. PMID- 26537220 TI - Purinergic signalling mediates bidirectional crosstalk between chemoreceptor type I and glial-like type II cells of the rat carotid body. AB - KEY POINTS: Carotid body chemoreceptors are organized in clusters containing receptor type I and contiguous glial-like type II cells. While type I cells depolarize and release ATP during chemostimulation, the role of type II cells which express purinergic P2Y2 receptors (P2Y2Rs) and ATP-permeable pannexin-1 (Panx-1) channels, is unclear. Here, we show that in isolated rat chemoreceptor clusters, type I cell depolarization induced by hypoxia, hypercapnia, or high K(+) caused delayed intracellular Ca(2+) elevations (Delta[Ca(2+)]i) in nearby type II cells that were inhibited by the P2Y2R blocker suramin, or by the nucleoside hydrolase apyrase. Likewise, stimulation of P2Y2Rs on type II cells caused a delayed, secondary Delta[Ca(2+)]i in nearby type I cells that was inhibited by blockers of Panx-1 channels, adenosine A2A receptors and 5' ectonucleotidase. We propose that reciprocal crosstalk between type I and type II cells contributes to sensory processing in the carotid body via purinergic signalling pathways. ABSTRACT: The mammalian carotid body (CB) is excited by blood-borne stimuli including hypoxia and acid hypercapnia, leading to respiratory and cardiovascular reflex responses. This chemosensory organ consists of innervated clusters of receptor type I cells, ensheathed by processes of adjacent glial-like type II cells. ATP is a major excitatory neurotransmitter released from type I cells and type II cells express purinergic P2Y2 receptors (P2Y2Rs), the activation of which leads to the opening of ATP-permeable, pannexin 1 (Panx-1) channels. While these properties support crosstalk between type I and type II cells during chemotransduction, direct evidence is lacking. To address this, we first exposed isolated rat chemoreceptor clusters to acute hypoxia, isohydric hypercapnia, or the depolarizing stimulus high K(+), and monitored intracellular [Ca(2+)] using Fura-2. As expected, these stimuli induced intracellular [Ca(2+)] elevations (Delta[Ca(2+)]i) in type I cells. Interestingly, however, there was often a delayed, secondary Delta[Ca(2+)]i in nearby type II cells that was reversibly inhibited by the P2Y2R antagonist suramin, or by the nucleoside hydrolase apyrase. By contrast, type II cell stimulation with the P2Y2R agonist uridine-5'-triphosphate (100 MUm) often led to a delayed, secondary Delta[Ca(2+)]i response in nearby type I cells that was reversibly inhibited by the Panx-1 blocker carbenoxolone (5 MUm). This Delta[Ca(2+)]i response was also strongly inhibited by blockers of either the adenosine A2A receptor (SCH 58261) or of the 5'-ectonucleotidase (AOPCP), suggesting it was due to adenosine arising from breakdown of ATP released through Panx-1 channels. Collectively, these data strongly suggest that purinergic signalling mechanisms mediate crosstalk between CB chemoreceptor and glial cells during chemotransduction. PMID- 26537221 TI - Giant Ulcer on Abdominal Wall: A Quiz. PMID- 26537222 TI - Uptake and impact of vaccinating school age children against influenza during a season with circulation of drifted influenza A and B strains, England, 2014/15. AB - The 2014/15 influenza season was the second season of roll-out of a live attenuated influenza vaccine (LAIV) programme for healthy children in England. During this season, besides offering LAIV to all two to four year olds, several areas piloted vaccination of primary (4-11 years) and secondary (11-13 years) age children. Influenza A(H3N2) circulated, with strains genetically and antigenically distinct from the 2014/15 A(H3N2) vaccine strain, followed by a drifted B strain. We assessed the overall and indirect impact of vaccinating school age children, comparing cumulative disease incidence in targeted and non targeted age groups in vaccine pilot to non-pilot areas. Uptake levels were 56.8% and 49.8% in primary and secondary school pilot areas respectively. In primary school age pilot areas, cumulative primary care influenza-like consultation, emergency department respiratory attendance, respiratory swab positivity, hospitalisation and excess respiratory mortality were consistently lower in targeted and non-targeted age groups, though less for adults and more severe end points, compared with non-pilot areas. There was no significant reduction for excess all-cause mortality. Little impact was seen in secondary school age pilot only areas compared with non-pilot areas. Vaccination of healthy primary school age children resulted in population-level impact despite circulation of drifted A and B influenza strains. PMID- 26537223 TI - The Distant Siblings-A Phylogenomic Roadmap Illuminates the Origins of Extant Diversity in Fungal Aromatic Polyketide Biosynthesis. AB - In recent years, the influx of newly sequenced fungal genomes has enabled sampling of secondary metabolite biosynthesis on an unprecedented scale. However, explanations of extant diversity which take into account both large-scale phylogeny reconstructions and knowledge gained from multiple genome projects are still lacking. We analyzed the evolutionary sources of genetic diversity in aromatic polyketide biosynthesis in over 100 model fungal genomes. By reconciling the history of over 400 nonreducing polyketide synthases (NR-PKSs) with corresponding species history, we demonstrate that extant fungal NR-PKSs are clades of distant siblings, originating from a burst of duplications in early Pezizomycotina and thinned by extensive losses. The capability of higher fungi to biosynthesize the simplest precursor molecule (orsellinic acid) is highlighted as an ancestral trait underlying biosynthesis of aromatic compounds. This base activity was modified during early evolution of filamentous fungi, toward divergent reaction schemes associated with biosynthesis of, for example, aflatoxins and fusarubins (C4-C9 cyclization) or various anthraquinone derivatives (C6-C11 cyclization). The functional plasticity is further shown to have been supplemented by modularization of domain architecture into discrete pieces (conserved splice junctions within product template domain), as well as tight linkage of key accessory enzyme families and divergence in employed transcriptional factors. Although the majority of discord between species and gene history is explained by ancient duplications, this landscape has been altered by more recent duplications, as well as multiple horizontal gene transfers. The 25 detected transfers include previously undescribed events leading to emergence of, for example, fusarubin biosynthesis in Fusarium genus. Both the underlying data and the results of present analysis (including alternative scenarios revealed by sampling multiple reconciliation optima) are maintained as a freely available web-based resource: http://cropnet.pl/metasites/sekmet/nrpks_2014. PMID- 26537224 TI - Defining the Genome Features of Escherichia albertii, an Emerging Enteropathogen Closely Related to Escherichia coli. AB - Escherichia albertii is a recently recognized close relative of Escherichia coli. This emerging enteropathogen possesses a type III secretion system (T3SS) encoded by the locus of enterocyte effacement, similar to enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC). Shiga toxin-producing strains have also been identified. The genomic features of E. albertii, particularly differences from other Escherichia species, have not yet been well clarified. Here, we sequenced the genome of 29 E. albertii strains (3 complete and 26 draft sequences) isolated from multiple sources and performed intraspecies and intragenus genomic comparisons. The sizes of the E. albertii genomes range from 4.5 to 5.1 Mb, smaller than those of E. coli strains. Intraspecies genomic comparisons identified five phylogroups of E. albertii. Intragenus genomic comparison revealed that the possible core genome of E. albertii comprises 3,250 genes, whereas that of the genus Escherichia comprises 1,345 genes. Our analysis further revealed several unique or notable genetic features of E. albertii, including those responsible for known biochemical features and virulence factors and a possibly active second T3SS known as ETT2 (E. coli T3SS 2) that is inactivated in E. coli. Although this organism has been observed to be nonmotile in vitro, genes for flagellar biosynthesis are fully conserved; chemotaxis related genes have been selectively deleted. Based on these results, we have developed a nested polymerase chain reaction system to directly detect E. albertii. Our data define the genomic features of E. albertii and provide a valuable basis for future studies of this important emerging enteropathogen. PMID- 26537225 TI - Predicting RAD-seq Marker Numbers across the Eukaryotic Tree of Life. AB - High-throughput sequencing of reduced representation libraries obtained through digestion with restriction enzymes--generically known as restriction site associated DNA sequencing (RAD-seq)--is a common strategy to generate genome-wide genotypic and sequence data from eukaryotes. A critical design element of any RAD seq study is knowledge of the approximate number of genetic markers that can be obtained for a taxon using different restriction enzymes, as this number determines the scope of a project, and ultimately defines its success. This number can only be directly determined if a reference genome sequence is available, or it can be estimated if the genome size and restriction recognition sequence probabilities are known. However, both scenarios are uncommon for nonmodel species. Here, we performed systematic in silico surveys of recognition sequences, for diverse and commonly used type II restriction enzymes across the eukaryotic tree of life. Our observations reveal that recognition sequence frequencies for a given restriction enzyme are strikingly variable among broad eukaryotic taxonomic groups, being largely determined by phylogenetic relatedness. We demonstrate that genome sizes can be predicted from cleavage frequency data obtained with restriction enzymes targeting "neutral" elements. Models based on genomic compositions are also effective tools to accurately calculate probabilities of recognition sequences across taxa, and can be applied to species for which reduced representation data are available (including transcriptomes and neutral RAD-seq data sets). The analytical pipeline developed in this study, PredRAD (https://github.com/phrh/PredRAD), and the resulting databases constitute valuable resources that will help guide the design of any study using RAD-seq or related methods. PMID- 26537227 TI - Predicted Growth of Two-Dimensional Topological Insulator Thin Films of III-V Compounds on Si(111) Substrate. AB - We have carried out systematic first-principles electronic structure computations of growth of ultrathin films of compounds of group III (B, Al, In, Ga, and Tl) with group V (N, P, As, Sb, and Bi) elements on Si(111) substrate, including effects of hydrogenation. Two bilayers (BLs) of AlBi, InBi, GaBi, TlAs, and TlSb are found to support a topological phase over a wide range of strains, in addition to BBi, TlN, and TlBi which can be driven into the nontrivial phase via strain. A large band gap of 134 meV is identified in hydrogenated 2 BL film of InBi. One and two BL films of GaBi and 2 BL films of InBi and TlAs on Si(111) surface possess nontrivial phases with a band gap as large as 121 meV in the case of 2 BL film of GaBi. Persistence of the nontrivial phase upon hydrogenations in the III-V thin films suggests that these films are suitable for growing on various substrates. PMID- 26537226 TI - Inferring Indel Parameters using a Simulation-based Approach. AB - In this study, we present a novel methodology to infer indel parameters from multiple sequence alignments (MSAs) based on simulations. Our algorithm searches for the set of evolutionary parameters describing indel dynamics which best fits a given input MSA. In each step of the search, we use parametric bootstraps and the Mahalanobis distance to estimate how well a proposed set of parameters fits input data. Using simulations, we demonstrate that our methodology can accurately infer the indel parameters for a large variety of plausible settings. Moreover, using our methodology, we show that indel parameters substantially vary between three genomic data sets: Mammals, bacteria, and retroviruses. Finally, we demonstrate how our methodology can be used to simulate MSAs based on indel parameters inferred from real data sets. PMID- 26537228 TI - Context-dependent associations between heterozygosity and immune variation in a wild carnivore. AB - BACKGROUND: A multitude of correlations between heterozygosity and fitness proxies associated with disease have been reported from wild populations, but the genetic basis of these associations is unresolved. We used a longitudinal dataset on wild Galapagos sea lions (Zalophus wollebaeki) to develop a relatively new perspective on this problem, by testing for associations between heterozygosity and immune variation across age classes and between ecological contexts. RESULTS: Homozygosity by locus was negatively correlated with serum immunoglobulin G production in pups (0-3 months of age), suggesting that reduced genetic diversity has a detrimental influence on the early development of immune defence in the Galapagos sea lion. In addition, homozygosity by locus was positively correlated with total circulating leukocyte concentration in juveniles (6-24 months of age), but only in a colony subject to the anthropogenic environmental impacts of development, pollution and introduced species, which suggests that reduced genetic diversity influences mature immune system activity in circumstances of high antigen exposure. CONCLUSIONS: These findings demonstrate the environmental context-dependency of the phenotypic expression of immune variation, which is implicit in the theory of ecoimmunology, but which has been rarely demonstrated in the wild. They also indicate that heterozygosity may be linked to the maintenance of heterogeneity in mammalian immune system development and response to infection, adding to the body of evidence on the nature of the mechanistic link between heterozygosity and fitness. PMID- 26537229 TI - Syntheses, structures, and magnetic properties of homodinuclear lanthanide complexes based on dinucleating Schiff base ligands. AB - The first two families of homodinuclear lanthanide(III) complexes, formulated as [(L(OEt))2Ln2(L1)] and [(LOEt)2Ln2(L2)] (Ln(3+) = Dy(3+), Tb(3+), Ho(3+), Gd(3+), and Y(3+); L1(4-) = 2,2',2'',2'''-[1,2,4,5 benzenetetrayltetrakis(nitrilomethylidyne)]tetrakisphenolate; L2(4-) = 2,2',2'',2'''-[[1,1'-biphenyl]-3,3',4,4' tetrayltetrakis(nitrilomethylidyne)]tetrakis(4-chlorophenolate); L(OEt)(-) = (eta(5)-cyclopentadienyl)tris(diethylphosphito-p)cobaltate(III)), were successfully synthesized based on Klaui's tripodal building block NaL(OEt) and two dinucleating Schiff base ligands, H(4)L1 and H(4)L2, respectively. Single crystal X-ray analyses show that these lanthanide complexes have two seven coordinated metal binding sites, linked to each other with a phenyl or biphenyl bridge. Variable temperature dc magnetic measurements reveal the weakly antiferromagnetic coupling between paramagnetic lanthanide ions, while ac magnetic data exhibit the field-induced relaxation of magnetization for the corresponding Dy2 complexes 1 and 6. A further magnetic dilution study for 1 suggests that the slow magnetic relaxation originates from the single-ion magnetic behaviour of Dy(3+) ions. PMID- 26537230 TI - Artepillin C and Other Herbal PAK1-blockers: Effects on Hair Cell Proliferation and Related PAK1-dependent Biological Function in Cell Culture. AB - PAK1 (RAC/CDC42-activated kinase 1) is the major oncogenic kinase, and a number of herbal PAK1-blockers such as propolis and curcumin have been shown to be anti oncogenic and anti-melanogenic as well as anti-alopecia (promoting hair growth). Previously, we found several distinct PAK1-inhibitors in Okinawa plants including Alpinia zerumbet (alpinia). Thus, here, we tested the effects of these herbal compounds and their derivatives on the growth of cancer or normal hair cells, and melanogenesis in cell culture of A549 lung cancer, hair follicle dermal papilla cell, and B16F10 melanoma. Among these herbal PAK1-inhibitors, cucurbitacin I from bitter melon (Goya) turned out to be the most potent to inhibit the growth of human lung cancer cells with the IC50 around 140 nM and to promote the growth of hair cells with the effective dose around 10 nM. Hispidin, a metabolite of 5,6 dehydrokawain from alpinia, inhibited the growth of cancer cells with the IC50 of 25 MUM as does artepillin C, the major anti-cancer ingredient in Brazilian green propolis. Mimosine tetrapeptides (MFWY, MFYY, and MFFY) and hispidin derivatives (H1-3) also exhibited a strong anti-cancer activity with the IC50 ranging from 16 to 30 MUM. Mimosine tetrapeptides and hispidin derivatives strongly suppressed the melanogenesis in melanoma cells. PMID- 26537231 TI - Genetic interactions contribute less than additive effects to quantitative trait variation in yeast. AB - Genetic mapping studies of quantitative traits typically focus on detecting loci that contribute additively to trait variation. Genetic interactions are often proposed as a contributing factor to trait variation, but the relative contribution of interactions to trait variation is a subject of debate. Here we use a very large cross between two yeast strains to accurately estimate the fraction of phenotypic variance due to pairwise QTL-QTL interactions for 20 quantitative traits. We find that this fraction is 9% on average, substantially less than the contribution of additive QTL (43%). Statistically significant QTL QTL pairs typically have small individual effect sizes, but collectively explain 40% of the pairwise interaction variance. We show that pairwise interaction variance is largely explained by pairs of loci at least one of which has a significant additive effect. These results refine our understanding of the genetic architecture of quantitative traits and help guide future mapping studies. PMID- 26537232 TI - Prediction of Long-term Post-operative Testosterone Replacement Requirement Based on the Pre-operative Tumor Volume and Testosterone Level in Pituitary Macroadenoma. AB - Non-functioning pituitary macroadenomas (NFPAs) are the most prevalent pituitary macroadenomas. One common symptom of NFPA is hypogonadism, which may require long term hormone replacement. This study was designed to clarify the association between the pre-operative tumor volume, pre-operative testosterone level, intraoperative resection status and the need of long-term post-operative testosterone replacement. Between 2004 and 2012, 45 male patients with NFPAs were enrolled in this prospective study. All patients underwent transsphenoidal surgery. Hypogonadism was defined as total serum testosterone levels of <2.4 ng/mL. The tumor volume was calculated based on the pre- and post-operative magnetic resonance images. We prescribed testosterone to patients with defined hypogonadism or clinical symptoms of hypogonadism. Hormone replacement for longer than 1 year was considered as long-term therapy. The need for long-term post operative testosterone replacement was significantly associated with larger pre operative tumor volume (p = 0.0067), and lower pre-operative testosterone level (p = 0.0101). There was no significant difference between the gross total tumor resection and subtotal resection groups (p = 0.1059). The pre-operative tumor volume and testosterone level impact post-operative hypogonadism. By measuring the tumor volume and the testosterone level and by performing adequate tumor resection, surgeons will be able to predict post-operative hypogonadism and the need for long-term hormone replacement. PMID- 26537233 TI - The use of extracorporeal carbon dioxide removal to avoid intubation in patients failing non-invasive ventilation--a cost analysis. AB - BACKGROUND: To evaluate the economic implications of the pre-emptive use of extracorporeal carbon dioxide removal (ECCO2R) to avoid invasive mechanical ventilation (IMV) in patients with hypercapnic ventilatory insufficiency failing non-invasive ventilation (NIV). METHODS: Retrospective ancillary cost analysis of data extracted from a recently published multicentre case-control-study (n = 42) on the use of arterio-venous ECCO2R to avoid IMV in patients with acute on chronic ventilatory failure. Cost calculations were based on average daily treatment costs for intensive care unit (ICU) and normal medical wards as well as on the specific costs of the ECCO2R system. RESULTS: In the group treated with ECCO2R IMV was avoided in 90 % of cases and mean hospital length of stay (LOS) was shorter than in the matched control group treated with IMV (23.0 vs. 42.0 days). The overall average hospital treatment costs did not differ between the two groups (41.134 vs. 39.366 ?, p = 0.8). A subgroup analysis of patients with chronic obstructive pulmonary disease (COPD) revealed significantly lower median ICU length of stay (11.0 vs. 35.0 days), hospital length of stay (17.5 vs. 51.5 days) and treatment costs for the ECCO2R group (19.610 vs. 46.552 ?, p = 0.01). CONCLUSIONS: Additional costs for the use of arterio-venous ECCO2R to avoid IMV in patients with acute-on-chronic ventilatory insufficiency failing NIV may be offset by a cost reducing effect of a shorter length of ICU and hospital stay. PMID- 26537234 TI - Prolonged use of human insulin increases breast cancer risk in Taiwanese women with type 2 diabetes. AB - BACKGROUND: Human insulin is commonly used to treat hyperglycemia in patients with diabetes, but its potential link with female breast cancer is under debate. This study investigated whether human insulin use might be associated with breast cancer risk in Taiwanese women with type 2 diabetes. METHODS: The reimbursement databases of all Taiwanese diabetic patients from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2004 and a total of 482,033 women with type 2 diabetes were followed up for breast cancer incidence until the end of 2009. Incidences for ever-users, never-users and subgroups of human insulin exposure (using tertile cutoffs of time since starting insulin, cumulative dose and cumulative duration of insulin) were calculated and the adjusted hazard ratios were estimated by Cox regression. The potential risk modification by concomitant treatment with metformin, statin and angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) was also evaluated. RESULTS: There were 59,798 ever-users and 422,235 never-users of human insulin, with respective numbers of incident breast cancer of 559 (0.93 %) and 4,711 (1.12 %), and respective incidence of 207.9 and 215.1 per 100,000 person years. The overall adjusted hazard ratio (95 % confidence interval) did not show a significant association with insulin [1.033 (0.936-1.139)]. However, patients in the third tertiles of dose-response parameters might show a significantly higher risk of breast cancer while compared to never-users: 1.185 (1.026-1.368), 1.260 (1.096-1.450) and 1.257 (1.094-1.446) for >=67 months for time since starting insulin, >=39,000 units for cumulative dose of insulin, and >=21.8 months for cumulative duration of insulin, respectively. Additional analyses suggested that the breast cancer risk associated with human insulin use might be beneficially modified by concomitant use of metformin, statin and ACEI/ARB. CONCLUSIONS: This study discloses a significantly higher risk of breast cancer associated with prolonged use of human insulin. The increased risk of breast cancer associated with human insulin use may be modified by medications such as metformin, statin and ACEI/ARB. PMID- 26537235 TI - Iodine-induced hyperthyroidism as combination of different etiologies: an overlooked entity in the elderly. AB - Iodine-induced thyrotoxicosis, which raises several diagnostic and therapeutical challenges, is often overlooked. Hyperthyroidism can induce atrial fibrillation, a harmful arrhythmia which can precipitate heart failure and cause stroke. We report the case of an elderly man who was diagnosed with tachyfibrillation secondary to hyperthyroidism. Thyroid hyperfunction was subsequently related both to previous amiodarone therapy (probably mixed form) and the recent use of iodinated contrast medium for computed tomography scan. Thyroid ultrasonography showed a plongeant multinodular goitre. After initial worsening, thyroid function improved slowly but progressively on high-dose thyreostatic therapy combined with steroid therapy; tachyfibrillation caused heart failure and a thrombus in the left atrium, and proved initially resistant to combined antiarrhythmic treatments. Progressive reduction in thyroid hormone levels, together with combined cardiologic therapies, controlled the heart rate, though atrial fibrillation persisted; anticoagulant therapy resolved the atrial thrombus. Alterations in thyroid function are common in amiodarone-treated patients, who therefore require regular hormonal checks. The different forms of amiodarone induced thyrotoxicosis must be investigated, since they require different therapies, though mixed forms often occur. The superimposition of further iodine excess due to other causes may be catastrophic and cause severe cardiac problems in these patients. PMID- 26537236 TI - Reliability of an anamnestic questionnaire for the diagnosis of benign paroxysmal positional vertigo in the elderly. AB - BACKGROUND: There is common agreement in the literature that it can result in an underestimation of benign paroxysmal positional vertigo (BPPV) in the elderly. AIMS: The aim of this work was to analyze the role of anamnesis in the diagnosis of BPPV in patients of different ages through the development and validation of a scored questionnaire. METHODS: The questionnaire is based on the presence/absence of six typical anamnestic features of BPPV. The Mini-Mental State Exam (MMS) was also administered to patients over 65 years of age. Bedsides, examination for BPPV was then carried out, assigning the outcome of the questionnaire and eventual MMS to the final diagnosis for each patient. RESULTS: The sensitivity and specificity of the questionnaire for high scores (>8) were found to be, respectively, 86 % and 80 % in all patients, 94 and 71 % in those under 65 years of age, 78 and 90 % in patients over 65, and, in particular, 63 and 83 % in those with MMS >24 and 100 and 100 % in those with MMS <=24. DISCUSSION: The reliability and average score of the questionnaire were statistically significantly lower in the group of elderly patients without cognitive deficits. The lower reliability of the questionnaire in the geriatric population, rather than the presence of cognitive deterioration, seems to correlate with other comorbidities or simply to a lower mobility of the head triggering positional symptoms. CONCLUSION: The use of the questionnaire could however reduce the risk of a missed diagnosis of BPPV given its good reliability across all ages. PMID- 26537237 TI - Expression of pRb and p16INK4 in human thymic epithelial tumors in relation to the presence of human polyomavirus 7. AB - BACKGROUND: We have recently reported the presence of the Human polyomavirus 7 (HPyV7) in human thymic epithelial tumors as assessed by diverse molecular techniques. Here we report on the co-expression of p16, retinoblastoma protein (pRb) and phosphorylated retinoblastoma protein (phospho-Rb) in human thymic epithelial tumors in relation to HPyV7. METHODS: PRB, phospho-RB and p16 expression was assessed by immuno-histochemistry in 37 thymomas and 2 thymic carcinomas. 17 thymomas (46 %) and 1 thymic carcinoma (50 %) were recently tested positive for HPyV7. In addition, 20 follicular hyperplasias were tested. RESULTS: Expression of pRb was observed in 35 thymomas (94.6 %), in 16 thymomas (43.2 %) the expression was strong. Phospho-Rb was observed in 31 thymomas (83.8 %). 19 thymomas (51.4 %) showed immunoreactivity for p16 of which 8 thymomas revealed very strong p16 expression. No p16 expression was detected in thymic carcinomas. In addition, no significant correlation between the presence of HPyV7 and pRb-, phospho-Rb- and p16-expression could be established. No correlation between pRb, phospho-Rb, p16 and WHO staging, Masaoka-Koga staging or the presence of MG was found. All 20 follicular hyperplasias showed expression of pRb and less expression of phospho-Rb. CONCLUSIONS: Although polyomaviruses have been shown to interact with cell cycle proteins no correlation between the presence of HPyV7 and the expression of pRb, phospho-Rb and p16 in human thymic epithelial tumors was observed. In as much HPyV7 contributes to human thymomagenesis remains to be established. Our data indicate pRb, phospho-Rb and p16 expression are rather unlikely to be involved in HPyV7 related thymomagenesis. PMID- 26537238 TI - Effects of Cryopreservation on Canine Multipotent Stromal Cells from Subcutaneous and Infrapatellar Adipose Tissue. AB - Adipose derived multipotent stromal cells (ASCs) isolated from brown versus white adipose tissues, may have distinct in vitro properties, including response to cryopreservation, due to differences in tissue physiology. This study was designed to determine the ultrastructure, immunophenotype, in vitro expansion capabilities and multipotentiality of paired canine ASCs harvested from subcutaneous (SUB) and infrapatellar (IFP) adipose tissue up to cell passage (P) 3 before and after cryopreservation. Adipocyte and ASC ultrastructure from the same tissue were distinct, and morphologies of both differed between tissue sources and with cryopreservation. Cell expansion and colony forming unit frequencies were similar between ASCs from both tissue sources before and after cryopreservation. Most fresh cells were CD29+, CD44+, CD90+ and CD34- up to P3. Cryopreserved P1 and P3 cells had lower percentages of CD29+ and 44+ cells, respectively, compared to fresh. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) gene expression and sex determining region Y-box 2 (SOX2), CD29 and CD44 protein expression was lower in cryopreserved versus fresh P3 ASCs. Both PPAR-gamma and osteopontin (OPN) protein expression increased in fresh and cryopreserved P3 ASCs cultured in adipogenic and osteogenic induction medium, respectively, while SOX2 decreased. Based on the study findings, in vitro expansion and multipotentiality are not distinct among canine SUB and IFP ASCs before or after cryopreservation. However, cryopreservation alters ASC ultrastructure, immunophenotype and transcription factor expression from both tissue sources. Future studies are necessary to determine the impact of cryopreservation on cell potential for therapy and de novo tissue generation. PMID- 26537240 TI - Safe Zone for the Plantar Portal: A Cadaveric Study. AB - BACKGROUND: Understanding the plantar nerve anatomy is crucial for safe endoscopic surgery of the sole. We aimed to anatomically dissect the lateral aspect and soles of cadaveric feet to investigate the safety of peroneus longus tendoscopy with a plantar lateral portal and the safe zones for plantar portals. METHODS: We studied 36 feet of 24 cadavers (mean age, 86.5 years). A cannula for 2.7-mm scope was inserted from the plantar lateral portal to the peroneus longus tendon, and the positional relationship between the cannula and sural nerve was observed. Then, the soft tissue of the sole was dissected, and the relationships between the plantar nerve and flexor digitorum longus tendon and flexor hallucis longus tendon was observed. The plantar nerve course was digitally imaged and uploaded into Image J software to determine nerve position. We further observed the positional relationship between the cannula and plantar nerve. RESULT: The mean minimum distance between the cannula and sural nerve was 13.8 mm, and the closest distance was 4.2 mm, allowing for the relatively safe creation of a plantar lateral portal. The use of the plantar lateral portal and evaluation of the peroneal tendon was safe with respect to the lateral plantar nerve as the nerve was in a different tissue layer of the foot. Dissection of the plantar foot demonstrated a relatively safe zone, 36.4% to 56% along a line between the medial aspect of the base of the first metatarsal bone to the proximal tip of the fifth metatarsal. This region may allow for a plantar endoscopic portal; however an anatomic variation may result in the plantar nerve being within this zone. The flexor digitorum longus tendon and peroneus longus tendon passed through the deep layer of the relatively safe zone. CONCLUSION: Peroneus longus tendoscopy was relatively safe to perform from a plantar lateral portal. No neurovascular structure exists on the slightly medial aspect of the central region of the sole, potentially allowing for a relatively safe creation of plantar central portal. An approach from the plantar central portal to the flexor digitorum longus tendon, flexor hallucis longus tendon, and peroneus longus tendon allows for a greater range of vision and treatment options as compared with conventional approaches. The combination of the plantar central portal with portals such as the plantar lateral portal may further the development of endoscopic surgery of the sole. CLINICAL RELEVANCE: We found the anatomic characteristics of a relatively safe zone for the plantar portal for plantar lateral portal. PMID- 26537241 TI - Operative and Nonoperative Management of Achilles Tendon Ruptures in Active Duty Military Population. AB - BACKGROUND: The optimal management of Achilles tendon ruptures continues to be a subject of debate in orthopedics. These injuries are common in the active duty military population. The purpose of this study was to retrospectively compare the results of operative and nonoperative management of Achilles tendon ruptures in the active duty military population following the publication of a landmark level I study that has influenced practice patterns. METHODS: All Achilles tendon injuries in active duty patients were identified at a single military institution from January 1, 2011, to January 1, 2014. Inclusion and exclusion criteria were applied and charts were reviewed. Demographic and treatment information were recorded along with return to duty status, deep vein thrombosis (DVT), rerupture, and other complication data. Rates of DVT, rerupture, other complications, and return to duty (including time to return) were then compared. Demographic data were described. Fifty-seven male patients met inclusion criteria with an average age of 31 years. There were 27 in the operative group and 30 in the nonoperative group. There were no significant differences in group demographics. RESULTS: There were no DVTs in either treatment group. There were no wound complications in the operative group. There were no significant differences in the rates of rerupture, return to duty, or other complications. There were 2 reruptures in the nonoperative group. Both were treated nonoperatively. There was one rerupture in the operative group that was treated nonoperatively. All reruptures were partial tears. Two patients underwent repair with flexor hallucis longus augmentation. Both of these patients were initially managed nonoperatively. When available data on time to return to duty was analyzed, patients who underwent operative management returned to duty on average approximately one and a half months earlier (6.7 vs 8.2 months) than nonoperative patients (P = .04). In 2011, 12% of injuries were treated nonoperatively; in 2012, 57%; and in 2013, 84%. CONCLUSIONS: Similar to previously published work, this retrospective analysis found no significant difference in complication, DVT, or rerupture rates. The rate of rerupture in this study was slightly higher than previously published work in the era of functional rehabilitation, but the sample size was small. The data were limited with respect to functional outcome for comparison; however, the rate of return to active duty was not significantly different. The data also demonstrate a shift in institutional treatment pattern for Achilles injuries in this population over the 3-year study period. Operatively treated patients did have a statistically significant reduction in the time required to return to active duty of approximately one and a half months, which may represent a clinically significant difference in highly active workers or highly active people. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 26537239 TI - Underlying Mechanisms of Gene-Environment Interactions in Externalizing Behavior: A Systematic Review and Search for Theoretical Mechanisms. AB - Over the last decade, several candidate genes (i.e., MAOA, DRD4, DRD2, DAT1, 5 HTTLPR, and COMT) have been extensively studied as potential moderators of the detrimental effects of postnatal family adversity on child externalizing behaviors, such as aggression and conduct disorder. Many studies on such candidate gene by environment interactions (i.e., cG * E) have been published, and the first part of this paper offers a systematic review and integration of their findings (n = 53). The overview shows a set of heterogeneous findings. However, because of large differences between studies in terms of sample composition, conceptualizations, and power, it is difficult to determine if different findings indeed illustrate inconsistent cG * E findings or if findings are simply incomparable. In the second part of the paper, therefore, we argue that one way to help resolve this problem is the development of theory-driven a priori hypotheses on which biopsychosocial mechanisms might underlie cG * E. Such a theoretically based approach can help us specify our research strategies, create more comparable findings, and help us interpret different findings between studies. In accordance, we describe three possible explanatory mechanisms, based on extant literature on the concepts of (1) emotional reactivity, (2) reward sensitivity, and (3) punishment sensitivity. For each mechanism, we discuss the link between the putative mechanism and externalizing behaviors, the genetic polymorphism, and family adversity. Possible research strategies to test these mechanisms, and implications for interventions, are discussed. PMID- 26537242 TI - Methods of high integrity RNA extraction from cell/agarose construct. AB - BACKGROUND: Agarose hydrogels are widely used for three-dimensional cell scaffolding in tissue engineering and cell biology. Recently, molecular profiles have been obtained with extraction of a minimal volume of RNA using fluorescent tagged quantitative polymerase chain reaction (qPCR), which requires high integrity RNA. However, the agarose interferes considerably with the quantity and quality of the extracted RNA. Moreover, little is known about RNA integrity when the RNA is extracted from cell/agarose construct. Thus, in order to obtain RNA of sufficient integrity, we examined various extraction methods and addressed reproducible methodologies for RNA extraction from cell/agarose constructs using spectrophotometry and microfluidic capillary electrophoresis. RESULTS: With various extraction methods using a mono-phasic solution of phenol and guanidine isothiocyanate, we evaluated quantity and quality of total RNA from cell/agarose construct. Extraction with solution of phenol and guanidine isothiocyanate followed by a silica based membrane filter column gave sufficient RNA integrity number, which allowed us to proceed to fluorescent-tagged qPCR for evaluating various cellular activities. CONCLUSIONS: The RNA extraction methods using phenol and guanidine isothiocyanate solution and a silica membrane column can be useful for obtaining high integrity RNA from cell/agarose constructs rich in polysaccharide and extracellular matrix. Our study contributes to further investigation using agarose hydrogels and other materials rich in polysaccharide in the field of cellular and tissue engineering. PMID- 26537243 TI - HSPC280, a winged helix protein expressed in the subventricular zone of the developing ganglionic eminences, inhibits neuronal differentiation. AB - Winged helix proteins have critical roles in a variety of developmental processes. During a screening for genes expressed in the developing forebrain, we identified HSPC280, a non-typical winged helix protein, which shares similarity with a protein-protein interaction domain found in the proteins of the actin binding Rho-activating protein family. In this work, we analyzed HSPC280 expression during mouse development as well as during neuronal differentiation of mouse Neuro2a cells. HSPC280 expression is tightly regulated; during mouse development, it was detected predominantly in the ganglionic eminences of the ventral telencephalon, from their appearance at E11.5 to P0, with the highest levels between E13.5 and E15.5, a period that correlates with the peak of neurogenesis in these structures. Comparative expression analysis of HSPC280 with Dlx2, cyclinD2 and Lhx6 revealed that, within the ganglionic eminences, HSPC280 was restricted in the proliferating cell population of the subventricular zone, in a pattern similar to that of cyclinD2. Finally, we showed that HSPC280 is a nuclear protein which, when overexpressed in Neuro2a cells, it inhibited neuronal differentiation in vitro, suggesting its involvement in the mechanisms controlling neural progenitor cells proliferation. PMID- 26537244 TI - DNA repair foci and late apoptosis/necrosis in peripheral blood lymphocytes of breast cancer patients undergoing radiotherapy. AB - PURPOSE: Double-strand breaks (DSB) repair and apoptosis are assumed to be key factors in the determination of individual variability in response to radiation treatment. In this study we investigated tumor protein p53 (TP53) binding protein 1 (53BP1) and phosphorylated histone 2A family member X (gammaH2AX) foci, gammaH2AX pan-staining and late apoptosis/necrosis (LAN) in lymphocytes from breast cancer (BC) patients undergoing radiotherapy. MATERIALS AND METHODS: BC patients were subjected to local radiotherapy with fractionated doses using linear accelerator. Adverse reactions of patients were classified according to the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) criteria. Blood samples were collected before treatment, at various time-points during and after radiotherapy. Residual 53BP1 and gammaH2AX foci, gammaH2AX pan-staining were analyzed in peripheral blood lymphocytes (PBL) using the Metafer system and confocal laser scanning microscopy. LAN cells were counted by the trypan blue (TB) exclusion assay. Statistical analysis was performed using Mann-Whitney test, Spearman rank correlation test and analysis of covariance (ANCOVA). RESULTS: No statistically significant changes were observed in the levels of gammaH2AX foci during radiotherapy. In contrast, radiation-induced residual 53BP1 were detected already after the first fraction. Increased individual variability in the 53BP1 focus formation was observed during treatment. The background level of DNA repair foci and its individual variability in response to radiotherapy decreased after the end of radiotherapy indicating successful removal of DNA-damaging effects. A correlation between stage of cancer and 53BP1 focus formation was established which suggests the prognostic value of this test. We show that the fraction of LAN cells negatively correlates with the level of 53BP1 and positively correlates with individual radiosensitivity. Only weak correlation was observed between gammaH2AX pan-staining and LAN cells. Due to large interindividual variability, both in vivo assays, LAN and focus formation, have shown relatively low predictive power at the individual level. CONCLUSIONS: It is likely that radiosensitive patients have less efficient mechanisms of elimination of apoptotic cells with DNA damage resulting in accumulation of LAN cells and facilitating adverse reactions. Our data suggested that the grade of adverse reaction may positively correlate with LAN cells in PBL before and during radiotherapy. PMID- 26537245 TI - A national epidemiological study investigating risk factors for police interrogation and false confession among juveniles and young persons. AB - PURPOSE: The principal aims of this study are to identify risk factors associated with police arrest and false confessions and to investigate whether the severity of the ADHD condition/symptoms increases the risk. METHODS: 22,226 young persons in Iceland anonymously completed self-report questionnaires screening for conduct disorder and ADHD. In addition, they stated whether they had a diagnosis of ADHD and had received ADHD medication, and their history of offending, police interrogation and false confession. Participants were stratified into two age groups, 14-16 and 17-24 years. RESULTS: The older group was significantly more likely to have been interrogated by the police but the younger group were much more vulnerable to false confession during interrogation. Males were more likely to be at risk for both than females. The severity of the ADHD condition increased the risk of both interrogation and false confession. Negative binomial regressions showed that age, gender, conduct disorder, offending, and ADHD symptoms were all significant predictors of both interrogations and number of false confessions. Conduct disorder was the single best predictor of police interrogation, but the findings were more mixed regarding false confessions. Young people presenting with a combination of severe ADHD and comorbid conduct disorder had the worst outcome for both interrogation and false confessions. CONCLUSIONS: The findings endorse the need for support of persons with ADHD to be put in place to ensure fair due process and to prevent miscarriages of justice. PMID- 26537246 TI - Lactobacillus rhamnosus GG Lysate Increases Re-Epithelialization of Keratinocyte Scratch Assays by Promoting Migration. AB - A limited number of studies have investigated the potential of probiotics to promote wound healing in the digestive tract. The aim of the current investigation was to determine whether probiotic bacteria or their extracts could be beneficial in cutaneous wound healing. A keratinocyte monolayer scratch assay was used to assess re-epithelialization; which comprises keratinocyte proliferation and migration. Primary human keratinocyte monolayers were scratched then exposed to lysates of Lactobacillus (L) rhamnosus GG, L. reuteri, L. plantarum or L. fermentum. Re-epithelialization of treated monolayers was compared to that of untreated controls. Lysates of L. rhamnosus GG and L. reuteri significantly increased the rate of re-epithelialization, with L. rhamnosus GG being the most efficacious. L. reuteri increased keratinocyte proliferation while L. rhamnosus GG lysate significantly increased proliferation and migration. Microarray analysis of L. rhamnosus GG treated scratches showed increased expression of multiple genes including the chemokine CXCL2 and its receptor CXCR2. These are involved in normal wound healing where they stimulate keratinocyte proliferation and/or migration. Increased protein expression of both CXCL2 and CXCR2 were confirmed by ELISA and immunoblotting. These data demonstrate that L. rhamnosus GG lysate accelerates re-epithelialization of keratinocyte scratch assays, potentially via chemokine receptor pairs that induce keratinocyte migration. PMID- 26537247 TI - Towards a strategy for malaria in pregnancy in Afghanistan: analysis of clinical realities and women's perceptions of malaria and anaemia. AB - BACKGROUND: Afghanistan has some of the worst maternal and infant mortality indicators in the world and malaria is a significant public health concern. Study objectives were to assess prevalence of malaria and anaemia, related knowledge and practices, and malaria prevention barriers among pregnant women in eastern Afghanistan. METHODS: Three studies were conducted: (1) a clinical survey of maternal malaria, maternal anaemia, and neonatal birthweight in a rural district hospital delivery-ward; (2) a case-control study of malaria risk among reproductive-age women attending primary-level clinics; and (3) community surveys of malaria and anaemia prevalence, socioeconomic status, malaria knowledge and reported behaviour among pregnant women. RESULTS: Among 517 delivery-ward participants (1), one malaria case (prevalence 1.9/1000), 179 anaemia cases (prevalence 346/1000), and 59 low-birthweight deliveries (prevalence 107/1000) were detected. Anaemia was not associated with age, gravidity, intestinal parasite prevalence, or low-birthweight at delivery. Among 141 malaria cases and 1010 controls (2), no association was found between malaria infection and pregnancy (AOR 0.89; 95 % CI 0.57-1.39), parity (AOR 0.95; 95 % CI 0.85-1.05), age (AOR 1.02; 95 % CI 1.00-1.04), or anaemia (AOR 1.00; 95 % CI 0.65-1.54). Those reporting insecticide-treated net usage had 40 % reduced odds of malaria infection (AOR 0.60; 95 % CI 0.40-0.91). Among 530 community survey participants (3), malaria and anaemia prevalence were 3.9/1000 and 277/1000 respectively, with 34/1000 experiencing severe anaemia. Despite most women having no formal education, malaria knowledge was high. Most expressed reluctance to take malaria preventive medication during pregnancy, deeming it potentially unsafe. CONCLUSIONS: Given the low malaria risk and reported avoidance of medication during pregnancy, intermittent preventive treatment is hard to justify or implement. Preventive strategy should instead focus on long-lasting insecticidal nets for all pregnant women. PMID- 26537248 TI - TLE6 mutation causes the earliest known human embryonic lethality. AB - BACKGROUND: Embryonic lethality is a recognized phenotypic expression of individual gene mutations in model organisms. However, identifying embryonic lethal genes in humans is challenging, especially when the phenotype is manifested at the preimplantation stage. RESULTS: In an ongoing effort to exploit the highly consanguineous nature of the Saudi population to catalog recessively acting embryonic lethal genes in humans, we have identified two families with a female-limited infertility phenotype. Using autozygosity mapping and whole exome sequencing, we map this phenotype to a single mutation in TLE6, a maternal effect gene that encodes a member of the subcortical maternal complex in mammalian oocytes. Consistent with the published phenotype of mouse Tle6 mutants, embryos from female patients who are homozygous for the TLE6 mutation fail to undergo early cleavage, with resulting sterility. The human mutation abrogates TLE6 phosphorylation, a step that is reported to be critical for the PKA-mediated progression of oocyte meiosis II. Furthermore, the TLE6 mutation impairs its binding to components of the subcortical maternal complex. CONCLUSION: In this first report of a human defect in a member of the subcortical maternal subcritical maternal complex, we show that the TLE6 mutation is gender-specific and leads to the earliest known human embryonic lethality phenotype. PMID- 26537249 TI - Elemental changes in the hippocampal formation following two different formulas of ketogenic diet: an X-ray fluorescence microscopy study. AB - The main purpose of the following study was the determination of elemental changes occurring within hippocampal formation as a result of high-fat and carbohydrate-restricted ketogenic diet (KD). To realize it, X-ray fluorescence microscopy was applied for topographic and quantitative analysis of P, S, K, Ca, Fe, Cu, Zn and Se in hippocampal formations taken from rats fed with two different KDs and naive controls. The detailed comparisons were done for sectors 1 and 3 of the Ammon's, the dentate gyrus and hilus of dentate gyrus. The results of elemental analysis showed that the KDs induced statistically significant changes in the accumulation of P, K, Ca, Zn and Se in particular areas of hippocampal formation and these alterations strongly depended on the composition of the diets. Much greater influence on the hippocampal areal densities of examined elements was found for the KD which was characterized by a lower content of carbohydrates, higher content of fats and increased proportion of unsaturated fatty acids. The levels of P, K and Zn decreased whilst those of Ca and Se increased as a result of the treatment with the KDs. PMID- 26537250 TI - Adverse Outcome Pathways-Organizing Toxicological Information to Improve Decision Making. AB - The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High-throughput screening commonly used for drug discovery has the potential to increase this capacity. The adverse outcome pathway (AOP) concept has emerged as a framework for connecting high-throughput toxicity testing (HTT) and other results to potential impacts on human and wildlife populations. As a result of international efforts, the AOP development process is now well-defined and efforts are underway to broaden the participation through outreach and training. One key principle is that AOPs represent the chemical-agnostic portions of pathways to increase the generalizability of their application from early key events to overt toxicity. The closely related mode of action framework extends the AOP as needed when evaluating the potential risk of a specific chemical. This in turn enables integrated approaches to testing and assessment (IATA), which incorporate results of assays at various levels of biologic organization such as in silico; HTT; chemical-specific aspects including absorption, distribution, metabolism, and excretion (ADME); and an AOP describing the biologic basis of toxicity. Thus, it is envisaged that provision of limited information regarding both the AOP for critical effects and the ADME for any chemical associated with any adverse outcome would allow for the development of IATA and permit more detailed AOP and ADME research, where higher precision is needed based on the decision context. PMID- 26537251 TI - Reading Comprehension Mediates the Relationship between Syntactic Awareness and Writing Composition in Children: A Longitudinal Study. AB - This research aimed to explore the relation between syntactic awareness and writing composition in 129 Hong Kong Chinese children. These children were from a ten-year longitudinal project. At each year, a number of measures were administered. The 129 children's data of nonverbal reasoning at age 4, phonological awareness, morphological awareness, vocabulary knowledge at age 8, reading comprehension at age 12 and syntactic awareness and writing composition skills at ages 11 and 12 were included in this study. Syntactic awareness was longitudinally and uniquely predictive of Chinese children's writing composition, and children's performance in early writing composition was uniquely associated with their later syntactic skills, even when controlling for the contributions from age, nonverbal and verbal abilities, phonological awareness, and morphological awareness. The relationship between syntactic awareness and writing composition was mediated by children's performance in reading comprehension. These findings may suggest a reciprocal relation between syntactic awareness and writing composition, and this association may vary with ability in reading comprehension in Chinese children. PMID- 26537252 TI - Additional factors to take into account when diagnosing miscarriage. PMID- 26537253 TI - RSV vaccine: Beating the virus at its own game. AB - Rational design hijacks RSV's own transcriptional machinery to pave the way for an innovative live attenuated vaccine (Karron et al., this issue). PMID- 26537254 TI - Liquid biopsy: Clues on prostate cancer drug resistance. AB - Analysis of tumor-derived cell-free DNA in blood yields insights into drug resistance in patients with castration-resistant prostate cancer (Romanel et al., this issue). PMID- 26537255 TI - A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children. AB - Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and a safe and effective vaccine for use in infancy and early childhood is needed. We previously showed that deletion of the coding sequence for the viral M2-2 protein (DeltaM2-2) down-regulated viral RNA replication and up-regulated gene transcription and antigen synthesis, raising the possibility of development of an attenuated vaccine with enhanced immunogenicity. RSV MEDI DeltaM2-2 was therefore evaluated as a live intranasal vaccine in adults, RSV-seropositive children, and RSV-seronegative children. When results in RSV-seronegative children were compared to those achieved with the previous leading live attenuated RSV candidate vaccine, vaccine virus shedding was significantly more restricted, yet the postvaccination RSV-neutralizing serum antibody achieved [geometric mean titer (GMT) = 1:97] was significantly greater. Surveillance during the subsequent RSV season showed that several seronegative RSV MEDI DeltaM2-2 recipients had substantial antibody rises without reported illness, suggesting that the vaccine was protective yet primed for anamnestic responses to RSV. Rational design appears to have yielded a candidate RSV vaccine that is intrinsically superior at eliciting protective antibody in RSV-naive children and highlights an approach for the development of live attenuated RSV vaccines. PMID- 26537256 TI - Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma. AB - Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. We used a MYC target gene signature that predicts poor neuroblastoma prognosis to identify the histone chaperone FACT (facilitates chromatin transcription) as a crucial mediator of the MYC signal and a therapeutic target in the disease. FACT and MYCN expression created a forward feedback loop in neuroblastoma cells that was essential for maintaining mutual high expression. FACT inhibition by the small-molecule curaxin compound CBL0137 markedly reduced tumor initiation and progression in vivo. CBL0137 exhibited strong synergy with standard chemotherapy by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN amplified neuroblastoma cells and suggesting a treatment strategy for MYCN-driven neuroblastoma. PMID- 26537257 TI - Sodium channel Nax is a regulator in epithelial sodium homeostasis. AB - The mechanisms by which the epidermis responds to disturbances in barrier function and restores homeostasis are unknown. With a perturbation of the epidermal barrier, water is lost, resulting in an increase in extracellular sodium concentration. We demonstrate that the sodium channel Nax functions as a sodium sensor. With increased extracellular sodium, Nax up-regulates prostasin, which results in activation of the sodium channel ENaC, resulting in increased sodium flux and increased downstream mRNA synthesis of inflammatory mediators. Nax is present in multiple epithelial tissues, and up-regulation of its downstream genes is found in hypertrophic scars. In animal models, blocking Nax expression results in improvement in scarring and atopic dermatitis-like symptoms, both of which are pathological conditions characterized by perturbations in barrier function. These findings support an important role for Nax in maintaining epithelial homeostasis. PMID- 26537258 TI - Plasma AR and abiraterone-resistant prostate cancer. AB - Androgen receptor (AR) gene aberrations are rare in prostate cancer before primary hormone treatment but emerge with castration resistance. To determine AR gene status using a minimally invasive assay that could have broad clinical utility, we developed a targeted next-generation sequencing approach amenable to plasma DNA, covering all AR coding bases and genomic regions that are highly informative in prostate cancer. We sequenced 274 plasma samples from 97 castration-resistant prostate cancer patients treated with abiraterone at two institutions. We controlled for normal DNA in patients' circulation and detected a sufficiently high tumor DNA fraction to quantify AR copy number state in 217 samples (80 patients). Detection of AR copy number gain and point mutations in plasma were inversely correlated, supported further by the enrichment of nonsynonymous versus synonymous mutations in AR copy number normal as opposed to AR gain samples. Whereas AR copy number was unchanged from before treatment to progression and no mutant AR alleles showed signal for acquired gain, we observed emergence of T878A or L702H AR amino acid changes in 13% of tumors at progression on abiraterone. Patients with AR gain or T878A or L702H before abiraterone (45%) were 4.9 and 7.8 times less likely to have a >=50 or >=90% decline in prostate specific antigen (PSA), respectively, and had a significantly worse overall [hazard ratio (HR), 7.33; 95% confidence interval (CI), 3.51 to 15.34; P = 1.3 * 10(-9)) and progression-free (HR, 3.73; 95% CI, 2.17 to 6.41; P = 5.6 * 10(-7)) survival. Evaluation of plasma AR by next-generation sequencing could identify cancers with primary resistance to abiraterone. PMID- 26537259 TI - Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair. AB - Chemical castration improves responses to radiotherapy in prostate cancer, but the mechanism is unknown. We hypothesized that this radiosensitization is caused by castration-mediated down-regulation of nonhomologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs). To test this, we enrolled 48 patients with localized prostate cancer in two arms of the study: either radiotherapy first or radiotherapy after neoadjuvant castration treatment. We biopsied patients at diagnosis and before and after castration and radiotherapy treatments to monitor androgen receptor, NHEJ, and DSB repair in verified cancer tissue. We show that patients receiving neoadjuvant castration treatment before radiotherapy had reduced amounts of the NHEJ protein Ku70, impaired radiotherapy-induced NHEJ activity, and higher amounts of unrepaired DSBs, measured by gamma-H2AX foci in cancer tissues. This study demonstrates that chemical castration impairs NHEJ activity in prostate cancer tissue, explaining the improved response of patients with prostate cancer to radiotherapy after chemical castration. PMID- 26537260 TI - A typology of uncertainty derived from an analysis of critical incidents in medical residents: A mixed methods study. AB - BACKGROUND: Medical uncertainty is inherently related to the practice of the physician and generally affects his or her patient care, job satisfaction, continuing education, as well as the overall goals of the health care system. In this paper, some new types of uncertainty, which extend existing typologies, are identified and the contexts and strategies to deal with them are studied. METHODS: We carried out a mixed-methods study, consisting of a qualitative and a quantitative phase. For the qualitative study, 128 residents reported critical incidents in their clinical practice and described how they coped with the uncertainty in the situation. Each critical incident was analyzed and the most salient situations, 45 in total, were retained. In the quantitative phase, a distinct group of 120 medical residents indicated for each of these situations whether they have been involved in the described situations and, if so, which coping strategy they applied. The analysis examines the relation between characteristics of the situation and the coping strategies. RESULTS: From the qualitative study, a new typology of uncertainty was derived which distinguishes between technical, conceptual, communicational, systemic, and ethical uncertainty. The quantitative analysis showed that, independently of the type of uncertainty, critical incidents are most frequently resolved by consulting senior physicians (49 % overall), which underscores the importance of the hierarchical relationships in the hospital. The insights gained by this study are combined into an integrative model of uncertainty in medical residencies, which combines the type and perceived level of uncertainty, the strategies employed to deal with it, and context elements such as the actors present in the situation. The model considers the final resolution at each of three levels: the patient, the health system, and the physician's personal level. CONCLUSIONS: This study gives insight into how medical residents make decisions under different types of uncertainty, giving account of the context in which the interactions take place and of the strategies used to resolve the incidents. These insights may guide the development of organizational policies that reduce uncertainty and stress in residents during their clinical training. PMID- 26537261 TI - THE BRAZILIAN SOCIETY OF BARIATRIC AND METABOLIC SURGERY - SBCBM - PRIORITIZES ENCOURAGING OF SCIENTIFIC PRODUCTION. PMID- 26537262 TI - POSITION OF THE SBCBM - NOMENCLATURE AND DEFINITION OF OUTCOMES OF BARIATRIC AND METABOLIC SURGERY. PMID- 26537263 TI - COMPLICATIONS REQUIRING HOSPITAL MANAGEMENT AFTER BARIATRIC SURGERY. AB - BACKGROUND: The actual gold standard technique for obesity treatment is the Roux en-Y gastric bypass. However, complications may occur and the surgeon must be prepared for them. AIM: To evaluate retrospectively the complications occurrence and associated factors in patients who underwent bariatric surgery. METHODS: In this study, 469 medical charts were considered, from patients and from data collected during outpatient consultations. The variables considered were gender, age, height, pre-operatory BMI, pre-operatory weight, pre-operatory comorbidities, time of hospital stay, postoperative complications that demanded re-admission to the hospital and the time elapsed between the procedure and the complication. The patients' follow up was, at least, one year. RESULTS: The incidence of postoperative complications that demanded a hospital care was 24,09%. The main comorbidity presented in this sample was hepatic steatosis. The comorbidity that was associated with the postoperative period was type 2 diabetes. There was a tendency for the female gender be related to the complications. The cholecystectomy was the most frequent complication. Complications occurred during the first year in 57,35%. CONCLUSION: The most frequent complication was the need to perform a cholecystectomy, where the most frequent comorbidity was hepatic steatosis. Over half the complications occurred during the first year postoperatively. Type 2 diabetes was associated with the occurrence of postoperative complications; women had the highest incidence; body mass index was not associated with the occurrence of complications. PMID- 26537264 TI - SURGICAL TREATMENT OF SEVERE OBESITY IN TEENS: LATE RESULTS. AB - BACKGROUND: In children is estimated that the prevalence of overweight and obesity has increased up to five times in developed countries and up to four in developing countries. In Brazil, the proportion of children and adolescents who are overweight also increased from approximately 4.1% to 13.9%. AIM: To evaluate the surgical results of severe obesity in adolescents. METHODS: Retrospective descriptive study of 2737 patients with severe obesity that underwent Roux-en-Y gastric bypass selecting from the total 44 patients with mean age of 18.1 years, 14 males and 30 females, most (37) operated by laparotomy. There was follow-up of 20 patients (45.45%). All were followed preoperatively by a multidisciplinary team and had indication confirmed for surgical unanimous approval of all team members. RESULTS: Among the 20 adolescent, 14 were female. From five teenagers using anti-hypertension or hypoglycemic drugs before surgery, four (80%) had drug discontinuation and one (20%) reduced the dose in 50% postoperatively. The average weight loss was 45.4 kg after a mean follow up of 60 months. There were no deaths or severe postoperative complications. Among those who underwent postoperative follow-up with a multidisciplinary team, 18 were with BMI<30. CONCLUSIONS: Adolescents undergoing Roux-en-Y gastric bypass has good response in relation to weight loss and improvement of comorbidities. There was a low rate of complications and no deaths. All patients were satisfied with their personal results. PMID- 26537265 TI - C-REACTIVE PROTEIN IN DIABETIC PATIENTS BEFORE GASTRIC BYPASS AS A POSSIBLE MARKER FOR POSTOPERATIVE COMPLICATION. AB - BACKGROUND: Obesity and type 2 diabetes mellitus are associated to inflammatory state, which can be set off by the adipose tissue, once it is a metabolically active organ that can cause a chronic mild inflammatory state. AIM: To evaluate the correlation between preoperative C-reactive protein and postoperative complications risk in obese patients (grades II and III) after Roux-en-Y gastric bypass, with and without type 2 diabetes mellitus. METHODS: Between 2008 and 2013 were analysed 209 patients (107 with diabetes), presenting body mass index >40 kg/m2 or >35 kg/m2 with comorbidities. During the postoperative period, two groups were evaluated: with and without complications. Preoperative ultra sensitive C-reactive protein was measured by immunonephelometry method. RESULTS: Complications occurred in seven patients (pulmonary thromboembolism, fistula, two cases of suture leak, pancreatitis, evisceration and upper digestive hemorrhage). No statistical significance was found regarding lipid profile and C-reactive protein between patients with and without type 2 diabetes mellitus. When compared to each other, both groups (with and without complications) presented with statistical significance regarding C-reactive protein level (7,2 mg/dl vs 3,7 mg/dl, p=0,016) and had similar weight loss percentage after 3, 6 and 12 months follow-up. CONCLUSIONS: Preoperative C-reactive protein serum level was higher in the group which presented complications after Roux-en-Y gastric bypass when compared to the group without postoperative complications. PMID- 26537266 TI - BARIATRIC SURGERY IN THE ELDERLY: RESULTS OF A MEAN FOLLOW-UP OF FIVE YEARS. AB - BACKGROUND: Surgical treatment of obesity in the elderly, particularly over 65, remains controversial; it is explained by the increased surgical risk or the lack of data demonstrating its long-term benefit. Few studies have evaluated the clinical effects of bariatric surgery in this population. AIM: To evaluate the results of surgical treatment of obesity in patients over 60 years, followed for an average period of five years. METHOD: This was a retrospective study evaluating 46 patients, 60 years or older, who underwent surgical treatment of obesity, by conventional gastric bypass technique (laparotomy). The average age was 64 years (60-71), mean BMI of 49.6 kg/m2 (38-66), mean follow-up of 5.9 years; 91% of patients were hypertensive, 56% diabetics and 39% had dyslipidemia. RESULTS: The incidence of complications (major and minor) in patients under 65 years was 26% and over 65 years 37% (p=0.002). There were no deaths in the group with less than 65 years and there were two deaths (12.5%) over 65 years. The average loss of overweight over 65 years or less was 72% vs 68% (p=0.56). There was total control of the diabetes mellitus in 77% and partial in 23%, with no difference between groups. There was improvement in arterial hypertension in 56% of patients, also no difference between groups. The average LDL levels did not differ between the pre and postoperative (106 mg/dl to 102 mg/dl), an increase of HDL (56 mg/dl to 68 mg/dL) and reduced triglyceride levels (136 mg/dl to 109 mg/dl). There was no statistical difference in the variation of the cholesterol fractions and triglycerides between the groups. Two patients in the group with less than 65 years died in late follow-up, of brain tumor and pneumonia, three and five years after bariatric surgery, respectively. CONCLUSIONS: Surgical morbidity and mortality were higher in patients over 65 years, and this group had the same benefits observed in patients lower 65 years for weight loss and comorbidities control. PMID- 26537267 TI - EXTERNAL VALIDATION OF THE DIAREM SCORE AS REMISSION PREDICTOR OF DIABETES MELLITUS TYPE 2 IN OBESE PATIENTS UNDERGOING ROUX-EN-Y GASTRIC BYPASS. AB - BACKGROUND: DiaRem score consists in preoperative model for predicting remission of type 2 diabetes mellitus in obese patients who underwent gastric bypass. AIM: To evaluate the applicability of DiaRem comparing the scores obtained preoperatively with remission of T2DM after surgery. METHOD: Preoperative parameters such as age, use of insulin, oral hypoglycemic agents and glycated hemoglobin, were retrospectively evaluated in diabetic patients undergoing gastric bypass during the period between July 2012 to July 2013. Through these data the DiaRem score were applied. The results of fasting blood glucose and glycated hemoglobin were requested prospectively. RESULTS: Were selected 70 patients; the remission of T2DM after surgery was found in 42 (60%) and no remission in 28 (40%). Checking the final score, it was observed that: from 0 to 2 points, 94.1% of patients remitted completely; between 3 and 7 had remission in 68.9%, of which 42.8% complete; from 8 to 12, 57.1% achieved complete remission; between 13 to 17, 87.5% did not achieve remission and was not seen this complete remission group; between 18 to 22, 88.9% were not remitted. CONCLUSION: The DiaRem score showed appropriate tool to assess remission of T2DM in obese patients who will undergo gastric bypass. PMID- 26537268 TI - VOCAL COMPLAINT, AUDITORY-PERCEPTUAL ASSESSMENT OF VOICE AND VOCAL SELF ASSESSMENT IN WOMEN WITH MORBID OBESITY. AB - BACKGROUND: Obese people often have altered breathing patterns and therefore may experience difficulties in voice production. AIM: To verify the presence of vocal complaints and the correlation between the auditory-perceptual analysis of voice and vocal self-assessment of a group of women with morbid obesity before and after bariatric surgery. METHODS: A longitudinal, exploratory, descriptive study of 21 morbidly obese women aged between 28 and 68 years, assessed before and after bariatric surgery, was performed. The women filled out a form containing identification data and type of vocal complaint. Perceptual evaluation of voice and vocal self-assessment were performed using a visual analog scale. For perceptual assessment of voice the women were asked to say three sentences from the Consensus Auditory-Perceptual Evaluation of Voice. RESULTS: Of the 21 patients, 14 (66.6%) reported vocal complaints, of which 10 (71%) vocal fatigue, eight (57.14%) voice failures and seven (50%) vocal effort. All participants reported improvements in the voice after surgery, irrespective of having reported vocal complaints before surgery. There was no correlation between vocal self assessment and auditory-perceptual assessment of the voice before or after the procedure. There was no correlation between vocal self-assessment and perceptual evaluation of the voice before surgery. CONCLUSION: Obesity interfered with voice production and influenced negative perception and therefore vocal complaints. Complaints about vocal production cannot be perceived by a speech therapist with the same impact as by patients, as both employ different criteria for vocal evaluation. Vocal self-assessment is an important tool in voice evaluation. PMID- 26537269 TI - GLYCEMIC BEHAVIOR IN 48 HOURS POSTOPERATIVE PERIOD OF PATIENTS WITH TYPE 2 DIABETES MELLITUS AND NON DIABETIC SUBMITTED TO BARIATRIC SURGERY. AB - Although there is no indication for surgery taking only into account the glycemic condition, results have shown that benefits can be obtained in glycemic control with bariatric surgery. AIM: To compare the glycemic behavior among type 2 diabetic and non-diabetic patients within 48 h after bariatric surgery, and clarify whether there is a reduction in blood glucose level in obese patients with diabetes before the loss of weight excess. METHODS: Descriptive epidemiological study with prospective cohort design with 31 obese patients undergoing Roux-en-Y gastric bypass and sleeve gastrectomy. The patients were controlled with hemoglucotests in different periods of time: preoperative, postoperative and each 6 h after surgery for 48 h. RESULTS: Average ambulatory blood glucose in diabetics was 120.7+/-2.9 mg/dl vs 91.8+/-13.9 mg/dl in the nondiabetic. After 48 h there was decrease in diabetics to 100.0+/-17.0 mg/dl (p=0.003), while the non-diabetic group did not change significantly (102.7+/ 25.4 mg/dl; p=0.097). There were no differences between the surgical techniques. There were no death. CONCLUSIONS: Diabetic patients significantly reduced blood glucose after surgery regardless of the use of exogenous insulin or oral hypoglycemic agents. PMID- 26537270 TI - Obesity prevalence and metabolic syndrome in a park users. AB - Background -Overweight and obesity are associated with metabolic syndrome and abdominal obesity, thereby increasing the risk of type 2 diabetes mellitus and cardiovascular diseases. In Brazil, there are still no precise data on the prevalence of these disorders, especially among individuals who carry out some kind of physical activity in public spaces and there are no education and prevention programs for obesity. AIM: To investigate the prevalence of metabolic syndrome and obesity among park users. METHODS: A prospective, cross-sectional, descriptive study was conducted with 619 individuals assessed and stratified by profile according to a specific protocol. The group was characterized as follows: female (50.1%) and mean age =50.6+/-14.8, with predominance of individuals aged between 50 and 59 years (26.8%) and with higher education (68%) and a household income of between 4 and 10 minimum wages (29.2%). RESULTS: Regular physical exercise was reported by 78% of the individuals and it was found that 70.7% were nevertheless of above normal weight: 45% overweight and 25.7% obese, of whom 20.7% had obesity grade I, 3.9% grade II and 1.1% grade III. The prevalence of metabolic syndrome was 4.3%, mostly in men (6.3%). Arterial hypertension and type 2 diabetes mellitus were detected in 17.8% and 5.5%, respectively. In view of the influence of obesity on the occurrence of type 2 diabetes mellitus and metabolic syndrome, it was found that this association was not significant for the two conditions (p=0.014 and 0.017, respectively). CONCLUSION: The findings demonstrate a high prevalence of overweight and obesity in the studied population, and metabolic syndrome in 4.3%, despite the fact that 70% reported engaging in regular physical activity. PMID- 26537271 TI - ENDOSCOPIC CHANGES RELATED TO GASTROESOPHAGEAL REFLUX DISEASE: COMPARATIVE STUDY AMONG BARIATRIC SURGERY PATIENTS. AB - BACKGROUND: Obesity is correlated with several comorbidities, including gastroesophageal reflux disease. Its main complications are detectable by endoscopy: erosive esophagitis and Barrett's esophagus. AIM: To correlate erosive esophagitis and hiatal hernia with the degree of body mass index (BMI). METHOD: Was performed a retrospective analysis of 717 preoperative endoscopic reports of bariatric patients. Fifty-six (8%) presented hiatal hernia, being 44 small, nine medium and five large. Esophagitis was classified by Los Angeles classification. RESULTS: There was no correlation between the presence and dimension of hiatal hernia with BMI. One hundred thirty-four (18.7%) patients presented erosive esophagitis. Among them, 104 (14.5%) had esophagitis grade A; 25 (3.5%) grade B; and five (0.7%) grade C. When considering only the patients with erosive esophagitis, 77.6% had esophagitis grade A, 18.7% grade B and 3.7% grade C. Were identified only two patients with Barrett's esophagus (0,28%). CONCLUSION: There was a positive correlation between the degree of esophagitis with increasing BMI. PMID- 26537272 TI - EVALUATION OF UPPER GASTROINTESTINAL ENDOSCOPY IN PATIENTS UNDERGOING BARIATRIC SURGERY. AB - BACKGROUND: Obesity has become epidemic, and is associated with greater morbidity and mortality. Treatment is multidisciplinary. Surgical treatment is a consistent resource in severe obesity. The indication of preoperative upper gastrointestinal endoscopy in asymptomatic patients is controversial; however, most studies recommend its implementation in all patients. AIM: To analyze endoscopic performance in patients who were in preoperative for bariatric surgery and compare them with control group. METHOD: A series of 35 obese patients in preoperative period for bariatric surgery compared with a control group of 30 patients submitted to upper endoscopy. There were analyzed clinical and endoscopic data. RESULTS: The mean age of the group of patients was 43.54 years. Most individuals in the group of patients were female with median BMI of 47.26 kg/m2 and in control group 24.21 kg/m2. The majority of patients were asymptomatic. Upper endoscopy was altered in 81.25% of asymptomatic patients. Endoscopic findings in the patient group were 57.1% resulting from peptic ulcer disease and 34.3% associated with GERD. The analysis of endoscopic findings in patients showed no significant difference in relation of the control group. The prevalence of H. pylori infection was 60% in patients. CONCLUSION: It is recommended that the upper endoscopy should be made in all patients in the preoperative bariatric surgery period, although the degree of obesity is not related to a greater number of endoscopic findings. Obese patients do not have more endoscopic findings that non-obese individuals. PMID- 26537273 TI - SECONDARY HYPERPARATHYROIDISM AFTER BARIATRIC SURGERY: TREATMENT IS WITH CALCIUM CARBONATE OR CALCIUM CITRATE? AB - BACKGROUND: Bariatric surgery, especially Roux-en-Y gastric bypass, can cause serious nutritional complications arising from poor absorption of essential nutrients. Secondary hyperparathyroidism is one such complications that leads to increased parathyroid hormone levels due to a decrease in calcium and vitamin D, which may compromise bone health. AIM: To compare calcium carbonate and calcium citrate in the treatment of secondary hyperparathyroidism. METHOD: Patients were selected on the basis of their abnormal biochemical test and treatment was randomly done with citrate or calcium carbonate. RESULTS: After 60 days of supplementation, biochemical tests were repeated, showing improvement in both groups. CONCLUSION: Supplementation with calcium (citrate or carbonate) and vitamin D is recommended after surgery for prevention of secondary hyperparathyroidism. PMID- 26537274 TI - THE USE OF THE INTERNET BY THE PATIENT AFTER BARIATRIC SURGERY: CONTRIBUTIONS AND OBSTACLES FOR THE FOLLOW-UP OF MULTIDISCIPLINARY MONITORING. AB - BACKGROUND: Bariatric surgery is presented as the last treatment option for obesity. It requires from all candidates a multidisciplinary evaluation and monitoring throughout treatment. The non-adherence to follow-up with health care teams is related to weight regain. It's possible that the use of internet influences the doctor-patient relationship and patients replace medical care or information provided by health professionals for information from the internet. AIM: Identify and analyze the pattern of internet use by patients after bariatric surgery and check the influence of such use in attending medical appointments with the multidisciplinary team. METHOD: Electronic questionnaire available on the Internet was used to verify patient's patterns of Internet use and its influence on in attending multidisciplinary care after surgery. RESULTS: Of the 103 participants, 95% were female, 64% married, 59% with children and 54% with higher education. The mean age was 35.69 years and the mean duration of performing surgery, 11.74 months. The surgical technique that prevailed was Roux en-Y gastric by-pass (90.3%), the local monitoring concentrated in the private care (93.2%). In the preoperative, most participants consulted more than three times with the surgeon (n=81), nutritionists (n=70), psychologist (n=70). After the surgery, p most patients maintained monitoring with the surgeon and nutritionist. Concerning the internet use, 51.5% accessed the internet in search of information about health and bariatric surgery every day. Facebook and search tools were the most used sites.Conclusion - Data showed the influence of the information contained on the Internet and the adherence to multidisciplinary monitoring. This fact requires the team to consider the use of the Internet as a variable that may interfere and must be handled during follow-up. It is suggested that an active participation of professionals on their websites and social networks and the diversification of services and interventions to stimulate follow-up after surgery. PMID- 26537275 TI - BINGE EATING DISORDER AND QUALITY OF LIFE OF CANDIDATES TO BARIATRIC SURGERY. AB - BACKGROUND: Obesity decreases the quality of life, which is aggravated by the association of comorbidities, and the binge eating disorder is directly related to body image and predisposes to overweight. AIM: Evaluate association between the presence and the level of binge eating disorder and the quality of life of the obese candidates for bariatric surgery. METHODS: Cross-sectional study analyzing anthropometric data (weight and height) and socioeconomics (age, sex, marital status, education and income). The application of Binge Eating Scale was held for diagnosis of Binge Eating Disorder and the Medical Outcomes Study 36 item Short-From Health Survey to assess the quality of life. RESULTS: Total sample studied was 96 patients, mean age 38.15+/-9.6 years, 80.2% female, 67.7% married, 41% with complete and incomplete higher education, 77.1% with lower income or equal to four the minimum salary, 59.3% with grade III obesity. Binge eating disorder was observed in 44.2% of patients (29.9% moderate and 14.3% severe), and these had the worst scores in all domains of quality of life SF36 scale; however, this difference was not statistically significant. Only the nutritional status presented significant statistically association with the presence of binge eating disorder. CONCLUSION: High prevalence of patients with binge eating disorder was found and they presented the worst scores in all domains of quality of life. PMID- 26537276 TI - CLINICAL AND NUTRITIONAL ASPECTS IN OBESE WOMEN DURING THE FIRST YEAR AFTER ROUX EN-Y GASTRIC BYPASS. AB - BACKGROUND: Clinic care for morbid obesity is not very effective. Bariatric surgery is being considered the best way of intervention for this kind of obesity. AIM: Evaluate the clinical and nutritional evolution during the first year of obese women submitted to Roux-en-Y gastric bypass. METHOD: Retrospective series non-concurrent with 61 women. The variables were weight, BMI, weight loss percentage, loss of excessive weight percentage, waist circumference, hip circumference, lipid profile, daily use of supplements, practice of physical exercise, occurrence of sickness, nausea, constipation, diarrhea, asthenia, alopecia, dry skin, cramps and brittle nails. RESULTS: They presented significant weight and IMC reduction as well as improvement in their lipid profile, in all consultations. After one year they presented 36,6% loss of the initial weight and 75% loss of excessive weight. The waist circumference also presented a considerable reduction on all the moments, decreasing from 122,1+/-13,4 cm to 94,1+/-10,6 cm. Regarding the intercurrences, the most frequent were alopecia, asthenia, dry skin and cramps. CONCLUSION: The Roux-en-Y gastric bypass was effective in promoting and maintenance weight loss during the period of the first postoperative year. PMID- 26537277 TI - MEDIUM-TERM FOLLOW-UP RESULTS WITH LAPAROSCOPIC SLEEVE GASTRECTOMY. AB - BACKGROUND: The indications for sleeve gastrectomy in the surgical treatment of morbid obesity have increased worldwide. Despite this, several aspects related to results at medium and long term remain in constant research. AIM: To present the experience of sleeve gastrectomy in a center of excellence in bariatric surgery by analyzing clinical outcomes, complications and follow-up in the medium term. METHODS: The study included 120 morbidly obese patients who underwent sleeve gastrectomy and who were followed for at least 24 months. Aspects related to surgical technique, surgical complications and clinical outcome were analyzed. RESULTS: Seventy-five patients were women (62.5%) and the average age was 36 years. The body mass index preoperatively ranged from 35.5 to 58 kg/m2(average of 40.2 kg/m2). The length of stay ranged from 1 to 4 days (mean 2.1 days). Comorbidities observed were hypertension (19%), type 2 diabetes mellitus (6.6%), dyslipidemia (7.5%), sleep apnea (16.6%), reflux esophagitis (10%) and orthopedic diseases (7.5%). The mean body mass index and total weight loss percentage with 3, 12, 18 and 24 months were 32.2 kg/m2-19,9%; 29.5 kg/m2-26,5%; 28.2 kg/m2-30,3% and 26.9 kg/m2-32,7%, respectively. Remission of diabetes and dyslipidemia occurred in all patients. In relation to hypertension, there was improvement or remission in 86%. There were only two complications (bronchial pneumonia and dehydration), with good response to clinical treatment. There was no evidence digestive fistula and mortality was zero. Eleven patients (9.1%) had regained weighing more than 5 kg. CONCLUSION: The sleeve gastrectomy is surgical technique that has proven safe and effective in the surgical treatment of obesity and control of their comorbidities in postoperative follow-up for two years. PMID- 26537278 TI - TECHNICAL ASPECTS OF LAPAROSCOPIC SLEEVE GASTRECTOMY. AB - BACKGROUND: The vertical gastrectomy indications for surgical treatment of morbid obesity have increased worldwide. Despite this increase, many aspects of surgical technique still remains in controversy. AIM: To contribute presenting surgical details in order to better realize the vertical gastrectomy technique in bariatric surgery. METHODS: Technical systematization, patient preparation, positioning of the trocars, operative technique and postoperative care are presented in details. RESULTS: During 12 months were enrolled 120 patients undergoing GV according to the technique described herein. The results are published in another ABCD article (ABCD 2015;28(Supl.1):61-64) in this same volume and number. CONCLUSION: The surgical technique proposed here presented itself viable and facilitating the surgeon's work on difficult points of the vertical gastrectomy. PMID- 26537279 TI - FIXING JEJUNAL MANEUVER TO PREVENT PETERSEN HERNIA IN GASTRIC BYPASS. AB - BACKGROUND: Among Roux-en-Y gastric bypass complications is the occurrence of intestinal obstruction by the appearance of internal hernias, which may occur in Petersen space or the opening in mesenteric enteroenteroanastomosis. AIM: To evaluate the efficiency and safety in performing a fixing jejunal maneuver in the transverse mesocolon to prevent internal hernia formation in Petersen space. METHOD: Two surgical points between the jejunum and the transverse mesocolon, being 5 cm and 10 cm from duodenojejunal angle are made. In all patients was left Petersen space open and closing the opening of the mesenteric enteroenteroanastomosis. RESULTS: Among 52 operated patients, 35 were women (67.3%). The age ranged 18-63 years, mean 39.2 years. BMI ranged from 35 to 56 kg/m2 (mean 40.5 kg/m2). Mean follow-up was 15.1 months (12-18 months). The operative time ranged from 68-138 min. There were no intraoperative complications, and there were no major postoperative complications and no reoperations. The hospital stay ranged from 2-3 days. During the follow-up, no one patient developed suspect clinical presentation of internal hernia. Follow-up in nine patients (17.3%) showed asymptomatic cholelithiasis and underwent elective laparoscopic cholecystectomy. During these procedures were verified the Petersen space and jejunal fixation. In all nine, there was no herniation of the jejunum to the right side in Petersen space. CONCLUSION: The fixation of the first part of the jejunum to left side of the transverse mesocolon is safe and effective to prevent internal Petersen hernia in RYGB postoperatively in the short and medium term. It may be interesting alternative to closing the Petersen space. PMID- 26537280 TI - BAROS METHOD CRITICAL ANALYSIS(BARIATRIC ANALYSIS AND REPORTING SYSTEM). AB - INTRODUCTION: Although it has received several criticisms, which is considered to be the most effective method used for global assessment of morbid obesity surgical treatment, still needs to be updated. OBJECTIVE: Critical analysis of BAROS constitution and method. METHOD: BAROS as headings was searched in literature review using data from the main bariatric surgery journals until 2009. RESULTS: Where found and assessed 121 papers containing criticisms on BAROS constitution and methodology. It has some failures and few researches show results on the use of this instrument, although it is still considered a standard method. Several authors that used it found imperfections in its methodology and suggested some changes addressed to improving its acceptance, showing the need of developing new methods to qualify the bariatric surgery results. CONCLUSION: BAROS constitution has failures and its methodology needs to be updated. PMID- 26537281 TI - ANALYSIS OF FOOD TOLERANCE IN PATIENTS SUBMITTED TO BARIATRIC SURGERY USING THE QUESTIONNAIRE QUALITY OF ALIMENTATION. AB - BACKGROUND: Due to the increased prevalence of obesity in many countries, the number of bariatric surgeries is increasing. They are considered the most effective treatment for obesity. In the postoperative there may be difficulties with the quality of alimentation, tolerance to various types of food, as well as vomiting and regurgitation. Few surveys are available to assess these difficulties in the postoperative. AIM: To perform a systematic literature review about food tolerance in patients undergoing bariatric surgery using the questionnaire "Quality of Alimentation", and compare the results between different techniques. METHOD: A descriptive-exploratory study where the portals Medline and Scielo were used. The following headings were used in english, spanish and portuguese: quality of alimentation, bariatric surgery and food tolerance. A total of 88 references were found, 14 used the questionnaire "Quality of Alimentation" and were selected. RESULTS: In total, 2745 patients were interviewed of which 371 underwent to gastric banding, 1006 to sleeve gastrectomy, 1113 to Roux-en-Y gastric bypass, 14 to biliopancreatic diversion associated with duodenal switch, 83 were non-operated obese, and 158 non-obese patients. The questionnaire showed good acceptability. The biliopancreatic diversion with duodenal switch had the best food tolerance in the postoperative when compared to other techniques, but it was evaluated in a single article with a small sample. The longer the time after the operation, the better is the food tolerance. Comparing the sleeve gastrectomy and the Roux-en-Y gastric bypass, there are still controversial results in the literature. The gastric banding had the worst score of food tolerance among all the techniques evaluated. CONCLUSION: The questionnaire is easy and fast to assess the food tolerance in patients after bariatric surgery. Biliopancreatic diversion with duodenal switch had the best food tolerance in the postoperative when compared to sleeve gastrectomy and the Roux-en-Y gastric bypass. Gastric banding still remains in controversy, due it presented the worst score. PMID- 26537282 TI - WHEN AND WHY OPERATE ELDERLY OBESE. AB - INTRODUCTION: Concurrently with the pandemic obesity is observed global aging phenomenon, with a significant increase of obesity in the elderly population. AIM: To review the indications for bariatric surgery for the elderly, mainly focusing on the morbidity and mortality of procedures. METHOD: Review of the literature in PubMed/Medline and Scielo focusing on the relationship of risk factors with different techniques of bariatric surgery in the elderly. The following descriptors were crossed in the form of AND/OR: Obesity; Bariatric surgery; Complications; Elderly. CONCLUSION: In people older than 60 years bariatric procedures represent acceptable and effective treatment option. The elderly should be treated in specialized centers with experience in major surgical procedures and low morbimortality. Going in this way, they experience the benefits of bariatric surgery with acceptable morbidity and mortality. However, age alone should not be considered as an absolute impediment for surgical indication. PMID- 26537283 TI - SPEECH, HEARING AND LANGUAGE SCIENCES THERAPY IN BARIATRIC SURGERY OF THE ELDERLY: CASE REPORT. PMID- 26537284 TI - CUSHING'S SYNDROME CAUSED BY AN ADRENOCORTICAL CARCINOMA AFTER A BARIATRIC SURGERY: CASE REPORT. PMID- 26537285 TI - Parent and trisubstituted triazacoronenes: synthesis, crystal structure and physicochemical properties. AB - A four-step synthesis of the C3-symmetric parent 1,5,9-triazacoronene (TAC) and its derivatives was achieved using a three-fold Bischler-Napieralski cyclization as the key step. The single-crystal X-ray diffraction of 1b (R = n-Bu) demonstrates that the azacoronene core is perfectly co-planar and the molecules adopt a favorable 2-D "brick-wall" arrangement with strong pi-pi interactions. The unique stacking, tunable photophysical and electronic properties, and high thermal stability should make them promising candidates for emissive and electron transport materials. PMID- 26537286 TI - A simple method for determining split renal function from dynamic (99m)Tc-MAG3 scintigraphic data. AB - PURPOSE: Commonly used methods for determining split renal function (SRF) from dynamic scintigraphic data require extrarenal background subtraction and additional correction for intrarenal vascular activity. The use of these additional regions of interest (ROIs) can produce inaccurate results and be challenging, e.g. if the heart is out of the camera field of view. The purpose of this study was to evaluate a new method for determining SRF called the blood pool compensation (BPC) technique, which is simple to implement, does not require extrarenal background correction and intrinsically corrects for intrarenal vascular activity. METHODS: In the BPC method SRF is derived from a parametric plot of the curves generated by one blood-pool and two renal ROIs. Data from 107 patients who underwent (99m)Tc-MAG3 scintigraphy were used to determine SRF values. Values calculated using the BPC method were compared to those obtained with the integral (IN) and Patlak-Rutland (PR) techniques using Bland-Altman plotting and Passing-Bablok regression. The interobserver variability of the BPC technique was also assessed for two observers. RESULTS: The SRF values obtained with the BPC method did not differ significantly from those obtained with the PR method and showed no consistent bias, while SRF values obtained with the IN method showed significant differences with some bias in comparison to those obtained with either the PR or BPC method. No significant interobserver variability was found between two observers calculating SRF using the BPC method. CONCLUSION: The BPC method requires only three ROIs to produce reliable estimates of SRF, was simple to implement, and in this study yielded statistically equivalent results to the PR method with appreciable interobserver agreement. As such, it adds a new reliable method for quality control of monitoring relative kidney function. PMID- 26537287 TI - Multimodal imaging based on MRI and PET reveals [(18)F]FLT PET as a specific and early indicator of treatment efficacy in a preclinical model of recurrent glioblastoma. AB - PURPOSE: The primary objective of this study was to compare the ability of PET and MRI biomarkers to predict treatment efficacy in a preclinical model of recurrent glioblastoma multiforme. METHODS: MRI (anatomical, diffusion, vasculature and oxygenation) and PET ([(18)F]FDG and [(18)F]FLT) parameters were obtained 3 days after the end of treatment and compared with late tumour growth and survival. RESULTS: Early after tumour recurrence, no effect of treatment with temozolomide combined with bevacizumab was observed on tumour volume as assessed by T2-W MRI. At later times, the treatment decreased tumour volume and increased survival. Interestingly, at the earlier time, temozolomide + bevacizumab decreased [(18)F]FLT uptake, cerebral blood volume and oedema. [(18)F]FLT uptake, oedema and cerebral blood volume were correlated with overall survival but [(18)F]FLT uptake had the highest specificity and sensitivity for the early prediction of treatment efficacy. CONCLUSION: The present investigation in a preclinical model of glioblastoma recurrence underscores the importance of multimodal imaging in the assessment of oedema, tumour vascular status and cell proliferation. Finally, [(18)F]FLT holds the greatest promise for the early assessment of treatment efficacy. These findings may translate clinically in that individualized treatment for recurrent glioma could be prescribed for patients selected after PET/MRI examinations. PMID- 26537288 TI - Metal-Free Ammonia-Borane Dehydrogenation Catalyzed by a Bis(borane) Lewis Acid. AB - The storage of energy in a safe and environmentally benign way is one of the main challenges of today's society. Ammonia-borane (AB=NH3 BH3 ) has been proposed as a possible candidate for the chemical storage of hydrogen. However, the efficient release of hydrogen is still an active field of research. Herein, we present a metal-free bis(borane) Lewis acid catalyst that promotes the evolution of up to 2.5 equivalents of H2 per AB molecule. The catalyst can be reused multiple times without loss of activity. The moderate temperature of 60 degrees C allows for controlling the supply of H2 on demand simply by heating and cooling. Mechanistic studies give preliminary insights into the kinetics and mechanism of the catalytic reaction. PMID- 26537289 TI - Homogeneous fluorescent specific PCR for the authentication of medicinal snakes using cationic conjugated polymers. AB - A label-free, homogenous and sensitive one-step method for the molecular authentication of medicinal snakes has been developed by combining a rapid PCR technique with water-soluble cationic conjugated polyelectrolytes (CCPs). Three medicinal snake materials (Deinagkistrodon acutus, Zaocys dhumnades and Bungarus multicinctus; a total of 35 specimens) and 48 snake specimens with similar morphologies and textures were clearly distinguished by the naked eye by utilizing a CCP-based assay in a high-throughput manner. The identification of medicinal snakes in patented Chinese drugs was successfully performed using this detection system. In contrast to previous fluorescence-labeled oligonucleotide detection and direct DNA stain hybridization assays, this method does not require designing dye-labeled primers, and unfavorable dimer fluorescence is avoided in this homogenous method. PMID- 26537290 TI - Formal synthesis of (-)-podophyllotoxin through the photocyclization of an axially chiral 3,4-bisbenzylidene succinate amide ester--a flow photochemistry approach. AB - We have developed a strategy for the stereoselective synthesis of cyclolignans related to podophyllotoxin and its derivatives. The crucial step of the synthesis is the photocyclization of a chiral atropoisomeric 1,2-bisbenzylidenesuccinate amide ester, which can be prepared from suitable aromatic aldehydes, diethyl succinate and l-prolinol. The photocyclization was found to be more efficient when irradiation was performed in a home-built continuous flow photochemical reactor. The in-flow irradiation also allowed us to perform the reaction on a multigram scale. The chiral auxiliary was removed by reductive cleavage with the Schwartz's reagent to give the cytotoxic 1R,2R-cis-podophyllic aldehyde, which in turn could be easily reduced to the corresponding alcohol, completing the formal synthesis of (-)-podophyllotoxin. PMID- 26537291 TI - Computer-assisted surgery and intraoral welding technique for immediate implant supported rehabilitation of the edentulous maxilla: case report and technical description. AB - BACKGROUND: Complications are frequently reported when combining computer assisted flapless surgery with an immediate loaded prefabricated prosthesis. The authors have combined computer-assisted surgery with the intraoral welding technique to obtain a precise passive fit of the immediate loading prosthesis. METHODS: An edentulous maxilla was rehabilitated with four computer assisted implants welded together intraorally and immediately loaded with a provisional restoration. RESULTS: A perfect passive fit of the metal framework was obtained that enabled proper osseointegration of implants. Computer assisted preoperative planning has been shown to be effective in reducing the intraoperative time of the intraoral welding technique. No complications were observed at 1 year follow up. CONCLUSIONS: This guided-welded approach is useful to achieve a passive fit of the provisional prosthesis on the inserted implants the same day as the surgery, reducing intraoperative time with respect to the traditional intraoral welding technique. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26537292 TI - Treatment strategies for coronary in-stent restenosis: systematic review and hierarchical Bayesian network meta-analysis of 24 randomised trials and 4880 patients. AB - STUDY QUESTION: What is the most safe and effective interventional treatment for coronary in-stent restenosis? METHODS: In a hierarchical Bayesian network meta analysis, PubMed, Embase, Scopus, Cochrane Library, Web of Science, ScienceDirect, and major scientific websites were screened up to 10 August 2015. Randomised controlled trials of patients with any type of coronary in-stent restenosis (either of bare metal stents or drug eluting stents; and either first or recurrent instances) were included. Trials including multiple treatments at the same time in the same group or comparing variants of the same intervention were excluded. Primary endpoints were target lesion revascularisation and late lumen loss, both at six to 12 months. The main analysis was complemented by network subanalyses, standard pairwise comparisons, and subgroup and sensitivity analyses. STUDY ANSWER AND LIMITATIONS: Twenty four trials (4880 patients), including seven interventional treatments, were identified. Compared with plain balloons, bare metal stents, brachytherapy, rotational atherectomy, and cutting balloons, drug coated balloons and drug eluting stents were associated with a reduced risk of target lesion revascularisation and major adverse cardiac events, and with reduced late lumen loss. Treatment ranking indicated that drug eluting stents had the highest probability (61.4%) of being the most effective for target lesion vascularisation; drug coated balloons were similarly indicated as the most effective treatment for late lumen loss (probability 70.3%). The comparative efficacy of drug coated balloons and drug eluting stents was similar for target lesion revascularisation (summary odds ratio 1.10, 95% credible interval 0.59 to 2.01) and late lumen loss reduction (mean difference in minimum lumen diameter 0.04 mm, 95% credible interval -0.20 to 0.10). Risks of death, myocardial infarction, and stent thrombosis were comparable across all treatments, but these analyses were limited by a low number of events. Trials had heterogeneity regarding investigation periods, baseline characteristics, and endpoint reporting, with a lack of information at long term follow-up. Direct and indirect evidence was also inconsistent for the comparison between drug eluting stents and drug coated balloons. WHAT THIS STUDY ADDS: Compared with other currently available interventional treatments for coronary in-stent restenosis, drug coated balloons and drug eluting stents are associated with superior clinical and angiographic outcomes, with a similar comparative efficacy. FUNDING, COMPETING INTERESTS, DATA SHARING: This study received no external funding. The authors declare no competing interests. No additional data available. PMID- 26537293 TI - Caveat medicus: medication non-adherence in children and adolescents with epilepsy. PMID- 26537294 TI - Automated PCR detection of BRAF mutations in colorectal adenocarcinoma: a diagnostic test accuracy study. AB - BACKGROUND: Testing for BRAF mutations in colorectal carcinoma (CRC) is important in the screening pathway for Lynch syndrome and is of prognostic value to guide management. This is a diagnostic accuracy study of the Idylla system, a novel and automated alternative PCR system. METHODS: 100 consecutive formalin-fixed, paraffin-embedded CRC resection cases were tested for BRAF mutations using the Idylla automated platform and compared with standard (Cobas) PCR. RESULTS: The sensitivity of the Idylla BRAF test was 100% and the specificity was 96%. Only one discordant Idylla positive/standard PCR negative result occurred and on Droplet Digital PCR demonstrated a mutation not identified by traditional PCR in this case. CONCLUSION: This study has validated the Idylla system for BRAF testing in CRC and demonstrated a possibly greater sensitivity, in addition to cost effectiveness and shorter turnaround time, when compared with standard PCR. PMID- 26537295 TI - Information-sharing between healthcare professionals, parents and children with cancer: more than a matter of information exchange. AB - This study examined participants' views on children's participation in information-sharing and communication interactions. A descriptive qualitative approach was taken with individual interviews held with children (The term 'children' is used to denote both children and adolescents and to avoid cumbersome repetition.) aged 7-16 years (n = 20), their parents (n = 22) and healthcare professionals (n = 40) at a children's hospital in Ireland. Data were analysed using the constant comparative method and managed with NVivo (version 8). The findings indicate that professionals strongly supported an open and honest approach to information-sharing; however, this viewpoint was not shared by all parents. The need to maintain hope and spirit and promote an optimistic identity influenced the amount and type of information shared by parents. Children trusted their parents to share information, and valued their parents' role as interpreters of information, advocates, and communication buffers. Most professionals endorsed parents' primacy as managers of information but experienced difficulty navigating a restricted stance. This study adds important insights into the complexities of information-sharing in triadic encounters. Professionals need to maintain an open mind about information-sharing strategies families may choose, remain sensitive to parents and children's information requirements and adopt a flexible approach to information provision. PMID- 26537296 TI - The Allen's test: revisiting the importance of bidirectional testing to determine candidacy and design of radial forearm free flap harvest in the era of trans radial endovascular access procedures. AB - BACKGROUND: The radial forearm free flap is a workhorse free flap. The radial artery, which supplies it, is increasingly being used for endovascular access. A complication of this is radial artery occlusion. Although often asymptomatic it can compromise future free tissue transfer. CASE PRESENTATION: Two patients who underwent RFFF harvest for head and neck reconstruction are presented; both of who likely had distal radial artery occlusion. The first patient had failure of flap perfusion, presumed secondary to radial artery occlusion from prior endovascular access at the distal radial artery. In the second case, we used the Allen's test in reverse to identify the same scenario and successfully redesigned the harvest. CONCLUSION: The Allen's test is a simple bedside test that should be performed bidirectionally to exclude radial artery occlusion, which may compromise flap harvest. Radial artery occlusion will become increasingly common as the radial artery is used more frequently for endovascular access procedures. PMID- 26537297 TI - Optimal individualized dosing strategies: A pharmacologic approach to developing dynamic treatment regimens for continuous-valued treatments. AB - There have been considerable advances in the methodology for estimating dynamic treatment regimens, and for the design of sequential trials that can be used to collect unconfounded data to inform such regimens. However, relatively little attention has been paid to how such methodology could be used to advance understanding of optimal treatment strategies in a continuous dose setting, even though it is often the case that considerable patient heterogeneity in drug response along with a narrow therapeutic window may necessitate the tailoring of dosing over time. Such is the case with warfarin, a common oral anticoagulant. We propose novel, realistic simulation models based on pharmacokinetic pharmacodynamic properties of the drug that can be used to evaluate potentially optimal dosing strategies. Our results suggest that this methodology can lead to a dosing strategy that performs well both within and across populations with different pharmacokinetic characteristics, and may assist in the design of randomized trials by narrowing the list of potential dosing strategies to those which are most promising. PMID- 26537298 TI - Association between apolipoprotein B gene polymorphisms and the risk of coronary heart disease (CHD): an update meta-analysis. AB - OBJECTIVE: Polymorphisms in the apolipoprotein B (apoB) gene have been reported to be associated with coronary heart disease (CHD). However, the results on this topic are conflicting. The present study aims to derive a more precise estimation of the relationship between CHD and apoB genetic polymorphisms by meta-analysis. METHODS: We identified a total of 54 studies involving 7236, 10,912, and 14,102 individuals, respectively, for EcoRI, XbaI, and SpIns/Del polymorphisms by searching in PubMed, Web of Science, Google Scholar, the Cochrane Library, Wanfang Data, SinoMed, and CNKI. We utilized RevMan 5.0 software to perform the meta-analyses. RESULTS: A significant statistical association between apoB EcoRI polymorphism and CHD was observed under an allelic (p = 0.001, odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.12-1.57), dominant (p = 0.005, OR = 1.22, 95% CI = 1.06-1.40), and recessive (p = 0.04, OR = 1.33, 95% CI = 1.01-1.74) model. We also found similar association of apoB SpIns/Del polymorphism with CHD. However, we did not find association between apoB XbaI polymorphism and CHD. CONCLUSION: The current meta-analysis found an association of EcoRI polymorphism and SpIns/Del polymorphism with an increased risk of CHD. No significant association between apoB XbaI polymorphism and CHD we observed in the present study. PMID- 26537299 TI - SERPINE1 rs1799768 polymorphism contributes to sepsis risk and mortality. AB - INTRODUCTION: The present meta-analysis aimed to investigate whether there is an association between SERPINE1 rs1799768 polymorphism and sepsis risk and mortality. MATERIALS AND METHODS: Published reports were searched in PubMed, PubMed Central, Gene, PubChem and Google Scholar. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were assessed in a random-effects model. RESULTS: The results of the overall meta-analysis indicated that an increased sepsis risk was evidently associated with SERPINE1 rs1799768 polymorphism (OR = 1.30; 95% CI 1.08-1.56; p = 0.006). When studies were stratified by ethnicity, no significant association was observed between SERPINE1 rs1799768 polymorphism and sepsis risk in the Asian group. As for the Caucasian population, overall OR was 1.24 (95% CI 1.02-1.51; p = 0.03). The results of the overall meta-analysis indicated that an increased sepsis mortality risk was evidently associated with SERPINE1 rs1799768 polymorphism (OR = 1.73; 95% CI 1.31 2.28; p < 0.0001). When studies were stratified by ethnicity, significant association was observed between SERPINE1 rs1799768 polymorphism and sepsis risk mortality in the Asian group and the Caucasian population. CONCLUSIONS: In conclusion, the meta-analysis suggests that there are significant associations between SERPINE1 rs1799768 polymorphism and risk of sepsis and sepsis mortality. PMID- 26537300 TI - CellProfiler Tracer: exploring and validating high-throughput, time-lapse microscopy image data. AB - BACKGROUND: Time-lapse analysis of cellular images is an important and growing need in biology. Algorithms for cell tracking are widely available; what researchers have been missing is a single open-source software package to visualize standard tracking output (from software like CellProfiler) in a way that allows convenient assessment of track quality, especially for researchers tuning tracking parameters for high-content time-lapse experiments. This makes quality assessment and algorithm adjustment a substantial challenge, particularly when dealing with hundreds of time-lapse movies collected in a high-throughput manner. RESULTS: We present CellProfiler Tracer, a free and open-source tool that complements the object tracking functionality of the CellProfiler biological image analysis package. Tracer allows multi-parametric morphological data to be visualized on object tracks, providing visualizations that have already been validated within the scientific community for time-lapse experiments, and combining them with simple graph-based measures for highlighting possible tracking artifacts. CONCLUSIONS: CellProfiler Tracer is a useful, free tool for inspection and quality control of object tracking data, available from http://www.cellprofiler.org/tracer/. PMID- 26537301 TI - Varying responses of PML-RARA with different genetic mutations to arsenic trioxide. AB - Resistance to arsenic and/or all-trans retinoic acid (ATRA) is a challenging problem in the clinical management of acute promyelocytic leukemia (APL). Acquired genetic mutations in the PML moiety of the PML-RARA fusion gene are found in some patients with relapsed/refractory APL. Whether all of the identified point mutations play a role and have a similar function in the mechanisms of arsenic resistance remains unknown. Here we performed in vitro functional analyses and a retrospective analysis of APL patients to investigate the effect of PML-RARA mutations in mediating resistance to arsenic trioxide. Among the 5-point mutations in the PML part of PML-RARA identified in patients with relapsed APL, we found that A216V, S214L, and A216T mutations could attenuate the negative regulation of arsenic on PML-RARA, resulting in the retention of oncoproteins. In contrast, L217F and S220G mutations functioned weakly in this context. Furthermore, we demonstrated that either increasing the concentration of arsenic trioxide or combining it with ATRA could overcome the mutation-triggered arsenic resistance in vitro. In addition to presenting more evidence to reinforce the correlation of genetic mutations in PML-RARA with arsenic efficacy, we provide novel insight into the functional difference of acquired mutations of PML-RARA both in vitro and in the clinical setting. Our findings may help predict the prognosis and select more effective strategies during APL therapy. PMID- 26537302 TI - Anatomy of the red cell membrane skeleton: unanswered questions. AB - The red cell membrane skeleton is a pseudohexagonal meshwork of spectrin, actin, protein 4.1R, ankyrin, and actin-associated proteins that laminates the inner membrane surface and attaches to the overlying lipid bilayer via band 3 containing multiprotein complexes at the ankyrin- and actin-binding ends of spectrin. The membrane skeleton strengthens the lipid bilayer and endows the membrane with the durability and flexibility to survive in the circulation. In the 36 years since the first primitive model of the red cell skeleton was proposed, many additional proteins have been discovered, and their structures and interactions have been defined. However, almost nothing is known of the skeleton's physiology, and myriad questions about its structure remain, including questions concerning the structure of spectrin in situ, the way spectrin and other proteins bind to actin, how the membrane is assembled, the dynamics of the skeleton when the membrane is deformed or perturbed by parasites, the role lipids play, and variations in membrane structure in unique regions like lipid rafts. This knowledge is important because the red cell membrane skeleton is the model for spectrin-based membrane skeletons in all cells, and because defects in the red cell membrane skeleton underlie multiple hemolytic anemias. PMID- 26537303 TI - Ultrasonographic findings of low-grade endometrial stromal sarcoma of the uterus with a focus on cystic degeneration. AB - PURPOSE: The goal of this study was to perform a retrospective analysis of the ultrasonographic findings associated with low-grade endometrial stromal sarcoma. METHODS: Ten pathologically confirmed cases of low-grade endometrial stromal sarcoma at our institution from January 2007 to April 2014 were retrospectively reviewed. All patients underwent a preoperative transvaginal ultrasound. Two radiologists came to a consensus regarding the location, size, margin, and echogenicity of the tumor, as well as the presence of intratumoral cystic degeneration and its extent and configuration. RESULTS: Low-grade endometrial stromal sarcoma manifested as an intramural mass protruding into the endometrial cavity (n=6) or as a purely intramural mass (n=4). The maximal diameter of the lesion ranged from 4 to 9.1 cm (mean, 6.2 cm). The imaging features of low-grade endometrial stromal sarcoma were variable: six cases involved predominantly solid masses containing cystic degeneration, one was a predominantly unilocular cystic mass, two were ill-defined infiltrative solid masses, and one was a well-defined solid mass. Among the seven cases with internal cystic degeneration, five patients showed a multiseptated cystic area or a cystic area with multiple small clusters, while a unilocular cystic area within the tumor was found in two patients. CONCLUSION: Low-grade endometrial stromal sarcoma is associated with variable ultrasonographic findings with regard to the location, margin, and configuration of the lesion. Multiseptated cystic areas and multiple small areas of cystic degeneration are common. PMID- 26537304 TI - The current status of three-dimensional ultrasonography in gynaecology. AB - Ultrasonography (US) is the most recent cross-sectional imaging modality to acquire three-dimensional (3D) capabilities. The reconstruction of volumetric US data for multiplanar display took a significantly longer time to develop in comparison with computed tomography and magnetic resonance imaging. The current equipment for 3D-US is capable of producing high-resolution images in three different planes, including real-time surface-rendered images. The use of 3D-US in gynaecology was accelerated through the development of the endovaginal volume transducer, which allows the automated acquisition of volumetric US data. Although initially considered an adjunct to two-dimensional US, 3D-US is now the imaging modality of choice for the assessment of Mullerian duct anomalies and the location of intrauterine devices. PMID- 26537305 TI - Commentary: What is Aging? Can it be Eliminated? PMID- 26537307 TI - Conference Report: The Myriad Pathways of Neurodegeneration Discussed at NEUROCON 2015. PMID- 26537306 TI - The Effect of Aerobic Exercise on Quantity and Quality of Sleep Among Elderly People Referring to Health Centers of Lar City, Southern of Iran; A Randomized Controlled Clinical Trial. AB - BACKGROUND AND OBJECTIVES: Aging is associated with reduced quality and quantity of sleep. 50% of senior citizens living in the community and 70% of those living in nursing homes suffer from sleep disorders. Moreover, insomnia increases the risk of mortality and morbidity in older adults. We aimed to investigate the effect of aerobic exercise on quantity and quality of sleep among the elderly people referring to health centers of Lar city, southern Iran. METHODS AND PATIENTS: We enrolled 60 elderly people whose age range was 60-75 years and (mean +/-SD) age was (64.8+/-5.2). Participants were randomly assigned into two groups of 30 each (case group= 30 and control group=30). The patients in the case group participated in exercise trainings consisted of three one-hour sessions per week for 12 consecutive weeks. Sleep quantity and quantity in the participants was evaluated before and after intervention using Pittsburgh Sleep Quality Index (PSQI). RESULTS: Independent t-test showed that sleep quality score was improved by 44.46% in the case group (p<0.0001). Furthermore, sleep duration was improved by 98/16% (p=0.038) and sleep latency was improved by 76/6% in the case group; while, the difference between the two groups regarding the changes in the sleep latency was not statistically significant (p=0.089). CONCLUSION: Aerobic exercise program could improve the sleep quality and quantity in the elderly. It could also be used as a cost effective and long lasting method of therapy with no side effect which could be used for the treatment of insomnia in older people. PMID- 26537308 TI - Repetitive Transcranial Magnetic Stimulation (rTMS) Treatment in Enduring Anorexia Nervosa: A Case Series. AB - OBJECTIVES: This case series examined the therapeutic potential of repetitive transcranial magnetic stimulation in five women with enduring anorexia nervosa. METHODS: Participants received ~20 sessions of neuronavigated high-frequency repetitive transcranial magnetic stimulation to the left dorsolateral prefrontal cortex. Body mass index, eating disorder (ED) symptoms and mood were assessed pre treatment and post-treatment, at 6-month and 12-month follow-up (FU). Qualitative feedback regarding the intervention was obtained from participants and carers. RESULTS: From pre-treatment to post-treatment, ED and affective symptoms improved significantly, and body mass index remained stable. Further improvements in ED symptoms/mood were seen at 6-month FU with 3/5 and 2/5 participants deemed 'recovered' on the Eating Disorders Examination Questionnaire and Depression, Anxiety and Stress Scale, respectively. However, most participants had lost some weight, and therapeutic effects on psychopathology had waned by 12-month FU. Qualitative feedback regarding the intervention was encouraging. DISCUSSION: Repetitive transcranial magnetic stimulation was well tolerated, and preliminary evidence is provided for its therapeutic potential in anorexia nervosa. PMID- 26537309 TI - Carbamazepine-induced HLA-A*3101 associated hypersensitivity syndrome mimicking mycosis fungoides. PMID- 26537310 TI - Molecular basis of the structural stability of hemochromatosis factor E: A combined molecular dynamic simulation and GdmCl-induced denaturation study. AB - Hemochromatosis factor E (HFE) is a member of class I MHC family and plays a significant role in the iron homeostasis. Denaturation of HFE induced by guanidinium chloride (GdmCl) was measured by monitoring changes in [theta]222 (mean residue ellipticity at 222 nm), intrinsic fluorescence emission intensity at 346 nm (F346 ) and the difference absorption coefficient at 287 nm (Deltaepsilon287) at pH 8.0 and 25 degrees C. Coincidence of denaturation curves of these optical properties suggests that GdmCl-induced denaturation (native (N) state <-> denatured (D) state) is a two-state process. The GdmCl-induced denaturation was found reversible in the entire concentration range of the denaturant. All denaturation curves were analyzed for DeltaGD0, Gibbs free energy change associated with the denaturation equilibrium (N state <-> D state) in the absence of GdmCl, which is a measure of HFE stability. We further performed molecular dynamics simulation for 40 ns to see the effect of GdmCl on the structural stability of HFE. A well defined correlation was established between in vitro and in silico studies. PMID- 26537311 TI - New mechanisms that regulate Saccharomyces cerevisiae short peptide transporter achieve balanced intracellular amino acid concentrations. AB - The budding yeast Saccharomyces cerevisiae is able to take up large quantities of amino acids in the form of di- and tripeptides via a short peptide transporter, Ptr2p. It is known that PTR2 can be induced by certain peptides and amino acids, and the mechanisms governing this upregulation are understood at the molecular level. We describe two new opposing mechanisms of regulation that emphasize potential toxicity of amino acids: the first is upregulation of PTR2 in a population of cells, caused by amino acid secretion that accompanies peptide uptake; the second is loss of Ptr2p activity, due to transporter internalization following peptide uptake. Our findings emphasize the importance of proper amino acid balance in the cell and extend understanding of peptide import regulation in yeast. PMID- 26537312 TI - Reply to: Letter to the Editor: Re Srinivasa et al., International Journal of Surgery 2014. PMID- 26537313 TI - HMGA1/HMGA2 protein expression and prognostic implications in gastric cancer. AB - BACKGROUND: The high mobility group A1 (HMGA1) and high mobility group A2 (HMGA2) proteins are architectural transcription factors that have been implicated in the pathogenesis and progression of multiple malignant tumors, including gastric cancer. The aim of this study was to explore the roles of HMGA1 and HMGA2 in gastric carcinogenesis. METHODS: The expression of HMGA1 and HMGA2 was examined in 110 gastric adenocarcinomas, 29 gastric adenomas, and 30 normal controls. The results were correlated with the clinicopathological parameters of the tumors and patient outcome. RESULTS: The levels of HMGA1 and HMGA2 proteins were significantly increased in gastric cancer samples compared with adenoma and normal gastric tissues. High HMGA1 nuclear immunoreactivity was not correlated with clinicopathological features; however, high levels of HMGA2 protein were significantly associated with T stage, N stage, lymphatic invasion, perineural invasion, and TNM stage. Moreover, HMGA2 expression was significantly associated with shorter recurrence free survival. Multivariate analysis showed that HMGA2 expression was an independent prognostic factor for tumor recurrence. CONCLUSIONS: Our results suggest that HMGA1 and HMGA2 are implicated in gastric carcinogenesis and may play a role in tumor progression towards a more malignant phenotype. The HMGA2 protein may be a useful prognostic marker for predicting tumor recurrence. PMID- 26537314 TI - Angioembolization for solid organ injury: A brief review. AB - INTRODUCTION: Non-operative management is the standard of care for blunt solid organ injuries in stable patients. Angioembolization is an important technique that improves success rates of non-operative management. We aimed to provide a brief review of the indications, effectiveness and complications associated with angioembolization for solid organ injuries. METHODS: We conducted a literature search of the PubMed database using the terms "trauma", "angioembolization", and "solid organ embolization" limited to studies published in the English language. Abstracts and full text were manually reviewed to identify suitable articles. RESULTS: The current brief review is based on content from the more recently published articles related to angioembolization for solid organ injuries after trauma. DISCUSSION: Angioembolization is appropriate for hemodynamically stable patients with contrast extravasation on CT scan or high-grade injury to a solid organ. Non-operative management success rates have improved with the adoption of angioembolization. The complications associated with angioembolization are acceptable in the context of avoiding a laparotomy, and are often related to the severity of the injury. CONCLUSION: Angioembolization is a natural extension of the move towards non-operative management for solid organ injuries. Randomized controlled trials are required to fully characterize the indications and efficacy of its use. PMID- 26537315 TI - Does an Advanced Pelvic Simulation Curriculum Improve Resident Performance on a Pediatric and Adolescent Gynecology Focused Objective Structured Clinical Examination? A Cohort Study. AB - STUDY OBJECTIVE: To determine the effect of an advanced pelvic simulation curriculum on resident performance on a pediatric and adolescent gynecology (PAG) focused objective structured clinical examination (OSCE). DESIGN: Obstetrics and gynecology residents in a single academic Canadian center participated in a PAG simulation curriculum. An OSCE on prepubertal vaginal bleeding was administered at the biannual OSCE examination 2 months before the simulation curriculum and again 3 months after the simulation curriculum. SETTING: Academic half-day at the University of Ottawa Skills and Simulation Centre. PARTICIPANTS: Obstetrics and gynecology residents from the University of Ottawa. INTERVENTIONS: Participants completed 4 stations teaching PAG-appropriate history-taking, genital examination, Tanner staging, vaginal sampling and flushing, hymenectomy, vaginoscopy, laparoscopic adnexal detorsion, and approach to the child and/or adolescent. Advanced pelvic models were used for procedure-specific stations. MAIN OUTCOME MEASURES: The primary outcome measure was change in mean score on a prepubertal vaginal bleeding OSCE station. Secondary outcome measures were changes in individual component scores. RESULTS: Fourteen residents completed the simulation curriculum and the PAG OSCE at the 2 separate time points (before and after simulation curriculum). The mean OSCE score before the simulation curriculum was 54.6% (20.5 of 37) and mean score after the curriculum was 78.1% (28.9 of 37; P < .001). Significant score increases were found in history-taking, examination, differential diagnosis, identification of organism, surgical procedures, and identification of foreign body (P < .01 for all). CONCLUSION: This innovative PAG simulation curriculum significantly increased residents' knowledge in PAG history-taking, examination skills, operative procedures, and approach to the child and/or adolescent. Obstetrics and Gynecology Program Directors should consider incorporating PAG simulation training into their curriculum to ensure that residents meet their learning objectives and increase their knowledge and confidence, which will ultimately benefit patient care. PMID- 26537316 TI - Prevalence of Menstrual Problems among Adolescent School Girls in Rural Tamil Nadu. AB - STUDY OBJECTIVE: Adolescent girls face a gamut of problems of which the menstrual problems are the most common. Because menstrual problems are subtle, the problems often are unreported. The objective of this study was to estimate the prevalence of menstrual problems, namely dysmenorrhea, menorrhagia, and irregular menstrual cycles. DESIGN: Cross sectional study. SETTING: School-based study conducted in a rural school of the Thiruvallur district, Tamil Nadu. PARTICIPANTS: The participants were adolescent girls who attained menarche at least 1 year before the data collection period were selected using a simple random sampling method. A total of 350 participants were included in the study. INTERVENTIONS: No interventions were done. A structured, pretested questionnaire was used to collect data. MAIN OUTCOME MEASURES: The main outcome measured in this study was the prevalence of menstrual problems, namely dysmenorrhea, menorrhagia, and irregular menstrual cycles. RESULTS: The mean age of the study participants was 14.74 years. The mean age at menarche was 12.4 years. In this study, 87.7% of the girls suffered from a menstrual problem. Overall, dysmenorrhea was prevalent in 72.6%, and menorrhagia and irregular menstrual cycles were present among 45.7% and 31.7% of the participants, respectively. CONCLUSION: Menstrual problems form an important domain of adolescent health and because these problems go unreported, it is necessary that adequate attention and care is provided. The consequences of the neglect of menstrual problems results in impaired reproductive and sexual health in older women. PMID- 26537317 TI - Effect of the EndoBarrier Gastrointestinal Liner on obesity and type 2 diabetes: a systematic review and meta-analysis. AB - Compared with bariatric surgery, less invasive and reversible techniques to counteract obesity and type 2 diabetes (T2D) have been developed, including the EndoBarrier Gastrointestinal Liner [duodenal-jejunal bypass sleeve (DJBS)]. We conducted a systematic review and meta-analyses of eligible trials to evaluate the efficacy and safety of the DJBS. Five randomized controlled trials (RCTs; 235 subjects) and 10 observational studies (211 subjects) were included. The risk of bias was evaluated as high in all studies. The mean body mass index ranged from 30 to 49.2 kg/m(2) and 10-100% of the subjects had T2D. Meta-analysis showed that the DJBS was associated with significant mean differences in body weight and excess weight loss of -5.1 kg [95% confidence interval (CI) -7.3, -3.0; four trials; n = 151; I(2) = 37%] and 12.6% (95% CI 9.0, 16.2; four trials; n = 166; I(2) = 24%), respectively, compared with diet modification. The mean differences in glycated haemoglobin (-0.9%; 95% CI -1.8, 0.0) and fasting plasma glucose ( 3.7 mM; 95% CI -8.2, 0.8) among subjects with T2D did not reach statistical significance. Adverse events consisted mainly of abdominal pain, nausea and vomiting. No deaths occurred. Future high-quality long-term RCTs are needed to further assess efficacy and safety. PMID- 26537318 TI - The C-terminal Domain Supports a Novel Function for CETPI as a New Plasma Lipopolysaccharide-Binding Protein. AB - Described by our group a few years ago, the cholesteryl-ester transfer protein isoform (CETPI), exclusively expressed in the small intestine and present in human plasma, lacked a functional identification for a role of physiological relevance. Now, this study introduces CETPI as a new protein with the potential capability to recognise, bind and neutralise lipopolysaccharides (LPS). Peptides derived from the C-terminal domain of CETPI showed that CETPI not only might interact with several LPS serotypes but also might displace LPS bound to the surface of cells. Peptide VSAK, derived from the last 18 residues of CETPI, protected against the cytotoxic effect of LPS on macrophages. At high concentrations, when different cell types were tested in culture, it did not exhibit cytotoxicity by itself and it did prevent the expression of pro inflammatory cytokines as well as the generation of oxidative stress conditions. In a rabbit model of septic shock, the infusion of peptide VSAK exerted a protective effect against the effects of LPS and reduced the presence of tumor necrosis factor-alpha (TNFalpha) in plasma. Therefore, CETPI is proposed as a new protein with the capability to advance the possibilities for better understanding and treatment of the dangerous effects of LPS in vivo. PMID- 26537319 TI - Light-Tunable Generation of Singlet Oxygen and Nitric Oxide with a Bichromophoric Molecular Hybrid: a Bimodal Approach to Killing Cancer Cells. AB - The design, synthesis, photochemical properties, and biological evaluation of a novel photoactivatable bichromophoric conjugate are reported. The compound 1, [4 (4,4-difluoro-2,6-diiodo-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)-N (3-((4-nitro-3-(trifluoromethyl)phenyl)amino)propyl)butanamide] combines a 2,6 diiodo-1,3,5,7-tetramethyl BODIPY derivative as singlet oxygen ((1) O2 ) photosensitizer and 4-nitro-3-(trifluoromethyl)aniline (NOPD) as nitric oxide (NO) photodonor, joined by an alkyl spacer. These two chromogenic units absorb in distinct regions of the visible spectrum, and their individual photochemical properties are conserved in the molecular conjugate. Irradiation of the bichromophoric conjugate with green light afforded (1) O2 in high quantum yields, whereas (1) O2 production was negligible with the use of blue light; under this latter condition, NO was released. Photogeneration of NO and cytotoxic (1) O2 can therefore be regulated by appropriately tuning the excitation light wavelength and intensity. Tested on melanoma cancer cells, this resulted in amplified photomortality relative to that of a structurally correlated model compound 2 [4 (4,4-difluoro-2,6-diiodo-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)-N (3-(p-tolylamino)propyl)butanamide] deprived of the NO-release capacity. The cellular uptake of 1, evaluated by confocal fluorescence microscopy, showed that the product is localized in the cytoplasm. PMID- 26537320 TI - [The gut microbiota is a new organ in our body]. PMID- 26537321 TI - [Inflammatory bowel disease and the intestinal microbiota]. PMID- 26537322 TI - [Gut microbiota in irritable bowel syndrome]. PMID- 26537323 TI - [Gut microbiota and NASH]. PMID- 26537324 TI - [Fecal microbiota transplantation therapy for patients with gastrointestinal tract diseases]. PMID- 26537325 TI - [A case of chronic pancreatitis occurring in gastric aberrant pancreas poorly distinguishable from gastric aberrant pancreas ductal carcinoma]. AB - A man in his 40s was referred to our hospital with abdominal pain. A gastric submucosal tumor (SMT) was diagnosed nine years previously, but the patient was lost to follow-up. Upon our evaluation, the SMT had enlarged, as demonstrated by esophagogastroduodenoscopy and abdominal computed tomography. Endoscopic ultrasonography revealed a hypoechoic and isoechoic mosaic mass, which primarily occupied the third and fourth layers of the gastric wall. Aspiration cytodiagnosis was performed, the results of which led to a suspicion of adenocarcinoma arising from gastric ectopic pancreas. Next, we conducted segmental gastrectomy. Pathological examination showed adiponecrosis, a pancreatic stone, chronic inflammatory cell infiltration, and fibrosis. Thus, the patient was diagnosed with chronic pancreatitis occurring in a gastric aberrant pancreas. PMID- 26537326 TI - [Synchronous gastrointestinal stromal tumors of the rectum and duodenum: a case report]. AB - An 85-year-old woman with anemia underwent colonoscopy, which revealed a 25-mm submucosal tumor with ulceration in the lower rectum. Histological examination of a biopsy showed that the lesion was a gastrointestinal stromal tumor (GIST). Subsequent esophagogastroduodenoscopy revealed a submucosal tumor in the duodenum, and examination of a biopsy obtained by endoscopic ultrasound-guided fine-needle aspiration also confirmed that this lesion was a GIST. The rectal lesion was surgically resected to control bleeding and was confirmed as a GIST histologically. Simultaneous development of GISTs in the rectum and duodenum is extremely rare. PMID- 26537327 TI - [A case of ruptured duodenal varices successfully treated by combination therapy with endoscopic clipping and balloon-occluded retrograde transvenous obliteration]. AB - An 80-year-old woman with a history of chronic hepatitis B was referred to our hospital because of upper gastrointestinal bleeding of unknown origin. Dynamic computed tomography revealed liver cirrhosis and hepatofugal collateral vessels around the duodenum. Emergency esophagogastroduodenoscopy showed duodenal varices with an erosive spot, highly suggestive of a variceal rupture site. We immediately performed endoscopic clipping of the ruptured site to achieve temporary hemostasis. Ten days later, elective balloon-occluded retrograde transvenous obliteration (B-RTO) was performed to prevent recurrence. We describe a successfully treated case of duodenal variceal rupture managed by combination therapy with endoscopic clipping and B-RTO. PMID- 26537328 TI - [Neuroendocrine tumor of the terminal ileum observed by magnifying endoscopy with narrow-band imaging: a case report]. AB - We report the case of an 88-year-old woman with localized intestinal obstruction caused by a midgut neuroendocrine tumor (NET) without endocrine symptoms. She was referred to our hospital for lower abdominal pain. Abdominal enhanced computed tomography revealed a thickened wall in the terminal ileum with dilated small bowel and multiple hepatic metastases upstream. Although the presenting symptoms resolved with short-term fasting and defecation, we performed further investigation. Colonoscopy confirmed the presence of submucosal tumors in the terminal ileum with a yellow-discolored surface but without ulceration or erosion. Magnifying endoscopy with narrow-band imaging clearly showed extended and dilated vessels, with the existing vessels maintained under the epithelium. Biopsies from these lesions were immunohistochemically positive for all neuroendocrine markers, and the Ki-67 index was 10%. Therefore, the patient was diagnosed with NET, and she underwent laparoscopic surgery to relieve the intestinal obstruction. Pathological examination of the resected specimen confirmed grade 2 NET with intramural metastasis and dissemination. After follow up for a month, octreotide long-acting repeatable therapy was initiated and the patient was free of symptoms at the 6-month follow-up. This is the first report of midgut NET observed by magnifying endoscopy with narrow-band imaging. PMID- 26537329 TI - [Giant gastric neuroendocrine cell carcinoma with extraluminal growth and direct invasion: a case report]. AB - A 68-year-old man presented to our hospital requesting an operation for an anal prolapse. However, because of appetite loss and general malaise, we performed screening gastroscopy that revealed a huge ulcerative lesion in the greater curvature of the middle stomach. Biopsy showed a solid tumor with marked dyskaryosis that was positive for synaptophysin on immunohistochemical staining. Abdominal computed tomography revealed a tumor measuring larger than 20 cm in diameter in the greater curvature of the stomach and two hepatic metastases. A preoperative diagnosis of neuroendocrine cell carcinoma (NEC) was made and the patient underwent surgery. The lesion displayed extraluminal growth and directly infiltrated the ileum and colon. We therefore performed distal gastrectomy with combined resection of the gallbladder, ileum, transverse colon, and sigmoid colon. However, despite transcatheter arterial chemoembolization for the liver metastases, the patient died 1 year 2 months after the initial surgery. Gastric NECs are rare and have poor outcomes, being associated with rapid progression of lymph node and liver metastases. Moreover, they rarely show extraluminal growth or invasion to other organs. We present a report of this case along with a review of the literature. PMID- 26537330 TI - [Radical surgery after successful chemotherapy in a case of primary small cell carcinoma of the liver]. AB - A 52-year-old woman was admitted to our hospital with right upper quadrant pain with gallbladder wall thickening and multiple liver tumors. Endoscopic ultrasound guided biopsy revealed small cell carcinomas of both the gallbladder and liver. After 10 cycles of chemotherapy with etoposide and cisplatin, marked shrinkage of the tumors was evident on computed tomography. The patient subsequently underwent hepatectomy and resection of the extrahepatic bile duct and gallbladder with curative intent. Although no viable tumor cells were found in the resected specimens, we confirmed phagocytosis of tumor cells killed by chemotherapy in the resected liver specimen. Therefore, we suspected that the patient had primary small cell carcinoma of the liver that had been successfully treated. This is a rare case of primary small cell carcinoma of the liver that showed pathological complete response to chemotherapy with etoposide and cisplatin. PMID- 26537331 TI - Look before you leap: Visual navigation and terrestrial locomotion of the intertidal killifish Fundulus heteroclitus. AB - Mummichogs (Fundulus heteroclitus; Cyprinodontiformes) are intertidal killifish that can breathe air and locomote on land. Our goals were to characterize the terrestrial locomotion of mummichogs and determine their method of navigation towards water in a terrestrial environment. We used high-speed video to record behavior during stranding experiments and found that mummichogs use a tail-flip jump to move overland, similarly to other Cyprinodontiformes. However, mummichogs also prop themselves upright into a prone position between each jump, a previously undescribed behavior. After becoming prone, mummichogs rotate about their vertical axis, directing the caudal fin towards the water. Then, they roll back onto their lateral aspect and use a tail-flip behavior to leap into a caudally-directed, ballistic flight path. We conducted experiments to determine the sensory stimulus used to locate a body of water by placing mummichogs on a square platform with one side adjacent to a sea table. Under artificial light, mummichogs moved towards the sea table with a higher frequency than towards the other sides. Under dark conditions, mummichogs did not show a preference for moving towards the sea table. When the surface of the water was covered with reflective foil, mummichogs moved towards it as if it were a body of water. These results suggest that mummichogs primarily use visual cues, specifically reflected light, to orient towards the water. The uprighting behavior that mummichogs perform between terrestrial jumps may provide an opportunity for these fish to receive visual information that allows them to safely return to the water. J. Exp. Zool. 325A:57-64, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26537332 TI - Hierarchical atom type definitions and extensible all-atom force fields. AB - The extensibility of force field is a key to solve the missing parameter problem commonly found in force field applications. The extensibility of conventional force fields is traditionally managed in the parameterization procedure, which becomes impractical as the coverage of the force field increases above a threshold. A hierarchical atom-type definition (HAD) scheme is proposed to make extensible atom type definitions, which ensures that the force field developed based on the definitions are extensible. To demonstrate how HAD works and to prepare a foundation for future developments, two general force fields based on AMBER and DFF functional forms are parameterized for common organic molecules. The force field parameters are derived from the same set of quantum mechanical data and experimental liquid data using an automated parameterization tool, and validated by calculating molecular and liquid properties. The hydration free energies are calculated successfully by introducing a polarization scaling factor to the dispersion term between the solvent and solute molecules. (c) 2015 Wiley Periodicals, Inc. PMID- 26537333 TI - Restricted distribution of mrg-1 mRNA in C. elegans primordial germ cells through germ granule-independent regulation. AB - The chromodomain protein MRG-1 is an essential maternal factor for proper germline development that protects germ cells from cell death in C. elegans. Unlike germ granules, which are exclusively segregated to the germline blastomeres at each cell division from the first cleavage of the embryo, MRG-1 is abundant in all cells in early embryos and is then gradually restricted to the primordial germ cells (PGCs) by the morphogenesis stage. Here, we show that this characteristic spatiotemporal expression pattern is dictated by the mrg-1 3'UTR and is differentially regulated at the RNA level between germline and somatic cells. Asymmetric segregation of germ granules is not necessary to localize MRG-1 to the PGCs. We found that MES-4, an essential chromatin regulator in germ cells, also accumulates in the PGCs in a germ granule-independent manner. We propose that C.elegans PGCs have a novel mechanism to accumulate at least some chromatin associated proteins that are essential for germline immortality. PMID- 26537334 TI - A Novel Role for the Receptor of the Complement Cleavage Fragment C5a, C5aR1, in CCR5-Mediated Entry of HIV into Macrophages. AB - The complement system is an ancient pattern recognition system that becomes activated during all stages of HIV infection. Previous studies have shown that C5a can enhance the infection of monocyte-derived macrophages and T cells indirectly through the production of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha and the attraction of dendritic cells. C5a exerts its multiple biologic functions mainly through activation of C5a receptor 1 (C5aR1). Here, we assessed the role of C5aR1 as an enhancer of CCR5-mediated HIV infection. We determined CCR5 and C5aR1 heterodimer formation in myeloid cells and the impact of C5aR1 blockade on HIV entry and genomic integration. C5aR1/CCR5 heterodimer formation was identified by immunoprecipitation and western blotting. THP-1 cells and monocyte-derived macrophages (MDM) were infected by R5 laboratory strains or HIV pseudotyped for the vesicular stomatitis virus (VSV) envelope. Levels of integrated HIV were measured by quantitative PCR after targeting of C5aR1 by a C5aR antagonist, neutralizing C5aR1 monoclonal antibody (mAb) or hC5a. C5aR1 was also silenced by specific siRNA prior to viral entry. We found that C5aR1 forms heterodimers with the HIV coreceptor CCR5 in myeloid cells. Targeting C5aR1 significantly decreased integration by R5 viruses but not by VSV-pseudotyped viruses, suggesting that C5aR1 is critical for viral entry. The level of inhibition achieved with C5aR1-blocking reagents was comparable to that of CCR5 antagonists. Mechanistically, C5aR1 targeting decreased CCR5 expression. MDM from CCR5Delta32 homozygous subjects expressed levels of C5aR1 similar to CCR5 WT individuals, suggesting that mere C5aR1 expression is not sufficient for HIV infection. HIV appeared to preferentially enter THP-1 cells expressing high levels of both C5aR1 and CCR5. Targeted reduction of C5aR1 expression in such cells reduced HIV infection by ~50%. Our data thus suggest that C5aR1 acts as an enhancer of CCR5-mediated HIV entry into macrophages, the targeting of which may prove useful to reduce HIV infection by R5 strains. PMID- 26537335 TI - The sensory origins of human position sense. AB - KEY POINTS: Position sense at the human forearm can be measured in blindfolded subjects by matching positions of the arms or by a subject pointing to the perceived position of an unseen arm. Effects on position sense tested were: elbow muscle conditioning with a voluntary contraction, muscle vibration, loading the arm and elbow skin stretch. Conditioning contractions and vibration produced errors in a matching task, consistent with the action of muscle spindles as position sensors. Position errors in a pointing task were not consistent with the action of muscle spindles. Loading the arm or skin stretch had no effect in either matching or pointing tasks. It is proposed that there are two kinds of position sense: (i) indicating positions of different body parts relative to one another, using signals from muscle spindles; and (ii) indicating position of the body in extrapersonal space, using signals from exteroceptors, vision, touch and hearing. ABSTRACT: Human limb position sense can be measured in two ways: in a blindfolded matching task, position of one limb is indicated with the other limb. Alternatively, position of a limb, hidden from view, is indicated with a pointer, moved by pressing a lever. These experiments examined the sensory basis of position sense measured in these two ways. Position errors were measured in 14 subjects after elbow flexors or extensors had been conditioned with a half maximum voluntary contraction. In agreement with previous studies, in the matching trials, position errors were distributed according to a pattern consistent with the action of muscle spindles as the position sensors. In the pointing trials, all errors lay in the direction of extension of the true position of the hidden arm and their distribution was inconsistent with influences arising in muscle spindles. Vibration of elbow muscles produced an illusion of muscle lengthening during a matching task, while during the pointing task no illusion was present. Finally, the matching-pointing error difference was preserved, even when one arm was loaded with a weight or skin over the elbow was stretched. It is proposed that there are two kinds of position sense. One is signalled by muscle spindles, indicating position of one part of the body relative to another. A second provides information about the position of the body in extrapersonal space and here we hypothesise that exteroceptors, including vision, touch and hearing, acting via a central map of the body, provide the spatial information. PMID- 26537336 TI - Effectiveness of Biologic and Conventional Systemic Therapies in Adults with Chronic Plaque Psoriasis in Daily Practice: A Systematic Review. AB - The efficacy of biologic or conventional systemic therapies for psoriasis has been shown in randomized controlled trials. Effectiveness, however, has been studied in daily practice cohorts, and no aggregation of effectiveness data is available. This systematic review searched PubMed and EMBASE and summarized the real-world evidence on effectiveness of biologics (adalimumab, etanercept, infliximab and ustekinumab) and conventional systemic therapies (acitretin, cyclosporine, fumarates and methotrexate) for the treatment of plaque psoriasis in adults. Thirty-two studies were included. Few data were available on infliximab, ustekinumab and conventional systemics. Results show that biologics and conventional systemics were effective in real-life treatment of psoriasis, with large ranges in the percentage of patients reaching 75% improvement in psoriasis area and severity index score compared with baseline, especially for etanercept and adalimumab treatment. Combination therapies of biologics with conventional systemics, and dose adjustments of biologics were frequently applied strategies and may explain the large range in improvements between cohorts. PMID- 26537337 TI - A new outbreak of brucellosis in Bulgaria detected in July 2015--preliminary report. AB - During July 2015 a brucellosis outbreak was detected in Kyustendil district, west Bulgaria. As of 15 August, 31 patients have been diagnosed all with an epidemiological connection to Rila town. Patients have not travelled/worked abroad. Breeding family-owned goats and/or improper use of their milk appear to be the main risk factors for transmission of the infection. This second autochthonous brucellosis outbreak in Bulgaria since 2006, affects the western part of the country. PMID- 26537338 TI - Quantification of dislocation nucleation stress in TiN through high-resolution in situ indentation experiments and first principles calculations. AB - Through in situ indentation of TiN in a high-resolution transmission electron microscope, the nucleation of full as well as partial dislocations has been observed from {001} and {111} surfaces, respectively. The critical elastic strains associated with the nucleation of the dislocations were analyzed from the recorded atomic displacements, and the nucleation stresses corresponding to the measured critical strains were computed using density functional theory. The resolved shear stress was estimated to be 13.8 GPa for the partial dislocation 1/6 <110> {111} and 6.7 GPa for the full dislocation 1/2 <110> {110}. Such an approach of quantifying nucleation stresses for defects via in situ high resolution experiment coupled with density functional theory calculation may be applied to other unit processes. PMID- 26537340 TI - Loss of Jagged1 in renin progenitors leads to focal kidney fibrosis. AB - The Notch signaling pathway is required to maintain renin expression within juxtaglomerular (JG) cells. However, the specific ligand which activates Notch signaling in renin-expressing cells remains undefined. In this study, we found that among all Notch ligands, Jagged1 is differentially expressed in renin cells with higher expression during neonatal life. We therefore hypothesized that Jagged1 was involved in renin expression and/or vascular integrity. We used a conditional knockout approach to delete Jagged1 in cells of the renin lineage. Deletion of Jagged1 specifically within renin cells did not result in decreased renin production within the kidney. However, animals with conditional deletion of Jagged1 did develop focal kidney fibrosis and elevated blood urea nitrogen. Our data demonstrate that Jagged1-mediated Notch signaling is dispensable in renin cells of the kidney in regard to renin expression. However, deletion of Jagged1 in renin cells descendants affects perivascular-interstitial integrity leading to focal fibrosis and diminished renal function. PMID- 26537339 TI - Implantation of customized 3-D printed titanium prosthesis in limb salvage surgery: a case series and review of the literature. AB - BACKGROUND: Although modular prosthesis is commercially available to meet requirements in most limb salvage surgeries, customized prosthesis is still needed. In contrast to traditional complicated procedures, rapid prototyping (RP) technique can directly manufacture customized titanium prosthesis. The objectives of this study were to describe the workflow of this technique and show the follow up results of patients. METHODS: Three patients with clavicle Ewing's sarcoma (ES), scapular ES, and pelvic chondrosarcoma (CS) were scanned by computer tomography (CT). The images were segmented and reconstructed for preoperative planning and prosthesis design. Then, the data of prosthesis were imported into an electron beam melting system to manufacture implants. These three patients received prosthesis implantation after tumor excision. They were followed up to evaluate survival rate, functional outcome, and complications. RESULTS: All patients were alive with no evidence of disease. The Musculoskeletal Tumor Society (MSTS) scores were 93, 73, and 90 % for patients with clavicle ES, scapular ES, and pelvic CS, respectively. No surgical complications including limb length discrepancy, screw loosening, and implant breakage were observed in current study. CONCLUSIONS: Electron beam melting (EBM) is a useful method to directly manufacture customized titanium prostheses. It might improve the effectiveness of limb salvage surgery for sarcomas in unusual sites. PMID- 26537341 TI - Maternal obesity disrupts the methionine cycle in baboon pregnancy. AB - Maternal intake of dietary methyl-micronutrients (e.g. folate, choline, betaine and vitamin B-12) during pregnancy is essential for normal maternal and fetal methionine metabolism, and is critical for important metabolic processes including those involved in developmental programming. Maternal obesity and nutrient excess during pregnancy influence developmental programming potentially predisposing adult offspring to a variety of chronic health problems. In the present study, we hypothesized that maternal obesity would dysregulate the maternal and fetal methionine cycle. To test this hypothesis, we developed a nulliparous baboon obesity model fed a high fat, high energy diet (HF-HED) prior to and during gestation, and examined methionine cycle biomarkers (e.g., circulating concentrations of homocysteine, methionine, choline, betaine, key amino acids, folate, and vitamin B-12). Animals were group housed allowing full physical activity and social interaction. Maternal prepregnancy percent body fat was 5% in controls and 19% in HF-HED mothers, while fetal weight was 16% lower in offspring of HF-HED mothers at term. Maternal and fetal homocysteine were higher, while maternal and fetal vitamin B-12 and betaine were lower in the HF-HED group. Elevations in circulating maternal folate were evident in the HF-HED group indicating impaired folate metabolism (methyl-trap) as a consequence of maternal vitamin B-12 depletion. Finally, fetal methionine, glycine, serine, and taurine were lower in the HF-HED fetuses. These data show that maternal obesity disturbs the methionine cycle in primate pregnancy, providing a mechanism for the epigenetic changes observed among obese pregnant women and suggesting diagnostic and therapeutic opportunities in human pregnancies complicated by obesity. PMID- 26537342 TI - Chronic exposure to low doses of lipopolysaccharide and high-fat feeding increases body mass without affecting glucose tolerance in female rats. AB - Obesity-related inflammation may have a causal role in the development of diabetes and insulin resistance, and studies using animal models of chronic experimental endotoxemia have shown the link. However, many studies use only males, and much less is known about the role of obesity-related inflammation in females. Therefore, we addressed how experimentally induced chronic inflammation affects body mass, energy intake, and glucose metabolism in female rats. Adult female Sprague Dawley rats were instrumented with slow release pellets that delivered a constant daily dose of 53 or 207 MUg of lipopolysaccharide (LPS) per rat for 60 days. Control rats were instrumented with vehicle pellets. Due to inflammatory nature of high-fat diet (HFD) half of the rats received HFD (60% of calories from lard), while the other half remained on control diet to detect possible interactions between two modes of induced inflammation. Our results showed that chronic LPS administration increased female rat body mass and calorie intake in a dose-dependent manner, and that HFD further exacerbated these effects. Despite these effects, no effects of LPS and HFD were evident on female rat glucose metabolism. Only LPS elevated expression of inflammatory markers in the hypothalamus. To conclude, female rats respond to experimentally induced chronic inflammation by increasing body mass, but do not develop glucose intolerance in the given period of time. PMID- 26537343 TI - BDNF contributes to angiotensin II-mediated reductions in peak voltage-gated K+ current in cultured CATH.a cells. AB - Increased central angiotensin II (Ang II) levels contribute to sympathoexcitation in cardiovascular disease states such as chronic heart failure and hypertension. One mechanism by which Ang II increases neuronal excitability is through a decrease in voltage-gated, rapidly inactivating K(+) current (IA); however, little is known about how Ang II signaling results in reduced IA. Brain-derived neurotrophic factor (BDNF) has also been demonstrated to decrease IA and has signaling components common to Ang II. Therefore, we hypothesized that Ang II mediated suppression of voltage-gated K(+) currents is due, in part, to BDNF signaling. Differentiated CATH.a, catecholaminergic cell line treated with BDNF for 2 h exhibited a reduced IA in a manner similar to that of Ang II treatment as demonstrated by whole-cell patch-clamp analysis. Inhibiting BDNF signaling by pretreating neurons with an antibody against BDNF significantly attenuated the Ang II-induced reduction of IA. Inhibition of a common component of both BDNF and Ang II signaling, p38 MAPK, with SB-203580 attenuated the BDNF-mediated reductions in IA. These results implicate the involvement of BDNF signaling in Ang II-induced reductions of IA, which may cause increases in neuronal sensitivity and excitability. We therefore propose that BDNF may be a necessary component of the mechanism by which Ang II reduces IA in CATH.a cells. PMID- 26537344 TI - Pseudohypoaldosteronism type 1 and Liddle's syndrome mutations that affect the single-channel properties of the epithelial Na+ channel. AB - These studies test whether three disease-causing mutations in genes (SCNN1A and SCNN1G) encoding subunits of the epithelial Na(+) channel, ENaC, affect the biophysical and gating properties of this important renal ion channel. The S562P missense mutation in alphaENaC and the K106_S108delinsN mutation in gammaENaC are associated with pseudohypoaldosteronism type 1 (PHA1). The N530S missense mutation in gammaENaC causes Liddle's syndrome. Incorporation of S562P into alphaENaC and K106_S108N into gammaENaC resulted in significant decreases in macroscopic ENaC currents. Conversely, incorporation of N530S into gammaENaC increased macroscopic ENaC current. The S562P substitution resulted in a nonfunctional channel. The K106_S108N mutation produced a functional channel having a normal macroscopic current-voltage relation, there was a slight but significant decrease in unitary conductance and a marked decrease in single channel open probability. The N530S substitution increased single-channel open probability having no effect on the macroscopic current-voltage relation or unitary conductance of the channel. These findings are consistent with mutation of residues at 562 in alphaENaC and 530 in gammaENaC, and a 3' splice site in SCNN1G (318-1 G->A; K106_108SdelinsN) resulting in aberrant ENaC activity due to changes in the biophysical and gating properties of the channel. Such changes likely contribute to the cellular mechanism underpinning the PHA1 and Liddle's syndrome caused by these mutations in ENaC subunits. PMID- 26537345 TI - Hemodynamic variability and cerebrovascular control after transient cerebral ischemia. AB - We investigated if hemodynamic variability, cerebral blood flow (CBF) regulation, and their interrelationships differ between patients with transient ischemic attack (TIA) and controls. We recorded blood pressure (BP) and bilateral middle cerebral artery flow velocity (MCAv) in a cohort of TIA patients (n = 17), and age-matched controls (n = 15). Spontaneous fluctuations in BP and MCAv were characterized by spectral power analysis, and CBF regulation was assessed by wavelet phase synchronization analysis in the very low- (0.02-0.07 Hz), low- (0.07-0.20 Hz), and high-frequency (0.20-0.40 Hz) ranges. Furthermore, cerebrovascular CO2 reactivity was assessed as a second metric of CBF regulation by inducing hypercapnia with 8% CO2 inhalation followed by hyperventilation driven hypocapnia. We found that TIA was associated with higher BP power (group effect, P < 0.05), but not MCAv power (P = 0.11). CBF regulation (assessed by wavelet phase synchronization and CO2 reactivity) was intact in patients (all P >= 0.075) across both hemispheres (all P >= 0.51). Pooled data (controls and affected hemisphere of patients) showed that BP and MCAv power were positively correlated at all frequency ranges (R(2) = 0.20-0.80, all P < 0.01). Furthermore, LF phase synchronization index was a significant determinant of MCAv power (P < 0.05), while VLF and HF phase synchronization index, and TIA were not (all P >= 0.50). These results indicate that CBF stability and control is maintained in TIA patients, but BPV is markedly elevated. BPV attenuation may be an important therapeutic strategy for enhancing secondary stroke prevention in patients who suffer a TIA. PMID- 26537346 TI - Effects of epimuscular myofascial force transmission on sarcomere length of passive muscles in the rat hindlimb. AB - Results from imaging studies and finite element models suggest epimuscular myofascial effects on sarcomere lengths in series within muscle fibers. However, experimental evidence is lacking. We evaluated epimuscular myofascial effects on (1) muscle belly, fiber, and mean sarcomere length and (2) sarcomere length distribution within passive fibers of the rat tibialis anterior (TA) and soleus (SO) muscles. Hindlimbs (n = 24) were positioned in predefined knee (55 degrees , 90 degrees , 125 degrees , 160 degrees ) and ankle (either 90 degrees or 125 degrees ) angles, and fixed in a formaldehyde solution. Varying knee joint angle causes changes in muscle-tendon unit length of SO and TA's synergists, but not of SO and TA. Whole fibers were taken from SO and TA and photographed along their length. Mean sarcomere length was assessed for the entire fiber and for the proximal, intermediate, and distal thirds (fiber segments) separately. Mean sarcomere length of the fiber was not affected by knee angle, neither for SO (mean: 2.44 +/- 0.03 MUm and 2.19 +/- 0.05 MUm for ankle angles of 90 degrees and 125 degrees , respectively) nor for TA (mean: 2.33 +/- 0.05 MUm and 2.51 +/- 0.07 MUm for ankle angle set to 90 degrees and 125 degrees , respectively). Only for TA, a significant interaction between knee angle and fiber segment was found, indicating changes in the distribution of lengths of in-series sarcomeres. Thus, while epimuscular myofascial force transmission did not cause mean sarcomere length changes within passive SO and TA, it did alter the length distribution of sarcomeres within passive TA. PMID- 26537347 TI - Reduced vagal control of the heart in high-fat diet mice: a potential role of increased butyrylcholinesterase. AB - Suppressed parasympathetic function is commonly present in cardiovascular diseases, aging, obesity, and various other health conditions. Impaired parasympathetic action is known as a detrimental factor and contributes to the adverse outcomes in these conditions. However, the underlying mechanisms remain to be fully addressed. In this study, using high-fat diet (HFD)-induced obese mice as a model, the potential peripheral mechanisms underlying the impaired parasympathetic vagal control of the heart was examined. The HFD induced obesity and metabolic disorder in mice. These obese mice exhibited an attenuated response in heart rate to vagal stimulation, indicating impairment of peripheral parasympathetic activity in the heart. In cholinergic function-related proteins in the atria, protein levels of choline transporter and vesicular acetylcholine transporter were not decreased but increased, and type 2 muscarinic receptors showed a trend toward a reduction in HFD mice atria as compared with regular diet (RD) mice controls. While the protein level of acetylcholinesterase was not different, butyrylcholinesterase (BChE) protein level showed a twofold increase in HFD mice atria as compared with RD mice. Functionally, inhibition of BChE activity partially and significantly improved the attenuated response in heart rate to vagal stimulation in HFD mice. Collectively, these data suggest that increased BChE activity in the atria may contribute to the decreased parasympathetic function in HFD-induced obese mice. PMID- 26537348 TI - Generation of Kcnma1fl-tdTomato, a conditional deletion of the BK channel alpha subunit in mouse. AB - BK large conductance calcium-activated K(+) channels (KC a1.1) are expressed widely across many tissues, contributing to systemic regulation of cardiovascular, neurological, and other specialized physiological functions. The pore-forming alpha subunit is encoded by the Kcnma1 gene, originally named mSlo1 in mouse and slowpoke in Drosophila. Global deletion in mouse (Kcnma1(-/-)) produces a plethora of defects in neuron and muscle excitability, as well as other phenotypes related to channel function in nonexcitable cells. While homozygous null mice are viable, the ubiquitous loss of BK function has complicated the interpretation of phenotypes involving the interaction of multiple cell types which independently express BK channels. Here, we report the generation of a targeted allele for conditional inactivation of Kcnma1 using the Cre-loxP system (Kcnma1(fl)-tdTomato). Cre-mediated recombination generates a null allele, and BK currents were not detectable in neurons and muscle cells from Nestin-Cre; Kcnma1(fl/fl) and SM22alpha-Cre; Kcnma1(fl/fl) mice, respectively. tdTomato expression was detected in Cre-expressing tissues, but not in Cre negative controls. These data demonstrate the utility of Kcnma1(fl)-tdTomato for conditional deletion of the BK channel, facilitating the understanding of tissue specific contributions to physiological function in vivo. PMID- 26537349 TI - The first scorpionate ligand based on diazaphosphole. AB - The reaction of PhBCl2 with 1H-1,2,4-lambda(3)-diazaphosphole in the presence of NEt3 gives a new scorpionate ligand, phenyl-tris(1,2,4-diazaphospholyl)borate (PhTdap). The coordination behaviour of this ligand toward transition and non transition metals has been comprehensively studied. In the thallium(I) complex, Tl(PhTdap), kappa(2)-N,N bonding supported with intramolecular eta(3)-phenyl coordination has been observed in the solid state. Tl(PhTdap) also shows unusual intermolecular pi-interactions between five-membered diazaphosphole rings and the thallium atom giving infinite molecular chains in the crystal. In the square planar complex [Pd(C,N-C6H4CH2NMe2)(PhTdap)], kappa(2)-bonded scorpionate has been detected in both solution and in the solid state. For other studied compounds with the central metal ion Ti(IV), Mo(II), Mn(I), Fe(II), Ru(II), Co(II), Co(III), Ni(II) and Cd(II), the kappa(3)-N,N,N coordination pattern was observed. Electronic properties of PhTdap and its ligand-field strength were elucidated from UV-Vis spectra of transition-metal species. The CH/P replacement on going from tris(pyrazolyl)borate to the ligand PhTdap causes a slight increase in electronic density rendered to the central metal atom. The following order of ligand-field strength has been established: HB(3,5-Me2pz)3 < PhB(pz)3 < HB(1,2,4 triazolyl) < HB(pz)3 < PhB(1,2,4-triazolyl) < PhTdap. The crystal structures of ten metal complexes bearing the new ligand are reported. The possibility of PhTdap coordination through the phosphorus atom is also briefly discussed. PMID- 26537350 TI - An integrative approach to phylogeography: investigating the effects of ancient seaways, climate, and historical geology on multi-locus phylogeographic boundaries of the Arboreal Salamander (Aneides lugubris). AB - BACKGROUND: Phylogeography is an important tool that can be used to reveal cryptic biodiversity and to better understand the processes that promote lineage diversification. We studied the phylogeographic history of the Arboreal Salamander (Aneides lugubris), a wide-ranging species endemic to the California floristic province. We used multi-locus data to reconstruct the evolutionary history of A. lugubris and to discover the geographic location of major genetic breaks within the species. We also used species distribution modeling and comparative phylogeography to better understand the environmental factors that have shaped the genetic history of A. lugubris. RESULTS: We found six major mitochondrial clades in A. lugubris. Nuclear loci supported the existence of at least three genetically distinct groups, corresponding to populations north of the San Francisco Bay and in the Sierra Nevada, in the Santa Cruz Mountains, and in the central coast and southern California. All of the genetic breaks in mitochondrial and nuclear loci corresponded to regions where historical barriers to dispersal have been observed in other species. Geologic or water barriers likely were the most important factors restricting gene flow among clades. Climatic unsuitability during glacial maximum may have contributed to the isolation of the mitochondrial clades in the central coast and southern California. A projection of our species distribution model to a future scenario with a moderate amount of climate change suggests that most of the range of A. lugubris will remain climatically suitable, but climatic conditions in the Sierra Nevada and low elevation areas in Southern California are likely to deteriorate. CONCLUSIONS: Aneides lugubris contains substantial cryptic genetic diversity as a result of historical isolation of populations. At least two (and perhaps three) evolutionarily significant units in A. lugubris merit protection; all six mitochondrial clades should be considered as management units within the species. PMID- 26537351 TI - The Effect of Verbascoside in Neuropathic Pain Induced by Chronic Constriction Injury in Rats. AB - We examined the effects of verbascoside in rats subjected to chronic constriction injury (CCI). Verbascoside (50, 100, and 200 mg/kg, i.p.), was administered from the day of surgery for 14 days. Spinal cord levels of apoptotic factors and glia markers were quantified on days 3, 7, and 14 post-CCI. Oxidative stress markers were assessed on days 7 and 14. CCI rats exhibited a marked mechanical allodynia, cold allodynia, and thermal hyperalgesia on days 3, 5, 7, 10, and 14 post-CCI. A significant increase in the levels of Iba (a marker of microglia activation) and Bax (a proapoptotic factor) was observed on day 3. Iba remained high on day 7. In contrast, there were no differences in glial fibrillary acidic protein contents between sham and CCI animals. Malondialdehyde increased and reduced glutathione decreased on day 14. Verbascoside significantly attenuated behavioral changes associated with neuropathy. Bax decreased, while Bcl-2 was increased by verbascoside on day 3. Verbascoside also reduced Iba protein on days 3 and 7. The results support evidence that microglial activation, apoptotic factors, and oxidative stress may have a pivotal role in the neuropathic pain pathogenesis. It is suggested that antinociceptive effects elicited by verbascoside might be through the inhibition of microglia activation, apoptotic pathways, and antioxidant properties. PMID- 26537352 TI - Thessaly test is no more accurate than standard clinical tests for meniscal tears. PMID- 26537353 TI - The addition of abdomen and pelvis CT to limited cancer screening does not increase diagnosis of cancer in patients with unprovoked venous thromboembolism. PMID- 26537354 TI - Cervical arthroplasty compares favourably to ACDF at half-decade follow-up. PMID- 26537355 TI - Are lifestyle cardiovascular disease risk factors associated with pre hypertension in 15-18 years rural Nigerian youth? A cross sectional study. AB - BACKGROUND: Cardiovascular disease (CVD) is a public health concern worldwide. Hypertensive heart disease is predominant in Nigeria. To effectively reduce CVD in Nigeria, the prevalence of, and factors associated with, pre-hypertension in Nigerian youth first need to be established. METHODS: A locally-validated CVD risk factor survey was completed by 15-18 year olds in a rural setting in south west Nigeria. Body Mass Index (BMI), waist-hip ratio and systolic and diastolic blood pressure was measured. Putative risk factors were tested in gender-specific hypothesized causal pathways for overweight/obesity, and for pre-hypertension. RESULTS: Of 1079 participants, prevalence of systolic pre-hypertension was 33.2 %, diastolic pre-hypertension prevalence approximated 5 %, and hypertension occurred in less than 10 % sample. There were no gender differences in prevalence of pre- hypertension, and significant predictors of systolic pre-hypertension (high BMI and older age) were identified. Considering high BMI, older age was a risk for both genders, whilst fried food preference was female-only risk, and low breakfast cereal intake was a male-only risk. CONCLUSION: Rural Nigerian adolescents are at-risk of future CVD because of lifestyle factors, and high prevalence of systolic pre-hypertension. Relevant interventions can now be proposed to reduce BMI and thus ameliorate future rural adult Nigerian CVD. PMID- 26537356 TI - Feasibility and accuracy evaluation of three human papillomavirus assays for FTA card-based sampling: a pilot study in cervical cancer screening. AB - BACKGROUND: Liquid-state specimen carriers are inadequate for sample transportation in large-scale screening projects in low-resource settings, which necessitates the exploration of novel non-hazardous solid-state alternatives. Studies investigating the feasibility and accuracy of a solid-state human papillomavirus (HPV) sampling medium in combination with different down-stream HPV DNA assays for cervical cancer screening are needed. METHODS: We collected two cervical specimens from 396 women, aged 25-65 years, who were enrolled in a cervical cancer screening trial. One sample was stored using DCM preservative solution and the other was applied to a Whatman Indicating FTA Elute(r) card (FTA card). All specimens were processed using three HPV testing methods, including Hybrid capture 2 (HC2), careHPVTM, and Cobas(r)4800 tests. All the women underwent a rigorous colposcopic evaluation that included using a microbiopsy protocol. RESULTS: Compared to the liquid-based carrier, the FTA card demonstrated comparable sensitivity for detecting high grade Cervical Intraepithelial Neoplasia (CIN) using HC2 (91.7 %), careHPVTM (83.3 %), and Cobas(r)4800 (91.7 %) tests. Moreover, the FTA card showed a higher specificity compared to a liquid-based carrier for HC2 (79.5 % vs. 71.6 %, P = 0.015), comparable specificity for careHPVTM (78.1 % vs. 73.0 %, P > 0.05), but lower specificity for the Cobas(r)4800 test (62.4 % vs. 69.9 %, P = 0.032). Generally, the FTA card-based sampling medium's accuracy was comparable with that of liquid based medium for the three HPV testing assays. CONCLUSIONS: FTA cards are a promising sample carrier for cervical cancer screening. With further optimization, it can be utilized for HPV testing in areas of varying economic development. PMID- 26537357 TI - Photo-generated carriers lose energy during extraction from polymer-fullerene solar cells. AB - In photovoltaic devices, the photo-generated charge carriers are typically assumed to be in thermal equilibrium with the lattice. In conventional materials, this assumption is experimentally justified as carrier thermalization completes before any significant carrier transport has occurred. Here, we demonstrate by unifying time-resolved optical and electrical experiments and Monte Carlo simulations over an exceptionally wide dynamic range that in the case of organic photovoltaic devices, this assumption is invalid. As the photo-generated carriers are transported to the electrodes, a substantial amount of their energy is lost by continuous thermalization in the disorder broadened density of states. Since thermalization occurs downward in energy, carrier motion is boosted by this process, leading to a time-dependent carrier mobility as confirmed by direct experiments. We identify the time and distance scales relevant for carrier extraction and show that the photo-generated carriers are extracted from the operating device before reaching thermal equilibrium. PMID- 26537358 TI - Long-term outcome of IgA nephropathy with minimal change disease: a comparison between patients with and without minimal change disease. AB - BACKGROUND: The clinicopathological characteristics, treatment response and long term outcome of immunoglobulin (Ig)A nephropathy with minimal change disease (MCD IgAN) are not well defined. METHODS: Patients with biopsy-proven MCD-IgAN from the Jinling Hospital IgA nephropathy Registry were systematically reviewed and compared with those with IgA nephropathy without minimal change disease (Non-MCD IgAN). RESULTS: We compared data of 247 MCD-IgAN patients and 1,121 Non-MCD-IgAN patients. Compared to Non-MCD-IgAN, MCD-IgAN patients were younger,with male predominance, had higher levels of proteinuria, total cholesterol and estimated glomerular filtration rate (eGFR), lower incidence of hypertension and microhematuria, lower level of serum creatinine, and had less severe glomerular, tubulointerstitial and vascular lesions in renal pathology. In the Non-MCD-IgAN group, 157 patients (14.0 %) reached the renal endpoint and 103 patients (9.2 %) entered end-stage renal disease (ESRD). The 5-,10-, 15- and 20-year cumulative renal survival rates from ESRD, calculated by Kaplan-Meier method, were 95.0, 83.0, 72.9 and 65.4 %, respectively. In the MCD-IgAN group, no patients entered ESRD and only 4 (1.6 %) reached the renal endpoint. Patients with MCD-IgAN had a significantly better renal outcome than Non-MCD-IgAN (p < 0.01). At multivariate Cox analysis, proteinuria >1.0 g/day, hypertension, eGFR <60 ml/min/1.73 m(2), hypoproteinemia and hyperuricemia were independent risk factors of renal survival for Non-MCD-IgAN patients [hazard ratio (HR) 3.43, p < 0.001; HR 1.65, p < 0.05; HR 2.61, p < 0.001; HR 2.40, p < 0.001; HR 2.27, p < 0.001, respectively), but not for patients with MCD-IgAN. CONCLUSIONS: The long-term outcome of patients with MCD-IgAN is significantly better than that of patients with Non-MCD-IgAN. PMID- 26537359 TI - Loss of HP1 causes depletion of H3K27me3 from facultative heterochromatin and gain of H3K27me2 at constitutive heterochromatin. AB - Methylated lysine 27 on histone H3 (H3K27me) marks repressed "facultative heterochromatin," including developmentally regulated genes in plants and animals. The mechanisms responsible for localization of H3K27me are largely unknown, perhaps in part because of the complexity of epigenetic regulatory networks. We used a relatively simple model organism bearing both facultative and constitutive heterochromatin, Neurospora crassa, to explore possible interactions between elements of heterochromatin. In higher eukaryotes, reductions of H3K9me3 and DNA methylation in constitutive heterochromatin have been variously reported to cause redistribution of H3K27me3. In Neurospora, we found that elimination of any member of the DCDC H3K9 methylation complex caused massive changes in the distribution of H3K27me; regions of facultative heterochromatin lost H3K27me3, while regions that are normally marked by H3K9me3 became methylated at H3K27. Elimination of DNA methylation had no obvious effect on the distribution of H3K27me. Elimination of HP1, which "reads" H3K9me3, also caused major changes in the distribution of H3K27me, indicating that HP1 is important for normal localization of facultative heterochromatin. Because loss of HP1 caused redistribution of H3K27me2/3, but not H3K9me3, these normally nonoverlapping marks became superimposed. Indeed, mass spectrometry revealed substantial cohabitation of H3K9me3 and H3K27me2 on H3 molecules from an hpo strain. Loss of H3K27me machinery (e.g., the methyltransferase SET-7) did not impact constitutive heterochromatin but partially rescued the slow growth of the DCDC mutants, suggesting that the poor growth of these mutants is partly attributable to ectopic H3K27me. Altogether, our findings with Neurospora clarify interactions of facultative and constitutive heterochromatin in eukaryotes. PMID- 26537360 TI - Targeted Gene Resequencing (Astrochip) to Explore the Tripartite Synapse in Autism-Epilepsy Phenotype with Macrocephaly. AB - The frequent co-occurrence of autism spectrum disorders (ASD) and epilepsy, or paroxysmal EEG abnormalities, defines a condition termed autism-epilepsy phenotype (AEP). This condition results, in some cases , from dysfunctions of glial inwardly rectifying potassium channels (Kir), which are mainly expressed in astrocytes where they mediate neuron-glia communication. Macrocephaly is also often comorbid with autism-epilepsy (autism-epilepsy phenotype with macrocephaly, MAEP), and it is tempting to hypothesize that shared pathogenic mechanisms might explain concurrence of these conditions. In the present study, we assessed whether protein pathways involved, along with Kir channels, in astrocyte-neuron interaction at the tripartite synapse play a role in the etiopathogenesis of MAEP. Using a targeted resequencing methodology, we investigated the coding regions of 35 genes in 61 patients and correlated genetic results with clinical features. Variants were subdivided into 12 classes and clustered into four groups. We detected rare or previously unknown predicted deleterious missense changes in GJA1, SLC12A2, SNTA1, EFNA3, CNTNAP2, EPHA4, and STXBP1 in seven patients and two high-frequency variants in DLG1 in six individuals. We also found that a group of variants (predicted deleterious and non-coding), segregating with the comorbid MAEP/AEP subgroups, belong to proteins specifically involved in glutamate transport and metabolism (namely, SLC17A6, GRM8, and GLUL), as well as in potassium conductance (KCNN3). This "endophenotype-oriented" study, performed using a targeted strategy, helped to further delineate part of the complex genetic background of ASD, particularly in the presence of coexisting macrocephaly and/or epilepsy/paroxysmal EEG, and suggests that use of stringent clinical clustering might be an approach worth adopting in order to unravel the complex genomic data in neurodevelopmental disorders. PMID- 26537361 TI - Macular edema with serous retinal detachment post-phacoemulsification followed by spectral domain optical coherence tomography: a report of two cases. AB - BACKGROUND: Macular edema and detachment at the first day after an uneventful cataract surgery is very rare, and has been reported previously with the use of high concentrations of intra-cameral cefuroxime. However, we hereby reported two cases of macular edema with extensive serous retinal detachment the first day after an uneventful phacoemulsification with intra-cameral injection of a standard dose of cefuroxime during the procedure. CASE PRESENTATION: A 68-year old female and a 63-year-old male without any special history both underwent an uneventful phacoemulsification surgery and 1 mg/0.1 ml of cefuroxime solution was injected into the anterior chamber at the end of the procedure. Macular edema with extensive serous retinal detachment around macula and optic disc area were observed the first day after surgery. Without surgical intervention, a quick recovery of the macular edema and retinal detachment was observed by spectral domain optical coherence tomography 1 week later in both cases. CONCLUSION: We presume that the retina injury in the two cases may be attributed to cefuroxime toxicity even under a use of a standard dose. But the retinal damages are restorable and routine anti-inflammatory treatment is enough. PMID- 26537362 TI - Tumor invasion depth is a useful pathologic assessment for predicting outcomes in cervical squamous cell carcinoma after neoadjuvant radiotherapy. AB - BACKGROUND: To evaluate whether tumor invasion depth can be a reliable and easily applicable pathologic assessment strategy to predict outcomes using surgically resected cervical squamous cell carcinoma specimens from patients who have received neoadjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). METHODS: We included 173 patients with cervical squamous cell carcinoma who received neoadjuvant CCRT (n = 125) or RT (n = 48) and underwent subsequent radical hysterectomy. Data for the pre-operative clinical International Federation of Gynecology and Obstetrics (FIGO) stage, post-operative pathologic FIGO stage, World Health Organization (WHO) double diameter measurement evaluation, response evaluation criteria in solid tumors (RECIST 1.1) criteria, tumor necrosis rate (TNR), and tumor regression grade (TRG) were investigated to identify correlations with outcomes related to distant metastasis and survival. The tumor invasion depth (TID) and the tumor invasion depth with cytokeratin immunostaining correction (TIDC) at the cervical internal surface were measured to assess their relations to patients' outcomes. RESULTS: Based on measurements taken via transvaginal ultrasound, the pre-operative clinical and post-operative pathologic FIGO staging as well as the WHO double diameter measurement evaluation and RECIST 1.1 criteria were predictive of distant metastasis and survival related outcomes. Also, lymph node involvement was found to be an independent prognostic factor for recurrence and distant metastasis. Finally, univariate analysis showed both the TID and TIDC were highly related to distant metastasis, overall survival, and progression-free survival, irrespective of the clinical stage of carcinomas. CONCLUSION: The TID or TIDC measured at the cervical internal surface is a useful and easily applied pathologic prognostic factor for distant metastasis and survival outcomes in patients with cervical squamous cell carcinoma treated with neoadjuvant RT or CCRT. PMID- 26537363 TI - Green synthesis of in situ electrodeposited rGO/MnO2 nanocomposite for high energy density supercapacitors. AB - This paper presents the preparation of in situ electrodeposited rGO/MnO2 nanocomposite as a binder-free electrode for supercapacitor application. The work describes and evaluates the performance of prepared electrode via green and facile electrodeposition technique of in situ rGO/MnO2-glucose carbon nanocomposites. The carbon content in the composite electrode increased after GO and D (+) glucose solution has been added in the deposition electrolyte. This study found that a suitable concentration of D (+) glucose in the deposition electrolyte can slow down the nucleation process of MnO2 particles and lead to uniform and ultrathin nanoflakes structure. The optimize electrode exhibited low transfer resistance and resulted on excellent electrochemical performance in three electrolyte systems viz. Na2SO4, KOH and KOH/K3Fe(CN)6 redox electrolytes. The optimum energy density and power density were 1851 Whkg(-1) and 68 kWkg(-1) at current density of 20 Ag(-1) in mixed KOH/K3Fe(CN)6 electrolyte. PMID- 26537364 TI - Development of a Multidimensional Functional Health Scale for Older Adults in China. AB - A first step to achieve successful aging is assessing functional wellbeing of older adults. This study reports the development of a culturally appropriate brief scale (the Multidimensional Functional Health Scale for Chinese Elderly, MFHSCE) to assess the functional health of Chinese elderly. Through systematic literature review, Delphi method, cultural adaptation, synthetic statistical item selection, Cronbach's alpha and confirmatory factor analysis, we conducted development of item pool, two rounds of item selection, and psychometric evaluation. Synthetic statistical item selection and psychometric evaluation was processed among 539 and 2032 older adults, separately. The MFHSCE consists of 30 items, covering activities of daily living, social relationships, physical health, mental health, cognitive function, and economic resources. The Cronbach's alpha was 0.92, and the comparative fit index was 0.917. The MFHSCE has good internal consistency and construct validity; it is also concise and easy to use in general practice, especially in communities in China. PMID- 26537365 TI - The effects of beetroot juice supplementation on indices of muscle damage following eccentric exercise. AB - PURPOSE: Foods rich in antioxidant and anti-inflammatory phytochemicals might attenuate skeletal muscle damage; thus, the present study investigated whether consuming an antioxidant rich beetroot juice would attenuate the muscle-damaging effects of eccentric exercise. METHODS: Using a double blind, independent groups design, 30 recreationally active males were allocated to consume a high dose of beetroot juice (H-BT; 250 ml), a lower dose of beetroot juice (L-BT; 125 ml), or an isocaloric placebo (PLA; 250 ml) immediately (*3 servings), 24 (*2 servings) and 48 h (*2 servings) following completion of 100-drop jumps. Maximal isometric voluntary contractions (MIVC), countermovement jumps (CMJ), pressure pain threshold (PPT), creatine kinase (CK), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) were measured pre, post, 2 (blood indices only), 24, 48 and 72 h following the drop jumps. RESULTS: CMJ performance recovered quicker (relative to baseline) in H-BT vs. PLA at 48 (91.7 +/- 12.2 vs. 74.4 +/- 17.3%; P = 0.009, ES = 1.00) and 72 h postexercise (93.4 +/- 7.7 vs. 86 +/- 5.9%; P = 0.046, ES = 1.25). PPT was greater in both the H-BT and L-BT vs. PLA at 24, 48 and 72 h postexercise (P < 0.001); PPT had returned to baseline in H-BT and L-BT at 72 h postexercise, but was still reduced in PLA (80.1 +/- 28.9% of baseline values). MIVC, CK, IL-6, TNF-alpha and IL-8 were unaffected by beetroot juice (P > 0.05). CONCLUSIONS: Acute beetroot juice supplementation attenuated muscle soreness and decrements in CMJ performance induced by eccentric exercise; further research on the anti-inflammatory effects of beetroot juice are required to elucidate the precise mechanisms. PMID- 26537366 TI - Wnt/beta-catenin coupled with HIF-1alpha/VEGF signaling pathways involved in galangin neurovascular unit protection from focal cerebral ischemia. AB - Microenvironmental regulation has become a promising strategy for complex disease treatment. The neurovascular unit (NVU), as the key structural basis to maintain an optimal brain microenvironment, has emerged as a new paradigm to understand the pathology of stroke. In this study, we investigated the effects of galangin, a natural flavonoid isolated from the rhizome of Alpina officinarum Hance, on NVU microenvironment improvement and associated signal pathways in rats impaired by middle cerebral artery occlusion (MCAO). Galangin ameliorated neurological scores, cerebral infarct volume and cerebral edema and reduced the concentration of Evans blue (EB) in brain tissue. NVU ultrastructural changes were also improved by galangin. RT-PCR and western blot revealed that galangin protected NVUs through the Wnt/beta-catenin pathway coupled with HIF-1alpha and vascular endothelial growth factor (VEGF). VEGF and beta-catenin could be the key nodes of these two coupled pathways. In conclusion, Galangin might function as an anti ischemic stroke drug by improving the microenvironment of NVUs. PMID- 26537367 TI - Cigarette Smoking, Tooth Loss, and Chronic Obstructive Pulmonary Disease: Findings From the Behavioral Risk Factor Surveillance System. AB - BACKGROUND: Cigarette smoking and tooth loss are seldom considered concurrently as determinants of chronic obstructive pulmonary disease (COPD). This study examines the multiplicative effect of self-reported tooth loss and cigarette smoking on COPD among United States adults aged >=18 years. METHODS: Data were taken from the 2012 Behavioral Risk Factor Surveillance System (n = 439,637). Log linear regression-estimated prevalence ratios (PRs) are reported for the interaction of combinations of tooth loss (0, 1 to 5, 6 to 31, or all) and cigarettes smoking status (never, former, or current) with COPD after adjusting for age, sex, race/ethnicity, marital status, educational attainment, employment, health insurance coverage, dental care utilization, and diabetes. RESULTS: Overall, 45.7% respondents reported having >=1 teeth removed from tooth decay or gum disease, 18.9% reported being current cigarette smokers, and 6.3% reported having COPD. Smoking and tooth loss from tooth decay or gum disease were associated with an increased likelihood of COPD. Compared with never smokers with no teeth removed, all combinations of smoking status categories and tooth loss had a higher likelihood of COPD, with adjusted PRs ranging from 1.5 (never smoker with 1 to 5 teeth removed) to 6.5 (current smoker with all teeth removed) (all P <0.05). CONCLUSIONS: Tooth loss status significantly modifies the association between cigarette smoking and COPD. An increased understanding of causal mechanisms linking cigarette smoking, oral health, and COPD, particularly the role of tooth loss, infection, and subsequent inflammation, is essential to reduce the burden of COPD. Health providers should counsel their patients about cigarette smoking, preventive dental care, and COPD risk. PMID- 26537368 TI - Investigation of the Association Between Cement Retention and Prevalent Peri Implant Diseases: A Cross-Sectional Study. AB - BACKGROUND: The aim of this study is to examine the association between retention type (cement-retained versus screw-retained restorations) and prevalence of peri implant diseases in a German university-treated population. METHODS: Data were analyzed from individuals that underwent clinical and radiographic peri-implant examinations as part of a university-based cross-sectional study from September 2011 to October 2012. RESULTS: Data from 139 individuals (mean age: 57.59 years) having 394 implants were analyzed: 192 implants supporting single crowns and 202 fixed partial dentures. Overall, 11.9% of the participants had peri-implantitis, whereas 68.9% had peri-implant mucositis. Crude odds ratios (95% confidence intervals) for peri-implantitis and peri-implant mucositis for cement- versus screw-retained restorations were 1.43 (0.45, 4.60) and 0.89 (0.53, 1.48), respectively. Results remained non-significant in multivariable models adjusting for type of restoration and smoking (all P values >0.50). There was also no effect of splinting restorations on disease prevalence in adjusted analyses (P values >0.32). CONCLUSIONS: In this university-treated sample, there is no association between the type of prosthesis retention and peri-implant diseases. Current findings show that, when appropriate selection and removal of cement is performed, cement retention is not a risk indicator for peri-implant diseases. PMID- 26537369 TI - Effects of Topical Antibiotic Prophylaxis on Wound Healing After Flapless Implant Surgery: A Pilot Study. AB - BACKGROUND: The purpose of this pilot study is to investigate the effects of local application of minocycline hydrochloride ointment (MHO) and erythromycin eye ointment (EEO) on wound healing after flapless implant surgery. METHODS: Forty patients with flapless implant surgery were enrolled and assigned randomly to three groups: 1) MHO group (n = 17); 2) EEO group (n = 18); and 3) control group (n = 5). All of them took systemic antibiotics; the control group did not receive the application of topical antibiotics. Three days after the surgical operation, clinical parameters, peri-implant crevicular fluid volume, and crevicular lipopolysaccharide (LPS) levels of all patients were collected, measured, and analyzed. RESULTS: Clinical outcomes of the two treatment groups were superior to results of the control group, indicating the effectivity of local antibiotics application in promoting early wound healing after flapless implant surgery. There was no obviously different effect between EEO and MHO in the early stages of healing. In addition, there were significant correlations between LPS level and all clinical parameters. CONCLUSIONS: The local application of antibiotics along with the systemic antibiotics could reduce the inflammatory response in wound healing after implant surgery. The EEO and MHO were equally effective in early wound healing. Compared to the MHO, the EEO has advantages of higher cost efficiency and convenience. Therefore, it is recommended to use the EEO in topical antibiotic prophylaxis for wound healing after flapless implant surgery. PMID- 26537370 TI - High Glucose Concentrations Suppress the Proliferation of Human Periodontal Ligament Stem Cells and Their Differentiation Into Osteoblasts. AB - BACKGROUND: Diabetes mellitus (DM) is a major risk factor for periodontal disease and affects various cellular functions. Periodontal ligament stem cells (PDLSCs) play an important role in periodontal tissue regeneration; however, the effect of hyperglycemia on PDLSCs is unclear. The aim of this study is to investigate whether hyperglycemia affects periodontal tissue regeneration, using human PDLSCs and high-glucose medium as a model of DM. METHODS: PDLSCs were obtained from healthy adult human mandibular third molars. Cell proliferation, osteoblastic differentiation, and proinflammatory cytokine expression were investigated by culturing PDLSCs in media supplemented with four different glucose concentrations representative of control patients (5.5 mM), patients with postprandial or controlled DM (8.0 mM), and patients with uncontrolled DM (12.0 and 24.0 mM). The molecular effects of hyperglycemia on PDLSC physiology were examined with a focus on the nuclear factor (NF)-(kappaB signaling pathway. The involvement of NF kappaB was investigated with a specific NF-kappaB inhibitor in PDLSCs under hyperglycemic conditions. RESULTS: High glucose levels inhibited PDLSC proliferation and differentiation into osteoblasts but induced NF-kappaB activation and subsequent interleukin (IL)-6 and IL-8 expression. Treatment with an NF-kappaB inhibitor rescued the defects in cell proliferation and osteoblastic differentiation and inhibited the IL-6 expression caused by the high-glucose environment. CONCLUSION: The results of this study demonstrate that hyperglycemia inhibits human PDLSC proliferation and osteoblastic differentiation. PMID- 26537371 TI - Testing an Adapted Modified Delphi Method: Synthesizing Multiple Stakeholder Ratings of Health Care Service Effectiveness. AB - BACKGROUND: The Affordable Care Act incentivizes health systems for better meeting patient needs, but often guidance about patient preferences for particular health services is limited. All too often vulnerable patient populations are excluded from these decision-making settings. A community-based participatory approach harnesses the in-depth knowledge of those experiencing barriers to health care. METHOD: We made three modifications to the RAND-UCLA appropriateness method, a modified Delphi approach, involving patients, adding an advisory council group to characterize existing knowledge in this little studied area, and using effectiveness rather than "appropriateness" as the basis for rating. As a proof of concept, we tested this method by examining the broadly delivered but understudied nonmedical services that community health centers provide. RESULTS: This method created discrete, new knowledge about these services by defining 6 categories and 112 unique services and by prioritizing among these services based on effectiveness using a 9-point scale. Consistent with the appropriateness method, we found statistical convergence of ratings among the panelists. DISCUSSION: Challenges include time commitment and adherence to a clear definition of effectiveness of services. This diverse stakeholder engagement method efficiently addresses gaps in knowledge about the effectiveness of health care services to inform population health management. PMID- 26537372 TI - Estimated Levels of Environmental Contamination and Health Risk Assessment for Herbicides and Insecticides in Surface Water of Ceara, Brazil. AB - Methodology using solid phase extraction and high performance liquid chromatography (SPE-C18/HPLC-DAD) was applied to pesticide determinations in ten water reservoirs in the semidarid region of northeastern Brazil. The validated method was suitable for determination of herbicides and insecticide in surface water. The recovery efficiency of atrazine, methyl-parathion and simazine was approximately 70%. The method also showed good linearity and selectivity with correlation coefficients (R) greater than 0.99. The limits of detection were below the maximum residue limits (MRLs) established by government agencies. Studied reservoirs showed presence of atrazine at mean levels from 7.0 to 15.0 ug/L. Simazine and methyl parathion were not detected during the period. The atrazine levels measured from this semiarid region are of the same magnitude as those found in regions with moderate to high agricultural activity. According to detected atrazine concentrations, the annual health risk to humans was insignificant. However, the control of herbicides is important to maintain the quality of water in the reservoirs of Ceara, Brazil. PMID- 26537373 TI - Bias in logistic regression due to imperfect diagnostic test results and practical correction approaches. AB - BACKGROUND: Logistic regression is a statistical model widely used in cross sectional and cohort studies to identify and quantify the effects of potential disease risk factors. However, the impact of imperfect tests on adjusted odds ratios (and thus on the identification of risk factors) is under-appreciated. The purpose of this article is to draw attention to the problem associated with modelling imperfect diagnostic tests, and propose simple Bayesian models to adequately address this issue. METHODS: A systematic literature review was conducted to determine the proportion of malaria studies that appropriately accounted for false-negatives/false-positives in a logistic regression setting. Inference from the standard logistic regression was also compared with that from three proposed Bayesian models using simulations and malaria data from the western Brazilian Amazon. RESULTS: A systematic literature review suggests that malaria epidemiologists are largely unaware of the problem of using logistic regression to model imperfect diagnostic test results. Simulation results reveal that statistical inference can be substantially improved when using the proposed Bayesian models versus the standard logistic regression. Finally, analysis of original malaria data with one of the proposed Bayesian models reveals that microscopy sensitivity is strongly influenced by how long people have lived in the study region, and an important risk factor (i.e., participation in forest extractivism) is identified that would have been missed by standard logistic regression. CONCLUSION: Given the numerous diagnostic methods employed by malaria researchers and the ubiquitous use of logistic regression to model the results of these diagnostic tests, this paper provides critical guidelines to improve data analysis practice in the presence of misclassification error. Easy-to-use code that can be readily adapted to WinBUGS is provided, enabling straightforward implementation of the proposed Bayesian models. PMID- 26537374 TI - The societal opportunities and challenges of genome editing. AB - The genome editing platforms currently in use have revolutionized the field of genetics. At an accelerating rate, these tools are entering areas with direct impact on human well being. Here, we discuss applications in agriculture and in medicine, and examine some associated societal issues. PMID- 26537375 TI - Evolution of Immunity and Pathogens. AB - Host and pathogen engage in a constant evolutionary struggle known as a "Red Queen Paradigm". In this struggle, natural selection favours the pathogen which evolves effective virulence mechanisms and the host which is able to field adequate resistance strategies. A number of factors limit what each side can do. These include the fact that the elaboration of virulence or resistance mechanisms results in costs in genetic fitness and requires the use of ever more of the limited number of genes available in the genome. In addition, since the pathogen usually has a very much shorter generation time than the host, it can fix new virulence mutations much more quickly than the host can evolve matching resistance mechanisms. Finally, the host must ensure that its defence system does not result in unacceptable levels of collateral damage to its own tissues. This chapter briefly outlines how these considerations shape host-pathogen interactions. PMID- 26537376 TI - A Host-Pathogen Interaction Reduced to First Principles: Antigenic Variation in T. brucei. AB - Antigenic variation is a common microbial survival strategy, powered by diversity in expressed surface antigens across the pathogen population over the course of infection. Even so, among pathogens, African trypanosomes have the most comprehensive system of antigenic variation described. African trypanosomes (Trypanosoma brucei spp.) are unicellular parasites native to sub-Saharan Africa, and the causative agents of sleeping sickness in humans and of n'agana in livestock. They cycle between two habitats: a specific species of fly (Glossina spp. or, colloquially, the tsetse) and the bloodstream of their mammalian hosts, by assuming a succession of proliferative and quiescent developmental forms, which vary widely in cell architecture and function. Key to each of the developmental forms that arise during these transitions is the composition of the surface coat that covers the plasma membrane. The trypanosome surface coat is extremely dense, covered by millions of repeats of developmentally specified proteins: procyclin gene products cover the organism while it resides in the tsetse and metacyclic gene products cover it while in the fly salivary glands, ready to make the transition to the mammalian bloodstream. But by far the most interesting coat is the Variant Surface Glycoprotein (VSG) coat that covers the organism in its infectious form (during which it must survive free living in the mammalian bloodstream). This coat is highly antigenic and elicits robust VSG specific antibodies that mediate efficient opsonization and complement mediated lysis of the parasites carrying the coat against which the response was made. Meanwhile, a small proportion of the parasite population switches coats, which stimulates a new antibody response to the prevalent (new) VSG species and this process repeats until immune system failure. The disease is fatal unless treated, and treatment at the later stages is extremely toxic. Because the organism is free living in the blood, the VSG:antibody surface represents the interface between pathogen and host, and defines the interaction of the parasite with the immune response. This interaction (cycles of VSG switching, antibody generation, and parasite deletion) results in stereotypical peaks and troughs of parasitemia that were first recognized more than 100 years ago. Essentially, the mechanism of antigenic variation in T. brucei results from a need, at the population level, to maintain an extensive repertoire, to evade the antibody response. In this chapter, we will examine what is currently known about the VSG repertoire, its depth, and the mechanisms that diversify it both at the molecular (DNA) and at the phenotypic (surface displayed) level, as well as how it could interact with antibodies raised specifically against it in the host. PMID- 26537377 TI - Antigenic Variation in Plasmodium falciparum. AB - Plasmodium falciparum is the protozoan parasite that causes most malaria associated morbidity and mortality in humans with over 500,000 deaths annually. The disease symptoms are associated with repeated cycles of invasion and asexual multiplication inside red blood cells of the parasite. Partial, non-sterile immunity to P. falciparum malaria develops only after repeated infections and continuous exposure. The successful evasion of the human immune system relies on the large repertoire of antigenically diverse parasite proteins displayed on the red blood cell surface and on the merozoite membrane where they are exposed to the human immune system. Expression switching of these polymorphic proteins between asexual parasite generations provides an efficient mechanism to adapt to the changing environment in the host and to maintain chronic infection. This chapter discusses antigenic diversity and variation in the malaria parasite and our current understanding of the molecular mechanisms that direct the expression of these proteins. PMID- 26537378 TI - Polymorphic Mucin-Like Proteins in Schistosoma mansoni, a Variable Antigen and a Key Component of the Compatibility Between the Schistosome and Its Snail Host. AB - The arms race between vertebrate hosts and parasites has led to diversification systems able to generate huge repertoires of immune recognition receptors and antigenic variants. Until recently, the invertebrate immunity was considered to be poorly specific, and consequently, antigenic variability was not expected to be high for their respective parasites. In the present chapter, we show how the study of the interaction between the snail Biomphalaria glabrata and its parasite Schistosome mansoni has shaken this paradigm. We show that the fate of the interaction between the snail and its parasite is at least partly the result of the concordance of highly variable repertoires of immune recognition receptors in the snail and corresponding antigenic variants in the parasite. We call these antigenic variants of the schistosome Schistosoma mansoni polymorphic mucins (SmPoMucs). We show that their high level of diversification is the result of a complex cascade of mechanisms, thus presenting evidence for antigenic variation in a parasite infecting an invertebrate species. PMID- 26537379 TI - Fibrinogen-Related Proteins (FREPs) in Mollusks. AB - Anti-parasite responses of the snail Biomphalaria glabrata involve antigen reactive plasma lectins termed fibrinogen-related proteins (FREPs) comprising a C terminal fibrinogen (FBG) domain and one or two upstream immunoglobulin domains. FREPs are highly polymorphic; they derive from several gene families with multiple loci and alleles that are diversified by exon loss, alternative splicing, and random somatic mutation (gene conversion and point mutations). Individual B. glabrata snails have dynamically distinct FREP sequence repertoires. The immune relevance of B. glabrata FREPs is indicated by FREP binding to polymorphic antigens of (snail-specific) digenean parasites and altered resistance of B. glabrata to digeneans following RNAi knockdown of FREPs. The compatibility polymorphism hypothesis proposes that FREP mutation increases the range of germline-encoded immune recognition in B. glabrata to counter antigenically-varied parasites. Somatic mutation may result from sequence exchange among tandemly arranged FREP genes in the genome, and analysis of sequence variants also suggests involvement of cytidine deaminase-like activity or epigenetic regulation. Without current indications of selection or retention of effective sequence variants toward immunological memory, FREP diversification is thought to afford B. glabrata immunity that is anticipatory but not adaptive. More remains to be learned about this system; other mollusks elaborate diversified lectins consisting of single FBG domains, and bona fide FREPs were reported from additional gastropod species, but these may not be diversified. Future comparative immunological studies and gene discovery driven by next generation sequencing will further clarify taxonomic distribution of FREP diversification and the underlying mutator mechanisms as a component of immune function in mollusks. PMID- 26537380 TI - Somatic and Germline Diversification of a Putative Immunoreceptor within One Phylum: Dscam in Arthropods. AB - Arthropod Dscam, the homologue of the human Down Syndrome cell adhesion molecule, is a receptor used by the nervous and immune systems. Unlike in vertebrates, evolutionary pressure has selected and maintained a vast Dscam diversity of isoforms, known to specifying neuronal identity during the nervous system differentiation. This chapter examines the different modes of Dscam diversification in the context of arthropods' evolution and that of their immune system, where its role is controversial. In the single Dscam gene of insects and crustaceans, mutually exclusive alternative splicing affects three clusters of duplicated exons encoding the variable parts of the receptor. The Dscam gene produces over 10,000 isoforms. In the more basal arthropods such as centipedes, Dscam diversity results from a combination of many germline genes (over 80) with, in about half of those, the possibility of alternative splicing affecting only one exon cluster. In the even more basal arthropods, such as chelicerates, no splicing possibility is detected, but there exist dozens of germline Dscam genes. Compared to controlling the expression of multiple germline genes, the somatic mutually alternative splicing within a single gene may offer a simplified way of expressing a large Dscam repertoire. Expressed by hemocytes, Dscam is considered a phagocytic receptor but is also encountered in solution. More information is necessary about its binding to pathogens, its role in phagocytosis, its possible role in specifying hemocyte identity, its kinetics of expression, and the regulation of its RNA splicing to understand how its diversity is linked to immunity. PMID- 26537381 TI - An Immune Effector System in the Protochordate Gut Sheds Light on Fundamental Aspects of Vertebrate Immunity. AB - A variety of germline and somatic immune mechanisms have evolved in vertebrate and invertebrate species to detect a wide array of pathogenic invaders. The gut is a particularly significant site in terms of distinguishing pathogens from potentially beneficial microbes. Ciona intestinalis, a filter-feeding marine protochordate that is ancestral to the vertebrate form, possesses variable region containing chitin-binding proteins (VCBPs), a family of innate immune receptors, which recognize bacteria through an immunoglobulin-type variable region. The manner in which VCBPs mediate immune recognition appears to be related to the development and bacterial colonization of the gut, and it is likely that these molecules are critical elements in achieving overall immune and physiological homeostasis. PMID- 26537382 TI - Variable Lymphocyte Receptors: A Current Overview. AB - Jawless vertebrates represented by lampreys and hagfish mount antigen-specific immune responses using variable lymphocyte receptors. These receptors generate diversity comparable to that of T-cell and B-cell receptors by assembling multiple leucine-rich repeat modules with highly variable sequences. Although it is true that jawed and jawless vertebrates have structurally unrelated antigen receptors, their adaptive immune systems have much in common. Most notable is the conservation of lymphocyte lineages. It appears that specialized lymphocyte lineages emerged in a common vertebrate ancestor and that jawed and jawless vertebrates co-opted different antigen receptors within the context of such lymphocyte lineages. PMID- 26537383 TI - Antibody Repertoires in Fish. AB - As in mammals, cartilaginous and teleost fishes possess adaptive immune systems based on antigen recognition by immunoglobulins (Ig), T cell receptors (TCR), and major histocompatibility complex molecules (MHC) I and MHC II molecules. Also it is well established that fish B cells and mammalian B cells share many similarities, including Ig gene rearrangements, and production of membrane Ig and secreted Ig forms. This chapter provides an overview of the IgH and IgL chains in cartilaginous and bony fish, including their gene organizations, expression, diversity of their isotypes, and development of the primary repertoire. Furthermore, when possible, we have included summaries of key studies on immune mechanisms such as allelic exclusion, somatic hypermutation, affinity maturation, class switching, and mucosal immune responses. PMID- 26537385 TI - The Evolution and Structure of Atypical T Cell Receptors. AB - The T cell receptor structure and genetic organization have been thought to have been stable in vertebrate evolution relative to the immunoglobulins. For the most part, this has been true and the content and organization of T cell receptor genes has been fairly conserved over the past 400 million years of gnathostome evolution. Analyses of TCRdelta chains in a broad range of vertebrate lineages over the past decade have revealed a remarkable and previously unrealized degree of plasticity. This plasticity can generally be described in two forms. The first is broad use of antibody heavy chain variable genes in place of the conventional Vdelta. The second form containing an unusual three extracellular domain structures has evolved independently in both cartilaginous fishes and mammals. Two well-studied vertebrate lineages, the eutherian mammals such as mice and humans and teleost fishes, lack any of these alternative TCR forms, contributing to why they went undiscovered for so long after the initial description of the conventional TCR chains three decades ago. This chapter describes the state of knowledge of these unusual TCR forms, both their structure and genetics, and current ideas on their function. PMID- 26537384 TI - Unique Features of Fish Immune Repertoires: Particularities of Adaptive Immunity Within the Largest Group of Vertebrates. AB - Fishes (i.e., teleost fishes) are the largest group of vertebrates. Although their immune system is based on the fundamental receptors, pathways, and cell types found in all groups of vertebrates, fishes show a diversity of particular features that challenge some classical concepts of immunology. In this chapter, we discuss the particularities of fish immune repertoires from a comparative perspective. We examine how allelic exclusion can be achieved when multiple Ig loci are present, how isotypic diversity and functional specificity impact clonal complexity, how loss of the MHC class II molecules affects the cooperation between T and B cells, and how deep sequencing technologies bring new insights about somatic hypermutation in the absence of germinal centers. The unique coexistence of two distinct B-cell lineages respectively specialized in systemic and mucosal responses is also discussed. Finally, we try to show that the diverse adaptations of immune repertoires in teleosts can help in understanding how somatic adaptive mechanisms of immunity evolved in parallel in different lineages across vertebrates. PMID- 26537386 TI - Diversification of the Primary Antibody Repertoire by AID-Mediated Gene Conversion. AB - Gene conversion, mediated by activation-induced cytidine deaminase (AID), has been found to contribute to generation of the primary antibody repertoire in several vertebrate species. Generation of the primary antibody repertoire by gene conversion of immunoglobulin (Ig) genes occurs primarily in gut-associated lymphoid tissues (GALT) and is best described in chicken and rabbit. Here, we discuss current knowledge of the mechanism of gene conversion as well as the contribution of the microbiota in promoting gene conversion of Ig genes. Finally, we propose that the antibody diversification strategy used in GALT species, such as chicken and rabbit, is conserved in a subset of human and mouse B cells. PMID- 26537387 TI - Antibody Isotype Switching in Vertebrates. AB - The humoral or antibody-mediated immune response in vertebrates has evolved to respond to diverse antigenic challenges in various anatomical locations. Diversification of the immunoglobulin heavy chain (IgH) constant region via isotype switching allows for remarkable plasticity in the immune response, including versatile tissue distribution, Fc receptor binding, and complement fixation. This enables antibody molecules to exert various biological functions while maintaining antigen-binding specificity. Different immunoglobulin (Ig) classes include IgM, IgD, IgG, IgE, and IgA, which exist as surface-bound and secreted forms. High-affinity autoantibodies are associated with various autoimmune diseases such as lupus and arthritis, while defects in components of isotype switching are associated with infections. A major route of infection used by a large number of pathogens is invasion of mucosal surfaces within the respiratory, digestive, or urinary tract. Most infections of this nature are initially limited by effector mechanisms such as secretory IgA antibodies. Mucosal surfaces have been proposed as a major site for the genesis of adaptive immune responses, not just in fighting infections but also in tolerating commensals and constant dietary antigens. We will discuss the evolution of isotype switching in various species and provide an overview of the function of various isotypes with a focus on IgA, which is universally important in gut homeostasis as well as pathogen clearance. Finally, we will discuss the utility of antibodies as therapeutic modalities. PMID- 26537388 TI - Childbearing and Economic Work: The Health Balance of Women in Accra, Ghana. AB - OBJECTIVES: This study aims to investigate (1) whether the health of working women with young children differs from that of working women without young children, and (2) which social factors mediate the relationship between economic and maternal role performance and health among mothers with young children. METHODS: The analyses uses panel data from 697 women present in both waves of the Women's Health Study for Accra (WHSA-I and WHSA-II); a community based study of women aged 18 years and older in the Accra Metropolitan Area of Ghana conducted in 2003 and 2008-2009. Change in physical and mental health between the survey waves is compared between women with a biological child alive at WHSA-II and born since WHSA-I and women without a living biological child at WHSA-II born in the interval. To account for attrition between the two survey waves selection models were used with unconditional change score models being used as the outcome model. RESULTS: We found in our sample of working women that those who had a child born between WHSA-I and WHSA-II who was still alive at WHSA-II did not experience a change in mental or physical health different from other women. Among working women with young children, educational status, relationship to the household head and household demography were associated with change in mental health at the 5 % level, whilst migration status and household demography was associated with change in physical health scores. CONCLUSION: The results suggest there are no health penalties of combining work and childbearing among women with young children in Accra, Ghana. PMID- 26537390 TI - Endoscopic-assisted removal of traumatic brain hemorrhage: case report and technical note. AB - The endoscopic technique has been described as a minimally invasive method for spontaneous hematoma evacuation, as a safe and effective treatment. Nevertheless, to our knowledge, there is no description of a technical report of traumatic intracerebral hematoma removal using the neuroendoscope. A 47-year-old man was admitted sustaining 13 points in Glasgow coma scale with brain computed tomography (CT) scan showing a temporal contusion. Guided by a 3D reconstructed CT, using the program OsiriX(r), the posterior limit of the hematoma was identified. A burr hole was placed at the posterior temporal region, and we used the neuroendoscope to assist the hematoma evacuation. The postoperative tomography showed adequate hematoma removal. He was discharged from hospital 48 h after surgery. Two weeks later, he was conscious and oriented temporally. This endoscopic-assisted technique can provide safe removal of traumatic hematomas of the temporal lobe. PMID- 26537389 TI - Risk Factors Associated with Very Low Birth Weight in a Large Urban Area, Stratified by Adequacy of Prenatal Care. AB - OBJECTIVES: This study examined risk and protective factors associated with very low birth weight (VLBW) for babies born to women receiving adequate or inadequate prenatal care. METHODS: Birth records from St. Louis City and County from 2000 to 2009 were used (n = 152,590). Data was categorized across risk factors and stratified by adequacy of prenatal care (PNC). Multivariate logistic regression and population attributable risk (PAR) was used to explore risk factors for VLBW infants. RESULTS: Women receiving inadequate prenatal care had a higher prevalence of delivering a VLBW infant than those receiving adequate PNC (4.11 vs. 1.44 %, p < .0001). The distribution of risk factors differed between adequate and inadequate PNC regarding Black race (36.4 vs. 79.0 %, p < .0001), age under 20 (13.0 vs. 33.6 %, p < .0001), <13 years of education (35.9 vs. 77.9 %, p < .0001), Medicaid status (35.7 vs. 74.9, p < .0001), primiparity (41.6 vs. 31.4 %, p < .0001), smoking (9.7 vs. 24.5 %, p < .0001), and diabetes (4.0 vs. 2.4 %, p < .0001), respectively. Black race, advanced maternal age, primiparity and gestational hypertension were significant predictors of VLBW, regardless of adequate or inadequate PNC. Among women with inadequate PNC, Medicaid was protective against (aOR 0.671, 95 % CI 0.563-0.803; PAR -32.6 %) and smoking a risk factor for (aOR 1.23, 95 % CI 1.01, 1.49; PAR 40.1 %) VLBW. When prematurity was added to the adjusted models, the largest PAR shifts to education (44.3 %) among women with inadequate PNC. CONCLUSIONS: Community actions around broader issues of racism and social determinants of health are needed to prevent VLBW in a large urban area. PMID- 26537391 TI - Update on bedside ultrasound (US) diagnosis of acute cholecystitis (AC). AB - Acute cholecystitis (AC) represents a principal cause of morbidity worldwide and is one of the most frequent reasons for hospitalization due to gastroenteric tract diseases. AC should be suspected in presence of clinical signs and of gallstones on an imaging study. Upper abdominal US represents the first diagnostic imaging step in the case of suspected AC. Computed tomography (CT) with intravenous contrast (IV) or magnetic resonance imaging (MRI) with gadolinium contrast and technetium hepatobiliary iminodiacetic acid (Tc-HIDA) can be employed to exclude complications. US examination should be performed with right subcostal oblique, with longitudinal and intercostal scans. Normal gallbladder US findings and AC major and minor US signs are described. Polyps, sludge and gallbladder wall thickening represent the more frequent pitfalls and they must be differentiated from stones, duodenal artifacts and many other non inflammatory conditions that cause wall thickening, respectively. By means of bedside ultrasound, the finding of gallstones in combination with acute pain, when the clinician presses the gallbladder with the US probe (the sonographic Murphy's sign), has a 92.2 % positive predictive value for AC. In our preliminary experience, bedside US-performed by echoscopy (ES) and/or point-of-care US (POCUS) demonstrated good reliability in detecting signs of AC, and was always integrated with physical examination and performed by a skilled operator. PMID- 26537392 TI - Regenerative Medicine Build-Out. AB - Regenerative technologies strive to boost innate repair processes and restitute normative impact. Deployment of regenerative principles into practice is poised to usher in a new era in health care, driving radical innovation in patient management to address the needs of an aging population challenged by escalating chronic diseases. There is urgency to design, execute, and validate viable paradigms for translating and implementing the science of regenerative medicine into tangible health benefits that provide value to stakeholders. A regenerative medicine model of care would entail scalable production and standardized application of clinical grade biotherapies supported by comprehensive supply chain capabilities that integrate sourcing and manufacturing with care delivery. Mayo Clinic has rolled out a blueprint for discovery, translation, and application of regenerative medicine therapies for accelerated adoption into the standard of care. To establish regenerative medical and surgical service lines, the Mayo Clinic model incorporates patient access, enabling platforms and delivery. Access is coordinated through a designated portal, the Regenerative Medicine Consult Service, serving to facilitate patient/provider education, procurement of biomaterials, referral to specialty services, and/or regenerative interventions, often in clinical trials. Platforms include the Regenerative Medicine Biotrust and Good Manufacturing Practice facilities for manufacture of clinical grade products for cell-based, acellular, and/or biomaterial applications. Care delivery leverages dedicated interventional suites for provision of regenerative services. Performance is tracked using a scorecard system to inform decision making. The Mayo Clinic roadmap exemplifies an integrated organization in the discovery, development, and delivery of regenerative medicine within a growing community of practice at the core of modern health care. SIGNIFICANCE: Regenerative medicine is at the vanguard of health care poised to offer solutions for many of today's incurable diseases. Accordingly, there is a pressing need to develop, deploy, and demonstrate a viable framework for rollout of a regenerative medicine model of care. Translation of regenerative medicine principles into practice is feasible, yet clinical validity and utility must be established to ensure approval and adoption. Standardized and scaled-up regenerative products and services across medical and surgical specialties must in turn achieve a value-added proposition, advancing intended outcome beyond current management strategies. PMID- 26537393 TI - Live demonstration versus procedural video: a comparison of two methods for teaching an orthodontic laboratory procedure. AB - BACKGROUND: To measure the effectiveness of procedural video compared to live demonstration in transferring skills for fabricating orthodontic Adam's Clasp. MATERIALS AND METHODS: Forty-nine fourth-year undergraduate male dental students were randomly assigned to two groups. The students in group A (n = 26) attended a live demonstration performed by one faculty, while students in group B (n = 23) watched a procedural video. Both the procedural video and live demonstration described identical steps involved in fabricating the Adam's Clasp. Students in both groups were asked to fabricate an Adam's Clasp in addition to completing a questionnaire, to measure their perceptions and satisfaction with the two teaching methods and lab exercise. Blind assessment was performed by one faculty for both groups. RESULTS: The mean students' scores in the fabrication of the Adam's clasp were 6.69 and 6.78 for the live demonstration (group A) and the procedural video (group B), respectively. No significant difference was detected between the two groups (P = 0.864). Statistically significant difference was found in the mean response between the two groups for statement 6 on the questionnaire, "The steps in the teaching method were presented in a clear fashion and were easy to understand". A higher mean response for group B was found compared to group A (P = 0.049). No significant differences were found between the two groups for the other statements (P > 0.05). CONCLUSION: Procedural video is equally as effective as a live demonstration. Both methods should be considered in teaching undergraduate orthodontic courses in order to improve the learning experience and to match different learning preferences of students. PMID- 26537394 TI - Combined posterolateral corner and acute anterior cruciate ligament injuries in an adolescent cohort: a magnetic resonance imaging analysis. AB - PURPOSE: Failure of a reconstructed anterior cruciate ligament (ACL) has significant morbidity in the paediatric and adolescent patient population. Untreated concomitant posterolateral corner (PLC) injury is an identified cause of failed ACL reconstruction; however, the injury pattern has yet to be defined for the paediatric population. METHODS: Magnetic resonance imaging (MRI) studies of the knee performed between 1 January 2009 and 1 January 2013 were retrospectively reviewed. Imaging reports indicating an intra-substance injury of the ACL were reviewed, and all associated injured structures were recorded. Injury patterns were categorised by age, gender, physis status and associated injuries. Logistic regression and chi-square analyses compared ACL disruptions with and without concomitant PLC injuries. RESULTS: One hundred and twenty-eight patients (74 boys and 54 girls, average age 15.27 years) sustained an ACL disruption. Concomitant injury to the PLC was seen in 13.3% of injuries. Associated PLC injuries were significantly associated with lateral meniscus injury and Segond fractures. Lateral meniscus injury was predictive of PLC injury (p = 0.05) upon logistic regression analysis. CONCLUSION: Concomitant PLC injuries were found in 13.3% of all ACL disruptions on MRI analysis. Lateral meniscus injuries associated with an ACL disruption were predictive of concomitant PLC injury. Combined injury of the ACL and lateral meniscus should prompt close scrutiny to PLC structures. PMID- 26537395 TI - Can the gracilis replace the anterior cruciate ligament in the knee? A biomechanical study. AB - PURPOSE: The purpose of this study was to determine whether a four-strand gracilis-only construct possesses the biomechanical properties needed to act as an anterior cruciate ligament (ACL) reconstruction graft. METHODS: This was a pilot study with 32 cadaver specimens. The biomechanical properties of three types of grafts were determined using validated tensile testing methods: patellar tendon (BTB), both hamstring tendons together (GST4) and gracilis alone (G4). RESULTS: The maximum load at failure of the G4 was 416.4 N (+/-187.7). The GST4 and BTB had a maximum load at failure of 473.5 N (+/-176.9) and 413.3 N (+/ 120.4), respectively. The three groups had similar mean maximum load and stiffness values. The patellar tendon had significantly less elongation at failure than the other two graft types. CONCLUSIONS: The biomechanical properties of a four-strand gracilis construct are comparable to the ones of standard grafts. This type of graft would be useful in the reconstruction of the anteromedial bundle in patients with partial ACL ruptures. PMID- 26537396 TI - Antibodies from combinatorial libraries use functional receptor pleiotropism to regulate cell fates. AB - To date, most antibodies from combinatorial libraries have been selected purely on the basis of binding. However, new methods now allow selection on the basis of function in animal cells. These selected agonist antibodies have given new insights into the important problem of signal transduction. Remarkably, when some antibodies bind to a given receptor they induce a cell fate that is different than that induced by the natural agonist to the same receptor. The fact that receptors can be functionally pleiotropic may yield new insights into the important problem of signal transduction. PMID- 26537397 TI - Torque, chemistry and efficiency in molecular motors: a study of the rotary chemical coupling in F1-ATPase. AB - Detailed understanding of the action of biological molecular machines must overcome the challenge of gaining a clear knowledge of the corresponding free energy landscape. An example for this is the elucidation of the nature of converting chemical energy to torque and work in the rotary molecular motor of F1 ATPase. A major part of the challenge involves understanding the rotary-chemical coupling from a non-phenomenological structure/energy description. Here we focused on using a coarse-grained model of F1-ATPase to generate a structure based free-energy landscape of the rotary-chemical process of the whole system. In particular, we concentrated on exploring the possible impact of the position of the catalytic dwell on the efficiency and torque generation of the molecular machine. It was found that the experimentally observed torque can be reproduced with landscapes that have different positions for the catalytic dwell on the rotary-chemical surface. Thus, although the catalysis is undeniably required for torque generation, the experimentally observed position of the catalytic dwell at 80 degrees might not have a clear advantage for the force generation by F1 ATPase. This further implies that the rotary-chemical couplings in these biological motors are quite robust and their efficiencies do not depend explicitly on the position of the catalytic dwells. Rather, the specific positioning of the dwells with respect to the rotational angle is a characteristic arising due to the structural construct of the molecular machine and might not bear any clear connection to the thermodynamic efficiency for the system. PMID- 26537398 TI - The nature of chemical innovation: new enzymes by evolution. AB - I describe how we direct the evolution of non-natural enzyme activities, using chemical intuition and information on structure and mechanism to guide us to the most promising reaction/enzyme systems. With synthetic reagents to generate new reactive intermediates and just a few amino acid substitutions to tune the active site, a cytochrome P450 can catalyze a variety of carbene and nitrene transfer reactions. The cyclopropanation, N-H insertion, C-H amination, sulfimidation, and aziridination reactions now demonstrated are all well known in chemical catalysis but have no counterparts in nature. The new enzymes are fully genetically encoded, assemble and function inside of cells, and can be optimized for different substrates, activities, and selectivities. We are learning how to use nature's innovation mechanisms to marry some of the synthetic chemists' favorite transformations with the exquisite selectivity and tunability of enzymes. PMID- 26537400 TI - Chiral discrimination in NMR spectroscopy. AB - Nuclear magnetic resonance is the most important form of molecular spectroscopy in chemistry and biochemistry but it is normally blind to chirality. It was predicted in 2004 that precessing nuclear spins in chiral molecules in a liquid in a strong magnetic field induce a rotating electric polarization that is of opposite sign for enantiomers. This polarization arises from the distortion of the electronic structure by the nuclear magnetic moment in the presence of the strong magnetic field and is equivalent to the linear effect of an electric field on the nuclear shielding tensor. The polarization is strongly enhanced in dipolar molecules through the partial orientation of the permanent dipole through the antisymmetric part of the nuclear magnetic shielding tensor. Alternatively, an applied electric field will induce a chirally sensitive magnetization perpendicular to the field and to the nuclear spin. Progress towards the experimental realization of chiral discrimination by NMR is assessed. PMID- 26537399 TI - Electron flow through biological molecules: does hole hopping protect proteins from oxidative damage? AB - Biological electron transfers often occur between metal-containing cofactors that are separated by very large molecular distances. Employing photosensitizer modified iron and copper proteins, we have shown that single-step electron tunneling can occur on nanosecond to microsecond timescales at distances between 15 and 20 A. We also have shown that charge transport can occur over even longer distances by hole hopping (multistep tunneling) through intervening tyrosines and tryptophans. In this perspective, we advance the hypothesis that such hole hopping through Tyr/Trp chains could protect oxygenase, dioxygenase, and peroxidase enzymes from oxidative damage. In support of this view, by examining the structures of P450 (CYP102A) and 2OG-Fe (TauD) enzymes, we have identified candidate Tyr/Trp chains that could transfer holes from uncoupled high-potential intermediates to reductants in contact with protein surface sites. PMID- 26537401 TI - Chemical materials and their regulation of the movement of molecules. AB - Materials chemistry has been fundamental to the enormous field that encompasses the delivery of molecules both to desired sites and/or at desired rates and durations. The field encompasses the delivery of molecules including fertilizers, pesticides, herbicides, food ingredients, fragrances and biopharmaceuticals. A personal perspective is provided on our early work in this field that has enabled the controlled release of ionic substances and macromolecules. Also discussed are new paradigms in creating biomaterials for human use, the non-invasive delivery of molecules through the skin and lungs, the development of intelligent delivery systems and extensions to nanomedicine. With the advent of potentially newer biopharmaceutics such as siRNA, mRNA and gene editing approaches and their use being limited by delivery, future research in this field may be more critical than ever before. PMID- 26537402 TI - A triazole linkage that mimics the DNA phosphodiester group in living systems. AB - We describe the development of a chemical process based on the CuAAC reaction (click chemistry) to ligate DNA strands and produce an unnatural triazole backbone linkage. The chemical reaction is templated by a complementary DNA splint which accelerates the reaction and provides the required specificity. The resultant 1,4-triazole linkage is read through by DNA and RNA polymerases and is biocompatible in bacterial and human cells. This work has implications for the synthesis of chemically modified genes and other large modified DNA and RNA constructs. PMID- 26537403 TI - Acceleration of reaction in charged microdroplets. AB - Using high-resolution mass spectrometry, we have studied the synthesis of isoquinoline in a charged electrospray droplet and the complexation between cytochrome c and maltose in a fused droplet to investigate the feasibility of droplets to drive reactions (both covalent and noncovalent interactions) at a faster rate than that observed in conventional bulk solution. In both the cases we found marked acceleration of reaction, by a factor of a million or more in the former and a factor of a thousand or more in the latter. We believe that carrying out reactions in microdroplets (about 1-15 MUm in diameter corresponding to 0.5 pl - 2 nl) is a general method for increasing reaction rates. The mechanism is not presently established but droplet evaporation and droplet confinement of reagents appear to be two important factors among others. In the case of fused water droplets, evaporation has been shown to be almost negligible during the flight time from where droplet fusion occurs and the droplets enter the heated capillary inlet of the mass spectrometer. This suggests that (1) evaporation is not responsible for the acceleration process in aqueous droplet fusion and (2) the droplet-air interface may play a significant role in accelerating the reaction. We argue that this 'microdroplet chemistry' could be a remarkable alternative to accelerate slow and difficult reactions, and in conjunction with mass spectrometry, it may provide a new arena to study chemical and biochemical reactions in a confined environment. PMID- 26537404 TI - A twisting story: how a single gene twists a snail? Mechanogenetics. AB - Left-right (l-r) symmetry breaking and the establishment of asymmetric animal body plan during embryonic development are fundamental questions in nature. The molecular basis of l-r symmetry breaking of snails is a fascinating topic as it is determined by a maternal single handedness-determining locus at a very early developmental stage. This perspective describes the current state of the art of the chiromorphogenesis, mainly based on our own work, i.e. the first step of l-r symmetry breaking, as proven by our "Mechanogenetics", before the start of zygotic gene expression, transfer of chirality information to the cell-fate determining stage, and the expression of nodal at the blastula stage. The Nodal signalling pathway is a common mechanism in vertebrates' chiromorphogenesis in later development. Studies on snails, especially Lymnaea (L.) stagnalis, shall give important insights into the molecular basis of chiromorphogenesis not only in Lophotrochozoa but in vertebrates as well. PMID- 26537405 TI - A sequence-specific DNA binding small molecule triggers the release of immunogenic signals and phagocytosis in a model of B-cell lymphoma. AB - Means to cause an immunogenic cell death could lead to significant insight into how cancer escapes immune control. In this study, we screened a library of five pyrrole-imidazole polyamides coding for different DNA sequences in a model of B cell lymphoma for the upregulation of surface calreticulin, a pro-phagocytosis signal implicated in immunogenic cell death. We found that hairpin polyamide 1 triggers the release of the damage-associated molecular patterns calreticulin, ATP and HMGB1 in a slow necrotic-type cell death. Consistent with this signaling, we observed an increase in the rate of phagocytosis by macrophages after the cancer cells were exposed to polyamide 1. The DNA sequence preference of polyamide 1 is 5'-WGGGTW-3' (where W = A/T), indicated by the pairing rules and confirmed by the Bind-n-Seq method. The close correspondence of this sequence with the telomere-repeat sequence suggests a potential mechanism of action through ligand binding at the telomere. This study reveals a chemical means to trigger an inflammatory necrotic cell death in cancer cells. PMID- 26537406 TI - Chromatin-remodeling and the initiation of transcription. AB - The nucleosome serves as a general gene repressor by the occlusion of regulatory and promoter DNA sequences. Repression is relieved by the SWI/SNF-RSC family of chromatin-remodeling complexes. Research reviewed here has revealed the essential features of the remodeling process. PMID- 26537407 TI - Unresolved questions in human copper pump mechanisms. AB - Copper (Cu) is an essential transition metal providing activity to key enzymes in the human body. To regulate the levels and avoid toxicity, cells have developed elaborate systems for loading these enzymes with Cu. Most Cu-dependent enzymes obtain the metal from the membrane-bound Cu pumps ATP7A/B in the Golgi network. ATP7A/B receives Cu from the cytoplasmic Cu chaperone Atox1 that acts as the cytoplasmic shuttle between the cell membrane Cu importer, Ctr1 and ATP7A/B. Biological, genetic and structural efforts have provided a tremendous amount of information for how the proteins in this pathway work. Nonetheless, basic mechanistic-biophysical questions (such as how and where ATP7A/B receives Cu, how ATP7A/B conformational changes and domain-domain interactions facilitate Cu movement through the membrane, and, finally, how target polypeptides are loaded with Cu in the Golgi) remain elusive. In this perspective, unresolved inquiries regarding ATP7A/B mechanism will be highlighted. The answers are important from a fundamental view, since mechanistic aspects may be common to other metal transport systems, and for medical purposes, since many diseases appear related to Cu transport dysregulation. PMID- 26537408 TI - Accelerated molecular dynamics simulations of ligand binding to a muscarinic G protein-coupled receptor. AB - Elucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein-ligand binding, especially the drug recognition of GPCRs. PMID- 26537409 TI - The evolution of primary hyperparathyroidism. PMID- 26537410 TI - Effectiveness of a serious game for medical education on insulin therapy: a pilot study. AB - OBJECTIVE: We report the preliminary assessment of InsuOnline(c), a serious game designed for medical education on insulin therapy. MATERIALS AND METHODS: We conducted a pilot study with 41 undergraduate medical students and Internal Medicine residents to assess the educational effectiveness of InsuOnline(c), as compared to a traditional educational activity (lecture, cases discussion). Knowledge, skills and beliefs on insulin therapy were evaluated by a questionnaire applied before, immediately after, and 3 months after both interventions. RESULTS: Mean knowledge/skills score was improved from 68% to 89% in traditional education group (n = 23; p < 0.001), and from 61% to 90% in game group (n = 18; p < 0.001). After 3 months, mean score decreased (to 80% in traditional education group, and to 78% in game group; p < 0.001 for both) but remained significantly higher than at baseline in both groups (p < 0.001 for both). Although mean score was lower in game group than in traditional education group at baseline (p = 0.04), no difference remained between groups either immediately or 3 months post-intervention. Score increment was better with the game (29%) than with traditional education (21%; p = 0.04). Beliefs improved in the game group only. CONCLUSIONS: InsuOnline(c) is at least as effective as a traditional educational activity for medical education on insulin therapy, and it can a good option for large-scale continuing medical education on diabetes. PMID- 26537411 TI - Indications for fine-needle aspiration in spongiform thyroid nodules. PMID- 26537412 TI - RET Y791F: alone or accompanied? PMID- 26537413 TI - Article on urgent cancer referral pathway did not take lead time bias into account. PMID- 26537414 TI - The usefulness of routine histopathology of bilateral nasal polyps - a systematic review, meta-analysis, and cost evaluation. AB - BACKGROUND: Controversy regarding the usefulness of routine histopathological examination of bilateral nasal polyps removed during endoscopic sinus surgery to identify occult diagnoses still exists. There is a paucity of high-level evidence in the literature. METHODS: A systematic review and meta-analysis was conducted. Two independent reviewers were used. Pooled proportions and numbers needed to screen were calculated. A cost per life year model was generated based on varying survival benefits and compared to other Canadian screening programs to provide financial context. RESULTS: Six studies (n = 3772 patients) were included. Of the 3772 patients, 3751 had a pre-operative clinical and post-operative pathological diagnosis of inflammatory nasal polyps. Agreement proportion was 99.44 %. There were 18 unexpected benign and three unexpected malignant diagnoses identified. This translated to a proportion of 0.48 and 0.08 % respectively. Number needed to screen was 210 and 1258 respectively. Pooled proportion for expected findings using a random effect model was 0.99 (95 % CI = 0.99-1). Pooled proportion for unexpected benign findings using a random effect model was 0.00522 (95 % CI = 0.00133-0.01). Pooled proportion for unexpected malignant findings using a random effect model was 0.00107 (95 % CI = 0.000147-0.00283). The cost to pick up one unexpected benign diagnosis was $14557.2. The cost to pick up 1 unexpected malignant diagnosis was $87204.56. Cost per quality life year calculated ranged from 3211.83 to $64677.58 based on varying assumptions on the survival benefits of identifying an unexpected malignancy. CONCLUSIONS: Routine pathological examination in screening for neoplasia may be low yield, however, no compelling evidence was found to cease such practice. Surgeons should exercise individual judgment in requesting routine examination. PMID- 26537415 TI - Outer domains of integrase within retroviral intasomes are dispensible for catalysis of DNA integration. AB - Retroviral DNA integration is mediated by nucleoprotein complexes (intasomes) comprising a pair of viral DNA ends synapsed by a tetramer of integrase. Current integrase inhibitors act on intasomes rather than free integrase protein. Structural and functional studies of intasomes are essential to understand their mechanism of action and how the virus can escape by mutation. To date, prototype foamy virus (PFV) is the only retrovirus for which high-resolution structures of intasomes have been determined. In the PFV intasome structure, only the core domains of the outer subunits are ordered; the N-terminal domain, C-terminal domain, and N-terminal extension domain are disordered. Are these "missing domains" required for function or are they dispensable? We have devised a strategy to assemble "hetero-intasomes" in which the outer domains are not present as a tool to assess the functional role of the missing domains for catalysis of integration. We find that the disordered domains of outer subunits are not required for intasome assembly or catalytic activity as catalytic core domains can substitute for the outer subunits in the case of both PFV and HIV-1 intasomes. PMID- 26537416 TI - Examining variations in prescribing safety in UK general practice: cross sectional study using the Clinical Practice Research Datalink. AB - STUDY QUESTION: What is the prevalence of different types of potentially hazardous prescribing in general practice in the United Kingdom, and what is the variation between practices? METHODS: A cross sectional study included all adult patients potentially at risk of a prescribing or monitoring error defined by a combination of diagnoses and prescriptions in 526 general practices contributing to the Clinical Practice Research Datalink (CPRD) up to 1 April 2013. Primary outcomes were the prevalence of potentially hazardous prescriptions of anticoagulants, anti-platelets, NSAIDs, beta blockers, glitazones, metformin, digoxin, antipsychotics, combined hormonal contraceptives, and oestrogens and monitoring by blood test less frequently than recommended for patients with repeated prescriptions of angiotensin converting enzyme inhibitors and loop diuretics, amiodarone, methotrexate, lithium, or warfarin. STUDY ANSWER AND LIMITATIONS: 49 927 of 949 552 patients at risk triggered at least one prescribing indicator (5.26%, 95% confidence interval 5.21% to 5.30%) and 21 501 of 182 721 (11.8%, 11.6% to 11.9%) triggered at least one monitoring indicator. The prevalence of different types of potentially hazardous prescribing ranged from almost zero to 10.2%, and for inadequate monitoring ranged from 10.4% to 41.9%. Older patients and those prescribed multiple repeat medications had significantly higher risks of triggering a prescribing indicator whereas younger patients with fewer repeat prescriptions had significantly higher risk of triggering a monitoring indicator. There was high variation between practices for some indicators. Though prescribing safety indicators describe prescribing patterns that can increase the risk of harm to the patient and should generally be avoided, there will always be exceptions where the indicator is clinically justified. Furthermore there is the possibility that some information is not captured by CPRD for some practices-for example, INR results in patients receiving warfarin. WHAT THIS STUDY ADDS: The high prevalence for certain indicators emphasises existing prescribing risks and the need for their appropriate consideration within primary care, particularly for older patients and those taking multiple medications. The high variation between practices indicates potential for improvement through targeted practice level intervention. FUNDING, COMPETING INTERESTS, DATA SHARING: National Institute for Health Research through the Greater Manchester Primary Care Patient Safety Translational Research Centre (grant No GMPSTRC-2012-1). Data from CPRD cannot be shared because of licensing restrictions. PMID- 26537417 TI - ODTbrain: a Python library for full-view, dense diffraction tomography. AB - BACKGROUND: Analyzing the three-dimensional (3D) refractive index distribution of a single cell makes it possible to describe and characterize its inner structure in a marker-free manner. A dense, full-view tomographic data set is a set of images of a cell acquired for multiple rotational positions, densely distributed from 0 to 360 degrees. The reconstruction is commonly realized by projection tomography, which is based on the inversion of the Radon transform. The reconstruction quality of projection tomography is greatly improved when first order scattering, which becomes relevant when the imaging wavelength is comparable to the characteristic object size, is taken into account. This advanced reconstruction technique is called diffraction tomography. While many implementations of projection tomography are available today, there is no publicly available implementation of diffraction tomography so far. RESULTS: We present a Python library that implements the backpropagation algorithm for diffraction tomography in 3D. By establishing benchmarks based on finite difference time-domain (FDTD) simulations, we showcase the superiority of the backpropagation algorithm over the backprojection algorithm. Furthermore, we discuss how measurment parameters influence the reconstructed refractive index distribution and we also give insights into the applicability of diffraction tomography to biological cells. CONCLUSION: The present software library contains a robust implementation of the backpropagation algorithm. The algorithm is ideally suited for the application to biological cells. Furthermore, the implementation is a drop-in replacement for the classical backprojection algorithm and is made available to the large user community of the Python programming language. PMID- 26537418 TI - An Enantiopure Hydrogen-Bonded Octameric Tube: Self-Sorting and Guest-Induced Rearrangement. AB - The assembly of a discrete hydrogen-bonded molecular tube from eight small identical monomers is reported. Tube assembly was accomplished by means of selective heterodimerization between isocytosine and ureidopyrimidinone hydrogen bonding motifs embedded in an enantiopure bicyclic building block, leading to the selective formation of an octameric supramolecular tube. Upon introduction of a fullerene guest molecule, the octameric tube rearranges into a tetrameric inclusion complex and the hydrogen-bonding mode is switched. The dynamic behavior of the system is further explored in solvent- and guest-responsive self-sorting experiments. PMID- 26537419 TI - Impact of CYP2D6 Genetic Variation on the Response of the Cardiovascular Patient to Carvedilol and Metoprolol. AB - Carvedilol and metoprolol are two of the most commonly prescribed beta-blockers in cardiovascular medicine and primarily used in the treatment of hypertension and heart failure. Cytochrome P450 2D6 (CYP2D6) is the predominant metabolizing enzyme of these two drugs. Since the first description of a CYP2D6 sparteinedebrisoquine polymorphism in the mid-seventies, substantial genetic heterogeneity has been reported in the human CYP2D6 gene, with ~100 different polymorphisms identified to date. Some of these polymorphisms render the enzyme completely inactive while others do not modify its activity. Based on all the identified variants, four metabolizer phenotypes are nowadays used to characterize drug metabolism via CYP2D6 in humans: ultra-rapid metabolizer (UM); extensive metabolizer (EM); intermediate metabolizer (IM); and poor metabolizer (PM) phenotypes. As a consequence of these CYP2D6 metabolizer phenotypes, pharmacokinetics and bioavailability of carvedilol and metoprolol can range from therapeutically ineffective levels (in the UM patients) to excessive (overdose) and potentially toxic concentrations (in PM patients). This, in turn, can result in elevated risks for either treatment failure (in terms of blood pressure reduction of hypertensive patients and of improving survival and cardiovascular function of heart failure patients) or for adverse effects (e.g. hypotension and bradycardia). The present review will discuss the impact of these CYP2D6 genetic polymorphisms on the therapeutic responses of cardiovascular patients treated with either of these two beta-blockers. In addition, the potential advantages and disadvantages of implementing CYP2D6 genetic testing in the clinic to guide/personalize therapy with these two drugs will be discussed. PMID- 26537420 TI - Acute exposure to bisphenol A and cadmium causes changes in the morphology of gerbil ventral prostates and promotes alterations in androgen-dependent proliferation and cell death. AB - Bisphenol A (BPA) and cadmium (Cd) are environmental pollutants that are implicated in potential reproductive effects, including damage to the prostate gland. Their action during puberty requires analysis to determine the relationship of these compounds with the testosterone peak that occurs during this phase. This study evaluated whether exposure to BPA and Cd during puberty can cause changes in the morphology, proliferation and cell death and androgen receptor (AR) immunostaining of the ventral prostates of normal and castrated male gerbils (Meriones unguiculatus), considering an acute exposure to the chemicals and evaluation after short (52d) and long (120d) periods. Generally, morphometric-stereological results demonstrated that administration of BPA and Cd (individually or in combination) increased epithelial height, smooth muscle layer (SML) thickness and nuclear area and perimeter, and that these parameters were reduced in castrated animals. In addition, these groups showed important inflammatory processes but not prostate lesions. The proliferation/death rates of prostatic cells obtained by PCNA and TUNEL immunostaining demonstrated increased cell death in the 52d groups; in contrast, the gland acquired a more proliferative nature in the 120d groups. AR immunostaining showed that BPA and Cd compounds interact with ARs in different ways depending on the evaluated period and the hormonal profile of the animal. We conclude that BPA and cadmium are important agents in changing the morphology, proliferation and death of prostatic cells, in addition to interacting with ARs in different patterns. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 48-61, 2017. PMID- 26537421 TI - Autoimmune myelofibrosis with pancytopenia as a presenting manifestation of systemic lupus erythematosus responsive to mycophenolate mofetil. AB - Hematological abnormalities, such as anemia, leucopenia, and thrombocytopenia, secondary to peripheral destruction, are common in systemic lupus erythematosus (SLE). However, cytopenias from autoimmune myelofibrosis (AIMF) are extremely uncommon in SLE, with less than 40 reported cases in the literature. We report the case of a 33-year-old female who presented with bullous skin lesions and pancytopenia as the presenting manifestation of what was ultimately diagnosed as SLE with AIMF. She responded well to glucocorticoids and mycophenolate mofetil. PMID- 26537422 TI - Long-term outcomes with multi-targeted immunosuppressive protocol in children with severe proliferative lupus nephritis. AB - We have previously reported the one-year outcomes of 16 children with severe proliferative lupus nephritis (LN) who were treated using a multi-targeted induction protocol based on intravenous (IV) pulse methylprednisolone (MP), mycophenolate mofetil (MMF) and cyclosporine (CSA). This study examined the long term renal outcomes of these 16 children, followed up for a median duration of 9.2 years (range 5.8-14.2 years). Primary treatment outcome was complete renal remission. Secondary outcomes included patient and renal survival as well as relapse-free and event-free survival. All patients achieved complete renal remission within 24 months (median 8.7 months, range 4.0-24.0 months). Comparing clinical and laboratory parameters at induction and last follow-up, respectively, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (25.4 +/- 8.7 vs. 0.4 +/- 0.8), serum complement C3 (47 +/- 21 vs. 107 +/- 27 mg/dL), estimated glomerular filtration rate (eGFR) (72 +/- 57 vs. 109.7 +/- 43 ml/min/1.73 m2) and urine protein (6.97 +/- 7.09 vs. 0.2 +/- 0.02 g/day/1.73 m2) improved significantly (p < 0.05). Kaplan-Meier survival analysis showed a cumulative ten year renal relapse-free survival of 73.3% when considering relapses with severe proteinuria >1 g/day/1.73 m2. Cumulative probability that hospitalization would not be required was 93.8% at one year, and 71.4% at ten years. Our multi-targeted protocol for induction and maintenance therapy in Asian children with severe proliferative LN resulted in good long-term patient survival and renal preservation, with a good safety profile. PMID- 26537423 TI - BF*F allotype of the alternative pathway of complement: A marker of protection against the development of antiphospholipid antibodies in patients with systemic lupus erythematosus. AB - BACKGROUND: B factor (BF) from the alternative complement pathway seems to participate in the pathophysiology of systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). OBJECTIVE: To study the allotypic variability of BF in SLE and their associations with clinical and autoantibodies profile. METHODS: BF allotypes were determined by high-voltage agarose gel electrophoresis, under constant cooling, followed by immunofixation with anti human BF antibody, in 188 SLE patients and 103 controls. Clinical and serological data were obtained from medical examination and records. RESULTS: No significant differences of BF variants between patients and controls were found, neither in relation to epidemiologic or clinical manifestations. Associations of phenotype BF SS07 and allotype BF*S07 were found with anticardiolipin IgM (aCl-IgM) antibodies (p = 0.014 and p = 0.009 respectively), but not with aCl-IgG, lupus anticoagulant (LA), anti beta2GPI or clinical APS. A significant decrease in BF*F allotype (p = 0.043) and BF SF phenotype (p = 0.018) was detected in patients with anti-phospholipid antibodies as a whole (aCl-IgG, aCl-IgM, LA and anti beta2GPI). CONCLUSIONS: There is a link between phenotype BF SS07 and allotype BF*S07 with aCl-IgM in SLE patients; BF*F allotype could be considered a marker of protection against the development of antiphospholipid antibodies in these patients. PMID- 26537424 TI - Solvent-induced emission of organogels based on tris(phenylisoxazolyl)benzene. AB - Luminescent organogels based on tris(phenylisoxazolyl)benzene possessing perylenebisimide 1 were synthesized. The emission properties of the gels varied depending on the solvent properties: 1,4-dioxane gel was highly emissive, pyridine gel was moderately emissive, and benzene gel was non-emissive. PMID- 26537425 TI - Effect of introducing aib in a designed helical inhibitor of hdm2-p53 interaction: A molecular dynamics study. AB - Although p53 is an intrinsically disordered protein, upon binding to Hdm2, a short stretch (residues 19-25) comprising the binding epitope assumes a helical backbone. Because the allowed conformational space of alpha-aminoisobutyric acid (Aib) is restricted to only the helical basin, Aib-containing helical mimics of p53 (binding epitope) are expected to inhibit interaction between p53 and Hdm2 with a much stronger affinity than the wild type p53 peptide (binding epitope), due to the entropic advantage associated with Aib. However, the IC50 values for the disruption of p53-Hdm2 interaction by Aib-p53 peptides and wild type p53 peptide were found to be comparable (J. Peptide Res. 2002, 60:88-94). To understand why incorporation of Aib didn't substantially increase Hdm2 affinity of Aib-p53 peptides, a series of molecular dynamics simulations were performed. It was found that despite stabilizing a helical backbone in the unbound state, the Aib residues in Aib-p53 peptide arrested two functionally important side chains (F19 and W23) in non-productive conformations, resulting in relative side chain orientations of the binding triad F19-W23-L26 incompatible with the bound conformation. Therefore, although a Aib-induced pre-formed helical peptide backbone in the unbound state is expected to favor binding, the locked side-chain orientations of the binding triad in non-productive modes would disfavor binding. This study shows that when using Aib to design functionally important helical peptides, care must be taken to consider potential interactions between side chains of neighboring residues and Aib in the unbound state. PMID- 26537426 TI - Cytomegalovirus Immunoglobulin for Prophylaxis and Treatment of Cytomegalovirus Infection in the (Val)Ganciclovir Era: A Single-Center Experience. AB - BACKGROUND: Evidence concerning the effectiveness of anti-cytomegalovirus immunoglobulin (CMVIg) following lung transplantation in the era of new antiviral agents is limited and controversial. MATERIAL AND METHODS: At-risk patients (donor seropositive/recipient seronegative [D+/R-] and R+) received valganciclovir for 3 months (R+) or 6 months (D+/R). CMVIg (2 mg/kg) was given to D+/R- patients on days 1, 4, 8, 15, and 30 post-transplant, then monthly for a further year. Patients with valganciclovir-induced leukopenia were switched to CMVIg (2 mg/kg) prophylaxis. Tissue-invasive disease was treated with intravenous ganciclovir with CMVIg (2 mg/kg) every other day for 1 week and then weekly until discharge. RESULTS: Of 159 patients analyzed, 26 (17%) were D+/R-. Cytomegalovirus (CMV) viremia was more frequent in D+/R- recipients than in R+ patients (61% vs. 35%; P<0.05), but developed at a similar time (mean 10+/-6 vs. 11+/-7 months) and resolved in all cases following treatment. One patient developed clinical and laboratory signs of CMV syndrome (fever >38 degrees C), leukopenia, and detection of CMV in blood. Ten patients developed tissue-invasive disease after completion of prophylaxis (5 pneumonitis and 5 gastrointestinal disease); all were successfully treated with combined intravenous ganciclovir and CMVIg. None of the 18 donor seropositive/recipient seronegative patients who were switched from valganciclovir to CMVIg for persistent leukopenia developed CMV viremia during treatment. No cases of CMV infection or disease were attributable to ganciclovir-resistant strains. During follow-up, 44 patients died (4/26 R+/D- [15%], 40/133 R+ [30%), none directly due to CMV infection. CONCLUSIONS: Combined prophylaxis with valganciclovir and CMVIg delayed CMV viremia and tissue-invasive disease in D+/R- lung transplant recipients, and prevented CMV-related mortality and development of ganciclovir resistance. CMVIg monotherapy prophylaxis was effective in R+ patients with ganciclovir-related toxicity. PMID- 26537428 TI - Assessment of local reaction to vaccines in live piglets with magnetic resonance imaging compared to histopathology. AB - The safety of veterinary vaccines is assessed in clinical trials in Europe. The assessment of the local tissue reaction to vaccination by magnetic resonance imaging (MRI) could reduce the number of animals needed because repeated examinations can be performed in the same animal over time. The present study compared the evaluation of local tissue reactions to vaccination using MRI in live pigs with histopathology of porcine tissue, the current gold standard in regulatory safety testing. Eight piglets each were administered one of two commercial vaccines into marked injection sites. All animals were sedated and scanned repeatedly by MRI using a contrast agent up to day 29 after vaccination. On day 29, the animals were euthanized and underwent a pathological examination. The MRI results were compared with the pathomorphological findings at the injection site by regression analysis. The MR images and the pathological examinations yielded matching results concerning the sizes of the affected tissue volumes or areas. The use of MRI for regulatory safety testing can reduce the number of animals needed to 8 per examination group. The volume of a local reaction and its progression over time can be evaluated and documented. If persistent lesions develop a final pathomorphological examination is needed to identify the kind and local distribution of the reaction. PMID- 26537427 TI - Spermatogenesis: The Commitment to Meiosis. AB - Mammalian spermatogenesis requires a stem cell pool, a period of amplification of cell numbers, the completion of reduction division to haploid cells (meiosis), and the morphological transformation of the haploid cells into spermatozoa (spermiogenesis). The net result of these processes is the production of massive numbers of spermatozoa over the reproductive lifetime of the animal. One study that utilized homogenization-resistant spermatids as the standard determined that human daily sperm production (dsp) was at 45 million per day per testis (60). For each human that means ~1,000 sperm are produced per second. A key to this level of gamete production is the organization and architecture of the mammalian testes that results in continuous sperm production. The seemingly complex repetitious relationship of cells termed the "cycle of the seminiferous epithelium" is driven by the continuous commitment of undifferentiated spermatogonia to meiosis and the period of time required to form spermatozoa. This commitment termed the A to A1 transition requires the action of retinoic acid (RA) on the undifferentiated spermatogonia or prospermatogonia. In stages VII to IX of the cycle of the seminiferous epithelium, Sertoli cells and germ cells are influenced by pulses of RA. These pulses of RA move along the seminiferous tubules coincident with the spermatogenic wave, presumably undergoing constant synthesis and degradation. The RA pulse then serves as a trigger to commit undifferentiated progenitor cells to the rigidly timed pathway into meiosis and spermatid differentiation. PMID- 26537429 TI - Integrated Genome-wide association and hypothalamus eQTL studies indicate a link between the circadian rhythm-related gene PER1 and coping behavior. AB - Animal personality and coping styles are basic concepts for evaluating animal welfare. Struggling response of piglets in so-called backtests early in life reflects their coping strategy. Behavioral reactions of piglets in backtests have a moderate heritability, but their genetic basis largely remains unknown. Here, latency, duration and frequency of struggling attempts during one-minute backtests were repeatedly recorded of piglets at days 5, 12, 19, and 26. A genome wide association study for backtest traits revealed 465 significant SNPs (FDR <= 0.05) mostly located in QTL (quantitative trait locus) regions on chromosome 3, 5, 12 and 16. In order to capture genes in these regions, 37 transcripts with significant SNPs were selected for expressionQTL analysis in the hypothalamus. Eight genes (ASGR1, CPAMD8, CTC1, FBXO39, IL19, LOC100511790, RAD51B, UBOX5) had cis- and five (RANGRF, PER1, PDZRN3, SH2D4B, LONP2) had trans-expressionQTL. In particular, for PER1, with known physiological implications for maintenance of circadian rhythms, a role in coping behavior was evidenced by confirmed association in an independent population. For CTC1 a cis-expression QTL and the consistent relationship of gene polymorphism, mRNA expression level and backtest traits promoted its link to coping style. GWAS and eQTL analyses uncovered positional and functional gene candidates for coping behavior. PMID- 26537430 TI - Membrane fusion in muscle development and repair. AB - Mature skeletal muscle forms from the fusion of skeletal muscle precursor cells, myoblasts. Myoblasts fuse to other myoblasts to generate multinucleate myotubes during myogenesis, and myoblasts also fuse to other myotubes during muscle growth and repair. Proteins within myoblasts and myotubes regulate complex processes such as elongation, migration, cell adherence, cytoskeletal reorganization, membrane coalescence, and ultimately fusion. Recent studies have identified cell surface proteins, intracellular proteins, and extracellular signaling molecules required for the proper fusion of muscle. Many proteins that actively participate in myoblast fusion also coordinate membrane repair. Here we will review mammalian membrane fusion with specific attention to proteins that mediate myoblast fusion and muscle repair. PMID- 26537431 TI - Spatially differentiated expression of quadruplicated green-sensitive RH2 opsin genes in zebrafish is determined by proximal regulatory regions and gene order to the locus control region. AB - BACKGROUND: Fish are remarkably diverse in repertoires of visual opsins by gene duplications. Differentiation of their spatiotemporal expression patterns and absorption spectra enables fine-tuning of feature detection in spectrally distinct regions of the visual field during ontogeny. Zebrafish have quadruplicated green-sensitive (RH2) opsin genes in tandem (RH2-1, -2, -3, -4), which are expressed in the short member of the double cones (SDC). The shortest wavelength RH2 subtype (RH2-1) is expressed in the central to dorsal area of the adult retina. The second shortest wave subtype (RH2-2) is expressed overlapping with RH2-1 but extending outside of it. The second longest wave subtype (RH2-3) is expressed surrounding the RH2-2 area, and the longest wave subtype (RH2-4) is expressed outside of the RH2-3 area broadly occupying the ventral area. Expression of the four RH2 genes in SDC requires a single enhancer (RH2-LCR), but the mechanism of their spatial differentiation remains elusive. RESULTS: Functional comparison of the RH2-LCR with its counterpart in medaka revealed that the regulatory role of the RH2-LCR in SDC-specific expression is evolutionarily conserved. By combining the RH2-LCR and the proximal upstream region of each RH2 gene with fluorescent protein reporters, we show that the RH2-LCR and the RH2-3 proximal regulatory region confer no spatial selectivity of expression in the retina. But those of RH2-1, -2 and -4 are capable of inducing spatial differentiation of expression. Furthermore, by analyzing transgenic fish with a series of arrays consisting of the RH2-LCR and multiple upstream regions of the RH2 genes in different orders, we show that a gene expression pattern related to an upstream region is greatly influenced by another flanking upstream region in a relative position-dependent manner. CONCLUSIONS: The zebrafish RH2 genes except RH2-3 acquired differential cis-elements in the proximal upstream regions to specify the differential expression patterns. The input from these proximal elements collectively dictates the actual gene expression pattern of the locus, context-dependently. Importantly, competition for the RH2-LCR activity among the replicates is critical in this collective regulation, facilitating differentiation of expression among them. This combination of specificity and generality enables seemingly complicated spatial differentiation of duplicated opsin genes characteristic in fish. PMID- 26537432 TI - Metabolomics for undergraduates: Identification and pathway assignment of mitochondrial metabolites. AB - Metabolomics is a key discipline in systems biology, together with genomics, transcriptomics, and proteomics. In this omics cascade, the metabolome represents the biochemical products that arise from cellular processes and is often regarded as the final response of a biological system to environmental or genetic changes. The overall screening approach to identify all the metabolites in a given biological system is called metabolic fingerprinting. Using high-resolution and high-mass accuracy mass spectrometry, large metabolome coverage, sensitivity, and specificity can be attained. Although the theoretical concepts of this methodology are usually provided in life-science programs, hands-on laboratory experiments are not usually accessible to undergraduate students. Even if the instruments are available, there are not simple laboratory protocols created specifically for teaching metabolomics. We designed a straightforward hands-on laboratory experiment to introduce students to this methodology, relating it to biochemical knowledge through metabolic pathway mapping of the identified metabolites. This study focuses on mitochondrial metabolomics since mitochondria have a well-known, medium-sized cellular sub-metabolome. These features facilitate both data processing and pathway mapping. In this experiment, students isolate mitochondria from potatoes, extract the metabolites, and analyze them by high-resolution mass spectrometry (using an FT-ICR mass spectrometer). The resulting mass list is submitted to an online program for metabolite identification, and compounds associated with mitochondrial pathways can be highlighted in a metabolic network map. PMID- 26537433 TI - A comparison of endoscopic submucosal dissection (ESD) and radical surgery for early gastric cancer: a retrospective study. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) has become one of the mainstays of treatment for early gastric cancer (EGC). Radical surgery is also a classical treatment method for EGC. There have been no systematic clinical studies of the curative effects and adverse events associated with ESD vs. radical surgery for EGC. This study investigated the therapeutic efficacy and safety of ESD and radical surgery for EGC. METHODS: Twenty-nine patients with EGC underwent ESD, and 59 underwent radical surgery at Weihai Municipal Hospital. The pathological characteristics, postoperative outcomes, hospital course, morbidity and mortality were retrospectively compared between the two groups. RESULTS: The oncological clearance was 93.1 % (27/29) in the ESD group. Postoperative delayed haemorrhage occurred in two patients. The hospital stay ranged from 10 to 23 days, and the average stay was 14.3 +/- 3.7 days. The patients were followed-up for 1 to 5 years, with a mean follow-up of 26.9 +/- 8.5 months. Regular endoscopic examinations showed that the wound had healed with no cancer recurrence in all of the patients. In the radical surgery group, the oncological clearance was 100 % (59/59). The hospital stay ranged from 11 to 55 days, and the average stay was 21.7 +/- 9.3 days. The patients were followed-up for 1 to 3.7 years, with a mean follow-up of 22.3 +/- 9.4 months. Nine patients developed complications, including acute postoperative adhesive ileus (1/59) and symptomatic residual gastritis (3/59). These complications were improved by an additional operation, drainage, gastrointestinal decompression and comprehensive therapy. CONCLUSIONS: ESD achieved similar efficacy and had many advantages compared with radical surgery for the treatment of EGC. PMID- 26537435 TI - Human sensory response to acetone/air mixtures. AB - The release of organic compounds from building products may influence the perceived air quality in the indoor environment. Consequently, building products are assessed for chemical emissions and for the acceptability of emitted odors. A procedure for odor evaluations in test chambers is described by the standard ISO 16000-28. A panel of eight or more trained subjects directly determines the perceived intensity Pi (unit pi) of an air sample via diffusers. For the training of the panelists, a comparative Pi-scale is applied. The panelists can use acetone/air mixtures in a concentration range between 20 mg/m(3) (0 pi) and 320 mg/m(3) (15 pi) as reference. However, the training and calibration procedure itself can substantially contribute to the method uncertainty. This concerns the assumed odor threshold of acetone, the variability of panelist responses, and the analytical determination of acetone concentrations in air with online methods as well as the influence of the diffuser geometry and the airflow profile. PMID- 26537434 TI - The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome. AB - The first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood-brain barrier, were associated with severe epileptic encephalopathy. Recently, dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic astatic epilepsy (MAE), and genetic generalized epilepsy (GGE). Our study aimed to investigate the possible role of SLC2A1 in various forms of epilepsy including MAE and absence epilepsy with early onset. We also aimed to estimate the frequency of GLUT1 deficiency syndrome in the Danish population. One hundred twenty patients with MAE, 50 patients with absence epilepsy, and 37 patients with unselected epilepsies, intellectual disability (ID), and/or various movement disorders were screened for mutations in SLC2A1. Mutations in SLC2A1 were detected in 5 (10%) of 50 patients with absence epilepsy, and in one (2.7%) of 37 patient with unselected epilepsies, ID, and/or various movement disorders. None of the 120 MAE patients harbored SLC2A1 mutations. We estimated the frequency of SLC2A1 mutations in the Danish population to be approximately 1:83,000. Our study confirmed the role of SLC2A1 mutations in absence epilepsy with early onset. However, our study failed to support the notion that SLC2A1 aberrations are a cause of MAE without associated features such as movement disorders. PMID- 26537436 TI - Steroid 5beta-Reductase from Leaves of Vitis vinifera: Molecular Cloning, Expression, and Modeling. AB - A steroid 5beta-reductase gene corresponding to the hypothetical protein LOC100247199 from leaves of Vitis vinifera (var. 'Chardonnay') was cloned and overexpressed in Escherichia coli. The recombinant protein showed 5beta-reductase activity when progesterone was used as a substrate. The reaction was stereoselective, producing only 5beta-products such as 5beta-pregnane-3,20-dione. Other small substrates (terpenoids and enones) were also accepted as substrates, indicating the highly promiscuous character of the enzyme class. Our results show that the steroid 5beta-reductase gene, encoding an orthologous enzyme described as a key enzyme in cardenolide biosynthesis, is also expressed in leaves of the cardenolide-free plant V. vinifera. We emphasize the fact that, on some occasions, different reductases (e.g., progesterone 5beta-reductase and monoterpenoid reductase) can also use molecules that are similar to the final products as a substrate. Therefore, in planta, the different reductases may contribute to the immense number of diverse small natural products finally leading to the flavor of wine. PMID- 26537437 TI - Towards structural classification of long non-coding RNAs. AB - While long non-coding RNAs play key roles in disease and development, few structural studies have been performed to date for this emerging class of RNAs. Previous structural studies are reviewed, and a pipeline is presented to determine secondary structures of long non-coding RNAs. Similar to riboswitches, experimentally determined secondary structures of long non-coding RNAs for one species, may be used to improve sequence/structure alignments for other species. As riboswitches have been classified according to their secondary structure, a similar scheme could be used to classify long non-coding RNAs. This article is part of a Special Issue titled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. PMID- 26537438 TI - Single molecule atomic force microscopy of aerolysin pore complexes reveals unexpected star-shaped topography. AB - Aerolysin is the paradigmatic member of a large family of toxins that convert from a water-soluble monomer/dimer into a membrane-spanning oligomeric pore. While there is x-ray crystallographic data of its water-soluble conformation, the most recent structural model of the membrane-inserted pore is based primarily on data of water-soluble tetradecamers of mutant protein, together with computational modeling ultimately performed in vacuum. Here we examine this pore model with atomic force microscopy (AFM) of membrane-associated wild-type complexes and all-atom molecular dynamics (MD) simulations in water. In striking contrast to a disc-shaped cap region predicted by the present model, the AFM images reveal a star-shaped complex, with a central ring surrounded by seven radial projections. Further, the MD simulations suggest that the locations of the receptor-binding (D1) domains in the present model are not correct. However, a modified model in which the D1 domains, rather than localized at fixed positions, adopt a wide range of configurations through fluctuations of an intervening linker is compatible with existing data. Thus our work not only demonstrates the importance of directly resolving such complexes in their native environment but also points to a dynamic receptor binding region, which may be critical for toxin assembly on the cell surface. PMID- 26537439 TI - Patient-reported outcomes among patients with type 2 diabetes mellitus treated with dapagliflozin in a triple-therapy regimen for 52 weeks. AB - Patients with type 2 diabetes (T2DM) and inadequate glycaemic control on combination metformin (MET) and sulphonylurea (SU) were enrolled in a 24-week, double-blind, randomized, placebo-controlled study with a 28-week extension. The five-dimension EuroQol questionnaire (EQ-5D), SHIELD Weight Questionnaire-9 (WQ 9), Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire and the Diabetes Treatment Satisfaction Questionnaire (DTSQ) were used to evaluate health status and health-related quality of life (HRQoL) at baseline and week 52. Patients with dapagliflozin 10 mg + MET + SU (n = 108) were compared with patients treated with placebo + MET + SU (n = 108), using a repeated-measures mixed model. EQ-5D visual analogue scale scores, IWQOL-Lite and DTSQ scores improved in the dapagliflozin and placebo groups from baseline to week 52; however, there was no significant difference between groups (p > 0.20). EQ-5D index scores remained the same from baseline to week 52 for dapagliflozin and placebo (p = 0.54). A numerically greater proportion of the dapagliflozin group reported improvement in all nine SHIELD WQ-9 items compared with placebo, and the difference was statistically significant for physical health (p = 0.017). Over 52 weeks of therapy, patients maintained their health status and HRQoL when dapagliflozin was added to the treatment. PMID- 26537440 TI - Can circulating biomarkers identify heart failure patients at low risk? PMID- 26537441 TI - Biphasic decay of the Ca transient results from increased sarcoplasmic reticulum Ca leak. AB - KEY POINTS: Ca leak from the sarcoplasmic reticulum through the ryanodine receptor (RyR) reduces the amplitude of the Ca transient and slows its rate of decay. In the presence of beta-adrenergic stimulation, RyR-mediated Ca leak produces a biphasic decay of the Ca transient with a fast early phase and a slow late phase. Two forms of Ca leak have been studied, Ca-sensitising (induced by caffeine) and non-sensitising (induced by ryanodine) and both induce biphasic decay of the Ca transient. Only Ca-sensitising leak can be reversed by traditional RyR inhibitors such as tetracaine. Ca leak can also induce Ca waves. At low levels of leak, waves occur. As leak is increased, first biphasic decay and then slowed monophasic decay is seen. The level of leak has major effects on the shape of the Ca transient. In heart failure, a reduction in Ca transient amplitude and contractile dysfunction can by caused by Ca leak through the sarcoplasmic reticulum (SR) Ca channel (ryanodine receptor, RyR) and/or decreased activity of the SR Ca ATPase (SERCA). We have characterised the effects of two forms of Ca leak (Ca-sensitising and non-sensitising) on calcium cycling and compared with those of SERCA inhibition. We measured [Ca(2+)]i with fluo-3 in voltage-clamped rat ventricular myocytes. Increasing SR leak with either caffeine (to sensitise the RyR to Ca activation) or ryanodine (non-sensitising) had similar effects to SERCA inhibition: decreased systolic [Ca(2+)]i , increased diastolic [Ca(2+)]i and slowed decay. However, in the presence of isoproterenol, leak produced a biphasic decay of the Ca transient in the majority of cells while SERCA inhibition produced monophasic decay. Tetracaine reversed the effects of caffeine but not of ryanodine. When caffeine (1 mmol l(-1)) was added to a cell which displayed Ca waves, the wave frequency initially increased before waves disappeared and biphasic decay developed. Eventually (at higher caffeine concentrations), the biphasic decay was replaced by slow decay. We conclude that, in the presence of adrenergic stimulation, Ca leak can produce biphasic decay; the slow phase results from the leak opposing Ca uptake by SERCA. The degree of leak determines whether decay of Ca waves, biphasic or monophasic, occurs. PMID- 26537442 TI - CO-CBS-H2 S Axis: From Vascular Mediator to Cancer Regulator. AB - CO is a gaseous mediator generated by HO. Our previous studies revealed that CO generated from inducible HO-1 or from constitutive HO-2 modulates function of different heme proteins or enzymes through binding to their prosthetic ferrous heme to alter their structures, regulating biological function of cells and organs. Such CO-directed target macromolecules include sGC and CBS. In the liver, CO serves as a sinusoidal dilator through its action on sGC in hepatic stellate cells, while the same gas accounts for vasoconstrictor that inhibits H2S generated by CO-sensitive CBS in astrocytes. Since molecular O2 is a substrate for HO, the latter mechanism contributes to hypoxic vasodilation in neurovascular units. We have recently uncovered that stress-inducible CO in and around cancer cells suppresses CBS to result in decreased methylation of PFKFB3, the enzyme regulating PFK-1, leading to a shift of glucose biotransformation from glycolysis toward pentose phosphate pathway; such a metabolic remodeling causes chemoresistance through increasing NADPH and reduced glutathione under stress conditions for cancer cells. This article reviews the intriguing networks of CO sensitive metabolic regulatory mechanisms in microcirculation and cancer. PMID- 26537443 TI - Congenital erosive and vesicular dermatosis associated with herpes simplex virus. PMID- 26537444 TI - Performance of BD Max StaphSR for Screening of Methicillin-Resistant Staphylococcus aureus Isolates among a Contemporary and Diverse Collection from 146 Institutions Located in Nine U.S. Census Regions: Prevalence of mecA Dropout Mutants. AB - This study determined the performance of BD Max StaphSR and the rate of methicillin-resistant Staphylococcus aureus (MRSA) with an unrecognized staphylococcal cassette chromosome mec (SCCmec) right-extremity junction (MREJ) region among 907 methicillin-resistant S. aureus (MRSA) and 900 methicillin susceptible S. aureus (MSSA) isolates. The rate of mecA/mecC dropout mutants was also evaluated. Only three MRSA isolates (99.7% sensitivity; 904/907) were classified as MSSA by the BD Max StaphSR assay, due to negative results for MREJ. Eight MSSA isolates (99.1% sensitivity; 892/900) were assigned as MRSA. However, six of these MSSA isolates had the mecA gene confirmed by PCR and sequencing (99.8% sensitivity; 898/900). Overall, 7.1% (64/900) of MSSA isolates showed results compatible with a mecA dropout genotype. PMID- 26537445 TI - Evaluation of the Biofire FilmArray BioThreat-E Test (v2.5) for Rapid Identification of Ebola Virus Disease in Heat-Treated Blood Samples Obtained in Sierra Leone and the United Kingdom. AB - Rapid Ebola virus (EBOV) detection is crucial for appropriate patient management and care. The performance of the FilmArray BioThreat-E test (v2.5) using whole blood samples was evaluated in Sierra Leone and the United Kingdom and was compared with results generated by a real-time Ebola Zaire PCR reference method. Samples were tested in diagnostic laboratories upon availability, included successive samples from individual patients, and were heat treated to facilitate EBOV inactivation prior to PCR. The BioThreat-E test had a sensitivity of 84% (confidence interval [CI], 64% to 95%) and a specificity of 89% (CI, 73% to 97%) in Sierra Leone (n = 60; 44 patients) and a sensitivity of 75% (CI, 19% to 99%) and a specificity of 100% (CI, 97% to 100%) in the United Kingdom (n = 108; 70 patients) compared to the reference real-time PCR. Statistical analysis (Fisher's exact test) indicated there was no significant difference between the methods at the 99% confidence level in either country. In 9 discrepant results (5 real-time PCR positives and BioThreat-E test negatives and 4 real-time PCR negatives and BioThreat-E test positives), the majority (n = 8) were obtained from samples with an observed or probable low viral load. The FilmArray BioThreat-E test (v2.5) therefore provides an attractive option for laboratories (either in austere field settings or in countries with an advanced technological infrastructure) which do not routinely offer an EBOV diagnostic capability. PMID- 26537446 TI - Evaluation of a Genus- and Group-Specific Rapid PCR Assay Panel on Synovial Fluid for Diagnosis of Prosthetic Knee Infection. AB - We evaluated a genus- and group-specific PCR assay panel using 284 prosthetic knee synovial fluid samples collected from patients presenting to our institution with implant failure. Using the Musculoskeletal Infection Society diagnostic criteria, 88 and 196 samples were classified as showing prosthetic joint infection (PJI) and aseptic failure (AF), respectively. Sensitivities of the synovial fluid PCR panel and culture were 55.6% and 76.1% (P <= 0.001), respectively, and specificities were 91.8% and 97.4% (P = 0.016), respectively. Among the 70 subjects who had received antibiotics within the month preceding synovial fluid aspiration (48 of whom had PJI), PCR panel and synovial fluid culture sensitivities were 64.5% and 85.4%, respectively (P < 0.0001). In this group, the PCR panel detected Staphylococcus aureus in two culture-negative PJI cases. Overall, the evaluated molecular diagnostic tool had low sensitivity when applied to synovial fluid. PMID- 26537447 TI - Detecting 16S rRNA Methyltransferases in Enterobacteriaceae by Use of Arbekacin. AB - 16S rRNA methyltransferases confer resistance to most aminoglycosides, but discriminating their activity from that of aminoglycoside-modifying enzymes (AMEs) is challenging using phenotypic methods. We demonstrate that arbekacin, an aminoglycoside refractory to most AMEs, can rapidly detect 16S methyltransferase activity in Enterobacteriaceae with high specificity using the standard disk susceptibility test. PMID- 26537448 TI - Implementation of Next-Generation Sequencing for Hepatitis B Virus Resistance Testing and Genotyping in a Clinical Microbiology Laboratory. AB - Sanger sequencing or DNA hybridization have been the primary modalities for hepatitis B (HBV) resistance testing and genotyping; however, there are limitations, such as low sensitivity and the inability to detect novel mutations. Next-generation sequencing (NGS) for HBV can overcome these limitations, but there is limited guidance for clinical microbiology laboratories to validate this novel technology. In this study, we describe an approach to implementing deep pyrosequencing for HBV resistance testing and genotyping in a clinical virology laboratory. A nested PCR targeting the pol region of HBV (codons 143 to 281) was developed, and the PCR product was sequenced by the 454 Junior (Roche). Interpretation was performed by ABL TherapyEdge based on European Association for the Study of the Liver (EASL) guidelines. Previously characterized HBV samples by INNO-LiPA (LiPA) were compared to NGS with discordant results arbitrated by Sanger sequencing. Genotyping of 105 distinct samples revealed a concordance of 95.2% (100/105), with Sanger sequencing confirming the NGS result. Resistance testing by NGS was concordant with LiPA in 85% (68/80) of previously characterized samples. Additional mutations were found in 8 samples, which related to the identification of low-level mutant subpopulations present at <10% (6/8). To balance the costs of testing for the validation study, reproducibility of the NGS was investigated through an analysis of sequence variants at loci not associated with resistance in a single patient sample. Our validation approach attempts to balance costs with efficient data acquisition. PMID- 26537449 TI - Novel genes associated with lymph node metastasis in triple negative breast cancer. AB - Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and no targeted treatments. TNBC patients are more likely to develop metastases and relapse than patients with other breast cancer subtypes. We aimed to identify TNBC-specific genes and genes associated with lymph node metastasis, one of the first signs of metastatic spread. A total of 33 TNBCs were used; 17 of which had matched normal adjacent tissues available, and 15 with matched lymph node metastases. Gene expression microarray analysis was used to reveal genes that were differentially expressed between these groups. We identified and validated 66 genes that are significantly altered when comparing tumours to normal adjacent samples. Further, we identified 83 genes that are associated with lymph node metastasis and correlated these with miRNA-expression. Pathway analysis revealed their involvement in DNA repair, recombination and cell death, chromosomal instability and other known cancer-related pathways. Finally, four genes were identified that were specific for TNBC, of which one was associated with overall survival. This study has identified novel genes involved in LN metastases in TNBC and genes that are TNBC specific that may be used as treatment targets or prognostic indicators in the future. PMID- 26537450 TI - Folic acid protects against arsenic-mediated embryo toxicity by up-regulating the expression of Dvr1. AB - As a nutritional factor, folic acid can prevent cardiac and neural defects during embryo development. Our previous study showed that arsenic impairs embryo development by down-regulating Dvr1/GDF1 expression in zebrafish. Here, we investigated whether folic acid could protect against arsenic-mediated embryo toxicity. We found that folic acid supplementation increases hatching and survival rates, decreases malformation rate and ameliorates abnormal cardiac and neural development of zebrafish embryos exposed to arsenite. Both real-time PCR analysis and whole in-mount hybridization showed that folic acid significantly rescued the decrease in Dvr1 expression caused by arsenite. Subsequently, our data demonstrated that arsenite significantly decreased cell viability and GDF1 mRNA and protein levels in HEK293ET cells, while folic acid reversed these effects. Folic acid attenuated the increase in subcellular reactive oxygen species (ROS) levels and oxidative adaptor p66Shc protein expression in parallel with the changes in GDF1 expression and cell viability. P66Shc knockdown significantly inhibited the production of ROS and the down-regulation of GDF1 induced by arsenite. Our data demonstrated that folic acid supplementation protected against arsenic-mediated embryo toxicity by up-regulating the expression of Dvr1/GDF1, and folic acid enhanced the expression of GDF1 by decreasing p66Shc expression and subcellular ROS levels. PMID- 26537451 TI - Recombinase-based conditional and reversible gene regulation via XTR alleles. AB - Synthetic biological tools that enable precise regulation of gene function within in vivo systems have enormous potential to discern gene function in diverse physiological settings. Here we report the development and characterization of a synthetic gene switch that, when targeted in the mouse germline, enables conditional inactivation, reports gene expression and allows inducible restoration of the targeted gene. Gene inactivation and reporter expression is achieved through Cre-mediated stable inversion of an integrated gene-trap reporter, whereas inducible gene restoration is afforded by Flp-dependent deletion of the inverted gene trap. We validate our approach by targeting the p53 and Rb genes and establishing cell line and in vivo cancer model systems, to study the impact of p53 or Rb inactivation and restoration. We term this allele system XTR, to denote each of the allelic states and the associated expression patterns of the targeted gene: eXpressed (XTR), Trapped (TR) and Restored (R). PMID- 26537452 TI - Nonrheumatoid Inflammatory Arthroses of the Hand and Wrist. AB - Various inflammatory and autoimmune conditions affecting joints of the hand and wrist can present with symptoms similar to those of rheumatoid arthritis. The most common of these nonrheumatoid arthroses are psoriatic arthritis, systemic lupus erythematosus, and systemic sclerosis. Management of these and several other conditions is typically medical in nature and continues to evolve with the development of biologically targeted medications. Surgical treatment is not frequently used but can be efficacious for severe cases to alleviate symptoms and correct deformities. PMID- 26537453 TI - Cornelia de Lange Syndrome. PMID- 26537454 TI - Tetraplegia Management Update. AB - Tetraplegia is a profound impairment of mobility manifesting as a paralysis of all 4 extremities owing to cervical spinal cord injury. The purpose of this article is to provide an update and analyze current management, treatment options, and outcomes of surgical reconstruction of arm and hand function. Surgical restoration of elbow and wrist extension or handgrip has tremendous potential to improve autonomy, mobility, and critical abilities, for example, eating, personal care, and self-catheterization and productive work in at least 70% of tetraplegic patients. Tendon and nerve transfers, tenodeses, and joint stabilizations reliably enable improved arm and hand usability, reduce muscle imbalance and pain in spasticity, and prevent joint contractures. One-stage combined procedures have proven considerable advantages over traditional multistage approaches. Immediate activation of transferred muscles reduces the risk of adhesions, facilitates relearning, avoids adverse effects of immobilization, and enhances functional recovery. Transfer of axillary, musculocutaneous, and radial nerve fascicles from above the spinal cord injury are effective and promising options to enhance motor outcome and sensory protection, especially in groups with limited resources. Improved communication between medical disciplines, therapists, patients, and their relatives should help that more individuals can benefit from these advances and could empower many thousands tetraplegic individuals "to take life into their own hands" and live more independently. PMID- 26537455 TI - A novel characterization of posterior keratoconus using anterior segment optical coherence tomography in an infant: a case report. AB - BACKGROUND: Posterior keratoconus is a rare cause of a corneal opacity in an infant. It is characterized by thinning of the posterior cornea without ectasia of the anterior cornea. Imaging of this condition with anterior segment optical coherence tomography (AS-OCT) has not been reported in the literature. CASE PRESENTATION: A six week old African-American male presented with a congenital corneal opacity of the right eye. He underwent an examination under anesthesia in which photography and AS-OCT were performed. AS-OCT confirmed the diagnosis of posterior keratoconus. The patient subsequently underwent an optical iridectomy for visual development. CONCLUSION: AS-OCT is a useful tool in cases when a child presents with a corneal opacity of unknown or unclear etiology. In our patient, AS-OCT showed the classic description of central corneal thinning seen in this condition. Additionally, it revealed an associated detached Descemet membrane, a feature which has not been previously described in posterior keratoconus. PMID- 26537456 TI - Independent prognostic value of left atrial function by two-dimensional speckle tracking imaging in patients with non -ST-segment-elevation acute myocardial infarction. AB - BACKGROUND: The objective of this study is to evaluate left atrial(LA) function and its prognostic value by two-dimensional speckle tracking echocardiography (STE) in patients with non-ST-segment-elevation acute myocardial infarction (NSTEAMI). METHODS: Global longitudinal LA S/SR data obtained by 2D speckle imaging with automated software (Echo PAC, GE Medical). RESULTS: Clinical variables and angiographic, echocardiographic, and STE parameters were studied in 65 patients with NSTEAMI (51 males and 14 females; mean age of 60.7 +/- 9.8 years) who underwent elective PCI. The final study population consisted of 51 individuals (43 males and 8 females; mean age of 62.9 +/- 11.1 years) and a 12 +/ 3 months follow-up was performed. A total of 22 combined cardiovascular events(20 patients) occurred. With the use of Univariable Cox regression, all parameters were evaluated in the prediction of cardiac events, ischemic events, and/or cardiac death. According to ROC analysis, baseline mean global left atrial SRs (ROC area 0.82, p = 0.001) and baseline mean global left atrial SRe (ROC area 0.68, p = 0.036) were the only predictive variables. CONCLUSIONS: In patients with NSTEAMI, we found that the novel global strain parameter of left atrial function is a valuable predictor of combined cardiovascular events over conventional echocardiography and may therefore be an important clinical tool for risk stratification in the acute phase of NSTEAMI. PMID- 26537457 TI - Dinuclear lanthanide(III)/zinc(II) complexes with methyl 2-pyridyl ketone oxime. AB - The first use of methyl 2-pyridyl ketone oxime (mpkoH) in zinc(II)/lanthanide(III) chemistry leads to the [ZnLn(mpko)3(mpkoH)3](ClO4)2 and [ZnLn(NO3)2(mpko)3(mpkoH)] families of dinuclear Zn(II)Ln(III) complexes displaying blue-green, ligand-based photoluminescence; the Zn(II)Dy(III) compound shows field-induced relaxation of magnetization. PMID- 26537458 TI - Short Communication: p21/CDKN1A Expression Shows Broad Interindividual Diversity in a Subset of HIV-1 Elite Controllers. AB - The p21/CDKN1A protein has been described in vitro as well as in a small subset of patients as a restriction factor for HIV infection. We evaluated p21/CDKN1A mRNA expression on CD4(+) T cells from HIV-infected individuals with two outcomes (18 elite controllers and 28 viremic progressors). Our results show broad interindividual variation in this factor, which is unrelated to the patient's phenotype. Considering the gene's genetic surroundings in chromosome 6, such as HLA genotype and single nucleotide polymorphisms (SNPs), there was a positive association with carrying HLA-B2705 alleles and the rs733590 SNP. Thus, this natural variation of p21/CDKN1A alone does not appear to be a prognostic indicator of effective viral control in vivo and other factors must be considered. PMID- 26537459 TI - An integrative quantifier of multistability in complex systems based on ecological resilience. AB - The abundance of multistable dynamical systems calls for an appropriate quantification of the respective stability of the (stable) states of such systems. Motivated by the concept of ecological resilience, we propose a novel and pragmatic measure called 'integral stability' which integrates different aspects commonly addressed separately by existing local and global stability concepts. We demonstrate the potential of integral stability by using exemplary multistable dynamical systems such as the damped driven pendulum, a model of Amazonian rainforest as a known climate tipping element and the Daisyworld model. A crucial feature of integral stability lies in its potential of arresting a gradual loss of the stability of a system when approaching a tipping point, thus providing a potential early-warning signal sufficiently prior to a qualitative change of the system's dynamics. PMID- 26537460 TI - Synthesis of Chain-End Functionalized Glycopolymers via Cyanoxyl-Mediated Free Radical Polymerization (CMFRP). AB - Glycopolymers are often used as glyco-macroligands for biological research and biomedical applications in carbohydrate recognitions. Chain-end functionalized glycopolymers show more potential for practical applications, such as protein modification and solid-phase bioassays. In particular, the chain-end group allows for direct one-to-one attachment or facilitates site-specific and oriented immobilization onto solid surfaces. A series of derivatized arylamine initiators are used to generate chain-end functionalized glycopolymers by cyanoxyl-mediated free radical polymerization (CMFRP). Important features of this strategy include the capacity to produce polymers of low polydispersity (PDI <1.5) under aqueous conditions using unprotected monomers bearing a wide range of functional groups. In addition, it provides a one-pot method to synthesize alpha,omega-telechelic glycopolymers with derivatized arylamine at one site and O-cyanate at the other site. In the process, the capacity to orthogonally label glycopolymers or otherwise conjugate them to proteins and other molecules is greatly enhanced. PMID- 26537461 TI - Protecting-Group-Free Synthesis of Well-Defined Glycopolymers Featuring Negatively Charged Oligosaccharides. AB - Control of the macromolecular architecture is essential to enable sophisticated functions for glycopolymers and to allow a precise correlation between these functions and the polymer structure. A number of biologically important ligands are negatively charged oligosaccharides that are difficult to manipulate in organic solvent and that are hardly amenable to protection/deprotection strategies. RAFT polymerization is a simple and robust technique that enables the synthesis of well-defined glycopolymers directly in aqueous solution and starting from unprotected vinyl glycomonomers. Here I describe how RAFT polymerization can be combined with reductive amination to transform negatively charged oligosaccharides having 5-20 monosaccharide units into well-defined glycopolymers directly in water and without the need to resort to protecting-group chemistry. PMID- 26537462 TI - Glycopolymers Prepared by Ring-Opening Metathesis Polymerization Followed by Glycoconjugation Using a Triazole-Forming "Click" Reaction. AB - We describe a protocol for the preparation of glycopolymers derived from the ring opening polymerization of a norbornene carboxylic acid derivative. Polymerization is followed by attachment of a linker and subsequent glycoconjugation via a triazole-forming azide-alkyne click reaction. The use of a protected amine terminating agent allows for the attachment of a probe molecule such as a fluorescein dye. The syntheses of a neutral galactopolymer as well a polyanionic poly-3-O-sulfo-galactopolymer are described. PMID- 26537463 TI - Protecting-Group-Free Synthesis of Glycopolymers and Their Binding Assay with Lectin and Influenza Virus. AB - Typical synthetic methods for glycopolymers are laborious and require multistep processes, including protection and deprotection steps. Here we describe a facile protecting-group-free synthetic approach to glycopolymers bearing oligosaccharides from free saccharides by direct azidation and click chemistry methods, followed by reversible addition-fragmentation chain transfer polymerization. This method can be applied not only to mono- and disaccharides, but also to large biologically relevant oligosaccharides having sialic acids. Due to the glycocluster effect, the glycopolymers strongly bind with the corresponding lectin and influenza A virus, as analyzed by the quartz crystal microbalance method and hemagglutination inhibition assay. PMID- 26537464 TI - Carbohydrate-Based Initiators for the Cationic Ring-Opening Polymerization of 2 Ethyl-2-Oxazoline. AB - The advancement in the field of living and controlled polymerization techniques provides the opportunity for careful bottom-up design of polymers for biomedical applications according to their specific needs. This contribution describes the detailed methodology to functionalize poly(2-ethyl-2-oxazoline), a polymer with properties very similar to polyethylene glycol, in a stereo-selective manner with a range of carbohydrates that can serve as biological targeting units. The obtained building blocks can subsequently be applied for the synthesis of more complex polymeric architectures. PMID- 26537465 TI - Heterofunctional Glycopolypeptides by Combination of Thiol-Ene Chemistry and NCA Polymerization. AB - Glycopolypeptides are prepared either by the polymerization of glycosylated amino acid N-carboxyanhydrides (NCAs) or by the post-polymerization functionalization of polypeptides with suitable functional groups. Here we present a method for the in-situ functionalization and (co-) polymerization of allylglycine N carboxyanhydride in a facile one-pot procedure, combining radical thiol-ene photochemistry and nucleophilic ring-opening polymerization techniques, to yield well-defined heterofunctional glycopolypeptides. PMID- 26537466 TI - Preparation of Proteoglycan Mimetic Graft Copolymers. AB - Proteoglycans are proteins with pendant glycosaminoglycan polysaccharide side chains. The method described here enables the preparation of graft copolymers with glycosaminoglycan side chains, which mimic the structure and composition of proteoglycans. By controlling the stoichiometry, graft copolymers can be obtained with a wide range of glycosaminoglycan side-chain densities. The method presented here uses a three-step reaction mechanism to first functionalize a hyaluronic acid backbone, followed by reductive amination to couple the glycosaminoglycan side chain to the backbone, by the reducing end. Proteoglycan mimics like the ones proposed here could be used to study the structure-property relationships of proteoglycans and to introduce the biochemical and biomechanical properties of proteoglycans into biomaterials and therapeutic formulations. PMID- 26537467 TI - Galactosylated Polymer Nano-objects by Polymerization-Induced Self-Assembly, Potential Drug Nanocarriers. AB - Glycopolymer-based nanostructures are invaluable tools to both study biological phenomena and to design future targeted drug delivery systems. Polymerization induced self-assembly, especially RAFT aqueous dispersion polymerization is a unique method to prepare such polymer nanostructures, as it enables the preparation of very-well-defined morphologies at very high concentrations. Here we describe the implementation of PISA to the synthesis of galactosylated spheres, wormlike micelles and vesicles, and the preliminary results of cell toxicity, cell uptake, and cargo delivering capacity of galactose-decorated vesicles. PMID- 26537468 TI - Synthetic Approach to Biotinylated Glyco-Functionalized Quantum Dots: A New Fluorescent Probes for Biomedical Applications. AB - Technological advances that allow deeper penetration in live tissues, such as the development of confocal and the generation of ever-new fluorophores that facilitate bright labeling of cells and tissue components have made imaging of vertebrate model organisms efficient and highly informative. Recently, high luminescence, single-excitation narrow emission, low photo bleaching properties, and low toxicity of high-quality water-soluble QDs have attracted attention for in vivo labeling/imaging of cells. Herein we describe a synthetic approach to biotinylated glycopolymer functionalized quantum dots, with special emphasis on the development of high-quality water-soluble and bioactive QDs with low toxicity for fluorescent probes in biomedical applications. PMID- 26537469 TI - Surface Modification of Polydivinylbenzene Microspheres with a Fluorinated Glycopolymer Using Thiol-Halogen Click Chemistry. AB - Distillation-precipitation polymerization of divinylbenzene was applied to obtain uniform-sized polymeric microspheres. The microspheres were then modified with polypentafluorostyrene chains utilizing surface-initiated atom transfer radical polymerization techniques. The hydrophobic fluoropolymer-coated microsphere was then converted to a hydrophilic biopolymer by performing thiol-halogen click chemistry between polypentafluorostyrene and 1-thio-beta-D-glucose sodium salt. The semi-fluorinated glycopolymer showed good binding ability with Concanavalin A as determined by confocal microscopy and turbidity experiments. PMID- 26537470 TI - Glycopolymer-Grafted Polymer Particles for Lectin Recognition. AB - Glycopolymers bearing carbohydrates have an advantage in protein recognition that is attributable to the multivalent effect (cluster effect) of side-chain carbohydrates. A variety of surface-modified polymer particles have been prepared concurrently with the development of new synthetic technology. Here we describe a synthetic method of glycopolymer-grafted polymer particles by surface-initiated living radical polymerization, i.e., atom-transfer radical polymerization (ATRP) and photoiniferter polymerization, for specific lectin recognition. PMID- 26537471 TI - Synthesis of Non-spherical Glycopolymer-Decorated Nanoparticles: Combing Thiol ene with Catecholic Chemistry. AB - Glycopolymers with carbohydrate side chains are currently being applied in many fields, with much potential for disease treatment. The shape of glycopolymer bearing nanoparticles has obvious effects on the nanoparticle-cell interaction and is therefore important for the applications of glycopolymers in biological systems. Here a synthetic approach to prepare non-spherical glycopolymer-coated iron oxide nanoparticles is provided, by combing the convenience of inorganic shape control, catecholic chemistry, and thiol-ene reaction. PMID- 26537472 TI - Synthetic Approach to Glycopolymer Base Nanoparticle Gold(I) Conjugate: A New Generation of Therapeutic Agents. AB - Advances in nanotechnology have led to the fabrication of nano-constructs of organic or inorganic origins with well-defined structures, surface properties, and can be made to respond to physical or chemical stimuli. These nano-constructs can provide a shift in the way diagnostic and therapeutic drugs are delivered to achieve target specificity and increased retention of therapeutic doses for considerable improvement in the overall treatment of the tumors. In this case we describe here a synthetic approach to glycopolymer base nanoparticle gold(I) conjugate for cancer therapy. PMID- 26537473 TI - Multivalent Glycopolymer-Coated Gold Nanoparticles. AB - Glycosylated noble metal nanoparticles are a useful tool for probing biological binding events due to their aggregation-induced color changes, particularly for lectins that have multiple binding sites. To overcome the challenges of colloidal instability, which leads to false-positive results, it is essential to add polymeric coatings to these particles. Here we describe a versatile, and reliable, approach to enable coating of gold nanoparticles using well-defined polymers, with carbohydrate end groups. This produces multivalent nanoparticles that are both colloidally stable, but still retain their rapid colorimetric responses to lectin binding. PMID- 26537474 TI - Modulation of Multivalent Protein Binding on Surfaces by Glycopolymer Brush Chemistry. AB - The presentation of carbohydrates on an array can provide a means to model (mimic) oligosaccharides found on cell surfaces. Tuning the structural features of such carbohydrate arrays can therefore be used to help to elucidate the molecular mechanisms of protein-carbohydrate recognition on cell surfaces. Here we present a strategy to directly correlate the molecular and structural features of ligands presented on a surface with the kinetics and affinity of carbohydrate lectin binding. The Surface Plasmon Resonance (SPR) spectroscopy analysis identified that by varying the spatial distribution (3D organization) of carbohydrate ligands within the surface grafted polymer layer, the mode of binding changed from multivalent to monovalent: a near 1000-fold change in the equilibrium association constant was achieved. The rupture forces measured by atomic force microscopy (AFM) force spectroscopy also indicated that the mode of binding between lectin and carbohydrate ligands can be modulated by the organization of carbohydrate ligands within the glycopolymer brushes. PMID- 26537475 TI - Oriented Immobilized Sialyloligo-macroligand Microarray. AB - Silaic acid is the most common terminal glycan on cell surface glycoproteins and glycolipids, involving in many biological processes. Studying interactions between multivalent sialic acid scaffolds and proteins binding to it will give incredible information in understanding the biological process the sialic acid is involved in. Here we describe chemoenzymatic synthesis of chain-end functionalized sialyllactose-containing glycopolymers with different linkages and their oriented immobilization for glycoarray and SPR-based glyco-biosensor applications. PMID- 26537476 TI - Glycocalyx Remodeling with Glycopolymer-Based Proteoglycan Mimetics. AB - The cellular glycocalyx controls many of the crucial signaling pathways involved in cellular development. Synthetic materials that can mimic the multivalency and three-dimensional architecture of native glycans serve as important tools for deciphering and exploiting the roles of these glycans. Here we describe a chemical approach for the engineering of growth-factor interactions at the surfaces of stem cells using synthetic glycomimetic materials, with an eye towards promoting their commitment towards specific cell lineages with therapeutic potential. PMID- 26537477 TI - Age-associated changes in rich-club organisation in autistic and neurotypical human brains. AB - Macroscopic structural networks in the human brain have a rich-club architecture comprising both highly inter-connected central regions and sparsely connected peripheral regions. Recent studies show that disruption of this functionally efficient organisation is associated with several psychiatric disorders. However, despite increasing attention to this network property, whether age-associated changes in rich-club organisation occur during human adolescence remains unclear. Here, analysing a publicly shared diffusion tensor imaging dataset, we found that, during adolescence, brains of typically developing (TD) individuals showed increases in rich-club organisation and inferred network functionality, whereas individuals with autism spectrum disorders (ASD) did not. These differences between TD and ASD groups were statistically significant for both structural and functional properties. Moreover, this typical age-related changes in rich-club organisation were characterised by progressive involvement of the right anterior insula. In contrast, in ASD individuals, did not show typical increases in grey matter volume, and this relative anatomical immaturity was correlated with the severity of ASD social symptoms. These results provide evidence that rich-club architecture is one of the bases of functionally efficient brain networks underpinning complex cognitive functions in adult human brains. Furthermore, our findings suggest that immature rich-club organisation might be associated with some neurodevelopmental disorders. PMID- 26537478 TI - Timing of breakfast does not influence therapeutic efficacy of liquid levothyroxine formulation. AB - Oral levothyroxine (L-T4) is the mainstay of hypothyroidism treatment. Many factors may influence its absorption, including the timing of administration. Objective of the study is to demonstrate the therapeutic equivalence of administering liquid L-T4 with breakfast or 10 min before breakfast. This was a pilot study conducted with a crossover design AB/BA where A stays for L-T4 with breakfast and B for L-T4 10 min before breakfast. A post hoc analysis was conducted to compare L-T4 administered at breakfast or 10 min before breakfast with L-T4 administered 30 min before breakfast. Sixty-one hypothyroid patients were enrolled and assigned to one of the two treatment sequences. All patients were evaluated for TSH levels at the end of each period. Fifty-nine patients completed the study. The mean thyrotropin concentration was 1.52 +/- 0.73 uU/ml when L-T4 was administered with breakfast and 1.46 +/- 0.81 uU/ml when it was taken 10 min before breakfast, without clinically and statistically significant differences (P = 0.59), regardless of treatment sequence and period. The mean thyrotropin concentration was 1.54 +/- 0.9 uU/ml when L-T4 was administered at 0 10 min intervals before breakfast and 1.25 +/- 0.7 uU/ml when it was taken 30 min before breakfast (ratio = 1.23, within our definition of equivalence set at 0.8 1.25). There is therapeutic equivalence between liquid L-T4 administration at breakfast or 10 min before breakfast. We can also hypothesize that there are no clinically relevant differences between liquid L-T4 administration 30 min before breakfast or at shorter intervals. PMID- 26537479 TI - Raestur fiskur: air-dried fermented fish the Faroese way. AB - BACKGROUND: Fish has played an important role in the diet of the population of the mid-Atlantic Faroe Islands. Dried and fermented fish in particular have been an essential storable protein source in an economy where weather conditions and seasonal fluctuations affect the availability of food. For generations the islanders have prepared raestur fiskur, a home-made air-dried and fermented fish dish made of Atlantic cod (Gadus morhua L.) or saithe (Pollachius virens (L.)). Fermenting the fish is an efficient and valuable cultural strategy for preserving fish. METHODS: This ethnobiological study investigates the historical and present use of fermented fish in Faroese cuisine and examines its preservation as an everyday food that Faroese men pride themselves on making in high quality. This study is based on field notes collected through interviews and observations on the Faroe Islands since the mid-1990s. RESULTS: Processed fish could be stored for a long period of time; this was important in an economy where weather conditions and seasonal fluctuations affect food availability dramatically. For this reason, home-made air-dried fish has been central to the food security of the Faroese people. Usually consumed with tallow from sheep, the dish was once appreciated customarily on Christmas Eve and New Year's Eve, but has been largely replaced by Danish dishes. However, it has survived as everyday food until today. CONCLUSION: The presence of small-scale fishing, changing economic conditions, socially acquired taste-preferences, and the importance of old-fashioned dishes as key symbols of cultural identity, all contribute to the survival of raestur fiskur in Faroese food culture. Today, the dish is not only an essential food source, but its consumption is also an important act of identification and solidarity with the national identity of the islanders. PMID- 26537480 TI - Low utilization of postnatal care: searching the window of opportunity to save mothers and newborns lives in Islamabad capital territory, Pakistan. AB - BACKGROUND: Each year an estimated 289,000 maternal deaths occur worldwide; of which 50 % of maternal deaths occur around labor, delivery and immediate postpartum period. Postnatal care (PNC) is crucial but relatively neglected component in the continuum of care, and hence a missing link toward safe motherhood. Despite the significant improvement in child health and safe motherhood interventions, maternal mortality ratio, perinatal mortality and neonatal mortality still remain a challenge in achieving the Millennium Development Goals 4 and 5 in Pakistan. METHODS: This was a descriptive cross sectional study carried out in the four union councils of Islamabad capital territory, to understand the determinants of postnatal health care seeking. The study sample comprised 225 postpartum women with a child 0 to 1 month of age, and the health care providers from both public and private sector. A pre-tested semi structured questionnaire was used for data collection. One focus group discussion with health care providers was conducted, using open ended questions guide. RESULTS: Only 30 % women received PNC; amongst which 68 % went to a government health facility. According to the health service providers, 90 % women are not interested in PNC, and that is because they lack awareness, face mobility and transportation issues, and cannot afford the cost of health care. Besides many other determinants, women's education was significantly associated with the PNC utilization. CONCLUSION: More robust and culturally sensitive campaign on importance of PNC must be thought out by the national MNCH program to inform the less literate and peri urban inhabitants of Islamabad. Health providers ought to be sensitized and trained for promoting PNC to save maternal and newborn lives. PMID- 26537481 TI - Development of a radiofrequency ablation platform in a clinically relevant murine model of hepatocellular cancer. AB - RFA is used in treatment of patients with hepatocellular cancer (HCC); however, tumor location and size often limit therapeutic efficacy. The absence of a realistic animal model and a radiofrequency ablation (RFA) suitable for small animals presents significant obstacles in developing new strategies. To establish a realistic RFA platform that allows the development of effective RFA-integrated treatment in an orthotopic murine model of HCC, a human cardiac radiofrequency generator was modified for murine use. Parameters were optimized and RFA was then performed in normal murine livers and HCCs. The effects of RFA were monitored by measuring the ablation zone and transaminases. The survival of tumor-bearing mice with and without RFA was monitored, ablated normal liver and HCCs were evaluated macroscopically and histologically. We demonstrated that tissue-mimicking media was able to optimize RFA parameters. Utilizing this information we performed RFA in normal and HCC-bearing mice. RFA was applied to hepatic parenchyma and completely destroyed small tumors and part of large tumors. Localized healing of the ablation and normalization of transaminases occurred within 7 days post RFA. RFA treatment extended the survival of small tumor-bearing mice. They survived at least 5 months longer than the controls; however, mice with larger tumors only had a slight therapeutic effect after RFA. Collectively, we performed RFA in murine HCCs and observed a significant therapeutic effect in small tumor-bearing mice. The quick recovery of tumor-bearing mice receiving RFA mimics observations in human subjects. This platform provides us a unique opportunity to study RFA in HCC treatment. PMID- 26537482 TI - T2 relaxation time alterations underlying neurocognitive deficits in alcohol-use disorders (AUD) in an Indian population: A combined conventional ROI and voxel based relaxometry analysis. AB - Long-term heavy alcohol consumption has traditionally been associated with impaired cognitive abilities, such as deficits in abstract reasoning, problem solving, verbal fluency, memory, attention, and visuospatial processing. The present study aimed at exploring these neuropsychological deficits in alcohol-use disorders (AUD) in an Indian population using the Postgraduate Institute Battery of Brain Dysfunction (PGIBBD) and their possible correlation with alterations in T2 relaxation times (T2-RT), using whole-brain voxel-based relaxometry (VBR) and conventional region of interest (ROI) approach. Multi-echo T2 mapping sequence was performed on 25 subjects with AUD and 25 healthy controls matched for age, education, and socioeconomic status. Whole-brain T2-RT measurements were conducted using VBR and conventional ROI approach. The study was carried out on a 3T whole-body MR scanner. Post processing for VBR and ROI analysis was performed using SPM 8 software and vendor-provided software, respectively. A PGIBBD test battery was conducted on all subjects to assess their cognitive abilities, and the results were reported as raw scores. VBR and ROI results revealed that AUD subjects showed prolonged T2-RTs in cerebellum bilaterally, parahippocampal gyrus bilaterally, right anterior cingulate cortex, left superior temporal gyrus, left middle frontal gyrus, and left calcarine gyrus. A significant correlation was also observed between the neuropsychological test raw scores and alterations in T2-RT in AUD subjects. Our results are consistent with previous studies suggesting tissue disruption or gliosis or demyelination as a possible reason for prolonged T2-RTs. This damage to brain tissue, which is evident as prolonged T2 RT, could possibly be associated with impaired cognitive abilities noticeable in AUD subjects. PMID- 26537483 TI - Selection of cortical dynamics for motor behaviour by the basal ganglia. AB - The basal ganglia and cortex are strongly implicated in the control of motor preparation and execution. Re-entrant loops between these two brain areas are thought to determine the selection of motor repertoires for instrumental action. The nature of neural encoding and processing in the motor cortex as well as the way in which selection by the basal ganglia acts on them is currently debated. The classic view of the motor cortex implementing a direct mapping of information from perception to muscular responses is challenged by proposals viewing it as a set of dynamical systems controlling muscles. Consequently, the common idea that a competition between relatively segregated cortico-striato-nigro-thalamo cortical channels selects patterns of activity in the motor cortex is no more sufficient to explain how action selection works. Here, we contribute to develop the dynamical view of the basal ganglia-cortical system by proposing a computational model in which a thalamo-cortical dynamical neural reservoir is modulated by disinhibitory selection of the basal ganglia guided by top-down information, so that it responds with different dynamics to the same bottom-up input. The model shows how different motor trajectories can so be produced by controlling the same set of joint actuators. Furthermore, the model shows how the basal ganglia might modulate cortical dynamics by preserving coarse-grained spatiotemporal information throughout cortico-cortical pathways. PMID- 26537484 TI - Rectal Mass in a Pregnant Patient: How Come? AB - A 23-year-old pregnant Native American woman was initially evaluated at the onset of labor with the additional complaint of severe constipation and the finding of iron deficiency anemia. Immediately following manual disimpaction of feces, her rectum prolapsed revealing a 4 cm 9 4 cm bleeding mass. Following a successful Cesarean section, colonoscopy later revealed a 10 cm circumferential, necrotic mass with histologic characteristics of a moderately differentiated, invasive adenocarcinoma with IHC staining characteristic of LS. She left without resolving this problem. Because LS is a common cause of hereditary CRC, screening for LS and MSI is now increasingly being advocated. Early identification of those affected can reduce mortality from colon and a number of other cancers, particularly in females. Awareness of the issue is particularly important in Native American communities where screening rates are low and death rates from CRC are high, particularly in the western USA and in Alaska. PMID- 26537485 TI - The Diagnostic Yield of Site and Symptom-Based Biopsies for Acute Gastrointestinal Graft-Versus-Host Disease: A 5-Year Retrospective Review. AB - BACKGROUND: Graft-versus-host disease (GVHD) complicates half of hematopoietic stem cell transplants (HCT), and the gastrointestinal tract is commonly affected. Endoscopic biopsies have a key role in the diagnosis. The optimal procedure(s) to perform and site(s) to biopsy remain unclear. METHODS: We retrospectively analyzed the charts of all adult patients who underwent allogeneic HCT at Duke University Medical Center between 1/1/05 and 1/1/11 and extracted data from those who underwent endoscopic biopsy for suspected GVHD. All histology was re evaluated by blinded pathologists using 2006 NIH diagnostic criteria and then compared to the original clinical diagnosis of GVHD. RESULTS: A total of 169 adult patients underwent 250 endoscopic procedures to evaluate GVHD. The sensitivity of biopsies for clinical GVHD was 76 and 72% for upper and lower tract sites, respectively. In the presence of nausea, upper tract biopsies were positive for GVHD in 65%, 70% while lower tract biopsies were positive in 61-70%. In the presence of diarrhea, lower tract biopsies were positive in 65%, while upper tract sites were positive in 64-69%. Twenty six (40%) of the sixty-five endoscopies that simultaneously sampled upper and lower tract sites had discordant results. All were histologically positive for GVHD, yet 15% of upper tract biopsies and 25% of lower tract biopsies were negative. CONCLUSIONS: In this large review, the overall sensitivity of biopsies taken during EGD and Flex Sig was 76 and 72%, respectively. A symptom-driven biopsy approach was not clearly supported as upper tract and lower tract biopsies were similarly diagnostic for GVHD regardless of symptoms. PMID- 26537486 TI - Balloon-Occluded Retrograde Transvenous Obliteration of Jejunal Varices: A Case Report, Therapeutic Approach. PMID- 26537487 TI - Development and Validation of an Algorithm to Identify Nonalcoholic Fatty Liver Disease in the Electronic Medical Record. AB - BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Risk factors for NAFLD disease progression and liver-related outcomes remain incompletely understood due to the lack of computational identification methods. The present study sought to design a classification algorithm for NAFLD within the electronic medical record (EMR) for the development of large-scale longitudinal cohorts. METHODS: We implemented feature selection using logistic regression with adaptive LASSO. A training set of 620 patients was randomly selected from the Research Patient Data Registry at Partners Healthcare. To assess a true diagnosis for NAFLD we performed chart reviews and considered either a documentation of a biopsy or a clinical diagnosis of NAFLD. We included in our model variables laboratory measurements, diagnosis codes, and concepts extracted from medical notes. Variables with P < 0.05 were included in the multivariable analysis. RESULTS: The NAFLD classification algorithm included number of natural language mentions of NAFLD in the EMR, lifetime number of ICD-9 codes for NAFLD, and triglyceride level. This classification algorithm was superior to an algorithm using ICD-9 data alone with AUC of 0.85 versus 0.75 (P < 0.0001) and leads to the creation of a new independent cohort of 8458 individuals with a high probability for NAFLD. CONCLUSIONS: The NAFLD classification algorithm is superior to ICD-9 billing data alone. This approach is simple to develop, deploy, and can be applied across different institutions to create EMR-based cohorts of individuals with NAFLD. PMID- 26537488 TI - Clinical Outcomes of Postoperative Upper Gastrointestinal Leakage According to Treatment Modality. AB - BACKGROUND & AIM: We evaluated the clinical outcomes according to treatment modality for gastrointestinal anastomotic leakage. METHODS: Of the 19,207 patients who underwent gastrectomy for gastric cancer from March 2000 to April 2013, we retrospectively analyzed the 133 cases who developed anastomotic leakage. These patients were treated using endoscopic management, surgery, or conservative management (endoscopic treatment was introduced in 2009). To evaluate the efficacy of endoscopic treatment, we compared the clinical outcomes between the conservative management-only group before 2009 and the conservative or endoscopic management group from 2009; and between the surgical management only group before 2009 and the surgical or endoscopic management group from 2009. RESULTS: Seventy-three were initially managed conservatively, 35 were treated surgically, and 25 were treated using endoscopic procedures. Chronologically comparing each treatment group as 'before 2009' (n = 54) and 'from 2009' (n = 79), there were differences in the length of hospital stay (median 32 versus 27, p = 0.048) and duration of antibiotic use (median 28 versus 20, p = 0.013). Patients who underwent conservative or endoscopic management from 2009 showed a shorter hospital stay, period of fasting, and duration of antibiotic use than patients who underwent only conservative management before 2009. Patients who received surgery or endoscopic management from 2009 showed a shorter hospital stay and duration of antibiotic use than patients who underwent only surgery before 2009. CONCLUSION: Endoscopic management for selected cases can reduce duration of hospital stay and antibiotic administration in the treatment of anastomotic leakage after gastrectomy. PMID- 26537489 TI - Interferon-gamma production by CMV-specific CD8+ T lymphocytes provides protection against cytomegalovirus reactivation in critically ill patients. AB - PURPOSE: To evaluate the usefulness of the secretion of interferon-gamma (IFNgamma) by cytomegalovirus (CMV)-specific CD8+ T cells to determine the risk of CMV reactivation in critically ill non-immunosuppressed patients. METHODS: Two center prospective cohort study including critically ill non-immunosuppressed CMV seropositive patients admitted between December 2012 and March 2013. The incidence of CMV reactivation by polymerase chain reaction (real-time PCR) in plasma was investigated. IFNgamma secretion by CMV-specific CD8+ T lymphocytes was determined at the time of admission to the intensive care unit (ICU) by means of the QuantiFERON((r))-CMV (QF-CMV) test. Cox regression analyses were performed to investigate CMV reactivation risk factors. RESULTS: Fifty-three patients were included, of whom 13 (24.5%) presented CMV reactivation. Twenty-six patients (49.1%) were QF-CMV "reactive" (QF-CMV(R)). Of the 26 QF-CMV(R) patients, 11.5% (3/26) had CMV reactivation, whereas 37% (10/27) of QF-CMV "non reactive" patients (QF-CMV(NR)) presented reactivation (p = 0.03). By Cox regression, the presence of QF-CMV(R) at ICU admission (HR 0.09, 95% CI 0.02-0.44; p = 0.003) was associated with a decreased risk of CMV reactivation. The sensitivity, specificity, positive predictive value, and negative predictive value of QF-CMV were 77, 57, 37, and 88%, respectively. Eleven of the 53 patients (20.7%) died during the follow-up period. Mortality was more frequent in patients with CMV reactivation (6/13, 46.1 vs. 5/40, 12.5%; p = 0.015). CONCLUSIONS: In critically ill non-immunosuppressed patients, the presence of functional CMV-specific CD8+ T lymphocyte response at intensive care unit admission provides protection against CMV reactivation. PMID- 26537490 TI - Prognostic influence of psychofunctional status and comorbidity in very old cardiovascular patients admitted to the intensive care unit. PMID- 26537491 TI - Impact of acute liver failure on mortality during adult ECLS. PMID- 26537492 TI - The ethical issues regarding consent to clinical trials with pre-term or sick neonates: a systematic review (framework synthesis) of the empirical research. AB - BACKGROUND: Conducting clinical trials with pre-term or sick infants is important if care for this population is to be underpinned by sound evidence. Yet approaching parents at this difficult time raises challenges for the obtaining of valid informed consent to such research. This study asked: what light does the empirical literature cast on an ethically defensible approach to the obtaining of informed consent in perinatal clinical trials? METHODS: A systematic search identified 49 studies. Analysis began by applying philosophical frameworks which were then refined in light of the concepts emerging from empirical studies to present a coherent picture of a broad literature. RESULTS: Between them, studies addressed the attitudes of both parents and clinicians concerning consent in neonatal trials; the validity of the consent process in the neonatal research context; and different possible methods of obtaining consent. CONCLUSIONS: Despite a variety of opinions among parents and clinicians there is a strongly and widely held view that it is important that parents do give or decline consent for neonatal participation in trials. However, none of the range of existing consent processes reviewed by the research is satisfactory. A significant gap is evaluation of the widespread practice of emergency 'assent', in which parents assent or refuse their baby's participation as best they can during the emergency and later give full consent to ongoing participation and follow-up. Emergency assent has not been evaluated for its acceptability, how such a process would deal with bad outcomes such as neonatal death between assent and consent, or the extent to which late parental refusal might bias results. This review of a large number of empirical papers, while not making fundamental changes, has refined and developed the conceptual framework from philosophy for examining informed consent in this context. PMID- 26537493 TI - A WD40-repeat protein unique to malaria parasites associates with adhesion protein complexes and is crucial for blood stage progeny. AB - BACKGROUND: During development in human erythrocytes, Plasmodium falciparum parasites display a remarkable number of adhesive proteins on their plasma membrane. In the invasive merozoites, these include members of the PfMSP1 and PfAMA1/RON complexes, which facilitate contact between merozoites and red blood cells. In gametocytes, sexual precursor cells mediating parasite transmission to the mosquito vector, plasma membrane-associated proteins primarily belong to the PfCCp and 6-cys families with roles in fertilization. This study describes a newly identified WD40-repeat protein unique to Plasmodium species that associates with adhesion protein complexes of both merozoites and gametocytes. METHODS: The WD40-repeat protein-like protein PfWLP1 was identified via co-immunoprecipitation assays followed by mass spectrometry and characterized using biochemical and immunohistochemistry methods. Reverse genetics were employed for functional analysis. RESULTS: PfWLP1 is expressed both in schizonts and gametocytes. In mature schizonts, the protein localizes underneath the merozoite micronemes and interacts with PfAMA1, while in gametocytes PfWLP1 primarily accumulates underneath the plasma membrane and associates with PfCCp1 and Pfs230. Reverse genetics failed to disrupt the pfwlp1 gene, while haemagglutinin-tagging was feasible, suggesting a crucial function for PfWLP1 during blood stage replication. CONCLUSIONS: This is the first report on a plasmodial WD40-repeat protein associating with cell adhesion proteins. Since WD40 domains are known to mediate protein-protein contact by serving as a rigid scaffold for protein interactions, the presented data suggest that PfWLP1 supports the stability of adhesion protein complexes of the plasmodial blood stages. PMID- 26537494 TI - Relationship between brain volume loss and cognitive outcomes among patients with multiple sclerosis: a systematic literature review. AB - Patients with multiple sclerosis (MS) experience varying rates of brain volume (BV) loss ranging from 0.5 to 1.5 % per year. In addition, 66 % of patients with MS experience cognitive impairment, resulting in impact on daily activities. A systematic literature review (2003-2013) was conducted to identify all studies reporting a relationship between whole BV measures and selected patient outcomes measuring cognition, including the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT) and MS Functional Composite (MSFC) scores. We identified 18 studies reporting associations between whole BV and cognitive outcomes. Six studies (33 %) examined the association between BV and SDMT; all six studies reported that BV loss (BVL) was significantly associated with a decline in SDMT scores (all p < 0.05). Among 14 studies (78 %) that examined the association between BV and PASAT scores, 12 (86 %) found a significant relationship between BVL and lower PASAT scores (all p < 0.05). Of the seven studies (39 %) that looked at BV and MSFC, six studies (86 %) found BVL significantly associated with lower MSFC scores (all p < 0.05). Our study demonstrated that BVL is associated with declines in cognition in MS patients across several cognition measures. The results of this study suggest that BV is a critical component of disease activity and progression in MS and has implications for treatment decisions to minimize BVL and preserve cognitive functioning. PMID- 26537496 TI - A qualitative study of self-evaluation of junior doctor performance: is perceived 'safeness' a more useful metric than confidence and competence? AB - OBJECTIVES: The terms confidence and competence have been poorly defined and are often misused by junior doctors. Given safe practice relies on healthcare professionals being aware of their own skill sets improving self-assessment of confidence and competence is important. The aim of this work was to explore junior doctors' understanding of how they perceive their own performance in respect of managing feverish children in an emergency department. SETTING: A children's emergency department in a tertiary hospital in the East Midlands, UK. PARTICIPANTS: 22 Junior doctors volunteered to undertake focus groups via a meta planning methodology over 2 years (14 participants in the first year and 8 in the second). RESULTS: Although doctors were aware of the difference between confidence and competence they were not able to distinguish between them in practical terms. The feeling of being 'safe' emerged as a term in which there was a shared understanding compared to reported confidence and competence. CONCLUSIONS: A perception of 'safeness' is a concept that may aid self-evaluation and we present a matrix that might be used by supervisors and educators to examine this and its relationship with confidence and competence. PMID- 26537495 TI - A metabonomic investigation on the biochemical perturbation in post-stroke patients with depressive disorder (PSD). AB - A metabonomics study based on GC/MS and multivariate statistical analysis was performed involving 28 post stroke depressed (PSD) patients, 27 post-stroke non depressed (PSND) patients and 33 healthy subjects to investigate the biochemical perturbation in their plasma samples. The outcome of this study showed that there was distinctive metabolic profile for PSD patients. Seven sentinel metabolites showed marked perturbations in PSD patients' blood. The introduction of metabonomics approach may provide a novel metabonomic insight about PSD and the sentinel metabolites for classifying PSD. PMID- 26537497 TI - Exposure to secondhand smoke from neighbours and respiratory symptoms in never smoking adolescents in Hong Kong: a cross-sectional study. AB - OBJECTIVES: To investigate secondhand smoke (SHS) exposure at home from neighbours in Hong Kong adolescents and its association with respiratory symptoms in never-smokers. DESIGN: A cross-sectional study. SETTING: 79 randomly selected secondary schools in Hong Kong. PARTICIPANTS: 61,810 secondary 1 (USA grade 7) to 7 students, in which 50,762 never-smokers were identified and included in the analysis of the association between SHS exposure at home from neighbours and respiratory symptoms. MAIN OUTCOME MEASURES: Smoking status, family smoking status, SHS exposure at home from inside the home and from neighbours in the past 7 days, respiratory symptoms and sociodemographic characteristics were reported. Adjusted ORs (AORs) of respiratory symptoms for SHS exposure from the 2 sources in never-smokers were calculated using logistic regression. RESULTS: In all students, 33.2% were exposed to SHS at home, including 16.2% from inside the home only, 10.0% from neighbours only and 7.0% from both. The prevalence of SHS exposure from neighbours was 17.1%, including 13.5% for 1-4 days/week and 3.6% for 5-7 days/week. In never-smokers (n=50,762), respiratory symptoms were significantly associated with SHS exposure from neighbours with AORs (95% CI) of 1.29 (1.20 to 1.39) for any exposure (p<0.001), 1.21 (1.12 to 1.31) for 1-4 days/week (p<0.001) and 1.63 (1.44 to 1.86) for 5-7 days/week (p<0.001) (P for trend <0.001). Compared with no SHS exposure at home from any source, the AORs were 1.16 (1.07 to 1.25) for SHS from inside the home only (p<0.001), 1.20 (1.11 to 1.31) from neighbours only (p<0.001), and 1.74 (1.56 to 1.94) from both (p<0.001). CONCLUSIONS: SHS exposure at home from neighbours was prevalent in Hong Kong adolescents, and was associated with respiratory symptoms in never smokers. SHS exposure at home may be underestimated by ignoring the neighbouring source. Smoke-free housing policy is needed to protect children and adolescents from harms of SHS. PMID- 26537498 TI - Disparities in health and access to healthcare between asylum seekers and residents in Germany: a population-based cross-sectional feasibility study. AB - OBJECTIVES: To assess disparities in health and healthcare between asylum seekers (AS) and residents in Germany as a proof of concept using European Core Health Indicators (ECHI). DESIGN: Population-based cross-sectional feasibility study. PARTICIPANTS: All AS (aged 18 years or above) registered in three counties in Germany during a 3-month study period (N=1017). Cross-sectional data on the resident population were taken from the German Health Interview (2008-2011, N=8152), and the European Union Statistics on Income and Living Conditions (2012, N=23,065). OUTCOME MEASURES: Self-reported health status and healthcare access (utilisation and unmet medical need) in line with ECHI. METHOD: Inequalities in health and access to healthcare were quantified both by crude and age stratified/sex-stratified ORs with 95% CI using cross-tabulations. RESULTS: A total of N=156 AS (15.34%) participated in the study. Compared with residents, AS were significantly more likely to report a bad health status (OR=1.72 (1.23 to 2.41)), activity limitations (OR=1.97 (1.39 to 2.79)) or (only younger age groups) any chronic morbidity (18-24 years: OR=6.23 (2.62 to 14.57); 25-49 years: OR=2.05 (1.23 to 3.37)). AS had significantly lower odds for consulting any physician (OR=0.1 (0.07 to 0.16)) or general practitioners (OR=0.44 (0.31 to 0.62)), but higher odds for hospital admissions (OR=2.29 (1.54 to 3.34)), visits to psychotherapists (OR=4.07 (2.48 to 6.43)) and unmet needs (OR=3.74 (2.62 to 5.21)). The direction of healthcare-related associations was consistent across all strata despite variation in magnitude and statistical significance. CONCLUSIONS: Quantifying disparities between AS and the resident population by means of selected ECHI proved to be feasible. The approach yielded first quantitative evidence for disparities in health and access to healthcare in the German context. Further research is needed to generate representative estimates, for example, by including AS in national health monitoring programmes. PMID- 26537499 TI - The impact of meeting locations for men having sex with men on the risk for bacterial sexually transmitted infections: analyses from a cross-sectional online survey. AB - OBJECTIVES: Opportunities for men having sex with men (MSM) to meet each other have very much improved by new communication technologies. Meeting venue-based characteristics can impact how many partners are met and how much sexual risk is taken. We analysed the association between physical and virtual venues and the risk for bacterial sexually transmitted infections (bSTIs) among participants in an MSM online survey. METHODS: Data were collected during 2013/2014 with a survey targeting MSM living in Germany. The impact of the meeting place with the last non-steady anal sex partner on diagnosis with a bSTI in the previous year was analysed using bivariate and multivariate regression analysis, taking into account self-reported HIV status, serostatus communication, condom use, partner number, age and city size. RESULTS: The study sample consisted of 8878 respondents (7799 not diagnosed with HIV; 1079 diagnosed with HIV). Meeting partners online was most common (62% HIV-/51% HIV+), followed by sex venues (11% HIV-/25% HIV+); other venues were each reported by 2-6% of the respondents. Venue dependent proportions reporting bSTIs in the recent year were 2-4 folds higher among men diagnosed with HIV. In multivariate analysis, HIV status was the strongest predictor for bSTIs (OR=5.0; 95% CI 2.8 to 8.7). Compared with meeting partners online, sex (OR 1.6; 95% CI 1.0 to 2.5) and social venues (OR 1.9; 95% CI 1.4 to 2.6) were associated with increased bSTI risk for men not diagnosed with HIV, but the risk when meeting partners by smartphone apps was only of borderline significance (OR 1.5; 95% CI 0.9 to 2.3). For men diagnosed with HIV, bSTI risk increased for sex venues (OR 1.5; 95% CI 1.1 to 2.1), and was lower for non-gay/other venues (OR 0.2; 95% CI 0.1 to 0.5). CONCLUSIONS: Venues are connected to social-behavioural facets of corresponding sexual encounters, and may be important arenas for differential HIV and STI education, treatment and prevention. PMID- 26537500 TI - Supervised pharmacy student-led medication review in primary care for patients with type 2 diabetes: a randomised controlled pilot study. AB - OBJECTIVE: To pilot and feasibility-test supervised final year undergraduate pharmacy student-led medication reviews for patients with diabetes to enable definitive trial design. METHOD: Third year pharmacy students were recruited from one UK School of Pharmacy and trained to review patient's medical records and provide face-to-face consultations under supervision while situated within the patient's medical practice. Patients with type 2 diabetes were recruited by postal invitation letter from their medical practice and randomised via automated system to intervention or usual care. Diabetes-related clinical data, quality of life, patient reported beliefs, adherence and satisfaction with medicines information were collected with validated tools at baseline and 6 months postintervention. The process for collecting resource utilisation data was tested. Stakeholder meetings were held before and after intervention to develop study design and learn from its implementation. Recruitment and attrition rates were determined plus the quality of the outcome data. Power calculations for a definitive trial were performed on the different outcome measures to identify the most appropriate primary outcome measure. RESULTS: 792 patients were identified as eligible from five medical practices. 133 (16.8%) were recruited and randomised to control (n=66) or usual care (n=67). 32 students provided the complete intervention to 58 patients. Initial data analysis showed potential for impact in the right direction for some outcomes measured including glycated haemoglobin, quality of life and patient satisfaction with information about medicines. The intervention was found to be feasible and acceptable to patients. The pilot and feasibility study enabled the design of a future full randomised controlled trial. CONCLUSIONS: Student and patient recruitment are possible. The intervention was well received and demonstrated some potential benefits. While the intervention was relatively inexpensive and provided an experiential learning opportunity for pharmacy students, its cost-effectiveness remains to be determined. TRIAL REGISTRATION NUMBER: ISRCTN26445805; Results. PMID- 26537501 TI - Observing temporal trends in cardiac rehabilitation from 1996 to 2010 in Ontario: characteristics of referred patients, programme participation and mortality rates. AB - OBJECTIVES: We sought to describe temporal trends in the sociodemographic and clinical characteristics of participants referred to cardiac rehabilitation (CR), and its effect on programme participation and all-cause mortality over 14 years. SETTING: A large CR centre in Toronto, Canada. PARTICIPANTS: Consecutive patients between 1996 and 2010. PRIMARY AND SECONDARY OUTCOME MEASURES: Referrals received were deterministically linked to administrative data, to complement referral form abstraction. Out-of-hospital deaths were identified using vital statistics. Patients were tracked until 2012, and mortality was ascertained. Percentage attendance at prescribed sessions was also assessed. RESULTS: There were 29,171 referrals received, of which 28,767 (98.6%) were successfully linked, of whom 22,795 (79.2%) attended an intake assessment. The age of the referred population steadily increased, with more females, less affluent and more single patients referred over time (p<0.001). More patients were referred following percutaneous coronary intervention and less following coronary artery bypass graft surgery (p<0.001). The number of comorbidities decreased (p<0.001). Hypertension increased over time (p<0.001), yet the control of cholesterol steadily improved over time. The proportion of smokers decreased over time (p<0.001). Participation in CR significantly declined, and there were no significant changes in mortality. 3-year mortality rates were less than 5%. CONCLUSIONS: Characteristics of referred patients tended to reflect broader trends in risk factors and cardiovascular disease burden. Physicians appear to be referring more sociodemographically diverse patients to CR; however, programmes may need to better adapt to engage these patients to fully participate. More complex patients should be referred, using explicit criteria-based referral processes. PMID- 26537502 TI - Does physical exposure throughout working life influence chair-rise performance in midlife? A retrospective cohort study of associations between work and physical function in Denmark. AB - OBJECTIVES: Our aim was to study associations between physical exposures throughout working life and physical function measured as chair-rise performance in midlife. METHODS: The Copenhagen Aging and Midlife Biobank (CAMB) provided data about employment and measures of physical function. Individual job histories were assigned exposures from a job exposure matrix. Exposures were standardised to ton-years (lifting 1000 kg each day in 1 year), stand-years (standing/walking for 6 h each day in 1 year) and kneel-years (kneeling for 1 h each day in 1 year). The associations between exposure-years and chair-rise performance (number of chair-rises in 30 s) were analysed in multivariate linear and non-linear regression models adjusted for covariates. RESULTS: Mean age among the 5095 participants was 59 years in both genders, and, on average, men achieved 21.58 (SD=5.60) and women 20.38 (SD=5.33) chair-rises in 30 s. Physical exposures were associated with poorer chair-rise performance in both men and women, however, only associations between lifting and standing/walking and chair-rise remained statistically significant among men in the final model. Spline regression analyses showed non-linear associations and confirmed the findings. CONCLUSIONS: Higher physical exposure throughout working life is associated with slightly poorer chair-rise performance. The associations between exposure and outcome were non-linear. PMID- 26537503 TI - Roles of glycans in interactions between gp120 and HIV broadly neutralizing antibodies. AB - Many novel broadly neutralizing antibodies against human immunodeficiency virus (HIV) have been identified during the past decade, providing promising templates for the development of an effective HIV-1 vaccine. Structural studies reveal that the epitopes of some of these antibodies involve one or more crucial glycans, without which the binding is completely abolished. In this study, we have investigated the critical roles of glycans in interactions between HIV-1 gp120 and two broadly neutralizing antibodies PG9 (targeting V1/V2) and PGT128 (targeting V3) that are able to neutralize more than 70% of HIV-1 isolates. We have performed molecular dynamics simulations of a number of systems including antibody-gp120 complex with and without glycans, antibody, gp120 with and without glycans, and glycan-only systems. The simulation results show that the complex structures are stabilized by the glycans, and the multivalent interactions between the antibody and gp120 promote cooperativities to further enhance the binding. In the free gp120, the glycans increase the flexibility of the V1/V2 and V3 loops, which likely increases the entropy cost of the antibody recognition. However, the antibodies are able to bind the flexible interface by recognizing the preexisting glycan conformation, and penetrating the glycan shield with flexible complementarity determining region loops that sample the bound conformations occasionally. PMID- 26537504 TI - Structural characterization and biological implications of sulfated N-glycans in a serine protease from the neotropical moth Hylesia metabus (Cramer [1775]) (Lepidoptera: Saturniidae). AB - Contact with the urticating setae from the abdomen of adult females of the neo tropical moth Hylesia metabus gives rise to an urticating dermatitis, characterized by intense pruritus, generalized malaise and occasionally ocular lesions (lepidopterism). The setae contain a pro-inflammatory glycosylated protease homologous to other S1A serine proteases of insects. Deglycosylation with PNGase F in the presence of a buffer prepared with 40% H2 (18)O allowed the assignment of an N-glycosylation site. Five main paucimannosidic N-glycans were identified, three of which were exclusively alpha(1-6)-fucosylated at the proximal GlcNAc. A considerable portion of these N-glycans are anionic species sulfated on either the 4- or the 6-position of the alpha(1-6)-mannose residue of the core. The application of chemically and enzymatically modified variants of the toxin in an animal model in guinea pigs showed that the pro-inflammatory and immunological reactions, e.g. disseminated fibrin deposition and activation of neutrophils, are due to the presence of sulfate-linked groups and not on disulfide bonds, as demonstrated by the reduction and S-alkylation of the toxin. On the other hand, the hemorrhagic vascular lesions observed are attributed to the proteolytic activity of the toxin. Thus, N-glycan sulfation may constitute a defense mechanism against predators. PMID- 26537505 TI - Influence of Serum and Hypoxia on Incorporation of [(14)C]-D-Glucose or [(14)C]-L Glutamine into Lipids and Lactate in Murine Glioblastoma Cells. AB - Glucose and glutamine are essential energy metabolites for brain tumor growth and survival under both normoxic and hypoxic conditions. Both metabolites can contribute their carbons to lipid biosynthesis. We used uniformly labeled [(14)C] U-D-glucose and [(14)C]-U-L-glutamine to examine the profile of de novo lipid biosynthesis in the VM-M3 murine glioblastoma cells. The major lipids synthesized included phosphatidylcholine (PtdCho), phosphatidylethanolamine (EtnGpl), phosphatidylinositol (PtdIns), phosphatidylserine (PtdSer), sphingomyelin (CerPCho), bis(monoacylglycero)phosphate (BMP)/phosphatidic acid (PtdOH), cholesterol (C), cardiolipin (Ptd2Gro), and gangliosides. Endogenous lipid synthesis, using either glucose or glutamine, was greater in media without fetal bovine serum (FBS) than in media containing 10 % FBS under normoxia. De novo lipid synthesis was greater using glucose carbons than glutamine carbons under normoxia. The reverse was observed for most lipids under hypoxia suggesting an attenuation of glucose entering the TCA cycle. Lactate was produced largely from glucose carbons with minimal lactate derived from glutamine under either normoxia or hypoxia. Accumulation of triacylglycerols (TAG), containing mostly saturated and mono-unsaturated fatty acids, was observed under hypoxia using carbons from either glucose or glutamine. The data show that the incorporation of labeled glucose and glutamine into most synthesized lipids was dependent on the type of growth environment, and that the VM-M3 glioblastoma cells could acquire lipids, especially cholesterol, from the external environment for growth and proliferation. PMID- 26537506 TI - A longitudinal study of the characteristics and performances of medical students and graduates from the Arab countries. AB - BACKGROUND: While international physician migration has been studied extensively, more focused and regional explorations are not commonplace. In many Arab countries, medical education is conducted in English and students/graduates seek postgraduate opportunities in other countries such as the United States (US). Eligibility for residency training in the US requires certification by the Educational Commission for Foreign Medical Graduates (ECFMG). This study investigates ECFMG application trends, examination performance, and US physician practice data to quantify the abilities and examine the career pathways of Arab trained physicians. METHODS: Medical students and graduates from 15 Arab countries where English is the language of medical school instruction were studied. The performances (1(st) attempt pass rates) of individuals on the United States Medical Licensing Examination Step 1, Step 2CK (clinical knowledge), and and a combination of Step 2CS (clinical skills) and ECFMG CSA (clinical skills assessment) were tallied and contrasted by country. Based on physician practice data, the contribution of Arab-trained physicians to the US healthcare workforce was explored. Descriptive statistics (means, frequencies) were used to summarize the collected data. RESULTS: Between 1998 and 2012, there has been an increase in the number of Arab trained students/graduates seeking ECFMG certification. Examination performance varied considerably across countries, suggesting differences in the quality of medical education programs in the Eastern Mediterranean Region. Based on current US practice data, physicians from some Arab countries who seek postgraduate opportunities in the US are less likely to stay in the US following specialty training. CONCLUSION: Countries, or regions, with concerns about physician migration, physican performance, or the pedagogical quality of their training programs should conduct longitudinal research studies to help inform medical education policies. PMID- 26537508 TI - Adult presentation of Bartter syndrome type IV with erythrocytosis. AB - Bartter syndrome comprises a group of rare autosomal-recessive salt-losing disorders with distinct phenotypes, but one unifying pathophysiology consisting of severe reductions of sodium reabsorption caused by mutations in five genes expressed in the thick ascending limb of Henle, coupled with increased urinary excretion of potassium and hydrogen, which leads to hypokalemic alkalosis. Bartter syndrome type IV, caused by loss-of-function mutations in barttin, a subunit of chloride channel CLC-Kb expressed in the kidney and inner ear, usually occurs in the antenatal-neonatal period. We report an unusual case of late onset presentation of Bartter syndrome IV and mild phenotype in a 20 years-old man who had hypokalemia, deafness, secondary hyperparathyroidism and erythrocytosis. PMID- 26537509 TI - Comparative study of quality of life of adult survivors of childhood acute lymphocytic leukemia and Wilms' tumor. AB - OBJECTIVE: To analyze and compare the health-related quality of life of adult survivors of acute lymphocytic leukemia and Wilms' tumor amongst themselves and in relation to healthy participants. METHODS: Ninety participants aged above 18 years were selected and divided into three groups, each comprising 30 individuals. The Control Group was composed of physically healthy subjects, with no cancer history; and there were two experimental groups: those diagnosed as acute lymphocytic leukemia, and those as Wilms' Tumor. Quality of life was assessed over the telephone, using the Medical Outcomes Study 36-Item Short Form Health Survey. RESULTS: Male survivors presented with better results as compared to female survivors and controls in the Vitality domain, for acute lymphocytic leukemia (p=0.042) and Wilms' tumor (p=0.013). For acute lymphocytic leukemia survivors, in Social aspects (p=0.031), Mental health (p=0.041), and Emotional aspects (p=0.040), the latter also for survivors of Wilms' tumor (p=0.040). The best results related to the Functional capacity domain were recorded for the experimental group that had a late diagnosis of acute lymphocytic leukemia. There were significant differences between groups except for the Social and Emotional domains for self-perceived health, with positive responses that characterized their health as good, very good, and excellent. CONCLUSION: Survivors of acute lymphocytic leukemia showed no evidence of relevant impairment of health-related quality of life. The Medical Outcomes Study 36-Item Short Form Health Survey (via telephone) can be a resource to access and evaluate survivors. PMID- 26537510 TI - A lesson learnt: retrospection in a case of pilomatricoma mimicking as parotid neoplasm. PMID- 26537511 TI - Femoral quadriceps neuromuscular electrical stimulation after total knee arthroplasty: a systematic review. AB - The purpose of this study was to evaluate the effects of neuromuscular electrical stimulation in patients submitted to total knee arthroplasty. This was a systematic review with no language or publication status restriction. Our search was made in Cochrane Library, MEDLINE, Embase and LILACS. Randomized or quasi randomized clinical trials evaluating neuromuscular electrical stimulation after total knee arthroplasty were included. Four studies with moderate risk of bias and low statistical power were included, totalizing 376 participants. There was no statistically significant difference in knee function, pain and range of motion during 12 month follow-up. This review concluded that neuromuscular electrical stimulation was less effective than traditional rehabilitation in function, muscular strength and range of motion. However, this technique was useful for quadriceps activation during the first days after surgery. PMID- 26537512 TI - The Effect of Transconjunctival Blepharoplasty on Margin Reflex Distance 2. AB - BACKGROUND: The objective of this study was to determine the effects of lower eyelid transconjunctival blepharoplasty (TCB) on lower eyelid position. METHODS: Transconjunctival blepharoplasty was performed alone in 15 lower eyelids without simultaneous canthoplasty or upper eyelid procedure. In this study, blepharoplasty was performed by the transconjunctival approach without removal of skin. Four eyes received TCB plus Erbium laser, two patients received TCB plus trichloroacetic acid peel (TCA), and three patients received TCB plus fat transposition. Pre-operative and post-operative margin reflex distance 1 (MRD 1) and margin reflex distance 2 (MRD 2) were compared, with MRD 1 acting as the control. RESULTS: Average time to post-operative photo was 4.6 months (1-10 months). The changes in MRD 2 and MRD 1 were compared pre- and post-operatively, and the difference reached significance by one-tailed comparison (P < 0.05). In 11/15 eyes (73 %), MRD 2 decreased post-operatively. In 6/7 eyes (86 %), lower lid scleral show was eliminated post-operatively. There were no cases of lid retraction noted. CONCLUSIONS: Transconjunctival blepharoplasty (+/- skin resurfacing) did not induce lid retraction but elevated the lower lid in majority of patients. Elevation of the lower lid can reduce or eliminate scleral show inferiorly, providing further cosmetic advantage. The presumed mechanism of lower lid height elevation is partial recession of the lower lid retractors during the surgical approach to the fat pockets. LEVEL OF EVIDENCE IV: This journal requires that the authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26537513 TI - Outcomes of Tissue Expander Application for Scalp Reconstruction in Extensive Aplasia Cutis Congenita. AB - INTRODUCTION: Aplasia cutis congenita (ACC) is a rare congenital disorder. The purpose of this study was to present outcomes of tissue expander application for scalp reconstruction in extensive ACC. PATIENT/METHODS: In this retrospective study, medical records were reviewed for six patients who underwent serial tissue expander application for scalp reconstruction in ACC between 2000 and 2015. Patient average age was 14.5 (range, 4-25 years). One of the six cases had frontal bone defect, the others had bone and soft tissue defect at the vertex. In the newborn period, all patients have been managed by split-thickness skin grafts without cranioplasty procedures. After grafting and calvarial regeneration, one (or more) sessions of tissue expanders and scalp flap applications were performed for alopecia and soft tissue correction. Radiologic and clinical examination was performed for complications and outcomes. RESULTS: Computerized tomography showed intact calvarium with patchy hyperostosis in all patients. The mean size of grafted areas was 69.5 cm(2) (range, 32-148.5 cm(2)). Minimal distal flap necrosis (6 * 1 cm) was observed in one patient. Serial scalp tissue expansion was performed with at least one session in a 1-year interval. One expander was extracted due to exposition and infection. No total flap losses and no calvarial defects were observed during follow-up (mean; 8.6 years). Clinical examination revealed acceptable cosmetic results in all patients. CONCLUSION: We advocate late expander scalp reconstruction for management of extensive ACC cases. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26537514 TI - Serratia aquatilis sp. nov., isolated from drinking water systems. AB - A cream-white-pigmented, oxidase-negative bacterium (strain 2015-2462-01T), isolated from a drinking water system, was investigated in detail to determine its taxonomic position. Cells of the isolate were rod-shaped and stained Gram negative. A comparison of the 16S rRNA gene sequence of strain 2015-2462-01T with sequences of the type strains of closely related species of the genus Serratia revealed highest similarity to Serratia fonticola (98.4 %), Serratia proteamaculans (97.8 %), Serratia liquefaciens and Serratia grimesii (both 97.7 %). 16S rRNA gene sequence similarities to all other Serratia species were below 97.4 %. Multilocus sequence analysis (MLSA) on the basis of concatenated partial gyrB, rpoB, infB and atpD gene sequences showed a clear distinction of strain 2015-2462-01T from the type strains of the closest related Serratia species. The fatty acid profile of the strain consisted of C16 : 1 omega7c, C16 : 0; C14 : 0 and C14 : 0 3-OH/iso-C16 : 1 I as major components. DNA-DNA hybridizations between 2015-2462-01T and S. fonticola ATCC 29844T resulted in a relatedness value of 27 % (reciprocal 20 %). This DNA-DNA hybridization result in combination with the MLSA results and the differential biochemical properties indicated that strain 2015-2462-01T represents a novel species of the genus Serratia, for which the name Serratia aquatilis sp. nov. is proposed. The type strain is 2015-2462 01T ( = LMG 29119T = CCM 8626T). PMID- 26537515 TI - Not too little, not too much: problems of selecting oral antibiotic dose for children. PMID- 26537516 TI - Urgent cancer referral pathway: the difficulty in diagnosing head and neck cancers. PMID- 26537517 TI - Coping strategies for food insecurity among adolescent girls during the lean season in East Nusa Tenggara, Indonesia: a qualitative study. AB - One in eight people suffer from chronic hunger, leading to an insecure food situation. Chronic hunger mostly occurs in developing countries and includes adolescent girls. Our qualitative study, with data collected in December 2012, provided the results of an exploration of the experiences and strategies implemented by fifteen adolescent girls who tried to cope with their condition of living in food-insecure families. The age of the girls ranged from 10 to 19 years. Their coping strategies were grouped into self-initiated and parent initiated strategies. Self-initiated coping strategies that were the girls' own initiatives included eating only rice without any vegetables or side dish, eating less-desirable food, reducing portion size, skipping meals, saving pocket money and earning money to buy food. The parent-initiated coping strategies that were initiated by the parents and followed by the girls included selling their own field produce and livestock, asking for food, borrowing food and storing maize for 6 months up to 1 year. These results show that adolescent girls living in food-insecure areas implement several coping strategies in severe conditions, which parents may not be aware of, and such conditions may compromise their growth and health. The acknowledgement of such coping strategies and the girls' food insecurity condition can lead to a useful and suitable food insecurity alleviation programme for the girls and their families. PMID- 26537518 TI - Iterative sub-network component analysis enables reconstruction of large scale genetic networks. AB - BACKGROUND: Network component analysis (NCA) became a popular tool to understand complex regulatory networks. The method uses high-throughput gene expression data and a priori topology to reconstruct transcription factor activity profiles. Current NCA algorithms are constrained by several conditions posed on the network topology, to guarantee unique reconstruction (termed compliancy). However, the restrictions these conditions pose are not necessarily true from biological perspective and they force network size reduction, pruning potentially important components. RESULTS: To address this, we developed a novel, Iterative Sub-Network Component Analysis (ISNCA) for reconstructing networks at any size. By dividing the initial network into smaller, compliant subnetworks, the algorithm first predicts the reconstruction of each subnetwork using standard NCA algorithms. It then subtracts from the reconstruction the contribution of the shared components from the other subnetwork. We tested the ISNCA on real, large datasets using various NCA algorithms. The size of the networks we tested and the accuracy of the reconstruction increased significantly. Importantly, FOXA1, ATF2, ATF3 and many other known key regulators in breast cancer could not be incorporated by any NCA algorithm because of the necessary conditions. However, their temporal activities could be reconstructed by our algorithm, and therefore their involvement in breast cancer could be analyzed. CONCLUSIONS: Our framework enables reconstruction of large gene expression data networks, without reducing their size or pruning potentially important components, and at the same time rendering the results more biological plausible. Our ISNCA method is not only suitable for prediction of key regulators in cancer studies, but it can be applied to any high-throughput gene expression data. PMID- 26537519 TI - Sexual health in transition: A social representations study with indigenous Mexican young women. AB - This study asked whether traceable knowledge transformations are occurring among indigenous Mexican women and, if so, the processes through which these shape their engagements with sexual health values and views. Thirty-nine interviews with rural and urban indigenous Mexican female adolescents were analysed through the lenses of social representations theory. Results evince that participants express transformations in terms of their social context, what constitutes a healthy youth and the uses of folk medicine, which are brought about by selecting, displacing and hybridising knowledge. Discussion centres on the consistency of themes across the sample and the variety of processes mapped. PMID- 26537520 TI - Younger British men's understandings of prostate cancer: A qualitative study. AB - The purpose of this study was to explore young British men's understandings of prostate health and cancer of the prostate. A total of 16 White-British men between 31-50 years of age took part in interviews face-to-face or through computer-mediated communication. Thematic analysis broadly informed by grounded theory identified two key themes; 'limited knowledge about the prostate' and 'early detection & unpleasant procedures'. Accounts are discussed with reference to implications for improving men's understandings of prostate cancer, and likelihood of self-referral for prostate screening where necessary. PMID- 26537521 TI - An assessment of fatigue in patients with postural orthostatic tachycardia syndrome. AB - Individuals with postural orthostatic tachycardia syndrome share many symptoms with those who have chronic fatigue syndrome; one of which is severe fatigue. Previous literature found that those with chronic fatigue syndrome experience many forms of fatigue. The goal of this study was to investigate whether individuals with postural orthostatic tachycardia syndrome also experience multidimensional fatigue and whether these individuals can be clustered into subgroups based on the types of fatigue they endorse. A convenience sample of 138 participants (aged 14-29) with postural orthostatic tachycardia syndrome completed questionnaires that assessed fatigue, brain fog symptom severity, activities that improve brain fog, and brain fog-related disability. An exploratory factor analysis was conducted on the Fatigue Types Questionnaire, and a three-factor solution was produced. Factor scores were then used to cluster the patients into groups using a TwoStep cluster analysis. This resulted in two clusters, a high severity group and a low severity group. The clusters were then compared on a number of items related to symptom expression. Individuals within the more severe cluster had significantly more brain fog at the beginning and end of the survey when compared to cluster two. Those in the more severe cluster also described more activity impairment as well as more frequent, more severe, and more debilitation from postural orthostatic tachycardia syndrome and brain fog. The findings of the factor analysis suggest that patients with postural orthostatic tachycardia syndrome experience fatigue as a multidimensional construct and they also can be subgrouped based on symptom severity. PMID- 26537522 TI - Perceptions of exercise consistency: Relation to exercise-related cognitive errors and cognitions. AB - This study examined psychological differences between individuals (1) with varying perceptions of their exercise adherence pattern and (2) who do and do not make exercise-related cognitive errors. A total of 364 adults completed an exercise pattern and cognitive errors questionnaire. Individuals perceiving themselves as consistent exercisers reported more adaptive social cognitive outcomes (e.g. higher self-regulatory efficacy) than those perceiving themselves as inconsistent. Individuals expressing stronger exercise-related cognitive errors exercised less and reported problematic cognitions (e.g. more struggle with exercise decisions). These results link inconsistent adherence perceptions to weaker social cognitions and exercise-related cognitive errors, a novel form of bias related to limited exercise engagement. PMID- 26537523 TI - Drug-Induced QTc Interval Prolongation: A Multicenter Study to Detect Drugs and Clinical Factors Involved in Every Day Practice. AB - OBJECTIVE: The actual prevalence of drug induced QTc prolongation in clinical practice is unknown. Our objective was to determine the occurrence and characteristics of drug-induced QT prolongation in several common clinical practices. Additionally, a subgroup of patients treated with dextropropoxyphene of particular interest for the regulatory authority was analysed. RESEARCH DESIGN AND METHODS: Medical history and comorbidities predisposing to QT interval prolongation were registered for 1270 patient requiring medical assistance that involved drug administration. Three ionograms and ECGs were performed: baseline, intra- and after treatment; QT interval was corrected with Bazzet formula. RESULTS: Among patients, 9.9% presented QTc >450/470 ms, 3% QTc > 500 ms, 12.7% DeltaQTc >30 ms and 5.2% DeltaQTc >60 ms. QTc prolongation associated with congestive heart failure, ischemic cardiopathy, diabetes, renal failure, arrhythmias, hypothyroidism, and bradycardia. At univariate analysis, clarithromycin, haloperidol, tramadol, amiodarone, glyceryl trinitrate, amoxicillin + clavulanic acid, amoxicillin + sulbactam, ampicillin + sulbactam, fentanyl, piperacillin + tazobactam, and diazepam prolonged QTc. Prolongation remained significantly associated with furosemide, clarithromycin, glyceryl trinitrate and betalactamase inhibitors after multivariate analysis. CONCLUSION: QT interval prolongation in everyday practice is frequent, in association to clinical factors and drugs that can be easily identified for monitoring and prevention strategies. PMID- 26537524 TI - Lamotrigine Induced Whole Body Tics: A Case Report and Literature Review. AB - Lamotrigine is an anticonvulsant medication that also has utility in the treatment of bipolar disorder. It has been associated with many side effects, including rashes that can progress to Stevens-Johnson syndrome or toxic epidermal necrolysis. It has also been associated with the development of motor tics, most commonly in the head, neck, and shoulders. We will now present the case of a 45 year-old woman who developed tics that involved the entire left side of her body after her dose of lamotrigine was increased from 200 mg daily (2.0 mg/kg/day) to 225 mg daily (2.3 mg/kg/day). We will review the prior cases of lamotrigine induced tics, and compare them to the circumstances surrounding our patient. We will also discuss the neurobiology of tics and make suggestions to improve the tics, based on the reported cases. PMID- 26537525 TI - The Impact of State AIDS Drug Assistance Policies on Clinical and Economic Outcomes of People With HIV. AB - We investigated the effect of changes to state AIDS Drug Assistance Programs (ADAP) policies, which govern access to antiretroviral therapy (ART), on clinical and economic outcomes among low-income people living with HIV/AIDS. Retrospective analyses of ART access were conducted on state ADAP policies, using data from ADAP Monitoring Reports and Kaiser Family Foundation from 2006 to 2010. We found stricter eligibility requirements reduce the number of HIV-positive individuals with ART access through ADAP, and decreased ART use increases mortality by 2.67 quality-adjusted life years (QALYs) per beneficiary. If the ADAP income eligibility cutoff were decreased by 50 percentage points in each state, 4,626 individuals would lose ART access nationwide. Based on a $22,143 cost/QALY, this policy would save $274 million in health care expenditures (2012 dollars), but result in 12,352 QALYs lost, valued at $1.2 billion. Therefore, states should exercise caution in restricting programs that increase ART access for low-income people living with HIV/AIDS. PMID- 26537526 TI - Acylsilanes in Iridium-Catalyzed Directed Amidation Reactions and Formation of Heterocycles via Siloxycarbenes. AB - Exposing ortho-amido aroylsilanes to visible light or heat leads to cyclization reactions that provide N-heterocyclic compounds via siloxycarbenes as key intermediates. The previously unreported starting materials have been prepared by directed amidations of aromatic acylsilanes in the presence of an iridium catalyst followed by N-alkylation. PMID- 26537527 TI - Thalassemia 2016: Modern medicine battles an ancient disease. AB - Thalassemia was first clinically described nearly a century ago and treatment of this widespread genetic disease has greatly advanced during this period. DNA based diagnosis elucidated the molecular basis of the disease and clarified the variable clinical picture. It also paved the way for modern methods of carrier identification and prevention via DNA-based prenatal diagnosis. Every aspect of supportive care, including safer blood supply, more regular transfusions, specific monitoring of iron overload, parenteral and oral chelation, and other therapies, has prolonged life and improved the quality of life of these patients. Significant advances have also been made in allogenic bone marrow transplantation, the only curative therapy. Recently, there has been a rejuvenated interest in studying thalassemia at the basic science level, leading to the discovery of previously unknown mechanisms leading to anemia and enabling the development of novel therapies. These will potentially improve the treatment of, and possibly cure the disease. Pathways involving activin receptors, heat shock proteins, JAK2 inhibitors and macrophage targeted therapy, among others, are being studied or are currently in clinical trials for treating thalassemia. Novel types of genetic therapies are in use or under investigation. In addition to the challenges of treating each individual patient, the longer survival of thalassemia patients has raised considerations regarding worldwide control of thalassemia, since prevention is not universally implemented. This review will trace a number of the original medical milestones of thalassemia diagnosis and treatment, as well as some of the most recent developments which may lead to innovative therapeutic modalities. PMID- 26537528 TI - Taiwanin C selectively inhibits arecoline and 4-NQO-induced oral cancer cell proliferation via ERK1/2 inactivation. AB - Arecoline, the most abundant alkaloid in betel nut is known to promote abnormal proliferation of epithelial cells by enhancing epidermal growth factor receptor (EGFR) activation and cyclooxygenase-2 (COX2) expression. Taiwanin C, a naturally occurring lignan extracted from Taiwania cryptomerioides, has been found to be a potential inhibitor of COX2 expression. Based on the MTT assay results, taiwanin C was found to be effective in inhibiting the tumorous T28 cell than the non tumorous N28 cells. The modulations in the expression of relevant proteins were determined to understand the mechanism induced by taiwanin C to inhibit T28 cell proliferation. The levels of activated EGFR and COX2 were found to be abnormally high in the T28 oral cancer cells. However, taiwanin C was found to inhibit the activation of EGFR and regulated other related downstream proteins and thereby inhibited the T28 cell proliferation. In conclusion the results indicate that taiwanin C suppresses COX2-EGFR and enhances P27 pathways to suppress arecoline induced oral cancer cell proliferation via ERK1/2 inactivation. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 62-69, 2017. PMID- 26537529 TI - Factors influencing long-term efficacy and tolerability of bosutinib in chronic phase chronic myeloid leukaemia resistant or intolerant to imatinib. AB - The dual SRC/ABL1 tyrosine kinase inhibitor bosutinib is indicated for adults with Ph+ chronic myeloid leukaemia (CML) resistant/intolerant to prior therapy. This analysis of an ongoing phase 1/2 study (NCT00261846) assessed effects of baseline patient characteristics on long-term efficacy and safety of bosutinib 500 mg/day in adults with imatinib (IM)-resistant (IM-R; n = 196)/IM-intolerant (IM-I; n = 90) chronic phase (CP) CML. Median treatment duration was 24.8 months (median follow-up, 43.6 months). Cumulative major cytogenetic response (MCyR) rate [95% confidence interval (CI)], was 59% (53-65%); Kaplan-Meier (KM) probability of maintaining MCyR at 4 years was 75% (66-81%). Cumulative incidence of on-treatment progression/death at 4 years was 19% (95% CI, 15-24%); KM 2-year overall survival was 91% (87-94%). Significant baseline predictors of both MCyR and complete cytogenetic response (newly attained/maintained from baseline) at 3 and 6 months included prior IM cytogenetic response, baseline MCyR, prior interferon therapy and <6 months duration from diagnosis to IM treatment initiation and no interferon treatment before IM. The most common adverse event (AE) was diarrhoea (86%). Baseline bosutinib-sensitive BCR-ABL1 mutation was the only significant predictor of grade 3/4 diarrhoea; no significant predictors were identified for liver-related AEs. Bosutinib demonstrates durable efficacy and manageable toxicity in IM-R/IM-I CP-CML patients. PMID- 26537530 TI - A Patient with Autoimmune Pancreatitis Type 1 with Previously Known Lymphadenopathy, Both in the Context of IgG4-related Disease. AB - BACKGROUND: Autoimmune pancreatitis (AIP) is an important clinical pathologic concept of IgG-4-related disease. AIP is a rare cause of chronic pancreatitis, characterized by a fibroinflammatory process by lymphoplasmacytic infiltrates, storiform fibrosis, obliterative phlebitis, and increased IgG4+ plasma cells, leading to dysfunction of the pancreas. Affected patients with AIP frequently have disease affecting other organs or sites with similar histologic changes, elevated IgG4+ plasma cell infiltrate, and good response to corticosteroid therapy. These diseases often are not limited to the pancreas and the pancreas may not be involved at all. CASE REPORT: We report a 62-year-old man with obstructive jaundice with pre-existent submandibular lymphadenopathy. Diagnosis of AIP was based on diagnostic criteria by the HISORT-criteria in combination with elevated IgG-4 serum levels. CT revealed a focal enlargement of the head of the pancreas, as well as mesenteric peripancreatic and mediastinal lymphadenopathy. He was treated with high-dose steroid in combination with azathioprine and showed good clinical response. CONCLUSIONS: We report a case with pre-existent submandibular lymphadenopathy and obstructive jaundice based on AIP type 1, both in the context of IgG4-related disease. PMID- 26537531 TI - Could Ethical Tensions in Oral Healthcare Management Revealed by Adults with Intellectual Disabilities and Caregivers Explain Unmet Oral Health Needs? Participatory Research with Focus Groups. AB - BACKGROUND: Cognitively impaired patients often present poor oral health status that may be explained by ethical tensions in oral healthcare management. This participatory study explored such tensions among adults with intellectual disabilities and with caregivers. The second objective was to specify, with caregivers, the points that should be developed in a future study among dentists. MATERIALS AND METHODS: Three focus groups involving adults with intellectual disabilities, family caregivers and professional caregivers were organized in France in 2013. RESULTS: The thematic content analysis identified discrepancies between experiences and expectations, which were particularly marked for the dentist's competence and attitudes, the dentist's role in decisions, the dental care management and the French socio-political context. CONCLUSIONS: These discrepancies could partly explain multiple attempts to find the 'right' dentist or the fact that care was abandoned, and could at least contribute to oral health needs being unmet. PMID- 26537532 TI - Evaluation of fluoropyruvate as nucleophile in reactions catalysed by N-acetyl neuraminic acid lyase variants: scope, limitations and stereoselectivity. AB - The catalysis of reactions involving fluoropyruvate as donor by N-acetyl neuraminic acid lyase (NAL) variants was investigated. Under kinetic control, the wild-type enzyme catalysed the reaction between fluoropyruvate and N-acetyl mannosamine to give a 90 : 10 ratio of the (3R,4R)- and (3S,4R)-configured products; after extended reaction times, equilibration occurred to give a 30 : 70 mixture of these products. The efficiency and stereoselectivity of reactions of a range of substrates catalysed by the E192N, E192N/T167V/S208V and E192N/T167G NAL variants were also studied. Using fluoropyruvate and (2R,3S)- or (2S,3R)-2,3 dihydroxy-4-oxo-N,N-dipropylbutanamide as substrates, it was possible to obtain three of the four possible diastereomeric products; for each product, the ratio of anomeric and pyranose/furanose forms was determined. The crystal structure of S. aureus NAL in complex with fluoropyruvate was determined, assisting rationalisation of the stereochemical outcome of C-C bond formation. PMID- 26537533 TI - Versatile Molding Process for Tough Cellulose Hydrogel Materials. AB - Shape-persistent and tough cellulose hydrogels were fabricated by a stepwise solvent exchange from a homogeneous ionic liquid solution of cellulose exposure to methanol vapor. The cellulose hydrogels maintain their shapes under changing temperature, pH, and solvents. The micrometer-scale patterns on the mold were precisely transferred onto the surface of cellulose hydrogels. We also succeeded in the spinning of cellulose hydrogel fibers through a dry jet-wet spinning process. The mechanical property of regenerated cellulose fibers improved by the drawing of cellulose hydrogel fibers during the spinning process. This approach for the fabrication of tough cellulose hydrogels is a major advance in the fabrication of cellulose-based structures with defined shapes. PMID- 26537534 TI - Guidelines for good pharmacoepidemiology practice (GPP). PMID- 26537535 TI - Fungicide-induced transposon movement in Monilinia fructicola. AB - Repeated applications of fungicides with a single mode of action are believed to select for pre-existing resistant strains in a pathogen population, while the impact of sub-lethal doses of such fungicides on sensitive members of the population is unknown. In this study, in vitro evidence is presented that continuous exposure of Monilinia fructicola mycelium to some fungicides can induce genetic change in form of transposon transposition. Three fungicide sensitive M. fructicola isolates were exposed in 12 weekly transfers of mycelia to a dose gradient of demethylation inhibitor fungicide (DMI) SYP-Z048 and quinone outside inhibitor fungicide (QoI) azoxystrobin in solo or mixture treatments. Evidence of mutagenesis was assessed by monitoring Mftc1, a multicopy transposable element of M. fructicola, by PCR and Southern blot analysis. Movement of Mftc1 was observed following azoxystrobin and azoxystrobin plus SYP Z048 treatments in two of the three isolates, but not in the non-fungicide treated controls. Interestingly, the upstream promoter region of MfCYP51 was a prime target for Mftc1 transposition in these isolates. Transposition of Mftc1 was verified by Southern blot in two of three isolates from another, similar experiment following prolonged, sublethal azoxystrobin exposure, although in these isolates movement of Mftc1 in the upstream MfCYP51 promoter region was not observed. More research is warranted to determine whether fungicide-induced mutagenesis may also happen under field conditions. PMID- 26537536 TI - Enhancing CVD graphene's inter-grain connectivity by a graphite promoter. AB - Graphene's impact on future applications is intimately linked to advances in the synthesis of high quality materials. Chemical vapor deposition (CVD) shows great potential in this area but insufficient connectivity between single-crystalline domains deteriorates the achievable electrical and mechanical performance. We here demonstrate that the inter-grain connectivity can be significantly improved by adding a second material in the vicinity of the growth substrate. This promoter decreases the amount of structural defects that remain at the grain boundaries of conventionally grown graphene even after 6 hour growth. A two-step growth process was employed to selectively enhance the grain connectivity while maintaining an identical graphene grain morphology with and without a promoter. Graphite was found to yield the largest enhancement in the connectivity of graphene grains due to its high catalytic activity compared to other promoter materials. A novel cap-design ensured a large scale and uniform improvement of the inter-grain connectivity results which led to an enhancement of large scale carrier mobilities from 2700 cm(2) V(-1) s(-1) to 4000 cm(2) V(-1) s(-1) and highlights the potential of our approach to improving the connectivity of CVD grown graphene. PMID- 26537537 TI - Concepts first, jargon second improves student articulation of understanding. AB - In this experiment, students in a large undergraduate biology course were first exposed to the concepts without new technical vocabulary ("jargon") in a pre class reading assignment. Their learning of the concepts and jargon was compared with that of an equivalent group of students in another section of the same course, whose pre-class reading presented both the jargon and concepts together in the traditional manner. Both groups had the same active-learning classes with the same instructor, and then completed the same post-test. Although the two groups performed the same on the multiple choice questions of the post-test, the group exposed to concepts first and jargon second included 1.5 times and 2.5 times more correct arguments on two free-response questions about the concepts. The correct use of jargon between the two groups was similar, with the exception of one jargon term that the control group used more often. These results suggest that modest instructional changes whereby new concepts are introduced in a concepts-first, jargon-second manner can increase student learning, as demonstrated by their ability to articulate their understanding of new concepts. PMID- 26537538 TI - Proteomic Discovery and Development of a Multiplexed Targeted MRM-LC-MS/MS Assay for Urine Biomarkers of Extracellular Matrix Disruption in Mucopolysaccharidoses I, II, and VI. AB - The mucopolysaccharidoses (MPS) are lysosomal storage disorders that result from defects in the catabolism of glycosaminoglycans. Impaired muscle, bone, and connective tissue are typical clinical features of MPS due to disruption of the extracellular matrix. Markers of MPS disease pathology are needed to determine disease severity and monitor effects of existing and emerging new treatments on disease mechanisms. Urine samples from a small cohort of MPS-I, -II, and -VI patients (n = 12) were analyzed using label-free quantative proteomics. Fifty three proteins including many associated with extracellular matrix organization were differently expressed. A targeted multiplexed peptide MRM LC-MS/MS assay was used on a larger validation cohort of patient samples (MPS-I n = 18, MPS-II n = 12, MPS-VI n = 6, control n = 20). MPS-I and -II groups were further subdivided according to disease severity. None of the markers assessed were altered significantly in the mild disease groups compared to controls. beta galactosidase, a lysosomal protein, was elevated 3.6-5.7-fold significantly (p < 0.05) in all disease groups apart from mild MPS-I and -II. Collagen type Ialpha, fatty-acid-binding-protein 5, nidogen-1, cartilage oligomeric matrix protein, and insulin-like growth factor binding protein 7 concentrations were elevated in severe MPS I and II groups. Cartilage oligomeric matrix protein, insulin-like growth factor binding protein 7, and beta-galactosidase were able to distinguish the severe neurological form of MPS-II from the milder non-neurological form. Protein Heg1 was significantly raised only in MPS-VI. This work describes the discovery of new biomarkers of MPS that represent disease pathology and allows the stratification of MPS-II patients according to disease severity. PMID- 26537539 TI - Does office space occupation matter? The role of the number of persons per enclosed office space, psychosocial work characteristics, and environmental satisfaction in the physical and mental health of employees. AB - The study examined the effects of office space occupation, psychosocial work characteristics, and environmental satisfaction on physical and mental health of office workers in small-sized and open-plan offices as well as possible underlying mechanisms. Office space occupation was characterized as number of persons per one enclosed office space. A total of 207 office employees with similar jobs in offices with different space occupation were surveyed regarding their work situation (psychosocial work characteristics, satisfaction with privacy, acoustics, and control) and health (psychosomatic complaints, irritation, mental well-being, and work ability). Binary logistic and linear regression analyses as well as bootstrapped mediation analyses were used to determine associations and underlying mechanisms. Employee health was significantly associated with all work characteristics. Psychosocial work stressors had the strongest relation to physical and mental health (OR range: 1.66-3.72). The effect of office space occupation on employee health was mediated by stressors and environmental satisfaction, but not by psychosocial work resources. As assumed by sociotechnical approaches, a higher number of persons per enclosed office space was associated with adverse health effects. However, the strongest associations were found with psychosocial work stressors. When revising office design, a holistic approach to work (re)design is needed. PMID- 26537540 TI - Outbreak of Yersinia pseudotuberculosis O:1 infection associated with raw milk consumption, Finland, spring 2014. AB - In March 2014, a Yersinia pseudotuberculosis (YP) outbreak was detected by a municipal authority in southern Finland. We conducted epidemiological, microbiological and traceback investigations to identify the source. We defined a case as a person with YP infection notified to the National Infectious Disease Registry between February and April 2014, or their household member, with abdominal pain and fever>=38 degrees C or erythema nodosum. Healthy household members were used as household-matched controls. We identified 43 cases and 50 controls. The illness was strongly associated with the consumption of raw milk from a single producer. The odds ratio of illness increased with the amount of raw milk consumed. Also previously healthy adults became infected by consuming raw milk. Identical YP strains were identified from cases' stool samples, raw milk sampled from a case's refrigerator and from the milk filter at the producer's farm. The producer fulfilled the legal requirements for raw milk production and voluntarily recalled the raw milk and stopped its production. We advised consumers to heat the raw milk to 72 degrees C for 15 s. Current legislation for raw milk producers should be reviewed and public awareness of health risks linked to raw milk consumption should be increased. PMID- 26537543 TI - The Effect of Age on Attention Level: A Comparison of Two Age Groups. AB - In the present study, a computerized test was used to compare the attention level of a group of healthy older participants aged 75 with that of a group of students aged 31. The second part of the study examined only the older participants and sought to discover how three measures of lifestyle were related to measures of attention. The results showed that the young group performed better on measures of attention. No differences between the two age groups were found on measures of impulsivity and on four measures of sustained attention. A discriminant function analysis found that reaction time and standard deviation of reaction time can explain 87.50% of the variance in both groups. The older participants' answers to the lifestyle questions showed that variables of attention correlated significantly with time spent watching television and reading. The results indicate that attention level declines with age; however, no decline was observed on measures of impulsivity and sustained attention. PMID- 26537541 TI - Interaction of smoking and obesity susceptibility loci on adolescent BMI: The National Longitudinal Study of Adolescent to Adult Health. AB - BACKGROUND: Adolescence is a sensitive period for weight gain and risky health behaviors, such as smoking. Genome-wide association studies (GWAS) have identified loci contributing to adult body mass index (BMI). Evidence suggests that many of these loci have a larger influence on adolescent BMI. However, few studies have examined interactions between smoking and obesity susceptibility loci on BMI. This study investigates the interaction of current smoking and established BMI SNPs on adolescent BMI. Using data from the National Longitudinal Study of Adolescent to Adult Health, a nationally-representative, prospective cohort of the US school-based population in grades 7 to 12 (12-20 years of age) in 1994-95 who have been followed into adulthood (Wave II 1996; ages 12-21, Wave III; ages 18-27), we assessed (in 2014) interactions of 40 BMI-related SNPs and smoking status with percent of the CDC/NCHS 2000 median BMI (%MBMI) in European Americans (n = 5075), African Americans (n = 1744) and Hispanic Americans (n = 1294). RESULTS: Two SNPs showed nominal significance for interaction (p < 0.05) between smoking and genotype with %MBMI in European Americans (EA) (rs2112347 (POC5): beta = 1.98 (0.06, 3.90), p = 0.04 and near rs571312 (MC4R): beta 2.15 ( 0.03, 4.33) p = 0.05); and one SNP showed a significant interaction effect after stringent correction for multiple testing in Hispanic Americans (HA) (rs1514175 (TNNI3K): beta 8.46 (4.32, 12.60), p = 5.9E-05). Stratifying by sex, these interactions suggest a stronger effect in female smokers. CONCLUSIONS: Our study highlights potentially important sex differences in obesity risk by smoking status in adolescents, with those who may be most likely to initiate smoking (i.e., adolescent females), being at greatest risk for exacerbating genetic obesity susceptibility. PMID- 26537544 TI - Career Influences in Bridge Employment Among Retired Police Officers. AB - The careful examination of factors influencing bridge employment among retired police officers is largely absent in the literature. Two hundred and eleven retired police officers participated in a survey exploring factors that contributed to the participation in bridge employment or employment upon retiring from primary careers in law enforcement. The results indicate that retired officers who held part-time positions while fully employed as police officers were more likely to participate in bridge employment when compared with individuals who did not hold additional part-time employment while fully employed as police officers. Opportunities for training and interventions exist to help retired police officers navigate the working transition at this later-life juncture. PMID- 26537547 TI - Comparing research investment to United Kingdom institutions and published outputs for tuberculosis, HIV and malaria: a systematic analysis across 1997 2013. AB - BACKGROUND: The "Unfinished Agenda" of infectious diseases is of great importance to policymakers and research funding agencies that require ongoing research evidence on their effective management. Journal publications help effectively share and disseminate research results to inform policy and practice. We assess research investments to United Kingdom institutions in HIV, tuberculosis and malaria, and analyse these by numbers of publications and citations and by disease and type of science. METHODS: Information on infection-related research investments awarded to United Kingdom institutions across 1997-2010 were sourced from funding agencies and individually categorised by disease and type of science. Publications were sourced from the Scopus database via keyword searches and filtered to include only publications relating to human disease and containing a United Kingdom-based first and/or last author. Data were matched by disease and type of science categories. Investment (United Kingdom pounds) and publications were compared to generate an 'investment per publication' metric; similarly, an 'investment per citation' metric was also developed as a measure of the usefulness of research. RESULTS: Total research investment for all three diseases was L1.4 billion, and was greatest for HIV (L651.4 million), followed by malaria (L518.7 million) and tuberculosis (L239.1 million). There were 17,271 included publications, with 9,322 for HIV, 4,451 for malaria, and 3,498 for tuberculosis. HIV publications received the most citations (254,949), followed by malaria (148,559) and tuberculosis (100,244). According to UK pound per publication, tuberculosis (L50,691) appeared the most productive for investment, compared to HIV (L61,971) and malaria (L94,483). By type of science, public health research was most productive for HIV (L27,296) and tuberculosis (L22,273), while phase I-III trials were most productive for malaria (L60,491). According to UK pound per citation, tuberculosis (L1,797) was the most productive area for investment, compared to HIV (L2,265) and malaria (L2,834). Public health research was the most productive type of science for HIV (L2,265) and tuberculosis (L1,797), whereas phase I-III trials were most productive for malaria (L1,713). CONCLUSIONS: When comparing total publications and citations with research investment to United Kingdom institutions, tuberculosis research appears to perform best in terms of efficiency. There were more public health-related publications and citations for HIV and tuberculosis than other types of science. These findings demonstrate the diversity of research funding and outputs, and provide new evidence to inform research investment strategies for policymakers, funders, academic institutions, and healthcare organizations. PMID- 26537548 TI - Distribution of CD163-positive cell and MHC class II-positive cell in the normal equine uveal tract. AB - Antigen-presenting cells (APCs) in the uveal tract participate in ocular immunity including immune homeostasis and the pathogenesis of uveitis. In horses, although uveitis is the most common ocular disorder, little is known about ocular immunity, such as the distribution of APCs. In this study, we investigated the distribution of CD163-positive and MHC II-positive cells in the normal equine uveal tract using an immunofluorescence technique. Eleven eyes from 10 Thoroughbred horses aged 1 to 24 years old were used. Indirect immunofluorescence was performed using the primary antibodies CD163, MHC class II (MHC II) and CD20. To demonstrate the site of their greatest distribution, positive cells were manually counted in 3 different parts of the uveal tract (ciliary body, iris and choroid), and their average number was assessed by statistical analysis. The distribution of pleomorphic CD163- and MHC II-expressed cells was detected throughout the equine uveal tract, but no CD20-expressed cells were detected. The statistical analysis demonstrated the distribution of CD163- and MHC II-positive cells focusing on the ciliary body. These results demonstrated that the ciliary body is the largest site of their distribution in the normal equine uveal tract, and the ciliary body is considered to play important roles in uveal and/or ocular immune homeostasis. The data provided in this study will help further understanding of equine ocular immunity in the normal state and might be beneficial for understanding of mechanisms of ocular disorders, such as equine uveitis. PMID- 26537549 TI - Epidemiology and vaccine of porcine epidemic diarrhea virus in China: a mini review. AB - Porcine epidemic diarrhea (PED) is an intestinal infectious disease caused by porcine epidemic diarrhea virus (PEDV); manifestations of the disease are diarrhea, vomiting and dehydration. Starting from the end of 2010, a PED outbreak occurred in several pig-producing provinces in southern China. Subsequently, the disease spread throughout the country and caused enormous economic losses to the pork industry. Accumulating studies demonstrated that new PEDV variants that appeared in China were responsible for the PED outbreak. In the current mini review, we summarize PEDV epidemiology and vaccination in China. PMID- 26537550 TI - Multiplex PCR serogrouping of Listeria monocytogenes isolated in Japan. AB - PCR serogrouping methods were used to examine strains of L. monocytogenes isolated in Japan. Among 187 strains, 99.5% were classified into 4 PCR serogroups corresponding to conventional serotypes. Only one isolate had a new PCR profile, which may be a variant of serogroup IVb. PMID- 26537551 TI - Microsatellite loci analysis for individual identification in Shiba Inu. AB - Eighteen autosomal microsatellite loci were examined using 275 Shiba Inus in Japan. Eighteen dogs representing eight trios were obtained from four breeders to calculate mutation rates, and 257 dogs kept by owners were collected through veterinary clinics throughout Japan to calculate population genetic parameters and estimate discrimination power. After two loci (INU005 and AHTk253) were excluded, average expected heterozygosity (He), polymorphic information content (PIC) and fixation index (F) were 0.665, 0.623 and 0.046, respectively. The combined power of discrimination over the 16 microsatellite markers was more than 0.9999. Therefore, it is suggested that these 16 microsatellite loci recommended by the International Society for Animal Genetics (ISAG) are applicable for individual identification and parentage testing of domestic Shiba Inu in Japan. PMID- 26537552 TI - BODIPY/Nile-Red-Based Efficient FRET Pair: Selective Assay of Endoplasmic Reticulum Membrane Fluidity. AB - We synthesized a boron-dipyrromethene (BODIPY)/Nile Red hybrid probe capable of selectively recognizing fluidity changes in the endoplasmic reticulum (ER) membrane due to its preferential localization to the ER and strong energy transfer from BODIPY to the Nile Red moiety, emitting only in nonaqueous environments. ER membrane fluidity in HepG2 cells was markedly reduced by a cell model of metabolic syndrome. PMID- 26537553 TI - Crafting Appealing Text Messages to Encourage Colorectal Cancer Screening Test Completion: A Qualitative Study. AB - BACKGROUND: mHealth interventions that incorporate text messages have great potential to increase receipt of preventive health services such as colorectal cancer screening. However, little is known about older adult perspectives regarding the receipt of text messages from their health care providers. OBJECTIVE: To assess whether older adults would value and access text messages from their physician's practice regarding colorectal cancer screening. METHODS: We conducted four focus groups with 26 adults, aged 50 to 75 years, who had either recently completed or were overdue for colorectal cancer screening. A trained moderator followed a semistructured interview guide covering participant knowledge and attitudes regarding colorectal cancer screening, potential barriers to colorectal cancer screening, attitudes about receiving electronic communications from a doctor's office, and reactions to sample text messages. RESULTS: Participant responses to three primary research questions were examined: (1) facilitators and barriers to colorectal cancer screening, (2) attitudes toward receiving text messages from providers, and (3) characteristics of appealing text messages. Two themes related to facilitators of colorectal cancer screening were perceived benefits/need and family experiences and encouragement. Themes related to barriers included unpleasantness, discomfort, knowledge gaps, fear of complications, and system factors. Four themes emerged regarding receipt of text messages from health care providers: (1) comfort and familiarity with technology, (2) privacy concerns/potential for errors, (3) impact on patient provider relationship, and (4) perceived helpfulness. Many participants expressed initial reluctance to receiving text messages but responded favorably when shown sample messages. Participants preferred messages that contained content that was important to them and were positive and reassuring, personalized, and friendly to novice texters (eg, avoided the use of texting shorthand phrases and complicated replies); they did not want messages that contain bad news or test results. They wanted the ability to choose alternative options such as email or phone calls. CONCLUSIONS: Older adults are receptive to receiving cancer screening text messages from health care providers. Sharing sample messages with patients may increase acceptance of this tool in the clinic setting. Supportive tailored text messaging reminders could enhance uptake of colorectal cancer screening by enhancing patient self-efficacy and providing cues to action to complete colonoscopy or fecal occult blood testing. PMID- 26537554 TI - Term neonates with infection and shock display high cortisol precursors despite low levels of normal cortisol. AB - AIM: Neonatal therapy-resistant septic shock is a common problem in middle and low-income countries. We investigated whether newborn infants with infection and therapy-resistant hypotension showed evidence of abnormal levels of cortisol or cortisol precursors. METHODS: A total of 60 term or near term neonates with evidence of infection were enrolled after informed consent. Of these, 30 had an infection and refractory shock and 30 had an infection without shock. There were no detectable differences between the groups in the length of gestation, birth weight or gender distribution. Serum was obtained during days four and 14 after birth. Cortisol and cortisol precursor concentrations were analysed using liquid chromatography-tandem mass spectrometry. RESULTS: The cortisol concentrations were low considering the expected responses to stress and they did not differ between the groups. The infants with infection and shock had higher serum dehydroepiandrosterone (DHEA) levels than those without shock (319.0 +/- 110.3 MUg/dL, versus 22.3 +/- 18.3 MUg/dL; p < 0.0001) and they also had higher 17 hydroxy-pregnenolone, pregnenolone and progesterone concentrations. There were no detectable differences in the levels of 17-hydroxy-progesterone, 11-deoxy cortisol, cortisol or cortisone. CONCLUSION: Septic newborn infants with therapy resistant hypotension had very high DHEA levels, suggesting that 3-beta hydroxysteroid dehydrogenase activity limited the rate of cortisol synthesis. PMID- 26537555 TI - Use of incretin agents and risk of pancreatic cancer: a population-based cohort study. AB - AIM: To investigate the association between the use of incretin agents and the risk of pancreatic cancer. METHODS: A retrospective population-based cohort study, using data from the Clinical Practice Research Datalink, 2007-2012, was conducted. Patients (n = 182 428) with at least one non-insulin antidiabetic drug (NIAD) prescription and aged >=18 years during data collection, were matched one to-one to control patients without diabetes. Multivariable Cox proportional hazards models and a new user design were used to estimate the hazard ratio (HR) of pancreatic cancer in incretin users (n = 28 370) compared with control subjects without diabetes and other NIAD-treated patients. Time-dependent adjustments were made for age, sex, lifestyle, comorbidities and drug use. RESULTS: The mean duration of follow-up was 4.1 years for incretin users. Current NIAD use was associated with a fourfold increased risk of pancreatic cancer [HR 4.28, 95% confidence interval (CI) 3.49-5.24]. This risk was almost doubled among current incretin users as compared with control subjects. Incretin use was not associated with pancreatic cancer when compared with control subjects with diabetes (HR 1.36, 95% CI 0.94-1.96); however, the 'new user' design did show an association between incretin use and pancreatic cancer when compared with control subjects with diabetes. In both cohorts with prevalent and incident users of antidiabetic drugs, the risk of pancreatic cancer almost doubled in those who had recently initiated incretin therapy (up to seven prescriptions), whereas this elevated risk dropped to baseline levels with prolonged use. CONCLUSIONS: We found that incretin use was not associated with pancreatic cancer after adjustment for the severity of the underlying Type 2 Diabetes Mellitus (T2DM). The elevated risk of pancreatic cancer in those recently initiating incretin agents is likely to be caused by protopathic bias or other types of unknown distortion. The presence of considerable confounding by disease severity and the lack of a duration-of-use relationship do not support a causal explanation for the association between incretin agents and pancreatic cancer. PMID- 26537556 TI - Reducing left liver lobe grafts, more or less? Don't throw out the baby with the bath water.... PMID- 26537559 TI - Lessons from 20 cases of digit malignant melanoma. PMID- 26537557 TI - Mitochondrial dynamics, mitophagy and cardiovascular disease. AB - Cardiac hypertrophy is often initiated as an adaptive response to haemodynamic stress or myocardial injury, and allows the heart to meet an increased demand for oxygen. Although initially beneficial, hypertrophy can ultimately contribute to the progression of cardiac disease, leading to an increase in interstitial fibrosis and a decrease in ventricular function. Metabolic changes have emerged as key mechanisms involved in the development and progression of pathological remodelling. As the myocardium is a highly oxidative tissue, mitochondria play a central role in maintaining optimal performance of the heart. 'Mitochondrial dynamics', the processes of mitochondrial fusion, fission, biogenesis and mitophagy that determine mitochondrial morphology, quality and abundance have recently been implicated in cardiovascular disease. Studies link mitochondrial dynamics to the balance between energy demand and nutrient supply, suggesting that changes in mitochondrial morphology may act as a mechanism for bioenergetic adaptation during cardiac pathological remodelling. Another critical function of mitochondrial dynamics is the removal of damaged and dysfunctional mitochondria through mitophagy, which is dependent on the fission/fusion cycle. In this article, we discuss the latest findings regarding the impact of mitochondrial dynamics and mitophagy on the development and progression of cardiovascular pathologies, including diabetic cardiomyopathy, atherosclerosis, damage from ischaemia-reperfusion, cardiac hypertrophy and decompensated heart failure. We will address the ability of mitochondrial fusion and fission to impact all cell types within the myocardium, including cardiac myocytes, cardiac fibroblasts and vascular smooth muscle cells. Finally, we will discuss how these findings can be applied to improve the treatment and prevention of cardiovascular diseases. PMID- 26537560 TI - Prenatal and postnatal markers of severity in congenital diaphragmatic hernia have similar prognostic ability. AB - OBJECTIVES: The purpose of this study was to compare prenatal versus postnatal markers of congenital diaphragmatic hernia (CDH) severity at a single fetal-care center. METHODS: A retrospective study was performed of patients having a complete prenatal evaluation and surgical repair (n = 55). Observed-to-expected lung-to-head ratio (o/eLHR), observed-to-expected total lung volume (o/eTLV), liver position (LP), a predictive dependent variable from logistic regression of o/eLHR and liver position (o/eLHR + LP), and diaphragmatic defect size per the CDH Study Group A-D classification were plotted into receiver-operating characteristics (ROC) curves. Survival and need for extracorporeal membrane oxygenation (ECMO) were primary outcomes. RESULTS: Survival was 69%, and ECMO utilization was 56%. Distribution was 80% left-sided defects. In the survival ROC curve, the area under the curve (AUC) for o/eLHR was 0.73, o/eTLV 0.74, LP 0.73, o/eLHR + LP 0.78, and defect size 0.84 (p = 0.23). The ROC curve for ECMO support showed o/eLHR had an AUC of 0.82, o/eTLV 0.89, LP 0.79, o/eLHR + LP 0.87, and defect size 0.90 (p = 0.19). The AUCs were similar when only left-sided CDH was analyzed. CONCLUSIONS: These data suggest that prenatal evaluation was equivalent to the postnatal diaphragmatic defect classification for predicting survival and need for ECMO in CDH patients. PMID- 26537561 TI - AINTEGUMENTA and AINTEGUMENTA-LIKE6/PLETHORA3 Induce LEAFY Expression in Response to Auxin to Promote the Onset of Flower Formation in Arabidopsis. AB - Proper timing of the onset to flower formation is critical for reproductive success. Monocarpic plants like Arabidopsis (Arabidopsis thaliana) switch from production of branches in the axils of leaves to that of flowers once in their lifecycle, during the meristem identity transition. The plant-specific transcription factor LEAFY (LFY) is necessary and sufficient for this transition. Previously, we reported that the plant hormone auxin induces LFY expression through AUXIN RESPONSE FACTOR5/MONOPTEROS (ARF5/MP). It is not known whether MP is solely responsible for auxin-directed transcriptional activation of LFY. Here, we show that two transcription factors belonging to the AINTEGUMENTA LIKE/PLETHORA family, AINTEGUMENTA (ANT) and AINTEGUMENTA-LIKE6/PLETHORA3 (AIL6/PLT3), act in parallel with MP to upregulate LFY in response to auxin. ant ail6 mutants display a delay in the meristem identity transition and in LFY induction. ANT and AIL6/PLT3 are expressed prior to LFY and bind to the LFY promoter to control LFY mRNA accumulation. Genetic and promoter/reporter studies suggest that ANT/AIL6 act in parallel with MP to promote LFY induction in response to auxin sensing. Our study highlights the importance of two separate auxin-controlled pathways in the meristem identity transition. PMID- 26537562 TI - The MTL1 Pentatricopeptide Repeat Protein Is Required for Both Translation and Splicing of the Mitochondrial NADH DEHYDROGENASE SUBUNIT7 mRNA in Arabidopsis. AB - Mitochondrial translation involves a complex interplay of ancient bacteria-like features and host-derived functionalities. Although the basic components of the mitochondrial translation apparatus have been recognized, very few protein factors aiding in recruiting ribosomes on mitochondria-encoded messenger RNA (mRNAs) have been identified in higher plants. In this study, we describe the identification of the Arabidopsis (Arabidopsis thaliana) MITOCHONDRIAL TRANSLATION FACTOR1 (MTL1) protein, a new member of the Pentatricopeptide Repeat family, and show that it is essential for the translation of the mitochondrial NADH dehydrogenase subunit7 (nad7) mRNA. We demonstrate that mtl1 mutant plants fail to accumulate the Nad7 protein, even though the nad7 mature mRNA is produced and bears the same 5' and 3' extremities as in wild-type plants. We next observed that polysome association of nad7 mature mRNA is specifically disrupted in mtl1 mutants, indicating that the absence of Nad7 results from a lack of translation of nad7 mRNA. These findings illustrate that mitochondrial translation requires the intervention of gene-specific nucleus-encoded PPR trans-factors and that their action does not necessarily involve the 5' processing of their target mRNA, as observed previously. Interestingly, a partial decrease in nad7 intron 2 splicing was also detected in mtl1 mutants, suggesting that MTL1 is also involved in group II intron splicing. However, this second function appears to be less essential for nad7 expression than its role in translation. MTL1 will be instrumental to understand the multifunctionality of PPR proteins and the mechanisms governing mRNA translation and intron splicing in plant mitochondria. PMID- 26537563 TI - Protein S-Acyltransferase 14: A Specific Role for Palmitoylation in Leaf Senescence in Arabidopsis. AB - The Asp-His-His-Cys-Cys-rich domain-containing Protein S-Acyl Transferases (PATs) are multipass transmembrane proteins that catalyze S-acylation (commonly known as S-palmitoylation), the reversible posttranslational lipid modification of proteins. Palmitoylation enhances the hydrophobicity of proteins, contributes to their membrane association, and plays roles in protein trafficking and signaling. In Arabidopsis (Arabidopsis thaliana), there are at least 24 PATs; previous studies on two PATs established important roles in growth, development, and stress responses. In this study, we identified a, to our knowledge, novel PAT, AtPAT14, in Arabidopsis. Complementation studies in yeast (Saccharomyces cerevisiae) and Arabidopsis demonstrate that AtPAT14 possesses PAT enzyme activity. Disruption of AtPAT14 by T-DNA insertion resulted in an accelerated senescence phenotype. This coincided with increased transcript levels of some senescence-specific and pathogen-resistant marker genes. We show that early senescence of pat14 does not involve the signaling molecules jasmonic acid and abscisic acid, or autophagy, but associates with salicylic acid homeostasis and signaling. This strongly suggests that AtPAT14 plays a pivotal role in regulating senescence via salicylic acid pathways. Senescence is a complex process required for normal plant growth and development and requires the coordination of many genes and signaling pathways. However, precocious senescence results in loss of biomass and seed production. The negative regulation of leaf senescence by AtPAT14 in Arabidopsis highlights, to our knowledge for the first time, a specific role for palmitoylation in leaf senescence. PMID- 26537564 TI - Inhibition of Cell Expansion by Rapid ABP1-Mediated Auxin Effect on Microtubules? A Critical Comment. PMID- 26537565 TI - Biomarker- and similarity coefficient-based approaches to bacterial mixture characterization using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). AB - MALDI-TOF MS profiling has been shown to be a rapid and reliable method to characterize pure cultures of bacteria. Currently, there is keen interest in using this technique to identify bacteria in mixtures. Promising results have been reported with two- or three-isolate model systems using biomarker-based approaches. In this work, we applied MALDI-TOF MS-based methods to a more complex model mixture containing six bacteria. We employed: 1) a biomarker-based approach that has previously been shown to be useful in identification of individual bacteria in pure cultures and simple mixtures and 2) a similarity coefficient based approach that is routinely and nearly exclusively applied to identification of individual bacteria in pure cultures. Both strategies were developed and evaluated using blind-coded mixtures. With regard to the biomarker-based approach, results showed that most peaks in mixture spectra could be assigned to those found in spectra of each component bacterium; however, peaks shared by two isolates as well as peaks that could not be assigned to any individual component isolate were observed. For two-isolate blind-coded samples, bacteria were correctly identified using both similarity coefficient- and biomarker-based strategies, while for blind-coded samples containing more than two isolates, bacteria were more effectively identified using a biomarker-based strategy. PMID- 26537566 TI - Evictions and suicide: a follow-up study of almost 22,000 Swedish households in the wake of the global financial crisis. AB - BACKGROUND: Millions of families across the world are evicted every year. However, very little is known about the impact that eviction has on their lives. This lack of knowledge is also starting to be noticed within the suicidological literature, and prominent scholars are arguing that there is an urgent need to explore the extent to which suicides may be considered a plausible consequence of being faced with eviction. METHOD: The present study's sample consists of all persons served with an application for execution of an eviction order during 2009 2012. This group is compared to a random 10% sample of the general Swedish population, ages 16 years and over. The analysis is based on penalised maximum likelihood logistic regressions. RESULTS: Those who had lost their legal right to their dwellings and for whom the landlord had applied for the eviction to be executed were approximately four times more likely to commit suicide than those who had not been exposed to this experience (OR=4.42), controlling for several demographic, socioeconomic and mental health conditions prior to the date of the judicial decision. CONCLUSIONS: Home evictions have a significant and detrimental impact on individuals' risk of committing suicide, even when several other well known suicidogenic risk factors are controlled for. Our results reinforce the importance of ongoing attempts to remove the issue of evictions from its status as a hidden and neglected social problem. PMID- 26537567 TI - AAV-IL-22 modifies liver chemokine activity and ameliorates portal inflammation in murine autoimmune cholangitis. AB - There remain significant obstacles in developing biologics to treat primary biliary cholangitis (PBC). Although a number of agents have been studied both in murine models and human patients, the results have been relatively disappointing. IL-22 is a member of the IL-10 family and has multiple theoretical reasons for predicting successful usage in PBC. We have taken advantage of an IL-22 expressing adeno-associated virus (AAV-IL-22) to address the potential role of IL 22 in not only protecting mice from autoimmune cholangitis, but also in treating animals with established portal inflammation. Using our established mouse model of 2-OA-OVA immunization, including alpha-galactosylceramide (alpha-GalCer) stimulation, we treated mice both before and after the onset of clinical disease with AAV-IL-22. Firstly, AAV-IL-22 treatment given prior to 2-OA-OVA and alpha GalCer exposure, i.e. before the onset of disease, significantly reduces the portal inflammatory response, production of Th1 cytokines and appearance of liver fibrosis. It also reduced the liver lymphotropic chemokines CCL5, CCL19, CXCL9, and CXCL10. Secondly, and more importantly, therapeutic use of AAV-IL-22, administered after the onset of disease, achieved a greater hurdle and significantly improved portal pathology. Further the improvements in inflammation were negatively correlated with levels of CCL5 and CXCL10 and positively correlated with levels of IL-22. In conclusion, we submit that the clinical use of IL-22 has a potential role in modulating the inflammatory portal process in patients with PBC. PMID- 26537568 TI - Multipole plasmons and their disappearance in few-nanometre silver nanoparticles. AB - Electron energy-loss spectroscopy can be used for detailed spatial and spectral characterization of optical excitations in metal nanoparticles. In previous electron energy-loss experiments on silver nanoparticles with radii smaller than 20 nm, only the dipolar surface plasmon resonance was assumed to play a role. Here, applying electron energy-loss spectroscopy to individual silver nanoparticles encapsulated in silicon nitride, we observe besides the usual dipole resonance an additional surface plasmon resonance corresponding to higher angular momenta for nanoparticle radii as small as 4 nm. We study the radius and electron beam impact position dependence of both resonances separately. For particles smaller than 4 nm in radius the higher-order surface plasmon mode disappears, in agreement with generalized non-local optical response theory, while the dipole resonance blueshift exceeds our theoretical predictions. Unlike in optical spectra, multipole surface plasmons are important in electron energy loss spectra even of ultrasmall metallic nanoparticles. PMID- 26537569 TI - Modification of sperm morphology during long-term sperm storage in the reproductive tract of the Chinese soft-shelled turtle, Pelodiscus sinensis. AB - Sperm storage in vivo extends the time window for fertilisation in several animal species, from a few days to several years. The underlying storage mechanisms, however, are largely unknown. In this study, spermatozoa from the epididymis and oviduct of Chinese soft-shelled turtles were investigated to identify potentially relevant morphological features and transformations at different stages of sperm storage. Large cytoplasmic droplets (CDs) containing lipid droplets (LDs) were attached to the midpiece of most spermatozoa in the epididymis, without migrating down the sperm tail. However, they were absent from the oviductal spermatozoa, suggesting that CDs with LDs may be a source of endogenous energy for epididymal spermatozoa. The onion-like mitochondria recovered their double-membrane morphology, with typical cristae, within the oviduct at a later stage of storage, thus implying that mitochondrial metabolism undergoes alterations during storage. Furthermore, a well developed fibrous sheath on the long principal piece was the integrating ultrastructure for glycolytic enzymes and substrates. These novel morphological characteristics may allow turtle spermatozoa to use diverse energy metabolism pathways at different stages of storage. PMID- 26537570 TI - Tecla: a telephone- and text-message based telemedical concept for patients with severe mental health disorders--study protocol for a controlled, randomized, study. AB - BACKGROUND: Severe mental disorders like psychotic disorders including schizophrenia and schizoaffective disorders have a 12-month-prevalence of 2.6, bipolar disorders of 1.5% in Germany. The relapse risk is high; so many patients need intensive monitoring and lifelong treatment. A high medication adherence is essential for a successful treatment. But in practice, medication adherence is low and decreases over time. Telemedical care concepts might improve treatment and bridge gaps between in- and outpatient treatment. A telemedical care concept based on regular telephone calls and short text messages was developed. The primary objective is to assess whether regular telephone calls and text messages can improve the medication adherence of patients. Secondary objectives are the reduction of rehospitalization rates, the improvement of quality of life and of the severity of symptoms. METHODS/DESIGN: The Tecla study (Post stationary telemedical care of patients with severe psychiatric disorders) is a two-armed prospective randomized controlled trial. The participants in the intervention group receive in addition to usual care regular telephone calls every 2 weeks and weekly text messages on patient-individual topics during a 6 months period. Patients in the control group receive only regular care. Inclusion criteria are a physician-diagnosed bipolar disorder, schizoaffective disorder or schizophrenia and a signed informed consent. Exclusion criteria are planned inpatient treatments within the next 6 months and being non-reachable by phone. After 3 and 6 months both groups receive follow up assessments. DISCUSSION: The primary objective of this study is the medication adherence that is measured with the Medication Adherence Report Scale, German version (MARS-D). The MARS-D is a self report with five items. Adherent behaviour is mostly overestimated using self reports. The strength of the MARS-D is to detect non-adherent behaviour. The original Medication Adherence Report Scale in English language (MARS-5) was developed to encourage the patient to answer truthfully to the questions that are asked in a non-threatening and non-judgmental way to minimize social desirability bias in admitting non-adherent behaviour. TRIAL REGISTRATION: This study is registered at 2015?05?21 at the German Clinical Trials Register DRKS00008548. PMID- 26537572 TI - Synthesis and characterization of a family of M(2+) complexes supported by a trianionic ONO(3-) pincer-type ligand: towards the stabilization of high-spin square-planar complexes. AB - High-spin square-planar molecular compounds are rare. In an effort to access this unique combination of geometry and spin state, we report the synthesis of a series of M(II) compounds stabilized by a trianionic pincer-type ligand, highlighting the formation of a high-spin square-planar Co(II) complex. Low temperature, variable-frequency EPR measurements reveal that the ground electronic state of the Co(II) analogue is a highly anisotropic Kramers doublet (effective g values 7.35, 2.51, 1.48). This doublet can be identified with the lowest doublet of a quartet, S = 3/2 spin state that exhibits a very large ZFS, D >= 50 cm(-1). The observation of an effective g value considerably greater than the largest spin-only value 6, demonstrates that the orbital angular moment is essentially unquenched along one spatial direction. Density Functional Theory (DFT) and time-dependent DFT calculations reveal the electronic configurations of the ground and excited orbital states. A qualitative crystal field description of the geff tensor shows that it originates from the spin-orbit coupling acting on states obtained through the transfer of a beta electron from the doubly occupied xy to the singly-occupied {xz/yz} orbitals. PMID- 26537571 TI - Substrate recognition and catalysis by LytB, a pneumococcal peptidoglycan hydrolase involved in virulence. AB - Streptococcus pneumoniae is a major cause of life-threatening diseases worldwide. Here we provide an in-depth functional characterization of LytB, the peptidoglycan hydrolase responsible for physical separation of daughter cells. Identified herein as an N-acetylglucosaminidase, LytB is involved also in colonization and invasion of the nasopharynx, biofilm formation and evasion of host immunity as previously demonstrated. We have shown that LytB cleaves the GlcNAc-beta-(1,4)-MurNAc glycosidic bond of peptidoglycan building units. The hydrolysis occurs at sites with fully acetylated GlcNAc moieties, with preference for uncross-linked muropeptides. The necessity of GlcN acetylation and the presence of a single acidic moiety (Glu585) essential for catalysis strongly suggest a substrate-assisted mechanism with anchimeric assistance of the acetamido group of GlcNAc moieties. Additionally, modelling of the catalytic region bound to a hexasaccharide tripentapeptide provided insights into substrate binding subsites and peptidoglycan recognition. Besides, cell-wall digestion products and solubilisation rates might indicate a tight control of LytB activity to prevent unrestrained breakdown of the cell wall. Choline-independent localization at the poles of the cell, mediated by the choline-binding domain, peptidoglycan modification, and choline-mediated (lipo)teichoic-acid attachment contribute to the high selectivity of LytB. Moreover, so far unknown chitin hydrolase and glycosyltransferase activities were detected using GlcNAc oligomers as substrate. PMID- 26537573 TI - Short Communication: Analysis of Minor Populations of Human Immunodeficiency Virus by Primer Identification and Insertion-Deletion and Carry Forward Correction Pipelines. AB - Accurate analysis of minor populations of drug-resistant HIV requires analysis of a sufficient number of viral templates. We assessed the effect of experimental conditions on the analysis of HIV pol 454 pyrosequences generated from plasma using (1) the "Insertion-deletion (indel) and Carry Forward Correction" (ICC) pipeline, which clusters sequence reads using a nonsubstitution approach and can correct for indels and carry forward errors, and (2) the "Primer Identification (ID)" method, which facilitates construction of a consensus sequence to correct for sequencing errors and allelic skewing. The Primer ID and ICC methods produced similar estimates of viral diversity, but differed in the number of sequence variants generated. Sequence preparation for ICC was comparably simple, but was limited by an inability to assess the number of templates analyzed and allelic skewing. The more costly Primer ID method corrected for allelic skewing and provided the number of viral templates analyzed, which revealed that amplifiable HIV templates varied across specimens and did not correlate with clinical viral load. This latter observation highlights the value of the Primer ID method, which by determining the number of templates amplified, enables more accurate assessment of minority species in the virus population, which may be relevant to prescribing effective antiretroviral therapy. PMID- 26537574 TI - Stabilization of magnetic helix in exchange-coupled thin films. AB - Based on micromagnetic simulations, we report on a novel magnetic helix in a soft magnetic film that is sandwiched between and exchange-coupled to two hard magnetic layers with different anisotropies. We show that such a confined helix stays stable without the presence of an external magnetic field. The magnetic stability is determined by the energy minimization and is a result of an internal magnetic field created by the exchange interaction. We show that this internal field stores a magnetic energy density of a few kJ/m(3). We also find that it dramatically modifies ferromagnetic resonances, such that the helix can be used as a ferromagnetic resonance filter and a fast acting attenuator. PMID- 26537575 TI - A measure of the impact of CV incompleteness on prediction error estimation with application to PCA and normalization. AB - BACKGROUND: In applications of supervised statistical learning in the biomedical field it is necessary to assess the prediction error of the respective prediction rules. Often, data preparation steps are performed on the dataset-in its entirety before training/test set based prediction error estimation by cross-validation (CV)-an approach referred to as "incomplete CV". Whether incomplete CV can result in an optimistically biased error estimate depends on the data preparation step under consideration. Several empirical studies have investigated the extent of bias induced by performing preliminary supervised variable selection before CV. To our knowledge, however, the potential bias induced by other data preparation steps has not yet been examined in the literature. In this paper we investigate this bias for two common data preparation steps: normalization and principal component analysis for dimension reduction of the covariate space (PCA). Furthermore we obtain preliminary results for the following steps: optimization of tuning parameters, variable filtering by variance and imputation of missing values. METHODS: We devise the easily interpretable and general measure CVIIM ("CV Incompleteness Impact Measure") to quantify the extent of bias induced by incomplete CV with respect to a data preparation step of interest. This measure can be used to determine whether a specific data preparation step should, as a general rule, be performed in each CV iteration or whether an incomplete CV procedure would be acceptable in practice. We apply CVIIM to large collections of microarray datasets to answer this question for normalization and PCA. RESULTS: Performing normalization on the entire dataset before CV did not result in a noteworthy optimistic bias in any of the investigated cases. In contrast, when performing PCA before CV, medium to strong underestimates of the prediction error were observed in multiple settings. CONCLUSIONS: While the investigated forms of normalization can be safely performed before CV, PCA has to be performed anew in each CV split to protect against optimistic bias. PMID- 26537576 TI - Cerebral Lipid Accumulation Detected by MRS in a Child with Carnitine Palmitoyltransferase 2 Deficiency: A Case Report and Review of the Literature on Genetic Etiologies of Lipid Peaks on MRS. AB - The majority of lipids in the brain are located in the bilayer membranes. These lipids are not visible by magnetic resonance spectroscopy since they have restricted mobility. Only mobile lipids, such as cholesterol esters or triglycerides in neutral lipid droplets, have enough rotational freedom to generate a signal on spectroscopy. These signals are detected as peaks at 1.3 ppm, originating from the methylene groups in the fatty acid chain, and 0.9 ppm, originating from the distal methyl group. We review the literature on the different genetic conditions that have been found to show lipid peaks on brain spectroscopy and report the first patient with carnitine palmitoyltransferase 2 deficiency shown to have such lipid peaks, thus indicating brain fat accumulation. PMID- 26537577 TI - LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure. AB - Pathogenic variants in mitochondrial aminoacyl-tRNA synthetases result in a broad range of mitochondrial respiratory chain disorders despite their shared role in mitochondrial protein synthesis. LARS2 encodes the mitochondrial leucyl-tRNA synthetase, which attaches leucine to its cognate tRNA. Sequence variants in LARS2 have previously been associated with Perrault syndrome, characterized by premature ovarian failure and hearing loss (OMIM #615300). In this study, we report variants in LARS2 that are associated with a severe multisystem metabolic disorder. The proband was born prematurely with severe lactic acidosis, hydrops, and sideroblastic anemia. She had multisystem complications with hyaline membrane disease, impaired cardiac function, a coagulopathy, pulmonary hypertension, and progressive renal disease and succumbed at 5 days of age. Whole exome sequencing of patient DNA revealed compound heterozygous variants in LARS2 (c.1289C>T; p.Ala430Val and c.1565C>A; p.Thr522Asn). The c.1565C>A (p.Thr522Asn) LARS2 variant has previously been associated with Perrault syndrome and both identified variants are predicted to be damaging (SIFT, PolyPhen). Muscle and liver samples from the proband did not display marked mitochondrial respiratory chain enzyme deficiency. Immunoblotting of patient muscle and liver showed LARS2 levels were reduced in liver and complex I protein levels were reduced in patient muscle and liver. Aminoacylation assays revealed p.Ala430Val LARS2 had an 18-fold loss of catalytic efficiency and p.Thr522Asn a 9-fold loss compared to wild-type LARS2. We suggest that the identified LARS2 variants are responsible for the severe multisystem clinical phenotype seen in this baby and that mutations in LARS2 can result in variable phenotypes. PMID- 26537578 TI - Lower Urinary Tract Symptoms and Incontinence in Children with Pompe Disease. AB - BACKGROUND: Pompe disease (PD) is a disorder of lysosomal glycogen storage. The introduction of enzyme replacement therapy (ERT) has shifted the focus of care from survival to quality of life. The presence of lower urinary tract symptoms (LUTS) and incontinence has not been previously described in children with PD. METHODS: Children with PD followed in the Duke Lysosomal Storage Disease Clinic completed a validated bladder control symptom score (BCSS) and additional questions regarding urinary tract infections (UTIs), giggle, and stress incontinence. Descriptive statistics were used to discriminate urinary symptoms between gender, age, and different types of PD. RESULTS: Sixteen of 23 children (aged 4-14 years) seen in our clinic participated. Seven were girls; ten had classic infantile PD, two atypical infantile PD, and four childhood presentation late-onset PD (LOPD). When stratified by PD subtype, median BCSS was worst for the classic PD subtype followed by atypical PD and LOPD. Daytime urinary incontinence accompanied by constipation was noted in six. Eight reported urinary incontinence with laughing: giggle incontinence in six and stress incontinence in two. Four girls reported a history of UTI. Longitudinal follow-up in 11 patients showed stable BCSS in six, improvement in three, and worsening in two. Worsening corresponded with changes in bowel function and improvement with increase in ERT dose or treatment of constipation. CONCLUSIONS: LUTS and incontinence are common in children with PD with greater symptoms noted with infantile-type PD. Improved bowel function and increase in ERT dose may lead to improvements in BCSS. PMID- 26537579 TI - Lightning up the worm: How to probe fungal virulence in an alternative mini-host by bioluminescence. PMID- 26537580 TI - The association between methylenetetrahydrofolate reductase gene C677T polymorphisms and breast cancer risk in Chinese population. AB - With great interest, we read the recent article entitled "Methylenetetrahydrofolate reductase polymorphisms and breast cancer risk in Chinese population: a meta-analysis of 22 case-control studies" published online in Tumor Biology, 2014, 35: 1695-1701. This article suggests that methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism was significantly associated with breast cancer risk in Chinese population. The result is encouraging. Nevertheless, three key issues in this meta-analysis are worth noticing. PMID- 26537581 TI - MicroRNAs as biomarkers and prospective therapeutic targets in colon and pancreatic cancers. AB - Colon and pancreatic cancers have high mortality rates due to early metastasis prior to the onset of symptoms. Screening tests for colorectal cancer are invasive and expensive. No effective screening is available for pancreatic cancer. Identification of biomarkers for early detection in both of these cancers is being extensively researched. MicroRNAs (miRNA) are small non-coding molecule biomarkers that regulate cancers. Measurement of miRNAs in pancreatic fluid or blood could be a preferred non-invasive screening method. The regulation of colon and pancreatic cancers by miRNA is complex. miRNA play a central role in inflammation, invasiveness, and tumor progression in these two cancers, as well as regulation of the NF-kappaB pathway. miRNA's evolving role in screening is also reviewed. PMID- 26537582 TI - Down-regulation of ribosomal protein S15A inhibits proliferation of human glioblastoma cells in vivo and in vitro via AKT pathway. AB - Ribosomal protein s15a (RPS15A), a highly conserved cytoplasmic protein, promotes mRNA/ribosome interaction in translation. Recent evidence showed that RPS15A is essential for tumor growth. RPS15A expression level was measured in glioblastoma tissue samples and normal brain (NB) tissue samples. RPS15A RNAi stable cell line U87 and U251 was generated by the pLVTHM-GFP lentiviral RNAi expression system. The knockdown efficiency was confirmed by quantitative real-time PCR and western blot. Molecular mechanisms and the effect of RPS15A on cell growth and migration were investigated by using western blot, MTT assay, wound healing assay, transwell migration assay, and tumorigenesis in nude mice. Here, we report that RPS15A is overexpressed in human glioblastoma tumor tissues. RPS15A knockdown inhibits proliferation and migration of glioblastoma cells in vitro. Knocking down RPS15A leads to the level of p-Akt decrease and cell cycle arrested in G0/G1 phase in U87 and U251 cells. Furthermore, the growth of glioblastoma cell transplanted tumors in nude mice is inhibited by transduction with Lv-shRPS15A. Our findings indicate that RPS15A promotes cell proliferation and migration in glioblastoma for the first time. RPS15A might play a distinct role in glioblastoma and serve as a potential target for therapy. PMID- 26537583 TI - MEK-dependent IL-8 induction regulates the invasiveness of triple-negative breast cancer cells. AB - Interleukin-8 (IL-8) serves as a prognostic marker for breast cancer, and its expression level correlates with metastatic breast cancer and poor prognosis. Here, we investigated the levels of IL-8 expression in a variety of breast cancer cells and the regulatory mechanism of IL-8 in triple-negative breast cancer (TNBC) cells. Our results showed that IL-8 expression correlated positively with overall survival in basal-type breast cancer patients. The levels of IL-8 mRNA expression and protein secretion were significantly increased in TNBC cells compared with non-TNBC cells. In addition, the invasiveness of the TNBC cells was dramatically increased by IL-8 treatment and then augmented invasion-related proteins such as matrix metalloproteinase (MMP)-2 or MMP-9. We observed that elevated IL-8 mRNA expression and protein secretion were suppressed by a specific MEK1/2 inhibitor, UO126. In contrast, the overexpression of constitutively active MEK significantly increased the level of IL-8 mRNA expression in BT474 non-TNBC cells. Finally, we investigated the effect of UO126 on the tumorigenecity of TNBC cells. Our results showed that anchorage-independent growth, cell invasion, and cell migration were also decreased by UO126 in TNBC cells. As such, we demonstrated that IL-8 expression is regulated through MEK/ERK-dependent pathways in TNBC cells. A diversity of MEK blockers, including UO126, may be promising for treating TNBC patients. PMID- 26537584 TI - MicroRNA-100 suppresses the migration and invasion of breast cancer cells by targeting FZD-8 and inhibiting Wnt/beta-catenin signaling pathway. AB - Wnt/beta-catenin signaling pathway plays a major role in the cancer metastasis. Several microRNAs (miRNAs) are contributed to the inhibition of breast cancer metastasis. Here, we attempted to find novel targets and mechanisms of microRNA 100 (miR-100) in regulating the migration and invasion of breast cancer cells. In this study, we found that miR-100 expression was downregulated in human breast cancer tissues and cell lines. The overexpression of miR-100 inhibited the migration and invasion of MDA-MB-231 breast cancer cells. Inversely, the downregulation of miR-100 increased the migration and invasion of MCF-7 breast cancer cells. Furthermore, FZD-8, a receptor of Wnt/beta-catenin signaling pathway, was demonstrated a direct target of miR-100. The overexpression of miR 100 decreased the expression levels not only FZD-8 but also the key components of Wnt/beta-catenin pathway, including beta-catenin, metalloproteniase-7 (MMP-7), T cell factor-4 (TCF-4), and lymphoid enhancing factor-1 (LEF-1), and increased the protein expression levels of GSK-3beta and p-GSK-3beta in MDA-MB-231 cells, and the transfection of miR-100 inhibitor in MCF-7 cells showed the opposite effects. In addition, the expression of miR-100 was negatively correlated with the FZD-8 expression in human breast cancer tissues. Overall, these findings suggest that miR-100 suppresses the migration and invasion of breast cancer cells by targeting FZD-8 and inhibiting Wnt/beta-catenin signaling pathway and manipulation of miR 100 may provide a promoting therapeutic strategy for cancer breast treatment. PMID- 26537585 TI - Application of multispectral imaging in quantitative immunohistochemistry study of breast cancer: a comparative study. AB - Multispectral imaging (MSI) based on imaging and spectroscopy, as relatively novel to the field of histopathology, has been used in biomedical multidisciplinary researches. We analyzed and compared the utility of multispectral (MS) versus conventional red-green-blue (RGB) images for immunohistochemistry (IHC) staining to explore the advantages of MSI in clinical pathological diagnosis. The MS images acquired of IHC-stained membranous marker human epidermal growth factor receptor 2 (HER2), cytoplasmic marker cytokeratin5/6 (CK5/6), and nuclear marker estrogen receptor (ER) have higher resolution, stronger contrast, and more accurate segmentation than the RGB images. The total signal optical density (OD) values for each biomarker were higher in MS images than in RGB images (all P < 0.05). Moreover, receiver operator characteristic (ROC) analysis revealed that a greater area under the curve (AUC), higher sensitivity, and specificity in evaluation of HER2 gene were achieved by MS images (AUC = 0.91, 89.1 %, 83.2 %) than RGB images (AUC = 0.87, 84.5, and 81.8 %). There was no significant difference between quantitative results of RGB images and clinico-pathological characteristics (P > 0.05). However, by quantifying MS images, the total signal OD values of HER2 positive expression were correlated with lymph node status and histological grades (P = 0.02 and 0.04). Additionally, the consistency test results indicated the inter observer agreement was more robust in MS images for HER2 (inter-class correlation coefficient (ICC) = 0.95, r s = 0.94), CK5/6 (ICC = 0.90, r s = 0.88), and ER (ICC = 0.94, r s = 0.94) (all P < 0.001) than that in RGB images for HER2 (ICC = 0.91, r s = 0.89), CK5/6 (ICC = 0.85, r s = 0.84), and ER (ICC = 0.90, r s = 0.89) (all P < 0.001). Our results suggest that the application of MS images in quantitative IHC analysis could obtain higher accuracy, reliability, and more information of protein expression in relation to clinico-pathological characteristics versus conventional RGB images. It may become an optimal IHC digital imaging system used in quantitative pathology. PMID- 26537586 TI - Chemotherapy promotes tumour cell hybridization in vivo. AB - Spontaneous cell-cell fusion has been recognized to be an important mechanism for tissue and organ development and repair. In cancer, cell fusion is critically involved in tumourigenesis, metastasis and drug resistance, as illustrated by in vitro experiments. However, there has been no direct detection of tumour cell fusion or hybridization in an in vivo tumour environment, and the features of hybridized cells under selective pressures, such as chemotherapy, are unknown. Here, we expressed two fluorescent marker proteins in the human breast cancer cell line SKBR3 to detect tumour cell hybridization in vivo and performed a xenograft chemotherapy experiment in mice to evaluate the chemotherapeutic response of the hybrids. The mice treated by epirubicin showed that chemotherapy promoted tumour cell hybridization in vivo, which elicited the production of more hybrids in the outer section of the tumour. These results provide the first in vivo evidence of tumour cell fusion and indicate that chemotherapy may contribute to a poor prognosis by enriching for fused cells, which are more malignant. It is therefore necessary to reassess chemotherapy strategies. PMID- 26537587 TI - What do we know about endometrial receptivity in women with endometriosis? A molecular perspective. PMID- 26537589 TI - Redesigning printed educational materials for primary care physicians: design improvements increase usability. AB - BACKGROUND: Printed educational materials (PEMs) are a frequently used tool to disseminate clinical information and attempt to change behavior within primary care. However, their effect on clinician behavior is limited. In this study, we explored how PEMs can be redesigned to better meet the needs of primary care physicians (PCPs) and whether usability and selection can be increased when design principles and user preferences are used. METHODS: We redesigned a publicly available PEM using physician preferences, design principles, and graphic designer support. We invited PCPs to select their preferred document between the redesigned and original versions in a discrete choice experiment, followed by an assessment of usability with the System Usability Scale and a think aloud process. We conducted this study in both a controlled and opportunistic setting to determine whether usability testing results vary by study location. Think aloud data was thematically analyzed, and results were interpreted using the Technology Acceptance Model. RESULTS: One hundred and eighty four PCPs participated in the discrete choice experiment at the 2014 Family Medicine Forum, a large Canadian conference for family physicians. Of these, 87.7 % preferred the redesigned version. Follow-up interviews were held with a randomly selected group of seven participants. We repeated this in a controlled setting in Toronto, Canada, with a set of 14 participants. Using the System Usability Scale, we found that usability scores were significantly increased with the redesign (p < 0.001). We also found that when PCPs were given the choice between the two versions, they selected the redesigned version as their preferred PEM more often than the original (p < 0.001). Results did not appear to differ between the opportunistic and controlled setting. We used the results of the think aloud process to add to a list of end user preferences developed in a previous study. CONCLUSIONS: We found that redesigning a PEM with user preferences and design principles can improve its usability and result in the PEM being selected more often than the original. We feel this finding supports the involvement of the user, application of design principles, and the assistance of a graphic designer in the development of PEMs. PMID- 26537590 TI - Compression or expansion of dementia in Germany? An observational study of short term trends in incidence and death rates of dementia between 2006/07 and 2009/10 based on German health insurance data. AB - INTRODUCTION: There have been recent reports about a decline in dementia incidence, but only little is known about trends in the mortality of patients with dementia. Only the simultaneous analysis of both trends can inform whether the reported decline in dementia has led to a compression of dementia into higher ages. METHODS: We used health claims data from the largest public health insurer in Germany over the two time periods 2004/07 and 2007/10. Dementia was defined according to the International Classification of Disease 10th revision (ICD-10) numbers G30, G31.0, G31.82, G23.1, F00, F01, F02, F03 and F05.1 or by a prescription of cholinesterase inhibitors or memantine or both. In the two time periods, we observed 502,065 person-years of exposure and 10,881 incident dementia cases and 10,013 person-years of exposure among the newly demented and 3049 deaths. We estimated the relative risks of the two time periods applying proportional hazard models and calculated years with or without dementia using the illness-death model. RESULTS: Dementia incidence was significantly higher in 2006/07 than in 2009/10, whereas mortality with dementia tended to be lower in the first period, albeit statistically significant among women only. Mortality without dementia tended to be higher in the first period for men and remained stable for women. Combining these trends, we found that at age 65 remaining life years with dementia were compressed by a yearly 0.4 months for men and 1.4 months for women. At the same time, remaining life years without dementia increased by a yearly 1.4 months for men and 1.1 months for women. CONCLUSIONS: This study provides evidence that the increase in dementia-free life years went together with an absolute compression of life years with dementia. This positive trend was particularly strong among women. Results were controlled for trends in multi morbidity and care need, suggesting that the postponement in dementia incidence is not simply caused by a delay in diagnosis. PMID- 26537591 TI - Suitability for human consumption and agriculture purposes of Sminja aquifer groundwater in Zaghouan (north-east of Tunisia) using GIS and geochemistry techniques. AB - In Tunisia, the water resources are limited, partially renewable and unequally distributed between the wet north and the dry south of the country. The Sminja aquifer in Zaghouan city is located in north-east of Tunisia, between latitudes 36 degrees 38' and 36 degrees 47' and longitudes 9 degrees 95' and 10 degrees 12'. This aquifer is used to satisfy the population needs for their domestic purposes and agricultural activities. Water analyses results are expressed by many methods, among which are geochemical methods combined with the geographic information system (GIS) (all schematic presentations of the diagram software (Piper, Riverside, Wilcox...), which can be used to assess the suitability of the Sminja aquifer groundwater for human consumption and irrigation purposes. A total of 23 wells were sampled in January 2013, and the concentrations of major cations (Na(+), Ca(2+), Mg(2+) and K(+)), major anions (Cl(-), SO4 (2-) and HCO3 (-)), electrical conductivity and total dissolved solids were analysed. In the Sminja groundwater, the order of the cations dominance was Na > Ca > Mg > K and that of the anions was Cl > HCO3 > SO4. All of the analysed samples of the study area exceed chemical values recommended by the World Health Organisation guidelines and Tunisian Standards (NT.09.14) for potability but with different percentages. The aquifer spatial distribution of saturation indices reveals that all groundwater samples are under-saturated with gypsum, halite and anhydrite and are over-saturated with respect to calcite and dolomite based on water quality evaluation parameters for irrigation purposes; here, 87 % of samples in Sminja aquifer groundwater are suitable, whereas 13 % are unsuitable for irrigation uses. PMID- 26537592 TI - Size-dependent characterisation of historical gold mine wastes to examine human pathways of exposure to arsenic and other potentially toxic elements. AB - Abandoned historical gold mining wastes often exist as geographically extensive, unremediated, and poorly contained deposits that contain elevated levels of As and other potentially toxic elements (PTEs). One of the key variables governing human exposure to PTEs in mine waste is particle size. By applying a size resolved approach to mine waste characterisation, this study reports on the proportions of mine waste relevant to human exposure and mobility, as well as their corresponding PTE concentrations, in four distinct historical mine wastes from the gold province in Central Victoria, Australia. To the best of our knowledge, such a detailed investigation and comparison of historical mining wastes has not been conducted in this mining-affected region. Mass distribution analysis revealed notable proportions of waste material in the readily ingestible size fraction (<=250 um; 36.1-75.6 %) and the dust size fraction (<=100 um; 5.9 45.6 %), suggesting a high potential for human exposure and dust mobilisation. Common to all mine waste types were statistically significant inverse trends between particle size and levels of As and Zn. Enrichment of As in the finest investigated size fraction (<=53 um) is of particular concern as these particles are highly susceptible to long-distance atmospheric transport. Human populations that reside in the prevailing wind direction from a mine waste deposit may be at risk of As exposure via inhalation and/or ingestion pathways. Enrichment of PTEs in the finer size fractions indicates that human health risk assessments based on bulk contaminant concentrations may underestimate potential exposure intensities. PMID- 26537594 TI - Erratum to: Patient demographics and surgical characteristics in ACL revision: a comparison of French, Norwegian, and North American cohorts. PMID- 26537593 TI - Physiological role of aquaporin 5 in salivary glands. AB - Regarding the 13 known mammalian aquaporins (AQPs), their functions in their expressing tissues, effects of their mutation/polymorphisms in humans, and effects of knockout of their genes are summarized in this review article. The roles of AQP5, an exocrine gland-type water channel, in the salivary gland under normal and pathophysiological conditions are reviewed in detail. First, the involvement of AQP5 in water secretion from acinar cells was demonstrated by measuring volume changes of acini/acinar cells, as well as activation energy (E a) in transepithelial water movement by NMR spectrometry, and a functional linkage between AQP5 and TRPV4 was suggested. Next, involvement of the parasympathetic nervous system on the AQP5 levels in the acinar cells of the submandibular and that of a beta-adrenergic agonist on those in the parotid gland are described. That is, chorda tympani denervation induces autophagy of the submandibular gland, causing AQP5 degradation/metabolism, whereas isoproterenol, a beta-adrenergic agonist, causes first an increase then decrease in AQP5 levels in the parotid gland, which action is coupled with the secretory-restoration cycle of amylase-containing secretory granules. The PG also responded to endotoxin, a lipopolysaccharide that activates NF-kappaB and MAPK pathways. Elevated NF-kappaB and AP-1 (c-Fos/c-Jun) form a complex that can bind to the NF kappaB-responsive element on the AQP5 promoter and thus potentially downregulate AQP5 transcription. Salivary gland pathologies and conditions involving AQP5 and possible treatments are described as well. PMID- 26537595 TI - The effect of patient, provider and surgical factors on survivorship of high tibial osteotomy to total knee arthroplasty: a population-based study. AB - PURPOSE: The aim of this study was to identify the survivorship of high tibial osteotomy (HTO) to total knee arthroplasty (TKA) on a population level, and identify the patient, provider and surgical factors that influenced eventual TKA. METHODS: Administrative records from physician billings and hospital admissions were used to identify all adults in Ontario, Canada, who underwent an HTO from 1994 to 2010. The primary outcome was time to TKA, which was estimated using Kaplan-Meier (KM) survival analysis. A Cox proportional hazards model examined the risk associated with patient factors (age, sex, income and co-morbidity score), provider factors (hospital status, surgeon volume and surgeon year in practice) and surgical factors (concurrent ligament reconstruction or bone grafting; and previous chondral or meniscal surgery). RESULTS: A total of 2671 patients who underwent HTO met inclusion. The median age was 46 years (interquartile range 39-53 years), and 62 % were male. The KM survivorship of HTO to TKA at 10 years was 0.67 +/- 0.01. Older age [HR 1.05 (95 % CI 1.04, 1.06), p < 0.001; 5 % increased risk for each year over age 46], female sex [HR 1.35 (95 % CI 1.17, 1.55), p < 0.001], higher comorbidity score [HR 1.58 (95 % CI 1.12, 2.22), p = 0.009] and a prior history of arthroscopy/meniscectomy [HR 1.24 (95 % CI 1.08, 1.43), p = 0.002] increased the risk of eventual TKA. However, HTO with concurrent ligament reconstruction was associated with lower [HR 0.62 (95 % CI 0.43, 0.88), p = 0.008] risk of eventual TKA. CONCLUSION: In this population, two thirds of patients were able to avoid a TKA for 10 years after HTO. Specific factors such as older age, female sex, higher comorbidity and prior meniscectomy lowered survival rates. An understanding of patient risk factors for conversion to TKA may help guide surgeons in their selection of patients who will benefit most from HTO. LEVEL OF EVIDENCE: Retrospective cohort study, III. PMID- 26537596 TI - Preserving the PCL during the tibial cut in total knee arthroplasty. AB - PURPOSE: Previous studies have shown that the PCL insertion may be damaged during the tibial cut performed in total knee arthroplasty. We investigated the maximum thickness of a tibial cut that preserves the PCL insertion and to what extent the posterior slope of the tibial cut and that of the patient's tibial plateaus affect the outcome. METHODS: MR images of 83 knees were analysed. The maximum thickness of a tibial cut that preserves the PCL using a posterior slope of 0 degrees , 3 degrees , 5 degrees and parallel to the patient's slope of the tibial plateau, was evaluated. Correlations between the results and the degrees of the posterior slope of the patient's tibial plateaus were also investigated. RESULTS: The maximum thickness of a tibial cut that preserves the entire PCL insertion was, on average, 5.5, 4.7, 4.2 and 3.1 mm when a posterior slope of 0 degrees , 3 degrees , 5 degrees and parallel to the patients' tibial plateaus was used, respectively. When the 25th percentile was considered, the maximum thickness of a tibial cut that preserved the PCL was 4 and 3 mm with a tibial cut of 0 degrees and 5 degrees of posterior slope, respectively. The maximum thickness of a tibial cut that preserved the PCL was significantly greater in patients with a sagittal slope of the tibial plateaus more than 8 degrees than in those with a sagittal slope less than 8 degrees . CONCLUSION: In cruciate retaining implants, the PCL insertion may be spared in the majority of patients by performing a tibial cut of 4 mm, or even less when a posterior slope of 3 degrees -5 degrees is used. The clinical relevance of our study is that the execution of a conservative tibial cut, followed by a second tibial resection to achieve the thickness required for the tibial component to be implanted, may be an alternative technique to spare the PCL in CR TKA. LEVEL OF EVIDENCE: II. PMID- 26537597 TI - Upright weight-bearing CT of the knee during flexion: changes of the patellofemoral and tibiofemoral articulations between 0 degrees and 120 degrees . AB - PURPOSE: To prospectively compare patellofemoral and tibiofemoral articulations in the upright weight-bearing position with different degrees of flexion using CT in order to gain a more thorough understanding of the development of diseases of the knee joint in a physiological position. MATERIALS AND METHODS: CT scans of the knee in 0 degrees , 30 degrees , 60 degrees flexion in the upright weight bearing position and in 120 degrees flexion upright without weight-bearing were obtained of 10 volunteers (mean age 33.7 +/- 6.1 years; range 24-41) using a cone beam extremity-CT. Two independent readers quantified tibiofemoral and patellofemoral rotation, tibial tuberosity-trochlear groove distance (TTTG) and patellofemoral distance. Tibiofemoral contact points were assessed in relation to the anteroposterior distance of the tibial plateau. Significant differences between degrees of flexion were sought using Wilcoxon signed-rank test (P < 0.05). RESULTS: With higher degrees of flexion, internal tibiofemoral rotation increased (0 degrees /120 degrees flexion; mean, 0.5 degrees +/- 4.5/22.4 degrees +/- 7.6); external patellofemoral rotation decreased (10.6 degrees +/- 7.6/1.6 degrees +/- 4.2); TTTG decreased (11.1 mm +/-3.7/-2.4 mm +/-6.4) and patellofemoral distance decreased (38.7 mm +/-3.0/21.0 mm +/-7.0). The CP shifted posterior, more pronounced laterally. Significant differences were found for all measurements at all degrees of flexion (P = 0.005-0.037), except between 30 degrees and 60 degrees . ICC was almost perfect (0.80-0.99), except for the assessment of the CP (0.20-0.96). CONCLUSION: Knee joint articulations change significantly during flexion using upright weight-bearing CT. Progressive internal tibiofemoral rotation leads to a decrease in the TTTG and a posterior shift of the contact points in higher degrees of flexion. This elucidates patellar malalignment predominantly close to extension and meniscal tears commonly affecting the posterior horns. PMID- 26537598 TI - Radiographic measurement of the posterior femoral offset is not precise. AB - PURPOSE: The posterior femoral offset may significantly impact the final flexion range after total knee arthroplasty (TKA). The purpose of the present study was to compare a conventional, radiologic-based technique with an intra-operative, surgical navigation-based technique for the measurement of posterior femoral offset. The tested hypothesis was that the two measurement techniques produce different results both before and after TKA. METHODS: One-hundred consecutive cases referred for end-stage knee osteoarthritis have been studied. Posterior femoral offsets, measured pre- and post-TKA from radiographs, as well as those measured from a navigation system intra-operatively, were analysed. The pre-TKA measured offsets, post-TKA measured offsets and the changes (pre- vs. post-TKA) in the offsets were statistically compared between the radiologic and the navigated measurement techniques at a 0.05 level of significance. RESULTS: The mean paired difference between pre-TKA radiologic and navigated measurement was 4 +/- 4 mm (p < 0.001). There was a significant and moderate positive correlation with a good coherence between the two measurements. The mean paired difference between post-TKA radiologic and navigated measurement was 6 +/- 5 mm (p < 0.001). There was a significant and moderate positive correlation but a poor coherence between the two measurements. CONCLUSIONS: The conventional radiologic technique for the measurement of the posterior femoral offset cannot be reliably used either for pre-TKA planning of the posterior femoral resection and antero posterior sizing of the femoral component, or for post-TKA quality control of the reconstruction of the posterior femoral offset. LEVEL OF EVIDENCE: Level IV. PMID- 26537599 TI - Self-Harm Intervention: Family Therapy (SHIFT), a study protocol for a randomised controlled trial of family therapy versus treatment as usual for young people seen after a second or subsequent episode of self-harm. AB - BACKGROUND: Self-harm is common in the community with a lifetime prevalence of 13 %. It is associated with an elevated risk of overall mortality and suicide. People who harm themselves are high users of public services. Estimates of the 1 year risk of repetition vary between 5 and 15 % per year. Currently, limited evidence exists on the effectiveness of clinical interventions for young people who engage in self-harm. Recent reviews have failed to demonstrate any effect on reducing repetition of self-harm among adolescents receiving a range of treatment approaches. Family factors are particularly important risk factors associated with fatal and non-fatal self-harm among children and adolescents. Family therapy focuses on the relationships, roles and communication patterns between family members, but there have been relatively few studies of specifically family focused interventions with this population. The Self-Harm Intervention: Family Therapy (SHIFT) Trial was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (grant no. 07/33/01) following a commissioned call for this research. METHODS/DESIGN: SHIFT is a pragmatic, phase III, multicentre, individually randomised, controlled trial comparing Family Therapy (FT) with treatment as usual (TAU) for adolescents aged 11 to 17 who have engaged in at least two episodes of self-harm. Both therapeutic interventions were delivered within the National Health Service (NHS) Child and Adolescent Mental Health Services (CAMHS) in England. Participants and therapists were, of necessity, aware of treatment allocation, but the researchers were blind to the allocations to allow unbiased collection of follow-up data. Primary outcome data (repetition of self-harm leading to hospital attendance 18 months post randomisation) were collected from the Health and Social Care Information Centre (HSCIC), augmented by directed searches of medical records at Acute Trusts. Secondary outcome data (including suicidal intent, depression, hopelessness and health economics) were collected at 12 and 18 months post-randomisation via researcher-participant interviews and by post at 3 and 6 months. DISCUSSION: SHIFT will provide a well-powered evaluation of the clinical and cost effectiveness of Family Therapy for young people who have self-harmed on more than one occasion. The study will be reported in 2016, and the results will inform clinical practice thereafter. TRIAL REGISTRATION: ISRCTN59793150 . 26 January 2009. PMID- 26537601 TI - Motherhood and the "Madness of Hunger": "...Want Almal Vra vir My vir 'n Stukkie Brood" ("...Because Everyone Asks Me for a Little Piece of Bread"). AB - It is widely assumed that the social and economic conditions of poverty can be linked to common mental disorders in low-, middle- and high-income countries. Despite the considerable increase in quantitative studies investigating the link between poverty and mental health, the nature of the connection between poverty and emotional well-being/distress is still not fully comprehended. In this qualitative study, exploring how one group of Coloured South African women, diagnosed with depression and residing in a semi-rural low-income South African community, subjectively understand and experience their emotional distress, data was collected by means of in-depth semi-structured interviews and social constructionist grounded theory was used to analyse the data. We will attempt to show (1) that the depressed women in this group of respondents frequently refer to the emotional distress caused by hungry children and (2) that the emotional distress described by the respondents included emotions typically associated with depression (such as sadness, hopelessness and guilt), but also included emotions not necessarily associated with depression (such as anxiety, anger and anomie). In our attempt to understand (both psychologically and politically) the complex emotional response of mothers to their children's hunger, we argue that powerful gender and neo-liberal discourses within which mothers are interpellated to care for children, and more specifically, to make sure that children are not hungry, mean that the mothers of hungry children felt that they were not fulfilling their responsibilities and thus felt guilty and ashamed. This shame seemed, in turn, to lead to anger and/or anomie, informing acting out behaviours ranging from verbal and physical aggression to passive withdrawal. A vicious cycle of hunger, sadness and anxiety, shame, anger and anomie, aggression and withdrawal, negative judgement, and more shame, are thus maintained. As such, the unbearable rebukes of hungry children can be thought of as evoking a kind of "madness" in low-income mothers. PMID- 26537602 TI - Bacteria associated with Amblyomma cajennense tick eggs. AB - Ticks represent a large group of pathogen vectors that blood feed on a diversity of hosts. In the Americas, the Ixodidae ticks Amblyomma cajennense are responsible for severe impact on livestock and public health. In the present work, we present the isolation and molecular identification of a group of culturable bacteria associated with A. cajennense eggs from females sampled in distinct geographical sites in southeastern Brazil. Additional comparative analysis of the culturable bacteria from Anocentor nitens, Rhipicephalus sanguineus and Ixodes scapularis tick eggs were also performed. 16S rRNA gene sequence analyses identified 17 different bacterial types identified as Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas fluorescens, Enterobacter spp., Micrococcus luteus, Ochrobactrum anthropi, Bacillus cereus and Staphylococcus spp., distributed in 12 phylogroups. Staphylococcus spp., especially S. sciuri, was the most prevalent bacteria associated with A. cajennense eggs, occurring in 65% of the samples and also frequently observed infecting A. nitens eggs. S. maltophilia, S. marcescens and B. cereus occurred infecting eggs derived from specific sampling sites, but in all cases rising almost as pure cultures from infected A. cajennense eggs. The potential role of these bacterial associations is discussed and they possibly represent new targets for biological control strategies of ticks and tick borne diseases. PMID- 26537603 TI - Comparative study of curcumin and curcumin formulated in a solid dispersion: Evaluation of their antigenotoxic effects. AB - Curcumin (CMN) is the principal active component derived from the rhizome of Curcuma longa (Curcuma longa L.). It is a liposoluble polyphenolic compound that possesses great therapeutic potential. Its clinical application is, however, limited by the low concentrations detected following oral administration. One key strategy for improving the solubility and bioavailability of poorly water-soluble drugs is solid dispersion, though it is not known whether this technique might influence the pharmacological effects of CMN. Thus, in this study, we aimed to evaluate the antioxidant and antigenotoxic effects of CMN formulated in a solid dispersion (CMN SD) compared to unmodified CMN delivered to Wistar rats. Cisplatin (cDDP) was used as the damage-inducing agent in these evaluations. The comet assay results showed that CMN SD was not able to reduce the formation of cDDP-DNA crosslinks, but it decreased the formation of micronuclei induced by cDDP and attenuated cDDP-induced oxidative stress. Furthermore, at a dose of 50 mg/kg b.w. both CMN SD and unmodified CMN increased the expression of Tp53 mRNA. Our results showed that CMN SD did not alter the antigenotoxic effects observed for unmodified CMN and showed effects similar to those of unmodified CMN for all of the parameters evaluated. In conclusion, CMN SD maintained the protective effects of unmodified CMN with the advantage of being chemically water soluble, with maximization of absorption in the gastrointestinal tract. Thus, the optimization of the physical and chemical properties of CMN SD may increase the potential for the therapeutic use of curcumin. PMID- 26537604 TI - Acetosyringone, pH and temperature effects on transient genetic transformation of immature embryos of Brazilian wheat genotypes by Agrobacterium tumefaciens. AB - Low transformation efficiency is one of the main limiting factors in the establishment of genetic transformation of wheat via Agrobacterium tumefaciens. To determine more favorable conditions for T-DNA delivery and explant regeneration after infection, this study investigated combinations of acetosyringone concentration and pH variation in the inoculation and co cultivation media and co-culture temperatures using immature embryos from two Brazilian genotypes (BR 18 Terena and PF 020037). Based on transient expression of uidA, the most favorable conditions for T-DNA delivery were culture media with pH 5.0 and 5.4 combined with co-culture temperatures of 22 degrees C and 25 degrees C, and a 400 MUM acetosyringone supplement. These conditions resulted in blue foci in 81% of the embryos. Media with more acidic pH also presented reduced A. tumefaciens overgrowth during co-culture, and improved regeneration frequency of the inoculated explants. BR 18 Terena was more susceptible to infection by A. tumefaciens than PF 020037. We found that it is possible to improve T-DNA delivery and explant regeneration by adjusting factors involved in the early stages of A. tumefaciens infection. This can contribute to establishing a stable transformation procedure in the future. PMID- 26537605 TI - Plant growth-promoting bacteria as inoculants in agricultural soils. AB - Plant-microbe interactions in the rhizosphere are the determinants of plant health, productivity and soil fertility. Plant growth-promoting bacteria (PGPB) are bacteria that can enhance plant growth and protect plants from disease and abiotic stresses through a wide variety of mechanisms; those that establish close associations with plants, such as the endophytes, could be more successful in plant growth promotion. Several important bacterial characteristics, such as biological nitrogen fixation, phosphate solubilization, ACC deaminase activity, and production of siderophores and phytohormones, can be assessed as plant growth promotion (PGP) traits. Bacterial inoculants can contribute to increase agronomic efficiency by reducing production costs and environmental pollution, once the use of chemical fertilizers can be reduced or eliminated if the inoculants are efficient. For bacterial inoculants to obtain success in improving plant growth and productivity, several processes involved can influence the efficiency of inoculation, as for example the exudation by plant roots, the bacterial colonization in the roots, and soil health. This review presents an overview of the importance of soil-plant-microbe interactions to the development of efficient inoculants, once PGPB are extensively studied microorganisms, representing a very diverse group of easily accessible beneficial bacteria. PMID- 26537606 TI - Expression profiles of sugarcane under drought conditions: Variation in gene regulation. AB - Drought is a major factor in decreased sugarcane productivity because of the resulting morphophysiological effects that it causes. Gene expression studies that have examined the influence of water stress in sugarcane have yielded divergent results, indicating the absence of a fixed pattern of changes in gene expression. In this work, we investigated the expression profiles of 12 genes in the leaves of a drought-tolerant genotype (RB72910) of sugarcane and compared the results with those of other studies. The genotype was subjected to 80-100% water availability (control condition) and 0-20% water availability (simulated drought). To analyze the physiological status, the SPAD index, Fv/Fm ratio, net photosynthesis (A), stomatal conductance (gs) and stomatal transpiration (E) were measured. Total RNA was extracted from leaves and the expression of SAMDC, ZmPIP2 1 protein, ZmTIP4-2 protein, WIP protein, LTP protein, histone H3, DNAj, ferredoxin I, beta-tubulin, photosystem I, gene 1 and gene 2 was analyzed by quantitative real-time PCR (RT-PCR). Important differences in the expression profiles of these genes were observed when compared with other genotypes, suggesting that complex defense mechanisms are activated in response to water stress. However, there was no recognizable pattern for the changes in expression of the different proteins associated with tolerance to drought stress. PMID- 26537607 TI - Characterization of the core microbiota of the drainage and surrounding soil of a Brazilian copper mine. AB - The core microbiota of a neutral mine drainage and the surrounding high heavy metal content soil at a Brazilian copper mine were characterized by 16S rDNA pyrosequencing. The core microbiota of the drainage was dominated by the generalist genus Meiothermus. The soil samples contained a more heterogeneous bacterial community, with the presence of both generalist and specialist bacteria. Both environments supported mainly heterotrophic bacteria, including organisms resistant to heavy metals, although many of the bacterial groups identified remain poorly characterized. The results contribute to the understanding of bacterial communities in soils impacted by neutral mine drainage, for which information is scarce, and demonstrate that heavy metals can play an important role in shaping the microbial communities in mine environments. PMID- 26537608 TI - The time-course of protection of the RTS,S vaccine against malaria infections and clinical disease. AB - BACKGROUND: Recent publications have reported follow-up of the RTS,S/AS01 malaria vaccine candidate Phase III trials at 11 African sites for 32 months (or longer). This includes site- and time-specific estimates of incidence and efficacy against clinical disease with four different vaccination schedules. These data allow estimation of the time-course of protection against infection associated with two different ages of vaccination, both with and without a booster dose. METHODS: Using an ensemble of individual-based stochastic models, each trial cohort in the Phase III trial was simulated assuming many different hypothetical profiles for the vaccine efficacy against infection in time, for both the primary course and boosting dose and including the potential for either exponential or non exponential decay. The underlying profile of protection was determined by Bayesian fitting of these model predictions to the site- and time-specific incidence of clinical malaria over 32 months (or longer) of follow-up. Using the same stochastic models, projections of clinical efficacy in each of the sites were modelled and compared to available observed trial data. RESULTS: The initial protection of RTS,S immediately following three doses is estimated as providing an efficacy against infection of 65 % (when immunizing infants aged 6-12 weeks old) and 91 % (immunizing children aged 5-17 months old at first vaccination). This protection decays relatively rapidly, with an approximately exponential decay for the 6-12 weeks old cohort (with a half-life of 7.2 months); for the 5 17 months old cohort a biphasic decay with a similar half-life is predicted, with an initial rapid decay followed by a slower decay. The boosting dose was estimated to return protection to an efficacy against infection of 50-55 % for both cohorts. Estimates of clinical efficacy by trial site are consistent with those reported in the trial for all cohorts. CONCLUSIONS: The site- and time specific clinical observations from the RTS,S/AS01 trial data allowed a reasonably precise estimation of the underlying vaccine protection against infection which is consistent with common underlying efficacy and decay rates across the trial sites. This calibration suggests that the decay in efficacy against clinical disease is more rapid than that against infection because of age shifts in the incidence of disease. The dynamical models predict that clinical effectiveness will continue to decay and that likely effects beyond the time scale of the trial will be small. PMID- 26537609 TI - Texture and wettability of metallic lotus leaves. AB - Superhydrophobic surfaces with the self-cleaning behavior of lotus leaves are sought for drag reduction and phase change heat transfer applications. These superrepellent surfaces have traditionally been fabricated by random or deterministic texturing of a hydrophobic material. Recently, superrepellent surfaces have also been made from hydrophilic materials, by deterministic texturing using photolithography, without low-surface energy coating. Here, we show that hydrophilic materials can also be made superrepellent to water by chemical texturing, a stochastic rather than deterministic process. These metallic surfaces are the first analog of lotus leaves, in terms of wettability, texture and repellency. A mechanistic model is also proposed to describe the influence of multiple tiers of roughness on wettability and repellency. This demonstrated ability to make hydrophilic materials superrepellent without deterministic structuring or additional coatings opens the way to large scale and robust manufacturing of superrepellent surfaces. PMID- 26537610 TI - Do academic knowledge brokers exist? Using social network analysis to explore academic research-to-policy networks from six schools of public health in Kenya. AB - The potential for academic research institutions to facilitate knowledge exchange and influence evidence-informed decision-making has been gaining ground. Schools of public health (SPHs) may play a key knowledge brokering role-serving as agencies of and for development. Understanding academic-policymaker networks can facilitate the enhancement of links between policymakers and academic faculty at SPHs, as well as assist in identifying academic knowledge brokers (KBs). Using a census approach, we administered a sociometric survey to academic faculty across six SPHs in Kenya to construct academic-policymaker networks. We identified academic KBs using social network analysis (SNA) in a two-step approach: First, we ranked individuals based on (1) number of policymakers in their network; (2) number of academic peers who report seeking them out for advice on knowledge translation and (3) their network position as 'inter-group connectors'. Second, we triangulated the three scores and re-ranked individuals. Academic faculty scoring within the top decile across all three measures were classified as KBs. Results indicate that each SPH commands a variety of unique as well as overlapping relationships with national ministries in Kenya. Of 124 full-time faculty, we identified 7 KBs in 4 of the 6 SPHs. Those scoring high on the first measure were not necessarily the same individuals scoring high on the second. KBs were also situated in a wide range along the 'connector/betweenness' measure. We propose that a composite score rather than traditional 'betweenness centrality', provides an alternative means of identifying KBs within these networks. In conclusion, SNA is a valuable tool for identifying academic-policymaker networks in Kenya. More efforts to conduct similar network studies would permit SPH leadership to identify existing linkages between faculty and policymakers, shared linkages with other SPHs and gaps so as to contribute to evidence-informed health policies. PMID- 26537611 TI - Unproven stem cell-based interventions and achieving a compromise policy among the multiple stakeholders. AB - BACKGROUND: In 2004, patient advocate groups were major players in helping pass and implement significant public policy and funding initiatives in stem cells and regenerative medicine. In the following years, advocates were also actively engaged in Washington DC, encouraging policy makers to broaden embryonic stem cell research funding, which was ultimately passed after President Barack Obama came into office. Many advocates did this because they were told stem cell research would lead to cures. After waiting more than 10 years, many of these same patients are now approaching clinics around the world offering experimental stem cell-based interventions instead of waiting for scientists in the US to complete clinical trials. How did the same groups who were once (and often still are) the strongest supporters of stem cell research become stem cell tourists? And how can scientists, clinicians, and regulators work to bring stem cell patients back home to the US and into the clinical trial process? DISCUSSION: In this paper, we argue that the continued marketing and use of experimental stem cell-based interventions is problematic and unsustainable. Central problems include the lack of patient protection, US liability standards, regulation of clinical sites, and clinician licensing. These interventions have insufficient evidence of safety and efficacy; patients may be wasting money and time, and they may be forgoing other opportunities for an intervention that has not been shown to be safe and effective. Current practices do not contribute to scientific progress because the data from the procedures are unsuitable for follow-up research to measure outcomes. In addition, there is no assurance for patients that they are receiving the interventions promised or of what dosage they are receiving. Furthermore, there is inconsistent or non-existent follow-up care. Public policy should be developed to correct the current situation. CONCLUSION: The current landscape of stem cell tourism should prompt a re-evaluation of current approaches to study cell-based interventions with respect to the design, initiation, and conduct of US clinical trials. Stakeholders, including scientists, clinicians, regulators and patient advocates, need to work together to find a compromise to keep patients in the US and within the clinical trial process. Using HIV/AIDS and breast cancer advocate cases as examples, we identify key priorities and goals for this policy effort. PMID- 26537612 TI - Normal karyotype acute myeloid leukemia patients with CEBPA double mutation have a favorable prognosis but no survival benefit from allogeneic stem cell transplant. AB - Normal karyotype acute myeloid leukemia (NK-AML) with CCAAT/enhancer binding protein alpha (CEBPA) mutations is known to have a more favorable prognosis. However, direct comparison of the clinical significance according to consolidation therapy has not been widely performed in patients with NK-AML. A total of 404 patients with NK-AML who received intensive induction chemotherapy were included in the present study. Diagnostic samples from the patients were evaluated for CEBPA mutations by direct sequencing. CEBPA single (sm) or double mutation (dm) was observed in 27 (6.7 %) and 51 (12.6 %) patients, respectively. CEBPA (dm) was associated with GATA2 (mut), and it was less frequently associated with FLT3-ITD(pos), NPM1 (mut), and DNMT3A (mut) in comparison with CEBPA (wild) or CEBPA (sm) (all p values <0.05). On multivariate analysis, CEBPA (dm) (p = 0.007, OR 39.593) was an independent risk factor for achievement of complete remission (CR). With a median follow-up of 40.1 months, CEBPA (dm) showed a favorable overall survival (OS), event-free survival (EFS), and lower relapse incidence (RI) in comparison with CEBPA (wild) (all p values <0.005). Comparison of clinical outcome analyses (consolidation chemotherapy vs. allogeneic hematopoietic cell transplantation (HCT)) demonstrated the role of consolidation treatment in patients with CEBPA (dm). Allogeneic HCT was associated with lower EFS and RI and a trend of higher non-relapse mortality. However, there was no statistically significant difference in OS. In conclusion, CEBPA (dm) was associated with other molecular mutations. Consolidation chemotherapy alone may overcome higher relapse rates by reducing the treatment mortality and increasing survival after relapse events in patients with CEBPA (dm) in NK-AML. PMID- 26537613 TI - Non-Hodgkin lymphoma in the Far East: review of 730 cases from the international non-Hodgkin lymphoma classification project. AB - Large and systematic studies of non-Hodgkin lymphoma (NHL) in the Far East (FE) with good comparative data are scarce in the literature. In this study, five expert hematopathologists classified 730 consecutive cases of newly-diagnosed NHL from four sites in the FE (excluding Japan) using the World Health Organization classification. The results were compared to 399 cases from North America (NA). We found a significantly higher male to female ratio in the FE compared to NA (1.7 versus 1.1; p < 0.05). The median ages of patients with low-grade (LG) and high-grade (HG) B-NHL in the FE (58 and 51 years, respectively) were significantly lower than in NA (64 and 68 years, respectively). The FE had a significantly lower relative frequency of B-NHL and a higher frequency of T-NHL (82 vs. 18 %) compared to NA (90.5 vs. 9.5 %). Among mature B cell lymphomas, the FE had a significantly higher relative frequency of HG B-NHL (54.8 %) and a lower frequency of LG B-NHL (27.2 %) than NA (34.3 and 56.1 %, respectively). Diffuse large B cell lymphoma was more common in the FE (49.4 %) compared to NA (29.3 %), whereas the relative frequency of follicular lymphoma was lower in the FE (9.4 %) compared to NA (33.6 %). Among T-NHL, nasal NK/T cell NHL was more frequent in the FE (5.2 %) compared to NA (0 %). Peripheral T cell lymphoma was also more common in the FE (9.1 %) than in NA (5.3 %). Further epidemiologic studies are needed to better understand the pathobiology of these differences. PMID- 26537614 TI - A pilot study to determine whether using a lightweight, wearable micro-camera improves dietary assessment accuracy and offers information on macronutrients and eating rate. AB - A major limitation in nutritional science is the lack of understanding of the nutritional intake of free-living people. There is an inverse relationship between accuracy of reporting of energy intake by all current nutritional methodologies and body weight. In this pilot study we aim to explore whether using a novel lightweight, wearable micro-camera improves the accuracy of dietary intake assessment. Doubly labelled water (DLW) was used to estimate energy expenditure and intake over a 14-d period, over which time participants (n 6) completed a food diary and wore a micro-camera on 2 of the days. Comparisons were made between the estimated energy intake from the reported food diary alone and together with the images from the micro-camera recordings. There was an average daily deficit of 3912 kJ using food diaries to estimate energy intake compared with estimated energy expenditure from DLW (P=0.0118), representing an under reporting rate of 34 %. Analysis of food diaries alone showed a significant deficit in estimated daily energy intake compared with estimated intake from food diary analysis with images from the micro-camera recordings (405 kJ). Use of the micro-camera images in conjunction with food diaries improves the accuracy of dietary assessment and provides valuable information on macronutrient intake and eating rate. There is a need to develop this recording technique to remove user and assessor bias. PMID- 26537615 TI - Predicting drug side effects by multi-label learning and ensemble learning. AB - BACKGROUND: Predicting drug side effects is an important topic in the drug discovery. Although several machine learning methods have been proposed to predict side effects, there is still space for improvements. Firstly, the side effect prediction is a multi-label learning task, and we can adopt the multi label learning techniques for it. Secondly, drug-related features are associated with side effects, and feature dimensions have specific biological meanings. Recognizing critical dimensions and reducing irrelevant dimensions may help to reveal the causes of side effects. METHODS: In this paper, we propose a novel method 'feature selection-based multi-label k-nearest neighbor method' (FS MLKNN), which can simultaneously determine critical feature dimensions and construct high-accuracy multi-label prediction models. RESULTS: Computational experiments demonstrate that FS-MLKNN leads to good performances as well as explainable results. To achieve better performances, we further develop the ensemble learning model by integrating individual feature-based FS-MLKNN models. When compared with other state-of-the-art methods, the ensemble method produces better performances on benchmark datasets. CONCLUSIONS: In conclusion, FS-MLKNN and the ensemble method are promising tools for the side effect prediction. The source code and datasets are available in the Additional file 1. PMID- 26537616 TI - Off-label drug use is associated with raised risk of adverse events, study finds. PMID- 26537617 TI - Ligand-Enabled Catalytic C-H Arylation of Aliphatic Amines by a Four-Membered Ring Cyclopalladation Pathway. AB - A palladium-catalyzed C?H arylation of aliphatic amines with arylboronic esters is described, proceeding through a four-membered-ring cyclopalladation pathway. Crucial to the successful outcome of this reaction is the action of an amino-acid derived ligand. A range of hindered secondary amines and arylboronic esters are compatible with this process and the products of the arylation can be advanced to complex polycyclic molecules by sequential C?H activation reactions. PMID- 26537618 TI - The market in healthcare data. PMID- 26537619 TI - Watchful waiting in aortic stenosis: are we ready for individualizing the risk assessment? PMID- 26537620 TI - Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness. AB - AIMS: Increased left ventricular wall thickness (LVWT) is a common finding in cardiology. It is not known how often hereditary transthyretin-related familial amyloid cardiomyopathy (mTTR-FAC) is responsible for LVWT. Several therapeutic modalities for mTTR-FAC are currently in clinical trials; thus, it is important to establish the prevalence of TTR mutations (mTTR) and the clinical characteristics of the patients with mTTR-FAC. METHODS AND RESULTS: In a prospective multicentre, cross-sectional study, the TTR gene was sequenced in 298 consecutive patients diagnosed with increased LVWT in primary cardiology clinics in France. Among the included patients, median (25-75th percentiles) age was 62 [50;74]; 74% were men; 23% were of African origin; and 36% were in NYHA Class III IV. Median LVWT was 18 (16-21) mm. Seventeen (5.7%; 95% confidence interval [CI]: [3.4;9.0]) patients had mTTR of whom 15 (5.0%; 95% CI [2.9;8.2]) had mTTR-FAC. The most frequent mutations were V142I (n = 8), V50M (n = 2), and I127V (n = 2). All mTTR-FAC patients were older than 63 years with a median age of 74 [69;79]. Of the 15 patients with mTTR-FAC, 8 were of African descent while 7 were of European descent. In the African descendants, mTTR-FAC median age was 74 [72;79] vs. 55 [46;65] years in non-mTTR-FAC (P < 0.001). In an adjusted multivariate model, African origin, neuropathy, carpal tunnel syndrome, electrocardiogram (ECG) low voltage, and late gadolinium enhancement (LGE) at cardiac-magnetic resonance imaging were all independently associated with mTTR-FAC. CONCLUSION: Five per cent of patients diagnosed with hypertrophic cardiomyopathy have mTTR FAC. Mutated transthyretin genetic screening is warranted in elderly subjects with increased LVWT, particularly, those of African descent with neuropathy, carpal tunnel syndrome, ECG low voltage, or LGE. PMID- 26537621 TI - Intensive LDL lowering therapy for prevention of recurrent cardiovascular events: a word of caution. PMID- 26537622 TI - Characteristics of a rapid, point-of-care lateral flow immunoassay for the diagnosis of sickle cell disease. AB - Sickle cell disease (SCD) is a common and life-threatening hematological disorder, affecting approximately 400,000 newborns annually worldwide. Most SCD births occur in low-resource countries, particularly in sub-Saharan Africa, where limited access to accurate diagnostics results in early mortality. We evaluated a prototype immunoassay as a novel, rapid, and low-cost point-of-care (POC) diagnostic device (Sickle SCAN) designed to identify HbA, HbS, and HbC. A total of 139 blood samples were scored by three masked observers and compared to results using capillary zone electrophoresis. The sensitivity (98.3-100%) and specificity (92.5-100%) to detect the presence of HbA, HbS, and HbS were excellent. The test demonstrated 98.4% sensitivity and 98.6% specificity for the diagnosis of HbSS disease and 100% sensitivity and specificity for the diagnosis of HbSC disease. Most variant hemoglobins, including samples with high concentrations of HbF, did not interfere with the ability to detect HbS or HbC. Additionally, HbS and HbC were accurately detected at concentrations as low as 1 2%. Dried blood spot samples yielded clear positive bands, without loss of sensitivity or specificity, and devices stored at 37 degrees C gave reliable results. These analyses indicate that the Sickle SCAN POC device is simple, rapid, and robust with high sensitivity and specificity for the detection of HbA, HbS, and HbC. The ability to obtain rapid and accurate results with both liquid blood and dried blood spots, including those with newborn high-HbF phenotypes, suggests that this POC device is suitable for large-scale screening and potentially for accurate diagnosis of SCD in limited resource settings. PMID- 26537623 TI - Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study. AB - In anecdotal reports, some patients with immune thrombocytopenia (ITP) maintained platelet counts after discontinuing romiplostim. Here, we examined rates of platelet response (>=50 * 10(9) /l), remission, splenectomy and adverse events in patients with primary ITP duration <=6 months who were treated with romiplostim for <=12 months. The starting dose of romiplostim was 1 MUg/kg; concomitant and rescue treatments were permitted to maintain platelet counts. Patients with platelet counts >=50 * 10(9) /l at the end of 12 months entered a dose taper in which the romiplostim dose was decreased as long as platelet counts were maintained. Remission (platelet count >=50 * 10(9) /l for 24 consecutive weeks with no ITP treatments) was evaluated in patients once romiplostim was discontinued. Over the 12 months, a high response rate (>90%) was observed. Platelet response occurred quickly (median, ~2 weeks) and was observed for a cumulative median of 11 months. Remission was observed in 24 patients (32%); there were no significantly predictors of remission. Most (20/24) patients had remission start before the forced taper. No new safety signals were identified. Thus, in patients with early-stage ITP, romiplostim was well tolerated and induced rapid responses, with remission occurring in approximately one-third of patients (NCT01143038, Amgen 20080435). PMID- 26537624 TI - Phloroglucinol Reduces Photodamage in Hairless Mice via Matrix Metalloproteinase Activity Through MAPK Pathway. AB - We investigated the photoprotective activity of phloroglucinol on ultraviolet B (UVB)-induced deleterious effects in hairless mice in vivo. To assess the photoprotective effect of phloroglucinol, phloroglucinol-treated HR-1 hairless male mice were exposed to UVB irradiation. The inhibitory activity of phloroglucinol on wrinkle formation was determined by analysis of skin replicas, epidermal thickness based on histological examination and collagen damage. Matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase (TIMP) mRNA levels were measured by real-time PCR. UVB induced transcription of proinflammatory cytokines, including interleukin-1 beta (IL-1beta, IL-6) and IL-8 (IL-8). The protective effects of phloroglucinol on UVB-induced skin photoaging were examined by measuring protein levels of MMPs and mitogen-activated protein (MAP) kinases. The results of these experiments suggest that phloroglucinol has a significant beneficial effect on the barrier function of the skin. In hairless mice, signs of photoaging and photodamage, including coarse wrinkle formation, epidermal thickness and elastic fiber degeneration, were reduced in severity by phloroglucinol application. The phloroglucinol-treated group showed remarkably decreased mRNA levels of MMP-1, MMP-9 and inflammatory cytokines in comparison with those of the UVB-induced group. Oral administration of phloroglucinol attenuated phosphorylation of MAP kinases, including extracellular signal-regulated kinase, c-Jun N-terminal kinase and p38. PMID- 26537625 TI - TSG101 Silencing Suppresses Hepatocellular Carcinoma Cell Growth by Inducing Cell Cycle Arrest and Autophagic Cell Death. AB - BACKGROUND: The tumor susceptibility gene 101 (TSG101) was originally identified as a tumor-suppressor gene that mediates many molecular and biological processes, such as ubiquitination, endosomal trafficking, cell survival, and virus budding, but its role in hepatocellular carcinoma (HCC) is currently unknown. MATERIAL AND METHODS: We assessed the expression of TSG101 in HCC and paracancerous tissues using qPCR. Then, we used the TSG101-specific siRNA mix to disrupt the expression of TSG101 to investigate the subsequent effect on human hepatoma-7 (Huh7) cells. Western blot was used to detect the protein expression of TSG101 and other molecules. Cell growth assay was performed using CCK8. Transwell assay was used to investigate the migration and invasion ability of Huh7 cells after transfection with of TSG101 siRNA. Flow cytometry was used to estimate the effect of TSG101 knockdown on cell cycle and apoptosis. Confocal laser scanning microscopy was used to observe the actin filaments change and the formation of autophagy. RESULTS: TSG101 was over-expressed in HCC tissues. TSG101 silence was able to suppress Huh7 cell proliferation, migration, and invasion. Furthermore, silencing of TSG101 could induce cell cycle arrest at G1 phase and inhibit the expression of cyclin A and cyclin D, while up-regulating the expression of CDK2. The mechanism might be induction of autophagic cell death and inactivation of Akt and ERK1/2. CONCLUSIONS: TSG101 plays an important role in the development of HCC and may be a target for molecular therapy. PMID- 26537626 TI - Does vaginal estrogen treatment with support pessaries in vaginal prolapse reduce complications? AB - OBJECTIVE: Pelvic organ prolapse is often co-existant with atrophy of the genital tract in older women who tend to prefer vaginal pessaries for prolapse. Vaginal estrogen therapy is used by some along with a support pessary for prolapse with no robust evidence to back this practice. We aimed to evaluate differences in complications of support pessaries for vaginal prolapse in postmenopausal women, with and without vaginal estrogen use. STUDY DESIGN: We prospectively assessed postmenopausal women attending the urogynaecology clinic for a pessary change. We asked them about the level of discomfort during pessary change (visual analogue scale for pain), discharge, bleeding and infection. Ethics approval was not required as this was a service evaluation project. Statistical analysis for relative risk was performed, including sub-group analysis for 'ring pessary' and 'non-ring group' (Shelf, Gellhorn, Shaatz). RESULTS: Between July 2013 and December 2014, we assessed 120 postmenopausal women using support pessaries for prolapse. The mean age was 70 years; 45% of the patients used vaginal estrogen. There were no statistically significant differences in complications with or without vaginal estrogen use, although the trend was higher amongst non-users. The 'non-ring' sub-group not using vaginal estrogen had a higher risk of vaginal ulceration, bleeding and discharge. CONCLUSION: Postmenopausal women may have lesser complications when using vaginal estrogen with a support pessary for prolapse, particularly with pessaries other than the ring. An adequately powered randomised controlled trial is needed to assess conclusively whether vaginal estrogen enhances comfort and reduces complications of support pessaries for prolapse. PMID- 26537627 TI - Tuning the LSPR in copper chalcogenide nanoparticles by cation intercalation, cation exchange and metal growth. AB - Localized surface plasmon resonances (LSPRs) of degenerately doped copper chalcogenide nanoparticles (NPs) (Cu2-xSe berzelianite and Cu1.1S covellite) have been modified applying different methods. The comparison of the cation exchange (Cu2-xSe) and intercalation (Cu1.1S) of Ag(I) and Cu(I) has shown that Ag(I) causes a non reversible, air stable shift of the LSPR. This was compared to the influence of Au(I) cation exchange into Cu1.1S platelets under the formation of Cu1.1S-Au2S mixed nanoplatelets. Furthermore, we show the growth of Au domains on Cu2-xSe, and discuss the interaction of the two plasmonic parts of the obtained dual plasmonic Cu2-xSe-Au hybrid particles. PMID- 26537628 TI - The high-risk surgical patient: a role for a multi-disciplinary team approach? PMID- 26537629 TI - Risk assessment tools validated for patients undergoing emergency laparotomy: a systematic review. AB - Emergency laparotomies are performed commonly throughout the world, but one in six patients die within a month of surgery. Current international initiatives to reduce the considerable associated morbidity and mortality are founded upon delivering individualised perioperative care. However, while the identification of high-risk patients requires the routine assessment of individual risk, no method of doing so has been demonstrated to be practical and reliable across the commonly encountered spectrum of presentations, co-morbidities and operative procedures. A systematic review of Embase and Medline identified 20 validation studies assessing 25 risk assessment tools in patients undergoing emergency laparotomy. The most frequently studied general tools were APACHE II, ASA-PS and P-POSSUM. Comparative, quantitative analysis of tool performance was not feasible due to the heterogeneity of study design, poor reporting and infrequent within study statistical comparison of tool performance. Reporting of calibration was notably absent in many prognostic tool validation studies. APACHE II demonstrated the most consistent discrimination of individual outcome across a variety of patient groups undergoing emergency laparotomy when used either preoperatively or postoperatively (area under the curve 0.76-0.98). While APACHE systems were designed for use in critical care, the ability of APACHE II to generate individual risk estimates from objective, exclusively preoperative data items may lead to better-informed shared decisions, triage and perioperative management of patients undergoing emergency laparotomy. Future endeavours should include the recalibration of APACHE II and P-POSSUM in contemporary cohorts, modifications to enable prediction of morbidity and assessment of the impact of adoption of these tools on clinical practice and patient outcomes. PMID- 26537630 TI - Opioids and neovascularization; pro or anti? PMID- 26537631 TI - Longitudinal evidence linking processing speed to the development of reasoning. AB - Age-related change in processing speed has been linked directly to increases in reasoning as well as indirectly via increases in the capacity of working memory (WM). Most of the evidence linking change in speed to reasoning has come from cross-sectional research; in this article we present the findings from a 21/2 year longitudinal study of 277 6- to-13-year-olds. On three occasions, speed of information processing was assessed with Visual Matching and Cross Out; WM was assessed with reading, listening, backward digit, alphabet, and operation span tasks; and nonverbal reasoning was assessed with Raven's progressive matrices. The results provided consistent evidence of direct links from processing speed to reasoning but inconsistent evidence for indirect links from speed to WM to reasoning. These findings suggest that variations in processing speed may constrain the development of reasoning, directly and perhaps indirectly. A video abstract of this article can be viewed at: https://youtu.be/nc0VlFdi468. PMID- 26537632 TI - Linker proteins enable ultrafast excitation energy transfer in the phycobilisome antenna system of Thermosynechococcus vulcanus. AB - We applied a femtosecond flash method, using induced transient absorption changes, to obtain a time-resolved view of excitation energy transfer in intact phycobilisomes of Thermosynechococcus vulcanus at room temperature. Our measurement of an excitation energy transfer rate of 888 fs in phycobilisomes shows the existence of ultrafast kinetics along the phycocyanin rod subcomplex to the allophycocyanin core that is faster than expected for previous excitation energy transfer based on Forster theory in phycobilisomes. Allophycocyanin in the core further transfers energy to the terminal emitter(s) in 17 ps. In the phycobilisome, rod doublets composed of hexameric phycocyanin discs and internal linker proteins are arranged in a parallel fashion, facilitating direct rod-rod interactions. Excitonic splitting likely drives rod absorption at 635 nm as a result of strong coupling between beta84 chromophores (20 +/- 1 A) in adjacent hexamers. In comparison to the absorbance of the phycobilisome antenna system of the cyanobacterium Acaryochloris marina, which possesses a single rod structure, the linkers in T. vulcanus rods induce a 17 nm red shift in the absorbance spectrum. Furthermore, the kinetics of 888 fs indicates that the presence of the linker protein induces ultrafast excitation energy transfer between phycocyanin and allophycocyanin inside the phycobilisome, which is faster than all previous excitation energy transfer in phycobilisome subunits or sub-complexes reported to date. PMID- 26537633 TI - Substrates of the ASB2alpha E3 ubiquitin ligase in dendritic cells. AB - Conventional dendritic cells (cDCs) comprise distinct populations with specialized immune functions that are mediators of innate and adaptive immune responses. Transcriptomic and proteomic approaches have been used so far to identify transcripts and proteins that are differentially expressed in these subsets to understand the respective functions of cDCs subsets. Here, we showed that the Cullin 5-RING E3 ubiquitin ligase (E3) ASB2alpha, by driving degradation of filamin A (FLNa) and filamin B (FLNb), is responsible for the difference in FLNa and FLNb abundance in the different spleen cDC subsets. Importantly, the ability of these cDC subsets to migrate correlates with the level of FLNa. Furthermore, our results strongly point to CD4 positive and double negative cDCs as distinct populations. Finally, we develop quantitative global proteomic approaches to identify ASB2alpha substrates in DCs using ASB2 conditional knockout mice. As component of the ubiquitin-proteasome system (UPS) are amenable to pharmacological manipulation, these approaches aimed to the identification of E3 substrates in physiological relevant settings could potentially lead to novel targets for therapeutic strategies. PMID- 26537634 TI - Socio-demographic patterns of disability among older adult populations of low income and middle-income countries: results from World Health Survey. AB - OBJECTIVE: Our objective was to quantify disability prevalence among older adults of low- and middle-income countries, and measure socio-demographic distribution of disability. METHODS: World Health Survey data included 53,447 adults aged 50 or older from 43 low- and middle-income countries. Disability was a binary classification, based on a composite score derived from self-reported functional difficulties. Socio-demographic variables included sex, age, marital status, area of residence, education level, and household economic status. A multivariate Poisson regression model with robust variance was used to assess associations between disability and socio-demographic variables. RESULTS: Overall, 33.3 % (95 % CI 32.2-34.4 %) of older adults reported disability. Disability was 1.5 times more common in females, and was positively associated with increasing age. Divorced/separated/widowed respondents reported higher disability rates in all but one study country, and education and wealth levels were inversely associated with disability rates. Urban residence tended to be advantageous over rural. Country-level datasets showed disparate patterns. CONCLUSIONS: Effective approaches aimed at disability prevention and improved disability management are warranted, including the inclusion of equity considerations in monitoring and evaluation activities. PMID- 26537636 TI - Reagent for Evaluating Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Performance in Bottom-Up Proteomic Experiments. AB - We present a novel proteomic standard for assessing liquid chromatography-tandem mass spectrometry (LC-MS/MS) instrument performance, in terms of chromatographic reproducibility and dynamic range within a single LC-MS/MS injection. The peptide mixture standard consists of six peptides that were specifically synthesized to cover a wide range of hydrophobicities (grand average hydropathy (GRAVY) scores of -0.6 to 1.9). A combination of stable isotope labeled amino acids ((13)C and (15)N) were inserted to create five isotopologues. By combining these isotopologues at different ratios, they span four orders of magnitude within each distinct peptide sequence. Each peptide, from lightest to heaviest, increases in abundance by a factor of 10. We evaluate several metrics on our quadrupole orbitrap instrument using the 6 * 5 LC-MS/MS reference mixture spiked into a complex lysate background as a function of dynamic range, including mass measurement accuracy (MMA) and the linear range of quantitation of MS1 and parallel reaction monitoring experiments. Detection and linearity of the instrument routinely spanned three orders of magnitude across the gradient (500 fmol to 0.5 fmol on column) and no systematic trend was observed for MMA of targeted peptides as a function of abundance by analysis of variance analysis (p = 0.17). Detection and linearity of the fifth isotopologue (i.e., 0.05 fmol on column) was dependent on the peptide and instrument scan type (MS1 vs PRM). We foresee that this standard will serve as a powerful method to conduct both intra instrument performance monitoring/evaluation, technology development, and inter instrument comparisons. PMID- 26537635 TI - Computational exploration of a protein receptor binding space with student proposed peptide ligands. AB - Computational molecular docking is a fast and effective in silico method for the analysis of binding between a protein receptor model and a ligand. The visualization and manipulation of protein to ligand binding in three-dimensional space represents a powerful tool in the biochemistry curriculum to enhance student learning. The DockoMatic tutorial described herein provides a framework by which instructors can guide students through a drug screening exercise. Using receptor models derived from readily available protein crystal structures, docking programs have the ability to predict ligand binding properties, such as preferential binding orientations and binding affinities. The use of computational studies can significantly enhance complimentary wet chemical experimentation by providing insight into the important molecular interactions within the system of interest, as well as guide the design of new candidate ligands based on observed binding motifs and energetics. In this laboratory tutorial, the graphical user interface, DockoMatic, facilitates docking job submissions to the docking engine, AutoDock 4.2. The purpose of this exercise is to successfully dock a 17-amino acid peptide, alpha-conotoxin TxIA, to the acetylcholine binding protein from Aplysia californica-AChBP to determine the most stable binding configuration. Each student will then propose two specific amino acid substitutions of alpha-conotoxin TxIA to enhance peptide binding affinity, create the mutant in DockoMatic, and perform docking calculations to compare their results with the class. Students will also compare intermolecular forces, binding energy, and geometric orientation of their prepared analog to their initial alpha-conotoxin TxIA docking results. PMID- 26537637 TI - Peptide-stimulated angiogenesis: Role of lung endothelial caveolar signaling and nitric oxide. AB - Endothelial nitric oxide (NO) synthase (eNOS)-derived NO plays a critical role in the modulation of angiogenesis in the pulmonary vasculature. We recently reported that an eleven amino acid (SSWRRKRKESS) cell penetrating synthetic peptide (P1) activates caveolar signaling, caveloae/eNOS dissociation, and enhance NO production in lung endothelial cells (EC). This study examines whether P1 promote angiogenesis via modulation of caveolar signaling and the level of NO generation in EC and pulmonary artery (PA) segments. P1-enhanced tube formation and cell sprouting were abolished by caveolae disruptor Filipin (FIL) in EC and PA, respectively. P1 enhanced eNOS activity and angiogenesis were attenuated by inhibition of eNOS as well as PLCgamma-1, PKC-alpha but not PI3K-mediated caveolar signaling in intact EC and/or PA. P1 failed to enhance the catalytic activity of eNOS and angiogenesis in caveolae disrupted EC by FIL. Lower (0.01 mM) concentration of NOC-18 enhanced angiogenesis without inhibition of eNOS activity whereas higher concentration of NOC-18 (1.0 mM) inhibited eNOS activity and angiogenesis in EC. Inhibition of eNOS by l-NAME in the presence of P1 resulted in near total loss of tube formation in EC. Although P1 enhanced angiogenesis mimicked only by lower concentrations of NO generated by NOC-18, this response is independent of caveolar signaling/integrity. These results suggest that P1-enhanced angiogenesis is regulated by dynamic process involving caveolar signaling-mediated increased eNOS/NO activity or by the direct exposure to NOC-18 generating only physiologic range of NO independent of caveolae in lung EC and PA segments. PMID- 26537638 TI - Relationship between Arginase 1 and Arginase 2 levels and genetic polymorphisms with erectile dysfunction. AB - Arginase 1 and Arginase 2 are homologous enzymes that convert l-Arginine to Urea and l-ornithine and compete with nitric oxide synthases for l-Arginine. Increased Arginase 1 and 2 activity may reduce nitric oxide production by the endothelium in disease states, including erectile dysfunction (ED). Here we aimed at assessing whether Arginase 1 and 2 plasma levels, plasma arginase activity, or genetic factors are associated with ED risk and severity. Blood samples were collected from healthy controls (n = 106) and from patients with ED (n = 110) after completion of the IIEF questionnaire (international index of erectile function). Plasma Arginase 1 and 2 concentrations were assessed by ELISA, while plasma arginase activity was measured by spectrophotometry. Genotypes of ARG1 (rs2781659, rs2781667, rs2246012 and rs17599586) and ARG2 (rs3742879 and rs10483801) were determined by Taqman genotyping assays by real-time polymerase chain reaction. Increased Arginase 2 concentrations were found in clinical ED and are associated with increased risk for ED. ARG1 rs2781659 AA and rs2781667 TT genotypes are associated with lower IIEF scores (higher severity) only in clinical ED. Similarly, the ARG1 GTCC haplotype is associated with higher IIEF scores in clinical ED. This study shows that plasma Arginase 2 concentrations may serve as risk factor for ED. Besides, Arginase 1 genetic variations affect ED severity. PMID- 26537639 TI - Moraxella catarrhalis-produced nitric oxide has dual roles in pathogenicity and clearance of infection in bacterial-host cell co-cultures. AB - In humans, the free radical nitric oxide (NO) is a concentration-dependent multifunctional signaling or toxic molecule that modulates various physiological and pathological processes, and innate immunity against bacterial infections. Because the expression of bacterial genes encoding nitrite reductase (AniA) and NO reductase (NorB) is highly upregulated in biofilms in vitro, it is important to investigate whether bacterial NO-metabolism might subvert host NO signaling and play pathogenic roles during infection. The Moraxella catarrhalis AniA and NorB directly function in production and reduction of NO. Using M. catarrhalis human bronchial epithelial cell (HBEC) co-cultures, we recently reported AniA/nitrite-dependent cytotoxic effects on HBECs, including altered protein profiles of HBECs and induced HBEC apoptosis, suggesting bacterial nitrite reduction likely dysregulates host cell gene expression. To further clarify whether nitrite reduction-derived NO or nitrite-dependent stimulation of bacterial growth was responsible for adverse effects on HBECs, we monitored bacterial nitrite reduction, levels of NO in co-cultures and resulted dynamic effects on HBEC proliferation and bacterial viability. This study demonstrated that M. catarrhalis nitrite reduction-derived NO was responsible for observed adverse effects on HBECs at mid-to-late stages of infection. More importantly, our data showed that while nitrite promoted bacterial growth and biofilm formation at early hours of infection, nitrite reduction-derived NO was toxic towards M. catarrhalis in maturing biofilms, suggesting nitrite reduction-derived NO might be a possible dualistic mechanism by which M. catarrhalis promotes diseases and spontaneous resolutions. PMID- 26537640 TI - Using zebrafish in systems toxicology for developmental toxicity testing. AB - With the high cost and the long-term assessment of developmental toxicity testing in mammals, the vertebrate zebrafish has become a useful alternative model organism for high-throughput developmental toxicity testing. Zebrafish is also very favorable for the 3R perspective in toxicology; however, the methodologies used by research groups vary greatly, posing considerable challenges to integrative analysis. In this review, we discuss zebrafish developmental toxicity testing, focusing on the methods of chemical exposure, the assessment of morphological abnormalities, housing conditions and their effects on the production of healthy embryos, and future directions. Zebrafish as a systems toxicology model has the potential to elucidate developmental toxicity pathways, and to provide a sound basis for human health risk assessments. PMID- 26537641 TI - Non-epithelial neoplasms of the larynx and hypopharynx - 12 - years of experience. AB - OBJECTIVE: The non-epithelial neoplasms of larynx and hypopharynx are of rare incidence but may originate from various histological tissues. These effect in the difficulty of final diagnosis and often delay the proper treatment. MATERIAL AND METHODS: There was performed retrospective analysis of patients with histopathologicaly confirmed non-epithelial neoplasms of larynx or hypopharynx between 2001 and 2013, that included the evaluation of epidemiology, diagnostic methods and treatment. RESULTS: Non-epithelial neoplasms of larynx and hypopharynx were established in 18 patients (9 women, 9 men), mean age - 60,3 years. The malignant neoplasms were diagnosed in 10 patients and benign - in 8. The soft tissue neoplasms were the most common - 8 patients. There were also 4 lymphomas, 4 chondrosarcomas, 1 paraganglioma and 1 malignant melanoma. Tumors manifested clinically as covered by unchanged mucosa. Characteristic features were observed on computed tomography for certain cases of these neoplasms. The results of the tumor biopsy were in most of the cases not diagnostic. Intralaryngeal microsurgery was applied in benign neoplasms, chemiotherapy - for lymphomas and total laryngectomy for chondrosarcomas and malignant melanoma. PMID- 26537642 TI - The evaluation of the neck torsion test in subjective examinations of patients with vertigo and/or hearing loss. AB - INTRODUCTION: The aim of this work was to evaluate the diagnostic value of the neck torsion test in VNG, Doppler ultrasonography and brainstem auditory evoked potentials in patients with vertigo and/or hearing loss due to intracranial vascular malformations. MATERIAL AND METHODS: The study covered 47 patients, 30 female and 17 male (mean age, 55.5 years; range, 19-74 years) with vertigo and/or hearing disorders and the asymmetry of vertebral arteries. Each patient underwent a subjective examination, an otolaryngological examination, otoneurological diagnostics, VNG with gaze tracking in the straight ahead position and in the 600 left and right neck torsion, the neck torsion test, audiological diagnostics including I-, III- and V-wave latency of the brainstem evoked potentials in the straight ahead position and the right ear stimulation in the 600 right neck torsion and the left ear stimulation in the neck torsion to the left, Doppler ultrasonography with measuring the diameter of vertebral arteries and the velocity of the blood flow in these vessels with the use of the neck torsion test. RESULTS: In own study, in VNG, the positive neck torsion test was observed in 76.5% of the study patients, while square waves in both directions were found in 46.5% and in one direction in 10.6%. Cervical nystagmus was noticed in 19.1% of these patients. In the auditory evoked potentials test, the differences in I-, III- and V-wave latency time were not statistically significant, either at rest or in the neck torsion. In the Doppler ultrasound examination, the asymmetry of vertebral arteries were present (below 25%) in 7 women (14.9%) and 4 men (8.5%), whereas large asymmetries (above 25%) were observed in 23 women (48.9%) and 13 (27.7%) men (range, 25% - 215%) and was statistically insignificant. The resting blood flow velocity in vertebral arteries of large asymmetries, both in systole and diastole heart phases, was significantly higher in the artery with larger asymmetry. CONCLUSION: The neck torsion test can be diagnostically useful in monitoring the vertebrobasilar system as well as qualify for microsurgical procedures if the vertebrobasilar insufficiency has been diagnosed. PMID- 26537643 TI - Auditory deficits in neurological disorders. AB - Neurological diseases present with diverse and often complex symptomatology. Focal neurological signs such as paresis, aphasia or visual field deficits together with often serious general state of a neurological patient usually push auditory symptoms into the background. Here, we present a review of literature on central and peripheral auditory disturbances that can appear in the course of most common neurological diseases. We present: cerebral stroke, cochleovestibular nerve compression syndrome, cerebral palsy, multiple sclerosis, epilepsy, myasthenia gravis and brain tumors. We focus on the neuroanatomical basis of auditory dysfunctions, their character and prevalence typical for the abovementioned diseases. Theoretical considerations are supported by broad audiological and neuroimaging studies of our patients. Auditory symptoms in neurological diseases seem to be rare. However, knowledge of these symptoms and their origin can be helpful in proper diagnosis and comprehensive patient management. PMID- 26537644 TI - Evaluation of selected indicators of antioxidant status in patients with head and neck cancer. AB - INTRODUCTION: The aim of the study was to evaluate lipid peroxidation (TBARS) and the antioxidant enzymatic barrier in patients with head and neck cancer and in healthy controls. MATERIAL AND METHODS: Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and malondialdehyde (MDA) were measured by spectrometry in red blood cells of 22 patients and healthy controls. RESULTS: Decreased activity of SOD, CAT, and GPx as well as an increased concentration of MDA was found in cancer patients in comparison to healthy controls. DISCUSSION: Increased lipid peroxidation in red blood cells of cancer patients indicates an intensification of oxidative stress reactions. Measurements of the activity of the antioxidant enzymes point unambiguously to a reduced antioxidant capacity in head and neck cancer patients. However, this was a pilot study with a low number of participants. Moreover, future research should take into account genetic and extragenetic factors. PMID- 26537645 TI - Towards personalized screening: Cumulative risk of breast cancer screening outcomes in women with and without a first-degree relative with a history of breast cancer. AB - Several reviews have estimated the balance of benefits and harms of mammographic screening in the general population. The balance may, however, differ between individuals with and without family history. Therefore, our aim is to assess the cumulative risk of screening outcomes; screen-detected breast cancer, interval cancer, and false-positive results, in women screenees aged 50-75 and 40-75, with and without a first-degree relative with a history of breast cancer at the start of screening. Data on screening attendance, recall and breast cancer detection were collected for each woman living in Nijmegen (The Netherlands) since 1975. We used a discrete time survival model to calculate the cumulative probability of each major screening outcome over 19 screening rounds. Women with a family history of breast cancer had a higher risk of all screening outcomes. For women screened from age 50-75, the cumulative risk of screen-detected breast cancer, interval cancer and false-positive results were 9.0, 4.4 and 11.1% for women with a family history and 6.3, 2.7 and 7.3% for women without a family history, respectively. The results for women 40-75 followed the same pattern for women screened 50-75 for cancer outcomes, but were almost doubled for false-positive results. To conclude, women with a first-degree relative with a history of breast cancer are more likely to experience benefits and harms of screening than women without a family history. To complete the balance and provide risk-based screening recommendations, the breast cancer mortality reduction and overdiagnosis should be estimated for family history subgroups. PMID- 26537646 TI - Tick-borne encephalitis in north-east Italy: a 14-year retrospective study, January 2000 to December 2013. AB - Italy is considered at low incidence of tick-borne encephalitis (TBE), and the occurrence of human cases of TBE appears to be geographically restricted to the north east of the country. However, most information to date derives from case series, with no systematic data collection. To estimate incidence rates (IR) and spatial distribution of TBE cases, we conducted a retrospective study in north eastern Italy. Data were collected through the infectious disease units and public health districts of three regions (Friuli Venezia Giulia, Trentino Alto Adige and Veneto) between 2000 and 2013. Overall, 367 cases were identified (IR: 0.38/100,000). The cases' median age was 56 years and 257 (70%) were male. Central nervous system involvement was reported in 307 cases (84%). Annual fluctuations in case numbers occurred, with peaks in 2006 and in 2013, when 44 and 42 cases were respectively observed. A strong seasonality effect was noted, with the highest number of cases in July. In terms of geographical location, three main endemic foci with high TBE IR (>10/100,000) were identified in three provinces, namely Belluno (Veneto region), Udine (Friuli Venezia Giulia) and Trento (Trentino Alto-Adige). When investigating the whole study area in terms of altitude, the IR between 400 and 600 m was greater (2.41/100,000) than at other altitudes (p<0.01). In conclusion, the incidence of TBE in Italy is relatively low, even considering only the three known affected regions. However, three endemic foci at high risk were identified. In these areas, where the risk of TBEV infection is likely high, more active offer of TBE vaccination could be considered. PMID- 26537647 TI - [Development of a Novel Method for Quantifying Quassin and Neoquassin in Jamaica Quassia Extracts Using the Molar Absorption Coefficient Ratio]. AB - A novel HPLC-based method employing molar absorption coefficient ratios to 4 hydroxybenzoic acid (4HBA) was developed for the determination of quassin and neoquassin in Jamaica quassia extract, which is used as a food additive in Japan. Based on comparisons of quantitative NMR (qNMR) spectra and HPLC chromatograms of an artificial mixture of quassin, neoquassin, and 4HBA, the molar absorption coefficient ratios of quassin and neoquassin to 4HBA were determined as 0.84 and 0.85, respectively. Quassin and neoquassin were quantified in food additives by qNMR and HPLC based on molar absorption coefficient ratios using 1,4 bis(trimethylsilyl)benzene-d4 and 4HBA as internal standards, respectively. The differences in quantitation values between qNMR and HPLC analyses were below 1.2%. Our proposed novel HPLC-based quantitation method employing the molar absorption coefficient ratios is a reliable tool for determining levels of quassin and neoquassin in food additives and processed foods. PMID- 26537648 TI - Molecular Cloning and Expression of a New Major Allergen, Ani s 14, from Anisakis simplex. AB - The nematode Anisakis simplex is a representative parasite infecting marine animals. When third stage larvae of A. simplex infecting fish and squids are ingested by humans, individuals previously sensitized by this parasite may experience IgE-mediated allergic reactions. So far, as many as 13 kinds of proteins (Ani s 1-13) have been identified as A. simplex allergens but several more unknown allergens are suggested to exist. In this study, therefore, chemiluminescent immunoscreening of an expression cDNA library constructed from the third stage larvae was conducted to identify a new allergen. As a result, an IgE-positive clone coding for a 23.5 kDa protein (named Ani s 14) composed of 217 amino acid residues was isolated. The regions 4-147 and 34-123 of Ani s 14 share 31% identity with the region 796-940 of Ani s 7 and 32% identity with the region 2-91 of Ani s 12, respectively. Recombinant Ani s 14 was successfully expressed in Escherichia coli as a His-tagged protein and shown to be IgE reactive to 14 (54%) of 26 sera from Anisakis-allergic patients. In conclusion, Ani s 14 is a new major allergen of A. simplex that is specific to Anisakis-allergic patients. PMID- 26537649 TI - [Development of a New Method for Determination of Sodium Saccharin and Acesulfame Potassium with the Aid of Coagulant]. AB - An HPLC method for determination of sodium saccharin and acesulfame potassium was newly developed, employing coagulant pretreatment to remove particles dispersed in the sample extract. The method showed recovery of 96-101% for both analytes with a repeatability of less than 1% and a reproducibility of less than 2%. The limit of quantification for sodium saccharin was 0.025 g/kg and that for acesulfame potassium was 0.025 g/kg. Only about 20 min was required for preparation of the test solution, whereas the dialysis method takes much longer. PMID- 26537650 TI - [Development of Determination Method of Ipfencarbazone in Agricultural Products, Livestock Products and Seafood by LC-MS/MS]. AB - A method for the determination of ipfencarbazone in agricultural products, livestock products and seafood by LC-MS/MS was developed. Agricultural samples were extracted with acetone. An aliquot of crude extract was partitioned with n hexane and sat. sodium chloride solution. Clean-up was performed using GC/PSA and C18 cartridges. In the case of livestock products and seafood, samples were extracted with a mixture of acetone and n-hexane, and the organic layer was collected. After acetonitrile-hexane partitioning, the extract was cleaned up using PAS and C18 cartridges. The gradient LC separation was performed on a C18 column with acetonitrile-water containing acetic acid as a mobile phase, and MS with positive ion electrospray ionization was used for detection. The average recoveries (n=5) of ipfencarbazone from 16 kinds of agricultural products, livestock products and seafood spiked at the MRLs or at the uniform limits (0.01 ppm) were 73-101%, and the relative standard deviations were 1.3-5.1%. The limit of quantitation of the developed method was 0.01 mg/kg for ipfencarbazone. PMID- 26537651 TI - [Safety Evaluation of Rare Sugar Syrup: Single-dose Oral Toxicity in Rats, Reverse Mutation Assay, Chromosome Aberration Assay, and Acute Non-Effect Level for Diarrhea of a Single Dose in Humans]. AB - The safety of rare sugar syrup obtained from high-fructose corn syrup under slightly alkaline conditions was studied. Mutagenicity of rare sugar syrup was assessed by a reverse mutation assay using Salmonella typhimurium and Escherichia coli, and an in vitro chromosomal aberration assay using Chinese hamster lung cell line (CHL/IU). No mutagenicity of rare sugar syrup was detected under these experimental conditions. Oral administration of single dose (15,000 mg/kg) of rare sugar syrup to rats caused no abnormalities, suggesting no adverse effect of rare sugar syrup. In humans, the acute non-effect level of rare sugar syrup for causing diarrhea was estimated as 0.9 g/kg body weight as dry solid base in both males and females. PMID- 26537652 TI - [Determination of the Plant Origin of Licorice Oil Extract, a Natural Food Additive, by Principal Component Analysis Based on Chemical Components]. AB - "Licorice oil extract" (LOE) (antioxidant agent) is described in the notice of Japanese food additive regulations as a material obtained from the roots and/or rhizomes of Glycyrrhiza uralensis, G. inflata or G. glabra. In this study, we aimed to identify the original Glycyrrhiza species of eight food additive products using LC/MS. Glabridin, a characteristic compound in G. glabra, was specifically detected in seven products, and licochalcone A, a characteristic compound in G. inflata, was detected in one product. In addition, Principal Component Analysis (PCA) (a kind of multivariate analysis) using the data of LC/MS or (1)H-NMR analysis was performed. The data of thirty-one samples, including LOE products used as food additives, ethanol extracts of various Glycyrrhiza species and commercially available Glycyrrhiza species-derived products were assessed. Based on the PCA results, the majority of LOE products was confirmed to be derived from G. glabra. This study suggests that PCA using (1)H-NMR analysis data is a simple and useful method to identify the plant species of origin of natural food additive products. PMID- 26537653 TI - [Rapid Determination of Seven Fungicides in Citrus Fruits]. AB - A rapid and simple determination method of seven fungicides, thiabendazole (TBZ), pyrimethanil (PYR), o-phenylphenol (OPP), fludioxonil (FLD), azoxystrobin (AZX), imazalil (IMZ) and diphenyl (DP) in citrus fruits by LC-MS and HPLC-FL was developed. The seven fungicides were extracted with acetonitrile from citrus fruits and cleaned up with Z-Sep/C18 cartridges. The LC separation was performed on a phenyl-hexyl column with methanol-acetonitrile-10 mmol/L ammonium formate (10 : 35 : 55) as a mobile phase. The recoveries from citrus fruits fortified with the compounds at the MRLs and at 0.1 MUg/g ranged from 85.4 to 106.3% and from 75.8 to 99.7%, respectively. The quantitation limits (S/N=10) were 0.03-0.07 MUg/g. PMID- 26537654 TI - Extension of the LOPLS-AA Force Field for Alcohols, Esters, and Monoolein Bilayers and its Validation by Neutron Scattering Experiments. AB - The recently presented LOPLS-AA all-atom force field for long hydrocarbon chains, based on the OPLS-AA force field, was extended to alcohols, esters, and glyceryl monooleate (GMO) lipids as a model lipid. Dihedral angles were fitted against high level ab initio calculations, and ester charges were increased to improve their hydration properties. Additionally, the ester Lennard-Jones parameters were readjusted to reproduce experimental liquid bulk properties, densities, and heats of vaporization. This extension enabled the setup of LOPLS-AA parameters for GMO molecules. The properties of the lipid force field were tested for the liquid crystalline phase of a GMO bilayer. The obtained area per lipid for GMO is in good agreement with experiment. Additionally, the lipid dynamics on the subpicosecond to the nanosecond time scale is in excellent agreement with results from time-of-flight (TOF) quasielastic neutron scattering (QENS) experiments on a multilamellar monoolein system, enabling here for the first time the critical evaluation of the short-time dynamics obtained from a molecular dynamics simulation of a membrane system. PMID- 26537655 TI - Development of an SRM method for absolute quantitation of MYDGF/C19orf10 protein. AB - PURPOSE: To develop a MS-based selected reaction monitoring (SRM) assay for quantitation of myeloid-derived growth factor (MYDGF) formerly chromosome 19 open reading frame (C19orf10). EXPERIMENTAL DESIGN: Candidate reporter peptides were identified in digests of recombinant MYDGF. Isotopically labeled forms of these reporter peptides were employed as internal standards for assay development. Two reference peptides were selected SYLYFQTFFK and GAEIEYAMAYSK with respective LOQ of 42 and 380 attomole per injection. RESULTS: Application of the assay to human serum and synovial fluid determined that the assay sensitivity was reduced and quantitation was not achievable. However, the partial depletion of albumin and immunoglobulin from synovial fluids provided estimates of 300-650 femtomoles per injection (0.7-1.6 nanomolar (nM) fluid concentrations) in three of the six samples analyzed. CONCLUSIONS AND CLINICAL RELEVANCE: A validated sensitive assay for the quantitation of MYDGF in biological fluids was developed. However, the endogenous levels of MYDGF in such fluids are at or below the current levels of quantitation. The levels of MYDGF are lower than those previously reported using an ELISA. The current results suggest that additional steps may be required to remove high abundance proteins or to enrich MYDGF for SRM-based quantitation. PMID- 26537656 TI - Health App Use Among US Mobile Phone Owners: A National Survey. AB - BACKGROUND: Mobile phone health apps may now seem to be ubiquitous, yet much remains unknown with regard to their usage. Information is limited with regard to important metrics, including the percentage of the population that uses health apps, reasons for adoption/nonadoption, and reasons for noncontinuance of use. OBJECTIVE: The purpose of this study was to examine health app use among mobile phone owners in the United States. METHODS: We conducted a cross-sectional survey of 1604 mobile phone users throughout the United States. The 36-item survey assessed sociodemographic characteristics, history of and reasons for health app use/nonuse, perceived effectiveness of health apps, reasons for stopping use, and general health status. RESULTS: A little over half (934/1604, 58.23%) of mobile phone users had downloaded a health-related mobile app. Fitness and nutrition were the most common categories of health apps used, with most respondents using them at least daily. Common reasons for not having downloaded apps were lack of interest, cost, and concern about apps collecting their data. Individuals more likely to use health apps tended to be younger, have higher incomes, be more educated, be Latino/Hispanic, and have a body mass index (BMI) in the obese range (all P<.05). Cost was a significant concern among respondents, with a large proportion indicating that they would not pay anything for a health app. Interestingly, among those who had downloaded health apps, trust in their accuracy and data safety was quite high, and most felt that the apps had improved their health. About half of the respondents (427/934, 45.7%) had stopped using some health apps, primarily due to high data entry burden, loss of interest, and hidden costs. CONCLUSIONS: These findings suggest that while many individuals use health apps, a substantial proportion of the population does not, and that even among those who use health apps, many stop using them. These data suggest that app developers need to better address consumer concerns, such as cost and high data entry burden, and that clinical trials are necessary to test the efficacy of health apps to broaden their appeal and adoption. PMID- 26537657 TI - Comparative genome analysis identifies two large deletions in the genome of highly-passaged attenuated Streptococcus agalactiae strain YM001 compared to the parental pathogenic strain HN016. AB - BACKGROUND: Streptococcus agalactiae (S. agalactiae), also known as group B Streptococcus (GBS), is an important pathogen for neonatal pneumonia, meningitis, bovine mastitis, and fish meningoencephalitis. The global outbreaks of Streptococcus disease in tilapia cause huge economic losses and threaten human food hygiene safety as well. To investigate the mechanism of S. agalactiae pathogenesis in tilapia and develop attenuated S. agalactiae vaccine, this study sequenced and comparatively analyzed the whole genomes of virulent wild-type S. agalactiae strain HN016 and its highly-passaged attenuated strain YM001 derived from tilapia. METHODS: We performed Illumina sequencing of DNA prepared from strain HN016 and YM001. Sequencedreads were assembled and nucleotide comparisons, single nucleotide polymorphism (SNP) , indels were analyzed between the draft genomes of HN016 and YM001. Clustered regularly interspaced short palindromic repeats (CRISPRs) and prophage were detected and analyzed in different S. agalactiae strains. RESULTS: The genome of S. agalactiae YM001 was 2,047,957 bp with a GC content of 35.61 %; it contained 2044 genes and 88 RNAs. Meanwhile, the genome of S. agalactiae HN016 was 2,064,722 bp with a GC content of 35.66 %; it had 2063 genes and 101 RNAs. Comparative genome analysis indicated that compared with HN016, YM001 genome had two significant large deletions, at the sizes of 5832 and 11,116 bp respectively, resulting in the deletion of three rRNA and ten tRNA genes, as well as the deletion and functional damage of ten genes related to metabolism, transport, growth, anti-stress, etc. Besides these two large deletions, other ten deletions and 28 single nucleotide variations (SNVs) were also identified, mainly affecting the metabolism- and growth-related genes. CONCLUSIONS: The genome of attenuated S. agalactiae YM001 showed significant variations, resulting in the deletion of 10 functional genes, compared to the parental pathogenic strain HN016. The deleted and mutated functional genes all encode metabolism- and growth-related proteins, not the known virulence proteins, indicating that the metabolism- and growth-related genes are important for the pathogenesis of S. agalactiae. PMID- 26537658 TI - Operative and Functional Outcome After Pulmonary Endarterectomy for Advanced Thromboembolic Pulmonary Hypertension. AB - AIM: To evaluate the midterm hemodynamic and functional outcome of pulmonary endarterectomy (PEA) for patients with advanced chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Thirty-eight consecutive patients underwent PEA for CTEPH from May 2004 to March 2012. All patients were followed prospectively at six months postoperatively and annually thereafter. Each patient underwent serial cardiopulmonary exercise testing (CPET) and transthoracic echocardiography, and were followed for up to four years. RESULTS: Overall, 31.5% (12/38) of patients had Jamieson class II disease while 65.8% (25/38) had class III disease. There were three in-hospital mortalities (7.9%), all of which had baseline pulmonary vasculature resistance (PVR) greater than 1400 dynes-sec-cm( 5) . Preoperative PVR and mean pulmonary artery pressure were 1209 +/- 723 dynes sec-cm(-5) and 50 +/- 14 mmHg, respectively, signifying a high-risk operative group. Ninety-seven percent of patients were in NYHA class III or IV preoperatively. At median follow-up of 29 months 89.5% (17/19) of patients were in NYHA class I or II. CPET revealed a progressive increase in peak oxygen consumption from 16.5 +/- 4.1 ml/kg/min at first follow-up, to a plateau of 20.2 +/- 5.6 ml/kg/min (p = 0.032) at two years. CONCLUSIONS: CPET can be used to quantify progress in functional capacity post-CTEPH, although improvements in peak oxygen consumption plateau at two years. PMID- 26537659 TI - Seizing the strategic opportunities of emerging technologies by building up innovation system: monoclonal antibody development in China. AB - BACKGROUND: Monoclonal antibodies (mAbs), as an emerging technology, have become increasingly important in the development of human therapeutic agents. How developing countries such as China could seize this emerging technological opportunity remains a poorly studied issue in prior literature. Thus, this paper aims to investigate the research and development of mAbs in China based on an innovation system functions approach and probes into the question of how China has been taking advantage of emerging technologies to overcome its challenges of building up a complete innovation system in developing mAbs. METHODS: Mixed research methods were applied by combining archival data and field interviews. Archival data from the China Food and Drug Administration, Web of Science, the United States Patent and Trademark Office, the Chinese Clinical Trial Registry, and the National Science and Technology Report Service were used to examine the status quo of the technology and research and development (R&D) activities in China, while the opinions of researchers and managers in this field were synthesized from the interviews. RESULTS: From the perspective of innovation system functions, technological development of mAb in China is being driven by incentives such as the subsidies from the State and corporate R&D funding. Knowledge diffusion has been well served over the last 10 years through exchanging information on networks and technology transfer with developed countries. The State has provided clear guidance on search of emerging mAb technologies. Legitimacy of mAb in China has gained momentum owing to the implementation of government policies stipulated in the "The Eleventh Five-year Plan" in 2007, as well as national projects such as the "973 Program" and "863 Program", among others. The potential of market formation stays high because of the rising local demand and government support. Entrepreneurial activities for mAb continue to prosper. In addition, the situation of resource supply has been improved with the support of the State. CONCLUSIONS: This study finds that a complete innovation system for mAb has begun to take shape in China. MAb innovators in China are capitalizing on this emerging technological opportunity to participate in the global drive of developing the value chain for the innovative drug. In the long run, the build-up of the research system for mAb in China could bring about more driving forces to the mAb innovation system. PMID- 26537660 TI - Determinants of residual viraemia during combination HIV treatment: Impacts of baseline HIV RNA levels and treatment choice. AB - OBJECTIVES: Effective HIV therapy reflects suppression of plasma HIV RNA levels below assay detection thresholds, although lower levels of "residual viraemia" have also been demonstrated over extended periods of effective antiretroviral treatment. Here we examine the determinants of HIV RNA suppression below the standard assay threshold (40 HIV-1 RNA copies/mL) as well as factors associated with detectable HIV RNA below this reported detection limit. METHODS: Between 2007 and 2010, 11 575 consecutive viral load (VL) tests were obtained from 1540 patients, including 356 on effective antiretroviral therapy followed since initiation (1996-2001: n = 165; 2002-2009: n = 191). Analyses modelled the probability of an undetectable VL given successful suppression to < 200 copies/mL, and the probability of residual viraemia given an undetectable result. RESULTS: Detectable HIV RNA amplification was demonstrated in 20% of samples with a VL result < 40 copies/mL. Longitudinal analyses from 356 patients revealed that the likelihood of achieving results < 40 copies/mL was increased with current nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy [odds ratio (OR) 2.0; P < 0.05] and reduced with prior virological rebound (OR 0.5; P < 0.05). In contrast, the presence of detectable HIV RNA < 40 copies/mL was strongly associated with pretreatment HIV RNA levels among those on current protease inhibitor (PI) treatment (OR 1.5 per log10 copies/mL increase; P = 0.02) as well as those on NNRTIs (OR 1.7; P = 0.002). CONCLUSIONS: While HIV treatment history was associated with plasma HIV RNA levels below the detection limit, residual viraemia results were dominantly determined by pretreatment VL. These findings support the concept of a stable, long-lived reservoir of latently infected cells as a source of residual viraemia despite effective HIV treatment. PMID- 26537661 TI - Long-Term Intrathecal Analgesia With a Wireless Analgesia Pump System in the Home Care of Patients With Advanced Cancer. AB - BACKGROUND: Intrathecal analgesia is more effective than conservative delivery methods such as drugs administered orally or intravenously. Programmable devices such as Medtronic's SynchroMed systems have often been applied for long-term intrathecal analgesia. However, the totally implanted systems are very expensive in China. Considering cost-effectiveness, a reliable transmission protocol for a ZigBee-Based wireless analgesia pump system was used for long-term intrathecal analgesia in the home care of patients. METHODS: We retrospectively investigated the efficacy, side effects, and complications of long-term intrathecal analgesia in the home care of patients via the wireless analgesia pump system. Follow-up visits occurred monthly for the initial 3 months after implantation and then every 3 months until patient death, withdrawal from the study, or removal of the device by a designated staff. At each follow-up visit, daily average pain score, pain frequency, satisfaction level, Spitzer Quality of Life Index, and side effects for every patient were recorded. RESULTS: Pain intensity and frequency were significantly decreased by intrathecal analgesia via a wireless analgesia pump system. There were no significant differences in the satisfaction levels between hospitalization and each follow-up visit. The Spitzer Quality of Life Indexes were improved compared with patients who were hospitalized. No serious side effects were observed in this study. CONCLUSION: Intrathecal analgesia is an effective and safe method for control of refractory cancer pain, and wireless analgesia pump systems can be safely and effectively used for long-term intrathecal analgesia management in the home care of patients with advanced cancer. PMID- 26537663 TI - Pseudofulvibacter gastropodicola sp. nov., isolated from a marine conch and emended descriptions of the genus Pseudofulvibacter Yoon et al. 2013 and Pseudofulvibacter geojedonensis. AB - A Gram-stain-negative, aerobic, rod-shaped and non-motile marine bacterium, designated MEBiC08749T, was isolated from a marine conch collected at Samcheok Port in the East Sea, Korea (also known as the Sea of Japan). 16S rRNA gene sequence analysis revealed that strain MEBiC08749T shared highest similarity with Pseudofulvibacter geojedonensis YCS-9T (94.9 %). Growth was observed at 5-31 degrees C (optimum, 25 degrees C), at pH 6.0-8.5 (optimum, pH 7.5) and with 0-6 % (w/v) NaCl (optimum, 2.5 %). The predominant cellular fatty acids were iso-C15 : 0, iso-C15 : 1 G, iso-C15 : 0 3-OH, iso-C17 : 0 3-OH, summed feature 3 (comprising C16 : 1omega6c and/or C16 : 1omega7c) and summed feature 9 (comprising 10-methyl C16 : 0 and/or iso-C17 : 1omega9c). The DNA G+C content was 30 mol%. The only respiratory quinone was menaquinone-6 (MK-6). Phosphatidylethanolamine, two unidentified lipids and two unidentified aminolipids were detected as major polar lipids. Several phenotypic characteristics, such as production of acetoin, activity of cystine arylamidase, utilization of some carbohydrates, organic acids and amino acids, differentiated strain MEBiC08749T from P. geojedonensis KCTC 23884T. On the basis of data from this polyphasic taxonomic study, strain MEBiC08749T should be classified as representing a novel species in the genus Pseudofulvibacter, for which the name Pseudofulvibacter gastropodicola sp. nov. is proposed. The type strain is MEBiC08749T ( = KCCM 43046T = JCM 30369T). Emended descriptions of the genus PseudofulvibacterYoon et al. 2013 and of Pseudofulvibacter geojedonensis are also given. PMID- 26537662 TI - Synapse-specific expression of calcium-permeable AMPA receptors in neocortical layer 5. AB - KEY POINTS: In the hippocampus, calcium-permeable AMPA receptors have been found in a restricted subset of neuronal types that inhibit other neurons, although their localization in the neocortex is less well understood. In the present study, we looked for calcium-permeable AMPA receptors in two distinct populations of neocortical inhibitory neurons: basket cells and Martinotti cells. We found them in the former but not in the latter. Furthermore, in basket cells, these receptors were associated with particularly fast responses. Computer modelling predicted (and experiments verified) that fast calcium-permeable AMPA receptors enable basket cells to respond rapidly, such that they promptly inhibit neighbouring cells and shut down activity. The results obtained in the present study help our understanding of pathologies such as stroke and epilepsy that have been associated with disordered regulation of calcium-permeable AMPA receptors. ABSTRACT: AMPA-type glutamate receptors (AMPARs) lacking an edited GluA2 subunit are calcium-permeable (CP) and contribute to synaptic plasticity in several hippocampal interneuron types, although their precise role in the neocortex is not well described. We explored the presence of CP-AMPARs at pyramidal cell (PC) inputs to Martinotti cells (MCs) and basket cells (BCs) in layer 5 of the developing mouse visual cortex (postnatal days 12-21). GluA2 immunolabelling was stronger in MCs than in BCs. A differential presence of CP-AMPARs at PC-BC and PC MC synapses was confirmed electrophysiologically, based on measures of spermine dependent rectification and CP-AMPAR blockade by 1-naphtyl acetyl spermine using recordings from synaptically connected cell pairs, NPEC-AMPA uncaging and miniature current recordings. In addition, CP-AMPAR expression in BCs was correlated with rapidly decaying synaptic currents. Computer modelling predicted that this reduces spike latencies and sharpens suprathreshold responses in BCs, which we verified experimentally using the dynamic clamp technique. Thus, the synapse-specific expression of CP-AMPARs may critically influence both plasticity and information processing in neocortical microcircuits. PMID- 26537664 TI - A treatment algorithm to identify therapeutic approaches for leg ulcers in patients with sickle cell disease. AB - Sickle cell leg ulcers (SCLUs) are a common complication of sickle cell disease (SCD). Patients who develop ulcers appear to have a more severe haemolysis associated vasculopathy than individuals who do not develop them, and manifest other complications such as priapism and pulmonary hypertension. SCLUs are slow to heal and often recur, affecting both the emotional and physical well-being of patients. Here we summarise what is known about the pathophysiology of SCLUs, describe available treatment options and propose a treatment algorithm. PMID- 26537665 TI - MEFV gene mutation in two cases of pyoderma gangrenosum with aseptic arthritis. PMID- 26537666 TI - An overview of the safety and biological effects of Bacillus thuringiensis Cry toxins in mammals. AB - Crystal proteins (Cry) produced during the growth and sporulation phases of Bacillus thuringiensis (Bt) bacterium are known as delta endotoxins. These toxins are being used worldwide as bioinsecticides to control pests in agriculture, and some Cry toxins are used against mosquitoes to control vector transmission. This review summarizes the relevant information currently available regarding the biosafety and biological effects that Bt and its insecticidal Cry proteins elicit in mammals. This work was performed because of concerns regarding the possible health impact of Cry toxins on vertebrates, particularly because Bt toxins might be associated with immune-activating or allergic responses. The controversial data published to date are discussed in this review considering earlier toxicological studies of B. thuringiensis, spores, toxins and Bt crops. We discussed the experimental studies performed in humans, mice, rats and sheep as well as in diverse mammalian cell lines. Although the term 'toxic' is not appropriate for defining the effects these toxins have on mammals, they cannot be considered innocuous, as they have some physiological effects that may become pathological; thus, trials that are more comprehensive are necessary to determine their effects on mammals because knowledge in this field remains limited. PMID- 26537667 TI - Neuropathic Pain Features in Patients with Bone Metastases. AB - AIMS: The results of previous randomised controlled trials suggest that radiation oncologists should consider the presence of neuropathic pain when they prescribe dose fractionations for painful bone metastases. Although validated screening tools for neuropathic pain features are currently available, the prevalence of such features among patients with painful bone metastases is still poorly understood. The purpose of this study was to estimate the prevalence of neuropathic pain features among patients who received palliative radiotherapy for painful bone metastases. MATERIALS AND METHODS: We conducted a cohort survey of consecutive patients who received palliative radiotherapy for painful bone metastases at St Luke's International Hospital between 2013 and 2014. Patients were prospectively assessed before radiotherapy using the validated screening questionnaire to identify neuropathic pain components in Japanese patients. Pain with neuropathic features was prospectively defined using the total score of the seven-item questionnaire and a cut-off score >=9. The pain response was assessed 2 months after the start of radiotherapy according to the criteria defined by the International Bone Metastases Consensus Working Party. RESULTS: Eighty-seven patients were assessed. Twenty-four per cent of patients (95% confidence interval: 16-35%) were diagnosed as having pain with neuropathic features. On multivariate analysis, no significant correlations were seen between neuropathic pain features and patient characteristics. Sixty-four patients (74%) were assessable 2 months after the start of radiotherapy. Overall response rates were 59% (95% confidence interval: 33-82%) in patients with neuropathic features and 55% (95% confidence interval: 40-70%) in those without such features. CONCLUSIONS: A considerable proportion of the patients were proven to have bone pain with neuropathic features. Further investigations are warranted to validate symptom assessment tools in cooperation with pain distribution and image findings, and to clarify if the presence of neuropathic pain affects the response to palliative radiotherapy. PMID- 26537668 TI - The Frenkel Line: a direct experimental evidence for the new thermodynamic boundary. AB - Supercritical fluids play a significant role in elucidating fundamental aspects of liquid matter under extreme conditions. They have been extensively studied at pressures and temperatures relevant to various industrial applications. However, much less is known about the structural behaviour of supercritical fluids and no structural crossovers have been observed in static compression experiments in any temperature and pressure ranges beyond the critical point. The structure of supercritical state is currently perceived to be uniform everywhere on the pressure-temperature phase diagram, and to change only in a monotonic way even moving around the critical point, not only along isotherms or isobars. Conversely, we observe structural crossovers for the first time in a deeply supercritical sample through diffraction measurements in a diamond anvil cell and discover a new thermodynamic boundary on the pressure-temperature diagram. We explain the existence of these crossovers in the framework of the phonon theory of liquids using molecular dynamics simulations. The obtained results are of prime importance since they imply a global reconsideration of the mere essence of the supercritical phase. Furthermore, this discovery may pave the way to new unexpected applications and to the exploration of exotic behaviour of confined fluids relevant to geo- and planetary sciences. PMID- 26537669 TI - The dune effect on sand-transporting winds on Mars. AB - Wind on Mars is a significant agent of contemporary surface change, yet the absence of in situ meteorological data hampers the understanding of surface atmospheric interactions. Airflow models at length scales relevant to landform size now enable examination of conditions that might activate even small-scale bedforms (ripples) under certain contemporary wind regimes. Ripples have the potential to be used as modern 'wind vanes' on Mars. Here we use 3D airflow modelling to demonstrate that local dune topography exerts a strong influence on wind speed and direction and that ripple movement likely reflects steered wind direction for certain dune ridge shapes. The poor correlation of dune orientation with effective sand-transporting winds suggests that large dunes may not be mobile under modelled wind scenarios. This work highlights the need to first model winds at high resolution before inferring regional wind patterns from ripple movement or dune orientations on the surface of Mars today. PMID- 26537670 TI - Circulating microRNAs correlated with the level of coronary artery calcification in symptomatic patients. AB - The purpose of this study was to find the circulating microRNAs (miRNAs) co related with the severity of coronary artery calcification (CAC), and testify whether the selected miRNAs could reflect the obstructive coronary artery disease in symptomatic patients. Patients with chest pain and moderated risk for coronary artery disease (CAD) were characterized with coronary artery calcium score (CACS) from cardiac computed tomography (CT). We analyzed plasma miRNA levels of clinical matched 11 CAC (CACS > 100) and 6 non-CAC (CACS = 0) subjects by microarray profile. Microarray analysis identified 34 differentially expressed miRNAs between CAC and non CAC groups. Eight miRNAs (miR-223, miR-3135b, miR-133a 3p, miR-2861, miR-134, miR-191-3p, miR-3679-5p, miR-1229 in CAC patients) were significantly increased in CAC plasma in an independent clinical matched cohort. Four miRNAs (miR-2861, 134, 1229 and 3135b) were correlated with the degree of CAC. Validation test in angiographic cohort showed that miR-134, miR-3135b and miR-2861 were significantly changed in patients with obstructive CAD . We identified three significantly upregulated circulating miRNAs (miR-134, miR-3135b and 2861) correlated with CAC while detected obstructive coronary disease in symptomatic patients. PMID- 26537671 TI - Efficacy of Selected Insecticides Applied to Hybrid Rice Seed. AB - Hybrid rice and insecticide seed treatments targeting rice water weevil, Lissorhoptrus oryzophilus Kuschel, have altered the landscape of rice production. The effect of reduced seeding rates on seed treatment efficacy in hybrid rice has not been studied. During 2011 and 2012, an experiment was conducted at seven locations to determine the relationship between low seeding rates used in hybrid rice and efficacy of selected insecticidal seed treatments as measured by rice water weevil densities and yield. Labeled rates of thiamethoxam, chlorantraniliprole, and clothianidin were compared with higher rates of these products to determine if labeled rates provide an acceptable level of control of the rice water weevil. Study locations were divided into low, moderate, and high groups based on rice water weevil larval densities. All seed treatments and seed treatment rates reduced rice water weevil densities. However, there was no observed yield or economic benefit from the use of an insecticidal seed treatment in areas of low pressure. Differences in yield were observed among seed treatments and seed treatment rates in moderate and high pressure locations, and all seed treatments yielded better than the untreated plots, but these differences were not always economical. All seed treatments showed an economic advantage in areas of high weevil pressure, and there were no differences among seed treatment products or rates, suggesting that currently labeled seed treatment rates in hybrid rice are effective for rice water weevil management. PMID- 26537672 TI - Small Interfering RNA Pathway Modulates Initial Viral Infection in Midgut Epithelium of Insect after Ingestion of Virus. AB - Numerous viruses are transmitted in a persistent manner by insect vectors. Persistent viruses establish their initial infection in the midgut epithelium, from where they disseminate to the midgut visceral muscles. Although propagation of viruses in insect vectors can be controlled by the small interfering RNA (siRNA) antiviral pathway, whether the siRNA pathway can control viral dissemination from the midgut epithelium is unknown. Infection by a rice virus (Southern rice black streaked dwarf virus [SRBSDV]) of its incompetent vector (the small brown planthopper [SBPH]) is restricted to the midgut epithelium. Here, we show that the siRNA pathway is triggered by SRBSDV infection in continuously cultured cells derived from the SBPH and in the midgut of the intact insect. Knockdown of the expression of the core component Dicer-2 of the siRNA pathway by RNA interference strongly increased the ability of SRBSDV to propagate in continuously cultured SBPH cells and in the midgut epithelium, allowing viral titers in the midgut epithelium to reach the threshold (1.99 * 10(9) copies of the SRBSDV P10 gene/MUg of midgut RNA) needed for viral dissemination into the SBPH midgut muscles. Our results thus represent the first elucidation of the threshold for viral dissemination from the insect midgut epithelium. Silencing of Dicer-2 further facilitated the transmission of SRBSDV into rice plants by SBPHs. Taken together, our results reveal the new finding that the siRNA pathway can control the initial infection of the insect midgut epithelium by a virus, which finally affects the competence of the virus's vector. IMPORTANCE: Many viral pathogens that cause significant global health and agricultural problems are transmitted via insect vectors. The first bottleneck in viral infection, the midgut epithelium, is a principal determinant of the ability of an insect species to transmit a virus. Southern rice black streaked dwarf virus (SRBSDV) is restricted exclusively to the midgut epithelium of an incompetent vector, the small brown planthopper (SBPH). Here, we show that silencing of the core component Dicer-2 of the small interfering RNA (siRNA) pathway increases viral titers in the midgut epithelium past the threshold (1.99 * 10(9) copies of the SRBSDV P10 gene/MUg of midgut RNA) for viral dissemination into the midgut muscles and then into the salivary glands, allowing the SBPH to become a competent vector of SRBSDV. This result is the first evidence that the siRNA antiviral pathway has a direct role in the control of viral dissemination from the midgut epithelium and that it affects the competence of the virus's vector. PMID- 26537673 TI - HIV-1 Vpr- and Reverse Transcription-Induced Apoptosis in Resting Peripheral Blood CD4 T Cells and Protection by Common Gamma-Chain Cytokines. AB - HIV-1 infection leads to the progressive depletion of the CD4 T cell compartment by various known and unknown mechanisms. In vivo, HIV-1 infects both activated and resting CD4 T cells, but in vitro, in the absence of any stimuli, resting CD4 T cells from peripheral blood are resistant to infection. This resistance is generally attributed to an intracellular environment that does not efficiently support processes such as reverse transcription (RT), resulting in abortive infection. Here, we show that in vitro HIV-1 infection of resting CD4 T cells induces substantial cell death, leading to abortive infection. In vivo, however, various microenvironmental stimuli in lymphoid and mucosal tissues provide support for HIV-1 replication. For example, common gamma-chain cytokines (CGCC), such as interleukin-7 (IL-7), render resting CD4 T cells permissible to HIV-1 infection without inducing T cell activation. Here, we find that CGCC primarily allow productive infection by preventing HIV-1 triggering of apoptosis, as evidenced by early release of cytochrome c and caspase 3/7 activation. Cell death is triggered both by products of reverse transcription and by virion-borne Vpr protein, and CGCC block both mechanisms. When HIV-1 RT efficiency was enhanced by SIVmac239 Vpx protein, cell death was still observed, indicating that the speed of reverse transcription and the efficiency of its completion contributed little to HIV-1-induced cell death in this system. These results show that a major restriction on HIV-1 infection in resting CD4 T cells resides in the capacity of these cells to survive the early steps of HIV-1 infection. IMPORTANCE: A major consequence of HIV-1 infection is the destruction of CD4 T cells. Here, we show that delivery of virion-associated Vpr protein and the process of reverse transcription are each sufficient to trigger apoptosis of resting CD4 T cells isolated from peripheral blood. While these 2 mechanisms have been previously described in various cell types, we show for the first time their concerted effect in inducing resting CD4 T cell depletion. Importantly, we found that cytokines such as IL-7 and IL-4, which are particularly active in sites of HIV-1 replication, protect resting CD4 T cells from these cytopathic effects and, primarily through this protection, rather than through enhancement of specific replicative steps, they promote productive infection. This study provides important new insights for the understanding of the early steps of HIV-1 infection and T cell depletion. PMID- 26537674 TI - Specialization of Hepatitis C Virus Envelope Glycoproteins for B Lymphocytes in Chronically Infected Patients. AB - Hepatitis C virus (HCV) productively infects hepatocytes. Virion surface glycoproteins E1 and E2 play a major role in this restricted cell tropism by mediating virus entry into particular cell types. However, several pieces of evidence have suggested the ability of patient-derived HCV particles to infect peripheral blood mononuclear cells. The viral determinants and mechanisms mediating such events remain poorly understood. Here, we aimed at isolating viral determinants of HCV entry into B lymphocytes. For this purpose, we constructed a library of full E1E2 sequences isolated from serum and B lymphocytes of four chronically infected patients. We observed a strong phylogenetic compartmentalization of E1E2 sequences isolated from B lymphocytes in one patient, indicating that E1E2 glycoproteins can represent important mediators of the strong segregation of two specialized populations in some patients. Most of the E1E2 envelope glycoproteins were functional and allowed transduction of hepatocyte cell lines using HCV-derived pseudoparticles. Strikingly, introduction of envelope glycoproteins isolated from B lymphocytes into the HCV JFH-1 replicating virus switched the entry tropism of this nonlymphotropic virus from hepatotropism to lymphotropism. Significant detection of viral RNA and viral proteins within B cells was restricted to infections with JFH-1 harboring E1E2 from lymphocytes and depended on an endocytic, pH-dependent entry pathway. Here, we achieved for the first time the isolation of HCV viral proteins carrying entry related lymphotropism determinants. The identification of genetic determinants within E1E2 represents a first step for a better understanding of the complex relationship between HCV infection, viral persistence, and extrahepatic disorders. IMPORTANCE: Hepatitis C virus (HCV) mainly replicates within the liver. However, it has been shown that patient-derived HCV particles can slightly infect lymphocytes in vitro and in vivo, highlighting the existence of lymphotropism determinants within HCV viral proteins. We isolated HCV envelope glycoproteins from patient B lymphocytes that conferred to a nonlymphotropic HCV the ability to enter B cells, thus providing a platform for characterization of HCV entry into lymphocytes. This unusual tropism was accompanied by a loss of entry function into hepatocytes, suggesting that HCV lymphotropic variants likely constitute a distinct but parallel source for viral persistence and immune escape within chronically infected patients. Moreover, the level of genetic divergence of B-cell-derived envelopes correlated with their degree of lymphotropism, underlining a long-term specialization of some viral populations for B lymphocytes. Consequently, the clearance of both hepatotropic and nonhepatotropic HCV populations may be important for effective treatment of chronically infected patients. PMID- 26537675 TI - KAP1 Is a Host Restriction Factor That Promotes Human Adenovirus E1B-55K SUMO Modification. AB - Once transported to the replication sites, human adenoviruses (HAdVs) need to ensure decondensation and transcriptional activation of their viral genomes to synthesize viral proteins and initiate steps to reprogram the host cell for viral replication. These early stages during adenoviral infection are poorly characterized but represent a decisive moment in the establishment of a productive infection. Here, we identify a novel host viral restriction factor, KAP1. This heterochromatin-associated transcription factor regulates the dynamic organization of the host chromatin structure via its ability to influence epigenetic marks and chromatin compaction. In response to DNA damage, KAP1 is phosphorylated and functionally inactive, resulting in chromatin relaxation. We discovered that KAP1 posttranslational modification is dramatically altered during HAdV infection to limit the antiviral capacity of this host restriction factor, which represents an essential step required for efficient viral replication. Conversely, we also observed during infection an HAdV-mediated decrease of KAP1 SUMO moieties, known to promote chromatin decondensation events. Based on our findings, we provide evidence that HAdV induces KAP1 deSUMOylation to minimize epigenetic gene silencing and to promote SUMO modification of E1B-55K by a so far unknown mechanism. IMPORTANCE: Here we describe a novel cellular restriction factor for human adenovirus (HAdV) that sheds light on very early modulation processes in viral infection. We reported that chromatin formation and cellular SWI/SNF chromatin remodeling play key roles in HAdV transcriptional regulation. We observed that the cellular chromatin-associated factor and epigenetic reader SPOC1 represses HAdV infection and gene expression. Here, we illustrate the role of the SPOC1-interacting factor KAP1 during productive HAdV growth. KAP1 binds to the viral E1B-55K protein, promoting its SUMO modification, therefore illustrating a crucial step for efficient viral replication. Simultaneously, KAP1 posttranslational modification is dramatically altered during infection. We observed an HAdV-mediated decrease in KAP1 SUMOylation, known to promote chromatin decondensation events. These findings indicate that HAdV induces the loss of KAP1 SUMOylation to minimize epigenetic gene silencing and to promote the SUMO modification of E1B-55K by a so far unknown mechanism. PMID- 26537676 TI - Identification of an HIV-1 Mutation in Spacer Peptide 1 That Stabilizes the Immature CA-SP1 Lattice. AB - Upon release of HIV-1 particles from the infected cell, the viral protease cleaves the Gag polyprotein at specific sites, triggering maturation. During this process, which is essential for infectivity, the capsid protein (CA) reassembles into a conical core. Maturation inhibitors (MIs) block HIV-1 maturation by interfering with protease-mediated CA-spacer peptide 1 (CA-SP1) processing, concomitantly stabilizing the immature CA-SP1 lattice; virions from MI-treated cells retain an immature-like CA-SP1 lattice, whereas mutational abolition of cleavage at the CA-SP1 site results in virions in which the CA-SP1 lattice converts to a mature-like form. We previously reported that propagation of HIV-1 in the presence of MI PF-46396 selected for assembly-defective, compound dependent mutants with amino acid substitutions in the major homology region (MHR) of CA. Propagation of these mutants in the absence of PF-46396 resulted in the acquisition of second-site compensatory mutations. These included a Thr-to Ile substitution at SP1 residue 8 (T8I), which results in impaired CA-SP1 processing. Thus, the T8I mutation phenocopies PF-46396 treatment in terms of its ability to rescue the replication defect imposed by the MHR mutations and to impede CA-SP1 processing. Here, we use cryo-electron tomography to show that, like MIs, the T8I mutation stabilizes the immature-like CA-SP1 lattice. These results have important implications for the mechanism of action of HIV-1 MIs; they also suggest that T8I may provide a valuable tool for structural definition of the CA-SP1 boundary region, which has thus far been refractory to high resolution analysis, apparently because of conformational flexibility in this region of Gag. IMPORTANCE: HIV-1 maturation involves dissection of the Gag polyprotein by the viral protease and assembly of a conical capsid enclosing the viral ribonucleoprotein. Maturation inhibitors (MIs) prevent the final cleavage step at the site between the capsid protein (CA) and spacer peptide 1 (SP1), apparently by binding at this site and denying the protease access. Additionally, MIs stabilize the immature-like CA-SP1 lattice, preventing release of CA into the soluble pool. We previously found that T8I, a mutation in SP1, rescues a PF-46396 dependent CA mutant and blocks CA-SP1 cleavage. In this study, we imaged T8I virions by cryo-electron tomography and showed that T8I mutants, like MI-treated virions, contain an immature CA-SP1 lattice. These results lay the groundwork needed to understand the structure of the CA-SP1 interface region and further illuminate the mechanism of action of MIs. PMID- 26537677 TI - Induction of the Lytic Cycle Sensitizes Epstein-Barr Virus-Infected B Cells to NK Cell Killing That Is Counteracted by Virus-Mediated NK Cell Evasion Mechanisms in the Late Lytic Cycle. AB - Epstein-Barr Virus (EBV) persists for the lifetime of the infected host despite eliciting strong immune responses. This persistence requires a fine balance between the host immune system and EBV immune evasion. Accumulating evidence suggests an important role for natural killer (NK) cells in this balance. NK cells can kill EBV-infected cells undergoing lytic replication in vitro, and studies in both humans and mice with reconstituted human immune systems have shown that NK cells can limit EBV replication and prevent infectious mononucleosis. We now show that NK cells, via NKG2D and DNAM-1 interactions, recognize and kill EBV-infected cells undergoing lytic replication and that expression of a single EBV lytic gene, BZLF1, is sufficient to trigger sensitization to NK cell killing. We also present evidence suggesting the possibility of the existence of an as-yet-unidentified DNAM-1 ligand which may be particularly important for killing lytically infected normal B cells. Furthermore, while cells entering the lytic cycle become sensitized to NK cell killing, we observed that cells in the late lytic cycle are highly resistant. We identified expression of the vBcl-2 protein, BHRF1, as one effective mechanism by which EBV mediates this protection. Thus, contrary to the view expressed in some reports, EBV has evolved the ability to evade NK cell responses. IMPORTANCE: This report extends our understanding of the interaction between EBV and host innate responses. It provides the first evidence that the susceptibility to NK cell lysis of EBV-infected B cells undergoing lytic replication is dependent upon the phase of the lytic cycle. Induction of the lytic cycle is associated with acquired sensitization to NK cell killing, while progress through the late lytic cycle is associated with acquired resistance to killing. We provide mechanistic explanations for this novel observation, indicating important roles for the BZLF1 immediate early transactivator, the BHRF1 vBcl-2 homologue, and a novel ligand for the DNAM-1 NK cell receptor. PMID- 26537678 TI - A Betabaculovirus-Encoded gp64 Homolog Codes for a Functional Envelope Fusion Protein. AB - The GP64 envelope fusion protein is a hallmark of group I alphabaculoviruses. However, the Diatraea saccharalis granulovirus genome sequence revealed the first betabaculovirus species harboring a gp64 homolog (disa118). In this work, we have shown that this homolog encodes a functional envelope fusion protein and could enable the infection and fusogenic abilities of a gp64-null prototype baculovirus. Therefore, GP64 may complement or may be in the process of replacing F protein activity in this virus lineage. PMID- 26537679 TI - Functional Characterization of the Serine-Rich Tract of Varicella-Zoster Virus IE62. AB - The immediate early 62 protein (IE62) of varicella-zoster virus (VZV), a major viral trans-activator, initiates the virus life cycle and is a key component of pathogenesis. The IE62 possesses several domains essential for trans-activation, including an acidic trans-activation domain (TAD), a serine-rich tract (SRT), and binding domains for USF, TFIIB, and TATA box binding protein (TBP). Transient transfection assays showed that the VZV IE62 lacking the SRT trans-activated the early VZV ORF61 promoter at only 16% of the level of the full-length IE62. When the SRT of IE62 was replaced with the SRT of equine herpesvirus 1 (EHV-1) IEP, its trans-activation activity was completely restored. Herpes simplex virus 1 (HSV-1) ICP4 that lacks a TAD very weakly (1.5-fold) trans-activated the ORF61 promoter. An IE62 TAD-ICP4 chimeric protein exhibited trans-activation ability (10.2-fold), indicating that the IE62 TAD functions with the SRT of HSV-1 ICP4 to trans-activate viral promoters. When the serine and acidic residues of the SRT were replaced with Ala, Leu, and Gly, trans-activation activities of the modified IE62 proteins IE62-SRTDeltaSe and IE62-SRTDeltaAc were reduced to 46% and 29% of wild-type activity, respectively. Bimolecular complementation assays showed that the TAD of IE62, EHV-1 IEP, and HSV-1 VP16 interacted with Mediator 25 in human melanoma MeWo cells. The SRT of IE62 interacted with the nucleolar-ribosomal protein EAP, which resulted in the formation of globular structures within the nucleus. These results suggest that the SRT plays an important role in VZV viral gene expression and replication. IMPORTANCE: The immediate early 62 protein (IE62) of varicella-zoster virus (VZV) is a major viral trans-activator and is essential for viral growth. Our data show that the serine-rich tract (SRT) of VZV IE62, which is well conserved within the alphaherpesviruses, is needed for trans activation mediated by the acidic trans-activation domain (TAD). The TADs of IE62, EHV-1 IEP, and HSV-1 VP16 interacted with cellular Mediator 25 in bimolecular complementation assays. The interaction of the IE62 SRT with nucleolar-ribosomal protein EAP resulted in the formation of globular structures within the nucleus. Understanding the mechanisms by which the TAD and SRT of IE62 contribute to the function of this essential regulatory protein is important in understanding the gene program of this human pathogen. PMID- 26537680 TI - Priming of the Respiratory Tract with Immunobiotic Lactobacillus plantarum Limits Infection of Alveolar Macrophages with Recombinant Pneumonia Virus of Mice (rK2 PVM). AB - Pneumonia virus of mice (PVM) is a natural rodent pathogen that replicates in bronchial epithelial cells and reproduces many clinical and pathological features of the more severe forms of disease associated with human respiratory syncytial virus. In order to track virus-target cell interactions during acute infection in vivo, we developed rK2-PVM, bacterial artificial chromosome-based recombinant PVM strain J3666 that incorporates the fluorescent tag monomeric Katushka 2 (mKATE2). The rK2-PVM pathogen promotes lethal infection in BALB/c mice and elicits characteristic cytokine production and leukocyte recruitment to the lung parenchyma. Using recombinant virus, we demonstrate for the first time PVM infection of both dendritic cells (DCs; CD11c(+) major histocompatibility complex class II(+)) and alveolar macrophages (AMs; CD11c(+) sialic acid-binding immunoglobulin-like lectin F(+)) in vivo and likewise detect mKATE2(+) DCs in mediastinal lymph nodes from infected mice. AMs support both active virus replication and production of infectious virions. Furthermore, we report that priming of the respiratory tract with immunobiotic Lactobacillus plantarum, a regimen that results in protection against the lethal inflammatory sequelae of acute respiratory virus infection, resulted in differential recruitment of neutrophils, DCs, and lymphocytes to the lungs in response to rK2-PVM and a reduction from ~ 40% to <10% mKATE2(+) AMs in association with a 2-log drop in the release of infectious virions. In contrast, AMs from L. plantarum-primed mice challenged with virus ex vivo exhibited no differential susceptibility to rK2 PVM. Although the mechanisms underlying Lactobacillus-mediated viral suppression remain to be fully elucidated, this study provides insight into the cellular basis of this response. IMPORTANCE: Pneumonia virus of mice (PVM) is a natural mouse pathogen that serves as a model for severe human respiratory syncytial virus disease. We have developed a fully functional recombinant PVM strain with a fluorescent reporter protein (rK2-PVM) that permits us to track infection of target cells in vivo. With rK2-PVM, we demonstrate infection of leukocytes in the lung, notably, dendritic cells and alveolar macrophages. Alveolar macrophages undergo productive infection and release infectious virions. We have shown previously that administration of immunobiotic Lactobacillus directly to the respiratory mucosa protects mice from the lethal sequelae of PVM infection in association with profound suppression of the virus-induced inflammatory response. We show here that Lactobacillus administration also limits infection of leukocytes in vivo and results in diminished release of infectious virions from alveolar macrophages. This is the first study to provide insight into the cellular basis of the antiviral impact of immunobiotic L. plantarum. PMID- 26537681 TI - Correlation between Virus Replication and Antibody Responses in Macaques following Infection with Pandemic Influenza A Virus. AB - Influenza virus infection of nonhuman primates is a well-established animal model for studying pathogenesis and for evaluating prophylactic and therapeutic intervention strategies. However, usually a standard dose is used for the infection, and there is no information on the relation between challenge dose and virus replication or the induction of immune responses. Such information is also very scarce for humans and largely confined to evaluation of attenuated virus strains. Here, we have compared the effect of a commonly used dose (4 * 10(6) 50% tissue culture infective doses) versus a 100-fold-higher dose, administered by intrabronchial installation, to two groups of 6 cynomolgus macaques. Animals infected with the high virus dose showed more fever and had higher peak levels of gamma interferon in the blood. However, virus replication in the trachea was not significantly different between the groups, although in 2 out of 6 animals from the high-dose group it was present at higher levels and for a longer duration. The virus-specific antibody response was not significantly different between the groups. However, antibody enzyme-linked immunosorbent assay, virus neutralization, and hemagglutination inhibition antibody titers correlated with cumulative virus production in the trachea. In conclusion, using influenza virus infection in cynomolgus macaques as a model, we demonstrated a relationship between the level of virus production upon infection and induction of functional antibody responses against the virus. IMPORTANCE: There is only very limited information on the effect of virus inoculation dose on the level of virus production and the induction of adaptive immune responses in humans or nonhuman primates. We found only a marginal and variable effect of virus dose on virus production in the trachea but a significant effect on body temperature. The induction of functional antibody responses, including virus neutralization titer, hemagglutination inhibition titer, and antibody-dependent cell-mediated cytotoxicity, correlated with the level of virus replication measured in the trachea. The study reveals a relationship between virus production and functional antibody formation, which could be relevant in defining appropriate criteria for new influenza virus vaccine candidates. PMID- 26537682 TI - A Subset of CD4/CD8 Double-Negative T Cells Expresses HIV Proteins in Patients on Antiretroviral Therapy. AB - A major goal in HIV eradication research is characterizing the reservoir cells that harbor HIV in the presence of antiretroviral therapy (ART), which reseed viremia after treatment is stopped. In general, it is assumed that the reservoir consists of CD4(+) T cells that express no viral proteins. However, recent findings suggest that this may be an overly simplistic view and that the cells that contribute to the reservoir may be a diverse population that includes both CD4(+) and CD4(-) cells. In this study, we directly infected resting CD4(+) T cells and used fluorescence-activated cell sorting (FACS) and fiber-optic array scanning technology (FAST) to identify and image cells expressing HIV Gag. We found that Gag expression from integrated proviruses occurred in resting cells that lacked surface CD4, likely resulting from Nef- and Env-mediated receptor internalization. We also extended our approach to detect cells expressing HIV proteins in patients suppressed on ART. We found evidence that rare Gag(+) cells persist during ART and that these cells are often negative for CD4. We propose that these double-negative alpha/beta T cells that express HIV protein may be a component of the long-lived reservoir. IMPORTANCE: A reservoir of infected cells persists in HIV-infected patients during antiretroviral therapy (ART) that leads to rebound of virus if treatment is stopped. In this study, we used flow cytometry and cell imaging to characterize protein expression in HIV-infected resting cells. HIV Gag protein can be directly detected in infected resting cells and occurs with simultaneous loss of CD4, consistent with the expression of additional viral proteins, such as Env and Nef. Gag(+) CD4(-) cells can also be detected in suppressed patients, suggesting that a subset of infected cells express proteins during ART. Understanding the regulation of viral protein expression during ART will be key to designing effective strategies to eradicate HIV reservoirs. PMID- 26537683 TI - Epstein-Barr Virus BZLF1-Mediated Downregulation of Proinflammatory Factors Is Essential for Optimal Lytic Viral Replication. AB - Elevated secretion of inflammatory factors is associated with latent Epstein-Barr virus (EBV) infection and the pathology of EBV-associated diseases; however, knowledge of the inflammatory response and its biological significance during the lytic EBV cycle remains elusive. Here, we demonstrate that the immediate early transcriptional activator BZLF1 suppresses the proinflammatory factor tumor necrosis factor alpha (TNF-alpha) by binding to the promoter of TNF-alpha and preventing NF-kappaB activation. A BZLF1Delta207-210 mutant with a deletion of 4 amino acids (aa) in the protein-protein binding domain was not able to inhibit the proinflammatory factors TNF-alpha and gamma interferon (IFN-gamma) and reduced viral DNA replication with complete transcriptional activity during EBV lytic gene expression. TNF-alpha depletion restored the viral replication mediated by BZLF1Delta207-210. Furthermore, a combination of TNF-alpha- and IFN gamma-neutralizing antibodies recovered BZLF1Delta207-210-mediated viral replication, indicating that BZLF1 attenuates the antiviral response to aid optimal lytic replication primarily through the inhibition of TNF-alpha and IFN gamma secretion during the lytic cycle. These results suggest that EBV BZLF1 attenuates the proinflammatory responses to facilitate viral replication. IMPORTANCE: The proinflammatory response is an antiviral and anticancer strategy following the complex inflammatory phenotype. Latent Epstein-Barr virus (EBV) infection strongly correlates with an elevated secretion of inflammatory factors in a variety of severe diseases, while the inflammatory responses during the lytic EBV cycle have not been established. Here, we demonstrate that BZLF1 acts as a transcriptional suppressor of the inflammatory factors TNF-alpha and IFN gamma and confirm that BZLF1-facilitated escape from the TNF-alpha and IFN-gamma response during the EBV lytic life cycle is required for optimal viral replication. This finding implies that the EBV lytic cycle employs a distinct strategy to evade the antiviral inflammatory response. PMID- 26537684 TI - Structural Studies of Chikungunya Virus-Like Particles Complexed with Human Antibodies: Neutralization and Cell-to-Cell Transmission. AB - Chikungunya virus is a positive-stranded RNA alphavirus. Structures of chikungunya virus-like particles in complex with strongly neutralizing antibody Fab fragments (8B10 and 5F10) were determined using cryo-electron microscopy and X-ray crystallography. By fitting the crystallographically determined structures of these Fab fragments into the cryo-electron density maps, we show that Fab fragments of antibody 8B10 extend radially from the viral surface and block receptor binding on the E2 glycoprotein. In contrast, Fab fragments of antibody 5F10 bind the tip of the E2 B domain and lie tangentially on the viral surface. Fab 5F10 fixes the B domain rigidly to the surface of the virus, blocking exposure of the fusion loop on glycoprotein E1 and therefore preventing the virus from becoming fusogenic. Although Fab 5F10 can neutralize the wild-type virus, it can also bind to a mutant virus without inhibiting fusion or attachment. Although the mutant virus is no longer able to propagate by extracellular budding, it can, however, enter the next cell by traveling through junctional complexes without being intercepted by a neutralizing antibody to the wild-type virus, thus clarifying how cell-to-cell transmission can occur. IMPORTANCE: Alphaviral infections are transmitted mainly by mosquitoes. Chikungunya virus (CHIKV), which belongs to the Alphavirus genus, has a wide distribution in the Old World that has expanded in recent years into the Americas. There are currently no vaccines or drugs against alphaviral infections. Therefore, a better understanding of CHIKV and its associated neutralizing antibodies will aid in the development of effective treatments. PMID- 26537685 TI - Structural Insights into HIV-1 Vif-APOBEC3F Interaction. AB - The HIV-1 Vif protein inactivates the cellular antiviral cytidine deaminase APOBEC3F (A3F) in virus-infected cells by specifically targeting it for proteasomal degradation. Several studies identified Vif sequence motifs involved in A3F interaction, whereas a Vif-binding A3F interface was proposed based on our analysis of highly similar APOBEC3C (A3C). However, the structural mechanism of specific Vif-A3F recognition is still poorly understood. Here we report structural features of interaction interfaces for both HIV-1 Vif and A3F molecules. Alanine-scanning analysis of Vif revealed that six residues located within the conserved Vif F1-, F2-, and F3-box motifs are essential for both A3C and A3F degradation, and an additional four residues are uniquely required for A3F degradation. Modeling of the Vif structure on an HIV-1 Vif crystal structure revealed that three discontinuous flexible loops of Vif F1-, F2-, and F3-box motifs sterically cluster to form a flexible A3F interaction interface, which represents hydrophobic and positively charged surfaces. We found that the basic Vif interface patch (R17, E171, and R173) involved in the interactions with A3C and A3F differs. Furthermore, our crystal structure determination and extensive mutational analysis of the A3F C-terminal domain demonstrated that the A3F interface includes a unique acidic stretch (L291, A292, R293, and E324) crucial for Vif interaction, suggesting additional electrostatic complementarity to the Vif interface compared with the A3C interface. Taken together, these findings provide structural insights into the A3F-Vif interaction mechanism, which will provide an important basis for development of novel anti-HIV-1 drugs using cellular cytidine deaminases. IMPORTANCE: HIV-1 Vif targets cellular antiviral APOBEC3F (A3F) enzyme for degradation. However, the details on the structural mechanism for specific A3F recognition remain unclear. This study reports structural features of interaction interfaces for both HIV-1 Vif and A3F molecules. Three discontinuous sequence motifs of Vif, F1, F2, and F3 boxes, assemble to form an A3F interaction interface. In addition, we determined a crystal structure of the wild-type A3F C-terminal domain responsible for the Vif interaction. These results demonstrated that both electrostatic and hydrophobic interactions are the key force driving Vif-A3F binding and that the Vif-A3F interfaces are larger than the Vif-A3C interfaces. These findings will allow us to determine the configurations of the Vif-A3F complex and to construct a structural model of the complex, which will provide an important basis for inhibitor development. PMID- 26537686 TI - Differential Recognition of Influenza A Viruses by M158-66 Epitope-Specific CD8+ T Cells Is Determined by Extraepitopic Amino Acid Residues. AB - Natural influenza A virus infections elicit both virus-specific antibody and CD4(+) and CD8(+) T cell responses. Influenza A virus-specific CD8(+) cytotoxic T lymphocytes (CTLs) contribute to clearance of influenza virus infections. Viral CTL epitopes can display variation, allowing influenza A viruses to evade recognition by epitope-specific CTLs. Due to functional constraints, some epitopes, like the immunodominant HLA-A*0201-restricted matrix protein 1 (M158 66) epitope, are highly conserved between influenza A viruses regardless of their subtype or host species of origin. We hypothesized that human influenza A viruses evade recognition of this epitope by impairing antigen processing and presentation by extraepitopic amino acid substitutions. Activation of specific T cells was used as an indication of antigen presentation. Here, we show that the M158-66 epitope in the M1 protein derived from human influenza A virus was poorly recognized compared to the M1 protein derived from avian influenza A virus. Furthermore, we demonstrate that naturally occurring variations at extraepitopic amino acid residues affect CD8(+) T cell recognition of the M158-66 epitope. These data indicate that human influenza A viruses can impair recognition by M158 66-specific CTLs while retaining the conserved amino acid sequence of the epitope, which may represent a yet-unknown immune evasion strategy for influenza A viruses. This difference in recognition may have implications for the viral replication kinetics in HLA-A*0201 individuals and spread of influenza A viruses in the human population. The findings may aid the rational design of universal influenza vaccines that aim at the induction of cross-reactive virus-specific CTL responses. IMPORTANCE: Influenza viruses are an important cause of acute respiratory tract infections. Natural influenza A virus infections elicit both humoral and cellular immunity. CD8(+) cytotoxic T lymphocytes (CTLs) are directed predominantly against conserved internal proteins and confer cross-protection, even against influenza A viruses of various subtypes. In some CTL epitopes, mutations occur that allow influenza A viruses to evade recognition by CTLs. However, the immunodominant HLA-A*0201-restricted M158-66 epitope does not tolerate mutations without loss of viral fitness. Here, we describe naturally occurring variations in amino acid residues outside the M158-66 epitope that influence the recognition of the epitope. These results provide novel insights into the epidemiology of influenza A viruses and their pathogenicity and may aid rational design of vaccines that aim at the induction of CTL responses. PMID- 26537687 TI - Genome-Wide Mapping of the Binding Sites and Structural Analysis of Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 2 Reveal that It Is a DNA-Binding Transcription Factor. AB - The oncogenic herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is known to encode four viral interferon regulatory factors (vIRF1 to -4) to subvert the host antiviral immune response, but their detailed DNA-binding profiles as transcription factors in the host remain uncharacterized. Here, we first performed genome-wide vIRF2-binding site mapping in the human genome using chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq). vIRF2 was capable of binding to the promoter regions of 100 putative target genes. Importantly, we confirmed that vIRF2 can specifically interact with the promoters of the genes encoding PIK3C3, HMGCR, and HMGCL, which are associated with autophagosome formation or tumor progression and metastasis, and regulate their transcription in vivo. The crystal structure of the vIRF2 DNA-binding domain (DBD) (referred to here as vIRF2DBD) showed variable loop conformations and positive-charge distributions different from those of vIRF1 and cellular IRFs that are associated with DNA-binding specificities. Structure-based mutagenesis revealed that Arg82 and Arg85 are required for the in vitro DNA-binding activity of vIRF2DBD and can abolish the transcription regulation function of vIRF2 on the promoter reporter activity of PIK3C3, HMGCR, and HMGCL. Collectively, our study provided unique insights into the DNA-binding potency of vIRF2 and suggested that vIRF2 could act as a transcription factor of its target genes in the host antiviral immune response. IMPORTANCE: The oncogenic herpesvirus KSHV is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. KSHV has developed a unique mechanism to subvert the host antiviral immune responses by encoding four homologues of cellular interferon regulatory factors (vIRF1 to -4). However, none of their DNA binding profiles in the human genome have been characterized until now, and the structural basis for their diverse DNA-binding properties remain poorly understood. In this study, we performed the first genome-wide vIRF2-binding site mapping in the human genome and found vIRF2 can bind to the promoter regions of 100 target cellular genes. X-ray structure analysis and functional studies provided unique insights into its DNA-binding potency and regulation of target gene expression. Our study suggested that vIRF2 could act as a transcription factor of its target genes and contribute to KSHV infection and pathogenesis through versatile functions. PMID- 26537688 TI - Subclinical decelerations during developing hypotension in preterm fetal sheep after acute on chronic lipopolysaccharide exposure. AB - Subclinical (shallow) heart rate decelerations occur during neonatal sepsis, but there is limited information on their relationship with hypotension or whether they occur before birth. We examined whether subclinical decelerations, a fall in fetal heart rate (FHR) that remained above 100 bpm, were associated with hypotension in preterm fetal sheep exposed to lipopolysaccharide (LPS). Chronically-instrumented fetal sheep at 0.7 gestation received continuous low dose LPS infusions (n = 15, 100 ng/kg over 24 h, followed by 250 ng/kg/24 h for 96 h) or saline (n = 8). Boluses of 1 MUg LPS or saline were given at 48 and 72 h. FHR variability (FHRV) was calculated, and sample asymmetry was used to assess the severity and frequency of decelerations. Low-dose LPS infusion did not affect FHR. After the first LPS bolus, 7 fetuses remained normotensive, while 8 developed hypotension (a fall in mean arterial blood pressure of >=5 mmHg). Developing hypotension was associated with subclinical decelerations, with a corresponding increase in sample asymmetry and FHRV (p < 0.05). The second LPS bolus was associated with similar but attenuated changes in FHR and blood pressure (p < 0.05). In conclusion, subclinical decelerations are not consistently seen during prenatal exposure to LPS, but may be a useful marker of developing inflammation-related hypotension before birth. PMID- 26537689 TI - Association between neck and shoulder pain, back pain, low back pain and body composition parameters among the Japanese general population. AB - BACKGROUND: Neck and shoulder pain, back pain and low back pain are common symptoms in Japanese subjects, and it is important to elucidate the pathology and associated factors of these pains due to their frequency and impact on the quality of life (QOL) and activities of daily living (ADL). The purpose of the present study was to investigate whether body composition is associated with these pains. METHODS: We collected the data of 273 Japanese subjects regarding the presence and the visual analogue scale (VAS) of neck and shoulder pain, back pain, low back pain and body composition parameters calculated using bioelectrical impedance analysis (BIA) technology. Furthermore, we investigated the association between these pains and the body composition using statistical methods. RESULTS: According to a multivariate analysis adjusted for age and gender, lower total body water ratio was significantly associated with the presence of neck and shoulder pain at present (P < 0.05); additionally, total body muscle mass (standardized beta = -0.26, 95 % CI, -0.17 - -0.008, P < 0.05), total body water (standardized beta = -0.27, 95 % CI, -0.23 - -0.04, P < 0.01), appendicular muscle mass (standardized beta = -0.29, 95 % CI, -0.36 - -0.04, P < 0.05), and the appendicular muscle mass index (AMI) (standardized beta = -0.24, 95 % CI, -1.18 - -0.20, P <0.01) were negatively correlated with the VAS of neck and shoulder pain, whereas no body composition parameters were significantly associated with back pain, low back pain at present and any type of chronic pain. CONCLUSIONS: The present study demonstrated that some body composition parameters regarding body water and body muscle were associated or correlated with the presence or intensity of neck and shoulder pain. PMID- 26537690 TI - Relation of apparent diffusion coefficient with Ki-67 proliferation index in meningiomas. AB - OBJECTIVE: The purpose of this study was to investigate the relationship between Ki-67 proliferation indexes and apparent diffusion coefficient (ADC) values of low-grade and atypical/anaplastic (high-grade) meningiomas. METHODS: Pre operative diffusion-weighted imaging and histopathological evaluation of 44 patients with meningiomas were performed retrospectively. Regions of interest (ROIs) were manually drawn on the ADC images. In total six ROI measurements were taken in three consecutive slices, and the average of the mean ADC value was used. The relationship between the ADC and Ki-67 values was investigated, and the ADC values of the low-grade and high-grade meningiomas were compared. RESULTS: 31 (70%) patients had low-grade the meningiomas. 10 (23%) patients had atypical and 3 (7%) had anaplastic meningiomas. ADC values of the low-grade and high-grade meningiomas were 0.81 +/- 0.12 * 10(-3) and 0.66 +/- 0.08 * 10(-3) mm(2) s(-1), respectively. Ki-67 proliferation indexes were 2.19% +/- 1.14% for low-grade and 11.20% +/- 9.80% for high-grade meningiomas. A statistically significant negative correlation between Ki-67 proliferation index and ADC values of the low-grade and high-grade meningiomas was detected (r(2) = 0.326, p < 0.001). High-grade meningiomas had lower ADC values than that of low-grade meningiomas. There was statistically significant difference between the ADC values of the low-grade and high-grade meningiomas (p < 0.001). CONCLUSION: Our data provide an inverse correlation between the ADC and Ki-67 proliferation index values of meningiomas. ADC values can be used for histopathological characterization of the meningiomas and pre-surgical planning. ADVANCES IN KNOWLEDGE: The purpose of this study was to investigate the relationship between Ki-67 proliferation indexes and ADC values of low-grade and atypical/anaplastic (high-grade) meningiomas. In addition, we compared the ADC and Ki-67 proliferative index values of the low grade and atypical/anaplastic (high-grade) meningiomas. We concluded that there was an inverse correlation between the ADC and Ki-67 proliferation index values in meningiomas, and we have found statistically significant difference between the ADC values of the low-grade and high-grade meningiomas. ADC values can be used for histopathological characterization of the meningiomas and pre-surgical planning. PMID- 26537691 TI - The feasibility of dual-energy CT in differentiation of vertebral compression fractures. AB - OBJECTIVE: To prospectively evaluate the ability of dual-energy CT (DECT), compared with MRI, to identify vertebral compression fractures in acute trauma patients. METHODS: This institutional review board-approved study included 23 consecutive patients with 32 vertebral fractures who underwent both DECT and MRI of the spine between February 2014 and September 2014. A total of 209 vertebrae were evaluated for the presence of abnormal bone marrow attenuation on DECT and signal on MRI by five experienced radiologists. The specificity, sensitivity, predictive values and intraobserver and interobserver agreements were calculated. RESULTS: MRI revealed a total of 47 vertebrae (22.4% of all vertebrae) and DECT revealed 44 vertebrae (21.0% of all vertebrae) with oedema. Using MRI as the reference standard, DECT had sensitivity, specificity, positive-predictive value, negative-predictive value and accuracy of 89.3, 98.7, 95.4, 96.9 and 96.6%, respectively. With respect to establishing the presence of oedema, the interobserver agreement was almost perfect (k = 0.82), and the intraobserver agreement was substantial (k = 0.80). CONCLUSION: Compared with MRI, DECT can provide an accurate demonstration of acute vertebral fractures and can be used as an alternative imaging modality for the assessment of vertebral fractures in patients with contraindications for MRI. ADVANCES IN KNOWLEDGE: Distinguishing of acute and chronic vertebral compression fracture is important for treatment choices. DECT is very fast compared with MRI and is an alternative imaging modality for the assessment of vertebral fractures in patients with contraindications for MRI. PMID- 26537693 TI - Effect of molecular characteristics on the formation of nitrosamines during chlor(am)ination of phenylurea herbicides. AB - The objective of this study was to investigate the formation of different nitrosamines during chlorination or chloramination (chlor(am)ination) of five phenylurea herbicides (fluometuron, diuron, linuron, metobromuron, and propanil), with the effects of disinfection approaches, additional inorganic nitrogen, and reaction pH being studied. By analyzing six nitrosamines, N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR) formation was observed. The dimethylamine functional group was the key to determining whether a particular phenylurea herbicide was an important nitrosamine precursor, as the NDMA conversion ratio was much higher. Chlorination with ammonium or dichloramination enhanced the NDMA formation. NPYR formation from the herbicides that did not form NDMA was detected and was more vigorous during dichloramination or in the presence of either ammonium or nitrite. The NPYR formation was possibly related to the aniline molecular fragment from the phenylurea herbicides. Both NDMA and NPYR formation were higher at pH 8. Overall, the maximum nitrosamine conversions decreased in the order: fluometuron > diuron > propanil > metobromuron > linuron (up to 0.99%, 0.46%, 0.005%, 0.004%, and 0.003% molar conversion rates, respectively) during chlorination or chloramination and dichloramine > free chlorine > monochloramine (up to 0.99%, 0.41%, and 0.005% molar conversion rates, respectively) for given herbicide, chlorine, and nitrogen doses. Applying the results of this study, phenylurea herbicide concentrations ranging from several to tens of MUg L(-1) will yield a NDMA concentration in drinking water above the level for a theoretical 10(-6) lifetime cancer risk. NPYR formation will increase the risk of these phenylurea herbicide concentrations to downstream water users. The true adverse environmental impacts of these phenylurea herbicides are important to emphasize given their high loadings as non-point source pollutants and their typical environmental scenarios (e.g., at neutral pH or with the co-occurrence of inorganic nitrogen), likely resulting in more efficient nitrosamine formation. PMID- 26537692 TI - Ultrasound-guided intervention in the ankle and foot. AB - In this comprehensive review, we discuss the main interventions performed in the foot and ankle for Achilles tendinopathy, Morton's neuromas and Plantar fasciitis as well as techniques for intra-articular and peritendinous injections. We present the different imaging techniques and injectable agents that can be used in clinical practice, trying to help the reader decide the most appropriate way of managing the patient with a problem in the ankle and foot. PMID- 26537694 TI - A striking reduction of simple loudness adaptation in autism. AB - Reports of sensory disturbance, such as loudness sensitivity or sound intolerance, are ubiquitous in Autism Spectrum Disorder (ASD) but a mechanistic explanation for these perceptual differences is lacking. Here we tested adaptation to loudness, a process that regulates incoming sensory input, in adults with ASD and matched controls. Simple loudness adaptation (SLA) is a fundamental adaptive process that reduces the subjective loudness of quiet steady state sounds in the environment over time, whereas induced loudness adaptation (ILA) is a means of generating a reduction in the perceived volume of louder sounds. ASD participants showed a striking reduction in magnitude and rate of SLA relative to age and ability-matched typical adults, but in contrast ILA remained intact. Furthermore, rate of SLA predicted sensory sensitivity coping strategies in the ASD group. These results provide the first evidence that compromised neural mechanisms governing fundamental adaptive processes might account for sound sensitivity in ASD. PMID- 26537696 TI - Field, discipline, and profession: Understanding three major labels of emergency management. AB - The "field," "discipline," and "profession"--three major labels of emergency management--have often been interchanged as if any of these define the others. In this work, the authors examine these major labels to provide meaning, explanation, and application to each one based on the emergency management literature currently available. The authors accomplish this by the following: 1) defining and describing the established field's progression through the years; 2) examining how close we are to a discipline in today's emergency management arena; 3) discussing the advancement to becoming a profession; and 4) providing recommendations for the future. Clarifying these three major labels, the development of the field into a formidable and mature discipline as well as a distinguished and noble profession may be hastened. PMID- 26537695 TI - Transcriptome analysis of Campylobacter jejuni polyphosphate kinase (ppk1 and ppk2) mutants. PMID- 26537697 TI - A Flex-Model for long-term assessment of community-residing older adults following disasters. AB - For the rapidly growing older adult population, disaster consequences are frequently life disruptive and even life threatening. By 2050, it is estimated that the global older adult population will reach 22 percent of the total. With declining health, this population poses a particular risk needing to be addressed in emergency preparedness and disaster recovery. The purpose of this article is to describe a Flex-Model (F-M) for the long-term assessment of older adults following a disaster. An F-M is a series of three-dimensional representations of an archetype with flexible components, both linear and parallel, that can be adapted to situations, time, place, and needs. The model incorporates the Life Patterns Model and provides a template that can be adjusted to meet the needs of a local community, healthcare providers, and emergency management officials, regardless of the country or region, during the months after a disaster. The focus is on changes resulting from the disaster including roles, relationships, support systems, use of time, self-esteem, and life structure. Following a baseline assessment, each of these life patterns is assessed through the model with options for interventions over time. A pilot study was conducted in Georgia to gain information that would be helpful in developing a more specific assessment tool following a severe winter storm. While this is a local study, the findings can nevertheless be used to refine and focus the F-M for future implementation. Results indicated that older adults used high-risk heating and lighting sources and many were totally responsible for their own welfare. Findings have implications for emergency preparedness and long-term recovery. PMID- 26537698 TI - Managing nuclear power plant induced disasters. AB - OBJECTIVE: To understand the management process of nuclear power plant (NPP) induced disasters. The study shields light on phases and issues associated with the NPP induced disaster management. SETTING: This study uses Palo Verde Nuclear Generation Station as study subject and Arizona State as study area. DESIGN: This study uses the Radiological Assessment System for Consequence Analysis (RASCAL) Source Term to Dose (STDose) of the Nuclear Regulatory Commission, a computer software to project and assess the source term dose and release pathway. This study also uses ArcGIS, a geographic information system to analyze geospatial data. A detailed case study of Palo Verde Nuclear Power Generation (PVNPG) Plant was conducted. RESULTS: The findings reveal that the NPP induced disaster management process is conducted by various stakeholders. To save lives and to minimize the impacts, it is vital to relate planning and process of the disaster management. CONCLUSIONS: Number of people who expose to the radioactive plume pathway and level of radioactivity could vary depending on the speed and direction of wind on the day the event takes place. This study findings show that there is a need to address the burning issue of different racial and ethnic groups' unequal exposure and unequal protection to potential risks associated with the NPPs. PMID- 26537699 TI - An assessment of Chemical, Biological, Radiologic, Nuclear, and Explosive preparedness among emergency department healthcare providers in an inner city emergency department. AB - INTRODUCTION: Emergency healthcare providers are required to care for victims of Chemical, Biological, Radiologic, Nuclear, and Explosive (CBRNE) agents. However, US emergency departments are often ill prepared to manage CBRNE casualties. Most providers lack adequate knowledge or experience in the areas of patient decontamination, hospital-specific disaster protocols, interagency familiarization, and available supply of necessary medical equipment and medications. This study evaluated the CBRNE preparedness of physicians, nurses, and midlevel providers in an urban tertiary care emergency department. METHODS: This retrospective observational survey study used a previously constructed questionnaire instrument. A total of 205 e-mail invitations were sent to 191 eligible providers through an online survey distribution tool (Survey Monkey(r)). Respondents were enrolled from February 1, 2014 to March 15, 2014. Simple frequencies of correct answers were used to determine the level of preparedness of each group. Cronbach's coefficient alpha was used to validate the precision of the study instrument. Finally, validity coefficients and analysis of variance ANOVA were used to determine the strength of correlation between demographic variables, as well as the variation between individual responses. RESULTS: Fifty nine providers responded to the questionnaire (31.14 percent response rate). The overall frequency of correct answers was 66.26 percent, indicating a relatively poor level of CBRNE preparedness. The study instrument lacked precision and reliability (coefficient alpha 0.4050). Significant correlations were found between the frequency of correct answers and the respondents' gender, practice experience, and previous experience with a CBRNE incident. Significant variance exists between how providers believe casualties should be decontaminated, which drugs should be administered, and the interpretation of facility-specific protocols. CONCLUSIONS: Emergency care providers are inadequately prepared to manage CBRNE incidents. Furthermore, a valid and precise instrument capable of measuring preparedness needs to be developed. Standardized educational curriculums that consider healthcare providers' genders, occupations, and experience levels may assist in closing the knowledge gaps between providers and reinforce emergency departments' CBRNE preparedness. PMID- 26537700 TI - Oil terrorism-militancy link: Mediating role of moral disengagement in emergency and crisis management. AB - The controversial issues of terrorism and militancy have generated contemporary interests and different interpretations have emerged on how to combat and manage these dangerous events. This study widens understanding of moral disengagement mechanism application in the perpetuation of inhumanities within the context of oil terrorist and militant behaviors. The research findings and model are explicit on how people form moral evaluations of agents who are forced to make morally relevant decisions over times in context of crisis situations. Quite crucially, understanding the context of terrorism and militancy provides policymakers, emergency and crisis managers better analysis and response to such events. The research fundamental purpose was to investigate the mediating role of moral disengagement on delinquency of oil terrorism and militancy; and considered implications for emergency and crisis management practices. The study found that situational-induced crises such as oil terrorism and militancy were sufficient to account for an individual's misdeeds and unethical or inhumane decisions made under frustration and agitation may be perceived as less indicative of one's fundamental character. Findings suggest that more repugnant delinquencies could have been committed in the name of justice than in the name of injustice, avenues for future research. In context, the result of the moral disengagement scale shows that morality of delinquency (oil terrorism and militancy) is accomplished by cognitively redefining the morality of such acts. The main finding is that people in resistance movements are rational actors making rational choices. The authors argue that theorists, policymakers, and practitioners must give meaningful attention to understanding the multidimensional nature of emergency, crisis and disaster management for better strength of synthesis between theory and practice. The research is concluded by thorough examination of the implication and limitations for future research and practice. PMID- 26537701 TI - Rodent-borne infectious disease outbreaks after flooding disasters: Epidemiology, management, and prevention. AB - OBJECTIVE: To alert clinicians to the climatic conditions that can precipitate outbreaks of the rodent-borne infectious diseases most often associated with flooding disasters, leptospirosis (LS), and the Hantavirus-caused diseases, hemorrhagic fever with renal syndrome (HFRS) and Hantavirus pulmonary syndrome (HPS); to describe the epidemiology and presenting clinical manifestations and outcomes of these rodent-borne infectious diseases; and to recommend both prophylactic therapies and effective control and prevention strategies for rodent borne infectious diseases. DESIGN: Internet search engines, including Google(r), Google Scholar(r), Pub Med, Medline, and Ovid, were queried with the key words as search terms to examine the latest scientific articles on rodent-borne infectious disease outbreaks in the United States and worldwide to describe the epidemiology and presenting clinical manifestations and outcomes of LS and Hantavirus outbreaks. SETTING: Not applicable. PARTICIPANTS: Not applicable. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Rodent-borne infectious disease outbreaks following heavy rainfall and flooding disasters. RESULTS: Heavy rainfall encourages excessive wild grass seed production that supports increased outdoor rodent population densities; and flooding forces rodents from their burrows near water sources into the built environment and closer to humans. CONCLUSIONS: Healthcare providers should maintain high levels of suspicion for LS in patients developing febrile illnesses after contaminated freshwater exposures following heavy rainfall, flooding, and even freshwater recreational events; and for Hantavirus-caused infectious diseases in patients with hemorrhagic fevers that progress rapidly to respiratory or renal failure following rodent exposures. PMID- 26537702 TI - Laboratory evaluation of airborne particulate control treatments for simulated aircraft crash recovery operations involving carbon fiber composite materials. AB - OBJECTIVE: This study compared four treatment protocols to reduce airborne composite fiber particulates during simulated aircraft crash recovery operations. DESIGN: Four different treatments were applied to determine effectiveness in reducing airborne composite fiber particulates as compared to a "no treatment" protocol. Both "gold standard" gravimetric methods and real-time instruments were used to describe mass per volume concentration, particle size distribution, and surface area. The treatment protocols were applying water, wetted water, wax, or aqueous film-forming foam (AFFF) to both burnt and intact tickets of aircraft composite skin panels. The tickets were then cut using a small high-speed rotary tool to simulate crash recovery operations. SETTING: Aerosol test chamber. SUBJECTS, PARTICIPANTS: None. INTERVENTIONS: Airborne particulate control treatments. MAIN OUTCOME MEASURES: Measures included concentration units of milligrams per cubic meter of air, particle size distribution as described by both count median diameter and mass median diameter and geometric standard deviation of particles in micrometers, and surface area concentration in units of square micrometers per cubic centimeter. Finally, a Monte Carlo simulation was run on the particle size distribution results. Comparison was made via one-way analysis of variance. RESULTS: A significant difference (p<0.0001) in idealized particle size distribution was found between the water and wetted water treatments as compared to the other treatments for burnt tickets. CONCLUSIONS: Emergency crash recovery operations should include a treatment of the debris with water or wetted water. The resulting increase in particle size will make respiratory protection more effective in protecting the response crews. PMID- 26537703 TI - Experiences of tobacco smoking and quitting in smokers with and without chronic obstructive pulmonary disease-a qualitative analysis. AB - BACKGROUND: Smokers with chronic obstructive pulmonary disease (COPD) seem to be a special subgroup of smokers that have a more urgent need to quit smoking but might find it more difficult to do so. This study aimed to explore which justifications for tobacco smoking and experiences of quitting were commonly shared in smokers with and without COPD, and which, if any, were specific to smokers with COPD. METHODS: In ten primary healthcare centres in the Netherlands, we conducted semi-structured, in-depth interviews in 10 smokers with and 10 smokers without COPD. RESULTS: Three themes were generated: 'balancing the impact on health of smoking', 'challenging of autonomy by social interference', 'prerequisites for quitting'. All participants trivialized health consequences of smoking; those with COPD seemed to be less knowledgeable about smoking and health. Both groups of smokers found autonomy very important. Smokers with COPD were indignant about a perceived lack of empathy in their communication with doctors. Furthermore, smokers with COPD in particular had little faith in the efficacy of smoking cessation aids. Lastly, motivation for quitting was dominated by fluctuation and smokers with COPD specifically maintained that their vision of life was linked with quitting. CONCLUSIONS: The participants showed many similarities in their reasoning about smoking and quitting. The corresponding themes argue for a less paternalistic regime in the communication with smokers with attention required for the motivational stage and room made for smokers' own views, and with clear information and education. Furthermore, addressing social interactions, health perceptions and moral agendas in the communication with smokers with COPD may help to make smoking cessation interventions more suitable for them. PMID- 26537704 TI - One Small Step for Empagliflozin, One Giant Leap for Diabetology. AB - This article discusses the recently published EMPA-REG OUTCOME trial, which assessed cardiovascular outcomes with empagliflozin therapy in persons with type 2 diabetes mellitus and coexisting cardiovascular disease. The article describes the background and challenges of modern cardiovascular outcome trials, points out the strengths of the EMPA-REG OUTCOME study, and places the results in perspective. It highlights the significant impact that these results will have on cardiovascular preventive pharmacotherapy, and on future drug development in diabetes. At the same time, it reminds readers of the limitations of the results, and lists the questions raised by, or left unanswered by, the trial. PMID- 26537705 TI - Sleep Optimization and Diabetes Control: A Review of the Literature. AB - Pre-diabetes and diabetes occur secondary to a constellation of pathophysiological abnormalities that culminate in insulin resistance, which results in reduced cellular glucose uptake and increased glucose production. Although pre-diabetes and diabetes have a strong genetic basis, they are largely environmentally driven through lifestyle factors. Traditional lifestyle factors such as diet and physical activity do not fully explain the dramatic rise in the incidence and prevalence of diabetes mellitus. Sleep has emerged as an additional lifestyle behavior, important for metabolic health and energy homeostasis. In this article, we review the current evidence surrounding the sleep-diabetes association. PMID- 26537706 TI - Outcomes for implementation science: an enhanced systematic review of instruments using evidence-based rating criteria. AB - BACKGROUND: High-quality measurement is critical to advancing knowledge in any field. New fields, such as implementation science, are often beset with measurement gaps and poor quality instruments, a weakness that can be more easily addressed in light of systematic review findings. Although several reviews of quantitative instruments used in implementation science have been published, no studies have focused on instruments that measure implementation outcomes. Proctor and colleagues established a core set of implementation outcomes including: acceptability, adoption, appropriateness, cost, feasibility, fidelity, penetration, sustainability (Adm Policy Ment Health Ment Health Serv Res 36:24 34, 2009). The Society for Implementation Research Collaboration (SIRC) Instrument Review Project employed an enhanced systematic review methodology (Implement Sci 2: 2015) to identify quantitative instruments of implementation outcomes relevant to mental or behavioral health settings. METHODS: Full details of the enhanced systematic review methodology are available (Implement Sci 2: 2015). To increase the feasibility of the review, and consistent with the scope of SIRC, only instruments that were applicable to mental or behavioral health were included. The review, synthesis, and evaluation included the following: (1) a search protocol for the literature review of constructs; (2) the literature review of instruments using Web of Science and PsycINFO; and (3) data extraction and instrument quality ratings to inform knowledge synthesis. Our evidence-based assessment rating criteria quantified fundamental psychometric properties as well as a crude measure of usability. Two independent raters applied the evidence based assessment rating criteria to each instrument to generate a quality profile. RESULTS: We identified 104 instruments across eight constructs, with nearly half (n = 50) assessing acceptability and 19 identified for adoption, with all other implementation outcomes revealing fewer than 10 instruments. Only one instrument demonstrated at least minimal evidence for psychometric strength on all six of the evidence-based assessment criteria. The majority of instruments had no information regarding responsiveness or predictive validity. CONCLUSIONS: Implementation outcomes instrumentation is underdeveloped with respect to both the sheer number of available instruments and the psychometric quality of existing instruments. Until psychometric strength is established, the field will struggle to identify which implementation strategies work best, for which organizations, and under what conditions. PMID- 26537707 TI - G-computation demonstration in causal mediation analysis. AB - Recent work has considerably advanced the definition, identification and estimation of controlled direct, and natural direct and indirect effects in causal mediation analysis. Despite the various estimation methods and statistical routines being developed, a unified approach for effect estimation under different effect decomposition scenarios is still needed for epidemiologic research. G-computation offers such unification and has been used for total effect and joint controlled direct effect estimation settings, involving different types of exposure and outcome variables. In this study, we demonstrate the utility of parametric g-computation in estimating various components of the total effect, including (1) natural direct and indirect effects, (2) standard and stochastic controlled direct effects, and (3) reference and mediated interaction effects, using Monte Carlo simulations in standard statistical software. For each study subject, we estimated their nested potential outcomes corresponding to the (mediated) effects of an intervention on the exposure wherein the mediator was allowed to attain the value it would have under a possible counterfactual exposure intervention, under a pre-specified distribution of the mediator independent of any causes, or under a fixed controlled value. A final regression of the potential outcome on the exposure intervention variable was used to compute point estimates and bootstrap was used to obtain confidence intervals. Through contrasting different potential outcomes, this analytical framework provides an intuitive way of estimating effects under the recently introduced 3- and 4-way effect decomposition. This framework can be extended to complex multivariable and longitudinal mediation settings. PMID- 26537708 TI - Risk for childhood leukemia associated with maternal and paternal age. AB - The role of reproductive factors, such as parental age, in the pathogenesis of childhood leukemias is being intensively examined; the results of individual studies are controversial. This meta-analysis aims to quantitatively synthesize the published data on the association between parental age and risk of two major distinct childhood leukemia types in the offspring. Eligible studies were identified and pooled relative risk (RR) estimates were calculated using random effects models, separately for childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Subgroup analyses were performed by study design, geographical region, adjustment factors; sensitivity analyses and meta-regression analyses were also undertaken. 77 studies (69 case-control and eight cohort) were deemed eligible. Older maternal and paternal age were associated with increased risk for childhood ALL (pooled RR = 1.05, 95 % CI 1.01-1.10; pooled RR = 1.04, 95 % CI 1.00-1.08, per 5 year increments, respectively). The association between maternal age and risk of childhood AML showed a U-shaped pattern, with symmetrically associated increased risk in the oldest (pooled RR = 1.23, 95 % CI 1.06-1.43) and the youngest (pooled RR = 1.23, 95 % CI 1.07-1.40) extremes. Lastly, only younger fathers were at increased risk of having a child with AML (pooled RR = 1.28, 95 % CI 1.04-1.59). In conclusion, maternal and paternal age represents a meaningful risk factor for childhood leukemia, albeit of different effect size by leukemia subtype. Genetic and socio-economic factors may underlie the observed associations. Well-adjusted studies, scheduled by large consortia, are anticipated to satisfactorily address methodological issues, whereas the potential underlying genetic mechanisms should be elucidated by basic research studies. PMID- 26537709 TI - Predicting Alzheimer's disease development: a comparison of cognitive criteria and associated neuroimaging biomarkers. AB - INTRODUCTION: The definition of "objective cognitive impairment" in current criteria for mild cognitive impairment (MCI) varies considerably between research groups and clinics. This study aims to compare different methods of defining memory impairment to improve prediction models for the development of Alzheimer's disease (AD) from baseline to 24 months. METHODS: The sensitivity and specificity of six methods of defining episodic memory impairment (< -1, -1.5 or -2 standard deviations [SD] on one or two memory tests) were compared in 494 non-demented seniors from the Alzheimer's Disease Neuroimaging Initiative using the area under the curve (AUC) for receiver operating characteristic analysis. The added value of non-memory measures (language and executive function) and biomarkers (hippocampal and white-matter hyperintensity volume, brain parenchymal fraction [BPF], and APOEepsilon4 status) was investigated using logistic regression. RESULTS: Baseline scores < -1 SD on two memory tests predicted AD with 75.91 % accuracy (AUC = 0.80). Only APOE epsilon4 status further improved prediction (B = 1.10, SE = 0.45, p = .016). A < -1.5 SD cut-off on one test had 66.60 % accuracy (AUC = 0.77). Prediction was further improved using Trails B/A ratio (B = 0.27, SE = 0.13, p = .033), BPF (B = -15.97, SE = 7.58, p = .035), and APOEepsilon4 status (B = 1.08, SE = 0.45, p = .017). A cut-off of < -2 SD on one memory test (AUC = 0.77, SE = 0.03, 95 % CI 0.72-0.82) had 76.52 % accuracy in predicting AD. Trails B/A ratio (B = 0.31, SE = 0.13, p = .017) and APOE epsilon4 status (B = 1.07, SE = 0.46, p = .019) improved predictive accuracy. CONCLUSIONS: Episodic memory impairment in MCI should be defined as scores < -1 SD below normative references on at least two measures. Clinicians or researchers who administer a single test should opt for a more stringent cut-off and collect and analyze whole brain volume. When feasible, ascertaining APOE epsilon4 status can further improve prediction. PMID- 26537710 TI - Chlorophyll fluorescence imaging as a tool to monitor the progress of a root pathogen in a perennial plant. AB - MAIN CONCLUSION: The chlorophyll fluorescence parameter PhiNO is an excellent metric for the non-destructive monitoring of disease progression, measured over a broad range of light intensities. The suitability of the slow induction chlorophyll fluorescence parameters PhiPSII, PhiNPQ, and PhiNO to monitor in vivo disease progression in a host-root pathogen pathosystem was evaluated and compared to the established method of monitoring disease by measuring Fv/Fm. Using the infection of ginseng plants (Panax quinquefolius L.) with Pythium irregulare Buisman as a model, light response curves were used to establish the optimal irradiance for the resolution of differences between fluorescence parameters PhiPSII, PhiNPQ and PhiNO. As infection progressed only changes in PhiNO remained consistent with increased irradiance, and increased as infection progressed. Furthermore, PhiNO showed a high sensitivity for distinguishing increased disease load. In contrast, the magnitude in change of PhiPSII and PhiNPQ were sensitive to irradiance levels. The magnitude of increase in PhiNO per unit disease score was equivalent to the corresponding decline in Fv/Fm values. Thus PhiNO is as sensitive as Fv/Fm in monitoring biotic stress. The ability to measure PhiNO under a wide range of light intensities, including natural light, potentially without the need for dark adaptation, means that it can be used in the development of a general protocol for non-invasive, in vivo monitoring of plant health, from the laboratory to the field scale. PMID- 26537711 TI - Risk factors for hip fracture in very old people: a population-based study. AB - SUMMARY: Knowledge of risk factors for hip fracture among very old people is limited. Walking indoors with help from <=1 person, Parkinson's disease, currently smoking, delirium in the previous month, underweight, and age were associated with increased risk of hip fracture and could be important for preventive strategy development. INTRODUCTION: The purpose of this study is to investigate risk factors for hip fracture among a representative sample of very old people. METHODS: In total, 953 participants from the Umea 85+/Gerontological Regional Database population-based cohort study were interviewed and assessed during home visits. Associations of baseline characteristics with hip fracture during the maximum 5-year follow-up period were analyzed using Cox proportional hazards regression. RESULTS: Participants had a mean age of 89.3 +/- 4.7 years; 65.8% were women, 36.8% lived in residential care facilities, 33.6% had dementia, and 20.4% had histories of hip fracture. During a mean follow-up period of 2.7 years, 96 (10.1%) individuals sustained hip fracture. Walking indoors with help from no more than one person (hazard ratio [HR] = 8.57; 95% confidence interval [CI], 1.90-38.71), Parkinson's disease (HR = 5.12; 95% CI, 1.82-14.44), currently smoking (HR = 4.38; 95% CI 2.06-9.33), delirium in the previous month (HR = 2.01; 95% CI, 1.15-3.49), underweight (body mass index <22; HR = 1.74, 95% CI, 1.09 2.77), and age (HR = 1.09; 95% CI, 1.04-1.14) were associated independently with an increased risk of hip fracture. Hip prosthesis at baseline decreased the risk of hip fracture (HR = 0.37; 95% CI, 0.15-0.91), but only for those with bilateral hip prostheses. CONCLUSIONS: Seven factors were associated independently with incident hip fracture during follow-up in this sample of very old people. These factors could have important clinical implications in identifying persons at high risk of hip fracture, as well as in the development of effective preventive strategies. PMID- 26537713 TI - The clinical challenge of achieving marginal adaptation in direct and indirect restorations. PMID- 26537714 TI - Marginal integrity of restorations produced with a model composite based on polyhedral oligomeric silsesquioxane (POSS). AB - Marginal integrity is one of the most crucial aspects involved in the clinical longevity of resin composite restorations. OBJECTIVE: To analyze the marginal integrity of restorations produced with a model composite based on polyhedral oligomeric silsesquioxane (POSS). MATERIAL AND METHODS: A base composite (B) was produced with an organic matrix with UDMA/TEGDMA and 70 wt.% of barium borosilicate glass particles. To produce the model composite, 25 wt.% of UDMA were replaced by POSS (P25). The composites P90 and TPH3 (TP3) were used as positive and negative controls, respectively. Marginal integrity (%MI) was analyzed in bonded class I cavities. The volumetric polymerization shrinkage (%VS) and the polymerization shrinkage stress (Pss - MPa) were also evaluated. RESULTS: The values for %MI were as follows: P90 (100%) = TP3 (98.3%) = B (96.9%) > P25 (93.2%), (p<0.05). The %VS ranged from 1.4% (P90) to 4.9% (P25), while Pss ranged from 2.3 MPa (P90) to 3.9 MPa (B). For both properties, the composite P25 presented the worst results (4.9% and 3.6 MPa). Linear regression analysis showed a strong positive correlation between %VS and Pss (r=0.97), whereas the correlation between Pss and %MI was found to be moderate (r=0.76). CONCLUSIONS: The addition of 25 wt.% of POSS in methacrylate organic matrix did not improve the marginal integrity of class I restorations. Filtek P90 showed lower polymerization shrinkage and shrinkage stress when compared to the experimental and commercial methacrylate composite. PMID- 26537715 TI - Acinar autolysis and mucous extravasation in human sublingual glands: a microscopic postmortem study. AB - Although some morphological investigations on aged human sublingual glands (HSG) found eventual phenomena identified as autolysis and mucous extravasation, the exact meaning of these findings has not been elucidated. OBJECTIVE: The aim of this work is to investigate whether acinar autolysis and mucous extravasation are related to the aging process in human sublingual glands. We also speculate if autolytic changes may assist forensic pathologists in determining time of death. MATERIAL AND METHODS: 186 cadavers' glands were allocated to age groups: I (0-30 years); II (31-60), and III (61-90). Time and mode of death were also recorded. Acinar autolysis and mucous extravasation were classified as present or absent. Ultrastructural analysis was performed using transmission electron microscopy (TEM). Data were compared using Mann-Whitney U, Spearman's correlation coefficient, Kruskal-Wallis, and Dunn tests (p<0.05). RESULTS: There was correlation between age and acinar autolysis (r=0.38; p=0.0001). However, there was no correlation between autolysis and time of death. No differences were observed between genders. TEM showed mucous and serous cells presenting nuclear and membrane alterations and mucous cells were more susceptible to autolysis. CONCLUSION: Acinar autolysis occurred in all age groups and increased with age while mucous extravasation was rarely found. Both findings are independent. Autolysis degrees in HSG could not be used to determine time of death. PMID- 26537716 TI - Biocompatibility and bioactivity of calcium silicate-based endodontic sealers in human dental pulp cells. AB - Mineral Trioxide Aggregate (MTA) is a calcium silicate-based material. New sealers have been developed based on calcium silicate as MTA Fillapex and MTA Plus. OBJECTIVE: The aim of this study was to evaluate biocompatibility and bioactivity of these two calcium silicate-based sealers in culture of human dental pulp cells (hDPCs). MATERIAL AND METHODS: The cells were isolated from third molars extracted from a 16-year-old patient. Pulp tissue was sectioned into fragments with approximately 1 mm3 and kept in supplemented medium to obtain hDPCs adherent cultures. Cell characterization assays were performed to prove the osteogenic potential. The evaluated materials were: MTA Plus (MTAP); MTA Fillapex (MTAF) and FillCanal (FC). Biocompatibility was evaluated with MTT and Neutral Red (NR) assays, after hDPCs exposure for 24 h to different dilutions of each sealer extract (1:2, 1:3 and 1:4). Unexposed cells were the positive control (CT). Bioactivity was assessed by alkaline phosphatase (ALP) enzymatic assay in cells exposed for one and three days to sealer extracts (1:4 dilution). All data were analyzed by ANOVA and Tukey post-test (p<=0.05%). RESULTS: MTT and NR results showed suitable cell viability rates for MTAP at all dilutions (90-135%). Cells exposed to MTAF and FC (1:2 and 1:4 dilutions) showed significant low viability rate when compared to CT in MTT. The NR results demonstrated cell viability for all materials tested. In MTAP group, the cells ALP activity was similar to CT in one and three days of exposure to the material. MTAF and FC groups demonstrated a decrease in ALP activity when compared to CT at both periods of cell exposure. CONCLUSIONS: The hDPCs were suitable for the evaluation of new endodontic materialsin vitro. MTAP may be considered a promising material for endodontic treatments. PMID- 26537717 TI - Altered beta-catenin expression in oral mucosal dysplasia: a comparative study. AB - OBJECTIVE: The current study aimed to investigate the beta-catenin expression in oral leukoplakia (OL) with different degrees of epithelial dysplasia and normal oral mucosa. MATERIAL AND METHODS: Formalin-fixed, paraffin-embedded tissue samples of 39 OL (mild dysplasia n=19, moderate dysplasia n=13, and severe dysplasia n=7), and 10 normal oral mucosa (control group) were submitted to immunohistochemical reactions to anti-beta-catenin primary antibody. A qualitative beta-catenin analysis was performed based on the percentage of positive cells. The cellular location and the epithelial layer were also considered. The Chi-square test and the Fisher's exact test were used to verify possible differences in the beta-catenin expression among the OL groups. A p value of <0.05 was considered statistically significant. RESULTS: Membranous expression of beta-catenin in parabasal and basal layers was gradually lost in the higher degrees of epithelial dysplasia. In normal oral mucosa, beta-catenin was detected only in the cytoplasmic membrane. However, a significant increase in cytoplasmic beta-catenin could be observed between mild and moderate dysplasia (Fisher Exact test - p<0.001) and between mild and severe dysplasia (p<0.001). CONCLUSIONS: The beta-catenin cytoplasmic expression observed in this study may represent the initial stage of modifications in the E-cadherin-catenin complex, along with morphological cellular changes. PMID- 26537718 TI - Cone beam computed tomography study of apical root resorption induced by Herbst appliance. AB - OBJECTIVE: This study evaluated the frequency of root resorption during the orthodontic treatment with Herbst appliance by Cone Beam Computed Tomography (CBCT). MATERIAL AND METHODS: The sample comprised 23 patients (11 men, 12 women; mean ages 15.76+/-1.75 years) with Class II division 1 malocclusion, treated with Herbst appliance. CBCT was obtained before treatment (T0) and after Herbst treatment (T1). All the dental roots, except third molars, were evaluated, and apical root resorption was determined using the axial guided navigation method. Paired t-tests and Wilcoxon T Test were used to compare the dependent samples in parametric and nonparametric cases, respectively. Chi-Square Test with Yates' correction was used to evaluate the relationship between apical root resorption and gender. Results were considered at a significance level of 5%. RESULTS: Apical resorption was detected by CBCT in 57.96% of 980 roots that underwent Herbst appliance treatment. All patients had minimal resorption and there was no statistical significance between the genders. CONCLUSION: CBCT three-dimensional evaluation showed association between Herbst appliance and minimal apical root resorption, mostly in the anchoring teeth, without clinical significance. PMID- 26537719 TI - Protective effect of experimental mouthrinses containing NaF and TiF4 on dentin erosive loss in vitro. AB - OBJECTIVE: This in vitro study assessed the anti-erosive effect of experimental mouthrinses containing TiF4 and NaF on dentin erosive loss. MATERIAL AND METHODS: Bovine dentin specimens were randomly allocated into the groups (n=15): (1) SnCl2/NaF/AmF (Erosion Protection/GABA, pH 4.5, positive control); (2) experimental solution with 0.0815% TiF4(pH 2.5); (3) 0.105% NaF (pH 4.5); 4) 0.042% NaF+0.049% TiF4 (pH 4.4); (5) 0.063% NaF+0.036% TiF4 (pH 4.5); (6) no treatment (negative control). Each specimen was cyclically demineralized (Sprite Zero, pH 2.6, 4x90 s/day) and exposed to artificial saliva between the erosive challenges for 7 days. The treatment with the fluoride solutions was done 2x60 s/day, immediately after the first and the last erosive challenges of the day. Dentin erosive loss was measured by profilometry (MUm). The data were analyzed using Kruskal Wallis/Dunn tests (p<0.05). RESULTS: Mouthrinses containing TiF4or Sn/F were able to show some protective effect against dentin erosive loss compared to negative control. The best anti-erosive effect was found for experimental solution containing 0.0815% TiF4 (100% reduction in dentin loss), followed by 0.042% NaF+0.049% TiF4 (58.3%), SnCl2/NaF/AmF (52%) and 0.063% NaF+0.036% TiF4 (40%). NaF solution (13.3%) did not significantly differ from control. CONCLUSION: The daily application of experimental mouthrinse containing TiF4 and NaF has the ability to reduce dentin erosion, as well as Erosion Protection and TiF4 alone. PMID- 26537720 TI - Serum big endothelin-1 as a biomarker in oral squamous cell carcinoma patients: an analytical study. AB - Detection of abnormally elevated levels of molecules in patients with oral cancer may be useful in early diagnosis. These markers can be included in current Histopathology grading and in TNM staging systems of Oral Squamous Cell Carcinoma (OSCC) to make it more efficient. Several pro-angiogenic molecules have been assessed for the same reason. Endothelin-1 (ET-1) is a vasoactive peptide associated with the development and spread of many solid tumors, including Squamous Cell Carcinoma (SCC), but its utility in OSCC has not been confirmed. OBJECTIVE: This study aims to evaluate the role of the serum big ET-1 as a biomarker of OSCC, by correlating it with the clinical staging and the histopathological grading. MATERIAL AND METHODS: Serum levels of big ET-1 measured by the sandwich Enzyme-Linked Immunosorbent Assay (ELISA) in 40 OSCC cases were compared with the levels from the control group using independent t test. Clinical stages and histopathological grades of OSCC cases were compared in relation to their mean levels of serum big ET-1, one using the Analysis of Variance (ANOVA) test and the other the independent t-test, respectively. The significance of the mean difference between the groups was evaluated by Tukey's multiple comparison test. All statistical analyses were performed on GraphPad statistical software version 5.0. RESULTS: By comparing the mean of the big ET-1 concentrations of cases and controls, the independent t-test revealed significant higher big ET-1 concentration of OSCC cases when compared to controls (p<0.0001). Tukey's multiple comparison test also revealed statistically significant difference among all OSCC stages in relation to the mean levels of serum big ET 1. However, the mean of the big ET-1 concentrations of cases of grade I and of grade II did not differ statistically (p=0.729). CONCLUSION: Serum big ET-1 levels may be useful as a diagnostic tool in OSCC and as an adjunct to OSCC staging. However, its use as a prognostic marker warrants larger prospective studies. PMID- 26537721 TI - Effects on gastric mucosa induced by dental bleaching--an experimental study with 6% hydrogen peroxide in rats. AB - The value of aesthetic dentistry has precipitated several developments in the investigation of dental materials related to this field. The free marketing of these products is a problem and it is subject to various interpretations regarding its legality. There are several techniques for tooth whitening, the most used one being the external bleaching. It is the later version of such technique that poses the greatest danger of ingesting the product. The present study analysed the systemic effect of these products when they are swallowed. OBJECTIVE: This experimental study aimed to observe the effects of a tooth whitening product, whose active agent is 6% hydrogen peroxide, on the gastric mucosa of healthy and non-tumour gastric pathology animals. MATERIAL AND METHODS: Fifty Wistar-Han rats were used and then distributed into 5 groups, one for control and four test groups in which the bleaching product was administered in animals with and without non-tumour gastric pathology (induced by the administration of 1 sample of 50% ethanol and 5% of drinking water during 6 days) at different times of study by gavage. There was a decrease in body weight in animals of groups handled during the study period, which was most pronounced in IV and VA groups. Changes in spleen weight relative to body weight revealed no statistically significant changes. An analysis of the frequency was performed on the results of macroscopic observation of the gastric mucosa. RESULTS: The gastric mucosa revealed lesions in all manipulated groups, being more frequent in groups III and IV. It appears that there is a synergism when using hydrogen peroxide and 50% ethanol in the same group. CONCLUSION: Therefore, it seems that there are some signs of toxicity 3 to 4 days after administration of 6% hydrogen peroxide. The prescription of these therapies must be controlled by the clinician and the risks must be minimized. PMID- 26537722 TI - Effect of software version and parameter settings on the marginal and internal adaptation of crowns fabricated with the CAD/CAM system. AB - OBJECTIVE: This study investigated the marginal and internal adaptation of individual dental crowns fabricated using a CAD/CAM system (Sirona's BlueCam), also evaluating the effect of the software version used, and the specific parameter settings in the adaptation of crowns. MATERIAL AND METHODS: Forty digital impressions of a master model previously prepared were acquired using an intraoral scanner and divided into four groups based on the software version and on the spacer settings used. The versions 3.8 and 4.2 of the software were used, and the spacer parameter was set at either 40 MUm or 80 MUm. The marginal and internal fit of the crowns were measured using the replica technique, which uses a low viscosity silicone material that simulates the thickness of the cement layer. The data were analyzed using a Friedman two-way analysis of variance (ANOVA) and paired t-tests with significance level set at p<0.05. RESULTS: The two-way ANOVA analysis showed the software version (p<0.05) and the spacer parameter (p<0.05) significantly affected the crown adaptation. The crowns designed with the version 4.2 of the software showed a better fit than those designed with the version 3.8, particularly in the axial wall and in the inner margin. The spacer parameter was more accurately represented in the version 4.2 of the software than in the version 3.8. In addition, the use of the version 4.2 of the software combined with the spacer parameter set at 80 MUm showed the least variation. On the other hand, the outer margin was not affected by the variables. CONCLUSION: Compared to the version 3.8 of the software, the version 4.2 can be recommended for the fabrication of well-fitting crown restorations, and for the appropriate regulation of the spacer parameter. PMID- 26537723 TI - Microbial contamination and disinfection methods of pacifiers. AB - OBJECTIVES: To evaluate the microbial contamination of pacifiers by Mutans Streptococci(MS) and the efficacy of different methods for their disinfection. METHODS: Twenty-eight children were assigned to a 4-stage changeover system with a 1-week interval. In each stage, children received a new pacifier and the parents were instructed to maintain their normal habits for 1 week. After this time, the pacifiers were subjected to the following 4 disinfection methods: spraying with 0.12% chlorhexidine solution, Brushtox or sterile tap water, and immersion in boiling tap water for 15 minutes. Microbiological culture for MS and Scanning Electron Microscopy (SEM) were performed. The results were analyzed statistically by Friedman's non-parametric test (a=0.05). RESULTS: The 0.12% chlorhexidine spray was statistically similar to the boiling water (p>0.05) and more effective than the Brushtox spray and control (p<0.05). The analysis of SEM showed the formation of a cariogenic biofilm in all groups with positive culture. CONCLUSIONS: Pacifiers become contaminated by MS after their use by children and should be disinfected routinely. Spraying with a 0.12% chlorhexidine solution and immersion in boiling water promoted better disinfection of the pacifiers compared with a commercial antiseptic toothbrush cleanser (Brushtox). PMID- 26537724 TI - Differential expression of CC chemokines (CCLs) and receptors (CCRs) by human T lymphocytes in response to different Aggregatibacter actinomycetemcomitans serotypes. AB - In Aggregatibacter actinomycetemcomitans, different serotypes have been described based on LPS antigenicity. Recently, our research group has reported a differential immunogenicity when T lymphocytes were stimulated with these different serotypes. In particular, it was demonstrated that the serotype b of A. actinomycetemcomitans has a stronger capacity to trigger Th1- and Th17-type cytokine production. OBJECTIVE: This study aimed to quantify the expression of different CC chemokines (CCLs) and receptors (CCRs) in T lymphocytes stimulated with the differentA. actinomycetemcomitans serotypes. In addition, the expression of the transcription factors T-bet, GATA-3, RORC2, and Foxp3, master-switch genes implied in the Th1, Th2, Th17, and T-regulatory differentiation, respectively, was analysed in order to determine T-cell phenotype-specific patterns of CCL and CCR expression upon A. actinomycetemcomitans stimulation. MATERIAL AND METHODS: Human naive CD4+ T lymphocytes were obtained from healthy subjects and stimulated with autologous dendritic cells primed with the differentA. actinomycetemcomitans serotypes. The expression levels for the chemokines CCL1, CCL2, CCL3, CCL5, CCL11, CCL17, CCL20, CCL21, CCL25, and CCL28, as well as the chemokine receptors CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 were quantified by qPCR. Similarly, the expression levels for the transcription factors T-bet, GATA-3, RORC2, and Foxp3 were quantified and correlated with the CCL and CCR expression levels. RESULTS: Higher expression levels of CCL2, CCL3, CCL5, CCL20, CCL21, CCL28, CCR1, CCR2, CCR5, CCR6, CCR7, and CCR9 were detected in T lymphocytes stimulated with the serotype b of A. actinomycetemcomitans compared with the other serotypes. In addition, these higher expression levels of CCLs and CCRs positively correlated with the increased levels of T-bet and RORC2 when T lymphocytes were stimulated with the serotype b. CONCLUSION: A T-lymphocyte response biased towards a Th1- and Th17-pattern of CCL and CCR expression was detected under stimulation with the serotype b ofA. actinomycetemcomitans. PMID- 26537726 TI - Polygonal instabilities on interfacial vorticities. AB - We report the results of a theoretical investigation of the stability of a toroidal vortex bound by an interface. Two distinct instability mechanisms are identified that rely on, respectively, surface tension and fluid inertia, either of which may prompt the transformation from a circular to a polygonal torus. Our results are discussed in the context of three experiments, a toroidal vortex ring, the hydraulic jump, and the hydraulic bump. PMID- 26537725 TI - A new primary dental care service compared with standard care for child and family to reduce the re-occurrence of childhood dental caries (Dental RECUR): study protocol for a randomised controlled trial. AB - BACKGROUND: In England and Scotland, dental extraction is the single highest cause of planned admission to the hospital for children under 11 years. Traditional dental services have had limited success in reducing this disease burden. Interventions based on motivational interviewing have been shown to impact positively dental health behaviours and could facilitate the prevention of re-occurrence of dental caries in this high-risk population. The objective of the study is to evaluate whether a new, dental nurse-led service, delivered using a brief negotiated interview based on motivational interviewing, is a more cost effective service than treatment as usual, in reducing the re-occurrence of dental decay in young children with previous dental extractions. METHODS/DESIGN: This 2-year, two-arm, multicentre, randomised controlled trial will include 224 child participants, initially aged 5 to 7 years, who are scheduled to have one or more primary teeth extracted for dental caries under general anaesthesia (GA), relative analgesia (RA: inhalation sedation) or local anaesthesia (LA). The trial will be conducted in University Dental Hospitals, Secondary Care Centres or other providers of dental extraction services across the United Kingdom. The intervention will include a brief negotiated interview (based on the principles of motivational interviewing) delivered between enrollment and 6 weeks post extraction, followed by directed prevention in primary dental care. Participants will be followed up for 2 years. The main outcome measure will be the dental caries experienced by 2 years post-enrollment at the level of dentine involvement on any tooth in either dentition, which had been caries-free at the baseline assessment. DISCUSSION: The participants are a hard-to-reach group in which secondary prevention is a challenge. Lack of engagement with dental care makes the children and their families scheduled for extraction particularly difficult to recruit to an RCT. Variations in service delivery between sites have also added to the challenges in implementing the Dental RECUR protocol during the recruitment phase. TRIAL REGISTRATION: ISRCTN24958829 (date of registration: 27 September 2013), Current protocol version: 5.0. PMID- 26537727 TI - Disentangling the triadic interactions in Navier-Stokes equations. AB - We study the role of helicity in the dynamics of energy transfer in a modified version of the Navier-Stokes equations with explicit breaking of the mirror symmetry. We select different set of triads participating in the dynamics on the basis of their helicity content. In particular, we remove the negative helically polarized Fourier modes at all wave numbers except for those falling on a localized shell of wave number, |k| ~ k(m). Changing k(m) to be above or below the forcing scale, k(f), we are able to assess the energy transfer of triads belonging to different interaction classes. We observe that when the negative helical modes are present only at a wave number smaller than the forced wave numbers, an inverse energy cascade develops with an accumulation of energy on a stationary helical condensate. Vice versa, when negative helical modes are present only at a wave number larger than the forced wave numbers, a transition from backward to forward energy transfer is observed in the regime when the minority modes become energetic enough. PMID- 26537728 TI - Erratum to: Colloquium: Mechanical formalisms for tissue dynamics. PMID- 26537729 TI - Ethyl 3-(2,4-dioxocyclohexyl)propanoate as a novel precursor for N-substituted 4,4a,5,6-tetrahydroquinoline-2,7(1H,3H)-diones and their corresponding 3,4 dihydro-7-hydroxyquinolin-2(1H)-ones and 7-hydroxyquinolin-2(1H)-ones synthesis. AB - Ethyl 3-(2,4-dioxocyclohexyl)propanoate has been explored as a precursor for the synthesis of N-substituted 4,4a,5,6-tetrahydroquinoline-2,7(1H,3H)-diones following conventional protecvtion, selective amidation, and deprotective cyclization approaches. Moreover, a facile process for the selective dehydrogenative aromatization of these diones was developed to afford the corresponding N-substituted 3,4-dihydro-7-hydroxyquinolin-2(1H)-ones and N substituted 7-hydroxyquinolin-2(1H)-ones under mild conditions. PMID- 26537730 TI - New linear antiplasmodial peptides related to angiotensin II. AB - BACKGROUND: Antiplasmodial activities of angiotensin II and its analogues have been extensively investigated in Plasmodium gallinaceum and Plasmodium falciparum parasite species. Due to its vasoconstrictor property angiotensin II cannot be used as an anti-malarial drug. METHODS: This work presents the solid-phase syntheses and liquid chromatography and mass spectrometry characterization of ten linear peptides related to angiotensin II against mature P. gallinaceum sporozoites and erythrocyte invasion by P. falciparum. Conformational analyses were performed by circular dichroism. IC50 assays were performed to identify the ideal concentration used on the biological tests and haemolytical erythrocytic assays were made to verify the viability of the biological experiments. The contractile responses of the analogues were made to evaluate if they are promising candidates to be applied as antiplasmodial drugs. RESULTS: The results indicate two short-peptides constituted by hydrophobic residues (5 and 6) with antiplasmodial activity in these models, 89 and 94 % of biological activity against P. gallinaceum sporozoite, respectively, and around 50 % of activity against P. falciparum. Circular dichroism spectra suggested that all the peptides adopted beta-turn conformation in different solutions, except peptide 3. Besides the biological assays IC50, the haemolysis assays and contractile response activities were applied for peptides 5 and 6, which did not present expressive results. CONCLUSIONS: The hydrophobic portion and the arginine, tyrosine, proline, and phenylalanine, when present on peptide primary sequence, tend to increase the antiplasmodial activity. This class of peptides can be explored, as anti-malarial drugs, after in vivo model tests. Graphical abstract: The most active peptide presented 94 % activity on P. gallinaceum sporozoites and 53 % inhibited P. falciparum ring forms invasion. PMID- 26537731 TI - Knowledge and attitudes of doctors towards e-health use in healthcare delivery in government and private hospitals in Northern Uganda: a cross-sectional study. AB - BACKGROUND: E-health is an essential information sharing tool in healthcare management and delivery worldwide. However, utilization of e-health may only be possible if healthcare professionals have positive attitudes towards e-health. This study aimed to determine the relationships between healthcare professionals' attitudes towards e-health, level of ICT skills and e-Health use in healthcare delivery in government and private hospitals in northern Uganda. METHODS: Cross sectional survey design was used. Sixty-eight medical doctors in three government hospitals and four private hospitals in Northern Uganda participated in the study. A pretested self-administered questionnaire was used to collect the required data. Data was analysed using SPSS software Version 19. RESULTS: Out of the 68 respondents, 39 (57.4 %) reported access to computer and 29 (48.5 %) accessed Internet in the workplace. Majority of healthcare professionals had positive attitudes towards e-health attributes (mean 3.5). The level of skills was moderate (mean 3.66), and was the most important and significant predictor of ICT use among healthcare professionals (r = .522, p < .001); however, attitudes towards e-health attributes did not contribute significantly in predicting e health use. CONCLUSIONS: The findings suggest need for hospitals managements to strengthen e-health services in healthcare delivery in Northern Uganda. PMID- 26537732 TI - Newly diagnosed rheumatic heart disease among indigenous populations in the Pacific. AB - OBJECTIVES: Rheumatic heart disease (RHD) remains the leading acquired heart disease in the young worldwide. We aimed at assessing outcomes and influencing factors in the contemporary era. METHODS: Hospital-based cohort in a high-income island nation where RHD remains endemic and the population is captive. All patients admitted with newly diagnosed RHD according to World Heart Federation echocardiographic criteria were enrolled (2005-2013). The incidence of major cardiovascular events (MACEs) including heart failure, peripheral embolism, stroke, heart valve intervention and cardiovascular death was calculated, and their determinants identified. RESULTS: Of the 396 patients, 43.9% were male with median age 18 years (IQR 10-40)). 127 (32.1%) patients presented with mild, 131 (33.1%) with moderate and 138 (34.8%) with severe heart valve disease. 205 (51.8%) had features of acute rheumatic fever. 106 (26.8%) presented with at least one MACE. Among the remaining 290 patients, after a median follow-up period of 4.08 (95% CI 1.84 to 6.84) years, 7 patients (2.4%) died and 62 (21.4%) had a first MACE. The annual incidence of first MACE and of heart failure were 59.050/00 (95% CI 44.35 to 73.75) and 29.060/00 (95% CI 19.29 to 38.82), respectively. The severity of RHD at diagnosis (moderate vs mild HR 3.39 (0.95 to 12.12); severe vs mild RHD HR 10.81 (3.11 to 37.62), p<0.001) and ongoing secondary prophylaxis at follow-up (HR 0.27 (0.12 to 0.63), p=0.01) were the two most influential factors associated with MACE. CONCLUSIONS: Newly diagnosed RHD is associated with poor outcomes, mainly in patients with moderate or severe valve disease and no secondary prophylaxis. PMID- 26537733 TI - BitTorious volunteer: server-side extensions for centrally-managed volunteer storage in BitTorrent swarms. AB - BACKGROUND: Our publication of the BitTorious portal [1] demonstrated the ability to create a privatized distributed data warehouse of sufficient magnitude for real-world bioinformatics studies using minimal changes to the standard BitTorrent tracker protocol. In this second phase, we release a new server-side specification to accept anonymous philantropic storage donations by the general public, wherein a small portion of each user's local disk may be used for archival of scientific data. We have implementated the server-side announcement and control portions of this BitTorrent extension into v3.0.0 of the BitTorious portal, upon which compatible clients may be built. RESULTS: Automated test cases for the BitTorious Volunteer extensions have been added to the portal's v3.0.0 release, supporting validation of the "peer affinity" concept and announcement protocol introduced by this specification. Additionally, a separate reference implementation of affinity calculation has been provided in C++ for informaticians wishing to integrate into libtorrent-based projects. CONCLUSIONS: The BitTorrent "affinity" extensions as provided in the BitTorious portal reference implementation allow data publishers to crowdsource the extreme storage prerequisites for research in "big data" fields. With sufficient awareness and adoption of BitTorious Volunteer-based clients by the general public, the BitTorious portal may be able to provide peta-scale storage resources to the scientific community at relatively insignificant financial cost. PMID- 26537734 TI - Former Chelsea team doctor alleges victimisation against Mourinho. PMID- 26537735 TI - Fish oil supplemented for 9 months does not improve glycaemic control or insulin sensitivity in subjects with impaired glucose regulation: a parallel randomised controlled trial. AB - The effects of fish oil (FO) supplementation on glycaemic control are unclear, and positive effects may occur only when the phospholipid content of tissue membranes exceeds 14% as n-3 PUFA. Subjects (n 36, thirty-three completed) were paired based on metabolic parameters and allocated into a parallel double-blind randomised trial with one of each pair offered daily either 6 g of FO (3.9 g n-3 PUFA) or 6 g of maize oil (MO) for 9 months. Hyperinsulinaemic-euglycaemic euaminoacidaemic (HIEGEAA) clamps (with [6,6 2H2 glucose]) were performed at the start and end of the intervention. Endogenous glucose production (EGP) and whole body protein turnover (WBPT) were each measured after an overnight fast. The primary outcome involved the effect of oil type on insulin sensitivity related to glycaemic control. The secondary outcome involved the effect of oil type on WBPT. Subjects on FO (n 16) had increased erythrocyte n-3 PUFA concentrations >14%, whereas subjects on MO (n 17) had unaltered n-3 PUFA concentrations at 9%. Type of oil had no effect on fasting EGP, insulin sensitivity or total glucose disposal during the HIEGEAA clamp. In contrast, under insulin-stimulated conditions, total protein disposal (P=0.007) and endogenous WBPT (P=0.001) were both increased with FO. In an associated pilot study (n 4, three completed), although n-3 PUFA in erythrocyte membranes increased to >14% with the FO supplement, the enrichment in muscle membranes remained lower (8%; P<0.001). In conclusion, long-term supplementation with FO, at amounts near the safety limits set by regulatory authorities in Europe and the USA, did not alter glycaemic control but did have an impact on WBPT. PMID- 26537736 TI - Does defensive medicine protect doctors against malpractice claims? PMID- 26537737 TI - Comparison of orthologous cytochrome P450 genes relative expression patterns in the bark beetles Dendroctonus rhizophagus and Dendroctonus valens (Curculionidae: Scolytinae) during host colonization. AB - Bark beetles of the genus Dendroctonus are important components of coniferous forests. During host colonization, they must overcome the chemical defences of their host trees, which are metabolized by cytochrome P450 (CYP or P450) enzymes to compounds that are readily excreted. In this study, we report the relative expression (quantitative real-time PCR) of four orthologous cytochrome P450 genes (CYP6BW5, CYP6DG1, CYP6DJ2 and CYP9Z20) in Dendroctonus rhizophagus and Dendroctonus valens forced to attack host trees at 8 and 24 h following forced attack and in four stages during natural colonization [solitary females boring the bark (T1); both male and female members of couples before oviposition (T2); both male and female members of couples during oviposition (T3), and solitary females inside the gallery containing eggs (T4)]. For both species gene expression was different compared with that observed in insects exposed to single monoterpenes in the laboratory, and the expression patterns were significantly different amongst species, sex, gut region and exposure time or natural colonization stage. The induction of genes (CYP6BW5v1, CYP6DJ2v1 and CYP9Z20v1 from D. rhizophagus, as well as CYP6DG1v3 from D. valens) correlated with colonization stage as well as with the increase in oxygenated monoterpenes in the gut of both species throughout the colonization of the host. Our results point to different functions of these orthologous genes in both species. PMID- 26537741 TI - Modelling the superspreading of surfactant-laden droplets with computer simulation. AB - The surfactant-driven superspreading of droplets on hydrophobic substrates is considered. A key element of the superspreading mechanism is the adsorption of surfactant molecules from the liquid-vapour interface onto the substrate through the contact line, which must be coordinated with the replenishment of interfaces with surfactant from the interior of the droplet. We use molecular dynamics simulations with coarse-grained force fields to provide a detailed structural description of the droplet shape and surfactant dynamics during the superspreading process. We also provide a simple method for accurate estimation of the contact angle subtended by the droplets at the contact line. PMID- 26537742 TI - Intermolecular Interactions and Protein Dynamics by Solid-State NMR Spectroscopy. AB - Understanding the dynamics of interacting proteins is a crucial step toward describing many biophysical processes. Here we investigate the backbone dynamics for protein GB1 in two different assemblies: crystalline GB1 and the precipitated GB1-antibody complex with a molecular weight of more than 300 kDa. We perform these measurements on samples containing as little as eight nanomoles of GB1. From measurements of site-specific (15) N relaxation rates including relaxation dispersion we obtain snapshots of dynamics spanning nine orders of magnitude in terms of the time scale. A comparison of measurements for GB1 in either environment reveals that while many of the dynamic features of the protein are conserved between them (in particular for the fast picosecond-nanosecond motions), much greater differences occur for slow motions with motions in the >500 ns range being more prevalent in the complex. The data suggest that GB1 can potentially undergo a small-amplitude overall anisotropic motion sampling the interaction interface in the complex. PMID- 26537743 TI - Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. AB - OBJECTIVE: Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks. METHODS: A retrospective review was made of patient records to assess demographic/diagnostic data, attack characteristics, therapies, and the short-term remission status (complete remission [CR], partial remission [PR], no remission [NR]). Inclusion criteria were NMO according to Wingerchuk's 2006 criteria or aquaporin-4 antibody-positive NMO spectrum disorder (NMOSD). Remission status was analyzed with generalized estimating equations (GEEs), a patient-based statistical approach. RESULTS: A total of 871 attacks in 185 patients (142 NMO/43 NMOSD, 82% female) were analyzed. The 1,153 treatment courses comprised high-dose intravenous steroids (HD-S; n = 810), plasma exchange (PE; n = 192), immunoadsorption (IA; n = 38), other (n = 80), and unknown (n = 33) therapies. The first treatment course led to CR in 19.1%, PR in 64.5%, and NR in 16.4% of attacks. Second, third, fourth, and fifth treatment courses were given in 28.2%, 7.1%, 1.4%, and 0.5% of attacks, respectively. This escalation of attack therapy significantly improved outcome (p < 0.001, Bowker test). Remission rates were higher for isolated optic neuritis versus isolated myelitis (p < 0.001), and for unilateral versus bilateral optic neuritis (p = 0.020). Isolated myelitis responded better to PE/IA than to HD-S as first treatment course (p = 0.037). Predictors of CR in multivariate GEE analysis were age (odds ratio [OR] = 0.97, p = 0.011), presence of myelitis (OR = 0.38, p = 0.002), CR from previous attack (OR = 6.85, p < 0.001), and first-line PE/IA versus HD-S (OR = 4.38, p = 0.006). INTERPRETATION: Particularly myelitis and bilateral optic neuritis have poor remission rates. Escalation of attack therapy improves outcome. PE/IA may increase recovery in isolated myelitis. PMID- 26537744 TI - Differences in the efficacy of carboxylic acid amide fungicides against less sensitive strains of Plasmopara viticola. AB - BACKGROUND: Plasmopara viticola is controlled by fungicides with different modes of action, including carboxylic acid amides (CAAs). The aim of this study was to evaluate differences in the response of CAA-resistant P. viticola strains towards CAAs. RESULTS: The G1105S mutation affects all four CAAs, but with different impacts. While this confirms that they have the same mode of action, it shows that differences between CAAs can occur. CONCLUSION: Further molecular modelling and docking studies are needed to gain a better understanding of the different behaviours reported here. (c) 2015 Society of Chemical Industry. PMID- 26537745 TI - NADPH Oxidase-Derived ROS Signaling and Therapeutic Opportunities. PMID- 26537746 TI - Surgical management of damaged inferior alveolar nerve caused by endodontic overfilling of calcium hydroxide paste. AB - AIM: To evaluate the neurosensory outcome of management of damaged inferior alveolar nerves caused by endodontic overfilling and to assess the efficacy of delayed surgical intervention. METHODOLOGY: Nine patients who underwent surgical removal of extruded endodontic material were included. All patients were evaluated for neurosensory function using a set of standardized tests. The outcome of surgical intervention was evaluated through patient interview and quantitative statistical analysis. RESULTS: Surgical procedures included foreign body removal, microsurgical external/internal decompression, excision of neuroma followed by nerve repair, and excision of damaged nerve segment with interpositional nerve graft. Seven of the nine patients had significant improvement according to the follow-up neurosensory assessment. Four patients reported significant improvement, three patients reported mild improvement and two patients reported no appreciable improvement in the Visual Analog Scale (VAS). Two patients who reported no appreciable improvement in VAS also did not achieve FSR. In these patients, calcium hydroxide was spread widely along the IAN and a surgical approach was obtained via sagittal spit osteotomy. The mean time to reach FSR was 222.7 (+/-41.8) days with a range of 106-397 days. In the early repair group who received surgery within 60 days, three out of five patients achieved FSR in a mean time of 198.0 (+/-76.2) days. The mean time to FSR in all four subjects who received surgical attention over 60 days after injury was 241.3 (+/-139.8) days with a range of 106-397 days. As all four cases in the late repair group with limited amount of nerve injury achieved FSR, only 3 of 5 early repair cases with wide-spread injury achieved a similar outcome. CONCLUSION: The results of this case series confirmed the notion that surgical management of the inferior alveolar nerve is effective in the treatment of nerve injuries caused by endodontic extrusion of calcium hydroxide paste. Delayed surgical repair of the inferior alveolar nerve can be indicated and helpful for the neurosensory recovery of damaged IAN, however, the surgical management was less effective in case of widespread nerve injuries. PMID- 26537747 TI - Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years. AB - Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of uncontrolled immune activation that has gained increasing attention over the past decade. Although classically known as a familial disorder of children caused by mutations that affect cytotoxic T-cell function, an acquired form of HLH in adults is now widely recognized. This is often seen in the setting of malignancy, infection or rheumatological disorders. We performed a retrospective review across 3 tertiary care centres and identified 68 adults with HLH. The average age was 53 years (range 18-77 years) and 43 were male (63%). Underlying disorders included malignancy in 33 patients (49%), infection in 22 (33%), autoimmune disease in 19 (28%) and idiopathic HLH in 15 (22%). Patients were treated with disease-specific therapy and immunomodulatory agents. After a median follow-up of 32.2 months, 46 patients had died (69%). The median overall survival was 4 months (95% CI: 0.0 10.2 months). Patients with malignancy had a worse prognosis compared to those without (median survival 2.8 months versus 10.7 months, P = 0.007). HLH is a devastating disorder with a high mortality. Further research is needed to improve treatment and outcomes. PMID- 26537748 TI - Immune-checkpoint blockade: the springboard for immuno-combination therapy. PMID- 26537749 TI - Mesophyll conductance plays a central role in leaf functioning of Oleaceae species exposed to contrasting sunlight irradiance. AB - The ability to modify mesophyll conductance (gm ) in response to changes in irradiance may be a component of the acclimation of plants to shade-sun transitions, thus influencing species-specific distributions along light gradients, and the ecological niches for the different species. To test this hypothesis we grew three woody species of the Oleaceae family, the evergreen Phillyrea latifolia (sun-requiring), the deciduous Fraxinus ornus (facultative sun-requiring) and the hemi-deciduous Ligustrum vulgare (shade tolerant) at 30 or 100% sunlight irradiance. We show that neither mesophyll conductance calculated with combined gas exchange and chlorophyll fluorescence techniques (gm) nor CO2 assimilation significantly varied in F. ornus because of sunlight irradiance. This corroborates previous suggestions that species with high plasticity for light requirements, do not need to undertake extensive reorganization of leaf conductances to CO2 diffusion to adapt to different light environments. On the other hand, gm steeply declined in L. vulgare and increased in P. latifolia exposed to full-sun conditions. In these two species, leaf anatomical traits are in part responsible for light-driven changes in gm , as revealed by the correlation between gm and mesophyll conductance estimated by anatomical parameters (gmA). Nonetheless, gm was greatly overestimated by gmA when leaf metabolism was impaired because of severe light stress. We show that gm is maximum at the light intensity at which plant species have evolved and we conclude that gm actually plays a key role in the sun and shade adaptation of Mediterranean species. The limits of gmA in predicting mesophyll conductance are also highlighted. PMID- 26537750 TI - Action observation network in childhood: a comparative fMRI study with adults. AB - Very little is known about the action observation network and the mirror neuron system (AON/MNS) in children and its age-related properties compared with those observed in adults. In the present fMRI study we explored the activation of areas belonging to the AON/MNS in children and adults during observation of complex hand-grasping actions, as compared to observation of simple grasping acts executed with the left and the right hand, seen from a first person perspective. The results indicate that during the action observation tasks in children there was activation of a cortical network similar to that found in adults, including the premotor cortex, the posterior part of the inferior frontal gyrus and the posterior parietal lobe. However, the activation in children was more widespread and showed a higher inter-subject variability compared with adults. Furthermore, the activated network seems more lateralized to the left hemisphere in adults and more bilateral in children, with a linear growth of lateralization index as a function of age. Finally, in children the activation in the anterior intraparietal cortex (AIP) of each hemisphere was higher during observation of the contralateral hand (hand identity effect) and during the observation of complex actions relative to simple grasping acts, confirming the role of AIP for action-related hand identity previously described in adults. These results support the assumption that structure and size of action representations are sensitive to mechanisms of development and show physiological plasticity. These properties of the AON/MNS could constitute a powerful tool for spontaneous reorganization and recovery of motor deficits after brain injury in children and in adults, as well as for specific rehabilitation programmes. PMID- 26537752 TI - Erratum. AB - Deason K, Miller-Little WA and Stuve O. Natalizumab and monocytes in multiple sclerosis: The dim haze of mystery and the enchantment of pursuit. Multiple Scleroris Journal 2015; DOI: 10.1177/1352458515574150The above editorial, originally published online on the 26th of May 2015 and amended on the 5th of October 2015, was published in error.SAGE offers its apologies for this mistake. PMID- 26537751 TI - Slc15a1 is involved in the transport of synthetic F5-peptide into the seminiferous epithelium in adult rat testes. AB - Spermiation and BTB restructuring, two critical cellular events that occur across seminiferous epithelium in mammalian testis during spermatogenesis, are tightly coordinated by biologically active peptides released from laminin chains. Our earlier study reported that F5-peptide, synthesized based on a stretch of 50 amino acids within laminin-gamma3 domain IV, could reversibly induce the impairment of spermatogenesis, disruption of BTB integrity, and germ cell loss, and thus is a promising male contraceptive. However, how F5-peptide when administered intratesticularly enters seminiferous tubules and exerts effects beyond BTB is currently unknown. Here we demonstrated that Slc15a1, a peptide transporter also known as Pept1, was predominantly present in peritubular myoid cells, interstitial Leydig cells, vascular endothelial cells and germ cells, while absent in Sertoli cells or BTB site. The steady-state protein level of Slc15a1 in adult rat testis was not affected by F5-peptide treatment. Knockdown of Slc15a1 by in vivo RNAi in rat testis was shown to prevent F5-peptide induced disruptive effects on spermatogenesis. This study suggests that Slc15a1 is involved in the transport of synthetic F5-peptide into seminiferous epithelium, and thus Slc15a1 is a novel target in testis that could be genetically modified to improve the bioavailability of F5-peptide as a prospective male contraceptive. PMID- 26537753 TI - Bacterial and plant HAD enzymes catalyse a missing phosphatase step in thiamin diphosphate biosynthesis. AB - The penultimate step of thiamin diphosphate (ThDP) synthesis in plants and many bacteria is dephosphorylation of thiamin monophosphate (ThMP). Non-specific phosphatases have been thought to mediate this step and no genes encoding specific ThMP phosphatases (ThMPases) are known. Comparative genomic analysis uncovered bacterial haloacid dehalogenase (HAD) phosphatase family genes (from subfamilies IA and IB) that cluster on the chromosome with, or are fused to, thiamin synthesis genes and are thus candidates for the missing phosphatase (ThMPase). Three typical candidates (from Anaerotruncus colihominis, Dorea longicatena and Syntrophomonas wolfei) were shown to have efficient in vivo ThMPase activity by expressing them in an Escherichia coli strain engineered to require an active ThMPase for growth. In vitro assays confirmed that these candidates all preferred ThMP to any of 45 other phosphate ester substrates tested. An Arabidopsis thaliana ThMPase homologue (At4g29530) of unknown function whose expression pattern and compartmentation fit with a role in ThDP synthesis was shown to have in vivo ThMPase activity in E. coli and to prefer ThMP to any other substrate tested. However, insertional inactivation of the At4g29530 gene did not affect growth or the levels of thiamin or its phosphates, indicating that Arabidopsis has at least one other ThMPase gene. The Zea mays orthologue of At4g29530 (GRMZM2G035134) was also shown to have ThMPase activity. These data identify HAD genes specifying the elusive ThMPase activity, indicate that ThMPases are substrate-specific rather than general phosphatases and suggest that different evolutionary lineages have recruited ThMPases independently from different branches of the HAD family. PMID- 26537754 TI - The role of N-glycans and the C-terminal loop of the subunit rBAT in the biogenesis of the cystinuria-associated transporter. AB - The transport system b(0,+) mediates reabsorption of dibasic amino acids and cystine in the kidney. It is made up of two disulfide-linked membrane subunits: the carrier, b(0,+)AT and the helper, rBAT (related to b(0,+) amino acid transporter). rBAT mutations that impair biogenesis of the transporter cause type I cystinuria. It has been shown that upon assembly, b(0,+)AT prevents degradation and promotes folding of rBAT; then, rBAT traffics b(0,+)AT from the endoplasmic reticulum (ER) to the plasma membrane. The role of the N-glycans of rBAT and of its C-terminal loop, which has no homology to any other sequence, in biogenesis of system b(0,+) is unknown. In the present study, we studied these points. We first identified the five N-glycans of rBAT. Elimination of the N-glycan Asn(575), but not of the others, delayed transporter maturation, as measured by pulse chase experiments and endoglycosidase H assays. Moreover, a transporter with only the N-glycan Asn(575) displayed similar maturation compared with wild type, suggesting that this N-glycan was necessary and sufficient to achieve the maximum rate of transporter maturation. Deletion of the rBAT C-terminal disulfide loop (residues 673-685) prevented maturation and prompted degradation of the transporter. Alanine-scanning mutagenesis uncovered loop residues important for stability and/or maturation of system b(0,+). Further, double-mutant cycle analysis showed partial additivity of the effects of the Asn(679) loop residue and the N-glycan Asn(575) on transporter maturation, indicating that they may interact during system b(0,+) biogenesis. These data highlight the important role of the N-glycan Asn(575) and the C-terminal disulfide loop of rBAT in biogenesis of the rBAT-b(0,+)AT heterodimer. PMID- 26537755 TI - Safety and efficacy of miniaturized extracorporeal circulation when compared with off-pump and conventional coronary artery bypass grafting: evidence synthesis from a comprehensive Bayesian-framework network meta-analysis of 134 randomized controlled trials involving 22 778 patients. AB - OBJECTIVES: Coronary artery bypass grafting (CABG) remains the standard of care in patients with extensive coronary artery disease. Yet the use of cardiopulmonary bypass (CPB) is believed to be a major determinant of perioperative morbidity. Novel techniques are sought to tackle the shortcomings of CPB, among them off-pump coronary artery bypass (OPCAB) and miniaturized extracorporeal circulation (MECC) systems have been extensively tested in randomized controlled trials (RCTs). To assess perioperative safety and efficacy of MECC and OPCAB when compared with conventional extracorporeal circulation (CECC). METHODS: Published literature and major congress proceedings were screened for RCTs evaluating the safety and efficacy of MECC, OPCAB and CECC. Selected end-points such as 30-day all-cause mortality, myocardial infarction (MI), cerebral stroke, postoperative atrial fibrillation (POAF) and renal dysfunction were assessed in a Bayesian-framework network meta-analysis. RESULTS: A total of 134 studies with 22 778 patients were included. When compared with CECC, both OPCAB and MECC significantly reduced 30-day all-cause mortality [odds ratios (95% credible intervals): 0.75 (0.51-0.99) and 0.46 (0.22-0.91)], respectively. No differences in respect to MI were demonstrated with either strategy. OPCAB, when compared with CECC, reduced the odds of cerebral stroke [0.57 (0.34-0.80)]; 60% reduction was observed with MECC when compared with CECC [0.40 (0.19-0.78)]. Both OPCAB and MECC reduced the odds of POAF [0.66 (0.48 0.90) and 0.62 (0.35-0.98), respectively] when compared with CECC. OPCAB conferred over 30% reduction of renal dysfunction when compared with CECC [0.69 (0.46-0.92)]. MECC reduced these odds by more than 50% [0.47 (0.24-0.89)]. Ranking of treatments emerging from the probability analysis (highest to lowest SUCRA values) was MECC followed by OPCAB and CECC. CONCLUSIONS: MECC and OPCAB both improve perioperative outcomes following coronary bypass surgery when compared with conventional CABG performed with extracorporeal circulation. MECC may represent an attractive compromise between OPCAB and CECC. PMID- 26537756 TI - Myasthenia gravis with thymic epithelial tumour: a retrospective analysis of a Japanese database. AB - OBJECTIVES: Myasthenia gravis (MG) has been reported to correlate with earlier stage and Type B thymomas by the World Health Organization classification. We analysed a large database of clinical characteristics of patients with MG and thymic epithelial tumours to elucidate whether the severity of MG affected postoperative survival of those with thymic epithelial neoplasms. METHODS: We conducted a multi-institutional study on the patients who had undergone surgical treatment for thymic epithelial tumours between 1991 and 2010. We examined Masaoka stage, pathological type, serum titre of antiacetylcholine receptor antigen, severity of MG and postoperative prognosis of the patients with or without MG. RESULTS: Of the 2835 registered patients at 32 institutes belonging to the Japanese Association for Research on the Thymus, 2638 were eligible for the study. MG was present in 598 patients (23%). Patients with MG had thymic epithelial tumours with significantly earlier stage (P = 0.0082) and significantly smaller tumours (P = 0.000) than those without. Type A, Type AB thymomas and thymic carcinomas were less frequently observed in patients with MG. Three of 304 patients (1%) with thymic carcinomas had MG preoperatively. Serum titres of antiacetylcholine receptor antibodies were positive in 98% of patients with MG, and 23% of those without. Patients with generalized MG had significantly higher titres of antiacetylcholine receptor antibodies than those with ocular MG (P = 0.000). The postoperative 30-day mortality rate was 0.3%. Postoperative 5- and 10-year survival rates of thymoma patients with MG and those without MG were 94 and 96, and 89 and 89%, respectively. We found no statistical difference in the postoperative survival rate or recurrence-free rate between the two groups. We found no significant statistical differences of these rates by MGFA classification or surgical approach. CONCLUSIONS: We conclude that earlier stage, smaller size or Type B thymomas are more frequently associated with MG, and MG may have no impact on the overall survival of patients with thymoma. We suggest that postoperative survival time of the patients with MG and thymic epithelial tumours may be mainly affected by the tumours, not by MG. PMID- 26537757 TI - Cyclodextrin capped CdTe quantum dots as versatile fluorescence sensors for nitrophenol isomers. AB - Cyclodextrin (CD) capped CdTe quantum dots (QDs) were prepared with uniform dimension (average diameter ~5 nm) and high quantum yield (ca. 65%). By taking advantage of the inclusion complexation of CD, beta-CD-CdTe QDs exhibited strong fluorescence quenching in a linear relationship with the concentration of o-, m- and p-nitrophenol in the range of 20-100 MUM. The detection limit reached 0.05 MUM for o-/p-nitrophenol and 0.3 MUM for m-nitrophenol. The fluorescence decay study revealed the stabilization effect of CD covering on CdTe QDs and fine tuning of the fluorescence for selective ultrasensitive detection of nitrophenol isomers. PMID- 26537758 TI - A course-based undergraduate research experience investigating p300 bromodomain mutations. AB - Course-based undergraduate research experiences (CUREs) provide an opportunity for students to engage in experiments with outcomes that are unknown to both the instructor and students. These experiences allow students and instructors to collaboratively bridge the research laboratory and classroom, and provide research experiences for a large number of students relative to traditional individual mentored research. Here, we describe a molecular biology CURE investigating the impact of clinically relevant mutations found in the bromodomain of the p300 transcriptional regulator on acetylated histone interaction. In the CURE, students identified missense mutations in the p300 bromodomain using the Catalogue of Somatic Mutations in Cancer (COSMIC) database and hypothesized the effects of the mutation on the acetyl-binding function of the domain. They cloned and purified the mutated bromodomain and performed peptide pulldown assays to define its potential to bind to acetylated histones. Upon completion of the course, students showed increased confidence performing molecular techniques and reported positively on doing a research project in class. In addition, results generated in the classroom were further validated in the research laboratory setting thereby providing a new model for faculty to engage in both course-based and individual undergraduate research experiences. PMID- 26537760 TI - Designing Drug Conjugates Based on Sugar Decorated V-Shape and Star Polymethacrylates: Influence of Composition and Architecture of Polymeric Carrier. AB - Amphiphilic ethylenediamine (EDA)-functionalized V-shape and star copolymers with centrally placed methyl-alpha,D-glucopyranoside were designed as nanocarriers. Anticancer doxorubicin (DOX) was conjugated in water via amine groups in copolymers to form ketimine linkers. Variations of arm length and number (40-65 units per arm and 2 vs 3 vs 4 arms), DOX feed amount, and conjugation site content (50-160 units of EDA groups), as responsible for efficiency of drug attachment (10-60 units of conjugated DOX) and its release at various pH (5.0 vs 7.4), were studied to demonstrate potential for drug delivery. Size of conjugate particles (10-195 nm) formed in aqueous solution was strongly dependent on the polymer composition and topology. The broad range of drug amounts (25-95%) were detected by the precipitation method, showing pH sensitivity by some polymeric conjugates with faster DOX release in acidic conditions. PMID- 26537759 TI - A Markov chain model for N-linked protein glycosylation--towards a low-parameter tool for model-driven glycoengineering. AB - Glycosylation is a critical quality attribute of most recombinant biotherapeutics. Consequently, drug development requires careful control of glycoforms to meet bioactivity and biosafety requirements. However, glycoengineering can be extraordinarily difficult given the complex reaction networks underlying glycosylation and the vast number of different glycans that can be synthesized in a host cell. Computational modeling offers an intriguing option to rationally guide glycoengineering, but the high parametric demands of current modeling approaches pose challenges to their application. Here we present a novel low-parameter approach to describe glycosylation using flux-balance and Markov chain modeling. The model recapitulates the biological complexity of glycosylation, but does not require user-provided kinetic information. We use this method to predict and experimentally validate glycoprofiles on EPO, IgG as well as the endogenous secretome following glycosyltransferase knock-out in different Chinese hamster ovary (CHO) cell lines. Our approach offers a flexible and user-friendly platform that can serve as a basis for powerful computational engineering efforts in mammalian cell factories for biopharmaceutical production. PMID- 26537761 TI - Maternal protein restriction that does not have an influence on the birthweight of the offspring induces morphological changes in kidneys reminiscent of phenotypes exhibited by intrauterine growth retardation rats. AB - Severe restriction of maternal protein intake to 6-8% protein diet results in intrauterine growth retardation (IUGR), low birthweight and high risk of metabolic syndrome in the adult life of the offspring. However, little information is available on the effects of maternal protein restriction on offspring under the conditions that does not have an influence on their birthweight of the offspring,. In the present study, pregnant rats were kept on a diet consisting of either 9% (low-protein, Lp rats) or 18% (normal-protein, Np rats) protein by weight/volume/etc. After birth, both Lp and Np rats were kept on a diet containing 18% protein. Neonatal body weight was significantly lower in Lp rats compared to Np rats from 4 days to 5 weeks after birth. While glomerular number per unit volume (1 mm(3) ) of the kidney (Nv) was comparable between Lp and Np rats 4 weeks after birth, the Nv was significantly decreased in Lp rats at 20 weeks after birth. Four and 20 weeks after birth, glomerular sclerosis index, interstitial fibrosis score, and ratio of ED1-positive cell ratio were all significantly higher in Lp compared to Np rats. Transforming growth factor-beta1 positive cells were observed in the distal tubules in the kidney of 4- and 20 week-old Lp rats kidneys, but not in those of age-matched Np rats. Altogether, these findings revealed that maternal protein restriction that does not have an influence on the birthweight of the offspring, induces similar changes as those seen in the kidneys of IUGR neonates. PMID- 26537762 TI - [Learning from a critical incident reporting system in the pediatric intensive care unit]. AB - BACKGROUND: To record and analyze critical incidents is of paramount importance for any organization dedicated to improving patient safety. Therefore, many hospitals have implemented a critical incident reporting system (CIRS). However, the impact, benefits and use of such CIRS systems on patient safety have often been reported to be unsatisfactory. AIM: What have we learned over the past decade about the effective and optimal use of a CIRS? MATERIAL AND METHODS: Following the Yorkshire contributory factors framework, the potential benefits of a CIRS are illustrated with selected examples from the neonatal and pediatric intensive care unit. Based on a literature search in PubMed from January 2000 to December 2014 this article also describes critical factors and concepts for the successful use of a CIRS. RESULTS: A positive mind-set towards errors, high psychological safety and the conviction that a CIRS can be beneficial are important factors to encourage individual healthcare personnel to report critical incidents and learn from errors. On the part of the organization, adequate resources of personnel, systematic analysis of the reported incidents as well as dissemination of the results and implementation of safety improvement strategies are critical factors for the effective use of a CIRS. All incidents with potential relevance for patient safety should be reported. The categorization of the reported incidents facilitates the analysis and identification of relevant conclusions. As an organization dedicated to improve patient safety we have to learn from errors as well as from successes. CONCLUSION: The successful use of a CIRS depends on the motivation of individual healthcare providers as well as on organizational features that encourage critical incident reporting. PMID- 26537763 TI - Immunodeficiency and the risk of cervical intraepithelial neoplasia 2/3 and cervical cancer: A nested case-control study in the Swiss HIV cohort study. AB - HIV-infected women are at increased risk of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC), but it has been difficult to disentangle the influences of heavy exposure to HPV infection, inadequate screening and immunodeficiency. A case-control study including 364 CIN2/3 and 20 ICC cases matched to 1,147 controls was nested in the Swiss HIV Cohort Study (1985-2013). CIN2/3 risk was significantly associated with low CD4+ cell counts, whether measured as nadir [odds ratio (OR) per 100-cell/MUL decrease = 1.15, 95% CI: 1.08, 1.22], or at CIN2/3 diagnosis (1.10, 95% CI: 1.04, 1.16). An association was evident even for nadir CD4+ 200-349 versus >=350 cells/MUL (OR = 1.57, 95% CI: 1.09, 2.25). After adjustment for nadir CD4+, a protective effect of >2-year cART use was seen against CIN2/3 (OR versus never cART use = 0.64, 95% CI: 0.42, 0.98). Despite low study power, similar associations were seen for ICC, notably with nadir CD4+ (OR for 50 vs. >350 cells/MUL= 11.10, 95% CI: 1.24, 100). HPV16-L1 antibodies were significantly associated with CIN2/3, but HPV16-E6 antibodies were nearly exclusively detected in ICC. In conclusion, worsening immunodeficiency, even at only moderately decreased CD4+ cell counts, is a significant risk factor for CIN2/3 and cervical cancer. PMID- 26537764 TI - Injection of new psychoactive substance snow blow associated with recently acquired HIV infections among homeless people who inject drugs in Dublin, Ireland, 2015. AB - In February 2015, an outbreak of recently acquired HIV infections among people who inject drugs (PWID) was identified in Dublin, following similar outbreaks in Greece and Romania in 2011. We compared drug and risk behaviours among 15 HIV cases and 39 controls. Injecting a synthetic cathinone, snow blow, was associated with recent HIV infection (AOR: 49; p=0.003). Prevention and control efforts are underway among PWID in Dublin, but may also be needed elsewhere in Europe. PMID- 26537765 TI - A Genetic Variant in Pre-miR-146a (rs2910164 C>G) Is Associated with the Decreased Risk of Acute Coronary Syndrome in a Chinese Population. AB - MicroRNAs (miRNAs) can contribute to the development of cardiovascular diseases, and single nucleotide polymorphisms (SNPs) in miRNA genes may influence disease susceptibility by altering mature miRNA expression levels. However, the effect of SNPs located in miR-146a and miR-196a2 genes on risk of acute coronary syndrome (ACS) has not been reported in the Chinese population. Two miRNA polymorphisms located in miRNA genes (miR-146a rs2910164 C>G and miR-196a2 rs11614913 T>C) were genotyped in 722 ACS patients and 721 control subjects. The CG genotype of rs2910164 was significantly associated with decreased risk of ACS [CG vs. CC, odds ratio (OR) = 0.72, 95% confidence interval (CI): 0.55-0.95, P = 0.020; dominant model, OR = 0.77, 95% CI: 0.60-0.99, P = 0.044]. We did not find any association of rs11614913 with the risk of ACS. Stratification analysis showed that the rs2910164 CG genotype was associated with decreased risk of ACS (dominant model) in males, subjects with body mass index more than 24 kg/m(2), and in hypertensive subjects. Significant combined effects were also observed between rs2910164 and blood lipids or C-reactive protein levels. In summary, this study provides the first evidence that the CG genotype of miR-146a rs2910164 is associated with a significantly decreased risk of ACS in a Chinese population. Moreover, rs2910164 and blood lipids or an inflammatory marker may have a combined effect on the onset of ACS. These findings indicate that miR-146a rs2910164 may act as a novel molecular marker for ACS susceptibility. PMID- 26537766 TI - 'Next-Generation' Surveillance: An Epidemiologists' Perspective on the Use of Molecular Information in Food Safety and Animal Health Decision-Making. AB - Advances in the availability and affordability of molecular and genomic data are transforming human health care. Surveillance aimed at supporting and improving food safety and animal health is likely to undergo a similar transformation. We propose a definition of 'molecular surveillance' in this context and argue that molecular data are an adjunct to rather than a substitute for sound epidemiological study and surveillance design. Specific considerations with regard to sample collection are raised, as is the importance of the relation between the molecular clock speed of genetic markers and the spatiotemporal scale of the surveillance activity, which can be control- or strategy-focused. Development of standards for study design and assessment of molecular surveillance system attributes is needed, together with development of an interdisciplinary skills base covering both molecular and epidemiological principles. PMID- 26537767 TI - Structure and functional analysis of the siderophore periplasmic binding protein from the fuscachelin gene cluster of Thermobifida fusca. AB - Iron acquisition is a complex, multicomponent process critical for most organisms' survival and virulence. Small iron chelating molecules, siderophores, mediate transport as key components of common pathways for iron assimilation in many microorganisms. The chemistry and biology of the extraordinary tight and specific metal binding siderophores is of general interest in terms of host/guest chemistry and is a potential target toward the development of therapeutic treatments for microbial virulence. The siderophore pathway of the moderate thermophile, Thermobifida fusca, is an excellent model system to study the process in Gram-positive bacteria. Here we describe the structure and characterization of the siderophore periplasmic binding protein, FscJ from the fuscachelin gene cluster of T. fusca. The structure shows a di-domain arrangement connected with a long alpha-helix hinge. Several X-ray structures detail ligand free conformational changes at different pH values, illustrating complex interdomain flexibility of the siderophore receptors. We demonstrated that FscJ has a unique recognition mechanism and details the binding interaction with ferric-fuscachelin A through ITC and docking analysis. The presented work provides a structural basis for the complex molecular mechanisms of siderophore recognition and transportation. PMID- 26537768 TI - The influence of metabolic and circulatory heterogeneity on the expression of pulmonary oxygen uptake kinetics in humans. AB - We examined the relationship amongst baseline work rate (WR), phase II pulmonary oxygen uptake (V(O2p)) time constant (tauV(O2p)) and functional gain (G(P)=DeltaV(O2p)/DeltaWR) during moderate-intensity exercise. Transitions were initiated from a constant or variable baseline WR. A validated circulatory model was used to examine the role of heterogeneity in muscle metabolism (V(O2m)) and blood flow (Q(m)) in determining V(O2p) kinetics. We hypothesized that tauV(O2p) and G(P) would be invariant in the constant baseline condition but would increase linearly with increased baseline WR. Fourteen men completed three to five repetitions of ?40 W step transitions initiated from 20, 40, 60, 80, 100 and 120 W on a cycle ergometer. The ?40 W step transitions from 60, 80, 100 and 120 W were preceded by 6 min of 20 W cycling, from which the progressive DeltaWR transitions (constant baseline condition) were examined. The V(O2p) was measured breath by breath using mass spectrometry and a volume turbine. For a given DeltaWR, both tauV(O2p) (22-35 s) and G(P) (8.7-10.5 ml min(-1) W(-1)) increased (P < 0.05) linearly as a function of baseline WR (20-120 W). The tauV(O2p) was invariant (P < 0.05) in transitions initiated from 20 W, but G(P) increased with DeltaWR (P < 0.05). Modelling the summed influence of multiple muscle compartments revealed that tauV(O2p) could appear fast (24 s), and similar to in vivo measurements (22 +/- 6 s), despite being derived from tauV(O2p) values with a range of 15-40 s and tauQ(m) with a range of 20-45 s, suggesting that within the moderate-intensity domain phase II V(O2p) kinetics are slowed dependent on the pretransition WR and are strongly influenced by muscle metabolic and circulatory heterogeneity. PMID- 26537769 TI - Nuclear expression and clinical significance of phosphohistidine phosphatase 1 in clear-cell renal cell carcinoma. AB - OBJECTIVE: To explore expression and clinical relevance of phosphohistidine phosphatase 1 (PHPT1) in clear-cell renal cell carcinoma. METHODS: Patients with clear-cell renal cell carcinoma who underwent radical or nephron-sparing nephrectomy were enrolled. Correlations between PHPT1 expression and demographic and clinical characteristics were analysed prospectively. RESULTS: In total, 122 patients (78 male/44 female) were included. In normal kidney tissue, PHPT1 expression was observed only in the proximal tubule. High PHPT1 expression levels were associated with larger tumour size, higher Fuhrman nuclear grade and advanced pathological tumour-node-metastasis (pTNM) stage compared with low PHPT1 expression levels. Patients with low PHPT1 expression showed better overall survival and progression-free survival compared with those with high PHPT1 expression. In addition, multivariate analysis showed that nuclear grade and pTNM stage were independent predictors of progression-free survival and overall survival in patients with clear-cell renal cell carcinoma. PHPT1 expression was also an independent predictor of overall survival but not progression-free survival. CONCLUSIONS: PHPT1 was expressed in the epithelium of proximal tubuli and nuclei of clear-cell renal cell carcinoma tissue samples. High levels of 14 kDa phosphohistidine phosphatase protein were negatively associated with overall survival and progression-free survival in patients with clear-cell renal cell carcinoma. PMID- 26537770 TI - The cold responsive mechanism of the paper mulberry: decreased photosynthesis capacity and increased starch accumulation. AB - BACKGROUND: Most studies on the paper mulberry are mainly focused on the medicated and pharmacology, fiber quality, leaves feed development, little is known about its mechanism of adaptability to abiotic stress. Physiological measurement, transcriptomics and proteomic analysis were employed to understand its response to cold stress in this study. METHODS: The second to fourth fully expanded leaves from up to down were harvested at different stress time points forthe transmission electron microscope (TEM) observation. Physiological characteristics measurement included the relative electrolyte leakage (REL), SOD activity assay, soluble sugar content, and Chlorophyll fluorescence parameter measurement. For screening of differentially expressed genes, the expression level of every transcript in each sample was calculated by quantifying the number of Illumina reads. To identify the differentially expressed protein, leaves of plants under 0, 6, 12, 24, 48 and 72 h cold stress wereharvested for proteomic analysis. Finally, real time PCR was used to verify the DEG results of the RNA seq and the proteomics data. RESULTS: Results showed that at the beginning of cold stress, respiratory metabolism was decreased and the transportation and hydrolysis of photosynthetic products was inhibited, leading to an accumulation of starch in the chloroplasts. Total of 5800 unigenes and 38 proteins were affected, including the repressed expression of photosynthesis and the enhanced expression in signal transduction, stress defense pathway as well as secondary metabolism. Although the transcriptional level of a large number of genes has been restored after 12 h, sustained cold stress brought more serious injury to the leaf cells, including the sharp rise of the relative electrolyte leakage, the declined Fv/Fm value, swelled chloroplast and the disintegrated membrane system. CONCLUSION: The starch accumulation and the photoinhibition might be the main adaptive mechanism of the paper mulberry responded to cold stress. Most of important, enhancing the transport and hydrolysis of photosynthetic products could be the potential targets for improving the cold tolerance of the paper mulberry. PMID- 26537771 TI - Trajectories of eating behaviors in a nationally representative cohort of U.S. adolescents during the transition to young adulthood. AB - BACKGROUND: Diets of U.S. adolescents and adults do not meet recommendations, increasing risk of chronic disease. This study examined trajectories and predictors of eating behaviors in U.S. youth from age 16-20 years, and evaluated longitudinal associations of eating behaviors with weight outcomes. METHODS: Data come from the first four waves (years) of the NEXT Generation Health Study, a nationally representative cohort of U.S. students in 10(th) grade during the 2009 2010 school year (n = 2785). Annual surveys queried frequency of food group intake (times/day of fruit and vegetables, whole grains, sugar-sweetened soda, sweet and salty snacks), and meal practices (days/week of breakfast, family meals, fast food, and television during meals). Body mass index (BMI, kg/m(2)) was calculated from self-reported height and weight. Adjusted generalized estimating equations and linear mixed models with multiple imputation for missing data estimated eating behavior trajectories overall and by baseline weight status (normal weight = 5 <= BMI%ile < 85, overweight = 85 <= BMI%ile < 95, obese = BMI%ile >= 95), accounting for the complex sampling design. Separate GEE models estimated longitudinal associations of food group frequencies with meal practices and of BMI with eating behaviors. RESULTS: Eating behaviors tracked strongly from wave 1-4 (residual intraclass correlation = 41% - 51%). Across all baseline weight categories, frequency of food group intake and meal practices decreased over time, except for fast food, which remained stable. Fruit/vegetable intake frequency was associated positively with family meals (beta +/- SE = 0.33 +/- 0.05) and breakfast (0.18 +/- 0.03), and inversely with fast food (-0.31 +/- 0.04), while whole grain intake frequency was associated positively with family meals (0.07 +/- 0.02), television meals (0.02 +/- 0.009) and breakfast (0.04 +/- 0.01). Soda and snacks were positively associated with television meals (0.08 +/- 0.008 and 0.07 +/- 0.009, respectively) and fast food (0.24 +/- 0.02 and 0.20 +/- 0.03, respectively), while soda was inversely associated with breakfast frequency (-0.05 +/- 0.01). Time-varying BMI was unrelated to eating behaviors other than an inverse association with time-varying snacks (-0.33 +/- 0.12). CONCLUSIONS: Strong tracking over time supports the importance of early establishment of health-promoting eating behaviors in U.S. adolescents. Findings suggest meal practices may be important intervention targets. Lack of evidence for hypothesized associations of BMI and eating behaviors indicates the need for research confirming these findings using more precise measures of dietary intake. PMID- 26537772 TI - Lacimicrobium alkaliphilum gen. nov., sp. nov., a member of the family Alteromonadaceae isolated from a salt lake. AB - A Gram-stain-negative, facultatively aerobic bacterium, strain X13M-12T, was isolated from a salt lake (Lake Xiaochaidan) in the Qaidam basin, Qinghai Province, PR China. Cells of strain X13M-12T were slightly curved, rod-shaped, 0.5-0.8 MUm wide and 1.2-2.3 MUm long, and motile by means of a polar flagellum. Strain X13M-12T was catalase- and oxidase-positive. Growth was observed in the presence of 0-15.0 % (w/v) NaCl (optimum 3.0-5.0 %), and at 4-40 degrees C (optimum 25-30 degrees C) and pH 6.0-11.0 (optimum pH 8.5). Strain X13M-12T contained Q-8 as the sole respiratory quinone, and phosphatidylglycerol and phosphatidylethanolamine as the major polar lipids. The major cellular fatty acids (>10 % of totals) were C16 : 0, C16 : 1omega7c and/or C16 : 1omega6c, and C18 : 1omega7c and/or C18 : 1omega6c. Phylogenetic analysis, based on 16S rRNA gene sequences, showed that strain X13M-12T belonged to the family Alteromonadaceae and formed a distinct lineage, showing low gene sequence similarities to closely related genera: Bowmanella, Aestuariibacter and Salinimonas (16S rRNA gene sequence similarities, 93.0-93.1 %, 92.3-93.1 % and 92.6-92.7 %, respectively). In addition, strain X13M-12T showed < 92.7 % gene sequence similarities to other species of the family Alteromonadaceae. The DNA G+C content of strain X13M-12T was 49 mol% (Tm). Based on the data presented above, strain X13M-12T is considered to represent a novel genus and species of the family Alteromonadaceae, for which the name Lacimicrobium alkaliphilum gen. nov., sp. nov. is proposed. The type strain is X13M-12T ( = CGMCC 1.12923T = KCTC 42674T). PMID- 26537773 TI - Primary Care Provider Perspectives on Electronic Medication Refill History. AB - Improvements in health information technology have made aggregate multipayer pharmacy claims data increasingly available through the electronic health record (EHR). The objective of this study was to assess the current awareness, utilization, and impact of pharmacy history data available in the EHR on primary care provider (PCP) decision making. A 14-question survey was distributed to all PCPs in a large medical practice. Of the 55/72 responding PCPs, 47 (85.5%) were aware of the EHR medication history function, and 36 (65.5%) had used it previously. Respondents indicated the medication history could be most useful when considering prescribing a narcotic (33/36, 92%) and when addressing nonadherence concerns (28/35, 80%). Barriers included delays in data loading and the time pressures of clinical practice. Access to aggregate multipayer pharmacy history data has the potential to affect medication reconciliation, yet future implementation should focus on making these data complete and easily available in routine practice. PMID- 26537774 TI - A Lepromatous Leprosy Patient with Permanent Disability. PMID- 26537775 TI - Brief Comment on the Article About Human Anaplasmosis by Arraga-Alvarado et al. PMID- 26537776 TI - Relative Utility of Performance and Symptom Validity Tests. AB - This investigation adds to the burgeoning body of research concerned with discriminating performance and symptom validity tests (SVTs) through examination of their differential relationships with cognitive performance and symptom self report measures. To the authors' current knowledge, prior studies have not assessed differences between participants who fail either a performance validity test (PVT) or an SVT but not both. As part of their neuropsychological evaluations at four Veterans Affairs medical centers across the United States, participants were administered a fixed, standardized battery that consisted of performance validity, symptom validity, cognitive performance, and symptom self report measures. Compared with participants who failed a PVT and an SVT, participants who passed both and participants who only passed a PVT demonstrated better cognitive performance and self-reported fewer symptoms. Results support differential clinical utility of performance validity and SVTs when assessing cognitive performance and symptom self-report. PMID- 26537777 TI - Verbal Learning Processes in Patients with Glioma of the Left and Right Temporal Lobes. AB - Recent research supports the utility of process variables in understanding mechanisms underlying memory impairments. The Hopkins Verbal Learning Test Revised (HVLT-R) was administered to 84 patients with left (LTL, n = 58) or right temporal lobe glioma (RTL, n = 26) prior to surgical resection. Primary HVLT-R measures of learning and memory and numerous learning process indices were computed. Both groups exhibited frequent memory impairment (>30%), with greater severity in the LTL group. Patients with LTL glioma also exhibited lower semantic clustering scores than RTL patients, which were highly associated with Total Recall (rho = 0.83) and Delayed Recall (rho = 0.68). Learning slope and a novel measure of learning efficiency were also significantly associated with primary memory measures, though scores were similar across the LTL and RTL groups. While lesions to either temporal lobe impact verbal memory, semantic encoding appears to depend upon the integrity of LTL structures in particular. PMID- 26537778 TI - Reevaluation for clinical manifestations of HTLV-I-seropositive patients with Sjogren's syndrome. AB - BACKGROUND: The aim of the study was to reassess the prevalence and characteristics of human T lymphotropic virus type I (HTLV-I)-associated Sjogren's syndrome (SS) and SS in HTLV-I-associated myelopathy (HAM) based on the American European Consensus Group (AECG) criteria in HTLV-I endemic area, Nagasaki prefecture. METHODS: The 349 patients who underwent a minor salivary gland biopsy (MSGB) for suspected SS were retrospectively classified by AECG classification criteria and divided with or without anti-HTLV-I antibody. RESULTS: The HTLV-I data-available 294 patients were investigated. One hundred seventy patients were classified as SS and 26.5 % were HTLV-I-seropositive. We have included 26 patients with HTLV-I-associated myelopathy (HAM) and 38.5 % were classified as having SS. The prevalences of ANA and anti-SS-A/Ro antibody of HAM + SS were significantly low compared to the HTLV-I asymptomatic carriers (AC) with SS and the HTLV-I-seronegative SS patients, although lacrimal dysfunction tended to be high in HAM + SS and significantly high in AC + SS patients compared with the patients with HTLV-I-seronegative SS. The focus scores of MSGB in the HAM + SS patients were similar to those of the AC + SS patients and the HTLV-I seronegative patients with SS. Among the MSGB-positive patients, there was a low prevalence of ANA in the HAM + SS patients. Similar results were obtained in case of anti-SS-A/Ro or SS-B/La antibody. CONCLUSION: In HTLV-I endemic area, high prevalence of anti-HTLV-I antibody among SS as well as the characteristics of HAM + SS and AC + SS was still determined by AECG classification criteria. PMID- 26537779 TI - Evaluation of Nd:YAG laser device efficacy on onychomycosis: a case series of 30 patients. AB - Until recently, pharmacologic molecules have been the only available treatments for onychomycosis. Laser treatments were introduced for recurrent or resistant cases or in patients in whom oral treatments are contra-indicated. Some devices were approved by the Food and Drug Administration (FDA). Neodymium yttrium aluminium garnet (Nd:YAG) is used for onychomycosis as a short-pulse or a long pulse system. We aim to evaluate the efficacy of the short-pulse Nd:YAG in treating onychomycosis, its side effects, cure rates, and 12-month recurrence rates. Efficacy was evaluated based on a subjective measure of patient satisfaction on a scale from 1 to 10, and an objective measure based on the results of the mycologic cultures. Medical records of 30 patients were reviewed. Ages ranged from 22 to 85, with a mean of 44. Mycologic cure at 12 months was not achieved in 5 patients (16.67%) who had received laser treatment. None of these patients showed any signs of clinical improvement. Twenty patients (66.67%) were completely cured at 12 months, with corroborating negative mycologic cultures. The remaining five patients (16.67%) had discordance between their clinical cure status and their mycologic cultures. Side effects were reported by 7 patients out of 30 (33%): pain within 48 hours of the treatment session, burning sensation in the treated nail bed area. Our primary end point of negative mycologic cultures at 12 months was seen in 24 out of 30 (80%) of our patients. Similar culture cure rates have not been reported before, not even with systemic treatments with oral antifungals. However, few limitations should warrant us (False-negative results in fungal cultures; time limitation; sample size...). Still, we propose that this alternative should be offered for patients in whom antifungals are contraindicated or for patients previously treated, but not cured by oral antifungals, and in elderly and polymedicated patients. PMID- 26537780 TI - Surface and Bulk Carbide Transformations in High-Speed Steel. AB - We have studied the transformation of carbides in AISI M42 high-speed steels in the temperature window used for forging. The annealing was found to result in the partial transformation of the large, metastable M2C carbides into small, more stable grains of M6C, with an associated change in the crystal orientation. In addition, MC carbides form during the transformation of M2C to M6C. From the high speed-steel production point of view, it is beneficial to have large, metastable carbides in the cast structure, which later during annealing, before the forging, transform into a structure of polycrystalline carbides. Such carbides can be easily decomposed into several small carbides, which are then randomly distributed in the microstructure. The results also show an interesting difference in the carbide-transformation reactions on the surface versus the bulk of the alloy, which has implications for in-situ studies of bulk phenomena that are based on surface observations. PMID- 26537781 TI - Bio-inspired Construction of Advanced Fuel Cell Cathode with Pt Anchored in Ordered Hybrid Polymer Matrix. AB - The significant use of platinum for catalyzing the cathodic oxygen reduction reactions (ORRs) has hampered the widespread use of polymer electrolyte membrane fuel cells (PEMFCs). The construction of well-defined electrode architecture in nanoscale with enhanced utilization and catalytic performance of Pt might be a promising approach to address such barrier. Inspired by the highly efficient catalytic processes in enzymes with active centers embedded in charge transport pathways, here we demonstrate for the first time a design that allocates platinum nanoparticles (Pt NPs) at the boundaries with dual-functions of conducting both electrons by aid of polypyrrole and protons via Nafion((r)) ionomer within hierarchical nanoarrays. By mimicking enzymes functionally, an impressive ORR activity and stability is achieved. Using this brand new electrode architecture as the cathode and the anode of a PEMFC, a high mass specific power density of 5.23 W mg(-1)Pt is achieved, with remarkable durability. These improvements are ascribed to not only the electron decoration and the anchoring effects from the Nafion((r)) ionomer decorated PPy substrate to the supported Pt NPs, but also the fast charge and mass transport facilitated by the electron and proton pathways within the electrode architecture. PMID- 26537783 TI - Abnormal Brain Areas Common to the Focal Epilepsies: Multivariate Pattern Analysis of fMRI. AB - Individuals with focal epilepsy have heterogeneous sites of seizure origin. However, there may be brain regions that are common to most cases of intractable focal epilepsy. In this study, we aim to identify these using multivariate analysis of task-free functional MRI. Fourteen subjects with extratemporal focal epilepsy and 14 healthy controls were included in the study. Task-free functional MRI data were used to calculate voxel-wise regional connectivity with regional homogeneity (ReHo) and weighted degree centrality (DCw), in addition to regional activity using fraction of amplitude of low-frequency fluctuations (fALFF). Multivariate pattern analysis was applied to each of these metrics to discriminate brain areas that differed between focal epilepsy subjects and healthy controls. ReHo and DCw classified focal epilepsy subjects from healthy controls with high accuracy (89.3% and 75%, respectively). However, fALFF did not significantly classify patients from controls. Increased regional network activity in epilepsy subjects was seen in the ipsilateral piriform cortex, insula, and thalamus, in addition to the dorsal anterior cingulate cortex and lateral frontal cortices. Decreased regional connectivity was observed in the ventromedial prefrontal cortex, as well as lateral temporal cortices. Patients with extratemporal focal epilepsy have common areas of abnormality (ReHo and DCw measures), including the ipsilateral piriform cortex, temporal neocortex, and ventromedial prefrontal cortex. ReHo shows additional increase in the "salience network" that includes anterior insula and anterior cingulate cortex. DCw showed additional effects in the ipsilateral thalamus and striatum. These brain areas may represent key regional network properties underlying focal epilepsy. PMID- 26537782 TI - Structural and molecular regulation of lung maturation by intratracheal vascular endothelial growth factor administration in the normally grown and placentally restricted fetus. AB - Inhibition of hypoxia signalling leads to respiratory distress syndrome (RDS), whereas administration of vascular endothelial growth factor (VEGF), the most widely characterized hypoxia responsive factor, protects from RDS. In the lung of the chronically hypoxaemic placentally restricted (PR) fetus, there is altered regulation of hypoxia signalling. This leads to reduced surfactant maturation in late gestation and provides evidence for the increased risk of RDS in growth restricted neonates at birth. We evaluated the effect of recombinant human VEGF administration with respect to bypassing the endogenous regulation of hypoxia signalling in the lung of the normally grown and PR sheep fetus. There was no effect of VEGF administration on fetal blood pressure or fetal breathing movements. We examined the effect on the expression of genes regulating VEGF signalling (FLT1 and KDR), angiogenesis (ANGPT1, AQP1, ADM), alveolarization (MMP2, MMP9, TIMP1, COL1A1, ELN), proliferation (IGF1, IGF2, IGF1R, MKI67, PCNA), inflammation (CCL2, CCL4, IL1B, TNFA, TGFB1, IL10) and surfactant maturation (SFTP-A, SFTP-B, SFTP-C, SFTP-D, PCYT1A, LPCAT, LAMP3, ABCA3). Despite the effects of PR on the expression of genes regulating airway remodelling, inflammatory signalling and surfactant maturation, there were very few effects of VEGF administration on gene expression in the lung of both the normally grown and PR fetus. There were, however, positive effects of VEGF administration on percentage tissue, air space and numerical density of SFTP-B positive alveolar epithelial cells in fetal lung tissue. These results provide evidence for the stimulatory effects of VEGF administration on structural maturation in the lung of both the normally grown and PR fetus. PMID- 26537784 TI - Design, synthesis and antithrombotic evaluation of novel dabigatran etexilate analogs, a new series of non-peptides thrombin inhibitors. AB - Thrombin is a serine protease that plays a key role in blood clotting, which makes it a promising target for the treatment of thrombotic diseases. Dabigatran is direct potent thrombin inhibitor. Based on bioisosteric and scaffold hopping principle, two dabigatran mimics (I-1 and II-1) in which the benzamidine moiety of dabigatran was replaced by a tricyclic fused scaffold were designed, synthesized and evaluated for their in vitro activities for inhibiting thrombin. The results reveal that compounds I-1 (IC50=9.20nM) and II-1 (IC50=7.48nM) are potent direct thrombin inhibitors and the activity is in the range of reference drug. On this basis, twenty-two ester and carbamate derivatives of I-1 or II-1 were prepared and evaluated for their anticoagulant activity. Prodrugs I-4a (IC50=0.73MUM), I-4b (IC50=0.75MUM), II-2a (IC50=1.44MUM) and II-2b (IC50=0.91MUM) display excellent effects of inhibiting thrombin induced-platelet aggregation. Moreover, compounds I-9 and II-4, which contain a cleavable moiety with anti-platelet activity, show the best anticoagulant efficacy among the tested compounds in the rat venous thrombosis model. The compounds which have better in vitro and in vivo activity were subjected to rat tail bleeding test, and the result demonstrates that compound I-9 is less likely to have bleeding risk than dabigatran etexilate. PMID- 26537785 TI - Preliminary Characterization of a Leptin Receptor Knockout Rat Created by CRISPR/Cas9 System. AB - Leptin receptor, which is encoded by the diabetes (db) gene and is highly expressed in the choroid plexus, regulatesenergy homeostasis, the balance between food intake and energy expenditure, fertility and bone mass. Here, using CRISPR/Cas9 technology, we created the leptin receptor knockout rat. Homozygous leptin receptor null rats are characterized by obesity, hyperphagia, hyperglycemia, glucose intolerance, hyperinsulinemia and dyslipidemia. Due to long-term poor glycemic control, the leptin receptor knockout rats also develop some diabetic complications such as pancreatic, hepatic and renal lesions. In addition, the leptin receptor knockout rats show a significant decrease in bone volume and bone mineral density of the femur compared with their wild-type littermates. Our model has rescued some deficiency of the existing rodent models, such as the transient hyperglycemia of db/db mice in the C57BL/6J genetic background and the delayed onset of glucose intolerance in the Zucker rats, and it is proven to be a useful animal model for biomedical and pharmacological research on obesity and diabetes. PMID- 26537786 TI - High-density interspecific genetic linkage mapping provides insights into genomic incompatibility between channel catfish and blue catfish. AB - Catfish is the leading aquaculture species in the United States. The interspecific hybrid catfish produced by mating female channel catfish with male blue catfish outperform both of their parent species in a number of traits. However, mass production of the hybrids has been difficult because of reproductive isolation. Investigations of genome structure and organization of the hybrids provide insights into the genetic basis for maintenance of species divergence in the face of gene flow, thereby helping develop strategies for introgression and efficient production of the hybrids for aquaculture. In this study, we constructed a high-density genetic linkage map using the hybrid catfish system with the catfish 250K SNP array. A total of 26,238 SNPs were mapped to 29 linkage groups, with 12,776 unique marker positions. The linkage map spans approximately 3240 cM with an average intermarker distance of 0.25 cM. A fraction of markers (986 of 12,776) exhibited significant deviation from the expected Mendelian ratio of segregation, and they were clustered in major genomic blocks across 15 LGs, most notably LG9 and LG15. The distorted markers exhibited significant bias for maternal alleles among the backcross progenies, suggesting strong selection against the blue catfish alleles. The clustering of distorted markers within genomic blocks should lend insights into speciation as marked by incompatibilities between the two species. Such findings should also have profound implications for understanding the genomic evolution of closely related species as well as the introgression of hybrid production programs in aquaculture. PMID- 26537787 TI - Targeting of SUMO substrates to a Cdc48-Ufd1-Npl4 segregase and STUbL pathway in fission yeast. AB - In eukaryotes, the conjugation of proteins to the small ubiquitin-like modifier (SUMO) regulates numerous cellular functions. A proportion of SUMO conjugates are targeted for degradation by SUMO-targeted ubiquitin ligases (STUbLs) and it has been proposed that the ubiquitin-selective chaperone Cdc48/p97-Ufd1-Npl4 facilitates this process. However, the extent to which the two pathways overlap, and how substrates are selected, remains unknown. Here we address these questions in fission yeast through proteome-wide analyses of SUMO modification sites. We identify over a thousand sumoylated lysines in a total of 468 proteins and quantify changes occurring in the SUMO modification status when the STUbL or Ufd1 pathways are compromised by mutations. The data suggest the coordinated processing of several classes of SUMO conjugates, many dynamically associated with centromeres or telomeres. They provide new insights into subnuclear organization and chromosome biology, and, altogether, constitute an extensive resource for the molecular characterization of SUMO function and dynamics. PMID- 26537788 TI - Single Crystalline Film of Hexagonal Boron Nitride Atomic Monolayer by Controlling Nucleation Seeds and Domains. AB - A monolayer hexagonal boron nitride (h-BN) film with controllable domain morphology and domain size (varying from less than 1 MUm to more than 100 MUm) with uniform crystalline orientation was successfully synthesized by chemical vapor deposition (CVD). The key for this extremely large single crystalline domain size of a h-BN monolayer is a decrease in the density of nucleation seeds by increasing the hydrogen gas flow during the h-BN growth. Moreover, the well defined shape of h-BN flakes can be selectively grown by controlling Cu-annealing time under argon atmosphere prior to h-BN growth, which provides the h-BN shape varies in triangular, trapezoidal, hexagonal and complex shapes. The uniform crystalline orientation of h-BN from different nucleation seeds can be easily confirmed by polarized optical microscopy (POM) with a liquid crystal coating. Furthermore, seamlessly merged h-BN flakes without structural domain boundaries were evidence by a selective hydrogen etching after a full coverage of a h-BN film was achieved. This seamless large-area and atomic monolayer of single crystalline h-BN film can offer as an ideal and practical template of graphene based devices or alternative two-dimensional materials for industrial applications with scalability. PMID- 26537789 TI - Reablement in community-dwelling older adults: a randomised controlled trial. AB - BACKGROUND: There has been an increasing interest in reablement in Norway recently and many municipalities have implemented this form of rehabilitation despite a lack of robust evidence of its effectiveness. The aim of this study was to investigate the effectiveness of reablement in home-dwelling older adults compared with usual care in relation to daily activities, physical functioning, and health-related quality of life. METHODS: This is a parallel-group randomised controlled trial conducted in a rural municipality in Norway. Sixty-one home dwelling older adults with functional decline were randomised to an intervention group (n = 31) or a control group (n = 30). The intervention group received ten weeks of multicomponent home-based rehabilitation. The Canadian Occupational Performance Measure (COPM) was used to measure self-perceived activity performance and satisfaction with performance. In addition, physical capacity and health-related quality of life were measured. The participants were assessed at baseline and at 3- and 9-month follow-ups. RESULTS: There were significant improvements in mean scores favouring reablement in COPM performance at 3 months with a score of 1.5 points (p = 0.02), at 9 months 1.4 points (p = 0.03) and overall treatment 1.5 points (p = 0.01), and for COPM satisfaction at 9 months 1.4 points (p = 0.03) and overall treatment 1.2 points (p = 0.04). No significant group differences were found concerning COPM satisfaction at 3 months, physical capacity or health-related quality of life. CONCLUSION: A 10-week reablement program resulted in better activity performance and satisfaction with performance on a long-term basis, but not the other outcomes measured. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov November 20, 2012, identifier NCT02043262 . PMID- 26537790 TI - pEntYN10 a plasmid of Escherichia coli O169:H41 associated with adherence and toxin production. AB - In this issue of Virulence, Ban E et al. described the complete sequence of the pEntYN10 plasmid of Escherichia coli O169:H41. The plasmid has 182 coding sequences (CDs); among the identified CDs, some were identified as colonization factors (CFs), one was an enterotoxin and others were insertion sequences (IS). In this editorial, the main findings, as well as the epidemiological significance and spontaneous loss of pEntYN10 plasmid of E. coli O169:H41 strains are discussed. PMID- 26537791 TI - The Detection of Cholangiocarcinoma in Primary Sclerosing Cholangitis Patients: Single Center Experience. AB - PURPOSE: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease. Cholangiocarcinoma (CCA) is one of the feared complications of PSC. In our study, we aim to establish the success of brush cytology and CA 19-9 in putting the diagnosis of CCA. METHODS: The data of 30 PSC patients was retrospectively screened whom had brush cytology performed due to dominant strictures. The definitive diagnosis was established by histopathological examination or via radiological/clinic follow-up for at least 12 months. RESULTS: A total of four patients were excluded from the study. Twenty-six patients diagnosed with PSC, six of which were also diagnosed with CCA, were included in the study. The sensitivity and the specificity of the brush cytology in the diagnosis of CCA in PSC patients were 66.7 and 95%, respectively. CA 19-9 had high correlation with bilirubin level. The optimal level of CA 19-9 in the diagnosis of CCA was determined to be 138.5 U/ml. Superiority of Ramage scoring over CA 19-9 in the diagnosis of CCA in PSC patients was not established (sensitivity and specificity were 50%, 94.7% and 83.3%, 85%, respectively). CONCLUSION: Brush cytology has moderate sensitivity in differentiating strictures in PSC patients. CA 19-9 has high sensitivity but bilirubin level can affect the CA 19-9. Therefore, advanced techniques and parameters are needed for detecting CCA in PSC patients. PMID- 26537792 TI - Common Variable Immunodeficiency Disease and Rectal Squamous Cell Carcinoma: a Case Report of a Rare Syndromic Tumor Type. PMID- 26537793 TI - Synchronous Adenocarcinoma and Lymphoma of the Gallbladder: A Case Report. PMID- 26537794 TI - Bilingualism, dementia and the tale of many variables: Why we need to move beyond the Western World. Commentary on Lawton et al. (2015) and Fuller-Thomson (2015). PMID- 26537795 TI - Beyond a simple "yes" and "no". PMID- 26537797 TI - CFAssay: statistical analysis of the colony formation assay. AB - BACKGROUND: Colony formation assay is the gold standard to determine cell reproductive death after treatment with ionizing radiation, applied for different cell lines or in combination with other treatment modalities. Associated linear quadratic cell survival curves can be calculated with different methods. For easy code exchange and methodological standardisation among collaborating laboratories a software package CFAssay for R (R Core Team, R: A Language and Environment for Statistical Computing, 2014) was established to perform thorough statistical analysis of linear-quadratic cell survival curves after treatment with ionizing radiation and of two-way designs of experiments with chemical treatments only. METHODS: CFAssay offers maximum likelihood and related methods by default and the least squares or weighted least squares method can be optionally chosen. A test for comparision of cell survival curves and an ANOVA test for experimental two way designs are provided. RESULTS: For the two presented examples estimated parameters do not differ much between maximum-likelihood and least squares. However the dispersion parameter of the quasi-likelihood method is much more sensitive for statistical variation in the data than the multiple R (2) coefficient of determination from the least squares method. CONCLUSION: The dispersion parameter for goodness of fit and different plot functions in CFAssay help to evaluate experimental data quality. As open source software interlaboratory code sharing between users is facilitated. AVAILABILITY: The package is available at http://www.bioconductor.org/packages/release/bioc/html/CFAssay.html . PMID- 26537796 TI - Omega-3 fatty acids for depression in adults. AB - BACKGROUND: Major depressive disorder (MDD) is highly debilitating, difficult to treat, has a high rate of recurrence, and negatively impacts the individual and society as a whole. One emerging potential treatment for MDD is n-3 polyunsaturated fatty acids (n-3PUFAs), also known as omega-3 oils, naturally found in fatty fish, some other seafood, and some nuts and seeds. Various lines of evidence suggest a role for n-3PUFAs in MDD, but the evidence is far from conclusive. Reviews and meta-analyses clearly demonstrate heterogeneity between studies. Investigations of heterogeneity suggest differential effects of n 3PUFAs, depending on severity of depressive symptoms, where no effects of n 3PUFAs are found in studies of individuals with mild depressive symptomology, but possible benefit may be suggested in studies of individuals with more severe depressive symptomology. OBJECTIVES: To assess the effects of n-3 polyunsaturated fatty acids (also known as omega-3 fatty acids) versus a comparator (e.g. placebo, anti-depressant treatment, standard care, no treatment, wait-list control) for major depressive disorder (MDD) in adults. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Registers (CCDANCTR) and International Trial Registries over all years to May 2015. We searched the database CINAHL over all years of records to September 2013. SELECTION CRITERIA: We included studies in the review if they: were a randomised controlled trial; provided n-3PUFAs as an intervention; used a comparator; measured depressive symptomology as an outcome; and were conducted in adults with MDD. Primary outcomes were depressive symptomology (continuous data collected using a validated rating scale) and adverse events. Secondary outcomes were depressive symptomology (dichotomous data on remission and response), quality of life, and failure to complete studies. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We found 26 relevant studies: 25 studies involving a total of 1438 participants investigated the impact of n-3PUFA supplementation compared to placebo, and one study involving 40 participants investigated the impact of n-3PUFA supplementation compared to antidepressant treatment.For the placebo comparison, n-3PUFA supplementation results in a small to modest benefit for depressive symptomology, compared to placebo: standardised mean difference (SMD) -0.32 (95% confidence interval (CI) -0.12 to -0.52; 25 studies, 1373 participants, very low quality evidence), but this effect is unlikely to be clinically meaningful (an SMD of 0.32 represents a difference between groups in scores on the HDRS (17 item) of approximately 2.2 points (95% CI 0.8 to 3.6)). The confidence intervals include both a possible clinically important effect and a possible negligible effect, and there is considerable heterogeneity between the studies. Although the numbers of individuals experiencing adverse events were similar in intervention and placebo groups (odds ratio (OR) 1.24, 95% CI 0.95 to 1.62; 19 studies, 1207 participants; very low-quality evidence), the confidence intervals include a significant increase in adverse events with n-3PUFAs as well as a small possible decrease. Rates of remission and response, quality of life, and rates of failure to complete studies were also similar between groups, but confidence intervals are again wide.The evidence on which these results are based is very limited. All studies contributing to our analyses were of direct relevance to our research question, but we rated the quality of the evidence for all outcomes as low to very low. The number of studies and number of participants contributing to all analyses were low, and the majority of studies were small and judged to be at high risk of bias on several measures. Our analyses were also likely to be highly influenced by three large trials. Although we judge these trials to be at low risk of bias, they contribute 26.9% to 82% of data. Our effect size estimates are also imprecise. Funnel plot asymmetry and sensitivity analyses (using fixed effect models, and only studies judged to be at low risk of selection bias, performance bias or attrition bias) also suggest a likely bias towards a positive finding for n-3PUFAs. There was substantial heterogeneity in analyses of our primary outcome of depressive symptomology. This heterogeneity was not explained by the presence or absence of comorbidities or by the presence or absence of adjunctive therapy.Only one study was available for the antidepressant comparison, involving 40 participants. This study found no differences between treatment with n-3PUFAs and treatment with antidepressants in depressive symptomology (mean difference (MD) -0.70 (95% CI -5.88 to 4.48)), rates of response to treatment or failure to complete. Adverse events were not reported in a manner suitable for analysis, and rates of depression remission and quality of life were not reported. AUTHORS' CONCLUSIONS: At present, we do not have sufficient high quality evidence to determine the effects of n-3PUFAs as a treatment for MDD. Our primary analyses suggest a small-to-modest, non-clinically beneficial effect of n-3PUFAs on depressive symptomology compared to placebo; however the estimate is imprecise, and we judged the quality of the evidence on which this result is based to be low/very low. Sensitivity analyses, funnel plot inspection and comparison of our results with those of large well-conducted trials also suggest that this effect estimate is likely to be biased towards a positive finding for n-3PUFAs, and that the true effect is likely to be smaller. Our data, however, also suggest similar rates of adverse events and numbers failing to complete trials in n-3PUFA and placebo groups, but again our estimates are very imprecise. The one study that directly compares n-3PUFAs and antidepressants in our review finds comparable benefit. More evidence, and more complete evidence, are required, particularly regarding both the potential positive and negative effects of n-3PUFAs for MDD. PMID- 26537798 TI - Terminal Galactosylation and Sialylation Switching on Membrane Glycoproteins upon TNF-Alpha-Induced Insulin Resistance in Adipocytes. AB - Insulin resistance (IR) is a complex pathophysiological state that arises from both environmental and genetic perturbations and leads to a variety of diseases, including type-2 diabetes (T2D). Obesity is associated with enhanced adipose tissue inflammation, which may play a role in disease progression. Inflammation modulates protein glycosylation in a variety of cell types, and this has been associated with biological dysregulation. Here, we have examined the effects of an inflammatory insult on protein glycosylation in adipocytes. We performed quantitative N-glycome profiling of membrane proteins derived from mouse 3T3-L1 adipocytes that had been incubated with or without the proinflammatory cytokine TNF-alpha to induce IR. We identified the regulation of specific terminal N glycan epitopes, including an increase in terminal di-galactose- and a decrease in biantennary alpha-2,3-sialoglycans. The altered N-glycosylation of TNF-alpha treated adipocytes correlated with the regulation of specific glycosyltransferases, including the up-regulation of B4GalT5 and Ggta1 galactosyltransferases and down-regulation of ST3Gal6 sialyltransferase. Knockdown of B4GalT5 down-regulated the terminal di-galactose N-glycans, confirming the involvement of this enzyme in the TNF-alpha-regulated N-glycome. SILAC-based quantitative glycoproteomics of enriched N-glycopeptides with and without deglycosylation were used to identify the protein and glycosylation sites modified with these regulated N-glycans. The combined proteome and glycoproteome workflow provided a relative quantification of changes in protein abundance versus N-glycosylation occupancy versus site-specific N-glycans on a proteome wide level. This revealed the modulation of N-glycosylation on specific proteins in IR, including those previously associated with insulin-stimulated GLUT4 trafficking to the plasma membrane. PMID- 26537799 TI - N-glycosylation Profiling of Colorectal Cancer Cell Lines Reveals Association of Fucosylation with Differentiation and Caudal Type Homebox 1 (CDX1)/Villin mRNA Expression. AB - Various cancers such as colorectal cancer (CRC) are associated with alterations in protein glycosylation. CRC cell lines are frequently used to study these (glyco)biological changes and their mechanisms. However, differences between CRC cell lines with regard to their glycosylation have hitherto been largely neglected. Here, we comprehensively characterized the N-glycan profiles of 25 different CRC cell lines, derived from primary tumors and metastatic sites, in order to investigate their potential as glycobiological tumor model systems and to reveal glycans associated with cell line phenotypes. We applied an optimized, high-throughput membrane-based enzymatic glycan release for small sample amounts. Released glycans were derivatized to stabilize and differentiate between alpha2,3 and alpha2,6-linked N-acetylneuraminic acids, followed by N-glycosylation analysis by MALDI-TOF(/TOF)-MS. Our results showed pronounced differences between the N-glycosylation patterns of CRC cell lines. CRC cell line profiles differed from tissue-derived N-glycan profiles with regard to their high-mannose N-glycan content but showed a large overlap for complex type N-glycans, supporting their use as a glycobiological cancer model system. Importantly, we could show that the high-mannose N-glycans did not only occur as intracellular precursors but were also present at the cell surface. The obtained CRC cell line N-glycan features were not clearly correlated with mRNA expression levels of glycosyltransferases, demonstrating the usefulness of performing the structural analysis of glycans. Finally, correlation of CRC cell line glycosylation features with cancer cell markers and phenotypes revealed an association between highly fucosylated glycans and CDX1 and/or villin mRNA expression that both correlate with cell differentiation. Together, our findings provide new insights into CRC-associated glycan changes and setting the basis for more in-depth experiments on glycan function and regulation. PMID- 26537800 TI - Immunostimulatory effect of salmon prolactin on expression of Toll-like receptors in Oncorhynchus mykiss infected with Piscirickettsia salmonis. AB - In aquaculture, antibiotics are the traditional treatment used against bacterial infections. However, their use has increasingly come into question given their effects on fish and, possibly, on human health. Consequently, there is interest in developing alternative treatments aimed at stimulating the innate immune response of fish, which is the first line of defense against pathogens. In relation to this, the Toll-like receptors (TLR) aid in the selective identification of pathogens. The present study evaluated immunostimulatory activity of prolactin (PRL) hormone on expression levels of TLR1, 9, and 22, MyD88, and IL-1beta during in vitro infection with the fish pathogen Piscirickettsia salmonis, in primary cultures of Oncorhynchus mykiss head kidney cells. Results indicated that PRL increased expression of TLRs and MyD88 during the first hours of bacterial infection, while a constant increase in expression was found for IL-1beta. These findings suggest that PRL indirectly modulates expression of TLRs by activating expression of suppressors of cytokine signaling, thereby regulating immune response over long periods of time during bacterial infection. PMID- 26537802 TI - A novel long noncoding RNA-LOWEG is low expressed in gastric cancer and acts as a tumor suppressor by inhibiting cell invasion. AB - PURPOSE: Long noncoding RNA (lncRNA) have been reported to be involved in the development of multiple cancers. The aim of this study was to report the identification of lncRNA-CTD-2108O9.1, which we have named lncRNA low expressed in gastric cancer (lncRNA-LOWEG), and investigate its role in cancer development. METHODS: Total RNA was extracted from the tissues of 94 patients with GC, one normal gastric epithelial cell line and four GC cell lines. Expression levels of lncRNA-LOWEG were determined by real-time PCR. Moreover, CCK-8 proliferation assay, transwell cell invasion assay and flow cytometry were performed to study the effects of lncRNA-LOWEG on SGC-7901 cell proliferation, cell invasion and cell cycle progression. Lastly, western blot and real-time PCR were used to verify the potential target genes of lncRNA-LOWEG. RESULTS: Significantly reduced expression of lncRNA-LOWEG was found in gastric cancer tissues and cell lines (SGC-7901, AGS, BGC-823 and HG-27) compared with patient-matched nontumorous adjacent tissues (P < 0.01) or the normal gastric cell line GES-1 (P < 0.05). Moreover, the transwell assay showed that the number of cells capable of passing through the Matrigel was significantly reduced after lncRNA-LOWEG transfection (P < 0.05). However, lncRNA-LOWEG overexpression did not significantly influence cell proliferation (P > 0.05) and cell cycle progression (P > 0.05). Lastly, western blot and real-time PCR analysis suggested that lncRNA-LOWEG is positively correlated with the expression of leukemia inhibitory factor receptor (LIFR) gene at the translational level. CONCLUSIONS: LncRNA-LOWEG is a tumor suppressor that inhibits GC cell invasion. And LIFR gene is up-regulated by lncRNA-LOWEG. PMID- 26537803 TI - Editorial. PMID- 26537804 TI - Prevention of shoulder injuries in overhead athletes: a science-based approach. AB - The shoulder is at high risk for injury during overhead sports, in particular in throwing or hitting activities, such as baseball, tennis, handball, and volleyball. In order to create a scientific basis for the prevention of recurrent injuries in overhead athletes, four steps need to be undertaken: (1) risk factors for injury and re-injury need to be defined; (2) established risk factors may be used as return-to-play criteria, with cut-off values based on normative databases; (3) these variables need to be measured using reliable, valid assessment tools and procedures; and (4) preventative training programs need to be designed and implemented into the training program of the athlete in order to prevent re-injury. In general, three risk factors have been defined that may form the basis for recommendations for the prevention of recurrent injury and return to play after injury: glenohumeral internal-rotation deficit (GIRD); rotator cuff strength, in particular the strength of the external rotators; and scapular dyskinesis, in particular scapular position and strength. PMID- 26537806 TI - Critical review of the impact of core stability on upper extremity athletic injury and performance. AB - BACKGROUND: Programs designed to prevent or rehabilitate athletic injuries or improve athletic performance frequently focus on core stability. This approach is based upon the theory that poor core stability increases the risk of poor performance and/or injury. Despite the widespread use of core stability training amongst athletes, the question of whether or not sufficient evidence exists to support this practice remains to be answered. OBJECTIVES: 1) Open a dialogue on the definition and components of core stability. 2) Provide an overview of current science linking core stability to musculoskeletal injuries of the upper extremity. 3) Provide an overview of evidence for the association between core stability and athletic performance. DISCUSSION: Core stability is the ability to control the position and movement of the trunk for optimal production, transfer, and control of forces to and from the upper and lower extremities during functional activities. Muscle capacity and neuromuscular control are critical components of core stability. A limited body of evidence provides some support for a link between core stability and upper extremity injuries amongst athletes who participate in baseball, football, or swimming. Likewise, few studies exist to support a relationship between core stability and athletic performance. CONCLUSIONS: A limited body of evidence exists to support the use of core stability training in injury prevention or performance enhancement programs for athletes. Clearly more research is needed to inform decision making when it comes to inclusion or emphasis of core training when designing injury prevention and rehabilitation programs for athletes. PMID- 26537805 TI - A conceptual framework for a sports knee injury performance profile (SKIPP) and return to activity criteria (RTAC). AB - Injuries to the knee, including intra-articular fractures, ligamentous ruptures, and meniscal and articular cartilage lesions, are commonplace within sports. Despite advancements in surgical techniques and enhanced rehabilitation, athletes returning to cutting, pivoting, and jumping sports after a knee injury are at greater risk of sustaining a second injury. The clinical utility of objective criteria presents a decision-making challenge to ensure athletes are fully rehabilitated and safe to return to sport. A system centered on specific indicators that can be used to develop a comprehensive profile to monitor rehabilitation progression and to establish return to activity criteria is recommended to clear athletes to begin a progressive and systematic approach to activities and sports. Integration of a sports knee injury performance profile with return to activity criteria can guide clinicians in facilitating an athlete's safe return to sport, prevention of subsequent injury, and life-long knee joint health. PMID- 26537807 TI - Measuring sports injuries on the pitch: a guide to use in practice. AB - Sports participation is a major ally for the promotion of physical activity. However, sports injuries are important adverse effects of sports participation and should be monitored in sports populations. The purpose of this paper is to review the basic concepts of injury monitoring and discuss the implementation of these concepts in practice. The aspects discussed are: (1) sports injury definition; (2) classification of sports injuries; (3) population at risk, prevalence, and incidence; (4) severity measures; (5) economic costs; (6) systems developed to monitor sports injuries; and (7) online technology. Only with reliable monitoring systems applied in a continuous and long-term manner will it be possible to identify the burden of injuries, to identify the possible cases at an early stage, to implement early interventions, and to generate data for sports injury prevention. The implementation of sports injuries monitoring systems in practice is strongly recommended. PMID- 26537808 TI - Improving performance in golf: current research and implications from a clinical perspective. AB - Golf, a global sport enjoyed by people of all ages and abilities, involves relatively long periods of low intensity exercise interspersed with short bursts of high intensity activity. To meet the physical demands of full swing shots and the mental and physical demands of putting and walking the course, it is frequently recommended that golfers undertake golf-specific exercise programs. Biomechanics, motor learning, and motor control research has increased the understanding of the physical requirements of the game, and using this knowledge, exercise programs aimed at improving golf performance have been developed. However, while it is generally accepted that an exercise program can improve a golfer's physical measurements and some golf performance variables, translating the findings from research into clinical practice to optimise an individual golfer's performance remains challenging. This paper discusses how biomechanical and motor control research has informed current practice and discusses how emerging sophisticated tools and research designs may better assist golfers improve their performance. PMID- 26537809 TI - Sports injuries profile of a first division Brazilian soccer team: a descriptive cohort study. AB - OBJECTIVE: To establish the injury profile of soccer players from a first division Brazilian soccer team. In addition, we investigated the association between the characteristics of the injuries and the player's age and position. METHOD: Forty-eight players from a Brazilian first division soccer team were followed during one season. Descriptive statistics were used to characterize the injury profile. Spearman's tests were used to verify the association between the number and severity of injuries and the player's age. Chi-square test was used to verify the association between type of injury and player's position. Fisher's exact test was used to verify the association between the severity of injuries and player's position. RESULTS: The incidence of injuries was 42.84/1000 hours in matches and 2.40/1000 hours in training. The injury severity was 19.5+/-34.4 days off competition or training. Lower limb was the most common location of injury and most injuries were muscular/tendinous, overuse, non-recurrent, and non contact injuries. Player's age correlated with the amount and severity of muscle and tendon injuries. Defenders had more minimal injuries (1-3 days lost), while forwards had more moderate (8-28 days lost) and severe injuries (>28 days lost). Furthermore, wingbacks had more muscle and tendon injuries, while midfielders had more joint and ligament injuries. CONCLUSION: The injury profile of the Brazilian players investigated in this study reflected regional differences in soccer practices. Results confirm the influence of the player's age and position on the soccer injuries profile. PMID- 26537810 TI - Multicenter trial of motion analysis for injury risk prediction: lessons learned from prospective longitudinal large cohort combined biomechanical - epidemiological studies. AB - Our biodynamics laboratory group has conducted large cohort biomechanical epidemiological studies targeted at identifying the complex interactions among biomechanical, biological, hormonal, and psychosocial factors that lead to increased risk of anterior cruciate ligament (ACL) injuries. The findings from our studies have revealed highly sensitive and specific predictors for ACL injury. Despite the high incidence of ACL injuries among young athletes, larger cohorts are needed to reveal the underlying mechanistic causes of increased risk for ACL injury. In the current study, we have outlined key factors that contribute to the overall success of multicenter, biomechanical-epidemiological investigations designed to test a larger number of athletes who otherwise could not be recruited, screened, or tested at a single institution. Twenty-five female volleyball players were recruited from a single high school team and tested at three biodynamics laboratories. All athletes underwent three-dimensional motion capture analysis of a drop vertical jump task. Kinematic and kinetic variables were compared within and among laboratories. Reliability of peak kinematic variables was consistently rated good-to-excellent. Reliability of peak kinetic variables was consistently rated goodto-excellent within sites, but greater variability was observed between sites. Variables measured in the sagittal plane were typically more reliable than variables measured in the coronal and transverse planes. This study documents the reliability of biomechanical variables that are key to identification of ACL injury mechanisms and of athletes at high risk. These findings indicate the feasibility of executing multicenter, biomechanical investigations that can yield more robust, reliable, and generalizable findings across larger cohorts of athletes. PMID- 26537811 TI - Physical therapists' role in prevention and management of patellar tendinopathy injuries in youth, collegiate, and middle-aged indoor volleyball athletes. AB - Patellar tendinopathy is highly prevalent in all ages and skill levels of volleyball athletes. To illustrate this, we discuss the clinical, biomechanical, and ultrasound imaging presentation and the intervention strategies of three volleyball athletes at different stages of their athletic career: youth, middle aged, and collegiate. We present our examination strategies and interpret the data collected, including visual movement analysis and dynamics, relating these findings to the probable causes of their pain and dysfunction. Using the framework of the EdUReP concept, incorporating Education, Unloading, Reloading, and Prevention, we propose intervention strategies that target each athlete's specific issues in terms of education, rehabilitation, training, and return to sport. This framework can be generalized to manage patellar tendinopathy in other sports requiring jumping, from youth to middle age, and from recreational to elite competitive levels. PMID- 26537812 TI - Male and female runners demonstrate different sagittal plane mechanics as a function of static hamstring flexibility. AB - BACKGROUND: Injuries to runners are common. However, there are many potential contributing factors to injury. While lack of flexibility alone is commonly related to injury, there are clear differences in hamstring flexibility between males and females. OBJECTIVE: To compare the effect of static hamstring length on sagittal plane mechanics between male and female runners. METHOD: Forty subjects (30.0+/-6.4 years) participated and were placed in one of 4 groups: flexible males (n=10), inflexible males (n=10), flexible females (n=10), and inflexible females (n=10). All subjects were free of injury at the time of data collection. Three-dimensional kinematics and kinetics were collected while subjects ran over ground across 2 force platforms. Sagittal plane joint angles and moments were calculated at the knee and hip and compared with a 2-way (sex X flexibility) ANOVA (alpha=0.05). RESULTS: Males exhibited greater peak knee extension moment than females (M=2.80+/-0.47, F=2.48+/-0.52 Nm/kg*m, p=0.05) and inflexible runners exhibited greater peak knee extension moment than flexible runners (In=2.83+/-0.56, Fl=2.44+/-0.51 Nm/kg*m, p=0.01). For hip flexion at initial contact, a significant interaction existed (p<0.05). Flexible females (36.7+/ 7.4o) exhibited more hip flexion than inflexible females (27.9+/-4.6o, p<0.01) and flexible males (30.1+/-9.5o, p<0.05). No differences existed for knee angle at initial contact, peak knee angle, peak hip angle, or peak hip moment. CONCLUSION: Hamstring flexibility results in different mechanical profiles in males and females. Flexibility in the hamstrings may result in decreased moments via active or passive tension. These differences may have implications for performance and injury in flexible female runners. PMID- 26537813 TI - Clinical commentary of the evolution of the treatment for chronic painful mid portion Achilles tendinopathy. AB - The chronic painful Achilles tendon mid-portion was for many years, and still is in many countries, treated with intratendinous revision surgery. However, by coincidence, painful eccentric calf muscle training was tried, and it showed very good clinical results. This finding was unexpected and led to research into the pain mechanisms involved in this condition. Today we know that there are very few nerves inside, but multiple nerves outside, the ventral side of the chronic painful Achilles tendon mid-portion. These research findings have resulted in new treatment methods targeting the regions with nerves outside the tendon, methods that allow for a rapid rehabilitation and fast return to sports. PMID- 26537814 TI - Haemophilus influenzae triggers autophagy in HEp-2 cells. AB - The MAP-LC3 system regulates the intracellular formation of autophagy-associated vacuoles. These vacuoles contain the LC3 protein; thus it has been utilized as a marker to identify autophagosomes. The aim of our study was to investigate whether Haemophilus influenzae strains and their supernatants could activate autophagy in human larynx carcinoma cell line (HEp-2). We demonstrate that higher expression of the LC3B-II protein was induced, particularly by nontypeable Haemophilus influenzae (NTHi) 49766 and by supernatants, containing <50 kDa proteins, of both strains. Ultrastructural studies demonstrate vacuoles with a double membrane and/or membrane material inside, showing similar features to those of autophagic vacuoles. Together, our findings demonstrate that H. influenzae strains and their supernatants trigger an autophagic process. PMID- 26537815 TI - The OPVI trial - perioperative hemodynamic optimization using the plethysmographic variability index in orthopedic surgery: study protocol for a multicenter randomized controlled trial. AB - BACKGROUND: Hemodynamic optimization during surgery is of major importance to decrease postoperative morbidity and length of hospital stay. However, conventional cardiac output monitoring is rarely used at the bedside. Recently, the plethysmographic variability index (PVI) was described as a simplified alternative, using plug-and-play noninvasive technology, but its clinical utility remains to be established. METHODS/DESIGN: The hemodynamic optimization using the PVI (OPVI) trial is a multicenter randomized controlled two-arm trial, randomizing 440 patients at intermediate risk of postoperative complications after orthopedic surgery. Hemodynamic optimization was conducted using either the PVI (PVI group) or conventional mean arterial pressure (control group). The anesthesiologist performed the randomization the day before surgery using an interactive web response system, available 24 hours a day, 7 days a week. The randomization sequence was generated using permutated blocks and stratified by center and type of surgery (knee or hip arthoplasty). Patients and surgeons, but not anesthesiology staff, were blinded to the allocation group. The primary outcome measure is the length of hospital stay following surgery. The attending surgeon, who was blinded to group assessment, determined hospital discharge. Secondary outcome measures are theoretical length of hospital stay, determined using a dedicated discharge-from-hospital checklist, postoperative arterial lactate level in the recovery room, postoperative troponin level, presence of serious postoperative cardiac complications, and postoperative acute kidney insufficiency. DISCUSSION: The OPVI trial is the first multicenter randomized controlled study to investigate whether perioperative hemodynamic optimization using PVI during orthopedic surgery could decrease the length of hospital stay and postoperative morbidity. TRIAL REGISTRATION: ClinicalTrials.gov NCT02207296 . PMID- 26537816 TI - Neuroprotective Effects of Tanshinone I Against 6-OHDA-Induced Oxidative Stress in Cellular and Mouse Model of Parkinson's Disease Through Upregulating Nrf2. AB - In this study, we investigated whether tanshinone I (T-I) has therapeutic effects in cellular and animal model of Parkinson's disease (PD), and explore its possible mechanism. For this purpose, human neuroblastoma SH-SY5Y cells were cultured and exposed to 100 MUM 6-hydroxydopamine (6-OHDA) in the absence or presence of T-I (1, 2.5 and 5 MUM). The results revealed that 6-OHDA-induced cell death was reduced by T-I pretreatment as measured by MTT assay, lactate dehydrogenase release and flow cytomety analysis of cell apoptosis. The increase in the reactive oxygen species caused by 6-OHDA treatment was also attenuated by T-I in SH-SY5Y cells. T-I pretreatment was also shown to result in an increase in nuclear factor erythroid-2-related factor 2 (Nrf2) protein levels and its transcriptional activity as well as the upregulation of Nrf2-dependent genes encoding the antioxidant enzymes heme oxygenase-1, glutathione cysteine ligase regulatory subunit and glutathione cysteine ligase modulatory subunit in SH-SY5Y cells. Moreover, in the in vivo experiment, T-I treatment significantly attenuated 6-OHDA-induced striatal oxidative stress and ameliorated dopaminergic neurotoxicity in 6-OHDA-lesioned mice, as evidenced by western blot analysis of tyrosine hydroxylase (TH) and TH immunostaining of dopaminergic neurons in the substantia nigra and the striatum. Taken together, the results suggest that T-I may be beneficial for the treatment of neurodegenerative diseases like PD. PMID- 26537817 TI - Treatment with Hydrogen-Rich Saline Delays Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease, and accumulating evidence indicates that oxidative mechanisms contribute to ALS pathology, but classical antioxidants have not performed well in clinical trials. The aim of this work was to investigate the effect of treatment with hydrogen molecule on the development of disease in mutant SOD1 G93A transgenic mouse model of ALS. Treatment of mutant SOD1 G93A mice with hydrogen-rich saline (HRS, i.p.) significantly delayed disease onset and prolonged survival, and attenuated loss of motor neurons and suppressed microglial and glial activation. Treatment of mutant SOD1 G93A mice with HRS inhibited the release of mitochondrial apoptogenic factors and the subsequent activation of downstream caspase-3. Furthermore, treatment of mutant SOD1 G93A mice with HRS reduced levels of protein carbonyl and 3-nitrotyrosine, and suppressed formation of reactive oxygen species (ROS), peroxynitrite, and malondialdehyde. Treatment of mutant SOD1 G93A mice with HRS preserved mitochondrial function, marked by restored activities of Complex I and IV, reduced mitochondrial ROS formation and enhanced mitochondrial adenosine triphosphate synthesis. In conclusion, hydrogen molecule may be neuroprotective against ALS, possibly through abating oxidative and nitrosative stress and preserving mitochondrial function. PMID- 26537818 TI - Ketoacidosis in a non-diabetic woman who was fasting during lactation. AB - Ketoacidosis is a potential complication of type 1 diabetes. Severe ketoacidosis with a blood pH below 7.0 is only rarely seen in other diseases.Three weeks after delivery, a young woman was admitted because of tachypnoe and tachycardia. Blood gas analysis showed a severe metabolic acidosis with a high anion gap. Further workup revealed the presence of ketone bodies in the urine with normal blood glucose and no history of diabetes. The patient reported that she had not eaten for days because of abdominal pain. After initial treatment in the ICU and immediate re-feeding, the patient's condition rapidly improved.While under normal circumstances fasting causes at most only mild acidosis, it can be dangerous during lactation. Prolonged fasting in combination with different forms of stress puts breast feeding women at risk for starvation ketoacidosis and should therefore be avoided. PMID- 26537819 TI - The use of orthoses and gait analysis in children with AMC. AB - PURPOSE: Arthrogryposis multiplex congenita (AMC) can be described as a complex condition characterized by deformed joints with an intact sensory system. Consequences of muscle weakness and joint contractures in the lower limbs influence walking ability. With orthoses most children achieve functional ambulation. Based on four studies, the aim of this article was to describe gait pattern wearing habitual orthoses, to quantify quiet standing, to test and describe a new orthosis and compare gait differences with regular orthoses, in children with AMC. METHODS: In total 83 children, of which 35 with AMC took part in the studies. All children had underwent clinical examination. Based on joint range of motion and muscle strength they had been prescribed various orthosis types, ranging from insoles to knee-ankle-foot orthoses with locked knee joints. 3D gait and motion analysis was performed during standing and walking with 34 reflective markers aligned with anatomical landmarks. RESULTS: The findings are presented with respect to each of the included studies. CONCLUSIONS: According to the positive subjective impressions from parents and children, the clinical experiences of our research group, and the objective results from the gait assessments, continuously wearing of orthoses in persons with AMC is recommended. PMID- 26537820 TI - AMC: amyoplasia and distal arthrogryposis. AB - Arthrogryposis multiplex congenita (AMC) is a heterogeneous condition defined as multiple congenital joint contractures in two or more body areas. The common pathogenesis is impaired fetal movements. Amyoplasia, the most frequent form, is a sporadically occurring condition with hypoplastic muscles and joint contractures. Distal arthrogryposis (DA) syndromes are often hereditary, and joint involvement is predominantly in the hands and feet. In a Swedish study, 131 patients with arthrogryposis were investigated. The most frequent diagnoses were amyoplasia and DA. In amyoplasia, muscle strength was found to be more important than joint range of motion (ROM) for motor function. In DA, muscle weakness was present in 44 % of investigated patients. The clinical findings were found to be highly variable between families and also within families with DA. Fetal myopathy due to sarcomeric protein dysfunction can cause DA. An early multidisciplinary team evaluation of the child with arthrogryposis for specific diagnosis and planning of treatment is recommended. Attention should be directed at the development of muscle strength with early stimulation of active movements. Immobilization should be minimized. PMID- 26537821 TI - Fimbrial phase variation: stochastic or cooperative? AB - Surface fimbriae of pathogenic Escherichia coli facilitate sensing, adhesion and even invasion of host epithelial cells. While it is known that the pathogen has the potential to express a plethora of fimbrial variants susceptible to rapid phase ON/OFF variation, it is an open question if the fimbrial diversity seen at the population level is the product of random stochasticity or a concerted effort based on active communication. Here we discuss the possibility of a mechanism alternative to a stochastic fimbrial phase variation model affecting the dynamics of a heterogeneous population. PMID- 26537822 TI - Self-rated health and hospital services use in the Spanish National Health System: a longitudinal study. AB - BACKGROUND: Self-rated health is a subjective measure that has been related to indicators such as mortality, morbidity, functional capacity, and the use of health services. In Spain, there are few longitudinal studies associating self rated health with hospital services use. The purpose of this study is to analyze the association between self-rated health and socioeconomic, demographic, and health variables, and the use of hospital services among the general population in the Region of Valencia, Spain. METHODS: Longitudinal study of 5,275 adults who were included in the 2005 Region of Valencia Health Survey and linked to the Minimum Hospital Data Set between 2006 and 2009. Logistic regression models were used to calculate the odds ratios between use of hospital services and self-rated health, sex, age, educational level, employment status, income, country of birth, chronic conditions, disability and previous use of hospital services. RESULTS: By the end of a 4-year follow-up period, 1,184 participants (22.4%) had used hospital services. Use of hospital services was associated with poor self-rated health among both men and women. In men, it was also associated with unemployment, low income, and the presence of a chronic disease. In women, it was associated with low educational level, the presence of a disability, previous hospital services use, and the presence of chronic disease. Interactions were detected between self-rated health and chronic disease in men and between self rated health and educational level in women. CONCLUSIONS: Self-rated health acts as a predictor of hospital services use. Various health and socioeconomic variables provide additional predictive capacity. Interactions were detected between self-rated health and other variables that may reflect different complex predictive models, by gender. PMID- 26537823 TI - MEASURING EARLY LIFE DISPARITY IN INDIA. AB - Early life disparity - defined as the average life years lost due to death by the age of 60 years - can be used to assess more systematically the effect of savings from death at a young age. In addition, it can give valuable insight into the consequences of death in the early stages of life. Early life disparity can further be categorized into child life disparity (0-14 years) and adult life disparity (15-60 years). This study estimated early life disparity using complete life tables for the period 1970-1975 to 2006-2010, which were constructed from abridged life tables and death rates provided by the Sample Registration System (SRS) in India. The contribution of premature deaths to the difference in life disparity was estimated using a replacement algorithm. The findings clearly indicated an overall declining trend in early life disparity in India, with a notable reduction in child life disparity, and a deceleration of adult life disparity during the period 1970-1975 to 2006-2010. Interstate variations in early life disparity were seen to converge with time. Decomposition analysis suggested that these variations could be minimized further by averting death during childhood. PMID- 26537824 TI - DNA translocation through single-layer boron nitride nanopores. AB - Ultra-thin nanopores have become promising biological sensors because of their outstanding signal-to-noise ratio and spatial resolution. Here, we show that boron nitride (BN), which is a new two-dimensional (2D) material similar to graphene, could be utilized for making a nanopore with an atomic thickness. Using an all-atom molecular dynamics simulation, we investigated the dynamics of DNA translocation through the BN nanopore. The results of our simulations demonstrated that it is possible to detect different double-stranded DNA (dsDNA) sequences from the recording of ionic currents through the pore during the DNA translocation. Surprisingly, opposite to results for a graphene nanopore, we found the calculated blockage current for poly(A-T)40 in a BN nanopore to be less than that for poly(G-C)40. Also in contrast with the case of graphene nanopores, dsDNA models moved smoothly and in an unimpeded manner through the BN nanopores in the simulations, suggesting a potential advantage for using BN nanopores to design stall-free sequencing devices. BN nanopores, which display several properties (such as being hydrophilic and non-metallic) that are superior to those of graphene, are thus expected to find applications in the next generation of high-speed and low-cost biological sensors. PMID- 26537825 TI - Efficacy and effects of various anti-crib devices on behaviour and physiology of crib-biting horses. AB - REASONS FOR PERFORMING STUDY: Crib-biting is a common oral stereotypy. Although most treatments involve prevention, the efficacy of various anti-crib devices, including surgically implanted gingival rings, has thus far not been empirically tested. OBJECTIVES: Demonstrate the effect that 2 anti-crib collars, muzzle and gingival rings have on crib-biting, other maintenance behaviours, and cortisol levels in established crib-biting horses. STUDY DESIGN: Randomised, crossover clinical trial. METHODS: In Experiment I, 2 anti-crib collars and a muzzle were used on 8 established crib-biting horses; horses wore each of 3 devices for 7 days, with a 7-day device-free period between treatments. Horses were video recorded for 24 h at least 3 times each week prior to any device placement, and always the day after a device was removed. In Experiment II, gingival rings were used in 6 established crib-biting horses; horses were video recorded for 3 days prior to ring implantation and the day after surgery until the rings became ineffective. Plasma cortisol levels were assessed every day during Experiment II and on Days 1, 3 and 5 of each week during Experiment I. RESULTS: All devices significantly reduced crib-biting compared with control periods. There was no significant difference in crib-bite reduction amongst devices in Experiment I, or between pre-device periods and the first day the device was removed. The only increase in plasma cortisol occurred on the day of surgery in Experiment II. CONCLUSIONS: Common anti-crib devices are effective in reducing crib-biting and significant distress was not evident from our findings. We did not find a post inhibitory rebound effect. Surgical rings were successful only temporarily and implantation was probably painful to the horses. Because stereotypies involve suboptimal environmental conditions, efforts should be made to improve husbandry factors previously shown to contribute to crib-biting, and research into decreasing horses' motivation to crib-bite should continue. PMID- 26537826 TI - The natural fenhexamid-resistant grey mould populations from strawberry in Zhejiang Province are dominated by Botrytis cinerea group S. AB - BACKGROUND: Recently, a novel clade Botrytis cinerea group S was found to be common in B. cinerea populations from Germany and New Zealand. Fenhexamid, an effective antibotrytis fungicide, has not been registered in China, but our preliminary study detected fenhexamid-resistant (HydR) isolates from strawberry in Zhejiang Province. RESULTS: Genetic identification of 639 B. cinerea isolates from strawberry found that 331 (62.9%) belonged to B. cinerea group S. The frequency of HydR isolates ranged from 0 to 37.5% among the nine locations. Of the 74 HydR isolates, 71 were B. cinerea group S and moderately resistant to fenhexamid (HydR). Seven new mutations S9G, P57A, P269L, V365A, E368D, E375K and A378T in the target gene erg27 were reported for the first time. Sixty-two (83.8%) HydR isolates simultaneously carried P57A and A378T mutations, and further transformation assays showed that integration of one copy of erg27(P57A) (,) (A378T) into a wild-type strain led to partial resistance. Detached fruit studies showed that fenhexamid at the recommended field rate could control the disease incited by moderately resistant isolates but not by highly resistant isolates. CONCLUSION: B. cinerea group S isolates are widespread in all strawberry-growing locations in Zhejiang Province. The natural HydR populations from strawberry are dominated by B. cinerea group S. (c) 2015 Society of Chemical Industry. PMID- 26537827 TI - Joint use of over- and under-sampling techniques and cross-validation for the development and assessment of prediction models. AB - BACKGROUND: Prediction models are used in clinical research to develop rules that can be used to accurately predict the outcome of the patients based on some of their characteristics. They represent a valuable tool in the decision making process of clinicians and health policy makers, as they enable them to estimate the probability that patients have or will develop a disease, will respond to a treatment, or that their disease will recur. The interest devoted to prediction models in the biomedical community has been growing in the last few years. Often the data used to develop the prediction models are class-imbalanced as only few patients experience the event (and therefore belong to minority class). RESULTS: Prediction models developed using class-imbalanced data tend to achieve sub optimal predictive accuracy in the minority class. This problem can be diminished by using sampling techniques aimed at balancing the class distribution. These techniques include under- and oversampling, where a fraction of the majority class samples are retained in the analysis or new samples from the minority class are generated. The correct assessment of how the prediction model is likely to perform on independent data is of crucial importance; in the absence of an independent data set, cross-validation is normally used. While the importance of correct cross-validation is well documented in the biomedical literature, the challenges posed by the joint use of sampling techniques and cross-validation have not been addressed. CONCLUSIONS: We show that care must be taken to ensure that cross-validation is performed correctly on sampled data, and that the risk of overestimating the predictive accuracy is greater when oversampling techniques are used. Examples based on the re-analysis of real datasets and simulation studies are provided. We identify some results from the biomedical literature where the incorrect cross-validation was performed, where we expect that the performance of oversampling techniques was heavily overestimated. PMID- 26537828 TI - Genomic analysis of clonal origin of Langerhans cell histiocytosis following acute lymphoblastic leukaemia. PMID- 26537829 TI - Patellofemoral pain. PMID- 26537830 TI - Endothelial function does not improve with high-intensity continuous exercise training in SHR: implications of eNOS uncoupling. AB - Exercise training is a well-recognized way to improve vascular endothelial function by increasing nitric oxide (NO) bioavailability. However, in hypertensive subjects, unlike low- and moderate-intensity exercise training, the beneficial effects of continuous high-intensity exercise on endothelial function are not clear, and the underlying mechanisms remain unknown. The aim of this study was to investigate the impact of high-intensity exercise on vascular function, especially on the NO pathway, in spontaneous hypertensive rats (SHR). These effects were studied on WKY, sedentary SHR and SHR that exercised at moderate (SHR-MOD) and high intensity (SHR-HI) on a treadmill (1 h per day; 5 days per week for 6 weeks at 55% and 80% of their maximal aerobic velocity, respectively). Endothelial function and specific NO contributions to acetylcholine-mediated relaxation were evaluated by measuring the aortic ring isometric forces. Endothelial nitric oxide synthase (eNOS) expression and phosphorylation (ser1177) were evaluated by western blotting. The total aortic and eNOS-dependent reactive oxygen species (ROS) production was assessed using electron paramagnetic resonance in aortic tissue. Although the aortas of SHR-HI had increased eNOS levels without alteration of eNOS phosphorylation, high intensity exercise had no beneficial effect on endothelium-dependent vasorelaxation, unlike moderate exercise. This result was associated with increased eNOS-dependent ROS production in the aortas of SHR-HI. Notably, the use of the recoupling agent BH4 or a thiol-reducing agent blunted eNOS-dependent ROS production in the aortas of SHR-HI. In conclusion, the lack of a positive effect of high-intensity exercise on endothelial function in SHR was mainly explained by redox-dependent eNOS uncoupling, resulting in a switch from NO to O2(-) generation. PMID- 26537831 TI - Treatment for pulmonary hypertension due to left heart diseases. PMID- 26537832 TI - What is chemsex and why does it matter? PMID- 26537833 TI - Sensitization to reactive diluents and hardeners in epoxy resin systems. IVDK data 2002-2011. Part II: concomitant reactions. AB - BACKGROUND: Beside the basic resins, reactive diluents and hardeners are important sensitizers in epoxy resin systems (ERSs). Because of chemical similarities, immunological cross-reactivity may occur. OBJECTIVES: To analyse concomitant reactivity among reactive diluents and hardeners in the patients concerned, as one integral part of a research project on the sensitizing capacity of ERSs (FP-0324). METHODS: A retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2002-2011, was performed. RESULTS: There was close concomitant reactivity to 1,6-hexanediol diglycidyl ether and 1,4 butanediol diglycidyl ether (1,4-BDDGE), and to phenyl glycidyl ether (PGE) and cresyl glycidyl ether (CGE), whereas reactions to p-tert-butylphenyl glycidyl ether occurred more independently from those to PGE and CGE. Concomitant reactions to butyl glycidyl ether and 1,4-BDDGE may point to a common allergenic compound derived from the metabolism of 1,4-BDDGE. Among the structurally more diverse group of hardeners, there was no evidence of immunological cross reactions. CONCLUSIONS: More detailed knowledge of cross-reactivity among ERS components facilitates the interpretation of patch test results and will allow safer ERSs to be composed in the future. PMID- 26537834 TI - On the relationship between phonological awareness, morphological awareness and Chinese literacy skills: evidence from an 8-year longitudinal study. AB - The present study reported data on phonological awareness, morphological awareness, and Chinese literacy skills of 294 children from an 8-year longitudinal study. Results showed that mainland Chinese children's preliterate syllable awareness at ages 4 to 6 years uniquely predicted post-literate morphological awareness at ages 7 to 10 years. Preliterate syllable awareness directly contributed to character reading and writing at age 11 years, while post literate phonemic awareness predicted only character reading at age 11 years. In addition, preliterate syllable and morphological awareness at ages 4 to 6 years had indirect effects on character reading and writing, reading fluency, and reading comprehension at age 11 years, through post-literate morphological awareness at ages 7 to 10 years. Findings underscore the significant role of syllable awareness in Chinese character reading and writing, and the importance of morphological awareness in character-level processing and high-level literacy skills. More importantly, our results suggest the unique relation of syllable awareness and morphological awareness in Chinese as they focus on the same unit, which is also likely to map directly onto a character, the basic unit for high level Chinese reading skills. PMID- 26537835 TI - 2A self-cleaving peptide-based multi-gene expression system in the silkworm Bombyx mori. AB - Fundamental and applied studies of silkworms have entered the functional genomics era. Here, we report a multi-gene expression system (MGES) based on 2A self cleaving peptide (2A), which regulates the simultaneous expression and cleavage of multiple gene targets in the silk gland of transgenic silkworms. First, a glycine-serine-glycine spacer (GSG) was found to significantly improve the cleavage efficiency of 2A. Then, the cleavage efficiency of six types of 2As with GSG was analyzed. The shortest porcine teschovirus-1 2A (P2A-GSG) exhibited the highest cleavage efficiency in all insect cell lines that we tested. Next, P2A GSG successfully cleaved the artificial human serum albumin (66 kDa) linked with human acidic fibroblast growth factor (20.2 kDa) fusion genes and vitellogenin receptor fragment (196 kD) of silkworm linked with EGFP fusion genes, importantly, vitellogenin receptor protein was secreted to the outside of cells. Furthermore, P2A-GSG successfully mediated the simultaneous expression and cleavage of a DsRed and EGFP fusion gene in silk glands and caused secretion into the cocoon of transgenic silkworms using our sericin1 expression system. We predicted that the MGES would be an efficient tool for gene function research and innovative research on various functional silk materials in medicine, cosmetics, and other biomedical areas. PMID- 26537836 TI - Cryptic diversity in hymenolepidid tapeworms infecting humans. AB - An adult hymenolepidid tapeworm was recovered from a 52-year-old Tibetan woman during a routine epidemiological survey for human taeniasis/cysticercosis in Sichuan, China. Phylogenetic analyses based on sequences of nuclear 28S ribosomal DNA and mitochondrial cytochrome c oxidase subunit 1 showed that the human isolate is distinct from Hymenolepis diminuta and Hymenolepis nana, the common parasites causing human hymenolepiasis. Proglottids of the human isolate were unfortunately unsuitable for morphological identification. However, the resultant phylogeny demonstrated the human isolate to be a sister species to Hymenolepis hibernia from Apodemus mice in Eurasia. The present data clearly indicate that hymenolepidid tapeworms causing human infections are not restricted to only H. diminuta and H. nana. PMID- 26537837 TI - New type of pathogenicity of Thelohanellus kitauei Egusa & Nakajima, 1981 infecting the skin of common carp Cyprinus carpio L. AB - Thelohanellus kitauei Egusa & Nakajima, 1981 is a common parasite infecting the intestine of common carp Cyprinus carpio L., resulting in mass mortality or loss of economic value of cultured carp. In the present study, T. kitauei infecting host skin was detected. The morphological, molecular and histological data of this parasite in the new organ record are presented. Morphological analysis showed the current specimen morphologically similar to T. kitauei from the intestine. Despite the spore length and polar capsule length of the current specimen larger than those of T. kitauei from the intestine, ranges of dimensions overlap, which is more suggestive of intraspecific variation than distinct species. BLAST search revealed that the present small subunit ribosomal DNA gene sequence is identical to those of T. kitauei. Histologically, most of spores distributed in the stratum spongiosum of dermis, and some spores in the strata compactum of host skin were also observed. Above all, both morphology and molecular analysis indicated that the current species from the skin of common carp is conspecific with T. kitauei from the intestine of carp and organ habitats transfer of T. kitauei from host intestine to skin may have occurred. PMID- 26537838 TI - A systematic review of the implementation of recommended psychological interventions for schizophrenia: Rates, barriers, and improvement strategies. AB - PURPOSE: A systematic review of the literature exploring if the UK recommendations for psychological interventions for schizophrenia were being met was carried out. Rates of implementation for cognitive behavioural therapy (CBT) and family intervention (FI) were compared. The barriers against implementation and described strategies aimed at improving implementation were reviewed. METHODS: A literature search of electronic bibliography databases (Psychinfo, Medline, Pubmed, AMED, CINHAL, and EMBASE), reference and citation lists, the Evaluation and Review of NICE Implementation (ERNIE) database, a manual search of Clinical Psychology Forum, governmental reports, charity, and service user group reports was conducted. RESULTS: Twenty-six articles met the inclusion criteria, 11 provided data on implementation rates, 13 explored the barriers to implementation, and 10 gave information about improvement strategies. Rates of implementation varied from 4% to 100% for CBT and 0% to 53% for FI, and studies varied in the methodology used and quality of the articles. Previously reported barriers to implementation were found, with organisational barriers being most commonly followed by barriers met by staff members and service users. Implementation strategies discovered included training packages for CBT, FI, and psychosocial interventions as well as empirical evidence suggesting methods for engagement with service users. CONCLUSIONS: Rates of implementation for CBT and FI are still below recommended levels with wide variation of rates found. This suggests inequalities in the provision of psychological interventions for schizophrenia are still present. Previously identified barriers to implementation were confirmed. Attempted implementation strategies have been met with modest success. PRACTITIONER POINTS: Inequalities in the provision of psychological therapies for schizophrenia persist. Good quality cognitive behavioural therapy and FI training do not ensure implementation. Collaboration at all levels of healthcare is needed for effective implementation. PMID- 26537839 TI - Preparation of Conjugates of Cytotoxic Lupane Triterpenes with Biotin. AB - To better understand the mechanism of action of antitumor triterpenes, we are developing methods to identify their molecular targets. A promising method is based on combination of quantitative proteomics with SILAC and uses active compounds anchored to magnetic beads via biotin-streptavidin interaction. We developed a simple and fast solid-phase synthetic technique to connect terpenes to biotin through a linker. Betulinic acid was biotinylated from three different conjugation sites for use as a standard validation tool since many molecular targets of this triterpene are already known. Then, a set of four other cytotoxic triterpenoids was biotinylated. Biotinylated terpenes were similarly cytotoxic to their nonbiotinylated parents, which suggests that the target identification should not be influenced by linker or biotin. The developed solid-phase synthetic approach is the first attempt to use solid-phase synthesis to connect active triterpenes to biotin and is applicable as a general procedure for routine conjugation of triterpenes with other molecules of choice. PMID- 26537840 TI - How to set up a clinical database. PMID- 26537841 TI - Association of Streptococcus gallolyticus subspecies gallolyticus with colorectal cancer: Serological evidence. AB - The colonic opportunist Streptococcus gallolyticus subspecies gallolyticus (SGG) is potentially associated with colorectal cancer (CRC). Large-scale seroepidemiological data for SGG antibodies and their possible association with CRC is currently missing. Associations between CRC and antibody responses to SGG were examined in 576 CRC cases and 576 controls matched by sex, age and province from a population-based multicase-control project (MCC-Spain). MCC-Spain was conducted between 2008 and 2013 in 12 Spanish provinces. Antibody responses to recombinant affinity-purified SGG pilus proteins Gallo1569, 2039, 2178 and 2179 were analysed by multiplex serology. Polyomavirus (PyV) JC VP1 and PyV 6 VP1 proteins served as disease-specificity controls. In the control population, antibody responses to pilus proteins were mostly weak. Antibody responses to individual pilus proteins Gallo2039 (OR: 1.58, 95% CI: 1.09-2.28), Gallo2178 (OR: 1.58, 95% CI: 1.09-2.30) and Gallo2179 (OR: 1.45, 95% CI: 1.00-2.11) were significantly associated with CRC risk. The association was stronger for positivity to two or more pilus proteins of Gallo1569, Gallo2178 and Gallo2179 (OR:1.93, 95% CI: 1.04-3.56) and for double-positivity to Gallo2178 and Gallo2179 (OR: 3.54, 95% CI: 1.49-8.44). The association between SGG infection and CRC risk was stronger among individuals younger than 65 years. For the first time we demonstrated a statistically significant association of exposure to SGG antigens and CRC in a large seroepidemiological study. These results should stimulate further studies on the role of SGG in CRC pathogenesis. PMID- 26537842 TI - Isolation of an NDM-5-producing ST16 Klebsiella pneumoniae from a Dutch patient without travel history abroad, August 2015. AB - A New Delhi Metallo-beta-lactamase-5 (NDM-5)-producing ST16 Klebsiella pneumoniae strain was isolated from a Dutch patient in a long-term care facility without recent travel history abroad. Core genome multilocus sequence typing (cgMLST) revealed that the Dutch isolate was clonally related to isolates detected in four patients in Denmark in 2014. Public health experts and clinicians need to be informed; repetitive screening may be needed in patients without known risk factors for carbapenemases-producing Enterobacteriaceae who have undergone antibiotic treatment. PMID- 26537843 TI - Greater Reduction of Balance as a Result of Increased Plantar Fascia Elasticity at Ovulation during the Menstrual Cycle. AB - One of the sexual hormones, estrogen, increases elasticity of human connective tissue such as the anterior cruciate ligament during the menstrual cycle in women. In the present investigation, the plantar fascia was investigated to see if there is a difference in elasticity with the menstrual cycle. Fifteen young healthy females in the age range of 18-35 years old with a regular menstrual cycle were tested twice throughout one full menstrual cycle; once during the early follicular phases and once at ovulation. Foot length, while standing on both feet and one foot were used to assess plantar fascia elasticity, ultrasound measured plantar fascia thickness while lying and standing, and posture sway and tremor using a balance platform during 8 different balance tests were assessed to see the impact of elasticity changes. Foot length increased significantly at ovulation compared to menstruation when standing on two feet (p = 0.03) and standing on one foot (p < 0.001). There was also a significant increase in plantar fascia in thinning per kilogram weight applied to the foot at ovulation compared to menstruation (p = 0.014). Associated with this increase in elasticity at ovulation, there was a reduction in balance in the most difficult balance tasks and an increase in tremor during ovulation (p < 0.05). Plantar fascia elasticity change during the menstrual cycle might have effects on posture sway and tremor, which could have a potential risk of falling. Therefore, healthy professionals working with young female adults should recognize these physiological effects. PMID- 26537844 TI - Detection and Molecular Characterization of Salmonella enterica Serovar Eppendorf Circulating in Chicken Farms in Tunisia. AB - Salmonella enterica subsp. enterica serovar Eppendorf, with antigenic formula 1,4,12,[27]:d:1,5, is an infrequent serovar. However, 14% (20 of 142) of the isolates recovered during June-July 2012 in chicken farms in Tunisia belonged to S. Eppendorf. These isolates were analysed for resistance and virulence profiles. None of them were susceptible to all antimicrobials tested, while 70%, 60%, 50%, 50%, 20% and 5% were resistant to sulphonamides (sul1, sul2 and sul3), streptomycin (aadA1-like), trimethoprim (dfrA1-like), nalidixic acid (GyrA Asp87 >Asn and not identified), gentamicin (not identified) and ampicillin (blaTEM -1 like). About 30% of the isolates showed decreased susceptibility to ciprofloxacin and carried the qnrB gene; 65% of the isolates were multidrug resistant and contained class 1 integrons with sul1 or sul3 in the 3' conserved segment. The orgA, ssaQ, mgtC, siiD and sopB virulence genes located on SPI1 to SPI5 and the fimbrial bcfC gene were present in all isolates; the sopE1 and sodC1 carried by prophages were variably detected; however, the prophage gipA gene and the spvC gene of serovar-specific virulence plasmids were absent. Altogether, ten resistance and three virulence profiles were identified. Typing of the isolates with XbaI- and BlnI-PFGE supports a close relationship, although they appear to be evolving under selective pressure probably caused by antimicrobial use in chicken husbandry. As far as we know, this is the first study investigating the molecular bases of antimicrobial drug resistance, the virulence gene content and the PFGE profiles of S. Eppendorf. The epidemiological surveillance of this serovar would be necessary to evaluate its possible impact on human health, particularly in Tunisia and other African countries where it was already reported. PMID- 26537845 TI - Complementary benefits of tourism and hunting to communal conservancies in Namibia. AB - Tourism and hunting both generate substantial revenues for communities and private operators in Africa, but few studies have quantitatively examined the trade-offs and synergies that may result from these two activities. We evaluated financial and in-kind benefit streams from tourism and hunting on 77 communal conservancies in Namibia from 1998 to 2013, where community-based wildlife conservation has been promoted as a land-use that complements traditional subsistence agriculture. We used data collected annually for all communal conservancies to characterize whether benefits were derived from hunting or tourism. We classified these benefits into 3 broad classes and examined how benefits flowed to stakeholders within communities under the status quo and under a simulated ban on hunting. Across all conservancies, total benefits from hunting and tourism increased at roughly the same rate, although conservancies typically started generating benefits from hunting within 3 years of formation as opposed to after 6 years for tourism. Disaggregation of data revealed that the main benefits from hunting were income for conservancy management and food in the form of meat for the community at large. The majority of tourism benefits were salaried jobs at lodges. A simulated ban on trophy hunting significantly reduced the number of conservancies that could cover their operating costs, whereas eliminating income from tourism did not have as severe an effect. Given that the benefits generated from hunting and tourism typically begin at different times in a conservancy's life-span (earlier vs. later, respectively) and flow to different segments of local communities, these 2 activities together may provide the greatest incentives for conservation on communal lands in Namibia. A singular focus on either hunting or tourism would reduce the value of wildlife as a competitive land-use option and have grave repercussions for the viability of community-based conservation efforts in Namibia, and possibly other parts of Africa. PMID- 26537846 TI - [Surgery in Crohn's disease]. AB - Surgical treatment is primarily used to treat complications of Crohn's disease but also to improve the quality of life. An adequate preoperative preparation including improvement of the nutritional status, weaning off or stopping immunosuppressive medication and preoperative drainage of abscesses can decrease the complication rate. With the exception of when neoplasia is present, bowel sparing techniques (e. g. strictureplasty and limited resection) are now standard, which has resulted in a low risk of short bowel syndrome. The laparoscopic approach is possible for most indications even in the case of recurrent disease, in primary ileocecal resection the laparoscopic approach has been shown to be superior to the open approach. None of the available techniques for anastomotic reconstruction of the bowels has been shown to be superior. A drainage seton is a good option to retain the quality of life in complex fistulas and reconstructive repair should only be considered when the rectum is free from inflammation. PMID- 26537847 TI - Sympathetic overactivity occurs before hypertension in the two-kidney, one-clip model. AB - Our knowledge of mechanisms responsible for both the development and the maintenance of hypertension remains incomplete in the Goldblatt (two-kidney, one clip; 2K1C) model. We tested the hypothesis that elevated sympathetic nerve activity (SNA) occurs before the onset of hypertension in 2K1C rats, considering the time course of the increase in SNA in relationship to the onset of the hypertension. We used a decorticated in situ working heart-brainstem preparation of three groups of male Wistar rats, namely sham-operated animals (SHAM, n = 7) and animals 3 weeks post-2K1C, of which some were hypertensive (2K1C-H, n = 6) and others normotensive (2K1C-N, n = 9), as determined in vivo a priori. Perfusion pressure was higher in both 2K1C groups (2K1C-H, 76 +/- 1 mmHg; 2K1C-N, 74 +/- 3 mmHg; versus SHAM, 60 +/- 2 mmHg, P < 0.05). The SNA was significantly elevated in both 2K1C groups (2K1C-H, 47.7 +/- 6.1 MUV; 2K1C-N, 32.8 +/- 2.8 MUV; versus SHAM, 20.5 +/- 2.5 MUV, P < 0.05) owing to its increased respiratory modulation; the chemoreflex was augmented and baroreflex depressed. Precollicular transection reduced SNA in all groups (2K1C-H, -32.5 +/- 7.5%; 2K1C-NH, -48 +/- 6.9%; versus SHAM, -13.2 +/- 1%, P < 0.05). Subsequent medullary spinal cord transection abolished SNA in both SHAM and 2K1C-N groups, but decreased it by only 57 +/- 5.5% in 2K1C-H preparations. Thus, SNA is raised before the onset of hypertension, by the third week after renal artery clipping, and this originates, in part, from its enhanced respiratory modulation. Spinal circuits contribute to the elevation of SNA in the 2K1C model, but only after hypertension has developed. PMID- 26537849 TI - Multiple successional pathways in human-modified tropical landscapes: new insights from forest succession, forest fragmentation and landscape ecology research. AB - Old-growth tropical forests are being extensively deforested and fragmented worldwide. Yet forest recovery through succession has led to an expansion of secondary forests in human-modified tropical landscapes (HMTLs). Secondary forests thus emerge as a potential repository for tropical biodiversity, and also as a source of essential ecosystem functions and services in HMTLs. Such critical roles are controversial, however, as they depend on successional, landscape and socio-economic dynamics, which can vary widely within and across landscapes and regions. Understanding the main drivers of successional pathways of disturbed tropical forests is critically needed for improving management, conservation, and restoration strategies. Here, we combine emerging knowledge from tropical forest succession, forest fragmentation and landscape ecology research to identify the main driving forces shaping successional pathways at different spatial scales. We also explore causal connections between land-use dynamics and the level of predictability of successional pathways, and examine potential implications of such connections to determine the importance of secondary forests for biodiversity conservation in HMTLs. We show that secondary succession (SS) in tropical landscapes is a multifactorial phenomenon affected by a myriad of forces operating at multiple spatio-temporal scales. SS is relatively fast and more predictable in recently modified landscapes and where well-preserved biodiversity rich native forests are still present in the landscape. Yet the increasing variation in landscape spatial configuration and matrix heterogeneity in landscapes with intermediate levels of disturbance increases the uncertainty of successional pathways. In landscapes that have suffered extensive and intensive human disturbances, however, succession can be slow or arrested, with impoverished assemblages and reduced potential to deliver ecosystem functions and services. We conclude that: (i) succession must be examined using more comprehensive explanatory models, providing information about the forces affecting not only the presence but also the persistence of species and ecological groups, particularly of those taxa expected to be extirpated from HMTLs; (ii) SS research should integrate new aspects from forest fragmentation and landscape ecology research to address accurately the potential of secondary forests to serve as biodiversity repositories; and (iii) secondary forest stands, as a dynamic component of HMTLs, must be incorporated as key elements of conservation planning; i.e. secondary forest stands must be actively managed (e.g. using assisted forest restoration) according to conservation goals at broad spatial scales. PMID- 26537848 TI - Transcriptome, microRNA, and degradome analyses of the gene expression of Paulownia with phytoplamsa. AB - BACKGROUND: Paulownia witches' broom (PaWB) is a fatal disease of Paulownia caused by a phytoplasma. In previous studies, we found that plants with PaWB symptoms would revert to a healthy morphology after methyl methane sulfonate (MMS) treatment. To completely understand the gene expression profiles of the Paulownia-phytoplasma interaction, three high-throughput sequencing technologies were used to investigate changes of gene expression and microRNAs (miRNAs) in healthy Paulownia tomentosa plantlets, PaWB-infected plantlets, and PaWB-infected plantlets treated with 60 mg . L(-1) MMS. METHODS: Transcriptome, miRNAs and degradome sequencing were performed to explore the global gene expression profiles in the process of Paulownia tomentosa with phytoplasma infection. RESULTS: A total of 98,714 all-unigenes, 62 conserved miRNAs, and 35 novel miRNAs were obtained, among which 902 differentially expressed genes (DEGs) and 24 miRNAs were found to be associated with PaWB disease. Subsequently, the target genes of these miRNAs were predicted by degradome sequencing. Interestingly, we found that 19 target genes of these differentially expressed miRNAs were among the 902 DEGs. The targets of pau-miR156g, pau-miR403, and pau-miR166c were significantly up-regulated in the P. tomentosa plantlets infected with phytoplasma. Interaction of miRNA -target genes mediated gene expression related to PaWB were identified. CONCLUSIONS: The results elucidated the possible roles of the regulation of genes and miRNAs in the Paulownia-phytoplasma interaction, which will enrich our understanding of the mechanisms of PaWB disease in this plant. PMID- 26537850 TI - Predictors of thrombotic complications and mass effect exacerbation after pipeline embolization: The significance of adenosine diphosphate inhibition, fluoroscopy time, and aneurysm size. AB - BACKGROUND: The mechanisms leading to delayed rupture, distal emboli and intraparenchymal hemorrhage in relation to pipeline embolization device (PED) placement remain debatable and poorly understood. The aim of this study was to identify clinical and procedural predictors of these perioperative complications. METHODS: We conducted a retrospective review of consecutive patients who underwent PED placement. We utilized a non-commercial platelet aggregation method measuring adenosine diphosphate (ADP)% inhibition for evaluation of clopidogrel response. To our knowledge, this is the first study to test ADP in neurovascular procedures. Multivariable regression analysis was used to identify the strongest predictor of three separate outcomes: (1) thrombotic complications, (2) hemorrhagic complications, and (3) aneurysm mass effect exacerbation RESULTS: Permanent complication-related morbidity and mortality at 3 months was 6% (3/48). No specific predictors of hemorrhagic complications were identified. In the univariate analysis, the strongest predictors of thrombotic complications were: ADP% inhibition<49 (p=0.01), aneurysm size (p=0.04) and fluoroscopy time (p=0.002). In the final multivariate analysis, among all baseline variables, fluoroscopy time exceeding 52 min was the only factor associated with thrombotic complications (p=0.007). Aneurysm size>=18 mm was the single predictor of mass effect exacerbation (p=0.039). CONCLUSIONS: Procedural complexity, reflected by fluoroscopy time, is the strongest predictor of thrombotic complications in this study. ADP% inhibition is a reliable method of testing clopidogrel response in neurovascular procedures and values of <50% may predict thrombotic complications. Interval mass effect exacerbation after PED placement may be anticipated in large aneurysms exceeding 18 mm. PMID- 26537851 TI - Safety of allogeneic bone marrow derived mesenchymal stromal cell therapy in renal transplant recipients: the neptune study. AB - BACKGROUND: Mesenchymal stromal cells (MSC) may serve as an attractive therapy in renal transplantation due to their immunosuppressive and reparative properties. While most studies have used autologous MSCs, allogeneic MSCs offer the advantage of immediate availability for clinical use. This is of major importance for indications where instant treatment is needed, for example allograft rejection or calcineurin inhibitor toxicity. Clinical studies using allogeneic MSCs are limited in number. Although these studies showed no adverse reactions, allogeneic MSCs could possibly elicit an anti-donor immune response, which may increase the incidence of rejection and impact the allograft survival in the long term. These safety issues should be addressed before further studies are planned with allogeneic MSCs in the solid organ transplant setting. METHODS/DESIGN: 10 renal allograft recipients, 18-75 years old, will be included in this clinical phase Ib, open label, single center study. Patients will receive two doses of 1.5 * 10(6) per/kg body weight allogeneic bone marrow derived MSCs intravenously, at 25 and 26 weeks after transplantation, when immune suppression levels are reduced. The primary end point of this study is safety by assessing biopsy proven acute rejection (BPAR)/graft loss after MSC treatment. Secondary end points, all measured before and after MSC infusions, include: comparison of fibrosis in renal biopsy by quantitative Sirius Red scoring; de novo HLA antibody development and extensive immune monitoring; renal function measured by cGFR and iohexol clearance; CMV and BK infection and other opportunistic infections. DISCUSSION: This study will provide information on the safety of allogeneic MSC infusion and its effect on the incidence of BPAR/graft loss. TRIAL REGISTRATION: NCT02387151. PMID- 26537852 TI - Bartonella apis sp. nov., a honey bee gut symbiont of the class Alphaproteobacteria. AB - Here, we report the culture and characterization of an alphaproteobacterium of the order Rhizobiales, isolated from the gut of the honey bee Apis mellifera. Strain PEB0122T shares >95 % 16S rRNA gene sequence similarity with species of the genus Bartonella, a group of mammalian pathogens transmitted by bloodsucking arthropods. Phylogenetic analyses showed that PEB0122T and related strains from the honey bee gut form a sister clade of the genus Bartonella. Optimal growth of strain PEB0122T was obtained on solid media supplemented with defibrinated sheep blood under microaerophilic conditions at 35-37 degrees C, which is consistent with the cultural characteristics of other species of the genus Bartonella. Reduced growth of strain PEB0122T also occurred under aerobic conditions. The rod shaped cells of strain PEB0122T had a mean length of 1.2-1.8 MUm and revealed hairy surface structures. Strain PEB0122T was positive for catalase, cytochrome c oxidase, urease and nitrate reductase. The fatty acid composition was comparable to those of other species of the genus Bartonella, with palmitic acid (C16 : 0) and isomers of 18- and 19-carbon chains being the most abundant. The genomic DNA G+C content of PEB0122T was determined to be about 45.5 mol%. The high 16S rRNA gene sequence similarity with species of Bartonella and its close phylogenetic position suggest that strain PEB0122T represents a novel species within the genus Bartonella, for which we propose the name Bartonella apis sp. nov. The type strain is PEB0122T ( = NCIMB 14961T = DSM 29779T). PMID- 26537853 TI - Impact of Prostate Cancer Treatment on the Sexual Quality of Life for Men-Who Have-Sex-with-Men. AB - INTRODUCTION: With earlier prostate cancer (PCa) diagnosis and an increased focus on survivorship, post-treatment sexual quality of life (QoL) has become increasingly important. Research and validated instruments for sexual QoL assessment based on heterosexual samples have limited applicability for men-who have-sex-with-men (MSM). AIM: We aimed to create a validated instrument for assessing sexual needs and concerns of MSM post-PCa treatment. Here we explore post-PCa treatment sexual concerns for a sample of MSM, as the first part of this multi-phase project. METHODS: Individual semi-structured interviews were conducted with 16 MSM face-to-face or via Internet-based video conferencing. Participants were asked open-ended questions about their experiences of sexual QoL following PCa. Interviews were recorded, transcribed verbatim, uploaded to NVivo 8(TM) , and analyzed using qualitative methodology. MAIN OUTCOME MEASURE: We have conducted semi-structure qualitative interviews on 16 MSM who were treated for PCa. Focus was on post-treatment sexual concerns. RESULTS: The following themes were inductively derived: (i) erectile, urinary, ejaculation, and orgasmic dysfunctions; (ii) challenges to intimate relationships; and (iii) lack of MSM-specific oncological and psychosocial support for PCa survivorship. Sexual practices pre-treatment ranked in order of frequency were masturbation, oral sex, and anal sex, an ordering that prevailed post-treatment. Sexual QoL decreased with erectile, urinary, and ejaculation dysfunctions. Post-treatment orgasms were compromised. Some single men and men in non-monogamous relationships reported a loss of confidence or difficulty meeting other men post-treatment. Limited access to targeted oncological and psychosocial supports posed difficulties in coping with PCa for MSM. CONCLUSIONS: The negative impact on sexual QoL can be severe for MSM and requires targeted attention. Penile-vaginal intercourse and erectile function have been the primary focus of sexual research and rehabilitation for men with PCa, and do not adequately reflect the sexual practices of MSM. Our findings suggest that future research dedicated to MSM with PCa is needed to incorporate their sexual practices and preferences specifically into treatment decisions, and that targeted oncological and psychosocial support services are also warranted. PMID- 26537854 TI - Electrogenerated Chemiluminescence of Cationic Triangulene Dyes: Crucial Influence of the Core Heteroatoms. AB - Trianguleniums are fascinating conjugated hexacyclic cations that exhibit interesting electronic and optical properties. Herein, the electrogenerated chemiluminescence (ECL) emission of this family of fluorescent dyes is reported for the first time. Redox behavior and fluorescence properties of eight cationic triangulene luminophores with different heteroatom patterns in the core structure and various pending substituents were examined to rationalize the ECL. Clearly, the more electron-rich the carbocation, the more efficient the corresponding ECL; two very distinct classes of triangulenes can be drawn from these studies by using an ECL wall sufficiency formalism. PMID- 26537855 TI - Eryptosis Indices as a Novel Predictive Parameter for Biocompatibility of Fe3O4 Magnetic Nanoparticles on Erythrocytes. AB - Fe3O4 magnetic nanoparticles (Fe3O4-MNPs) have been widely used in clinical diagnosis. Hemocompatibility of the nanoparticles is usually evaluated by hemolysis. However, hemolysis assessment does not measure the dysfunctional erythrocytes with pathological changes on the unbroken cellular membrane. The aim of this study is to evaluate the use of suicidal death of erythrocytes (i.e. eryptosis indices) as a novel predictive and prognostic parameter, and to determine the impact of Fe3O4-MNPs on cellular membrane structure and the rheology properties of blood in circulation. Our results showed that phosphatidylserine externalization assessment was significantly more sensitive than classical hemolysis testing in evaluating hemocompatibility. Although no remarkable changes of histopathology, hematology and serum biochemistry indices were observed in vivo, Fe3O4-MNPs significantly affected hemorheology indices including erythrocyte deformation index, erythrocyte rigidity index, red blood cell aggregation index, and erythrocyte electrophoresis time, which are related to the mechanical properties of the erythrocytes. Oxidative stress induced calcium influx played a critical role in the eryptotic activity of Fe3O4-MNPs. This study demonstrated that Fe3O4-MNPs cause eryptosis and changes in flow properties of blood, suggesting that phosphatidylserine externalization can serve as a predictive parameter for hemocompatibility assay. PMID- 26537856 TI - Clinical presentation, diagnosis, therapy and outcome of alveolar echinococcosis in dogs. AB - Alveolar echinococcosis (AE), a parasitic disease primarily of the liver caused by the larval stage of Echinococcus multilocularis, is highly endemic in Switzerland. In contrast to well-established management protocols in people, little is known with regard to optimal treatment strategies in dogs. The objective of this study was to describe the clinical signs and diagnostic procedures in dogs with AE and to evaluate outcome following medical treatment alone or surgery and medical treatment. Of 23 putative AE cases between 2004 and 2014, 20 were classified as confirmed (n=18) or probable (n=2) AE, based on abdominal ultrasound, serology, cytology, histology and/or PCR. Most dogs presented with abdominal distension in an advanced stage of disease. Dogs receiving specific treatment (radical or debulking surgery together with medical treatment, or medical treatment alone) survived longer than dogs left untreated, but no difference was found between treatment types. Survival at one year was associated with absence of free abdominal fluid, absence of abdominal distension and treatment of any type. However, dogs treated with debulking surgery all faced relapse. Findings of this study suggest that in AE-affected dogs for which a therapeutic approach is regarded appropriate by owners and veterinarians, radical surgical resection and medical treatment or, if total resection is not possible, medical treatment alone should be considered. However, studies on larger numbers of dogs are necessary before definitive treatment recommendations can be made. PMID- 26537858 TI - Erratum to: Hyaluronic acid increases tendon derived cell viability and collagen type I expression in vitro: Comparative study of four different Hyaluronic acid preparations by molecular weight. PMID- 26537857 TI - Impacts of El Nino Southern Oscillation and Indian Ocean Dipole on dengue incidence in Bangladesh. AB - Dengue dynamics are driven by complex interactions between hosts, vectors and viruses that are influenced by environmental and climatic factors. Several studies examined the role of El Nino Southern Oscillation (ENSO) in dengue incidence. However, the role of Indian Ocean Dipole (IOD), a coupled ocean atmosphere phenomenon in the Indian Ocean, which controls the summer monsoon rainfall in the Indian region, remains unexplored. Here, we examined the effects of ENSO and IOD on dengue incidence in Bangladesh. According to the wavelet coherence analysis, there was a very weak association between ENSO, IOD and dengue incidence, but a highly significant coherence between dengue incidence and local climate variables (temperature and rainfall). However, a distributed lag nonlinear model (DLNM) revealed that the association between dengue incidence and ENSO or IOD were comparatively stronger after adjustment for local climate variables, seasonality and trend. The estimated effects were nonlinear for both ENSO and IOD with higher relative risks at higher ENSO and IOD. The weak association between ENSO, IOD and dengue incidence might be driven by the stronger effects of local climate variables such as temperature and rainfall. Further research is required to disentangle these effects. PMID- 26537859 TI - Mindfulness and emotion regulation in older and young adults. AB - OBJECTIVES: Research shows that dispositional mindfulness is associated with metrics of overall well-being, with enhanced emotion regulation potentially underlying these salutary effects. However, the role of regulation strategy use remains poorly understood. In this study, we examined age-variant associations between dispositional mindfulness, emotion regulation strategies, and emotion dysregulation. METHOD: Self-report data were collected from 50 older and 50 young adults on mindfulness, emotion dysregulation, and recent strategy use. For the current study, we examined if cognitive reappraisal, experiential suppression, and thought avoidance use mediated the association between mindfulness and emotion dysregulation. RESULTS: Thought avoidance, but not reappraisal or suppression strategies, partially mediated the association between mindfulness and emotion dysregulation. Age group moderated the observed mediation, such that for young adults, lower mindfulness was associated with greater use of thought avoidance, and in turn with greater emotion dysregulation (e.g., difficulties engaging in goal-directed behavior in the face of strong emotions). CONCLUSION: The current cross-sectional study suggests that reduced avoidance of thoughts may partially explain the relationship between trait mindfulness and enhanced emotion regulation, with this mediational pathway being stronger for young compared with older adults. PMID- 26537860 TI - Compromised cortical bone compartment in type 2 diabetes mellitus patients with microvascular disease. AB - OBJECTIVE AND DESIGN: Patients with type 2 diabetes mellitus (T2D) have an increased fracture risk despite a normal or elevated bone mineral density (BMD). The aim of this cross-sectional in vivo study was to assess parameters of peripheral bone microarchitecture, estimated bone strength and bone remodeling in T2D patients with and without diabetic microvascular disease (MVD+ and MVD- respectively) and to compare them with healthy controls. METHODS: Fifty-one T2D patients (MVD+ group: n=25) were recruited from Funen Diabetic Database and matched for age, sex and height with 51 healthy subjects. High-resolution peripheral quantitative tomography (HR-pQCT) was used to assess bone structure at the non-dominant distal radius and tibia. Estimated bone strength was calculated using finite element analysis. Biochemical markers of bone turnover were measured in all participants. RESULTS: After adjusting for BMI, MVD+ patients displayed lower cortical volumetric BMD (P=0.02) and cortical thickness (P=0.02) and higher cortical porosity at the radius (P=0.02) and a trend towards higher cortical porosity at the tibia (P=0.07) compared to controls. HR-pQCT parameters did not differ between MVD- and control subjects. Biochemical markers of bone turnover were significantly lower in MVD+ and MVD- patients compared to controls (all P<0.01). These were no significant correlations between disease duration, glycemic control (average glycated hemoglobin over the previous 3 years) and HR pQCT parameters. CONCLUSION: Cortical bone deficits are not a characteristic of all T2D patients but of a subgroup characterized by the presence of microvascular complications. Whether this influences fracture rates in these patients needs further investigation. PMID- 26537861 TI - MECHANISMS IN ENDOCRINOLOGY: Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus. AB - Subjects with type 1 diabetes mellitus (T1DM) have decreased bone mineral density and an up to sixfold increase in fracture risk. Yet bone fragility is not commonly regarded as another unique complication of diabetes. Both animals with experimentally induced insulin deficiency syndromes and patients with T1DM have impaired osteoblastic bone formation, with or without increased bone resorption. Insulin/IGF1 deficiency appears to be a major pathogenetic mechanism involved, along with glucose toxicity, marrow adiposity, inflammation, adipokine and other metabolic alterations that may all play a role on altering bone turnover. In turn, increasing physical activity in children with diabetes as well as good glycaemic control appears to provide some improvement of bone parameters, although robust clinical studies are still lacking. In this context, the role of osteoporosis drugs remains unknown. PMID- 26537862 TI - THERAPY OF ENDOCRINE DISEASE: Testosterone supplementation and body composition: results from a meta-analysis study. AB - OBJECTIVE: The role of testosterone (T) in regulating body composition is conflicting. Thus, our goal is to meta-analyse the effects of T supplementation (TS) on body composition and metabolic outcomes. METHODS: All randomized controlled trials (RCTs) comparing the effect of TS on different endpoints were considered. RESULTS: Overall, 59 trials were included in the study enrolling 3029 and 2049 patients in TS and control groups respectively. TS was associated with any significant modification in body weight, waist circumference and BMI. Conversely, TS was associated with a significant reduction in fat and with an increase in lean mass as well as with a reduction of fasting glycaemia and insulin resistance. The effect on fasting glycaemia was even higher in younger individuals and in those with metabolic diseases. When only RCTs enrolling hypogonadal (total T <12 mol/l) subjects were considered, a reduction of total cholesterol as well as triglyceride (TGs) levels were also detected. Conversely, an improvement in HDL cholesterol levels as well as in both systolic and diastolic blood pressure was not observed. CONCLUSION: Our data suggest that TS is able to improve body composition and glycometabolic profile particularly in younger subjects and in those with metabolic disturbances. Specifically designed studies are urgently needed to confirm this point. PMID- 26537863 TI - Toxicological Implications and Inflammatory Response in Human Lymphocytes Challenged with Oxytetracycline. AB - Antibiotics are widely used in zoo technical and veterinary practices as feed supplementation to ensure wellness of farmed animals and livestock. Several evidences have been suggesting both the toxic role for tetracyclines, particularly for oxytetracycline (OTC). This potential toxicity appears of great relevance for human nutrition and for domestic animals. This study aimed to extend the evaluation of such toxicity. The biologic impact of the drug was assessed by evaluating the proinflammatory effect of OTC and their bone residues on cytokine secretion by in vitro human peripheral blood lymphocytes. Our results showed that both OTC and OTC-bone residues significantly induced the T lymphocyte and non-T cell secretion of interferon (IFN)-gamma, as cytokine involved in inflammatory responses in humans as well as in animals. These results may suggest a possible implication for new potential human and animal health risks depending on the entry of tetracyclines in the food-processing chain. PMID- 26537864 TI - The use of the transparotid approach for surgical treatment of condylar fractures - Own experience. AB - AIM: To assess the results of surgical treatment of condylar fractures using the transparotid approach. MATERIAL AND METHODS: The transparotid approach was used in 38 patients with unilateral condylar fracture. In four cases a single 2.0 plate was used, in the latter - 3D plates were used. All the patients were subjected to control clinical examination including: occlusion, facial nerve function, mandibular movements, pain presence, subjective assessment of the scar aesthetics and the presence of salivary fistula or salivary cyst on the first day following surgery and after 1, 3 and 6 months. Control radiography of the mandible in at least two projections was made on the first day after surgery and after 3 months. RESULTS: In 3 patients a partial paresis of the facial nerve was noticed followed by a spontaneous recovery 3 months postoperatively. In 2 patients acoustic effects, without pain in the temporomandibular joint of the fractured side were still present 6 months postoperatively. Plate fractures were found in two out of four patients operated on with single-plate technique. Loosening and displacement of a fixation screw occurred in 4 patients; in 3 cases it referred to a single 2.0 plate and in one, a Delta plate. Post-operation scar was accepted by all the patients. CONCLUSION: The transparotid approach allows for direct visualisation of the fracture providing proper reduction and osteosynthesis, with a low risk of facial nerve paresis. Precise wound closure in layers, especially of the parotid capsule allows avoiding a salivary fistula. PMID- 26537865 TI - Specific N-glycans of Hepatocellular Carcinoma Cell Surface and the Abnormal Increase of Core-alpha-1, 6-fucosylated Triantennary Glycan via N acetylglucosaminyltransferases-IVa Regulation. AB - Glycosylation alterations of cell surface proteins are often observed during the progression of malignancies. The specific cell surface N-glycans were profiled in hepatocellular carcinoma (HCC) with clinical tissues (88 tumor and adjacent normal tissues) and the corresponding serum samples of HCC patients. The level of core-alpha-1,6-fucosylated triantennary glycan (NA3Fb) increased both on the cell surface and in the serum samples of HCC patients (p < 0.01). Additionally, the change of NA3Fb was not influenced by Hepatitis B virus (HBV)and cirrhosis. Furthermore, the mRNA and protein expression of N-acetylglucosaminyltransferase IVa (GnT-IVa), which was related to the synthesis of the NA3Fb, was substantially increased in HCC tissues. Knockdown of GnT-IVa leads to a decreased level of NA3Fb and decreased ability of invasion and migration in HCC cells. NA3Fb can be regarded as a specific cell surface N-glycan of HCC. The high expression of GnT IVa is the cause of the abnormal increase of NA3Fb on the HCC cell surface, which regulates cell migration. This study demonstrated the specific N-glycans of the cell surface and the mechanisms of altered glycoform related with HCC. These findings lead to better understanding of the function of glycan and glycosyltransferase in the tumorigenesis, progression and metastasis of HCC. PMID- 26537866 TI - PEG3 domain gene expression in maternal and foetal placenta in intrauterine growth restricted bovine foetuses. AB - We used a genetic (MIMT1(Del)) model of intrauterine growth restriction to investigate dysregulation of PEG3 domain gene expression in bovine foetal and maternal placenta. ZIM2, APEG3 and PEG3 expressions were similarly reduced in MIMT1(Del/) (WT) foetal placenta, suggesting coordinated regulation. Methylation of DNA CpG sites associated with these genes showed no differences, but differences in the levels of MIMT1 RNA methylation at three CpG sites were found in foetal placenta. Our data are consistent with the presence of a bidirectional promoter 5' of MIMT1 and suggest a regulatory role for the MIMT1 non-coding transcript. PEG3 domain expression on the maternal placenta side was not affected by the foetal mutation. PMID- 26537867 TI - Metabotropic GABA signalling modulates longevity in C. elegans. AB - The nervous system plays an important but poorly understood role in modulating longevity. GABA, a prominent inhibitory neurotransmitter, is best known to regulate nervous system function and behaviour in diverse organisms. Whether GABA signalling affects aging, however, has not been explored. Here we examined mutants lacking each of the major neurotransmitters in C. elegans, and find that deficiency in GABA signalling extends lifespan. This pro-longevity effect is mediated by the metabotropic GABAB receptor GBB-1, but not ionotropic GABAA receptors. GBB-1 regulates lifespan through G protein-PLCbeta signalling, which transmits longevity signals to the transcription factor DAF-16/FOXO, a key regulator of lifespan. Mammalian GABAB receptors can functionally substitute for GBB-1 in lifespan control in C. elegans. Our results uncover a new role of GABA signalling in lifespan regulation in C. elegans, raising the possibility that a similar process may occur in other organisms. PMID- 26537868 TI - Putting flexible animal prospection into context: escaping the theoretical box. AB - The debate on non-human future-oriented cognition has long revolved around the question whether such cognition at all occurs. Closer inspection reveals just how much cognition in general-down to its simplest forms-is geared toward predicting the future in a bid to maintain homeostasis and fend off entropy. Over the course of life's existence on Earth, evolution and natural selection have, through a series of evolutionary arms races, gotten increasingly good at achieving this. Prospection has reached its current pinnacle based partly on a system for episodic cognition that-as research increasingly is showing-is not limited principally to human beings. Nevertheless, and despite some notable recent defections, many researchers remain convinced of the merits of the Bischof-Kohler Hypothesis with its claim that no species other than human beings is able to anticipate future needs or otherwise live in anything other than the immediate present moment. What might, at first, appear to be empirical disputes turn out to reveal largely unquestioned theoretical divides. Without due care, one risks setting out conditions for 'true' future orientation that are irrelevant for describing human cognition. In sorting out the theoretical and terminological muddle framing contemporary debate, this article makes a plea for moving beyond past dogmas while putting animal prospection research into the context of evolution and contemporary cognitive science. For further resources related to this article, please visit the WIREs website. PMID- 26537869 TI - Habitual Sleep Duration and Risk of Childhood Obesity: Systematic Review and Dose response Meta-analysis of Prospective Cohort Studies. AB - A meta-analysis of cross-sectional studies found that shorter-time sleep was correlated with increased risk of obesity in children. However, findings from prospective cohort studies were inconsistent. PubMed and other data resources were searched through May 2015. Twenty-five eligible studies were identified including 56,584 children and adolescents with an average 3.4-year follow-up. Compared with children having the longest sleep duration (~12.2 hours), kids with the shortest sleep duration (~10.0 hours) were 76% more likely to be overweight/obese (pooled odds ratio [OR]: 1.76; 95% confidence interval [CI]: 1.39, 2.23); and had relatively larger annual BMI gain (pooled beta coefficient: 0.13; 95% CI: 0.01, 0.25 kg/m(2)). With every 1 hour/day increment in sleep duration, the risk of overweight/obesity was reduced by 21% (OR: 0.79; 95% CI: 0.70, 0.89); and the annual BMI gain declined by 0.05 kg/m(2) (beta = -0.05; 95% CI: -0.09, -0.01). The observed associations were not appreciably modified by region, baseline age or the length of follow-up. Accumulated literature indicates a modest inverse association between sleep duration and the risk of childhood overweight/obesity. Further research is needed to determine the age and gender specified optimal hours of sleep and ideal sleep pattern with respect to obesity prevention in children. PMID- 26537870 TI - Lamin A/C deficiency is an independent risk factor for cervical cancer. AB - BACKGROUND: In the past, cervical cancer has been linked to Human Papilloma Virus (HPV) infection. Previously, we found that pre-neoplastic breast and ovarian lesions may be associated with lamin A/C deficiency, resulting in abnormal nuclear morphologies and chromosomal instability. Ultimately, these phenomena are thought to lead to cancer. Here, we assessed lamin A/C deficiency as an indicator for the risk to develop cervical cancer. METHODS: The expression of lamin A/C was assessed by Western blotting in cervical uterine smears (CUS) of 76 adult women from Benin concomitant with nuclear morphology assessment and HPV genotyping using microscopy and PCR-based assays, respectively. In vitro analyses were performed to uncover the mechanism underlying lamin A/C expression alterations observed in vivo. The presence of cervical intra-epithelial neoplasia (CIN) was assessed by colposcopy. RESULTS: Normal lamin A/C expression (group A) was observed in 39% of the CUS, weak lamin A/C expression (group B) was observed in 28% of the CUS and no lamin A/C expression (group C) was observed in 33% of the CUS tested. Infection with oncogenic HPV was found to be significantly higher in group C (36%) than in groups A (17%) and B (14%). Two years after our first assessment, CIN was observed in 20% of the women in group C. The in vitro application of either a histone deacetylase inhibitor (trichostatin) or a protein kinase inhibitor (staurosporine) was found to restore lamin A/C expression in cervical cancer-derived cells. CONCLUSION: Lamin A/C deficiency may serve as an independent risk factor for CIN development and as an indicator for preventive therapy in cervical cancer. PMID- 26537871 TI - Deleting the Ig-Like Domain of Alicyclobacillus acidocaldarius Endoglucanase Cel9A Causes a Simultaneous Increase in the Activity and Stability. AB - Endoglucanase Cel9A from Alicyclobacillus acidocaldarius (AaCel9A) is a monomeric enzyme with 537 residues. This enzyme has an Ig-like domain in the N-terminus of the catalytic domain. In this study, the role of the Ig-like domain on the activity, stability, and structural rigidity of AaCel9A and the effect of calcium on enzyme activity and stability were examined by comparing a truncated enzyme with deletion of the Ig-like domain (AaCel9ADeltaN) to the wild-type enzyme. Our results showed that the deletion of the Ig-like domain increased the catalytic efficiency of the truncated enzyme up to threefold without any significant changes in the K m of the enzyme. Furthermore, pH and temperature optimum for activity were shifted from 6.5 to 7.5 and from 65 to 60 degrees C, respectively, by deletion of the Ig-like domain. The thermal stability and fluorescence quenching results indicated that the stability and rigidity of the truncated enzyme have been more than that of the wild-type enzyme. Calcium similarly increased the catalytic efficiency of the enzymes (up to 40 %) and remarkably raised the stability of the AaCel9A compared to the AaCel9ADeltaN. This shows that Ig-like domain has a role in the increase of the enzyme stability by calcium in the wild-type enzyme. PMID- 26537872 TI - Way Forward: an Indigenous approach to well-being. AB - OBJECTIVE: Aboriginal and Torres Strait Islander individuals are overrepresented in mental health services in the state of Queensland (QLD), Australia; indicating greater prevalence and less preventative management of mental illness. This paper describes a project to enhance the model of care to improve mental health, alcohol and other drug outcomes for Aboriginal and Torres Strait Islander Community members in two metropolitan Hospital and Health Services, in Brisbane, Australia. METHODS: Individual and focus group consultations were conducted with stakeholders, to determine key themes. RESULTS: The consultative phase of the project revealed three priority areas for action: governance and supervision arrangements for the workforce in the area of Indigenous mental health, alcohol and other drugs; the cultural capability of non-Indigenous clinicians; and consumer access to services. CONCLUSIONS: The Way Forward project is a broad workforce redesign approach to address these three key areas. This approach is designed to acknowledge the strengths among the Indigenous Aboriginal and Torres Strait Islander workforce and to utilise their specialised cultural knowledge. This strategy will also include working in relationships with key Community controlled health and other organisations. The approach will be reviewed and evaluated. PMID- 26537873 TI - Balint groups: an Australasian perspective for psychiatrists. AB - OBJECTIVE: This paper aims to provide a brief overview of the history and scope of the Balint movement; to outline how Balint groups work; to describe what is entailed in leading a Balint group; and to give a brief overview of the current state of Balint work in Australia and New Zealand. CONCLUSIONS: Balint groups provide a unique setting in which clinicians can learn how to deal well with challenging doctor-patient relationships and the feelings evoked in clinical practice. Balint work is relatively undeveloped in Australasia. There is scope for involvement by psychiatrists and trainees as both participants and facilitators. PMID- 26537874 TI - Parents with Borderline Personality Disorder - approaches to early intervention. AB - OBJECTIVE: This paper aims to describe the issues confronting parents with a history of attachment-related trauma and Borderline Personality Disorder (BPD) and outline contemporary approaches to intervention. METHOD: The paper discusses recent reviews of parenting and BPD and outlines recent clinical developments. RESULT: BPD raises significant challenges for parents, with potential adverse impact on infant attachment and development. CONCLUSION: Approaches to early intervention should focus on improving the parental capacity as an attachment figure and their sensitivity to infant emotional communication. PMID- 26537875 TI - Post-intubation tracheal stenosis after management of complicated aortic dissection: a case series. AB - BACKGROUND: Patients undergoing total aortic arch replacement or aortic dissecting aneurysmectomy are generally managed with medications to control hypotension and blood coagulation to minimize mortality and morbidity. However, prolonged mechanical ventilation via tracheal intubation increases the risk of tracheal stenosis in such patients. CASE PRESENTATION: We present 2 cases (a 49 year-old woman and a 62-year-old man) of post-intubation tracheal stenosis occurring after surgery for the correction of complicated aortic dissection; both cases were successfully managed by tracheal cryotherapy. CONCLUSION: Continuous monitoring of cuff pressure and regular cuff palpation are necessary to minimize the incidence of tracheal stenosis. If the patients have concomitant local or systemic infection, adequate preventive measures should be taken to reduce the incidence of post-intubation tracheal stenosis. Tracheal cryotherapy is recommendable for the management of post-intubation tracheal stenosis. PMID- 26537876 TI - Fractionation of the stable carbon isotope ratio of essential fatty acids in zebrafish Danio rerio and mud snails Bellamya chinensis. AB - Fractionation of stable carbon (C) isotopes in the essential fatty acids 18:2n-6, 18:3n-3, 20:4n-6, 20:5n-3, and 22:6n-3 was investigated in the zebrafish Danio rerio and the mud snail Bellamya chinensis fed the same two diets. These diets differed in essential fatty acid compositions: (1) TetraMin contained all five fatty acids, and (2) Chlorella contained only two, 18:2n-6 and 18:3n-3. On average, the isotopic fractionation was -0.5 +/- 0.9 0/00 for 18:2n-6 and 18:3n-3 for all experiments, indicating that the fractionation of these essential fatty acids was negligible. However, the isotopic fractionation of 20:4n-6, 20:5n-3, and 22:6n-3 varied greatly between species and between diets. The isotopic fractionation of the Chlorella diet was -0.2 and -6.9 0/00 for zebrafish and mud snail, but 4.2 and -1.3 0/00, respectively, when these consumers were fed TetraMin. This variation could be explained by the different amount of assimilation and the biosynthesis of these fatty acids from their precursors (i.e., 18:2n-6 and 18:3n-3). These results indicate that the isotopic composition of C20 and C22 essential fatty acids was strongly influenced by the fatty acid composition in the diets. Thus the stable C isotope ratios of C18 essential fatty acids in consumers are more useful as dietary tracers in food web studies. PMID- 26537877 TI - Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. AB - The currently available techniques for the safety evaluation of candidate drugs are usually cost-intensive and time-consuming and are often insufficient to predict human relevant cardiotoxicity. The purpose of this study was to develop an in vitro repeated exposure toxicity methodology allowing the identification of predictive genomics biomarkers of functional relevance for drug-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The hiPSC-CMs were incubated with 156 nM doxorubicin, which is a well-characterized cardiotoxicant, for 2 or 6 days followed by washout of the test compound and further incubation in compound-free culture medium until day 14 after the onset of exposure. An xCELLigence Real-Time Cell Analyser was used to monitor doxorubicin-induced cytotoxicity while also monitoring functional alterations of cardiomyocytes by counting of the beating frequency of cardiomyocytes. Unlike single exposure, repeated doxorubicin exposure resulted in long-term arrhythmic beating in hiPSC-CMs accompanied by significant cytotoxicity. Global gene expression changes were studied using microarrays and bioinformatics tools. Analysis of the transcriptomic data revealed early expression signatures of genes involved in formation of sarcomeric structures, regulation of ion homeostasis and induction of apoptosis. Eighty-four significantly deregulated genes related to cardiac functions, stress and apoptosis were validated using real-time PCR. The expression of the 84 genes was further studied by real-time PCR in hiPSC-CMs incubated with daunorubicin and mitoxantrone, further anthracycline family members that are also known to induce cardiotoxicity. A panel of 35 genes was deregulated by all three anthracycline family members and can therefore be expected to predict the cardiotoxicity of compounds acting by similar mechanisms as doxorubicin, daunorubicin or mitoxantrone. The identified gene panel can be applied in the safety assessment of novel drug candidates as well as available therapeutics to identify compounds that may cause cardiotoxicity. PMID- 26537878 TI - Visual impairment and blindness in type 2 diabetics: Ife-Ijesa diabetic retinopathy study. AB - Diabetes and blindness are important health issues globally; we determined the prevalence of blindness, diabetic retinopathy, and other eye diseases in Nigerian type 2 diabetics. A prospective, cross-sectional study was conducted on consenting type 2 diabetic patients who had scheduled comprehensive eye examination including dilated funduscopy with +78DS. Visual status was graded using the WHO criteria. Approval from Institutional Ethics Committee was obtained. Primary outcome measures were the prevalence and causes of blindness as well as prevalence of diabetic retinopathy. Secondary outcome measures were the presence of other eye diseases. Data were analyzed using SPSS version 13. Two hundred and sixty-six eyes of 133 type 2 diabetic patients aged 22-89 years were studied; 69 (51.9 %) were males while 64 (48.1 %) were females. Five (3.8 %) patients were blind while 27 (20.3 %) were visually impaired. Cataract was the leading cause of blindness (60 %) and visual impairment was found in 59.3 %. Diabetic retinopathy was present in 37 (27.8 %) diabetic patients of which 5 (3.8 %) were proliferative. Diabetic macular edema was present in 31 (23.3 %) patients. Severe visual impairment and blindness were commoner in those with diabetic retinopathy. Refractive error 67 (25.2 %), cataract 63 (23.7 %), and chronic glaucoma 44 (16.5 %) were the most prevalent non-diabetic retinopathy eye diseases. High prevalence of blindness, diabetic retinopathy, and other diseases are seen in type 2 diabetics. Health education, early diagnosis as well as treatment of diabetic retinopathy and other diseases will largely alleviate these ocular morbidities. PMID- 26537879 TI - Negative pressure wound therapy for high-risk wounds in lower extremity revascularization: study protocol for a randomized controlled trial. AB - BACKGROUND: Rates of surgical site infections (SSIs) following groin incision for femoral artery exposure are much higher than expected of a clean operation. The morbidity and mortality is high, particularly with the use of prosthetic grafts. The vascular surgery population is at an increased risk of SSIs related to peripheral vascular disease (PVD), diabetes, obesity, previous surgery and presence of tissue loss. Negative pressure wound therapy (NPWT) dressings have been used on primarily closed incisions to reduce surgical site infections in other surgical disciplines. We have not come across any randomized controlled trials to support the prophylactic use of negative pressure wound therapy in high risk vascular patients undergoing lower limb revascularization. METHODS/DESIGN: In this single-center, prospective randomized controlled trial, patients scheduled for a lower limb revascularization requiring open femoral artery exposure who are at a high risk (BMI > 30 kg/m(2), previous femoral cutdown or Rutherford V or VI category for chronic limb ischemia) will be eligible for the study. A total of 108 groin incisions will be randomized to the use of a negative pressure wound device or standard adhesive gauze dressing. Patients will be followed in hospital and reassessed within the first 30 days postoperatively. The primary outcome is SSI within the first 30 days of surgery and will be determined using the intention-to-treat principle. Secondary outcomes include length of stay, emergency room visits, reoperation, amputation and mortality. A cost analysis will be performed. DISCUSSION: The trial is expected to define the role of NPWT in SSI prophylaxis for lower limb revascularization in high-risk vascular patients. The results of the study will be used to inform current best practice for perioperative care and the minimization of SSIs. TRIAL REGISTRATION: NCT02084017 , March 2014. PMID- 26537880 TI - Minimal Traumatic Brain Injury in Mice: Protease-Activated Receptor 1 and Thrombin-Related Changes. AB - Minimal traumatic brain injury (mTBI) is partially defined by the existence of retrograde amnesia and is associated with microscopic bleeds containing activated coagulation factors. In a previous study, we have found that mTBI immediately releases thrombin-like activity in the brain, which induces amnesia by activating protease-activated receptor 1 (PAR-1) and blocking long-term potentiation (LTP). In the present study, we assessed the effects of mTBI on thrombin and PAR-1 levels in the brain using the same model. After the immediate elevation, thrombin activity returned to baseline 1 h post-trauma and increased again 72 h later (42% relative to control; p < 0.005). These changes were associated with a significant increase in PAR-1 levels 24 (17%; p < 0.05) and 72 h (20%; p < 0.05) post-trauma. Interestingly, the late elevation in thrombin-like activity was also associated with elevation of the major central nervous system thrombin inhibitor, protease nexin-1, 72 h post-mTBI (10%; p < 0.005). When thrombin was injected into brain ventricles, an increased sensitivity to seizure-like activity was detected at 72 h post-mTBI. The results are compatible with astrocyte activation post-mTBI resulting in increased thrombin secretion, PAR-1 expression, and seizure sensitivity. PMID- 26537881 TI - Developing a kinematic understanding of chest compressions: the impact of depth and release time on blood flow during cardiopulmonary resuscitation. AB - BACKGROUND: Effective cardiopulmonary resuscitation is a critical component of the pre-hospital treatment of cardiac arrest victims. Mechanical chest compression (MCC) devices enable the delivery of MCC waveforms that could not be delivered effectively by hand. While chest compression generated blood flow has been studied for more than 50 years, the relation between sternum kinematics (depth over time) and the resulting blood flow have not been well described. Using a five parameter MCC model, we studied the effect of MCC depth, MCC release time, and their interaction on MCC generated blood flow in a highly instrumented swine model of cardiac arrest. METHODS: MCC hemodynamics were studied in 17 domestic swine (~30 kg) using multiple extra-vascular flow probes and standard physiological monitoring. After 10 min of untreated ventricular fibrillation, mechanical MCC were started. MCC varied such that sternal release occurred over 100, 200, or 300 ms. MCC were delivered at a rate of 100 per min and at a depth of 1.25" (n = 9) or at a depth of 1.9" (n = 8) for a total of 18 min. Transitions between release times occurred every 2 min and were randomized. Linear Mixed Models were used to estimate the effect of MCC depth, MCC release time, and the interaction between MCC depth and release time on physiological outcomes. RESULTS: Blood pressures were optimized by a 200 ms release. End tidal carbon dioxide (EtCO2) was optimized by a 100 ms release. Blood flows were significantly lower at a 300 ms release than at either a 100 or 200 ms release (p < 0.05). 1.9" deep MCC improved EtCO2, right atrial pressure, coronary perfusion pressure, inferior vena cava blood flow, carotid blood flow, and renal vein blood flow relative to 1.25" MCC. CONCLUSIONS: Deeper MCC improved several hemodynamic parameters. Chest compressions with a 300 ms release time generated less blood flow than chest compressions with faster release times. MCC release time is an important quantitative metric of MCC quality and, if optimized, could improve MCC generated blood flows and pressures. PMID- 26537882 TI - Clinical Relevance of Androgen Receptor Splice Variants in Castration-Resistant Prostate Cancer. AB - OPINION STATEMENT: Metastatic castration-resistant prostate cancer (mCRPC) currently benefits from a wealth of treatment options, yet still remains lethal in the vast majority of patients. It is becoming increasingly understood that this disease entity continues to evolve over time, acquiring additional and diverse resistance mechanisms with each subsequent therapy used. This dynamic relationship between treatment pressure and disease resistance can be challenging for the managing clinician. The recent discovery of alternate splice variants of the androgen receptor (AR) is one potential mechanism of escape in mCRPC, and recognizing this resistance mechanism might be important for optimal treatment selection for our patients. AR-V7 appears to be the most relevant AR splice variant, and early clinical data suggest that it is a negative prognostic marker in mCRPC. Emerging evidence also suggests that detection of AR-V7 may be associated with resistance to novel hormonal therapy (abiraterone and enzalutamide) but may be compatible with sensitivity to taxane chemotherapy (docetaxel and cabazitaxel). Adding to this complexity is the observation that AR V7 is a dynamic marker whose status may change across time and depending on selective pressures induced by different therapies. Finally, it is possible that AR-V7 may represent a therapeutic target in mCRPC if drugs can be designed that degrade or inhibit AR splice variants or block their transcriptional activity. Several such agents (including galeterone, EPI-506, and bromodomain/BET inhibitors) are now in clinical development. PMID- 26537883 TI - Ureaplasma urealyticum and Mycoplasma hominis infections and semen quality in 19,098 infertile men in China. AB - OBJECTIVE: This study aimed to determine the incidence of Ureaplasma urealyticum and Mycoplasma hominis infections in infertile and fertile men and to investigate their effects on the semen quality. The study also aimed to analyze the drug susceptibility of UU and MH to provide guidance for reasonable antibiotic use. METHODS: A total of 19,098 semen specimens were obtained from infertile men at our hospital from January to December 2014. In addition to these specimens, 3368 semen specimens of sperm were obtained from donors at the sperm bank of our hospital from January 2011 to December 2014. Semen analysis was performed using the methods outlined by the World Health Organization. RESULTS: The prevalence of UU and MH significantly differed between infertile and fertile men. The mean progressive motility, total motility, and normal forms in the semen samples of infertile males positive for UU significantly differed from the corresponding values of uninfected men. However, the semen parameters did not differ between MH infected and uninfected men. In the antibiotic sensitivity test, UU, MH, and UU mixed with MH were all found susceptible to doxycycline and josamycin with drug resistance rates below 6 %, but both species were highly resistant to ciprofloxacin. CONCLUSIONS: Clinical assessment revealed a significant relationship between UU and MH infections and male infertility. UU was found to significantly affect sperm quality, but this was not the case with MH. Doxycycline and josamycin should be preferred for clinically treating UU and MH infections. PMID- 26537884 TI - Barriers in physical access to maternal health services in rural Ethiopia. AB - BACKGROUND: Identifying women with poor access to health services may inform strategies for improving maternal and child health outcomes. The aim of this study was to explore risk factors associated with access to health facilities (in terms of physical distance) among women of reproductive age (15-49 years) in Dabat district, a rural area of north-western Ethiopia. METHODS: A randomly selected cross sectional survey of 1,456 rural households was conducted. Data were collected during home visits. Data on household assets and socio-demographic data (including age, education level, occupation, religion and ethnicity) were collected on 1,420 women. A geographic information system (GIS) was used to map locations of all households, the district health centre and the smaller health posts. Travel time from households to health facilities was estimated, incorporating information on the topography and terrain of the area. The primary outcomes were: 1) travel time from household to nearest health post 2) travel time from household to health centre. Analysis was conducted using multiple linear regression models and likelihood ratio tests. RESULTS: This study found evidence that educated women lived closer to health centres than uneducated women (adjusted mean difference (adj MD) travel time -41 min (95% CI: -50,-31)) in this community. Woman's age was also associated with distance to the health centre. Women aged 15-20 years were more likely to live in a poor access area compared with women aged 21-30 years (adj MD travel time -11 min (95% CI: -23, 0)), and with women aged 31-49 years (adj MD travel time -32 min (95% CI: -47,-17)). There was no evidence to suggest that travel time to the health centre was associated with household wealth. CONCLUSIONS: Our main aim was to address the almost total lack of research evidence on what socio-demographic characteristics of women of reproductive age influence access to health facilities (in terms of physical distance). We have done so by reporting that our study found an association that women with no education and women who are younger live, on average, further away from a health facility in this rural Ethiopian community. While we have generated this valuable information to those who are responsible for providing maternal and child health services locally, to fully understand access in health care and to promote equitable access to health care, our study could thus be extended to other components of access and explore how our findings fit into the wider context of other factors influencing maternal health outcomes and utilisation of maternal health services such as antenatal care or delivery at health facility. PMID- 26537885 TI - Evaluation of shotgun metagenomics sequence classification methods using in silico and in vitro simulated communities. AB - BACKGROUND: The field of metagenomics (study of genetic material recovered directly from an environment) has grown rapidly, with many bioinformatics analysis methods being developed. To ensure appropriate use of such methods, robust comparative evaluation of their accuracy and features is needed. For taxonomic classification of sequence reads, such evaluation should include use of clade exclusion, which better evaluates a method's accuracy when identical sequences are not present in any reference database, as is common in metagenomic analysis. To date, relatively small evaluations have been performed, with evaluation approaches like clade exclusion limited to assessment of new methods by the authors of the given method. What is needed is a rigorous, independent comparison between multiple major methods, using the same in silico and in vitro test datasets, with and without approaches like clade exclusion, to better characterize accuracy under different conditions. RESULTS: An overview of the features of 38 bioinformatics methods is provided, evaluating accuracy with a focus on 11 programs that have reference databases that can be modified and therefore most robustly evaluated with clade exclusion. Taxonomic classification of sequence reads was evaluated using both in silico and in vitro mock bacterial communities. Clade exclusion was used at taxonomic levels from species to class identifying how well methods perform in progressively more difficult scenarios. A wide range of variability was found in the sensitivity, precision, overall accuracy, and computational demand for the programs evaluated. In experiments where distilled water was spiked with only 11 bacterial species, frequently dozens to hundreds of species were falsely predicted by the most popular programs. The different features of each method (forces predictions or not, etc.) are summarized, and additional analysis considerations discussed. CONCLUSIONS: The accuracy of shotgun metagenomics classification methods varies widely. No one program clearly outperformed others in all evaluation scenarios; rather, the results illustrate the strengths of different methods for different purposes. Researchers must appreciate method differences, choosing the program best suited for their particular analysis to avoid very misleading results. Use of standardized datasets for method comparisons is encouraged, as is use of mock microbial community controls suitable for a particular metagenomic analysis. PMID- 26537886 TI - Persistent post-surgical pain and signs of nerve injury: the Tromso Study. AB - BACKGROUND: The contribution of nerve lesions and neuropathic pain to persistent post-surgical pain (PPSP) is poorly established. The aim of this study was to assess the association between PPSP and symptoms and signs of possible nerve injury in an unselected surgical sample. METHODS: Eighty-one individuals with and without persistent pain after surgical procedures, were recruited from a cross sectional study. Follow-up examination with questionnaires and quantitative sensory testing was performed 15-32 months later (21-64 months after surgery). RESULTS: The median rating of maximum pain intensity among individuals with PPSP decreased from numerical rating scale 4/10 at baseline to 2/10 at follow-up, but considerable changes occurred in both directions. Individuals with PPSP at follow up were significantly more likely to self-report sensory abnormalities than those without PPSP; however, results from sensory testing did not differ significantly between the groups. Self-report of sensory disturbances at the site of surgery was associated with increased warm detection thresholds and tactile pain thresholds. Among individuals with PPSP, 61% had positive findings on sensory testing, suggesting probable neuropathic pain. CONCLUSION: In this study, associations between self-reported symptoms and PPSP were stronger than associations between self-reported symptoms and results of psychophysical tests. Fluctuations in pain intensity together with wide ranges for normal variability in sensory functions, hampers detection of significant group differences. Methodological aspects of quantitative sensory testing applied in a mixed clinical sample are discussed. PMID- 26537887 TI - How to make less more: empathy can fill the gap left by reducing unnecessary care. PMID- 26537888 TI - Safety, trust, and money are uncomfortable bedfellows. PMID- 26537889 TI - Validation of a six degree-of-freedom robotic system for hip in vitro biomechanical testing. AB - Currently, there exists a need for a more thorough understanding of native hip joint kinematics to improve the understanding of pathological conditions, injury mechanisms, and surgical interventions. A biomechanical testing system able to accomplish multiple degree-of-freedom (DOF) movements is required to study the complex articulation of the hip joint. Therefore, the purpose of this study was to assess the repeatability and comparative accuracy of a 6 DOF robotic system as a testing platform for range of motion in vitro hip biomechanical analysis. Intact human cadaveric pelvises, complete with full femurs, were prepared, and a coordinate measuring machine collected measurements of pertinent femoral and pelvic bony landmarks used to define the anatomic hip axes. Passive flexion/extension path and simulated clinical exam kinematics were recorded using a 6 DOF robotic system. The results of this study demonstrate that the 6 DOF robotic system was able to identify hip passive paths in a highly repeatable manner (median RMS error of <0.1mm and <0.4 degrees ), and the robotically simulated clinical exams were consistent and repeatable (rotational RMS error <=0.8 degrees ) in determining hip ranges of motion. Thus, a 6 DOF robotic system is a valuable and effective tool for range of motion in vitro hip biomechanical analysis. PMID- 26537890 TI - [Practical aspects of molecular diagnostics in genodermatoses]. AB - Genodermatoses are rare genetic disorders with a broad spectrum of cutaneous and extracutaneous manifestations that have a genetic background. A thorough clinical examination, laboratory workup and morphological analyses of the skin remain crucial for the diagnosis in the era of next generation sequencing (NGS). The diagnostic algorithm depends on the clinical and molecular heterogeneity and should be adapted for each group of genodermatoses. In cases with uncharacteristic phenotypes which cannot be classified, NGS-based testing accelerates the time to diagnosis and leads to the identification of new disorders and new disease-associated genes. The new knowledge on genotype phenotype correlations should enable revision of the classification of genodermatoses on a molecular basis. PMID- 26537891 TI - Analysis of the FnrL regulon in Rhodobacter capsulatus reveals limited regulon overlap with orthologues from Rhodobacter sphaeroides and Escherichia coli. AB - BACKGROUND: FNR homologues constitute an important class of transcription factors that control a wide range of anaerobic physiological functions in a number of bacterial species. Since FNR homologues are some of the most pervasive transcription factors, an understanding of their involvement in regulating anaerobic gene expression in different species sheds light on evolutionary similarity and differences. To address this question, we used a combination of high throughput RNA-Seq and ChIP-Seq analysis to define the extent of the FnrL regulon in Rhodobacter capsulatus and related our results to that of FnrL in Rhodobacter sphaeroides and FNR in Escherichia coli. RESULTS: Our RNA-seq results show that FnrL affects the expression of 807 genes, which accounts for over 20 % of the Rba. capsulatus genome. ChIP-seq results indicate that 42 of these genes are directly regulated by FnrL. Importantly, this includes genes involved in the synthesis of the anoxygenic photosystem. Similarly, FnrL in Rba. sphaeroides affects 24 % of its genome, however, only 171 genes are differentially expressed in common between two Rhodobacter species, suggesting significant divergence in regulation. CONCLUSIONS: We show that FnrL in Rba. capsulatus activates photosynthesis while in Rba. sphaeroides FnrL regulation reported to involve repression of the photosystem. This analysis highlights important differences in transcriptional control of photosynthetic events and other metabolic processes controlled by FnrL orthologues in closely related Rhodobacter species. Furthermore, we also show that the E. coli FNR regulon has limited transcriptional overlap with the FnrL regulons from either Rhodobacter species. PMID- 26537893 TI - Executive Functioning Predicts Academic But Not Social Adjustment to University. AB - OBJECTIVE: Adjusting well academically and socially has been associated with enhanced academic performance and student retention. The purpose of this study was to examine subthreshold levels of ADHD symptoms such as inattention, hyperactivity, and executive functioning as potential predictors of academic and social adjustment in a healthy sample of university students. METHOD: Participants were 135 undergraduate university students who completed self-report questionnaires. RESULTS: Hierarchical regression analyses revealed that metacognition (an aspect of executive function), gender, and age were significant predictors of academic adjustment beyond hyperactivity, inattention, and depression. Depression was the only significant predictor of social adjustment. CONCLUSION: The BASC-College form may identify depression symptoms predictive of social adjustment, but symptoms of inattention or hyperactivity are not sufficiently sensitive to predict academic adjustment. Measures of executive function that include metacognition such as the BRIEF-A may be most promising in identifying skills predictive of academic adjustment. PMID- 26537892 TI - Application of Nanotrap technology for high sensitivity measurement of urinary outer surface protein A carboxyl-terminus domain in early stage Lyme borreliosis. AB - OBJECTIVES: Prompt antibiotic treatment of early stage Lyme borreliosis (LB) prevents progression to severe multisystem disease. There is a clinical need to improve the diagnostic specificity of early stage Lyme assays in the period prior to the mounting of a robust serology response. Using a novel analyte harvesting nanotechnology, Nanotrap particles, we evaluated urinary Borrelia Outer surface protein A (OspA) C-terminus peptide in early stage LB before and after treatment, and in patients suspected of late stage disseminated LB. METHOD: We employed Nanotrap particles to concentrate urinary OspA and used a highly specific anti OspA monoclonal antibody (mAb) as a detector of the C-terminus peptides. We mapped the mAb epitope to a narrow specific OspA C-terminal domain OspA236-239 conserved across infectious Borrelia species but with no homology to human proteins and no cross-reactivity with relevant viral and non-Borrelia bacterial proteins. 268 urine samples from patients being evaluated for all categories of LB were collected in a LB endemic area. The urinary OspA assay, blinded to outcome, utilized Nanotrap particle pre-processing, western blotting to evaluate the OspA molecular size, and OspA peptide competition for confirmation. RESULTS: OspA test characteristics: sensitivity 1.7 pg/mL (lowest limit of detection), % coefficient of variation (CV) = 8 %, dynamic range 1.7-30 pg/mL. Pre-treatment, 24/24 newly diagnosed patients with an erythema migrans (EM) rash were positive for urinary OspA while false positives for asymptomatic patients were 0/117 (Chi squared p < 10(-6)). For 10 patients who exhibited persistence of the EM rash during the course of antibiotic therapy, 10/10 were positive for urinary OspA. Urinary OspA of 8/8 patients switched from detectable to undetectable following symptom resolution post-treatment. Specificity of the urinary OspA test for the clinical symptoms was 40/40. Specificity of the urinary OspA antigen test for later serology outcome was 87.5 % (21 urinary OspA positive/24 serology positive, Chi squared p = 4.072e(-15)). 41 of 100 patients under surveillance for persistent LB in an endemic area were positive for urinary OspA protein. CONCLUSIONS: OspA urinary shedding was strongly linked to concurrent active symptoms (e.g. EM rash and arthritis), while resolution of these symptoms after therapy correlated with urinary conversion to OspA negative. PMID- 26537894 TI - Characteristics of patients with low back and leg pain seeking treatment in primary care: baseline results from the ATLAS cohort study. AB - BACKGROUND: Patients with back pain radiating to the leg(s) report worse symptoms and poorer recovery than those with back pain alone. Robust evidence regarding their epidemiological profile is lacking from primary care, the setting where most of these patients will present and be managed. Our objective was to describe the characteristics of patients with back and leg pain, including sciatica, seeking treatment in primary care. METHODS: Adults visiting their general practitioner with back and leg pain, of any duration and severity, were invited to participate. Participants completed questionnaires, underwent clinical assessments and received MRI scans. Characteristics of the sample are described, and differences between patients diagnosed with referred leg pain and those with sciatica are analysed. RESULTS: Six hundred nine patients participated; 62.6 % were female, mean (SD) age 50.2 (13.9). 67.5 % reported pain below the knee, 60.7 % were in paid employment with 39.7 % reporting time off work. Mean disability (RMDQ) was 12.7 (5.7) and mean pain intensity was 5.6 (2.2) and 5.2 (2.4) for back and leg respectively. Mean sciatica bothersomeness index (SBI) was 14.9 (5.1). Three quarters (74.2 %) were clinically diagnosed as having sciatica. In the sciatica group, leg pain intensity, neuropathic pain, pain below the knee, leg pain worse than back pain, SBI and positive MRI findings were significantly higher as compared to patients with referred leg pain. CONCLUSIONS: This primary care cohort reported high levels of disability and pain. This is the first epidemiological study of unselected primary care patients seeking healthcare for back and leg pain. Follow-up of this cohort will investigate the prognostic value of their baseline characteristics. This new information will contribute to our understanding of the characteristics and clinical features of this population, and will underpin future research aimed at defining prognostic subgroups to enable better targeting of health care provision. PMID- 26537895 TI - Arrays of high quality SAM-based junctions and their application in molecular diode based logic. AB - This paper describes a method to fabricate a microfluidic top-electrode that can be utilized to generate arrays of self-assembled monolayer (SAM)-based junctions. The top-electrodes consist of a liquid-metal of GaOx/EGaIn mechanically stabilized in microchannels and through-holes in polydimethylsiloxane (PDMS); these top-electrodes form molecular junctions by directly placing them onto the SAM supported by template-stripped (TS) Ag or Au bottom-electrodes. Unlike conventional techniques to form multiple junctions, our method does not require lithography to pattern the bottom-electrode and is compatible with TS bottom electrodes, which are ultra-flat with large grains, free from potential contamination of photoresist residues, and do not have electrode-edges where the molecules are unable to pack well. We formed tunneling junctions with n alkanethiolate SAMs in yields of ~80%, with good reproducibility and electrical stability. Temperature dependent J(V) measurements indicated that the mechanism of charge transport across the junction is coherent tunneling. To demonstrate the usefulness of these junctions, we formed molecular diodes based on SAMs with Fc head groups. These junctions rectify currents with a rectification ratio R of 45. These molecular diodes were incorporated in simple electronic circuitry to demonstrate molecular diode-based Boolean logic. PMID- 26537896 TI - Erratum to: Diagnosis of neglected tropical diseases among patients with persistent digestive disorders (diarrhoea and/or abdominal pain >=14 days): a multi-country, prospective, non-experimental case-control study. PMID- 26537897 TI - Application effect of extensively hydrolyzed milk protein formula and follow-up in preterm children with a gestational age of less than 34 weeks: study protocol for a randomized controlled trial. AB - BACKGROUND: The average incidence of preterm birth in the world is up to 11.1 %, and deaths of preterm children account for more than 50 % of neonatal deaths. Gastrointestinal function of preterm children with a gestational age less than 34 weeks is immaturely developed. For preterm children who can only be fed with formula due to their mothers' sickness, choosing a suitable formula can not only meet the high nutritional needs of preterm children, but also solve their low gastrointestinal tolerability, and is thus very important. METHODS/DESIGN: The study is a prospective, randomized, single-blind and controlled clinical trial. Preterm children with a gestational age less than 34 weeks meeting the inclusion criteria who cannot be breastfed will be included. To demonstrate the application effect of extensively hydrolyzed milk protein formula on the target population, preterm children will be randomized into two groups, 185 subjects in each group. The observation group will be fed with extensively hydrolyzed milk protein (100 % whey protein) formula, while the control group will be fed with preterm children's formula until the children are discharged from the neonatal intensive care unit (NICU). All the formula involved in this study will be from Dumex. After discharge, both groups will be uniformly fed with formula for 0 to 6-month old infants. For statistical analysis, a chi-square test and Student's t test will be applied using SAS 9.4. DISCUSSION: This will be the first randomized controlled clinical study with long-term observation of the growth and development of preterm children during the NICU stay and at 3-month follow-up after discharge from the NICU. Results from this study will be used to determine whether the extensively hydrolyzed formula is more suitable for the low gastrointestinal tolerability of preterm children, and also whether feeding preterm children who are fed with such formula during the NICU stay with ordinary infant formula after discharge from the NICU would affect the normal growth and development of preterm children in the early stage of their lives. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ) with number ChiCTR-IOR-14005696 , on December 22, 2014. PMID- 26537898 TI - Transplantation of mesenchymal stem cells in a laryngeal carcinoma patient with radiation myelitis. AB - Radiation myelitis is a rather rare but devastating complication following therapeutic irradiation to neoplasms when the spinal cord is included within the radiation field. Symptoms of radiation myelitis with the therapeutic doses of radiation commonly employed are usually delayed and most often appear about 6 to 24 months following irradiation. So far, no treatment has proved satisfactory.Transplantation of allogeneic mesenchymal stem cells has been a promising therapy strategy for many disorders in the central nervous system, such as multiple sclerosis, neuromyelitis optica, and autoimmune encephalomyelitis. The cell-base therapy has shown to act to limit inflammation of central nervous system, stimulate neurogenesis, protect axons and promote remyelination. But it has not been established as a therapeutic option for radiation myelitis.In this report, we describe the outcome of allogeneic umbilical cord-derived mesenchymal stem cell transplantation in a patient with laryngeal carcinoma who developed radiation-induced myelitis of his spinal cord with characteristic magnetic resonance imaging changes. PMID- 26537899 TI - Unemployment and health selection in diverging economic conditions: Compositional changes? Evidence from 28 European countries. AB - Unemployment and health selection in diverging economic conditions: Compositional changes? Evidence from 28 european countries. INTRODUCTION: People with ill health tend to be overrepresented among the unemployment population. The relationship between health and unemployment might, however, be sensitive to the overall economic condition. Specifically, the health composition of the unemployment population could change dramatically when the economy takes a turn for the worse. METHODS: Using EU-SILC cross sectional data from 2007 (pre-crisis) and 2011 (during crisis) and linear regression models, this paper investigates the relationship between health and unemployment probabilities under differing economic conditions in 28 European countries. The countries are classified according to (i) the level of and (ii) increase in unemployment rate (i.e. >10 percent and doubling of unemployment rate = crisis country). RESULTS: Firstly, the unemployment likelihood for people with ill health is remarkably stable over time in Europe: the coefficients are very similar in pre-crisis and crisis years. Secondly, people with ill health have experienced unemployment to a lesser extent than those with good health status in the crisis year (when we pool the data and compare 2007 and 2011), but only in the countries with a high and rising unemployment rate. CONCLUSION: The health composition of the unemployment population changes significantly for the better, but only in those European countries that have been severely hit by the current economic crisis. PMID- 26537900 TI - Neurofibromin Regulates Seizure Attacks in the Rat Pilocarpine-Induced Model of Epilepsy. AB - Studies have shown that neurofibromin (NF1) restricts GABA release at inhibitory synapses and regulates dendritic spine formation, which may play an important role in temporal lobe epilepsy (TLE). NF1 expression was detected by double-label immunofluorescence, immunohistochemistry, and western blot analysis in the brains of pilocarpine-induced epilepsy model rats at 6 h, 24 h, 72 h, 7 days, 14 days, 30 days, and 60 days after kindling. NF1 was localized primarily in the nucleus and cytoplasm of neurons. NF1 protein levels significantly increased in the chronic phase (from 7 days until 60 days) in this epileptic rat model. After NF1 expression was knocked down by specific siRNA, the effects of kindling with pilocarpine were evaluated on the 7th day after kindling. The onset latencies of pilocarpine-induced seizures were elevated, and the seizure frequency and duration were reduced in these rats. Our study demonstrates that NF1 promoted seizure attacks in rats with pilocarpine-induced epilepsy. PMID- 26537901 TI - Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease. AB - Mitochondria are the primary source for energy generation in the cell, which manifests itself in the form of the adenosine triphosphate (ATP). Nicotinamide dinucleotide (NADH) molecules are the first to enter the so-called electron transport chain or ETC of the mitochondria. The ETC represents a chain of reducing agents organized into four major protein-metal complexes (I-IV) that utilize the flow of electrons to drive the production of ATP. An additional integral protein that is related to oxidative phosphorylation is ATP synthase, referred to as complex V. Complex V carries out ATP synthesis as a result of the electron flow through the ETC. The coupling of electron flow from NADH to molecular oxygen to the production of ATP represents a process known as oxidative phosphorylation. In this review, we describe mainly the bioenergetic properties of mitochondria, such as those found in the ETC that may be altered in Alzheimer's disease (AD). Increasing evidence points to several mitochondrial functions that are affected in AD. Furthermore, it is becoming apparent that mitochondria are a potential target for treatment in early-stage AD. With growing interest in the mitochondria as a target for AD, it has been hypothesized that deficit in this organelle may be at the heart of the progression of AD itself. The role of mitochondria in AD may be significant and is emerging as a main area of AD research. PMID- 26537903 TI - Reproductive outcome in pregnant women with recurrent pregnancy loss. AB - PURPOSETo estimate the future pregnancy success rate in women with a history of recurrent pregnancy loss.METHODSA retrospective cohort study including 103 women seen at a clinic for recurrent pregnancy loss (loss group) between January 2006 and December 2010 and a control group including 204 pregnant women seen at a low risk prenatal care unit between May 2007 and April 2008. Both groups were seen in the university teaching hospital the Maternidade Climerio de Oliveira, Salvador, Bahia, Brazil. Reproductive success rate was defined as an alive-birth, independent of gestational age at birth and survival after the neonatal period. Continuous variables Means and standard deviations (SD) were compared using Student's t-test and nominal variables proportions by Pearson chi2test.RESULTSOut of 90 who conceived, 83 (91.2%) had reproductive success rate. There were more full-term pregnancies in the control than in the loss group (174/187; 92.1 versus 51/90; 56.7%; p<0.01). The prenatal visits number was satisfactory for 76 (85.4%) women in the loss group and 125 (61.3%) in the control (p<0.01). In this, the beginning of prenatal care was earlier (13.3; 4.2 versus 19.6; 6.9 weeks). During pregnancy, the loss group women increased the weight more than those in the control group (58.1 versus 46.6%; p=0.04). Although cervix cerclage was performed in 32/90 women in the loss group, the pregnancy duration mean was smaller (34.8 weeks; SD=5.6 versus 39.3 weeks; SD=1.6; p<0.01) than in the control group. Due to gestational complications, cesarean delivery predominated in the loss group (55/83; 64.7 versus 73/183; 39.5%; p<0.01).CONCLUSIONA very good reproductive success rate can be attributed to greater availability of healthcare services to receive pregnant women, through prenatal visits (scheduled or not), cervical cerclage performed on time, and available hospital care for the mother and newborn. PMID- 26537902 TI - Frontotemporal Lobar Degeneration: Mechanisms and Therapeutic Strategies. AB - Frontotemporal lobar degeneration (FTLD) is characterized by progressive deterioration of frontal and anterior temporal lobes of the brain and often exhibits frontotemporal dementia (FTD) on clinic, in <65-year-old patients at the time of diagnosis. Interdisciplinary approaches combining genetics, molecular and cell biology, and laboratory animal science have revealed some of its potential molecular mechanisms. Although there is still no effective treatment to delay, prevent, and reverse the progression of FTD, emergence of agents targeting molecular mechanisms has been beginning to promote potential pharmaceutical development. Our review summarizes the latest new findings of FTLD and challenges in FTLD therapy. PMID- 26537904 TI - Bioprosthetic tricuspid valve endocarditis caused by Acinetobacter baumannii complex, a case report and brief review of the literature. AB - BACKGROUND: Species of the genus Acinetobacter are Gram-negative and highly drug resistant bacilli that normally reside on the skin, oropharynx, and perineum. Several previous studies have reported prosthetic valve endocarditis due to A. baumannii infection. CASE PRESENTATION: Here we present a case of late endocarditis of a bioprosthetic tricuspid valve due to A. baumannii complex in a patient who had surgical replacement with a bioprosthetic tricuspid valve six years previously. CONCLUSIONS: We completed tricuspid valve replacement using a 29 mm St. June mechanical prosthetic valve for the patient. Postoperatively, she received intravenous cefoperazone sodium and sulbactam sodium for 2 months and had good recovery. PMID- 26537905 TI - Long-term follow-up results of endoscopic treatment of gastroesophageal reflux disease with the MUSETM endoscopic stapling device. AB - BACKGROUND: The initial 6-month data for MUSETM (Medigus, Omer, Israel) endoscopic stapling device were reported (Zacherl et al. in Surg Endosc 29:220 229, 2015). The current study aims to evaluate the long-term clinical outcome of 37 patients who received endoscopic gastroesophageal reflux disease (GERD) treatment with the MUSETM device. METHODS: Efficacy and safety data for 37 patients were analyzed at baseline, 6 months, and 4 years post-procedure. In one center (IU), efficacy and safety data were evaluated at baseline, 6 months post procedure, and then annually up to 4 years. RESULTS: No new complications have been reported in our long-term analysis. The proportions of patients who remained off daily PPI were 83.8 % (31/37) at 6 months and 69.4 % (25/36) at 4 years post procedure. GERD-Health Related Quality of Life (HRQL) scores (off PPI) were significantly decreased from baseline to 6 months and 4 years post-procedure. The daily dosage of GERD medications, measured as omeprazole equivalents (mean +/- SD, mg), decreased from 66.1 +/- 33.2 at baseline to 10.8 +/- 15.9 at 6 months and 12.8 +/- 19.4 at 4 years post-procedure (P < 0.01). CONCLUSIONS: In our multi center prospective study, the MUSETM stapling device appears to be safe and effective in improving symptom scores as well as reducing PPI use in patients with GERD. These results appeared to be equal to or better than those of the other devices for endoluminal GERD therapy. Future studies with larger patient series, sham control group, and greater number of staples are awaited. PMID- 26537906 TI - BRAVO esophageal pH monitoring: more cost-effective than empiric medical therapy for suspected gastroesophageal reflux. AB - INTRODUCTION: Early referral for catheter-based esophageal pH monitoring is more cost-effective than empiric proton-pump inhibitor (PPI) therapy to diagnose gastroesophageal reflux disease (GERD). We hypothesize that BRAVO wireless pH monitoring will also demonstrate substantial cost-savings compared to empiric PPI therapy, given its superior sensitivity and comfort. METHODS: We reviewed 100 consecutive patients who underwent wireless pH monitoring for suspected GERD at our institution. A cost model and a cost equivalence calculation were generated. Cost-saving analyses were performed for both esophageal and extraesophageal symptoms. RESULTS: Eighty-seven patients were available for analysis. Median PPI use prior to referral was 215 weeks (range 0-520). Forty-three patients (49 %) had BRAVO results diagnosing GERD; 98 % of these had esophageal symptoms. Patients with negative BRAVO studies had a median of 113 (0-520) weeks of unnecessary PPI therapy. Cost-savings ranged from $1048 to $15,853 per patient, depending on sensitivity (75-95 %), PPI dosage, and brand. Maximum cost-savings occurred in patients with extraesophageal symptoms ($2948-$31,389 per patient). The PPI cost equivalence of BRAVO placement was 36 and 6 weeks for low- and high dose therapy, respectively. CONCLUSIONS: BRAVO wireless pH testing is more cost effective than prolonged empiric medical management for GERD and should be incorporated early in the treatment algorithm. PMID- 26537907 TI - COLOR III: a multicentre randomised clinical trial comparing transanal TME versus laparoscopic TME for mid and low rectal cancer. AB - INTRODUCTION: Total mesorectal excision (TME) is an essential component of surgical management of rectal cancer. Both open and laparoscopic TME have been proven to be oncologically safe. However, it remains a challenge to achieve complete TME with clear circumferential resections margin (CRM) with the conventional transabdominal approach, particularly in mid and low rectal tumours. Transanal TME (TaTME) was developed to improve oncological and functional outcomes of patients with mid and low rectal cancer. METHODS: An international, multicentre, superiority, randomised trial was designed to compare TaTME and conventional laparoscopic TME as the surgical treatment of mid and low rectal carcinomas. The primary endpoint is involved CRM. Secondary endpoints include completeness of mesorectum, residual mesorectum, morbidity and mortality, local recurrence, disease-free and overall survival, percentage of sphincter-saving procedures, functional outcome and quality of life. A Quality Assurance Protocol including centralised MRI review, histopathology re-evaluation, standardisation of surgical techniques, and monitoring and assessment of surgical quality will be conducted. DISCUSSION: The difference in involvement of CRM between the two treatment strategies is thought to be in favour of the TaTME. TaTME is therefore expected to be superior to laparoscopic TME in terms of oncological outcomes in case of mid and low rectal carcinomas. PMID- 26537908 TI - The pharmacokinetic disposition of delta-9-tetrahydrocannabinol and its metabolite in elderly patients with dementia--role of differential presystemic conversion? PMID- 26537909 TI - Comment on Technology-Based Intervention Research for Individuals on the Autism Spectrum. AB - The purpose of this letter to the editor is to comment on several review papers recently published in the current Journal of Autism and Developmental Disorders, Special Issue on Technology: Software, Robotics, and Translational Science. These reviews address a variety of aspects relating to technology-aided intervention and instruction for individuals with Autism Spectrum Disorders (ASDs). Here, I comment on and evaluate the overall status of research and development in this area, including reflection on current challenges in this area in the context of previous challenges and resolutions in behavioral intervention research. From these reviews and the current evaluation, I further discuss important next steps for the field which may be critical for guiding progress toward meaningful impacts upon individuals with ASD. PMID- 26537910 TI - Participation in Daily Activities of Young Adults with High Functioning Autism Spectrum Disorder. AB - Young adults with an autism spectrum disorder (ASD) struggle to assume adult roles. This research assessed the feasibility of using the Adolescent and Young Adult Activity Card Sort (AYA-ACS) with emerging adults with high functioning ASD. Two phases were utilized during this research: (1) comparing the activity participation reported by emerging adults with an ASD and that reported by their caring adult; (2) examining the barriers to participation reported. Preliminary results demonstrate that the AYA-ACS appears to be a reliable and valid method of identifying emerging adults' participation strengths as well as personal and environmental challenges in a variety of age-appropriate activities. The AYA-ACS could assist service providers by providing an understanding of the challenges to participation faced by this population and aid in developing client centered interventions. PMID- 26537911 TI - Pediatric glioblastoma: a single institution experience. AB - PURPOSE: The aim of this study was to evaluate characteristics of childhood glioblastoma multiforme, effectiveness of treatment modalities, and detect factors related to outcome. METHODS: A detailed analysis was performed on a series of 15 patients treated between 2000 and 2013, based on their clinical, radiologic, pathologic, treatment, and follow-up data. RESULTS: Median survival time of children with glioblastoma was 13.5 months. One- and 2-year overall survival probabilities were 66.7 and 20 %, respectively. There were no significant differences in survival based on patients' gender, age, disease presentation with or without epileptic seizures, signs/symptoms of increased intracranial pressure, or tumor location. The presence of neurological deficit initially, as well as prior to radiotherapy, which was quantified by neurologic function score (NFS), had an impact on overall survival. Children with NFS 0 lived longer compared to others (p = 0.001). Survival of children that underwent gross total resection was longer than that of children that underwent subtotal resection (p = 0.030). Mean survival time of children with gross total resection was 73.5 months, compared to 13 months in children with subtotal resection. There was no significant correlation between outcome and type of radiotherapy. In four patients with gigantocellular glioblastoma, we found no evidence of a better prognosis. Two long-term survivors were recorded. Both of them underwent gross total resection and were assigned a NFS 0. CONCLUSIONS: Gross total resection is essential for longer overall survival among pediatric patients with glioblastoma and offers a possibility for long-term survival. Severity of neurologic symptoms quantified by NFS can be considered as a potential predictor of outcome. PMID- 26537912 TI - Halorubrum halodurans sp. nov., an extremely halophilic archaeon isolated from a hypersaline lake. AB - Two extremely halophilic archaea, strains Cb34T and C170, belonging to the genus Halorubrum, were isolated from the brine of the hypersaline lake Aran-Bidgol in Iran. Cells of the two strains were motile, pleomorphic rods, stained Gram variable and produced red-pigmented colonies. Strains Cb34T and C170 required 25 % (w/v) salts, pH 7.0 and 37 degrees C for optimal growth under aerobic conditions; 0.3 M Mg2+ was required. Cells of both isolates were lysed in distilled water and hypotonic treatment with < 10 % NaCl provoked cell lysis. Phylogenetic analysis based on 16S rRNA gene sequence similarities showed that these two strains were closely related to Halorubrum cibi B31T (98.8 %) and other members of the genus Halorubrum. In addition, studies based on the rpoB' gene revealed that strains Cb34T and C170 are placed among the species of Halorubrum and are closely related to Halorubrum cibi B31T, with rpoB' gene sequence similarity less than or equal to 95.7 %. The polar lipid patterns of both strains consisted of phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol sulfate and sulfated mannosyl glucosyl diether. The DNA G+C content was 62.1-62.4 mol%. DNA-DNA hybridization studies confirmed that strains Cb34T and C170 constitute a distinct species. Data obtained in this study show that the two strains represent a novel species, for which the name Halorubrum halodurans sp. nov. is proposed. The type strain is Cb34T ( = CECT 8745T = IBRC-M 10233T). PMID- 26537913 TI - Horizontal gene transfer in bdelloid rotifers is ancient, ongoing and more frequent in species from desiccating habitats. AB - BACKGROUND: Although prevalent in prokaryotes, horizontal gene transfer (HGT) is rarer in multicellular eukaryotes. Bdelloid rotifers are microscopic animals that contain a higher proportion of horizontally transferred, non-metazoan genes in their genomes than typical of animals. It has been hypothesized that bdelloids incorporate foreign DNA when they repair their chromosomes following double strand breaks caused by desiccation. HGT might thereby contribute to species divergence and adaptation, as in prokaryotes. If so, we expect that species should differ in their complement of foreign genes, rather than sharing the same set of foreign genes inherited from a common ancestor. Furthermore, there should be more foreign genes in species that desiccate more frequently. We tested these hypotheses by surveying HGT in four congeneric species of bdelloids from different habitats: two from permanent aquatic habitats and two from temporary aquatic habitats that desiccate regularly. RESULTS: Transcriptomes of all four species contain many genes with a closer match to non-metazoan genes than to metazoan genes. Whole genome sequencing of one species confirmed the presence of these foreign genes in the genome. Nearly half of foreign genes are shared between all four species and an outgroup from another family, but many hundreds are unique to particular species, which indicates that HGT is ongoing. Using a dated phylogeny, we estimate an average of 12.8 gains versus 2.0 losses of foreign genes per million years. Consistent with the desiccation hypothesis, the level of HGT is higher in the species that experience regular desiccation events than those that do not. However, HGT still contributed hundreds of foreign genes to the species from permanently aquatic habitats. Foreign genes were mainly enzymes with various annotated functions that include catabolism of complex polysaccharides and stress responses. We found evidence of differential loss of ancestral foreign genes previously associated with desiccation protection in the two non-desiccating species. CONCLUSIONS: Nearly half of foreign genes were acquired before the divergence of bdelloid families over 60 Mya. Nonetheless, HGT is ongoing in bdelloids and has contributed to putative functional differences among species. Variation among our study species is consistent with the hypothesis that desiccating habitats promote HGT. PMID- 26537914 TI - Emergency care specialists renew call for out-of-hours services to be located in hospitals. PMID- 26537915 TI - Three simple rules to ensure reasonably credible subgroup analyses. PMID- 26537916 TI - Cd1d regulates B cell development but not B cell accumulation and IL10 production in mice with pathologic CD5(+) B cell expansion. AB - BACKGROUND: CD1d is a widely expressed lipid antigen presenting molecule required for CD1d-restricted invariant natural killer T (iNKT) cell development. Elevated CD1d expression is detected in CD5(+) IL10-producing B cells, called B10 B cells, and is correlated with poorer prognosis in chronic lymphocytic leukemia (CLL), a CD5(+) B cell malignancy with B10-like functional properties. Whether CD1d expression regulates CD5(+) B cell accumulation, IL10 competence, and antibody production in naive mice with pathologic CD5(+) B cell expansion remains untested. RESULTS: Using three different transgenic mouse models of benign or leukemic CD5(+) B cell expansion, we found that CD1d was differentially expressed on CD5(+) B cells between the three models, but loss of CD1d expression had no effect on CD5(+) B cell abundance or inducible IL10 expression in any of the models. Interestingly, in the CLL-prone EMU-TCL1 model, loss of CD1d expression suppressed spontaneous IgG (but not IgM) production, whereas in the dnRAG1xEMU TCL1 (DTG) model of accelerated CLL, loss of CD1d expression was associated with elevated numbers of splenic CD4(+) and CD8(+) T cells and an inverted CD4(+):CD8(+) T cell ratio. Unexpectedly, before leukemia onset, all three transgenic CD1d-deficient mouse strains had fewer splenic transitional B cells than their CD1d-proficient counterparts. CONCLUSIONS: The results show that CD1d expression and iNKT cells are dispensable for the development, accumulation, or IL10 competence of CD5(+) B cells in mice prone to benign or leukemic CLL-like B cell expansion, but reveal a novel role for iNKT cells in supporting B cell progression through the transitional stage of development in these animals. These results suggest CD1d-directed therapies to target CLL could be evaded by downregulating CD1d expression with little effect on continued leukemic CD5(+) B cell survival. The data also imply that iNKT cells help restrain pro-leukemic CD8(+) T cell expansion in CLL, potentially explaining a reported correlation in human CLL between disease progression, the loss of NKT cells, and a paradoxical increase in CD8(+) T cells. PMID- 26537917 TI - Smoking, Porphyromonas gingivalis and the immune response to citrullinated autoantigens before the clinical onset of rheumatoid arthritis in a Southern European nested case-control study. AB - BACKGROUND: Antibodies to citrullinated proteins (ACPA) occur years before RA diagnosis. Porphyromonas gingivalis expresses its own peptidylarginine deiminase (PPAD), and is a proposed aetiological factor for the ACPA response. Smoking is a risk factor for both ACPA-positive RA and periodontitis. We aimed to study the relation of these factors to the risk of RA in a prospective cohort. METHODS: We performed a nested case-control study by identifying pre-RA cases in four populations from the European Prospective Investigation into Cancer and nutrition, matched with three controls. Data on smoking and other covariates were obtained from baseline questionnaires. Antibodies to CCP2 and citrullinated peptides from alpha-enolase, fibrinogen, vimentin and PPAD were measured. Antibodies to arginine gingipain (RgpB) were used as a marker for P.gingivalis infection and validated in a separate cohort of healthy controls and subjects with periodontitis. RESULTS: We studied 103 pre-RA cases. RA development was associated with several ACPA specificities, but not with antibodies to citrullinated PPAD peptides. Antibody levels to RgpB and PPAD peptides were higher in smokers but were not associated with risk of RA or with pre-RA autoimmunity. Former but not current smoking was associated with antibodies to alpha-enolase (OR 4.06; 95 % CI 1.02, 16.2 versus 0.54; 0.09-3.73) and fibrinogen peptides (OR 4.24; 95 % CI 1.2-14.96 versus 0.58; 0.13-2.70), and later development of RA (OR 2.48; 95 % CI 1.27-4.84 versus 1.57; 0.85-2.93), independent of smoking intensity. CONCLUSIONS: Smoking remains a risk factor for RA well before the clinical onset of disease. In this cohort, P.gingivalis is not associated with pre-RA autoimmunity or risk of RA in an early phase before disease-onset. Antibodies to PPAD peptides are not an early feature of ACPA ontogeny. PMID- 26537918 TI - Effect of abacavir on sustained virologic response to HCV treatment in HIV/HCV co infected patients, Cohere in Eurocoord. AB - BACKGROUND: Contradicting results on the effect of abacavir (ABC) on hepatitis C virus (HCV) treatment responses in HIV/HCV co-infected patients have been reported. We evaluated the influence of ABC on the response to pegylated interferon (pegIFN) and ribavirin (RBV)-containing HCV treatment in HIV/HCV co infected patients in a large European cohort collaboration, including data from different European countries. METHODS: HIV/HCV co-infected patients were included if they were aged >=16 years, received pegIFN alfa-2a or 2b and RBV combination treatment and were enrolled in the COHERE cohort collaboration. Logistic regression was used to evaluate the impact of abacavir on achieving a sustained virologic response (SVR) to HCV treatment. RESULTS: In total 1309 HIV/HCV co infected patients who had received HCV therapy were included, of whom 490 (37 %) had achieved an SVR. No statistically significant difference was seen for patients using ABC-containing regimens compared to patients using an emtricitabine + tenofovir (FTC + TDF)-containing backbone, which was the most frequently used backbone. In the multivariate analyses, patients using a protease inhibitor (PI)-boosted regimen were less likely to achieve an SVR compared to patients using a non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen (OR: 0.61, 95 % CI: 0.41-0.91). The backbone combinations zidovudine&lamivudine (AZT + 3TC) and stavudine&lamivudine (d4t + 3TC) were associated with lower SRV rates (0.45 (0.24-0.82) and 0.46 (0.22-0.96), respectively). CONCLUSION: The results of this large European cohort study validate that SVR rates are generally not affected by ABC. Use of d4T or AZT as part of the HIV treatment regimen was associated with a lower likelihood of achieving an SVR. PMID- 26537919 TI - Foreshortening produces errors in the perception of angles pictured as on the ground. AB - Observers viewed pictures of a simulated ground plane and judged the orientation of lines pictured as lying on the ground. We presented three lines at a time and manipulated three factors: (1) the declination of the lines below the horizon (depicting distance to the target angles), (2) their length, and (3) whether or not they converged to a point on the horizon. Only the first factor had a substantial effect on these errors. We conclude that perspective foreshortening in pictures produces errors in perceived 3-D orientation. Our explanation is based on the different rates of change of elevation and azimuth with distance. PMID- 26537920 TI - Presence of inclusions positive for polyglycine containing protein, FMRpolyG, indicates that repeat-associated non-AUG translation plays a role in fragile X associated primary ovarian insufficiency. AB - STUDY QUESTION: Does repeat-associated non-AUG (RAN) translation play a role in fragile X-associated primary ovarian insufficiency (FXPOI), leading to the presence of polyglycine containing protein (FMRpolyG)-positive inclusions in ovarian tissue? SUMMARY ANSWER: Ovaries of a woman with FXPOI and of an Fmr1 premutation (PM) mouse model (exCGG-KI) contain intranuclear inclusions that stain positive for both FMRpolyG and ubiquitin. WHAT IS KNOWN ALREADY: Women who carry the FMR1 PM are at 20-fold increased risk to develop primary ovarian insufficiency (FXPOI). A toxic RNA gain-of-function has been suggested as the underlying mechanism since the PM results in increased levels of mRNA containing an expanded repeat, but reduced protein levels of fragile X mental retardation protein (FMRP). Recently, RAN translation has been shown to occur from FMR1 mRNA that contains PM repeat expansions, leading to FMRpolyG inclusions in brain and non-CNS tissues of fragile X-associated tremor/ataxia syndrome (FXTAS) patients. STUDY DESIGN, SIZE, DURATION: Ovaries of a woman with FXPOI and women without PM (controls), and ovaries from wild-type and exCGG-KI mice were analyzed by immunohistochemistry for the presence of inclusions that stained for ubiquitin and FMRpolyG . The ovaries from wild-type and exCGG-KI mice were further characterized for the number of follicles, Fmr1 mRNA levels and FMRP protein expression. The presence of inclusions was also analyzed in pituitaries of a man with FXTAS and the exCGG-KI mice. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human ovaries from a woman with FXPOI and two control subjects and pituitaries from a man with FXTAS and a control subjects were fixed in 4% formalin. Ovaries and pituitaries of wild-type and exCGG mice were fixed in Bouin's fluid or 4% paraformaldehyde. Immunohistochemistry was performed on the human and mouse samples using FMRpolyG, ubiquitin and Fmrp antibodies. Fmr1 mRNA and protein expression were determined in mouse ovaries by quantitative RT-PCR and Western blot analysis. Follicle numbers in mouse ovaries were determined in serial sections by microscopy. MAIN RESULTS AND THE ROLE OF CHANCE: FMRpolyG-positive inclusions were present in ovarian stromal cells of a woman with FXPOI but not in the ovaries of control subjects. The FMRpolyG-positive inclusions colocalized with ubiquitin-positive inclusions. Similar inclusions were also observed in the pituitary of a man with FXTAS but not in control subjects. Similarly, ovaries of 40-week-old exCGG-KI mice, but not wild-type mice, contained numerous inclusions in the stromal cells that stained for both FMRpolyG- and ubiquitin, while the ovaries of 20-week-old exCGG-KI contained fewer inclusions. At 40 weeks ovarian Fmr1 mRNA expression was increased by 5-fold in exCGG-KI mice compared with wild type mice, while Fmrp expression was reduced by 2-fold. With respect to ovarian function in exCGG-KI mice: (i) although the number of healthy growing follicles did not differ between wild-type and exCGG-KI mice, the number of atretic large antral follicles was increased by nearly 9-fold in 40-week old exCGG-KI mice (P < 0.001); (ii) at 40 weeks of age only 50% of exCGG-KI mice had recent ovulations compared with 89% in wild-type mice (P = 0.07) and (iii) those exCGG-KI mice with recent ovulations tended to have a reduced number of fresh corpora lutea (4.8 +/- 1.74 versus 8.50 +/- 0.98, exCGG-KI versus wild-type mice, respectively, P = 0.07). LIMITATIONS, REASONS FOR CAUTION: Although FMRpolyG-positive inclusions were detected in ovaries of both a woman with FXPOI and a mouse model of the FMR1 PM, we only analyzed one ovary from a FXPOI subject. Caution is needed to extrapolate these results to all women with the FMR1 PM. Furthermore, the functional consequence of FMRpolyG-positive inclusions in the ovaries for reproduction remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that a dysfunctional hypothalamic-pituitary-gonadal-axis may contribute to FXPOI in FMR1 PM carriers. STUDY FUNDING/COMPETING INTERESTS: This study was supported by grants from NFXF, ZonMW, the Netherlands Brain Foundation and NIH. The authors have no conflict of interest to declare. PMID- 26537921 TI - The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies. AB - STUDY QUESTION: What is the recommended diagnostic work-up of female genital anomalies according to the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) system? SUMMARY ANSWER: The ESHRE/ESGE consensus for the diagnosis of female genital anomalies is presented. WHAT IS KNOWN ALREADY: Accurate diagnosis of congenital anomalies still remains a clinical challenge because of the drawbacks of the previous classification systems and the non-systematic use of diagnostic methods with varying accuracy, some of them quite inaccurate. Currently, a wide range of non invasive diagnostic procedures are available enriching the opportunity to accurately detect the anatomical status of the female genital tract, as well as a new objective and comprehensive classification system with well-described classes and sub-classes. STUDY DESIGN, SIZE, DURATION: The ESHRE/ESGE CONgenital UTerine Anomalies (CONUTA) Working Group established an initiative with the goal of developing a consensus for the diagnosis of female genital anomalies. The CONUTA working group and imaging experts in the field have been appointed to run the project. PARTICIPANTS/MATERIALS, SETTING, METHODS: The consensus is developed based on: (i) evaluation of the currently available diagnostic methods and, more specifically, of their characteristics with the use of the experts panel consensus method and of their diagnostic accuracy by performing a systematic review of evidence and (ii) consensus for the definition of where and how to measure uterine wall thickness and the recommendations for the diagnostic work-up of female genital anomalies, based on the results of the previous evaluation procedure, with the use of the experts panel consensus method. MAIN RESULTS AND THE ROLE OF CHANCE: Uterine wall thickness is defined as the distance between the interostial line and external uterine profile at the midcoronal plane of the uterus; alternatively, if a coronal plane is not available, the mean anterior and posterior uterine wall thickness at the longitudinal plane could be used. Gynecological examination and two-dimensional ultrasound (2D US) are recommended for the evaluation of asymptomatic women. Three-dimensional (3D) US is recommended for the diagnosis of female genital anomalies in 'symptomatic' patients belonging to high risk groups for the presence of a female genital anomaly and in any asymptomatic woman suspected to have an anomaly from routine evaluation. Magnetic resonance imaging (MRI) and endoscopic evaluation are recommended for the subgroup of patients with suspected complex anomalies or in diagnostic dilemmas. Adolescents with symptoms suggestive for the presence of a female genital anomaly should be thoroughly evaluated with 2D US, 3D US, MRI and endoscopically. LIMITATIONS, REASONS FOR CAUTION: The various diagnostic methods should always be used in the proper way and evaluated by experts to avoid mis-, over- and underdiagnosis. WIDER IMPLICATIONS OF THE FINDINGS: The role of a combined US examination and outpatient hysteroscopy should be prospectively evaluated. It is a challenge for further research, based on diagnosis, to objectively evaluate the clinical consequences related to various degrees of uterine deformity. STUDY FUNDING/COMPETING INTERESTS: None. PMID- 26537922 TI - How do cumulative live birth rates and cumulative multiple live birth rates over complete courses of assisted reproductive technology treatment per woman compare among registries? AB - STUDY QUESTION: How do the national cumulative (multiple) live birth rates over complete assisted reproduction technology (ART) courses of treatment per woman in Belgium compare to those in other registries? SUMMARY ANSWER: Cumulative live birth rates (CLBRs) remain high with a low cumulative multiple live birth rate when compared with other registries and publications. WHAT IS KNOWN ALREADY: In ART, a reduction in the multiple live birth rate could be achieved by reducing the number of embryos transferred. It has been shown that by doing so, live birth rates per cycle were maintained, particularly when the augmentation effect of attached frozen-thawed cycles was considered. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study included all patients with a Belgian national insurance number who were registered in the national ART registry (Belrap) and who started a first fresh ART cycle between 1 July 2009 until 31 December 2011 with follow up until 31 December 2012. We analysed 12 869 patients and 38 008 cycles (both fresh and attached frozen cycles). PARTICIPANTS, MATERIALS, SETTINGS, METHODS: CLBRs per patient who started a first ART cycle including fresh and consecutive frozen cycles leading to a live birth. Conservative estimates of cumulative live birth assumed that patients who did not return for treatment had no chance of achieving an ART-related live birth, whereas optimal estimates assumed that women discontinuing treatment would have the same chance of achieving a live birth as those continuing treatment. A maximum of six fresh ART cycles with corresponding frozen cycles was investigated and compared with other registries and publications. MAIN RESULTS AND ROLE OF CHANCE: The CLBR was age dependent and declined from 62.9% for women <35 years, to 51.4% for women 35 37 years, to 34.1% for women 38-40 years and 17.7% for women 41-42 years in the conservative analysis after six cycles. In the optimal estimate, the CLBR declined from 85.9% for women <35 years, to 72.0% for women 35-37 years, to 50.4% for women 38-40 years and 36.4% for women 41-42 years. The cumulative multiple live birth rates for the whole population were 5.1 and 8.6% for the conservative and optimal estimate, respectively. LIMITATIONS, REASONS FOR CAUTION: Conservative and optimal estimates use assumptions for the whole ART population and do not take the individual patient into account. WIDER IMPLICATIONS OF THE FINDINGS: These data reinforce the validity of the Belgian model of coupling reimbursement of ART costs to a restriction in the number of embryos transferred. Our data can improve decision-making in medical ART practice both on the patient level and for society at large and could provide health care takers and insurance companies with a valid model. STUDY FUNDING COMPETING INTERESTS: none. PMID- 26537923 TI - The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis. AB - BACKGROUND: Fucosidosis results from lack of alpha-L-fucosidase activity, with accumulation of fucose-linked substrates in the nervous system and viscera leading to progressive motor and mental deterioration, and death. The naturally occurring dog model of fucosidosis was used to evaluate the neuropathological responses to partial enzyme replacement, and substrate reduction in early disease following treatment with recombinant canine alpha-L-fucosidase delivered through cerebrospinal fluid. METHODS: Neuropathology in both treated (n = 3) and untreated fucosidosis-affected (n = 3) animals was evaluated with immunohistochemistry, image analysis, manual quantification and gene expression analysis and compared with unaffected age-matched controls (n = 3) in an extension of our previous biochemical report on the same cohort. Data were analyzed by ANOVA. RESULTS: Quantification demonstrated a consistent trend to reduction in vacuolation, pyramidal neuron loss, astrocytosis, microgliosis, perivascular storage, apoptosis, oligodendrocyte loss, and hypomyelination throughout the central nervous system of enzyme treated animals compared to placebo-treated, age-matched affected controls. Key lesions including lysosomal expansion in neurons of deep cortex, astrocytosis in cerebral cortex and medulla, and increased lysosomal membrane associated protein-1 (LAMP-1) gene expression were ameliorated in treated animals. There was no change in spheroid formation and loss of Purkinje cells, but Purkinje cell vulnerability to apoptosis was reduced with treatment. CONCLUSIONS: Despite reduced severity of fucosidosis neuropathology with partial enzyme replacement, more complete and sustained biochemical correction is required to halt neuropathological processes in this large animal model of lysosomal storage disease. PMID- 26537924 TI - Addressing unresolved tensions to build effective partnerships: lessons from an Aboriginal cancer support network. AB - BACKGROUND: Cancer is the second leading cause of death among Aboriginal and Torres Strait Islander people and their survival once diagnosed with cancer is lower compared to that of other Australians. This highlights the need to improve cancer-related health services for Indigenous Australians although how to achieve this remains unclear. Cancer support groups provide emotional and practical support, foster a sense of community and belonging and can improve health outcomes. However, despite evidence on their positive effects on people affected by cancer, there is scarce information on the function and effectiveness of Indigenous-specific cancer peer-support programs in Australia. Using qualitative data from an evaluation study, this paper explores different understandings of how a cancer support group should operate and the impact of unresolved tensions following the establishment of an Indigenous women cancer peer-support network in a regional town in Western Australia. METHODS: Data were collected through semi structured interviews with 24 participants purposively selected among Indigenous and mainstream healthcare service providers, and group members and clients. Interviews were audiotaped and transcribed verbatim. Transcripts were subjected to inductive thematic analysis. NVivo was used to manage the data and assist in the data analysis. Rigour was enhanced through team member checking, coding validation and peer debriefing. RESULTS: Flexibility and a resistance to formal structuring were at the core of how the group operated. It was acknowledged that the network partly owned its success to its fluid approach; however, most mainstream healthcare service providers believed that a more structured approach was needed for the group to be sustainable. This was seen as acting in opposition to the flexible, organic approach considered necessary to adequately respond to Indigenous women's needs. At the core of these tensions were opposing perspectives on the constructs of 'structure' and 'flexibility' between Indigenous and non-Indigenous participants. CONCLUSIONS: Despite the group's achievements, unresolved tensions between opposing perspectives on how a support group should operate negatively impacted on the working relationship between the group and mainstream service providers, and posed a threat to the Network's sustainability. Our results support the need to acknowledge and address different perspectives and world views in order to build strong, effective partnerships between service providers and Indigenous communities. PMID- 26537926 TI - LC-QTOF-MS-based targeted metabolomics of arginine-creatine metabolic pathway related compounds in plasma: application to identify potential biomarkers in pediatric chronic kidney disease. AB - Chronic kidney disease (CKD) is a major epidemiologic problem which causes several disturbances in adults and in pediatrics. Despite being a worldwide public health problem, information available for CKD in the pediatric population is scarce. For that reason, an ion-pair reversed-phase liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) method has been developed and validated in order to analyze 16 amino acids, amino acid derivatives, and analogous compounds related to the arginine-creatine metabolic pathway that are suspicious of being increased or decreased in plasma from patients with CKD. The analytical method involved the addition of dithiothreitol, a reducing agent which reduces disulfide and thus giving total aminothiol concentration, as well as a simple precipitation of plasma proteins. Moreover, despite amino acids being usually derivatized to improve their retention time and to enhance their signal, for this method, an ion-pairing reagent was used, thus avoiding the need for derivatization. Subsequently, analysis of plasma from pediatric patients suffering from CKD and control pediatrics was carried out. As a result, glycine, citrulline, creatinine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were significantly increased in patients with CKD, regardless of their creatinine level, whereas in addition to these compounds dimethylglycine was also increased when CKD patients had plasma creatinine concentrations above 12 MUg mL(-1), thus all are suggested as potential biomarkers for renal impairment. PMID- 26537925 TI - Pressure-actuated microfluidic devices for electrophoretic separation of pre-term birth biomarkers. AB - We have developed microfluidic devices with pressure-driven injection for electrophoretic analysis of amino acids, peptides, and proteins. The novelty of our approach lies in the use of an externally actuated on-chip peristaltic pump and closely spaced pneumatic valves that allow well-defined, small-volume sample plugs to be injected and separated by microchip electrophoresis. We fabricated three-layer poly(dimethylsiloxane) (PDMS) microfluidic devices. The fluidic layer had injection and separation channels, and the control layer had an externally actuated on-chip peristaltic pump and four pneumatic valves around the T intersection to carry out sample injection. An unpatterned PDMS membrane layer was sandwiched between the fluidic and control layers as the actuated component in pumps and valves. Devices with the same peristaltic pump design but different valve spacings (100, 200, 300, and 400 MUm) from the injection intersection were fabricated using soft lithographic techniques. Devices were characterized through fluorescent imaging of captured plugs of a fluorescein-labeled amino acid mixture and through microchip electrophoresis separations. A suitable combination of peak height, separation efficiency, and analysis time was obtained with a peristaltic pump actuation rate of 50 ms, an injection time of 30 s, and a 200-MUm valve spacing. We demonstrated the injection of samples in different solutions and were able to achieve a 2.4-fold improvement in peak height and a 2.8-fold increase in separation efficiency though sample stacking. A comparison of pressure-driven injection and electrokinetic injection with the same injection time and separation voltage showed a 3.9-fold increase in peak height in pressure-based injection with comparable separation efficiency. Finally, the microchip systems were used to separate biomarkers implicated in pre-term birth. Although these devices have initially been demonstrated as a stand-alone microfluidic separation tool, they have strong potential to be integrated within more complex systems. PMID- 26537927 TI - Determination of ethyl glucuronide in hair to assess excessive alcohol consumption in a student population. AB - Hair analysis for ethyl glucuronide (EtG) was used to evaluate the pattern of alcohol consumption amongst the Portuguese university student population. A total of 975 samples were analysed. For data interpretation, the 2014 guidelines from the Society of Hair Testing (SoHT) for the use of alcohol markers in hair for the assessment of both abstinence and chronic excessive alcohol consumption were considered. EtG concentrations were significantly higher in the male population. The effect of hair products and cosmetics was evaluated by analysis of variance (ANOVA), and significant lower concentrations were obtained when conditioner or hair mask was used or when hair was dyed. Based on the analytical data and information obtained in the questionnaires from the participants, receiver operating characteristic (ROC) curves were constructed in order to determine the ideal cut-offs for our study population. Optimal cut-off values were estimated at 7.3 pg/mg for abstinence or rare occasional drinking control and 29.8 pg/mg for excessive consumption. These values are very close to the values suggested by the SoHT, proving their adequacy to the studied population. Overall, the obtained EtG concentrations demonstrate that participants are usually well aware of their consumption pattern, correlating with the self-reported consumed alcohol quantity, consumption habits and excessive consumption close to the time of hair sampling. PMID- 26537928 TI - Distinct urinary lipid profile in children with focal segmental glomerulosclerosis. AB - BACKGROUND: Focal segmental glomerulosclerosis (FSGS) accounts for the majority of new-onset end-stage renal disease (ESRD) during adolescence. FSGS treatment is a great challenge for pediatric nephrologists due to intertwined molecular pathways underlining its complex pathophysiology. There is emerging evidence showing that perturbed lipid metabolism plays a role in the pathophysiology of FSGS. METHODS: We postulate that the nephrotic milieu in FSGS differs from minimal change disease (MCD) and that urinary lipidomics can be used as a tool for early diagnosis of FSGS. We explored the urinary lipid profile of patients with FSGS and MCD using an unbiased metabolomics approach. RESULTS: We discovered a unique lipid signature characterized by increased concentration of fatty acid (FA) and lysophosphatidylcholines (LPC) and a decrease in urinary concentration of phosphatidylcholine (PC) in patients with FSGS. These findings indicate increased metabolism of membrane phospholipid PC by phospholipase A2 (PLA2), resulting in higher urinary concentrations of LPC and FA. CONCLUSIONS: We propose that increased PC by-products can be used as a biomarker to diagnose FSGS and shed light on the mechanism of tubular and podocyte damage. Validation of identified urinary lipids as a biomarker in predicting the diagnosis and progression of FSGS in a larger patient population is warranted. PMID- 26537929 TI - Irregular cleavage of early preimplantation human embryos: characteristics of patients and pregnancy outcomes. AB - PURPOSE: This is a retrospective analysis of the morphokinetics, prevalence, and implantation potential of embryos with irregular first and second cleavages as identified by time-lapse microscopy. METHODS: The study included 253 women who underwent 387 assisted reproduction treatments with intracytoplasmic sperm injection (ICSI). Each patient was assigned to one of three groups based on embryo cleavage results. In group I, one to two embryos per cycle showed irregular cleavage; group II, at least three embryos with abnormal cleavage; and in group III (the control group), all embryos cleaved normally. The number of embryos that cleaved from 1 to >=3 cells or from 2 to >=5 cells for each patient was recorded. Their prevalence and association with women's characteristics and pregnancy outcome were evaluated. RESULTS: The prevalence of irregular cleavage was 15.6 % among 1772 ICSI embryos. In 101 cycles, 1-2 embryos per cycle showed irregular cleavage (group I). In 32 cycles, at least 3 embryos showed abnormal cleavage (group II). In 254 cycles, all embryos cleaved normally (group III). The average age of the women in group II was significantly lower in comparison with groups I and III (32.5 +/- 4.2 vs. 35.1 +/- 4.9 and 35.5 +/- 5.1, respectively, p < 0.02). In comparison of groups I and II, the odds ratio for >=3 embryos with irregular cleavage in women younger than 35 was 3.48 (95 % CI, 1.28 to 9.46). Embryos with irregular cleavage were transferred in 16 women. Three live births were achieved following the transfer of single blastocysts derived from embryos with irregular cleavage from two to five cells. CONCLUSIONS: Early embryos with irregular cleavage are significantly more prevalent in younger women. When these embryos develop to the blastocyst stage, they may have normal implantation potential, leading to the birth of healthy babies. PMID- 26537930 TI - Improving Visibility of Stereo-Radiographic Spine Reconstruction with Geometric Inferences. AB - Complex deformities of the spine, like scoliosis, are evaluated more precisely using stereo-radiographic 3D reconstruction techniques. Primarily, it uses six stereo-corresponding points available on the vertebral body for the 3D reconstruction of each vertebra. The wireframe structure obtained in this process has poor visualization, hence difficult to diagnose. In this paper, a novel method is proposed to improve the visibility of this wireframe structure using a deformation of a generic spine model in accordance with the 3D-reconstructed corresponding points. Then, the geometric inferences like vertebral orientations are automatically extracted from the radiographs to improve the visibility of the 3D model. Biplanar radiographs are acquired from five scoliotic subjects on a specifically designed calibration bench. The stereo-corresponding point reconstruction method is used to build six-point wireframe vertebral structures and thus the entire spine model. Using the 3D spine midline and automatically extracted vertebral orientation features, a more realistic 3D spine model is generated. To validate the method, the 3D spine model is back-projected on biplanar radiographs and the error difference is computed. Though, this difference is within the error limits available in the literature, the proposed work is simple and economical. The proposed method does not require more corresponding points and image features to improve the visibility of the model. Hence, it reduces the computational complexity. Expensive 3D digitizer and vertebral CT scan models are also excluded from this study. Thus, the visibility of stereo-corresponding point reconstruction is improved to obtain a low-cost spine model for a better diagnosis of spinal deformities. PMID- 26537931 TI - Comparison-Bot: an Automated Preliminary-Final Report Comparison System. AB - Regular comparison of preliminary to final reports is a critical part of radiology resident and fellow education as prior research has documented substantial preliminary to final discrepancies. Unfortunately, there are many barriers to this comparison: high study volume; overnight rotations without an attending; the ability to finalize reports remotely; the subtle nature of many changes; and lack of easy access to the preliminary report after finalization. We developed a system that automatically compiles and emails a weekly summary of report differences for all residents and fellows. Trainees can also create a custom report using a date range of their choice and can view this data on a resident dashboard. Differences between preliminary and final reports are clearly highlighted with links to the associated study in Picture Archiving and Communication Systems (PACS) for efficient review and learning. Reports with more changes, particularly changes made in the impression, are highlighted to focus attention on those exams with substantive edits. Our system provides an easy way for trainees to review changes to preliminary reports with immediate access to the associated images, thereby improving their educational experience. Departmental surveys showed that our report difference summary is easy to understand and improves the educational experience of our trainees. Additionally, interesting descriptive statistics help us understand how reports are changed by trainee level, by attending, and by exam type. Finally, this system can be easily ported to other departments who have access to their Health Level 7 (HL7) data. PMID- 26537932 TI - Impact of the Introduction of Digital Mammography in an Organized Screening Program on the Recall and Detection Rate. AB - In 2012, the Reggio Emilia Breast Cancer Screening Program introduced digital mammography in all its facilities at the same time. The aim of this work is to analyze the impact of digital mammography introduction on the recall rate, detection rate, and positive predictive value. The program actively invites women aged 45-74 years. We included women screened in 2011, all of whom underwent film screen mammography, and all women screened in 2012, all of whom underwent digital mammography. Double reading was used for all mammograms, with arbitration in the event of disagreement. A total of 42,240 women underwent screen-film mammography and 45,196 underwent digital mammography. The recall rate increased from 3.3 to 4.4% in the first year of digital mammography (relative recall adjusted by age and round 1.46, 95% CI = 1.37-1.56); the positivity rate for each individual reading, before arbitration, rose from 3 to 5.7%. The digital mammography recall rate decreased during 2012: after 12 months, it was similar to the recall rate with screen-film mammography. The detection rate was similar: 5.9/1000 and 5.2/1000 with screen-film and digital mammography, respectively (adjusted relative detection rate 0.95, 95% CI = 0.79-1.13). The relative detection rate for ductal carcinoma in situ remained the same. The introduction of digital mammography to our organized screening program had a negative impact on specificity, thereby increasing the recall rate. The effect was limited to the first 12 months after introduction and was attenuated by the double reading with arbitration. We did not observe any relevant effects on the detection rate. PMID- 26537933 TI - [Tonsillectomy in adults: Length of hospital stay has no influence on the frequency of postoperative hemorrhage]. AB - BACKGROUND: Tonsillectomies (TE) in Germany are traditionally performed during inpatient hospital stays. Socioeconomic changes in the healthcare system have resulted in shorter hospital stays. OBJECTIVES: The aim of the study was to investigate whether a shorter hospital stay of 2 days leads to increased postoperative bleeding after TE. Factors affecting the duration of hospitalization were also studied. MATERIALS AND METHODS: The relevant data of all patients (>= 14 years) undergoing TE in the ENT Clinic of the Charite Universitatsmedizin Berlin, Campus Benjamin Franklin, between 2011 and 2013 were recorded anonymously. Risk factors for bleeding after TE were analyzed. Additionally, patients who had a hospital stay of 2 days (since 2013) were compared with patients hospitalized for >= 3 days, and the influence of various risk factors on the length of hospital stay was analyzed. RESULTS: During the study period 2011-2013, 376 procedures were performed and data from 213 patients was collected for analysis. Median patient age was 26 years (range 14-73 years). The rate of primary hemorrhage (up to 24 hours after TE) was 2% and the rate of secondary bleeding (later than 24 hours) was 24%. In 7% of patients with postoperative haemorrhage (primary and secondary) surgical hemostasis was performed. Male gender was associated with a significantly higher haemorrhage rate. Shortening postdischarge surveillance to only 2 days did not affect the postoperative bleeding rate. CONCLUSION: The duration of stationary monitoring following TE should not only be based on the rate of secondary bleeding, but also on patient comfort and safety. A shortening of postoperative monitoring to only 2 days had no effect on the haemorrhage frequency after TE and can therefore, be considered for adults who do not live alone and are within a reasonable distance to a hospital. PMID- 26537934 TI - [Head and neck paragangliomas: An interdisciplinary challenge]. AB - BACKGROUND: Current treatment strategies for head and neck paragangliomas are moving away from radical resection and toward surgical tumor reduction, in order to preserve function and reduce morbidity. Radiotherapy modalities are alternative primary treatment options. MATERIALS AND METHODS: A PubMed search of the relevant literature on genetics and treatment of head and neck paragangliomas was conducted. RESULTS: The rapid progress made in genetic research was mainly triggered by two factors: firstly, the establishment of central registries for paraganglioma patients and secondly, the availability of next-generation sequencing methods. Exome sequencing and a gene-panel sequencing approach have already been successfully applied to paraganglioma syndromes. The latter method in particular is rapid and cost-effective, and may soon replace complex genotyping algorithms. The literature provides good evidence that diversified modern treatment options are available to realize individual treatment concepts for almost all paraganglioma manifestations. Generally, small and symptomatic tumors should be completely resected, particularly in younger patients. Considering the patient's age, symptoms, morbidity risk, and comorbidities, larger tumors should be surgically treated in a function-preserving manner. In these cases, primary radiotherapy is an equivalent alternative option. A "wait and scan" strategy is possible in selected cases. DISCUSSION: The potential morbidity of surgical treatment must be weighed against the expectable quality of life. Comprehensive consultation with the patient about possible treatment modalities is mandatory. Treatment decision making should involve a multidisciplinary team of experts. PMID- 26537935 TI - Habitual intake of flavonoid subclasses and risk of colorectal cancer in 2 large prospective cohorts. AB - BACKGROUND: Flavonoids inhibit the growth of colon cancer cells in vitro. In a secondary analysis of a randomized controlled trial, the Polyp Prevention Trial, a higher intake of one subclass, flavonols, was statistically significantly associated with a reduced risk of recurrent advanced adenoma. Most previous prospective studies on colorectal cancer evaluated only a limited number of flavonoid subclasses and intake ranges, yielding inconsistent results. OBJECTIVE: In this study, we examined whether higher habitual dietary intakes of flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols, and anthocyanins) were associated with a lower risk of colorectal cancer. DESIGN: Using data from validated food-frequency questionnaires administered every 4 y and an updated flavonoid food composition database, we calculated flavonoid intakes for 42,478 male participants from the Health Professionals Follow-Up Study and for 76,364 female participants from the Nurses' Health Study. RESULTS: During up to 26 y of follow-up, 2519 colorectal cancer cases (1061 in men, 1458 in women) were documented. Intakes of flavonoid subclasses were not associated with risk of colorectal cancer in either cohort. Pooled multivariable adjusted RRs (95% CIs) comparing the highest with the lowest quintiles were 1.04 (0.91, 1.18) for flavonols, 1.01 (0.89, 1.15) for flavones, 0.96 (0.84, 1.10) for flavanones, 1.07 (0.95, 1.21) for flavan-3-ols, and 0.98 (0.81, 1.19) for anthocyanins (all P values for heterogeneity by sex >0.19). In subsite analyses, flavonoid intake was also not associated with colon or rectal cancer risk. CONCLUSION: Our findings do not support the hypothesis that a higher habitual intake of any flavonoid subclass decreases the risk of colorectal cancer. PMID- 26537937 TI - Safety and efficacy of cocoa flavanol intake in healthy adults: a randomized, controlled, double-masked trial. AB - BACKGROUND: Evidence from dietary intervention studies shows that the intake of flavanols and procyanidins can be beneficial for cardiovascular health. Nevertheless, there is a clear need for advancing our understanding with regard to safe amounts of intake for these bioactives. OBJECTIVE: The aim was to investigate in healthy adults the effects of cocoa flavanol (CF) intake amount and intake duration on blood pressure, platelet function, metabolic variables, and potential adverse events (AEs). DESIGN: This investigation consisted of 2 parts. Part 1 was an open-label, intake-amount escalation study, in which 34 healthy adults (aged 35-55 y) consumed escalating amounts of CFs, ranging from 1000 to 2000 mg/d over 6 wk. Primary outcomes were blood pressure and platelet function, select metabolic variables, and the occurrence and severity of AEs. Secondary outcomes included plasma concentrations of CF-derived metabolites and methylxanthines. On the basis of the outcomes of study part 1, and assessing the same outcome measures, part 2 of this investigation was a controlled, randomized, double-masked, 2-parallel-arm dietary intervention study in which healthy participants (aged 35-55 y) were asked to consume for 12 consecutive weeks up to 2000 mg CFs/d (n = 46) or a CF-free control (n = 28). RESULTS: Daily intake of up to 2000 mg CFs/d for 12 wk was not associated with significant changes in blood pressure or platelet function compared with CF-free controls in normotensive, healthy individuals who exhibited a very low risk of cardiovascular disease. There were no clinically relevant changes in the metabolic variables assessed in either of the groups. AEs reported were classified as mild in severity and did not significantly differ between study arms. CONCLUSION: The consumption of CFs in amounts up to 2000 mg/d for 12 wk was well tolerated in healthy men and women. This trial was registered at clinicaltrials.gov as NCT02447770 (part 1) and NCT02447783 (part 2). PMID- 26537936 TI - Fish, n-3 PUFA consumption, and pancreatic cancer risk in Japanese: a large, population-based, prospective cohort study. AB - BACKGROUND: Most previous prospective studies in Western countries found no association between consumption of fish and n-3 (omega-3) polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), for which the main source is fish, and pancreatic cancer risk. However, prospective evidence is still lacking among populations who have a relatively higher fish consumption. OBJECTIVE: We investigated the association between fish and n-3 PUFA consumption and pancreatic cancer risk in a population-based, prospective study in Japanese men and women. DESIGN: The Japan Public Health Center-based Prospective Study (JPHC study) has enrolled 140,420 subjects. We analyzed data on 82,024 eligible participants aged 45-74 y without a history of cancer who responded to a validated food-frequency questionnaire that included 138 items in 1995 for cohort I and in 1998 for cohort II. Participants were followed through 2010. HRs and corresponding 95% CIs for the highest compared with lowest quartile were calculated by using multivariable-adjusted Cox proportional hazards regression models. RESULTS: During 1,068,774 person-years of follow-up, 449 newly diagnosed pancreatic cancers were identified. After the exclusion of pancreatic cancer cases in the first 3 y of follow-up, we found an inverse association of marine n-3 PUFA (EPA+DPA+DHA) and DHA consumption with pancreatic cancer risk: compared with the lowest quartile, multivariate-adjusted HRs in the highest quartile were 0.70 (95% CI: 0.51, 0.95; P-trend = 0.07) and 0.69 (0.51, 0.94; P-trend = 0.03), respectively. Associations for total fish, n-3 PUFA, EPA, and DPA consumption were similar but were not significant. CONCLUSION: High n-3 PUFA, especially marine n-3 PUFAs, and DHA consumption was associated with a lower risk of pancreatic cancer in a population with a large variation in fish consumption, although the data apply to only a portion of the JPHC study subjects. PMID- 26537938 TI - Carbohydrate quality and quantity and risk of type 2 diabetes in US women. AB - BACKGROUND: Carbohydrate quality may be an important determinant of type 2 diabetes (T2D); however, relations between various carbohydrate quality metrics and T2D risk have not been systematically investigated. OBJECTIVE: The purpose of this study was to prospectively examine the association between carbohydrates, starch, fibers, and different combinations of these nutrients and risk of T2D in women. DESIGN: We prospectively followed 70,025 women free of cardiovascular disease, cancer, and diabetes at baseline from the Nurses' Health Study (1984 2008). Diet information was collected with the use of a validated questionnaire every 4 y. Cox regression was used to evaluate associations with incident T2D. RESULTS: During 1,484,213 person-years of follow-up, we ascertained 6934 incident T2D cases. In multivariable analyses, when extreme quintiles were compared, higher carbohydrate intake was not associated with T2D (RR = 0.98; 95% CI: 0.89, 1.08; P-trend = 0.84), whereas starch was associated with a higher risk (RR = 1.23; 95% CI: 1.12, 1.35; P-trend <0.0001). Total fiber (RR = 0.80; 95% CI: 0.72, 0.89; P-trend < 0.0001), cereal fiber (RR = 0.71, 95% CI: 0.65, 0.78; P-trend < 0.0001), and fruit fiber (RR = 0.79; 95% CI: 0.72, 0.85; P-trend < 0.0001) were associated with a lower T2D risk. The ratio of carbohydrate to total fiber intake was marginally associated with a higher risk of T2D (RR = 1.09; 95% CI: 1.00, 1.20; P-trend = 0.04). On the other hand, we found positive associations between the ratios of carbohydrate to cereal fiber (RR = 1.28; 95% CI: 1.17, 1.39; P trend < 0.0001), starch to total fiber (RR = 1.12; 95% CI: 1.02, 1.23; P-trend = 0.03), and starch to cereal fiber (RR = 1.39; 95% CI: 1.27, 1.53; P-trend < 0.0001) and T2D. CONCLUSIONS: Diets with high starch, low fiber, and a high starch-to-cereal fiber ratio were associated with a higher risk of T2D. The starch-to-cereal fiber ratio of the diet may be a novel metric for assessing carbohydrate quality in relation to T2D. PMID- 26537939 TI - Cross-sectional and prospective associations between dietary and plasma vitamin C, heel bone ultrasound, and fracture risk in men and women in the European Prospective Investigation into Cancer in Norfolk cohort. AB - BACKGROUND: Vitamin C sufficiency may help prevent osteoporosis and fractures by mediating osteoclastogenesis, osteoblastogenesis, and bone collagen synthesis. OBJECTIVE: We determined whether dietary intakes and plasma concentrations of vitamin C were associated with a heel ultrasound and hip and spine fracture risks in older men and women. DESIGN: Participants were recruited from the European Prospective Investigation into Cancer in Norfolk study with 7-d diet diary estimates of vitamin C intake and plasma concentrations. A random subset (4000 of 25,639 subjects) was available for the cross-sectional (ultrasound) study of broadband ultrasound attenuation (BUA) and velocity of sound (VOS), which were determined during the second health examination. The prospective (fracture) study was a case-cohort sample of all participants with a fracture up to March 2009 and the random subset (n = 5319). ANCOVA-determined associations between quintiles of vitamin C intake and plasma status with adjusted BUA and VOS and adjusted Prentice-weighted Cox proportional HRs were calculated for fracture risk. RESULTS: Women were 58% of the population (39-79 y old), and the median follow-up was 12.6 y (range: 0-16 y). Positive associations across all quintiles of vitamin C intake but not plasma status were significant for VOS in men (beta = 2.47 m/s, P = 0.008) and BUA in women (beta = 0.82 dB/MHz, P = 0.004). Vitamin C intake was not associated with fracture risk, but there was an inverse association with plasma concentrations in men, with quintile 4 having significantly lower risks of hip fractures (HR: 0.35; 95% CI: 0.16, 0.80) and spine fractures (HR: 0.26; 95% CI: 0.10, 0.69) than quintile 1. CONCLUSIONS: Higher vitamin C intake was significantly associated with higher heel ultrasound measures in men and women, and higher plasma vitamin C concentrations were significantly associated with reduced fracture risk in men only. Our findings that vitamin C intake and status were inconsistently associated with bone health variables suggest that additional research is warranted. PMID- 26537940 TI - Effects on weight loss in adults of replacing diet beverages with water during a hypoenergetic diet: a randomized, 24-wk clinical trial. AB - BACKGROUND: Obese people believe that drinking diet beverages (DBs) may be a simple strategy to achieve weight loss. However, nutritionists advise drinking water when attempting to lose weight. It is unclear how important drinking water instead of DBs is during a weight-loss program. OBJECTIVE: In this study, we compared the effect on weight loss of either replacing DBs with water or continuing to consume DBs in adults during a 24-wk weight-loss program. DESIGN: Overweight and obese women [n = 89; body mass index (BMI; in kg/m(2)): 27-40; age: 18-50 y] who usually consumed DBs in their diet were asked to either substitute water for DBs (water group) or continue drinking DBs 5 times/wk after their lunch for 24 wk (DB group) while on a weight-loss program. RESULTS: Sixty two participants (71%) completed the trial (32 in the DB group, 30 in the water group). Baseline variables were not statistically significantly different between groups. A statistically significant reduction in anthropometric measurements and statistically significant improvements in cardiometabolic risk characteristics were observed over 24 wk in both groups. Compared with the DB group, the water group had a greater decrease in weight (mean +/- SD: water: -8.8 +/- 1.9 kg; DBs: -7.6 +/- 2.1 kg; P = 0.015, time * group), fasting insulin (mean +/- SD: water: 2.84 +/- 0.77 mU/L; DBs: -1.78 +/- 1.25 mU/L, P < 0.001), homeostasis model assessment of insulin resistance (mean +/- SD: water: -0.097 +/- 0.049; DBs: 0.057 +/- 0.042, P < 0.001), and 2-h postprandial glucose (mean +/- SD: water: 1.02 +/- 0.25 mmol/L; DBs: -0.72 +/- 0.27 mmol/L; P < 0.001) over the 24 wk. However, there was no significant time * group interaction for waist circumference, fasting plasma glucose, and lipid profiles within both groups over 24 wk. CONCLUSIONS: Replacement of DBs with water after the main meal may lead to greater weight reduction during a weight-loss program. It may also offer clinical benefits to improve insulin resistance. This trial was registered at www.irct.ir/ as IRCT201402177754N5. PMID- 26537941 TI - Antiretroviral therapy provided to HIV-infected Malawian women in a randomized trial diminishes the positive effects of lipid-based nutrient supplements on breast-milk B vitamins. AB - BACKGROUND: Little information is available on B vitamin concentrations in human milk or on how they are affected by maternal B vitamin deficiencies, antiretroviral therapy, or maternal supplementation. OBJECTIVE: The objective was to evaluate the effects of antiretroviral therapy and/or lipid-based nutrient supplements (LNSs) on B vitamin concentrations in breast milk from HIV-infected women in Malawi. DESIGN: Breast milk was collected from 537 women recruited within the Breastfeeding, Antiretrovirals, and Nutrition study at 2 or 6 wk and 24 wk postpartum. Women were assigned to receive antiretrovirals and LNSs, antiretrovirals only, LNSs only, or a control. Antiretrovirals and LNSs were given to the mothers from weeks 0 to 28. The antiretrovirals were zidovudine/lamivudine and nelfinavir or lopinavir/ritonavir. LNSs provided 93 118% of the Recommended Dietary Allowances of thiamin, riboflavin, niacin, pyridoxine, and vitamin B-12. Infants were exclusively breastfed. RESULTS: LNSs increased milk concentrations of all vitamins except thiamin, whereas antiretrovirals lowered concentrations of nicotinamide, pyridoxal, and vitamin B 12. Although antiretrovirals alone had no significant effect on riboflavin concentrations, they negatively affected the LNS-induced increase in this vitamin. Thiamin was not influenced by the study interventions. Concentrations of all B vitamins were much lower than usually accepted values. CONCLUSIONS: All B vitamins were low in milk, and all but thiamin were increased by maternal supplementation with LNSs. Antiretrovirals alone decreased concentrations of some B vitamins in milk. When LNS was given in addition to antiretrovirals, the negative effect of antiretrovirals offset the positive effect of LNSs for all vitamins except thiamin. This trial was registered at clinicaltrials.gov as NCT00164762. PMID- 26537942 TI - Dietary acid load in early life and bone health in childhood: the Generation R Study. AB - BACKGROUND: Dietary contribution to acid-base balance in early life may influence subsequent bone mineralization. Previous studies reported inconsistent results regarding the associations between dietary acid load and bone mass. OBJECTIVE: We examined the associations of dietary acid load in early life with bone health in childhood. DESIGN: In a prospective, multiethnic, population-based cohort study of 2850 children, we estimated dietary acid load as dietary potential renal acid load (dPRAL), based on dietary intakes of calcium, magnesium, phosphorus, potassium, and protein, and as a protein intake to potassium intake ratio (Pro:K) at 1 y of age and in a subgroup at 2 y of age : Bone mineral density, bone mineral content (BMC), area-adjusted BMC, and bone area were assessed by dual energy X-ray absorptiometry at the median age of 6 y. Data were analyzed by using multivariable linear regression models. RESULTS: After adjusting for relevant maternal and child factors, dietary acid load estimated as either dPRAL or Pro:K ratio was not consistently associated with childhood bone health. Associations did not differ by sex, ethnicity, weight status, or vitamin D supplementation. Only in those children with high protein intake in our population (i.e., >42 g/d), a 1-unit increase in dPRAL (mEq/d) was inversely associated with BMC (difference: -0.32 g; 95% CI: -0.64, -0.01 g). CONCLUSIONS: Dietary acid load in early life was not consistently associated with bone health in childhood. Further research is needed to explore the extent to which dietary acid load in later childhood may affect current and future bone health. PMID- 26537943 TI - Long-term effect of high-dose supplementation with DHA on visual function at school age in children born at <33 wk gestational age: results from a follow-up of a randomized controlled trial. AB - BACKGROUND: Children born preterm are at risk of visual-processing impairments. Several lines of evidence have contributed to the rationale that docosahexaenoic acid (DHA) supplementation of preterm infants may improve outcomes in visual processing. OBJECTIVE: The aim was to determine whether at 7 y of age children who were born very preterm and who received a high-DHA diet have better visual processing outcomes than do infants fed a standard-DHA diet. DESIGN: This was a follow-up study in a subgroup of children from a randomized controlled trial. Infants were randomly assigned to milk containing a higher concentration of DHA (1% of total fatty acids; high-DHA group) or a standard amount of DHA (0.2-0.3% of total fatty acids as DHA; control group). The randomization schedule was stratified by sex and birth weights of <1250 or >=1250 g. A total of 104 (49 in the high-DHA group and 55 in the standard-DHA group) children aged 7 y were assessed on a range of visual-processing measures, including visual acuity, contrast sensitivity, vernier acuity, binocular stereopsis, and visual perception. RESULTS: There was no evidence of differences between the high-DHA and standard-DHA groups in any of the visual-processing measures. In the majority (12 of 13) of variables assessed, the direction of effect favored the control group. The study was large enough to detect a moderate treatment effect, if one truly existed. CONCLUSION: Supplementing human milk with DHA at a dose of ~1% of total fatty acids given in the first months of life to very preterm infants does not appear to confer any long-term benefit for visual processing at school age. This trial was registered at anzctr.org/au as ACTRN12606000327583. PMID- 26537944 TI - Acute load-dependent effects of oral whey protein on gastric emptying, gut hormone release, glycemia, appetite, and energy intake in healthy men. AB - BACKGROUND: In healthy individuals, intraduodenal whey protein load-dependently modulates gastrointestinal motor and hormonal functions and suppresses energy intake. The effect of oral whey, particularly the impact of load, has not been evaluated. OBJECTIVE: The purpose of this study was to quantify gastric emptying of 30 and 70 g of oral whey protein loads and their relation to gastrointestinal hormone, glycemic, and appetitive responses. DESIGN: On 3 separate occasions in a randomized, double-blind order, 18 lean men [mean +/- SEM age: 24.8 +/- 1.4 y; body mass index (in kg/m(2)): 21.6 +/- 0.5] received iso-osmolar, equally palatable drinks (~450 mL) containing 30 g pure whey protein isolate (L), 70 g pure whey protein isolate (H), or saline (control). Gastric emptying (with the use of 3-dimensional ultrasound), plasma cholecystokinin, glucagon-like peptide 1, glucose-dependent insulinotropic peptide, insulin, glucagon, total amino acids, and blood glucose were measured for 180 min after consumption of the drinks, and energy intake at a buffet-style lunch was quantified. RESULTS: Gastric emptying of the L and H drinks was comparable when expressed in kilocalories per minute (L: 2.6 +/- 0.2 kcal/min; H: 2.9 +/- 0.3 kcal/min) and related between individuals (r = 0.54, P < 0.01). Gastrointestinal hormone, insulin, and glucagon responses to the L and H drinks were comparable until ~45 60 min after ingestion, after which time the responses became more differentiated. Blood glucose was modestly reduced after the H drink between t = 45 and 150 min when compared with the L drink (all P < 0.05). Energy intake was suppressed by both L and H drinks compared with control (P < 0.05) (control: 1174 +/- 91 kcal; L: 1027 +/- 81 kcal; and H: 997 +/- 71 kcal). CONCLUSION: These findings indicate that, in healthy lean men, the rate of gastric emptying of whey protein is independent of load and determines the initial gastrointestinal hormone response. This study was registered at www.anzctr.org.au as 12611000706976. PMID- 26537945 TI - No difference in ad libitum energy intake in healthy men and women consuming beverages sweetened with fructose, glucose, or high-fructose corn syrup: a randomized trial. AB - BACKGROUND: Increased energy intake is consistently observed in individuals consuming sugar-sweetened beverages (SSBs), likely mainly because of an inadequate satiety response to liquid calories. However, SSBs have a high content of fructose, the consumption of which acutely fails to trigger responses in key signals involved in energy homeostasis. It is unclear whether the fructose content of SSBs contributes to the increased energy intake in individuals drinking SSBs. OBJECTIVE: We investigated whether the relative amounts of fructose and glucose in SSBs modifies ad libitum energy intake over 8 d in healthy adults without fructose malabsorption. DESIGN: We conducted 2 randomized, controlled, double-blind crossover studies to compare the effects of consuming 4 servings/d of a fructose-, glucose-, or aspartame-sweetened beverage (study A; n = 9) or a fructose-, glucose-, or high-fructose corn syrup (HFCS)-sweetened beverage (study B; n = 24) for 8 d on overall energy intake. SSBs were provided at 25% of estimated energy requirement, or an equivalent volume of the aspartame sweetened beverage, and consumption was mandatory. All solid foods were provided at 125% of estimated energy requirements and were consumed ad libitum. RESULTS: In study A, ad libitum energy intake was 120% +/- 10%, 117% +/- 12%, and 102% +/- 15% of estimated energy requirements when subjects consumed the fructose-, glucose-, and aspartame-sweetened beverages. Energy intake was significantly higher in the fructose and glucose phases than in the aspartame phase (P < 0.003 for each), with no difference between the fructose and glucose phases (P = 0.462). In study B, total energy intake during the fructose, HFCS, and glucose phases was 116% +/- 14%, 116% +/- 16%, and 116% +/- 16% of the subject's estimated total energy requirements (P = 0.880). CONCLUSIONS: In healthy adults, total 8-d ad libitum energy intake was increased in individuals consuming SSBs compared with aspartame-sweetened beverages. The energy overconsumption observed in individuals consuming SSBs occurred independently of the relative amounts of fructose and glucose in the beverages. These trials were registered at clinicaltrials.gov as NCT00475475 and NCT01424306. PMID- 26537946 TI - Selenium metabolism to the trimethylselenonium ion (TMSe) varies markedly because of polymorphisms in the indolethylamine N-methyltransferase gene. AB - BACKGROUND: Selenium is an essential element, but its metabolism in humans is not well characterized. A few small studies indicate that the trimethylselenonium ion (TMSe) is a common selenium metabolite in humans. OBJECTIVE: This study aimed to elucidate the human metabolism of selenium to TMSe. DESIGN: Study individuals constituted subsamples of 2 cohorts: 1) pregnant women (n = 228) and their 5-y old children (n = 205) in rural Bangladesh with poor selenium status [median urinary selenium (U-Se): 6.4 MUg/L in mothers, 14 MUg/L in children] and 2) women in the Argentinian Andes (n = 83) with adequate selenium status (median U-Se: 24 MUg/L). Total U-Se and blood selenium were measured by inductively coupled plasma mass spectrometry (ICPMS), and urinary concentrations of TMSe were measured by high-performance liquid chromatography/vapor generation/ICPMS. A genomewide association study (GWAS) was performed for 1,629,299 (after filtration) single nucleotide polymorphisms (SNPs) in the Bangladeshi women (n = 72) by using Illumina Omni5M, and results were validated by using real-time polymerase chain reaction. RESULTS: TMSe "producers" were prevalent (approximately one-third) among the Bangladeshi women and their children, in whom TMSe constituted ~10-70% of U-Se, whereas "nonproducers" had, on average, 0.59% TMSe. The TMSe-producing women had, on average, 2-MUg U-Se/L higher concentrations than did the nonproducers. In contrast, only 3 of the 83 Andean women were TMSe producers (6 15% TMSe in the urine); the average percentage among the nonproducers was 0.35%. Comparison of the percentage of urinary TMSe in mothers and children indicated a strong genetic influence. The GWAS identified 3 SNPs in the indolethylamine N methyltransferase gene (INMT) that were strongly associated with percentage of TMSe (P < 0.001, false-discovery rate corrected) in both cohorts. CONCLUSIONS: There are remarkable population and individual variations in the formation of TMSe, which could largely be explained by SNPs in INMT. The TMSe-producing women had higher U-Se concentrations than did nonproducers, but further elucidation of the metabolic pathways of selenium is essential for the understanding of its role in human health. The MINIMat trial was registered at isrctn.org as ISRCTN16581394. PMID- 26537947 TI - Characterization of proliferating cell nuclear antigen (PCNA) from pathogenic yeast Candida albicans and its functional analyses in S. cerevisiae. AB - BACKGROUND: Proliferating cell nuclear antigen (PCNA/POL30) an essential protein forms a homotrimeric ring encircling dsDNA and serves as a molecular scaffold to recruit various factors during DNA replication, repair and recombination. According to Candida Genome Database (CGD), orf19.4616 sequence is predicted to encode C. albicans PCNA (CaPCNA) that has not been characterized yet. RESULTS: Molecular modeling studies of orf19.4616 using S. cerevisiae PCNA sequence (ScPCNA) as a template, and its subsequent biochemical characterizations suggest that like other eukaryotic PCNAs, orf19.4616 encodes for a conventional homotrimeric sliding clamp. Further we showed by surface plasmon resonance that CaPCNA physically interacted with yeast DNA polymerase eta. Plasmid segregation in genomic knock out yeast strains showed that CaPCNA but not its G178S mutant complemented for cell survival. Unexpectedly, heterologous expression of CaPCNA in S. cerevisiae exhibited slow growth phenotypes, sensitivity to cold and elevated temperatures; and showed enhanced sensitivity to hydroxyurea and various DNA damaging agents in comparison to strain bearing ScPCNA. Interestingly, wild type strains of C. albicans showed remarkable tolerance to DNA damaging agents when compared with similarly treated yeast cells. CONCLUSIONS: Despite structural and physiochemical similarities; we have demonstrated that there are distinct functional differences between ScPCNA and CaPCNA, and probably the ways both the strains maintain their genomic stability. We propose that the growth of pathogenic C. albicans which is evolved to tolerate DNA damages could be controlled effectively by targeting this unique fungal PCNA. PMID- 26537948 TI - Effectiveness of septoplasty versus non-surgical management for nasal obstruction due to a deviated nasal septum in adults: study protocol for a randomized controlled trial. AB - BACKGROUND: Septoplasty, i.e., surgical correction of the deviated nasal septum, is the most common ear, nose and throat (ENT) operation in adults. Currently the main indication to perform septoplasty is nasal obstruction. However, the effectiveness of septoplasty for nasal obstruction in adults with a deviated nasal septum remains uncertain. Scientific evidence is scarce and inconclusive, and internationally accepted guidelines are lacking. Moreover, there is no consensus on whether or not septoplasty should be combined with concurrent turbinate surgery. The objective of the current ongoing trial is to study the effectiveness of septoplasty (with or without concurrent turbinate surgery) as compared to non-surgical management for nasal obstruction in adults with a deviated nasal septum, both in terms of subjective (health-related quality of life) as well as objective (nasal patency) outcome measures. METHODS/DESIGN: The study is designed as a pragmatic, multicenter, parallel-group, randomized controlled trial. A total of 200 adults will be enrolled with nasal obstruction based on a deviated nasal septum and an indication for septoplasty according to current medical practice in the Netherlands. Participants will be randomized to either septoplasty (with or without concurrent turbinate surgery as originally indicated by the otorhinolaryngologist) or a non-surgical watchful waiting strategy. Follow-up visits will be scheduled at 0, 3, 6, 12, and 24 months. During each follow-up visit, health-related quality of life questionnaires will be administered and measurements of four-phase rhinomanometry and peak nasal inspiratory flow will be performed. Costs will be studied using a patient-based diary. Effects of septoplasty on health-related quality of life (primary outcome) and nasal patency will be calculated as mean differences with 95 % confidence intervals. Subgroup analyses according to gender, age, and severity of the septal deviation will be performed. All analyses will be performed on an intention-to treat basis. DISCUSSION: With the results of this study we aim to contribute to the development of evidence-based guidelines regarding indications for septoplasty. TRIAL REGISTRATION: Nederlands Trial Register/Dutch Trial Registry ( www.trialregister.nl ), trial identifying number: NTR3868 . Registered on 21 February 2013. PMID- 26537949 TI - Three-dimensional postoperative accuracy of extra-articular forearm osteotomies using CT-scan based patient-specific surgical guides. AB - BACKGROUND: Computer assisted corrective osteotomy of the diaphyseal forearm and the distal radius based on computer simulation and patient-specific guides has been described as a promising technique for accurate reconstruction of forearm deformities. Thereby, the intraoperative use of patient-specific drill and cutting guides facilitate the transfer of the preoperative plan to the surgery. However, the difference between planned and performed reduction is difficult to assess with conventional radiographs. The aim of this study was to evaluate the accuracy of this surgical technique based on postoperative three-dimensional (3D) computed tomography (CT) data. METHODS: Fourteen patients (mean age 23.2 (range, 12-58) years) with an extra-articular deformity of the forearm had undergone computer assisted corrective osteotomy with the healthy anatomy of the contralateral uninjured side as a reconstruction template. 3D bone surface models of the pathological and contralateral side were created from CT data for the computer simulation. Patient-specific drill and cutting guides including the preoperative planned screw direction of the angular-stable locking plates and the osteotomy planes were used for the intraoperative realization of the preoperative plan. There were seven opening wedge osteotomies and nine closing wedge (or single-cut) osteotomies performed. Eight-ten weeks postoperatively CT scans were obtained to assess bony consolidation and additionally used to generate a 3D model of the forearm. The simulated osteotomies- preoperative bone models with simulated correction - and the performed osteotomies - postoperative bone models were analyzed for residual differences in 3D alignment. RESULTS: On average, a significant higher residual rotational deformity was observed in opening wedge osteotomies (8.30 degrees +/- 5.35 degrees ) compared to closing wedge osteotomies (3.47 degrees +/- 1.09 degrees ). The average residual translation was comparable small in both groups, i.e., below 1.5 mm and 1.1 mm for opening and closing wedge osteotomies, respectively. CONCLUSIONS: The technique demonstrated high accuracy in performing closing wedge (or single-cut) osteotomies. However, for opening wedge osteotomies with extensive lengthening, probably due to the fact that precise reduction was difficult to achieve or maintain, the final corrections were less accurate. PMID- 26537950 TI - Periostin is critical for improving the therapeutic properties of adipocyte derived stem cells. AB - Periostin is a matricellular protein that is reactivated during tissue damage and repair and has been shown to be a critical regulator of multiple biological pathways involved in the repair of tissue after myocardial infarction, peripheral vascular disease, and skin wounds. The tissue repair properties attributed to periostin make it an ideal candidate to enhance the therapeutic properties of donor cells such as mesenchymal stem cells from adipocyte tissue. In a recent article in Stem Cell Research & Therapy, Qin et al. demonstrated enhanced therapeutic properties of adipocyte-derived stem cells by genetically engineering them to express periostin. PMID- 26537951 TI - Non-typhoidal Salmonella serotypes, antimicrobial resistance and co-infection with parasites among patients with diarrhea and other gastrointestinal complaints in Addis Ababa, Ethiopia. AB - BACKGROUND: Non-typhoidal Salmonella (NTS) is an important public health problem worldwide. Consumption of animal-derived food products and direct and/or indirect contact with animals are the major routes of acquiring infection with NTS. Published information, particularly on the serotype distribution of NTS among human patients with gastroenteritis and associated risk factors, is scarce in Ethiopia. This study investigated the prevalence, risk factors, serotype distribution and antimicrobial susceptibility of Salmonella species among diarrheic out-patients attending health centers in Addis Ababa and patients with various gastrointestinal complaints at Tikur Anbessa Specialized Hospital (TASH). METHODS: Stool samples were cultured for Salmonella species according to the WHO Global Foodborne Infections Network laboratory protocol. Salmonella serotyping was conducted using slide agglutination and microplate agglutination techniques. Antibiotic susceptibility testing was performed using the disk diffusion method according to Clinical and Laboratory Standards Institute guidelines. RESULTS: A total of 59 (6.2 %) stool samples, out of 957 were culture positive for Salmonella species. Fifty-five (7.2 %) of 765 diarrheic patients from health centers and 4 (2.1 %) of 192 patients from TASH were culture positive for Salmonella species. Multivariable logistic regression analysis after adjusting for all other variables revealed statistically significant association of Salmonella infection with consumption of raw vegetables (OR = 1.91, 95 % CI = 1.29-2.83, chi(2) = 4.74, p = 0.025) and symptom of watery diarrhea (OR = 3.3, 95 % CI = 1.23-8.88, chi(2) = 10.54, p = 0.005). Eleven serotypes were detected, and the most prominent were S. Typhimurium (37.3 %), S. Virchow (34 %), and S. Kottbus (10.2 %). Other serotypes were S. Miami, S. Kentucky, S. Newport, S. Enteritidis, S. Braenderup, S. Saintpaul, S. Concord and S. V:ROUGH-O. Resistance to three or more antimicrobials was detected in 27 (40.3 %) of the isolates. Resistance to five or more antimicrobials was detected in 17 (25.4 %). Resistance to individual antimicrobials was found at varying proportions: streptomycin (50; 74.6 %), nitrofurantoin (27; 40.3 %), sulfisoxazole (26; 38.8 %), kanamycin (23; 34.3 %), cephalothin (12; 17.9 %), and ampicillin (11; 16.4 %) respectively. Two S. Kentucky, one S. Typhimurium and one S. Concord isolates were multi-drug resistant to more than 10 antimicrobials. CONCLUSIONS: The study demonstrated significant association of Salmonella infection with consumption of raw vegetables. There was no significant association of Salmonella infection with co occurring parasites. The study also showed the dominance of S. Typhimurium and S. Virchow in primary health care units. Overall, prevalence of MDR was low compared to previous studies. Although their proportion was low, S. Kentucky and S. Concord demonstrated wider spectrum of MDR. Continuous monitoring of circulating serotypes, antimicrobial resistance profile and characterization on molecular resistance determinants is essential for proper treatment of patients and for identifying potential environmental origins of antimicrobial resistance. PMID- 26537952 TI - A monolingual mind can have two time lines: Exploring space-time mappings in Mandarin monolinguals. AB - Can a mind accommodate two time lines? Miles, Tan, Noble, Lumsden and Macrae (Psychonomic Bulletin & Review 18, 598-604, 2011) shows that Mandarin-English bilinguals have both a horizontal space-time mapping consistent with linguistic conventions within English and a vertical representation of time commensurate with Mandarin. However, the present study, via two experiments, demonstrates that Mandarin monolinguals possess two mental time lines, i.e., one horizontal and one vertical line. This study concludes that a Mandarin speaker has two mental time lines not because he/she has acquired L2 English, but because there are both horizontal and vertical expressions in Mandarin spatiotemporal metaphors. Specifically, this study highlights the fact that a horizontal time line does exist in a Mandarin speaker's cognition, even if he/she is a Mandarin monolingual instead of a ME bilingual. Taken together, the evidence in hand is far from sufficient to support Miles et al.'s (2011) conclusion that ME bilinguals' horizontal concept of time is manipulated by English. Implications for theoretical issues concerning the language-thought relationship in general and the effect of bilingualism on cognition in particular are discussed. PMID- 26537953 TI - Evaluating quantitative and conceptual models of speech production: how does SLAM fare? AB - In a previous publication, we presented a new computational model called SLAM (Walker & Hickok, Psychonomic Bulletin & Review doi: 10.3758/s13423-015-0903 ), based on the hierarchical state feedback control (HSFC) theory (Hickok Nature Reviews Neuroscience, 13(2), 135-145, 2012). In his commentary, Goldrick (Psychonomic Bulletin & Review doi: 10.3758/s13423-015-0946-9 ) claims that SLAM does not represent a theoretical advancement, because it cannot be distinguished from an alternative lexical + postlexical (LPL) theory proposed by Goldrick and Rapp (Cognition, 102(2), 219-260, 2007). First, we point out that SLAM implements a portion of a conceptual model (HSFC) that encompasses LPL. Second, we show that SLAM accounts for a lexical bias present in sound-related errors that LPL does not explain. Third, we show that SLAM's explanatory advantage is not a result of approximating the architectural or computational assumptions of LPL, since an implemented version of LPL fails to provide the same fit improvements as SLAM. Finally, we show that incorporating a mechanism that violates some core theoretical assumptions of LPL-making it more like SLAM in terms of interactivity allows the model to capture some of the same effects as SLAM. SLAM therefore provides new modeling constraints regarding interactions among processing levels, while also elaborating on the structure of the phonological level. We view this as evidence that an integration of psycholinguistic, neuroscience, and motor control approaches to speech production is feasible and may lead to substantial new insights. PMID- 26537954 TI - Achilles is not alone!!! Ciprofloxacin induced tendinopathy of gluteal tendons. PMID- 26537955 TI - Candida growth in urine cultures: a contemporary analysis of species and antifungal susceptibility profiles. AB - BACKGROUND: Recent publications suggest the distribution of Candida species causing candiduria may vary geographically, which has implications for the continued efficacy of antifungal therapy and emerging resistance. AIM: To investigate the incidence of Candiduria at a university hospital in the UK. Further, to assess the distribution of species and the accompanying antifungal susceptibility profile, in order to monitor the clinical utility of current antifungal treatment guidelines for candiduria so that patients receive the best possible outcomes from the most up to date care. DESIGN: Retrospective audit. METHODS: From 1st January 2005 to 31st October 2014, we retrospectively reviewed 37 538 positive urine cultures recorded in a computerized laboratory results database. Identification and susceptibility testing was performed using the VITEK(r) 2 fungal susceptibility card (bioMerieux, Marcy d'Etoile, France). RESULTS: In total, 96 cultures were positive for Candida species, of which 69 (72%) were C.albicans, which translates to a prevalence of 2.6 per 1000 positive urine cultures. Candiduria was more common in younger patients, males and catheterized females. We report 94 and 73% of isolates of C.albicans and other non-C.albicans Candida species were susceptible to fluconazole. All isolates were susceptible to amphotericin B. CONCLUSIONS: Our results add weight to the evidence supporting current European and North American guidelines recommending fluconazole or amphotericin B for treatment of candiduria, if antifungal treatment is clinically indicated. PMID- 26537956 TI - Assessing fibrosis in pulmonary sarcoidosis: late-enhanced MRI compared to anatomic HRCT imaging. PMID- 26537957 TI - Ceruloplasmin functional changes in Parkinson's disease-cerebrospinal fluid. AB - BACKGROUND: Ceruloplasmin, a ferroxidase present in cerebrospinal fluid (CSF), plays a role in iron homeostasis protecting tissues from oxidative damage. Its reduced enzymatic activity was reported in Parkinson's disease (PD) contributing to the pathological iron accumulation. We previously showed that ceruloplasmin is modified by oxidation in vivo, and, in addition, in vitro by deamidation of specific NGR-motifs that foster the gain of integrin-binding function. Here we investigated whether the loss of ceruloplasmin ferroxidase activity in the CSF of PD patients was accompanied by NGR-motifs deamidation and gain of function. RESULTS: We have found that endogenous ceruloplasmin in the CSF of PD patients showed structural changes, deamidation of the (962)NGR-motif which is usually hidden within the ceruloplasmin structure, and the gain of integrin-binding function. These effects occur owing to the presence of abnormal levels of hydrogen peroxide we detected in the CSF of PD patients. Interestingly, the pathological CSF's environment of PD patients promoted the same modifications in the exogenously added ceruloplasmin, which in turn resulted in loss of ferroxidase-activity and acquisition of integrin-binding properties. CONCLUSIONS: We show that in pathological oxidative environment of PD-CSF the endogenous ceruloplasmin, in addition to loss-of-ferroxidase function, is modified as to gain integrin-binding function. These findings, beside the known role of ceruloplasmin in iron homeostasis, might have important pathogenic implications due to the potential triggering of signals mediated by the unusual integrin binding in cells of central nervous system. Furthermore, there are pharmacological implications because, based on data obtained in murine models, the administration of ceruloplasmin has been proposed as potential therapeutic treatment of PD, however, the observed CSF's pro-oxidant properties raise the possibility that in human the ceruloplasmin-based therapeutic approach might not be efficacious. PMID- 26537958 TI - Multi-Targeted Agents in Cancer Cell Chemosensitization: What We Learnt from Curcumin Thus Far. AB - BACKGROUND: Research over the past several years has developed many mono-targeted therapies for the prevention and treatment of cancer, but it still remains one of the fatal diseases in the world killing 8.2 million people annually. It has been well-established that development of chemoresistance in cancer cells against mono targeted chemotherapeutic agents by modulation of multiple survival pathways is the major cause of failure of cancer chemotherapy. Therefore, inhibition of these pathways by non-toxic multi-targeted agents may have profoundly high potential in preventing drug resistance and sensitizing cancer cells to chemotherapeutic agents. OBJECTIVE: To study the potential of curcumin, a multi-targeted natural compound, obtained from the plant Turmeric (Curcuma longa) in combination with standard chemotherapeutic agents to inhibit drug resistance and sensitize cancer cells to these agents based on available literature and patents. METHOD: An extensive literature survey was performed in PubMed and Google for the chemosensitizing potential of curcumin in different cancers published so far and the patents published during 2014-2015. RESULT: Our search resulted in many in vitro, in vivo and clinical reports signifying the chemosensitizing potential of curcumin in diverse cancers. There were 160 in vitro studies, 62 in vivo studies and 5 clinical studies. Moreover, 11 studies reported on hybrid curcumin: the next generation of curcumin based therapeutics. Also, 34 patents on curcumin's biological activity have been retrieved. CONCLUSION: Altogether, the present study reveals the enormous potential of curcumin, a natural, non-toxic, multi targeted agent in overcoming drug resistance in cancer cells and sensitizing them to chemotherapeutic drugs. PMID- 26537959 TI - Eye and hand movement strategies in older adults during a complex reaching task. AB - The kinematics of upper limb movements and the coordination of eye and hand movements are affected by ageing. These age differences are exacerbated when task difficulty is increased, but the exact nature of these differences remains to be established. We examined the performance of 12 older adults (mean age = 74) and 11 younger adults (mean age = 20) on a multi-phase prehension task. Participants had to reach for a target ball with their preferred hand, pick it up and place it in a tray, then reach for a second target ball and place that in the same tray. On half the trials (stabilising condition), participants were required to hold the tray just above the surface of the table with their non-preferred hand and keep it as still as possible. Hand and eye movements were recorded. Older adults took longer to complete their movements and reached lower peak velocities than the younger adults. Group differences were most apparent in the stabilising condition, suggesting that the added complexity had a greater effect on the performance of the older adults than the young. During pickup, older adults preferred to make an eye movement to the next target as soon as possible, but spent longer fixating the current target during placement, when accuracy requirements were higher. These latter observations suggest that older adults employed a task-dependent eye movement strategy, looking quickly to the next target to allow more time for planning and execution when possible, but fixating on their hand and successful placement of the ball when necessary. PMID- 26537960 TI - Facilitation of visual target detection by pre-perceptual processing of negative emotion driven by simple geometric shapes. AB - Emotional processing that occurs partially in advance of perceptual processing is known as pre-perceptual emotional processing. The facilitation of sensory processing due to pre-perceptual emotional processing can be observed in visual search and attentional blink tasks. However, previous event-related potential studies have suggested that pre-perceptual emotional processing affects the lower order range of sensory processing, which differs from the processing involved in visual search and attentional blink tasks. Therefore, we investigated the facilitation of earlier visual processing due to pre-perceptual emotional processing using simple geometric shapes. We found that the target detection sensitivity for a negative emotional stimulus was higher than that for a neutral stimulus. Moreover, this higher sensitivity was not attributed to attentional bias within the visual field or to object novelty. These results suggest that negative emotion induced by simple geometric shapes facilitates visual target detection due to pre-perceptual emotional processing. Furthermore, it was suggested that the facilitation of visual perception by pre-perceptual processing occurs at various stages, from early to later stage. PMID- 26537961 TI - Event-related frontal alpha asymmetries: electrophysiological correlates of approach motivation. AB - Over the last decades, frontal alpha asymmetries observed during resting state periods of several minutes have been used as a marker of affective-motivational states. To date, there is no evidence that alpha asymmetries can be observed in response to brief affective-motivational stimuli, as typically presented in event related designs. As we argue, frontal alpha asymmetry might indeed be elicited by brief events if they are salient enough. In an event-related design, we used erotic pictures, i.e., highly salient incentives to elicit approach motivation, and contrasted them with pictures of dressed attractive women. As expected, we found significant alpha asymmetries for erotic pictures as compared to control pictures. Our findings suggest that the highly reactive reward system can lead to immediate, phasic changes in frontal alpha asymmetries. We discuss the findings with respect to the notion that high salience of erotic pictures derives from their potential of satisfying an individuals' need by mere visual inspection, which is not the case for pictures showing other types of motivational stimuli such as food. PMID- 26537962 TI - Projections of temperature-attributable premature deaths in 209 U.S. cities using a cluster-based Poisson approach. AB - BACKGROUND: A warming climate will affect future temperature-attributable premature deaths. This analysis is the first to project these deaths at a near national scale for the United States using city and month-specific temperature mortality relationships. METHODS: We used Poisson regressions to model temperature-attributable premature mortality as a function of daily average temperature in 209 U.S. cities by month. We used climate data to group cities into clusters and applied an Empirical Bayes adjustment to improve model stability and calculate cluster-based month-specific temperature-mortality functions. Using data from two climate models, we calculated future daily average temperatures in each city under Representative Concentration Pathway 6.0. Holding population constant at 2010 levels, we combined the temperature data and cluster based temperature-mortality functions to project city-specific temperature attributable premature deaths for multiple future years which correspond to a single reporting year. Results within the reporting periods are then averaged to account for potential climate variability and reported as a change from a 1990 baseline in the future reporting years of 2030, 2050 and 2100. RESULTS: We found temperature-mortality relationships that vary by location and time of year. In general, the largest mortality response during hotter months (April - September) was in July in cities with cooler average conditions. The largest mortality response during colder months (October-March) was at the beginning (October) and end (March) of the period. Using data from two global climate models, we projected a net increase in premature deaths, aggregated across all 209 cities, in all future periods compared to 1990. However, the magnitude and sign of the change varied by cluster and city. CONCLUSIONS: We found increasing future premature deaths across the 209 modeled U.S. cities using two climate model projections, based on constant temperature-mortality relationships from 1997 to 2006 without any future adaptation. However, results varied by location, with some locations showing net reductions in premature temperature-attributable deaths with climate change. PMID- 26537963 TI - 1H, 13C, and 15N chemical shift assignments of cyanobacteriochrome NpR6012g4 in the green-absorbing photoproduct state. AB - Cyanobacteriochromes (CBCRs) are cyanobacterial photosensory proteins with a tetrapyrrole (bilin) chromophore that belong to the phytochrome superfamily. Like phytochromes, CBCRs photoconvert between two photostates with distinct spectral properties. NpR6012g4 from Nostoc punctiforme is a model system for widespread CBCRs with conserved red/green photocycles. Atomic-level structural information for the photoproduct state in this subfamily is not known. Here, we report NMR backbone chemical shift assignments of the light-activated state of NpR6012g4 (BMRB no. 26577) as a first step toward determining its atomic resolution structure. PMID- 26537964 TI - Working memory, reasoning, and expertise in medicine-insights into their relationship using functional neuroimaging. AB - Clinical reasoning is dependent upon working memory (WM). More precisely, during the clinical reasoning process stored information within long-term memory is brought into WM to facilitate the internal deliberation that affords a clinician the ability to reason through a case. In the present study, we examined the relationship between clinical reasoning and WM while participants read clinical cases with functional magnetic resonance imaging (fMRI). More specifically, we examined the impact of clinical case difficulty (easy, hard) and clinician level of expertise (2nd year medical students, senior gastroenterologists) on neural activity within regions of cortex associated with WM (i.e., the prefrontal cortex) during the reasoning process. fMRI was used to scan ten second-year medical students and ten practicing gastroenterologists while they reasoned through sixteen clinical cases [eight straight forward (easy) and eight complex (hard)] during a single 1-h scanning session. Within-group analyses contrasted the easy and hard cases which were then subsequently utilized for a between-group analysis to examine effects of expertise (novice > expert, expert > novice). Reading clinical cases evoked multiple neural activations in occipital, prefrontal, parietal, and temporal cortical regions in both groups. Importantly, increased activation in the prefrontal cortex in novices for both easy and hard clinical cases suggests novices utilize WM more so than experts during clinical reasoning. We found that clinician level of expertise elicited differential activation of regions of the human prefrontal cortex associated with WM during clinical reasoning. This suggests there is an important relationship between clinical reasoning and human WM. As such, we suggest future models of clinical reasoning take into account that the use of WM is not consistent throughout all clinical reasoning tasks, and that memory structure may be utilized differently based on level of expertise. PMID- 26537966 TI - [Calcium and vitamin D in bone metabolism: Clinical importance for fracture treatment]. AB - A balanced calcium homeostasis is of critical importance not only for bone remodeling, the physiological process of bone resorption and bone formation that constantly renews bone throughout life but also for normal fracture healing. Given that disturbances of calcium homeostasis are present in 50 % of the German population and that this might result in delayed fracture healing after correct surgical treatment, this paper focusses on calcium and vitamin D in the daily practice in orthopedics and trauma surgery. To ensure the required enteral calcium uptake the following three conditions are required: (1) sufficient calcium intake via the nutrition, (2) a 25-hydroxyvitamin D serum level > 30 ug/l and (3) the presence of sufficient gastric acidification. Given the endemic vitamin D deficiency in Germany as well as the constantly increasing number of people using proton pump inhibitors on a regular basis, it is necessary to closely connect trauma orthopedic surgery and osteological treatment. The first issue to be dealt with is to control and if needed normalize calcium homeostasis in order to allow a normal undisturbed fracture healing process after both conservative as well as operative treatment of fractures. PMID- 26537967 TI - Geriatric fracture centers-improved patient care and economic benefits : English Version. AB - The world's population is aging resulting in changes in the way we manage geriatric care. Furthermore, this population has a considerable risk of fragility fractures, most notably hip fractures. Hip fractures are associated with significant morbidity and mortality and have large economic consequences. It is due to these factors that the concept of an elderly trauma center was developed. These trauma centers utilize the expertise in orthopedic and geriatric disciplines to provide coordinated care to the elderly hip fracture patient. As a result, studies have demonstrated improvements in clinical outcomes within the hospital stay, a reduction in iatrogenic complications, and improvements in 1 year mortality rates compared to the usual care given at a similar facility. Furthermore, economic models have demonstrated that there is a role for regionalized hip fracture centers that can be both profitable and provide more efficient care to these patients. PMID- 26537968 TI - [Therapy of scoliosis from a historical perspective]. AB - Scoliosis can be considered as one of the classical orthopedic diseases of the spine. The history of orthopedics is closely connected to the development of the therapy of scoliosis. In the eighteenth and the beginning of the nineteenth centuries the therapy of scoliosis was mainly a conservative corrective orthopedic treatment with a variety of corset forms and extension bed treatment. In the middle of the nineteenth century physiotherapy (movement therapy) became established as an supplementary active treatment. The first operations for treatment of scoliosis were carried out in 1839. The real success with surgical procedures for improvement in corrective options was connected to the introduction of metal spinal implants in the early 1960s. PMID- 26537969 TI - [Prevalence of blood-borne pathogens among 275 trauma patients : A prospective observational study]. AB - BACKGROUND: Previous studies have indicated that the prevalence of human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) virus infections among trauma patients seems to be higher compared to the general population. OBJECTIVE: This study investigated the seroprevalence of blood-borne pathogens among patients with suspected severe multiple trauma in a German university hospital (level I trauma center). METHODS: Routine blood samples taken from trauma patients at the university hospital Frankfurt were tested for HBV, HCV and HIV (from 1 February 2014 to 31 January 2015). RESULTS: Overall, 275 patients with a median injury severity score (ISS) of 9 points (range 0-54) were included in the study representing 84.4 % of all trauma room admissions during this time period. Altogether 3.3 % (n = 9) of the patients were infected with blood-borne pathogens, where 7 patients were infected with HCV and 2 patients had an active HBV infection. None of the patients were tested HIV positive and only one initial diagnosis for HCV was made. A further six samples (five HCV and one HIV) showed a weak reaction in the screening assay that could not be verified by the confirmatory assay. CONCLUSION: To the best of our knowledge this study is the first report on the prevalence of blood-borne infections among trauma patients at a level I trauma center in an urban area in Germany. Compared to the general population the prevalence of blood-borne infections was higher but considerably lower than indicated in previous international studies. Considering the broad implications of occupationally transmitted blood-borne infections occupational safety is of paramount importance. PMID- 26537970 TI - [Imitation of an Anderson type II dens fracture by a motion artefact in computed tomography : Four case examples]. AB - Computed tomography (CT) is the method of choice in the diagnosis and classification of odontoid fractures with a sensitivity of more than 99 % and a specificity almost equally as high. In this article we report on four cases where CT-generated motion artefacts exactly mimicked an Anderson type II fracture of the dens axis, initially leading to a wrong diagnosis. Although this seems to be a very rare event, these cases indicate that overlooked CT motion artefacts can lead to severe consequences and attention must be paid to the radiological signs outlined in this report. PMID- 26537971 TI - Internal Structure of Kidney Calculi as a Predictor for Shockwave Lithotripsy Success. AB - INTRODUCTION: The internal structure of renal calculi can be determined on CT using bone windows and may be classified as homogeneous or inhomogeneous with void regions. In vitro studies have shown homogeneous stones to be less responsive to extracorporeal shockwave lithotripsy (SWL). The objective was to evaluate whether the internal morphology of calculi defined by CT bone window influences SWL outcome in vivo. MATERIALS AND METHODS: One hundred eleven patients with solitary renal calculi treated with SWL were included. Treatment data were registered prospectively and follow-up data were collected retrospectively. All patients had noncontrast computed tomography (NCCT) performed before SWL and at 3-month follow-up. The stones were categorized as homogeneous or inhomogeneous. At follow-up, the patient's stone status was registered. Stone-free status was defined as no evidence of calculi on NCCT. Treatment was considered successful if the patient was either stone free or had clinically insignificant residual fragments. RESULTS: Using simple logistic regression, the odds for being stone free 3 months post-SWL were significantly reduced in the patients with inhomogeneous stones compared with patients with homogeneous stones (odds ratio 0.43 [95% confidence interval 0.20, 0.92; p < 0.05]). However, when adjusting for stone size by multiple logistic regression, including stone size (area) as a covariate, this difference became insignificant. CONCLUSION: The internal structure of kidney stones did not predict the outcome of SWL in vivo. PMID- 26537972 TI - [Perceive and accompany aging appropriately and humanely]. PMID- 26537973 TI - [Room for possibilities as space: Remarks from the perspective of environmental gerontology]. PMID- 26537974 TI - Molecular characterization of a new efficiently transducing bacteriophage identified in meticillin-resistant Staphylococcus aureus. AB - In Staphylococcus aureus, generalized transduction mediated by temperate bacteriophages represents a highly efficient way of transferring antibiotic resistance genes between strains. In the present study, we identified and characterized in detail a new efficiently transducing bacteriophage of the family Siphoviridae, designated phiJB, which resides as a prophage in the meticillin resistant S. aureus (MRSA) strain Jevons B. Whole-genome sequencing followed by detailed in silico analysis uncovered a linear dsDNA genome consisting of 43 ,12 bp and comprising 70 ORFs, of which ~40 encoded proteins with unknown function. A global genome alignment of phiJB and other efficiently transducing phages phi11, phi53, phi80, phi80alpha and phiNM4 showed a high degree of homology with phiNM4 and substantial differences with regard to other phages. Using a model transduction system with a well-defined donor and recipient, phiJB transferred the tetracycline resistance plasmid pT181 and a penicillinase plasmid with outstanding frequencies, beating most of the above-mentioned phages by an order of magnitude. Moreover, phiJB demonstrated high frequencies of transferring antibiotic resistance plasmids even upon induction from a lysogenic donor strain. Considering such transducing potential, phiJB and related bacteriophages may serve as a suitable tool for elucidating the nature of transduction and its contribution to the spread of antibiotic resistance genes in naturally occurring MRSA populations. PMID- 26537976 TI - Relationship between depression and health-related quality of life in patients undergoing coronary artery bypass grafting: a MOTIV-CABG substudy. AB - CONTEXT/OBJECTIVES: Depression is associated with higher risk of death and major adverse cardiac events among patients undergoing coronary artery bypass grafting (CABG). This study aimed to investigate the impact of preoperative depression on health-related quality of life (HRQoL) changes over the first 12 postoperative months. METHODS: Patients were the participants in the MOTIV-CABG study that was a single-center, non-stratified, randomized, double-blind, parallel-group, phase 4 trial, conducted between January 2006 and February 2012 at University Hospital, Besancon, France. The effect of preoperative depression (measured using the Beck Depression Inventory, BDI) on changes in SF-36 component summary scores [mental (MCS) and physical (PCS)] over time was tested using a generalized linear model for repeated measures. The presence of depression was defined as a BDI score >3. RESULTS: There were 359 patients in this study: 217 (60.4 %) had no preoperative depression, and 142 (39.6 %) had preoperative depression. During follow-up, the MCS and PCS scores increased in both groups. The improvement was of smaller magnitude in the group of patients depressed baseline as compared to those with no depression (difference in LSM = -7.45, p < 10(-3), for MCS, and -6.80, p < 10( 3), for PCS). CONCLUSION: Preoperative depression has a negative impact on HRQoL improvement during postoperative follow-up after CABG. It seems important to detect depression before CABG to begin antidepressant therapy and improve patients' HRQoL. PMID- 26537975 TI - Adolescent Intermittent Alcohol Exposure: Dysregulation of Thrombospondins and Synapse Formation are Associated with Decreased Neuronal Density in the Adult Hippocampus. AB - BACKGROUND: Adolescent intermittent alcohol exposure (AIE) has profound effects on neuronal function. We have previously shown that AIE causes aberrant hippocampal structure and function that persists into adulthood. However, the possible contributions of astrocytes and their signaling factors remain largely unexplored. We investigated the acute and enduring effects of AIE on astrocytic reactivity and signaling on synaptic expression in the hippocampus, including the impact of the thrombospondin (TSP) family of astrocyte-secreted synaptogenic factors and their neuronal receptor, alpha2delta-1 (alpha2delta-1). Our hypothesis is that some of the influences of AIE on neuronal function may be secondary to direct effects on astrocytes. METHODS: We conducted Western blot analysis on TSPs 1 to 4 and alpha2delta-1 from whole hippocampal lysates 24 hours after the 4th and 10th doses of AIE, then 24 days after the last dose (in adulthood). We used immunohistochemistry to assess astrocyte reactivity (i.e., morphology) and synaptogenesis (i.e., colocalization of pre- and postsynaptic puncta). RESULTS: Adolescent AIE reduced alpha2delta-1 expression, and colocalized pre- and postsynaptic puncta after the fourth ethanol (EtOH) dose. By the 10th dose, increased TSP2 levels were accompanied by an increase in colocalized pre- and postsynaptic puncta, while alpha2delta-1 returned to control levels. Twenty-four days after the last EtOH dose (i.e., adulthood), TSP2, TSP4, and alpha2delta-1 expression were all elevated. Astrocyte reactivity, indicated by increased astrocytic volume and area, was also observed at that time. CONCLUSIONS: Repeated EtOH exposure during adolescence results in long-term changes in specific astrocyte signaling proteins and their neuronal synaptogenic receptor. Continued signaling by these traditionally developmental factors in adulthood may represent a compensatory mechanism whereby astrocytes reopen the synaptogenic window and repair lost connectivity, and consequently contribute to the enduring maladaptive structural and functional abnormalities previously observed in the hippocampus after AIE. PMID- 26537977 TI - The course of health status and (health-related) quality of life following fracture of the lower extremity: a 6-month follow-up study. AB - PURPOSE: The aim of this prospective study was to describe the course of health status (HS), health-related quality of life, and quality of life (QOL) in patients with lower extremity fractures (LEF) up to 6 months post-fracture. METHODS: Patients (n = 171; age range 18-100 years) completed the World Health Organization Quality of Life assessment instrument-Bref (WHOQOL-Bref) and the Short Musculoskeletal Function Assessment questionnaire (SMFA) at time of diagnosis (i.e., pre-injury status), 1 week, and 6 months post-fracture. Linear mixed modeling was performed. RESULTS: Interaction effects of time with treatment were detected for the WHOQOL-Bref facet Overall QOL and General health (p = .002) and Physical health (p = .003). Patients did not return to their pre-injury Physical health, Psychological health, and Environment 6 months post-fracture (p < .05). No effects were found for Social relationships. The SMFA subscale Lower extremity dysfunction showed main effects for time and treatment (p < .0001) with full recovery at 6 months (p = .998). An interaction effect of time with treatment was found for Daily life consequences (p < .0001) with nonoperatively treated patients showing full recovery (p = 1.00), whereas surgically treated patients did not (p = .002). CONCLUSIONS: Six months after LEF, patients still experienced impaired physical and psychological health on the WHOQOL-Bref compared to their pre-injury status. However, patients showed full recovery on SMFA Lower extremity dysfunction, indicating that the choice of the questionnaire influences the derived conclusions. LEF did not affect satisfaction with social relationships. PMID- 26537978 TI - Molecular dynamics investigations of mechanical behaviours in monocrystalline silicon due to nanoindentation at cryogenic temperatures and room temperature. AB - Molecular dynamics simulations of nanoindentation tests on monocrystalline silicon (010) surface were conducted to investigate the mechanical properties and deformation mechanism from cryogenic temperature being 10 K to room temperature being 300 K. Furthermore, the load-displacement curves were obtained and the phase transformation was investigated at different temperatures. The results show that the phase transformation occurs both at cryogenic temperatures and at room temperature. By searching for the presence of the unique non-bonded fifth neighbour atom, the metastable phases (Si-III and Si-XII) with fourfold coordination could be distinguished from Si-I phase during the loading stage of nanoindentation process. The Si-II, Si-XIII, and amorphous phase were also found in the region beneath the indenter. Moreover, through the degree of alignment of the metastable phases along specific crystal orientation at different temperatures, it was found that the temperature had effect on the anisotropy of the monocrystalline silicon, and the simulation results indicate that the anisotropy of monocrystalline silicon is strengthened at low temperatures. PMID- 26537979 TI - Effects of exercise and horticultural intervention on the brain and mental health in older adults with depressive symptoms and memory problems: study protocol for a randomized controlled trial [UMIN000018547]. AB - BACKGROUND: Depressive symptoms and memory problems are significant risk factors for dementia. Exercise can reduce depressive symptoms and improve cognitive function in older people. In addition, the benefits of horticultural activity on physical and mental well-being have been demonstrated in people with dementia. Although evidence of such non-pharmacological interventions is mounting, no studies have examined whether physical exercise and horticultural activity exert a positive impact on brain and mental health (e.g., depressive symptoms) in non demented older adults at high risk of cognitive impairment and depression. Therefore, we propose a randomized controlled trial to assess the efficacy and efficiency of physical exercise and horticultural activity in improving brain and mental health in community-dwelling older adults with memory problems and depressive symptoms. METHODS/DESIGN: The 20-week randomized controlled trial will include 90 community-dwelling adults aged 65 years or older with memory problems and depressive symptoms. Participants will be randomized to one of three experiments: exercise, horticultural activity, or educational control group, using a 1:1:1 allocation ratio. The combined exercise program and horticultural activity program will consist of 20 weekly 90-minute sessions. Participants in the exercise group will practice aerobic exercise, muscle strength training, postural balance retraining, and dual-task training. The horticultural activity program will include crop-related activities, such as field cultivation, growing, and harvesting. Participants in the educational control group will attend two 90 minute educational classes during the 6-month trial period. Depressive symptoms and memory performance will be measured by the Geriatric Depression Scale-15, and the Logical Memory subtests of the Wechsler Memory Scale-Revised will be used to measure depressive symptoms and memory performance as primary outcomes, at baseline (prior to randomization), immediately following intervention (6 months from baseline), and 6 months after intervention. Hippocampal volume will be measured at baseline and immediately after intervention, using magnetic resonance imaging. Secondary outcomes will comprise cognitive function, including language, attention/executive performance, and processing speed; brain-derived neurotrophic factor serum levels; and health-related quality of life. DISCUSSION: This intervention study will determine the clinical importance and efficacy of physical exercise and horticultural activity as non-pharmacological interventions in community-dwelling older adults at high risk of poor brain and mental health. TRIAL REGISTRATION: UMIN000018547 ; registered 7 August 2015. PMID- 26537980 TI - Managing Cancer Care: a psycho-educational intervention to improve knowledge of care options and breast cancer self-management. AB - OBJECTIVE: We tested the feasibility and acceptability of a psycho-educational self-management intervention, Managing Cancer Care: A Personal Guide (MCC), to improve knowledge of care options (curative, palliative, and hospice care) among a range of breast cancer self-management skills. METHODS: We conducted a one group, pre-post-test study among women with non-metastatic breast cancer (n = 105). We gave participants the printed, self-guided, seven-module intervention following enrollment. At baseline and 2 months, we measured knowledge of care options, desired and actual role in self-management, medical communication skills, experience and management of transitions, anxiety, depression, uncertainty, and self-efficacy. We conducted interviews to obtain module ratings and qualitative data on strengths and limitations of MCC. RESULTS: Knowledge of care options (delta = 0.40 (1.11), p = 0.0005) and desired role in self management (delta = -0.28 (1.08), p = 0.0177) significantly improved. Less skilled medical communicators significantly improved their communication (delta = 3.47, standard deviation = 6.58, p = 0.0449). Multivariate modeling showed that changes in our primary outcomes of medical communication and management of transitions seemed to drive positive changes in our secondary outcomes of anxiety, depression, uncertainty, and self-efficacy. Participants highly rated MCC and reported the importance of understanding care options despite non metastatic disease. CONCLUSIONS: MCC is a feasible and acceptable means of improving knowledge of care options and other aspects of breast cancer self management. The combination of modules offered in MCC appears to have beneficial interactive effects. We are currently testing MCC more rigorously in a randomized controlled trial to explore mediating and moderating relationships. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26537981 TI - Latent structure of cognition in schizophrenia: a confirmatory factor analysis of the MATRICS Consensus Cognitive Battery (MCCB). PMID- 26537983 TI - Research Study Participants: Who Actually Qualifies as Athlete? PMID- 26537986 TI - Brain training games help older adults perform essential tasks, study finds. PMID- 26537987 TI - The presentation and management of complex female genital malformations. AB - BACKGROUND: Common uterine anomalies are important owing to their impact on fertility, and complex mesonephric anomalies and certain Mullerian malformations are particularly important because they cause serious clinical symptoms and affect woman's quality of life, in addition to creating fertility problems. In these cases of complex female genital tract malformations, a correct diagnosis is essential to avoid inappropriate and/or unnecessary surgery. Therefore, acquiring and applying the appropriate embryological knowledge, management and therapy is a challenge for gynaecologists. Here, we considered complex malformations to be obstructive anomalies and/or those associated with cloacal and urogenital sinus anomalies, urinary and/or extragenital anomalies, or other clinical implications or symptoms creating a difficult differential diagnosis. METHODS: A diligent and comprehensive search of PubMed and Scopus was performed for all studies published from 1 January 2011 to 15 April 2015 (then updated up to September 2015) using the following search terms: 'management' in combination with either 'female genital malformations' or 'female genital tract anomalies' or 'Mullerian anomalies'. The MeSH terms 'renal agenesis', 'hydrocolpos', 'obstructed hemivagina' 'cervicovaginal agenesis or atresia', 'vaginal agenesis or atresia', 'Herlyn-Werner-Wunderlich syndrome', 'uterine duplication' and 'cloacal anomalies' were also used to compile a list of all publications containing these terms since 2011. The basic embryological considerations for understanding female genitourinary malformations were also revealed. Based on our experience and the updated literature review, we studied the definition and classification of the complex malformations, and we analysed the clinical presentation and different therapeutic strategies for each anomaly, including the embryological and clinical classification of female genitourinary malformations. RESULTS: From 755 search retrieved references, 230 articles were analysed and 120 studied in detail. They were added to those included in a previous systematic review. Here, we report the clinical presentation and management of: agenesis or hypoplasia of one urogenital ridge; unilateral renal agenesis and ipsilateral blind or obstructed hemivagina or unilateral cervicovaginal agenesis; cavitated and non-communicating uterine horns and Mullerian atresias or agenesis, including Rokitansky syndrome; anomalies of the cloaca and urogenital sinus, including congenital vagino-vesical fistulas and cloacal anomalies; malformative combinations and other complex malformations. The clinical symptoms and therapeutic strategies for each complex genitourinary malformation are discussed. In general, surgical techniques to correct genital malformations depend on the type of anomaly, its complexity, the patient's symptoms and the correct embryological interpretation of the anomaly. Most anomalies can typically be resolved vaginally or by hysteroscopy, but laparoscopy or laparotomy is often required as well. We also include additional discussion of the catalogue and classification systems for female genital malformations, the systematic association between renal agenesis and ipsilateral genital malformation, and accessory and cavitated uterine masses. CONCLUSIONS: Knowledge of the correct genitourinary embryology is essential for the understanding, study, diagnosis and subsequent treatment of genital malformations, especially complex ones and those that lead to gynaecological and reproductive problems, particularly in young patients. Some anomalies may require complex surgery involving multiple specialties, and patients should therefore be referred to centres that have experience in treating complex genital malformations.